PMID- 22195892 TI - Genipin-crosslinked N-carboxymethyl chitosan microcapsules prepared by electrostatic spray method. PMID- 22195893 TI - Locally infused gene containg nanoparticles to inhibit rabbit intimal hyperplasia. PMID- 22195894 TI - Preparation and characterization of a new copolymer poly (l-glutamic acid)-block poly (lactic-co-glycolic acid). PMID- 22195895 TI - Synthesis and characterization of a novel dendritic magnetic resonance imaging contrast agent. PMID- 22195896 TI - Effect of nano-structured polymer surfaces on osteoblast adhesion and proliferation. PMID- 22195897 TI - Active targeting and fluorescence-labeled micelles: preparation, characterization and cellular uptake evaluation. PMID- 22195898 TI - Studies on pH-sensitive micellar structures for sustained drug delivery: experiments and computer simulations. PMID- 22195899 TI - Preliminary study of the relationship between water absorbency and zeta potentials of crosslinked poly(acrylic acid). PMID- 22195900 TI - Self-assembly of novel core/shell structured blue fluorescent silica nanoparticles. PMID- 22195901 TI - Mechanical property evaluation of polymeric biomaterials via finite element simulation method. PMID- 22195902 TI - Synthesis and characterization of a novel biodegradable amphiphilic MPEG dendritic block copolymer containing (glycolic acid)-alt-(lactic acid) oligomer and glycerol. PMID- 22195903 TI - Surface-functionalized silk fibroin film with controllable cell adhesion by surface-initiated atom transfer radical polymerization. PMID- 22195904 TI - Synthesis of glucose-sensitive block glycopolymers based on phenylboronic acid via RAFT polymerization. PMID- 22195905 TI - Controlled heparin release from electrospun gelatin fibers. PMID- 22195906 TI - PEGylated liposomes modified with LHRH analogs for tumor targeting. PMID- 22195907 TI - Controlled release of hydrogel modified textile products. PMID- 22195908 TI - Photosensitizer-loaded dendrimer-modified multi-walled carbon nanotubes for photodynamic therapy. PMID- 22195909 TI - In vitro evaluation of Konjac glucomannan as novel excipients for floating systems. PMID- 22195910 TI - Reduction-responsive polymeric micelles for anticancer drug delivery. PMID- 22195911 TI - Synthesis of novel mesoporous silica nanoparticles for loading and release of ibuprofen. PMID- 22195912 TI - Preparation and characterization of aspirin/chitosan nanoparticles by nucleation and ionic crosslinking in micro emulsions. PMID- 22195913 TI - A smart polymer for drug delivery sensitive to tumor extracellular pH. PMID- 22195914 TI - Experimental study on biodegradable polymer-paclitaxel conjugate micelles for chemotherapy of C6 glioma. PMID- 22195915 TI - Tailoring the PLATMC chain microstructure for stable cyclosporine A release. PMID- 22195916 TI - Anti-cancer effects of docetaxel loaded thermo-reversible hydrogels in a tumor xenograft mice model. PMID- 22195917 TI - Formation of concentric multi-layer chitosan hydrogel loaded with isoniazid. PMID- 22195918 TI - Chitosan hydrogels with 3D Liesegang ring structure for rifampicin release. PMID- 22195919 TI - Functionalized dextran-coated liposomes for doxorubicin loading. PMID- 22195920 TI - Effect of resistant starch film properties on the colon-targeting release of drug from coated pellets. PMID- 22195921 TI - A novel oral colon-targeting drug delivery system based on resistant starch acetate. PMID- 22195922 TI - Supramolecular polymer micelles self-assembled from alpha-cyclodextrin and PLLA PCL based copolymers. PMID- 22195923 TI - Reversibly crosslinked poly(vinyl alcohol) nanoparticles for triggered release of doxorubicin. PMID- 22195924 TI - Injectable hybrid laponite/alginate hydrogels for sustained release of methylene blue. PMID- 22195925 TI - Novel hyaluronan based biodegradable hydrogel and its drug release behavior. PMID- 22195926 TI - Multifunctional polyethylenimine-conjugated superparamagnetic nanoparticles for drug delivery and imaging. PMID- 22195927 TI - Poly(L-glutamic acid)-based star-block copolymers as pH-responsive release systems. PMID- 22195928 TI - Controlled acid hydrolysis and acetylation of glucomannans as drug carriers with designed pharmacokinetic behaviors. PMID- 22195929 TI - Hydrogel integrated with liposome: a two-stage drug delivery system. PMID- 22195930 TI - The synergistic effect of herceptin and docetaxel in polylactide-D-alpha tocopheryl polyethylene glycol succinate (PLA-TPGS) nanoparticles. PMID- 22195931 TI - Synthesis and characterisation of silica-polymer hybrid core-shell and hollow spheres for drug delivery applications. PMID- 22195932 TI - pH-responsive polymeric-cargo encapsulated magnetic nanoparticles for selective release and imaging. PMID- 22195933 TI - A novel dual stimuli-responsive drug carrier biomaterial based on BSA/PVP polymers. PMID- 22195934 TI - Rapidly pH-responsive degradable polymersomes for triggered release of hydrophilic and hydrophobic anticancer drugs. PMID- 22195935 TI - Preparation and in vitro release of spray-dried chitosan microspheres for levofloxacin delivery. PMID- 22195936 TI - Investigation on the preparation and application of chitosan/alginate microcapsules. PMID- 22195937 TI - Hydrogel-based drug carriers for controlled release of hydrophobic drugs and proteins. PMID- 22195938 TI - Radiopaque microspheres for improved transarterial chemical embolization (TACE). PMID- 22195939 TI - Thermosensitive, biocompatible and antifouling nanogels prepared via aqueous raft dispersion polymerization for targeted drug delivery. PMID- 22195940 TI - Degradable water soluble hyperbranched polymers for drug delivery. PMID- 22195941 TI - Microencapsulation of vitamin C by interfacial/emulsion reaction: characterization of release properties of microcapsules. PMID- 22195942 TI - Biomineralized hydrophobically modified alginate membrane for sustained drug delivery. PMID- 22195943 TI - Nanogated vessel based on polypseudorotaxane-capped mesoporous silica via a highly acid-labile benzoic-imine linker. PMID- 22195944 TI - Dual drug release from coaxial electrospun nanofibers. PMID- 22195945 TI - Reduction-responsive shell-sheddable biodegradable micelles for intracellular doxorubicin delivery. PMID- 22195946 TI - Novel reduction-sensitive micelles for triggered intracellular drug release. PMID- 22195947 TI - Nontoxic gemini cationic biodegradable polyurethane drug carriers: synthesis, self-assembly and in vitro cytotoxicity. PMID- 22195948 TI - beta-Cyclodextrin-based biodegradable dendrimers for drug delivery. PMID- 22195949 TI - Single chain variable fragment CD7 antibody conjugated PLGA/HDAC inhibitor immuno nanoparticles: developing human T cell-specific nano-technology for delivery of therapeutic drugs targeting latent HIV. PMID- 22195950 TI - Preparation and characterization of camptothecin (CPT)-loaded folate-conjugated dextran nanoparticles for tumor-targeted drug delivery using supercritical antisolvent method. PMID- 22195951 TI - Keratin films from chicken feathers for controlled drug release. PMID- 22195952 TI - Novel pH-sensitive zwitterionic poly(amino acid) derivatives for drug delivery. PMID- 22195953 TI - Biocompatible hydrogels based on chitosan and poly(p-dioxanone). PMID- 22195954 TI - Tumor-targeted drug carriers and their enhanced intracellular delivery by pH sensitivity. PMID- 22195955 TI - Synthesis of amphiphilic hyperbranched polymers for the controlled release of double-guest molecules. PMID- 22195956 TI - In vitro and in vivo evaluation of ibuprofen-paeonol conjugate. PMID- 22195958 TI - Who put the "A" in Atg12: autophagy or apoptosis? AB - Much deliberation surrounds how the two homeostatic pathways, autophagy and apoptosis, converge; in the December 9 issue of Molecular Cell, Rubinstein et al. (2011) identify a proapoptotic role for the autophagic protein Atg12, based on a BH3-like domain, which enables binding and inhibition of antiapoptotic Bcl-2 family proteins. PMID- 22195959 TI - Flicking the Warburg switch-tyrosine phosphorylation of pyruvate dehydrogenase kinase regulates mitochondrial activity in cancer cells. AB - In this issue of Molecular Cell, Hitosugi et al. (2011) show that the switch from oxidative phosphorylation to glycolysis in cancer cells is regulated by tyrosine phosphorylation of PDHK1. PMID- 22195960 TI - R we there yet? R-loop hazards to finishing the journey. AB - RNA:DNA hybrids in the genome are constantly being generated as a by-product of transcription; in this issue, two papers, from Helmrich et al. (2011) and Wahba et al. (2011), provide insight into how RNA:DNA hybrids lead to genetic instability. PMID- 22195961 TI - The cAMP/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD(+). AB - The NAD(+)-dependent deacetylase SIRT1 is an evolutionarily conserved metabolic sensor of the Sirtuin family that mediates homeostatic responses to certain physiological stresses such as nutrient restriction. Previous reports have implicated fluctuations in intracellular NAD(+) concentrations as the principal regulator of SIRT1 activity. However, here we have identified a cAMP-induced phosphorylation of a highly conserved serine (S434) located in the SIRT1 catalytic domain that rapidly enhanced intrinsic deacetylase activity independently of changes in NAD(+) levels. Attenuation of SIRT1 expression or the use of a nonphosphorylatable SIRT1 mutant prevented cAMP-mediated stimulation of fatty acid oxidation and gene expression linked to this pathway. Overexpression of SIRT1 in mice significantly potentiated the increases in fatty acid oxidation and energy expenditure caused by either pharmacological beta-adrenergic agonism or cold exposure. These studies support a mechanism of Sirtuin enzymatic control through the cAMP/PKA pathway with important implications for stress responses and maintenance of energy homeostasis. PMID- 22195962 TI - Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. AB - Many tumor cells rely on aerobic glycolysis instead of oxidative phosphorylation for their continued proliferation and survival. Myc and HIF-1 are believed to promote such a metabolic switch by, in part, upregulating gene expression of pyruvate dehydrogenase (PDH) kinase 1 (PDHK1), which phosphorylates and inactivates mitochondrial PDH and consequently pyruvate dehydrogenase complex (PDC). Here we report that tyrosine phosphorylation enhances PDHK1 kinase activity by promoting ATP and PDC binding. Functional PDC can form in mitochondria outside of the matrix in some cancer cells and PDHK1 is commonly tyrosine phosphorylated in human cancers by diverse oncogenic tyrosine kinases localized to different mitochondrial compartments. Expression of phosphorylation deficient, catalytic hypomorph PDHK1 mutants in cancer cells leads to decreased cell proliferation under hypoxia and increased oxidative phosphorylation with enhanced mitochondrial utilization of pyruvate and reduced tumor growth in xenograft nude mice. Together, tyrosine phosphorylation activates PDHK1 to promote the Warburg effect and tumor growth. PMID- 22195963 TI - Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild type K-Ras. AB - K-Ras mutations are frequent in colorectal cancer (CRC), albeit K-Ras is the only Ras isoform that can elicit apoptosis. Here, we show that mutant K-Ras directly binds to the tumor suppressor RASSF1A to activate the apoptotic MST2-LATS1 pathway. In this pathway LATS1 binds to and sequesters the ubiquitin ligase Mdm2 causing stabilization of the tumor suppressor p53 and apoptosis. However, mutant Ras also stimulates autocrine activation of the EGF receptor (EGFR) which counteracts mutant K-Ras-induced apoptosis. Interestingly, this protection requires the wild-type K-Ras allele, which inhibits the MST2 pathway in part via AKT activation. Confirming the pathophysiological relevance of the molecular findings, we find a negative correlation between K-Ras mutation and MST2 expression in human CRC patients and CRC mouse models. The small number of tumors with co-expression of mutant K-Ras and MST2 has elevated apoptosis rates. Thus, in CRC, mutant K-Ras transformation is supported by the wild-type allele. PMID- 22195964 TI - Incorporation of the Rpn12 subunit couples completion of proteasome regulatory particle lid assembly to lid-base joining. AB - The 26S proteasome, the central eukaryotic protease, comprises a core particle capped by a 19S regulatory particle (RP). The RP is divisible into base and lid subcomplexes. Lid biogenesis and incorporation into the RP remain poorly understood. We report several lid intermediates, including the free Rpn12 subunit and a lid particle (LP) containing the remaining eight subunits, LP2. Rpn12 binds LP2 in vitro, and each requires the other for assembly into 26S proteasomes. Stable Rpn12 incorporation depends on all other lid subunits, indicating that Rpn12 distinguishes LP2 from smaller lid subcomplexes. The highly conserved C terminus of Rpn12 bridges the lid and base, mediating both stable binding to LP2 and lid-base joining. Our data suggest a hierarchical assembly mechanism where Rpn12 binds LP2 only upon correct assembly of all other lid subunits, and the Rpn12 tail then helps drive lid-base joining. Rpn12 incorporation thus links proper lid assembly to subsequent assembly steps. PMID- 22195965 TI - A specific function for the histone chaperone NASP to fine-tune a reservoir of soluble H3-H4 in the histone supply chain. AB - Proper genome packaging requires coordination of both DNA and histone metabolism. While histone gene transcription and RNA processing adequately provide for scheduled needs, how histone supply adjusts to unexpected changes in demand remains unknown. Here, we reveal that the histone chaperone nuclear autoantigenic sperm protein (NASP) protects a reservoir of soluble histones H3-H4. The importance of NASP is revealed upon histone overload, engagement of the reservoir during acute replication stress, and perturbation of Asf1 activity. The reservoir can be fine-tuned, increasing or decreasing depending on the level of NASP. Our data suggest that NASP does so by balancing the activity of the heat shock proteins Hsc70 and Hsp90 to direct H3-H4 for degradation by chaperone-mediated autophagy. These insights into NASP function and the existence of a tunable reservoir in mammalian cells demonstrate that contingency is integrated into the histone supply chain to respond to unexpected changes in demand. PMID- 22195966 TI - Dynamics of histone H3 deposition in vivo reveal a nucleosome gap-filling mechanism for H3.3 to maintain chromatin integrity. AB - Establishment of a proper chromatin landscape is central to genome function. Here, we explain H3 variant distribution by specific targeting and dynamics of deposition involving the CAF-1 and HIRA histone chaperones. Impairing replicative H3.1 incorporation via CAF-1 enables an alternative H3.3 deposition at replication sites via HIRA. Conversely, the H3.3 incorporation throughout the cell cycle via HIRA cannot be replaced by H3.1. ChIP-seq analyses reveal correlation between HIRA-dependent H3.3 accumulation and RNA pol II at transcription sites and specific regulatory elements, further supported by their biochemical association. The HIRA complex shows unique DNA binding properties, and depletion of HIRA increases DNA sensitivity to nucleases. We propose that protective nucleosome gap filling of naked DNA by HIRA leads to a broad distribution of H3.3, and HIRA association with Pol II ensures local H3.3 enrichment at specific sites. We discuss the importance of this H3.3 deposition as a salvage pathway to maintain chromatin integrity. PMID- 22195967 TI - The acidic transcription activator Gcn4 binds the mediator subunit Gal11/Med15 using a simple protein interface forming a fuzzy complex. AB - The structural basis for binding of the acidic transcription activator Gcn4 and one activator-binding domain of the Mediator subunit Gal11/Med15 was examined by NMR. Gal11 activator-binding domain 1 has a four-helix fold with a small shallow hydrophobic cleft at its center. In the bound complex, eight residues of Gcn4 adopt a helical conformation, allowing three Gcn4 aromatic/aliphatic residues to insert into the Gal11 cleft. The protein-protein interface is dynamic and surprisingly simple, involving only hydrophobic interactions. This allows Gcn4 to bind Gal11 in multiple conformations and orientations, an example of a "fuzzy" complex, where the Gcn4-Gal11 interface cannot be described by a single conformation. Gcn4 uses a similar mechanism to bind two other unrelated activator binding domains. Functional studies in yeast show the importance of residues at the protein interface, define the minimal requirements for a functional activator, and suggest a mechanism by which activators bind to multiple unrelated targets. PMID- 22195968 TI - The little elongation complex regulates small nuclear RNA transcription. AB - Eleven-nineteen lysine-rich leukemia (ELL) participates in the super elongation complex (SEC) with the RNA polymerase II (Pol II) CTD kinase P-TEFb. SEC is a key regulator in the expression of HOX genes in mixed lineage leukemia (MLL)-based hematological malignancies, in the control of induced gene expression early in development, and in immediate early gene transcription. Here, we identify an SEC like complex in Drosophila, as well as a distinct ELL-containing complex that lacks P-TEFb and other components of SEC named the "little elongation complex" (LEC). LEC subunits are highly enriched at RNA Pol II-transcribed small nuclear RNA (snRNA) genes, and the loss of LEC results in decreased snRNA expression in both flies and mammals. The specialization of the SEC and LEC complexes for mRNA and snRNA-containing genes, respectively, suggests the presence of specific classes of elongation factors for each class of genes transcribed by RNA polymerase II. PMID- 22195969 TI - Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. AB - We show that the time required to transcribe human genes larger than 800 kb spans more than one complete cell cycle, while their transcription speed equals that of smaller genes. Independently of their expression status, we find the long genes to replicate late. Regions of concomitant transcription and replication in late S phase exhibit DNA break hot spots known as common fragile sites (CFSs). This CFS instability depends on the expression of the underlying long genes. We show that RNA:DNA hybrids (R-loops) form at sites of transcription/replication collisions and that RNase H1 functions to suppress CFS instability. In summary, our results show that, on the longest human genes, collisions of the transcription machinery with a replication fork are inevitable, creating R-loops and consequent CFS formation. Functional replication machinery needs to be involved in the resolution of conflicts between transcription and replication machineries to ensure genomic stability. PMID- 22195971 TI - Cotranslational control of DNA transposition: a window of opportunity. AB - Transposable elements are important in genome dynamics and evolution. Bacterial insertion sequences (IS) constitute a major group in number and impact. Understanding their role in shaping genomes requires knowledge of how their transposition activity is regulated and interfaced with the host cell. One IS regulatory phenomenon is a preference of their transposases (Tpases) for action on the element from which they are expressed (cis) rather than on other copies of the same element (trans). Using IS911, we show in vivo that activity in cis was ~200 fold higher than in trans. We also demonstrate that a translational frameshifting pause signal influences cis preference presumably by facilitating sequential folding and cotranslational binding of the Tpase. In vitro, IS911 Tpase bound IS ends during translation but not after complete translation. Cotranslational binding of nascent Tpase permits tight control of IS proliferation providing a mechanistic explanation for cis regulation of transposition involving an unexpected partner, the ribosome. PMID- 22195972 TI - Mechanism of isoprenylcysteine carboxyl methylation from the crystal structure of the integral membrane methyltransferase ICMT. AB - The posttranslational modification of C-terminal CAAX motifs in proteins such as Ras, most Rho GTPases, and G protein gamma subunits, plays an essential role in determining their subcellular localization and correct biological function. An integral membrane methyltransferase, isoprenylcysteine carboxyl methyltransferase (ICMT), catalyzes the final step of CAAX processing after prenylation of the cysteine residue and endoproteolysis of the -AAX motif. We have determined the crystal structure of a prokaryotic ICMT ortholog, revealing a markedly different architecture from conventional methyltransferases that utilize S-adenosyl-L methionine (SAM) as a cofactor. ICMT comprises a core of five transmembrane alpha helices and a cofactor-binding pocket enclosed within a highly conserved C terminal catalytic subdomain. A tunnel linking the reactive methyl group of SAM to the inner membrane provides access for the prenyl lipid substrate. This study explains how an integral membrane methyltransferase achieves recognition of both a hydrophilic cofactor and a lipophilic prenyl group attached to a polar protein substrate. PMID- 22195970 TI - RNase H and multiple RNA biogenesis factors cooperate to prevent RNA:DNA hybrids from generating genome instability. AB - Genome instability, a hallmark of cancer progression, is thought to arise through DNA double strand breaks (DSBs). Studies in yeast and mammalian cells have shown that DSBs and instability can occur through RNA:DNA hybrids generated by defects in RNA elongation and splicing. We report that in yeast hybrids naturally form at many loci in wild-type cells, likely due to transcriptional errors, but are removed by two evolutionarily conserved RNase H enzymes. Mutants defective in transcriptional repression, RNA export and RNA degradation show increased hybrid formation and associated genome instability. One mutant, sin3Delta, changes the genome profile of hybrids, enhancing formation at ribosomal DNA. Hybrids likely induce damage in G1, S and G2/M as assayed by Rad52 foci. In summary, RNA:DNA hybrids are a potent source for changing genome structure. By preventing their formation and accumulation, multiple RNA biogenesis factors and RNase H act as guardians of the genome. PMID- 22195973 TI - Analysis of expression sequence tags from a full-length-enriched cDNA library of developing sesame seeds (Sesamum indicum). AB - BACKGROUND: Sesame (Sesamum indicum) is one of the most important oilseed crops with high oil contents and rich nutrient value. However, genetic improvement efforts in sesame could not get benefit from molecular biology technology due to poor DNA and RNA sequence resources. In this study, we carried out a large scale of expressed sequence tags (ESTs) sequencing from developing sesame seeds and further conducted analysis on seed storage products-related genes. RESULTS: A normalized and full-length enriched cDNA library from 5 ~ 30 days old immature seeds was constructed and randomly sequenced, leading to generation of 41,248 expressed sequence tags (ESTs) which then formed 4,713 contigs and 27,708 singletons with 44.9% uniESTs being putative full-length open reading frames. Approximately 26,091 of all these uniESTs have significant matches to the counterparts in Nr database of GenBank, and 21,628 of them were assigned to one or more Gene ontology (GO) terms. Homologous genes involved in oil biosynthesis were identified including some conservative transcription factors regulating oil biosynthesis such as LEAFY COTYLEDON1 (LEC1), PICKLE (PKL), WRINKLED1 (WRI1) and majority of them were found for the first time in sesame seeds. One hundred and 17 ESTs were identified possibly involved in biosynthesis of sesame lignans, sesamin and sesamolin. In total, 9,347 putative functional genes from developing seeds were identified, which accounts for one third of total genes in the sesame genome. Further analysis of the uniESTs identified 1,949 non-redundant simple sequence repeats (SSRs). CONCLUSIONS: This study has provided an overview of genes expressed during sesame seed development. This collection of sesame full length cDNAs covered a wide variety of genes in seeds, in particular, candidate genes involved in biosynthesis of sesame oils and lignans. These EST sequences enriched with full length will contribute to comparative genomic studies on sesame and other oilseed plants and serve as an abundant information platform for functional marker development and functional gene study. PMID- 22195974 TI - [Syphilitic gastritis: an aetiology to consider]. PMID- 22195975 TI - Histone H3 methylation patterns in Brassica nigra, Brassica juncea, and Brassica carinata species. AB - Core histones are subjected to various post-translational modifications, and one of them, most intensively studied in plants, is the methylation of histone H3. In the majority of analyzed plant species, dimethylation of H3 at lysine 9 (H3K9me2) is detected in heterochromatin domains, whereas methylation of H3 at lysine 4 (H3K4me2) is detected in euchromatin domains. The distribution of H3K9me2 in the interphase nucleus seems to be correlated with genome size, chromatin organization, but also with tissue specificity. In this paper, we present the analysis of the pattern and level of histone H3 methylation for two allotetraploid and one diploid Brassica species. We have found that the pattern of H3K9me2 in interphase nuclei from root meristematic tissue is comparable within the analyzed species and includes both heterochromatin and euchromatin, but the level of modification differs not only among species but even among nuclei in the same phase of the cell cycle within one species. Moreover, the differences in the level of H3K9me2 are not directly coupled with DNA content in the nuclei and are probably tissue specific. PMID- 22195976 TI - Graft selection for aortic root replacement in complex active endocarditis: does it matter? AB - BACKGROUND: Endocarditis affecting the aortic valve, with abscess formation and root destruction, remains a challenge to treat. Aortic root homografts have been advocated because of a perceived lower risk of infective complications than with other root replacement grafts. However, the theoretical advantage of homografts has not been re-evaluated in the modern era. This report is based on an examination of our results for all aortic root replacements in complex, active endocarditis affecting the aortic valve. METHODS: From 2000 to 2010, 134 patients (70.9% male; mean age 58.3+/-14.8 years) at our institution underwent aortic root replacement for active endocarditis. Ninety of the patients (67.2%) had a previously implanted prosthetic aortic valve. Our findings for these patients included one or more of the following: abscess (n=110, 82.1%), valve vegetation (n=98, 73.1%), and pseudoaneurysm or rupture or both (n=62, 46.3%). We retrospectively reviewed data for the patients from hospital records and the social security data base. RESULTS: A mechanical composite graft (MC) was used in 43 of the patients (32.1%), a non-homograft biologic valve conduit (BC) in 55 patients (41.0%), and a homograft (HG) valve in 36 patients (26.9%). There was no significant difference among the groups in the incidence of major complications or in-hospital mortality. During a mean follow-up of 32.1+/-29.4 months, the rates of readmission, reinfection, and reoperation were similar for the three groups. The mean 5-year survival in the study was 58+/-9% for the MC group, 62+/ 7% for the BC group, and 58 +/- 9% for the HG group, respectively (p=0.48). CONCLUSIONS: Aortic root replacement in the presence of complex active infection is associated with significant morbidity and mortality. We report that the rates of major complications and late mortality were similar among MC, BC, and HG groups in our study. PMID- 22195977 TI - Kinetics of transcription of infectious laryngotracheitis virus genes. AB - The kinetics of expression of only a few genes of infectious laryngotracheitis virus (ILTV) have been determined, using northern blot analysis. We used quantitative reverse transcriptase PCR to examine the kinetics of expression of 74 ILTV genes in LMH cells. ICP4 was the only gene fully expressed in the presence of cycloheximide, and thus classified as immediate-early. The genes most highly expressed early in infection, and thus classified as early, included UL1 (gL), UL2, UL3, UL4, UL5, UL6, UL7, UL8, UL13, UL14, UL19, UL20, UL23 (TK), UL25, UL28, UL29, UL31, UL33, UL34, UL38, UL39, UL40, UL42, UL43, UL44 (gC), UL47, UL48 (alpha-TIF), UL49, UL54 (ICP27), US3 and US10. ORF A, ORF B, ORF C, ORF E, sORF 4/3, UL[-1], UL0, UL3.5, UL9, UL10 (gM), UL11, UL15a, UL15b, UL18, UL22 (gH), UL24, UL26, UL30, UL32, UL36, UL45, UL49.5 (gN), UL52, US2, US4 (gG), US5 (gJ) and US9 were most highly expressed late in infection and were thus considered late genes. Several genes, including ORF D, UL12, UL17, UL21, UL27 (gB), UL35, UL37, UL41, UL46, UL50, UL51, UL53 (gK), US8 (gE), US6 (gD) and US7 (gI), had features of both early and late genes and were classified as early/late. Our findings suggest transcription from most of ILTV genes is leaky or subject to more complex patterns of regulation than those classically described for herpesviruses. This is the first study examining global expression of ILTV genes and the data provide a basis for future investigations of the pathogenesis of infection with ILTV. PMID- 22195978 TI - Electric-field-controlled flow in nanoscale-thin wetting films. AB - A novel nanofluidic system based on electroosmotic flow in nanoscale-thin aqueous wetting films is reported. The water films formed spontaneously on mica substrates in a saturation humidity environment. The film thickness was determined to be a few tens of nanometers by optical interference and fluorescence intensity measurements and was consistent with a theoretical evaluation of the thickness of a film based on the competing forces of electrostatic repulsion and capillary pressure. Lateral flow was induced by applying a dc electric field tangential to the film and characterized by tracking the position of a fluorescent probe. The mobilities of the thin fluid layer and the flow marker were lower than the predictions of the electrokinetic theory, which may be a result of adsorption of the fluorescent molecules to the mica. Confinement of the film to two-dimensional "channels" was achieved by microcontact printing of patterned hydrophobic monolayers onto the substrate. This system has the advantage of simple and inexpensive fabrication in comparison to nanofluidic devices made by traditional lithography techniques. PMID- 22195980 TI - Asymmetric synthesis of polyhydroxylated N-alkoxypiperidines by ring-closing double reductive amination: facile preparation of isofagomine and analogues. AB - A de novo synthesis of novel polyhydroxylated N-alkoxypiperidines based on the ring-closing double reductive amination of 1,5-dialdehydes, obtained by oxidative cleavage of cyclopentene derivatives, with O-substituted hydroxylamines is reported. Isofagomine was accessed by cleavage of the N-O bond of an N alkoxypiperidine. PMID- 22195982 TI - Assessment of stereoelectronic factors that influence the CO2 fixation ability of N-heterocyclic carbenes: a DFT study. AB - The CO(2) fixation ability of N-heterocyclic carbenes (NHC) has been assessed on the basis of electronic and steric properties of the N- and C-substituents, measured in terms of molecular electrostatic potential minimum, observed at the carbene lone pair region of NHC (V(min1)) as well as at the carboxylate region of the NHC-CO(2) adduct (V(min2)). Both V(min1) and V(min2) are found to be simple and efficient descriptors of the stereoelectronic effect of NHCs. The V(min) based analysis also proved that the stereoelectronic effect of N- and C substituents is additive. When only C-substituents are present in NHC, its CO(2) affinity solely depends on the electronic effect, whereas if the N-center bears the substituents, the steric factor plays a major role in the carboxylation/decarboxylation process. For standard substituents, maximum CO(2) binding energy of 18.0 kcal/mol is observed for the most electron-donating combination of NMe(2) as the C-substituent and Me as the N-substituent. Introduction of ring strain through five-membered ring fusion at the NC bond slightly increased the electron-rich character of the carbene lone pair and also enhanced the CO(2) binding energy to 20.9 kcal/mol. To further improve the CO(2) fixing ability of NHCs, we have proposed the use of CH(2)OH, CH(2)NHCOMe, and CH(2)NHPh as N-substituents, as they participate in intramolecular hydrogen bond interaction with the carboxylate. With the new strategy, considerable improvement in the CO(2) binding energy (26.5 to 33.0 kcal/mol) is observed. PMID- 22195983 TI - [Infusion way error during epidural anaesthesia: arguments for colorized infusion devices]. PMID- 22195985 TI - Biomineralized N-doped CNT/TiO2 core/shell nanowires for visible light photocatalysis. AB - We report an efficient and environmentally benign biomimetic mineralization of TiO(2) at the graphitic carbon surface, which successfully created an ideal TiO(2)/carbon hybrid structure without any harsh surface treatment or interfacial adhesive layer. The N-doped sites at carbon nanotubes (CNTs) successfully nucleated the high-yield biomimetic deposition of a uniformly thick TiO(2) nanoshell in neutral pH aqueous media at ambient pressure and temperature and generated N-doped CNT (NCNT)/TiO(2) core/shell nanowires. Unlike previously known organic biomineralization templates, such as proteins or peptides, the electroconductive and high-temperature-stable NCNT backbone enabled high temperature thermal treatment and corresponding crystal structure transformation of TiO(2) nanoshells into the anatase or rutile phase for optimized material properties. The direct contact of the NCNT surface and TiO(2) nanoshell without any adhesive interlayer introduced a new carbon energy level in the TiO(2) band gap and thereby effectively lowered the band gap energy. Consequently, the created core/shell nanowires showed a greatly enhanced visible light photocatalysis. Other interesting synergistic properties such as stimuli responsive wettabilites were also demonstrated. PMID- 22195986 TI - Validation of a PicoGreen-based DNA quantification integrated in an RNA extraction method for two-dimensional and three-dimensional cell cultures. AB - DNA measurement and RNA extraction are two frequently used methods for cell characterization. In the conventional protocols, they require similar, but separate samples and in most cases, different pretreatments. The few combined protocols that exist still include time-consuming steps. Hence, to establish an efficient combined RNA extraction and DNA measurement protocol for two dimensional (2D) and three-dimensional (3D) cell cultures, a PicoGreen-based DNA measurement was integrated in an existing RNA extraction protocol. It was validated by analysis of the influence of different lysis buffers, RLT, RA1, or Trizol, used for RNA extraction on the measured DNA concentration. The DNA cell yield was evaluated both in cell suspensions (2D) and on 3D cell-seeded scaffolds. Results showed that the different RNA lysis buffers caused a concentration-dependent perturbation of the PicoGreen signal. The measured DNA concentrations in 2D and 3D using RLT and RA1 buffer were comparable, also to the positive control. We, therefore, concluded that RNA extraction protocols using RA1 or RLT buffer allow the integration of a DNA quantification step without the buffer influencing the results. Hence, the combined DNA measurement and RNA extraction offer an alternative for DNA measurement techniques that is time and sample saving, for both 2D cell cultures and specific 3D constructs. PMID- 22195987 TI - Circulating LH/hCG receptor (LHCGR) may identify pre-treatment IVF patients at risk of OHSS and poor implantation. AB - BACKGROUND: Successful pregnancy via in vitro fertilization (IVF) depends on the recovery of an adequate number of healthy oocytes and on blastocyst implantation following uterine transfer. Two hormones, LH and hCG, utilize a common LH/hCG receptor (LHCGR), variations in which have profound implications in human reproduction. Soluble LHCGR (sLHCGR) is released from experimental cell lines and placental explants and it can be detected in the follicular fluid and serum. METHODS: To evaluate the impact of circulating soluble LHCGR (sLHCGR) in fertility treatment, we measured sLHCGR and LH-sLHCGR complex in serum from women seeking IVF using specifically developed quantitative enzyme-linked immunosorbent assays (ELISA). Following an IVF cycle of treatment, patients were grouped according to oocyte yield into low (lower than or equal to 7 oocytes), intermediate (8-14 oocytes) and high (greater than or equal to 15 oocytes) responders and pregnancy outcome noted. RESULTS: Pre-treatment sLHCGR identified many women at risk of ovarian hyperstimulation. Low levels of sLHCGR were associated with pregnancy in both high and low responders but sLHCGR did not significantly affect the treatment outcome of intermediate responders. Low responders who failed to become pregnant had high levels of circulating sLHCGR bound to LH (LH-sLHCGR). CONCLUSIONS: Pre-treatment measurement of sLHCGR could be used to tailor individual fertility treatment programs and improve outcomes by avoiding ovarian hyperstimulation and poor embryo implantation. PMID- 22195989 TI - Systemic upregulation of NADPH oxidase in diet-induced obesity in rats. AB - Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is upregulated in a variety of tissues in obesity. It is still unclear as to whether NADPH oxidase upregulation in a specific tissue is part of a systemic response. Here we analyzed the expression pattern of NADPH oxidase in vascular, adipose, and kidney tissues in a rat model of diet-induced obesity. After weaning, rats were fed either a normal or high-fat diet for 12 weeks. The high-fat diet resulted in 20% increased body weight. In the aorta, Nox4 expression was increased by three fold in obese rats. Upregulations of p22phox and p47phox in adipose, and Nox4, p22phox, and p47phox in kidney were observed in obesity. Marked increases in plasma leptin and insulin were observed, with more modest changes in adiponectin in obese rats. The average systolic blood pressure in the obese group was 11 mmHg higher than that of lean rats (P < 0.005). There was a significant correlation between blood pressure and aortic Nox4 expression (P < 0.01). In cultured vascular smooth muscle cells, adiponectin reduced the expression of Nox4 in a protein kinase A-dependent manner. Our results suggest that upregulation of NADPH oxidase in multiple tissues during obesity appears to be a systemic response. At least in vitro, adiponectin may have a protective antioxidant role by suppressing vascular NADPH oxidase expression. The association between NADPH oxidase Nox4 expression in the vasculature and the elevated blood pressure in obesity requires further investigation. PMID- 22195990 TI - Oxidative stress and antioxidant defenses in pregnant women. AB - OBJECTIVES: Oxidative stress (OS) is defined as an imbalance in the production of reactive oxygen species and the capacity of antioxidant defenses. The objective of this work was to investigate OS and antioxidant capacity in pregnant women. METHODS: Parameters of the oxidative status and antioxidant capacity in serum and whole blood were evaluated in thirty-nine women with normal pregnancy. RESULTS: The assessment of antioxidants indicated an increase in superoxide dismutase and catalase activities (P<0.05 and P<0.01) and a decrease in ascorbic acid levels and the total content of sulfhydryl (P<0.05 and P<0.001). Additionally, when the pro-oxidant system was investigated we found an increase (P<0.01) in malondialdehyde and no significant change (P>0.05) in protein carbonylation. DISCUSSION: This study demonstrates that there is a change in the pro-oxidant and antioxidant defenses associated with body and circulation changes that are inherent to the pregnancy process. PMID- 22195988 TI - Modifications of glycans: biological significance and therapeutic opportunities. AB - Carbohydrates play a central role in a wide range of biological processes. As with nucleic acids and proteins, modifications of specific sites within the glycan chain can modulate a carbohydrate's overall biological function. For example, acylation, methylation, sulfation, epimerization, and phosphorylation can occur at various positions within a carbohydrate to modulate bioactivity. Therefore, there is significant interest in identifying discrete carbohydrate modifications and understanding their biological effects. Additionally, enzymes that catalyze those modifications and proteins that bind modified glycans provide numerous targets for therapeutic intervention. This review will focus on modifications of glycans that occur after the oligomer/polymer has been assembled, generally referred to as post-glycosylational modifications. PMID- 22195991 TI - Caloric restriction and redox state: does this diet increase or decrease oxidant production? AB - Calorie restriction (CR) is well established to enhance the lifespan of a wide variety of organisms, although the mechanisms are still being uncovered. Recently, some authors have suggested that CR acts through hormesis, enhancing the production of reactive oxygen species (ROS), activating stress response pathways, and increasing lifespan. Here, we review the literature on the effects of CR and redox state. We find that there is no evidence in rodent models of CR that an increase in ROS production occurs. Furthermore, results in Caenorhabditis elegans and Saccharomyces cerevisiae suggesting that CR increases intracellular ROS are questionable, and probably cannot be resolved until adequate, artifact free, tools for real-time, quantitative, and selective measurements of intracellular ROS are developed. Overall, the largest body of work indicates that CR improves redox state, although it seems improbable that a global improvement in redox state is the mechanism through which CR enhances lifespan. PMID- 22195992 TI - Exploration of pro-oxidant and antioxidant activities of the flavonoid myricetin. AB - OBJECTIVES: Flavonoids are ubiquitous phenolic plant metabolites. Many of them are well known for their pro- and antioxidant properties. Myricetin has been reported to be either a potent antioxidant or a pro-oxidant depending on the conditions. The reaction conditions for the pro- and antioxidant activities were therefore investigated using variations of the deoxyribose degradation assay systems. METHODS: The deoxyribose degradation assay systems were conducted as follows; H(2)O(2)/Fe(III)/ascorbic acid, H(2)O(2)/Fe(III), Fe(III)/ascorbic acid, and Fe(III). Each system was carried out in two variants, FeCl(3) (iron ions added as FeCl(3)) and FeEDTA (iron added in complex with ethylenediaminetetraacetic acid). RESULTS: When ascorbic acid was present, myricetin showed antioxidant properties, especially when it occurred in complex with iron. In ascorbic acid-free systems, pro-oxidant activities prevailed, which where enhanced if iron was in complex with EDTA. DISCUSSION: Myricetin's antioxidant activity depends on both the reactive oxygen species (ROS) scavenging and iron ions chelation properties. The pro-oxidative properties are caused by reduction of molecular oxygen to ROS and iron(III) to iron(II). Myricetin is able to substitute for ascorbic acid albeit less efficiently. PMID- 22195993 TI - Autoimmune reactivity of IgM acquired after oxidation. AB - OBJECTIVES: Redox-reactive antibodies, mainly of the IgG class, gained a wide area of interest after their autoimmune reactivity was revealed following the application of chemical and physiological oxidants. In this study, we examined the susceptibility of IgMs to oxidation and evaluated their binding to the autoantigens important in some autoimmune diseases. METHODS: IgM and IgG fractions, isolated from healthy individuals' sera, were oxidized using direct electric current or physiological oxidant hemin. Specificities towards beta-2 glycoprotein I (beta(2)-GPI), cardiolipin (CL), and rheumatoid factor were evaluated with the enzyme-linked immunosorbent assays (ELISAs). Post translational modification was investigated by 2,4-dinitrophenylhydrazine reaction. RESULTS: Electrochemically oxidized IgM fractions exhibited altered immunoreactivity - low to medium titers in anti-CL and low positive titers in anti-beta(2)-GPI ELISA but exhibited no rheumatoid factor reactivity. Oxidized IgG and IgM fractions exhibited 2.5- and 5-fold increase in the carbonyl content, respectively. DISCUSSION: An increase in the carbonyl content along with increased immunoreactivity after oxidation suggests modifications of the IgM paratopes. These results point towards possible modifications of native IgMs to their autoimmune state despite the fact that IgMs were less susceptible to oxidation than IgGs. The importance of an individual's redox status in maintenance of autoimmune reactions was emphasized by in vitro diagnostic tests. PMID- 22195994 TI - Visual control of prey-capture flight in dragonflies. AB - Interacting with a moving object poses a computational problem for an animal's nervous system. This problem has been elegantly solved by the dragonfly, a formidable visual predator on flying insects. The dragonfly computes an interception flight trajectory and steers to maintain it during its prey-pursuit flight. This review summarizes current knowledge about pursuit behavior and neurons thought to control interception in the dragonfly. When understood, this system has the potential for explaining how a small group of neurons can control complex interactions with moving objects. PMID- 22195995 TI - The effects of birth weight and gender on neonatal mortality in north central Nigeria. AB - BACKGROUND: Worldwide 15.5% of neonates are born with low birth weight, 95.6% of them in the developing countries. Prematurity accounts for 10% of neonatal mortality globally. The purpose of this study was to evaluate the effects of birth weight and gender on neonatal outcome. FINDINGS: The data of 278 neonates managed in the Special Care Baby Unit (SCBU) of Jos University Teaching Hospital (JUTH) over a 2 year period from July 2006 to June 2008 were analyzed.One hundred and fifty nine (57.2%) were males and 119(42.8%) females. There were 87(31.3%) preterm and 191 (68.7%) term babies. Twelve of the babies died. Seven (2.52%) and 5 (1.80%) being males and females respectively. The neonatal mortality rate by gender was not significant (p > 0.05). The neonatal mortality was 25.2 deaths per 1000 live births for boys and 18.0 for girls. The mean birth weights of the preterm and term babies were 1.88 +/- 0.47 kg and 3.02 +/- 0.50 kg respectively, with a mean gestational age of 30.62 +/- 3.65 weeks and 38.29 +/- 0.99 weeks respectively.Eighty seven (31.3%) of the babies were of low birth weight, 188(67.6%) were of normal birth weight and 3(1.1%) high birth weight. Of the low birth weight babies, 6(2.2%) were term small for gestational age. Six (2.2%) of the preterm infants had normal birth weight.Eleven of the babies that died were preterm low birth weight. The overall mortality rate was 4.32%. The birth weight specific mortality rate was 126 per 1000 for the preterm low birth weight and 5 per 1000 for the term babies. Birth weight unlike gender is a significant predictor of mortality, mortality being higher in neonates of <2.5 kg (OR = 0.04; 95% Cl 0.005-0.310, p = 0.002) (p = 0.453). Seven (58.3%) and 4(33.3%) of the pre terms that died were appropriate and large for gestational age respectively. Gestational age is not a significant predictor of neonatal mortality (p = 0.595). Babies delivered at less than 37 weeks of gestation recorded a higher rate of mortality than those of 37 weeks and above (p = 0.000).The subjects showed one or more major clinical indications for admission. The major clinical indications for the preterm and term babies were respectively as follows: neonatal sepsis 63(22.7%) and 124(44.6%); neonatal jaundice 32(11.1%) and 71(24.7%); malaria 9(3.1%) and 13(4.5%); birth asphyxia 3(1.0%) and 7(2.4%). Neonatal sepsis was a common denominator among the babies that died. CONCLUSION: Birth weight unlike gender is a significant predictor of neonatal outcome. PMID- 22195998 TI - [Initial assessment and follow-up of benign prostatic hyperplasia: systematic review of the literature by the LUTS committee of the French Urological Association]. AB - PURPOSE: To perform an update on the initial evaluation and follow-up of benign prostatic hyperplasia (BPH). METHOD: A systematic review of recent literature was performed. Level of evidence of publications was evaluated. RESULTS AND CONCLUSIONS: Objectives of the initial evaluation are to assess the link between low urinary tract symptoms (LUTS) and BPH, to evaluate the bother associated to LUTS, assess a complicated bladder outlet obstruction (BOO), diagnose an adenocarcinoma of the prostate if it modifies the therapeutic strategy, and establish an evolutive profile of the disease. Clinical assessment with digital rectal examination, evaluation of symptoms by a dedicated questionnaire and urine analysis are the first steps of BPH evaluation. Bladder diary is useful to objective storage symptoms. Uroflowmetry and post-void residual volume assessment are useful if BOO is suspected. Measure of serum creatinine and ultrasound exam of the urinary tract are second line explorations. Urine cytology, neurological evaluation, urethrocystoscopy, urodynamics with pressure-flow studies are useful if the link between LUTS and BPH is unclear. PSA dosage is used for prostate cancer screening or as a prognostic marker of BPH evolution. PMID- 22195999 TI - [Benign prostatic hyperplasia medical treatment: systematic review of the literature by the CTMH/AFU]. AB - INTRODUCTION AND OBJECTIVES: The medical treatment of lower urinary tract symptoms related to benign prostatic hyperplasia (LUTS-BPH) has dramatically evolved within the last years: new drugs have been commercialized and others that used to be contra-indicated may now be prescribed. Our objective was to provide with an updated review of the scientific literature on the medical treatment of LUTS-BPH. PATIENT AND METHOD: A systematic review of the most recent scientific literature was performed. The query was addressed to the PubMed database using the following keywords: "benign prostatic hyperplasia" and "medical treatment". A very large amount of publications, from year 1990 until 2011, were reviewed to select the publications with level of evidence 1 and 2. These publications were analysed and the 30 most relevant were selected to serve as references for this article. RESULTS: There are many randomized clinical trials in the field of LUTS BPH medical treatment. Recently, anti-muscarinic agents have been assessed and have proven their efficacy and tolerance as long as the storage symptoms are predominant over the voiding symptoms. Combination therapies using alpha-blockers and 5-alpha reductase (5-ARI) inhibitors, but also anti-muscarinic agents and PDEF-5 inhibitors may also be prescribed depending on the patient' complaint. CONCLUSION: The publication of recent randomized clinical trials allows the urologists to use new drugs and new combination therapies in the medical treatment of LUTS-BPH. In 2011, the medical treatment decision-making may better integrate the patient' complaint and medical history. PMID- 22196000 TI - [Chemoradiotherapy for muscle-invasive cancer: methods, surveillance and results. An update from the cancer committee of the French National Association of Urology]. AB - Radical cystectomy is the treatment of choice for non-metastatic, muscle infiltrating bladder cancer. However, bladder-sparing approaches can be discussed in carefully selected patients. Bladder-preservation protocols aim to guaranty local control and survival with a functional bladder and a good quality of life. The ideal candidate for bladder-preservation therapy is a patient with a small tumor, stage T2, in whom a complete trans-urethral resection of the bladder tumor is achievable, who has no associated carcinoma in situ or hydronephrosis, and who is medically fit to receive chemotherapy. The 5- and 10-year survival rates for muscle-invasive tumors are approximately 50% and 35%, comparable to the results achievable with cystectomy. Approximately 80% of long-term survivors will preserve a native bladder, and approximately 75% of them will have a normal functioning bladder. PMID- 22196001 TI - [Five years follow-up of infections with extended-spectrum beta-lactamase producing enterobacteriaceae]. AB - INTRODUCTION: Actually, epidemiology of extended-spectrum beta-lactamase (ESBL) producing enterobacteriaceae is increasing worldwide, especially in urinary tract infections (UTI). The objective of the study was to investigate the epidemiology of ESBL producers in a department of urology. PATIENTS AND METHODS: This was a retrospective, monocentric study, which included all patients with positive culture showing an ESBL producing enterobacteriaceae in a department of urology between 2005 and 2009 included. RESULTS: The prevalence of ESBL producers in UTI was 2/113 (1.8%) in 2005 and 3/196 (1.5%) in 2009 (P=0.87). Twenty-seven isolates were included: 66.7% of Escherichia coli, 11.1% of Klebsiella pneumoniae, 11.1% of Enterobacter cloacae. ESBL producers were resistant to another antibiotic family in 24 cases (88.8%). The mean age in this study was 70.4 years, 70% of patients had another antibiotherapy in the past 6 months, 87% an hospitalization within 90% had surgery. Among the patients, 56.5% had a material. The infection was community-acquired in three cases only. Thirty-five percent of patients had no symptoms, 26% presented with severe sepsis. CONCLUSION: This report was a five year retrospective study of BLSE-positive bacteria showing the nosocomial infection with ESBL producers and their multiresistance to usual antibiotics without any increase of their prevalence. PMID- 22196002 TI - [Urinary complications of one-stitch ureteroneocystostomy in renal transplantation]. AB - PURPOSE: To assess urinary complications related to the "one-stitch" technique extravesical ureteroneocystostomy in renal transplantation, and evaluate the impact of such complications on kidney graft and patient survival. PATIENTS AND METHODS: A single-institution, retrospective study was performed on 202 renal transplant recipients, from January 2004 to December 2008. Two combined kidney and liver transplantations were excluded. The "one-stitch" extravesical ureteroneocystostomy technique, fast and easy to perform, was systematically used. The evaluated urinary complications were urinary fistula, ureteral stenosis, symptomatic ureteral reflux, stone formation and complicated hematuria. We tried to point out factors impacting urinary complications occurrence and studied grafts and patients survival according to the existence of urinary complications. RESULTS: Fifty-five patients presented urinary complications (27.5%). The most frequent urinary complications were complicated hematuria (36 over 200, 18%), ureteral stenosis (15 over 200, 7.5%). Few cases of stone disease (one over 200, 0.5%), urinary fistula (two over 200, 1%) and symptomatic ureteral reflux (one over 200, 0.5%) were noted. Male gender (100 vs 34, P=0.95), age (46.78 +/- 14.17 vs 48.06 +/- 14.19 years, P=0.58), Body mass index (24.14 +/- 5.04 vs 24.28 +/- 4.83, P=0.86) and past history of renal transplantations (16 +/ 3% vs 10 +/- 3%, P=0.27) as well as cold ischemia time (17.08 +/- 7.07 vs 16.9 +/- 8.95 hours, P=0.71) were not significantly different in the urinary complications group and the non-urinary complications group. Median hospitalization time was similar in both groups (14 vs 12 days, P=0.37). The existence of urinary complications didn't affect the 5 years kidney graft survival (91.9% vs 89.9%, HR 1.21, CI 95% [0.37-3.3], P=0.83) neither the 5 years patient survival (94.8% vs 92.15%, HR 0.52 CI 95% [0.13-2.07], P=0.85). CONCLUSION: If benign urinary complications in "one-stitch" ureteroneocystostomy were frequent in our study (17% grade II Clavien Dindo), kidney graft and patients survivals were not affected. PMID- 22196003 TI - [Laparoscopic sentinel lymph node (SLN) dissection for clinically localized prostate carcinoma: results obtained in the first 70 patients]. AB - OBJECTIVES: The lymph node metastasis is an important prognostic factor in prostatic cancer. The aim of this prospective study was to evaluate the relevance of the sentinel lymph node biopsy by laparoscopy in staging locoregional patients with clinically localized PC. PATIENTS AND METHODS: A transrectal ultrasound guided injection by 0.3 mL/100 MBq (99m)Tc-sulfur rhenium colloid in each prostatic lobe was performed the day before surgery. The detection was realized intraoperatively with a laparoscopic probe (Clerad((r)) Gamma Sup) followed by extensive dissection. Counts of SLN were performed in vivo and confirmed ex vivo. The histological analysis was performed by hematoxyline-phloxine-safran staining and followed by immunochemistry if SLN is free. RESULTS: Seventy patients with carcinoma of the prostate at intermediate or high risk of lymph node metastases were included. The intraoperative detection rate was 68/70 (97%). Fourteen patients had lymph node metastases, six only in SLN. The false negative rate was 2/14 (14%). The internal iliac region was the first metastatic site (40.9%). A metastatic sentinel node in common iliac region beyond the ureteral junction was present in 18.2%. A non-negligible sentinel metastatic region was the common iliac area (18.2%). Limited or standard lymph node dissection would have ignored respectively 72.7% and 59% of lymph node metastases. CONCLUSION: The laparoscopy is adapted to a broad identification of SLN and targeted dissection of these lymph nodes significantly limited the risk of surgical extended dissection while maintaining the accuracy of the information. PMID- 22196004 TI - [Endothelin-1 and receptor A: predictive value for biochemical relapse on patients with advanced and metastatic prostate cancer]. AB - INTRODUCTION: Pathological endothelin axis is known to be involved in prostate cancer progression. Our study evaluates immunohistochemical expression of ET-1 and ET-AR on prostate biopsy specimen and the predictive value for biochemical relapse on patients with advanced and metastatic cancer. We also evaluated the impact of ET-1 and ET-AR expression on local progression and metastatic bone progression for these patients. PATIENTS AND METHOD: From 1992 to June 2009, 44 patients with clinical T3 stage and metastatic lymph nodes were included. PSA levels, Gleason score in biopsy cores, number of invaded lymph nodes, the existence of nodular capsule transgression and hormonal treatment given to the patient, were analyzed. Biopsy cores were submitted to immunohistochemical study of the expression of ET-1 and ET-AR. Semi-quantitative ET-1 and ET-AR staining assessment was always realised by the same pathologist. RESULTS: The average age of the cohort was 65.6 (standard deviation 6.3), median PSA level was 52.8 ng /ml (3-227), median time of follow-up was 70 months (6-144). Biochemical relapse was observed in 62.8%. Statistically significant stronger ET-1 expression was observed in biopsies of patients with a biochemical relapse (p=0.014). Eighty percent of patients with a biochemical relapse had a high level of ET-AR expression, but no statistical significance has been shown (p=0.109). The relative risk for progression under hormonal therapy was 1.9 in case of high level of ET-1 expression and biochemical relapse was confirmed 8 months earlier in average. High level of ET-AR expression on biopsy cores may indicate earlier local progression and metastatic bone progression but there were no statistical proof. CONCLUSION: In our study, the strength of ET-1 expression in prostate cancer biopsy cores is a prognostic factor of biochemical relapse for cT3 stage patients with metastatic lymph nodes. We have not been able to prove that ET-1 is an independent prognostic factor. A high level of ET-AR expression on prostate biopsy cores is not, in our study, a prognosis factor for predicting the biochemical relapse. PMID- 22196005 TI - [Management of testicular lesions in a population of infertile patients]. AB - INTRODUCTION: Testicular parenchyma abnormalities and testis cancers are more frequent in infertile men, hence the guidelines recommending a systematic scrotal ultrasound. METHODS: A retrospective review of all patients treated with total or partial orchidectomy, from January, 2000 to July, 2010, for a testicular lesion discovered during an infertility evaluation work-up. Physical, examination data, type of surgery and pathological results were reported. RESULTS: Forty-five patients were treated. The majority of tumors (80%) were non palpable, and incidentally discovered with scrotal ultrasonography. Eight cases were partial orchidectomies, and 37 cases were radical orchidectomies. A frozen section examination was performed in 13 cases, and led to two radical orchidectomies. Standard histological examination revealed 33 (73.3%) benign lesions (11 Leydig cell hyperplasias, 17 Leydig cell tumors, five Sertoli cell tumors) and 10 (22.2%) malignant lesions (nine seminomas and one teratoma). Ten patients had a Klinefelter syndrome, for whom all the lesions were benign. CONCLUSION: The majority of non-palpable testicular lesions, discovered by ultrasonography in a population of infertile men were benign tumors. Conservative management in this context appears to be an option, to preserve the endocrine function and the fertility of these patients, while being ontologically safe. PMID- 22196006 TI - [Fertility after prostate brachytherapy with Iode 125 permanent implants for localized prostate cancer]. AB - OBJECTIVES: Preservation of fertility in men of middle age is an issue that is experiencing a growing interest. Prostate cancer is the second most common cancer in men and is diagnosed earlier than before. Brachytherapy is a treatment for prostate cancer that preserves ejaculation. Our aim was to study the fertility of men treated with prostate brachytherapy in order to improve patient information. PATIENTS AND METHODS: In a series of 270 sexually active men with localized prostate cancer treated with brachytherapy (permanent implants of Iode 125) at the Institute Claudius Regaud between 2000 and 2006, mean age 65 years (43-80), four patients spontaneously expressed their interest in the preservation of fertility and had an andrological evaluation. RESULTS: Four patients were aged 43, 48, 57 and 61 years, all working (including two businessmen), their partner was aged respectively 42, 37, 47 and 38 years. All four had a post-treatment semen analysis (done over a year after brachytherapy) rich in spermatozoa, with moderate asthenospermia, the main anomaly being severe hypospermia. These spermiograms were nonetheless consistent with the occurrence of spontaneous pregnancy (occurrence of miscarriage in the patient 1). CONCLUSION: There is an interest in applying to men with prostate cancer their position on fertility in order to inform them about the morbidity of various treatments, options for fertility preservation, and the need to continue a contraception after brachytherapy if the partner is not menopausal. PMID- 22196007 TI - [Outcome of severe closed kidney injuries in children]. AB - AIMS: To analyze the results of treatment of major renal injuries according imaging data in order to determine their function after follow-up. PATIENTS AND METHODS: This is a retrospective study of 22 cases of fracture of the kidney (grade V) in two pediatric surgical services that were reviewed over a period of 16 years. After initial conservative treatment in 19 patients (86.5%), a scan and/or Uro-MRI were realized in all patients in monitoring evolving. Three children with vascular injury were treated by interventional radiology. The morphology and functional evolution of the injured kidney were determined. RESULTS: A DMSA scan investigation was performed in 21 patients (95.5%) associated with Uro-MRI in two cases; one patient was only explored with Uro-MRI. A complete restitution of the renal parenchyma was confirmed in 10 children (45.5%), we noted an atrophy of the upper pole in 30%, a lower pole atrophy in 4.5%, two complete renal atrophy in 9%. An urinoma was present in six patients (27%) that required drainage in five cases and declined during the surveillance in one case. Normal function of the injured kidney was noticed in half of grade V (11 of 22 patients) with a mean follow-up of 19 months. None of our patients did present hypertension. CONCLUSION: Non-operative conservative treatment in severe renal trauma was efficient, morphological and functional sequelae were present in 50% on scintigraphy and/or Uro-MRI. PMID- 22196008 TI - [Circumcision accidents in Yaounde, Cameroon: a report on five cases]. AB - MATERIAL AND METHOD: Within a period of two months, (from July to August 2007), five accidents resulting from circumcisions were recorded in the pediatric surgical unit of Gynaeco-Obstetric and Paediatric Hospital Yaounde. RESULTS: Average age was 7.75 years within a range of 4-10 years. Anatomic/clinical pathologies recorded were: (a) one case of haemorrhage; one case of balanitis; (b) one case of amputation of the glans penis and (d) two cases of urethral fistula. CONCLUSION: This study brings out the ritualistic nature of circumcision rather than its therapeutic approach. Knowing fully the impact of accidents arising from the act of circumcision, there is no doubt that circumcision is entirely a surgical procedure requiring primarily the services of a paediatric surgeon. Its practice by other health care personnel like wise tradi-practioners should be under strict control. PMID- 22196009 TI - [Patient information and professional responsibility: reversal of jurisprudence of the Court of cassation]. AB - The Court of cassation is the highest court in the French judiciary. In a recent decision on June 3, 2010, the supreme jurisdiction quashed partially a court of appeal judgement. A patient developed erectile dysfunction following open prostatectomy for benign prostatic hyperplasia. The patient was not informed of this risk before the surgery. The judges recall that failure to provide information, including very exceptional risks, asserts in itself the physician's responsibility and allows financial reparation for patients. In accordance with this decision, a new jurisprudence in medical responsibility is born. PMID- 22196010 TI - [Buschke-Lowenstein tumor associated with scrotal melanoma. A case report]. AB - Buschke-Lowenstein tumour (BLT) is a giant condyloma acumina, which is rare entity and represents only 1% of all populace. It is a rare viral disease, essentially transmitted by sexual intercourse, characterized by a potential for malignant transformation, invasion and recurrence after treatment. We report a case of BLT associated with perinea-scrotal melanoma. This association was never described in the literature. The purpose of our case report is to discuss the clinical and pathological appearances of these two entities and to outline the recent studies of molecular biology, which can explain this association. PMID- 22196012 TI - Evidence that the spindle assembly checkpoint does not regulate APC(Fzy) activity in Drosophila female meiosis. AB - The spindle assembly checkpoint (SAC) plays an important role in mitotic cells to sense improper chromosome attachment to spindle microtubules and to inhibit APC(Fzy)-dependent destruction of cyclin B and Securin; consequent initiation of anaphase until correct attachments are made. In Drosophila , SAC genes have been found to play a role in ensuring proper chromosome segregation in meiosis, possibly reflecting a similar role for the SAC in APC(Fzy) inhibition during meiosis. We found that loss of function mutations in SAC genes, Mad2, zwilch, and mps1, do not lead to the predicted rise in APC(Fzy)-dependent degradation of cyclin B either globally throughout the egg or locally on the meiotic spindle. Further, the SAC is not responsible for the inability of APC(Fzy) to target cyclin B and promote anaphase in metaphase II arrested eggs from cort mutant females. Our findings support the argument that SAC proteins play checkpoint independent roles in Drosophila female meiosis and that other mechanisms must function to control APC activity. PMID- 22196011 TI - Conducting online expert panels: a feasibility and experimental replicability study. AB - BACKGROUND: This paper has two goals. First, we explore the feasibility of conducting online expert panels to facilitate consensus finding among a large number of geographically distributed stakeholders. Second, we test the replicability of panel findings across four panels of different size. METHOD: We engaged 119 panelists in an iterative process to identify definitional features of Continuous Quality Improvement (CQI). We conducted four parallel online panels of different size through three one-week phases by using the RAND's ExpertLens process. In Phase I, participants rated potentially definitional CQI features. In Phase II, they discussed rating results online, using asynchronous, anonymous discussion boards. In Phase III, panelists re-rated Phase I features and reported on their experiences as participants. RESULTS: 66% of invited experts participated in all three phases. 62% of Phase I participants contributed to Phase II discussions and 87% of them completed Phase III. Panel disagreement, measured by the mean absolute deviation from the median (MAD-M), decreased after group feedback and discussion in 36 out of 43 judgments about CQI features. Agreement between the four panels after Phase III was fair (four-way kappa=0.36); they agreed on the status of five out of eleven CQI features. Results of the post completion survey suggest that participants were generally satisfied with the online process. Compared to participants in smaller panels, those in larger panels were more likely to agree that they had debated each others' view points. CONCLUSION: It is feasible to conduct online expert panels intended to facilitate consensus finding among geographically distributed participants. The online approach may be practical for engaging large and diverse groups of stakeholders around a range of health services research topics and can help conduct multiple parallel panels to test for the reproducibility of panel conclusions. PMID- 22196013 TI - Lymph nodes harbor viral reservoirs that cause rebound of plasma viremia in SIV infected macaques upon cessation of combined antiretroviral therapy. AB - Attempts to find a cure for HIV infection are hindered by the presence of viral reservoirs that resist highly active antiretroviral therapy. To identify the properties of these reservoirs, four SIV239-infected Rhesus macaques were treated with combined antiretroviral therapy (cART) for 1 year. While plasma viral RNA (vRNA) was effectively suppressed, a systemic analysis revealed that vRNA was distributed in the following order: lymphatic tissues>lungs and intestine>other tissues. Histochemistry yielded no cells with viral signals. To increase the chance of detection, two additional SIV-infected animals were treated and analyzed on Day 10 after the cessation of cART. These animals exhibited similar vRNA distribution patterns to the former animals, and immunohistochemistry revealed Nef-positive T lymphocytes predominantly in the follicles of mesenteric lymph nodes (MLNs). These data suggest that lymphatic tissues, including MLNs, contain major cellular reservoirs that cause rebound of plasma viremia upon cessation of therapy. PMID- 22196015 TI - [Visit of the extermination camp Auschwitz-Birkenau: what lessons for medical students?]. PMID- 22196018 TI - Zinc metalloenzymes as new targets against the bacterial pathogen Brucella. AB - Brucella, a facultative intracellular pathogen, is one of the most common zoonotic diseases worldwide. Considering the alarming health problem caused by the emergence of resistance and multi-resistance of intracellular pathogen, the challenge is currently to identify and to validate novel pharmaceutical targets in this bacteria species. Brucella's genome encodes metalloproteins involved in various biosynthetic processes, some of them being essential during intracellular growth phase and virulence. The potential of prokaryotic zinc metalloproteins such as carbonic anhydrase (CA) and histidinol dehydrogenase (HDH) as anti Brucella targets has only recently been taken into consideration in the search of novel anti-infective agents that lack of cross-resistance to existing drugs. These enzymes have a growing significance in modern medicine as they are required for growth and/or virulence in several intracellular pathogen species. This review illustrates and describes the progress which has been made in the design and the discovery of selective inhibitors of these bacterial enzymes as new potential anti-Brucella agents. PMID- 22196016 TI - Characterization of Zn(II)-responsive ribosomal proteins YkgM and L31 in E. coli. AB - RT-PCR and DNA microarrays were used to probe for Zn(II)-responsive genes in E. coli cells that were made Zn(II) deficient. Microarray data revealed 114 genes were significantly up-regulated and 146 genes were significantly down-regulated in Zn(II) deficient conditions. The three most up-regulated genes were (1) znuA, which encodes for a periplasmic protein known to be involved with Zn(II) import, (2) yodA, which encodes for a periplasmic protein with unknown function, and (3) ykgM, which encodes for a ribosomal protein that is thought to be a paralog of ribosomal protein L31. YodA was over-expressed and purified as a maltose binding protein (MBP) fusion protein and shown to tightly bind 4 equivalents of Zn(II). Metal analyses showed that MBP-YkgM does not bind Zn(II). On the other hand, MBP L31 tightly binds 1 equivalent of Zn(II). EXAFS studies on MBP-L31 suggest a ligand field of 1 histidine, 1 cysteine, and 2 additional N/O scatterers. Site directed mutagenesis studies suggest that Cys16 coordinates Zn(II) in MBP-L31 and that the other three cysteines do not bind metal. These results are discussed in light of Zn(II) starvation model that has been postulated for B. subtilis. PMID- 22196017 TI - Apoprotein isolation and activation, and vibrational structure of the Helicobacter mustelae iron urease. AB - The micro aerophilic pathogen Helicobacter mustelae synthesizes an oxygen-labile, iron-containing urease (UreA2B2) in addition to its standard nickel-containing enzyme (UreAB). An apoprotein form of the iron urease was prepared from ureA2B2 expressing recombinant Escherichia coli cells that were grown in minimal medium. Temperature-dependent circular dichroism measurements of holoprotein and apoprotein demonstrate an enhancement of thermal stability associated with the UreA2B2 metallocenter. In parallel to the situation reported for nickel activation of the standard urease apoprotein, incubation of UreA2B2 apoprotein with ferrous ions and bicarbonate generated urease activity in a portion of the nascent active sites. In addition, ferrous ions were shown to be capable of reductively activating the oxidized metallocenter. Resonance Raman spectra of the inactive, aerobically-purified UreA2B2 holoprotein exhibit vibrations at 495cm( 1) and 784cm(-1), consistent with nu(s) and nu(as) modes of an Fe(III)OFe(III) center; these modes undergo downshifts upon binding of urea and were unaffected by changes in pH. The low-frequency mode also exhibits an isotopic shift from 497 to 476cm(-1) upon (16)O/(18)O bulk water isotope substitution. Expression of subunits of the conventional nickel-containing Klebsiella aerogenes urease in cells grown in rich medium without nickel resulted in iron incorporation into a portion of the protein. The inactive iron-loaded species exhibited a UV-visible spectrum similar to oxidized UreA2B2 and was capable of being reductively activated under anoxic conditions. Results from these studies more clearly define the formation and unique properties of the iron urease metallocenter. PMID- 22196019 TI - Health implications of the distribution of arsenic species in airborne particulate matter. AB - Airborne particle samples were taken between 2001 and 2008 at an urban site (Huelva) in southwestern Spain. Arsenic was found in the samples due to the presence of a near-by copper smelter, sometimes at concentrations above the target value of 6 ng m(-3) proposed by EU regulations (annual means from 4.6 to 10.4 ng As m(-3) in PM10, and 3.0 to 9.1 ng As m(-3) in PM2.5). The results obtained by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) showed that arsenic accumulates preferentially (ca. 70-80%) in the particles with smaller diameter (PM2.5 versus PM10), representing a threat to human health due to the higher capacity of the finer particles to enter the organism through the respiratory system. Moreover, the toxicity of the inorganic arsenic species depends also on the oxidation state, As(III) being more toxic that As(V). The speciation analysis performed with High Performance Liquid Chromatography-Hydride Generation- Atomic Fluorescence Spectrometry (HPLC-HG-AFS) with samples collected between 2006 and 2008, showed that As(V) represented the main arsenic species, but As(III) was also found at significant concentration, representing a 5-10% of the total arsenic content. The results also indicate that the more toxic As(III) tends to concentrate preferentially in the finer fraction PM2.5 in comparison with As(V), thus representing an added health risk for the local population. PMID- 22196020 TI - Secondary interactions involving zinc-bound ligands: roles in structural stabilization and macromolecular interactions. AB - A large number of proteins contain bound zinc ions. These zinc ions are frequently coordinated by a combination of histidine and cysteine residues. In addition to atoms that coordinate directly to the zinc ions, these side chains have groups that can donate or accept hydrogen bonds from other groups. These secondary interactions can help stabilize the zinc-binding sites, can contribute to protein folding and stability, and, on occasion, can participate in interactions with other macromolecules. Five examples of these secondary interactions are discussed: carbonic anhydrase (where secondary interactions involving histidine residues stabilize the zinc-binding site thermodynamically and kinetically), retroviral nucleocapsid proteins and TRAF proteins (where cysteinate sulfur to peptide NH hydrogen bonds contribute to the structural relationships between adjacent domains), and nucleic acid binding proteins, Zif268 and TIS11 where secondary interactions participate in protein-nucleic acid interactions. PMID- 22196021 TI - New perspectives of zinc coordination environments in proteins. AB - Zinc is more widely used as a cofactor in proteins than any other transition metal ion. In addition to catalytic and structural functions, zinc(II) ions have a role in information transfer and cellular control. They bind transiently when proteins regulate zinc concentrations and re-distribute zinc and when proteins are regulated by zinc. Transient zinc-binding sites employ the same donors of amino acid side chains as catalytic and structural sites but differ in their coordination chemistry that can modulate zinc affinities over at least ten orders of magnitude. Redox activity of the cysteine ligands, multiple binding modes of the oxygen, sulfur and nitrogen donors, and protein conformational changes induce coordination dynamics in zinc sites and zinc ion mobility. Functional annotations of the remarkable variation of coordination environments in zinc proteomes need to consider how the primary coordination spheres interact with protein structure and dynamics, and the adaptation of coordination properties to the biological context in extracellular, cellular, or subcellular locations. PMID- 22196022 TI - Alkene metathesis approach to beta-unsubstituted anti-allylic alcohols and their use in ene-yne metathesis. AB - The synthesis of beta-unsubstituted, anti-allylic alcohols using a catalytic Evans aldol reaction conjoined with a relay-type ring-closing alkene metathesis is reported. The metathesis step serves to remove a beta-alkenyl group, which facilitated the aldol step. The beta-substituted enals serve as acrolein surrogates. The products were employed in ene-yne cross metathesis. PMID- 22196024 TI - Dynamic properties of bicellar lipid mixtures observed by rheometry and quadrupole echo decay. AB - In bicellar dispersions of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC), the transition from isotropic reorientation to partial orientational order, on warming, is known to coincide with a sharp increase in viscosity. In this work, cone-and-plate rheometry, (2)H NMR spectroscopy, and quadrupole echo decay observations have been used to obtain new insights into the dynamics of phases observed in bicellar DMPC/DHPC mixtures. Samples with 25% of the DMPC component deuterated were used to correlate rheological measurements with phase behavior observed by (2)H NMR spectroscopy. Mixtures containing only normal DMPC (DMPC/DHPC) or only chain perdeuterated DMPC (DMPC-d(54)/DHPC) were used to refine rheology and quadrupole echo decay measurements respectively. The viscosity peaked at 4-9 Pa.s, just above the isotropic-to-nematic transition, and then dropped as samples were warmed through the nematic-to-lamellar transition. Quadrupole echo decay times above the nematic to-lamellar transition were significantly longer than typically observed in the liquid crystalline phase of saturated lipid multilamellar vesicles. This may indicate a damping of slow bilayer undulations resulting from the coupling of opposite bilayer surfaces by DHPC-lined pores. PMID- 22196025 TI - Using the graphene Moire pattern for the trapping of C60 and homoepitaxy of graphene. AB - The graphene Moire superstructure offers a complex landscape of humps and valleys to molecules adsorbing and diffusing on it. Using C(60) molecules as the classic hard sphere analogue, we examine its assembly and layered growth on this corrugated landscape. At the monolayer level, the cohesive interactions of C(60) molecules adsorbing on the Moire lattice freeze the molecular rotation of C(60) trapped in the valley sites, resulting in molecular alignment of all similarly trapped C(60) molecules at room temperature. The hierarchy of adsorption potential well on the Moire lattice causes diffusion-limited dendritic growth of C(60) films, as opposed to isotropic growth observed on a smooth surface like graphite. Due to the strong binding energy of the C(60) film, part of the dentritic C(60) films polymerize at 850 K and act as solid carbon sources for graphene homoepitaxy. Our findings point to the possibility of using periodically corrugated graphene in molecular spintronics due to its ability to trap and align organic molecules at room temperature. PMID- 22196027 TI - Peroxiredoxin 4: a multifunctional biomarker worthy of further exploration. AB - Currently, there is much interest in identifying clinically relevant biomarkers, as they have the potential to be high utility non-invasive tools for early diagnosis and reliable patient monitoring in numerous conditions. Since its discovery almost 15 years ago, research on the ubiquitous antioxidant enzyme peroxiredoxin 4 (Prx4) has culminated in the recognition that Prx4 levels are different in blood drawn from the healthy general population and patients with acute or chronic diseases. In this commentary, the most striking research data from different in vitro approaches, animal models and human observational studies are discussed collectively, highlighting the clinical importance of Prx4 as a multifunctional staging and prognosis biomarker. In this context, the oxidative state of patients may be reflected by intra- and extracellular Prx4 levels, redox state, oligomerization and nitro-oxidative modifications of the enzyme. A consolidated model of the potential role and origin of circulating Prx4 is presented to stimulate further investigations in light of the current biomarker situation. PMID- 22196028 TI - Optimization of HNO production from N,O-bis-acylated hydroxylamine derivatives. AB - A wide range of N,O-bis-acylated hydroxylamine derivatives with chloro or arenesulfonyl leaving groups, and a related set of N-hydroxy-N-acylsulfonamides, have been synthesized and evaluated for nitroxyl (HNO) production. Mechanistic studies have revealed that the observed aqueous chemistry is more complicated than originally anticipated, and have been used to develop a new series of efficient HNO precursors (4u-4x, 7c-7d) with tunable half-lives. PMID- 22196026 TI - Unraveling the complexity of ubiquitin signaling. AB - Protein ubiquitination, the covalent attachment of ubiquitin to target proteins, has emerged as one of the most prevalent posttranslational modifications (PTMs), regulating nearly every cellular pathway. The diversity of signaling associated with this particular PTM stems from the myriad ways in which a target protein can be modified by ubiquitin, e.g., monoubiquitin, multi-monoubiquitin, and polyubiquitin linkages. In this Review, we focus on developments in both enzymatic and chemical methods that engender ubiquitin with new chemical and physical properties. Moreover, we highlight how these methods have enabled studies directed toward (i) characterizing enzymes responsible for reversing the ubiquitin modification, (ii) understanding the influence of ubiquitin on protein function and crosstalk with other PTMs, and (iii) uncovering the impact of polyubiquitin chain linkage and length on downstream signaling events. PMID- 22196031 TI - Evaluation of bone marrow-derived mesenchymal stem cells after cryopreservation and hypothermic storage in clinically safe medium. AB - Achievements in tissue engineering using mesenchymal stem cells (MSC) demand a clinically acceptable "off-the-shelf" cell therapy product. Efficacy of cryopreservation of human bone marrow-derived MSC in clinically safe, animal product-free medium containing 2%, 5%, and 10% dimethyl sulfoxide (DMSO) was evaluated by measuring cell recovery, viability, apoptosis, proliferation rate, expression of a broad panel of MSC markers, and osteogenic differentiation. Rate controlled freezing in CryoStor media was performed in a programmable cell freezer. About 95% of frozen cells were recovered as live cells after freezing in CryoStor solutions with 5% and 10% DMSO followed by storage in liquid nitrogen for 1 month. Cell recovery after 5 months storage was 72% and 80% for 5% and 10% DMSO, respectively. Measurements of caspase 3 activity demonstrated that 15.5% and 12.8% of cells after 1 month and 18.3% and 12.9% of cells after 5 months storage in 5% and 10% DMSO, respectively, were apoptotic. Proliferation of MSC recovered after cryopreservation was measured during 2 weeks post-plating. Proliferation rate was not compromised and was even enhanced. Cryopreservation did not alter expression of MSC markers. Quantitative analysis of alkaline phosphatase (ALP) activity, ALP surface expression and Ca++ deposition in previously cryopreserved MSC and then differentiated for 3 weeks in osteogenic medium demonstrated the same degree of osteogenic differentiation as in unfrozen parallel cultures. Cell viability and functional parameters were analyzed in MSC after short-term storage at 4 degrees C in HypoThermosol-FRS solution, also free of animal products. Hypothermic storage for 2 and 4 days resulted in about 100% and 85% cell recovery, respectively, less than 10% of apoptotic cells, and normal proliferation, marker expression, and osteogenic potential. Overall, our results demonstrate that human MSC could be successfully cryopreserved for banking and clinical applications and delivered to the bedside in clinically safe protective reagents. PMID- 22196032 TI - Prevalence of Toxoplasma gondii infection in Myocastor coypus in a protected Italian wetland. AB - BACKGROUND: Toxoplasma gondii is the causative agent for a major zoonosis with cosmopolitan distribution. Water has been implicated in outbreaks of toxoplasmosis in recent years. Coypus (Myocastor coypus), commonly nutria, are large semi-aquatic invasive rodents, naturalized throughout European countries, including most wetlands of Central Italy. The habitat of these animals is both terrestrial and aquatic, making them a species highly exposed to the parasite. FINDINGS: The occurrence of the infection was evaluated using a modified agglutination test (MAT) in 74 adult coypus from a naturalized population living in a wetland of Central Italy. Nested PCR (n-PCR) assay was carried out on some of them. Positive T. gondii MAT results were found in 44 animals (59.4%), 30 males (68.2%) and 14 females (31.8%). Antibody titers were ranging from 20 to 40960, while 12 out of 23 (52.2%), examined animals, 8 males (66.7%) and 4 females (33.3%), resulted positive to n-PCR. All n-PCR positive animals were seropositive, showing antibody titers ranging from 640 to 40960. CONCLUSIONS: Our results indicate that examined animals are heavily parasitized with Toxoplasma. This suggests that coypus could be a reservoir of this parasite, because they can be eaten both by scavenger animals and by humans, and that these animals would play a role in maintaining the cycle of T. gondii. PMID- 22196034 TI - Conditional survival of patients with urothelial carcinoma of the urinary bladder treated with radical cystectomy. AB - AIM OF STUDY: To examine the impact of survival probability according to duration of survivorship following radical cystectomy (RC) in patients diagnosed with urothelial carcinoma of the urinary bladder (UCUB). METHODS: Overall, 4991 UCUB patients who underwent RC were abstracted. The cumulative survival estimates were used to generate conditional survival rates. Cox regression analyses were performed for prediction of cancer-specific mortality (CSM), according to duration of survivorship. RESULTS: The five-year CSM-free survival rate was 63.9% at RC, and increased to 71.0%, 77.5%, 81.7%, 85.9% and 86.3% in patients who survived >= 1, 2, 3, 4 and 5 years, respectively. Patients with pT2-4 disease benefitted from the highest increase in survivorship two years after RC. The same findings were recorded according to patients' nodal status. CONCLUSION: The survival of the first two years after RC markedly improves individual patient prognosis. The prognostic gains differ according to patient and tumour characteristics. PMID- 22196033 TI - Safety of bevacizumab in metastatic breast cancer patients undergoing surgery. AB - BACKGROUND: Evaluate the safety of surgery in relation to bevacizumab in the first-line treatment of metastatic breast cancer (mBC) in two international trials. PATIENTS AND METHODS: The incidence, type and timing of post-surgical bleeding events and wound-healing complications were assessed in surgical patients in the AVastin And DOcetaxel (AVADO) (NCT00333775) and Avastin THErapy for advaNced breAst cancer (ATHENA) (NCT00448591) trials. Both study protocols followed recommendations to withhold bevacizumab for at least 6 weeks before elective surgery and to wait 28 days (or until the wound was fully healed) after major surgery before recommencing bevacizumab therapy. RESULTS: In AVADO, 221 surgical procedures (55 major, 166 minor) were performed in 155 patients. In ATHENA, 1190 surgical procedures (435 major, 755 minor) were performed in 672 patients. One bevacizumab-treated AVADO patient (0.9%) who underwent surgery experienced a grade 3 bleeding event. In ATHENA, six patients (0.9%) who underwent surgery experienced grade 3 bleeding events and one patient (0.1%) experienced a grade 4 bleeding event. No grade 5 bleeding events in patients undergoing surgery were reported in either study. One grade 3 wound-healing complication was reported in each of the AVADO arms: placebo (n=46, 2.2%), bevacizumab 7.5mg/kg (n=57, 1.8%) and bevacizumab 15mg/kg (n=52, 1.9%). Incidence of grade 3-4 wound-healing complications in ATHENA was 2.2% and 1.3% in patients undergoing minor or major surgery, respectively. CONCLUSIONS: Surgery can be performed on patients with mBC undergoing bevacizumab therapy with a low risk of severe bleeding or wound-healing complications post surgery, if current labelling recommendations are adhered to. PMID- 22196035 TI - Socio-economic implications of cancer survivorship: results from the PROFILES registry. AB - INTRODUCTION: The goal of this large population-based study was to examine the socio-economic implications of cancer survivorship. METHODS: Individuals alive and diagnosed with colorectal cancer and melanoma between 1998 and 2007 or Hodgkin lymphoma, non-Hodgkin lymphoma or multiple myeloma between 1999 and 2008 as registered in the Eindhoven Cancer Registry received a questionnaire on work changes and problems with obtaining a new (or extended) health care insurance, life insurance or a home loan; 70% (n = 2892) responded. RESULTS: Results showed that 28% of all cancer patients experienced changes in their work situation after cancer. Most of them switched to part-time work or stopped working entirely. Patients (3.4%) who tried to obtain a different or upgrade their health care insurance experienced problems and in most cases, these were eventually resolved. Problems with life insurance were somewhat more common with 18% of those who tried to obtain a life insurance experiencing problems. The majority of these patients was rejected by the insurance company (61%) or was accepted at a higher premium (22%). Of the 21% who tried to obtain a home loan, 9% experienced problems. However, 22.2% got accepted eventually, 27.8% got accepted but at a higher mortgage payment and 22.2% got rejected but were eventually accepted by another bank. CONCLUSIONS: Almost a third of cancer survivors experienced changes in their work situation after cancer. Problems with obtaining health insurance, life insurance and home loans were also common. PMID- 22196036 TI - [Primary care pediatrics in the public health system of the twenty-first century. SESPAS report 2012]. AB - Today in our country, the primary care pediatrician is the first contact between children and adolescents with the health system, being also a highly resolving specialist that addresses over 90% of the health needs of this population, monitors growth and development and participates in all activities of prevention, health promotion and health education within primary care teams with nurses and family doctors. Witnessing rapid and profound demographic, social, cultural, scientific and technological changes as well as the demands and expectations of health care for citizens, which should enhance the value and response capacity of primary care. These changes also affect infant morbidity and health care priorities in child and adolescent, posing new challenges for primary care practice and reinforce the role of the pediatrician in primary care. Primary care is not only the gateway to the health system. Primary care teams have to take responsibility for the care of people assigned to coordinate the necessary resources and advising citizens on their health problems and his itinerary care by the health system. It identifies the need to foster teamwork within the health department involved nursing staff to take care activities in this age group. It aims to foster a model based on cooperation and complementarity. A recent systematic review recommended maintaining the figure of the pediatrician in primary care teams and strengthen their specific role as first point of contact with the child's health care system, found significant benefits for children. PMID- 22196037 TI - [Spanish experiences to promote personal autonomy in the elderly]. AB - OBJECTIVES: To identify studies analyzing the development of initiatives and the requisite characteristics of programs that promote personal autonomy, to identify the initiatives and policies developed in Spain to promote active aging and to determine whether the programs developed are consistent with the evidence in this field. METHOD: We performed a literature review and analyzed the policies developed in each Spanish region. Programs to promote personal autonomy were identified and analyzed through a questionnaire sent to the autonomous regions. RESULTS: Personal autonomy should be promoted through interventions to improve physical, cognitive, social and psycho-affective functions and by eliminating barriers that hamper independent living. Functional capacities are promoted through leisure activities (83%), reading and cognitive rehabilitation. Independent living is encouraged through podiatry services (38.9%) and food services at home (38.9%). Thirteen autonomous communities and the Biscay Regional Council have developed specific policies to promote personal autonomy. Personal autonomy activities are often conducted in senior or day centers. CONCLUSIONS: There are differences in the provision of programs to promote active aging. The development and implementation of these programs depends on the competent authority (Institute for the Elderly and Social Services, town councils, subsidized private entities, etc.). More evidence and a framework that defines common standards and criteria for the development of effective programs are required. PMID- 22196038 TI - Bayesian cost-effectiveness analysis for censored data: an application to antiplatelet therapy. AB - OBJECTIVE: Cost-effectiveness analysis (CEA) on trial-based data has played an important role in pharmacoeconomics. A regression model can be used to account for patient-level heterogeneity throughout covariates adjustment in CEA. However, the estimates from CEA could be biased if ignoring the censoring issue on effectiveness and costs. This study is to propose a regression model to account for both time-to-event effectiveness and cost. METHODS: A bivariate regression model was proposed to analyze both effectiveness and cost simultaneously, while censored observations were also taken into account. The regression coefficients were estimated using a Bayesian approach by drawing a random sample from their posterior distribution derived from the Markov chain Monte Carlo (MCMC) method. The proposed method was illustrated using empirical data of anti-platelet therapies to the management of cardiovascular diseases for those patients with high risk of gastrointestinal (GI) bleeding, where cost-effectiveness between different therapies was analyzed under both censored and non-censored circumstances, where the effectiveness was defined as the time to re hospitalization due to GI complications, and the cost was measured by the total drug expenditure. RESULTS: Under censored circumstances, aspirin plus proton-pump inhibitors (PPIs) was considered more cost-effective than clopidogrel with/without PPIs, as shown in the cost-effectiveness acceptability curve, and clopidogrel was preferred to aspirin for a willingness-to-pay of 89 NTD for delaying 1 day to hospitalization due to GI complications. CONCLUSIONS: Ignoring censoring problems could possibly bias the results in CEA. This study has provided an appropriate method to conduct regression-based CEA to improve the estimation which serves its purpose for CEA concerns. LIMITATIONS: The normality assumption for the cost and effectiveness in the bivariate normal regression needs to be examined, and the conclusions may be biased if this assumption is violated. However, when sample size is sufficiently large, a slight deviation from normality would not be a serious problem. PMID- 22196040 TI - Linear and nonlinear optical properties of colloidal photonic crystals. PMID- 22196043 TI - Chemical compounds and toxicological assessments of drinking water stored in polyethylene terephthalate (PET) bottles: A source of controversy reviewed. AB - A declaration of conformity according to European regulation No. 10/2011 is required to ensure the safety of plastic materials in contact with foodstuffs. This regulation established a positive list of substances that are authorized for use in plastic materials. Some compounds are subject to restrictions and/or specifications according to their toxicological data. Despite this, the analysis of PET reveals some non-intentionally added substances (NIAS) produced by authorized initial reactants and additives. Genotoxic and estrogenic activities in PET-bottled water have been reported. Chemical mixtures in bottled water have been suggested as the source of these toxicological effects. Furthermore, sample preparation techniques, such as solid-phase extraction (SPE), to extract estrogen like compounds in bottled water are controversial. It has been suggested that inappropriate extraction methods and sample treatment may result in false negative or positive responses when testing water extracts in bioassays. There is therefore a need to combine chemical analysis with bioassays to carry out hazard assessments. Formaldehyde, acetaldehyde and antimony are clearly related to migration from PET into water. However, several studies have shown other theoretically unexpected substances in bottled water. The origin of these compounds has not been clearly established (PET container, cap-sealing resins, background contamination, water processing steps, NIAS, recycled PET, etc.). Here, we surveyed toxicological studies on PET-bottled water and chemical compounds that may be present therein. Our literature review shows that contradictory results for PET-bottled water have been reported, and differences can be explained by the wide variety of analytical methods, bioassays and exposure conditions employed. PMID- 22196041 TI - Effects of thyroid hormone analogue and a leukotrienes pathway-blocker on renal ischemia/reperfusion injury in mice. AB - BACKGROUND: Acute renal failure (ARF) is an important clinical problem with a high mortality and morbidity. One of the primary causes of ARF is ischemia/reperfusion (I/R). Inflammatory process and oxidative stress are thought to be the major mechanisms causing I/R. MK-886 is a potent inhibitor of leukotrienes biosynthesis which may have anti-inflammatory and antioxidant effects through inhibition of polymorphonuclear leukocytes (PMNs) infiltration into renal tissues. 3, 5-diiodothyropropionic acid (DITPA) have evidences of improving effects on I/R in heart through modulation of cellular signaling in response to ischemic stress. The objective of present study was to assess the effects of MK-886 and DITPA on renal I/R injury. METHODS: A total of 24 Adult males of Swiss albino mice were randomized to four groups: I/R group (n = 6), mice underwent 30 minute bilateral renal ischemia and 48 hr reperfusion. Sham group (n = 6), mice underwent same anesthetic and surgical procedures except for ischemia induction. MK-886-treated group: (n = 6), I/R + MK-886 (6 mg/kg) by intraperitoneal injection. DITPA-treated group: (n = 6), I/R + DITPA (3.75 mg/kg) by intraperitoneal injection.After the end of reperfusion phase mice were sacrificed, blood samples were collected directly from the heart for determination of serum TNF-a, IL-6, urea and Creatinine. Both kidney were excised, the right one homogenized for oxidative stress parameters (MDA and GSH) measurements and the left kidney fixed in formalin for histological examination. RESULTS: Serum TNF-alpha, IL-6, urea and Creatinine, kidney MDA levels and scores of histopathological changes were significantly (P < 0.05) elevated in I/R group as compared with that of sham group. Kidney GSH level was significantly (P < 0.05) decreased in I/R group as compared with that of sham group. MK-886 treated group has significantly (P < 0.05) lowered levels of all study parameters except for GSH level which was significantly (P < 0.05) higher as compared with that of I/R group. DITPA caused non-significant (P > 0.05) changes in levels of all study parameters as compared with that of I/R group. CONCLUSION: The results of the present study show that MK-886 significantly ameliorated kidney damage that resulted from I/R. For DITPA, as its administration might not be successful, administration using a different protocol may give different effects on I/R. PMID- 22196044 TI - A phenomenological retention tank model using settling velocity distributions. AB - Many authors have observed the influence of the settling velocity distribution on the sedimentation process in retention tanks. However, the pollutants' behaviour in such tanks is not well characterized, especially with respect to their settling velocity distribution. This paper presents a phenomenological modelling study dealing with the way by which the settling velocity distribution of particles in combined sewage changes between entering and leaving an off-line retention tank. The work starts from a previously published model (Lessard and Beck, 1991) which is first implemented in a wastewater management modelling software, to be then tested with full-scale field data for the first time. Next, its performance is improved by integrating the particle settling velocity distribution and adding a description of the resuspension due to pumping for emptying the tank. Finally, the potential of the improved model is demonstrated by comparing the results for one more rain event. PMID- 22196045 TI - Total synthesis and biological evaluation of pacidamycin D and its 3'-hydroxy analogue. AB - Full details of the total synthesis of pacidamycin D (4) and its 3'-hydroxy analogue 32 are described. The chemically labile Z-oxyacyl enamide moiety is the most challenging chemical structure found in uridylpeptide natural products. Key elements of our approach to the synthesis of 4 include the efficient and stereocontrolled construction of the Z-oxyvinyl halides 6 and 7 and their copper catalyzed cross-coupling with the tetrapeptide carboxamide 5, a thermally unstable compound containing a number of potentially reactive functional groups. This synthetic route also allowed us to easily prepare 3'-hydroxy analogue 32. The assemblage by cross-coupling of the Z-oxyvinyl halide 6 and the carboxamide 5 at a late stage of the synthesis provided ready access to a range of uridylpeptide antibiotics and their analogues, despite their inherent labile nature with potential epimerization, simply by altering the tetrapeptide moiety. PMID- 22196046 TI - Sleep duration buffers diurnal cortisol increases in older adulthood. AB - This study examined the long-term associations between reports of sleep duration and diurnal cortisol secretion in older adulthood. It was hypothesized that longer sleep would protect older adults against increases in diurnal cortisol secretion over time. We tested this hypothesis using three waves of data from a 4 year longitudinal study involving 157 older adults. Results from growth curve and cross-lagged panel analyses demonstrated that levels and increases in sleep duration buffered long-term elevations of diurnal cortisol secretion. Reversed analyses indicated that diurnal cortisol secretion did not predict changes in sleep duration over time. These results were independent from sociodemographic characteristics (i.e., age, sex, partnership status, and education) and health related variables (i.e., chronic illness, medication usage, body mass index, and smoking). They suggest that long sleep exerts restorative functions and protects older adults from exhibiting increases in diurnal cortisol secretion over time. PMID- 22196047 TI - Identification and expression profile of a new cytochrome P450 isoform (CYP414A1) in the hepatopancreas of Venerupis (Ruditapes) philippinarum exposed to benzo[a]pyrene, cadmium and copper. AB - With the objective to identify promising molecular biomarkers for marine pollution monitoring, a new cytochrome P450 gene was identified from Venerupis (Ruditapes) philippinarum and classified as a member of a new subfamily, CYP414A1. Phylogenetic analysis showed that CYP414A1 was closely related to members of the CYP2 family. CYP414A1 mRNA expression was significantly induced by 50 MUg/L B[a]P at 96 h, while no significant change was found in 5 MUg/L B[a]P exposed samples. For heavy metals exposure, the expression of CYP414A1 was significantly up-regulated by Cd but sharply depressed by Cu exposure. These results suggested that CYP414A1 responded to various xenobiotics stresses, and could be used as a candidate biomarker of heavy metals and B[a]P. PMID- 22196048 TI - Correlation between EGFR Y1068 tyrosine phosphorylation and AP-1 activation by tumor promoter 12-O-tetradecanoylphorbol-13-acetate in mouse skin. AB - The mouse skin carcinogenesis is unique model for our understating of molecular events leading to tumor development. The tumor promoter, 12-O tetradecanoylphorbol-13-acetate (TPA) activates a variety of signaling pathways, including MAPK/AP-1. In this study, we examined the time course of EGFR phosphorylation and AP-1 activation in mouse epidermis after topical application of a single 10 nmol dose of TPA. Remarkable differences in the phosphorylation kinetics of EGFR tyrosine residues were observed. While the maximal level of Y1068 tyrosine phosphorylation occurred 4h after TPA treatment, the Y1173 residue phosphorylation was initially down-regulated, and reached the highest level after 24 h. Phosphorylation of Y1068 tyrosine was correlated with AP-1 activation and c Jun N-terminal kinase (JNK) activity. These results indicate that the stimulation of AP-1 in mouse epidermis by TPA may be the effect of EGFR activation, but not all tyrosine residues forming its catalytic center are equally involved in this process. PMID- 22196049 TI - Modulation in the mRNA expression of ecdysone receptor gene in aquatic midge, Chironomus riparius upon exposure to nonylphenol and silver nanoparticles. AB - Chironomus riparius, a non-biting midge (Chironomidae, Diptera), is extensively used as a model organism in aquatic ecotoxicological studies, although little is known about its genome sequences. Ecdysteroids are steroid hormones that play an important role in development, growth, moulting of larva, and reproduction in Chironomus spp. The effect of ecdysteroids is mediated by their binding to the ecdysteroid receptor (EcR). To study the effect of environmental stressors, nonylphenol and silver nanoparticles (AgNPs), on the modulation of EcR mRNA, in this study, full length cDNA of C. riparius ecdysone receptor (CrEcR) was identified from the Expressed Sequence Tags (ESTs) database and expression of the corresponding mRNA was analyzed following exposure to nonylphenol and AgNPs. The CrEcR cDNA was 2548 base pairs (bp) in length, with a 5' untranslated region (UTR) of 242 bp and a 3' UTR of 684 bp. The open reading frame contains 1617 nucleotides, encoding 539 amino acids with a predicted molecular weight of 61 kDa and pI of 5.89, and revealed the presence of several domains associated with DNA binding, dimerization, ligand binding and transcriptional activation characteristic of steroid receptor family members. It was found that the expression level of CrEcR was significantly up-regulated on exposure to nonylphenol and significant up or down regulation was observed on exposure to AgNPs. These finding shows that nonylphenol as well as AgNPs could modulate the ecdysone nuclear receptor and may have significant implications in different developmental stages in C. riparius. PMID- 22196050 TI - Polyphenolic fraction of Pilea microphylla (L.) protects Chinese hamster lung fibroblasts against gamma-radiation-induced cytotoxicity and genotoxicity. AB - Present study was designed to compare cytoprotective and antigenotoxic activity of the polyphenolic fraction of Pilea microphylla (PM1) with that of its active polyphenolic constituents against gamma-radiation in V79 cells. PM1 was standardized with respect to the polyphenols present by RP-HPLC. It was evaluated for its free radical scavenging potential using Fenton reaction-induced DNA damage and lipid peroxidation. Further, PM1 was subjected against gamma-radiation induced cytotoxicity and genotoxicity in V79 cells. PM1 significantly reduced free radical-mediated calf thymus DNA damage and lipid peroxidation. Among the concentrations tested (12.5, 25 and 50 MUg/ml) for radioprotection, PM1 at 25 MUg/ml exhibited maximum protection. Further, when compared with constituent polyphenols viz., rutin, quercetin and chlorogenic acid (concentrations equivalent to that present in PM1-25 MUg/ml), a combination of polyphenols was found most effective in preventing gamma-radiation-induced cytotoxicity and genotoxicity. To conclude, radioprotection is possibly a synergistic effect of the phytochemicals present in the herbal extract, rather than any single component. PMID- 22196052 TI - Impact of perinatal somatic and common mental disorder symptoms on functioning in Ethiopian women: the P-MaMiE population-based cohort study. AB - BACKGROUND: Little is known of the relationship between perinatal somatic and common mental disorder (CMD) symptoms and impaired functioning in women from settings where the burden of undernutrition and infectious disease morbidity is high. METHODS: A population-based sample of 1065 women from Butajira, Ethiopia, was recruited in pregnancy (86.4% of those eligible) and reassessed two months postnatal (954 with singleton, live infants). At both time-points, women were administered a modified version of the Patient Health Questionnaire-15 and the Self-Reporting Questionnaire (locally-validated) to assess somatic and CMD symptoms, respectively. Negative binomial regression was used to investigate associations of CMD and somatic symptoms with functional impairment (World Health Organisation Disability Assessment Scale, version-II), after adjusting for maternal anthropometric measures, physical ill-health and sociodemographic factors. RESULTS: In pregnancy, somatic and CMD symptoms were independently associated with worse maternal functional impairment after adjustment for confounders (WHODAS-II score multiplied by 1.09 (95%CI 1.06, 1.13) and 1.11 (95%CI 1.08, 1.14) respectively for each additional symptom). In the postnatal period, the size of association between somatic symptoms and functional impairment was diminished, but the association with CMD symptoms was virtually unchanged (multiplier value 1.04 (95%CI 1.00, 1.09) and 1.11 (95%CI 1.07, 1.16) respectively). LIMITATIONS: Use of largely self-report measures. CONCLUSIONS: Somatic and CMD symptoms were independently associated with functional impairment in both pregnancy and the postnatal period, with CMD symptoms showing a stronger and more consistent association. This emphasises the public health relevance of both CMD and somatic symptoms in the perinatal period. PMID- 22196053 TI - Synthesis of tetrafluorinated aromatic amino acids with distinct signatures in 19F NMR. AB - Fluorinated amino acids serve as powerful tools in protein chemistry. We synthesized a series of para-substituted tetrafluorophenylalanines via the regioselective S(NAr) chemistry of the commercially available pentafluorophenylalanine Boc-Z. These novel unnatural amino acids display distinct (19)F NMR signatures, making them powerful tools for analyzing protein membrane interactions with NMR spectroscopy. PMID- 22196054 TI - Effectiveness of heart failure management programmes with nurse-led discharge planning in reducing re-admissions: a systematic review and meta-analysis. AB - BACKGROUND: Heart failure (HF) is a clinical condition with major socioeconomic burden. Scientists are trying to find effective solutions to eliminate the effects of the disease and the current innovations in research address the introduction of HF management programmes (HF-MPs). OBJECTIVES: A meta-analysis was undertaken to estimate the effect of HF-MP with a nurse-driven pre-discharge phase on the outcomes of HF and all-cause re-admission. DATA SOURCES: A systematic search of PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Cochrane Library (reviews and clinical trials) was performed to locate randomised controlled trials (RCTs), published in English language, which implemented any HF-MP with discharge planning carried out by a nurse. Identified articles were further screened for additional studies. STUDY SELECTION: Two reviewers independently screened relevant abstracts or titles using a standardised predefined check list. Pilot studies, studies additionally assessing other conditions and studies that evolved technology utilities or included medication management beyond optimisation of therapy, were excluded. DATA EXTRACTION: Selected articles were thoroughly screened and data of interest (characteristics and outcomes) were obtained. Quality assessment was done by two reviewers separately. DATA SYNTHESIS: Nineteen RCTs were selected for the meta analysis. The overall pooled effect (relative risk, RR) of the intervention group compared with the control group was estimated by using a random effects analysis (95% confidence interval (CI)) for the outcomes of HF-related re-admission and all-cause re-admission. The overall RR of HF re-admissions was 0.68, 95% CI (0.53, 0.86), p<0.05 and of all-cause re-admission was 0.85, 95% CI (0.76, 0.94), p<0.05 favouring the intervention. Metaregression analysis was performed while trying to explain the observed heterogeneity but none of the factors (environment, duration of follow-up, origin and complexity) were significantly related with the RR. No significant publication bias was observed regarding both HF and all-cause re-admission. CONCLUSIONS: The results of the current meta analysis highlight the potential of HF-MPs with nurse-driven pre-discharge interventions to reduce hospital re-admissions. Essential characteristics or components of a successful HF-MP are still to be determined; thus more studies are required to solve this issue. PMID- 22196055 TI - Engineered piezoelectricity in graphene. AB - We discover that piezoelectric effects can be engineered into nonpiezoelectric graphene through the selective surface adsorption of atoms. Our calculations show that doping a single sheet of graphene with atoms on one side results in the generation of piezoelectricity by breaking inversion symmetry. Despite their 2D nature, piezoelectric magnitudes are found to be comparable to those in 3D piezoelectric materials. Our results elucidate a designer piezoelectric phenomenon, unique to the nanoscale, that has potential to bring dynamical control to nanoscale electromechanical devices. PMID- 22196056 TI - Complete reaction mechanism of indoleamine 2,3-dioxygenase as revealed by QM/MM simulations. AB - Indoleamine 2,3-dioxygenase (IDO) and tryptophan dioxygenase (TDO) are two heme proteins that catalyze the oxidation reaction of tryptophan (Trp) to N formylkynurenine (NFK). Human IDO (hIDO) has recently been recognized as a potent anticancer drug target, a fact that triggered intense research on the reaction and inhibition mechanisms of hIDO. Our recent studies revealed that the dioxygenase reaction catalyzed by hIDO and TDO is initiated by addition of the ferric iron-bound superoxide to the C(2)?C(3) bond of Trp to form a ferryl and Trp-epoxide intermediate, via a 2-indolenylperoxo radical transition state. The data demonstrate that the two atoms of dioxygen are inserted into the substrate in a stepwise fashion, challenging the paradigm of heme-based dioxygenase chemistry. In the current study, we used QM/MM methods to decipher the mechanism by which the second ferryl oxygen is inserted into the Trp-epoxide to form the NFK product in hIDO. Our results show that the most energetically favored pathway involves proton transfer from Trp-NH(3)(+) to the epoxide oxygen, triggering epoxide ring opening and a concerted nucleophilic attack of the ferryl oxygen to the C(2) of Trp that leads to a metastable reaction intermediate. This intermediate subsequently converts to NFK, following C(2)-C(3) bond cleavage and the associated back proton transfer from the oxygen to the amino group of Trp. A comparative study with Xantomonas campestris TDO (xcTDO) indicates that the reaction follows a similar pathway, although subtle differences distinguishing the two enzyme reactions are evident. The results underscore the importance of the NH(3)(+) group of Trp in the two-step ferryl-based mechanism of hIDO and xcTDO, by acting as an acid catalyst to facilitate the epoxide ring-opening reaction and ferryl oxygen addition to the indole ring. PMID- 22196058 TI - Lipoprotein(a) in vascular disease, cancer and longevity. AB - Lipoprotein(a) [Lp(a)] is a unique lipoprotein with controversial functions. Lp(a) contains apolipoprotein(a) [apo(a)] covalently attached to apolipoprotein B on the low-density lipoprotein (LDL) particle. The distribution of blood Lp(a) concentrations in several populations have been found to be skewed with Lp(a) being mostly present at low level (0-200 mg/L). A high Lp(a) concentration (greater than 200 mg/L) in blood increases the risk of various vascular diseases including chronic heart disease, acute myocardial infarction and cerebral thrombosis. With Lp(a) potentially having such deleterious effects, there is a need to ask what are the evolutionary benefit(s) of Lp(a) to humans and other mammals that have it. Lp(a) has been reported to offer a number of benefits such as providing protection from LDL cholesterol and providing a source of cholesterol in wound tissue. Furthermore, some evidence is emerging that Lp(a) has anti-tumor properties. Other surveys have indicated that Lp(a) is advantageous because it promotes longevity. Lp(a) is only found in humans, old world monkeys and hedgehogs. Individuals who do not express Lp(a) do not show any disease symptoms, which indicates that Lp(a) is not essential for human life. It still remains unclear why mysterious Lp(a) has evolved and is present in humans. PMID- 22196059 TI - Transposon-based vector systems for gene therapy clinical trials: challenges and considerations. AB - Much progress has been made in gene therapy, but significant challenges remain. One is development of a range of different tools that can be used for different therapeutic purposes. Another is site-specific gene targeting for safe and faithful therapeutic gene expression. Viruses have long been considered the most promising tools for human gene therapy. However, fatal side effects associated with viral vectors have hampered their clinical application. DNA transposons, widely utilized for decades as genetic tools in plants and insects, are now emerging as viable vectors for gene therapy. In this article, we will give a brief review of the adverse effects associated with virus-based gene therapy followed by a glimpse of the adeno-associated virus vector system, which is currently the most promising viral vector for gene therapy. The development of DNA transposon-based gene delivery systems and the advantages and limits of the most commonly used DNA transposon systems, Sleeping Beauty, Tol2, and piggyBac, will be extensively discussed Finally, we will focus on the most promising transposon system for gene therapy, piggyBac. Challenges and considerations for advancing piggyBac for therapeutic application will be critically addressed. PMID- 22196060 TI - In vitro activities of nine current antibiotics against culprit bacteria in nosocomial infections in an institution in Northern Taiwan. AB - BACKGROUND: In recent years, there has been a rapid worldwide emergence of multidrugresistant (MDR) pathogens, especially in cases of nosocomial infections. This study assesses the in vitro activities of ampicillin/sulbactam, cefpirome, colistin, daptomycin, ertapenem, meropenem, teicoplanin, tigecycline and vancomycin against 208 aerobic bacterial pathogens that caused 197 nosocomial infections in 184 patients. METHODS: Antimicrobial susceptibility was evaluated by Etest. Broth dilution method was utilized in tigecycline susceptibility testing. RESULTS: Most (140/208, 67%) of the isolates were facultative Gram negative bacilli. Of the 31 oxacillin-resistant S. aureus (ORSA) isolates, 16 were susceptible to daptomycin (16/31, 51.6%) according to the breakpoint <= 1 MUg/ml. All 31 ORSA isolates were susceptible to teicoplanin, and vancomycin but MICs of vancomycin for all 31 ORSA isolates were >= 1 MUg/ml. Of the 21 isolates of A. baumannii that were multiple-drug-resistant, 19 isolates (19/21, 90%) were susceptible to colistin and 18 isolates (18/21, 86%) sensitive to tigecycline. Of the 22 isolates of E. coli with extended-spectrum beta-lactamase (ESBL), the most susceptible antimicrobial agent were colistin (20/22, 91%), ertapenem (21/22, 96%), meropenem and tigecycline (22/22, 100%). Of the 11 isolates of P. aeruginosa, 6 isolates were susceptible to colistin (6/11, 55%) and all isolates were susceptible to meropenem (11/11, 100%). CONCLUSION: For nosocomial infections caused by MDR-Acinetobacter baumannii, colistin and tigecycline are usually susceptible according to the result of this study. For nosocomial infections caused by ORSA, ORSA has reduced susceptibility to vancomycin, teicoplanin and daptomycin. For MDR-P. aeruginosa, further study is needed. PMID- 22196061 TI - A phase II study of irinotecan in combination with cisplatin as second-line chemotherapy in patients with metastatic or locally advanced gastric cancer. AB - BACKGROUND: Gastric cancer remains one of the leading causes of cancer death worldwide. Currently, no standard secondary-line chemotherapy for locally advanced or metastatic gastric cancer is recommended. The aim of this study is to demonstrate and confirm the overall objective response rate to irinotecan plus cisplatin for previously treated patients with metastatic or locally advanced gastric cancer in Taiwan. METHODS: Patients in this study had been diagnosed with gastric adenocarcinoma with evidence of advanced disease and had failure of first line chemotherapy or documented disease progression while receiving adjuvant chemotherapy. Patients had good Eastern Cooperative Oncology Group performance status and adequate hematologic, renal and liver function. Patients received irinotecan 60 mg/m2 followed by cisplatin 30 mg/m2 on days 1 and 8, every 3 weeks. Treatment was administered until disease progression, intolerable toxicity or consent withdrawal. Evaluation was conducted every two cycles using the Response Evaluation Criteria in Solid Tumors. The toxicity was recorded by National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0, year 2003. RESULTS: From January 2007 to December 2008, 24 patients were enrolled. Their median age was 54 years (range 30 to 77 years). Fifteen patients (63%) were men. Five patients (21%) achieved partial response, while ten patients (42%) remained stable. The median progression-free survival was 109 days and median overall survival was 222 days. The major grade 3/4 toxicities were neutropenia (20.9%) and diarrhea (8.3%). CONCLUSIONS: Second-line chemotherapy with irinotecan and cisplatin for advanced gastric cancer is effective and has acceptable toxicity. PMID- 22196062 TI - Short-term inhalation of sevoflurane during induction of general anesthesia can inhibit the A-line ARX index response to intubation: a randomized trial. AB - BACKGROUND: Monitoring hypnotic depth is used to prevent awareness during general anesthesia. We used the A-line ARX index (AAI) to assess the effect of shortterm inhalation of sevoflurane in the prevention of intubation-induced inadequate hypnotic depth during anesthetic induction. METHODS: Thirty patients were randomly divided into the sevoflurane and non-sevoflurane groups, both of which were given 3 MUg kg-1 fentanyl, 4 mg kg-1 thiamylal, and 0.2 mg kg-1 cis atracurium intravenously to induce general anesthesia. The sevoflurane group then inhaled 6% sevoflurane and 4 L/min O2 for 3 minutes, whereas the non-sevoflurane group was given 4 L/min O2 alone. Both groups were intubated 3 minutes after induction. Measurements of the AAI, non-invasive blood pressure, and heart rate were performed every minute, starting 3 minutes prior to induction until 9 minutes after intubation. RESULTS: Intubation induced a significant AAI elevation in the non-sevoflurane group (47.13 +/- 20.88, 48.13 +/- 20.05, 40.87 +/- 15.86 and 31.27 +/- 15.26 at 1, 2, 3 and 4 minutes after intubation, respectively, vs. 17.67 +/- 6.44 at 3 minutes after induction; p < 0.05), whereas the AAI remained unchanged for the sevoflurane group following intubation. Moreover, the non sevoflurane group demonstrated higher AAI values after intubation compared with the sevoflurane group. There were no significant differences in blood pressure and heart rate between the two groups throughout the study. CONCLUSION: Adding 6% sevoflurane with 4 L/min O2 for 3 minutes during the induction period prevented inadequate hypnotic depth caused by intubation but was not sufficient to inhibit fluctuations in hemodynamics. PMID- 22196063 TI - Comparison of salivary antioxidants in healthy smoking and non-smoking men. AB - BACKGROUND: Tobacco use is known as a serious global public health problem, and is also an important risk factor for oral diseases. Saliva is the first biological medium encountered during inhalation of cigarette smoke. Therefore, the main aim of this study was to compare the levels of salivary antioxidants between healthy smoking and non-smoking men. METHODS: Unstimulated whole saliva samples were collected from 80 men. Forty subjects were smokers with a daily consumption of 20 cigarettes for at least 10 years and 40 subjects were non smokers. The salivary levels of uric acid, superoxide dismutase, glutathione peroxidase, and peroxidase were measured and compared between studied groups. RESULTS: The mean levels of salivary superoxide dismutase, glutathione peroxidase, and peroxidase were significantly lower in smokers than non-smokers. There was no statistically significant difference in the salivary uric acid level between smokers and non-smokers. CONCLUSIONS: Measurement of antioxidant agents in human saliva might be useful for estimating the level of oxidative stress caused by cigarette smoke. PMID- 22196064 TI - A comprehensive study of the extensor tendons to the medial four digits of the hand. AB - BACKGROUND: Awareness of the anatomy and variations of the extensor tendons on the dorsum of the hand is necessary when assessing the traumatized or diseased hand and when considering tendons for repair or transfer. A complete quantitative documentation of the extensor tendons is lacking. METHOD: The arrangements of extensor tendons to the medical four fingers namely, the extensor digitorum communis (EDC), extensor indicis proprius (EIP) and extensor digiti minimi (EDM) on the dorsum of the hand and the intertendinous connections between them were studied in 100 upper limb specimens. The findings were photographed, tabulated and analyzed statistically. RESULTS: In 98% of the specimens, the EIP was a single tendon with a single insertion, whereas in two right upper limbs there were two EIP tendons with two insertions. In 77% of the specimens the EDC distally had tendons to the middle three fingers (EDC index, EDC longus and EDC ring). The EDC small was present in only 34% of samples and the EDM showed normal anatomy in only 20%. The most common types of juncturae tendinum in the 2nd, 3rd and 4th intermetacarpal spaces were Type 1, 2 and 3r, respectively. Two accessory muscles were seen. One was the extenson medii proprius in 5% of samples and the other, the extensor digitorum brevis manus, was seen in 3%. CONCLUSION: Variations of the extensor tendons were common in this study, especially for the middle and ring fingers which showed multiple tendons of the EDC. PMID- 22196065 TI - Association of body mass index and depressive symptoms in a Chinese community population: results from the Health Promotion Knowledge, Attitudes, and Performance Survey in Taiwan. AB - BACKGROUND: The association between obesity and depression remains equivocal. The aims of this study were to examine the association between body mass index (BMI) and depressive symptoms in the Chinese adult population. METHODS: In this study, data from the Health Promotion Knowledge, Attitudes, and Performance Survey, conducted in 2002 among 20,385 Taiwanese adults (aged 18-64 years), were used. Depressive symptoms were assessed by the Taiwanese Depression Questionnaire (cut off point 19). Weight status was categorized as underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5- 23.9 kg/m2), overweight (BMI 24-26.9 kg/m2), and obese (BMI >= 27 kg/m2). RESULTS: Bivariate analyses revealed that underweight men and women had higher risks of depressive symptoms than normal weight individuals. After controlling for education, income, occupation, smoking status, marital status, presence of chronic disease, exercise, and weight control measures, we found that underweight men were significantly more likely to have depressive symptoms than normal weight men (Adjusted odds ratio [AOR] 2.68, 95% confidence interval [CI] 1.85-3.88). On the contrary, obese women were significantly less likely to have depressive symptoms than normal weight women (AOR 0.62, 95% CI 0.46-0.83). CONCLUSION: The associations of BMI and depressive symptoms were different between genders. Underweight men ran a higher risk of depression than normal weight men, and overweight women had a lower risk than normal weight women. These findings support the "jolly fat" hypothesis among the adult population in the Chinese community. PMID- 22196066 TI - Periventricular nodular heterotopia and cardiovascular defects. AB - BACKGROUND: Periventricular nodular heterotopia (PNH) is a rare congenital anomaly of the brain presenting as nodular heterotopia along the paraventricular region. Ten cases of PNH complicated by aortic aneurysm have been reported in the literature, and 9 of them also had symptoms of Ehlers-Danlos syndrome (EDS). This study investigated the association of PNH and cardiovascular anomalies in Asians. METHODS: Patients with a diagnosis of brain heterotopia on magnetic resonance imaging at Chang Gung Memorial Hospital between 1994 and 2010 were screened for both typical PNH and cardiovascular anomalies. The family members of the index cases were also evaluated. RESULTS: One family (5 patients) and a sporadic case were found to have both typical PNH and cardiovascular anomalies. Two of them had aortic root aneurysm, one had aortic regurgitation, and one had minor valvular disease. Two patients had a history of seizures, but none of them had EDS. CONCLUSIONS: Clinical heterogeneity exists in the patients with PNH. Overlap in the symptoms of PNH, cardiovascular anomalies, aortic aneurysm, and EDS were reviewed. EDS is unusual in Asians with PNH. Aortic aneurysm and other valvular heart diseases are common cardiovascular anomalies in PNH patients. PMID- 22196067 TI - Prognosis of patients on extracorporeal membrane oxygenation plus continuous arteriovenous hemofiltration. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been utilized for critically ill patients such as those with life-threatening respiratory failure or post-cardiotomy cardiogenic shock. Patients on ECMO with acute renal failure have high mortality rates. This study identifies specific predictors of hospital mortality for patients receiving ECMO and continuous arteriovenous hemofiltration (CAVH). METHODS: This study reviewed the medical records of 123 critically ill patients on ECMO plus CAVH at a cardiovascular surgical intensive care unit (CVSICU) at a tertiary care university hospital between March 2003 and August 2010. Patient baseline, clinical, and laboratory data were collected retrospectively as survival predicators. RESULTS: The overall mortality rate was 85.4%. The most common conditions requiring ECMO plus CAVH were cardiogenic shock and oliguria. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score and organ system failure (OSF) score both indicated good discriminative power (area under the receiver operating characteristic curve [AUROC] 0.812 +/- 0.048 and 0.758 +/- 0.057, respectively). Multiple logistic regression analysis indicated that age, mean arterial pressure, and OSF score on day 1 of ECMO plus CAVH were independent risk factors for hospital mortality. Cumulative survival rates at the 6-month follow-up differed significantly (p < 0.001) between those with an OSF score <= 4 vs. those with an OSF score > 4. CONCLUSIONS: During ECMO plus CAVH support, both the OSF and APACHE II scores showed good discriminative power in predicting hospital mortality for these patients. PMID- 22196068 TI - Fatal serotonin toxicity caused by moclobemide and fluoxetine overdose. AB - Both moclobemide and fluoxetine are used in the treatment of depression, and have been shown to produce fewer side effects than conventional tricyclic antidepressants. A combination of moclobemide and fluoxetine has been used in refractory depression, however there is potential for severe serotonin toxicity. We describe a lethal case of serotonin toxicity in a 36 year-old woman after she ingested multiple drugs, including moclobemide 4500 mg, fluoxetine 200 mg, propranolol 300 mg and several benzodiazepines. The clinical features included coma, mydriasis, hyperthermia, tremor, hyperreflexia, rhabdomyolysis, renal failure and respiratory insufficiency. Eventually, the patient died of disseminated intravascular coagulation and circulatory collapse at 22.5 h postingestion. Toxicological analysis of the patient's blood confirmed high levels of moclobemide 150 MUg/mL (therapeutic 1-3 MUg/mL), fluoxetine 3750 ng/mL (therapeutic 47-469 ng/mL) and several benzodiazepines. In conclusion, a combination of moclobemide and fluoxetine should be avoided in depressed patients with high suicidal tendencies. Moreover, early recognition and aggressive intervention are the mainstays in the management of potentially life-threatening serotonin toxicity. PMID- 22196069 TI - Possible role of repetitive practice of activities requiring reflexive responses in the treatment of Tourette's disorder. AB - We report 2 boys, 11 and 7 years old, whose Tourette's disorder improved significantly after a period of repeated, sustained practice of activities requiring reflexive responses One boy engaged in physical exercise including hand eye co-ordination (table tennis for 6 hours every weekday) and the other learned foreign languages (5 languages within 3 years). Tics may be thought of as a kind of overflow of energy, and excessive energy consumption with physical or mental exercise may improve the motor disorder and associated comorbidities. However, the exercise may require a quick, reflexive response to visual or verbal stimuli. PMID- 22196070 TI - Inhibitory effect of high-strength ammonia nitrogen on bio-treatment of landfill leachate using EGSB reactor under mesophilic and atmospheric conditions. AB - The inhibitory effect of high-strength NH(3)-N on anaerobic biodegradation of landfill leachates in an EGSB bioreactor has been investigated. The research compared start-up performance of the reactor treating the landfill leachate with NH(3)-N in 242-1200 mg/l to that treating the compost leachate with NH(3)-N in 38 410 mg/l. The observations showed that the performance of the reactor treating the landfill leachate was only marginally worse than that treating the compost leachate at the mesophilic temperature when NH(3)-N concentration was under 1500 mg/l. We also noted that NH(3)-N at the concentration of 1500-3000 mg/l inhibited the biodegradation. The comparative biodegradation performance at the mesophilic and atmospheric temperature demonstrated that the maximal OLR of atmospheric digestion was only reduced to 44 kg COD/m(3)d. These findings indicate that landfill leachates with NH(3)-N less than 1500 mg/l could be efficiently treated in the EGSB bioreactor even under the atmospheric condition with methane generated. PMID- 22196071 TI - Xylitol production from D-xylose and horticultural waste hemicellulosic hydrolysate by a new isolate of Candida athensensis SB18. AB - This paper describes the production of xylitol from d-xylose and horticultural waste hemicellulosic hydrolysate by a new strain of Candida athensensis SB18. Strain SB18 completely consumed 250 and 300 g L(-1) D-xylose and successful converted it to xylitol in the respective yield of 0.83 and 0.87 g g(-1), resulting in 207.8 and 256.5 g L(-1) of xylitol, respectively. The respective volumetric productivity were 1.15 and 0.97 g L(-1) h(-1). Approximately 100.1 g L(-1) of xylitol was obtained from the bioconversion of detoxified horticultural waste hemicellulosic hydrolysate using strain SB18. The yield and productivity were 0.81 g g(-1) xylose and 0.98 g L(-1) h(-1), respectively. Strain C. athensensis SB18 was able to completely utilize glucose, mannose, xylose and partially arabinose. This work demonstrates that stain C. athensensis SB18 is a promising strain for high-titer and high-yield xylitol production and it has great potential in bioconversion of hemicellulosic hydrolysate. PMID- 22196072 TI - A feasible method for growing fungal pellets in a column reactor inoculated with mycelium fragments and their application for dye bioaccumulation from aqueous solution. AB - In the present paper, a feasible method was developed to grow fungal pellets in an air lift column reactor inoculated with mycelium fragments for improving separation effect of biomass from solution and reducing clogging effect of biomass; bioaccumulation of dye by the growing fungal pellets in the case of mycelium fragments inoculation was investigated. The results showed that inoculation with the mycelium fragments without any pre-treatment did not witness the formation of pellets; only pre-treated fragments using maize as both nucleus and carbon source for 72 h incubation guaranteed the formation of pellets in the air lift column reactor. Nearly 100% of dye removal was obtained by bioaccumulation of the growing pellets in successive three batches of dye wastewater treatment. The formation of pellets not only resulted in low clogging effect to promote mass transfer and dye bioaccumulation but also caused quick separation of dye-loaded biomass from treated wastewater. PMID- 22196073 TI - Initiating methanogenesis of vegetable waste at low inoculum-to-substrate ratio: importance of spatial separation. AB - With the goal of starting-up the methanogenesis of easily biodegradable waste with minimum inoculum, the present work evaluated different inoculum-to-substrate ratios (r(I/S)) in completely mixed systems and in the systems with spatial separation of inoculum and waste. It was found difficult to initiate methanogenesis in the completely mixed systems, even at high r(I/S) 1.105 on a volatile solid basis. Fermentation efficiencies were independent of r(I/S). In the spatial-separation systems with a low total r(I/S) 0.053, the ultimate methane yield (35 degrees C, 1 atm) reached 445 mL/g-VS added for the inoculum waste initially completely separated system. The yields decreased to 285, 181, and 34 mL/g-VS added, respectively, for partially separated systems with the ratios controlled at 1.105, 0.254, and 0.113 in the inoculum-containing reactors. This demonstrates the importance of setting spatial separation between inoculum and waste when inoculation is employed. An appropriate inoculation method would initiate methanogenesis rapidly even at low inoculum-to-substrate ratios. PMID- 22196074 TI - Improvement of enzymatic saccharification of sugarcane bagasse by dilute-alkali catalyzed hydrothermal treatment and subsequent disk milling. AB - Dilute-alkali-catalyzed hydrothermal treatment (HT) was conducted to improve the enzymatic degradability of sugarcane bagasse. Wet-disk milling (DM) was also performed after HT. Sodium carbonate with 0-6% concentration on dry weight basis of bagasse was used as the alkali catalyst. A content of more than 4% of the alkali catalyst was necessary for producing a higher amount of glucose than that produced after HT without an alkali catalyst. HT with 6% of the alkali catalyst, which decreased the pH to the neutral region, retained more xylan and less lignin than HT without an alkali. Subsequent DM improved the enzymatic degradability further and increased the specific surface area. For a substrate concentration of 10%, the amounts of glucose and xylose produced were 344 and 188 mg/g-bagasse, respectively. These values corresponded to yields of 77% and 67% on the basis of the glucan and xylan contents in raw bagasse, respectively. PMID- 22196075 TI - A systematic review of the effectiveness of interprofessional education in health professional programs. AB - OBJECTIVE: The objective of this systematic review was to identify the best available evidence for the effectiveness of university-based interprofessional education for health students. BACKGROUND: Currently, most health professional education is delivered in a traditional, discipline specific way. This approach is limited in its ability to equip graduates with the necessary knowledge, skills and attitudes for effective interprofessional collaboration and for working as part of a complex health care team. Interprofessional education is widely seen as a way to improve communication between health professionals, ultimately leading to improved patient outcomes. INCLUSION CRITERIA: The review included all randomised controlled trials and quasi-experimental studies in which two or more undergraduate or post-graduate health professional groups are engaged in interprofessional education. REVIEW METHODS: A three-stage comprehensive search of ten electronic databases as well as grey literature was conducted. Two independent reviewers assessed each paper prior to inclusion using the standardised critical appraisal instruments for evidence of effectiveness developed by the Joanna Briggs Institute. RESULTS: Nine published studies consisting of three randomised controlled trials, five controlled before and after studies and one controlled longitudinal study were included in the review. CONCLUSION: Student's attitudes and perceptions towards interprofessional collaboration and clinical decision-making can be potentially enhanced through interprofessional education. However, the evidence for using interprofessional education to teach communication skills and clinical skills is inconclusive and requires further investigation. IMPLICATIONS FOR RESEARCH: Future randomised controlled studies explicitly focused on interprofessional education with rigorous randomisation procedures, allocation concealment, larger sample sizes, and control groups, would improve the evidence base for interprofessional education. PMID- 22196076 TI - An exploration of the midwifery continuity of care program at one Australian University as a symbiotic clinical education model. AB - OBJECTIVE: This discussion paper analyses a midwifery Continuity of Care program at an Australian University with the symbiotic clinical education model, to identify strengths and weakness, and identify ways in which this new pedagogical approach can be improved. BACKGROUND: In 2002 a major change in Australian midwifery curricula was the introduction of a pedagogical innovation known as the Continuity of Care experience. This innovation contributes a significant portion of clinical experience for midwifery students. It is intended as a way to give midwifery students the opportunity to provide continuity of care in partnership with women, through their pregnancy and childbirth, thus imitating a model of continuity of care and continuity of carer. METHODS: A qualitative study was conducted in 2008/9 as part of an Australian Learning and Teaching Council Associate Fellowship. Evidence and findings from this project (reported elsewhere) are used in this paper to illustrate the evaluation of midwifery Continuity of Care experience program at an Australian university with the symbiotic clinical education model. FINDINGS: Strengths of the current Continuity of Care experience are the strong focus on relationships between midwifery students and women, and early clinical exposure to professional practice. Improved facilitation through the development of stronger relationships with clinicians will improve learning, and result in improved access to authentic supported learning and increased provision of formative feedback. This paper presents a timely review of the Continuity of Care experience for midwifery student learning and highlights the potential of applying the symbiotic clinical education model to enhance learning. CONCLUSION: Applying the symbiotic clinical education framework to evidence gathered about the Continuity of Care experience in Australian midwifery education highlights strengths and weaknesses which may be used to guide curricula and pedagogical improvements. PMID- 22196077 TI - Effect of topical application of fluoride gel NaF 2% on enzymatic and non enzymatic antioxidant parameters of saliva. AB - OBJECTIVE: The aim of the study was to evaluate the effect of topical fluoride gel NaF 2% application on antioxidant parameters of whole saliva from children. DESIGN: The saliva mechanically stimulated with parafilm was collected from 25 children (6-12 years) attending the Clinic of Paediatric Dentistry of Universidade Cruzeiro do Sul, Sao Paulo, Brazil, before (control group) and immediately after application of neutral fluoride gel NaF 2% (fluoride-gel group), according to the Standards for Research Using Human Subjects, Resolution 196/96 of the USA National Health Council of 10/10/1996. Afterwards, pre-post ferric-reducing antioxidant power (FRAP), trolox-equivalent antioxidant capacity (TEAC), uric acid, reduced/oxidised glutathione content (GSH/GSSG) and total peroxidase activity (TPO) were evaluated in whole saliva of both groups. RESULTS: All non-enzymatic antioxidant parameters were augmented by fluoride-gel NaF 2% application, whereas a notable reduction (31%) of peroxidase activity was concomitantly observed in the children's saliva (p <= 0.05). Nevertheless, the reducing power of saliva was kept unaltered under these circumstances (p <= 0.05). CONCLUSIONS: Despite the reduced activity of peroxidase (an important antimicrobial and antioxidant enzyme), the topical fluoride gel NaF 2% favourably stimulated the release of non-enzymatic antioxidant components of saliva, sustaining the reducing power of saliva and the natural defences of the oral cavity. PMID- 22196078 TI - Topography as a modifier of breeding habitats and concurrent vulnerability to malaria risk in the western Kenya highlands. AB - BACKGROUND: Topographic parameters such as elevation, slope, aspect, and ruggedness play an important role in malaria transmission in the highland areas. They affect biological systems, such as larval habitats presence and productivity for malaria mosquitoes. This study investigated whether the distribution of local spatial malaria vectors and risk of infection with malaria parasites in the highlands is related to topography. METHODS: Four villages each measuring 9 Km2 lying between 1400-1700 m above sea level in the western Kenya highlands were categorized into a pair of broad and narrow valley shaped terrain sites. Larval, indoor resting adult malaria vectors and infection surveys were collected originating from the valley bottom and ending at the hilltop on both sides of the valley during the rainy and dry seasons. Data collected at a distance of <= 500 m from the main river/stream were categorized as valley bottom and those above as uphill. Larval surveys were categorized by habitat location while vectors and infections by house location. RESULTS: Overall, broad flat bottomed valleys had a significantly higher number of anopheles larvae/dip in their habitats than in narrow valleys during both the dry (1.89 versus 0.89 larvae/dip) and the rainy season (1.66 versus 0.89 larvae/dip). Similarly, vector adult densities/house in broad valley villages were higher than those within narrow valley houses during both the dry (0.64 versus 0.40) and the rainy season (0.96 versus 0.09). Asymptomatic malaria prevalence was significantly higher in participants residing within broad than those in narrow valley villages during the dry (14.55% vs. 7.48%) and rainy (17.15% vs. 1.20%) season. Malaria infections were wide spread in broad valley villages during both the dry and rainy season, whereas over 65% of infections were clustered at the valley bottom in narrow valley villages during both seasons. CONCLUSION: Despite being in the highlands, local areas within low gradient topography characterized by broad valley bottoms have stable and significantly high malaria risk unlike those with steep gradient topography, which exhibit seasonal variations. Topographic parameters could therefore be considered in identification of high-risk malaria foci to help enhance surveillance or targeted control activities in regions where they are most needed. PMID- 22196079 TI - The re-emergence of measles in developed countries: time to develop the next generation measles vaccines? PMID- 22196082 TI - [Missed right post-traumatic diaphragmatic injuries: a review of six cases]. AB - INTEREST: Right posttraumatic diaphragmatic injuries are rare; literature relates mainly isolated cases or small series and most often rupture are succeeding of blunt trauma. This series is interesting because the number of cases and the existence of two injuries following a right stab wound. PATIENTS AND METHODS: Retrospective study between January 2002 and September 2010. We collected the data of initial trauma, clinical, radiological, operative and follow-up for six patients supported for right posttraumatic diaphragmatic injuries. RESULTS: All injuries were in late presentation. Four injuries were secondary to road traffic accident, and two after stab wound. The time to diagnosis was between 47 days and 15 years. Right posterolateral thoracotomy was the elective approach in the cases with diaphragmatic hernia (5 patients). In one case, video-assisted thoracoscopic surgery permits the diagnosis and repair of injury. Mortality was null and morbidity was present in one case from six. Follow-up ranging from 8 months and 42 months don't objectified complications. CONCLUSION: Right diaphragmatic hernia is terrible sequelae after thoracoabdominal trauma. Surgery becomes more complex at this stage and can be done by thoracotomy. With strong suspicious signs at the first assessment of trauma, exploration by thoracoscopy can always avoid the occurrence of long-term sequelae. PMID- 22196083 TI - Diabetes in pregnancy among indigenous women in Australia, Canada, New Zealand, and the United States: a method for systematic review of studies with different designs. AB - BACKGROUND: Diabetes in pregnancy, which includes gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM), is associated with poor outcomes for both mother and infant during pregnancy, at birth and in the longer term. Recent international guidelines recommend changes to the current GDM screening criteria. While some controversy remains, there appears to be consensus that women at high risk of T2DM, including indigenous women, should be offered screening for GDM early in pregnancy, rather than waiting until 24-28 weeks as is current practice. A range of criteria should be considered before changing screening practice in a population sub-group, including: prevalence, current practice, acceptability and whether adequate treatment pathways and follow-up systems are available. There are also specific issues related to screening in pregnancy and indigenous populations. The evidence that these criteria are met for indigenous populations is yet to be reported. A range of study designs can be considered to generate relevant evidence for these issues, including epidemiological, observational, qualitative, and intervention studies, which are not usually included within a single systematic review. The aim of this paper is to describe the methods we used to systematically review studies of different designs and present the evidence in a pragmatic format for policy discussion. METHODS/DESIGN: The inclusion criteria will be broad to ensure inclusion of the critical perspectives of indigenous women. Abstracts of the search results will be reviewed by two persons; the full texts of all potentially eligible papers will be reviewed by one person, and 10% will be checked by a second person for validation. Data extraction will be standardised, using existing tools to identify risks for bias in intervention, measurement, qualitative studies and reviews; and adapting criteria for appraising risk for bias in descriptive studies. External validity (generalisability) will also be appraised. The main findings will be synthesised according to the criteria for population-based screening and summarised in an adapted "GRADE" tool. DISCUSSION: This will be the first systematic review of all the published literature on diabetes in pregnancy among indigenous women. The method provides a pragmatic approach for synthesizing relevant evidence from a range of study designs to inform the current policy discussion. PMID- 22196085 TI - Quantum Monte Carlo and related approaches. PMID- 22196084 TI - Interferon regulatory factor-7 modulates experimental autoimmune encephalomyelitis in mice. AB - BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with unknown etiology. Interferon-beta (IFN-beta), a member of the type I IFN family, is used as a therapeutic for MS and the IFN signaling pathway is implicated in MS susceptibility. Interferon regulatory factor 7 (IRF7) is critical for the induction and positive feedback regulation of type I IFN. To establish whether and how endogenous type I IFN signaling contributes to disease modulation and to better understand the underlying mechanism, we examined the role of IRF7 in the development of MS-like disease in mice. METHODS: The role of IRF7 in development of EAE was studied by immunizing IRF7-KO and C57BL/6 (WT) mice with myelin oligodendrocyte glycoprotein using a standard protocol for the induction of EAE. We measured leukocyte infiltration and localization in the CNS using flow cytometric analysis and immunohistochemical procedures. We determined levels of CD3 and selected chemokine and cytokine gene expression by quantitative real-time PCR. RESULTS: IRF7 gene expression increased in the CNS as disease progressed. IRF7 message was localized to microglia and infiltrating leukocytes. Furthermore, IRF7-deficient mice developed more severe disease. Flow cytometric analysis showed that the extent of leukocyte infiltration into the CNS was higher in IRF7-deficient mice with significantly higher number of infiltrating macrophages and T cells, and the distribution of infiltrates within the spinal cord was altered. Analysis of cytokine and chemokine gene expression by quantitative real-time PCR showed significantly greater increases in CCL2, CXCL10, IL-1beta and IL17 gene expression in IRF7-deficient mice compared with WT mice. CONCLUSION: Together, our findings suggest that IRF7 signaling is critical for regulation of inflammatory responses in the CNS. PMID- 22196086 TI - Release of methane from aerobic soil: an indication of a novel chemical natural process? AB - Methane (CH(4)) formation under aerobic conditions has been intensely debated, especially since the discovery of CH(4) generation by both dried plant material and living plants. In this study we test the hypothesis that non-microbial CH(4) formation also occurs in soils. All lyophilised soil samples investigated under aerobic conditions released CH(4) at temperatures ranging from 30 to 70 degrees C exceeding that allowing normal enzymatic activity to proceed. No emissions were observed for single mineral soil components such as quartz sand, clay mineral and iron oxide. Methane release rates from the soils investigated were found to increase both with increasing temperature and higher organic carbon content. Addition of water to dried soils increased CH(4) release rates up to 8-fold those observed with the dried material. Our results suggest the existence of a chemical process in soils that produces CH(4) under aerobic conditions, a finding which has not been hitherto reported. PMID- 22196087 TI - Field dissipation of 4-nonylphenol, 4-t-octylphenol, triclosan and bisphenol A following land application of biosolids. AB - The persistence of contaminants entering the environment through land application of biosolids needs to be understood to assess the potential risks associated. This study used two biosolids treatments to examine the dissipation of four organic compounds: 4-nonylphenol, 4-t-octylphenol, bisphenol A and triclosan, under field conditions in South Australia. The pattern of dissipation was assessed to determine if a first-order or a biphasic model better described the data. The field dissipation data was compared to previously obtained laboratory degradation data. The concentrations of 4-nonylphenol, 4-t-octylphenol and bisphenol A decreased during the field study, whereas the concentration of triclosan showed no marked decrease. The time taken for 50% of the initial concentration of the compounds in the two biosolids to dissipate (DT50), based on a first-order model, was 257 and 248 d for 4-nonylphenol, 231 and 75 d for 4-t octylphenol and 289 and 43 d for bisphenol A. These field DT50 values were 10- to 20-times longer for 4-nonylphenol and 4-t-octylphenol and 2.5-times longer for bisphenol A than DT50 values determined in the laboratory. A DT50 value could not be determined for triclosan as this compound showed no marked decrease in concentration. The biphasic model provided a significantly improved fit to the 4 t-octylphenol data in both biosolids treatments, however, for 4-nonylphenol and bisphenol A it only improved the fit for one treatment. This study shows that the use of laboratory experiments to predict field persistence of compounds in biosolids amended soils may greatly overestimate degradation rates and inaccurately predict patterns of dissipation. PMID- 22196088 TI - The occurrence of synthetic musks in human breast milk in Sichuan, China. AB - Human breast milk samples collected from mothers (n=110) who lived in Chengdu, Sichuan Province, southwestern China in 2009 were analyzed to determine the concentrations of 13 musk compounds. Possible relationships between musk concentrations and some personal characteristics were also studied. Only five target analytes were detected in the milk samples analyzed, with median concentration values of 16.5, 11.5, 7.85, <1.5 and <1.4ngg(-1)lipid weight for AHTN (7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene), HHCB (1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta[gamma]-2-benzopyran), HHCB-lactone (1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta[gamma]-2 benzopyran-1-one), OTNE ([1,2,3,4,5,6,7,8-octahydro-2,3,8,8-tetramethylnaphthalen 2yl]ethan-1-one) and musk ketone (4-tert-butyl-2,6-dimethyl-3,5 dinitroacetophenone, MK), respectively. Mothers who reported high use of hand cleaning agents, body-cleaning agents, shampoo and hair conditioners, hair dyes and hair gels had significantly elevated milk concentrations of HHCB whereas elevated milk concentrations of AHTN were observed among mothers reporting high use of body-cleaning agents, body lotions, shampoos, hair dyes and hair gels. Younger age showed a significantly positive effect on milk concentrations of both HHCB and AHTN whereas BMI after delivery, the number of children nursed and place of residence (urban or rural) had no significant effect. The estimated median daily intakes of synthetic musks for breast-fed infants were considerably lower than the current provisional tolerable daily intake amounts suggested for adults. PMID- 22196089 TI - Synthesis of 6-substituted 2-pyrrolyl and indolyl benzoxazoles by intramolecular O-arylation in photostimulated reactions. AB - The synthesis of a series of 6-substituted 2-pyrrolyl and 2-indolyl benzoxazoles by photostimulated C-O cyclization of anions from 2-pyrrole carboxamides, 2 indole carboxamides, or 3-indole carboxamides has been found to proceed in good to excellent yields (41-100%) in DMSO and liquid ammonia. The pyrrole and indole carboxamides are obtained in good to very good isolated yields by an amidation reaction of different 2-haloanilines with 2-carboxylic acid of pyrrole and 2- or 3-carboxylic acid of indole. To explain the regiochemical outcome of these reactions (C-O arylation vs C-N or C-C arylation), a theoretical analysis was performed using DFT methods and the B3LYP functional. PMID- 22196090 TI - Consumer implications of the WCRF's permanent update on colorectal cancer. AB - The last update published by the World Cancer Research Fund on colorectal cancer shows that there is convincing evidence that physical activity could contribute to the prevention of this type of cancers, while highlighting red meat and meat products consumption and alcohol among the factors that increase the disease's risk. The main message of this document is that the best prevention of colorectal cancer is the combination of higher physical activity with a fibre-rich and meat products poor diet. This information is useful the consumer who should make his food choices according to the scientific evidence. This contribution highlights challenges in communication and possible effects from the consumer perspective. PMID- 22196091 TI - Effect of rosemary extract dose on lipid oxidation, colour stability and antioxidant concentrations, in reduced nitrite liver pates. AB - The oxidative stability of liver pate was investigated in relation to different doses of rosemary extract (RE) and sodium nitrite. Colour stability, lipid oxidation (TBARS) and concentrations of ascorbic acid, alpha-tocopherol, carnosic acid and nitrite were measured on the batters before cooking and on the cooked liver pate before and after exposure to light and air for 48 h at 4 degrees C. Results showed that the use of RE significantly reduced lipid oxidation, whereas it had no effect on colour stability. Ascorbic acid and nitrite concentrations were significantly higher and lower respectively when RE was added. RE dose dependently increased the concentration of carnosic acid. Lower sodium nitrite doses resulted in significantly lower nitrite concentrations and slightly lower TBARS values. It was concluded that in liver pate sodium nitrite levels may be lowered to 80 mg/kg without negatively affecting colour and lipid stability and that the use of RE may help in maintaining lipid stability. PMID- 22196092 TI - Same tools, but a shift of context. PMID- 22196093 TI - Severe Graves' ophthalmopathy after percutaneous ethanol injection in a nontoxic thyroid nodule. AB - BACKGROUND: Percutaneous ethanol injection (PEI) is used to treat cystic or mixed benign thyroid nodules. This treatment can result in rare complications, and three cases of Graves' disease (GD) without Graves' ophthalmopathy (GO) have been reported after PEI treatment of toxic thyroid adenomas. Here we present a 55-year old male patient who developed GD and severe GO after PEI treatment of a mixed cystic-solid, nontoxic thyroid nodule. PATIENT FINDINGS: Six months after PEI, the nodule volume had decreased from 8.9 to 3.0 mL, but we observed severe hyperthyroidism with elevated serum free triiodothyronine, free thyroxine, and thyrotropin receptor antibody levels. We also observed ophthalmopathy with symmetrical orbit and soft tissue involvement (grade b/c) and a clinical activity score of 4/7. The diagnosis of GO was confirmed by bilateral corneal damage, increased intraocular pressure on upgaze, and inconstant diplopia. A computed tomography scan showed that the inferior, medial, and superior extraocular muscles were bilaterally enlarged, the perineural space at the orbital cone was slightly reduced and the ophthalmic vein was congested. SUMMARY: A cause-effect relationship between PEI and GD/GO was likely in this patient because of the temporal sequence. Although the mechanism was unknown, we speculated that the thyroid tissue damage caused by PEI released a large amount of antigenic materials from follicular thyroid cells, including thyrotropin receptor protein, which triggered the autoimmune inflammatory response against the thyroid itself and the orbital soft tissues. The patient did not have any risk factors for either GD or GO. CONCLUSIONS: This observation raises the concern, therefore, that unpredictable and severe complications, such as GD and GO, may occur in a few patients treated with PEI. PMID- 22196094 TI - Tandem middle cerebral artery-internal carotid artery occlusions: reduced occlusion-to-revascularization time using a trans-anterior communicating artery approach with a penumbra device. AB - Rapid revascularization of tandem extracranial and intracranial acute thromboembolic occlusions can be challenging and can delay restoration of blood flow to the cerebral circulation. Taking advantage of collateral pathways in the circle of Willis for thrombectomy can reduce the occlusion-to-revascularization time significantly, thereby protecting brain tissue from ischemic injury. The authors report using the trans-anterior communicating artery (ACoA) approach by using the Penumbra microcatheter to rapidly restore blood flow to the middle cerebral artery (MCA) territory prior to treating the ipsilateral internal carotid artery (ICA) occlusion. Two patients with acute onset of tandem ipsilateral ICA and MCA occlusions and a competent ACoA underwent rapid revascularization of the MCA using a trans-ACoA approach for pharmaceutical and mechanical thrombolysis with the 0.026-in Penumbra microcatheter. Subsequently, once blood flow was reestablished in the MCA territory via cross-filling from the contralateral ICA, the proximally occluded ICA dissection was revascularized with a stent. Both patients had rapid revascularization of the MCA territory (both Thrombolysis in Myocardial Infarction Grade 3) with the trans-ACoA approach (19 and 36 minutes) followed by treatment of the ipsilateral proximal ICA occlusion. This prevented prolonged MCA ischemia time (72 and 47 minutes for ICA revascularization time saved) that would have otherwise occurred if the dissections were treated prior to revascularization of the MCA. Both patients had improved NIH Stroke Scale scores after the procedure. No adverse events from crossing the ACoA with the Penumbra microcatheter were encountered during the revascularization procedure. The trans-ACoA approach with the Penumbra microcatheter for rapid revascularization of an acutely thrombosed MCA in the setting of a simultaneous ipsilateral proximal ICA occlusion is feasible in patients with a competent ACoA. This technique can significantly minimize ischemic injury by reducing the occlusion-to-revascularization time and allow for MCA perfusion via collateral circulation while treating a proximal occlusion. To the best of the authors' knowledge, this is the first reported trans-ACoA approach with the Penumbra microcatheter and the first to report the utilization of the collateral intracranial circulation to reduce occlusion-to revascularization time. PMID- 22196095 TI - The posterior cervical triangle approach for high carotid artery exposure in carotid endarterectomy. AB - A new approach in carotid endarterectomy (CEA) was developed for high carotid artery lesions. With the authors' use of the posterior cervical triangle approach, 20 patients with a high carotid artery lesion were successfully treated with CEA. Accessory nerve palsy in 1 patient and hoarseness in 4 patients were encountered postoperatively as transient complications. There were no permanent procedure-related complications. Although this method has some risks, it is a useful method in CEA for high carotid artery lesions. PMID- 22196097 TI - The "suprasellar notch," or the tuberculum sellae as seen from below: definition, features, and clinical implications from an endoscopic endonasal perspective. AB - OBJECT: The tuberculum sellae is a bony elevation ridge that lines up the anterior aspect of the sella, dividing it from the chiasmatic groove. The recent use of the endoscopic endonasal transtuberculum approach has provided surgeons with a method to reach the suprasellar area, offering a new surgical point of view somehow "opposite" of this area. The authors of this study aimed to define the tuberculum sellae as seen from the endoscopic endonasal view while also providing CT-based systematic measurements to objectively detail the anatomical features of such a structure, which was renamed the "suprasellar notch." METHODS: The authors analyzed routine skull CT scans from 24 patients with no brain pathology or fractures and measured the interoptic distance at the level of the limbus sphenoidale, the chiasmatic groove sulcal length and width, and the angle of the suprasellar notch. Indeed, the suprasellar notch was defined as the angle between 2 lines, the first passing through the tuberculum sellae midpoint and perpendicular to the cribriform plate, and a second line passing between 2 points, the midpoints of the limbus sphenoidale and the tuberculum sellae. Moreover, the authors performed on 15 cadaveric heads an endoscopic endonasal transplanum transtuberculum approach with the aid of a neuronavigator to achieve a step-by-step comparison with the radiological data. The whole CT scanning set was statistically analyzed to determine the statistical interdependency of the suprasellar notch angle with the other 3 measurements, that is, the sulcal length at the midline, the interoptic distance at the optic canal entrance, and the interoptic distance at the limbus. RESULTS: Based on the endoscopic endonasal view and CT imaging analysis, the authors identified a certain anatomical variability and thus introduced a new classification of the suprasellar notch: Type I, angle < 118 degrees ; Type II, angle of 118 degrees -138 degrees ; and Type III, angle > 138 degrees . They then analyzed the surgical implications of the endoscopic endonasal approach to the suprasellar area, which could be affected by each of these structural types. CONCLUSIONS: The new classification identifies 3 different types of suprasellar notch and, accordingly, their surgical relevance. Above all, the authors found that the different types of suprasellar notch can affect the osteodural defect reconstruction technique, namely the positioning/wedging of the buttress in the extradural space. A precise endoscopic anatomical knowledge of the neurovascular and bony relationships- especially in cases of a less pneumatized sphenoid sinus--is crucial when approaching the anterior skull base via a transtuberculum transplanum route. PMID- 22196096 TI - Are routine repeat imaging and intensive care unit admission necessary in mild traumatic brain injury? AB - OBJECT: More than 1.5 million Americans suffer a traumatic brain injury (TBI) each year. Seventy-five percent of these patients have a mild TBI, with Glasgow Coma Scale (GCS) Score 13-15. At the authors' institution, the usual practice has been to admit those patients with an associated intracranial hemorrhage (ICH) to an ICU and to obtain repeat head CT scans 12-24 hours after admission. The purpose of this study was to determine if there exists a subpopulation of mild TBI patients with an abnormal head CT scan that requires neither repeat brain imaging nor admission to an ICU. This group of patients was further classified based on initial clinical factors and imaging characteristics. METHODS: A retrospective review of all patients admitted to a Level I trauma center from January 2007 through December 2008 was performed using the hospital Trauma Registry Database, medical records, and imaging data. The inclusion criteria were as follows: 1) an admission GCS score >= 13; 2) an isolated head injury with no other injury requiring ICU admission; 3) an initial head CT scan positive for ICH; and 4) an initial management plan that was nonoperative. Collected data included age, etiology, initial GCS score, time of injury, duration of ICU stay, duration of hospital stay, and anticoagulation status. Primary outcomes measured were the occurrence of neurological or medical decline and the need for neurosurgical intervention. Imaging data were analyzed and classified based on the predominant blood distribution found on admission imaging. Data were further categorized based on the Marshall CT classification, Rotterdam score, and volume of intraparenchymal hemorrhage (IPH). Progression was defined as an increase in the Marshall classification, an increase in the Rotterdam score, or a 30% increase in IPH volume. RESULTS: Three hundred twenty-one of 1101 reviewed cases met inclusion criteria for the study. Only 4 patients (1%) suffered a neurological decline and 4 (1%) required nonemergent neurosurgical intervention. There was a medical decline in 18 of the patients (6%) as a result of a combination of events such as respiratory distress, myocardial infarction, and sepsis. Both patient age and the transfusion of blood products were significant predictors of medical decline. Overall patient mortality was 1%. Based on imaging data, the rate of injury progression was 6%. The only type of ICH found to have a significant rate of progression (53%) was a subfrontal/temporal intraparenchymal contusion. Other variables found to be significant predictors of progression on head CT scans were the use of anticoagulation, an age over 65 years, and a volume of ICH > 10 ml. CONCLUSIONS: Most patients with mild TBI have a good outcome without the necessity of neurosurgical intervention. Mild TBI patients with a convexity SAH, small convexity contusion, small IPH (<= 10 ml), and/or small subdural hematoma do not require admission to an ICU or repeat imaging in the absence of a neurological decline. PMID- 22196098 TI - Consistent focal cerebral ischemia without posterior cerebral artery occlusion and its real-time monitoring in an intraluminal suture model in mice. AB - OBJECT: In the intraluminal suture model of middle cerebral artery occlusion (MCAO) in the mouse, disturbance of blood flow from the internal carotid artery to the posterior cerebral artery (PCA) may affect the size of the infarction. In this study, PCA involvement in the model was investigated and modified for consistent MCAO without involving the PCA territory. METHODS: Thirty-seven C57Bl/6 mice were randomly divided into 4 groups according to the length of coating over the tip of the suture (1, 2, 3, or 4 mm) and subjected to transient MCAO for 2 hours. Real-time topographical cerebral blood flow was monitored over both hemispheres by laser speckle flowmetry. After 24 hours of reperfusion, the infarct territories and volumes were evaluated. RESULTS: The 1- and 2-mm coating groups showed all lesions in the MCA territory. In the 3- and 4-mm coating groups, 62.5% and 75% of mice, respectively, showed lesions in both the MCA and the PCA territories and other lesions in the MCA territory. Mice in the 1- and 2 mm coating groups had significantly smaller infarct volumes than the 3- and 4-mm groups. Laser speckle flowmetry was useful to distinguish whether the PCA territory would undergo infarction. CONCLUSIONS: Small changes in the coating length of the intraluminal suture may be critical, and 1-2 mm of coating appeared to be optimal to produce consistent MCAO without involving the PCA territory. Laser speckle flowmetry could predict the territory of infarction and improve the consistency of the infarct size. PMID- 22196099 TI - Decompressive craniectomy in a neurologically devastated pregnant woman to maintain fetal viability. AB - Severe traumatic brain injury (TBI) in pregnant women can result in devastating outcomes for both the mother and the fetus. Historically, there has been concern regarding the issues involved when the fetus is not yet viable outside the womb. Currently, the ability to treat severe TBI with aggressive management of intracranial pressure (ICP) has led to the possibility of sustaining maternal life until the fetus is of a viable age and can be delivered. The authors present the case of a young woman 21 weeks pregnant with a severe TBI (Glasgow Coma Scale Score 3) in whom safe medical ICP management became ineffective. A decompressive craniectomy was performed to obviate the need for aggressive medical management of elevated ICP using fetal-toxic medications, and thus providing the fetus the best chance of continued in utero development until a viable gestational age was reached. PMID- 22196100 TI - Tentorial detachment technique in the combined petrosal approach for petroclival meningiomas. AB - OBJECT: The combined petrosal approach is a suitable technique for the resection of medium-to-large petroclival meningiomas (PCMs). Multiple technical modifications have been reported to increase the surgical corridor, including the method of dural and tentorial opening. The authors describe their method of dural opening and tentorial resection, and detail the microanatomy related to their technique to clarify pitfalls and effects. METHODS: The relationship of temporal bridging veins and cranial nerves (CNs) around the tentorial resection area was examined during the combined petrosal approach in 20 cadaveric specimens. The authors also reviewed their 23 consecutive clinical cases treated using this technique between 2002 and 2010, focusing on the effects and risks of the procedure. RESULTS: In the authors' method, the tentorial resection extends from 5 to 10 mm anterior to the junction of the sigmoid sinus and the superior petrosal sinus ("sinodural point") to the trigeminal fibrous ring and the dural sleeve of CN IV. Temporal bridging veins enter the transverse sinus no more than 5 mm anterior to the sinodural point. The CN IV should be freed from its tentorial dural sleeve while avoiding disruption of the posterior cavernous sinus. The clinical data demonstrate a total resection rate of 78.3%, intraoperative estimated blood loss < 400 ml at a rate of 80.9%, and a venous congestion rate of 0%. CONCLUSIONS: Understanding the anatomical relationship between the tentorium and temporal bridging veins and CNs IV-VI allows neurosurgeons the ability to develop a combined petrosal approach to PCMs that will effectively supply a wide operative corridor after resecting the tentorium, while significantly devascularizing tumors. PMID- 22196102 TI - Enantioselective synthesis of pyrrolidine-, piperidine-, and azepane-type N heterocycles with alpha-alkenyl substitution: the CpRu-catalyzed dehydrative intramolecular N-allylation approach. AB - A cationic CpRu complex of chiral picolinic acid derivatives [(R)- or (S)-Cl-Naph PyCOOCH(2)CH?CH(2)] catalyzes asymmetric intramolecular dehydrative N-allylation of N-substituted omega-amino- and -aminocarbonyl allylic alcohols with a substrate/catalyst ratio of up to 2000 to give alpha-alkenyl pyrrolidine-, piperidine-, and azepane-type N-heterocycles with an enantiomer ratio of up to >99:1. The wide range of applicable N-substitutions, including Boc, Cbz, Ac, Bz, acryloyl, crotonoyl, formyl, and Ts, significantly facilitates further manipulation toward natural product synthesis. PMID- 22196105 TI - The basis and value of currently used immunomodulatory therapies in recurrent miscarriage. AB - Recurrent miscarriage (RM) without an obvious identifiable cause may arise from excessive maternal T and natural killer (NK) cell activity against the trophoblast or early embryo. Impaired regulatory T cell function leading to increased pro-inflammatory Th17 and NK cell cytotoxicity may be central. Ongoing subclinical endometrial infection and/or inflammation with increased secretion of TNFalpha and stimulation of autoimmunity to heat shock proteins may also be contributory. Therapies with a varying theoretical basis and clinical evidence aimed at reducing excessive endometrial immune activity have been used non selectively in women with RM with variable success. Recent work has now improved our understanding of the role of the different immune cells and proteins that are important at each stage of a normal pregnancy. The vulnerability of the early embryo to T and NK cell-mediated rejection suggests that immune-based therapies need to be maximally effective during early pregnancy. Targeting RM women with demonstrable T and NK cell activity may improve the overall clinical efficacy of these treatments. It may also prevent costly and possibly harmful use in women who are unlikely to respond, and make better use of scarce resources. This report describes the underlying principles behind the use of the different immune-based therapies. The broad evidence supporting their efficacy is also described, as are the possible adverse consequences. Suggestions are also made on how the maternal immune system may be positively modulated using current, widely available treatments that have minimal or no side effects. PMID- 22196106 TI - Comprehensive analysis of the transcriptional response of human decidual cells to lipopolysaccharide stimulation. AB - Decidual cells are central to innate immunity at the maternal/fetal interface. We sought to characterize the response of decidual cells to stimulation and then removal of lipopolysaccharide (LPS) using a whole genome approach. Decidual cells were isolated from term unlabored cesarean sections. Cells were stimulated with LPS and RNA isolated both pre-stimulation and 2 and 24 h post-stimulation. Media were changed and RNA extracted 48 h later. Gene expression was measured using Agilent 44K whole genome microarrays. Data were visualized and interpreted using Ingenuity Pathway Analysis (IPA) software and selected (n=5) target gene expression was verified with quantitative real-time PCR. Genes related to immune function were up-regulated at 2 and 24 h after LPS exposure and then generally returned to baseline or were at least substantially reduced after LPS removal. Pathway analysis also revealed that genes involved in lipid metabolism (specifically cholesterol and steroid biosynthesis), iron metabolism, and the plasminogen system were coordinately altered following exposure to LPS. Our novel, preliminary findings provide insight into possible mechanisms via which the host inflammatory response could contribute to preterm birth and warrant further investigation in preterm samples. PMID- 22196108 TI - Brain dynamics and conscious sequencing. PMID- 22196107 TI - Intralipid therapy for recurrent implantation failure: new hope or false dawn? AB - Recurrent embryo implantation failure (RIF) is a disorder with potentially devastating physiological and psychological manifestations for those affected. Although its prevalence is not uncommon, many of the mechanisms involved still require elucidation. Both organ-specific and systemic autoimmunity are associated with an increased prevalence of recurrent miscarriage and reproductive failure, rendering the role of the maternal immunological system in fertility a key concept. It is believed by some that central to this theme is the maternal cytokine profile, with particularly T-helper (Th) cells. Immune modulating therapies have therefore been mooted as potential therapeutic strategies. Recent reports of high pregnancy rates achievable in women with RIF have added fuel to the debate regarding the effectiveness of intralipid in modulating the immune system. We would like to assess if there is sufficient current evidence of acceptable quality to permit an assumption that intralipid therapy is an effective treatment for women undergoing repeated assisted reproduction cycles. We have concluded that appropriately controlled, large-scale, confirmatory studies are necessary to prove the efficacy of intralipid before it can be recommended for routine use. PMID- 22196109 TI - An EEG study of brain connectivity dynamics at the resting state. AB - We investigated the dynamical behavior of resting state functional connectivity using EEG signals. Employing a recently introduced methodology that considers the time variations of phase coupling among signals from different channels, a sequence of functional connectivity graphs (FCGs) was constructed for different frequency bands and analyzed based on graph theoretic tools. In the first stage of analysis, hubs were detected in the FCGs based on local and global efficiency. The probability of each node to be identified as a hub was estimated. This defined a topographic function that showed widespread distribution with prominence over the frontal brain regions for both local and global efficiency. Hubs consistent across time were identified via a summarization technique and found to locate over forehead. In the second stage of analysis, the modular structure of each single FCG was delineated. The derived time-dependent signatures of functional structure were compared in a systematic way revealing fluctuations modulated by frequency. Interestingly, the evolution of functional connectivity can be described via abrupt transitions between states, best described as short-lasting bimodal functional segregations. Based on a distance function that compares clusterings, we discovered that these segregations are recurrent. Entropic measures further revealed that the apparent fluctuations are subject to intrinsic constraints and that order emerges from spatially extended interactions. PMID- 22196110 TI - Cognitive aspects of chaos in random networks. AB - A special case of deterministic chaos that is independent of the architecture of the connections has been observed in a computer model of a purely excitatory neuronal network. Chaos onsets when the level of connectivity is critically low. The results indicate a typical period-doubling route to chaos as the connectivity decreases. A cognitive interpretation of such type of chaos, based on information theory and phase-transitions, is proposed. PMID- 22196111 TI - Understanding neuromotor strategy during functional upper extremity tasks using symbolic dynamics. AB - The ability to model and quantify brain activation patterns that pertain to natural neuromotor strategy of the upper extremities during functional task performance is critical to the development of therapeutic interventions such as neuroprosthetic devices. The mechanisms of information flow, activation sequence and patterns, and the interaction between anatomical regions of the brain that are specific to movement planning, intention and execution of voluntary upper extremity motor tasks were investigated here. This paper presents a novel method using symbolic dynamics (orbital decomposition) and nonlinear dynamic tools of entropy, self-organization and chaos to describe the underlying structure of activation shifts in regions of the brain that are involved with the cognitive aspects of functional upper extremity task performance. Several questions were addressed: (a) How is it possible to distinguish deterministic or causal patterns of activity in brain fMRI from those that are really random or non-contributory to the neuromotor control process? (b) Can the complexity of activation patterns over time be quantified? (c) What are the optimal ways of organizing fMRI data to preserve patterns of activation, activation levels, and extract meaningful temporal patterns as they evolve over time? Analysis was performed using data from a custom developed time resolved fMRI paradigm involving human subjects (N=18) who performed functional upper extremity motor tasks with varying time delays between the onset of intention and onset of actual movements. The results indicate that there is structure in the data that can be quantified through entropy and dimensional complexity metrics and statistical inference, and furthermore, orbital decomposition is sensitive in capturing the transition of states that correlate with the cognitive aspects of functional task performance. PMID- 22196112 TI - The dynamic matching of neural and cognitive growth cycles. AB - In recent years complex systems biology has developed detailed numerical models mimicking the establishment, modulation, and fine-tuning of neural networks. Current research within the framework of Dynamic Systems Theory (DST) emphasizes the nexus between dynamic cycles in the brain and cognitive development which unfold in a nonlinear way and allow for individual variation. Careful observations over multiple timescales and levels of organization suggest a link to system-specific developmental changes in the central nervous system with more functional specialization opening up more efficient information processing. This can be seen in spurts of EEG energy and altered cortical coherence. Data of age- and experience-related changes in synaptic density and metabolism, shifts in blood flow and improvement of (sub)cortical connections are projected on a dynamic trajectory of cognition moving from diffuse to more refined constructions in the various subsystems, each of which exhibiting its own developmental path. Pending questions are the generation of rules amidst diversity and fluctuation, and the correlation of growth rate and critical mass in developmental dynamics and interaction. PMID- 22196113 TI - Network analysis and the connectopathies: current research and future approaches. AB - Complex network analysis has been applied to capture the structure and functional dynamics of the brain. These studies have revealed normal and abnormal network topologies. Network differences are observed in conditions such as Alzheimer's disease, Schizophrenia, Depression and ADHD. Such findings suggest that a number of different pathologies have sufficiently similar features that the term 'connectopathies' has been introduced to describe these common topological characteristics. This paper examines the evidence for network properties and failures found in certain disorders, concluding with a brief discussion of maps and the Human Connectome Project's value to understanding brain disorders and dynamics. PMID- 22196114 TI - The transience of virtual fractals. AB - Artists have a long and fruitful tradition of exploiting electronic media to convert static images into dynamic images that evolve with time. Fractal patterns serve as an example: computers allow the observer to zoom in on virtual images and so experience the endless repetition of patterns in a matter that cannot be matched using static images. This year's featured cover artist, Susan Lowedermilk, instead plans to employ persistence of human vision to bring virtual fractals to life. This will be done by incorporating her prints of fractal patterns into zoetropes and phenakistoscopes. PMID- 22196116 TI - Ensemble and single-molecule spectroscopic study on excitation energy transfer processes in 1,3-phenylene-linked perylenebisimide oligomers. AB - 1,3-Phenylene-bridged perylenebisimide dimer (PBI2) and trimer (PBI3) were prepared along with monomer reference (PBI1) using perylene imide-anhydride 5 as a key precursor. 3,3-Dimethylbut-1-yl substituents were introduced at the 2,5 positions of perylenebisimide (PBI) to improve the solubilities of PBI oligomers. Actually, no serious aggregation of PBI2 and PBI3 was detected in their dilute CH(2)Cl(2) solutions. Under these conditions, intramolecular electronic interactions among PBI chromophores have been revealed by measuring the photophysical properties at their ensemble and single-molecule levels. The excitation energy transfer times of PBI2 (0.16 ps) and PBI3 (0.60 ps) were determined from the two different observables, anisotropy depolarization, and singlet-singlet annihilation, respectively, which are considered as the incoherent Forster-type energy hopping (EEH) times as compared with the EEH time constant (1.97 ps) calculated on the basis of the Forster mechanism. The relatively short EEH times compared to similar PBI oligomers can be attributed to 1,3-phenylene linker, which assures a short distance between the chromophores and, as a consequence, makes it hard to treat the PBI unit as a point dipole. The limitation of point-dipole approximation to describe the PBI oligomers and additional through-bond type interactions can be attributed as the causes of the discrepancies in excitation energy transfer times. Considering these photophysical properties, we can suggest that 1,3-phenylene-linked PBI oligomers have potentials as molecular photonic devices including the artificial light harvesting system. PMID- 22196117 TI - Identification of triazolopyridazinones as potent p38alpha inhibitors. AB - Structure-activity relationship (SAR) investigations of a novel class of triazolopyridazinone p38alpha mitogen activated protein kinase (MAPK) inhibitors are disclosed. From these studies, increased in vitro potency was observed for 2,6-disubstituted phenyl moieties and N-ethyl triazolopyridazinone cores due to key contacts with Leu108, Ala157 and Val38. Further investigation led to the identification of three compounds, 3g, 3j and 3m that are highly potent inhibitors of LPS-induced MAPKAP kinase 2 (MK2) phosphorylation in 50% human whole blood (hWB), and possess desirable in vivo pharmacokinetic and kinase selectivity profiles. PMID- 22196118 TI - Structural modification of ginsenoside Rh(2) by fatty acid esterification and its detoxification property in antitumor. AB - Ginsenoside Rh(2), one of the most important ginsenosides with anticancer properties in red ginseng, has been developed as principal antitumor ingredient for clinical use. However, the cytotoxicity test in human hepatocyte cell line QSG-7701 (IC(50) 37.3MUM) indicated that Rh(2) might show strong cytotoxic side effect on the normal liver cells. For blunting the toxicity, Rh(2) was structurally modified by reacting with octanoyl chloride to give a dioctanoyl ester of Rh(2) (D-Rh(2)) in the present study. MTT assay in QSG-7701 cell line in vitro showed that the cytotoxicity of D-Rh(2) on human hepatocyte cells (IC(50) 80.5MUM) was significantly lower than that of Rh(2). While antitumor xenograft assay in mice bearing H22 liver cancer cells in vivo showed that the antitumor activity of D-Rh(2) retained to be strong as that of Rh(2). According to previous pharmacokinetic studies, the fatty acid esterification of Rh(2) might be of detoxification reaction to cells. Additionally, D-Rh(2) showed significant enhancement on increasing thymus index at the dose of 10mg/kg compared with vehicle treated control group. Thus, D-Rh(2) might indirectly affect tumor growth by stimulating lymphocytes to become cytotoxic to tumor cells. Finally, our findings suggested that D-Rh(2), the fatty acid ester of Rh(2), might attenuate the side-effect by detoxification to human normal cell and could be a more potential candidate for developing as an antitumor drug. PMID- 22196119 TI - Solid-state NMR analysis of calcium and d-mannose binding of BMY-28864, a water soluble analogue of pradimicin A. AB - Pradimicin A (PRM-A) is a unique antibiotic with a lectin-like ability to recognize d-mannopyranosides (Man) in the presence of Ca(2+) ion. BMY-28864 (1) is a water-soluble analogue of PRM-A, which has been extensively used for studies on the mode of Man recognition and antifungal action of pradimicins. Although it has been assumed that PRM-A and 1 bind Man in a similar fashion, direct experimental evidence has yet to be provided. In this report, we compared Ca(2+) and Man binding of 1 with that of PRM-A through two solid-state NMR experiments. The solid-state (113)Cd NMR analysis using (113)Cd(2+) ion as a surrogate for Ca(2+) ion suggested the similarity in Ca(2+) coordination of PRM-A and 1. The dipolar assisted rotational resonance (DARR) analysis using (13)C-labeled 1 clearly showed that 1 as well as PRM-A binds Man near its carboxyl group. These results collectively indicate that the mode of binding of Ca(2+) ion and Man is nearly identical between PRM-A and 1. PMID- 22196120 TI - Inhibitory effects of polyphenols toward HCV from the mangrove plant Excoecaria agallocha L. AB - Four new polyphenols namely excoecariphenols A-D (1-4) were isolated from the Chinese mangrove plant Excoecaria agallocha L. together with 23 known phenolic compounds. The structures of new compounds were elucidated on the basis of extensive spectroscopic analyses including IR, MS, NMR, and CD data. Excoecariphenols A and B presented as the unusual flavane-based 1-thioglycosides. Part of the isolated polyphenols were tested against hepatitis C NS3-4A protease and HCV RNA in huh 7.5 cells. Excoecariphenol D, corilagin, geraniin, and chebulagic acid showed potential inhibition toward HCV NS3-4A protease with IC(50) values in a range of 3.45-9.03MUM, while excoecariphenol D and corilagin inhibited HCV RNA in huh 7.5 cells significantly. A primary structure-activity relationship (SAR) is discussed. PMID- 22196121 TI - A simple oxazolidine linker for solid-phase synthesis of peptide aldehydes. AB - A very simple and cheap linker has been used for solid-phase synthesis of peptide aldehydes. Protected amino acid aldehydes are immobilized on 2-Cl(trt) resin as oxazolidine formation via diethanolamine. After classical Fmoc SPPS, treatment of the resin with AcOH/DCM/H(2)O (8:1:1) affords peptide aldehydes in high yield and purity. PMID- 22196122 TI - Synthesis and biological evaluation of 7-O-modified oroxylin A derivatives. AB - Oroxylin A (5,7-dihydroxy-6-methoxyflavone) is a naturally occurring monoflavonoid isolated from the root of Scutellaria baicalensis Georgi, and exhibits potent anticancer activities in vitro and in vivo. In this study, we synthesized three series of oroxylin derivatives by connecting a nitrogen containing hydrophilic, heterocyclic ring to the C7-OH via a varying length of carbon chain. All the derivatives were screened for anti-proliferative activities against three tumor cell lines. Some of the derivatives displayed higher activities compared to oroxylin A. The most potent antitumor compound, 5f, also induced apoptosis in HepG2 cell. The difference of 5f between the inhibiting rates of cell proliferation and the apoptotic rates indicated that 5f was more likely to be a necrosis-inducing agent or both apoptosis/necrosis inducer. PMID- 22196123 TI - Structure-based de novo design and biochemical evaluation of novel BRAF kinase inhibitors. AB - VRAF murine sarcoma viral oncogene homologue B1 (BRAF) kinase has been considered to be a promising therapeutic target for various human cancers. We have been able to identify 24 novel BRAF kinase inhibitors with K(d) values ranging from 0.4 to 10MUM utilizing a structure-based de novo design method with the two known inhibitor scaffolds. Because these discovered inhibitors were also screened for having desirable physicochemical properties as a drug candidate, they deserve consideration for further investigation as anticancer agents. Structural features relevant to the stabilization of the newly identified inhibitors in the ATP binding site of BRAF are discussed in detail. PMID- 22196124 TI - Potent and selective pyrazolo[1,5-a]pyrimidine based inhibitors of B-Raf(V600E) kinase with favorable physicochemical and pharmacokinetic properties. AB - Herein we describe a novel series of ATP competitive B-Raf inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with improved physicochemical and pharmacokinetic properties. PMID- 22196125 TI - Multicenter randomized controlled trial comparing early versus late aquatic therapy after total hip or knee arthroplasty. AB - OBJECTIVE: To evaluate if the timing of aquatic therapy influences clinical outcomes after total knee arthroplasty (TKA) or total hip arthroplasty (THA). DESIGN: Multicenter randomized controlled trial with 3-, 6-, 12-, and 24-month follow-up. SETTING: Two university hospitals, 1 municipal hospital, and 1 rural hospital. PARTICIPANTS: Patients (N=465) undergoing primary THA (n=280) or TKA (n=185): 156 men, 309 women. INTERVENTION: Patients were randomly assigned to receive aquatic therapy (pool exercises aimed at training of proprioception, coordination, and strengthening) after 6 versus 14 days after THA or TKA. MAIN OUTCOME MEASURES: Primary outcome was self-reported physical function as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 3-, 6-, 12-, and 24-months postoperatively. Results were compared with published thresholds for minimal clinically important improvements. Secondary outcomes included the Medical Outcomes Study 36-Item Short-Form Health Survey, Lequesne Hip/Knee-Score, WOMAC-pain and stiffness scores, and patient satisfaction. RESULTS: Baseline characteristics of the 2 groups were similar. Analyzing the total study population did not result in statistically significant differences at all follow-ups. However, when performing subanalysis for THA and TKA, opposite effects of early aquatic therapy were seen between TKA and THA. After TKA all WOMAC subscales were superior in the early aquatic therapy group, with effect sizes of WOMAC physical function ranging from .22 to .39. After THA, however, all outcomes were superior in the late aquatic therapy group, with WOMAC effect sizes ranging from .01 to .19. However, the differences between treatment groups of these subanalyses were not statistically significant. CONCLUSIONS: Early start of aquatic therapy had contrary effects after TKA when compared with THA and it influenced clinical outcomes after TKA. Although the treatment differences did not achieve statistically significance, the effect size for early aquatic therapy after TKA had the same magnitude as the effect size of nonsteroidal anti inflammatory drugs in the treatment of osteoarthritis of the knee. However, the results of this study do not support the use of early aquatic therapy after THA. The timing of physiotherapeutic interventions has to be clearly defined when conducting studies to evaluate the effect of physiotherapeutic interventions after TKA and THA. PMID- 22196127 TI - Expression of therapeutic targets in Ewing sarcoma family tumors. AB - Ewing sarcoma family tumor is an aggressive malignant tumor of bone and soft tissue in children and adolescents. Despite advances in modern therapy, metastasis occurs in 20% to 25% of cases and results in mortality in 80% of patients. Intracellular molecules mammalian target of rapamycin, Akt, vascular endothelial growth factor, nuclear factor kappaB, and BRAF are important kinases and transcription factors that regulate the proliferation of tumor cells. We studied the expression of these proteins in 72 Ewing sarcoma family tumors. Patients' survival data were available in 55 cases. Formalin-fixed, paraffin embedded tumor sections were stained with antibodies against phosphorylated mammalian target of rapamycin, Akt, BRAF, vascular endothelial growth factor, and nuclear factor kappaB proteins. Stained sections were analyzed for percentage and strength of staining, and a composite score (0-200) was subsequently generated. Although most tumors expressed mammalian target of rapamycin, Akt, nuclear factor kappaB, and vascular endothelial growth factor, only 37%, 86%, 55%, and 12%, respectively, showed high expression (staining score >= 100). There was no significant correlation between mammalian target of rapamycin and Akt expression and clinical outcome. High nuclear factor kappaB expression was significantly associated with tumors in pelvic locations. Decreased vascular endothelial growth factor expression (score <100) was significantly associated with better prognosis (P < .05). BRAF was not expressed in most cases and showed negative or weak staining (score <100) in 97% of cases. Thus, except for BRAF, Ewing sarcoma family tumors may be amenable to treatment that targets the expressed proteins. High Akt expression suggests potential universal response to Akt-targeted therapy. BRAF kinase inhibitors are unlikely to be effective in the treatment of Ewing sarcoma family tumors. PMID- 22196128 TI - The Broad Street pump revisited: dairy farms and an ongoing outbreak of inflammatory bowel disease in Forest, Virginia. AB - We report an ongoing outbreak of ulcerative colitis and Crohn's disease in Forest, Virginia involving 15 unrelated children and teenagers who resided in close proximity to dairy farms. Some of our cases demonstrated serologic evidence of Mycobacterium avium subspecies paratuberculosis infection, suggesting its potential role as an etiologic agent. PMID- 22196130 TI - Light-emitting coaxial nanofibers. AB - Ionic transition-metal complex (iTMCs)-based electro-luminescent nanofibers (TELFs) are developed by using coelectrospinning. A single TELF consists of a Galistan liquid metal core (cathode), an iTMC-based polymer shell, and an ITO thin film coating (anode). Lights emitted from the TELFs can be detected by a CCD camera at 4.2 V and seen by naked eyes at 5.6 V in nitrogen. The TELFs are structurally self-supporting but do not require a physical substrate (generally relatively bulky and heavy) to support them, rendering one-dimensional light sources more flexible, lightweight, and conformable. This technology can be beneficial to many research and development areas such as optoelectronic textile, bioimaging, chemical and biological sensing, high-resolution microscopy, and flexible panel displays, particularly as iTMCs with emission at different wavelengths are available. PMID- 22196131 TI - 20 Gy versus 44 Gy of supplemental external beam radiotherapy with palladium-103 for patients with greater risk disease: results of a prospective randomized trial. AB - PURPOSE: The necessity of external beam radiotherapy (EBRT) as a supplement to prostate brachytherapy remains unknown. We report brachytherapy outcomes for patients with higher risk features randomized to substantially different supplemental EBRT regimens. METHODS AND MATERIALS: Between December 1999 and June 2004, 247 patients were randomized to 20 Gy vs. 44 Gy EBRT followed by a palladium-103 boost (115 Gy vs. 90 Gy). The eligibility criteria included clinically organ-confined disease with Gleason score 7-10 and/or pretreatment prostate-specific antigen (PSA) level 10-20 ng/mL. The median follow-up period was 9.0 years. Biochemical progression-free survival (bPFS) was defined as a PSA level of <=0.40 ng/mL after nadir. The median day 0 prescribed dose covering 90% of the target volume was 125.7%; 80 men received androgen deprivation therapy (median, 4 months). Multiple parameters were evaluated for their effect on bPFS. RESULTS: For the entire cohort, the cause-specific survival, bPFS, and overall survival rates were 97.7%, 93.2%, and 80.8% at 8 years and 96.9%, 93.2%, and 75.4% at 10 years, respectively. The bPFS rate was 93.1% and 93.4% for the 20-Gy and 44-Gy arms, respectively (p = .994). However, no statistically significant differences were found in cause-specific survival or overall survival were identified. When stratified by PSA level of <=10 ng/mL vs. >10 ng/mL, Gleason score, or androgen deprivation therapy, no statistically significant differences in bPFS were discerned between the two EBRT regimens. On multivariate analysis, bPFS was most closely related to the preimplant PSA and clinical stage. For patients with biochemically controlled disease, the median PSA level was <0.02 ng/mL. CONCLUSION: The results of the present trial strongly suggest that two markedly different supplemental EBRT regimens result in equivalent cause-specific survival, bPFS, and overall survival. It is probable that the lack of benefit for a higher supplemental EBRT dose is the result of the high-quality brachytherapy dose distributions. PMID- 22196129 TI - Study of Women, Infant Feeding, and Type 2 diabetes mellitus after GDM pregnancy (SWIFT), a prospective cohort study: methodology and design. AB - BACKGROUND: Women with history of gestational diabetes mellitus (GDM) are at higher risk of developing type 2 diabetes within 5 years after delivery. Evidence that lactation duration influences incident type 2 diabetes after GDM pregnancy is based on one retrospective study reporting a null association. The Study of Women, Infant Feeding and Type 2 Diabetes after GDM pregnancy (SWIFT) is a prospective cohort study of postpartum women with recent GDM within the Kaiser Permanente Northern California (KPNC) integrated health care system. The primary goal of SWIFT is to assess whether prolonged, intensive lactation as compared to formula feeding reduces the 2-year incidence of type 2 diabetes mellitus among women with GDM. The study also examines whether lactation intensity and duration have persistent favorable effects on blood glucose, insulin resistance, and adiposity during the 2-year postpartum period. This report describes the design and methods implemented for this study to obtain the clinical, biochemical, anthropometric, and behavioral measurements during the recruitment and follow-up phases. METHODS: SWIFT is a prospective, observational cohort study enrolling and following over 1, 000 postpartum women diagnosed with GDM during pregnancy within KPNC. The study enrolled women at 6-9 weeks postpartum (baseline) who had been diagnosed by standard GDM criteria, aged 20-45 years, delivered a singleton, term (greater than or equal to 35 weeks gestation) live birth, were not using medications affecting glucose tolerance, and not planning another pregnancy or moving out of the area within the next 2 years. Participants who are free of type 2 diabetes and other serious medical conditions at baseline are screened for type 2 diabetes annually within the first 2 years after delivery. Recruitment began in September 2008 and ends in December 2011. Data are being collected through pregnancy and early postpartum telephone interviews, self-administered monthly mailed questionnaires (3-11 months postpartum), a telephone interview at 6 months, and annual in-person examinations at which a 75 g 2-hour OGTT is conducted, anthropometric measurements are obtained, and self- and interviewer administered questionnaires are completed. DISCUSSION: This is the first, large prospective, community-based study involving a racially and ethnically diverse cohort of women with recent GDM that rigorously assesses lactation intensity and duration and examines their relationship to incident type 2 diabetes while accounting for numerous potential confounders not assessed previously. PMID- 22196132 TI - Regional differences in stem and transit cell proliferation and apoptosis in the terminal ileum and colon of mice after 12 Gy. AB - PURPOSE: The intestinal epithelium has a high rate of cell turnover, which is regulated by stem cells located near the base of crypts. We aimed to investigate stem cell-dependent characteristics of cell proliferation, apoptosis, and crypt size in terminal ileum and different regions of the colon. METHODS AND MATERIALS: Mice were studied under steady-state conditions and after radiation-induced stem cell apoptosis. Percentage of proliferating or apoptotic cells at a particular cell position (cp) along the crypt axis was expressed as labeling or apoptotic index. RESULTS: Under steady-state conditions: crypt size was smallest in the ascending colon. In contrast to other regions of the colon, the distribution profile of proliferating cells in ascending colon showed some similarity to that in the terminal ileum. Postirradiation: apoptotic cells were prominent at the bottom of the crypt of mid- and descending colon but in the ascending colon, they were seen with similar frequency from cp 1 to 4. During regeneration, a constant proliferative capacity was seen above Paneth cells in the terminal ileum. In the ascending (but not mid- or descending) colon, the profile of proliferating cells over the first 4 days after irradiation showed a similarity to that in the terminal ileum. CONCLUSIONS: Profiles of proliferating epithelial cells (under steady-state conditions and postirradiation) and apoptotic cells (postirradiation) suggest similarities in the location of stem cells in the ascending colon and terminal ileum. PMID- 22196134 TI - Rh[III]-catalyzed direct C-H amination using N-chloroamines at room temperature. AB - An efficient Rh(III)-catalyzed direct C-H amination of N-pivaloyloxy benzamides with N-chloroamines proceeding at room temperature was achieved. The versatile directing group allows for selective mono- and diamination and can be readily converted to give valuable benzamide or aminoaniline derivatives. Mechanistic studies have been carried out to elucidate the reaction pathway. PMID- 22196139 TI - Ulcerative keratitis following particulate elemental gold deposition. AB - PURPOSE: To describe a case of 68-year-old male industrial chemist who received a chemical injury after a gold/amine compound exploded causing bilateral eye injuries. No apparent long-term problems were anticipated. After cataract extraction 40 years later, he developed a localized ulcerative keratitis adjacent to embedded gold in the cornea. METHODS: To describe the clinical features, management, and outcomes. RESULTS: Successful treatment with topical hydrocortisone was achieved. Subsequently, 3 further episodes of ulcerative keratitis were treated with topical steroid therapy without need for systemic immunosuppression. A systemic vasculitic/autoimmune screen was normal. DISCUSSION: Ocular chrysiasis is well recognized after systemic gold administration and is normally considered inert, but in this case exogenous gold deposition might have been a contributing factor to very localized and repeated episodes of stromal erosion in this man, many years after the original injury. To the best of our knowledge this is the first such reported case. PMID- 22196138 TI - Participation of MCP-induced protein 1 in lipopolysaccharide preconditioning induced ischemic stroke tolerance by regulating the expression of proinflammatory cytokines. AB - BACKGROUND: Lipopolysaccharide (LPS) preconditioning-induced neuroprotection is known to be related to suppression of the inflammatory response in the ischemic area. This study seeks to determine if monocyte chemotactic protein-induced protein 1 (MCPIP1), a recently identified CCCH Zn finger-containing protein, plays a role in focal brain ischemia and to elucidate the mechanisms of LPS induced ischemic brain tolerance. METHODS: Transcription and expression of MCPIP1 gene was monitored by qRT-PCR and Western blot. Mouse microglia was prepared from cortices of C57BL/6 mouse brain and primary human microglia was acquired from Clonexpress, Inc. Wild type and MCPIP1 knockout mice were treated with LPS (0.2 mg/kg) 24 hours before brain ischemia induced by transient middle cerebral artery occlusion (MCAO). The infarct was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. RESULTS: MCPIP1 protein and mRNA levels significantly increased in both mouse and human microglia and mouse brain undergoing LPS preconditioning. MCPIP1 mRNA level significantly increased in mice ipsilateral brain than that of contralateral side after MCAO. The mortality of MCPIP1 knockout mice was significantly higher than that of wild-type after MCAO. MCPIP1 deficiency caused significant increase in the infarct volume compared with wild type mice undergoing LPS preconditioning. MCPIP1 deficiency caused significant upregulation of proinflammatory cytokines in mouse brain. Furthermore, MCPIP1 deficiency increased c-Jun N terminal kinase (JNK) activation substantially. Inhibition of JNK signaling decreased the production of proinflammatory cytokines in MCPIP1 knock out mice after MCAO. CONCLUSIONS: Our data indicate that absence of MCPIP1 exacerbates ischemic brain damage by upregulation of proinflammatory cytokines and that MCPIP1 participates in LPS-induced ischemic stroke tolerance. PMID- 22196140 TI - mRNA expression of metabolic enzymes in human cornea, corneal cell lines, and hemicornea constructs. AB - PURPOSE: Drugs from ophthalmic formulations are mainly absorbed into the eye via the corneal route. However, little is known about drug metabolism during the transcorneal passage. The objective of this study was to determine the mRNA expression of phase I and II isoenzymes in human corneal epithelial tissue, corneal cell lines, and a tissue-engineered cornea equivalent (a hemicornea construct) as in vitro model for drug absorption studies. METHODS: The reverse transcription polymerase chain reaction was used to profile the mRNA expression of 10 cytochrome P450 enzymes (CYP) and seven phase II enzymes in the three human corneal cell lines and the hemicornea construct. The human corneal epithelial cell line (HCE-T), human corneal keratocyte cell line (HCK-Ca) and human corneal endothelial cell line (HENC) were used. Human liver tissue, human corneal epithelium from donor corneas, and the human colon adenocarcinoma cell line Caco 2 were also investigated. RESULTS: All the phase I and II mRNAs were expressed in the human liver tissue. The Caco-2 cell line showed an expression pattern similar to the liver tissue, although the signals for CYP1A2 and CYP3A4 were absent. In the case of the donor human corneal epithelium, all the detected phase I mRNAs had lower levels than did the liver tissue. By contrast, the phase II mRNA expression pattern was heterogeneous to the liver tissue. The expression patterns in the three human corneal cell lines were comparable, although the signals for a few phase I enzymes and N-acetyltransferase (NAT2) mRNAs were only detectable in the HCE-T. In the hemicornea construct, all the investigated phase I and II mRNA (except for CYP1A2, CYP2B6, CYP2C19, and NAT2) were expressed. CONCLUSIONS: Overall, the mRNA expressions of the tested phase I and phase II enzymes in the hemicornea construct and the three corneal cell lines correlated well with the expression patterns of the ex vivo human corneal epithelium. PMID- 22196141 TI - Prenatal diagnosis: types and techniques. AB - Up to 3% of UK pregnancies will be affected by congenital abnormality. Prenatal diagnosis allows the parents to make informed decisions about their pregnancy, healthcare professionals to optimise the antenatal care and families prepare for the birth of the baby. There are many techniques employed which range from the non-invasive ultrasonography to the highly invasive amniocentesis. This review explores the methods currently available in the UK as well as considering the newer minimally-invasive technologies available including cell-free fetal DNA and pre-implantation genetic diagnosis. PMID- 22196142 TI - Best practice guidelines: fetal surgery. AB - Fetal intervention encompasses a range of procedures on the fetus with congenital structural anomalies, whilst still on the placental circulation. The concept of fetal surgery was conceived in order to prevent fetal or early postnatal death, or to prevent permanent irreversible organ damage. The benefit of these procedures has to be balanced with risks to both the mother and the fetus. Open fetal surgery, more commonly conducted in North American centres, involves open surgery to the uterus in order to operate on the fetus. Fetal intervention centres in Europe more commonly use minimally invasive fetoscopic surgery. This paper elaborates on the various strategies used in dealing with anomalies of different organ systems of the fetus. PMID- 22196145 TI - Systematic review of the current evidence in the use of postoperative radiotherapy for oral squamous cell carcinoma. AB - Improved disease-free survival for oral squamous cell carcinoma (SCC) with the use of postoperative radiotherapy (PORT) has to be balanced against the risk of recurrence, the relative morbidity of radiotherapy, reduced options for treatment, and survival with recurrent disease. In the absence of randomised trials, a review of current evidence is timely because of increasing differences in outcome and response to treatment for cancers of the larynx, oropharynx, and oral cavity. From a search of 109 papers, 25 presented relevant data in tabular form, and reported local, regional, and total recurrence, and overall survival. Most data come from non-randomised studies that compared the effects of interventions with previous or historical information. A summary of the results shows local recurrence of 11%, 17%, and 15% for early, late, and all stages after operation alone, compared with 13%, 16%, and 19% after PORT. Regional recurrence is reported as 13%, 12%, and 11% for early, late, and all stages after operation alone compared with 6%, 11%, and 9% after PORT. Overall survival is reported as 76%, 74%, and 77% for operation alone compared with 65%, 62%, and 62% for early, late and all stages of oral SCC, respectively. It is acknowledged that this is a weak level of evidence as patients who have PORT probably have a high pathological-stage of disease. Knowing that PORT increases morbidity and reduces salvage rates and options for treating recurrent disease, this difference in overall survival emphasises the need for randomised studies or a re-evaluation of our current protocols. PMID- 22196146 TI - Incidence of central giant cell granuloma of the jaws with clinical and histological confirmation: an archival study in Northern India. AB - To record the demographics, and correlate histological findings in central giant cell granulomas (CGCGs) of the jaws with their clinical behaviour, 30 paraffin embedded samples of CGCG were retrieved from the archives of the Department of Oral Pathology and Microbiology, Subharti Dental College, Meerut, India. The diagnosis in each case was made on the basis of clinical, radiographic, and histological findings. Data about age, sex, anatomical site, presentation, radiological features, and laboratory investigations were analysed. Histomorphometric analyses were made in each case with respect to the number of giant cells, mean number of nuclei and giant cells, fractional surface area occupied by giant cells, index of relative size, and mitotic activity. The peak incidence of CGCG was during the second decade of life with a slight female predilection, and the mandible was the most common site. Of the 30 samples considered, 20 tumours were classified clinically as non-aggressive, and 10 as aggressive, based on their clinical behaviour. Histomorphometric analysis showed significant changes between the two groups with respect to the number of giant cells, the fractional surface area, and the mitotic activity. The data obtained showed clinical and histomorphometric features that may be reliable indicators for the differentiation between aggressive and non-aggressive CGCG. These data should be taken into consideration to improve planning of individual treatment and follow-up. PMID- 22196147 TI - Aesthetic incision for neck dissection. PMID- 22196148 TI - Identification of differentially expressed protective genes in liver of two rainbow trout strains. AB - Since 1975, the rainbow trout strain BORN (Germany) has been bred in brackish water from a coastal form imported from Denmark. Accompanying phenotypic monitoring of the adapted BORN trout until now revealed that this selection strain manifested a generally elevated resistance towards high stress and pathogenic challenge including lower susceptibility towards Aeromonas salmonicida infections in comparison to other trout strains in local aqua farms. We focus on the elucidation of both, genetic background and immunological basis for the increased survivorship to infections. A first comparison of gene expression profiles in liver tissue of healthy rainbow trout from the local selection strain BORN and imported trout using a GRASP 16K cDNA microarray revealed six differentially expressed genes evoking pathogen and wounding responses, LEAP2A (encoding for liver-expressed antimicrobial peptide), SERPINA1 (alpha-1 antitrypsin), FTH1 (middle subunit of ferritin), FGL2 (fibroleukin), CLEC4E (macrophage-inducible C-type lectin), and SERPINF2 (alpha-2 antiplasmin). Since the latter gene is not described in salmonid species so far, our first aim was to characterize the respective sequence in rainbow trout. Two trout SERPINF2 genes were identified, which share only 48% identical amino acid residues and a characteristic SERPIN domain. Second, we aimed to analyse the expression of those genes after temperature challenge (8 degrees C and 23 degrees C). Only FTH1 was upregulated in BORN and import trout after increase of temperature, while SERPINA1 and FGL2 were only elevated in import trout. Third, the expression of all named genes was analyzed after pathogen challenge with A. salmonicida subsp. salmonicida. As a main finding, we detected a comparably faster regeneration of LEAP2A mRNA abundance in BORN trout following bacterial infection. Ingenuity Pathways Analysis suggested a functional interplay among the mentioned factors and the pro-inflammatory cytokine TNF, whose stronger expression was validated in liver of BORN trout. This data indicate that the examined genes contribute to an improved first barrier against invading pathogens in BORN trout. PMID- 22196149 TI - A classic collaboration: Michael Davies on plaque vulnerability. AB - The British Heart Foundation sponsors the Michael Davies Young Investigator Award, and at its presentation in the Spring of 2009 two collaborators of Michael Davies spoke regarding their experiences on the Plaque Vulnerability project with him. This was to provide the winner and other nominees for the award, and colleagues at the meeting, descriptions of collaborating with Michael to sustain more than his name in association with the award. This article is an expansion of the personal reminiscences given at the time as a tribute to him, and to provide an inside story of how collaboration with such a prominent cardiac pathologist worked. PMID- 22196153 TI - The excess mortality risk of diabetes associated with functional decline in older adults: results from a 7-year follow-up of a nationwide cohort in Taiwan. AB - BACKGROUND: Diabetes is associated with an increased risk of functional decline in older adults. Few studies have investigated the contribution of functional decline to excess mortality risk in older people with diabetes. The aim of this study was to examine how diabetes in combination with different levels of functional decline affects 7-year mortality in older adults. METHODS: We analyzed data from a nationally representative sample of people aged 65 years and over, participating in the 2001 National Health Interview Survey in Taiwan. A total of 1873 participants were followed through 2002-2008, of whom 286 (15.3%) had a history of diabetes confirmed by a medical professional. Participants were divided into three functional status groups: (1) high functioning-no limitations involving activities of daily living (ADLs), instrumental activities of daily living (IADLs), or physical functioning; (2) low functioning-limitations in one or more ADLs; (3) middle functioning-all participants in between groups 1 and 2. RESULTS: The crude mortality rate was 52.7 per 1,000 person-years in those with diabetes and 34.1 per 1,000 person-years in those without diabetes. After adjustment for other factors, diabetes alone was not associated with an increased mortality risk in those with high functioning. However, diabetes alone had a hazard ratio (HR) for mortality of 1.90 (95%CI = [1.02-3.53]) in those with middle functioning and 3.67 (95%CI = [1.55-8.69]) in those with low functioning. The presence of diabetes and one or more other chronic conditions was associated with a HR for mortality of 2.46 (95%CI = [1.61-3.77]) in those with middle functioning and 4.03 (95%CI = [2.31-7.03]) in those with low functioning. CONCLUSIONS: Our results indicate that diabetes is not associated with increased mortality in those with high functioning. There was a gradient effect of functional decline on mortality in individuals with diabetes. Additionally, among participants with other chronic conditions, functional decline was associated with a greater burden of mortality in older adults with diabetes. These findings highlight the critical importance of the prevention of cardiovascular disease morbidity and the maintenance of functional abilities in order to reduce mortality risk in older adults with diabetes. PMID- 22196150 TI - Adiponectin is associated with increased mortality and heart failure in patients with stable ischemic heart disease: data from the Heart and Soul Study. AB - OBJECTIVE: Serum adiponectin protects against incident ischemic heart disease (IHD). However, in patients with existing IHD, higher adiponectin levels are paradoxically associated with worse outcomes. We investigated this paradox by evaluating the relationship between adiponectin and cardiovascular events in patients with existing IHD. METHODS: We measured total serum adiponectin and cardiac disease severity by stress echocardiography in 981 outpatients with stable IHD who were recruited for the Heart and Soul Study between September 2000 and December 2002. Subsequent heart failure hospitalizations, myocardial infarction, and death were recorded. RESULTS: During an average of 7.1 years of follow-up, patients with adiponectin levels in the highest quartile were more likely than those in the lowest quartile to be hospitalized for heart failure (23% vs. 13%; demographics-adjusted hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.04-2.56, p=0.03) or die (49% vs. 31%; HR 1.67, 95% CI 1.24-2.26, p<0.008), but not more likely to have a myocardial infarction (12% vs. 17%; HR 0.64, 95% CI 0.38-1.06, p=0.08). The combined outcome of myocardial infarction, heart failure, or death occurred in 56% (136/245) of participants in the highest quartile of adiponectin vs. 38% (94/246) of participants in the lowest quartile (HR 1.54, 95% CI 1.31-2.21, p<0.002). Adjustment for left ventricular ejection fraction, diastolic dysfunction, inducible ischemia, C-reactive protein, and NT proBNP attenuated the association between higher adiponectin and increased risk of subsequent events (HR 1.43, 95% CI 0.98-2.09, p=0.06). CONCLUSIONS: Higher concentrations of adiponectin were associated with heart failure and mortality among patients with existing IHD. PMID- 22196154 TI - Functionalized squaraine donors for nanocrystalline organic photovoltaics. AB - We study a family of functionalized squaraine (fSQ) donors for absorbing in the near-infrared (NIR) and green spectral regions. The NIR-absorbing materials are the symmetric molecules 2,4-bis[4-(N-phenyl-1-naphthylamino)-2,6 dihydroxyphenyl]squaraine (1-NPSQ), 2,4-bis[4-(N,N-diphenylamino)-2,6 dihydroxyphenyl]squaraine, and 2,4-bis[4-(N,N-dipropylamino)-2,6 dihydroxyphenyl]squaraine. The green light absorbing donors are asymmetric squaraines, namely, 2,4-bis[4-(N,N-diphenylamino)-2,6-dihydroxyphenyl]squaraine and 2-[4-(N,N-diisobutylamino)-2,6-dihydroxyphenyl]-4-diphenylamino]squaraine. Substitution of the arylamine groups enhances intermolecular packing, thereby increasing hole transport and the possibility of forming extended nanocrystalline junctions when annealed. Nanocrystalline solar cells based on fSQ and a C(60) acceptor have V(oc) = 1.0 V and fill factors 0.73 +/- 0.01. Solar cells incorporating annealed 1-NPSQ films result in a power conversion efficiency of 5.7 +/- 0.6% at 1 sun, AM1.5G illumination. PMID- 22196155 TI - Acid phosphatase-positive globular inclusions is a good diagnostic marker for two patients with adult-onset Pompe disease lacking disease specific pathology. AB - Diagnosis of adult-onset Pompe disease is sometimes challenging because of its clinical similarities to muscular dystrophy and the paucity of disease-specific vacuolated fibers in the skeletal muscle pathology. We describe two patients with adult-onset Pompe disease whose muscle pathology showed no typical vacuolated fibers but did show unique globular inclusions with acid phosphatase activity. The acid phosphatase-positive globular inclusions may be a useful diagnostic marker for adult-onset Pompe disease even when typical vacuolated fibers are absent. PMID- 22196156 TI - Stature estimation from complete long bones in the Middle Pleistocene humans from the Sima de los Huesos, Sierra de Atapuerca (Spain). AB - Systematic excavations at the site of the Sima de los Huesos (SH) in the Sierra de Atapuerca (Burgos, Spain) have allowed us to reconstruct 27 complete long bones of the human species Homo heidelbergensis. The SH sample is used here, together with a sample of 39 complete Homo neanderthalensis long bones and 17 complete early Homo sapiens (Skhul/Qafzeh) long bones, to compare the stature of these three different human species. Stature is estimated for each bone using race- and sex-independent regression formulae, yielding an average stature for each bone within each taxon. The mean length of each long bone from SH is significantly greater (p < 0.05) than the corresponding mean values in the Neandertal sample. The stature has been calculated for male and female specimens separately, averaging both means to calculate a general mean. This general mean stature for the entire sample of long bones is 163.6 cm for the SH hominins, 160.6 cm for Neandertals and 177.4 cm for early modern humans. Despite some overlap in the ranges of variation, all mean values in the SH sample (whether considering isolated bones, the upper or lower limb, males or females or more complete individuals) are larger than those of Neandertals. Given the strong relationship between long bone length and stature, we conclude that SH hominins represent a slightly taller population or species than the Neandertals. However, compared with living European Mediterranean populations, neither the Sima de los Huesos hominins nor the Neandertals should be considered 'short' people. In fact, the average stature within the genus Homo seems to have changed little over the course of the last two million years, since the appearance of Homo ergaster in East Africa. It is only with the emergence of H. sapiens, whose earliest representatives were 'very tall', that a significant increase in stature can be documented. PMID- 22196157 TI - How to do it: the difficult thyroid. AB - There is a paucity of publications detailing how to deal with the difficult thyroid cancer. When compared to other cancers, it is relatively rare with several histopathological subtypes which run differing clinical courses and respond to different therapies. It is a condition predominately treated by specifically trained General and now ENT surgeons who already have a thorough knowledge of vocal fold assessment and rehabilitation as well as emergency airways management both to avoid and treat common complications should they occur.Good surgery involves a team effort to produce good results consistently. All members of the team are essential to quality service delivery. Communication with the team and the patient is paramount. We describe our approach to the difficult thyroid. PMID- 22196158 TI - Journal of Critical Reviews in Biomedical Engineering. Preface. PMID- 22196159 TI - Computational modeling of mitochondrial energy transduction. AB - Mitochondria are the power plant of the heart, burning fat and sugars to supply the muscle with the adenosine triphosphate (ATP) free energy that drives contraction and relaxation during each heart beat. This function was first captured in a mathematical model in 1967. Today, interest in such a model has been rekindled by ongoing in silico integrative physiology efforts such as the Cardiac Physiome project. Here, the status of the field of computational modeling of mitochondrial ATP synthetic function is reviewed. PMID- 22196160 TI - Cardiac models in drug discovery and development: a review. AB - Cardiovascular diseases are among the leading causes of death in the developed world. Developing novel therapies for diseases like heart failure is crucial, but this is hampered by the high attrition rate in drug development. The withdrawal of drugs at the final hurdle of approval is mostly because of their unpredictable effects on normal cardiac rhythm. The advent of cardiac computational modeling in the last 5 decades has aided the understanding of heart function significantly. Recently, these models increasingly have been applied toward designing and understanding therapies for cardiac disease. This article will discuss how cellular models of electrophysiology, cell signaling, and metabolism have been used to investigate pharmacologic therapies for cardiac diseases including arrhythmia, ischemia, and heart failure. PMID- 22196165 TI - Alkylative ring opening of N-methylaziridinium ions and a formal synthesis of tyroscherin. AB - Alkylative ring-opening reactions of stable 2-substituted N-methylaziridinium ions proceeded with various alkyl- or arylmagnesium bromides in the presence of CuI to yield synthetically valuable and optically pure alkylated acyclic amines in a completely regio- and stereoselective manner. This was applied to a formal synthesis of the cytotoxic natural product tyroscherin. PMID- 22196167 TI - Enhanced anger superiority effect in generalized anxiety disorder and panic disorder. AB - People are typically faster and more accurate to detect angry compared to happy faces, which is known as the anger superiority effect. Many cognitive models of anxiety suggest anxiety disorders involve attentional biases towards threat, although the nature of these biases remains unclear. The present study used a Face-in-the-Crowd task to investigate the anger superiority effect in a control group and patients diagnosed with either generalized anxiety disorder (GAD) or panic disorder (PD). The main finding was that both anxiety groups showed an enhanced anger superiority effect compared to controls, which is consistent with key theories of anxiety. Furthermore, both anxiety groups showed a differential pattern of enhanced bias towards threat depending on the crowd in the displays. The different attentional bias patterns between the GAD and PD groups may be related to the diverse symptoms in these disorders. These findings have implications for the diagnosis and treatment of anxiety. PMID- 22196163 TI - Mathematical and computational models of oxidative and nitrosative stress. AB - The importance of nitric oxide (NO), superoxide (O2-), and peroxynitrite (ONOO-), interactions in physiologic functions and pathophysiological conditions such as cardiovascular disease, hypertension, and diabetes have been established extensively in in vivo and in vitro studies. Despite intense investigation of NO, O2-, and ONOO- biochemical interactions, fundamental questions regarding the role of these molecules remain unanswered. Mathematical models based on fundamental principles of mass balance and reaction kinetics have provided significant results in the case of NO. However, the models that include interaction of NO, O2 , and ONOO- have been few because of the complexity of these interactions. Not only do these mathematical and computational models provided quantitative knowledge of distributions and concentrations of NO, O2-, and ONOO- under normal physiologic and pathophysiologic conditions, they also can help to answer specific hypotheses. The focus of this review article is on the models that involve more than one of the 3 molecules (NO, O2-, and ONOO-). Specifically, kinetic models of O2- dismutase and tyrosine nitration and biotransport models in the microcirculation are reviewed. In addition, integrated experimental and computational models of dynamics of NO/O2-/ONOO- in diverse systems are reviewed. PMID- 22196161 TI - Nitric oxide signaling in the microcirculation. AB - Several apparent paradoxes are evident when one compares mathematical predictions from models of nitric oxide (NO) diffusion and convection in vasculature structures with experimental measurements of NO (or related metabolites) in animal and human studies. Values for NO predicted from mathematical models are generally much lower than in vivo NO values reported in the literature for experiments, specifically with NO microelectrodes positioned at perivascular locations next to different sizes of blood vessels in the microcirculation and NO electrodes inserted into a wide range of tissues supplied by the microcirculation of each specific organ system under investigation. There continues to be uncertainty about the roles of NO scavenging by hemoglobin versus a storage function that may conserve NO, and other signaling targets for NO need to be considered. This review describes model predictions and relevant experimental data with respect to several signaling pathways in the microcirculation that involve NO. PMID- 22196162 TI - Modeling Ca2+ signaling in the microcirculation: intercellular communication and vasoreactivity. AB - A network of intracellular signaling pathways and complex intercellular interactions regulate calcium mobilization in vascular cells, arteriolar tone, and blood flow. Different endothelium-derived vasoreactive factors have been identified and the importance of myoendothelial communication in vasoreactivity is now well appreciated. The ability of many vascular networks to conduct signals upstream also is established. This phenomenon is critical for both short-term changes in blood perfusion as well as long-term adaptations of a vascular network. In addition, in a phenomenon termed vasomotion, arterioles often exhibit spontaneous oscillations in diameter. This is thought to improve tissue oxygenation and enhance blood flow. Experimentation has begun to reveal important aspects of the regulatory machinery and the significance of these phenomena for the regulation of local perfusion and oxygenation. Mathematical modeling can assist in elucidating the complex signaling mechanisms that participate in these phenomena. This review highlights some of the important experimental studies and relevant mathematical models that provide the current understanding of these mechanisms in vasoreactivity. PMID- 22196169 TI - Hospital staff opinions concerning loved ones' understanding of the patient's life-limiting disease and the loved ones' need for support. AB - The aim of this study was to investigate the opinions of nurses, assistant nurses, and doctors about whether the patient's loved ones understand that the patient has a life-limiting disease, and if they talk about these matters with the patient or staff. The study was quantitative in design with data collected by means of a semi-structured questionnaire. The study was conducted at geriatric, oncology, and urology wards at a university hospital in western Sweden. Results indicate a perception that loved ones understand the seriousness and consequences of the disease. Professional caregivers perceived an association between the loved ones' understanding of the fatal disease and their ability to cope with the situation. In addition, the study found that follow-up activities after the patient's death are mostly lacking. PMID- 22196171 TI - An overview of human prion diseases. AB - Prion diseases are transmissible, progressive and invariably fatal neurodegenerative conditions associated with misfolding and aggregation of a host encoded cellular prion protein, PrP(C). They have occurred in a wide range of mammalian species including human. Human prion diseases can arise sporadically, be hereditary or be acquired. Sporadic human prion diseases include Cruetzfeldt Jacob disease (CJD), fatal insomnia and variably protease-sensitive prionopathy. Genetic or familial prion diseases are caused by autosomal dominantly inherited mutations in the gene encoding for PrP(C) and include familial or genetic CJD, fatal familial insomnia and Gerstmann-Straussler-Scheinker syndrome. Acquired human prion diseases account for only 5% of cases of human prion disease. They include kuru, iatrogenic CJD and a new variant form of CJD that was transmitted to humans from affected cattle via meat consumption especially brain. This review presents information on the epidemiology, etiology, clinical assessment, neuropathology and public health concerns of human prion diseases. The role of the PrP encoding gene (PRNP) in conferring susceptibility to human prion diseases is also discussed. PMID- 22196172 TI - Binding conformation of 2-oxoamide inhibitors to group IVA cytosolic phospholipase A2 determined by molecular docking combined with molecular dynamics. AB - The group IVA cytosolic phospholipase A(2) (GIVA cPLA(2)) plays a central role in inflammation. Long chain 2-oxoamides constitute a class of potent GIVA cPLA(2) inhibitors that exhibit potent in vivo anti-inflammatory and analgesic activity. We have now gained insight into the binding of 2-oxoamide inhibitors in the GIVA cPLA(2) active site through a combination of molecular docking calculations and molecular dynamics simulations. Recently, the location of the 2-oxoamide inhibitor AX007 within the active site of the GIVA cPLA(2) was determined using a combination of deuterium exchange mass spectrometry followed by molecular dynamics simulations. After the optimization of the AX007-GIVA cPLA(2) complex using the docking algorithm Surflex-Dock, a series of additional 2-oxoamide inhibitors have been docked in the enzyme active site. The calculated binding affinity presents a good statistical correlation with the experimental inhibitory activity (r(2) = 0.76, N = 11). A molecular dynamics simulation of the docking complex of the most active compound has revealed persistent interactions of the inhibitor with the enzyme active site and proves the stability of the docking complex and the validity of the binding suggested by the docking calculations. The combination of molecular docking calculations and molecular dynamics simulations is useful in defining the binding of small-molecule inhibitors and provides a valuable tool for the design of new compounds with improved inhibitory activity against GIVA cPLA(2). PMID- 22196173 TI - What a year! PMID- 22196174 TI - Don't throw the scientific self-ligation baby out with the commercial bathwater. PMID- 22196175 TI - Who determines when orthodontic treatment is complete? PMID- 22196176 TI - We must learn to learn from each other. PMID- 22196177 TI - "Publish or perish"--who publishes and who perishes? PMID- 22196179 TI - Orthodontic dental casts: the case for routine articulator mounting. PMID- 22196180 TI - Orthodontic dental casts: the case against routine articulator mounting. PMID- 22196181 TI - Intrarater agreement about the etiology of Class II malocclusion and treatment approach. AB - INTRODUCTION: The management of patients with Class II malocclusion has been an ongoing discussion in orthodontics. The aim of this study was to determine whether orthodontists agree among themselves and with each other about the etiology, timing, and difficulty of treating subjects with Class II malocclusion. METHODS: The initial records of 159 Class II subjects were sent to 8 orthodontists. In this sample, duplicate records of 18 subjects were dispersed. A questionnaire was sent with the records. RESULTS: The intrarater consistency values were 65% when determining the type of malocclusion, 60% when deciding which arch was at fault, and 81% when determining the need for immediate treatment. Consistency values were 33% regarding case difficulty and 77% regarding phase 2 treatment need. There was a significant negative correlation between the consistency of the orthodontists' responses and the peer assessment rating score. CONCLUSIONS: We found that practitioners had only moderate agreement among themselves when diagnosing a patient's type of malocclusion and which arch was at fault when a skeletal discrepancy was noted. Intrarater agreement improved as the peer assessment rating score increased, but the correlation was weak, and this was not consistent for all examiners. Because of insufficient intrarater agreement, interrater agreement was not examined. PMID- 22196182 TI - Molecular detection of in-vivo microbial contamination of metallic orthodontic brackets by checkerboard DNA-DNA hybridization. AB - INTRODUCTION: Knowing the microbiota that colonizes orthodontic appliances is important for planning strategies and implementing specific preventive measures during treatment. The purpose of this clinical trial was to evaluate in vivo the contamination of metallic orthodontic brackets with 40 DNA probes for different bacterial species by using the checkerboard DNA-DNA hybridization (CDDH) technique. METHODS: Eighteen patients, 11 to 29 years of age having fixed orthodontic treatment, were enrolled in the study. Each subject had 2 new metallic brackets bonded to different premolars in a randomized manner. After 30 days, the brackets were removed and processed for analysis by CDDH. Data on bacterial contamination were analyzed descriptively and with the Kruskal-Wallis and Dunn post tests (alpha = 0.05). Forty microbial species (cariogenic microorganisms, bacteria of the purple, yellow, green, orange complexes, "red complex +Treponema socranskii," and the cluster of Actinomyces) were assessed. RESULTS: Most bacterial species were present in all subjects, except for Streptococcus constellatus, Campylobacter rectus, Tannerella forsythia, T socranskii, and Lactobacillus acidophillus (94.4%), Propionibacterium acnes I and Eubacterium nodatum (88.9%), and Treponema denticola (77.8%). Among the cariogenic microorganisms, Streptococcus mutans and Streptococcus sobrinus were found in larger numbers than L acidophillus and Lactobacillus casei (P <0.001). The periodontal pathogens of the orange complex were detected in larger numbers than those of the "red complex +T socranskii" (P <0.0001). Among the bacteria not associated with specific pathologies, Veillonella parvula (purple complex) was the most frequently detected strain (P <0.0001). The numbers of yellow and green complex bacteria and the cluster of Actinomyces were similar (P >0.05). CONCLUSIONS: Metallic brackets in use for 1 month were multi-colonized by several bacterial species, including cariogenic microorganisms and periodontal pathogens, reinforcing the need for meticulous oral hygiene and additional preventive measures to maintain oral health in orthodontic patients. PMID- 22196183 TI - Local osteoprotegerin gene transfer inhibits relapse of orthodontic tooth movement. AB - INTRODUCTION: In orthodontic treatment, teeth can relapse after tooth movement without retention. The aim of this study was to evaluate the inhibition effects of local osteoprotegerin (OPG) gene transfer on orthodontic relapse. METHODS: Eighteen male Wistar rats were divided into 3 groups. The maxillary right first molars of all animals were subjected to orthodontic force and moved mesially. Three weeks later, the force was removed, and the teeth relapsed. During the 2 week relapse period, the 3 groups of rats received local OPG gene transfer (experimental group), mock vector transfer (mock group), and no injections (control group). Tooth movement and relapse were measured by using palatal superimpositions of 3-dimensional digital models. Histomorphometric analysis was used to quantify osteoclasts, and microcomputed tomography analysis was done to quantify the alveolar bone and the tibia. RESULTS: Relapse was significantly inhibited and the number of osteoclasts was reduced in the experimental group. On the other hand, bone mineral density and bone volume fraction of alveolar bone were significantly increased. Bone mineral density and bone volume fraction of the tibia showed no significant difference between the groups. CONCLUSIONS: Local OPG gene transfer to periodontal tissues could inhibit relapse after orthodontic tooth movement, through the inhibition of osteoclastogenesis. PMID- 22196184 TI - Accuracy of cone-beam computed tomography at different resolutions assessed on the bony covering of the mandibular anterior teeth. AB - INTRODUCTION: The aim of this study was to determine the accuracy of cone-beam computed tomography (CBCT) with different voxel resolutions. Measurements were made of the bony covering of the mandibular anterior teeth because this region is crucial in orthodontic treatment planning. METHODS: CBCT data at 2 resolutions (0.125-mm and 0.4-mm voxels) were collected from 8 intact cadaver heads. The vertical position of the mucogingival junction was clinically assessed. After removal of the gingiva, vertical and horizontal bony measurements were taken, and the buccal alveolar bone margin was determined. Anatomic bony measures were compared with the CBCT measures, and the correlation of the mucogingival junction measures to the buccal alveolar bone margin measures was evaluated. RESULTS: Bony measures obtained with CBCT were accurate and differed only slightly from the physical findings. The mean differences, ranging from -0.13 to +0.13 mm, were statistically not significant, but the limits of agreement showed discrepancies in the measurements as large as 2.10 mm, depending on measurement and resolution. Buccal alveolar bone margin measurements correlated with the mucogingival junction measurements (P <0.001). On average, the mucogingival junction was 1.67 mm more apical than the buccal alveolar bone margin (CI 95%, 1.35-1.98 mm). CONCLUSIONS: CBCT renders anatomic measures reliably and is an appropriate tool for linear measurements. Presence of soft tissue as well as different voxel size affect the precision of the data. A customized resolution protocol must be chosen according to the accuracy needed. However, even the 0.125-mm voxel protocol does not depict the thin buccal alveolar bone covering reliably, and there is a risk of overestimating fenestrations and dehiscences. The mucogingival junction appears to follow the buccal alveolar bone margin in a parallel line. PMID- 22196185 TI - Genetic variation in myosin 1H contributes to mandibular prognathism. AB - INTRODUCTION: Several candidate loci have been suggested as influencing mandibular prognathism (1p22.1, 1p22.2, 1p36, 3q26.2, 5p13-p12, 6q25, 11q22.2 q22.3, 12q23, 12q13.13, and 19p13.2). The goal of this study was to replicate these results in a well-characterized homogeneous sample set. METHODS: Thirty three single nucleotide polymorphisms spanning all candidate regions were studied in 44 prognathic and 35 Class I subjects from the University of Pittsburgh School of Dental Medicine Dental Registry and DNA Repository. The 44 subjects with mandibular prognathism had an average age of 18.4 years; 31 were female and 13 male; and 24 were white, 15 African American, 2 Hispanic, and 3 Asian. The 36 Class I subjects had an average age of 17.6 years; 27 were female and 9 male; and 27 were white, 6 African American, 1 Hispanic, and 2 Asian. Skeletal mandibular prognathism diagnosis included cephalometric values indicative of Class III such as an ANB smaller than 2 degrees , a negative Wits appraisal, and a positive A-B plane. Additional mandibular prognathism criteria included negative overjet and visually prognathic (concave) profile as determined by the subject's clinical evaluation. Orthognathic subjects without jaw deformations were used as the comparison group. The mandibular prognathic and orthognathic subjects were matched by race, sex, and age. Genetic markers were tested by polymerase chain reaction with TaqMan chemistry. Chi-square and Fisher exact tests were used to determine overrepresentation of marker allele with an alpha of 0.05. RESULTS: An association was unveiled between a marker in MYO1H (rs10850110) and the mandibular prognathism phenotype (P = 0.03). MYO1H is a Class I myosin that is in a different protein group than the myosin isoforms of muscle sarcomeres, which are the basis of skeletal muscle fiber typing. Class I myosins are necessary for cell motility, phagocytosis, and vesicle transport. CONCLUSIONS: More strict clinical definitions might increase homogeneity and aid the studies of genetic susceptibility to malocclusions. We provide evidence that MYO1H can contribute to mandibular prognathism. PMID- 22196186 TI - Long-term skeletal and dental stability of mandibular symphyseal distraction osteogenesis with a hybrid distractor. AB - INTRODUCTION: The purpose of this study was to examine the long-term skeletal and dental stability of mandibular symphyseal distraction osteogenesis (MSDO) with a tooth-borne and bone-borne hybrid distractor. To differentiate the effects of MSDO from the orthodontic movement and relapse, each phase of treatment was analyzed. METHODS: Twenty-five patients were included in the study, ranging in age from 12.0 to 30.9 years at the initiation of treatment (mean, 15.8 +/- 4.8 years). Of this group, 16 patients were recalled at a mean of 7.5 +/- 0.9 years (range, 6.3-9.6 years) after distraction for long-term analysis of skeletal and dental changes. Orthodontic records were taken at 5 times: T1, pretreatment; T2, predistraction; T3, postdistraction; T4, posttreatment, and T5, postretention. The data were statistically analyzed by using repeated-measures analysis of variance (ANOVA). RESULTS: There were significant increases in all interdental transverse measurements except the mandibular intersecond molar distance from T1 to T4. The largest overall expansion was achieved between the mandibular second premolars (4.32 +/- 0.60 mm), followed by the interfirst premolar (3.44 +/- 0.44 mm), the interfirst molar (2.60 +/- 0.65 mm), and the intercanine (1.87 +/- 0.44 mm) widths. The overall amount of transverse dental expansion was substantially less when analyzed from the time of the mandibular symphyseal osteotomy to posttreatment (T2-T4). From T3 to T4, there were significant decreases between the mandibular intersecond premolars (-3.10 +/- 0.52 mm), interfirst premolars ( 3.90 +/- 0.35 m), intercanines (-4.47 +/- 0.38 mm), and intercentral incisors ( 5.60 +/- 0.32 mm). There were no significant changes in bicondylar, bigonial, and biantigonial widths. At the long-term follow-up, there were no significant changes in the interdental or skeletal measurements between T4 and T5, except for interincisor apices. The irregularity index significantly decreased during the orthodontic treatment but significantly increased in the long-term follow-up period (T4-T5). After the MSDO, T3 to T5, the results indicated symphyseal basal bone skeletal stability. CONCLUSIONS: The results indicate that the expansion of the mandibular arch with MSDO and conventional orthodontic mechanics produces no statistically significant transverse changes from posttreatment to long-term follow-up. The risks of using a surgical procedure and MSDO to achieve additional expansion should be evaluated by the clinician and compared with more traditional orthodontic methods. PMID- 22196187 TI - Analysis of stress in bone and microimplants during en-masse retraction of maxillary and mandibular anterior teeth with different insertion angulations: a 3 dimensional finite element analysis study. AB - INTRODUCTION: The proper angle of microimplant insertion is important for cortical anchorage, patient safety, and biomechanical control. However, the actual impact of different insertion angulations on stability is unknown. METHODS: To perform 3-dimensional finite element analysis, finite element models of a maxilla and a mandible with types D3 and D2 bone quality, and of microimplants with a diameter of 1.3 mm and lengths of 8 and 7 mm were generated. The microimplants were inserted at 30 degrees , 45 degrees , 60 degrees , and 90 degrees to the bone surface. A simulated horizontal orthodontic force of 200 g was applied to the center of the microimplant head, and stress distribution and its magnitude were analyzed with a 3-dimensional finite element analysis program. RESULTS: The maximum von Mises stresses in the microimplant and the cortical bone decreased as the insertion angle increased. Analysis of the stress distribution in the cortical and cancellous bones showed that the stress was absorbed mostly in the cortical bone, and little was transmitted to the cancellous bone. The maximum von Mises stress was higher in type D3 bone quality than type D2 bone quality. CONCLUSIONS: Placement of microimplants at a 90 degrees angulation in the bone reduces the stress concentration, thereby increasing the likelihood of implant stabilization. Perpendicular insertion offers more stability to orthodontic loading. PMID- 22196188 TI - Vertical alveolar growth in subjects with infraoccluded mandibular deciduous molars. AB - INTRODUCTION: Our objective was to compare vertical alveolar growth in areas adjacent to infraoccluded deciduous molars with growth in areas of deciduous molars and normal occlusion for a period of at least 1 year by using digital subtraction radiography. METHODS: This case-control study included 40 pairs of panoramic radiographs of growing patients with infraoccluded deciduous molars and 40 pairs of radiographs of patients without infraoccluded deciduous molars. One radiograph at baseline was obtained at diagnosis, and the other at least 1 year later. The subjects and the controls were matched according to chronologic age and time interval between the 2 radiographs. The 2 groups were compared with regard to vertical alveolar growth and vertical tooth movement. Measurements were assessed by using nonparametric tests (Mann-Whitney and Friedman) and a multiple comparison test. Significance was set at 5%. RESULTS: A statistically significant difference was observed between the groups with regard to vertical alveolar growth measured on the bone crest between the first permanent molars and second premolars. CONCLUSIONS: Vertical alveolar growth between the first permanent molar and the second premolar adjacent to the infraoccluded teeth was smaller than in areas adjacent to teeth with normal occlusion. PMID- 22196189 TI - Upper lip changes and gingival exposure on smiling: vertical dimension analysis. AB - INTRODUCTION: Our objectives were to evaluate and quantify upper lip soft-tissue changes in the vertical dimensions both at rest and at maximum smile, and to examine the correlation between upper labial vestibular attachment height and maxillary gingival exposure on smiling. METHODS: Seventy-two volunteers (36 men, 36 women) aged 20 to 40 (mean, 30.49 years) were recruited for this study. For each subject, 9 measurements of upper lip position and maxillary incisor crown height at rest and in maximum smile were recorded. RESULTS: A statistically significant sexual dimorphism was apparent in most of the measured variables. Relaxed external upper lip length was 3.1 mm shorter in the women than in the men. The mean maxillary central incisor display at rest was 1.78 mm greater in the women than in the men. A high smile line was 2.5 times more prevalent in the women. The upper lip was shortened by 30% in subjects with a high smile line compared with 23% in subjects with a low smile line. CONCLUSIONS: The following findings were observed in subjects with a high smile pattern: (1) short upper lip length, (2) low smiling/resting upper lip length ratio, (3) inferior attachment of the upper labial vestibule, and (4) prominent upper lip vermilion. PMID- 22196190 TI - Orthognathic treatment for a patient with facial asymmetry associated with unilateral scissors-bite and a collapsed mandibular arch. AB - Subapical mandibular surgeries have been used to correct vertical malocclusion and interdental problems associated with mandibular deformity. Subapical surgery to the anterior part of the mandible is applicable in many patients with anterior open bite and deepbite. Surgery of the posterior part of the mandible is needed less frequently than surgery of the anterior part. This case report describes the surgical-orthodontic treatment of a 21-year-old woman who underwent posterior subapical mandibular surgery. Her chief complaint was facial asymmetry, and she had a collapsed mandibular arch with a scissors-bite of the right premolars and molars. After subapical osteotomy, surgically assisted correction of the collapsed right mandibular arch was performed with a lingual arch appliance. Comprehensive orthodontic treatment was initiated in both arches after this correction. Le Fort I osteotomy and sagittal split ramus osteotomy were used to correct the facial asymmetry. Her facial appearance and temporomandibular problems were markedly improved, and she achieved a functional and stable occlusion after these treatments. This case report demonstrates the efficiency of posterior subapical mandibular surgery for a patient with a collapsed mandibular arch and a scissors-bite. PMID- 22196191 TI - Is traditional treatment a good option for an adult with a Class II deepbite malocclusion? AB - The Tweed-Merrifield directional force technique is a useful treatment approach for a patient with a Class II malocclusion with dentoalveolar protrusion. The purpose of this case report was to present the diagnosis and treatment descriptions of a patient with an Angle Class II malocclusion complicated by tooth losses, severe dentoalveolar protrusion, and skeletal discrepancy. Treatment involved extraction of the maxillary first premolars, high-pull headgear to enhance anchorage, and high-pull J-hook headgear to retract and intrude the maxillary anterior segments. A successful outcome was achieved with traditional orthodontic treatment in this borderline surgical case. PMID- 22196192 TI - Eagle's syndrome in an orthodontic patient. AB - This purpose of this article was to report the clinical case of a patient with Eagle's syndrome. She was referred to the orthodontic clinic by her general clinician, with the complaint of temporomandibular dysfunction. The orthodontic records showed a styloid process elongation accompanied by calcification and fracture on the right side. Eagle's syndrome was diagnosed, and the patient was referred to a buccomaxillofacial surgeon for surgical correction. PMID- 22196193 TI - Digital live-tracking 3-dimensional minisensors for recording head orientation during image acquisition. AB - INTRODUCTION: Our objective was to test the value of minisensors for recording unrestrained head position with 6 degrees of freedom during 3-dimensional stereophotogrammetry. METHODS: Four 3-dimensional pictures (3dMD, Atlanta, Ga) were taken of 20 volunteers as follows: (1) in unrestrained head position, (2) a repeat of picture 1, (3) in unrestrained head position wearing a headset with 3 dimensional live tracking sensors (3-D Guidance trackSTAR; Ascension Technology, Burlington, Vt), and (4) a repeat of picture 3. The sensors were used to track the x, y, and z coordinates (pitch, roll, and yaw) of the head in space. The patients were seated in front of a mirror and asked to stand and take a walk between each acquisition. Eight landmarks were identified in each 3-dimensional picture (nasion, tip of nose, subnasale, right and left lip commissures, midpoints of upper and lower lip vermilions, soft-tissue B-point). The distances between correspondent landmarks were measured between pictures 1 and 2 and 3 and 4 with software. The Student t test was used to test differences between unrestrained head position with and without sensors. RESULTS: Interlandmark distances for pictures 1 and 2 (head position without the sensors) and pictures 3 and 4 (head position with sensors) were consistent for all landmarks, indicating that roll, pitch, and yaw of the head are controlled independently of the sensors. However, interlandmark distances were on average 17.34 +/- 0.32 mm between pictures 1 and 2. Between pictures 3 and 4, the distances averaged 6.17 +/- 0.15 mm. All interlandmark distances were significantly different between the 2 methods (P <0.001). CONCLUSIONS: The use of 3-dimensional live-tracking sensors aids the reproducibility of patient head positioning during repeated or follow-up acquisitions of 3-dimensional stereophotogrammetry. Even with sensors, differences in spatial head position between acquisitions still require additional registration procedures. PMID- 22196194 TI - Litigation and legislation. Statistical evidence: admissible or not? PMID- 22196195 TI - Randomization. Part 3: allocation concealment and randomization implementation. PMID- 22196196 TI - Physical properties of root cementum: Part 22. Root resorption after the application of light and heavy extrusive orthodontic forces: a microcomputed tomography study. AB - INTRODUCTION: Extrusive tooth movement has been overlooked in the literature on root resorption. The aims of this study were to quantify the effects of light and heavy controlled extrusive forces on root resorption and to localize the sites of prevalence in premolars. METHODS: Ten patients (7 girls, 3 boys) who required bilateral maxillary first premolar extractions as part of their orthodontic treatment participated in this study. The total sample consisted of 20 maxillary first premolars. Light (25 g) or heavy (225 g) forces were applied to the right or left first premolar for 28 days. After the experimental period, the teeth were extracted without root damage and analyzed with microcomputed tomography. Each specimen was studied in 3 dimensions, and specially designed software was used to measure the volume of each crater. Wilcoxon signed rank tests were used for the statistical analysis. RESULTS: There was a significant difference in the total root resorption caused by light and heavy forces (P = 0.037). The discrepancy between the light and heavy groups was not significant for the cervical, middle, and apical regions separately. Only the distal surfaces were significantly different between the light and heavy forces (P = 0.008). CONCLUSIONS: Greater root resorption was observed after heavy extrusive forces when compared with light forces. The distal surfaces of the tooth root were significantly more affected than other root surfaces and might be influenced by root morphology and initial angulation of the tooth. There was no significant difference in the cervical, middle, and apical thirds in relation to root resorption after light or heavy extrusive forces. PMID- 22196197 TI - One-phase vs 2-phase treatment for developing Class III malocclusion: a comparison of identical twins. AB - Despite the known influence of early treatment on the facial appearance of growing patients with skeletal Class III malocclusion, few comparative reports on the long-term effects of different treatment regimens (1-phase vs 2-phase treatment) have been published. Uncertainty remains regarding the effects of early intervention on jaw growth and its effectiveness and efficiency in the long term. In this case report, we compared the effects of early orthodontic intervention as the first phase of a 2-phase treatment vs 1-phase fixed appliance treatment in identical twins over a period of 11 years. Facial and dental changes were recorded, and cephalometric superimpositions were made at 4 time points. In spite of the different treatment approaches, both patients showed identical dentofacial characteristics in the retention phase. Through this case report, we intended to clarify the benefits of undergoing 1-phase treatment against 2-phase treatment protocols for treating growing skeletal Class III patients. PMID- 22196198 TI - Relapse of a maxillary median diastema: closure and permanent retention. AB - The purpose of this article was to describe the closure of a maxillary median diastema of a 26-year-old woman that had been corrected before during orthodontic treatment but reopened after dental trauma in a car accident. A clear esthetic device made from a tray like those used for home bleaching was used, providing a comfortable, nearly undetectable, and efficient solution. A permanent fixed retainer was bonded again to the maxillary central incisors to prevent relapse. PMID- 22196199 TI - Cholesterol-dependent macropinocytosis and endosomal escape control the transfection efficiency of lipoplexes in CHO living cells. AB - Here we investigate the cellular uptake mechanism and final intracellular fate of two cationic liposome formulations characterized by similar physicochemical properties but very different lipid composition and efficiency for intracellular delivery of DNA. The first formulation is made of cationic lipid 1,2-dioleoyl-3 trimethylammonium-propane (DOTAP) and the zwitterionic helper dioleoylphosphocholine (DOPC), while the second one is made of the cationic 3beta [N-(N,N-dimethylaminoethane)-carbamoyl] cholesterol (DC-Chol) and the zwitterionic lipid dioleoylphosphatidylethanolamine (DOPE). Combining pharmacological and imaging approaches we show that both DOTAP-DOPC/DNA and DC Chol-DOPE/DNA lipoplexes are taken up in Chinese hamster ovary (CHO) living cells mainly through fluid-phase macropinocytosis. Our results also indicate that lipoplex macropinocytosis is a cholesterol-sensitive uptake mechanism. On the other side, both clathrin-mediated and caveolae-mediated endocytosis play a minor role, if any, in the cell uptake. Colocalization of fluorescently tagged lipoplexes and Lysosensor, a primary lysosome marker, reveals that poorly efficient DOTAP-DOPC/DNA lipoplexes are largely degraded in the lysosomes, while efficient DC-Chol-DOPE/DNA systems can efficiently escape from endosomal compartments. PMID- 22196201 TI - S100B modulates growth factors and costimulatory molecules expression in cultured human astrocytes. AB - S100B is a Ca(2+)-binding protein expressed in the nervous system. Increased levels of S100B in the extracellular space have been detected in several neurological disorders. We investigated the response of human astrocytes to micromolar chronic concentrations of this protein measuring the expression of some costimulatory molecules, such as CD137, CD137-L, CD40, CD40-L, the chemokine RANTES and two growth factors FGF-2 and TGF-beta2. Our findings suggest that high levels of S100B in the brain parenchyma may modulate the activation status of astrocytes decreasing their neuroprotective role and modifying their interaction with microglia and other inflammatory cells. This effect may contribute to evolution of some neurological disorders. PMID- 22196203 TI - Excellence in oral & dental research. PMID- 22196204 TI - Invasive mycoses: evolving challenges and opportunities in antifungal therapy. Introduction. PMID- 22196205 TI - Invasive mycoses: diagnostic challenges. AB - Despite the availability of newer antifungal drugs, outcomes for patients with invasive fungal infections (IFIs) continue to be poor, in large part due to delayed diagnosis and initiation of appropriate antifungal therapy. Standard histopathologic diagnostic techniques are often untenable in at-risk patients, and culture-based diagnostics typically are too insensitive or nonspecific, or provide results after too long a delay for optimal IFI management. Newer surrogate markers of IFIs with improved sensitivity and specificity are needed to enable earlier diagnosis and, ideally, to provide prognostic information and/or permit therapeutic monitoring. Surrogate assays should also be accessible and easy to implement in the hospital. Several nonculture-based assays of newer surrogates are making their way into the medical setting or are currently under investigation. These new or up-and-coming surrogates include antigens/antibodies (mannan and antimannan antibodies) or fungal metabolites (d-arabinitol) for detection of invasive candidiasis, the Aspergillus cell wall component galactomannan used to detect invasive aspergillosis, or the fungal cell wall component and panfungal marker beta-glucan. In addition, progress continues with use of polymerase chain reaction- or other nucleic acid- or molecular-based assays for diagnosis of either specific or generic IFIs, although the various methods must be better standardized before any of these approaches can be more fully implemented into the medical setting. Investigators are also beginning to explore the possibility of combining newer surrogate markers with each other or with more standard diagnostic approaches to improve sensitivity, specificity, and capacity for earlier diagnosis, at a time when fungal burden is still relatively low and more responsive to antifungal therapy. PMID- 22196206 TI - Invasive mycoses: strategies for effective management. AB - Effective management of invasive fungal infections (IFIs) depends on early individualized therapy that optimizes efficacy and safety. Considering the negative consequences of IFI, for some high-risk patients the potential benefits of prophylactic therapy may outweigh the risks. When using a prophylactic, empiric, or preemptive therapeutic approach, clinicians must take into account the local epidemiology, spectrum of activity, pharmacokinetic and pharmacodynamic parameters, and safety profile of different antifungal agents, together with unique host-related factors that may affect antifungal efficacy or safety. Therapeutic drug monitoring is increasingly recognized as important or necessary when employing lipophilic triazoles (itraconazole, voriconazole, posaconazole) or flucytosine. Because early diagnostics remain limited for uncommon, yet emerging opportunistic molds (e.g., Mucorales), and treatment delay is associated with increased mortality, early effective management often depends on a high index of suspicion, taking into account predisposing factors, host cues favoring mucormycosis, and local epidemiology. Antifungal options for mucormycosis are limited, and optimal management depends on a multimodal approach that includes early diagnosis/clinical suspicion, correction of underlying predisposing factors, radical debridement of affected tissues, and extended antifungal therapy. This article discusses strategies for the effective management of invasive mycoses, with a particular focus on antifungal hepatotoxicity. PMID- 22196207 TI - Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. AB - Antifungal resistance continues to grow and evolve and complicate patient management, despite the introduction of new antifungal agents. In vitro susceptibility testing is often used to select agents with likely activity for a given infection, but perhaps its most important use is in identifying agents that will not work, i.e., to detect resistance. Standardized methods for reliable in vitro antifungal susceptibility testing are now available from the Clinical and Laboratory Standards Institute (CLSI) in the United States and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in Europe. Data gathered by these standardized tests are useful (in conjunction with other forms of data) for calculating clinical breakpoints and epidemiologic cutoff values (ECVs). Clinical breakpoints should be selected to optimize detection of non-wild type (WT) strains of pathogens, and they should be species-specific and not divide WT distributions of important target species. ECVs are the most sensitive means of identifying strains with acquired resistance mechanisms. Various mechanisms can lead to acquired resistance of Candida species to azole drugs, the most common being induction of the efflux pumps encoded by the MDR or CDR genes, and acquisition of point mutations in the gene encoding for the target enzyme (ERG11). Acquired resistance of Candida species to echinocandins is typically mediated via acquisition of point mutations in the FKS genes encoding the major subunit of its target enzyme. Antifungal resistance is associated with elevated minimum inhibitory concentrations, poorer clinical outcomes, and breakthrough infections during antifungal treatment and prophylaxis. Candidemia due to Candida glabrata is becoming increasingly common, and C glabrata isolates are increasingly resistant to both azole and echinocandin antifungal agents. This situation requires continuing attention. Rates of azole-resistant Aspergillus fumigatus are currently low, but there are reports of emerging resistance, including multi-azole resistant isolates in parts of Europe. PMID- 22196208 TI - The impact of the host on fungal infections. AB - Outcomes of fungal infections in immunocompromised individuals depend on a complex interplay between host and pathogen factors, as well as treatment modalities. Problems occur when host responses to an infection are either too weak to effectively help eradicate the pathogen, or when they become too strong and are associated with host damage rather than protection. Immune reconstitution syndrome (IRS) can be generally defined as a restoration of host immunity in a previously immunosuppressed patient that becomes dysregulated and overly robust, resulting in host damage and sometimes death. IRS associated with opportunistic mycoses presents as new or worsening clinical symptoms or radiographic signs consistent with an inflammatory process that occur during receipt of an appropriate antifungal, and that cannot be explained by a newly acquired infection. Because there are currently no established tests or biomarkers for IRS, it can be difficult to distinguish from progression of the original infection, although culture and biomarkers for the fungal pathogen or infection are typically negative during diagnostic workup. IRS was originally characterized in human immunodeficiency virus-infected patients receiving antiretroviral therapy, but has subsequently been described in solid-organ transplant recipients, neutropenic patients, women in the postpartum period, and recipients of tumor necrosis factor-alpha inhibitor therapy. In each of these cases, recovery of the host's immunity during treatment of an initial infection results in a powerful proinflammatory environment that overshoots and leads to host damage. Optimal management of IRS has not been established at present, but often involves treatment with a corticosteroid or other anti-inflammatory compounds. This article uses a number of patient cases to explore the intricacies of diagnosing and managing a patient with IRS, as well as the other extreme, namely patients who are so immunocompromised without immune recovery that they essentially become breeding grounds for a wide range of opportunistic pathogens, often simultaneously. PMID- 22196209 TI - Compressive force magnitude and intervertebral joint flexion/extension angle influence shear failure force magnitude in the porcine cervical spine. AB - Despite the findings that peak anterior shear load is highly correlated with low back pain reporting, very little research has been conducted to determine how vertebral shear injury potential is influenced. The current study quantified the combined effects of vertebral joint compression and flexion/extension postural deviation from neutral on ultimate shear failure. Ninety-six porcine cervical specimens (48C3-C4, 48C5-C6) were tested. Each specimen was randomly assigned to one of twelve combinations of compressive force (15%, 30%, 45%, or 60% of predicted compressive failure force) and flexion/extension postural deviation (extended, neutral, or flexed). Vertebral joint shear failure was induced by applying posterior shear displacement of the caudal vertebra at a constant rate of 0.15 mm/s. Throughout shear failure tests, vertebral joint kinematics were measured using an optoelectronic camera and a series of infrared light emitting diodes while shear force was measured from load cells rigidly interfaced in series with linear actuators that applied the shear displacement. Measurements of shear stiffness, ultimate force, displacement, and energy stored were made from the force-displacement data. Compressive force and postural deviation demonstrated main effects without a statistically significant interaction for any of the measurements. Shear failure force increased by 11.1% for each 15% increment in compressive force (p<0.05). Postural deviation from neutral impacted ultimate shear failure force by a 12.8% increase with extension (p<0.05) and a 13.2% decrease with flexion (p<0.05). Displacement at ultimate failure was not significantly altered by either compressive force or postural deviation. These results demonstrate that shear failure force may be governed by changes in facet articulation, either by postural deviation or by reducing vertebral joint height through compression that alter the moment arm length between the center of facet contact pressure and the pars interarticularis location. However, objective evidence of this alteration currently does not exist. Both compression and flexion/extension postural deviation should be equally considered while assessing shear injury potential. PMID- 22196210 TI - A statistical mechanical model of cholesterol/phospholipid mixtures: linking condensed complexes, superlattices, and the phase diagram. AB - Despite extensive studies for nearly three decades, lateral distribution of molecules in cholesterol/phospholipid bilayers remains elusive. Here we present a statistical mechanical model of cholesterol/phospholipid mixtures that is able to rationalize almost every critical mole fraction (X(cr)) value previously reported for sterol superlattice formation as well as the observed biphasic changes in membrane properties at X(cr). This model is able to explain how cholesterol superlattices and cholesterol/phospholipid condensed complexes are interrelated. It gives a more detailed characterization of the LG(I)region (a broader region than the liquid disordered-liquid ordered mixed-phase region), which is considered to be a sludgelike mixture of fluid phase and aggregates of rigid clusters. A rigid cluster is formed by a cholesterol molecule and phospholipid molecules that are condensed to the cholesterol. Rigid clusters of similar size tend to form aggregates, in which cholesterol molecules are regularly distributed into superlattices. According to this model, the extent and type of sterol superlattices, thus the lateral distribution of the entire membrane, should vary with cholesterol mole fraction in a delicate, predictable, and nonmonotonic manner, which should have profound functional implications. PMID- 22196211 TI - Surgical preferences of patients at risk of hip fractures: hemiarthroplasty versus total hip arthroplasty. AB - BACKGROUND: The optimal treatment of displaced femoral neck fractures in patients over 60 years is controversial. While much research has focused on the impact of total hip arthroplasty (THA) and hemiarthroplasty (HA) on surgical outcomes, little is known about patient preferences for either alternative. The purpose of this study was to elicit surgical preferences of patients at risk of sustaining hip fracture using a novel decision board. METHODS: We developed a decision board for the surgical management of displaced femoral neck fractures presenting risks and outcomes of HA and THA. The decision board was presented to 81 elderly patients at risk for developing femoral neck fractures identified from an osteoporosis clinic. The participants were faced with the scenario of sustaining a displaced femoral neck fracture and were asked to state their treatment option preference and rationale for operative procedure. RESULTS: Eighty-five percent (85%) of participants were between the age of 60 and 80 years; 89% were female; 88% were Caucasian; and 49% had some post-secondary education. Ninety-three percent (93%; 95% confidence interval [CI], 87-99%) of participants chose THA as their preferred operative choice. Participants identified several factors important to their decision, including the perception of greater walking distance (63%), less residual pain (29%), less reoperative risk (28%) and lower mortality risk (20%) with THA. Participants who preferred HA (7%; 95% CI, 1-13%) did so for perceived less invasiveness (50%), lower dislocation risk (33%), lower infection risk (33%), and shorter operative time (17%). CONCLUSION: The overwhelming majority of patients preferred THA to HA for the treatment of a displaced femoral neck fracture when confronted with risks and outcomes of both procedures on a decision board. PMID- 22196212 TI - Chemically directed assembly of photoactive metal oxide nanoparticle heterojunctions via the copper-catalyzed azide-alkyne cycloaddition "click" reaction. AB - Metal oxides play a key role in many emerging applications in renewable energy, such as dye-sensitized solar cells and photocatalysts. Because the separation of charge can often be facilitated at junctions between different materials, there is great interest in the formation of heterojunctions between metal oxides. Here, we demonstrate use of the copper-catalyzed azide-alkyne cycloaddition reaction, widely referred to as "click" chemistry, to chemically assemble photoactive heterojunctions between metal oxide nanoparticles, using WO(3) and TiO(2) as a model system. X-ray photoelectron spectroscopy and Fourier-transform infrared spectroscopy verify the nature and selectivity of the chemical linkages, while scanning electron microscopy reveals that the TiO(2) nanoparticles form a high density, conformal coating on the larger WO(3) nanoparticles. Time-resolved surface photoresponse measurements show that the resulting dyadic structures support photoactivated charge transfer, while measurements of the photocatalytic degradation of methylene blue show that chemical grafting of TiO(2) nanoparticles to WO(3) increases the photocatalytic activity compared with the bare WO(3) film. PMID- 22196213 TI - Temporal patterns of anxious and depressed mood in generalized anxiety disorder: a daily diary study. AB - Research suggests that anxiety disorders tend to temporally precede depressive disorders, a finding potentially relevant to understanding comorbidity. The current study used diary methods to determine whether daily anxious mood also temporally precedes daily depressed mood. 55 participants with generalized anxiety disorder (GAD) and history of depressive symptoms completed a 21-day daily diary tracking anxious and depressed mood. Daily anxious and depressed moods were concurrently associated. Daily anxious mood predicted later depressed mood at a variety of time lags, with significance peaking at a two-day lag. Depressed mood generally did not predict later anxious mood. Results suggest that the temporal antecedence of anxiety over depression extends to daily symptoms in GAD. Implications for the refinement of comorbidity models, including causal theories, are discussed. PMID- 22196214 TI - WNTing embryonic stem cells. AB - Embryonic stem cells (ESCs) - undifferentiated cells originating from preimplantation stage embryos - have prolonged self-renewal capacity and are pluripotent. Activation of the canonical Wnt pathway is implicated in maintenance of and exit from the pluripotent state. Recent findings demonstrate that the essential mediator of canonical Wnt signaling, beta-catenin, is dispensable for ESC maintenance; however, its activation inhibits differentiation through derepression of T cell factor 3 (Tcf3)-bound genes. Wnt agonists are useful in deriving ESCs from recalcitrant mouse strains and the rat and in nuclear reprogramming of somatic stem cells. We discuss recent advances in our understanding of the role of canonical Wnt signaling in the regulation of ESC self-renewal and how its manipulation can improve pluripotent ESC derivation and maintenance. PMID- 22196216 TI - Vascular mimicry in cultured head and neck tumour cell lines. AB - INTRODUCTION: Vascuologenesis is the de novo establishment of blood vessels and vascular networks from mesoderm-derived endothelial cell precursors (angioblasts). Recently a novel mechanism, by which some genetically deregulated and aggressive tumour cells generate "micro-vascular" channels without the participation of endothelial cells and independent of angiogenesis, has been proposed. This has been termed "vasculogenic mimicry" and has implications beyond angiogenesis and adds another layer of complexity to the current concept for the generation of tumour micro-circulation. We suggest this is common phenomenon in head and neck squamous cell carcinoma (HNSCC) cell lines and other aggressive tumour cell lines. We present experimental evidence of vasculogenic mimicry in HNSCC cell lines and compare them with other tumours and a positive control vascular cell line. MATERIALS AND METHODS: The cell lines used were HUVEC, HN 2a, 2b (primary and metastatic tongue base squamous carcinoma cell line), HCT116 (colonic carcinoma cell line) and DU145 (prostate carcinoma cell line).Pilot experiments were undertaken to assess growth of a bank of tumour cell lines on (growth factor reduced) matrigel (Sigma) with standard media (DMEM with 10% Fetal Calf Serum).A functional growth assay was performed by preparing the appropriate cell suspension in serum free medium plated onto either bare plastic or a well pre-coated with growth factor reduced type 4 collagen analogues.Phase contrast photomicrographs were taken at 4 hours and 24 hours. Image analysis was performed; particular features of interest were two dimensional area (surrogate of growth and migration), branch points and end point measurements (surrogate of intercellular complexity). RESULTS: There were observable differences in growth of the cells on laboratory plastic and collagen matrix. Tumour cells formed capillary like networks similar to HUVEC cells. Metastatic HNSCC cells lines were found to have vasculogenic properties similar to HUVEC cell lines when compared to cell lines from their corresponding primary tumour. The endothelial growth factor antibodies used did not inhibit or stimulate cell growth when compared to control but did discourage vascular mimicry. Other tumour cell lines also displayed this property. DISCUSSION: Tumour "vasculogenic mimicry" must still be regarded as a controversial issue whose existence is not proven. The clinical importance of this phenomenon however, is that it does explain the lack of complete efficacy of current anti-angiogenic treatments due to the added layer of complexity. It provides a feasible mechanism of early tumour vascular supply which can co-exist and incorporate with later angiogenic mechanisms. We suggest that "vasculogenic mimicry" maybe a common neoplastic phenomena which appears to also be dictated by the cells micro-environment. Its existence also suggests a further process that of the development of tumour mosaic vessels as the neo vasculature integrates with the existing endothelial lined systems. PMID- 22196215 TI - SAGA function in tissue-specific gene expression. AB - The Spt-Ada-Gcn5-acetyltransferase (SAGA) transcription coactivator plays multiple roles in regulating transcription because of the presence of functionally independent modules of subunits within the complex. We have recently identified a role for the ubiquitin protease activity of SAGA in regulating tissue-specific gene expression in Drosophila. Here, we discuss the modular nature of SAGA and the different mechanisms through which SAGA is recruited to target promoters. We propose that the genes sensitive to loss of the ubiquitin protease activity of SAGA share functional characteristics that require deubiquitination of monoubiquitinated histone H2B (ubH2B) for full activation. We hypothesize that deubiquitination of ubH2B by SAGA destabilizes promoter nucleosomes, thus enhancing recruitment of RNA polymerase II (Pol II) to weak promoters. In addition, SAGA-mediated deubiquitination of ubH2B may facilitate binding of factors that are important for the transition of paused Pol II into transcription elongation. PMID- 22196217 TI - [The guidelines: what should we expect?]. PMID- 22196218 TI - [Pathophysiology of preeclampsia: some recent data]. AB - Placental ischemia is the background of the pathophysiology of preeclampsia. It is mainly - but not exclusively - caused by an immunological conflict between maternal NK cells of the decidua and of the uterine junctional zone, and the HLA C antigens shared by interstitial trophoblast. The maternal disease is the consequence of the placental ischemia, and is characterized by an inflammatory syndrome with an oxidative stress and an endothelial cell dysfunction. Genetics play an essential part in each of these steps. PMID- 22196220 TI - Role of pyruvate dehydrogenase kinase 4 in regulating PDH activation during acute muscle contraction. AB - The oxidation of carbohydrates in mammals is regulated by the pyruvate dehydrogenase (PDH) complex, which is covalently regulated by four PDH kinases (PDK1-4) and two PDH phosphatases (PDP1-2) unique to the PDH complex. To investigate the role that PDK4 plays in regulating PDH activation (PDHa) during muscle contraction, mouse extensor digitorum muscle was removed from wild type (WT) and PDK4-knockout (PDK4-KO) mice after a 24 h fast and stimulated for 3 min either at 10 Hz (low-intensity contraction), 40 Hz (moderate-intensity contraction), or allowed to rest. Force was recorded and muscle PDHa activity and metabolite concentrations were measured. PDHa activity was ~2.5-fold higher at rest in PDK4-KO mice than WT mice (P = 0.009) and ~2-fold higher in PDK4-KO mice at both 10 Hz (P < 0.001) and 40 Hz (P < 0.001). Force relative to muscle weight was similar at 10 Hz, but was 5.8 +/- 0.7 mN.g(-1) in PDK4-KO mice and 3.5 +/- 0.7 mN.g(-1) in WT mice at 40 Hz (P < 0.001), with a similar rate of fatigue in both genotypes. From these results it was concluded that PDK4 plays a role in reducing PDHa activity during low to moderate-intensity muscle stimulation, and that absence of PDK4 and the subsequent changes in carbohydrate utilization may alter force production. PMID- 22196221 TI - A short bout of stair climbing-descending exercise attenuates postprandial hyperglycemia in middle-aged males with impaired glucose tolerance. AB - Exercise is a useful modality to ameliorate postprandial hyperglycemia. Here we show that a short bout (~6 min) of stair climbing-descending exercise (STAIR) starting at 90 min after meal accelerates the decrease in blood glucose concentrations in middle-aged sedentary men with impaired glucose tolerance, although STAIR is easy to perform and keeps the exercise intensity at a moderate level. PMID- 22196223 TI - Mechanisms of stem subsidence in femoral impaction allografting. AB - Failure of the femoral component of total hip arthroplasty is often accompanied by bone loss that can pose a significant challenge to the orthopaedic surgeon. Femoral impaction allografting has attractive potential for restoring bone stock in deficient femurs. However, there have been reports of problematic postoperative stem subsidence with this procedure. Subsidence is highly variable among patients, and there is disagreement over the mechanisms that cause it. This article reviews the various mechanisms that can contribute to subsidence in femoral impaction allografting. Variables such as graft density, cement penetration profile, use of synthetic graft substitutes, or other graft additives are discussed, as well as their potential impact on subsidence. Finally, recommendations are made for future studies aiming to reduce the risk of excessive subsidence in femoral impaction allografting. PMID- 22196222 TI - Encapsulated cell grafts to treat cellular deficiencies and dysfunction. AB - Cell transplantation provides a therapeutic alternative to whole organ transplantation in the management of diseases arising from the absence or failure of specialized cells. Though allogenic transplantation is favorable in terms of graft acceptance, xenotransplantation can provide a potentially unlimited source of cells and can overcome shortage of human donors. Effective immunoisolation of the xenografts is critical for their long term survival and function. Encapsulation of cells in polymeric matrices, organic or inorganic, provides a physical selectively permeable barrier between the host and the graft, thereby immunoisolating the graft. Microencapsulation of cells in alginate hydrogels has been pervasive, but this approach does not provide precise control over porosity, whereas micro- and nano-fabrication technologies can provide precise and reproducible control over porosity. We highlight both encapsulation approaches in this review, with their relative advantages and challenges. We also highlight the therapeutic potential of encapsulated cells for treating a variety of diseases, detailing the xenotransplantation of pancreatic islets in diabetes therapy as well as the grafting of engineered cells that facilitate localized enzyme-prodrug therapy of pancreatic cancer. PMID- 22196225 TI - Role of substrates in diabetes therapy: stem cell differentiation and islet transplantation. AB - Type 1 diabetes affects more than a million people in the United States and many more across the world. While pharmaceutical interventions and insulin supplementation are the most commonplace treatment of diabetes, these are not essentially cures and can potentially lead to long-term complications. Transplantation of insulin-producing Islets of Langerhans from donor pancreas has been established as a promising alternative to diabetes therapy. While successful islet transplantation has the potential of providing a cure, the primary hurdles to be overcome for it to be clinically viable are the scarcity of donor islets and immune rejection of transplanted islets. Recent advances in stem cell culture and differentiation techniques have established stem cells as a likely source of transplantable islets. Different stem cell sources have been induced toward pancreatic differentiation using specific chemical perturbations along with use of specific substrates. An approach to overcoming the second hurdle of immune rejection of transplantable islets is to encapsulate the islets in specific biomaterials. In this review, we discuss the extensive use of various substrates for pancreatic differentiation of different stem cell sources, along with different biomaterial designs used for islet transplantation. PMID- 22196227 TI - The challenge of prescribing drugs in older people. PMID- 22196224 TI - Advanced stoichiometric analysis of metabolic networks of mammalian systems. AB - Metabolic engineering tools have been widely applied to living organisms to gain a comprehensive understanding about cellular networks and to improve cellular properties. Metabolic flux analysis (MFA), flux balance analysis (FBA), and metabolic pathway analysis (MPA) are among the most popular tools in stoichiometric network analysis. Although application of these tools into well known microbial systems is extensive in the literature, various barriers prevent them from being utilized in mammalian cells. Limited experimental data, complex regulatory mechanisms, and the requirement of more complex nutrient media are some major obstacles in mammalian cell systems. However, mammalian cells have been used to produce therapeutic proteins, to characterize disease states or related abnormal metabolic conditions, and to analyze the toxicological effects of some medicinally important drugs. Therefore, there is a growing need for extending metabolic engineering principles to mammalian cells in order to understand their underlying metabolic functions. In this review article, advanced metabolic engineering tools developed for stoichiometric analysis including MFA, FBA, and MPA are described. Applications of these tools in mammalian cells are discussed in detail, and the challenges and opportunities are highlighted. PMID- 22196228 TI - Revisiting the general solubility equation: in silico prediction of aqueous solubility incorporating the effect of topographical polar surface area. AB - The General Solubility Equation (GSE) is a QSPR model based on the melting point and log P of a chemical substance. It is used to predict the aqueous solubility of nonionizable chemical compounds. However, its reliance on experimentally derived descriptors, particularly melting point, limits its applicability to virtual compounds. The studies presented show that the GSE is able to predict, to within 1 log unit, the experimental aqueous solubility (log S) for 81% of the compounds in a data set of 1265 diverse chemical structures (-8.48 < log S < 1.58). However, the predictive ability of the GSE is reduced to 75% when applied to a subset of the data (1160 compounds -6.00 < log S < 0.00), which discounts those compounds occupying the sparsely populated regions of data space. This highlights how sparsely populated extremities of data sets can significantly skew results for linear regression-based models. Replacing the melting point descriptor of the GSE with a descriptor which accounts for topographical polar surface area (TPSA) produces a model of comparable quality to the GSE (the solubility of 81% of compounds in the full data set predicted accurately). As such, we propose an alternative simple model for predicting aqueous solubility which replaces the melting point descriptor of the GSE with TPSA and hence can be applied to virtual compounds. In addition, incorporating TPSA into the GSE in addition to log P and melting point gives a three descriptor model that improves accurate prediction of aqueous solubility over the GSE by 5.1% for the full and 6.6% for the reduced data set, respectively. PMID- 22196229 TI - Investigating the relationship between in vitro-in vivo genotoxicity: derivation of mechanistic QSAR models for in vivo liver genotoxicity and in vivo bone marrow micronucleus formation which encompass metabolism. AB - Strategic testing as part of an integrated testing strategy (ITS) to maximize information and avoid the use of animals where possible is fast becoming the norm with the advent of new legislation such as REACH. Genotoxicity is an area where regulatory testing is clearly defined as part of ITS schemes. Under REACH, the specific information requirements depend on the tonnage manufactured or imported. Two types of test systems exist to meet these information requirements, in vivo genotoxicity assays, which take into account the whole animal, and in vitro assays, which are conducted outside the living mammalian organism using microbial or mammalian cells under appropriate culturing conditions. Clearly, with these different broad experimental categories, results for a given chemical can often differ, which presents challenges in the interpretation as well as in attempting to model the results in silico. This study attempted to compare the differences between in vitro and in vivo genotoxicity results, to rationalize these differences with plausible hypothesis in concert with available data. Two proof of concept (Q)SAR models were developed, one for in vivo genotoxicity effects in liver and a second for in vivo micronucleus formation in bone marrow. These "mechanistic models" will be of practical value in testing strategies, and both have been implemented into the TIMES software platform ( http://oasis-lmc.org ) to help predict the genotoxicity outcome of new untested chemicals. PMID- 22196231 TI - Social determinants of HIV/AIDS and sexually transmitted diseases among black women: implications for health equity. AB - Recent epidemiologic reports show that black women are at risk for HIV infection and other sexually transmitted diseases (STDs). In this report, we go beyond race and consider a number of social and economic trends that have changed the way many black women experience life. We discuss poverty, loss of status and support linked to declining marriage participation, and female-headed single-parent household structure-all of which influence sexual risks. We also discuss the Centers for Disease Control and Prevention-led national efforts to advance consideration of social determinants of health (SDH) and promotion of health equity in public health activities that may have impact on black and other women. PMID- 22196233 TI - An operationally adaptive system for rapid acoustic transmission loss prediction. AB - An operationally adaptive (OA) system for prediction of acoustic transmission loss (TL) in the atmosphere is developed in this paper. This system uses expert neural network predictors, each corresponding to a specific range of source elevation. The outputs of the expert predictors are combined using a weighting mechanism and a nonlinear fusion system. Using this prediction methodology the computational intractability of traditional acoustic propagation models is eliminated. The proposed system is tested on a synthetically generated acoustic data set for a wide range of geometric, source, environmental, and operational conditions. The results show a significant improvement in both accuracy and reliability over a benchmark prediction system. PMID- 22196234 TI - Move it or lose it? A survey of the aims of treatment when using passive movements in intensive care. AB - OBJECTIVES: To identify the aims of treatment when physiotherapists use passive movements (PMs) for ventilated and sedated patients on intensive care in the UK. METHOD: Postal questionnaires distributed to senior physiotherapists working within all National Health Service (NHS) trusts with open level 3 ICU beds. Open questionnaire items surveyed the aims of using PMs in different clinical areas (neurology, cardiology, orthopaedics/trauma, general surgery, medicine, other). RESULTS: The vast majority of respondents stated that the aim of using PMs was to maintain joint range of movement (ROM) in ventilated and sedated patients across all clinical areas. Respondents also identified additional uses of PMs for neurological patients. CONCLUSION: There appears to be a high level of consensus amongst physiotherapists that PMs influence joint range and that there will be a loss of range if PMs are not carried out. Currently this is not supported by empirical evidence. Therefore, future research should investigate the actual physiological effects of PMs and the clinical reasoning underpinning their use in critically ill patients. PMID- 22196235 TI - Single-molecule force spectroscopy from nanodiscs: an assay to quantify folding, stability, and interactions of native membrane proteins. AB - Single-molecule force spectroscopy (SMFS) can quantify and localize inter- and intramolecular interactions that determine the folding, stability, and functional state of membrane proteins. To conduct SMFS the membranes embedding the membrane proteins must be imaged and localized in a rather time-consuming manner. Toward simplifying the investigation of membrane proteins by SMFS, we reconstituted the light-driven proton pump bacteriorhodopsin into lipid nanodiscs. The advantage of using nanodiscs is that membrane proteins can be handled like water-soluble proteins and characterized with similar ease. SMFS characterization of bacteriorhodopsin in native purple membranes and in nanodiscs reveals no significant alterations of structure, function, unfolding intermediates, and strengths of inter- and intramolecular interactions. This demonstrates that lipid nanodiscs provide a unique approach for in vitro studies of native membrane proteins using SMFS and open an avenue to characterize membrane proteins by a wide variety of SMFS approaches that have been established on water-soluble proteins. PMID- 22196236 TI - Agonist-selective effects of opioid receptor ligands on cytosolic calcium concentration in rat striatal neurons. AB - BACKGROUND: Buprenorphine is an opioid receptor ligand whose mechanism of action is incompletely understood. METHODS: Using Ca(2+) imaging, we assessed the effects of buprenorphine, beta-endorphin, and morphine on cytosolic Ca(2+) concentration [Ca(2+)](i), in rat striatal neurons. RESULTS: Buprenorphine (0.01 1 MUM) increased [Ca(2+)](i) in a dose-dependent manner in a subpopulation of rat striatal neurons. The effect of buprenorphine was largely reduced by naloxone, a non-selective opioid receptor antagonist, but not by MU, kappa, delta or NOP selective antagonists. beta-Endorphin (0.1 MUM) increased [Ca(2+)](i) with a lower amplitude and slower time course than buprenorphine. Similar to buprenorphine, the effect of beta-endorphin was markedly decreased by naloxone, but not by opioid-selective antagonists. Morphine (0.1-10 MUM), did not affect [Ca(2+)](i) in striatal neurons. CONCLUSIONS: Our results suggest that buprenorphine and beta-endorphin act on a distinct type/subtype of plasmalemmal opioid receptors or activate intracellular opioid-like receptor(s) in rat striatal neurons. PMID- 22196240 TI - Structural characterizations of oligopyridyl foldamers, alpha-helix mimetics. AB - Protein-protein interactions are central to many biological processes, from intracellular communication to cytoskeleton assembly, and therefore represent an important class of targets for new therapeutics. The most common secondary structure in natural proteins is an alpha-helix. Small molecules seem to be attractive candidates for stabilizing or disrupting protein-protein interactions based on alpha-helices. In our study, we assessed the ability of oligopyridyl scaffolds to mimic the alpha-helical twist. The theoretical as well as experimental studies (X-ray diffraction and NMR) on conformations of bipyridines in the function of substituent and pyridine nitrogen positions were carried out. Furthermore, the experimental techniques showed that the conformations observed in bipyridines are maintained within a longer oligopyridyl scaffold (quaterpyridines). The alignment of the synthesized quaterpyridine with two methyl substituents showed that it is an alpha-helix foldamer; their methyl groups overlap very well with side chain positions, i and i + 3, of an ideal alpha-helix. PMID- 22196238 TI - Failure of available scoring systems to predict ongoing infection in patients with abdominal sepsis after their initial emergency laparotomy. AB - BACKGROUND: To examine commonly used scoring systems, designed to predict overall outcome in critically ill patients, for their ability to select patients with an abdominal sepsis that have ongoing infection needing relaparotomy. METHODS: Data from a RCT comparing two surgical strategies was used. The study population consisted of 221 patients at risk for ongoing abdominal infection. The following scoring systems were evaluated with logistic regression analysis for their ability to select patients requiring a relaparotomy: APACHE-II score, SAPS-II, Mannheim Peritonitis Index (MPI), MODS, SOFA score, and the acute part of the APACHE-II score (APS). RESULTS: The proportion of patients requiring a relaparotomy was 32% (71/221). Only 2 scores had a discriminatory ability in identifying patients with ongoing infection needing relaparotomy above chance: the APS on day 1 (AUC 0.61; 95%CI 0.52-0.69) and the SOFA score on day 2 (AUC 0.60; 95%CI 0.52-0.69). However, to correctly identify 90% of all patients needing a relaparotomy would require such a low cut-off value that around 80% of all patients identified by these scoring systems would have negative findings at relaparotomy. CONCLUSIONS: None of the widely-used scoring systems to predict overall outcome in critically ill patients are of clinical value for the identification of patients with ongoing infection needing relaparotomy. There is a need to develop more specific tools to assist physicians in their daily monitoring and selection of these patients after the initial emergency laparotomy. PMID- 22196242 TI - Surface energies of hydrophobic interaction chromatography media by inverse liquid chromatography. AB - Hydrophobicity of hydrophobic interaction chromatography media is currently ranked according to retention of reference proteins. A new method, suitable for porous media, is presented here to determine the surface energy and its Lifshitz van-der-Waals, Lewis acid and Lewis base contributions. The theory of van Oss has been adapted for data obtained by inverse liquid chromatography. Furthermore, this method is characterized by the independence of the determination of the phase ratio. The retention of probes with different molecular properties was used to calculate the surface energy and the Lifshitz-van-der-Waals as well as Lewis acid and Lewis base contributions to the surface energy. The media with polymethacrylate backbone had a higher surface energy (gamma ~ 200 mJ/m(2)) and Lifshitz-van-der-Waals contribution (gamma(LW) ~ 140 mJ/m(2)) than the agarose based media (gamma ~ 90-180 mJ/m(2) and gamma(LW) ~ 50-160 mJ/m(2)). PMID- 22196243 TI - Silanol suppressing potency of alkyl-imidazolium ionic liquids on C18 stationary phases. AB - Residual silanols on C18 columns yield undesirable slow-kinetics ion-exchange interactions with positively charged basic compounds that result in asymmetrical peaks, low efficiencies and long retention times. The purity of the silica employed as supporting material, and the technique used to form the bonded phase, which varies with the brand and manufacturer, give rise to different amounts of residual silanols in the packings, and consequently, different chromatographic performance. One of the most efficient and widespread strategies to reduce or even eliminate the different performance among columns is the addition of a reagent to the mobile phase to block the silanol sites. However, the intrinsic nature of both stationary phase and additive leads to particular results. In this work, a group of basic compounds were analysed using six C18 stationary phases (Zorbax SB-C18, X-Terra MS C18, Kromasil, Lichrospher, Nucleosil, and Spherisorb) and acetonitrile-water mixtures. Two ionic liquids (ILs), 1-butyl- and 1-hexyl-3 methyl-imidazolium tetrafluoroborates, were added to the mobile phases to evaluate their silanol suppressing potency, based on the decreased retention of the basic compounds when the silanols are blocked (described by the Horvath equation), and the improvement in peak profile (described by the plots of the peak half-widths at diverse retention times). The suppressing potency based on the retention can be misleading when the adsorption of the IL anion is not negligible, since the anion attracts the cationic basic compounds increasing the retention. However, the accessibility of basic compounds to the silanols is prevented by both IL cation and anion, improving the peak profiles for all stationary phases. This was especially remarkable for Spherisorb, which in the absence of additive yielded by far the worst performance. 1-Hexyl-3-methyl imidazolium tetrafluoroborate was the best additive in terms of retention and peak profile (width and asymmetry). PMID- 22196244 TI - Ammonium molybdophosphate impregnated alumina microspheres as a new generation sorbent for chromatographic 137Cs/(137m)Ba generator. AB - Barium-137m availed from a (137)Cs/(137m)Ba generator is an attractive industrial radiotracer for liquid flow rate measurement owing to its short half-life (T(1/2)=2.5 min) and emission of highly energetic gamma radiation (E(gamma)=661.7 keV). Ammonium molybdophosphate (AMP) impregnated alumina microspheres (AMP Al(2)O(3)), an engineered form of sorbent material was synthesized by Gel Entrapment Technique (GET). The utility of the material in the preparation of (137)Cs/(137m)Ba generator was evaluated. Various experimental parameters were optimized for efficient retention of (137)Cs and selective elution of (137m)Ba. A chromatographic 0.74 GBq (20 mCi) (137)Cs/(137m)Ba generator was developed using this material and its performance was evaluated for 6 months. Barium-137m could be eluted from the generator using 0.1 M NH(4)NO(3)+0.5 M HNO(3) solution with >80% yield and with acceptable radionuclidic purity suitable for industrial radiotracer investigations. PMID- 22196246 TI - Effect of NaCl additive on properties of aqueous PEG-sodium sulfate two-phase system. AB - The concentrations of all components in the phases of aqueous two-phase polyethylene glycol-sodium sulfate system of a fixed composition with different concentrations of NaCl additive were determined. Solvatochromic solvent features of aqueous media in the phases of all the systems were characterized in terms of solvent dipolarity/polarizability, solvent hydrogen bond donor acidity and hydrogen bond acceptor basicity. Partitioning of a homologous series of dinitrophenylated amino acids with aliphatic alkyl side chain was examined in all the systems, and the differences between the relative hydrophobicity and electrostatic properties of the phases were quantified. These differences were described in terms of solvatochromic solvent features of the phases. The previously reported partition coefficients of twelve different nonionic compounds in all the systems were expressed in terms of solute descriptors. It is demonstrated that two solvatochromic solvent descriptors (solvent dipolarity/polarizability, and solvent hydrogen bond donor acidity) could adequately describe the partitioning of the solutes in all the systems employed. PMID- 22196247 TI - Determination of octopamine and tyramine traces in dietary supplements and phytoextracts by high performance liquid chromatography after derivatization with 2,5-dimethyl-1H-pyrrole-3,4-dicarbaldehyde. AB - The use of 2,5-dimethyl-1H-pyrrole-3,4-dicarbaldehyde (DPD) as a pre-column derivatization reagent for HPLC (high performance liquid chromatography) analysis of octopamine (oct) and tyramine (tyr) is proposed. The compound reacts under mild conditions (2 min at ambient temperature) with primary amino groups. The derivatization conditions were optimized by considering different parameters (temperature, time and reagent concentration). The synthesized oct and tyr adducts were characterized by (1)H NMR (nuclear magnetic resonance), ESI-MS (electrospray ionization mass spectrometry), IR (infrared) and UV (ultraviolet). Derivative chromatographic separations were performed on a Sinergy Hydro-RP column (150 mm * 4.6 mm i.d.) using a mobile phase consisting of methanol and triethylammonium phosphate buffer (pH 3; 10mM) at varying composition gradient elution and at a flow rate of 0.8 mL/min. Detection was set at lambda=320 nm. The obtained results were compared with those achieved by a validated direct HPLC method with detection at lambda=275 nm using a Sinergy Polar-RP column (250 mm * 3 mm i.d.) by isocratic elution conditions with a mobile phase consisting of methanol/acetonitrile/sodium pentanesulphonate (SPS; pH 3; 10mM), 7.5:7.5:85 (v/v/v) at a flow rate of 0.3 mL/min. Derivatization method sensitivity proved to be ten times higher than direct method. Limit of detection of oct and tyr was 0.010 and 0.008 MUg/mL, respectively. The reliability of the pre-column method was satisfactory also in terms of linearity (from 0.028 to 1.255 and 0.024 to 1.244 MUg/mL for oct and tyr, respectively), precision (relative standard deviation <=2, without significant differences between intra-day and inter-day data) and recovery (from 98.9 to 101.2%). The proposed method showed to be suitable for a reliable determination of oct and tyr traces in commercially available phytoproducts using the instrumentation usually present in any analytical laboratory. PMID- 22196248 TI - Maternal leave policies and vaccination coverage: a global analysis. AB - Childhood vaccination is a proven and cost-effective way to reduce childhood mortality; however, participation in vaccination programs is not universal even where programs are free or low cost. Studies in diverse countries have reported work conflicts as limiting parents' ability to vaccinate their children. Using policy data for 185 UN member countries, we explore the hypothesis that an increased opportunity for parents to bring children to vaccination sites will translate into higher childhood vaccination rates. To do so, we use OLS regression to examine the relationship between the duration of adequately paid maternal leave and the uptake of vaccines. We find that a higher number of full time equivalent weeks of paid maternal leave is associated with higher childhood vaccination rates, even after controlling for GDP per capita, health care expenditures, and social factors. Further research is needed to assess whether this association is upheld in longitudinal and intervention studies, as well as whether other forms of leave such as paid leave to care for the health of family members is effective at increasing the ability of parents to bring children for needed preventive care. PMID- 22196249 TI - Taming troubled teens: the social production of mental morbidity amongst young mothers in Pelotas, Brazil. AB - Explanations for the association between teen-childbearing and subsequent mental morbidity vary considerably, from those based on neurological theories of development to those investigating underlying social and economic determinants. Based on longitudinal epidemiological and ethnographic sub-studies of the 1982 Pelotas birth cohort study, this paper explores the hypothesis that teen childbearing and subsequent mental morbidity have become associated through the interplay of culture, society, and biology in situations where teen pregnancy has become a stigmatised object of scientific and public health attention. Results show that the effect of teen childbearing on subsequent mental morbidity remained significant in the multivariate analysis. Ethnographic analysis, together with epidemiological effect modification analyses, suggest that this association is partially accounted for by the fact that it is more pronounced amongst a specific subgroup of women of low socio-economic status who, being more politicised about societal injustice, were also more critically engaged with - and thus troubled by - the inequitable institutionalisation of life-cycle transitions. With time, these women became highly critical of the institutionalised identification of early childbearing as a key violation of life-cycle norms and the differential class-based application of scientific knowledge on its causes and consequences. Public health campaigns should consider how the age-based institutionalisation of developmental norms has enabled the stigmatisation of those identified as transgressors. PMID- 22196250 TI - Emotion awareness and coping in children with functional abdominal pain: a controlled study. AB - Literature on somatization suggests that patients suffering from medically unexplained symptoms are less aware of their emotions and use maladaptive coping strategies when coping with everyday problems. In addition, coping is hypothesized to mediate between emotion awareness and medically unexplained symptoms. Scientific evidence for the relevance of this hypothesis for children with functional abdominal pain (FAP) is, however, lacking. Therefore, the purpose of the present study was to investigate this hypothesis in Dutch children with functional abdominal pain (FAP), aged 7-18 years. Between April 2007 and April 2010, a total of 114 referred children with FAP, 235 schoolchildren without abdominal pain and 407 schoolchildren with some abdominal pain (AP) of diverse etiology filled out questionnaires concerning their pain, emotion awareness and coping. MANOVA was used to investigate group differences in emotional awareness and coping. Structural equation modeling was used to investigate the mediational role of coping. The results showed that children with FAP scored significantly lower on most aspects of emotion awareness than children without AP, although these differences were small. Contrary to expectations, children with FAP were more aware of a link between emotions and bodily sensations than children without AP. As for coping, we found that children with FAP used avoidant coping more often than children without AP. Overall, children with FAP mostly did not differ in their emotional awareness and coping compared to children with some AP. Problem focused coping had a small mediating effect for two aspects of emotion awareness. We conclude that children with FAP show only small differences in emotion awareness and coping compared to children without AP, and are practically no different from children with some AP. Contrary to common belief, it can be questioned whether emotion awareness and general coping are useful targets for psychological treatments of FAP to focus on. PMID- 22196251 TI - Carbohydrate restricted diet in conjunction with metformin and liraglutide is an effective treatment in patients with deteriorated type 2 diabetes mellitus: Proof of-concept study. AB - BACKGROUND: Type 2 diabetes mellitus is a chronic progressive disease. During the course of the disease intensive treatment is often necessary resulting in multiple interventions including administration of insulin. Although dietary intervention is highly recommended, the clinical results of the widely prescribed diets with low fat content and high carbohydrates are disappointing. In this proof-of-concept study, we tested the effect of dietary carbohydrate-restriction in conjunction with metformin and liraglutide on metabolic control in patients with type 2 diabetes. METHODS: Forty patients with type 2 diabetes already being treated with two oral anti-diabetic drugs or insulin treatment and who showed deterioration of their glucose metabolism (i.e. HbA1c >7.5), were treated. A carbohydrate-restricted diet and a combination of metformin and liraglutide were instituted, after stopping either insulin or oral anti-diabetic drugs (excluding metformin). After enrollment, the study patients were scheduled for follow-up visits at one, two, three and six months. Primary outcome was glycemic control, measured by HbA1c at six months. Secondary outcomes were body weight, lipid profile and treatment satisfaction. RESULTS: Thirty-five (88%) participants completed the study. Nearly all participating patients experienced a drop in HbA1c and body weight during the first three months, an effect which was maintained until the end of the study at six months. Seventy-one percent of the patients reached HbA1c values below 7.0%. The range of body weight at enrollment was extreme, reaching 165 kg as the highest initial value. The average weight loss after 6 months was 10%. Most patients were satisfied with this treatment. During the intervention no significant change of lipids was observed. Most patients who were on insulin could maintain the treatment without insulin with far better metabolic control. CONCLUSIONS: Carbohydrate restriction in conjunction with metformin and liraglutide is an effective treatment option for patients with advanced diabetes who are candidates for instituting insulin or who are in need of intensified insulin treatment. This proof-of-principle study showed a significant treatment effect on metabolic control. PMID- 22196252 TI - A tribute to Professor John G. Farmer. PMID- 22196253 TI - High fat diet enhances cardiac abnormalities in SHR rats: Protective role of heme oxygenase-adiponectin axis. AB - BACKGROUND: High dietary fat intake is a major risk factor for development of cardiovascular and metabolic dysfunction including obesity, cardiomyopathy and hypertension. METHODS: The present study was designed to examine effect of high fat (HF) diet on cardio-vascular structure and function in spontaneously hypertensive rats (SHR), fed HF diet for 15 weeks, a phenotype designed to mimic metabolic syndrome. RESULTS: Development of metabolic syndrome like phenotype was confirmed using parameters, including body weight, total cholesterol and blood pressure levels. High fat diet impaired vascular relaxation by acetylcholine and exacerbated cardiac dysfunction in SHRs as evidenced by lower left ventricular function, and higher coronary resistance (CR) as compared to controls (p < 0.05). The histological examination revealed significant myocardial and peri-vascular fibrosis in hearts from SHRs on HF diet. This cardiac dysfunction was associated with increased levels of inflammatory cytokines, COX-2, NOX-2, TxB2 expression and increase in superoxide (O2-) levels in SHR fed a HF diet (p < 0.05). HO-1 induction via cobalt-protoporphyrin (CoPP,3 mg/kg), in HF fed rats, not only improved cardiac performance parameters, but also prevented myocardial and perivascular fibrosis. These effects of CoPP were accompanied by enhanced levels of cardiac adiponectin levels, pAMPK, peNOS and iNOS expression; otherwise significantly attenuated (p < 0.05) in HF fed SHRs. Prevention of such beneficial effects of CoPP by the concurrent administration of the HO inhibitor stannic mesoporphyrin (SnMP) corroborates the role of HO system in mediating such effects. CONCLUSION: In conclusion, this novel study demonstrates that up regulation of HO-1 improves cardiac and vascular dysfunction by blunting oxidative stress, COX-2 levels and increasing adiponectin levels in hypertensive rats on HF diet. PMID- 22196254 TI - The Food and Drug Administration's 2011 warning regarding adverse effects related to mesh implants for pelvic floor reconstruction--personal perspectives. PMID- 22196255 TI - AAGL practice report: practice guidelines for the diagnosis and management of endometrial polyps. AB - Endometrial polyps are a common gynecologic disease that may be symptomatic, with abnormal vaginal bleeding being the most common presentation. They may be found incidentally in symptom-free women investigated for other indications. Increasing age is the most important risk factor, with medications such as tamixifen also implicated. Specific populations at risk include women with infertility. Malignancy arising in polyps is uncommon, and specific risks for malignancy include increasing age and postmenopausal bleeding. Management may be conservative, with up to 25% of polyps regressing, particularly if less than 10 mm in size. Hysteroscopic polypectomy remains the mainstay of management, and there are no differences for outcomes in the modality of hysteroscopic removal. Symptomatic postmenopausal polyps should be excised for histologic assessment, and removal of polyps in infertile women improves fertility outcomes. Blind removal is not indicated where instrumentation for guided removal is available. Surgical risks associated with hysteroscopic polypectomy are low. PMID- 22196256 TI - Partial constriction of left infundibulopelvic ligament. PMID- 22196257 TI - Utero-ovarian vessel after uterine artery embolization. PMID- 22196258 TI - Laparoscopic surgery for endometrial cancer: why don't all patients go home the day after surgery? AB - STUDY OBJECTIVE: To identify risk factors for hospital length of stay (LOS) longer than 1 postoperative day in patients undergoing laparoscopic hysterectomy because of endometrial cancer. DESIGN: Retrospective observational study (Canadian Task Force classification II-2). SETTING: Tertiary-care university hospital. PATIENTS: One hundred thirty-three patients undergoing laparoscopic hysterectomy because of endometrial cancer between August 2006 and August 2010. INTERVENTIONS: One hundred thirty-three women underwent traditional laparoscopy. In 101 of these patients, lymph node sampling was performed. MEASUREMENTS AND MAIN OUTCOMES: Seventy-four women (55%) were discharged on postoperative day 1. The percentage of women discharged on postoperative day 1 (POD1) vs after POD 1 did not differ by extent of staging. Risk of perioperative complications was associated with hospital LOS longer than POD1 (odds ratio [OR], 11.45; 95% confidence interval [CI], 1.40-94.39). Procedure start time after 3:00 pm (OR, 3.20; 95% CI, 1.14-9.04) and procedure end time after 5:00 pm (OR, 2.47; 95% CI, 1.17-5.20) were independent factors associated with hospital LOS beyond POD1. There was a nonsignificant tendency toward later hospital discharge with administration of intravenous narcotic agents. CONCLUSIONS: Laparoscopic surgery to treat endometrial cancer should be preferentially scheduled early in the day to facilitate discharge on POD1. The extent of staging lymphadenectomy performed does not increase hospital stay beyond POD1. PMID- 22196259 TI - Laparoscopic extramucosal partial bladder resection in a patient with symptomatic deep-infiltrating endometriosis of the bladder. AB - Endometriosis is a complex disease, affecting the urinary tract, mainly the bladder, in 1% to 2% of cases. Thus far, partial cystectomy has been the treatment of choice for long-term relief of symptoms. Here, we describe the case of a 26-year-old patient with deep-infiltrating bladder endometriosis who was completely cured by laparoscopic extramucosal bladder resection. Diagnostic standards and factors affecting the rate of success for this additional option in endometriosis surgery are discussed. PMID- 22196260 TI - Colouterine fistula complicating diverticulitis diagnosed at hysteroscopy: case report. AB - Since Noecker first reported a colouterine fistula secondary to diverticulitis in 1929, about 20 cases have been reported in the literature. Methods for diagnosis have yet to be established. Herein we report the first case of a colouterine fistula at the level of the isthmus diagnosed at hysteroscopy. Diagnostic hysteroscopy enabled rapid diagnosis of the colouterine fistula. Diagnostic hysteroscopy is the first-choice diagnostic tool for investigation of any abnormal vaginal discharge such as blood or stool because it enables direct vision and biopsy of the lesions of the lower genital tract quickly and at low cost. PMID- 22196261 TI - Laparoscopic management of internal hernia of small intestine through a broad ligament defect. AB - Internal herniation through a defect in the broad ligament is a rare condition. A 42-year-old multiparous woman presented with a long-standing history of right sided abdominal pain. Laparoscopy revealed herniation of small bowel through a defect in the right broad ligament. The hernia was reduced, and the defect was corrected laparoscopically. The postoperative recovery was uneventful, and the previously persistent abdominal pain has resolved. PMID- 22196262 TI - Lymphatic-venous anastomosis for the radical cure of a large pelvic lymphocyst. AB - Therapeutic efficacy of lymphatic-venous anastomosis (LVA) has been shown, but expansion of the indication is desirable because LVA is a procedure with low invasiveness and is applicable over a wide area. This is the first reported case of intractable pelvic lymphocyst for which LVA was effective. LVA may be useful for pelvic lymphocyst at an early stage after cancer resection and lymph node dissection. PMID- 22196263 TI - Uterine artery embolization complicated by uterine perforation at the site of previous myomectomy. AB - A 46-year-old woman had an unusual complication from uterine myoma embolization by development of extensive necrosis with subsequent uterine perforation at the location of a previous myomectomy. We suggest that a scarred uterus may be a risk factor for uterine fibroid embolization complications, such as uterine necrosis. PMID- 22196264 TI - Leiomyoma recurrent at the cervical stump: report of two cases. AB - Although supracervical hysterectomy is an increasingly popular modality for surgical management of benign uterine conditions data exploring all of its consequences are still forth coming. This case report will discuss the scenario of leiomyoma recurrence at the cervical stump after supracervical hysterectomy. After supracervical hysterectomy, the remnant cervix has the potential for leiomyoma formation. Surgeons performing supracervical hysterectomy should be aware of this possible outcome. PMID- 22196265 TI - Letter to the editor. PMID- 22196267 TI - CEACAM1 in malignant melanoma: a diagnostic and therapeutic target. AB - CEACAM1 adhesion molecule is broadly expressed, participates in pivotal cellular and immunological processes and is involved in cancer. Originally identified as a tumor suppressor, it is now known that in several cancers, including malignant melanoma, CEACAM1 expression correlates with tumor progression and poor survival. Here we review the findings connecting CEACAM1 to malignant melanoma, encompassing in-vitro, in-vivo and patients-derived data. A CEACAM1-mediated mechanism used by melanoma cells to evade immune attack is described in detail. Finally, the potential value of CEACAM1 as a melanoma biomarker and therapeutic target is being discussed. PMID- 22196268 TI - The role of angiogenesis inhibitors in the management of melanoma. AB - Metastatic melanoma has a very poor prognosis and systemic therapies - both cytotoxic and biological - have not improved outcome in this disease so far. For this reason, novel therapeutic strategies are urgently required. Angiogenesis represents a relevant process to modulate in melanoma, as pro-angiogenic ligands and their receptors are overexpressed and have been found to correlate with disease progression and prognosis. The angiogenic axis may be targeted at many different levels, which are still being defined. This article presents an overview of the importance of angiogenesis in melanoma and draws attention to some of the key molecules that are currently being targeted rationally within clinical studies. We discuss a number of anti-angiogenic and anti-vascular agents and their mechanisms of action. An overview of the efficacy and toxicity of these treatments in clinical trials performed so far in melanoma is presented and future directions for anti-angiogenic strategies in melanoma are considered. PMID- 22196269 TI - Newly identified tumor antigens as promising cancer vaccine targets for malignant melanoma treatment. AB - Immunogenicity of tumour cells, immunomodulation and direct targeting of signalling pathways are promising avenues and matter of dated and innovative research in melanoma. Unfortunately, tumour cells are considered to be antigenic, but not immunogenic, either due to presentation of weakly recognized antigens or to the inability of the immune system to recognize them. However, spontaneous complete remission can be rarely observed in patients affected by melanoma, which are mainly attributed to the immune response against the tumour. Also, an elevated frequency of spontaneous humoral immune responses against tumour antigens was occasionally found in patients. These data confirm the existence of an interaction of the immune system with the tumour which can be used as a promising pathway for intervention and incorporates all portions of the immune system. The cancer immunotherapy approach is based on artificial activation of the immune system against the tumour and groups several types of treatments including immunization/vaccination but also modulation of immunity by cytokines or antibodies. Immunization approaches could either be based on undefined tumour antigens (e.g. whole tumour cells, tumour cell lysates, or tumour-antigen enriched fractions) or aimed at eliciting T-cell responses against specific tumour antigens. Novel and contemporary antigen-targeted therapy strategies, mainly directed to Cancer Testis and Heat Shock Proteins, leading to a possible active immunization against melanoma through T-cell specific activation, are discussed in this review. PMID- 22196270 TI - Ipilimumab targeting CD28-CTLA-4 axis: new hope in the treatment of melanoma. AB - Ipilimumab, a fully human monoclonal antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), is the new hope in the treatment of patients with advanced melanoma. Anti-CTLA-4 antibodies enhance T cell responses in vitro and in vivo and activate proliferation of tumour-specific T cells. The blockade of CTLA-4 by ipilimumab leads to immune-mediated tumor regression. Ipilimumab has been studied in metastatic melanoma in a number of clinical trials. Recently, a phase III, multi-center, randomized, double-blind trial showed a significant improvement in overall survival in patients with advanced melanomas treated with ipilimumab. Thus, ipilimumab was the first drug to demonstrate effect on overall survival in patients with metastatic melanoma. However, patients treated with ipilimumab develop various immune-related adverse events (irAEs), which are associated with objective and durable clinical responses. Use of new immune related response criteria is recommended in patients on ipilimumab therapy to avoid premature treatment discontinuation. Further research is necessary to elucidate role of ipilimumab in adjuvant setting as well as in synergy with other novel modalities for the treatment of metastatic melanoma. PMID- 22196272 TI - Editorial [hot topic: the medicinal chemistry of melanoma (guest editor: Marko Lens)]. PMID- 22196271 TI - Melphalan in regional chemotherapy for locally recurrent metastatic melanoma. AB - In-transit metastases occur in approximately 3% of melanoma patients, can be very symptomatic and survival in this group may be prolonged. Regional chemotherapy with melphalan delivered by isolated limb perfusion (ILP) or isolated limb infusion (ILI) are effective treatment options which are generally well tolerated. ILI is a less invasive and simpler alternative to ILP. ILI is tolerated better than ILP, though is probably less effective. Complete response rates are 45- 69% for ILP and 23-44% for ILI. The limb is often warmed to lower temperatures in ILI compared to ILP and the limb becomes progressively more hypoxic and acidotic during ILI, each of these parameters potentially having an effect on outcome. ILP & ILI are used primarily as palliative options when excision of in-transit metastases is unfeasible but can be used as an adjunctive procedure to surgery, for other tumour types such as merkel cell carcinoma, and can be repeated if indicated. For ILI correction of melphalan dose for ideal body weight has been shown to substantially decrease the rates of severe local toxicity while maintaining complete response rates, but overall response rate is reduced. Combination treatment with tumour necrosis factor alpha has been used with variable outcomes and new combinations with buthionine sulfoximine and ADH-1 are being investigated. PMID- 22196273 TI - siRNA based approaches in medicinal chemistry and drug discovery. PMID- 22196274 TI - siRNA delivery with lipid-based systems: promises and pitfalls. AB - A key hurdle for the further development of RNA interference (RNAi) therapeutics like small interfering RNA (siRNA) is their safe and effective delivery. Lipids are promising and versatile carriers because they are based on Nature's own building blocks and can be provided with properties which allow for protection of the siRNA, steric stabilization, targeting, membrane fusion and triggered drug release. At present a variety of lipid-based transfectants for siRNA delivery have been used for in vitro and in vivo purposes. The majority bears a cationic charge to electrostatically complex the siRNA into more hydrophobic lipoplexes, which promote passage of the siRNA across cellular membrane barriers, especially when lipids are added that facilitate membrane fusion. Despite these attractive features, siRNA delivery vehicles are facing a number of challenges such as the limited delivery efficiency in vivo, toxicity and non-specific stimulation of the immune system. To optimally design and tailor the lipidic systems for siRNA delivery, better insight is needed into the mechanisms of cell delivery. More specifically, further clarification is need regarding the nature of cell surface interactions, routes of internalization, passage of intracellular membranes, and mechanisms of immune activation. This review provides an overview of the main constituents currently employed in lipid-based siRNA carriers, and recent research into improvements of cell delivery. In addition, pitfalls related to immune activation and side effects are discussed, and possible ways to overcome them are highlighted. PMID- 22196275 TI - Matrix systems for siRNA delivery. AB - Over the last decade, considerable effort has been put in the implementation of RNA interference (RNAi) as a treatment for various disorders. As RNAi occurs in the cytoplasm of cells, it is imperative that RNAi mediators such as small interfering RNA (siRNA) cross several extracellular and intracellular barriers to reach this site of action. Among the extensive range of proposed delivery systems for siRNA, matrix systems possess interesting properties to promote the delivery of siRNA to a target tissue. In this review, a number of recently developed matrix and hybrid systems for siRNA delivery are discussed. PMID- 22196276 TI - Intracellular localization and routing of miRNA and RNAi pathway components. AB - Several different pathways, generally termed RNA silencing pathways, utilize small RNA molecules guiding sequence-specific silencing effects of ribonucleoprotein effector complexes, traditionally termed RNA-induced silencing complex (RISC). Three RNA silencing pathways were recognized in mammalian cells: RNA interference (RNAi), where short RNAs produced from long double-stranded RNA guide cleavage of cognate mRNAs, microRNA (miRNA) pathway, where endogenously encoded miRNAs typically induce translational repression, and piRNA pathway, where piRNAs (PIWI-associated RNAs) guide repression of repetitive sequences in the germline. Originally, RNAi and miRNA pathways were thought to act in the cytoplasm, however, there is a growing body of evidence that these pathways also have a nuclear component. This text reviews the current evidence concerning nuclear localization and function of miRNA and RNAi pathway components. We provide evidence that TRBP, Dicer and AGO2, proteins found in the RISC-loading complex (RLC) and RISC itself, are present in the nucleus. Nonetheless, fully functional RLC is not found in the nuclear compartment which is consistent with the recent findings obtained by Fluorescence Cross-Correlation Spectroscopy experiments illustrating that RISC is specifically loaded within the cytoplasm and shuttles subsequently between the nuclear and cytoplasmic compartment, thereby allowing small RNA gene regulation in both compartments. The function of nuclear TRBP and Dicer proteins remains elusive. We also discuss the consequences of nucleotide analogs introduced into siRNAs which can severely interfere with the natural cytoplasmic localization mediated by Exportin-5 which is required for efficient RISC loading in the cytoplasm. PMID- 22196277 TI - RNA interference-mediated validation of survivin and Apollon/BRUCE as new therapeutic targets for cancer therapy. AB - The ability to evade apoptosis is one of the defining hallmarks of cancer. It enables the survival of cancer cells under abnormal growth stimulation and mediates their increased resistance to treatment with cytotoxic drugs and radiation. Therefore, antiapoptotic proteins that counteract apoptosis signaling represent promising new therapeutic targets to impair cancer cell growth and enhance treatment response. As soon as RNA interference (RNAi) was demonstrated in mammalian cells, it rapidly became an essential tool for gene knockdown in preclinical models, making it possible to define the role of specific genes in the onset and progression of cancer and explore their potential as therapeutic targets. The present review summarizes the findings from studies relying on the use of RNAi-based approaches to functionally validate two members of the inhibitors of apoptosis protein family, survivin and Apollon/BRUCE, as new cancer therapeutic targets. Results collected thus far indicate that targeting the survivin network efficiently inhibits tumor growth potential and increases spontaneous and treatment-induced apoptosis of cancer cells. Based on these findings, the applicability of survivin-directed strategies for the clinical treatment of human tumors is currently under investigation. As regards Apollon/ BRUCE, although very preliminary, results of RNAi-mediated gene knockdown point to the possibility to significantly impair tumor cell proliferation through the induction of apoptosis. PMID- 22196278 TI - Polymeric carrier systems for siRNA delivery. AB - RNA interference is a technique to induce sequence-specific gene silencing, but is hampered by inefficient delivery of its mediator, short interfering RNA, into target cells. This review describes recent advances in siRNA delivery using polymeric carrier systems. Structural variations that have been applied to these polymers for optimizing their intracellular trafficking are discussed, as well as strategies for stabilization and targeting to diseased tissues in vivo. Recent findings have highlighted safety issues that need to be taken into account in the design of nanoparticles for clinical application. PMID- 22196280 TI - Hans Geiger-German physicist and the Geiger counter. PMID- 22196281 TI - Lymphangiomatosis and Gorham's Disease. PMID- 22196282 TI - Lymphatic Research and Biology. Special issue on lymphangiomatosis. Introduction. PMID- 22196283 TI - Lymphangiomatosis: clinical overview. AB - "Lymphangiomatosis" is a general term for excessive growth of aberrant lymphatic vessels. The impact of lymphangiomatosis can be devastating due to osteolysis and/or multi-organ involvement. The disorders are heterogeneous, and treatment is dependent upon disease location and symptoms. Most reports are single cases or small case series, predominantly in the orthopedic and radiologic literature. Basic research focused on lymphatic disorders may translate into new therapies for these disorders. PMID- 22196284 TI - Pulmonary lymphangiomatosis. AB - Lymphangiomatosis is a rare disease characterized by diffuse infiltration of lymphangiomas in the lung, bone, and other tissues. Due to its rarity, the spectrum of lymphangiomatosis is beginning to be elucidated based on case reports. The limited pathological, radiological, and clinical studies have shed light on this disease. Treatments have been tested in unblinded manner with promising results; however, further understanding of the pathogenesis of disease, as well as its natural history, is needed to facilitate drug development. PMID- 22196285 TI - Animal models for the mechanistic study of systemic lymphangiomatosis. AB - The systematic study of focused animal models has produced an explosion of information regarding the mechanisms governing lymphatic development and the diseases associated with lymphatic dysfunction. Nevertheless, the pathogenesis of systemic lymphangiomatosis has, thus far, eluded mechanistic comprehension. In this review, recent molecular advances in lymphatic vascular development are considered within the context of the animal models that have produced evolving insights. The emerging role of the zebrafish within lymphatic investigation is discussed. Specific models of the human disease pathology are considered in detail. While much has been learned about the molecular framework that surrounds normal lymphatic vascular development, the defect responsible for systemic lymphangiomatosis remains elusive. Development of more robust, recapitulative models will also be invaluable to investigate new and emerging therapeutics for the often devastating disease of systemic lymphangiomatosis. PMID- 22196286 TI - Progressive lymphangiomatosis and Gorham's disease: case report and clinical implications. AB - Lymphangiomatosis is a rare proliferative disorder of the lymphatic system. The etiology is unknown, rendering it difficult to manage. This case report of lymphangiomatosis with features of Gorham's disease reveals the progressive and unexpected nature of the condition. It highlights the need for further research into the pathophysiology and management of lymphangiomatosis as current treatment options are limited. PMID- 22196287 TI - Head and neck lymphatic tumors and bony abnormalities: a clinical and molecular review. AB - Lymphatic malformations and lymphatic-derived tumors commonly involve the head and neck, where they may be associated with bony abnormalities and other systemic symptoms. The reasons for the association between these disorders and local skeletal changes are largely unknown, but such changes may cause significant disease-related morbidity. Ongoing work in molecular and developmental biology is beginning to uncover potential reasons for the bony abnormalities found in head and neck lymphatic disease; this article summarizes current knowledge on possible mechanisms underlying this association. PMID- 22196289 TI - "How did this ever get published?". PMID- 22196290 TI - Commentary on "Duration of postoperative dressing after mini-open carpal tunnel release: a prospective, randomized trial". PMID- 22196291 TI - Remodeling potential of phalangeal distal condylar malunions in children. AB - PURPOSE: Distal condylar phalangeal (DCP) fractures in children are uncommon, but their periarticular location makes them problematic. Malunions are particularly difficult to treat. These fractures are generally thought to have a poor remodeling potential because their location is far from the phalangeal physis. We present 8 cases of DCP malunion in children with a mean 5-year follow-up demonstrating consistent remodeling. METHODS: In this study, DCP fractures were defined as those occurring at or distal to the collateral ligament recess of the proximal or middle phalanx in skeletally immature patients. Radiographic parameters examined at the time of established malunion and at final follow-up included coronal and sagittal plane deformity and translational malalignment of the distal fragment in relation to the proximal shaft. Range of motion was measured, and a brief questionnaire was implemented to establish patient satisfaction. RESULTS: We examined 8 patients with a minimum 1-year follow-up (mean, 5.3 y). Average age at injury was 8.8 years (range, 2-14 y). In the sagittal plane, fractures remodeled from an initial mean deformity of 30.9 degrees to 0.0 degrees ; in the coronal plane, from 10.5 degrees to 3.9 degrees . Fracture translation in the sagittal plane corrected, as well, from a mean 57.5% at injury to 0.0% at final follow-up. There was no functionally limiting loss of motion of the digit in any patient. Subjectively, only 2 patients complained of cosmetic deformity, both of which were coronal plane deformities of the small finger. CONCLUSIONS: In this case series, DCP malunions in children remodeled significantly and completely in the sagittal plane, and all patients had good final range of motion. Furthermore, patients were satisfied with nonsurgical treatment at long-term follow-up. This series describes the remodeling potential of DCP fractures in children, lending support to the previously reported cases. These findings support treating late-presenting pediatric DCP malunions nonsurgically. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 22196292 TI - Objective functional outcomes and patient satisfaction after silicone metacarpophalangeal arthroplasty for rheumatoid arthritis. AB - PURPOSE: Patient satisfaction is an essential measure of quality of care for rheumatoid arthritis. Prior research demonstrates that patient satisfaction improves after silicone metacarpophalangeal arthroplasty (SMPA) despite minimal change in hand function. The purpose of this study was to identify the level of objective functional recovery that yields satisfaction after SMPA. We hypothesized that measurable gains in objective hand function after SMPA will discriminate between satisfied and dissatisfied patients. METHODS: In this prospective, multicenter, cohort study, we observed 46 patients with rheumatoid arthritis and metacarpophalangeal (MCP) joint subluxation for 2 years after reconstructive surgery. We derived satisfaction scores from the Michigan Hand Outcomes Questionnaire, ranging from 0 (least satisfied) to 100 (most satisfied), and dichotomized them using the Cohen large effect size. We measured hand function at baseline and follow-up including strength (grip strength and pinch strength), finger position (extensor lag and ulnar drift), and MCP arc of motion. We constructed receiver operating characteristic curves to identify optimal cutoffs in hand function that correspond with satisfaction. RESULTS: At 2 years of follow-up, patients who achieved an extension lag of 30 degrees or less were considered satisfied, which represented a 52% improvement (preoperative lag = 63 degrees ). Similarly, patients who gained improvement in ulnar drift from an average of preoperatively 62 degrees to 9 degrees postoperatively were satisfied. Finally, patients who achieved an improvement in MCP arc of motion from an average of 21 degrees to 31 degrees postoperatively were satisfied. No improvements in grip or pinch strength corresponded with postoperative patient satisfaction. CONCLUSIONS: Patients were satisfied with only modest gains in grip and pinch strength after silicone metacarpophalangeal arthroplasty. However, maintaining finger position, without recurrence of ulnar drift or extensor lag, and MCP arc of motion corresponded with patient satisfaction in the postoperative period. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 22196293 TI - A randomized study comparing corticosteroid injection to corticosteroid iontophoresis for lateral epicondylitis. AB - PURPOSE: We designed a prospective, randomized study to evaluate the effects of iontophoresis delivery of dexamethasone versus corticosteroid injection therapy on patient outcomes. METHODS: We randomized 82 patients to 10 mg dexamethasone via iontophoresis using a self-contained patch with a 24-hour battery; 10 mg dexamethasone injection; or 10 mg triamcinolone injection. All patients received the same hand therapy protocol. Primary outcomes tracked were change in grip strength (flexion vs extension), pain, and function scores on a validated questionnaire. The secondary outcome was return-to-work status. Patients were evaluated at baseline, completion of physical therapy, and 6-month follow-up. RESULTS: The iontophoresis patients had statistically significant improvement in grip strength at the conclusion of hand therapy compared with baseline. They were also more likely to get back to work without restriction. By 6-month follow-up, all groups had equivalent results for all measured outcomes. CONCLUSIONS: Dexamethasone via iontophoresis produced short-term benefits because for this group grip strength and unrestricted return to work were significantly better. This study suggests that this iontophoresis technique for delivery of corticosteroid may be considered a treatment option for patients with lateral epicondylitis. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 22196294 TI - Commentary on "iontophoresis for the treatment of lateral epicondylitis of the elbow". PMID- 22196295 TI - The Apert hand--angiographic planning of a single-stage, 5-digit release for all classes of deformity. AB - PURPOSE: To demonstrate the utility of computed tomography angiographic planning of a single-stage, complete release of syndactyly in Apert syndrome. METHODS: Computed tomography angiograms were performed as a preoperative planning tool in 6 patients. Five came to surgery. All had a single-stage operation for complete release of their syndactyly. RESULTS: Five patients, ranging from Upton type 1 to type 3 Apert hand deformities, have had preoperative computed tomography angiography that delineated the vascular anatomy. This allowed planning and execution of a single-stage syndactyly release in all patients. The preoperative imaging identified noteworthy abnormalities in vascular anatomy that were incorporated into surgical planning. CONCLUSIONS: The protocol presented allows preoperative planning and single-stage operation for complete release of syndactyly in patients with Apert syndrome. PMID- 22196296 TI - The use of smartphones in hand surgery. PMID- 22196297 TI - Skin cancers of the hand and upper extremity. AB - Skin cancers represent the most common primary malignancies of the hand. They typically present as painless lesions on areas of high sun exposure, such as the dorsum of the hand and upper extremity. The most common malignancy is squamous cell carcinoma, followed by basal cell carcinoma and melanoma. The key to successful treatment is early and accurate diagnosis and treatment. Unlike open biopsies, which are indicated for deep soft tissue and bone lesions, biopsies for skin cancer can be performed under local anesthesia in the office setting in the form of shave or punch biopsies. A number of nonsurgical treatment options are available for treatment. However, when surgical excision is indicated, appropriate margin resections are dictated by the grade and stage of the malignancy. PMID- 22196298 TI - Conflicts of interest with the hand surgeon's relationship with industry. AB - Many advances in hand surgery have been supported and enabled by the integral relationship that exists between the profession of hand surgery and industry. This relationship takes many forms, including medical education, development of new technology and methodology, research, and opportunities for patient education. As with all of these endeavors, the primary focus of both the physician and industry must be the care of the patient. When a collaborative relationship exists between physicians and industry, a conflict of interest is present and must be recognized as such and managed to avoid any detriment to patient care. Although the hand surgeon, the patient, and industry share the common interest of advancement of patient care, there does exist real and potential conflicts of interest, which are unavoidable, but not necessarily undesirable. Multiple guidelines exist to govern relationships between industry and physicians. The cooperative relationship between the physician and industry is not only helpful, but it can be critical to the advancement of and innovations in patient care. When properly managed, collaboration between the physician and industry can effectively achieve the common goal of serving the best interest of the patient. PMID- 22196299 TI - Letter on "Wrist denervation for painful conditions of the wrist". PMID- 22196301 TI - Letter regarding "Influence of locking stitch size in a four-strand cross-locked cruciate flexor tendon repair". PMID- 22196303 TI - Letter regarding "Ligament reconstruction of the trapezial-metacarpal joint for early arthritis: a preliminary report". PMID- 22196306 TI - The characteristics and related influencing factors of ambulatory EEGs in patients seizure-free for 3-5 years. AB - OBJECTIVE: Epileptic patients have a higher relapse risk when EEGs before the initiation of anti-epileptic drug (AED) withdrawal show epileptiform activity. The purpose of this study is to assess the characteristics of ambulatory EEGs before the decision to withdraw AEDs and to clarify potential influencing factors for abnormal EEGs. METHODS: 214 epileptic patients were included in the study. These patients were seizure-free for 3-5 years on AED medication. Ambulatory 24-h EEGs were performed before the decision to withdraw AEDs. The demographical data and clinical information of the patients were used for the analysis of influencing factors for EEG findings. RESULTS: Ambulatory EEGs showed abnormalities in 41.1% of the patients (88/214). Of 88 patients with abnormal EEGs, 43 had unequivocal epileptic discharges; and 45 only had nonspecific EEG abnormalities. In our analysis, the potential factors for abnormal EEGs included female, delayed therapy, longer duration of intractability/treatment response time and medications failed. CONCLUSIONS: In many patients ambulatory EEGs remain abnormal even after seizure-free for 3-5 years; and many factors influenced the characteristics of the EEGs. The findings can assist in establishment of therapeutic principles. PMID- 22196307 TI - Olanzapine-associated myoclonus. AB - Olanzapine is an atypical antipsychotic drug that infrequently has been reported to cause seizures and myoclonus despite a small proconvulsant risk. This is the first report of generalized myoclonus induced in a patient who had been maintained on low dose olanzapine for over seven years without any change in her dose. Olanzapine was discontinued, and the myoclonic jerks completely resolved within 48 h. PMID- 22196308 TI - Extensions to regret-based decision curve analysis: an application to hospice referral for terminal patients. AB - BACKGROUND: Despite the well documented advantages of hospice care, most terminally ill patients do not reap the maximum benefit from hospice services, with the majority of them receiving hospice care either prematurely or delayed. Decision systems to improve the hospice referral process are sorely needed. METHODS: We present a novel theoretical framework that is based on well established methodologies of prognostication and decision analysis to assist with the hospice referral process for terminally ill patients. We linked the SUPPORT statistical model, widely regarded as one of the most accurate models for prognostication of terminally ill patients, with the recently developed regret based decision curve analysis (regret DCA). We extend the regret DCA methodology to consider harms associated with the prognostication test as well as harms and effects of the management strategies. In order to enable patients and physicians in making these complex decisions in real-time, we developed an easily accessible web-based decision support system available at the point of care. RESULTS: The web-based decision support system facilitates the hospice referral process in three steps. First, the patient or surrogate is interviewed to elicit his/her personal preferences regarding the continuation of life-sustaining treatment vs. palliative care. Then, regret DCA is employed to identify the best strategy for the particular patient in terms of threshold probability at which he/she is indifferent between continuation of treatment and of hospice referral. Finally, if necessary, the probabilities of survival and death for the particular patient are computed based on the SUPPORT prognostication model and contrasted with the patient's threshold probability. The web-based design of the CDSS enables patients, physicians, and family members to participate in the decision process from anywhere internet access is available. CONCLUSIONS: We present a theoretical framework to facilitate the hospice referral process. Further rigorous clinical evaluation including testing in a prospective randomized controlled trial is required and planned. PMID- 22196309 TI - The body configuration at step contact critically determines the successfulness of balance recovery in response to large backward perturbations. AB - The mechanical efficiency of stepping to recover balance can be expressed by a biomechanical model that includes the trunk inclination angle and the angle of the leg at the instant of stepping-foot contact. The aim of the present study was to test the hypothesis that this model would accurately predict the successfulness of recovery attempts (recovery vs. falls) following large backward perturbations. Ten young participants were exposed to a series of 12 very large postural perturbations in the backward direction by means of a support-surface translation. At the instant of stepping-foot contact, we calculated the trunk inclination angle and the angle of the stepping leg with the vertical. Reaction time, step duration, step velocity and step length were also determined. A logistic regression analysis revealed that the model with leg and trunk inclination angles accurately predicted successful recovery, with a more forward tilted trunk and a further backward positioned leg increasing the probability of success. The set of spatiotemporal step variables was significantly less predictive. Over the course of the experiment, participants gradually became more successful in recovering balance, which coincided with an increase in leg but not in trunk angles. In conclusion, the body configuration at the instant of first stepping-foot contact accurately predicted successful balance recovery after a backward postural perturbation. Given the observation that participants improved their performance by increasing their leg angles, which suggests that it may be easier to improve this variable, compared to the trunk angle, by exercise interventions. PMID- 22196311 TI - Depressive disorders and the menopause transition. AB - AIM: Depressive disorders and symptoms are common among middle-aged women. The effects of hormones on depression remain unclear. This review aims to clarify the nature of depressive disorders during the menopause transition as well as their links with climacteric syndrome, sexuality, cardiovascular risk and cognitive function. MATERIAL AND METHODS: The recent literature on depressive disorders and menopause is reviewed. RESULTS AND CONCLUSIONS: Women are more vulnerable than men to depressive disorders. Endocrine influences have been postulated but differences in, for example, coping style and response to stress may also contribute to the gender difference in the prevalence of depressive disorders. Gender differences in socialization may lead to higher rates of depression in women. There are data top suggest that menopause and depression are associated, although there is not a common clear causative factor. Women with climacteric symptoms (hot flushes, night sweats, vaginal dryness and dyspareunia) are more likely to report anxiety and/or depressive symptoms. Bothersome vasomotor symptoms could be associated with sleep disturbances, which in turn can increase reports of anxiety and depressive symptoms. Biopsychosocial and partner factors have a significant influence on middle-aged women's sexuality and depressive disorders, and most antidepressants can have a negative effect on sexual response. Lastly, studies have consistently shown that women with high levels of depressive symptoms are at greater cardiovascular risk and have poorer cognitive function than non-depressed women. At present, a direct relationship between psychiatric symptoms and hormonal changes such as estrogen decrease has not been clearly found. Stress, educational level, ethnicity, socioeconomic factors and partner status may influence the prevalence and clinical course of both menopause symptoms and depressive disorders. Since in many cases depression is a lifelong condition, and is associated with severe comorbid conditions, further studies are needed to improve the early diagnosis of depression; it may be advisable to monitor a woman's mental health during the menopause transition to prevent a depressive disorder having long-term negative consequences. PMID- 22196312 TI - An update on selective estrogen receptor modulators for the prevention and treatment of osteoporosis. AB - Several selective estrogen receptor modulators are in clinical development for postmenopausal osteoporosis. Bazedoxifene has shown significant reductions in vertebral and non-vertebral (in higher-risk women) fracture risk, with no evidence of breast or endometrial stimulation. Lasofoxifene has demonstrated significant reductions in vertebral and non-vertebral fracture risk, but has been associated with endometrial/uterine effects. Both selective estrogen receptor modulators were generally safe and well tolerated but have been associated with some "class effects" (e.g., hot flushes, venous thromboembolic events). A tissue selective estrogen complex partnering bazedoxifene with conjugated estrogens is under clinical investigation for the treatment of menopausal symptoms and osteoporosis prevention. Future directions in selective estrogen receptor modulator research include ospemifene and RAD 1901. PMID- 22196314 TI - Experts' recommendations for treating maladaptive aggression in youth. AB - BACKGROUND: Psychiatric treatment for children and adolescents with clinically significant aggression is common and often involves the use of antipsychotic medications. Increasingly, pediatricians are initiating or managing such treatments despite limited evidence on optimal diagnostic, psychosocial, and medication approaches for pediatric aggression. AIMS: The objective of this study was to gather clinicians' and researchers' expertise concerning the treatment of maladaptive aggression, using expert consensus survey methods to aid the development of guidelines for pediatricians and psychiatrists on the outpatient treatment of maladaptive aggression in youth (T-MAY). METHODS: Forty-six experts (psychiatrists, pediatricians, and researchers) with >10 years of clinical and/or research experience in the treatment of pediatric aggression completed a 27-item survey (>400 treatment alternatives) about optimal diagnostic, psychosocial, and medication treatments. Data were analyzed using descriptive statistics and confidence intervals. RESULTS: Expert consensus methodology clearly differentiated optimal versus nonoptimal treatment strategies for maladaptive aggression. In contrast to current practice trends, results indicated that experts support the use of psychosocial interventions and parent education and training before the use of medication for maladaptive aggression at every stage of medication treatment, from diagnosis to maintenance to medication discontinuation. CONCLUSION: Overall findings indicate that evidence-informed strategies for outpatient treatment of pediatric maladaptive aggression, guided by systematically derived expert opinions, are attainable. In light of the gap between the research literature and clinical practice, expert consensus opinion supports specific practices for optimal outpatient management in children and adolescents with severe and persistent behavioral difficulties. PMID- 22196315 TI - Pharmacotherapy and academic achievement among children with attention deficit/hyperactivity disorder. AB - This study examined the association of pharmacological treatments and academic achievement among children with attention-deficit/hyperactivity disorder (ADHD). Results examining the association of pharmacological treatments and academic achievement among children with ADHD are mixed. Our objective was to examine this association using structural equation modeling (SEM) techniques, which may be considered more sophisticated and advanced over traditional regression techniques. To achieve the purpose, we employed a sample of children with ADHD derived from the Early Childhood Longitudinal Study-Kindergarten (ECLS-K) data. The ECLS-K provides a large, community-based, nationally representative sample of children to examine across time with respect to academic achievement outcomes. The present study reveals a statistically nonsignificant association between pharmacological treatment and academic achievement among children with ADHD. These results derived from a large, community-based, nationally representative sample, using SEM techniques, may be considered highly generalizable. PMID- 22196318 TI - Fragile X syndrome and attention-deficit/hyperactivity disorder symptoms. PMID- 22196322 TI - De novo CNVs in bipolar disorder: recurrent themes or new directions? AB - In this issue of Neuron, Malhotra and colleagues report an enrichment of de novo copy number variants in bipolar disorder and schizophrenia when compared with those of controls. The study highlights the importance of a genetic model involving rare and disruptive variants to further our understanding of complex neuropsychiatric traits. PMID- 22196323 TI - Observations on clustered synaptic plasticity and highly structured input patterns. AB - In this issue of Neuron, Makino and Malinow and Kleindienst et al. present evidence of a behaviorally induced form of synaptic plasticity that would encourage the development of fine-scale structured input patterns and the binding of features within single neurons. PMID- 22196324 TI - Exploring the next frontier of mouse vision. AB - Two studies in this issue of Neuron apply in vivo functional imaging techniques to map out and record from mouse extrastriate visual cortex. They find that distinct areas show hallmarks of processing for different types of visual input and provide a promising path forward to investigate how complex image analysis is performed in the mouse visual system. PMID- 22196325 TI - A role for phasic dopamine neuron firing in habit learning. AB - In this issue of Neuron, Wang et al. (2011) show that mice with dopamine neuron specific NMDAR1 deletion have attenuated phasic dopamine neuron firing and a deficit in habit learning. These findings indicate that brain regions sensitive to phasic dopamine signals may underlie habit learning. PMID- 22196326 TI - The trouble with sex differences. AB - Sex differences in the brain are real and clinically important but often grossly distorted in popular discourse. Considering the public's deep fascination with sex difference research and its impact on issues from mental health to education and workplace equity, neuroscientists should pay greater heed to its misappropriation and to studying how gender enculturation shapes neural function. PMID- 22196327 TI - Sodium leak channels in neuronal excitability and rhythmic behaviors. AB - Extracellular K+, Na+, and Ca2+ ions all influence the resting membrane potential of the neuron. However, the mechanisms by which extracellular Na+ and Ca2+ regulate basal neuronal excitability are not well understood. Recent findings suggest that NALCN, in association with UNC79 and UNC80, contributes a basal Na+ leak conductance in neurons. Mutations in Nalcn, Unc79, or Unc80 lead to severe phenotypes that include neonatal lethality and disruption in rhythmic behaviors. This review discusses the properties of the NALCN complex, its regulation, and its contribution to neuronal function and animal behavior. PMID- 22196329 TI - A hippocampal marker of recollection memory ability among healthy young adults: contributions of posterior and anterior segments. AB - The hippocampus is known to support recollection memory, but the relation between its structure and recollection in healthy adults has not been established. Here we show that the hippocampus (including subiculum, DG, and CA1-CA4), when separated into posterior and anterior segments, can reliably predict recollection in healthy young adults. Better memory was associated with larger posterior and smaller anterior segments, as evaluated relative to the uncal apex. Overall hippocampal volume, however, did not predict memory. This pattern was confirmed in four separate data sets from different studies and laboratories. The relationship between the posterior hippocampus and memory was mediated by the structure's functional connectivity with a neocortical network identified during a postencoding resting-state scan. The relationship was also weakest in an experiment involving no appreciable study-test interval. These findings suggest that enhanced posterior-hippocampal postencoding processes may account for the memory benefit associated with larger posterior hippocampi. PMID- 22196328 TI - A behavioral framework to guide research on central auditory development and plasticity. AB - The auditory CNS is influenced profoundly by sounds heard during development. Auditory deprivation and augmented sound exposure can each perturb the maturation of neural computations as well as their underlying synaptic properties. However, we have learned little about the emergence of perceptual skills in these same model systems, and especially how perception is influenced by early acoustic experience. Here, we argue that developmental studies must take greater advantage of behavioral benchmarks. We discuss quantitative measures of perceptual development and suggest how they can play a much larger role in guiding experimental design. Most importantly, including behavioral measures will allow us to establish empirical connections among environment, neural development, and perception. PMID- 22196330 TI - A Cre-dependent, anterograde transsynaptic viral tracer for mapping output pathways of genetically marked neurons. AB - Neurotropic viruses that conditionally infect or replicate in molecularly defined neuronal subpopulations, and then spread transsynaptically, are powerful tools for mapping neural pathways. Genetically targetable retrograde transsynaptic tracer viruses are available to map the inputs to specific neuronal subpopulations, but an analogous tool for mapping synaptic outputs is not yet available. Here we describe a Cre recombinase-dependent, anterograde transneuronal tracer, based on the H129 strain of herpes simplex virus (HSV). Application of this virus to transgenic or knockin mice expressing Cre in peripheral neurons of the olfactory epithelium or the retina reveals widespread, polysynaptic labeling of higher-order neurons in the olfactory and visual systems, respectively. Polysynaptic pathways were also labeled from cerebellar Purkinje cells. In each system, the pattern of labeling was consistent with classical circuit-tracing studies, restricted to neurons, and anterograde specific. These data provide proof-of-principle for a conditional, nondiluting anterograde transsynaptic tracer for mapping synaptic outputs from genetically marked neuronal subpopulations. PMID- 22196331 TI - High frequencies of de novo CNVs in bipolar disorder and schizophrenia. AB - While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 [1.4,16.0], p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 [1.7,22.6], p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 [1.5,16.8], p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases. PMID- 22196332 TI - insomniac and Cullin-3 regulate sleep and wakefulness in Drosophila. AB - In a forward genetic screen in Drosophila, we have isolated insomniac, a mutant that severely reduces the duration and consolidation of sleep. Anatomically restricted genetic manipulations indicate that insomniac functions within neurons to regulate sleep. insomniac expression does not oscillate in a circadian manner, and conversely, the circadian clock is intact in insomniac mutants, suggesting that insomniac regulates sleep by pathways distinct from the circadian clock. The protein encoded by insomniac is a member of the BTB/POZ superfamily, which includes many proteins that function as adaptors for the Cullin-3 (Cul3) ubiquitin ligase complex. We show that Insomniac can physically associate with Cul3, and that reduction of Cul3 activity in neurons recapitulates the insomniac phenotype. The extensive evolutionary conservation of insomniac and Cul3 suggests that protein degradation pathways may have a general role in governing the sleep and wakefulness of animals. PMID- 22196333 TI - Role for mTOR signaling and neuronal activity in morphine-induced adaptations in ventral tegmental area dopamine neurons. AB - While the abuse of opiate drugs continues to rise, the neuroadaptations that occur with long-term drug exposure remain poorly understood. We describe here a series of chronic morphine-induced adaptations in ventral tegmental area (VTA) dopamine neurons, which are mediated via downregulation of AKT-mTORC2 (mammalian target of rapamycin complex-2). Chronic opiates decrease the size of VTA dopamine neurons in rodents, an effect seen in humans as well, and concomitantly increase the excitability of the cells but decrease dopamine output to target regions. Chronic morphine decreases mTORC2 activity, and overexpression of Rictor, a component of mTORC2, prevents morphine-induced changes in cell morphology and activity. Further, local knockout of Rictor in VTA decreases DA soma size and reduces rewarding responses to morphine, consistent with the hypothesis that these adaptations represent a mechanism of reward tolerance. Together, these findings demonstrate a novel role for AKT-mTORC2 signaling in mediating neuroadaptations to opiate drugs of abuse. PMID- 22196334 TI - The pore of the voltage-gated proton channel. AB - In classical tetrameric voltage-gated ion channels four voltage-sensing domains (VSDs), one from each subunit, control one ion permeation pathway formed by four pore domains. The human Hv1 proton channel has a different architecture, containing a VSD, but lacking a pore domain. Since its location is not known, we searched for the Hv permeation pathway. We find that mutation of the S4 segment's third arginine R211 (R3) compromises proton selectivity, enabling conduction of a metal cation and even of the large organic cation guanidinium, reminiscent of Shaker's omega pore. In the open state, R3 appears to interact with an aspartate (D112) that is situated in the middle of S1 and is unique to Hv channels. The double mutation of both residues further compromises cation selectivity. We propose that membrane depolarization reversibly positions R3 next to D112 in the transmembrane VSD to form the ion selectivity filter in the channel's open conformation. PMID- 22196335 TI - Compartmentalized versus global synaptic plasticity on dendrites controlled by experience. AB - Synapses in the brain are continuously modified by experience, but the mechanisms are poorly understood. In vitro and theoretical studies suggest threshold lowering interactions between nearby synapses that favor clustering of synaptic plasticity within a dendritic branch. Here, a fluorescently tagged AMPA receptor based optical approach was developed permitting detection of single-synapse plasticity in mouse cortex. Sensory experience preferentially produced synaptic potentiation onto nearby dendritic synapses. Such clustering was significantly reduced by expression of a phospho-mutant AMPA receptor that is insensitive to threshold-lowering modulation for plasticity-driven synaptic incorporation. In contrast to experience, sensory deprivation caused homeostatic synaptic enhancement globally on dendrites. Clustered synaptic potentiation produced by experience could bind behaviorally relevant information onto dendritic subcompartments; global synaptic upscaling by deprivation could equally sensitize all dendritic regions for future synaptic input. PMID- 22196336 TI - Activity-dependent clustering of functional synaptic inputs on developing hippocampal dendrites. AB - During brain development, before sensory systems become functional, neuronal networks spontaneously generate repetitive bursts of neuronal activity, which are typically synchronized across many neurons. Such activity patterns have been described on the level of networks and cells, but the fine-structure of inputs received by an individual neuron during spontaneous network activity has not been studied. Here, we used calcium imaging to record activity at many synapses of hippocampal pyramidal neurons simultaneously to establish the activity patterns in the majority of synapses of an entire cell. Analysis of the spatiotemporal patterns of synaptic activity revealed a fine-scale connectivity rule: neighboring synapses (<16 MUm intersynapse distance) are more likely to be coactive than synapses that are farther away from each other. Blocking spiking activity or NMDA receptor activation revealed that the clustering of synaptic inputs required neuronal activity, demonstrating a role of developmentally expressed spontaneous activity for connecting neurons with subcellular precision. PMID- 22196337 TI - Functional specialization of mouse higher visual cortical areas. AB - The mouse is emerging as an important model for understanding how sensory neocortex extracts cues to guide behavior, yet little is known about how these cues are processed beyond primary cortical areas. Here, we used two-photon calcium imaging in awake mice to compare visual responses in primary visual cortex (V1) and in two downstream target areas, AL and PM. Neighboring V1 neurons had diverse stimulus preferences spanning five octaves in spatial and temporal frequency. By contrast, AL and PM neurons responded best to distinct ranges of stimulus parameters. Most strikingly, AL neurons preferred fast-moving stimuli while PM neurons preferred slow-moving stimuli. By contrast, neurons in V1, AL, and PM demonstrated similar selectivity for stimulus orientation but not for stimulus direction. Based on these findings, we predict that area AL helps guide behaviors involving fast-moving stimuli (e.g., optic flow), while area PM helps guide behaviors involving slow-moving objects. PMID- 22196338 TI - Functional specialization of seven mouse visual cortical areas. AB - To establish the mouse as a genetically tractable model for high-order visual processing, we characterized fine-scale retinotopic organization of visual cortex and determined functional specialization of layer 2/3 neuronal populations in seven retinotopically identified areas. Each area contains a distinct visuotopic representation and encodes a unique combination of spatiotemporal features. Areas LM, AL, RL, and AM prefer up to three times faster temporal frequencies and significantly lower spatial frequencies than V1, while V1 and PM prefer high spatial and low temporal frequencies. LI prefers both high spatial and temporal frequencies. All extrastriate areas except LI increase orientation selectivity compared to V1, and three areas are significantly more direction selective (AL, RL, and AM). Specific combinations of spatiotemporal representations further distinguish areas. These results reveal that mouse higher visual areas are functionally distinct, and separate groups of areas may be specialized for motion related versus pattern-related computations, perhaps forming pathways analogous to dorsal and ventral streams in other species. PMID- 22196340 TI - Multifocal attention filters targets from distracters within and beyond primate MT neurons' receptive field boundaries. AB - Visual attention has been classically described as a spotlight that enhances the processing of a behaviorally relevant object. However, in many situations, humans and animals must simultaneously attend to several relevant objects separated by distracters. To account for this ability, various models of attention have been proposed including splitting of the attentional spotlight into multiple foci, zooming of the spotlight over a region of space, and switching of the spotlight among objects. We investigated this controversial issue by recording neuronal activity in visual area MT of two macaques while they attended to two translating objects that circumvented a third distracter object located inside the neurons' receptive field. We found that when the attended objects passed through or nearby the receptive field, neuronal responses to the distracter were either decreased or remained unaltered. These results demonstrate that attention can split into multiple spotlights corresponding to relevant objects while filtering out interspersed distracters. PMID- 22196339 TI - NMDA receptors in dopaminergic neurons are crucial for habit learning. AB - Dopamine is crucial for habit learning. Activities of midbrain dopaminergic neurons are regulated by the cortical and subcortical signals among which glutamatergic afferents provide excitatory inputs. Cognitive implications of glutamatergic afferents in regulating and engaging dopamine signals during habit learning, however, remain unclear. Here, we show that mice with dopaminergic neuron-specific NMDAR1 deletion are impaired in a variety of habit-learning tasks, while normal in some other dopamine-modulated functions such as locomotor activities, goal-directed learning, and spatial reference memories. In vivo neural recording revealed that dopaminergic neurons in these mutant mice could still develop the cue-reward association responses; however, their conditioned response robustness was drastically blunted. Our results suggest that integration of glutamatergic inputs to DA neurons by NMDA receptors, likely by regulating associative activity patterns, is a crucial part of the cellular mechanism underpinning habit learning. PMID- 22196341 TI - Altered low-gamma sampling in auditory cortex accounts for the three main facets of dyslexia. AB - It has recently been conjectured that dyslexia arises from abnormal auditory sampling. What sampling rate is altered and how it affects reading remains unclear. We hypothesized that by impairing phonemic parsing abnormal low-gamma sampling could yield phonemic representations of unusual format and disrupt phonological processing and verbal memory. Using magnetoencephalography and behavioral tests, we show in dyslexic subjects a reduced left-hemisphere bias for phonemic processing, reflected in less entrainment to ~30 Hz acoustic modulations in left auditory cortex. This deficit correlates with measures of phonological processing and rapid naming. We further observed enhanced cortical entrainment at rates beyond 40 Hz in dyslexics and show that this particularity is associated with a verbal memory deficit. These data suggest that a single auditory anomaly, i.e., phonemic oversampling in left auditory cortex, accounts for three main facets of the linguistic deficit in dyslexia. PMID- 22196342 TI - Activity of polymyxin B and the novel polymyxin analogue CB-182,804 against contemporary Gram-negative pathogens in New York City. AB - Multidrug-resistant Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa have become common in many regions, often requiring therapy with colistin or polymyxin B. An increase in resistance to these agents would render many infections untreatable. We tested the activity of polymyxin B and the novel polymyxin analogue CB-182,804 against over 5,000 recent Gram negative clinical isolates from New York City, a region with a high prevalence of multiresistant strains. Over 96% of Escherichia coli, K. pneumoniae, A. baumannii, and P. aeruginosa were susceptible to polymyxin B; only 76% of Enterobacter spp. was susceptible. The MICs of CB-182,804 were generally two-fold higher than polymyxin B and cross-resistance was observed. The addition of rifampin resulted in synergistic inhibition and bactericidal activity in time kill studies, and restored activity against all polymyxin-resistant strains. The synergistic effect of the combination with rifampin was most pronounced against A. baumannii strains, and was slightly greater with CB-182,804 than with polymyxin B against K. pneumoniae and Enterobacter spp. Despite considerable usage of polymyxin B and colistin in this region, polymyxin B retains excellent activity against most Gram-negative isolates. CB-182,804 shows similar activity, particularly when combined with rifampin. The clinical utility of CB-182,804 remains to be determined. PMID- 22196343 TI - Effect of support and pre-treatment conditions on Pt-Sn catalysts: application to nitrate reduction in water. AB - The effect of the support (activated carbon or titanium dioxide) on the catalytic activity and selectivity to nitrogen of Pt-Sn catalysts in nitrate reduction was studied. The effects of the preparation conditions and the Pt:Sn atomic ratio were also evaluated. It was observed that the support plays an important role in nitrate reduction and that different preparation conditions lead to different catalytic activities and selectivities. Generally, the catalysts supported on activated carbon were less active but more selective to nitrogen than those supported on titanium dioxide. The monometallic Pt catalyst is active for nitrate reduction only when supported on titanium dioxide, which is explained by the involvement of the support in the reaction mechanism. The catalysts were characterized by different techniques, and significant changes on metal chemical states were observed for the different preparation conditions used. Only metallic Pt and oxidized Sn were observed at low calcination and reduction temperatures, but some metallic Sn was also present when high temperatures were used, being also possible the formation of Pt-Sn alloys. PMID- 22196344 TI - Preparation of trimethylchlorosilane-modified acid vermiculites for removing diethyl phthalate from water. AB - A hybrid organic-inorganic material based on vermiculite was prepared to remove diethyl phthalate (DEP) from aqueous solution. Natural vermiculite was activated with HCl to improve the specific surface area and was then modified by silanization using trimethylchlorosilane. Organovermiculite prepared by ion exchange with hexadecyl trimethylammonium bromide (HDTMAB) was also tested for comparison. The leaching of 2 mol L(-1) HCl at 80 degrees C increased the specific surface area of vermiculite from 14.4 to 500.0m(2)g(-1), and the average pore-diameter was decreased from 7.90 nm to 2.75 nm. Fourier transform infrared spectroscopy (FTIR) spectra indicated that trimethysilyl groups were grafted covalently on the surface of acid vermiculites. The specific surface area of trimethylchlorosilane-modified acid vermiculites (TMAVs) (355.4 m(2) g(-1)) was much larger than that of organovermiculite (6.0 m(2) g(-1)). The isotherm adsorption experiments of DEP showed that TMAVs exhibited linear isotherms, suggesting that the uptake of DEP was controlled by partitioning mechanism. The maximal partition coefficient (K(d)) of TMAVs was 3.1 times higher than that of organovermiculite, implying that TMAVs had stronger organic affinity than organovermiculite. The results demonstrate that the adsorption capacity and mechanism of organoclays were controlled by the specific surface area and organic loading, whereas the length of alkyl chain of organic modifier was not the key factor. PMID- 22196345 TI - Selective patterning of Si-based biosensor surfaces using isotropic silicon etchants. AB - Ultra-sensitive, label-free biosensors have the potential to have a tremendous impact on fields like medical diagnostics. For the majority of these Si-based integrated devices, it is necessary to functionalize the surface with a targeting ligand in order to perform specific biodetection. To do this, silane coupling agents are commonly used to immobilize the targeting ligand. However, this method typically results in the bioconjugation of the entire device surface, which is undesirable. To compensate for this effect, researchers have developed complex blocking strategies that result in selective patterning of the sensor surface. Recently, silane coupling agents were used to attach biomolecules to the surface of silica toroidal biosensors integrated on a silicon wafer. Interestingly, only the silica biosensor surface was conjugated. Here, we hypothesize why this selective patterning occurred. Specifically, the silicon etchant (xenon difluoride), which is used in the fabrication of the biosensor, appears to reduce the efficiency of the silane coupling attachment to the underlying silicon wafer. These results will enable future researchers to more easily control the bioconjugation of their sensor surfaces, thus improving biosensor device performance. PMID- 22196346 TI - Short time spreading and wetting of offset printing liquids on model calcium carbonate coating structures. AB - Spreading of oils and water on porous and pre-saturated model carbonate coating structures was studied with high speed video imaging. The short-time data were complemented with long time absorption and wicking experiments. The results indicate a strong dependence between surface structural features of the pigment tablets and water spreading at short times, both in non-saturated and water pre saturated cases, while the oil spreading is mainly dependent on the liquid properties. Sodium polyacrylate dispersant on pigment surfaces is shown to contribute to water spreading and absorption. On pre-saturated structures the liquid-liquid interactions are dominant and the majority of results support spreading according to the molecular kinetic model. The evidence supports the hypothesis of S. Rousu, P. Gane, and D. Eklund, ["Influence of coating pigment chemistry and morphology on the chromatographic separation of offset ink constituents," in The Science of Papermaking Transactions of the 12th Fundamental Research Symposium, FRC The Pulp & Paper Fundamental Research Society, Oxford, UK, 2001, p. 1115] that at long times the oils absorb into the porous structure at a rate proportional to the ratio of viscosity and surface tension, provided there is no sorptive action with the binder. A combination of nanosized pores and large surface area is useful for providing sufficient absorption capability for carbonate based coatings. PMID- 22196347 TI - Effect of plasma etching on photoluminescence of SnO(x)/Sn nanoparticles deposited on DOPC lipid membrane. AB - The photoluminescence characteristic of the SnO(x)/Sn nanoparticles deposited on a solid supported liquid-crystalline phospholipid (1,2-dioleoyl-sn-glycero-3 phosphocholine) membrane was probed after plasma etching the nanoparticle monolayer. It was shown that the plasma etching of the nanoparticle surface greatly altered the particle morphology and enhanced the PL effect, especially when the particle size was below 10 nm in spite of strong presence of surrounding carbon. The enhancement mainly stemmed from the growth of a new PL peak due to the additional defect states produced on the nanoparticle surface by the plasma etching. It was also shown that hydrating the SnO(x)/Sn nanoparticles similarly improved the PL response of the nanoparticles as the hydration produced an additional oxygen-rich oxide layer on the particle surface. PMID- 22196348 TI - Wettability switching of SDS-doped polyaniline from hydrophobic to hydrophilic induced by alkaline/reduction reactions. AB - In this paper, sodium dodecyl sulfate (SDS) is used as dopant to manipulate both morphology and wettability of polyaniline (PANI). When SDS amount is controlled within a certain range, micro/nano double-rough PANI with hydrophobic surface can be obtained, while insufficient or excess SDS can only lead to hydrophilic PANI. The double-rough PANI shows stimuli-responsive change in wettability to either alkaline reaction or reduction reaction from hydrophobicity to hydrophilicity. This quick response can be applied to quantitatively estimate NaOH concentrations within the range of 10(-3)-10(-1)M and to detect various reducing liquids. PMID- 22196349 TI - Surface modification of poly(2-methoxy-5-(2'-ethyl-hexyloxy)-1,4-phenylene vinylene) (MEH-PPV) by confined photo-catalytic oxidation. AB - In this study, the surface of pi-conjugated polymer, poly(2-methoxy-5-(2'-ethyl hexyloxy)-1,4-phenylene vinylene) (MEH-PPV), was successfully modified with the sulfate anion (SO(4-)) groups by the confined photo-catalytic oxidation (CPO). After the surface modification, the water contact angle of MEH-PPV is changed from 95.5 degrees to 82.1 degrees without influence on its optical properties (based on the UV and PL spectra), and the water droplet can be absorbed on the modified MEH-PPV surface without sliding even at substrate tilt angles of 90 degrees and 180 degrees . The CPO on the MEH-PPV surface is able to further expand the use of MEH-PPV for applications. In addition, the water transport test indicates that the modified MEH-PPV can be a candidate for transporting water droplet. PMID- 22196350 TI - Microwrinkles: shape-tunability and applications. AB - Recently, spontaneously formed microwrinkle patterns on hard coating-capped elastomer surfaces have attracted the attention of both the scientific and applied research communities, because of their simple fabrication process and practical potential in diverse applications. The periodicity and statistical orientation of the microwrinkle stripes can be controlled by applying uniaxial or isotropic compressive strain. Thus, microwrinkles have been applied to cell patterning, optical gratings, pattern templates for further patterning, surfaces with anisotropic wetting properties, surfaces with unique adhesion properties, and metrology of ultrathin film properties. Our group has focused on tuning the structure of microwrinkles by exerting additional strain. This is almost impossible for micropatterns fabricated on a hard Si wafer; therefore, our technique is based on a soft substrate and the non-linear response of the system to external strain. The dynamic shape-tunability of the micropatterns shows potential for new applications, in which switching states of a system could be induced by a change in the physical boundary conditions, namely, the shape of microwrinkles. This feature article summarizes our laboratory's recent work on controlling the stripe pattern of microwrinkles and the application of shape tunable microwrinkles to liquid manipulation and liquid crystal alignment. For liquid manipulation, the microgrooves of the microwrinkles are used as an open channel capillary, in which the tunable groove depth controls the capillary action of the liquid in the grooves. Further changes in the direction of the microgrooves, which are filled with liquid, can induce the division of the liquids into small droplets. Such methods for shaping liquids are made possible by only macroscopic control of the strain applied to the sample. The alignment of a nematic liquid crystal was also investigated. Nematic liquid crystals can be aligned by anisotropic microgrooves; therefore, we have demonstrated that microwrinkles can be used for this purpose. In addition, because microwrinkles are shape-tunable, the liquid crystal alignment could be repeatedly switched. Our research demonstrates that shape-tunable microwrinkles provide new physical boundary conditions that can control the states of the bounded material, for example: the shape of liquid droplets and the alignment of a nematic director. We expect that many other systems that interact with the tunable boundary will lead to the discovery of new phenomena and technologies. PMID- 22196351 TI - Can sonication enhance release from liquid-core capsules with a hydrogel membrane? AB - The objective is to investigate the influence of sonication on the mechanical and release properties of hydrogel capsules. A new fabrication process is developed to fabricate millimetric capsules made of a highly-viscous liquid core protected by a thin hyperelastic alginate membrane. At high intensities and/or long exposure times, sonication can lead to the capsule rupture, because it induces fatigue in the membrane. Below the breakup threshold, no remnant effect of sonication is, however, measured on the capsule mechanical properties. The release is studied by sonicating capsules filled with blue dextran suspended in an aqueous solution. The mass release that results from sonication is found to be proportional to the sonication duration time and pressure wave amplitude. A possible physical interpretation is that the acoustic streaming flow induced by the ultrasonic wave enhances convection in the vicinity of the capsule membrane and thus mass release. We have finally quantified the passive release subsequent to low-intensity sonications: it is on average identical to the one measured on non-sonicated capsules. Overall the membrane therefore recovers its physical and mechanical properties after sonication. If sonication leads to an increase in porosity of the capsule membrane, the increase is temporary and reverses back at the end of the ultrasonic stimulation. PMID- 22196352 TI - pH dependent stability of aqueous suspensions of graphene with adsorbed weakly ionisable cationic polyelectrolyte. AB - Stable graphene suspensions were prepared through ultrasonic exfoliation followed by surface modification with the cationic polyelectrolyte poly(ethyleneimine) (PEI). The stability of the suspensions was found to be dependent upon the pH of the solution and the molecular weight of the PEI adsorbed. For the graphene sheets with adsorbed PEI with a molecular weigh of 600 Da, the particles were stabilised through an increased electrostatic repulsion at low pH inferred from in an increase in the measured zeta potential of the particles. However, the graphene with higher molecular weight PEI (70 kDa) was stable over a comparatively larger pH range through a combination of electrostatic repulsion at low pH and steric repulsion at elevated pH. Thus, solution conditions allowing the control of the colloidal sized graphene particles can be easily tuned through judicious management of solution conditions as well as polymer layer properties. PMID- 22196353 TI - Exploring polypharmacology using a ROCS-based target fishing approach. AB - Polypharmacology has emerged as a new theme in drug discovery. In this paper, we studied polypharmacology using a ligand-based target fishing (LBTF) protocol. To implement the protocol, we first generated a chemogenomic database that links individual protein targets with a specified set of drugs or target representatives. Target profiles were then generated for a given query molecule by computing maximal shape/chemistry overlap between the query molecule and the drug sets assigned to each protein target. The overlap was computed using the program ROCS (Rapid Overlay of Chemical Structures). We validated this approach using the Directory of Useful Decoys (DUD). DUD contains 2950 active compounds, each with 36 property-matched decoys, against 40 protein targets. We chose a set of known drugs to represent each DUD target, and we carried out ligand-based virtual screens using data sets of DUD actives seeded into DUD decoys for each target. We computed Receiver Operator Characteristic (ROC) curves and associated area under the curve (AUC) values. For the majority of targets studied, the AUC values were significantly better than for the case of a random selection of compounds. In a second test, the method successfully identified off-targets for drugs such as rimantadine, propranolol, and domperidone that were consistent with those identified by recent experiments. The results from our ROCS-based target fishing approach are promising and have potential application in drug repurposing for single and multiple targets, identifying targets for orphan compounds, and adverse effect prediction. PMID- 22196354 TI - Characterization of uncertainty in the classification of multivariate assays: application to PAM50 centroid-based genomic predictors for breast cancer treatment plans. AB - BACKGROUND: Multivariate assays (MVAs) for assisting clinical decisions are becoming commonly available, but due to complexity, are often considered a high risk approach. A key concern is that uncertainty on the assay's final results is not well understood. This study focuses on developing a process to characterize error introduced in the MVA's results from the intrinsic error in the laboratory process: sample preparation and measurement of the contributing factors, such as gene expression. METHODS: Using the PAM50 Breast Cancer Intrinsic Classifier, we show how to characterize error within an MVA, and how these errors may affect results reported to clinicians. First we estimated the error distribution for measured factors within the PAM50 assay by performing repeated measures on four archetypal samples representative of the major breast cancer tumor subtypes. Then, using the error distributions and the original archetypal sample data, we used Monte Carlo simulations to generate a sufficient number of simulated samples. The effect of these errors on the PAM50 tumor subtype classification was estimated by measuring subtype reproducibility after classifying all simulated samples. Subtype reproducibility was measured as the percentage of simulated samples classified identically to the parent sample. The simulation was thereafter repeated on a large, independent data set of samples from the GEICAM 9906 clinical trial. Simulated samples from the GEICAM sample set were used to explore a more realistic scenario where, unlike archetypal samples, many samples are not easily classified. RESULTS: All simulated samples derived from the archetypal samples were classified identically to the parent sample. Subtypes for simulated samples from the GEICAM set were also highly reproducible, but there were a non-negligible number of samples that exhibit significant variability in their classification. CONCLUSIONS: We have developed a general methodology to estimate the effects of intrinsic errors within MVAs. We have applied the method to the PAM50 assay, showing that the PAM50 results are resilient to intrinsic errors within the assay, but also finding that in non-archetypal samples, experimental errors can lead to quite different classification of a tumor. Finally we propose a way to provide the uncertainty information in a usable way for clinicians. PMID- 22196355 TI - Bacterial phosphoproteomic analysis reveals the correlation between protein phosphorylation and bacterial pathogenicity. AB - Increasing evidence shows that protein phosphorylation on serine, threonine and tyrosine residues is a major regulatory post-translational modification in the bacteria. This review focuses on the implications of bacterial phosphoproteome in bacterial pathogenicity and highlights recent development of methods in phosphoproteomics and the connectivity of the phosphorylation networks. Recent technical developments in the high accuracy mass spectrometry have dramatically transformed proteomics and made it possible the characterization of a few exhaustive site-specific bacterial phosphoproteomes. The high abundance of tyrosine phosphorylations in a few bacterial phosphoproteomes suggests their roles in the pathogenicity, especially in the case of pathogen-host interactions; the high abundance of multi-phosphorylation sites in bacterial phosphoprotein is a compensation of the relatively small phosphorylation size and an indicator of the delicate regulation of protein functions. PMID- 22196356 TI - Computational identification of protein-protein interactions in rice based on the predicted rice interactome network. AB - Plant protein-protein interaction networks have not been identified by large scale experiments. In order to better understand the protein interactions in rice, the Predicted Rice Interactome Network (PRIN; http://bis.zju.edu.cn/prin/) presented 76,585 predicted interactions involving 5,049 rice proteins. After mapping genomic features of rice (GO annotation, subcellular localization prediction, and gene expression), we found that a well-annotated and biologically significant network is rich enough to capture many significant functional linkages within higher-order biological systems, such as pathways and biological processes. Furthermore, we took MADS-box domain-containing proteins and circadian rhythm signaling pathways as examples to demonstrate that functional protein complexes and biological pathways could be effectively expanded in our predicted network. The expanded molecular network in PRIN has considerably improved the capability of these analyses to integrate existing knowledge and provide novel insights into the function and coordination of genes and gene networks. PMID- 22196357 TI - Genome-wide comparative in silico analysis of calcium transporters of rice and sorghum. AB - The mechanism of calcium uptake, translocation and accumulation in Poaceae has not yet been fully understood. To address this issue, we conducted genome-wide comparative in silico analysis of the calcium (Ca(2+)) transporter gene family of two crop species, rice and sorghum. Gene annotation, identification of upstream cis-acting elements, phylogenetic tree construction and syntenic mapping of the gene family were performed using several bioinformatics tools. A total of 31 Ca(2+) transporters, distributed on 9 out of 12 chromosomes, were predicted from rice genome, while 28 Ca(2+) transporters predicted from sorghum are distributed on all the chromosomes except chromosome 10 (Chr 10). Interestingly, most of the genes on Chr 1 and Chr 3 show an inverse syntenic relationship between rice and sorghum. Multiple sequence alignment and motif analysis of these transporter proteins revealed high conservation between the two species. Phylogenetic tree could very well identify the subclasses of channels, ATPases and exchangers among the gene family. The in silico cis-regulatory element analysis suggested diverse functions associated with light, stress and hormone responsiveness as well as endosperm- and meristem-specific gene expression. Further experiments are warranted to validate the in silico analysis of the predicted transporter gene family and elucidate the functions of Ca(2+) transporters in various biological processes. PMID- 22196358 TI - Cloning, expression, and homology modeling of GroEL protein from Leptospira interrogans serovar autumnalis strain N2. AB - Leptospirosis is an infectious bacterial disease caused by Leptospira species. In this study, we cloned and sequenced the gene encoding the immunodominant protein GroEL from L. interrogans serovar Autumnalis strain N2, which was isolated from the urine of a patient during an outbreak of leptospirosis in Chennai, India. This groEL gene encodes a protein of 60 kDa with a high degree of homology (99% similarity) to those of other leptospiral serovars. Recombinant GroEL was overexpressed in Escherichia coli. Immunoblot analysis indicated that the sera from confirmed leptospirosis patients showed strong reactivity with the recombinant GroEL while no reactivity was observed with the sera from seronegative control patient. In addition, the 3D structure of GroEL was constructed using chaperonin complex cpn60 from Thermus thermophilus as template and validated. The results indicated a Z-score of -8.35, which is in good agreement with the expected value for a protein. The superposition of the Ca traces of cpn60 structure and predicted structure of leptospiral GroEL indicates good agreement of secondary structure elements with an RMSD value of 1.5 A. Further study is necessary to evaluate GroEL for serological diagnosis of leptospirosis and for its potential as a vaccine component. PMID- 22196359 TI - An approach for searching insertions in bacterial genes leading to the phase shift of triplet periodicity. AB - The concept of the phase shift of triplet periodicity (TP) was used for searching potential DNA insertions in genes from 17 bacterial genomes. A mathematical algorithm for detection of these insertions has been developed. This approach can detect potential insertions and deletions with lengths that are not multiples of three bases, especially insertions of relatively large DNA fragments (>100 bases). New similarity measure between triplet matrixes was employed to improve the sensitivity for detecting the TP phase shift. Sequences of 17,220 bacterial genes with each consisting of more than 1,200 bases were analyzed, and the presence of a TP phase shift has been shown in ~16% of analysed genes (2,809 genes), which is about 4 times more than that detected in our previous work. We propose that shifts of the TP phase may indicate the shifts of reading frame in genes after insertions of the DNA fragments with lengths that are not multiples of three bases. A relationship between the phase shifts of TP and the frame shifts in genes is discussed. PMID- 22196360 TI - Mining genomic patterns in Mycobacterium tuberculosis H37Rv using a web server Tuber-Gene. AB - Mycobacterium tuberculosis (MTB), causative agent of tuberculosis, is one of the most dreaded diseases of the century. It has long been studied by researchers throughout the world using various wet-lab and dry-lab techniques. In this study, we focus on mining useful patterns at genomic level that can be applied for in silico functional characterization of genes from the MTB complex. The model developed on the basis of the patterns found in this study can correctly identify 99.77% of the input genes from the genome of MTB strain H37Rv. The model was tested against four other MTB strains and the homologue M. bovis to further evaluate its generalization capability. The mean prediction accuracy was 85.76%. It was also observed that the GC content remained fairly constant throughout the genome, implicating the absence of any pathogenicity island transferred from other organisms. This study reveals that dinucleotide composition is an efficient functional class discriminator for MTB complex. To facilitate the application of this model, a web server Tuber-Gene has been developed, which can be freely accessed at http://www.bifmanit.org/tb2/. PMID- 22196361 TI - Junker: an intergenic explorer for bacterial genomes. AB - In the past few decades, scientists from all over the world have taken a keen interest in novel functional units such as small regulatory RNAs, small open reading frames, pseudogenes, transposons, integrase binding attB/attP sites, repeat elements within the bacterial intergenic regions (IGRs) and in the analysis of those "junk" regions for genomic complexity. Here we have developed a web server, named Junker, to facilitate the in-depth analysis of IGRs for examining their length distribution, four-quadrant plots, GC percentage and repeat details. Upon selection of a particular bacterial genome, the physical genome map is displayed as a multiple loci with options to view any loci of interest in detail. In addition, an IGR statistics module has been created and implemented in the web server to analyze the length distribution of the IGRs and to understand the disordered grouping of IGRs across the genome by generating the four-quadrant plots. The proposed web server is freely available at the URL http://pranag.physics.iisc.ernet.in/junker/. PMID- 22196362 TI - Anti-phospholipid antibodies contribute to arteriosclerosis in patients with systemic lupus erythematosus through induction of tissue factor expression and cytokine production from peripheral blood mononuclear cells. AB - INTRODUCTION: In systemic lupus erythematosus (SLE) patients, the prevalence of arteriosclerosis obliterans (ASO) is high despite a lack of common risk factors for ASO. The main objective of this study was to investigate a possible direct role of anti-phospholipid antibodies (aPLs), which are frequently detected in SLE patients, in the pathogenesis of ASO. MATERIALS AND METHODS: We examined tissue factor (TF) expression on the monocyte surface by flow cytometric analysis in 89 SLE patients with or without ASO and/or aPLs and studied the in vitro effect of purified IgG fractions from plasma of SLE patients or normal healthy volunteers (aPLs(+) IgG, n=8; aPLs(-) IgG, n=6; Normal IgG, n=6) on the expression of TF and production of TNF-alpha and IL-1beta in healthy peripheral blood mononuclear cells (PBMCs) or isolated monocytes. RESULTS: We confirmed that high expression of monocyte TF was strongly associated with the prevalence of ASO and the presence of aPLs. Treatments of PBMCs with aPLs(-) IgG or normal IgG did not significantly increase expression of TF, TNF-alpha, and IL-1beta messenger RNA (mRNA) and the production of TNF-alpha and IL-1beta. However, stimulation of PBMCs with aPLs(+) IgG caused significant increase in expression of TF, TNF alpha, and IL-1beta mRNA. Moreover, aPLs(+) IgG stimulated PBMCs and significantly enhanced the production of TNF-alpha and IL-1beta. CONCLUSION: These results suggest that IgG-aPLs cause persistently high TF expression and inflammatory cytokine production by interacting with peripheral blood monocytes and lymphocytes, which may be an important mechanism in the pathogenesis of ASO peculiar to SLE patients. PMID- 22196363 TI - Oncostatin M induces heat hypersensitivity by gp130-dependent sensitization of TRPV1 in sensory neurons. AB - Oncostatin M (OSM) is a member of the interleukin-6 cytokine family and regulates eg. gene activation, cell survival, proliferation and differentiation. OSM binds to a receptor complex consisting of the ubiquitously expressed signal transducer gp130 and the ligand binding OSM receptor subunit, which is expressed on a specific subset of primary afferent neurons. In the present study, the effect of OSM on heat nociception was investigated in nociceptor-specific gp130 knock-out (SNS-gp130-/-) and gp130 floxed (gp130fl/fl) mice.Subcutaneous injection of pathophysiologically relevant concentrations of OSM into the hind-paw of C57BL6J wild type mice significantly reduced paw withdrawal latencies to heat stimulation. In contrast to gp130fl/fl mice, OSM did not induce heat hypersensitivity in vivo in SNS-gp130-/- mice. OSM applied at the receptive fields of sensory neurons in in vitro skin-nerve preparations showed that OSM significantly increased the discharge rate during a standard ramp-shaped heat stimulus. The capsaicin- and heat-sensitive ion channel TRPV1, expressed on a subpopulation of nociceptive neurons, has been shown to play an important role in inflammation-induced heat hypersensitivity. Stimulation of cultured dorsal root ganglion neurons with OSM resulted in potentiation of capsaicin induced ionic currents. In line with these recordings, mice with a null mutation of the TRPV1 gene did not show any signs of OSM-induced heat hypersensitivity in vivo.The present data suggest that OSM induces thermal hypersensitivity by directly sensitizing nociceptors via OSMR-gp130 receptor mediated potentiation of TRPV1. PMID- 22196364 TI - Linear sweep voltammetric studies on the complex of alizarin red s with aloe polysaccharide and determination of aloe polysaccharide. AB - A new electrochemical method for the determination of aloe polysaccharide based on its interaction with alizarin red s was established on a pretreated glassy carbon electrode in pH 3.5 Britton-Robinson buffer solution by linear sweep voltammetry in this work. The decrease of the second order derivative linear sweep voltammetric reductive peak current of alizarin red s is in proportion to aloe polysaccharide concentration due to the formation of a complex between them in the range from 0.032 to 0.448MUmolL(-1), and the detection limit is 0.0051MUmolL(-1) (3sigma). The binding ratio and the binding constant of the complex were calculated as 1:1 and 2.75*10(4), respectively. Different kinds of complex samples of aloe polysaccharide were detected satisfactorily by this method. PMID- 22196365 TI - Structure of the O-polysaccharide chain of the lipopolysaccharide of Psychrobacter muricolla 2pS(T) isolated from overcooled water brines within permafrost. AB - Psychrotrophic bacteria of the genus Psychrobacter have not been studied in respect to lipopolysaccharide structure. In this work, we determined the structure of the O-specific polysaccharide of the lipopolysaccharide of Psychrobacter muricolla 2pS(T) isolated from overcooled (-9 degrees C) water brines within permafrost. The polysaccharide was found to be acidic due to the presence of an amide of 2-acetamido-2-deoxy-l-guluronic acid with glycine (l GulNAcA6Gly), which has not been hitherto found in nature. The following structure of the disaccharide repeating unit of the polysaccharide was established using composition analysis along with 1D and 2D (1)H and (13)C NMR spectroscopy: ->4)-alpha-l-GulpNAcA6Gly-(1->3)-beta-d-GlcpNAc-(1-> PMID- 22196368 TI - Something old, something new. PMID- 22196369 TI - The development of RNA interference therapeutics. PMID- 22196370 TI - Dual or triple activation of TLR7, TLR8, and/or TLR9 by single-stranded oligoribonucleotides. AB - The toll-like receptors (TLRs) 7, 8, and 9 stimulate innate immune responses upon recognizing pathogen nucleic acids. Certain GU- or AU-rich RNA sequences were described to differentiate between human TLR7- and TLR8-mediated immune effects. Those single-stranded RNA molecules require endosomal delivery for stabilization against ribonucleases. We have discovered RNA sequences that preferentially activate TLR7, form higher ordered structures, and do not require specific cellular delivery. In addition, a dual activation of TLR8 and TLR9 without affecting TLR7 can be achieved by chimeric molecules consisting of GU-rich RNA and Cytosin (C) phosphordiester or phosphorthioat (p) guanine (CpG) motif DNA sequences. Such chimeras stimulate TLR9-mediated type I interferon (IFN) and TLR8 depending proinflammatory cytokine and chemokine production upon primary human cell activation. However, an RNA-dependent TLR7 IFN-alpha cytokine release is suppressed by the phosphorothioate DNA sequence contained in the chimeric molecule. To convert the immune response of a single-stranded RNA from TLR7/8 to TLR9, a simple chemical modification at the 5' end proves to be sufficient. Such 8-oxo-2'-deoxy-guanosine or 8-bromo-2'-deoxy-guanosine modifications of the first guanosine in GU-rich single-stranded RNAs convert the immune response to include TLR9 activation and demonstrate strong additive effects for type I IFN immune responses in human primary cells. PMID- 22196371 TI - Rehearsal dynamics in elementary school children. AB - Several studies on free recall suggest that processes responsible for recall are analogous to processes responsible for rehearsal. In children, the relationship between cumulative rehearsal and recall performance has been proven to be critical; however, the locus of the effect of rehearsal is not yet fully understood. To unfold the mechanisms that come into play in an overt rehearsal free recall task, we assessed rehearsal and recall sequences in children between 8 and 10 years of age. These sequences give information about the context in which items are repeated and rearranged throughout the list and subsequently recalled. Rehearsal sequences consisted mainly of items from neighboring list positions in their original temporal order. The same characteristics were true for recall sequences. Qualitatively, order effects during study and recall did not differ over age groups. However, in older children who were using cumulative rehearsal more intensively, successive rehearsal and recall of items in their original order was more pronounced. Therefore, we suggest that a main feature of item rehearsal with regard to facilitating recall is the strengthening of interitem associations based on the temporal order within a list and that this characteristic develops with age. PMID- 22196372 TI - Formulation and in vitro evaluation of self-emulsifying formulations of Cinnarizine. AB - The main objectives of this study were to improve the aqueous solubility and to modify in vitro dissolution profile of hydrophobic drug using self-emulsifying drug delivery systems (SEDDS). SEDDS were formulated using Capmul PG-12, Cremophor RH 40 and Tween 20 at different weight ratios and incorporated with Cinnarizine. The drug incorporation into pre-concentrate and drug solubility in phosphate buffer (pH 7.2) were investigated. In addition, the mean droplet size and drug release profile of the SEDDS were also determined. The drug incorporation was over 120 mg per 0.5 g pre-concentrate regardless of the composition of the formulations. The solubility of Cinnarizine in phosphate buffer (pH 7.2) was at least 1500 MUM in the SEDDS. Formulations with only 10% w/w Capmul PG-12 were less than 20 nm in mean diameter while those produced with at least 20% w/w Capmul PG-12 were more than 100 nm regardless of the ratios of Cremophor RH 40 to Tween 20. SEDDS showed a significant increase of the mean percentage drug release than pure drug (p < 0.0001). In general, the SEDDS with 30% w/w of Capmul PG-12 provided the greatest enhancement in drug solubility in phosphate buffer as well as rapid drug release despite forming larger droplets upon emulsification. The combination of Capmul PG-12, Tween 20 and Cremophor RH 40 can produce SEDDS which can be used as an alternative dosage form for poorly water soluble drug. PMID- 22196373 TI - The order of expression is a key factor in the production of active transglutaminase in Escherichia coli by co-expression with its pro-peptide. AB - BACKGROUND: Streptomyces transglutaminase (TGase) is naturally synthesized as zymogen (pro-TGase), which is then processed to produce active enzyme by the removal of its N-terminal pro-peptide. This pro-peptide is found to be essential for overexpression of soluble TGase in E. coli. However, expression of pro-TGase by E. coli requires protease-mediated activation in vitro. In this study, we developed a novel co- expression method for the direct production of active TGase in E. coli. RESULTS: A TGase from S. hygroscopicus was expressed in E. coli only after fusing with the pelB signal peptide, but fusion with the signal peptide induced insoluble enzyme. Therefore, alternative protocol was designed by co expressing the TGase and its pro-peptide as independent polypeptides under a single T7 promoter using vector pET-22b(+). Although the pro-peptide was co expressed, the TGase fused without the signal peptide was undetectable in both soluble and insoluble fractions of the recombinant cells. Similarly, when both genes were expressed in the order of the TGase and the pro-peptide, the solubility of TGase fused with the signal peptide was not improved by the co expression with its pro-peptide. Interestingly, active TGase was only produced by the cells in which the pro-peptide and the TGase were fused with the signal peptide and sequentially expressed. The purified recombinant and native TGase shared the similar catalytic properties. CONCLUSIONS: Our results indicated that the pro-peptide can assist correct folding of the TGase inter-molecularly in E. coli, and expression of pro-peptide prior to that of TGase was essential for the production of active TGase. The co-expression strategy based on optimizing the order of gene expression could be useful for the expression of other functional proteins that are synthesized as a precursor. PMID- 22196374 TI - Could petroleum biodegradation be a joint achievement of aerobic and anaerobic microrganisms in deep sea reservoirs? AB - Several studies suggest that petroleum biodegradation can be achieved by either aerobic or anaerobic microorganisms, depending on oxygen input or other electron acceptors and appropriate nutrients. Evidence from in vitro experiments with samples of petroleum formation water and oils from Pampo Field indicate that petroleum biodegradation is more likely to be a joint achievement of both aerobic and anaerobic bacterial consortium, refining our previous observations of aerobic degradation. The aerobic consortium depleted, in decreasing order, hydrocarbons > hopanes > steranes > tricyclic terpanes while the anaerobic consortium depleted hydrocarbons > steranes > hopanes > tricyclic terpanes. The oxygen content of the mixed consortia was measured from time to time revealing alternating periods of microaerobicity (O2 ~0.8 mg.L-1) and of aerobicity (O2~6.0 mg.L-1). In this experiment, the petroleum biodegradation changed from time to time, alternating periods of biodegradation similar to the aerobic process and periods of biodegradation similar to the anaerobic process. The consortia showed preferences for metabolizing hydrocarbons > hopanes > steranes > tricyclic terpanes during a 90-day period, after which this trend changed and steranes were more biodegraded than hopanes. The analysis of aerobic oil degrading microbiota by the 16S rRNA gene clone library detected the presence of Bacillus, Brevibacterium, Mesorhizobium and Achromobacter, and the analysis of the anaerobic oil degrading microbiota using the same technique detected the presence of Bacillus and Acinetobacter (facultative strains). In the mixed consortia Stenotrophomonas, Brevibacterium, Bacillus, Rhizobium, Achromobacter and 5% uncultured bacteria were detected. This is certainly a new contribution to the study of reservoir biodegradation processes, combining two of the more important accepted hypotheses. PMID- 22196375 TI - Host specificity determinants as a genetic continuum. AB - Host specificity is an important concept that underlies the interaction of all clinically and agriculturally relevant microbes with their hosts. Changes in the host specificity of animal pathogens, in particular, are often of greatest concern due to their immediate and unexpected impact on human health. Host switching or host jumps can often be traced to modification of key microbial pathogenicity factors that facilitate the formation of particular host associations. An increase in the number of genome-level studies has begun revealing that almost any type of change, from the simplest to the most complex, can potentially impact host specificity. This review highlights examples of host specificity determinants of viruses, bacteria and fungi, and presents them from within a genetic continuum that spans from the single residue through to entire genomic islands. PMID- 22196377 TI - Influence of TRAF1/C5 and STAT4 genes polymorphisms on susceptibility and severity of rheumatoid arthritis in Egyptian population. AB - Rheumatoid arthritis (RA) is the most common cause of adult inflammatory arthritis. Recent genome-wide association scans have disclosed several single nucleotide polymorphisms associated with RA susceptibility. The aim of this study was to determine whether the polymorphisms of TRAF1/C5 (tumor necrosis factor (TNF)-receptor associated factor 1)/(complement component 5) and STAT4 (signal transducers and activators of transcription 4) confer susceptibility, activity and severity to RA in Egyptian populations. One hundred and seventy-two RA patients and 160 controls were enrolled in the study. Polymorphisms of TRAF1/C5 and STAT4 genes were determined using restriction fragment length polymorphism polymerase chain reaction. The TRAF1/C5 A and STAT4 T alleles were significantly associated with RA in Egyptian population. TRAF1/C5 A allele and STAT4 TT genotype were significantly associated with RA severity. In conclusion the mutant alleles or genotypes of both examined polymorphisms are associated with the development of RA in Egyptian population. PMID- 22196378 TI - TNF-alpha inhibitor reverse the effects of human umbilical cord-derived stem cells on experimental arthritis by increasing immunosuppression. AB - To demonstrate the therapeutic potential for cartilage repair of mesenchymal stem cells derived from human umbilical cord (HUCSC), we studied the clinical and histopathological effects of intra-articular injection of HUCSCs in a collagen induced arthritis (CIA) model. In our study, intra-articular injection of HUCSCs had no benefit in CIA mice; and accelerated the progression of arthritis in the presence of TNF-alpha. To determine the role of TNF-alpha, we injected the combination with HUCSCs and TNF inhibitor, showed reduced the disease signs in CIA mice. On exposure of TNF-alpha, stem cells significantly decreased the expression of CD90, HLA-G, and the levels of IL-10 in vitro and in vivo. Our data showed that TNF-alpha blocks the immunosuppressive effects of HUCSCs and that inhibition of TNF-alpha decreases cartilage destruction by suppressing the immunogenicity of HUCSCs. Injecting both a TNF inhibitor and HUCSCs may be a potential effective therapy for ameliorating the disease. PMID- 22196379 TI - Prevention of fasting-mediated bone marrow atrophy by leptin administration. AB - Leptin is an adipokine that regulates body weight. In the current study, we demonstrate that continuous injection of leptin prevents the lymphocyte reduction observed in fasted mice, especially the immature B cell populations in the bone marrow. Although leptin administration reduced apoptotic cells in the bone marrow of fasted mice, it did not prevent glucocorticoid-mediated apoptosis in vitro. Bone marrow atrophy has also been shown in the leptin receptor-deficient db/db mice. In order to investigate the mechanisms underlying these processes, we transplanted bone marrow cells from db/db or control (+m/+m) mice into C.B-17/lcr scid/scid mice. We found that the spleen and bone marrow B cell populations were completely reconstituted when db/db and +m/+m cells were transplanted into scid mice. Our findings suggest that direct interactions between leptin and bone marrow cells are not essential for the development of B cells in a metabologically normal environment. PMID- 22196380 TI - Chemical cross-linking and H/D exchange for fast refinement of protein crystal structure. AB - A combination of chemical cross-linking and hydrogen-deuterium exchange coupled to high resolution mass spectrometry was used to describe structural differences of NKR-P1A receptor. The loop region extended from the compact core in the crystal structure was found to be closely attached to the protein core in solution. Our approach has potential to refine protein structures in solution within a few days and has very low sample consumption. PMID- 22196381 TI - Electrochemical carbon-nanotube filter performance toward virus removal and inactivation in the presence of natural organic matter. AB - The performance of an electrochemical multiwalled carbon nanotube (EC-MWNT) filter toward virus removal and inactivation in the presence of natural organic matter was systematically evaluated over a wide range of solution chemistries. Viral removal and inactivation were markedly enhanced by applying DC voltage in the presence of alginate and Suwannee River natural organic matter (SRNOM). Application of 2 or 3 V resulted in complete (5.8 to 7.4 log) removal and significant inactivation of MS2 viral particles in the presence of 5 mg L(-1) of SRNOM or 1 mg L(-1) of alginate. The EC-MWNT filter consistently maintained high performance over a wide range of solution pH and ionic strengths. The underlying mechanisms of enhanced viral removal and inactivation were further elucidated through EC-MWNT filtration experiments using carboxyl latex nanoparticles. We conclude that enhanced virus removal is attributed to the increased viral particle transport due to the applied external electric field and the attractive electrostatic interactions between the viral particles and the anodic MWNTs. The adsorbed viral particles on the MWNT surface are then inactivated through direct surface oxidation. Minimal fouling of the EC-MWNT filter was observed, even after 4-h filter runs with solutions containing 10 mg L(-1) of natural organic matter and 1 mM CaCl(2). Our results suggest that the EC-MWNT filter has a potential for use as a high performance point-of-use device for the removal of viruses from natural and contaminated waters with minimal power requirements. PMID- 22196383 TI - Sliding of two lag screw designs in a highly comminuted fracture model. AB - A fracture construct, representing a worst-case model of a comminuted intertrochanteric fracture, was created in order to compare the fixation stability of two different cephalomedullary nails: one where the lag screw can telescope within itself to achieve displacement of the head-neck fragment, and the other where the solid lag screw slides only. After nail fixation, the models were loaded and then cycled, and positions of the head-neck fragment and lag screw were determined. Both nails similarly acted to limit motion of the head neck fragment by the sliding of their lag screws, causing impingement of the fragment against the nail. Fragment movement was achieved with significantly less force with the telescoping lag screws, which also showed no final lateral projection from the nail. This was in contrast to the solid lag screws that demonstrated lateral projection in all cases. PMID- 22196382 TI - Electronic measurement of soft-tissue balancing reduces lateral releases in total knee arthroplasty. AB - Soft tissue balancing during total knee arthroplasty (TKA) has a direct affect on patello-femoral tracking and knee range of motion, which are necessary for a well functioning TKA postoperatively. We report on the use of an electronic pressure sensing instrument for soft tissue balancing of the knee before completion of all intraoperative bone cuts, as a way to improve patellar tracking. In a retrospective study of 99 consecutive TKAs, with intraoperative electronic instrument guided soft tissue balancing performed, a reduction in the incidence of lateral patellar retinacular release was found, as compared with the 100 consecutive TKAs prior to its use (5.5% v 12%, respectively). Electronic measurement of soft tissue balancing during TKA reduced the need for lateral patellar retinacular release. PMID- 22196384 TI - Finite element analysis of femoral neck stress in relation to pelvic width. AB - Hip resurfacing arthroplasty has been developed as an alternative to traditional total hip arthroplasty, in an effort to minimize the loss of native bone in young patients with symptomatic hip osteoarthritis. Femoral neck fracture following hip resurfacing is a unique complication; several risk factors are associated with this complication, including female gender. In the present study, we used finite element models of the proximal femur to simulate stresses across the femoral neck in pelvis models with varying widths. This analysis demonstrated an increase in hip reaction forces as the width of the pelvis increases, a condition that simulates a resurfacing condition in a female pelvis. This difference in peak stress on the femoral neck may explain the increased incidence of femoral neck fractures seen in female patients following hip resurfacing. PMID- 22196385 TI - Biomechanical comparison of translaminar screw versus pedicle screw supplementation of anterior femoral ring allografts in one-level lumbar spine fusion. AB - Pedicle screws (PS) can provide initial stabilization of anterior interbody femoral ring allograft (FRA) lumbar constructs. Translaminar screws (TLS) have also been advocated for this procedure. The objective of this study was to use an in vitro human cadaveric model to compare the stability of one-level anterior interbody lumbar constructs stabilized with PS and those stabilized with TLS. Five human cadaveric spinal motion segments (L4-S2) were biomechanically evaluated in the intact condition and using the follow- ing methods of stabilization: anterior interbody fusion with FRA, anterior FRA supplemented with PS, and anterior FRA supplemented with TLS. Stability was determined for each construct by measuring construct displacement as a function of applied load under the following conditions: compression, flexion, extension, lateral bending to each side, and axial torsion. There were no statistically significant differences in construct stability between FRA supplemented with PS and FRA supplemented with TLS under any of the loading conditions. In selected cases, supplementation of anterior femoral ring allograft with translaminar screws is a viable alternative to supplementation with pedicle screws. PMID- 22196386 TI - MRI criteria of developmental lumbar spinal stenosis revisited. AB - PURPOSE: It is somewhat surprising that radiographic criteria for lumbar stenosis have been transposed from radiography and CT to MR without scientific validation. As these radiographic criteria were developed via population studies with criteria defined by two standard deviations from the mean, we sought to perform the same methodology via MR. METHODS: The study was approved by the institutional review board; the requirement for informed consent was waived. One-hundred patients referred for possible metastatic disease, aged 4 to 94 were studied. Measurements were obtained on a midline sagittal T2-weighted (6000/120) image at each disc level, as well as at the mid-vertebral level. The distributive mean, and standard deviations were calculated and -2 SD was used as a "cutoff" for spinal stenosis. To assess for interobserver variation, 20% of the measurements were repeated by a second observer. To assess for intraobserver variation, another 20% of the measurements were repeated a second time at a minimum of a two month interval. RESULTS: The spinal canal was narrowest at L5-S1 (mean: 1.16 cm), and widest at L1-L2 (mean: 1.56 cm). Overall the narrowest measurements were at the intervertebral disc space and were narrower at the lower disc spaces. In our population, the lowest cutoff limit (two standard deviations below the mean) had a range between 0.38 cm at the L3-L4 disc space and 0.9 cm at the L1 vertebral level. Notably at the L3 level the size range was from 0.77 to 1.75 CONCLUSION: Traditional measurements of canal diameters may be too large when applied to soft tissue analysis on MR. We suggest using a cutoff of smaller than 0.90 cm for developmental stenosis. PMID- 22196387 TI - Correlation between nutritional status and Staphylococcus colonization in hip and knee replacement patients. AB - Orthopaedic patients with poor nutritional status are at an increased risk of postoperative complications, such as infection and wound healing. Nasal colonization with Staphylococcus aureus, especially with methicillin-resistant Staphylococcus aureus, has been shown to be a risk factor for surgical-site infections. We examined the incidence of nutritional depletion in our arthroplasty population and its correlation with Staphylococcus aureus colonization. We conducted a retrospective review of prospectively collected data of our arthroplasty patient population. Patients with known Staphylococcus aureus colonization or surgical-site infection were compared with a random cohort of patients. Patient demographics, preoperative nasal culture, and two nutritional screening scores were collected. Six hundred and fifty-two patients underwent arthroplasty and completed preoperative nasal cultures and nutritional assessment. A high percentage (27%) of our patients demonstrated some level of nutritional depletion prior to joint replacement. Overall nutritional scores were not significantly associated with surgery-type, preoperative nasal culture, or surgical- site infection in our patient population. PMID- 22196388 TI - Surgical site infection prevention initiative - patient attitude and compliance. AB - BACKGROUND: Although the effect of Staphylococcus aureus (SA) decolonization on surgical site infection (SSI) rates has been studied, patient tolerance and acceptance of these regimens has not been assessed. Surgical patients at our hospital's Pre-Admission Testing Clinic (PAT) receive SA reduction protocols instructing the preoperative use of chlorhexidine gluconate (CHG) soap and intranasal mupirocin ointment (MO). Certain insurers do not cover MO costs resulting in out of pocket (OOP) expenses for some patients. OBJECTIVE: This study assessed patient attitudes and compliance with our hospital's SA decolonization regimen. METHODS: One-hundred-forty-six patients received surveys. Descriptive statistics were used for analysis. RESULTS: Of respondents fitting inclusion criteria, 81% followed the MO protocol (MO users) while 89% followed the CHG protocol (CHG users). Fifty-four percent of MO users reported OOP expenses and 13% reported a hard or very hard financial burden. Ninety-three percent of CHG users reported the protocol was easy or very easy to follow. CONCLUSION: Eighty-one percent of patients receiving the SA protocol were fully compliant despite cost or difficulty obtaining MO. Given these barriers and some difficulty with CHG application, we hypothesize compliance may be improved if MO is provided to patients without OOP expenses and if the CHG application method is simplified. PMID- 22196389 TI - Outcomes analysis of anterior-posterior fusion for low grade isthmic spondylolisthesis. AB - BACKGROUND: Traditional surgical treatment of isthmic spondylolisthesis is posterior-lateral fusion, but the addition of anterior surgery has been explored. The purpose of this study was to evaluate the surgical and clinical outcomes of anterior-posterior surgical treatment for low-grade isthmic spondylolisthesis. METHODS: Retrospectively, we enrolled 23 consecutive patients (mean age of 50) who underwent surgical treatment for low grade isthmic spondylolisthesis. The mean follow-up was 10 months. Basic demographic and radiographic data was collected. Pre- and post-surgical clinical surveys (VAS, ODI, and SF-36) were collected. RESULTS: All 23 patients underwent anterior interbody fusion with a femoral ring allograft or ICBG in combination with posterior lumbar decompression and fusion with instrumentation. The average slip percentage decreased from 23.2% to 19.0% (p = 0.24) while slip angle increased from 9.8 degrees to 17.9 degrees (p < 0.001) and average disc height decreased from 1.9 cm to 0.80 cm (p < 0.001). VAS scores decreased from 7.1 to 2.4 (p < 0.001), ODI scores decreased from 52.5 to 28.1 (p < 0.001), and SF-36 scores increased in the Physical Component Scale (PCS) from 29.5 to 42.6 (p < 0.001). CONCLUSION: In our study, patients demonstrated an improvement in the ODI as well the physical component scores of the SF-36, thus having a good clinical outcome. PMID- 22196390 TI - The diagnosis and management of spontaneous and post-arthroscopy osteonecrosis of the knee. AB - Spontaneous osteonecrosis of the knee (SPONK) and osteo necrosis in the postoperative knee (ONPK) are two clinical entities that have the potential to cause significant morbidity in affected patients. In addition to the knowledge of the patient population at risk and the classic presentation and imaging characteristics of SPONK and ONPK, the treating orthopaedic surgeon needs to maintain a high index of suspicion for these disorders since early diagnosis and treatment may allow for an improved clinical outcome. The following review presents the current knowledge regarding these two pathological processes of the knee. PMID- 22196391 TI - Degenerative arthritis of the knee secondary to ochronosis. AB - Alkaptonuria is a rare disease in which a deficiency in the homogentisate 1, 2 dioxygenase enzyme results in a buildup of homogentisic acid. Ochronosis, the deposition of excess homogentisic acid in connective tissue, causes brownish black pigmentation and weakening of the tissue ultimately resulting in chronic inflammation, degeneration, and osteoarthritis. There is currently no definitive cure for alkaptonuric ochronosis, and management is usually symptomatic. However, total joint replacements in severe cases of ochronotic osteoarthritis have comparable outcomes to osteoarthritic patients without ochronosis. We report a case of a patient with ochronotic arthritis of the knee treated with total knee arthroplasty. PMID- 22196392 TI - Isolated Hoffa fracture of the medial femoral condyle in a skeletally immature patient. AB - Intraarticular coronal fracture of the femoral condyle is rare, and an isolated medial Hoffa fracture in a child is extremely rare. To our knowledge, such a case has not yet been reported in the literature. Early diagnosis and prompt treatment are essential for a good long-term outcome. We report a case of 12-year-old male who suffered a traffic accident and sustained an isolated medial Hoffa fracture. Open reduction was performed using a subvastus approach and the joint surface congruity restored and secured by two large fragment partially threaded screws placed from anterior to posterior in the epiphysis. At the 36-month follow-up, the fracture was united, and the patient had full extension and approximately 130 degrees flexion of knee. There was no varus or valgus instability or limb length discrepancy. This case highlights the importance of early diagnosis and prompt treatment in the form of epiphyseal fixation for the management of these fractures in skeletally immature individuals. PMID- 22196393 TI - Multi-level spondylolysis. AB - The incidence of isthmic spondylolysis is approximately 3% to 6% in the general population. Spondylolytic defects involving multiple vertebral levels, on the other hand, are extremely rare. Only a handful of reports have examined the outcomes of surgical treatment of multi-level spondylolysis. Here, we present one case of bilateral pars defects at L3, L4, and L5. The patient, a 46-year-old female, presented with lower back pain radiating into the left lower extremity. Radiographs and CT scans of the lumbar spine revealed bilateral pars defects at L3-L5. The patient underwent lumbar discectomy and interbody fusion of L4-S1 as well as direct repair of the pars defect at L3. There were no postoperative complications, and by seven months the patient had improved clinically. While previous reports describe the use of either direct repair or fusion in the treatment of spondylolysis, we are unaware of reports describing the use of both techniques at adjacent levels. PMID- 22196394 TI - New insights into meticillin-resistant Staphylococcus aureus (MRSA) pathogenesis, treatment and resistance. AB - Meticillin-resistant Staphylococcus aureus (MRSA) remains one of the principal multiply resistant bacterial pathogens causing serious healthcare-associated and community-onset infections. This paper reviews recent studies that have elucidated the virulence strategies employed by MRSA, key clinical trials of agents used to treat serious MRSA infections, and accumulating data regarding the implications of antibacterial resistance in MRSA for clinical success during therapy. Recent pre-clinical data support a species-specific role for Panton Valentine leukocidin in the development of acute severe S. aureus infections and have elucidated other virulence mechanisms, including novel modes of internalisation, varying post-invasion strategies (featuring both upregulation and downregulation of virulence factors) and phenotypic switching. Recent double blind, randomised, phase III/IV clinical trials have demonstrated the efficacy of linezolid and telavancin in hospital-acquired pneumonia (HAP) and complicated skin and skin-structure infections (cSSSIs) caused by MRSA. Tigecycline was non inferior to imipenem/cilastatin in non-ventilator-associated HAP but was inferior in ventilator-associated pneumonia and has shown a higher rate of death than comparators on meta-analysis. Ceftaroline was clinically and microbiologically non-inferior to vancomycin/aztreonam in the treatment of MRSA cSSSI. Key resistance issues include a rise in vancomycin minimum inhibitory concentrations in MRSA, reports of clonal isolates with linezolid resistance mediated by acquisition of the chloramphenicol/florfenicol resistance gene, and case reports of daptomycin resistance resulting in clinical failure. Novel antimicrobial targets must be identified with some regularity or we will face the risk of untreatable S. aureus infections. PMID- 22196395 TI - Introduction to the MRSA series of reviews. PMID- 22196396 TI - Central hemodynamics and arterial stiffness during the finals of the world cup soccer championship 2010. AB - BACKGROUND: Emotional stress is considered a risk factor for cardiovascular events, the underlying pathophysiology remains unclear. METHODS: To evaluate how emotional stress effects hemodynamics, thirteen healthy German soccer fans (mean 37.6 years, 24-56 years) were studied during live TV coverage of the finals with German national team participation (GP) and the respective finals without German participation (noGP). Peripheral blood pressure, heart rate, central blood pressure, augmentation pressure and index, cardiac output and peripheral resistance were measured. RESULTS: In the 1st hour before the match all parameters were not significantly different between the groups. In the GP group peripheral systolic pressure (1st halftime noGP 118 +/- 1(s.e.m) versus GP 126 +/ 2 mmHg, p<0.05, 2nd 117 +/- 1 vs. 125 +/- 2 mmHg, p<0.05), mean blood pressure, diastolic blood pressure, heart rate (1st 73 +/- 2 vs. 86 +/- 3 bpm, p<0.05, 2nd 75 +/- 2 vs. 87 +/- 2 bpm, p<0.05), cardiac output (1st 4,4 +/- 0,1 versus 4,8 +/ 0,1L/min, p<0.05, 2nd 4,6 +/- 0,1 versus 4,7 +/- 0,11 L/min, p>0.05) and peripheral resistance were significantly increased compared to the noGP group during the matches. Systolic central aortic pressure (noGP: 101 +/- 2 versus GP 107 +/- 2 mmHg, p<0.05) and central pulse pressure (noGP: 31.3 +/- 1.3 mmHg vs. GP: 38.5 +/- 2.7 mmHg, p<0,05) remained elevated during the second hour after the match. CONCLUSIONS: We observed persistent changes in central hemodynamics 2h after emotional stress. Despite normalization of peripheral values after the end of the finals, we observed prolonged elevation of central systolic blood and pulse pressure. Our findings contribute to the understanding of the increased risk of cardiovascular events in emotional stress. PMID- 22196397 TI - Education in mental health promotion and its impact on the participants' attitudes and perceived mental health. AB - BACKGROUND: Although the promotion of mental health (MHP) through education and training is widely accepted, there is scarce evidence for its effectiveness in the literature from outcome studies worldwide. The present study aimed to assess the effect of a three-semester MHP educational program on the recipients' opinions towards mental illness and on their own self-assessed health. METHODS: Respondents were 78 attendees who completed the assessment battery at the first (baseline) and the last session (end) of the training course. They were primary care physicians or other professionals, or key community agents, working in the greater Athens area. The course consisted of 44 sessions (4 h each), over a 3 semester period, focusing on the principles and methods of mental health promotion, the main aspects of major psychiatric disorders, and on relevant to health skills. Assessment instruments included the Opinion about Mental Illness (OMI) scale and the General Health Questionnaire (GHQ-28). RESULTS: The mean scores of three OMI factors, that is, social discrimination, social restriction and social integration, and the two GHQ-28 subscales, that is, anxiety/insomnia and social dysfunction, were significantly improved by the end of the training course. CONCLUSIONS: The results of this study provide evidence, with limitations, for the short-term effectiveness of the implemented educational MHP program on an adult group of recipients-key agents in their community. Because interventions for strengthening positive opinions about mental illness and enhancing self-assessed health constitute priority aims of mental health promotion, it would be beneficial to further investigate the sustainability of the observed positive changes. In addition it would be useful to examine (a) the possible interplay between the two outcome measures, that is, the effect of opinions of recipients about mental health on their perceived health, and (b) the applicability of this intervention in individuals with different sociodemographic profiles. PMID- 22196398 TI - [Facial dog bite injuries in children: retrospective study of 77 cases]. AB - INTRODUCTION: The face is the area most vulnerable for dog bites in children. Surgical management is an emergency to prevent infection, functional and aesthetic outcomes. The aim of this study was to define a new gravity scale, and to determine a prevention policy. PATIENTS AND METHODS: In our maxillofacial and plastic surgery department, we conducted a retrospective study from 2002 to 2010, including 77 children under 16 years old, victims of facial dog bite. We analyzed epidemiological, clinical data, surgical outcomes. RESULTS: The mean age was 5.36 years. Dogs were principally represented by class I and II dogs; 27,7% of them had ever bitten before. In almost all the cases, the dogs belong to the family or closers. Twenty-one percent of children belong to an unfavourable social environment; 71.43% of dog bites interested the central area of the face. The bites were deep in 77% of cases with amputation or extensive loss of substance in 31% of cases. The healing time was 10.54 months. Nearly a third of patients required several surgeries; 41.56% of patients had aesthetic and functional sequelae; 35.1% of children had psychological problems afterward. CONCLUSION: Facial children dog bites require a multidisciplinary approach, and a long-term follow-up. We propose a new classification of dog bite severity, more appropriate to the face. PMID- 22196399 TI - A pangenomic study of Bacillus thuringiensis. AB - Bacillus thuringiensis (B. thuringiensis) is a soil-dwelling Gram-positive bacterium and its plasmid-encoded toxins (Cry) are commonly used as biological alternatives to pesticides. In a pangenomic study, we sequenced seven B. thuringiensis isolates in both high coverage and base-quality using the next generation sequencing platform. The B. thuringiensis pangenome was extrapolated to have 4196 core genes and an asymptotic value of 558 unique genes when a new genome is added. Compared to the pangenomes of its closely related species of the same genus, B. thuringiensis pangenome shows an open characteristic, similar to B. cereus but not to B. anthracis; the latter has a closed pangenome. We also found extensive divergence among the seven B. thuringiensis genome assemblies, which harbor ample repeats and single nucleotide polymorphisms (SNPs). The identities among orthologous genes are greater than 84.5% and the hotspots for the genome variations were discovered in genomic regions of 2.3-2.8Mb and 5.0 5.6Mb. We concluded that high-coverage sequence assemblies from multiple strains, before all the gaps are closed, are very useful for pangenomic studies. PMID- 22196400 TI - Evolution of vertebrate central nervous system is accompanied by novel expression changes of duplicate genes. AB - The evolution of the central nervous system (CNS) is one of the most striking changes during the transition from invertebrates to vertebrates. As a major source of genetic novelties, gene duplication might play an important role in the functional innovation of vertebrate CNS. In this study, we focused on a group of CNS-biased genes that duplicated during early vertebrate evolution. We investigated the tempo-spatial expression patterns of 33 duplicate gene families and their orthologs during the embryonic development of the vertebrate Xenopus laevis and the cephalochordate Brachiostoma belcheri. Almost all the identified duplicate genes are differentially expressed in the CNS in Xenopus embryos, and more than 50% and 30% duplicate genes are expressed in the telencephalon and mid hindbrain boundary, respectively, which are mostly considered as two innovations in the vertebrate CNS. Interestingly, more than 50% of the amphioxus orthologs do not show apparent expression in the CNS in amphioxus embryos as detected by in situ hybridization, indicating that some of the vertebrate CNS-biased duplicate genes might arise from non-CNS genes in invertebrates. Our data accentuate the functional contribution of gene duplication in the CNS evolution of vertebrate and uncover an invertebrate non-CNS history for some vertebrate CNS-biased duplicate genes. PMID- 22196401 TI - A novel mutation in the MITF may be digenic with GJB2 mutations in a large Chinese family of Waardenburg syndrome type II. AB - Waardenburg syndrome type II (WS2) is associated with syndromic deafness. A subset of WS2, WS2A, accounting for approximately 15% of patients, is attributed to mutations in the microphthalmia-associated transcription factor (MITF) gene. We examined the genetic basis of WS2 in a large Chinese family. All 9 exons of the MITF gene, the single coding exon (exon 2) of the most common hereditary deafness gene GJB2 and the mitochondrial DNA (mtDNA) 12S rRNA were sequenced. A novel heterozygous mutation c.[742_743delAAinsT;746_747delCA] in exon 8 of the MITF gene co-segregates with WS2 in the family. The MITF mutation results in a premature termination codon and a truncated MITF protein with only 247 of the 419 wild type amino acids. The deaf proband had this MITF gene heterozygous mutation as well as a c.[109G>A]+[235delC] compound heterozygous pathogenic mutation in the GJB2 gene. No pathogenic mutation was found in mtDNA 12S rRNA in this family. Thus, a novel compound heterozygous mutation, c.[742_743delAAinsT;746_747delCA] in MITF exon 8 was the key genetic reason for WS2 in this family, and a digenic effect of MITF and GJB2 genes may contribute to deafness of the proband. PMID- 22196402 TI - Identification of quantitative trait loci associated with salt tolerance at seedling stage from Oryza rufipogon. AB - Soil salinity is one of the major abiotic stresses affecting plant growth and crop production. In the present study, salt tolerance at rice seedling stage was evaluated using 87 introgression lines (ILs), which were derived from a cross between an elite indica cultivar Teqing and an accession of common wild rice (Oryza rufipogon Griff.). Substantial variation was observed for four traits including salt tolerance score (STS), relative root dry weight (RRW), relative shoot dry weight (RSW) and relative total dry weight (RTW). STS was significantly positively correlated with all other three traits. A total of 15 putative quantitative trait loci (QTLs) associated with these four traits were detected using single-point analysis, which were located on chromosomes 1, 2, 3, 6, 7, 9 and 10 with 8%-26% explaining the phenotypic variance. The O. rufipogon-derived alleles at 13 QTLs (86.7%) could improve the salt tolerance in the Teqing background. Four QTL clusters affecting RRW, RSW and RTW were found on chromosomes 6, 7, 9 and 10, respectively. Among these four QTL clusters, a major cluster including three QTLs (qRRW10, qRSW10 and qRTW10) was found near the maker RM271 on the long arm of chromosome 10, and the O. rufipogon-derived alleles at these three loci increased RRW, RSW and RTW with additive effects of 22.7%, 17.3% and 18.5%, respectively, while the phenotypic variance explained by these three individual QTLs for the three traits varied from 19% to 26%. In addition, several salt tolerant ILs were selected and could be used for identifying and utilizing favorable salt tolerant genes from common wild rice and used in the salt tolerant rice breeding program. PMID- 22196403 TI - Development and high-throughput genotyping of substitution lines carring the chromosome segments of indica 9311 in the background of japonica Nipponbare. AB - Chromosome segment substitution lines (CSSLs) are useful for the precise mapping of quantitative trait loci (QTLs) and dissection of the genetic basis of complex traits. In this study, two whole-genome sequenced rice cultivars, the japonica Nipponbare and indica 9311 were used as recipient and donor, respectively. A population with 57 CSSLs was developed after crossing and back-crossing assisted by molecular markers, and genotypes were identified using a high-throughput resequencing strategy. Detailed graphical genotypes of 38 lines were constructed based on resequencing data. These CSSLs had a total of 95 substituted segments derived from indica 9311, with an average of about 2.5 segments per CSSL and eight segments per chromosome, and covered about 87.4% of the rice whole genome. A multiple linear regression QTL analysis mapped four QTLs for 1000-grain weight. The largest-effect QTL was located in a region on chromosome 5 that contained a cloned major QTL GW5/qSW5 for grain size in rice. These CSSLs with a background of Nipponbare may provide powerful tools for future whole-genome discovery and functional study of essential genes/QTLs in rice, and offer ideal materials and foundations for japonica breeding. PMID- 22196405 TI - Risk factors and quality of life for post-prostatectomy vesicourethral anastomotic stenoses. AB - OBJECTIVE: To evaluate the difference in vesicourethral anastomotic stenosis (VUAS) rates after open radical retropubic prostatectomy (RRP) vs robot-assisted radical prostatectomy (RARP), and to analyze associated factors and effect on quality of life. METHODS: From 2001 to 2009, a total of 1038 patients underwent RARP and 707 patients underwent open RRP. Perioperative factors and Expanded Prostate Cancer Index Composite (EPIC) quality of life scores were compared between patients who did and did not develop a VUAS. Independent significant predictors of VUAS development were identified using multivariable modeling. RESULTS: The incidence of VUAS in open RRP cases was higher (53/707, 7.5%) than for RARP (22/1038, 2.1%) (P<.0001). Intervention consisted of dilation in 34 of 75 cases (45.3%), internal urethrotomy in 8 of 75 (10.7%), and multiple procedures in 30 of 75 (40%). Open technique (P<.0001, odds ratio [OR]=3.0, 95% confidence interval [CI]=1.8-5.2), prostate-specific antigen (PSA) recurrence (P=.02, OR=2.2, 95% CI=1.2-4.1), postoperative hematuria (P=.02, OR=3.7, 95% CI=1.2-11.3), urinary leak (P=.002, OR=6.0, 95% CI=1.9-19.2), and urinary retention (P=.004, OR=3.5, 95% CI=1.5-8.7) were significant independent predictors of VUAS development. EPIC incontinence scores were similar between VUAS and non-VUAS patients, whereas irritative voiding scores were worse initially with VUAS but became similar by 12 months. CONCLUSION: There is a higher rate of VUAS after open RRP vs RARP. Most cases of VUAS require endoscopic intervention. Predictors include open surgery, PSA recurrence, and postoperative hematuria, urinary leak, and retention. There is no diminution of quality of life scores at 12 months. PMID- 22196406 TI - Relative efficacy of perioperative gemcitabine and cisplatin versus methotrexate, vinblastine, adriamycin, and cisplatin in the management of locally advanced urothelial carcinoma of the bladder. AB - OBJECTIVE: To compare the outcomes of patients treated in the perioperative setting with methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) versus gemcitabine and cisplatin (GC). Systemic cisplatin-based chemotherapy regimens are the mainstay of treatment for patients with advanced bladder cancer. GC has often been used interchangeably with MVAC in neoadjuvant or adjuvant settings for patients with locally advanced (cT2N0M0-cT4N2M0) bladder cancer without adequate evidence. METHODS: A total of 114 patients treated with systemic chemotherapy for Stage T2-T4N0-N2M0 urothelial cell carcinoma of the bladder were included in the present study. The survival times were estimated and compared using the Kaplan Meier method and log-rank test, respectively. Univariate and multivariate Cox proportional hazards models were used to determine the statistical significance. RESULTS: Of the 114 patients included in the present study, 37 (32%) were treated with GC and 77 (68%) with MVAC. In the neoadjuvant group, no difference was found between the 2 chemotherapeutic regimens in terms of the pathologic complete response rate at either cystectomy or during cystoscopy (14 [31%] of 45 MVAC patients vs 4 [25%] of 16 GC patients; P=.645). On multivariate analysis, the choice of regimen was not an independent predictor of cancer-specific death (hazard ratio 1.3, 95% confidence interval 0.67-2.57; P=.421) or overall survival (hazard ratio 1.3, 95% confidence interval 0.76-2.24; P=.330). CONCLUSION: Despite the lack of data on the relative efficacy of GC versus MVAC in the neoadjuvant and adjuvant settings, these regimens have been used interchangeably. The present investigation did not find the choice of cisplatin-based regimen to be an independent predictor of survival. A trend was seen toward improved survival and a greater complete response rate in the MVAC group. PMID- 22196407 TI - Doxazosin versus tizanidine for treatment of dysfunctional voiding in children: a prospective randomized open-labeled trial. AB - OBJECTIVE: To examine the efficacy and tolerability of tizanidine for the treatment of dysfunctional voiding in children compared with those of doxazosin. METHODS: A total of 40 children with dysfunctional voiding were enrolled in a prospective, randomized, 2-parallel group, flexible-dose study. The evaluations were performed in accordance with the International Children's Continence Society guidelines. The children were followed up after 1 week and then monthly for 6 months for the clinical, urine culture, and urodynamic parameters. The degree of improvement was assessed using a satisfaction scale that ranged from 0 (no improvement at all) to 10 (total improvement). RESULTS: A total of 40 patients with a mean+/-SD age of 7+/-2.6 years were enrolled. The clinical and urodynamic parameters were comparable between both groups. At the last follow-up visit, both groups had had similar improvement in the severity of symptoms, satisfaction scale, and noninvasive flowmetry parameters. In the doxazosin group, urge episodes was the only symptom that showed a significant reduction compared with the baseline values (P=.028). However, the incidence of nocturnal enuresis, urgency attacks, and daytime incontinence were significantly reduced compared with baseline in the tizanidine group (P=.003, P=.008, and P=.017, respectively). Adverse effects were recorded in 6 patients (15%). Epigasteric pain was reported in 2 children (10%) who received doxazosin. In the tizanidine group, a loss of appetite was noted in 2 children (10%), epigastric pain in 1 (5%), and headache in 1 (5%). CONCLUSION: Tizanidine could be a safe and effective treatment of children with dysfunctional voiding due to pelvic floor/skeletal sphincter dysfunction. More placebo-controlled trails with larger sample sizes are needed. PMID- 22196408 TI - Is it transitional cell carcinoma or renal cell carcinoma on computed tomography image? AB - We report on a 58-year-old female patient with renal cell carcinoma simulating transitional cell carcinoma on computed tomography. The computed tomography scan showed an enhancing 2.5-cm left renal pelvic mass without renal parenchymal mass. Urinalysis revealed microscopic hematuria. Cystoscopy and urine cytology was negative for transitional cell carcinoma. Laparoscopic nephroureterectomy was done under the preoperative diagnosis of localized transitional cell carcinoma of the renal pelvis according to the computed tomography findings. The histologic result, however, was a clear cell renal cell carcinoma. PMID- 22196409 TI - Effect of small interfering RNA targeting hypoxia-inducible factor-1alpha on radiosensitivity of PC3 cell line. AB - OBJECTIVE: To evaluate the effect of silencing hypoxia-inducible factor-1alpha (HIF-1alpha) expression by small interfering RNA (siRNA) on the radiosensitivity of the PC3 cell line. METHODS: The expression of HIF-1alpha in PC3, a p53-null and androgen-independent prostate cancer cell line, was knocked down by siRNA. Irradiation was performed at 48 hours after transfection. The cells were divided into 3 groups: the PC3 group, control group (transfected with scramble siRNA), and HIF-1alpha silence group. HIF-1alpha expression was determined using real time polymerase chain reaction and Western immunoblotting. A clonogenic assay and the cell counting kit-8 assay were performed to determine the radiosensitivity. Flow cytometry was used to assess apoptosis and cell cycle distribution. RESULTS: HIF-1alpha siRNA downregulated HIF-1alpha expression in PC3 cells on the mRNA level and protein level, and its silencing effect on mRNA level was evident at 24 72 hours. The HIF-1alpha silence group had a low final slope of exponential part of a radiation survival curve, survival fraction of 2 Gy, quasi-threshold dose, and extrapolation number, and the sensitizing enhancement ratio was 1.24. The cell counting kit-8 assay showed decreased cellular viability (24 hours, F = 139.74, P < .01; 48 hours, F = 495.49, P < .01; 72 hours, F = 426.89, P < .01; 96 hours, F = 471.11, P < .01) in the HIF-1alpha silence group. Silencing HIF-1alpha also induced more apoptosis (PC3, 17.9% +/- 1.65%; control group, 18.6% +/- 1.37%; HIF-1alpha silence group, 29.1% +/- 2.16%; F = 169.9, P < .01) and cell cycle arrest at the S, G(2)/M phase. CONCLUSION: The suppression of HIF-1alpha in PC3 cells sensitizes the PC3 cells to irradiation. We have shown that HIF-1alpha inhibition attenuates repair of postradiation injury, with an increase in both interphase death and reproductive death after irradiation, apoptotic potential, and cell cycle arrest at the proliferative phase. PMID- 22196410 TI - Can we avoid percutaneous nephrolithotomy in high-risk elderly patients using the Charlson comorbidity index? AB - OBJECTIVE: To determine whether Charlson comorbidity index (CCI) predicts the postoperative complications after percutaneous nephrolithotomy (PCNL) and could be a plausible option to avoid surgery and its potential risks in elderly patients with significant comorbidites. METHODS: The data from 283 elderly patients (age >= 60 years) who underwent PCNL in 4 large referral hospitals were reviewed in the present multicenter study. For each patient, we evaluated pre existing comorbidities and calculated the CCI score. The patients were classified to 3 CCI score categories (0, 1, >= 2) and compared regarding the stone-free and complications rates. RESULTS: The mean patient age was 64.7, 65.6, and 67.7 years in the 3 groups. The stone-free rate after primary PCNL was 85.7% in group 1, 86.1% in group 2, and 75.0% in group 3. These rates increased to 90.8%, 95.4%, and 83.9% after a second intervention (P = .049). The overall postoperative complication rate was 38.8%. The most common complication was hemorrhage necessitating blood transfusion in 34 patients (12%), and we found an increased risk of hemorrhage associated with the CCI score (P = .011). Life-threatening medical complications developed in 7.6% of the patients in group 1, 12% of the patients in group 2, and 28.6% of the patients in group 3 (P = .001). A multivariate logistic regression analysis showed that a high CCI score, bleeding, and operative time had significant influence on the postoperative medical complication in this population. CONCLUSION: Conservative management of asymptomatic large kidney stones appears to be a safe alternative to PCNL in elderly patients with significant comorbidites. PMID- 22196411 TI - Safety and efficacy of ultrasound-guided percutaneous nephrolithotomy for treatment of urinary stone disease in children. AB - OBJECTIVE: To present the feasibility and efficacy of ultrasound-guided percutaneous nephrolithotomy for the treatment of urinary stone disease in children. METHODS: The medical records and files of 17 patients with renal stones (17 renal units) who were aged <= 16 years who had undergone ultrasound-guided percutaneous nephrolithotomy from 2008 to 2010 were retrospectively reviewed and analyzed. Ultrasonography was used for guidance in all patients in every step of the procedure. Fluoroscopy was used to aid in tract dilation in the initial cases of the series and to evaluate for stone clearance in all cases. The operative and postoperative findings were assessed. RESULTS: The average age of the patients was 8.8 +/- 2.86 years (range 5-15). The mean stone size was calculated as 337.4 +/- 52.9 mm(2) (range 260-446). The mean operative time was 67.9 +/- 14.58 minutes (range 45-95). Fever, urine leakage, and bleeding requiring blood transfusion were observed in 3, 1, and 1 patient, respectively. The fluoroscopic screening time was limited to 17.76 +/- 15.5 seconds (range 1-54). Neighboring organ injuries were not observed. The overall success rate improved from 82.35% to 100% with additional treatment modalities (shock wave lithotripsy in 2 and ureteroscopy in 1). CONCLUSION: Percutaneous nephrolithotomy can be safely performed with ultrasound guidance in children, providing the advantages of less radiation exposure, no adjacent organ injury, and similar success and complication rates compared with fluoroscopic guidance. PMID- 22196412 TI - An evaluation of the effects of long-term cell phone use on the testes via light and electron microscope analysis. AB - OBJECTIVE: To investigate whether the low-intensity electromagnetic waves transmitted by cell phones cause histopathological or ultrastructural changes in the testes of rats. MATERIALS AND METHODS: Wistar-Kyoto male rats were placed into either a control group or a group that was exposed to an electromagnetic field (EMF). Two cell phones with Specific Absorbation Rate values of 1.58 were placed and left off in cages that housed 15 rats included in the control group, and four cell phones were placed and left on in cages that housed 30 rats included in the experimental group. After 3 months, weights, seminiferous tubule diameters, and spermatogenic cell conditions of all testes of the rats were evaluated. One half of each testis was examined also under an electron microscope. RESULTS: No significant differences were observed between the testis weights, seminiferous tubule diameters, and histopathological evaluations between rats that had and had not been exposed to EMF. Electron microscope analysis revealed that the membrana propria thickness and the collagen fiber contents were increased and the capillary veins extended in the experimental group. Common vacuolization in the cytoplasm of the Sertoli cells, growth of electron-dense structures, and existence of large lipid droplets were noted as the remarkable findings of this study. CONCLUSION: Although the cells that had been exposed to long-term, low-dose EMF did not present any findings that were contrary to the control conditions, the changes observed during ultrastructural examination gave the impression that significant changes may occur if the study period were to be extended. Longer studies are needed to better understand the effects of EMFs on testis tissue. PMID- 22196413 TI - We need a better marker for prostate cancer. How about renaming PSA? PMID- 22196414 TI - Anorchia masked by septo-optic dysplasia. AB - Hypogonadism affecting the male pediatric population is uncommon, with that attributed to multiple unrelated etiologies being exceedingly rare. We report a case of septo-optic dysplasia, an atypical cause of delayed puberty, with subsequent workup unveiling 2 coexistent conditions: hypogonadotropic hypogonadism and anorchia. Primary and secondary etiologies must be considered in patients with undescended testes. Thorough evaluation is mandatory to ensure proper diagnosis and care, because Occam's razor can, on unique occasions, be double-edged. PMID- 22196415 TI - A muscle-sparing modified Gibson incision for hand-assisted retroperitoneoscopic nephroureterectomy and bladder cuff excision--an approach through a window behind the rectus abdominis muscle. AB - OBJECTIVE: To report our technique using a modified muscle-sparing Gibson incision for hand-assisted retroperitoneoscopic nephroureterectomy (HARN) and open bladder cuff excision. MATERIALS AND METHODS: Thirty-four patients with upper tract transitional cell carcinoma received HARN and open bladder cuff excision using the modified muscle-sparing Gibson incision-an approach through a window behind the rectus abdominis muscle with the patient in a supine position with the legs extended and abducted at 45-60 degrees with the surgeon standing between the legs of the patient. The window behind the rectus muscle was identified with ease. HARN and open bladder cuff excision were performed uneventfully using this incision. Mean estimated blood loss was 119 mL. Mean operation time was 139 minutes. Morphine was required for pain relief for 1-3 days (mean 16.5 mg). Mean time to oral intake was 1.5 days and to ambulation was 2.1 days. No lower abdominal bulge was found during a 15.4-month follow-up. CONCLUSION: This modified muscle-sparing Gibson incision for retroperitoneal hand assisted laparoscopic nephrectomy has the benefit of easier retroperitoneal approach of the Gibson incision. Iliohypogastric nerves can be spared under direct vision. By merely retracting and not incising or splitting the rectus abdominis muscle, this incision may decrease wound-related morbidity. This window could be an important portal for hand-assisted laparoscopic surgeries. PMID- 22196419 TI - Commentary on myofascial release therapy in systemic lupus erythematosus and scleroderma. PMID- 22196421 TI - Feasibility and effects of a group kickboxing program for individuals with multiple sclerosis: a pilot report. AB - BACKGROUND AND PURPOSE: Balance and mobility impairments are common in persons with multiple sclerosis (MS). The primary purpose of this pilot program was to evaluate the feasibility and the effects of group kickboxing on balance and mobility in individuals with MS. METHODS: Four individuals with relapsing remitting or secondary progressive MS participated in a group kickboxing program two times per week for 8 weeks. Outcome measures included the Berg Balance Scale (BBS), Dynamic Gait Index (DGI), Timed Up and Go (TUG), walking speed and the Activities Specific Balance Confidence Scale (ABC). RESULTS: Following training, 3 of 4 participants had improvements in BBS performance. All participants demonstrated improvements in the DGI. Changes in the TUG, ABC, and walking speed were more variable. CONCLUSION: Group kickboxing appears to be a feasible exercise activity for individuals with MS and may lead to improvement in select measures of balance. Further investigation may be warranted. PMID- 22196422 TI - Understanding gait control in post-stroke: implications for management. AB - The role of the brain in post-stroke gait is not understood properly, although the ability to walk becomes impaired in more than 80% of post-stroke patients. Most, however, regain some ability to walk with either limited mobility or inefficient, asymmetrical or unsafe gait. Conventional intervention focuses on support of weak muscles or body part by use of foot orthosis and walking aids. This review provides an overview of available evidence of neuro-kinesiology & neurophysiology of normal and post-stroke gait. The role of the spinal cord has been explored, more in animals than humans. Mammalian locomotion is based on a rhythmic, "pacemaker" activity of the spinal stepping generators. Bipedal human locomotion is different from quadripedal animal locomotion. However, knowledge derived from the spinal cord investigation of animals, is being applied for management of human gait dysfunction. The potential role of the brain is now recognized in the independent activation of muscles during walking. The brain modifies the gait pattern during the complex demands of daily activities. Though the exact role of the motor cortex in control of gait is unclear, available evidence may be applied to gait rehabilitation of post-stroke patients. PMID- 22196423 TI - Noninvasively measuring the hemodynamic effects of massage on skeletal muscle: a novel hybrid near-infrared diffuse optical instrument. AB - Increase in tissue blood flow is one of the most acknowledged potential effects of massage; however, actual research studies examining this phenomenon are inconsistent and inconclusive. One possible reason for continued uncertainty regarding this topic is methodology, specifically how tissue blood flow is measured because limitations exist in previously utilized technologies. Near infrared spectroscopy (NIRS) affords massage researchers a versatile and non invasive measurement option by providing dynamic information on oxy- and deoxy hemoglobin concentrations, total hemoglobin concentration, and blood oxygen saturation in deep tissue. Near-infrared diffuse correlation spectroscopy (DCS) is an innovative technique for continuous non-invasive measurement of blood flow in deep tissue. The combination of these two technologies has resulted in a novel hybrid diffuse optical instrument for simultaneous measurement of limb muscle blood flow and oxygenation. The purposes of this short report are to review previous blood flow measurement techniques and limitations in massage therapy research, introduce a novel hybrid near-infrared diffuse optical instrument that addresses previous limitations in the assessment of hemodynamic properties, outline a proposed massage therapy pilot study utilizing the novel measurement technology, and present sample data from a pilot participant using the introduced novel technology. PMID- 22196424 TI - The effect of two manipulative therapy techniques and their outcome in patients with sacroiliac joint syndrome. AB - OBJECTIVES: To compare the effect of sacroiliac joint (SIJ) manipulation with SIJ and lumbar manipulation for the treatment of SIJ syndrome. METHODS: Thirty-two women with SIJ syndrome were randomly divided into two groups of 16 subjects. One group received the high-velocity low-amplitude (HVLA) manipulation to the SIJ and the other group received both SIJ and lumbar HVLA manipulation to both the SIJ and lumbar spine in a single session. The outcomes were assessed using visual analogue scale (VAS) at baseline, immediately, 48 h and one month after the treatment for pain and also Oswestry Disability Index (ODI) questionnaire at baseline, 48 h and one month after the treatment. RESULTS: Analysis revealed a statistically significant improvement immediately, at 48 h and one month after treatment for pain and significant improvement at 48 h and one month after treatment for functional disability in the SIJ manipulated group. A significant improvement immediately, at 48 h and one month after treatment for pain and significant improvement at 48 h and one month after treatment for functional disability in the SIJ and lumbar manipulated group was also found. Furthermore, there were significant differences within groups in ODI and VAS when using Friedman test in both groups. By using Wilcoxon rank sum test no differences were observed in change scores between the two groups immediately, 48 h and one month after the treatment for VAS, or after 48 h and one month after the treatment for the ODI. CONCLUSION: A single session of SIJ and lumbar manipulation was more effective for improving functional disability than SIJ manipulation alone in patients with SIJ syndrome. Spinal HVLA manipulation may be a beneficial addition to treatment for patients with SIJ syndrome. PMID- 22196425 TI - A holistic approach to movement education in sport and fitness: a systems based model. AB - The typical model used by movement professionals to enhance performance relies on the notion that a linear increase in load results in steady and progressive gains, whereby, the greater the effort, the greater the gains in performance. INTRODUCTION: Traditional approaches to movement progression typically rely on the proper sequencing of extrinsically based activities to facilitate the individual in reaching performance objectives. However, physical rehabilitation or physical performance rarely progresses in such a linear fashion; instead they tend to evolve non-linearly and rather unpredictably. A dynamic system can be described as an entity that self-organizes into increasingly complex forms. Applying this view to the human body, practitioners could facilitate non-linear performance gains through a systems based programming approach. SYSTEMIC MODEL: Utilizing a dynamic systems view, the Holistic Approach to Movement Education (HADME) is a model designed to optimize performance by accounting for non-linear and self-organizing traits associated with human movement. In this model, gains in performance occur through advancing individual perspectives and through optimizing sub-system performance. This inward shift of the focus of performance creates a sharper self-awareness and may lead to more optimal movements. PMID- 22196426 TI - Evidence-based medicine: revisiting the pyramid of priorities. AB - Evidence-based medicine (EBM) is beset with numerous problems. In addition to the fact that varied audiences have each customarily sought differing types of evidence, EBM traditionally incorporated a hierarchy of clinical research designs, placing systematic reviews and meta-analyses at the pinnacle. Yet the canonical pyramid of EBM excludes numerous sources of research information, such as basic research, epidemiology, and health services research. Models of EBM commonly used by third party payers have ignored clinical judgment and patient values and expectations, which together form a tripartite and more realistic guideline to effective clinical care. Added to this is the problem in which enhanced placebo treatments in experimentation may obscure verum effects seen commonly in practice. Compounding the issue is that poor systematic reviews which comprise a significant portion of EBM are prone to subjective bias in their inclusion criteria and methodological scoring, shown to skew outcomes. Finally, the blinding concept of randomized controlled trials is particularly problematic in applications of physical medicine. Examples from the research literature in physical medicine highlight conclusions which are open to debate. More progressive components of EBM are recommended, together with greater recognition of the varying audiences employing EBM. PMID- 22196428 TI - Therapeutic effects of traditional Thai massage on pain, muscle tension and anxiety in patients with scapulocostal syndrome: a randomized single-blinded pilot study. AB - The purpose of this study was to investigate the therapeutic effects of traditional Thai massage (TTM) on pain intensity, pressure pain threshold (PPT), muscle tension and anxiety associated with scapulocostal syndrome (SCS). Twenty patients were randomly allocated to receive a 30-min session of either TTM or physical therapy modalities (PT: ultrasound therapy and hot pack) for 9 sessions over a period of 3 weeks. Pain intensity, PPT, muscle tension and anxiety were measured before and immediately after the first treatment session, 1 day after the last treatment session and 2 weeks after the last treatment session. Results indicated that the TTM group showed a significant improvement in all parameters after the first treatment session and at 1 day and 2 weeks after the last treatment session (p < 0.05). For all outcomes, similar changes were observed in the PT group except for PPT (p < 0.05). The adjusted post-test mean values of each assessment time point for pain intensity and muscle tension were significantly lower in the TTM group than those of the PT group (p < 0.01). In addition, the values for PPT were significantly higher in the TTM group (p > 0.05). We therefore suggest that TTM could be an alternative treatment for the patient with SCS. PMID- 22196427 TI - A preliminary report of musculoskeletal dysfunction in female chronic pelvic pain: a blinded study of examination findings. AB - INTRODUCTION AND HYPOTHESIS: Female chronic pelvic pain is prevalent and causes disability. Can women with self-reported chronic pelvic pain (CPP) be distinguished from pain-free women by demonstrating a greater number of abnormal musculoskeletal findings on examination? METHODS: In this cross-sectional study, blinded examiners performed 9 physical exam maneuvers on 48 participants; 19 with CPP, and 29 pain-free. Frequency of positive findings between groups, total number of positive exam findings, cluster analysis, and sensitivity - specificity analyses were performed. RESULTS: Women with CPP presented with significantly more abnormal findings than pain-free women. By using two examination maneuvers, examiners correctly classified women with self-reported CPP from pain-free women 85% of the time. CONCLUSIONS: Abnormal findings on musculoskeletal exam are more common in women with self-reported CPP. Women with CPP might benefit from a faster time to diagnosis and improved treatment outcomes if a musculoskeletal contribution to CPP was identified earlier. PMID- 22196429 TI - Fascia science and clinical applications: a clinician/researcher's perspectives. PMID- 22196430 TI - Fascia research--a narrative review. AB - This article reviews fascia research from our laboratory and puts this in the context of recent progress in fascia research which has greatly expanded during the past seven or eight years. Some readers may not be familiar with the terminology used in fascia research articles and are referred to LeMoon (2008) for a glossary of terms used in fascia-related articles. PMID- 22196431 TI - Visceral mobilization can lyse and prevent peritoneal adhesions in a rat model. AB - OBJECTIVE: Peritoneal adhesions are almost ubiquitous following surgery. Peritoneal adhesions can lead to bowel obstruction, digestive problems, infertility, and pain, resulting in many hospital readmissions. Many approaches have been used to prevent or treat adhesions, but none offer reliable results. A method that consistently prevented or treated adhesions would benefit many patients. We hypothesized that an anatomically-based visceral mobilization, designed to promote normal mobility of the abdominal contents, could manually lyse and prevent surgically-induced adhesions. MATERIAL AND METHODS: Cecal and abdominal wall abrasion was used to induce adhesions in 3 groups of 10 rats (Control, Lysis, and Preventive). All rats were evaluated 7 days following surgery. On postoperative day 7, unsedated rats in the Lysis group were treated using visceral mobilization, consisting of digital palpation, efforts to manually lyse restrictions, and mobilization of their abdominal walls and viscera. This was followed by immediate post-mortem adhesion evaluation. The rats in the Preventive group were treated daily in a similar fashion, starting the day after surgery. Adhesions in the Control rats were evaluated 7 days after surgery without any visceral mobilization. RESULTS: The therapist could palpate adhesions between the cecum and other viscera or the abdominal wall. Adhesion severity and number of adhesions were significantly lower in the Preventive group compared to other groups. In the Lysis and Preventive groups there were clear signs of disrupted adhesions. CONCLUSIONS: These initial observations support visceral mobilization may have a role in the prevention and treatment of post-operative adhesions. PMID- 22196432 TI - A theoretical framework for the role of fascia in manual therapy. AB - A theoretical framework for the role that fascia may play in apparently diverse passive manual therapies is presented. The relevant anatomy of fascia is briefly reviewed. Therapies are divided into myofascial ('soft tissue') and manipulative ('joint-based') and comparisons are made between them on a qualitative basis using measures of pain, function and 'autonomic activation'. When these three outcomes are evaluated between therapies it is observed that they are usually comparable in the quality, if not the quantity of the measures. Viewed from a patients' perspective alone the therapeutic benefits are hard to distinguish. It is proposed that a biologically plausible mechanism which may generate a significant component of the observed effects of manual therapies of all descriptions, is the therapeutic stimulation of fascia in its various forms within the body. Such considerations may help explain why diverse therapies apparently give comparable results. PMID- 22196434 TI - Pilates: release or recruit? PMID- 22196433 TI - Strain hardening of fascia: static stretching of dense fibrous connective tissues can induce a temporary stiffness increase accompanied by enhanced matrix hydration. AB - This study examined a potential cellular basis for strain hardening of fascial tissues: an increase in stiffness induced by stretch and subsequent rest. Mice lumbodorsal fascia were isometrically stretched for 15 min followed by 30 min rest (n=16). An increase in stiffness was observed in the majority of samples, including the nonviable control samples. Investigations with porcine lumbar fascia explored hydration changes as an explanation (n=24). Subject to similar loading procedures, tissues showed decreases in fluid content immediately post stretch and increases during rest phases. When allowed sufficient resting time, a super-compensation phenomenon was observed, characterised by matrix hydration higher than initial levels and increases in tissue stiffness. Therefore, fascial strain hardening does not seem to rely on cellular contraction, but rather on this super-compensation. Given a comparable occurrence of this behaviour in vivo, clinical application of routines for injury prevention merit exploration. PMID- 22196435 TI - Pilates: practical thoughts on release or recruit? PMID- 22196436 TI - The effect of Pilates exercises on body composition: a systematic review. AB - OBJECTIVE: The purpose of this systematic review was to determine how Pilates exercises have impacted body composition (BC) on selected populations. METHODS: A comprehensive literature search was performed using the keywords 'Pilates, body composition, systematic review, literature review, overweight, obesity, healthy weight, underweight' and their combination. RESULTS: Seven studies met the inclusion criteria and after further quality analyses it was determined that there is currently poor empirical quantitative evidence indicating a positive effect of Pilates exercises on BC. Several methodological flaws were observed in the studies analyzed, including few full-text published studies looking into the effects of Pilates exercises on BC, a lack of true experimental research designs, limited standardization in measurement techniques, insufficient or no control of the nutritional status, and inconsistent instructor qualifications. CONCLUSION: Well-designed research is needed to determine how Pilates exercises impact BC on selected populations. PMID- 22196437 TI - Case report: the effects of massage therapy on lumbar spondylolisthesis. AB - OBJECTIVE: This study seeks to find out the impact of massage techniques, including myofascial and muscle energy techniques, on the symptoms of pain, muscular hypertonicity, and structural misalignment associated with isthmic lumbar spondylolisthesis. METHODS: A 30-year-old female was diagnosed with spondylolisthesis at age 12, has chronic mild to moderate back pain during prolonged walking/standing, hyperlordosis and anterior rotation of the pelvis. A 7-session treatment series of muscle energy techniques, and a type of myofascial bodywork known as active myofascial technique, was carried out, measuring rotational changes of the ilia, and the length of standing/walking time before low back pain onset. RESULTS: The onset of low back pain was delayed during walking/standing over the course of treatment, hyperlordosis decreased, and hypertonicity of iliopsoas and quadrates lumborum muscles decreased. Bilateral net reduction of illial rotation was achieved, but with irregular changes. CONCLUSION: Due to inconsistent and unreliable data, results were not conclusive. However, this study brings into question the role of hip flexor and spinal extensor muscles in normalizing postural misalignment associated with spondylolisthesis. It also highlights the importance of precise and detailed measures in massage research, as well the function of body awareness in this condition. Future research is needed to support the efficacy of massage therapy as a conservative strategy for lumbar isthmic spondylolisthesis. PMID- 22196438 TI - The baby get-up. PMID- 22196439 TI - Global host metabolic response to Plasmodium vivax infection: a 1H NMR based urinary metabonomic study. AB - BACKGROUND: Plasmodium vivax is responsible for the majority of malarial infection in the Indian subcontinent. This species of the parasite is generally believed to cause a relatively benign form of the disease. However, recent reports from different parts of the world indicate that vivax malaria can also have severe manifestation. Host response to the parasite invasion is thought to be an important factor in determining the severity of manifestation. In this paper, attempt was made to determine the host metabolic response associated with P. vivax infection by means of NMR spectroscopy-based metabonomic techniques in an attempt to better understand the disease pathology. METHODS: NMR spectroscopy of urine samples from P. vivax-infected patients, healthy individuals and non malarial fever patients were carried out followed by multivariate statistical analysis. Two data analysis techniques were employed, namely, Principal Component Analysis [PCA] and Orthogonal Projection to Latent Structure Discriminant Analysis [OPLS-DA]. Several NMR signals from the urinary metabolites were further selected for univariate comparison among the classes. RESULTS: The urine metabolic profiles of P. vivax-infected patients were distinct from those of healthy individuals as well as of non-malarial fever patients. A highly predictive model was constructed from urine profile of malarial and non-malarial fever patients. Several metabolites were found to be varying significantly across these cohorts. Urinary ornithine seems to have the potential to be used as biomarkers of vivax malaria. An increasing trend in pipecolic acid was also observed. The results suggest impairment in the functioning of liver as well as impairment in urea cycle. CONCLUSIONS: The results open up a possibility of non invasive analysis and diagnosis of P. vivax using urine metabolic profile. Distinct variations in certain metabolites were recorded, and amongst these, ornithine may have the potential of being used as biomarker of malaria. Pipecolic acid also showed increasing trend in the malaria patient compared to the other groups. PMID- 22196440 TI - Malignant progression in O6-methylguanine-DNA methyltransferase-deficient esophageal cancer cells is associated with Ezrin protein. AB - The abnormal function of O(6)-methylguanine-DNA methyltransferase (MGMT) is reported to be associated with the occurrence of various tumors and malignant tumor progression. However, little evidence is available to describe its role in esophageal carcinogenesis. To address this issue, we constructed a stable MGMT silenced esophageal cancer cell line by RNA interference, and exposed the cells to N-methyl-N-nitro-N-nitrosoguanidine (MNNG) to investigate the role that MGMT plays in toxicity. During this time, we also observed the malignant behavior of cells in vitro and in vivo. In addition, two-dimensional electrophoresis and mass spectrometry were used to detect and confirm the proteins that were differentially expressed in the MGMT-deficient and MGMT-proficient cells, which might be responsible for the malignant alteration of cells. Results showed that the IC(50) of MGMT-deficient and MGMT-proficient cells exposed to MNNG was 30 MUM and 65 MUM, respectively, and MGMT-deficient cells had more aggressive motility and invasive abilities compared with MGMT-proficient cells. Nineteen differentially expressed proteins were detected between the MGMT-deficient and MGMT-proficient cells, 14 of which were identified, including the membrane cytoskeleton linker protein, Ezrin, which was confirmed by both mass spectrometry and western blot analysis. The correlation between MGMT, Ezrin expression, and the malignant behavior of one normal epithelial esophageal cell line and seven esophageal cancer lines is discussed. In conclusion, loss of MGMT expression leads EC109 esophageal cancer cells to have increased malignant behavior, which may correlate with its high Ezrin protein expression. PMID- 22196443 TI - Regarding the novel drug OMS103HP. PMID- 22196446 TI - Novel drug in arthroscopic meniscectomy. PMID- 22196448 TI - Questions about remnant preservation and a femoral tensioning technique. PMID- 22196449 TI - All-arthroscopic implant-free iliac crest bone grafting: new technique and case report. AB - Glenoid bone loss is a recognized risk for recurrent instability. Open J-graft augmentation has been reported as a well-established procedure for anterior shoulder instability. Few data are available on arthroscopic techniques for the repair of bony Bankart lesions. We describe an all-arthroscopic implant-free iliac crest bone grafting technique and present the case of a 32-year-old hockey player who underwent glenoid reconstruction using this novel arthroscopic repair technique after 2 failed soft-tissue procedures. After 13 months, the patient reached nearly full range of motion with a slight loss of external rotation. The computed tomography scan showed a restoration of the glenoid cavity and complete healing of the graft. PMID- 22196450 TI - DNA methylation is associated with downregulation of the organic cation transporter OCT1 (SLC22A1) in human hepatocellular carcinoma. AB - BACKGROUND: Organic cation transporters (OCTs) determine not only physiological processes but are also involved in the cellular uptake of anticancer agents. Based on microarray analyses in hepatocellular carcinoma (HCC), SLC22A1/OCT1 mRNA seems to be downregulated, but systematic protein expression data are currently missing. Moreover, the underlying molecular mechanisms responsible for altered SLC22A1 expression in HCC are not fully understood. Therefore, we investigated the role of DNA methylation in the transcriptional regulation of the family members SLC22A1/OCT1, SLC22A2/OCT2 and SLC22A3/OCT3 in HCC. METHODS: Semiquantitative immunohistochemistry of SLC22A1 protein expression was performed in paired HCC and histological normal adjacent liver tissues (n = 71) using tissue microarray analyses, and the results were correlated with clinicopathological features. DNA methylation, quantified by MALDI-TOF mass spectrometry and gene expression of SLC22A1, SLC22A2 and SLC22A3 were investigated using fresh-frozen HCC (n = 22) and non-tumor adjacent liver tissues as well as histologically normal liver samples (n = 120) from a large-scale liverbank. RESULTS: Based on tissue microarray analyses, we observed a significant downregulation of SLC22A1 protein expression in HCC compared to normal adjacent tissue (P < 0.0001). SLC22A1 expression was significantly inverse correlated with expression of the proliferation marker MIB1/Ki-67 (rs = -0.464, P < 0.0001). DNA methylation of SLC22A1 was significantly higher in HCC compared with non-tumor adjacent liver tissue and was lowest in histologically normal liver tissue. Methylation levels for SLC22A1 in combination with RASSF1A resulted in a specificity of > 90% and a sensitivity of 82% for discriminating HCC and tumor-free liver tissue. CONCLUSIONS: DNA methylation of SLC22A1 is associated with downregulation of SLC22A1 in HCC and might be a new biomarker for HCC diagnosis and prognosis. Moreover, targeting SLC22A1 methylation by demethylating agents may offer a novel strategy for anticancer therapy of HCC. PMID- 22196451 TI - Different dimerisation mode for TLR4 upon endosomal acidification? AB - TLR4 is unique among pathogen-recognition receptors in that it initiates different pathways in different cellular locations. Binding of a bridging factor, Mal, allows recruitment of an adapter protein, MyD88, at the plasma membrane, which leads to the production of proinflammatory cytokines. Upon internalization, TLR4 uses a different bridging factor, TRAM, to activate a MyD88-independent pathway that results in type I interferon expression. Interestingly, both Mal and TRAM are localised initially at the plasma membrane. In this Opinion, I suggest a possible mechanism by which endosomal acidification triggers the differential adaptor usage of TLR4. I discuss the evidence of the pH sensitivity of TLR4 and propose a new dimerisation mode for TLR4 based on the crystal structure of the related receptor TLR3 bound to its ligand, double-stranded RNA. PMID- 22196453 TI - An analysis of outcomes after use of the Maxwell-Brancheau Arthroereisis implant. AB - The authors present a retrospective study of 35 consecutive patients (60 feet) treated with the Maxwell-Brancheau Arthroereisis (MBA) implant. The mean age of the cohort at the time of surgery was 14.3 (range 5 to 46) years, and 22 (62.86%) men and 13 (37.14%) women were included. Preoperative and postoperative anteroposterior and lateral foot radiographs were compared at a mean of 36 (range 18 to 48) months postoperatively, and the following mean changes were reported: talocalcaneal angle 24.15 degrees +/- 7.97 degrees to 18.53 degrees +/- 8.23 degrees , calcaneocuboid angle 18.67 degrees +/- 8.72 degrees to 11.76 degrees +/- 8.49 degrees , first to second intermetatarsal angle 9.42 degrees +/- 2.67 degrees to 7.61 degrees +/- 2.69 degrees , calcaneal inclination angle 11.93 degrees +/- 6 degrees to 14.93 degrees +/- 5.85 degrees , and talar declination angle 34.0 degrees +/- 8.59 degrees to 28.02 degrees +/- 6.85 degrees ; all of these differences were statistically significant (p < .0001). A subgroup of 24 (68.57%) patients also answered a subjective questionnaire at a mean of 33 (range 12 to 55) months postoperatively. The presenting chief complaints were resolved in 23 patients (95.83%) of the subgroup, and 21 patients (87.5%) returned postoperatively to either the same or a greater activity level in sports. Twenty-three (95.83% of the subgroup) patients said they were 75% to 100% satisfied with their surgical outcome, and that they would recommend the surgery to a friend or family member with the same condition, whereas 1 (4.17%) claimed 0% satisfaction after placement of inappropriately sized implants (which were later replaced to the patient's clinical satisfaction) in both feet. PMID- 22196454 TI - Infected internal fixation after ankle fractures--a treatment path. AB - In the emergency treatment of infected internal fixation after ankle fractures, the infection needs to be resolved quickly to protect the implants, bone, and tendons. Vacuum wound therapy (topical negative pressure therapy) has been used for more than 15 years to assist in closure and to accelerate healing of a wide range of wounds. In the present report, we describe the results of treatment of 7 angiopathic (dysvascular) patients who developed a deep wound infection after ankle osteosynthesis. Each patient was treated with initial surgical debridement, followed by vacuum wound therapy and meshed split-thickness skin graft transplantation. The mean inpatient length of vacuum wound therapy was 14.0 +/- 4.31 days, and the mean total duration of vacuum treatment was 54.43 +/- 7.74 days. PMID- 22196455 TI - Extraosseous talotarsal stabilization using HyProCure(r) in adults: a 5-year retrospective follow-up. AB - The purpose of this retrospective study was to determine long-term functional outcomes and device tolerance achieved in adult patients who chose to undergo an extraosseous talotarsal stabilization procedure HyProCure((r)) for the treatment of flexible talotarsal joint deformity. Eighty-three adult patients participated in this study. Postoperative subjective assessment of device performance was evaluated using Maryland Foot Scores, which were collected at a mean follow-up period of 51 months. The mean postoperative Maryland Foot Score was 88 out of 100; postoperatively, 52% of cases reported complete alleviation of foot pain, 69% of cases had no limitations on their foot functional abilities, and 80% of cases reported complete satisfaction with the appearance of their feet. The implant was removed in 7 out of 117 cases (removal rate: 6%) due to prolonged pain of the anterior talofibular ligament (4 cases), psychogenic reaction (2 cases), and postoperative infection (1 case). The long-term positive subjective outcomes and excellent patient satisfaction obtained in this study may imply that extraosseous talotarsal stabilization was effective in stabilizing the talotarsal joint complex and eliminating excessive abnormal pronation, thus reducing pain and improving quality of life of the patients; it represents a possible treatment option for partial talotarsal dislocation in cases with flexible and reducible deformity. PMID- 22196456 TI - Prognostic difference between soft tissue abscess and osteomyelitis of the foot in patients with diabetes: data from a consecutive series of 452 hospitalized patients. AB - From January 2008 to December 2010, 452 patients with diabetes were admitted to our diabetic foot unit because of deep soft tissue abscess (group A: n = 210) or chronic osteomyelitis (group B: n = 242). Patients from group A underwent emergency debridement in the operating room. Patients from group B underwent elective surgery. Twenty-six (5.8%) major amputations were performed: of these, 18 (8.57%) were performed in patients from group A and 8 (3.31%) were performed in patients from group B (p = .024). Multivariate analysis showed the independent role on amputation outcome of the abscess (odds ratio, 2.64; p = .029; confidence interval [CI] 1.11 to 6.28), dialysis treatment (odds ratio, 3.17; p = .039, CI 1.06-9.51), and C-reactive protein > 0.5 mg/dL (odds ratio, 3.75; p = .022, CI 1.21-11.64). In group A, 43 (22.6%) patients healed only with drainage, and 147 (70.0%) minor amputations were performed: 53 (36.1%) at the level of the forefoot and 94 (63.9%) at the level of the midfoot. In group B, 234 (96.7%) minor amputations were performed, 208 (88.9%) at the forefoot and 26 (11.1%) at the midfoot level (p < .001). Fourteen postoperative complications occurred in patients from group A and 2 in patients from group B (p < .001). In group A, 3 patients died during hospitalization, 1 from septic shock and 2 from sudden death. None of the group B patients died. This study demonstrates that the severity of a foot soft tissue abscess is not comparable with that of a chronic osteomyelitis not only because of a higher rate of major amputation, but also because of a much more proximal level of minor amputation. PMID- 22196458 TI - Publication rates of poster presentations at the American College of Foot and Ankle Surgeons annual scientific conference between 1999 and 2008. AB - Publication is the desired end point of scientific research. Ultimately, it is desired that research presented in poster format at a scientific conference will be developed into a report and become published in a peer-reviewed scientific journal. Moreover, poster presentations of research studies are often referenced and, as a result, influence treatment care plans. No data exist for the actual publication rate of podiatric foot and ankle surgery poster presentations. Therefore, the objective of the present study was to determine the actual publication rates of poster presentations at the American College of Foot and Ankle Surgeons (ACFAS) annual scientific conference (ASC) during a 10-year period. Print or electronic media for the ACFAS ASC official program from 1999 to 2008 were obtained. Each year's official program was manually searched for any poster presentation and, when identified, the authors and title were individually searched using Internet-based search engines to determine whether a poster presentation had been followed by publication. Of the 825 posters, 198 (24%) poster presentations were ultimately published in 1 of 32 medical journals within a weighted mean of 17.6 months. Of the 32 journals, 25 (78.1%) represented peer reviewed journals. The publication rate of poster presentations at the ACFAS ASC was less than that of oral manuscripts presented at the same meeting during the same period and was also less than the orthopedic subspecialty poster presentation publication rates. Therefore, attendees of the ACFAS ASC should be aware that only a few of the posters presented at the ACFAS ASC will be valid because they will not survive the rigors of publication 76% of the time. Additionally, more stringent selection criteria should be used so that the selected poster presentations can ultimately withstand the publication process. PMID- 22196457 TI - Bicortical fixation of medial malleolar fractures: a review of 23 cases at risk for complicated bone healing. AB - Several methods have been described for fixation of unstable medial malleolar fractures. Certain patient populations, including the elderly, those with osteoporosis and osteopenia, and patients with diabetes mellitus, are generally known to be susceptible to complications associated with ankle fracture healing. The goal of the present retrospective investigation was to review the outcomes of a series of patients who had undergone medial malleolar fracture repair using fully threaded bicortical interfragmental compression screw fixation. Patients were included in the present series if they had undergone bicortical fixation of an unstable ankle fracture with a medial malleolar fracture component, in addition to having at least 1 of the following comorbidities: age 55 years or older, osteoporosis or osteopenia, diabetes mellitus, peripheral arterial disease, end-stage renal disease, chronic kidney disease, previous kidney transplantation, peripheral neuropathy, or current tobacco use. A total of 23 ankle fractures in 22 consecutive patients met the inclusion criteria. The mean age of the patients was 69.52 (range 45 to 89) years; 17 were female (77.27%) and 5 were male (22.73%). Of the 23 medial malleolar fractures, 21 (91.3%) achieved complete, uncomplicated healing. The mean interval to union was 62.6 (range 42 to 156) days. A total of 4 complications (17.39%) were noted, including 1 nonunion (4.35%), 1 malunion (4.35%), and 2 cases of painful retained hardware (8.7%). From our experience with this series of patients, bicortical screw fixation for medial malleolus fractures appears to be an acceptable alternative for fixation that provides a stable construct for patients at greater risk of bone healing complications. PMID- 22196459 TI - Incidence of acute deep vein thrombosis and pulmonary embolism in foot and ankle trauma: analysis of the National Trauma Data Bank. AB - The incidence of deep vein thrombosis (DVT) after foot and ankle surgery is generally believed to be low. However, little information is available regarding DVT as it specifically relates to foot and ankle trauma. The National Trauma Data Bank data set (2007 to 2009) was used to evaluate the incidence of thromboembolism in foot and ankle trauma. Also, the risk factors associated with the thromboembolic events were identified. Data regarding the demographics, comorbidities, procedures, trauma types, and complications, including DVT and pulmonary embolism (PE), were collected from the data set for analysis. The incidence of DVT and PE was 0.28% and 0.21%, respectively. The risk factors statistically significantly associated and clinically relevant for both DVT and PE in foot and ankle trauma were older age (DVT, odds ratio [OR] 1.02, 95% confidence interval [CI] 1.01 to 1.03; PE, OR 1.02, 95% CI 1.01 to 1.03), obesity (DVT, OR 2.35, 95% CI 1.33 to 4.14; PE, OR 3.06, 95% CI 1.68 to 5.59), and higher injury severity score (DVT, OR 1.22, 95% CI 1.16 to 1.28; PE, OR 1.21, 95% CI 1.14 to 1.29). Owing to the low incidence, routine pharmacologic thromboprophylaxis might be contraindicated in foot and ankle trauma. Instead, careful, individualized assessment of the risk factors associated with DVT/PE is important. PMID- 22196460 TI - Surgical intervention for congenital nail fold hypertrophy. AB - Congenital nail fold hypertrophy of the hallux is an uncommon abnormality affecting the periungual soft tissue of the great toe. It is usually identified at birth or shortly thereafter, and is known to spontaneously resolve in most cases. In this report, we describe the case of a 14-month-old boy presenting with nail fold hypertrophy of both great toes. The completely united skin bridge covering the nail on the right was excised and the nail folds recreated, with debulking of the left hypertrophic nail fold. We propose that management should be conservative in the first instance and that surgery should be reserved for cases in which 1) inflammation is unresponsive to conservative measures, 2) there is a dense condensation of tissue crossing the nail surface, or 3) there is significant hypertrophy persisting past 1 year of age with no signs of resolution. PMID- 22196461 TI - Lateral supramalleolar flap for coverage of ankle and foot defects in children. AB - The lower part of the leg, the ankle and the foot, is a difficult region to cover especially with exposure of bones or tendons. There are many options for covering soft tissue defect in these areas. The supramalleolar flap is an interesting procedure. The lateral supramalleolar flap was used in 8 cases for the reconstruction of skin defects of the ankle, heel, and foot that compromised the Achilles tendon and the osteoarticular system. Of the 8 patients, 5 were males and 3 were females, with an average age of 6.4 (range 2 to 10) years. The skin defect was secondary to trauma in all cases. The mean follow-up period was 31 (range 19 to 47) months; at the last follow-up visit, the region had been successfully covered in all cases. No necrosis of the flap was reported. The donor site morbidity was minimal. The lateral supramalleolar flap is an interesting surgical technique to salvage the lower extremity in children because this flap has a large skin paddle and a wide rotation arc and is based on a secondary vascular axis. PMID- 22196462 TI - Protein microspheres as suitable devices for piroxicam release. AB - Bovine serum albumin-piroxicam (BSA-piroxicam) and human serum albumin-piroxicam (HSA-piroxicam) microspheres were sonochemically prepared and characterized. The use of polyvinyl alcohol (PVA) lead to an improvement of formulation characteristics, including smaller size, lower polydispersity index (PDl), higher entrapment efficiency and higher stability. The release kinetics of these proteinaceous microspheres was determined in presence of protease, indicating an anomalous drug transport mechanism (diffusion and polymer degradation). In presence of higher protease concentration, BSA microspheres exhibit Case II transport, leading to zero order release (protein degradation). These proteinaceous devices did not show cytotoxicity against human skin fibroblasts in vitro, for range concentrations below to 300 mg L(-1), greatly supporting their potential application in the treatment of inflammatory diseases. PMID- 22196463 TI - Scanning surface potential microscopy of spore adhesion on surfaces. AB - The adhesion of spores of Bacillus anthracis - the cause of anthrax and a likely biological threat - to solid surfaces is an important consideration in cleanup after an accidental or deliberate release. However, because of safety concerns, directly studying B. anthracis spores with advanced instrumentation is problematic. As a first step, we are examining the electrostatic potential of Bacillus thuringiensis (Bt), which is a closely related species that is often used as a simulant to study B. anthracis. Scanning surface potential microscopy (SSPM), also known as Kelvin probe force microscopy (KPFM), was used to investigate the influence of relative humidity (RH) on the surface electrostatic potential of Bt that had adhered to silica, mica, or gold substrates. AFM/SSPM side-by-side images were obtained separately in air, at various values of RH, after an aqueous droplet with spores was applied on each surface and allowed to dry before measurements. In the SSPM images, a negative potential on the surface of the spores was observed compared with that of the substrates. The surface potential decreased as the humidity increased. Spores were unable to adhere to a surface with an extremely negative potential, such as mica. PMID- 22196465 TI - Clinical implications of the metabolic syndrome and hyperuricemia. PMID- 22196466 TI - Screening for oral cancers--which method is most effective? PMID- 22196464 TI - Transfusion of fresh frozen plasma in non-bleeding ICU patients--TOPIC trial: study protocol for a randomized controlled trial. AB - BACKGROUND: Fresh frozen plasma (FFP) is an effective therapy to correct for a deficiency of multiple coagulation factors during bleeding. In past years, use of FFP has increased, in particular in patients on the Intensive Care Unit (ICU), and has expanded to include prophylactic use in patients with a coagulopathy prior to undergoing an invasive procedure. Retrospective studies suggest that prophylactic use of FFP does not prevent bleeding, but carries the risk of transfusion-related morbidity. However, up to 50% of FFP is administered to non bleeding ICU patients. With the aim to investigate whether prophylactic FFP transfusions to critically ill patients can be safely omitted, a multi-center randomized clinical trial is conducted in ICU patients with a coagulopathy undergoing an invasive procedure. METHODS: A non-inferiority, prospective, multicenter randomized open-label, blinded end point evaluation (PROBE) trial. In the intervention group, a prophylactic transfusion of FFP prior to an invasive procedure is omitted compared to transfusion of a fixed dose of 12 ml/kg in the control group. Primary outcome measure is relevant bleeding. Secondary outcome measures are minor bleeding, correction of International Normalized Ratio, onset of acute lung injury, length of ventilation days and length of Intensive Care Unit stay. DISCUSSION: The Transfusion of Fresh Frozen Plasma in non-bleeding ICU patients (TOPIC) trial is the first multi-center randomized controlled trial powered to investigate whether it is safe to withhold FFP transfusion to coagulopathic critically ill patients undergoing an invasive procedure. TRIAL REGISTRATION: Trial registration: Dutch Trial Register NTR2262 and ClinicalTrials.gov: NCT01143909. PMID- 22196467 TI - Assessment of first-year post-graduate residents: usefulness of multiple tools. AB - BACKGROUND: Objective Structural Clinical Examination (OSCE) usually needs a large number of stations with long test time, which usually exceeds the resources available in a medical center. We aimed to determine the reliability of a combination of Direct Observation of Procedural Skills (DOPS), Internal Medicine in-Training Examination (IM-ITE((r))) and OSCE, and to verify the correlation between the small-scale OSCE+DOPS+IM-ITE((r))-composited scores and 360-degree evaluation scores of first year post-graduate (PGY(1)) residents. METHODS: Between 2007 January to 2010 January, two hundred and nine internal medicine PGY1 residents completed DOPS, IM-ITE((r)) and small-scale OSCE at our hospital. Faculty members completed 12-item 360-degree evaluation for each of the PGY(1) residents regularly. RESULTS: The small-scale OSCE scores correlated well with the 360-degree evaluation scores (r = 0.37, p < 0.021). Interestingly, the addition of DOPS scores to small-scale OSCE scores [small-scale OSCE+DOPS composited scores] increased it's correlation with 360-degree evaluation scores of PGY(1) residents (r = 0.72, p < 0.036). Further, combination of IM-ITE((r)) score with small-scale OSCE+DOPS scores [small-scale OSCE+DOPS+IM-ITE((r)) composited scores] markedly enhanced their correlation with 360-degree evaluation scores (r = 0.85, p < 0.016). CONCLUSION: The strong correlations between 360 degree evaluation and small-scale OSCE+DOPS+IM-ITE((r))-composited scores suggested that both methods were measuring the same quality. Our results showed that the small-scale OSCE, when associated with both the DOPS and IM-ITE((r)), could be an important assessment method for PGY(1) residents. PMID- 22196468 TI - Impact of advanced age on inpatients with pyogenic liver abscess in Taiwan: a nationwide claim-based analysis. AB - BACKGROUND: Pyogenic liver abscess (PLA) is seen as an endemic disease in population of Taiwan. The impact of advanced age on inpatients with PLA remains unclear. METHODS: Data was collected and analyzed from claims of discharges by inpatients with PLA, using the National Health Insurance Research Database of 2007. RESULTS: A total of 2319 subjects and 2651 related discharges were enrolled, including 939 subjects/1077 discharges >=65 years and 1380 subjects/1574 discharges <65 years. Subjects >=65 years had significantly higher ratios of females to males, nephropathy, biliary tract diseases, liver cirrhosis and gastroenterological cancers than those <65 years. Hepatic/intra-hepatic duct cancers accounted for the most comorbid gastroenterological cancers. Discharged of subjects >=65 years had longer hospital stays, more in-hospital death/critical discharge, and a higher ratio of acute low respiratory conditions (ALRC) and urological infections than those of subjects <65 years (p<0.05). The inpatient costs for subjects >=65 years were significantly higher than those for subjects age<65 years in blood products, hemodialysis and total hospitalization. Co morbidities, such as nephropathy, biliary tract diseases, liver cirrhosis, gastroenterological cancers, ALRC and urological infections were predictive variables associated with age >=65 years in patients with PLA, as were being female and in-hospital death/critical discharge. Nephropathy and gastroenterological cancers were predictive variables associated with poor prognosis (in-hospital death/critical discharge) in both PLA patients age < and >=65 years (p<0.05). Diabetes mellitus featured predominantly, but had no impact on distribution and prognosis. CONCLUSION: Advanced age (>=65 years) had an impact on the aforementioned characteristics and predictive variables in inpatients with PLA. Physicians should pay attention and treat aged PLA patients with greater care, especially those cares with comorbid nephropathy or gastroenterological cancers. PMID- 22196469 TI - A multicenter open-label phase I/II study to assess the safety, tolerability, and efficacy of three dose levels of TuNEX in patients with rheumatoid arthritis. AB - BACKGROUND: Tumor necrosis factor (TNF)-alpha is a pivotal inflammatory cytokine in the pathogenesis of rheumatoid arthritis (RA). TuNEX, a recombinant TNF-alpha receptor protein, can effectively bind TNF-alpha. The purpose of this phase I/II dose-escalation study was to assess the safety and preliminary efficacy of three dose levels of TuNEX in Taiwanese patients with RA. METHODS: Eighteen patients with active RA from three medical centers who had failed previous therapy with at least one disease modifying antirheumatic drug (DMARD) were enrolled. The primary efficacy endpoint was a 20% improvement in the American College of Rheumatology criteria (ACR20) in the fourth week. The occurrence of treatment-emergent adverse events (TEAEs) was the primary safety variable. RESULTS: The highest percentage of TuNEX 25-mg- and 35-mg-treated patients achieved an ACR20 response (60% and 100%, respectively) for the first time at Week 2 during the 4-week treatment period. There was a strong trend toward a superior ACR20 response rate in the TuNEX 15-mg group (83.3%) in comparison with the TuNEX 25-mg group (40.0%) and the TuNEX 35-mg group (50.0%) at week 4. Patients who received 15-mg TuNEX, 25-mg TuNEX, and 35-mg TuNEX had 35.99%, 16.85%, and 21.86% reduction of disability indices of Health Assessment Questionnaire after drug treatment, respectively. The most commonly reported adverse event was injection-site reaction. The TEAEs were comparable between the three TuNEX-treated groups. CONCLUSION: TuNEX reduced the signs and symptoms of RA and improved physical function, with clinically acceptable safety and tolerability in patients who had previously received DMARDs. PMID- 22196470 TI - PSA density as a better predictor of prostate cancer than percent-free PSA in a repeat biopsy. AB - BACKGROUND: The aim of our study was to identify the optimal predictor of prostate cancer among several prostate-specific antigen (PSA) derivatives in repeat prostate biopsy. METHODS: We retrospectively assessed the repeat prostate biopsy specimens, obtained between 1999 and 2008, of 212 patients with a total PSA (tPSA) of 4-10 ng/ml and normal digital rectal examination. Using a receiver operating characteristic (ROC) analysis, we assessed the predictive power of tPSA, percent free PSA (f/t PSA), PSA density (PSAD), and PSA velocity (PSAV) for the detection of prostate cancer. RESULTS: Repeat prostate biopsy specimens were positive for prostate cancer in the case of 26 patients and negative in the case of 186 patients. The areas under the receiver operating characteristic (ROC) curves for tPSA, f/tPSA, PSAD, and PSAV were 72.7%, 57.9%, 74.4%, and 64.8%, respectively. The ROC curve analysis revealed that PSAD was a better predictor of prostate cancer than f/t PSA. Moreover, when PSAD at an optimal cutoff of 0.18 ng/ml/cc was considered as the predictor, the detection of prostate cancer was found to have a high sensitivity and specificity (77% and 69%, respectively). CONCLUSION: In a repeat prostate biopsy, PSAD is superior to f/t PSA as a predictor of prostate cancer. And, by assessing this predictor, an unnecessary repeat biopsy of patients with tPSA of 4-10 ng/ml can be avoided. PMID- 22196471 TI - Comparison of oxygenation among different supplemental oxygen methods during flexible bronchoscopy in infants. AB - BACKGROUND: Supplemental oxygen (O(2)) is mandatory during flexible bronchoscopy (FB) in infants, but there are limited studies that deal with the efficacy of different O(2) delivery methods. This study aims to compare the oxyhemoglobin saturation in infants during FB among three different O(2) delivery methods, as measured by pulse oximeter (SpO(2)). METHODS: A prospective study enrolled infants with two criteria: (1) less than 2 years old; and (2) needing FB examination. All infants received intravenous sedation and topical anesthesia. They were randomly placed into the following three groups: (1) nasal cannula (NC; 0.5 L/kg/min); (2) nasal prongs with continuous positive airway pressure (NP CPAP; 5-10 L/min, pressure 5 cmH(2)O); and (3) nasopharyngeal catheter (NPC; 0.3 0.5 L/kg/min). SpO(2), heart rate, blood pressure and respiratory rate were measured and compared at different stages: (1) prior to the FB (baseline); the FB tip at (2) the nose tip; (3) the pharynx; (4) the carina and (5) 30 minutes after the FB. RESULTS: A total of 75 infants, with 25 infants per group, were enrolled during a 2-year period. There were no significant differences in basic characteristics and baseline SpO(2). After the designated O(2) was delivered, SpO(2) decreased significantly (p<0.05) when the FB tip was advanced from the nostril to the pharynx, and further decreased (p<0.01) when at the carina in all groups, especially in the NC group. After FB, SpO(2) returned to baseline levels in all three groups. The NC group had the lowest SpO(2) at the pharynx (p<0.01) and carina (p<0.01). The NP-CPAP and NPC groups had better SpO(2). CONCLUSION: Supplemental O(2) via NPC is a simple and cost-effective method to maintain good SpO(2) during FB examination of infants. PMID- 22196472 TI - Visual screening of oral cavity cancer in a male population: experience from a medical center. AB - BACKGROUND: We aimed to evaluate the effectiveness of an oral cavity cancer visual screening program conducted in a tertiary academic medical center. We also wanted to determine which group of participants was at greater risk of contracting oral cavity cancer. METHODS: Participants were first asked to relate their personal habits during the past 6 months. Visual screening of the oral cavity was then performed under adequate lighting and with proper instruments. RESULTS: From March 2005 to January 2010, 13,878 participants were enrolled in this study. The average age was 54.6 years. Positive lesions were identified in 726 participants (5.2%), and 282 of those participants (2.1%) had oral cavity cancers confirmed. The sensitivity and specificity of this study were 98.9% and 98.7%, respectively. Those participants who were habitual smokers, alcohol consumers, and betel quid chewers had the highest risk of developing oral cavity cancer when compared with those who did not have these habits (odds ratio=46.90, 95% confidence interval=33.15-66.35, p<0.001). CONCLUSION: The oral screening program conducted in a tertiary medical center was effective. We suggest that individuals aged >=40 years or who are habitual cigarette smokers, alcohol consumers, and betel quid chewers should receive oral screening regularly so that potential oral cancer can be detected as early as possible. PMID- 22196473 TI - Persistent sacrococcygeus ventralis muscle in an adult human pelvic wall: a variation for surgeons to note. AB - Occurrence of abnormal muscles in the pelvic wall is very rare. During a routine dissection of the pelvic wall, an abnormal muscle referred to as sacrococcygeus ventralis was noted in a 65-year-old South Indian cadaver. The fleshy fibers of the muscle were arising from the lateral part of the ventral surface of the sacrum at the level of S3 segment. The muscle passed downwards in front of the S4 and S5 sacral segments, halfway through its course it became tendinous and finally became inserted in the ventral surface of the coccyx. Sacrococcygeus ventralis is a muscle which is well developed in animals where it acts on their tail. In human beings, sacrococcygeus ventralis is seen only during fetal life. A rare case of its persistence in an adult pelvic wall is reported and discussed here. PMID- 22196474 TI - Neck mass as the first presentation of metastatic prostatic adenocarcinoma. AB - Adenocarcinoma of the prostate (CAP) is a rare diagnosis in men younger than 50 years of age; this age group accounts for less than 0.1% of all patients with prostatic cancer. Left supraclavicular lymphadenopathy (LSCL) as the presenting symptom of metastatic CAP is even rarer. No cases of CAP presenting as LSCL in men younger than 45 years have been reported in the literature. Here we report a 42-year-old male with the uncommon presentation of CAP as LSCL. In adult males with persistent LSCL, even if younger than 45 years, measurement of serum prostate specific antigen is warranted at the time of initial presentation, and the lymph node biopsy should be subsequently stained for prostate specific antigen immunohistochemically. These examinations are crucial to establish a definitive diagnosis of CAP and, in turn, to institute appropriate management and achieve the best possible outcome. PMID- 22196475 TI - Non-vitrectomizing vitreous surgery and adjuvant intravitreal tissue plasminogen activator for non-recent massive premacular hemorrhage. AB - Massive premacular hemorrhage can cause sudden visual loss. We sought to evaluate the efficacy, safety and visual outcome of nonvitrectomizing vitreous surgery with intravitreal tissue plasminogen activator (t-pa) for long-lasting thick premacular hemorrhage. This retrospective, interventional study examined three consecutive eyes of three patients who received nonvitrectomizing vitreous surgery with intravitreal t-pa for the treatment of non-recent massive premacular hemorrhage. Detailed ophthalmoscopic examinations were performed pre- and postoperatively to evaluate the visual outcome, the resolution of premacular hemorrhage and the changes in lenticular opacity.In all three eyes, the premacular hemorrhage cleared after the procedure. Final best-corrected visual acuities improved from 6/30 to 6/10 in patient 1, 2/60 to 6/4 in patient 2, and 3/60 to 6/6 in patient 3. Operated and fellow eyes did not differ in terms of nuclear sclerosis. No complications from the procedure were noted.In these selected cases, nonvitrectomizing vitreous surgery with intravitreal t-pa was an effective and safe alternative treatment for non-recent massive premacular hemorrhage. PMID- 22196476 TI - Evaluating the potential of effluents and wood feedstocks from pulp and paper mills in Brazil, Canada, and New Zealand to affect fish reproduction: chemical profiling and in vitro assessments. AB - This study investigates factors affecting reproduction in fish exposed to pulp and paper mill effluents by comparing effluents from countries with varying levels of documented effects. To explore the hypothesis of wood as a common source of endocrine disrupting compounds, feedstocks from each country were analyzed. Analyses included in vitro assays for androgenic activity (binding to goldfish testis androgen receptors), estrogenic activity (yeast estrogen screen), and neurotransmitter enzyme inhibition (monoamine oxidase and glutamic acid decarboxylase). Chemical analyses included conventional extractives, known androgens, and gas chromatograph index (GCI) profiles. All effluents and wood contained androgenic activity, particularly in nonpolar fractions, although known androgens were undetected. Effluents with low suspended solids, having undergone conventional biotreatment had lower androgenic activities. Estrogenic activity was only associated with Brazilian effluents and undetected in wood. All effluents and wood inhibited neurotransmitter enzymes, predominantly in polar fractions. Kraft elemental chlorine free mills were associated with the greatest neurotransmitter inhibition. Effluent and wood GCI profiles were correlated with androgenic activity and neurotransmitter enzyme inhibition. Differences in feedstock bioactivities were not reflected in effluents, implying mill factors mitigate bioactive wood components. No differences in bioactivities could be discerned on the basis of country of origin, thus we predict effluents in regions lacking monitoring would affect fish reproduction and therefore recommend implementing such programs. PMID- 22196477 TI - Clinical phenotypes of COPD: identification, definition and implications for guidelines. AB - The term phenotype in the field of COPD is defined as "a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes". Among all phenotypes described, there are three that are associated with prognosis and especially are associated with a different response to currently available therapies. There phenotypes are: the exacerbator, the overlap COPD-asthma and the emphysema-hyperinflation. The exacerbator is characterised by the presence of, at least, two exacerbations the previous year, and on top of long-acting bronchodilators, may require the use of antiinflammatory drugs. The overlap phenotype presents symptoms of increased variability of airflow and incompletely reversible airflow obstruction. Due to the underlying inflammatory profile, it uses to have a good therapeutic response to inhaled corticosteroids in addition to bronchodilators. Lastly, the emphysema phenotype presents a poor therapeutic response to the existing antiinflammatory drugs and long-acting bronchodilators together with rehabilitation are the treatments of choice. Identifying the peculiarities of the different phenotypes of COPD will allow us to implement a more personalised treatment, in which the characteristics of the patients, together with their severity will be key to choose the best treatment option. PMID- 22196478 TI - Factors associated with hospital admission for exacerbation of chronic obstructive pulmonary disease. AB - INTRODUCTION: Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) that require hospital admission have a major impact on the progression of disease and generate high health costs. METHOD: A multi-center, cross-sectional, observational, study was conducted with the aim to identify factors associated with hospital admission in patients with COPD. We obtained data of socio demographic and anthropometric characteristics, quality of life, respiratory symptoms, anxiety and depression, physical activity and pulmonary function tests. We analyzed their association with hospital admission with a multivariate analysis using a logistic regression model. RESULTS: We analyzed 127 patients, 50 (39%) of whom had been hospitalized. 93.7% were men, mean age 67 years (SD=9) and a FEV1 of 41.9% (SD=15.3). In the first model obtained, the baseline SpO(2), the BODE index and emergency room (ER) visits were associated with hospital admission and the area under the ROC curve (AUC) was 0.809. In a second model we included only variables readily available (without the 6 minutes walking test) and only the SpO(2) and previous visits to the ER were significant with an AUC ROC 0.783. CONCLUSIONS: hospital admission for exacerbation of COPD is associated with poor SpO(2), higher BODE index score and a greater number of visits to the ER. In case you do not have the 6 minutes walking test, the other two variables offer a similar discriminative ability. PMID- 22196480 TI - Design of triazole-stapled BCL9 alpha-helical peptides to target the beta catenin/B-cell CLL/lymphoma 9 (BCL9) protein-protein interaction. AB - The interaction between beta-catenin and B-cell CLL/lymphoma 9 (BCL9), critical for the transcriptional activity of beta-catenin, is mediated by a helical segment from BCL9 and a large binding groove in beta-catenin. Design of potent, metabolically stable BCL9 peptides represents an attractive approach to inhibit the activity of beta-catenin. In this study, we report the use of the Huisgen 1,3 dipolar cycloaddition reaction to generate triazole-stapled BCL9 alpha-helical peptides. The high efficiency and mild conditions of this "click" reaction combined with the ease of synthesis of the necessary unnatural amino acids allows for facile synthesis of triazole-stapled peptides. We have performed extensive optimization of this approach and identified the optimal combinations of azido and alkynyl linkers necessary for stapling BCL9 helices. The unsymmetrical nature of the triazole staple also allowed the synthesis of double-stapled BCL9 peptides, which show a marked increase in helical character and an improvement in binding affinity and metabolic stability relative to wild-type and linear BCL9 peptides. This study lays the foundation for further optimization of these triazole-stapled BCL9 peptides as potent, metabolically stable, and cell permeable inhibitors to target the beta-catenin and BCL9 interaction. PMID- 22196481 TI - Establishing a pediatric cognitive rehabilitation program: insurance issues and clinical rationale. AB - Technological and medical advances have greatly improved survival rates for many disorders; therefore, more attention is being given to functional outcomes in individuals who have been diagnosed with neurological diseases or disorders. One example of such an endeavor consists of a cognitive rehabilitation program to improve attentional abilities. The current study uses a modification of the original Cognitive Remediation Program to address attentional deficits in children with a variety of neurological disorders. The abbreviated program is designed as a focused, time-limited program that can be easily implemented in inpatient, partial day, or outpatient medical settings using third party payment to fund the program. This article seeks to inform psychologists about how to establish a cognitive rehabilitation program with emphasis placed on providing information about insurance reimbursement and billing procedures. Information is presented regarding billing codes, materials required for reimbursement, the denial/approval process, and percent of the Usual Customary Reasonable charge that was covered. Recommendations to improve the timeliness and efficiency of the reimbursement process, as well as to increase the amount of reimbursement, are highlighted. Directions for future research, including continued documentation of the effectiveness of cognitive rehabilitation programs to establish credibility for procurement of third party payment, are also offered. PMID- 22196482 TI - Effect of yoghurt containing Bifidobacterium lactis Bb12(r) on faecal excretion of secretory immunoglobulin A and human beta-defensin 2 in healthy adult volunteers. AB - BACKGROUND: Probiotics are used to provide health benefits. The present study tested the effect of a probiotic yoghurt on faecal output of beta-defensin and immunoglobulin A in a group of young healthy women eating a defined diet. FINDINGS: 26 women aged 18-21 (median 19) years residing in a hostel were given 200 ml normal yoghurt every day for a week, followed by probiotic yoghurt containing Bifidobacterium lactis Bb12(r) (109 in 200 ml) for three weeks, followed again by normal yoghurt for four weeks. Stool samples were collected at 0, 4 and 8 weeks and assayed for immunoglobulin A and human beta-defensin-2 by ELISA. All participants tolerated both normal and probiotic yoghurt well. Human beta-defensin-2 levels in faeces were not altered during the course of the study. On the other hand, compared to the basal sample, faecal IgA increased during probiotic feeding (P = 0.0184) and returned to normal after cessation of probiotic yoghurt intake. CONCLUSIONS: Bifidobacterium lactis Bb12(r) increased secretory IgA output in faeces. This property may explain the ability of probiotics to prevent gastrointestinal and lower respiratory tract infections. PMID- 22196483 TI - Excipients with specialized functions for effective drug delivery. AB - INTRODUCTION: There is a growing need for the development of pharmaceutical excipients that could improve product performance and overcome the shortcomings of new drug moieties, such as their poor solubility and membrane permeability, as well as to aid with modern manufacturing processes. AREAS COVERED: Different types of functional excipients are discussed in this paper, in terms of their roles in modern dosage forms to optimize drug delivery and manufacturability. Functions of specialized excipients that are covered in this article include the enhancement of drug membrane permeability, the improvement of drug solubility and stability, the regulation of drug release in response to feedback mechanisms and assistance with the production of dosage forms. EXPERT OPINION: Modern drug delivery systems rely on sophisticated excipients with multiple functions to improve overall product performance. The excipient market is expected to grow substantially with emerging trends in the development of these advanced drug delivery systems. PMID- 22196485 TI - Spinal muscular atrophy: a clinical and research update. AB - Spinal muscular atrophy, a hereditary degenerative disorder of lower motor neurons associated with progressive muscle weakness and atrophy, is the most common genetic cause of infant mortality. It is caused by decreased levels of the "survival of motor neuron" (SMN) protein. Its inheritance pattern is autosomal recessive, resulting from mutations involving the SMN1 gene on chromosome 5q13. However, unlike many other autosomal recessive diseases, the SMN gene involves a unique structure (an inverted duplication) that presents potential therapeutic targets. Although no effective treatment for spinal muscular atrophy exists, the field of translational research in spinal muscular atrophy is active, and clinical trials are ongoing. Advances in the multidisciplinary supportive care of children with spinal muscular atrophy also offer hope for improved life expectancy and quality of life. PMID- 22196486 TI - Childhood onset of limb-girdle muscular dystrophy. AB - Limb-girdle muscular dystrophies comprise a rare heterogeneous group of genetic muscular dystrophies, involving 15 autosomal recessive subtypes and seven autosomal dominant subtypes. Autosomal recessive dystrophy is far more common than autosomal dominant dystrophy. Typical clinical features include progressive limb muscle weakness and atrophy (proximal greater than distal), varying from very mild to severe. Significant overlap of clinical phenotypes, with genetic and clinical heterogeneity, constitutes the rule for this group of diseases. Muscle biopsies are useful for histopathologic and immunolabeling studies, and DNA analysis is the gold standard to establish the specific form of muscular dystrophy. A definitive diagnosis among various subtypes is challenging, and the data presented here provide neuromuscular clinicians with additional information to help attain that goal. PMID- 22196487 TI - Genes of early-onset epileptic encephalopathies: from genotype to phenotype. AB - Early-onset epileptic encephalopathies are severe disorders in which cognitive, sensory, and motor development is impaired by recurrent clinical seizures or prominent interictal epileptiform discharges during the neonatal or early infantile periods. They include Ohtahara syndrome, early myoclonic epileptic encephalopathy, West syndrome, Dravet syndrome, and other diseases, e.g., X linked myoclonic seizures, spasticity and intellectual disability syndrome, idiopathic infantile epileptic-dyskinetic encephalopathy, epilepsy and mental retardation limited to females, and severe infantile multifocal epilepsy. We summarize recent updates on the genes and related clinical syndromes involved in the pathogenesis of early-onset epileptic encephalopathies: Aristaless-related homeobox (ARX), cyclin-dependent kinase-like 5 (CDKL5), syntaxin-binding protein 1 (STXBP1), solute carrier family 25 member 22 (SLC25A22), nonerythrocytic alpha spectrin-1 (SPTAN1), phospholipase Cbeta1 (PLCbeta1), membrane-associated guanylate kinase inverted-2 (MAGI2), polynucleotide kinase 3'-phosphatase (PNKP), sodium channel neuronal type 1alpha subunit (SCN1A), protocadherin 19 (PCDH19), and pyridoxamine 5-prime-phosphate oxidase (PNPO). PMID- 22196488 TI - Impact of amplitude-integrated electroencephalograms on clinical care for neonates with seizures. AB - Amplitude-integrated electroencephalography (aEEG) was recently introduced into neonatal intensive care in the United States. We evaluated whether aEEG has changed clinical care for neonates with seizures. This study included all 202 neonates treated for seizures at our hospital from 2002-2007. Neonates monitored with aEEG (n = 67) were compared with contemporary control neonates who were not monitored, despite the availability of aEEG (n = 57), and a historic control group of neonates treated for seizures before our neonatal intensive care unit initiated aEEG (n = 78). Eighty-two percent of those receiving phenobarbital (137/167) continued treatment after discharge, with no difference among groups. Adjusted for gestational age and length of stay, no difference among groups was evident in number of neuroimaging studies or number of antiepileptic drugs per patient. Fewer patients undergoing aEEG, compared with contemporary (16/67 vs 29/57, respectively, P = 0.001) or historic (n = 38/78, P = 0.002) controls, were diagnosed clinically with seizures without electrographic confirmation. We conclude that aEEG did not increase neuroimaging tests, and did not alter antiepileptic drug use. However, diagnostic precision regarding neonatal seizures improved with aEEG because fewer neonates were treated for seizures based solely on clinical findings, without electrographic confirmation. PMID- 22196489 TI - Interleukin-6 gene polymorphism in febrile seizures. AB - Febrile seizures comprise a common type of pediatric convulsion. Inflammation and genetics may be involved in their pathogenesis. Regarding the role of cytokines (especially interleukin-6) in febrile responses, we performed a case control study of interleukin-6 gene (-174, -572, and -597) single-nucleotide polymorphisms to learn if correlations existed between these particular polymorphisms and febrile seizures. We isolated the genomic DNA of 92 children with febrile seizures and 98 healthy control subjects. We genotyped individuals for their polymorphisms, using polymerase chain reaction-restriction fragment length polymorphism. In our study, the frequencies of -174 G alleles and of the 174 and -572 GG genotypes were observed to be significantly higher in patients than in control subjects. The -174 GG genotype frequency was significantly higher in children with a family history of febrile seizures. PMID- 22196490 TI - Phenotypic variability in a portuguese family with x-linked creatine transport deficiency. AB - Cerebral creatine transporter deficiency, attributable to mutations in the SLC6A8 gene, causes X-linked mental retardation, language delay, epilepsy, and autistic features. In contrast with creatine synthesis defects, the vast majority of patients with SLC6A8 deficiency do not respond to treatment. We describe a Portuguese family with a mutation (c.456C>T; p.Gln486X) in the SL6CA8 gene: two adult monozygotic twin brothers, with psychomotor delay and severe speech impairment. The family also includes their maternal half-sister with psychomotor retardation, predominantly in language, and their mentally retarded mother. This family illustrates the remarkable phenotypic variability in this condition. Investigation of creatine metabolism is mandatory in patients with developmental delay of unknown etiology, to detect this condition. PMID- 22196491 TI - Henoch-Schonlein purpura with posterior reversible encephalopathy syndrome. AB - We describe atypical Henoch-Schonlein purpura with posterior reversible encephalopathy syndrome in a normotensive 11-year-old girl. Her Henoch-Schonlein purpura was atypical because she initially presented with abdominal pain and vomiting and neurologic complications, rather than with the classic rash of Henoch-Schonlein Purpura. This previously healthy child was also unusual because she manifested the radiologic and clinical features of posterior reversible encephalopathy syndrome in the absence of hypertension induced by Henoch Schonlein purpura. Her abnormal findings resolved with supportive therapy. We discuss the association of posterior reversible encephalopathy syndrome with Henoch-Schonlein purpura in three previously reported cases. PMID- 22196492 TI - Language impairment associated with arachnoid cysts: recovery after surgical treatment. AB - Supporting data from the literature, we observe that large arachnoid cysts may affect cognitive function. Neuropsychologic assessment plus magnetic resonance imaging allowed for documentation of associations between left temporal arachnoid cysts, language impairment, and other cognitive dysfunctions. Significant cognitive improvements were evident soon after cysto-peritoneal shunting. These observations reinforce the rationale for neuropsychologic assessments of patients with developmental delay and arachnoid cysts, and support the potential benefit of surgical decompression for arachnoid cysts associated with neurologic deficits, even if surgery is performed well after the occurrence of neurologic deficits. PMID- 22196493 TI - Rotavirus cerebellitis: new aspects to an old foe? AB - Rotavirus infection is a significant cause of childhood morbidity and mortality worldwide. Although infection primarily causes gastroenteritis and dehydration, systemic signs and neurologic manifestations in rotavirus infection are widely recognized. The pathophysiologic origins of neurologic signs in rotavirus infection remain incompletely understood. We present a 4-year-old girl with clinical features of severe cerebellitis in association with abnormalities detected on magnetic resonance imaging. Rotavirus nucleic acid was demonstrated in both serum and cerebrospinal fluid. Severe neurologic sequelae remain after 2 years of follow-up. This report adds further evidence supporting a direct role for rotavirus in neurologic illness. PMID- 22196494 TI - Reversible parainfectious bilateral "striatal necrosis". AB - Bilateral striatal necrosis is usually associated with either endogenous or exogenous toxins, and with poor neurodevelopmental outcomes. We describe two patients with acute bilateral striatal clinical syndrome and magnetic resonance signal changes who made a complete clinical and radiologic recovery within 3 months. After an uneventful pregnancy, normal birth, and normal development, both boys presented at ages 3 and 5 years, respectively, after a viral illness with slurring of speech, bradykinesia, and an extrapyramidal movement disorder. On examination, both manifested bilateral cog wheel rigidity, with a broad-based gait and flexor plantar response. Cranial magnetic resonance imaging in both children indicated bilateral, symmetric, high signal changes in the lentiform nucleus, predominately in the putamen, with sparing of the globus pallidi bilaterally. The brain parenchyma was otherwise normal. Neurometabolic investigations produced normal results in both patients. The pathogenesis is uncertain, but could be immune-mediated. Both children, at 3-year and 1-year follow-ups, respectively, are doing well neurologically and academically. Our patients demonstrate that abnormal imaging findings during acute stages do not preclude good clinical and radiologic recovery. PMID- 22196495 TI - Multiple involvement of the central nervous system in Rosai-Dorfman disease. AB - Rosai-Dorfman disease is a rare, benign, idiopathic histio-proliferative disorder. Only 5% of cases involve the central nervous system. We describe a 10 year-old girl with pain in her lower limbs and back. Spinal magnetic resonance imaging revealed an intradural extramedullary lesion at T9-T10. We decided on surgical treatment. An anatomic/pathologic examination revealed histiocytic-like cells and extensive fibrosis. Immunohistochemistry revealed positivity for CD68 protein and negativity for CD1a protein. Craniospinal magnetic resonance imaging demonstrated an extra-axial lesion in the right frontal region, a small nodule in the left middle cerebellar peduncle, and another small lesion in the right ventral pons. We performed a complete removal of the frontal lesion. The histologic examination produced results compatible with Rosai-Dorfman disease. Most lesions in intracranial Rosai-Dorfman disease mimic meningioma. The definitive diagnosis relies on pathologic and immunohistochemical characteristics. Surgical removal is generally regarded as the treatment of choice. Disease progression after surgical resection is uncommon. Surgical treatment is not recommended until clear disease progression is detected, or focal disease causes neurologic compression. This disease must be included in the differential diagnosis of lesions that mimic meningioma. PMID- 22196496 TI - Diagnosis of Sjogren-Larsson syndrome by magnetic resonance spectroscopy. PMID- 22196497 TI - Effects of melatonin should be studied separately in each neurodevelopmental disorder and with specific sleep diagnoses. PMID- 22196499 TI - Efficacy of oral or intrauterine device-delivered progestin in patients with complex endometrial hyperplasia with atypia or early endometrial adenocarcinoma: a meta-analysis and systematic review of the literature. AB - OBJECTIVES: To investigate the efficacy of progestin treatment to achieve pathological complete response (pCR) in patients with complex atypical endometrial hyperplasia (CAH) or early endometrial adenocarcinoma (EC). METHODS: A systematic search identified 3245 potentially relevant citations. Studies containing less than ten eligible CAH or EC patients in either oral or intrauterine treatment arm were excluded. Only information from patients receiving six or more months of treatment and not receiving other treatments was included. Weighted proportions of patients achieving pCR were calculated using R software. RESULTS: Twelve studies met the selection criteria. Eleven studies reported treatment of patients with oral (219 patients, 117 with CAH, 102 with grade 1 Stage I EC) and one reported treatment of patients with intrauterine progestin (11 patients with grade 1 Stage IEC). Overall, 74% (95% confidence interval [CI] 65-81%) of patients with CAH and 72% (95% CI 62-80%) of patients with grade 1 Stage I EC achieved a pCR to oral progestin. Disease progression whilst on oral treatment was reported for 6/219 (2.7%), and relapse after initial complete response for 32/159 (20.1%) patients. The weighted mean pCR rate of patients with grade 1 Stage I EC treated with intrauterine progestin from one prospective pilot study and an unpublished retrospective case series from the Queensland Centre of Gynaecologic Oncology (QCGC) was 68% (95% CI 45-86%). CONCLUSIONS: There is a lack of high quality evidence for the efficacy of progestin in CAH or EC. The available evidence however suggests that treatment with oral or intrauterine progestin is similarly effective. The risk of progression during treatment is small but longer follow-up is required. Evidence from prospective controlled clinical trials is warranted to establish how the efficacy of progestin for the treatment of CAH and EC can be improved further. PMID- 22196500 TI - Noninfectious factors associated with pneumonia and pleuritis in slaughtered pigs from 143 farrow-to-finish pig farms. AB - A cross-sectional study involving 143 farrow-to-finish herds was carried out to identify herd-level noninfectious factors associated with pneumonia and pleuritis in slaughter pigs. Data related to herd characteristics, biosecurity, management and housing conditions were collected by questionnaire during a farm visit. Climatic conditions were measured over 20 h in the post-weaning and finishing rooms where the slaughter pigs were kept. After these on-farm investigations, the finishing pigs were examined at slaughter for lung lesions. A sample of 30 randomly selected pigs per herd was scored for pneumonia and pleuritis. Herds were grouped into three categories according to their pneumonia median score (class 1: <= 0.5; class 2: 0.53.75). For pleuritis, a herd was deemed affected if at least one pig had a high pleuritis score (>= 3). A multinomial logistic regression model was used to identify factors associated with pneumonia classes 2 and 3. A logistic regression for binary outcome was used to identify risk factors for severe pleuritis. An interval of less than four weeks between successive batches (OR=4.5, 95% confidence interval (95% CI): 1.5 13.6, p<0.01), large finishing room size (OR=4.3, 95% CI: 1.6-11.6, p<0.01) and high mean CO(2) concentration in the finishing room (OR=4.2, 95%CI: 1.6-11.3, p<0.01), significantly increased the odds for a herd to be in class 2 for pneumonia. The same risk factors were found for class 3 and, in addition, a direct fresh air inlet from outside or from the corridor in the post-weaning room vs an appropriate ceiling above the pigs (OR=5.1, 95% CI: 1.4-18.8, p=0.01). The risk for a herd to have at least one pig with a high pleuritis score was increased when the farrowing facilities were not disinsected (OR=2.7, 95% CI: 1.2 5.8, p=0.01), when tail docking was performed later than 1.5 days after birth (OR=2.6, 95% CI: 1.2-5.7, p=0.01) and if the piglets were castrated when more than 14 days old (OR=2.7, 95%CI: 1.1-6.8, p=0.03). A temperature range of less than 5 degrees C for the ventilation control rate in the farrowing room (OR=2.7, 95% CI: 1.2-5.9, p=0.01), a mean temperature in the finishing room below 23 degrees C (OR=3.0, 95% CI: 1.3-6.8, p<0.01) and large herd size (OR=3.1, 95% CI: 1.4-6.9, p<0.01) were also associated with increased risk of pleuritis. The factors affecting pneumonia and pleuritis seemed to be different. All rearing steps from farrowing to finishing must be taken into account in any health programme aimed at controlling pneumonia and pleuritis and lung health may be improved through several pathways, i.e. correcting managerial and hygienic factors, implementing an appropriate and well-functioning ventilation in order to offer favorable climatic conditions. PMID- 22196501 TI - Auditory brainstem implantation. AB - The use of cochlear implants for selected individuals with bilateral severe to profound sensorineural hearing loss who derive limited benefit from conventional hearing aids is well established. There are situations where cochlear implantation is contraindicated. Auditory brainstem implantation (ABI) is the only solution to restore hearing when the cochlear nerve is disrupted together with pathologies where the cochlea does not provide a suitable location for cochlear implant. Labyrinthine and cochlear aplasia and cochlear nerve aplasia constitute the congenital indications for ABI. In the present review article history and development of ABI, indications, side selection criteria, surgery and audiological outcome are presented. PMID- 22196502 TI - Acupuncture as cancer symptom therapy: what a difference a decade makes. AB - The author reviews the use of acupuncture in cancer symptom management based on mainly what his group has done for the past 10 years and new directions are presented for the future investigations. PMID- 22196503 TI - Effects of manual acupuncture at GB34 on carbon tetrachloride-induced acute liver injury in rats. AB - Manual acupuncture at Yanglingquan (GB34) is reported to have a beneficial effect on chronic liver damage. We, therefore, studied the effect of manual acupuncture at GB34 on acute liver damage. Rats were administered carbon tetrachloride (CCl(4)) or olive oil, and direct manual acupuncture was subsequently performed at GB34 or at a sham point (a nonacupoint). In rats administered with CCl(4), the serum levels of aspartate aminotransferase and alanine aminotransferase, the total cholesterol concentration, and the levels of hepatic thiobarbituric-acid reactive substances were suppressed by acupuncture at GB34 when compared with acupuncture at the sham point. By contrast, there was little histological difference in the liver between acupuncture at GB34 and that at the sham point in rats administered with CCl(4). These results suggest that manual acupuncture at GB34 tends to improve acute liver damage but is not sufficient by itself to completely resolve the hepatic injury. PMID- 22196504 TI - The effect of needle-embedding therapy and pharmacopuncture therapy on patients with urinary incontinence. AB - OBJECTIVES: This study was designed to evaluate the effect of traditional Korean medical therapy, consisting of needle-embedding therapy and pharmacopuncture therapy, on patients with urinary incontinence. METHODS: Twenty-nine patients with urinary incontinence underwent two sessions of traditional Korean medical therapy in a month. The pressure and the duration of pelvic muscle contraction were measured and compared. The primary endpoint of the study was improvement in the strength of pelvic floor muscle contraction. The paired t-test was used for the statistical analysis. RESULTS: Before treatment, a maximum pressure of 16.03 +/- 6.28 mmHg and an average pressure of 9.62 +/- 4.98 mmHg were measured, and the duration was 11.82 +/- 12.08 seconds. After the first treatment, the pressures were 27.41 +/- 10.46 mmHg (maximum) and 18.62 +/- 9.72 mmHg (average), and the duration was 40.75 +/- 60.02 seconds. After the second treatment, the pressures were 29 +/- 14.86 mmHg (maximum) and 20.31 +/- 11.51 mmHg (average), and the duration was 34.62 +/- 42.02 seconds. Comparisons between before treatment and first treatment results and between before treatment and second treatment results showed statistically significant changes but the difference between the first treatment result and the second treatment result was not statistically significant. CONCLUSIONS: Patients receiving traditional Korean medical therapy showed improved pelvic muscle contraction ability after a single treatment. If strength of pelvic floor muscle contraction is improved, symptoms of urinary incontinence also get better. Traditional Korean medical therapy, with a focus on needle-embedding therapy and pharmacopuncture therapy, may be effective for treating urinary incontinence. PMID- 22196506 TI - Ayurvedic formulation of Liv-Pro-08 reduces nonalcoholic fatty liver disease in rats fed with high-fat diet. AB - Nonalcoholic fatty liver disease (NAFLD) has emerged as a serious obesity-related disorder, and it will continue to be a major liver health issue worldwide in the coming decades. We aimed to determine the effect of Liv-Pro-08 (Nigella sativa, Entada pursaetha, and Ficus glomerata) an oral ayurvedic formulation on rats fed with high-fat diet. Rats were given a high-fat diet for a period of 7 days. After this period, Liv-Pro-08 (250, 500, and 750 mg/kg.body weight was given orally for 7 days. We examined the effect of the high-fat diet on various parameters related to obesity and insulin resistance. In the experimental rats who received the extract of Liv-Pro-08, their lipoprotein profiles were significantly improved compared with those that are not receiving the extract. Also, a slight reduction was observed in serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase enzymes. Moreover, Liv-Pro-08 significantly decreased their fasting serum glucose and fasting insulin levels. This experimental study suggests that Liv-Pro-08 can act as a therapeutic tool in preventing NAFLD progression (i.e., reducing hepatic lipid accumulation). Although further investigations and large randomized trials should be conducted, ayurvedic Liv-Pro 08 oral formulation may be a potential natural drug for NAFLD in the future. PMID- 22196505 TI - Anti-invasive activity of ethanol extracts of Ganoderma lucidum through tightening of tight junctions and inhibition of matrix metalloproteinase activities in human gastric carcinoma cells. AB - This study investigated the effect of ethanol extracts of Ganoderma lucidum (EGL) on the correlation between tightening of the tight junctions (TJs) and the anti invasive activity in human gastric adenocarcinoma AGS cells to elucidate further the possible anticancer mechanisms that G lucidum exerts. Within the concentrations of EGL that were not cytotoxic, EGL markedly inhibited the cell motility and invasiveness in a concentration-dependent manner. The activities of matrix metalloproteinases (MMP)-2 and MMP-9 in AGS cells were dose-dependently inhibited by treatment with EGL, and this was correlated with a decrease in expression of their mRNA and proteins and the upregulation of the expression of the tissue inhibitors of metalloproteinases. The anti-invasive activity of EGL was also found to be associated with the increased tightness of the TJ, which was demonstrated by an increase in transepithelial electrical resistance. Additionally, EGL repressed the levels of the claudin family members, which are major components of TJs that play a key role in the control and selectivity of paracellular transport. Furthermore, the levels of E-cadherin, a type I transmembrane glycoprotein, were inhibited by EGL treatment, however, those of snail, an epithelial to mesenchymal transition regulator and zinc finger transcription factor, were concentration-dependently increased in response to EGL treatment. Although further studies are needed, the present study indicates that TJs and MMPs are crucial targets of EGL-induced anti-invasiveness in human gastric cancer AGS cells. PMID- 22196507 TI - Antinociceptive, anti-inflammatory effects and acute toxicity of aqueous and ethanolic extracts of Myrtus communis L. Aerial parts in mice. AB - Myrtus communis L. aerial parts have been used in traditional medicine for the treatment of inflammatory disease. In this study 350 mice were divided into three main groups: negative (saline), positive (morphine or diclofenac) controls, and test groups. The acute toxicity was assessed for 2 days. Antinociceptive activity was performed using hot plate and writhing tests. The anti-inflammatory effect was investigated using xylene-induced ear edema and a cotton pellet test. According to phytochemical screening, the extracts contained tannins, alkaloids, and flavonoids. The LD50 values of the aqueous and ethanolic extracts were 0.473 and 0.79 g/kg, respectively. In hot plate test, the aqueous and ethanolic extracts showed significant antinociceptive activity that was inhibited by naloxone. The extracts exhibited antinociceptive activity against acetic acid induced writhing and also showed significant activity against acute inflammation which was dose dependent for aqueous extract. The ethanolic (0.05 g/kg) and aqueous extracts (0.005, 0.015, and 0.03 g/kg) demonstrated anti-inflammatory effects against chronic inflammation. The aqueous and ethanolic extracts of the aerial parts of M communis L. showed antinociceptive effects and these may be mediated by opioid receptors. PMID- 22196508 TI - In vitro antiproliferative and antioxidant activities and total phenolic contents of the extracts of Melastoma malabathricum leaves. AB - The present study aims to determine the in vitro antiproliferative and antioxidant activities of various extracts from the leaves of Melastoma malabathricum using various established in vitro assays. The aqueous extract inhibited the proliferation of Caov-3 and HL-60 cell lines, while the chloroform extract exhibited antiproliferative activity against the Caov-3, HL-60, and CEM SS cell lines. The methanol extract demonstrated antiproliferative activity against more cell lines, including the MCF-7, HeLa, Caov-3, HL-60, CEM-SS, and MDA-MB-231 cancer cell lines. Interestingly, all extracts did not inhibit the proliferation of 3T3 cells, thus indicating their noncytotoxic properties. Unlike the chloroform extracts, the aqueous and methanol extracts of M malabathricum (20, 100, and 500 MUg/ml) produced high antioxidant activity for the superoxide scavenging assay with only the 500 MUg/ml aqueous and methanol extracts exhibited high activity for the 2,2-diphenyl -1-picrylhydrazyl radical scavenging assay. The total phenolic content recorded for the aqueous, methanol, and chloroform extracts were 3344.2 +/- 19.1, 3055.1 +/- 8.7, and 92.5 +/- 7.3 mg/100 g of gallic acid, respectively. The M malabathricum leaves possessed potential antiproliferative and antioxidant activities that could be attributed to its high content of phenolic compounds. PMID- 22196509 TI - Significant neurological improvement in two patients with amyotrophic lateral sclerosis after 4 weeks of treatment with acupuncture injection point therapy using enercel. AB - Amyotrophic lateral sclerosis (ALS) is a progressive, uniformly fatal, degenerative disorder of the upper motor neurons that does not currently have an effective treatment regimen. Here, we report two patients with ALS who were treated with 4 weeks of acupuncture injection point therapy using Enercel. These patients were administered 0.25-0.5 cc Enercel Plus IM to specific acupuncture points for 5 days per week for 4 weeks. Patient #1 presented with flaccid paralysis of all four extremities and impaired speech and swallowing. By Week 4, she demonstrated significant improvement in her motor strength in all four extremities (R>L) and improved speech and swallowing. However, she did not continue to receive the Enercel acupoint injections, and she subsequently demonstrated a slow, progressive loss of neurological function during the ensuing 3 months, as shown on follow-up examinations. Patient #2 had significantly impaired speech and mild motor loss in the upper extremities and the left leg. After 4 weeks of treatment, his voice had significantly improved to the point where his speech was understandable and his motor functions had returned to normal. He continued receiving Enercel acupoint injections during the 3-month follow-up period and his clinical improvements were maintained. Thus, these two patients with ALS showed clinical improvements after 4 weeks of Enercel acupoint injection therapy. Follow-up data suggests that ongoing therapy may be necessary in order to maintain these positive effects. This preliminary study merits further study and confirmation. PMID- 22196510 TI - Safety of 4-week indirect-moxibustion therapy at CV4 and CV8. AB - PURPOSE: Moxibustion therapy is a commonly used treatment in Oriental medicine. Here, we provide evidence for the safety of long-term moxibustion therapy. SUBJECTS: and design: Forty-five subjects (10 men and 35 women) who complained of chronic fatigue were divided into control (5 men and 15 women) and experimental groups (5 men and 20 women) in a randomized double-blind setting. The experimental group was treated with moxibustion to CV4 and CV8 for 4 weeks (administered three times per week); the control group was exposed to simulated burning of moxibustion. Complete blood counts, blood chemistry, and urinalysis results were analyzed before and after each trial. RESULTS: The absolute and relative number of peripheral blood cells did not differ between the pre- and posttreatment measurements of either group. No significant changes in blood chemistry or urinalysis data were observed in either group. CONCLUSIONS: These results suggest that indirect moxibustion has no effect on blood chemistry or urine and is safe for clinical use. These data could be used as reference data for further moxibustion studies. PMID- 22196512 TI - 4-Aminoethylpiperazinyl aryl ketones with 5-HT1A/5-HT7 selectivity. AB - The well-known 5-HT(1A)/5-HT(7) selectivity issue was tackled by a new series of 4-aminoethylpiperazinyl aryl ketones (1a-1l) specifically designed to distinguish the two hydrophobic sites centered at the anchoring salt bridge. The 4 aminoethylpiperazinyl aryl ketones showed a wide spectrum of activity and selectivity for the 5-HT receptors depending on the type of the hydrophobic groups attached at the aryl piperazinyl ketone scaffold. Docking study of the most active compounds against 5-HT(7)R and 5-HT(1A)R revealed that both receptors have two hydrophobic pockets around the anchoring salt bridge. These two binding sites are perpendicular to each other in 5-HT(7)R but parallel in 5-HT(1A)R, and this observation is well matched with the previous report which claimed that 5 HT(7)R affinity arises from bent conformation of the bound ligand whereas an extended one is best suited for 5-HT(1A)R selectivity. Also, as these pockets have different size and shape, inhibitory activity as well as selectivity of the 4-aminoethylpiperazinyl aryl ketones against 5-HT(7)R and 5-HT(1A)R seemed to be determined by combination of two hydrophobic substituents attached at both ends of the title compounds. PMID- 22196513 TI - Synthesis, biological evaluation and mechanistic studies of totarol amino alcohol derivatives as potential antimalarial agents. AB - Herein we report on the semisynthesis and biological evaluation of beta-amino alcohol derivatives of the natural product totarol and other simple aromatic systems. All beta-amino alcohol derivatives of totarol exhibited higher antiplasmodial activity than totarol [IC(50): 11.69 MUM (K1, chloroquine and multi-drug resistant strain), and 11.78 MUM (D10, chloroquine sensitive strain)] 12e was the most active [IC(50): 0.63 MUM (K1), and 0.61 MUM (D10)]. The phenyl and naphthyl beta-amino alcohol derivatives were much less active than their corresponding totarol equivalents. The majority of the beta-amino alcohol derivatives of totarol were more active against K1 than the D10 strains of Plasmodium falciparum, a trend similar to the inverse relationship observed with the established aryl-amino alcohol antimalarial mefloquine. Selected compounds were shown to affect erythrocyte morphology, inhibit erythrocyte invasion and trigger CQ accumulation. PMID- 22196514 TI - Pyrrolo[1,2-b]pyridazines, pyrrolo[2,1-f]triazin-4(3H)-ones, and related compounds as novel corticotropin-releasing factor 1 (CRF1) receptor antagonists. AB - To identify structurally novel corticotropin-releasing factor 1 (CRF(1)) receptor antagonists, a series of bicyclic core analogs pyrrolo[1,2-b]pyridazines and pyrrolo[2,1-f]triazin-4(3H)-ones, which were designed based on a monocyclic core antagonist, was synthesized and evaluated. Among the compounds tested, 2 difluoromethoxy-4-methylpyridin-5-yl analog 27 was found to show efficacy in a dose-dependent manner in an elevated plus maze test in rats. The discovery process and structure-activity relationship is presented. PMID- 22196515 TI - Design, synthesis and evaluation of polar head group containing 2-keto-oxazole inhibitors of FAAH. AB - 2-alpha-Keto oxazoles containing polar head groups in their C5-side chains were designed as fatty acid amide hydrolase (FAAH) inhibitors. Variation in the spacer length resulted in submicromolar alpha-keto-oxazole FAAH inhibitor (IC(50)=436 nM) presenting electrostatic stabilizing interactions between its polar head group contained in the C5-side chain and the hydrophilic pocket of the enzyme. PMID- 22196518 TI - Mycobacterium fortuitum prosthetic valve endocarditis: a case for the pathogenetic role of biofilms. AB - BACKGROUND: Prosthetic valve endocarditis presents unique challenges for both diagnosis and treatment. A potential role of biofilm has been hypothesized in the pathogenesis of these infections. METHODS: A patient with infective endocarditis involving a stentless (Freestyle) porcine prosthetic aortic valve with annular abscess and paravalvular leak 8 months after implantation is reported. RESULTS: The infected valve did not show vegetations or perforations, but histiocytic inflammation was seen along the endocardial surfaces of the valve. Auramine rhodamine staining revealed many acid-fast organisms associated with the inflammation. There was also an acellular matrix material with ultrastructural features of biofilm. Blood cultures grew Mycobacterium fortuitum, a biofilm associated microbe. CONCLUSIONS: The role of biofilm in prosthetic valve endocarditis is discussed. The importance of microscopy for prosthetic valves, even when no vegetations are present, is highlighted along with correlation of pathologic findings with culture results. PMID- 22196519 TI - [Quality of food intake after bariatric surgery: vertical gastrectomy versus gastric bypass]. AB - INTRODUCTION: The different bariatric surgical techniques have an influence on food tolerance and the presence of vomiting. There have been few studies on the impact of these techniques on the quality of food intake. PATIENTS AND METHOD: A prospective and comparative study was performed on a consecutive patient cohort operated on due to morbid obesity between May 2008 and November 2010. The quality of the diet was evaluated before and at 3, 6, 12 and 24 months postoperatively, using the questionnaire described by Suter et al. RESULTS: One hundred and five patients (64 vertical gastrectomy [VG] and 41 gastric bypass [GB]) completed the questionnaire before the surgery, and 87 at 3 months, 79 at 6 months, 53 at 12 months, and 18 at 24 months after surgery. The overall score of the questionnaire before surgery was 23.5 +/- 2.6, with a significant difference at 3 months (20.4 +/- 3.8, P<.001), at 6 months (21.3 +/- 4.6, P<.001) and at 12 months (22.4 +/- 3.3, P<.044), and with no difference at 24 months (23.2 +/- 2.5, P<.622), after surgery. On comparing food intake of VG versus GB, the scores were similar before surgery (23.8 +/- 2.4 vs 23.0 +/- 2.8, P<.125) as well as in the post-surgical follow up at 3 months (20.5 +/- 3,9 vs 20.2 +/- 3.7, P<.599), 6 months (21.1 +/- 5.3 vs 21.7 +/- 3.4, P<.243), 12 months (22.3 +/- 3.3 vs 22.7 +/- 3.4, P<.140) and 24 months (22.9 +/- 3.0 vs 23.6 +/- 2.2, P = 1.00). CONCLUSIONS: The worsening of the quality of food intake is common in the first months after bariatric surgery, gradually improving and with no differences being seen between VG and GB. PMID- 22196520 TI - Respiratory health effects of air pollution: update on biomass smoke and traffic pollution. AB - Mounting evidence suggests that air pollution contributes to the large global burden of respiratory and allergic diseases, including asthma, chronic obstructive pulmonary disease, pneumonia, and possibly tuberculosis. Although associations between air pollution and respiratory disease are complex, recent epidemiologic studies have led to an increased recognition of the emerging importance of traffic-related air pollution in both developed and less-developed countries, as well as the continued importance of emissions from domestic fires burning biomass fuels, primarily in the less-developed world. Emissions from these sources lead to personal exposures to complex mixtures of air pollutants that change rapidly in space and time because of varying emission rates, distances from source, ventilation rates, and other factors. Although the high degree of variability in personal exposure to pollutants from these sources remains a challenge, newer methods for measuring and modeling these exposures are beginning to unravel complex associations with asthma and other respiratory tract diseases. These studies indicate that air pollution from these sources is a major preventable cause of increased incidence and exacerbation of respiratory disease. Physicians can help to reduce the risk of adverse respiratory effects of exposure to biomass and traffic air pollutants by promoting awareness and supporting individual and community-level interventions. PMID- 22196521 TI - Effects of air pollutants on innate immunity: the role of Toll-like receptors and nucleotide-binding oligomerization domain-like receptors. AB - Interactions between exposure to ambient air pollutants and respiratory pathogens have been shown to modify respiratory immune responses. Emerging data suggest key roles for Toll-like receptor (TLR) and nucleotide-binding oligomerization domain like receptor (NLR) signaling in pathogen-induced immune responses. Similarly, immune responses elicited by exposure to air pollutants are mediated by specific TLR- and NLR-dependent mechanisms. This review article will summarize current knowledge about how air pollutants modify TLR- and NLR-dependent signaling and host defense responses in the lung. PMID- 22196523 TI - Roles of pollution in the prevalence and exacerbations of allergic diseases in Asia. AB - The prevalence of asthma and allergic diseases has been found to be increasingly rapidly, especially in developing countries. Environmental factors have been found to be important contributors to the manifestations of allergic diseases. Air pollution has been extensively studied in different regions of the world. The levels of ambient air pollutants in many Asian countries are very high when compared with those in developed Western countries. However, the prevalence of asthma was relatively low across many Asian countries. Many studies have clearly documented that environmental air pollution is an important factor resulting in exacerbations of asthma. In particular, levels of traffic-related pollutants are increasing rapidly across many Asian countries in parallel with the level of urbanization and economic development. The loss of protective factors associated with a rural environment will further contribute to the adverse effect on patients with allergic diseases such as asthma. In this review the roles of air pollution were examined in relation to the inception and exacerbations of allergic diseases in Asia. PMID- 22196524 TI - Severe asthma: advances in current management and future therapy. AB - Effective treatment of severe asthma is a major unmet need because patients' symptoms are not controlled on maximum treatment with inhaled therapy. Asthma symptoms can be poorly controlled because of poor adherence to controller therapy, and this might be addressed by using combination inhalers that contain a corticosteroid and long-acting beta(2)-agonist as reliever therapy in addition to maintenance treatment. New bronchodilators with a longer duration of action are in development, and recent studies have demonstrated the benefit of a long-acting anticholinergic bronchodilator in addition to beta(2)-agonists in patients with severe asthma. Anti-IgE therapy is beneficial in selected patients with severe asthma. Several new blockers of specific mediators, including prostaglandin D(2), IL-5, IL-9, and IL-13, are also in clinical trials and might benefit patients with subtypes of severe asthma. Several broad-spectrum anti-inflammatory therapies that target neutrophilic inflammation are in clinical development for the treatment of severe asthma, but adverse effects after oral administration might necessitate inhaled delivery. Macrolides might benefit some patients with infection by atypical bacteria, but recent results are not encouraging, although there could be an effect in patients with predominant neutrophilic asthma. Corticosteroid resistance is a major problem in patients with severe asthma, and several molecular mechanisms have been described that might lead to novel therapeutic approaches, including drugs that could reverse this resistance, such as theophylline and nortriptyline. In selected patients with severe asthma, bronchial thermoplasty might be beneficial, but thus far, clinical studies have not been encouraging. Finally, several subtypes of severe asthma are now recognized, and in the future, it will be necessary to find biomarkers that predict responses to specific forms of therapy. PMID- 22196525 TI - Advances in pediatric asthma in 2011: moving forward. AB - Last year's "Advances in pediatric asthma" concluded with the following statement: "Perhaps new directions in personalized medicine and improved health care access and communication will help maintain steady progress in alleviating the burden of this disease in children, especially young children." This year's summary will focus on recent advances in pediatric asthma that show significant accomplishments in reducing asthma morbidity and mortality over the last 10 years and discuss some pathways to further reduce asthma burden, as indicated in Journal of Allergy and Clinical Immunology publications in 2011. Some of the recent reports continue to shed light on methods to improve asthma management through steps to reduce asthma exacerbations, identify features of the disease in early childhood, alter asthma progression, intervene with nutrition, and more effectively implement the asthma guidelines. As new information evolves, it is also time to consider a revision of the asthma guidelines based on key studies that affect our management of the disease since the last revision in 2007. Now is also the time to use information recorded in electronic medical records to develop innovative disease management plans that will track asthma over time and enable timely decisions on interventions to maintain control that can lead to disease remission and prevention. PMID- 22196522 TI - Genetic and epigenetic influence on the response to environmental particulate matter. AB - Ambient air pollution, including particulate matter (PM) and gaseous pollutants, represents important environmental exposures that adversely affect human health. Because of their heritable and reversible nature, epigenetic modifications provide a plausible link between the environment and alterations in gene expression that might lead to disease. Epidemiologic evidence supports that environmental exposures in childhood affect susceptibility to disease later in life, supporting the belief that epigenetic changes can affect ongoing development and promote disease long after the environmental exposure has ceased. Indeed, allergic disorders often have their roots in early childhood, and early exposure to PM has been strongly associated with the subsequent development of asthma. The purpose of this review is to summarize recent findings on the genetic and epigenetic regulation of responses to ambient air pollutants, specifically respirable PM, and their association with the development of allergic disorders. Understanding these epigenetic biomarkers and how they integrate with genetic influences to translate the biologic effect of particulate exposure is critical to developing novel preventative and therapeutic strategies for allergic disorders. PMID- 22196526 TI - Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2011. AB - This review highlights some of the research advances in anaphylaxis; hypersensitivity reactions to foods, drugs, and insects; and allergic skin diseases that were reported in the Journal in 2011. Food allergy appears to be increasing in prevalence and carries a strong economic burden. Risk factors can include dietary ones, such as deficiency of vitamin D and timing of complementary foods, and genetic factors, such as filaggrin loss-of-function mutations. Novel mechanisms underlying food allergy include the role of invariant natural killer T cells and influences of dietary components, such as isoflavones. Among numerous preclinical and clinical treatment studies, promising observations include the efficacy of sublingual and oral immunotherapy, a Chinese herbal remedy showing promising in vitro results, the potential immunotherapeutic effects of having children ingest foods with baked-in milk if they tolerate it, and the use of anti IgE with or without concomitant immunotherapy. Studies of allergic skin diseases, anaphylaxis, and hypersensitivity to drugs and insect venom are elucidating cellular mechanisms, improved diagnostics, and potential targets for future treatment. The role of skin barrier abnormalities, as well as the modulatory effects of the innate and adaptive immune responses, are major areas of investigation. PMID- 22196528 TI - The suppressive role of IL-10 in contact and atopic dermatitis. PMID- 22196530 TI - Role of environmental control in the management of asthma and allergy. PMID- 22196529 TI - Airway cells from atopic asthmatic patients exposed to ozone display an enhanced innate immune gene profile. PMID- 22196533 TI - Effect of microbial polymers on the sorption and transport of phenanthrene in a low-carbon sand. PMID- 22196531 TI - Polymerase chain reaction and histology in diagnosis of placental malaria in an area of unstable malaria transmission in Central Sudan. AB - BACKGROUND: Prevalence of placental malaria has been widely used as a standard indicator to characterize malaria infection in epidemiologic surveys. Placental malaria poses a greater diagnostic challenge, accurate and sensitive diagnostic tool for malaria infections in pregnancy is needed. METHODS: A cross sectional study was conducted at Medani Hospital, which serves catchment area which is characterized by unstable malaria transmission. One hundred and seven placentae were investigated for malaria infection using polymerase chain reaction (PCR) and histology. RESULTS: out of 107 investigated placentae, 33 (30.8%) and 34 (31.8%) were positive for malaria by histology (two (2%) and 31(29.0%) were acute and past infections, respectively) and PCR, respectively. Out of 33 positive by histology, 15 were positive by the PCR while 18 were negative. The sensitivity of the PCR was 45.5% (95% CI: 29.2%- 62.5%). Out of 74 which were negative by histology, 19 were positive by the PCR. This is translated in specificity of 74.3% (95% CI: 63.5%- 83.3%). Of those tested positive by the PCR, 15 were positive by the histology, while 19 were negative. This is translated into a positive predictive value of 44.1% (95% CI: 28.3%- 61.0%). Of those 73 tested negative by the PCR, 55 were negative according to histology while 23 were positive. This is translated into a negative predictive value of 75.3% (95% CI: 64.5%-84.2%). CONCLUSION: PCR had low sensitivity and specificity in comparison to placental histology, perhaps because the vast majority of the placental infections were past infections. Further research is needed. PMID- 22196532 TI - [An infrequent complication of RSV acute bronchiolitis in an infant]. AB - We report the case of a 10-month-old girl hospitalized with RSV acute bronchiolitis who developed necrotizing pneumonia with pyopneumothorax due to Panton-Valentine leukocidin-secreting Staphylococcus aureus. The outcome was fortunately favorable with antibiotics and pleural drainage. PMID- 22196534 TI - Comparative rates of photolysis of polychlorinated dibenzofurans in organic solvents and in aqueous solutions. PMID- 22196535 TI - Size distributions of polycyclic aromatic hydrocarbons and elemental carbon. 1. Sampling, measurement methods, and source characterization. PMID- 22196537 TI - Reaction of a lignin model dimer sequentially with chlorine and sodium hydroxide. PMID- 22196536 TI - Size distributions of polycyclic aromatic hydrocarbons and elemental carbon. 2. Ambient measurements and effects of atmospheric processes. PMID- 22196538 TI - Speciation and fate of arsenic in three lakes of the aberjona watershed. PMID- 22196539 TI - Luminescence Studies of Metal Ion-Binding Sites on Datura innoxia Biomaterial. PMID- 22196540 TI - Multispectral identification of chlorine dioxide disinfection byproducts in drinking water. PMID- 22196541 TI - Preferential Dealkylation Reactions of s-Triazine Herbicides in the Unsaturated Zone. PMID- 22196543 TI - Modeling Adsorption of TCE by Activated Carbon Preloaded by Background Organic Matter. PMID- 22196542 TI - Degradative pathways for aqueous chlorination of orcinol. PMID- 22196544 TI - Influence of Postcombustion Temperature Profiles on the Formation of PCDDs, PCDFs, PCBzs, and PCBs in a Pilot Incinerator. PMID- 22196545 TI - Microbial reductive dechlorination of trichlorobiphenyls in anaerobic sediment slurries. PMID- 22196546 TI - XPS and XANES Studies of Uranium Reduction by Clostridium sp. PMID- 22196547 TI - Adsorption of organic vapors on polar mineral surfaces and on a bulk water surface: development of an empirical predictive model. PMID- 22196548 TI - In situ formation of lead phosphates in soils as a method to immobilize lead. PMID- 22196549 TI - High-volume air sampler for particle and gas sampling.2.use of backup filters to correct for the adsorption of gas-phase polycyclic aromatic hydrocarbons to the front filter. PMID- 22196550 TI - Lead migration in forest soils: response to changing atmospheric inputs. PMID- 22196551 TI - New Reactor Design for Photocatalytic Wastewater Treatment with TiO2 Immobilized on Fused-Silica Glass Fibers: Photomineralization of 4-Chlorophenol. PMID- 22196552 TI - Uptake of Phosphate by Iron Hydroxides during Seepage in Relation to Development of Groundwater Composition in Coastal Areas. PMID- 22196553 TI - Quantification of 3-(2-Hydroxypropyl)-5-methyl-2-oxazolidinone in Groundwater and Sludge by Isotope Dilution Gas Chromatography/Mass Spectrometry. PMID- 22196554 TI - In situ Measurements of Tetraphenylboron Degradation Kinetics on Clay Mineral Surfaces by IR. PMID- 22196555 TI - Transformation of carbon tetrachloride by pyrite in aqueous solution. PMID- 22196557 TI - Polychlorinated biphenyl congeners in emergent mayflies from the upper Mississippi river. PMID- 22196556 TI - Dechlorination of chlorinated benzenes by an anaerobic microbial consortium that selectively mediates the thermodynamic most favorable reactions. PMID- 22196558 TI - Atmospheric Chemistry of Unsaturated Carbonyls: Butenedial, 4-Oxo-2-pentenal, 3 Hexene-2,5-dione, Maleic Anhydride, 3H-Furan-2-one, and 5-Methyl-3H-furan-2-one. PMID- 22196559 TI - Chromium speciation and distribution in the great lakes. PMID- 22196560 TI - Electrokinetically enhanced sedimentation of colloidal contaminants. PMID- 22196561 TI - Reductive dechlorination of tetrachloroethylene by a chlorobenzoate-enriched biofilm reactor. PMID- 22196562 TI - Quantitation of the microcystin hepatotoxins in water at environmentally relevant concentrations with the protein phosphatase bioassay. PMID- 22196563 TI - Additions and corrections: interfacial films in coal tar nonaqueous-phase liquid water systems. PMID- 22196565 TI - Age, sex, disease, ethnicity et al - are complementary therapies reaching the parts? PMID- 22196566 TI - Feasibility and effectiveness of massage therapy for symptom relief in cardiac catheter laboratory staff: a pilot study. AB - A pilot study was conducted to assess the feasibility and efficacy of massage therapy for cardiac catheterization laboratory staff. Staff members (N = 50) were randomly assigned to 5 or 10 weekly 30-min massages, followed by outcomes assessment. A control group (n = 10) receiving no massage therapy underwent comparable assessment. Visual analog scales, the t test, and the repeated measures model evaluated fatigue, pain, relaxation, stress/anxiety, tension/discomfort, and scheduling ease at baseline, 5 weeks, and 10 weeks. The Aickin separation test was used to assess feasibility of further research. Overall, 90% (337/375) of massage appointments were used. No significant effects were observed, but the Aickin separation test supported further research on massage therapy for fatigue, pain, relaxation, and tension/discomfort. Conducting massage therapy in the workplace is logistically feasible. Larger, longitudinal trials are warranted to better evaluate its effects on staff. PMID- 22196567 TI - Effect of an integrated support programme on the concerns and wellbeing of women with breast cancer: a national service evaluation. AB - PURPOSE: To carry out a national service evaluation of the integrated cancer support programme offered by The Haven using the Measure Yourself Concerns and Wellbeing (MYCaW) outcome questionnaire. METHODS: Breast cancer survivors who visited one of three Haven centres in the UK completed the MYCaW questionnaire before and after 6 one-hour complementary therapy sessions. RESULTS: Statistically significant decreases in mean baseline scores (indicating improvement) for concerns and wellbeing were observed after treatment: concern 1 (5.09 +/- 1.04 vs 3.17 +/- 1.60, p < 0.0001, n = 402), concern 2 (4.69 +/- 1.08 vs 3.08 +/- 1.56, p < 0.0001, n = 372), and wellbeing (3.30 +/- 1.41 vs 2.63 +/- 1.28, p < 0.0001, n = 402). The therapies most commonly used were acupuncture, nutrition, massage and aromatherapy, shiatsu, counselling and reflexology. After therapy, 91% of reported scores (n = 328) rated the concern as being a little better, much better or gone. CONCLUSIONS: These findings suggest that women with breast cancer find the Haven integrated support programme valuable for addressing their main concerns and improving their feeling of wellbeing. PMID- 22196568 TI - Complementary and alternative medicine use amongst Palestinian diabetic patients. AB - OBJECTIVES: To measure the frequency of herbal medicine use among patients with diabetes mellitus in Palestine; to determine demographic characteristics that may increase the likelihood of Complementary and Alternative Medicine (CAM) use and to find out how benefits, if any, were perceived by patients. METHOD: Cross sectional survey of patients attending the outpatient diabetes departments at 7 Governmental Hospitals. The method was based on semi-structured questionnaires. RESULTS: A total of 1883 patients with diabetes were interviewed. Of the participants, 51.9% (n = 977) reported taking herbs primarily bought from Palestine (98%) and used in crude form mainly as decoctions (44.1%). The five most common herbal products used were: Trigonella berythea (Fabaceae) (n = 191, 19.6%), Rosmarinus officinalis (Lamiaceae) (n = 132, 13.5%), Olea europaea (Oleaceae) (n = 131, 13.4%), Teucrium capitatum (Lamiaceae) (n = 111, 11.4%), and Cinnamomum zeylanicum (Lauraceae) (n = 105, 10.8%). Most CAM users were above 40 years old 79.6% (n = 778), predominantly female (53.2%) and residents of refugee camps and rural areas (59.3, and 53.5, respectively). The recommendations of a family member or friend was the main factor prompting the use of CAM (40.2 and 37.1%). Most CAM users (71.7%) were satisfied with the perceived effects. Interestingly, 68% of patients recruited in the study did not disclose CAM use to their physicians or pharmacists. CONCLUSION: Use of herbal therapies in diabetes is highly prevalent in Palestine. More than 70% of those using CAM (977, 51.9%) reported positive benefits including a feeling of slowing down disease progression, symptom relief, disease resolution or a reduction in the side effects of allopathic medication. Use of CAM should be explored with patients before clinical decisions are made. There is a need for health education relating to herbal use in conjunction with conventional medicines in diabetes. PMID- 22196569 TI - Ginger to reduce nausea and vomiting during pregnancy: evidence of effectiveness is not the same as proof of safety. AB - Ginger is a common traditional remedy taken by numerous women experiencing nausea and vomiting in pregnancy (NVP). There is considerable evidence to support its effectiveness as an anti-emetic, but also increasing concern over its safety. Ginger is a powerful herbal medicine which acts pharmacologically and thus has specific indications, contraindications, precautions and side-effects, the most notable of which is an anticoagulant action. Midwives and other professionals advising women in early pregnancy about strategies for coping with NVP should be aware of the risks and benefits of ginger in order to provide comprehensive and safe information to expectant mothers. This paper reviews some of the contemporary research evidence which demonstrates that ginger is not a universally appropriate or safe choice for women with NVP and offers a checklist for professionals advising expectant mothers. PMID- 22196570 TI - Tai Chi effects on neuropsychological, emotional, and physical functioning following cancer treatment: a pilot study. AB - OBJECTIVE: To examine the effects of a 10-week Tai Chi (TC) program on neuropsychological, psychological, and physical health of female cancer survivors. DESIGN: Twenty-three women with a history of cancer participated in 60 min TC classes two times/week for 10-weeks. MAIN OUTCOME MEASURES: Before and after the intervention, participants completed neuropsychological tests (memory, executive functioning, language, and attention); 5 tests of balance; and self report questionnaires of neuropsychological complaints, stress and mood, and fatigue. RESULTS: After the 10-week session, participants evidenced fewer neuropsychological complaints and enhanced neuropsychological functioning. They also demonstrated improved balance and reported better psychological functioning. CONCLUSIONS: Results suggest that TC may promote gains in neuropsychological functioning, in addition to previously demonstrated improvements in physical and psychological health. These findings support the need for controlled trials examining the potential benefits of TC on neuropsychological functioning after cancer. PMID- 22196571 TI - The healers journey: a literature review. AB - While much important research has gone into identifying the efficacy and importance that healing interventions can make to healthcare this paper seeks to synthesise some of the core themes of the processes that healers go through in their journey to becoming a healer. Through the process of a literature review of seminal texts and current literature the paper identifies the key themes of, healer as facilitator, connecting to sources of healing, an appreciation of the healee, an expanded sense of spirituality, an acknowledgement of the wider archetypal significance of the healer, the importance of the wound and the role that these can play in the process of personal transformation and also acceptance. In doing so it hopes to offer that the journey of the healer plays a crucial role in guiding the quality of the healing that healers share in a healing encounter. PMID- 22196572 TI - Delivering shiatsu in a primary care setting: benefits and challenges. AB - AIM: To pilot the delivery of shiatsu in primary care and investigate the non clinical impact on the general practice, its patients and staff. DESIGN: Ten patients, referred by four GPs, were each offered six shiatsu treatments with a qualified practitioner. SETTING: An inner-city general practice in Sheffield, England. METHODS: 36 semi-structured interviews, evaluated with Interpretative Phenomenological Analysis and practitioner research including a reflective journal. FINDINGS: GPs welcomed having more options of care, especially for patients with complex, chronic symptoms, and patients appreciated the increased time and holistic, patient-centred approach during shiatsu consultations. Participants claimed the clinic increased equality of access to complementary medicine, improved perceptions of the general practice, reduced consultation and prescription rates, enhanced GP-patient relationships and the working practices of the GPs and shiatsu practitioner. CONCLUSION: The study successfully integrated a shiatsu clinic into a general practice and offers a model for future research on complementary medicine in primary care. PMID- 22196573 TI - Place visualization: conventional or unconventional practice? AB - This paper explores the traditional notion that two discrete forms of medicine exist. One being bio-medically led, the other being holistic in origin. A qualitative study of place visualization in nursing is used to illustrate how health care may not always fit neatly into one of these paradigms. It is suggested that, through the use of this practice, an organically occurring therapeutic intervention emerges that includes core elements of each category. Based on the findings of this small scale inductive study, it is suggested that greater attention be afforded to areas of practice shared by both health care approaches. PMID- 22196574 TI - Use of complementary and alternative medicine by patients seen at the dermatology department of a tertiary care center. AB - The use of complementary and alternative medicine (CAM) among patients with dermatologic conditions has not been well studied. The aim of this study was to evaluate the frequency and pattern of CAM use in patients referred to the dermatology department of a tertiary care center. Patients referred to the dermatology department of an academic tertiary referral center between February 2, 2010, and February 10, 2010, were invited to participate in an 86-question survey regarding CAM use during the previous year. A total of 300 patients completed the survey, of whom 154 (51%) were women. Eighty-two percent (n = 247) of the respondents had used some type of CAM during the previous year. The most frequently used treatment and technique was massage therapy (33%), and the most commonly used vitamin was vitamin C (31%). Herbs or other dietary supplements were used by 58% (n = 173) of patients. Seventy-eight percent (n = 235) of patients stated that physicians should consider incorporating CAM approaches into their treatment recommendations, and 89% of patients (n = 267) stated that our dermatology department should study CAM approaches in research studies. CAM utilization is high among patients at a large academic dermatology department. Patients indicated a strong preference for having CAM approaches incorporated into their treatment recommendations and believed in the value of clinical studies to further refine the role of CAM. PMID- 22196575 TI - Exercise research on children and adolescents. AB - This paper is a review of studies published during the last several years on exercise effects on overweight, growth, chronic illnesses, depression and anxiety in children and adolescents. Although the lion's share of the research involves aerobic exercise, studies on yoga and tai chi are also reviewed. Following exercise, body mass index and lipid profiles have improved in overweight children, and those with asthma, diabetes and depression have also benefited from exercise. The yoga studies reviewed here focused on ADHD and anxiety, and the tai chi studies involved children with ADHD and asthma. A potential underlying mechanism for the positive effects of exercise, yoga and tai chi may be the stimulation of pressure receptors leading to increased vagal activity, decreased stress hormones and increased production of anti-pain and antidepressant neurotransmitters such as serotonin. Further studies are needed using convergent behavioral, physiological and biochemical measures. Nonetheless, the current literature highlights the importance of adding exercise programs to clinics, schools and families for the physical and psychological well-being of children and adolescents. PMID- 22196576 TI - Impact of self-administered relaxation and guided imagery techniques during final trimester and birth. AB - The objective of this study was to test if and how self-administered practice of relaxation techniques, positive affirmation and guided imagery, in the final part of pregnancy had an impact on giving birth. Further to see if the use of a simple method, a CD with a booklet, with no previous training or specific support of the participants (neither required nor delivered), affected the birth experience. Outcome measures were monitored both during and after delivery: During delivery, pain and anxiety were measured at different stages of birth. Post-delivery Wellbeing (Edmonton Scale 0-10, where 10 is the worst possible feeling of Wellbeing), pain, anxiety, Apgar score, duration of birth, complications and anesthesia/analgesic were recorded. Those in the CD-intervention group also reported how many times they had practiced the techniques. The study employed a randomized controlled trial. Results show that the CD-intervention group had a significantly better score on total Wellbeing, as measured by the ESAS (0-10) Edmonton Scale. PMID- 22196577 TI - Episiotomy pain relief: Use of Lavender oil essence in primiparous Iranian women. AB - INTRODUCTION: Post-episiotomy discomfort and its consequences can affect maternal quality of life and mental health as well as the mother and baby relationship. Complementary medicine is increasingly used and Lavender oil is frequently prescribed due to its antiseptic and healing properties. METHOD: This clinical trial involved 60 qualified primiparous women admitted for labor in Kamali Hospital in Karaj, Iran. They were randomly categorized into two groups: case (using Lavender oil) and control (usual hospital protocol). Participants pain and discomfort were recorded using a Visual Analogue Scale (VAS) and a Redness, Edema, Ecchymosis, Discharge Scale (REEDA). Pain was evaluated at 4 h, 12 h and 5 days following episiotomy. Collected data was analyzed in SPSS 14 using an independent t-test and chi-square. RESULTS: There was a statistical difference in pain intensity scores between the 2 groups after 4 h (p = 0.002, and 5 days (p = 0.000) after episiotomy. However, differences in pain intensity between the two groups, at 12 h post-surgery, were not significant (p = 0.066). The REEDA score was significantly lower in the experimental group (Lavender oil group) 5 days after episiotomy (p = 0.000). CONCLUSION: According to these findings, use of Lavender oil essence can be effective in reducing perineal discomfort following episiotomy. It is suggested that Lavender oil essence may be preferably to the use of Betadine for episiotomy wound care. PMID- 22196578 TI - A response to: The use of complementary and alternative medicine by patients with cancer: a Turkey survey, by Akyol and Oz. 17 (2011) 229-233. PMID- 22196579 TI - Cancer preventive agents 11. Novel analogs of dimethyl dicarboxylate biphenyl as potent cancer chemopreventive agents(?). AB - CONTEXT: Dimethyl dicarboxylate biphenyl (DDB) is a clinically used hepatoprotectant and has also been found to have chemopreventive activity. MATERIALS AND METHODS: Sixteen novel analogs (5-20) were designed, synthesized, and evaluated for their cancer preventive activity. The 2,2'-bismethyl ester (5 18) and ether (19, 20) DDB analogs were synthesized by insertion of various linear alkyl, short fatty acid, polar, and aromatic groups. All synthesized analogs were evaluated in an in vitro short-term 12-O-tetradecanoylphorbol-13 acetate (TPA)-induced Epstein Barr virus early antigen (EBA-EA) activation assay. Three of the most potent compounds were also tested for inhibitory effects on skin tumor promotion in an in vivo two-stage mouse-skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter. RESULTS: Compound 19 with bisprenyl ethers had the most significant cancer preventive activity (100% inhibition of activation at 1 * 10(3) mol ratio/TPA, 78.4%, 49.7%, and 10.9% inhibition at 5 * 10(2), 1 * 10(2), 1 * 10 mol ratio/TPA, respectively) in vitro. Compound 19 also exhibited a remarkable inhibitory effect on skin tumor promotion in the in vivo two-stage mouse-skin carcinogenesis test. DISCUSSION AND CONCLUSIONS: Thus, DDB analog 19 could be a valuable candidate as a cancer preventive agent or as a lead for the development of new antitumor promoter drugs. PMID- 22196580 TI - Syringolin B-inspired proteasome inhibitor analogue TIR-203 exhibits enhanced biological activity in multiple myeloma and neuroblastoma. AB - CONTEXT: The bacterium Pseudomonas syringae pv. syringae (Pss) is a pathogen of many plant species and causes, for example, brown spot disease in bean plants (Phaseolus vulgaris). Pss excretes the syringolins, natural product molecules that act as a virulence factors and inhibit the proteasome of the host plants. OBJECTIVE: Proteasome inhibitors belong to an important class of anticancer agents and bortezomib (Velcade((r))) has been Food and Drug Administration approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma. Syringolins represent a new class of proteasome inhibitors and the present work was undertaken to design a potent syringolin-inspired analogue (TIR-203) for anticancer drug development. MATERIALS AND METHODS: TIR-203 was tested against human MM and neuroblastoma (NB) cells. Cancer cells were treated with TIR-203 at various concentrations (0-10 uM) and the cell viability was measured using the MTS assay. To determine the effects on proteasomal activities, the cell culture based proteasome inhibition assay was used. Syringolin A (SylA) and bortezomib were included as controls. RESULTS: TIR-203 inhibited the cell proliferation of MM and NB cells in a dose-dependent manner at significantly lower concentrations than SylA. In MM cells, TIR-203 effectively inhibited the chymotrypsin-like (CT L), caspase-like (C-L), and trypsin-like (T-L) activities of the proteasome. In NB cells, TIR-203 inhibited the CT-L and C-L activities, but not the T-L activity. DISCUSSION AND CONCLUSIONS: The newly designed proteasome inhibitor TIR 203 is more potent than the natural product SylA and strongly inhibits the cell viability and proteasomal activity of MM and NB cells. PMID- 22196582 TI - Antimalarial natural products drug discovery in Panama. AB - CONTEXT: Malaria is still a major public health problem. The biodiversity of the tropics is extremely rich and represents an invaluable source of novel bioactive molecules. For screening of this diversity more sensitive and economical in vitro methods are needed, Flora of Panama has been studied based on ethnomedical uses for discovering antimalarial compounds. OBJECTIVE: This review aims to provide an overview of in vitro screening methodologies for antimalarial drug discovery and to present results of this effort in Panama during the last quarter century. METHODS: A literature search in SciFinder and PubMed and original publications of Panamanian scientists was performed to gather all the information on antimalarial drug discovery from the Panamanian flora and in vitro screening methods. RESULTS AND CONCLUSIONS: A variety of colorimetric, staining, fluorometric, and mass spectrometry and radioactivity-based methods have been provided. The advantages and limitations of these methods are also discussed. Plants used in ethnomedicine for symptoms of malaria by three native Panamanian groups of Amerindians, Kuna, Ngobe Bugle and Teribes are provided. Seven most active plants with IC(50) values < 10 MUg/mL were identified Talisia nervosa Radlk. (Sapindaceae), Topobea parasitica Aubl.(Melastomataceae), Monochaetum myrtoideum Naudin (Melastomataceae), Bourreria spathulata (Miers) Hemsl.(Boraginaceae), Polygonum acuminatum Kunth (Polygonaceae), Clematis campestris A. St.-Hil. (Ranunculaceae) and Terminalia triflora (Griseb.) Lillo (Combretaceae). Thirty bioactive compounds belonging to a variety of chemical classes such as spermine and isoquinoline alkaloids, glycosylflavones, phenylethanoid glycosides, ecdysteroids, quercetin arabinofuranosides, clerodane-type diterpenoids, sipandinolid, galloylquercetin derivatives, gallates, oleamide and mangiferin derivatives. PMID- 22196581 TI - Ethnobotanical approach versus random approach in the search for new bioactive compounds: support of a hypothesis. AB - CONTEXT: Whether natural product drug discovery programs should rely on wild plants collected "randomly" from the natural environment, or whether they should also include plants collected on the basis of use in traditional medicine remains an open question. OBJECTIVE: This study analyzes whether plants with ethnomedical uses from Vietnam and Laos have a higher hit rate in bioassay testing than plants collected from a national park in Vietnam with the goal of maximizing taxonomic diversity ("random" collection). MATERIALS AND METHODS: All plants were extracted and subjected to bioassay in the same laboratories. Results of assays of plant collections and plant parts (samples) were scored as active or inactive based on whether any extracts had a positive result in a bioassay. Contingency tables were analyzed using chi(2) statistics. RESULTS: Random collections had a higher hit rate than ethnomedical collections, but for samples, ethnomedical plants were more likely to be active. Ethnomedical collections and samples had higher hit rates for tuberculosis, while samples, but not collections, had a higher hit rate for malaria. Little evidence was found to support an advantage for ethnomedical plants in HIV, chemoprevention and cancer bioassays. Plants whose ethnomedical uses directly correlated to a bioassay did not have a significantly higher hit rate than random plants. DISCUSSION: Plants with ethnomedical uses generally had a higher rate of activity in some drug discovery bioassays, but the assays did not directly confirm specific uses. CONCLUSIONS: Ethnomedical uses may contribute to a higher rate of activity in drug discovery screening. PMID- 22196583 TI - Anti-depressant-like effect of peony: a mini-review. AB - CONTEXT: Depression is a common psychiatric disorder, yet the clinical efficacy of antidepression therapies is unsatisfactory. Thus, the search for new anti depressants continues, and natural products remain a promising source of new therapeutic agents. The root part of Paeonia lactiflora Pall. (Ranunculaceae), known as peony, is often used in Chinese herbal prescriptions for the treatment of depression-like disorders. OBJECTIVES: The objective of this review is to provide scientific evidence to support further research on peony as a potential anti-depressant drug. METHODS: This review summarizes the results obtained in our laboratory, together with other literature data obtained through a comprehensive search in databases including PubMed, ScienceDirect, Scirus, and Web of Science. RESULTS: The peony extract is active in the mouse forced swim test and tail suspension test, and it produces anti-depressant effects in chronic unpredictable mild stress-induced depression model in mice and rats. The anti-depressant mechanisms of peony are likely mediated by the inhibition of monoamine oxidase activity, neuro-protection, modulation of the function of hypothalamic-pituitary adrenal axis, inhibition of oxidative stress, and the up-regulation of neurotrophins. CONCLUSIONS: Peony is used clinically to treat depression-like symptoms in Chinese medicine, and it has been shown to possess anti-depressant property in a battery of test models using laboratory animals. Its effect is likely mediated by multiple targets. Further studies are warranted to delineate the molecular mechanisms of action, determine the pharmacokinetics, establish the toxicological profile, and assess the potentials of peony in clinical applications. Identification of the clinically active ingredient(s) is also warranted. PMID- 22196584 TI - Prenylated caged xanthones: chemistry and biology. AB - CONTEXT: Prenylated caged xanthones are "privileged structure" characterized by the presence of the unusual 4-oxo-tricyclo[4.3.1.0(3,7)]dec-8-en-2-one scaffold. The natural sources of these compounds confines mainly in the Garcinia genus in the family of Guttiferae. Gambogic acid is the most abundant substance and most of the studies have been done on this compound, particularly as a new potential antitumor agent. The history, sources, structural diversity, and biological activities of these compounds are covered. OBJECTIVE: This review is written with the intention to provide additional aspects from what have been published of prenylated caged xanthones, including history, sources, structural diversity, and biological activities. METHODS: This review has been compiled using information from a number of reliable references mainly from major databases including SciFinder, ScienceDirect, and PubMed. RESULTS: More than 120 prenylated caged xanthones have been found in the plant genera Garcinia, Cratoxylum, and Dascymaschalon. These compounds exhibited various potentially useful biological activities such as anticancer, anti-HIV-1, antibacterial, anti-inflammatory, and neurotrophic activities. CONCLUSIONS: Prenylated caged xanthones, both naturally occurring and synthetic analogues, have been identified as promising bioactive compounds, especially for anticancer agents. Gambogic acid has been demonstrated to be a highly valuable lead compound for antitumor chemotherapy. The structure activity relationship (SAR) study of its analogues is still the subject of intensive research. Apoptosis cytotoxic mechanism has been identified as the major pathway. Research on the delineation of the in-depth mechanism of action is still on-going. Analogues of gambogic acid had been identified to be effective against a rare and special form of liver cancer, cholangiocarcinoma for which currently there is no chemotherapeutic treatment available. PMID- 22196585 TI - Effect of Emex spinosa, Leptadenia pyrotechnica, Haloxylon salicornicum and Ochradenus baccatus extracts on the reproductive organs of adult male rats. AB - CONTEXT: Emex spinosa (L.) Campd. (Polygonaceae), Leptadenia pyrotechnica (Forsk.) Decne (Asclepiadaceae), Haloxylon salicornicum (Moq.) Bunge ex Bioss. (Chenopodiaceae) and Ochradenus baccatus Delile (Resedaceae) are used in folk medicine for treatment of male sexual disorders. OBJECTIVE: To investigate the effects of E. spinosa, L. pyrotechnica, H. salicornicum and O. baccatus extracts on the reproductive system of male rats after prolonged period of treatment. METHODS: Seventy-eight healthy adult male Wistar rats were divided into 13 groups (6 animals, each). The plant extracts (100, 200 and 400 mg/kg) were given daily by gavage to different groups of rats for 65 days. The thirteenth group (control) received the vehicle only. Test and control rats were mated with estrus female rats on days 30, 45 and 60 of treatment. Body and relative reproductive organ weights, and sperm parameters were recorded. RESULTS: Animals treated with the ethanol extracts of E. spinosa and L. pyrotechnica showed significant improvement of the relative weight of reproductive organs, sperm count, sperm motility and total sperm abnormality. The mean sperm count for E. spinosa group (400 mg/kg) was 233.7 +/- 4.50 * 10(6)/mL, for L. pyrotechnica (200 and 400 mg/kg) groups were 237.0 +/- 5.22 * 10(6)/mL and 240.3 +/- 4.64 * 10(6)/mL, respectively and that of the control group was 218.1 +/- 4.28 * 10(6)/mL. The sperm motility of the control group was 77.5 +/- 2.12, those of E. spinosa (400 mg/kg) group was 87.3 +/- 3.50% and those of L. pyrotechnica (200 and 400 mg/kg) groups were 86.0 +/- 3.11 and 89.7 +/- 2.90%, respectively. Ethanol extracts of E. spinosa (400 mg/kg) and L. pyrotechnica (200 and 400 mg/kg) significantly elevate the serum levels of testosterone (5.30 +/- 0.15, 5.32 +/- 0.20 and 5.66 +/- 0.19 ng/mL, respectively vs 4.64 +/- 0.16 ng/mL) and luteinizing hormone (0.69 +/- 0.03, 0.70 +/- 0.03 and 0.74 +/- 0.03 mIU/mL, respectively vs 0.59 +/- 0.02 mIU/mL). On the other hand, no alterations were observed in body and relative organ weights, sperm numbers as well as sperm morphology of the male rats after the exposure to the H. salicornicum and O. baccatus extracts for 65 days. CONCLUSIONS: E. spinosa and L. pyrotechnica extracts appear to possess fertility improvement activity in male rats due to their testosterone increasing property. Moreover, the results suggest the absence of male reproductive toxicity of the H. salicornicum and O. baccatus extracts at tested doses. PMID- 22196586 TI - Sedative effects of essential oils obtained from Baccharis uncinella. AB - CONTEXT: Essential oils (EOs) have been reported to possess pharmacological properties, of which those related to the central nervous system have been especially attributed to mono- and sesquiterpenes. Baccharis uncinella DC. (Asteraceae) is used by the Laklano Indians (Santa Catarina, Brazil) for sedative purposes. Interestingly, the species does not seem to be used medicinally elsewhere in Brazil. OBJECTIVE: This study was designed to compare the composition and sedative properties of B. uncinella EOs obtained closer (BU-SC) and farther (BU-PR) to the Laklano Indian Reserve. MATERIALS AND METHODS: BU-SC and BU-PR obtained by hydrodistillation were analyzed by CG-MS. Mice treated with BU-SC and BU-PR (50 and 100 mg/kg) were evaluated regarding pentobarbital-induced sleeping time, body temperature, and locomotion. RESULTS: BU-SC presents a higher monoterpene/sesquitherpene ratio (0.31); alpha-pinene (6.42%), limonene (7.21%), caryophyllene (26.13%), spathulenol (13.39%) and caryophyllene oxide (13.26%) were identified as major components. BU-PR presents a low monoterpene/sesquitepene ratio (0.004); spathulenol (32.93%), caryophyllene oxide (27.78%), viridiflorol (5.29%) and alpha-cadinol (2.42%) were identified as the main components. Both samples significantly (p < 0.05, ANOVA) decreased locomotion and body temperature, as well as increased sleeping time. The hypnotic activity was sensitive to the differences in monoterpene composition. CONCLUSIONS: In comparison with a sample collected in Parana State, B. uncinella EO collected closer to the Laklano Indians possess a composition that better justifies the claimed sedative properties. The study confirms the value of traditional information to guide bioactivity assessment in medicinal plants, and gives notice to the ecological factors that can interfere with the conclusions of such assessments. PMID- 22196587 TI - Isolation of the detoxification enzyme EgP450 from an oil palm EST library. AB - CONTEXT: Sequencing of cDNA clones from plant tissue to generate expressed sequence tags (ESTs) is an effective tool for gene discovery. Together with powerful bioinformatics tools, EST sequences allow the prediction of functions of putative bioactive compounds that can later be confirmed. OBJECTIVE: To isolate a detoxification enzyme from an EST library from the oil palm (Elaeis guineensis Jacq. Arecaceae). METHODS: In total, 750 clones from an oil palm cDNA library were randomly sequenced and analyzed. A clone homologous to cytochrome P450 monooxygenases (P450) was selected from the list of highly expressed genes. The full-length cDNA of P450 from E. guineensis (EgP450) was generated and transformed into a bacterial host to produce recombinant protein. A 3D model of EgP450 was generated and used in a molecular docking analysis to screen for target herbicide substrates. Finally, the detoxification activity of EgP450 was confirmed by an herbicide tolerance test with rice seedlings. RESULTS AND DISCUSSION: The full-length EgP450 has an open reading frame (ORF) of 1515 bp that encodes a protein of 505 amino acids. Docking analysis showed that EgP450 bound to phenylurea-like herbicides such as isoproturon, chlortoluron and fluometuron. The herbicide tolerance test demonstrated that the presence of EgP450 protected the rice seedlings from the killing action of the phytotoxic agent isoproturon. CONCLUSIONS: The gene EgP450 was detected in the roots and stems of oil palm tissues, and its recombinant product was shown to protect rice seedlings from exogenous herbicides of the phenylurea family. PMID- 22196591 TI - Editorial: Acid deposition in the western U.S. PMID- 22196592 TI - Letters. Ocean incineration. PMID- 22196589 TI - Utility of contrast echocardiography for pulmonary arteriovenous malformation screening in pediatric hereditary hemorrhagic telangiectasia. AB - OBJECTIVE: To evaluate the utility of transthoracic contrast echocardiography (TTCE) as a screening tool for pulmonary arteriovenous malformations (PAVMs) in children with hereditary hemorrhagic telangiectasia (HHT). STUDY DESIGN: This was a single-center study of children who underwent baseline screening for PAVMs using both TTCE and chest computed tomography (CT) for evaluation of HHT. The CT and TTCE results were prospectively reviewed independently by 2 radiologists and 2 cardiologists blinded to the study results. RESULTS: Both intraobserver and interobserver agreement for interpreting TTCE results were excellent (kappa = 0.97 and 0.92, respectively) and higher than the interobserver agreement for CT interpretation (kappa = 0.75). The sensitivity and specificity of TTCE to predict PAVMs were 1 and 0.82, respectively, and the positive predictive and negative predictive values were 0.39 and 1, respectively. CONCLUSION: TTCE is a sensitive test for PAVMs in children with suspected HHT and can be a useful initial screening tool in pediatric HHT. PMID- 22196593 TI - Letters. Cancer risk. PMID- 22196594 TI - Currents. PMID- 22196596 TI - Editorial Correction. "Transport of organic contaminants in ground water". PMID- 22196595 TI - Letters. Contaminants in Ground water. PMID- 22196597 TI - Mortality and air pollution: is there a meaningful connection? PMID- 22196599 TI - Regulatory Focus: Waste management regulations. PMID- 22196598 TI - Acid deposition and drinking water. PMID- 22196600 TI - Deposition and processing of airborne nitrogen pollutants in Mediterranean-type ecosystems of southern California. PMID- 22196601 TI - Sorbent concentration effects in liquid/solid partitioning. PMID- 22196602 TI - Trace element concentration as a function of particle size in fly ash from a pulverized coal utility boiler. PMID- 22196603 TI - Kinetics and mechanism of ozonation of free cyanide species in water. PMID- 22196604 TI - Transfer of active chlorine from chloramine to nitrogenous organic compounds. 2. Mechanism. PMID- 22196605 TI - Detection of sulfuric acid aerosols by ultraviolet scattering. PMID- 22196606 TI - Diffusion and reaction of pollutants in stratus clouds: application to nocturnal acid formation in plumes. PMID- 22196607 TI - Variability of aluminum concentrations in organs and whole bodies of smallmouth bass (Micropterus dolomieui). PMID- 22196608 TI - Effect of environmental factors on filter alkalinity and artifact formation. PMID- 22196609 TI - Bioavailability and biotransformation of aromatic hydrocarbons in benthic organisms exposed to sediment from an urban estuary. PMID- 22196611 TI - Production of organic nitrates from hydroxide and nitrate reaction with propylene. PMID- 22196610 TI - Bioconcentration factors of some halogenated organics for rainbow trout: limitations in their use for prediction of environmental residues. PMID- 22196612 TI - Chlorinated hydrocarbon cycling in the benthic nepheloid layer of Lake Superior. PMID- 22196613 TI - Response of chemiluminescence NOx analyzers and ultraviolet ozone analyzers to organic air pollutants. PMID- 22196614 TI - Comment on: "Predicting future pollution exceedances under emission controls". PMID- 22196615 TI - Rebuttal to: "Predicting future pollution exceedances under emission controls". PMID- 22196616 TI - Comment on: "Equilibrium adsorption of polycyclic aromatic hydrocarbons from water onto activated carbon". PMID- 22196617 TI - Rebuttal to: "Equilibrium adsorption of polycyclic aromatic hydrocarbons from water onto activated carbon". PMID- 22196618 TI - Acute toxicity screening of water pollutants using a bacterial electrode. Reply to comments. PMID- 22196619 TI - Acute toxicity screening of water pollutants using a bacterial electrode. Comments. PMID- 22196620 TI - Effect of different protein sources on satiation and short-term satiety when consumed as a starter. AB - BACKGROUND: Because the source of protein may play a role in its satiating effect, we investigated the effect of different proteins on satiation and short term satiety. METHODS: Two randomized single-blind cross-over studies were completed. In the first study, we investigated the effect of a preload containing 20 g of casein, whey, pea protein, egg albumin or maltodextrin vs. water control on food intake 30 min later in 32 male volunteers (25 +/- 4 yrs, BMI 24 +/- 0.4 kg/m(2)). Subjective appetite was assessed using visual analogue scales at 10 min intervals after the preload. Capillary blood glucose was measured every 30 min during 2 hrs before and after the ad libitum meal. In the second study, we compared the effect of 20 g of casein, pea protein or whey vs. water control on satiation in 32 male volunteers (25 +/- 0.6 yrs, BMI 24 +/- 0.5 kg/m(2)). The preload was consumed as a starter during an ad libitum meal and food intake was measured. The preloads in both studies were in the form of a beverage. RESULTS: In the first study, food intake was significantly lower only after casein and pea protein compared to water control (P = 0.02; 0.04 respectively). Caloric compensation was 110, 103, 62, 56 and 51% after casein, pea protein, whey, albumin and maltodextrin, respectively. Feelings of satiety were significantly higher after casein and pea protein compared to other preloads (P < 0.05). Blood glucose response to the meal was significantly lower when whey protein was consumed as a preload compared to other groups (P < 0.001). In the second study, results showed no difference between preloads on ad libitum intake. Total intake was significantly higher after caloric preloads compared to water control (P < 0.05). CONCLUSION: Casein and pea protein showed a stronger effect on food intake compared to whey when consumed as a preload. However, consuming the protein preload as a starter of a meal decreased its impact on food intake as opposed to consuming it 30 min before the meal. PMID- 22196622 TI - Effect of embryo age and recipient asynchrony on pregnancy rates in a commercial equine embryo transfer program. AB - In the present study, 809 uterine flushes and 454 embryo transfers performed in mares over a 4-yr interval were examined to evaluate the effects of: (1) the day of embryo collection on recovery rates; (2) the degree of synchrony between donor and recipient mares on pregnancy rates; (3) the recipient day post ovulation on pregnancy rates; and (4) the age of the embryo at recovery on pregnancy rates at 60 days. Uterine flushes were performed on Days 6, 7, 8, 9, and 10 (Day 0 = ovulation) and embryos were transferred to recipients with degrees of synchrony varying between +1 to -6 (recipient ovulated 1 day before through 6 days after the donor). Recipient mares ranged from 2 to 8 days post ovulation. Embryo recovery rates were similar for flushes performed on Day 7 (61%), Day 8 (66%), Day 9 (59%), and Day 10 (56%), but the embryo recovery rate was lower (P < 0.03) for flushes performed on Day 6 (42%) compared with all other days. Pregnancy rates for various degrees of synchrony were as follows: +1 (71%), 0 (77%), -1 (68%), -2 (63%), -3 (66%), -4 (76%), -5 (61%), and -6 (27%). The -6 day of degree of synchrony had the lowest (P < 0.05) pregnancy rate compared with all other days, but there was no significant difference among +1 to -5 days. There was a lower (P < 0.05) pregnancy rate for embryos transferred to recipient mares on Day 2 (33%) compared with mares on Day 3 (66%), Day 4 (66%), Day 5 (62%), Day 6 (55%), Day 7 (58%), and Day 8 (56%). Pregnancy rate was higher (P < 0.05) for Day 7 (76%) embryos compared with Day 6 (50%), Day 8 (64%), and Day 9 (44%) embryos; Day 9 embryos resulted in lower (P < 0.05) pregnancy rates than Days 7 or 8 embryos. In conclusion, this study demonstrated that: (1) embryo recovery rates between Days 7 and 10 were similar and acceptable (e.g., 63% 488/771); (2) the degree of synchrony between donor and recipient mares does not need to be as restricted as previously reported in horses. Acceptable pregnancy rates (e.g., 70%, 99/142) were obtained even when recipient mares ovulated 4 to 5 days after the donors; (3) similar pregnancy rates were obtained when recipient mares received embryos within a large range of days post ovulation (Days 3 to 8); and (4) Day 7 embryos produced higher pregnancy rates when compared with Days 8 and 9 embryos. In clinical terms, the application of these new findings will be beneficial to large equine embryo transfer operations in producing more pregnancies per season. PMID- 22196621 TI - Discovery of (S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1 yl)propanamido)nicotinic acid as a hepatoselective glucokinase activator clinical candidate for treating type 2 diabetes mellitus. AB - Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic beta-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes. PMID- 22196623 TI - Doppler sonography of the uterine and ovarian arteries during a superovulatory program in horses. AB - The aim of the present study was to investigate the effects of a gonadotropin treatment to induce superovulation on ovarian and uterine blood flow and its relationship with steroid hormone levels and ovarian response in mares, using color Doppler sonography. Each of six mares were examined sonographically in five cycles for 3 d (t1 to t3) during the follicular development phase (FDP) beginning at a follicle size of >= 22 mm, and for 4 d (D-4 to D-1; D0 = Ovulation) in the preovulatory phase (POP). After each examination, total estrogens (E(tot)) and progesterone (P(4)) levels were determined in peripheral plasma. Cycles 1, 3, and 5 (c(1), c3, c5) were unstimulated cycles (USC); in c2 and c4, the mares were stimulated (SC) with eFSH and inseminated when in estrus at 12 and 24 h after hCG administration. Embryo recovery was performed 6.5 d post ovulation. Cycle 5 c5 was an unstimulated cycle with hCG treatment, insemination, and embryo recovery. Ovarian and uterine blood flow was quantified by the blood flow volume (BFV) and the pulsatility index (PI) in ovarian and uterine arteries. The mean number of ovulations and developing CL was 1.3 +/- 0.4 in USC and 4.4 +/- 3.1 in stimulated cycles (SC) with no difference (P >= 0.05) between the ovaries within mares. No difference (P > 0.05) was observed in utBFV and utPI during FDP between USC and SC, but during POP, utPI was lower (P < 0.05) and utBFV higher (P < 0.001) in SC than USC. The ovBFV was higher (P < 0.01) and ovPI lower (P < 0.05) in SC compared to USC. All uterine and ovarian blood flow parameters were related to the number of developing follicles in SC. Parameters utPI (r = -0.67; P < 0.001) and ovPI (r = -0.53; P < 0.001) were negatively correlated with the number of ovulations on t3, and with the number of collected embryos on t3 (utPI: r = 0.81; P < 0.001), D-4 (utPI: r = -0.64; P < 0.0001), and D-1 (ovPI: r = -0.41; P < 0.01). P(4) levels were not positively correlated with utBFV (P > 0.05), but E(tot) concentrations (D-4: r = 0.790; D3: r = 0.639; P < 0.001; D-1: r = 0.48; P < 0.001) and ovBFV from D-4 to D-1 (r = 0.64; P < 0.001) in SC were. The results of the present study show that in mares treatment with gonadotropins to induce superovulation is associated with a marked increase in uterine and ovarian perfusion, concurrent with the development of multiple follicles and an increase in E(tot) levels. The increased blood flow seems to be related to the effectiveness of ovarian response to stimulation. PMID- 22196625 TI - Clostridium difficile pouchitis after proctocolectomy with ileal pouch-anal anastomosis. PMID- 22196626 TI - Endoclip migration into the duodenum: an unusual complication after laparoscopic cholecystectomy. PMID- 22196627 TI - Local treatment of an end colostomy prolapse 6 months after abdominoperineal resection. PMID- 22196628 TI - Traumatic duodenal hematoma in a pediatric patient treated by percutaneous drainage. PMID- 22196629 TI - Primary intrapulmonary thymoma mimicking lung cancer. PMID- 22196630 TI - Symptomatic aneurysm of ileocolic artery presenting as gastrointestinal bleed. PMID- 22196631 TI - Percutaneous drainage and vacuum-assisted closure system in the management of a sigmoid cancer presenting with an abscess of the anterior abdominal wall. PMID- 22196632 TI - The Gross clinic, the Agnew clinic, and the Listerian revolution. PMID- 22196633 TI - Nonfatal perineal impalement injury traversing pelvic, abdominal, and thoracic cavities. PMID- 22196634 TI - Rescue surgery for cervical soft tissue late recurrence of Hurthle cell carcinoma. PMID- 22196635 TI - Symptomatic external carotid artery stenosis. PMID- 22196636 TI - Klippel-Trenaunay syndrome complicated with splenomegaly. PMID- 22196637 TI - Twitter and mobile technology as diagnostic aids in the Democratic Republic of Congo. PMID- 22196638 TI - Transverse colon volvulus and Chilaiditi syndrome: an exceptional association. PMID- 22196639 TI - Spontaneous umbilical endometriosis: a rare but clinically important entity. PMID- 22196640 TI - Umbilical node as first clinical appearance in a patient with a high tumor burden. PMID- 22196641 TI - Intrapericardial diaphragmatic hernia after pediatric pacemaker placement. PMID- 22196642 TI - Inferior hemorrhoidal artery pseudoaneurysm presenting as gastrointestinal bleed. PMID- 22196643 TI - Complete closure by dermal tension reduction suture for skin defects. PMID- 22196644 TI - Parathyroid cyst. PMID- 22196645 TI - Subhepatic appendicitis. PMID- 22196646 TI - Robert Milton Zollinger, M.D., teacher, surgeon, soldier, and farmer. PMID- 22196647 TI - Robert M. Zollinger: 25 years on. PMID- 22196648 TI - Robert M. Zollinger, Sr., as a father, teacher, and mentor. PMID- 22196649 TI - Virginia Commonwealth University: committed to the professional growth of women in surgery. AB - Academic surgery programs need to offer avenues not only to increase recruitment of women, but also to provide support so women can stay in the surgical field successfully. Virginia Commonwealth University has served to enable the growth of women surgeons in their careers. This article reviews the aspects in which this institution has provided with the necessary support for career and personal growth. PMID- 22196650 TI - Medical student mentorship in a university setting as a strategy for a career in surgery. AB - Gender balance in surgery is a respectable and necessary goal. At the University of Louisville (UL) School of Medicine, we have compared percentages of UL medical student applicants to general surgery or surgical subspecialty residency programs, surgical residents, and surgical faculty with the rest of the nation. Although UL has at times paralleled or exceeded the nation in many of these categories, there is room for improvement and the comparison data allow for strategic planning initiatives. To promote gender balance among future generations of surgeons at UL, we recently implemented a mentoring program that pairs medical students with residents and faculty in surgery. We plan to track the success over time and correct any shortcomings of this program. Virginia Commonwealth University's commitment to gender balance in surgery is exemplary. As part of a more comprehensive vision to create a mentorship program for female medical students at the UL School of Medicine, we have recently recruited female surgical residents and faculty, whom we hope will provide the type of inspiration and guidance that will increase the number of women from UL who decide to train in general surgery and the surgical specialties. To understand why women across the nation are not generally at numerical parity in these fields, it is important to consider the length and intensity of the surgical residency programs in the context of the other goals and objectives that a woman might have for her future. This article does not address this broad topic but provides a perspective of how a medical school can evaluate and perhaps intervene to mentor medical students more effectively about the satisfaction derived from a career in surgery. As part of this project, we have evaluated each step of the path through medical school and a surgical residency by comparing data for our students, residency programs, and faculty with national data. PMID- 22196651 TI - Perspectives on career advancement for women. PMID- 22196652 TI - Breaking down the walls: removing structural barriers for women in academic surgery. PMID- 22196653 TI - Results of proximal arch replacement using deep hypothermia for circulatory arrest: is moderate hypothermia really justifiable? AB - The use of selective cerebral perfusion with warmer temperatures during circulatory arrest has been increasingly used for arch replacement over concerns regarding the safety of deep hypothermic circulatory arrest (DHCA). However, little data actually exist on outcomes after arch replacement and DHCA. This study examines modern results with DHCA for proximal arch replacement to provide a benchmark for comparison against outcomes with lesser degrees of hypothermia. Between July 2005 and June 2010, 245 proximal arch replacements ("hemiarch") were performed using deep hypothermia; mean minimum core and nasopharyngeal temperatures were 18.0 +/- 2.1 degrees C and 14.1 +/- 1.6 degrees C, respectively. Adjunctive cerebral perfusion was used in all cases. Concomitant ascending aortic replacement was performed in 41 per cent, ascending plus aortic valve replacement in 23 per cent, and aortic root replacement in 32 per cent. Mean age was 58 +/- 14 years; 36 per cent procedures were urgent/emergent. Mean duration of DHCA was 20.4 +/- 6.2 minutes. Thirty-day/in-hospital mortality was 2.9 per cent. Rates of stroke, renal failure, and respiratory failure were 4.1 per cent (0.8% for elective cases), 1.2 per cent, and 0.4 per cent, respectively. Deep hypothermia with adjunctive cerebral perfusion for circulatory arrest during proximal arch replacement affords excellent neurologic as well as nonneurologic outcomes. Centers using lesser degrees of hypothermia for arch surgery, the safety of which remains unproven, should ensure comparable results. PMID- 22196654 TI - Prognostic factors after pancreatoduodenectomy for distal bile duct cancer. AB - Prognostic factors influencing long-term survival after radical resection for distal bile duct cancer have not been well established because of the rarity of this malignancy. The goal of this study was to identify main prognostic factors in patients undergoing pancreatoduodenectomy for distal bile duct carcinoma. A retrospective study consisting of 122 patients with distal bile duct cancer who underwent pancreatoduodenectomy in three major university hospitals was performed to identify the main prognostic factors. Major surgical complications occurred in 40 patients (32.8%), of whom eight died (6.6%) in the hospital. Overall actuarial survival (excluding hospital deaths) at 1-, 3-, and 5-year follow-up was 82.9, 49.4, and 32.7 per cent, respectively, with a median survival of 36 months. Univariate analysis showed that papillary tumor (P = 0.045), negative surgical margin (R0 resection, P = 0.005), earlier pT (P = 0.005), pTNM stage (P < 0.001), and absence of lymph node involvement (P < 0.0001) were significant predictors of survival. On multivariate analysis, only lymph node metastasis was shown to be an independent prognostic factor of survival (P = 0.036). Lymph node involvement was the most important survival predictor after a Whipple resection in patients with distal cholangiocarcinoma. PMID- 22196655 TI - Squamous cell carcinoma complicating chronic suppurative hydradenitis. AB - A 69-year-old male patient underwent excision of hidradenitis suppurativa (HS) affecting both gluteal areas and the perineum. The perineal specimen contained a 1-cm superficially invasive, well-differentiated keratinizing squamous cell carcinoma. The patient was free of recurrence 1 year after surgery. A 66-year old male patient was diagnosed with massive perineal HS more than 40 years previously. More than 30 abscesses and suppurative sinus tracts were surgically treated over the years. He eventually died of unresectable pelvic squamous carcinoma. Search of the literature and available bibliography revealed 47 retrospective studies of skin carcinoma arising in HS since 1959, including a total of 64 patients together with the two patients treated by our team. Squamous cell carcinoma is a rare but potentially fatal complication of HS. Surgery is the only known treatment method that provides a real chance for cure for both HS and a carcinoma that complicates it. HS must be treated early with complete excision to avoid chronic progression of the disease that can cause cancerous degeneration. A high index of suspicion, early tissue diagnosis, and immediate referral for radical surgery carry the only hope for cure in those whose HS harbors malignancy. PMID- 22196656 TI - Colorectal cancer surgery in patients older than 80 years of age: experience at one nonteaching hospital in Japan. AB - The safety and efficacy of surgical treatment for colorectal cancer in patients older than 80 years of age are seldom assessed. The aim of the present study was to compare short- and long-term outcomes after surgery between younger and elderly patients at a single nonteaching hospital. In all, 342 consecutive patients who underwent surgical resection for invasive primary colorectal cancer between April 1999 and April 2007 were included in the study. Patients were divided into two groups according to their age at the time of surgery, those younger than 79 years of age (n = 283) and those older than 80 years of age (n = 59). A greater proportion of elderly patients had concurrent disease before surgery, right-sided colon cancer, and postoperative complications. Cox proportional hazards model (multivariate analysis) identified three independent risk factors for a poor outcome after surgery (excluding death by other causes): 1) the presence of preoperative symptoms; 2) noncurative resection for colorectal cancer; and 3) the presence of lymph node metastases. Age older than 80 years was not a risk factor for a poor postoperative prognosis. At our nonteaching hospital, surgical resection appears to be a safe and beneficial treatment option for elderly patients (older than 80 years of age) who have colorectal cancer. PMID- 22196657 TI - Does alvimopan enhance return of bowel function in laparoscopic right colectomy? AB - Alvimopan, a peripherally acting Mu-opioid receptor antagonist, has been shown to enhance recovery of gastrointestinal (GI) function in open bowel resection. The aim of this study was to determine the effect of Alvimopan on patients undergoing laparoscopic right colectomies in preventing postoperative ileus (POI). A prospective, nonrandomized trial of laparoscopic right colectomies was carried out with and without perioperative Alvimopan. The length of stay (LOS), time to first flatus, bowel movement, and tolerance of solid foods were recorded. Additionally, any occurrences of POI defined as the need for insertion of a nasogastric tube (NGT) were also noted. Student t tests were used for statistical analysis. A total of 33 patients underwent laparoscopic right colectomies for both benign and malignant diseases from October 2008, to December 2009. Sixteen patients received Alvimopan, whereas 17 patients did not. The demographics of both patient groups were similar. Patients receiving Alvimopan had an accelerated return of bowel function in terms of first flatus (2.37 vs 3.34; P = 0.03), tolerance of solid food (2.75 vs 3.94; P = 0.03), and first stool (2.53 vs 3.80; P = 0.04). There was a trend toward shorter LOS in patients receiving Alvimopan (P = 0.07). Two patients with POI requiring NGT did not receive Alvimopan. Alvimopan was successful in enhancing return of GI function in laparoscopic right colectomies and avoiding POI. The decreased LOS trended but did not approach statistical significance. A large randomized prospective trial will be needed to determine the validity of this study. PMID- 22196658 TI - The role of laparoscopic evaluation to detect a contralateral defect at initial presentation for inguinal hernia repair. AB - Our objective was to determine the accuracy of laparoscopic evaluation to detect a contralateral patent processus vaginalis (CPPV) at initial presentation for inguinal hernia (IH) repair and the rate of CPPV relative to age, sex, and initial hernia side. We performed a 5-year retrospective review of 1580 pediatric patients with unilateral IH in which surgeons selectively used laparoscopy to evaluate for a CPPV. There were 1205 boys and 303 girls; 980 (65%) presented with right IH (RIH) and 528 (35%) with left IH (LIH). Laparoscopic evaluation was performed in 459 (47%) patients presenting with RIH and 225 (43%) patients presenting with LIH. Laparoscopic evaluation was positive for CPPV in 32 per cent of patients with RIH and 42 per cent of patients with LIH (P = 0.0168). CPPV was associated with prematurity (P = 0.0003) and age younger than 6 months (P = 0.0001) but not with sex (P = 0.55). The future contralateral occurrence rate was 1.6 per cent and recurrence rate 0.2 per cent. This study supports the accuracy of CPPV evaluation by laparoscopy. Although the rate of CPPV decreases after 6 months of age, girls older than 2 years of age have a significantly higher rate of CPPV than boys, supporting laparoscopic evaluation in older girls. PMID- 22196659 TI - An intraoperative localization technique for a postexcision specimen of nonpalpable breast calcifications: a pilot study. AB - The specimens obtained through excisional biopsy (EB) are commonly large in size and it is difficult to remove the tissues containing nonpalpable calcifications accurately from them for pathologic examination. Therefore, the aim of the study is to develop a novel method of subarea localization technique (SLT) for sampling from the postexcisional specimens. A retrospective clinical study of 48 consecutive patients with breast microcalcifications were divided into a study group (n = 24 patients, 25 breasts) and a control group (n = 24 patients, 24 breasts) in time sequence. The specimens of study group were localized by SLT performed by cutting lines and/or metallic markers. The main study end points were the duration of intraoperative pathologic diagnosis (DIPD) and duration of conclusive pathology diagnosis (DCPD). The number of frozen blocks, number of paraffin blocks, number of sections, and other parameters correlated with pathologic diagnosis were compared between the two groups. SLT was succeeded in 48 of 48 (100%) patients, which shortened DIPD (29.3 vs 45.5 minutes, P < 0.01) significantly with less frozen blocks (6.2 vs 12.6, P < 0.01) and less frozen sections (8.5 vs 13.7, P = 0.01) than that of the control group. Moreover, SLT shortened DCPD (4.1 vs 5.1 days, P = 0.02) with less paraffin blocks (12.2 vs 21.7, P < 0.01) and less paraffin sections (20.0 vs 39.9, P < 0.01) than that of the control group. SLT decreased workload of the specimens sampling procedure and SLT may be recommended as a reliable specimens sampling method to guide pathology test for EB specimens containing calcifications. PMID- 22196660 TI - Athlete's hernia--a true, early direct inguinal hernia: diagnosis, pathophysiology, and surgical treatment. AB - Athlete's hernia (AH) is an activity limiting condition that presents as chronic inguinal pain in elite athletes. The diagnosis involves a thorough history and physical examination and can be aided by ultrasound interrogation of the groin. Operative treatment with a direct tissue repair of the inguinal floor successfully alleviates symptoms and allows for full return to activity. A retrospective analysis of patients with the diagnosis of AH from January 1998 to May 2010 who underwent operative repair was reviewed. Patients were evaluated based on age, gender, sport, time to presentation, subjective and objective physical findings, imaging findings, operative findings, length of follow-up, and return to activity. Ninety-six patients (6 females) with a median age of 22.6 years were evaluated. In the majority of these patients, operative exploration revealed a wide external ring with separation of the fibers of the external oblique aponeurosis and an unprotected and bulging transverses abdominis aponeurosis, very akin to an early direct inguinal hernia. The mean initial follow-up time was 6 weeks at which point all but two of the patients were able to resume their full level of activity without restrictions. The diagnosis of AH, although somewhat elusive, can be easily established with a high degree of suspicion after doing a thorough history and physical exam augmented with ultrasonography. AH is equivalent to an early direct inguinal hernia found in young athletes and can be surgically corrected allowing return to full activity. PMID- 22196661 TI - Application of the titanium plate fixation system in sternum transverse incisions. AB - The purpose of this study was to review the application of the titanium plate fixation system in sternum transverse incisions and assess its advantages over the conventional methods of steel wire fixation. Sternal healing of 249 patients who underwent a thymectomy and/or excision of the thymoma with a transverse sternal incision was compared between patients who underwent titanium plate fixation or steel wire fixation. Short-term results: The stability of the sternum was significantly superior in the titanium plate group compared with the steel wire group (P < 0.01). Out-of-bed activities started earlier for patients in the titanium plate group compared with the steel wire group (P < 0.01). Long-term results: The sternal healing rate in the titanium plate group was significantly higher than the steel wire group (P < 0.05). Titanium plate fixation improves the postoperative sternal stability in patients with transverse sternal incisions for thymectomy and/or excision of a thymoma. Titanium plate fixation also reduces postoperative pain, enhances the patient's physical activity, and decreases the long-term nonunion rate of the sternum. PMID- 22196662 TI - Effect of glycemic state on hospital mortality in critically ill surgical patients. AB - Intensive insulin therapy can reduce mortality. Hypoglycemia related to intensive therapy may worsen outcomes. This study compared risk adjusted mortality for different glycemic states. A retrospective review of patients admitted to a surgical intensive care unit over 4 years was performed. Patients were divided into glycemic groups: HYPER (>=1 episode > 180 mg/dL, any <60), HYPO (>=1 episode < 60 mg/dL, any >180), BOTH (>=1 episode < 60 and >=1 episode > 180 mg/dL), NORMO (all episodes 60-180 mg/dL), HYPER-Only (>=1 episode > 180, none <60 mg/dL), and HYPO-Only (>=1 episode < 60, none >180 mg/dL). Observed to expected Acute Physiology and Chronic Health Evaluation (APACHE) III mortality ratios (O/E) were studied. Number of adverse glycemic events was compared with mortality. Hypoglycemia and hyperglycemia occurred in 18 per cent and 50 per cent of patients. Mortality was 12.4 per cent (O/E = 0.88). BOTH had the highest O/E ratio (1.43) with HYPO the second highest (1.30). Groups excluding hypoglycemia (NORMO and HYPER-only) had the lowest O/E ratios: 0.56 and 0.88. Increasing number of hypoglycemic events were associated with increasing O/E ratio: 0.69 O/E for no events, 1.19 for 1-3 events, 1.35 for 4-6 events, 1.9 for 7-9 events, and 3.13 for >= 10 events. Ten or more hyperglycemic events were needed to significantly associate with worse mortality (O/E 1.53). Hyper- and hypoglycemia increase mortality compared with APACHE III expected mortality, with highest mortality risk if both are present. Hypoglycemia is associated with worse risk. Glucose control may need to be loosened to prevent hypoglycemia and reduce glucose variability. PMID- 22196663 TI - Minor hepatic resection for hepatocellular carcinoma in cirrhotic patients: Kelly clamp crushing resection versus heat coagulative necrosis with bipolar radiofrequency device. AB - Hemorrhage and postoperative liver insufficiency are frequent and serious complications of hepatic resection in cirrhotic patients. The aim of this study was to assess retrospectively whether the surgical techniques using Kelly clamp crushing resection or heat coagulative necrosis with a bipolar radiofrequency device can reduce the incidence of the above complications and an eventual recurrence of neoplasia on the liver slice. We retrospectively reviewed the results of 35 patients who had undergone resection for monofocal hepatocellular carcinoma at our center. Thirteen patients (Group A) had undergone liver resection with Kelly clamp crushing resection, 22 patients (Group B) had had liver resection assisted with a bipolar radiofrequency device. Radiofrequency assisted liver resection was associated with diminished blood loss (P < 0.0001), a lower blood transfusion rate (P < 0.005), reduced operative time (P < 0.0001), and better postoperative serum albumin levels (P < 0.03). This nonrandomized retrospective study suggests that radiofrequency-assisted liver resection is associated with better results than the Kelly clamp crushing resection technique in cirrhotic patients with focal hepatocellular carcinoma and preserved liver function. These results should now be assessed prospectively in a randomized clinical trial. PMID- 22196664 TI - Role of high-intensity focused ultrasound in treatment of hepatocellular carcinoma. AB - About 70 per cent of patients with hepatocellular carcinoma are diagnosed at intermediate or advanced stages, and most of them are technically unresectable. As a novel, emerging therapeutic modality, high intensity focused ultrasound (HIFU) has a great potential for tumor treatment. In this review, principle of HIFU technique is introduced, and an overview of clinical applications and limitations of HIFU for HCC treatment, as well as prospects for future development, is provided. Consequently, HIFU has been considered a safe and feasible procedure for HCC treatment. PMID- 22196665 TI - Incidental findings on computed tomography scans for acute appendicitis: prevalence, costs, and outcome. AB - CT scan is increasingly being used to diagnose appendicitis due to its specificity and literature suggesting its cost-effectiveness. CT scans are associated with incidental findings. We sought to investigate the rates of incidental findings identified on CT scans, the follow-up of these findings, and the added cost associated with this follow-up. A retrospective review of patients who underwent appendectomies for acute appendicitis between 2003 and 2005 was completed at Elmhurst Hospital Center (Elmhurst, NY). Incidental findings were grouped into low and high significance, based on workup or follow-up needed. The diagnostic workup and cost of each incidental finding was ascertained. For patients who did not receive a workup due to lack of follow-up, an estimate of the minimum workup was calculated. Of 1142 patients with acute appendicitis, 876 (77%) had a CT scan. This rate increased over time (from 66% in 2003 to 85% in 2005, P < 0.01) and with age (70% in patients under 20 and 98% in patients over 50, P < 0.001). Incidental findings were common and increased with age (23% in the youngest group vs 78% in patients older than 50, P < 0.001). The cost associated with workup of these incidental findings increased with age as well. The increased use of CT scans is associated with a high rate of incidental findings. These findings are usually of low clinical significance but may require further workup and follow-up. Physicians need to be aware of the high rate of incidental findings, the need for further workup, and the associated costs. PMID- 22196666 TI - Increasing utilization of laparoscopic gastric banding in the adolescent: data from academic medical centers, 2002-2009. AB - Bariatric surgery in the adolescent continues to be a controversial topic. This study compared the utilization and perioperative outcomes of adolescent bariatric surgery performed at academic centers from 2002 to 2006 versus 2007 to 2009. We obtained data from the University HealthSystem Consortium for all adolescent patients (ages 12-18 years) who underwent bariatric surgery for the treatment of morbid obesity between 2002 and 2009. Outcomes including type of procedure, characteristics, length of stay, 30-day readmission, morbidity, and in-hospital mortality were compared between the two time periods. From 2007 to 2009, 340 adolescents underwent bariatric surgery at 63 academic hospitals. The mean number of adolescent bariatric procedures performed/year increased from 61.8 in 2002 to 2006 to 113.3 procedures/year in 2007 to 2009. There was an increase in utilization of laparoscopic gastric banding from 29 per cent to 50 per cent with a decrease in utilization of gastric bypass from 62 per cent to 48 per cent, respectively. For 2007 to 2009, the overall morbidity was 2.9 per cent with a 30 day readmission of 1.5 per cent and an in-hospital mortality of 0 per cent. Within the context of academic medical centers, adolescent bariatric surgery is associated with low morbidity and no mortality. Compared with 2002 to 2006, there has been an increase in the number of adolescent bariatric operations with increase in utilization of the laparoscopic gastric banding. PMID- 22196667 TI - Osteopontin induced by macrophages contribute to metachronous liver metastases in colorectal cancer. AB - Even after radical surgery for stage II and stage III colorectal cancer, metachronous liver metastasis is frequently observed. The aim of this study was to identify the risk of metachronous liver metastasis with retrospective clinicopathological study. Immunohistochemistry was performed to evaluate the expression of Osteopontin (OPN), CD-68, and CD105 in 41 cases of stage II and stage III colorectal cancer tissue. Stage II and stage III colorectal cancer patients who had undergone R0 resection were classified into two groups: with metachronous liver metastasis (m-LM; n = 17) and without liver metastases (control; n = 24). Additionally, double-immunofluorescence staining was performed using antibodies to OPN and CD68. OPN-positive cells were frequently colocalized with CD68 immunoreactivity. OPN and microvascular density expression in the central area were significantly higher in the m-LM (OPN; control 4.3 +/- 0.56, m LV 10.8 +/- 1.48, P < 0.05; microvascular density control 18.5 +/- 2.86, m-LV 31.4 +/- 4.39, P < 0.05), while CD68 expression in the invasive margin was significantly higher in the control group (control 98.9 +/- 7.31, m-LV 28.2 +/- 3.18, P < 0.05). These results suggest that the risk of metachronous liver metastasis could be well predicted by immunohistochemical staining of OPN in the central areas, and CD68 in the invasive margins of tumors. PMID- 22196668 TI - Popliteal artery injuries in an urban trauma center with a rural catchment area: do delays in definitive treatment affect amputation? AB - Extended length of time from injury to definitive vascular repair is considered to be a predictor of amputation in patients with popliteal artery injuries. In an urban trauma center with a rural catchment area, logistical issues frequently result in treatment delays, which may affect limb salvage after vascular trauma. We examined how known risk factors for amputation after popliteal trauma are affected in a more rural environment, where patients often experience delays in definitive surgical treatment. All adult patients admitted to the Level I trauma center, the University of Mississippi Medical Center, with a popliteal artery injury between January 2000 and December of 2007 were identified. Demographic information management and outcome data were collected. Body mass index, mangled extremity severity score (MESS), Guistilo open fracture score, injury severity score, and time from injury to vascular repair were examined. Fifty-one patients with popliteal artery injuries (53% blunt and 47% penetrating) were identified, all undergoing operative repair. There were nine amputations (17.6%) and one death. Patients requiring amputation had a higher MESS, 7.8 versus 5.3 (P < 0.01), and length of stay, 43 versus 15 days (P < 0.01), compared with those with successful limb salvage. Body mass index, injury severity score, Guistilo open fracture score, or time from injury to repair were not different between the two groups. Patients with a blunt mechanism of injury had a slightly higher amputation rate compared with those with penetrating trauma, 25.9 per cent versus 8.3 per cent (P = non significant). MESS, though not perfect, is the best predictor of amputation in patients with popliteal artery injuries. Morbid obesity is not a significant predictor for amputation in patients with popliteal artery injuries. Time from injury to repair of greater than 6 hours was not predictive of amputation. This study further demonstrates that a single scoring system should be used with caution when determining the need for lower extremity amputation. PMID- 22196669 TI - Total laparoscopic distal pancreatectomy: beyond selected patients. AB - Laparoscopic distal pancreatectomy (LDP) has emerged as the procedure of choice for selected patients. This study is to evaluate the feasibility of LDP and procedural outcomes in a series of consecutive nonselected patients. All patients undergoing distal pancreatectomy over 18 months were identified from a prospectively maintained database, under institutional review board approval. A completely laparoscopic (non hand-assisted) procedure was performed using a 4 trocar technique. Conversion to an open procedure, operative time (OR), estimated blood loss (EBL), transfusion requirements, postoperative length of stay (LOS), and complications were assessed. Sixteen patients were identified; 2/16 patients had undergone distal pancreatectomy as a component of another multiorgan open procedure, and were thus excluded. The remaining 14 patients had consented for LDP. Conversion occurred in 4/14 cases. Converted patients trended towards increased OR, EBL, and LOS (P = not significant). No mortalities occurred, and overall morbidities included: pancreatic fistula (n = 2), splenic abscess (n = 1), and pneumonia (n = 1). LDP-splenectomy (n = 3/14) was associated with both increased EBL (683 mL +/- 388 vs 168 +/- 141, P < 0.002) and increased transfusion rate (3/3 vs 3/11, P = 0.05), as compared with LDP-splenic preservation. LDP with splenic artery preservation (LDP-SAP) was completed in 7 of 14 patients, with less OR (2 hours 29 minutes +/- 53 minutes vs 3 hours 40 minutes +/- 1 hour, P < 0.05), a decreased transfusion rate (14% vs 71%, P = 0.05), and decreased LOS (2.8 days vs 6.8 days, P = 0.002) compared with LDP without SAP. Pathology was intraductal papillary mucinous neoplasm (IPMN) (n = 5), ductal carcinoma (n = 3), high grade dysphasia (n = 2), neuroendocrine tumor (n = 2), and pancreatitis (n = 2). Patients undergoing LDP-SAP demonstrated superior peri-procedural outcomes. This series of nonselected consecutive patients supports that LDP is technically feasible with a comparable procedural outcome to the selected-patient literature, suggesting potentially expanded indications for LDP. PMID- 22196670 TI - Endoscopic versus surgical treatment of downstream pancreatic duct stones in chronic pancreatitis. AB - Pancreatic duct stone is thought not only to be the cause of abdominal pain but also to be a risk factor for pancreatic cancer. Several treatment options have been implemented in the treatment of pancreatic duct stones. Stone location is a critical factor in selecting treatment. We present the results of 27 endoscopic treatments and 35 surgical treatments performed in three hospitals at a single university between January 2000 and January 2005. The results were compared retrospectively in terms of success rate of stone removal, length of hospital stay, complications, pain relief, and changes of pancreatic functions. In our study, endoscopy resulted in a similar success rate of stone removal and short term pain relief rate as the surgical approach and with a shorter length of hospital stay. However, the surgical group had a more favorable long-term clinical result, as well as a lower number of hospital readmissions at the 5 year follow-up point. Based on long-term results, surgical treatment is more effective than endoscopy. PMID- 22196671 TI - When is the best time to initiate peri-operative heparin therapy in general surgery patients? A risk-benefit dilemma. AB - We sought optimal timing for heparin therapy in general surgery (GS) patients. From 2001 to 2008, 95 GS patients with documented thromboembolic events (TE) were identified and compared with matched controls (age, gender, type of operation, date of operation, malignancy, and body mass index [BMI]). Timing of heparin therapy, characteristics of TE or bleeding events, and risk factors for TE were collected. Mean age (57 years), BMI (33 kgM-2), gender (55% male), malignancy (53%), and duration of operation (204 vs 191 minutes, P = not significant) were similar in both groups. Peri-operative (within 24 hours) heparin administration (study 56% vs control 64%, P = 0.2) was no different. Preoperative therapy was more common in the control group (77% vs 51%, P = 0.001). The regression model showed a protective effect for heparin if given preoperatively (odds ratio = 0.37, P = 0.047) with no effect if started >10 hours from incision. Mean blood transfusion (97 and 106 mL) and hemorrhagic events (4.5% and 5%) were similar in both groups (P = not significant). Median (range) length of hospital stay and mortality was higher in TE cases [19 (0-201) vs 6 (0-66) days, 11 vs 2 mortality in 100-person-years (P < 0.05)]. Heparin administration before GS is associated with >2-fold reduction in TE. The optimal time to start heparin seems to be 1 to 10 hours before the time of incision. PMID- 22196672 TI - Retrocolic spaces: anatomy of the surgical planes in laparoscopic right hemicolectomy for cancer. AB - To explore the regional anatomy of the fasciae and spaces around the right-side colon from laparoscopic perspective, we observed the location, extension, and boundaries of the spaces around the right-side colon in seven cadavers and in 49 patients undergoing laparoscopic right hemicolectomy for cancer, and reviewed computed tomography images from patients and healthy individuals. Between the ascending mesocolon and prerenal fascia (PRF), there was a right retrocolic space (RRCS), which extended in all directions. The anterior, posterior, medial, lateral, cranial, and caudal boundaries of the RRCS were the ascending mesocolon, PRF, superior mesenteric vein, right paracolic sulcus, inferior margin of the duodenum, and inferior margin of the mesentery radix, respectively. Between the transverse mesocolon and the pancreas and duodenum, there was a transverse retrocolic space, which was enclosed cranially by the radix of the transverse mesocolon. In CT images, healthy PRF was noted as slender line of middle density, continuing to the transverse fascia. The retrocolic spaces was unidentifiable, unless they were filled with retroperitoneal lesions. The RRCS and transverse retrocolic space are natural surgical planes for laparoscopic right hemicolectomy for cancer. The boundaries of these fusion fascial spaces are the best access, and the PRF is the best guide. PMID- 22196673 TI - Incidental carcinoma in multinodular goiter: risk factors. AB - The aim of the study was to analyze the frequency of incidental thyroid carcinoma (unknown tumor smaller than or equal to 10 mm) in a consecutive series of 462 total thyroidectomies for multinodular goiter and to investigate the clinical risk factors for this type of malignancy. A retrospective, single-center study of outcome data collected from patients with preoperative diagnosis of multinodular goiter who underwent total thyroidectomy at the General Surgery Unit of Pavia (Italy) between January 2000 and December 2008 was performed. Possible risk factors for malignancy were: gender, age, time of evolution of goiter, presence of a dominant nodule in multinodular goiter, hyperthyroidism, history of radiation to the neck, residence in an area of endemic goiter, prior thyroid surgery, calcifications in the goiter detected by neck ultrasound or chest X rays, and a family history of thyroid diseases. In a 9-year period, 462 patients underwent total thyroidectomy. We found 41 cases of incidental thyroid carcinoma; the most common histopathological type was papillary. The multivariable analysis demonstrated that the clinical variables associated with occult carcinoma were a personal history of radiation therapy to the neck, the presence of calcifications detected by ultrasound or neck X-rays, and a family history of thyroid diseases; residence in an area of endemic goiter was a protective factor. A personal history of radiation to the neck, detection of calcifications by ultrasound or by neck X-rays, and a family history of thyroid diseases should be considered clinical risk factors for malignancy in multinodular goiter. PMID- 22196674 TI - Louis XIV and the College of Surgeons. PMID- 22196675 TI - Pseudomonas aeruginosa necrotizing fasciitis in a patient with methimazole induced agranulocytosis. PMID- 22196676 TI - Morbidity and mortality of the Confederate generals during the American Civil War. PMID- 22196677 TI - Radiosynthesis of 1-[18F]fluoroethyl-L-tryptophan as a novel potential amino acid PET tracer. AB - (18)F labeled natural amino acids have been introduced as promising tumor imaging agents. A novel [(18)F]fluoro amino acid analog 1-[(18)F]fluoroethyl-L-tryptophan (1-[(18)F]FETrp) was designed and synthesized by a two-pot three-step procedure, including the synthesis of 1-[(18)F]fluoro-2- (tosyloxy)ethane, the [(18)F]fluoroethylation of the precursor N-Boc-L-tryptophan ethyl ester and following the deprotection of the tert-butoxycarbonyl and ethyl ester protecting groups. 1-[(18)F]FETrp was resulted in 0.9 +/- 0.2% (n=5) radiochemical yields (no decay corrected) by HPLC purification, within a total synthesis time of 65 min. The radiochemical purity of 1-[(18)F]FETrp was 95-97%. The radiosynthetic method needs to be further optimized to get a satisfying radiochemical yield. PMID- 22196678 TI - Natural radioactivity in tap water and associated age-dependent dose and lifetime risk assessment in Amman, Jordan. AB - With the aim of assessing potential public impact, preliminary investigations on tap waters collected from highly populated areas in Amman and Aqaba, Jordan were conducted by measuring gross alpha and beta activities as well as uranium and radium radionuclides. Gross activities deduced by liquid scintillation counting (LSC) were ranged in <50-250 +/- 23 mBq l(-1) for alpha and <188-327 +/- 29 mBq l(-1) for beta in Amman whereas higher concentrations were found in Aqaba. The results show that gross beta activities are generally higher than the corresponding gross alpha activities and direct correlations between gross activities and total dissolved solids (TDS) exist. Moreover, the effect of TDS on gross analyses was studied and devoted to the optimization of LSC parameters. (234)U, (235)U and (238)U concentrations were determined by alpha spectrometry after separation from the matrix by extraction chromatography and electroplating. (226)Ra and (228)Ra concentrations were measured, respectively, using de-gassing and gas proportional counter techniques. Uranium and radium concentrations do not reach the WHO recommended levels and the radioisotopic activity ratios were discussed. The associated age-dependent dose from water ingestion in Amman was estimated. The total dose for adults had an average value of 0.15 mSv y(-1), which exceeds the WHO recommended limit of 0.1 mSv y(-1) but still below the Jordanian limit of 0.5 mSv y(-1). Although the Jordanian limit was exceeded for babies and infants, the lifetime risk assessment showed values as low as 10(-4). Thereby it is concluded that tap waters of Amman is radiologically safe and pose no significant hazard to the public. Finally, a comparison of the investigated waters with worldwide data was made. PMID- 22196679 TI - Evaluation of the voltage quantities measured with different noninvasive meters for quality control at a calibration laboratory. AB - In this work the peak kilovoltage (kVp), practical peak voltage (PPV) and air kerma rate were measured with the noninvasive meters Radcal Accu-kV(r) Diagnostic SensorTM model 40*12-W, and PTW Diavolt. The results were compared in order to ensure the quality control, compare the meters and establish the new quantity PPV, at the Calibration Laboratory of IPEN. These tests were performed using the standard diagnostic radiology quality beam RQR5, and the results are in good agreement. PMID- 22196680 TI - Feasibility of using anatomical surrogates for predicting the position of lung tumours. AB - We studied the use of internal anatomical surrogates (carina and diaphragm) for the purpose of predicting the 3D position of lung tumours in 41 patients, in whom repeat 4DCT scans were available. Despite using two surrogates, significant prediction errors were observed, which varied depending on tumour position, baseline tumour motion and respiratory phase. PMID- 22196681 TI - A dual centre study of setup accuracy for thoracic patients based on cone-beam CT data. AB - BACKGROUND AND PURPOSE: To compare setup uncertainties at two different institutions by using identical imaging and analysis techniques for thoracic patients with different fixation equipments. METHODS AND MATERIALS: Patient registration results from Cone-Beam CT (CBCT) scans of 174 patients were evaluated (1068 CBCT scans). Patients were fixated using a standard or custom made fixation at Royal Marsden Hospital and Odense University Hospital, respectively. Five imaging protocols were retrospectively simulated to compare the fixation equipments. Systematic and random setup uncertainties were calculated to estimate sufficient treatment margins. RESULTS: The setup uncertainties are of similar sizes at the two institutions and there is no observable drift in the precision of the fixation equipments during the treatment course. When a correcting imaging protocol is performed there is a significant increase of the systematic setup uncertainties in between imaging fractions. A margin reduction of >=0.2 cm can be achieved for patients with peak-to-peak respiration amplitudes of >=1.2 cm when changing from 4D-CT to Active Breathing CoordinatorTM (ABC). CONCLUSIONS: The setup uncertainties at the two institutions are the same despite different fixation equipments. Hence margins cannot be reduced by changing fixating equipment. PMID- 22196682 TI - Optimal "work-up" of stillbirth: evidence! PMID- 22196684 TI - Evaluation of 1025 fetal deaths: proposed diagnostic workup. AB - OBJECTIVE: We sought to evaluate the contribution of different diagnostic tests for determining cause of fetal death. Our goal was to propose a workup guideline. STUDY DESIGN: In a multicenter prospective cohort study from 2002 through 2008, for 1025 couples with fetal death >=20 weeks' gestation, an extensive nonselective diagnostic workup was performed. A panel classified cause and determined contribution of diagnostics for allocating cause. RESULTS: A Kleihauer Betke, autopsy, placental examination, and cytogenetic analysis were abnormal in 11.9% (95% confidence interval [CI], 9.8-14.2), 51.5% (95% CI, 47.4-55.2), 89.2% (95% CI, 87.2-91.1), and 11.9% (95% CI, 8.7-15.7), respectively. The most valuable tests for determination of cause were placental examination (95.7%; 95% CI, 94.2-96.8), autopsy (72.6%; 95% CI, 69.2-75.9), and cytogenetic analysis (29.0%; 95% CI, 24.4-34.0). CONCLUSION: Autopsy, placental examination, cytogenetic analysis, and testing for fetal maternal hemorrhage are basic tests for workup after fetal death. Based on the results of these tests or on specific clinical characteristics, further sequential testing is indicated. PMID- 22196685 TI - A problematic pathway: a patient with asymptomatic gross hematuria. PMID- 22196686 TI - Discussion: 'Long-acting reversible contraception and repeat abortion' by Rose et al. AB - In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Rose SB, Lawton BA. Impact of long-acting reversible contraception on return for repeat abortion. Am J Obstet Gynecol 2012;206:37.e1-6. PMID- 22196687 TI - [Designing a therapeutic education program for patients with lymphedema: live with lymphedema]. AB - BACKGROUND: Lymphedema is a chronic condition considered to be rare in its primary form and potentially frequent in women after breast surgery for cancer: 27,000 new cases annually. Therapeutic management is a serious challenge. In France, the health authorities (Haute Autorite de sante [HAS]) have recently proposed that appropriate management practices for lymphedema include "patient education". The HAS and the National institute for health care prevention and education also published a methodology guide devoted to structuring a therapeutic education program for patients with chronic disease. Current hospital regulations state that this education program is part of the care to be delivered to patients with chronic disease and that it must comply with the national directives. The purpose of our present work was to present the concept and the contents of a patient education program entitled "Live with lymphedema" designed for patients with lymphedema and developed within the inpatient-outpatient network GRANTED in Sud-Isere. METHODS: A standard detailed educative approach was applied. It was designed after the educational program for patients with lower limb arterial occlusive disease authorized by the Rhone-Alpes regional health agency. It was adapted to the specific problematic of patients with lymphedema, including medical management, rehabilitation, dermatology and nutritional aspects. It was developed in cooperation with patients and favors local associative actions. RESULTS: The specifically structured program included three therapeutic education consultations and five workshops. Less than one year after its institution, more than 30 patients have participated in the program. DISCUSSION: We report a structured patient education program designed for patients with lymphedema. This program was authorized by the Rhone-Alpes regional health agency in March 2011 and is in compliance with the national directives and HAS guidelines. PMID- 22196690 TI - Ovarian vein thrombosis mimicking acute abdomen: a case report and literature review. AB - BACKGROUND: Ovarian vein thrombosis (OVT) is a rare, but serious condition that affects mostly postpartum women. A high index of suspicion is required in order to diagnose this unusual cause of abdominal pain. CASE PRESENTATION: A 19-year old woman at three days postpartum was admitted to our hospital because of severe right lower quandrant abdominal pain and fever 38.5'C. Physical examination revealed an acutely ill patient and right lower quadrant tenderness with positive rebound and Giordano signs. The patient underwent appendectomy which proved to be negative for acute appendicitis. Postoperatively fever and pain persisted and abdominal CT-scan with intravenous contrast agent demonstrated a thrombosed right ovarian vein. The patient was initiated on low-molecular weight heparin (LMWH) and antibiotic treatment and a month later a new abdominal CT-scan showed a patent right ovarian vein. DISCUSSION: Pathophysiologically, OVT is explained by Virchow's triad, because pregnancy is associated with a hypercoagulable state, venous stasis due to compression of the inferior vena cava by the uterus and endothelial trauma during delivery or from local inflammation. Common symptoms and signs of OVT include lower abdomen or flank pain, fever and leukocytosis usually within the first ten days after delivery. The reported incidence of OVT ranges 0,05-0,18% of pregnancies and in most cases the right ovarian vein is the one affected. Anticoagulation and antibiotics is the mainstay of treatment of OVT. Complications of OVT include sepsis, extension of the thrombus to the inferior vena cava and renal veins, and pulmonary embolism. The incidence of pulmonary embolism is reported to be 13.2% and represents the main source of mortality due to OVT. CONCLUSIONS: OVT is a rare condition, usually in the postpartum period. A high index of suspicion is required for the prompt diagnosis and management especially in cases that mimic acute abdomen. PMID- 22196688 TI - Identification of low-abundance cancer biomarker candidate TIMP1 from serum with lectin fractionation and peptide affinity enrichment by ultrahigh-resolution mass spectrometry. AB - As investigating a proteolytic target peptide originating from the tissue inhibitor of metalloproteinase 1 (TIMP1) known to be aberrantly glycosylated in patients with colorectal cancer (CRC), we first confirmed that TIMP1 is to be a CRC biomarker candidate in human serum. For this, we utilized matrix-assisted laser desorption/ionization (MALDI) Fourier transform ion cyclotron resonance (FTICR) mass spectrometry (MS) showing ultrahigh-resolution and high mass accuracy. This investigation used phytohemagglutinin-L(4) (L-PHA) lectin, which shows binding affinity to the beta-1,6-N-acetylglucosamine moiety of N-linked glycan on a protein, to compare fractionated aberrant protein glycoforms from both noncancerous control and CRC serum. Each lectin-captured fraction containing aberrant glycoforms of TIMP1 was digested by trypsin, resulting in the tryptic target peptide, representative of the serum glycoprotein TIMP1. The resulting target peptide was enriched using a stable isotope standard and capture by the antipeptide antibody (SISCAPA) technique and analyzed by a 15 T MALDI FTICR mass spectrometer with high mass accuracy (Delta < 0.5 ppm to the theoretical mass value of the target peptide). Since exact measurement of multiplex isotopic peaks of the target peptide could be accomplished by virtue of high mass resolution (Rs > 400,000), robust identification of the target peptide is only achievable with 15 T FTICR MS. Also, MALDI data obtained in this study showed that the L-PHA captured glycoforms of TIMP1 were measured in the pooled CRC serum with about 5 times higher abundance than that in the noncancerous serum, and were further proved by MRM mass analysis. These results confirm that TIMP1 in human serum is a potent CRC biomarker candidate, demonstrating that ultrahigh-resolution MS can be a powerful tool toward identifying and verifying potential protein biomarker candidates. PMID- 22196692 TI - Cerinolactone, a hydroxy-lactone derivative from Trichoderma cerinum. AB - A novel metabolite, 3-hydroxy-5-(6-isopropyl-3-methylene-3,4,4a,5,6,7,8,8a octahydronaphthalen-2-yl)dihydrofuran-2-one, trivially named cerinolactone (1), has been isolated from culture filtrates of Trichoderma cerinum together with three known butenolides containing the 3,4-dialkylfuran-2(5H)-one nucleus, harzianolide (2), T39butenolide (3), and dehydroharzianolide (4). The structure of 1 was determined by spectroscopic methods, including UV, MS, and 1D and 2D NMR analyses. In vitro tests with the purified compound exhibited activity against Pythium ultimum, Rhizoctonia solani, and Botrytis cinerea. PMID- 22196693 TI - Relationship between metal enrichments and a biological adverse effects index in sediments from Todos Santos Bay, northwest coast of Baja California, Mexico. AB - In 1992 and 2004, heavy metals concentrations were measured in surficial sediments from Todos Santos Bay, located in Ensenada, Baja California, Mexico. The aim was to search for relationships between metal enrichment factors and a biological adverse effects index. Unlike Ni, the elements Cd, Cu and Zn showed significant correlations (p<0.05) between enrichment factors and the biological adverse effects index. Cu showed a 0.74:1 relationship, which means that any enrichment above 0.74 could represent biological adverse effects. On the other hand, Cd and Zn enrichments must be >5.5 and >1.5, respectively, in order for the sediments to be considered toxic. In general, data showed that most of the metal concentrations in Todos Santos Bay sediments could not cause adverse effects to biota. Only Ensenada's harbor and the zone next to a dredging dumping site showed metal enrichments that could be toxic. PMID- 22196696 TI - Currents. PMID- 22196695 TI - Editorial: Drinking water and risk. PMID- 22196697 TI - Great lakes water quality improvement. PMID- 22196698 TI - Visibility: An evolving issue. PMID- 22196699 TI - Regulatory Focus: The greenhouse effect. PMID- 22196700 TI - Drinking-water standards. PMID- 22196701 TI - Personal exposure to nitrogen dioxide: relationship to indoor/outdoor air quality and activity patterns. PMID- 22196702 TI - Measured and calculated evaporation losses of two petroleum hydrocarbon herbicide mixtures under laboratory and field conditions. PMID- 22196703 TI - Non-methane organic composition in the Lincoln Tunnel. PMID- 22196704 TI - Formation and decomposition of trialkyllead compounds in the atmosphere. PMID- 22196705 TI - Source emission characterization of residential wood-burning stoves and fireplaces: fine particle methyl chloride ratios for use in chemical mass balance modeling. PMID- 22196706 TI - Aqueous solubilities of six polychlorinated biphenyl congeners at four temperatures. PMID- 22196707 TI - Model describing the rates of transfer processes of organic chemicals between atmosphere and water. PMID- 22196708 TI - Relative copper binding capacities of dissolved organic compounds in a coastal plain estuary. PMID- 22196709 TI - Alteration of chemical and disinfectant properties of hypochlorite by sodium, potassium, and lithium. PMID- 22196710 TI - Recovery of several volatile organic compounds from simulated water samples: effect of transport and storage. PMID- 22196711 TI - Effects of solute concentration and cosolvents on the aqueous activity coefficient of halogenated hydrocarbons. PMID- 22196712 TI - Potential artifacts in the determination of metal partitioning in sediments by a sequential extraction procedure. PMID- 22196713 TI - Sex-related differences in association of oxidative stress status with coronary artery disease. AB - OBJECTIVE: To assess oxidative stress status in coronary artery disease (CAD) patients according to gender. DESIGN: Case-controlled, observational, retrospective study. SETTING: Clinical and research center. PATIENT(S): A total of 55 postmenopausal women and 108 men (mean age: 66 +/- 9 years), including 72 patients with angiographically proven CAD (CAD(+), 19 women) and a group of 91 age-matched controls (CAD(-), 36 women). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Oxidant/antioxidant balance as a global index (oxidative index) obtained using two commercial assays (d-ROMs and OXY Adsorbent Test, respectively) for estimation of levels of reactive oxygen metabolites and total antioxidant status. RESULT(S): There was a statistically significant difference in oxidative stress status between men and women who were CAD(-) (-0.424 +/- 1.3 vs. 0.64 +/- 1.1 arbitrary units, respectively), but the CAD(+) women had oxidative stress levels almost three times those of the CAD(+) men (2.45 +/- 2.5 vs. 0.9 +/- 1.6 arbitrary units, respectively). After adjustment in the multivariate model, age and oxidative stress status in women and diabetes and age in men remained as statistically significant predictors of positive CAD findings. CONCLUSION(S): Oxidative stress status was a powerful predictor of CAD in women. This result may have important implications for the differences between sexes in CAD physiopathology. PMID- 22196714 TI - Informing egg donors of the potential for embryonic research: a survey of consent forms from U.S. in vitro fertilization clinics. AB - OBJECTIVE: To understand whether and to what extent U.S. IVF clinics inform egg donors that resultant embryos initially intended to be implanted for reproductive purposes may in fact be used for research instead. DESIGN: Four hundred seventy U.S. IVF clinics were asked to respond to a questionnaire and provide a copy of the egg donor consent form(s) used at the clinic. SETTING: Four hundred seventy U.S. IVF clinics listed in a Centers for Disease Control and Prevention database; only forms from clinics that both accepted donor eggs and provided excess embryos for research were analyzed for content. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Responses to the questionnaire, demographic data from a Centers for Disease Control and Prevention database, and the content of egg donor consent forms. RESULT(S): Of 222 U.S. IVF clinics that responded to our query, 100 clinics both accepted donor eggs and provided some excess embryos for research. We received 66 consent forms from these 100 clinics, which showed that although most egg donor consent forms inform donors that they will not have control over embryos resulting from their eggs, 30% inform them that some embryos may be used for research, and even fewer mention stem cell research. CONCLUSION(S): Egg donors in the United States, including some who may have a moral objection to research and stem cell research, are not being informed that embryos created with their donated eggs may in fact be used for these purposes. This can be corrected with the inclusion of succinct, nontechnical language in egg donor consent forms. PMID- 22196715 TI - Immunization of male mice with B-cell epitopes in transmembrane domains of CatSper1 inhibits fertility. AB - OBJECTIVE: To evaluate the contraceptive ability of two B-cell epitopes in CatSper1. DESIGN: In vivo study with mice. SETTING: University laboratory animal service center. ANIMAL(S): BALB/c mice. INTERVENTION(S): Two predicted B-cell epitopes in the extracellular part of transmembrane domains and pore region of CatSper1 were synthesized to immunize male mice. MAIN OUTCOME MEASURE(S): Fertility, epididymal sperm function, and the presence of specific antibody in immunized males were investigated. RESULT(S): Significant reduction of fertility was observed in mating trial with no evident systemic illness or abnormal mating behavior. Epididymal sperm of epitope-immunized males exhibited impaired ability to fertilize eggs in vitro, and showed sperm agglutination in some animals, while presenting no changes in sperm viability or progressive motility. High titer of antibodies was induced in the sera, and the antibodies' specificity was confirmed. The binding of the antibodies to epididymal sperm of epitope-immunized males was observed. CONCLUSION(S): CatSper members could be the effective and viable targets for immunocontraception. These two epitopes in CatSper1 share high identity between mouse and human and may be effective for fertility regulation in humans. PMID- 22196716 TI - Elective single-embryo transfer. AB - As in vitro fertilization implantation rates have improved, the practice of transfering multiple embryos must be evaluated. The purpose of this document is to reassess the literature on elective single-embryo transfer, to provide guidance for patient selection, and to discuss barriers to utilization. PMID- 22196717 TI - Physiologic activation of nuclear factor kappa-B in the endometrium during the menstrual cycle is altered in endometriosis patients. AB - OBJECTIVE: To evaluate nuclear factor kappaB (NF-kappaB) activation and NF-kappaB p65 subunit activation, immunolocalization, and expression in the endometrium of healthy women and endometriosis patients throughout the menstrual cycle. DESIGN: Prospective observational study. SETTING: Affiliated hospital and university research laboratory. PATIENT(S): Twenty-four healthy women and 24 endometriosis patients. INTERVENTION(S): Menstrual, proliferative, and secretory endometrial biopsies. MAIN OUTCOME MEASURE(S): Assessment of NF-kappaB and p65 activation by protein-DNA binding assays and p65 localization and expression by immunohistochemistry. RESULT(S): Total NF-kappaB-DNA binding was constitutive and variable in human endometrium accross the menstrual cycle. Healthy women (physiologic conditions) showed higher p65-DNA binding in proliferative than in menstrual and secretory endometrium. Conversely, in endometriosis patients, p65 DNA binding was higher in proliferative and secretory endometrium than in menstrual endometrium. Endometrial epithelial cells showed higher p65 expression level score than endometrial stromal cells. CONCLUSION(S): NF-kappaB activity is constitutive, physiologic, and variable in human endometrium. The physiologic cyclic p65 activation pattern was altered in endometriosis patients, showing no cyclic variation between the proliferative and secretory phase of the menstrual cycle. The absence of decreased p65 activity in secretory endometrium from endometriosis patients is concurrent with progesterone resistance and could participate in endometrial biologic alterations during the implantation window in endometriosis patients. PMID- 22196718 TI - Predicting the need for CT imaging in children with minor head injury using an ensemble of Naive Bayes classifiers. AB - OBJECTIVE: Using an automatic data-driven approach, this paper develops a prediction model that achieves more balanced performance (in terms of sensitivity and specificity) than the Canadian Assessment of Tomography for Childhood Head Injury (CATCH) rule, when predicting the need for computed tomography (CT) imaging of children after a minor head injury. METHODS AND MATERIALS: CT is widely considered an effective tool for evaluating patients with minor head trauma who have potentially suffered serious intracranial injury. However, its use poses possible harmful effects, particularly for children, due to exposure to radiation. Safety concerns, along with issues of cost and practice variability, have led to calls for the development of effective methods to decide when CT imaging is needed. Clinical decision rules represent such methods and are normally derived from the analysis of large prospectively collected patient data sets. The CATCH rule was created by a group of Canadian pediatric emergency physicians to support the decision of referring children with minor head injury to CT imaging. The goal of the CATCH rule was to maximize the sensitivity of predictions of potential intracranial lesion while keeping specificity at a reasonable level. After extensive analysis of the CATCH data set, characterized by severe class imbalance, and after a thorough evaluation of several data mining methods, we derived an ensemble of multiple Naive Bayes classifiers as the prediction model for CT imaging decisions. RESULTS: In the first phase of the experiment we compared the proposed ensemble model to other ensemble models employing rule-, tree- and instance-based member classifiers. Our prediction model demonstrated the best performance in terms of AUC, G-mean and sensitivity measures. In the second phase, using a bootstrapping experiment similar to that reported by the CATCH investigators, we showed that the proposed ensemble model achieved a more balanced predictive performance than the CATCH rule with an average sensitivity of 82.8% and an average specificity of 74.4% (vs. 98.1% and 50.0% for the CATCH rule respectively). CONCLUSION: Automatically derived prediction models cannot replace a physician's acumen. However, they help establish reference performance indicators for the purpose of developing clinical decision rules so the trade-off between prediction sensitivity and specificity is better understood. PMID- 22196719 TI - ceRNAs: miRNA target mimic mimics. PMID- 22196720 TI - Food for thought: linking caloric intake to behavior via sirtuin activity. AB - Sirtuins are thought to form crucial links between energy levels and cellular metabolism. Libert et al. now provide evidence that SIRT1 activity in the brain modifies mammalian emotional behavior via monoamine signaling and that changes in this pathway might contribute to human affective disorders. PMID- 22196721 TI - Transcription and mRNA stability: parental guidance suggested. AB - The level of an mRNA within a cell depends on both its rate of synthesis and rate of decay. Now, independent studies by Bregman et al. and Trcek et al. provide evidence that these two processes are integrated. They show that transcription factors and DNA promoters can directly influence the relative stability of transcripts that they produce. PMID- 22196722 TI - Learning to protect your genome on the fly. AB - Piwi-interacting RNAs (piRNAs) help defend host genomes against germline transposons. In this issue of Cell, Khurana et al. show how alterations in the piRNA-encoding loci within a single generation allow a naive fly genome to overcome the initially insurmountable challenge imposed by a newly encountered mobile element. PMID- 22196723 TI - Metabolic connections during apoptotic cell engulfment. AB - Billions of cells die via apoptosis every day and are swiftly removed. When a phagocyte engulfs an apoptotic cell, it essentially doubles its cellular contents, raising the question of how a phagocyte may manage the excess metabolic load. This Minireview discusses phagocyte cellular metabolism, the digestion of the ingested apoptotic cell, and the impact of these processes on engulfment. PMID- 22196725 TI - Promoter elements regulate cytoplasmic mRNA decay. AB - Promoters are DNA elements that enable transcription and its regulation by trans acting factors. Here, we demonstrate that yeast promoters can also regulate mRNA decay after the mRNA leaves the nucleus. A conventional yeast promoter consists of a core element and an upstream activating sequence (UAS). We find that changing UASs of a reporter gene without altering the transcript sequence affects the transcript's decay kinetics. A short cis element, comprising two Rap1p binding sites, and Rap1p itself, are necessary and sufficient to induce enhanced decay of the reporter mRNA. Furthermore, Rap1p stimulates both the synthesis and the decay of a specific population of endogenous mRNAs. We propose that Rap1p association with target promoter in the nucleus affects the composition of the exported mRNP, which in turn regulates mRNA decay in the cytoplasm. Thus, promoters can play key roles in determining mRNA levels and have the capacity to coordinate rates of mRNA synthesis and decay. PMID- 22196724 TI - The microbial opsin family of optogenetic tools. AB - The capture and utilization of light is an exquisitely evolved process. The single-component microbial opsins, although more limited than multicomponent cascades in processing, display unparalleled compactness and speed. Recent advances in understanding microbial opsins have been driven by molecular engineering for optogenetics and by comparative genomics. Here we provide a Primer on these light-activated ion channels and pumps, describe a group of opsins bridging prior categories, and explore the convergence of molecular engineering and genomic discovery for the utilization and understanding of these remarkable molecular machines. PMID- 22196726 TI - Single-molecule mRNA decay measurements reveal promoter- regulated mRNA stability in yeast. AB - Messenger RNA decay measurements are typically performed on a population of cells. However, this approach cannot reveal sufficient complexity to provide information on mechanisms that may regulate mRNA degradation, possibly on short timescales. To address this deficiency, we measured cell cycle-regulated decay in single yeast cells using single-molecule FISH. We found that two genes responsible for mitotic progression, SWI5 and CLB2, exhibit a mitosis-dependent mRNA stability switch. Their transcripts are stable until mitosis, when a precipitous decay eliminates the mRNA complement, preventing carryover into the next cycle. Remarkably, the specificity and timing of decay is entirely regulated by their promoter, independent of specific cis mRNA sequences. The mitotic exit network protein Dbf2p binds to SWI5 and CLB2 mRNAs cotranscriptionally and regulates their decay. This work reveals the promoter-dependent control of mRNA stability, a regulatory mechanism that could be employed by a variety of mRNAs and organisms. PMID- 22196727 TI - Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. AB - Numerous chromatin regulators are required for embryonic stem (ES) cell self renewal and pluripotency, but few have been studied in detail. Here, we examine the roles of several chromatin regulators whose loss affects the pluripotent state of ES cells. We find that Mbd3 and Brg1 antagonistically regulate a common set of genes by regulating promoter nucleosome occupancy. Furthermore, both Mbd3 and Brg1 play key roles in the biology of 5-hydroxymethylcytosine (5hmC): Mbd3 colocalizes with Tet1 and 5hmC in vivo, Mbd3 knockdown preferentially affects expression of 5hmC-marked genes, Mbd3 localization is Tet1-dependent, and Mbd3 preferentially binds to 5hmC relative to 5-methylcytosine in vitro. Finally, both Mbd3 and Brg1 are themselves required for normal levels of 5hmC in vivo. Together, our results identify an effector for 5hmC, and reveal that control of gene expression by antagonistic chromatin regulators is a surprisingly common regulatory strategy in ES cells. PMID- 22196728 TI - A poised chromatin platform for TGF-beta access to master regulators. AB - Specific chromatin marks keep master regulators of differentiation silent yet poised for activation by extracellular signals. We report that nodal TGF-beta signals use the poised histone mark H3K9me3 to trigger differentiation of mammalian embryonic stem cells. Nodal receptors induce the formation of companion Smad4-Smad2/3 and TRIM33-Smad2/3 complexes. The PHD-Bromo cassette of TRIM33 facilitates binding of TRIM33-Smad2/3 to H3K9me3 and H3K18ac on the promoters of mesendoderm regulators Gsc and Mixl1. The crystal structure of this cassette, bound to histone H3 peptides, illustrates that PHD recognizes K9me3, and Bromo binds an adjacent K18ac. The interaction between TRIM33-Smad2/3 and H3K9me3 displaces the chromatin-compacting factor HP1gamma, making nodal response elements accessible to Smad4-Smad2/3 for Pol II recruitment. In turn, Smad4 increases K18 acetylation to augment TRIM33-Smad2/3 binding. Thus, nodal effectors use the H3K9me3 mark as a platform to switch master regulators of stem cell differentiation from the poised to the active state. PMID- 22196729 TI - Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. AB - Thousands of long intervening noncoding RNAs (lincRNAs) have been identified in mammals. To better understand the evolution and functions of these enigmatic RNAs, we used chromatin marks, poly(A)-site mapping and RNA-Seq data to identify more than 550 distinct lincRNAs in zebrafish. Although these shared many characteristics with mammalian lincRNAs, only 29 had detectable sequence similarity with putative mammalian orthologs, typically restricted to a single short region of high conservation. Other lincRNAs had conserved genomic locations without detectable sequence conservation. Antisense reagents targeting conserved regions of two zebrafish lincRNAs caused developmental defects. Reagents targeting splice sites caused the same defects and were rescued by adding either the mature lincRNA or its human or mouse ortholog. Our study provides a roadmap for identification and analysis of lincRNAs in model organisms and shows that lincRNAs play crucial biological roles during embryonic development with functionality conserved despite limited sequence conservation. PMID- 22196730 TI - Adaptation to P element transposon invasion in Drosophila melanogaster. AB - Transposons evolve rapidly and can mobilize and trigger genetic instability. Piwi interacting RNAs (piRNAs) silence these genome pathogens, but it is unclear how the piRNA pathway adapts to invasion of new transposons. In Drosophila, piRNAs are encoded by heterochromatic clusters and maternally deposited in the embryo. Paternally inherited P element transposons thus escape silencing and trigger a hybrid sterility syndrome termed P-M hybrid dysgenesis. We show that P-M hybrid dysgenesis activates both P elements and resident transposons and disrupts the piRNA biogenesis machinery. As dysgenic hybrids age, however, fertility is restored, P elements are silenced, and P element piRNAs are produced de novo. In addition, the piRNA biogenesis machinery assembles, and resident elements are silenced. Significantly, resident transposons insert into piRNA clusters, and these new insertions are transmitted to progeny, produce novel piRNAs, and are associated with reduced transposition. P element invasion thus triggers heritable changes in genome structure that appear to enhance transposon silencing. PMID- 22196731 TI - Hot spots for allosteric regulation on protein surfaces. AB - Recent work indicates a general architecture for proteins in which sparse networks of physically contiguous and coevolving amino acids underlie basic aspects of structure and function. These networks, termed sectors, are spatially organized such that active sites are linked to many surface sites distributed throughout the structure. Using the metabolic enzyme dihydrofolate reductase as a model system, we show that: (1) the sector is strongly correlated to a network of residues undergoing millisecond conformational fluctuations associated with enzyme catalysis, and (2) sector-connected surface sites are statistically preferred locations for the emergence of allosteric control in vivo. Thus, sectors represent an evolutionarily conserved "wiring" mechanism that can enable perturbations at specific surface positions to rapidly initiate conformational control over protein function. These findings suggest that sectors enable the evolution of intermolecular communication and regulation. PMID- 22196732 TI - A calmodulin-dependent translocation pathway for small secretory proteins. AB - Metazoans secrete an extensive array of small proteins essential for intercellular communication, defense, and physiologic regulation. Their synthesis takes mere seconds, leaving minimal time for recognition by the machinery for cotranslational protein translocation into the ER. The pathway taken by these substrates to enter the ER is not known. Here, we show that both in vivo and in vitro, small secretory proteins can enter the ER posttranslationally via a transient cytosolic intermediate. This intermediate contained calmodulin selectively bound to the signal peptides of small secretory proteins. Calmodulin maintained the translocation competence of small-protein precursors, precluded their aggregation and degradation, and minimized their inappropriate interactions with other cytosolic polypeptide-binding proteins. Acute inhibition of calmodulin specifically impaired small-protein translocation in vitro and in cells. These findings establish a mammalian posttranslational pathway for small-protein secretion and identify an unexpected role for calmodulin in chaperoning these precursors safely through the cytosol. PMID- 22196733 TI - Interaction between differentiating cell- and niche-derived signals in hematopoietic progenitor maintenance. AB - Maintenance of a hematopoietic progenitor population requires extensive interaction with cells within a microenvironment or niche. In the Drosophila hematopoietic organ, niche-derived Hedgehog signaling maintains the progenitor population. Here, we show that the hematopoietic progenitors also require a signal mediated by Adenosine deaminase growth factor A (Adgf-A) arising from differentiating cells that regulates extracellular levels of adenosine. The adenosine signal opposes the effects of Hedgehog signaling within the hematopoietic progenitor cells and the magnitude of the adenosine signal is kept in check by the level of Adgf-A secreted from differentiating cells. Our findings reveal signals arising from differentiating cells that are required for maintaining progenitor cell quiescence and that function with the niche-derived signal in maintaining the progenitor state. Similar homeostatic mechanisms are likely to be utilized in other systems that maintain relatively large numbers of progenitors that are not all in direct contact with the cells of the niche. PMID- 22196734 TI - SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1. AB - The assembly of synapses and neuronal circuits relies on an array of molecular recognition events and their modification by neuronal activity. Neurexins are a highly polymorphic family of synaptic receptors diversified by extensive alternative splicing. Neurexin variants exhibit distinct isoform-specific biochemical interactions and synapse assembly functions, but the mechanisms governing splice isoform choice are not understood. We demonstrate that Nrxn1 alternative splicing is temporally and spatially controlled in the mouse brain. Neuronal activity triggers a shift in Nrxn1 splice isoform choice via calcium/calmodulin-dependent kinase IV signaling. Activity-dependent alternative splicing of Nrxn1 requires the KH-domain RNA-binding protein SAM68 that associates with RNA response elements in the Nrxn1 pre-mRNA. Our findings uncover SAM68 as a key regulator of dynamic control of Nrxn1 molecular diversity and activity-dependent alternative splicing in the central nervous system. PMID- 22196735 TI - The functional organization of cutaneous low-threshold mechanosensory neurons. AB - Innocuous touch of the skin is detected by distinct populations of neurons, the low-threshold mechanoreceptors (LTMRs), which are classified as Abeta-, Adelta-, and C-LTMRs. Here, we report genetic labeling of LTMR subtypes and visualization of their relative patterns of axonal endings in hairy skin and the spinal cord. We found that each of the three major hair follicle types of trunk hairy skin (guard, awl/auchene, and zigzag hairs) is innervated by a unique and invariant combination of LTMRs; thus, each hair follicle type is a functionally distinct mechanosensory end organ. Moreover, the central projections of Abeta-, Adelta-, and C-LTMRs that innervate the same or adjacent hair follicles form narrow LTMR columns in the dorsal horn. These findings support a model of mechanosensation in which the activities of Abeta-, Adelta-, and C-LTMRs are integrated within dorsal horn LTMR columns and processed into outputs that underlie the perception of myriad touch sensations. PMID- 22196736 TI - Combinatorial patterning of chromatin regulators uncovered by genome-wide location analysis in human cells. AB - Hundreds of chromatin regulators (CRs) control chromatin structure and function by catalyzing and binding histone modifications, yet the rules governing these key processes remain obscure. Here, we present a systematic approach to infer CR function. We developed ChIP-string, a meso-scale assay that combines chromatin immunoprecipitation with a signature readout of 487 representative loci. We applied ChIP-string to screen 145 antibodies, thereby identifying effective reagents, which we used to map the genome-wide binding of 29 CRs in two cell types. We found that specific combinations of CRs colocalize in characteristic patterns at distinct chromatin environments, at genes of coherent functions, and at distal regulatory elements. When comparing between cell types, CRs redistribute to different loci but maintain their modular and combinatorial associations. Our work provides a multiplex method that substantially enhances the ability to monitor CR binding, presents a large resource of CR maps, and reveals common principles for combinatorial CR function. PMID- 22196737 TI - SnapShot: Cell PictureShow. PMID- 22196738 TI - Blindness following severe midfacial trauma--case report and review. AB - PURPOSE: Severe trauma of the viscerocranium or neurocranium may result in impaired visual acuity or even blindness. Case based epidemiology, pathomechanism and actual strategies in midfacial trauma for initial therapy and prevention of posttraumatic blindness are discussed. CASE AND REVIEW: A 58-year old patient was treated at our Department of Oral and Maxillofacial Plastic Surgery after his central midface had been hit by a swinging steel girder. Initially he was blind on both eyes. Initial treatment started by applying 24 mg of dexamethasone and omeprazole. During the following 2 weeks, amaurosis persisted on the left eye. On the right eye complete visual acuity was regained. On the basis of data from our Department of Oral and Maxillofacial Plastic Surgery an Odds Ratio of 0.12 was calculated for the combination of blindness and midfacial trauma. Today cortisol therapy is still used. However, hypothermia, anti-Trendelenburg position, and application of mannitol seem to be more effective therapeutic strategies. Erythropoetine and progesterone are promising drugs with neuroprotective, anti inflammatory as well as anti-oedematous effects. CONCLUSION: The risk of blindness is higher than expected. Latest findings regarding the neuroprotective effects of erythropoetine or/and progesterone seem to promise a more successful treatment. PMID- 22196739 TI - Preliminary report of Ki-67 reactivity in synovial chondromatosis of the temporomandibular joint: an immunohistochemical study. AB - BACKGROUND: Synovial chondromatosis (SC) is rare benign condition characterized by the formation of metaplastic cartilaginous nodules in the synovial membrane and joint space. Cartilaginous nodules from and may become pedunculated and detached from the synovial membrane, so becoming loose bodies within the joint space. PURPOSE: The aim of this study was to determine the proliferative activity of loose body and synovial membrane of SC in temporomandibular joint by using Ki 67 antibody. MATERIAL AND METHODS: We obtained 4 specimens (4 female) of released loose body and 2 specimens of synovial membrane with attached loose bodies by surgical operation. The specimens were fixed in 10% formalin solution, and embedded in paraffin. The immunohistochemical study was carried out using an anti human Ki-67 monoclonal antibody. The sections were visualized by 3, 3' diaminobenzidine-tetrahydrochloride (DAB). RESULTS: The expression of Ki-67 was scarcely detected in all cases of loose bodies. In second phase cases, the mild expression of Ki-67 was detected at both cases of synovial membrane which were attached loose bodies. CONCLUSION: These results suggested that released loose bodies into the joint compartment did not have independent proliferating activity. However, the synovial membrane may play a very important role in the proliferation of the loose bodies. PMID- 22196740 TI - O matrices and eco-evolutionary dynamics. PMID- 22196741 TI - Don't neglect pre-establishment individual selection in deliberate introductions. PMID- 22196742 TI - Colateralization of Broca's area and the visual word form area in left-handers: fMRI evidence. AB - Language production has been found to be lateralized in the left hemisphere (LH) for 95% of right-handed people and about 75% of left-handers. The prevalence of atypical right hemispheric (RH) or bilateral lateralization for reading and colateralization of production with word reading laterality has never been tested in a large sample. In this study, we scanned 57 left-handers who had previously been identified as being clearly left (N=30), bilateral (N=7) or clearly right (N=20) dominant for speech on the basis of fMRI activity in the inferior frontal gyrus (pars opercularis/pars triangularis) during a silent word generation task. They were asked to perform a lexical decision task, in which words were contrasted against checkerboards, to test the lateralization of reading in the ventral occipitotemporal region. Lateralization indices for both tasks correlated significantly (r=0.59). The majority of subjects showed most activity during lexical decision in the hemisphere that was identified as their word production dominant hemisphere. However, more than half of the sample (N=31) had bilateral activity for the lexical decision task without a clear dominant role for either the LH or RH, and three showed a crossed frontotemporal lateralization pattern. These findings have consequences for neurobiological models relating phonological and orthographic processes, and for lateralization measurements for clinical purposes. PMID- 22196744 TI - Cardiac CT angiography in children with congenital heart disease. AB - Cardiac imaging plays an important role in both congenital and acquired heart diseases. Cardiac computed tomography (angiography) cCT(A) is a non-invasive, increasingly popular, complementary modality to echocardiography in evaluation of congenital heart diseases (CHD) in children. Despite radiation exposure, cCT(A) is now commonly used for evaluation of the complex CHD, giving information of both intra-cardiac and extra-cardiac anatomy, coronary arteries, and vascular structures. This review article will focus on the fundamentals and essentials for performing cCT(A) in children, including radiation dose awareness, basic techniques, and strengths and weaknesses of cCT(A) compared with cardiac magnetic resonance imaging (cMRI), and applications. The limitations of this modality will also be discussed, including the CHD for which cMRI may be substituted. PMID- 22196745 TI - Recognizing prosody across modalities, face areas and speakers: examining perceivers' sensitivity to variable realizations of visual prosody. AB - Prosody can be expressed not only by modification to the timing, stress and intonation of auditory speech but also by modifying visual speech. Studies have shown that the production of visual cues to prosody is highly variable (both within and across speakers), however behavioural studies have shown that perceivers can effectively use such visual cues. The latter result suggests that people are sensitive to the type of prosody expressed despite cue variability. The current study investigated the extent to which perceivers can match visual cues to prosody from different speakers and from different face regions. Participants were presented two pairs of sentences (consisting of the same segmental content) and were required to decide which pair had the same prosody. Experiment 1 tested visual and auditory cues from the same speaker and Experiment 2 from different speakers. Experiment 3 used visual cues from the upper and the lower face of the same talker and Experiment 4 from different speakers. The results showed that perceivers could accurately match prosody even when signals were produced by different speakers. Furthermore, perceivers were able to match the prosodic cues both within and across modalities regardless of the face area presented. This ability to match prosody from very different visual cues suggests that perceivers cope with variation in the production of visual prosody by flexibly mapping specific tokens to abstract prosodic types. PMID- 22196746 TI - Bladder cancer: a window of opportunity to understand carcinogenesis. AB - Bladder cancer provides a unique opportunity to apply our knowledge of the molecular biology of the malignancy to its clinical behavior and prognosis. Urologists should apply the increasing fund of basic science knowledge to the clinical management of bladder cancer. PMID- 22196747 TI - Measurement of PSA density by 3 imaging modalities and its correlation with the PSA density of radical prostatectomy specimen. AB - OBJECTIVE: To evaluate the difference between the PSA density (PSAD) calculated with 3 imaging modalities and the PSAD of the radical prostatectomy specimen. MATERIALS AND METHODS: The PSAD of 60 men with clinically localized prostate cancer was calculated with transabdominal ultrasound (TAUS), transrectal ultrasound (TRUS), and computed tomography (CT) before radical retropubic prostatectomy, and was compared with the PSAD of the surgical specimen using the paired t-test. The relationship of the real prostate volume and the difference between the PSAD calculated with the 3 imaging modalities and that of the PSAD of the specimen was analyzed using Pearson's correlation coefficient. Finally, the sensitivity of PSAD calculated with the examined imaging modalities and the specimen was also studied. RESULTS: The mean difference between the PSAD calculated by each one of the 3 imaging modalities and the PSAD of the specimen was -0.01 ng/ml/cm(3) (P = 0.28) for TAUS, 0.01 ng/ml/cm(3) (P = 0.37) for TRUS, and -0.03 ng/ml/cm(3) (P = 0.001) for CT. This difference has not been shown to depend on the real prostate volume according to Pearson's correlation coefficient, which was 0.056 (P = 0.673) for TAUS, -0.014 (P = 0.917) for TRUS, and 0.184 (P = 0.159) for CT. The sensitivity of PSAD calculated with TAUS, TRUS, and CT was 58.3%, 65%, and 45%, respectively, while that of the specimen was 70%. CONCLUSIONS: Although PSAD showed a moderate sensitivity, TRUS and TAUS are the imaging modalities that calculate it closer to the real PSAD of the specimen. PMID- 22196748 TI - Electric-field-enhanced nutrient consumption in dielectric biomaterials that contain anchorage-dependent cells. AB - This research contribution addresses electric-field stimulation of intra-tissue mass transfer and cell proliferation in viscoelastic biomaterials. The unsteady state reaction-diffusion equation is solved according to the von Karman Pohlhausen integral method of boundary layer analysis when nutrient consumption and tissue regeneration occur in response to harmonic electric potential differences across a parallel-plate capacitor in a dielectric-sandwich configuration. The partial differential mass balance with diffusion and electro kinetic consumption contains the Damkohler (Lambda(2)) and Deborah (De) numbers. Zero-field and electric-field-sensitive Damkohler numbers affect nutrient boundary layer growth. Diagonal elements of the 2nd-rank diffusion tensor are enhanced in the presence of weak electric fields, in agreement with the formalism of equilibrium and nonequilibrium thermodynamics. Induced dipole polarization density within viscoelastic biomaterials is calculated via the real and imaginary components of the complex dielectric constant, according to the Debye equation, to quantify electro-kinetic stimulation. Rates of nutrient consumption under zero field conditions are described by third-order kinetics that include local mass densities of nutrients, oxygen, and attached cells. Thinner nutrient boundary layers are stabilized at shorter dimensionless diffusion times when the zero field intra-tissue Damkohler number increases above its initial-condition sensitive critical value [i.e., {Lambda(2)(zero-field)}(critical)>=53, see Eq. (23)], such that the biomaterial core is starved of essential ingredients required for successful proliferation. When tissue regeneration occurs above the critical electric-field-sensitive intra-tissue Damkohler number, the electro kinetic contribution to nutrient consumption cannot be neglected. The critical electric-field-sensitive intra-tissue Damkohler number is proportional to the Deborah number. PMID- 22196749 TI - Model-based PEEP optimisation in mechanical ventilation. AB - BACKGROUND: Acute Respiratory Distress Syndrome (ARDS) patients require mechanical ventilation (MV) for breathing support. Patient-specific PEEP is encouraged for treating different patients but there is no well established method in optimal PEEP selection. METHODS: A study of 10 patients diagnosed with ALI/ARDS whom underwent recruitment manoeuvre is carried out. Airway pressure and flow data are used to identify patient-specific constant lung elastance (E lung) and time-variant dynamic lung elastance (E drs) at each PEEP level (increments of 5 cm H2O), for a single compartment linear lung model using integral-based methods. Optimal PEEP is estimated using E lung versus PEEP, Edrs-Pressure curve and E drs Area at minimum elastance (maximum compliance) and the inflection of the curves (diminishing return). Results are compared to clinically selected PEEP values. The trials and use of the data were approved by the New Zealand South Island Regional Ethics Committee. RESULTS: Median absolute percentage fitting error to the data when estimating time-variant E drs is 0.9% (IQR = 0.5-2.4) and 5.6% [IQR: 1.8-11.3] when estimating constant E lung. Both E lung and E drs decrease with PEEP to a minimum, before rising, and indicating potential over inflation. Median E drs over all patients across all PEEP values was 32.2 cmH2O/l [IQR: 26.1-46.6], reflecting the heterogeneity of ALI/ARDS patients, and their response to PEEP, that complicates standard approaches to PEEP selection. All E drs-Pressure curves have a clear inflection point before minimum E drs, making PEEP selection straightforward. Model-based selected PEEP using the proposed metrics were higher than clinically selected values in 7/10 cases. CONCLUSION: Continuous monitoring of the patient-specific E lung and E drs and minimally invasive PEEP titration provide a unique, patient-specific and physiologically relevant metric to optimize PEEP selection with minimal disruption of MV therapy. PMID- 22196750 TI - Neuromyology III. PMID- 22196751 TI - Atrophy/hypertrophy cell signaling in muscles of young athletes trained with vibrational-proprioceptive stimulation. AB - OBJECTIVE: To compare the effects of isokinetic (ISO-K) and vibrational proprioceptive (VIB) trainings on muscle mass and strength. METHODS: In 29 ISO-K- or VIB-trained young athletes we evaluated: force, muscle fiber morphometry, and gene expression of muscle atrophy/hypertrophy cell signaling. RESULTS: VIB training increased the maximal isometric unilateral leg extension force by 48.1%. ISO-K training improved the force by 24.8%. Both improvements were statistically significant (P?0.01). The more functional effectiveness of the VIB training in comparison with the ISO-K training was shown by the statistical significance changes only in VIB group in: rate of force development in time segment 0-50 ms (P<0.001), squat jump (P<0.05) and 30-m acceleration running test (P<0.05). VIB training induced a highly significant increase of mean diameter of fast fiber (+9%, P<0.001), but not of slow muscle fibers (-3%, not significant). No neural cell adhesion molecule-positive (N-CAM(+)) and embryonic myosin heavy chain positive (MHC-emb(+)) myofibers were detected. VIB induced a significant twofold increase (P<0.05) of the skeletal muscle isoform insulin-like growth factor-1 (IGF-1) Ec mRNA. Atrogin-1 and muscle ring finger-1 (MuRF-1) did not change, but myostatin was strongly downregulated after VIB training (P<0.001). Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) expression increased in post-training groups, but only in VIB reached statistical significance (+228%, P<0.05). DISCUSSION: We demonstrated that both trainings are effective and do not induce muscle damage. Only VIB-trained group showed statistical significance increase of hypertrophy cell signaling pathways (IGF-1Ec and PGC-1alpha upregulation, and myostatin downregulation) leading to hypertrophy of fast twitch muscle fibers. PMID- 22196752 TI - Epineurial sheath tube (EST) technique: an experimental peripheral nerve repair model. AB - OBJECTIVE: Here we present the epineurial sheath tube (EST) technique as a modified microsurgical rat sciatic nerve model. The EST technique provides a cavity or pouch consisting of an outer epineurial sleeve that has been freed from nerve fascicles. This cavity may be appropriate to test the effectiveness and biocompatibility of implanted growth factors, cell suspensions (embedded in solutions or gels), or bioartificial nerve guide constructs. METHODS: A total number of 10 rats underwent the surgical procedure for the EST technique. Cylinders made of fibrin gel served as implants and place-holders. Three animals were euthanized directly after operation, while the others survived for 6 weeks. After immersion fixation (3.9% glutaraldehyde), both conventional histology [semi thin sections (1 MUm), toluidine blue] and scanning electron microscopy were performed. RESULTS: Conventional histology and scanning electron microscopy of samples that had been fixed directly after the surgical procedure displayed the integrity of the closed epineurial tube with the fibrin cylinder in its center. Even after 6 weeks, the outer epineurium was not lacerated, the stitches did not loosen, and the lumen did not collapse, but remained open. DISCUSSION: The practicability of the EST technique could be verified regarding feasibility, reproducibility, mechanical stability, and openness of the lumen. The EST technique can be adapted to other nerve models (e.g. median or facial nerve). It provides a cavity or pouch, which can be used for different neuroscientific approaches including concepts to improve the therapeutic benefit of autologous nerve grafting or therapies to be used as an alternative to autologous nerve grafting. PMID- 22196753 TI - Skeletal muscle ultrasound. AB - Muscle ultrasound is a convenient technique to visualize normal and pathological muscle tissue as it is non-invasive and real-time. Neuromuscular disorders give rise to structural muscle changes that can be visualized with ultrasound: atrophy can be objectified by measuring muscle thickness, while infiltration of fat and fibrous tissue increases muscle echo intensity, i.e. the muscles become whiter on the ultrasound image. Muscle echo intensity needs to be quantified to correct for age-related increase in echo intensity and differences between individual muscles. This can be done by gray scale analysis, a method that can be easily applied in daily clinical practice. Using this technique, it is possible to detect neuromuscular disorders with predictive values of 90%. Only in young children and metabolic myopathies the sensitivity is lower. Ultrasound is a dynamic technique and therefore capable of visualizing normal and pathological muscle movements. Fasciculations can easily be differentiated from other muscle movements. Ultrasound appeared to be even more sensitive in detecting fasciculations compared to Electromyography (EMG) and clinical observations, because it can visualize a large muscle area and deeper located muscles. With improving resolution and frame rate it has recently become clear that also smaller scale spontaneous muscle activity such as fibrillations can be detected by ultrasound. This opens the way to a broader use of muscle ultrasound in the diagnosis of peripheral nerve and muscle disorders. PMID- 22196754 TI - Distal myopathy with rimmed vacuoles: clinical and muscle morphological characteristics and spectrum of GNE gene mutations in 53 Chinese patients. AB - OBJECTIVES: Distal myopathy with rimmed vacuoles (DMRV) is a typical autosomal recessive hereditary inclusion body myopathy, characterized by slowly progressive distal muscle weakness with relative sparing of the quadriceps. This study aimed to investigate the variability of clinical and morphological presentation and the spectrum of Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE) mutations in Chinese DMRV patients. METHODS: We retrospectively reviewed the medical records of 37 patients with DMRV in PLA General Hospital from 1986 to 2011, and further conducted a review of 16 reported Chinese DMRV patients from other hospitals. We systematically analyzed the clinical, muscle morphological features and GNE gene mutation status of all DMRV patients. RESULTS: A total of 53 DMRV patients were studied. Fourteen cases had family history and other 39 cases were sporadic. Fifteen cases showed atypical pathological presentation as mononuclear cell invasion into necrotic or non-necrotic muscle fibers. Rare initial symptom, earlier age of onset and more dysmorphic presentations were shown in sporadic patients. Eighteen mutations in GNE gene were identified. c.317T>C (p.I106T) was a novel GNE gene mutation. c.1892C>T (p.A631V), c.527A>T (p.D176V) and c.1523T>C (p.L508S) were the common GNE mutations in Chinese DMRV patients. DISCUSSION: The clinical, pathological and genetic characteristics of DMRV are distinct in Chinese patients. PMID- 22196755 TI - Recurrence rate, time to progression and facial nerve function in microsurgery of vestibular schwannoma. AB - OBJECTIVE: Recurrence rate, time to progression, and facial nerve function were analysed by comparing patients with complete and near total tumor removal after suboccipital craniotomy for vestibular schwannoma surgery. METHODS: From 1996 to 2004, 118 patients with vestibular schwannoma were operated with an interdisciplinary approach. Fifty patients fulfilled the inclusion criteria and were included in the study. Progression was defined as an increase of ?2 mm in the largest diameter in the magnetic resonance imaging. Preoperative tumor size, facial nerve function estimated using the House-Brackmann score (HBS), time to progression, and recurrence rate were analysed and related to the extent of resection. RESULTS: In 28 cases (group I), a capsular remnant was left. In 22 cases (group II), tumor removal was complete. In group I, nine patients (32.1%) showed progression. In group II, two patients (9.1%) developed a recurrent tumor, no significance (P = 0.085). In groups I and II, 53.6 and 59.6% had a good function of the facial nerve (HBS I+II), 28.6% in group I and 13.5% in group II had a moderate disturbance (HBS III+IV), and 17.9% in group I and 27.7% in group II had a poor function (HBS V+VI). There was no significant difference between median preoperative tumor size and facial nerve function within patients with HBS III and IV. CONCLUSION: Complete tumor removal may be associated with a risk of functional loss, whereas near total tumor removal may be associated with a higher risk of progression. PMID- 22196756 TI - A simple clinical and MRI scale to predict good outcome in t-PA patients. AB - BACKGROUND AND PURPOSE: The frequency of good outcome at 3 months after tissue plasminogen activator (t-PA) therapy is ~35%. The present study aimed to devise a simple scale to predict good outcome using clinical factors and magnetic resonance imaging (MRI) findings before and immediately after t-PA infusion. METHODS: Consecutive patients with acute ischemic stroke treated with t-PA within 3 hours of stroke onset were studied prospectively. We assessed clinical factors independently associated with good outcome [modified Rankin scale (mRS): 0-1] at 3 months after t-PA therapy. We created a simple scale to predict good outcome in t-PA patients using factors selected by multivariate logistic regression analysis. RESULTS: Subjects comprised 105 patients (69 men; median age, 74 years). Multivariate logistic regression analysis revealed the following independent factors associated with good outcome: baseline National Institutes of Health Stroke Scale (NIHSS) <11 [odds ratio (OR), 13.64; 95% confidence interval (CI), 3.588-51.822; P = 0.0001], glucose <150 mg/dl (OR, 3.76; 95%CI, 1.014 13.963; P = 0.0475), and early recanalization within 1 hour after t-PA infusion (OR, 5.28; 95%CI, 1.179-23.656; P = 0.0296). Those three variables were selected for use in the good outcome scale, with NIHSS <11 as 2 points, glucose <150 mg/dl as 1 point, and early recanalization as 1 point. Frequencies of patients with good outcome for each score were as follows: score 0, 0.0%; score 1, 7.1%; score 2, 43.5%; score 3, 65.4%; and score 4, 71.4%. The C statistic for the score was 0.849 (95%CI, 0.776-0.922). CONCLUSION: A simple clinical and MRI scale can predict good outcome in t-PA patients. PMID- 22196757 TI - Morphometric MRI evaluation of corpus callosum and ventricles in normal adults. AB - OBJECTIVES: The aim of this study was to determine the normal values of subregions of corpus callosum and ventricles in healthy adult people in our population using magnetic resonance imaging (MRI) and to establish gender differences. METHODS: The MRI of 52 healthy individuals (29 females and 23 males) aged 20-50 years was obtained. The measurements were performed from MRI on a workstation. The midsagittal images were used for measurements of the subregions of corpus callosum and axial images were for lateral and third ventricles. RESULTS: The mean values of the widths of genu, body, splenium, and height of the corpus callosum were 13.28+/-2.10, 7.64+/-1.07, 12.52+/-1.35, and 25.47+/-2.20 mm, respectively in females; whereas, the same measurements were 13.23+/-2.41, 6.89+/-2.12, 11.90+/-1.94, and 25.03+/-3.38 mm, respectively in males. Moreover, the mean value for the longitudinal dimension of the brain was 150.12+/-5.04 mm, while that for the corpus callosum was 71.27+/-3.70 mm in females. Additionally, the mean frontal horn width of the lateral ventricle and the transverse inner diameter of the skull were 34.06+/-3.05 and 130.76+/-6.71 mm in females and 34.03+/-2.78 and 129.96+/-10.61 mm in males, respectively. Due to these measurements, the values of Evans index which is reflecting the lateral ventricle enlargement were estimated to be 0.25+/-1.90 and 0.25+/-1.14 in females and males, respectively. According to our last measurement result, the mean values for the third ventricle width were 3.79+/-0.85 and 4.12+/-0.94 mm in females and males, respectively. These findings show that there are differences between the averages of some indices of corpus callosum of our population and the other populations. PMID- 22196758 TI - Protective effects of baicalein against excess L-DOPA-induced dopamine quinone neurotoxicity. AB - OBJECTIVES: Baicalein, a flavonoid derived from the root of Scutelaria baicalensis Georgi, possesses anti-oxidative properties including reactive oxygen species scavenging and lipid peroxidation inhibiting activities. The present study was undertaken to investigate the neuroprotective effect of baicalein against dopamine (DA) neurotoxicity induced by exposure to a synthetic DA precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), in cultured dopaminergic CATH.a cells. METHODS AND RESULTS: Exposure to L-DOPA for 24 hours reduced the number of viable cells and enhanced protein-bound quinone (quinoprotein) formation in the cell. Both effects were prevented by simultaneous treatment with baicalein. In addition, baicalein prevented the formation of DA semiquinone radicals from DA in an in vitro cell-free system. Long-term baicalein treatment for 96 hours also protected against excess L-DOPA-induced cell death, and also increased glutathione (GSH) levels in CATH.a cells. DISCUSSION: Our results indicate that baicalein has neuroprotective properties against excess L-DOPA-induced DA neurotoxicity through the suppression of DA quinone formation. Furthermore, the long-term treatment of baicalein upregulates intracellular GSH contents, which may also exert neuroprotective effects against oxidative stress-induced neuronal damage. PMID- 22196759 TI - Proteomic analysis shows differential protein expression in endothelial progenitor cells between healthy subjects and ischemic stroke patients. AB - OBJECTIVE: An increase in the circulating concentration of endothelial progenitor cells (EPCs) is associated with a better outcome in patients with acute ischemic stroke. Likewise, EPCs are heterogeneous cells, with functional differences and different protein expressions. Our objective was to compare protein expressions of EPCs from ischemic stroke patients and healthy subjects. METHODS: Eleven ischemic stroke patients and 11 healthy subjects, matched by age and gender, were included in this study. EPC colonies were defined as early outgrowth colony forming unit-endothelial cell. Cells were lysed and proteins were purified and separated on two-dimensional gels. Gel images were analyzed using the PDQuest software and protein differences between EPCs from ischemic stroke patients and healthy subjects were identified by mass spectrometry. Results were finally validated by western blot. RESULTS: Proteomic analysis revealed three qualitative differences between EPCs from healthy subjects and ischemic stroke patients. Two of them, endoplasmatic reticulum protein-29 and CdC-42, were only expressed in EPCs from healthy subjects, whereas elongation factor-2 was only identified in EPCs from ischemic stroke patients. Furthermore, we identified one protein, peroxiredoxin-1, whose expression was 10 times stronger in ischemic stroke patients than in healthy subjects. Western blot analysis showed greater expression of endoplasmatic reticulum protein-29 in EPCs from healthy subjects and elongation factor-2 and peroxiredoxin-1 in EPCs from ischemic stroke patients. CONCLUSION: Proteomic analysis showed differences in protein expressions of EPCs from ischemic stroke patients and healthy subjects that may be involved in mechanisms related to functional impairment. PMID- 22196760 TI - Suboptimal awareness and control of hypertension increases the risk of subarachnoid hemorrhage in the community: results from the ACROSS. AB - BACKGROUND: High blood pressure (BP) is a major risk factor for stroke and all of its pathological subtypes including subarachnoid hemorrhage (SAH). However, there is little evidence demonstrating whether failure to have regular BP measured could result in underestimation of people at risk for SAH. Therefore, we aimed to estimate the effects of control of hypertension, diagnosing hypertension, and subsequent regular BP measurement on the risk of SAH in a population-based case control setting. METHODS: In 381 incident SAH cases and 465 frequency-matched community SAH-free controls, data were collected on time of last BP measurement and ever diagnosed and treated hypertension. RESULTS: After adjusting for covariates, the risks of SAH were both significantly higher among individuals who had never had their BP measured (OR: 2.81, 95% CI: 1.27-6.22), who had their BP measured and been diagnosed with hypertension (treated: OR: 1.79, 95% CI: 1.22 2.62; untreated: OR: 1.82, 95% CI: 1.11-3.00), and who had been diagnosed with hypertension but had not had their BP treated or measured in the last year (OR: 4.65, 95% CI: 2.09-10.32). CONCLUSIONS: Compared to controls, cases of SAH are more likely to have never had their blood pressure measured and, among those who have been diagnosed with hypertension, cases of SAH are less likely to have had their blood pressure measured in the past year. These results highlight the potential benefits of screening for hypertension and vigilantly controlling hypertension in reducing SAH rate at both population and individual levels. PMID- 22196761 TI - An experimental study on artificially induced CSF pulse waveform morphological modifications. AB - OBJECTIVE: The analysis of cerebrospinal fluid (CSF) pulse pressure waveform has been considered as a reliable method to investigate the intracranial system (ICS) dynamics. We have examined the morphological changes of the CSF pulse wave and of the sagittal sinus pressure (SSP) wave during a progressive increase in intracranial pressure (ICP) in order to investigate the ICS dynamics. METHODS: Four dogs were anesthetized. Blood pressure, ICP, and SSP were simultaneously recorded. Two vertical tubes were inserted inside one lateral ventricle, thus allowing the half-opening (one tube open) and opening (both tubes open) of the ICS. ICP was modified by varying the height of the liquid column into the tubes. Pressures were analyzed by applying the fast Fourier transformation on each pulse pressure wave. We distinguished two peaks (first and second peaks) and a notch in each pulse pressure wave. The pressure was raised from resting pressure up to 50 mmHg. RESULTS: A progressive and distinct change in the CSF pulse pressure shape was evident when opening the ICS to the atmosphere: a reduction in the height of the dicrotic notch and in the amplitude of the second peak and a corresponding positive shift of the first harmonic with respect to the onset of the CSF pulse pressure wave. DISCUSSION: A decrease in the amplitude of the CSF pulse waveform second peak and a positive phase shift of its first harmonic indicate an opening of the ICS to the atmosphere, i.e. an increase in the intracranial compliance. PMID- 22196762 TI - Generation of neural stem cell-like cells from bone marrow-derived human mesenchymal stem cells. AB - Under appropriate culture conditions, bone marrow (BM)-derived mesenchymal stem cells are capable of differentiating into diverse cell types unrelated to their phenotypical embryonic origin, including neural cells. Here, we report the successful generation of neural stem cell (NSC)-like cells from BM-derived human mesenchymal stem cells (hMSCs). Initially, hMSCs were cultivated in a conditioned medium of human neural stem cells. In this culture system, hMSCs were induced to become NSC-like cells, which proliferate in neurosphere-like structures and express early NSC markers. Like central nervous system-derived NSCs, these BM derived NSC-like cells were able to differentiate into cells expressing neural markers for neurons, astrocytes, and oligodendrocytes. Whole-cell patch clamp recording revealed that neuron-like cells, differentiated from NSC-like cells, exhibited electrophysiological properties of neurons, including action potentials. Transplantation of NSC-like cells into mouse brain confirmed that these NSC-like cells retained their capability to differentiate into neuronal and glial cells in vivo. Our data show that multipotent NSC-like cells can be efficiently produced from BM-derived hMSCs in culture and that these cells may serve as a useful alternative to human neural stem cells for potential clinical applications such as autologous neuroreplacement therapies. PMID- 22196763 TI - CT evaluation of caudal versus lumbar access to the intradural space. AB - BACKGROUND: Percutaneous intraspinal navigation is a new procedure that enables visualization of the central nervous system using a lumbar puncture technique. Past research shows promising potential, but is limited by damage to expensive fiberscopes due to the sharp angle of manipulation at L3-L4. Our objective in this study is to analyse the feasibility of a novel access through the sacral hiatus to eliminate this problem. METHODS: We retrospectively reviewed computed tomography images of the sacrum of 132 subjects, of which nine were excluded either secondary to incomplete imaging of the sacrum or variant anatomy that precluded any possible measurements. Of the remaining 123 patients, we measured kyphotic and lordotic curvature of the sacral canal in comparison to the angle of lumbar puncture. We also measured the anteroposterior diameters of the sacral canal at the distal, middle, and proximal portions. RESULTS: There were no significant differences according to sex or age. The kyphotic angle was a wide angle with a mean value of 167.89+/-11.71 degrees . The lordotic angle had a mean value of 133.35+/-7.84 degrees , making it 25.52 degrees more obtuse than the average angle for lumbar puncture. The smallest diameter of the sacral canal was at the sacral hiatus and had a mean value of 4.49+/-1.66 mm. CONCLUSION: The size and anatomy of the sacral canal is feasible for PIN procedure and appears more favorable as compared to entry via lumbar puncture. The canal opening is wide enough to accommodate most small-diameter fiberscopes without difficulty, and the angles are obtuse enough to limit damage to the expensive fiberscopes. PMID- 22196764 TI - Ammonia-induced brain swelling and neurotoxicity in an organotypic slice model. AB - OBJECTIVES: Acute liver failure (ALF) produces cerebral dysfunction and edema, mediated in part by elevated ammonia concentrations, often leading to coma and death. The pathophysiology of cerebral edema in ALF is incompletely understood. In vitro models of the cerebral effects of ALF have predominately consisted of dissociated astrocyte cultures or acute brain slices. We describe a stable long term culture model incorporating both neural and glial elements in a three dimensional tissue structure offering significant advantages to the study of astrocytic-neuronal interactions in the pathophysiology of cerebral edema and dysfunction in ALF. METHODS: We utilized chronic organotypic slice cultures from mouse forebrain, applying ammonium acetate in iso-osmolar fashion for 72 hours. Imaging of slice thickness to assess for tissue swelling was accomplished in living slices with optical coherence tomography, and confocal microscopy of fluorescence immunochemical and histochemical staining served to assess astrocyte and neuronal numbers, morphology, and volume in the fixed brain slices. RESULTS: Ammonia exposure at 1-10 mM produced swelling of immunochemically identified astrocytes, and at 10 mM resulted in macroscopic tissue swelling, with slice thickness increasing by about 30%. Astrocytes were unchanged in number. In contrast, 10 mM ammonia treatment severely disrupted neuronal morphology and reduced neuronal survival at 72 hours by one-half. DISCUSSION: Elevated ammonia produces astrocytic swelling, tissue swelling, and neuronal toxicity in cerebral tissues. Ammonia-treated organotypic brain slice cultures provide an In vitro model of cerebral effects of conditions relevant to ALF, applicable to pathophysiological investigations. PMID- 22196765 TI - Expression of deltaNp73 in hippocampus of APP/PS1 transgenic mice following GFP BMSCs transplantation. AB - OBJECTIVE: To study the effect of hippocampal bone marrow stromal cells (GFP BMSCs) transplantation on spatial memory and DeltaNp73 expression in APP/PS1 transgenic mice. METHODS: Twelve APP/PS1 transgenic mice randomly received either 10 MUl GFP-BMSCs suspension in medium (GFP-BMSCs transplantation group) or 10 MUl complete medium (sham-operated group). Learning and memory function of mice in both groups were observed and tested in Morris water maze experiment at 2 weeks after surgery. Senile plaques and DeltaNp73 protein in hippocampuses were determined by immunohistochemistry and western blot at 3 weeks after surgery, respectively. RESULTS: APP/PS1 mice treated with BMSCs performed significantly better on the water maze test than those in sham-operated group (P<0.05). Immunohistochemistry showed that GFP-BMSCs distributed uniformly and the number of Alzheimer's senile plaques reduced after transplantation. Western blot showed that quantified DeltaNp73 protein expression was significantly higher in BMSCs transplantation group when compared with sham-operated group (P<0.01). CONCLUSIONS: Our results suggest that BMSCs transplatation could retard Alzheimer's disease (AD) like pathology and upregulate DeltaNp73 expression in hippocampuses of APP/PS1 transgenic mice. GFP-BMSCs transplantation will be a potential treatment for AD. PMID- 22196766 TI - Polymeric nanomaterials for islet targeting and immunotherapeutic delivery. AB - Here we report a proof-of-concept for development of pancreatic islet-targeting nanoparticles for immunomodulatory therapy of autoimmune type 1 diabetes. Modified with a unique islet-homing peptide, these polymeric nanomaterials exhibit 3-fold greater binding to islet endothelial cells and a 200-fold greater anti-inflammatory effect through targeted islet endothelial cell delivery of an immunosuppressant drug. Our findings also underscore the need to carefully tailor drug loading and nanoparticle dosage to achieve maximal vascular targeting and immunosuppression. PMID- 22196767 TI - Resolution enhancement of ion mobility spectrometry by improving the three-zone properties of the Bradbury-Nielsen gate. AB - A simple space compression-dispersion model for ion transport at ambient pressure was mathematically established. On the basis of this model and aided by SIMION simulation, a three-zone theory was proposed to characterize the Bradbury-Nielsen gating electric field features as three zones: the depletion zone, the dispersion zone, and the compression zone. Then, the influences of gating voltage difference increases on the full width at half-maximum of the Cl(-) peak were investigated in detail to verify the theory. For example, at a gating voltage difference of 350 V and a gate pulse width of 0.34 ms, the ion packets injected were reduced to as low as 60% of their original widths, with the peak height increased from 756 to 808 pA and the resolution from 18 to 33, enhanced by 7% and ~80%, respectively. The ion mobility spectrometry (IMS) efficiency ratios, R(m)/R(c) and R(m)/R(p), were also raised above theoretical values and reached about 182% and 175%, respectively. The experimental results were explained using the proposed theory with good consistency. Finally, a compression coefficient was extracted by fitting the experimental data to the applied gate pulse width, presenting a good linearity. All this shows a potential application in improving the performances of ion mobility spectrometry. PMID- 22196768 TI - The effects of an H3 receptor antagonist (PF-03654746) with fexofenadine on reducing allergic rhinitis symptoms. AB - BACKGROUND: Nasal H(3) receptors might have a role in mediating the effects of histamine in patients with allergic rhinitis. OBJECTIVE: This study explored the effect of the potent oral H(3) receptor antagonist PF-03654746 in combination with an oral H(1) receptor antagonist on the objective (acoustic rhinometry) and subjective (symptoms) responses to nasal allergen challenge. METHODS: Twenty patients with out-of-season allergic rhinitis displaying a 30% or greater decrease in minimum nasal cross-sectional area (A(min)) after bolus (ragweed) complete nasal allergen challenge at screening were studied by using a randomized, double-blind, single-dose, 4-way crossover design. Treatments included 10 mg of PF-03654746 plus 60 mg of fexofenadine (group 1), 1 mg of PF 03654746 plus 60 mg of fexofenadine (group 2), 60 mg of fexofenadine/120 mg of pseudoephedrine (group 3), and placebo (group 4). After dosing, subjects underwent complete nasal allergen challenge. Nasal symptom scores (no. of sneezes and 0- to 5-point scores for severity of congestion, itching, and rhinorrhea), A(min) (in square centimeters), and nasal volume (in cubic centimeters) were recorded 15, 30, 45, and 60 minutes after allergen. There was a minimum 10-day washout between periods. RESULTS: The following symptom scores were significantly (P <= .05) reduced by active treatments versus placebo: group 1, congestion of 0.7 (SE, 0.3), itching of -1.0 (SE, 0.3), rhinorrhea of -1.3 (SE, 0.3), and sneeze of -8.8 (SE, 1.5); group 2, itching of -0.6 (SE, 0.3), rhinorrhea of -0.8 (SE, 0.3), and sneeze of -9.1 (SE, 1.5); and group 3, rhinorrhea of -0.7 (SE, 0.3) and sneeze of -7.0 (SE, 1.5). There was no significant effect of any treatment on mean A(min) proportion or nasal volume proportion after nasal allergen challenge. CONCLUSIONS: In combination with fexofenadine, single doses of PF-03654746 caused a reduction in allergen-induced nasal symptoms. H(3) receptor antagonism might be a novel therapeutic strategy to further explore in patients with allergic rhinitis. PMID- 22196770 TI - A suspicion of antibiotic allergy in children is often incorrect. PMID- 22196771 TI - Airway remodeling and inflammation in competitive swimmers training in indoor chlorinated swimming pools. AB - BACKGROUND: Airway disorders are common in regular chlorinated swimming pool attendees, particularly competitive athletes, but the impact of intense swimming training on airway function and structure remains unclear. OBJECTIVE: This study aimed to evaluate airway inflammation and remodeling in elite swimmers. METHODS: Twenty-three elite swimmers were tested during off-training season. All had exhaled nitric oxide measurement, methacholine test, eucapnic voluntary hyperpnea challenge, allergy skin prick tests, and bronchoscopy with bronchial biopsies. Clinical data and tissues from 10 age-matched mild-asthmatic and 10 healthy nonallergic subjects were used for comparison. RESULTS: Swimmers had increased airway mucosa eosinophil and mast cell counts than did controls (P < .05). They had more goblet cell hyperplasia and higher mucin expression than did healthy or asthmatic subjects (P < .05). A greater submucosal type I and III collagen expression and tenascin deposition was also observed in swimmers than in controls (P < .05). Neither exhaled nitric oxide nor airway responsiveness to methacholine or eucapnic voluntary hyperpnea challenge correlated with these inflammatory and remodeling changes. CONCLUSION: Intense, long-term swimming training in indoor chlorinated swimming pools is associated with airway changes similar to those seen in mild asthma, but with higher mucin expression. These changes were independent from airway hyperresponsiveness. The long-term physiological and clinical consequences of these changes remain to be clarified. PMID- 22196772 TI - Protease-activated receptor 2-dependent fluid secretion from airway submucosal glands by house dust mite extract. AB - BACKGROUND: The submucosal gland (SMG) is important in the control of airway surface fluid. Protease-activated receptor (PAR) 2 contributes to the pathophysiology of allergies in response to nonspecific allergens bearing proteases and anion secretion. House dust mites (HDMs) have abundant proteases that can activate PAR2, but little is known about the direct effect of HDM on SMG secretion. OBJECTIVE: The aim of this study was to investigate the effect of HDMs on glandular secretion and its mechanism in allergic patients, patients with chronic rhinosinusitis (CRS), or both. METHODS: Inferior nasal turbinates were harvested from 55 patients and classified into 4 groups (the control, allergic rhinitis [AR], CRS, and AR+CRS groups). A microscope attached to a digital camera was used to quantify mucus bubbles from individual SMGs while stimulated with HDM extract, PAR2-activating peptide, and carbachol. PAR2 expression in the SMG was determined by means of immunostaining with anti-PAR2 mAb. RESULTS: HDM induced a significantly higher secretion rate and number of responding glands in the AR and AR+CRS groups than in the control group. Interestingly, patients in the CRS group, who had no HDM-specific IgE antibody, showed a higher response than the control group, and its response was suppressed by a PAR2-selective antagonist. The responses to PAR2-activating peptide were similar to those to HDM, and their secretion rates positively correlated with HDM responses. PAR2 was highly expressed in all 3 disease groups with immunostaining. CONCLUSIONS: HDM allergens can induce glandular secretion in patients with AR, CRS, or both, and PAR2 represents a possible mechanism for nonspecific hyperreactivity in inflammatory airway diseases. PMID- 22196773 TI - Tolerance-like mediated suppression by mesenchymal stem cells in patients with dust mite allergy-induced asthma. AB - BACKGROUND: Mesenchymal stem cells (MSCs) can suppress and enhance immune functions. MSCs show promise as off-the-shelf cellular therapy for several disorders, including inflammation. OBJECTIVE: We investigated the effects of MSCs on the proliferation of PBMCs to allergic subjects (dust mite [DM]), allergic asthmatic subjects, or both. METHODS: Proliferation was studied by using tritiated thymidine uptake with or without MSCs. The refractoriness of PBMCs to DM was examined after preconditioning with MSCs and after repeated challenge with low-dose DM. Flow cytometry was used to study regulatory T cells and dendritic cells (DCs), and ELISA was used to study cytokine production. RESULTS: Seven subjects with allergic asthma met the inclusion/exclusion criteria. MSCs significantly (P < .05) reduced the proliferation of 6 subjects with allergic asthma but not those with allergy alone. The effect was specific to the allergen because MSCs did not affect challenges to tetanus toxoid. There was no change in CD4/CD25/forkhead box protein 3-positive cells, although there were decreased IFN gamma and increased IL-10 levels. Numbers of mature DCs were increased 6-fold. Refractoriness to DM was achieved by means of repeated exposure to low-dose DM and MSCs and also MSC- preconditioned MSC. CONCLUSION: MSCs suppressed the proliferation of DM-challenged PBMCs from allergic asthmatic subjects but not from allergic subjects without asthma. MSCs blunted the maturation of DCs but not regulatory T cells. Repeated exposure to low-dose DM and MSCs, as well as preconditioning of PBMCs with MSCs, caused refractoriness to DM. These findings have implications for the use of MSCs in attenuation of the inflammatory responses to allergic triggers in asthmatic patients with off-the-shelf MSCs. PMID- 22196774 TI - Necrotizing fasciitis: literature review of contemporary strategies for diagnosing and management with three case reports: torso, abdominal wall, upper and lower limbs. AB - Necrotizing fasciitis (NF) is an uncommon soft tissue infection, usually caused by toxin-producing virulent bacteria. It is characterized by widespread fascial necrosis primarily caused by Streptococcus hemolyticus. Shortly after the onset of the disease, patients become colonized with their own aerobic and anaerobic microflora from the gastrointestinal and/or urogenital tracts. Early diagnosis with aggressive multidisciplinary treatment is mandatory. We describe three clinical cases with NF. The first is a 69 years old man with diabetes mellitus type II, who presented with NF on the posterior chest wall, shoulder and arm. He was admitted to the intensive care unit (ICU) with a clinical picture of severe sepsis. Outpatient treatment and early surgical debridement of the affected zones (inside 3 hours after admittance) and critical care therapy were performed. The second case is of a 63 years old paraplegic man with diabetes mellitus type I. Pressure sores and perineal abscesses progressed to Fournier's gangrene of the perineum and scrotum. He had NF of the anterior abdominal wall and the right thigh. Outpatient treatment and early surgical debridement of the affected zones (inside 6 hour after admittance) and critical care therapy were performed. The third patient was a 56 year old man who had NF of the anterior abdominal wall, flank and retroperitoneal space. He had an operation of the direct inguinal hernia, which was complicated with a bowel perforation and secondary peritonitis. After establishing the diagnosis of NF of the abdominal wall and retroperitoneal space (RS), he was transferred to the ICU. There he first received intensive care therapy, after which emergency surgical debridement of the abdominal wall, left colectomy, and extensive debridement of the RS were done (72 hours after operation of inquinal hernia). On average, 4 serial debridements were performed in each patient. The median of serial debridement in all three cases was four times. Other intensive care therapy with a combination of antibiotics and adjuvant hyperbaric oxygen therapy (HBOT) was applied during the treatment. After stabilization of soft tissue wounds and the formation of fresh granulation tissue, soft tissue defect were reconstructed using simple to complex reconstructive methods. PMID- 22196775 TI - Carotid intimal-medial thickness in active professional American football players aged 23 to 35 years. AB - Risk of cardiovascular disease and death in retired professional American football players may be higher than that in the general population. Previously published data have demonstrated that American football players have less glucose intolerance, less smoking, similar lipid profiles, and higher blood pressure despite a much larger body compared to the general population, although the presence of subclinical atherosclerosis in these subjects has not been evaluated. This study compared the prevalence of subclinical atherosclerosis in active professional American football players to that in age-, gender-, and race-matched controls derived from the Bogalusa Heart Study. Carotid intimal-medial thickness (CIMT) was used as an indicator of subclinical atherosclerosis in 75 active American football players (23 to 35 years old, 31 white, 44 African-American) as measured by B-mode ultrasonography at Mayo Clinic, Scottsdale, Arizona, on September 13 and 14, 2009. CIMT measurements of 75 athletes were compared to those of 518 matched controls who had CIMT determinations in 1995 and 1996. Two group t tests determined population similarities between groups. In a generalized linear model, players (overall and by race) had lower CIMT values than controls after age and race adjustment (p <0.001 for all comparisons). Nonlinemen and linemen had lower CIMT values than controls (p < 0.001 and p = 0.004, respectively). In conclusion, active professional American football players, regardless of position, had mean CIMT values similar to or lower than those in a matched general population cohort, suggesting that if the prevalence of subclinical atherosclerosis is increased in retired professional American football players, this occurs after retirement. PMID- 22196776 TI - Effect of timing of chronic preoperative aspirin discontinuation on morbidity and mortality in patients having combined coronary artery bypass grafting and valve surgery. AB - The objective of this study was to determine if late use of aspirin before coronary artery bypass grafting (CABG) with valve surgery affects bleeding events and major adverse cardiovascular events. Aspirin has been shown to decrease postoperative CABG mortality and ischemic events. There are no data on the time of aspirin discontinuation and its effect on CABG with valve surgery and bleeding complications. From January 1, 2002 to January 31, 2008, 1,963 patients undergoing nonurgent plus valve surgery at the Cleveland Clinic were on preoperative aspirin; 1,404 (72%) discontinued aspirin >= 6 days before surgery (early discontinuation) and 559 (28%) continued aspirin within 5 days of surgery (late use). Propensity-score analysis and matching were employed for fair comparison of outcomes. There was no difference between early-discontinuation and late-use groups in the composite outcome of in-hospital mortality, myocardial infarction, and stroke (5.3% in the 2 groups). More patients in the late-use group received postoperative transfusions (49% vs 42%, p = 0.02). There was a trend toward increased reoperation for bleeding (6.1% vs 3.7%, p = 0.08) in the late-use group. In conclusion, in patients undergoing CABG with valve surgery, there was an increased use of postoperative red blood cell transfusion and a trend toward increased reoperation for bleeding in the late-use group. There was no difference in major adverse cardiac events between groups. Late use of aspirin in CABG with valve surgery must be weighed against an increased risk of bleeding. PMID- 22196777 TI - Incidence of cardiac arrhythmias in asymptomatic hereditary hemochromatosis subjects with C282Y homozygosity. AB - It is not well known whether systemic iron overload per se in hereditary hemochromatosis (HH) is associated with cardiac arrhythmias before other signs and symptoms of cardiovascular disease occur. In the present study, we examined the incidence of cardiac arrhythmia in cardiac asymptomatic subjects with HH (New York Heart Association functional class I) and compared it to that in age- and gender-matched normal volunteers. The 42 subjects with HH and the 19 normal control subjects were recruited through the National Heart, Lung, and Blood Institute-sponsored "Heart Study of Hemochromatosis." They completed 48-hour Holter electrocardiography ambulatory monitoring at the baseline evaluation. The subjects with HH were classified as newly diagnosed (group A) and chronically treated (group B) subjects. All subjects with HH had C282Y homozygosity, and the normal volunteers lacked any HFE gene mutations known to cause HH. Although statistically insignificant, the incidence of ventricular and supraventricular ectopy tended to be greater in the combined HH groups than in the controls. Supraventricular ectopy was more frequently noted in group B compared to in the controls (ectopy rate per hour 11.1 +/- 29.9 vs 1.5 +/- 3.5, p < 0.05, using the Kruskal-Wallis test). No examples of heart block, other than first-degree atrioventricular node block, were seen in any of the subjects. The incidence of cardiac arrhythmias was not significantly reduced after 6 months of intensive iron removal therapy in the group A subjects. No life-threatening arrhythmias were observed in our subjects with HH. In conclusion, our data suggest that the incidence of cardiac arrhythmias is, at most, marginally increased in asymptomatic subjects with HH. A larger clinical study is warranted to further clarify our observation. PMID- 22196778 TI - Outcomes of patients treated with triple antithrombotic therapy after primary percutaneous coronary intervention for ST-elevation myocardial infarction (from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI] trial). AB - In the setting of ST-segment elevation myocardial infarction (STEMI), patients at high risk of systemic emboli who undergo primary percutaneous coronary intervention (PCI) using stents might require triple antithrombotic therapy (a combination of aspirin, thienopyridine, and vitamin K antagonist [VKA]). The risks and benefits of such therapy in the setting of STEMI have been incompletely characterized. We, therefore, assessed the outcomes of patients who received triple therapy after primary PCI in the large-scale, contemporary Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI] trial. Among the 3,320 patients triaged to primary PCI, 126 (3.8%) were prescribed triple therapy and 3,194 (96.2%) were prescribed dual antiplatelet therapy. The most frequent indications for VKA treatment were a severely reduced left ventricular ejection fraction with a large akinetic area, atrial fibrillation (23.8% each), and mural thrombus (23.0%). The assignment to triple therapy was associated with older age, female gender, rhythm disturbances, Killip class > 1 on admission, lower left ventricular ejection fraction, left anterior descending artery territory infarcts, and Final Thrombolysis In Myocardial Infarction flow grade < 3. Patients treated with triple versus dual therapy had comparable short- and long-term ischemic outcomes but had significantly increased rates of major bleeding during the index hospitalization (17.1% vs 6.5%, p < 0.0001), resulting in premature VKA discontinuation in 14.3% of those patients. In conclusion, in the setting of STEMI treated with primary PCI, the combination of aspirin, thienopyridine, and VKA results in an excess of bleeding complications and premature discontinuation of VKA. The risk of adding oral anticoagulation to patients admitted for STEMI should be carefully considered before choosing drug-eluting or bare metal stents. PMID- 22196779 TI - By desperate appliance relieved? On the clinical relevance of risk stratification to therapeutic decision-making. AB - Risk stratification is a mainstay of current cardiovascular care. Its practical relevance to therapeutic decision making depends, however, on the often unverified assumption that higher risk patients experience greater treatment benefit. The truth of this assumption depends, in turn, on the particular set of variables in the putative risk prediction model, the pathophysiology of the underlying disease, and the associated goal(s) of therapy. If the operative set of risk predictors is incomplete (ignoring variables affected by treatment) or inconsistent (including variables unaffected by treatment), this will influence the relation between pretreatment risk and post-treatment benefit in complex ways having material clinical consequences. In conclusion, the clinical appropriateness of risk stratification must not be assumed. Instead, risk stratification guidelines specific to a particular disease and a particular treatment should be founded on prospective empiric validation. PMID- 22196780 TI - Morphologic and functional remodeling of the right ventricle in pulmonary hypertension by real time three dimensional echocardiography. AB - The aims of this study were to assess the right ventricle in different causes of pulmonary hypertension (PH) and to assess the changes of the tricuspid apparatus during this remodeling. The functional and morphologic changes of the right ventricle and the tricuspid apparatus in relation to different causes of PH remain elusive. A total of 141 consecutive patients were prospectively recruited, of whom 55 had pulmonary arterial hypertension (PAH), 32 had chronic thromboembolic disease (CTED), and 34 had PH secondary to mitral regurgitation (MR). Twenty age- and gender-matched healthy volunteers were also studied to serve as controls. Real-time 3-dimensional echocardiography was used to assess right ventricular (RV) volumes and tricuspid valve mobility. Overall, RV diastolic volumes were greater and RV ejection fractions lower in patients with PAH compared to those with CTED and MR (186.4 +/- 48.8 vs 113.5 vs 109.4 ml, p < 0.001, and 33.2% vs 36.8% vs 66.8%, p < 0.001, respectively). Among the 3 PH groups, tricuspid valve mobility was most restricted in the CTED group and least restricted in the MR group. Tricuspid tenting volume was greater in the CTED and PAH groups than in the MR group (p < 0.01). Most patients with PAH (54.6%) had at least moderate tricuspid regurgitation, while in the CTED group, most (59.4%) had mild and only 37.5% had moderate tricuspid regurgitation (p < 0.01). Conversely, patients with MR (85%) had only mild tricuspid regurgitation. There was no correlation between RV systolic pressures and the RV ejection fraction or tenting volume. In conclusion, this study demonstrates that different causes of PH may lead to diverse RV remodeling, with the most adverse remodeling being in patients with PAH. In addition, changes of the tricuspid apparatus also differed, with the most adverse effects seen in patients with CTED. PMID- 22196781 TI - Echocardiographic knowledge-based reconstruction for quantification of the systemic right ventricle in young adults with repaired D-transposition of great arteries. AB - The systemic right ventricle (RV) in congenital heart disease is susceptible to progressive dilation and dysfunction. A 2-dimensional echocardiographic means for serial monitoring of the RV would be of great value in this clinical setting. We used 2-dimensional echocardiography with knowledge-based reconstruction (2DE-KBR) for evaluation of systemic RV. Patients with d-transposition of great arteries repaired with an atrial switch and without implanted pacemakers were prospectively recruited for same-day 2DE-KBR and cardiac magnetic resonance (CMR) imaging. RV images were acquired in various 2-dimensional imaging planes using a 3-dimensional space-localizing device attached to the imaging transducer and 3 dimensional reconstruction was performed. RV end-diastolic volume, end-systolic volume, and ejection fraction (EF) were calculated and compared to volumetric CMR analysis. Fifteen patients (7 women, 8 men, 24 +/- 7 years old, weight 67 +/- 12 kg) were studied. There was good agreement of 2DE-KBR and CMR measurements. Mean RV end-diastolic volume was 221 +/- 39 ml with 2DE-KBR and 231 +/- 35 ml with CMR (r = 0.80); mean end-systolic volume was 129 +/- 35 ml with KBR and 132 +/- 30 ml with CMR (r = 0.82), and EF was 42 +/- 10% with KBR and 43 +/- 7% with CMR (r = 0.86). For 2DE-KBR mean interobserver variabilities were 4.6%, 2.6%, and 4.3%; intraobserver variabilities were 3.2%, 3.1%, and 2.3%, respectively, for end diastolic volume, end-systolic volume, and EF. In conclusion, this study demonstrates the clinical feasibility of quantifying systemic RV volumes and function using 2DE-KBR in adolescents and young adults with repaired d transposition of great arteries and good agreement of measurements with CMR. PMID- 22196782 TI - Prognostic significance of postprocedural sustained ventricular tachycardia or fibrillation in patients undergoing primary percutaneous coronary intervention (from the HORIZONS-AMI Trial). AB - The prognostic significance of postprocedure sustained ventricular tachycardia or ventricular fibrillation (VT/VF) in patients undergoing primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) has rarely been studied, although a previous study has suggested that its occurrence portends decreased survival. We examined outcomes from the prospective large-scale multicenter randomized HORIZONS-AMI trial to evaluate the incidence, clinical correlates, and outcomes of in-hospital sustained VT/VF after PPCI. Of 3,485 patients undergoing PPCI in whom VT/VF did not occur before or during the procedure, 181 patients (5.2%) developed VT/VF after PPCI. Most postprocedural VT/VF episodes (85%) occurred in the first 48 hours. Patients with postprocedural VT/VF were more likely men with Killip class > I on presentation but had a lower prevalence of hypertension and diabetes. Patients with postprocedural VT/VF were also less frequently taking beta blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers at admission. Mean door-to-balloon time was shorter and Thrombolysis In Myocardial Infarction grade 0 flow before PPCI was more common in patients with VT/VF, although Thrombolysis In Myocardial Infarction grade 3 flow rates after PPCI did not vary. There were no significant differences in adjusted 3-year rates of mortality (hazard ratio 0.73, 95% confidence interval 0.30 to 1.79) or composite major adverse clinical events (death, myocardial infarction, target vessel revascularization, or stroke; hazard ratio 0.71, 95% confidence interval 0.44 to 1.15) in patients with versus without postprocedural sustained VT/VF. In conclusion, sustained VT/VF after PPCI in the HORIZONS-AMI trial was not significantly associated with 3-year mortality or major adverse clinical events. Further studies are required to address the prognostic significance of VT/VF in patients with STEMI undergoing PPCI. PMID- 22196783 TI - Relation of ruptured plaque culprit lesion phenotype and outcomes in patients with ST elevation acute myocardial infarction. AB - We used virtual histology intravascular ultrasound (VH-IVUS) to assess culprit plaque rupture in 172 patients with ST-segment elevation acute myocardial infarction. VH-IVUS-defined thin-capped fibroatheroma (VH-TCFA) had necrotic core (NC) > 10% of plaque area, plaque burden > 40%, and NC in contact with the lumen for >= 3 image slices. Ruptured plaques were present in 72 patients, 61% of which were located in the proximal 30 mm of a coronary artery. Thirty-five were classified as VH-TCFA and 37 as non-VH-TCFA. Vessel size, lesion length, plaque burden, minimal lumen area, and frequency of positive remodeling were similar in VH-TCFA and non-VH-TCFA. However, the NC areas within the rupture sites of VH TCFAs were larger compared to non-VH-TCFAs (p = 0.002), while fibrofatty plaque areas were larger in non-VH-TCFAs (p < 0.0001). Ruptured plaque cavity size was correlated with distal reference lumen area (r = 0.521, p = 0.00002), minimum lumen area (r = 0.595, p < 0.0001), and plaque area (r = 0.267, p = 0.033). Sensitivity and specificity curve analysis showed that a minimum lumen area of 3.5 mm2, a distal reference lumen area of 7.5 mm2, and a maximum NC area of 35% best predicted plaque rupture. Although VH-TCFA (35 of 72) was the most frequent phenotype of plaque rupture in ST-segment elevation myocardial infarction, plaque rupture also occurred in non-VH-TCFA: pathologic intimal thickening (8 of 72), thick-capped fibroatheroma (1 of 72), and fibrotic (14 of 72) and fibrocalcified (14 of 72) plaque. In conclusion, not all culprit plaque ruptures in patients with ST-segment elevation myocardial infarction occur as a result of TCFA rupture; a prominent fibrofatty plaque, especially in a proximal vessel, may be another form of vulnerable plaque. Further study should identify additional factors causing plaque rupture. PMID- 22196784 TI - Prevalence of coronary atherosclerosis in asymptomatic middle-age men with high aerobic fitness. AB - Good aerobic fitness is associated with favorable cardiovascular outcomes. However, it is not well known whether aerobic fitness correlates to the degree of coronary atherosclerosis, which affects cardiovascular prognosis. The aim of the present study was to investigate the relation between aerobic fitness and coronary atherosclerosis. A total of 8,565 apparently healthy men underwent routine health screening, including both cardiopulmonary function testing and coronary calcium scoring. The subjects with clinical cardiovascular disease or abnormal exercise electrocardiographic findings were excluded. A treadmill exercise test was done using the modified Bruce protocol, and the Agatston coronary artery calcium (CAC) score was measured using multidetector computed tomography. Advanced CAC was defined as a score > 75th percentile according to the age group. The mean age was 51 +/- 7 years, the average maximum oxygen uptake was 32 +/- 5 ml/kg/min, and 34% had a positive CAC score. On univariate analysis, age, blood pressure, lipid profile, body mass index, hemoglobin A1c, fasting glucose, calculated 10-year risk for coronary disease, and maximum oxygen uptake were significantly associated with advanced CAC. In the multiple logistic regression model, the subjects in the highest quartile of the maximum oxygen uptake for age were less likely to have advanced CAC for age compared to those in the lowest quartile (odds ratio 0.60, 95% confidence interval 0.48 to 0.73), with adjustment for age, hypertension, hemoglobin A1c, current smoking, body mass index, and regular exercise habit. In conclusion, greater aerobic fitness was associated with less prevalent advanced coronary atherosclerosis in an asymptomatic male population. The degree of subclinical coronary artery disease might be 1 of the mechanisms connecting aerobic fitness and cardiovascular outcome. PMID- 22196785 TI - Usefulness of cardiovascular magnetic resonance imaging to predict the need for intervention in patients with coarctation of the aorta. AB - Cardiovascular magnetic resonance (CMR) imaging can predict hemodynamically significant coarctation of the aorta (CoA) with a high degree of discrimination. However, the ability of CMR to predict important clinical outcomes in this patient population is unknown. Therefore, we sought to define the ability of CMR to predict the need for surgical or transcatheter intervention in patients with CoA. We retrospectively reviewed the data from 133 consecutive patients who had undergone CMR for the evaluation of known or suspected CoA. The characteristics of the CMR-derived variables predicting the need for surgical or transcatheter intervention for CoA within 1 year were determined through logistic regression analysis. Therapeutic aortic intervention was performed in 41 (31%) of the 133 patients during the study period. The indexed minimum aortic cross-sectional area was the strongest predictor of subsequent intervention (area under the receiver operating characteristic curve 0.975) followed by heart rate-corrected deceleration time in the descending aorta (area under the receiver operating characteristic curve 0.951), and the percentage of flow increase (area under the receiver operating characteristic curve 0.867). The combination of the indexed minimum aortic cross-sectional area and rate-corrected deceleration time in the descending aorta provided the best predictive model (area under the receiver operating characteristic curve 0.986). In conclusion, CMR findings can predict the need for subsequent intervention in CoA. These findings reinforce the "gate keeper role" of CMR to cardiac catheterization by providing valuable diagnostic and powerful prognostic information and could guide additional treatment of patients with CoA with the final intent of reducing the number of diagnostic catheterizations in such patients. PMID- 22196786 TI - Usefulness of B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide as biomarkers for heart failure in young children with single ventricle congenital heart disease. AB - Children with single ventricle (SV) physiology have increased ventricular work and are at risk of heart failure (HF). However, a HF diagnosis is especially difficult, because few objective measures of HF have been validated in this cohort. We have previously shown that plasma B-type natriuretic peptide (BNP) levels are sensitive and specific for detecting HF in a small, heterogeneous SV cohort. The aim of the present study was to define the effect of SV morphology and stage of palliation on the correlation between BNP and HF. We also examined the utility of N-terminal pro-BNP (NT-proBNP), a more stable product of pre-BNP processing, as a biomarker of HF in these patients. A cross-sectional observational study of SV children aged 1 month to 7 years was conducted. The presence of HF was defined as a Ross score > 2. The association of BNP or NT proBNP with HF was assessed using logistic regression analysis and receiver operating characteristic curves. Of the 71 included children, 22 (31%) had clinical HF. A doubling of BNP was associated with an odds ratio for HF of 2.20 (95% confidence interval 1.36 to 3.55, p = 0.001) with a c-statistic > 75%, yielding a detection threshold of >= 45 pg/ml. This threshold was preserved when patients were stratified by the right ventricular morphology or stage of surgical palliation. Similarly, a doubling of NT-proBNP was associated with an odds ratio for HF of 1.92 (95% confidence interval 1.17 to 3.14, p = 0.009). In contrast to BNP, the threshold value of NT-proBNP for predicting HF decreased with the stage of palliation. In conclusion, plasma BNP and NT-proBNP are reliable tests for clinical HF in young children with SV physiology, specifically those with right ventricular morphology, regardless of the stage of palliation. PMID- 22196787 TI - Meta-analysis of ten trials on the effectiveness of the radial versus the femoral approach in primary percutaneous coronary intervention. AB - The radial approach in primary percutaneous coronary intervention (PCI) has been recently assessed in both randomized and observational studies. However, observational studies have several biases that favor the radial approach. We conducted a meta-analysis of randomized controlled trials to compare the clinical outcomes of radial and femoral approach in primary PCI for ST-segment elevation myocardial infarction. The outcomes of interest included death, major bleeding, vascular complications/hematoma, and procedure time. The data were pooled using random-effects models. Ten randomized controlled trials involving 3,347 patients met our inclusion criteria. The radial approach was associated with improved survival (odds ratio 0.53, 95% confidence interval 0.33-0.84) and reduced vascular complications/hematoma (odds ratio 0.35, 95% confidence interval 0.24 0.53). A nonsignificant trend was found toward reduced major bleeding with the radial approach (odds ratio 0.63, 95% confidence interval 0.35-1.12). The procedural time with the radial approach was longer by < 2 minutes (mean difference 1.76 minutes, 95% confidence interval 0.59-2.92). In conclusion, in patients undergoing primary PCI, the radial approach is associated with lower short-term mortality. When feasible, the radial approach should be the favored route in primary PCI. PMID- 22196788 TI - Relation of coronary artery calcium to cardiovascular risk in patients with combined diabetes mellitus and systemic hypertension. AB - Certain patients with type 2 diabetes mellitus (DM) do not have increased cardiovascular (CV) risk. The aim of the present study was to stratify hypertensive adults with DM into those with low or high CV risk according to the absence or presence of coronary artery calcium (CAC). The study group included 423 patients, a subgroup of the 544 participants in the calcification side arm of the International Nifedipine Study: Intervention as Goal for Hypertension Therapy. All underwent a baseline computed tomography scan with an unenhanced dual-detector spiral computed tomography scan for CAC measurements. All were free of CV disease and completed 3 years (short-term) of follow-up. A total of 268 patients were included in the 15-year (long-term) follow-up period. The study group was divided into 4 subgroups according to the presence or absence of DM and CAC and was analyzed for a first CV event. Of the 423 patients, 164 (39%) had DM. Cardiovascular events occurred in 41 patients during the first 3 years and in 111 of 268 patients during the long-term follow-up. The rate of CV events was greater in the patients with DM with CAC than in those without (15% vs 7% after 3 years and 52% vs 32% after 15 years). Compared to those without DM without CAC, the short-term adjusted hazard ratio for CV event in those with DM with and without CAC was 6.6 (95% confidence interval 1.4 to 30.5) and 3.9 (95% confidence interval 0.7 to 22.6), respectively. A similar trend was seen in the long-term follow-up study. In conclusion, patients with hypertension and DM can be stratified into a lower CV risk in the absence of CAC. PMID- 22196789 TI - Sex differences in management and mortality of patients with ST-elevation myocardial infarction (from the Korean Acute Myocardial Infarction National Registry). AB - There has been controversy over the disparity between men and women with regard to the management and prognosis of acute myocardial infarction. Analyzing nationwide multicenter prospective registries in Korea, the aim of this study was to determine whether female gender independently imposes a risk for mortality. Data from 14,253 patients who were hospitalized for ST-segment elevation myocardial infarction from November 2005 to September 2010 were extracted from registries. Compared to men, women were older (mean age 56 +/- 12 vs 67 +/- 10 years, p < 0.001), and female gender was associated with a higher frequency of co morbidities, including hypertension, diabetes, and dyslipidemia. Women had longer pain-to-door time and more severe hemodynamic status than men. All-cause mortality rates were 13.6% in women and 7.0% in men at 1 year after the index admission (hazard ratio for women 2.01, 95% confidence interval 1.80 to 2.25, p < 0.001). The risk for death after ST-segment elevation myocardial infarction corresponded highly with age. Although the risk remained high after adjusting for age, further analyses adjusting for medical history, clinical performance, and hemodynamic status diminished the gender effect (hazard ratio 1.00, 95% confidence interval 0.86 to 1.17, p = 0.821). Propensity score matching, as a sensitivity analysis, corroborated the results. In conclusion, this study shows that women have a comparable risk for death after ST-segment elevation myocardial infarction as men. The gender effect was accounted for mostly by the women's older age, complex co-morbidities, and severe hemodynamic conditions at presentation. PMID- 22196792 TI - p-Terphenyl and diterpenoid metabolites from endophytic Aspergillus sp. YXf3. AB - Six new p-terphenyl derivatives, named 4"-deoxy-3-hydroxyterphenyllin (1), 4" deoxy-5'-desmethyl-terphenyllin (2), 5'-desmethylterphenyllin (3), 4" deoxycandidusin A (4), 4,5-dimethoxycandidusin A (5), and terphenolide (6), four new diterpenoids with norcleistanthane (aspergiloid A (12) and aspergiloid B (13)), cleistanthane (aspergiloid C (14)), and isopimarane (aspergiloid D (15)) type skeletons, and five known p-terphenyl compounds (7-11) were isolated from the fermentation broth of the plant endophytic fungus Aspergillus sp. Their structures were elucidated on the basis of detailed spectroscopic analysis and by comparison of their NMR data with those reported in the literature. Compounds 4, 6, 7, and 9 displayed moderate neuraminidase inhibitory activity with IC(50) values ranging from 4.34 to 9.17 MUM. PMID- 22196793 TI - Multiple branchial cleft anomalies in conjunction with a congenital dermal fistula of the lower extremity: first report of the Guarisco-Winters syndrome. AB - Branchial cleft anomalies are congenital remnants of the embryologic branchial clefts persisting past the embryo stage. Most occur singly and sporadically, though syndromic associations are described. Multiple branchial cleft anomalies coincident in the same patient are exceptionally rare, and rarer still are peripheral dermal sinus tracts on the extremities, with one prior documented case. We report the first case of multiple branchial cleft anomalies with a peripheral dermal sinus of the ipsilateral lower extremity. Numerous concurrent congenital anomalies exist in the patient, representing the first description of the Guarisco-Winters syndrome. The patient is intellectually and developmentally age-appropriate in all other regards. PMID- 22196795 TI - Treatment of Epstein-Barr virus-associated gastric carcinoma with endoscopic submucosal dissection. PMID- 22196794 TI - Novel rat model of tympanostomy tube otorrhea. AB - OBJECTIVE: Tympanostomy tube otorrhea (TTO), caused by the presence of pathogenic bacteria in the middle ear, is the most common complication of TT insertion. No studies have described a reproducible animal model of TTO. We aimed to develop a rat model of TTO which, in turn, could be used to assay the levels of TNF-alpha and IL-1beta through the course of the infection. METHODS: The left Eustachian tubes of 55 male Sprague-Dawley albino rats were occluded with gutta-percha (ETO=Eustachian Tube Occlusion). Middle ear (ME) effusion was ascertained by weekly otomicroscopy. At 3 weeks tympanostomy tubes were placed bilaterally and the MEs were inoculated bilaterally with Streptococcus pneumoniae through the tubes. The rats were randomly assigned to one of two daily ototopical treatments: ciprofloxacin/dexamethasone (CDX) or placebo. The animals in each of the two treatment groups were further divided to receive 1, 2, 5 or 7 days of treatment. The rats were sacrificed after treatment was finished. The rates of otorrhea, positive middle ear (ME) cultures, and levels of TNF-alpha and IL-1beta in the ME fluid were measured. RESULTS: Left ETO followed by ME inoculation with S. pneumoniae and treatment with placebo resulted in persistent infection (100% culture-positive ME fluid at 10 days) and otorrhea (85.7%). Persistent infection of the left ear was accompanied by significantly elevated the levels of IL-1beta and TNF-alpha. Ears treated with CDX had lower rates of otorrhea at all time points and lower levels of IL-1beta and TNF-alpha. CONCLUSIONS: This study is the first to describe a reproducible animal model of acute TTO. Surgical obstruction of the ET, followed by TT placement and ME inoculation with S. pneumoniae induced persistent otorrhea and infection. Both IL-1beta and TNF-alpha appear to be potential markers of persistent middle ear infection. This novel model may be used in future studies of the pathogenesis and therapy of TTO. PMID- 22196796 TI - Adaptive radiotherapy using helical tomotherapy for head and neck cancer in definitive and postoperative settings: initial results. AB - AIMS: To assess whether routine mid-treatment replanning in head and neck squamous cell carcinoma patients results in meaningful improvements in target or normal tissue dosimetry and to assess which patients derive the greatest benefit. MATERIALS AND METHODS: Twenty patients treated with either postoperative chemoradiotherapy or definitive chemoradiotherapy with primary or nodal disease >=3cm in size were included in this prospective pilot study. Seven patients received adjuvant chemoradiotherapy and 13 received definitive chemoradiotherapy. Patients were planned and treated on a helical tomotherapy system. All patients had a second computed tomography scan after 15 fractions and a new plan based on this was initiated from fraction 20. RESULTS: Relative volume changes between computed tomography scans were: GTV 29%; CTV60 (adjuvant patients) 4%; parotid volume 17.5%; median reduction in neck separation 6-7 mm; weight loss 3%. For the group overall and for the definitively treated patient cohort, respectively, adapted plans resulted in reductions in PTV66 D(1) (0.3Gy, P=0.01 and 0.5Gy, P=0.01); PTV54 D(1) (0.6Gy, P<0.0001 and 0.9Gy, P=0.0002); spinal cord maximum (0.5Gy, P=0.004 and 0.6Gy, P=0.04) and volume of skin receiving >=50Gy (16 cm(2), P=0.01 and 19 cm(2), P=0.001). Definitively treated patients also had a reduction in mean parotid dose (0.6Gy, P=0.046) and volume of normal tissue receiving >=50Gy (67 cm(3), P=0.02). Patients with nasopharyngeal carcinoma received the greatest benefits with treatment adaptation with reduction in spinal cord maximum 1.2Gy, mean parotid dose 1.2Gy and parotid V(26) 6.3%. There was no significant benefit for adjuvant patients. Other factors associated with greater benefits were greater weight loss and greater reduction in neck separation and higher T stage. CONCLUSIONS: There is minimal benefit to routine adaptive replanning in unselected patients, and no benefit in adjuvantly treated patients. Patients with nasopharyngeal carcinoma or with greater weight loss or reduction in neck separation did have clinically significant benefits. These patients should be targeted for adaptive strategies. PMID- 22196797 TI - Study on the interaction between methyl jasmonate and the coiled-coil domain of rice blast resistance protein Pi36 by spectroscopic methods. AB - Interaction between the coiled-coil domain of rice blast resistance protein Pi36 and methyl-jasmonate (MeJA) was studied by fluorescence and UV-vis spectroscopic techniques. The quenching mechanism of fluorescence of MeJA by this domain was discussed to be a static quenching procedure. Fluorescence quenching was explored to measure the number of binding sites n and apparent binding constants K. The thermodynamics parameters DeltaH, DeltaG, DeltaS were also calculated. The results indicate the binding reaction was not entropy-driven but enthalpy-driven, and hydrophobic binding played major role in the interaction. The binding sites of MeJA with the coiled-coil structural domain of rice blast resistance protein Pi36 were found to approach the microenvironment of both Tyr and Trp by the synchronous fluorescence spectrometry. The distance r between donor (the coiled coil domain of rice blast resistance protein Pi36) and acceptor (MeJA) was obtained according to Forster theory of non-radioactive energy transfer. PMID- 22196798 TI - A new Schiff base based on vanillin and naphthalimide as a fluorescent probe for Ag+ in aqueous solution. AB - A new Schiff base based on vanillin and naphthalimide was designed and synthesized as fluorescent probe. The probe showed high selectivity for Ag(+) over other metal ions such as Pb(2+), Na(+), K(+), Cd(2+), Ba(2+), Cr(3+), Zn(2+), Cu(2+), Ni(2+), Ca(2+), Al(3+) and Mg(2+) in aqueous solution. A new fluorescence emission was observed at 682 nm in the presence of Ag(+) ion. The fluorescence intensity quenched with increasing the concentration of Ag(+) at 682 nm. The method of job's plot confirmed the 1:2 complex between Ag(+) and probe, and the mechanism was proposed. PMID- 22196799 TI - The relationship of host nutritional status to immune function. PMID- 22196800 TI - Functional complementation of dwf4 mutants of Arabidopsis by overexpression of CYP724A1. AB - An essential step in the biosynthesis of bioactive brassinosteroids (BRs) in plants is the hydroxylation at C-22, a reaction catalyzed by P450 enzymes of the CYP90B and CYP724B subfamilies. Genes for both types of enzymes are present in many species, and in rice (Oryza sativa) and tomato (Solanum lycopersicum) both CYP90B and CYP724B enzymes contribute to C-22 hydroxylation. In Arabidopsis (Arabidopsis thaliana), C-22 hydroxylation of BRs is catalyzed by CYP90B1 (encoded by DWF4) and null dwf4 mutants show severe symptoms of BR-deficiency. CYP724A1 (At5g14400), an Arabidopsis gene of unknown function and limited expression, encodes a P450 sharing less than 55% sequence identity to CYP724B proteins. We used transgenic plants of the null mutants dwf4-102 and a novel allele, bashful (bsf), ectopically expressing the CYP724A1 gene to investigate the potential activity of CYP724A1 as a C-22 hydroxylase of BRs. Defects associated with BR deficiency were reversed and a normal growth habit restored in transgenic dwf4-102 and bsf plants overexpressing CYP724A1. The vegetative phase was prolonged and the transgenic plants were on average larger than wild type plants with respect to several morphometric parameters. Fertility was restored in the transgenic plants but individual siliques yielded fewer and heavier seeds than those of wild type plants. The implications of these findings with regard to the functions of CYP724A1 and the activity of its encoded enzyme are discussed. PMID- 22196801 TI - Pharmacokinetics and brain dispositions of tacrine and its major bioactive monohydroxylated metabolites in rats. AB - The current study aims to investigate the pharmacokinetics and brain disposition of tacrine and its three major bioactive monohydroxylated metabolites (1 hydroxytacrine, 2-hydroxytacrine and 4-hydroxytacrine). An assay for simultaneous quantification of tacrine and three above metabolites in rat plasma and brain tissue was developed. Four analytes together with internal standard were extracted from rat plasma or brain tissue homogenate by liquid-liquid extraction using ethyl acetate. Baseline separation of the four studied compounds was achieved by a Thermo Hypersil BDS C(18) column with gradient elution using acetonitrile and ammonium formate-triethylamine (pH 4.0) under fluorescence detection. Extraction recoveries of all analytes ranged from 82.1% to 93.2% in both rat plasma and brain tissue. The intra- and inter-day precision and accuracy of each analyte at lower limit of quantification (LLOQ) and three quality control (QC) concentrations (low, middle and high) was within 12% RSD and within 11% bias in both biological matrices. The LLOQ for tacrine, 1-hydroxytacrine, 2 hydroxytacrine and 4-hydroxytacrine were found to be 2.5, 6.7, 2.1 and 2.1 ng/ml in plasma, and 12.3, 33.5, 10.6 and 10.5 ng/g in brain tissue, respectively. All four analytes were stable during analysis. The developed method provides a simple, sensitive and reproducible procedure for pharmacokinetics and brain disposition study of tacrine and its three major metabolites in rats after oral administration of tacrine. Pharmacokinetic study demonstrated that tacrine could be quickly absorbed and extensively metabolized to its monohydroxylated metabolites in vivo. In addition, rat brain disposition study showed that tacrine and its monohydroxylated metabolites were evenly distributed in different brain regions except for a slight lower concentration of tacrine in olfactory region. Moreover, tacrine and 4-hydroxytacrine exhibited a much higher brain-to-plasma ratio than that of 1-hydroxytacrine and 2-hydroxytacrine. PMID- 22196802 TI - Simultaneous determination of tetrandrine and fangchinoline in herbal medicine Stephania tetrandra S. Moore by liquid chromatography with electrochemical detection. AB - A simple and selective method was developed for the simultaneous determination of tetrandrine and fangchinoline in herbal medicine by HPLC with electrochemical detection (ECD) on a bare glassy carbon electrode. The HPLC separation and ECD conditions have been optimized. The separation was carried out on a WondaSil C18 WR column (4.6 mm * 250 mm, 5 MUm), with the mobile phase of acetonitrile ammonium acetate buffer (pH 6.5; 40 mM) (32:68, v/v) using an isocratic elution at the flow rate of 0.5 mL/min. The electrochemical detection potential was set at +0.9 V. The obtained LODs for tetrandrine and fangchinoline were 0.26 and 0.27 MUmol/L, respectively. The method was successfully applied to the analysis of tetrandrine and fangchinoline contents in Stephania tetrandra S. Moore. It has been demonstrated that the LC-ECD method is an excellent technique for analysis of the herbal medicine. The mean recoveries were in the range of 95-105%, while the precision expressed as repetition of peak area was lower than 2.7%. PMID- 22196803 TI - Determination of cinacalcet hydrochloride in human plasma by liquid chromatography-tandem mass spectrometry. AB - A sensitive and selective high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed to determine the cinacalcet hydrochloride in human plasma. The analyte was extracted from plasma samples using a 96-well plate automatic solid-phase extraction (SPE) device and chromatographed on an Inertsil SIL-150 (2.1 mm * 50 mm, i.d. 5 MUm) column using acetonitrile-water-formic acid (90:10:1) as the mobile phase with an isocratic flow rate of 0.35 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode using positive electrospray ionization (ESI). The method was validated over the concentration range of 0.1-25 ng/mL. The indicators of inter- and intra-day precision (RSD%) were all within 15.1%, and the accuracy (RE%) was within +/- 15%. The lower limit of quantitation (LLOQ) was 0.1 ng/mL. The average extraction recovery was 51.7%, and the detection was not affected by the matrix. The method was successfully applied to a pharmacokinetic study of cinacalcet hydrochloride in healthy Chinese volunteers. PMID- 22196804 TI - Determination of alamifovir disoproxil fumarate and its active metabolite 602076 in rat plasma by LC-MS/MS: application to a pharmacokinetic study. AB - Alamifovir disoproxil fumarate (ADF) is a novel ester prodrug of alamifovir, which is currently as a promising antiviral candidate under investigation. This paper is aimed to develop rapid, sensitive and specific LC-MS/MS methods for the quantification of ADF and its active metabolite 602076 in rat plasma. According to the significantly different chemical properties of the compounds, two sets of liquid chromatography and ionization modes were used for determining the concentration of ADF and 602076 in rat plasma, separately. Following liquid liquid extraction with n-hexane:dichloromethane:isopropanol (100:50:5, v/v/v), the ADF and internal standard (gliclazide) were separated on a Phenomenex Gemini C(18) column (150 mm * 2.0 mm, 5 MUm) with a mobile phase consisting of methanol:water:formic acid (70:30:0.1, v/v/v). A tandem mass spectrometer equipped with electrospray ionization (ESI) source was used as the detector and operated in positive ion mode. The metabolite 602076 and the internal standard ZHY81018 were extracted from plasma by protein precipitation with acetonitrile. Chromatographic separation was performed on a Capcell MG C(18) column (150 mm * 2.0 mm, 5 MUm) with a mobile phase consisting of acetonitrile and water (20:80, v/v). The MS/MS detection was operated in negative ion mode using an ESI source. The linear concentration ranges of the calibration curves were 2.5-500 ng/mL for ADF and 2.5-1000 ng/mL for 602076. The intra-assay RSD for quality control (QC) samples were from 3.3% to 6.7% for ADF, and 4.0% to 6.1% for 602076. The inter assay RSD for QC samples were from 4.9% to 14.7% for ADF, and 2.6% to 4.4% for 602076. The relative errors for QC samples were from -10.6% to 1.9% for ADF, and 0.2% to 2.6% for 602076. The methods were successfully applied in the investigation of the pharmacokinetic profile of ADF, alamifovir and 602076 in rats. The results showed that ADF was rapidly metabolized to its active metabolite 602076 after oral absorption, with no detectable unchanged drug. The oral bioavailability of ADF was about 3 times higher than that of alamifovir. PMID- 22196805 TI - Growth condition study of algae function in ecosystem for CO2 bio-fixation. AB - Algae niche play a crucial role on carbon cycle and have great potential for CO(2) sequestration. This study was to investigate the CO(2) bio-fixation by the high rate pond (HRP) to mimic the algae function of nature. All the reactors can keep CO(2) consumption efficiencies over 100%. The statistical analyses proved HRPs were close to the natural system from all the growth conditions. The HRP could show the "natural optimization as nature" to perform as well as the artificial reactor of continuously stirred tank reactor (CSTR). In the nutrition study, the carbon mass balance indicated CO(2) was the main carbon source. Accordingly, the HRPs can keep a neutral pH range to provide dissolved oxygen (DO), to promote total nitrogen (TN)/total phosphorous (TP) removal efficiencies and to demonstrate self-purification process. Furthermore, the observations of different nitrogen species in the reactors demonstrated that the major nitrogen source was decided by pH. This finding logically explained the complex nitrogen uptake by algae in nature. Consequently, this study took advantage of HRP to explore the processes of efficient CO(2) uptake with the corresponding growth condition in the ecosystem. Those results contributed the further understanding of the role of CO(2) bio-fixation in nature and demonstrated HRP could be a potential ecological engineering alternative. PMID- 22196807 TI - Prospective, randomized comparison of 3 different hemoclips for the treatment of acute upper GI hemorrhage in an established experimental setting. AB - BACKGROUND: Recently, endoscopic clip application devices have undergone redesign and improvements to optimize their clinical use and effectiveness. Initially designed for the treatment of bleeding nonvariceal lesions, these devices are also increasingly used for the closure of perforations, fistulas, and anastomotic leaks. Several clinical studies, both randomized and nonrandomized, have used endoscopic hemoclips for hemostasis. However, no comparative studies have yet been reported in the literature comparing the latest endoscopic clip devices for usability and effectiveness for hemostasis of acute upper GI hemorrhage. OBJECTIVE: We aimed to compare the usability and efficacy of 3 different types of endoscopic clip application devices in an established experimental setting by using a porcine ex-vivo simulator of upper GI hemorrhage. DESIGN: Randomized, controlled, ex-vivo study. SETTING: Academic medical center. METHODS: Spurting vessels were created within ex-vivo porcine stomachs as published in prior studies. The vessels were attached to a pressure transducer to record the pressure of the circulating blood replacement. Before the initiation of bleeding, each vessel was randomized to 1 of 3 endoscopic clipping devices: 2 different commonly used hemoclips deployed through the working channel and 1 novel clip deployed via an over-the-scope applications device. Two investigators treated 45 bleeding sites (15 bleeding sites for each device at various randomized locations in the stomach: fundus, body, and antrum). MAIN OUTCOME MEASUREMENTS: Usability was measured via the endpoints of procedure time and quantity of clips required to achieve hemostasis. Efficacy was measured via the endpoint of pressure increase (Deltap) from baseline to after treatment. RESULTS: All of the 45 hemostasis treatments were carried out successfully. The mean procedure times were significantly different among the hemoclips, with the clip deployed in an over-the-scope fashion requiring significantly less time to attain hemostasis compared with the other 2 clips. For number of clips needed to attain hemostasis, the clip deployed in an over-the-scope fashion was significantly superior to the others. There were also significant differences among the changes in pressure (Deltap +/- SD) among the different hemoclips tested. LIMITATIONS: Ex-vivo study. CONCLUSIONS: In this prospective, randomized ex-vivo study, we observed significant differences in the usability (time to achieve hemostasis and number of clips required) and the efficacy (change in pressure achieved by the hemoclips) among the 3 clips. The clip applied in the over-the-scope fashion was superior to the other 2 tested clips with regard to time to achieve hemostasis and number of clips required. PMID- 22196808 TI - Much ado about very little (lamina propria)? PMID- 22196809 TI - Deeper and deeper into the pediatric small bowel. PMID- 22196810 TI - Quality benchmarking for colonoscopy: how do we pick products from the shelf? PMID- 22196811 TI - Randomized, controlled trial of standard, large-capacity versus jumbo biopsy forceps for polypectomy of small, sessile, colorectal polyps. AB - BACKGROUND: Polypectomy with cold biopsy forceps is a frequently used technique for removal of small, sessile, colorectal polyps. Jumbo forceps may lead to more effective polypectomy because of the larger size of the forceps cup. OBJECTIVE: To evaluate the efficiency of cold jumbo biopsy forceps compared with standard forceps for polypectomy of small, sessile, colorectal polyps. DESIGN: Randomized, controlled trial. SETTING: Outpatient endoscopy center. PATIENTS: This study involved 140 patients found to have at least one eligible polyp defined as a sessile polyp measuring <=6 mm. INTERVENTION: Polypectomy with cold biopsy forceps. MAIN OUTCOME MEASUREMENTS: Complete visual polyp eradication with one forceps bite. RESULTS: In 140 patients, a total of 305 eligible polyps were detected (151 removed with jumbo forceps and 154 with standard forceps). Complete visual eradication of the polyp with one forceps bite was achieved in 78.8% of the jumbo forceps group and 50.7% of the standard forceps group (P < .0001). Biopsies from the polypectomy sites of adenomatous polyps thought to be visually completely eradicated with one bite showed a trend toward a higher complete histologic eradication rate with the jumbo forceps (82.4%) compared with the standard forceps (77.4%), but the difference did not reach statistical significance (P = .62). The withdrawal time for visual inspection of the colon and time to perform polypectomies were significantly shorter in the jumbo forceps group (mean 21.43 vs 18.23 minutes; P = .02). LIMITATIONS: Lack of blinding to the type of forceps used. CONCLUSION: The jumbo biopsy forceps is superior to the standard forceps in removing small, sessile polyps. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00855790.). PMID- 22196812 TI - Looking over your shoulder during colonoscopy: potential roles for videorecording colonoscopy withdrawals. PMID- 22196813 TI - A primer on endoscopic movie production (with videos). PMID- 22196814 TI - Endoscopic full-thickness GI wall resection: current status. PMID- 22196815 TI - Technical feasibility and safety of a new, implantable reflux control system to prevent gastroesophageal reflux in patients with stents placed through the lower esophageal sphincter (with video). AB - BACKGROUND: When an esophageal stent is placed through the lower esophageal sphincter (LES), gastroesophageal reflux symptoms may persist despite high-dose proton pump inhibitor therapy. A recently developed, short segment, uncovered nitinol stent with a tricuspid-like valve can be placed inside a previously placed esophageal stent. OBJECTIVE: To evaluate the technical feasibility and safety of a reflux control system (RCS) in distally placed esophageal stents. DESIGN: A prospective case series. SETTING: Two tertiary-care referral centers. PATIENTS: This study involved 10 patients who had an "open" stent placed through the LES and 1 patient with severe bile reflux after esophagojejunostomy. INTERVENTION: Placement of an RCS with fluoroscopic and (in selected cases) endoscopic guidance, from April to October 2010. MAIN OUTCOME MEASUREMENTS: Technical success of RCS placement and complications. RESULTS: Placement of an RCS was successful on the first attempt in all patients; complete expansion to the wall of the host stent was confirmed by fluoroscopy in all cases. In 3 patients, the host stent migrated in <1 month with the RCS still inside. In 8 patients, the RCS was in place for a median of 134 days (range 33-225 days). Three patients died because of malignant disease progression. Eight RCSs were removed endoscopically, together with the host stent without complications. RCS migration did not occur. LIMITATIONS: Small number of patients, nonrandomized design, lack of pH measurements. CONCLUSION: Placement of an RCS in a host stent is technically feasible and safe. An RCS can be considered in symptomatic patients with open esophageal stents to prevent gastroesophageal reflux. PMID- 22196817 TI - Extensive intramural esophageal dissection: an unusual endoscopic complication. PMID- 22196816 TI - Computer-aided system for predicting the histology of colorectal tumors by using narrow-band imaging magnifying colonoscopy (with video). AB - BACKGROUND: Narrow-band imaging (NBI) classification of colorectal lesions is clinically useful in determining treatment options for colorectal tumors. There is a learning curve, however. Accurate NBI-based diagnosis requires training and experience. In addition, objective diagnosis is necessary. Thus, we developed a computerized system to automatically classify NBI magnifying colonoscopic images. OBJECTIVE: To evaluate the utility and limitations of our automated NBI classification system. DESIGN: Retrospective study. SETTING: Department of endoscopy, university hospital. MAIN OUTCOME MEASUREMENTS: Performance of our computer-based system for classification of NBI magnifying colonoscopy images in comparison to classification by two experienced endoscopists and to histologic findings. RESULTS: For the 371 colorectal lesions depicted on validation images, the computer-aided classification system yielded a detection accuracy of 97.8% (363/371); sensitivity and specificity of types B-C3 lesions for a diagnosis of neoplastic lesion were 97.8% (317/324) and 97.9% (46/47), respectively. Diagnostic concordance between the computer-aided classification system and the two experienced endoscopists was 98.7% (366/371), with no significant difference between methods. LIMITATIONS: Retrospective, single-center in this initial report. CONCLUSION: Our new computer-aided system is reliable for predicting the histology of colorectal tumors by using NBI magnifying colonoscopy. PMID- 22196818 TI - Hidden treasure-esophageal diverticulum retained "foreign" bodies. PMID- 22196819 TI - A quarter causing intermittent gastric outlet obstruction. PMID- 22196820 TI - Hepatic artery aneurysm: a rare presentation as cholangitis and portal hypertension. PMID- 22196821 TI - Ascaris lumbricoides-induced acute pancreatitis. PMID- 22196822 TI - Percutaneous versus endoscopic approach in treatment of acute cholecystitis. PMID- 22196824 TI - EUS-guided double cystgastrostomy of two infected pseudocysts in series: a novel case of endoscopic cystocystgastrostomy. PMID- 22196825 TI - Albumin and C-reactive protein levels predict short-term mortality, which may not be associated with PEG. PMID- 22196827 TI - Improving the quality of colonoscopy. PMID- 22196829 TI - Natural population die-offs: causes and consequences for terrestrial mammals. AB - Extreme changes in the environment can generate high mortalities in wildlife populations. When these mortalities are attributable to extreme natural events, they are referred to as natural population die-offs. Despite growing reports of such die-offs, a consensus on how to define them has not emerged. Furthermore, although anthropogenically caused extreme events are predicted to occur at a higher frequency and intensity compared with natural events, an integrative synthesis assessing their significance for wildlife population viability is lacking. These issues hamper the ability to identify populations most at risk. Here, we propose a functional definition of natural population die-offs, an assessment of extrinsic and intrinsic processes shaping these die-offs, and a framework for assessing the vulnerability of terrestrial mammals to natural and anthropogenically caused extreme events. PMID- 22196830 TI - Maximising canine welfare in veterinary practice and research: a review. AB - This article looks at the existing evidence-base by which veterinary surgeons can make welfare-focused treatment choices. Narrative and structured reviews were conducted. Papers were categorised under headings based on (1) themes in the UK Animal Welfare Act (AWA 2006) - behaviour, environment, nutrition, company and health; (2) iatrogenic harm induced by treatment; (3) decision-making methods, and (4) the subjects' context (e.g. home versus laboratory). There is more information available about 'overt' problems (e.g. acute disease), than 'covert' issues (e.g. chronic pain, lack of company and obesity). Forty of 109 papers covered pain, suffering, injury and disease, compared to 69 across four other themes in the AWA. Twelve papers were identified as focusing on welfare assessment and clinical decision-making. Veterinary surgeons should consider each of the five welfare themes described in the AWA in both veterinary practice and in determining veterinary research priorities. PMID- 22196831 TI - Recurrent aspiration and upper lobe cavitation. PMID- 22196832 TI - Competitive binding between 4,4'-diphenylmethane-bis(methyl) carbamate and RAGE ligand MG-H1 on human umbilical vein endothelial cell by cell membrane chromatography. AB - The compound 4,4'-diphenylmethane-bis(methyl) carbamate (CM1) has a protective activity on AGEs-induced endothelial dysfunction on human umbilical vein endothelial cell (HUVEC) in our previous study. It suggested that CM1 which may act as a competitive antagonist to the blockade of AGEs to receptor of AGEs (RAGE) and attenuate the HUVEC damage. In order to testify that hypothesis, the cell membrane chromatography (CMC) combined with high performance liquid chromatography (HPLC) was developed for analyzing the competitive binding properties on RAGE of HUVEC between CM1 and MG-H1, the agonist of RAGE. The results from saturation binding of CM1 and MG-H1 on cells demonstrated that dissociation equilibrium constants (K(d)) of CM1 and MG-H1 were 3.653 nM and 4.12 nM, respectively; while maximum binding capacity (B(max)) of CM1 and MG-H1 were 30.08 and 18.72 fmol/mg protein, respectively. In competition experiments, IC50 of CM1 with pre-incubation 10-10 M and 10-9 M MG-H1 were 1.37 * 10-9 M and 4.56 * 10-8 M, respectively. The present findings indicated that CM1 conjugated competitively to cells with RAGE ligand MG-H1. The primary study illustrated that CMC combined with HPLC analysis method could be an alternative, rapid and efficient approach for the interaction of drug molecule and receptor, and that CM1 intervene the AGEs inducing HUVEC damage may via the competitively block the AGEs-RAGE path way. PMID- 22196833 TI - Metabolism of mequindox and its metabolites identification in chickens using LC LTQ-Orbitrap mass spectrometry. AB - Mequindox (MEQ), 3-methyl-2-quinoxalinacetyl-1,4-dioxide, is widely used in Chinese veterinary medicine as an antimicrobial and feed additive. Its toxicities have been reported to be closely related to its metabolism. To understand more clearly the metabolic pathways of MEQ, its metabolism in chickens was studied using liquid chromatography coupled with electrospray ionization hybrid linear trap quadrupole orbitrap (LC-LTQ-Orbitrap) mass spectrometry. The structures of the MEQ metabolites and their product ions were easily and reliably characterized based on the accurate MS-squared spectra and known structure of MEQ. Twenty-four metabolites were detected in chicken plasma, bile, faeces, and tissues, of which 12 were detected in vivo for the first time. The major metabolic pathways reported previously for in vitro metabolism of MEQ in chicken microsomes were confirmed in this study, including N->O group reduction, carbonyl reduction, and methyl mono-hydroxylation. In addition, deacetylation and acetyl-hydroxylation of MEQ were shown to be important metabolic pathways. Collectively, these data contribute to our understanding of the in vivo metabolism of MEQ. PMID- 22196834 TI - Profiling and characterization of volatile secretions from the European stink bug Graphosoma lineatum (Heteroptera: Pentatomidae) by two-dimensional gas chromatography/time-of-flight mass spectrometry. AB - An efficient method combining the headspace solid-phase microextraction (HS-SPME) sampling procedure and comprehensive two-dimensional gas-chromatography/time-of flight mass spectrometry (GC*GC/TOF-MS) was established to study the volatile secretion components of stink bugs (Heteroptera: Pentatomidae). The combined power of this approach is illustrated by the identification of fifty-seven compounds in the secretion of a European stink-bug representative, Graphosoma lineatum. (E)-4-oxohex-2-enal and (E)-dec-2-enal were found to be the major components in the adult bug secretions followed by lower amounts of n-alkenal (C5 C12), n-alkenyl acetate (C5-C11), n-alkane (C11-C17) homologs, dienals and other compounds. More than thirty known compounds have been identified that had not been described before in G. lineatum adults. Of these compounds, (E)-4-oxohex-2 enal is of particular interest, since its isolation and identification, while calling some previous reports into question, clearly demonstrates a potential ability of our approach to yield artifact-free secretion profiles. PMID- 22196835 TI - Effect of a medication-taking behavior feedback theory-based intervention on outcomes in patients with heart failure. AB - BACKGROUND: Medication nonadherence contributes to hospitalization and mortality, yet there have been few interventions tested that improve adherence and reduce hospitalization and mortality in heart failure (HF). Our objective was to determine whether an education intervention improved medication adherence and cardiac event-free survival. METHODS AND RESULTS: A randomized controlled trial was conducted on 82 HF patients. The intervention was based on the theory of planned behavior (TPB) and included feedback of medication-taking behavior using the Medication Event Monitoring System (MEMS). Patients were assigned to one of three groups: 1) theory-based education plus MEMS feedback; 2) theory-based education only; or 3) usual care (control). Cardiac events were collected for 9 months. Patients in both intervention groups were more adherent over follow-up compared with the control group. In Cox regression, patients in either intervention group had a longer event-free survival compared with those in the control group before and after controlling age, marital status, financial status, ejection fraction, New York Heart Association functional class, angiotensin converting enzyme inhibitor use, and presence or absence of a significant other during the intervention (P < .05). CONCLUSIONS: Use of an intervention based on the TPB improves medication adherence and outcomes in patients with HF and therefore offers promise as a clinically applicable intervention to help patients with HF to adhere to their prescribed regimen. PMID- 22196837 TI - Characteristics and outcomes of peripartum versus nonperipartum cardiomyopathy in women using a wearable cardiac defibrillator. AB - BACKGROUND: Peripartum cardiomyopathy (PPCM) mortality rates vary between 2% and 56%, with half occurring <=12 weeks'; postpartum. Although risk factors for PPCM have been identified, predicting sudden cardiac death among PPCM patients remains difficult. This study describes the characteristics and outcomes of PPCM patients and controls referred for a wearable cardioverter defibrillator (WCD). METHODS AND RESULTS: Deidentified WCD medical orders between 2003 and 2009 and death index searches were used to characterize women (ages 17-43) with PPCM (n = 107) or matched nonpregnant women with nonischemic dilated cardiomyopathy (NIDCM; n = 159). Demographics were similar. WCD use averaged 124 +/- 123 days and 96 +/- 83 days among PPCM and NIDCM patients, respectively. No PPCM patients received an appropriate shock for ventricular tachycardia/ventricular fibrillation; 1 NIDCM patient received 2 successful shocks. No PPCM patient died during WCD use versus 11 concurrent NIDCM deaths. After WCD use, 3 PPCM and 13 NIDCM patients died, respectively. CONCLUSIONS: The mortality rate of 2.8% (over 3.0 +/- 1.2 years) in PPCM patients is low compared to published data. The role of WCD therapy among PPCM patients deserves further study. PMID- 22196836 TI - Cognitive therapy improves three-month outcomes in hospitalized patients with heart failure. AB - BACKGROUND: Patients with heart failure (HF) experience depressive symptoms that contribute to poorer outcomes. We tested the effects of a brief cognitive therapy intervention on depressive symptoms, negative thinking, health-related quality of life, and cardiac event-free survival. METHODS AND RESULTS: Hospitalized patients with depressive symptoms (n = 41, 66 +/- 11 years, 45% female, 81% New York Heart Association Class III/IV) were randomly assigned to control group or a brief, nurse-delivered cognitive therapy intervention, delivered during hospitalization and followed by a 1-week booster phone call. Depressive symptoms, negative thinking, and health-related quality of life were measured at 1 week and 3 months. Cardiac event-free survival was assessed at 3 months. Mixed models repeated measures analysis of variance, Kaplan-Meier, and Cox regression were used for data analysis. There were significant improvements in depressive symptoms and health-related quality of life in both groups but no interactions between group and time. The control group had shorter 3-month cardiac event-free survival (40% versus 80%, P < .05) and a 3.5 greater hazard of experiencing a cardiac event (P = .04) than the intervention group. CONCLUSION: Nurses can deliver a brief intervention to hospitalized patients with heart failure that may improve short-term, event-free survival. Future research is needed to verify these results with a larger sample size. PMID- 22196838 TI - Myocardial recovery in peripartum cardiomyopathy: prospective comparison with recent onset cardiomyopathy in men and nonperipartum women. AB - BACKGROUND: Whether myocardial recovery occurs more frequently in peripartum cardiomyopathy (PPCM) than in recent onset cardiomyopathies in men and nonperipartum women has not been prospectively evaluated. This was examined through an analysis of outcomes in the Intervention in Myocarditis and Acute Cardiomyopathy 2 (IMAC2) registry. METHODS AND RESULTS: IMAC2 enrolled 373 subjects with recent onset nonischemic dilated cardiomyopathy. Left ventricular ejection fraction (LVEF) was assessed at entry and 6 months, and subjects followed for up to 4 years. Myocardial recovery was compared between men (group 1), nonperipartum women (group 2) and subjects with PPCM (group 3). The cohort included 230 subjects in group 1, 104 in group 2, and 39 in group 3. The mean LVEF at baseline in groups 1, 2, and 3 was 0.23 +/- 0.08, 0.24 +/- 0.08, and 0.27 +/- 0.07 (P = .04), and at 6 months was 0.39 +/- 0.12, 0.42 +/- 0.11, and 0.45 +/ 0.14 (P = .007). Subjects in group 3 had a much greater likelihood of achieving an LVEF >0.50 at 6 months than groups 1 or 2 (19 %, 34%, and 48% respectively, P = .002). CONCLUSIONS: Prospective evaluation confirms myocardial recovery is greatest in women with PPCM, poorest in men, and intermediate in nonperipartum women. On contemporary therapy, nearly half of women with PPCM normalize cardiac function by 6 months. PMID- 22196839 TI - Relationship between diastolic function and heart rate recovery after symptom limited exercise. AB - BACKGROUND: Autonomic abnormalities have been implicated in both diastolic dysfunction and abnormal heart rate (HR) recovery; however, few studies have assessed whether diastolic dysfunction is associated with abnormal HR recovery and whether both modify exercise capacity. METHODS AND RESULTS: Exercise echocardiography with diastolic assessment was performed in 2,826 patients with normal wall motion responses to symptom-limited exercise testing. HR recovery was defined as the difference in HR from peak exercise to 1 minute in recovery; abnormal HR recovery was defined as the lowest quartile. Mean HR recovery was 32 +/- 14 beats per minute. Patients with diastolic dysfunction or abnormal HR recovery had lower exercise capacity, and those with both had the lowest exercise capacity (P < .0001 compared with normal responses). Indices of abnormal diastolic function were correlated with abnormal HR recovery. In multivariable analysis, after age diastolic dysfunction (referent: normal diastolic function) was the strongest predictor of abnormal HR recovery (adjusted odds ratio [OR] 1.47, 95% confidence interval [CI] 1.20-1.80) and incrementally predictive of chronotropic incompetence (adjusted OR 1.42, 95% CI 1.16-1.74). CONCLUSIONS: Diastolic dysfunction is independently associated with abnormal HR recovery after symptom-limited exercise. Further studies are needed to determine if diastolic function modifies the adverse outcomes observed in those with abnormal HR recovery. PMID- 22196840 TI - Comorbid diabetes and end-of-life expenditures among Medicare beneficiaries with heart failure. AB - BACKGROUND: Diabetes is associated with increased risk of mortality in heart failure. We examined the association of diabetes with expenditures, hospitalizations, and procedures among Medicare beneficiaries with heart failure during the last 6 months of life. METHODS AND RESULTS: In a 5% national Medicare sample, the prevalence of diabetes was 41.7% among 16,613 beneficiaries who died in 2007 with a diagnosis of heart failure. Diabetes was associated with higher expenditures during the last 6 months of life (mean $39,042 vs $29,003; P < .001), even after adjusting for covariates, including age, sex, race, geographic location, comorbidities, and preceding hospitalizations (cost ratio 1.08, 95% CI 1.05-1.12). For both diabetic and nondiabetic adults, more than one-half of Medicare expenditures were related to hospitalization costs (mean $22,516 vs $15,721; P < .001). Compared with their counterparts without diabetes, beneficiaries with diabetes had higher rates of hospitalization (adjusted incidence rate ratio 1.09, 95% CI 1.05-1.12) and days spent in the intensive care unit. CONCLUSIONS: Comorbid diabetes was common in heart failure and associated with higher expenditures, much of which was driven by increased rates of hospitalizations. Programs that focus on prevention of hospitalizations may reduce the substantial costs associated with heart failure near the end of life. PMID- 22196841 TI - Comorbidity drives mortality in newly diagnosed heart failure: a study among geriatric outpatients. AB - BACKGROUND: Elderly heart failure (HF) patients frequently have multiple comorbidities. The prognostic impact of combined comorbidities is poorly quantified in these patients. We assessed the impact of comorbidities on 3-year mortality in geriatric outpatients with newly diagnosed HF. METHODS AND RESULTS: Of 93 geriatric outpatients with HF (mean age 82.7 years, 36.6% men), 52 patients (55.9%) died within 3 years after HF was diagnosed. Comorbidity was measured with the Charlson Comorbidity Index (CCI). Age- and gender-adjusted hazard ratio (HR) for 3-year mortality was 1.6 (95% confidence interval [CI] 0.9-3.2) for patients with 3-4 CCI points and 3.2 (95% CI 1.5-6.8) for those with >4 CCI points, compared with 1-2 CCI points. After adjustment for age, gender, left ventricular ejection fraction (LVEF), and N-terminal pro-B-type natriuretic peptide, CCI remained predictive of death (CCI 3-4: HR 1.5 (95% CI 0.7-2.9); CCI >4: HR 4.0 (95% CI 1.9-8.8)). In addition to age and gender, the c-statistics for CCI and LVEF were similar (0.63 [95% CI 0.55-0.70] and 0.64 [95% CI 0.56-0.72], respectively). CONCLUSIONS: The majority of geriatric outpatients with new HF die within 3 years. Comorbidity, summarized in the CCI, is the strongest independent predictor of mortality. PMID- 22196842 TI - Myocardial G protein receptor-coupled kinase expression correlates with functional parameters and clinical severity in advanced heart failure. AB - BACKGROUND: In heart failure (HF), sympathetic hyperactivation induces deleterious effects in myocardial beta-adrenergic signaling, with receptor down regulation and desensitization mediated by G protein receptor-coupled kinases (GRKs). We hypothesised that changes in GRK isoforms may be associated with clinical status in advanced HF, using the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) scale. METHODS: We included 31 patients with advanced HF undergoing transplantation. According to INTERMACS profiles, mRNA and protein levels of GRK isoforms in left ventricular (LV) myocardium were analyzed and compared with nonfailing LV samples. RESULTS: In failing LV myocardium, GRK2 and GRK5 (but not GRK3) protein was up-regulated compared with control samples. Among HF patients, an increase in GRK2 and GRK5 mRNA and protein abundance was observed in beta-agonist-treated patients (vs beta-blockers: P < .05) and in higher-risk INTERMACS status (profiles 2 and 3 vs 4 and 5: P < .05). A significant negative correlation of GRK2 expression with LV stroke volume supported these findings. CONCLUSIONS: Increased GRK2 correlates with clinical severity using the INTERMACS scale and LV stroke volume, supporting it as a potential target in advanced HF. These changes are paralleled by GRK5 expression in the failing myocardium, suggesting a relevant role in human HF. PMID- 22196843 TI - The "obesity paradox": does it persist among Israeli patients with decompensated heart failure? A subanalysis of the Heart Failure Survey in Israel (HFSIS). AB - BACKGROUND: Earlier studies among heart failure (HF) patients reported a paradox of reduced mortality rates in those with increased body mass index (BMI). Recently, however, it has been shown that obesity was not associated with better prognosis in certain groups. The aim of this study was to evaluate the "obesity paradox" among patients included in the Heart Failure Survey in Israel (HFSIS). METHODS AND RESULTS: Clinical, demographic, and laboratory characteristics of 2,323 patients hospitalized with a diagnosis of acute or decompensated chronic HF in 25 public Israeli hospitals between March 1 and April 30, 2003, were categorized by BMI as: normal weight (18.5-24.9 kg/m(2); n = 837), overweight (25.0-29.9 kg/m(2); n = 877), or obese (>=30.0 kg/m(2); n = 574), excluding 35 patients with BMI <18.5 kg/m(2). Survival over 15 months was inversely related to BMI category. Age-adjusted mortality hazard ratio (HR) was 0.95 (95% confidence interval [CI] 0.79-1.14) for overweight patients and 0.70 (95% CI 0.55-0.88) for obese patients compared with normal-weight patients. After further adjustment for gender, ejection fraction, New York Heart Association functional class, ischemic heart disease, diabetes, hypertension, dyslipidemia, renal function, and medications (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, spironolactone), obesity was associated with a nonsignificant HR of 0.79 (95% CI 0.59-1.05). Hypertension and dyslipidemia were also paradoxically associated with better survival in our model (HR 0.74, CI 0.59 0.92; and HR 0.77, CI 0.63-0.94; respectively; both P < .05). CONCLUSIONS: Our study falls in line with the obesity paradox observation (in obese but not overweight patients) in a large survey of HF patients, although this finding was not statistically significant on multivariate adjustment analysis. PMID- 22196844 TI - Long-term prognostic value of CA 125 serum levels in mild to moderate heart failure patients. AB - BACKGROUND: Plasma levels of tumor marker carbohydrate 125 antigen (CA 125) have been found elevated among patients with advanced heart failure (HF). We evaluated the prognostic value of CA125 in a population of patients with mild to moderate HF. METHODS AND RESULTS: Serum levels of CA 125 were obtained in 102 patients with mild to moderate HF from idiopathic (48%) or ischemic (52%) dilated cardiomyopathy (age 64 +/- 10.4 years, left ventricular ejection fraction: 34.4 +/- 8.5%), under optimized medical therapy. During follow-up (43 +/- 15 months), 16 (15.7%) cardiovascular deaths and 23 (22.5%) cardiovascular deaths + HF hospitalizations were recorded. Considering cardiac death, comparison of Kaplan Meier survival curves by the log-rank test showed that patients with CA 125 levels higher than the cut-off value (30 U/mL) had a worse survival (P < .0001). This was observed also when considering cardiovascular death+ HF hospitalizations as the secondary end point (P = .0003). Event-free survival was assessed by Kaplan-Meier method and log-rank test. Multivariable Cox proportional stepwise hazards regression analysis was performed and showed that CA 125 and systolic pulmonary artery pressure (sPAP) were significantly associated with the risk of cardiovascular deaths + HF hospitalizations (HR 1.01, 95% CI 1.02-1.06, and HR 1.07, 95% CI 1.02-1.1, P < .001, respectively). CONCLUSIONS: In mild-to-moderate HF patients under optimized therapy, higher plasma CA 125 levels are an effective long-term prognostic marker in forecasting cardiovascular events and HF hospitalization and may contribute to a better risk stratification. PMID- 22196845 TI - Hyponatremia and long-term outcomes in chronic heart failure--an observational study from the Duke Databank for Cardiovascular Diseases. AB - BACKGROUND: Hyponatremia is a well known predictor of short-term outcomes in heart failure (HF); however, its impact on long-term survival in HF patients with systolic dysfunction is not well established. METHODS AND RESULTS: Using the Duke Databank for Cardiovascular Diseases, we identified 1,045 patients with HF and systolic dysfunction undergoing cardiac catheterization from January 2000 through December 2008. The effect of hyponatremia as independent predictor of all-cause death and cardiovascular death/rehospitalization was examined using a multivariable Cox proportional regression model. Hyponatremia was present in 107/1,045 patients (10.2%). Hyponatremic patients were older, more likely to be anemic, with higher heart rate and levels of blood urea nitrogen, lower blood pressure, and more severe HF. Using an unadjusted analysis, hyponatremia was associated with higher risk of all-cause death (hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.44-2.49; P < .0001) and of cardiovascular death/rehospitalization (HR 1.40, 95% CI 1.11-1.77; P = .005) at 4.5 years. When entered into a multivariable Cox model, hyponatremia remained significant for all cause death (HR 1.42, 95% CI 1.07-1.88) and for cardiovascular death/rehospitalization (HR 1.45, 95% CI 1.14-1.86). CONCLUSIONS: Hyponatremia is relatively common in HF patients with LV dysfunction and is independently associated with increased risk of all-cause mortality and cardiovascular mortality/rehospitalization. PMID- 22196846 TI - Patient characteristics from a regional multicenter database of acute decompensated heart failure in Asia Pacific (ADHERE International-Asia Pacific). AB - BACKGROUND: Heart failure (HF) is a leading cause of hospitalization. Although a number of multicenter international HF hospital registries have been published, there are limited data for the Asia Pacific region. METHODS: ADHERE (ie, Acute Decompensated Heart Failure Registry) International-Asia Pacific is an electronic web-based observational database of 10,171 patients hospitalized with a principal diagnosis of HF from 8 Asia-Pacific countries between January 2006 and December 2008. RESULTS: The median age (67 years) varied by more than 2 decades across the region. Fifty-seven percent of patients were male. Ninety percent of patients were Asian and 8.4% were white. Dyspnea was the presenting symptom in 95%, with 80% having documented rales. During the index hospitalization, left ventricular function was assessed in 50%, and intravenous therapies included diuretics (85%), vasodilators (14%), and positive inotropes (15%). In-hospital mortality was 4.8%. Discharge medications included angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers (63%), beta-blockers (41%), and aldosterone antagonists (31%). CONCLUSIONS: Compared with other multicenter registries, patients hospitalized with acute HF in the Asia Pacific region tend to present with more severe clinical symptoms and signs and are younger, especially in countries at an earlier stage in their epidemiological transition. Echocardiography and disease-modifying medications are used less often, highlighting potential opportunities to improve outcomes. PMID- 22196847 TI - Diagnostic efficacy of [11C]choline positron emission tomography/computed tomography compared with conventional computed tomography in lymph node staging of patients with bladder cancer prior to radical cystectomy. AB - BACKGROUND: Current imaging techniques are of limited value for lymph node (LN) staging in bladder cancer (BCa) patients scheduled for radical cystectomy (RC). OBJECTIVE: Evaluate the diagnostic efficacy of [11C]choline positron emission tomography in combination with computed tomography (PET/CT) for LN staging of patients with BCa scheduled for RC and compare that efficacy with the diagnostic efficacy of CT and the gold standard of histopathologic evaluation. DESIGN, SETTING, AND PARTICIPANTS: From June 2004 to May 2007, 44 patients with localized BCa were staged with [11C]choline PET with low-dose CT for attenuation correction and simultaneous intravenous and rectal contrast-enhanced diagnostic CT before RC and pelvic lymph node dissection (PLND). LNs were dissected from the internal and external iliac arteries up to the origin of the inferior mesentery artery according to a template with 14 predefined anatomic fields. INTERVENTION: Diagnostic [11C]choline PET/CT before RC and regional LN dissection. MEASUREMENTS: Histopathologic findings of resected LN were correlated with the results of [11C]choline PET/CT and CT alone in a patient- and field-based manner. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of [11C]choline PET/CT and CT were assessed. RESULTS AND LIMITATIONS: LN metastases were found in 12 of 44 patients (27%). On patient based analysis, sensitivity, specificity, PPV, NPV, and accuracy for [11C]choline PET/CT were calculated as 58%, 66%, 39%, 81%, and 64%, respectively; and for CT the calculated percentages were 75%, 56%, 39%, 86%, and 61%, respectively. Twenty five of 471 dissected LN fields (5%) showed metastases. On field-based analysis, sensitivity, specificity, PPV, NPV, and accuracy for [11C]choline PET/CT were 28%, 95%, 21%, 96%, and 91%, respectively; for CT, the calculated percentages were 39%, 92%, 20%, 96%, and 90%, respectively. Limitations of this study are small patient number and the fact that not all patients underwent extensive PLND. CONCLUSIONS: In patients with BCa who were scheduled for RC, preoperative LN staging with [11C]choline PET/CT was not able to improve diagnostic efficacy compared with conventional CT alone. PMID- 22196848 TI - Eculizumab in the treatment of atypical hemolytic uremic syndrome in infants. AB - A 28-day-old male newborn weighing 3.6 kg was given a diagnosis of atypical hemolytic-uremic syndrome, new-onset thrombotic microangiopathy (TMA; hemoglobin, 7.7 g/dL; schistocytes, 9%), thrombocytopenia (platelets, 49 * 10(3)/MUL [49 * 10(9)/L]), and acute kidney failure (serum creatinine, 1.13 mg/dL [99.8 MUmol/L], corresponding to estimated glomerular filtration rate [eGFR] of 15 mL/min/1.73 m(2) [0.25 mL/s/1.73 m(2)]). Repeated high-volume plasma infusions were ineffective. Plasma exchange was attempted, but not tolerated. The patient required mechanical ventilation and continuous renal replacement therapy. He developed multiple intestinal perforations and leg skin necrosis due to systemic TMA. A low C3 level (36 mg/dL) suggested complement activation. Eculizumab, 300 mg, was administered, and within 48 hours the patient recovered from acute kidney failure, with complete hematologic remission 2 weeks later. The infant, 14 months old at the time of writing, continues to receive eculizumab, 300 mg, every 3 weeks; he is free of disease activity and has a normal creatinine level of 0.2 mg/dL (17.68 MUmol/L; corresponding to eGFR of 110 mL/min/1.73 m(2) [1.83 mL/s/1.73 m(2)]), but mild proteinuria (urinary protein-creatine ratio, 1 mg/g). Results of additional studies, including probing for cobalamin anomalies and measuring levels of ADAMTS13, complement factor H (CFH), factor I (CFI), and membrane cofactor protein (MCP), were unremarkable. Antibodies to CFH were undetectable, and mutation testing of the genes for CFH, CFI, and MCP gave negative results. Treatment with eculizumab was life saving, and with continued treatment, the patient showed sustained freedom from clinical TMA complications. PMID- 22196849 TI - Natural air leak test without submergence for spontaneous pneumothorax. AB - BACKGROUND: Postoperative air leaks are frequent complications after surgery for a spontaneous pneumothorax (SP). We herein describe a new method to test for air leaks by using a transparent film and thoracic tube in a closed system. METHOD: Between 2005 and 2010, 35 patients underwent a novel method for evaluating air leaks without submergence, and their clinical records were retrospectively reviewed. The data on patient characteristics, surgical details, and perioperative outcomes were analyzed. RESULTS: The differences in the clinical background and intraoperative factors did not reach a statistically significant level between the new and classical methods. The incidence of recurrence was also equivalent to the standard method. However, the length of the operation and drainage periods were significantly shorter in patients evaluated using the new method than the conventional method. Further, no postoperative complications were observed in patients evaluated using the new method. CONCLUSIONS: This simple technique is satisfactorily effective and does not result in any complications. PMID- 22196850 TI - DNA origami nanopores. AB - We demonstrate the assembly of functional hybrid nanopores for single molecule sensing by inserting DNA origami structures into solid-state nanopores. In our experiments, single artificial nanopores based on DNA origami are repeatedly inserted in and ejected from solid-state nanopores with diameters around 15 nm. We show that these hybrid nanopores can be employed for the detection of lambda DNA molecules. Our approach paves the way for future development of adaptable single-molecule nanopore sensors based on the combination of solid-state nanopores and DNA self-assembly. PMID- 22196851 TI - Nonsteroidal antiinflammatory drug use among women and the risk of birth defects. AB - OBJECTIVE: We examined whether the use of nonsteroidal antiinflammatory drugs (NSAIDs) in early pregnancy was associated with a range of structural birth defects. STUDY DESIGN: Data were from the National Birth Defects Prevention Study, a multisite population-based, case-control study of risk factors for birth defects. RESULTS: Among women in the National Birth Defects Prevention Study, 22.6% reported the use of NSAIDs in the first trimester of pregnancy, most commonly ibuprofen, aspirin, and naproxen. Of the 29 defect groups that were examined, most were not associated with NSAID use. Small-to-moderate increased risks of some oral cleft groups, some neural tube defect groups, anophthalmia/microphthalmia, pulmonary valve stenosis, amniotic bands/limb body wall defects, and transverse limb deficiencies were associated with ibuprofen, aspirin, and naproxen exposure. CONCLUSION: The use of NSAIDs in early pregnancy does not appear to be a major risk factor for birth defects, although there were a few moderate associations between NSAIDs and specific birth defects. PMID- 22196852 TI - Consumption of Pistacia lentiscus foliage alleviates coccidiosis in young goats. AB - Coccidiosis near weaning is a major cause of diarrhea, ill-thrift, and impaired performance in small ruminants. A recent survey showed that in villages of the Samaria Hills, Israel, shepherds treat young, weaned goat kids afflicted with diarrhea by cutting and feeding them the foliage of Pistacia lentiscus L. (lentisk) or by tethering them close to lentisk bushes which they browse. The aim of the present study was to assess whether lentisk leaves do indeed have anti coccidial value, and, if positive, to ascertain the role of tannins in this effect. We monitored for 24 (Experiment 1) and 30 (Experiment 2) days the effect of lentisk feeding on the development of naturally occurring coccidiosis in weaned kids artificially infected with parasitic nematodes. In Experiment 1, kids were infected with nematodes and fed lentisk foliage (PIS) or cereal hay (HAY). Coccidiosis developed at the early stage of the nematode infection, when dietary treatments were initiated. Kids in the PIS group had a lower (P<0.02) concentration of oocysts per gram feces (opg). In Experiment 2, aimed at verifying if tannins are the active component in lentisk foliage, coccidiosis occurred at the peak of the nematode infection, before experimental diets were initiated. Dietary treatments were: cereal hay (HAY), or lentisk foliage consumed without (PIS) or with (PISPEG) a 20-g daily supplement of polyethylene glycol (PEG; MW 4000), a molecule that impairs tannin-bonding with proteins. Goats fed the PIS diet had lower fecal opg counts than counterparts of the HAY (P<0.001) and PISPEG (P<0.002) treatments. Fecal opg counts for the HAY and PISPEG treatments did not differ, suggesting that the anti-coccidial moiety in lentisk was indeed tannins. Our results strongly suggest that: (i) in agreement with the ethno-veterinary anecdotal evidence, exposure of young, weaned goat kids to lentisk foliage alleviates coccidiosis; and (ii) this positive effect is associated with tannins. As coccidiosis is a major affliction of kids, providing them with tannin-rich browse near weaning could be an environmentally friendly way of improving their welfare and health status, in particular under bio-organic farm management. PMID- 22196853 TI - Comparison of cleaning efficacy between in-use disinfectant and electrolysed water in an English residential care home. AB - BACKGROUND: Infection control in hospitals and care homes remains a key issue. They are regularly inspected regarding standards of hygiene, but visual assessment does not necessarily correlate with microbial cleanliness. Pathogens can persist in the inanimate environment for extended periods of time. AIM: This prospective study compared the effectiveness of a novel sanitizer containing electrolysed water, in which the active ingredient is stabilized hypochlorous acid (AqualutionTM), with the effectiveness of the quaternary ammonium disinfectant in current use for microbial removal from hand-touch surfaces in a care home. The study had a two-period crossover design. METHODS: Five surfaces were cleaned daily over a four-week period, with screening swabs taken before and after cleaning. Swabs were cultured in order to compare levels of surface microbial contamination [colony-forming units (cfu)/cm(2)] before and after cleaning with each product. FINDINGS: Cleaning with electrolysed water reduced the mean surface bacterial load from 2.6 [interquartile range (IQR) 0.30-30.40] cfu/cm(2) to 0.10 (IQR 0.10-1.40) cfu/cm(2) [mean log(10) reduction factor 1.042, 95% confidence interval (CI) 0.79-1.30]. Cleaning with the in-use quaternary ammonium disinfectant increased the bacterial load from 0.90 (IQR 0.10-8.50) cfu/cm(2) to 93.30 (IQR 9.85-363.65) cfu/cm(2) (mean log(10) reduction -1.499, 95% CI -1.87 to -1.12) (P < 0.0001). Using two proposed benchmark standards for surface microbial levels in hospitals, electrolysed water resulted in a higher 'pass rate' than the in-use quaternary ammonium disinfectant (80-86% vs 15-21%, P < 0.0001). CONCLUSION: Electrolysed water exerts a more effective bacterial kill than the in-use quaternary ammonium disinfectant, which suggests that it may be useful as a surface sanitizer in environments such as care homes. PMID- 22196854 TI - Emerging cellular targets for influenza antiviral agents. AB - At the global level, influenza A virus (IAV) is considered a major health threat because it causes significant morbidity. Different treatment and prevention options have been developed; however, these are insufficient in the face of recent IAV outbreaks. In particular, available antiviral agents have limited effectiveness owing to IAV resistance to these virus-directed drugs. Recent advances in understanding of IAV replication have revealed a number of cellular drug targets that counteract viral drug resistance. This review summarizes current knowledge on IAV replication with a focus on emerging cellular drug targets. Interestingly, for many of these targets, compounds for which safety testing has been carried out in humans are available. It is possible that some of these compounds, such as inhibitors of heat shock protein 90, proteasome, importin alpha5 or protein kinase C, will be used for treatment of IAV infections after careful evaluation in human primary cells and severely ill flu patients. PMID- 22196855 TI - Isoflurane-induced spatial memory impairment by a mechanism independent of amyloid-beta levels and tau protein phosphorylation changes in aged rats. AB - OBJECTIVES: The molecular mechanism of postoperative cognitive dysfunction is largely unknown. Isoflurane has been shown to promote Alzheimer's disease neuropathogenesis. We set out to determine whether the effect of isoflurane on spatial memory is associated with amyloid-beta (A-beta) levels and tau phosphorylation in aged rats. METHODS: Eighteen-month-old male Sprague-Dawley rats were randomly assigned as anesthesia group (n = 31, received 1.4% isoflurane for 2 hours and had behavioral testing), training group (n = 20, received no anesthesia but had behavioral testing), and control group (n = 10, received no anesthesia and had no behavioral testing). Spatial memory was measured before and 2 days after the anesthesia by the Morris water maze. We divided the anesthesia group into an isoflurane-induced severe memory impairment group (SIG, n = 6) and a no severe memory impairment group (NSIG, n = 25), according to whether the escape latency was more than 1.96 stand deviation of that from the training group. Levels of A-beta and tau in the hippocampus were determined by enzyme linked immunosorbent assay and quantitative western blot at the end of behavioral testing. RESULTS: We found that isoflurane increased the escape latency in the SIG as compared to that in the training group and NSIG without affecting swimming speed. However, there were no differences in the levels of A-beta and tau among SIG, NSIG, training, and control groups. CONCLUSIONS: Isoflurane may induce spatial memory impairment through non-A-beta or tau neuropathogenesis mechanisms in aged rats. PMID- 22196856 TI - Magnesium increases iberiotoxin-sensitive large conductance calcium activated potassium currents on the basilar artery smooth muscle cells in rabbits. AB - OBJECTIVES: Magnesium has been known for treating vasospasm following subarachnoid hemorrhage. However, its action mechanism in cerebral vascular relaxation is not clear. Potassium channels play a pivotal role in the relaxation of smooth muscle cells. To investigate their role in magnesium-induced relaxation of basilar smooth muscle cells, we examined the effect of magnesium on potassium channels using the patch clamp technique on acutely isolated smooth muscle cells from rabbit basilar artery. METHOD: Fresh smooth muscle cells were isolated from the basilar artery by enzyme treatment. To identify which potassium channels are involved in the magnesium-induced currents, we used the potassium channel blockers tetraethylammonium (TEA), glibenclamide, apamin and iberiotoxin (IBX). RESULTS: Magnesium (5 mM) increased the step pulse-induced outward K+ currents by 46% over control level (P < 0.01). The outward K+ current was decreased to 22% (P < 0.01) by TEA (10 mM), a non-specific K+ channel blocker, and to 60% of control level (P < 0.01) by IBX (0.1 MUM,), a large-conductance Ca2+-activated K+ (BK) channel blocker, but was not inhibited by apamin (1 nM), a small-conductance Ca2+ -activated potassium (SK) channel blocker, or glibenclamide (3 mM), an adenosine triphosphate (ATP)-sensitive K+) channel blocker. Caffeine (3 mM) enhanced outward K+ currents. Magnesium-induced increase of outward K+ currents persisted in the presence of apamin. However, magnesium failed to increase the outward K+ currents in the presence of IBX. DISCUSSION: These results demonstrate that BK channels are functionally expressed in rabbit basilar smooth muscle cells and suggest that BK channels may play a pivotal role in magnesium-induced relaxation. PMID- 22196857 TI - Cerebrovascular time constant: dependence on cerebral perfusion pressure and end tidal carbon dioxide concentration. AB - OBJECTIVE: The cerebrovascular time constant (tau) describes the time to establish a change in cerebral blood volume after a step transient in arterial blood pressure (ABP). We studied the relationship between tau, ABP, intracranial pressure (ICP), and end-tidal carbon dioxide concentration (EtCO2). METHOD: Recordings from 46 anaesthetized, paralysed and ventilated New Zealand rabbits were analysed retrospectively. ABP was directly monitored in the femoral artery, transcranial Doppler (TCD) cerebral blood flow velocity (CBFV) from the basilar artery, and ICP using an intraparenchymal sensor. In nine animals end-tidal CO2 (EtCO2) was monitored continuously. ABP was decreased with injection of trimetophan (n = 11) or haemorrhage (n = 6) and increased by boluses of dopamine (n = 11). ICP was increased by infusion of normal saline into the lumbar cerebrospinal fluid space (n = 9). Changes in cerebral compliance (C(a)) were estimated as a ratio of the pulse amplitude of the cerebral arterial blood volume (CBV) and the pulse amplitude of ABP. Changes in cerebrovascular resistance (CVR) were expressed as mean ABP or cerebral perfusion pressure (CPP) divided by mean CBFV. Time constant tau was calculated as the product of CVR and C(a). RESULTS: The time constant changed inversely to the direction of the change in ABP (during arterial hypo- and hypertension) and CPP (during intracranial hypertension). C(a) increased with decreasing CPP, while CVR decreased. During a decrease in CPP, changes in C(a) exceeded changes in CVR. In contrast, during hypercapnia, the decrease in CVR was more pronounced than the increase in C(a), resulting in a decrease in tau. CONCLUSION: Cerebrovascular time constant tau is modulated by ABP, ICP, and EtCO2. PMID- 22196858 TI - Hepatocyte nuclear factor-1alpha mediated upregulation of albumin expression in focal ischemic rat brain. AB - OBJECTIVE: Exogenous human albumin has been shown to be neuroprotective in experimental ischemic stroke and it is currently investigated in clinical trials. However, the role of endogenous expression of albumin and its transcriptional regulation in the ischemic brain is not known. We have previously reported the upregulation of de novo synthesis of albumin in the ischemic rat brain (at 0 and 22 hours of reperfusion after 2 hours of ischemia). In this study, we analyzed the role of transcription factors in albumin expression in ischemic rat brain. METHODS: The putative transcription factor binding sites for the albumin promoter was analyzed using transcription factor search computational tool and validated in rat middle cerebral artery occlusion model of transient cerebral ischemia. RESULTS: Computational analysis predicted approximately 20 transcription factor binding sites including hepatocyte nuclear factor-1alpha (HNF-1alpha). We found for the first time mRNA and protein expression of HNF-1alpha in the control and ischemic rat brain. There was no significant difference in mRNA and protein expression of HNF-1alpha between control and ischemic (0, 2 and 22 hours of reperfusion) group but there was increased interaction of HNF-1alpha with p300 (known interacting partner for HNF-1alpha, a histone acetyl-transferase) in 0- and 22-hour reperfusion groups. Also albumin promoter binding activity of HNF 1alpha in ischemic animals of 0- and 22-hour reperfusion groups significantly increased compared to respective control group animals. DISCUSSION: Although, HNF 1alpha is mainly expressed in the rat liver and involved in hepatic expression of albumin, our study conclusively shows for the first time de novo synthesis of HNF-1alpha in rat brain. Moreover, an increased interaction of HNF-1alpha with p300 and albumin promoter seems to be responsible for overexpression of albumin in ischemic conditions. PMID- 22196859 TI - Neuroprotective effects of diallyl sulfide against transient focal cerebral ischemia via anti-apoptosis in rats. AB - OBJECTIVES: Diallyl sulfide (DAS) is the main organosulfur component of garlic and it is known for multiple pharmacological actions. Recent studies have demonstrated that DAS has neuroprotective effects against ischemia/reperfusion injury. While some of the possible mechanisms behind this protection have been explored, its ability to inhibit apoptosis has yet to be fully explained. In the present study, the effects of DAS on focal cerebral ischemia in rats were tested and its anti-apoptotic action was explored. METHODS: To examine the protective effects of DAS, focal cerebral ischemia/reperfusion was induced in rats by transient middle cerebral artery occlusion for 2 hours followed by reperfusion for 24 hours. The animals received DAS in quantities of 100, 150, and 200 mg/kg (intraperitoneal; every day), for 7 days before transient middle cerebral artery occlusion. The neurological score and infarct volume were measured at 24 hours after the end of reperfusion. Apoptotic cells were counted by terminal dUTP nick end labeling staining and apoptotic mechanisms were studied by fluorescence immunohistochemistry staining and western blot analysis. RESULTS: For animals with induced ischemia/reperfusion, those pretreated with 200 mg/kg DAS showed an infarct volume (22.36 +/- 0.67%) significantly lower than that of the non-treated ischemia/reperfusion group (38.23 +/- 0.72%), and the percentage of terminal dUTP nick-end labeling-positive cells (23.46 +/- 1.02%) of the DAS-pretreated group was also significantly decreased compared to non-treated (36.41 +/- 1.58%). Fluorescence immunohistochemistry staining and western blot analysis indicated that DAS reduced caspase-3 expression and increased Bcl-2 expression. CONCLUSION: These results suggest that the mechanism by which DAS protects the brain from ischemia/reperfusion injury is related to its anti-apoptotic effects in part. PMID- 22196860 TI - Differentiation of HT22 neurons induces expression of NMDA receptor that mediates homocysteine cytotoxicity. AB - INTRODUCTION: Neurotoxic homocysteine (Hcy) is thought to be an independent risk factor for neurodegenerative diseases, including Alzheimer's disease. This study is to determine whether HT22 cells, a murine hippocampal neuronal model, can be used as an in vitro model, besides the primary neuronal cultures, to investigate the effects of Hcy. MATERIALS AND METHODS: MTS assay and Hoechst 33342/propidium iodide discrimination were used to assess the cell viability and cell death on undifferentiated and differentiated HT22 cells. Semi-quantitative reverse transcription polymerase chain reaction and western blot were used to determine the expression of N-methyl D-aspartate (NMDA) receptor. RESULTS: We found that undifferentiated and differentiated HT22 cells responded to Hcy toxicity differentially, with the undifferentiated cells resistant while the differentiated cells sensitive. The underlying mechanism appeared to be the differential expression levels of NMDA glutamate receptor between the undifferentiated and differentiated cells. Similar to what have been observed in primary neuronal cultures, the Hcy toxicity in the differentiated HT22 cells was largely attenuated by NMDA receptor antagonists, MK-801 and memantine. CONCLUSION: These results suggest for the first time that the differentiation of HT22 cells could induce the expression of NMDA receptors, which lead to Hcy mediate concentration-dependent apoptosis-necrotic continuum of HT22 cell death. The differentiation status of the HT22 cells is important for modeling neurons in vitro, with the differentiated HT22 neurons resembling more characteristics of primary hippocampal neurons while the undifferentiated HT22 cells being proliferating neuronal precursor cells. The differentiated HT22 neurons can be used as a platform to study Hcy toxicity. PMID- 22196861 TI - Neuroprotective effect of oleuropein following spinal cord injury in rats. AB - OBJECTIVES: Oleuropein (OE) is a well-known antioxidant polyphenol from olive oil. The purpose of this study was to determine the potential neuroprotective effects of oleuropein in an experimental spinal cord injury model. METHODS: Rats were randomly divided into four groups of 21 rats each as follows: sham-operated group, trauma group, and OE treatment groups (20 mg/kg, i.p., immediately and 1 hour after spinal cord injury). Spinal cord samples were taken 24 hours after injury and studied for determination of malondialdehyde and glutathione levels, histopathological assessment, immunohistochemistry of Bax and Bcl-2, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling reaction. Behavioral testing was performed weekly up to 6 weeks post-injury. RESULTS: The results showed that malondialdehyde levels were significantly decreased, and glutathione levels were significantly increased in OE treatment groups. Greater Bcl-2 and attenuated Bax expression could be detected in the OE-treated rats. OE significantly reduced terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive reaction and improved behavioral function than the trauma group. DISCUSSION: These findings indicate that OE may be effective in protecting rat spinal cord from secondary injury. PMID- 22196862 TI - Cerebral metabolism, magnetic resonance spectroscopy and cognitive dysfunction in early multiple sclerosis: an exploratory study. AB - OBJECTIVES: Positron emission tomography (PET) studies have shown that cortical cerebral metabolic rate of glucose (CMRglc) is reduced in multiple sclerosis (MS). Quantitative magnetic resonance spectroscopy (MRS) measures of N-acetyl aspartate (NAA) normalized to creatine (NAA/Cr) assess neuronal deterioration, and several studies have shown reductions in MS. Furthermore, both PET and MRS reductions correlate with cognitive dysfunction in MS. Our aim was to determine if changes in cortical CMRglc in early MS correlate with NAA/Cr measurements of neuronal deterioration, as well as cognitive dysfunction and neurological disability. METHODS: We studied 20 recently diagnosed, clinically definite, relapsing-remitting MS patients. Global and cortical CMRglc was estimated using PET with 18-F-deoxyglucose and NAA/Cr ratio was measured using multislice echo planar spectroscopic imaging. All subjects were neuro-psychologically tested and a cognitive dysfunction factor (CDF) was calculated. RESULTS: Cortical CMRglc correlated with cortical NAA/Cr (r = 0.45; P < 0.05), but there were no correlation between CMRglc and other NAA/Cr measurements, conventional magnetic resonance imaging measurements, or CDF. Stepwise regression analysis showed association between cortical NAA/Cr and CMRglc of the left ventrolateral prefrontal cortex (P < 0.001), left putamen (P = 0.010), and left hippocampus (P = 0.011). Furthermore, CDF was related to CMRglc in the left cerebellum (P = 0.001) and the left caudate nucleus (P = 0.013). The results of the statistical analysis should be regarded as exploratory, since we did not correct for multiple comparisons. CONCLUSION: Our findings suggest that reductions in cortical CMRglc are associated with reductions in cortical NAA/Cr in early MS. These changes affect cortical and subcortical neural circuits of importance to cognitive function. PMID- 22196863 TI - Ozone oxidative post-conditioning reduces oxidative protein damage in patients with disc hernia. AB - INTRODUCTION/OBJECTIVES: Although inflammation in disc hernia (DH) has been recognized and it is a well-known process mediated by loss of the cellular redox balance, only a few studies about the impact of chronic oxidative stress on this neurological disorder have been made. Ozone therapy has been widely used with clinical efficacy in DH. This work aimed at characterizing the systemic redox status of patients with low back pain and neck pain as well as studying if ozone oxidative post-conditioning modified the pathological oxidative stress and protected against oxidative protein damage and if there is any relationship between oxidative changes and pain in both DH. METHODS: Redox status of 33 patients with diagnosis of DH by computerized axial tomography, nuclear magnetic resonance, and clinical evaluations was studied. Ozone was administered by paravertebral way. After ozone treatment, plasmatic levels of antioxidant/pro oxidant markers, pain, and life quality disability parameters were evaluated. RESULTS: One hundred percent of patients showed a severe oxidative stress. Major changes in superoxide dismutase activity, total hydroperoxides, advanced oxidation protein products, fructolysine content, and malondialdehyde were observed. After ozone oxidative post-conditioning, there was a re-establishment of patients' cellular redox balance as well as a decrease in pain in both DH. A relationship between indicators of oxidative protein damage and pain was demonstrated. CONCLUSIONS: Ozone therapy protected against oxidation of proteins and reduced the pain. Relationship between markers of oxidative protein damage, disability parameters, and pain suggests the role of oxidative stress in the pathological processes involved in DH. PMID- 22196864 TI - Glycoprotein Ib-alpha Kozak polymorphism in ischemic stroke. AB - BACKGROUND: Recently, a T/C polymorphism in the Kozak sequence of glycoprotein Ib alpha (GPIb-alpha) gene at position -5 from the initiator ATG codons, has been identified. The presence of -5C allele increases the surface expression of GPIb IX-V complex in a gene dosage-dependent manner. It has been suggested that higher receptor levels might increase the adhesiveness of the platelets and confer risk for thrombosis. In this study, we aimed to investigate the association between GPIb-alpha Kozak polymorphism and ischemic stroke. METHODS: We prospectively and consecutively recruited 231 patients (118 women and 113 men; mean age: 65 +/- 14.2 years) with first ever ischemic stroke admitted to Istanbul Faculty of Medicine Edip Aktin Stroke Unit between April 2007 and June 2009. Demographic features, risk factors, clinical, and etiological subtypes were analyzed. As the control group, 220 unrelated healthy subjects were included. RESULTS: We found that 156 patients had TT, 70 patients had TC, and 5 patients had CC genotype. At least one copy of C allele carriers were overrepresented in the ischemic stroke group (32.5%) compared with controls (23%) [odds ratio (OR): 0.61; 95% confidence interval (CI): 0.40-0.93; P = 0.03]. Among etiologic subtypes, the distribution of C allele carriers was the highest in patients with undetermined etiology (45%) and it was significantly higher than controls (OR: 0.36; 95% CI: 0.20-0.65; P = 0.0008). In other subtypes, there was no association with Kozak -5C allele. CONCLUSION: In conclusion, these encouraging preliminary results show that GPIb alpha T/C polymorphism might increase the risk of ischemic stroke, especially in those with undetermined etiology. PMID- 22196865 TI - Different effect of hyperglycemia on stroke outcome in non-diabetic and diabetic patients--a cohort study. AB - OBJECTIVES: Relationship between hyperglycemia and stroke outcome is unclear, partly due to the small sample size in most studies, and partly due to lack of consensus concerning the cutoff level for hyperglycemia. METHODS: In a cohort study, we investigated whether on-admission hyperglycemia is an independent predictor for 30-day case fatality by analyzing data of 2496 consecutive computed tomography (CT) verified acute ischemic stroke patients (2077 non-diabetic and 419 diabetic) included in the prospective, hospital-based Debrecen Stroke Database. Instead of using an arbitrary cutoff level for hyperglycemia, quartiles of on-admission glucose level were used for Kaplan-Meier survival curves and Cox proportional hazard modeling. RESULTS: The four quartiles of serum glucose level were in the range as follows: <5.2 mmol/l, 5.201-6.1 mmol/l, 6.101-7.5 mmol/l, and >7.501 mmol/l (n = 664, 618, 597, and 617, respectively). Among all 2496 participants, the adjusted hazard ratios for death increased with each quartile of admission glucose 1.96 [95% confidence interval (CI): 1.07-3.60; P = 0.03], 1.56 (95% CI: 0.83-2.94; P = 0.17), and 3.04 (95% CI: 1.70-5.44; P < 0.0001) for the second, third, and fourth quartiles, respectively). Upon stratification with respect to diabetes, we found similarly high risk for poor outcome among non diabetic patients, while the risk was considerably lower among diabetic patients. DISCUSSION: These data suggest that even mild elevation of on-admission glucose levels is an independent predictor of 30-day case fatality. So, we propose that the ideal target blood glucose level is lower for non-diabetic than diabetic patients. PMID- 22196866 TI - Effect of DSP-4 induced central noradrenergic depletion on tactile learning in rat. AB - OBJECTIVE: There is general agreement that norepinephrine could modulate neuronal responses to non-monoaminergic synaptic inputs in the somatosensory cortex. In the present study, we investigated the effect of central norepinephrine depletion on tactile learning in rats. METHODS: Central norepinephrine depletion was induced using 50 mg/kg of N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP-4) and verified by high performance liquid chromatography. Memory performance was assessed 1 and 5 weeks after DSP-4 treatment using novel object recognition test. RESULT: We observed a learning impairment in both DSP-4 groups, as the preference index was not significantly altered when compared to chance level (50%). DISCUSSION: These findings suggest that depletion of central norepinephrine by DSP-4 leads to impairment of the tactile learning in rats, which can last at least for 35 days. PMID- 22196867 TI - Protective effects of erythropoietin in experimental spinal cord injury by reducing the C/EBP-homologous protein expression. AB - OBJECTIVES: Erythropoietin (EPO) is a variety of tissue-protective functions, including spinal cord. This study aimed to determine the neuron protective effect of erythropoietin on spinal cord injury (SCI) by assessing C/EBP-homologous protein (CHOP) in the development of a rat model of SCI. METHODS: Sixty Sprague Dawley rats were randomly assigned to three groups: sham-operation control group, SCI group, and EPO treatment group. By using a weight-drop contusion SCI model, the rats in the SCI group and EPO treatment group were killed at 1 and 7 days subsequently. The Basso, Beattie, and Bresnahan (BBB) scores were examined for locomotor function. Pathological changes were observed after hematoxylin-eosin (H&E) staining. The expression of CHOP was determined by immunohistochemical staining and RT-PCR analysis. RESULTS: BBB scores showed more quick recovery in the erythropoietin treatment group than that in the SCI group (P < 0.01). Pathological changes also revealed a reduction in the volume of cavitations and more neurons regeneration in the EPO treatment rats than that of the SCI rats. The number of CHOP positive cells in the SCI group on day 1 and 7 days after SCI increased compared with the erythropoietin treatment group and sham-operation control group (P < 0.01). CHOP mRNA folds in sham-operation control rat from 1 to 7 days showed the same trend. CONCLUSIONS: Endoplasmic reticulum (ER) stress was triggered at the early stage of SCI. Increased expression of CHOP can be found in the injured segment of the spinal cord after injury. EPO treatment could prevent pathological alterations from severe spinal cord injury by reducing expression of CHOP. PMID- 22196868 TI - Special features of subarachnoid hemorrhage of unknown origin: a review of a series of 179 cases. AB - OBJECTIVES: The aim of this study was to work out the special features of subarachnoid hemorrhage (SAH) of unknown origin in respect of diagnostic evaluation, clinical course, and outcome in a large cohort of patients. METHODS: We reviewed the data of 179 patients with SAH of unknown origin during 1991 and 2008. The differentiation between perimesencephalic (PM-SAH) and non perimesencephalic SAH (NON-PM-SAH) was done under consideration of the bleeding pattern on CT scanning. RESULTS: Among 1226 treated patients with spontaneous SAH over a time period of 17 years, a bleeding source remained undetected on first digital subtraction angiogram (DSA) in 179 patients (16.7%)--47 PM-SAH (26.3%) and 132 NON-PM-SAH (73.7%). The clinical signs of patients with PM-SAH were less marked compared to those with NON-PM-SAH, equally to the Hunt and Hess grade. magnetic resonance imaging (MRI) and MR angiography had 100% negative findings for non-aneurismal bleeding sources in all patients. Second DSA revealed a bleeding source in the NON-PM group in 10.8%. The clinical course of the patients with NON-PM-SAH showed a significantly higher rate of complications and a mortality of about 10%. The outcome was excellent in the PM group, in contrast to a fatal course in 13 cases in the NON-PM group. DISCUSSION: PM-SAH imposed with a mild clinical course and an excellent outcome, without severe complications. In contrast to this, NON-PM-SAH has a significant higher rate of dreaded complications and mortality. It is crucial to make an exact diagnosis of PM-SAH, considering CT scanning during the first 24 hours after occurrence of symptoms and the radiological features. PMID- 22196869 TI - High frequency ultrasound evaluation of traumatic peripheral nerve injuries. AB - OBJECTIVE: Accurate diagnosis and localization of peripheral nerve traumatic injury remains difficult. Early diagnosis and repair of nerve discontinuity lesions lead to better outcome than delayed repair. MATERIALS AND METHODS: We used new high frequency ultrasound to evaluate 24 patients with 29 traumatic nerve injuries. There were a variety of causes including gunshot wounds, blunt injuries, burns, stabbings, and motor vehicle accidents. The patients were then either treated surgically with nerve status directly observed or followed clinically for recovery of nerve function. RESULTS: The ultrasound findings correspond with the clinical outcome of 28 of the 29 nerves. CONCLUSION: While this is a study limited by a small patient number, ultrasound evaluation should be considered in the evaluation of nerve injury and can lead to early diagnosis and treatment of surgical nerve injuries. PMID- 22196870 TI - Trichodysplasia spinulosa is characterized by active polyomavirus infection. AB - BACKGROUND: Recently a new polyomavirus was identified in a patient with trichodysplasia spinulosa (TS), a rare follicular skin disease of immunocompromised patients characterized by facial spines and overgrowth of inner root sheath cells. Seroepidemiological studies indicate that TSPyV is ubiquitous and latently infects 70% of the healthy individuals. OBJECTIVE: To corroborate the relationship between active TSPyV infection and TS disease by analyzing the presence, load, and precise localization of TSPyV infection in TS patients and in controls. STUDY DESIGN: TS lesional and non-lesional skin samples were retrieved from TS patients through a PubMed search. Samples were analyzed for the presence and load of TSPyV DNA with quantitative PCR, and for expression and localization of viral protein with immunofluorescence. Findings obtained in TS patients (n=11) were compared to those obtained in healthy controls (n=249). RESULTS: TSPyV DNA detection was significantly associated with disease (P<0.001), with 100% positivity of the lesional and 2% of the control samples. Quantification revealed high TSPyV DNA loads in the lesional samples (~10(6)copies/cell), and low viral loads in the occasionally TSPyV-positive non-lesional and control samples (<10(2)copies/cell). TSPyV VP1 protein expression was detected only in lesional TS samples, restricted to the nuclei of inner root sheath cells over-expressing trichohyalin. CONCLUSIONS: The high prevalence and load of TSPyV DNA only in TS lesions, and the abundant expression of TSPyV protein in the affected hair follicle cells demonstrate a tight relation between TSPyV infection and TS disease, and indicate involvement of active TSPyV infection in TS pathogenesis. PMID- 22196871 TI - Epidemiological and genetic analyses of a diffuse outbreak of hepatitis A in Japan, 2010. AB - BACKGROUND: Hepatitis A virus (HAV) is still one of the most common causative agents of acute hepatitis in Japan. Although a relatively small number of annual acute hepatitis A cases (approximately 100-150, 0.78-1.17 per million) were recently reported, a larger number of cases (346, 2.71 per million) were reported in 2010. OBJECTIVES: To investigate the causes of the 2010 HAV resurgence in Japan by using molecular epidemiological and genetic analyses. STUDY DESIGN: HAV specimens were obtained from 61 cases from 22 different prefectures. These viral specimens were genotyped by PCR amplification and sequencing of the VP1/2A region of HAV genome. RESULTS: Phylogenetic analysis revealed that 61 HAV strains could be divided into three genotypes: IA (44 cases), IB (1 case) and IIIA (16 cases). The IA genotype consisted of two genomic sub-lineages. The sequences of one of the two IA sub-lineages (corresponding to 31 cases) were very similar, 26 of these 31 isolates had 100% identity. The other IA sub-lineage corresponded to strains endemic to Japan. The sequences of Japanese IIIA strains were similar to those of strains that caused a large epidemic in the Republic of Korea from 2007 to 2009. CONCLUSIONS: The resurgence of HAV in 2010 can be attributed to importation of two newly emerged HAV genotypes. PMID- 22196872 TI - Establishing diagnostic cut-off criteria for the COBAS AmpliPrep/COBAS TaqMan HIV 1 Qualitative test through validation against the Amplicor DNA test v1.5 for infant diagnosis using dried blood spots. AB - BACKGROUND: As antibody testing cannot confirm HIV-1 infection in children less than 18 months of age, diagnosis in these children depends on nucleic acid testing. The COBAS((r)) AmpliPrep/COBAS((r)) TaqMan((r)) (CAP/CTM, Roche((r)) Molecular Systems, Inc., Branchburg, NJ) HIV-1 Qualitative test is a total nucleic acid real-time PCR assay utilising whole EDTA blood or dried blood spots (DBS), which recently replaced the Roche((r)) AMPLICOR((r)) DNA test v1.5 (Amplicor) as the diagnostic HIV PCR assay in many South African laboratories. For the Amplicor assay, stringent diagnostic criteria were previously formulated for the local population, and a comparison reported the CAP/CTM's sensitivity at 99.7% and specificity at 100% for both sample types compared to these Amplicor criteria. OBJECTIVES: To validate the assay prior to introduction in our laboratory and to define stringent diagnostic cut-off criteria. STUDY DESIGN: Whole EDTA blood samples from patients younger than 18 months sent for routine HIV-1 diagnosis were tested by Amplicor, and positive results were confirmed from DBS. CAP/CTM assays were subsequently performed from DBS. RESULTS: The CAP/CTM had a sensitivity of 98.8% and a specificity of 97.1%, but a positive predictive value (PPV) of only 78.7% compared to the Amplicor assay. Samples positive by CAP/CTM but negative by Amplicor displayed poor amplification curves compared to concordant positive samples. Upon re-testing those with sufficient material available by CAP/CTM, all showed negative results. CONCLUSIONS: The decreased PPV may either be due to false positive CAP/CTM results, or increased sensitivity compared to the Amplicor assay. Criteria were formulated for defining presumed false-positive results. PMID- 22196873 TI - Telestroke in South Carolina. AB - BACKGROUND: The administration of thrombolysis to eligible patients is often limited to centers with expertise. This study was intended to report on the safety and efficacy (in increasing thrombolysis availability) of telemedicine in the acute assessment and treatment of stroke patients presenting to hospitals in distant locations from a designated stroke center. METHODS: A web-based telestroke tool (remote evaluation of acute ischemic stroke at Medical University of South Carolina [REACH-MUSC]), was implemented to provide acute stroke care 24 hours per day, 7 days per week to 12 community hospitals in South Carolina. RESULTS: Nine hundred sixty-five consults were performed. Among the 525 patients with a National Institutes of Health Stroke Score >3, 185 (35.7%) were treated with intravenous tissue plasminogen activator (t-PA) alone, 15 (2.9%) received combination of intravenous and intra-arterial thrombolysis/thrombectomy, and 11 (2.1%) were treated with intra-arterial therapy alone. Of those who received intravenous t-PA, 119 (64.3%) were transferred to the hub; the medians (interquartile range) for onset to treatment for the intravenous t-PA and the intravenous t-PA and intra-arterial groups were 152 (range 115-193) minutes and 147 (range 107-179) minutes, respectively. Three patients (1.6%) who received intravenous t-PA alone experienced symptomatic intracerebral hemorrhage. The most common reason for not receiving thrombolysis was patient presentation outside the time window for treatment. CONCLUSIONS: Telestroke can have a major impact in increasing thrombolysis rates in remote areas from specialized centers, and in particular in areas where t-PA is underutilized. PMID- 22196874 TI - Population trends and disparities in outpatient utilization of neurologists for ischemic stroke. AB - BACKGROUND: Inpatient stroke utilization may be decreasing over time and may vary by patient demographics. Less is known about temporal trends and demographic variations in outpatient stroke utilization. We assessed ischemic stroke (IS) related outpatient utilization across physician specialty and time, exploring any demographic variability, using recent US population-based data. METHODS: We identified all outpatient medical visits for IS by adults (>= 18 years) using the National Ambulatory Medical Care Survey (NAMCS) years 1998 to 2009. Physician numbers were derived from American Medical Association or American Osteopathic Association data by NAMCS. We assessed IS-related outpatient visits to neurologists and generalists over time and by patient demographics. RESULTS: We identified 9.7 million IS-related visits from 1998 to 2009. The rate of IS related visits to neurologists increased from 0.56 million visits in 1998 to 2000 to 0.90 million visits in 2007 to 2009, representing a 62% increase over the study period. The rate of IS-related visits to generalists declined from 2.0 million visits in 1998 to 2000 to 1.6 million visits in 2007 to 2009 (18% decrease). Between 1998 and 2009, the number of neurologists increased by 23% and the number of generalists grew by 19%. The IS visit rate per 100 physicians increased by 90% for neurologists but decreased by 31% for generalists. Fewer ambulatory IS-related visits to neurologists were reported among stroke survivors who were older, female, nonwhite, or living in rural areas. CONCLUSIONS: Between 1998 and 2009, IS-related outpatient utilization increased substantially to neurologists but declined to generalists. We identified demographic variations in outpatient utilization of neurologists that potentially lead to disparities in stroke evaluation and management. PMID- 22196875 TI - In vitro monitoring of i-NOS concentrations with an immunosensor: the inhibitory effect of endocrine disruptors on i-NOS release. AB - The amperometric immunosensor has demonstrated the toxicity of endocrine disrupters (EDs) through monitoring the in vitro i-NOS concentration change, where the antibody of inducible nitric oxide synthase (i-NOS) was immobilized on the conducting polymer-gold nanoparticles composite. The performance of the sensor and the experimental parameters affecting the immunoreaction were optimized. Neuronal cells treated by EDs decreased in the in vitro i-NOS concentration. The effect of bisphenol A (BPA) on the i-NOS concentration released in the cells was investigated with different incubation times, and the interfering by nonspecific binding species present in a neuronal cell lysate was also examined. Of all the tested EDs, BPA showed the inhibitoriest effect and the minimum inhibitory concentration of BPA affecting the i-NOS concentration was 0.09 +/- 0.005 MUM. The result shows that monitoring of i-NOS in the neuronal cells treated by EDs will be a useful method to evaluate the toxic behavior of EDs. PMID- 22196876 TI - Detection of organophosphorus compounds using a molecularly imprinted photonic crystal. AB - A label free molecularly imprinted photonic crystal (MIPC) was developed to detect the degradation product of nerve agents. Mono-dispersed poly-methyl methacrylate colloidal particles with the diameter of 280 nm were used to fabricate a closely packed colloidal crystal array (CCA), and a methyl phosphonic acid (MPA) imprinted hydrogel was prepared within the CCA using 2-hydroxyethyl methacrylate and N-isopropylacrylamide as monomers, ethyleneglycol dimethacrylate and N, N'-methylenebisacrylamide as cross-linkers, a mixture of n-octanol and acetonitrile as porogen. The diffraction intensity of the MIPC decreased significantly upon the MPA adsorption with a limit of detection (LOD) of 10(-6) molL(-1). Furthermore, the diffraction intensity decreased and blue shifted with the increase of temperature, decreased and red shifted with the increase of ionic strength. At higher pH, the diffraction intensity increased without obvious diffraction shift. The MIPC provides an indirect path to detect nerve agents (Sarin, Soman, VX and R-VX) by monitoring the MPA released from the hydrolysis of nerve agents, with LODs of 3.5 * 10(-6) molL(-1), 2.5 * 10(-5) molL(-1), 7.5 * 10(-5) molL(-1) and 7.5 * 10(-5) molL(-1) for Sarin, Soman, VX and R-VX, respectively. PMID- 22196877 TI - Electrochemically amplified molecular beacon biosensor for ultrasensitive DNA sequence-specific detection of Legionella sp. AB - An electrochemically amplified molecular beacon (EAMB) biosensor is constructed using thiolated hairpin DNA-ferrocene probes on gold electrode. The switching from "on" to "off" states of individual probes in the presence of complementary DNA target influences the electrode potential, besides the current, owing to changes in surface density of the electroactive hairpin DNA-ferrocene probes. The EAMB biosensor demonstrates linear range over 8 orders of magnitude with ultrasensitive detection limit of 2.3 * 10(-14)M for the quantification of a 21 mer DNA sequence. Its applicability is tested against PCR amplicons derived from genomic DNA of live Legionella pneumophila. Excellent specificity down to one and three nucleotides mismatches in another strain of L. pneumophila and a different bacterium species, respectively, is demonstrated. PMID- 22196878 TI - Real-time luminescence-based colorimetric determination of double-strand DNA in droplet on demand. AB - We have developed a new luminescence-based colorimetric droplet platform for the determination of double-stranded DNAs (dsDNA). This colorimetric sensor was realized via choosing a fluorescent ensemble probe comprising water-soluble N acetylcysteine-capped CdTe quantum dots (QDs) and Ru(bpy)(2)(dppx)(2+) (Ru). To provide a convenient and low cost droplet platform for colorimetry, the microvalve technique was adapted to adjust droplet size precisely, achieve the desired fusion of multiple droplets and trap droplets on demand, as well as implement concentration gradients of DNA on a single chip. In the colorimetric sensor, Ru served as both an effective quencher for QDs and a reporter for dsDNA. With increasing concentration of dsDNA, a gradually enhanced color response was observed because of the competition of dsDNA with QDs for Ru. Under the optimum conditions, this biosensing system exhibited not only good sensitivity and specificity for calf thymus DNA with the detection limit of 1.0 pg, but also coincident performances in diluted human serum with the detection limit of 0.9 pg. The droplet biosensor provides a highly efficient, rapid and visual method for dsDNA analysis. The colorimetric droplet platform could be useful as a simple research tool for the study of limited and precious regents such as protein and virus samples, etc. PMID- 22196879 TI - Facile and rapid magnetic relaxation switch immunosensor for endocrine-disrupting chemicals. AB - In order to develop facile, fast and sensitive detection methods for endocrine disrupting chemicals (EDCs), we described a sensitive biosensing system involving magnetic relaxation switch, based on the assembly of cross-linked superparamagnetic iron oxide (CLIO) nanoparticles induced by the antigen-antibody biorecognition. The design of smart CLIO-based superparamagnetic iron oxide nanoparticles and antigen-OVA was described for the detection of bisphenol A [2,2 bis (4-hydroxyphenol) propane (BPA)]. The addition of BPA to the rapid magnetic relaxation switch immunosensor led to transverse relaxation time (T2) shortening compared to a blank control as shown by NMR relaxometry measurements. This process was also applied to the rapid and facile determination of concentrations of BPA in drinking water (tap water). Good linearity for all calibration curves was obtained, and the limit of detection (LOD) for BPA was 0.4 ng/mL in tap water. PMID- 22196880 TI - Novel impedimetric immunosensor for the detection and quantitation of Adenovirus using reduced antibody fragments immobilized onto a conducting copolymer surface. AB - The number of Adenovirus (Ad) infections detected in immunocompromised people has increased due to the number of patients receiving transplants, as well as the HIV pandemic. Ads cause life-threatening diseases specific to the infected organs of immunocompromised hosts, with discontinuation of immunosuppressive agents necessary to prevent morbidity. The methodology in this paper has been employed to develop a novel impedimetric based assay platform to detect and quantify human Ads, which is comparable in performance to current methods, such as ELISA and PCR, but is also less expensive and faster. Novel immunosensors have been fabricated using polyclonal antibodies raised against a human Ad (Ad5) capsid protein, which were selectively cleaved into antibody fragments by 2 mercaptoethylamine. The fragments were immobilized onto a functionalized conducting copolymer matrix comprising polyaniline and 2-aminobenzylamine. Fully fabricated sensors were incubated with two immunologically distinct serotypes of Ad, Ad5 and Ad3, with between 10 and 10(12)virus particles/mL prior to sensor interrogation. Electrochemical impedance spectroscopy was used to measure the charge transfer resistance of the sensors over a range of frequencies from 25 kHz to 0.1 Hz. Our data demonstrate that the immunosensors specifically detect, and differentiate between, closely related human Ad serotypes with a limit of detection of 10(3)virus particles/mL. In addition, atomic force microscopy was applied to study the sensor surface nanostructure. Future work looks to test virus containing clinical samples but this could be a viable and valuable alternative for point-of-care virus detection and quantification. PMID- 22196881 TI - The effects of cigarette smoke on airway inflammation in asthma and COPD: therapeutic implications. AB - Asthma and COPD are two chronic inflammatory disorders of the airway characterized by airflow limitation. While many similarities exist between these two diseases, they are pathologically distinct due to the involvement of different inflammatory cells; predominantly neutrophils, CD8 lymphocytes in COPD and eosinophils and CD4 lymphocytes in asthma. Cigarette smoking is associated with accelerated decline of lung function, increased mortality, and worsening of symptoms in both asthma and COPD. Furthermore, exposure to cigarette smoke can alter the inflammatory mechanisms in asthma to become similar to that seen in COPD with increasing CD8 cells and neutrophils and may therefore alter the response to therapy. Cigarette smoke exposure has been associated with a poor response to inhaled corticosteroids which are recommended as first line anti inflammatory medications in asthma and as an add-on therapy in patients with severe COPD with history of exacerbations. While the main proposed mechanism for this altered response is the reduction of the histone deacetylase 2 (HDAC2) enzyme system, other possible mechanisms include the overexpression of GR-beta, activation of p38 MAPK pathway and increased production of inflammatory cytokines such as IL-2, 4, 8, TNF-alpha and NF-Kbeta. Few clinical trials suggest that leukotriene modifiers may be an alternative to corticosteroids in smokers with asthma but there are currently no drugs which effectively reduce the progression of inflammation in smokers with COPD. However, several HDAC2 enhancers including low dose theophylline and other potential anti-inflammatory therapies including PDE4 inhibitors and p38 MAPK inhibitors are being evaluated. PMID- 22196882 TI - An effective measure for assessing the quality of biclusters. AB - Biclustering is becoming a popular technique for the study of gene expression data. This is mainly due to the capability of biclustering to address the data using various dimensions simultaneously, as opposed to clustering, which can use only one dimension at the time. Different heuristics have been proposed in order to discover interesting biclusters in data. Such heuristics have one common characteristic: they are guided by a measure that determines the quality of biclusters. It follows that defining such a measure is probably the most important aspect. One of the popular quality measure is the mean squared residue (MSR). However, it has been proven that MSR fails at identifying some kind of patterns. This motivates us to introduce a novel measure, called virtual error (VE), that overcomes this limitation. Results obtained by using VE confirm that it can identify interesting patterns that could not be found by MSR. PMID- 22196883 TI - Left ventricular diastolic dysfunction as a predictor of rapid decline of residual renal function in patients with peritoneal dialysis. AB - BACKGROUND: The aim of this study was to evaluate whether diastolic dysfunction at the start of dialysis could influence renal and cardiovascular survival rates in 82 patients undergoing peritoneal dialysis. METHODS: Diastolic dysfunction was determined using left ventricular hypertrophy, the ratio of early peak transmitral inflow velocity to peak diastolic mitral annular velocity (E/E'), and left atrial volume index (LAVI). Residual renal function (RRF) was measured with 24-hour urine collections at baseline (within 1 month of beginning peritoneal dialysis) and thereafter at 6-month intervals for 2 years. To evaluate the long term prognostic significance of diastolic dysfunction, the 4-year cardiac event free survival was also evaluated. RESULTS: The median slope of RRF decline was 0.07 mL/min/mo/1.73 m(2). Forty-five patients (54.9%) with rapid RRF declines (< 0.07 mL/min/mo/1.73 m(2)) had a higher prevalence of diabetes and eccentric left ventricular hypertrophy, as well as significantly elevated E/E' ratios and LAVIs. There was a close relationship between baseline E/E' ratio (r = -0.221, P = .048), LAVI (r = -0.276, P = .015), and RRF decline rate, and both E/E' > 15 (odds ratio, 3.61; 95% confidence interval, 1.07-12.12) and LAVI > 32 mL/m(2) (odds ratio, 3.54; 95% confidence interval, 1.08-11.58) were significant independent predictors of the loss of RRF. Furthermore, E/E' > 15 also provided additional prognostic value in predicting future cardiac events (hazard ratio, 6.74; 95% confidence interval, 1.07-12.12; P = .023). CONCLUSIONS: Left ventricular diastolic dysfunction may be a significant predictor of rapid decline in RRF and adverse cardiac outcomes in patients starting peritoneal dialysis. PMID- 22196884 TI - Right ventricular function with standard and speckle-tracking echocardiography and clinical events in adults with D-transposition of the great arteries post atrial switch. AB - BACKGROUND: The prognostic value of deformation parameters of the systemic right ventricle in adults with D-transposition of the great arteries and prior atrial switch has not been reported. METHODS: Sixty-four adults with D-transposition of the great arteries and prior atrial switch (mean age, 29 +/- 6 years; 22 women; mean right ventricular [RV] fractional area change, 22.9 +/- 7.5%; 31 with pacemakers at baseline) and no histories of heart failure or ventricular tachycardia were prospectively evaluated. Global longitudinal strain (GS), global systolic strain rate (GSRs), and global early diastolic strain rate (GSRe) of the right ventricle were measured using speckle tracking from apical views and compared with standard parameters of RV function (fractional area change, tricuspid annular plane systolic excursion, tissue Doppler velocities, and isovolumic acceleration) for association with and potential prediction of clinical events, defined as incident stage C heart failure or ventricular tachycardia. RESULTS: Baseline RV GS, GSRs, and GSRe were -12.5 +/- 3.0%, -0.59 +/- 0.14 sec(-1), and 0.68 +/- 0.22 sec(-1), respectively. After a median of 2.4 years (interquartile range, 1.5-4.1 years), 12 patients (19%) presented with clinical events (heart failure in 11 patients, ventricular tachycardia in one patient). In Cox models, RV GS had the strongest association with clinical events (hazard ratio [HR] per 1%, 1.35; 95% confidence interval [CI], 1.14-1.58; P < .001), followed by GSRs (HR per 0.01 sec(-1), 1.06; 95% CI, 1.02-1.11; P = .006), GSRe (HR per -0.01 sec(-1), 1.04; 95% CI, 1.00-1.07; P = .031), and fractional area change (HR per -1%, 1.08; 95% CI, 1.00-1.17; P = .047). Other measures of RV function were not significantly associated with risk for events. In receiver operating characteristic analysis, RV GS >= -10% optimally predicted future events (C = 0.83; 95% CI, 0.71-0.91; P < .001). CONCLUSIONS: Reduced longitudinal GS of the systemic right ventricle is associated with increased risk for clinical events among patients with D-transposition of the great arteries and prior atrial switch. PMID- 22196885 TI - Improvements in transcatheter aortic valve implantation outcomes in lower surgical risk patients: a glimpse into the future. AB - OBJECTIVES: The purpose of this study was to investigate the evolution of patient selection criteria for transcatheter aortic valve implantation (TAVI) and its impact on clinical outcomes. BACKGROUND: Anecdotal evidence suggests that patient selection for TAVI is shifting toward lower surgical risk patients. The extent of this shift and its impact on clinical outcomes, however, are currently unknown. METHODS: We conducted a single-center study that subcategorized TAVI patients into quartiles (Q1 to Q4) defined by enrollment date. These subgroups were subsequently examined for differences in baseline characteristics and 30-day and 6-month mortality rate. The relationship between quartiles and mortality rate was examined using unadjusted and adjusted (for baseline characteristics) Cox proportional hazard models. RESULTS: Each quartile included 105 patients (n = 420). Compared with Q4 patients, Q1 patients had higher logistic EuroSCORES (25.4 +/- 16.1% vs. 17.8 +/- 12.0%, p < 0.001), higher Society of Thoracic Surgeons scores (7.1 +/- 5.5% vs. 4.8 +/- 2.6%, p > 0.001), and higher median N-terminal pro-B-type natriuretic peptide levels (3,495 vs. 1,730 ng/dl, p < 0.046). From Q1 to Q4, the crude 30-day and 6-month mortality rate decreased significantly from 11.4% to 3.8% (unadjusted hazard ratio [HR]: 0.33; 95% confidence interval [CI]: 0.11 to 1.01; p = 0.053) and from 23.5% to 12.4% (unadjusted HR: 0.49; 95 CI: 0.25 to 0.95; p = 0.07), respectively. After adjustment for baseline characteristics, there were no significant differences between Q1 and Q4 in 30 day mortality rate (adjusted HR ratio: 0.29; 95% CI: 0.08 to 1.08; p = 0.07) and 6-month mortality rate (HR: 0.67; 95% CI: 0.25 to 1.77; p = 0.42). CONCLUSIONS: The results of this study demonstrate an important paradigm shift toward the selection of lower surgical risk patients for TAVI. Significantly better clinical outcomes can be expected in lower than in higher surgical risk patients undergoing TAVI. PMID- 22196886 TI - IKKalpha activation of NOTCH links tumorigenesis via FOXA2 suppression. AB - Proinflammatory cytokine TNFalpha plays critical roles in promoting malignant cell proliferation, angiogenesis, and tumor metastasis in many cancers. However, the mechanism of TNFalpha-mediated tumor development remains unclear. Here, we show that IKKalpha, an important downstream kinase of TNFalpha, interacts with and phosphorylates FOXA2 at S107/S111, thereby suppressing FOXA2 transactivation activity and leading to decreased NUMB expression, and further activates the downstream NOTCH pathway and promotes cell proliferation and tumorigenesis. Moreover, we found that levels of IKKalpha, pFOXA2 (S107/111), and activated NOTCH1 were significantly higher in hepatocellular carcinoma tumors than in normal liver tissues and that pFOXA2 (S107/111) expression was positively correlated with IKKalpha and activated NOTCH1 expression in tumor tissues. Therefore, dysregulation of NUMB-mediated suppression of NOTCH1 by TNFalpha/IKKalpha-associated FOXA2 inhibition likely contributes to inflammation mediated cancer pathogenesis. Here, we report a TNFalpha/IKKalpha/FOXA2/NUMB/NOTCH1 pathway that is critical for inflammation mediated tumorigenesis and may provide a target for clinical intervention in human cancer. PMID- 22196887 TI - Polycomb protein Ezh1 promotes RNA polymerase II elongation. AB - Polycomb group (PcG) proteins initiate the formation of repressed chromatin domains and regulate developmental gene expression. A mammalian PcG protein, enhancer of zeste homolog 2 (Ezh2), triggers transcriptional repression by catalyzing the addition of methyl groups onto lysine 27 of histone H3 (H3K27me2/3). This action facilitates the binding of other PcG proteins to chromatin for purposes of transcriptional silencing. Interestingly, there exists a paralog of Ezh2, termed Ezh1, whose primary function remains unclear. Here, we provide evidence for genome-wide association of Ezh1 complex with active epigenetic mark (H3K4me3), RNA polymerase II (Pol II), and mRNA production. Ezh1 depletion reduced global Pol II occupancy within gene bodies and resulted in delayed transcriptional activation during differentiation of skeletal muscle cells. Conversely, overexpression of wild-type Ezh1 led to premature gene activation and rescued Pol II occupancy defects in Ezh1-depleted cells. Collectively, these findings reveal a role for a PcG complex in promoting mRNA transcription. PMID- 22196888 TI - Spinal reflex properties in the long term after stroke. AB - In the long term after stroke, secondary functional deterioration may be observed while patients also get older. Possible underlying mechanisms are largely unknown. We aimed to assess neuromuscular degeneration represented by alterations in peripheral reflex loop characteristics as a function of follow-up time after stroke, controlled for age. Twenty-one stroke survivors within a small age range (62-67 years) but large variance in follow-up time after stroke (1-15 years) and both five age matched (59-62 years) and young subjects (28-36 years) participated. Short and long latency reflexes evoked by ramp and hold stretches were identified from EMG traces of the m. flexor carpi radialis. Short latency reflex onset time was not enhanced (mean difference 1.6ms compared to age matched controls) and did not relate to follow-up time after stroke (p=0.81). Young controls showed significantly lower reflex delay times (mean difference 7.2ms with respect to older subjects, p=0.009). No evidence was found for peripheral neuromuscular deterioration as a function of follow up time after stroke. Functional deterioration as a result of ageing of stroke patients that may interact with post stroke follow-up time is of further interest. PMID- 22196889 TI - Sperm parameters and male fertility after bariatric surgery: three case series. AB - Recent studies have underlined the impact of obesity on sperm parameters, but very few data are available on the effect of weight loss on male fertility. This article reports the case series of three male patients who underwent rapid and major weight loss following bariatric surgery and the consequences of this surgery on semen parameters and fertility. A severe worsening of semen parameters was observed during the months after bariatric surgery, including extreme oligoasthenoteratozoospermia, but azoospermia was not observed. This effect may hypothetically be the result of two opposite mechanisms: (i) the suppression of the deleterious effects of obesity; and (ii) the negative impact of both nutritional deficiencies and the release of toxic substances. Information about potential reproductive consequences of bariatric surgery should be given to patients and sperm cryopreservation before surgery proposed. However, for one case, the alterations of spermatogenesis were reversible 2 years after the surgical procedure. Finally, intracytoplasmic sperm injection with fresh spermatozoa after male bariatric surgery can be successful, as demonstrated here, where clinical pregnancies were obtained for two out of the three couples. PMID- 22196890 TI - Oocyte vitrification technology has made egg-sharing donation easier in China. AB - When infertile women undergoing IVF or intracytoplasmic sperm injection (ICSI) have more than 20 mature oocytes retrieved, at least 15 oocytes are inseminated by their husband's spermatozoa. The extra oocytes are cryopreserved by vitrification. If the patients became pregnant and have healthy live births, the patients are encouraged to donate their remaining cryopreserved oocytes. Forty seven egg-sharing donors were recruited after having normal deliveries and they donated their remaining oocytes, totalling 395 cryopreserved oocytes, to 75 recipients. The survival rate of vitrified-warmed oocytes was 83.0%. Following insemination by ICSI, the fertilization and cleavage rates were 83.8% and 89.8%, respectively. Out of 75 recipients, 71 recipients completed the treatment cycles and 30 of them became pregnant with clinical pregnancy and implantation rates of 42.3% and 25.5%, respectively. The birthweight of the new-born infants (22 from singleton and two from one set of twins) were 3344.5 +/- 669.1g and 2425.0 +/- 742.5 g, respectively. No birth defects were observed for the live births. These results indicate that oocyte vitrification is an effective methodology for an egg sharing donation programme, with acceptable pregnancy and implantation rates. PMID- 22196891 TI - Triggering with GnRH agonist in oocyte-donation cycles: oestradiol monitoring is not necessary during ovarian stimulation. AB - This prospective observational study evaluated the efficacy and safety of oocyte donation cycles triggered with a gonadotrophin-releasing hormone (GnRH) agonist without monitoring oestradiol concentrations during ovarian stimulation. A total of 97 oocyte donors received recombinant FSH (150-225/day) and GnRH antagonists (0.25mg/day). Oocyte maturation was triggered with 0.2mg triptorelin s.c. Donors aged 25.4 +/- 4.1 years were stimulated for 8.8 +/- 0.9 days and underwent 2.9 +/ 0.5 (2-4) ultrasound assessments. Total FSH dose was 1703.4 +/- 304.7IU, antagonists were administered for 4.3 +/- 1.0 days, 14.7 +/- 8.8 oocytes were retrieved and there were no cases of ovarian hyperstimulation syndrome. Recipients (n=123) aged 40.3 +/- 3.4 years received 10.9 +/- 4.3 oocytes, 88.7% of which were metaphase II. Intracytoplasmic sperm injection fertilization rate was 79% and 2.18 +/- 0.6 (1-3) embryos were transferred. The pregnancy, clinical pregnancy and twin pregnancy rates were 64.2%, 57.7% and 19.7%, respectively. In conclusion, given the high efficacy and safety of the GnRH-antagonist protocol triggered with a GnRH agonist, the monitoring of oestradiol concentrations is not necessary. Ultrasound monitoring is enough for an adequate follow up of the stimulation cycle in oocyte donors. PMID- 22196892 TI - Sperm FISH analysis of a 46,XY,t(3;6)(p24;p21.2),inv (8)(p11;2q21.2) double chromosomal rearrangement. AB - A complex chromosome rearrangement (CCR) can be defined as a structural chromosomal aberration that involves at least three breakpoints located on two or more chromosomes. Highly unbalanced gametes may lead to infertility or congenital malformations. Here is reported a double rearrangement considered as the simplest possible CCR and, in a sense, not a true CCR, meiotic segregation for a 46,XY,t(3;6)(p24;p21.2),inv(8)(p11;2q21.2) male patient referred after his partner had undergone three early miscarriages. Sperm fluorescence in-situ hybridization was used to screen for translocation and inversion segregation and an interchromosomal effect (ICE) for 13 chromosomes not involved in CCR. The malsegregation rates for the reciprocal translocation and pericentric inversion were 61.2% and 1.7%, respectively. ICE analysis revealed that the observed chromosome aneuploidy rates of between 0.1% and 0.8% did not differ significantly from control values. A slight increase in cumulative ICE (P=0.049) was observed in the patient, relative to control spermatozoa (with rates of 4.6% and 3.1%). The sperm DNA fragmentation rate differed significantly from control values (5.0%; P=0.001). Reciprocal translocation had no impact on meiotic segregation of the pericentric inversion in this double rearrangement. No conclusion could be drawn regarding the impact of pericentric inversion on translocation. PMID- 22196893 TI - Extra-embryonic human Wharton's jelly stem cells do not induce tumorigenesis, unlike human embryonic stem cells. AB - Tumorigenesis is the major obstacle of tissues derived from human embryonic stem cells (ESC) and human induced pluripotent stem cell (IPSC) for transplantation therapy. This prompted a search for other sources of ESC. This study isolated and characterized stem cells from the extra-embryonic human umbilical cord Wharton's jelly (WJSC). These cells are non-controversial, available in abundance, proliferative, multipotent and hypoimmunogenic. However, their tumorigenic potential has not been properly addressed. Their tumour-producing capabilities were compared with human ESC using the immunodeficient mouse model. Unlabelled human ESC+matrigel (2*10(6)cells/site), labelled human WJSC (red fluorescent protein; 5*10(6)cells/site) and unlabelled human WJSC+matrigel (5*10(6)cells/site) were injected via three routes (s.c., i.m. and i.p.). Animals that received human ESC+matrigel developed teratomas in 6 weeks (s.c. 85%; i.m. 75%; i.p. 100%) that contained tissues of ectoderm, mesoderm and endoderm. No animal that received human WJSC developed tumours or inflammatory reactions at the injection sites when maintained for a prolonged period (20 weeks). Human WJSC produced increases in anti-inflammatory cytokines in contrast to human ESC, which increased pro-inflammatory cytokines. Human WJSC, being hypoimmunogenic and non tumorigenic, have the potential for safe cell-based therapies. PMID- 22196894 TI - A tunable general purpose Q-band resonator for CW and pulse EPR/ENDOR experiments with large sample access and optical excitation. AB - We describe a frequency tunable Q-band cavity (34 GHz) designed for CW and pulse Electron Paramagnetic Resonance (EPR) as well as Electron Nuclear Double Resonance (ENDOR) and Electron Electron Double Resonance (ELDOR) experiments. The TE(011) cylindrical resonator is machined either from brass or from graphite (which is subsequently gold plated), to improve the penetration of the 100 kHz field modulation signal. The (self-supporting) ENDOR coil consists of four 0.8mm silver posts at 2.67 mm distance from the cavity center axis, penetrating through the plunger heads. It is very robust and immune to mechanical vibrations. The coil is electrically shielded to enable CW ENDOR experiments with high RF power (500 W). The top plunger of the cavity is movable and allows a frequency tuning of +/-2 GHz. In our setup the standard operation frequency is 34.0 GHz. The microwaves are coupled into the resonator through an iris in the cylinder wall and matching is accomplished by a sliding short in the coupling waveguide. Optical excitation of the sample is enabled through slits in the cavity wall (transmission ~60%). The resonator accepts 3mm o.d. sample tubes. This leads to a favorable sensitivity especially for pulse EPR experiments of low concentration biological samples. The probehead dimensions are compatible with that of Bruker flexline Q-band resonators and it fits perfectly into an Oxford CF935 Helium flow cryostat (4-300 K). It is demonstrated that, due to the relatively large active sample volume (20-30 MUl), the described resonator has superior concentration sensitivity as compared to commercial pulse Q-band resonators. The quality factor (Q(L)) of the resonator can be varied between 2600 (critical coupling) and 1300 (over-coupling). The shortest achieved pi/2-pulse durations are 20 ns using a 3 W microwave amplifier. ENDOR (RF) pi-pulses of 20 MUs ((1)H @ 51 MHz) were obtained for a 300 W amplifier and 7 MUs using a 2500 W amplifier. Selected applications of the resonator are presented. PMID- 22196895 TI - Characterization of CCR9 expression and thymus-expressed chemokine responsiveness of the murine thymus, spleen and mesenteric lymph node. AB - CC chemokine receptor 9 (CCR9) is a receptor expressed at high levels in immature thymocytes, small intestine trafficking T cells and IgA-producing plasma cells. CCR9 mediates chemotaxis in response to thymus-expressed chemokine (TECK) selectively expressed in the thymus and small intestine. CCR9 expression in different subpopulations of thymus, spleen and mesenteric lymph node (MLN) cells was analyzed by flow cytometry and TECK responsiveness of those lymphoid cells was assessed by a Transwell migration assay. CCR9 surface expression level did not completely correlate with cellular chemotaxis to its cognate ligand TECK. The active chemotaxis to TECK was observed in CD4 single positive thymocytes and CD4( )B220(hi) splenocyte and MLN cells, which poorly expressed CCR9 on their surface. TECK responsiveness of CCR9-abundant subpopulations in the thymus and MLN was unremarkable except for CD4(+)B220(hi) subset of the MLN, and was evident in the CCR3(+) subsets of the thymus and spleen. Exposure to TECK did not affect CCR9 expression in the thymus, spleen and MLN, except for the CD4(+)CD8(+) thymocyte. CCR9 was exuberantly expressed in the cytoplasm of lymphoid cells. CCR9 may act in concert with CCR3 for in terms of TECK responsiveness. Its cytoplasmic location may allow precise regulation of leukocyte responsiveness to TECK. PMID- 22196896 TI - Formamide and the origin of life. AB - The complexity of life boils down to the definition: "self-sustained chemical system capable of undergoing Darwinian evolution" (Joyce, 1994) [1]. The term "self-sustained" implies a set of chemical reactions capable of harnessing energy from the environment, using it to carry out programmed anabolic and catabolic functions. We briefly present our opinion on the general validity of this definition. Running anabolic and catabolic functions entails complex chemical information whose stability, reproducibility and evolution constitute the core of what is dubbed genetics. Life as-we-know-it is made of the intimate interaction of metabolism and genetics, both built around the chemistry of the most common elements of the Universe (hydrogen, oxygen, nitrogen, carbon). Other elements like phosphorus and sulphur play important but ancillary and potentially replaceable roles. The reproducible interaction of metabolic and genetic cycles results in the hypercycles of organization and de-organization of chemical information that we consider living entities. In order to approach the problem of the origin of life it is therefore reasonable to start from the assumption that both metabolism and genetics had a common origin, shared a common chemical frame, were embedded in physical-chemical conditions favourable for the onset of both. The most abundant three-atoms organic compound in interstellar environment is hydrogen cyanide HCN, the most abundant three-atoms inorganic compound is water H(2)O. The combination of the two results in the formation of formamide H(2)NCOH. We have explored the chemistry of formamide in conditions compatible with the synthesis and the stability of compounds of potential pre-genetic and pre metabolic interest. We discuss evidence showing (i) that all the compounds necessary for the build-up of nucleic acids are easily obtained abiotically, (ii) that essentially all the steps leading to the spontaneous generation of RNA are abiotically possible, (iii) that the key compounds of extant metabolic cycles are obtained in the same chemical frame, often in the same test tube. How close are these observations to a plausible scenario for the origin of life? PMID- 22196897 TI - The fracture load and failure types of veneered anterior zirconia crowns: an analysis of normal and Weibull distribution of complete and censored data. AB - OBJECTIVES: The aim of this study was to compare the fracture load of veneered anterior zirconia crowns using normal and Weibull distribution of complete and censored data. METHODS: Standardized zirconia frameworks for maxillary canines were milled using a CAD/CAM system and randomly divided into 3 groups (N=90, n=30 per group). They were veneered with three veneering ceramics, namely GC Initial ZR, Vita VM9, IPS e.max Ceram using layering technique. The crowns were cemented with glass ionomer cement on metal abutments. The specimens were then loaded to fracture (1 mm/min) in a Universal Testing Machine. The data were analyzed using classical method (normal data distribution (MU, sigma); Levene test and one-way ANOVA) and according to the Weibull statistics (s, m). In addition, fracture load results were analyzed depending on complete and censored failure types (only chipping vs. total fracture together with chipping). RESULTS: When computed with complete data, significantly higher mean fracture loads (N) were observed for GC Initial ZR (MU=978, sigma=157; s=1043, m=7.2) and VITA VM9 (MU=1074, sigma=179; s=1139; m=7.8) than that of IPS e.max Ceram (MU=798, sigma=174; s=859, m=5.8) (p<0.05) by classical and Weibull statistics, respectively. When the data were censored for only total fracture, IPS e.max Ceram presented the lowest fracture load for chipping with both classical distribution (MU=790, sigma=160) and Weibull statistics (s=836, m=6.5). When total fracture with chipping (classical distribution) was considered as failure, IPS e.max Ceram did not show significant fracture load for total fracture (MU=1054, sigma=110) compared to other groups (GC Initial ZR: MU=1039, sigma=152, VITA VM9: MU=1170, sigma=166). According to Weibull distributed data, VITA VM9 showed significantly higher fracture load (s=1228, m=9.4) than those of other groups. SIGNIFICANCE: Both classical distribution and Weibull statistics for complete data yielded similar outcomes. Censored data analysis of all ceramic systems based on failure types is essential and brings additional information regarding the susceptibility to chipping or total fracture. PMID- 22196898 TI - In vitro performance of full-contour zirconia single crowns. AB - OBJECTIVES: Zirconia based restorations exhibited high failure rates due to veneering-porcelain fractures. Milling to full-contour might be an alternative approach for zirconia restorations. The aim of this study was to evaluate full contour zirconia crowns in terms of light-transmission, contact wear (restoration and antagonist) and load-bearing capacity. Powder build-up veneered zirconia substructures and CAD/CAM-veneered zirconia substructures served as controls. METHODS: Four different kinds of crowns were fabricated on 12 metal dies: zirconia substructure with powder build-up porcelain (veneering technique), zirconia substructure with CAD/CAM generated veneering (sintering technique), full-contour zirconia glazed (glazed full-contour) and full-contour zirconia polished (polished full-contour). All crowns had the same dimensions. After light transmission was measured the crowns were cemented on the corresponding metal dies. The specimens were loaded according to a special wear method in the chewing simulator (120,000 mechanical cycles, 5 kg load, 0.7 mm sliding movement, 320 thermocycles). Wear of the restoration and the antagonist were measured. All specimens were loaded until failure. One-way ANOVA and a LSD post-hoc test were used to compare data at a level of 5%. RESULTS: Polished full-contour showed significantly higher light transmission than the other groups (p=0.003; ANOVA). Polished full-contour exhibited significantly less contact wear at the restoration (p=0.01; ANOVA) and higher contact wear at the antagonist (p=0.016; ANOVA) compared to the other groups. Glazed full-contour zirconia showed similar contact wear at the antagonist compared to veneering technique (p=0.513, post-hoc LSD). Crowns with conventional veneering showed significantly lower load-bearing capacity (p<0.001; ANOVA). SIGNIFICANCE: Milling zirconia to full-contour with glazed surface might be an alternative to traditionally veneered restorations. PMID- 22196899 TI - The role of hydrogels with tethered acetylcholine functionality on the adhesion and viability of hippocampal neurons and glial cells. AB - In neural tissue engineering, designing materials with the right chemical cues is crucial in providing a permissive microenvironment to encourage and guide neuronal cell attachment and differentiation. Modifying synthetic hydrogels with biologically active molecules has become an increasingly important route in this field to provide a successful biomaterial and cell interaction. This study presents a strategy of using the monomer 2-methacryloxyethyl trimethylammonium chloride (MAETAC) to provide tethered neurotransmitter acetylcholine-like functionality with a complete 2-acetoxy-N,N,N-trimethylethanaminium segment, thereby modifying the properties of commonly used, non-adhesive PEG-based hydrogels. The effect of the functional monomer concentration on the physical properties of the hydrogels was systematically studied, and the resulting hydrogels were also evaluated for mice hippocampal neural cell attachment and growth. Results from this study showed that MAETAC in the hydrogels promotes neuronal cell attachment and differentiation in a concentration-dependent manner, different proportions of MAETAC monomer in the reaction mixture produce hydrogels with different porous structures, swollen states, and mechanical strengths. Growth of mice hippocampal cells cultured on the hydrogels showed differences in number, length of processes and exhibited different survival rates. Our results indicate that chemical composition of the biomaterials is a key factor in neural cell attachment and growth, and integration of the appropriate amount of tethered neurotransmitter functionalities can be a simple and effective way to optimize existing biomaterials for neuronal tissue engineering applications. PMID- 22196900 TI - A 3D microfibrous scaffold for long-term human pluripotent stem cell self-renewal under chemically defined conditions. AB - Realizing the potential of human pluripotent stem cell (hPSC)-based therapy requires the development of defined scalable culture systems with efficient expansion, differentiation and isolation protocols. We report an engineered 3D microfiber system that efficiently supports long-term hPSCs self-renewal under chemically defined conditions. The unique feature of this system lies in the application of a 3D ECM-like environment in which cells are embedded, that affords: (i) uniform high cell loading density in individual cell-laden constructs (~10(7) cells/ml); (ii) quick recovery of encapsulated cells (<10min at 37 degrees C) with excellent preservation of cell viability and 3D multicellular structure; (iii) direct cryopreservation of the encapsulated cells in situ in the microfibers with >17-fold higher cell viability compared to those cultured on Matrigel surface; (iv) long-term hPSC propagation under chemically defined conditions. Four hPSC lines propagated in the microfibrous scaffold for 10 consecutive passages were capable of maintaining an undifferentiated phenotype as demonstrated by the expression of stem cell markers and stable karyotype in vitro and the ability to form derivatives of the three germ layers both in vitro and in vivo. Our 3D microfibrous system has the potential for large-scale cultivation of transplantable hESCs and derivatives for clinical applications. PMID- 22196901 TI - A pyrene-imidazolium derivative that selectively recognizes G-quadruplex DNA. AB - G-quadruplexes, formed of four stranded guanine bases stabilized by monovalent cations, serve important role in cancer cell growth and control gene expression in telomere. Since there are various types of quadruplex structures, rapid and simple screening methods with high selectivity, sensitivity and nontoxicity are required for understanding about the biological roles of quadruplex DNA as well as in designing therapeutics. Herein, we report a pyrene-imidazolium derivative, JY-1, which can with high selectivity recognize G-quadruplex using fluorescence and NMR spectroscopy. This is the first example based on the imidazolium derivative, which can detect the G-quadruplex directly to utilize the excimer/monomer emission change in pyrene fluorophore. The selectivity of strong binding to a specific sequence can allow for quadruplex sensing and the detection method presented here is very simple, using fluorescence and NMR study. Also, the groove binding characteristic of JY-1 to the G-quadruplex has a relatively low nonspecific toxicity and the structure-specific differences in fluorescent character between DNA duplex and G-quadruplex may offer more discovery and application in biological study. PMID- 22196903 TI - Soft tissue and bone MRSA infections. PMID- 22196902 TI - pH-responsive drug delivery system based on luminescent CaF(2):Ce(3+)/Tb(3+) poly(acrylic acid) hybrid microspheres. AB - In this study, we design a controlled release system based on CaF(2):Ce(3+)/Tb(3+)-poly(acrylic acid) (PAA) composite microspheres, which were fabricated by filling the pH-responsive PAA inside CaF(2):Ce(3+)/Tb(3+) hollow spheres via photopolymerization route. The CaF(2):Ce(3+)/Tb(3+) hollow spheres prepared by hydrothermal route possess mesoporous structure and show strong green fluorescence from Tb(3+) under UV excitation. Doxorubicin hydrochloride (DOX), a widely used anti-cancer drug, was used as a model drug to evaluate the loading and controlled release behaviors of the composite microspheres due to the good biocompatibility of the samples using MTT assay. The composite carriers provide a strongly pH-dependent drug release behavior owing to the intrinsic property of PAA and its interactions with DOX. The endocytosis process of drug-loaded microspheres was observed using confocal laser scanning microscopy (CLSM) and the in vitro cytotoxic effect against SKOV3 ovarian cancer cells of the DOX-loaded carriers was investigated. In addition, the extent of drug release could be monitored by the altering of photoluminescence (PL) intensity of CaF(2):Ce(3+)/Tb(3+). Considering the good biocompatibility, high drug loading content and pH-dependent drug release of the materials, these hybrid luminescent microspheres have potential applications in drug controlled release and disease therapy. PMID- 22196904 TI - Treatment of MRSA soft tissue infections: an overview. AB - MRSA is becoming increasingly common worldwide. With the emergence of new highly spreadable strains (community associated or CA-MRSA) novel presentation skin and soft tissue infections (SSTI) are being seen. Recurrent SSTI, including folliculitis, furunculosis and abscesses account for an increasing proportion of SSTI seen in the emergency department. Empirical antimicrobial management choices can be difficult, but clues to the nature of the MRSA may be gleaned from the history and clinical presentation. More severe SSTI due to necrotising fasciitis and purpura fulminans are emerging and warrant the broadest possible empirical Gram-positive cover, ideally with antimicrobials that stop exotoxin production, and sometimes intravenous immunoglobulin to neutralise exotoxins already produced. PMID- 22196905 TI - Management of bone infections in adults: the surgeon's and microbiologist's perspectives. AB - Bone infection in adults is a potentially devastating complication following trauma or surgery. The clinician should diagnose osteomyelitis based on certain clinical manifestations and on laboratory and imaging findings. For pathogen identification, the treating surgeon should take appropriate tissue samples. Close collaboration with microbiologists is of paramount importance to dictate the appropriate duration and type of antibiotics to be administered. Treatment of acute osteomyelitis requires surgical debridement and prolonged course of antibiotics. Debate exists regarding the maintenance or the removal of any internal fixation device. Treatment of chronic osteomyelitis is more complicated. For its eradication the treatment course is often prolonged and frustrating. Based on the current literature an algorithm of treatment for both acute and chronic bone infections is recommended. PMID- 22196906 TI - Patients' views and experience of intravenous and oral antimicrobial therapy: room for change. AB - Little is known about patients' views or preferences about the route of administration of antimicrobials. In this study semi-structured interviews were carried out to assess patients' perceptions of an infection that required IV antimicrobial therapy in hospital, their preference for intravenous, IV followed by oral and discharge on oral therapy or home IV therapy. Interviews were transcribed and the content analysed. Twelve patients were interviewed while in hospital or by telephone after discharge. Patients' information about their infection was incomplete and many expressed the view that they would like more information. Many patients expressed a preference for oral therapy over IV therapy although this was dependent on it being of equal efficacy. Contrary views were related to personal difficulty with tablets. Patients varied in their acceptance of home IV therapy and expressed concern about adequate support but the majority expressed a preference for being discharged on oral therapy once they were well enough. PMID- 22196907 TI - Treatment of post-operative infections following proximal femoral fractures: our institutional experience. AB - Proximal femoral fractures (PFFs) are a major health concern in the elderly population. Improvements made in implants and surgical techniques resulted in faster rehabilitation and shorter length of hospital stay. Despite this, the reduced physiological reserve, associated co-morbidities and polypharmacy intake of the elderly population put them at high risk of postoperative complications particularly of infectious origin. Out of 10061 patients with proximal femoral fractures 105 (1.05%) developed surgical site infection; 76 (72%) infections occurred in patients who had sustained intracapsular (IC) fractures with the remaining 29 (28%) infections occurring in patients with extracapsular (EC) neck of femur fractures. The median number of additional surgical debridements was 2 (range 1-7). MRSA was isolated in 49 (47%) of the cases; 38 patients (36%) ultimately underwent a Girdlestone's excisional arthroplasty. Mortality at 30 days and 3 months was 10% and 31%, respectively. It was noted that post-operative hip infection predisposed to a prolonged length of stay in the acute unit and subsequently to a more dependent destination after discharge. PMID- 22196908 TI - MRSA prevention strategies and current guidelines. AB - We review prevention strategies to minimise the risk of MRSA soft tissue and bone infections, which can be devastating for the patient and costly for the healthcare provider. Department of Health (England) policy is that screening for emergency admissions will be mandatory from 2011, in addition to existent elective admission screening. Rapid screening technology has not been shown to be cost-effective, meaning that there will be a lag time between admission and the patient's MRSA status being known. Thus, standard infection control policies regarding isolation of high-risk patients will remain, with a continuing focus on MRSA decolonisation, aimed at minimising the risks of auto-infection and transmission to other patients. Antimicrobial prescribing policies should be designed to take into account the local burden of resistant organisms, but also minimise unnecessary antibiotic use. There is an increasing realisation that reducing the use of fluoroquinolones and third-generation cephalosporins (which have been associated with increased carriage of MRSA) in patient populations where MRSA is prevalent can be a useful control measure. Prevention of orthopaedic infections clearly involves general operating theatre protocols, such as suitable antiseptic skin preparation, and additional measures including the use of laminar airflow. Antibiotic prophylaxis is adjusted in patients known to have MRSA to include a glycopeptide, and local guidelines may adopt such regimens for all patients due to the burden of MRSA in the local patient population. A future development that may have an effect on practice is the development of a Staphylococcus aureus vaccine, which has been shown to be cost-effective in a computer-modelled evaluation. PMID- 22196909 TI - Infections in vascular surgery. AB - Infections in vascular surgery are usually of multifactorial nature resulting from a complex interplay of patient, surgical and environmental factors. Preventative measures initiated from the stage of pre-operative screening, maintenance of patient homeostasis and the use of organism-directed antibiotics can contribute to reduce infection rates. Graft preservation techniques are becoming increasingly popular as a method to treat established graft infections. In this article we report on the current trends and techniques on the management of infections in vascular surgery. Ongoing studies are required to continue to accumulate data on the effectiveness of these techniques. PMID- 22196910 TI - MRSA new treatments on the horizon: current status. AB - There is a choice of anti-MRSA antibiotic available with proven efficacy in the treatment of complicated skin and skin structure infection (cSSSI). Additional anti-MRSA antibiotics are in development, which have the potential to influence how such infections are managed. The emergence of resistance to current anti-MRSA agents, toxicity, and general lack of oral agents with proven efficacy for deep seated infection justify the development of new agents. However, there is a relative dearth of information specific to patients with orthopaedic-related infection. Combination therapy is often used in these patients, although there is a paucity of controlled trial data to support particular antibiotic combinations. As the choice of anti-MRSA agents increases, so does the need to identify which are best for the large variety of infections included in the group of cSSSIs. This is particular true for infections occurring in orthopaedic patients where poorly vascularised tissue, trauma or implanted prosthetic material, pose specific challenges. PMID- 22196911 TI - Pharmacological agents for soft tissue and bone infected with MRSA: which agent and for how long? AB - Methicillin-resistant Staphylococcus aureus (MRSA) infections cause an important number of soft tissue and bone infections, although exact rates vary across different countries and institutions. The length of antibiotic treatment required depends upon the severity of infection and pre-existing co-morbidities. Monitoring response to treatment is important to ensure cure of infection whilst preventing excessive antibiotic use. Debridement and drainage, in addition to prosthesis removal, may be necessary. Numerous antibiotics are effective at treating soft tissue and bone infected with MRSA. Oral antibiotics, such as clindamycin, doxycycline and linezolid, generally offer good bioavailability and tissue penetration. They are separated largely by side effect profile and drug interactions, which should be considered carefully prior to use. There are also several agents only available in the intravenous (IV) form, for example glycopeptides, daptomycin and tigecycline. These are normally reserved for the treatment of severe infections. Whilst tissue penetration is variable within this group, it is the adverse events linked with each antibiotic that are most effective in determining the preferred agent. PMID- 22196912 TI - Analyses of sexual dimorphism of reconstructed pelvic computed tomography images of contemporary Japanese using curvature of the greater sciatic notch, pubic arch and greater pelvis. AB - Three-dimensional pelvic images were reconstructed from multi-slice CT data of contemporary Japanese (males: 124; females: 104, 25-92 years old), and curvature analysis to examine sexual dimorphism was carried out in the great sciatic notch (GSN), the pubic arch and the greater pelvis in the images. Reconstructed pelvic CT images were visualized fairly well and anatomical landmarks were easily recognizable. When calculating the radii (curvature radii) of the best-fit circles for the spline curve lines set along the edges of the GSNs and of the pubic arches, sexes from these regions were correctly identified in 89.1% (males: 93.8%; females: 83.7%) and 94.7% (males: 97.3%; females: 91.8%) of cases, respectively, by setting an appropriate cut-off value. Furthermore, sexing was possible even in deeper regions of the GSN which are relatively resistant to postmortem damage. Curvature radii of the best-fit spheres of greater pelves showed no significant difference between sexes. However, curvature of the best fit sphere for the left iliac fossa was significantly larger than that of the right one (p<10(-24)) in males, and the ratios were >1.0 in 88% of all male specimens analyzed. Meanwhile, no significant difference was observed among female samples. Although some left-sided dominancy has been reported in 2 dimensional measurements of the human pelvis, this 3-dimensional laterality in males was much more significant, and is a potential index of sex difference. PMID- 22196913 TI - First practical applications of eye temperature measurements for estimation of the time of death in casework. Report of three cases. AB - This paper presents first three successive cases of death where at scene measurements of the internal eyeball temperature soon after death allowed to precisely estimate the times of deaths based on this data (33.1 degrees C, 32.2 degrees C and 29.5 degrees C, respectively), which were later confirmed during the police investigation. Simultaneously the rectal temperatures in all three cases were measured and appeared to be between 36.3 and 36.8 degrees C-reflecting a living individual's body temperature. Thanks to a significantly faster postmortem decrease of the eye temperature and a residual or nonexistent plateau effect affecting the eye, using the formula developed in previous comprehensive studies in pigs, the time of death in real cases could be estimated with good precision: 1 h 33 min, 2 h 24 min and 3 h 17 min since death respectively. The actual TOD established during investigation appeared to be: between 1 h 30 min and 1 h 50 min in case 1; 1 h 55 min in case 2 and between 2 h 55 min and 3 h 05 min in case 3. Such precise estimation, mainly due to the plateau effect lasting up to a few hours, could not have been done based only on rectal temperature, commonly measured in forensic practice. PMID- 22196914 TI - [Severe symptomatic hyponatraemia: what is the correct sodium correction rate?]. PMID- 22196915 TI - [Cerebrovascular disease in childhood: a retrospective analysis of hospital admissions in a tertiary hospital in the community of Valencia in the last ten years]. AB - INTRODUCTION: There has been increasing interest in stroke in children in the last few years. A literature review produced little information on risk factors and other clinical questions. The aim of this study is to describe the characteristics of stroke in children, mainly in order to identify the risk factors, clinical presentation and outcomes. PATIENTS AND METHODS: A retrospective study was conducted on patients admitted to the Hospital La Fe in Valencia between January 2000 to September 2010 with the diagnosis of ischaemic or haemorrhagic stroke. RESULTS: A total of 76 patients were identified, of whom 44.7% had an ischaemic stroke and 55.3% had a haemorrhagic one. The average age of presentation was 6.8 years; 8.4 years for haemorrhagic strokes and 4.7 years for ischaemic strokes. Headache was the most frequent symptom of presentation. The most frequent risk factor was vascular malformations in haemorrhagic cerebral stroke, and vascular and cardiac disorders in ischaemic stroke. A study of prothrombotic factors was conducted on 34 patients, which was positive in 64.7% of them. As regards outcome, 17% of the patients died; only 3 patients had a secondary epilepsy, and 31% and 60% of the haemorrhagic and ischaemic stokes, respectively, had a hemiparesis. CONCLUSIONS: In this study we identified the principal risk factors as well as, the age of presentation, symptomatology and outcome. We would like to emphasise that the age of presentation was earlier in ischaemic strokes than in haemorrhagic ones. PMID- 22196916 TI - [Whooping cough and cardiorespiratory arrest secondary to a bradycardia during coughing spells]. PMID- 22196917 TI - [Acute lymphoblastic leukaemia initially diagnosed and treated as chronic juvenile arthritis]. PMID- 22196918 TI - [Impact of a change of computer software on prescription drug errors in an emergency department]. AB - INTRODUCTION: Changing the computer software is a known risk factor of increased prescription drug errors. The aim of this study was to evaluate the effectiveness of preventive measures to prevent these errors at our centre. MATERIAL AND METHODS: In 2007 (period 1), knowing that a change of computer software was coming, a study to determine the prescription drug errors was performed and an improvement plan was designed. Errors were classified as: type of error (indication, dosage, route of administration), severity and associated risk factors (emergency level, patient age, physician experience, day of week, time of day). Following the introduction of the new computer software (year 2009) (period 2), the same parameters were re-evaluated and compared with the previous period. All Paediatric Emergency Department (PED) reports, where some treatment was administered in the Emergency room in the same week and month for both periods, were reviewed. RESULTS: A total of 615 prescriptions were written during period 1, of which 92 (15%) were classified as errors, and in period 2, 445 were written and 51 (11.5%) had errors, with no significant differences between both periods. There was a significant decrease in inappropriate indication errors (8.1% in period 1 vs 3.6% in period 2; P=.04), with no differences in dosage, route of administration and severity of errors. There was a significant error reduction in more experienced physicians, and an increase in errors by external rotation physicians (who were not skilled in the use of the new program). CONCLUSIONS: The knowledge of the previous situation and the use of preventive measures ensured that errors did not increase after a change of computer software. PMID- 22196919 TI - Targeted agents in non-small cell lung cancer (NSCLC): clinical developments and rationale for the combination with thoracic radiotherapy. AB - In recent years there has been undoubted progress in the evaluation and development of targeted agents for non-small cell lung cancer (NSCLC). A major contributor has been the discovery of molecular subtypes harbouring a critical oncogenic driver mutation, specifically sensitizing mutations in the epidermal growth factor receptor (EGFR) gene and the EML4-ALK gene translocation. Radiotherapy is a cornerstone of therapy for the curative intent treatment of early stage, localized disease; and for the palliation of symptoms in advanced, metastatic disease. In this molecular targeted era there is limited understanding of how best to combine targeted agents with radiotherapy and in general clinical studies with radiotherapy have lagged behind studies of targeted agents with chemotherapy. Here we summarise the progress made to date and highlight future directions. PMID- 22196920 TI - Forest carbon stocks and fluxes in physiographic zones of India. AB - BACKGROUND: Reducing carbon Emissions from Deforestation and Degradation (REDD+) is of central importance to combat climate change. Foremost among the challenges is quantifying nation's carbon emissions from deforestation and degradation, which requires information on forest carbon storage. Here we estimated carbon storage in India's forest biomass for the years 2003, 2005 and 2007 and the net flux caused by deforestation and degradation, between two assessment periods i.e., Assessment Period first (ASP I), 2003-2005 and Assessment Period second (ASP II), 2005-2007. RESULTS: The total estimated carbon stock in India's forest biomass varied from 3325 to 3161 Mt during the years 2003 to 2007 respectively. There was a net flux of 372 Mt of CO2 in ASP I and 288 Mt of CO2 in ASP II, with an annual emission of 186 and 114 Mt of CO2 respectively. The carbon stock in India's forest biomass decreased continuously from 2003 onwards, despite slight increase in forest cover. The rate of carbon loss from the forest biomass in ASP II has dropped by 38.27% compared to ASP I. CONCLUSION: With the Copenhagen Accord, India along with other BASIC countries China, Brazil and South Africa is voluntarily going to cut emissions. India will voluntary reduce the emission intensity of its GDP by 20-25% by 2020 in comparison to 2005 level, activities like REDD+ can provide a relatively cost-effective way of offsetting emissions, either by increasing the removals of greenhouse gases from the atmosphere by afforestation programmes, managing forests, or by reducing emissions through deforestation and degradation. PMID- 22196921 TI - Increased loss of the Y chromosome in peripheral blood cells in male patients with autoimmune thyroiditis. AB - Multiple mechanisms have been proposed to explain the peculiar distribution of autoimmune thyroiditis (AIT) among women and men. Most attention has been focused on the detection of the role of estrogens and the X chromosome. Specifically, a potential role for X haploinsufficiency has been proposed in the female patient population and an association with the disease has been confirmed. Our knowledge of the etiopathogenesis of autoimmunity in male patients remains, however, limited. Next to the possible role of androgens and their imbalances, the Y chromosome appears as a potential candidate for influence of the immune function in men. Herein we analyzed a population of male patients with AIT (n=31) and healthy controls (n=88) to define a potential association of disease and the loss of the Y chromosome. Y chromosome loss increases in AIT compared to unaffected subjects; these phenomenon increases with aging as expected, however, the degree of loss is significantly increased in the patient population compared to the healthy controls. We were, thus, able to confirm the existence of an analogous mechanism in the male population to previously identified X haploinsufficiency in female patients with AIT. We propose that this commonality might represent a relevant feature in the etiopathogenesis of AIT that should be further investigated. PMID- 22196922 TI - WITHDRAWN: A brief autobiography. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jaut.2011.05.017 The duplicate article has therefore been withdrawn. PMID- 22196923 TI - Anti-phospholipid induced murine fetal loss: novel protective effect of a peptide targeting the beta2 glycoprotein I phospholipid-binding site. Implications for human fetal loss. AB - beta2 glycoprotein I (beta2GPI)-dependent anti-phospholipid antibodies (aPL) induce thrombosis and affect pregnancy. The CMV-derived synthetic peptide TIFI mimics the PL-binding site of beta2GPI and inhibits beta2GPI cell-binding in vitro and aPL-mediated thrombosis in vivo. Here we investigated the effect of TIFI on aPL-induced fetal loss in mice. TIFI inhibitory effect on in vitro aPL binding to human trophoblasts was evaluated by indirect immunofluorescence and ELISA. TIFI effect on aPL-induced fetal loss was investigated in pregnant C57BL/6 mice treated with aPL or normal IgG (NHS). Placenta/fetus weight and histology and RNA expression were analyzed. TIFI, but not the control peptide VITT, displayed a dose-dependent inhibition of aPL binding to trophoblasts in vitro. Injection of low doses of aPL at day 0 of pregnancy caused growth retardation and increased fetal loss rate, both significantly reduced by TIFI but not VITT. Consistent with observations in humans, histological analysis showed no evidence of inflammation in this model, as confirmed by the absence of an inflammatory signature in gene expression analysis, which in turn revealed a TIFI-dependent modulation of molecules involved in differentiation and development processes. These findings support the non-inflammatory pathogenic role of aPL and suggest innovative therapeutic approaches to aPL-dependent fetal loss. PMID- 22196924 TI - Cardiopulmonary bypass transiently inhibits intraventricular vortex ring formation in patients undergoing coronary artery bypass graft surgery. AB - OBJECTIVE: Transmitral blood flow during early left ventricular (LV) filling produces an intraventricular rotational body of fluid known as a "vortex ring" that enhances the hydraulic efficiency of early LV filling. The authors tested the hypothesis that exposure to cardiopulmonary bypass (CPB) attenuates intraventricular vortex formation time (VFT) in patients with normal preoperative LV systolic and diastolic function undergoing coronary artery bypass graft (CABG) surgery. DESIGN: A prospective, observational study. PARTICIPANTS: Ten men (65 +/ 4 years, 91 +/- 11 kg, and 175 +/- 8 cm) with a normal preoperative LV ejection fraction (58% +/- 6%) scheduled for elective CABG surgery were studied after institutional review board approval. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Anesthesia was induced with etomidate, fentanyl, and rocuronium and maintained with isoflurane. Myocardial protection during CPB consisted of antegrade and retrograde cold blood cardioplegia administered at 15-minute intervals, systemic and topical hypothermia, and warm continuous antegrade cardioplegia before aortic cross-clamp removal. The peak early LV filling and atrial systole blood flow velocities (E and A, respectively) and corresponding velocity-time integrals (VTI-E and VTI-A, respectively) were obtained with pulse wave Doppler echocardiography and used to determine E/A and atrial filling fraction (beta, VTI-A/[VTI-E + VTI-A]), respectively. Mitral valve diameter (D) was calculated as the average of minor and major axis lengths obtained in the midesophageal bicommissural and long-axis transesophageal echocardiographic imaging planes, respectively. VFT was calculated 30 minutes before and 15, 30, and 60 minutes after CPB as 4 * (1 - beta) * stroke volume (SV)/piD(3), where SV is the stroke volume measured using thermodilution. All patients separated from CPB in sinus rhythm without pacing or vasoactive drug support. Systemic and pulmonary hemodynamics were similar before compared with all times after CPB. CPB significantly (p < 0.05) reduced VFT (5.3 +/- 1.8 to 4.0 +/- 1.5 15 minutes after CPB); the recovery of VFT (to 4.7 +/- 1.6, p > 0.05 v baseline) was noted 60 minutes after CPB. A reduction in E/A (1.26 +/- 0.22 to 0.96 +/- 0.27) and an increase in beta (0.33 +/- 0.04 to 0.41 +/- 0.07) occurred 15 minutes after CPB. E/A and beta also recovered gradually toward control values after CPB (1.25 +/- 0.22 and 0.36 +/- 0.04, respectively, 60 minutes after CPB; p > 0.05 v. baseline). CONCLUSIONS: The results indicated that CPB transiently attenuate VFT in patients with normal preoperative LV systolic and diastolic function undergoing CABG surgery. These data suggest that CPB adversely affects diastolic transmitral flow efficiency by reducing intraventricular vortex ring formation in vivo. PMID- 22196925 TI - Fast-starts in hunting fish: decision-making in small networks of identified neurons. AB - Decision-making networks must be tuned according to the rules that govern which action will be rewarded for a given constellation of current sensory information. Somehow these rules must be implemented in the networks that translate the sensory cues to actions but the nature of this representation is enigmatic. Recent findings suggest that Mauthner-associated networks in some fish can govern surprisingly sophisticated and plastic decisions in which the rules of prey motion govern what speed and direction must be selected to be at the right point at the right time. With the key cellular players individually identifiable, fish can help us to discover the nature of how rules are represented in decision making circuitry of the vertebrate brain. PMID- 22196926 TI - Structural studies of the O-antigenic polysaccharide from Plesiomonas shigelloides strain AM36565. AB - The structure of the repeating unit of the O-antigenic polysaccharide from Plesiomonas shigelloides strain AM36565 has been determined. Component analysis and (1)H and (13)C NMR spectroscopy experiments were employed to elucidate the structure. Inter-residue correlations were determined by (1)H,(13)C heteronuclear multiple-bond correlation, (1)H,(1)H-NOESY, and (1)H,(13)C-HSQC-(1)H,(1)H-NOESY experiments. The O-antigen polysaccharide is composed of repeating units with the following structure: ->3)-alpha-L-Rhap-(1->2)-alpha-L-Rhap-(1->4)[beta-D-GalpNAc (1->3)]-alpha-D-GlcpNAc-(1->, in which the monosaccharide side-chain substitutes the backbone in half of the repeating units. A matrix-assisted laser desorption/ionization mass spectrometry experiment suggested that the polysaccharide consists of two regions, one with tetrasaccharide repeating units and one with trisaccharide repeating units. PMID- 22196927 TI - Synthesis and hydrolysis studies of novel glyco-functionalized platinum complexes. AB - Cisplatin and some of its derivatives are among the most active cytostatics for cancer treatment. Unfortunately, application of platinum complexes always indicates side effects, and frequently primary or developed resistance of tumour cells appear. Therefore, development of novel analogues especially with natural ligands is expedited. Glyco-functionalized ligands were obtained via ether synthesis with omega-halo ethers, Finkelstein reaction, with further treatment with malonate and final deprotection followed by preparation of the disodium salts. Subsequent complexation led to novel platinum derivatives, the stabilities of which in aqueous solution media were studied. PMID- 22196928 TI - Hepatoprotective glycosides from Leonurus japonicus Houtt. AB - Two new phenylethanoid glycosides 1 and 2 named leonoside E and leonoside F, and one new sesquiterpene glycoside (3) identified as 7alpha (H)-eudesmane-4,11 (12) diene-3-one-2beta-hydroxy-13-beta-d-glucopyranoside, together with seven known glycosides (4-10), were isolated from the aerial part of Leonurus japonicus Houtt. Their structures were elucidated on the basis of spectroscopic data and chemical evidence. When tested in in vitro assays, compounds 1, 2, 4, and 6 exhibited potent hepatoprotective activity against d-galactosamine-induced toxicity in HL-7702 cells at concentration of 1*10(-5) M. PMID- 22196929 TI - The structure of cell-matrix adhesions: the new frontier. AB - Adhesions between the cell and the extracellular matrix (ECM) are mechanosensitive multi-protein assemblies that transmit force across the cell membrane and regulate biochemical signals in response to the chemical and mechanical environment. These combined functions in force transduction, signaling and mechanosensing contribute to cellular phenotypes that span development, homeostasis and disease. These adhesions form, mature and disassemble in response to actin organization and physical forces that originate from endogenous myosin activity or external forces by the extracellular matrix. Despite advances in our understanding of the protein composition, interactions and regulation, our understanding of matrix adhesion structure and organization, how forces affect this organization, and how these changes dictate specific signaling events is limited. Insights across multiple structural levels are acutely needed to elucidate adhesion structure and ultimately the molecular basis of signaling and mechanotransduction. Here we describe the challenges and recent advances and prospects for unraveling the structure of cell-matrix adhesions and their response to force. PMID- 22196930 TI - Multiscale dynamics in nucleocytoplasmic transport. AB - The nuclear pore complex (NPC) has long been viewed as a point-like entry and exit channel between the nucleus and the cytoplasm. New data support a different view whereby the complex displays distinct spatial dynamics of variable duration ranging from milliseconds to events spanning the entire cell cycle. Discrete interaction sites outside the central channel become apparent, and transport regulation at these sites seems to be of greater importance than currently thought. Nuclear pore components are highly active outside the NPC or impact the fate of cargo transport away from the nuclear pore. The NPC is a highly dynamic, crowded environment-constantly loaded with cargo while providing selectivity based on unfolded proteins. Taken together, this comprises a new paradigm in how we view import/export dynamics and emphasizes the multiscale nature of NPC mediated cellular transport. PMID- 22196932 TI - miRNAs and morphogen gradients. AB - Morphogens induce biological diversity by operating in a dose-dependent manner. Here we review recent evidences indicating that microRNAs (miRNAs) are ideally suited to serve the morphogen cause. miRNAs regulate the establishment of morphogen gradients, including TGFbeta, Wnt and other growth factors by acting on their secretion, distribution and clearance. miRNA are also critical in receiving cells, establishing context-dependency and threshold responses. Moreover, miRNAs contributes to gene networks that transform the graded activity of a morphogen into robust cell fate decisions. Finally, we discuss in the perspective section the implication of the new ceRNA hypothesis for morphogen biology. PMID- 22196931 TI - Kinetochores and disease: keeping microtubule dynamics in check! AB - The essential role of microtubules in cell division has long been known. Yet the mechanism by which microtubule attachment to chromosomes at kinetochores is regulated has only been recently revealed. Here, we review the role of kinetochore-microtubule (kMT) attachment dynamics in the cell cycle as well as emerging evidence linking deregulation of kMT attachments to diseases where chromosome mis-segregation and aneuploidy play a central role. Evidence indicates that the dynamic behavior of kMTs must fall within narrow permissible boundaries, which simultaneously allow a level of stability sufficient to establish and maintain chromosome-microtubule attachments and a degree of instability that permits error correction required for accurate chromosome segregation. PMID- 22196933 TI - Calcium gradients underlying cell migration. AB - The calcium ion is the simplest and most versatile second messenger in biology. Harboring a myriad of calcium effector proteins, migrating cells display an exquisite multiscaled and multilayered architecture of intracellular calcium dynamics. In motile fibroblasts, for instance, there are transient calcium microdomains ('calcium flickers') of ~5 MUm in diameter and 10-2000 ms in duration, a rising flicker activity gradient along the rear-to-front axis, and a shallow background calcium concentration gradient in the opposite direction. When subjected to external gradients of guidance cues, local flicker gradients are created de novo in the leading edge, which steer cells to turn in new directions as defined by the asymmetry of the flicker activity, apparently by a stochastic decision-making mechanism. These recent findings provide a glimpse into how spatiotemporally coordinated calcium gradients orchestrate cellular behavior as complex as directional movement. PMID- 22196934 TI - Daphnane-type diterpene esters with cytotoxic and anti-HIV-1 activities from Daphne acutiloba Rehd. AB - Seven previously unreported daphnane-type diterpene esters named acutilobins A-G, together with 12 known ones, were isolated from EtOAc extract of Daphne acutiloba Rehd. Their structures were elucidated based on the spectroscopic data. The cytotoxic and anti-HIV-1 activities of these daphnane-type diterpene esters were evaluated through bioassays. Fourteen of these isolates exhibited definite cytotoxic activities against the five human tumor cell lines HL-60, SMMC-7721, A 549, MCF-7, and SW480. Additionally, anti-HIV-1 activities were observed in 13 daphnane-type diterpene esters, among which acutilobins A-G exhibited significant anti-HIV-1 activities with EC50 below 1.5 nM and SI over 10,000. Particularly, genkwanineVIII showed the strongest activity with EC50 0.17 nM and SI 187,010. PMID- 22196935 TI - Recently postmenopausal women have the same prevalence of subclinical carotid atherosclerosis as age and traditional risk factor matched men. AB - OBJECTIVE: To compare the prevalence of subclinical atherosclerosis between postmenopausal women and men of similar age early after the onset of menopause. METHODS: In the first part of this cross-sectional study 186 non-diabetic young postmenopausal women (n = 101, menopausal age <= 10 years) and men (n = 85) aged 40-60 years without overt CVD were consecutively recruited from the outpatients clinics of an academic hospital. Subclinical carotid atherosclerosis was assessed by high-resolution ultrasonography. The presence of carotid atherosclerosis was defined as either increased carotid intima-media thickness (IMT>0.9 mm) and/or the presence of plaques. In the second part, 1:1 matching for age and traditional risk factors (hyperlipidemia, smoking, hypertension and BMI) was performed between men and women of this cohort resulting in a matched sub-sample of 76 subjects. RESULTS: By multivariate analysis, gender was not an independent determinant of any measure of carotid atherosclerosis. In the matched sub-sample, carotid IMT and the number of segments with atherosclerosis did not significantly differ between women and men (0.734 +/- 0.119 mm and 1.47 +/- 1.6 versus 0.717 +/ 0.138 mm and 1.47 +/- 1.5, p = 0.575 and p = 0.999, respectively). Also, the prevalence of increased IMT (60.5% in both genders), carotid plaques and subclinical atherosclerosis (31.6% and 63.2% versus 28.9% and 65.8%, p = 0.803 and p = 0.811, respectively) was similar between men and women. CONCLUSIONS: The prevalence and severity of carotid atherosclerosis was similar between men and young postmenopausal women matched for traditional risk factors. Whether these women may be better risk stratified irrespective of gender should be further assessed in prospective studies. PMID- 22196936 TI - The effect of ABCG1 deficiency on atherosclerotic lesion development in LDL receptor knockout mice depends on the stage of atherogenesis. AB - OBJECTIVE: As ABCG1 plays a role in cholesterol efflux, macrophage ABCG1 expression has been suggested to protect against atherosclerosis. However, we and others observed varying effects of ABCG1 deficiency on atherosclerotic lesion size. The objective of this study was to define the effect of ABCG1 deficiency during atherosclerotic lesion progression in LDL receptor knockout (LDLr(-/-)) mice. METHODS AND RESULTS: ABCG1(-/-)/LDLr(-/-) and ABCG1(+/+)/LDLr(-/-) littermates were fed a Western-type diet for 10 and 12 weeks in order to study the effect of ABCG1 deficiency in the exponential phase of atherosclerotic lesion formation. At 10 weeks of diet feeding, a significant 1.5-fold increase in early atherosclerotic lesion size (130+/-12*10(3) MUm(2)) was observed in ABCG1(-/ )/LDLr(-/-) mice compared to ABCG1(+/+)/LDLr(-/-) mice (88+/-11*10(3) MUm(2); p<0.05). Interestingly, in more advanced lesions, induced by 12 weeks of WTD feeding, ABCG1(-/-)/LDLr(-/-) mice showed a significant 1.7-fold decrease in atherosclerotic lesion size (160+/-20*10(3) MUm(2) vs 273+/-19*10(3) MUm(2) in control mice; p<0.01), indicating that in the ABCG1(-/-)/LDLr(-/-) mice progression of lesion formation is retarded as compared to ABCG1(+/+)/LDLr(-/-) mice. In addition, correlation analysis performed on 7 independent published studies and the current study confirmed that ABCG1 is atheroprotective in early lesions, while the development of advanced lesions is stimulated. CONCLUSIONS: It appears that the effect of ABCG1 deficiency on lesion development in LDLr(-/-) mice depends on the stage of atherogenesis, whereby the absence of ABCG1 leads to increased lesions at sizes<167*10(3) MUm(2) while in more advanced stages of atherosclerosis enhanced apoptosis and/or compensatory mechanisms lead to retarded lesion progression. PMID- 22196937 TI - Prophylactic effect of Lactobacillus oral vaccine expressing a Japanese cedar pollen allergen. AB - Lactic acid bacteria (LAB) represent an attractive delivery vehicle for oral allergy vaccine because of their safety as a food microorganism as well as their potent adjuvant activity triggering anti-allergic immune response. Here, we report the generation of recombinant LAB expressing a major Japanese cedar pollen allergen Cry j 1 (Cry j 1-LAB), and their prophylactic effect in vivo. To facilitate heterologous expression, the codon usage in the Cry j 1 gene was optimized for the host LAB strain Lactobacillus plantarum by the recursive PCR based exhaustive site-directed mutagenesis. Use of the codon-optimized Cry j 1 cDNA and a lactate dehydrogenase gene fusion system led to a successful production of recombinant Cry j 1 in L. plantarum NCL21. We also found that oral vaccination with the Cry j 1-LAB suppressed allergen-specific IgE response and nasal symptoms in a murine model of cedar pollinosis. PMID- 22196938 TI - Evaluation of Indian sacred tree Crataeva magna (Lour.) DC. for antioxidant activity and inhibition of key enzymes relevant to hyperglycemia. AB - In the present investigation, leaf and stem bark of Crataeva magna are evaluated for their antioxidant activity and inhibition of key enzymes relevant to hyperglycemia. Both the parts exhibited significant antioxidant and anti-alpha glucosidase activity. The results will lead in favor of the use of this plant as a potential additive/nutraceutical antioxidant compound. PMID- 22196939 TI - Identification of extracellular siderophores and a related peptide from the endophytic fungus Epichloe festucae in culture and endophyte-infected Lolium perenne. AB - A number of genes encoding non-ribosomal peptide synthetases (NRPSs) have been identified in fungi of Epichloe/Neotyphodium species, endophytes of Pooid grasses, including sidN, putatively encoding a ferrichrome siderophore synthesizing NRPS. Targeted gene replacement and complementation of sidN in Epichloe festucae has established that extracellular siderophore epichloenin A is the major product of the SidN enzyme complex (Johnson et al., 2007a). We report here high resolution mass spectrometric fragmentation experiments and NMR analysis of an isolated fraction establishing that epichloenin A is a siderophore of the ferrichrome family, comprising a cyclic sequence of four glycines, a glutamine and three N(delta)-trans-anhydromevalonyl-N(delta)-hydroxyornithine (AMHO) moieties. Epichloenin A is unusual among ferrichrome siderophores in comprising an octapeptide rather than hexapeptide sequence, and in incorporating a glutamine residue. During this investigation we have established that desferrichrome siderophores with pendant trans-AMHO groups can be distinguished from those with pendant cis-AMHO groups by the characteristic neutral loss of an hydroxyornithine moiety in the MS/MS spectrum. A minor component, epichloenin B, has been characterized as the triglycine variant by mass spectrometry. A peptide characterized by mass spectrometry as the putative deoxygenation product, epichloeamide has been detected together with ferriepichloenin A in guttation fluid from ryegrass (Lolium perenne) plants infected with wild-type E. festucae, but not in plants infected with the DeltasidN mutant strain, and also detected at trace levels in wild-type E. festucae fungal culture. PMID- 22196940 TI - Cardiac glycosides from Yellow Oleander (Thevetia peruviana) seeds. AB - Thevetia cardiac glycosides can lead to intoxication, thus they are important indicators for forensic and pharmacologic surveys. Six thevetia cardiac glycosides, including two with unknown structures, were isolated from the seeds of the Yellow Oleander (Thevetia peruviana (Pers.) K. Shum., Apocynaceae). LC ESI+-MS(/MS) analysis under high-resolution conditions used as a qualitative survey of the primary glycosides did not lead to fragmentation of the aglycones. Acid hydrolysis of the polar and non-volatile thevetia glycosides under severe conditions yielded the aglycones of the thevetia glycosides and made them amenable to GC-MS analysis. Comparison of mass spectral fragmentation patterns of the aglycones, as well as high-resolution mass spectrometric and NMR data of four of the primary thevetia glycosides including the two unknowns, revealed the structures of the complete set of six thevetia glycosides. The identified compounds are termed thevetin C and acetylthevetin C and differ by an 18,20-oxido 20,22-dihydro functionality from thevetin B and acetylthevetin B, respectively. The absence of an unsaturated lactone ring renders the glycosides cardio inactive. The procedures developed in this study and the sets of analytical data obtained will be useful for screening and structure assessment of other, particularly polar, cardiac glycosides. PMID- 22196941 TI - Alkaloid and coumarins from the green fruits of Aegle marmelos. AB - Five (1-5) and 15 known compounds were isolated from the acetone extract of the green fruits of Aegle marmelos. The structure of compounds 1-5, marmesiline (1), 6-(4-acetoxy-3-methyl-2-butenyl)-7-hydroxycoumarin (2), 6-(2-hydroxy-3 hydroxymethyl-3-butenyl)-7-hydroxycoumarin (3), marmelonine (4) and 8 hydroxysmyrindiol (5), were determined on the basis of spectroscopic analyses. Antifungal and antibacterial activities of selected compounds were also evaluated. PMID- 22196942 TI - DRB1*12:01 presents a unique subset of epitopes by preferring aromatics in pocket 9. AB - This study characterized the unique peptide-binding characteristics of HLA DRB1*12:01 (DR1201), an allele studied in the context of various autoimmune diseases, using a peptide competition assay and structural modeling. After defining Influenza A/Puerto Rico/8/34 Matrix Protein M1 (H1MP) 40-54 as a DR1201 restricted epitope, the critical anchor residues within this sequence were confirmed by measuring the relative binding of peptides with non-conservative substitutions in competition with biotin labeled H1MP(40-54) peptide. Based on this information, a set of peptides was designed with single amino acid substitutions at these anchor positions. The overall peptide binding preferences for the DR1201 allele were deduced by incubating these peptides in competition with the reference H1MP(40-54) to determine the relative binding affinities of each to recombinant DR1201 protein. As expected, pocket 1 preferred methionine and aliphatic residues, and tolerated phenylalanine. Pocket 4 was mostly composed of hydrophobic residues, thereby preferentially accommodating aliphatic residues, but could also weakly accommodate lysine due to its slightly acidic environment. Pocket 6 accepted a wide range of amino acids because of the diverse residues that comprise this pocket. Pocket 9 accepted aliphatic and negatively charged amino acids, but showed a remarkable preference for aromatic residues due to the conformation of the pocket, which lacks the typical salt bridge between beta57Asp and alpha76Arg. These binding characteristics contrast with the closely related DR1104 allele, distinguishing DR1201 among the alleles of the HLA-DR5 group. These empirical results were used to develop an algorithm to predict peptide binding to DR1201. This algorithm was used to verify T cell epitopes within novel antigenic peptides identified by tetramer staining and within peptides from published reports that contain putative DR1201 epitopes. PMID- 22196943 TI - What's past is prologue: advances in cardiovascular imaging. PMID- 22196944 TI - Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial. AB - BACKGROUND: In patients with suspected coronary heart disease, single-photon emission computed tomography (SPECT) is the most widely used test for the assessment of myocardial ischaemia, but its diagnostic accuracy is reported to be variable and it exposes patients to ionising radiation. The aim of this study was to establish the diagnostic accuracy of a multiparametric cardiovascular magnetic resonance (CMR) protocol with x-ray coronary angiography as the reference standard, and to compare CMR with SPECT, in patients with suspected coronary heart disease. METHODS: In this prospective trial patients with suspected angina pectoris and at least one cardiovascular risk factor were scheduled for CMR, SPECT, and invasive x-ray coronary angiography. CMR consisted of rest and adenosine stress perfusion, cine imaging, late gadolinium enhancement, and MR coronary angiography. Gated adenosine stress and rest SPECT used (99m)Tc tetrofosmin. The primary outcome was diagnostic accuracy of CMR. This trial is registered at controlled-trials.com, number ISRCTN77246133. FINDINGS: In the 752 recruited patients, 39% had significant CHD as identified by x-ray angiography. For multiparametric CMR the sensitivity was 86.5% (95% CI 81.8-90.1), specificity 83.4% (79.5-86.7), positive predictive value 77.2%, (72.1-81.6) and negative predictive value 90.5% (87.1-93.0). The sensitivity of SPECT was 66.5% (95% CI 60.4-72.1), specificity 82.6% (78.5-86.1), positive predictive value 71.4% (65.3 76.9), and negative predictive value 79.1% (74.8-82.8). The sensitivity and negative predictive value of CMR and SPECT differed significantly (p<0.0001 for both) but specificity and positive predictive value did not (p=0.916 and p=0.061, respectively). INTERPRETATION: CE-MARC is the largest, prospective, real world evaluation of CMR and has established CMR's high diagnostic accuracy in coronary heart disease and CMR's superiority over SPECT. It should be adopted more widely than at present for the investigation of coronary heart disease. FUNDING: British Heart Foundation. PMID- 22196945 TI - Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Nevirapine given once-daily for the first 6, 14, or 28 weeks of life to infants exposed to HIV-1 via breastfeeding reduces transmission through this route compared with single-dose nevirapine at birth or neonatally. We aimed to assess incremental safety and efficacy of extension of such prophylaxis to 6 months. METHODS: In our phase 3, randomised, double-blind, placebo-controlled HPTN 046 trial, we assessed the incremental benefit of extension of once-daily infant nevirapine from age 6 weeks to 6 months. We enrolled breastfeeding infants born to mothers with HIV-1 in four African countries within 7 days of birth. Following receipt of nevirapine from birth to 6 weeks, infants without HIV infection were randomly allocated (by use of a computer-generated permuted block algorithm with random block sizes and stratified by site and maternal antiretroviral treatment status) to receive extended nevirapine prophylaxis or placebo until 6 months or until breastfeeding cessation, whichever came first. The primary efficacy endpoint was HIV-1 infection in infants at 6 months and safety endpoints were adverse reactions in both groups. We used Kaplan-Meier analyses to compare differences in the primary outcome between groups. This study is registered with ClinicalTrials.gov, number NCT00074412. FINDINGS: Between June 19, 2008, and March 12, 2010, we randomly allocated 1527 infants (762 nevirapine and 765 placebo); five of whom had HIV-1 infection at randomisation and were excluded from the primary analyses. In Kaplan-Meier analysis, 1.1% (95% CI 0.3 1.8) of infants who received extended nevirapine developed HIV-1 between 6 weeks and 6 months compared with 2.4% (1.3-3.6) of controls (difference 1.3%, 95% CI 0 2.6), equating to a 54% reduction in transmission (p=0.049). However, mortality (1.2% for nevirapine vs 1.1% for placebo; p=0.81) and combined HIV infection and mortality rates (2.3%vs 3.2%; p=0.27) did not differ between groups at 6 months. 125 (16%) of 758 infants given extended nevirapine and 116 (15%) of 761 controls had serious adverse events, but frequency of adverse events, serious adverse events, and deaths did not differ significantly between treatment groups. INTERPRETATION: Nevirapine prophylaxis can safely be used to provide protection from mother-to-child transmission of HIV-1 via breastfeeding for infants up to 6 months of age. FUNDING: US National Institutes of Health. PMID- 22196946 TI - Involvement of hydrogen peroxide in heat shock- and cadmium-induced expression of ascorbate peroxidase and glutathione reductase in leaves of rice seedlings. AB - Hydrogen peroxide (H2O2) is considered a signal molecule inducing cellular stress. Both heat shock (HS) and Cd can increase H2O2 content. We investigated the involvement of H2O2 in HS- and Cd-mediated changes in the expression of ascorbate peroxidase (APX) and glutathione reductase (GR) in leaves of rice seedlings. HS treatment increased the content of H2O2 before it increased activities of APX and GR in rice leaves. Moreover, HS-induced H2O2 production and APX and GR activities could be counteracted by the NADPH oxidase inhibitors dipehenylene iodonium (DPI) and imidazole (IMD). HS-induced OsAPX2 gene expression was associated with HS-induced APX activity but was not regulated by H2O2. Cd-increased H2O2 content and APX and GR activities were lower with than without HS. Cd did not increase the expression of OsAPX and OsGR without HS treatment. Cd increased H2O2 content by Cd before it increased APX and GR activities without HS. Treatment with DPI and IMD effectively inhibited Cd induced H2O2 production and APX and GR activities. Moreover, the effects of DPI and IMD could be rescued with H2O2 treatment. H2O2 may be involved in the regulation of HS- and Cd-increased APX and GR activities in leaves of rice seedlings. PMID- 22196947 TI - Seasonal influence on gene expression of monoterpene synthases in Salvia officinalis (Lamiaceae). AB - Garden sage (Salvia officinalis L., Lamiaceae) is one of the most important medicinal and aromatic plants and possesses antioxidant, antimicrobial, spasmolytic, astringent, antihidrotic and specific sensorial properties. The essential oil of the plant, formed mainly in very young leaves, is in part responsible for these activities. It is mainly composed of the monoterpenes 1,8 cineole, alpha- and beta-thujone and camphor synthesized by the 1,8-cineole synthase, the (+)-sabinene synthase and the (+)-bornyl diphosphate synthase, respectively, and is produced and stored in epidermal glands. In this study, the seasonal influence on the formation of the main monoterpenes in young, still expanding leaves of field-grown sage plants was studied in two cultivars at the level of mRNA expression, analyzed by qRT-PCR, and at the level of end-products, analyzed by gas chromatography. All monoterpene synthases and monoterpenes were significantly influenced by cultivar and season. 1,8-Cineole synthase and its end product 1,8-cineole remained constant until August and then decreased slightly. The thujones increased steadily during the vegetative period. The transcript level of their corresponding terpene synthase, however, showed its maximum in the middle of the vegetative period and declined afterwards. Camphor remained constant until August and then declined, exactly correlated with the mRNA level of the corresponding terpene synthase. In summary, terpene synthase mRNA expression and respective end product levels were concordant in the case of 1,8 cineole (r=0.51 and 0.67 for the two cultivars, respectively; p<0.05) and camphor (r=0.75 and 0.82; p<0.05) indicating basically transcriptional control, but discordant for alpha-/beta-thujone (r=-0.05 and 0.42; p=0.87 and 0.13, respectively). PMID- 22196948 TI - New aspects of the molecular evolution of legumains, Asn-specific cysteine proteinases. AB - The molecular evolution of asparagine-specific cysteine proteinases, called legumains, from plants and animals was analyzed using newly available related amino acid sequences from lower eukaryotes, bacteria and Archaea. The results suggest that genuine legumains originate from prokaryote pro-legumains. The evolutionary roots of genuine legumains from plants and animals descend from Parabasalia and Alveolata before developing into their respective separate branches headed by Chlorophyta and Placozoa. The branch of legumain-like plant/animal glycosylphosphatidyl inositol transamidases separated from the general evolutionary stem of legumains at the level of lower eukaryotes. Modeling of the 3D structure of a plant genuine legumain underlined the previously suggested similarity of the active site geometry of legumains with caspases, which are Asp-specific bacterial and eukaryote proteinases. PMID- 22196949 TI - Spontaneous splenic hemorrhage after initiation of dabigatran (Pradaxa) for atrial fibrillation. AB - Dabigatran etexilate (Pradaxa; Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT) is an oral anticoagulant that produces a reliable, dose-dependent anticoagulant effect without the need for routine laboratory monitoring. Dabigatran is a direct thrombin inhibitor, acting like other members in its class (bivalirudin, argatroban) to impede the clotting process through selective and reversible binding with both free and clot-bound thrombin. Dabigatran anticoagulates rapidly: plasma levels peak 2 hours after absorption, with a half life that ranges between 12 and 17 hours. Dabigatran was approved by the Food and Drug Administration in October 2010 after it compared favorably with warfarin in a large clinical trial studying its efficacy in stroke prevention in atrial fibrillation. Currently, there is no laboratory test on the market by which a physician can quantify the anticoagulation effect of dabigatran, nor is there any antidote to reverse a life-threatening bleed should it occur. We present a case of a patient with splenic hemorrhagic soon after initiation of dabigatran. PMID- 22196950 TI - An electrocardiographic sign of tumor invasion of the myocardium. AB - Lung cancer is one of the most common neoplasms associated with cardiac metastasis, and the pericardium is often affected. However, isolated myocardial involvement in these patients is very uncommon. Most tumor invasions into the heart are nonspecific and clinically silent. Myocardial metastasis rarely mimics an acute myocardial infarction. We report a case of a 59-year-old man with a metastatic lung cancer into the myocardium mimicking an acute myocardial infarction. PMID- 22196951 TI - Concurrent filtration and solar photocatalytic disinfection/degradation using high-performance Ag/TiO2 nanofiber membrane. AB - A facile polyol synthesis was used for the deposition of Ag nanoparticles on electrospun TiO2 nanofibers for the subsequent fabrication of Ag/TiO2 nanofiber membrane. The permeate flux of the Ag/TiO2 nanofiber membrane was remarkably high compared to commercial P25 deposited membrane. The Ag/TiO2 nanofiber membrane achieved 99.9% bacteria inactivation and 80.0% dye degradation under solar irradiation within 30 min. The Ag/TiO2 nanofiber membrane also showed excellent antibacterial capability without solar irradiation. Considering the excellent intrinsic antibacterial activity and high-performance photocatalytic disinfection/degradation under solar irradiation, this novel membrane proved to have promising applications in water purification industry. PMID- 22196952 TI - Polymer flocculation mechanism in animal slurry established by charge neutralization. AB - Flocculation and filtration of animal manure is practically and environmentally beneficial. However, the flocculation mechanism in manure need to be clarified to use the technique efficiently rather than relying on trial-and-error. Manures were flocculated with polyacrylamides. Floc size, dewaterability, dry matter and turbidity were measured. At optimal polymer volume, the charge neutralization was determined, i.e. amount of negative manure particle charge neutralized by positive polymer charge. The optimal cationic polymer properties were linear and very high molecular weight, which caused efficient particle catching. And it had medium charge density, which caused efficient particle attachment. The required charge neutralization was 5-23% (15% for the optimal polymer). Polymer bridging proved the dominant flocculation mechanism; patch flocculation may be slightly significant for some polymers, while coagulation proved insignificant. Manure's high ionic strength, high dry matter content and highly charged small molecules caused bridging to be more dominant in manure than in other typically flocculated media. PMID- 22196953 TI - Source apportionment of heavy metals and ionic contaminants in rainwater tanks in a subtropical urban area in Australia. AB - Due to prolonged droughts in recent years, the use of rainwater tanks in urban areas has increased in Australia. In order to apportion sources of contribution to heavy metal and ionic contaminants in rainwater tanks in Brisbane, a subtropical urban area in Australia, monthly tank water samples (24 sites, 31 tanks) and concurrent bulk deposition samples (18 sites) were collected during mainly April 2007-March 2008. The samples were analysed for acid-soluble metals, soluble anions, total inorganic carbon and total organic carbon, and characteristics such as total solid and pH. The Positive Matrix Factorisation model, EPA PMF 3.0, was used to apportion sources of contribution to the contaminants. Four source factors were identified for the bulk deposition samples, including 'crustal matter/sea salt', 'car exhausts/road side dust', 'industrial dust' and 'aged sea salt/secondary aerosols'. For the tank water samples, apart from these atmospheric deposition related factors which contributed in total to 65% of the total contaminant concentration on average, another six rainwater collection system related factors were identified, including 'plumbing', 'building material', 'galvanizing', 'roofing', 'steel' and 'lead flashing/paint' (contributing in total to 35% of the total concentration on average). The Australian Drinking Water Guideline for lead was exceeded in 15% of the tank water samples. The collection system related factors, in particular the 'lead flashing/paint' factor, contributed to 79% of the lead in the tank water samples on average. The concentration of lead in tank water was found to vary with various environmental and collection system factors, in particular the presence of lead flashing on the roof. The results also indicated the important role of sludge dynamics inside the tank on the quality of tank water. PMID- 22196954 TI - Soluble CD40 ligand, high sensitive C-reactive protein and fetuin-A levels in patients with essential thrombocythemia. AB - BACKGROUND: CD40 ligand (CD40L) is expressed on the surface of activated platelets and activated T lymphocytes. Circulating soluble CD40 ligand (sCD40L) is formed from these molecules proteolytically. Fetuin-A is a potent antiinflammatory cytokine. AIM OF THE STUDY: In this study, we aim to investigate sCD40L levels to determine whether there is platelet activation and to measure high sensitive C-reactive protein (hs-CRP) levels to demonstrate if this leads to an inflammatory process and also to study fetuin-A levels to see if there is any concomitant antiinflammatory event in patients with essential thrombocythemia (ET). METHODS: We compared 30 patients with essential thrombocythemia with 30 control subjects and in these patients we measured levels of sCD40L, hs-CRP and fetuin-A. RESULTS: sCD40L levels were significantly higher in the ET group compared to the control group (30.6+/-14.4 vs. 18.5+/-8.9, p=0.001). Although fetuin-A levels showed a slight trend to be increased in ET patients, the difference did not reach significance (4.5+/-4.2 vs. 3.2+/-2.1, p=0.158). There were no statistically significant differences in hs-CRP levels (24.6+/-4.9 vs. 25.0+/-5.2, p=0.750). CONCLUSION: sCD40L was significantly higher in patients with an ET without any association with an inflammatory process and we believe this may be a marker of platelet regeneration. PMID- 22196955 TI - Mutation analysis of VCP in familial and sporadic amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons in the motor cortex, brain stem and spinal cord. Mutations in the valosin-containing protein gene (VCP) were recently described in ALS families. Some of these families included diagnoses of other clinical features including frontotemporal dementia, Paget's disease, inclusion body myopathy, Parkinsonism and limb weakness. We sought to determine the prevalence of VCP mutations in Australian familial (n = 131) and sporadic (n = 48) ALS cohorts diagnosed with classic ALS. No mutations were identified indicating that VCP mutations are not a common cause of classic ALS among Australian cases with predominantly European ancestry. PMID- 22196956 TI - Prognostic implications of leg ulcers from hydroxycarbamide therapy in patients with essential thrombocythaemia. AB - Essential thrombocythemia (ET) is a clonal stem-cell disorder characterized by persistent thrombocytosis. Patients with ET and risk factors for thrombotic complications have been shown to benefit from cytoreductive therapy, the most common agent used being, hydroxycarbamide. Although this agent is usually well tolerated, one of the recognized adverse effects is the development of leg ulcers. We undertook retrospective analysis of consecutive ET patients treated with hydroxcarbamide and identified several specific features for this complication including advanced age, female preponderance, reduced overall survival, tendency to develop future vascular events and intolerance to the second line agent, anagrelide. PMID- 22196957 TI - Comparison between multiparameter flow cytometry and WT1-RNA quantification in monitoring minimal residual disease in acute myeloid leukemia without specific molecular targets. AB - Despite a high remission rate, a significant number of patients with acute myeloid leukemia (AML) relapse. Thus, the evaluation of minimal residual disease (MRD) in AML is an important strategy to better identify high risk patients. Most sensitive methodology to detect MRD is molecular polymerase chain reaction (PCR) but its applicability is restricted to AML with leukemia-specific molecular targets (e.g. AML1-ETO, CBFB-MYH11, MLL, FLT-3). In our study, MRD was monitored at different time points with both MFC and WT1-RNA quantification in 23 AML patients who did not present specific molecular targets. As previously published, we considered values of 10(-3) (0.1%) in MFC and 90 WT1-RNA * 10(4) ABL copies as optimal thresholds. Receiver operating characteristics (ROC) analysis was used to confirm these data. To realize the methodology that better identify high risk patients, an analysis of sensitivity, specificity, predictive values (PV) and likelihood ratio (LR) was provided and similar results were showed. MRD levels >= 10(-3) in MFC as well MRD levels >= 90 WT1-RNA copies in RQ-PCR, identify risk groups of patients with poor prognosis. Therefore, MFC and WT1-RNA quantification showed a comparable capacity in terms of technical performance and clinical significance to identify high risk patients who eventually relapsed. PMID- 22196958 TI - Substituent effects on the structure-property relationship of unsymmetrical methyloxy and methoxycarbonyl phthalocyanines: DFT and TDDFT theoretical studies. AB - Density functional theory (DFT) and time-dependent density functional theory (TD DFT) calculations were carried out to simulate the molecular and electronic structures together with the electronic absorption spectra of a series of peripheral methyloxy/methoxycarbonyl substituented phthalocyanines M[Pc(beta OMe)(2n)(beta-COOMe)(8-2n)] (M=2H, Zn; n=0, 1, 2, 3, and 4). Fragment charge distribution and electrostatic potential analysis indicate that the presence of electron-withdrawing and -donation groups leads to the redistribution of charges and obvious polarization effects to the unsymmetrical phthalocyanine series. Peripheral methyloxy/methoxycarbonyl groups introduced onto phthalocyanine ring were revealed to destroy the degeneracy of LUMOs, resulting in significant Q-band splitting for the unsymmetrical phthalocyanine compounds. In addition, metal-free and zinc phthalocyanine compounds display similar electronic structures and absorptions due to the almost none contribution of the zinc atom or inner hydrogens to the frontier molecular orbitals. The microscopic mechanism of the UV Vis spectra has been clarified on the basis of multi-band photon-induced electron transference. These theoretical studies would be helpful for the molecular design of novel unsymmetrical phthalocyanines. PMID- 22196959 TI - Clinical practice guidelines for the diagnosis and management of acute otitis media (AOM) in children in Japan. AB - OBJECTIVE: To (1) indicate methods of diagnosis and testing for acute otitis media (AOM) in children (under 15 years of age); and (2) recommend methods of treatment in accordance with the evidence based consensus reached by the subcommittee on clinical practice guidelines for the diagnosis and management of AOM in children (subcommittee on clinical practice guidelines), in light of the causative bacteria of AOM in Japan and their susceptibility to antimicrobial agents. METHODS: We investigated the most recently detected bacteria causing childhood AOM in Japan as well as their antimicrobial susceptibility, developed clinical questions concerning the diagnosis, testing methods, and treatment of AOM, searched the literature published during 2000-2004, and issued the 2006 guidelines. In the 2009 guidelines we performed the same investigation with the addition of literature that was published during 2005-2008 and that was not included in the 2006 guidelines. RESULTS: We categorized AOM as mild, moderate, or severe on the basis of otoscopic findings and clinical symptoms, and presented a recommended treatment for each degree of severity. CONCLUSION: Accurate assessment of otoscopic findings, as well as other signs and symptoms, is important for judging the degree of severity and selecting a method of treatment. PMID- 22196960 TI - Use of electromyography in the diagnosis of inflammatory myopathies. AB - Inflammatory myopathies are a heterogeneous group of myopathies in which there is biopsy-evident inflammation. In its evaluation it is essential to use neurophysiological techniques that provide information on the nature of the process. This paper reviews the electromigram pattern characteristic of inflammatory myopathies, its diagnostic value, limitations, and some clues on the interpretation of the results of neurophysiological techniques in the assessment of inflammatory myopathies. PMID- 22196961 TI - [The forthcoming reforms of residency and post-residency in obstetrics and gynaecology: Why and how?]. PMID- 22196962 TI - [Use of ezetimibe in the treatment of familial hypercholesterolemia in children and adolescents]. AB - Heterozygous familial hypercholesterolemia (FH) is the most common inherited type of primary hyperlipidemia. Patients with familial hypercholesterolemia have an increased level of LDL cholesterol since childhood, and present early associated cardiovascular disease. Ezetimibe reduces LDL by blocking sterol absorption in enterocytes. AIM: to show our experience on the use of ezetimibe in children and adolescents with familial hypercholesterolemia, with short and medium term follow up. PATIENTS AND METHODS: Retrospective and longitudinal study. Patients who were receiving ezetimibe as monotherapy from 2003 to 2009 were included. The primary efficacy parameter was the effect of ezetimibe on the LDL after three months of treatment. Serum levels of aspartate aminotransferase, alanine aminotransferase and creatine kinase were monitored. Patients were asked if they experienced any side effect with the ezetimibe treatment. If the Patients did not achieve therapeutical goals with ezetimibe as monotherapy a statin was added. Outcome at medium term follow-up is analysed. RESULTS: The study included a total of 32 patients. The mean age at the start of ezetimibe was 9.5 years (range: 2 to 15.5). The mean total time of Ezetimibe was 2.45 years (r: 0.4 - 5.9).The decrease in mean LDL levels was -25.7% +/- 12.3 or 59.5 +/- 34 mg% (P<.0001; 95% CI: 47.3-71.5, t test). There were no side effects with ezetimibe monotherapy. At the end of the study, 11 patients required added statins due to failing to achieve the treatment goal. CONCLUSIONS: Ezetimibe is effective and safe for children and adolescents with FH in short and medium term follow-up. PMID- 22196963 TI - [Contact dermatitis associated with the use of extraoral orthodontic appliances: a presentation of 3 cases]. PMID- 22196964 TI - Health, wealth and ways of life: what can we learn from the Swedish, US and UK experience? Introduction to the commentaries. PMID- 22196966 TI - Approach/avoidance in dreams. AB - The influential threat simulation theory (TST) asserts that dreaming yields adaptive advantage by providing a virtual environment in which threat-avoidance may be safely rehearsed. We have previously found the incidence of biologically threatening dreams to be around 20%, with successful threat avoidance occurring in approximately one-fifth of such dreams. TST asserts that threat avoidance is over-represented relative to other possible dream contents. To begin assessing this issue, we contrasted the incidence of 'avoidance' dreams with that of their opposite: 'approach' dreams. Because TST states that the threat-avoidance function is only fully activated in ecologically valid (biologically threatening) contexts, we also performed this contrast for populations living in both high- and low-threat environments. We find that 'approach' dreams are significantly more prevalent across both contexts. We suggest these results are more consistent with the view that dreaming is generated by reward-seeking systems than by fear conditioning systems, although reward-seeking is clearly not the only factor determining the content of dreams. PMID- 22196965 TI - Women's social networks and birth attendant decisions: application of the network episode model. AB - This paper examines the association of women's social networks with the use of skilled birth attendants in uncomplicated pregnancy and childbirth in Matlab, Bangladesh. The network-episode model was applied to determine if network structure variables (density/kinship homogeneity/strength of ties) together with network content (endorsement for or against a particular type of birth attendant) explain the type of birth attendant used by women above and beyond the variance explained by women's individual attributes. Data were collected by interviewing a representative sample of 246 women, 18-45 years of age, using survey and social network methods between October and December 2008. Logistic regression models were used to examine the associations. Results suggest that the structural properties of networks did not add to explanatory value but instead network content or the perceived advice of network members add significantly to the explanation of variation in service use. Testing aggregate network variables at the individual level extends the ability of the individual profile matrix to explain outcomes. Community health education and mobilization interventions attempting to increase demand for skilled attendants need to reflect the centrality of kinship networks to women in Bangladesh and the likelihood of women to heed the advice of their network of advisors with regard to place of birth. PMID- 22196967 TI - [Incidence, prevalence and mortality of kidney cancer in Spain: estimates and projections for the 1998-2022 period]. AB - OBJECTIVE: To estimate kidney cancer incidence and prevalence in Spain, based on mortality and survival data from the period 1998-2007, and to provide projections of incidence, prevalence and mortality until the year 2022. MATERIAL AND METHODS: All-cause and kidney-cancer mortality rates were obtained from the National Statistics Institute and survival data were obtained from the EUROCARE study. Estimations were carried out using the MIAMOD program. The Joinpoint program was used to quantify the expected annual change in the projections. RESULTS: An increase in the incidence rate is expected in men from, this going from 11.92 (Adjusted Rate - AR=8.66) per 100,000 inhabitants/year to 15.7 (AR=9.55). Prevalence would increase from 72.84 (AR=51.62) to 94.47 (AR=59.57), and mortality would increase from 5.77 (AR=7.29) to 7.29 (AR=4.56). The incidence rate in women would increase from 5.56 (AR=3.86) to 26.77 (AR=16.4). Prevalence would increase from 24.6 (AR=17.28) to 133.69 (81.37), and for mortality, the expected increase would be from 2.46 (AR=1.54) to 11.65 (AR=6.56) cases per 100.000 inhabitants/year. CONCLUSION: The projections indicate that kidney cancer in Spain follows an increasing trend in incidence, mortality and prevalence. This needs to be considered in order to plan more effective prevention and treatment measures. PMID- 22196968 TI - Health-related quality of life in patients with high-risk melanoma randomised in the Nordic phase 3 trial with adjuvant intermediate-dose interferon alfa-2b. AB - PURPOSE: To compare health-related quality of life (HRQoL) and side-effects in patients with high-risk melanoma participating in a randomised phase III trial of adjuvant interferon alfa-2b (IFN). PATIENTS AND METHODS: A total of 855 patients with histologically verified resected cutaneous melanoma in AJCC stage IIb (T4 N0 M0) or stage III (Tx N1-3 M0) were randomised to: Arm A: observation only (n = 284); Arm B: 1-year treatment: induction: IFN alfa-2b, 10 MU (flat dose), SC, 5 days/week, 4 weeks, maintenance: IFN alfa-2b, 10 MU (flat dose), SC, 3 days/week for 12 months (n = 285); or Arm C: 2 years of same treatment as Arm B. HRQoL was assessed using The European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) before randomisation and at 8 pre-defined time points during 2 years. IFN-related side-effects were assessed by a study-specific questionnaire. RESULTS: > 80% of eligible patients returned questionnaires at the different assessment points. Statistically significant interactions between randomisation arm and time after randomisation were found for almost all EORTC QLQ-30 variables. While patients in Arm A improved or remained at baseline levels; patients in Arms B and C reported decreased functioning and quality of life, and an increase in side-effects during their treatment. Patients in Arm B improved after the 12th month assessment, when IFN treatment was scheduled to end, to the 16th month assessment (p < 0.001). The same pattern of improvement was found for 5 of 7 interferon-related side-effects. CONCLUSION: A significant negative impact on HRQoL of IFN treatment was demonstrated, however the impact were reversible when treatment was stopped. PMID- 22196969 TI - The prophylactic use of granulocyte-colony stimulating factor during remission induction is associated with increased leukaemia-free survival of adults with acute lymphoblastic leukaemia: a joint analysis of five randomised trials on behalf of the EWALL. AB - BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) is used to prevent febrile neutropenia and support intense chemotherapy. However, its impact on long term outcome in oncological patients including adults with acute lymphoblastic leukaemia (ALL) has not been determined so far. METHODS: In the current study follow-up data from individual patients recruited in five multicentre, prospective, randomised trials were pooled to perform a joint analysis. Among 347 adults and adolescents with ALL, 185 were assigned to receive prophylactically G CSF along with induction chemotherapy while 162 patients were treated without G CSF support. RESULTS: With the median follow-up of 5.3years, there was a tendency towards increased 5year probability of the overall survival for the G-CSF arm compared to the controls (32%+/-4% versus 23%+/-4%, p=.07), which reached statistical significance in a subgroup of T-ALL (51%+/-8% versus 29%+/-9%, p=.01) and among patients aged 21-40years (44%+/-6% versus 27%+/-6%, p=.03). The probability of leukaemia-free survival was 38%+/-4% and 24%+/-4% (p=.01) while the median remission duration equalled 33 and 17months (p=.007), respectively. In a multivariate analysis the prophylactic use of G-CSF was independently associated with reduced risk of relapse (hazard ratio (HR)=.64, p=.007) and treatment failure (HR=.67, p=.02). CONCLUSIONS: The prophylactic use of G-CSF during induction of ALL is associated with improved long-term outcome and should be recommended especially in a setting of T-ALL and in 'young adults'. Our analysis provides the first direct evidence coming from prospective trials for the impact of primary G-CSF prophylaxis on disease-free survival of oncological patients. PMID- 22196970 TI - Reprogramming cardiomyocyte mechanosensing by crosstalk between integrins and hyaluronic acid receptors. AB - The elastic modulus of bioengineered materials has a strong influence on the phenotype of many cells including cardiomyocytes. On polyacrylamide (PAA) gels that are laminated with ligands for integrins, cardiac myocytes develop well organized sarcomeres only when cultured on substrates with elastic moduli in the range 10 kPa-30 kPa, near those of the healthy tissue. On stiffer substrates (>60 kPa) approximating the damaged heart, myocytes form stress fiber-like filament bundles but lack organized sarcomeres or an elongated shape. On soft (<1 kPa) PAA gels myocytes exhibit disorganized actin networks and sarcomeres. However, when the polyacrylamide matrix is replaced by hyaluronic acid (HA) as the gel network to which integrin ligands are attached, robust development of functional neonatal rat ventricular myocytes occurs on gels with elastic moduli of 200 Pa, a stiffness far below that of the neonatal heart and on which myocytes would be amorphous and dysfunctional when cultured on polyacrylamide-based gels. The HA matrix by itself is not adhesive for myocytes, and the myocyte phenotype depends on the type of integrin ligand that is incorporated within the HA gel, with fibronectin, gelatin, or fibrinogen being more effective than collagen I. These results show that HA alters the integrin-dependent stiffness response of cells in vitro and suggests that expression of HA within the extracellular matrix (ECM) in vivo might similarly alter the response of cells that bind the ECM through integrins. The integration of HA with integrin-specific ECM signaling proteins provides a rationale for engineering a new class of soft hybrid hydrogels that can be used in therapeutic strategies to reverse the remodeling of the injured myocardium. PMID- 22196971 TI - The effects of angiotensin II on the coupled microstructural and biomechanical response of C57BL/6 mouse aorta. AB - RATIONALE: Abdominal aortic aneurysm (AAA) is a complex disease that leads to a localized dilation of the infrarenal aorta, the rupture of which is associated with significant morbidity and mortality. Animal models of AAA can be used to study how changes in the microstructural and biomechanical behavior of aortic tissues develop as disease progresses in these animals. We chose here to investigate the effect of angiotensin II (AngII) in C57BL/6 mice as a first step towards understanding how such changes occur in the established ApoE(-/-) AngII infused mouse model of AAA. OBJECTIVE: The objective of this study was to utilize a recently developed device in our laboratory to determine how the microstructural and biomechanical properties of AngII-infused C57BL/6 wildtype mouse aorta change following 14 days of AngII infusion. METHODS: C57BL/6 wildtype mice were infused with either saline or AngII for 14 day. Aortas were excised and tested using a device capable of simultaneously characterizing the biaxial mechanical response and load-dependent (unfixed, unfrozen) extracellular matrix organization of mouse aorta (using multiphoton microscopy). Peak strains and stiffness values were compared across experimental groups, and both datasets were fit to a Fung-type constitutive model. The mean mode and full width at half maximum (FWHM) of fiber histograms from two photon microscopy were quantified in order to assess the preferred fiber distribution and degree of fiber splay, respectively. RESULTS: The axial stiffness of all mouse aorta was found to be an order of magnitude larger than the circumferential stiffness. The aortic diameter was found to be significantly increased for the AngII infused mice as compared to saline infused control (p=0.026). Aneurysm, defined as a percent increase in maximum diameter of 30% (defined with respect to saline control), was found in 3 of the 6 AngII infused mice. These three mice displayed adventitial collagen that lacked characteristic fiber crimp. The biomechanical response in the AngII infused mice showed significantly reduced circumferential compliance. We also noticed that the ability of the adventitial collagen fibers in AngII infused mice to disperse in reaction to circumferential loading was suppressed. CONCLUSIONS: Collagen remodeling is present following 14 days of AngII infusion in C57BL/6 mice. Aneurysmal development occurred in 50% of our AngII infused mice, and these dilatations were accompanied with adventitial collagen remodeling and decreased circumferential compliance. PMID- 22196972 TI - [Do the quality of prenatal care have an impact on obstetrical outcomes?]. AB - OBJECTIVES: To assess the rate of pregnant women not having accurate prenatal care utilization. The others goals were to assess the impact of an inadequate quantitative or qualitative prenatal care on obstetrical outcomes. PATIENTS AND METHODS: Historical cohort study with a prospective data registration. Hospitalised patients at the maternity ward of the University Hospital of Pointe a-Pitre were eligible if they gave birth after 22 weeks (or>=500g) at home, outside a maternity ward or in another maternity ward. Early postpartum maternal transfers were included but not medical abortions. The principal outcome was preterm birth (before 37 weeks' gestation). RESULTS: Patients without an appointment before 15weeks or without an appointment each month before their delivery represented 27.4% of women (n=2344). We stressed more preterm deliveries outside the maternity ward among the group with an inadequate prenatal care utilization vs. the other group (3,89% vs. 0,88%) (p<0,0001). We did not find any difference concerning the perinatal outcomes among the women with an inadequate quality prenatal care. DISCUSSION AND CONCLUSION: Our study did not stress a difference concerning perinatal outcomes among women with an inadequate quantitative or qualitative prenatal care utilization. PMID- 22196973 TI - Effective prevention of Pseudomonas aeruginosa cross-infection at a cystic fibrosis centre - results of a 10-year prospective study. AB - Pseudomonas aeruginosa is the major pathogen in chronic lung infections of individuals with cystic fibrosis (CF). Unrelated CF patients may acquire P. aeruginosa from the environment or by cross-infection in the CF setting. We tested the efficacy of measures to prevent nosocomial acquisition of P. aeruginosa at a Paediatric CF centre in a prospective 10-year study. P. aeruginosa-positive and P. aeruginosa-negative patients were seen in alternating weeks at the outpatient clinic. Faucets were equipped with filters to prevent bacterial contamination of tap water. Serial isolates were collected since the first documentation of a P. aeruginosa-positive culture and genotyped with a multimarker microarray. During the 10-year study, the annual prevalence of patients with at least one P. aeruginosa-positive culture was 39+/-6% in a population of 149+/-12 patients. P. aeruginosa was detected for the first time in 54 patients of whom 11 patients became chronically colonised with P. aeruginosa. Transient colonisations were recorded 97 times. A nosocomial acquisition of P. aeruginosa at the CF centre probably happened in one case. The worldwide dominant clones in the global P. aeruginosa population were also the most abundant clones in the panel of 324 early CF isolates. No rare clone had expanded by nosocomial transmission. It can be concluded that cross-infection with P. aeruginosa was prevented with simple hygienic measures at a CF centre that had experienced local outbreaks of nosocomial spread among unrelated patients in the past. PMID- 22196974 TI - Association between circulating angiotensin-converting enzyme and exercise induced pulmonary haemorrhage in Thoroughbred racehorses. AB - Exercise-induced pulmonary haemorrhage has an impact on racehorse performance. Although endoscopic diagnosis (with or without the aid of bronchoalveolar lavage) is considered to be the standard diagnostic method for this condition, the use of biomarkers that could aid in quantifying risk and severity of the condition would represent an advance in equine sport medicine. This preliminary research investigated the use of angiotensin-converting enzyme (ACE) activity in plasma of racehorses and demonstrated that ACE activity is increased in horses with higher degrees of haemorrhage and is a promising biomarker for EIPH in racehorses. PMID- 22196975 TI - A comparative assessment of alpha-lipoic acid N-phenylamides as non-steroidal androgen receptor antagonists both on and off gold nanoparticles. AB - A group of alpha-lipoic acid N-phenylamides were synthesized employing a variety of amide coupling protocols utilizing electron deficient anilines. These compounds were then assessed for their ability to block androgen-stimulated proliferation of a human prostate cancer cell line, LNCaP. These structurally simple compounds displayed anti-proliferative activities at, typically, 5-20 MUM concentrations and were comparable to a commonly used anti-androgen Bicalutamide(r). The inclusion of a disulfide (RS-SR) moiety, serving as an anchor to several metal nanoparticle systems (Au, Ag, Fe(2)O(3), etc.), does not impede any biological activity. Conjugation of these compounds to a gold nanoparticle surface resulted in a high degree of cellular toxicity, attributed to the absence of a biocompatible group such as PEG within the organic scaffold. PMID- 22196976 TI - Improved refractive outcome for ciliary sulcus-implanted intraocular lenses. AB - OBJECTIVE: To investigate the ideal correction of intraocular lens (IOL) power for sulcus implantation. DESIGN: Retrospective, comparative case series. PARTICIPANTS: The records of 679 patients undergoing cataract surgery from June 2007 to June 2008 were reviewed. INTERVENTION: Eyes in this series underwent phacoemulsification and IOL implantation with local anesthesia. Patients in our study population had their IOL power reduced by 0.5 or 1 diopter (D) from that calculated by the SRK-T formula for in-the-bag implantation. The IOL implanted was the foldable 3-piece acrylic Acrysof MA60AC (Alcon Laboratories Inc., Fort Worth, TX). MAIN OUTCOME MEASURES: In each case, the difference between actual spherical equivalent (SE) refraction and that predicted by biometry using the SRK T formula was calculated. RESULTS: Posterior capsule tears requiring implantation of IOL in the ciliary sulcus occurred in 36 eyes. When comparing eyes in which the power was reduced by 0.5 D with those in which the reduction was 1.0 D, those with a power reduction of 1.0 D had significantly less unexpected error (0.49 vs. 1.01 D SE). After stratifying eyes by axial length (AL), we found higher unexpected refractive error in short eyes (<22 mm AL). Likewise, eyes with a predicted IOL power >25 D had a greater postoperative refractive error. CONCLUSIONS: This is the first comparative clinical review examining adjustment of power of the sulcus-implanted IOL. We found that the IOL power should be adjusted according to the measured AL and predicted IOL power. For patients with a predicted IOL power from 18 to 25 D, power should be reduced by at least 1 D; for lenses >25 D, power should be reduced by 1.5 to 2 D. PMID- 22196977 TI - A twenty-year follow-up study of trabeculectomy: risk factors and outcomes. AB - PURPOSE: This study was undertaken to determine the performance of trabeculectomy surgery over a 20-year period and examine the associations between outcome and risk factors for trabeculectomy failure. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 234 patients (330 procedures) who had undergone trabeculectomy surgery at Addenbrooke's Hospital, Cambridge, United Kingdom, between January 1988 and December 1990. METHODS: Patients were identified through surgical logbooks (n = 521 procedures on 380 patients); after this, a case-note review was undertaken, which identified 234 patients (330 procedures) who had available case notes. MAIN OUTCOME MEASURES: Surgical success was defined as "complete success" while intraocular pressure (IOP) remained <21 mm Hg with no additional medication and as "qualified success" if those requiring additional topical medication were included. Functional success was defined if patients did not progress to legal blindness (visual acuity <3/60 or visual field <10 degrees). RESULTS: After 20 years, 57% were classified as complete success, 88% were classified as qualified success, and 15% had become blind. Those at risk of trabeculectomy failure were younger or had uveitic glaucoma. Those with pseudoexfoliation or aphakia were more likely to progress to blindness. Furthermore, those using 2 or more topical medications or with advanced visual field loss at the time of surgery were more at risk of both trabeculectomy failure and blindness. CONCLUSIONS: This study indicates that trabeculectomy survival at 20 years may be approximately 60% with no topical medication and approximately 90% with additional topical medication. Patient age, preoperative topical medication use, glaucoma type, and glaucoma severity will independently influence this outcome. Trabeculectomy surgery is therefore a long-term solution to IOP control. PMID- 22196978 TI - A multi-center study of pediatric uroflowmetry data using patterning software. AB - OBJECTIVE: We created software for patterning uroflowmetry (UFM) curves, and validated its utility. PATIENTS AND METHODS: The software patterns a given UFM curve upon four parameters: sex, voided volume, maximal flow rate, and amplitude of fluctuation. Using the software, 6 urologists from 4 institutes assessed 30 test curves. Further, 329 UFM curves obtained from children presenting to 3 institutes for daytime and/or nighttime wetting were assessed. Clinical presentation was divided into 3 groups: group A, daytime incontinence; group B, non-monosymptomatic nocturnal enuresis without daytime wetting; and group C, monosymptomatic nocturnal enuresis. RESULTS: Using the software, inter-rater agreement ranged from 0.85 to 1.00 (mean, 0.93 +/- 0.04). It could pattern 310 out of 329 clinical curves. In each institute, the tower pattern was prevalent according to severity of daytime symptoms, although not significantly. The merged data showed that the percent tower pattern significantly correlated with presence of daytime symptoms (groups A, B, and C, 29.7%, 27.0%, and 16.3%, respectively; p < 0.05). No correlation with daytime symptoms was noted for fluctuated (staccato and interrupted) and plateau patterns. CONCLUSION: The software creates a common platform for evaluating pediatric UFM, enabling extraction of common and biased features of different cohorts, and their integration into one single cohort. PMID- 22196979 TI - Surgical margins for melanoma in situ. AB - BACKGROUND: A controversy in the treatment of melanoma in situ is the required width of surgical margin. The currently accepted 5-mm margin is based on a 1992 consensus opinion, despite data since then showing this is inadequate. OBJECTIVE: We sought to develop guidelines for predetermined surgical margins for excision of melanoma in situ. METHODS: A prospectively collected series of 1072 patients with 1120 melanoma in situs was studied. All lesions were excised by Mohs micrographic surgery with frozen-section examination of the margin. The minimal surgical margin was 6 mm, and the total margin was calculated by adding an additional 3 mm for each subsequent stage required. The minimum surgical margin that would successfully remove 97% of all tumors was calculated. Local recurrence was also tabulated. RESULTS: In all, 86% of melanoma in situs were successfully excised with a 6-mm margin; 9 mm removed 98.9% of melanoma in situs. The superiority of 9-mm to 6-mm margins was significant (P < .001). Gender, location, and diameter did not affect results. Recurrence rate for this set of patients treated with Mohs micrographic surgery was 0.3% (n = 3). LIMITATIONS: Margins less than 6 mm were not studied. This is a referral center for melanoma in situ and 10% of tumors were previously treated before presentation to our clinic. CONCLUSION: The frequently recommended 5-mm margin for melanoma is inadequate. Standard surgical excision of melanoma in situ should include 9 mm of normal appearing skin, similar to that recommended for early invasive melanoma. PMID- 22196980 TI - Assessing students' ability to detect melanomas using standardized patients and moulage. AB - BACKGROUND: Detection of melanoma by physicians via opportunistic surveillance during focused physical examinations may reduce mortality. Medical students may not encounter a clinical case of melanoma during a dermatology clerkship. OBJECTIVE: This study examined the proficiency of fourth-year University of Illinois at Chicago medical students at detecting melanomas. METHODS: Melanoma moulages were applied to the second digit of the left hand of standardized patients (SPs) participating in a wrist pain scenario during a required clinical skills examination. An observer reviewed videotapes of the examination, written SP checklists, and student notes for evidence that the student noticed the moulage, obtained a history, or provided counseling. RESULTS: Among the 190 fourth-year medical students, 56 students were observed noticing the lesion; however, 13 failed to write it in their notes or advise the patient. The detection rate was 22.6% (43 of 190 students). Students who detected the probable melanoma consistently inquired about changes in the lesion and symptoms, but did not examine the rest of the skin or regularly palpate for adenopathy. LIMITATIONS: Testing one class of students from a single medical school with a time-restricted SP encounter while focusing the students' attention toward a different presenting symptom may hinder exploration of medical issues. CONCLUSION: The low detection rate and failure of students who noticed the moulage to identify the lesion as atypical represents a lost opportunity to provide a patient intervention. Use of SP examinations may help physicians in training build confidence and competence in cutaneous malignancy screening. PMID- 22196981 TI - Weight loss and resting energy expenditure in patients with chronic hepatitis C before and during standard treatment. AB - OBJECTIVE: Infection with hepatitis C virus (HCV) is a serious public health problem worldwide. In clinical studies, weight loss has been reported in 11% to 29% of patients treated with pegylated interferon-alpha-2a/2b. Few reports have tried to explain such a weight loss. The aim of this study was to evaluate nutritional status, body composition, and resting energy expenditure (REE) in patients with chronic hepatitis C before and during treatment with pegylated interferon and ribavirin. METHODS: This was a prospective study with the evaluation of patients with hepatitis C virus before and after 12 wk of treatment with pegylated interferon and ribavirin. The evaluation consisted of anthropometry (weight, height, body mass index, and waist circumference), and body composition was determined by bioelectrical impedance analysis. The REE of each individual was obtained by indirect calorimetry. To compare the two phases of treatment, the Wilcoxon test was used. The significance level was 5%. RESULTS: Subjects had significant weight loss during treatment with a consequent decrease in body mass index. This weight decrease was accompanied by a significant decrease in body fat and no decrease in fat-free mass. There was a significant decrease in energy intake as assessed by 24-h recall. However, there was no change in REE and in REE corrected for fat-free mass. CONCLUSION: Our study of patients with hepatitis C treatment showed that these patients had significant weight loss and this was not associated with changes in energy expenditure. However, we observed a significant decrease in energy intake, pointing to a possible need for intervention measures to decrease the damage. PMID- 22196982 TI - The association between self-consciousness about appearance and psychological adjustment among newly diagnosed breast cancer patients and survivors: the moderating role of appearance investment. AB - This study examined the moderating role of two facets of appearance investment (self-evaluative salience (SES) and motivational salience (MS)) in the relationship between self-consciousness about appearance and psychological adjustment (depression, anxiety and psychological quality of life (QoL)) in a sample of 134 breast cancer patients (68 newly diagnosed patients and 66 survivors). No significant differences were found between groups on body image variables. Among survivors, the associations between self-consciousness about appearance and the outcome variables were only significant at high (depression, psychological QoL) levels and at moderate (psychological QoL) levels of SES. Self consciousness about appearance contributed to poor adjustment in both groups. This study demonstrates that appearance investment plays a key role in patients' adjustment and highlights the SES-MS distinction. SES seems to be a vulnerability factor for poor adjustment, and MS seems to be a protective factor that helps women cope with changes in appearance. PMID- 22196983 TI - Optogenetic modulation of neural circuits that underlie reward seeking. AB - The manifestation of complex neuropsychiatric disorders, such as drug and alcohol addiction, is thought to result from progressive maladaptive alterations in neural circuit function. Clearly, repeated drug exposure alters a distributed network of neural circuit elements. However, a more precise understanding of addiction has been hampered by an inability to control and, consequently, identify specific circuit components that underlie addictive behaviors. The development of optogenetic strategies for selectively modulating the activity of genetically defined neuronal populations has provided a means for determining the relationship between circuit function and behavior with a level of precision that has been previously unobtainable. Here, we briefly review the main optogenetic studies that have contributed to elucidate neural circuit connectivity within the ventral tegmental area and the nucleus accumbens, two brain nuclei that are essential for the manifestation of addiction-related behaviors. Additional targeted manipulation of genetically defined neural populations in these brain regions, as well as afferent and efferent structures, promises to delineate the cellular mechanisms and circuit components required for the transition from natural goal-directed behavior to compulsive reward seeking despite negative consequences. PMID- 22196985 TI - Factors that affect HIV testing and counseling services among heterosexuals in Canada and the United Kingdom: an integrated review. AB - OBJECTIVE: To examine factors that affect the utilization of HIV testing and counseling (HTC) services among heterosexual populations in Canada and the U.K. METHODS: We conducted an integrated review of published and unpublished literature (1996-September 2010) using Scopus, OVID-EMBASE, CSA illumina, CINHAL, PROQuest, Web of Science, and Google. RESULTS: Twenty-seven studies met the inclusion criteria. We identified and categorized the key factors into three broad categories depending on their source. Personal-related factors included socio-demographic characteristics, risk perception, illness, HIV-related stigma, level of HIV and testing knowledge, and culture. Provider-related factors included provider-recommended HIV testing, provision of culturally and linguistically appropriate services, and doctor-patient relationship. System related factors included integrating HIV testing with other health care services, anonymity of testing services, suitability of testing venues, technical aspects of HIV testing, and funding for immigrant health services. CONCLUSION: The findings from our review indicate that HTC behaviors of heterosexuals in the Canada and the U.K. are likely influenced by several unchangeable (socio demographic characteristics) and amenable factors. There is need to step-up research to confirm whether these associations are causal using stronger research designs. PRACTICAL IMPLICATION: We have made several recommendations that could be used to improve existing services in Canada. PMID- 22196984 TI - The stress-induced cytokine interleukin-6 decreases the inhibition/excitation ratio in the rat temporal cortex via trans-signaling. AB - BACKGROUND: Although it is known that stress elevates the levels of pro inflammatory cytokines and promotes hyper-excitable central conditions, a causal relationship between these two factors has not yet been identified. Recent studies suggest that increases in interleukin 6 (IL-6) levels are specifically associated with stress. We hypothesized that IL-6 acutely and directly induces cortical hyper-excitability by altering the balance between synaptic excitation and inhibition. METHODS: We used patch-clamp to determine the effects of exogenous or endogenous IL-6 on electrically evoked postsynaptic currents on a cortical rat slice preparation. We used control subjects or animals systemically injected with lipopolysaccharide or subjected to electrical foot-shock as rat models of stress. RESULTS: In control animals, IL-6 did not affect excitatory postsynaptic currents but selectively and reversibly reduced the amplitude of inhibitory postsynaptic currents with a postsynaptic effect. The IL-6-induced inhibitory postsynaptic currents decrease was inhibited by drugs interfering with receptor trafficking and/or internalization, including wortmannin, Brefeldin A, 2 Br-hexadecanoic acid, or dynamin peptide inhibitor. In both animal models, stress induced decrease in synaptic inhibition/excitation ratio was prevented by prior intra-ventricular injection of an analog of the endogenous IL-6 trans-signaling blocker gp130. CONCLUSIONS: Our results suggest that stress-induced IL-6 shifts the balance between synaptic inhibition and excitation in favor of the latter, possibly by decreasing the density of functional gamma-aminobutyric acid A receptors, accelerating their removal and/or decreasing their insertion rate from/to the plasma membrane. We speculate that this mechanism could contribute to stress-induced detrimental long-term increases in central excitability present in a variety of neurological and psychiatric conditions. PMID- 22196986 TI - Diabetes self-management in patients with low health literacy: ordering findings from literature in a health literacy framework. AB - OBJECTIVE: To review studies on the association between health literacy (HL), diabetes self-management and possible mediating variables. METHODS: We systematically searched for empirical studies in PubMed. Findings were ordered by a HL framework that outlines routes between HL, sociocognitive determinants and health actions. RESULTS: Of the 11 relevant studies, three reported a significant positive association between HL and specific diabetes self-management domains. Ten studies investigated the association between HL and knowledge (n=8), beliefs (n=2), self-efficacy (n=3) and/or social support (n=1). Significant associations were found between HL and knowledge (n=6), self-efficacy (n=1) and social support (n=1). Of the three studies evaluating the effect of these sociocognitive variables on diabetes self-management, only one found proof for a mediating variable (social support) in the pathway between HL and self-management. CONCLUSION: There is only limited evidence for a significant association between HL and diabetes self-management, and for the mediating role of sociocognitive variables in this pathway. PRACTICE IMPLICATIONS: Longitudinal studies, including HL, diabetes self-management and potential mediators, are needed to substantiate possible associations between these variables. Such research is essential to enable evidence-based development of interventions to increase adequate and sustainable self-management in diabetic patients with low HL. PMID- 22196987 TI - Uncovering and validating clinicians' experiential knowledge when facing difficult conversations: a cross-cultural perspective. AB - OBJECTIVE: To explore clinicians' experiential knowledge when conducting difficult conversations; and to verify if experiential knowledge is culturally based. METHOD: Data were collected in Italy and the United States during the Program to Enhance Relational and Communication Skills (PERCS) workshops. At the beginning of each workshop, during a whiteboard exercise, clinicians shared the strategies they had found helpful in difficult conversations. The strategies were analyzed in each country through content analysis. Upon completion of this primary analysis, the themes identified within each country were synthesized into second-order themes by means of aggregated concept analysis. RESULTS: We conducted 14 Italian and 12 American PERCS-workshops enrolling a total of 304 clinicians. The suggestions that were similar across both countries were related to: organizational aspects and setting preparation; communication and relational skillfulness; clinician mindfulness; interpersonal qualities and sensibilities; and teamwork and care coordination. Additionally, US participants identified attention to cultural differences as a helpful strategy. CONCLUSION: Clinicians can access relational strategies, tied to their experience, that are typically unrecognized in medical education. The whiteboard exercise is an effective teaching tool to uncover and validate already-existing relational knowledge. PRACTICE IMPLICATIONS: Communication training programs can foster clinicians' sense of preparation by building upon their already-existing knowledge. PMID- 22196988 TI - Concurrent inhibition of TGF-beta and mitogen driven signaling cascades in Dupuytren's disease - non-surgical treatment strategies from a signaling point of view. AB - Dupuytren's disease (DD) is a benign progressive fibro-proliferative disorder of the fascia palmaris of the hand. Currently, treatment consists of surgical excision with a relatively high recurrence rate and risk of complications. To improve long-term outcome of DD treatment, research focus has shifted towards molecular targets for DD as an alternative to surgery. Therefore, complete and exact understanding of the cause of DD is needed. Transforming growth factor (TGF)-beta is considered a key player in DD. We recently showed that increased TGF-beta expression in DD correlates not only with elevated expression and activation of downstream Smad effectors, but also with overactive ERK1/2 MAP kinase signaling. Both TGF-beta/Smad and non-Smad signaling pathways increase expression of key fibrotic markers and contractility of Dupuytren's myofibroblasts. What is not yet known is whether these two signaling cascades each accelerate DD autonomously, successively or in conjunction. Elucidation of this mechanism will help develop new potential non-surgical treatments. We hypothesize that TGF-beta-induced short-term activation of the MAPK pathway leads to an autonomous non-Smad driven fibrosis. Therefore, successful treatment strategies will target not only TGF-beta/Smad, but also intracellular MAPK signaling. In this review we discuss possible scenarios in which such a drift from TGF-beta induced Smad signaling to autonomous non-Smad signaling could be observed in DD. The potential therapeutic effects of small cytokine signaling cascades inhibitors, such as TGF-beta type I receptor-, (pan-) tyrosine- or ERK1/2 MAP-kinase inhibitor will be highlighted. To abrogate the fibrotic trait and the recurrence of DD, we speculate on sequential and co-application of such molecules in order to provide possible new non-operative strategies for DD. PMID- 22196989 TI - Improving maternal mortality at a university teaching hospital in Nnewi, Nigeria. AB - OBJECTIVE: To evaluate the impact of the introduction of the Service Compact with all Nigerians (SERVICOM) contract on maternal health at Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria. METHODS: A retrospective and comparative study of maternal deaths between 2004 and 2010 was carried out. The main outcome measures were yearly maternal mortality ratio (MMR), relative risk (RR) of maternal mortality, and presentation-intervention interval. The yearly MMR and the RR of maternal mortality were compared with the figures from 2004, which represented the pre-SERVICOM era. RESULTS: There were 4916 live births and 54 maternal deaths during the study period, giving an MMR of 1098 per 100,000 live births. Pre-eclampsia/eclampsia was the most common direct cause (25.0%), followed by hemorrhage (18.8%) and sepsis (8.3%). Anemia (12.5%) was the most common indirect cause. There was a progressive reduction in MMR and RR of maternal mortality, with a corresponding increase in live births. The presentation-intervention interval improved significantly from 2006. CONCLUSION: A positive change in the attitude of health workers and the elimination of fee for-service in emergency obstetric care would reduce type 3 delays in public health facilities, and consequently reduce maternal mortality. PMID- 22196990 TI - Availability and quality of emergency obstetric and neonatal care services in Afghanistan. AB - OBJECTIVE: To assess the availability and utilization of emergency obstetric and neonatal care (EmONC) facilities in Afghanistan, as defined by UN indicators. METHODS: In a cross-sectional study of 78 first-line referral facilities located in secure areas of Afghanistan, EmONC service delivery was evaluated by using Averting Maternal Deaths and Disabilities (AMDD) Program assessment tools. RESULTS: Forty-two percent of peripheral facilities did not perform all 9 signal functions required of comprehensive EmONC facilities. The study facilities delivered 17% of all neonates expected in their target populations and treated 20% of women expected to experience direct complications. The population-based rate of cesarean delivery was 1%. Most maternal deaths (96%) were due to direct causes. The direct and indirect obstetric case fatality rates were 0.8% and 0.2%, respectively. CONCLUSION: Notable progress has been made in Afghanistan over the past 8 years in improving the quality, coverage, and utilization of EmONC services, but gaps remain. Re-examination of the criteria for selecting and positioning EmONC facilities is recommended, as is the provision of high-quality, essential maternal and neonatal health services at all levels of the healthcare system, linked by appropriate communication and functional referral systems. PMID- 22196991 TI - External cephalic version in East, Central, and Southern Africa. AB - OBJECTIVE: To evaluate the views of maternity care providers in East, Central, and Southern Africa on external cephalic version (ECV), and its determinants, with the aim of drawing lessons for practice. METHODS: In February 2009, a cross sectional survey using self-administered semi-structured questionnaires was conducted among delegates attending a regional conference of obstetricians and gynecologists. Descriptive statistical analysis was undertaken, and comments were analyzed for themes. RESULTS: Of the 70 questionnaires issued to eligible delegates, 64 were fully completed (response rate 91%). Seventy-nine percent of respondents did not offer ECV. Approximately a third (31%) of the practitioners offered elective vaginal breech delivery. Clinicians offering ECV did so at varying gestational ages. Clinicians not offering ECV gave various reasons including concerns about the procedure's safety and lack of training and experience with it, policy restrictions, medico-legal concerns, clinician or client reluctance, and poor results with the procedure. CONCLUSION: Overall, ECV is not widely practiced in East, Central, and Southern Africa, mainly owing to concerns related to safety and policy. Efforts aimed at reviving ECV in these regions should address these concerns. A conceptual framework of such efforts is proposed herein. PMID- 22196992 TI - Costs and benefits of multidrug, multidose antiretroviral therapy for prevention of mother-to-child transmission of HIV in the Dominican Republic. AB - OBJECTIVE: To investigate whether costs of multidose antiretroviral regimens (MD ARVs), including highly active antiretroviral therapy (HAART), for prevention of mother-to-child transmission (PMTCT) of HIV might be offset by savings gained from treating fewer perinatally acquired infections. METHODS: Rates of MTCT reported in the Dominican Republic among mother-infant pairs treated with single dose nevirapine (SD-NVP; n=39) and MD-ARVs (n=91) for PMTCT were compared. Annual births to women infected with HIV were estimated from seroprevalence studies. Antiretroviral costs for both PMTCT and for HAART during the first 2 years of life (in cases of perinatal infection) were based on 2008 low-income country price estimates. RESULTS: Rates of MTCT were 3.3% and 15.4% for the MD-ARV and SD NVP groups, respectively (P=0.02). Assuming that 5775 of 231 000 annual births (2.5%) were to HIV-positive women, it was estimated that 191 perinatally acquired infections would occur using MD-ARVs and 889 using SD-NVP. High costs of maternal MD-ARVs (HAART, US$914,760 versus SD-NVP, $1155) would be offset by lower 2-year HAART costs ($250,344 versus $1,168,272 for infants in the SD-NVP group) for the lower number of children with prenatally acquired infection (191 versus 889) associated with the use of MD-ARVs for PMTCT (net national saving $3168). CONCLUSION: Despite the high costs, use of MD-ARVs, such as HAART, for PMTCT offer societal savings because fewer perinatally acquired infections are anticipated to require treatment. PMID- 22196993 TI - The value of adding a universal booking scan to an existing protocol of routine mid-gestation ultrasound scan. AB - OBJECTIVE: To compare 2 routine obstetric ultrasound protocols regarding number of clinically relevant events detected and total ultrasound workload. METHODS: An interventional before-and-after study comparing 2 groups of 750 consecutive low risk pregnant women was conducted. The 1st group was routinely offered mid trimester ultrasound and selective ultrasound examinations for specific indications; the 2nd group was, in addition to this, offered a scan at 1st prenatal visit. RESULTS: The groups were comparable at baseline, and 78% underwent booking scan. The expanded protocol showed no improvement in detection of most clinically relevant findings but did detect twins slightly earlier (P=0.3) and significantly reduced the number of presumed post-term deliveries (8.4% vs 13.1%; OR 0.61 [95% CI, 0.41-0.90]). Although more women were scanned at any point or <24 weeks (P<0.001), the increase in women receiving a properly timed fetal anomaly scan was small (60.7% vs 52.3%; P=0.003). Total ultrasound workload increased by 74%, mainly because of more follow-up scans (323 vs 122) and more women being scanned for the 1st time >24 weeks (146 vs 51; P<0.001). CONCLUSION: The results do not support a policy of routine booking scans and revealed no significant benefit apart from a small reduction in presumed post term pregnancies. PMID- 22196994 TI - Obstetric, clinical, and perinatal implications of H1N1 viral infection during pregnancy. AB - OBJECTIVE: To determine perinatal outcome and epidemiologic, clinical, and obstetric characteristics among pregnant women infected with the H1N1 virus admitted to a Brazilian university hospital. METHODS: A cross-sectional study was conducted of pregnant women infected with H1N1 who were admitted to the University Hospital at the School of Medicine, Federal University of Mato Grosso do Sul, Campo Grande, Brazil, during the 2009 pandemic. Data were obtained via a questionnaire, which was administered during the hospital evaluation of patients' medical records. RESULTS: Thirty-one patients were included in the study. Antiviral therapy was initiated within 48 hours of the onset of symptoms in 64.5% of cases. Infection with the H1N1 virus was associated with severe clinical complications in 22.6% of patients and adverse perinatal outcomes in 41.9% of cases. The rate of maternal and perinatal mortality was 9.7%. There was a statistically significant association between late treatment with oseltamivir and increase in systemic complications in pregnancy (odds ratio 22.80 [95% confidence interval, 2.20-235.65]; P=0.007). CONCLUSION: Early treatment with oseltamivir may prevent serious complications associated with H1N1 infection in pregnant women but it does not affect perinatal outcome. PMID- 22196995 TI - Admissions of women in the third trimester of pregnancy to an intensive care unit in Morocco over a 4-year period. PMID- 22196996 TI - Nitric oxide metabolite levels and assessment of cervical length in the prediction of preterm delivery among women undergoing symptomatic preterm labor. AB - OBJECTIVE: To evaluate the diagnostic accuracy of measuring cervical length (CL) in combination with cervical and plasma nitric oxide metabolite (NOx) levels to identify women undergoing preterm labor (PTL) who will deliver preterm. METHODS: A hospital-based prospective cohort study of 730 women undergoing spontaneous PTL between 24 and 33 weeks+6 days of pregnancy was conducted. Measurement of cervical and plasma NOx levels and ultrasonographic assessment of CL were performed to find the best model to predict preterm delivery (PTD). Optimal cut off values were calculated by receiver operating characteristic (ROC) curve analysis. Logistic regression analysis and rank correlation tests were also performed. RESULTS: CL of 15 mm or less, cervical NOx levels greater than 87.6 MUmol/L, and plasma NOx levels greater than 123 MUmol/L (P<0.0001) were the only factors significantly associated with PTD within 7 days of sampling. This combined model provided high diagnostic accuracy (sensitivity 80.0%; specificity 99.2%). Both cervical and plasma NOx levels were negatively correlated with CL (r=-0.453, P<0.0001 and r=-0.362, P<0.0001, respectively). CONCLUSION: Combined measurement of CL and levels of cervical and plasma NOx could help identify women undergoing symptomatic PTL who are at increased risk of PTD. PMID- 22196997 TI - Amplitude-integrated electroencephalogram 1 h after birth in a preterm infant with cystic periventricular leukomalacia. AB - We report a preterm infant, who showed abnormal amplitude-integrated electroencephalogram (aEEG) findings 1 h after birth and later developed cystic periventricular leukomalacia (PVL). The patient was a girl with a gestational age of 29 weeks. She was delivered by emergency cesarean section because of placental abruption and intrauterine co-twin demise. Artificial ventilation and administration of surfactant were needed to treat respiratory distress syndrome. Her cardiovascular condition was stable with artificial ventilation. Cranial ultrasonography showed extended cystic PVL after 11 days of age. aEEG 1 h after birth showed a consistently inactive pattern that resolved completely 28 h after birth. The neurophysiological findings of this patient suggest that aEEG findings during the very early period after birth provide significant information for predicting PVL. PMID- 22196998 TI - The superficial palmar arch and median artery as an example of misleading results due to a small number of investigated specimens or the use of different classifications. AB - BACKGROUND: Small numbers of investigated specimens might lead to misinterpretations. Different classifications can change results dramatically. This is demonstrated by an investigation of the superficial palmar arch and the palmar median artery. MATERIALS AND METHODS: A total of 702 upper limbs were investigated. Data were collected during eight dissection courses for advanced medical students and one workshop of hand surgery (number of investigated limbs per course between 52 and 111). The variations of superficial palmar arches were documented according to the classification of Lippert and Pabst as well as the occurrence of a palmar median artery. The results of each course were compared among each other, to the total result and compared to allocation according Jaschtschinski's classification. RESULTS: In total, the results show complete arches in 52.15%. Incomplete arches with the ulnar artery supplying the thumb in 15.38%, reaching the index in 22.15% and the middle finger in 10.32%. Median arteries were documented in 4.5%. Individual course results varied concerning complete arches from 41.1% (37 out of 90) and 65% (35 out of 55), median arteries were found between 0 (0 of 69 hands) and 9.1% (5 of 55 hands). Classifying our total result with Jaschtschinski's classification there would have been complete arches in 67.8% (individual course result: 43.3-81.8%). CONCLUSIONS: Small numbers of investigated specimens can lead to confounding results. The classification used has to be precisely determined. Both classifications need to be known to interpret results correctly. A repetition of investigation might be performed to confirm results. PMID- 22196999 TI - Chronic eosinophilic pneumonia: autoimmune phenomenon or immunoallergic disease? Case report and literature review. AB - Eosinophilic pneumonia is classified by its acute or chronic presentation, the distinguishing characteristics of which are based on the presence of cough, dyspnea, fever and pulmonary infiltrates with accumulation of inflammatory cells, predominantly eosinophils. The association of eosinophilia and rheumatologic disorders is well known, as in the case of eosinophilic fasciitis and the Churg Strauss syndrome. The coexistence of chronic eosinophilic pneumonia and rheumatoid arthritis has been reported, either early rheumatoid arthritis of definitive disease. The pathophysiological role of eosinophils in autoimmune diseases is not well defined, however it has been shown that the production of pro-inflammatory cytokines stimulate and activates different cell groups, and can simultaneously induce autoantibodies and/or increased infiltration of eosinophils in various tissues, without an underlying autoimmune disease. The case of a young woman with rheumatic chronic eosinophilic pneumonia manifestations and the presence of autoantibodies, which resolved spontaneously, is presented here. PMID- 22197000 TI - Ultrasound-assisted aza-Michael reaction in water: a green procedure. AB - The conjugate addition of amines to conjugated alkenes (commonly known as aza Michael reaction) constitutes a key step for the synthesis of various complex natural products, antibiotics, alpha-amino alcohols and chiral auxiliaries. Ultrasound-induced addition of several amines to alpha, beta-unsaturated ketones, esters and nitriles has been carried out very efficiently in water as well as under solvent-free conditions. No catalysts or solid supports have been used in this method. Remarkable enhancement of reaction rate has been observed in water under ultrasound-induced method. This environmentally benign procedure has provided clean formation of the products with better selectivity. PMID- 22197001 TI - Effect of atorvastatin with or without prednisolone on Freund's adjuvant induced arthritis in rats. AB - Rheumatoid arthritis is a chronic systemic inflammatory disease where cardiovascular diseases have been recognized as major determinants of early morbidity and mortality. Recently, there has been renewed interest in medication with glucocorticoids to decrease joint damage, but in long-term they incur substantial increase in the risk of cardiovascular diseases and their overall risk/benefit ratio is deemed unfavorable. So, the proposed role of statins in treatment of rheumatoid arthritis when corticosteroids indicated as traditional therapy needs to be investigated. Fifty albino rats were divided into 5 equal groups; normal control group, Freund's adjuvant induced arthritis group, group of induced arthritis treated with atorvastatin, group of induced arthritis treated with prednisolone, and group of induced arthritis treated with atorvastatin and prednisolone. The change in paw volume, serum levels of malondialdehyde (MDA), paraoxonase1 (PON1) activity, nitrites, C-reactive protein (CRP) and lipid profile was determined. The results revealed that treatment by atorvastatin in combination with prednisolone produced better satisfactory results than in either remedy alone evidenced by significant decrease in volume of hind paw, levels of MDA, nitrites, CRP, significant increase in PON1 activity and HDL and amelioration of other lipid profile parameters that were impaired by prednisolone. The present work demonstrated that statins exert beneficial anti inflammatory and antioxidant effects beyond their basic cholesterol-lowering activity. Thus, we suggest that if corticosteroid therapy is indicated in rheumatoid arthritis, atorvastatin could be added to get benefit from its pleiotropic effects. However, further studies are needed to verify to what extent statin therapy contribute to clinical benefits in human. PMID- 22197002 TI - Effect of tramadol on pain-related behaviors and bladder overactivity in rodent cystitis models. AB - Tramadol is a widely used analgesic that stimulates the MU opioid receptor and inhibits serotonin and noradrenalin reuptake. There have been studies on the analgesic effects of tramadol based on the tail-flick test, the formalin test, and the induction of allodynia by sciatic-nerve ligation. However, the effects of tramadol on behaviors related to bladder pain and bladder overactivity induced by cystitis have not been reported. To investigate the usefulness of tramadol for patients with cystitis, we investigated these effects of tramadol in rodent cystitis models. Intraperitoneal injection of cyclophosphamide caused bladder specific inflammation and increases in pain-related behaviors, the number of voids and bladder weight in mice. Tramadol suppressed the cyclophosphamide induced pain-related behaviors but did not affect the number of voids or the bladder weight. During continuous-infusion cystometrograms in anesthetized rats, cyclophosphamide shortened the intercontraction interval, indicating bladder overactivity. Tramadol significantly prolonged the intercontraction interval, and the effect was partially blocked by the opioid antagonist naloxone. This finding indicates that MU opioid receptors may be involved in the action of tramadol. In conclusion, tramadol ameliorated cyclophosphamide-induced bladder-pain-related behaviors and bladder overactivity in rodents. These findings suggest that tramadol might be a treatment option for cystitis-induced bladder pain and bladder overactivity. PMID- 22197003 TI - Cortisol has enhancing, rather than impairing effects on memory retrieval in PTSD. AB - BACKGROUND: In the present study, we aimed to compare the effect of exogenous cortisol on memory retrieval in posttraumatic stress disorder (PTSD) with the effects in healthy controls. In healthy participants, administration of cortisol impairs declarative memory retrieval. Only a few studies have investigated these effects in PTSD yielding mixed results. METHODS: In a placebo-controlled crossover study, 44 patients with PTSD and 65 healthy controls received either placebo or 10mg of hydrocortisone orally before memory testing. In addition to declarative memory retrieval (word list learning), we also tested autobiographical memory retrieval specificity. RESULTS: In both tasks opposing effects of cortisol on memory were observed when comparing patients with controls. In controls, cortisol had impairing effects on memory retrieval, while in PTSD patients cortisol had enhancing effects on memory retrieval in both memory domains. CONCLUSIONS: The present results suggest beneficial effects of acute cortisol elevations on hippocampal mediated memory processes in PTSD. Possible neurobiological mechanisms underlying these findings are discussed. PMID- 22197004 TI - Retrospective study of tracheostomy indications and perioperative complications on oral and maxillofacial surgery service. AB - PURPOSE: Tracheostomy is an extremely common procedure performed by a variety of surgical specialties. The purpose of the present study was to review the intraoperative and perioperative management and complications, present our surgical technique, and discuss the role of our service in providing this care within a large community hospital setting. PATIENTS AND METHODS: The 112 patients in our retrospective study were divided into 3 subsets: those referred by medical specialties, tumor/reconstructive surgery patients, and trauma victims. Cases of percutaneous dilational and intensive care unit bedside tracheostomy were excluded. Intraoperative and immediately postoperative complications were included. Bleeding complications were defined as those necessitating a return to the operating room. The patients were followed up for a 24-hour period postoperatively. RESULTS: The medical referral, tumor/reconstructive, and trauma patients made up 55%, 29%, and 16% of the included patients, respectively. The overall complication rate was 2.7%. CONCLUSIONS: Conventional open tracheostomy in an operating room is associated with a low complication rate. The low incidence of perioperative bleeding can be attributed to the use of electrocautery in the division of the thyroid isthmus. This service provided an exceedingly safe and efficient surgical treatment by focusing on precise surgical protocols in an operating room setting. Intense coordination of consultation response, operating room scheduling, and communication with other services involved in these patients' care is critical to develop and maintain the privilege to provide this treatment. Our report can be used to educate the medical community regarding the role of an oral and maxillofacial surgery service in providing tracheostomy. PMID- 22197005 TI - Clinical application of a hyperdry amniotic membrane on surgical defects of the oral mucosa. AB - PURPOSE: The aim of this study was to evaluate the usefulness of a hyperdry amniotic membrane (AM), a novel preservable human amnion, as a wound-dressing material for surgical defects of the oral mucosa. MATERIALS AND METHODS: A hyperdry AM was used in the treatment of 10 patients who had developed secondary defects in the tongue and buccal mucosa after the surgical removal of cancerous or precancerous lesions. The effectiveness of the hyperdry AM was assessed by scoring its operability during the surgical procedure and by the hemostatic status, pain relief, feeding situation, epithelialization, and scar contracture in the postoperative period. Its usefulness was evaluated by considering its effectiveness and safety based on the absence of wound infection and graft rejection. RESULTS: The membrane was found to be easy to handle as an oral dressing material. It adhered well to the bare connective and muscular tissues. One lingual case showed slight postoperative bleeding, which astriction then stopped. No remarkable adverse effects were observed in the process of wound healing. The average score of the patients was 11.2 points (10 to 13 points) in the present evaluation, with 14 being the highest possible score. CONCLUSIONS: This study showed the clinical usefulness of the hyperdry AM as an intraoral wound-dressing material. Although the number of cases was small, the results suggested that the hyperdry AM is biologically acceptable to oral wounds and could be a suitable clinical alternative for the repair of the oral mucosa. PMID- 22197006 TI - Effect of rigid fixation on orthodontic finishing after mandibular bilateral sagittal split setback: the case for miniplate monocortical fixation. AB - PURPOSE: This report reviews the diagnosis and management of patients with Class III skeletal patterns and discusses the rationale for monocortical plate fixation after bilateral sagittal split osteotomy for surgical precision, stability, and postsurgical management of patients with setback. MATERIALS AND METHODS: Two cases with significant Class III sagittal skeletal discrepancies were identified. The cases, which required maxillary advancement and mandibular setback surgery, are presented to describe the rationale and advantages for the monocortical rigid fixation method. CONCLUSIONS: Monocortical plate fixation after bimaxillary surgery for the correction of Class III skeletal malocclusions has the advantages of excellent stability and latent postsurgical adjustability, qualities that are essential for favorable treatment outcomes. PMID- 22197007 TI - Neutrophil function of neonatal foals is enhanced in vitro by CpG oligodeoxynucleotide stimulation. AB - Rhodococcus equi is an intracellular bacterium that causes pneumonia in foals and immunocompromised adult horses. Evidence exists that foals become infected with R. equi early in life, a period when innate immune responses are critically important for protection against infection. Neutrophils are innate immune cells that play a key role in defense against this bacterium. Enhancing neutrophil function during early life could thus help to protect foals against R. equi infection. The objective of our study was to determine whether in vitro incubation with the TLR9 agonist CpG 2142 would enhance degranulation and gene expression of cytokines and Toll-like receptor 9 (TLR9) by neutrophils collected from foals at 2, 14, and 56 days of life, and to determine whether these stimulated responses varied among ages. Neutrophil degranulation was enhanced at all ages by in vitro stimulation with either CpG alone, R. equi alone, or in combination with either R. equi or N-formyl-methionyl-leucyl-phenylalanine (fMLP) (P<0.05), but not by in vitro stimulation with fMLP alone. There were no significant differences among ages in CpG-induced cytokine expression, except for IL-12p40, which was induced more at 56 days of age than on days 2 or 14. Collapsing data across ages, CpG 2142 significantly (P<0.05) increased IL-6 and IL-17 mRNA expression. We concluded that in vitro stimulation of foal neutrophils with CpG enhances their function by promoting degranulation and inducing mRNA expression of IL-6 and IL-17, regardless of age. PMID- 22197008 TI - Modulation of equine neutrophil adherence and migration by the annexin-1 derived N-terminal peptide, Ac2-26. AB - Neutrophil activation, whilst a key component of host defence, must be tightly regulated in order to avoid an inappropriate cellular response. Annexin-1, which is present in large amounts in neutrophils, and its N-terminal peptides, reduce neutrophil accumulation but annexin peptides have also been shown to exhibit neutrophil activating properties. We have recently shown annexin-1 to be present in equine neutrophils and demonstrated that the annexin-1-derived peptide, Ac2 26, can both reduce superoxide production by these cells in response to other stimuli and directly induce free radical production at a higher concentration. In the present study, we have further characterised the effects of Ac2-26 on equine neutrophil function. In addition, as anti-inflammatory glucocorticoids are known to up-regulate annexin-1, we have examined the effects of dexamethasone on annexin-1 expression in equine leukocytes. The effects of Ac2-26 alone and on agonist (CXCL8, leukotriene (LT)B(4) and PAF)-induced adherence and migration were examined by measuring adhesion of neutrophils to serum-coated plastic and by use of a ChemoTx migration assay. The role of formyl peptide receptors (FPRs) in mediating the effects of Ac2-26 was examined using the pan-FPR antagonist, BOC-2. Flow cytometry was used to measure the effects of dexamethasone on annexin-1 expression. Pre-incubation with Ac2-26 (10(-5)M) significantly inhibited neutrophil adhesion and migration in response to other agonists but when used alone could also induce these responses. The stimulatory and inhibitory effects of Ac2-26 were reduced by BOC-2, indicating a dependency on FPR activation. Dexamethasone increased the percentage of annexin-1 positive neutrophils and mononuclear cells by 1h post treatment (from 45+/-5% to 93+/-1% and 62+/-14% to 87+/-9% for neutrophils and monocytes, respectively) but by 4h there was no difference from control cells. No difference was seen between the percentages of annexin-1 positive cells pre- and post-treatment in animals that had undergone a dexamethasone suppression test. The attenuation of agonist-induced adherence and migration by Ac2-26 may play a part in regulating recruitment of equine neutrophils in inflammatory conditions of the horse. However, if high concentrations are produced in vivo following release of annexin-1 from activated cells, direct stimulatory effects may occur which could be either beneficial or detrimental. The therapeutic efficacy of anti-inflammatory steroids in the horse may be mediated in part by increasing annexin-1 expression although this effect appears to be short-lived. PMID- 22197009 TI - Interleukin 4 increases CCR9 expression and homing of lymphocytes to gut associated lymphoid tissue in chickens. AB - The effects of in vitro and in vivo IL-4 supplementation on thymocyte and splenocyte CCR9 mRNA amount and migration were studied. Thymocytes, splenocytes, splenocytes+thymocytes (2:1), and splenocytes+bursocyte cells (2:1) were supplemented with either 0 or 5 ng/ml IL-4 for 5d. CCR9 mRNA was undetectable in all experimental groups supplemented with 0 ng/ml IL-4. IL-4 treatment (5 ng/ml) upregulated (P=0.01) CCR9 mRNA only in the splenocyte+thymocyte cell culture. IL 4-mediated CCR9 mRNA induction in the splenocyte+thymocyte cell culture was dependent on the in vitro dose of IL-4 supplementation. IL-4-treated splenocyte+thymocyte cells when injected in vivo preferentially migrated to cecal tonsils. In vivo supplementation of IL-4 was achieved through in ovo injection of recombinant chicken IL-4 plasmid. Cecal tonsils in chicks hatched from IL-4 plasmid-injected eggs weighed more, had a higher amount of CCR9 mRNA, and had a higher percentage of CD8(+) cells than cecal tonsils from chicks hatched from PBS injected eggs. It could be concluded that IL-4 induces CCR9 mRNA in thymocytes and splenocytes and directs the migration of cells to gut-associated lymphoid tissue. PMID- 22197010 TI - Development and characterization of mouse monoclonal antibodies reactive with chicken CD83. AB - This study was carried out to develop and characterize mouse monoclonal antibodies (mAbs) against chicken CD83 (chCD83), a membrane-bound glycoprotein belonging to the immunoglobulin superfamily that is primarily expressed on mature dendritic cells (DCs). A recombinant chCD83/IgG4 fusion protein containing the extracellular region of chCD83 was expressed in Chinese Hamster Ovary (CHO) cells and isolated from the spent cell culture medium by protein G affinity chromatography. The extracellular region of the chCD83 protein was purified and used to immunize mice. A cell fusion was performed, from which 342 hybridomas were screened for mAbs to chCD83. Two mAbs, chCD83-159 and chCD83-227, stained the greatest percentage of chCD83-transfected CHO cells and were selected for further characterization. By flow cytometry, both mAbs reacted with a chicken macrophage cell line, HD11. Both mAbs also recognized a single 53 kDa protein on Western blots of lysates from lipopolysaccharide-stimulated spleen mononuclear cells or unstimulated HD11 cells. Immunostaining of chicken secondary lymphoid organs identified chCD83(+) cells with morphologic and subtissue localization properties comparable to mammalian DCs. In vitro stimulation of spleen mononuclear cells with concanavalin A (Con A) decreased the percentage of chCD83(+) cells compared with cells treated with medium alone. Interestingly, spleen cells treated with Con A in the presence of chCD83-227 mAb exhibited decreased percentage of MHCII(+) cells compared with cells treated with an isotype-matched negative control mAb. These chCD83 mAbs may be useful for future investigations of chicken immune cell maturation and mechanisms of action. PMID- 22197011 TI - Risk factors for hepatitis C virus infection among Egyptian healthcare workers in a national liver diseases referral centre. AB - Little is known about the prevalence of hepatitis C virus (HCV) among healthcare workers (HCW) in Egypt, where the highest worldwide prevalence of HCV exists. The prevalence of HCV, hepatitis B virus and Schistosoma mansoni antibodies was examined in 842 HCWs at the National Liver Institute in the Nile Delta, where >85% of patients are HCV antibody-positive. The mean age of HCWs was 31.5 years and they reported an average of 0.6+/-1.2 needlesticks/HCW/year. The prevalence of anti-HCV, hepatitis B surface antigen (HBsAg) and co-infection was 16.6%, 1.5% and 0.2%, respectively. HCV-RNA was present in 72.1% of anti-HCV-positive HCWs, and all but one subject were infected with HCV genotype 4. Schistosoma mansoni antibodies were present in 35.1%. The anti-HCV rate increased sharply with age and employment duration, but not among those with needlestick history. After adjusting for other risk factors, the anti-HCV rate was higher among older HCWs [P<0.001; risk ratio (RR) = 1.086, 95% CI 1.063-1.11], males (P=0.002; RR=1.911, 95% CI 1.266-2.885) and those with rural residence (P<0.001; RR=2.876, 95% CI 1.830-4.52). Occupation (P=0.133), duration of employment (P=0.272) or schistosomal antibody positivity (P=0.152) were not significant risk factors for anti-HCV positivity. In conclusion, although one in six HCWs had been infected with HCV, the infections were more likely to be community-acquired and not occupationally related. PMID- 22197012 TI - Semi-recumbent body position fails to prevent healthcare-associated pneumonia in Vietnamese patients with severe tetanus. AB - Healthcare-associated pneumonia (HCAP) is a common complication in patients with severe tetanus. Nursing tetanus patients in a semi-recumbent body position could reduce the incidence of HCAP. In a randomised controlled trial we compared the occurrence of HCAP in patients with severe tetanus nursed in a semi-recumbent (30 degrees ) or supine position. A total of 229 adults and children (aged >=1 year) with severe tetanus admitted to hospital in Vietnam, were randomly assigned to a supine (n=112) or semi-recumbent (n=117) position. For patients maintaining their assigned positions and in hospital for>48h there was no significant difference between the two groups in the frequency of clinically suspected pneumonia [22/106 (20.8%) vs 26/104 (25.0%); p=0.464], pneumonia rate/1000 intensive care unit days (13.9 vs 14.6; p=0.48) and pneumonia rate/1000 ventilated days (39.2 vs 38.1; p=0.72). Mortality in the supine patients was 11/112 (9.8%) compared with 17/117 (14.5%) in the semi-recumbent patients (p=0.277). The overall complication rate [57/112 (50.9%) vs 76/117 (65.0%); p=0.03] and need for tracheostomy [51/112 (45.5%) vs 69/117 (58.9%); p=0.04) was greater in semi-recumbent patients. Semi recumbent body positioning did not prevent the occurrence of HCAP in severe tetanus patients. PMID- 22197013 TI - [HIV infected male with fever and bilateral pulmonary nodules after Highly Active Antiretroviral Treatment]. PMID- 22197015 TI - Metal stabilization mechanism of incorporating lead-bearing sludge in kaolinite based ceramics. AB - The feasibility and mechanism of incorporating simulated lead-laden sludge into low-cost ceramic products was investigated by observing the reaction of lead with two kaolinite-based precursors under sintering conditions. To investigate the phase transformation process of lead, lead oxide (PbO) mixed with a kaolinite or mullite precursor were fired at 500-950 degrees C for 3h. Detailed X-ray diffraction analysis of sintered products revealed that both precursors had crystallochemically incorporated lead into the lead feldspar (PbAl(2)Si(2)O(8)) crystalline structure. By mixing lead oxide with kaolinite, lead feldspar begins to crystallize at 700 degrees C; maximum incorporation of lead into this structure occurred at 950 degrees C. However, two intermediate phases, Pb(4)Al(4)Si(3)O(16) and a polymorph of lead feldspar, were detected at temperatures between 700 and 900 degrees C. By sintering lead oxide with the mullite precursor, lead feldspar was detected at temperatures above 750 degrees C, and an intermediate phase of Pb(4)Al(4)Si(3)O(16) was observed in the temperature range of 750-900 degrees C. This study compared the lead leachabilities of PbO and lead feldspar using a prolonged leaching test (at pH 2.9 for 23d) modified from the toxicity characteristic leaching procedure. The results indicate the superiority of lead feldspar in stabilizing lead and suggest a promising and reliable strategy to stabilize lead in ceramic products. PMID- 22197014 TI - Comparison of prostate volume, shape, and contouring variability determined from preimplant magnetic resonance and transrectal ultrasound images. AB - PURPOSE: To compare preimplant prostate contours and contouring variability between magnetic resonance (MR) and transrectal ultrasound images. METHODS AND MATERIALS: Twenty-three patients were imaged using ultrasound (US) and MR before permanent brachytherapy treatment. Images were anonymized, randomized, and duplicated, and the prostate was independently delineated by five radiation oncologists. Contours were compared in terms of volume, dimensions, posterior rectal indentation, and observer variability. The Jaccard index quantified spatial overlap between contours from duplicated images. RESULTS: The mean US/MR volume ratio was 0.99+/-0.08 (p=0.5). The width, height, and length ratios for the prostate were 0.98+/-0.06 (p=0.09), 0.99+/-0.08 (p=0.4), and 1.05+/-0.14 (p=0.1). Rectal indentation was larger on US by 0.18mL (p=0.01) and correlated with prostate volume (p<0.01). MR and US interobserver variability in volume were similar at 3.5+/-1.7 and 3.3+/-1.9mL (p=0.6). Intraobserver variability was smaller on US at 1.4+/-1.1mL compared with MR at 2.4+/-2.2mL (p=0.01). Local intraobserver variability was lower on US at the midgland slice (p<0.01) but lower on MR at the base (p<0.01) and apex (p<0.01) slices. CONCLUSIONS: US is comparable to MR for preimplant prostate delineation, with no significant difference in volume and dimensions. Rectal indentation because of the transrectal ultrasound probe was measurable, although the effects were small. Intraobserver variability was lower on US for the prostate volume but was lower on MR locally at the base and apex. However, the difference was not observed for the interobserver variability, which was similar between MR and US. PMID- 22197016 TI - Removal of polycyclic aromatic hydrocarbons from soil: a comparison between bioremoval and supercritical fluids extraction. AB - Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic substances which are resistant to environmental degradation due to their highly hydrophobic nature. Soils contaminated with PAHs pose potential risks to human and ecological health, therefore concern over their adverse effects have resulted in extensive studies on their removal from contaminated soils. The main purpose of this study was to compare experimental results of PAHs removal, from a natural certified soil polluted with PAHs, by biological methods (using bioaugmentation and biostimulation in a solid-state culture) with those from supercritical fluid extraction (SFE), using supercritical ethane as solvent. The comparison of results between the two methods showed that maximal removal of naphthalene, acenaphthene, fluorene, and chrysene was performed using bioremediation; however, for the rest of the PAHs considered (fluoranthene, pyrene, and benz(a)anthracene) SFE resulted more efficient. Although bioremediation achieved higher removal ratios for certain hydrocarbons and takes advantage of the increased rate of natural biological processes, it takes longer time (i.e. 36 d vs. half an hour) than SFE and it is best for 2-3 PAHs rings. PMID- 22197017 TI - Electro-migration of heavy metals in an aged electroplating contaminated soil affected by the coexisting hexavalent chromium. AB - Cr(VI) was often reported to oxidize soil organic matter at acidic environments due to its high ORP, probably thus changing cationic metal species bound to soil organic matter, and influencing their electro-migration patterns. However, such an effect on the electro-migration was not confirmed in most previous studies. Therefore, this study applied a fixed voltage direct current field on an aged electroplating contaminated clayed soil, with a special interest in the direct or indirect influence of Cr(VI) on the electro-migration of other coexisting metals. After 353 h electrokinetic process, 81% of Zn, 53% of Ni and 22% of Cu in the original soil were electro-migrated into the electrolyte, and most of the remaining concentrated near the cathode. The Cr(VI) oxidized some soil organic matter along its migration pathway, with a pronounced reaction occurred near the anode at low pHs. The resulting Cr(III) reversed its original movement, and migrated towards the cathode, leading to the occurrence of a second Cr concentration peak in the soil. Metal species analyses showed that the amount of metals bound to soil organic matter significantly decreased, while a substantial increase in the Cr species bound to Fe/Mn (hydro-)oxides was observed, suggesting an enhancement of cationic metal electro-migration by the reduction of Cr(VI) into Cr(III). However, the Cr(VI) may form some stable lead chromate precipitates, and in turn demobilize Pb in the soil, as the results showed a low Pb removal and an increase in its acid-extractable and residual fractions after electrokinetic remediation. PMID- 22197018 TI - Sulfadimethoxine and sulfaguanidine: their sorption potential on natural soils. AB - Sulfonamides (SAs) are one of the oldest groups of veterinary chemotherapeutic agents. As these compounds are not completely metabolized in animals, a high proportion of the native form is excreted in feces and urine. They are therefore released either directly to the environment in aquacultures and by grazing animals, or indirectly during the application of manure or slurry. Once released into the environment, SAs become distributed among various environmental compartments and may be transported to surface or ground waters. The physicochemical properties of SAs, dosage and nature of the matrix are the factors mainly responsible for their distribution in the natural environment. Although these rather polar compounds have been in use for over half a century, knowledge of their fate and behavior in soil ecosystems is still limited. Therefore, in this work we have determined the sorption potential of sulfadimethoxine and sulfaguanidine on various natural soils. The influence on sorption of external factors, such as ionic strength and pH, were also determined. The sorption coefficients (K(d)) obtained for the sulfonamides investigated were quite low (from 0.20 to 381.17 mL g(-1) for sulfadimethoxine and from 0.39 to 35.09 mL g(-1) for sulfaguanidine), which indicated that these substances are highly mobile and have the potential to run off into surface waters and/or infiltrate ground water. Moreover, the sorption of these pharmaceuticals was found to be influenced by OC, soil solution pH and ionic strength, with higher K(d) values for soils of higher OC and lower K(d) values with increasing pH and ionic strength. PMID- 22197019 TI - Ultrasound-assisted extraction of oleanolic acid and ursolic acid from Ligustrum lucidum Ait. AB - Oleanolic acid and ursolic acid are the main bioactive compounds in fruit of Ligustrum lucidum Ait, which possess anti-inflammatory, antioxidative, antiprotozoal, antimutagenic and anticancer properties. In this study, the ultrasound-assisted extraction of oleanolic acid and ursolic acid from L. lucidum Ait was investigated with HPLC-photodiode array detection. Effects of several experimental parameters, such as type and concentration of extraction solvent, ratio of liquid to material, extraction temperature and extraction time, on extraction efficiencies of oleanolic acid and ursolic acid from L. lucidum were evaluated. The influence of experimental parameters on extraction efficiency of ursolic acid was more significant than that of oleanolic acid. The optimal extraction conditions were 95% ethanol, the ratio of material to liquid at 1:20, and extraction for 10 min at 40 degrees C under ultrasonic irradiation. Under the optimal conditions, the yields of oleanolic acid and ursolic acid were 6.3 +/- 0.25 and 9.8 +/- 0.30 mg/g, respectively. The results indicated that the ultrasound-assisted extraction is a very useful method for the extraction of oleanolic acid and ursolic acid from L. lucidum. PMID- 22197020 TI - Behaviour of the isothermal retention indices of n-alkylbenzenes on stationary phases of different polarity. AB - Isothermal retention indices (I) of benzene, toluene, ethylbenzene, n propylbenzene and n-butylbenzene were determined at 323-423 K on twelve WCOT capillary columns covering a broad stationary phase polarity spectrum. These I values have been tested carrying out a comparison with the NIST database values. The effect of the stationary phase polarity on I values was studied. But for the poly(3,3,3-trifluoropropylmethyl siloxane) column, a good linear correlation was found. At each temperature, the dependence on I of the alkyl chain length (z) attached to the ring of the n-alkylbenzenes was linear and of similar magnitude for the stationary phases of low to middle polarity, but lower for the more polar ones. Moreover, an important influence of the column temperature on the slope of the I vs. z plots was observed for the only non polysiloxane-type stationary phase studied, i.e., poly(ethylene glycol), due to its higher chain stiffness. Finally, different expressions describing the effect of the temperature on the retention index have been compared. I values of the n-alkylbenzenes in the 323 423 K range increase with increasing column temperature according to the Antoine type (I=alpha+beta(gamma+T)(-1)) and the extended (I=a+bT(-1)+clnT) models. No significant differences were observed between them, except for the poly[70% bis(3 cyanopropyl) 30% dimethyl silphenylene-siloxane] column, for which the Antoine type model was slightly better. PMID- 22197021 TI - Synthesis and characterisation of bonded mercaptopropyl silica intermediate stationary phases prepared using multifunctional alkoxysilanes in supercritical carbon dioxide as a reaction solvent. AB - This research employed (29)Si and (13)C Cross-Polarisation/Magic Angle Spinning (CP/MAS) NMR spectroscopy to characterise the nature and amount of surface species of di-and trifunctional mercaptopropylsilane (MPS) bonded silica using supercritical carbon dioxide (sc-CO(2)) as a reaction solvent without additives (co-solvent) or catalysts. The MPS stationary phases were prepared within 1h at a temperature and pressure of 70 degrees C and 414 bar, respectively. Complementary analysis including elemental analysis, thermogravimetric analysis (TGA), DRIFT spectroscopy and BET surface area measurements were employed to characterise the bonded MPS intermediate stationary phases in support of data obtained from solid state NMR analysis. The results revealed that modification of silica with a trimethoxymercaptopropylsilane (MPTMS) results in ligand surface coverage that is larger than when dimethoxymethylmercaptopropysilane (MPDMMS) is employed as a silanisation reagent. This observation is attributed to greater reactivity and cross-linkage of trifunctional silane. Reaction in sc-CO(2) in comparison to reflux in organic solvents, is rapid, reducing product recovery procedures. PMID- 22197022 TI - Morphology and separation efficiency of a new generation of analytical silica monoliths. AB - The heterogeneous morphology of current silica monoliths hinders this column type to reach its envisioned performance goals. We present a new generation of analytical silica monoliths that deliver a substantially improved separation efficiency achieved through several advances in monolith morphology. Analytical silica monoliths from the 1st and 2nd Chromolith generation are characterized and compared by chromatographic methods, mercury intrusion porosimetry, scanning electron microscopy, and confocal laser scanning microscopy. The latter method is instrumental to quantify morphological differences between the monolith generations and to probe the radial variation of morphological properties. Compared with the 1st generation, the new monoliths possess not only smaller macropores, a more homogeneous macropore space, and a thinner silica skeleton, but also radial homogeneity of these structural parameters as well as of the local external or macroporosity. The 66.5% reduction in minimum plate height observed between silica monoliths of the 1st and 2nd Chromolith generation can thus be attributed to two key improvements: a smaller domain size at simultaneously increased macropore homogeneity and the absence of radial morphology gradients, which are behind the considerable peak asymmetry of the 1st generation. PMID- 22197023 TI - Decrease of internal exposure to chlororganic compounds and heavy metals in children in Baden-Wurttemberg between 1996/1997 and 2008/2009. AB - From 1996/1997 to 2008/2009, blood and urine were sampled from 9- to 11-year-old pupils in the state of Baden-Wurttemberg, South-West Germany. In blood samples the chlororganics DDE, HCB, PCB-138, PCB-153 and PCB-180 were analysed by gas chromatography and ECD detection. PCDD/PCDF were measured in pooled blood samples using GC/MS. Lead concentrations in blood were quantified by graphite furnace atomic absorption spectrometry (AAS), mercury in urine by using cold vapour AAS. For all chlororganics and heavy metals a distinct decrease of the internal concentration could be shown within the 12-year investigation period. For DDE, the median decreased from 0.32 MUg/l to 0.11 MUg/l. The median of HCB fell from 0.19 MUg/l to 0.07 MUg/l. The median of the sum of the three PCB-congeners PCB 138, PCB-153 and PCB-180 decreased from 0.47 MUg/l to 0.18 MUg/l. The burden of PCDD/PCDF in pooled blood samples resulted in approximately half the concentration after the 12-year period. The internal concentrations of the chlororganics were distinctly higher in breastfed children than in non-breastfed children. In 2008/2009, these differences were strongest for PCB and DDE (2 fold), moderate for PCDD/PCDF (1.6-fold), and slight for HCB (1.2-fold). The median of lead concentrations in blood dropped from 23.6 MUg/l to 15.9 MUg/l. The median of mercury concentrations in urine decreased from 0.25 MUg/l to a value below the limit of quantification of 0.2 MUg/l; the 95th percentile was reduced from 3.1 MUg/l to less than 0.2 MUg/l. The decline of amalgam fillings in children during the investigation period had a strong influence on internal concentrations of mercury. The internal concentration of the persistent xenobiotics investigated here decreased to a low level not likely to be of concern for human health. PMID- 22197024 TI - The prevalance of respiratory viruses among healthcare workers serving pilgrims in Makkah during the 2009 influenza A (H1N1) pandemic. AB - Despite the high risk of acquiring respiratory infections, healthcare workers who treat pilgrims at Hajj have not been studied in previous research on respiratory diseases during Hajj. The objective of this study was to determine the prevalence of different respiratory viruses among healthcare workers who treated pilgrims during Hajj 2009, the year of the influenza A H1N1 pandemic. A cross-sectional study was performed just before and after Hajj (25-29 November, 2009). Nasal and throat swabs were tested for 18 respiratory virus types and subtypes. A total of 184 healthcare workers were examined. Most were men (85%) with an average age of 41 years. Before the Hajj, rates of seasonal influenza vaccination were higher (51%) than rates of pandemic influenza A H1N1 vaccination (22%). After the Hajj, participants reported high rates of maintaining hand hygiene (98%), cough etiquette (89%), and wearing a face mask (90%). Among all the viruses tested, only two were detected: rhinovirus was detected in 12.6% and Coronavirus 229E in 0.6%. Rhinovirus was detected in 21% of those who had respiratory symptoms during Hajj. Influenza A (including H1N1), influenza B. respiratory syncytial virus, other coronaviruses, parainfluenza viruses, human metapneumovirus, adenovirus, and human bocavirus were not detected. The finding of high rates of rhinovirus infection corresponds to their frequent occurrence in adults. None of the participants had influenza A H1N1 2009, possibly because it was also infrequent among the 2009 pilgrims. PMID- 22197025 TI - Arachidonic acid mobilizes Ca2+ from the endoplasmic reticulum and an acidic store in rat pancreatic beta cells. AB - In rat pancreatic beta cells, arachidonic acid (AA) triggered intracellular Ca(2+) release. This effect could be mimicked by eicosatetraynoic acid, indicating that AA metabolism is not required. The AA-mediated Ca(2+) signal was not affected by inhibition of ryanodine receptors or emptying of ryanodine sensitive store but was reduced by ~70% following the disruption of acidic stores (treatment with bafilomycin A1 or glycyl-phenylalanyl-beta-naphthylamide (GPN)). The action of AA did not involve TRPM2 channels or NAADP receptors because intracellular dialysis of adenosine diphosphoribose (ADPR; an activator of TRPM2 channels) or NAADP did not affect the AA response. In contrast, stimulation of IP(3) receptors via intracellular dialysis of adenophostin A, or exogenous application of ATP largely abolished the AA-mediated Ca(2+) signal. Intracellular dialysis of heparin abolished the ATP-mediated Ca(2+) signal but not the AA response, suggesting that the action of AA did not involve the IP(3)-binding site. Treatment with the SERCA pump inhibitor, thapsigargin, reduced the amplitude of the AA-mediated Ca(2+) signal by ~70%. Overall, our finding suggests that AA mobilizes Ca(2+) from the endoplasmic reticulum as well as an acidic store and both stores could be depleted by IP(3) receptor agonist. The possibility of secretory granules as targets of AA is discussed. PMID- 22197026 TI - Deoxygenation-induced and Ca(2+) dependent phosphatidylserine externalisation in red blood cells from normal individuals and sickle cell patients. AB - Phosphatidylserine (PS) is usually confined to the inner leaflet of the red blood cell (RBC) membrane. It may become externalised in various conditions, however, notably in RBCs from patients with sickle cell disease (SCD) where exposed PS may contribute to anaemic and ischaemic complications. PS externalisation requires both inhibition of the aminophospholipid translocase (or flippase) and activation of the scramblase. Both may follow from elevation of intracellular Ca(2+). Flippase inhibition occurs at low [Ca(2+)](i), about 1MUM, but [Ca(2+)](i) required for scrambling is reported to be much higher (around 100MUM). In this work, FITC-labelled lactadherin and FACS were used to measure externalised PS, with [Ca(2+)](i) altered using bromo-A23187 and EGTA/Ca(2+) mixtures. Two components of Ca(2+)-induced scrambling were apparent, of high (EC(50) 1.8+/ 0.3MUM) and low (306+/-123MUM) affinity, in RBCs from normal individuals and the commonest SCD genotypes, HbSS and HbSC. The high affinity component was lost in the presence of unphysiologically high [Mg(2+)] but was unaffected by high K(+) (90mM) or vanadate (1mM). The high affinity component accounted for PS scrambling in >=2/3rd RBCs. It is likely to be most significant in vivo and may be involved in the pathophysiology of SCD or other conditions involving eryptosis. PMID- 22197027 TI - (18)FDG-PET/CT for detection of mediastinal nodal metastasis in non-small cell lung cancer: a meta-analysis. AB - BACKGROUND: We performed a meta-analysis to evaluate the role of (18)F fluorodeoxyglucos -e positron emission tomography/computed tomography ((18)FDG PET/CT) in detecting mediastinal nodal metastasis in patients with non-small cell lung cancer (NSCLC). METHODS: Studies about (18)FDG-PET/CT for detecting mediastinal nodal metastasis in patient with NSCLC were systematically searched in the MEDLINE, EMBASE, and EBM Review databases from January 1, 2000 to July 26, 2011. A software called "Meta-Disc" was used to obtain pooled estimates of sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR), respectively. We also calculated summary receiver operating characteristic (SROC) curves, and the Q* index. RESULTS: 20 articles fulfilled all inclusion criteria (3028 eligible patients). The pooled sensitivity, and specificity with 95% confidence interval for PET/CT on a per patient analysis were 0.719 (0.683-0.753), and 0.898 (0.882-0.912). Corresponding values for PET/CT on a per-nodal-station analysis were 0.610 (0.582-0.636), 0.924 (0.918-0.930). The Q* index estimates under SROC were 0.8464 and 0.8067, respectively. CONCLUSIONS: (18)FDG-PET/CT had more specificity but less sensitivity for mediastinal nodal metastasis in patients with NSCLC. PMID- 22197028 TI - Anatomy of the infratemporal crest: implications for cross-facial nerve grafting in temporal myoplasty. AB - Temporalis transfers for reanimation in facial palsy have been criticised for the lack of neural input from a functioning facial nerve. Cross-facial nerve grafting to the deep temporal nerves may provide a solution. An anatomical study was performed to further elucidate the deep temporal nerves (DTN) and arteries, examining anatomical variation and infratemporal distribution. Seventeen temporalis muscles were dissected from 13 cadavers as part of a BSc project. The number, branching pattern, length and diameter of DTN were recorded. Arteries supplying the deep surface of temporalis and their relation to DTN were noted. Six specimens were processed using Sihler's staining technique. Arteries were injected with Iodixanol X-ray contrast medium and radiographs taken. All specimens displayed a single DTN originating from the anterior branch of V(3). A mean of 3 branches was observed. The nerve length was 14.22+/-3.95 mm. The point of entry of DTN into temporalis showed great consistency. Upon exiting the infratemporal fossa, the posterior deep temporal artery was deep and posterior to DTN in 65% of specimens. The branching pattern of DTN can be classified into three types. The deep arterial supply to temporalis was constant in all specimens. This study provides an anatomical basis for the planning and execution of cross-facial nerve grafting to temporalis, and for protection of vital structures. Furthermore, it helps to clarify inconsistencies in the literature regarding nomenclature of the nerve branching pattern of the deep temporal nerves. PMID- 22197029 TI - Nasal patency after open rhinoplasty with spreader grafts. AB - BACKGROUND: Spreader grafts have been used in cosmetic rhinoplasty, but little information is available about the objective results of treatment. This study sought to determine subjective and objective functional results of open cosmetic rhinoplasty with spreader grafts. METHODS: Twenty patients (14 women, six men; mean age, 31 +/- 6 years) had open cosmetic rhinoplasty. Surgery included dissection of the upper lateral cartilages, from the septum, and placement of spreader grafts, symmetrically, along the dorsal edge of the septal cartilage. Preoperative and postoperative evaluation included breathing quality score, acoustic rhinometry and a modified Glatzel mirror test. RESULTS: Evaluation after surgery (range, 5-18 months) showed significant improvement of breathing quality (before surgery, 8; after surgery, 9.4; P <= 0.001) and a mean minimal cross sectional area of the left side (before surgery, 0.6 cm(2); after surgery, 0.9 cm(2); P <= 0.01). There was no significant change of the mean minimal cross sectional area of the right side (acoustic rhinometry) or nasal patency (modified Glatzel mirror test) between preoperative and postoperative evaluation. Complications included postoperative synechiae in two patients and septal granuloma in one patient. CONCLUSIONS: Open structure rhinoplasty using spreader grafts is effective in reconstructing the internal nasal valve and preserving or improving nasal patency. LEVEL OF EVIDENCE: IV (case series with preoperative and postoperative testing). PMID- 22197031 TI - The fusion of unattended duration representations as indexed by the mismatch negativity (MMN). AB - Within a single train of same-duration (standard) stimuli, an occasional longer duration (deviant) sound elicits mismatch negativity (MMN) with a peak latency (measured relative to sound onset) reflecting the standard duration representation. When two such trains are presented in a dichotic paradigm, a separate duration representation arises for each train. We examined the role of attention in this segregation. Four sound trains of differing frequencies (1000 and 1200 Hz to one ear, 2000 and 2400 Hz to the other ear) were presented simultaneously. Participants attended the lower frequency (Low) sounds (always 100 ms) in one ear. Duration of the other (High) sounds varied: 100 ms in the Equal condition; 40 ms in the Short condition. If attention was necessary for separation of sound representations, the two attended ear representations were hypothesised to segregate whilst the two unattended ear's representations would remain fused. Duration MMN was recorded to occasional (1 in 18) 150 ms deviants in all trains. In the Short condition, if unattended ear representations fused, earlier peaking unattended Low sound MMN was expected, relative to when this ear was attended. In the same condition, the MMN for unattended High sounds was expected to peak later, relative to when attended. Low sound unattended MMN latency was indeed earlier by ~30 ms relative to when attended. High sound unattended MMN latency, however, only increased ~9 ms in the same transition. This smaller magnitude change is explained by a minimum MMN onset latency. Attention alone appears to offer a basis for segregating MMN representations. PMID- 22197030 TI - Glutamate receptor subunit GluA1 is necessary for long-term potentiation and synapse unsilencing, but not long-term depression in mouse hippocampus. AB - Receptor subunit composition is believed to play a major role in the synaptic trafficking of AMPA receptors (AMPARs), and thus in activity-dependent synaptic plasticity. To isolate a physiological role of GluA1-containing AMPARs in area CA3 of the hippocampus, pair recordings were performed in organotypic hippocampal slices taken from genetically modified mice lacking the GluA1 subunit. We report here that long-term potentiation (LTP) is impaired not only at active but also at silent synapses when the GluA1 subunit is absent. The GluA1 knockout mice also exhibited reduced AMPAR-mediated evoked currents between pairs of CA3 pyramidal neurons under baseline conditions suggesting a significant role for GluA1 containing AMPARs in regulating basal synaptic transmission. In two independent measures, however, long-term depression (LTD) was unaffected in tissue from these mice. These data provide a further demonstration of the fundamental role that GluA1-containing AMPARs play in activity-dependent increases in synaptic strength but do not support a GluA1-dependent mechanism for reductions in synaptic strength. PMID- 22197032 TI - HIV-1 Tat protein increases the permeability of brain endothelial cells by both inhibiting occludin expression and cleaving occludin via matrix metalloproteinase 9. AB - Brain homeostasis is maintained by the blood-brain barrier (BBB), which prevents the entrance of circulating molecules and immune cells into the central nervous system. The BBB is formed by specialized brain endothelial cells that are connected by tight junctions (TJ). Previous studies have proven that the Tat protein of human immunodeficiency virus type 1 (HIV-1) alters TJ protein expression. However, the mechanisms by which the alterations occur have not been characterized in detail. In this study, primary human brain microvascular endothelial cells (HBMEC) were exposed to recombinant HIV-1 Tat protein, and the effects on occludin were observed. Tat treatment decreased occludin mRNA and protein levels. This effect was partially abrogated by addition of the RhoA inhibitor C3 exoenzyme and the p160-Rho-associated coiled kinase (ROCK) inhibitor Y-27632. Meanwhile, Tat also induced MMP-9 expression. RNA interference targeting MMP-9 reduced both the paracellular permeability of Tat-treated HBMEC and the concentration of soluble occludin in supernatants from the cells. Taken together, these results show that the HIV-1 Tat protein disrupts BBB integrity, at least in part by decreasing the production of occludin. PMID- 22197033 TI - A cross-sectional MRI study of brain regional atrophy and clinical characteristics of temporal lobe epilepsy with hippocampal sclerosis. AB - PURPOSE: Applying a cross-sectional design, we set out to further characterize the significance of extrahippocampal brain atrophy in a large sample of 'sporadic' mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS). By evaluating the influence of epilepsy chronicity on structural atrophy, this work represents an important step towards the characterization of MRI-based volumetric measurements as genetic endophenotypes for this condition. METHODS: Using an automated brain segmentation technique, MRI-based volume measurements of several brain regions were compared between 75 patients with 'sporadic' MTLE+HS and 50 healthy controls. Applying linear regression models, we examined the relationship between structural atrophy and important clinical features of MTLE+HS, including disease duration, lifetime number of partial and generalized seizures, and history of initial precipitating insults (IPIs). RESULTS: Significant volume loss was detected in ipsilateral hippocampus, amygdala, thalamus, and cerebral white matter (WM). In addition, contralateral hippocampal and bilateral cerebellar grey matter (GM) volume loss was observed in left MTLE+HS patients. Hippocampal, amygdalar, and cerebral WM volume loss correlated with duration of epilepsy. This correlation was stronger in patients with prior IPIs history. Further, cerebral WM, cerebellar GM, and contralateral hippocampal volume loss correlated with lifetime number of generalized seizures. CONCLUSION: Our findings confirm that multiple brain regions beyond the hippocampus are involved in the pathogenesis of MTLE+HS. IPIs are an important factor influencing the rate of regional atrophy but our results also support a role for processes related to epilepsy chronicity. The consequence of epilepsy chronicity on candidate brain regions has important implications on their application as genetic endophenotypes. PMID- 22197034 TI - Incidence and mortality of Parkinson's disease in older Canadians. AB - OBJECTIVE: To estimate the age-specific incidence of Parkinson's disease (PD) in elderly persons in the Canadian province of British Columbia (BC). All-cause and injury mortalities and relative risk of death for those persons with PD were also examined. METHODS: A historical cohort study was conducted using 5 provincial administrative databases from 1991/92 to 2000/2001. A series of algorithms based on the databases were created for case ascertainment of PD for persons 65 years or older. Crude and age-specific incidence and mortality rates were calculated using person-years of follow-up as the denominator. The impact of PD on all-cause and injury mortalities was examined using multivariate Cox regression models to provide adjusted hazard ratios. RESULTS: 10,910 incidence cases over 6,051,682 person-years of follow-up were identified. The crude annual incidence rate was 252 per 100,000 person-years. Over the nine year period, age standardized incidence for males ranged from 207 to 396 per 100,000 person-years and 127 to 259 per 100,000 person-years for females. Persons with PD were at a 43% greater risk of all-cause mortality and specifically, 51% greater risk of injury mortality. CONCLUSIONS: Incidence of PD is substantially higher in advanced age with age adjusted increases for both all-cause and injury mortalities. These findings also highlight falls as a primary factor for injury mortality in PD. PMID- 22197035 TI - Gastrointestinal stromal tumors (GISTs): CD117, DOG-1 and PKCtheta expression. Is there any advantage in using several markers? AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. Expression of CD117, DOG1 and PKCtheta was investigated immunohistochemically in a series of 99 paraffin-embedded GISTs in order to determine the sensitivity and diagnostic value of these markers. KIT exons 9, 11, 13 and 17 and PDGFRA exons 12 and 18 were amplified by PCR and sequenced. A total of 94/99 (94%) GISTs stained positive for CD117, 81/99 (82%) for PKCtheta and 90/99 (91%) for DOG-1. A significant correlation was noted between CD117 and DOG 1 expression (p=0.0001). All three markers were expressed in 74% (73/99) of GISTs. Of the five CD117-negative cases, two were PKCtheta-negative/DOG1-negative and had mutations in KIT exon 11. Two were PKCtheta-positive/DOG1-positive and had mutations in PDGFRA (one each in exons 12 and 18), and one was DOG1 negative/PKCtheta-positive, with a PDGFRA exon 18 mutation. The most sensitive marker was CD117, followed by DOG-1 and PKCtheta. Although PKCtheta was less sensitive, and its staining is more challenging and difficult to interpret, the use of this marker is highly recommended, particularly in CD117-negative/DOG-1 negative GISTs. PMID- 22197036 TI - Molecular cloning and partial functional characterization of a proliferation inducing ligand (APRIL) in zebrafish (Danio rerio). AB - Here we describe the identification of a Danio rerio homologue of a proliferation inducing ligand (APRIL) of the TNF family (designated zAPRIL). Sequence analysis showed that the open reading frame of zAPRIL consists of 600 bases encoding a protein of 199-amino acids. Recombinant soluble APRIL (zsAPRIL) was constructed consisting of fluorescence-enhanced green fluorescent protein (EGFP) and cloned into a pET28a vector. SDS-PAGE and western blotting analysis indicated a high level expression of soluble EGFP/zsAPRIL protein in Escherichia coli BL21 (DE3). Observation by confocal microscopy demonstrated that EGFP/zsAPRIL could successfully bind to the surface receptors of zebrafish lymphocytes. In vitro survival analysis revealed that purified EGFP/zsAPRIL was able to promote the survival of zebrafish lymphocytes in a dose-dependent manner. The biological role of APRIL does not seem to be restricted to proliferation induction. Zebrafish may could served as a model organism for further study of APRIL. PMID- 22197037 TI - [Obstructive sleep apnea in general anaesthesia with spontaneous ventilation: the noninvasive ventilation (NIV) benefit]. PMID- 22197038 TI - Iatrogenic tension pneumopericardium in a patient with posttraumatic acute respiratory distress syndrome. PMID- 22197039 TI - [The paediatric pain clinic in Reims (France)]. AB - The activity of a paediatric chronic pain clinic is described. The author highlight the importance of the first visit of the child with its parents, and of a multidisciplinary approach adapted to the child's individual needs. PMID- 22197040 TI - [Early blood transfusion in damage control resuscitation]. PMID- 22197041 TI - [The surgeon's viewpoint concerning Complex Regional Pain Syndrome 1]. AB - The complex regional pain syndrome type 1 from the surgeon's point of view: description of the symptoms, imaging (nuclear medicine, MRI) and of the associated psychological context. Importance of the need for a multi-disciplinary organization from the diagnostic to the therapeutic care. PMID- 22197042 TI - [Postpartum haemorrhage and factor VII deficiency]. AB - During pregnancy, the plasma concentration of factor VII increases to reach values during the third trimester that can be twice the normal values (N: 70% to 140%). Congenital factor VII deficiency is a rare condition which may lead to haemorrhage. We report the case of a patient with a congenital factor VII deficiency who presented with severe postpartum haemorrhage requiring resuscitation with blood transfusion and surgical haemostasis. We discuss the treatment of congenital factor VII deficiency and its anaesthetic management, as well as the hemorrhagic risk during pregnancy. PMID- 22197043 TI - [TAP block analgesia after iliac bone surgery]. AB - We report two cases of iliac bone surgery (repair of a symphysis disjunction and fixation of a fracture of the iliac ala) where TAP blocks were effective for postoperative analgesia. In the first case, we performed a bilateral block, and only a unilateral block in the second case. We discuss possible mechanisms to explain the efficacy of the TAP blocks in such surgeries. As for the femoral nerve block in major knee surgery, we think that blocking the parietal pain from skin and blocking parietal muscles contracture, can reduce postoperative pain in such surgeries. PMID- 22197044 TI - [Fast recovery of haemodynamic and ventilatory functions after sugammadex bolus following rocuronium-induced anaphylactic shock refractory to conventional treatment]. AB - Recently, three case reports have suggested the possible efficacy of sugammadex in anaphylactic shock refractory to conventional treatment induced by rocuronium. We report a new case of severe anaphylactic reaction to rocuronium treated with sugammadex. After 18 minutes of conventional treatment because of persistent cardiocirculatory failure and bronchospasm, a bolus of 2000 mg (18 mg/kg) of sugammadex was injected. This was associated with rapid correction of arterial hypotension and bronchoconstriction. The underlying pathophysiological mechanisms that explain the potential beneficial effect of sugammadex in this context are unknown but it is important to know that refractory anaphylactic shock to rocuronium can be potentially corrected with sugammadex. PMID- 22197045 TI - Reasons for substance use among people with mental disorders. AB - BACKGROUND: Comorbidity of mental disorders and substance use continues to be a major problem. To inform the development of more effective interventions for these co-existing disorders, this paper aimed to determine if there are clear variations in the reasons for tobacco, alcohol or cannabis use across people with different mental disorders. METHODS: Data from five randomized controlled trials on co-existing disorders that measured reasons for tobacco, alcohol or cannabis use using the Drug Use Motives Questionnaire, Reasons for Smoking Questionnaire or via free response are reported and combined. Two studies involved participants with depression, two involved participants with a psychotic disorder and one involved participants with a range of mental disorders. A series of logistic regressions were conducted to examine differences in reasons for tobacco, alcohol or cannabis use and to compare these reasons between people with psychotic disorders or depression. RESULTS: Participants had a mean age of 38 (SD=12) and just over half (60%) were male. Forty-six percent of participants had a psychotic disorder and 54% experienced depression. Data from 976 participants across the five studies were included in the analyses. Tobacco and alcohol were primarily used to cope, while cannabis was primarily used for pleasure. People with psychotic disorders were more likely than people with depression to use tobacco for coping, pleasure and illness motives. People with depression, in contrast, were more likely to use alcohol for these reasons and social reasons. CONCLUSIONS: It may be important to tailor interventions for co-existing mental disorders and substance use by substance type and type of mental disorder. For example, interventions might be improved by including alternative coping strategies to tobacco and/or alcohol use, by addressing the social role of alcohol and by helping people with mental disorders using cannabis to gain pleasure from their lives in other ways. PMID- 22197046 TI - Posttraumatic hypothermia increases doublecortin expressing neurons in the dentate gyrus after traumatic brain injury in the rat. AB - Previous studies have demonstrated that moderate hypothermia reduces histopathological damage and improves behavioral outcome after experimental traumatic brain injury (TBI). Further investigations have clarified the mechanisms underlying the beneficial effects of hypothermia by showing that cooling reduces multiple cell injury cascades. The purpose of this study was to determine whether hypothermia could also enhance endogenous reparative processes following TBI such as neurogenesis and the replacement of lost neurons. Male Sprague-Dawley rats underwent moderate fluid-percussion brain injury and then were randomized into normothermia (37 degrees C) or hypothermia (33 degrees C) treatment. Animals received injections of 5-bromo-2'-deoxyuridine (BrdU) to detect mitotic cells after brain injury. After 3 or 7 days, animals were perfusion-fixed and processed for immunocytochemistry and confocal analysis. Sections were stained for markers selective for cell proliferation (BrdU), neuroblasts and immature neurons (doublecortin), and mature neurons (NeuN) and then analyzed using non-biased stereology to quantify neurogenesis in the dentate gyrus (DG). At 7 days after TBI, both normothermic and hypothermic TBI animals demonstrated a significant increase in the number of BrdU-immunoreactive cells in the DG as compared to sham-operated controls. At 7 days post-injury, hypothermia animals had a greater number of BrdU (ipsilateral cortex) and doublecortin (ipsilateral and contralateral cortex) immunoreactive cells in the DG as compared to normothermia animals. Because adult neurogenesis following injury may be associated with enhanced functional recovery, these data demonstrate that therapeutic hypothermia sustains the increase in neurogenesis induced by TBI and this may be one of the mechanisms by which hypothermia promotes reparative strategies in the injured nervous system. PMID- 22197047 TI - Spinal cord injury with unilateral versus bilateral primary hemorrhage--effects of glibenclamide. AB - In spinal cord injury (SCI), block of Sur1-regulated NC(Ca-ATP) channels by glibenclamide protects penumbral capillaries from delayed fragmentation, resulting in reduced secondary hemorrhage, smaller lesions and better neurological function. All published experiments demonstrating a beneficial effect of glibenclamide in rat models of SCI have used a cervical hemicord impact calibrated to produce primary hemorrhage located exclusively ipsilateral to the site of impact. Here, we tested the hypothesis that glibenclamide also would be protective in a model with more extensive, bilateral primary hemorrhage. We studied the effect of glibenclamide in 2 rat cervical hemicord contusion models with identical impact force (10 g, 25 mm), one with the impactor positioned laterally to yield unilateral primary hemorrhage (UPH), and the other with the impactor positioned more medially, yielding larger, bilateral primary hemorrhages (BPH) and 6-week lesion volumes that were 45% larger. Functional outcome measures included: modified (unilateral) Basso, Beattie, and Bresnahan scores, angled plane performance, and rearing times. In the UPH model, the effects of glibenclamide were similar to previous observations, including a functional benefit as early as 24h after injury and 6-week lesion volumes that were 57% smaller than controls. In the BPH model, glibenclamide exerted a significant benefit over controls, but the functional benefit was smaller than in the UPH model and 6-week lesion volumes were 33% smaller than controls. We conclude that glibenclamide is beneficial in different models of cervical SCI, with the magnitude of the benefit depending on the magnitude and extent of primary hemorrhage. PMID- 22197048 TI - Nocturnal gastroesophageal reflux, lung function and symptoms of obstructive sleep apnea: Results from an epidemiological survey. AB - BACKGROUND: Nocturnal gastroesophageal reflux (nGER) has received increasing interest as a predisposing factor for respiratory diseases and sleep disturbances. The possible role of obstructive sleep apnea (OSA) contributing to nGER is of special interest. The aim of this study was to explore the association between nGER and respiratory diseases, lung function and symptoms of OSA. METHODS: Participants in the Burden of Obstructive Lung Disease (BOLD) initiative in Iceland and Sweden, a random sample from the general population of 1325 adults aged 40+ (>70% response rate), were compared by pre- and post-bronchodilator spirometry, answers to questionnaires about OSA and respiratory symptoms, health, and symptoms of GER. RESULTS: Altogether 102 (7.7%) reported nGER and 249 had used medication against GER. The participants were divided into three groups: 1) No nGER (n = 1040), 2) treated GER without nGER (n = 183) and 3) nGER (n = 102). The nGER group had a significantly higher prevalence of respiratory and OSA symptoms than subjects without nGER. The nGER group also had a higher prevalence of COPD (GOLD stage 1+), (25.0% vs. 15.6%) (p = 0.02) and lower FEV(1)/FVC ratio (95.9% vs. 98.9% of the predicted, p = 0.01). These associations remained significant after adjusting for smoking, weight and other possible confounders. No independent association was found between having treated GER and lung function, respiratory or OSA symptoms. CONCLUSIONS: In our cross-sectional epidemiological study, untreated nGER is strongly associated with both respiratory and OSA symptoms as well as airflow obstruction. PMID- 22197049 TI - Stereological characterization of left ventricular cardiomyocytes, capillaries, and innervation in the nondiabetic, obese mouse. AB - BACKGROUND: Obesity is associated with left ventricular hypertrophy and dysfunction, but little is known about the structural remodeling of cardiomyocytes, capillaries, and nerve fibers in this state. We hypothesized that all three compartments should show quantitative structural alterations. METHODS: Ten C57Bl6 mice were randomly assigned to a control or obesity group. Lean mice received standard chow, whereas obese mice received a high-fat Western diet. After 28 weeks, the mice were sacrificed, and the hearts were prepared for design based stereology using light and electron microscopy. RESULTS: Body mass and left ventricular mass were significantly elevated in obese vs. control mice. The left ventricular hypertrophy was accompanied by a significant increase in cardiomyocyte lipid droplets and total myocyte volume. The volume fractions of myofibrils, free sarcoplasm, and mitochondria did not differ between the groups. The total length of capillaries was significantly enhanced in obese vs. control mice, whereas the total length of axons ramifying between cardiomyocytes was not different. CONCLUSIONS: Obesity is associated with significant structural alterations in cardiomyocytes and capillaries, whereas no structural changes in the myocardial innervation were observed. The structural characteristics in obese mice do not provide a clear basis for functional changes observed in obesity related cardiac hypertrophy. PMID- 22197050 TI - Intracardiac thrombi in extracardiac disorders: an autopsy study. AB - INTRODUCTION: Intracardiac thrombi (ICT), more commonly encountered at autopsy, are well documented with underlying cardiovascular disease. Occurrence of ICT in systemic diseases without an intrinsic cardiac disorder is rare. The aim of this autopsy study was to highlight such an occurrence. METHODS: From 1996 to 2010, cases with ICT unrelated to primary cardiac disorders were selected at autopsy and analyzed. Clinical and investigational data were obtained from the medical records. The location, morphology, size, and histological appearance of the thrombi were noted. The thrombi were then classified on the basis of their location, nature, and histology (fresh and/or organized); this was correlated with the clinical setting. RESULTS: Among a total of 11,724 autopsies performed in 15 years, 276 patients (2.4%) had ICT. Of these, 45 patients (0.4%) had ICT that were unrelated to primary cardiac diseases. There were 25 men and 20 women with a mean age of 46.1 years. Antemortem diagnosis was not made in any of these patients. Eight patients each (35.6%) showed isolated left-sided and multichambered involvement, while the rest of the hearts (64.4%) had thrombi in the right-sided chamber(s). The recognizable risk factors were underlying cancers (24.4%), prolonged immobilization (20%), systemic lupus erythematosus (6.7%), pregnancy (4.4%), nephropathy (4.4%), primary antiphospholipid antibody syndrome (2.2%), and ulcerative colitis (2.2%). However, 16 patients (35.7%) had no obvious predisposing factor, although investigations for prothrombotic markers had not been done. Diabetes mellitus, chronic alcoholism, and deep vein thrombosis of the lower limbs had been clinically documented in some of them. The cause of death in most patients (73.3%) had been related to pulmonary and/or systemic thromboembolism. CONCLUSIONS: This autopsy study emphasizes the great need for a higher index of suspicion of in situ thrombosis in the heart in hypercoagulable states so as to curtail the morbidity and mortality of the primary disease process. PMID- 22197051 TI - Incidence and short-term consequences of delirium in critically ill patients: A prospective observational cohort study. AB - BACKGROUND: Delirium is a serious and frequent psycho-organic disorder in critically ill patients. Reported incidence rates vary to a large extent and there is a paucity of data concerning delirium incidence rates for the different subgroups of intensive care unit (ICU) patients and their short-term health consequences. OBJECTIVES: To determine the overall incidence and duration of delirium, per delirium subtype and per ICU admission diagnosis. Furthermore, we determined the short-term consequences of delirium. DESIGN: Prospective observational study. PARTICIPANTS AND SETTING: All adult consecutive patients admitted in one year to the ICU of a university medical centre. METHODS: Delirium was assessed using the Confusion Assessment Method-ICU three times a day. Delirium was divided in three subtypes: hyperactive, hypoactive and mixed subtype. As measures for short-term consequences we registered duration of mechanical ventilation, re-intubations, incidence of unplanned removal of tubes, length of (ICU) stay and in-hospital mortality. RESULTS: 1613 patients were included of which 411 (26%) developed delirium. The incidence rate in the neurosurgical (10%) and cardiac surgery group (12%) was the lowest, incidence was intermediate in medical patients (40%), while patients with a neurological diagnosis had the highest incidence (64%). The mixed subtype occurred the most (53%), while the hyperactive subtype the least (10%). The median delirium duration was two days [IQR 1-7], but significantly longer (P<0.0001) for the mixed subtype. More delirious patients were mechanically ventilated and for a longer period of time, were more likely to remove their tube and catheters, stayed in the ICU and hospital for a longer time, and had a six times higher chance of dying compared to non-delirium ICU patients, even after adjusting for their severity of illness score. Delirium was associated with an extended duration of mechanical ventilation, length of stay in the ICU and in-hospital, as well as with in-hospital mortality. CONCLUSIONS: The delirium incidence in a mixed ICU population is high and differs importantly between ICU admission diagnoses and the subtypes of delirium. Patients with delirium had a significantly higher incidence of short-term health problems, independent from their severity of illness and this was most pronounced in the mixed subtype of delirium. Delirium is significantly associated with worse short-term outcome. PMID- 22197052 TI - Identifying patient deterioration: using simulation and reflective interviewing to examine decision making skills in a rural hospital. AB - OBJECTIVES: The study aim was to examine how Registered Nurses identify and respond to deteriorating patients during in-hospital simulation exercises. DESIGN: Mixed methods study using simulated actors. SETTING: A rural hospital in Victoria, Australia. PARTICIPANTS: Thirty-four Registered Nurses each completed two simulation exercises. METHODS: Data were obtained from the following sources: (a) Objective Structured Clinical Examination (OSCE) rating to assess performance of Registered Nurses during two simulation exercises (chest pain and respiratory distress); (b) video footage of the simulation exercises; (c) reflective interview during participants' review of video footage. Qualitative thematic analysis of video and interview data was undertaken. RESULTS: Themes generated from the data were: (1) exhausting autonomous decision-making; (2) misinterpreting the evidence; (3) conditioned response; and (4) missed cues. Assessment steps were more likely to be omitted in the chest pain simulation, for which there was a hospital protocol in place. CONCLUSIONS: Video review revealed additional insights into nurses' decision-making that were not evident from OSCE scoring alone. Feedback during video review was a highly valued component of the simulation exercises. PMID- 22197053 TI - Development and preliminary validation of a composite Spiritual Care-Giving Scale. AB - BACKGROUND: Spiritual care is a central element of holistic nursing, but is not often made explicit in the theoretical and practical components of pre registration nursing programmes. A composite scale will assist in identifying students' perceptions and issues to be addressed in curricula and practice settings. OBJECTIVE: To develop and test the Spiritual Care-Giving Scale that measures student nurses' perceptions towards spirituality and spiritual care. METHOD: Following a critical review of the literature, review by an expert panel and a pilot study, the SCGS, was administered to a convenience sample of final year nursing students. Participants also completed the Spirituality and Spiritual Care Rating Scale and Student Survey of Spiritual Care to assess construct validity. Internal reliability was assessed using Cronbach's alpha and test retest reliability was assessed at 1 week. Principal component analysis was used and the 68-item Spiritual Care-Giving Scale was reduced to 35-items. RESULTS: 745 (out of 1204) students completed the survey giving a 61.9% response rate. A 5 factor solution explaining 61.2% of the variance was supported. Cronbach's alpha of the 35-item scale was 0.86 and test-retest reliability was stable over time (r=0.811). Concurrent validity with the Spirituality and Spirituality Care Rating scale (r=0.587, p<0.01) and Student Survey of Spiritual Care (r=0.507, p<=0.01) showed significant correlation. CONCLUSION: The Spiritual Care-Giving Scale was found to be a valid and reliable instrument for measuring the multifaceted perspectives of spirituality and spiritual care in practice by students. Further testing of this scale is required with other student populations and clinicians. PMID- 22197054 TI - The cis-bis(decanoate)tin phthalocyanine/DPPC film at the air/water interface. AB - Films made of cis-bis-decanoate-tin(IV) phthalocyanine (PcSn10) and racemic dipalmitoylphosphatidylcholine (DPPC) are studied with compression isotherms and Brewster angle microscopy (BAM) at the air/water interface. Films enriched in PcSn10 present phase separation elliptical-shaped domains. These domains present optical anisotropy and molecular order. They are enriched in PcSn10, and the film outside these domains is enriched in DPPC, as shown in by high-angle annular dark field transmission electron microscopy on Langmuir-Blodgett (LB) transferred films. Film collapse area and atomic force microscopy images of LB transferred films on mica indicate that the films are actually multilayers. A computational survey was performed to determine how the PcSn10 molecules prefer to self assemble, in films basically made of PcSn10. The relative energetic stability for several dimeric assemblies was obtained, and a crystal model of the film was developed through packing and repeating the PcSn10 molecules, along the crystallographic directions of the unit cell. Our results contribute to understanding the strong interaction between PcSn10 and DPPC at the air/water interface, where even small quantities of DPPC (~1-2%) can modify the film in an important way. PMID- 22197055 TI - Correlation between catalytic activity and surface ligands of monolayer protected gold nanoparticles. AB - Gold nanoparticles (GNPs) are known to be a very good catalyst. Also, the anchoring of GNPs with stabilizing ligands is essential for surface modification, tuning of size and shapes, and to prevent from aggregation in suspension. But the effect of ligand on the catalytic property of ligand-capped GNP is yet to be explored in detail. In this paper, we perform an in-depth study of effect of ligands on the catalytic activity of monolayer protected GNPs. For this study, a series of different ligand functionalized GNPs in suspension as well as functionalized GNPs' thin film on glass substrate are prepared and used as catalysts in two model reactions, viz. borohydride reduction of 4-nitrophenol and redox reaction between potassium ferricyanide and sodium thiosulfate. The functionalization of GNPs with any ligand reduces its virgin catalytic activity, no matter whether the GNPs are suspended or supported as thin film. An increase in alkyl chain length of alkanethiols and alkylamines ligands and their graft density to the surface of GNP reduces its catalytic activity. Interestingly, the capping of GNPs with 11-mercaptoundecanoic acid and 11-mercaptoundecanol ligands completely destroys its catalytic activity. The effect of anchoring group of ligand molecules on the catalytic activity of ligand-protected GNPs is also discussed. PMID- 22197056 TI - Preparation of organic/inorganic hybrid and hollow particles by catalytic deposition of silica onto core/shell heterocoagulates modified with poly[2-(N,N dimethylamino)ethyl methacrylate]. AB - The organic/inorganic hybrid particles PSt/P(St-CPEM)(theta)-g-PDMAEMA/SiO(2) were prepared by catalytic hydrolysis and subsequent polycondensation of tetraethoxysilane in the poly[2-(N,N-dimethylamino)ethyl methacrylate] (PDMAEMA) layers grafted on the PSt/P(St-CPEM)(theta) core/shell heterocoagulates. The micron-sized PSt core and the submicron-sized P(St-CPEM) shell particles bearing ATRP initiating groups were synthesized by dispersion polymerization of styrene (St) and emulsifier-free emulsion polymerization of St with 2 chloropropionyloxyethyl methacrylate (CPEM), respectively. The raspberry-shaped PSt/P(St-CPEM)(theta) heterocoagulates with a controlled surface coverage (theta=0.51, 0.81) were prepared by hydrophobic coagulation between the core and the shell particles in an aqueous NaCl solution near the T(g) of P(St-CPEM). Surface modification of heterocoagulates was carried out by ATRP of DMAEMA from the shell particles adsorbed on the core particles. Silica deposition was performed by simply adding tetraethoxysilane to a water/methanol dispersion of PSt/P(St-CPEM)(theta)-g-PDMAEMA. The SEM and TGA revealed that the resulting PSt/P(St-CPEM)(theta)-g-PDMAEMA/SiO(2) composites maintain a raspberry-like morphology after deposition of silica onto the PDMAEMA layer grafted on heterocoagulates. The micron-sized, raspberry-shaped or the submicron-sized, hole structured silica hollow particles were obtained selectively by thermal decomposition of the PSt/P(St-CPEM)(theta)-g-PDMAEMA/SiO(2). The oriented particle array was fabricated by dropping anisotropically perforated silica particles onto a glass substrate settled at the bottom of a bottle filled with chloroform. PMID- 22197057 TI - Adsorption/bioadsorption of phthalic acid, an organic micropollutant present in landfill leachates, on activated carbons. AB - This study investigated the adsorption of phthalic acid (PA) in aqueous phase on two activated carbons with different chemical natures, analyzing the influence of: solution pH, ionic strength, water matrix (ultrapure water, ground water, surface water, and wastewater), the presence of microorganisms in the medium, and the type of regime (static and dynamic). The activated carbons used had a high adsorption capacity (242.9 mg/g and 274.5 mg/g), which is enhanced with their phenolic groups content. The solution pH had a major effect on PA adsorption on activated carbon; this process is favored at acidic pHs. PA adsorption was not affected by the presence of electrolytes (ionic strength) in solution, but was enhanced by the presence of microorganisms (bacteria) due to their adsorption on the carbon, which led up to an increase in the activated carbon surface hydrophobicity. PA removal varies as a function of the water type, increasing in the order: ground waterSBA-15-TMPS>SBA-15-PTMS, which is directly associated with the surface area, pore size and pore volume. As compared with homogeneous catalyst, SBA-15-SO(3)H-MPTMS heterogeneous catalyst shows remarkable performance, such as separation, recovery and reusability. PMID- 22197059 TI - Semantic similarity, predictability, and models of sentence processing. AB - The effects of word predictability and shared semantic similarity between a target word and other words that could have taken its place in a sentence on language comprehension are investigated using data from a reading time study, a sentence completion study, and linear mixed-effects regression modeling. We find that processing is facilitated if the different possible words that could occur in a given context are semantically similar to each other, meaning that processing is affected not only by the nature of the words that do occur, but also the relationships between the words that do occur and those that could have occurred. We discuss possible causes of the semantic similarity effect and point to possible limitations of using probability as a model of cognitive effort. PMID- 22197060 TI - Temporal expectation and information processing: a model-based analysis. AB - People are able to use temporal cues to anticipate the timing of an event, enabling them to process that event more efficiently. We conducted two experiments, using the fixed-foreperiod paradigm (Experiment 1) and the temporal cueing paradigm (Experiment 2), to assess which components of information processing are speeded when subjects use such temporal cues to predict the onset of a target stimulus. We analyzed the observed temporal expectation effects on task performance using sequential-sampling models of decision making: the Ratcliff diffusion model and the shifted-Wald model. The results from the two experiments were consistent: temporal expectation affected the duration of nondecision processes (target encoding and/or response preparation) but had little effect on the two main components of the decision process: response threshold setting and the rate of evidence accumulation. Our findings provide novel evidence about the psychological processes underlying temporal-expectation effects on reaction time. PMID- 22197061 TI - New method for determining in vitro structure stiffness of ceramic acetabular liners under different impact conditions. AB - Increasing both patient mobility and prosthesis life span requires improvements in the range of motion and wear behavior of the liner. With the use of new composite alumina-zirconia ceramic materials, the same stability of the liner can be achieved at lower wall thickness than it is possible with alumina-only materials. The aim of this study was developing a method for determining the in vitro structure stiffness of ceramic acetabular liners against impact stresses. The first trials were performed with a common alumina acetabular liner type (Ceramtec; Biolox forte; diameter 28 mm; thickness 7 mm) and a new type of alumina-zirconia (Ceramtec Biolox delta; same dimensions) liner. The clinically established alumina liner was reproducibly damaged using worst case Separation/subluxation equivalent to one-fourth or half of the head diameter, and an impact load of 15 J. The liners containing the new alumina-zirconia material were not damaged in any of the trials up to an impact load of 20 J and half head diameter offset. PMID- 22197062 TI - The Vindija Neanderthal scapular glenoid fossa: comparative shape analysis suggests evo-devo changes among Neanderthals. AB - Although the shape of the scapular glenoid fossa (SGF) may be influenced by epigenetic and developmental factors, there appears to be strong genetic control over its overall form, such that variation within and between hominin taxa in SGF shape may contain information about their evolutionary histories. Here we present the results of a geometric morphometric study of the SGF of the Neanderthal Vi 209 from Vindjia Cave (Croatia), relative to samples of Plio-Pleistocene, later Pleistocene, and recent hominins. Variation in overall SGF shape follows a chronological trend from the plesiomorphic condition seen in Australopithecus to modern humans, with pre-modern species of the genus Homo exhibiting intermediate morphologies. Change in body size across this temporal series is not linearly directional, which argues against static allometry as an explanation. However, life history and developmental rates change directionally across the series, suggesting an ontogenetic effect on the observed changes in shape (ontogenetic allometry). Within this framework, the morphospace occupied by the Neanderthals exhibits a discontinuous distribution. The Vindija SGF and those of the later Near Eastern Neanderthals (Kebara and Shanidar) approach the modern condition and are somewhat segregated from both northwestern European (Neandertal and La Ferrassie) and early Mediterranean Neanderthals (Krapina and Tabun). Although more than one scenario may account for the pattern seen in the Neanderthals, the data is consistent with palaeogenetic evidence suggesting low levels of gene flow between Neanderthals and modern humans in the Near East after ca. 120-100 ka (thousands of years ago) (with subsequent introgression of modern human alleles into eastern and central Europe). Thus, in keeping with previous analyses that document some modern human features in the Vindija Neanderthals, the Vindija G(3) sample should not be seen as representative of 'classic'--that is, unadmixed, pre contact--Neanderthal morphology. PMID- 22197063 TI - Is a composite score of physical performance measures more useful than usual gait speed alone in assessing functional status? AB - Overall physical performance can be represented by a composite score that is derived from upper and lower extremity performance measures. We aimed to identify whether composite scores of performance measures, particularly the lower extremity performance (LEP) score, upper extremity performance (UEP) score, and an overall score, are more accurate than usual gait speed (UGS) for assessing a wide range of functional status. We conducted a cross-sectional analysis on data from 701 community-dwelling older women (mean age 74.3 years). Trained testers measured UGS and the seven tests included in the composite scores. Using self reported questionnaires, we assessed multiphasic functional status: physical function, higher-level functional capacity, mobility limitation, activities of daily living (ADLs), and falls. We compared the areas under the receiver operating characteristic curves (AUCs) of UGS with LEP, UEP, and overall scores for each status. We found no significant differences between the AUCs of UGS and LEP score for each status. The UEP score had significantly smaller AUCs for low physical function (0.73) and mobility limitation (0.78) than UGS alone (0.81 and 0.85, respectively), and the differences were substantial. Although the overall score had significantly greater AUCs for low higher-level functional capacity (0.83) and ADLs disability (0.83) than UGS alone (0.78 and 0.80, respectively), the differences were only 3-5%. The UGS should not be regarded solely as a measure of lower extremity function; this single test may represent overall physical performance. The UGS alone, which can be measured quickly and easily, suffice for assessing a wide range of functional status in older women. PMID- 22197064 TI - [Does Alzheimer's disease exist in all primates? Alzheimer pathology in non-human primates and its pathophysiological implications (I)]. AB - INTRODUCTION: Many publications consider that Alzheimer's disease (AD) is exclusive to the human species, and that no other animal species suffers from the disease. However, various studies have shown that some species can present with some of the defining characteristics of the human disease, including both neuropathological changes and cognitive-behavioural symptoms. DEVELOPMENT: In this work, the results published (PubMed) on senile brain changes in non-human primates of different degrees of evolution, are reviewed. The neuropathological changes associated with the accumulation of amyloid or highly phosphorylated tau protein are rare outside the primate order, but in all the sub-orders, families, genera and species of non-human primates that have been studied, some senile individuals have shown amyloid accumulation in the brain. In fact, in some species the presence of these deposits in senility is constant. Changes related to the accumulation of tau protein are always of very little significance, and have been detected only in some non-human primate species, both little evolved and highly evolved. In different species of non-human primates, some types of cognitive-behavioural changes are more common in some senile individuals when compared with both normal adult individuals and other senile individuals of the species. The importance of determining the longevity of the species in different habitats (natural habitats, new habitats, semi-captivity, captivity) is stressed in these studies. CONCLUSIONS: Morphological, histochemical and cognitive behavioural features similar to those observed in elderly humans are present in senile non-human primates. Moreover, other characteristics seen in non-human primates could be indicative of a pathological "Alzheimer type" ageing. PMID- 22197065 TI - The lumbar spine of the young cricket fast bowler: an MRI study. AB - OBJECTIVES: To describe the prevalence and nature of lumbar spinal abnormalities in adolescent cricket fast bowlers. DESIGN: Observational study. METHODS: 46 asymptomatic fast bowlers aged 13-18 years participated in the study and were grouped into under-15 (U15), under-17 (U17) and under-19 (U19) classifications. All participants underwent magnetic resonance imaging of the lumbar spine and abnormalities of the pars interarticularis and intervertebral discs were graded according to type and severity. Other abnormalities were also noted. RESULTS: Fifteen bowlers (33%) had at least one pars interarticularis abnormality. Six bilateral and 10 unilateral defects were identified. Of the 10 unilateral pars abnormalities, 6 occurred on the non-dominant side. Nineteen of the abnormalities occurred at the L5 vertebral level, 2 at L4 and 1 at L3. The most common type of pars abnormality was the subtotal stress fracture, which was found in 38% of bowlers aged 16 years and under. Sixteen participants (35%) were found to have degeneration of at least 1 lumbar disc and the prevalence increased with each successive age group (29% U15, 33% U17 and 43% U19). Of the 25 discs with signs of degeneration, 9 occurred at L4/5 and 7 at L5/S1. Eleven of these were classified as mild degeneration, 13 as moderate, and 1 as severe. Disc bulges were found in 33% of participants. CONCLUSIONS: Lumbar radiological abnormalities are common in asymptomatic adolescent fast bowlers. Acute bone stress reactions of the lumbar pars interarticularis are visible on magnetic resonance imaging and, in some instances, occur before the onset of activity-related pain. PMID- 22197066 TI - Relationship between interchange usage and risk of hamstring injuries in the Australian Football League. AB - OBJECTIVES: To study risk factors for hamstring injury in the Australian Football League (AFL), in particular the effect of recent changes in match participation (increased use of the interchange bench) on hamstring injury. DESIGN: Analysis of hamstring match injury statistics extracted from an injury database combined with match participation statistics extracted from a player statistics database. METHODS: 56,320 player matches in the AFL over the period 2003-2010 were analyzed, in which 416 hamstring injuries occurred. RESULTS: In a Generalized Estimating Equation (GEE) analysis accounting for clustering of different teams, significant predictors of hamstring injuries were recent hamstring injury (RR 4.16, 95% CI 3.19-5.43), past history of ACL reconstruction (RR 1.69, 95% CI 1.09 2.60), past history of calf injury (RR 1.58, 95% CI 1.37-1.82), opposition team making 60 or more interchanges during the game (RR 1.38, 95% CI 1.12-1.68) and player having made 7 or more interchanges off the field in the last 3 weeks (protective RR 0.74, 95% CI 0.59-0.93). CONCLUSIONS: These findings suggest that regular interchanges protect individual players against hamstring injuries, but increase the risk of hamstring injury for opposition players. These findings can be explained by a model in which both fatigue and average match running speed are risk factors for hamstring injury. A player who returns to the ground after a rest on the interchange bench may himself have some short-term protection against hamstring injury because of the reduced fatigue, but his rested state may contribute to increased average running speed for his direct opponent, increasing the risk of injury for players on the opposition team. PMID- 22197067 TI - Does muscle imbalance affect fatigue after soccer specific intermittent protocol? AB - OBJECTIVES: This study investigated the muscular strength imbalance dependence of the effect of fatigue induced by an exhaustive laboratory-based soccer-specific exercise on different hamstrings:quadriceps (H:Q) ratios of soccer players. DESIGN: Repeated measures. METHODS: Twenty-one male professional soccer players (23.2+/-3.5 years) performed a pre-test to assess the concentric (con) and eccentric (ecc) strength of the knee extensors (KE) and flexors (KF) at 60 degrees s-1 and 180 degrees s-1. Then performed an exhaustive laboratory-based soccer-specific exercise and a post-test similar to the pre-test. The players were allocated into one of two groups in accordance to their conventional H(con):Q(con) (balanced group, BG=H(con):Q(con)>0.60; unbalanced group, UNBG=H(con):Q(con)<0.60). RESULTS: The KE(con) (BG=4%, p<0.05; UNBG=6%, p<0.01) and KF(con) (BG=7%, p<0.01; UNBG=8%, p<0.01) at 60 degrees s-1 were significantly reduced after exercise for both groups. However, KF(ecc) at 180 degrees s-1 was significantly reduced only in BG (16%, p<0.01). The H(con):Q(con) and H(ecc):Q(con) were significantly reduced after exercise in BG (0.65+/-0.03 vs. 0.62+/-0.04, p<0.05; 1.38+/-0.2 vs. 1.20+/-0.2, p<0.01; respectively), but not in UNBG (0.55+/-0.04 vs. 0.54+/-0.07; 1.19+/-0.1 vs. 1.13+/-0.2, respectively). CONCLUSIONS: The effect of fatigue induced by an exhaustive laboratory-based soccer-specific exercise on H(con):Q(con) and H(ecc):Q(con) in the dominant leg of professional soccer players is dependent on muscular strength balance. Thus, experimental designs and prevention programmes should consider that muscular strength balance might also module the game-induced fatigue of professional soccer players. PMID- 22197068 TI - A robust method for the synthesis and isolation of beta-gluco-isosaccharinic acid ((2R,4S)-2,4,5-trihydroxy-2-(hydroxymethyl)pentanoic acid) from cellulose and measurement of its aqueous pK(a). AB - In alkaline pulping wood pulp is reacted with concentrated aqueous alkali at elevated temperatures. In addition to producing cellulose for the manufacture of paper, alkaline pulping also generates large amounts of isosaccharinic acids as waste products. Isosaccharinic acids are potentially useful raw materials: they are good metal chelating agents and, in their enantiomerically pure form, they are valuable carbon skeletons with predefined stereochemistry that can be easily functionalised for use in synthesis. Despite this, there is no simple procedure for isolating pure beta-(gluco)isosaccharinic acid and very limited work has been undertaken to determine the chemical and physical properties of this compound. We report here a very simple but effective method for the synthesis of a mixture containing equal portions of the two isosaccharinic acids ((2S,4S)-2,4,5 trihydroxy-2-(hydroxymethyl)pentanoic acid and (2R,4S)-2,4,5-trihydroxy-2 (hydroxymethyl)pentanoic acid) and the separation of the two as their tribenzoate esters. We also report for the first time the aqueous pK(a) of beta (gluco)isosaccharinic acid (3.61). PMID- 22197069 TI - Structural characterization of novel sophorolipid biosurfactants from a newly identified species of Candida yeast. AB - Sophorolipids are a group of O-acylsophorose-based biosurfactants produced by several yeasts of the Starmerella clade. The known sophorolipids are typically partially acetylated 2-O-beta-D-glucopyranosyl-D-glucopyranose (sophorose) O-beta glycosidically linked to 17-L-hydroxy-Delta9-octadecenoic acid, where the acyl carboxyl group often forms a 4"-lactone to the terminal glucosyl residue. In a recent MALDI-TOFMS-based screen for sophorolipid-producing yeasts we identified a new species, Candida sp. NRRL Y-27208, that produces significant amounts of novel sophorolipids. This paper describes the structural characterization of these new compounds, using carbohydrate and lipid analysis, mass spectrometry, and NMR spectroscopy. Unlike those reported previously, the NRRL Y-27208 sophorolipids contain an omega-hydroxy-linked acyl group (typically 18-hydroxy-Delta9 octadecenoate), and occur predominantly in a non-lactone, anionic form. In addition, 17 dimeric and trimeric sophoroses were identified by MALDI-TOFMS from this strain. The surfactant-like properties of these sophorolipids have value as potential replacements for petroleum-based detergents and emulsifiers. PMID- 22197070 TI - A new method based on fiber-optic sensing for the determination of deacetylation degree of chitosans. AB - A novel method for determining the degree of deacetylation of chitosan is described. This involves a two-abrupt-change of the refractive index of solutions. Principle of the method is that the sample reacts with excessive acid, and the excessive acid is measured by alkaline titration. The refractive index of an aqueous chitosan solution was monitored and recorded in the course of acid base titration. This gives a titration curve having two inflexion points and the difference between the two points corresponds to the volume of base required to neutralize the ammonium groups. It was proved that flocculation did not interfere with the measurement. The method is found to be low-cost, precise, and easy to operate for industrial applications. The DD values of three chitosan samples obtained with this new method show good agreement with those yielded from (1)H NMR. Such a mechanism of refractive index monitoring should open up a new application in the field of chitosanolytic enzymes, such as chitosanase, that are important in bioprocesses. PMID- 22197071 TI - Treatment of hereditary angioedema with nanofiltered C1-esterase inhibitor concentrate (Cetor(r)): multi-center phase II and III studies to assess pharmacokinetics, clinical efficacy and safety. AB - From 1997, plasma-derived C1-inhibitor concentrate (Cetor(r)) has been available to HAE and AAE patients. Recently, a virus reducing 15 nm nanofiltration step has been introduced in the production process. A randomized, double-blind controlled cross-over study was performed to compare the pharmacokinetics (PK) of nanofiltered (C1-INH-NF) with conventional C1-inhibitor (C1-INH). Efficacy and safety were investigated in an open-label, on-demand and a prophylactic study. No differences in pharmacokinetic parameters between C1-INH and C1-INH-NF were found (13 non-symptomatic HAE patients). Both C1-inhibitor products equally increased plasma C4 levels. In the on-demand study, 14 acute angioedema attacks in 8 patients were analyzed. In the prophylactic study, 1 AAE and 5 HAE patients experienced in total 31 attacks during 748 observation days. In total 180,000 units of C1-INH-NF were administered. No product-related adverse events occurred, and no anti-C1-antibodies were induced. Nanofiltration in the production process of C1-inhibitor did not affect the pharmacokinetics, efficacy, and safety. PMID- 22197072 TI - A modular continuous flow reactor system for the selective bio-oxidation of iron and precipitation of schwertmannite from mine-impacted waters. AB - A novel modular bioremediation system which facilitates the selective removal of soluble iron from extremely acidic (pH ~2) metal-rich wastewaters by ferrous iron oxidation and selective precipitation of the ferric iron produced is described. In the first of the three modules, rapid ferrous iron oxidation was mediated by the recently-characterized iron-oxidizing autotrophic acidophile, "Ferrovum myxofaciens", which grew as long "streamers" within the reactor. Over 90% of the iron present in influent test liquors containing 280mg/L iron was oxidized at a dilution rate of 0.41h(-1), in a proton-consuming reaction. The ferric iron-rich solutions produced were pumped into a second reactor where controlled addition of sodium hydroxide caused the water pH to increase to 3.5 and ferric iron to precipitate as the mineral schwertmannite. Addition of a flocculating agent promoted rapid aggregation and settling of the fine-grain schwertmannite particles. A third passive module (a packed-bed bioreactor, also inoculated with "Fv. myxofaciens") acted as a polishing reactor, lowering soluble iron concentrations in the processed water to <1mg/L. The system was highly effective in selectively removing iron from a synthetic acidic (pH 2.1) mine water that contained soluble aluminum, copper, manganese and zinc in addition to iron. Schwertmannite was again produced, with little or no co-precipitation of other metals. PMID- 22197073 TI - Different laccase detoxification strategies for ethanol production from lignocellulosic biomass by the thermotolerant yeast Kluyveromyces marxianus CECT 10875. AB - In this work, laccase enzymes were evaluated to detoxify the whole slurry from steam-exploded wheat straw. For it, two different strategies, laccase treatment before or after enzymatic hydrolysis, were employed. The detoxification efficiency was analyzed on enzymatic hydrolysis and fermentation levels by the thermotolerant yeast Kluyveromyces marxianus. Laccases reduced phenolic compounds without affecting weak acids and furan derivates. A lower glucose recovery was observed when laccase treatments were carried out before enzymatic hydrolysis, phenomenon that was not showed after enzymatic hydrolysis. In contrast, both laccase treatment strategies enhanced ethanol concentrations, reducing significantly the lag phase of the yeast and allowing substrate loading increments of saccharification and fermentation broths. PMID- 22197074 TI - Reactor performance and bacterial pathogen removal in response to sludge retention time in a mesophilic anaerobic digester treating sewage sludge. AB - The effects of sludge retention time (SRT) on reactor performance and bacterial pathogen removal of sludge mesophilic anaerobic digestion (MAD) were investigated in a continuous stirred tank reactor. The average volatile solids removal remained around 20% and the biogas production rate varied from 100 to 132ml/ld. The MAD process was efficient to remove Salmonella sp. and Escherichia coli with removal efficiencies increased with SRT from 11d, 16d to 25d. However, the Shigella sp. removal was insignificant. The difference in the resistance of the three pathogens to sludge MAD process is helpful to the selection of pathogen indicators in the biosolids. Log reduction of pathogens determined by MPN was much higher than the data by quantitative PCR, suggesting the presence of viable but non-culturable pathogen cells. This study confirms that the control of appropriate SRT for sludge MAD should take both reactor performance and pathogen removal into account. PMID- 22197075 TI - Transesterification of sunflower oil on single step sol-gel made Al2O3 supported CaO catalysts: effect of basic strength and basicity on turnover frequency. AB - The activities of single step sol-gel made calcium oxide on alumina catalysts were studied as a function of CaO loading, methanol/oil molar ratio and the amount of the catalyst in the transesterification of sunflower oil at 50 degrees C. Also, the turnover frequency (TOF) of the catalysts was calculated to better understand the relationship between the basicity/basic strength and the catalytic activity. From volcano curve (TOF vs. basic strength), it was found that under 50 degrees C and methanol/oil molar ratio of 9, 60% CaO/Al(2)O(3) had the highest turnover frequency, 0.028s(-1), whereas 85% CaO/Al(2)O(3) showed the highest biodiesel yield, ~96.6%, but TOF obtained on it was 0.012s(-1). It seemed that 60% CaO catalyst had the proper basic strength to obtain the highest TOF. PMID- 22197076 TI - Effect of solids retention time on antibiotics removal performance and microbial communities in an A/O-MBR process. AB - The effect of solids retention time on reactor performance and microbial community composition in anoxic/aerobic membrane bioreactors (A/O-MBR) were investigated in this study. Experimental results showed high removal efficiencies of conventional pollutants. Antibiotics removal efficiencies were obviously affected by SRT changes. Longer SRT (above 30days) was proved to be suitable operational condition for antibiotics removal. Denaturing gradient gel electrophoresis (DGGE) and clone library analysis revealed that bacteria belong to Betaproteobacteria and Gammaproteobacteria were the dominant species during wastewater treatment and antibiotics removal. SRT significantly influenced the relative numbers of nitrifying bacteria. Removal efficiency of total nitrogen (TN) decreased when SRT was 3days, because nitrogen loading exceeded the denitrification ability of the reactors. Unlike tet C and tet E genes, sulfa antibiotics resistance gene presented a decreasing tendency with the decrease of SRT, and finally affected sulfa antibiotics removal efficiencies. PMID- 22197077 TI - Fractionation of triticale, wheat, barley, oats, canola, and mustard straws for the production of carbohydrates and lignins. AB - Five cereal (triticale, durum wheat, CPS wheat, feed barley, oats) and two oilseed (canola, mustard) straws were fractionated with pressurized low polarity water in a flow-through reactor at 165 degrees C with a flow rate of 115mL/min and a solvent-to-solid ratio of 60mL/g. The conversion and extraction of the major carbohydrates and lignin from the reactor system during hydrothermal treatment was largely completed within the first 20-30min. Glucan content of all straws were enriched by the process. More than 90% of the xylan and nearly 50% of the lignin were extracted and there was no effect on yield due to crop species. However, there were differences in solid residue and liquid extract composition. Cereal crops yielded a residue richer in glucan and lower in lignin. Oilseed crop residues contained very low levels of ash. Xylo-oligosaccharides from oilseed crops contain more acetyl and uronic acid substituents. PMID- 22197078 TI - Changes in galanin and GalR1 gene expression in discrete brain regions after transient occlusion of the middle cerebral artery in female rats. AB - Injury to neurons results in up-regulation of galanin in some central and peripheral systems, and it has been suggested that this neuropeptide may play a protective and trophic role, primarily mediated by galanin receptor 2 (GalR2). The objective of the present study was to investigate galanin, GalR1, GalR2 and GalR3 gene expression in the female rat brain 7 days after a 60-min unilateral occlusion of the middle cerebral artery followed by reperfusion. Quantitative real-time PCR was employed in punch-biopsies from the locus coeruleus, somatosensory cortex and dorsal hippocampal formation, including sham-operated rats as controls. Galanin gene expression showed a ~2.5-fold increase and GalR1 a ~1.5-fold increase in the locus coeruleus of the ischemic hemisphere compared to the control side. Furthermore, the GalR1 mRNA levels decreased by 35% in somatosensory cortex of the ischemic hemisphere. Immunohistochemical analysis indicated a depletion of galanin from cell bodies and dendrites in the locus coeruleus after middle cerebral artery occlusion. The present results suggest that a stroke-induced forebrain lesion up-regulates synthesis of galanin and GalR1 in the locus coeruleus, a noradrenergic cell group projecting to many forebrain areas, including cortex and the hippocampal formation. These results support the notion that galanin may play a role in the response of the central nervous system to injury. PMID- 22197079 TI - [Quality of information on adverse events provided by the surgical patient]. AB - OBJECTIVE: To determine whether patients are a good information source on the occurrence of adverse events (AE). DESIGN: Analytical retrospective study using in-depth interviews in a double-blind protocol, and in parallel, to ensure whether the patient had actually suffered an AE. The Harvard method was also applied to review the medical records using a screening guide. Agreement between the physician and patient point of view of the surgery outcome was also estimated. PARTICIPANTS: A total of 28 randomly selected surgical patients discharged from a general hospital were interviewed. Ten patients (28% of the total suffering an AE yearly) who had experienced an AE, confirmed after a medical record review, and 18 patients who did not suffer an AE. RESULTS: Intraclass correlation coefficient for the agreement between the medical criterion and the patient point of view was 0.35 (95% CI; 0.2-0.6), and the number of correct classifications was 20/28 (71%, 95% CI; 51-86). Reporting an error reduces the likelihood of the hospital being considered as safe (Fisher's exact p=0.012). Errors were attributed to workload and to the intrinsic randomness of human activity. CONCLUSIONS: Patients can contribute in identifying an AE affecting them in a reasonable manner, providing us with additional information for enhancing patient safety and the quality of medical records. PMID- 22197080 TI - The efficacy of supported employment for middle-aged and older people with schizophrenia. AB - OBJECTIVE: Supported employment is the evidence-based treatment of choice for assisting individuals with severe mental illness to achieve competitive employment, but few supported employment programs specifically target older clients with psychiatric illness. The purpose of this study was to evaluate the efficacy of supported employment for middle-aged or older people with schizophrenia. METHOD: Participants included 58 outpatients with schizophrenia or schizoaffective disorder aged 45 or older who were recruited from a community mental health clinic. Participants were randomly assigned to receive Individual Placement and Support (IPS; the manualized version of supported employment) or conventional vocational rehabilitation (CVR) for one year, and completed assessments at baseline, six months, and twelve months. RESULTS: IPS was superior to CVR on nearly all work outcome measures, including attainment of competitive employment, weeks worked, and wages earned. Fifty-seven percent of IPS participants worked competitively, compared with 29% of CVR participants; 70% of IPS participants obtained any paid work, compared with 36% of CVR participants. Within the IPS group, better baseline functional capacity (as measured by the UCSD Performance Based Skills Assessment) and more recent employment were modestly associated with better work outcomes. CONCLUSIONS: Middle-aged and older adults with schizophrenia are good candidates for supported employment services. PMID- 22197081 TI - Priming the brain to learn: the future of therapy? AB - Neuromodulatory techniques with the ability to alter cortical excitability are gaining interest for their potential to enhance the brain's sensitivity to traditional therapies. Neuromodulatory techniques that prime the brain prior to manual or exercise therapy hold therapeutic promise for enhancing clinical outcomes in musculoskeletal and neurological conditions. The integration of these techniques into physiotherapy practice represents an exciting opportunity for the therapists of the future. Here, an overview is provided of three neuromodulatory techniques (peripheral electrical stimulation, transcranial direct current stimulation and repetitive transcranial magnetic stimulation) and the potential implications of these techniques for therapists discussed. Understanding these techniques and their therapeutic implications will ensure that therapists are well positioned to contribute to their clinical translation and adoption into clinical practice in an appropriate time frame. A therapeutic landscape defined by neuromodulatory techniques and improved clinical outcomes across a range of conditions is no longer far-fetched. PMID- 22197082 TI - Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. AB - This paper reviews that cell-mediated-immune (CMI) activation and inflammation contribute to depressive symptoms, including anhedonia; anxiety-like behaviors; fatigue and somatic symptoms, e.g. illness behavior or malaise; and mild cognitive impairment (MCI). These effects are in part mediated by increased levels of pro-inflammatory cytokines (PICs), e.g. interleukin-1 (IL-1), IL-6 and tumor necrosis factor (TNF)alpha, and Th-1-derived cytokines, such as IL-2 and interferon (IFN)gamma. Moreover, new pathways, i.e. concomitants and sequels of CMI activation and inflammation, were detected in depression: (1) Induction of indoleamine 2,3-dioxygenase (IDO) by IFNgamma and some PICs is associated with depleted plasma tryptophan, which may interfere with brain 5-HT synthesis, and increased production of anxiogenic and depressogenic tryptophan catabolites. (2) Increased bacterial translocation may cause depression-like behaviors by activating the cytokine network, oxidative and nitrosative stress (O&NS) pathways and IDO. (3) Induction of O&NS causes damage to membrane omega3 PUFAs, functional proteins, DNA and mitochondria, and autoimmune responses directed against intracellular molecules that may cause dysfunctions in intracellular signaling. (4) Decreased levels of omega3 PUFAs and antioxidants, such as coenzyme Q10, glutathione peroxidase or zinc, are associated with an increased inflammatory potential; more oxidative damage; the onset of specific symptoms; and changes in the expression or functions of brain 5-HT and N-methyl-d-aspartate receptors. (5) All abovementioned factors cause neuroprogression, that is a combination of neurodegeneration, neuronal apoptosis, and lowered neurogenesis and neuroplasticity. It is concluded that depression may be the consequence of a complex interplay between CMI activation and inflammation and their sequels/concomitants which all together cause neuroprogression that further shapes the depression phenotype. Future research should employ high throughput technologies to collect genetic and gene expression and protein data from patients with depression and analyze these data by means of systems biology methods to define the dynamic interactions between the different cell signaling networks and O&NS pathways that cause depression. PMID- 22197084 TI - The development of rhythm regularity, neuromuscular strategies, and movement smoothness during repetitive reaching in typically developing children. AB - INTRODUCTION: This study examined the development of paced coordinated reaching characterized by the successful entrainment of the movement to an external pacer, synchronous muscle activations and movement smoothness. METHODS: Thirty children, 5-10 years of age, and ten adults were instructed to repeatedly reach for and move an object from a lower shelf to an upper shelf in time to a metronome. Surface electromyography data were recorded. Amplitude and cross-correlations were calculated on three muscle pairs crossing the shoulder and elbow. A motion capture system captured the space curve accelerations of hand, forearm and upper arm segments to quantify movement smoothness. RESULTS: The 5-6 year old children showed the greatest amount of temporal variability, followed by 7-10 year olds and then the adults. Correlations between muscle pairs stabilizing the shoulder girdle were higher in each group as compared to the other two muscle pairs but the correlations for all pairs were consistently higher for adults. Movement smoothness for children 9-10 years of age was closer to an adult-like pattern with respect to control of the upper arm, but the hand segment had the greatest variability across groups. CONCLUSIONS: The increased temporal variability and decreased movement smoothness of the hand and forearm segments suggest that control of more distal musculature may be more difficult in children. The neuromuscular strategies adopted by adults were more optimal than those adopted by children as reflected by smoother and more consistent reaching. PMID- 22197083 TI - Basis for spinal manipulative therapy: a physical therapist perspective. AB - Physical therapists internationally provide spinal manipulative therapy (SMT) to patients with musculoskeletal pain complaints. SMT has been a part of physical therapist practice since the profession's beginning. Early physical therapist clinical decision making for SMT was influenced by the approaches of osteopathic and orthopedic physicians at the time. Currently a segmental clinical decision making approach and a responder clinical decision making approach are two of the more common models through which physical therapist clinical use of SMT is directed. The focus of segmental clinical decision making is upon identifying a dysfunctional vertebral segment with the application of SMT to restore mobility and/or alleviate pain. The responder clinical decision making approach attempts to categorize individuals based on a pattern of signs and symptoms suggesting a likely positive response to SMT. The present manuscript provides an overview of common physical therapist clinical decision making approaches to SMT and presents areas requiring further study in order to optimize patient response. PMID- 22197085 TI - Pathologic validation of a model based on diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging for tumor delineation in the prostate peripheral zone. AB - PURPOSE: For focal boost strategies in the prostate, the robustness of magnetic resonance imaging-based tumor delineations needs to be improved. To this end we developed a statistical model that predicts tumor presence on a voxel level (2.5*2.5*2.5 mm3) inside the peripheral zone. Furthermore, we show how this model can be used to derive a valuable input for radiotherapy treatment planning. METHODS AND MATERIALS: The model was created on 87 radiotherapy patients. For the validation of the voxelwise performance of the model, an independent group of 12 prostatectomy patients was used. After model validation, the model was stratified to create three different risk levels for tumor presence: gross tumor volume (GTV), high-risk clinical target volume (CTV), and low-risk CTV. RESULTS: The model gave an area under the receiver operating characteristic curve of 0.70 for the prediction of tumor presence in the prostatectomy group. When the registration error between magnetic resonance images and pathologic delineation was taken into account, the area under the curve further improved to 0.89. We propose that model outcome values with a high positive predictive value can be used to define the GTV. Model outcome values with a high negative predictive value can be used to define low-risk CTV regions. The intermediate outcome values can be used to define a high-risk CTV. CONCLUSIONS: We developed a logistic regression with a high diagnostic performance for voxelwise prediction of tumor presence. The model output can be used to define different risk levels for tumor presence, which in turn could serve as an input for dose planning. In this way the robustness of tumor delineations for focal boost therapy can be greatly improved. PMID- 22197086 TI - High-dose-rate brachytherapy as monotherapy delivered in two fractions within one day for favorable/intermediate-risk prostate cancer: preliminary toxicity data. AB - PURPOSE: To report the toxicity profile of high-dose-rate (HDR)-brachytherapy (BT) as monotherapy in a Human Investigation Committee-approved study consisting of a single implant and two fractions (12 Gy * 2) for a total dose of 24 Gy, delivered within 1 day. The dose was subsequently increased to 27 Gy (13.5 Gy * 2) delivered in 1 day. We report the acute and early chronic genitourinary and gastrointestinal toxicity. METHODS AND MATERIALS: A total of 173 patients were treated between December 2005 and July 2010. However, only the first 100 were part of the IRB-approved study and out of these, only 94 had a minimal follow-up of 6 months, representing the study population for this preliminary report. All patients had clinical Stage T2b or less (American Joint Committee on Cancer, 5th edition), Gleason score 6-7 (3+4), and prostate-specific antigen level of <=12 ng/mL. Ultrasound-guided HDR-BT with real-time dosimetry was used. The prescription dose was 24 Gy for the first 50 patients and 27 Gy thereafter. The dosimetric goals and constraints were the same for the two dose groups. Toxicity was scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. The highest toxicity scores encountered at any point during follow-up are reported. RESULTS: The median follow-up was 17 months (range, 6-40.5). Most patients had Grade 0-1 acute toxicity. The Grade 2 acute genitourinary toxicity was mainly frequency/urgency (13%), dysuria (5%), hematuria, and dribbling/hesitancy (2%). None of the patients required a Foley catheter at any time; however, 8% of the patients experienced transient Grade 1 diarrhea. No other acute gastrointestinal toxicities were found. The most common chronic toxicity was Grade 2 urinary frequency/urgency in 16% of patients followed by dysuria in 4% of patients; 2 patients had Grade 2 rectal bleeding and 1 had Grade 4, requiring laser treatment. CONCLUSIONS: Favorable-risk prostate cancer patients treated with a single implant HDR-BT to 24-27 Gy in two fractions within 1 day have excellent tolerance with minimal acute and chronic toxicity. Longer follow-up is needed to confirm these encouraging early results. PMID- 22197087 TI - Predicting chest wall pain from lung stereotactic body radiotherapy for different fractionation schemes. AB - PURPOSE: Recent studies with two fractionation schemes predicted that the volume of chest wall receiving >30 Gy (V30) correlated with chest wall pain after stereotactic body radiation therapy (SBRT) to the lung. This study developed a predictive model of chest wall pain incorporating radiobiologic effects, using clinical data from four distinct SBRT fractionation schemes. METHODS AND MATERIALS: 102 SBRT patients were treated with four different fractionations: 60 Gy in three fractions, 50 Gy in five fractions, 48 Gy in four fractions, and 50 Gy in 10 fractions. To account for radiobiologic effects, a modified equivalent uniform dose (mEUD) model calculated the dose to the chest wall with volume weighting. For comparison, V30 and maximum point dose were also reported. Using univariable logistic regression, the association of radiation dose and clinical variables with chest wall pain was assessed by uncertainty coefficient (U) and C statistic (C) of receiver operator curve. The significant associations from the univariable model were verified with a multivariable model. RESULTS: 106 lesions in 102 patients with a mean age of 72 were included, with a mean of 25.5 (range, 12-55) months of follow-up. Twenty patients reported chest wall pain at a mean time of 8.1 (95% confidence interval, 6.3-9.8) months after treatment. The mEUD models, V30, and maximum point dose were significant predictors of chest wall pain (p < 0.0005). mEUD improved prediction of chest wall pain compared with V30 (C = 0.79 vs. 0.77 and U = 0.16 vs. 0.11). The mEUD with moderate weighting (a = 5) better predicted chest wall pain than did mEUD without weighting (a = 1) (C = 0.79 vs. 0.77 and U = 0.16 vs. 0.14). Body mass index (BMI) was significantly associated with chest wall pain (p = 0.008). On multivariable analysis, mEUD and BMI remained significant predictors of chest wall pain (p = 0.0003 and 0.03, respectively). CONCLUSION: mEUD with moderate weighting better predicted chest wall pain than did V30, indicating that a small chest wall volume receiving a high radiation dose is responsible for chest wall pain. Independently of dose to the chest wall, BMI also correlated with chest wall pain. PMID- 22197088 TI - Use of fusion imaging combining contrast-enhanced ultrasonography with a perflubutane-based contrast agent and contrast-enhanced computed tomography for the evaluation of percutaneous radiofrequency ablation of hypervascular hepatocellular carcinoma. AB - OBJECTIVE: We evaluated the efficacy of fusion imaging, which fuses contrast enhanced ultrasonography images with arterial-phase, contrast-enhanced CT images as a reference on a single screen in real time, for the evaluation of the effectiveness of radiofrequency ablation for treatment of hypervascular hepatocellular carcinoma. MATERIALS AND METHODS: Eighty hepatocellular carcinoma lesions with a maximum diameter of between 1 and 3 cm that were scheduled for treatment with radiofrequency ablation were enrolled in this prospective study. After bolus injection of perflubutane-based contrast agent, fusion imaging combining contrast-enhanced ultrasonography images and arterial-phase, contrast enhanced CT images was performed one day after radiofrequency ablation. We used two functions, which were subsets of the fusion imaging, to confirm the location of the hepatocellular carcinoma lesions in the ablated areas and to evaluate the presence or absence of an adequate safety margin. Contrast-enhanced CT was performed one month after the ablation. Two blinded observers reviewed the images obtained using both modalities to evaluate the effect of ablation. RESULTS: When the one-month contrast-enhanced CT images were used as the reference standard, the sensitivity, specificity, and accuracy of the one-day fusion imaging for the diagnosis of adequate ablation were 97%, 83%, and 96%, respectively; the kappa value for the agreement between the findings obtained using the two modalities was 0.75. CONCLUSION: Fusion imaging combining contrast-enhanced ultrasonography images and arterial-phase, contrast-enhanced CT images as a reference appears to be a useful method for the early evaluation of the efficacy of radiofrequency ablation for the treatment of hypervascular hepatocellular carcinoma. PMID- 22197089 TI - Magnesium sulfate as an oral contrast medium in magnetic resonance imaging of the small intestine. AB - BACKGROUND: To explore the use of magnesium sulfate (MgSO4) as an oral contrast medium (CM) in MRI of the small intestine. METHODS: By comparing MgSO4 SNRs at different concentrations, we determined that 2.5% MgSO4 is the ideal concentration for small bowel MRI. Twenty volunteers underwent MRI after drinking 2.5% MgSO4. Thirty-one patients with clinical suspicion of small intestinal pathology underwent both MRI and the air-barium contrast examination. The patient's tolerance, side effects and complications were noted. RESULTS: 2.5% MgSO4 can decrease the absorption of water and fully fill the enteric cavity, thereby increasing the contrast between the intestinal wall and lumen and facilitating radiographic examination of the small bowel. The mean diameter of the small intestine was 19.8+/-1.21 mm in the 20 volunteers consuming 2.5% MgSO4 and 12.7+/-0.84 mm in the 20 volunteers given water. There was a significant difference (P<0.05) between the diameters of the small intestine of the two groups. But there were no significant differences (P>0.05) in side effects between MgSO4 and water groups. Small intestinal MRI was successfully performed in all 31 patients, who were also examined by the double contrast barium, which gave almost identical diagnoses to MRI in all cases except for 1 patient with small intestinal hemorrhage. CONCLUSIONS: MRI with 2.5% MgSO4 can demonstrate intestinal abnormalities. Therefore, 2.5% MgSO4 solution is an ideal oral CM for small bowel MRI. PMID- 22197090 TI - Diffusion weighted MRI and 18F-FDG PET/CT in non-small cell lung cancer (NSCLC): does the apparent diffusion coefficient (ADC) correlate with tracer uptake (SUV)? AB - INTRODUCTION: To investigate the potential correlation of the apparent diffusion coefficient assessed by diffusion-weighted MRI (DWI) and glucose metabolism determined by the standardized uptake value (SUV) at 18F-FDG PET/CT in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: 18F-FDG PET/CT and DWI (TR/TE, 2000/66 ms; b-values, 0 and 500 s/mm(2)) were performed in 41 consecutive patients with histologically verified NSCLC. Analysing the PET-CT data calculation of the mean (SUV(mean)) and maximum (SUV(max)) SUV was performed. By placing a region-of-interest (ROI) encovering the entire tumor mean (ADC(mean)) and minimum ADC (ADC(min)) were determined by two independent radiologists. Results of 18F-FDG PET-CT and DWI were compared on a per-patient basis. For statistical analysis Pearson's correlation coefficient, Bland-Altman and regression analysis were assessed. RESULTS: Data analysis revealed a significant inverse correlation of the ADC(min) and SUV(max) (r=-0.46; p=0.032). Testing the correlation of the ADC(min) and SUV(max) for each histological subtype separately revealed that the inverse correlation was good for both adenocarcinomas (r=-0.47; p=0.03) and squamouscell carcinomas (r=-0.71; p=0.002), respectively. No significant correlation was found for the comparison of ADC(min) and SUV(mean) (r=-0.29; p=0.27), ADC(mean) vs. SUV(mean) (r=-0.28; p=0.31) or ADC(mean) vs. SUV(max) (r=-0.33; p=0.23). The kappa-value of 0.88 indicated a good agreement between both observers. CONCLUSION: This preliminary study is the first to verify the relation between the SUV and the ADC in NSCLC. The significant inverse correlation of these two quantitative imaging approaches points out the association of metabolic activity and tumor cellularity. Therefore, DWI with ADC measurement might represent a new prognostic marker in NSCLC. PMID- 22197091 TI - CT in children: why and what to consider for CT in children. PMID- 22197092 TI - The size does not matter - the presence of microvascular obstruction but not its extent corresponds to larger infarct size in reperfused STEMI. AB - BACKGROUND: Microvascular obstruction (MVO) is a cardiac magnetic resonance (CMR) marker of no-reflow in ST-segment elevation myocardial infarction (STEMI). It remains unresolved whether the infarct size corresponds only to the presence of MVO or also to its extent. METHODS: The study included 53 patients with first STEMI (median age 61.5 years, 77% male) treated with percutaneous coronary intervention (PCI) who underwent CMR after median 5 days from PCI. Small MVO was defined as patchy, non-confluent spots of dark areas of absent contrast surrounded by late gadolinium enhancement (LGE). Large MVO was defined as confluent areas of MVO comprising a large amount of the infarct zone. RESULTS: Microvascular obstruction was observed in 32 patients (60%) including 18 patients with small MVO (36%) and 14 patients with large MVO (24%). Patients with MVO were more likely to have TIMI 0/1 grade flow on initial angiogram, higher levels of necrotic markers, larger infarct size, larger left ventricular end-diastolic and end-systolic volume and lower ejection fraction in comparison to patients without MVO. These differences were not observed between patients with large and small MVO. CONCLUSIONS: The presence of MVO but not its extent corresponds to larger infarct size in STEMI. PMID- 22197093 TI - Imaging of primary bone tumors in veterinary medicine: which differences? AB - Veterinary medicine is most often a mysterious world for the human doctors. However, animals are important for human medicine thanks to the numerous biological similarities. Primary bone tumors are not uncommon in veterinary medicine and especially in small domestic animals as dogs and cats. As in human medicine, osteosarcoma is the most common one and especially in the long bones extremities. In the malignant bone tumor family, chondrosarcoma, fibrosarcoma and hemangiosarcoma are following. Benign bone tumors as osteoma, osteochondroma and bone cysts do exist but are rare and of little clinical significance. Diagnostic modalities used depend widely on the owner willing to treat his animal. Radiographs and bone biopsy are the standard to make a diagnosis but CT, nuclear medicine and MRI are more an more used. As amputation is treatment number one in appendicular bone tumor in veterinary medicine, this explains on the one hand why more recent imaging modalities are not always necessary and on the other hand, that prognostic on large animals is so poor that it is not much studied. Chemotherapy is sometimes associated with the surgery procedure, depending on the aggressivity of the tumor. Although, the strakes differs a lot between veterinary and human medicine, biological behavior are almost the same and should led to a beneficial team work between all. PMID- 22197094 TI - Computed tomographic angiography (CTA) of major thoracic vessels in children--a pictorial assay on common findings also discussing CTA technique. AB - CTA plays an important role in evaluation of the major thoracic vessels in children. The purpose of this review is to describe the application of CTA in evaluation of the thoracic aorta, the pulmonary arteries and veins, and potential aortic-pulmonary collaterals. Indications, consideration, technical details of how to perform these investigations in children, restrictions and representative illustration are presented and discussed. PMID- 22197095 TI - Association of environmental tobacco smoke with dementia and Alzheimer's disease among never smokers. AB - BACKGROUND: Environmental tobacco smoke (ETS) is known to be harmful; however, its association with dementia remains controversial and with Alzheimer's disease (AD) is unknown. METHODS: Using a standard interview method, the author carried out a multicenter cross-sectional study of dementia in China by examining 2692 never-smoking people aged >=60 years. Relative risks (RRs) of AD and all dementia, as diagnosed by psychiatrists, in relation to ETS were calculated in a multivariate regression model. RESULTS: The adjusted RR for all dementia was 1.78 (95% confidence interval [CI]: 1.18-2.68). The increased risk was mainly from exposure to ETS at home (1.87, 95% CI: 1.19-2.93), and it was associated with exposure duration. The adjusted RR for AD was 2.28 (95% CI: 1.82-2.84); the matched figure for ETS exposure at home, at work, and at other places was 2.15 (95% CI: 1.69-2.74), 2.04 (95% CI: 1.72-2.42), and 1.80 (95% CI: 0.96-3.38), respectively. The association of the increased risk with a total cumulative exposure dose was at borderline significance. CONCLUSIONS: The risk of dementia and AD increased with ETS exposure. Banning smoking in public areas may help reduce a dementia epidemic worldwide. PMID- 22197096 TI - [Usefulness of skin biopsy in the diagnosis of small fiber neuropathy]. AB - Diagnosis of small fiber neuropathy may be challenging due to subtle clinical signs and to the normality of nerve conduction studies. Skin biopsy is a non invasive method which allows to quantify intraepidermal nerve fiber density after a simple immunostaining. The values measured must ideally be compared to normative data obtained on control subjects in order to determine their significance. When the diagnosis of small fiber neuropathy has been made by means of skin biopsy, possibly combined with laser evoked potentials, a diagnostic work up has to be done in order to find one of the classical causes of this disorder. To date, skin biopsy is useful to confirm the diagnosis of small fiber neuropathy but lacks utility to find its etiology. PMID- 22197097 TI - Analysis of MC4R polymorphism in Italian Large White and Italian Duroc pigs: association with carcass traits. AB - The melanocortin-4 receptor (MC4R) gene codes for a G protein transmembrane receptor playing an important role in energy homeostasis control. In pig a single nucleotide polymorphism c.1426G>A has been identified and associated to average daily gain, feed intake and fatness traits but a lack of agreement on the effects of the gene on carcass traits in different breeds comes out from many studies. In the present study the c.1426G>A polymorphism is analysed in two Italian pig breeds, Large White and Duroc to study the association of the MC4R gene with some carcass traits. The results show that the c.1426G>A polymorphism affects daily gain, feed conversion ratio and ham weight in both breeds, lean cuts in the Italian Duroc and backfat thickness in the Italian Large White. The presence of MC4R mRNA transcript in different porcine tissues was analysed. PMID- 22197098 TI - Effect of pre-slaughter management regarding transportation and time in lairage on certain stress parameters, carcass and meat quality characteristics in Kivircik lambs. AB - Thirty Kivircik lambs were used to investigate effect of pre-slaughter treatment on certain haematological and biochemical parameters, carcass and meat quality characteristics. Lambs were divided into three treatments: 75 min transport and lairage for 18 h (TS-L18 h); 75 min transport and lairage for 30 min (TS-L30 min) and no pre-slaughter transport and lairage for 30 min (NTS). Treatment, as a main effect, did not influence haematological and biochemical parameters, but sampling time significantly affected these parameters, except total protein. Plasma cortisol concentration at exsanguination in TS-18 h, TS-30 min and NTS treatments were 117.34, 119.23 and 72.51 ng/ml, respectively. pH of longissimus dorsi muscle was higher in TS-L30 min than other treatments. TS-L30 min lambs had the highest shear force value, the lowest WHC and cooking loss. TS-L30 min treatment yielded the darkest meat immediately after cutting and 1 h later. Meat redness, yellowness and chroma values were similar in treatments. PMID- 22197099 TI - Effect of sodium chloride, sodium nitrite and temperature on desorption isotherms of previously frozen beef. AB - Moisture desorption isotherms of beef were determined in the relative humidity range of 23 to 90% at 5, 15 and 25 degrees C and at 2.5% NaCl and 2.5% NaCl+150 ppm NaNO(2) content. Desorption isotherms were found to be typical type II sigmoid. The water content at equilibrium was higher in beef with NaCl and NaCl+NaNO(2) than control samples. Experimental data were fitted to various mathematical models and it was found that the Peleg model was best in describing the equilibrium moisture content relationship for beef samples over the entire range of temperatures. The net isosteric heat of sorption was estimated from equilibrium desorption data, using the Clausius-Clapeyron equation. Isosteric heats of desorption were found to increase with decreasing moisture content. PMID- 22197100 TI - Durable cofactor immobilization in sol-gel bio-composite thin films for reagentless biosensors and bioreactors using dehydrogenases. AB - A new strategy directed to the durable immobilization of NAD(+)/NADH cofactors has been tested, along with a suitable redox mediator (ferrocene), in biocompatible sol-gel matrices encapsulating a bi-enzymatic system (a dehydrogenase and a diaphorase, this latter being useful to the safe regeneration of the cofactor), which were deposited as thin films onto glassy carbon electrode surfaces. It involves the chemical attachment of NAD(+) to the silica matrix using glycidoxypropylsilane in the course of the sol-gel process (in smooth chemical conditions). This approach based on chemical bonding of the cofactor (which was checked by infrared spectroscopy) led to good performances in terms of long-term stability of the electrochemical response. The possibility to integrate all components (proteins, cofactor, mediator) in the sol-gel layer in an active and durable form gave rise to reagentless devices with extended operational stability (i.e. high amperometric response maintained for more than 12h of continuous use under constant potential, whereas the signal completely vanished within the first few minutes of working with non-covalently bonded NAD(+)). To confirm the wide applicability of the proposed approach, the same strategy has been applied to the elaboration of biosensors for D-sorbitol, D-glucose and L lactate with using D-sorbitol dehydrogenase, D-glucose dehydrogenase and L lactate dehydrogenase respectively. The analytical characteristics of the glucose sensors are given and compared to previous approaches described in the literature for the elaboration of reagentless biosensors. PMID- 22197101 TI - Grating-based surface plasmon resonance detection of core-shell nanoparticle mediated DNA hybridization. AB - In this report, we have investigated enhanced surface plasmon resonance (SPR) detection of DNA hybridization using gold core - silica shell nanoparticles in localized plasmonic fields. The plasmonic fields were localized by periodic linear gratings. Experimental results measured for hybridization of 24-mer single stranded DNA oligomers suggest that core-shell nanoparticles (CSNPs) on gratings of 400 nm period provide enhanced optical signatures by 36 times over conventional thin film-based SPR detection. CSNP-mediated DNA hybridization produced 3 times larger angular shift compared to gold nanoparticles of the same core size. We have also analyzed the effect of structural variation. The enhancement using CSNPs was associated with increased surface area and index contrast that is combined by improved plasmon coupling with localized fields on gratings. The combined approach for conjugated measurement of a biomolecular interaction on grating structures is expected to lower the limit of detection to the order of a few tens of fg/mm(2). PMID- 22197102 TI - Geranyl modification on the tryptophan residue of ComXRO-E-2 pheromone by a cell free system. AB - ComX pheromone is an isoprenoidal oligopeptide containing a modified tryptophan residue, which stimulates natural genetic competence in the gram-positive bacterium Bacillus. Since posttranslational prenylation on the tryptophan residue has not been reported except in ComX pheromone, the universality of this modification has not yet been elucidated. In this paper, we established a cell free system, whereby the tryptophan residue in peptides is modified with a geranyl group by modifying enzyme ComQ. In addition, we investigated enzymatic reaction conditions using an in vitro enzyme reaction system. This is the first report of in vitro geranylation on the tryptophan residue. This system is potentially a useful tool for elucidating the universality of prenylation on the tryptophan residue. PMID- 22197103 TI - Lifetimes of photosystem I and II proteins in the cyanobacterium Synechocystis sp. PCC 6803. AB - The half-life times of photosystem I and II proteins were determined using (15)N labeling and mass spectrometry. The half-life times (30-75h for photosystem I components and <1-11h for the large photosystem II proteins) were similar when proteins were isolated from monomeric vs. oligomeric complexes on Blue-Native gels, suggesting that the two forms of both photosystems can interchange on a timescale of <1h or that only one form of each photosystem exists in thylakoids in vivo. The half-life times of proteins associated with either photosystem generally were unaffected by the absence of Small Cab-like proteins. PMID- 22197104 TI - Environmental enrichment ameliorated high-fat diet-induced Abeta deposition and memory deficit in APP transgenic mice. AB - The pathogenesis of Alzheimer's disease (AD) is tightly associated with metabolic dysfunctions. In particular, a potential link between type 2 diabetes (T2DM) and AD has been suggested epidemiologically, clinically, and experimentally, and some studies have suggested that exercise or dietary intervention reduces risk of cognitive decline. However, there is little solid molecular evidence for the effective intervention of metabolic dysfunctions for prevention of AD. In the present study, we established the AD model mice with diabetic conditions through high-fat diet (HFD) to examine the effect of environmental enrichment (EE) on HFD induced AD pathophysiology. Here, we demonstrated that HFD markedly deteriorated memory impairment and increased beta-amyloid (Abeta) oligomers as well as Abeta deposition in amyloid precursor protein (APP) transgenic mice, which was reversed by exposure to an enriched environment for 10 weeks, despite the continuation of HFD. These studies provide solid evidence that EE is a useful intervention to ameliorate behavioral changes and AD pathology in HFD-induced aggravation of AD symptoms in APP transgenic mice. PMID- 22197106 TI - Very late stent thrombosis immediately after recurrent inappropriate shock delivery by an implantable cardioverter defibrillator. AB - The case of a 49-year-old man who developed an ST segment elevation myocardial infarction because of very late stent thrombosis occurring in the immediate aftermath of a "storm" of recurrent inappropriate implantable cardioverter defibrillator (ICD) shocks caused by a fracture of a Medtronic Sprint Fidelis (Medtronic Inc., Minneapolis, MN) right ventricular lead is described. A causal relationship between recurrent ICD shocks and stent thrombosis is proposed. This deleterious association is an important observation given the increasing population of patients who receive both coronary stents and ICDs. PMID- 22197105 TI - Factors associated with development of prolonged QRS duration over 20 years in healthy young adults: the Coronary Artery Risk Development in Young Adults study. AB - BACKGROUND: Data describing factors associated with the development of a prolonged QRS duration (QRSd) from young adulthood to middle age are sparse. METHODS: We analyzed 12-lead electrocardiograms (ECGs) from the Coronary Artery Risk Development in Young Adults study over 20 years. We performed logistic regression to examine the associations of baseline (year 0) or average (years 0 20) risk factors with incident prolonged QRSd (QRS >100 milliseconds). RESULTS: We included 2537 participants (57.2% women, 44.7% black; mean age, 25 years); 292 (11.5%) developed incident QRSd greater than 100 milliseconds by year 20. In univariate analyses, baseline covariates associated with incident QRSd prolongation included white race, male sex, ECG-left ventricular mass index, and baseline QRSd. Similar results were observed after multivariable adjustment. CONCLUSION: We found no long-term associations of modifiable risk factors with incident QRSd >100 milliseconds. Men, whites, and those with higher ECG-left ventricular mass index and QRSd in young adulthood are at an increased risk for incident prolonged QRSd by middle age. PMID- 22197107 TI - Free jejunal diversionary conduit flaps following radiation damage to the pharynx: a technique for regaining oral feeding while preserving vocal function. AB - Radiotherapy is an accepted primary treatment modality for head and neck malignancies. However, in severe cases, the chronic radiation damage has resulted in dysphagia, aspiration and choking. Failure in conservative therapeutic strategies for this swallowing dysfunction will result in either preservation of voice with loss of oral feeding, or vice versa. We introduce our surgical technique based on the free jejunal diversionary conduit flaps, which helps patients to resume oral feeding and preserves vocal function, while reducing the risk of aspiration. METHOD: Six patients suffering from swallowing dysfunction following radiotherapy were enrolled. All were dependent on tube feeding. A subcutaneously transferred free jejunal flap connected the left buccogingival sulcus to the cervical oesophagus, which permanently separates the airway from the native aerodigestive tract by creating a new inlet for food passage. Simultaneously created pharyngostomy drains accumulation of saliva and food residue in the epiglottic vallecula and the pyriform sinus. For the cases with tight fibrotic neck skin, we divided this technique into two stages. RESULTS: All cases could take at least semi-solid food orally, with some minor complications in the initial four cases. Five cases were independent of tube feeding. Two recent cases with modifications did not experience any complication and could start oral intake much earlier (7 days after surgery) than previous cases (118 days on average). CONCLUSION: The free jejunal diversionary conduit flaps offer post-radiotherapy patients with swallowing dysfunction the option to resume oral feeding while preserving their voice and reducing the risk of aspiration. PMID- 22197108 TI - Change in upper lip height and nostril sill after alveolar bone grafting in unilateral cleft lip alveolus patients. AB - INTRODUCTION: Alveolar bone grafting is known to reduce nasal asymmetry by supporting a defective alar base and a sunken nostril. However, there are no studies which include details of changes to the upper lip with appropriate measurements. The purpose of this study was to measure the change in the upper lip height and nostril sill after alveolar bone grafting, using photogrammetry. MATERIALS AND METHODS: The study included 18 unilateral cleft lip alveolus (UCLA) patients who were diagnosed with unilateral cleft lip and palate (mean age, 9.87 years). The patients underwent alveolar bone grafting with iliac bone between June 2007 and June 2008. The average follow-up period was 16.6 months. The average bone graft volume was 2.39 cm(3). We obtained photographs of the frontal, lateral and basal views using standardised photographic techniques. We defined 14 landmarks and measured the distance of 11 points (distance items) for the determination of upper lip height, upper lip projection and nostril sill elevation. We defined the proportion index as the ratio of the cleft side to non cleft side or reference line (R). We compared the preoperative proportion index with the postoperative proportion index for each distance items. RESULTS: The height of the upper lip increased significantly in four of five distance items. The projection of the upper lip was more prominent, but it was not statistically significant. The nostril sill was significantly elevated in all four distance items. CONCLUSION: The height of the upper lip was elongated and the nostril sill was elevated after alveolar bone grafting in UCLA patients. PMID- 22197110 TI - Occurrence of synthetic musk fragrances in effluent and non-effluent impacted environments. AB - Synthetic musk fragrances (SMFs) are considered micropollutants and can be found in various environmental matrices near wastewater discharge areas. These emerging contaminants are often detected in wastewater at low concentrations; they are continuously present and constitute a constant exposure source. Objectives of this study were to investigate the environmental fate, transport, and transformation of SMFs. Occurrence of six polycyclic musk compounds (galaxolide, tonalide, celestolide, phantolide, traseolide, cashmeran) and two nitro musk compounds (musk xylene and musk ketone) was monitored in wastewater, various surface waters and their sediments, as well as groundwater, soil cores, and plants from a treated wastewater land application site. Specifically, samples were collected quarterly from (1) a wastewater treatment plant to determine initial concentrations in wastewater effluent, (2) a storage reservoir at a land application site to determine possible photolysis before land application, (3) soil cores to determine the amount of sorption after land application and groundwater recharge to assess lack thereof, (4) a lake system and its sediment to assess degradation, and (5) non-effluent impacted local playa lakes and sediments to assess potential sources of these compounds. All samples were analyzed using gas chromatography coupled with mass spectrometry (GC-MS). Data indicated that occurrence of SMFs in effluent-impacted environments was detectable at ng/L and ng/g concentrations, which decreased during transport throughout wastewater treatment and land application. However, unexpected concentrations, ng/L and ng/g, were also detected in playa lakes not receiving treated effluent. Additionally, soil cores from land application sites had ng/g concentrations, and SMFs were detected in plant samples at trace levels. Galaxolide and tonalide were consistently found in all environments. Information on occurrence is critical to assessing exposure to these potential endocrine disrupting compounds. Such information could provide a scientific framework for establishing the need for environmental regulations. PMID- 22197109 TI - Adrenalectomy improves increased carotid intima-media thickness and arterial stiffness in patients with aldosterone producing adenoma. AB - CONTEXT: Primary aldosteronism (PA) is the most frequent cause of secondary hypertension, and is associated with more prominent vascular stiffness and atherosclerosis. However, the effect of adrenalectomy on reversibility of vascular damage is unclear. OBJECTIVE: Our objective was to investigate the vascular changes and possibility of reversibility after adrenalectomy in PA patients. METHODS: We prospectively analyzed 20 patients with aldosterone producing adenoma (APA) that received adrenalectomy from October 2006 to December 2008 and 21 patients with essential hypertension (EH) were enrolled as the control group. Carotid intima media thickness (CIMT) measurement by B-mode ultrasound of the right common carotid arteries and pulse wave velocity (PWV) measurement including brachial-ankle PWV (baPWV) and heart-ankle PWV (haPWV) were performed in both groups. The follow-up measurements were performed one-year after adrenalectomy in APA group. RESULTS: APA patients had significantly higher diastolic blood pressure, plasma aldosterone concentration (PAC) and aldosterone renin ratio (ARR), but lower serum potassium level and plasma renin activity (PRA) than EH patients. APA patients had significantly higher CIMT (0.64+/-0.13 vs. 0.53+/-0.10 mm, p=0.006), higher baPWV (1589+/-296 vs. 1405+/-187 cm/s, p=0.024) and haPWV (1095+/-150 vs. 987+/-114 cm/s, p=0.013) comparing with EH patients. One-year after adrenalectomy, CIMT reduced significantly from 0.64+/ 0.13 mm to 0.59+/-0.14 mm (p=0.014), and baPWV and haPWV also showed significant reduction (baPWV, 1589+/-296 to 1463+/-188 cm/s, p=0.035; haPWV, 1095+/-150 to 1017+/-109 cm/s, p=0.019). CONCLUSION: APA patients have higher degree of early atherosclerosis and vascular stiffness. Adrenalectomy not only corrects the high blood pressure and biochemical parameters but also reverse adverse vascular change in APA patients. PMID- 22197111 TI - Estimation of soil respiration using automated chamber systems in an oak (Quercus mongolica) forest at the Nam-San site in Seoul, Korea. AB - Soil respiration (R(soil)) is the largest component of ecosystem respiration produced by the autotrophic and heterotrophic respirations. Its variability on multiple time scales strongly depends on environmental variables such as temperature and moisture. To investigate the temporal variations of R(soil) in a cool-temperate oak (Quercus mongolica) forest at the Nam-San site in Seoul, Korea, continuous measurements of R(soil) using the automated chamber systems, air and soil temperatures and soil moisture are made for the period from April 2010 to March 2011. The observed data indicate that the R(soil) shows a remarkable seasonal variation in accordance with temperatures with high in summer and low in winter. The R(soil) is found to be strongly correlated with soil temperature (T(s)) at the 5cm depth throughout the year. However, the high fluctuation of R(soil) is found to be related with soil moisture content (M(s)) during the forest growing season. The estimated annual Q(10) value using the 1.5m high air temperature is found to be 2.4 that is comparable with other studies in temperate forest ecosystems. The optimal regression equation of R(soil) with the T(s) at 5cm depth and the M(s) at 15cm depth is found to be R(soil)=124.3 exp (0.097T(s))-55.3 (M(s))(2)+2931.9 (M(s))-38516 for T(s)>=0 degrees C and R(soil)=0 for T(s)<0 degrees C with r(2)=0.97, P<0.01, suggesting the importance of T(s) and M(s) for R(soil). The annual total soil respiration estimated by the optimal regression equation is found to be 1264gCm(-2) with a maximum of 685gCm( 2) in the summer season and a minimum of 33gCm(-2) in the winter season. The present study can be implemented for the determination of the carbon balance of a cool-temperate Q. mongolica forest with the provision of photosynthesis. PMID- 22197112 TI - Kinetics of polychlorinated biphenyl partitioning to marine Chrysophyte Isochrysis galbana. AB - This study focused on the uptake kinetics of polychlorinated biphenyl (PCB) congeners by the Chrysophyte, Isochrysis galbana. A gas-purging experimental system was used to maintain constant dissolved PCB concentrations. Three phases of absorption were observed: first, a rapid absorption phase within the first 15min, second, a first order process reaching the maximum concentration within 48h of exposure, and third, a plateau phase as yet to be determined with very slight increases in concentration. In this study, the percentage of the maximum concentration reached within the first phase varied from 10% to 67%, depending on the size of the PCB (as determined by molecular weight and total surface area), whereas the uptake rate (k(u)) during the second phase was more comparable across different PCBs. In addition, for the first phase, the bioconcentration factor (BCF) of PCBs deviated from its expected relationship with hydrophobicity, as determined by K(ow), and was instead related to the molecular structure of the compound. PMID- 22197113 TI - Nitrous oxide and methane fluxes vs. carbon, nitrogen and phosphorous burial in new intertidal and saltmarsh sediments. AB - Carbon (C), nitrogen (N) and phosphorous (P) burial rates were determined within natural saltmarsh (NSM) and 'managed realignment' (MR) sediments of the Blackwater estuary, UK. Methane (CH(4)) and nitrous oxide (N(2)O) fluxes were measured along with their ability to offset a portion of the C burial to give net C sequestration. C and N densities (Crho and Nrho) of NSM sediments (0.022 and 0.0019 g cm(-3)) are comparable to other UK NSM sediments. Less vegetationally developed MR sediments have lower Crho and Nrho (0.012 and 0.0011 g cm(-3)) while the more vegetationally developed sites possess higher Crho and Nrho (0.023 and 0.0030 g cm(-3)) than NSM. Both NSM and MR areas were small CH(4) (0.10-0.40 g m( 2)yr(-1)) and N(2)O (0.03-0.37 g m(-2) yr(-1)) sources. Due to their large Global Warming Potentials, even these relatively small greenhouse gas (GHG) fluxes reduced the net C sequestration within MR marshes by as much as 49%, but by only 2% from NSM. Potential MR areas within the Blackwater estuary (29.5 km(2) saltmarsh and 23.7 km(2) intertidal mudflat) could bury 5478 t C yr(-1) and 695.5 t N yr(-1), with a further 476t N yr(-1) denitrified. The saltmarsh MR would also sequester 139.4 t Pyr(-1). GHG fluxes would reduce the C burial benefit by 24% giving a C sequestration rate of 4174 t Cyr(-1). Similar areas within the Humber estuary (74.95 km(2)) could bury 3597 t Cyr(-1) and 180 t N yr(-1), with a further 442 t Nyr(-1) denitrified. GHG fluxes would reduce the C burial benefit by 31% giving a C sequestration rate of 2492 t C yr(-1). Overall, MR sites provide sustainable coastal defence options with significant biogeochemical value and, despite being net sources of CH(4) and N(2)O, can sequester C and reduce estuarine nutrient loads. PMID- 22197114 TI - Using partial decision trees to predict Parkinson's symptoms: a new approach for diagnosis and therapy in patients suffering from Parkinson's disease. AB - In this work we present a method based on partial decision trees and association rules for the prediction of Parkinson's disease (PD) symptoms. The proposed method is part of the PERFORM system. PERFORM is used for the treatment of PD patients and even advocate specific combinations of medications. The approach presented in this paper is included in the data miner module of PERFORM. A patient performs some initial examinations and the module predicts the future occurrence of the symptoms based on the initial examinations and medications taken. Using the method, the expert can prescribe specific medications that will not cause, or postpone the appearance of specific symptoms to the patient. The approach employed is able to provide interpretation for the predictions made, by providing rules. The models have been developed and evaluated using real patient's data and the respective results are reported. Another functionality of the data miner module is the extraction of rules through a user friendly interface using association rule mining algorithms. These rules can be used for the prediction analysis of patient's reaction to certain treatment plans. The accuracy of the symptoms' prediction ranges from 57.1 to 77.4%, depending on the symptom. PMID- 22197115 TI - Real time decision support system for diagnosis of rare cancers, trained in parallel, on a graphics processing unit. AB - In the present study a new strategy is introduced for designing and developing of an efficient dynamic Decision Support System (DSS) for supporting rare cancers decision making. The proposed DSS operates on a Graphics Processing Unit (GPU) and it is capable of adjusting its design in real time based on user-defined clinical questions in contrast to standard CPU implementations that are limited by processing and memory constrains. The core of the proposed DSS was a Probabilistic Neural Network classifier and was evaluated on 140 rare brain cancer cases, regarding its ability to predict tumors' malignancy, using a panel of 20 morphological and textural features Generalization was estimated using an external 10-fold cross-validation. The proposed GPU-based DSS achieved significantly higher training speed, outperforming the CPU-based system by a factor that ranged from 267 to 288 times. System design was optimized using a combination of 4 textural and morphological features with 78.6% overall accuracy, whereas system generalization was 73.8%+/-3.2%. By exploiting the inherently parallel architecture of a consumer level GPU, the proposed approach enables real time, optimal design of a DSS for any user-defined clinical question for improving diagnostic assessments, prognostic relevance and concordance rates for rare cancers in clinical practice. PMID- 22197116 TI - Comparison of drug-eluting versus bare-metal stents after rotational atherectomy for the treatment of calcified coronary lesions. PMID- 22197117 TI - Cardiac cycle efficiency: a new parameter able to fully evaluate the dynamic interplay of the cardiovascular system. PMID- 22197118 TI - Aortic valve calcium score as a predictor for outcome after TAVI using the CoreValve revalving system. AB - BACKGROUND: TAVI is a novel treatment option for patients at too high risk for surgery. Risk scores for surgical valve replacement failed to accurately predict outcomes after TAVI and alternative risk parameters are lacking so far. OBJECTIVE: We evaluated the CT-derived aortic valve calcification score as a predictor for outcome during and after TAVI. METHODS: Transfemoral TAVI using the CoreValve device was performed in 68 patients, in whom the aortic valve calcium score was determined from preprocedural 64-sclice ECG gated CT-scans. RESULTS: 30 day MACE rate (death, stroke, MI) was 10.3%, 1-year mortality was 11.8%. Using linear regression analysis the aortic valve calcium score was the only significant predictor for 30-day MACE and for 1-year mortality and was also associated with the incidence and severity of post procedural aortic regurgitation (r=0.33, p<0.05). Patients withvalve calcium scores >750 had a significant lower 1-year survival rate compared to patients with scores <750 (58% vs. 98%, p<0.05). The aortic valve calcium score is also inversely associated with the absolute improvement of NYHA-class after TAVI (regression coefficient= 0.43, p<0.02). CONCLUSION: The degree of aortic valve calcification is associated with post procedural aortic regurgitation, procedural complications, 1-year mortality and with the degree of functional improvement of patients who underwent TAVI using the CoreValve device. Due to the fact that the aortic valve calcium score can be determined from CT-datasets that are used for preprocedural planning, this parameter may be incorporated in the general work up and may be used for risk stratification and patient selection. PMID- 22197119 TI - Effect of pre-infarction angina on platelet reactivity in acute myocardial infarction. AB - BACKGROUND: Previous studies demonstrated that patients with PIA have a smaller infarct and better in-hospital outcome after acute myocardial infarction, than those without angina. This protective effects has been attributed to ischemic preconditioning (PC), to earlier reperfusion after fibrinolysis or its better collateral circulation development. In this study we aimed at assessing platelet reactivity in patients with history of pre-infarction angina (PIA) in the acute phase of ST segment elevation myocardial infarction (STEMI) and 1 month later. METHODS: 85 consecutive patients (63 +/- 10.5 years, 60 male) with a first STEMI treated by primary percutaneous coronary intervention (PCI) were studied at admission and 1 month later. Platelet reactivity was evaluated by flow cytometry with and without adenosine diphosphate (ADP) stimulation, by measuring monocyte platelet aggregates (MPAs) and glycoprotein IIb/IIIa (CD41) expression in the MPA gate, and CD41 and fibrinogen receptor (PAC-1) expression in the platelet gate. RESULTS: MPAs and expression of platelet receptors CD41 and PAC-1 were significantly lower in patients with than patients without PIA, both with and without ADP stimulation. After 1 month, all cytometry variables both with and without ADP stimulation were similar in the two groups. CONCLUSIONS: This study shows, for the first time, that patients with a first STEMI who experience PIA show a lower platelet reactivity as compared with those without history of PIA. PMID- 22197120 TI - Aerobic interval training improves oxygen uptake efficiency by enhancing cerebral and muscular hemodynamics in patients with heart failure. AB - BACKGROUND: Abnormal ventilatory/hemodynamic responses to exercise contribute to functional impairment in patients with heart failure (HF). This study investigates how interval and continuous exercise regimens influence functional capacity by modulating ventilatory efficiency and hemodynamic function in HF patients. METHODS: Forty-five HF patients were randomized to perform either aerobic interval training (AIT; 3-minute intervals at 40% and 80% VO(2peak)) or moderate continuous training (MCT; sustained 60% VO()for 30 min/day, 3 days/week for 12 weeks, or to a control group that received general healthcare (GHC). A noninvasive bio-reactance device was adopted to measure cardiac hemodynamics, whereas a near-infrared spectroscopy was employed to assess perfusion/O2 extraction in frontal cerebral lobe (?[THb]FC/?[HHb]FC) and vastus lateralis (?[THb]VL/?[HHb]VL), respectively. RESULTS: Following the 12-week intervention, the AIT group exhibited higher oxygen uptake efficiency slope (OUES) and lower VE VCO2 slope than the MCT and GHC groups. Furthermore, AIT, but not MCT, boosted cardiac output (CO) and increased ?[THb]FC, ?[THb]VL, and ?[HHb]VL during exercise. In multivariate analyses, CO was the dominant predictor of VO(2peak). ?[THb]FC and ?[THb]VL, which modulated the correlation between CO and OUES, were significantly correlated with OUES. Simultaneously, ?[THb]VL was the only factor significantly associated with VE-VCO2 slope. Additionally, AIT reduced plasma brain natriuretic peptide, myeloperoxidase, and interleukin-6 levels and increased the Short Form-36 physical/mental component scores and decreased the Minnesota Living with Heart Failure questionnaire score. CONCLUSIONS: AIT effectively improves oxygen uptake efficiency by enhancing cerebral/muscular hemodynamics and suppresses oxidative stress/inflammation associated with cardiac dysfunction, and also promotes generic/disease-specific qualities of life in patients with HF. PMID- 22197121 TI - Treatment of advanced Parkinson's disease with levodopa/carbidopa intestinal gel is associated with improvements in Hoehn and Yahr stage. PMID- 22197122 TI - Group I nonreciprocal inhibition in restless legs syndrome secondary to chronic renal failure. AB - BACKGROUND: Neurophysiological investigations disclosed spinal cord hyperexcitability in primary restless legs syndrome (p-RLS). Uremic RLS (u-RLS) is the most common secondary form, but its pathophysiological mechanisms remain unsettled. Aim of this study was to explore spinal cord excitability by evaluating group I nonreciprocal (Ib) inhibition in u-RLS patients in comparison with p-RLS patients and healthy subjects. METHODS: Eleven u-RLS patients undergoing long-term hemodialysis treatment, nine p-RLS patients and ten healthy subjects were studied. Soleus H reflex latency (HR-L), H(max)/M(max) ratio, and Ib inhibition were evaluated. Ib inhibition was tested measuring the amplitude changes in soleus H reflex following stimulation of the synergist gastrocnemius medialis (GM) nerve at rest. Nerve conduction studies were performed in the uremic patients. RESULTS: The H(max)/M(max) ratio did not differ in the three groups. The u-RLS patients showed a normal Ib inhibition comparable with the healthy group, whereas the p-RLS group had evidence of a reduced active inhibition compared with both u-RLS patients (P = 0.04) and controls (P = 0.007), prominently at 5 ms (P = 0.007) and at 6 ms (P = 0.02) of conditioning-test interval. Neurophysiological examination disclosed abnormalities ranging from higher HR-L to clear-cut polyneuropathy in most u-RLS patients. CONCLUSIONS: Unlike p-RLS patients, u-RLS patients had normal Ib inhibition, suggesting a regular supraspinal control of Ib spinal interneurons. Subclinical peripheral nerve abnormalities were detected in most uremic patients. Peripherally disrupted sensory modulation may represent the major pathophysiological determinant of uremic RLS. PMID- 22197123 TI - Gelastic seizures involving the left parietal lobe. AB - Gelastic seizures have been described in various epilepsies arising from the temporal or frontal lobes, although the most commonly encountered form is related to the presence of a hypothalamic hamartoma. We describe a patient with gelastic seizures involving the left parietal lobe. Our patient, an 8-year-old girl, underwent interictal video/EEG monitoring and MRI. The seizures consisted of brief staring followed by smiling and laughing. Electroencephalography during the gelastic seizures showed rhythmic spikes and waves in the left parietal lobe. MRI revealed the characteristic features of focal cortical dysplasia. Our findings suggest that the left parietal lobe may actively participate in the particular epileptogenic network generating gelastic seizures. PMID- 22197124 TI - Lacosamide use in refractory idiopathic primary generalized epilepsy. AB - Treatment of refractory idiopathic primary generalized epilepsy can be very challenging, with limited drug options, especially in young women of childbearing age. Here we describe the cases of two young women with refractory idiopathic primary generalized epilepsy refractory to multiple antiepileptic drugs in monotherapy or combination before achieving a long-term remission with adjunctive lacosamide (LCS) treatment. Larger, randomized prospective studies are necessary to establish the effectiveness of lacosamide in these patients. PMID- 22197125 TI - Predictive value of Spanish neuropsychological testing for laterality in patients with epilepsy. AB - In presurgical treatment planning for patients with epilepsy, neuropsychological testing assists in lateralization of the seizure focus. Previous research with English speakers has shown that patients with left hemisphere (LH) onsets versus right hemisphere (RH) onsets perform worse on naming and other verbal skills tests, but similar findings with Hispanic patients are limited. Thirty-nine Spanish-speaking patients were administered a comprehensive battery of neuropsychological tests in Spanish. LH-onset patients performed significantly worse than RH-onset patients on verbal comprehension (P=0.006), visual matching (P=0.047), the Ponton-Satz Boston Naming Test (P=0.001), and the dominant hand trial of the Grooved Pegboard Test (P=0.012). A stepwise regression model to predict seizure laterality from these tests was significant (F=12.10, P=0.001), but only the Ponton-Satz Boston Naming Test was retained. This comprehensive battery of neuropsychological tests in Spanish proved useful in predicting lateralization in patients with partial epilepsy. PMID- 22197126 TI - Ovarian stimulation and intrauterine insemination in women aged 40 years or more. AB - Fertility decreases with advancing age. This study retrospectively reviewed the results of ovarian stimulation and intrauterine insemination (IUI) in women 40 years old with diminished ovarian reserve or unexplained infertility who underwent treatment with ovarian stimulation/IUI with clomiphene citrate or gonadotrophin and compared them with the results of IVF and in-vitro maturation (IVM) treatments. The main outcome measures were pregnancy and live-birth rates. The profiles of the patients in ovarian stimulation, IVM and IVF groups were comparable. There were no clinical pregnancies in the clomiphene citrate and IVM groups. The clinical-pregnancy rates in the gonadotrophin and IVF groups were 2.6% and 16.9% and the live-birth rates were 2.6% and 13.7%, respectively. Compared with ovarian stimulation, IVF is most effective for women aged 40 years or more. Attempting success with ovarian stimulation or IVM will delay conception unnecessarily. PMID- 22197127 TI - Follicular and endocrine profiles associated with different GnRH-antagonist regimens: a randomized controlled trial. AB - This trial assessed the impact of early initiation of gonadotrophin-releasing hormone (GnRH) antagonist on follicular and endocrine profiles compared with the fixed GnRH-antagonist protocol. Eighty-five oocyte donors were randomized to GnRH antagonist starting in the mid-luteal phase of the prestimulation cycle (degarelix-ML group), on stimulation day 1 (early follicular phase, degarelix-EF group) or day 6 (fixed protocol) (mid-follicular phase, ganirelix-MF group). Subjects in the degarelix-EF and ganirelix-MF groups received placebo in the prestimulation cycle. At start of stimulation, serum concentrations of FSH (4.6 +/- 2.3 versus 6.0 +/- 1.8IU/l), LH (2.7 +/- 1.4 versus 4.7 +/- 1.9IU/l) and oestradiol (87 +/- 35 versus 129 +/- 50pmol/l) were markedly lower (P<0.001) in the degarelix-ML group than in the placebo group. The coefficients of variation of follicle size (36.7 +/- 5.5% versus 39.2 +/- 9.4%) were not significantly different. No differences in endometrial histology, embryo quality and pregnancy rates in recipient cycles were observed between the regimens. In conclusion, early administration of GnRH antagonist altered the endocrine profile without modifying the follicular synchrony for the majority of subjects. Whether patients with a more heterogeneous follicle size at start of stimulation may benefit from an earlier intervention remains to be proven. PMID- 22197128 TI - Spontaneous LH surges prior to HCG administration in unstimulated-cycle frozen thawed embryo transfer do not influence pregnancy rates. AB - LH surges are the start of a period of optimal endometrial receptivity. Missing these surges in an unstimulated-cycle frozen-thawed embryo transfer (FET) based on ultrasound alone might lead to incorrect timing of embryo transfer. This prospective, non-randomized trial established the incidence and effect of spontaneous LH surges on ongoing pregnancy rates and assessed the use of ultrasound without LH monitoring in planning FET. All patients undergoing unstimulated-cycle FET in the study centre over a 2-year period were included in this analysis (n=233). All patients had regular menstrual cycles. Serum LH analysis took place before human chorionic gonadotrophin administration. The main outcome measure was ongoing pregnancy. LH surges occurred in over half of patients. Overall pregnancy rate was 34.3%. Relative risks for ongoing pregnancy for cycles with or without a spontaneous LH surge were not significantly different (ongoing pregnancy rate 33.4% versus 34.8%; RR 1.02, 95% CI 0.7-1.5). Based on these results, it was concluded that LH surges >=10 IU/l occurred in over 50% of patients, but LH surges demonstrated no significant effect on pregnancy rates. Single LH determination prior to ovulation induction in unstimulated-cycle FET does not seem to have added clinical value. PMID- 22197129 TI - Absence of SYCP3 mutations in women with recurrent miscarriage with at least one trisomic miscarriage. AB - Mutations within the coding regions of the synaptonemal complex gene SYCP3 have previously been reported in women with recurrent miscarriage. The present study found no mutations in any of the coding exons or the intron/exon boundaries among 50 recurrent miscarriage patients with at least one documented trisomic miscarriage, suggesting that mutations in SYCP3 do not contribute significantly to risk for recurrent miscarriage through maternal meiotic nondisjunction. PMID- 22197130 TI - The luteal phase after GnRH-agonist triggering of ovulation: present and future perspectives. AB - In stimulated IVF/intracytoplasmic sperm injection cycles, the luteal phase is disrupted, necessitating luteal-phase supplementation. The most plausible reason behind this is the ovarian multifollicular development obtained after ovarian stimulation, resulting in supraphysiological steroid concentrations and consecutive inhibition of LH secretion by the pituitary via negative feedback at the level of the hypothalamic-pituitary axis. With the introduction of the gonadotrophin-releasing hormone-(GnRH) antagonist, an alternative to human chorionic gonadotrophin triggering of final oocyte maturation is the use of GnRH agonist (GnRHa) which reduces or even prevents ovarian hyperstimulation syndrome (OHSS). Interestingly, the current regimens of luteal support after HCG triggering are not sufficient to secure the early implanting embryo after GnRHa triggering. This review discusses the luteal-phase insufficiency seen after GnRHa triggering and the various trials that have been performed to assess the most optimal luteal support in relation to GnRHa triggering. Although more research is needed, GnRHa triggering is now an alternative to HCG triggering, combining a significant reduction in OHSS with high ongoing pregnancy rates. PMID- 22197131 TI - Sphingosine-sphingosine-1-phosphate pathway regulates trophoblast differentiation and syncytialization. AB - Sphingosine and sphingosine-1-phosphate (S1P) are involved in regulating cell differentiation. This study postulated that changes in sphingolipid biosynthesis and metabolism are important in trophoblast syncytialization and therefore examined the production, metabolism and actions of sphingosine and S1P during spontaneous trophoblast differentiation and fusion in vitro. Significant declines in intracellular sphingosine concentration (P<=0.05) and sphingosine kinase 1 (SPHK1) expression (P<=0.01) were observed during trophoblast syncytialization. Secreted S1P concentrations dropped steeply after 72h, before rising to basal concentrations with syncytialization. Intracellular S1P concentrations were undetectable throughout. Treating cells with exogenous sphingosine (P<=0.01), S1P (P<=0.001) or a specific SPHK1 inhibitor (P<=0.05) for up to 72h in culture significantly inhibited trophoblast differentiation (measured as reduced human chorionic gonadotrophin production); effects on other biochemical and morphological markers of differentiation were absent or inconsistent. Phosphorylation of Akt, an established down-stream target of S1P that spontaneously declines with trophoblast differentiation, was markedly reduced by S1P (P<=0.05). In conclusion, changes in the sphingosine-S1P pathway are involved in the regulation of trophoblast differentiation in term human placenta. Dysregulation of sphingolipid homeostasis could, therefore, disrupt placental formation and function with deleterious consequences for pregnancy outcome. PMID- 22197132 TI - The Edwards and Steptoe Research Trust: commemorating the two great pioneers of our field and supporting their aspirations. PMID- 22197133 TI - Response: low-intensity IVF: real progress? PMID- 22197134 TI - Standardization of catheter load speed during embryo transfer: comparison of manual and pump-regulated embryo transfer. AB - The position of transfer air bubbles after embryo transfer is related to the pregnancy rate. With the conventional manual embryo-transfer technique it is not possible to predict the final position of the air bubbles. This position mainly depends on the catheter load speed at transfer (injection speed), a parameter that remains uncontrollable with the conventional technique even after standardization of the protocol. Therefore, the development of an automated device that generates a standardized injection speed is desirable. This study aimed to examine the variation in injection speeds in manual embryo transfer and pump-regulated embryo transfer (PRET). Seven laboratory technicians were asked to perform simulated transfers using the conventional embryo-transfer technique. Their injection speeds were compared with that of a PRET device. The results indicate that in manually performed transfers, even after standardization of the protocol, there is still a large variation in injection speed, while a PRET device generates a reliable and reproducible injection speed and therefore brings new possibilities for further standardization of the embryo-transfer procedure. Future research should reveal whether these experiments mimic real clinical circumstances and if a standardized injection speed results in more exact positioning of the transferred embryos and therefore higher pregnancy rates. PMID- 22197135 TI - A concise synthesis of viscolin, and its anti-inflammatory effects through the suppression of iNOS, COX-2, ERK phosphorylation and proinflammatory cytokines expressions. AB - In the present report, a concise synthesis of viscolin (1) has been achieved. The anti-inflammatory effect of viscolin was investigated in vitro and in vivo. Viscolin blocked the expression of iNOS and COX-2, and it also inhibited the ERK for the activation of NF-kappaB in LPS-stimulated RAW 264.7 macrophages. Western blotting and immunohistochemical analysis revealed that viscolin decreased Carr induced iNOS and COX-2 expressions. These results could help to deduce the anti inflammatory mechanisms. PMID- 22197136 TI - Synthesis and structure-activity relationship of 5-pyridazin-3-one phenoxypiperidines as potent, selective histamine H(3) receptor inverse agonists. AB - Optimization of the R(2) and R(6) positions of (5-{4-[3-(R)-2-methylpyrrolin-1-yl propoxy]phenyl}-2H-pyridazin-3-one) 2a with constrained phenoxypiperidines led to the identification of 5-[4-(cyclobutyl-piperidin-4-yloxy)-phenyl]-6-methyl-2H pyridazin-3-one 8b as a potent, selective histamine H(3) receptor antagonist with favorable pharmacokinetic properties. Compound 8b had an excellent safety genotoxocity profile for a CNS-active compound in the Ames and micronucleus tests, also displayed potent H(3)R antagonist activity in the brain in the rat dipsogenia model and robust wake activity in the rat EEG/EMG model. PMID- 22197137 TI - 4-Piperidin-4-ylidenemethyl-benzamides as delta-opioid receptor agonists for CNS indications: identifying clinical candidates. AB - A series of 4-piperidin-4-ylidenemethyl-benzamide delta-opioid receptor agonists is described with an emphasis on balancing the potency, subtype selectivity and in vitro ADME and safety properties. The three sites impacting SAR are substitutions on the aryl group (R(1)), the piperidine nitrogen (R(2)), and the amide (R(3)). Each region contributes to the balance of properties for delta opioid activity and a desirable CNS profile, and two clinical candidates (20 and 24) were advanced. PMID- 22197138 TI - In vitro and in silico studies of polycondensed diazine systems as anti-parasitic agents. AB - Parasitic diseases caused by protozoarian agents are still relevant today more than ever. Recently, we synthesized several polycondensed diazine derivatives by means 1,3-dipolar cycloaddition reactions. A broad selection of these compounds were submitted to in vitro biological screening against Plasmodium falciparum, Leishmania infantum, Trypanosoma brucei, and Trypanosoma cruzi, resulting active at micromolar level. Induced Fit Docking/MM-GBSA studies were performed giving interesting indications about the probable mechanism of action of the most active compounds. PMID- 22197139 TI - Multiparameter exploration of piperazine derivatives as delta-opioid receptor agonists for CNS indications. AB - A novel series of piperazine derivatives exhibits sub-nanomolar binding and enhanced subtype selectivity as delta-opioid agonists. The synthesis and SAR are described as well as the application of computational models to improve in vitro ADME and safety properties suitable for CNS indications, specifically microsomal clearance, permeability, and hERG channel inhibition. PMID- 22197140 TI - Discovery of 3-aryloxy-lactam analogs as potent androgen receptor full antagonists for treating castration resistant prostate cancer. AB - High throughput cell-based screening led to the identification of 3-aryloxy lactams as potent androgen receptor (AR) antagonists. Refinement of these leads to improve the ADME profile and remove residual agonism led to the discovery of 12, a potent full antagonist with greater oral bioavailability. Improvements in the ADME profile were realized by designing more ligand-efficient molecules with reduced molecular weights and lower lipophilicities. PMID- 22197141 TI - Discovery of dehydro-oxopiperazine acetamides as novel bradykinin B1 receptor antagonists with enhanced in vitro potency. AB - In a series of bradykinin B1 antagonists, we discovered that replacement of oxopiperazine acetamides with dehydro-oxopiperazine acetamides provided compounds with enhanced activity against the B1 receptor. The synthesis and SAR leading to potent analogs with reduced molecular weight will be discussed. PMID- 22197142 TI - Development of a more highly selective M(1) antagonist from the continued optimization of the MLPCN Probe ML012. AB - This Letter describes the continued optimization of an MLPCN probe molecule (ML012) through an iterative parallel synthesis approach. After exploring extensive modifications throughout the parent structure, we arrived at a more highly M(1)-selective antagonist, compound 13l (VU0415248). Muscarinic subtype selectivity across all five human and rat receptors for 13l, along with rat selectivity for the lead compound (ML012), is presented. PMID- 22197143 TI - Structure-based optimization of morpholino-triazines as PI3K and mTOR inhibitors. AB - A virtual screen of our in-house database using various fingerprint techniques returned several triazine hits which were found to be mTOR inhibitors with a slight selectivity over PI3Kalpha. Using structure-guided lead optimization the inhibitory activity towards mTOR and PI3Kalpha was increased to the low nanomolar range. Exploiting shape differences in the binding-site allowed for the design of mTOR selective inhibitors. Focus on ligand efficiency ensured the inhibitors retained a low molecular weight and desirable drug-like properties. PMID- 22197144 TI - Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 1: quaternary amines. AB - We report the identification of a novel series of human epithelial sodium channel (ENaC) blockers that are structurally distinct from the pyrazinoyl guanidine chemotype found in prototypical ENaC blockers such as amiloride. Following a rational design hypothesis a series of quaternary amines were prepared and evaluated for their ability to block ion transport via ENaC in human bronchial epithelial cells (HBECs). Compound 11 has an IC(50) of 200nM and is efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED(50) of 44MUgkg(-1) at 1h. As such, pyrazinoyl quaternary amines represent the first examples of a promising new class of human ENaC blockers. PMID- 22197145 TI - Symmetric dimers of ent-kaurane diterpenoids with cytotoxic activity from Croton tonkinensis. AB - Breast cancer is the most common malignant tumor in women these days accounting for approximately 24% of all cancer. During our screening program searching for cytotoxic materials from natural products, two new symmetric dimers of ent kaurane diterpenoid, crotonkinensins C (1) and D (2), with connectivity at C-17 were isolated from the leaves of the Vietnamese endemic medicinal plant Croton tonkinensis. Their structures were determined on the basis of physicochemical and spectroscopic data. Compound 2 showed a potent cytotoxic activity against MCF-7, tamoxifen-resistant MCF-7 (MCF-7/TAMR), adriamycin-resistant MCF-7 (MCF-7/ADR), and MDA-MB-231 breast cancer cell lines. PMID- 22197146 TI - Mental health promotion: guidance and strategies. AB - Public mental health incorporates a number of strategies from mental well-being promotion to primary prevention and other forms of prevention. There is considerable evidence in the literature to suggest that early interventions and public education can work well for reducing psychiatric morbidity and resulting burden of disease. Educational strategies need to focus on individual, societal and environmental aspects. Targeted interventions at individuals will also need to focus on the whole population. A nested approach with the individual at the heart of it surrounded by family surrounded by society at large is the most suitable way to approach this. This Guidance should be read along with the European Psychiatric Association (EPA) Guidance on Prevention. Those at risk of developing psychiatric disorders also require adequate interventions as well as those who may have already developed illness. However, on the model of triage, mental health and well-being promotion need to be prioritized to ensure that, with the limited resources available, these activities do not get forgotten. One possibility is to have separate programmes for addressing concerns of a particular population group, another that is relevant for the broader general population. Mental health promotion as a concept is important and this will allow prevention of some psychiatric disorders and, by improving coping strategies, is likely to reduce the burden and stress induced by mental illness. PMID- 22197147 TI - A raison d'etre for two distinct pathways in the early steps of plant isoprenoid biosynthesis? AB - When compared to other organisms, plants are atypical with respect to isoprenoid biosynthesis: they utilize two distinct and separately compartmentalized pathways to build up isoprene units. The co-existence of these pathways in the cytosol and in plastids might permit the synthesis of many vital compounds, being essential for a sessile organism. While substrate exchange across membranes has been shown for a variety of plant species, lack of complementation of strong phenotypes, resulting from inactivation of either the cytosolic pathway (growth and development defects) or the plastidial pathway (pigment bleaching), seems to be surprising at first sight. Hundreds of isoprenoids have been analyzed to determine their biosynthetic origins. It can be concluded that in angiosperms, under standard growth conditions, C20-phytyl moieties, C30-triterpenes and C40 carotenoids are made nearly exclusively within compartmentalized pathways, while mixed origins are widespread for other types of isoprenoid-derived molecules. It seems likely that this coexistence is essential for the interaction of plants with their environment. A major purpose of this review is to summarize such observations, especially within an ecological and functional context and with some emphasis on regulation. This latter aspect still requires more work and present conclusions are preliminary, although some general features seem to exist. PMID- 22197148 TI - DPP-4 inhibitors in the management of type 2 diabetes: a critical review of head to-head trials. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors offer new options for the management of type 2 diabetes. Direct comparisons with active glucose-lowering comparators in drug-naive patients have demonstrated that DPP-4 inhibitors exert slightly less pronounced HbA(1c) reduction than metformin (with the advantage of better gastrointestinal tolerability) and similar glucose-lowering effects as with a thiazolidinedione (TZD; with the advantage of no weight gain). In metformin treated patients, gliptins were associated with similar HbA(1c) reductions compared with a sulphonylurea (SU; with the advantage of no weight gain, considerably fewer hypoglycaemic episodes and no need for titration) and a TZD (with the advantage of no weight gain and better overall tolerability). DPP-4 inhibitors also exert clinically relevant glucose-lowering effects compared with a placebo in patients treated with SU or TZD (of potential interest when metformin is either not tolerated or contraindicated), and as oral triple therapy with a good tolerability profile when added to a metformin-SU or pioglitazone-SU combination. Several clinical trials also showed a consistent reduction in HbA(1c) when DPP-4 inhibitors were added to basal insulin therapy, with no increased risk of hypoglycaemia. Because of the complex pathophysiology of type 2 diabetes and the complementary actions of glucose-lowering agents, initial combination of a DPP-4 inhibitor with either metformin or a glitazone may be applied in drug-naive patients, resulting in greater efficacy and similar safety compared with either drug as monotherapy. However, DPP-4 inhibitors were less effective than GLP-1 receptor agonists for reducing HbA(1c) and body weight, but offer the advantage of being easier to use (oral instead of injected administration) and lower in cost. Only one head-to-head trial demonstrated the non-inferiority of saxagliptin vs sitagliptin. Clearly, more trials of direct comparisons between different incretin-based therapies are needed. Because of their pharmacokinetic characteristics, pharmacodynamic properties (glucose dependent glucose-lowering effect) and good overall tolerability profile, DPP-4 inhibitors may have a key role to play in patients with renal impairment and in the elderly. The role of DPP-4 inhibitors in the therapeutic armamentarium of type 2 diabetes is rapidly evolving as their potential strengths and weaknesses become better defined mainly through controlled clinical trials. PMID- 22197150 TI - Assessing metacognitive skills in waking and sleep: a psychometric analysis of the Metacognitive, Affective, Cognitive Experience (MACE) questionnaire. AB - The Metacognitive, Affective, Cognitive Experience (MACE) questionnaire was designed to assess metacognition across sleep and waking (Kahan & LaBerge, 1996). The present research evaluates the psychometric properties of the MACE. Data from two recent studies (N=185) were used to assess the inter-item consistency, test retest reliability, and factorial, convergent, and discriminant validity of the MACE. Results show that the MACE is a reliable measure with good construct validity. Exploratory factor analyses revealed one self-regulation and two monitoring factors. One monitoring factor emphasized monitoring internal conditions; the other emphasized monitoring external conditions. This factor structure is consistent with the Metacognitive Model (Nelson & Narens, 1990). Tests of convergent and discriminant validity suggest that the MACE is assessing metacognition and is appropriately related to similar constructs such as mindfulness and self-consciousness. The implication of these findings as well as suggestions for research and clinical applications of the MACE are discussed. PMID- 22197149 TI - Auras in mysticism and synaesthesia: a comparison. AB - In a variety of synaesthesia, photisms result from affect-laden stimuli as emotional words, or faces of familiar people. For R, who participated in this study, the sight of a familiar person triggers a mental image of "a human silhouette filled with colour". Subjective descriptions of synaesthetic experiences induced by the visual perception of people's figures and faces show similarities with the reports of those who claim to possess the ability to see the aura. It has been proposed that the purported auric perception may be easily explained by the presence of a specific subtype of cross-modal perception. We analyse the subjective reports of four synaesthetes who experience colours in response to human faces and figures. These reports are compared with descriptions of alleged auric phenomena found in the literature and with claims made by experts in esoteric spheres. The discrepancies found suggest that both phenomena are phenomenologically and behaviourally dissimilar. PMID- 22197151 TI - Physical and emotional abuse of primary school children by teachers. AB - The existence of child abuse is unfortunately a reality of contemporary society. Although various organizations and researchers have been making progress in the struggle against abuse, it has not been decisively dealt with thus far. Most of the research on abuse has focused on the abuse of children in their family environment. OBJECTIVE: The aim of the present study was the investigation of abuse in the school environment and the effects of the gender and school grade of pupils, as well as the gender of teachers on the various forms of abuse. METHODS: The study utilized a questionnaire with a 5-point rating scale, with questions concerning physical abuse, emotional abuse and neglect, which was completed in class by a sample of schoolchildren. The sample consisted of 1,339 pupils in the 4th, 5th, and 6th grade of primary school in the Republic of Cyprus, who lived in both urban and rural areas. Two pilot studies were conducted initially to ensure the appropriateness of the questionnaire. Permission to conduct the study was gained by the headmasters of the schools, and authorization to participate in the study was granted by the students' parents. RESULTS: More than half (52.9%) of the pupils reported neglect, almost a third (33.1%) reported emotional abuse, and almost one tenth (9.6%) reported physical abuse. The results of the statistical analysis revealed statistically significant differences between the 2 genders (p<.001), with boys being the most vulnerable group, with regards to all forms of abuse, but no significant differences between the 3 grades and the teachers' gender (p>.05). There were no significant differences between the 2 genders, the 3 grades and the teachers' gender with regards to the frequency of any form of abuse (p>.05). CONCLUSIONS: The gender of the pupils seems to be related to abuse, since more boys than girls reported being victims of abuse, while abuse is not depended on the school grade, or the teacher's gender. The findings from this study may justify some concern on behalf of the Ministry of Education, but also from educators and parents in the Republic of Cyprus. PMID- 22197152 TI - Locally adaptive Nakagami-based ultrasound similarity measures. AB - The derivation of statistically optimal similarity measures for intensity-based registration is possible by modeling the underlying image noise distribution. The parameters of these distributions are, however, commonly set heuristically across all images. In this article, we show that the estimation of the parameters on the present images largely improves the registration, which is a consequence of the more accurate characterization of the image noise. More precisely, instead of having constant parameters over the entire image domain, we estimate them on patches, leading to a local adaptation of the similarity measure. While this basic idea of creating locally adaptive metrics is interesting for various fields of application, we present the derivation for ultrasound imaging. The domain of ultrasound is particularly appealing for this approach, due to the inherent contamination with speckle noise. Furthermore, there exist detailed analyses of suitable noise distributions in the literature. We present experiments for applying a bivariate Nakagami distribution that facilitates modeling of several scattering scenarios prominent in medical ultrasound. Depending on the number of scatterers per resolution cell and the presence of coherent structures, different Nakagami parameters are required to obtain a valid approximation of the intensity statistics and to account for distributional locality. Our registration results on radio-frequency ultrasound data confirm the theoretical necessity for a spatial adaptation of similarity metrics. PMID- 22197154 TI - Bioavailability study of triamterene and xipamide using urinary pharmacokinetic data following single oral dose of each drug or their combination. AB - An efficient chromatographic method for the simultaneous determination of triamterene (TRI) and xipamide (XIP) in urine samples, based on high performance liquid chromatography with photodiode array detector (HPLC-DAD) has been developed. The HPLC separation was performed on a RP stainless-steel C-18 analytical column (250 mm * 4.6 mm, 5 MUm) with a gradient elution system of 0.05 M phosphate buffer adjusted to pH 4.0 and methanol as the mobile phase. The method was used to determine the urinary excretion profile and to calculate different urinary pharmacokinetic parameters following oral dose of their combination compared with single oral doses of each drug and hence comparing their bioavailability. Quantitation was performed using chlorthalidone as internal standard. The calibration graphs of each drug were rectilinear in the range of 0.2-40 MUg/mL urine for TRI and 0.2-15 MUg/mL urine for XIP. An HPLC-DAD method was also successfully developed for the simultaneous determination of the investigated drugs in pharmaceutical preparations. The methods were validated in terms of linearity, accuracy, precision, selectivity, limits of detection and quantitation and other aspects of analytical validation. PMID- 22197153 TI - Measurement of drug diffusivities in pharmaceutical solvents using Taylor dispersion analysis. AB - Knowledge of drug diffusivity is of key importance in the understanding of a number of pharmaceutical and biological processes. However, experimentally determined diffusion coefficients and hydrodynamic radii are only reported for a limited number of drug substances. In this work, Taylor dispersion analysis conducted using capillary electrophoresis instrumentation coupled with a UV imaging detector, with two detection windows along the capillary, is introduced as a powerful method for the determination of drug diffusivities in nanoliter samples. Several potential advantages associated with applying two detection windows instead of one window as done in most previous studies were identified. Overall diffusion coefficient measurements performed using two detection windows are more robust and correction for changes in flow rate and sample volume is not required. The experimental conditions applied were suboptimal for performing single detection window measurements due to the relatively large sample volumes and may be optimized to alleviate the need for tedious correction procedures for this setup. The diffusivities of eleven aromatic compounds in water at 25 degrees C were determined, and showed a good agreement with the literature values. Furthermore, the diffusivities and hydrodynamic radii of four selected drug substances were determined in acetonitrile, methanol, isopropyl myristate, medium chain triglyceride, and propylene glycol in addition to water. The solvent viscosity was determined simultaneously along with the measurement of analyte diffusivity. Drug diffusivities decreased with increasing solvent viscosity. Taylor dispersion analysis is a robust, simple and automated method of quantification of diffusion coefficients even in media with a relatively higher viscosity than water. PMID- 22197155 TI - Method development and validation for rapid quantification of hydroxychloroquine in human blood using liquid chromatography-tandem mass spectrometry. AB - A novel and specific liquid chromatography-tandem mass spectrometric method (LC MS/MS) was developed and validated for the quantification of hydroxychloroquine in human blood using its stable labeled isotope, hydroxychloroquine-d4 as the internal standard. Chromatographic separation of analytes was achieved using an Agilent ZORBAX Eclipse XDB - C8 analytical HPLC column (50 mm * 2.1 mm, 5 MUm). The mobile phase comprising water containing 0.1% formic acid-acetonitrile (94:6, v/v) was delivered isocratically at a flow rate of 0.5 mL/min. The column effluent was detected by API 4000 triple quadrupole mass spectrometer using electrospray ionization (ESI) and monitored by multiple reaction monitoring with positive mode. The precursor to product ion transitions of m/z 336 -> 247 and m/z 340 -> 251 were used to measure the analyte and IS, respectively. The assay demonstrated a good linear dynamic range of 5-2000 ng/mL for hydroxychloroquine in human blood, with coefficient of determination (r(2)) of =0.9999. The values for intra-day and inter-day precisions of hydroxychloroquine were <= 7.86% with the accuracies ranged from 93.8% to 107.6%. The chromatographic run time was 3 min, making it possible to achieve a high throughput analysis. This method was used as a bio-analytical tool in a phase I clinical trial to quantify blood hydroxychloroquine concentrations in patients with non-small cell lung cancer receiving both hydroxychloroquine and gefitinib in their treatment. PMID- 22197156 TI - [Bronchopulmonary amyloidosis: report of four cases]. AB - Amyloidosis limited to bronchopulmonary apparatus is expressed as tracheobronchial deposits in diffuse plaques that can cause stenosis or parenchymal nodules or masses. In this regard, we report four cases of pulmonary amyloidosis and discuss the diagnostic difficulties of this location. These are two women and two men aged 60, 68, 44 and 57 years. They presented a pulmonary parenchymal amyloidosis in all cases associated with bronchial in one case. The diagnosis was confirmed by histology in all cases. The staging was negative in all cases. The evolution was marked by the stabilization of the lesions in all cases. Localized amyloidosis, which may be the only telltale sign of a systemic illness, its diagnosis requires finding other locations to better tailor the treatment strategy. PMID- 22197157 TI - [Pulmonary sarcomatoid carcinoma: Clinical and prognostic characteristics, a case report]. AB - Sarcomatoid carcinoma is a rare malignancy in the family of non-small-cell lung cancer. They belong to a mixed group of poorly differenciated neoplasia, including sarcomatous cells or sarcomatoid-like cells with giant or spindle cells. We report the case of a 69-year-old man with sarcomatoid carcinoma. We describe the main characteristics of these tumors. Diagnosis is frequently delayed and lesions are locally advanced. The prognostic is poorer than other non small-cell lung cancer. Chemotherapy is often not efficient. PMID- 22197158 TI - [Which organization for the management of thoracic cancer? Results from a French survey in Rhone-Alpes region]. AB - This survey, conducted in Rhone-Alpes region (France), aims to better understand the actual conditions of practice in thoracic oncology. A questionnaire was distributed to all oncologists, pulmonologists, radiotherapy physicians and thoracic surgeons in the region. Of 401 questionnaires, the response rate was 56%. Among the responders 46% reported exercising the Thoracic Oncology (TO). Most physicians practicing TO are pulmonologists (62%). The majority (45%) are engaged in secondary hospital or university hospital (27%). However, practitioners with the most important activity exerts in university hospitals and cancer centre (71% of physicians practicing in secondary hospitals and 75% of those in private practice reported to manage fewer than 80 new NSCLC cases per year in structure). Furthermore, 91% are regularly involved in a multidisciplinary team. Radiation oncologist, pulmonologists and thoracic surgeons are assiduous to these meeting; however radiologists and, to a lesser extent, pathologists are less attentive. Moreover, 92% of practitioners belong to cancer networks. Similarly, over one third of working together in a cooperative clinical research institution and nearly half are involved in clinical trials (with nearly half in secondary hospital). These results highlight the reality of practice in Rhone-Alpes and will serve as the basis for coordinating authorities to correct dysfunctions or monitor certain activities of interest (clinical trials). PMID- 22197159 TI - [Desmoid tumor of mediastinum revealed by superior vena cava syndrome and tamponade]. AB - Desmoid tumors are rare forms of low grade malignancies. They are characterized by a strong potential of local invasion. Although they are considered histologically benign they behave aggressive locally. They typically occur in the abdominal wall or within the abdomen. Mediastinal localisation is very rare. The only curative treatment is wide surgical excision but the surgery is difficult and the risk of local recurrence is high. PMID- 22197160 TI - Validation of the Dutch version of the Simple Shoulder Test. AB - BACKGROUND: The Simple Shoulder Test (SST) is an internationally used patient reported outcome for clinical practice and research purposes. It was developed for measuring functional limitations of the affected shoulder in patients with shoulder dysfunction and contains 12 questions (yes/no). The purpose of this study was to create a Dutch translation of the SST and to assess the reliability and validity. MATERIALS AND METHODS: The SST was translated into Dutch using forward and backward translations. A consecutive cohort of patients with shoulder problems visiting an orthopedic clinic completed the Dutch version of the SST twice within 28 days. In addition, the Dutch validated versions of the Disabilities of the Arm, Shoulder and Hand, Oxford Shoulder Score, and Constant Murley shoulder assessment were completed for assessing construct validity. RESULTS: One hundred ten patients with a mean age of 39 years (SD, 14 years), 72% male, completed the questionnaires. The internal consistency was high (Cronbach alpha, 0.78). The test-retest reliability was very good (intraclass correlation coefficient, 0.92) (n = 55). The measurement error expressed in the standard error of measurement was 1.18, and the smallest detectable change was 3.3 on a scale from 0 to 12. The construct validity was supported by expected high correlations between the Dutch version of the SST and the Disabilities of the Arm, Shoulder and Hand (r = -0.74) and between the SST and the Oxford Shoulder Score (r = -0.74) and an expected moderate correlation between the SST and the Constant-Murley shoulder assessment (r = 0.59). CONCLUSION: The Dutch version of the SST seems to be a reliable and valid instrument for evaluating functional limitations in patients with shoulder complaints. PMID- 22197161 TI - In vivo temperature measurement in the subacromial bursa during arthroscopic subacromial decompression. AB - BACKGROUND: The purpose of the study was to evaluate whether use of a bi-polar radiofrequency (RF) ablation wand would cause excess heating, which may lead to collateral damage to the surrounding tissues during arthroscopic subacromial decompression. Cadaveric studies have shown that high temperatures can potentially be reached when using RF ablation wands in arthroscopic shoulder surgery. Only 1 other published study assesses these temperature rises in the clinical setting. METHODS: Fifteen patients were recruited to participate in the study. A standard arthroscopic subacromial decompression was performed using continuous flow irrigation, with intermittent use of the RF ablation wand for soft tissue debridement. The temperature of the irrigation fluid within the subacromial bursa and the outflow fluid from the suction port of the wand were measured during the procedure using fiber-optic thermometers. RESULTS: The mean peak temperature recorded in the subacromial bursa was 32.0 degrees C (29.3-43.1 degrees C), with a mean rise from baseline of 9.8 degrees C. The mean peak temperature recorded from the outflow fluid from the wand was 71.6 degrees C (65.6-77.6 degrees C), with a mean rise from baseline of 49.4 degrees C. CONCLUSION: High temperatures were noted in the outflow fluid from the wand; however, this was not evident in the subacromial bursa itself. Use of room temperature inflow fluid, maintenance of flow through the bursa, and avoidance of prolonged uninterrupted use of the wand all appear to ensure that safe temperatures are maintained in the subacromial bursa not only in the laboratory but also in a clinical setting. PMID- 22197162 TI - Bed nucleus of the stria terminalis and the cardiovascular responses to chemoreflex activation. AB - Several studies from our group have indicated that the BNST play an important role in baroreflex modulation. However, the involvement of the BNST in the chemoreflex activity is unknown. Thus, in the present study, we investigated the effect of the local bed nucleus of stria terminalis (BNST) neurotransmission inhibition by bilateral microinjections of the non-selective synaptic blocker cobalt chloride (CoCl(2)) on the cardiovascular responses to chemoreflex activation in rats. For this purpose, chemoreflex was activated with KCN (i.v.) before and after microinjections of CoCl(2) into the BNST. Reversible BNST inactivation produced no significant changes in the magnitude and durations of both pressor and bradycardic responses to intravenous KCN infusion. These findings suggesting that BNST neurotransmission have not influence on both sympathoexcitatory and parasympathoexcitatory components of the peripheral chemoreflex activation. PMID- 22197163 TI - Upper gastrointestinal bleeding in a patient with multiple myeloma. PMID- 22197164 TI - An uncommon cause of epigastric pain and emesis. PMID- 22197165 TI - An extremely unusual and large cause of anemia. PMID- 22197166 TI - A rare but important cause of acute abdomen. PMID- 22197167 TI - A common disease with an unusual complication of acute abdomen. PMID- 22197168 TI - To snare a snare, or not to snare? PMID- 22197169 TI - Transient ischemic attack in a patient with cirrhosis. PMID- 22197170 TI - Dysphagia in an HIV patient: a rare culprit. PMID- 22197171 TI - Microbial communities involved in enhanced biological phosphorus removal from wastewater--a model system in environmental biotechnology. AB - Enhanced biological phosphorus removal (EBPR) is one of the most advanced and complicated wastewater treatment processes applied today, and it is becoming increasingly popular worldwide as a sustainable way to remove and potentially reuse P. It is carried out by complex microbial communities consisting primarily of uncultured microorganisms. The EBPR process is a well-studied system with clearly defined boundaries which makes it very suitable as a model ecosystem in microbial ecology. Of particular importance are the transformations of C, N, and P, the solid-liquid separation properties and the functional and structural stability. A range of modern molecular methods has been used to study these communities in great detail including single cell microbiology, various -omics methods, flux analyses, and modeling making this one of the best studied microbial ecosystems so far. Recently, an EBPR core microbiome has been described and we present in this article some highlights and show how this complex microbial community can be used as model ecosystem in environmental biotechnology. PMID- 22197172 TI - [Influenza A, will it keep on mutating?]. PMID- 22197173 TI - A case of complete hydatidiform mole in a perimenopausal woman with diagnostic usefulness of p57(kip2) immunohistochemistry and HER2 fluorescent in situ hybridization. AB - Gestational trophoblastic disease in perimenopausal women is very rare. A 53-year old perimenopausal woman complained about amenorrhea lasting over a period of 4months. Ultrasound showed enlargement of the uterus with a complex echogeneous area in the uterine cavity. Serum human chorionic gonadotropin was 67,611mIU/ml. Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. The uterus contained hemorrhagic and fragile tumor with grape-like vesicles in the enlarged endometrial cavity. Microscopic examination revealed hydropically degenerated villi with circumferential hyperplasia of atypical trophoblast and cistern formation. p57(kip2) immnostaining was negative in villous cytotrophoblasts and stromal cells. Moreover, fluorescent in situ hybridization for HER2 was scored as diploid. These findings are consistent with complete hydatidiform mole. The diagnosis of hydatidiform mole must be considered in perimenopausal women, and the combination of p57(kip2) immunostaining and HER2 fluorescent in situ hybridization seems to be a very useful testing strategy for difficult situations regarding the differential diagnosis of completed and partial hydatidiform mole. PMID- 22197174 TI - Destination memory in Alzheimer's Disease: when I imagine telling Ronald Reagan about Paris. AB - Destination memory refers to remembering the destination of information that people output. This present paper establishes a new distinction between external and internal processes within this memory system for both normal aging and Alzheimer's Disease (AD). Young adults, older adults, and mild AD patients were asked either to tell facts (i.e., external destination memory condition) or to imagine telling facts (i.e., internal destination memory condition) to pictures of famous people. The experiment established three major findings. First, the destination memory performance of the AD patients was significantly poorer than that of older adults, which in turn was poorer than that of the young adults. Furthermore, internal destination processes were more prone to being forgotten than external destination memory processes. In other words, participants had more difficulty in remembering whether they had previously imagined telling the facts to the pictures or not (i.e., imagined condition) than in remembering whether they had previously told the facts to the pictures or not (i.e., enacted condition). Second, significant correlations were detected between performances on destination memory and several executive measures such as the Stroop, the Plus Minus and the Binding tasks. Third, among the executive measures, regression analyses showed that performance on the Stroop task was a main factor in explaining variance in destination memory performance. Our findings reflect the difficulty in remembering the destination of internally generated information. They also demonstrate the involvement of inhibitory processes in destination memory. PMID- 22197175 TI - A cohort study of preweaning piglet mortality and farrowing accommodation on 112 commercial pig farms in England. AB - A cohort study was carried out on 112 breeding pig farms in England to investigate the impact of type of farrowing accommodation on preweaning mortality in piglets. Four types of farrowing accommodation were studied; farrowing crates, indoor loose pens, crate/loose systems (where the sow was restrained in a crate during birth and the first days of lactation before being moved to a loose pen) and outdoor farrowing in arcs in paddocks. Four estimates of preweaning mortality were collected: an oral estimate from the farmer before the visit, an estimate from the 6-month rolling average from computer records, records from 20 litters observed when the farm was visited and prospective records collected from 20 farrowings after the visit. These four estimates were significantly correlated. The prospective records also included a farmer reported date and cause of death. From the prospective data there were 25,031 piglets from 2143 litters from 112 farms, 6.5% of piglets were stillborn while live born preweaning mortality was 12%. Mixed effect discrete time survival, binomial and competing risk, models were used to investigate the association between preweaning mortality and farrowing accommodation, controlling for sow parity, litter size and number of piglets stillborn and fostered. There was a reduced risk of stillbirths in outdoor farrowing systems compared with crated systems. Farmers reported that crushing of healthy piglets was the most frequent cause of death accounting for 55% of live born preweaning mortality. There was no significant difference in mortality in live born piglets by farrowing system. There was a significantly higher risk of farmer reported crushing of healthy live born piglets in outdoor arcs compared with piglets reared with sows in farrowing crates and a significantly reduced risk of death from causes other than crushing in piglets reared outdoors or in crate/loose systems compared with piglets reared in crated systems. We conclude that, in the farms in this study, farrowing crates reduced the risk of preweaning live born mortality attributable to crushing but piglets in this system were at increased risk of death from other causes. Consequently crates had no significant effect on overall preweaning mortality percentage. In all four commercial production systems; outdoor, farrowing crates, crate/loose farrowing systems and indoor loose housed systems, there were similar levels of mortality. PMID- 22197176 TI - A genetic playground for enhancing grain number in cereals. AB - Improving the yield stability of cereal crops with a view to bolstering global food security is an important priority. The components of final grain number per plant at harvest are determined by fertile spikes per plant, number of fertile spikelets per spike and number of grains per spikelet. In this review article, we focus on the genetic factors of floral development and inflorescence architecture known to influence grain number and provide a broad overview of genes and genetic pathways that potentially can be manipulated to increase the yield of cereal crops, in particular wheat (Triticum aestivum) and barley (Hordeum vulgare). In addition, we discuss the outcome of multidisciplinary genomics knowledge to identify potential gene targets to develop conceptual ideotypes to meet the future demand. PMID- 22197177 TI - Tissue factor/TFPI and blood cells. AB - Vascular injury-induced access of blood to tissue factor (TF) leads to the formation of a TF-FVII/FVIIa complex and the triggering of blood coagulation. The activated TF-dependent pathway is regulated by Tissue Factor Pathway Inhibitor (TFPI), which binds and inhibits FXa, but more importantly forms an inactive quaternary complex with TF-FVIIa-FXa, effectively shutting off the TF activity. The old view of TF residing in extravascular sites exclusively has recently been challenged by several reports on TF expression in various blood cells. The latter arena has unfortunately been marred by many contradictions, apparently related to inferior tools and/or study design, notably the widespread use of antibodies with inferior and misleading specificity and TF activity assays of low sensitivity/specificity. Our own studies along with many other reports, compels the conclusion that in blood of healthy individuals TF is exclusively associated with and expressed in circulating monocytes. In this short review the distribution of TF and TFPI in blood is discussed. PMID- 22197179 TI - Animal models of trauma-induced coagulopathy. AB - Resurgent study of trauma-induced coagulopathy (TIC) has delivered considerable improvements in survival after injury. Robust, valid and clinically relevant experimental models of TIC are essential to support the evolution of our knowledge and management of this condition. The aims of this study were to identify and analyze contemporary animal models of TIC with regard to their ability to accurately characterize known mechanisms of coagulopathy and/or to test the efficacy of therapeutic agents. A literature review was performed. Structured search of the indexed online database MEDLINE/PubMed in July 2010 identified 43 relevant articles containing 23 distinct animal models of TIC. The main aim of 26 studies was to test a therapeutic and the other 17 were conducted to investigate pathophysiology. A preponderance of porcine models was identified. Three new models demonstrating an endogenous acute traumatic coagulopathy (ATC) have offered new insights into the pathophysiology of TIC. Independent or combined effects of induced hypothermia and metabolic acidosis have been extensively evaluated. Recently, a pig model of TIC has been developed that features all major etiologies of TIC, although not in correct chronological order. This review identifies a general lack of experimental research to keep pace with clinical developments. Tissue injury and hemorrhagic shock are fundamental initiating events that prime the hemostatic system for subsequent iatrogenic insults. New animal models utilizing a variety of species that accurately simulate the natural clinical trajectory of trauma are urgently needed. PMID- 22197178 TI - Heparin modulates the conformation and signaling of platelet integrin alphaIIbbeta3. AB - INTRODUCTION: The glycosaminoglycan heparin has been shown to bind to platelet integrin alphaIIbbeta3 and induce platelet activation and aggregation, although the relationship between binding and activation is unclear. We analyzed the interaction of heparin and alphaIIbbeta3 in detail, to obtain a better understanding of the mechanism by which heparin acts on platelets. METHODS: We assessed conformational changes in alphaIIbbeta3 by flow cytometry of platelets exposed to unfractionated heparin. In human platelets and K562 cells engineered to express alphaIIbbeta3, we assayed the effect of heparin on key steps in integrin signaling: phosphorylation of the beta3 chain cytoplasmic tail, and activation of src kinase. We measured the heparin binding affinity of purified alphaIIbbeta3, and of recombinant fragments of alphaIIb and beta3, by surface plasmon resonance. RESULTS AND CONCLUSIONS: Heparin binding results in conformational changes in alphaIIbbeta3, similar to those observed upon ligand binding. Heparin binding alone is not sufficient to induce tyrosine phosphorylation of the integrin beta3 cytoplasmic domain, but the presence of heparin increased both beta3 phosphorylation and src kinase activation in response to ligand binding. Specific recombinant fragments derived from alphaIIb bound heparin, while recombinant beta3 did not bind. This pattern of heparin binding, compared to the crystal structure of alphaIIbbeta3, suggests that heparin-binding sites are located in clusters of basic amino acids in the headpiece and/or leg domains of alphaIIb. Binding of heparin to these clusters may stabilize the transition of alphaIIbbeta3 to an open conformation with enhanced affinity for ligand, facilitating outside-in signaling and platelet activation. PMID- 22197180 TI - Diabetes mellitus and thrombosis. AB - Atherothrombosis is the leading cause of morbidity and mortality in patients with diabetes mellitus. Several mechanisms contribute to the diabetic prothrombotic state, including endothelial dysfunction, coagulative activation and platelet hyper-reactivity. In particular, diabetic platelets are characterised by dysregulation of several signaling pathways leading to enhanced adhesion, activation and aggregation. These alterations result from the interaction among hyperglycemia, insulin resistance, inflammation and oxidative stress. This review will provide an overview of the current status of knowledge on mechanisms of accelerated atherothrombosis in patients with diabetes mellitus. PMID- 22197181 TI - Factor XIII, clot structure, thrombosis. AB - Blood coagulation factor XIII (FXIII) is a tetrameric protein consisting of two catalytic A (FXIII-A) and two carrier/inhibitory B (FXIII-B) subunits. It is a zymogen, which becomes transformed into an active transglutaminase (FXIIIa) in the final phase of coagulation cascade by thrombin and Ca(2+). FXIII is essential for hemostasis, its deficiency results in severe bleeding diathesis. FXIIIa mechanically stabilizes fibrin by cross-linking its alpha-, and gamma-chains. It also protects newly formed fibrin from fibrinolysis, primarily by cross-linking alpha(2)-plasmin inhibitor to fibrin. Beside the above prothrombotic effects, it is involved in limiting thrombus growth by down-regulating platelet adhesion to fibrin. Elevated FXIII level seems to be a gender-specific risk factor of both coronary artery disease and peripheral arterial disease, it represents an increased risk only in females. The association of FXIII level with the risk of ischemic stroke and venous thromboembolism was investigated only in a few studies from which no clear conclusion could be drawn. Among the FXIII subunit polymorphisms, concerning their effect on the risk of thrombotic diseases, only FXIII-A p.Val34Leu was investigated extensively. Meta-analyses of reported data suggest that this polymorphism provides a moderate protection against coronary artery disease and venous thromboembolism, but not against ischemic stroke. Gene gene and gene-environmental interactions might modify its effect. Further studies are required to explore the effect of other FXIII subunit polymorphism on the risk of thrombotic diseases. PMID- 22197182 TI - Teres major muscle tear in two professional ice hockey players: cases study and literature review. AB - Ice hockey is a sport renowned for its numerous injuries; different studies report between 13.8 and 20 lesions per 1000 athlete exposures. Exactly 65.5% of these injuries occur during games, compared to 34.5% during training sessions. And 35.1% of all injuries involve the lower extremity and 29.7% the upper extremity (results drawn from games and training combined). Determining whether muscle injuries are extrinsic (contusions) or intrinsic (tears) is of utmost importance since the former generally require simple follow-up, whereas the latter necessitates further investigations, appropriate treatment and often prolonged absence from sports for the injured athlete. To our knowledge, no publication to date has reported isolated damage of the teres major muscle in Ice Hockey players. Seven cases were reported amongst baseball pitchers. Two cases presented after a waterskiing traction accident and a further case has been described in a tennis player. In the present study, we report two cases of isolated teres major tear in ice hockey players. These two athletes were both professional players competing at the highest level in the Swiss Ice Hockey League. PMID- 22197183 TI - Ultra-low dose of Mycobacterium tuberculosis aerosol creates partial infection in mice. AB - A murine low dose (LD) aerosol model is commonly used to test tuberculosis vaccines. Doses of 50-400 CFU (24h lung CFU) infect 100% of exposed mice. The LD model measures progression from infection to disease based on organ CFU at defined time points. To mimic natural exposure, we exposed mice to an ultra-low dose (ULD) aerosol. We estimated the presented dose by sampling the aerosol. Female C57BL/6 mice were exposed to Mycobacterium tuberculosis H37Rv aerosol at 1.0, 1.1, 1.6, 5.4, and 11 CFU presented dose, infecting 27%, 36%, 36%, 100%, and 95% of mice, respectively. These data are compatible with a stochastic infection event (Poisson distribution, weighted R(2)=0.97) or with a dose-response relationship (sigmoid distribution, weighted R(2)=0.97). Based on the later assumption, the ID50 was 1.6CFU presented dose (95% confidence interval, 1.2 2.1). We compared organ CFU after ULD and LD aerosols (5.4 vs. 395CFU presented dose). Lung burden was 30-fold lower in the ULD model at 4 weeks (3.4 vs. 4.8 logs, p<0.001) and 18 weeks (<=3.6 vs. 5.0 logs, p=0.01). Mice exposed to ULD aerosols as compared to LD aerosols had greater within-group CFU variability. Exposure to ULD aerosols leads to infection in a subset of mice, and to persistently low organ CFU. The ULD aerosol model may resemble human pulmonary tuberculosis more closely than the standard LD model, and may be used to identify host or bacterial factors that modulate the initial infection event. PMID- 22197184 TI - Wartime spine injuries: understanding the improvised explosive device and biophysics of blast trauma. AB - The improvised explosive device (IED) has been the most significant threat by terrorists worldwide. Blast trauma has produced a wide pattern of combat spinal column injuries not commonly experienced in the civilian community. Unfortunately, explosion-related injuries have also become a widespread reality of civilian life throughout the world, and civilian medical providers who are involved in emergency trauma care must be prepared to manage casualties from terrorist attacks using high-energy explosive devices. Treatment decisions for complex spine injuries after blast trauma require special planning, taking into consideration many different factors and the complicated multiple organ system injuries not normally experienced at most civilian trauma centers. Therefore, an understanding about the effects of blast trauma by spine surgeons in the community has become imperative, as the battlefield has been brought closer to home in many countries through domestic terrorism and mass casualty situations, with the lines blurred between military and civilian trauma. We set out to provide the spine surgeon with a brief overview on the use of IEDs for terrorism and the current conflicts in Iraq and Afghanistan and also a perspective on the biophysics of blast trauma. PMID- 22197185 TI - Muscle fatigue--from motor units to clinical symptoms. AB - Reductionist approaches have provided little insight on the fatigue experienced by humans during activities of daily living. Some of the reasons for this lack of progress include the persistence of outdated concepts, the misinterpretation of experimental recordings, and a failure to embrace a global perspective on fatigue. This paper summarizes the three examples of these limitations that were discussed in the 2011 Muybridge Award lecture: motor unit types and muscle fatigue, myoelectric manifestations of fatigue, and fatigue and fatigability. Although the motor units in a population do exhibit a range of fatigability values, there are not distinct groups of motor units and the concept that some motor units are resistant to fatigue emerged from protocols in which motor units were activated by electrical stimulation rather than voluntary activation. The concept of distinct motor unit types should be abandoned. The second example discussed in the lecture was the use of surface EMG signals to assess fatigue related adjustments in motor unit activity. The critical assumption with this approach is that the association between surface EMG amplitude and muscle force remains constant during fatiguing contractions. Unfortunately, the relation does not remain constant and a series of computational studies demonstrate the magnitude of the discrepancy, including the absence of an association with the activation signal emerging from the spinal cord and that received by the muscle. The third example concerned the concepts of fatigue and fatigability. It has long been recognized that fatigue involves both sensations and impairments in motor function, and the final part of the lecture urged the integration of the two constructs into a single scheme in which fatigue can be modulated either independently or by interactions between perceptions of fatigue and the mechanisms that establish levels of fatigability. The expectation is that such critical evaluations of the concepts and approaches to the study of fatigue will provide a more effective foundation from which to identify the factors that contribute to fatigue in health and disease. PMID- 22197186 TI - Intervertebral disc viscoelastic parameters and residual mechanics spatially quantified using a hybrid confined/in situ indentation method. AB - With advancing age, injury, musculoskeletal pathology or a combination of these, a degenerative cascade of biomechanical, biochemical, and nutritional alterations diminish the intervertebral discs' ability to maintain its structure and function. While the biomechanics of isolated disc tissues has been investigated across this degenerative spectrum, none have attempted to retain the in situ disc endplate morphology during compressive tissue characterization. The objective of this study was to spatially quantify the viscoelastic parameters of the intervertebral disc throughout degeneration, including the as yet unreported residual stress/strain. This required the development of a hybrid confined/in situ indentation methodology, which preserves the disc structural morphology. At four locations of the disc (anterior-AF, right and left lateral AF, and NP) stress-relaxation tests were performed using the hybrid confined/in situ indentation method, which utilizes the vertebral endplate as the porous indenter tip. This method allows the endplate to remain interwoven with the disc tissue, retaining its native orientation. Healthy disc tissue exhibited significantly higher residual stress values compared to both moderate and severe degeneration in all locations (p<0.0156). Furthermore, the equilibrium stress at 15% strain (stress relaxation) was significantly diminished with advancing disc degeneration (p<0.0241). The equilibrium viscoelastic parameters show healthy discs encounter higher forces at the same strain level, and are able to maintain this force, where degenerated discs are unable to maintain this force throughout time. This morphology-conserved method provides insight into the spatial compressive mechanical properties of the intervertebral disc across the degeneration spectrum and will aid in modeling these tissue changes. PMID- 22197187 TI - A Becker myotonia patient with compound heterozygosity for CLCN1 mutations and Prinzmetal angina pectoris. AB - Becker myotonia is a recessive muscle disease with prevalence of > 1:50,000. It is caused by markedly reduced function of the chloride channel encoded by CLCN1. We describe a Polish patient with severe myotonia, transient weakness, and muscle cramps who only responds to lidocaine. In addition, the patient has Prinzmetal angina pectoris and multiple lipomatosis. He is compound heterozygeous for a novel p.W303X and a frequent p.R894X CLCN1 mutation. CLCN1 exon number variation was excluded by MLPA. His son with latent myotonia was heterozygeous for p.R894X. We discuss the potential relations of the three rare diseases and the inheritance of p.R894X. PMID- 22197188 TI - A missense mutation in the skeletal muscle chloride channel 1 (CLCN1) as candidate causal mutation for congenital myotonia in a New Forest pony. AB - A 7-month-old New Forest foal presented for episodes of recumbency and stiffness with myotonic discharges on electromyography. The observed phenotype resembled congenital myotonia caused by CLCN1 mutations in goats and humans. Mutation of the CLCN1 gene was considered as possible cause and mutation analysis was performed. The affected foal was homozygous for a missense mutation (c.1775A>C, p.D592A) located in a well conserved domain of the CLCN1 gene. The mutation showed a recessive mode of inheritance within the reported pony family. Therefore, this CLCN1 polymorphism is considered to be a possible cause of congenital myotonia. PMID- 22197189 TI - Comparison of the Cobas 4800 Human Papillomavirus test against a combination of the Amplicor Human Papillomavirus and the Linear Array tests for detection of HPV types 16 and 18 in cervical samples. AB - The greater prevalence of human papillomavirus (HPV) types 16 and 18 compared to the other high-risk HPV types of cervical cancer led to the development of clinical tests that detect both types separately from other genotypes. One method is the Roche Cobas 4800 HPV test, which is based on a real-time PCR. The aim of this study was to evaluate the performance of the Cobas 4800 HPV test for detecting genotypes 16 and 18 by comparing the results with those obtained in a combination of the Roche Amplicor HPV assay and the Roche Linear Array (LA) HPV genotyping assay. Excellent concordance was found between both methods (92.7%, kappa value=0.872). The Cobas 4800 HPV test could be used as a single test for identifying HPV types 16 and 18 directly from clinical specimens. PMID- 22197191 TI - Efficient theory of dipolar recoupling in solid-state nuclear magnetic resonance of rotating solids using Floquet-Magnus expansion: application on BABA and C7 radiofrequency pulse sequences. AB - This article describes the use of an alternative expansion scheme called Floquet Magnus expansion (FME) to study the dynamics of spin system in solid-state NMR. The main tool used to describe the effect of time-dependent interactions in NMR is the average Hamiltonian theory (AHT). However, some NMR experiments, such as sample rotation and pulse crafting, seem to be more conveniently described using the Floquet theory (FT). Here, we present the first report highlighting the basics of the Floquet-Magnus expansion (FME) scheme and hint at its application on recoupling sequences that excite more efficiently double-quantum coherences, namely BABA and C7 radiofrequency pulse sequences. The use of Lambda(n)(t) functions available only in the FME scheme, allows the comparison of the efficiency of BABA and C7 sequences. PMID- 22197190 TI - Development of a recombinant ELISA using yeast (Pichia pastoris)-expressed polypeptides for detection of antibodies against avian influenza A subtype H5. AB - Two truncated sequences (designated P1 and rHA1) of influenza A virus subtype H5 haemagglutinin (HA) were cloned and expressed in yeast Pichia pastoris (P. pastoris). These polypeptides were used in an indirect recombinant ELISA (rELISA) for detection of H5 antibodies in poultry. Serum samples obtained from broiler chickens vaccinated with commercial inactivated vaccine (H5N2) and control negative sera from non-vaccinated chickens against influenza were tested using rP1-ELISA, rHA1-ELISA, whole H5N1-ELISA, Western blot, agar gel immunodiffusion (AGID) and haemagglutination inhibition (HI) tests. The rHA1-ELISA proved to be highly sensitive and specific. To study the validity of rHA1-ELISA, a total of 179 serum samples obtained from commercial broiler chickens vaccinated previously with commercial H5N2 inactivated vaccines, were tested by rHA1-ELISA, commercial ELISA (cELISA) and HI. The relative sensitivity and specificity between rHA1 ELISA, and HI tests were 100% and 70%, respectively, and between cELISA and HI were 100% and 57%, respectively. The agreement ratio between rHA1-ELISA and HI was 84.9% and between cELISA and HI tests was 76.5%. Serum samples obtained from ducks vaccinated with commercial inactivated H5N2 were tested by rHA1-ELISA and the results showed significant reactivity with duck sera. In conclusion, the results demonstrate the potential applicability of the rELISA for the determination of antibodies to H5 influenza virus in chickens and ducks. PMID- 22197192 TI - [Should the treatment of anal carcinoma be adapted in the elderly? A retrospective analysis of acute toxicities in a French centre and a review of the literature]. AB - PURPOSE: To study the tolerance to radiotherapy, with or without chemotherapy, followed by brachytherapy, in elderly patients (75 years or older) suffering from anal cancer. PATIENTS AND METHODS: We treated 12 elderly patients with a curative intent. Median age was 78 years (range: 75-90). Ten patients had a stage II or IIIA (UICC 2009) tumour and six out of 12 were N+. Taking into account the age, the Eastern Cooperative Oncology Group (ECOG) performance status and comorbidities, five patients received exclusive radiotherapy ("RT group") and seven a concomitant radiochemotherapy ("RT-CT group"). All patients received a boost by interstitial brachytherapy. One patient of the "RT-CT group" presented rectorragies during brachytherapy. The irradiation was completed by external beam radiotherapy focalized on the tumour volume. RESULTS: Grade 3 acute reactions (Radiation Therapy Oncology Group [RTOG]) were reported in three out of 12 patients. One grade 2-3 leucopoenia was observed in one out of 7 patients ("RT-CT group"). After brachytherapy, one grade 3 rectal toxicity (rectorragia) (in "RT group") and one grade 4 (in "RT-CT group") were observed. One patient ("RT-CT group") presented a late grade 3 rectal toxicity (evaluated only for patients with at least 12 months of follow-up). CONCLUSIONS: Concomitant radiochemotherapy followed by brachytherapy showed an acceptable toxicity profile, and seems to be adapted in selected elderly patients. It could be recommended as reference treatment in elderly patients with a good physiological status. PMID- 22197193 TI - [In vitro activity of tigecycline on 760 bacterial strains isolated in the hospital university of Angers--2006-2009 TEST study]. AB - Tigecycline (TGC), an antibiotic belonging to glycylcyclines, is active against Gram-positive bacteria, including multi-resistant bacteria, and most of the Gram negative bacteria, including extended spectrum beta-lactamase-producers (ESBL) and Acinetobacter sp. TGC is not active on Pseudomonas aeruginosa. The microbiological laboratory from the university hospital of Angers participates in the Tigecycline Evaluation and Surveillance Trial (TEST) since 2006. The objective of this study is to evaluate the effectiveness of TGC and of various comparators against nosocomial and community-acquired pathogens. We also evaluated the effectiveness of TGC on a panel of strains isolated between 2006 and 2009 in the university hospital of Angers. Minimum inhibitory concentrations (MIC) were determined using the microdilution method. A total of 760 clinical strains were tested. TGC had a very good activity against Gram-positive bacteria, with 100 % of susceptibility for all the strains tested, irrespective of their resistance profile. Concerning Gram-negative bacteria, TGC was active against 93 % of Enterobacteriaceae, with a MIC 90 not exceeding 2mg/L. Whole of the 20 strains ESBL-producers tested were susceptible to TGC. Acinetobacter sp. were also inhibited at low concentrations of TGC, with a MIC 90 of 1mg/L. These results suggest that TGC can be a useful therapeutic alternative, especially for infections involving multiresistant bacteria. PMID- 22197194 TI - [Association of HLA class I antigens with Behcet disease in South Tunisia]. AB - PURPOSE: To study antigen HLA class I association with different clinical forms of Behcet's disease in South Tunisian population. PATIENTS AND METHODS: We retrospectively reviewed 129 clinical case patients. All of the patients fulfilled the criteria of the international study group for Behcet's disease, and were followed at the department of internal medicine of the university hospital of Sfax. HLA class I phenotyping was performed by microlymphocytotoxicity complement dependent for our 129 patients and for 123 healthy controls. We used the program SPSS 11.0 to analyse clinical data and to compare HLA class I antigen distribution between these two populations. RESULTS: The study group concerned a total of 129 patients (81 males and 48 females). The mean age at disease onset was of 32 years. HLA-B51 antigen was the only antigen significantly more frequent among patients (24.81%) than controls (9.76%, p=0.002). HLA-B44 was significantly more frequent among patients having familial history of recurrent buccal aphthosis or Behcet disease. HLA-A11 antigen was associated with early disease onset, and HLA-A1 was negatively associated with severe form of the disease (neurological, vascular or ocular manifestations). CONCLUSION: Our study confirmed the HLA-B51 association with Behcet disease. Nevertheless, B51 frequency in South Tunisian patients was lower than that found in other studies regardless of the clinical manifestation. PMID- 22197195 TI - A case of rapid diagnosis of Boerhaave syndrome by thoracic drainage. AB - BACKGROUND: Boerhaave syndrome is a rare and often fatal syndrome. Delayed diagnosis and treatment is closely associated with prolonged morbidity and increased mortality. In general, esophagography is usually chosen as the diagnostic procedure, but it has a relatively high false-negative rate. There are no reports, to our knowledge, regarding the efficacy of thoracic drainage, although it is easier to perform and more immediate than esophagography in the emergency department. OBJECTIVES: To report the efficacy of thoracic drainage for rapid diagnosis and treatment of Boerhaave syndrome. CASE REPORT: An 80-year-old woman was admitted with vomiting and sudden onset of postprandial chest pain radiating to the back. Initially, myocardial infarction or aortic dissection was suspected, but was excluded by point-of-care tests and computed tomography (CT) scan, which revealed a left-sided pneumothorax, heterogeneous left pleural effusion, and pneumomediastinum at the lower level of the esophagus. Boerhaave syndrome was suspected and confirmed by thoracic drainage, which drained off bloody fluid and residual food such as broccoli. Emergency thoracotomy was performed within 4 h after onset of symptoms. The patient made an uneventful recovery. CONCLUSION: Findings in this case indicate that chest pain, left-sided massive effusion on chest radiography, and left-sided massive heterogeneous effusion on CT scan are important for the diagnosis of Boerhaave syndrome. Subsequent thoracic drainage is useful for confirming Boerhaave syndrome, and such a strategy might lead to a good prognosis for patients with this rare but critical disease. PMID- 22197196 TI - Destructive cervical spine osteoblastoma at C5 in a young patient initially presenting with quadriparesis: case report and review of the literature. AB - BACKGROUND: Osteoblastomas are rare benign bone tumors that are mostly found in the posterior spinal elements; about 20% are located in the cervical spine. OBJECTIVE: The case of a destructive cervical osteoblastoma at C5 is reported in a 19-year-old man who initially presented with spastic quadriparesis. CASE REPORT: A 19-year-old man was self-referred, reporting symptoms in keeping with a progressive spastic quadriparesis, which had suddenly developed 6 days earlier. Preceding symptoms included mild non-specific neck pain for 3 weeks. The patient was afebrile, and no ambulatory X-ray study had been performed until the time of referral. A cervical spine computed tomography (CT) scan revealed a lytic lesion involving the spinal process and the pedicles of the C5 vertebra. Cervical spine magnetic resonance imaging performed on an inpatient basis revealed a well circumscribed, destructive lesion of the C5 vertebra, measuring approximately 3 cm. The spinal cord was significantly compressed. The patient underwent open surgical resection of the tumor through a midline posterior approach. Histopathology of the tumor specimen was in keeping with a diagnosis of osteoblastoma. CONCLUSION: Neuroimaging should be performed with either conventional plain X-ray study, which seems to be sufficient in patients presenting with non-specific symptomatology related to cervical spine damage, or with advanced techniques in the case of patients with persistent neck pain or neurological deficit. PMID- 22197197 TI - The dilated vestibular aqueduct: a diagnosis not to be missed. PMID- 22197198 TI - Medical reconciliation in patients discharged from the emergency department. AB - BACKGROUND: Medication errors are considered to be a significant cause of morbidity and mortality. For each patient, emergency departments (EDs) are expected to compile a list of medications, reconcile them, and pass them along to the next provider. The electronic medical record provides a method to automatically capture and propagate what may be incorrect information. OBJECTIVES: The aim of this study was to compare the medication information that patients ultimately discharged from the ED provide to the ED staff vs. the medication information the patients provide at follow-up, and to classify and quantify the types of discrepancies between the two. METHODS: We conducted a retrospective descriptive study of a convenience sample of 36 patients who were discharged from the ED and who reported taking five or more medications. Discrepancies were identified by comparing information collected at the time of the index ED visit with that gleaned from follow-up contact within 7 days of discharge. RESULTS: Of the 36 charts analyzed, 286 medications were provided by patients at the time of their ED visit. Subsequent determination of actual medication use on follow-up found 120 discrepancies, for a discrepancy rate of 42.0% (95% confidence interval [CI] 36.4-47.8%). One or more discrepancies were found on 86.1% of charts (95% CI 74.8-97.4%). CONCLUSIONS: Frequent discrepancies are found in the medication information that patients provide in the ED. Requiring the ED to reconcile medication information and to pass it on to the next provider can be a source of treatment errors in the outpatient setting. PMID- 22197199 TI - Does a simple bedside sonographic measurement of the inferior vena cava correlate to central venous pressure? AB - BACKGROUND: Bedside ultrasound has been suggested as a non-invasive modality to estimate central venous pressure (CVP). OBJECTIVE: Evaluate a simple bedside ultrasound technique to measure the diameter of the inferior vena cava (IVC) and correlate to simultaneously measured CVP. Secondary comparisons include anatomic location, probe orientation, and phase of respiration. METHODS: An unblinded prospective observation study was performed in an emergency department and critical care unit. Subjects were a convenience sample of adult patients with a central line at the superior venocaval-atrial junction. Ultrasound measured transverse and longitudinal diameters of the IVC at the subxiphoid, suprailiac, and mid-abdomen, each measured at end-inspiration and end-expiration. Correlation and regression analysis were used to relate CVP and IVC diameters. RESULTS: There were 72 subjects with a mean age of 67 years (range 21-94 years), 37 (53%) male, enrolled over 9 months. Seven subjects were excluded for tricuspid valvulopathy. Primary diagnoses were: respiratory failure 12 (18%), sepsis 11 (17%), and pancreatitis 3 (5%). There were 28 (43%) patients mechanically ventilated. Adequate measurements were obtainable in 57 (89%) using the subxiphoid, in 44 (68%) using the mid-abdomen, and in 28 (43%) using the suprailiac views. The correlation coefficients were statistically significant at 0.49 (95% confidence interval [CI] 0.26-0.66), 0.51 (95% CI 0.23-0.71), and 0.50 (95% CI 0.14-0.74) for end-inspiratory longitudinal subxiphoid, midpoint, and suprailiac views, respectively. Transverse values were statistically significant at 0.42 (95% CI 0.18-0.61), 0.38 (95% CI 0.09-0.61), and 0.67 (95% CI 0.40-0.84), respectively. End-expiratory measurements gave similar or slightly less significant values. CONCLUSION: The subxiphoid was the most reliably viewed of the three anatomic locations; however, the suprailiac view produced superior correlations to the CVP. Longitudinal views generally outperformed transverse views. A simple ultrasound measure of the IVC yields weak correlation to the CVP. PMID- 22197200 TI - Memory rehabilitation and brain training for surgical temporal lobe epilepsy patients: a preliminary report. AB - The short term impact of a memory rehabilitation programme on verbal memory test performance and subjective ratings of memory in everyday life was assessed in healthy controls and left temporal lobe epilepsy (LTLE) surgical patients. The intervention involved training in the use of external and internal memory support strategies. Half of the sample in addition undertook computerised brain training exercises as homework. LTLE patients were seen either before surgery or 3-6 months after their operation. Improvements in verbal memory were observed in both groups. An effect of brain training was recorded but this did not occur in a consistent direction. Subjective ratings of memory indicated improvements that were significant for the LTLE group but not the controls. Positive changes in the memory outcome measures were associated with improvements in mood. Pre-operative memory rehabilitation was not associated with better outcomes than post-operative intervention. Further research is needed to explore the persistence of the changes observed and to explore if pre-operative rehabilitation offsets post operative memory decline. PMID- 22197201 TI - [NSAIDS and cardiovascular risk]. PMID- 22197202 TI - Hand hygiene prior to contact lens handling is problematical. AB - PURPOSE: To establish guidelines for contact lens wearers' hand hygiene practices which achieve a balance between minimising risk of infection and reasonable expectations on the ability of patients to follow them. METHODS: Evidence has been obtained from publications via PubMed, Advanced Medline Search, Cochrane Reviews, Google Scholar and using the key words hand hygiene, washing and contact lens. RESULTS: Guidelines for effective hand washing and the bother involved vary according to the level of hygiene required. High levels of non-compliance with hand hygiene practices, even among healthcare workers, gives an indication of how important the level of bother involved when following guidelines can be in contributing to non-compliance. CONCLUSIONS: Better patient education to improve hand washing techniques as well as patient attitudes toward hand hygiene are needed to reduce high non-compliance levels. Better hand hygiene techniques and higher frequency of their application give the prospect of reduced risk of infection and of any discomfort that arises from increased lens and ocular bioburden. In order that adoption rates might be maximised, the guidelines which have been distilled from this review attempt to strike a balance between technique redundancy and the associated higher levels of hygiene achieved and the possibility that the perception of too much bother involved could reduce participation rates. The guidelines have been expanded by the inclusion of suggested explanatory information in the expectation that helping patients to understand why the recommendations are made will have the effect of increasing their adoption. PMID- 22197203 TI - Pharmacological effect of TRK-380, a novel selective human beta3-adrenoceptor agonist, on mammalian detrusor strips. AB - OBJECTIVE: To clarify the potential of TRK-380 as a drug for overactive bladder in humans by evaluating the agonistic activities for human beta-adrenergic receptors (beta-ARs) and the relaxing effects on isolated detrusor strips. METHODS: The agonistic activities for human beta-ARs were evaluated in SK-N-MC cells (for human beta(3)-ARs) and Chinese hamster ovary cells expressing human beta(1)- or human beta(2)-ARs using the cyclic adenosine monophosphate accumulation assay. The relaxing effects on the resting tension in isolated detrusor strips from humans, monkeys, dogs, and rats and on carbachol- or KCl induced contractions in human detrusor strips were evaluated. RESULTS: In the cyclic adenosine monophosphate accumulation assay, the agonistic activity of TRK 380 for human beta(3)-ARs was potent and equivalent to that of the potent nonselective beta-AR agonist isoproterenol and superior to that of selective beta(3)-AR agonists, such as BRL-37344 and CL316,243. TRK-380 showed no agonistic activity for human beta(1)-ARs and a weak agonistic effect on human beta(2)-ARs. In isolated detrusor strips, the concentration-dependent relaxing effects of TRK 380 on the resting tension were equivalent to those of isoproterenol in humans, monkeys, and dogs but weaker than the effects in rats. The selective beta(3)-AR antagonist SR59230A shifted the concentration-response curve in a concentration dependent manner to TRK-380 for the resting tension of human detrusor strips to the right. TRK-380 had a concentration-dependent relaxing effect on the contractile responses to carbachol and KCl in human detrusor strips. CONCLUSION: TRK-380 was a potent and selective human beta(3)-AR agonist, and the isolated human detrusor relaxation was mainly mediated by activation of the beta(3)-AR. Consequently, TRK-380 might be a promising compound for the treatment of overactive bladder. PMID- 22197205 TI - Expression and alpha1-adrenoceptor regulation of caldesmon in human prostate smooth muscle. AB - OBJECTIVE: To investigate expression and alpha1-adrenergic regulation of caldesmon in the human prostate. Caldesmon is an important mediator and regulator of contraction in different smooth muscle types. However, this has not been investigated in the prostate to date. The activity of caldesmon may be tightly regulated by serine-789 phosphorylation. MATERIALS AND METHODS: Prostate tissue was obtained from patients undergoing radical prostatectomy. Caldesmon expression was studied by Western blot analysis and immunohistochemistry. The adrenergic regulation of caldesmon phosphorylation was investigated by Western blot analyses with a site- and phosphospecific antibody. RESULTS: Caldesmon expression was detectable by Western blot analysis in all investigated samples of human prostates (n = 8 patients). Immunoreactivity after staining with a caldesmon antibody was strong in smooth muscle cells, but not observed in glandular or epithelial cells (n = 5 patients). In double fluorescence staining, caldesmon co localized with alpha1A-adrenoceptors and alpha-smooth muscle actin (n = 6 patients). Stimulation of prostate tissue with noradrenaline (30 MUM, n = 6 patients) or the alpha1-adrenergic agonist phenylephrine (10 MUM, n = 6 patients) resulted in progressive phosphorylation of caldesmon at serine-789. Noradrenaline induced caldesmon phosphorylation was 1.5 +/- 0.2-fold after 5 minutes (P<.04 vs basal phosphorylation), and 1.6 +/- 0.2-fold after 10 minutes (P<.04). Phenylephrine-induced caldesmon phosphorylation was 1.7 +/- 0.2-fold after 10 minutes (P<.02 vs basal phosphorylation), and 2.4 +/- 0.6-fold after 20 minutes (P<.05). CONCLUSIONS: Caldesmon is an effector of alpha1-adrenoceptors in the human prostate. Caldesmon activation may be of importance for alpha1-adrenergic prostate contraction, and during therapy with alpha1-blockers. PMID- 22197204 TI - Label retaining and stem cell marker expression in the developing rat urinary bladder. AB - OBJECTIVE: To identify potential stem cells in urinary bladder by label-retaining cell (LRC) strategy and immunostaining for putative stem cell markers. METHODS: Newborn rats were intraperitoneally injected with 5-ethynyl-2-deoxyuridine (EdU) and their bladders harvested at 4 different time points afterward. The bladders were processed for EdU staining and immunofluorescence staining for stem cell markers Lgr5, CD34, SSEA-1, and c-kit. EdU-positive cells were counted and colocalization with stem cell markers determined. RESULTS: At day 1 post-EdU injection, 1804.0 +/- 227.7 bladder cells were labeled in each cross-section. As time increased, fewer bladders remained labeled, dropping to 236.5 +/- 53.0 cells per field. In the 1-day bladders, 27.5% +/- 4.9% of the epithelial cells were labeled as compared to 12.1% +/- 2.8% in the detrusor. The labeling rates in these 2 tissue compartments gradually equalized, reaching at approximately 5.5% in the 8-week samples. Distribution of LRC was random, without preferential labeling of basal cells. Lgr5 and SSEA-1 were detectable in the urothelium, and CD34 and c-kit in the lamina propria and detrusor. Approximately 30%-40% of c-kit positive cells were EdU positive. CONCLUSION: Labeling of bladder cells by EdU occurred randomly, and label retaining was not associated with expression of Lgr5, CD34, or SSEA-1. The strong association between label retaining and c-kit expression appears to relate to interstitial cells of Cajal, not stem cells. PMID- 22197206 TI - Service user involvement in the assessment of student nurses: a note of caution. PMID- 22197207 TI - Isolation and characterization of cyp19a1a and cyp19a1b promoters in the protogynous hermaphrodite orange-spotted grouper (Epinephelus coioides). AB - Aromatase (CYP19A1) catalyzes the conversion of androgens to estrogens. In teleosts, duplicated copies of cyp19a1 genes, namely cyp19a1a and cyp19a1b, were identified, however, the transcriptional regulation of these two genes remains poorly understood. In the present study, the 5'-flanking regions of the orange spotted grouper cyp19a1a (gcyp19a1a) and cyp19a1b (gcyp19a1b) genes were isolated and characterized. The proximal promoter regions of both genes were relatively conserved when compared to those of the other teleosts. Notably, a conserved FOXO transcriptional factor binding site was firstly reported in the proximal promoter of gcyp19a1a, and deletion of the region (-112 to -60) containing this site significantly decreased the promoter activities. The deletion of the region (-246 to -112) containing the two conserved FTZ-F1 sites also dramatically decreased the transcriptional activities of gcyp19a1a promoter, and both two FTZ-F1 sites were shown to be stimulatory cis-acting elements. A FTZ-F1 homologue isolated from ricefield eel (eFTZ-F1) up-regulated gcyp19a1a promoter activities possibly via the FTZ-F1 sites, however, a previously identified orange-spotted grouper FTZ F1 homologue (gFTZ-F1) did not activate the transcription of gcyp19a1a promoter unexpectedly. As to gcyp19a1b promoter, all the deletion constructs did not show good promoter activities in either TM4 or U251-MG cells. Estradiol (100nM) up regulated gcyp19a1b promoter activities by about 13- and 36-fold in TM4 and U251 MG cells, respectively, via the conserved ERE motif, but did not stimulate gcyp19a1a promoter activities. These results are helpful to further elucidate the regulatory mechanisms of cyp19a1a and cyp19a1b expression in the orange-spotted grouper as well as other teleosts. PMID- 22197208 TI - Further evidence on acetylation-induced inhibition of the pigment-dispersing activity of alpha-melanocyte-stimulating hormone. AB - Our previous studies showed that in barfin flounder, alpha-melanocyte-stimulating hormone (alpha-MSH) stimulates pigment dispersion in xanthophores, while it shows negligible effects in melanophores. The present study was undertaken to evaluate whether these results are limited to barfin flounder by using Japanese flounder. Three subtypes of proopiomelanocortin gene encoding melanocortins (MCs) were expressed in the Japanese flounder pituitary, one of which was also expressed in the skin. Expression of melanocortin 5 receptor gene (Mc5r) was observed in isolated xanthophores, while that of Mc1r and Mc5r was found in melanophores. In the xanthophores of Japanese flounder skin, alpha-MSH as well as desacetyl (Des Ac)-alpha-MSH and diacetyl (Di-Ac)-alpha-MSH exhibited dose-dependent pigment dispersing activities, indicating that the signals of alpha-MSH-related peptides were mediated by MC5R. On the other hand, alpha-MSH did not stimulate pigment dispersion in melanophores, while Des-Ac-alpha-MSH and Di-Ac-alpha-MSH did, thus indicating that the expression of two different types of Mcr is related to the decrease in alpha-MSH activity. Thus, the molecular repertoire in MC system observed in Japanese flounder is similar to that in barfin flounder. Moreover, the relationship between the pigment-dispersing activities of alpha-MSH-related peptides and the expression of Mcr subtypes in xanthophores and melanophores were also similar between Japanese flounder and barfin flounder. Consequently, we hypothesize that inhibition of alpha-MSH activity could be due to the formation of heterodimers comprising MC1R and MC5R, often observed in G-protein-coupled receptors. PMID- 22197209 TI - Urinary hormone metabolites identify sex and imply unexpected winter breeding in an endangered, subterranean-nesting frog. AB - Urinary hormone analysis has proved accurate for identifying sex and breeding periods in dimorphic amphibians with known reproductive cycles. We examined whether these techniques could provide this much needed information for a monomorphic anuran with an unconfirmed mating season in the wild. We analysed urinary estrone conjugate, testosterone, and progesterone metabolites to infer the time of breeding and to identify sex in the endangered Maud Island frog, Leiopelma pakeka. Testosterone metabolites in males and estrone and progesterone metabolites in females were at their peak during winter for both wild and captive frogs. These urinary metabolite patterns were consistent with the high proportion of females exhibiting enlarged ovarian follicles in winter months. Sex identification based on urinary estrone metabolite levels was 94% correct in this monomorphic species, in which the sexes overlap in snout-to-vent length (SVL) for over half of their adult size range and in which no other sexually dimorphic trait is known. The seasonal profiles imply unexpected winter or early spring breeding in L. pakeka. Overall, these results demonstrate use of urinary hormone metabolites for reproductive monitoring and sex identification in one of the world's most threatened and evolutionarily distinct amphibians. PMID- 22197210 TI - Molecular characterization, mRNA expression of prolactin receptor (PRLR) gene during pregnancy, nonpregnancy in the yak (Bos grunniens). AB - Prolactin (PRL) plays central roles in a wide range of body functions in mammals, and the actions are mediated by the specific cell surface receptor, the prolactin receptor (PRLR). To better understand the role of PRL in the yak (Bos grunniens), in the present study, we first cloned yak PRLR cDNA, and compared its mRNA expression in several tissues with cattle (Bos taurus). By reverse transcriptase polymerase chain reaction (RT-PCR) strategy, we obtained full-length of yak PRLR cDNA sequence comprised of an open reading frame of 1746bp encoding a 581 amino acid protein, and contained a signal sequence and a transmembrane region. The intracellular domain had two pairs of cysteine residues and a WSXWS motif. The cytoplasmic domain comprised 323 residues and contained box 1 sequence. The yak PRLR shared 66.0-98.5% protein sequence identity with mammalian homologs. Real time PCR analysis revealed that PRLR mRNA was higher in mammary tissue than in ovary and endometrium (P<0.01). During pregnancy, the ovary and mammary PRLR mRNA expression increased by 33- and 2.9-fold in yak, respectively, and increased by 46- and 3.8-fold in cattle, respectively. PRLR mRNA expression was higher (P<0.05) in mammary tissue and ovary of pregnant cow than that of pregnant yak. It is proposed that the increased ovarian and mammary PRLR mRNA expression during pregnancy may be associated with corpus luteum function for maintenance of pregnancy and mammary development for subsequent lactation. PMID- 22197211 TI - The eyes have it: A brief history of crustacean neuroendocrinology. AB - To help celebrate the 50th anniversary of General and Comparative Endocrinology, the history of only a small portion of crustacean endocrinology is presented here. The field of crustacean endocrinology dates back to the decades prior to the establishment of General and Comparative Endocrinology and the first article about crustacean endocrinology published in this journal was concerned with the anatomy of neurosecretory and neurohemal structures in brachyuran crabs. This review looks at the history of neuroendocrinology in crustaceans during that time and tries to put perspective on the future of this field. PMID- 22197212 TI - Atypical brain oscillations: a biological basis for dyslexia? AB - Examining rhythms in the brain reveals a biological basis for dyslexia. A new study provides evidence of atypical oscillatory patterns and hemispheric specialization in dyslexic adults. These patterns inform phonological processing and verbal memory problems, known to be core deficits in dyslexia. PMID- 22197214 TI - Quality of life and psychiatric work impairment in compulsive buying: increased symptom severity as a function of acquisition behaviors. AB - The aims of the current study were to determine if compulsive acquisition behaviors are meaningfully related to quality of life and psychiatric work impairment and to determine if compulsive buyers who engage in 2 forms of acquisition (buying and excessive acquisition of free items) are more impaired than individuals who only engage in 1 form of acquisition. In a community recruited sample, analysis of covariance conducted between groups identified as noncompulsive buyers (NCB) (n = 30), compulsive buyers who did not acquire free items (CBB) (n = 30), and compulsive buyers who also acquired free items (CBF) (n = 35) revealed that both acquisition groups reported higher levels of depression and stress and lower quality of psychological well-being than the NCB group, despite a comparable number of individuals self-reporting a current mental health disorder in each group. The CBF group reported higher levels of anxiety and general distress as well as greater work inefficiency days compared with the NCB and CBB groups. Furthermore, regression analyses supported the unique contribution of acquisition of free items to the prediction of psychiatric work impairment. Taken together, the findings highlight the serious impact of compulsive buying on work functioning, general quality of life, and psychological well-being and provide avenues for future research to investigate the role of acquisition of free items in symptom severity. Limitations and future directions are discussed. PMID- 22197215 TI - A comparative study of Arab and Jewish patients admitted for psychiatric hospitalization in Jerusalem: the demographic, psychopathologic aspects, and the drug abuse comorbidity. AB - BACKGROUND: The influence of ethnicity on different aspects of psychiatric hospitalization is far from clear. THE AIM OF THE STUDY: The main aim of the study was to compare the Arab and the Jewish inpatients, at the time of admission, for the demographic factors, severity of psychotic, and affective psychopathology and comorbid drug abuse rate. POPULATION, METHOD, AND TOOLS: Among 250 consecutively admitted patients in the Jerusalem Mental Health Center Kfar Shaul Hospital, 202 Jews and 42 Arabs (aged 18-65 years) were examined within 48 hours after admission. The psychiatric diagnoses were made according to the criteria of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. For the differential measurement of psychopathologic severity, the following rating scales were used: 21-item Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Positive and Negative Syndrome Scale (PANSS), and Young Mania Rating Scale. Urine tests for Delta9-tetrahydrocannabinol (THC), cocaine, opiates, amphetamines, and methamphetamine were performed using the Sure Step TM kits (Applied Biotech, Inc, San Diego, CA, USA). The Structured Clinical Interview Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for drug abuse were applied based on self-report and results of urine analysis. RESULTS: The comparison of the 2 population showed that among the Arab inpatients, there were more males (81% vs 67.4%; P < .005). No significant difference in psychiatric diagnosis was observed. The overall severity of positive symptoms (PANSS positive) in Arab group was higher, but only slightly so (P = .05). No significant difference was observed for total rates of PANSS negative subscale. The rates of PANSS-general were also similar. The Arab patients were significantly less depressive according to 21-item Hamilton Depression Rating Scale (P = .032), and the total score of Hamilton Anxiety Rating Scale for the Jewish group was significantly higher (P = .001). No significant difference in general severity of manic symptoms for 2 groups was detected according to Young Mania Rating Scale. The rate of comorbid drug abuse for Jewish inpatients was borderline higher (P = .068). CONCLUSIONS: The issue of referral to psychiatric hospitalization could be culturally influenced; it may be the result of disparities in demographic, psychopathologic, and drug abuse comorbid presenting symptoms, which are demonstrated upon admission by patients of different ethnic origins. PMID- 22197213 TI - Auditory hallucinations in a cross-diagnostic sample of psychotic disorder patients: a descriptive, cross-sectional study. AB - BACKGROUND: Auditory hallucinations (AH) are a cardinal feature of schizophrenia spectrum disorders. They are not disease specific, however, and can occur in other conditions, including affective psychoses. METHODS: In this descriptive, cross-sectional study, we examined AH in relation to other psychotic symptoms, mood symptoms, illness severity, and functional status in 569 patients with psychosis (n = 172 schizophrenia, n = 153 schizoaffective disorder, n = 244 bipolar disorder with psychotic features). RESULTS: A total of 323 (56.7%) patients reported a lifetime history of AH (75.6% of patients with schizophrenia, 71.9% schizoaffective disorder, and 34.0% bipolar disorder). The mean score for the hallucinations item (P3) of the Positive and Negative Syndrome Scale in the AH group was 3.66 +/- 1.79, indicating mild to moderate state hallucinations severity. Auditory hallucinations were strongly associated with hallucinations in other sensory modalities and with the first-rank symptoms of delusions of control, thought insertion, and thought broadcasting. Multivariate analysis showed that AH were associated with lower education even after controlling for diagnosis, age, and sex. There was no association between AH and functional status as measured by the Multnomah Community Ability Scale. CONCLUSIONS: Auditory hallucinations are associated with specific clinical features across the continuum of both schizophrenic and affective psychoses independent of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis. PMID- 22197216 TI - Right ventricular systolic dysfunction in patients with reperfused ST-segment elevation acute myocardial infarction. PMID- 22197217 TI - Clustering of 37 circulating biomarkers by exploratory factor analysis in patients following complicated acute myocardial infarction. AB - BACKGROUND: The objective of this study was to elucidate the complex interactions between families of circulating biomarkers representing different biochemical responses to the pathophysiology following complicated acute myocardial infarction (AMI). METHODS: Blood samples, drawn at a median of 3 days post AMI were obtained from 236 patients with complicated AMI and evidence of heart failure or left ventricular dysfunction. Using exploratory factor analysis, 37 biomarkers were grouped according to their collinearity to each other into clusters. The clusters were used as a model to elucidate interdependencies between individual biomarkers. Each cluster defines a specific pathophysiological process, called factor. These factors were used as covariates in multivariable Cox-proportional hazard regression analyses for prediction of all-cause death and the combined endpoint of cardiovascular death and re-infarction. RESULTS: Exploratory factor analysis grouped the biomarkers under 5 factors. The composition of these groups was partially unexpected but biological plausible. In multivariable analysis, only 1 factor proved to be an independent predictor of outcome. Major contributions (factor loadings>0.50) in this cluster came from: mid-regional pro-adrenomedullin, tumor necrosis factor receptor, pro-endothelin 1, growth differentiation factor 15, C-terminal pro arginine vasopressin, uric acid, chromogranin A and procollagen type III N-terminal. CONCLUSION: Clustering of multiple biomarkers by exploratory factor analysis might prove useful in exploring the biological interactions between different biomarkers in cardiovascular disease and thus increase our understanding of the complicated orchestral interplay at the molecular level. PMID- 22197218 TI - Sexuality and body image in long-term survivors of testicular cancer. AB - OBJECTIVE: This study explores sexual function and the influence of different treatment modalities on sexual function and body image among long-term survivors of testicular cancer (TCSs). METHODS: A long-term follow-up assessment of all testicular cancer patients treated at Aarhus University Hospital, Denmark, from 1990 to 2000 was conducted. A total of 401 survivors (mean age: 46.6years; response rate: 66%) completed questionnaires concerning sexuality and changes in body image. Based on the treatment received, patients were categorised into one of four groups: surveillance, radiotherapy, chemotherapy, or chemotherapy supplemented with retroperitoneal lymph node dissection (RPLND). RESULTS: Sexual dysfunctions were reported: 24% reduced sexual interest, 43% reduced sexual activity, 14% reduced sexual enjoyment, 18% erectile dysfunction, 7% ejaculatory problems and 3% increased sexual discomfort. Seventeen percent of the long-term TCSs reported changes in body image, and this was significantly associated with all six parameters of sexual dysfunction. When comparing treatments, only the RPLND procedure was associated with sexual dysfunction in the form of ejaculatory dysfunction. CONCLUSION: Apart from RPLND, which was associated with ejaculatory dysfunction, treatment strategies for testicular cancer appeared not to influence sexual dysfunction. The level of erectile dysfunction seen in this sample of TCSs seemed to be higher than the level observed in the general male population and high levels of erectile dysfunction were associated with negative changes in body image. The results suggest that changes in body image are of importance when explaining the variation in sexual dysfunctions, but further prospective studies are needed to clarify this issue. PMID- 22197219 TI - CXCL5, a promoter of cell proliferation, migration and invasion, is a novel serum prognostic marker in patients with colorectal cancer. AB - PURPOSE: Serum CXCL5 levels in patients with colorectal cancer (CRC) were assessed to evaluate correlation with clinicopathologic features and prognosis. The effects of CXCL5 on CRC cells were also investigated in vitro. METHODS: Based on cytokine array analysis, CXCL5 was identified as a novel prognostic serum marker. Serum levels of CXCL5 were assessed in 250 CRC patients and 33 normal volunteers by enzyme-linked immunosorbent assay (ELISA), and their relation to clinicopathologic findings and survival investigated. CXCL5 levels in CRC cell lines were also measured by ELISA, and CXCL5 and CXCR2 expression was evaluated by immunohistochemistry. To investigate the biological role of the CXCL5/CXCR2 axis, recombinant human CXCL5 and CXCR2 neutralisation antibodies were used for proliferation, migration and invasion assays. RESULTS: Preoperative serum CXCL5 was significantly elevated in patients with CRC compared with healthy volunteers (p=0.013). High serum CXCL5 was significantly associated with female sex (p=0.0098) and liver metastasis (p=0.0040). Univariate analysis correlated elevated CXCL5 with poor overall survival (p=0.0002). Multivariate analysis showed that elevated CXCL5 was a significant and independent prognostic factor of survival in all CRC patients (p=0.038). CRC cells secreted CXCL5, and administration of recombinant human CXCL5 promoted proliferation, migration and partial invasion. These effects were generally inhibited by CXCR2 neutralisation antibody. CONCLUSIONS: Preoperative serum CXCL5 could serve as a novel predictive marker for prognosis determination of CRC patients. CXCL5/CXCR2 axis might be associated with colorectal cancer progression. PMID- 22197220 TI - Cigarette smoking strongly modifies the association of complement factor H variant and the risk of lung cancer. AB - The complement system is an important immunosurveillance mechanism against tumors, and complement factor H (CFH) is a key regulator for activation of the complement system. Expression of complement factor H has been demonstrated in cell lines from several malignancies. In this study we examined the contribution of the single-nucleotide polymorphism (SNP) Try402His (Y402H) (rs1061170) in the CFH gene to the risk of lung cancer in a case-control study with 1000 cases and 1000 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed by logistic regression. The frequencies for CFH Y402H genotypes among the cases were statistically significantly different from those among controls (chi(2)=8.66, P=0.003), with 402His/His or 402His/Try genotypes being over represented among patients compared with controls (13.6% versus 9.4%, P<0.004). A multivariate regression analysis showed that a significantly increased risk of lung cancer for the 402His/His or 402His/Try carriers with OR (95% CI), 1.50 (1.12-2.00). When stratified by smoking status, the elevated risk of the cancer associated with variant CFH genotypes was observed among smokers, but not among non-smokers. When analyzed with cumulative smoking dose (pack-years), a super multiplicative interaction was observed at different smoking levels. Among carriers with the 402Tyr/His or His/His genotype, the ORs of developing lung cancer for smoking<16, 16-28, or >28 pack-years were 0.98 (0.49-1.94), 2.36 (1.14 4.90), and 6.39 (3.49-11.68), respectively. These findings suggest that CFH Y402H polymorphism may interact with cigarette smoking to effect the development of lung cancer in the Chinese population. PMID- 22197221 TI - Decision making among different treatment options for neurologically impaired boys with undescended testis: a multinational pediatric survey. AB - OBJECTIVE: To determine the attitude of referring pediatricians towards the decision of treatment modalities for undescended testis (UDT) in neurologic impaired boys (NIB). METHODS AND MATERIALS: An online questionnaire was offered to registered pediatricians in Austria and Germany for online completion. RESULTS: 221 male (61.6%) and 138 female (38.4%) pediatricians completed the survey; 326 (90.8%) believe that UDT should be treated according to national guidelines; 31 (8.6%) believe that UDT should be treated according to the parental wish, whereas only 2 (0.6%) tend to no treatment at all. Tumor prophylaxis, further sexual life, legal concerns, risks of anesthesia, and the choice of the parents have major impact on the perception of UDT. Moreover, fertility and limited life expectancy seem to be of minor importance only. In general, Pearson chi2 test could not identify age and sex of pediatricians as significant predictor of how the importance of the treatment of UDT is appraised. CONCLUSION: From the pediatric point of view UDT in NIB is an important issue and should be treated according to guidelines. Nevertheless, this study indicates the problems in decision-making and choosing the best management for UDT in NIB. Undoubtedly, further ethical discussion is needed to optimize treatment of UDT in NIB. PMID- 22197223 TI - Effects of pH on the ability of flavonoids to act as Pickering emulsion stabilizers. AB - The flavonoids tiliroside, rutin and naringin have been investigated as stabilizers of Pickering oil-in-water (O/W) emulsions. The mean droplet size of tetradecane emulsions was considerably smaller at higher pH, especially for rutin. The solubility of flavonoids in the aqueous phase was 4-6 times higher at pH 8 compared to pH 2 for tiliroside and rutin, although all absolute solubilities remained low (<1 mM). This agreed with a slight increase in surface activity of tiliroside and rutin at the O-W interface at pH 8 compared to pH 2. However, improved emulsion stabilization at higher pH is better explained by the significant increase in zeta-potential of the flavonoid particles to more negative values at pH 8, which will improve particle dispersion and increase the charge on the droplets stabilized by them. A buckwheat tea extract, rich in rutin, was also shown to be an effective stabilizer of sunflower O/W emulsions. PMID- 22197222 TI - Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression. AB - Here we show that Rab25 permits the sorting of ligand-occupied, active conformation alpha5beta1 integrin to late endosomes/lysosomes. Photoactivation and biochemical approaches show that lysosomally targeted integrins are not degraded but are retrogradely transported and recycled to the plasma membrane at the back of invading cells. This requires CLIC3, a protein upregulated in Rab25 expressing cells and tumors, which colocalizes with active alpha5beta1 in late endosomes/lysosomes. CLIC3 is necessary for release of the cell rear during migration on 3D matrices and is required for invasion and maintenance of active Src signaling in organotypic microenvironments. CLIC3 expression predicts lymph node metastasis and poor prognosis in operable cases of pancreatic ductal adenocarcinoma (PDAC). The identification of CLIC3 as a regulator of a recycling pathway and as an independent prognostic indicator in PDAC highlights the importance of active integrin trafficking as a potential drive to cancer progression in vivo. PMID- 22197224 TI - Electrochemical performance of gold nanoparticle-cytochrome c hybrid interface for H2O2 detection. AB - Here, we describe the formation of a hybrid biointerface consisting of gold nanoparticle (AuNP) and cytochrome c (cyt c) on indium tin oxide (ITO) electrodes using a two-step immobilization procedure. The Au nanoparticles were attached to the ITO electrodes by 3-mercaptopropyl trimethoxysilane (3-MPTMS). The electrode was then incubated with 11-mercapundecanoic acid (11-MUA) and the nanoparticles were activated to allow for coupling to cyt c. This process resulted in the formation of the AuNP/cyt c hybrid on the ITO electrode. The ITO/AuNP/cyt c substrate surfaces were characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM) and X-ray diffraction analysis (XRD), and cyclic voltammetry (CV) techniques. Further analysis regarding the surface roughness properties of ITO, ITO/AuNP and ITO/AuNP/cyt c were also performed. The ITO/AuNP/cyt c immobilized ITO electrode displayed a pair of well-defined redox peaks (E(pa) at 0.09 V and E(pc) at 0.02 V) at pH 7.0 in HEPES buffer solution. Differential pulse voltammetry (DPV) and amperometric i-t measurements on the modified electrode showed a linear response after the addition of hydrogen peroxide (H(2)O(2)). The developed electrode sensor had an electron transfer rate constant (k(s)) of 0.69 s(-1) with a detection limit of 0.5 MUM. The results of this study suggest that the hybrid layers were well fabricated on the ITO surface and the developed ITO/AuNP/cyt c electrode displayed an excellent electrocatalytic response for the detection of H(2)O(2). PMID- 22197225 TI - Enhanced antibacterial activity of amino acids-functionalized multi walled carbon nanotubes by a simple method. AB - Multi-walled carbon nanotubes (MWCNTs) were first functionalized by arginine and lysine under microwave radiation. Surface functionalization was confirmed by Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, and transmission electron microscopy (TEM). After the MWCNTs were functionalized by arginine and lysine, the antibacterial activity of all treated samples was increased significantly against all bacteria that were tested. Based on the observed minimum inhibitory concentration and radial diffusion assay, the sequence of antibacterial activity was MWCNTs-arginine>MWCNTs-lysine>pristine MWCNTs. The functionalized MWCNTs were especially effective against gram-negative bacteria (e.g., Escherichia coli and Salmonella typhimurium). Interestingly, the MWCNT samples were effective against the resistant strain Staphylococcos aureus. The enhanced antibacterial activity was attributed to electrostatic adsorption of bacteria membrane due to positive charges of the functional groups on MWCNTs surface. Since MWCNTs have lower cytotoxicity than single-walled carbon nanotubes, their functionalization with cationic amino acids could be a beneficial approach in the disinfection industry. PMID- 22197226 TI - Pharmacological protection from radiation +/- cisplatin-induced oral mucositis. AB - PURPOSE: To evaluate if two pharmacological agents, Tempol and D-methionine (D met), are able to prevent oral mucositis in mice after exposure to ionizing radiation +/- cisplatin. METHODS AND MATERIALS: Female C3H mice, ~8 weeks old, were irradiated with five fractionated doses +/- cisplatin to induce oral mucositis (lingual ulcers). Just before irradiation and chemotherapy, mice were treated, either alone or in combination, with different doses of Tempol (by intraperitoneal [ip] injection or topically, as an oral gel) and D-met (by gavage). Thereafter, mice were sacrificed and tongues were harvested and stained with a solution of Toluidine Blue. Ulcer size and tongue epithelial thickness were measured. RESULTS: Significant lingual ulcers resulted from 5 * 8 Gy radiation fractions, which were enhanced with cisplatin treatment. D-met provided stereospecific partial protection from lingual ulceration after radiation. Tempol, via both routes of administration, provided nearly complete protection from lingual ulceration. D-met plus a suboptimal ip dose of Tempol also provided complete protection. CONCLUSIONS: Two fairly simple pharmacological treatments were able to markedly reduce chemoradiation-induced oral mucositis in mice. This proof of concept study suggests that Tempol, alone or in combination with D-met, may be a useful and convenient way to prevent the severe oral mucositis that results from head-and-neck cancer therapy. PMID- 22197227 TI - Impact of screening and risk factors for local recurrence and survival after conservative surgery and radiotherapy for early breast cancer: results from a large series with long-term follow-up. AB - PURPOSE: To investigate conventional prognostic factors for ipsilateral breast tumor recurrence (IBTR), distant metastasis (DM), and survival after breast conserving therapy (BCT) in screen-detected and symptomatic cases on surveillance up to 25 years. PATIENTS AND METHODS: A total of 1812 consecutive patients in three cohorts (1981-1989, 1990-1992, and 1993-1998) with T12N01M0 invasive breast cancer were treated with BCT (median follow-up, 14 years). Tumor type and grade were reviewed by a single pathologist. Hormone receptor status was measured by immunohistochemistry on tissue microarrays. A Cox proportional hazards model was used to assess independent prognostic variables for relapse and survival. RESULTS: A total of 205 IBTR occurred, with 5-, 10-, 15-, and 20-year actuarial relapse rates of 4.5% (95% confidence interval [CI] 3.35-5.5%), 8.4% (95% CI 7.1 9.8%), 14.1% (95% CI 12.0-16%), and 17.4% (95% CI 14.5-20.2%). Number of nodes, young age, pathologic tumor size, and multifocality were significant factors for IBTR. Three hundred seventy-eight patients developed DM. The actuarial metastatic rate was 12% at 5 years and 17.9% at 10 years. Young age, number of positive nodes, pathologic tumor size, and tumor grade were significant factors for DM relapse. When conventional prognostic indices were taken into account screen detected cancers showed no improvement in overall relapse or survival rate compared with symptomatic cases but did show a reduced risk of DM after IBTR. After 10 years IBTR relapse continued at a constant rate of 0.87% per annum. CONCLUSIONS: The Edinburgh BCT series has shown that screen-detected invasive breast cancers do not have significantly different clinical outcomes compared with symptomatic cases when pathologic risk factors are taken into account. This suggests that these patients be managed in a similar way. PMID- 22197228 TI - Determination of internal target volume from a single positron emission tomography/computed tomography scan in lung cancer. AB - PURPOSE: The use of four-dimensional computed tomography (4D-CT) to determine the tumor internal target volume (ITV) is usually characterized by high patient radiation exposure. The objective of this study was to propose and evaluate an approach that relies on a single static positron emission tomography (PET)/CT scan to determine the ITV, thereby eliminating the need for 4D-CT and thus reduce patient radiation dose. METHODS AND MATERIALS: The proposed approach is based on the concept that the observed PET image is the result of a joint convolution of an ideal PET image (free from motion and partial volume effect) with a motion blurring kernel (MBK) and partial volume effect. In this regard, the MBK and tumor ITV are then estimated from the deconvolution of this joint model. To test this technique, phantom and patient studies were performed using different sphere/tumor sizes and motion trajectories. In all studies, a 4D-CT and a PET/CT image of the sphere/tumor were acquired. The ITV from the proposed technique was then compared to the maximum intensity projection (MIP) volume of the 4D-CT images. A Dice coefficient of the two volumes was calculated to represent the similarity between the two ITVs. RESULTS: The average ITVs of the proposed technique were 97.2% +/- 0.3% and 81.0% +/- 16.7% similar to the MIP volume in the phantom and patient studies, respectively. The average dice coefficients were 0.87 +/- 0.05 and 0.73 +/- 0.16, respectively, for the two studies. CONCLUSION: Using the proposed approach, a single static PET/CT scan has the potential to replace a 4D-CT to determine the tumor ITV. This approach has the added advantage of reducing patient radiation exposure and determining the tumor MBK compared to 4D-CT/MIP-CT. PMID- 22197229 TI - Monitoring dosimetric impact of weight loss with kilovoltage (kV) cone beam CT (CBCT) during parotid-sparing IMRT and concurrent chemotherapy. AB - PURPOSE: Parotid-sparing head-and-neck intensity-modulated radiotherapy (IMRT) can reduce long-term xerostomia. However, patients frequently experience weight loss and tumor shrinkage during treatment. We evaluate the use of kilovoltage (kV) cone beam computed tomography (CBCT) for dose monitoring and examine if the dosimetric impact of such changes on the parotid and critical neural structures warrants replanning during treatment. METHODS AND MATERIALS: Ten patients with locally advanced oropharyngeal cancer were treated with contralateral parotid sparing IMRT concurrently with platinum-based chemotherapy. Mean doses of 65 Gy and 54 Gy were delivered to clinical target volume (CTV)1 and CTV2, respectively, in 30 daily fractions. CBCT was prospectively acquired weekly. Each CBCT was coregistered with the planned isocenter. The spinal cord, brainstem, parotids, larynx, and oral cavity were outlined on each CBCT. Dose distributions were recalculated on the CBCT after correcting the gray scale to provide accurate Hounsfield calibration, using the original IMRT plan configuration. RESULTS: Planned contralateral parotid mean doses were not significantly different to those delivered during treatment (p > 0.1). Ipsilateral and contralateral parotids showed a mean reduction in volume of 29.7% and 28.4%, respectively. There was no significant difference between planned and delivered maximum dose to the brainstem (p = 0.6) or spinal cord (p = 0.2), mean dose to larynx (p = 0.5) and oral cavity (p = 0.8). End-of-treatment mean weight loss was 7.5 kg (8.8% of baseline weight). Despite a >=10% weight loss in 5 patients, there was no significant dosimetric change affecting the contralateral parotid and neural structures. CONCLUSIONS: Although patient weight loss and parotid volume shrinkage was observed, overall, there was no significant excess dose to the organs at risk. No replanning was felt necessary for this patient cohort, but a larger patient sample will be investigated to further confirm these results. Nevertheless, kilovoltage CBCT is a valuable tool for patient setup verification and monitoring of dosimetric variation during radiotherapy. PMID- 22197230 TI - Role of insulin-like growth factor-1 signaling pathway in cisplatin-resistant lung cancer cells. AB - PURPOSE: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non-small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. METHODS AND MATERIALS: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. RESULTS: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. CONCLUSIONS: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment. PMID- 22197231 TI - Dosimetric study of current treatment options for radiotherapy in retinoblastoma. AB - PURPOSE: To determine the best treatment technique for patients with retinoblastoma requiring radiotherapy to the whole eye. METHODS AND MATERIALS: Treatment plans for 3 patients with retinoblastoma were developed using 10 radiotherapy techniques including electron beams, photon beam wedge pair (WP), photon beam three-dimensional conformal radiotherapy (3D-CRT), fixed gantry intensity-modulated radiotherapy (IMRT), photon volumetric arc therapy (VMAT), fractionated stereotactic radiotherapy, and helical tomotherapy (HT). Dose-volume analyses were carried out for each technique. RESULTS: All techniques provided similar target coverage; conformity was highest for VMAT, nine-field (9F) IMRT, and HT (conformity index [CI] = 1.3) and lowest for the WP and two electron techniques (CI = 1.8). The electron techniques had the highest planning target volume dose gradient (131% of maximum dose received [D(max)]), and the CRT techniques had the lowest (103% D(max)) gradient. The volume receiving at least 20 Gy (V(20Gy)) for the ipsilateral bony orbit was lowest for the VMAT and HT techniques (56%) and highest for the CRT techniques (90%). Generally, the electron beam techniques were superior in terms of brain sparing and delivered approximately one-third of the integral dose of the photon techniques. CONCLUSIONS: Inverse planned image-guided radiotherapy delivered using HT or VMAT gives better conformity index, improved orbital bone and brain sparing, and a lower integral dose than other techniques. PMID- 22197232 TI - The impact of skin-sparing mastectomy with immediate reconstruction in patients with Stage III breast cancer treated with neoadjuvant chemotherapy and postmastectomy radiation. AB - PURPOSE: The safety and efficacy of skin-sparing mastectomy (SSM) with immediate reconstruction (IR) in patients with locally advanced breast cancer are unclear. The purpose of this study is to compare the outcomes of women with noninflammatory Stage III SSM with IR vs. non-SSM-treated women who underwent neoadjuvant chemotherapy and adjuvant radiation therapy (XRT). METHODS AND MATERIALS: Between October 1997 and March 2010, 100 consecutive patients (40 SSM with IR vs. 60 non-SSM) with Stage III breast cancer received anthracycline- and/or taxane-based neoadjuvant chemotherapy, mastectomy, and adjuvant XRT. Clinical stage (SSM with IR vs. for non-SSM) was IIIA (75% vs. 67%), IIIB (8% vs. 18%), and IIIC (8% vs. 8%). Tumors greater than 5 cm were found in 74% vs. 69%; 97% of patients in both groups were clinically node positive; and 8% vs. 18% had T4b disease. RESULTS: The time from initial biopsy to XRT was prolonged for SSM IR patients (274 vs. 254 days, p = 0.04), and there was a trend toward XRT delay of more than 8 weeks (52% vs. 31%, p = 0.07) after surgery. The rate of complications requiring surgical intervention was higher in the SSM-IR group (37.5% vs. 5%, p < 0.001). The 2-year actuarial locoregional control, breast cancer-specific survival, and overall survival rates for SSM with IR vs. non-SSM were 94.7% vs. 97.4%, 91.5% vs. 86.3%, and 87.4% vs. 84.8%, respectively (p = not significant). CONCLUSIONS: In our small study with limited follow-up, SSM with IR prolonged overall cancer treatment time and trended toward delaying XRT but did not impair oncologic outcomes. Complication rates were significantly higher in this group. Longer follow-up is needed. PMID- 22197233 TI - Effects of irradiation on brain vasculature using an in situ tumor model. AB - PURPOSE: Damage to normal tissue is a limiting factor in clinical radiotherapy (RT). We tested the hypothesis that the presence of tumor alters the response of normal tissues to irradiation using a rat in situ brain tumor model. METHODS AND MATERIALS: Intravital microscopy was used with a rat cranial window to assess the in situ effect of rat C6 glioma on peritumoral tissue with and without RT. The RT regimen included 40 Gy at 8 Gy/day starting Day 5 after tumor implant. Endpoints included blood-brain barrier permeability, clearance index, leukocyte-endothelial interactions and staining for vascular endothelial growth factor (VEGF) glial fibrillary acidic protein, and apoptosis. To characterize the system response to RT, animal survival and tumor surface area and volume were measured. Sham experiments were performed on similar animals implanted with basement membrane matrix absent of tumor cells. RESULTS: The presence of tumor alone increases permeability but has little effect on leukocyte-endothelial interactions and astrogliosis. Radiation alone increases tissue permeability, leukocyte endothelial interactions, and astrogliosis. The highest levels of permeability and cell adhesion were seen in the model that combined tumor and irradiation; however, the presence of tumor appeared to reduce the volume of rolling leukocytes. Unirradiated tumor and peritumoral tissue had poor clearance. Irradiated tumor and peritumoral tissue had a similar clearance index to irradiated and unirradiated sham-implanted animals. Radiation reduces the presence of VEGF in peritumoral normal tissues but did not affect the amount of apoptosis in the normal tissue. Apoptosis was identified in the tumor tissue with and without radiation. CONCLUSIONS: We developed a novel approach to demonstrate that the presence of the tumor in a rat intracranial model alters the response of normal tissues to irradiation. PMID- 22197234 TI - Intensity-modulated radiotherapy for pancreatic adenocarcinoma. AB - PURPOSE: To report the outcomes and toxicities in patients treated with intensity modulated radiotherapy (IMRT) for pancreatic adenocarcinoma. METHODS AND MATERIALS: Forty-seven patients with pancreatic adenocarcinoma were treated with IMRT between 2003 and 2008. Of these 47 patients, 29 were treated adjuvantly and 18 definitively. All received concurrent 5-fluorouracil chemotherapy. The treatment plans were optimized such that 95% of the planning target volume received the prescription dose. The median delivered dose for the adjuvant and definitive patients was 50.4 and 54.0 Gy, respectively. RESULTS: The median age at diagnosis was 63.9 years. For adjuvant patients, the 1- and 2-year overall survival rate was 79% and 40%, respectively. The 1- and 2-year recurrence-free survival rate was 58% and 17%, respectively. The local-regional control rate at 1 and 2 years was 92% and 80%, respectively. For definitive patients, the 1-year overall survival, recurrence-free survival, and local-regional control rate was 24%, 16%, and 64%, respectively. Four patients developed Grade 3 or greater acute toxicity (9%) and four developed Grade 3 late toxicity (9%). CONCLUSIONS: Survival for patients with pancreatic cancer remains poor. A small percentage of adjuvant patients have durable disease control, and with improved therapies, this proportion will increase. Systemic therapy offers the greatest opportunity. The present results have demonstrated that IMRT is well tolerated. Compared with those who received three-dimensional conformal radiotherapy in previously reported prospective clinical trials, patients with pancreatic adenocarcinoma treated with IMRT in our series had improved acute toxicity. PMID- 22197235 TI - Changes in global function and regional ventilation and perfusion on SPECT during the course of radiotherapy in patients with non-small-cell lung cancer. AB - PURPOSE: This study aimed to (1) examine changes in dyspnea, global pulmonary function test (PFT) results, and functional activity on ventilation (V)/perfusion (Q) single-photon emission computerized tomography (SPECT) scans during the course of radiation (RT), and (2) factors associated with the changes in patients with non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Fifty-six stage I to III NSCLC patients treated with definitive RT with or without chemotherapy were enrolled prospectively. Dyspnea was graded according to Common Terminology Criteria for Adverse Events version 3.0 prior to and weekly during RT. V/Q SPECT computed tomography (CT) and PFTs were performed prior to and during RT at approximately 45 Gy. Functions of V and Q activities were assessed using a semiquantitative scoring of SPECT images. RESULTS: Breathing improved significantly at the third week (mean dyspnea grade, 0.8 vs. 0.6; paired t-test p = 0.011) and worsened during the later course of RT (p > 0.05). Global PFT results did not change significantly, while regional lung function on V/Q SPECT improved significantly after ~45 Gy. The V defect score (DS) was 4.9 pre-RT versus 4.3 during RT (p = 0.01); Q DS was 4.3 pre-RT versus 4.0 during RT (p < 0.01). Improvements in V and Q functions were seen primarily in the ipsilateral lung (V DS, 1.9 pre-RT versus 1.4 during RT, p < 0.01; Q DS, 1.7 pre-RT versus 1.5 during RT, p < 0.01). Baseline primary tumor volume was significantly correlated with pre-RT V/Q DS (p < 0.01). Patients with central lung tumors had greater interval changes in V and Q than those with more peripheral tumors (p <0.05 for both V and Q DS). CONCLUSIONS: Regional ventilation and perfusion improved during RT at 45 Gy. This suggests that adaptive planning based on V/Q SPECT during RT may allow sparing of functionally recoverable lung tissue. PMID- 22197236 TI - Failure mode and effect analysis for delivery of lung stereotactic body radiation therapy. AB - PURPOSE: To improve the quality and safety of our practice of stereotactic body radiation therapy (SBRT), we analyzed the process following the failure mode and effects analysis (FMEA) method. METHODS: The FMEA was performed by a multidisciplinary team. For each step in the SBRT delivery process, a potential failure occurrence was derived and three factors were assessed: the probability of each occurrence, the severity if the event occurs, and the probability of detection by the treatment team. A rank of 1 to 10 was assigned to each factor, and then the multiplied ranks yielded the relative risks (risk priority numbers). The failure modes with the highest risk priority numbers were then considered to implement process improvement measures. RESULTS: A total of 28 occurrences were derived, of which nine events scored with significantly high risk priority numbers. The risk priority numbers of the highest ranked events ranged from 20 to 80. These included transcription errors of the stereotactic coordinates and machine failures. CONCLUSION: Several areas of our SBRT delivery were reconsidered in terms of process improvement, and safety measures, including treatment checklists and a surgical time-out, were added for our practice of gantry-based image-guided SBRT. This study serves as a guide for other users of SBRT to perform FMEA of their own practice. PMID- 22197237 TI - Tumor, lymph node, and lymph node-to-tumor displacements over a radiotherapy series: analysis of interfraction and intrafraction variations using active breathing control (ABC) in lung cancer. AB - PURPOSE: To estimate errors in soft tissue-based image guidance due to relative changes between primary tumor (PT) and affected lymph node (LN) position and volume, and to compare the results with bony anatomy-based displacements of PTs and LNs during radiotherapy of lung cancer. METHODS AND MATERIALS: Weekly repeated breath-hold computed tomography scans were acquired in 17 lung cancer patients undergoing radiotherapy. PTs and affected LNs were manually contoured on all scans after rigid registration. Interfraction and intrafraction displacements in the centers of mass of PTs and LNs relative to bone, as well as LNs relative to PTs (LN-PT), were calculated. RESULTS: The mean volume after 5 weeks was 65% for PTs and 63% for LNs. Systematic and random interfraction displacements were 2.6 to 4.6 mm and 2.7 to 2.9 mm, respectively, for PTs; 2.4 to 3.8 mm and 1.4 to 2.7 mm, respectively, for LNs; and 2.3 to 3.9 mm and 1.9 to 2.8 mm, respectively, for LN-PT. Systematic and random intrafraction displacements were less than 1 mm except in the superoinferior direction. Interfraction LN-PT displacements greater than 3 mm were observed in 67% of fractions and require a safety margin of 12 mm in the lateral direction, 11 mm in the anteroposterior direction, and 9 mm in the superoinferior direction. LN-PT displacements displayed significant time trends (p < 0.0001) and depended on the presence of pathoanatomic conditions of the ipsilateral lung, such as atelectasis. CONCLUSION: Interfraction LN-PT displacements were mostly systematic and comparable to bony anatomy-based displacements of PTs or LNs alone. Time trends, large volume changes, and the influence of pathoanatomic conditions underline the importance of soft tissue based image guidance and the potential of plan adaptation. PMID- 22197238 TI - A four-dimensional computed tomography analysis of multiorgan abdominal motion. AB - PURPOSE: To characterize and quantify multiorgan respiration-induced motion in the abdomen in liver and pancreatic cancer patients. METHODS AND MATERIALS: Four dimensional computed tomography scans were acquired for 18 patients treated for abdominal tumors. Contours of multiple abdominal organs were drawn by the radiation oncologist at one respiratory phase; these contours were propagated to other respiratory phases by deformable registration. Three-dimensional organ models were generated from the resulting contours at each phase. Motions of the bounding box and center of mass were extracted and analyzed for the clinical target volume and organs at risk. RESULTS: On average, the center of mass motion for liver clinical target volumes was 9.7 mm (SD 5 mm) in the superior-inferior direction, with a range of 3 to 18 mm; for pancreatic tumors, the average was 5 mm (SD 1 mm) m with a range of 3 to 7 mm. Abdominal organs move in unison, but with varying amplitudes. Gating near exhale (T40-T60) reduces the range of motion by a factor of ~10. CONCLUSION: We have used deformable registration to calculate the trajectories of abdominal organs in four dimensions, based on center of mass and bounding box motion metrics. Our results are compared with previously reported studies. Possible reasons for differences are discussed. PMID- 22197239 TI - Spinal cord tolerance to reirradiation with single-fraction radiosurgery: a swine model. AB - PURPOSE: This study was performed to determine swine spinal cord tolerance to single-fraction, partial-volume irradiation 1 year after receiving uniform irradiation to 30 Gy in 10 fractions. METHODS AND MATERIALS: A 10-cm length of spinal cord (C3-T1) was uniformly irradiated to 30 Gy in 10 consecutive fractions and reirradiated 1 year later with a single radiosurgery dose centered within the previously irradiated segment. Radiosurgery was delivered to a cylindrical volume approximately 5 cm in length and 2 cm in diameter, which was positioned laterally to the cervical spinal cord, resulting in a dose distribution with the 90%, 50%, and 10% isodose lines traversing the ipsilateral, central, and contralateral spinal cord, respectively. Twenty-three pigs were stratified into six dose groups with mean maximum spinal cord doses of 14.9 +/- 0.1 Gy (n = 2), 17.1 +/- 0.3 Gy (n = 3), 19.0 +/- 0.1 Gy (n = 5), 21.2 +/- 0.1 Gy (n = 5), 23.4 +/- 0.2 Gy (n = 5), and 25.4 +/- 0.4 Gy (n = 3). The mean percentage of spinal cord volumes receiving >=10 Gy for the same groups were 34% +/- 1%, 40% +/- 1%, 46% +/- 3%, 52% +/- 1%, 56 +/- 3%, and 57% +/- 1%. The study endpoint was motor neurologic deficit as determined by a change in gait during a 1- year follow-up period. RESULTS: A steep dose-response curve was observed with a 50% incidence of paralysis (ED(50)) for the maximum point dose of 19.7 Gy (95% confidence interval, 17.4-21.4). With two exceptions, histology was unremarkable in animals with normal neurologic status, while all animals with motor deficits showed some degree of demyelination and focal white matter necrosis on the irradiated side, with relative sparing of gray matter. Histologic comparison with a companion study of de novo irradiated animals revealed that retreatment responders had more extensive tissue damage, including infarction of gray matter, only at prescription doses >20 Gy. CONCLUSION: Pigs receiving spinal radiosurgery 1 year after receiving 30 Gy in 10 fractions were not at significantly higher risk of developing motor deficits than pigs that received radiosurgery alone. PMID- 22197240 TI - A role for the melatonin-related receptor GPR50 in leptin signaling, adaptive thermogenesis, and torpor. AB - The ability of mammals to maintain a constant body temperature has proven to be a profound evolutionary advantage, allowing members of this class to thrive in most environments on earth. Intriguingly, some mammals employ bouts of deep hypothermia (torpor) to cope with reduced food supply and harsh climates [1, 2]. During torpor, physiological processes such as respiration, cardiac function, and metabolic rate are severely depressed, yet the neural mechanisms that regulate torpor remain unclear [3]. Hypothalamic responses to energy signals, such as leptin, influence the expression of torpor [4-7]. We show that the orphan receptor GPR50 plays an important role in adaptive thermogenesis and torpor. Unlike wild-type mice, Gpr50(-/-) mice readily enter torpor in response to fasting and 2-deoxyglucose administration. Decreased thermogenesis in Gpr50(-/-) mice is not due to a deficit in brown adipose tissue, the principal site of nonshivering thermogenesis in mice [8]. GPR50 is highly expressed in the hypothalamus of several species, including man [9, 10]. In line with this, altered thermoregulation in Gpr50(-/-) mice is associated with attenuated responses to leptin and a suppression of thyrotropin-releasing hormone. Thus, our findings identify hypothalamic circuits involved in torpor and reveal GPR50 to be a novel component of adaptive thermogenesis in mammals. PMID- 22197241 TI - Children's development of self-regulation in speech production. AB - Species-specific vocalizations fall into two broad categories: those that emerge during maturation, independent of experience, and those that depend on early life interactions with conspecifics. Human language and the communication systems of a small number of other species, including songbirds, fall into this latter class of vocal learning. Self-monitoring has been assumed to play an important role in the vocal learning of speech and studies demonstrate that perception of your own voice is crucial for both the development and lifelong maintenance of vocalizations in humans and songbirds. Experimental modifications of auditory feedback can also change vocalizations in both humans and songbirds. However, with the exception of large manipulations of timing, no study to date has ever directly examined the use of auditory feedback in speech production under the age of 4. Here we use a real-time formant perturbation task to compare the response of toddlers, children, and adults to altered feedback. Children and adults reacted to this manipulation by changing their vowels in a direction opposite to the perturbation. Surprisingly, toddlers' speech didn't change in response to altered feedback, suggesting that long-held assumptions regarding the role of self-perception in articulatory development need to be reconsidered. PMID- 22197242 TI - Semaphorin and Eph receptor signaling guide a series of cell movements for ventral enclosure in C. elegans. AB - BACKGROUND: In the last stage of the Caenorhabditis elegans body wall closure, an open pocket in the epidermis is closed by the migration of marginal epidermal P/pocket cells to the ventral midline. The cellular and molecular mechanisms of this closure remain unknown. RESULTS: Cells within the pocket align to form a bridge for migration of contralateral P cell pair P9/10 L,R (and neighboring P cells) to the midline. Bridge formation involves rearrangement of five sister pairs of PLX-2/plexin and VAB-1/Eph receptor expressing "plexin band" cells, of which three pairs form a scaffold for bridge assembly and two pairs form the bridge. Bridge formation requires VAB-1 kinase-dependent extension of presumptive bridge cells over scaffold cells toward the ventral midline. An unassembled vab-1 null mutant bridge obstructs P cell migration, which is largely overcome by plexin band expression of VAB-1 or VAB-1(delC) (a kinase deletion of VAB-1). VAB 1 also functions redundantly with MAB-20/semaphorin to prevent perdurant gaps between sister plexin band cells that block P cell migration. CONCLUSIONS: The Eph receptor mediates cellular extensions required for bridge formation, independently facilitates P cell migration to the midline, and functions redundantly with PLX-2/plexin to prevent gaps in the bridge used for P9/10 cell migration in body wall closure. PMID- 22197243 TI - Emergence of patterned activity in the developing zebrafish spinal cord. AB - BACKGROUND: Developing neural networks display spontaneous and correlated rhythmic bursts of action potentials that are essential for circuit refinement. In the spinal cord, it is poorly understood how correlated activity is acquired and how its emergence relates to the formation of the spinal central pattern generator (CPG), the circuit that mediates rhythmic behaviors like walking and swimming. It is also unknown whether early, uncorrelated activity is necessary for the formation of the coordinated CPG. RESULTS: Time-lapse imaging in the intact zebrafish embryo with the genetically encoded calcium indicator GCaMP3 revealed a rapid transition from slow, sporadic activity to fast, ipsilaterally correlated, and contralaterally anticorrelated activity, characteristic of the spinal CPG. Ipsilateral correlations were acquired through the coalescence of local microcircuits. Brief optical manipulation of activity with the light-driven pump halorhodopsin revealed that the transition to correlated activity was associated with a strengthening of ipsilateral connections, likely mediated by gap junctions. Contralateral antagonism increased in strength at the same time. The transition to coordinated activity was disrupted by long-term optical inhibition of sporadic activity in motoneurons and ventral longitudinal descending interneurons and resulted in more neurons exhibiting uncoordinated activity patterns at later time points. CONCLUSIONS: These findings show that the CPG in the zebrafish spinal cord emerges directly from a sporadically active network as functional connectivity strengthens between local and then more distal neurons. These results also reveal that early, sporadic activity in a subset of ventral spinal neurons is required for the integration of maturing neurons into the coordinated CPG network. PMID- 22197244 TI - A genome-wide SNP genotyping array reveals patterns of global and repeated species-pair divergence in sticklebacks. AB - Genes underlying repeated adaptive evolution in natural populations are still largely unknown. Stickleback fish (Gasterosteus aculeatus) have undergone a recent dramatic evolutionary radiation, generating numerous examples of marine freshwater species pairs and a small number of benthic-limnetic species pairs found within single lakes [1]. We have developed a new genome-wide SNP genotyping array to study patterns of genetic variation in sticklebacks over a wide geographic range, and to scan the genome for regions that contribute to repeated evolution of marine-freshwater or benthic-limnetic species pairs. Surveying 34 global populations with 1,159 informative markers revealed substantial genetic variation, with predominant patterns reflecting demographic history and geographic structure. After correcting for geographic structure and filtering for neutral markers, we detected large repeated shifts in allele frequency at some loci, identifying both known and novel loci likely contributing to marine freshwater and benthic-limnetic divergence. Several novel loci fall close to genes implicated in epithelial barrier or immune functions, which have likely changed as sticklebacks adapt to contrasting environments. Specific alleles differentiating sympatric benthic-limnetic species pairs are shared in nearby solitary populations, suggesting an allopatric origin for adaptive variants and selection pressures unrelated to sympatry in the initial formation of these classic vertebrate species pairs. PMID- 22197245 TI - Cleavage furrow organization requires PIP(2)-mediated recruitment of anillin. AB - Cell division is achieved by a plasma membrane furrow that must ingress between the segregating chromosomes during anaphase [1-3]. The force that drives furrow ingression is generated by the actomyosin cytoskeleton, which is linked to the membrane by an as yet undefined molecular mechanism. A key component of the membrane furrow is anillin. Upon targeting to the furrow through its pleckstrin homology (PH) domain, anillin acts as a scaffold linking the actomyosin and septin cytoskeletons to maintain furrow stability (reviewed in [4, 5]). We report that the PH domain of anillin interacts with phosphatidylinositol phosphate lipids (PIPs), including PI(4,5)P(2), which is enriched in the furrow. Reduction of cellular PI(4,5)P(2) or mutations in the PH domain of anillin that specifically disrupt the interaction with PI(4,5)P(2), interfere with the localization of anillin to the furrow. Reduced expression of anillin disrupts symmetric furrow ingression that can be restored by targeting ectopically expressed anillin to the furrow using an alternate PI(4,5)P(2) binding module, a condition where the septin cytoskeleton is not recruited to the plasma membrane. These data demonstrate that the anillin PH domain has two functions: targeting anillin to the furrow by binding to PI(4,5)P(2) to maintain furrow organization and recruiting septins to the furrow. PMID- 22197246 TI - A neuronal network switch for approach/avoidance toggled by appetitive state. AB - Concrete examples of computation and implementation of cost/benefit decisions at the level of neuronal circuits are largely lacking. Such decisions are based on appetitive state, which is the integration of sensation, internal state, and memory. Value-based decisions are accessible in neuronal circuitry of simple systems. In one such system, the predatory sea slug Pleurobranchaea, appetite is readily quantified in behavior and related to approach/avoidance decision. Moreover, motor aspects of feeding and turning can be observed as fictive motor output in the isolated central nervous system (CNS). Here we found that the excitation state of the feeding motor network both manifested appetitive state and controlled expression of orienting versus avoidance. In isolated CNSs, spontaneous feeding network activity varied proportionally to donor feeding thresholds. CNSs from low- and high-feeding-threshold donors expressed fictive orienting or avoidance, respectively, in response to brief stimulation of sensory nerves. Artificially exciting the feeding network converted fictive avoidance to orienting. Thus, the feeding network embodied appetitive state and toggled approach/avoidance decision by configuring response symmetry of the premotor turn network. A resulting model suggests a basic cost/benefit decision module from which to consider evolutionary elaboration of the circuitry to serve more intricate valuation processes in complex animals. PMID- 22197247 TI - In vitro inhibition of influenza A virus infection by marine microalga-derived sulfated polysaccharide p-KG03. AB - The sulfated polysaccharide, p-KG03, purified from the marine microalga, Gyrodinium impudium, is a unique compound comprising homogenous galactose units conjugated to uronic acid and sulfated groups. Although previous studies showed that p-KG03 suppresses tumor cell growth and infection by encephalomyocarditis virus, its effect against enveloped virus infection and the biological mechanism of action have not been elucidated. In this report, the inhibitory activity of p KG03 against influenza virus was examined and compared with that of other sulfated polysaccharides (fucoidan and pentosan polysulfate) and antiviral agents (oseltamivir phosphate, oseltamivir carboxylate, amantadine, and ribavirin). The results of a cytopathic effect reduction assay using MDCK cells demonstrated that p-KG03 exhibited the 50% effective concentration (EC(50)) values of 0.19-0.48 MUg/ml against influenza type A virus infection (selectivity index >200) but not all influenza type B viruses. Mechanism studies showed that inhibition of influenza virus replication was maximized when p-KG03 was added during or within 6 h after viral infection, suggesting that mainly the viral adsorption and internalization steps are targeted by this compound. The results of influenza virus binding assay to p-KG03 and fluorescence microscopy indicate that the antiviral activity of p-KG03 is directly associated with its interaction with viral particles. The sulfated polysaccharide p-KG03 is a potent and specific influenza A viral entry inhibitor and may be a candidate for antiviral drug development. PMID- 22197248 TI - The development of Chinese specific human cytomegalovirus polyepitope recombinant vaccine. AB - Human cytomegalovirus (HCMV) infection is a major cause of morbidity in the recipients of organ transplants and in the congenitally infected infants. HCMV vaccine has emerged as an effective approach to prevent HCMV infection particularly for the development of multiple viral antigens vaccination and human leukocyte antigen (HLA)-restricted polyepitope technology. As the Chinese population makes up more than one fifth of the population worldwide, it is important to develop HCMV vaccines more specific for the Chinese population by targeting Chinese-restricted HLA alleles and antigens. In the present study, we designed a novel chimeric polyepitope vaccine based on the replication-deficient adenovirus Ad5F35, which encodes 83 HCMV T cell epitopes from 15 different HCMV antigens, restricted to 14 HLA I and 7 HLA II alleles that cover 92% of the Chinese population. Our results show that the recombinant adenovirus vaccine Ad5F35-CTL.Th can be efficiently transfected and expressed in peripheral blood mononuclear cells (PBMCs) with little cytopathic activity. Ad5F35-CTL.Th can also be endogenously processed and presented by PBMCs. Ad5F35-CTL.Th-stimulated HCMV specific cytotoxic T lymphocytes (CTLs) showed strong cytolytic activity against HCMV polyepitope-sensitized target cells. The CTL activity was accompanied by high levels of IFN-gamma production after Ad5F35-CTL.Th stimulation. The specificity and vigorous response to the recombinant adenovirus vaccine in vitro makes it a potential candidate to be used for transplantation recipients or congenitally infected infants. PMID- 22197249 TI - MiR-342-5p suppresses coxsackievirus B3 biosynthesis by targeting the 2C-coding region. AB - Coxsackievirus B type 3 (CVB3) is one of the major pathogens associated with human heart disease. miRNAs are a class of short, noncoding RNA that can post transcriptionally modulate gene expression. By comparing the CVB3 genome and miR 342-5p sequences, we found there were potential miR-342-5p targets in the CVB3 genome. To verify the effect of miR-342-5p on CVB3 biosynthesis, HeLa cells were infected with a Renilla luciferase (RLuc)-expressing CVB3 variant (RLuc-CVB3). We observed that miR-342-5p could significantly inhibit the expression of RLuc in infected cells. In HeLa cells infected with an enhanced green fluorescence protein (EGFP)-expressing CVB3 variant (EGFP-CVB3), EGFP expression was also significantly inhibited by miR-342-5p. The inhibitory effect of miR-342-5p on EGFP expression in EGFP-CVB3-infected cells could be reversed by transfection with anti-miR-342-5p oligonucleotide (AMO-miR-342-5p). Moreover, RNA and protein biosynthesis in wild-type CVB3 was significantly inhibited by miR-342-5p. By mutating the putative targets of miR-342-5p in the 2C-coding region, a sequence, nt4989-nt5015, was identified as the miR-342-5p target. The conserved nt4989 nt5015 sequences of CVB type 1-5 suggest miR-342-5p may exert its inhibitory effect in other types of coxsackievirus besides CVB3. Western blotting indicated that miR-342-5p could indeed suppress protein expression in CVB type 1 and 5. There was a moderate abundance of miR-342-5p in the gut, heart, and brain of Balb/c mice, suggesting that miR-342-5p may interact with CVB3 in vivo. Taken together, these results indicate that miR-342-5p can inhibit CVB3 biosynthesis by targeting its 2C-coding region and therefore may be a potential therapeutic agent in the treatment of CVB3 infection. PMID- 22197250 TI - Rewiring two-component signal transduction with small RNAs. AB - Bacterial two-component systems (TCSs) and small regulatory RNAs (sRNAs) form densely interconnected networks that integrate and transduce information from the environment into fine-tuned changes of gene expression. Many TCSs control target genes indirectly through regulation of sRNAs, which in turn regulate gene expression by base-pairing with mRNAs or targeting a protein. Conversely, sRNAs may control TCS synthesis, thereby recruiting the TCS regulon to other regulatory networks. Several TCSs control expression of multiple homologous sRNAs providing the regulatory networks with further flexibility. These sRNAs act redundantly, additively or hierarchically on targets. The regulatory speed of sRNAs and their unique features in gene regulation make them ideal players extending the flexibility, dynamic range or timing of TCS signaling. PMID- 22197251 TI - A liquid chromatography-tandem mass spectrometry method for the detection of economically motivated adulteration in protein-containing foods. AB - A new analytical method was developed to determine the presence of six (6) compounds with the potential to be used in economic adulteration to enhance the nitrogen content in milk products and bulk proteins. Residues were extracted from the matrix with 2% formic acid, after which acetonitrile (ACN) was added to induce precipitation of the proteins. Extracts were analyzed by liquid chromatography using a ZIC-HILIC column with tandem mass spectrometry (LC-MS/MS) using electrospray ionization (ESI). Single-laboratory method validation data was collected in six matrices fortified at concentrations down to 1.0 MUg/g (ppm). Average recoveries and average relative standard deviations (RSD) using spiked matrix calibration standard curves were the following: cyromazine (CY) 95.9% (7.5% RSD), dicyandiamide (DC) 98.1% (5.6% RSD), urea 102.5% (8.6% RSD), biuret (BU) 97.2% (6.6% RSD), triuret (TU) 97.7% (5.7% RSD), and amidinourea (AU) 93.4% (7.4% RSD). This method provides a rapid and effective approach to proactively combat economically motivated adulteration in protein-containing products. PMID- 22197252 TI - Purification of L-alpha glycerylphosphorylcholine by column chromatography. AB - Colorless L-alpha glycerylphosphorylcholine (L-alpha-GPC) was obtained at 99.8% purity, 69.8% recovery, and with a specific rotation of -2.5 degrees via a five step procedure. L-alpha-GPC was first produced by phospholipase A(1) hydrolysis of soy lecithin powder. Ca(2+) and Cl(-) were then effectively removed using two successive 001*7 cation and D311 anion exchange resin column chromatography procedures. Silica gel column chromatography and decoloration with active carbon were then applied to remove remaining impurities and colorant. Characterization of the L-alpha-GPC product was well in agreement with the standard. The resin and silica gel showed remarkable ability for L-alpha-GPC isolation after 10 uses. Thus, this study presents a simple and cost-effective method for preparing L alpha-GPC with high yield and purity, low cost, and environmental friendliness, and encourages future investigation into its adaptation for industrial applications. PMID- 22197253 TI - Three-phase hollow fiber microextraction based on two immiscible organic solvents for determination of tricyclic antidepressant drugs: comparison with conventional three-phase hollow fiber microextraction. AB - The aim of this research was to compare the extraction efficiencies of two modes of three-phase hollow fiber microextraction (HF-LLLME) based on aqueous and organic acceptor phases for analysis of tricyclic antidepressant (TCA) drugs. High-performance liquid chromatography with photodiode array detection (HPLC-DAD) was applied for determination of the drugs. In order to examine the ability of the new concept of HF-LLLME based on organic acceptor solvent in comparison with aqueous acceptor phase to extract the analytes, four TCAs were selected. The effect of different extraction conditions (i.e., type of acceptor phase, hollow fiber length, ionic strength, stirring rate, and extraction time) on the extraction efficiency of the TCAs was investigated and optimized using central composite design (CCD) as a powerful tool. Both methods were characterized by good linearity and high repeatability, but HF-LLLME with organic acceptor provided higher extraction efficiency and thus lower limits of detection (LODs). Calibration curves were linear (r(2)>0.996) in the range of 0.2-200 MUgL(-1). LODs for all the TCAs ranged from 0.08 to 0.2 MUgL(-1) using HPLC-DAD. Also an improvement in sensitivity of several orders of magnitude was achieved using single-ion monitoring GC-MS analyses (0.04 MUgL(-1)) due to compatibility of this technique with GC instrument. The applicability of the proposed HF-LLLME/GC-MS and HPLC-DAD methods was demonstrated by analyzing the drugs in spiked urine and plasma samples. The obtained recoveries of the drugs in the range of 87.9-109.2% indicated the excellent capability of the developed method for extraction of TCAs from complex matrices. PMID- 22197254 TI - Thin-film octadecyl-silica glass coating for automated 96-blade solid-phase microextraction coupled with liquid chromatography-tandem mass spectrometry for analysis of benzodiazepines. AB - A thin-film octadecyl (C18)-silica glass coating was developed as the extraction phase for an automated 96-blade solid-phase microextraction (SPME) system coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Various factors (e.g., sol-gel composition and aging time, coating preparation speed, coating thickness, and drying conditions) affecting the quality of C18-silica glass thin film coating were studied and optimized. The results showed that the stability and durability of the coating are functions of the coating thickness and drying conditions. Coating thickness is controlled by sol-gel composition, aging time and the withdrawal speed in the dipping method. Automated sample preparation was achieved using a robotic autosampler that enabled simultaneous preparation of 96 samples in a 96-well plate format. Under the optimum SPME conditions the proposed system requires a total of 140 min for preparation of all 96 samples (i.e., 30 min preconditioning, 40 min equilibrium extraction, 40 min desorption and 30 min carry over step). The performance of the C18-silica glass 96-blade SPME system was evaluated for high-throughput analysis of benzodiazepines from phosphate buffered saline solution (PBS) and human plasma, and the reusability, repeatability, and validity of the system were evaluated. When analysing spiked PBS and human plasma, the inter-blade reproducibility for four benzodiazepines was obtained in the ranges of 4-8% and 9-11% RSD (relative standard deviation), respectively, and intra-blade reproducibility were in the ranges of 3-9% and 8 13% RSD, respectively. The limits of detection and quantitation for plasma analysis were in the ranges of 0.4-0.7 ng/mL and 1.5-2.5 ng/mL for all four analytes. PMID- 22197255 TI - Purification of egg yolk phosvitin by anion exchange chromatography. AB - The objective of this study was to develop a simple method of phosvitin purification from hen egg yolk without using organic solvents. Egg yolk was diluted with equal volume of water and stirred for one hour at room temperature, followed by centrifugation to remove soluble proteins along with most of the yolk lipids in the supernatant. The granules were collected as the precipitate containing minimum amount of lipids (dry granules). The dry granules were dissolved in 0.05 M carbonate-bicarbonate buffer at pH 9.6, which yields a light yellowish solution used for anion exchange chromatography. Phosvitin fraction was collected from anion exchange chromatography as the last eluting peak with a purity of 92.6% and a yield of 35.4% of total phosvitin in the yolk or a recovery of 1.9% of total yolk dry matter, which are comparable to current methods employing organic solvents or chromatography after salt fractionation and dialysis. This method developed is simple and fast without using organic solvents. PMID- 22197256 TI - Dummy molecularly imprinted polymers on silica particles for selective solid phase extraction of tetrabromobisphenol A from water samples. AB - Surface molecular imprinted polymers (MIPs) on silica gel particles for highly selective recognition of tetrabromobisphenol A (TBBPA) were prepared by a sol-gel process. Diphenolic Acid (DPA) and bisphenol A (BPA), whose structures were similar to that of TBBPA were selected as dummy template molecules, and 3 aminopropyltriethoxysilane (APTES) and tetramethoxysilane (TEOS) were chosen as functional monomer and cross-linker, respectively. The obtained materials were characterized by FT-IR with diffuse reflectance accessory and the results indicated polymers were successfully grafted on the surface of silica gel supporters. The maximum static adsorption capacities for TBBPA of the DPA-MIPs, BPA-MIPs and non-imprinted polymers (NIPs) were 45, 38 and 22 mg g(-1) respectively, and the results of dynamic adsorption showed that the adsorption equilibrium can be achieved within 15 min for DPA- and BPA-MIPs. Both the DPA- and BPA-MIPs have higher selectivity for TBBPA than that of NIP when they are used as the sorbents for the solid phase extraction (SPE), while the adsorption property of DPA-MIPs was superior to that of BPA-MIPs at low concentration levels of TBBPA. The results indicated DPA-MIPs had more high affinity binding sites for TBBPA, which demonstrated that the strong interactions between the template and the functional monomer were favorable to form high affinity binding sites and improve the selectivity of the polymers. A corresponding analytical method for determination of the TBBPA residues in environmental samples was developed. The recoveries of TBBPA in tap water, river water and lake water were in the range from 85% to 97% with relative standard deviations below 7%, and its limit of detection can reach 2 ng mL(-1). PMID- 22197257 TI - [The utility of the short stay unit in patients with community acquired pneumonia]. PMID- 22197258 TI - [Care quality in patients with community-acquired pneumonia]. PMID- 22197259 TI - Photoperiod modulates access of 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) to the brain and its effect on gonadotropin and thyroid hormones in adult ewes. AB - The effects of photoperiod on the cerebrospinal fluid (CSF) concentration of six ortho-substituted polychlorinated biphenyls (PCBs: PCB28, PCB52, PCB101, PCB138, PCB153, and PCB180), the effects of an orally administered low dose of PCB153 (0.3mg/kg, three times a week for three weeks) on PCBs and thyroid hormones (THs) concentrations in the CSF and plasma, and the release of luteinizing hormone (LH) were determined in ovariectomized, estradiol-implanted ewes (2.5 years old) maintained indoors under artificial long day (LD, 16L: 8D) and short day (SD, 8L: 16D) conditions. Concentrations of two PCBs (PCB28 and PCB153) in the plasma and four PCBs in the CSF (PCB101, PCB138, PCB153, and PCB180) were significantly higher during LD than SD. Following PCB153 treatment, its concentration in the plasma was higher in SD (1.2 +/- 0.3 ng/ml) than LD (0.2 +/- 0.05 ng/ml), but similar in the CSF (10.2 +/- 3.7 pg/ml vs. 13 +/- 0.7 pg/ml) under both photoperiods. During SD, the concentration of PCB153 in the CSF was higher in treated animals than controls, while no differences were noted under LD. These findings indicate that in ewes, exposure of the brain to more highly chlorinated, ortho-substituted PCBs may be modulated by photoperiod. PCB153 treatment had no effect on plasma THs, but reduced total triiodothyronine concentration during LD and free thyroxine during SD in the CSF. Under both photoperiods, PCB153 reduced basal plasma LH and reinforced the inhibition of pulsatile LH release during LD. As PCB153 reduced LH and THs (which are involved in the seasonal control of reproduction in ewes), it may have a braking effect on seasonal transitions between active and inactive phases of reproduction. PMID- 22197260 TI - Short self-assembling peptides as building blocks for modern nanodevices. AB - Short, self-assembling peptides form a variety of stable nanostructures used for the rational design of functional devices. Peptides serve as organic templates for conjugating biorecognition elements, and assembling ordered nanoparticle arrays and hybrid supramolecular structures. We are witnessing the emergence of a new phase of bionanotechnology, particularly towards electronic, photonic and plasmonic applications. Recent advances include self-assembly of photoluminescent semiconducting nanowires and peptide-conjugated systems for sensing, catalysis and energy storage. Concurrently, methods and tools have been developed to control and manipulate the self-assembled nanostructures. Furthermore, there is growing knowledge on nanostructure properties such as piezoelectricity, dipolar electric field and stability. This review focuses on the emerging role of short, linear self-assembling peptides as simple and versatile building blocks for nanodevices. PMID- 22197262 TI - Bombecke K et al., "Medical students trained in communication skills show a decline in patient-centred attitudes: an observational study comparing two cohorts during clinical clerkships" [Patient Educ. Couns. 11 (2011) 310-318]. PMID- 22197261 TI - Factors affecting frequency of communication about family health history with family members and doctors in a medically underserved population. AB - OBJECTIVE: Family history contributes to risk for many common chronic diseases. Little research has investigated patient factors affecting communication of this information. METHODS: 1061 adult community health center patients were surveyed. We examined factors related to frequency of discussions about family health history (FHH) with family members and doctors. RESULTS: Patients who talked frequently with family members about FHH were more likely to report a family history of cancer (p =.012) and heart disease (p < .001), seek health information frequently in newspapers (p < .001) and in general (p < .001), and be female (p < .001). Patients who talked frequently with doctors about FHH were more likely to report a family history of heart disease (p = .011), meet physical activity recommendations (p = .022), seek health information frequently in newspapers (p < .001) and in general (p < .001), be female (p < .001), and not have experienced racial discrimination in healthcare (p < .001). CONCLUSION: Patients with a family history of some diseases, those not meeting physical activity recommendations, and those who do not frequently seek health information may not have ongoing FHH discussions. PRACTICE IMPLICATIONS: Interventions are needed to encourage providers to update patients' family histories systematically and assist patients in initiating FHH conversations in order to use this information for disease prevention and control. PMID- 22197263 TI - Inorganic nitrogen, sterols and bacterial source tracking as tools to characterize water quality and possible contamination sources in surface water. AB - The effects of agricultural activities on stream water quality were assessed by nitrogen analysis, further investigated by gas chromatography mass spectrometry (GC-MS) sterol analysis (including chemometric analysis), and characterized by bacterial source tracking (BST). Surface water samples were collected from five sites, throughout the agriculturally-influenced Nathan Creek watershed, British Columbia, Canada and a nearby control site between October 2005 and March 2006. From a total of 48 samples, Canadian Water Quality Guidelines were exceeded nineteen times for nitrate (NO3-; guideline value: 2.94 mg/L N) and four times for un-ionized ammonia (NH3; guideline value 0.019 mg/L N). Gas chromatography mass spectrometry single ion monitoring (GC-MS SIM) analysis of 18 sterols showed that five fecal sterols (coprostanol, episoprostanol, cholesterol, cholestanol, desmosterol) were detected at all sites except the control site (where only cholesterol, cholestanol and desmosterol were detected). Three phytosterols (campesterol, stigmasterol and beta-sitosterol) were also detected at all sites while the hormone estrone was present at one site on two occasions at concentrations of 0.01 and 0.04 MUg/L. Chemometric analysis (principal component analysis and cluster analysis) grouped sites based on their similarities in sterol composition. Analysis of ten sterol ratios (seven for identifying human fecal contamination and four for differentiating sources of fecal contamination) showed multiple instances of human and animal contamination for every site but the control site. Application of a Bacteroides-BST method confirmed contamination from ruminant animals, pigs and dogs in varying combinations at all impact sites. Together, these results confirmed the impact of agricultural activities on the Nathan Creek watershed and support a need for better land management practices to protect water quality and aquatic life. PMID- 22197264 TI - Enhanced hydrogen production from waste activated sludge by cascade utilization of organic matter in microbial electrolysis cells. AB - Fermentative hydrogen production from waste activated sludge (WAS) has low H2 yield because WAS contains limited amounts of carbohydrate suitable for use by hydrogen-producing bacteria. Here, augmentation of hydrogen production from WAS by microbial electrolysis cells (MECs) was implemented. H2 yields of 3.89+/-0.39 mg-H2/g-DS (5.67+/-0.61 mg-H2/g-VSS) from raw WAS and 6.78+/-0.94 mg-H2/g-DS (15.08+/-1.41 mg-H2/g-VSS) from alkaline-pretreated WAS were obtained in the two chamber MECs (TMECs). This was several times higher than yields obtained previously by fermentation. Single-chamber MECs (SMECs) with low internal resistance showed a H2 production rate that 13 times that of TMECs with similar H2 yield when alkaline-pretreated WAS was used. However, methanogenesis was detected after several batch cycles. A yield balance calculation revealed that carbohydrates were not the only substrates for electrohydrogenesis. Protein and its acidification products, such as volatile fatty acids are also responsible for a portion of H2 generation in MEC. Characterization of WAS in TMECs by three dimensional excitation-emission matrix (EEM) fluorescence spectroscopy with parallel factor analysis indicated that electrohydrogenesis reacted on the extracellular polymeric substances and intracellular substances of WAS. Cascade utilization of organic matter in MECs increased hydrogen production from WAS. MECs showed high hydrogen yield from WAS, fewer H2 sinks, and insensitivity to temperature. Optimizing MEC configurations and operation conditions and improving the pretreatment processes of WAS are necessary before practical application can take place on a large scale. PMID- 22197265 TI - Ecotoxicological assessment of grey water treatment systems with Daphnia magna and Chironomus riparius. AB - In order to meet environmental quality criteria, grey water was treated in four different ways: 1) aerobic 2) anaerobic+aerobic 3) aerobic+activated carbon 4) aerobic+ozone. Since each treatment has its own specific advantages and disadvantages, the aim of this study was to compare the ecotoxicity of differently treated grey water using Chironomus riparius (96 h test) and Daphnia magna (48 h and 21d test) as test organisms. Grey water exhibited acute toxicity to both test organisms. The aerobic and combined anaerobic+aerobic treatment eliminated mortality in the acute tests, but growth of C. riparius was still affected by these two effluents. Post-treatment by ozone and activated carbon completely removed the acute toxicity from grey water. In the chronic toxicity test the combined anaerobic+aerobic treatment strongly affected D. magna population growth rate (47%), while the aerobic treatment had a small (9%) but significant effect. Hence, aerobic treatment is the best option for biological treatment of grey water, removing most of the toxic effects of grey water. If advanced treatment is required, the treatment with either ozone or GAC were shown to be very effective in complete removal of toxicity from grey water. PMID- 22197266 TI - Electrochemical potential of Microgramma vaccinifolia rhizome lectin. AB - This work reports the isolation of Microgramma vaccinifolia rhizome lectin (MvRL) and the determination of electrochemical potentials of MvRL in the presence of Ca2+, Mg2+ and human type O erythrocytes. MvRL showed the highest specific hemagglutinating activity with human type O erythrocytes and showed a single polypeptide band of 17 kDa on SDS-PAGE. MvRL hemagglutinating activity was neutralized after dialysis with EDTA, and addition of Ca2+ and Mg2+ restored the activity. Electrochemical potentials of MvRL in the presence of 100 mM Ca2+ (882 mV) and 60 mM Mg2+ (1051 mV) were higher (p<0.05) than in the presence of only 0.15 M NaCl (247 mV), indicating that the electrochemical system was sensitive to structural and physico-chemical changes promoted by these ions. MvRL potential did not change in the presence of type O erythrocytes. The electrochemical system was able to detect changes in electrochemical potentials of MvRL promoted by Ca2+ and Mg2+, even in a complex environment (human serum supplemented with 40 and 60mM of these ions). The study reveals that the stimulatory effect of Ca2+ and Mg2+ on hemagglutinating activity may be linked to conformational change and/or alterations in surface charge distribution of MvRL. PMID- 22197267 TI - [Bacterial vaginosis in 2011: a lot of questions remain]. AB - Bacterial vaginosis is one of the most frequent vaginal affections. It results from a deep imbalance of the vaginal ecosystem whose mechanisms remain mysterious, even if recent progress were accomplished in their comprehension: if the flora implied in the bacterial vaginosis is recognized like polymorphic, it appears that Gardnerella vaginalis plays a major part with two genomically different forms: a commensal form (slightly adhesive to the epithelial cells), and a pathogenic one (strongly adhesive to the epithelial cells); the changes in lactobacilli are also to take into account: L. iners could be a marker of the vaginal flora imbalance whereas L. crispatus is generally met in the normal vaginal flora. These findings could influence the composition of coming probiotics; it is recognized that bacterial vaginosis is involved in the risk of prematurity but molecular quantification of G. vaginalis (and of Atopobium vaginae) is more sensitive for the diagnosis of BV what could improve the detection of high-risk pregnant women. The isolated antibiotic treatments are not very effective on the prevention of recurrences. The rebalancing of the vaginal flora is essential. In this field, the local estrogens showed some effectiveness. The use of probiotics is promising and can be recommended in complement of the antibiotic treatment even if the results of the clinical studies are still too heterogeneous to lead to precise indications. PMID- 22197268 TI - Unexpected high responses to tuberculin skin-test in farmed red deer: implications for tuberculosis control. AB - Tuberculosis (TB) in deer is a serious zoonotic disease of worldwide distribution. Detection of infected animals is usually performed using single or comparative skin-testing (SST/CST), although false responses due to sensitization to other mycobacteria may occur, hampering diagnostic specificity. We describe the evolution of the responses to the SST, CST and to an in-house serological assay in a red deer farm subjected to regular TB testing in southern Spain in an attempt to understand the dynamics of possible non-specific reactions occurring under field conditions. We performed 2288 skin-tests and ELISAs in nine sampling periods between May 2009 and January 2011. In May 2010, a strong increase in skin fold thickness in response to avian purified protein derivative (PPD) (mean=4.0mm, 95% CI=3.5-4.5) and bovine PPD (mean=1.8mm, 95% CI=1.6-2.0) was observed in yearling deer hinds (n=150), compared to values recorded for the same individuals in November 2009 (avian PPD: mean=0.7 mm, 95% CI=0.6-0.8 and bovine PPD: mean=0.7 mm, 95% CI=0.6-0.7) and in January 2011 (avian PPD: mean=2.2mm, 95% CI=1.9-2.4 and bovine PPD: mean=1.1mm, 95% CI=1.0-1.2). Using SST, 54 animals (36%) of the yearlings tested in May 2010 would have been classified as positive reactors, while none of them was positive in the CST. The five animals with highest skin fold increases to mycobacterial antigens were culled and subjected to post-mortem analysis, which confirmed the absence of Mycobacterium tuberculosis complex (MTBC) infection but demonstrated the presence of environmental mycobacteria and closely related bacteria in four out of the five analyzed animals. Our results demonstrated how non-specific responses to mycobacterial antigens can adversely affect the specificity of TB diagnosis based on the SST. Thus, once TB infection has been ruled out using confirmatory techniques, application of comparative diagnostic tests is highly advisable to maximize test specificity and avoid the slaughter of false positive reactors. PMID- 22197269 TI - Toward understanding how early-life social experiences alter oxytocin- and vasopressin-regulated social behaviors. AB - The early-life social environment has profound effects on brain development and subsequent expression of social behavior. Oxytocin and vasopressin are expressed and released in the brain and are important regulators of social behavior. Accordingly, the early social environment may alter social behaviors via changes in the oxytocin and/or vasopressin systems. To test this hypothesis, and to gain mechanistic insights, rodent models mimicking either a deprived (e.g. maternal separation) or enriched (e.g. neonatal handling) early social environment have been utilized. Findings indeed show that differences in the quality of the early social environment are associated with brain region-specific alterations in oxytocin and vasopressin expression and oxytocin receptor and vasopressin 1a receptor binding. Early social environment-induced changes in oxytocin and vasopressin systems were associated with changes in several forms of social behavior, including maternal care, aggression, play-fighting, and social recognition. First studies provide evidence for a causal link between altered vasopressin responsiveness and impairments in social recognition in rats exposed to maternal separation and a role for epigenetic mechanisms to explain persistent increases in vasopressin expression in mice exposed to maternal separation. Overall, initial findings suggest that oxytocin and vasopressin systems may mediate early social environment-induced alterations in social behavior. Additional comprehensive studies will be necessary to advance our understanding to what extent changes in oxytocin and vasopressin underlie early social environment-induced alterations in social behavior. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID- 22197271 TI - Modulating social behavior with oxytocin: how does it work? What does it mean? AB - Among its many roles in body and brain, oxytocin influences social behavior. Understanding the precise nature of this influence is crucial, both within the broader theoretical context of neurobiology, social neuroscience and brain evolution, but also within a clinical context of disorders such as anxiety, schizophrenia, and autism. Research exploring oxytocin's role in human social behavior is difficult owing to its release in both body and brain and its interactive effects with other hormones and neuromodulators. Additional difficulties are due to the intricacies of the blood-brain barrier and oxytocin's instability, which creates measurement issues. Questions concerning how to interpret behavioral results of human experiments manipulating oxytocin are thus made all the more pressing. The current paper discusses several such questions. We highlight unresolved fundamental issues about what exactly happens when oxytocin is administered intranasally, whether such oxytocin does in fact reach appropriate receptors in brain, and whether central or peripheral influences account for the observed behavioral effects. We also highlight the deeper conceptual issue of whether the human data should be narrowly interpreted as implicating a specific role for oxytocin in complex social cognition, such a generosity, trust, or mentalizing, or more broadly interpreted as implicating a lower-level general effect on general states and dispositions, such as anxiety and social motivation. Using several influential studies, we show how seemingly specific, higher-level social-cognitive effects can emerge via a process by which oxytocin's broad influence is channeled into a specific social behavior in a context of an appropriate social and research setting. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID- 22197270 TI - The neuropharmacology of prolactin secretion elicited by 3,4 methylenedioxymethamphetamine ("ecstasy"): a concurrent microdialysis and plasma analysis study. AB - 3,4-methylenedioxymethamphetamine (MDMA) is a substituted phenethylamine that is widely abused as the street drug "ecstasy". Racemic MDMA (S,R(+/-)-MDMA) and its stereoisomers elicit complex spectrums of psychobiological, neurochemical, and hormonal effects. In this regard, recent findings demonstrated that S,R(+/-)-MDMA and its stereoisomer R(-)-MDMA elicit increases in striatal extracellular serotonin levels and plasma levels of the hormone prolactin in rhesus monkeys. In the present mechanistic study, we evaluated the role of the serotonin transporter and the 5-HT(2A) receptor in S,R(+/-)-MDMA- and R(-)-MDMA-elicited prolactin secretion in rhesus monkeys through concurrent microdialysis and plasma analysis determinations and drug interaction experiments. Concurrent neurochemical and hormone determinations showed a strong positive temporal correlation between serotonin release and prolactin secretion. Consistent with their distinct mechanisms of action and previous studies showing that the serotonin transporter inhibitor fluoxetine attenuates the behavioral and neurochemical effects of S,R(+/-)-MDMA, pretreatment with fluoxetine attenuated serotonin release elicited by either S,R(+/-)-MDMA or R(-)-MDMA. As hypothesized, at a dose that had no significant effects on circulating prolactin levels when administered alone, fluoxetine also attenuated prolactin secretion elicited by S,R(+/-)-MDMA. In contrast, combined pretreatment with both fluoxetine and the selective 5-HT(2A) receptor antagonist M100907 was required to attenuate prolactin secretion elicited by R(-)-MDMA, suggesting that this stereoisomer of S,R(+/-)-MDMA elicits prolactin secretion through both serotonin release and direct agonism of 5-HT(2A) receptors. Accordingly, these findings inform our understanding of the neuropharmacology of both S,R(+/-)-MDMA and R(-)-MDMA and the regulation of prolactin secretion. PMID- 22197272 TI - Photoperiod-dependent effects of neuronal nitric oxide synthase inhibition on aggression in Siberian hamsters. AB - Many nontropical species undergo physiological and behavioral adaptations in response to seasonal changes in photoperiod, or day length. In most rodent species, short winter photoperiods reduce testosterone concentrations, which provoke gonadal regression and reduce testosterone-dependent behaviors such as mating and aggression. Seasonally-breeding Siberian hamsters, however, are paradoxically more aggressive in short-days, despite much reduced reproductive activity and testosterone concentrations. Nitric oxide (NO) signaling has been proposed as part of an alternate mechanism underlying this phenomenon. A reduction in neuronal nitric oxide synthase (nNOS), the enzyme responsible for synthesizing NO in the brain, is associated with increased aggression in male short-day hamsters. In the present study, we hypothesized that pharmacological inhibition of nNOS would increase aggressive behavior in long days, but not in short days because nNOS is already reduced. Adult male Siberian hamsters were housed in either long (LD 16:8h) or short (LD 8:16h) photoperiods for 8weeks, then treated with either the selective nNOS inhibitor, 3-bromo-7-nitroindazole (3BrN) or oil vehicle, and subsequently tested for aggression in a resident intruder test. Treatment with 3BrN increased attack frequency and duration in long days, but had no effect in short days. Short days also reduced testosterone concentrations, without any effect of treatment. These data provide further evidence linking reduced nNOS to elevated short-day aggression and support a role for NO signaling in this phenomenon. PMID- 22197274 TI - International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. AB - BACKGROUND: There are a limited number of publications on the management of gynecologic/obstetric events in female patients with hereditary angioedema caused by C1 inhibitor deficiency (HAE-C1-INH). OBJECTIVE: We sought to elaborate guidelines for optimizing the management of gynecologic/obstetric events in female patients with HAE-C1-INH. METHODS: A roundtable discussion took place at the 6th C1 Inhibitor Deficiency Workshop (May 2009, Budapest, Hungary). A review of related literature in English was performed. RESULTS: Contraception: Estrogens should be avoided. Barrier methods, intrauterine devices, and progestins can be used. Pregnancy: Attenuated androgens are contraindicated and should be discontinued before attempting conception. Plasma-derived human C1 inhibitor concentrate (pdhC1INH) is preferred for acute treatment, short-term prophylaxis, or long-term prophylaxis. Tranexamic acid or virally inactivated fresh frozen plasma can be used for long-term prophylaxis if human plasma-derived C1-INH is not available. No safety data are available on icatibant, ecallantide, or recombinant human C1-INH (rhC1INH). Parturition: Complications during vaginal delivery are rare. Prophylaxis before labor and delivery might not be clinically indicated, but pdhC1INH therapeutic doses (20 U/kg) should be available. Nevertheless, each case should be treated based on HAE-C1-INH symptoms during pregnancy and previous labors. pdhC1INH prophylaxis is advised before forceps or vacuum extraction or cesarean section. Regional anesthesia is preferred to endotracheal intubation. Breast cancer: Attenuated androgens should be avoided. Antiestrogens can worsen angioedema symptoms. In these cases anastrozole might be an alternative. Other issues addressed include special features of HAE-C1-INH treatment in female patients, genetic counseling, infertility, abortion, lactation, menopause treatment, and endometrial cancer. CONCLUSIONS: A consensus for the management of female patients with HAE-C1-INH is presented. PMID- 22197273 TI - CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia. AB - BACKGROUND: CD27 is a lymphocyte costimulatory molecule that regulates T-cell, natural killer (NK) cell, B-cell, and plasma cell function, survival, and differentiation. On the basis of its function and expression pattern, we considered CD27 a candidate gene in patients with hypogammaglobulinemia. OBJECTIVE: We sought to describe the clinical and immunologic phenotypes of patients with genetic CD27 deficiency. METHODS: A molecular and extended immunologic analysis was performed on 2 patients lacking CD27 expression. RESULTS: We identified 2 brothers with a homozygous mutation in CD27 leading to absence of CD27 expression. Both patients had persistent symptomatic EBV viremia. The index patient was hypogammaglobulinemic, and immunoglobulin replacement therapy was initiated. His brother had aplastic anemia in the course of his EBV infection and died from fulminant gram-positive bacterial sepsis. Immunologically, lack of CD27 expression was associated with impaired T cell dependent B-cell responses and T-cell dysfunction. CONCLUSION: Our findings identify a role for CD27 in human subjects and suggest that this deficiency can explain particular cases of persistent symptomatic EBV viremia with hypogammaglobulinemia and impaired T cell-dependent antibody generation. PMID- 22197275 TI - [Evaluation of the costs of transient elastography (FibroScan((r))) in the diagnosis of liver fibrosis in HIV patients with hepatitis C virus]. AB - INTRODUCTION: The assessment of liver fibrosis is crucial for taking therapeutic decisions in patients infected with HIV/AIDS coinfected with HCV, because it allows the prognosis of the disease and the prioritization of hepatitis C treatment in these patients. METHODS: A discrete events model simulation (DEMS) and a Markov model have been developed to represent the evolution of liver fibrosis to cirrhosis in patients coinfected with HIV/HVC. The model evaluated two alternatives for the diagnosis and monitoring of these patients, transient elastography performed annually and liver biopsy performed every seven years. The models have been developed under Health Care System perspective and only considered direct medical costs (disease treatment and health state costs). One way sensitivity analyses were carried out to assess the impact of parameters with higher uncertainty. A discount rate of 3% was applied. RESULTS: Base case analysis shows that the diagnosis and monitoring of patients with transient elastography is a dominant strategy compared with to liver biopsy, resulting in greater life expectancy at lower cost. The sensitivity analysis performed confirmed the robustness of these results. CONCLUSION: Transient elastography has proved to be a dominant strategy compared to liver biopsy in the diagnosis and monitoring of liver fibrosis in patients coinfected with HIV/HCV in Spain. PMID- 22197276 TI - [Can we advance the diagnosis of the sustained virological response to 12 weeks after finishing HVC treatment?]. PMID- 22197277 TI - [With paroxysmal nocturnal haemoglobinuria and treatment with eculizumab]. PMID- 22197278 TI - Monitoring of East Channel dredge areas benthic fish population and its implications. AB - Regional annual sampling of commercial fish stocks formed a high priority for monitoring studies attendant with the granting of aggregate dredging licenses in the Eastern Channel Region (ECR) which had previously not been dredged. An assessment of 4 m beam trawl sampling between 2005 and 2008 following the granting of licences in 2006 is provided. The majority of fish species have shown marked reductions in abundance since commencement of dredging. Draghead entrainment has been identified as a possible contributory cause based upon the known vulnerability of selected species (Drabble, 2012). Other environmental factors considered offer no explanation for the changes in abundance. Comparative analyses with ICES data for plaice and sole over the study period demonstrate that changes in the ECR do not result from seasonal flux in the wider populations. An alternative impact model and potential mitigation measures are suggested. PMID- 22197279 TI - Comment on Stadmark and Conley (2011) "Mussel farming as a nutrient reduction measure in the Baltic Sea: consideration of nutrient biogeochemical cycles". PMID- 22197280 TI - Projected entrainment of fish resulting from aggregate dredging. AB - Previous research to assess impacts from aggregate dredging has focussed on infaunal species with few studies made of fish entrainment. Entrainment evidence from hydraulic dredging studies is reviewed to develop a sensitivity index for benthic fish. Environmental monitoring attendant with the granting of new licences in the Eastern Channel Region (ECR) in 2006 offers a unique opportunity to assess the effects of dredging upon fish. Projected theoretical fish entrainment rates are calculated based upon: abundance data from 4m beam trawl sampling of fish species over the period 2005-2008; sensitivity data; and dredging activity and footprint derived from Electronic monitoring System (EMS) data. Results have been compared with actual entrainment rates and also against summary results from independent analysis of the changes in fish population over the period 2005-2008 (Drabble, 2012). The case is made for entrainment surveys to form part of impact monitoring for marine aggregate dredging. PMID- 22197281 TI - Bilateral talar avulsion fractures secondary to seizure: a case report. AB - Musculoskeletal injury as a result of seizure activity is not uncommon, posterior shoulder dislocation being a well-described example. In this report, we describe what we believe to be the first published case of bilateral talar avulsion fractures secondary to seizure. PMID- 22197282 TI - Do weight-bearing films affect decision making in hallux valgus surgery? AB - Hallux valgus is a complex deformity of the first ray and forefoot that can be surgically treated using different procedures and osteotomies. Preoperative planning includes anteroposterior and lateral plain films. The effect of weight bearing on the results of the standardized measurements is still the subject of debate. We evaluated the effect of weight-bearing on the results of measurements and decision making by expert evaluators. A total of 21 foot and ankle surgeons were given weight-bearing and non-weight-bearing anteroposterior plain foot films of patients with hallux valgus. They were asked to measure 3 standard angles and then to select the most appropriate procedure from a short list. Using a paired Student's t test, no difference in the angles measured nor in the procedures chosen was detected between the weight-bearing and non-weight-bearing films. Although it is generally accepted that decisions regarding the treatment of hallux valgus should be based on plain weight-bearing films, in the present study, we established that non-weight-bearing films can reliably be used to choose the surgical procedure. PMID- 22197283 TI - Failure after soft-tissue release with tendon transfer for flexible iatrogenic hallux varus: a systematic review. AB - Hallux valgus is a common forefoot pathology often requiring surgical intervention for symptomatic relief. One complication of hallux valgus correction is flexible hallux varus. Iatrogenic flexible hallux varus often requires surgical repair; however, the most advantageous surgical procedure for repair of iatrogenic flexible hallux varus and their sustainability remains unclear. Therefore, we performed a systematic review to determine the sustainability of soft-tissue release with tendon transfer for the correction of iatrogenic flexible hallux varus. Studies were eligible for inclusion only if they involved failure of soft-tissue release with tendon transfer for flexible iatrogenic hallux varus. Eight studies met our inclusion criteria, seven of which were evidence-based medicine level IV studies and one was level V. A total of 52 patients, all female, involving 68 feet, were included. All studies included soft tissue release of the first metatarsal-phalangeal joint capsule and 1 of the following procedures: Johnson transfer of the extensor hallucis longus tendon with arthrodesis of the hallux interphalangeal joint (41 feet); Hawkins transfer of the abductor hallucis tendon (9 feet); reverse Hawkins transfer (7 feet); Valtin transfer of the first dorsal interosseous tendon (7 feet); and Myerson transfer of the extensor hallucis brevis tendon (4 feet). The weighted mean age of the patients was 50.4 years, and the weighted mean follow-up was 30.2 months. A total of 11 complications (16.2%) occurred. Of note, only 3 cases (4.4%) of recurrent hallux varus deformity developed, all of which occurred after Johnson transfer of the extensor hallucis longus tendon, with arthrodesis of the hallux interphalangeal joint. Our results support that sustainable correction of iatrogenic flexible hallux varus can be achieved with soft-tissue release of the first metatarsal-phalangeal joint combined with a variety of tendon transfer procedures. However, given the limited data available, potential areas for additional prospective investigation remain. PMID- 22197284 TI - Reduction calcaneoplasty and local muscle rotation flap as a salvage option for calcaneal osteomyelitis with soft tissue defect. AB - Plantar heel wounds with infection remain a surgical challenge. Reduction calcaneoplasty combined with local muscle flap is an alternative technique to achieve limb salvage when standard wound therapy fails to resolve complex wounds of the plantar heel complicated by osteomyelitis of the calcaneus. PMID- 22197285 TI - Arthroscopy of the first metatarsophalangeal joint in 59 consecutive cases. AB - The authors analyzed the results of 59 consecutive cases of the first metatarsophalangeal (MTP-I) joint arthroscopy to verify the efficacy and safety of the procedure. Fifty-nine patients were followed for >18 months after MTP-I joint arthroscopic procedures. The mean duration of follow-up was 25 months. Clinically, the American Orthopaedic Foot and Ankle Society (AOFAS) hallux metatarsophalangeal-interphalangeal scale and the satisfaction of the patients were evaluated. Hallux valgus angle, the first intermetatarsal angle, and medial sesamoid position were analyzed in cases of hallux valgus. The American Orthopaedic Foot and Ankle Society hallux metatarsophalangeal-interphalangeal scale score was increased from 69 points preoperatively to 92 points postoperatively (p < .05). Radiologically, the mean hallux valgus angle was decreased from 29.2 degrees preoperatively to 9.7 degrees postoperatively (p < .05). The mean first intermetatarsal angle was decreased from 14.8 degrees preoperatively to 7.7 degrees postoperatively (p < .05). The medial sesamoid position was improved from 4.8 preoperatively to 2.0 postoperatively (p < .05). Ninety-five percent of the patients were satisfied with the procedures. There was 1 case of a wound problem and 1 case of temporary digital nerve injury as complications. Based on our experience, arthroscopy of MTP-I joint appears to be a safe and reproducible procedure for selected cases of MTP-I joint disorders. PMID- 22197286 TI - The validity of self-report as a technique for measuring short-term complications after total hip arthroplasty in a joint replacement registry. AB - This study evaluated concordance between self-reports and surgeon assessments of short-term complications. A total of 3976 primary total hip arthroplasty patients consented for an institutional registry (5/2007-12/2008); 3186 (80.1%) completed a 6-month survey; 137 (4.4%) reported deep venous thrombosis, pulmonary embolism, major bleeding, fracture, or dislocation. Patients reporting complications were called. Positive predictive values and 95% confidence intervals (95% CI) for patient self-report were measured, using surgeon assessment for comparison: pulmonary embolism, 88.9% (95% CI, 78.4%-99.4%); dislocation, 81.1% (95% CI, 75.9%-86.5%); fracture, 73.7% (95% CI, 63.8%-83.5%); deep venous thrombosis, 69.7% (95% CI, 61.9%-77.5%); major bleeding, 32.0% (95% CI, 19.4%-44.5%); any bleeding, 88.0% (95% CI, 75.3%-99.9%). Of 97 confirmed complications, 64.95% presented to outside institutions. Registry data on self-reported complications may overcome limitations of traditional methods, but data should be interpreted cautiously. Concordance was high for PE and dislocation but low for major bleeding. PMID- 22197287 TI - The effect of patellar replacement technique on patellofemoral complications and anterior knee pain. AB - Routine patella replacement with total knee arthroplasty has not been universally adopted because of associated patellofemoral complications such as anterior knee pain (AKP). In the proposed technique, the articular surface of the lateral facet of the patella is excised to the depth of the subchondral bone, and the medial facet is then cut parallel to the anterior surface. We evaluated any correlation between various radiographic parameters and AKP in 100 consecutive fixed-bearing posterior-stabilized total knee arthroplasties. There were no cases of fracture, avascular necrosis, subluxation, dislocation, patellar baja, or overstuffing of the patella. Anterior knee pain was present in 11% of cases, and no cases were severe or disabling. There were no correlations between AKP, range of motion, patellar size and shape, and any of the radiographic parameters. PMID- 22197289 TI - Effectiveness of false profile radiographs in detection of pelvic discontinuity. AB - Pelvic dissociation is a rare but serious potential complication of total hip arthroplasty. The purpose of this study is to evaluate the effectiveness of the false profile view compared with traditional radiographs in detecting pelvic dissociation. Ten cadaver pelves were skeletonized, and noncemented acetabular hip arthroplasty components were implanted. Anteroposterior, lateral, iliac oblique, and false profile radiographs were obtained before and after creating pelvic dissociations and analyzed in a blinded fashion. The sensitivity of the false profile view for detecting pelvic dissociation was 79% (confidence interval, 70-86), which was greater than the sensitivity for anteroposterior and lateral views. This difference was statistically significant. False profile views are a potentially valuable addition to the traditional radiographic evaluation of pelvic discontinuity in hip arthroplasty. PMID- 22197290 TI - Analysis of a kinetic multi-segment foot model part II: kinetics and clinical implications. AB - Kinematic multi-segment foot models have seen increased use in clinical and research settings, but the addition of kinetics has been limited and hampered by measurement limitations and modeling assumptions. In this second of two companion papers, we complete the presentation and analysis of a three segment kinetic foot model by incorporating kinetic parameters and calculating joint moments and powers. The model was tested on 17 pediatric subjects (ages 7-18 years) during normal gait. Ground reaction forces were measured using two adjacent force platforms, requiring targeted walking and the creation of two sub-models to analyze ankle, midtarsal, and 1st metatarsophalangeal joints. Targeted walking resulted in only minimal kinematic and kinetic differences compared with walking at self selected speeds. Joint moments and powers were calculated and ensemble averages are presented as a normative database for comparison purposes. Ankle joint powers are shown to be overestimated when using a traditional single segment foot model, as substantial angular velocities are attributed to the mid tarsal joint. Power transfer is apparent between the 1st metatarsophalangeal and mid-tarsal joints in terminal stance/pre-swing. While the measurement approach presented here is limited to clinical populations with only minimal impairments, some elements of the model can also be incorporated into routine clinical gait analysis. PMID- 22197291 TI - Sustainable policies to improve health and prevent climate change. PMID- 22197292 TI - Interim evaluation of a large scale sanitation, hygiene and water improvement programme on childhood diarrhea and respiratory disease in rural Bangladesh. AB - Started in 2007, the Sanitation Hygiene Education and Water Supply in Bangladesh (SHEWA-B) project aims to improve the hygiene, sanitation and water supply for 20 million people in Bangladesh, and thus reduce disease among this population. This paper assesses the effectiveness of SHEWA-B on changing behaviors and reducing diarrhea and respiratory illness among children < 5 years of age. We assessed behaviors at baseline in 2007 and after 6 months and 18 months by conducting structured observation of handwashing behavior in 500 intervention and 500 control households. In addition we conducted spot checks of water and sanitation facilities in 850 intervention and 850 control households. We also collected monthly data on diarrhea and respiratory illness from 500 intervention and 500 control households from October 2007 to September 2009. Participants washed their hands with soap < 3% of the time around food related events in both intervention and control households at baseline and after 18 months. Washing both hands with soap or ash after cleaning a child's anus increased from 22% to 36%, and no access to a latrine decreased from 10% to 6.8% from baseline to 18 months. The prevalence of diarrhea and respiratory illness, among children <5 years of age were similar in intervention and control communities throughout the study. This large scale sanitation, hygiene and water improvement programme resulted in improvements in a few of its targeted behaviors, but these modest behavior changes have not yet resulted in a measurable reduction in childhood diarrhea and respiratory illness. PMID- 22197293 TI - Altered social cohesion and adverse psychological experiences with chronic food insecurity in the non-market economy and complex households of Burkina Faso. AB - Food insecurity negatively impacts outcomes in adults and children including parenting practices, child development, educational achievement, school performance, diet, and nutritional status. Ethnographic and quantitative research suggests that food insecurity affects well-being not only through the lack food, poor diet, and hunger, but also through social and psychological consequences that are closely linked to it. These studies are limited in number, and have mostly been carried out in contexts with market economies where household access to food depends almost solely on income. This study considers the social and psychological experiences closely linked to food insecurity in northern Burkina Faso, a context marked by subsistence farming, chronic food insecurity with a strong seasonal pattern, and a complex social structure. A total of 33 men and women from ten households were interviewed in February 2001 using semi-structured interview guides. Data were analyzed following the principles of thematic analysis. Food insecurity is closely linked with consequences such as concern, worries, and anxiety that ultimately lead to weight and sleep loss. Food insecurity results in feelings of alienation (e.g., shame) and deprivation (e.g., guilt), and alters household cohesion leading to disputes and difficulties keeping children at home. Decisions made by household members to manage and cope with food insecurity are shaped by their fear of alienation and other cultural and social norms. These findings, although derived from data collected 10 years ago before the 2008 food and fuel crises, remain valid in the study context, and emphasize the importance of social and psychological consequences closely linked to food insecurity and their negative impact on the well-being at both individual and household levels in contexts of non-market economy and chronic food insecurity. Attention to these non-nutritional consequences will improve the design, implementation, and evaluation of food insecurity programs in this and similar contexts. PMID- 22197294 TI - Multicentre validation of different predictive tools of non-sentinel lymph node involvement in breast cancer. AB - Sentinel lymph node (SN) biopsy offers the possibility of selective axillary treatment for breast cancer patients, but there are only limited means for the selective treatment of SN-positive patients. Eight predictive models assessing the risk of non-SN involvement in patients with SN metastasis were tested in a multi-institutional setting. Data of 200 consecutive patients with metastatic SNs and axillary lymph node dissection from each of the 5 participating centres were entered into the selected non-SN metastasis predictive tools. There were significant differences between centres in the distribution of most parameters used in the predictive models, including tumour size, type, grade, oestrogen receptor positivity, rate of lymphovascular invasion, proportion of micrometastatic cases and the presence of extracapsular extension of SN metastasis. There were also significant differences in the proportion of cases classified as having low risk of non-SN metastasis. Despite these differences, there were practically no such differences in the sensitivities, specificities and false reassurance rates of the predictive tools. Each predictive tool used in clinical practice for patient and physician decision on further axillary treatment of SN-positive patients may require individual institutional validation; such validation may reveal different predictive tools to be the best in different institutions. PMID- 22197295 TI - Deposition of continuous platinum shells on gold nanoparticles by chemical precipitation. AB - Continuous platinum shells consisting of ~5 atomic layers were deposited onto preformed gold seeds in aqueous medium by reducing hexachloroplatinic acid with ascorbic acid. By controlling the reduction kinetics of Pt(IV) species and the properties of the substrate, it was possible to ensure a slow and controlled deposition of platinum atoms onto the gold cores. Electrochemical evaluations revealed the presence of a compact platinum shell. The mass specific oxygen reduction activity of platinum in the AuPt core-shell nanoparticles was found to be four times higher than that of platinum black and comparable to that of polycrystalline bulk metal. PMID- 22197296 TI - Sensorimotor gating, working and social memory deficits in mice with reduced expression of the vesicular glutamate transporter VGLUT1. AB - Glutamate is the main excitatory neurotransmitter in the central nervous system. A hypoglutamatergic state is believed to play an important role in the pathophysiology of schizophrenia. The release of glutamate in the brain is modulated by a class of vesicular glutamate transporters, VGLUT1-3. Among them, VGLUT1 represents the isoform predominantly expressed in the neocortex and hippocampus. Here we investigated the potential involvement of VGLUT1 deficiency in generating schizophrenia-like abnormalities by testing mice with diminished expression of VGLUT1 in several behavioural tests relevant for schizophrenia. We found behavioural alterations in these mice resembling correlates of schizophrenia, such as working- and social memory impairments and deficits in prepulse inhibition (PPI) of the acoustic startle reflex (ASR), but normal locomotor behaviour under basal conditions. Our data may be important for a better understanding of the contribution of reduced VGLUT1-mediated presynaptic glutamatergic neurotransmission in the generation of several behavioural abnormalities associated with schizophrenia. PMID- 22197297 TI - The antidepressant-like effect of fisetin involves the serotonergic and noradrenergic system. AB - Flavonoids, which are polyphenolic compounds, have been reported to possess remarkable antioxidant and anti-inflammatory activities. Among the dietary flavonoids, fisetin (3,3',4',7-tetrahydroxyflavone) possesses a significant spectrum of biochemical and pharmacological actions. The present study aimed to investigate the antidepressant potential of fisetin and its possible mechanism. Two mouse models of despair tests were used to evaluate the antidepressant-like effect of fisetin. The results suggested that fisetin (10 and 20mg/kg, p.o.) dose dependently inhibited the immobility time in both behavioral tests, while the doses that affected the immobile response did not affect locomotor activity. Two behavioral models, reserpine-induced hypothermia and ptosis, and p chlorophenylalanine (PCPA)-induced depletion of serotonin, were used to explore the possible involvement of fisetin in the noradrenergic and serotonergic system. The higher dose of fisetin was found to effectively antagonize the hypothermia, but not ptosis, induced by reserpine. Pre-treatment with PCPA abolished the anti immobility effect of fisetin in the forced swimming and tail suspension tests. Moreover, neurochemical assays showed that fisetin produced an increase in serotonin and noradrenaline levels in the frontal cortex and hippocampus. Monoamine oxidase (MAO) activity in the mouse brain was inhibited by 14.7% after treatment with fisetin, while MAO-B activity was not affected. These findings indicate that the antidepressant-like effect of fisetin involves the regulation of the central serotonin and noradrenaline levels. PMID- 22197298 TI - Cognitive phenotyping of amyloid precursor protein transgenic J20 mice. AB - Transgenic mice that express familial Alzheimer's disease mutant forms of the human amyloid precursor protein (hAPP) have proved to be invaluable in determining the impact that the neurotoxic amyloid-beta peptide has in vivo. In addition to the propensity to accumulate cerebral amyloid plaques, a crucial characteristic of hAPP mouse models is their cognitive impairments. To date the most widely used test for analyzing cognitive impairment in hAPP mice is the Morris water maze (MWM) which, due to the fact that mice are not "natural" swimmers, may not always be the ideal paradigm to investigate cognitive behaviours. Furthermore, not all cognitive impairments have been replicated across research laboratories. In the current study, we characterised the cognitive abilities of the J20 transgenic mouse line (expressing the Swedish 670/671(KM->NL) and Indiana (717(V->F)hAPP mutations) and non-transgenic mice. Mice were assessed in the cheeseboard task (i.e., a 'dry version' of the MWM) and a variety of other cognitive paradigms to test fear conditioning, object recognition and short-term memory to broaden the understanding of the cognitive deficits in J20 mice. hAPP transgenic mice perform normally in tasks for fear conditioning, short-term object recognition and short-term memory of context familiarity. However, they were profoundly impaired in their spatial reference memory capabilities in the cheeseboard task. The cheeseboard task has potential to replace the MWM task in situations where the MWM is not suitable for particular mouse models. PMID- 22197299 TI - Neurotransmission of the antidepressant-like effects of the growth hormone releasing hormone antagonist MZ-4-71. AB - MZ-4-71 is an antagonist of growth hormone-releasing hormone (GH-RH) which suppresses the secretion of GH-RH. It has been shown that MZ-4-71 has antidepressive-like effects in a modified forced swimming test (FST) in mice, exerts anxiolytic effects in an elevated plus maze test, improves memory consolidation in passive avoidance learning, and corrects the impairment of memory consolidation caused by beta-amyloid 25-35 in mice. However, little is known about the mechanisms of action of MZ-4-71 on brain functions. The involvement of the adrenergic, serotonergic, cholinergic, dopaminergic or GABA ergic receptors in the antidepressant-like action of MZ-4-71 (1.0 MUg/2 MUl, intracerebroventricular (i.c.v.)) was studied in a modified mouse forced swimming test (FST). Mice were pretreated with a non-selective alpha-adrenergic receptor antagonist, phenoxybenzamine, an alpha1/alpha2beta-adrenergic receptor antagonist prazosin, an alpha2-adrenergic receptor antagonist, yohimbine, a beta-adrenergic receptor antagonist, propranolol, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist methysergide, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a non-selective muscarinic acetylcholine receptor antagonist, atropine, a D2, D3, D4 dopamine receptor antagonist, haloperidol or a gamma aminobutyric acid subunit A (GABA-A) receptor antagonist bicuculline. Phenoxybenzamine, prazosin, methysergide, cyproheptadine and atropine prevented the effects of MZ-4-71 on the immobility, the climbing and the swimming times. Yohimbine, propranolol, haloperidol and bicuculline did not change the effects of MZ-4-71. The results demonstrated that the antidepressant-like effects of MZ-4-71 in this modified mouse FST are mediated, at least in part, by the an interaction of the alpha1-adrenergic, 5-HT1/5-HT2 serotonergic, and muscarinic acetylcholine receptors. PMID- 22197301 TI - Randomized trial comparing computer-delivered and face-to-face personalized feedback interventions for high-risk drinking among college students. AB - This study evaluated the efficacy of two brief personalized feedback interventions (PFIs) using identical feedback and motivational interviewing strategies aimed at reducing alcohol consumption and alcohol-related problems to two control conditions among a sample of high-risk drinking college students. Students (N = 152) were randomly assigned to a computer-delivered PFI with a video interviewer, a face-to-face PFI with a live interviewer, a comprehensive assessment condition, or a minimal assessment-only condition. At 10 weeks posttreatment, the face-to-face PFI significantly reduced weekly drinking quantity and peak and typical blood alcohol concentration compared with the comprehensive assessment and minimal assessment-only conditions (d values ranged from 0.32 to 0.61). No significant between-group differences were evidenced for the computer-delivered PFI condition, although effect sizes were comparable to other college drinking studies using computer-delivered interventions (d values ranged from 0.20 to 0.27). Results provide further support for the use of a face to-face PFI to help reduce college students' alcohol consumption and suggest that a video interviewer in the context of a computer-delivered PFI is likely a helpful but not necessarily a complete substitute for a live interviewer. PMID- 22197300 TI - Temporal relationship between substance use and delinquent behavior among young psychiatrically hospitalized adolescents. AB - There is considerable evidence linking substance use and delinquent behavior among adolescents. However, the nature and temporal ordering of this relationship remain uncertain, particularly among early adolescents and those with significant psychopathology. This study examined the temporal ordering of substance use and delinquent behavior in a sample of psychiatrically hospitalized early adolescents. Youth (N = 108) between the ages of 12 and 15 years completed three assessments over 18 months following hospitalization. Separate cross-lagged panel models examined the reciprocal relationship between delinquent behavior and two types of substance use (e.g., alcohol and marijuana). Results provided evidence of cross-lagged effects for marijuana: Delinquent behavior at 9 months predicted marijuana use at 18 months. No predictive effects were found between alcohol use and delinquent behavior over time. Findings demonstrate the stability of delinquent behavior and substance use among young adolescents with psychiatric concerns. Furthermore, results highlight the value of examining alcohol and marijuana use outcomes separately to better understand the complex pathways between substance use and delinquent behavior among early adolescents. PMID- 22197302 TI - Prevalence, predictors, and service utilization of patients with recurrent use of Veterans Affairs substance use disorder specialty care. AB - Although substance use disorders (SUDs) are chronic conditions for many patients, the prevalence, predictors, and health care utilization patterns of those who reenter SUD specialty care are understudied. We identified 1,640 patients who initiated SUD specialty care at 1 Veterans Affairs (VA) medical center and categorized them, using their subsequent 24 and prior 60 months receipt of VA SUD care, as index episode only (35.7%, 33.5-38.1), index and prior episode(s) (24.6%, 22.5-22.7), and index and postindex episodes (39.6%, 37.3-42.0). Compared with the index episode-only group, the postindex episode(s) group had modestly higher percentages of men, divorced/separated, and alcohol use, cocaine use, bipolar disorder, and psychotic disorders. Patients with postindex episodes averaged 2 times more postindex emergency visits and mental health hospitalizations than patients with an index only episode. Results document the prevalence, overall health care utilization, and limited predictability of SUD treatment reentry and support development of new models of care for these complex patients. PMID- 22197303 TI - Effects of sialidase knockout and complementation on virulence of Mycoplasma gallisepticum. AB - Reannotation of the pathogenic Mycoplasma gallisepticum strain R(low) genome identified the hypothetical gene MGA_0329 as a homolog of the sialidase gene MS53_0199 of Mycoplasma synoviae strain MS53. Potent sialidase activity was subsequently quantitated in several M. gallisepticum strains. Because sialidase activity levels correlate significantly with differing M. synoviae strain virulence, we hypothesized this enzyme may also influence the virulence of M. gallisepticum. MGA_0329 was disrupted in strain R(low) to create mutants 6, 358 and P1C5, which resulted in the loss of sialidase activity in all three mutants. Chickens infected with the knockout mutants had significantly less severe (P<0.05) tracheal lesions and tracheal mucosal thickening than chickens infected with equal doses of strain R(low). Significantly fewer (P<0.05) CCU especially of strains 6 and P1C5 were recovered at necropsy. Mini-Tn4001tet plasmid pTF20 carrying a wild-type copy of MGA_0329 with its native promoter was used to complement the genetic lesion in strain P1C5. Three clones derived from P1C5, each having one copy of MGA_0329 stably transposed into a different site in its genome, expressed sialidase restored to wild-type activity levels (1.58*10( 8)U/CFU). Complementation of P1C5 with MGA_0329 did not restore it to wild-type levels of virulence, indicating that the contribution of sialidase to M. gallisepticum virulence is not straightforward. PMID- 22197304 TI - Rare case of an unroofed coronary sinus. AB - Unroofed coronary sinus (CS) is a rare congenital cardiac anomaly described by a communication between the CS and the left atrium due to the partial or complete absence of the CS roof. Echocardiography is the most widely used imaging modality for suspected unroofed CS, but it is limited in its ability to visualize the posterior cardiac structures. Multidetector computed tomography has allowed the visualization and accurate anatomic and morphologic evaluation of these structures. We report a rare case of unroofed CS found incidentally in a 41-year old man who was studied by echocardiography and multidetector computed tomography. PMID- 22197305 TI - Legionella pneumophila community-acquired pneumonia (CAP) in a post-splenectomy patient with myelodysplastic syndrome (MDS). AB - Legionnaire's disease is a cause of community-acquired pneumonia (CAP) in normal hosts, but those with impaired cell-mediated immunity (CMI) and T-lymphocyte function are particularly predisposed to Legionella species CAP. Myelodysplastic syndrome (MDS) is a disorder of the elderly that is associated with impaired CMI. Cases of MDS or Legionella species CAP are rare. Splenectomized patients primarily have impaired humoral immunity and B-lymphocyte function, and, to a lesser extent, some decrease in CMI. For this reason, Legionnaire's disease has rarely been reported in splenectomized patients. We believe this to be the first reported case of Legionella pneumophila CAP in an asplenic patient with MDS. PMID- 22197306 TI - Three-dimensional volume off-line analysis as compared to real-time ultrasound for assessing adnexal masses. AB - OBJECTIVE: To assess the agreement between three-dimensional volume off-line analysis as compared to real-time ultrasound for assessing adnexal masses. STUDY DESIGN: Ninety-nine non-consecutive women diagnosed as having an adnexal mass were assessed by transvaginal power Doppler ultrasound. One single examiner performed all ultrasound examinations. Based on the examiner's subjective evaluation using gray scale and Doppler ultrasound findings a presumptive diagnosis (benign or malignant) was provided after real-time ultrasound was performed. Once real-time was done a 3D volume of the adnexal mass was acquired and stored by this examiner. Two examiners, unaware of the real-time ultrasound results, evaluated the 3D volumes using multiplanar display and virtual navigation and also had to provide a presumptive diagnosis (benign or malignant). These two examiners, like the first one, had information about patient's age, menopausal status and complaints. All women underwent surgery or were followed-up until cyst resolution. Histologic diagnosis was used as gold standard. Cysts that resolved spontaneously were considered as benign for analytical purposes. The Kappa index was used to assess the agreement between real time ultrasound and 3D volume analysis. Sensitivity and specificity of both methods were calculated and compared using McNemar test. RESULTS: Forty-one masses were malignant and 58 were benign. Agreement between real-time ultrasound and 3D volume analysis was good for both off-line examiners (Kappa index: 0.82, 95% CI: 0.70-0.93 and 0.78, 95% CI: 0.65-0.90). Sensitivities for real-time ultrasound and 3D volume analyses were 100%, 93% and 90%, respectively (p>0.05). Specificities for real-time ultrasound and 3D volume analyses were 91%, 84% and 86%, respectively (p>0.05). CONCLUSIONS: Off-line 3D volume analysis may be a useful method for assessing adnexal masses, showing a good agreement with real-time ultrasound and having a similar diagnostic performance. PMID- 22197307 TI - Amenorrhea and weight loss: not only anorexia nervosa. PMID- 22197308 TI - Using a discrete choice experiment to estimate health state utility values. AB - In this study we explored a novel application of the discrete choice experiment (DCE) that resembles the time trade off (TTO) task to estimate values on the health utility scale for the EQ-5D. The DCE was tested in a survey alongside the TTO in a sample of English-speaking Canadians recruited by a market research company. The study found that the DCE is able to derive logical and consistent values for health states valued on the full health - dead scale. The DCE overcame some issues identified in the version of TTO currently used to value EQ-5D, notably allowing for fewer data exclusions and incorporating values considered worse than dead without introducing a separate valuation procedure. This has important implications for providing robust values that represent the preferences of all respondents. PMID- 22197310 TI - Single versus combined exposure of Hyalella azteca to zinc contaminated sediment and food. AB - The amphipod Hyalella azteca was exposed for 28 d to different combinations of Zn contaminated sediment and food. Sediment exposure (+clean food) resulted in increased Zn body burdens, increased mortality and decreased body mass when the molar concentrations of simultaneously extracted Zn were greater than the molar concentration of Acid Volatile Sulfide (SEM(Zn)-AVS>0), suggesting that dissolved Zn was a dominant route of exposure. No adverse effect was noted in the food exposure (+clean sediment), suggesting selective feeding or regulation. Combined exposure (sediment+food) significantly increased adverse effects in comparison with sediment exposure, indicating contribution of dietary Zn to toxicity and bioaccumulation. The observed enhanced toxicity also supports the assumption on the presence of an avoidance/selective feeding reaction of the amphipods in the single sediment or food exposures. During 14 d post-exposure in clean medium, the organisms from the same combined exposure history received two feeding regimes, i.e. clean food and Zn spiked food. Elevated Zn bioaccumulation and reduced reproduction were noted in amphipods that were offered Zn spiked food compared to the respective organisms that were fed clean food. This was explained by the failure of avoidance/selective feeding behavior in the absence of an alternative food source (sediment), forcing the amphipods to take up Zn while feeding. Increasing Zn body burdens rejected the assumption that Zn uptake from food was regulated by H. azteca. Our results show that the selective feeding behavior should be accounted for when assessing ecological effects of Zn or other contaminants, especially when contaminated food is a potential exposure route. PMID- 22197309 TI - Transcription coactivator Eya2 is a critical regulator of physiological hypertrophy. AB - Despite its significant clinical implications, physiological hypertrophy remains poorly understood. In this study, the transcription coactivator Eya2 was shown to be up-regulated during physiological hypertrophy. Transgene- or adenovirus mediated overexpression of Eya2 led to up-regulation of mTOR, a critical mediator of physiological hypertrophy. Luciferase reporter and chromatin immunoprecipitation assays revealed that Eya2 directly binds to and activates mTOR expression. The phosphorylation of mTOR downstream molecules was significantly enhanced in Eya2 transgenic (TG) hearts, implying that the Eya2 mediated induction of mTOR expression leads to an elevated mTOR activity. The transcription factor Six1 was also up-regulated during physiological hypertrophy and formed a complex with Eya2. Luciferase reporter and electrophoretic mobility shift assays revealed that the Eya2-Six1 complex binds to and enhances the expression of mTOR in a synergistic manner. Under pressure overload, Eya2 transgenic hearts developed hypertrophy which exhibited important molecular signatures of physiological hypertrophy, as assessed by gene expression profiling and measurements of expression levels of physiological hypertrophy-related genes by quantitative (q) RT-PCR. Examination of heart sections under electron microscopy revealed that the mitochondrial integrity remained largely intact in Eya2 transgenic mice, but not in wild-type littermates, under pressure overload. This finding was confirmed by measurements of mitochondrial DNA contents and the expression levels of mitochondrial function-related genes by qRT-PCR. These data suggest that Eya2 in a physical complex with Six1 plays a critical role in physiological hypertrophy. The cardioprotective effect of Eya2 appears to be due, at least in part, to its preservation of mitochondrial integrity upon pressure overload. PMID- 22197311 TI - Simultaneous determination of organochlorine pesticides and bisphenol A in edible marine biota by GC-MS. AB - A study to assess the level of organochlorine pesticides (OCPs) and bisphenol A (BPA) in edible marine biota collected from coastal waters of Malaysia was conducted using GC-MS and SPE extraction. An analytical method was developed and validated to measure the level of 15 OCPs and BPA simultaneously from five selected marine species. It was observed that some samples had low levels of p,p' DDE, p,p'-DDT and p,p'- DDD ranging from 0.50 ng g(-1) to 22.49 ng g(-1) dry weight (d.w) but significantly elevated level of endosulfan I was detected in a stingray sample at 2880 ng g(-1) d.w. BPA was detected in 31 out of 57 samples with concentration ranging from below quantification level (LOQ: 3 ng g(-1)) to 729 ng g(-1) d.w. The presence of OCPs is most likely from past use although there is also indication of illegal use in recent times. The study also reveals that BPA is more widely distributed in coastal species caught off the coast of the most developed state. The potential health risk from dietary intakes of OCPs and BPA from the analysed fish species was negligible. PMID- 22197312 TI - Ex situ remediation of contaminated sediments using mineral additives: assessment of pollutant bioavailability with the Microtox solid phase test. AB - The aim of this work is to assess the potential ecotoxicological effects of contaminated sediments treated with mineral additives. The Microtox solid phase test was used to evaluate the effect of mineral additives on the toxicity of sediment suspensions. Four Mediterranean port sediments were studied after dredging and bioremediation: Sample A from navy harbor, sample B from commercial port and samples C and D from pleasure ports. Sediment samples were stabilized with three mineral additives: hematite, zero-valent iron and zeolite. Results show that all studied mineral additives can act as stabilizer agent in highly contaminated sediments (A and C) by decreasing dissolved metal concentrations and sediment toxicity level. On the contrary, for the less contaminated samples (B and D) hematite and zeolite can provoke toxic effect towards Vibrio fischeri since additive particles can favor bacteria retention and decrease bioluminescence emission. PMID- 22197314 TI - Solvation thermodynamics and the physical-chemical meaning of the constant in Abraham solvation equations. AB - Abraham solvation equations find widespread use in environmental chemistry. Until now, the intercept in these equations was determined by fitting experimental data. To simplify the determination of the coefficients in Abraham solvation equations, this study derives theoretical expressions for the value of the intercept for various partition processes. To that end, a modification of the description of the Ben-Naim standard state into the van der Waals volume is proposed. Differences between predicted and fitted values of the Abraham solvation equation intercept for the enthalpy of solvation, the entropy of solvation, solvent-water partitioning, air-solvent partitioning, partitioning into micelles, partitioning into lipid membranes and lipids, and chromatographic retention indices are comparable to experimental uncertainties in these values. PMID- 22197313 TI - Ecotoxicity of siloxane D5 in soil. AB - Decamethylcyclopentasiloxane (D5) is a cyclic volatile methyl siloxane (cVMS) commonly found in commercially available products. D5 is expected to enter the terrestrial environment through the deposit of biosolids from sewage treatment plants onto agricultural fields for nutrient enrichment. Little to no information currently exists as to the risks of D5 to the terrestrial environment. In order to evaluate the potential risk to terrestrial organisms, the toxicity of a D5 contaminated biosolid in an agricultural soil was assessed with a battery of standardized soil toxicity tests. D5 was spiked into a surrogate biosolid and then mixed with a sandy loam soil to create test concentrations ranging from 0 to 4074 mg kg(-1). Plant (Hordeum vulgare (barley) and Trifolium pratense (red clover)) and soil invertebrates (Eisenia andrei (earthworm) and Folsomia candida (springtail)) toxicity tests were completed to assess for lethal and sub-lethal effects. Plant testing evaluated the effects on seedling emergence, shoot and root length, and shoot and root dry mass. Invertebrate test endpoints included adult lethality, juvenile production, and individual juvenile dry mass (earthworms only). Soil samples were collected over time to confirm test concentrations and evaluate the loss of chemical over the duration of a test. The toxicity of the D5 was species and endpoint dependent, such that no significant adverse effects were observed for T. pratense or E. andrei test endpoints, however, toxicity was observed for H. vulgare plant growth and F. candida survival and reproduction. Chemical losses of up to 50% were observed throughout the tests, most significantly at high concentrations. PMID- 22197315 TI - Indium-mediated allylation and Reformatsky reaction on glyoxylic oximes under ultrasound irradiation. AB - A novel and more convenient method for the indium-promoted allylation of glyoxylic oximes based on the use of ultrasonic waves is reported. A similar procedure was used to develop the first example reported in the literature of an indium-mediated Reformatsky reaction on oxime ethers. PMID- 22197316 TI - Child neurodevelopment in a Bolivian mining city. AB - This study evaluates the neurodevelopment of children living near contaminated mining industries during their first year of life. Participants from the city of Oruro (Bolivia) were prospectively recruited during pregnancy. Follow-up occurred between May 2007 and November 2009. Information about the socioeconomic status and medical history of the pregnant women were collected using questionnaires. Neurodevelopment was evaluated for 246 children using the Bayley Scales of Infant Development (BSID) at 10.5-12.5 months of age. Exposure to trace elements (Pb, As, Cd, Sb, Cs, Zn, Fe, Cu, Se, Rb, and Sr) during prenatal life was evaluated by testing maternal blood concentrations before delivery. Almost all measured levels were lower than the control limits. The blood lead concentration of pregnant women was low, considering the contaminated environmental context. The geometric mean was 1.76 MUg/dL (95% CI: 1.68-1.84), a level comparable with those observed in non-contaminated areas. The only element found to be relatively elevated was antimony, with a geometric mean of 1.03 MUg/dL (95% CI: 0.96-1.11). Our results suggest that women from this mining area were not highly exposed. The Bayley Scales of Infant Development (BSID) did not reveal mental or psychomotor abnormalities. Surprisingly, at the observed low levels, lead was positively associated with the children's BSID performance. PMID- 22197317 TI - The effects of blood pressure control levels on the renoprotection of type 2 diabetic patients without overt proteinuria. AB - BACKGROUND: There is little evidence regarding the target blood pressure level in patients with type 2 diabetes mellitus without overt proteinuria. METHODS AND RESULTS: We followed 608 Japanese patients with type 2 diabetes without apparent cardiovascular disease and overt proteinuria who underwent cerebral magnetic resonance imaging for a mean of 7.5 years. The patients were categorized according to their mean systolic blood pressure during the follow-up period (strict: <130 mm Hg, moderate: >=130 and <140 mm Hg, poor: >= 140 mm Hg). The risks for the primary composite outcome of death or end-stage renal disease were not different among the three groups. The renal risk of the doubling of serum creatinine for the poor group was significantly higher than those in other groups. In addition, among the patients without silent cerebral infarction (SCI), the renal risk was significantly lower in the strict group than in the moderate group. Further, in both the SCI and non-SCI groups, strict blood pressure control slowed the progression of albuminuria. CONCLUSIONS: In nonproteinuric diabetic patients without SCI, strict blood pressure control was associated with improved renal outcomes. There may be different effects of intensive blood pressure control on the renoprotection of diabetic patients according to their complications. PMID- 22197318 TI - Individual variability of salivary gland proteins in three Phlebotomus species. AB - Pooled salivary gland samples are frequently used to ensure the sufficient amount of material for the experiments; however, this could mask an individual variability. Thus, we compared salivary protein profiles in seven colonies of three Phlebotomus species: Phlebotomus sergenti, Phlebotomus perniciosus, and Phlebotomus papatasi. Surprisingly, the individual profiles differed significantly between the colonies as well as between individuals. The highest variability was observed in proteins with molecular masses of 42-46 kDa corresponding to the yellow-related proteins. The phenogram constructed from salivary gland profiles revealed the existence of two main groups in P. sergenti, corresponding well with the geographical origin. The F1 progeny obtained from cross-mating studies between P. sergenti colonies of different geographical origin formed a distinct subgroup within the parental groups. In P. papatasi, several groups of protein profiles were observed with no relationship to the geographical origin. The biological role of salivary proteins variability is discussed. PMID- 22197319 TI - Making communities age friendly: state and municipal initiatives in Canada and other countries. AB - To promote healthy, active aging, the age-friendly community initiative has evolved in Canada, Spain, Brazil and Australia, among other countries. An age friendly community provides accessible and inclusive built and social environments where older adults can enjoy good health, participate actively and live in security. The rapid expansion of the initiative in all states can largely be explained by common key activities undertaken by the state, municipal and -in the case of Canada- also federal, governments. These initiatives include strategic engagements and policy action in all states, and knowledge development and exchange in Canada in particular. Strategic engagements involve creating or strengthening collaborative intersectoral relationships to access multiple arenas of decision-making, and addressing all areas that constitute an age-friendly community. With variations across states, policy actions have included the following: declaring the initiative as an official policy direction; establishing model cities to be emulated by other cities; funding community projects; implementing consistent methodology; evaluating implementation, enhancing public visibility, and aligning age-friendly community policy with other state-level policy directions. To stimulate knowledge development and exchange, Canadian efforts have included the creation of a community of practice and of a research and policy network to encourage the development and translation of scientific evidence on aging-supportive communities. These activities are expected to result in a strong and durable integration of older persons' views, aspirations, rights and needs in municipal, as well as state, planning and policy. PMID- 22197320 TI - [Longitudinality, prestige, good reputation (social and professional) and general/family medicine. Clinical and public health aspects. SESPAS Report 2012]. AB - The reform of primary care in Spain in 1984 focussed mainly on skills and knowledge (physician training and working hours) and material resources (new buildings). The reform did not succeed in improving longitudinal care nor did it give primary care physicians greater power, that is, the reform did not increase coordination or strengthen the central role of the family physician in services provision. The lack of longitudinality has persisted over the years since the working methods that encourage it (and its resulting clinical and public health benefits) have not been stimulated. Longitudinality is the personal relationship established over the years between general practitioners and their patients and is defined as (a) care by the same family physician of most of the patient's problems throughout his or her life, and (b) the recognition by patients and the population of a stable source of care to be used for initial contact and for the follow-up of problems. The tendency in the medical profession and society at large is to respond to an increasing number of health problems more quickly and intensely, with increasingly powerful means and with a greater number of specialists. In turn, this tendency makes medical activities dangerous. To counteract this tendency, a motto of "less is better" should be adopted, implying greater longitudinality. Many initiatives could improve longitudinality, such as incentives for not moving, increasing the capitation component of remuneration to nearly 50%, broadening the range of general practitioners' skills, including family members in the same patient list, and transforming the role of specialists into that of consultants. PMID- 22197321 TI - [Access tests to specialized health training for doctors and other healthcare professionals in Spain: examining the exam and the examined candidates]. AB - OBJECTIVES: This study examines the accessing tests to Specialised Health Training for 2005 and 2006 calls. It aims to assess the quality of exams and explore candidates' variables that allow predicting the final score. METHODS: The Ministry of Health provided the 23,136 candidates' answer from both calls, plus demographic variables and the normalised value of their student record. RESULTS: Item's analysis is made from candidates' answers for evaluating the test reliability. In addition, it's been calculated linear regression models for studying which variables allow predicting a candidate's final score. CONCLUSIONS: the accessing tests to Specialised Health Training have excellent psychometric quality. It would be improved by reducing the number of choices and eliminating some items more afterwards. Finally, Spanish students are the ones who achieved best adjusted mean score. PMID- 22197322 TI - Trends in leisure time and work-related physical activity in the Spanish working population, 1987-2006. AB - OBJECTIVE: To analyze time trends in the prevalence of leisure time (LTPA) and work-related (WRPA) physical activity between 1987 and 2006 in the Spanish working population. METHODS: We analyzed data taken from the Spanish National Health Surveys for 1987 (n = 29,647), 1993 (n = 20,707), 1995-1997 (n = 12,800), 2001 (n = 21,058), 2003 (n = 21,650), and 2006 (n = 29,478). The main variables were LTPA and WRPA in working adults aged 18-64 years old. We analyzed sociodemographic characteristics, self-perceived health status, lifestyle habits and associated comorbidities using multivariate logistic regression models. RESULTS: The prevalences of LTPA and WRPA were lower in women than in men (p < 0.05). The practice of LTPA (OR: 1.54, 95%CI: 1.32-1.80 for women; OR = 1.15, 95%CI: 1.02-1.31 for men) and WRPA (OR = 1.73, 95%CI: 1.38-2.19 for women; OR = 1.55, 95%CI: 1.44-1.91 for men) significantly increased from 1987 to 2006. In both genders, the variables associated with a higher likelihood of practicing LTPA were greater age, higher educational level and being an ex- or non-smoker, while negative predictors included being married, worse self-perceived health, and obesity. Factors that increased the probability of reporting WRPA were being married, worse self-rated health status, and sleeping > 8h per day. The only factor that reduced the probability of reporting WRPA was being an ex- or non smoker. CONCLUSIONS: We found an increase in LTPA and WRPA in the last 20 years in the Spanish working population. Several factors were associated with a higher or lower likelihood of practicing LTPA or WRPA in this population. PMID- 22197323 TI - [Dysmenorrhea: a problem for the pediatrician?]. AB - Dysmenorrhea is common in adolescent years, especially after the onset of ovulatory cycles, usually 2 to 3 years after menarche. Pain and symptoms are responsible for school absenteeism and interruption of sports and social activities. OBJECTIVES: This study aims to measure the prevalence of severe dysmenorrhea and its consequences on adolescent girls in Switzerland. Treatment of dysmenorrhea is discussed and recommendations for clinical practice are given. STUDY DESIGN: Cross sectional survey (SMASH 02) on a nationally representative sample of adolescents (n=7548; 3340 females), aged 16 to 20 years who attended post-mandatory education. A self-administered questionnaire was used to assess the severity of dysmenorrhea and its consequences on daily life pursuit of medical help and medications used. RESULTS: Among 3340 girls, 86.6% suffered from dysmenorrhea-related symptoms: 12.4% described having severe dysmenorrhea and 74.2% moderate dysmenorrhea. Girls with severe dysmenorrhea described heavier consequences on daily activities compared with girls without dysmenorrhea: 47.8% of girls with severe dysmenorrhea reported staying at home and 66.5% declared reducing their sportive activities. Yet, fewer than half have consulted a physician for this complaint and even fewer were treated properly. RECOMMENDATION: The pediatrician has a pivotal role in screening young patients for dysmenorrhea, as well as, educating and effectively treating adolescent girls with menstruation-associated symptoms. Non-steroidal anti-inflammatory drugs are considered the first-line of treatment for dysmenorrhea, and adolescents with symptoms that do not respond to this treatment for 3 menstrual periods should be offered combined oestroprogestative contraception and must be followed up, as non responders may have an underlying organic pathology. CONCLUSION: Dysmenorrhea is a frequent health problem in adolescent years and adolescent care providers should be able to care for these patients in an efficient way. PMID- 22197324 TI - Coordination of triacylglycerol and cholesterol homeostasis by DHR96 and the Drosophila LipA homolog magro. AB - Although transintestinal cholesterol efflux has been identified as an important means of clearing excess sterols, the mechanisms that underlie this process remain poorly understood. Here, we show that magro, a direct target of the Drosophila DHR96 nuclear receptor, is required in the intestine to maintain cholesterol homeostasis. magro encodes a LipA homolog that is secreted from the anterior gut into the intestinal lumen to digest dietary triacylglycerol. Expression of magro in intestinal cells is required to hydrolyze cholesterol esters and promote cholesterol clearance. Restoring magro expression in the intestine of DHR96 mutants rescues their defects in triacylglycerol and cholesterol metabolism. These studies show that the central role of the intestine in cholesterol efflux has been conserved through evolution, that the ancestral function of LipA is to coordinate triacylglycerol and cholesterol metabolism, and that the region-specific activities of magro correspond to the metabolic functions of its upstream regulator, DHR96. PMID- 22197326 TI - Total endovascular repair of thoracoabdominal aortic aneurysms. AB - BACKGROUND: Endovascular graft designs incorporating sidebranches, fenestrations and scallops offer a minimally-invasive alternative to open surgery and hybrid approaches for thoracoabdominal aortic aneurysms (TAAA). Our unit has offered total endovascular TAAA repair to selected higher-risk patients since 2008. We report the largest UK series to date of total endovascular TAAA repair. METHODS: Retrospective analysis of a prospectively-maintained operative database. RESULTS: 31 patients (21 male, 10 female) median age 71 years (range 58-84), with TAAA (12 Crawford type I, 13 type III, 6 type IV), median diameter 6.4 (4.3 (mycotic)- 9.9) underwent endovascular TAAA repair (total 48 sidebranches, 26 fenestrations, 13 scallops) between July 2008 and January 2011. Median operating time 225 min (65-540 min), X-ray screening time 58 min (4-212 min), contrast dose 175 ml (70 500 ml), blood loss 325 ml (100-400 ml). Median post-operative length of hospital stay 6 days (2-22 days). Three patients (3/31, 9.7%) died within 30 days of operation: multisystem organ failure (1) acute renal failure and paraplegia (1) and paraplegia (1). There were no other cases of in-hospital organ failure, paraplegia or major complications. The median change in pre-discharge from pre operative renal function was 3.4% deterioration in eGFR (range: 32.7% deterioration to 73.0% improvement) One patient presented with late-onset paraparesis, a second developed acute renal failure 8 months after repair. One early high-pressure endoleak (type 3) required correction. Three patients had died by median follow-up 12 months (1-36), 2 from heart disease and one from haemopericardium secondary to acute dissection of the ascending aorta (the dissection did not involve, nor extend close to, the endovascular graft). CONCLUSIONS: Total endovascular repair of TAAA offers patients a minimally invasive alternative to open surgery with early results at least comparable to those seen with open or hybrid surgical approaches. PMID- 22197325 TI - Impaired generation of 12-hydroxylated bile acids links hepatic insulin signaling with dyslipidemia. AB - The association of type 2 diabetes with elevated plasma triglyceride (TG) and very low-density lipoproteins (VLDL), and intrahepatic lipid accumulation represents a pathophysiological enigma and an unmet therapeutic challenge. Here, we uncover a link between insulin action through FoxO1, bile acid (BA) composition, and altered lipid homeostasis that brings new insight to this longstanding conundrum. FoxO1 ablation brings about two signature lipid abnormalities of diabetes and the metabolic syndrome, elevated liver and plasma TG. These changes are associated with deficiency of 12alpha-hydroxylated BAs and their synthetic enzyme, Cyp8b1, that hinders the TG-lowering effects of the BA receptor, Fxr. Accordingly, pharmacological activation of Fxr with GW4064 overcomes the BA imbalance, restoring hepatic and plasma TG levels of FoxO1 deficient mice to normal levels. We propose that generation of 12alpha hydroxylated products of BA metabolism represents a signaling mechanism linking hepatic lipid abnormalities with type 2 diabetes, and a treatment target for this condition. PMID- 22197328 TI - Effect of dosing sequence and solution pH on floc properties of the compound bioflocculant-aluminum sulfate dual-coagulant in kaolin-humic acid solution treatment. AB - The compound bioflocculant (CBF)-aluminum sulfate (AS) dual-coagulant and AS were comparatively studied for the coagulation of kaolin-humic acid solution. Floc properties including floc growth rate, size, strength, recoverability and fractal dimension under different pH conditions were investigated by Mastersizer 2000. Results indicated that, the flocs formed by AS-CBF (AS dosed first) showed the largest size and the best recoverability across the pH range investigated. While flocs formed by CBF-AS gave the most compact structure. The three coagulants exhibited similar floc growth rate and strength. Moreover, flocs formed in acidic conditions were stronger and more recoverable but showed lower growth rate, smaller size and looser structure compared to those formed at pH>6 regardless of the coagulant used. Charge neutralization was the dominant mechanism for AS at low pH, while the coagulation mechanism transformed to enmeshment as the pH increased. There was an additional adsorption bridging effect for AS-CBF and CBF AS. PMID- 22197327 TI - Diversity, biogenesis and function of microbial amyloids. AB - Amyloid is a distinct beta-sheet-rich fold that many proteins can acquire. Frequently associated with neurodegenerative diseases in humans, including Alzheimer's, Parkinson's and Huntington's diseases, amyloids are traditionally considered the product of protein misfolding. However, the amyloid fold is now recognized as a ubiquitous part of normal cellular biology. Functional amyloids have been identified in nearly all facets of cellular life, with microbial functional amyloids leading the way. Unlike disease-associated amyloids, functional amyloids are assembled by dedicated, directed pathways and ultimately perform a physiological function that benefits the organism. The evolved amyloid assembly and disassembly pathways of microbes have provided novel insights into how cells have harnessed the amyloid assembly process for productive means. An understanding of functional amyloid biogenesis promises to provide a fresh perspective on the molecular events that underlie disease-associated amyloidogenesis. Here, we review functional microbial amyloids with an emphasis on curli fibers and their role in promoting biofilm formation and other community behaviors. PMID- 22197329 TI - Scalable microbial fuel cell (MFC) stack for continuous real wastewater treatment. AB - A tubular air-cathode microbial fuel cell (MFC) stack with high scalability and low material cost was constructed and the ability of simultaneous real wastewater treatment and bioelectricity generation was investigated under continuous flow mode. At the two organic loading rates (ORLs) tested (1.2 and 4.9kg COD/m(3)d), five non-Pt MFCs connected in series and parallel circuit modes treating swine wastewater can enable an increase of the voltage and the current. The parallel stack retained high power output and the series connection underwent energy loss due to the substrate cross-conduction effect. With continuous electricity production, the parallel stack achieved 83.8% of COD removal and 90.8% of NH(4)(+)-N removal at 1.2kg COD/m(3)d, and 77.1% COD removal and 80.7% NH(4)(+)-N removal at 4.9kg COD/m(3)d. The MFC stack system in this study was demonstrated to be able to treat real wastewater with the added benefit of harvesting electricity energy. PMID- 22197330 TI - Management of food industry waste employing vermicomposting technology. AB - This paper reports the vermicomposting of food industry sludges (FIS) mixed with different organic wastes employing Eisenia fetida. A total of 10 vermicomposting units containing different wastes combinations were established. After 15 weeks significant increase in total nitrogen (N(total)) (60-214%), total available phosphorous (P(avail)) (35.8-69.6%), total sodium (Na(total)) (39-95%), and total potassium (K(total)) (43.7-74.1%), while decrease in pH (8.45-19.7%), total organic carbon (OC(total)) (28.4-36.1%) and C:N ratio (61.2-77.8%) was recorded. The results indicated that FIS may be converted into good quality manure by vermicomposting if spiked with other organic wastes in appropriate quantities. PMID- 22197331 TI - Production of a robust nanobiocatalyst for municipal wastewater treatment. AB - Immobilization is a fundamental method to improve both enzyme activity and stability. In the present work, the process previously described for immobilizing laccase - an enzyme oxidizing phenolic compounds - onto fumed silica was optimized, in order to efficiently produce industrially relevant amounts of a nanobiocatalyst for biological micropollutant elimination, whilst saving 80% of surface modification agent (3-aminopropyl triethoxy silane) and 90% of cross linker (glutaraldehyde). Minimized losses during preparation and favorable effects of immobilization yielded conjugates with drastically increased enzymatic activity (164% of invested activity). Long-term stability and activity regarding bisphenol A (2,2-bis(4-hydroxyphenyl)propane) removal of the synthesized biocatalyst were assessed under application-relevant conditions. With 81.1+/-0.4% residual activity after 7 days, stability of conjugates was drastically higher than of free laccase, which showed virtually no activity after 1.5 days. These results illustrate the huge potential of fumed silica nanoparticles/laccase composites for innovative biological wastewater treatment. PMID- 22197332 TI - Continuous two stage acetone-butanol-ethanol fermentation with integrated solvent removal using Clostridium acetobutylicum B 5313. AB - The objective of this study was to optimize continuous acetone-butanol-ethanol (ABE) fermentation using a two stage chemostat system integrated with liquid liquid extraction of solvents produced in the first stage. This minimized end product inhibition by butanol and subsequently enhanced glucose utilization and solvent production in continuous cultures of Clostridium acetobutylicum B 5313. During continuous two-stage ABE fermentation, sugarcane bagasse was used as the cell holding material for the both stages and liquid-liquid extraction was performed using an oleyl alcohol and decanol mixture. An overall solvent production of 25.32g/L (acetone 5.93g/L, butanol 16.90g/L and ethanol 2.48g/L) was observed as compared to 15.98g/L in the single stage chemostat with highest solvent productivity and solvent yield of 2.5g/Lh and of 0.35g/g, respectively. Maximum glucose utilization (83.21%) at a dilution rate of 0.051/h was observed as compared to 54.38% in the single stage chemostat. PMID- 22197333 TI - ADM1-based modeling of methane production from acidified sweet sorghum extract in a two stage process. AB - The present study focused on the application of the Anaerobic Digestion Model 1 on the methane production from acidified sorghum extract generated from a hydrogen producing bioreactor in a two-stage anaerobic process. The kinetic parameters for hydrogen and volatile fatty acids consumption were estimated through fitting of the model equations to the data obtained from batch experiments. The simulation of the continuous reactor performance at all HRTs tested (20, 15, and 10d) was very satisfactory. Specifically, the largest deviation of the theoretical predictions against the experimental data was 12% for the methane production rate at the HRT of 20d while the deviation values for the 15 and 10d HRT were 1.9% and 1.1%, respectively. The model predictions regarding pH, methane percentage in the gas phase and COD removal were in very good agreement with the experimental data with a deviation less than 5% for all steady states. Therefore, the ADM1 is a valuable tool for process design in the case of a two-stage anaerobic process as well. PMID- 22197334 TI - One-step enzymatic synthesis of nucleosides from low water-soluble purine bases in non-conventional media. AB - The effect of several water-miscible cosolvents on activity and stability of soluble and immobilized 2'-deoxyribosyltransferase from Lactobacillus reuteri on Sepabeads(r) has been studied in order to establish optimal conditions for enzymatic synthesis of nucleosides using purine bases with low solubility in aqueous buffer. As a rule of thumb, there was a general reduction of soluble enzyme activity when cosolvent content was gradually increased in reaction medium. In contrast, immobilized enzyme activity was enhanced 1.2-1.4-fold at 20% of methanol, ethanol, 2-propanol, diethylene glycol, and acetone; and at 10% and 30% acetonitrile. Likewise, highest increased activity (1.8-fold) was also obtained in presence of 20% acetonitrile. Immobilized enzyme was successfully used in the synthesis of 2'-deoxyxanthosine and 2'-deoxyguanosine using 2' deoxyuridine as sugar donor and the corresponding poor water-soluble base in the presence of 30% of methanol, ethanol, 2-propanol, ethylene glycol, acetonitrile, and DMSO, giving high nucleoside yields at 4h. PMID- 22197335 TI - High performance SiO2-nanoparticles-immobilized-Penicillium funiculosum for bioaccumulation and solid phase extraction of lead. AB - Novel biosorbent systems were designed, investigated and implemented for bioaccumulation of Pb(II) from aqueous solutions. These are based on the combination of SiO(2)-nanoparticles (N-Si) with Penicillium funiculosum fungus (Pen) for the formation of (N-Si-Pen) as well as heat inactivated Penicillium funiculosum (Pen). The SiO(2)-nanoparticles were also investigated as a solid sorbent phase. Surface characterization and immobilization were examined and confirmed by using FT-IR and SEM analysis. A batch equilibrium technique was used to follow-up the adsorption processes of lead under the effect of pH, contact time, sorbent dosage and initial metal concentration. The maximum capacity values were 1200.0 and 1266.7MUmolg(-1) for (Pen) and (N-Si-Pen), respectively at pH 5. Sorption equilibria were established in ~20min and their data were well described by Langmuir, Freundlich and Dubinin-Radushkevich models. The potential applications of these biosorbents for extraction of Pb(II) from real samples contaminated with lead, were successfully accomplished. PMID- 22197336 TI - Purification and characterization of maltooligosaccharide-forming alpha-amylase from moderately halophilic Marinobacter sp. EMB8. AB - Maltooligosaccharides especially maltotriose and maltotetraose producing amylases are highly desirable for application in bread making and other food industries. A maltotriose and maltotetraose producing amylase from moderately halophilic Marinobacter sp. EMB8 is described. Under optimized culture conditions, 48.0 IU/mL amylase was obtained. The enzyme was purified to homogeneity by ultrafiltration, DEAE cellulose and Sephadex G-75 column chromatography with 52% yield and 76-fold purification. It was a monomeric protein of 72 kDa. The amylase had many novel features viz. stability up to 20% NaCl, 80 degrees C temperature, pH 6.0-11.0 and in wide range of organic solvents at high concentrations. The enzyme efficiently hydrolyzed starch into maltooligosaccharides rich in maltotriose and maltotetraose. These novel properties make the Marinobacter sp. amylase a potentially useful enzyme. PMID- 22197337 TI - Batch and dynamic biosorption of basic dyes from binary solutions by alkaline treated cypress cone chips. AB - A simple alkaline pre-treatment of Cupressus sempervirens cone chips was performed to improve their biosorption capacity towards methylene blue and rhodamine B from aqueous solutions, in batch and continuous modes. Biosorption kinetics were determined from single and binary dyes solutions, and properly described by the pseudo-second-order rate model. Experimental single-dye equilibrium isotherms fitted the Langmuir-Freundlich model, with maximum biosorption capacities of 0.68mmol/g for methylene blue and 0.50mmol/g for rhodamine B. Single-dye dynamic biosorption showed that breakthrough time for methylene blue biosorption was almost four times longer than for rhodamine B and that the alkaline modification of the chips greatly improved the biosorption performance. Competitive dynamic biosorption demonstrated the preference of the modified cone chips for biosorbing methylene blue, confirmed by the exit concentration overshoots obtained in the breakthrough curves of rhodamine B. PMID- 22197338 TI - Lignin depolymerisation in supercritical carbon dioxide/acetone/water fluid for the production of aromatic chemicals. AB - Valorisation of lignin plays a key role in further development of lignocellulosic biorefinery processes the production of biofuels and bio-based materials. In the present study, organosolv hardwood and wheat straw lignins were converted in a supercritical fluid consisting of carbon dioxide/acetone/water (300-370 degrees C, 100bar) to a phenolic oil consisting of oligomeric fragments and monomeric aromatic compounds with a total yield of 10-12% based on lignin. These yields are similar to the state-of-the-art technologies such as base-catalysed thermal processes applied for lignin depolymerisation. Addition of formic acid increases the yield of monomeric aromatic species by stabilizing aromatic radicals. Supercritical depolymerisation of wheat straw and hardwood lignin yielded monomeric compounds in different compositions with a maximum yield of 2.0% for syringic acid and 3.6% for syringol, respectively. The results of the present study showed that under the applied conditions competition occurred between lignin depolymerisation and recondensation of fragments. PMID- 22197339 TI - Evaluation of sponge tray-membrane bioreactor (ST-MBR) for primary treated sewage effluent treatment. AB - The membrane bioreactor system (MBR) with pre-treatment of sponge tray bioreactor (STB) was evaluated at different operating conditions for treating primary treated sewage (PTS). The result indicated the successful removal of DOC with the efficiency of higher than 95%. The highest nutrient removal efficiency of 83.6% (NH(4)-N) and 75.5% (PO(4)-P) was observed at sludge concentration of 330 mg/L. Specific oxygen uptake rate (SOUR) of activated sludge in MBR kept increasing up to 6 mg O(2)/g VSS h during stage IV. The sludge volume index (SVI) of less than 100mL/g during the operation indicated the good settling property of the sludge. At highest sludge concentration of 5 g/L, trans-membrane pressure (TMP) was increasing dramatically during first 15 d up to 25 kPa; however it was only 6 kPa at lower sludge concentrations. It is concluded that the system showed the highest performance at stage III with sludge concentration of 330 mg/L. PMID- 22197340 TI - Posttraumatic stress disorder symptom severity predicts aggression after treatment. AB - This study examined the relation between posttraumatic stress disorder (PTSD) severity and aggression (verbal, psychological, and physical aggression) in a longitudinal dataset. Participants were 175 males in PTSD residential treatment who were assessed at pre-treatment, post-treatment, and at 4-month follow-up. Post-treatment PTSD severity predicted aggression at post-treatment and 4-month follow-up, adjusting for age, pre-treatment PTSD severity, and pre-treatment aggression. When examining the relation between aggression and specific PTSD symptom clusters, post-treatment Reexperiencing, Avoidance/Numbing and Hyperarousal symptoms predicted aggression at posttreatment and 4-month follow up. These results support the hypothesis that post-treatment PTSD severity may be an important marker of post-treatment aggression risk and may offer unique information important to clinicians and patients focused on the development and maintenance of adaptive, non-aggressive relationships after intensive PTSD treatment. PMID- 22197341 TI - Psychometric properties of the Dutch version of the Meta-Cognitions Questionnaire Adolescent Version (MCQ-A) in non-clinical adolescents and adolescents with obsessive-compulsive disorder. AB - Although the meta-cognitive model (Wells, 1997, 2000) for obsessive-compulsive disorder (OCD) has clearly influenced research and treatment of OCD, little research has been performed in youth samples. In the present study the psychometric properties of the Dutch Meta-Cognitions Questionnaire-Adolescent Version (MCQ-A; Cartwright-Hatton et al., 2004) were examined in a clinical sample of adolescents with OCD (N = 40, 12-18 years) and a non-clinical sample (N = 317; 12-18 years). Results provided support for the 5-factor structure, and showed fair to good internal consistency and generally good retest reliability. Overall, adolescents with OCD reported more meta-cognitive beliefs than non clinical adolescents. Several subscales were associated with self-reported obsessive-compulsive symptoms, anxiety and depression, but not with clinician rated OCD severity. In conclusion, results suggest that the Dutch MCQ-A is a reliable and valid questionnaire to examine meta-cognitive beliefs in adolescents. PMID- 22197342 TI - Bcl2 at the endoplasmic reticulum protects against a Bax/Bak-independent paraptosis-like cell death pathway initiated via p20Bap31. AB - Bap31 is an integral ER membrane protein which functions as an escort factor in the sorting of newly synthesized membrane proteins within the endoplasmic reticulum (ER). During apoptosis signaling, Bap31 is subject to early cleavage by initiator caspase-8. The resulting p20Bap31 (p20) fragment has been shown to initiate proapoptotic ER-mitochondria Ca2+ transmission, and to exert dominant negative (DN) effects on ER protein trafficking. We now report that ectopic expression of p20 in E1A/DNp53-transformed baby mouse kidney epithelial cells initiates a non-apoptotic form of cell death with paraptosis-like morphology. This pathway was characterized by an early rise in ER Ca2+ stores and massive dilation of the ER/nuclear envelope, dependent on intact ER Ca2+ stores. Ablation of the Bax/Bak genes had no effect on these ER/nuclear envelope transformations, and delayed but did not prevent cell death. ER-restricted expression of Bcl2 in the absence of Bax/Bak, however, delayed both ER/nuclear envelope dilation and cell death. This prosurvival role of Bcl2 at the ER thus extended beyond inhibition of Bax/Bak, and correlated with its ability to lower ER Ca2+ stores. Furthermore, these results indicate that ER restricted Bcl2 is capable of antagonizing not only apoptosis, but also a non-apoptotic, Bax/Bak independent, paraptosis-like form of cell death. PMID- 22197343 TI - [Application of ultrasound in paediatric abdominal trunk blocks]. AB - Although relatively few studies have compared US guidance with established "blind" techniques, the available evidence suggests that the use of US guidance is a safe and effective way to facilitate correct needle placement and adequate spread of LA for abdominal wall nerve blocks. It improves block effectiveness and safety by reducing LA doses and by detecting anatomic variants or unsuspected pathologies. Different techniques are described and discussed: the transverse abdominal nerve blocks, the paraombilical block, the inguinal field block and the fascia transversalis block. Matched with improving technology, the use of US has significant benefits over conventional techniques to perform classic and new abdominal wall nerve blocks in children. However, more studies are required to evaluate the potential of US to support this finding. PMID- 22197344 TI - [Medication errors in anaesthesia: a review of reports from the French Health Products Agency]. AB - BACKGROUND: The purpose of this study was to assess medication errors and risks of medication errors during anaesthetic practice reported at the French Health Products Agency (Afssaps) from 2005 to 2010. STUDY DESIGN: Descriptive study. METHODS: The data are issued of "Medication errors and risks of medication errors" file which group together all cases received by the Medication Errors Unit at Afssaps since 2005. RESULTS: A total of 263 cases were observed by the Medication Errors Unit at Afssaps. Among them, 159 cases were risks of medication errors, 76 cases were patent medication errors and 28 were near misses. Among the 76 cases of patent medication errors, out of which 47 cases were appreciated with adverse reaction and 35 cases were classified as serious. Adverse events were classified as haemodynamic, respiratory and neurologic events. Most of the errors occurred during administration (65%), followed by dispensing errors (14%), storage errors (15%) or preparation errors (4%). Sixty-nine percent of cases of wrong drug errors were found, followed by 26% of errors of strength, 3% of incorrect route of administration errors and 2% of patient errors. In most of cases, similarity in packaging was underlined (n=83). CONCLUSION: This study showed that the majority of medication errors and risks of medication errors during anaesthetic practice, underline similarity in packaging. Results highlighted the importance of vial labeling presentation (readability and mention understanding) in anaesthetic practice. PMID- 22197345 TI - FT-IR, FT-Raman and UV spectral investigation: computed frequency estimation analysis and electronic structure calculations on chlorobenzene using HF and DFT. AB - In this work, the vibrational spectral analysis was carried out by using FT-Raman and FT-IR spectroscopy in the range 100-4000 cm(-1) and 400-4000 cm(-1) respectively, for the title molecule. The molecular structure, fundamental vibrational frequencies and intensity of the vibrational bands are interpreted with the aid of structure optimizations and normal coordinate force field calculations based on Hartree Fock (HF) and density functional theory (DFT) method and different basis sets combination. The complete vibrational assignments of wavenumbers were made on the basis of potential energy distribution (PED). The scaled B3LYP/6-311++G(d,p) results show the best agreement with the experimental values over the other methods. The effects due to the substitution of halogen bond were investigated. The results of the calculations were applied to simulated spectra of the title compound, which show excellent agreement with observed spectra. The energy and oscillator strength calculated by Time-Dependent Density Functional Theory (TD-DFT) results complements with the experimental findings. Besides, frontier molecular orbitals (FMO), molecular electrostatic potential (MEP), and thermodynamic properties were performed. The thermodynamic properties of the title compound at different temperatures have been calculated, revealing the correlations between heat capacity (C), entropy (S), and enthalpy changes (H) and temperatures. PMID- 22197346 TI - Study on monomer suitability toward the template in molecularly imprinted polymer: an ab initio approach. AB - Study of monomer-template interactions in molecularly imprinted polymer (MIP) is inevitable to comprehend best selectivity at the molecular level in pre-polymer solution. In the present work, binding energies of tryptophan, an amino acid template, complexed with different monomers were computed using second order Moller Plesset theory (MP2) at 6-311++g** level in gas phase. This helped in recommending a generic MIP, suitable for the selective and sensitive diagnosis of tryptophan, in clinical setting as disease biomarker, at primitive level. The tryptophan is an important biomarker owing to its highly regulated physiological process in the treatment of premenstrual dysphoric disorder and pellagra like diseases. Frequency calculations were performed using Density Functional Theory (DFT) at B3LYP employing 6-31+g (2d, 2p) level including thermal and entropy corrections. The monomer, p-nitrophenyl acrylate (2 mol), was adjudged having giving best binding score for the complexation at ground state with tryptophan (1 mol) for MIP development. PMID- 22197347 TI - Overactive bladder: diagnosis and management. AB - Overactive bladder (OAB) is a clinical syndrome describing the symptom complex of urgency, with or without urgency incontinence and is usually associated with frequency and nocturia. Whilst a number of women may be managed based on a clinical diagnosis alone urodynamic studies may be useful in those women with complex or refractory symptoms. In the first instance all women will benefit from a conservative approach using bladder retraining although a number will require antimuscarinic therapy. For those women with persistent symptoms following medical therapy alternative treatment modalities such as intravesical Botulinum Toxin, neuromodulation or reconstructive surgery may be considered. This review, whilst giving an overview of the syndrome, will focus on a practical clinical approach to managing women with symptoms of overactive bladder (OAB). PMID- 22197348 TI - Serum cathepsin K levels are not suitable to differentiate women with chronic bone disorders such as osteopenia and osteoporosis from healthy pre- and postmenopausal women. AB - OBJECTIVES: Cathepsin K (CatK) is expressed in high levels in osteoplasts and therefore plays an important role in bone resorption. Thus CatK serum levels may be useful in the diagnosis of chronic bone disorders such as osteopenia and osteoporosis. Therefore we aimed at studying CatK levels in women putatively free of known skeletal disorders. STUDY DESIGN: In total, 121 voluntary women, 27 premenopausal women aged between 20 and 45 years, and 94 postmenopausal women aged 59-81 years, all free of known skeletal disorders were included. All women underwent bone density measurement, routine labor parameter and measurement of serum CatK levels. MAIN OUTCOME MEASURES: Based on WHO criteria, women were stratified in four groups (premenopausal: healthy; postmenopausal: healthy, osteopenia, osteoporosis), and their CatK levels were statistically analyzed. RESULTS: Using WHO criteria 21 postmenopausal women had normal bone mineral density (BMD), 49 had osteopenia and 24 had osteoporosis. All 27 premenopausal women had normal BMD. There were no significant differences in CatK between these groups. ROC analysis resulted in poor diagnostic validity of CatK, where the area under curve was 0.544. There was no correlation neither between CatK and other biomarkers as C-telopeptide crosslaps (CTX) or bone-specific alkaline phosphatase (BAP) nor between CatK and age. CONCLUSIONS: Serum levels of CatK are not suitable to differentiate women with osteoporosis from healthy subjects. PMID- 22197349 TI - Nonneutral evolution of volume fluctuations in lysozymes revealed by normal-mode analysis of compressibility. AB - The evolution of structural fluctuations of proteins was examined by calculating the isothermal compressibility (beta(T)) values of chicken lysozyme and its six evolutionary mutants at Thr40, Ile55, and Ser91 (a ternary mutant corresponding to bobwhite lysozyme) from their X-ray structures by normal-mode analysis at 300 K. The beta(T) values of the two extant lysozymes from chicken and bobwhite were 1.61 and 1.59 Mbar(-1), respectively, but five other evolutionary mutants showed larger beta(T) values of up to 2.17 Mbar(-1). These results suggest that ancestral lysozymes exhibit larger volume fluctuations than extant ones, and hence that the molecular evolution of lysozymes has followed a nonneutral evolutionary pathway. The evolutionary mutants contained large amount of cavities, although no change was visible in the X-ray structures. There was a linear correlation between beta(T) and total cavity volume, predicting that the cavity volume or atomic packing is an important factor regulating volume fluctuations during the molecular evolution of this protein. PMID- 22197350 TI - Studying salt effects on protein stability using ribonuclease t1 as a model system. AB - Salt ions affect protein stability in a variety of ways. In general, these effects have either been interpreted from a charge solvation/charge screening standpoint or they have been considered to be the result of ion-specific interactions with a particular protein. Recent theoretical work suggests that a major contribution to salt effects on proteins is through the interaction of salt ions that are located near the protein surface and their induced point image charges that are located in the low-dielectric protein cavity. These interactions form the basis of "salting-out" interactions. Salt ions induce an image charge of the same sign in the low dielectric protein medium. The interaction between the induced charge and its mirror charge is repulsive and consequently thermodynamically destabilizing. However, a folded protein that has a much smaller surface area will be less destabilized than the unfolded state. Consequently, the folded state will be stabilized relative to the unfolded state. This work analyzes salt effects in the model enzyme ribonuclease t1, and demonstrates that interactions between salt ions and their induced point charges provide a major contribution to the observed salt-induced increase in protein stability. This work also demonstrates that in the case of weakly-binding ions (ions with binding constants that are in the order of 50 M(-1) and less), salting out effects should still be considered in order to provide a more realistic interpretation of ion binding. These results should therefore be considered when salt effects are used to analyze electrostatic contributions to protein structure or are used to study the thermodynamics of proteins associated with halophillic organisms. PMID- 22197351 TI - [Trends in perinatal health in France between 1995 and 2010: Results from the National Perinatal Surveys]. AB - OBJECTIVE: To study trends in the main indicators of health, medical practice and risk factors in France. POPULATION AND METHOD: A sample of all births during one week was set-up in 1995 (n=13,318), 1998 (n=13,718), 2003 (n=14,737) and 2010 (n=14,903), and we compared data from these four years. RESULTS: Between 1995 and 2010, maternal age and body mass index increased steadily, but tobacco smoking decreased. In 2010, 39.4% of pregnant women had a visit with a midwife in maternity unit, versus 26.6% in 2003. Deliveries occurred in large public hospitals more and more frequently. The increase in caesarean sections was no longer significant between 2003 and 2010. In general medical decisions during pregnancy and delivery were closer to professional recommendations in 2010 than in the previous years. Live births before 37 weeks increased steadily from 5.4% in 1995 to 6.6% in 2010, but the proportion of births below 2500g or under the 10th percentile stopped increasing since 2003. CONCLUSION: Routine national perinatal surveys highlight major trends in maternal characteristics, obstetric practice, organisation of services and perinatal health. PMID- 22197352 TI - Assessment of hypoxia and radiation response in intramuscular experimental tumors by dynamic contrast-enhanced magnetic resonance imaging. AB - BACKGROUND AND PURPOSE: Studies of intradermal melanoma xenografts have suggested that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may be a useful method for assessing the extent of hypoxia in tumors. Because the microvascular network of tumors is influenced significantly by the site of growth, we challenged this possibility in the present work by studying relationships between DCE-MRI-derived parameters and hypoxia in intramuscular melanoma xenografts. MATERIALS AND METHODS: Intramuscular R-18, U-25, and V-27 tumors were subjected to DCE-MRI and measurement of the fraction of radiobiologically hypoxic cells (HF(Rad)). Parametric images of K(trans) and v(e) were produced by pharmacokinetic analysis, and K(trans) and v(e) were related to HF(Rad) in individual tumors. RESULTS: K(trans) decreased with increasing HF(Rad). The correlations between K(trans) and HF(Rad) were similar for the three tumor lines and were highly significant (P<0.00001). There was no correlation between v(e) and HF(Rad). However, v(e) decreased significantly with increasing cell survival after single dose irradiation. CONCLUSION: Intramuscular melanoma xenografts show similar inverse correlations between K(trans) and HF(Rad) as intradermal tumors, which support the current clinical attempts to establish DCE MRI as a method for detecting hypoxia and defining therapeutic targets in tumors. PMID- 22197353 TI - Cone beam CT for organs motion evaluation in pediatric abdominal neuroblastoma. AB - BACKGROUND AND PURPOSE: To quantify the organ motion relative to bone in different breathing states in pediatric neuroblastoma using cone beam CT (CBCT) for better definition of the planning margins during abdominal IMRT. METHODS AND MATERIALS: Forty-two datasets of kV CBCT for 9 pediatric patients with abdominal neuroblastoma treated with IMRT were evaluated. Organs positions on planning CT scan were considered the reference position against which organs and target motions were evaluated. The position of the kidneys and the liver was assessed in all scans. The target movement was evaluated in four patients who were treated for gross residual disease. RESULTS: The mean age of the patients was 4.1 +/- 1.6 years. The range of target movement in the craniocaudal direction (CC) was 5mm. In the CC direction, the range of movement was 10mm for the right kidney, and 8mm for the left kidney. Similarly, the liver upper edge range of motion was 11 mm while the lower edge range of motion was 13 mm. CONCLUSIONS: With the use of daily CBCT we may be able to reduce the PTV margin. If CBCT is not used daily, a wider margin is needed. PMID- 22197354 TI - Urethra sparing - potential of combined Nickel-Titanium stent and intensity modulated radiation therapy in prostate cancer. AB - BACKGROUND AND PURPOSE: To investigate a novel method for sparing urethra in external beam radiotherapy of prostate cancer and to evaluate the efficacy of such a treatment in terms of tumour control using a mathematical model. MATERIALS AND METHODS: This theoretical study includes 20 patients previously treated for prostate cancer using external beam radiotherapy. All patients had a Nickel Titanium (Ni-Ti) stent inserted into the prostate part of urethra. The stent has been used during the treatment course as an internal marker for patient positioning prior to treatment. In this study the stent is used for delineating urethra while intensity modulated radiotherapy was used for lowering dose to urethra. Evaluation of the dose plans were performed using a tumour control probability model based on the concept of uniform equivalent dose. RESULTS: The feasibility of the urethra dose reduction method is validated and a reduction of about 17% is shown to be possible. Calculations suggest a nearly preserved tumour control probability. CONCLUSIONS: A new concept for urethra dose reduction is presented. The method relies on the use of a Ni-Ti stent as a fiducial marker combined with intensity modulated radiotherapy. Theoretical calculations suggest preserved tumour control. PMID- 22197355 TI - Multi-component bioactive glasses of varying fluoride content for treating dentin hypersensitivity. AB - OBJECTIVE: Dentin hypersensitivity (DH) is a commonly occurring dental condition, and bioactive glasses (BG) are used in dentifrice formulations for treating DH by forming a surface layer of hydroxycarbonate apatite (HCA) on the tooth, thereby occluding exposed dentinal tubules. Fluoride-containing BG, however, form fluorapatite, which is more stable toward acid attack, and provide a more sustainable option for treating DH. METHODS: Melt-derived multi-component BG (SiO(2)-P(2)O(5)-CaO-CaF(2)-SrO-SrF(2)-ZnO-Na(2)O-K(2)O) with increasing CaF(2)+SrF(2) content (0-32.7 mol%) were prepared. Apatite formation, occlusion of dentinal tubules in dentin discs and ion release in Tris buffer were characterized in vitro over up to 7 days using X-ray diffraction, infrared spectroscopy, scanning electron microscopy and inductively coupled plasma emission spectroscopy. RESULTS: The fluoride-containing bioactive glasses formed apatite from as early as 6h, while the fluoride-free control did not form apatite within 7 days. The glasses successfully occluded dentinal tubules by formation of apatite crystals and released ions such as fluoride, strontium and potassium. SIGNIFICANCE: Fluoride significantly improved apatite formation of the BG, allowing for treatment of DH by occlusion of dentinal tubules. The BG also released therapeutically active ions, such as strontium and fluoride for caries prevention, zinc for bactericidal properties and potassium, which is used as a desensitizing agent in dentifrices. PMID- 22197356 TI - Comparative studies of mononuclear Ni(II) and UO2(II) complexes having bifunctional coordinated groups: synthesis, thermal analysis, X-ray diffraction, surface morphology studies and biological evaluation. AB - Two Schiff base ligands derived from condensation of phthalaldehyde and o phenylenediamine in 1:2 (L(1)) and 2:1 (L(2)) having bifunctional coordinated groups (NH(2) and CHO groups, respectively) and their metal complexes with Ni(II) and UO(2)(II) have been synthesized and characterized by elemental analysis, molar conductance, magnetic susceptibilities and spectral data (IR, (1)H NMR, mass and solid reflectance) as well as thermal, XRPD and SEM analysis. The formula [Ni(L(1))Cl(2)].2.5H(2)O, [UO(2)(L(1))(NO(3))(2)].2H(2)O, [Ni(L(2))Cl(2)].1.5H(2)O and [UO(2)(L(2))(NO(3))(2)] have been suggested for the complexes. The vibrational spectral data show that the ligands behave as neutral ligands and coordinated to the metal ions in a tetradentate manner. The Ni(II) complexes are six coordinate with octahedral geometry and the ligand field parameters: D(q), B, beta and LFSE were calculated while, UO(2)(II) complexes are eight coordinate with dodecahedral geometry and the force constant, F(U-O) and bond length, R(U-O) were calculated. The thermal decomposition of complexes ended with metal chloride/nitrate as a final product and the highest thermal stability is displayed by [UO(2)(L(2))(NO(3))(2)] complex. The X-ray powder diffraction data revealed the formation of nano sized crystalline complexes. The SEM analysis provides the morphology of the synthesized compounds and SEM image of [UO(2)(L(2))(NO(3))(2)] complex exhibits nano rod structure. The growth inhibiting potential of the ligands and their complexes has been assessed against a variety of bacterial and fungal strains. PMID- 22197357 TI - Concentration profiles of collagen and proteoglycan in articular cartilage by Fourier transform infrared imaging and principal component regression. AB - Fourier-transform infrared imaging (FT-IRI) technique with the principal component regression (PCR) method was used to quantitatively determine the 2D images and the depth-dependent concentration profiles of two principal macromolecular components (collagen and proteoglycan) in articular cartilage. Ten 6 MUm thick sections of canine humeral cartilage were imaged at a pixel size of 6.25 MUm in FT-IRI. The infrared spectra extracted from FT-IRI experiments were imported into a PCR program to calculate the quantitative distributions of both collagen and proteoglycan in dry cartilage, which were subsequently converted into the wet-weight based concentration profiles. The proteoglycan profiles by FT IRI and PCR significantly correlated in linear regression with the proteoglycan profiles by the non-destructive MUMRI (the goodness-of-fit 0.96 and the Pearson coefficient 0.98). Based on these concentration relationships, the concentration images of collagen and proteoglycan in both healthy and lesioned articular cartilage were successfully constructed two dimensionally. The simultaneous construction of both collagen and proteoglycan concentration images demonstrates that this combined imaging and chemometrics approach could be used as a sensitive tool to accurately resolve and visualize the concentration distributions of macromolecules in biological tissues. PMID- 22197358 TI - Principles of obstacle avoidance with a transfemoral prosthetic limb. AB - In this study, conditions that enable a prosthetic knee flexion strategy in transfemoral amputee subjects during obstacle avoidance were investigated. This study explored the hip torque principle and the static ground principle as object avoidance strategies. A prosthetic limb simulator device was used to study the influence of applied hip torques and static ground friction on the prosthetic foot trajectory. Inverse dynamics were used to calculate the energy produced by the hip joint. A two-dimensional forward dynamics model was used to investigate the relation between obstacle-foot distance and the necessary hip torques utilized during obstacle avoidance. The study showed that a prosthetic knee flexion strategy was facilitated by the use of ground friction and by larger active hip torques. This strategy required more energy produced by the hip compared to a knee extension strategy. We conclude that when an amputee maintains enough distance between the distal tip of the foot and the obstacle during stance, he or she produces sufficiently high, yet feasible, hip torques and uses static ground friction, the amputee satisfies the conditions for enable stepping over an obstacle using a knee flexion strategy. PMID- 22197359 TI - Fission-fusion and the evolution of hominin social systems. AB - The course of hominin evolution has involved successive migrations towards higher absolute latitudes over the past three million years. Poorer habitat quality further from the equator has led to the necessity for groups occupying higher latitudes to live at lower population densities. Coupled with a trend towards increasing group size over this time period, this tendency towards expansion has led to exponential increases in the area requirements of hominin groups, and a concomitant need to adjust foraging patterns. The current analyses suggest that the development of increasingly complex, multi-level fission-fusion social systems could have freed hominins of the foraging constraints imposed by large group sizes and low population densities. Analyses of the fossil record suggest latitudinally-driven differences in area requirements of the australopithecines from East and South Africa, and African and Asian Homo erectus. In contrast, chronologically-driven differences appear between H. erectus as a whole and Homo heidelbergensis, and between H. heidelbergensis and the Neanderthals. These results are discussed in relation to studies of the foraging patterns of primates and hunter-gatherers. PMID- 22197360 TI - [Superior vena cava syndrome and collateral circulation in the abdominal wall by a fibrosing mediastinitis]. PMID- 22197361 TI - [Stimulating factors for cardiac repair: when the ischemic myocardium asks for help]. PMID- 22197363 TI - [Vitamin D status in osteoporotic postmenopausal women taking oral recommended vitamin D supplementation]. AB - BACKGROUND AND OBJECTIVE: To assess the effectiveness of currently recommended daily intakes of vitamin D (25[OH]D) to bring optimal serum concentrations (30ng/ml) in postmenopausal osteoporotic women. PATIENTS AND METHODS: We reviewed 25(OH)D serum concentrations in 165 consecutive osteoporotic postmenopausal women who were taking oral vitamin D daily supplements above 800IU during at least 3 months. The proportion of patients who achieved 25(OH)D levels of 20, 30 and 40ng/ml were compared according to daily vitamin D intakes (group 1: 800-1,000IU, group 2: 1,001-1,600IU, group 3:>1,600IU). RESULTS: Mean patient age was 69 (10) years. Percentage of patients with serum 25(OH)D levels above 20ng/ml was 79.5% (63.5-88.5%), 92.7%(78.7-96%) and 97.6% (90.6-100%) in group 1, 2, and 3 patients, respectively (P=.009). Serum levels above 30ng/ml were achieved in 27.7% (14.7-44.7%), 53.6% (37.6-70%) and 90.2% (81.2-96.6%), respectively (P<.001). Serum levels above 40ng/ml were reached in 7.2% (1-20%), 24.4% (12-40%) and 61% (49-72%), respectively (P<.001). CONCLUSION: Daily reference intakes of vitamin D supplements (800-1,000IU) may be insufficient to achieve optimal serum levels of vitamin D in postmenopausal osteoporotic women. PMID- 22197364 TI - [Anticoagulation, iron, erythropoietin and transfusion in nocturnal paroxysmal hemoglobinuria]. PMID- 22197365 TI - [Is human immunodeficiency virus infection an inflammatory disease?]. PMID- 22197366 TI - [Analysis of confirmed severe cases of influenza in the first season after the pandemic]. PMID- 22197367 TI - [Hypertension and health policy in Catalonia, Spain: from theory to practice]. PMID- 22197368 TI - [Factors influencing mobilisation of endothelial progenitor cells and angiogenic cytokines after an extensive acute myocardial infarction]. AB - BACKGROUND AND OBJECTIVES: Following an acute myocardial infarction (AMI), bone marrow derived endothelial progenitor cells (EPC) are mobilised into the peripheral blood. Our aim was to examine the factors influencing this spontaneous cell mobilisation. PATIENTS AND METHODS: In this study we analysed 47 patients with extensive AMI (left ventricular ejection fraction [LVEF] <50% by echocardiography during the first week post-AMI); we studied the peripheral blood EPC populations expressing CD133(+), CD34(+), KDR(+), CXCR4(+), as well as the cytokines VEGF (vascular endothelial growth factor), SDF-1 (stromal cell-derived factor 1) and TSP-1 (thrombospondin 1), measured on day 5+/-2.5 after AMI. RESULTS: The extension of AMI (CPK peak) correlated with the number of CD133(+) mobilised cells: (r=0.40; P=.011). Patients who did not receive perfusion during the acute phase (34%) had more CD34(+)CXCR4(+) cells with a median (interquartile ranges) of 2,401 (498-7,004) vs. 999 (100-1,600), P=.048, and strong correlations between VEGF and CD133(+)CD34(+)KDR(+) (r=.84; P<.01) and SDF-1 and CD34(+)CXCR4(+) (r=.67; P<.01), and between these 2 cytokines (r=.57; P=.01). In the reperfused patients, the correlation between VEGF and CD133(+)CD34(+)KDR(+) was lower (r=.38; P=.03) and the correlation between SDF-1 and CD34(+)CXCR4(+) and VEGF disappeared. Multivariate analysis showed that a VEGF >7pg/mL (P<.01) predicted the mobilisation of CD133(+)CD34(+)KDR(+), whereas hypertension showed a trend (P=.055). Diabetes (P=.045) predicted the number of CD34(+)CXCR4(+), with reperfusion treatment showing a trend in this subpopulation (P=.054). CONCLUSIONS: Mobilisation of progenitor cells after AMI is influenced by factors such as diabetes and the cytokine VEGF. Hypertension and reperfusion therapy during the acute phase also tend to influence the cell response. PMID- 22197369 TI - [Vitamin D supplements. Recommended doses are not enough]. PMID- 22197370 TI - [Ollier's disease]. PMID- 22197372 TI - Two immunoglobulin tandem proteins with a linking beta-strand reveal unexpected differences in cooperativity and folding pathways. AB - The study of the folding of single domains, in the context of their multidomain environment, is important because more than 70% of eukaryotic proteins are composed of multiple domains. The structures of the tandem immunoglobulin (Ig) domain pairs A164-A165 and A168-A169, from the A-band of the giant muscle protein titin, reveal that they form tightly associated domain arrangements, connected by a continuous beta-strand. We investigate the thermodynamic and kinetic properties of these tandem domain pairs. While A164-A165 apparently behaves as a single cooperative unit at equilibrium, unfolding without the accumulation of a large population of intermediates, domains in A168-A169 behave independently. Although A169 appears to be stabilized in the tandem protein, we show that this is due to nonspecific stabilization by extension. We elucidate the folding and unfolding pathways of both tandem pairs and show that cooperativity in A164-A165 is a manifestation of the relative refolding and unfolding rate constants of each individual domain. We infer that the differences between the two tandem pairs result from a different pattern of interactions at the domain/domain interface. PMID- 22197371 TI - Ligand binding and membrane insertion compete with oligomerization of the BclXL apoptotic repressor. AB - B-cell lymphoma extra large (BclXL) apoptotic repressor plays a central role in determining the fate of cells to live or die during physiological processes such as embryonic development and tissue homeostasis. Herein, using a myriad of biophysical techniques, we provide evidence that ligand binding and membrane insertion compete with oligomerization of BclXL in solution. Of particular importance is the observation that such oligomerization is driven by the intermolecular binding of its C-terminal transmembrane (TM) domain to the canonical hydrophobic groove in a domain-swapped trans fashion, whereby the TM domain of one monomer occupies the canonical hydrophobic groove within the other monomer and vice versa. Binding of BH3 ligands to the canonical hydrophobic groove displaces the TM domain in a competitive manner, allowing BclXL to dissociate into monomers upon hetero-association. Remarkably, spontaneous insertion of BclXL into DMPC/DHPC (1,2-dimyristoyl-sn-glycero-3 phosphocholine/1,2-dihexanoyl-sn-glycero-3-phosphocholine) bicelles results in a dramatic conformational change such that it can no longer recognize the BH3 ligands in what has come to be known as the "hit-and-run" mechanism. Collectively, our data suggest that oligomerization of a key apoptotic repressor serves as an allosteric switch that fine-tunes its ligand binding and membrane insertion pertinent to the regulation of apoptotic machinery. PMID- 22197373 TI - Basic N-terminus of yeast Nhp6A regulates the mechanism of its DNA flexibility enhancement. AB - HMGB (high-mobility group box) proteins are members of a class of small proteins that are ubiquitous in eukaryotic cells and nonspecifically bind to DNA, inducing large-angle DNA bends, enhancing the flexibility of DNA, and likely facilitating numerous important biological interactions. To determine the nature of this behavior for different HMGB proteins, we used atomic force microscopy to quantitatively characterize the bend angle distributions of DNA complexes with human HMGB2(Box A), yeast Nhp6A, and two chimeric mutants of these proteins. While all of the HMGB proteins bend DNA to preferred angles, Nhp6A promoted the formation of higher-order oligomer structures and induced a significantly broader distribution of angles, suggesting that the mechanism of Nhp6A is like a flexible hinge more than that of HMGB2(Box A). To determine the structural origins of this behavior, we used portions of the cationic N-terminus of Nhp6A to replace corresponding HMGB2(Box A) sequences. We found that the oligomerization and broader angle distribution correlated directly with the length of the N-terminus incorporated into the HMGB2(Box A) construct. Therefore, the basic N-terminus of Nhp6A is responsible for its ability to act as a flexible hinge and to form high order structures. PMID- 22197374 TI - A central swivel point in the RFC clamp loader controls PCNA opening and loading on DNA. AB - Replication factor C (RFC) is a five-subunit complex that loads proliferating cell nuclear antigen (PCNA) clamps onto primer-template DNA (ptDNA) during replication. RFC subunits belong to the AAA(+) superfamily, and their ATPase activity drives interactions between the clamp loader, the clamp, and the ptDNA, leading to topologically linked PCNA.ptDNA. We report the kinetics of transient events in Saccharomyces cerevisiae RFC-catalyzed PCNA loading, including ATP induced RFC activation, PCNA opening, ptDNA binding, ATP hydrolysis, PCNA closing, and PCNA.ptDNA release. This detailed perspective enables assessment of individual RFC-A, RFC-B, RFC-C, RFC-D, and RFC-E subunit functions in the reaction mechanism. Functions have been ascribed to RFC subunits previously based on a steady-state analysis of 'arginine-finger' ATPase mutants; however, pre steady-state analysis provides a different view. The central subunit RFC-C serves as a critical swivel point in the clamp loader. ATP binding to this subunit initiates RFC activation, and the clamp loader adopts a spiral conformation that stabilizes PCNA in a corresponding open spiral. The importance of RFC subunit response to ATP binding decreases as RFC-C>RFC-D>RFC-B, with RFC-A being unnecessary. RFC-C-dependent activation of RFC also enables ptDNA binding, leading to the formation of the RFC.ATP.PCNA(open).ptDNA complex. Subsequent ATP hydrolysis leads to complex dissociation, with RFC-D activity contributing the most to rapid ptDNA release. The pivotal role of the RFC-B/C/D subunit ATPase core in clamp loading is consistent with the similar central location of all three ATPase active subunits of the Escherichia coli clamp loader. PMID- 22197375 TI - Structural basis of C-terminal beta-amyloid peptide binding by the antibody ponezumab for the treatment of Alzheimer's disease. AB - Alzheimer's disease, the most common cause of dementia in the elderly and characterized by the deposition and accumulation of plaques, is composed in part of beta-amyloid (Abeta) peptides, loss of neurons, and the accumulation of neurofibrillary tangles. Here, we describe ponezumab, a humanized monoclonal antibody, and show how it binds specifically to the carboxyl (C)-terminus of Abeta40. Ponezumab can label Abeta that is deposited in brain parenchyma found in sections from Alzheimer's disease casualties and in transgenic mouse models that overexpress Abeta. Importantly, ponezumab does not label full-length, non-cleaved amyloid precursor protein on the cell surface. The C-terminal epitope of the soluble Abeta present in the circulation appears to be available for ponezumab binding because systemic administration of ponezumab greatly elevates plasma Abeta40 levels in a dose-dependent fashion after administration to a mouse model that overexpress human Abeta. Administration of ponezumab to transgenic mice also led to a dose-dependent reduction in hippocampal amyloid load. To further explore the nature of ponezumab binding to Abeta40, we determined the X-ray crystal structure of ponezumab in complex with Abeta40 and found that the Abeta40 carboxyl moiety makes extensive contacts with ponezumab. Furthermore, the structure-function analysis supported this critical requirement for carboxy group of AbetaV40 in the Abeta-ponezumab interaction. These findings provide novel structural insights into the in vivo conformation of the C-terminus of Abeta40 and the brain Abeta-lowering efficacy that we observed following administration of ponezumab in transgenic mouse models. PMID- 22197376 TI - Engineering antibody fitness and function using membrane-anchored display of correctly folded proteins. AB - A hallmark of the bacterial twin-arginine translocation (Tat) pathway is its ability to export folded proteins. Here, we discovered that overexpressed Tat substrate proteins form two distinct, long-lived translocation intermediates that are readily detected by immunolabeling methods. Formation of the early translocation intermediate Ti-1, which exposes the N- and C-termini to the cytoplasm, did not require an intact Tat translocase, a functional Tat signal peptide, or a correctly folded substrate. In contrast, formation of the later translocation intermediate, Ti-2, which exhibits a bitopic topology with the N terminus in the cytoplasm and C-terminus in the periplasm, was much more particular, requiring an intact translocase, a functional signal peptide, and a correctly folded substrate protein. The ability to directly detect Ti-2 intermediates was subsequently exploited for a new protein engineering technology called MAD-TRAP (membrane-anchored display for Tat-based recognition of associating proteins). Through the use of just two rounds of mutagenesis and screening with MAD-TRAP, the intracellular folding and antigen-binding activity of a human single-chain antibody fragment were simultaneously improved. This approach has several advantages for library screening, including the unique involvement of the Tat folding quality control mechanism that ensures only native like proteins are displayed, thus eliminating poorly folded sequences from the screening process. PMID- 22197378 TI - ATP binding and hydrolysis-driven rate-determining events in the RFC-catalyzed PCNA clamp loading reaction. AB - The multi-subunit replication factor C (RFC) complex loads circular proliferating cell nuclear antigen (PCNA) clamps onto DNA where they serve as mobile tethers for polymerases and coordinate the functions of many other DNA metabolic proteins. The clamp loading reaction is complex, involving multiple components (RFC, PCNA, DNA, and ATP) and events (minimally: PCNA opening/closing, DNA binding/release, and ATP binding/hydrolysis) that yield a topologically linked clamp.DNA product in less than a second. Here, we report pre-steady-state measurements of several steps in the reaction catalyzed by Saccharomyces cerevisiae RFC and present a comprehensive kinetic model based on global analysis of the data. Highlights of the reaction mechanism are that ATP binding to RFC initiates slow activation of the clamp loader, enabling it to open PCNA (at ~2 s( 1)) and bind primer-template DNA (ptDNA). Rapid binding of ptDNA leads to formation of the RFC.ATP.PCNA(open).ptDNA complex, which catalyzes a burst of ATP hydrolysis. Another slow step in the reaction follows ATP hydrolysis and is associated with PCNA closure around ptDNA (8 s(-1)). Dissociation of PCNA.ptDNA from RFC leads to catalytic turnover. We propose that these early and late rate determining events are intramolecular conformational changes in RFC and PCNA that control clamp opening and closure, and that ATP binding and hydrolysis switch RFC between conformations with high and low affinities, respectively, for open PCNA and ptDNA, and thus bookend the clamp loading reaction. PMID- 22197379 TI - The transition of human estrogen sulfotransferase from generalist to specialist using directed enzyme evolution. AB - Broad specificity is believed to be a property of primordial enzymes that diverged during natural protein evolution to produce highly specific and efficient enzymes. Human estrogen sulfotransferase (SULT1E1) is a broad specificity enzyme that detoxifies a variety of chemicals, including estrogens, by the transfer of sulfate. To study the molecular basis for the broad specificity of this enzyme and to investigate the process of SULT1E1 specialization, we have adopted a directed enzyme evolution approach. Using two iterative rounds of evolution, we generated SULT1E1 mutants with increased thermostability and narrower specificity from the broadly specific wild-type enzyme. To identify mutants with enhanced specificity, we developed an unbiased screening assay to assess sulfate transfer to three different acceptors in parallel. Such an assay enabled the isolation of SULT1E1 mutants with enhanced or wild-type activity toward an estrogen acceptor and significantly reduced activity for phenol or coumarin type of acceptors, leading to up to 3 orders of magnitude increase in specificity. We found that mutations conferring novel specificity are located in the vicinity of the active site and thus may play a direct role in reshaping the acceptor-binding site. Finally, such mutations resulted in reduced SULT1E1 thermostability, revealing a trade-off between SULT1E1 thermostability and acquisition of novel function. PMID- 22197377 TI - Amyloid fibril formation by the glaucoma-associated olfactomedin domain of myocilin. AB - Myocilin is a protein found in the extracellular matrix of trabecular meshwork tissue, the anatomical region of the eye involved in regulating intraocular pressure. Wild-type (WT) myocilin has been associated with steroid-induced glaucoma, and variants of myocilin have been linked to early-onset inherited glaucoma. Elevated levels and aggregation of myocilin hasten increased intraocular pressure and glaucoma-characteristic vision loss due to irreversible damage to the optic nerve. In spite of reports on the intracellular accumulation of mutant and WT myocilin in vitro, cell culture, and model organisms, these aggregates have not been structurally characterized. In this work, we provide biophysical evidence for the hallmarks of amyloid fibrils in aggregated forms of WT and mutant myocilin localized to the C-terminal olfactomedin (OLF) domain. These fibrils are grown under a variety of conditions in a nucleation-dependent and self-propagating manner. Protofibrillar oligomers and mature amyloid fibrils are observed in vitro. Full-length mutant myocilin expressed in mammalian cells forms intracellular amyloid-containing aggregates as well. Taken together, this work provides new insights into and raises new questions about the molecular properties of the highly conserved OLF domain, and suggests a novel protein-based hypothesis for glaucoma pathogenesis for further testing in a clinical setting. PMID- 22197380 TI - A cost-effectiveness analysis of screening methods for dysphagia after stroke. AB - OBJECTIVE: To provide a cost-effectiveness analysis of dysphagia screening in the acute poststroke period with use of a videofluoroscopic swallowing study, a clinical bedside swallowing evaluation, or a combined approach. DESIGN: Decision analysis model. METHODS: A decision-analysis model was used with information derived from multiple data sources, including meta-analyses and other relevant clinical studies. Univariate and probabilistic sensitivity analyses were performed. MAIN OUTCOME MEASURES: The analysis assessed direct medical costs of pneumonia. Strategies were compared on the basis of an incremental cost effectiveness analysis, with effectiveness measured in quality-adjusted life years. RESULTS: The strategy of having each patient undergo a videofluoroscopic swallowing study for dysphagia was more effective and less costly than the strategies of clinical bedside swallowing evaluation alone or a combined approach. The model was most influenced by the reduction in the risk of pneumonia attributable to the treatment of mild/moderate and severe dysphagia, the effectiveness of treatment with clinical bedside swallowing evaluation, the baseline probability of pneumonia, and the cost of a videofluoroscopic swallowing study. CONCLUSIONS: A videofluoroscopic swallowing study is cost-effective and often saves costs compared with a clinical bedside swallowing evaluation alone or a combined approach. Research aimed at improving the understanding of the effectiveness of treatment for dysphagia in the prevention of aspiration pneumonia and resulting mortality would improve the model. PMID- 22197381 TI - Binding sites of retinol and retinoic acid with serum albumins. AB - Retinoids are effectively transported in the bloodstream via serum albumins. We report the complexation of bovine serum albumin (BSA) with retinol and retinoic acid at physiological conditions, using constant protein concentration and various retinoid contents. FTIR, CD and fluorescence spectroscopic methods and molecular modeling were used to analyze retinoid binding site, the binding constant and the effects of complexation on BSA stability and secondary structure. Structural analysis showed that retinoids bind BSA via hydrophilic and hydrophobic interactions with overall binding constants of K(Ret)(-BSA) = 5.3 (+/ 0.8) * 10(6) M(-1) and K(Retac-BSA) = 2.3 (+/-0.4) * 10(6) M(-1). The number of bound retinoid molecules (n) was 1.20 (+/-0.2) for retinol and 1.8 (+/-0.3) for retinoic acid. Molecular modeling showed the participation of several amino acids in retinoid-BSA complexes stabilized by H-bonding network. The retinoid binding altered BSA conformation with a major reduction of alpha-helix from 61% (free BSA) to 36% (retinol-BSA) and 26% (retinoic acid-BSA) with an increase in turn and random coil structures indicating a partial protein unfolding. The results indicate that serum albumins are capable of transporting retinoids in vitro and in vivo. PMID- 22197382 TI - High-resolution diffusion-weighted magnetic resonance imaging in patients with locally advanced breast cancer. AB - RATIONALE AND OBJECTIVES: The aim of this study was to evaluate differences in tumor depiction and measured tumor apparent diffusion coefficient (ADC) with the use of a high-resolution diffusion-weighted (DW) magnetic resonance imaging (MRI) sequence, compared to a standard DW MRI sequence, in patients with locally advanced breast cancer. MATERIALS AND METHODS: Patients with locally advanced breast cancer were scanned with a reduced-field of view (rFOV) DW MRI sequence (high resolution) and a standard-field of view diffusion sequence (standard resolution), and differences between the two sequences were evaluated quantitatively (by calculating tumor ADC distribution parameters) and qualitatively (by radiologists' visual assessments of images). RESULTS: Although the mean tumor ADC for both sequences was similar, differences were found in other parameters, including the 12.5th percentile (P = .042) and minimum tumor ADC (P = .003). Qualitatively, visualization of tumor morphologic detail, heterogeneity, and conspicuity was improved with rFOV DW MRI, and image quality was higher. CONCLUSIONS: Differences in ADC distribution parameters and qualitative image features suggest that the sequences differ in their ability to capture tumor heterogeneity. These differences are not apparent when the mean is used to evaluate tumor ADC. In particular, differences found in lower ADC values are compatible with reduced partial voluming in rFOV DW MRI, suggesting that rFOV DW MRI may be valuable in imaging the lower ADCs expected to correspond to viable tumor in most invasive breast cancers. PMID- 22197384 TI - Structure-based computational analysis of protein binding sites for function and druggability prediction. AB - Protein binding sites are the places where molecular interactions occur. Thus, the analysis of protein binding sites is of crucial importance to understand the biological processes proteins are involved in. Herein, we focus on the computational analysis of protein binding sites and present structure-based methods that enable function prediction for orphan proteins and prediction of target druggability. We present the general ideas behind these methods, with a special emphasis on the scopes and limitations of these methods and their validation. Additionally, we present some successful applications of computational binding site analysis to emphasize the practical importance of these methods for biotechnology/bioeconomy and drug discovery. PMID- 22197383 TI - Sec62 bridges the gap from 3q amplification to molecular cell biology in non small cell lung cancer. AB - The molecular carcinogenesis of lung cancer has yet to be clearly elucidated. We investigated the possible oncogenic function of SEC62 in lung cancer, which was predicted based on our previous findings that lung and thyroid cancer tissue samples exhibited increased Sec62 protein levels. The SEC62 gene locus is at 3q26.2, and 3q amplification is reportedly the most common genomic alteration in non-small cell lung cancer. We analyzed SEC62 mRNA and protein levels in tissue samples from lung cancer patients by real-time quantitative PCR, Western blot, and IHC and found significantly increased SEC62 mRNA and protein levels in tumors compared with tumor-free tissue samples from the same patients. Correlation analyses revealed significantly higher Sec62 levels in tumors with lymph node metastases compared with nonmetastatic tumors, as well as in poorly compared with moderately differentiated tumors. On the basis of these promising results, we examined the role of Sec62 in cancer cell biology in vitro. Cell migration assays with lung and thyroid cancer cells showed distinct stimulation of migration in SEC62-overexpressing cells and inhibition of migration in Sec62-depleted cells. Moreover, we found that SEC62 silencing sensitized the cells to thapsigargin induced endoplasmic reticulum stress. Thus, our results indicate that SEC62 represents a potential candidate oncogene in the amplified 3q region in cases of non-small cell lung cancer and harbors various functions in cancer cell biology. PMID- 22197385 TI - Older bariatric surgery candidates: is there greater psychological risk than for young and midlife candidates? AB - BACKGROUND: Although severe obesity is dramatically increasing in older adults, many bariatric programs use age cutoffs due to concerns about greater perioperative morbidity and mortality risks. More recently, surgical outcomes have been reported in older adults. However, a paucity of data is available on the psychological risks of older bariatric candidates. Our objective is to examine psychiatric risk factors and weight loss outcomes in older (>=65 yr) versus midlife (40-55 yr) versus young adult (18-29 yr) patients. METHODS: Older, midlife, and young adults (n = 608) who underwent weight loss surgery (74.6% women, 75.6% white, mean body mass index 48.07 +/- 9.61 kg/m2) at the Cleveland Clinic Bariatric and Metabolic Institute completed a psychiatric diagnostic interview, and the Minnesota multiphasic personality inventory-2-restructured form, binge eating scale, and Cleveland Clinic behavioral rating scale before surgery. The data gathered from follow-up visits and weight loss outcomes at 1, 3, 6, 9, 12, and 18 months after surgery were measured. RESULTS: Young adults had a greater reduction in excess body mass index than those at midlife in the first 6 months but no age differences were noted in the following year. Older patients were less likely to have a suicide history but the groups were equivalent on other psychiatric variables and self-report measures. Psychologist evaluators rated older adults less favorably on the capacity to consent and realistic nature of expectations. CONCLUSION: Although medical risks may cause concern, older adults do not demonstrate any increased psychological risk factors compared with midlife or young adult surgical candidates and evidenced equivalent weight loss. However, concerns with lower ratings on consent and expectations warrant additional research. PMID- 22197386 TI - Methylenetetrahydrofolate reductase gene 677CT polymorphism and isolated congenital heart disease in a Mexican population. AB - INTRODUCTION AND OBJECTIVES: The frequency of the 677C>T mutation in the methylenetetrahydrofolate reductase gene in Mexico is one of the highest worldwide. Some studies have shown that both the homozygous state of this mutation and a high homocysteine concentration are associated with congenital heart disease. The aim of this study was to determine whether this association exists in the Mexican population. METHODS: Genotypes were analyzed in 60 patients with congenital heart disease and in their mothers, and the levels of homocysteine were determined in the latter group. The genotypes were compared with those of a control group (n=62) and of their mothers. All the possible mother-child genotype combinations were also compared. RESULTS: There were no significant differences in allele or genotype frequencies between the patients with congenital heart disease and the controls or their respective mothers (P>.05). Although no significant differences were observed when the homocysteine concentrations in the presence of the CC or the TT genotype were compared, a clear trend was observed (P=.0621). We found no significant differences in homocysteine concentrations in relation to folic acid intake. The study cases and controls did not differ in terms of the possible combinations of mother-child genotypes. CONCLUSIONS: The frequencies obtained were consistent with those reported for Mexico. No significant differences were found between groups. Nor did we find any association between TT mutations in both the mother and child and hyperhomocysteinemia. There was no evidence of an association between any of the mother-child genotype combinations and congenital heart disease. Similar studies with larger numbers of patients are required to confirm or refute some of the trends observed in this report. PMID- 22197387 TI - Discovery of novel antitubercular 1,5-dimethyl-2-phenyl-4-([5-(arylamino)-1,3,4 oxadiazol-2-yl]methylamino)-1,2-dihydro-3H-pyrazol-3-one analogues. AB - In search of potential therapeutics for tuberculosis, we describe herewith the synthesis, characterization and antimycobacterial activity of 1,5-dimethyl-2 phenyl-4-([5-(arylamino)-1,3,4-oxadiazol-2-yl]methylamino)-1,2-dihydro-3H-pyrazol 3-one analogues. Among the synthesized compounds, 4-[(5-[(4-fluorophenylamino] 1,3,4-oxadiazol-2-yl)methylamino]-1,2-dihydro-1,5-dimethyl-2-phenylpyrazol-3-one (4a) was found to be the most promising compound active against Mycobacterium tuberculosis H(37)Rv and isoniazid resistant M. tuberculosis with minimum inhibitory concentrations, 0.78 and 3.12MUg/mL, respectively, free from any cytotoxicity (>62.5MUg/mL). PMID- 22197388 TI - 6-Amino quinazolinedione sulfonamides as orally active competitive AMPA receptor antagonists. AB - A new set of quinazolinedione sulfonamide derivatives as competitive AMPA receptor antagonist with improved properties compared to 1 is disclosed. By modulating physico-chemical properties, compound 29 was identified with a low ED(50) of 5.5mg/kg in an animal model of anticonvulsant activity after oral dosage. PMID- 22197389 TI - Design, synthesis and evaluation of novel molecules with a diphenyl ether nucleus as potential antitubercular agents. AB - A series of compounds with a diphenyl ether nucleus were synthesized by incorporating various amines into the diphenyl ether scaffold with an amide bond. Their antitubercular activities were evaluated against Mycobacterium tuberculosis H(37)Rv by a microdilution method, with MIC values ranging from 4 to 64MUg/mL. Through structure-activity relationship studies, the two chlorine atoms at 3 and 4 positions in the phenyl ring of R(2) group were found to play a significant role in the antitubercular activity. The most potent compound 6c showed an MIC value of 4MUg/mL and a good safety profile in HepG2 cell line by the MTT assay. Compound 6c was further found to be effective in a murine model of BCG infection, providing a good lead for subsequent optimization. PMID- 22197390 TI - The discovery of potent antagonists of NPBWR1 (GPR7). AB - The synthesis and evaluation of small molecule antagonists of the G protein coupled receptor NPBWR1 (GPR7) are reported for the first time. [4-(5 Chloropyridin-2-yl)piperazin-1-yl][(1S,2S,4R)-4-{[(1R)-1-(4 methoxyphenyl)ethyl]amino}-2-(thiophen-3-yl)cyclohexyl]methanone (1) emerged as a hit from a high-throughput screen. Examination of substituents that focused on replacing the 5-chloropyridine and 4-methoxybenzylamino groups of 1 led to the identification of compounds that exhibited subnanomolar potencies as low as 660pM (9k) in the functional assay and 200pM in the binding assay (9i). PMID- 22197391 TI - Steroidal C-21 heteroaryl thioethers (Part 2): discovery of orally bioavailable selective glucocorticoid receptor modulators (dissociated steroids). AB - The prednisolone C-21 heteroaryl thioethers have been synthesized and evaluated in cell based transrepression and transactivation assays. Most of the compounds demonstrated weak transactivational activity in both human and rat tyrosineaminotransferase functional assay while keeping potent anti-inflammatory activity. The benzimidazole thioether 7 exhibited comparable anti-inflammatory activity and improved safety profile compared to the classical oral steroid prednisolone. PMID- 22197392 TI - Capture hydrolysis signals in the microsomal stability assay: molecular mechanisms of the alkyl ester drug and prodrug metabolism. AB - The hydrolysis of carboxylic acid esters is often catalyzed by carboxylesterases in human liver microsomes, which is also a common 'noise' in the microsomal stability assay, a widely used screening protocol in drug discovery to monitor the activity of cytochrome P450 enzymes. Herein, we captured this 'noise', the hydrolysis signal of small alkyl ester drugs and prodrugs with a unique pairwise analysis of Pfizer's microsomal clearance database. The hydrolysis mechanisms were further elucidated with density functional theory and molecular docking approaches. The results suggested that the electronic properties of ester moieties, tetrahedral intermediate formation energies, and specific drug-enzyme molecular interactions are key factors for the determination of the metabolic fate of the studied alkyl esters, but individually these factors failed to correlate with the observed rate of hydrolysis. PMID- 22197393 TI - Induction of microtubule-damage, mitotic arrest, Bcl-2 phosphorylation, Bak activation, and mitochondria-dependent caspase cascade is involved in human Jurkat T-cell apoptosis by aruncin B from Aruncus dioicus var. kamtschaticus. AB - Exposure of human Jurkat T cells to aruncin B, purified from Aruncus dioicus, caused apoptosis along with microtubule damage, G(2)/M-arrest, Bcl-2 phosphorylation, Bak activation, mitochondrial membrane potential (Deltapsim) loss, cytochrome c release, activation of multiple caspases, and PARP degradation. Analyses by employing Bcl-2 overexpression and selective caspase inhibitors revealed that G(2)/M-arrest and Bcl-2 phosphorylation occurred prior to mitochondria-dependent activation of caspase-9, -3, and -8. The IC(50) values for human resting T cells, activated T cells, and Jurkat T cells were >60MUg/ml, 49MUg/ml, and 22MUg/ml, respectively. These results demonstrate the apoptogenic activity of a novel microtubule-damaging agent aruncin B. PMID- 22197394 TI - Development and evaluation of a reverse dot blot assay for the simultaneous detection of common alpha and beta thalassemia in Chinese. AB - Thalassemia is the commonest inherited autosomal recessive disorders of hemoglobin in southern China. We developed and evaluated a reverse dot blot (RDB) assay combined with flow-through hybridization technology platform for the rapid and simultaneous identification of 5 types of alpha-thalassemia and 16 types of beta-thalassemia common in Chinese. Reliable genotyping of wild-type and thalassemic genomic DNA samples was achieved by means of a gene chip on which allele-specific oligonucleotide probes were immobilized on a nylon membrane. This method involved two multiplex PCR amplification systems of alpha-thalassemia and beta-thalassemia and one time of hybridization. The whole procedure starting from blood sampling to the identification of thalassemia genotype required less than 4h. The diagnostic reliability of this reverse dot blot assay was evaluated on 427 samples (387 cases of thalassemia and 40 healthy persons) by using direct DNA sequence analysis and gap-PCR in a blind study. These samples included 377 cases of blood, 7 cases of amniotic fluid, 18 cases of chorionic villus, and 25 cases of cord blood. The RDB gene chip was in complete concordance with the reference method. The reverse dot blot assay was a simple, rapid, accurate, and cost effective method to identify common thalassemia genotypes in the Chinese population. PMID- 22197395 TI - Oxidative folding of lysozyme with aromatic dithiols, and aliphatic and aromatic monothiols. AB - In vitro protein folding of disulfide containing proteins is aided by the addition of a redox buffer, which is composed of a small molecule disulfide and/or a small molecule thiol. In this study, we examined redox buffers containing asymmetric dithiols 1-5, which possess an aromatic and aliphatic thiol, and symmetric dithiols 6 and 7, which possess two aromatic thiols, for their ability to fold reduced lysozyme at pH 7.0 and 8.0. Most in vivo protein folding catalysts are dithiols. When compared to glutathione and glutathione disulfide, the standard redox buffer, dithiols 1-5 improved the protein folding rates but not the yields. However, dithiols 6 and 7, and the corresponding monothiol 8 increased the folding rates 8-17 times and improved the yields 15-42% at 1mg/mL lysozyme. Moreover, aromatic dithiol 6 increased the in vitro folding yield as compared to the corresponding aromatic monothiol 8. Therefore, aromatic dithiols should be useful for protein folding, especially at high protein concentrations. PMID- 22197396 TI - Novel (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids: peroxisome proliferator-activated receptor gamma selective agonists with protein-tyrosine phosphatase 1B inhibition. AB - A novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and (S)-2-[(2E,4E)-hexadienoyl]-7-(2-{5-methyl-2-[(1E)-5 methylhexen-1-yl]oxazol-4-yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (14i) was identified as a potent human peroxisome proliferator-activated receptor gamma (PPARgamma) selective agonist (EC(50)=0.03 MUM) and human protein tyrosine phosphatase 1B (PTP-1B) inhibitor (IC(50)=1.18 MUM). C(max) after oral administration of 14i at 10mg/kg was 2.2 MUg/ml (4.5 MUM) in male SD rats. Repeated administration of 14i and rosiglitazone for 14 days dose-dependently decreased plasma glucose levels, ED(50)=4.3 and 23 mg/kg/day, respectively, in male KK-A(y) mice. In female SD rats, repeated administration of 14i at 12.5 100mg/kg/day for 28 days had no effect on the hematocrit value (Ht) and red blood cell count (RBC), while rosiglitazone significantly decreased them from 25mg/kg/day. In conclusion, 14i showed about a fivefold stronger hypoglycemic effect and fourfold or more weaker hemodilution effect than rosiglitazone, indicating that 14i is 20-fold or more safer than rosiglitazone. Compound 14i is a promising candidate for an efficacious and safe anti-diabetic drug targeting PPARgamma and PTP-1B. PMID- 22197397 TI - Pyridobenzothiazole derivatives as new chemotype targeting the HCV NS5B polymerase. AB - Hepatitis C virus (HCV) infection has been recognized as the major cause of liver failure that can lead to hepatocellular carcinoma. Among all the HCV proteins, NS5B polymerase represents a leading target for drug discovery strategies. Herein, we describe our initial research efforts towards the identification of new chemotypes as allosteric NS5B inhibitors. In particular, the design, synthesis, in vitro anti-NS5B and in cellulo anti-HCV evaluation of a series of 1 oxo-1H-pyrido[2,1-b][1,3]benzothiazole-4-carboxylate derivatives are reported. Some of the newly synthesized compounds showed an IC(50) ranging from 11 to 23 MUM, and molecular modeling and biochemical studies suggested that the thumb domain could be the target site for this new class of NS5B inhibitors. PMID- 22197398 TI - Acute renal failure after intragastric balloon in morbidly-obese metformin treated diabetic patients. Report of two cases. PMID- 22197400 TI - [Drugs adjustment dosage at hospital discharge for patients with renal failure: study of 326 medical records]. AB - INTRODUCTION: The objective of our study was to identify the misuse of drugs necessitating an adaptation to renal function and/or contra-indicated in case of renal failure at discharge. DESIGN: We conducted a 2-month retrospective study in a French teaching hospital for all patients with at least a moderate renal impairment (eDFG<60 mL/min/1.73 m(2)) discharge from eight units (medical and surgical) and compared their prescriptions to guidelines. We classified each drug prescription as N: drug that do not need adaptation or non contra-indicated for the renal status of patient; A: drug that need an adaptation to kidney but those was correctly done; I: drug that need an adaptation to kidney, those incorrectly done; C: drug contra-indicated in case of renal failure; D: drug for which it is impossible to conclude without an expertise of the patient file. RESULTS: For patient with eDFG less than 60 mL/min/1.73 m(2), 326 prescriptions corresponding to 2137 drugs were analysed. Misuses concerned 19.0% of patients (n=69). For patient with eDFG less than 30 mL/min/1.73 m(2), 42 prescriptions corresponding to 291 drugs were analysed. Misuses concerned 57.1% of patients (n=24). DISCUSSION/CONCLUSION: The misuse observed at patient's discharge may have consequences in further prescriptions; discharge prescriptions are often considered as "validated" by general practitioners. Improving solution should be offered to prescribers and as well as to pharmacists to manage drug dosage adaptation to renal function. PMID- 22197401 TI - [Rare association between chronic lymphocytic leukemia and systemic lupus erythematosus]. PMID- 22197402 TI - Comparison of NASCET and WASID criteria for the measurement of intracranial stenosis using digital subtraction and computed tomography angiography of the middle cerebral artery. AB - BACKGROUND AND PURPOSE: Intracranial large-artery atherosclerosis is considered a frequent cause of stroke worldwide, particularly in Asian populations. The current evidence suggests that symptomatic patients with severe stenosis may benefit from intracranial stents. There are two methods for calculating the degree of intracranial stenosis, Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) and North American Symptomatic Carotid Endarterectomy Trial (NASCET), but they have never been compared. METHODS: A total of 25 patients with suspected middle cerebral artery (MCA) stenosis based on their acute presentation were imaged by computed tomography angiography (CTA), then confirmed by digital subtraction angiography (DSA). Measurements were carried out on symptomatic MCA using both methods for determining the degree of stenosis. RESULTS: The degree of stenosis was significantly different using NASCET and WASID methods in DSA (48.2% vs. 54.6%; P<0.01), whereas CTA values did not differ significantly (54.2% vs. 52.0%; P = 0.9). All measurements were highly correlated between methods (Spearman r = 0.92 and 0.89, respectively; P<0.01). CONCLUSION: The results of this study suggest that NASCET and WASID measures are, on average, generally similar, although substantial disagreement in a given patient may be seen. PMID- 22197403 TI - Neuroimaging findings in a case of fluoxetine overdose. AB - Brain MRI and 18F-FDG PET/CT scans were performed in a patient who had survived a suicide attempt by fluoxetine overdose. The patient presented with the following clinical signs and symptoms, and neuroimaging findings: severe signs of serotonin toxicity, including comatose state, akinetic rigid syndrome and dysautonomia; bilateral globus pallidus changes consistent with extensive pallidal necrosis and subsequent reversible diffuse ischemic changes in white matter, with posterior predominance, involving the splenium of the corpus callosum on brain MRI; and marked hypometabolism in the frontal, parietal and temporal cortical regions as well as in both caudate nuclei on 18F-FDG PET/CT performed 37 days later. These findings suggest that acute severe serotonin toxicity can induce structural and long-standing functional changes in multiple cortical and subcortical brain regions that are associated with cognitive and extrapyramidal syndromes. PMID- 22197404 TI - Multiparametric magnetic resonance imaging to differentiate high-grade gliomas and brain metastases. AB - PURPOSE: To assess the performance of parameters used in conventional magnetic resonance imaging (MRI), perfusion-weighted MR imaging (PWI) and visual texture analysis, alone and in combination, to differentiate a single brain metastasis (MET) from glioblastoma multiforme (GBM). PATIENTS AND METHODS: In a retrospective study of 50 patients (41 GBM and 14 MET) who underwent T2/FLAIR/T1(post-contrast) imaging and PWI, morphological (circularity, surface area), perfusion (rCBV in the ring-like tumor area, rCBV in the peritumoral area, percentage of signal intensity recovery at the end of first pass) and texture parameters in the peritumoral area were estimated. Statistical differences and performances were assessed using Wilcoxon's test and receiver operating characteristic curves, respectively. Multiparametric classification of tumors was performed using k-means clustering. RESULTS: Significant statistical differences in circularity, surface area, rCBVs, percentage of signal intensity recovery and texture parameters (energy, entropy, homogeneity, correlation, inverse differential moment, sum average) were observed between MET and GBM (P<0.05). Moderate-to-good classification performances were found with these parameters. Clustering based on rCBV and texture parameters (contrast, sum average) differentiated MET from GBM with a sensitivity of 92% and a specificity of 71%. CONCLUSION: Combining perfusion and visual texture parameters within a statistical classifier significantly improved the differentiation of a single brain MET and GBM. PMID- 22197405 TI - Neuroimaging features and pathology of mixed glioblastoma--AVM complex: a case report. AB - This report is of a rare case of glioblastoma coexisting with an arteriovenous malformation in a 65-year-old man. Multimodal magnetic resonance imaging (MRI) performed at 3T revealed a necrotic and cystic lesion in the left hemisphere; morphological and metabolic findings were consistent with an infiltrating high grade glioma, but the presence of dark vessel-like signals on T2* and susceptibility-weighted imaging (SWI) suggested the coexistence of a vascular malformation. The arteriovenous malformation was confirmed by MR angiography and cerebral angiography. The patient was operated on, and histological examination revealed atypical cells characteristic of glioblastoma multiforme and, in the same area, arteriovenous malformation. The possible role of angiogenic factors in this case is also addressed. PMID- 22197406 TI - Perfusion-CT assessment of blood-brain barrier permeability in patients with aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: The goal of this study was to determine which clinical and radiographic variables in patients with subarachnoid hemorrhage (SAH) are associated with in vivo blood-brain barrier permeability (BBBP) assessments obtained using perfusion-CT (PCT) technology. METHODS: SAH patients with confirmed aneurysm etiology and with PCT and angiogram within 24 hours of each other were included, and relationships between clinical and imaging variables were analyzed using random-effects generalized linear models. RESULTS: One thousand one hundred and sixty two vascular territories from 83 patients were evaluated in this study. The mean BBBP increased by severity of vasospasm on DSA, however, in multivariate analysis, only mean transit time (MTT), cerebral blood volume (CBV), and severity of hydrocephalus were significantly associated with BBBP. Increased BBBP was not associated with angiographic vasospasm severity in multivariate analysis. CONCLUSION: Perfusion-CT assessment of BBBP may serve as a unique and useful biomarker in conjunction with angiography, additional perfusion CT parameters, and clinical assessments, especially in characterizing microvascular dysfunction, or even in targeting treatments. However, future prospective studies will be required to definitively establish its clinical utility in the care of SAH patients. PMID- 22197407 TI - Civic commitment in young activists: emergent processes in the development of personal and collective identity. AB - Through a qualitative approach this study documents life experiences that youth with a history of sustained social and political participation judge as significant in the development of their civic commitment. Data is drawn from in depth interviews to 6 Chilean youth (3 ages 16-19; 3 ages 20-24 years) of diverse socioeconomic condition, with a history of 3-7 years of active participation in prosocial and political organizations. Grounded theory was used to generate inductive knowledge of the processes that led to commitment and further sustained civic participation. Participants' trajectories of commitment illustrate both individual and contextual sources that motivate their sustained action. Participants identify with social and political causes and integrate them to their personal identities. Their sustained social action is related to identification with the goals of the organizations they belong to. Their accounts convey a collective sense of we developed through working toward shared goals with other organization members. Findings speak to the role that youth can play in advancing social and political ideologies and are discussed in light of identity theory and sociopolitical development. PMID- 22197408 TI - BLCA-4 expression is related to MMP-9, VEGF, IL-1alpha and IL-8 in bladder cancer but not to PEDF, TNF-alpha or angiogenesis. AB - AIM: BLCA-4 is a specific nuclear matrix protein found in bladder cancer and there is a dearth of study on functional analysis upon this factor. We aimed to discover whether BLCA-4 is related to angiogenesis in bladder cancer. METHODS: Fifty-three bladder cancer samples were included for immunohistochemical staining of BLCA-4, matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), interleukin-1alpha (IL-1alpha), IL-8, pigment epithelium-derived factor (PEDF), tumour necrosis factor-alpha (TNF-alpha) and von Willebrand factor (vWF) for microvessel density (MVD). Expressional levels were scored and grouped by clinicopathological parametres for statistical analysis for correlations. RESULTS: Positive correlations were identified between expression of BLCA-4 and IL-1alpha (p=0.038), IL-8 (p=0.001), VEGF (p=0.002), and MMP-9 (p=0.013). No correlation was found for PEDF (p=0.182), TNF-alpha (p=0.531) or MVD (p=0.932). Positive correlations were also obtained in cases of advanced grade or stage, larger, recurrent and multiple tumours. Positive correlation between BLCA-4 and MMP-9 was also found in papillary urothelial neoplasm of low malignant potential (PUNLMP). CONCLUSION: BLCA-4 may not effect pro-angiogenic pathways in bladder cancer, it can however interact with IL-1alpha, IL-8, VEGF and MMP-9 to enhance tumourigenesis and tumour invasiveness. PMID- 22197409 TI - Lessons from the learning curve. PMID- 22197410 TI - Transcatheter aortic valve implantation: assessing the learning curve. AB - OBJECTIVES: The aim of this study was to assess the learning curve for the implantation of the percutaneous aortic valve via the transfemoral route. BACKGROUND: Transcutaneous aortic valve insertion is a fundamentally new procedure for the treatment of aortic valve stenosis. The number of cases needed to gain proficiency with concomitant ease and familiarity (i.e., the "learning curve") with the procedure is unknown. METHODS: We performed a retrospective analysis of the first 44 consecutive patients who underwent transcatheter aortic valve implantation as part of the PARTNER (Placement of Aortic Transcatheter Valves) trial at our institution between November 2008 and May 2011. RESULTS: The median age of the patients was 83 years (interquartile range: 77 to 87 years) and a median Society of Thoracic Surgery risk score of 9.6. Pre-procedural assessment of the aortic valve revealed a mean gradient of 53.5 mm Hg, mean aortic valve area of 0.7 mm(2), and a median ejection fraction of 59.5%. Patients were divided into tertiles based on sequence. Significant decreases in median contrast volume (180 to 160 to 130 ml, p = 0.003), valvuloplasty to valve deployment time (12.0 to 11.6 to 7.0 min, p < 0.001) and fluoroscopy times, from 26.1 to 17.2 and 14.3 min occurred from tertiles 1 to 3, p < 0.001. Significant decreases in radiation doses were also seen across the 3 tertiles, p < 0.001. The 30-day mortality for the entire cohort was 11%. CONCLUSIONS: Experience accumulated over 44 transfemoral aortic valve implantations led to significant decreases in procedural times, radiation, and contrast volumes. Our data show increasing proficiency with evidence of plateau after the first 30 cases. More studies are needed to confirm these findings. PMID- 22197411 TI - Stepping down as editor-in-chief. PMID- 22197412 TI - Long term use of triclosan toothpaste and thyroid function. AB - The long term effects of usage of triclosan-containing toothpaste on thyroid function are currently unknown. Triclosan is structurally similar to thyroid hormones and reductions in serum thyroid hormone levels have been observed in animal studies following oral administration of triclosan. Therefore, an assessment of thyroid function over 4 years was undertaken in a subset of individuals in a randomised, placebo controlled clinical trial comparing the effects of 0.3% triclosan toothpaste with placebo toothpaste in subjects with coronary heart disease. Thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), antithyroglobulin antibody (anti-TGab) and antithyroid peroxidase antibody (TPOab) were measured. Paired serum samples at year 1 and year 5 from 132 subjects (64 triclosan group, 68 placebo group) were analysed. At year 1 there were no significant differences in thyroid function between the groups: mean (SD) TSH 1.4 (0.8) and 1.6 (0.9) mU/L, triclosan and placebo groups respectively, fT4 15.8 (2.2) and 15.2 (2.1) pmol/L; fT3 4.8 (0.5) and 4.8 (0.5) pmol/L. Similarly, for antithyroid antibodies there were no group differences at year 1. Median (25th, 75th percentile) for anti-TGab, 38 (34, 42) and 37 (30, 42) U/mL triclosan and placebo groups respectively; anti-TPOab, 15 (10, 22) and 18 (10, 24) U/mL. At year 5, fT4 was the only measure to show a significant difference between groups (mean and 95% Confidence Interval) 15.6 (15.1, 16.1) and 14.7 (14.2, 15.1) pmol/L triclosan and placebo respectively (p=0.01). This reflects reduced levels in the placebo group but no change in the triclosan group. In conclusion, over 4 years triclosan toothpaste had no detectable effect on thyroid function. The data support the view that 0.3% triclosan in toothpaste is safe and free of significant thyroid adverse effects. PMID- 22197413 TI - Increased migration in host-pathogen metapopulations can cause host extinction. AB - There are at least two potentially counteracting effects of migration in host pathogen metapopulations. On the one hand increased migration leads to increased colonization of empty habitats by healthy hosts; on the other hand migrants can carry infectious diseases to susceptible populations. Earlier metapopulation models have found that the beneficial effects of increasing migration (reduced infection) are likely to dominate, and a general recommendation for managers of endangered metapopulations has been to increase connectivity between habitat patches. We extend the model framework to simultaneously allow for (1) Allee effects in host colonization rate, (2) spillover of pathogens from a second host species, and (3) differential colonization success by infected and healthy hosts. We find that the dynamics of a host-pathogen system can be highly sensitive to increased migration rates. Allee effects make host populations vulnerable to spillover of pathogens from other hosts, and metapopulation extinction can emerge from seemingly stable situations of endemic coexistence. Increasing connectivity in endangered metapopulations can be a risky management action unless the details of the biology of the host-pathogen system are known. PMID- 22197414 TI - Storytellers as partners in developing a genetics education resource for health professionals. AB - Advances in genetics are bringing unprecedented opportunities for understanding health and disease, developing new therapies and changes in healthcare practice. Many nurses and midwives lack competence and confidence in integrating genetics into professional practice. One approach to enhance understanding of genetics is to simulate clinical exposure through storytelling. Stories are acknowledged as a powerful learning tool, being understandable and memorable, stimulating critical thinking, and linking theory to practice. Telling Stories, Understanding Real Life Genetics is a freely accessible website that sets people's stories within an education framework. The links between the stories and professional practice are made explicit and additional features support learning and teaching. Care of the storytellers within an ethical framework is of paramount importance. Storytellers are viewed as partners in the project. The challenges encountered include preserving the authentic voice and dignity of the storyteller. Project team members have also experienced 'professional shame' when negative experiences have been recounted, and the stories have had an impact on the team. The experience of working with storytellers has been positive. The storytellers want to be heard so that others will benefit from their stories. They serve as a reminder of why this work is important. PMID- 22197415 TI - The effective time of centrifugation for the analysis of boundary spreading in sedimentation velocity experiments. AB - This investigation establishes a likely order of magnitude for the zero-time correction factor governing the effective time of centrifugation that is pertinent in the analysis of boundary spreading in sedimentation velocity experiments. This correction is shown to be too small to unduly affect the magnitudes of sedimentation and diffusion coefficients deduced from the application of computer software incorporating the printout value of omega2t and an effective position of the air-solution meniscus that is obtained as an additional parameter in the analysis involving nonlinear least-squares curve fitting of sedimentation velocity distributions to the Lamm equation. Although this procedure slightly underestimates the actual meniscus position (r(a)), uncertainty about its exact location precludes adoption of the alternative approach with r(a) fixed and the correction to omega2t regarded as the additional curve-fitting parameter. PMID- 22197416 TI - Elucidation of a novel lacto-N-decaose core structure in human milk using nonlinear analytical technique combinations. AB - Detailed structural analysis of high molecular weight human milk oligosaccharides (HMOs) is still a challenging task. Here we present a modular strategy for a flexible de novo structural characterization of this class of molecules. The protocol combines established techniques such as separation by two-dimensional high-performance liquid chromatography with different types of mass spectrometry, exoglycosidase digestion, and linkage analysis in an individual glycan-based manner. As a proof of principle, this approach was applied to two distinct HMO isomers representing a difucosylated octaose core and a trifucosylated decaose core. Obtained data revealed the presence of one terminal Lewis A and one internal Lewis X epitope in the case of the octaose and led to the identification of this molecule as a difucosylated iso-lacto-N-octaose. The trifucosylated, doubly branched lacto-N-neo-decaose was shown to represent a new type of HMO core structure in which the branched antenna is linked to carbon atom 3 of the innermost galactosyl residue. Hence, using this analytical protocol a novel HMO structure could be defined. Our results further demonstrate that a combination of different techniques may be required for de novo structural analysis of these molecules. PMID- 22197417 TI - Detection of Pb2+ at attomole levels by using dynamic light scattering and unmodified gold nanoparticles. AB - Lead ion (Pb2+) accumulation in nature can affect the environment and human health severely. Thus, rapid and sensitive detection is of great importance. One step detection of Pb2+ at attomole levels was realized by using dynamic light scattering (DLS) technique coupled with unmodified gold nanoparticles (AuNPs). Pb2+-dependent DNAzyme was double-stranded and could not adsorb on the surface of AuNPs, while the substrate strand could be cleaved into ssDNA fragments on addition of Pb2+. The ssDNA fragments could adsorb on the surface of AuNPs and prevent them from aggregating in the presence of NaCl. Therefore, the disperse state of AuNPs changed on addition of Pb2+ in the presence of DNAzyme and NaCl, which was estimated with an average hydrodynamic diameter by using DLS. Under optimum conditions, the average diameter of the solution decreased linearly with the concentration of Pb2+ over the range from 10 to 300 pM, with a detection limit of 6.2 pM. Moreover, satisfactory results were obtained when the proposed method was applied in the detection of Pb2+ in water samples. PMID- 22197418 TI - Quantitative measurement of genome-wide DNA methylation by a reliable and cost efficient enzyme-linked immunosorbent assay technique. AB - DNA methylation, the conversion of cytosine to 5-methylcytosine, is an important epigenetic modification involved in gene regulation. DNA methylation is essential for normal development whereas abnormal methylation has been implicated in pathological conditions including cancer. To evaluate the extent and variation of genome-wide DNA methylation and its changes during cellular differentiation and tumorgenesis as well as the interplay with histone modifications, accurate and reproducible quantification of the genomic DNA methylation level is required. These measurements have so far been achieved only by sophisticated and costly techniques. Here we report the generation of an enzyme-linked immunosorbent assay (methDNA-ELISA) for the accurate quantification of global DNA methylation levels. The linear region of this methDNA-ELISA ranges from 1 to 10%, making it highly suitable for the typical ranges from 2 to 6% in mammalian genomes. This method requires 10 ng of isolated DNA per sample, thus permitting investigation with minimal amounts of DNA previously not applicable for global DNA methylation analysis, e.g., clinical biopsies or cells collected by microdissection. PMID- 22197419 TI - A high-throughput fluorescence polarization anisotropy assay for the 70N domain of replication protein A. AB - Replication protein A (RPA) interacts with multiple checkpoint proteins and promotes signaling through the ATR kinase, a key regulator of checkpoint pathways in the mammalian response to DNA damage. In cancer cells, increased DNA repair activity contributes to resistance to chemotherapy. Therefore, small molecules that block binding of checkpoint proteins to RPA may inhibit the DNA damage response and, thus, sensitize cancer cells to DNA-damaging agents. Here we report on the development of a homogeneous, high-throughput fluorescence polarization assay for identifying compounds that block the critical protein-protein interaction site in the basic cleft of the 70N domain of RPA (RPA70N). A fluorescein isothiocyanate (FITC)-labeled peptide derived from the ATR cofactor, ATRIP, was used as a probe in the binding assay. The ability of the assay to accurately detect relevant ligands was confirmed using peptides derived from ATRIP, RAD9, MRE11, and p53. The assay was validated for use in high-throughput screening using the Spectrum collection of 2000 compounds. The FPA assay was performed with a Z' factor of >= 0.76 in a 384-well format and identified several compounds capable of inhibiting the RPA70N binding interface. PMID- 22197421 TI - Modeling Taylor dispersion injections: determination of kinetic/affinity interaction constants and diffusion coefficients in label-free biosensing. AB - A new method based on Taylor dispersion has been developed that enables an analyte gradient to be titrated over a ligand-coated surface for kinetic/affinity analysis of interactions from a minimal number of injections. Taylor dispersion injections generate concentration ranges in excess of four orders of magnitude and enable the analyte diffusion coefficient to be reliably estimated as a fitted parameter when fitting binding interaction models. A numerical model based on finite element analysis, Monte Carlo simulations, and statistical profiling were used to compare the Taylor dispersion method with standard fixed concentration injections in terms of parameter correlation, linearity of parameter error space, and global versus local model fitting. A dramatic decrease in parameter correlations was observed for TDi curves relative to curves from standard fixed concentration injections when surface saturation was achieved. In FCI the binding progress is recorded with respect to injection time, whereas in TDi the second time dependency encoded in the analyte gradient increases resolving power. This greatly lowers the dependence of all parameters on each other and on experimental interferences. When model parameters were fitted locally, the performance of TDis remained comparable to global model fitting, whereas fixed concentration binding response curves yielded unreliable parameter estimates. PMID- 22197420 TI - Studying protein-peptide interactions using benzophenone units: a case study of protein kinase B/Akt and its inhibitor PTR6154. AB - Protein-protein interactions (PPIs) govern nearly all processes in living cells. Peptides play an important role in studying PPIs. Peptides carrying photoaffinity labels that covalently bind the interacting protein can be used to obtain more accurate information regarding PPIs. Benzophenone (BP) is a useful photoaffinity label that is widely used to study PPIs. We developed a one-pot two-step synthesis for the preparation of novel BP units. To map the binding site more thoroughly, linkers of various lengths were attached to the BP moiety. These units can be incorporated into peptide sequences using well-established solid phase peptide synthesis (SPPS) protocols. As a proof of concept, we studied the interaction between protein kinase B (PKB/Akt) and its synthetic peptide inhibitor, PTR6154. The methodology is general and can be implemented to study PPIs in a variety of biological systems. PMID- 22197422 TI - Evaluation of Taylor dispersion injections: determining kinetic/affinity interaction constants and diffusion coefficients in label-free biosensing. AB - In label-free biomolecular interaction analysis, a standard injection provides an injection of uniform analyte concentration. An alternative approach exploiting Taylor dispersion produces a continuous analyte titration allowing a full analyte dose response to be recorded in a single injection. The enhanced biophysical characterization that is possible with this new technique is demonstrated using a commercially available surface plasmon resonance-based biosensor. A kinetic interaction model was fitted locally to Taylor dispersion curves for estimation of the analyte diffusion coefficient in addition to affinity/kinetic constants. Statistical confidence in the measured parameters from a single Taylor dispersion injection was comparable to that obtained for global analysis of multiple standard injections. The affinity constants for multisite interactions were resolved with acceptable confidence limits. Importantly, a single analyte injection could be treated as a high-resolution real-time affinity isotherm and was demonstrated using the complex two-site interaction of warfarin with human serum albumin. In all three model interactions tested, the kinetic/affinity constants compared favorably with those obtained from standard kinetic analysis and the estimates of analyte diffusion coefficients were in good agreement with the expected values. PMID- 22197423 TI - Genetic and phylogenetic analyses of capsid protein gene in feline calicivirus isolates from Rio Grande do Sul in southern Brazil. AB - Feline calicivirus (FCV) is an important pathogen that affects domestic cats, inducing acute oral and upper respiratory tract clinical signs. The aim of this study was to analyze the variability of the capsid protein in different FCV isolates from southern Brazil. The sequencing analyses of thirteen Brazilian FCV samples, phylogenetic analyses and assessments of ten previously published sequences were conducted by examining the open reading frame 2 (ORF2, regions B F). Comparisons of the predicted amino acid sequences of the ORF2 in Brazilian FCV isolates with those of the FCV-F9 strain indicated that the main differences are located within the regions C and hypervariable E (HVR_E). Epitopes that were mapped to the regions D, 5'HVR_E and conserved E also presented with some variability when compared to the strain F9. This is the first study describing sequence analyses and the phylogenetic relationships among FCV isolates from Brazil. The results presented here may expand upon current knowledge regarding aspects of FCV biology, epidemiology and genetic diversity and provide insights into improving the efficacies of current FCV vaccines. PMID- 22197424 TI - Development of Dengue type-2 virus replicons expressing GFP reporter gene in study of viral RNA replication. AB - Insertion of green fluorescent protein (GFP) encoding-gene into virus genes has provided a valuable tool for flavivirus research. This study aimed to develop dengue virus (DENV) replicons expressing GFP reporter that would provide a fast in vitro system to analyze functional roles of specific DENV sequences in viral replication. Two classes of recombinant replicon constructs were generated; one was a RNA-launched replicon with a GFP gene directly inserted into a full-length DENV genome (FL-DENV/GFP), and the other consisted of 4 types of DNA-launched DENV subgenomic replicons with GFP replacement at various structural genes (Delta DENV/GFP). The FL-DENV/GFP resulted in GFP expression in transfected cells with no viable DENV being recovered from the transfection. The Delta-DENV/GFP constructs with partial structural gene deletion (DeltaC-, DeltaCprM/M-, DeltaprM/M-, or DeltaE-) expressed bright and long lasting GFP. The GFP expression intensity in living cells correlated well with the level of RNA replication. Various mutations in the 5'noncoding region of DENV-2 previously shown to be important genetic determinants for virus replication and mouse virulence were incorporated into the 5 different replicon constructs. Characterizations of 29 mutants demonstrated that these replicons can provide a useful platform for a quick and powerful in vitro system to analyze genetic determinants of DENV replication. These constructs can also be useful for development of vectors expressing foreign genes for various researches. PMID- 22197425 TI - Antigenic analysis monoclonal antibodies against different epitopes of sigmaB protein of Muscovy duck reovirus. AB - sigmaB is one of the major structural proteins of Muscovy duck reovirus (DRV), which is able to induce protective immune response in target birds. Four anti-DRV sigmaB MAbs were identified belong to two distinct epitopes, designated A (1E5, 4E3, and 5D8) and B (2F7) (Liu et al., 2010). To understand antigenic determinants of the sigmaB protein, a set of 20 (P1-P20), partially overlapping and consecutive peptides spanning sigmaB were expressed and then screened by MAbs. With Western blot and enzyme-linked immunosorbent assay (ELISA), two minimal units of the linear epitopes, 19YIRAPACWD27 (epitope B) and 65TDGVCFPHHK74 (epitope A), were identified within N-terminal region of the sigmaB protein. The epitope B was highly conserved among DRV and avian reovirus (ARV) strains through sequence alignment analysis. Immunofluorescence assays (IFA) and ELISA, confirmed that epitope B is a broad group-specific epitope among DRV and ARV. Epitope A could only react with chicken embyonated fibroblast cells (CEF) infected with DRV, but not ARV. However, both peptides have good immunogenicity and could induce antibodies against DRV in BALB/c mice. This report documents the first identification of sigmaB epitopes in the precise locations. The two probes would be useful in the development of discriminating diagnostic kits for DRV and ARV infection. PMID- 22197426 TI - Distal myopathies--new genetic entities expand diagnostic challenge. AB - Distal myopathies are a group of muscle diseases which share the clinical pattern of predominant weakness in the feet and/or hands. Rapid advance in the understanding of underlying gene defects have to date separated more than 20 distinct disorders and many are yet without genetic characterisation. No definite diagnosis can be made on other grounds than identification of the final molecular genetic defect. Besides usual investigations including EMG and muscle biopsy, muscle imaging is very important in defining the precise pattern of muscle involvement. Based on the combination of age at onset, mode of inheritance, pathology and muscle imaging, the number of underlying candidate genes for a certain disease can be significantly reduced, which is of help for the molecular genetic approach. PMID- 22197427 TI - PTPN22 and myasthenia gravis: replication in an Italian population and meta analysis of literature data. AB - Polymorphisms in PTPN22 are associated with many autoimmune diseases; while rs2476601 is supposed to play a major role, other experimental data suggest that rs2488457 may be even more important. Results in myasthenia gravis are controversial. In 356 Italian myasthenic patients and 439 controls genotyped for both polymorphisms, we found that rs2476601 was not associated with myasthenia, presence of autoantibodies, thymus pathology, sex or onset age unlike previous studies on other European populations (confirmed by the present meta-analysis). On the other hand, while rs2488457 was not associated with myasthenia or thymus pathology, we found a correlation of rs2488457 with low autoantibody titers and a trend of association with a less severe disease. Both polymorphisms were in tight linkage disequilibrium in controls, not in patients. Our results suggest that SNPs in this gene different from rs2476601, and/or epigenetic interactions, could play a greater role. PMID- 22197430 TI - Non-specific interactions of CdTe/Cds Quantum Dots with human blood mononuclear cells. AB - In order to study biological events, researchers commonly use methods based on fluorescence. These techniques generally use fluorescent probes, commonly small organic molecules or fluorescent proteins. However, these probes still present some drawbacks, limiting the detection. Semiconductor nanocrystals - Quantum Dots (QDs) - have emerged as an alternative tool to conventional fluorescent dyes in biological detection due to its topping properties - wide absorption cross section, brightness and high photostability. Some questions have emerged about the use of QDs for biological applications. Here, we use optical tools to study non-specific interactions between aqueous synthesized QDs and peripheral blood mononuclear cells. By fluorescence microscopy we observed that bare QDs can label cell membrane in live cells and also label intracellular compartments in artificially permeabilized cells, indicating that non-specific labeling of sub structures inside the cells must be considered when investigating an internal target by specific conjugation. Since fluorescence microscopy and flow cytometry are complementary techniques (fluorescence microscopy provides a morphological image of a few samples and flow cytometry is a powerful technique to quantify biological events in a large number of cells), in this work we also used flow cytometry to investigate non-specific labeling. Moreover, by using optical tweezers, we observed that, after QDs incubation, zeta potentials in live cells changed to a less negative value, which may indicate that oxidative adverse effects were caused by QDs to the cells. PMID- 22197431 TI - Nuclear localization of reporter genes activated by curved DNA. AB - Curved DNA structures with a left-handed superhelical conformation can activate eukaryotic transcription. Mechanistically, these structures favor binding to histone cores and can function as a docking site for sliding nucleosomes. Thus, promoters with this kind of curved DNA can adopt a more open structure, facilitating transcription initiation. However, whether the curved DNA segment can affect localization of a reporter gene is an open question. Localization of a gene in the nucleus often plays an important role in its expression and this phenomenon may also have a curved DNA-dependent mechanism. We examined this issue in transient and stable assay systems using a 180-bp synthetic curved DNA with a left-handed superhelical conformation. The results clearly showed that curved DNA of this kind does not have a property to deliver reporter constructs to nuclear positions that are preferable for transcription. We also identify the spatial location to which electroporation delivers a reporter plasmid in the nucleus. PMID- 22197432 TI - Persistent cardiac pain: a burgeoning science requiring a new approach. PMID- 22197434 TI - Efficacy and complications of super-selective intra-ophthalmic artery melphalan for the treatment of refractory retinoblastoma. AB - PURPOSE: To report the efficacy of super-selective intra-ophthalmic artery melphalan (IAM) for the treatment of refractory retinoblastoma and any associated complications of this treatment. DESIGN: A prospective case series. PARTICIPANTS: Eyes with retinoblastoma that had been treated with systemic chemotherapy or local therapy and had a relapse of their condition. METHODS: All patients receiving IAM between May 2009 and September 2010 were included in the study. Intra-ophthalmic artery melphalan was offered to patients who had failed to respond adequately to systemic chemotherapy and local treatment where appropriate or because of a new recurrence of retinoblastoma that could not be treated with local therapies. None of the patients were excluded because of central nervous system abnormalities. Patients received 2 treatments of IAM given 4 weeks apart. All patients received an orthoptic assessment 3 weeks after each treatment and an examination under anesthesia (EUA). A third treatment was given if an unsatisfactory response was observed on EUA after 2 treatments. MAIN OUTCOME MEASURES: The response of the retinoblastoma tumor(s) and any associated local side effects from the treatment. RESULTS: A total of 15 eyes in 14 patients were treated with IAM during the study period. The mean age at the time of IAM was 31.5 months (median 17.3, range 11.2-150.7 months), and the mean follow-up was 8.7 months (3-16.3 months). Tumor control was achieved in 12 eyes (80%), and 12 eyes (80%) had local side effects that included third cranial nerve palsy in 6 (40%), orbital edema in 3 (20%), permanent retinal detachment in 1 (7%), and vitreous hemorrhage in 4 (27%). Seven eyes (47%) developed significant retinal pigment epithelium changes. CONCLUSIONS: Intra-ophthalmic artery melphalan is an effective treatment for retinoblastoma, achieving a high level of remission in refractory tumors. It can be associated with significant local side effects that can result in loss of vision and possible amblyogenesis. Clinicians and parents need to consider the benefits and potential local side effects before embarking on treatment. PMID- 22197433 TI - Risk factors for cortical, nuclear, posterior subcapsular, and mixed lens opacities: the Los Angeles Latino Eye Study. AB - PURPOSE: To identify sociodemographic and biological risk factors associated with having cortical, nuclear, posterior subcapsular (PSC), and mixed lens opacities. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: A total of 5945 Latinos aged >= 40 years from 6 census tracts in Los Angeles, California. METHODS: Participants underwent an interview and detailed eye examination, including best-corrected visual acuity and slit-lamp assessment of lens opacities using the Lens Opacities Classification System II. Univariate and stepwise logistic regression analyses were used to identify independent risk factors associated with each type of lens opacity. MAIN OUTCOME MEASURES: Odds ratios for sociodemographic and biological risk factors associated with cortical only, nuclear only, PSC only, and mixed lens opacities. RESULTS: Of the 5945 participants with gradable lenses, 468 had cortical only lens opacities, 217 had nuclear only lens opacities, 27 had PSC only opacities, and 364 had mixed lens opacities. Older age, higher hemoglobin A(1c), and history of diabetes mellitus were independent risk factors for cortical only lens opacities. Older age, smoking, and myopic refractive error were independent risk factors for nuclear only lens opacities. Higher systolic blood pressure and history of diabetes were independent risk factors for PSC lens opacities. Older age, myopic refractive error, history of diabetes, higher systolic blood pressure, female gender, and presence of large drusen were independent risk factors for mixed lens opacities. CONCLUSIONS: The modifiable and non-modifiable risk factors identified in this study provide insight into the mechanisms related to the development of lens opacification. Improved glycemic control, smoking cessation and prevention, and blood pressure control may help to reduce the risk of having lens opacities and their associated vision loss. PMID- 22197435 TI - Multiple radial midpupil lid distances: a simple method for lid contour analysis. AB - PURPOSE: To describe a new computerized method for the analysis of lid contour based on the measurement of multiple radial midpupil lid distances. DESIGN: Evaluation of diagnostic technology. PARTICIPANTS AND CONTROLS: Monocular palpebral fissure images of 35 patients with Graves' upper eyelid retraction and of 30 normal subjects. METHODS: Custom software was used to measure the conventional midpupil upper lid distance (MPLD) and 12 oblique MPLDs on each 15 degrees across the temporal (105 degrees , 120 degrees , 135 degrees , 150 degrees , 165 degrees , and 180 degrees ) and nasal (75 degrees , 60 degrees , 45 degrees , 30 degrees , 15 degrees , and 0 degrees ) sectors of the lid fissure. MAIN OUTCOME MEASURES: Mean, standard deviation, 5th and 95th percentiles of the oblique MPLDs obtained for patients and controls. Temporal/nasal MPLD ratios of the same angles with respect to the midline. RESULTS: The MPLDs increased from the vertical midline in both nasal and temporal sectors of the fissure. In the control group the differences between the mean central MPLD (90 degrees ) and those up to 30 degrees in the nasal (75 degrees and 60 degrees ) and temporal sectors (105 degrees and 120 degrees ) were not significant. For greater eccentricities, all temporal and nasal mean MPLDs increased significantly. When the MPLDs of the same angles were compared between groups, the mean values of the Graves' patients differed from control at all angles (F = 4192; P<0.0001). The greatest temporal/nasal asymmetry occurred 60 degrees from the vertical midline. CONCLUSIONS: The measurement of radial MPLD is a simple and effective way to characterize lid contour abnormalities. In patients with Graves' upper eyelid retraction, the method demonstrated that the maximum amplitude of the lateral lid flare sign occurred at 60 degrees from the vertical midline. PMID- 22197436 TI - Ocular mucous membrane pemphigoid after Lyell syndrome: occasional finding or predisposing event? AB - PURPOSE: Ocular mucous membrane pemphigoid (OMMP) is an autoimmune disease involving the eye and characterized by subepithelial detachment resulting from an immunologic reaction against conjunctival basal membrane zone (BMZ) antigens. Lyell syndrome (LS) is a drug-induced, T cell-mediated, cytotoxic reaction involving the mucocutaneous areas. Two patients with LS are presented in whom OMMP developed. DESIGN: Report of 2 cases. PARTICIPANTS: Two male patients, 80 and 60 years old, with persistent corneal ulcerations, corneal melting, and inflammation some months after an LS episode. METHODS: Conjunctival biopsy samples were obtained to perform direct immunofluorescence (DIF) and histologic analyses. Indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) also were performed. MAIN OUTCOME MEASURES: Immunodeposit findings on the conjunctival BMZ obtained by DIF and IIF, inflammatory infiltration of the corneoconjunctival samples studied by histologic analysis, and autoantibodies of patient sera directed against BMZ antigens tested by ELISA. RESULTS: Direct immunofluorescence analyses showed immunoglobulin G and complement 3 component deposits along the BMZ in a linear pattern. Histologic analysis revealed the presence of eosinophils, neutrophils, and mast cells with fibrin deposition in the substantia propria of both patients; the data confirmed the clinical suspicion of OMMP. The IIF and ELISA results were negative. CONCLUSIONS: Chronic eye surface injury associated with LS may promote autoimmunization against ocular epithelial BMZ antigens, playing a strategic role in the subsequent onset of OMMP. The occurrence of OMMP after LS could be an occasional finding, or conversely, LS could be an underestimated predisposing factor in the development of OMMP. PMID- 22197437 TI - Congenital fibrovascular pupillary membranes: clinical and histopathologic findings. AB - PURPOSE: To report the clinical and histopathologic findings associated with congenital fibrovascular pupillary membranes. DESIGN: Case series. PARTICIPANTS: Seven infants were included, 6 with a unilateral congenital pupillary membrane and 1 with classic persistent fetal vasculature (PFV). METHODS: Patients underwent a membranectomy, pupilloplasty, or lensectomy. Histopathologic examination was performed on the excised membranes. MAIN OUTCOME MEASURES: Visual acuity and pupil size. RESULTS: Four of the 6 patients with a unilateral congenital pupillary membrane had 1 or more recurrences after a membranectomy and pupilloplasty. The most recent pupil size ranged from 2 to 5 mm in the affected eye. When last tested, the vision in the affected eye was excellent in 4 of the 6 patients. The 2 patients without recurrences of the pupillary membranes underwent multiple iris sphincterotomies at the time of the initial surgery. Histopathologic examination of 2 primary pupillary membranes showed fibrovascular tissue that did not stain for neuron-specific enolase. Smooth muscle actin was only present in vascular walls. In contrast, histopathology of a recurrent pupillary membrane revealed collagenized fibrovascular tissue that was immunoreactive for smooth muscle actin. Finally, histopathology of the retrolenticular membrane excised from an infant with classic PFV was similar to the latter aside from hypercellularity. CONCLUSIONS: Congenital fibrovascular pupillary membranes in infants are likely a variant of PFV that may recur if incompletely excised. The risk of these membranes recurring may be reduced by excising as much as the membrane as possible and enlarging the pupil with iris sphincterotomies. A lensectomy should be avoided if possible. PMID- 22197439 TI - Corneal higher-order aberrations after Descemet's membrane endothelial keratoplasty. AB - PURPOSE: We compared corneal higher-order aberrations (HOAs) in eyes after Descemet's membrane endothelial keratoplasty (DMEK), Descemet's stripping automated endothelial keratoplasty (DSAEK), and penetrating keratoplasty (PK), and in a control group that had not undergone surgery. DESIGN: Retrospective analysis of clinical data. PARTICIPANTS: Thirty eyes of 30 patients who had undergone standard DMEK, 20 eyes of 20 patients after DSAEK, 20 eyes of 20 patients after PK, and 20 eyes of 20 controls were analyzed. METHODS: In addition to standard postoperative examinations, each participant was analyzed with the Pentacam high-resolution rotating Scheimpflug imaging system (Pentacam HR, Oculus, Wetzlar, Germany). Data were compared between groups. MAIN OUTCOME MEASURES: Visual acuity and HOAs. RESULTS: The mean follow-up was 6.5 +/- 1.2 months after DMEK, 22.6 +/- 11.8 months after DSAEK, and 103.1 +/- 74.2 months after PK. There were no statistically significant differences for the anterior 4.0-mm zones between the DMEK group and the controls or between the DMEK and DSAEK groups. The DMEK procedure compared with PK showed statistically significant differences in all terms for the 4.0-mm zones. All combined Zernike terms for mean posterior aberrations of the central 4.0-mm zones showed statistically significant higher aberrations for DMEK compared with controls. The DMEK procedure compared with DSAEK showed statistically significant lower mean values for all combined Zernike terms, except for coma and coma-like terms in the central 4.0-mm zones of the posterior corneal surface. Compared with PK, DMEK showed statistically significant lower mean values for all combined Zernike terms for the central 4.0-mm zones of the posterior corneal surface, except for spherical aberration (SA) and SA-like terms. Best spectacle-corrected visual acuity (BSCVA) after DMEK was statistically significantly better than after DSAEK (P=0.001) and PK (P=0.005). There was no statistically significant difference when BSCVA was compared with controls (P=0.998). CONCLUSIONS: Both DSAEK and PK exhibit increased posterior corneal HOAs even years after surgery. Patients receiving DMEK display only slight changes in posterior corneal HOAs. PMID- 22197438 TI - Age-related macular degeneration and incident cardiovascular disease: the Multi Ethnic Study of Atherosclerosis. AB - OBJECTIVE: To determine whether age-related macular degeneration (AMD) is a risk indicator for coronary heart disease (CHD) and cardiovascular disease (CVD) events independent of other known risk factors in a multi-ethnic cohort. DESIGN: Population-based prospective cohort study. PARTICIPANTS: A diverse population sample of 6233 men and women aged 45 to 84 years without known CVD from the Multi Ethnic Study of Atherosclerosis (MESA). METHODS: Participants in the MESA had retinal photographs taken between 2002 and 2003. Photographs were evaluated for AMD. Incident CHD and CVD events were ascertained during clinical follow-up visits for up to 8 years after the retinal images were taken. MAIN OUTCOME MEASURES: Incident CHD and CVD events. RESULTS: Of the 6814 persons at risk of CHD, there were 893 participants with early AMD (13.1%) and 27 patients (0.5%) at baseline. Over a mean follow-up period of 5.4 years, there was no statistically significant difference in incident CHD or CVD between the AMD and non-AMD groups (5.0% vs. 3.9%, P = 0.13 for CHD and 6.6% vs. 5.5%, P = 0.19 for CVD). In Cox regression models adjusting for CVD risk factors, there was no significant relationship between presence of any AMD and any CHD/CVD events (hazard ratio 0.99; 95% confidence interval, 0.74-1.33; P = 0.97). No significant association was found between subgroups of early AMD or late AMD and incident CHD/CVD events. CONCLUSIONS: In persons without a history of CVD, AMD was not associated with an increased risk of CHD or CVD. PMID- 22197440 TI - Re: Gianluca Giannarini, Thomas M. Kessler, Frederic D. Birkhauser, George N. Thalmann, Urs E. Studer. Antegrade perfusion with bacillus Calmette-Guerin in patients with non-muscle-invasive urothelial carcinoma of the upper urinary tract: who may benefit? Eur Urol 2011;60:955-60. PMID- 22197441 TI - Should partial nephrectomy be offered to all patients whenever technically feasible? PMID- 22197442 TI - Re-localisation of a biopsy site in endoscopic images and characterisation of its uncertainty. AB - Endoscopy guided probe-based optical biopsy is a new method for detecting sites for tissue biopsy and treatment. After detection, it can be useful to provide a visual aid in the endoscopic images to the endoscopist for example for guidance of forceps to the biopsy sites detected optically. A new method for re localisation of these sites during the endoscopic examination is presented in this paper. It makes use of a sequence of endoscopic images, where the biopsy site location is known, in order to derive the same number of epipolar lines as images in the sequence projected onto a subsequent target image where the re localised biopsy site needs to be computed. The location of the re-localised biopsy site is found by minimisation of the sum of squared distances to the epipolar lines. The method also determines analytically the uncertainty of the re localised biopsy site. This provides the endoscopist with a confidence region around the re-localised biopsy site and a measure of the re-localisation precision. Simulations confirmed that the analytical uncertainty has the potential to be a good estimation of the experimental uncertainty. The method was tested on a physical phantom and on real data from four patients with eight sequences of images acquired during gastroscopy. The re-localisation precision and accuracy were estimated at 1 millimetre or better, which is sufficient for re localisation of optical biopsy sites. PMID- 22197444 TI - Assessment of transduction of Escherichia coli Stx2-encoding phage in dairy process conditions. AB - In the environment, bacteriophages are regarded as natural vector for the transmission of Shiga-toxin genes among Shiga-toxin Escherichia coli strains. The possibility of transduction has been noticed in intestinal tract of various animals but experimental observations on this phenomenon in food processes are lacking. To investigate the transduction in milk at different temperature profiles and cell concentrations, an experimental plan including two different Stx(2)-phages (phiGV2412 and phiL34), induced respectively from E. coli O157:H7 181181/2 and E. coli O157:H7 EC34, and two recipient E. coli strains (CNCTC 6896, WG5) was performed. The donor strains were generated by lysogenization of CNCTC 6896 with phiGV2412 and phiL34 respectively. Spectinomycin resistance gene (aadA) was inserted into stx(2) operon in order to select transduced cells. Transductants were never observed at 4 degrees C up to 24 h, whereas after a treatment at 37 degrees C for 2 h and at 25 degrees C for 22 h they were detected in 67% of the trials with a ratio of transduction varying from 1.13 10(-6) to 7.87 10(-8). A treatment at 48 degrees C for 2 h followed by a second step at 25 degrees C for 22 h showed an occurrence of transduction events in only 19% of cases with a ratio of transduction varying from 2.22 10(-7) to 2.67 10(-8). The generation of transductants and the spontaneous induction of phages in milk were not affected by initial or final concentration of the donor or recipient strains. The results show that transduction phenomenon occurs when the cells are metabolically active and it does not take place at low temperatures. Therefore, the maintenance of the chilling chain proved to be a main factor to prevent the spread of Stx-genes in dairy processes. PMID- 22197443 TI - A liquid chromatography tandem mass spectrometry method for simultaneous determination of acid/alkaline phytohormones in grapes. AB - A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for simultaneous determination of five acid/alkaline phytohormones, i.e., indole-3-acetic acid (IAA), indole-3-butyric acid (IBA), naphthylacetic acid (NAA), gibberellic acid (GA(3)) and isopentenyladenine (2IP), in grapes was developed. After optimization, the samples were extracted with methanol containing 1% formic acid and purified by Oasis HLB SPE cartridges. The analytes were separated on a Thermo Hypersil Gold column (100 mm*2.1 mm, 3.0 MUm) with water and acetonitrile, then determined with Thermo tandem quadrupole mass spectrometer operating in negative electro-spray ionization using selected reaction monitoring (SRM) mode. The established method was further validated by determining the linearity (R2 >= 0.9990), average recovery (82.5-105.4%), sensitivity (0.05-1.00 ng mL-1), precision (RSD <=1 3.0%) and stability (RSD >= 82.0%). Finally, the application of the approach proposed to thirty grape samples convinced its desirable performance for rapid analysis of multiclass phytohormones, supporting its sufficient capability for multiresidue analyses or other analytical system targeting phytohormones in agriculture field. PMID- 22197445 TI - [Organisation of a cochlear implant programme]. AB - A cochlear implant (CI) programme brings together a number of professionals who, during the stages of selection, surgery, programming, rehabilitation and monitoring, develop a series of tasks aimed at promoting comprehensive attention to the implanted patient. The aim of this paper was to describe in detail the tasks in each of the phases described in a programme of CI, materials and necessary equipment and the role of the professionals involved. It also raised a number of recommendations on how to develop a CI programme gradually to facilitate the progression from the simplest to the most complex cases. PMID- 22197446 TI - Schwannoma of the larynx. An infrequent laryngeal tumour. AB - Schwannomas are benign tumours, rare among tumours of the larynx. They normally present as supraglottic masses (because they may arise from the internal branch of the superior laryngeal nerve), most commonly involving aryepiglottic folds or false vocal folds. Most patients present with a globus sensation, dysphagia or hoarseness. Conservative surgery is the treatment of choice. We report a case of a laryngeal asymptomatic neuroma that was diagnosed accidentally in an imaging test. Complete excision of the tumour was performed through a transoral CO2 laser microsurgery without resorting to a tracheotomy. We discuss the clinical, pathologic and imaging findings and the management of this neoplasm. We also try to update the knowledge on the management of these tumours. PMID- 22197447 TI - The auditory P200 is both increased and reduced in schizophrenia? A meta-analytic dissociation of the effect for standard and target stimuli in the oddball task. AB - OBJECTIVE: Conflicting reports of P200 amplitude and latency in schizophrenia have suggested that this component is increased, reduced or does not differ from healthy subjects. A systematic review and meta-analysis were undertaken to accurately describe P200 deficits in auditory oddball tasks in schizophrenia. METHODS: A systematic search identified 20 studies which were meta-analyzed. Effect size (ES) estimates were obtained: P200 amplitude and latency for target and standard tones at midline electrodes. RESULTS: The ES obtained for amplitude (Cz) for standard and target stimuli indicate significant effects in opposite directions: standard stimuli elicit smaller P200 in patients (d = -0.36; 95% CI [ 0.26, -0.08]); target stimuli elicit larger P200 in patients (d = 0.48; 95% CI [0.16, 0.82]). A similar effect occurs for latency at Cz, which is shorter for standards (d = -0.32; 95% CI [-0.54, -0.10]) and longer for targets (d = 0.42; 95% CI [0.23, 0.62]). Meta-regression analyses revealed that samples with more males show larger ES for amplitude of target stimuli, while the amount of medication was negatively associated with the ES for the latency of standards. CONCLUSIONS: The results obtained suggest that claims of reduced or augmented P200 in schizophrenia based on the sole examination of standard or target stimuli fail to consider the stimulus effect. SIGNIFICANCE: Quantification of effects for standard and target stimuli is a required first step to understand the nature of P200 deficits in schizophrenia. PMID- 22197449 TI - Factor XI: hemostasis, thrombosis, and antithrombosis. AB - Coagulation factor FXI (FXI), a plasma serine protease zymogen, has important roles in both intrinsic and extrinsic coagulation pathways and bridges the initiation and amplification phases of plasmatic hemostasis. Recent studies have provided new insight into the molecular structure and functional features of FXI and have demonstrated distinct structural and biological differences between activated factor XII (FXIIa)-mediated FXI activation and tissue factor/thrombin mediated FXI activation. The former is important in thrombosis; the latter is more essential in hemostasis. Activated partial thromboplastin tine (aPTT) artificially reflects FXIIa-initiated intrinsic coagulation pathway in vitro. Conversely, FXIIa-inhibited diluted thromboplastin time assay may reflect tissue factor/thrombin-mediated FXI activation in vivo. Further explication of the genetic mutations of FXI deficiency has improved the understanding of the structure-function relationship of FXI. Besides its procoagulant activity, the antifibrinolytic activity of FXI was well documented in a wealth of literature. Finally, the new emerging concept of inhibiting FXI as a novel antithrombotic approach with an improved benefit-risk ratio has been supported through observations from human FXI deficiency and various animal models. Large- and small-molecule FXI inhibitors have shown promising antithrombotic effects. The present review summarizes the recent advancements in the molecular physiology of FXI and the molecular pathogenesis of FXI deficiency and discusses the evidence and progress of FXI-targeting antithrombotics development. PMID- 22197450 TI - Hematologic malignancies and thrombosis. AB - Patients with hematologic malignancies have an increased risk of venous thromboembolism (VTE), particularly at diagnosis and during the treatment with chemotherapy, asparaginase or immunomodulatory drugs (IMiDs). A disease-dependent hypercoagulable condition associated with other risk factors like drugs, central venous catheter (CVC), immobility and infections are responsible for this high VTE rate. Thrombotic complications have a significant impact on morbidity and in some cases also on mortality of patients with onco-hematologic diseases, therefore thromboprophylaxis to prevent VTE in this setting is needed. However, thrombocytopenia and hemorrhagic complications pone many difficulties in the management of an anticoagulant or antiaggregant treatment in these patients. Recommendations from current guidelines are limited to multiple myeloma patients treated with thalidomide or lenalidomide associated with dexamethasone or chemotherapy, but hematological clinical departments should implement a policy for prevention and treatment of thromboembolic complications in hematologic malignancies. PMID- 22197448 TI - Mitogen-activated protein kinase phosphatase (MKP)-1 in immunology, physiology, and disease. AB - Mitogen-activated protein kinases (MAPKs) are key regulators of cellular physiology and immune responses, and abnormalities in MAPKs are implicated in many diseases. MAPKs are activated by MAPK kinases through phosphorylation of the threonine and tyrosine residues in the conserved Thr-Xaa-Tyr domain, where Xaa represents amino acid residues characteristic of distinct MAPK subfamilies. Since MAPKs play a crucial role in a variety of cellular processes, a delicate regulatory network has evolved to control their activities. Over the past two decades, a group of dual specificity MAPK phosphatases (MKPs) has been identified that deactivates MAPKs. Since MAPKs can enhance MKP activities, MKPs are considered as an important feedback control mechanism that limits the MAPK cascades. This review outlines the role of MKP-1, a prototypical MKP family member, in physiology and disease. We will first discuss the basic biochemistry and regulation of MKP-1. Next, we will present the current consensus on the immunological and physiological functions of MKP-1 in infectious, inflammatory, metabolic, and nervous system diseases as revealed by studies using animal models. We will also discuss the emerging evidence implicating MKP-1 in human disorders. Finally, we will conclude with a discussion of the potential for pharmacomodulation of MKP-1 expression. PMID- 22197451 TI - Absence of JAK2V617F mutation in Chinese deep vein thrombosis patients without myeloproliferative neoplasms. PMID- 22197453 TI - Selenoglucosinolates and their metabolites produced in Brassica spp. fertilised with sodium selenate. AB - Glucosinolates are sulphur-containing glycosides found in many Brassica spp. that are important because their aglycone hydrolysis products protect the plant from herbivores and exhibit anti-cancer properties in humans. Recently, synthetically produced selenium analogues have been shown to be more effective at suppressing cancers than their sulphur counterparts. Although selenium is incorporated into a number of Brassica amino acids and peptides, firm evidence has yet to be presented for the presence of selenium in the glucosinolates and their aglycones in planta. In this study broccoli and cauliflower florets, and roots of forage rape, all obtained from plants treated with sodium selenate, were analysed for the presence of organoselenides. GC-MS analysis of pentane/ether extracts identified six organoselenium compounds including selenium analogues of known myrosinase-derived Brassica volatiles: 4-(methylseleno)butanenitrile, 5 (methylseleno)pentanenitrile, 3-(methylseleno)propylisothiocyanate, 4 (methylseleno)butylisothiocyanate, and 5-(methylseleno)pentylisothiocyanate. LC MS analysis of ethanolic extracts identified three selenoglucosinolates: 3 (methylseleno)propylglucosinolate (glucoselenoiberverin), 4 (methylseleno)butylglucosinolate (glucoselenoerucin), and 5 (methylseleno)pentylglucosinolate (glucoselenoberteroin). LC-MS/MS analysis was used to locate the position of the selenium atom in the selenoglucosinolate and indicates preferential incorporation of selenium via selenomethionine into the methylselenyl moiety rather than into the sulphate or beta-thioglucose groups. In forage rape, selenoglucosinolates and their aglycones (mainly isothiocyanates), occurred at concentrations up to 10% and 70%, respectively, of their sulphur analogues. In broccoli, concentrations of the selenoglucosinolates and their aglycones (mainly nitriles) were up to 60% and 1300%, respectively of their sulphur analogues. These findings indicate the potential for the incorporation of high levels of selenium into Brassica glucosinolates. PMID- 22197452 TI - Acute and chronic corticosteroid treatment of ten patients with paralytic form of Sydenham's chorea. AB - AIMS: To determine efficacy and safety of corticosteroid treatment in patients with severe Sydenham's chorea paralytic form. METHODS: This is a 4 years observational study on ten patient with severe paralytic form of Sydenham's chorea unresponsive to neuroleptics and antiepileptics agents, treated with intravenous methylprednisolone followed by oral deflazacort therapy. Chorea paralytica patients were bedridden, unable to take independent steps, showed severe generalized hypotonia and were hospitalized for 3-4 weeks. Additional clinical evaluations were undertaken at 1, 3 and 6 months and 1, 2 and 4 years from onset of chorea. Severity chorea at the onset and during follow up was rated according to Universidade Federal de Minas Gerais (UFMG) Sydenham's Chorea Rating Scale (USCRS). In all children video-recording was performing at onset and during clinical follow-up. RESULTS: We reported a significant improvement in swallowing and chewing with partial recovery of language 2-3 days after starting intravenous methylprednisolone treatment and complete disappearance of movement disorders after 3-4 weeks of treatment. All our patients were followed for 4 years from onset and none experienced relapse of chorea, other movement disorders or psychiatric disturbances. The treatment with deflazacort was well-tolerated in all children with no significant side effects reported. CONCLUSION: Our data showed that high dose of methylprednisolone intravenously followed by deflazacort therapy may be effective and well-tolerated in children with severe paralytic form of Sydenham's chorea. PMID- 22197454 TI - Influence of vitamin A status on the antiviral immunity of children with hand, foot and mouth disease. AB - BACKGROUND & AIMS: Vitamin A (VA) deficiency has been shown to affect antiviral immunity and thus may be related to the progress and outcome of hand, foot and mouth disease (HFMD) in young children. Our objective was to determine whether children with HFMD associated with VA insufficiency displayed a decline in antiviral immunity. METHODS: 450 children with HFMD and 113 non-infected children were included in this study. Dietary investigations were performed using a 24-h dietary questionnaire. The serum concentrations of VA were measured by high performance liquid chromatography. The serum levels of interferon-alpha (IFN alpha) and enterovirus 71 (EV71) IgM antibodies were detected using an enzyme linked immunosorbent assay (ELISA). RESULTS: The mean serum VA concentration for all patients was 0.73 +/- 0.26 MUmol/L, and 237 (52.7%) of them presented low concentrations (<= 0.7 MUmol/L). Both serum concentrations of VA and IFN-alpha in the patients with complications were significantly lower than in patients without complications (P < 0.01). The decreased concentrations of IFN-alpha and EV71-IgM were positively related to lower VA levels (correlation coefficient = 0.58 and 0.41, respectively, P < 0.001). CONCLUSIONS: Most of the children with HFMD presented VA insufficiency, which was associated with their reduced immunity and more severe illness. PMID- 22197455 TI - Variations on cardiovascular risk factors in metabolic syndrome after consume of a citrus-based juice. AB - BACKGROUND & AIMS: Inflammation and oxidative stress plays a critical role in cardiovascular disease and metabolic syndrome often occurs with these two variables. The aim of the study is to estimate variations on cardiovascular risk factors in Metabolic Syndrome patients after consume of a citrus-based juice compared with control groups. METHODS: The study comprised 20 healthy subjects and 33 patients with Metabolic Syndrome. 18 patients consume daily 300 mL of a citrus-based juice during 6 month and 15 patients consume 300 mL of a placebo beverage. The control group consumes a citrus-based juice. Before, at fourth month and at sixth month after treatment the following parameters were determined: lipid profile, oxidized LDL, C-Reactive Protein and Homocysteine. The study was carried out in accordance with the Helsinki Declaration, and the Ethical Committee of the San Antonio Catholic University and approved the protocol (6 November 2006, register number: 1424). RESULTS: After six months of citrus-based juice consuming, there is significant differences at 95% confidence in oxidized LDL, C-Reactive Protein, and Homocysteine in Metabolic Syndrome patients who consume citrus-based juice. We have not found significant differences in other groups. CONCLUSIONS: Consume of citrus-based juice improve lipid profile and inflammation markers in Metabolic Syndrome patients. PMID- 22197457 TI - Wegener's granulomatosis causing bilateral facial paralysis and deafness. AB - Bilateral facial paralysis (BFP) is an uncommon condition that typically occurs as a manifestation of systemic disease. We present a female patient with Wegener's granulomatosis (WG), particularly upper respiratory and ear impairment who develops hypoacusis and BFP, resistant to immunosuppressive therapy and steroid boluses. Her imaging tests showed no involvement of the facial nerve as it passed through the ear structures. The patient finally improved the BFP; however, deafness is permanent and she has entered into a cochlear implant program. Published papers on BFP are rare and they make no reference to WG as a possible aetiology. PMID- 22197456 TI - [Childhood obesity and sleep-related breathing disorders]. AB - INTRODUCTION: The increasing prevalence of childhood obesity leads to an increase risk of sleep-disordered breathing and may exacerbate their comorbidities. PURPOSE: To assess the rate of obesity in children with sleep-disordered breathing and to study the possible clinical and epidemiological differences between children with and without overweight in a private hospital in the Mediterranean area. MATERIALS AND METHODS: We prospectively studied 340 children between 2 and 10 years. There were 170 children with sleep-disordered breathing (study group) and 170 healthy children (control group). In the problem group, the apnea-hypopnea index was around 7.61 +/- 6.3. RESULTS: The comparison of the percentage of cases with a BMI percentile >=85 (overweight) between problem and control groups (44: 25.9% vs 34: 20%) or with a BMI >=95 (obesity) (30: 17.6% vs 20: 11.8%) showed no statistically-significant differences. In addition, the comparison of clinical and epidemiological variables in the problem group, cases with (44/170: 25.9%) and without (126/170: 74.1%) overweight, did not show significant differences in any of the parameters analysed. CONCLUSION: In the population studied, it does not appear that the group of children with sleep breathing disorders presents higher rates of obesity, nor does obesity influence its presentation clinically. These results had probably been influenced by the characteristics of the studied population and therefore should not be an obstacle for being attentive to the possible association of respiratory disease to obesity and its negative consequences. PMID- 22197458 TI - Inhibition of hyaluronan synthesis reduced inflammatory response in mouse synovial fibroblasts subjected to collagen-induced arthritis. AB - Hyaluronan (HA) fragments are able to induce inflammation by stimulating both CD44 and toll-like receptor 4 (TLR-4). CD44 and TLR-4 activation stimulates the liberation of NF-kB and pro-inflammatory cytokine responses. The aim of this study was to investigate the effects of hyaluronidase (HYAL) treatment, which depolymerises HA into small fragments, and of the addition of specific hyaluronan synthases-1, 2, and 3 small interference RNA (HASs siRNA), which silence HASs activity, on normal mouse synovial fibroblasts (NSF) and on rheumatoid arthritis synovial fibroblasts (RASF) obtained from mice subjected to collagen induced arthritis (CIA). The addition of HYAL to NSF and/or RASF significantly increased the TLR-4, CD44 and NF-kB activity, as well as the pro-inflammatory cytokines, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-33 (IL-33) in both groups, but to a greater extent in RASF. The addition to NSF and/or RASF of the HASs siRNA, which block HASs activity and therefore the availability of HA substrate for HYAL, was able to reduce HYAL effects in both NSF and RASF. Finally, the HA evaluation confirmed the increment of HA at low molecular weight after HYAL treatment. PMID- 22197460 TI - Life time fatality risk assessment due to variation of indoor radon concentration in dwellings in western Haryana, India. AB - Indoor radon measurements in 60 dwellings belonging to 12 villages of Sirsa, Fatehbad and Hisar districts of western Haryana, India, have been carried out, using LR-115 type II cellulose nitrate films in the bare mode. The annual average indoor radon value in the studied area varies from 76.00 to 115.46 Bq m(-3), which is well within the recommended action level 200-300 Bq m(-3) (ICRP, 2009). The winter/summer ratio of indoor radon ranges from 0.78 to 2.99 with an average of 1.52. The values of annual average dose received by the residents and Life time fatality risk assessment due to variation of indoor radon concentration in dwellings of studied area suggests that there is no significance threat to the human beings due to the presence of natural radon in the dwellings. PMID- 22197459 TI - Protective effect of Moringa oleifera leaves against gentamicin-induced nephrotoxicity in rabbits. AB - Oxidative stress due to abnormal production of reactive oxygen species has been implicated in the nephrotoxicity induced by gentamicin. The nephroprotective effect of aqueous-ethanolic extract of Moringa oleifera leaves (150 and 300 mg/kg) was evaluated against gentamicin-induced (80 mg/kg) renal injury in rabbits. Serum urea and creatinine levels were evaluated as the markers of renal nephrotoxicity. At the end of the experiment, the kidneys of rabbits were excised for histological examinations and determination of lipid peroxidation levels. Serum urea and creatinine levels were reduced in the M. oleifera (150 and 300 mg/kg) plus gentamicin treated groups. On histological examinations, kidney of intoxicated rabbits groups which received M. oleifera extract showed reparative tendencies. A highly significant (p < 0.01) elevation was observed in lipid peroxidation (LPO) level in the kidneys of gentamicin-intoxicated rabbits whereas combined treatment of M. oleifera and gentamicin group showed a highly significant (p < 0.01) depletion in LPO. The present study indicates that aqueous ethanolic extract of M. oleifera leaves attenuates renal injury in rabbits treated with gentamicin, possibly by inhibiting lipid peroxidation. PMID- 22197461 TI - Evaluate the radioactivity along the central thimble hole of a decommissioned heavy water research reactor using TLD approach. AB - The radioactivity along the central thimble hole of a decommissioned heavy water research reactor, TRR, was evaluated using TLD approach. The decay radionuclide was verified to be Co-60. The dose along the TRR central thimble hole was detected and revised by performing an unfolding analysis. The revised data reduced to 70-90% of the original data (for example, the maximum dose rate was reduced from 6447 to 4831 mSv/h,) and were more reliable. PMID- 22197462 TI - Determination of U and Th alpha-emitters in NORM samples through extraction chromatography by using new and recycled UTEVA resins. AB - This manuscript describes a protocol for the determination of U and Th isotopes via alpha spectrometry in NORM samples containing high concentrations of these radionuclides, up to kBq kg(-1). This technique is based on extraction chromatography with UTEVA (Triskem Int.) resins and it has been tested using both NORM samples from a phosphate industry and reference materials. The results proved that this method is highly optimized in terms of accuracy and precision when dealing with NORM samples. Recycling of UTEVA columns was also checked using NORM samples and successful results were obtained for both U and Th isotopes, thus proving the feasibility of re-using these type of columns. PMID- 22197464 TI - Psychosocial adjustment in a Dutch sample of children with cerebral palsy. AB - BACKGROUND: Over the last couple of years, there has been increasing interest for QoL in children with CP. Psychosocial adjustment in these children remains underrepresented in current literature. AIMS: To describe psychosocial adjustment in children with CP by means of the Psychosocial Adjustment and Role Skills Scale III (PARS-III), to describe the psychometric properties of this questionnaire, to identify a cut-off score for psychosocial maladjustment and to investigate the relationship between patient characteristics (i.e. predictive factors) and psychosocial adjustment. METHODS: The parents of 93 children with CP (59 boys, 34 girls; mean age 12.3 years, SD 3.8; 4-18; GMFCS 1: 28, GMFCS 2: 5, GMFCS 3: 19, GMFCS 4: 18, GMFCS 5: 23) completed the PARS-III and the Child Behavior Checklist (CBCL) concerning the psychosocial and behavioral functioning of their child. RESULTS: Cronbach's alpha-coefficient for the PARS-III was 0.89 indicating good internal consistency. High correlation with the CBCL was found. Confirmatory factor analysis confirmed the 6 domain structure of the PARS-III. Overall, children with CP achieved lower psychosocial adjustment scores compared to healthy children. A cut-off score (1 SD below the mean) of 78 was found. When predicting psychosocial maladjustment in children with CP, less gross motor function, hand function, communication skills and bilateral involvement of CP are the most important factors, but these can only explain 36% of variation in psychosocial adjustment. CONCLUSION: Using the by-proxy version of the PARS-III it was found that children with CP are reported to achieve lower psychosocial adjustment scores than healthy children. PMID- 22197465 TI - Obesity, asthma, and sleep-disordered breathing. PMID- 22197466 TI - Moving from PANDAS to CANS. PMID- 22197467 TI - C-reactive protein in children with active ulcerative colitis. PMID- 22197468 TI - Modulation of intracellular Ca2+ levels in chromaffin cells by nanoelectropulses. AB - Exposing chromaffin cells to a single 5 ns, 5 MV/m pulse causes Ca(2+) influx and a rapid, transient rise in intracellular calcium concentration ([Ca(2+)](i)). A comparison of responses at room temperature versus 37 degrees C revealed no effect of temperature on the magnitude of the increase in [Ca(2+)](i). The Ca(2+) transient, however, was shortened in duration almost twofold at 37 degrees C, indicating that the rate of recovery was temperature-sensitive. Temperature also affected the interval required for a second pulse to elicit another maximal rise in [Ca(2+)](i), which was shorter at the higher temperature. In addition, a second pulse applied 5s after the first pulse was sufficient to cause cells at room temperature to become refractory to subsequent stimulation. At 37 degrees C, cells became refractory after 5 pulses regardless of whether pulse delivery was at low (1 and 10 Hz) or high (1 kHz) rates. When refractory, cells showed no signs of swelling or uptake of the impermeant dye YO-PRO-1. These results demonstrate that temperature plays a role in determining how chromaffin cells respond to and become refractory to nanoelectropulses. They also indicate that despite the ultra-short duration of the pulses, pronounced effects on cell excitability result from the application of only very few pulses. PMID- 22197470 TI - The benefits of risk assessment tools for prostate cancer. PMID- 22197473 TI - Aquaporin 3 protein expression in transitional cell carcinoma: a potential marker with regard to tumour progression and prognosis? PMID- 22197474 TI - Efficacy and safety of doxepin 6 mg in a four-week outpatient trial of elderly adults with chronic primary insomnia. AB - INTRODUCTION: The efficacy and safety of doxepin (DXP), a histamine H(1) receptor antagonist, was evaluated in elderly adults with sleep maintenance insomnia. METHODS: This was a randomized, double-blind, placebo-controlled outpatient trial. Elderly adults meeting DSM-IV-TR criteria for primary insomnia were randomized to four weeks of nightly treatment with either DXP 6 mg (N=130) or placebo (PBO; N=124). Efficacy was assessed using patient self-report instruments and clinician ratings. Patient-reported endpoints included subjective total sleep time (sTST), subjective wake after sleep onset (sWASO), latency to sleep onset (LSO), sleep quality, and a Patient Global Impression scale (PGI). The primary endpoint was sTST at week 1. RESULTS: DXP 6 mg produced significantly more sTST and less sWASO at week 1 (both p-values <0.0001) than PBO. These significant improvements versus placebo were maintained at weeks 2-4 (all p-values <0.05). There were no significant differences in LSO for DXP 6 mg versus PBO. DXP 6 mg significantly improved sleep quality (weeks 1, 3, and 4, p<0.05) and several outcome-related parameters, including several items on the PGI, the severity and improvement items of the Clinician Global Impression scale (CGI; weeks 1 and 2) and the Insomnia Severity Index (ISI; weeks 1-4), all versus PBO. There were no reports of anticholinergic effects (e.g., dry mouth) or memory impairment. The safety profile of DXP 6 mg was comparable to that of PBO. CONCLUSIONS: In elderly adults with insomnia, DXP 6 mg produced significant improvements in sleep maintenance, sleep duration, and sleep quality endpoints that were sustained throughout the trial. These data suggest that DXP 6 mg is effective for treating sleep maintenance insomnia and is well-tolerated in elderly adults with chronic primary insomnia. PMID- 22197475 TI - Arsenic-glutathione conjugate transport by the human multidrug resistance proteins (MRPs/ABCCs). AB - Millions of people world-wide are chronically exposed to inorganic forms of the environmental toxicant arsenic in drinking water. This has led to a public health crisis because arsenic is a human carcinogen, and causes a myriad of other adverse health effects. In order to prevent and treat arsenic-induced toxicity it is critical to understand the cellular handling of this metalloid. A large body of literature describes the importance of the cellular tripeptide glutathione (gamma-Glu-Cys-Gly,GSH/GS) in the excretion of arsenic. The triglutathione conjugate of arsenite [As(III)(GS)(3)] and the diglutathione conjugate of monomethylarsonous acid [MMA(III)(GS)(2)] have been isolated from rat bile and mouse urine, and account for the majority of excreted arsenic, suggesting these are important transportable forms. The ATP-binding cassette (ABC) transporter proteins, multidrug resistance protein 1 (MRP1/ABCC1) and the related protein MRP2 (ABCC2), are thought to play an important role in arsenic detoxification through the cellular efflux of arsenic-GSH conjugates. Current knowledge on the cellular handling of arsenic with a special emphasis on the transport pathways of the arsenic-GSH conjugates As(III)(GS)(3), MMA(III)(GS)(2), and dimethylarsenic glutathione DMA(III)(GS), as well as, the seleno-bis(S-glutathionyl) arsinium ion [(GS)(2)AsSe](-) are reviewed. PMID- 22197476 TI - Comparative studies in series of cytochrome c oxidase models. AB - This study compares the behavior as cytochrome c oxidase (CcO) functional and structural models of a series of reported and unreported ligands that provide either a binding site for copper without a built-in proximal base, or both a flexible binding site for copper and a built-in proximal base, or a fixed binding site for copper with a built-in proximal base. The comparisons of the models show that the relative position of the two metal sites is not only a crucial parameter in the control of the catalytic behavior but also essential in mimicking other features of the enzyme such as CO exchange between the ferrous heme a(3) and the cuprous Cu(B) center. PMID- 22197477 TI - Neural circuits underlying the pathophysiology of mood disorders. AB - Although mood disorders constitute leading causes of disability, until recently little was known about their pathogenesis. The delineation of anatomical networks that support emotional behavior (mainly derived from animal studies) and the development of neuroimaging technologies that allow in vivo characterization of anatomy, physiology, and neurochemistry in human subjects with mood disorders have enabled significant advances towards elucidating the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). In this review, we integrate insights from human and animal studies, which collectively suggest that MDD and BD involve dysfunction within an extended network including the medial prefrontal cortex and anatomically-related limbic, striatal, thalamic and basal forebrain structures. PMID- 22197478 TI - Simultaneous EUS-guided transbulbar pancreaticobiliary drainage (with video). PMID- 22197479 TI - Denitrification prevails over anammox in tropical mangrove sediments (Goa, India). AB - Denitrification, anammox (Anx) and di-nitrogen fixation were examined in two mangrove ecosystems- the anthropogenically influenced Divar and the relatively pristine Tuvem. Stratified sampling at 2 cm increments from 0 to 10 cm depth revealed denitrification as the main process of N2 production in mangrove sediments. At Divar, denitrification was ~3 times higher than at Tuvem with maximum activity of 224.51 +/- 6.63 nmol N2 g-1 h-1 at 0-2 cm. Denitrifying genes (nosZ) numbered up to 2 * 107 copies g-1 sediment and belonged to uncultured microorganisms clustering within Proteobacteria. Anammox was more prominent at deeper depths (8-10 cm) mainly in Divar with highest activity of 101.15 +/- 87.73 nmol N2 g-1 h-1 which was 5 times higher than at Tuvem. Di-nitrogen fixation was detected only at Tuvem with a maximum of 12.47 +/- 8.36 nmol N2 g-1 h-1. Thus, in these estuarine habitats prone to high nutrient input, N2-fixation is minimal and denitrification rather than Anx serves as an important mechanism for counteracting N loading. PMID- 22197480 TI - The temporal relationship between per capita alcohol consumption and harm: a systematic review of time lag specifications in aggregate time series analyses. AB - BACKGROUND: Changes in per capita alcohol consumption are temporally linked to changes in rates of alcohol-related harm. Methodological approaches for analysing this relationship have been suggested, however, the problem of time lags is not well-addressed. This study provides a review of time lag specifications, looking at (a) time to first effect on harm, (b) time to full effect and (c) the functional form of the effect accumulation from first to full effect to inform modelling of the relationship between changes in aggregate alcohol consumption and changes in rates of harm. METHODS: Bibliographic databases were searched and citation and reference checking was used to identify studies. Included studies were time series analyses of the relationship between aggregated population alcohol consumption and rates of alcohol-related harms where time lag specifications had been derived or tested. RESULTS: 36 studies were included with liver cirrhosis, heart disease and suicide dominating the evidence base. For a large number of alcohol-related harms, no literature was identified. There was strong evidence of an immediate first effect following a change in consumption for most harms. Recommended lag specifications are proposed for a set of alcohol attributable harms. CONCLUSIONS: Research on time lag specifications is under developed for most harms although we provide suggested specifications based on the findings of the review. Greater methodological attention needs to be given to the rationale for choosing or applying lag specifications and the inherent complexity of the time lag process. More consistent and transparent reporting of methodological decisions would aide progress in the field. PMID- 22197481 TI - Formaldehyde-induced mutagenesis in Saccharomyces cerevisiae: molecular properties and the roles of repair and bypass systems. AB - Although DNA-protein cross-links (DPCs) pose a significant threat to genome stability, they remain a poorly understood class of DNA lesions. To define genetic impacts of DPCs on eukaryotic cells in molecular terms, we used a sensitive Saccharomyces cerevisiae frameshift-detection assay to analyze mutagenesis by formaldehyde (HCHO), and its response to nucleotide excision repair (NER) and translesion DNA synthesis (TLS). Brief exposure to HCHO was mutagenic for NER-defective rad14 strains but not for a corresponding RAD14 strain, nor for a rad14 strain lacking both Polzeta and Poleta TLS polymerases. This confirmed that HCHO-generated DNA lesions can trigger error-prone TLS and are substrates for the NER pathway. Sequencing revealed that HCHO-induced single base-pair insertions occurred primarily at one hotspot; most of these insertions were also complex, changing an additional base-pair nearby. Most of the HCHO induced mutations required both Polzeta and Poleta, providing a striking example of cooperativity between these two TLS polymerases during bypass of a DNA lesion formed in vivo. The similar molecular properties of HCHO-induced and spontaneous complex +1 insertions detected by this system suggest that DPCs which form in vivo during normal metabolism may contribute characteristic events to the spectra of spontaneous mutations in NER-deficient cells. PMID- 22197482 TI - A human cell-based reporter detects microhomology-mediated end joining. AB - DNA double-strand breaks (DSBs) are most often repaired by two pathways in mammalian cells, homologous recombination or non-homologous end joining. Biochemical and genetic studies showed that DSBs can also be joined via microhomology-mediated end joining (MHEJ), which is always mutagenic and may result in diseases, such as cancer. In this study we established a human cell based reporter system to determine the prevalence of MHEJ events and factors that modulate MHEJ. A nonfunctional puromycin acetyltransferase (Pac) gene, disrupted by an insertion flanked by two microhomologous repeats, was integrated into chromosomes of human HT1080 cells. Repair of DSBs via MHEJ using the repeats resulted in deletion of the insertion and restoration of the Pac gene function, thus rendering the cells puromycin resistant. Our results showed that MHEJ spontaneously occurs at the reporter locus (loci), manifested by formation of puromycin resistant (puro(r)) colonies after culturing reporter cells in medium containing puromycin. The frequency of puro(r) cells can be greatly increased by site-directed DSB inside the insertion. Our results also demonstrated that the frequency of puro(r) cells is affected by the length of the repeat and by the size of the intervening sequence. Thus, this cell-based assay provides a platform for evaluating factors modulating in vivo MHEJ. PMID- 22197483 TI - Cerebral cavernous malformations: spectrum of neuroradiological findings. AB - Cavernous malformations (cavernomas) are hamartomatous lesions formed by sinusoidal vascular spaces, with no cerebral parenchyma between them. Seizures are the most usual clinical presentation. They are dynamic lesions, producing changes throughout their evolution. The majority are located in the supratentorial region, but up to 20% of cases they are found in the posterior fossa. In computed tomography (CT) and in magnetic resonance (MR) their typical presentation is as a well defined round or oval lesion, with or without a minimal mass effect or oedema, with little or no contrast enhancement. Their appearance in MRI will depend on the stage of the haemorrhage, a T2 echo gradient being the most sensitive sequence. Angiography do not usually detect cavernomas. However, it may demonstrate a venous developmental anomaly. Cavernomas may present with atypical characteristics, as regards their size, appearance, location and number. PMID- 22197484 TI - Contribution of AT-, GC-, and methylated cytidine-rich DNA to chromatin composition in Malpighian tubule cell nuclei of Panstrongylus megistus (Hemiptera, Reduviidae). AB - The Malpighian tubule cell nuclei of male Panstrongylus megistus, a vector of Chagas disease, contain one chromocenter, which is composed solely of the Y chromosome. Considering that different chromosomes contribute to the composition of chromocenters in different triatomini species, the aim of this study was to determine the contribution of AT-, GC-, and methylated cytidine-rich DNA in the chromocenter as well as in euchromatin of Malpighian tubule cell nuclei of P. megistus in comparison with published data for Triatoma infestans. Staining with 4',6-diamidino-2-phenylindole/actinomycin D and chromomycin A(3)/distamycin, immunodetection of 5-methylcytidine and AgNOR test were used. The results revealed AT-rich/GC-poor DNA in the male chromocenter, but equally distributed AT and GC DNA sequences in male and female euchromatin, like in T. infestans. Accumulation of argyrophilic proteins encircling the chromocenter did not always correlate with that of GC-rich DNA. Methylated DNA identified by immunodetection was found sparsely distributed in the euchromatin of both sexes and at some points around the chromocenter edge, but it could not be considered responsible for chromatin condensation in the chromocenter, like in T. infestans. However, unlike in T. infestans, no correlation between the chromocenter AT-rich DNA and nucleolus organizing region (NOR) DNA was found in P. megistus. PMID- 22197485 TI - Coherent NMR Stark spectroscopy. AB - We demonstrate phase-coherent Stark effects from a radiofrequency E field at twice the NMR frequency (2omega(0)) of (69)Ga in GaAs. The 2omega(0) phase (phi(E)) selects component responses from the nuclear quadrupole Hamiltonian (H(Q)). This is possible by synchronizing few-MUs 2omega(0) pulses with an NMR line-narrowing sequence, which averages the Stark interaction to dominate spectra on a background with 10(3)* enhanced resolution. Spectra vs phi(E) reveal relative sizes of tensorial factors in H(Q). Comparative modeling and numerical simulations evaluate spectral features unexplained by average Hamiltonian theory, and suggest improvements for quantitative calibration of individual response components. Application of this approach to bulk samples is of value to define Stark responses that may later be used to interrogate the internal electrostatics of structured samples. PMID- 22197486 TI - Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. AB - Kabuki syndrome (KS) is a rare genetic disease that causes developmental delay and congenital anomalies. Since the identification of MLL2 mutations as the primary cause of KS, such mutations have been identified in 56%-76% of affected individuals, suggesting that there may be additional genes associated with KS. Here, we describe three KS individuals with de novo partial or complete deletions of an X chromosome gene, KDM6A, that encodes a histone demethylase that interacts with MLL2. Although KDM6A escapes X inactivation, we found a skewed X inactivation pattern, in which the deleted X chromosome was inactivated in the majority of the cells. This study identifies KDM6A mutations as another cause of KS and highlights the growing role of histone methylases and histone demethylases in multiple-congenital-anomaly and intellectual-disability syndromes. PMID- 22197487 TI - Exome sequencing identifies SLCO2A1 mutations as a cause of primary hypertrophic osteoarthropathy. AB - By using whole-exome sequencing, we identified a homozygous guanine-to-adenine transition at the invariant -1 position of the acceptor site of intron 1 (c.97 1G>A) in solute carrier organic anion transporter family member 2A1 (SLCO2A1), which encodes a prostaglandin transporter protein, as the causative mutation in a single individual with primary hypertrophic osteoarthropathy (PHO) from a consanguineous family. In two other affected individuals with PHO from two unrelated nonconsanguineous families, we identified two different compound heterozygous mutations by using Sanger sequencing. These findings confirm that SLCO2A1 mutations inactivate prostaglandin E(2) (PGE(2)) transport, and they indicate that mutations in SLCO2A1 are the pathogenic cause of PHO. Moreover, this study might also help to explain the cause of secondary hypertrophic osteoarthropathy. PMID- 22197488 TI - Exome sequence identifies RIPK4 as the Bartsocas-Papas syndrome locus. AB - Pterygium syndromes are complex congenital disorders that encompass several distinct clinical conditions characterized by multiple skin webs affecting the flexural surfaces often accompanied by craniofacial anomalies. In severe forms, such as in the autosomal-recessive Bartsocas-Papas syndrome, early lethality is common, complicating the identification of causative mutations. Using exome sequencing in a consanguineous family, we identified the homozygous mutation c.1127C>A in exon 7 of RIPK4 that resulted in the introduction of the nonsense mutation p.Ser376X into the encoded ankyrin repeat-containing kinase, a protein that is essential for keratinocyte differentiation. Subsequently, we identified a second mutation in exon 2 of RIPK4 (c.242T>A) that resulted in the missense variant p.Ile81Asn in the kinase domain of the protein. We have further demonstrated that RIPK4 is a direct transcriptional target of the protein p63, a master regulator of stratified epithelial development, which acts as a nodal point in the cascade of molecular events that prevent pterygium syndromes. PMID- 22197490 TI - Renal actions of dendroaspis natriuretic peptide in rabbits. AB - Dendroaspis natriuretic peptide (DNP) is one of four members of the natriuretic peptide family sharing functional and structural properties. The purpose of the present study was to elucidate the physiological role of DNP on renal functions and its cellular mechanism in the rabbit kidney. DNP (5 MUg/kg/min) infused intravenously increased urine volume and urinary excretion of electrolytes. These renal actions induced by DNP were more pronounced than those caused by atrial natriuretic peptide (ANP). We compared profiles of (125)I-ANP and (125)I-DNP by reverse-phase HPLC during incubation in rabbit plasma at 37 degrees C for 1, 2, and 4h. While (125)I-ANP was quickly degraded within 1h, (125)I-DNP was still stable in plasma for 4h. DNP induced the greatest cyclic guanosine monophosphate (cGMP) production in the glomeruli in a dose-dependent manner, when compared to other renal structures including cortical tubules, outer medullary tubules, and inner medullary tubules. Affinity cross-linking analysis revealed NPR-A is selective receptor for DNP in glomeruli. Forskolin, a stimulator of adenylyl cyclase, significantly decreased cGMP production in the renal glomeruli but not in the renal medulla. In summary, DNP is a more effective activator of renal functions than ANP, possibly because of the degradation resistance of DNP against the endogenous peptidases in plasma or tissues. These findings suggest that DNP plays a pivotal role as a renal regulating peptide via specific natriuretic peptide receptors with a guanylyl cyclase domain. PMID- 22197491 TI - Antimicrobial decapeptide KSL-W enhances neutrophil chemotaxis and function. AB - Mammalian cationic antimicrobial peptides have received increased attention over the last decade, due to their prokaryotic selectivity and decreased risk of microbial resistance. In addition, antimicrobial peptides display differential biological effects on mammalian immune cell function, such as migration, adhesion, and modulation of respiratory burst, which make them even more attractive as therapeutic agents. Synthetic combinatorial libraries provide a time-efficient and cost-effective source for these diverse molecules. The novel synthetic antimicrobial peptide, KSLW (KKVVFWVKFK-NH(2)), has been shown to display a broad spectrum of antimicrobial activity against Gram (+) and Gram (-) bacteria, fungi and viruses. In this study, we evaluated the alternative biological activity of the decapeptide on neutrophil migration and function. KSLW was demonstrated to be chemotactic for neutrophils in micromolar amounts, and neutrophil treatment with KSLW, after 1 min, resulted in significant increases in F-actin polymerization. KSLW was shown to inhibit oxygen radical production in PMA- and LPS-stimulated neutrophils. Future studies, to determine if KSLW regulates neutrophil phagocytosis, adhesion, and apoptosis, or examining the effect of KSLW on other mammalian cell types, such as cell populations of healing impaired wounds, would provide significant insight for the potential therapeutic strategies offered by antimicrobial peptides. PMID- 22197489 TI - Mutations in RIPK4 cause the autosomal-recessive form of popliteal pterygium syndrome. AB - The autosomal-recessive form of popliteal pterygium syndrome, also known as Bartsocas-Papas syndrome, is a rare, but frequently lethal disorder characterized by marked popliteal pterygium associated with multiple congenital malformations. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this malformation syndrome to chromosomal region 21q22.3. Direct sequencing of RIPK4 (receptor-interacting serine/threonine kinase protein 4) showed a homozygous transversion (c.362T>A) that causes substitution of a conserved isoleucine with asparagine at amino acid position 121 (p.Ile121Asn) in the serine/threonine kinase domain of the protein. Additional pathogenic mutations-a homozygous transition (c.551C>T) that leads to a missense substitution (p.Thr184Ile) at a conserved position and a homozygous one base-pair insertion mutation (c.777_778insA) predicted to lead to a premature stop codon (p.Arg260ThrfsX14) within the kinase domain-were observed in two families. Molecular modeling of the kinase domain showed that both the Ile121 and Thr184 positions are critical for the protein's stability and kinase activity. Luciferase reporter assays also demonstrated that these mutations are critical for the catalytic activity of RIPK4. RIPK4 mediates activation of the nuclear factor-kappaB (NF-kappaB) signaling pathway and is required for keratinocyte differentiation and craniofacial and limb development. The phenotype of Ripk4(-/ ) mice is consistent with the human phenotype presented herein. Additionally, the spectrum of malformations observed in the presented families is similar, but less severe than the conserved helix-loop-helix ubiquitous kinase (CHUK)-deficient human fetus phenotype; known as Cocoon syndrome; this similarity indicates that RIPK4 and CHUK might function via closely related pathways to promote keratinocyte differentiation and epithelial growth. PMID- 22197492 TI - Modulation of neuropeptide FF (NPFF) receptors influences the expression of amphetamine-induced conditioned place preference and amphetamine withdrawal anxiety-like behavior in rats. AB - Many data indicate that endogenous opioid system is involved in amphetamine induced behavior. Neuropeptide FF (NPFF) possesses opioid-modulating properties. The aim of the present study was to determine whether pharmacological modulation of NPFF receptors modify the expression of amphetamine-induced conditioned place preference (CPP) and amphetamine withdrawal anxiety-like behavior, both processes relevant to drug addiction/abuse. Intracerebroventricular (i.c.v.) injection of NPFF (5, 10, and 20 nmol) inhibited the expression of amphetamine CPP at the doses of 10 and 20 nmol. RF9, the NPFF receptors antagonist, reversed inhibitory effect of NPFF (20 nmol, i.c.v.) at the doses of 10 and 20 nmol and did not show any effect in amphetamine- and saline conditioned rats. Anxiety-like effect of amphetamine withdrawal was measured 24h after the last (14 days) amphetamine (2.5mg/kg, i.p.) treatment in the elevated plus-maze test. Amphetamine withdrawal decreased the percent of time spent by rats in the open arms and the percent of open arms entries. RF9 (5, 10, and 20 nmol, i.c.v.) significantly reversed these anxiety-like effects of amphetamine withdrawal and elevated the percent of time spent by rats in open arms at doses of 5 and 10 nmol, and the percent of open arms entries in all doses used. NPFF (20 nmol) pretreatment inhibited the effect of RF9 (10 nmol). Our results indicated that stimulation or inhibition of NPFF receptors decrease the expression of amphetamine CPP and amphetamine withdrawal anxiety, respectively. These findings may have implications for a better understanding of the processes involved in amphetamine dependence. PMID- 22197494 TI - Resveratrol inhibits the release of soluble fms-like tyrosine kinase (sFlt-1) from human placenta. AB - OBJECTIVE: Soluble vascular endothelial growth factor receptor-1 (also know as soluble fms-like tyrosine kinase [sFlt]-1) is a key causative factor of preeclampsia. Resveratrol, a plant phytoalexin, has antiinflammatory and cardioprotective properties. We sought to determine the effect of resveratrol on sFlt-1 release. STUDY DESIGN: Human umbilical vein endothelial cells, transformed human trophoblast-8 (HTR/SVneo)-8/SVneo trophoblast cells, or placental explants were incubated with cytokines and/or resveratrol. Conditioned media were assayed for sFlt-1 by enzyme-linked immunosorbent assay and cell proteins used for Western blotting. RESULTS: Resveratrol inhibited cytokine-induced release of sFlt 1 from normal placental explants and from preeclamptic placental explants. Preincubation of human umbilical vein endothelial cells or HTR-8/SVneo cells with resveratrol abrogated sFlt-1 release. Resveratrol prevented the up-regulation of early growth response protein-1 (Egr-1), a transcription factor necessary for induction of the vascular endothelial growth factor receptor-1 gene and caused up regulation of heme oxygenase-1, a cytoprotective enzyme found to be dysfunctional in preeclampsia. CONCLUSION: In summary, resveratrol can inhibit sFlt-1 release and up-regulate heme oxygenase-1; thus, may offer therapeutic potential in preeclampsia. PMID- 22197493 TI - Central and peripheral apelin receptor distribution in the mouse: species differences with rat. AB - The G protein-coupled apelin receptor (APJ) binds the endogenous peptide apelin and has been shown to have roles in many physiological systems. Thus far, distribution studies have predominantly been conducted in the rat and there is limited knowledge of the cellular distribution of APJ in mouse or human tissues. As recent functional studies have been conducted in APJ knock-out mice (APJ KO), in this study we undertook to characterize APJ mRNA and I(125)[Pyr(1)]apelin-13 binding site distribution in mouse tissues to enable correlation of distribution with function. We have utilized in situ hybridization histochemistry (ISHH) using APJ riboprobes, which revealed strong hybridization specifically in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus and in the anterior pituitary, with marginally lower levels in the posterior pituitary. In the periphery, strong hybridization was observed in the lung, heart, adrenal cortex, renal medulla, ovary and uterus. Autoradiographic binding to APJ with I(125)[Pyr(1)]apelin-13 exhibited significant binding in the anterior pituitary, while lower levels were observed in the posterior pituitary and PVN and SON. In the periphery, strong receptor binding was observed in tissues exhibiting intense riboprobe hybridization, indicating a good correlation between receptor transcription and translation. While the distribution of APJ mRNA and functional protein in the mouse shows similarities to that of the rat, we report a species difference in central APJ distribution and in the pituitary gland. PMID- 22197495 TI - Ultrastructural immunolocalization of involucrin in the medulla and inner root sheath of the human hair. AB - The participation of involucrin in the cornification of the human hair has been studied by light and electron microscopy immunohistochemistry. Immunoreactivity for involucrin is absent in keratinized cuticle and cortical cells although some immunolabeling is observed in the corneous membrane of internal cortical cells surrounding the hair medulla. Conversely, immunolabeling for involucrin is present in the cytoplasm of keratinizing cells of the medulla and inner root sheath. During the maturation and final cornification of medullary and inner root sheath cells the immunolabeling for involucrin tends to concentrate in the peripheral cytoplasm and along the cornified cell plasma membrane in both medullary and inner root sheath cells, a pattern similar to that known for corneocytes of the epidermis. This observation suggests that in the hair involucrin mainly participates in the formation of the corneous material of the medulla and inner root sheath in conjunction with trichohyalin, probably by the formation of isopeptide-bonds. Therefore, together with trichohyalin, the cross linking due to involucrin is also responsible for the mechanical resistance of the corneous trabeculae present among the empty spaces of the medulla of the human hair. PMID- 22197496 TI - Peptide 19-containing neurons in the medullary dorsal horn, subnuclei interpolaris and oralis, and nucleus principalis of the rat. AB - Peptide 19 (PEP 19) is a 7.6 kDa polypeptide which can bind to calmodulin and inhibit calcium-calmodulin signaling. In this study, PEP 19-immunoreactivity (ir) was examined in the rat trigeminal sensory nuclei. Numerous PEP 19-immunoreactive (ir) neurons were detected in the medullary dorsal horn (MDH) and rostral parts of the trigeminal sensory nuclei (subnuclei interpolaris and oralis, and nucleus principalis). The mean numbers +/- S.D. per section of PEP 19-ir neurons were 104.2 +/- 30.4 in the MDH, 137.8 +/- 39.5 in the subnucleus interpolaris, 129.2 +/- 46.9 in the subnucleus oralis and 157.2 +/- 34.1 in the nucleus principalis. In the MDH, small to medium-sized PEP 19-ir neurons were abundant within superficial laminae. PEP 19-ir neurons with various cell body sizes were also distributed in the rostral parts of the trigeminal sensory nuclei. A double immunofluorescence analysis also demonstrated that many PEP 19-ir neurons co expressed parvalbumin (PV)-ir in the MDH (9.0%), subnucleus oralis (7.7%) and nucleus principalis (19.7%). In the subnucleus interpolaris, such neurons were relatively rare (1.7%). PEP 19-ir neurons were mostly devoid of calbindin D-28k. In addition, a retrograde tracing method revealed that a substantial number of PEP 19-ir neurons projected to the thalamus. PV-ir was common in thalamus projecting PEP 19-ir neurons. These findings suggest that PEP 19-ir neurons in the MDH may have a function in modulation of nociceptive and thermo-receptive signaling. It is also likely that PEP 19-ir neurons in rostral parts of the trigeminal sensory nuclei are related to transduction of mechano-receptive information from facial regions to the thalamus. PMID- 22197497 TI - Isolation and characterization of a soluble and thermostable phosphite dehydrogenase from Ralstonia sp. strain 4506. AB - Phosphite dehydrogenase (PtxD), which catalyzes the nearly irreversible oxidation of phosphite to phosphate with the concomitant reduction of NAD(+) to NADH, has great potential for NADH regeneration in industrial biocatalysts. Here, we isolated a soil bacterium, Ralstonia sp. strain 4506, that grew at 45 degrees C on a minimal medium containing phosphite as the sole source of phosphorus. A recombinant PtxD of Ralstonia sp. (PtxD(R4506)) appeared in the soluble fraction in Escherichia coli. The purified PtxD(R4506) showed 6.7-fold greater catalytic efficiency (V(max)/K(m)) than the first characterized PtxD of Pseudomonas stutzeri (PtxD(PS)). Moreover, the purified PtxD(R4506) showed maximum activity at 50 degrees C, and its half-life of thermal inactivation at 45 degrees C was 80.5h, which is approximately 3,450-fold greater than that of PtxD(PS). Therefore, we concluded that PtxD(R4506), which shows high catalytic efficiency, solubility, and thermostability, would be useful for NADH regeneration applications. PMID- 22197498 TI - Enhancement of retinal production by supplementing the surfactant Span 80 using metabolically engineered Escherichia coli. AB - The optimal temperature and pH for retinal production using metabolically engineered Escherichia coli in a 7-l fermentor were found to be 30 degrees C and 7.0, respectively. The agitation speed was a critical factor for retinal production. The optimal agitation speed was 400 rpm (oxygen transfer coefficient, k(L)a, = 92 1/h) in batch culture and 600 rpm (k(L)a=148 1/h) in a fed-batch culture of glycerol. Span 80 was selected as a surfactant for retinal production in metabolically engineered E. coli because Span 80 had proven the most effective for increased retinal production among the tested surfactants. Under the optimal conditions in the fed-batch culture with 5 g/l Span 80, the cell mass and the concentration, content, and productivity of retinal were 24.7 g/l, 600 mg/l, 24.3mg/g-cells, and 18 mg l(-1)h(-1) after 33 h, respectively. They were 1.2-, 2.7-, 2.3-, and 2.7-fold higher than those in the fed-batch culture without Span 80, respectively. The concentration and productivity of retinal in this study were the highest ever reported. The hydrophilic portion of Span 80 (sorbitan) did not affect cell growth and retinal production, but the hydrophobic portion (oleic acid) stimulated cell growth. However, oleic acid plus sorbitan did not stimulate retinal production. Thus, Span 80, as a linked compound of oleic acid and sorbitan produced by esterification, proved to be an effective surfactant for the enhancement of retinal production. PMID- 22197499 TI - Immunosuppressive drug rapamycin restores sporulation competence in industrial yeasts. AB - Industrial yeasts, including a sake yeast strain Kyokai no. 7 (K7), are generally unable to sporulate. Previously, we have reported that in K7 (Saccharomyces cerevisiae) cells, deletion of the G1 cyclin gene CLN3, a key activator of the cell cycle, allows the cells to induce IME1 transcription and sporulate under sporulation conditions. Here we show that treatment with the immunosuppressive drug rapamycin also restores sporulation competence in K7 cells. Moreover, sporulation was observed after rapamycin treatment in other industrial yeasts, namely bottom fermenting yeast strains and a wine yeast strain, which are not able to sporulate under normal sporulation conditions. These findings suggest that activation of TORC1 under sporulation conditions leads to sporulation incompetence in these yeasts. Thus, rapamycin treatment will be useful to restore sporulation competence in industrial yeasts. PMID- 22197500 TI - Intramolecular acyl migration and enzymatic hydrolysis of 2-O-alpha-D glucopyranosyl-6-O-(2-pentylheptanoyl)-L-ascorbic acid. AB - 2-O-alpha-D-Glucopyranosyl-6-O-(2-pentylheptanoyl)-L-ascorbic acid (6-bDode-AA 2G) underwent an intramolecular acyl migration to yield approximately 12% of 2-O alpha-D-glucopyranosyl-5-O-(2-pentylheptanoyl)-L-ascorbic acid (5-bDode-AA-2G) in neutral solutions for 3 days. In small intestine homogenate from guinea pigs for 12h, 6-bDode-AA-2G, which hardly underwent acyl migration to give 5-bDode-AA-2G, was predominantly hydrolyzed with alpha-glucosidase and then with esterase to ascorbic acid. PMID- 22197501 TI - The time dependent Dirac-Frenkel-McLachlan variation of parameters: an NMR application. AB - The time dependent variation of parameters solution to the time dependent Schrodinger equation pioneered by Dirac, Frenkel, and McLachlan is described in terms useful for immediate application to complex time dependent problems in magnetic resonance. A benchmark comparison of the theory to one dimensional images and spin echo envelope signals in simple spatially varying magnetic fields with molecular diffusion is provided. PMID- 22197502 TI - Measuring T2 and T1, and imaging T2 without spin echoes. AB - During adiabatic excitation, the nuclear magnetization in the transverse plane is subject to T(2) (spin-spin) relaxation, depending on the pulse length tau. Here, this property is exploited in a method of measuring T(2) using the ratio of NMR signals acquired with short and long-duration self-refocusing adiabatic pulses, without spin-echoes. This Dual-tau method is implemented with B(1)-insensitive rotation (BIR-4) pulses. It is validated theoretically with Bloch equation simulations independent of flip-angle, and experimentally in phantoms. Dual tauT(2) measurements are most accurate at short T(2) where results agree with standard spin-echo measures to within 10% for T(2) <= 100 ms. Dual-tau MRI performed with a long 0 degrees BIR-4 pre-pulse provides quantitative T(2) imaging of phantoms and the human foot while preserving desired contrast and functional properties of the rest of the MRI sequence. A single 0 degrees BIR-4 pre-pulse can provide T(2) contrast-weighted MRI and serve as a "T(2)-prep" sequence with a lower B(1) requirement than prior approaches. Finally, a Tri-tau experiment is introduced in which both tau and flip-angle are varied, enabling measurement of T(2), T(1) and signal intensity in just three acquisitions if flip angles are well-characterized. These new methods can potentially save time and simplify relaxation measurements and/or contrast-weighted NMR and MRI. PMID- 22197503 TI - Membrane microdomain components of Histoplasma capsulatum yeast forms, and their role in alveolar macrophage infectivity. AB - Analysis of membrane lipids of Histoplasma capsulatum showed that ~40% of fungal ergosterol is present in membrane microdomain fractions resistant to treatment with non-ionic detergent at 4 degrees C. Specific proteins were also enriched in these fractions, particularly Pma1p a yeast microdomain protein marker (a plasma membrane proton ATPase), a 30kDa laminin-binding protein, and a 50kDa protein recognized by anti-alpha5-integrin antibody. To better understand the role of ergosterol-dependent microdomains in fungal biology and pathogenicity, H. capsulatum yeast forms were treated with a sterol chelator, methyl-beta cyclodextrin (mbetaCD). Removal of ergosterol by mbetaCD incubation led to disorganization of ergosterol-enriched microdomains containing Pma1p and the 30kDa protein, resulting in displacement of these proteins from detergent insoluble to -soluble fractions in sucrose density gradient ultracentrifugation. mbetaCD treatment did not displace/remove the 50kDa alpha5-integrin-like protein nor had effect on the organization of glycosphingolipids present in the detergent resistant fractions. Ergosterol-enriched membrane microdomains were also shown to be important for infectivity of alveolar macrophages; after treatment of yeasts with mbetaCD, macrophage infectivity was reduced by 45%. These findings suggest the existence of two populations of detergent-resistant membrane microdomains in H. capsulatum yeast forms: (i) ergosterol-independent microdomains rich in integrin-like proteins and glycosphingolipids, possibly involved in signal transduction; (ii) ergosterol-enriched microdomains containing Pma1p and the 30kDa laminin-binding protein; ergosterol and/or the 30kDa protein may be involved in macrophage infectivity. PMID- 22197504 TI - Probing molecular interactions of poly(styrene-co-maleic acid) with lipid matrix models to interpret the therapeutic potential of the co-polymer. AB - To understand and maximize the therapeutic potential of poly(styrene-co-maleic acid) (SMA), a synthetic, pharmacologically-active co-polymer, its effect on conformation, phase behavior and stability of lipid matrix models of cell membranes were investigated. The modes of interaction between SMA and lipid molecules were also studied. While, attenuated total reflection-Fourier-transform infrared (ATR-FTIR) and static (31)P nuclear magnetic resonance (NMR) experiments detected SMA-induced conformational changes in the headgroup region, differential scanning calorimetry (DSC) studies revealed thermotropic phase behavior changes of the membranes. (1)H NMR results indicated weak immobilization of SMA within the bilayers. Molecular interpretation of the results indicated the role of hydrogen-bond formation and hydrophobic forces between SMA and zwitterionic phospholipid bilayers. The extent of membrane fluidization and generation of isotropic phases were affected by the surface charge of the liposomes, and hence suggested the role of electrostatic interactions between SMA and charged lipid headgroups. SMA was thus found to directly affect the structural integrity of model membranes. PMID- 22197506 TI - Optic atrophy plus phenotype due to mutations in the OPA1 gene: two more Italian families. AB - Autosomal Dominant Optic Atrophy (ADOA) is characterized by the selective degeneration of retinal ganglion cells. The occurrence of mutations in the gene encoding the dynamin-like GTPase protein Optic Atrophy 1 (OPA1) has been observed in about 60-70% of ADOA cases. A subset of missense mutations, mostly within the GTPase domain, has recently been associated with a syndromic ADOA form called "OPA1 plus" phenotype presenting, at muscle level, mitochondrial DNA (mtDNA) instability. In this study we disclosed two OPA1 gene mutations in independent probands from two families affected by OPA1 plus phenotype: the previously reported c.985-2A>G substitution and a novel microdeletion (c.2819-1_2821del). The correlation between genotype and phenotype and the effects of these variants at the transcript level and in the muscle tissue were investigated, confirming the broad complexity in the phenotypic spectrum associated with these OPA1 mutations. PMID- 22197507 TI - Study I: effects of 0.06% and 0.10% blood alcohol concentration on human postural control. AB - Alcohol intoxication causes many accidental falls presented at emergency departments, with the injury severity often related to level of blood alcohol concentration (BAC). One way to evaluate the decline in postural control and the fall risk is to assess standing stability when challenged. The study objective was to comprehensively investigate alcohol-related impairments on postural control and adaptive motor learning at specific BAC levels. Effects of alcohol intoxication at 0.06% and 0.10% BAC were examined with posturography when unperturbed or perturbed by calf vibration. Twenty-five participants (mean age 25.1 years) were investigated standing with either eyes open or closed. Our results revealed several significant findings: (1) stability declined much faster from alcohol intoxication between 0.06% and 0.10% BAC (60-140%) compared with between 0.0% and 0.06% BAC (30%); (2) sustained exposure to repeated balance perturbations augmented the alcohol-related destabilization; (3) there were stronger effects of alcohol intoxication on stability in lateral direction than in anteroposterior direction; and (4) there was a gradual degradation of postural control particularly in lateral direction when the balance perturbations were repeated at 0.06% and 0.10% BAC, indicating adaptation deficits when intoxicated. To summarize, alcohol has profound deteriorating effects on human postural control, which are dose dependent, time dependent and direction specific. The maximal effects of alcohol intoxication on physiological performance might not be evident initially, but may be revealed first when under sustained sensory-motor challenges. PMID- 22197508 TI - Gender differences in the association between depressive mood and mortality: a 12 year follow-up population-based study. AB - BACKGROUND: Depressive mood has been associated with all-cause mortality in both men and women. This study aimed at exploring gender differences in the association between depressive mood and specific causes of mortality as well as factors that may account for it, including education, marital status, social support, health behaviors, and chronic diseases. METHODS: A population-based survey including 6043 subjects (2892 men and 3151 women) was conducted in 1996 in the north-east of France with a questionnaire covering education, marital status, social support, health behaviors (smoking status, alcohol consumption, body mass index), and chronic diseases. Depressive mood was measured using the Duke Health Profile questionnaire. Cox regression models were used to examine its association with subsequent natural all-cause mortality, and cardiovascular and cancer mortality. RESULTS: During a follow-up of 12.5 years, 406 men and 303 women died from a natural cause. Adjusting for all covariates, depressive mood predicted natural mortality in both men [Hazard Ratio (HR)=1.30; 95% confidence interval (CI): 1.00-1.69] and women (HR=1.37; 95% CI: 1.06-1.77). However, this association was significant for cardiovascular mortality in men (HR=1.63; 95% CI: 1.00-2.65) whereas it was significant for cancer mortality in women (HR=1.71; 95% CI: 1.11-2.64). LIMITATIONS: Baseline data were self-reported and the response rate was low. DISCUSSION: Preventive strategies aiming at reducing the increased mortality associated with depressive mood should take gender into account. Depressed men may warrant a better screening for cardiovascular risk factors and diseases, whereas depressed women may benefit from better cancer prevention measures. PMID- 22197509 TI - Psychosocial predictors of depression and anxiety in patients with epilepsy: a systematic review. AB - BACKGROUND: People with epilepsy (PWE) have a high chance of experiencing depression and anxiety disorders over their lifetime. However, those most at risk are unknown. Psychosocial variables have been suggested as potentially important risk factors. A systematic review was conducted in order to critically assess available evidence regarding the psychosocial predictors of depression and anxiety in adults with epilepsy. METHODS: Electronic databases searched were MEDLINE, PsycINFO and Web of Science. Studies were included if they assessed depressive or anxiety symptoms using a validated questionnaire, and controlled for the role of potentially important epilepsy factors. Eleven studies were identified and assessed for research standards using the Quality Index Scale (QIS). RESULTS: Ten of the eleven studies found at least one significant predictor of depression and all six studies that assessed anxiety found one or more significant predictors. LIMITATIONS: Overall QIS score was only 7.5 out of 15, indicating significant design limitations of many included studies. There was also large variability between studies in measures used to assess psychosocial variables. CONCLUSION: Studies did not support the importance of attributional theory and stigma in the development of depression in epilepsy. There was inconsistent support for the role of illness representations but likely support for the role of stress and self-efficacy. Consistent support was found for the role of coping strategies and perceived social support. Given that psychosocial factors are potentially modifiable, a better understanding of their role in the development of depression in people with epilepsy is urgently needed to guide effective treatments. PMID- 22197510 TI - Medically serious versus non-serious suicide attempts: relationships of lethality and intent to clinical and interpersonal characteristics. AB - BACKGROUND: The study of near-fatal suicide attempts may provide insight into the minds of suicidal subjects. The aim of the study was to investigate the relationship of intent and lethality in medically serious and medically non serious suicide attempts and to examine relationship of specific psychological and clinical variables with the subjective and objective components of suicide intent. METHODS: The study group included 102 participants, 35 consecutive subjects hospitalized for a medically serious suicide attempt and 67 subjects who presented to the same tertiary medical center after a medically non-serious suicide attempt. All were interviewed with the SCID-I and completed the Suicide Intent Scale (SIS), the Lethality Rating Scale, and instruments measuring mental pain and communication difficulties. RESULTS: Patients who made medically serious suicide attempts had higher total SIS score and higher objective and subjective subscale scores. The objective component of the SIS was highly correlated with the lethality of the suicide attempt and communication difficulties; the subjective component was associated with mental pain variables. The interaction of mental pain and communication difficulties was predictive of the severity of the objective suicide intent. LIMITATIONS: Relatively small number of patients with medically serious suicide attempt and the relatively large number of questionnaires which may to some extent have diminished informant reliability. CONCLUSIONS: Suicidal individuals with depression and hopelessness who cannot signal their pain to others are at high risk of committing a medically serious suicide attempts. PMID- 22197511 TI - Strengths and limitations of HBM--imprecision matters. PMID- 22197512 TI - Exposure and effective dose biomarkers for perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in infertile subjects: preliminary results of the PREVIENI project. AB - Perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) have been used as surfactants in various industry and consumer products. PFOS/PFOA are very persistent in the environment and bioaccumulate in humans. They are potential reproductive and developmental toxicants and are considered to be emerging endocrine disrupters (EDs). The Italian project PREVIENI, funded by the Italian Environment Ministry, aims to link environment and human health through the investigation of selected endocrine disrupters (EDs) exposure and associated biomarkers related to human infertility conditions. In the early PREVIENI phase, PFOS and PFOA were determined in 53 couples affected by an infertility status, enrolled in a metropolitan area, according to established inclusion criteria and informed consensus. Nuclear receptors related to chemical compounds interactions were selected as biomarkers of effect and their gene expression modulations were analyzed in human peripheral blood mononuclear cell (PBMC). Among couples, subjects not presenting infertility factors (IF--) were separated from affected subjects (IF++). Most IF-- serum samples showed PFOS and PFOA concentrations overlapping the limit of detection (LOD) of 0.5 ng/g wet weight (ww). A substantial percentage of IF++ serum samples showed PFOS concentrations >20-fold the LOD, i.e. from 3 to 50 ng/g ww. In male (50%, n=26) and from 3 to 144 ng/g ww in female (37%, n=30) samples. PFOA values were below the LOD levels in 90% of the total samples. Peroxisome proliferator-activated receptor-gamma (PPARgamma) and aryl hydrocarbon receptor (AhR) showed a low level of expression in PBMC of both IF++ and IF-- groups. Whereas alpha and beta estrogen receptors (ERalpha and ERbeta), androgen receptor (AR), and pregnane X receptor (PXR) were all upregulated in IF++ of both sexes with respect to IF-- group. Our preliminary results related to the metropolitan area indicate that subjects affected by infertility factors tend to have both higher PFOS levels and higher gene expression of specific nuclear receptors. PMID- 22197513 TI - Environmental and biological monitoring of arsenic in outdoor workers exposed to urban air pollutants. AB - The aim of this study is to evaluate personal exposure to As in urban air in two groups of outdoor workers (traffic policemen and police drivers) of a big Italian city through: (a) environmental monitoring of As obtained by personal samples and (b) biological monitoring of total urinary As. The possible influence of smoking habit on urinary As was evaluated. We studied 122 male subjects, all Municipal Police employees: 84 traffic policemen and 38 police drivers exposed to urban pollutants. Personal exposure to As in air was significantly higher in traffic policemen than in police drivers (p=0.03). Mean age, length of service, alcohol drinking habit, number of cigarettes smoked/day and BMI were comparable between the groups of subjects studied. All subjects were working in the same urban area where they had lived for at least 5 yrs. Dietary habits and consumption of water from the water supply and/or mineral water were similar in traffic policemen and in police drivers. The values of total urinary As were significantly higher in traffic policemen (smokers and non smokers) than in police drivers (smokers and non smokers) (p=0.02). In the subgroup of non-smokers the values of total urinary As were significantly higher in traffic policemen than in police drivers (p=0.03). In traffic policemen and in police drivers total urinary As values were significantly correlated to the values of As in air (respectively r=0.9 and r=0.8, p<0.001). This is the first research in literature studying the exposure to As in outdoor workers occupationally exposed to urban pollutants, such as traffic policemen and police drivers. Personal exposure to As in the air, as well as the urinary excretion of As, is significantly higher in traffic policemen compared to drivers. These results can provide information about exposure to As in streets and in car for other categories of outdoor workers similarly exposed. PMID- 22197514 TI - Random models of Menzerath-Altmann law in genomes. AB - Recently, a random breakage model has been proposed to explain the negative correlation between mean chromosome length and chromosome number that is found in many groups of species and is consistent with Menzerath-Altmann law, a statistical law that defines the dependency between the mean size of the whole and the number of parts in quantitative linguistics. Here, the central assumption of the model, namely that genome size is independent from chromosome number is reviewed. This assumption is shown to be unrealistic from the perspective of chromosome structure and the statistical analysis of real genomes. A general class of random models, including that random breakage model, is analyzed. For any model within this class, a power law with an exponent of -1 is predicted for the expectation of the mean chromosome size as a function of chromosome length, a functional dependency that is not supported by real genomes. The random breakage and variants keeping genome size and chromosome number independent raise no serious objection to the relevance of correlations consistent with Menzerath Altmann law across taxonomic groups and the possibility of a connection between human language and genomes through that law. PMID- 22197515 TI - Modifications of the input currents on VTA dopamine neurons following acute versus chronic cocaine exposure. AB - Excitatory synapses on dopamine (DA) neurons in the ventral tegmental area (VTA) are modulated following exposure to various addictive drugs, including cocaine. Previously we have shown that cocaine affects GABA(A) receptor (GABA(A)R) mediated neurotransmission in VTA DA neurons. This finding led us to reexamine the modulation of the excitatory synapse on these neurons in response to cocaine exposure, while the activity of GABA(A)R is uninterrupted. Using rat brain slices, evoked post synaptic currents (ePSC) were monitored and inhibitors of NMDA receptor (NMDAR) and AMPA receptor (AMPAR) were gradually added to inhibitors-free bath solution. Modifications in the efficacy of the excitatory synapses were evaluated by comparing AMPAR-mediated and NMDAR-mediated currents (AMPA/NMDA ratio). The lack of GABA(A)R inhibitors enabled us to examine parallel changes in the relation between GABA(A)R-mediated and NMDAR-mediated currents (GABA(A)/NMDA ratio). First, we found that AMPA/NMDA ratio measured under complete availability of GABA(A)R, is significantly higher than the ratio measured under GABA(A)R blockade. In addition, GABA(A)/NMDA ratio, but not AMPA/NMDA ratio, is augmented a few hours following in vitro acute cocaine exposure. When measured 24 h after in vivo single cocaine injection, no change in GABA(A)/NMDA ratio was observed, however, the AMPA/NMDA ratio was found to be significantly higher. Finally, a decrease in both ratios was detected in rats repeatedly injected with cocaine. Taken together, these results lead to a better understanding of the means by which cocaine modifies synaptic inputs on VTA DA neurons. The parallel changes in GABA(A)/NMDA ratio may suggest an interaction between inhibitory and excitatory neural systems. PMID- 22197516 TI - Effects of general anaesthetics on 5-HT neuronal activity in the dorsal raphe nucleus. AB - The ascending 5-HT system has been and continues to be the subject of much research. The majority of in vivo electrophysiological and neurochemical studies of 5-HT function in rodents have been conducted in animals under anaesthesia - usually chloral hydrate or urethane. However, the effects of anaesthetics, on 5 HT function have not been systematically investigated. Here we used in vitro electrophysiology in dorsal raphe slices, to determine the effects of anaesthetically relevant concentrations of chloral hydrate (100 MUM and 1 mM), urethane (10 and 30 mM), pentobarbitone (10 and 100 MUM) and ketamine (10, 100 and 300 MUM) on regulators of 5-HT firing activity. We examined i) basal firing (driven by alpha(1) adrenoceptors), ii) the excitatory response to N-methyl-d aspartate (NMDA), iii) the 5-HT(1A) autoreceptor-mediated inhibitory response to 5-HT and iv) the GABA(A) receptor-mediated inhibitory response to 4,5,6,7 tetrahydroisoxazolo[5,4-c]pyridinyl-3-ol (THIP, gaboxadol). Pentobarbitone selectively enhanced the response to THIP. Ketamine decreased basal firing, attenuated the response to NMDA, and enhanced responses to both 5-HT and THIP. Chloral hydrate had marginal effects on basal firing, slightly attenuated the NMDA response, and enhanced both the 5-HT and THIP responses. Urethane increased basal firing, decreased the NMDA response, increased the response to THIP, but had no effect on the 5-HT response. Our data indicate that all anaesthetics tested significantly affect the regulators of 5-HT neuronal function. These findings will aid in the interpretation of previous reports of in vivo studies of the 5-HT system and will allow researchers to make a rational selection of anaesthetic for future studies. PMID- 22197517 TI - The rewarding and locomotor-sensitizing effects of repeated cocaine administration are distinct and separable in mice. AB - Repeated psychostimulant exposure progressively increases their potency to stimulate motor activity in rodents. This behavioral or locomotor sensitization is considered a model for some aspects of drug addiction in humans, particularly drug craving during abstinence. However, the role of increased motor behavior in drug reward remains incompletely understood. Intracranial self-stimulation (ICSS) was measured concurrently with locomotor activity to determine if acute intermittent cocaine administration had distinguishable effects on motor behavior and perception of brain stimulation-reward (BSR) in the same mice. Sensitization is associated with changes in neuronal activity and glutamatergic neurotransmission in brain reward circuitry. Expression of AMPA receptor subunits (GluR1 and GluR2) and CRE binding protein (CREB) was measured in the ventral tegmental area (VTA), dorsolateral striatum (STR) and nucleus accumbens (NAc) before and after a sensitizing regimen of cocaine, with and without ICSS. Repeated cocaine administration sensitized mice to its locomotor-stimulating effects but not its ability to potentiate BSR. ICSS increased GluR1 in the VTA but not NAc or STR, demonstrating selective changes in protein expression with electrical stimulation of discrete brain structures. Repeated cocaine reduced GluR1, GluR2 and CREB expression in the NAc, and reductions of GluR1 and GluR2 but not CREB were further enhanced by ICSS. These data suggest that the effects of repeated cocaine exposure on reward and motor processes are dissociable in mice, and that reduction of excitatory neurotransmission in the NAc may predict altered motor function independently from changes in reward perception. PMID- 22197518 TI - Multicriteria benefit-risk assessment using network meta-analysis. AB - OBJECTIVE: To enable multicriteria benefit-risk (BR) assessment of any number of alternative treatments using all available evidence from a network of clinical trials. STUDY DESIGN AND SETTING: We design a general method for multicriteria decision aiding with criteria measurements from Mixed Treatment Comparison (MTC) analyses. To evaluate the method, we apply it to BR assessment of four second generation antidepressants and placebo in the setting of a published peer reviewed systematic review. RESULTS: The analysis without preference information shows that placebo is supported by a wide range of possible preferences. Preference information provided by a clinical expert showed that although treatment with antidepressants is warranted for severely depressed patients, for mildly depressed patients placebo is likely to be the best option. It is difficult to choose between the four antidepressants, and the results of the model indicate a high degree of uncertainty. CONCLUSIONS: The designed method enables quantitative BR analysis of alternative treatments using all available evidence from a network of clinical trials. The preference-free analysis can be useful in presenting the results of an MTC considering multiple outcomes. PMID- 22197519 TI - Within-person study designs had lower precision and greater susceptibility to bias because of trends in exposure than cohort and nested case-control designs. AB - OBJECTIVE: To compare precision and apparent bias between cohort, nested case control, self-controlled case series, case-crossover, and case-time-control study designs. STUDY DESIGN AND SETTING: Study designs were implemented to evaluate the association between thiazolidinediones (TZDs) and heart failure, TZDs and fracture, and liver enzyme-inducing anticonvulsants and fracture. RESULTS: Effect estimates were similar for the cohort and case-control study; for the association between TZDs and fracture in women, the hazard ratio was 1.36 (1.18, 1.56) and odds ratio (OR) was 1.44 (1.21, 1.70). For this clinical example, the self controlled case series gave upward bias when follow-up was censored at the outcome (incidence rate ratio [IRR], 7.08; 4.96, 10.09) but was otherwise unbiased (IRR, 1.41; 1.14, 1.75). The retrospective case-crossover OR was 3.24 (2.18, 4.80), which was reduced by either bidirectional sampling (OR, 1.20; 0.98, 1.46) or with the case-time-control design (OR, 1.40; 1.09, 1.81). Findings on apparent bias were similar for the other two clinical examples. In each clinical example, within-person designs had considerably lower precision than the cohort or case-control study designs. CONCLUSION: When long-term exposures are analyzed, within-person study designs may have lower precision and greater susceptibility to bias. Bias may be reduced by sampling follow-up both before and after the outcome or with the case-time-control study design. PMID- 22197520 TI - Tradeoffs between accuracy measures for electronic health care data algorithms. AB - OBJECTIVE: We review the uses of electronic health care data algorithms, measures of their accuracy, and reasons for prioritizing one measure of accuracy over another. STUDY DESIGN AND SETTING: We use real studies to illustrate the variety of uses of automated health care data in epidemiologic and health services research. Hypothetical examples show the impact of different types of misclassification when algorithms are used to ascertain exposure and outcome. RESULTS: High algorithm sensitivity is important for reducing the costs and burdens associated with the use of a more accurate measurement tool, for enhancing study inclusiveness, and for ascertaining common exposures. High specificity is important for classifying outcomes. High positive predictive value is important for identifying a cohort of persons with a condition of interest but that need not be representative of or include everyone with that condition. Finally, a high negative predictive value is important for reducing the likelihood that study subjects have an exclusionary condition. CONCLUSION: Epidemiologists must often prioritize one measure of accuracy over another when generating an algorithm for use in their study. We recommend researchers publish all tested algorithms-including those without acceptable accuracy levels-to help future studies refine and apply algorithms that are well suited to their objectives. PMID- 22197521 TI - Viral evolution in deep time: lentiviruses and mammals. AB - Lentiviruses are a distinctive genus of retroviruses that cause chronic, persistent infections in mammals, including humans. The emergence of pandemic HIV type-1 (HIV-1) infection during the late 20th century shaped a view of lentiviruses as 'modern' viruses. However, recent research has revealed an entirely different perspective, elucidating aspects of an evolutionary relationship with mammals that extends across many millions of years. Such deep evolutionary history is likely to be typical of many host-virus systems, fundamentally underpinning their interactions in the present day. For this reason, establishing the deep history of virus and host interaction is key to developing a fully informed approach to tackling viral diseases. Here, I use the example of lentiviruses to illustrate how paleovirological, geographic and genetic calibrations allow observations of virus and host interaction across a wide range of temporal and spatial scales to be integrated into a coherent ecological and evolutionary framework. PMID- 22197522 TI - Diploe thickness and cranial dimensions in males and females in mid-Anatolian population: an MRI study. AB - BACKGROUND: The objective of this study is the classification of the thickness of diploe and dimensions of cranium at different points of cranium in men and women according to age groups. MATERIAL AND METHOD: In the radiology archive, measurements were made at different points in magnetic resonance (MR) images of 305 (188 females and 117 males) patients, the average ages of whom were 40.98+/ 20.44 (age range: 4-90) and who had no disorder of the bones. To determine diploe thickness, midfrontal, back and front bregma, lambda, opisthocranion and euryon points were used in the measurement. As for the determination of cranial volume, distances between glabella-opisthocranion, basion-vertex, basion-opisthion, euryon-euryon, nasion-basion, nasion-bregma, bregma-lambda and lambda opisthocranion were measured. The data were loaded to Statistical Package for the Social Sciences (SPSS) 16.0 program. T-test, Mann-Whitney U, Pearson correlation coefficient and Kruskal-Wallis variance analysis were used in the statistical assessment. Results with a p value smaller than 0.05 were accepted as significant. RESULTS: There was a statistically significant positive correlation between age and diploe thickness in all measurement points. The diploe thickness was also increased with age (p<0.05). In all points, average diploe thickness was higher in age 61 and over than the other groups (p<0.001). At the same time, diploe thickness in parietal bones was lower than frontal and occipital bones in both sexes. According to craniometric results cranium in males was bigger (p<0.001). While the distance between glabella-opisthocranion increased in both sexes aged 61 and over, basion-vertex height decreased in women in the same group (p<0.05). Interestingly, there was no meaningful statistical difference among age groups in terms of maximum cranial width (p>0.05). Foramen magnum length decreased related to age in both men and women (p<0.001). CONCLUSION: These results related to diploe thickness and cranium dimension may be leading in the determination of sex and age; surgical interventions to the cranium and bone graft choice may increase the reliability of the operation. PMID- 22197523 TI - Paradoxical pulmonary embolism with spontaneous aortocaval fistula. AB - BACKGROUND: Paradoxical pulmonary embolisms are uncommon emergencies and can occur as a consequence of an aortocaval fistula due to unrecognized dislodgement of thrombus from aortic sac into pulmonary circulation. This study reviewed current literature and therapeutic options in this emergency condition requiring prompt management and repair. METHODS: Literature was systematically searched for paradoxical pulmonary embolism associated with aortocaval rupture. RESULTS: Eight published cases were identified. However, many other paradoxical pulmonary emboli could have remained undiagnosed due to challenging clinical presentation. Symptoms of high-output cardiac failure and respiratory distress in the presence of large aortoiliac aneurysm and venous hypertension are findings of a possible major abdominal arteriovenous fistula with paradoxical pulmonary embolism. Successful treatment depends on prevention of new embolism and proper management of perioperative hemodynamics and massive bleeding during fistula repair. Endovascular procedures have been recently used as useful tools in this field. Cava filter placement may be a first step to prevent further thrombus dislodgements during aortocaval repair. Immediate subsequent aortic stent grafting can allow repair of aortocaval communication and exclusion of the abdominal aortic aneurysm from circulation with successful reversal of altered hemodynamic features. However, experience (especially in the long-term) is limited. CONCLUSIONS: Paradoxical pulmonary embolism from aortocaval fistula represents an extremely rare but true clinical emergency with high fatality rate. Recent advances in diagnostic technology and endovascular techniques can substantially improve outcomes of the disease. Clinical competence in early detection and diagnosis is essential for appropriate emergent management. PMID- 22197524 TI - A positron emission tomography/computed tomography (PET/CT) evaluation of asymptomatic abdominal aortic aneurysms: another point of view. AB - BACKGROUND: To assess the prevalence of increased (18)F-fluorodeoxyglucose (FDG) uptake in aneurysmal walls, adopting a case-control approach in a population of asymptomatic patients with abdominal aortic aneurysm (AAA). METHODS: This study included 40 males (mean age: 74 years, range: 59-93 years), consecutive, white Caucasian patients, with asymptomatic infrarenal AAA. The mean diameter of AAA was 4.9 cm (range: 4.8-5.4 cm), detected by computed tomography (CT) scan. Control Subjects: 44 age-matched controls subjects (mean age: 71 years, range: 59 85 years, 24 males, 20 females) who were selected according to a case-control criterion among a population of patients without any clinical evidence of atherosclerotic disease. Patients and controls underwent simultaneous FDG positron emission tomography (PET) and CT imaging from the skull base to the femoral neck by using an integrated PET/CT scanner. PET/CT studies were analysed both visually and quantitatively. For quantitative analysis, circular CT-based regions of interest (ROIs) were drawn on the AAA, on all the aortic segments, and on the large vessel included in the study (carotid, subclavian, and iliac arteries). FDG uptake was quantified by calculating the mean and maximum standardized uptake values (SUVs) within each ROI and normalizing for the blood pool SUV to obtain the final target-to-background ratio. Arterial calcium load was graded according to a semiquantitative five-point scale based on calcification of the arterial ring. RESULTS: Metabolic activity in the aneurysmal aortic segment was even lower with respect to both the adjacent--nonaneurysmal- samples of patient group and the corresponding arterial segments of control subjects (P < 0.001 and P < 0.01, respectively). In visual analysis, no patients showed an increased focal uptake of degree adequate to identify the aneurysmal arterial wall. AAA patients showed significantly higher values of total calcium load (ACL) than controls in ascending aorta and subclavian and iliac arteries (P < 0.01), and only in AAA patient group, a significant correlation was present between values of ACL in both iliac arteries and abdominal aorta on one side and wall metabolic activity in the same arteries on the other (P < 0.05). CONCLUSIONS: In conclusion, our results suggest that FDG hot spot, as well an increased diffuse uptake of FDG, in PET/CT studies is an extremely rare finding in patients with AAA of diameter close to surgical indications. PMID- 22197525 TI - Update on endovenous radio-frequency closure ablation of varicose veins. AB - Until recent years, the gold standard for treatment of truncal varicose veins has been high ligation and stripping of the saphenous vein. In the course of the last decade, new minimally invasive techniques based on endothermal ablation are progressively supplanting conventional surgery in the treatment of varicose veins. The endovenous treatment of varicose veins has been developed to reduce complications associated with conventional surgery and to improve quality of life. Radio frequency ablation (RFA) available since 1999 is now established as a safe and efficacious treatment for the ablation of refluxing saphenous veins. Among the emerging therapies, RFA with VNUS ClosureFAST is promising because it has eliminated almost all disadvantages associated with conventional surgery by "stripping" (bruises, scars, ecchymosis, inguinal recurrence, neovascularization, and mainly, prolonged incapacity) with an immediate occlusion rate close to 100%. When it is compared with endovenous laser ablation, RFA technology is associated with less postprocedural pain, less ecchymosis and tenderness, and better quality of life (QOL) measures. The aim of this article is to summarize the available evidence in the RFA treatment of varicose veins. PMID- 22197526 TI - Metabolic stress and inflammatory response in high-yielding, periparturient dairy cows. AB - Increased disease rates are commonly reported among high-yielding dairy cows in the transition period, extending from 3 weeks before to 3 weeks after calving, and characterized by the occurrence of an inflammatory response in terms of both positive and negative acute phase proteins (APP+ and APP-). To determine the above inflammatory response, the authors had developed the Liver Functionality Index (LFI), which defines the above condition on the basis of some APP- responses (albumin, cholesterol sensu stricto+bilirubin) during the first month of lactation. In this respect, low LFI values are associated to a high inflammatory response and vice versa. The relationship between LFI and inflammatory cytokine response was investigated from day -28 to day +28 with respect to calving in 12 periparturient dairy cows showing the six highest and six lowest LFI values within a cohort of 54 high-yielding dairy cows. The hypothesis being tested was that LFI and APP- on the whole could be used as readout of successful vs. non-successful adaptation to the transition period, with a strong association to disease occurrence. In fact, low LFI cows experienced many more disease cases (13 vs. 3 in high LFI Group) and related drug treatments till day +28. Interleukin-6 (IL-6) serum concentrations were always higher in low LFI cows (P<0.05 on day +28). The greater IL-6 levels were correlated with higher ceruloplasmin (APP+) and lower lysozyme serum concentrations (P<0.05 and <0.1, respectively). This latter finding was correlated with a clear role in vitro of lysozyme in a dose-dependent modulation of the inflammatory response of swine intestinal epithelial cells and bovine peripheral blood mononuclear cells. Hematological examinations showed no significant differences between the two groups under study. On the whole, our results indicate that LFI and LFI-related parameters could be used to identify cows at risk in the transition period toward an improved farm management. Also, our study indicates that disease cases in periparturient, high-yielding dairy cows are correlated with signs of accentuated IL-6 response and other markers of inflammatory phenomena. These likely start in the late lactation period or around dry-off, as suggested by our prepartal data, and proceed at much greater levels after calving. PMID- 22197527 TI - Effects of renin-angiotensin system blockades on cardiovascular outcomes in patients with diabetes mellitus: A systematic review and meta-analysis. AB - AIM: To determine whether renin-angiotensin system (RAS) blockade is beneficial for cardiovascular outcomes in patients with diabetes mellitus (DM) using meta analysis. METHODS: The MEDLINE and Cochrane library databases were searched for randomized controlled trials published up to June 2010. We also reviewed reference lists from identified trials and review articles to identify any other relevant studies, and the ClinicalTrials.gov website to identify randomized controlled trials that were registered as completed but not yet published. A random-effects model was used to combine the estimates for risk ratios (RR). RESULTS: Eligible studies were randomized controlled trials (including post hoc analyses) assessing the effects of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on cardiovascular events compared to controls in patients with DM. Nineteen clinical trials with 41,042 patients and 6039 cardiovascular events were identified. RAS blockade significantly reduced the risk of major cardiovascular events (RR 0.92, 95% confidence interval [CI] 0.84 1.00, I(2) statistic 53%) and myocardial infarction (RR 0.82, 95% CI 0.72-0.94, I(2)=55%). There were trends towards fewer strokes and lower all-cause mortality but these were not statistically significant. CONCLUSIONS: The available evidence shows that treatment with RAS blockade can routinely be considered for diabetic patients to reduce major cardiovascular events. PMID- 22197528 TI - Competitive dynamics in the brain: Comment on "Information flow dynamics in the brain" by M.I. Rabinovich et al. PMID- 22197529 TI - Nonlinear dynamics and higher cognitive mental functions: Comment on "Information flow dynamics in the brain" by M.I. Rabinovich et al. PMID- 22197530 TI - Prospective long-term analysis of nerve-sparing extravesical robotic-assisted laparoscopic ureteral reimplantation. AB - OBJECTIVE: To prospectively review our experience with extravesical robotic assisted laparoscopic ureteral reimplantation to determine whether postoperative voiding dysfunction can be avoided with pelvic plexus visualization and to assess the efficacy of this approach for the treatment of vesicoureteral reflux (VUR). METHODS: We prospectively followed 150 patients who underwent bilateral extravesical robotic-assisted laparoscopic ureteral reimplantation by a single surgeon at an academic institution. Each patient was followed for a 2-year period. All 150 patients had primary VUR of grade 3 or greater bilaterally, with 127 having parenchymal defects found on renal scans. All patients were toilet trained before surgical intervention. The operation was performed with an extravesical transperitoneal approach with robotic assistance using the daVinci Surgical System. All patients underwent voiding cystourethrography at 3 months postoperatively to document the resolution of VUR. Voiding dysfunction was assessed in each patient by uroflow, postvoid residual urine volume, and a validated questionnaire. RESULTS: The operative success rate was 99.3% for VUR resolution on voiding cystourethrography. One patient with bilateral grade 5 VUR that was downgraded to unilateral grade 2 VUR was considered to have treatment failure. This patient ultimately underwent subsequent subureteral injection therapy after an episode of pyelonephritis. No patient experienced de novo voiding dysfunction. CONCLUSION: Bilateral nerve-sparing robotic-assisted extravesical reimplantation has the same success rate as the traditional open approaches, with minimal morbidity and no voiding complications in our series. PMID- 22197531 TI - Radioactive pollution in Athens, Greece due to the Fukushima nuclear accident. AB - As a result of the nuclear accident in Fukushima Dai-ichi power plant, which started on March 11, 2011, radioactive pollutants were transferred by air masses to various regions of the Northern hemisphere, including Europe. Very low concentrations of (131)I, (137)Cs and (134)Cs in airborne particulate matter were measured in Athens, Greece during the period of March 24 to April 28, 2011. The maximum air concentration of (131)I was measured on April 6, 2011 and equaled 490 +/- 35 MUBq m(-3). The maximum values of the two cesium isotopes were measured on the same day and equaled 180 +/- 40 MUBq m(-3) for (137)Cs and 160 +/- 30 MUBq m( 3) for (134)Cs. The average activity ratio of (131)I/(137)Cs in air was 3.0 +/- 0.5, while the corresponding ratio of (137)Cs/(134)Cs equaled 1.1 +/- 0.3. No artificial radionuclides could be detected in air after April 28, 2011. Traces of (131)I as a result of radioactive deposition were measured in grass, soil, sheep milk and meat. The total deposition of (131)I (dry + wet) was 34 +/- 4 Bq m(-2), and of (137)Cs was less than 10 Bq m(-2). The maximum concentration of (131)I in grass was 2.1 +/- 0.4 Bg kg(-1), while (134)Cs was not detected. The maximum concentrations of (131)I and (137)Cs in sheep milk were 1.7 +/- 0.16 Bq kg(-1) and 0.6 +/- 0.12 Bq kg(-1) respectively. Concentrations of (131)I up to 1.3 +/- 0.2 Bq kg(-1) were measured in sheep meat. Traces of (131)I were found in a number of soil samples. The radiological impact of the Fukushima nuclear accident in Athens region was practically negligible, especially as compared to that of the Chernobyl accident and also to that of natural radioactivity. PMID- 22197532 TI - Indicators of the Fukushima radioactive release in NW Romania. AB - As a result of the Fukushima nuclear release, (131)I was found in different environmental media (rainwater, sheep and cow milk, herbage, sheep meat and thyroid tissue) in north-west Romania. On April 4, 2011 a maximum value of 1.40 +/- 0.21 Bq/L in (131)I activity was found in rainwater obtained from the Arad region. The obtained value corresponded with the maximum of (131)I concentration in air, as measured by Toma et al. (2011) for the Pitesti area. One day later, sheep milk from the Cluj area was found to contain a maximum activity of 9.22 +/- 0.95 Bq/L. A value of 0.85 +/- 0.07 MUSv was calculated as the total monthly effective dose received by the population as a result of the ingestion of sheep milk and sheep meat contaminated with (131)I. Only rainwater samples contained (134)Cs and (137)Cs at levels close to minimum detectable activity. Since the determined values could be influenced by Chernobyl (137)Cs, the (137)Cs concentrations are subject to uncertainty. The radioiodine transfer coefficients (Fm) and the concentration ratio (CR) from herbage to sheep milk, as well as sheep meat, from the Cluj-Apahida area are also presented. PMID- 22197533 TI - Risk factor analysis for second-stage palliation of single ventricle anatomy. AB - BACKGROUND: Single ventricle hearts can be surgically palliated by a series of operations culminating in the Fontan procedure, which establishes a total cavopulmonary connection. The second-stage procedure creates a physiologic connection between the superior vena cava and the pulmonary artery. METHODS: From 1998 to 2010, 557 patients with single ventricle heart disease underwent second stage surgical palliation. This cohort was retrospectively analyzed to assess patient outcome by a number of anatomic, physiologic, and procedural factors. The analysis excluded patients undergoing hybrid first-stage procedures. RESULTS: The median age at operation was 165 days (range, 59 days to 49 years). The most common anatomic subtypes were hypoplastic left heart syndrome (52%), tricuspid atresia (12%), unbalanced atrioventricular septal defect (10%), double inlet left ventricle (9%), or other (17%). Left ventricular hypoplasia was present in 70%. A hemi-Fontan procedure was done in 89%, and 11% received a bidirectional Glenn. Concomitant atrioventricular valve repair was necessary in 9%. Early mortality was 4.7%, and 5.9% died after discharge but before Fontan. No early or late deaths occurred in patients with tricuspid atresia and double inlet left ventricle. Multivariate analysis demonstrated ventricular dysfunction, atrioventricular valve regurgitation, and unbalanced atrioventricular septal defect were significant adverse risk factors for survival to Fontan. CONCLUSIONS: Second-stage palliation can be performed at low risk for patients with left ventricular dominance, but significant risk remains for patients with left ventricular hypoplasia and unbalanced atrioventricular septal defect. Atrioventricular valve insufficiency is a persistent problem that has not been neutralized by repair strategies. PMID- 22197534 TI - Clinical outcomes in patients with prolonged intensive care unit length of stay after cardiac surgical procedures. AB - BACKGROUND: Advances in critical care medicine have allowed for improved care of patients requiring prolonged intensive care unit length of stay (prICULOS) after cardiac operations, yet little is known regarding their eventual outcomes. The purpose of this study was to examine short- and long-term outcomes in patients undergoing cardiac operations with prICULOS. METHODS: All cases of coronary artery bypass grafting (CABG), aortic valve, mitral valve, and combined CABG/valve surgical procedures performed at a single institution from July 2002 to July 2007 were identified. All-cause mortality in patients discharged alive from the hospital was determined until December 2007 through linkage with the Social Security Death Index. Patients who experienced intraoperative death or those with missing or invalid social security numbers were excluded. The definition of prICULOS was total ICULOS greater than 7 days. RESULTS: A total of 3,478 patients met inclusion criteria. One hundred thirty-seven of three thousand four hundred seventy-eight patients (3.9%) experienced prICULOS. These patients were more likely to be older than 70 years (55.5% versus 30.5%; p<0.0001) and to have had recent myocardial infarction (28.5% versus 20.1%; p=0.02), previous cardiac operation (18.3% versus 6.9%; p<0.0001), and emergent status (9.5% versus 1.6%; p<0.0001). They experienced greater in-hospital mortality (37.2% versus 1.7%; p<0.0001) and those who were discharged alive had worse long-term survival (log-rank, p<0.0001). After risk adjustment, prICULOS emerged as a significant predictor of in-hospital death (odds ratio [OR] 20.9; 95% confidence interval [CI], 12.9-33.7) and decreased long-term survival (hazard ratio [HR] 2.9; 95% CI, 2.0-4.3). CONCLUSIONS: Patients with prICULOS after cardiac operations have worse overall outcomes. These data may be used to inform these patients and their families of realistic expectations regarding their clinical course. PMID- 22197535 TI - Human leukocyte antigen (HLA) and pharmacogenetics: screening for HLA-B*57:01 among human immunodeficiency virus-positive patients from southern Alberta. AB - The field of pharmacogenetics is witnessing a growing interest in the role of the human leukocyte antigen (HLA) in manifestation of adverse drug reactions (ADR). Here we report a retrospective analysis of the association of HLA-B*5701 with abacavir hypersensitivity syndrome (AHS) in a large Canadian cohort of 489 human immunodeficiency virus-1-positive patients exposed to abacavir. A total of 3.7% of abacavir-exposed patients had developed AHS. Using polymerase chain reaction sequence-specific primer-based genotyping, the HLA-B*5701 allele was observed in 20 patients (4.1%). Of the 20 HLA-B*5701(+) abacavir-treated patients, 18 (90%) had developed AHS. Carriage of the HLA-B*5701 allele indicated a strong association with abacavir hypersensitivity (p < 0.0001; odds ratio = 6,934; 95% confidence interval = 321-149,735). HLA-B*5701 genotyping demonstrated high sensitivity, specificity, and positive and negative predictive values. The data derived from the study highlight the importance of engaging histocompatibility and immunogenetics laboratories in taking a lead in mapping other less characterized HLA and immunogenetic markers associated with ADRs. PMID- 22197536 TI - Effects of different nitrogen sources on the biogas production - a lab-scale investigation. AB - For anaerobic digestion processes nitrogen sources are poorly investigated although they are known as possible process limiting factors (in the hydrolysis phase) but also as a source for fermentations for subsequent methane production by methanogenic archaea. In the present study different complex and defined nitrogen sources were investigated in a lab-scale experiment in order to study their potential to build up methane. The outcome of the study can be summarised as follows: from complex nitrogen sources yeast extract and casamino acids showed the highest methane production with approximately 600 ml methane per mole of nitrogen, whereas by the use of skim milk no methane production could be observed. From defined nitrogen sources L-arginine showed the highest methane production with almost 1400 ml methane per mole of nitrogen. Moreover it could be demonstrated that the carbon content and therefore C/N-ratio has only minor influence for the methane production from the used substrates. PMID- 22197537 TI - Characterization of fusidic acid-resistant Staphylococcus aureus isolates in the community of Casablanca (Morocco). AB - Resistance to fusidic acid in Staphylococcus aureus is caused by mutation of the elongation factor G (EF-G) encoded by fusA or by expression of a protein, encoded by fusB or fusC, that protects the drug target. Other mechanisms involved in this resistance are mutations in the riboprotein L6 operon within rplF. The aim of this study was to determine the prevalence and mechanisms of resistance to fusidic acid in clinical isolates of S. aureus in Casablanca (Morocco) and to define the phenotypic and genotypic traits of these isolates and their clonal relationship. All fusidic acid-resistant S. aureus (FAR-SA) isolates were tested for fusB and fusC genes and were evaluated for the detection of mutations in fusA and fusE (rplF). fusB-positive strains were tested for a cadDX operon, encoding cadmium resistance. The agr group and the presence of toxin genes were monitored to characterize all FAR-SA isolates which were typed by pulsed-field gel electrophoresis (PFGE) and spa typing. Among 140 clinical S. aureus isolates collected in 2007 and 2008, 18 (~13%) exhibited resistance to fusidic acid. The most common resistance determinant was fusC, found in 16 isolates. Molecular typing showed that 14 of them harboured an agr group III and belonged to the same clonal complex (CC) spa type 127 and identical clonotype (cluster labelled A). These isolates also possessed the staphylococcal enterotoxin H gene. The second resistance determinant was fusB found in two isolates. These two isolates lacked cadDX gene and were found to belong to two unrelated clusters and spa types. While no isolate carrying mutations in rplF was found, 15 expressed a silent mutation in fusA (nucleotide 342). Only acquired fusidic acid resistance genes (mainly fusC) were prevalent among FAR-SA isolates with almost all of the clinical specimens belonging to CC-spa type 127. This study provides valuable data on the prevalence of fusidic acid-resistant S. aureus with the associated molecular mechanisms of resistance and the genetic background of the strains in Casablanca. PMID- 22197538 TI - Commentary: development and validation of the Asian Migraine Criteria (AMC). AB - Precise and manageable diagnostic criteria are vital for researchers and clinicians dealing with headache. The lack of clear and accessible markers of the biological distinctions between different types of headache means that criteria are determined by expert consensus. The International Classification of Headache Disorders (ICHD) criteria are the current benchmark and are evolving. They are effective for research as they exclude questionable cases from consideration, but in clinical practice they are used inconsistently by neurologists, and rarely by general practitioners, because of complexity. In this issue of the Journal of Clinical Neuroscience, Ghandehari et al. have proposed a new set of criteria, the Asian Migraine Criteria (AMC). These criteria perform well against the gold standard ICHD, but are almost as complex. They do not have the simplicity of the ID Migraine tool. Nevertheless, they are welcome: any tool that general practitioners may be attracted to use that increases the accuracy of headache diagnosis is to be applauded. PMID- 22197539 TI - Resolution of extra-axial collections after decompressive craniectomy for ischemic stroke. AB - Extra-axial fluid collections are known consequences of decompressive hemicraniectomy. Studies have examined these collections and their management. We retrospectively reviewed 12 consecutive patients who underwent decompressive hemicraniectomy for the treatment of malignant cerebral edema after infarction and evaluated the evolution, resolution and treatment of post-operative extra axial fluid collections. All patients underwent standard-sized frontotemporoparietal hemicraniectomy with duraplasty as treatment for medically intractable malignant cerebral edema at an average of 3 days after the stroke (median 2 days). Their 30-day mortality was 25%. Three patients developed some extra-axial fluid collections after craniectomy: two patients developed the collections early in their post-operative course, 3 days and 5 days after the craniectomy. Both experienced spontaneous resolution of the collections without corrective cranioplasty or shunt placement at 34 days and 58 days after surgery. The third patient developed a collection 55 days after the operation related to a subgaleal bacterial infection. In the final analysis, 18% of patients developed extra-axial collections and all resolved spontaneously. The incidence of extra axial collections after decompressive hemicraniectomy following ischemic stroke was lower in our retrospective series than has been reported by others. The collections resolved spontaneously, suggesting that early anticipatory, corrective treatment with cerebrospinal fluid diversion or cranioplasty may not be warranted. PMID- 22197540 TI - Clinicopathologic and biomarker analysis of invasive pleomorphic lobular carcinoma as compared with invasive classic lobular carcinoma: an experience in our institution and review of the literature. AB - Pleomorphic lobular carcinoma (PLC) is a distinct morphological variant of invasive lobular carcinoma (ILC). Although PLC retains the distinctive loosely cohesive and single-file growth pattern of ILC, it has specific distinguishable characteristics, including enlarged nuclei with greater nuclear irregularity, increased hyperchromasia, prominent nucleoli, increased mitotic activity, and abundant eosinophilic cytoplasm. We compared the clinicopathologic features and biomarker expression of PLC and ILC. Fifty-eight cases of classic ILC (5.3%) and 7 cases of PLC (0.6%) were identified from our file between January 2002 and December 2010. Histopathologic data and tumor biomarkers were recorded. Clinical follow-up information (3-93 months; median, 29 months) for distant metastasis and survival was also gathered. Fisher exact test was used, and results were considered statistically significant if P value is less than .05. Our results showed that compared with classic ILC, PLC was more frequently grade III (P < .01), estrogen receptor negative (P < .001), and has Ki-67 greater than 10% (P < .002). In conclusion, PLC is more frequently higher grade and may exhibit an adverse biomarker profile (negative estrogen receptor and high Ki-67) as compared with classic ILC. However, no significant differences were found between PLC and classic ILC for axillary lymph node/distant metastases and survival. PMID- 22197541 TI - Significance of Ki-67 and p53 immunoexpression in the differential diagnosis of oral necrotizing sialometaplasia and squamous cell carcinoma. AB - Necrotizing sialometaplasia (NS) is a benign condition that usually involves the hard palate and can be mistaken for invasive squamous cell carcinoma (SCC). In this study, we have demonstrated that p53 and Ki-67 staining may assist in the differential diagnosis of NS from SCC. Thirteen cases of NS and 20 cases of oral cavity SCC were randomly selected from our surgical pathology archive from 1992 to 2009. Each case was additionally stained with Ki-67, p53, BCL-2, p16, and epidermal growth factor receptor (EGFR) antibodies. All 13 cases of NS were negatively stained for BCL-2, EGFR, and Ki-67. Three cases (23%) showed weak and focal positive nuclear staining for p53. Two cases (15%) showed positive staining for p16. In 16 well-differentiated SCC cases, p53 was positive in 12 cases (75%); BCL-2, p16, EGFR were positive in 3 cases (18%); and Ki-67 was positive in all cases (100%). In 4 moderately differentiated SCC cases, p53 expression was positive in all cases. Two tumors (50%) had a positive expression of BCL-2. Three cases (75%) had a positive p16 staining, and 1 (25%) had a positive EGFR staining. All cases were positive with high nuclear staining greater than 35% of cells for Ki-67. Ki-67 and p53 showed more intense staining and increased in moderately differentiated SCC comparing with well-differentiated SCC and NS. BCL 2, EGFR, and p16 had the same pattern of staining with the same extent in NS and SCCs. The diagnosis of NS may be difficult and may be supplemented via immunohistochemistry by demonstrating focal or absent p53, low to absent Ki-67 (<10% of cells). Although Ki-67 and p53 staining are generally more intense and are increased in malignancy, these findings may be helpful adjuncts in the differential diagnosis of NS from SCC in appropriate clinical setting. PMID- 22197542 TI - Deceiving high-grade cervical dysplasias identified as human papillomavirus non 16 and non-18 types by Invader human papillomavirus assays. AB - High-grade cervical intraepithelial lesions (HGCINs) are easily diagnosed by established histologic criteria. However, we encountered problematic cases that are difficult to diagnose because features intermediate between dysplasia and metaplasia are present. p16 and Ki-67 immunostains proved HGCIN in these difficult and unusual cases. Because these are unusual cases of cervical dysplasia, we decided to type the human papillomavirus (HPV) using the Invader HPV test with analyte-specific reagents developed by Third Wave Technologies (Madison, WI, USA) (a new HPV screening assay applicable to tissue and amenable to rapid, sensitive, and specific detection of 14 high- to intermediate-risk HPV types) and a panel of immunostains. Results of these difficult cases are compared with classic HGCIN cases. We searched our pathology files over a period of 16 months for high-grade squamous intraepithelial lesion, cervical intraepithelial neoplasia II, cervical intraepithelial neoplasia III, and p16. To identify cases of difficult HGCIN with features intermediate between dysplasia and metaplasia, we reviewed all surgical cases of HGCIN that required p16 and Ki-67 diagnosis confirmation. Cases of interest were also stained with ProExC. Human papillomavirus screening and HPV 16/18 typing were performed by the Invader assays as described previously. Ten cases of classic HGCIN were easily diagnosed by hypercellularity, significant atypia, mitotic figures, and diffuse staining by p16, Ki67 and ProExC. The Invader assay identified HPV 16 (A9 positive/HPV16 positive) in 7 of 10 cases; the 3 others were A7 positive/not HPV18 (1) and A9 positive/not HPV16 (2). Eight cases of difficult HGCIN were identified. These showed only mild-to-moderate cellularity, a lack of significant atypia, absent-to rare mitotic figures, and diffuse staining by p16, Ki-67, and ProExC. Human papillomavirus DNA was detected in 5 of 8 cases: only 1 was A9 positive/HPV16 positive, 1 was A5/A6 positive, 1 was A7 positive/not HPV18, and 2 were A9 positive/not HPV16. Three remaining cases demonstrated sufficient DNA to be analyzed by the Invader assay, but results were negative. This is a poorly recognized unusual group of cervical HGCIN with features intermediate between dysplasia and metaplasia that is easily confused by histologic examination. Immunostains prove the high-grade nature of these lesions, and Invader assay demonstrates association with HPV types other than 16/18 (ie, other HPV types detected by Invader assay). In this study, we present an unusual group of cases of high-grade dysplasia, not recognized by hematoxylin and eosin but identified by Ki67 and P16. It is very important to emphasize that this unusual group of high-grade dysplasias is associated with high-risk HPV but with types other than 16/18. PMID- 22197543 TI - Detection of PAX3/PAX7-FKHR fusion transcripts in rhabdomyosarcoma and other small round cell tumors by 1-step reverse transcriptase polymerase chain reaction: a novel tool for diagnosis and differentiation. AB - Rhabdomyosarcoma (RMS) is one of the most frequent soft tissue sarcomas in children. It is sometimes difficult to distinguish it from other small round cell tumors (SRCTs) depending on microscopic observations; although their treatment and prognosis varied widely, the same happens between alveolar RMS (ARMS) and embryonal RMS (ERMS). The role of PAX3/PAX7-FKHR fusion gene has been reported in ARMS but not in ERMS and SRCT. The aim of this study was to explore its value in RMS diagnosis and differentiation. Ninety-eight patients with ARMS (n = 13), ERMS (n = 25), pleomorphic RMS (n = 5), Ewing sarcoma (n = 11), neuroblastoma (n = 18), lymphoma (n = 24), and uncertain SRCT (n = 2) were analyzed. One hundred fifteen RNA samples were extracted from the primary tumor tissue at initial presentation and relapse. One-step reverse transcriptase polymerase chain reaction assays for the PAX3/PAX7-FKHR fusion transcripts were performed. Molecular findings were compared with original histologic diagnoses. PAX3-FKHR fusion transcript was detected in 9 ARMS samples, PAX7-FKHR fusion transcript was detected in 7 ARMS samples, and 2 uncertain SRCTs were detected; none of them were detected in ERMS, Ewing sarcoma, neuroblastoma, and lymphoma. Direct sequencing of PAX3 coding regions revealed a heterozygous mutation A->G (nt1380) at codon 448 (AAT->GAT), resulting in substitution of Asn-448 for Asp. Detection of PAX3/PAX7-FKHR fusion transcripts by 1-step reverse transcriptase polymerase chain reaction is a novel tool for RMS diagnosis and differentiation. PMID- 22197544 TI - Absence of IDH1-R132H mutation predicts rapid progression of nonenhancing diffuse glioma in older adults. AB - Advanced age and contrast enhancement portend a poor prognosis in diffuse glioma (DG). Diffuse glioma may present as nonenhancing tumors that rapidly progress in weeks to months to a pattern of ring enhancement, characteristic of glioblastoma (GBM). Mutations involving isocitrate dehydrogenase 1 (IDH1) have recently emerged as important diagnostic and prognostic markers in DG. R132H is the most common mutation, expressed in more than 80% of DG and secondary GBM but in less than 10% of primary GBM. Adults older than 50 years with nonenhancing, rapidly progressing DG were identified. A comparison group comprised randomly selected, age-matched patients with nonenhancing, nonprogressing DG. Isocitrate dehydrogenase 1 status was evaluated using anti-IDH1-R132H antibodies (Dianova, Hamburg, Germany). The results were correlated with the clinical outcomes. We identified 4 patients who presented with nonenhancing DG that rapidly progressed to ring-enhancing lesions that were subsequently diagnosed on surgical resection as GBM. This group showed absent IDH1-R132H expression, which is characteristic of primary GBM. The comparison group of 5 patients presented with nonenhancing, nonprogressing DG, and all 5 tumors showed IDH1-R132H expression. In conclusion, negative IDH1-R132H mutation status in nonenhancing DG of older adults is a poor prognostic factor associated with rapid progression to ring-enhancing GBM. The shorter interval of progression and negative IDH1-R132H mutation status suggest a similar molecular pathway as seen in primary GBM. PMID- 22197545 TI - Up-regulation of Notch-1 in psoriasis: an immunohistochemical study. AB - The Notch pathway plays a key role in differentiation, proliferation, and influencing cell fate decision in multiple organisms and tissues including the epidermis and its appendages. The role of Notch-1 in psoriasis has not been widely evaluated; therefore, the current study aimed to evaluate its role in etiopathogenesis of this common skin disease. The current study used immunohistochemical technique to evaluate Notch-1 expression in 35 lesional biopsies of patients having chronic plaque psoriasis in comparison with normal skin biopsies, representing the control group. Notch-1 was expressed in the epidermis of both normal and psoriatic skins; however, the intensity was in favor of psoriatic lesion, and the nuclear form of Notch-1 was more frequently and diffusely seen in psoriasis. Exacerbation of psoriasis as assessed by the Psoriasis Area and Severity Index score was significantly associated with intense (P = .005) and nuclear form of Notch-1 expression (P = .0001). The nuclear form of Notch-1 was also correlated with female sex (P = .043). From this study, up regulation and not down-regulation of Notch-1 may have a role in pathogenesis of psoriasis. The nuclear form is responsible for the exacerbation of symptoms, and it is the one that may disappear by the effect of psoralen and ultraviolet A radiation (PUVA) therapy. PMID- 22197546 TI - Is p16 immunohistochemistry a more cost-effective method for identification of human papilloma virus-associated head and neck squamous cell carcinoma? AB - Tobacco and alcohol use are established risk factors for head and neck squamous cell carcinoma (HNSCC). However, patients with a unique subset of human papilloma virus (HPV)-associated HNSCC have been documented to have a better survival outcome. These tumors occur more frequently in the tonsils and oropharyngeal sites, among younger patients, higher socioeconomic group, and those exposed to more sexual partners and oral sex compared with HPV-negative HNSCC. Although tobacco- and alcohol-related HNSCCs appear to be on the decline, tonsillar and oropharyngeal HPV-associated tumors seem to be on the rise, and their prevalence varies widely in published reports, ranging from 20% to 60%. Human papilloma virus detection methods in tumor tissue vary and include polymerase chain reaction, in situ hybridization (ISH) technique for HPV DNA, and E6/E7 messenger RNA, with p16 immunohistochemistry (IHC) as a surrogate marker. The sensitivity and specificity of the different methods used are likely contributory factors to this wide variation. This study compares the p16 IHC staining patterns in HNSCC and laryngeal papillomas and assesses the concordance of p16 and high-risk HPV ISH to determine the usefulness of p16 as a first-line marker. Using an objective criterion of diffuse intense confluent staining pattern as definite positive (akin to the 3+ of HER2/neu in breast cancer) and focal scattered staining pattern as equivocal reaction requiring confirmatory HPV assay, p16 IHC expression shows good concordance with high-risk HPV-ISH and can be used as a first-line marker. We propose p16 overexpression as a suitable surrogate and screening marker, with high potential of impacting the standard of care. PMID- 22197547 TI - Tapentadol increases levels of noradrenaline in the rat spinal cord as measured by in vivo microdialysis. AB - Spinal noradrenaline is thought to play an important role in descending pain inhibitory pathways and the modulation of nociceptive information at the spinal level. Tapentadol is a MU-opioid receptor (MOR) agonist and noradrenaline reuptake inhibitor (NRI). We showed previously that tapentadol, in contrast to morphine, elevates levels of noradrenaline, but not serotonin, in the ventral hippocampus of rats. The aim of this study was to examine the effects of tapentadol, morphine and venlafaxine on spinal monoamine levels. Rats were implanted with spinal microdialysis probes. Drugs were administered intraperitoneally, and samples were collected for 3h in isoflurane-anesthetized animals and analysed for monoamine content using HPLC-MS/MS. In terms of area under-curve (AUC, 0-180 min), tapentadol (4.64-21.5mg/kg) produced a dose dependent, significant increase in extracellular spinal noradrenaline levels (9275+/-4346 min% at the highest dose versus -1047+/-889 min% for vehicle). A maximum increase of 182+/-32% of baseline was reached 60 min after administration of 10mg/kg tapentadol. Venlafaxine (10mg/kg) produced an effect of similar magnitude. In contrast, tapentadol decreased extracellular spinal serotonin levels (non-significantly compared to vehicle), while venlafaxine increased spinal serotonin to 267+/-74% of baseline. In contrast to tapentadol and venlafaxine, morphine slightly decreased levels of noradrenaline and serotonin. This study demonstrates that analgesic doses of tapentadol (and venlafaxine), but not morphine, increase spinal noradrenaline levels and that tapentadol is devoid of a relevant serotonergic effect. It supports the suggestion that the NRI component of tapentadol is functionally relevant and contributes to its mechanism of action. PMID- 22197548 TI - Electrochemical study of hydrogen peroxide formation in isolated mitochondria. AB - Mitochondrial respiration generates reactive oxygen species that are involved in physiological and pathological processes. The majority of methods, with exception of electron paramagnetic resonance, used to evaluate the identity, the rate and the conditions of the reactive oxygen species produced by mitochondria, are mainly based on oxidation sensitive markers. Following latest electrochemical methodology, we implemented a novel electrochemical assay for the investigation of aerobic metabolism in preparations of isolated mitochondria through simultaneous measurement of O2 consumption and reactive species production. This electrochemical assay reveals active H2O2 production by respiring mouse liver mitochondria, and shows that ATP synthase activation and moderate depolarization increase the rate of H2O2 formation, suggesting that ATP synthesizing (state 3) mitochondria might contribute to oxidative stress or signaling. PMID- 22197549 TI - Microelectrode-based dielectric spectroscopy of glucose effect on erythrocytes. AB - The dielectric response of biconcave erythrocytes exposed to D-glucose and L glucose has been investigated using a double array of planar interdigitated microelectrodes on a glass microchip. Erythrocytes are analyzed under physiological conditions suspended in hypo-osmolar balanced solutions containing different glucose concentrations (0-20 mM). The glucose effect on the cellular dielectric properties is evaluated by analyzing the spectra using two different approaches, the equivalent circuit model and a modified model for ellipsoidal particles. The results show that at elevated glucose concentration (15 mM) the membrane capacitance increases by 36%, whereas the cytosol conductivity slightly decreases with a variation of about 15%. On the contrary, no variation has been registered with L-glucose, a biologically inactive enantiomer of D-glucose. The paper discusses the possible mechanism controlling the membrane dielectric response. As the external D-glucose increases, the number of activated glucose transporter in the erythrocyte membrane raises and the transition from sugar-free state to sugar-bounded state induces a change in the dipole moments and in the membrane capacitance. PMID- 22197550 TI - Peptide molecular junctions: distance dependent electron transmission through oligoprolines. AB - We have investigated the efficiency of electron transmission through thiolated oligoproline derivatives of general formula: Cys-(Pro)(n)-CSA, where CSA is a cystamine linker and n=1-4. The conductance measurements were performed using STM based molecular junction approach. We have noted that the conductance of the oligoprolines decays exponentially with increasing length of the molecules and the decay constant was 4.3 nm(-1). This indicates that electron transfer is dominated by superexchange mechanism. Based on this observation, we have concluded that the height of the barrier is affected by the specific conformation of the peptide backbone. Such conclusion is supported by the fact that the oligoprolines do not form intramolecular hydrogen bonds, which could provide alternative electron transfer pathways. PMID- 22197551 TI - Chiari I malformation, syringomyelia and liver disease: an unusual resolution with implications for clinical practice. PMID- 22197552 TI - Ethnic rhinoplasty. AB - This article examines the surgical techniques of rhinoplasty in relation to aesthetic considerations of various ethnic groups. Rhinoplasty in general is challenging, particularly in the ethnic population. When considering rhinoplasty in ethnic patients one must determine their aesthetic goals, which in many cases might deviate from the so-called norm of the "North European nose." An experienced rhinoplastic surgeon should be able to navigate his or her way through the nuances of the various ethnic subsets. Keeping this in mind and following the established tenets in rhinoplasty, one can expect a pleasing and congruous nose without radically violating ethnicity. PMID- 22197553 TI - Enhanced tolerance to NaCl and LiCl stresses by over-expressing Caragana korshinskii sodium/proton exchanger 1 (CkNHX1) and the hydrophilic C terminus is required for the activity of CkNHX1 in Atsos3-1 mutant and yeast. AB - Sodium/proton exchangers (NHX antiporters) play important roles in plant responses to salt stress. Previous research showed that hydrophilic C-terminal region of Arabidopsis AtNHX1 negatively regulates the Na(+)/H(+) transporting activity. In this study, CkNHX1 were isolated from Caragana korshinskii, a pea shrub with high tolerance to salt, drought, and cold stresses. Transcripts of CkNHX1 were detected predominantly in roots, and were significantly induced by NaCl stress in stems. Transgenic yeast and Arabidopsisthalianasos3-1 (Atsos3-1) mutant over-expressing CkNHX1 and its hydrophilic C terminus-truncated derivative, CkNHX1-DeltaC, were generated and subjected to NaCl and LiCl stresses. Expression of CkNHX1 significantly enhanced the resistance to NaCl and LiCl stresses in yeast and Atsos3-1 mutant. Whereas, compared with expression of CkNHX1, the expression of CkNHX1-DeltaC had much less effect on NaCl tolerance in Atsos3-1 and LiCl tolerance in yeast and Atsos3-1. All together, these results suggest that the predominant expression of CkNHX1 in roots might contribute to keep C. korshinskii adapting to the high salt condition in this plant's living environment; CkNHX1 could recover the phenotype of Atsos3-1 mutant; and the hydrophilic C-terminal region of CkNHX1 should be required for Na(+)/H(+) and Li(+)/H(+) exchanging activity of CkNHX1. PMID- 22197554 TI - Histone post-translational modifications associated to BAALC expression in leukemic cells. AB - BAALC expression is an indicator of aggressiveness in acute myelogenous leukemia (AML). Overexpression of this gene is associated to poor of clinical outcome. It is known that post-translational histone modifications control gene transcription. Thus, here we have investigated BAALC expression and post translational histone modifications in leukemia cell lines. We show that Kasumi-6 and Kyo cells have high and low BAALC mRNA levels, respectively. Moreover, we demonstrate that these cell lines present distinct profiles in terms of histone post-translational modifications (H3K9K14 acetylation, H3K4 trimethylation and H3K23 trimethylation) at the level of BAALC promoter. These findings, in light of recent data on how histone post-translational modifications control gene expression, indicate that BAALC gene is "paused" and that in leukemia cells its transcription can be activated or repressed by mechanisms acting on epigenetic marks. PMID- 22197555 TI - SIRT1 prevents replicative senescence of normal human umbilical cord fibroblast through potentiating the transcription of human telomerase reverse transcriptase gene. AB - SIRT1, the mammalian homolog of sirtuins, has emerged as a mediator of the beneficial effects of calorie restriction. Among them, we focused on the SIRT1 induced prevention of cellular senescence, and tried to reveal the molecular mechanisms that define the effects of SIRT1. Firstly in this study, we observed that overexpression of SIRT1 resulted in the prevention of cellular senescence of normal human umbilical cord fibroblast HUC-F2 cells. Here, we focused on the human telomerase reverse transcriptase (hTERT) gene as a target of the SIRT1 induced prevention of cellular senescence. Results showed that SIRT1, SIRT1 activator, resveratrol, and SIRT1 activating condition, starved condition, increased the transcription of hTERT in HUC-F2 cells. Next, we found that SIRT1 increased hTERT transcription in a c-MYC-dependent manner, triggered the transcription of the c-MYC gene and increased the amount of c-MYC recruited to the hTERT promoter. Further, SIRT1 increased the transcriptional activation ability of c-MYC and correspondingly increased the amount of acetylated H4 histone at the hTERT promoter. All of these results indicated that SIRT1 activates hTERT transcription through the involvement of c-MYC, and suggested that this SIRT1-induced augmentation of hTERT transcription resulted in the extension of the cellular life span of HUC-F2 cells. PMID- 22197556 TI - Microbiological monitoring of bivalves from the Ria Formosa Lagoon (south coast of Portugal): a 20 years of sanitary survey. AB - The microbiological pollution of coastal waters is a major problem, especially in shellfish areas. This article shows the faecal contamination in bivalves from the Ria Formosa Lagoon (south coast of Portugal) along 20 years (1990-2009). The highest values of Escherichia coli in bivalves were obtained during the 90s, related with the discharge of untreated wastewaters and agricultural runoff. In the 2000s contamination levels decreased, with 83% of the population already served by new or remodelled sewage treatment plants. The highest levels were found in bivalves close to the largest city, where punctual and diffuse contamination sources still exist. Bivalves from the less impacted site showed the lowest contamination, an area with more water renewal. Seasonally, the highest levels were in autumn and winter, due to the runoff of waters from rainfall. These were opposite to those in spring and summer, when the highest temperatures and salinity showed a bactericidal effect. PMID- 22197557 TI - FAS/FAS-L dependent killing of activated human monocytes and macrophages by CD4+CD25- responder T cells, but not CD4+CD25+ regulatory T cells. AB - Conclusive resolution of an immune response is critical for the prevention of autoimmunity and chronic inflammation. We report that following co-culture with autologous CD4+CD25- responder T cells, human CD14+ monocytes and monocyte derived macrophages become activated but also significantly more prone to apoptosis than monocytes/macrophages cultured alone. In contrast, in the presence of CD4+CD25+ regulatory T cells (Tregs), monocytes and macrophages survive whilst adopting an anti-inflammatory phenotype. The induction of monocyte death requires responder T cell activation and cell-contact between responder T cells and monocytes. We demonstrate a critical role for FAS/FAS-L ligation in responder T cell-induced monocyte killing since responder T cells, but not Tregs, upregulate FAS-ligand (FAS-L) mRNA, and induce FAS expression on monocytes. Furthermore, responder T cell-induced monocyte apoptosis is blocked by neutralising FAS/FAS-L interaction, and is not observed when monocytes from an autoimmune lymphoproliferative syndrome (ALPS) patient with complete FAS-deficiency are used as target cells. Finally, we show that responder T cell-induced killing of monocytes is impaired in patients with active rheumatoid arthritis (RA). Our data suggest that resolution of inflammation in the course of a healthy immune response is aided by the unperturbed killing of monocytes with inflammatory potential by responder T cells and the induction of longer-lived, Treg-induced, anti-inflammatory monocytes. PMID- 22197558 TI - Feasibility of fly ash-based composite coagulant for coal washing wastewater treatment. AB - In this study, several fly ash (FA)-based composite coagulants, leached by hydrochloric acid, were prepared to treat coal washing wastewater. The concentrations of Al(3+) and Fe(2+)/Fe(3+) in the leachates and coagulants were analyzed, and optimal experimental conditions, including coagulant dosage and initial pH, were determined using various analytical techniques (scanning electron microscopy, energy dispersive spectrometry, X-ray diffraction (XRD), X ray fluorescence (XRF), particle-size analysis, zeta potential, pH and conductivity measurements). A suspended solids (SS) and chemical oxygen demand (COD) removal efficiency from the effluent treated by one of the coagulants reached 99.61% and 96.48%, respectively, at dosages of 10 g l(-1) (initial pH of 9, adjusted by CaO). This indicates that the coagulant was an effective agent for coal washing wastewater treatment, and that the leached Al(3+) and Fe(3+) and introduced Ca(2+) may have improved the coagulation process. Analysis of the dry sludge composition and slurry particle size distribution of the coal washing wastewater showed that charged colloidal particles and the fine particle distribution in the coal washing wastewater make the wastewater treatment a difficult process. Results from this study could provide a novel approach for the treatment of coal washing wastewater and coal fly ash utilization. PMID- 22197559 TI - Sorption of aromatic hydrocarbons onto montmorillonite as affected by norfloxacin. AB - Effect of norfloxacin (Nor) on the sorption of 1,3-dinitrobenzene (1,3-DNB), and PAHs (naphthalene (NAPH), phenanthrene (PHEN) and pyrene (PYR)) to K(+) montmorillonite was studied. Nor suppressed 1,3-DNB sorption due to their competition for the same sorption sites. 1,3-DNB was sorbed on K(+) montmorillonite surface via cation-polar interaction and n-pi electron donor acceptor interaction. Nor also was sorbed on these sites through cation exchange, cation bridging and/or surface complexation. Nor increased three PAHs sorption on montmorillonite and the enhanced magnitude was positively correlated with the pi donor strength of three PAHs. The enhanced sorption of PAHs by Nor was primarily attributed to pi-pi interaction between pi-electron-depleted quinoline ring of Nor and pi-electron-rich PAHs. Compared with cation (Nor(+)) and anion (Nor(-)), zwitterion (Nor(+/-)) of Nor increased PHEN and PYR sorption more pronounced due to additional cation-pi interaction between the sorbed Nor(+/-) and PAHs. (1)H NMR spectrum provided direct evidence for pi-pi and cation-pi complexation between PAHs and Nor(+) in solution by ring-current-induced upfield chemical shifts of amino group and methylene group of Nor(+). PMID- 22197560 TI - Toxicity of sediment-associated unresolved complex mixture and its impact on bioavailability of polycyclic aromatic hydrocarbons. AB - Unresolved complex mixtures (UCMs) and polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in sediment originating from oil leaks, shipping, and other human activities and thus it is necessary to understand the role of UCM on sediment toxicity and PAH bioaccumulation. In the current study, lethal and sublethal effects of sediment-associated UCM were examined in two benthic invertebrates (Chironomus dilutus and Lumbriculus variegatus) using two spiked sediments. Results showed that UCM alone was toxic to the organisms and its toxicity was species-dependent. Approximately 1% of UCM in sediment caused 50% mortality in C. dilutus, which indicated UCM at environmentally relevant concentrations can directly cause sub-lethal and lethal effects to benthic invertebrates. Moreover, bioaccumulation testing of sediment-associated PAHs to L. variegatus showed that the addition of UCM to sediment at low concentration (0.01%) increased PAH bioavailability. These findings were further confirmed by assessing bioavailability using Tenax extraction. In contrast, high concentrations of UCM in sediment (0.5%) may have formed non-aqueous phase liquids, which served as an alternative sorption phase for PAHs and reduced PAH bioavailability. Understanding the role of UCM in the overall oil toxicity and its impact on other contaminants would improve risk assessment of sediments impacted by petroleum products in the future. PMID- 22197561 TI - Preparation and characterization of La(III) encapsulated silica gel/chitosan composite and its metal uptake studies. AB - Lanthanum loaded silica gel/chitosan composite (LaSiCS) was prepared by mixing silica gel, LaCl(3) . 7H(2)O and chitosan which was then cross-linked with glutaraldhyde. The LaSiCS composite was characterized using FT-IR, SEM-EDAX, XRD and BET. The adsorption of chromium(VI) ions onto LaSiCS composite has been investigated. The LaSiCS composite was found to have excellent chromium adsorption capacity than the silica gel/chitosan composite (SiCS), silica gel (Si) and chitosan (CS). The sorption experiments were carried out in batch mode to optimize various parameters viz., contact time, pH, initial chromium ion concentration, co-ions and temperature that influence the sorption. Langmuir and Freundlich adsorption models were applied to describe isotherm constants. Equilibrium data agreed very well with the Langmuir model. Thermodynamic studies revealed that the nature of chromium sorption was spontaneous and endothermic. The LaSiCS composite removes chromium by electrostatic adsorption coupled reduction/ion-exchange. PMID- 22197562 TI - Electrodialytic remediation of suspended soil--Comparison of two different soil fractions. AB - Electrodialytic remediation (EDR) can be used for removal of heavy metals from suspended soil, which allows for the soil remediation to be a continuous process. The present paper focused on the processing parameters for remediation of a soil polluted with Cu and As from wood preservation. Six electrodialytic treatments lasting from 5 to 22 days with different liquid to solid ratio (L/S) and current intensity were conducted. Among treatments, the highest removal was obtained from the soil fines with 5 mA current at L/S 3.5 after 22 days where 96% of Cu and 64% of As were removed. Comparing the removal from the original soil and the soil fines in experiments with identical charge transportation, higher removal efficiency was observed from the soil fines. Constant current with 5 mA could be maintained at L/S 3.5 for the soil fines while not for the original soil. Doubling current to 10 mA could not be maintained for the soil fines either, and doubling L/S to 7 at 5 mA entailed a very fast acidification which impeded the removal. The results showed that a very delicate balancing of current density and L/S must be maintained to obtain the most efficient removal. PMID- 22197563 TI - Prediction of Cd and Pb toxicity to Vibrio fischeri using biotic ligand-based models in soil. AB - Biotic ligand-based models to predict site-specific toxicity of Cd and Pb contaminated soil were developed by using a Vibrio fischeri toxicity test. Firstly, competition effect by cations (i.e., Ca, Mg, K) commonly found in soil solution was incorporated into the models. For this purpose, biotic ligand-based model parameters including conditional binding constants of cations and metal ions to binding sites (i.e., biotic ligands) and the fractions of binding sites occupied by the metal ions were determined. Data from aqueous phase toxicity test showed that the difference between model-predicted EC(50) values of Cd and Pb and experimentally determined EC(50) values ranged within a factor of two, suggesting that the developed model parameters were reliable. Secondly, the use of soil solution to predict soil toxicity of Cd and Pb was experimentally verified with freshly spiked and field-aged soils. The results showed linear relationships in both soils, meaning that toxicity of soil solution can be representative of toxicity of soil. Finally, applicability of the developed models in Cd- or Pb spiked soils was investigated by comparing predicted toxic effects (i.e., % bioluminescence inhibition at given cations and metal activities in soil solution) and experimentally obtained toxic effects determined by Microtox((r)) solid phase toxicity test. Our data demonstrate that toxicity of Cd- or Pb contaminated soil can be predicted by using the developed biotic ligand-based model with the chemical analysis data of soil solution as input data. PMID- 22197564 TI - The regeneration of waste foundry sand and residue stabilization using coal refuse. AB - The processes for recycling waste foundry sand are divided between regeneration and beneficial reuse, and the potential for regeneration is higher than that of reuse. In this study, two processes for the recycling and residue stabilization of waste foundry sands were considered. One is the dry mechanical process for recycling, and the other is the stabilization process for powdered residue. The dry mechanical process of regeneration consists of crushing, grinding, separation, and classification. To stabilize the residues that were generated through the regeneration process, powdered residues were pelletized by a high shear pelletizer, and the surfaces of the pellets were subsequently coated with coal refuse powders that contained sodium silicate as a binder. Coated pellets were sintered by a self-propagating combustion method. The refractory index of the recycled sands, as measured by the Seger cone method, was over -34, and their SiO(2) contents of 94% was similar to that of green sand. The general conclusion that coal refuse and sodium silicate stabilize heavy metals better than other processes may lead to the development of a cost-effective solution for stabilizing heavy metals in residues. PMID- 22197565 TI - Structural analysis of effector functions related motifs, complement activation and hemagglutinating activities in Lama glama heavy chain antibodies. AB - Heavy chain antibodies (HCAbs), devoid of the light chains and the CH(1) domain, are present in the serum of camelids. IgG(2) and IgG(3) are HCAbs; whereas IgG(1) has the conventional structure. In order to study the immunological properties of llama HCAbs, from which to date little is known, llamas (Lama glama) HCAbs cDNA were cloned, sequenced and compared with other mammalian Igs. The sequence analysis showed that llama HCAbs cDNA organization is similar to other mammalian Igs and the presence of conserved binding motifs to Protein A, Protein G, FcgammaRI, FcgammaRIII and C1q in HCAbs were observed. In a previous work, different IgG isotypes purified by Protein A and Protein G chromatography, were assayed for their ability to fix complement. Both IgG(1) and the total serum were able to fix complement, whereas IgG(2) and IgG(3) fixed complement even in the absence of antigen (anti-complementary activity). Therefore, in this work we performed the complement activating activity of the different IgG isotypes purified under physiological conditions using Sephadex G-150 and their ability to induce hemagglutination. Llamas were immunized with sheep red blood cells (RBC) stroma and the different isotypes were purified from sera. Whole serum and IgG(1) could activate complement; however, HCAbs (IgG(2)+IgG(3)) could not, despite the presence of the C1q binding motif in their primary sequence. Unlike IgG(1), the fraction corresponding to IgG(2)+IgG(3) did not display hemagglutinating activity. Our findings suggest that HCAbs cannot crosslink efficiently with different antigens and that the C1q binding site might be hindered by the proximity of the variable domains. PMID- 22197566 TI - A case of malignant migrating partial seizures in infancy as a continuum of infantile epileptic encephalopathy. AB - The syndrome of malignant migrating partial seizures in infancy (MMPSI) is characterized by onset before the age of 6 months, nearly continuous electrographic seizures involving multiple independent areas of onset in both hemispheres, and poor developmental outcome. This report presents a case involving a patient with MMPSI, who later developed West syndrome. At the age of 2 months old, he showed multifocal partial seizures, which were refractory to antiepileptic drugs. His electroencephalogram (EEG) revealed characteristic migrating multifocal epileptiform activities and neuroimaging finding was normal. The focal seizures were refractory to antiepileptic drugs and ketogenic diet. When he was 9 months old, epilepic spasms were observed with hypsarrhythmia on EEG. He also showed severe developmental delay. MMPSI may be a continuum of infantile epileptic encephalpathy and could evolve to West syndrome. PMID- 22197567 TI - Ambiguous cardiac troponin recommendations. PMID- 22197568 TI - Switchable adhesive substrates: revealing geometry dependence in collective cell behavior. AB - Collective cell migration plays a major role in cancer metastasis and wound healing, therefore, several in vitro assays for studying such behavior have been developed. Using photoswitchable surfaces, we studied collective cell expansion behavior from initially precisely controlled adhesive patterns. A non-adhesive poly(ethylene glycol) (PEG) layer is conjugated to a glass coverslip via 2 nitrobenzyl groups, which cleave upon exposure to UV light, changing the surface from non-cell-adhesive to cell-adhesive without mechanical interference. Initial cell attaching areas are generated in arbitrary shapes via projection exposure through a photomask. After a growth phase, epithelial cell sheets are released from their confinement by a second illumination allowing for collective cell expansion. Our experiments with epithelial cells show that cluster size and boundary curvature modulate the expansion of the cell sheet and the formation of leader cells. At a certain cluster size, characteristics of the expansion behavior change and cells in the core are hardly affected by the boundary release. With donut-like ring structures, we demonstrate a break in symmetry between the behavior of cells along the outer convex boundary and along the inner concave boundary. Additionally, we observe that collective migration characteristics are modulated by the initial incubation time of the cell sheet. PMID- 22197569 TI - The efficiency of tumor-specific pH-responsive peptide-modified polymeric micelles containing paclitaxel. AB - The acidic pH in tumor tissues could be used for targeting solid tumors. In the present study, we designed a tumor-specific pH-responsive peptide H(7)K(R(2))(2), which could respond to the acidic pH in tumor tissues, and prepared H(7)K(R(2))(2)-modified polymeric micelles containing paclitaxel (PTX-PM H(7)K(R(2))(2)) in order to evaluate their potential targeting of tumor cells and tumor endothelial cells and their anti-tumor activity in mice with tumor cells. PTX-PM-H(7)K(R(2))(2) was prepared by a thin-film hydration method. The in vitro release of PTX from PTX-PM-H(7)K(R(2))(2) was tested. The in vitro targeting characteristics of H(7)K(R(2))(2)-modified polymeric micelles on HUVEC (human umbilical vein endothelial cells) and MCF-7 (human breast adenocarcinoma cells) were evaluated. The in vivo targeting activity of H(7)K(R(2))(2)-modified polymeric micelles and the in vivo anti-tumor activity of PTX-PM-H(7)K(R(2))(2) were also investigated in MCF-7 tumor-bearing mice. The released PTX from the PTX PM-H(7)K(R(2))(2) was not affected by the pH. The targeting activity of the H(7)K(R(2))(2)-modified polymeric micelles was demonstrated by in vitro flow cytometry and confocal microscopy as well as in vivo biodistribution. PTX-PM H(7)K(R(2))(2) produced very marked anti-tumor and anti-angiogenic activity in MCF-7 tumor-bearing mice in vivo. PMID- 22197571 TI - Statistical learning effects in musicians and non-musicians: an MEG study. AB - This study aimed to assess the effect of musical training in statistical learning of tone sequences using Magnetoencephalography (MEG). Specifically, MEG recordings were used to investigate the neural and functional correlates of the pre-attentive ability for detection of deviance, from a statistically learned tone sequence. The effect of long-term musical training in this ability is investigated by means of comparison of MMN in musicians to non-musicians. Both groups (musicians and non-musicians) showed a mismatch negativity (MMN) response to the deviants and this response did not differ amongst them neither in amplitude nor in latency. Another interesting finding of this study is that both groups revealed a significant difference between the standards and the deviants in the response of P50 and this difference was significantly larger in the group of musicians. The increase of this difference in the group of musicians underlies that intensive, specialized and long term exercise can enhance the ability of the auditory cortex to discriminate new auditory events from previously learned ones according to transitional probabilities. A behavioral discrimination task between the standard and the deviant sequences followed the MEG measurement. The behavioral results indicated that the detection of deviance was not explicitly learned by either group, probably due to the lack of attentional resources. These findings provide valuable insights on the functional architecture of statistical learning. PMID- 22197570 TI - Mechanical derivation of functional myotubes from adipose-derived stem cells. AB - Though reduced serum or myoblast co-culture alone can differentiate adipose derived stem cells (ASCs) into mesenchymal lineages, efficiency is usually not sufficient to restore function in vivo. Often when injected into fibrotic muscle, their differentiation may be misdirected by the now stiffened tissue. Here ASCs are shown to not just simply reflect the qualitative stiffness sensitivity of bone marrow-derived stem cells (BMSCs) but to exceed BMSC myogenic capacity, expressing the appropriate temporal sequence of muscle transcriptional regulators on muscle-mimicking extracellular matrix in a tension and focal adhesion dependent manner. ASCs formed multi-nucleated myotubes with a continuous cytoskeleton that was not due to misdirected cell division; microtubule depolymerization severed myotubes, but after washout, ASCs refused at a rate similar to pre-treated values. BMSCs never underwent stiffness-mediated fusion. ASC-derived myotubes, when replated onto non-permissive stiff matrix, maintained their fused state. Together these data imply enhanced mechanosensitivity for ASCs, making them a better therapeutic cell source for fibrotic muscle. PMID- 22197572 TI - Unconscious processing of emotions and the right hemisphere. AB - This survey takes into account the unconscious aspects of emotions and the critical role played in them by the right hemisphere, considering different acceptations of the term 'unconscious'. In a preliminary step, the nature of emotions, their componential and hierarchical organization and the relationships between emotions and hemispheric specialization are shortly discussed, then different aspects of emotions are surveyed: first are reviewed studies dealing with the unconscious processing of emotional information, taking separately into account various lines of research. All these studies suggest that unconscious processing of emotional information is mainly subsumed by a right hemisphere subcortical route, through which emotional stimuli quickly reach the amygdala. We afterwards inquire if a right hemisphere dominance can also be observed in automatic emotional action schemata and if 'non-removed preverbal implicit memories' also have a preferential link with the right hemisphere. Finally, we try to evaluate if the right hemisphere may also play a critical role in dynamic unconscious phenomena, such as anosognosia/denial of hemiplegia in patients with unilateral brain lesions. In the last part of the review, the reasons that could subsume the right hemisphere dominance for unconscious emotions are shortly discussed. PMID- 22197573 TI - Peri-implantitis. AB - The number of osseointegrated dental implants is increasing. Healthy peri-implant soft and hard tissues are required for the stability and survival of dental implants. In this paper we review factors that lead to peri-implant mucositis and peri-implantitis, and review treatment. PMID- 22197574 TI - Associations between diet quality, health status and diabetic complications in patients with type 2 diabetes and comorbid obesity. AB - OBJECTIVE: Patients with type 2 diabetes (T2DM) demonstrate low dietary adherence and this is further aggravated with comorbid obesity. The aim of the present study was to assess diet quality in patients with T2DM and comorbid obesity compared to patients with T2DM alone and to examine the associations between comorbidities and diet quality. METHODS: The sample consisted of 59 adult patients with diabesity (T2DM and comorbid obesity) and 94 patients with T2DM alone. All diabetes comorbidities and complications were recorded and diet quality was assessed with the Healthy Eating Index (HEI). RESULTS: Mean raw HEI of the diabese subjects was 81.9+/-7.1 and the diabetic subjects was 80.2+/-6.9. When HEI was adjusted to the sex, age and weight status, the diabese demonstrated a higher HEI. Among comorbidities, only renal disease decreased HEI. According to the principal component analysis of the total sample, adequate diet quality was explained by cardiovascular disease, cigarette smoking, alcohol consumption, peptic ulcer, sex, diabesity and diabetic foot syndrome. In the diabese, adequate HEI was explained by diabetic foot syndrome, smoking, drinking alcohol and having a family history of diabetes. CONCLUSIONS: Adult patients with T2DM demonstrate adequate diet quality. Different factors are associated with the adoption of a high quality diet between the diabese and the T2DM alone. PMID- 22197576 TI - Have we underestimated the efficacy of pulmonary rehabilitation in improving mood? AB - BACKGROUND: Patients with COPD have a high prevalence of anxiety and depression. The efficacy of pulmonary rehabilitation (PR) in treating more severe anxiety and depression is unknown. The study aimed to explore the effectiveness of PR in reducing symptoms of anxiety and depression across a spectrum of severities. METHODS: The study used principles of comparative effectiveness research. Data was analysed from 518 patients with COPD [57.5% male, mean (SD) age 69.2 years (+/- 8.8 years)]. Patients were categorised into 3 groups based on their hospital anxiety and depression scale (HADS) scores pre PR ('none' 0-7, 'probable' 8-10 and 'presence' 11-21). A responder was defined as achieving a change of >= 48 m on the incremental shuttle walk test (ISWT). Patients were categorised as 'completers' if they attended their discharge assessment for PR. RESULTS: Anxiety and depression did not reduce following PR in patients with no symptoms (p > 0.05). Patients with a 'probable' or 'presence' of symptoms had significant reductions (both p < 0.001). There was a difference between sub-groups in change for anxiety and depression with patients scoring highest on the HADS having the greatest reductions (p < 0.001). There was no correlation between anxiety or depression and completion of PR (p > 0.05). Responders and non-responders did not differ in their anxiety or depression levels (p > 0.05). CONCLUSION: PR is effective in reducing symptoms of anxiety and depression. Previous studies may have underestimated the effectiveness of the PR programme in improving mood. PMID- 22197575 TI - Characterizing and predicting the functional and conformational diversity of seven-transmembrane proteins. AB - The activation of seven-transmembrane receptors (7TMRs) allows cells to sense their environment and convert extracellular signals (like hormone binding) into intracellular signals (through G protein-coupled and/or beta arrestin-coupled pathways). A single 7TMR is capable of transducing a wide spectrum of physiological responses inside a cell by coupling to these pathways. This intracellular pleiotropic action is enabled by multiple conformations exhibited by these receptors. Developments in membrane protein structure determination technologies have led to a rapid increase in crystal structures for many 7TMRs. Majority of these receptors have been crystallized in their inactive conformation and, for some, one of the many active conformations has also been crystallized. Given the topological constraints of a lipid bilayer that results in a single fold of seven almost parallel TM helices connected by mostly unstructured loops, these structures exhibit a diversity of conformations not only across the receptors but also across the different functional forms for receptors with structures for one of the functionally active conformations. Here we present a method to characterize this conformational diversity in terms of transmembrane helix topology (TMHTOP) parameters and how to use these helix orientation parameters to predict functionally-distinct multiple conformations for these receptors. The TMHTOP parameters enable a quantification of the structural changes that underlie 7TMR activation and also sheds a unique mechanistic light on the pleiotropic nature of these receptors. It provides a common language to describe the 7TMR activation mechanisms as well as differences across many receptors in terms of visually intuitive structural parameters. Protein structure prediction methods can use these parameters to describe 7TMR conformational ensembles, which coupled to experimental data can be used to develop testable hypotheses for the structural basis of 7TMR functions. PMID- 22197577 TI - Chronic bronchitis in the general population: influence of age, gender and socio economic conditions. AB - Chronic bronchitis (CB) is an indicator of an increased risk of developing COPD, but its symptoms are often underestimated. Demographic and socio-economic conditions might influence its prevalence, reporting and impact. Data from a large epidemiological survey of the French general population were analyzed to determine the burden of CB, the magnitude of under-diagnosis and the influence of age, gender and socio-economic conditions. Altogether, 9050 participants aged 45 years or more provided complete data. The prevalence of symptoms and diagnosis of CB was 3.5% and 3.4%, respectively. CB was associated with impaired health status and activity and, in women, work loss. Among subjects with symptoms of CB, only 28.6% declared a known diagnosis of respiratory disease. Factors associated with symptoms of CB in multivariate analysis were male gender, active smoking, lower income and occupational category: the highest prevalence was observed in manual workers (5.6%) and self-employed subjects (5.2%). The under-diagnosis of CB was more marked in men and subjects of higher socio-economic categories. These results confirm that CB is markedly under-diagnosed in the general population. Socio-economic conditions influence both its prevalence (higher in low categories) and rate of diagnosis (lower in high categories), which should be considered when elaborating prevention and detection campaigns. PMID- 22197578 TI - AZD9668, a neutrophil elastase inhibitor, plus ongoing budesonide/formoterol in patients with COPD. AB - BACKGROUND: Neutrophil elastase (NE) is implicated in chronic obstructive pulmonary disease (COPD). AZD9668 is a reversible and selective inhibitor of NE, well tolerated at doses of 60 mg bid during Phase I/IIa development. METHODS: This 12-week, randomised, double-blind, placebo-controlled, Phase IIb, trial (NCT01023516), investigated the efficacy and safety of AZD9668 (60 mg bid) versus placebo in patients with symptomatic COPD and a history of exacerbation receiving maintenance budesonide/formoterol. Primary outcome variable: forced expiratory volume in one second (FEV1). Secondary endpoints included: post-bronchodilator FEV1, pre- and post-bronchodilator forced vital capacity, FEV6, forced expiratory flow between 25% and 75% of vital capacity and inspiratory capacity; peak expiratory flow and FEV1 measured at home; EXAcerbations of Chronic pulmonary disease Tool and Breathlessness, Cough and Sputum Scores; St George's respiratory questionnaire for COPD (SGRQ-C) scores; exacerbations; and safety assessments. RESULTS: Six hundred and fifteen patients were randomised: placebo (302), AZD9668 60 mg bid (313). AZD9668 showed no effect on lung function: change in mean pre bronchodilator FEV1 versus placebo was 0.01L (95% confidence interval: -0.03, 0.05; p=0.533). AZD9668 did not significantly improve respiratory signs and symptoms, SGRQ-C score or time to first exacerbation. Adverse events were similar for AZD9668 and placebo. CONCLUSIONS: Three months' treatment with AZD9668 did not improve lung function, respiratory signs and symptoms or SGRQ-C score when added to budesonide/formoterol maintenance therapy in patients with COPD. In the absence of definitive biomarkers of short-term disease progression, further research is needed to determine the optimal duration of studies to evaluate NE inhibitors as disease-modifying agents. PMID- 22197579 TI - The concept of vaccination failure. AB - Despite remarkable success of immunization programmes on a global perspective, vaccines are neither 100% efficacious nor 100% effective. Therefore, vaccination failure, i.e. occurrence of a specific disease in an individual despite previous vaccination, may occur. Vaccination failure may be due to actual vaccine failure or failure to vaccinate appropriately. Universally accepted concepts and definitions of vaccination failure are required to assess and compare the benefit of vaccines used in populations. Here we propose general definitions for types of vaccination failure. In the future, these should be complemented by specific definitions for specific vaccines as needed depending on public health considerations. PMID- 22197580 TI - Are immunosuppressive medications associated with decreased responses to routine immunizations? A systematic review. AB - BACKGROUND: Long-term immunosuppressive medications are being used more commonly for a variety of medical conditions, including immune-mediated diseases and organ transplantation. While these medications are often necessary, they are associated with an increased risk of serious infections. Vaccination may be a way to prevent a variety of infections but vaccine responses among patients receiving immunosuppressive therapies have been variable. PURPOSE: To systematically review the literature describing immune responses among patients on immunosuppressive therapies to vaccinations including influenza, pneumococcal, meningococcal, hepatitis A and B, tetanus toxoid, pertussis, varicella, and zoster. DATA SOURCES: English language citations in the MEDLINE and EMBASE databases from 1985 to 2010. STUDY SELECTION: Two reviewers independently screened titles and abstracts to identify prospective, controlled studies reporting pre- and post vaccination titers of recommended vaccines in patients receiving long-term immunosuppressive therapies for full-text review. DATA EXTRACTION: Three reviewers independently assessed study characteristics including treatment regimens and pre- and post-vaccination titers. DATA SYNTHESIS: Of the 972 identified titles, fifteen met inclusion criteria. Ten studies assessed the effects of immunosuppressive medications on responses to influenza vaccine, four studies investigated responses following pneumococcal vaccination, and one study assessed both influenza and pneumococcal vaccination. Five of the studies that evaluated influenza vaccination showed partially diminished responses among individuals receiving immunosuppressive therapies, while one of the pneumococcal vaccine studies showed significantly decreased responses following vaccination. Patients treated with more than one immunosuppressive medication were the least likely to respond to vaccination. LIMITATIONS: The heterogeneity of reported outcomes limits generalizeability. CONCLUSIONS: Immunosuppressive therapy, particularly combination regimens, may blunt response to influenza and pneumococcal vaccinations. To ensure the best chance of response, immunizations should be administered prior to initiation of immunosuppressive medications whenever possible. PMID- 22197581 TI - Evidence-based decision making for vaccines: the need for an ethical foundation. AB - Evidence-based decision making (EBDM) is a tool to assess the value of medical interventions by weighing costs and health outcomes that has increasingly been applied to vaccines. However, many of the ethical considerations that support EBDM when used to evaluate therapeutic care do not readily translate to prevention. This mismatch can result in policy decisions that produce unanticipated negative consequences, including public resistance. In its emphasis on quantifiable outcomes, EBDM invokes the ethical principle of rule utilitarianism, which values the optimal long-run balance of benefit over harm. Vaccines raise a number of competing ethical concerns in ways that individual medical treatments do not. They rely on widespread compliance for effectiveness, which can limit individual autonomy, emphasize population over individual effects, which can obscure the imperative of beneficence to help the vulnerable, require a just allocation process within populations, and sometimes challenge strong social norms. For EBDM to effectively guide vaccine policy makers, such as the Advisory Committee on Immunization Practices (ACIP) in the United States, an ethical foundation is needed that systematically considers all relevant values and transparently places vaccination recommendations in the context of social norms and individual concerns. PMID- 22197582 TI - How diverse was the leisure time physical activity of older Australians over the past decade? AB - OBJECTIVES: Public health recommendations for older adults highlight the need to engage in a combination of aerobic, muscle strength, flexibility and balance activities. This study characterised leisure time physical activity in older Australians (>= 65 years), examining the diversity in reported activities DESIGN: Cross-sectional monitoring. METHODS: The Exercise Recreation and Sport Surveys (2001-2009) were combined and analysed for 22,050 elderly. RESULTS: Walking was reported by 45.6%, of those 53% engaged exclusively in walking. Prevalent sports (i.e., >1%) were bowls (9.4%), aerobics/callisthenics exercise (9.1%), golf (7.7%), swimming (6.4%), gym work (5.2%), cycling (3.2%), tennis (2.9%), dancing (2.1%), fishing (2.0%), tai chi (1.4%), weight lifting (1.2%) and yoga (1.1%). Significant gender differences were apparent. Over time, significant increases were reported in walking, aerobic/callisthenics and gym workout in both genders. In the previous year, 32.0% of older adults participated in "nil" activity, 40.6% engaged in one activity, 19.5% and 8.0% participated in two or three or more activities, respectively. Common combinations were walking with another aerobic activity. Only 2.6% reported a combination of aerobic, balance and strength activities. Multiple-activity participation increased over the years, but declined with increasing age, education and for the most disadvantaged, compared to single-activity participation. Partially or exclusively organised participation, combined, was reported by 42.5% of older adults. Women were more likely to combine mode of participation. Geographic region was associated with multiple-activity participation and organised-only participation. CONCLUSIONS: Most elderly people engage in one activity, if at all. An increase in participation in balance enhancing activities and weight training is warranted to maximize health benefits. PMID- 22197584 TI - Proximal tubule overexpression of a locally acting IGF isoform, Igf-1Ea, increases inflammation after ischemic injury. AB - OBJECTIVE: IGF-1 is an important regulator of postnatal growth in mammals. In mice, a non-circulating, locally acting isoform of IGF-1, IGF-1Ea, has been documented as a central regulator of muscle regeneration and has been shown to improve repair in the heart and skin. In this study, we examine whether local production of IGF1-Ea protein improves tubular repair after renal ischemia reperfusion injury. DESIGN: Transgenic mice in which the proximal-tubule specific promoter Sglt2 was driving the expression of an Igf-1Ea transgene. These animals were treated with an ischemic-reperfusion injury and the response at 24h and 5days compared with wildtype littermates. RESULTS: Transgenic mice demonstrated rapid and enhanced renal injury in comparison to wild type mice. Five days after injury the wild type and low expressing Igf-1Ea transgenic mice showed significant tubular recovery, while high expressing Igf-1Ea transgenic mice displayed significant tubular damage. This marked injury was accompanied by a two fold increase in the number of F4/80 positive macrophages and a three-fold increase in the number of Gr1-positive neutrophils in the kidney. At the molecular level, Igf-1Ea expression resulted in significant up-regulation of proinflammatory cytokines such as TNF-alpha and Ccl2. Expression of Nfatc1 was also delayed, suggesting reduced tubular proliferation after kidney injury. CONCLUSIONS: These data indicate that, unlike the muscle, heart and skin, elevated levels of IGF-1Ea in the proximal tubules exacerbates ischemia reperfusion injury resulting in increased recruitment of macrophages and neutrophils and delays repair in a renal setting. PMID- 22197583 TI - Newborn with an absent red reflex. PMID- 22197585 TI - [Iatrogenic false aneurysm of the splenic artery after cephalic duodenopancreatectomy]. AB - Splenic artery aneurysms are rare entities with many causes. Rupture can be fatal and usually occurs when the aneurismal diameter is greater than 2 cm. Nevertheless, smaller aneurysms, especially false aneurysms, can also rupture. We report a case of iatrogenic, false aneurysm of the splenic artery subsequent to percutaneous drainage of a retrogastric collection after cephalic duodenopancreatectomy. Splenectomy enabled favorable recovery. PMID- 22197586 TI - [Vascular involvement in Cogan's syndrome. A case report]. AB - Vascular manifestations of Cogan's syndrome are rarely reported. We report the case of a young woman followed for typical Cogan's disease. Serious vascular involvement was found only during work-up for arterial hypertension. This case highlights potentially asymptomatic nature of extensive vasculitis affecting large and medium-sized vessels in Cogan's disease. Careful screening is required to prevent life-threatening complications. PMID- 22197587 TI - Interleukin-17A increases leptin production in human bone marrow mesenchymal stem cells. AB - Lineage commitment of human bone marrow mesenchymal stem cells (hBM-MSCs) to adipocytes or osteoblasts has been suggested as a model system to study the relationship between type II diabetes and abnormal bone metabolism. Leptin and IL 17A inhibit adipogenesis whereas they promote osteogenesis in MSCs. Due to pathophysiologic roles of IL-17A in human metabolic diseases and bone metabolism, it was evaluated whether IL-17A-dependent inverse regulation on adipogenesis and osteogenesis was related to endogenous leptin production in hBM-MSCs. In the analysis of adiponectin and leptin secretion profiles of hBM-MSCs in response to various combinations of differentiation inducing factors, it was found that dexamethasone, a common molecule used for both adipogenesis and osteogenesis, increased leptin production in hBM-MSCs. Importantly, the level of leptin production during osteogenesis in hBM-MSCs was higher than that during adipogenesis, implicating a significant leptin production in extra-adipose tissues. IL-17A increased leptin production in hBM-MSCs and also under the condition of osteogenesis. In spite of direct inhibition on adipogenesis, IL-17A up-regulated leptin production in hBM-MSC-derived adipocytes. Anti-leptin antibody treatment partially antagonized the IL-17A dependent inhibition of adipogenesis in hBM-MSCs, suggesting a role of leptin in mediating the inverse regulation of IL-17A on osteogenesis and adipogenesis in hBM-MSCs. Therefore, the IL-17A-induced leptin production may provide a key clue to understand a molecular mechanism on the lineage commitment of hBM-MSCs into adipocytes or osteoblasts. In addition, leptin production in extra-adipose tissues like MSCs and osteoblasts should be considered in future studies on leptin-associated human diseases. PMID- 22197588 TI - Urocontrin, a novel UT receptor ligand with a unique pharmacological profile. AB - In recent years, several studies have demonstrated that urotensin II (UII) and urotensin II-related peptide (URP) can exhibit differential biological activity. So far, known antagonists of the urotensin II receptor (UT) are of limited usefulness for investigating the specific pathophysiological role of UII or URP. Therefore, identification of new compounds able to discriminate UII- and URP associated biological activities is crucially needed. In the present study, we report preliminary data regarding the pharmacological properties of a novel UT ligand termed urocontrin, i.e. [Bip(4)]URP, that is able to reduce the ex vivo efficacy of hUII- but not URP-induced vasoconstriction in rat aortic rings. In vivo studies support the pharmacological profile described above. Although urocontrin exert some residual agonist activity, this compound should be useful for the rational design of potent molecules that would allow discriminating specific biological action mediated by UII or URP. PMID- 22197589 TI - Segment choice and cup stability influence wear measurements using radiostereometric analysis: a radiostereometric study comparing wear measured by markers in the polyethylene with markers in the periacetabular bone. AB - BACKGROUND: Radiostereometry is a well documented method to measure the polyethylene wear after total hip replacements. Wear is measured according to the point motion of the head center in relation to the polyethylene as the reference segment. Increasing head sizes and new cup materials may diminish visibility of markers deteriorating the segment and leading to study drop outs. Alternatively markers in the periacetabular bone may be easier to detect rendering this segment more stable. Our aim was to compare wear measurements against the cup, the acetabuluar bone and a calculated wear estimation including cup migration. METHODS: A prospective randomized controlled trial comparing reverse hybrid with cemented total hip replacement was conducted. 31 patients had tantalum markers in the polyethylene and in the periacetabular bone making it possible to measure wear using both as reference segments. We used a uniplanar radiostereometric technique. FINDINGS: Wear in the y-axis was overestimated by 53% when markers in the periacetabular bone were used (P<0.001). Proximal wear was 0.34 mm (95% CI of mean: 0.29-0.38) when using the polyethylene as the reference and 0.52 mm (95% CI of mean: 0.38-0.65) using the acetabular bone. Migration of the cup seemed to influence the wear calculations, overestimating wear when markers in the periacetabular bone were used as the reference segment. INTERPRETATION: Wear measured with periacatebular bone markers is influenced by cup migration, overestimating wear measurements. We therefore recommend not using the acetabular bone as the reference segment. PMID- 22197591 TI - Crystal structure of D-serine dehydratase from Escherichia coli. AB - D-Serine dehydratase from Escherichia coli is a member of the beta-family (fold type II) of the pyridoxal 5'-phosphate-dependent enzymes, catalyzing the conversion of D-serine to pyruvate and ammonia. The crystal structure of monomeric D-serine dehydratase has been solved to 1.97A-resolution for an orthorhombic data set by molecular replacement. In addition, the structure was refined in a monoclinic data set to 1.55A resolution. The structure of DSD reveals a larger pyridoxal 5'-phosphate-binding domain and a smaller domain. The active site of DSD is very similar to those of the other members of the beta family. Lys118 forms the Schiff base to PLP, the cofactor phosphate group is liganded to a tetraglycine cluster Gly279-Gly283, and the 3-hydroxyl group of PLP is liganded to Asn170 and N1 to Thr424, respectively. In the closed conformation the movement of the small domain blocks the entrance to active site of DSD. The domain movement plays an important role in the formation of the substrate recognition site and the catalysis of the enzyme. Modeling of D-serine into the active site of DSD suggests that the hydroxyl group of D-serine is coordinated to the carboxyl group of Asp238. The carboxyl oxygen of D-serine is coordinated to the hydroxyl group of Ser167 and the amide group of Leu171 (O1), whereas the O2 of the carboxyl group of D-serine is hydrogen-bonded to the hydroxyl group of Ser167 and the amide group of Thr168. A catalytic mechanism very similar to that proposed for L-serine dehydratase is discussed. PMID- 22197592 TI - Assessment of silk fibroin for the repair of buccal mucosa in a rat model. AB - This study evaluated the effectiveness of silk fibroin materials for wound repair confined to the buccal mucosa in a rat model by assessing several key clinical parameters and the associated local and systemic immune response. Ninety male SD rats were subjected to microscopic oral surgery to establish a full thickness wound on the buccal mucosa. Rats were randomly divided into three groups based on the treatments received: group A, covered with polyporous silk fibroin scaffold; group B, repaired with crosslinking silk fibroin film; and group C, control. Visual observation of the wounds suggests that wound shrinkage 5 days after the operation was significantly lower in both silk fibroin repaired groups (A and B) than that in the controls. The distribution of inflammatory neutrophils in group A was significantly lower than those in the control group throughout the entire study. The percentage of fibroblasts and capillary endothelia (CD34(+)), and the subgroups of peripheral lymphocytes (CD3(+), CD4(+), CD8(+)) were similar amongst the groups. The results revealed that placement of silk fibroin in an oral buccal defect can reduce the degree of wound shrinkage and enhance the growth of mucosal epithelial cells without any local or systemic immunological incompatibility. PMID- 22197593 TI - A role for inflammatory mediators in the modulation of the neurotrophin receptor p75NTR on human muscle precursor cells. AB - The neurotrophin receptor p75NTR is a marker for human differentiation-prone muscle satellite cells and regulates myogenesis. Here, we wondered whether inflammation could modify p75NTR expression on muscle precursor cells in vitro and in vivo. In vitro experiments on human primary skeletal myoblasts demonstrated that exposure to IFN-gamma or IL-1alpha decreased transcript and protein levels of p75NTR. Furthermore, histological investigations showed a reduction in the pool of p75NTR expressing satellite cells in inflammatory myopathy biopsies. These data suggest a link between muscle inflammation and reduction of p75NTR expression on precursor cells. PMID- 22197590 TI - Mechanistic studies of the radical SAM enzyme spore photoproduct lyase (SPL). AB - Spore photoproduct lyase (SPL) repairs a special thymine dimer 5-thyminyl-5,6 dihydrothymine, which is commonly called spore photoproduct or SP at the bacterial early germination phase. SP is the exclusive DNA photo-damage product in bacterial endospores; its generation and swift repair by SPL are responsible for the spores' extremely high UV resistance. The early in vivo studies suggested that SPL utilizes a direct reversal strategy to repair the SP in the absence of light. The research in the past decade further established SPL as a radical SAM enzyme, which utilizes a tri-cysteine CXXXCXXC motif to harbor a [4Fe-4S] cluster. At the 1+ oxidation state, the cluster provides an electron to the S adenosylmethionine (SAM), which binds to the cluster in a bidentate manner as the fourth and fifth ligands, to reductively cleave the CS bond associated with the sulfonium ion in SAM, generating a reactive 5'-deoxyadenosyl (5'-dA) radical. This 5'-dA radical abstracts the proR hydrogen atom from the C6 carbon of SP to initiate the repair process; the resulting SP radical subsequently fragments to generate a putative thymine methyl radical, which accepts a back-donated H atom to yield the repaired TpT. SAM is suggested to be regenerated at the end of each catalytic cycle; and only a catalytic amount of SAM is needed in the SPL reaction. The H atom source for the back donation step is suggested to be a cysteine residue (C141 in Bacillus subtilis SPL), and the H-atom transfer reaction leaves a thiyl radical behind on the protein. This thiyl radical thus must participate in the SAM regeneration process; however how the thiyl radical abstracts an H atom from the 5'-dA to regenerate SAM is unknown. This paper reviews and discusses the history and the latest progress in the mechanistic elucidation of SPL. Despite some recent breakthroughs, more questions are raised in the mechanistic understanding of this intriguing DNA repair enzyme. This article is part of a Special Issue entitled: Radical SAM enzymes and Radical Enzymology. PMID- 22197594 TI - The association of serum oestradiol level, age, and education with cognitive performance in peri- and late postmenopausal women. AB - OBJECTIVES: To evaluate whether healthy women show cognitive changes after menopause and whether the possible changes are oestrogen-, age- or education dependent. METHODS: Forty-eight women, 21 perimenopausal (aged 43-51 years) and 27 late postmenopausal (aged 59-71 years), participated in the study. Verbal and visuomotor functions, visuoconstructive skills, visual and verbal episodic memory as well as attention were evaluated. RESULTS: Perimenopausal women performed better than postmenopausal women. Serum oestradiol (E(2)) level was included in the model in perimenopausal women only given the lack of endogenous oestrogen in postmenopausal women who were also not using hormone therapy (HT). In perimenopausal women, lower E(2) was associated with better visual episodic memory (p<.05), and older age was related to poorer verbal episodic memory (p<.05). In postmenopausal women, more education was associated with better performance in verbal and visuomotor functions, attention as well as verbal episodic memory (p<.05), older age was related to poorer performance in the visuoconstructive test and visual episodic memory (p<.05). CONCLUSIONS: Perimenopausal women had better cognitive performance compared to late postmenopausal women. In perimenopausal women the effect of E(2) was minor. In both groups, age modified cognitive performance, but more so in postmenopausal women. Education did not have any effect on cognitive performance in perimenopausal women, whereas in postmenopausal women education exceeded age as a source of variation. Thus the relevance of education for better cognition was accentuated after menopause. PMID- 22197596 TI - Combined extraction of acyl carnitines and 26:0 lysophosphatidylcholine from dried blood spots: prospective newborn screening for X-linked adrenoleukodystrophy. AB - X-linked adrenoleukodystrophy (X-ALD) is a severe genetic disorder that affects the nervous system, and the adrenal cortex. Newborn screening for X-ALD has been proposed to allow improved diagnosis along with prospective monitoring and treatment for this severe disorder. Newborn dried whole blood spot (DBS) 26:0 lysophosphatidyl choline was validated as a diagnostic marker for X-ALD and other peroxisomal disorders of peroxisomal beta-oxidation. In this study, we developed a new one step extraction procedure that simultaneously extracts acyl carnitines and the lysophosphatidyl cholines from DBS. Further analysis of these metabolites has been performed by two different high throughput LC-MS/MS methods. The 26:0 lysophosphatidyl choline levels in this study were consistent with previously published values and discriminate between healthy and abnormal profiles. There is a very minor modification to the original acyl carnitine extraction procedure and our data indicates that there is no significant effect on acyl carnitine levels in DBS. Our new method potentially can be complementary to the current newborn screening panel. It successfully combines the existing method for acyl carnitine analysis and 26:0 lysophosphatidyl choline that can be applied for prospective X ALD newborn screening. PMID- 22197595 TI - Isolation of Metarhizium anisopliae carboxypeptidase A with native disulfide bonds from the cytosol of Escherichia coli BL21(DE3). AB - The carboxypeptidase A enzyme from Metarhizium anisopliae (MeCPA) has broader specificity than the mammalian A-type carboxypeptidases, making it a more useful reagent for the removal of short affinity tags and disordered residues from the C termini of recombinant proteins. When secreted from baculovirus-infected insect cells, the yield of pure MeCPA was 0.25mg per liter of conditioned medium. Here, we describe a procedure for the production of MeCPA in the cytosol of Escherichia coli that yields approximately 0.5mg of pure enzyme per liter of cell culture. The bacterial system is much easier to scale up and far less expensive than the insect cell system. The expression strategy entails maintaining the proMeCPA zymogen in a soluble state by fusing it to the C-terminus of maltose-binding protein (MBP) while simultaneously overproducing the protein disulfide isomerase DsbC in the cytosol from a separate plasmid. Unexpectedly, we found that the yield of active and properly oxidized MeCPA was highest when coexpressed with DsbC in BL21(DE3) cells that do not also contain mutations in the trxB and gor genes. Moreover, the formation of active MeCPA was only partially dependent on the disulfide-isomerase activity of DsbC. Intriguingly, we observed that most of the active MeCPA was generated after cell lysis and amylose affinity purification of the MBP-proMeCPA fusion protein, during the time that the partially purified protein was held overnight at 4 degrees C prior to activation with thermolysin. Following removal of the MBP-propeptide by thermolysin digestion, active MeCPA (with a C-terminal polyhistidine tag) was purified to homogeneity by immobilized metal affinity chromatography (IMAC), ion exchange chromatography and gel filtration. PMID- 22197597 TI - [Long-term combined treatment with cinacalcet and bisphosphonates in persistent primary hyperparathyroidism after surgery]. PMID- 22197598 TI - [New trends in the treatment of amyloidosis]. AB - Amyloidosis is a clinical disorder caused by extracellular deposition of proteins that are normally soluble as insoluble fibrils that damage different organs. More than 20 proteins can form amyloid deposits. All types of amyloid fibrils have a secondary structure with a beta folded shape that is characteristic and makes them to adopt a green birefringence after stained with Congo red and viewed under cross-polarized light. Amyloidosis can be acquired or hereditary, systemic or localized, and are classified by the fibril precursor protein. Advances in the knowledge of the pathogenesis of amyloidosis allows the development of new diagnostic and therapeutical schemes that are currently under investigation. PMID- 22197599 TI - [Clinical manifestations of hematological non-neoplastic diseases in Dentistry]. AB - Systemic disease can cause clinical manifestations in the oral and maxillofacial area, which is important to recognize because it could be the first symptom of an undiagnosed illness. There are different oral signs that could suggest the clinician a blood disorder, such as pallor, petechiae, ecchymosis, ulcerations, gingival hypertrophy or spontaneous gingival bleeding. In addition, blood disorders will determine the dental management of these patients and the protocol for limiting possible complications that may arise due to the treatment itself. This paper reviews the oral manifestations and dental management of non neoplastic alterations of red cells, white cells and hemostasis, with emphasis on two-way relationship that must exist between the dentist and the patient's hematologist for making a treatment plan. PMID- 22197600 TI - [Vaccination of patients with paroxysmal nocturnal hemoglobinuria under eculizumab treatment]. PMID- 22197601 TI - [Overweight and obesity among physicians in Spain; results from the ICARIA Study]. PMID- 22197602 TI - Neurotrophins (BDNF and NGF) in follicular fluid of women with different infertility diagnoses. AB - Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are intra ovarian signalling peptides that are important in follicle development and oocyte maturation. In the ovary, neurotrophin expression is regulated by gonadotrophins. Therefore, this study postulates that aetiology of infertility will affect follicular-fluid BDNF and NGF concentrations. Follicular fluid from the first follicle aspirated from 190 infertile women attending a university-affiliated fertility programme (McMaster University and ONE Fertility, Burlington, Ontario) was collected between February 2004 and November 2010. The relationship between follicular-fluid BDNF and NGF concentration and age, day-3 FSH and peak serum oestradiol concentrations and antral follicle count was determined. Participants were aged between 24 and 44 years (mean+/-SEM, 35.2+/-0.3years) of age. The median concentrations of BDNF and NGF in the follicular fluid was 19.4pg/ml and 344.6ng/ml, respectively. The concentrations of BDNF and NGF were significantly related (P=0.028) but only the BDNF concentration was significantly higher (P<0.05) in women with unexplained infertility compared with other causes of infertility. It is concluded that, apart from unexplained infertility, the underlying cause of infertility did not affect ovarian output of BDNF and NGF in response to ovulation induction. PMID- 22197603 TI - Apolipoprotein E-containing HDL-associated platelet-activating factor acetylhydrolase activities and malondialdehyde concentrations in patients with PCOS. AB - PAF and PAF-like oxidized phospholipids hydrolysed by platelet-activating factor (PAF) acetylhydrolase (AH) are potent lipid mediators involved in inflammation and atherosclerosis. Apolipoprotein (apo) E-containing high-density lipoprotein (HDL) has antioxidant, anti-inflammatory and anti-atherogenic properties. The study investigated apoE-containing HDL-associated PAF-AH (HDL-PAF-AH) and total (apoE-containing+apoE-poor) HDL-PAF-AH activities as well as malondialdehyde (MDA) concentration in 291 patients with polycystic ovary syndrome (PCOS) using the Rotterdam consensus criteria and 281 control women. Compared with the control women, patients with hyperandrogenism+oligo/anovulation+polycystic ovaries (PCO) or hyperandrogenism+PCO had lower total, apoE-containing and apoE-poor HDL-PAF-AH activities, while those with oligo/anovulation+PCO showed decreased total and apoE-poor HDL-PAF-AH activities. Other factors including insulin resistance and obesity in PCOS had the adverse effects associated with the HDL-PAF-AH activities. Serum MDA concentration was associated with PCOS, hyperandrogenism, insulin resistance and hypertriglyceridaemia in patients with PCOS. Decreased total and apoE-containing HDL-PAF-AH activities and increased serum MDA concentration may contribute to the pathogenesis of PCOS and potentially link to related complications responsible for oxidative stress and inflammation such as an increased risk for type 2 diabetes mellitus and/or future cardiovascular diseases in PCOS patients. PMID- 22197604 TI - Cryptic sperm defects may be the cause for total fertilization failure in oocyte donor cycles. AB - In conventional IVF cycles with total fertilization failure, rescue intracytoplasmic sperm injection (ICSI) performed 24h after insemination has yielded poor results. However, when ICSI is used, total fertilization failure is a rare event. The aim of the present study is to investigate the degree of sperm contribution to fertilization failures using the egg-sharing model in oocyte donor cycles. The study included only the oocyte donor cycles of sibling oocytes with total fertilization failure in at least one of the matched recipients. Oocytes from 49 oocyte donor cycles were equally shared among 98 recipients undergoing conventional IVF. Due to total fertilization failure in half of the recipients, rescue ICSI was carried out. Compared with the conventional IVF only group, the rescue ICSI group had a lower pregnancy rate (30.61% versus 71.43%), clinical pregnancy rate (28.57% versus 67.35%) and ongoing pregnancy rate (28.57% versus 63.27%) (all P<0.01). Cryptic sperm defects in apparently normal spermatozoa may be the cause of total fertilization failure, indicating the need for simple routine tests to detect them. PMID- 22197605 TI - Microdrop preparation factors influence culture-media osmolality, which can impair mouse embryo preimplantation development. AB - Because media osmolality can impact embryo development, the effect of conditions during microdrop preparation on osmolality was examined. Various sizes of microdrops were prepared under different laboratory conditions. Drops were pipetted directly onto a dish and covered by oil (standard method) or pipetted on the dish, overlaid with oil before removing the underlying media and replaced with fresh media (wash-drop method). Drops were made at 23 degrees C or on a heated stage (37 degrees C) and with or without airflow. Osmolality was assessed at 5 min and 24h. The biological impact of osmolality change was demonstrated by culturing 1-cell mouse embryos in media with varying osmolality. Reduced drop volume, increased temperature and standard method were associated with a significant increase in osmolality at both 5 min and 24h (P-values <0.001, <0.0001 and <0.0001, respectively). There was a significant interaction between airflow, decreased volume, increased temperature and standard method that caused a significant increase in osmolality (40mOsm/kg) compared with controls (P<0.04). There was no significant change in osmolality over time. Mouse embryo development was significantly reduced in media with elevated osmolality (>310mOsm/kg; P<0.05). Procedures in the IVF laboratory can alter osmolality and impact embryo development. PMID- 22197606 TI - Separation of two constituents from purple sweet potato by combination of silica gel column and high-speed counter-current chromatography. AB - It is known that the choice of solvent system for high speed counter-current chromatography separation is of utmost importance. In this study, a simple and rapid thin layer chromatograph coupling with fluorometric (TLC-F) method has been used to determine the partition coefficient of target compounds in HSCCC solvent system. Two components, 6,7-dimethoxycoumarin and 5-hydroxymethyl-2-furfural were successfully separated from purple sweet potato extracts by successive sample injection for the first time, using n-hexane-ethyl acetate-methanol-water (1:2:1:1, v/v/v/v) as the solvent system. Additionally, statistical analysis showed that there was no significant difference in partition coefficient obtained by the TLC-F method and by HPLC, which demonstrated the usefulness of TLC-F method. PMID- 22197607 TI - The role of liquid chromatography-tandem mass spectrometry in the clinical laboratory. AB - Liquid chromatography coupled to mass spectrometry (LC-MS/MS) is increasingly used as a routine methodology in clinical laboratories for the analysis of low molecular weight molecules. The high specificity in combination with high sensitivity and multi-analyte potential makes it an attractive complementary method to traditional methodology used for routine applications. Its strength and weaknesses in this context will be discussed and examples of successful clinical applications will be given. For LC-MS/MS to truly fulfil its promise in clinical diagnosis, the prerequisite steps being sample pre-treatment, chromatographic separation and detection by selected reaction monitoring must become more integrated as they are in conventional clinical analysers. The availability of ready-to-use reagents kits, eliminating efforts needed for method development and extensive validation, are likely to contribute to a wider acceptance of LC-MS/MS in clinical laboratories. Growing applicability of LC-MS/MS in the clinical laboratory field is expected from quantitative protein analysis. PMID- 22197608 TI - Development and validation of a sensitive solid-phase-extraction (SPE) method using high-performance liquid chromatography/tandem mass spectrometry (LC-MS/MS) for determination of risedronate concentrations in human plasma. AB - Risedronate is a commonly prescribed bisphosphonate for the treatment of bone disorders. Due to its high polarity and low oral bioavailability, low concentrations of risedronate are expected in human plasma and therefore a sensitive assay is required to serve in pharmacokinetic studies. Here, we describe the development and validation of an LC-MS/MS assay for the measurement of risedronate concentrations in human plasma. Risedronate and the internal standard, risedronate-d4, were derivatized on an anion exchange solid-phase extraction cartridge. Trimethylsilyl-diazomethane which is a thermally stable and relatively non-toxic derivatization agent was used to methylate the risedronate phosphonic acid groups and decrease analyte polarity. Following extraction, the analytes were separated on a Phenomenex Gemini C18 column (150 mm*2.0 mm, 5 MUm), using a gradient of ammonium acetate 10 mM and acetonitrile with a flow rate of 300 MUL/min. The assay calibration range was 0.2-25 ng/mL. The calibration curve of risedronate standards spiked in six individual plasma samples was linear (r2=0.9998). Accuracy (percent deviation from nominal) and precision (percent coefficient of variation) at concentrations 0.5, 5 and 20 ng/mL, and at the lower limit of quantification (LLOQ) of 0.2 ng/mL were excellent at <6%. Mean recovery was 54% for risedronate and 51% for the internal standard. Risedronate was stable in human plasma samples for at least 5 h at room temperature, 101 days frozen at 80 degrees C, 72 h in an autosampler at 10 degrees C, and for three freeze/thaw cycles. The validated assay method successfully quantified the concentrations of risedronate in plasma samples from informed consenting healthy volunteers administered a single 35 mg risedronate tablet. PMID- 22197609 TI - Salting-out homogeneous liquid-liquid extraction approach applied in sample pre processing for the quantitative determination of entecavir in human plasma by LC MS. AB - A convenient, robust, economical and selective sample preparation method for the quantitative determination of entecavir in human plasma by LC-MS was developed and validated. Entecavir and the internal standard of acyclovir were extracted from 500 MUL of human plasma by a salting-out homogeneous liquid-liquid extraction approach (SHLLE) with acetonitrile as the organic extractant and magnesium sulfate as the salting-out reagent. They were analyzed on a Hanbon(r) Lichrospher RP C18 HPLC column (150 mm*2.0 mm; 5 MUm) with gradient elution. The mobile phase comprised 0.1% acetic acid-0.2 mmol ammonium acetate in water (mobile phase A) and acetonitrile (mobile phase B). The flow rate is 0.2 mL/min. The analytes were detected by a LC-MS 2010 single quadrupole mass spectrometer instrument equipped with an electrospray ionization interface using selective ion monitoring positive mode. A "post cut" column switch technique was incorporated into the method to remove interferences of earlier and later eluting matrix components than entecavir and internal standard, including salting-out reagent used in sample pre-processing. The method was validated over the concentration range of 0.05-20 ng/mL. The intra-day and inter-day precision of the assay, as measured by the coefficient of variation (%CV), was within 3.59%, and the intra day assay accuracy was found to be within 4.88%. The average recovery of entecavir was about 50% and the ion suppression was approximately 44% over the standard curve. Comparison of matrix effect between SHLLE and SPE by continuous post column infusion showed that these two methods got similar, slight ion suppression. The SHLLE method has been successfully utilized for the analysis of entecavir in post-dose samples from a clinical study. PMID- 22197610 TI - Phorate-induced oxidative stress, DNA damage and transcriptional activation of p53 and caspase genes in male Wistar rats. AB - Male Wistar rats exposed to a systemic organophosphorus insecticide, phorate [O,O diethyl S-[(ethylthio) methyl] phosphorothioate] at varying oral doses of 0.046, 0.092 or 0.184mg phorate/kg bw for 14days, exhibited substantial oxidative stress, cellular DNA damage and activation of apoptosis-related p53, caspase 3 and 9 genes. The histopathological changes including the pyknotic nuclei, inflammatory leukocyte infiltrations, renal necrosis, and cardiac myofiber degeneration were observed in the liver, kidney and heart tissues. Biochemical analysis of catalase and glutathione revealed significantly lesser activities of antioxidative enzymes and lipid peroxidation in tissues of phorate exposed rats. Furthermore, generation of intracellular reactive oxygen species and reduced mitochondrial membrane potential in bone marrow cells confirmed phorate-induced oxidative stress. Significant DNA damage was measured through comet assay in terms of the Olive tail moment in bone marrow cells of treated animals as compared to control. Cell cycle analysis also demonstrated the G(2)/M arrest and appearance of a distinctive SubG(1) peak, which signified induction of apoptosis. Up-regulation of tumor suppressor p53 and caspase 3 and 9 genes, determined by quantitative real-time PCR and enzyme-linked immunosorbent assay, elucidated the activation of intrinsic apoptotic pathways in response to cellular stress. Overall, the results suggest that phorate induces genetic alterations and cellular toxicity, which can adversely affect the normal cellular functioning in rats. PMID- 22197611 TI - Azure B, a metabolite of methylene blue, is a high-potency, reversible inhibitor of monoamine oxidase. AB - Methylene blue (MB) has been shown to act at multiple cellular and molecular targets and as a result possesses diverse medical applications. Among these is a high potency reversible inhibition of monoamine oxidase A (MAO-A) that may, at least in part, underlie its adverse effects but also its psycho- and neuromodulatory actions. MB is metabolized to yield N-demethylated products of which azure B, the monodemethyl species, is the major metabolite. Similar to MB, azure B also displays a variety of biological activities and may therefore contribute to the pharmacological profile of MB. Based on these observations, the present study examines the interactions of azure B with recombinant human MAO-A and -B. The results show that azure B is a potent MAO-A inhibitor (IC50=11 nM), approximately 6-fold more potent than is MB (IC50=70 nM) under identical conditions. Measurements of the time-dependency of inhibition suggest that the interaction of azure B with MAO-A is reversible. Azure B also reversibly inhibits the MAO-B isozyme with an IC50 value of 968 nM. These results suggest that azure B may be a hitherto under recognized contributor to the pharmacology and toxicology of MB by blocking central and peripheral MAO-A activity and as such needs to be considered during its use in humans and animals. PMID- 22197612 TI - Trabectedin in patients with advanced non-small-cell lung cancer (NSCLC) with XPG and/or ERCC1 overexpression and BRCA1 underexpression and pretreated with platinum. AB - BACKGROUND: Previous studies in sarcoma found that a composite gene signature, including high expression of nucleotide excision repair (NER) genes (XPG and/or ERCC1) and low expression of homologous recombination repair (HR) genes (BRCA1), identifies a highly sensitive population of patients with significantly improved outcome to trabectedin. This exploratory phase II trial evaluated a customized trabectedin treatment according to this gene signature in patients with non-small cell lung cancer (NSCLC) after the failure of standard platinum-based treatment. METHODS: Patients were selected according to their mRNA expression (elevated XPG and/or ERCC1, with low BRCA1) using the following values as cutoff: XPG=0.99, ERCC1=3.47 and BRCA1=12.00. Trabectedin was administered as a 1.3mg/m(2) 3-hour intravenous infusion every 3 weeks (q3wk). The primary efficacy endpoint was the progression-free survival rate at 3 months. Objective response according to the Response Evaluation Criteria in Solid Tumors (RECIST) was a secondary efficacy endpoint. RESULTS: Two of 18 evaluable patients (11.1%; 95% CI, 1.38-34.7%) achieved progression-free survival rate at 3 months. The primary efficacy objective (at least 3 of 18 patients being progression-free at 3 months) was not met, and therefore the trial was early finalized. No objective responses per RECIST were achieved. Four patients had stable disease. Median PFS was 1.3 months, and median overall survival was 5.9 months. Trabectedin was usually well tolerated, with a safety profile similar to that described in patients with other tumor types. CONCLUSIONS: Customized treatment with trabectedin 1.3mg/m(2) 3-h q3wk according to composite gene signature (XPG and/or ERCC1 overexpression, and BRCA1 underexpression) was well tolerated, but had modest activity in NSCLC patients pretreated with platinum. Therefore, further clinical trials with trabectedin as single agent in this indication are not warranted. PMID- 22197613 TI - Vatalanib in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (CALGB 30107). AB - INTRODUCTION: The Cancer and Leukemia Group B (CALGB) conducted a multi-center phase II trial to evaluate the efficacy and safety of vatalanib in previously untreated patients with malignant mesothelioma and to evaluate potential biomarkers of disease response (CALGB 30107). METHODS: Treatment consisted of vatalanib 1250 mg given orally once daily. CT scans were obtained at baseline and every 6 weeks thereafter. Baseline serum levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), thrombospondin-1 (TSP-1), and mesothelin were obtained. The primary endpoint was 3-month progression-free survival (PFS). RESULTS: Forty-seven patients enrolled at 19 centers. The median age was 75 years, and the majority of patients (79%) had an ECOG performance status of 1. Tumors were classified as epithelial (77%), sarcomatoid (10%), or mixed (9%) histology. Toxicity was mild; the most common grade 3/4 adverse events were neutropenia (2%), nausea (15%), elevated alanine aminotransferase (11%), hypertension (2%), and gastrointestinal bleeding (2%). Partial responses were observed in 6% of patients and stable disease in 72% of patients. The 3-month PFS rate was 55% (95% CI: 40%, 68%). The median PFS was 4.1 months. Median overall survival was 10.0 months. There was no correlation between serum levels of VEGF, PDGF, TSP-1, or mesothelin and treatment response, PFS, or survival. CONCLUSIONS: Vatalanib as a single agent with this dose and schedule does not warrant further study in this disease. PMID- 22197614 TI - Characteristics of lung cancer in women: importance of hormonal and growth factors. AB - Based on epidemiological, clinical, and preclinical data, lung carcinogenesis can be distinctive in women, suggesting that women should be treated differently depending on the expression of various specific biomarkers. We aimed to describe the hormonal and genetic profile of lung cancer in both men and women to identify gender specificities. Primary lung-tumor tissues from surgically treated patients, (50 men, 50 women) were analyzed and compared for expression of estrogen receptors (ER) alpha and beta, progesterone receptors (PR), epidermal growth-factor receptor (EGFR), and HER2 (for EGFR and K-Ras mutations). These data were combined with clinical and outcome data. Fewer women with lung cancer were smokers (p=0.001) and they smoked fewer cigarettes (p=0.001). We observed a higher rate of EGFR mutations (p=0.02) and ERalpha expression (p=0.006) in women. ERbeta and EGFR were also expressed more frequently in women (p=0.29 and p=0.16). HER2 was overexpressed regardless of gender in three men and two women. K-Ras was mutated in 16% of both men and women. Interestingly, there was a positive link between EGFR expression and expression of ERalpha (p=0.028) and ERbeta (p=0.047) in both men and women. Expression of ERalpha was associated with improved disease free survival (p=0.007). Our findings provide further evidence on the specificities of lung cancer in women. The differential expression of specific biomarkers, which could be targeted by therapy, favors the development of gender based treatment guided by biomarker expression. PMID- 22197615 TI - Metabolic syndrome affects midterm outcome after coronary artery bypass grafting. AB - BACKGROUND: Metabolic syndrome (MetS) is frequently associated with coronary artery disease, but data on the impact of MetS on long-term outcome of patients undergoing coronary artery bypass grafting are still lacking. The aim of the present study was to assess the effect of MetS on mortality and morbidity late after coronary artery bypass grafting. METHODS: A total of 1,726 consecutive patients who had elective coronary artery bypass grafting were retrospectively reviewed and clinical follow-up was completed (mean follow-up time, 34.4 months; range, 6 to 79 months). The MetS was diagnosed using the modified Adult Treatment Panel III criteria, and to eliminate covariate differences, a propensity score adjustment was used. Major adverse cerebral and cardiovascular events were investigated, and C-reactive protein levels were assessed both preoperatively, postoperatively, and at follow-up. RESULTS: A total of 798 of 1,726 patients (46.2%) met the diagnostic criteria for MetS. At follow-up, all-cause mortality (7% versus 4.6%; p=0.04), cardiac arrhythmias (35.3% versus 25.2%; p<0.0001), renal failure (12% versus 8.7%; p=0.03), and major adverse cerebral and cardiovascular events (52.4% versus 39.5%; p<0.0001) showed a significantly higher incidence in MetS patients. Variables correlated with late mortality at propensity-adjusted Cox proportional-hazards regression were age (p=0.0008), preoperative left ventricular ejection fraction (p=0.001), preoperative renal failure (p=0.001), and MetS (p=0.006). Higher C-reactive protein levels were found preoperatively (8.6+/-2.3 versus 5.14+/-3.1 mg/L; p<0.0001) and both early (71.2+/-9 versus 49.6+/-8.7 mg/L; p<0.0001) and late (7.4+/-2.7 versus 4.8+/-2.5 mg/L; p<0.0001) after surgery. CONCLUSIONS: The main finding of our study was the association between MetS and mortality both early and late after coronary artery bypass grafting. Thus, MetS should be recognized as an independent preoperative variable that can lead to the identification of high-risk patients and as a risk factor to correct with lifestyle modifications and pharmacologic therapy. PMID- 22197616 TI - Off-pump bilateral skeletonized internal thoracic artery grafting in elderly patients. AB - BACKGROUND: The purpose of the present study was to compare outcome in propensity score-matched patients, aged 70 years or greater, undergoing isolated off-pump coronary bypass surgery using a bilateral (BITA) or single (SITA) skeletonized internal thoracic artery. METHODS: Of 912 consecutive patients undergoing isolated coronary bypass grafting (906 using the off-pump technique without emergent conversion to cardiopulmonary bypass), the 491 aged 70 years or greater undergoing off-pump skeletonized single (n=247) or bilateral (n=244) skeletonized internal thoracic artery grafting were retrospectively analyzed after excluding the 6 who were transferred to our hospital after receiving percutaneous cardiopulmonary bypass, the 72 who had only 1 target in the left coronary area, and the 343 aged less than 70 years. A total of 217 pairs were matched using propensity scores calculated from 9 preoperative factors (0.69). RESULTS: The rate of postoperative complications was similar between the groups. The 5-year estimated survival free from overall death and cardiac event, respectively, in the BITA group versus the SITA group were 86.4%+/-3.2% versus 73.5%+/-3.9% (p=0.01) and 93.2%+/-2.7% versus 87.5%+/-3.0% (p=0.01). In multivariate Cox models, bilateral internal thoracic artery grafting was significantly associated with a lower risk of overall death (hazard ratio 0.56; 95% confidence interval 0.31 to 0.99; p=0.04) and cardiac event (hazard ratio 0.36; 95% confidence interval 0.15 to 0.88; p=0.03). CONCLUSIONS: In elderly patients, off-pump in situ left-sided bilateral skeletonized internal thoracic artery grafting is associated with lower risk of overall death and cardiac event than single internal thoracic artery grafting and carries no increased operative risk. PMID- 22197617 TI - Midterm cost and effectiveness of thoracic endovascular aortic repair versus open repair. AB - BACKGROUND: Thoracic endovascular aneurysm repair (TEVAR) has been rapidly introduced as a primary treatment modality for thoracic aortic diseases with limited data available on midterm to late-term outcomes. METHODS: A retrospective single institution study comparing hospital and midterm outcomes and costs for TEVAR versus open elective repair of descending thoracic aneurysms was conducted. Fifty-seven patients were included between 2005 and 2007 (TEVAR=28; open=29) and were followed until May 2010. RESULTS: Patients in the TEVAR group were older (73.2 versus 62.3 years; p<0.001). Hospital mortality was higher in the open repair group (10.3% versus 3.6%; p=0.611). There was no statistical difference in stroke, paraparesis or paralysis, sepsis, or renal failure; however, a composite major adverse event variable showed a higher complication with open repair versus TEVAR (37.9% versus 14.3%; p=0.043). Mean follow-up was 42.6 months for open repair versus 26.9 for TEVAR (p=0.002). Kaplan-Meier survival analysis showed the initial survival benefit for TEVAR was lost in less than 6 months; however, the difference did not reach statistical significance during follow-up (log-rank test p=0.232). Mean surveillance imaging costs for a TEVAR patient were $1,800.38 higher than for an open patient at 2 years. Compliance of TEVAR patients with follow-up imaging was 78%, 64%, 50%, and 42% at 1, 6, 12, and 24 months, respectively, and was even lower in those not registered in device trials. CONCLUSIONS: Patients in the TEVAR group had favorable early outcomes; however, midterm survival was reduced secondary to comorbidities. This study raises concern for the ongoing costs of surveillance imaging in TEVAR as well as patient compliance with follow-up. PMID- 22197618 TI - Long-term results of 203 young and middle-aged patients with more than 10 years of follow-up after the original subcoronary Ross operation. AB - BACKGROUND: The choice of prosthesis for aortic valve replacement in young and middle-aged patients remains challenging owing to the accelerated degeneration of bioprostheses in these age groups and the risks of thromboembolism and bleeding with mechanical valves. Theoretically, the living pulmonary autograft (Ross operation) would be advantageous. Long-term results of the various Ross techniques are needed for defining the value of this surgical concept. METHODS: Of a total of 576 subcoronary Ross patients operated on between June 1994 and June 2011, we report on 203 consecutive subcoronary patients (mean age, 47.2+/ 13.6 years, 155 male, 2,491 patient-years) with a follow-up of at least 10 years (mean, 12.3+/-2.9 years). RESULTS: Early and late mortality were 0.98% (n=2) and 11.4% (n=23). Valve-related mortality was 2.5% (n=5). Survival did not differ from that of the general German population. Freedom from autograft or allograft reoperation was 92.2% at 10 years and 87.1% at 15 years. Five major bleeding (0.20%/patient-year) and 11 thromboembolic events (0.44%/patient-year) occurred in 5 and 10 patients, respectively. Neither a systematic increase in aortic regurgitation nor an increase in root dimensions with time could be observed. In the vast majority of patients, valvular hemodynamics at latest echocardiographic follow-up were excellent. CONCLUSIONS: Long-term results of the original subcoronary Ross operation reveal normal survival, excellent hemodynamics, low risk of thromboembolism or bleeding, and small risk for reoperation. These results favor the pulmonary autograft concept in young and middle-aged patients in experienced centers and may serve to better define its role in surgical treatment of aortic valve disease in these patients. PMID- 22197619 TI - Intrahepatic transplantation of CD34+ cord blood stem cells into newborn and adult NOD/SCID mice induce differential organ engraftment. AB - In vivo studies concerning the function of human hematopoietic stem cells (HSC) are limited by relatively low levels of engraftment and the failure of the engrafted HSC preparations to differentiate into functional immune cells after systemic application. In the present paper we describe the effect of intrahepatically transplanted CD34(+) cells from cord blood into the liver of newborn or adult NOD/SCID mice on organ engraftment and differentiation. Analyzing the short and long term time dependency of human cell recruitment into mouse organs after cell transplantation in the liver of newborn and adult NOD/SCID mice by RT-PCR and FACS analysis, a significantly high engraftment was found after transplantation into liver of newborn NOD/SCID mice compared to adult mice, with the highest level of 35% human cells in bone marrow and 4.9% human cells in spleen at day 70. These human cells showed CD19 B-cell, CD34 and CD38 hematopoietic and CD33 myeloid cell differentiation, but lacked any T-cell differentiation. HSC transplantation into liver of adult NOD/SCID mice resulted in minor recruitment of human cells from mouse liver to other mouse organs. The results indicate the usefulness of the intrahepatic application route into the liver of newborn NOD/SCID mice for the investigation of hematopoietic differentiation potential of CD34(+) cord blood stem cell preparations. PMID- 22197620 TI - Intussusceptive microvascular growth in tumors. AB - Intussusception is an alternative to the sprouting mode of angiogenesis. The advantage of this mechanism of vascular growth is that blood vessels are generated more rapidly and the capillaries thereby formed are less leaky. This review article summarizes our current knowledge concerning the role played by intussusceptive microvascular growth in tumor growth. Interestingly, an angiogenic switch from sprouting to intussusceptive angiogenesis occurs after treatment with angiogenesis inhibitors and may be considered as a tumor protective adaptative response. PMID- 22197621 TI - BRCA-1 promoter hypermethylation and silencing induced by the aromatic hydrocarbon receptor-ligand TCDD are prevented by resveratrol in MCF-7 cells. AB - Epigenetic mechanisms may contribute to reduced expression of the tumor suppressor gene BRCA-1 in sporadic breast cancers. Through environmental exposure and diet, humans are exposed to xenobiotics and food compounds that bind the aromatic hydrocarbon receptor (AhR). AhR-ligands include the dioxin-like and tumor promoter 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). The activated AhR regulates transcription through binding to xenobiotic response elements (XREs=GCGTG) and interactions with transcription cofactors. Previously, we reported on the presence of several XREs in the proximal BRCA-1 promoter and that the expression of endogenous AhR was required for silencing of BRCA-1 expression by TCDD. Here, we document that in estrogen receptor-alpha-positive and BRCA-1 wild-type MCF-7 breast cancer cells, the treatment with TCDD attenuated 17beta estradiol-dependent stimulation of BRCA-1 protein and induced hypermethylation of a CpG island spanning the BRCA-1 transcriptional start site of exon-1a. Additionally, we found that TCDD enhanced the association of the AhR; DNA methyl transferase (DNMT)1, DNMT3a and DNMT3b; methyl binding protein (MBD)2; and trimethylated H3K9 (H3K9me3) with the BRCA-1 promoter. Conversely, the phytoalexin resveratrol, selected as a prototype dietary AhR antagonist, antagonized at physiologically relevant doses (1 MUmol/L) the TCDD-induced repression of BRCA-1 protein, BRCA-1 promoter methylation and the recruitment of the AhR, MBD2, H3K9me3 and DNMTs (1, 3a and 3b). Taken together, these observations provide mechanistic evidence for AhR agonists in the establishment of BRCA-1 promoter hypermethylation and the basis for the development of prevention strategies based on AhR antagonists. PMID- 22197622 TI - Comparison of laparoscopy and laparotomy for endometrial cancer. AB - OBJECTIVE: To compare the safety and efficacy of laparoscopy and laparotomy on clinical outcomes among patients with endometrial cancer. METHODS: Eligible randomized controlled trials (RCTs) conducted between 1966 and June 2010 were analyzed by meta-analysis. RESULTS: Eight RCTs were included, with 3599 patients in total. No significant difference was observed between laparoscopy and laparotomy in overall (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.50 1.82; P=0.892), disease-free (OR, 0.96; 95% CI, 0.50-1.82; P=0.892), or cancer related (OR, 0.90; 95% CI, 0.27-3.08; P=0.871) survival. More intraoperative complications (OR, 1.33; 95% CI, 1.03-1.73; P=0.030), fewer postoperative complications (OR, 0.59; 95% CI, 0.46-0.75; P<0.001), longer operative time (standardized mean difference [SMD], 0.80; 95% CI, 0.46-1.15; P<0.001), lower blood loss (SMD, -2.29; 95% CI, -3.67 to -0.91; P=0.001), and shorter hospital stay (SMD, -2.60; 95% CI, -3.47 to -1.72; P<0.001) were associated with laparoscopy. There was no significant difference between the groups in pelvic (SMD, 0.22; 95% CI, -0.03 to 0.48; P=0.086) or para-aortic (SMD, 0.54; 95% CI, 0.04 to 1.11; P=0.067) lymph node yield. CONCLUSION: Laparoscopy has short-term advantages and seemingly equivalent long-term outcomes and, in experienced hands, might be a feasible alternative to laparotomy for endometrial cancer. PMID- 22197623 TI - Naphthalene animal carcinogenicity and human relevancy: overview of industries with naphthalene-containing streams. AB - Bioassays in mice and rats exposed via inhalation to naphthalene show incidences of lung and nasal cancer, respectively. To address the question of human relevancy, a literature search for cancer case reports in workers exposed to naphthalene was performed, along with an evaluation of major studies from industries with naphthalene-containing streams having the highest naphthalene exposures and/or most extensive epidemiology data. Although no epidemiologic studies of workers exposed solely to naphthalene were found, a population-based case-control study of oral and oropharynx cancer found no relation with naphthalene exposure. Limited case reports of laryngeal and colorectal cancer and naphthalene exposure exist, but these data are inadequate for evaluating human cancer risk. No case reports of nasal tumors were found, which is informative because case reports have historically identified several occupational carcinogens. Combined with anatomic and metabolic differences between rodent and human upper airways and data suggesting that cancer potency based on the rat bioassay is overestimated, relevancy of rat nasal tumors to humans is questionable. For lung cancer, existing human studies are insufficient to make firm conclusions about the presence or absence of a potential naphthalene-related risk, although no occupationally-related lung cancer risks were identified in the industries evaluated. PMID- 22197624 TI - Subacute toxicity assessment of carotenoids extracted from citrus peel (Nanfengmiju, Citrus reticulata Blanco) in rats. AB - The mixture of carotenoids extracted from citrus peel (Nanfengmiju, Citrus reticulata Blanco) was tested for subacute oral toxicity. In this study, dose levels of 0, 200, 500 and 2000 mg/kg body weight/day were administered by gavage to 10 Wistar rats/sex/group for 28 days. No statistically significant, dose related effect on food consumption, food efficiency, body weight gain, clinical signs or ophthalmoscopic parameters was observed in any treatment group. Urinalysis, hematological, blood coagulation and serum biochemical examination as well as necropsy or histopathology showed that no observed adverse effect was found. These findings suggested that the No-Observed-Adverse-Effect Level for the mixture of carotenoids extracted from citrus peel was at least 2000 mg/kg body weight/day. PMID- 22197625 TI - Assessing the non-cancer risk for RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) using physiologically based pharmacokinetic (PBPK) modeling. AB - RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) is an explosive used in military applications. It has been detected in ground water surrounding US military installations and at manufacturing facilities. RDX has been shown to produce hepatotoxicity, testicular, and neurological effects in animals, the latter also in humans. The current chronic oral reference dose (RfD) of 0.003 mg/kg/day was derived based on prostate effects in rats. Here, we provide a reevaluation of the risk associated with RDX exposure by examining old and new data and using physiologically based pharmacokinetic (PBPK) modeling approaches. Candidate non cancer endpoints in rodents were evaluated and the most plausible mode(s) of action were determined. A PBPK model was used to derive appropriate internal doses based on the mode of action, and then a benchmark dose (BMD) and the lower confidence limit on the BMD (BMDL) were determined using these internal doses in animals. Uncertainty factors (UF) were applied to the animal BMDL or no-observed effect level and a human PBPK model was used to determine a human equivalent dose resulting in the candidate RfDs (cRfDs). A proposed chronic RfD of 0.07 mg/kg/day, based on multiple effects observed in rats, was selected from among the cRfDs. PMID- 22197626 TI - Review: Biochemical markers to predict preeclampsia. AB - Worldwide the prevalence of preeclampsia (PE) ranges from 3 to 8% of pregnancies. 8.5 million cases are reported yearly, but this is probably an underestimate due to the lack of proper diagnosis. PE is the most common cause of fetal and maternal death and yet no specific treatment is available. Reliable biochemical markers for prediction and diagnosis of PE would have a great impact on maternal health and several have been suggested. This review describes PE biochemical markers in general and first trimester PE biochemical markers specifically. The main categories described are angiogenic/anti-angiogenic factors, placental proteins, free fetal hemoglobin (HbF), kidney markers, ultrasound and maternal risk factors. The specific biochemical markers discussed are: PAPP-A, s-Flt 1/PlGF, s-Endoglin, PP13, cystatin-C, HbF, and alpha1-microglobulin (A1M). PAPP-A and HbF both show potential as predictive biochemical markers in the first trimester with 70% sensitivity at 95% specificity. However, PAPP-A is not PE specific and needs to be combined with Doppler ultrasound to obtain the same sensitivity as HbF/A1M. Soluble Flt -1 and PlGF are promising biochemical markers that together show high sensitivity from the mid-second trimester. PlGF is somewhat useful from the end of the first trimester. Screening pregnant women with biochemical markers for PE can reduce unnecessary suffering and health care costs by early detection of mothers at increased risk for PE, thus avoiding unnecessary hospitalization of pregnant women with suspect or mild PE and enabling monitoring of the progression of the disease thereby optimizing time for delivery and hopefully reducing the number of premature births. PMID- 22197627 TI - Elsevier Trophoblast Research Award lecture: Molecular mechanisms underlying estrogen functions in trophoblastic cells--focus on leptin expression. AB - The steroid hormone 17beta-estradiol is an estrogen that influences multiple aspects of placental function and fetal development in humans. During early pregnancy it plays a role in the regulation of blastocyst implantation, trophoblast differentiation and invasiveness, remodeling of uterine arteries, immunology and trophoblast production of hormones such as leptin. Estradiol exerts some effects through the action of classical estrogen receptors ERalpha and ERbeta, which act as ligand-activated transcription factors and regulate gene expression. In addition, estradiol can elicit rapid responses from membrane associated receptors, like activation of protein-kinase pathways. Thus, the cellular effects of estradiol will depend on the specific receptors expressed and the integration of their signaling events. Leptin, the 16,000MW protein product of the obese gene, was originally considered an adipocyte-derived signaling molecule for the central control of metabolism. However, pleiotropic effects of leptin have been identified in reproduction and pregnancy. The leptin gene is expressed in placenta, where leptin promotes proliferation and survival of trophoblastic cells. Expression of leptin in placenta is highly regulated by key pregnancy molecules as hCG and estradiol. The aim of this paper is to review the molecular mechanisms underlying estrogen functions in trophoblastic cells; focusing on mechanisms involved in estradiol regulation of placental leptin expression. PMID- 22197628 TI - Placental characteristics in growth-discordant monochorionic twins: a matched case-control study. AB - OBJECTIVE: To compare the placental characteristics in monochorionic (MC) twin pregnancies with and without birth weight discordance (BWD). METHODS: We performed a matched case-control study to compare the placental characteristics of MC placentas from pregnancies with BWD (>=25%) (n = 47) with a control group of MC placentas without BWD (n = 47), matched for gestational age at birth. Placental sharing, angioarchitecture and diameter of the arterio-arterial (AA) anastomosis were assessed by placental injection with colored dye. RESULTS: The rate of velamentous cord insertion in MC placentas with and without BWD was 30% (28/94) and 16% (15/94), respectively (p = 0.036). Placental sharing discordance in MC placentas with and without BWD was 36% and 17%, respectively (p < 0.001). The mean diameter of the AA anastomosis in MC placentas with and without BWD was 2.2 mm and 1.8 mm, respectively (p = 0.024). CONCLUSION: MC placentas from growth discordant twins are more unequally shared, have a higher rate of velamentous cord insertions and larger diameter of AA anastomosis compared to gestational age matched controls. PMID- 22197629 TI - Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis. AB - BACKGROUND: Nonalcoholic fatty liver disease is a chronic metabolic disorder with significant impact on cardiovascular and liver mortality. AIMS: In this study, we examined the effects of silibinin on liver and myocardium injury in an experimental model of nonalcoholic fatty liver disease. METHODS: A four-week daily dose of silibinin (20 mg/kg i.p.) was administrated to db/db mice fed a methionine-choline deficient diet. Hepatic and myocardial histology, oxidative stress and inflammatory cytokines were evaluated. RESULTS: Silibinin administration decreased HOMA-IR, serum ALT and markedly improved hepatic and myocardial damage. Silibinin reduced isoprostanes, 8-deoxyguanosine and nitrites/nitrates in the liver and in the heart of db/db fed the methionine choline deficient diet, whereas glutathione levels were restored to lean mice levels in both tissues. Consistently, liver mitochondrial respiratory chain activity was significantly impaired in untreated mice and was completely restored in silibinin-treated animals. TNF-alpha was increased whereas IL-6 was decreased both in the liver and heart of db/db fed methionine-choline deficient diet. Silibinin reversed heart TNF-alpha and IL-6 expression to control mice levels. Indeed, liver JNK phosphorylation was reduced to control levels in treated animals. CONCLUSIONS: This study demonstrates a combined effectiveness of silibinin on improving liver and myocardial injury in experimental nonalcoholic fatty liver disease. PMID- 22197630 TI - Novel findings in the cephalic phase of digestion: a role for microcirculation? AB - The cephalic phase of digestion (CPD) has been extensively investigated in terms of digestion and metabolism. Nevertheless, microcirculatory changes required to prepare peripheral tissues in order to dispose nutrients have never been assessed. In this study, microvascular function has been evaluated to determine its behavior and potential association to hormonal secretions during CPD. Thirty nine healthy male subjects, 23.4 +/- 0.5 years (mean +/- SD) and BMI of 23.3 +/- 2.3 kg/m(2), were randomized into receiving cognitive-sensorial stimuli to elicit CPD (CPD group, n=20) or not (control group, n=19), after a 12-h overnight fast. Main outcomes were differences in resting and peak functional capillary density (FCD, cap/mm(2)); resting red blood cell velocity (RBCV), peak RBCV (RBCV(max)) and time taken to reach it (TRBCV(max)); peak flow and vasomotion, before and after CPD and their associations with insulin and/or pancreatic polypeptide (PP). In the CPD group, basal FCD (24.9 +/- 7.6 to 28.3 +/- 8.1, p=0.005), peak FCD (27.8 +/- 6.3 to 32.6 +/- 7.1, p=0.002), RBCV (0.306 +/- 0.031 to 0.330 +/- 0.027 mm/s, p=0.005), RBCV(max) (0.336 +/- 0.029 to 0.398 +/- 0.292 mm/s, p=0.005) and peak flow (23.5 +/- 14.3 to 26.9 +/- 15.8 PU, p<0.01) increased while TRBCV(max) decreased (4.9 +/- 1.5 to 3.5 +/- 1.2s, p=0.01). No significant changes could be detected in the control group. Groups have not presented differences for insulin, but PP significantly increased in the CPD group and was positively associated to basal FCD increase (rho=0.527, p=0.03). In conclusion, neurally-mediated anticipatory responses of digestion elicited functional capillary recruitment associated to PP in healthy men, suggesting a precocious role for microcirculation in the physiology of digestion and nutrient homeostasis. PMID- 22197631 TI - Contact pressure on ACL hamstring grafts in the bone tunnel with interference screw fixation--dynamic adaptation under load. AB - INTRODUCTION: Interference screws used in fixation of anterior cruciate ligament (ACL) hamstring grafts create mechanical hold by forcing the graft into frictional contact with the bone tunnel. We analyzed the resultant graft-tunnel contact pressure using an in vitro model of human cadaver 8mm hamstring grafts. METHODS: Contact characteristics were assessed using both pressure sensitive films and a force sensor. Two screw sizes were investigated (8 and 9 mm in an 8mm Sawbone tunnel), both with and without a bone wedge between graft and screw. Separately, time dependent relaxation of contact force was recorded over a one hour epoch and associated tendon water loss was measured. Pullout testing of 8mm tendon grafts from 8mm holes in Sawbone and porcine femora were performed after 1 min and 1h. RESULTS: During screw insertion, measured peak pressures (>40 MPa) exceeded the compressive failure stress of metaphyseal bone by more than an order of magnitude. Using a bone wedge between tendon and screw reduced local peak pressure by 85% but produced also inferior average contact pressure. In all approaches, initially achieved graft contact pressure rapidly decreased to approximately 25% within 30 min. Pullout strength was significantly reduced after 1h in comparison to 1 min in porcine bone as well as Sawbone. CONCLUSION: Viscoelastic adaptation of the tendon is severe and critically reduces effective graft-bone contact pressure. Consideration of this newly recognized effect may open new and improved approaches for tendon graft fixation. PMID- 22197632 TI - Computer assisted versus conventional total knee replacement: a comparison of tourniquet time, blood loss and length of stay. AB - AIMS AND INTRODUCTION: The aim of this study was to assess whether navigated total knee arthroplasty (TKA) reduces peri-operative blood loss and post operative length of stay when compared to conventional total knee arthroplasty techniques. PATIENTS AND METHODS: A retrospective case-note review of 143 patients undergoing primary elective total knee arthroplasty was carried out. Two surgeons in this institution perform conventional knee arthroplasty using intramedullary alignment with another two surgeons using the computer assisted technique. Blood losses were calculated using the Meunier et al. (2008) [23] method for calculation of peri-operative blood loss. This is based on changes in peri-operative blood indices compared to the patient's theoretical total blood volume which is calculated using the patient's pre-operative height and weight. Tourniquet time and post-operative length of stay for the two techniques of arthroplasty were also recorded. RESULTS: Sixty eight patients underwent conventional TKA and 75 patients had navigated TKA's performed. This data showed no significant difference in blood loss (p=0.56) or post-operative length of stay (p=0.36). A significant difference in tourniquet time between the two techniques was demonstrated (p=0.01). CONCLUSION: In this study there was no significant reduction in post-operative length of stay and peri-operative blood loss when using computer-assisted techniques. There was an increase in tourniquet time with the computer-assisted technique that may have implications upon work productivity for primary cemented knee arthroplasty. PMID- 22197633 TI - A comparison of risk factors for coronary heart disease and ischaemic stroke. PMID- 22197634 TI - Chipping behaviour of all-ceramic crowns with zirconia framework and CAD/CAM manufactured veneer. AB - OBJECTIVES: The aim of this in vitro study was to assess the ultimate load to failure of zirconia based crowns veneered with CAD/CAM manufactured ceramic. METHODS: 32 identical, anatoform zirconia (Sirona inCoris ZI, mono L F1) frameworks (thickness 0.6mm) were constructed (Sirona inLab 3.80). Afterwards, 16 crowns were completed using a CAD/CAM manufactured lithium disilicate ceramic veneer (IPS e.max CAD, Ivoclar Vivadent). The remaining 16 frames were veneered using conventional manual layering technique. For the CAD/CAM manufactured veneers, the connection between framework and veneer was accomplished via a glass fusion ceramics. Before fracture tests, half of the specimens underwent thermocycling and chewing simulation (1.2 million chewing cycles, force magnitude F(max)=108 N). To further investigate the new technique, finite element computations were carried out on the basis of the original geometry. RESULTS: Nearly all (87.5%) conventionally veneered crowns failed already during chewing simulation, whereas crowns with CAD/CAM manufactured veneers were non-sensitive to artificial ageing. Crowns veneered with lithium disilicate ceramic displayed ultimate loads to failure of about 1600 N. CONCLUSION: The CAD/CAM production of veneers for restorations with zirconia framework is a promising way to reduce failures originating from material fatigue. PMID- 22197635 TI - In vitro resistance selections using elvitegravir, raltegravir, and two metabolites of elvitegravir M1 and M4. AB - Elvitegravir is a strand transfer inhibitor of HIV-1 integrase that is currently undergoing phase 3 clinical testing. The two predominant metabolites of elvitegravir, M1 and M4 (elvitegravir hydroxide and elvitegravir glucuronide), have been shown to inhibit HIV-1 integrase in vitro. While they are markedly less potent than elvitegravir and present only at low levels in plasma clinically, we investigated their potential to select for elvitegravir resistance in vitro. Resistance selection experiments using metabolites M1 and M4 led to the development of the previously reported elvitegravir integrase resistance mutations H51Y, T66A, E92G, and S147G, as well as a novel S153F substitution. Additional resistance selection experiments using elvitegravir led to the development of previously reported integrase inhibitor resistance mutations (T66I, F121Y, and S153Y) as well as a novel R263K integrase mutation. Phenotypic analyses of site-directed mutants with these mutations demonstrated broad cross resistance between elvitegravir and its M1 and M4 metabolites with more limited cross-resistance to the integrase inhibitor raltegravir. Overall, our in vitro studies demonstrate that the resistance profile of the M1 and M4 metabolites of elvitegravir overlaps with that of the parent molecule elvitegravir; as such, their presence at low levels is not considered clinically relevant. PMID- 22197639 TI - Pain today - disability tomorrow. PMID- 22197636 TI - Novel antivirals inhibit early steps in HPV infection. AB - The future incidence of cervical cancer is forecast to decline because of the remarkably effective prophylactic vaccines against human papillomaviruses. However, lack of access to these expensive vaccines in the developing countries where cervical cancer is most frequent, and the restricted genotypes these vaccines protect against, will limit their impact. Clearly, there is still a need for identifying other modalities for preventing HPV infections. Ready access to effective, inexpensive antivirals represents one potentially valuable approach to the prevention of genital HPV infections. We developed a well-validated high throughput screening (HTS) assay for identifying compounds that inhibit HPV infection and applied this assay to identify lead compounds that act by inhibiting an early step in infection. We screened over 40,000 small molecules that were available at the University of Wisconsin Small Molecule Screening Facility (UW-SMSF). The top 22 compounds were chosen for further analyses based upon the pharmacological property, scaffold diversity, strength of the inhibitory activity and lack of nonspecific cytotoxicity. Of these compounds, #13 and #14 had the most acceptable properties of low to submicromolar IC(50)'s and low cytotoxicity. Optimal antiviral activities were elicited by exposure of cells to the #13 and #14 during the initial 12 h following infection. Twenty-nine #13-like and 15 #14-like analogs were identified in silico and tested for their antiviral activities corresponded to the altered structures comparing to #13 and #14, informing on the pharmacophore structure of each compound. Studies indicate that both compounds inhibit infection post-entry. PMID- 22197640 TI - Lysosomal Disease Network's WORLD SymposiumTM 2012. PMID- 22197641 TI - Antiproliferative and iron chelating efficiency of the new bis-8-hydroxyquinoline benzylamine chelator S1 in hepatocyte cultures. AB - If a new generation of iron chelators specifically devoted for cancer chemotherapy emerged these last years, any of them has not yet been approved at this time. Accordingly, there is a need to optimize new chelating molecules for iron chelation therapy and cancer treatment. So, the objective of the present investigation was to characterize the antiproliferative activity and the iron chelating capacity of the iron chelator S1 [bis-N-(8-hydroxyquinoline-5 ylmethyl)benzylamine]. Its effects were compared to O-trensox which binds ferric iron with a very high affinity (pFe(3+)=29.5). For this purpose, primary rat hepatocyte stimulated by EGF and human hepatoma HepaRG cell cultures were used. In these models, the anti-proliferative effect, the inhibition of DNA synthesis and the iron-chelating efficiency of increasing concentrations of S1 and O trensox (0 up to 200 MUM) were investigated. In the two cell culture models, we observed that S1 was about 100 times more efficient than O-trensox and the antiproliferative effect of S1 in HepaRG cells appeared at concentrations as low as 0.1 MUM without cytotoxicity. Moreover, the stoichiometry of S1 for iron seemed to be in the range S1/Fe(3+)=1. Using the calcein fluorescence assay, we demonstrated that the affinity of S1 for iron was better than that of O-trensox since it was at least two times more effective to restore the fluorescence of calcein previously quenched by iron. So, the iron chelating efficiency of S1 could explain at least partially its higher anti-proliferative effect compared to O-trensox. Finally, these results suggest that molecules such as S1 may constitute a promising starting point to improve cancer treatment. PMID- 22197642 TI - Antithrombotic phenolic compounds from Glycyrrhiza uralensis. AB - A new coumestan, named glycyrurol, and nine phenolic compounds were isolated from the ethyl acetate extract of the roots and rhizomes of Glycyrrhiza uralensis. Their structures were elucidated based on spectroscopic analysis and literature data, and anticoagulative assay found significant antithrombotic activity of compounds 4, 8 and 10. PMID- 22197643 TI - [Determinants of tuberculosis diagnosis delay in limited resources countries]. AB - BACKGROUND: Delayed diagnoses of pulmonary tuberculosis contribute to the spread of the epidemic. METHODS: This study aims to identify risk factors associated with patient delay (from symptoms onset to the first visit), health system delay (from the first visit to the tuberculosis treatment initiation) and total delay (sum of the patient and the health system delay) in low income and high tuberculosis burden countries. A systematic literature review has been performed using the keywords: "tuberculosis"; "delay", care seeking"; "health care seeking behavior"; "diagnosis" and "treatment". Only quantitative studies showing delays for pulmonary tuberculosis adult cases were included in this review. RESULTS: Low income, gender, rural life, unemployment, ageing and misunderstanding the microbial cause of tuberculosis are associated with delayed diagnoses. Systemic factors including low health care coverage, patient expenditures and entry into the health system by consulting a traditional healer or a non-skilled professional delay the beginning of tuberculosis treatment. CONCLUSION: Delays can be used as indicators to evaluate tuberculosis control programs. Active case finding in the households of contagious patients can help to diminish diagnostic delays in low-income countries with high endemicity. PMID- 22197644 TI - Clusterin interaction with Bcl-xL is associated with seizure-induced neuronal death. AB - Status epilepticus causes significant damage to the brain, and cellular injury due to prolonged seizures may cause the pathogenesis of epilepsy or cognitive deficits. Clusterin mediates several cell signaling pathways, including cell death or survival pathways in the brain. A nuclear form of clusterin protein has been suggested to have pro-apoptotic properties. Bcl-x(L) functions as a dominant negative modulator of the pro-apoptotic protein Bax. However, the relationship between clusterin and Bcl-x(L) in cell death signaling in the brain remains unknown. Therefore, we examined whether clusterin interacts with Bcl-x(L) after seizures or whether this interaction is related to neuronal death. We found increased levels of nuclear clusterin and cleaved caspase-3 in CA3 neurons after prolonged seizures induced by systemic kainic acid, along with extensive hippocampal cell death, as evidenced by terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and anti-active caspase-3 staining. Furthermore, co-immunoprecipitation and double immunofluorescence analyses revealed that clusterin interacted with Bcl-x(L) in dying CA3 neurons while the levels of Bcl-x(L), Bad or Bax remained constant. These findings provide evidence that nuclear clusterin signals cell death at least via an interaction with Bcl-x(L) in the hippocampus after seizures, suggesting that targeting nuclear clusterin may be a promising novel strategy to protect against seizure-induced neuronal injury. PMID- 22197645 TI - Dissipation and residue behavior of emamectin benzoate on apple and cabbage field application. AB - A LC-ESI-MS/MS method with QuEChERS for analysis of emamectin benzoate in cabbage, apple and soil was established. At fortification levels of 0.001, 0.01 and 0.1 mg/kg in cabbage, apple and soil, it was shown that recoveries ranged from 75.9 to 97.0 percent with relative standard deviation (RSD) of 4.4-19.0 percent. The limit of quantification (LOQ) was 0.001 mg/kg for cabbage, apple and soil. The dissipation half-lives of emamectin benzoate in cabbage, apple and soil were 1.34-1.72 day, 2.75-3.09 day and 1.89-4.89 day, respectively. The final residues of emamectin benzoate ranged from 0.001 to 0.052 mg/kg in cabbages, 0.003 to 0.090 mg/kg in apples and 0.001 to 0.089 mg/kg in soils, respectively. Therefore, it would be unlikely to cause health problems if emamectin benzoate was applied according to the use pattern suggested by the manufactures on the label. PMID- 22197646 TI - The effect of pymetrozine (Plenum WG-50) on proboscis extension conditioning in honey bees (Apis mellifera: Hybrid var. Buckfast). AB - Experiments are designed to examine the effects of pymetrozine (Plenum WG-50), a recent systemic pesticide of the pyridine-azomethin family, on Pavlovian conditioning of harnessed foragers. In one set of experiments bees learned a task in which they associated a conditioned stimulus with feeding. A second set of experiments required the bees to learn a discrimination task. Within each experiment, bees received 5 MUl of sucrose only, the recommended field dose of Plenum (5 MUL of .3 gL(-1), .16 gL(-1) of pymetrozine measured), or 100 times the field dose of Plenum WG 50 thirty minutes prior to training (5 MUL of 30 gL(-1), 14 gL(-1) of pymetrozine measured). The Plenum WG 50 was diluted with .88 M sucrose to facilitate the drinking of the pesticide. In addition to varying the concentration, we also investigated the effect of Plenum WG 50 on bees confined to an observation hive and a hive located outside. The results indicated that prior exposure to Plenum WG 50 affected Pavlovian conditioning only when bees were exposed to 100 times the recommended dosage. PMID- 22197647 TI - Nanoindentation characterization of the micro-lamellar arrangement of black coral skeleton. AB - Black corals (antipatharians) are colonial cnidarians whose branched tree-like skeleton is mostly constituted of chitin fibrils inside a lipoproteic matrix. The skeleton exhibits growth rings formed by chitin layers (micro-lamellae). In order to know the effect of the arrangement microlamellae of chitin of black corals and to improve the understanding of the role of chitin structure in the antipatharian skeleton, the mechanical properties of the skeleton of two black corals, Antipathes caribbeana and Antipathes pennacea, were examined using nanoindentation tests. Measurements of reduced elastic modulus, nanohardness and the viscoelastic behavior were measured with a spheroconical indenter. The results indicate variations in the values of the mechanical properties clearly associated with different structures present in the skeletons, the core being the one that invariably shows the maximum values. The solid multilamellar arrangement of black coral chitin, its viscoelastic behavior, and the anisotropic mechanical response, are relevant factors contributing to the successful adaptation of black coral colonies to shallow as well as to very deep waters. PMID- 22197648 TI - Water's potential role: Insights from studies of the p53 core domain. AB - Soluble proteins with amyloidogenic propensity such as the tumor suppressor protein p53 have high proportion of incompletely desolvated backbone H bonds (HB). Such bonds are vulnerable to water attack, thus potentially leading to the misfolding of these proteins. However, it is still not clear how the surrounding solvent influences the protein native states. To address this, systematic surveys by molecular dynamics simulations and entropy analysis were performed on the p53 core domain in this work. We examined seven wild/mutant X-ray structures and observed two types of water-network hydration in three "hot hydration centers" (DNA- or small molecule- binding surfaces of the p53 core domain). The "tight" water, resulting from the local collective hydrogen-bond interactions, is probably fundamental to the protein structural stability. The second type of water is highly "dynamical" and exchanges very fast within the bulk solution, which is unambiguously assisted by the local protein motions. An entropy mapping of the solvent around the protein and a temperature perturbation analysis further present the main features of the p53 hydration network. The particular environment created by different water molecules around the p53 core domain also partly explains the structural vulnerabilities of this protein. PMID- 22197649 TI - Different neuroprotective responses of Ginkgolide B and bilobalide, the two Ginkgo components, in ischemic rats with hyperglycemia. AB - Ginkgo biloba extracts show neuroprotective effects during cerebral ischemia, but with various components, the mechanisms of action remain unclear. In this study, we tested the effects of Ginkgolide B (GB) and bilobalide (BB) on normoglycemic and hyperglycemic rats subjected to transient cerebral ischemia. Rats were administered p.o. with different Ginkgo components GB (6 mg/kg) or BB (6 mg/kg) once daily for 7 days. Hyperglycemia was made by jugular vein infusion of glucose and transient middle cerebral artery occlusion/reperfusion was induced by a suture insertion technique. Results showed that both GB and BB exerted neuroprotection under normoglycemia, as determined by infarct volume and neurological deficit scores. Yet, BB showed less protective effects during hyperglycemic cerebral ischemia. Cerebral blood flow (CBF) was evaluated during occlusion and the first hour of reperfusion. BB but not GB caused acute increase in CBF after reperfusion, especially in hyperglycemia. Reactive oxygen species and malondialdehyde levels were reduced by GB in both models but BB were not effective in reactive oxygen species or malondialdehyde control in hyperglycemia ischemic rats. These results suggested that CBF plays crucial roles during early stage of reperfusion in the presence of hyperglycemia. Administration of compound that improves CBF may have little effect in hyperglycemic stroke. PMID- 22197650 TI - Low dose aspirin prevents duodenoesophageal reflux induced mucosal changes in wistar rat esophagus by MAP kinase mediated pathways. AB - BACKGROUND: Investigations of molecular mechanisms behind the progression of neoplastic changes in the esophagus have uncovered the role of the COX & 5-Lox pathways. Human squamous esophageal mucosa produces relatively large amounts of eicosanoids in the presence of inflammation. Laboratory and epidemiological data suggest that aspirin and non-steroidal anti-inflammatory drugs may be chemo preventive through their inhibitory effect on COX25, 10. Cell culture studies have shown that the members of the mitogen activated protein (MAP) kinase family plays an important role in the development of bile acid-induced carcinogenesis. Differences in MAPK pathways activated by bile exposure were also noted in esophageal squamous cell lines and biopsies from patients with GERD. The protective role of aspirin and its molecular mechanism is not well understood. AIMS: 1. The effect of duodenal reflux on esophageal mucosa. 2. The role of aspirin in preventing duodenal reflux induced esophageal mucosa changes. 3. If it is proven to be preventive, the mechanism of its action. A duodenal reflux rat animal model was used by an end- to-side esophago duodenostomy. METHODS: Total of 56 rats was included. 3 were "Naive control" animals which did not undergo the surgical procedure. The remaining animals were divided into two groups: Surgery alone (experimental) and Surgery + aspirin [therapy group], esophagoduodenostomy. At 40 weeks, the rats were euthanized and appropriate esophageal samples were analysed for histopathology and p38 & ERK MAP kinases, VEGF, protease activity and caspase 3 activities. RESULTS: The presence of gross mucosal nodularity was seen in 21 and 10 rats of the experimental and therapy group respectively (p = 0.03; Table 1). Reflux-associated changes such as basal cell hyperplasia were more common in the experimental group, however this association did not reach statistical significance (p = 0.15; Table 1). Epithelial hyperplasia was seen more in the experimental group, which was prevented by aspirin [p < 0.01]. Papillomatosis, as shown in Fig. 4 was more common in the experimental group (p = 0.02). Activation of p38 & ERK MAP kinases was prevented in aspirin group (p < 0.05, CI -1.796--0.014). Examination of protease activity by zymographic analysis of the esophageal samples revealed a number of gelatinolytic bands in 50% rats of the experimental group, not observed in the therapy group. No significant changes were seen in Caspase 3 [Normal areas -99.74 & nodular areas - 100.34 percent of controls] or VEGF [mean 0.64, sd +/- 0.76 Vs 0.69 +/- 0.96] activity. CONCLUSIONS: Our data demonstrated that low dose aspirin reduced the incidence of duodenoesophageal reflux induced histological changes in the esophagus by preventing activation of proliferative & anti-apoptotic MAP kinases such as p38 & ER as well as protease activity. Though Barretts' changes and adenocarcinoma have not developed, it could explain the role of duodenoesophageal reflux in the development of different histological but potential premalignant lesions and molecular level changes which are prevented by low dose aspirin. PMID- 22197651 TI - The synergy of working memory and inhibitory control: behavioral, pharmacological and neural functional evidences. AB - Concomitant deficits in working memory and behavioral inhibition in several psychiatric disorders like attention-deficit/hyperactivity disorder, addiction or mania, suggest that common brain mechanisms may underlie their etiologies. Based on the theoretical assumption that a continuum exists between health and mental disorders, we explored the relationship between working memory and inhibition in healthy individuals, through spontaneous inter individual differences in behavior, and tested the hypothesis of a functional link through the fronto striatal dopaminergic system. Rats were classified into three groups, showing good, intermediate and poor working memory and were compared for their inhibitory abilities. These two functions were simultaneously modulated by a dose-effect of d-amphetamine and in situ hybridization was used to quantify dopaminergic receptor (RD1) mRNAs in prefrontal cortex and striatal areas. A functional relationship between working memory and inhibition abilities was revealed. Both functions were similarly modulated by d-amphetamine according to an inverted-U shaped relationship and depending on initial individual performances. D amphetamine selectively improved working memory and inhibition of poor and intermediate performers at low doses whereas it impaired both processes in good performers at a higher dose. D1 receptors were less expressed in prelimbic, infralimbic and anterior cingulate cortices of good compared to intermediate and poor performers, whereas no difference was observed between groups in striatal areas. The synergy of working memory and inhibitory abilities, observed in both healthy and psychiatric populations, may originate from endogenous variability in dopaminergic prefrontal cortex activity. Such findings confirm the validity of a dimensional approach, based on the concept of continuity between health and mental disorders for identifying endophenotypes of mental disorders. PMID- 22197652 TI - Implementation of inpatient geriatric consultation teams and geriatric resource nurses in acute hospitals: a national survey study. AB - BACKGROUND: Inpatient geriatric consultation teams are multidisciplinary teams that advice and sensitize health care professionals in the hospital for the care of older patients. Despite the lack of clear evidence that these teams are effective, they were rated highly relevant and introduced in Belgian hospitals in 2007. OBJECTIVES: To evaluate the implementation and performance of geriatric consultation teams and geriatric resource nurses (GRNs) in Belgium. DESIGN: A cross-sectional survey was performed in March and April 2010. SETTING: Acute hospitals. PARTICIPANTS: Sixty-six hospitals completed the questionnaire (response rate of 68.8%); 63 geriatric consultation teams were included. METHODS: A newly developed questionnaire was sent to all hospitals. The head of the geriatric department completed the general parts of the questionnaire. The other parts, covering the organization of the consultation teams and geriatric resource nurses, respectively, were completed by the geriatrician or the head nurse of the geriatric consultation team. All data were analysed in a descriptive manner. RESULTS: The mean number of full time equivalents (FTE) per consultation team was 4.3 (SD+/-1.3; range 1.9-10.1). The nurse, represented by a mean of 1.7 FTE (SD+/ 0.8), was a core member in almost all teams (n=60; 98.4%). The occupational therapist, geriatrician, dietician, psychologist and speech therapist were core members in more than 59% of the teams. Twenty-seven teams (42.9%) estimated that more than 75% of the patients (>=75 years) were screened for having a geriatric profile. This screening was mostly performed using the Triage Risk Screening Tool (n=23) or the Identification of Seniors At Risk (n=20). A positive screening automatically resulted in a request for a geriatric consultation team intervention in 45 teams (71.4%). Thirty-five teams (55.5%) had an advisory role only, while the other 28 teams (44.5%) had both advisory and executive roles. The median number of patients for whom recommendations were formulated per year, was 423 (Q1=230; Q3=633). Most participants rated the function of GRNs as 'poor' or 'bad'. CONCLUSION: To increase their impact, inpatient geriatric consultation teams focus on frail older persons using screening tools for detection of high risk patients. More intense collaboration with GRNs is essential, and the function of GRNs needs further improvement. PMID- 22197653 TI - Cardiac rehabilitation and quality of life: a systematic review. AB - OBJECTIVE: The objective of this systematic review was to explore the effects of cardiac rehabilitation interventions on the quality of life of patients with coronary heart disease with a specific focus on interventions that could be delivered within the context of a publicly funded health service. DESIGN: Systematic review of trials reporting quality of life data as an outcome measure. Electronic databases (CINAHL, MEDLINE and PsycINFO) were searched from 1 January 1999 to 25 November 2010 in the English language. Inclusion criteria were: randomised controlled trials of cardiac rehabilitation as configured for a publicly funded health service. Data were extracted by one reviewer and checked by a second reviewer. RESULTS: The 16 papers reported RCTs conducted in nine countries. Fifteen measurement instruments were utilised to measure quality of life across the different studies precluding a meta-analysis. Four themes emerged from the thematic analysis of the selected papers: physical well-being (including fitness and symptoms); psychological well-being (including anxiety and depression); social well-being (including family life and relationships); and functional status (including return to work and previous life style). Physical domain outcomes suggest that cardiac rehabilitation may improve physical well being and levels of physical activity and thereby improved levels of physical fitness. Both physical and psychological domain outcomes suggest that home-based interventions are at least as effective as centre-based interventions. Relatively few trials reported on quality of life within the social domain and any difference between centre-based and home-based interventions appeared to favour the home-based intervention. CONCLUSIONS: This review indicates that cardiac rehabilitation improves the quality of life for coronary heart disease patients and that quality of life improvements have a bi-directional relationship with increased physical activity and vocational status. Further research is needed to explore the relationship of quality of life outcomes to cardiac mortality, the relationship between improved physical well-being and anxiety, and the quality of life and mortality effects of cardiac rehabilitation in older people. PMID- 22197654 TI - Haplotype frequency distribution for 7 microsatellites in chromosome 8 and 11 in relation to the metabolic syndrome in four ethnic groups: Tehran Lipid and Glucose Study. AB - INTRODUCTION: Different variants of haplotype frequencies may lead to various frequencies of the same variants in individuals with drug resistance and disease susceptibility at the population level. MATERIALS AND METHODS: In this study, the haplotype frequencies of 4 STR loci including the D8S1132, D8S1779, D8S514 and D8S1743, and 3 STR loci including D11S1304, D11S1998 and D11S934 were investigated in 563 individuals of four Iranian ethnic groups in the capital city of Iran, Tehran. One hundred thirty subjects had the metabolic syndrome. Haplotype frequencies of all markers were calculated. RESULTS: There were significant differences in the haplotype frequencies in short and long alleles between the metabolic affected subjects and controls. In addition, haplotype frequencies were significant in the four ethnic groups in both chromosomes 8 and 11. CONCLUSION: Our findings show a relation between the short allele of D8S1743 in all related haplotype frequencies of subjects with metabolic syndrome. These findings may require more studies of some candidate genes, including the lipoprotein lipase gene, in this chromosomal region. PMID- 22197655 TI - Genetic variation in the C-terminal domain of arginine vasotocin receptor in avian species. AB - Arginine vasotocin (AVT) is a neurohypophysial hormone that plays an essential role in various social behaviours. We investigated the degree of polymorphisms in the C-terminal domain of the AVT V2-type receptor (AVT2R) among avian species to determine the mechanism by which genetic polymorphisms in the neuropeptide receptor may contribute to different levels of signal transduction. In passerine birds, AVT2R was characterised by 2 variable regions, both of which were managed by insertion/deletion (indel); however, indels were rarely found in other avian taxa. The presence or absence of deletions in passerines largely affected the properties of the predicted palmitoylation sites at the proximal part of the C terminal tail. Moreover, we detected intraspecific polymorphisms in estrildid finches based on the number of tri-amino acid (GHQ/EHQ/EHR) repeats in another variable region. Our results indicate that amino acid substitutions and length variation at the C-terminus may impact subsequent signal transduction and affect behavioural traits in wild birds. PMID- 22197656 TI - PCR-RFLP analysis of mitochondrial DNA cytochrome b gene among Haruan (Channa striatus) in Malaysia. AB - Haruan (Channa striatus) is in great demand in the Malaysian domestic fish market. In the present study, mtDNA cyt b was used to investigate genetic variation of C. striatus among populations in Peninsular Malaysia. The overall population of C. striatus demonstrated a high level of haplotype diversity (h) and a low-to-moderate level of nucleotide diversity (pi). Analysis of molecular variance (AMOVA) results showed a significantly different genetic differentiation among 6 populations (F(ST)=0.37566, P=0.01). Gene flow (Nm) was high and ranged from 0.32469 to infinity (infinity). No significant relationship between genetic distance and geographic distance was detected. A UPGMA tree based on the distance matrix of net interpopulation nucleotide divergence (d(A)) and haplotype network of mtDNA cyt b revealed that C. striatus is divided into 2 major clades. The neutrality and mismatch distribution tests for all populations suggested that C. striatus in the study areas had undergone population expansion. The estimated time of population expansion in the mtDNA cyt b of C. striatus populations occurred 0.72-6.19 million years ago. Genetic diversity of mtDNA cyt b and population structure among Haruan populations in Peninsular Malaysia will be useful in fisheries management for standardization for Good Agriculture Practices (GAP) in fish-farming technology, as well as providing the basis for Good Manufacturing Practices (GMP). PMID- 22197657 TI - A novel silk-like shell matrix gene is expressed in the mantle edge of the Pacific oyster prior to shell regeneration. AB - During shell formation, little is known about the functions of organic matrices, especially about the biomineralization of shell prismatic layer. We identified a novel gene, shelk2, from the Pacific oyster presumed to be involved in the shell biosynthesis. The Pacific oyster has multiple copies of shelk2. Shelk2 mRNA is specifically expressed on the mantle edge and is induced during shell regeneration, thereby suggesting that Shelk2 is involved in shell biosynthesis. To our surprise, the database search revealed that it encodes a spider silk-like alanine-rich protein. Interestingly, most of the Shelk2 primary structure is composed of two kinds of poly-alanine motifs-GXNA(n)(S) and GSA(n)(S)-where X denotes Gln, Arg or no amino acid. Occurrence of common motifs of Shelk2 and spider silk led us to the assumption that shell and silk are constructed under similar strategies despite of their living environments. PMID- 22197658 TI - Properties of the inulinase gene levH1 of Lactobacillus casei IAM 1045; cloning, mutational and biochemical characterization. AB - Though some genetic features of lactobacillar fructan hydrolases were elucidated, information about their enzymology or mutational analyses were scarce. Lactobacillus casei IAM1045 exhibits extracellular activity degrading inulin. After partial purification of the inulin-degrading protein from the spent culture medium, several fragments were obtained by protease digestion. Based on their partial amino-acid sequences, oligonucleotide primers were designed, and its structural gene (levH1) was determined using the gene library constructed in the E. coli system. The levH1 gene encoded a protein (designated as LevH1), of which calculated molecular mass and pI were 138.8-kDa and 4.66, respectively. LevH1 (1296 amino-acids long) was predicted to have a four-domain structure, containing (i) an N-terminal secretion signal of 40 amino-acids, (ii) variable domain of about 140 residues whose function is unclear, (iii) a catalytic domain of about 630 residues with glycoside-hydrolase activity consisting of two modules, a five blade beta-propeller module linked to a beta-sandwich module, (iv) a C-terminal domain of about 490 residues comprising five nearly perfect repeat sequences of 80 residues homologous to equivalents of other hypothetical cell surface proteins, followed by 37-residues rich in Ser/Thr/Pro/Gly, a pentad LPQAG (the LPXTG homologue). When overproduced in E. coli, the putative variable-catalytic domain region of about 770 residues exhibited exo-inulinase activity. Deletion analyses demonstrated that the variable-catalytic domain region containing two modules is important for enzymatic activity. Presence of eight conserved motifs (I-VIII) was suggested in the catalytic domain by comparative analysis, among which motif VIII was newly identified in the beta-sandwich module in this study. Site-directed mutagenesis of conserved amino-acids in these motifs revealed that D198, R388, D389 and E440, were crucial for inulinase activity. Moreover, mutations of D502A and D683A in motif VI and VIII respectively caused significant decrease in the activity. These results suggested that the variable domain and beta-sandwich module, besides the beta-propeller module, are important for inulin degrading activity of LevH1. PMID- 22197659 TI - Transcriptome analysis of tree peony during chilling requirement fulfillment: assembling, annotation and markers discovering. AB - Tree peony (Paeonia suffruticosa Andrews) is a well-known horticultural and medicinal plant. The flower buds must go through a period of endo-dormancy before bud sprouting in winter, but very little information concerned with dormancy release is available. We obtained 625,342 sequencing reads with massive parallel pyrosequencing on the Roche 454 GS FLX platform (mean length: 358.1bp). De novo assemblies yielded 23,652 contigs and singletons. 15,284 contigs longer than 300bp were further annotated, among them 12,345 ESTs showed significant similarity with sequences present in public databases (with an E-value <1e-10). 484 putative transcription factors were obtained. In addition, 2253 potential Simple Sequence Repeats (SSR) loci were identified in the 454-ESTs. Total 149 pairs of primers were designed, and 121 pairs were amplified successfully in initial screening. In addition, 73 pairs of primers displayed polymorphism. This sequence collection provides a significant resource for gene discovery during endo-dormancy of tree peony. PMID- 22197660 TI - Variability of tetrodotoxin and of its analogues in the red-spotted newt, Notophthalmus viridescens (Amphibia: Urodela: Salamandridae). AB - Efts and adult specimens (n = 142) of the red-spotted newt Notophthalmus viridescens from various locations in Canada and USA were analyzed for the presence of tetrodotoxin (TTX) and of its analogues 6-epitetrodotoxin and 11 oxotetrodotoxin. Considerable individual variations in toxin levels were found within and among populations from New Hampshire, New York, Pennsylvania, and Virginia ranging from non-detectable to 69 MUg TTX per g newt. TTX and its analogues were absent in efts and adults from various locations in the Canadian province Nova Scotia, the northernmost distribution of the newt, and in adults from Florida. Newts kept in captivity for several years and reared on toxin-free diet lost their toxicity. Bayesian and maximum likelihood phylogenetic analysis of specimens from the various populations using three phylogenetic markers (COI, ND2 and 16S RNA) revealed that populations from the northern states of the USA and Canada are genetically homogenous, whereas the newts from Florida exhibited a much higher level of genetic divergence. An exogenous source of TTX in the newts either via the food chain or by synthesis of symbiotic bacteria is suggested to explain the high variability and lack of TTX in certain populations. PMID- 22197661 TI - Neurochemical consequence of steroid abuse: stanozolol-induced monoaminergic changes. AB - An extensive literature has documented adverse effects on mental health in anabolic androgenic steroids (AAS) abusers. Depression seems a common adverse reaction in AAS abusers. Recently it has been reported that in a rat model of AAS abuse stanozolol induces behavioural and biochemical changes related to the pathophysiology of major depressive disorder. In the present study, we used the model of AAS abuse to examine possible changes in the monoaminergic system, a neurobiological substrate of depression, in different brain areas of stanozolol treated animals. Wistar rats received repeated injections of stanozolol (5mg/kg, s.c.), or vehicle (propylene glycol, 1ml/kg) once daily for 4weeks. Twenty-four hours after last injection, changes of dopamine (DA) and relative metabolite levels, homovanilic acid (HVA) and 3,4-dihydroxy phenylacetic acid (DOPAC), serotonin (5-HT) and its metabolite levels, 5-hydroxy indolacetic acid (5-HIAA), and noradrenaline (NA) amount were investigated in prefrontal cortex (PFC), nucleus accumbens (NAC), striatum (STR) and hippocampus (HIPP). The analysis of data showed that after chronic stanozolol, DA levels were increased in the HIPP and decreased in the PFC. No significant changes were observed in the STR or in the NAC. 5-HT and 5-HIAA levels were decreased in all brain areas investigated after stanozolol exposure; however, the 5-HIAA/5-HT ratio was not altered. Taken together, our data indicate that chronic use of stanozolol significantly affects brain monoamines leading to neurochemical modifications possibly involved in depression and stress-related states. PMID- 22197662 TI - Physalins with anti-inflammatory activity are present in Physalis alkekengi var. franchetii and can function as Michael reaction acceptors. AB - Michael reaction acceptors (MRAs) are a class of active molecules that are directly or indirectly involved in various cellular processes, including the regulation of many signaling pathways. In this study, the inducible nitric oxide synthase (iNOS) assay was used to demonstrate that the dichloromethane extract of Physalis alkekengi var. franchetii (DCEP) possesses anti-inflammatory activity that might be attributed to the modification of key cysteine residues in IKKbeta by the MRAs in DCEP. To isolate these MRAs, glutathione (GSH) was employed, and a simple ultra-performance liquid chromatography/tandem mass spectrometry (UPLC MS/MS) screening method was developed to investigate the GSH conjugates with potential MRAs. Five physalins, including one new compound isophysalin A (2), together with four known steroidal compounds, physalin A (1), physalin O (3), physalin L (4) and physalin G (5), were isolated to evaluate the GSH conjugating abilities, and it was indicated that compounds 1, 2 and 3, which had a common alpha,beta-unsaturated ketone moiety, exhibited conjugating abilities with GSH and also showed significant nitric oxide (NO) production inhibiting activities. The anti-inflammatory activities of compounds 1, 2 and 3 might be attributed to their targeting multiple cysteine residues on IKKbeta; therefore, the alkylation of IKKbeta by compound 1 was further studied by micrOTOF-MS. The result showed that six cysteine residues (C(59), C(179), C(299), C(370), C(412), and C(618)) were alkylated, which indicated that IKKbeta is a potential target for the anti inflammatory activity of physalin A. PMID- 22197663 TI - Dyslipidemia in PCOS. AB - Life-long apolipoprotein lipid metabolic dysfunction in women with PCOS exaggerates the risk for cardiovascular disease (CVD) with aging. The dysfunction has involved insulin resistance (IR), which occurs in most women with PCOS. Women with PCOS have androgen excess, IR, variable amounts of estrogen exposure, and many environmental factors, all of which can influence lipid metabolism. On average, women with PCOS were higher triglyceride [26.39 95% CI (17.24, 35.54)], lower HDL-cholesterol [6.41 95% CI (3.69, 9.14)], and higher non HDL cholesterol levels [18.82 95% CI (15.53, 22.11)] than their non-PCOS counterparts. They have higher ApoCIII/ApoCII ratios and higher ApoCI even if they are not obese. ApoC1 elevation in women with PCOS needs to be further evaluated as a marker of dysfunction and potential CVD risk. ApoB measurements track with non-HDL cholesterol as a surrogate for increased atherogenic circulating small LDL particles. Elevated triglycerides and waist circumference predict CVD risk and women with PCOS often have these phenotypes. Diet and exercise interventions followed by selective lipid lowering medications are encouraged to normalize the dyslipidemia. PMID- 22197664 TI - Ability of Cricetomys rats to detect Mycobacterium tuberculosis and discriminate it from other microorganisms. AB - Trained African giant pouched rats (Cricetomys gambianus) have potential for diagnosis of tuberculosis (TB). These rats target volatile compounds of Mycobacterium tuberculosis (Mtb) that cause TB. Mtb and nontuberculous mycobacteria (NTM) species are related to Nocardia and Rhodococcus spp., which are also acid-fast bacilli and can be misdiagnosed as Mtb in smear microscopy. Diagnostic performance of C. gambianus on in vitro-cultured mycobacterial and related pulmonary microbes is unknown. This study reports on the response of TB detection rats to cultures of reference Mtb, clinical Mtb, NTM, Nocardia; Rhodococcus; Streptomyces; Bacillus; and yeasts. Trained rats significantly discriminated Mtb from other microbes (p < 0.008, Fisher's exact test). Detection of Mtb cultures was age-related, with exponential and early stationary phase detected more frequently than early log phase and late stationary phase (p < 0.001, Fisher's test) (sensitivity = 83.33%, specificity = 94.4%, accuracy = 94%). The detection of naturally TB-infected sputum exceeded that of negative sputum mixed with Mtb, indicating that C. gambianus are conditioned to detect odours of TB-positive sputum better than spiked sputum. Although further studies on volatiles from detectable growth phases of Mtb are vital for identification of Mtb-specific volatiles detected by rats, our study underline the potential of C. gambianus for TB diagnosis. PMID- 22197665 TI - A dynamic model for assessing the effects of management strategies on the reduction of construction and demolition waste. AB - During the past few decades, construction and demolition (C&D) waste has received increasing attention from construction practitioners and researchers worldwide. A plethora of research regarding C&D waste management has been published in various academic journals. However, it has been determined that existing studies with respect to C&D waste reduction are mainly carried out from a static perspective, without considering the dynamic and interdependent nature of the whole waste reduction system. This might lead to misunderstanding about the actual effect of implementing any waste reduction strategies. Therefore, this research proposes a model that can serve as a decision support tool for projecting C&D waste reduction in line with the waste management situation of a given construction project, and more importantly, as a platform for simulating effects of various management strategies on C&D waste reduction. The research is conducted using system dynamics methodology, which is a systematic approach that deals with the complexity - interrelationships and dynamics - of any social, economic and managerial system. The dynamic model integrates major variables that affect C&D waste reduction. In this paper, seven causal loop diagrams that can deepen understanding about the feedback relationships underlying C&D waste reduction system are firstly presented. Then a stock-flow diagram is formulated by using software for system dynamics modeling. Finally, a case study is used to illustrate the validation and application of the proposed model. Results of the case study not only built confidence in the model so that it can be used for quantitative analysis, but also assessed and compared the effect of three designed policy scenarios on C&D waste reduction. One major contribution of this study is the development of a dynamic model for evaluating C&D waste reduction strategies under various scenarios, so that best management strategies could be identified before being implemented in practice. PMID- 22197666 TI - Methane and carbon dioxide production from simulated anaerobic degradation of cattle carcasses. AB - Approximately 2.2million cattle carcasses require disposal annually in the United States. Land burial is a convenient disposal method that has been widely used in animal production for disposal of both daily mortalities as well as during catastrophic mortality events. To date, greenhouse gas production after mortality burial has not been quantified, and this study represents the first attempt to quantify greenhouse gas emissions from land burial of animal carcasses. In this study, anaerobic decomposition of both homogenized and unhomogenized cattle carcass material was investigated using bench-scale reactors. Maximum yields of methane and carbon dioxide were 0.33 and 0.09m(3)/kg dry material, respectively, a higher methane yield than that previously reported for municipal solid waste. Variability in methane production rates were observed over time and between reactors. Based on our laboratory data, annual methane emissions from burial of cattle mortalities in the United States could total 1.6Tg CO(2) equivalents. Although this represents less than 1% of total emissions produced by the agricultural sector in 2009, greenhouse gas emissions from animal carcass burial may be significant if disposal of swine and poultry carcasses is also considered. PMID- 22197667 TI - Leachate formation and characteristics from gasification and grate incineration bottom ash under landfill conditions. AB - Characteristics and formation of leachates from waste gasification and grate firing bottom ash were studied using continuous field measurements from 112 m(3) lysimeters embedded into landfill body for three years. In addition, the total element concentrations of the fresh ash were analysed and laboratory batch tests were performed to study leachate composition. The three-year continuous flow measurement showed that about one fifth of the leachates were formed, when the flow rate was >200 l/d, covering <3.5% of the study time. After three years, the liquid/solid-ratio for the quenched grate ash was 1 (l/kg (d.m.)) and for the initially dry gasification ash 0.4 (l/kg (d.m.)). The low initial water and residual carbon content of the gasification ash kept the leachate pH at a high level (>13) major part of the study. In the grate ash leachate pH was lower (<8) due to the presence of organic carbon and biodegradation indicated by biological oxygen demand and redox potential measurements. In the gasification ash the high pH probably delayed leaching of major elements such as Ca, therefore, raising the need for a longer after-care period. The high pH also explains the higher leaching of As from the gasification ash compared to the grate ash both in the batch test and under landfill conditions. PMID- 22197669 TI - Functional peptidomics of amphibian skin secretion: A novel Kunitz-type chymotrypsin inhibitor from the African hyperoliid frog, Kassina senegalensis. AB - Amphibian skin secretions are, for the most part, complex peptidomes. While many peptide components have been biologically- and structurally-characterised into discrete "families", some of which are analogues of endogenous vertebrate regulatory peptides, a substantial number are of unique structure and unknown function. Among the components of these secretory peptidomes is an array of protease inhibitors. Inhibitors of trypsin are of widespread occurrence in different taxa and are representative of many established structural classes, including Kunitz, Kazal and Bowman-Birk. However, few protease inhibitors with activity against other specific proteases have been described from this source. Here we report for the first time, the isolation and structural characterisation of an inhibitor of chymotrypsin of Kunitz-type from the skin secretion of the African hyperoliid frog, Kassina senegalensis. To this end, we employed a functional peptidomic approach. This scheme involves fractionation of the peptidome, functional end-point screening, structural characterisation of resultant actives followed by molecular cloning of biosynthetic precursor encoding cDNA(s). The novel mature and active polypeptide identified consisted of 62 amino acid residues (average molecular mass 6776.24 Da), of which 6 were positionally-conserved cysteines. The P(1) position within the active site was occupied by a phenylalanyl residue. Bioinformatic analysis of the sequence using BLAST, revealed a structural similarity to Kunitz-type chymotrypsin inhibitors from other organisms, ranging from silkworms to snakes. PMID- 22197668 TI - CB2: therapeutic target-in-waiting. AB - CB2 cannabinoid receptor agonists hold promise as a new class of therapeutics for indications as diverse as pain, neuroinflammation, immune suppression and osteoporosis. These potential indications are supported by strong preliminary data from multiple investigators using diverse preclinical models. However, clinical trials for CB2 agonists, when they have been reported have generally been disappointing. This review considers possible explanations for the mismatch between promising preclinical data and disappointing clinical data. We propose that a more careful consideration of CB2 receptor pharmacology may help move CB2 agonists from "promising" to "effective" therapeutics. PMID- 22197670 TI - Synthesis of quinolinomorphinan-4-ol derivatives as delta opioid receptor agonists. AB - The previously reported morphinan derivative SN-28 showed high selectivity and agonist activity for the delta opioid receptor. In the course of examining the structure-activity relationship of SN-28 derivatives, the derivatives with the 4 hydroxy group (SN-24, 26, 27) showed higher selectivities for the delta receptor over the MU receptor than the corresponding SN-28 derivatives with the 3-hydroxy group (SN-11, 23, 28). Derivatives with the 4-hydroxy group showed potent agonist activities for the delta receptor in the [(35)S]GTPgammaS binding assay. Although the 17-cyclopropylmethyl derivative (SN-11) with a 3-hydroxy group showed the lowest selectivity for the delta receptor among the morphinan derivatives, the agonist activity toward the delta receptor was the most potent for candidates with the 3-hydroxy group. PMID- 22197671 TI - Antioxidant properties of 4-quinolones and structurally related flavones. AB - Neurodegenerative disorders are frequently associated with increased oxidative damage to the brain as a result of free radicals produced by cellular respiration. The onset and progression of neurodegeneration may therefore be curbed by exogenous hydrogen-donating antioxidant moieties such as the naturally occurring flavonoids. A series of 2-phenylquinolin-4(1H)-ones was synthesised and displayed moderate to high antioxidant activity when compared to structurally related flavones and quinolines. Activity of the hydroxy-2-phenylquinolin-4(1H) ones (8-10) was established in reducing ferrous ions and diminishing hydrogen peroxide and hydroxyl radical production, in the FRAP (1.41-97.71% Trolox equivalents), ORAC (9.18-15.27 MUM Trolox equivalents at 0.00 1mM) and TBARS (0.05-0.72 nmol MDA/mg tissue) assays, respectively. The results indicated that the additional hydrogen donating groups on the synthesised 2-phenylquinolin-4(1H) one series increased antioxidant activity. PMID- 22197672 TI - Prediction of sites of metabolism in a substrate molecule, instanced by carbamazepine oxidation by CYP3A4. AB - In drug discovery process, improvement of ADME/Tox properties of lead compounds including metabolic stability is critically important. Cytochrome P450 (CYP) is one of the major metabolizing enzymes and the prediction of sites of metabolism (SOM) on the given lead compounds is key information to modify the compounds to be more stable against metabolism. There are two factors essentially important in SOM prediction. First is accessibility of each substrate atom to the oxygenated Fe atom of heme in a CYP protein, and the other is the oxidative reactivity of each substrate atom. To predict accessibility of substrate atoms to the heme iron, conventional protein-rigid docking simulations have been applied. However, the docking simulations without consideration of protein flexibility often lead to incorrect answers in the case of very flexible proteins such as CYP3A4. In this study, we demonstrated an approach utilizing molecular dynamics (MD) simulation for SOM prediction in which multiple MD runs were executed using different initial structures. We applied this strategy to CYP3A4 and carbamazepine (CBZ) complex. Through 10 ns MD simulations started from five different CYP3A4-CBZ complex models, our approach correctly predicted SOM observed in experiments. The experimentally known epoxidized sites of CBZ by CYP3A4 were successfully predicted as the most accessible sites to the heme iron that was judged from a numerical analysis of calculated DeltaG(binding) and the frequency of appearance. In contrast, the predictions using protein-rigid docking methods hardly provided the correct SOM due to protein flexibility or inaccuracy of the scoring functions. Our strategy using MD simulation with multiple initial structures will be one of the reliable methods for SOM prediction. PMID- 22197673 TI - Clostridium difficile and routine cleaning--alternative options to the use of stronger chlorine-releasing disinfectants. PMID- 22197674 TI - Serology and cytokine profiles in patients infected with the newly discovered Bundibugyo ebolavirus. AB - A new species of Ebolavirus, Bundibugyo ebolavirus, was discovered in an outbreak in western Uganda in November 2007. To study the correlation between fatal infection and immune response in Bundibugyo ebolavirus infection, viral antigen, antibodies, and 17 soluble factors important for innate immunity were examined in 44 patient samples. Using Luminex assays, we found that fatal infection was associated with high levels of viral antigen, low levels of pro-inflammatory cytokines, such as IL-1alpha, IL-1beta, IL-6, TNF-alpha, and high levels of immunosuppressor cytokines like IL-10. Also, acute infected patients died in spite of generating high levels of antibodies against the virus. Thus, our results imply that disease severity in these patients is not due to the multi organ failure and septic shock caused by a flood of inflammatory cytokines, as seen in infections with other Ebolavirus species. PMID- 22197675 TI - Renaissance of autologous stem cell transplantation for AML? PMID- 22197677 TI - Measuring thigmotaxis in larval zebrafish. AB - One of the most commonly used behavioral endpoints measured in preclinical studies using rodent models is thigmotaxis (or "wall-hugging"). Thigmotaxis is a well-validated index of anxiety in animals and humans. While assays measuring thigmotaxis in adult zebrafish have been developed, a thigmotaxis assay has not yet been validated in larval zebrafish. Here we present a novel assay for measurement of thigmotaxis in zebrafish larvae that is triggered by a sudden change in illumination (i.e. sudden light-to-darkness transition) and performed in a standard 24-well plate. We show that zebrafish larvae as young as 5 days post fertilization respond to this challenge by engaging in thigmotaxis. Thigmotaxis was significantly attenuated by anxiolytic (diazepam) and significantly enhanced by anxiogenic (caffeine) drugs, thus representing the first validated thigmotaxis assay for larval zebrafish. We also show that exposure to sudden darkness per se may represent an anxiogenic situation for larval zebrafish since less contrasting light-to-darkness transitions (achieved by lowering darkness degrees) significantly decreased thigmotaxis levels in a manner similar to what was achieved with diazepam. These findings suggest that stimuli such as exposure to sudden darkness could be used proficiently to trigger the expression of anxiety-like behaviors in laboratory settings. In sum, this is a versatile protocol allowing testing of both anxiolytic and anxiogenic drugs in a cost-effective manner (only 10 min). This assay is also amenable to medium to high-throughput capacity while constituting a valuable tool for stress and central nervous system research as well as for preclinical drug screening and discovery. PMID- 22197676 TI - Prediction of post-remission survival in acute myeloid leukaemia: a post-hoc analysis of the AML96 trial. AB - BACKGROUND: The optimum post-remission treatment (PRT) in acute myeloid leukaemia (AML) is still a matter of debate. Consolidation treatments include chemotherapy with high-dose cytarabine, or allogeneic or autologous haemopoietic stem cell transplantation (HSCT). In a post-hoc analysis of the AML96 trial (NCT00180115), our aim was to differentiate groups of patients according to the treatments that would provide them optimum benefit. METHODS: In the multicentre AML96 trial, 586 patients (aged 15-60 years) with AML--excluding those with t(8;21)--who were in complete remission after double induction treatment were consolidated with allogeneic HSCT, autologous HSCT, or chemotherapy containing high-dose cytarabine in a priority-based and risk-adapted manner. We assessed the association between potentially prognostic variables and overall survival after complete remission by use of a stratified Cox regression analysis. With the significant variables of the resulting model, we developed a PRT score in 452 patients with a complete dataset. This score was then validated by use of data from 407 patients from the AML2003 trial (NCT00180102). FINDINGS: Age, percentage of CD34-positive blasts, FLT3-ITD mutant-to-wild-type ratio, cytogenetic risk, and de-novo or secondary AML were identified as independent prognostic factors, and included in the PRT score. The PRT score separated patients in AML96 into three groups: favourable (n=190; 3-year survival 68%, 95% CI 60-74), intermediate (n=198; 49%, 42-56), and unfavourable (n=64; 20%, 12-31). All pair-wise comparisons of two of three PRT score groups were significant in the log-rank test (p<0.0001). Similar results were noted when data from AML2003 were used: 3-year survival for the favourable group (n=265) was 69% (62-76), for the intermediate group (n=114) it was 61% (50 71), and for the unfavourable group (n=28) it was 46% (24-65). The overall comparison between the three risk groups resulted in significantly different survival probabilities (p=0.015). We also analysed response to treatment in AML96 in each of the PRT score groups. In the favourable group, patients given allogeneic HSCT (n=60) had higher survival probabilities (82%, 69-89) than did those given chemotherapy (n=56, 55%, 41-67; p=0.0012) or autologous HSCT (n=74, 66%, 54-76; p=0.044). In the intermediate PRT score group, patients given autologous HSCT (n=69) had the best survival probabilities (62%, 50-72) compared with those given chemotherapy (n=72, 41%, 30-52; p=0.0006) or allogeneic HSCT (n=57, 44%, 31-56; p=0.0045). INTERPRETATION: The PRT score groups could help physicians to tailor treatment for patients with AML and our results lend support to the use of autologous HSCT in patients aged 60 years or younger with an intermediate PRT score. FUNDING: Deutsche Krebshilfe. PMID- 22197679 TI - Differential processing of social chemosignals obtained from potential partners in regards to gender and sexual orientation. AB - On an individual level, human body odors carry information about whether a person is an eligible mate. The current studies investigate if body odors also transmit information about individuals being potential partners in more general terms, namely in regards to gender and sexual orientation. In study 1, 14 gay and 14 heterosexual men were presented with body odors obtained from potential partners (gay male and heterosexual female body odors, respectively) and heterosexual male body odor as a control. In study 2, 14 lesbian and 14 heterosexual women were presented with lesbian female and heterosexual male body odors representing body odors of potential partners, and heterosexual female body odor as a control. Central nervous processing was analyzed using chemosensory event-related potentials and current source density analysis (64-channel EEG recording). Gay and heterosexual men responded with shorter P2 latencies to the body odors of their preferred sexual partners, and lesbian women responded with shorter P2 latencies to body odors of their preferred gender. In response to heterosexual male body odors, lesbian women displayed the most pronounced P3 amplitude, and distinct neuronal activation in medial frontal and parietal neocortical areas. A similar pattern of neuronal activation was observed in gay men when presented with heterosexual male body odor. Both the early processing advantage (P2) for desirable partners' body odors as well as the enhanced evaluative processing (P3, CSD) of undesirable partners' body odors suggest that human body odors indeed carry information about individuals being potential partners in terms of gender and sexual orientation. PMID- 22197678 TI - Expression of HIV-Tat protein is associated with learning and memory deficits in the mouse. AB - HIV-Tat protein has been implicated in the pathogenesis of HIV-1 neurological complications (i.e., neuroAIDS), but direct demonstrations of the effects of Tat on behavior are limited. GT-tg mice with a doxycycline (Dox)-inducible and brain selective tat gene coding for Tat protein were used to test the hypothesis that the activity of Tat in brain is sufficient to impair learning and memory processes. Western blot analysis of GT-tg mouse brains demonstrated an increase in Tat antibody labeling that seemed to be dependent on the dose and duration of Dox pretreatment. Dox-treated GT-tg mice tested in the Barnes maze demonstrated longer latencies to find an escape hole and displayed deficits in probe trial performance versus uninduced GT-tg littermates, suggesting Tat-induced impairments of spatial learning and memory. Reversal learning was also impaired in Tat-induced mice. Tat-induced mice additionally demonstrated long-lasting (up to one month) deficiencies in novel object recognition learning and memory performance. Furthermore, novel object recognition impairment was dependent on the dose and duration of Dox exposure, suggesting that Tat exposure progressively mediated deficits. These experiments provide evidence that Tat protein expression is sufficient to mediate cognitive abnormalities seen in HIV-infected individuals. Moreover, the genetically engineered GT-tg mouse may be useful for improving our understanding of the neurological underpinnings of neuroAIDS related behaviors. PMID- 22197680 TI - SMN deficiency attenuates migration of U87MG astroglioma cells through the activation of RhoA. AB - Spinal muscular atrophy (SMA) is a neurodegenerative disease that affects alpha motoneurons in the spinal cord caused by homozygous deletion or specific mutations in the survival motoneuron-1 (SMN1) gene. Cell migration is critical at many stages of nervous system development; to investigate the role of SMN in cell migration, U87MG astroglioma cells were transduced with shSMN lentivectors and about 60% reduction in SMN expression was achieved. In a monolayer wound-healing assay, U87MG SMN-depleted cells exhibit reduced cell migration. In these cells, RhoA was activated and phosphorylated levels of myosin regulatory light chain (MLC), a substrate of the Rho kinase (ROCK), were found increased. The decrease in cell motility was related to activation of RhoA/Rho kinase (ROCK) signaling pathway as treatment with the ROCK inhibitor Y-27632 abrogated both the motility defects and MLC phosphorylation in SMN-depleted cells. As cell migration is regulated by continuous remodeling of the actin cytoskeleton, the actin distribution was studied in SMN-depleted cells. A shift from filamentous to monomeric (globular) actin, involving the disappearance of stress fibers, was observed. In addition, profilin I, an actin-sequestering protein showed an increased expression in SMN-depleted cells. SMN is known to physically interact with profilin, reducing its actin-sequestering activity. The present results suggest that in SMN-depleted cells, the increase in profilin I expression and the reduction in SMN inhibitory action on profilin could lead to reduced filamentous actin polymerization, thus decreasing cell motility. We propose that the alterations reported here in migratory activity in SMN-depleted cells, related to abnormal activation of RhoA/ROCK pathway and increased profilin I expression could have a role in developing nervous system by impairing normal neuron and glial cell migration and thus contributing to disease pathogenesis in SMA. PMID- 22197681 TI - Characterization of subtypes of the influenza A hemagglutinin (HA) gene using profile hidden Markov models. AB - BACKGROUND: The influenza A virus has evolved into 16 hemagglutinin (HA) subtypes with different antigenic properties. Thus far typing has been primarily assay based, but the many sequences available from the US National Center for Biotechnology Information (NCBI) offer alternative ways of characterizing the HA gene. METHODS: All available HA sequences from the NCBI were analyzed. The software package HMMER was used to score how a training sequence fitted a profile hidden Markov model (profile HMM) constructed from the consensus sequence of one particular HA subtype, Hx, where x=1 to 16. Scores from sequences of the same subtype and from other subtypes were then compared to see if they were separable. This approach was implemented in a stepwise manner, utilizing a sliding window of 100 amino acids with 10-amino-acid increments to build many subtype-specific models, and then assessing which 100-amino acid segments yielded the desired differentiability. RESULTS: Segment-based analysis revealed domains that correlate to HA sequence heterogeneity from one subtype to the others. For example, we showed that H1 segments covering only the second half of HA are not statistically separable from H2, H5 and H6 within the same region, suggesting evolutionary relatedness for these subtypes. The HA1 domain was found to be mostly differentiable between subtypes, which is in line with wet-lab findings that the domain is antigenicity-rich. We also reported a couple of regions that can be conveniently used to characterize all HA subtypes. CONCLUSION: We established an analysis framework for assessing sequence-subtype association to provide insights into HA subtypes with close evolutionary relationships. PMID- 22197682 TI - You shouldn't take it with you: postmortem device reuse. PMID- 22197683 TI - Gap junctions, stem cells, and cell therapy: rhythmic/arrhythmic implications. PMID- 22197684 TI - Dihydrolipoyl dioleoylglycerol antioxidant capacity in phospholipid vesicles. AB - Antioxidants have critical roles in maintaining cellular homeostasis and disease state prevention. The multi-functional agent alpha-lipoic acid offers numerous beneficial effects to oxidatively stressed tissues. alpha-Lipoic acid was enzymatically incorporated into a triglyceride in conjunction with oleic acid, creating lipoyl dioleoylglycerol, and chemically reduced to form dihydrolipoyl dioleoylglycerol. The triglyceride forms of lipoic acid stabilized dioleoylphosphatidylcholine unilamellar liposomal vesicles, as judged by calcein cobalt leakage. Stabilization resulted from increased packing density of phospholipid acyl chains. Scavenging activity against the 2,2'-azobis(2 amidinopropane) dihydrochloride (AAPH) radical was monitored by oxidation of 4,4 difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a,4a-diaza-s-indacene-3-undecanoic acid (C(11)-Bodipy). Dihydrolipoyl dioleoylglycerol in vesicles demonstrated strong antioxidant capacity in comparison to the conventional Trolox standard. Fluorescence quenching measurements indicated the lipoyl moiety of dihydrolipoyl dioleoylglycerol is positioned near the vesicle aqueous/lipid boundary. Treatment of intact vesicles with a nonpenetrating sulfhydryl reagent indicated that 80% of the dihydrolipoyl dioleoylglycerol was available for reaction. Molecular modeling of lipoyl dioleoylglycerol and dihydrolipoyl dioleoylglycerol in a phospholipid layer confirmed the existence of an extended configuration for the molecules that accounts for the interfacial location of the lipoyl moiety, which may allow the antioxidant to readily react with radical species approaching membranes from the aqueous phase. PMID- 22197686 TI - Association between ABCB1 gene polymorphisms and fentanyl's adverse effects in Turkish patients undergoing spinal anesthesia. AB - The ATP-binding cassette transporter (ABCB1) gene product, P-glycoprotein plays an important role in the prevention of intracellular accumulation of potentially toxic substances and metabolites in various tissues. Single nucleotide polymorphisms in this gene are claimed to be correlated with changes in the function of P-glycoprotein. There is evidence that fentanyl, may be a substrate for P-glycoprotein. The aim of the study was to assess whether an association exists between ABCB1 gene polymorphism and early respiratory and sedative adverse effects of intravenous fentanyl in Turkish patients who underwent spinal anesthesia In all 83 unrelated Turkish patients were enrolled in this study. In this study, spinal anesthesia was provided and a single dose of intravenous fentanyl (2.5MUg.kg(-1)) at the beginning of surgery was used as a sedative agent. Bispectral index, respiration rate and peripheral oxygen saturation were measured continuously and recorded throughout the study. The allele and genotype frequencies were similar to previous data from Turkish population. Respiratory rate (RR) and SpO(2) parameters of the patients did not show any significant difference according to the genotype distribution for C1236T and C3435T SNPs. Fentanyl-induced decrease in respiration rate was most remarkable at 15min (23%) in CC genotype of C1236T, whereas in TT genotype of C3435T (18%) polymorphism. SpO(2) parameters in allele distribution were also not significant among the groups (p=0.374, p=0.985, respectively). For the C1236T polymorphism, patients carrying T allele showed a significant decrease in pH, and a significant increase in pCO(2) (p<0.001). ABCB1 polymorphisms did not seem to have a significant effect on sedation and respiratory depression caused by intravenous fentanyl in spinal anesthesia in Turkish patients. PMID- 22197685 TI - Synergy in cancer treatment between liposomal chemotherapeutics and thermal ablation. AB - Minimally invasive image-guided tumor ablation using short duration heating via needle-like applicators using energies such as radiofrequency or microwave has seen increasing clinical use to treat focal liver, renal, breast, bone, and lung tumors. Potential benefits of this thermal therapy include reduced morbidity and mortality compared to standard surgical resection and ability to treat non surgical patients. However, improvements to this technique are required as achieving complete ablation in many cases can be challenging particularly at margins of tumors>3 cm in diameter and adjacent to blood vessels. Thus, one very promising strategy has been to combine thermal tumor ablation with adjuvant nanoparticle-based chemotherapy agents to improve efficiency. Here, we will primarily review principles of thermal ablation to provide a framework for understanding the mechanisms of combination therapy, and review the studies on combination therapy, including presenting preliminary data on the role of such variables as nanoparticle size and thermal dose on improving combination therapy outcome. We will discuss how thermal ablation can also be used to improve overall intratumoral drug accumulation and nanoparticle content release. Finally, in this article we will further describe the appealing off-shoot approach of utilizing thermal ablation techniques not as the primary treatment, but rather, as a means to improve efficiency of intratumoral nanoparticle drug delivery. PMID- 22197688 TI - Early network alterations in the subiculum of offspring following gestational maternal immune activation. PMID- 22197687 TI - Heritability and genome-wide linkage analysis of migraine in the genetic isolate of Norfolk Island. AB - Migraine is a common neurovascular disorder with a complex envirogenomic aetiology. In an effort to identify migraine susceptibility genes, we conducted a study of the isolated population of Norfolk Island, Australia. A large portion of the permanent inhabitants of Norfolk Island are descended from 18th Century English sailors involved in the infamous mutiny on the Bounty and their Polynesian consorts. In total, 600 subjects were recruited including a large pedigree of 377 individuals with lineage to the founders. All individuals were phenotyped for migraine using International Classification of Headache Disorders II criterion. All subjects were genotyped for a genome-wide panel of microsatellite markers. Genotype and phenotype data for the pedigree were analysed using heritability and linkage methods implemented in the programme SOLAR. Follow-up association analysis was performed using the CLUMP programme. A total of 154 migraine cases (25%) were identified indicating the Norfolk Island population is high-risk for migraine. Heritability estimation of the 377-member pedigree indicated a significant genetic component for migraine (h(2)=0.53, P=0.016). Linkage analysis showed peaks on chromosome 13q33.1 (P=0.003) and chromosome 9q22.32 (P=0.008). Association analysis of the key microsatellites in the remaining 223 unrelated Norfolk Island individuals showed evidence of association, which strengthen support for the linkage findings (P<=0.05). In conclusion, a genome-wide linkage analysis and follow-up association analysis of migraine in the genetic isolate of Norfolk Island provided evidence for migraine susceptibility loci on chromosomes 9q22.22 and 13q33.1. PMID- 22197689 TI - Identification of glutaredoxin 1 and glutaredoxin 2 genes from Venerupis philippinarum and their responses to benzo[a]pyrene and bacterial challenge. AB - Glutaredoxin (abbreviated as Grx) is an important ubiquitous disulfide reductase, which can protect organisms against oxidative stresses. In the present study, a monothiol glutaredoxin gene (named as VpGrx1) and a dithiol glutaredoxin gene (named as VpGrx2) were identified from Venerupis philippinarum. Similar to most Grx2s, VpGrx2 possessed the conserved catalytic residues (C-P-Y-C) and other conserved features critical for the fundamental structure and function of Grx2s, while the active motif (C-G-Y-S) of VpGrx1 was different from the counterpart in other Grx1s. Quantitative Real-time PCR assay showed that VpGrx1 and VpGrx2 transcripts were detected in a wide range of tissues and mainly distributed in gills and hepatopancreas. After Vibrio challenge, both the expression levels of VpGrx1 and VpGrx2 mRNA in hemocytes were significantly up-regulated at 24 h. As concerned to benzo[a]pyrene (BaP) exposure, the expression levels of VpGrx1 and VpGrx2 transcripts in hepatopancreas were also significantly induced at 24 h. These results suggested that ROS could be induced through the respiratory burst to clear the invading bacteria and pollutants. VpGrx1 and VpGrx2 perhaps involved in the regulation of redox homeostasis and innate immune responses of V. philippinarum. PMID- 22197690 TI - Myxopapillary ependymoma on MR myelography. PMID- 22197691 TI - Intracranial subdural osteoma: a rare benign tumor that can be differentiated from other calcified intracranial lesions utilizing MR imaging. AB - We report the magnetic resonance (MR) imaging characteristics of subdural osteoma and other benign calcified intracranial lesions to highlight imaging features that differentiate between these disease entities. A 63-year-old woman presented with progressively altered mental status. Non-contrast CT demonstrated a densely calcified right middle cranial fossa extra-axial mass. MR imaging of the lesion demonstrated T1 and T2 hypointensity without evidence of contrast enhancement, parenchymal abnormality, or connection to adjacent venous structures. Diffusion weighted imaging demonstrated markedly decreased signal intensity and artificially reduced diffusion on apparent diffusion coefficient map. Histologically, the tumor was predominantly composed of lamellar bone and small fragments of residual dura consistent with subdural osteoma. This case demonstrates that radiological examination can provide additional insight into the origin of intracranial osteomas (extradural versus subdural versus sinonasal) and help distinguish from other diagnostic considerations including benign meningeal ossification and calcified meningioma prior to surgical resection. PMID- 22197692 TI - Surgical and nonsurgical hospitalization rates and charges for patients with ulcerative colitis in Italy: a 10-year cohort study. AB - BACKGROUND: Today we are observing an increasing incidence of ulcerative colitis associated with an improved survival of patients. AIM: To analyse current rates, outcomes, and costs of inpatient care for ulcerative colitis patients of central Italy. METHODS: The cohort included 644 ulcerative colitis patients, living in the Lazio region, with diagnosis made or confirmed by the staff of a single tertiary referral centre in Rome (1997-2006). Follow-up data on hospitalization rates, costs, and colectomy rates were collected from the Regional Hospital Information System. RESULTS: Overall hospitalization rates were 3 times higher than those of the region's general population, reflecting excess admissions for digestive or infectious diseases (standardized hospitalizations rates for digestive-tract: 15.9; for infectious diseases: 3.5). The overall cumulative risk for colectomy was 7.5%. On the average, hospitalizations for ulcerative colitis lasted 10 days. The mean reimbursement for a ulcerative colitis-related hospitalization was EUR 5120 (?4609 for nonsurgical admissions, ?8655 for surgical hospitalizations). CONCLUSION: Ulcerative colitis patients are 3 times more likely to be hospitalized than the general population. Colectomy rates in Italian ulcerative colitis patients resemble those of northern Europe, but most hospital admissions are for diagnostic procedures or medical therapy. Hospitalizations are almost twice as long as those reported in the United States although their mean cost is considerably lower. PMID- 22197693 TI - Contribution of spinal galectin-3 to acute herpetic allodynia in mice. AB - To identify endogenous factors involved in herpetic pain, we performed genome wide microarray analysis of the spinal cord of mice that suffered from herpetic allodynia induced by inoculation with herpes simplex virus type 1, which revealed marked induction of galectin-3, a beta-galactoside-binding lectin. Therefore, we investigated the role of galectin-3 in herpetic allodynia. The expression levels of galectin-3 mRNA and protein were increased with a temporal pattern similar to that of herpetic allodynia. Galectin-3-expressing cells were mainly localized in the superficial dorsal horn, round in shape, and positive for the macrophage/microglia markers Iba-1 and F4/80. In the deep dorsal horn, there were Iba-1-positive cells with ramified and stout processes, which were negative for galectin-3. In the superficial dorsal horn, there were many CD3-positive T cells, but most of the galectin-3-expressing cells were negative for CD3. Galectin-3 expressing cells were negative for the neuronal marker NeuN and the astrocyte marker glial fibrillary acidic protein antibody. Deficiency in galectin-3 markedly reduced herpetic allodynia, without showing an effect on herpes zoster like skin lesions. Intrathecal injection of galectin-3 produced mechanical allodynia in naive mice, and intrathecal injections of anti-galectin-3 antibodies significantly reduced herpetic allodynia. The present results suggest that galectin-3 in infiltrating macrophages and/or resident microglia in the spinal dorsal horn contributes to herpetic allodynia. Galectin-3 may be a new therapeutic target for the treatment of herpes zoster-associated pain. PMID- 22197694 TI - Persistent antinociception through repeated self-injury in patients with borderline personality disorder. AB - Patients with borderline personality disorder, mostly female, exhibit severe autoaggressive behavior, namely an intentionally performed, nonsuicidal self injury and severe blunting of pain perception, the mechanism of which is hitherto not understood. Because the nociceptive system displays a high degree of plasticity, the aim of this study was to analyze the relationship of pain perception to self-injurious behavior. Pain perception of mechanical and chemical noxious stimuli was studied by quantitative sensory testing in 22 patients (15 female, 7 male) with borderline personality disorder (BPD) according to DSM-IV and 22 age- and gender-matched controls. BPD patients exhibited a significantly higher pain threshold to pinprick stimuli (2.7 times higher than healthy control subjects), and significantly lower pain ratings to mechanical (pinprick, -28%) and chemical (capsaicin, -38%) stimulation. Capsaicin-induced pain decayed significantly faster in BPD patients (tau=49 seconds) than in controls (tau=76 seconds). These alterations of pain perception were generally present in the female, but not in the male subgroup of BPD patients. Analysis of pain intensity vs unpleasantness suggested that primarily the unpleasantness aspect of the pain experience was reduced. Blunting of pain sensation was significantly predicted by the recency of self-injurious behavior (multiple r=0.58). In line with recent data, we suggest an excess of endogenous antinociception in BPD patients resulting from self-inflicted multiple injuries. This exaggerated pain control is conceived to operate via an uncoupling of the evaluative or emotional-affective from the sensory-discriminative dimension of pain. PMID- 22197695 TI - On-off intermittency of thalamo-cortical oscillations in the electroencephalogram of rats with genetic predisposition to absence epilepsy. AB - Spike-wave discharges (SWD) are electroencephalographic hallmarks of absence epilepsy. SWD are known to originate from thalamo-cortical neuronal network that normally produces sleep spindle oscillations. Although sleep spindles and SWD are considered as thalamo-cortical oscillations, functional relationship between them is not obvious. The present study describes temporal dynamics of SWD and sleep spindles as determined in 24h EEG recorded in WAG/Rij rat model of absence epilepsy. SWD, sleep spindles (10-15 Hz) and 5-9 Hz oscillations were automatically detected in EEG using wavelet-based algorithm. It was found that non-linear dynamics of SWD fitted well to the law of 'on-off intermittency'. Sleep spindles also demonstrated 'on-off intermittency', in contrast to 5-9 Hz oscillations, whose dynamics could not be classified as having any known type of non-linear behavior. Intermittency in sleep spindles and SWD implies that (1) temporal dynamics of these oscillations are deterministic in nature, and (2) it might be controlled by a system-level mechanism responsible for circadian modulation of neuronal network activity. PMID- 22197696 TI - Tempo-spatial analysis of vision-related acupoint specificity in the occipital lobe using fMRI: an ICA study. AB - Functional acupoint specificity is one of the most debated topics in acupuncture neuroimaging research. Conventional studies investigating vision-related acupoint specificity empirically assume that acupuncture-induced hemodynamic response can be defined a priori and thus concentrate on distinguishing the spatial variations of response patterns across acupoints in the occipital lobe. However, evidence suggests that acupuncture-invoked BOLD signal changes are independent of a priori time shape. Additionally, temporal profiles reflect how a stimulus corresponds with the brain, implying the hemodynamic coherence induced by stimulation. Therefore, temporal information carried in acupuncture-related neural activity may be more crucial to specificity issues. This paper initiates the detection into tempo-spatial dimension and the goal of this study is to detect functional acupoint specificity by uniquely comparing the temporal activities of the occipital lobe among vision-related acupoints (VRA) and a non-acupoint (NAP). We utilized the independent component analysis (ICA) to extract temporal patterns of occipital response by stimulating a VRA, i.e. GB37, and a NAP. As an improvement over previous ones, another VRA, i.e., BL60 was employed to consolidate our findings. Results showed that although all groups showed V1 activity in the occipital lobe, dissociable temporal activities in this region categorized GB37 and NAP (r=0.05, p=0.64). This finding was replicable with regard to BL60 and NAP (r=-0.03, p=0.77). Intriguingly, stimulation at two VRAs induced highly correlated temporal activities (p<0.0001). This study adds positive evidence to the issue of vision-related acupoint specificity. The utilization of ICA and consideration of temporal dynamics may shed light on future studies. PMID- 22197697 TI - Inhibition of mitochondrial permeability transition pore opening contributes to the neuroprotective effects of ischemic postconditioning in rats. AB - Ischemic postconditioning (IPost) has been shown to attenuate cerebral ischemia reperfusion injury. However, the mechanism remains elusive. Because opening of the mitochondrial permeability transition pore (MPTP) is a crucial determinant of cell death after ischemia-reperfusion, we hypothesized that the neuroprotective effect of IPost may be associated with inhibition of MPTP opening. In part 1 of this study, pentobarbital-anesthetized rats subjected to middle cerebral artery occlusion for 90 min, followed by reperfusion for 72 h, were assigned to receive one of the following treatments: three cycles of IPost (15s each), intracerebroventricular injection of saline (control), administration of the MPTP inhibitor cyclosporin A (CsA) (2 MUmol/L, 15 MUL) or its vehicle alcohol, administration of the MPTP opener atractyloside (Atr) (2 mmol/L, 15 MUL), or IPost plus CsA/Atr treatment. Neurological deficit scores (NDS) and infarct volumes were assessed. Mitochondrial ultrastructure and swelling were also examined after reperfusion. In part 2, control and IPost groups underwent ischemia (90 min) and reperfusion (15 min). CsA and Atr groups were treated as described in part 1. Brain mitochondria were isolated after reperfusion and MPTP activity was evaluated. IPost or CsA treatment significantly improved NDS and reduced infarction volume, while Atr reversed the neuroprotective effects of IPost, and attenuated the decrease in mitochondrial swelling induced by IPost or CsA. Thus, inhibiting MPTP opening may play a crucial role in the neuroprotective effects of IPost, which may have potential clinical value against cerebral ischemia-reperfusion injury. PMID- 22197698 TI - Developmental AMPA receptor subunit specificity during experience-driven synaptic plasticity in the rat barrel cortex. AB - During early postnatal brain development, experience-driven delivery of AMPA receptors to synapses participates in the initial organization of cortical function. By combining virus-mediated in vivo gene delivery with in vitro whole cell recordings, we identified a subunit-specific developmental program of experience-driven AMPA receptor delivery to synapses in rat barrel cortex. We expressed green fluorescent protein (GFP)-tagged AMPA receptors (GFP-GluR1, or GFP-GluR4) into layer 2/3 pyramidal neurons at two distinct developmental periods, postnatal day (P)8-P10 and P12-P14. Two days after viral infection, acute brain slices were prepared, and synaptic transmission from layer 4 to layer 2/3 was analyzed by whole cell recordings. We found that whisker experience drives GluR4 but not GluR1 into these synapses early in postnatal development (P8 P10). However, at P12-14, GluR1 but not GluR4 is delivered into synapses by whisker experience. This precise developmental plan suggests unique plasticity properties endowed in different AMPA receptor subunits which shape the initial experience-driven organization of cortical function. PMID- 22197699 TI - Task difficulty modulates young-old differences in network expression. AB - The extent of task-related fMRI activation can vary as a function of task difficulty. Also the efficiency or capacity of the brain networks underlying task performance can change with aging. We asked whether the expression of a network underlying task performance would differ as a function of task demand in old and young individuals. 26 younger and 23 older healthy adults performed a delayed item recognition task that used the response signal method to parametrically manipulate the extrinsic difficulty of the task by imposing five different deadlines for recognition response. Both age groups showed a speed-accuracy trade off, but the younger group achieved greater discriminability at the longer deadlines. We identified a spatial pattern of fMRI activation during the probe phase whose expression increased as the response deadline shortened and the task became more difficult. This pattern was expressed to a greater degree by the old group at the long deadlines, when the task was easiest. By contrast, this pattern was expressed to a greater degree by the younger group at the short deadlines, when the task was hardest. This suggests reduced efficiency and capacity of this network in older subjects. These findings suggest that neuroimaging studies comparing task-related activation across groups with different cognitive abilities must be interpreted in light of the relative difficulty of the task for each group. PMID- 22197700 TI - Disrupted pro- and antioxidative balance as a mechanism of neurotoxicity induced by perinatal exposure to lead. AB - The aim of this paper was to examine if pre- and neonatal exposure that results in lead (Pb) concentration below 'safe level' (10 MUg/dL) in offspring blood may cause disruption of the pro/antioxidant balance in the developing rat brain. We studied oxidative stress intensity (malondialdehyde (MDA) concentration) as well as mRNA, protein expression and the activity of copper/zinc superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), glutathione peroxidase (GPx), phospholipid hydroperoxide glutathione peroxidase (GPx4), catalase (CAT), glutathione reductase (GSR). We also measured glutathione (GSH) concentrations in selected structures of the rat brain (forebrain cortex, FC, cerebellum, C, and hippocampus, H) and showed cellular localization of GPx4, SOD1 and SOD2 expressions in the hippocampus by immunohistochemical examinations. Despite low Pb level in blood we observed decrease of the activity of some antioxidant enzymes as well as mRNA and protein expression downregulation associated with an increase of MDA level and CAT expression upregulation, especially in the hippocampus region. At the subcellular level, downregulation of SOD2 expression and decreased enzyme activity as well as mitochondrial pool of GSH suggest also that mitochondrial mechanisms might account for Pb neurotoxicity mechanism. For some enzymes, we found differences in the effects of Pb on the level of expression and activity. The activity of CAT decreased despite an increase in mRNA and protein expression; and likewise the activities SOD1, GPx1 GPx4 decreased, despite substantially unchanged level of expression. These effects may be the result of impairment of catalytic function of the enzyme protein caused by Pb interaction or of reduction in the availability of cofactors. We conclude that antioxidant system of the hippocampus of immature rat brain is highly vulnerable to perinatal Pb exposure. Therefore, oxidative stress may be one of the possible mechanisms disturbing cellular metabolism in this structure. Disruption of pro- and antioxidant balance should be considered as a potential mechanism of the observed Pb adverse effects, leading to the impaired learning ability caused by Pb exposure in children. PMID- 22197701 TI - Over-expression of map kinase phosphatase-1 (MKP-1) suppresses neuronal death through regulating JNK signaling in hypoxia/re-oxygenation. AB - A pivotal role of c-jun N-terminal kinase (JNK) on neuronal apoptosis has been demonstrated in a rodent stroke model. MAP kinase phosphatase 1 (MKP-1) is an archetypal member of the dual-specificity protein phosphatase (DUSP) family, which inactivates mitogen-activated protein kinase (MAPK) including JNK through dephosphorylation. MKP-1, one of immediate early genes in stress conditions, was induced at transcriptional level in hypoxia/re-oxygenation (H/R) in neuroblastoma N1E115 cells, however the activation of JNK was not suppressed in the acute phase of re-oxygenation. Small interference RNA-mediated knock-down of MKP-1 enhanced phospho-JNK and neuronal death that is rescued by JNK inhibitor in H/R. Conversely, conditional over-expression of MKP-1 suppressed phospho-JNK, the expression of proapoptotic genes, and neuronal death in H/R. Further the immunoreactivity of MKP-1 was detected in the neurons and partially co-localized with that of phospho-JNK in the surrounding zone of ischemia in rat MCA-O (middle cerebral artery occlusion) reperfusion model. These findings indicate that over expression of MKP-1 could suppress neuronal death possibly through regulating JNK signaling in vitro and be a prominent neuroprotective target for the treatment of acute cerebral infarction. PMID- 22197702 TI - DTI reveals structural differences in white matter tracts between bilingual and monolingual children. AB - The impact of bilingualism on the microstructure of the white matter pathways related to language processing is assessed in elementary school children by magnetic resonance diffusion tensor imaging (MR-DTI). Forty children, 8-11 years old, subdivided into 3 different groups (15 simultaneous bilinguals, 15 sequential bilinguals and 10 monolinguals), were scanned. The hypothesis was that the starting age and the manner of second language acquisition would affect the characteristics of language circuitry. In each subject the mean fractional anisotropy (FA) was obtained for four major white matter pathways: 1 - the left arcuate fasciculus/superior longitudinal fasciculus (lAF/lSLF) that connects Broca's area in the opercular and triangular regions of the left inferior frontal gyrus to the posterior language zone, 2 - the left inferior occipitofrontal fasciculus (lIFOF), connecting anterior regions in the frontal lobe with posterior regions in the temporal occipital lobes, 3 - the bundle arising from the anterior part of the corpus callosum projecting to the orbital lobe (AC-OL) and 4 - the fibers emerging from the anterior midbody (AMB) of the corpus callosum that associate with the premotor and supplementary motor cortices (AMB PMC). The three groups did not show significant differences in mean FA over the lAF/lSLF or AMB-PMC tracts. In simultaneous bilingual subjects the lIFOF tracts had higher mean FA value compared to monolinguals and also sequential bilinguals, whereas the comparison for the AC-OL fibers yielded a significantly lower mean FA value in simultaneous bilingual subjects compared to monolinguals. In both cases the FA value for sequential bilinguals was intermediate to that of the other two groups. To our knowledge, this study provides the first evidence of bilingualism related adaptation of white matter microstructure in the human brain. PMID- 22197703 TI - Expression profiling of synaptic microRNAs from the adult rat brain identifies regional differences and seizure-induced dynamic modulation. AB - In recent years, microRNAs or miRNAs have been proposed to target neuronal mRNAs localized near the synapse, exerting a pivotal role in modulating local protein synthesis, and presumably affecting adaptive mechanisms such as synaptic plasticity. In the present study we have characterized the distribution of miRNAs in five regions of the adult mammalian brain and compared the relative abundance between total fractions and purified synaptoneurosomes (SN), using three different methodologies. The results show selective enrichment or depletion of some miRNAs when comparing total versus SN fractions. These miRNAs were different for each brain region explored. Changes in distribution could not be attributed to simple diffusion or to a targeting sequence inside the miRNAs. In silico analysis suggest that the differences in distribution may be related to the preferential concentration of synaptically localized mRNA targeted by the miRNAs. These results favor a model of co-transport of the miRNA-mRNA complex to the synapse, although further studies are required to validate this hypothesis. Using an in vivo model for increasing excitatory activity in the cortex and the hippocampus indicates that the distribution of some miRNAs can be modulated by enhanced neuronal (epileptogenic) activity. All these results demonstrate the dynamic modulation in the local distribution of miRNAs from the adult brain, which may play key roles in controlling localized protein synthesis at the synapse. PMID- 22197704 TI - Differential effects on cell motility, embryonic stem cell self-renewal and senescence by diverse Src kinase family inhibitors. AB - The Src family of non-receptor tyrosine kinases (SFKs) has been shown to play an intricate role in embryonic stem (ES) cell maintenance. In the present study we have focused on the underlying molecular mechanisms responsible for the vastly different effects induced by various commonly used SFK inhibitors. We show that several diverse cell types, including fibroblasts completely lacking SFKs, cannot undergo mitosis in response to SU6656 and that this is caused by an unselective inhibition of Aurora kinases. In contrast, PP2 and PD173952 block motility immediately upon exposure and forces cells to grow in dense colonies. The subsequent halt in proliferation of fibroblast and epithelial cells in the center of the colonies approximately 24 h post-treatment appears to be caused by cell-to cell contact inhibition rather than a direct effect of SFK kinase inhibition. Interestingly, in addition to generating more homogenous and dense ES cell cultures, without any diverse effect on proliferation, PP2 and PD173652 also promote ES cell self-renewal by reducing the small amount of spontaneous differentiation typically observed under standard ES cell culture conditions. These effects could not be mirrored by the use of Gleevec, a potent inhibitor of c-Abl and PDGFR kinases that are also inhibited by PP2. PMID- 22197705 TI - Reconstitution of the cellular response to DNA damage in vitro using damage activated extracts from mammalian cells. AB - In proliferating mammalian cells, DNA damage is detected by sensors that elicit a cellular response which arrests the cell cycle and repairs the damage. As part of the DNA damage response, DNA replication is inhibited and, within seconds, histone H2AX is phosphorylated. Here we describe a cell-free system that reconstitutes the cellular response to DNA double strand breaks using damage activated cell extracts and naive nuclei. Using this system the effect of damage signalling on nuclei that do not contain DNA lesions can be studied, thereby uncoupling signalling and repair. Soluble extracts from G1/S phase cells that were treated with etoposide before isolation, or pre-incubated with nuclei from etoposide-treated cells during an in vitro activation reaction, restrain both initiation and elongation of DNA replication in naive nuclei. At the same time, H2AX is phosphorylated in naive nuclei in a manner that is dependent upon the phosphatidylinositol 3-kinase-like protein kinases. Notably, phosphorylated H2AX is not focal in naive nuclei, but is evident throughout the nucleus suggesting that in the absence of DNA lesions the signal is not amplified such that discrete foci can be detected. This system offers a novel screening approach for inhibitors of DNA damage response kinases, which we demonstrate using the inhibitors wortmannin and LY294002. PMID- 22197706 TI - The estrogenic potential of salicylate esters and their possible risks in foods and cosmetics. AB - Salicylate esters (SEs), a class of chemicals extensively used as flavor and fragrance additives in foods, beverages and a wide variety of consumer products, are suspected to have estrogenic activity based on chemical analysis of in silica molecular docking. We evaluated the estrogenic potentials of phenyl salicylate (PhS), benzyl salicylate (BzS), phenethyl salicylate (PES), ethyl salicylate (ES) and methyl salicylate (MS) using an in vitro human estrogen receptor alpha (hERalpha)-coactivator recruiting assay and in vivo immature rodent uterotrophic bioassays. We found that PhS, BzS and PES showed obvious in vitro hERalpha agonistic activities; BzS in particular exhibited a higher estrogenic activity compared to bisphenol A (BPA). The uterine weights were significantly increased in mice treated with 11.1, 33.3, 100 and 300 mg/kg/day BzS and 33.3mg/kg/day PES and rats treated with 3.7, 11.1, 33.3 and 100mg/kg/day BzS for 3 days (P<0.05). Finally, we transformed the daily intakes and the dermal exposures of SEs in the real world into estradiol equivalent concentrations (EEQs). We found that the EEQ of BzS daily intake in consumers in the U.S. and the EEQs of dermal BzS and PES exposure among high-volume users worldwide were higher than the maximum secure daily estradiol intake recommended by the U.S. Food and Drug Administration (FDA). In particular, the EEQ for dermal BzS exposure was up to 162 ng EEQ/kg, which is 3.3 times higher than the maximal acceptable daily E(2) intake recommended by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). PMID- 22197707 TI - Urinary phthalate monoesters concentration in couples with infertility problems. AB - The widespread use of phthalates results in human exposure: phthalates are rapidly metabolized to their respective monoesters and other oxidative products, which are glucuronidated and excreted through the urine and feces. Several in vivo studies showed that some phthalates, in particular diethyl-hexyl phthalate (DEHP), diethyl phthalate (DEP), di(n-butyl)phthalate (DnBP) and n butylbenzylphthalate (BBzP), are able to interact with the human endocrine system, interfering with the reproduction ability. In this study, 56 couples were recruited from a centre of assisted reproduction. Spot urine samples were collected and five urinary metabolites of the above phthalates were determined using an HPLC/MS/MS analytical method with isotopic dilution. The results were compared with those of 56 couples of parents of one or more children and the statistical analysis revealed a significant difference between the two groups in terms of urinary concentrations of phthalates metabolites. A further step will be the correlation of these results with information on the life styles and working conditions collected through a specifically designed questionnaire. PMID- 22197708 TI - Antinociception induced by acute oral administration of sweet substance in young and adult rodents: the role of endogenous opioid peptides chemical mediators and MU(1)-opioid receptors. AB - The present work aimed to investigate the effects of acute sucrose treatment on the perception of painful stimuli. Specifically, we sought to determine the involvement of the endogenous opioid peptide-mediated system as well as the role of the MU(1)-opioid receptor in antinociception organisation induced by acute sucrose intake. Nociception was assessed with the tail-flick test in rats (75, 150 and 250 g) of different ages acutely pre-treated with 500 MUL of a sucrose solution (25, 50, 150 and 250 g/L) or tap water. Young and Adult rats (250 g) showed antinociception after treatment with 50 g/L (during 5 min) and 150 g/L and 250 g/L (during 20 min) sucrose solutions. Surprisingly, this antinociception was more consistent in mature adult rodents than in pups. To evaluate the role of opioid systems, mature adult rodents were pre-treated with different doses (0.25, 1 or 4 mg/kg) of the non-selective opioid receptor antagonist naloxone, the selective MU(1)-opioid receptor antagonist naloxonazine or vehicle followed by 250 g/L sucrose solution treatment. Sucrose-induced antinociception was reduced by pre-treatment with both naloxone and naloxonazine. The present findings suggest that sweet substance-induced hypo-analgesia is augmented by increasing sucrose concentrations in young and adult rodents. Acute oral sucrose treatment inhibits pain in laboratory animal by mediating endogenous opioid peptide and MU(1)-opioid receptor actions. PMID- 22197709 TI - Possible role of dopamine D1-like and D2-like receptors in behavioural activation and "contingent" reward evaluation in sodium-replete and sodium-depleted rats licking for NaCl solutions. AB - Based on the different effects of the dopamine D1-like and D2-like receptor antagonists SCH 23390 and raclopride on the measures of licking microstructure in rats, we suggested that the level of activation of reward-associated responses depends on dopamine D1-like receptor stimulation, and is updated, or "reboosted", on the basis of a dopamine D2-like receptor-mediated reward evaluation. To further test this hypothesis, we examined the effects of the dopamine D2-like receptor antagonist raclopride (0, 25, 125, 250MUg/kg) and of the dopamine D1 like receptor antagonist SCH 23390 (0, 10, 20 and 40MUg/kg) on the microstructure of licking for two different NaCl solutions (0.9% and 2.7%) in rats in sodium replete status and in the sodium-depleted status induced by the diuretic drug furosemide. Rats were exposed to each solution for 180 seconds after the first lick. Both in sodium-replete and in sodium-depleted status, SCH 23390 produced a decrease of burst number, a measure of behavioural activation, without affecting their size, a measure of reward evaluation. Raclopride reduced burst number but appeared also to exert some effects on burst size. Sodium depletion resulted in an increased intake for both NaCl solutions due to an increase in burst number and size, and in a reduced sensitivity to the effect of raclopride on lick number. These results are not in contrast with the proposed hypothesis and are consistent with previous evidence suggesting a role for dopamine D2-like receptors in the increased NaCl appetite induced by sodium depletion. PMID- 22197711 TI - Ginsenoside Re attenuates diabetes-associated cognitive deficits in rats. AB - OBJECTIVE: This study was designed to investigate the effect of ginsenoside Re (Re) on cognitive functions, oxidative stress and inflammation in streptozotocin induced diabetic rats. RESEARCH DESIGN AND METHOD: Diabetic rats were treated with Re (40mg/kg) for 8weeks, blood glucose and body weight were measured monthly and weekly, respectively. Cognitive performances were evaluated with Morris water maze. Brain was obtained for measurements of TNF-alpha and malondialdehyde (MDA) contents in both temporal cortex and hippocampus, blood was collected for assays of TNF-alpha, MDA and reduced glutathione (GSH) levels. RESULTS: Learning and memory abilities were significantly (both P<0.01) impaired in diabetic rats, accompanied by the marked (all P<0.01) elevations of TNF-alpha and MDA levels in temporal cortex and hippocampus. Increment of MDA and decrement of GSH in serum also occurred with significant differences (both P<0.01). Chronic treatment with Re markedly (P<0.05) improved the cognition of diabetic rats, evidenced by the decreased escape latency and the increased percentage of time spent in the target quadrant. Furthermore, Re treatment remarkably (P<0.05) reduced the levels of TNF alpha and MDA in both brain areas of diabetic rats. Decline of MDA level and elevation of GSH level in serum were also seen in Re-treated diabetic rats, coupled with decrease in serum glucose level, all with statistically significant differences. CONCLUSIONS: Our findings firstly provide the first evidence that ginsenoside Re can remarkably attenuate diabetes-associated cognitive decline, secondly confirm the involvement of oxidative stress and inflammation in the development of cognitive impairment caused by diabetes, finally point toward the potential of ginsenoside Re as an adjuvant therapy to conventional anti hyperglycemic regimens as well as diabetes-associated cognitive decline. PMID- 22197710 TI - Serotonergic and dopaminergic distinctions in the behavioral pharmacology of (+/ )-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). AB - RATIONALE: After decades of social stigma, hallucinogens have reappeared in the clinical literature demonstrating unique benefits in medicine. The precise behavioral pharmacology of these compounds remains unclear, however. OBJECTIVES: Two commonly studied hallucinogens, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane (DOI) and lysergic acid diethylamide (LSD), were investigated both in vivo and in vitro to determine the pharmacology of their behavioral effects in an animal model. METHOD: Rabbits were administered DOI or LSD and observed for head bob behavior after chronic drug treatment or after pretreatment with antagonist ligands. The receptor binding characteristics of DOI and LSD were studied in vitro in frontocortical homogenates from naive rabbits or ex vivo in animals receiving an acute drug injection. RESULTS: Both DOI- and LSD-elicited head bobs required serotonin(2A) (5-HT(2A)) and dopamine(1) (D(1)) receptor activation. Serotonin(2B/2C) receptors were not implicated in these behaviors. In vitro studies demonstrated that LSD and the 5-HT(2A/2C) receptor antagonist, ritanserin, bound frontocortical 5-HT(2A) receptors in a pseudo-irreversible manner. In contrast, DOI and the 5-HT(2A/2C) receptor antagonist, ketanserin, bound reversibly. These binding properties were reflected in ex vivo binding studies. The two hallucinogens also differed in that LSD showed modest D(1) receptor binding affinity whereas DOI had negligible binding affinity at this receptor. CONCLUSION: Although DOI and LSD differed in their receptor binding properties, activation of 5-HT(2A) and D(1) receptors was a common mechanism for eliciting head bob behavior. These findings implicate these two receptors in the mechanism of action of hallucinogens. PMID- 22197712 TI - Neurobehavioral and transcriptional effects of acrylamide in juvenile rats. AB - Acrylamide is a type-2 alkene monomer with established human neurotoxic effects. While the primary source of human exposure to acrylamide is occupational, other exposure sources include food, drinking water, and smoking. In this study, neurobehavioral assays coupled with transcriptional profiling analysis were conducted to assess both behavioral and gene expression effects induced by acrylamide neurotoxicity in juvenile rats. Acrylamide administration in rat pups induced significant characteristic neurotoxic symptoms including increased heel splay, decrease in grip strength, and decrease in locomotor activity. Transcriptome analysis with the Affymetrix Rat Genome 230 2.0 array indicated that acrylamide treatment caused a significant alteration in the expression of a few genes that are involved in muscle contraction, pain, and dopaminergic neuronal pathways. First, expression of the Mylpf gene involved in muscle contraction was downregulated in the spinal cord in response to acrylamide. Second, in sciatic nerves, acrylamide repressed the expression of the opioid receptor gene Oprk1 that is known to play a role in neuropathic pain regulation. Finally, in the cerebellum, acrylamide treatment caused a decrease in the expression of the nuclear receptor gene Nr4a2 that is required for development of dopaminergic neurons. Thus, our work examining the effect of acrylamide at the whole-genome level on a developmental mammalian model has identified a few genes previously not implicated in acrylamide neurotoxicity that might be further developed into biomarkers for assessing the risk of adverse health effects induced by acrylamide exposure. PMID- 22197713 TI - Physical activity induces depression-like behavior in intact male rats. AB - Testosterone affects behavior. Whether regular physical training does influence these effects is unknown. The assumption that testosterone induces muscular hypertrophy if combined with physical training has not been confirmed experimentally. The aim of this study was to evaluate whether activity and/or testosterone treatment affects depression-like behavior and to observe the effects of activity and testosterone on muscle fiber diameter. Forty-three male rats were divided into 4 groups: two groups (TST act and TST lazy) were treated with testosterone (5mg/kg) and two groups were used as control (CTRL act and CTRL lazy). Two of the groups (CTRL act and TST act) underwent 2weeks of exercise. The forced swim test was used as a test of depression-like behavior. Sex steroids were measured and the diameter of skeletal muscle fibers was evaluated. Testosterone was significantly higher in both testosterone-treated groups (p<0.001). Physically active groups had higher immobility times in the forced swim test than inactive groups. Groups CTRL act and TST lazy showed significantly larger diameter of muscle fibers in comparison to the TST act group. Our results suggest that physical activity induces depression-like behavior in rats. Controversial antagonistic effects of testosterone and physical activity on muscle fiber diameter were found. PMID- 22197714 TI - Verbascoside is not genotoxic in the ST and HB crosses of the Drosophila wing spot test, and its constituent, caffeic acid, decreases the spontaneous mutation rate in the ST cross. AB - Verbascoside (VB) is a phenylpropanoid isolated from Buddleja species, some of which originate in Mexico, and was first described in the sixteenth century in the codices of Mexican traditional medicine. VB is present in alcohol extracts and is widely used in the north of Mexico as a sunscreen. VB absorbs UV-A and UV B radiation and has high antioxidant and anti-inflammatory capacities. VB and its constituent caffeic acid (CA) were screened to determine their genotoxic activity using the Drosophila wing spot test. Third instar larvae (72+/-4 h) of the standard (ST) and high bioactivation (HB) crosses, with regulated and high levels of cytochrome P450s (Cyp450s), respectively, were exposed to VB or CA (0, 27, 57, 81, 135, and 173 mM). VB was not genotoxic at any of the concentrations tested in both crosses. The amount of VB residue as determined by HPLC in the adult flies that were fed with VB indicated a low metabolism of this compound, which explains the absence of genotoxicity. CA decreased the spontaneous frequencies of small and total spots and showed putative toxicity in the ST cross. PMID- 22197715 TI - Particulate air pollution induces arrhythmia via oxidative stress and calcium calmodulin kinase II activation. AB - Ambient particulate matter (PM) can increase the incidence of arrhythmia. However, the arrhythmogenic mechanism of PM is poorly understood. This study investigated the arrhythmogenic mechanism of PM. In Sprague-Dawley rats, QT interval was increased from 115.0+/-14.0 to 142.1+/-18.4ms (p=0.02) after endotracheal exposure of DEP (200MUg/ml for 30min, n=5). Ventricular premature contractions were more frequently observed after DEP exposure (100%) than baseline (20%, p=0.04). These effects were prevented by pretreatment of N acetylcysteine (NAC, 5mmol/L, n=3). In 12 Langendorff-perfused rat hearts, DEP infusion of 12.5MUg/ml for 20min prolonged action potential duration (APD) at only left ventricular base increasing apicobasal repolarization gradients. Spontaneous early afterdepolarization (EAD) and ventricular tachycardia (VT) were observed in 8 (67%) and 6 (50%) hearts, respectively, versus no spontaneous triggered activity or VT in any hearts before DEP infusion. DEP-induced APD prolongation, EAD and VT were successfully prevented with NAC (5mmol/L, n=5), nifedipine (10MUmol/L, n=5), and active Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) blockade, KN 93 (1MUmol/L, n=5), but not by thapsigargin (200nmol/L) plus ryanodine (10MUmol/L, n=5) and inactive CaMKII blockade, KN 92 (1MUmol/L, n=5). In neonatal rat cardiomyocytes, DEP provoked ROS generation in dose dependant manner. DEP (12.5MUg/ml) induced apoptosis, and this effect was prevented by NAC and KN 93. Thus, this study shows that in vivo and vitro exposure of PM induced APD prolongation, EAD and ventricular arrhythmia. These effects might be caused by oxidative stress and CaMKII activation. PMID- 22197716 TI - Luciferase inhibition by a novel naphthoquinone. AB - The novel naphthoquinone 12,13-dihydro-N-methyl-6,11,13-trioxo-5H benzo[4,5]cyclohepta[1,2-b]naphthalen-5,12-imine (hereafter called TU100) was created as a potential chemotherapeutic agent. Previous work showed it is an irreversible inhibitor of type I and II topoisomerases that alkylates specific enzyme thiols. While analyzing the effect of TU100 on cancer cells, we discovered it is a potent inhibitor of luciferase derived from both Photinus pyralis (fireflies) and Renilla reniformis (sea pansy). Pre-incubation experiments showed that TU100 does not irreversibly inactivate luciferase, indicating its mechanism is different from that observed with topoisomerases. Firefly luciferase generates light using ATP and luciferin as substrates (bioluminescence). An examination of TU100 inhibition at varying substrate concentrations revealed the drug is uncompetitive with respect to ATP and competitive with respect to luciferin. The TU100 binding constant (K(I)) is 2.5+/-0.7 MUM as determined by Dixon plot analysis. These data suggest TU100 specifically binds the luciferase-ATP complex and prevents its interaction with luciferin. Given the novel structure of TU100, unique mechanism of action, and ability to target luciferase from different species, these results identify TU100 as an important new reagent for investigating and regulating bioluminescent enzymes. PMID- 22197717 TI - Animal study results suggest that an antifungal drug works against neuronal loss in epilepsy. PMID- 22197718 TI - How can we identify psychiatric morbidity in patients with psychogenic nonepileptic seizures? PMID- 22197719 TI - Functional MRI and neuropsychological evidence for language plasticity before and after surgery in one patient with left temporal lobe epilepsy. AB - This study explores the language reorganization before and after surgery in a 55 year-old right-handed female patient presenting with left temporal refractory epilepsy. Two aspects of language were explored, phonological and semantic, by using neuropsychological assessments and fMRI protocols. To assess the possible reorganization of language, fMRI results for B.L. were compared with results obtained in a group of healthy control subjects (results not presented in detail). According to our results and compared with healthy subjects, B.L. shows reorganization of temporal regions only. The reorganization had various patterns according to the task. Before surgery, neuropsychological testing in B.L. revealed impairment in phonological abilities and fMRI suggested right temporal involvement (interhemisphere reorganization) during the phonological task; semantic abilities were unaltered and fMRI showed bilateral activation of temporal regions during the semantic task. After surgery, the phonological deficit disappeared and fMRI showed left perilesional location of temporal activation (intrahemispheric reorganization); semantic abilities remain preserved and temporal activation remained located bilaterally but predominantly to the right during the semantic task. Our results suggest that cerebral reorganization of language depends on the language operation tested. Moreover, the results underline the importance of differential assessment of language operations and show functional reorganization after beneficial surgery in an older patient. PMID- 22197720 TI - Comparative study with two different enrichments in the culture media used in the disinfectant efficacy assay. AB - Recent changes in Brazilian legislation for commercial disinfectants have been published due to the recent epidemic of nosocomial infections caused by rapidly growing mycobacteria (RGM) in many states of Brazil over the last 8years. One of these documents requires that all the manufacturers provide evidence of efficacy of sterilizing and disinfectant products, used for semi critical medical devices, against the Mycobacterium bovis BCG Moreau and Mycobacterium abscessus subsp. bolletii INCQS 00594 strains by using the Confirmative in vitro Test for Determining Tuberculocidal Activity of Disinfectants recommended by the Association of Official Analytical Chemists. These changes have caused additional costs and increased problems for importation of enrichment products at national laboratories where disinfectant efficacy assay service is performed. Middlebrook ADC Enrichment (ADC) is provided by a unique manufacturer and used in the official protocol. The aim of the present study was to evaluate an alternative in house low-cost enrichment composed of fetal bovine serum and glucose (FBSG) with ADC for performance of disinfectant efficacy assay against mycobacteria. After obtaining the growth curves for M. abscessus ATCC 19977, M. abscessus subsp. bolletii INCQS 00594, Mycobacterium chelonae ATCC 35752, and Mycobacterium fortuitum ATCC 6841 by using ADC enrichment and FBSG in Kirchners and 7H9 culture media. Through statistical analysis via the Kruskal-Wallis test on the evaluation of microorganism growth rate, it was observed that there was no inhibition of RGM growth by any of the enrichments used. These results suggest that low-cost enrichment FBSG may be used as a potential substitute of ADC for composition of media for mycobacterial growth, including in disinfectant tests. PMID- 22197721 TI - VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. AB - Diagnosis and classification of VWD is aided by molecular analysis of the VWF gene. Because VWF polymorphisms have not been fully characterized, we performed VWF laboratory testing and gene sequencing of 184 healthy controls with a negative bleeding history. The controls included 66 (35.9%) African Americans (AAs). We identified 21 new sequence variations, 13 (62%) of which occurred exclusively in AAs and 2 (G967D, T2666M) that were found in 10%-15% of the AA samples, suggesting they are polymorphisms. We identified 14 sequence variations reported previously as VWF mutations, the majority of which were type 1 mutations. These controls had VWF Ag levels within the normal range, suggesting that these sequence variations might not always reduce plasma VWF levels. Eleven mutations were found in AAs, and the frequency of M740I, H817Q, and R2185Q was 15%-18%. Ten AA controls had the 2N mutation H817Q; 1 was homozygous. The average factor VIII level in this group was 99 IU/dL, suggesting that this variation may confer little or no clinical symptoms. This study emphasizes the importance of sequencing healthy controls to understand ethnic-specific sequence variations so that asymptomatic sequence variations are not misidentified as mutations in other ethnic or racial groups. PMID- 22197722 TI - Nanostructured silver vanadate as a promising antibacterial additive to water based paints. AB - In this article, we report the use of nanostructured silver vanadate as a promising antibacterial additive to water-based paints that has potential for applications in bathrooms, kitchens, and hospital environments. This hybrid nanomaterial was prepared by a simple and fast precipitation reaction involving silver nitrate and ammonium vanadate, dismissing the hydrothermal treatment. The preparation involved using Ag vanadate nanowires (beta-AgVO(3)) with diameters ranging from 20 to 60 nm and decorated with silver (Ag) nanoparticles (NPs) with diameters ranging from 5 to 40 nm. Results of antibacterial tests show that this hybrid material has a promising antibacterial activity against several types of bacteria strains, such as methicillin-resistant Staphylococcus aureas (MRSA), Enterococcus faecalis, Escherichia coli, and Salmonella enterica Typhimurium. The evaluated material exhibits antibacterial activity 30 times larger than that of Oxacillin. In addition, this nanomaterial was tested as an antibacterial additive to water-based paints, and formulations with 1% show a 4-mm inhibition zone against a MRSA strain. PMID- 22197723 TI - Mono-dispersed high magnetic resonance sensitive magnetite nanocluster probe for detection of nascent tumors by magnetic resonance molecular imaging. AB - Sensitive molecular imaging and detection of tumors or their supporting neovascularity require high-avidity, target-specific probes, which produce robust signal amplification compatible with a sensitive high-resolution imaging modality. In this context, we fabricated a high magnetic resonance (MR)-sensitive magnetite nanocluster (MNC) probe specific for tumor angiogenesis by assembly of hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs) with (Mal)mPEG PLA copolymer into cluster and subsequent encoding c(RGDyC) peptide on the cluster (RGD-MNC) for detection of nascent tumors. We found that RGD-MNC is highly sensitive (r(2) = 464.94 s(-1)mM(-1)) and specific for alphavbeta3 positive cells. Both nascent (35 +/- 6.6 mm(3)) and large tumors (256 +/- 22.3 mm(3)) can be registered by RGD-MNC and detected by MR imaging (MRI), with the nascent tumors demonstrating more pronounced MR contrast. Immunohistochemical studies revealed that MR signal decrease was closely correlated with histological characteristics of tumors (microvessel density and alphavbeta3 expression levels) at different growth stages. PMID- 22197724 TI - Polystyrene nanoparticles affecting blood coagulation. AB - The association of nanoparticles (NPs) with blood coagulation proteins may influence the natural balance between pro- and anticoagulant pathways. We investigated whether polystyrene NPs, when added to human plasma, affected the generation of thrombin in plasma. Amine-modified NPs were found to decrease the thrombin formation due to binding of factors VII and IX to the NPs, which resulted in depletion of the respective protein in solution. In contrast, carboxyl-modified NPs were able to act as a surface for activation of the intrinsic pathway of blood coagulation in plasma. These results highlight the influence of NPs on a biologically important pathway. PMID- 22197725 TI - Characterization of high-affinity peptides and their feasibility for use in nanotherapeutics targeting leukemia stem cells. AB - Peptides featuring the LR(S/T) motif were identified that could specifically bind to the C-type lectin-like molecule-1 (CLL1), a protein preferentially expressed on acute myeloid leukemia stem cells (LSCs). Micellar nanoparticles were covalently decorated with CLL1-targeting peptides for targeted drug delivery. The resulting peptide-coated nanoparticles were 13.5 nm in diameter and could be loaded with 5 mg of daunorubicin per 20 mg of telodendrimers. These "targeting nanomicelles" transported the drug load to the interior of cells expressing CLL1 and to LSCs isolated from clinical specimens in vitro, but did not bind to normal blood or normal hematopoietic stem cells. The presence of CLL1-targeting peptides on the surface of the nanomicelles enabled the improved binding and delivery of substantially more daunorubicin into the cells expressing CLL1 and CD34(+) leukemic cells compared with unmodified nanomicelles. In conclusion, nanomicelles coated with CLL1-targeting peptides are potentially useful for eradicating LSCs and improving leukemia therapy. FROM THE CLINICAL EDITOR: Micellar nanoparticles covalently decorated with targeting peptides were used for targeted drug delivery of daunorubicin to address acute myeloid leukemia stem cells. PMID- 22197726 TI - Nanoscale surface modification favors benign biofilm formation and impedes adherence by pathogens. AB - We have found in vitro that a biofilm of benign Escherichia coli 83972 interferes with urinary catheter colonization by pathogens, and in human studies E. coli 83972-coated urinary catheters are associated with lower rates of catheter associated urinary tract infections. We hypothesized that modifying surfaces to present mannose ligands for the type 1 fimbriae of E. coli would promote formation of dense E. coli 83972 biofilms, thereby interfering with surface colonization by Enterococcus faecalis, a common uropathogen. We covalently immobilized mannose on silicon substrates by attaching amino-terminated mannose derivative to carboxylic acid-terminated monolayers via amidation. Fluorescence microscopy showed that E. coli 83972 adherence to mannose-modified surfaces increased 4.4-fold compared to unmodified silicon surfaces. Pre-exposing mannose modified surfaces to E. coli 83972 established a protective biofilm that reduced E. faecalis adherence by 83-fold. Mannose-fimbrial interactions were essential for the improved E. coli 83927 adherence and interference effects. From the Clinical Editor: Recurrent urinary tract infections remain major adverse events associated with catheter use. The authors report that modifying catheter surface to present mannose ligands for the type 1 fimbriae of benign Escherichia coli 83972 promotes formation of dense E. coli biofilms, which 100-fold reduces urinary catheter colonization of uropathogens. Future application of this technology is expected to result in substantial UTI risk reduction in catheter users. PMID- 22197727 TI - ERalpha signaling imparts chemotherapeutic selectivity to selenium nanoparticles in breast cancer. AB - The present study focuses on the synthesis of stable selenium nanoparticles (SeNPs) and the elucidation of their mechanism of action in preventing the growth of mammary tumors. Selenious acid and reduced glutathione in the presence of sodium alginate were used as precursors for synthesis of SeNPs. Cell viability and expression of apoptotic markers (pp38, Bax, and cytochrome c) were assessed in MCF-7 and MDA-MB-231 breast cancer cells treated with SeNPs. Reduction in tumor volume was measured in rats with dimethylbenz[a]anthracene-induced mammary tumors. Synthesized SeNPs ranged in size from 40 to 90 nm and were stable up to 3 months of storage. We report that SeNP-induced cell death and expression of pp38, Bax, and cytochrome c were significantly higher in estrogen receptor-alpha (ERalpha)-positive cells (MCF-7) but not in ERalpha-negative cells (MDA-MB-231). Interestingly, animals showing significant decrease in tumor volume (small tumors) had lower levels of ERalpha as compared with animals showing a nonsignificant decrease in tumor volume (large tumor). This is the first report in our knowledge suggesting that the anticancer activity of SeNPs correlates with the level of ERalpha in breast cancer cells both in vivo and in vitro. FROM THE CLINICAL EDITOR: This study focuses on the synthesis of selenium nanoparticles (SeNPs) with the goal of preventing the growth of breast cancer cells, suggesting that the anticancer activity of SeNPs correlates with the level of ERalpha in breast cancer cells both in vivo and in vitro. PMID- 22197728 TI - Quantitative characterization of the lipid encapsulation of quantum dots for biomedical applications. AB - The water solubilization of nanoparticles is key for many applications in biomedicine. Despite the importance of surface functionalization, progress has been largely empirical and very few systematic studies have been performed. Here we report on the water solubilization of quantum dots using lipid encapsulation. We systematically evaluate the monodispersity, zeta potential, stability, and quantum yield for quantum dots encapsulated with single and double acyl-chain lipids, pegylated double acyl-chain lipids, and single alkyl-chain surfactant molecules with charged head groups. We show that charged surfactants and pegylated lipids are important to obtain monodisperse suspensions with high yield and excellent long-term stability. FROM THE CLINICAL EDITOR: This study reports on solubilization of nanoparticles in water, a key, but often neglected aspect for biomedical applications. The authors demonstrate that charged surfactants and PEGylated lipids are important to obtain monodisperse suspensions with high yield and long-term stability. PMID- 22197729 TI - Assessment of chemokine profiles in human skin biopsies by an immunoaffinity capillary electrophoresis chip. AB - Atopic dermatitis is a skin condition resulting in a skin rash from exposure to environmental factors. Skin biopsies taken from patients suffering from atopic dermatitis were micro-dissected and analyzed using a microchip-based immunoaffinity CE system for the presence of CXCL1, CXCL5 and CXCL8 and CCL1, CCL3 and CCL5 chemokines. Disposable immunoaffinity disks with immobilized antibodies were used to capture the CXC and CC chemokines from the homogenized skin samples. The captured analytes were then labeled with AlexaFluor 633, eluted from the disk and separated by CE. The labeled chemokines were identified and quantified by laser induced fluorescence. The total analysis time was less than 40min, including the biopsy microdissection, pre-analysis preparation of the sample and the ICE-CHIP analysis, which took less than 10min with inter- and intra-assay CV's below 6.4%. Microchip-based immunoaffinity CE could distinguish between normal skin biopsies and those with inflammation. Patients with neutrophil cellular infiltrates by histopathology showed increased concentrations of CXCL1, CXCL5 and CXCL8 while increases of CCL1, CCL3 and CCL5 corresponded to the patient group demonstrating monocytic and T-lymphocyte infiltration by histopathology. This system demonstrates the ability to identify and quantify immunochemical analytes in frozen sections taken from clinical histopathology samples. PMID- 22197731 TI - Dynamic MDCT of the pancreas: is time-density curve morphology useful for the differential diagnosis of solid lesions? A preliminary report. AB - PURPOSE: CT perfusion has been proposed for pancreatic lesion characterization. However, scan and analysis protocols influence numerical data. To overcome this, the purpose of our study is to evaluate the use of time-density curves obtained from MDCT perfusion of the pancreas for the characterization of normal parenchyma, adenocarcinoma, chronic pancreatitis and endocrine tumors. METHODS: 31 patients with solid pancreatic lesions and 21 patients with renal cell carcinoma underwent 64-row MDCT perfusion of the pancreas after injection of 50 cc of a 370 mg I/ml solution at 5 cc/s. 63 time-density curves were obtained from normal parenchyma (21 patients), adenocarcinoma (25), endocrine tumors (4) and atrophic parenchyma (13). Two readers independently categorized the 63 time density curves into 4 different morphologies: normal wash-in and wash-out (A), low wash-in followed by plateau (B), low wash-in followed by faint wash-out (C) and high wash-in and wash-out (D). Interobserver agreement was calculated with kappa statistics. Fisher test was used to calculate sensitivity, specificity, positive (PPV) and negative (NPV) predictive values for each type of curve. RESULTS: Interobserver agreement was very good (Kappa=0.849). Curve A had 94.4% sensitivity, 91.1% specificity, 80.95% PPV, 97.6% NPV for 'normal parenchyma'. Curve B had 74.19% sensitivity, 93.75% specificity, 92% PPV, 78.95% NPV in diagnosing 'adenocarcinoma'. Curve C had 45.45% sensitivity, 84.62% specificity, 38.46% PPV, 88% NPV for 'chronic pancreatitis'. Curve D had 100% sensitivity, 98.33% specificity, 75% PPV, 100% NPV for 'endocrine tumor'. CONCLUSIONS: The morphology of MDCT perfusion time-density curves appears to be useful in characterizing pancreatic lesions, and might help overcome the differences in scan and postprocessing techniques. PMID- 22197730 TI - Toward structure determination using membrane-protein nanocrystals and microcrystals. AB - Membrane proteins are very important for all living cells, being involved in respiration, photosynthesis, cellular uptake and signal transduction, amongst other vital functions. However, less than 300 unique membrane protein structures have been determined to date, often due to difficulties associated with the growth of sufficiently large and well-ordered crystals. This work has been focused on showing the first proof of concept for using membrane protein nanocrystals and microcrystals for high-resolution structure determination. Upon determining that crystals of the membrane protein Photosystem I, which is the largest and most complex membrane protein crystallized to date, exist with only 100 unit cells with sizes of less than 200 nm on an edge, work was done to develop a technique that could exploit the growth of the Photosystem I nanocrystals and microcrystals. Femtosecond X-ray protein nanocrystallography was developed for use at the first high-energy X-ray free electron laser, the LCLS at SLAC National Accelerator Laboratory, in which a liquid jet brought fully hydrated Photosystem I nanocrystals into the interaction region of the pulsed X ray source. Diffraction patterns were recorded from millions of individual PSI nanocrystals and data from thousands of different, randomly oriented crystallites were integrated using Monte Carlo integration of the peak intensities. The short pulses (~70fs) provided by the LCLS allowed the possibility to collect the diffraction data before the onset of radiation damage, exploiting the diffract before-destroy principle. During the initial experiments at the AMO beamline using 6.9-A wavelength, Bragg peaks were recorded to 8.5-A resolution, and an electron-density map was determined that did not show any effects of X-ray induced radiation damage [94]. Many additional techniques still need to be developed to explore the femtosecond nanocrystallography technique for experimental phasing and time-resolved X-ray crystallography experiments. The first proof-of-principle results for the femtosecond nanocrystallography technique indicate the incredible potential of the technique to offer a new route to the structure determination of membrane proteins. PMID- 22197732 TI - The role of imaging for translational research in bone tumors. AB - Sarcomas are a heterogeneous group of rare connective tissue tumors, representing 1% of adult and 15% of childhood cancers for which biological and pathological information is still incomplete. In bone tumors patients with metastatic disease at onset, those who relapse and those with post-surgical secondary lesions still have a dismal outcome because of poor response to current therapies. Different molecular biology approaches have identified activated cell signalling pathways or specific molecular endpoints that may be considered potential drug targets or markers useful for diagnosis/prognosis in musculoskeletal pathology. Recently, advances in the field of molecular imaging allow visualization of cell and metabolic functions with the use of targets that include cell membrane receptors, enzymes of intracellular transport. Moreover advanced non-invasive newer imaging techniques like 18-FDG PET, quantitative dynamic-contrast MR imaging, diffusion weighted imaging have all shown a potential in distinguish malignant from benign lesions, in revealing the efficacy of therapy in tumors, the onset of recurrence and a good reliability in reckoning the percentage of necrosis in Ewing sarcoma and osteosarcoma. Thus, in vivo detection of imaging cancer biomarkers may be useful to better characterize those complex pathologic processes, such as apoptosis, proliferation and angiogenesis that determine tumor aggressiveness, providing not only complementary information of prognostic metabolic indicators, but also data in real-time on the efficacy of the treatment through the modulation of the cell metabolism. PMID- 22197733 TI - Coronary artery plaques: cardiac CT with model-based and adaptive-statistical iterative reconstruction technique. AB - OBJECTIVES: To compare image quality of coronary artery plaque visualization at CT angiography with images reconstructed with filtered back projection (FBP), adaptive statistical iterative reconstruction (ASIR), and model based iterative reconstruction (MBIR) techniques. METHODS: The coronary arteries of three ex vivo human hearts were imaged by CT and reconstructed with FBP, ASIR and MBIR. Coronary cross-sectional images were co-registered between the different reconstruction techniques and assessed for qualitative and quantitative image quality parameters. Readers were blinded to the reconstruction algorithm. RESULTS: A total of 375 triplets of coronary cross-sectional images were co registered. Using MBIR, 26% of the images were rated as having excellent overall image quality, which was significantly better as compared to ASIR and FBP (4% and 13%, respectively, all p<0.001). Qualitative assessment of image noise demonstrated a noise reduction by using ASIR as compared to FBP (p<0.01) and further noise reduction by using MBIR (p<0.001). The contrast-to-noise-ratio (CNR) using MBIR was better as compared to ASIR and FBP (44+/-19, 29+/-15, 26+/ 9, respectively; all p<0.001). CONCLUSIONS: Using MBIR improved image quality, reduced image noise and increased CNR as compared to the other available reconstruction techniques. This may further improve the visualization of coronary artery plaque and allow radiation reduction. PMID- 22197734 TI - IgG purification by bentonite-acrylamide-histidine microcomposite. AB - In this work, a new microcomposite composed of bentonite, acrylamide and histidine, as a pseudospecific ligand, was synthesized by bulk polymerization. The aim of this study was to improve IgG adsorption capacity of bentonite by incorporating histidine. The surface areas of the bentonite and bentonite acrylamide-histidine microcomposites were 33.4 and 1.42 m(2)/g, respectively. The amount of histidine was found to be 50 MUmol/g bentonite via elemental analysis. Adsorption capacity was at the value of 100mg/g from aqueous solution while adsorption capacity was 108 mg/g from human plasma with a purity of 90%. IgG biomolecules were able to be adsorbed and desorbed five times by using the same microcomposites without significant loss in their adsorption capacity. PMID- 22197735 TI - Salt effect on microscopic structure and stability of colloidal complex obtained from neutral/polyelectrolyte block copolymer and oppositely charged surfactant. AB - The salt effect on complex formation of poly(acrylamide)-block-poly(acrylic acid) (PAM-b-PAA) and dodecyltrimethylammonium bromide (DTAB) at different NaBr concentrations, C(NaBr), was investigated by laser light scattering (LLS) and small angle neutron scattering (SANS). LLS and SANS clearly indicates that the aqueous solution of PAM-b-PAA and DTAB associate into colloidal complexes. For low surfactant-to-polymer charge ratio Z lower than the critical value Z(C), the colloidal complexes are single DTAB micelles dressed by a few PAM-b-PAA. Above Z(C), the colloidal complexes form a core-shell microstructure. The complex formation in the PAM-b-PAA/DTAB is enhanced by addition of salt: Z(C) decreases with increasing C(NaBr). This is considered to similar to the cmc behavior for the pure surfactant system. The core of the complex consists of densely packed surfactant micelles (DTA(+)), and PAA block chains bind to these micelles, displace their counteranions (Br-) and bridge them. The corona of the complex is constituted from the PAM. Since the interaction between polyelectrolyte and oppositely charged surfactant is primarily electrostatic in nature, the core radius and the intermicellar distance of the DTA(+) micelles inside the core depend on C(NaBr). The addition of salt screens the electrostatic attraction between oppositely charged PAA block and DTAB, which weakens the interaction. With increasing C(NaBr), therefore, the core of the colloidal complex is considered to swell, which leads to the increases in the core radius R(C) and the intermicellar distance of the DTA(+) micelles inside the core. The aggregation number expressed in terms of DTA(+) micelles per complex is also evaluated using the analogy with the homopolyelectrolyte/surfactant system. PMID- 22197736 TI - Surface-quaternized chitosan particles as an alternative and effective organic antibacterial material. AB - Taking advantage of the large surface area that is covered with permanent positive charges of quaternary ammonium entities, this research aimed to develop environmentally friendly, organic antibacterial material from quaternized chitosan particles that may be applicable for biomedical devices, health and textile industries. The particles were formulated by ionic crosslinking of chitosan with tripolyphosphate followed by quaternization under heterogeneous conditions, via either direct methylation or reductive N-alkylation with a selected aldehyde followed by methylation. Sub-micron, spherical and positively charged quaternized chitosan particles were formed, as determined by (1)H NMR, FT IR, PCS and TEM analysis. Antibacterial activity tests, performed by viable cell (colony) counts, suggested that all quaternized chitosan particles exhibited superior antibacterial activity against the model Gram-positive bacteria, Staphylococcus aureus, as compared to the native chitosan particles at neutral pH. Only some quaternized chitosan particles, especially those having a high charge density and bearing large alkyl substituent groups, were capable of suppressing the growth of the model Gram-negative bacteria, Escherichia coli. The inhibitory efficiency of the quaternized chitosan particles was quantified in terms of the minimum inhibitory concentration (MIC). Damaging impact of the quaternized chitosan particles on the bacteria was also qualitatively determined by microscopic observation of the bacterial morphology. PMID- 22197737 TI - [Rheumatic fever versus post-streptococcal reactive arthritis. What would you say, Jones?]. PMID- 22197738 TI - [Endovascular treatment of pulmonary sequestration with Amplatzer(r) vascular plugs]. AB - Pulmonary sequestration is a rare malformation characterised by non-functioning lung tissue, separated from the tracheobronchial tree and with arterial supply from the systemic circulation. The classical therapeutic approach is surgical resection. In recent years, the endovascular embolisation technique is increasingly being used for the treatment of this disease. The embolisation materials used are coils and vascular plugs. The Amplatzer(r) vascular plug is a self-expandable cylindrical mesh device, particularly useful for the embolisation of large vessels with high flow. Three cases of pulmonary sequestration were treated by embolisation with Amplatzer(r) vascular plugs. In all cases the procedure was performed without complications, and the aortopulmonary collateral vessels were completely occluded. Our study provides new data on the safety and efficacy of pulmonary embolisation with Amplatzer(r) vascular plugs, and its preference over coils in the embolisation of large vessels. PMID- 22197739 TI - [Characteristics of limping patients in Rheumatology]. AB - INTRODUCTION: Limping is a frequent reason for consultation. Our aim is to describe the characteristics of patients who limp and are evaluated in Rheumatology. MATERIAL AND METHODS: Cross-sectional study from October 2009 to June 2010. Variables included: epidemiological data, clinical symptoms and laboratory and imaging tests. RESULTS: A total of 95 patients were studied and classified into four groups according to their diagnosis, inflammatory 22%, infectious 17%, transient hip synovitis 13%, and miscellaneous 48%. There were differences between groups in age (P<0.0001) and arthritis (P<0.0001). In this population, the probability of an infectious/inflammatory limp fulfils the criteria "less than 3 years and fever" was 79% and reached 100% if it was also associated with arthritis. CONCLUSIONS: Clinical evaluation and in particular, age, fever and arthritis seem to be the most relevant data in differentiating infectious/inflammation diagnosis in the child who limps. PMID- 22197741 TI - The effect of local perturbation fields on human DTI: characterisation, measurement and correction. AB - Indices derived from diffusion tensor imaging (DTI) data, including the mean diffusivity (MD) and fractional anisotropy (FA), are often used to better understand the microstructure of the brain. DTI, however, is susceptible to imaging artefacts, which can bias these indices. The most important sources of artefacts in DTI include eddy currents, nonuniformity and mis-calibration of gradients. We modelled these and other artefacts using a local perturbation field (LPF) approach. LPFs during the diffusion-weighting period describe the local mismatches between the effective and the expected diffusion gradients resulting in a spatially varying error in the diffusion weighting B matrix and diffusion tensor estimation. We introduced a model that makes use of phantom measurements to provide a robust estimation of the LPF in DTI without requiring any scanner hardware-specific information or special MRI sequences. We derived an approximation of the perturbed diffusion tensor in the isotropic-diffusion limit that can be used to identify regions in any DTI index map that are affected by LPFs. Using these models, we simulated and measured LPFs and characterised their effect on human DTI for three different clinical scanners. The small FA values found in grey matter were biased towards greater anisotropy leading to lower grey to-white matter contrast (up to 10%). Differences in head position due to e.g. repositioning produced errors of up to 10% in the MD, reducing comparability in multi-centre or longitudinal studies. We demonstrate the importance of the proposed correction by showing improved consistency across scanners, different head positions and an increased FA contrast between grey and white matter. PMID- 22197742 TI - Sleep duration during weekdays affects hippocampal gray matter volume in healthy children. AB - Sleep is essential for living beings, and sleep loss has been shown to affect hippocampal structure and function in rats by inhibiting cell proliferation and neurogenesis in this region of the brain. We aimed to analyze the correlation between sleep duration and the hippocampal volume using brain magnetic resonance images of 290 healthy children aged 5-18 years. We examined the volume of gray matter, white matter, and the cerebrospinal fluid (CSF) space in the brain using a fully automated and established neuroimaging technique, voxel-based morphometry, which enabled global analysis of brain structure without bias towards any specific brain region while permitting the identification of potential differences or abnormalities in brain structures. We found that the regional gray matter volume of the bilateral hippocampal body was significantly positively correlated with sleep duration during weekdays after adjusting for age, sex, and intracranial volume. Our results indicated that sleep duration affects the hippocampal regional gray matter volume of healthy children. These findings advance our understanding of the importance of sleep habits in the daily lives of healthy children. PMID- 22197744 TI - Dietary nitrite attenuates oxidative stress and activates antioxidant genes in rat heart during hypobaric hypoxia. AB - The nitrite anion represents the circulatory and tissue storage form of nitric oxide (NO) and a signaling molecule, capable of conferring cardioprotection and many other health benefits. However, molecular mechanisms for observed cardioprotective properties of nitrite remain largely unknown. We have evaluated the NO-like bioactivity and cardioprotective efficacies of sodium nitrite supplemented in drinking water in rats exposed to short-term chronic hypobaric hypoxia. We observed that, nitrite significantly attenuates hypoxia-induced oxidative stress, modulates HIF-1alpha stability and promotes NO-cGMP signaling in hypoxic heart. To elucidate potential downstream targets of nitrite during hypoxia, we performed a microarray analysis of nitrite supplemented hypoxic hearts and compared with both hypoxic and nitrite supplemented normoxic hearts respectively. The analysis revealed a significant increase in the expression of many antioxidant genes, transcription factors and cardioprotective signaling pathways which was subsequently confirmed by qRT-PCR and Western blotting. Conversely, hypoxia exposure increased oxidative stress, activated inflammatory cytokines, downregulated ion channels and altered expression of both pro- and anti-oxidant genes. Our results illustrate the physiological function of nitrite as an eNOS-independent source of NO in heart profoundly modulating the oxidative status and cardiac transcriptome during hypoxia. PMID- 22197745 TI - Protein tyrosine nitration of 15-hydroxy prostaglandin dehydrogenase in the human mast cell line LAD2. AB - Mast cells (MC) play a pivotal role in allergic inflammation and nitric oxide (NO) is known to regulate MC function. One mechanism of NO mediated actions is the post-translational modification protein tyrosine nitration mediated by reactive nitrogen species. In this study we identified targets for nitration in the human mast cell line LAD2 after treatment with a nitric oxide donor and with peroxynitrite. Using two dimensional gel electrophoresis and western blot analyses with monoclonal and polyclonal antibodies we identified 15-hydroxy prostaglandin dehydrogenase (PGDH), a major prostaglandin catabolizing enzyme, as a target for nitration in LAD2. This is the first report on expression of this enzyme in MC and also the first report that PGDH is a target of protein tyrosine nitration. Since MC synthesize and metabolize many prostaglandins including prostaglandin E(2), the major substrate for PGDH, nitration of this prostaglandin catabolizing enzyme is likely functionally significant. PMID- 22197743 TI - The functional connectivity of the human caudate: an application of meta-analytic connectivity modeling with behavioral filtering. AB - Meta-analysis based techniques are emerging as powerful, robust tools for developing models of connectivity in functional neuroimaging. Here, we apply meta analytic connectivity modeling to the human caudate to 1) develop a model of functional connectivity, 2) determine if meta-analytic methods are sufficiently sensitive to detect behavioral domain specificity within region-specific functional connectivity networks, and 3) compare meta-analytic driven segmentation to structural connectivity parcellation using diffusion tensor imaging. Results demonstrate strong coherence between meta-analytic and data driven methods. Specifically, we found that behavioral filtering resulted in cognition and emotion related structures and networks primarily localized to the head of the caudate nucleus, while perceptual and action specific regions localized to the body of the caudate, consistent with early models of nonhuman primate histological studies and postmortem studies in humans. Diffusion tensor imaging (DTI) revealed support for meta-analytic connectivity modeling's (MACM) utility in identifying both direct and indirect connectivity. Our results provide further validation of meta-analytic connectivity modeling, while also highlighting an additional potential, namely the extraction of behavioral domain specific functional connectivity. PMID- 22197740 TI - Neuroimaging of the periaqueductal gray: state of the field. AB - This review and meta-analysis aims at summarizing and integrating the human neuroimaging studies that report periaqueductal gray (PAG) involvement; 250 original manuscripts on human neuroimaging of the PAG were identified. A narrative review and meta-analysis using activation likelihood estimates is included. Behaviors covered include pain and pain modulation, anxiety, bladder and bowel function and autonomic regulation. Methods include structural and functional magnetic resonance imaging, functional connectivity measures, diffusion weighted imaging and positron emission tomography. Human neuroimaging studies in healthy and clinical populations largely confirm the animal literature indicating that the PAG is involved in homeostatic regulation of salient functions such as pain, anxiety and autonomic function. Methodological concerns in the current literature, including resolution constraints, imaging artifacts and imprecise neuroanatomical labeling are discussed, and future directions are proposed. A general conclusion is that PAG neuroimaging is a field with enormous potential to translate animal data onto human behaviors, but with some growing pains that can and need to be addressed in order to add to our understanding of the neurobiology of this key region. PMID- 22197746 TI - Nitric oxide restrain root growth by DNA damage induced cell cycle arrest in Arabidopsis thaliana. AB - Nitric oxide (NO) participates in the regulation of diverse functions in plant cells. However, different NO concentrations may trigger different pathways during the plant development. At basal levels of NO, plants utilize the NO signaling transduction pathway to facilitate plant growth and development, whereas higher concentrations trigger programmed cell death (PCD). Our results show that NO lower than the levels causing PCD, but higher than the basal levels induce DNA damage in root cells in Arabidopsis as witnessed by a reduction in root growth, rather than cell death, since cells retain the capacity to differentiate root hairs. The decrease in meristematic cells and increase in DNA damage signals in roots in responses to NO are in a dose dependent manner. The restraint of root growth is due to cell cycle arrest at G1 phase which is caused by NO induced DNA damage, besides a second arrest at G2/M existed in NO supersensitive mutant cue1. The results indicate that NO restrain root growth via DNA damage induced cell cycle arrest. PMID- 22197747 TI - Refugia-based strategies for sustainable worm control: factors affecting the acceptability to sheep and goat owners. AB - Sustainable nematode management programs aim to minimise animal production loss and prevent parasitic disease, without increasing the level of anthelmintic resistance. Resistance management strategies are now largely based on the "refugia" concept, by which populations of nematodes not recently exposed to treatment are deliberately allowed to survive. Progeny from the unselected parasites provide a source of less-resistant worms which can dilute resistant worms surviving anthelmintics, and hence reduce the rate of resistance development. This can be achieved by either modifying strategic treatment regimens to ensure the survival of infective worm larvae on pasture, or by avoiding treatments to individual animals identified as best able to cope with parasites. These strategies include "targeted treatment" (based on estimates of worm-burdens) and "targeted selective treatment" (based on indications of parasitic effects). However, the departure from conventional anthelmintic approaches represents a major conceptual challenge to many livestock owners. Factors that may affect the wide adoption of refugia strategies include the increased risk of parasitism and production loss, the effectiveness of reducing the development of resistance, the practicality of implementation, and the direct effects on costs and labour efficiency. The acceptance of particular strategies is likely to vary considerably according to environmental effects, nematode species, animal production aims and resource availability. However, recent indications that comparatively small changes to present practices can provide substantial refugia benefits suggest that appropriate resistance management approaches can be developed for different situations. PMID- 22197748 TI - Gender inequities, relationship power, and childhood immunization uptake in Nigeria: a population-based cross-sectional study. AB - BACKGROUND: This study aimed to simultaneously examine the association between multiple dimensions of gender inequities and full childhood immunization. METHODS: A multilevel logistic regression analysis was performed on nationally representative sample data from the 2008 Nigeria Demographic and Health Survey, which included 33,385 women aged 15-49 years who had a total of 28,647 live-born children; 24,910 of these children were included in this study. RESULTS: A total of 4283 (17%) children had received full immunization. Children of women whose spouse did not contribute to household earnings had a higher likelihood of receiving full childhood immunization (odds ratio (OR) 1.96, 95% confidence interval (95% CI) 1.02-3.77), and children of women who lacked decision-making autonomy had a lower likelihood of receiving full childhood immunization (OR 0.74, 95% CI 0.60-0.91). The likelihood of receiving full childhood immunization was higher among female children (OR 1.28, 95% CI 1.06-1.54), Yoruba children (OR 2.45, 95% CI 1.19-4.26), and children resident in communities with low illiteracy (OR 1.82, 95% CI 1.06-3.12), but lower for children of birth order 5 or above (OR 0.64, 95% CI 0.45-0.96), children of women aged <= 24 years (OR 0.66, 95% CI 0.50 0.87) and 25-34 years (OR 0.79, 95% CI 0.63-0.99), children of women with no education (OR 0.33, 95% CI 0.21-0.54) and primary education (OR 0.66, 95% CI 0.45 0.97), as well as children of women resident in communities with high unemployment (OR 0.34, 95% CI 0.20-0.57). CONCLUSIONS: The woman being the sole provider for her family (i.e., having a spouse who did not contribute to household earnings) was associated with a higher likelihood of fully immunizing the child, and the woman lacking decision-making autonomy was associated with a lower likelihood of fully immunizing the child. These findings draw attention to the need for interventions aimed at promoting women's employment and earning possibilities, whilst changing gender-discriminatory attitudes within relationships, communities, and society in general. PMID- 22197749 TI - Tetradecanoylphorbol-13-acetate (TPA) significantly increases AAV2/5 transduction of human neuronal cells in vitro. AB - Recombinant adeno-associated virus type 2 (AAV2) vectors have shown great promise in current ophthalmology clinical trials targeting gene delivery to the retinal pigment epithelium (RPE). To treat the majority of retinal diseases, however, gene delivery would need to be targeted to photoreceptor neurons of the outer retina. AAV2 pseudotyped with the AAV5 capsid (AAV2/5) has shown far greater transduction efficiency in photoreceptors compared to standard AAV2 vectors. For clinical trial applications using gene therapy, it is helpful to generate pre clinical data in human cells wherever possible. There is however very little data, indeed some controversy, as to whether AAV2/5 can be used effectively in differentiated neurons in culture. In this study we show that transduction of the human neuroblastoma cell line SH-SY5Y with recombinant AAV2/5 expressing GFP is well tolerated. Furthermore, we explore the mechanism whereby exposure to retinoic acid (RA) and the phorbol ester 12-O-Tetradecanoylphorbol-13- acetate (TPA) can induce this cell line to differentiate into a stable population of human neurons, with significantly increased levels of AAV2/5 transduction. These observations may be helpful for assessing AAV2/5 vectors in vitro, particularly where it is necessary to generate pre-clinical data for clinical trials of gene therapy to the human central nervous system. PMID- 22197751 TI - In-vitro recording of forward light-scatter by human lens capsules and different types of posterior capsule opacification. AB - The purpose of the present study was to elucidate the effect of posterior capsule opacification (PCO) on the straylight domain of visual function. PCO is heterogeneous with regard to morphology and severity; both aspects contribute to its functional effect. The isolated impact of capsule areas with specific morphology and severity on straylight was studied in-vitro by recording forward light-scatter. Forward light-scatter by four different capsule types, i.c. anterior capsule (AC), clear posterior capsule (PC), fibrotic and regeneratory PCO, was recorded at several visual angles with a goniometer, using different wavelengths. Angular (theta(a)) and wavelength dependencies (lambda(b)) were studied by determining exponents a and b. Recorded straylight values of isolated capsule areas varied between 10* below to 10* above the value normal for the human eye, depending on the capsule's condition (clear to opacified). The angular dependence of light scattered by clear PCs was weaker, whereas in the other capsule types it was stronger than in the normal eye. On average, the wavelength dependence of light scattered by different capsule types was similar, but the variation was considerable. At the smallest visual angles, increased angular and decreased wavelength dependence was found, especially in fibrotic and regeneratory PCO. It was concluded that the range of straylight values found in vitro in lens capsules properly corresponded to that found previously in in-vivo pseudophakics. Surprisingly, the wavelength dependence of PCO indicated that small-particle light-scattering is important in PCO. Refractile effects were more important at small visual angles, as indicated by the combined stronger angular and weaker wavelength dependence. PMID- 22197750 TI - Age-related changes in visual function in cystathionine-beta-synthase mutant mice, a model of hyperhomocysteinemia. AB - Homocysteine is an amino acid required for the metabolism of methionine. Excess homocysteine is implicated in cardiovascular and neurological disease and new data suggest a role in various retinopathies. Mice lacking cystathionine-beta synthase (cbs(-/-)) have an excess of retinal homocysteine and develop anatomical abnormalities in multiple retinal layers, including photoreceptors and ganglion cells; heterozygous (cbs(+/-)) mice demonstrate ganglion cell loss and mitochondrial abnormalities in the optic nerve. The purpose of the present study was to determine whether elevated homocysteine, due to absent or diminished cbs, alters visual function. We examined cbs(-/-) (3 weeks) and cbs(+/-) mice (5, 10, 15, 30 weeks) and results were compared to those obtained from wild type (WT) littermates. Conventional dark- and light-adapted ERGs were recorded, along with dc-ERG to assess retinal pigment epithelial (RPE) function. The visual evoked potential (VEP) was used to assess transmission to the visual cortex. The amplitudes of the major ERG components were reduced in cbs(-/-) mice at age 3 weeks and VEPs were delayed markedly. These findings are consistent with the early retinal disruption observed anatomically in these mice. In comparison, at 3 weeks of age, responses of cbs(+/-) mice did not differ significantly from those of WT mice. Functional abnormalities were not observed in cbs(+/-) mice until 15 weeks of age, at which time amplitude reductions were noted for the ERG a- and b wave and the light peak component, but not for other components generated by the RPE. VEP implicit times were delayed in cbs(+/-) mice at 15 and 30 weeks, while VEP amplitudes were unaffected. The later onset of functional defects in cbs(+/-) mice is consistent with a slow loss of ganglion cells reported previously in the heterozygous mutant. Light peak abnormalities indicate that RPE function is also compromised in older cbs(+/-) mice. The data suggest that severe elevations of homocysteine are associated with marked alterations of retinal function while modest homocysteine elevation is reflected in milder and delayed alterations of retinal function. The work lays the foundation to explore the role of homocysteine in retinal diseases such as glaucoma and optic neuropathy. PMID- 22197752 TI - Levels of lactoferrin, secretory IgA and serum albumin in the tear film of people with keratoconus. AB - Keratoconus is a degenerating disease of the eye which causes an irregularly shaped cornea leading to severe impairment of vision. Tear proteomics in keratoconus has been a topic of substantial discussion and speculation over many years. This study was designed to examine the levels of total protein, lactoferrin, secretory IgA and serum albumin in the tear film of people with keratoconus. Basal tears were collected using a capillary tube and corneal curvature was mapped using a topographer. Total protein in tears was estimated. The amount of regulated protein lactoferrin, constitutive protein sIgA and serum protein albumin was measured using specific ELISAs. The changes in protein concentrations in tears were correlated to the degree of corneal asphericity. There was a two-fold (p<0.0001) decrease in total protein levels between keratoconus (3.86 +/- 1.62 mg/ml) and normal (7.00 +/- 1.58 mg/ml) tears. The amount of lactoferrin (0.67 +/- 0.28 vs. 1.13 +/- 0.29 mg/ml) and secretory IgA (0.78 +/- 0.36 vs. 1.70 +/- 0.66 mg/ml) were significantly (p<0.0001) reduced in keratoconus tears. Variation in serum albumin levels between keratoconus (8.18 +/ 4.72 MUg/ml) and normal tears (11.66 +/- 8.20 MUg/ml) were not significant. The differences in total protein, lactoferrin and secretory IgA were not associated with contact lens wear, age, gender or atopy of subjects. The keratometry reading was negatively correlated to tear levels of total protein (r = -0.59, p < 0.01) lactoferrin (r = -0.40, p < 0.05) and secretory IgA (r = -0.34, p < 0.05). The tears of keratoconus subjects appear to have an altered protein profile, and one that might change with the severity of the disease. These findings may lead the way to understanding or monitoring disease progression. PMID- 22197753 TI - Individual differences in emotionality and peri-traumatic processing. AB - BACKGROUND AND OBJECTIVES: Recent cognitive models propose that intrusive trauma memories arise and persist because high levels of emotional arousal triggered by the trauma disrupt conceptual processing of elements of the event, while enhancing sensory/perceptual processing. A trauma film analogue design was used to investigate if the predicted facilitating effects on intrusions from inhibiting conceptual processing and predicted attenuating effects on intrusions from inhibiting sensory processing are moderated by individual differences in emotionality. METHODS: One hundred and five non-clinical participants viewed a traumatic film while undertaking a conceptual interference task, a sensory interference task, or no interference task. Participants recorded the frequency and intensity of intrusions over the following week. RESULTS: There was no facilitating effect for the conceptual interference task compared to no interference task. A significant attenuation of the frequency of intrusions was evident for those undertaking sensory interference (n(2) = .04). This effect, however, was only present for those with high trait anxiety (d = .82) and not for those with low trait anxiety (d = .08). Relative to high trait anxious controls, high anxious participants who undertook sensory interference also reported lower intensity of intrusions (d = .66). CONCLUSIONS: This is the first trauma film analogue study to show that the attenuating effect of concurrent sensory/perceptual processing on the frequency and intensity of subsequent intrusions is evident only for people with high trait anxiety. The results have implications for conceptual models of intrusion development and for their application to the prevention of post traumatic distress. PMID- 22197754 TI - Expectancy bias in a selective conditioning procedure: trait anxiety increases the threat value of a blocked stimulus. AB - BACKGROUND AND OBJECTIVES: In a blocking procedure, a single conditioned stimulus (CS) is paired with an unconditioned stimulus (US), such as electric shock, in the first stage. During the subsequent stage, the CS is presented together with a second CS and this compound is followed by the same US. Fear conditioning studies in non-human animals have demonstrated that fear responding to the added second CS typically remains low, despite its being paired with the US. Accordingly, the blocking procedure is well suited as a laboratory model for studying (deficits in) selective threat appraisal. The present study tested the relation between trait anxiety and blocking in human aversive conditioning. METHODS: Healthy participants filled in a trait anxiety questionnaire and underwent blocking treatment in the human aversive conditioning paradigm. Threat appraisal was measured through shock expectancy ratings and skin conductance. RESULTS: As hypothesized, trait anxiety was positively associated with shock expectancy ratings to the blocked stimulus. LIMITATIONS: In skin conductance responding, no significant effects of stimulus type could be detected during blocking training or testing. The current study does not allow strong claims to be made regarding the theoretical process underlying the expectancy bias we observed. CONCLUSIONS: The observed shock expectancy bias might be one of the mechanisms leading to non specific fear in individuals at risk for developing anxiety disorders. A deficit in blocking, or a deficit in selective threat appraisal at the more general level, indeed results in fear becoming non-specific and disconnected from the most likely causes or predictors of danger. PMID- 22197755 TI - Associative learning in flying phobia. AB - BACKGROUND AND OBJECTIVES: Modern learning theories suggest that particularly strong associative learning contributes to the etiology and maintenance of anxiety disorders, thus explaining why some individuals develop an anxiety disorder after a frightening (conditioning) event, whereas others do not. However, associative learning has rarely been investigated experimentally in specific phobias. The current study investigated associative learning in patients with flying phobia and healthy controls using a modified version of Olson and Fazio's associative learning paradigm (Olson & Fazio, 2001). METHODS: Under the guise of an attention task, patients with flying phobia (n = 33), and healthy controls (n = 39) viewed a series of distracters interspersed with pairings of novel objects (counterbalanced conditioned stimuli, CSs) with frightening and pleasant stimuli (unconditioned stimuli, USs). RESULTS: After the conditioning procedure patients with flying phobia rated both CSs more frightening and showed stronger discrimination between the CSs for valence compared to healthy controls. CONCLUSIONS: Our findings indicate a particularly stronger conditioning effect in flying phobia. These results contribute to the understanding of the etiology of specific phobia and may help to explain why only some individuals develop a flying phobia after an aversive event associated with flying. PMID- 22197756 TI - Global and regional hearing impairment prevalence: an analysis of 42 studies in 29 countries. AB - BACKGROUND: Hearing impairment is a leading cause of disease burden, yet population-based studies that measure hearing impairment are rare. We estimate regional and global hearing impairment prevalence from sparse data and calculate corresponding uncertainty intervals. METHODS: We accessed papers from a published literature review and obtained additional detailed data tabulations from investigators. We estimated the prevalence of hearing impairment by region, sex, age and hearing level using a Bayesian hierarchical model, a method that is effective for sparse data. As the primary objective of modelling was to produce regional and global prevalence estimates, including for those regions with scarce to no data, models were evaluated using cross-validation. RESULTS: We used data from 42 studies, carried out between 1973 and 2010 in 29 countries. Hearing impairment was positively related to age, male sex and middle- and low-income regions. We estimated that the global prevalence of hearing impairment (defined as an average hearing level of 35 decibels or more in the better ear) in 2008 was 1.4% (95% uncertainty interval 1.0-2.2%) for children aged 5-14 years, 9.8% (7.7 13.2%) for females >15 years of age and 12.2% (9.7-16.2%) for males >15 years of age. The model exhibited good external validity in the cross-validation analysis, with 87% of survey estimates falling within our final model's 95% uncertainty intervals. CONCLUSION: Our results suggest that the prevalence of child and adult hearing impairment is substantially higher in middle- and low-income countries than in high-income countries, demonstrating the global need for attention to hearing impairment. PMID- 22197757 TI - Preparation of vitamin E loaded nanocapsules by the nanoprecipitation method: from laboratory scale to large scale using a membrane contactor. AB - Vitamin E or alpha-tocopherol is widely used as a strong antioxidant in many medical and cosmetic applications, but is rapidly degraded, because of its light, heat and oxygen sensitivity. In this study, we applied the nanoprecipitation method to prepare vitamin E-loaded nanocapsules, at laboratory-scale and pilot scale. We scaled-up the preparation of nanocapsule with the membrane contactor technique. The effect of several formulation variables on the vitamin E-loaded nanocapsules properties (mean diameter, zeta potential, and drug entrapment efficiency) was investigated. The optimized formulation at laboratory-scale and pilot-scale lead to the preparation of vitamin E-loaded nanocapsules with mean diameter of 165 and 172 nm, respectively, and a high encapsulation efficiency (98% and 97%, respectively). PMID- 22197758 TI - Physicochemical characterization of curcuminoid-loaded solid lipid nanoparticles. AB - Curcuminoid-loaded solid lipid nanoparticles (SLN) were produced by melt homogenization. The used lipid matrices were medium chain triglycerides, trimyristin and tristearin. The resulting nanoparticles had an anisometric shape and a platelet-like structure. Curcuminoid-loaded trimyristin particles did not solidify when stored at room temperature. The supercooled state of trimyristin was studied by DSC and (1)H NMR experiments. A partial recrystallization of the lipid matrix was detected but no change of the mobility of the lipid was noted. Nanoparticles based on tristearin had an alpha- and beta-modification which was subsequently converted into the stable beta-phase. Curcuminoids did neither influence the melting behavior nor the crystalline or geometric structure of the particles. The interactions between the curcuminoids and the lipid matrix were investigated by Raman and fluorescence spectroscopy. The shape of the curcuminoid bands in the Raman spectra suggested that the drug was in an amorphous state. The fluorescence spectra showed an effect of the lipid matrix on fluorescence properties of the curcuminoids. It was further demonstrated that the drug was not secluded by the solid lipid matrix, but it was influenced by the surrounding aqueous environment. Fluorescence anisotropy measurements revealed a decreased mobility of the curcuminoids within the nanodispersions. From the results of Raman and fluorescence measurements it was concluded that the drug was mainly located on the surface of the crystalline particles. PMID- 22197759 TI - Effect of ergothioneine on acute lung injury and inflammation in cytokine insufflated rats. AB - OBJECTIVE: The Acute Respiratory Distress Syndrome (ARDS), the most severe form of Acute Lung Injury (ALI), is a highly-fatal, diffuse non-cardiogenic edematous lung disorder. The pathogenesis of ARDS is unknown but lung inflammation and lung oxidative stress are likely contributing factors. Since no specific pharmacologic intervention exists for ARDS, our objective was to determine the effect of treatment with ergothioneine-a safe agent with multiple anti-inflammatory and antioxidant properties on the development of lung injury and inflammation in rats insufflated with cytokines found in lung lavages of ARDS patients. METHOD: Sprague-Dawley rats (3-10/group) were given 15 mg/kg or 150 mg/kg l-ergothioneine intravenously 1h before or 18 h after cytokine (IL-1 and IFNgamma) insufflation. Lung injury (lavage LDH levels) and lung inflammation (lavage neutrophil numbers) were measured 24h after cytokine insufflation. RESULTS: Ergothioneine pre- and post-treatment generally decreased lung injury and lung inflammation in cytokine insufflated rats. CONCLUSION: Ergothioneine should be considered for additional testing as a potential therapy for treating and preventing ARDS. PMID- 22197760 TI - Oxidative stress-induced biomarkers for stem cell-based chemical screening. AB - Stem cells have been considered for their potential in pharmaceutical research, as well as for stem cell-based therapy for many diseases. Despite the potential for their use, the challenge remains to examine the safety and efficacy of stem cells for their use in therapies. Recently, oxidative stress has been strongly implicated in the functional regulation of cell behavior of stem cells. Therefore, development of rapid and sensitive biomarkers, related to oxidative stress is of growing importance in stem cell-based therapies for treating various diseases. Since stem cells have been implicated as targets for carcinogenesis and might be the origin of "cancer stem cells", understanding of how oxidative stress induced signaling, known to be involved in the carcinogenic process could lead to potential screening of cancer chemopreventive and chemotherapeutic agents. An evaluation of antioxidant states reducing equivalents like GSH and superoxide dismutase (SOD), as well as reactive oxygen species (ROS) and nitric oxide (NO) generation, can be effective markers in stem cell-based therapies. In addition, oxidative adducts, such as 4-hydroxynonenal, can be reliable markers to detect cellular changes during self-renewal and differentiation of stem cells. This review highlights the biomarker development to monitor oxidative stress response for stem cell-based chemical screening. PMID- 22197762 TI - Preventing the acute respiratory distress syndrome. AB - Laudable supportive advances have been made to improve the care of patients with the Acute Respiratory Distress Syndrome (ARDS) but no pharmacologic interventions are known to reduce the high mortality of this disorder once it is established. This commentary discusses some of the challenges that arise in preventing ARDS in at-risk individuals and the likely dependence of this approach on biomarker panels that can be done in real time. PMID- 22197763 TI - Study of influenza A virus in wild boars living in a major duck wintering site. AB - Wild birds, which are reservoirs of influenza viruses, are believed to be the original source of new influenza viruses-including highly pathogenic ones-that can be transmitted to domestic animals as well as humans and represent a potential epizootic and/or pandemic threat. Despite increasing knowledge on influenza A virus dynamics in wild birds, the viral circulation in wild boars remains largely unknown. This is of particular interest since pigs can be infected with both human and avian viruses; upon co-infection, they can act as a mixing vessel through reassortment, a mechanism that resulted in the emergence of the pandemic H1N1 virus in 2009. The Camargue (Southern France) appears as an ideal study area to investigate inter-species transmission of influenza A viruses from wild birds and possibly humans to wild boars. Indeed, the important local wild boar population shares wetland use with humans and the largest concentration of wintering ducks in France, that are both susceptible to infection by influenza A viruses. Additionally, wild boars occasionally prey on ducks. We conducted a virological and serological survey on wild boars in the Camargue (Southern France) between September 2009 and November 2010. No influenza A virus was detected in the collected nasal swabs (n=315) and no influenza specific antibodies were observed in the serological samples (n=20). As the study was mainly focused on viral excretion, which is limited in time, we cannot exclude that low or occasional influenza A virus circulation took place during the study period. Although, wild boars did not seem to be a key element in the dynamics of influenza A virus circulation in the Camargue, wild boar influenza A virus infections should be more widely studied to determine if the pattern observed here represents the normal situation or an exceptional one. PMID- 22197764 TI - Exchange of Newcastle disease viruses in Korea: the relatedness of isolates between wild birds, live bird markets, poultry farms and neighboring countries. AB - Newcastle disease virus (NDV) has a worldwide distribution and is often carried by wild ducks, which may represent one of the natural reservoirs. However, the epidemiological relatedness of NDV between wild ducks and domestic poultry is unclear. A total of 14 isolates were obtained from 8439 samples from live bird markets (LBMs) and wild bird populations in Korea during from 2007 to 2010. These isolates were characterized genetically and phylogenetic analysis was conducted to investigate the relatedness between isolates from wild birds, LBM and poultry farms. In phylogenetic analysis, all 14 isolates belonged to genotype I virus within class II. Of these, nine isolates from wild birds were most closely related to the Aomori-like cluster. The five LBM isolates were most closely related to the V4-like cluster. All isolates in this study were closely related to isolates from domestic duck farms in Korea and Chinese LBM isolates. The results indicate that NDV exchange occurs between wild birds, poultry farms, LBMs and neighboring countries. Enhanced NDV surveillance is required to monitor the introduction of variant NDV in consequence of evolution in LBMs and to investigate NDV epidemiology in various species of putative hosts. PMID- 22197765 TI - Population structure of the dengue viruses, Aragua, Venezuela, 2006-2007. Insights into dengue evolution under hyperendemic transmission. AB - During the past three decades there has been a notable increase in dengue disease severity in Venezuela. Nevertheless, the population structure of the viruses being transmitted in this country is not well understood. Here, we present a molecular epidemiological study on dengue viruses (DENV) circulating in Aragua State, Venezuela during 2006-2007. Twenty-one DENV full-length genomes representing all of the four serotypes were amplified and sequenced directly from the serum samples. Notably, only DENV-2 was associated with severe disease. Phylogenetic trees constructed using Bayesian methods indicated that only one genotype was circulating for each serotype. However, extensive viral genetic diversity was found in DENV isolated from the same area during the same period, indicating significant in situ evolution since the introduction of these genotypes. Collectively, the results suggest that the non-structural (NS) proteins may play an important role in DENV evolution, particularly NS1, NS2A and NS4B proteins. The phylogenetic data provide evidence to suggest that multiple introductions of DENV have occurred from the Latin American region into Venezuela and vice versa. The implications of the significant viral genetic diversity generated during hyperendemic transmission, particularly in NS protein are discussed and considered in the context of future development and use of human monoclonal antibodies as antivirals and tetravalent vaccines. PMID- 22197767 TI - Lifetime residential mobility history and self-rated health at midlife. AB - BACKGROUND: Little research focuses on the influence of lifetime residential mobility on health at midlife. We used a national survey of participant recall of residential mobility to assess this issue and explore the mediating and moderating effects of personal and environmental context. METHODS: In March 2010, we collected data from people in Taiwan aged 40 to 60 years. Based on the household registration system, data were collected using the population proportional-to-size sampling method and a computer-assisted telephone interview. A total of 2834 participants completed the interview. Based on the 3490 registered households, the overall response rate was 81.2%. RESULTS: The mean cumulative frequency of geographic relocation (CFGR) was 3.06 +/- 2.78 times and ranged from 0 to 21. After carefully adjusting for the heterogeneity of demographic and socioeconomic propensity, total CFGR was significantly positively associated with negative self-rated mental (odds ratio [OR] and 95% CI for increase per time: 1.06, 1.02-1.16) and physical (OR and 95% CI for increase per time: 1.16, 1.05-1.26) health. Social network support lessened the impact of total CFGR on self-rated mental health. In addition to the primary effect, the interaction (residential environmental satisfaction * total CFGR) significantly moderated negative mental health and negative physical health. CONCLUSIONS: Lifetime residential mobility history independently influenced midlife health. Social network support and satisfaction with the residential environment in past and current living places further mediated or moderated midlife health. Findings from these different perspectives offer insights for future medical care projects and epidemiologic studies. PMID- 22197768 TI - Freezing injury: the special case of the sperm cell. AB - The cellular damage that spermatozoa encounter at rapid rates of cooling has often been attributed to the formation of intracellular ice although no convincing evidence of intracellular ice formation has ever been obtained. We demonstrate that the high intracellular protein content together with the osmotic shrinkage associated with extracellular ice formation leads to intracellular vitrification of spermatozoa during cooling. At rapid rates of cooling the cell damage to spermatozoa is a result of an osmotic imbalance encountered during thawing, not intracellular ice formation. The osmotic imbalance occurs at rapid cooling rates due to a diffusion limited ice crystallisation in the extracellular fluid, i.e. the amount of ice forming during the cooling is less than expected from the equilibrium phase diagram. This explanation allows insights into other aspects of the cryobiology of spermatozoa and it is anticipated that this understanding will lead to specific improved methods of conventional cryopreservation for mammalian spermatozoa. It is also likely that this model will be relevant to the development of novel technologies for sperm preservation including vitrification and freeze drying. PMID- 22197766 TI - Molecular epidemiology, population genetics, and pathogenic role of Helicobacter pylori. AB - Helicobacter pylori infection is linked to various gastroduodenal diseases; however, only approximately 20% of infected individuals develop severe diseases. Despite the high prevalence of H. pylori infection in Africa and South Asia, the incidence of gastric cancer in these areas is much lower than in other countries. Furthermore, the incidence of gastric cancer tends to decrease from north to south in East Asia. Such geographic differences in the pathology can be explained, at least in part, by the presence of different types of H. pylori virulence factors, especially cagA, vacA, and the right end of the cag pathogenicity island. The genotype of the virulence genes is also useful as a tool to track human migration utilizing the high genetic diversity and frequent recombination between different H. pylori strains. Multilocus sequence typing (MLST) analysis using seven housekeeping genes can also help to predict the history of human migrations. Population structure analysis based on MLST has revealed seven modern population types of H. pylori, which derived from six ancestral populations. Interestingly, the incidence of gastric cancer is closely related to the distribution of H. pylori populations. The different incidence of gastric cancer can be partly attributed to the different genotypes of H. pylori circulating in different geographic areas. Although approaches by MLST and virulence factors are effective, these methods focus on a small number of genes and may miss information conveyed by the rest of the genome. Genome-wide analyses using DNA microarray or whole-genome sequencing technology give a broad view on the genome of H. pylori. In particular, next-generation sequencers, which can read DNA sequences in less time and at lower costs than Sanger sequencing, enabled us to efficiently investigate not only the evolution of H. pylori, but also novel virulence factors and genomic changes related to drug resistance. PMID- 22197769 TI - Improvement of flow and bulk density of pharmaceutical powders using surface modification. AB - Improvement in flow and bulk density, the two most important properties that determine the ease with which pharmaceutical powders can be handled, stored and processed, is done through surface modification. A limited design of experiment was conducted to establish a standardized dry coating procedure that limits the extent of powder attrition, while providing the most consistent improvement in angle of repose (AOR). The magnetically assisted impaction coating (MAIC) was considered as a model dry-coater for pharmaceutical powders; ibuprofen, acetaminophen, and ascorbic acid. Dry coated drug powders were characterized by AOR, particle size as a function of dispersion pressure, particle size distribution, conditioned bulk density (CBD), Carr index (CI), flow function coefficient (FFC), cohesion coefficient using different instruments, including a shear cell in the Freeman FT4 powder rheometer, and Hansen flowability index. Substantial improvement was observed in all the measured properties after dry coating relative to the uncoated powders, such that each powder moved from a poorer to a better flow classification and showed improved dispersion. The material intrinsic property such as cohesion, plotted as a function of particle size, gave a trend similar to those of bulk flow properties, AOR and CI. Property improvement is also illustrated in a phase map of inverse cohesion (or FFC) as a function of bulk density, which also indicated a significant positive shift due to dry coating. It is hoped that such phase maps are useful in manufacturing decisions regarding the need for dry coating, which will allow moving from wet granulation to roller compaction or to direct compression based formulations. PMID- 22197770 TI - Polyelectrolyte complex nanoparticles of amino poly(glycerol methacrylate)s and insulin. AB - Amino poly(glycerol methacrylate)s (PGOHMAs) were synthesized from linear or star shaped poly(glycidyl methacrylate)s (PGMA)s via ring opening reactions with 1,2 ethanediamine, 1,4-butanediamine and diethylenetriamine, respectively. The resulting cationic polymers were employed to form polyelectrolyte complexes (PECs) with insulin. Parameters influencing complex formation were investigated by dynamic light scattering (DLS). PECs in the size range of 100-200 nm were obtained under optimal conditions, i.e., the pH value of PECs was 5.58-6.27, the concentration of NaCl was 0.02 mol/L, and insulin-polymer weight ratio was 0.8. The insulin association efficiency (AE) of current system increased with zeta potentials of PECs. Circular dichroism (CD) analysis corroborated that the structure of insulin in the PEC nanoparticles was preserved after lyophilization. Fourier transform infrared (FT-IR) and X-ray diffraction (XRD) experiments demonstrated that weak physical interactions between insulin and amino PGOHMAs play an important role in the formation of PECs. The release of insulin depends on both structure and architecture of amino PGOHMAs. These PECs would be potentially useful for mucosal administration. PMID- 22197771 TI - Nano-sized flake carboxymethyl cassava starch as excipient for solid dispersions. AB - Nano-sized excipients were used in solid dispersions (SD) to enhance the dissolution rate of poorly water-soluble drug in this study. Nano-sized flake carboxymethyl cassava starch (CMCS) was firstly synthesized under ultrasonic irradiation. Then acetylsalicylic acid (ASA) was selected as water insoluble drug model to prepare solid dispersions using three different kinds of excipients. SD1 was prepared using native cassava starch as carrier. SD2 and SD3 were prepared using nano-sized CMCS (degree substitution, DS=1.15, 100-400 nm) and micro-sized CMCS (DS=0.36, 8-28 MUm), respectively. These solid dispersions were characterized by powder X-ray diffractometry, scanning electron micrographs and dissolution. The results suggested that the SD2 prepared by nano-sized CMCS had much better dispersion capability for the drug than the other two solid dispersions. And the dissolution rate of SD2 was considerably higher than that of pure drug. These results indicated that the nanoscale CMCS was a kind of good carrier for solid dispersion to improve the solubility of poorly water-soluble drugs. PMID- 22197772 TI - Dry powder inhalers: mechanistic evaluation of lactose formulations containing salbutamol sulphate. AB - The purpose of this study was to evaluate the relationships between physicochemical properties and aerosolisation performance of different grades of lactose. In order to get a wide range of physicochemical properties, various grades of lactose namely Flowlac 100 (FLO), Lactopress anhydrous 250 (LAC), Cellactose 80 (CEL), Tablettose 80 (TAB), and Granulac 200 (GRA) were used. The different lactose grades were carefully sieved to separate 63-90 MUm particle size fractions and then characterised in terms of size, shape, density, flowability, and solid state. Formulations were prepared by blending each lactose with salbutamol sulphate (SS) at ratio of 67.5:1 (w/w), and then evaluated in terms of SS content uniformity, lactose-SS adhesion properties, and in vitro aerosolisation performance delivered from the Aerolizer. Sieved lactose grades showed similar particle size distributions (PSDs) and good flow properties but different particle shape, particle surface texture, and particle solid state. Content uniformity assessments indicated that lactose particles with rougher surface produced improved SS homogeneity within DPI formulation powders. Lactose SS adhesion assessments indicated that lactose particles with more elongated shape and the rougher surface showed smaller adhesion force between lactose and salbutamol sulphate. Lactose powders with higher bulk density and higher tap density produced smaller emission (EM) and higher drug loss (DL) of SS. In vitro aerosolisation for various lactose grades followed the following rank order in terms of deposition performance: GRA>TAB>LAC ~ CEL>FLO. Linear relationships were established showing that in order to maximize SS delivery to lower airway regions, lactose particles with more elongated shape, more irregular shape, and rougher surface are preferred. Therefore, considerable improvement in DPI performance can be achieved by careful selection of grade of lactose included within DPI formulations. PMID- 22197773 TI - An investigation into the effect of formulation variables and process parameters on characteristics of granules obtained by in situ fluidized hot melt granulation. AB - The aim of this study was to investigate the influence of binder content, binder particle size, granulation time and inlet air flow rate on granule size and size distribution, granule shape and flowability, as well as on drug release rate. Hydrophilic (polyethyleneglycol 2000) and hydrophobic meltable binder (glyceryl palmitostearate) were used for in situ fluidized hot melt granulation. Granule size was mainly influenced by binder particle size. Binder content was shown to be important for narrow size distribution and good flow properties. The results obtained indicate that conventional fluid bed granulator may be suitable for production of highly spherical agglomerates, particularly when immersion and layering is dominant agglomeration mechanism. Granule shape was affected by interplay of binder content, binder particle size and granulation time. Solid state analysis confirmed unaltered physical state of the granulate components and the absence of interactions between the active and excipients. Besides the nature and amount of binder, the mechanism of agglomerate formation seems to have an impact on drug dissolution rate. The results of the present study indicate that fluidized hot melt granulation is a promising powder agglomeration technique for spherical granules production. PMID- 22197774 TI - Drug delivery and imaging in cancer. Editorial. PMID- 22197775 TI - Collagenase-1 injection improved tumor distribution and gene expression of cationic lipoplex. AB - Elevated interstitial fluid pressure (IFP) in a tumor is a barrier to tumor accumulation of systemic delivery of nanocarriers. In this study, we investigated whether intravenous injection of type I collagenase (collagenase-1) reduced IFP in tumors and increased the accumulation and gene expression of cationic liposome/plasmid DNA complex (lipoplex) in tumors after intravenous injection into mice bearing mouse lung carcinoma LLC tumors. Collagenase-1 reduced the amount of type I collagen in the tumor, and significantly decreased IFP by 65% at 1h after injection. Therefore, collagenase-1 induced 1.5-fold higher accumulation and 2-fold higher gene expression of lipoplex in tumors after intravenous injection. These findings indicated that intravenous injection of collagenase-1 improved the accumulation of lipoplex by decreasing IFP in tumors. These results support the potential use of collagen digestion as a strategy to improve systemic gene delivery into tumors. PMID- 22197776 TI - A combined score of pro- and anti-inflammatory interleukins improves mortality prediction in severe sepsis. AB - Identification of patients at increased risk of death is dramatically important in severe sepsis. Cytokines have been widely assessed as potential biomarkers in this disease, but none of the cytokines studied has evidenced a sufficient specificity or sensitivity to be routinely employed in clinical practice. In this pilot study, we profiled 17 immune mediators in the plasma of 29 consecutively recruited patients with severe sepsis or septic shock, during the first 24h following admission to the ICU, by using a Bio-Plex Human Cytokine 17-Plex Panel (Bio-Rad). Patients were 66.1year old in average. Twelve patients of our cohort died during hospitalization at the ICU, eight of them in the first 72h due to multiorganic dysfunction syndrom (MODS). Levels in plasma of three pro inflammatory mediators (IL-6, IL-8, MCP-1) and of an immunosuppressive one (IL 10) were higher in those patients with fatal outcome. We developed a combined score with those cytokines showing to better predict mortality in our cohort based on the results of Cox regression analysis. This way, IL-6, IL-8 and IL-10 were included in the score. Patients were split into two groups based on the percentile 75 (P75) of the plasma levels of these three interleukins. Those patients showing at least one interleukin value higher than P75 were given the value "1". Those patients showing IL-6, IL-8, IL-10 levels below P75 were given the value "0". Hazard ratios for mortality at day 3 and day 28th obtained with the combined score were 2-3-fold higher than those obtained with the individual interleukins values. In conclusion, we have described a combined cytokine score associated with a worse outcome in patients with sepsis, which may represent a new avenue to be explored for guiding treatment decisions in this disease. PMID- 22197777 TI - Nanobody-coupled microbubbles as novel molecular tracer. AB - Camelid-derived single-domain antibody-fragments (~15kDa), called nanobodies, are a new class of molecular tracers that are routinely identified with nanomolar affinity for their target and that are easily tailored for molecular imaging and drug delivery applications. We hypothesized that they are well-suited for the design of targeted microbubbles (MUBs) and aimed to develop and characterize eGFP and VCAM-1-targeted MUBs. Anti-eGFP (cAbGFP4) and anti-VCAM-1 (cAbVCAM1-5) nanobodies were site-specifically biotinylated in bacteria. This metabolic biotinylation method yielded functional nanobodies with one biotin located at a distant site of the antigen-binding region of the molecule. The biotinylated nanobodies were coupled to biotinylated lipid MUBs via streptavidin-biotin bridging. The ability of MUB-cAbGFP4 to recognize eGFP was tested as proof-of principle by fluorescent microscopy and confirmed the specific binding of eGFP to MUB-cAbGFP4. Dynamic flow chamber studies demonstrated the ability of MUB cAbVCAM1-5 to bind VCAM-1 in fast flow (up to 5 dynes/cm(2)). In vivo targeting studies were performed in MC38 tumor-bearing mice (n=4). MUB-cAbVCAM1-5 or control MUB-cAbGFP4 were injected intravenously and imaged using a contrast specific ultrasound imaging mode. The echo intensity in the tumor was measured 10min post-injection. MUB-cAbVCAM1-5 showed an enhanced signal compared to control MUBs (p<0.05). Using metabolic and site-specific biotinylation of nanobodies, a method to develop nanobody-coupled MUBs was described. The application of VCAM-1-targeted MUBs as novel molecular ultrasound contrast agent was demonstrated both in vitro and in vivo. PMID- 22197778 TI - Magnetic field-controlled gene expression in encapsulated cells. AB - Cell and gene therapies have an enormous range of potential applications, but as for most other therapies, dosing is a critical issue, which makes regulated gene expression a prerequisite for advanced strategies. Several inducible expression systems have been established, which mainly rely on small molecules as inducers, such as hormones or antibiotics. The application of these inducers is difficult to control and the effects on gene regulation are slow. Here we describe a novel system for induction of gene expression in encapsulated cells. This involves the modification of cells to express potential therapeutic genes under the control of a heat inducible promoter and the co-encapsulation of these cells with magnetic nanoparticles. These nanoparticles produce heat when subjected to an alternating magnetic field; the elevated temperatures in the capsules then induce gene expression. In the present study we define the parameters of such systems and provide proof-of-principle using reporter gene constructs. The fine-tuned heating of nanoparticles in the magnetic field allows regulation of gene expression from the outside over a broad range and within short time. Such a system has great potential for advancement of cell and gene therapy approaches. PMID- 22197781 TI - Gap junctional channels are parts of multiprotein complexes. AB - Gap junctional channels are a class of membrane channels composed of transmembrane channel-forming integral membrane proteins termed connexins, innexins or pannexins that mediate direct cell-to-cell or cell-to extracellular medium communication in almost all animal tissues. The activity of these channels is tightly regulated, particularly by intramolecular modifications as phosphorylations of proteins and via the formation of multiprotein complexes where pore-forming subunits bind to auxiliary channel subunits and associate with scaffolding proteins that play essential roles in channel localization and activity. Scaffolding proteins link signaling enzymes, substrates, and potential effectors (such as channels) into multiprotein signaling complexes that may be anchored to the cytoskeleton. Protein-protein interactions play essential roles in channel localization and activity and, besides their cell-to-cell channel forming functions, gap junctional proteins now appear involved in different cellular functions (e.g. transcriptional and cytoskeletal regulations). The present review summarizes the recent progress regarding the proteins capable of interacting with junctional proteins and highlights the function of these protein protein interactions in cell physiology and aberrant function in diseases. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and functions. PMID- 22197782 TI - Dynamic changes of elasticity, cross-sectional area, and fat infiltration of multifidus at different postures in men with chronic low back pain. AB - BACKGROUND CONTEXT: Multifidus cross-sectional area was often measured in chronic low back pain (LBP) patients to estimate the muscle activity for spinal stability. However, such estimation may be inadequate as the contribution of muscle elasticity in muscle activity is ignored. In vivo quantitative data on multifidus elasticity is therefore important for the study of muscle contractile function in response to motor control for spinal stability in chronic LBP patients. PURPOSE: The purpose of this study was to quantify the elasticity, cross-sectional area, and fat area of the multifidus for the contractile function and the distribution of deformable muscle tissue and nondeformable fat tissue at different postures in patients with and without chronic LBP. STUDY DESIGN/SETTING: This is a prospective study. Force-deformation data of the multifidus were acquired using ultrasound elastography. The anatomical changes of the multifidus were measured on the cross-sectional images of the multifidus acquired using B-mode ultrasound imaging. PATIENT SAMPLE: The sample comprised 12 adult male patients with chronic LBP and 12 asymptomatic male controls. OUTCOME MEASURES: The outcome measure was the elasticity of the multifidus at the L4 level for the assessment of muscle contractile function when patients were in the prone, upright, and 25 degrees and 45 degrees forward stooping positions. The cross-sectional area and fat area were also measured on the B-mode ultrasound images of the multifidus acquired at the same vertebral level and the postures. METHODS: With the patients in each of the prone, upright, and 25 degrees and 45 degrees forward stooping positions, ultrasound elastography and B-mode ultrasound imaging were performed on the left and right multifidus at the L4 level. The elasticity of multifidus indicated by the effective Young's modulus was derived from the force-deformation data acquired using ultrasound elastography. The cross-sectional area and fat area were assessed on the B-mode ultrasound images. The effective Young's modulus, cross-sectional area, and fat area were analyzed with multivariate general linear model analysis to investigate the possible effects of LBP and posture. RESULTS: There was an increasing stiffness of multifidus demonstrated by increasing effective Young's modulus from the prone to upright position and 25 degrees and 45 degrees forward stooping positions. Differences in multifidus stiffness between chronic LBP patients and asymptomatic controls were shown in the upright and 25 degrees and 45 degrees forward stooping positions but not in the prone position. The cross-sectional area of the multifidus increased from the prone position to the greatest value in the upright position and decreased in 25 degrees and 45 degrees forward stooping positions. Smaller multifidus cross-sectional area was demonstrated in chronic LBP patients than that in controls at all postures. No effect of posture on fat area within the multifidus was shown although the fat area within the multifidus was larger in chronic LBP patients. CONCLUSIONS: Different, changing patterns of elasticity and cross-sectional area were identified in the multifidus in relation to posture. Increased stiffness of multifidus in response to the physiologic range of static loads and smaller cross-sectional area was characterized in the chronic LBP condition for spinal stability. Ultrasound elastography offers in vivo assessment of muscle contractile function of deep trunk muscles, which benefits the future investigation of the neuromuscular regulating mechanism in LBP. It can also be applied to refine the palpatory skill for the physical assessment in sports training and physical therapy. PMID- 22197783 TI - Spinal glioblastoma multiforme of the conus medullaris with holocordal and intracranial spread in a child: a case report and review of the literature. AB - BACKGROUND CONTEXT: Spinal glioblastoma multiforme (GBM) is a rare clinical entity. According to our review of the literature, only 15 cases of spinal GBM originating from the conus medullaris (CM) have been reported. Furthermore, there has been no case of spinal GBM originating from the CM with holocordal and intracranial involvements, which were already present at the time of initial diagnosis. Despite a variety of treatments, the previous studies have uniformly reported poor results of this lethal condition. PURPOSE: The present report illustrates a 10-year-old girl with spinal GBM with rare involvement pattern, that is, the tumor originating from the CM with the holocordal and intracranial involvements, undergoing a novel chemotherapy regimen. STUDY DESIGN: A case report and review of literature. METHODS: Magnetic resonance (MR) imaging with gadolinium enhancement clearly revealed holocordal and intracranial lesions, which were otherwise unidentifiable by plane MR imaging. Open biopsy was performed. After histologic diagnosis, novel chemotherapy regimen, that is, simultaneous high-dose chemotherapy (cyclophosphamide, cisplatin, vincristine, and etoposide) combined with autologous peripheral blood stem cell transplantation (auto-PBSCT), intrathecal injections of both methotrexate and dexamethasone, and radiotherapy, which respected the tolerance threshold of the spinal cord, were performed. RESULTS: Novel chemotherapy regimen achieved marked tumor regression until the 12th month of treatment. The patient became ambulatory with T-shaped canes and has returned to the school life. Unfortunately, the patient died because of the relapse of the tumor 14 months after the initial diagnosis; however, this strategy has achieved longer survival than previously reported mean survival (12 months). CONCLUSIONS: The authors advocate enhanced MR imaging of the whole central nervous system for the potential spreading of this disease. This is the first report of simultaneous high-dose chemotherapy combined with auto-PBSCT, intrathecal injections of antineoplastic agents, and radiotherapy for the treatment of spinal GBM, which achieved marked tumor regression. We believe that accumulated experiences in the treatment of this lethal condition might contribute well to improve its therapeutic outcome. PMID- 22197784 TI - Crystal structure of Staphylococcal dual specific inositol monophosphatase/NADP(H) phosphatase (SAS2203) delineates the molecular basis of substrate specificity. AB - Inositol monophosphatase (IMPase) family of proteins are Mg(2+) activated Li(+) inhibited class of ubiquitous enzymes with promiscuous substrate specificity. Herein, the molecular basis of IMPase substrate specificity is delineated by comparative crystal structural analysis of a Staphylococcal dual specific IMPase/NADP(H) phosphatase (SaIMPase - I) with other IMPases of different substrate compatibility, empowered by in silico docking and Escherichia coli SuhB mutagenesis analysis. Unlike its eubacterial and eukaryotic NADP(H) non hydrolyzing counterparts, the composite structure of SaIMPase - I active site pocket exhibits high structural resemblance with archaeal NADP(H) hydrolyzing dual specific IMPase/FBPase. The large and shallow SaIMPase - I active site cleft efficiently accommodate large incoming substrates like NADP(H), and therefore, justifies the eminent NADP(H) phosphatase activity of SaIMPase - I. Compared to other NADP(H) non-hydrolyzing IMPases, the profound difference in active site topology as well as the unique NADP(H) recognition capability of SaIMPase - I stems from the differential length and orientation of a distant helix alpha4 (in human and bovine alpha5) and its preceding loop. We identified the length of alpha4 and its preceding loop as the most crucial factor that regulates IMPase substrate specificity by employing a size exclusion mechanism. Hence, in SaIMPase - I, the substrate promiscuity is a gain of function by trimming the length of alpha4 and its preceding loop, compared to other NADP(H) non-hydrolyzing IMPases. This study thus provides a biochemical - structural framework revealing the length and orientation of alpha4 and its preceding loop as the predisposing factor for the determination of IMPase substrate specificity. PMID- 22197785 TI - Strengthened functional connectivity in the brain during muscle fatigue. AB - Fatigue caused by sustaining submaximal-intensity muscle contraction(s) involves increased activation in the brain such as primary motor cortex (M1), primary sensory cortex (S1), premotor and supplementary motor area (PM&SMA) and prefrontal cortex (PFC). The synchronized increases in activation level in these cortical areas suggest fatigue-related strengthening of functional coupling within the motor control network. In the present study, this hypothesis was tested using the cross-correlation based functional connectivity (FC) analysis method. Ten subjects performed a 20-minute intermittent (3.5s ON/6.5s OFF, 120 trials total) handgrip task using the right hand at 50% maximal voluntary contraction (MVC) force level while their brain was scanned by a 3 T Siemens Trio scanner using echo planar imaging (EPI) sequence. A representative signal time course of the left M1 was extracted by averaging the time course data of a 2-mm cluster of neighboring voxels of local maximal activation foci, which was identified by a general linear model. Two FC activation maps were created for each subject by cross-correlating the time course data of the minimal (the first 10 trials) and significant (the last 10 trials) fatigue stages across all the voxels in the brain to the corresponding representative time course. Histogram and quantile regression analysis were used to compare the FC between the minimal and significant fatigue stages and the results showed a significant increase in FC among multiple cortical regions, including right M1 and bilateral PM&SMA, S1 and PFC. This strengthened FC indicates that when muscle fatigue worsens, many brain regions increase their coupling with the left M1, the primary motor output control center for the right handgrip, to compensate for diminished force generating capability of the muscle in a coordinated fashion by enhancing the descending command for greater muscle recruitment to maintain the same force. PMID- 22197786 TI - Neuronal correlates of reduced memory performance in overweight subjects. AB - There is growing evidence that excessive body weight correlates with impaired cognitive performance like executive function, attention and memory. In our study, we applied a visual working memory task to quantify associations between body weight and executive function. In total, 34 lean (BMI 22+/-2.1 kg/m(2)) and 34 obese (BMI 30.4+/-3.2 kg/m(2)) subjects were included. Magnetic brain activity and behavioral responses were recorded during a one-back visual memory task with food and non-food pictures, which were matched for color, size and complexity. Behavioral responses (reaction time and accuracy) were reduced in obese subjects independent of the stimulus category. Neuronal activity at the source level showed a positive correlation between the right dorsolateral prefrontal cortex (DLPFC) activity and BMI only for the food category. In addition, a negative correlation between BMI and neuronal activity was observed in the occipital area for both categories. Therefore we conclude that increased body weight is associated with reduced task performance and specific neuronal changes. This altered activity is probably related to executive function as well as encoding and retrieval of information. PMID- 22197788 TI - Steady-state evoked potentials to tag specific components of nociceptive cortical processing. AB - Studies have shown that the periodic repetition of a stimulus induces, at certain stimulation frequencies, a sustained electro-cortical response of corresponding frequency, referred to as steady-state evoked potential (SSEP). Using infrared laser stimulation, we recently showed that SSEPs can be used to explore nociceptive cortical processing. Here, we implemented a novel approach to elicit such responses, using a periodic intra-epidermal electrical stimulation of cutaneous Adelta-nociceptors (Adelta-SSEPs). Using a wide range of frequencies (3 43 Hz), we compared the scalp topographies and temporal dynamics of these Adelta SSEPs to the Abeta-SSEPs elicited by non-nociceptive transcutaneous electrical stimulation, as well as to the transient ERPs elicited by the onsets of the 10-s stimulation trains, applied to the left and right hand. At 3 Hz, we found that the topographies of Abeta- and Adelta-SSEPs were both maximal at the scalp vertex, and resembled closely that of the late P2 wave of transient ERPs, suggesting activity originating from the same neuronal populations. The responses also showed marked habituation, suggesting that they were mainly related to unspecific, attention-related processes. In contrast, at frequencies >3 Hz, the topographies of Abeta- and Adelta-SSEPs were markedly different. Abeta-SSEPs were maximal over the contralateral parietal region, whereas Adelta-SSEPs were maximal over midline frontal regions, thus indicating an entrainment of distinct neuronal populations. Furthermore, the responses showed no habituation, suggesting more obligatory and specific stages of sensory processing. Taken together, our results indicate that Abeta- and Adelta-SSEPs offer a unique opportunity to study the cortical representation of nociception and touch. PMID- 22197787 TI - Comparative evaluation of Logan and relative-equilibrium graphical methods for parametric imaging of dynamic [18F]FDDNP PET determinations. AB - Logan graphical analysis with cerebellum as reference region has been widely used for the estimation of the distribution volume ratio (DVR) of [(18)F]FDDNP as a measure of amyloid burden and tau deposition in human brain because of its simplicity and computational ease. However, spurious parametric DVR images may be produced with shorter scanning times and when the noise level is high. In this work, we have characterized a relative-equilibrium-based (RE) graphical method against the Logan analysis for parametric imaging and region-of-interest (ROI) analysis. METHODS: Dynamic [(18)F]FDDNP PET scans were performed on 9 control subjects and 12 patients diagnosed with Alzheimer's disease. Using the cerebellum as reference input, regional DVR estimates were derived using both the Logan analysis and the RE plot approach. Effects on DVR estimates obtained at voxel and ROI levels by both graphical approaches using data in different time windows were investigated and compared with the standard values derived using the Logan analysis on a voxel-by-voxel basis for the time window of 35-125 min used in previous studies. RESULTS: Larger bias and variability were observed for DVR estimates obtained by the Logan graphical analysis at the voxel level when short time windows (85-125 and 45-65 min) were used, because of high noise levels in voxel-wise parametric imaging. However, when the Logan graphical analysis was applied at the ROI level over those short time windows, the DVR estimates did not differ significantly from the standard values derived using the Logan analysis on the voxel level for the time window of 35-125 min, and their bias and variability were remarkably lower. Conversely, the RE plot approach was more robust in providing DVR estimates with less bias and variability even when short time windows were used. The DVR estimates obtained at voxel and ROI levels were consistent. No significant differences were observed in DVR estimates obtained by the RE plot approach for all paired comparisons with the standard values. CONCLUSIONS: The RE plot approach provides less noisy parametric images and gives consistent and reliable regional DVR estimates at both voxel and ROI levels, indicating that it is preferred over the Logan graphical analysis for analyzing [(18)F]FDDNP PET data. PMID- 22197789 TI - Biochemical label-free tissue imaging with subcellular-resolution synchrotron FTIR with focal plane array detector. AB - The critical questions into the cause of neural degeneration, in Alzheimer disease and other neurodegenerative disorders, are closely related to the question of why certain neurons survive. Answers require detailed understanding of biochemical changes in single cells. Fourier transform infrared microspectroscopy is an excellent tool for biomolecular imaging in situ, but resolution is limited. The mid-infrared beamline IRENI (InfraRed ENvironmental Imaging) at the Synchrotron Radiation Center, University of Wisconsin-Madison, enables label-free subcellular imaging and biochemical analysis of neurons with an increase of two orders of magnitude in pixel spacing over current systems. With IRENI's capabilities, it is now possible to study changes in individual neurons in situ, and to characterize their surroundings, using only the biochemical signatures of naturally-occurring components in unstained, unfixed tissue. We present examples of analyses of brain from two transgenic mouse models of Alzheimer disease (TgCRND8 and 3xTg) that exhibit different features of pathogenesis. Data processing on spectral features for nuclei reveals individual hippocampal neurons, and neurons located in the proximity of amyloid plaque in TgCRND8 mouse. Elevated lipids are detected surrounding and, for the first time, within the dense core of amyloid plaques, offering support for inflammatory and aggregation roles. Analysis of saturated and unsaturated fatty acid ester content in retina allows characterization of neuronal layers. IRENI images also reveal spatially-resolved data with unprecedented clarity and distinct spectral variation, from sub-regions including photoreceptors, neuronal cell bodies and synapses in sections of mouse retina. Biochemical composition of retinal layers can be used to study changes related to disease processes and dietary modification. PMID- 22197790 TI - Orbitofrontal reward sensitivity and impulsivity in adult attention deficit hyperactivity disorder. AB - Impulsivity symptoms of adult attention deficit hyperactivity disorder (ADHD) such as increased risk taking have been linked with impaired reward processing. Previous studies have focused on reward anticipation or on rewarded executive functioning tasks and have described a striatal hyporesponsiveness and orbitofrontal alterations in adult and adolescent ADHD. Passive reward delivery and its link to behavioral impulsivity are less well understood. To study this crucial aspect of reward processing we used functional magnetic resonance imaging (fMRI) combined with electrodermal assessment in male and female adult ADHD patients (N=28) and matched healthy control participants (N=28) during delivery of monetary and non-monetary rewards. Further, two behavioral tasks assessed risky decision making (game of dice task) and delay discounting. Results indicated that both groups activated ventral and dorsal striatum and the medial orbitofrontal cortex (mOFC) in response to high-incentive (i.e. monetary) rewards. A similar, albeit less strong activation pattern was found for low incentive (i.e. non-monetary) rewards. Group differences emerged when comparing high and low incentive rewards directly: activation in the mOFC coded for the motivational change in reward delivery in healthy controls, but not ADHD patients. Additionally, this dysfunctional mOFC activity in patients correlated with risky decision making and delay discounting and was paralleled by physiological arousal. Together, these results suggest that the mOFC codes reward value and type in healthy individuals whereas this function is deficient in ADHD. The brain-behavior correlations suggest that this deficit might be related to behavioral impulsivity. Reward value processing difficulties in ADHD should be considered when assessing reward anticipation and emotional learning in research and applied settings. PMID- 22197791 TI - Lynn Margulis (1938-2011). PMID- 22197792 TI - On genetic information uncertainty and the mutator phenotype in cancer. AB - Recent evidence supports the existence of a mutator phenotype in cancer cells, although the mechanistic basis remains unknown. In this paper, it is shown that this enhanced genetic instability is generated by an amplified measurement uncertainty on genetic information during DNA replication. At baseline, an inherent measurement uncertainty implies an imprecision of the recognition, replication and transfer genetic information, and forms the basis for an intrinsic genetic instability in all biological cells. Genetic information is contained in the sequence of DNA bases, each existing due to proton tunnelling, as a coherent superposition of quantum states composed of both the canonical and rare tautomeric forms until decoherence by interaction with DNA polymerase. The result of such a quantum measurement process may be interpreted classically as akin to a Bernoulli trial, whose outcome X is random and can be either of two possibilities, depending on whether the proton is tunnelled (X=1) or not (X=0). This inherent quantum uncertainty is represented by a binary entropy function and quantified in terms of Shannon information entropy H(X)=-P(X=1)log(2)P(X=1) P(X=0)log(2)P(X=0). Enhanced genetic instability may either be directly derived from amplified uncertainty induced by increases in quantum and thermodynamic fluctuation, or indirectly arise from the loss of natural uncertainty reduction mechanisms. PMID- 22197793 TI - N-Alkylations of chitosan promoted with sodium hydrogen carbonate under aqueous conditions. AB - Chitosan was reacted with four alkyl halides, monobromoacetic acid, benzyl bromide, 2-bromoethanol, and monochloroacetic acid, in the presence of NaHCO(3) in water. Chemical structures, degrees of substitution, and degrees of polymerization of reaction products were studied by FT-IR, NMR, SEC-MALLS, and elementary analyses. All alkyl groups were introduced selectively into the C2 amine groups of chitosan, and the yields of the N-alkyl chitosans were >90% by this method. N-Carboxymethyl chitosan (N-CMCh) and N-benzyl chitosan (N-BnCh) with high degrees of substitution (DS) up to 200% and 164% of the C2-amine groups, respectively, were obtained; N,N-dicarboxymethyl and N,N-dibenzyl chitosans were obtained in high yields. Degrees of polymerization (DP) of N-CMCh decreased during the reaction. The greater the amount of monobromoacetic acid added, the lower the DP of N-CMCh. PMID- 22197794 TI - Hydrophobically modified biomineralized polysaccharide alginate membrane for sustained smart drug delivery. AB - Hydrophobically modified biomineralized polysaccharide alginate membrane with smart drug release property using sodium palmitate as the hydrophobic component was prepared via a one-step method. The formation of CaHPO(4) in the membrane was clearly identified through scanning electron microscopy (SEM), energy dispersive X-ray spectrometer (EDS), X-ray diffraction (XRD) and Fourier transform infrared (FT-IR) spectroscopy. Indomethacin release profiles of the modified alginate membrane were found to be pH- and thermo-responsive. The drug release of modified alginate membrane was around 60% within 12 h, while that of the alginate membrane was higher than 90%. These results indicate that the hydrophobic and biomineralized polysaccharide components can hinder the permeation of the encapsulated drug and reduce the drug release effectively. The resulting membrane can be used as "smart" materials for sustained dual-responsive drug delivery. PMID- 22197795 TI - A polysaccharides MDG-1 augments survival in the ischemic heart by inducing S1P release and S1P1 expression. AB - Ophiopogon japonicus is a traditional Chinese medicine used to treat cardiovascular disease. Recent studies have confirmed the anti-ischemic properties of a water-soluble beta-D-fructan (MDG-1) from O. japonicus. The sphingosine 1-phosphate (S1P) signaling pathway is involved in its cytoprotective effects. Herein, we explore the role of the S1P signaling pathway in the anti ischemic effect of MDG-1 and assess one possible mechanism by which it induces S1P release and sphingosine 1-phosphate receptor 1 (S1P(1)) expression in human microvascular endothelial cells (HMEC-1) and cardiomyocytes. Our evidence demonstrates that MDG-1 promotes sphingosine kinase (SPHK) activity in HMEC-1 cells. An analytical method for measuring the mass of S1P using ESI/MS/MS was developed and we found that MDG-1 increases intracellular S1P levels. Meanwhile, MDG-1 is protective during hypoxia and ischemia through mechanisms that require S1P(1) receptor activation, which was confirmed both in oxygen glucose deprivation (OGD) and coronary artery ligation models by using transfection of cloned human S1P(1) receptor and RNA interference. These data indicate that the increase of intracellular S1P generation, particularly by activation of the SPHK enzyme, coupled with the autocrine and paracrine stimulation of cell surface S1P receptors, is a potential mechanism in the anti-ischemic and cell protective effect of MDG-1. PMID- 22197796 TI - [Acute disseminated encephalomyelitis associated with herpes virus infection: a case report]. AB - Acute disseminated encephalomyelitis (ADEM) is a demyelinating disease of the central nervous system, also called post-infectious encephalitis; it is triggered by an autoimmune mechanism and follows an infection or a vaccination after a free interval of 2 to 30 days. We report a case of ADEM in a 4-year-old girl, who was diagnosed based on the data from a brain MRI, which revealed multiple demyelinization foci in the periventricular white matter, the semi-oval centers, and the thalamic regions, both bilaterally and symmetrically. The clinical course was characterized by complete recovery 10 days after steroid therapy. In the literature, more than the half of the patients treated for ADEM had a good prognosis, with recovery and no sequelae. Clinical improvement is generally noted in the hours or days following the initiation of treatment. However, in the most severe cases of ADEM, the most frequent neurological sequelae consist in focal deficiencies of the limbs and ataxia or visual disorders. Cognitive and behavioral disorders are noted in 6 to 50% of pediatric patients. PMID- 22197797 TI - Modeling fan effects on the time course of associative recognition. AB - We investigated the time course of associative recognition using the response signal procedure, whereby a stimulus is presented and followed after a variable lag by a signal indicating that an immediate response is required. More specifically, we examined the effects of associative fan (the number of associations that an item has with other items in memory) on speed-accuracy tradeoff functions obtained in a previous response signal experiment involving briefly studied materials and in a new experiment involving well-learned materials. High fan lowered asymptotic accuracy or the rate of rise in accuracy across lags, or both. We developed an Adaptive Control of Thought-Rational (ACT R) model for the response signal procedure to explain these effects. The model assumes that high fan results in weak associative activation that slows memory retrieval, thereby decreasing the probability that retrieval finishes in time and producing a speed-accuracy tradeoff function. The ACT-R model provided an excellent account of the data, yielding quantitative fits that were as good as those of the best descriptive model for response signal data. PMID- 22197798 TI - Remembering kinds: new evidence that categories are privileged in children's thinking. AB - What are the representations and learning mechanisms that underlie conceptual development? The present research provides evidence in favor of the claim that this process is guided by an early-emerging predisposition to think and learn about abstract kinds. Specifically, three studies (N=192) demonstrated that 4- to 7-year-old children have better recall for novel information about kinds (e.g., that dogs catch a bug called "fep") than for similar information about individuals (e.g., that a particular dog catches a bug called "fep"). By showing that children are particularly likely to retain information about kinds, this work not only provides a first empirical demonstration of a phenomenon that may be key to conceptual development but also makes it apparent that young children's thinking is suffused with abstractions rather than being perceptually-based and concrete. PMID- 22197799 TI - Using incentives to reduce substance use and other health risk behaviors among people with serious mental illness. AB - INTRODUCTION: Serious mental illness (SMI) is associated with high rates of tobacco and other drug dependence, poor treatment compliance, obesity and low levels of physical activity, which have severe medical and psychosocial consequences. Interventions that effectively reduce these health risk behaviors among people with SMI are urgently needed. METHODS: Published reports from studies evaluating incentive-based treatments for promoting tobacco and other drug abstinence, treatment attendance, medication use and increased physical activity are reviewed. RESULTS: Results of this review indicate the efficacy of incentive-based treatments for reducing tobacco and other drug use among people with SMI. Few studies have examined whether incentive-based treatments improve treatment attendance, medication use and physical activity levels in people with SMI; however, initial evidence is positive and indicates that further research in these areas is warranted. CONCLUSION: Given the medical and psychosocial costs of tobacco and other drug use, treatment non-compliance and physical inactivity, and the efficacy of incentive-based treatments for improving these behaviors, such interventions should be further developed and integrated into behavioral health treatment programs for people with SMI. PMID- 22197800 TI - Physical activity, walking and leanness: an analysis of the Northern Ireland Sport and Physical Activity Survey (SAPAS). AB - OBJECTIVE: To report on the contribution walking makes to total weekly physical activity and the relationship between the volume and intensity of walking and leanness in a representative sample of the Northern Ireland population. METHOD: 4563 adults participated in this cross-sectional survey of physical activity behaviour. Self-reported height and weight was used to determine inverse body mass index (iBMI) as a measure of leanness. Data across all domains of physical activity including self-reported volume and intensity of walking (in bouts of 10 min or more) were analysed to determine their contribution to leanness using ANCOVA, having controlled for age, gender, socio-economic and smoking status. RESULTS: Over 68% of the participants reported walking >10 minutes during the previous week but only 24% report walking at a brisk or fast pace. Time walking at a brisk or fast pace for personal transport was identified as having the strongest positive association with being lean (F(1,4256)=10.45, beta=0.051 cm(2) kg(-1) min(-1) (SE=0.016),P=0.001). CONCLUSIONS: In addition to increasing the amount of walking and the percentage of people walking regularly, public health messages encouraging an increase in walking pace may be valuable to increase the proportion of the population meeting physical activity guidelines and gaining associated health benefits. PMID- 22197801 TI - Common data model for natural language processing based on two existing standard information models: CDA+GrAF. AB - An increasing need for collaboration and resources sharing in the Natural Language Processing (NLP) research and development community motivates efforts to create and share a common data model and a common terminology for all information annotated and extracted from clinical text. We have combined two existing standards: the HL7 Clinical Document Architecture (CDA), and the ISO Graph Annotation Format (GrAF; in development), to develop such a data model entitled "CDA+GrAF". We experimented with several methods to combine these existing standards, and eventually selected a method wrapping separate CDA and GrAF parts in a common standoff annotation (i.e., separate from the annotated text) XML document. Two use cases, clinical document sections, and the 2010 i2b2/VA NLP Challenge (i.e., problems, tests, and treatments, with their assertions and relations), were used to create examples of such standoff annotation documents, and were successfully validated with the XML schemata provided with both standards. We developed a tool to automatically translate annotation documents from the 2010 i2b2/VA NLP Challenge format to GrAF, and automatically generated 50 annotation documents using this tool, all successfully validated. Finally, we adapted the XSL stylesheet provided with HL7 CDA to allow viewing annotation XML documents in a web browser, and plan to adapt existing tools for translating annotation documents between CDA+GrAF and the UIMA and GATE frameworks. This common data model may ease directly comparing NLP tools and applications, combining their output, transforming and "translating" annotations between different NLP applications, and eventually "plug-and-play" of different modules in NLP applications. PMID- 22197803 TI - Suprageneric systematics of flea beetles (Chrysomelidae: Alticinae) inferred from multilocus sequence data. AB - Recent phylogenetic studies of flea beetles (Alticinae) based on morphological or molecular data have focused on the relationship and possible paraphyly with respect to the closely related Galerucinae, while the supra-generic classification mainly dates back to the 19th century. Here, phylogenetic analysis was performed on DNA sequences for two mitochondrial (rrnL and cox1) and two nuclear (SSU and LSU rRNA) genes from 158 genera and 165 species that cover most suprageneric groups of flea beetles proposed in the older literature. Various alignment strategies and tree search methods were used to test the stability of major clades. Besides confirmation of the placement of several alticine lineages within Galerucinae, a preliminary framework for classification of the main alticine clades was obtained. It is proposed to recognize 18 groups of genera based on well-supported nodes. These include the Altica, Amphimela, Aphthona, Blepharida, Chabria, Chaetocnema, Dibolia, Disonycha, Griva, Lactica, Longitarsus, Manobia, Monoplatus, Nisotra, Oedionychis, Pentamesa, Phygasia and Pseudodera groups. These groups provide a novel perspective to the existing classification. The analysis of 14 morphological characters used in the traditional classification of Alticinae and Galerucinae revealed high levels of homoplasy with respect to the DNA-based tree, but significant hierarchical structure in most of them. Even if not unique to any particular group of genera, these traits largely corroborate the groupings established with DNA sequences. PMID- 22197802 TI - Inhibition of the NF-kappaB signaling pathway by the curcumin analog, 3,5-Bis(2 pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties. AB - Nuclear factor kappa B (NF-kappaB) is a key signaling molecule in the elaboration of the inflammatory response. Data indicate that curcumin, a natural ingredient of the curry spice turmeric, acts as a NF-kappaB inhibitor and exhibits both anti inflammatory and anti-cancer properties. Curcumin analogs with enhanced activity on NF-kappaB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound 3,5-Bis(2-fluorobenzylidene)-4 piperidone (EF24). 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analog whose potency for NF-kappaB inhibition has yet to be determined. To examine the activity of EF31 compared to EF24 and curcumin, mouse RAW264.7 macrophages were treated with EF31, EF24, curcumin (1 100 MUM) or vehicle (DMSO 1%) for 1h. NF-kappaB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1 MUg/mL). EF31 (IC(50)~5 MUM) exhibited significantly more potent inhibition of LPS-induced NF-kappaB DNA binding compared to both EF24 (IC(50)~35 MUM) and curcumin (IC(50) >50 MUM). In addition, EF31 exhibited greater inhibition of NF-kappaB nuclear translocation as well as the induction of downstream inflammatory mediators including pro inflammatory cytokine mRNA and protein (tumor necrosis factor-alpha, interleukin 1beta, and interleukin-6). Regarding the mechanism of these effects on NF-kappaB, EF31 (IC(50)~1.92 MUM) exhibited significantly greater inhibition of IkappaB kinase beta compared to EF24 (IC(50)~131 MUM). Finally, EF31 demonstrated potent toxicity in NF-kappaB-dependent cancer cell lines while having minimal and reversible toxicity in RAW264.7 macrophages. These data indicate that EF31 is a more potent inhibitor of NF-kappaB activity than either EF24 or curcumin while exhibiting both anti-inflammatory and anticancer activities. Thus, EF31 represents a promising curcumin analog for further therapeutic development. PMID- 22197804 TI - Applications of next-generation sequencing to phylogeography and phylogenetics. AB - This is a time of unprecedented transition in DNA sequencing technologies. Next generation sequencing (NGS) clearly holds promise for fast and cost-effective generation of multilocus sequence data for phylogeography and phylogenetics. However, the focus on non-model organisms, in addition to uncertainty about which sample preparation methods and analyses are appropriate for different research questions and evolutionary timescales, have contributed to a lag in the application of NGS to these fields. Here, we outline some of the major obstacles specific to the application of NGS to phylogeography and phylogenetics, including the focus on non-model organisms, the necessity of obtaining orthologous loci in a cost-effective manner, and the predominate use of gene trees in these fields. We describe the most promising methods of sample preparation that address these challenges. Methods that reduce the genome by restriction digest and manual size selection are most appropriate for studies at the intraspecific level, whereas methods that target specific genomic regions (i.e., target enrichment or sequence capture) have wider applicability from the population level to deep-level phylogenomics. Additionally, we give an overview of how to analyze NGS data to arrive at data sets applicable to the standard toolkit of phylogeography and phylogenetics, including initial data processing to alignment and genotype calling (both SNPs and loci involving many SNPs). Even though whole-genome sequencing is likely to become affordable rather soon, because phylogeography and phylogenetics rely on analysis of hundreds of individuals in many cases, methods that reduce the genome to a subset of loci should remain more cost-effective for some time to come. PMID- 22197805 TI - Effect of genetic convergence on phylogenetic inference. AB - Phylogenetic reconstructions are a major component of many studies in evolutionary biology, but their accuracy can be reduced under certain conditions. Recent studies showed that the convergent evolution of some phenotypes resulted from recurrent amino acid substitutions in genes belonging to distant lineages. It has been suggested that these convergent substitutions could bias phylogenetic reconstruction toward grouping convergent phenotypes together, but such an effect has never been appropriately tested. We used computer simulations to determine the effect of convergent substitutions on the accuracy of phylogenetic inference. We show that, in some realistic conditions, even a relatively small proportion of convergent codons can strongly bias phylogenetic reconstruction, especially when amino acid sequences are used as characters. The strength of this bias does not depend on the reconstruction method but varies as a function of how much divergence had occurred among the lineages prior to any episodes of convergent substitutions. While the occurrence of this bias is difficult to predict, the risk of spurious groupings is strongly decreased by considering only 3rd codon positions, which are less subject to selection, as long as saturation problems are not present. Therefore, we recommend that, whenever possible, topologies obtained with amino acid sequences and 3rd codon positions be compared to identify potential phylogenetic biases and avoid evolutionarily misleading conclusions. PMID- 22197806 TI - Are pollen fossils useful for calibrating relaxed molecular clock dating of phylogenies? A comparative study using Myrtaceae. AB - The identification and application of reliable fossil calibrations represents a key component of many molecular studies of evolutionary timescales. In studies of plants, most paleontological calibrations are associated with macrofossils. However, the pollen record can also inform age calibrations if fossils matching extant pollen groups are found. Recent work has shown that pollen of the myrtle family, Myrtaceae, can be classified into a number of morphological groups that are synapomorphic with molecular groups. By assembling a data matrix of pollen morphological characters from extant and fossil Myrtaceae, we were able to measure the fit of 26 pollen fossils to a molecular phylogenetic tree using parsimony optimisation of characters. We identified eight Myrtaceidites fossils as appropriate for calibration based on the most parsimonious placements of these fossils on the tree. These fossils were used to inform age constraints in a Bayesian phylogenetic analysis of a sequence alignment comprising two sequences from the chloroplast genome (matK and ndhF) and one nuclear locus (ITS), sampled from 106 taxa representing 80 genera. Three additional analyses were calibrated by placing pollen fossils using geographic and morphological information (eight calibrations), macrofossils (five calibrations), and macrofossils and pollen fossils in combination (12 calibrations). The addition of new fossil pollen calibrations led to older crown ages than have previously been found for tribes such as Eucalypteae and Myrteae. Estimates of rate variation among lineages were affected by the choice of calibrations, suggesting that the use of multiple calibrations can improve estimates of rate heterogeneity among lineages. This study illustrates the potential of including pollen-based calibrations in molecular studies of divergence times. PMID- 22197807 TI - Sexual size dimorphism predicts rates of sequence evolution of SPerm Adhesion Molecule 1 (SPAM1, also PH-20) in monkeys, but not in hominoids (apes including humans). AB - Based on a dataset comprising coding DNA sequences of 23 anthropoid primates, we herein investigate if rates of sequence evolution of SPerm Adhesion Molecule1 (SPAM1, also PH-20), which participates in sperm-egg interaction, is lower in more sexually dimorphic species. For comparison, we analyze sequence evolution of apolipoproteinA-IV (APOA4) and apolipoprotein A-V (APOA5), which should evolve under less or even no sexual selection given their expression in blood, digestive tract, liver, and lungs. Regression analyses provides significant support for a negative dependence of SPAM1 derived branch-specific ratios of non-synonymous to synonymous substitution rates (dN/dS) on sexual size dimorphism (SSD) in a subsample comprising New World and Old World monkeys. We moreover observed a tendency for a positive correlation of substitution rates of SPAM1 with relative testes weight (RTW) and significantly lowered dN/dS estimates in uni-male and uni male/multi-male breeding monkeys. Importantly, the pattern was not reproduced when analyzing partial APOA4 and APOA5 sequences. These findings illustrate that different levels of sperm competition, probably fueled by female cryptic choice, account for species-specific sequence evolution of SPAM1 in monkeys. Remarkably, present data do not support a correlation of species-specific sequence evolution of SPAM1 with sexual selection levels in hominoids (apes including humans). This can partly be ascribed to a relaxation of functional constraint of SPAM1 in some hominoid species. Additional factors confounding regression analyses specifically in hominoids might be higher levels of sperm competition than reflected by SSD and RTW in some species, a rather strong effect of female mate choice on paternity rates in others, and - in particular in humans - socio-cultural factors not measurable by SSD and RTW. PMID- 22197808 TI - Cancer stem cells hypothesis and stem cells in head and neck cancers. AB - There is increasing evidence that the growth and spread of cancer is driven by a small subpopulation of cancer cells, defined as cancer stem cells (CSCs). Recent data indicate that the initiation, growth, recurrence and metastasis of cancers are related to the behavior of a small population of malignant cells with properties of stem cells, and information about them are potentially helpful in identifying the target for the tumor's therapeutic elimination. The presence of subpopulation cells with phenotypic and behavioral characteristics corresponding to both normal epithelial stem cells and to cells capable of initiating tumors has been also reported in head and neck squamous cell carcinomas (HNSCCs). PMID- 22197809 TI - High calorie diet augments age-associated sleep impairment in Drosophila. AB - The fruit fly, Drosophila melanogaster is an established model used for aging and longevity studies and more recently for sleep studies. Mammals and Drosophila share various physiological, pathological, pharmacological and genetic similarities in these processes. In particular, sleep is essential for survival in both species and both have age-associated sleep quality alterations. Here we report that a high calorie diet, which accelerates the aging process and reduces lifespan across species, also accelerates age-associated sleep changes in Drosophila. These changes are more evident in the dopamine transporter mutant, fumin, that displays a short sleep phenotype due to enhanced dopaminergic signaling. With normal food, fumin mutants sleep for only one third of the time that the control flies do, but still show equivalent longevity. However, when on a mildly high calorie diet, their sleep length shows a marked decrease and they have a reduced longevity. These data indicate that the age-associated change in sleep in Drosophila is a physiologically regulated aging process that is tightly linked to calorie intake and that the dopamine level plays an important role. In addition, this provides another evidence that sleep is essential for the longevity of Drosophila. PMID- 22197810 TI - Mdm2 is a novel activator of ApoCIII promoter which is antagonized by p53 and SHP inhibition. AB - We examined the effect of Mdm2 on regulation of the ApoCIII promoter and its cross-talk with p53 and nuclear receptor SHP. Overexpression of Mdm2 markedly enhanced ApoCIII promoter activity by HNF4alpha. A direct association of Mdm2 protein with the HNF4alpha protein was observed by co-immunoprecipitation. Ectopic expression of p53 decreased HNF4alpha activation of the ApoCIII promoter and antagonized the effect of Mdm2. Co-expression of SHP further strengthened p53 inhibition and abolished Mdm2 activation of the ApoCIII promoter. Mdm2 inhibited p53-mediated enrichment of HNF4alpha to the ApoCIII promoter while simultaneously reducing p53 binding and increasing recruitment of SHP to the ApoCIII promoter. The results from this study implicate a potentially important function of Mdm2 in regulation of lipoprotein metabolism. PMID- 22197811 TI - Calumin, a Ca2+-binding protein on the endoplasmic reticulum, alters the ion permeability of Ca2+ release-activated Ca2+ (CRAC) channels. AB - Store-operated channels (SOC) are Ca(2+)-permeable channels that are activated by IP(3)-receptor-mediated Ca(2+) depletion of the endoplasmic reticulum (ER). Recent studies identify a membrane pore subunits, Orai1 and a Ca(2+) sensor on ER, STIM1 as components of Ca(2+) release-activated Ca(2+) (CRAC) channels, which are well-characterized SOCs. On the other hand, proteins that act as modulators of SOC activity remain to be identified. Calumin is a Ca(2+)-binding protein that resides on the ER and functional experiments using calumin-null mice demonstrate that it is involved in SOC function, although its role is unknown. This study used electrophysiological analysis to explore whether calumin modulates CRAC channel activity. CRAC channel currents were absent in HEK293 cells co-expressing calumin with the CRAC channel components, Orai1 or STIM1. Meanwhile, HEK cells that co-expressed calumin with CRAC channels exhibited larger currents with slower inactivation than cells expressing CRAC channels alone. The current voltage relationship showed an inwardly rectifying current, but a negative shift in the reversal potential of greater than 60mV was observed in HEK cells co expressing calumin with CRAC channels. In addition, the permeability coefficient ratio of Ca(2+) over monovalent cations was much lower than that of cells expressing CRAC channels alone. Replacement of Na(+) with N-methyl-d-glucamine(+) in the external solution noticeably diminished the CRAC current in HEK cells co expressing calumin and CRAC channels. In a Cs(+)-based external solution, CRAC current was not observed in either cell-type. In addition, Ca(2+) imaging analysis revealed that co-transfection of calumin reduced extracellular Ca(2+) influx via CRAC channels. Further, calumin was shown to be directly associated with CRAC channels. These results reveal a novel mechanism for the regulation of CRAC channels by calumin. PMID- 22197812 TI - ER stress response during the differentiation of H9 cells induced by retinoic acid. AB - Endoplasmic reticulum (ER) stress occurs during early embryonic development. The aim of this study is to determine whether ER stress occurs during human embryonic stem cell differentiation induced by retinoic acid (RA). H9 human embryonic stem cells were subjected to RA treatment for up to 29days to induce differentiation. HEK293 cells were treated with RA as a control. The results demonstrate that several ER stress-responsive genes are differentially regulated in H9 and HEK293 cells in response to 5days of RA treatment. GRP78/Bip was upregulated in H9 cells but downregulated in HEK293 cells. eIF2alpha was downregulated in H9 cells but not in HEK293 cells. Phosphorylation of eIF2alpha was downregulated in H9 cells but upregulated in HEK293 cells. XBP-1 was downregulated immediately after RA treatment in H9 cells, but its downregulation was much slower in HEK293 cells. Additionally, two ER-resident E3 ubiquitin ligases, gp78 and Hrd1, were both upregulated in H9 cells following 5 days of exposure to RA. Moreover, the protein Bcl2 was undetectable in H9 cells and H9-derived cells but was expressed in HEK293 cells, and it expression in the two types of cells was unaltered by RA treatment. In H9 cells treated with RA for 29 days, GRP78/Bip, XBP-1 and Bcl2 were all upregulated. These results suggest that ER stress is involved in H9 cell differentiation induced by RA. PMID- 22197813 TI - The role of amino acid electron-donor/acceptor atoms in host-cell binding peptides is associated with their 3D structure and HLA-binding capacity in sterile malarial immunity induction. AB - Plasmodium falciparum malaria continues being one of the parasitic diseases causing the highest worldwide mortality due to the parasite's multiple evasion mechanisms, such as immunological silence. Membrane and organelle proteins are used during invasion for interactions mediated by high binding ability peptides (HABPs); these have amino acids which establish hydrogen bonds between them in some of their critical binding residues. Immunisation assays in the Aotus model using HABPs whose critical residues had been modified have revealed a conformational change thereby enabling a protection-inducing response. This has improved fitting within HLA-DRbeta1(*) molecules where amino acid electron-donor atoms present in beta-turn, random or distorted alpha-helix structures preferentially bound to HLA-DR53 molecules, whilst HABPs having amino acid electron-acceptor atoms present in regular alpha-helix structure bound to HLA DR52. This data has great implications for vaccine development. PMID- 22197814 TI - Pan-neuronal knockdown of the c-Jun N-terminal Kinase (JNK) results in a reduction in sleep and longevity in Drosophila. AB - Sleep is a unique behavioral state that is conserved between species, and sleep regulation is closely associated to metabolism and aging. The fruit fly, Drosophila melanogaster has been used to study the molecular mechanism underlying these physiological processes. Here we show that the c-Jun N-terminal Kinase (JNK) gene, known as basket (bsk) in Drosophila, functions in neurons to regulate both sleep and longevity in Drosophila. Pan-neuronal knockdown of JNK mRNA expression by RNA interference resulted in a decrease in both sleep and longevity. A heterozygous knockout of JNK showed similar effects, indicating the molecular specificity. The JNK knockdown showed a normal arousal threshold and sleep rebound, suggesting that the basic sleep mechanism was not affected. JNK is known to be involved in the insulin pathway, which regulates metabolism and longevity. A JNK knockdown in insulin-producing neurons in the pars intercerebralis had slight effects on sleep. However, knocking down JNK in the mushroom body had a significant effect on sleep. These data suggest a unique sleep regulating pathway for JNK. PMID- 22197815 TI - Both the Fab and Fc domains of IgG are essential for ROS emission from TNF-alpha primed neutrophils by IVIG. AB - Intravenous immunoglobulin (IVIG) is currently a very important therapeutic used for not only infectious diseases, but also for autoimmune diseases such as idiopathic thrombocytopenic purpura (ITP). Untoward reactions of IVIG have been thought to result from complement activation by aggregated IgG in IVIG. In addition, the aggregates have been known to activate neutrophils, which may result in the untoward reactions. However, the effect and mechanism of IVIG on neutrophils remain unclear. In this study, we investigated the activation of neutrophils by IVIG in terms of their reactive oxygen species (ROS) emission to elucidate the mechanisms. IVIG-induced ROS emission from purified neutrophils was remarkably augmented by TNF-alpha priming of the cells. The ROS emission from TNF alpha-primed neutrophils occurred by activation with whole gammaglobulin (GG) molecules, but not F(ab')(2), Fc, or a mixture of F(ab')(2) and Fc. ROS emission by GG was inhibited by the F(ab')(2) fragment and an inhibitory antibody against FcgammaRIII. These results suggest that binding of IVIG to not only surface antigen(s), but also FcgammaRIII on neutrophils, is involved in IVIG-induced ROS emission from TNF-alpha-primed neutrophils, and contribute to the untoward reactions of IVIG. PMID- 22197816 TI - Arg305 of Streptomyces L-glutamate oxidase plays a crucial role for substrate recognition. AB - Recently, we have solved the crystal structure of L-glutamate oxidase (LGOX) from Streptomyces sp. X-119-6 (PDB code: 2E1M), the substrate specificity of which is strict toward L-glutamate. By a docking simulation using L-glutamate and structure of LGOX, we selected three residues, Arg305, His312, and Trp564 as candidates of the residues associating with recognition of L-glutamate. The activity of LGOX toward L-glutamate was significantly reduced by substitution of selected residues with Ala. However, the enzyme, Arg305 of which was substituted with Ala, exhibited catalytic activity toward various L-amino acids. To investigate the role of Arg305 in substrate specificity, we constructed Arg305 variants of LGOX. In all mutants, the substrate specificity of LGOX was markedly changed by the mutation. The results of kinetics and pH dependence on activity indicate that Arg305 of LGOX is associated with the interaction of enzyme and side chain of substrate. PMID- 22197817 TI - Constitutively active lysophosphatidic acid receptor-1 enhances the induction of matrix metalloproteinase-2. AB - Lysophosphatidic acid (LPA) is a simple phospholipid which interacts with at least six G protein-coupled transmembrane LPA receptors (LPA(1)-LPA(6)). In rat neuroblastoma B103 cells, we have recently reported that each LPA receptor indicates the different cellular functions, including cell motility, invasion and tumorigenicity. Especially, mutated and constitutively active LPA(1) enhanced these cellular effects in B103 cells. In the present study, to better understand a role of mutated LPA(1) underlying progression of cancer cells, we measured the expression and activity levels of matrix metalloproteinases (MMPs) in constitutively active mutant Lpar1-expressing B103 cells (lpa1Delta-1), compared with each wild-type LPA receptor-expressing cells. LPA receptor-unexpressing cells were also used as control. In quantitative real time RT-PCR analysis, the expressions of Mmp-9 were detected at the same levels in all cells. By contrast, Mmp-2 expressions of lpa1Delta-1 were significantly higher than those of other cells. In gelatin zymography, proMmp-9 was observed at the same levels in all cells. Interestingly, markedly high levels of proMmp-2 and Mmp-2 were detected in lpa1Delta-1 cells, whereas no activation was in other cells. The increased expression and activity of Mmp-2 in lpa1Delta-1 cells were suppressed by the pretreatment with a Gq protein inhibitor. These results suggest that mutated LPA(1) may involve in the enhancement of Mmp-2 expression and activation in rat neuroblastoma cells. PMID- 22197818 TI - Endocrine disrupting chemicals affect the adipogenic differentiation of mesenchymal stem cells in distinct ontogenetic windows. AB - Endocrine disrupting chemicals (EDC) like bisphenol A (BPA), bis(2 ethylhexyl)phthalate (DEHP) and tributyltin (TBT) are ubiquitously present in the environment and in human tissues. They bind to nuclear hormone receptors and affect cellular and developmental processes. In this study, we show that BPA, DEHP and TBT affect the adipogenic differentiation of murine mesenchymal stem cells (MSC, C3H/10T1/2) in a concentration-, stage- and compound-specific manner. C3H/10T1/2 cells and embryonic stem cells (CGR8) were exposed to BPA, DEHP or TBT at different stages of cell determination and differentiation (undifferentiated growth, adipogenic induction and terminal adipogenic differentiation). The final amount of differentiated adipocytes, cellular triglyceride content and mRNA expression of adipogenic marker genes (adiponectin, FABP4, PPARgamma2, LPL) were quantified and compared with corresponding unexposed cells. BPA (10 MUM) decreased subsequent adipogenic differentiation of MSC, when cells were exposed during undifferentiated growth. In contrast, DEHP (100 MUM) during the hormonal induction period, and TBT (100 nM) in all investigated stages, enhanced adipogenesis. Importantly, exposure of undifferentiated murine embryonic stem cells did not show any effect of the investigated EDC on subsequent adipogenic differentiation. PMID- 22197819 TI - Erythropoietin promotes oligodendrogenesis and myelin repair following lysolecithin-induced injury in spinal cord slice culture. AB - Here, we sought to delineate the effect of EPO on the remyelination processes using an in vitro model of demyelination. We report that lysolecithin-induced demyelination elevated EPO receptor (EpoR) expression in oligodendrocyte progenitor cells (OPCs), facilitating the beneficial effect of EPO on the formation of oligodendrocytes (oligodendrogenesis). In the absence of EPO, the resultant remyelination was insufficient, possibly due to a limiting number of oligodendrocytes rather than their progenitors, which proliferate in response to lysolecithin-induced injury. By EPO treatment, lysolecithin-induced proliferation of OPCs was accelerated and the number of myelinating oligodendrocytes and myelin recovery was increased. EPO also enhanced the differentiation of neural progenitor cells expressing EpoR at high level toward the oligodendrocyte-lineage cells through activation of cyclin E and Janus kinase 2 pathways. Induction of myelin-forming oligodendrocytes by high dose of EPO implies that EPO might be the key factor influencing the final differentiation of OPCs. Taken together, our data suggest that EPO treatment could be an effective way to enhance remyelination by promoting oligodendrogenesis in association with elevated EpoR expression in spinal cord slice culture after lysolecithin-induced demyelination. PMID- 22197820 TI - Regulation of brefeldin A-induced ER stress and apoptosis by mitochondrial NADP+ dependent isocitrate dehydrogenase. AB - Brefeldin A (BFA), an endoplasmic reticulum (ER)-Golgi transport inhibitor, has been shown to cause accumulation of proteins in the ER, ER stress, and ultimately apoptosis. In this paper, we demonstrate that the knockdown of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDPm), a mitochondrial NADPH generating enzyme, by small interfering RNA (siRNA) enhanced BFA-induced apoptosis. However, attenuated IDPm activity results in the suppression of ER stress response, presumably, via the inhibition of the PI3K/Akt pathway. Collectively, our data suggest that the association of IDPm expression and ER stress confers a survival mechanism in A549 cells against BFA-induced apoptosis. PMID- 22197821 TI - MiR-19b-1 inhibits angiogenesis by blocking cell cycle progression of endothelial cells. AB - MicroRNAs are endogenously expressed small, non-coding RNAs that modulate biological processes by recognizing specific gene transcripts, leading to translational repression or degradation. Previous work showed that the miR-17-92 cluster is highly expressed in human endothelial cells that participate in angiogenesis. In this study we showed that miR-19b-1, a component of this cluster, controls the intrinsic angiogenic activity of human umbilical vein endothelial cells (HUVECs) in vitro. In silico and in vitro analyses have suggested that miR-19b-1 targets mRNA corresponding to the pro-angiogenic protein, FGFR2, and blocks the cell cycle from the S phase to the G(2)/M phase transition by controlling the expression of cyclin D1. Thus, miR-19b-1 may serve as a valuable therapeutic agent in the context of tumor angiogenesis. PMID- 22197822 TI - The calcineurin B subunit induces TNF-related apoptosis-inducing ligand (TRAIL) expression via CD11b-NF-kappaB pathway in RAW264.7 macrophages. AB - We showed previously that calcineurin B subunit (CnB) could inhibit S180 solid tumor growth in mice and prolong the survival of mice bearing H22 ascites tumors, but the underlying antitumor mechanism remained unclear. Here, we report that the calcineurin B subunit binds to CD11b on RAW264.7 macrophages and induces TRAIL expression and NF-kappaB activation in a dose and time dependent manner, and that CnB-induced TRAIL expression and NF-kappaB activation are both dependent on this CD11b. Furthermore, CnB-induced TRAIL expression is mediated by NF-kappaB. These findings reveal a novel signaling pathway (CnB-CD11b-NF-kappaB-TRAIL) regulating TRAIL expression and may help to understand the roles of the calcineurin B subunit in the regulation of innate immunity. PMID- 22197823 TI - Negative feedback regulation of Gq signaling by protein kinase C is disrupted by diacylglycerol kinase zeta in COS-7 cells. AB - Cellular response to G(q)-linked agonists is shaped by regulatory inputs which determine signal strength and duration. Stimulation of phospholipase C-beta (PLC beta) lipase activity results in an increase in the levels of diacylglycerol (DAG) and activation of protein kinase C (PKC) activity. PKC has been implicated in the feedback regulation of G(q) signaling through actions on PLC-beta and phospholipase D (PLD) lipase activity. As PKC activity is modulated by multiple layers of regulation, the physiological impact of PKC on G(q) signaling is unclear. PKC signaling can be terminated by diacylglycerol kinases (DGKs) which are regulated in a cell-specific manner. The present studies investigated the contribution of the ubiquitously expressed DGKzeta isoform in the regulation of PKC signaling and G(q) response in transfected COS-7 cells. Genetic depletion of DGKzeta protein with antisense oligonucleotides dramatically reduced DAG metabolism. The sustained increase in PKC signaling was associated with a pronounced inhibition of carbachol-stimulated lipase activity in cells co transfected with m1 muscarinic receptor, Galpha(q) and either with or without PLC beta(1). The data also reveal that sustained activation of PKC alone does not increase cellular PLD1 activity. Therefore, G(12)-activated RhoA is physiologically important for adequate stimulation of PLD1 activity. These data show that the impact of PKC on G(q) signal transduction is determined by the background of cell-specific processes. PMID- 22197824 TI - Foenumoside B from Lysimachia foenum-graecum inhibits adipocyte differentiation and obesity induced by high-fat diet. AB - We have previously reported anti-obesity effects of Lysimachia foenum-graecum in high-fat diet (HFD)-induced obesity model. Here we isolated a triterpene saponin foenumoside B as an active component of L. foenum-graecum. Foenumoside B blocked the differentiation of 3T3-L1 preadipocytes in a dose-dependent manner with an IC50 of 0.2 MUg/ml in adipogenesis assay and suppressed the induction of PPARgamma, the master regulator of adipogenesis. Foenumoside B induced the activation of AMP-activated protein kinase (AMPK), and modulated the expression of genes involved in lipid metabolism towards lipid breakdown in differentiated adipocytes. In mouse model, oral administration of foenumoside B (10mg/kg/day for 6 weeks) reduced HFD-induced body weight gain significantly without affecting food intake. Treatment of foenumoside B suppressed lipid accumulation in white adipose tissues and the liver, and lowered blood levels of glucose, triglycerides, ALT, and AST in HFD-induced obese mice. Consistent with the in vitro results, foenumoside B activated AMPK signaling, suppressed the expression of lipogenic genes, and enhanced the expression of lipolytic genes in vivo. Foenumoside B also blocked HFD-induced proinflammatory cytokine production in adipose tissue, suggesting its protective role against insulin resistance. Taken together, these findings demonstrate that foenumoside B represents the anti obesity effects of L. foenum-graecum, and suggest therapeutic potential of foenumoside B in obesity and obesity-related metabolic diseases. PMID- 22197825 TI - The effects of hydroxysafflor yellow A on blood pressure and cardiac function. AB - AIM OF THE STUDY: This work aims to investigate the effects of HSYA on cardiac function and blood pressure. MATERIALS AND METHODS: To evaluate changes in mean arterial pressure (MAP) and heart rate (HR), different groups of pentobarbitone anesthetized normotensive and spontaneously hypertensive rats (SHR) were treated with intravenous HSYA (0.1-3 mg/kg). Isolated WKY rat hearts in Langendorff system were employed for examining the effect of HSYA on hemodynamic. After 30 min equilibration time the isolated hearts were perfused with HSYA (30 MUmol/L) in a stepwise fashion. Potassium channel inhibitors were used to determine the role of potassium channel activation in HSYA effect. RESULTS: Intravenous injection of the HSYA significantly reduced MAP and HR in both normotensive rats and SHR in a dose-dependent manner. HSYA reduced left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), the maximum rate of increase of left ventricular pressure (+dp/dt(max)) and heart rate (HR) in a dose-dependent manner. HSYA had no remarkable effect on the maximum rate of decrease of left ventricular pressure (-dp/dt(max)); BK(Ca) and K(ATP) blocker can weakened the inhibitory effect of HSYA on heart function and HR, but K(V) and K(ACh) blocker did not significantly weaken the HSYA effects. CONCLUSION: Our results show that HSYA could significantly reduce blood pressure and heart rate, which may be related to activation of BK(Ca) and K(ATP) channels. PMID- 22197826 TI - Motor nerve terminal destruction and regeneration following anti-ganglioside antibody and complement-mediated injury: an in and ex vivo imaging study in the mouse. AB - Both the neural and glial components of the neuromuscular junction (NMJ) have been identified as potential sites for anti-ganglioside antibody (Ab) binding and complement-mediated injury in murine models for the human peripheral nerve disorder Guillain-Barre syndrome (GBS). Some patients suffering from the acute motor axonal neuropathy (AMAN) forms of GBS recover very rapidly from paralysis; it has been proposed that in these cases the injury was restricted to the distal motor axons and nerve terminals (NTs) which are able to regenerate over a very short time-frame. To test this hypothesis, the ventral neck muscles of mice (n=45) expressing cytosolic fluorescent proteins in their axons (CFP) and Schwann cells (GFP) were subjected to a single topical application of anti-ganglioside Ab followed by a source of complement. Group A (n=15) received Ab that selectively bound to the NTs, group B (n=15) received Abs that bound both to the NTs and the perisynaptic Schwann cells (pSCs) and group C (control animals; n=15) only received complement. Evolution of the injury was documented by in vivo imaging, and following euthanasia the muscles were reimaged ex vivo both quantitatively and qualitatively, either immediately, or after 1, 2, 3 or 5 days of regeneration (each n=3 per group). Within 15 minutes of complement application, a rapid loss of CFP overlying the NMJ could be seen; in group A, the GFP signal remained unchanged, whereas in group B the GFP signal was also lost. In group C no changes to either CFP or GFP were observed. At 24 h, 6% of the superficial NMJs in group A and 12% of the NMJs in group B exhibited CFP. In both groups, CFP returned within the next five days (group A: 93.5%, group B: 94%; p=0.739), with the recovery of CFP being preceded by a return of GFP-positive cells overlying the NMJ in group B. Auxiliary investigations revealed that the loss of CFP at the NMJ correlated with a loss of NT neurofilament immuno-reactivity and a return of CFP at the NMJ was accompanied by a return of neurofilament. In ultrastructural investigations, injured NTs were electron lucent and exhibited damaged mitochondria, a loss of filaments and a loss of synaptic vesicles. The examination of muscles after five days of regeneration revealed physiological NT profiles. The results described above indicate that following a single anti ganglioside Ab-mediated and complement-mediated attack, independent of whether there are healthy and mature perisynaptic Schwann cells overlying the NMJ, the murine NT is capable of recovering both its architectural and axolemmal integrity very rapidly. This data supports the notion that an equivalent mechanism may account for the rapid recovery seen in some clinical cases of AMAN. PMID- 22197827 TI - MCP-1/CCR-2-double-deficiency severely impairs the migration of hematogenous inflammatory cells following transient cerebral ischemia in mice. AB - Monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR-2 are known to play a major role in inflammatory responses after cerebral ischemia. Mice deficient in either MCP-1 or CCR-2 have been reported to develop smaller infarct sizes and show decreased numbers of infiltrating inflammatory cells. In the present study we used green fluorescent protein (GFP) transgenic mice to investigate the effect of MCP-1/CCR-2-double deficiency on the recruitment of inflammatory cells in a model of both, mild and severe cerebral ischemia. We show that MCP-1/CCR-2-double deficiency virtually entirely abrogates the recruitment of hematogenous macrophages and significantly reduces neutrophil migration to the ischemic brain 4 and 7 days following focal cerebral ischemia. This argues for a predominant role of the MCP-1/CCR-2 axis in chemotaxis of monocytes despite a wide redundancy in the chemokine-receptor-system. Chemokine analysis revealed that even candidates known to be involved in monocyte and neutrophil recruitment like MIP-1alpha, CXCL-1, C5a, G-CSF and GM-CSF showed a reduced and delayed or even a lack of relevant compensatory response in MCP-1(-/-)/CCR-2(-/-)-mice. Solely, chemokine receptor 5 (CCR-5) increased early in both, but rose above wildtype levels at day 7 in MCP-1(-/-)/CCR-2(-/-)-animals, which might explain the higher number of activated microglial cells compared to control mice. Our study was, however, not powered to investigate infarct volumes. Further studies are needed to clarify whether these mechanisms of inflammatory cell recruitment might be essential for early infarct development and final infarct size and to evaluate potential therapeutic implications. PMID- 22197828 TI - Bidirectional modulation of fear extinction by mediodorsal thalamic firing in mice. AB - The mediodorsal thalamic nucleus has been implicated in the control of memory processes. However, the underlying neural mechanism remains unclear. Here we provide evidence for bidirectional modulation of fear extinction by the mediodorsal thalamic nucleus. Mice with a knockout or mediodorsal thalamic nucleus-specific knockdown of phospholipase C beta4 exhibited impaired fear extinction. Mutant mediodorsal thalamic nucleus neurons in slices showed enhanced burst firing accompanied by increased T-type Ca(2+) currents; blocking of T channels in vivo rescued the fear extinction. Tetrode recordings in freely moving mice revealed that, during extinction, the single-spike (tonic) frequency of mediodorsal thalamic nucleus neurons increased in wild-type mice, but was static in mutant mice. Furthermore, tonic-evoking microstimulations of the mediodorsal thalamic nucleus, contemporaneous with the extinction tones, rescued fear extinction in mutant mice and facilitated it in wild-type mice. In contrast, burst-evoking microstimulation suppressed extinction in wild-type mice, mimicking the mutation. These results suggest that the firing mode of the mediodorsal thalamic nucleus is critical for the modulation of fear extinction. PMID- 22197829 TI - Computational design of enhanced learning protocols. AB - Learning and memory are influenced by the temporal pattern of training stimuli. However, the mechanisms that determine the effectiveness of a particular training protocol are not well understood. We tested the hypothesis that the efficacy of a protocol is determined in part by interactions among biochemical cascades that underlie learning and memory. Previous findings suggest that the protein kinase A (PKA) and extracellular signal-regulated kinase (ERK) cascades are necessary to induce long-term synaptic facilitation (LTF) in Aplysia, a neuronal correlate of memory. We developed a computational model of the PKA and ERK cascades and used it to identify a training protocol that maximized PKA and ERK interactions. In vitro studies confirmed that the protocol enhanced LTF. Moreover, the protocol enhanced the levels of phosphorylation of the transcription factor CREB1. Behavioral training confirmed that long-term memory also was enhanced by the protocol. These results illustrate the feasibility of using computational models to design training protocols that improve memory. PMID- 22197830 TI - Anatomical connectivity patterns predict face selectivity in the fusiform gyrus. AB - A fundamental assumption in neuroscience is that brain structure determines function. Accordingly, functionally distinct regions of cortex should be structurally distinct in their connections to other areas. We tested this hypothesis in relation to face selectivity in the fusiform gyrus. By using only structural connectivity, as measured through diffusion-weighted imaging, we were able to predict functional activation to faces in the fusiform gyrus. These predictions outperformed two control models and a standard group-average benchmark. The structure-function relationship discovered from the initial participants was highly robust in predicting activation in a second group of participants, despite differences in acquisition parameters and stimuli. This approach can thus reliably estimate activation in participants who cannot perform functional imaging tasks and is an alternative to group-activation maps. Additionally, we identified cortical regions whose connectivity was highly influential in predicting face selectivity within the fusiform, suggesting a possible mechanistic architecture underlying face processing in humans. PMID- 22197831 TI - Encapsulated therapeutic stem cells implanted in the tumor resection cavity induce cell death in gliomas. AB - Therapeutically engineered stem cells have shown promise for glioblastoma multiforme (GBM) therapy; however, key preclinical studies are urgently needed for their clinical translation. In this study, we investigated a new approach to GBM treatment using therapeutic stem cells encapsulated in biodegradable, synthetic extracellular matrix (sECM) in mouse models of human GBM resection. Using multimodal imaging, we first showed quantitative surgical debulking of human GBM tumors in mice, which resulted in increased survival. Next, sECM encapsulation of engineered stem cells increased their retention in the tumor resection cavity, permitted tumor-selective migration and release of diagnostic and therapeutic proteins in vivo. Simulating the clinical scenario of GBM treatment, the release of tumor-selective S-TRAIL (secretable tumor necrosis factor apoptosis inducing ligand) from sECM-encapsulated stem cells in the resection cavity eradicated residual tumor cells by inducing caspase-mediated apoptosis, delayed tumor regrowth and significantly increased survival of mice. This study demonstrates the efficacy of encapsulated therapeutic stem cells in mouse models of GBM resection and may have implications for developing effective therapies for GBM. PMID- 22197832 TI - Uncoupling the roles of synaptotagmin I during endo- and exocytosis of synaptic vesicles. AB - Synaptotagmin I (syt1) is required for normal rates of synaptic vesicle endo- and exocytosis. However, whether the kinetic defects observed during endocytosis in Syt1 knockout neurons are secondary to defective exocytosis or whether syt1 directly regulates the rate of vesicle retrieval remains unknown. To address this question, we sought to dissociate these two activities. We uncoupled the function of syt1 in exo- and endocytosis in mouse neurons either by re-targeting the protein or via mutagenesis of its tandem C2 domains. The effect of these manipulations on exo- and endocytosis were analyzed using electrophysiology, in conjunction with optical imaging of the vesicle cycle. Our results indicate that syt1 is directly involved in endocytosis. Notably, either of the C2 domains of syt1, C2A or C2B, was able to function as a Ca(2+) sensor for endocytosis. Thus, syt1 functions as a dual Ca(2+) sensor for both endo- and exocytosis, potentially coupling these two components of the vesicle cycle. PMID- 22197834 TI - Nutrition in systemic sclerosis. AB - Systemic sclerosis is a connective tissue disease characterized by inflammation and fibrosis of multiple organs (skin, gastrointestinal tract, lung, kidney and heart). After the skin, the organ most affected with a frequency of 75 to 90%, the gastrointestinal tract is more often involved. Gastrointestinal tract involvement is manifested by the appearance of oropharyngeal dysphagia, esophageal dysphagia, gastroesophageal reflux, gastroparesis, pseudo-obstruction, bacterial overgrowth and intestinal malabsorption, constipation, diarrhea and/or fecal incontinence. These effects influence food intake and intestinal absorption leading to the gradual emergence of nutritional deficiencies. About 30% of patients with systemic sclerosis are at risk of malnutrition. In 5-10%, gastrointestinal disorders are the leading cause of death. Therapeutic strategies currently available are limited and aimed at reducing clinical symptoms. The multidisciplinary management of these patients, including nutritional intervention, helps improve gastrointestinal symptoms, and avoid malnutrition, morbidity and improve quality of life. PMID- 22197833 TI - Chromatin modification of Notch targets in olfactory receptor neuron diversification. AB - Neuronal-class diversification is central during neurogenesis. This requirement is exemplified in the olfactory system, which utilizes a large array of olfactory receptor neuron (ORN) classes. We discovered an epigenetic mechanism in which neuron diversity is maximized via locus-specific chromatin modifications that generate context-dependent responses from a single, generally used intracellular signal. Each ORN in Drosophila acquires one of three basic identities defined by the compound outcome of three iterated Notch signaling events during neurogenesis. Hamlet, the Drosophila Evi1 and Prdm16 proto-oncogene homolog, modifies cellular responses to these iteratively used Notch signals in a context dependent manner, and controls odorant receptor gene choice and ORN axon targeting specificity. In nascent ORNs, Hamlet erases the Notch state inherited from the parental cell, enabling a modified response in a subsequent round of Notch signaling. Hamlet directs locus-specific modifications of histone methylation and histone density and controls accessibility of the DNA-binding protein Suppressor of Hairless at the Notch target promoter. PMID- 22197836 TI - n-ZnO/p-Si 3D heterojunction solar cells in Si holey arrays. AB - A wafer-scale, low-cost solar cell based on n-ZnO/p-Si 3D heterojunction arrays on holey Si substrates has been fabricated. This device shows a power-conversion efficiency of 1.2% and high photosensitivity. The present n-ZnO/p-Si heterojunction architectures are envisaged as potentially valuable candidates for next-generation photovoltaics. PMID- 22197850 TI - The transport of antiepileptic drugs by P-glycoprotein. AB - Epilepsy is the most common serious chronic neurological disorder. Current data show that one-third of patients do not respond to anti-epileptic drugs (AEDs). Most non-responsive epilepsy patients are resistant to several, often all, AEDs, even though the drugs differ from each other in pharmacokinetics, mechanisms of action, and interaction potential. The mechanisms underlying drug resistance of epilepsy patients are still not clear. In recent years, one of the potential mechanisms interesting researchers is over-expression of P-glycoprotein (P-gp, also known as ABCB1 or MDR1) in endothelial cells of the blood-brain barrier (BBB) in epilepsy patients. P-gp plays a central role in drug absorption and distribution in many organisms. The expression of P-gp is greater in drug resistant than in drug-responsive patients. Some studies also indicate that several AEDs are substrates or inhibitors of P-gp, implying that P-gp may play an important role in drug resistance in refractory epilepsy. In this article, we review the clinical and laboratory evidence that P-gp expression is increased in epileptic brain tissues and that AEDs are substrates of P-gp in vitro and in vivo. We discuss criteria for identifying the substrate status of AEDs and use structure-activity relationship (SAR) models to predict which AEDs act as P-gp substrates. PMID- 22197851 TI - Editorial. PMID- 22197853 TI - Perspectives on cost-effective medicine and the use of cost-effectiveness analyses. PMID- 22197852 TI - Test-retest consistency of speech-evoked auditory brainstem responses in typically-developing children. AB - The click-evoked auditory brainstem response (ABR) is widely used in clinical settings, partly due to its predictability and high test-retest consistency. More recently, the speech-evoked ABR has been used to evaluate subcortical processing of complex signals, allowing for the objective assessment of biological processes underlying auditory function and auditory processing deficits not revealed by responses to clicks. Test-retest reliability of some components of speech-evoked ABRs has been shown for adults and children over the course of months. However, a systematic study of the consistency of the speech-evoked brainstem response in school-age children has not been conducted. In the present study, speech-evoked ABRs were collected from 26 typically-developing children (ages 8-13) at two time points separated by one year. ABRs were collected for /da/ presented in quiet and in a 6-talker babble background noise. Test-retest consistency of response timing, spectral encoding, and signal-to-noise ratio was assessed. Response timing and spectral encoding were highly replicable over the course of one year. The consistency of response timing and spectral encoding found for the speech evoked ABRs of typically-developing children suggests that the speech-evoked ABR may be a unique tool for research and clinical assessment of auditory function, particularly with respect to auditory-based communication skills. PMID- 22197854 TI - Dietary supplement intake by 6-month-old Taiwanese infants. AB - OBJECTIVES: The objective of the present study was to investigate the types of dietary supplements administered to healthy 6-month-old infants and to identify the factors influencing the use of such supplements. SUBJECTS AND METHODS: The present study was based on the Taiwan Birth Cohort Study database. Questionnaires were used to collect information on the use of dietary supplements from birth, infant feeding practices, and other covariates at 6 months of age. We excluded low-birth-weight, preterm babies, and those whose caregivers returned incomplete questionnaires, leaving a sample size of 18,658. Multiple logistic regression was used to determine the characteristics capable of predicting the use of supplements in this population. A total of 34.9% of infants were fed dietary supplements from birth. RESULTS: The most common types of supplements administered to infants were probiotics, calcium, and multivitamin/mineral supplements. Formula feeding, earlier weaning, and earlier complementary feeding were positively related to the use of several supplements. CONCLUSIONS: The present study demonstrates that the use of pediatric dietary supplements is relatively common among infants in Taiwan, even in the earliest stages of life. For infants whose diet is adequate, no need exists for dietary supplements, and excessive intake can adversely influence health. Communication between health professionals and child caregivers should be promoted to increase understanding of infant feeding, as well as the safety and efficacy of dietary supplements. PMID- 22197856 TI - European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. AB - OBJECTIVE: Diagnostic criteria for coeliac disease (CD) from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) were published in 1990. Since then, the autoantigen in CD, tissue transglutaminase, has been identified; the perception of CD has changed from that of a rather uncommon enteropathy to a common multiorgan disease strongly dependent on the haplotypes human leukocyte antigen (HLA)-DQ2 and HLA-DQ8; and CD-specific antibody tests have improved. METHODS: A panel of 17 experts defined CD and developed new diagnostic criteria based on the Delphi process. Two groups of patients were defined with different diagnostic approaches to diagnose CD: children with symptoms suggestive of CD (group 1) and asymptomatic children at increased risk for CD (group 2). The 2004 National Institutes of Health/Agency for Healthcare Research and Quality report and a systematic literature search on antibody tests for CD in paediatric patients covering the years 2004 to 2009 was the basis for the evidence-based recommendations on CD-specific antibody testing. RESULTS: In group 1, the diagnosis of CD is based on symptoms, positive serology, and histology that is consistent with CD. If immunoglobulin A anti-tissue transglutaminase type 2 antibody titers are high (>10 times the upper limit of normal), then the option is to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory tests. In group 2, the diagnosis of CD is based on positive serology and histology. HLA-DQ2 and HLA-DQ8 testing is valuable because CD is unlikely if both haplotypes are negative. CONCLUSIONS: The aim of the new guidelines was to achieve a high diagnostic accuracy and to reduce the burden for patients and their families. The performance of these guidelines in clinical practice should be evaluated prospectively. PMID- 22197857 TI - Idiopathic Confetti-like leukoderma with unusual presentation. AB - Idiopathic Confetti-like leukoderma in a young Indian is illustrated, emphasizing its cardinal clinical features and histopathological findings, and its differential diagnosis is briefly outlined for instant glance. PMID- 22197858 TI - Adenomatous eccrine metaplasia--a novel reaction pattern. AB - We recently observed atypical adenomatous metaplasia of eccrine glands in an excisional biopsy of squamous cell carcinoma (SCC). This led us to this study in an effort to ascertain whether this reaction pattern is common to all excisional biopsies and, depending on its presence in association with residual tumor, whether it is lineage specific. We performed a retrospective review of 201 excisional biopsies and noted that adenomatous metaplasia was present in 35 of 201 (17%) of the cases, of which 19 had residual tumor. Adenomatous metaplasia seemed to be more frequent in epithelial neoplasms such as basal cell carcinomas 15 of 94 (16%) and SCCs 13 of 61 (21%) although only (3 of 41) 7% of nevomelanocytic proliferations exhibited this change. Residual tumor was noted in association with adenomatous metaplasia, in 11 of 15 cases (73%) in the basal cell carcinoma subgroup, in 8 of 13 cases (62%) in the SCC subgroup, and in none from the nevomelanocytic subgroup. Comparing frequencies of adenomatous metaplasia across groups, only SCC specimens with residual tumor demonstrated a statistically significant increase compared with nevomelanocytic neoplasm (35% vs. 7%, P = 0.01). Findings from the current study expand the spectrum of metaplastic change involving eccrine glands to include adenomatous metaplasia. Given that it seems to be more common to epithelial malignancies, it seems reasonable to posit that this reaction pattern is the consequence of hitherto undefined proteins induced by epithelial tumor cells resulting in exuberant stimulation of eccrine glands, although immunohistochemical and molecular studies are required to define the precise cause. PMID- 22197859 TI - Onychocytic matricoma presenting as pachymelanonychia longitudinal. A new entity (report of five cases). AB - Among the tumors of the epidermal appendages, only rare tumors have been proved as differentiating in the direction of the nail. Beside onychomatricoma, we report a new matrical tumor of the nail: onychocytic matricoma (acanthoma of the nail matrix producing onychocytes). The main differential diagnosis of onychocytic matricoma is seborrheic keratosis. However, if attention is paid to the nature of the different layers of the tumor and the peculiar microanatomy of the nail matrix, the differentiation is not difficult. Onychocytic matricoma is a localized (monodactylous) longitudinal melanonychia which is slightly raised. The term pachymelanonychia is used to define the 2 clinical features of the tumor. Pachyonychia indicate a localized thickening of the nail plate, and melanonychia indicate its longitudinal pigmented band. Onychocytic matricoma is composed of a basal compartment with a varying admixture of prekeratogenous cells and keratogenous cells. Endokeratinization originating in the deep portion of the tumor and nests of prekeratogenous and keratogenous cells in concentric arrangement are a characteristic feature. Three major patterns can be identified as follows: acanthotic, papillomatous, keratogenous type with retarded maturation. Given the peculiar thickening of the nail plate observed both in pigmented onychomatricoma and onychocytic matricoma, the term pachymelanonychia longitudinal could be proposed to specify clinically these 2 lesions, which the clinician sometimes mistakes for melanoma. PMID- 22197855 TI - Correlation of vitamin E, uric acid, and diet composition with histologic features of pediatric NAFLD. AB - OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children in the United States. Although changes in diet are often recommended to improve NAFLD, little is known regarding the influence of diet on histologic features of the disease. SUBJECTS AND METHODS: This was a prospective, cross-sectional registry-based study. Children (n = 149) enrolled in the multicenter nonalcoholic steatohepatitis (NASH) Clinical Research Network had demographic, anthropometric, clinical, laboratory, and histology data obtained, including the Block Brief Food Questionnaire. Subjects were grouped by presence or absence of steatohepatitis and grades of histologic features according to NASH Clinical Research Network criteria. RESULTS: No significant differences were found between children with steatosis compared with steatohepatitis for fraction of energy from fat, carbohydrates, and protein. Sugar-sweetened beverage consumption was low and did not correlate with histologic features, although uric acid, a surrogate marker for fructose intake, was significantly increased in those with definite NASH (P = 0.008). For all groups, vitamin E consumption was insufficient compared with the recommended daily allowance. Median consumption of vitamin E was lower in children with higher grade of steatosis (8.4 vs 6.1 vs 6.9 for grades I, II, and III, respectively, P = 0.05). Those consuming less vitamin C had increased ballooning degeneration (P = 0.05). CONCLUSIONS: Children with NAFLD have a diet that is insufficient in vitamin E and this may contribute to the pathophysiology of NAFLD. In children with NAFLD, reported sugar-sweetened beverage consumption is low; however, uric acid, which may reflect total fructose consumption, was significantly associated with NASH and should be further evaluated. PMID- 22197860 TI - On the development of neurocutaneous units--implications for the histogenesis of congenital, acquired, and dysplastic nevi. AB - This study of spontaneous abortions and fetal deaths in utero used immunostains to evaluate the structure of developing cutaneous nerves. Melan-A immunostains were also used to screen 25 cases of grossly normal fetal skin for occult fetal nevi. Discrete portions of epidermis were generally supplied by branches emanating from regularly spaced deep cutaneous nerves, producing a wedge shape, interpreted as neurocutaneous units (NCU). Deeper nerves embraced broader portions of epidermis. Some nerves ran parallel to epidermis, especially near the superficial vascular plexus at the junction of superficial and deep dermis. Nerve sheath stem cells in each NCU may supply the melanocytes needed by the corresponding portion of epidermis. Transformed nerve sheath stem cells may lead to formation of occult prenatal nevi, whose histology and histogenesis may best be understood in terms of NCUs. In particular, the size and shape of a nevus may be largely determined by its NCU of origin. Six fetal nevi were detected, and 3 occult lumbosacral Mongolian spots; all in deep dermis, no later than the middle of the second trimester, mainly with a pattern of singly dispersed deep dermal melanocytes. These findings suggest that congenital (prenatal) nevi begin as intradermal nevi. In addition to explaining congenital nevi, these findings have implications for the histogenesis of acquired (postnatal) nevi and dysplastic nevi. PMID- 22197861 TI - pHH3 immunostaining improves interobserver agreement of mitotic index in thin melanomas. AB - According to the seventh edition of the American Joint Committee on Cancer guidelines, the TNM staging category in thin cutaneous melanomas depends on the mitotic rate (MR). In this study, we analyze the interobserver agreement of the MR in a series of 92 thin cutaneous melanomas. Serial sections of the tumors were either stained with hematoxylin and eosin or immunohistochemically stained with pHH3, an antibody for phosphohistone H3, and analyzed by 4 observers. Determination of MR with pHH3 immunostaining resulted in higher sensitivity in counting mitosis for all observers. Moreover, interobserver agreement was higher with pHH3. Immunostaining with pHH3 is a sensitive method to detect mitosis in thin cutaneous melanomas, with good reproducibility of MR between independent observers. Further studies are needed to find out if higher sensitivity in the detection of mitosis by pHH3 immunostaining has additional prognostic relevance. PMID- 22197862 TI - Leukocytoclastic vasculitis as early manifestation of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly. AB - Extensive necrotizing vasculitis (ENV) is a rare paraneoplastic phenomenon, and the majority of cases reported are associated with hematolymphoid neoplasms. Histologically, most cases of ENV represent leukocytoclastic vasculitis (LCV). Here we report the clinicopahological features of a 68-year-old man with ENV associated to a Epstein Barr virus-positive diffuse large B-cell lymphoma (EBV+DLBCL) of the elderly, a newly recognized lymphoproliferative disorder, most likely representing a paraneoplastic manifestation. The patient was treated with standard chemotherapy regimen for malignant lymphoma. Due to the extensive involvement of the extremities by ENV, surgical debridement was not feasible and a novel therapy based on CHITOSAN apposits was initiated with overall good response and subsequent re-epithelization of the skin lesions. The patient died of sepsis secondary to a Pseudomona pneumonia 17 months after diagnosis. PMID- 22197863 TI - Identification of Helicobacter pylori in skin biopsy of prurigo pigmentosa. AB - A 23-year-old Chinese man presented with a 3-year history of a pruritic eruption. On examination, pink urticarial papules associated with hyperpigmented reticulated patches were noted on his neck, back, and upper chest. Histopathology revealed vacuolar interface dermatitis and numerous gram-negative rods within a dilated hair follicle. The organisms were reactive with anti-Helicobacter pylori immunohistochemisty. The histologic findings and clinical presentation support the diagnosis of prurigo pigmentosa. Additional testing demonstrated a positive urease breath test and serum H. pylori IgG antibodies. The patient was referred to gastroenterology and treated with appropriate antibiotics. After treatment, esophagogastroduodenoscopy revealed chronic gastritis without evidence of H. pylori infection and his skin showed reticulated hyperpigmented patches without evidence of active inflammatory papules. Although previous reports have associated prurigo pigmentosa to H. Pylori gastritis, this is the first report of H. pylori organisms identified in a skin biopsy of prurigo pigmentosa. PMID- 22197865 TI - Digital imaging for statistical analysis of tissue microarrays. PMID- 22197866 TI - Intracoronary imaging modalities for vulnerable plaques. AB - The concept of vulnerable plaque (VP) has been widely accepted as the primary cause of acute coronary syndrome (ACS) and sudden cardiac death. ACS is thought to result from sudden disruption of a VP with subsequent occlusive thrombosis. VP typically consists of several components; a large necrotic core, thin fibrous cap, increase in macrophage activity, increase in vaso vasorum, and positive remodeling. In recent years, invasive or non-invasive diagnostic imaging modalities have been developed for indentifying VP. VP has been recognized in various modalities not only by visualization of cross sectional images by high resolution imaging modalities, such as virtual histology intravascular ultrasound (VH-IVUS), integrated backscatter (IB) IVUS, and optical coherence tomography (OCT), but also by direct visualization by intracoronary angioscopy. VH-IVUS uses advanced radiofrequency signal analysis of ultrasound signals and allows detailed qualitative and quantitative assessment of plaque composition, while IB-IVUS analyzes the radiofrequency signal by applying a fast Fourier transformation of the component of the backscattered signals. Different tissue components reflect the radiofrequency signaling at different power levels, which could be used to differentiate various tissue components. Angioscopy allows direct visualization of internal surface of the lumen, providing the detailed information of characteristics of plaque and thrombus. Optical coherence tomography (OCT) is an analog of IVUS, but uses light instead of sound. OCT has a 10-fold higher image resolution (10-15 MUm) compared to conventional IVUS, therefore it is able to provide superior image quality. The commercially available versions of the technology used time-domain (TD) OCT (M2, M3, Lightlab, Westford, MA, USA) and fourier-domain (FD) OCT (C7XR, Lightlab, Westford, MA, USA). OCT is the only imaging modality with high enough resolution to measure fibrous cap thickness and neovascularization. Moreover OCT has a unique ability of detecting macrophages. In this review, we attempted to summarize the advantages and limitations of the currently available intravascular modalities. PMID- 22197864 TI - Imaging mass spectrometry--a new and promising method to differentiate Spitz nevi from Spitzoid malignant melanomas. AB - BACKGROUND: Differentiating Spitz nevus (SN) from Spitzoid malignant melanoma (SMM) is one the most difficult problems in dermatopathology. SPECIFIC AIM: To identify differences on proteomic level between SN and SMM. METHODS: We performed Imaging Mass Spectrometry analysis on formalin-fixed, paraffin-embedded tissue samples to identify differences on proteomic level between SN and SMM. The diagnosis of SN and SMM was based on histopathologic criteria, clinical features, and follow-up data, which confirmed that none of the lesions diagnosed as SN recurred or metastasized. The melanocytic component (tumor) and tumor microenvironment (dermis) from 114 cases of SN and SMM from the Yale Spitzoid Neoplasm Repository were analyzed. After obtaining mass spectra from each sample, classification models were built using a training set of biopsies from 26 SN and 25 SMM separately for tumor and for dermis. The classification algorithms developed on the training data set were validated on another set of 30 samples from SN and 33 from SMM. RESULTS: We found proteomic differences between the melanocytic components of SN and SMM and identified 5 peptides that were differentially expressed in the 2 groups. From these data, 29 of 30 SN and 26 of 29 SMM were recognized correctly based on tumor analysis in the validation set. This method correctly classified SN with 97% sensitivity and 90% specificity in the validation cohort. CONCLUSIONS: Imaging Mass Spectrometry analysis can reliably differentiate SN from SMM in formalin-fixed, paraffin-embedded tissue based on proteomic differences. PMID- 22197867 TI - Current surgical treatment for chronic pancreatitis. AB - Chronic pancreatitis (CP) is a painful, yet benign inflammatory process of the pancreas. Surgical management should be individualized because the pain is multifactorial and its mechanisms vary from patient to patient. Two main pathogenetic theories for the mechanisms of pain in CP have been proposed: the neurogenic theory and the theory of increased intraductal/intraparenchymal pressures. The latter theory is strongly supported by the good results of drainage procedures in the surgical management of CP. Other possible contributing factors include pancreatic ischemia; a centrally sensitized pain state; and the development of complications, such as pseudocysts and stenosis of the duodenum or common bile duct. Common indications for surgery include intractable pain, suspicion of neoplasm, and complications that cannot be resolved with radiological or endoscopic treatments. Operative procedures have been historically classified into 4 categories: decompression procedures for diseased and obstructed pancreatic ducts; resection procedures for the proximal, distal, or total pancreas; denervation procedures of the pancreas; and hybrid procedures. Pancreaticoduodenectomy and pylorus-preserving pancreaticoduodenectomy, once the standard operations for patients with CP, have been replaced by hybrid procedures, such as duodenum-preserving pancreatic head resection, the Frey procedure, and their variants. These procedures are safe and effective in providing long-term pain relief and in treating CP-related complications. Hybrid procedures should be the operations of choice for patients with CP. PMID- 22197868 TI - Tumor necrosis factor-alpha-induced mononuclear cell death may contribute to polymorphonuclear cell predominance in the cerebrospinal fluid of patients with bacterial meningitis. AB - BACKGROUND: Bacterial meningitis is characterized by a marked predominance of polymorphonuclear leukocytes (PMNs: segmented granulocytes or neutrophils) in the cerebrospinal fluid (CSF), whereas aseptic meningitis is characterized by a predominance of mononuclear leukocytes (MNs: lymphocytes or monocytes). However, the pathophysiology of this predominance of PMNs in the CSF of patients with bacterial meningitis has never, to our knowledge, been clearly described. METHODS: To investigate the predominant cell components of CSF from pediatric patients with bacterial meningitis, we investigated cell death in association with levels of tumor necrosis factor-alpha (TNF-alpha) in the CSF, using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay and flow cytometry. RESULTS: The MTT assay of the CSF revealed that the PMNs had survived, while the MNs rapidly had undergone cell death. Although PMNs survived in CSF with high levels of TNF-alpha, PMN apoptosis was demonstrated with flow cytometry. CONCLUSIONS: The present study suggests that the pathophysiology of PMN predominance in the CSF of patients in the acute phase of bacterial meningitis is related to the rapid cell death of MNs and the survival of PMNs brought about by high levels of TNF-alpha. PMID- 22197869 TI - Diagnosis of vertebral artery dissection with basiparallel anatomical scanning magnetic resonance imaging. AB - BACKGROUND AND PURPOSE: There is no consensus regarding the optimal method for diagnosing the dissection of intracranial arteries. We have developed a rapid and accurate examination method to diagnose vertebral artery dissection in the acute stage of cerebral infarction. METHODS: Twenty-two patients with severe headache and neck pain and/or symptoms of brain stem or cerebellar ischemia underwent magnetic resonance imaging (MRI) with a 1.5-T scanner. Our protocol generated 3 contrast-weighted scans (T2-weighted, diffusion-weighted, and basi-parallel anatomical scanning [BPAS]-MRI) and conventional angiographs within 3 hours of the onset of symptoms. Then, we retrospectively analyzed the findings to identify the most reliable imaging method for diagnosing vertebral artery dissection in the acute stage of cerebral infarction. RESULTS: Based on the symptoms and the findings of T2-weighted imaging and conventional angiography, the initial diagnosis was dissection in 17 patients, lacunar infarction in 3 patients, and atherothrombosis in 2 patients. After follow-up studies the diagnosis was changed in 7 patients. The diagnosis based on symptoms and the findings of T2-weighted MRI and BPAS-MRI was dissection in 13 patients, atherothrombosis in 6 patients, and lacunar infarction in 3 patients. In 3 patients the diagnosis was changed during the follow-up phase. CONCLUSIONS: The diagnostic accuracy rate was higher with T2-weighted MRI and BPAS-MRI than with T2-weighted MRI and conventional angiography. We suggest that when intracranial vascular dissection is suspected, both the inner and outer contours of vessels must be inspected and that BPAS-MRI should be performed instead of conventional angiography to establish the definite diagnosis. PMID- 22197870 TI - Safe technique for laparoscopic distal pancreatectomy involving a large cystic tumor. AB - BACKGROUND: In patients with large tumors, securing sufficient working space to perform laparoscopic resection can be difficult. The purpose of this technical note is to describe a technique for easy performance of laparoscopic distal pancreatectomy involving large cystic pancreatic tumors. SURGICAL TECHNIQUE: Early in surgery, a small incision was made in the abdominal wall directly above the tumor to remove the laparoscopically resected tissues from the abdominal cavity. After the margin of the incision was secured with a wound protector, a double-balloon catheter was used to remove the contents of the tumor under direct observation, without allowing any leakage into the abdominal cavity. The volume of the tumor could, thus, be safely reduced. As a result, laparoscopic distal pancreatectomy was safely performed, even for 17-cm-diameter mucinous cystic neoplasm of the pancreas. CONCLUSION: A wound protector and a double-balloon catheter are helpful for removing the contents of a cystic tumor. A small abdominal incision for removing the resected tissues can be used during the resection procedure to aspirate the tumor contents, and, as a result, laparoscopic distal pancreatectomy can be performed safely, even for large cystic pancreatic tumors. PMID- 22197871 TI - Novel hybrid mesh surgery combines sacrocolpopexy with transvaginal mesh placement for pelvic organ prolapse. AB - Mesh surgeries, such as sacrocolpopexy and transvaginal mesh surgery, are commonly used to treat pelvic organ prolapse. Although mesh surgeries have a high success rate, they are unsuitable for some patients. For a patient with pelvic organ prolapse and highly calcified multiple fibroids, we performed hybrid sacrocolpopexy combined with transvaginal mesh surgery with a method modified for the patient's condition. Three months after surgery, the results were highly satisfactory. This approach is simple, secure, and versatile for patients who are not good candidates for conventional mesh surgeries. This novel hybrid mesh surgery is an option for treating various types of pelvic organ prolapse. PMID- 22197872 TI - Case of bilateral Galeazzi fractures associated with dislocation of the right elbow. AB - We report an unusual case of bilateral Galeazzi fractures associated with dislocation of the right elbow and fracture of the right scaphoid caused by a motorbike accident in a 32-year-old man. Bilateral radiuses were fixed with plates, and the right scaphoid was fixed with a screw after closed reduction of the right elbow. A satisfactory result was obtained with a return to work and no radiographic problems 7 years after surgery. The mechanism of the injury was thought to be a high-velocity fall on the outstretched hands combined with extreme pronation of the forearms and extension of the wrists and the elbows. This case had a favorable outcome following operative stabilization of the fracture-dislocations and early mobilization. PMID- 22197873 TI - Case of fibrolipomatous hamartoma of the digital nerve without macrodactyly. AB - Fibrolipomatous hamartoma of nerves without macrodactyly is a rare lesion characterized by fibrofatty proliferation causing epineural and perineural fibrosis with fatty infiltration around the nerve bundles. We report an unusual case of fibromatous hamartoma of the ulnar digital nerve of the thumb in a 43 year-old woman. Magnetic resonance imaging revealed a large fusiform mass along the nerve. The findings were unusual and pathognomonic and included a coaxial cable-like appearance on axial sections and a spaghettilike appearance on coronal sections on both T1- and T2-weighted images; these findings were useful for the diagnosis and preoperative evaluation of this lesion. Surgical exploration revealed a yellow, cordlike mass of the digital nerve enlarged by fat. Gross excision could not be done without extensive damage to the nerve. Therefore, a limited excision with biopsy of the fibrolipomatous tissue around the nerve bundles was performed. The histological appearance was consistent with fibrolipomatous hamartoma. There was no recurrence of the mass and no neurological deficit 3 years after surgery. Some authors have suggested that invasive excision can cause catastrophic sensory or motor deficits because of the extensive fatty infiltration of the nerve fascicles. In conclusion, the recommended treatment for this lesion is limited excision with only biopsy to confirm the diagnosis. PMID- 22197874 TI - Medical relief activities, medical resourcing, and inpatient evacuation conducted by Nippon Medical School due to the Fukushima Daiichi Nuclear Power Plant accident following the Great East Japan Earthquake 2011. AB - On March 11, 2011, after the Great East Japan Earthquake and tsunami, the government declared a nuclear emergency following damage to the Fukushima Daiichi Nuclear Power Plant. A second hydrogen explosion occurred on March 14 at the plant's No. 3 reactor and injured 11 people. At that time the prime minister urged people living 20 to 30 km from the Daiichi plant to stay indoors. Under these circumstances, many residents of Iwaki City, which was largely outside the 30-km zone, left the city, making it difficult to get supplies to the remaining residents. The only transportation route open for supplies and medical resources was roads, and many drivers feared the rumor that the city was contaminated by radioactive materials and, so, refused to go there. Nippon Medical School (NMS) heard that medical resources were running short at Iwaki Kyoritsu Hospital, which requested water, medications, food, fuel (gasoline), medical support, and the evacuation of 300 inpatients. As a first step, NMS decided to evaluate the situation at the hospital and, on March 16, the director of the NMS Advanced Emergency Center visited the hospital and helped provide triage for about 200 patients. Critically ill patients receiving ventilatory support were given priority for evacuation because they would be most at risk of not being able to evacuate should the Japanese government order an immediate evacuation of the city. We tried to evacuate the inpatients via an official framework, such as the Disaster Medical Assistance Team (DMAT), but DMAT could not support this mission because this hospital was not within the 30-km evacuation zone. Moreover, the Iwaki City government could not support the evacuation efforts because they were fearful of the rumor that Iwaki was contaminated by radioactive material. Ultimately, we realized that we had to conduct the mission ourselves and, so, contacted our colleagues in the Tokyo metropolitan area to prepare enough hospital beds. We evacuated 15 patients to 8 hospitals over a 5-day period. As a result, we could reduce the number of patients at Iwaki Kyoritsu Hospital, and, thereby, the collapse of medical services in the city was avoided. In retrospect, someone might say the government--either central or local--should ideally have carried out this mission and created a system by which to do it. At the same time, however, to overcome any future bureaucratic issues, we should also prepare private networks, such as those used by NMS, because they can respond flexibly to unexpected large-scale disasters. PMID- 22197875 TI - Medical relief activities conducted by Nippon Medical School in the acute phase of the Great East Japan Earthquake 2011. AB - At 14:46 on March 11, 2011, the Great East Japan Earthquake and tsunami occurred off the coast of Honshu, Japan. In the acute phase of this catastrophe, one of our teams was deployed as a Tokyo Disaster Medical Assistance Team (DMAT) to Kudan Kaikan in Tokyo, where the ceiling of a large hall had partially collapsed as the result of the earthquake, to conduct triage at the scene: 6 casualties were assigned to the red category (immediate), which included 1 case of cardiopulmonary arrest and 1 of flail chest; 8 casualties in the yellow category (delayed); and 22 casualties in the green category (minor). One severely injured person was transported to our hospital. Separately, our medical team was deployed to Miyagi 2 hours after the earthquake in our multipurpose medical vehicle as part of Japan DMAT (J-DMAT). We were the first DMAT from the metropolitan area to arrive, but we were unable to start medical relief activities because the information infrastructure had been destroyed and no specific information had yet reached the local headquarters. Early next morning, J-DMAT decided to support Sendai Medical Center and search and rescue efforts in the affected area and to establish a staging care unit at Camp Kasuminome of the Japan Self-Defense Force. Our team joined others to establish the staging care unit. Because information was still confused until day 3 of the disaster and we could not adequately grasp onsite medical needs, our J-DMAT decided to provide onsite support at Ishinomaki Red Cross Hospital, a disaster base hospital, and relay information about its needs to the local J-DMAT headquarters. Although our medical relief teams were deployed as quickly as possible, we could not begin medical relief activities immediately owing to the severely damaged information infrastructure. Only satellite mobile phones could be operated, and information on the number of casualties and the severity of shortages of lifeline services could be obtained only through a "go and see" approach. Because there was no way to transmit or receive this vital information, disaster workers in the affected areas faced many challenges. For the future, network data links need to be made more resistant to infrastructure damage, and redundant or reach-back systems involving multitiered satellite, wireless, and radio frequency data links would provide definitive solutions. Such integrated systems should be designed around seamless connectivity based on an "always best connected" principle for maintaining communication quality. PMID- 22197876 TI - Onsite medical rounds and fact-finding activities conducted by Nippon Medical School in Miyagi prefecture after the Great East Japan Earthquake 2011. AB - This report describes our onsite medical rounds and fact-finding activities conducted in the acute phase and medical relief work conducted in the subacute phase in Miyagi prefecture following the Great East Japan Earthquake and subsequent tsunami that occurred off northeastern Honshu on March 11, 2011. As part of the All-Japan Hospital Association medical team deployed to the disaster area, a Nippon Medical School team conducted fact-finding and onsite medical rounds and evaluated basic life and medical needs in the affected areas of Shiogama and Tagajo. We performed triage for more than 2,000 casualties, but in our medical rounds of hospitals, clinics, and nursing homes, we found no severely injured person but did find 1 case of hyperglycemia. We conducted medical rounds at evacuation shelters in Kesennuma City during the subacute phase of the disaster, from March 17 through June 1, as part of the Tokyo Medical Association medical teams deployed. Sixty-seven staff members (17 teams), including 46 physicians, 11 nurses, 3 pharmacists, and 1 clinical psychotherapist, joined this mission. Most patients complained of a worsening of symptoms of preexisting conditions, such as hypertension, respiratory problems, and diabetes, rather than of medical problems specifically related to the tsunami. In the acute phase of the disaster, the information infrastructure was decimated and we could not obtain enough information about conditions in the affected areas, such as how many persons were severely injured, how severely lifeline services had been damaged, and what was lacking. To start obtaining this information, we conducted medical rounds. This proved to be a good decision, as we found many injured persons in evacuation shelters without medication, communication devices, or transportation. Also, basic necessities for life, such as water and food, were lacking. We were able to evaluate these basic needs and inform local disaster headquarters of them. In Kesennuma City, we found that some evacuation shelters could not contact others even after 1 week after the earthquake. We realized from our experiences that, unlike our activities following more localized earthquake disasters, the first task following such large-scale disasters is to acquire information on basic life needs, including medication needs, and the number of persons requiring assistance. We must provide medical relief according to the unique characteristics of the disaster-affected areas as well as the specific nature of the disaster, in this case, a tsunami. PMID- 22197880 TI - Mayack SR, Wagers AJ. Osteolineage niche cells initiate hematopoietic stem cell mobilization. Blood. 2008;112(3):519-531. PMID- 22197881 TI - The temporal orienting P3 effect to non-target stimuli: does it reflect motor inhibition? AB - Temporal orienting enhances early (N1) and late (P3) stages of auditory processing. However, the functional significance of these effects has not been settled yet. The present study tested a motor inhibition account on the temporal orienting P3 effect to non-target stimuli. A temporal cuing paradigm was used, where the level of motor preparation (high vs. low) was varied: If motor preparation is higher, more inhibition is necessary to withhold a response when a non-target is presented at the attended time point. Consequently, if the enhanced P3 to temporally attended non-targets reflected increased motor inhibition, higher motor preparation should further enhance the P3. Overall, temporal orienting enhanced both the N1 and the P3, thus replicating earlier findings. Moreover, the temporal orienting P3 effect was larger when motor preparation was higher. Inconsistent with the motor-inhibition account, however, the P3 to temporally attended non-targets did not differ as a function of motor preparation. PMID- 22197882 TI - Speeding up older adults: age-effects on error processing in speed and accuracy conditions. AB - Behavioral performance in older adults is often characterized by normal error rates but longer response latencies compared to younger adults. The slowing of reaction times might reflect a compensatory strategy to avoid errors and might be associated with performance monitoring alterations. The present study investigated whether the ability to compensate for potential deficits influences age-related differences in performance monitoring. A modified flanker task was used with either accuracy or speed instruction. Both groups showed reliable differences between conditions: accuracy, reaction times and error-related negativities were reduced in the speed compared with the accuracy condition. Older adults showed smaller error-related negativities compared with younger adults and the reduction was more pronounced in the speed condition. Further, similar-sized error-related and correct-related negativities were found in older adults. Results indicate that performance monitoring deficits in older adults are related to deficits in behavioral performance, at least if they are forced to respond quickly. PMID- 22197883 TI - MYB46 and MYB83 bind to the SMRE sites and directly activate a suite of transcription factors and secondary wall biosynthetic genes. AB - MYB46 and MYB83 are two functionally redundant Arabidopsis thaliana MYB transcription factors that act as master switches regulating secondary wall biosynthesis. Here, we report the identification of the transcriptional responsive elements and global analysis of the direct targets of MYB46 and MYB83. Using the estrogen-inducible direct activation system, we found that a number of previously identified MYB46 downstream transcription factors, including MYB43, MYB52, MYB54, MYB58, MYB63 and KNAT7, are direct targets of MYB46. Promoter deletion coupled with transactivation analysis of the MYB63 promoter led to the identification of a 7 bp sequence that is sufficient to be responsive to MYB46 activation, and therefore this sequence is designated as the secondary wall MYB responsive element (SMRE). Further single nucleotide mutation together with electrophoretic mobility shift assay mapped the SMRE consensus sequence as ACC(A/T)A(A/C)(T/C). Genome-wide analysis of direct targets of MYB46 demonstrated that it directly regulates the expression of not only a number of downstream transcription factors, but also a suite of secondary wall biosynthetic genes, some of which are also directly activated by secondary wall NAC (SWN) master switches or by MYB46 direct targets. Furthermore, MYB83 was found to bind to the same SMRE consensus sequence and activate the same set of direct targets as MYB46. Our study has revealed that the transcription program regulating secondary wall biosynthesis involves a multileveled feed-forward loop regulatory structure in which MYB46/MYB83 together with their regulators SWNs and their direct targets regulate an array of downstream genes thereby activating the secondary wall biosynthetic program. PMID- 22197884 TI - Variegated tobacco leaves generated by chloroplast FtsH suppression: implication of FtsH function in the maintenance of thylakoid membranes. AB - Mutants lacking a thylakoid membrane-bound metalloprotease, FtsH, are known to cause leaf variegation in Arabidopsis. However, the effect of reduced FtsH levels on leaf variegation has scarcely been examined in other plants. In this study, we performed RNA interference (RNAi) by which FtsH expression was suppressed in tobacco. The resulting FtsH knock-down tobacco plants showed variegation in their leaves, and a negative correlation between the degree of variegation and the level of FtsH, which supported earlier observations in Arabidopsis. A decrease of NtFtsH2 as well as NtFtsH1 suggested that these are the two major isoforms comprising the FtsH complex in tobacco chloroplasts. The RNAi tobacco lines also showed photoinhibition-vulnerable phenotypes, as evidenced by high-light sensitive PSII activity and retarded degradation of D1 protein. Interestingly, the formation of variegated sectors during leaf development appeared to differ between Arabidopsis and tobacco. In contrast to the formation of variegation in Arabidopsis, the yellow sectors in FtsH RNAi tobacco emerged from green leaves at a late stage of leaf development. A series of cytological observations implied that thylakoid membranes were dismantled after development had already occurred. Late formation of variegation in FtsH RNAi tobacco suggested that the heteromeric FtsH complex is important for maintaining thylakoid membranes. PMID- 22197885 TI - Reference genes for the normalization of gene expression in eucalyptus species. AB - Gene expression analysis is increasingly important in biological research, with reverse transcription-quantitative PCR (RT-qPCR) becoming the method of choice for high-throughput and accurate expression profiling of selected genes. Considering the increased sensitivity, reproducibility and large dynamic range of this method, the requirements for proper internal reference gene(s) for relative expression normalization have become much more stringent. Given the increasing interest in the functional genomics of Eucalyptus, we sought to identify and experimentally verify suitable reference genes for the normalization of gene expression associated with the flower, leaf and xylem of six species of the genus. We selected 50 genes that exhibited the least variation in microarrays of E. grandis leaves and xylem, and E. globulus xylem. We further performed the experimental analysis using RT-qPCR for six Eucalyptus species and three different organs/tissues. Employing algorithms geNorm and NormFinder, we assessed the gene expression stability of eight candidate new reference genes. Classic housekeeping genes were also included in the analysis. The stability profiles of candidate genes were in very good agreement. PCR results proved that the expression of novel Eucons04, Eucons08 and Eucons21 genes was the most stable in all Eucalyptus organs/tissues and species studied. We showed that the combination of these genes as references when measuring the expression of a test gene results in more reliable patterns of expression than traditional housekeeping genes. Hence, novel Eucons04, Eucons08 and Eucons21 genes are the best suitable references for the normalization of expression studies in the Eucalyptus genus. PMID- 22197886 TI - Spin-lattice relaxation rates and water content of freeze-dried articular cartilage. AB - OBJECTIVE: Nuclear magnetic resonance (NMR) spin-lattice relaxation rates were measured in bovine and porcine articular cartilage as a function of water content. METHODS: Water content was varied by freeze-drying samples for short periods of time (up to 15 min). The samples were weighed at all stages of drying so that water content could be quantified. Spin-lattice relaxation rates were measured using magnetic resonance imaging (MRI). RESULTS: Linear correlations were observed between relaxation rate and two measures of inverse water content: (1) solid-to-water ratio (rho), expressed as a ratio of the mass of the solid component of the cartilage (m(s)) and the mass of water at each freeze-drying time point (m(w)), and (2) a ratio of the total mass of the fully-hydrated cartilage and m(w) (1/w). These correlations did not appear significantly different for the bovine and porcine data. However, fitting the data to a piecewise-linear model revealed differences between these two species. We interpret the first two segments of the piecewise model as the depletion of different water phases but conjecture that the third segment is partially caused by changes in relaxation rates as a result of a reduction in macromolecular mobilities. CONCLUSIONS: Whilst we can produce linear correlations which broadly describe the dependence of the measured spin-lattice relaxation rate on (inverse) water content, the linear model seems to obscure a more complicated relationship which potentially provides us with more information about the structure of articular cartilage and its extracellular water. PMID- 22197888 TI - Right hip pain in a 20-year-old epee fencer. PMID- 22197887 TI - Consequences of RAS and MAPK activation in the ovary: the good, the bad and the ugly. AB - This review summarizes studies providing evidence (1) that endogenous RAS activation regulates important physiological events during ovulation and luteinization (2) that expression of the mutant, active KRAS(G12D) in granulosa cells in vivo causes abnormal follicle growth arrest leading to premature ovarian failure and (3) that KRAS(G12D) expression in ovarian surface epithelial (OSE) cells renders them susceptible to the pathological outcome of transformation and tumor formation. These diverse effects of RAS highlight how critical its activation is linked to cell- and stage-specific events in the ovary that control normal processes and that can also lead to altered granulosa cell and OSE cell fates. PMID- 22197889 TI - Profunda femoris pseudoaneurysm following Birmingham hip resurfacing: an important differential diagnosis for a periarticular cystic mass. AB - Vascular injury following hip resurfacing arthroplasty is rare: we present a case of profunda femoris pseudoaneurysm complicating hip resurfacing arthroplasty performed via an anterolateral approach. Over recent years, it has been recognized that an adverse reaction to metal debris from metal-on-metal arthroplasties can also result in the development of cystic masses around the hip. This case highlights a potential rare differential diagnosis that needs to be considered when imaging cystic mass lesions around the postoperative hip. Imaging can provide a definitive diagnosis if this entity is considered and its appearances recognized, resulting in appropriate management of this potentially limb- and life-threatening complication. PMID- 22197890 TI - Evaluation of the effectiveness of topical ciprofloxacin and prednisolone in the prevention of myringosclerosis. AB - An antibacterial drug, ciprofloxacin, has been reported to modulate the inflammatory and immune responses on monocytes. Our objective is to evaluate the effectiveness of ciprofloxacin in the prevention of myringosclerosis that is created by myringotomy in rats and to compare it with prednisolone. In this study, 24 healthy Sprague-Dawley type rats of age 3-4 months and 250-300 g weight were used. Rats have been divided into three random groups. Topical ciprofloxacin was administered to the rats in the first group and topical prednisolone was administered to the rats in the third group; no medication was applied to their opposite ears and they were determined as control group. Prednisolone was administered to one ear of the rats and ciprofloxacin was administered to their opposite sides in the second group. After bilateral myringotomies the treatments were applied for 20 days as five drops two times a day. Otomicroscopic examination was made on the 10th day and reperforations were made when necessary. Rats were killed on the 21st day and temporal bone dissections were done. When we evaluate in terms of myringosclerosis and tympanic membrane thickness, in the first group, myringosclerosis and thickness have been observed in two of seven ears (28.6%) where ciprofloxacin was administered and in five of the seven ears (71.4%) where no treatment was applied. In the second group where prednisolone and ciprofloxacin were compared, myringosclerosis and thickness have been observed in six of the ten ears (60.0%) where prednisolone was administered and in four of the ten ears (40.0%) where ciprofloxacin was administered. In the third group, myringosclerosis and thickness have been observed in three of seven ears (42.9%) where prednisolone was administered and in four of the seven ears (57.1%) where no treatment was applied. All histopathological evaluations were made by one pathologist in a blinded manner. In our study, the effect of the ciprofloxacin and prednisolone was similar in preventing the experimental myringosclerosis and TM thickness in rats. When compared with the control groups, this preventive effect was more obvious in the ciprofloxacin treatment group than that of prednisolone. PMID- 22197891 TI - Defect closure after oral and pharyngeal tumor resection with the superiorly pedicled myocutaneous platysma flap: indications, technique, and complications. AB - This study evaluated the myocutaneous platysma flap (MPF) as an alternative to free flaps for closing defects after head and neck tumor resection in selected cases. MPFs were used to close small to medium-sized full-thickness oral and pharyngeal defects after surgery for tumors staged cT1-3 (oral cavity 37.1%, oropharynx 24.3%, hypopharynx 38.6%) in 70 patients. Flap-related complications developed in 27% of cases (partial necrosis 7%, total necrosis 3%, salivary fistula 11.4%, bleeding/hematoma 5.7%) and donor-site complications in 10%. Defect closure was adequate in 97%; 62.5% of the patients required intraoperative tracheotomies (closed again in 72.5%). Postoperative swallowing was not significantly disturbed in 72% of the patients. The MPF allows closure of small to medium-sized defects in the head and neck region in selected patients, with acceptable aesthetic and functional outcomes. The success rate (>90%) is comparable with surgical alternatives associated with considerably greater surgical effort and risk. PMID- 22197892 TI - Isolation and characterization of galactinol synthases from hybrid poplar. AB - The raffinose family of oligosaccharides (RFOs) serve as transport carbohydrates in the phloem, storage compounds in sink tissues, and putative biological agents to combat both abiotic and biotic stress in several plant species. To investigate further the functional roles of this class of compounds in trees, two cDNAs encoding galactinol synthase (GolS, EC 2.4.1.123), which catalyses the first step in the biosynthesis of RFOs, were identified and cloned from hybrid poplar (Populus alba*grandidentata). Phylogenetic analyses of the Populus GolS isoforms with other known GolS proteins suggested a putative role for these enzymes during biotic or abiotic stress in hybrid poplar. The predicted protein sequences of both isoforms (Pa*gGolSI and Pa*gGolSII) showed characteristics of GolS proteins from other species, including a serine phosphorylation site and the ASAAP pentapeptide hydrophobic domain. Kinetic analyses of recombinant Pa*gGolSI and Pa*gGolSII resulted in K(m) values for UPD-galactose of 0.80 and 0.65 mM and V(max) values of 657.5 and 1245 nM min(-1), respectively. Pa*gGolSI inherently possessed a broader pH and temperature range when compared with Pa*gGolSII. Interestingly, spatial and temporal expression analyses revealed that Pa*gGolSII transcript levels varied seasonally, while Pa*gGolSI did not, implying temperature-regulated transcriptional control of this gene in addition to the observed thermosensitivity of the respective enzyme. This evidence suggested that Pa*gGolSI may be involved in basic metabolic activities such as storage, while Pa*gGolSII is probably involved in seasonal mobilization of carbohydrates. PMID- 22197893 TI - Cross-talk between calcium signalling and protein phosphorylation at the thylakoid. AB - The role of protein phosphorylation for adjusting chloroplast functions to changing environmental needs is well established, whereas calcium signalling in the chloroplast is only recently becoming appreciated. The work presented here explores the potential cross-talk between calcium signalling and protein phosphorylation in chloroplasts and provides the first evidence for targets of calcium-dependent protein phosphorylation at the thylakoid membrane. Thylakoid proteins were screened for calcium-dependent phosphorylation by 2D gel electrophoresis combined with phospho-specific labelling and PsaN, CAS, and VAR1, among other proteins, were identified repeatedly by mass spectrometry. Subsequently their calcium-dependent phosphorylation was confirmed in kinase assays using the purified proteins and chloroplast extracts. This is the first report on the protein targets of calcium-dependent phosphorylation of thylakoid proteins and provides ground for further studies in this direction. PMID- 22197895 TI - Role of magnesium chloride on the purity and activity of ovomucin during the isolation process. AB - Purification of ovomucin is still an empirical technique and sometimes insufficient quantities of ovomucin are purified to allow characterization. Here we aimed to investigate the effect of MgCl(2) on the purity and bioactivity of ovomucin during isoelectric precipitation process and to develop an effective protocol to prepare pure ovomucin with high bioactivity. It was found that addition of MgCl(2) is an alternative approach to remove lysozyme from ovomucin, and that the hemagglutination inhibition (HI) activity of ovomucin with MgCl(2) against New Disease Virus (NDV) was about two times higher than the protein without salts. Thus, an improved procedure comprises a precipitation with 0.05 mol/L CaCl(2) followed by precipitation with 0.05 mol/L MgCl(2) was developed for the isolation of ovomucin. Better adhesion property of ovomucin was observed when low concentration of MgCl(2) was added in the designed ELASA test, whereas the adhesion property of the pure ovomucin without salts to NDV was lower. Thus, magnesium (II) plays an important role in the activity of ovomucin, and the alternative method developed in this study may significantly facilitate the further research on the mechanism of ovomucin activity. PMID- 22197894 TI - NO, ROS, and cell death associated with caspase-like activity increase in stress induced microspore embryogenesis of barley. AB - Under specific stress treatments (cold, starvation), in vitro microspores can be induced to deviate from their gametophytic development and switch to embryogenesis, forming haploid embryos and homozygous breeding lines in a short period of time. The inductive stress produces reactive oxygen species (ROS) and nitric oxide (NO), signalling molecules mediating cellular responses, and cell death, modifying the embryogenic microspore response and therefore, the efficiency of the process. This work analysed cell death, caspase 3-like activity, and ROS and NO production (using fluorescence probes and confocal analysis) after inductive stress in barley microspore cultures and embryogenic suspension cultures, as an in vitro system which permitted easy handling for comparison. There was an increase in caspase 3-like activity and cell death after stress treatment in microspore and suspension cultures, while ROS increased in non-induced microspores and suspension cultures. Treatments of the cultures with a caspase 3 inhibitor, DEVD-CHO, significantly reduced the cell death percentages. Stress-treated embryogenic suspension cultures exhibited high NO signals and cell death, while treatment with S-nitrosoglutathione (NO donor) in control suspension cultures resulted in even higher cell death. In contrast, in microspore cultures, NO production was detected after stress, and, in the case of 4-day microspore cultures, in embryogenic microspores accompanying the initiation of cell divisions. Subsequent treatments of stress-treated microspore cultures with ROS and NO scavengers resulted in a decreasing cell death during the early stages, but later they produced a delay in embryo development as well as a decrease in the percentage of embryogenesis in microspores. Results showed that the ROS increase was involved in the stress-induced programmed cell death occurring at early stages in both non-induced microspores and embryogenic suspension cultures; whereas NO played a dual role after stress in the two in vitro systems, one involved in programmed cell death in embryogenic suspension cultures and the other in the initiation of cell division leading to embryogenesis in reprogrammed microspores. PMID- 22197896 TI - Homocysteine and its thiolactone impair plasmin activity induced by urokinase or streptokinase in vitro. AB - Mechanisms of homocysteine (Hcy) contribution to thrombosis are complex and only partly recognized. The available data suggest that the prothrombotic activity of homocysteine may be not only a result of the changes in coagulation process and endothelial dysfunction, but also the dysfunction of fibrinolysis. The aim of the present work was to assess the effects of homocysteine (10-100 MUM mM) and its thiolactone (HTL, 0.1-1 MUM) on plasminogen and plasmin functions in vitro. The amidolytic activity of generated plasmin in Hcy or HTL-treated plasminogen and plasma samples was measured by the hydrolysis of chromogenic substrate. Effects of Hcy and HTL on proteolytic activity of plasmin were monitored electrophoretically, by using of fibrinogen as a substrate. The exposure of human plasma and purified plasminogen to Hcy or HTL resulted in the decrease of urokinase-induced plasmin activity. In plasminogen samples treated with the highest concentration of homocysteine (100 MUM) or thiolactone (1 MUM), the activity of plasmin was inhibited by about 50%. In plasma samples, a reduction of amidolytic activity by about 30% (for 100 MUM Hcy) and 40% (for 1 MUM HTL), was observed. Both Hcy and HTL were also able to diminish the streptokinase-induced proteolytic activity of plasmin. In conclusion, the results obtained in this study demonstrate that Hcy and HTL may affect fibrinolytic properties of plasminogen and plasma, leading to the decrease of plasmin activity. PMID- 22197897 TI - Endothelial nitric oxide and 15-lipoxygenase-1 metabolites independently mediate relaxation of the rabbit aorta. AB - Endothelial 15-lipoxygenase-1 (15-LO-1) metabolites of arachidonic acid (AA), 11,12,15-trihydroxyeicosatrienoic acid (THETA) and 15-hydroxy-11,12 epoxyeicosatrienoic acid (HEETA) and nitric oxide (NO) mediate relaxations to acetylcholine (ACH). However, interactions between NO and the 15-LO-1 pathway have not been explored. Therefore, the effect of physiological and pharmacological concentrations of NO on 15-LO activity and relaxation was studied in rabbit aorta. In indomethacin-treated aortic rings, maximal ACH relaxations of 91.3+/-4.0%, decreased to 54.5+/-3.0% by the NO synthase inhibitor, nitro-l arginine (LNA), to 49.8+/-3% by the guanylate cyclase (GC) inhibitor, 1H [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, to 63.7+/-4.9% by the lipoxygenase (LO) inhibitor, nordihydroguaiaretic acid (NDGA) and were completely inhibited by the combination of LNA and NDGA. AA relaxations were not affected by GC inhibition but were reduced by LO inhibition. The NO donor, dipropylenetriamine-NONOate (DPTA) caused concentration-related relaxations (EC(50)=4.7*10(-6)M). Aortic metabolism of (14)C-AA to THETA and HEETA was not altered by EC(50) concentrations of DPTA but were reduced 10-fold by 10(-3)M DPTA. In LNA-treated aorta, DPTA (3*10(-6)M) caused relaxations of 38.2.5+/-4%. Maximum relaxations to ACH did not differ in the presence and absence 3*10(-6)M DPTA (49.5+/-5% and 44.2+/-4%, respectively). These results indicate that NO and 15-LO-1 act in parallel to mediate ACH relaxations and NO does not alter 15-LO-1 activity. PMID- 22197898 TI - Vascular effects of glycoprotein130 ligands--part I: pathophysiological role. AB - The vessel wall is no longer considered as only an anatomical barrier for blood cells but is recognized as an active endocrine organ. Dysfunction of the vessel wall occurs in various disease processes including atherosclerosis, hypertension, peripheral artery disease, aneurysms, and transplant and diabetic vasculopathies. Different cytokines were shown to modulate the behavior of the cells, which constitute the vessel wall such as immune cells, endothelial cells and smooth muscle cells. Glycoprotein 130 (gp130) is a common cytokine receptor that controls the activity of a group of cytokines, namely, interleukin (IL)-6, oncostatin M (OSM), IL-11, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), IL-27, and neuropoietin (NP). Gp130 and associated cytokines have abundantly diverse functions. Part I of this review focuses on the pathophysiological functions of gp130 ligands. We specifically describe vascular effects of these molecules and discuss the respective underlying molecular and cellular mechanisms. PMID- 22197899 TI - Identification of a new stilbene-derived inducer of paraoxonase 1 and ligand of the Aryl hydrocarbon Receptor. AB - Paraoxonase 1 (PON1) is a high-density lipoprotein-associated enzyme, synthesized in the liver and secreted into the blood. PON1 displays antioxidant properties and is involved in organophosphorous compounds and oxidized lipids degradation. Because of these beneficial effects, pharmacological regulation of PON1 appears to be highly relevant in toxicology and cardiology. Recent studies undertaken on the regulation of the PON1 promoter in our laboratory have identified resveratrol, through its activation of the Aryl hydrocarbon Receptor (AhR), as a putative inducer of PON1. We have tested a new modulator of AhR, (Z)-2,3-bis (4 nitrophenyl)-acrylonitrile, and established that it is a more potent inducer of PON1 at the mRNA, protein and enzymatic activity as compared to resveratrol. It also acts by activating the AhR. However, in contrast with traditional AhR agonists, it does not induce cyp1A1 transcription. (Z)-2,3-bis (4-nitrophenyl) acrylonitrile is therefore a specific AhR modulator targeting PON1. PMID- 22197900 TI - New insights into the pathogenesis of Behcet's disease. AB - Behcet's disease (BD) is a recurrent systemic inflammatory disorder of unknown origin characterized by oral and genital mucous ulcer, uveitis, and skin lesions. Involvement of large vessels, central nervous system (CNS), gastrointestinal tract and thrombotic events are less frequent but can be life threatening. The aim of this review is to provide new insights into the pathogenesis of BD. Over the past year substantial advances have been done in the understanding of the genetic [1,2] and immunology [3] of BD. BD is at the crossroad between autoimmune and autoinflammatory syndromes. In common with autoimmune diseases BD shares class I MHC association. However, in contrast to autoimmune disorders, BD has clinical features that seem to be mostly autoinflammatory. The pathogenesis of BD is still unknown, but major determinants of the genetic and immune system abnormalities have been reported recently. Triggering infectious factors are supposed to participate in the outbreak of BD in genetically predisposed patients. Two recent large genome-wide association study (GWAS) conducted in Turkey and Japan reported association between single nucleotide polymorphism (SNP) of interleukin (IL)-10 and IL-23R/IL-12RB2 genes and BD. New insights into the perturbations of T cell homeostasis of BD recently emerged. We have recently demonstrated the promotion of Th17 responses and the suppression of regulatory T cells (Tregs) that were driven by interleukin (IL)-21 production and that correlates with BD activity. Inflammatory cells within BD inflammatory lesions included mostly neutrophils, Th1 and Th17 cells, and cytotoxic CD8+ and gammadelta T cells. Altogether, the recent progresses in the knowledge of BD pathogenesis pave the way for innovative therapy. PMID- 22197901 TI - Cytokines and Behcet's disease. AB - Behcet's Disease (BD) is a systemic vasculitis of unknown etiology. Increasing studies find that a sophisticated interlacing cytokine network is closely implicated in the onset, evolution and even organ damages of the disease. Cytokines involved can be categorized as Th1 type, Th2 type, Th17 type, chemokines and other proinflammatory cytokines, etc. The vicious cycle of cytokine network plays a substantial role in the disease pathogenesis and even in organ lesions, and might be disorganized by blocking one of the key links of the cytokines, which in turn may provide essential clues to outlook the target therapy regimen of cytokine agents in BD. There have been a number of case reports of the positive efficacies of cytokine (and cytokine blocker) agents including Infiximab (Human murine chimeric Anti-TNF alpha monoclonal antibody), Anakinra (recombinant, non-glycosylated human IL1 receptor antagonist) etc in BD. IFN-alpha had been used clinically in treating BD with uveitis with beneficial efficacy ever since the 1980s. The studies to date suggested that IL6, IP10 are involved in BD with nervous system lesions, IL17, IL18 are relevant to the superimposed uveitis in patients with BD. Some cytokines i.e. IL8, RANTES, MIP 1alpha are associated with the disease activity, whereas others are exemplified by that of IL10, whose level shows negative relevance to the disease activity, might be potentially cytokine of protecting effect. According to the related genetic study, the SNPs of numerous cytokines including IL1, TNFalpha, IFNgamma, IL12, and IL18 are pertinent to BD. The recent GWAS (Genome Wide Association Studies) demonstrated that SNPs in the IL10 and IL23R-IL12RB2 region are associated with the disease. Most studies nowadays are confined within the cytokines in the peripheral blood levels, owing to the potentially significant roles of certain cytokines in local lesions. It warrants further in-depth study to address this issue. Moreover, it deserves multi-centre study considering the unique geographical "silk road" display picture of the disease. PMID- 22197902 TI - Vague abdominal discomfort for 5 years and a large upper abdominal mass in a 45 year-old woman. PMID- 22197903 TI - Blueberry extract prolongs lifespan of Drosophila melanogaster. AB - Blueberry possesses greater antioxidant capacity than most other fruits and vegetables. The present study investigated the lifespan-prolonging activity of blueberry extracts in fruit flies and explored its underlying mechanism. Results revealed that blueberry extracts at 5mg/ml in diet could significantly extend the mean lifespan of fruit flies by 10%, accompanied by up-regulating gene expression of superoxide dismutase (SOD), catalase (CAT) and Rpn11 and down-regulating Methuselah (MTH) gene. Intensive H(2)O(2) and Paraquat challenge tests showed that lifespan was only extended in Oregon-R wild type flies but not in SOD(n108) or Cat(n1) mutant strains. Chronic Paraquat exposure shortened the maximum survival time from 73 to 35days and decreased the climbing ability by 60% while blueberry extracts at 5mg/ml in diet could significantly increase the survival rate and partially restore the climbing ability with up-regulating SOD, CAT, and Rpn11. Furthermore, gustatory assay demonstrated that those changes were not due to the variation of food intake between the control and the experimental diet containing 5mg/ml blueberry extracts. It was therefore concluded that the lifespan-prolonging activity of blueberry extracts was at least partially associated with its interactions with MTH, Rpn11, and endogenous antioxidant enzymes SOD and CAT. PMID- 22197904 TI - The irreversible pan-HER inhibitor PF00299804 alone or combined with gemcitabine has an antitumor effect in biliary tract cancer cell lines. AB - Biliary tract cancer (BTC) is associated with poor survival and unresponsiveness to chemotherapy. Targeted therapies for BTC have been studied, and HER family members are promising therapeutic targets in BTC. In this study, we evaluated the efficacy of PF00299804, an irreversible pan-HER inhibitor, in eight BTC cell lines alone or combined with gemcitabine. PF00299804 potently inhibited the growth of two cell lines (SNU308 and SNU478) out of the eight BTC cell lines as a single agent. PF00299804 blocked HER family and downstream signaling pathways, inducing G1 arrest or apoptosis. Moreover, PF00299804 exerted synergistic effects with gemcitabine in seven of the eight BTC cell lines, possibly through the regulation of the genes involved in the response to gemcitabine, such as TS (thymidylate synthase), RRM1 (ribonucleotide reductase), and MAGEH1, which is negatively correlated with gemcitabine sensitivity. Our results support the need for further study of PF00299804 alone or combined with gemcitabine for the treatment of BTC. PMID- 22197905 TI - Counterion condensation theory of attraction between like charges in the absence of multivalent counterions. AB - There is abundant experimental evidence suggesting the existence of attractive interactions among identically charged polyelectrolytes in ordinary salt solutions. The presence of multivalent counterions is not required. We review the relevant literature in detail and conclude that it merits more attention than it has received. We discuss also some recent observations of a low ionic strength attraction of negatively charged DNA to the region of a negatively charged glass nanoslit where the floor of the nanoslit meets the walls, again in the absence of multivalent ions. On the theoretical side, it has become clear that purely electrostatic interactions require the presence of multivalent counterions if they are to generate like-charge attraction. Any theory of like-charge attraction in the absence of multivalent counterions must therefore contain a non electrostatic component. We point out that counterion condensation theory, which has predicted like-charge polyelectrolyte attraction in an intermediate range of distances in ordinary 1:1 salt conditions, contains both electrostatic and non electrostatic elements. The non-electrostatic component of the theory is the modeling constraint that the counterions fall into two explicit populations, condensed and uncondensed. As reviewed in the paper, this physically motivated constraint is supported by strong experimental evidence. We proceed to offer an explanation of the nanoslit observations by showing in an idealized model that the line of intersection of two intersecting planes is a virtual polyelectrolyte. Since we have previously developed a counterion condensation theory of attraction of two like-charged polyelectrolytes, our suggestion is that the DNA is attracted to the virtual polyelectrolytes that may be located in the nanoslit where floor meets walls. We present the detailed calculations needed to document this suggestion: an extension of previous theory to the case of polyelectrolytes with like but not identical charges; the demonstration of counterion condensation on a plane with bare charge density greater than an explicitly exhibited critical value; a calculation of the free energy of the plane; a calculation of the interaction of a line charge polyelectrolyte with a like-charged plane; and the detailed demonstration that the line of intersection of two planes is a virtual polyelectrolyte. PMID- 22197906 TI - Dynamics of semi-flexible tethered sheets : a simulation study using stochastic rotation dynamics. AB - The dynamics of a semi-flexible sheet or tethered membrane in a solvent is studied using the method of stochastic rotation dynamics. Hydrodynamic interactions between different parts of the sheet are naturally included in this method. We confirm the scaling law for the radius of gyration versus sheet size predicted for a self-avoiding tethered membrane. The mean-square displacement shows both sub-diffusive and diffusive behavior similar to linear polymers. In the intermediate scattering function the sub-diffusive behavior appears as stretched exponential which we reproduce in our simulations. Thereby, we confirm an early prediction between the roughness and the sub-diffusion exponent derived from Zimm dynamics (E. Frey, D.R. Nelson, J. Phys. I 1, 1715 (1991)). Finally, we show that the diffusion coefficient of the square sheet is inversely proportional to the edge length of the sheet again in good agreement with theoretical predictions. PMID- 22197907 TI - Dielectric and molecular dynamics study of the secondary relaxations of poly(styrene-co-methylmethacrylate) copolymers: Influence of the molecular architecture. AB - The effect of the structure of copolymers (random, alternate or diblock) on their dynamics has been studied by dielectric spectroscopy. Six copolymers of styrene and methyl methacrylate (three diblocks, one alternate and two random) have been studied. The results show that the sub- T (g) transitions of the diblock samples can be described by one asymmetric Havriliak-Negami (HN) function, while two are necessary for the rest of the copolymers (beta and gamma relaxations). The characteristic times of the sub- T (g) relaxations show an Arrhenius temperature dependence and there is a strong coupling of the alpha and beta relaxations at high temperatures. The deconvolution of the merging relaxations has been made in the framework of the Williams Ansatz set out in terms of Havriliak-Negami distributions. Because the 2D (2)H-NMR results excluded any significant contribution from the rotation of the methoxy group of the methacrylate group around the C-OCH(3) bond, the gamma relaxation may be assigned to the rotation of the methyl methacrylate group in a styrene-rich environment. The Molecular Dynamics simulations of a poly(methyl methacrylate) homopolymer and of the alternate copolymer are in qualitative agreement with the experimental results, although they predict smaller values for the activation energy of the sub- T (g) relaxations. PMID- 22197908 TI - Dynamical diagram and scaling in polymer driven translocation. AB - By analyzing the real space non-equilibrium dynamics of polymers, we elucidate the physics of driven translocation and propose its dynamical scaling scenario analogous to that in the surface growth phenomena. We provide a detailed account of the previously proposed tension-propagation formulation and extend it to cover the broader parameter space relevant to real experiments. In addition to a near equilibrium regime, we identify three distinct non-equilibrium regimes reflecting the steady-state property of a dragged polymer with finite extensibility. Finite size effects are also pointed out. These elements are shown to be crucial for the appropriate comparison with experiments and simulations. PMID- 22197909 TI - Stress distribution of faceted particles in a silo after its partial discharge. AB - We present experimental and numerical results of the effect that a partial discharge has on the morphological and micro-mechanical properties of non spherical, convex particles in a silo. The comparison of the particle orientation after filling the silo and its subsequent partial discharge reveals important shear-induced orientation, which affects stress propagation. For elongated particles, the flow induces an increase in the packing disorder which leads to a reduction of the vertical stress propagation developed during the deposit generated prior to the partial discharge. For square particles, the flow favors particle alignment with the lateral walls promoting a behavior opposite to the one of the elongated particles: vertical force transmission, parallel to gravity, is induced. Hence, for elongated particles the flow developed during the partial discharge of the silo leads to force saturation with depth whereas for squares the flow induces hindering of the force saturation observed during the silo filling. PMID- 22197910 TI - Effects of divided attention on swallowing in persons with idiopathic Parkinson's disease. AB - The purpose of this study was to determine whether attentional resources are involved in swallowing in persons with idiopathic Parkinson's disease, and if so, in which phase(s) of swallowing. The approach involved a dual-task, reaction time (RT) paradigm using ten participants with Parkinson's disease. Single-task baseline measures were obtained for durations of the anticipatory phase and oropharyngeal phase of swallowing and RTs were obtained for nonword auditory stimuli. A dual-task then required participants to swallow 5 ml of water from an 8-oz. cup while listening for a target nonword presented auditorily during the anticipatory or oropharyngeal phase. Target stimuli were randomized across baseline and dual-task trials. Durations of the anticipatory and oropharyngeal phases of swallowing and RTs during baseline and dual-task trials were determined. Results showed a nonsignificant change in speed of completion for both the anticipatory phase and the oropharyngeal phase of swallowing during dual task trials. However, there was a statistically significant increase in RT during the anticipatory phase during the dual-task condition. RT during the oropharyngeal phase remained unaffected. Given a need for additional research using more complex competing tasks, these data on attention are consistent with earlier claims of an automatic, nonresource-demanding, oropharyngeal swallowing mechanism that is preserved for persons with early-to-mid-stage Parkinson's disease. Clinical implications of these data suggest that disruptive environmental stimuli to individuals with early-to-mid-stage Parkinson's disease may alter feeding but have little effect on the oropharyngeal swallow. PMID- 22197911 TI - GluN2B-containing NMDA receptors as possible targets for the neuroprotective and antidepressant effects of fluoxetine. AB - Accumulating evidence has indicated the involvement of glutamatergic neurotransmission in the pathophysiology of excitotoxicity and in the mechanism of action of antidepressants. We have previously shown that tricyclic desipramine and the selective serotonin reuptake inhibitor fluoxetine inhibit NMDA receptors (NMDARs) in the clinically relevant, low micromolar concentration range. As the different subtypes of NMDARs are markedly different in their physiological and pathological functions, our aim was to investigate whether the effect of antidepressants is subtype-specific. Using whole-cell patch-clamp recordings in rat cortical cell cultures, we studied the age-dependence of inhibition of NMDA induced currents after treatment with desipramine and fluoxetine, as the expression profile of the NMDAR subtypes changes as a function of days in vitro. We also investigated the inhibitory effect of these antidepressants on NMDA induced currents in HEK 293 cell lines that stably expressed rat recombinant NMDARs with GluN1a/GluN2A or GluN1a/GluN2B subunit compositions. The inhibitory effect of desipramine was not age-dependent, whereas fluoxetine displayed a continuously decreasing inhibitory profile, which was similar to the GluN1/GluN2B subtype-selective antagonist ifenprodil. In HEK 293 cells, desipramine equally inhibited NMDA currents in both cell lines, whereas fluoxetine showed an inhibitory effect only in cells that expressed the GluN1/GluN2B subtype. Our data show that fluoxetine is a selective inhibitor of GluN2B-containing NMDARs, whereas desipramine inhibits both GluN1/GluN2A and GluN1/GluN2B subtypes. As the clinical efficacy of these drugs is very similar, the putative NMDAR-associated therapeutic effect of antidepressants may be mediated only via inhibition of the GluN2B-containing subtype. The manifestation of the GluN1/GluN2B-selectivity of fluoxetine suggests the neuroprotective potential for this drug in both acute and chronic neurodegenerative disorders. PMID- 22197912 TI - Generating recombinant C-terminal prion protein fragments of exact native sequence. AB - Transmissibility and distinctive neuropathology are hallmark features of prion diseases differentiating them from other neurodegenerative disorders, with pathogenesis and transmission appearing closely linked to misfolded conformers (PrP(Sc)) of the ubiquitously expressed cellular form of the prion protein (PrP(C)). Given the apparent pathogenic primacy of misfolded PrP, the utilisation of peptides based on the prion protein has formed an integral approach for providing insights into misfolding pathways and pathogenic mechanisms. In parallel with studies employing prion peptides, similar approaches in other neurodegenerative disorders such as Alzheimer Disease, have demonstrated that differential processing of parent proteins and quite minor variations in the primary sequence of cognate peptides generated from the same constitutive processing (such as Abeta1-40 versus Abeta1-42 produced from gamma-secretase activity) can be associated with very different pathogenic consequences. PrP(C) also undergoes constitutive alpha- or beta-cleavage yielding C1 (residues 112-231 human sequence) or C2 (residues 90-231), respectively, with the full cell biological significance of such processing unresolved; however, it is noteworthy that in prion diseases, such as Creutzfeldt-Jakob disease (CJD) and murine models, the moderately extended C2 fragment predominates in the brain suggesting that the two cleavage events and the consequent C-terminal fragments may differ in their pathogenic significance. Accordingly, studies characterising biologically relevant peptides like C1 and C2, would be most valid if undertaken using peptides completely free of any inherent non-native sequence that arises as a by-product of commonly employed recombinant production techniques. To achieve this aim and thereby facilitate more representative biophysical and neurotoxicity studies, we adapted the combination of high fidelity Taq TA cloning with a SUMO Hexa-His tag-type approach, incorporating the SUMO protease step. This technique consistently produced sufficient yields (~10 mg/L) of high purity peptides (>95%) equating to C1 and C2 of exact native primary sequence in the alpha-helical conformation suitable for biological and biophysical investigations. PMID- 22197913 TI - Molecular pharmacology of human NMDA receptors. AB - N-methyl-d-aspartate (NMDA) receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission. NMDA receptors are also important drug targets that are implicated in a number of pathophysiological conditions. To facilitate the transition from lead compounds in pre-clinical animal models to drug candidates for human use, it is important to establish whether NMDA receptor ligands have similar properties at rodent and human NMDA receptors. Here, we compare amino acid sequences for human and rat NMDA receptor subunits and discuss inter-species variation in the context of our current knowledge of the relationship between NMDA receptor structure and function. We summarize studies on the biophysical properties of human NMDA receptors and compare these properties to those of rat orthologs. Finally, we provide a comprehensive pharmacological characterization that allows side-by-side comparison of agonists, un-competitive antagonists, GluN2B-selective non-competitive antagonists, and GluN2C/D-selective modulators at recombinant human and rat NMDA receptors. The evaluation of biophysical properties and pharmacological probes acting at different sites on the receptor suggest that the binding sites and conformational changes leading to channel gating in response to agonist binding are highly conserved between human and rat NMDA receptors. In summary, the results of this study suggest that no major detectable differences exist in the pharmacological and functional properties of human and rat NMDA receptors. PMID- 22197914 TI - Role for monoaminergic systems in the antidepressant-like effect of ethanol extracts from Hemerocallis citrina. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hemerocallis citrina, a traditional herbal medicine, has been used for the improvement of emotions in Eastern-Asia countries. AIM OF THE STUDY: Herein, we explored the antidepressant-like effect and its monoaminergic mechanism of the ethanol extracts from Hemerocallis citrina (HCE). MATERIALS AND METHODS: Effect of HCE (90, 180 and 360 mg/kg, p.o.) on the immobility time was assessed in the mouse forced swim test (FST) and tail suspension test (TST), and locomotor activity was evaluated in the open-field test (OFT). Additionally, the monoamine neurotransmitters serotonin (5-HT), noradrenaline (NA) and dopamine (DA) levels involved in the antidepressant-like effect of HCE were also measured in the mice brain regions of frontal cortex and hippocampus. RESULTS: HCE (90, 180 and 360 mg/kg, p.o.) administration significantly reduced the immobility time in both the FST and TST without accompanying changes in locomotor activity in the OFT. The pretreatment of mice with WAY 100635 (0.1 mg/kg, s.c., a 5-HT(1A) receptor antagonist), cyproheptadine (3 mg/kg, i.p., a 5-HT(2) receptor antagonist), prazosin (62.5 MUg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2) adrenoceptor antagonist), propranolol (5 mg/kg, i.p., a beta-adrenoceptor antagonist) or sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist), but not SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) prevented the antidepressant-like effect of HCE (360 mg/kg, p.o.) in the TST. In addition, HCE enhanced 5-HT and NA levels in the frontal cortex and hippocampus as well as elevated DA levels in the frontal cortex. CONCLUSION: The results indicate that the antidepressant-like effect of HCE is dependent on the serotonergic (5-HT(1A) and 5-HT(2) receptors), noradrenergic (alpha(1)-, alpha(2) and beta-adrenoceptors) and dopaminergic (D(2) receptor) systems as well as the elevation of 5-HT, NA and DA levels in the mouse brain. PMID- 22197915 TI - Participation of hippocampal cholinergic system in memory persistence for inhibitory avoidance in rats. AB - Memory persistence needs a new event of consolidation 12h after the acquisition. We investigated the role of the cholinergic activity on the persistence of memory. For this purpose, we performed the treatments 9 or 12h after acquisition and the memory tested 2 or 7 days after inhibitory avoidance (IA) training. Here we report that activity of medial septum, by transitorily inactivating this structure with lidocaine 12h after IA training, is essential for memory persistence at the 7th day, but not for the formation at the 2nd day. We also report that muscarinic and nicotinic cholinergic receptors of CA1 area are engaged on memory persistence. Since scopolamine (mAChRs antagonist) and mecamylamine (nAChRs blocker) infusions, 12h post-training, demonstrated impairment on long term memory (LTM), persistence on the 7th day but no effect on LTM formation was found on the 2nd day in the IA test. The same effects were found with pirenzepine, an M1 antagonist. No effects on the formation and persistence of memory on the 2nd and 7th days were demonstrated after DHbetaE infusions (nAChRs subtype antagonist alpha4beta2, alpha3beta2). These findings suggest that mAChR and nAChR at the CA1 area, and also MS activation, are required for the persistence of memory. PMID- 22197929 TI - A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy. AB - We performed a two-stage genome-wide association study of IgA nephropathy (IgAN) in Han Chinese, with 1,434 affected individuals (cases) and 4,270 controls in the discovery phase and follow-up of the top 61 SNPs in an additional 2,703 cases and 3,464 controls. We identified associations at 17p13 (rs3803800, P = 9.40 * 10( 11), OR = 1.21; rs4227, P = 4.31 * 10(-10), OR = 1.23) and 8p23 (rs2738048, P = 3.18 * 10(-14), OR = 0.79) that implicated the genes encoding tumor necrosis factor (TNFSF13) and alpha-defensin (DEFA) as susceptibility genes. In addition, we found multiple associations in the major histocompatibility complex (MHC) region (rs660895, P = 4.13 * 10(-20), OR = 1.34; rs1794275, P = 3.43 * 10(-13), OR = 1.30; rs2523946, P = 1.74 * 10(-11), OR = 1.21) and confirmed a previously reported association at 22q12 (rs12537, P = 1.17 * 10(-11), OR = 0.78). We also found that rs660895 was associated with clinical subtypes of IgAN (P = 0.003), proteinuria (P = 0.025) and IgA levels (P = 0.047). Our findings show that IgAN is associated with variants near genes involved in innate immunity and inflammation. PMID- 22197930 TI - Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing. AB - We sequenced eight melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, we found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9. Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggest that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W333* variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma. PMID- 22197931 TI - Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. AB - We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1. PMID- 22197932 TI - Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. AB - Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 * 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 * 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 * 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis. PMID- 22197933 TI - A genome-wide association study in Chinese men identifies three risk loci for non obstructive azoospermia. AB - Non-obstructive azoospermia (NOA) is one of the most severe forms of male infertility. Its pathophysiology is largely unknown, and few genetic influences have been defined. To identify common variants contributing to NOA in Han Chinese men, we performed a three-stage genome-wide association study of 2,927 individuals with NOA and 5,734 controls. The combined analyses identified significant (P < 5.0 * 10(-8)) associations between NOA risk and common variants near PRMT6 (rs12097821 at 1p13.3: odds ratio (OR) = 1.25, P = 5.7 * 10(-10)), PEX10 (rs2477686 at 1p36.32: OR = 1.39, P = 5.7 * 10(-12)) and SOX5 (rs10842262 at 12p12.1: OR = 1.23, P = 2.3 * 10(-9)). These findings implicate genetic variants at 1p13.3, 1p36.32 and 12p12.1 in the etiology of NOA in Han Chinese men. PMID- 22197934 TI - Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. AB - Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS. In one kindred, we confirmed the de novo occurrence of the mutation. Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome. In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function. As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis. PMID- 22197936 TI - Diagnostic value of anti-deamidated gliadin peptide IgG antibodies for celiac disease in children and IgA-deficient patients. AB - OBJECTIVES: The aim of the study was to analyze the diagnostic performance of anti-deamidated gliadin peptide (dGp) immunoglobulin (Ig) G and IgA regarding the age at celiac disease (CD) diagnosis and the anti-dGp IgG usefulness for diagnosing CD IgA-deficient patients. METHODS: Anti-dGp IgG and IgA and anti native gliadin (nGlia) IgA were determined by enzyme fluoroimmunoassay in 100 newly diagnosed anti-tissue transglutaminase (tTG) IgA-positive pediatric and adult patients with CD and in 100 age-matched patients with other digestive pathologies. Anti-dGp IgG was evaluated in 6 CD IgA-deficient patients. RESULTS: When analyzing all of the patients, the anti-dGp IgG assay showed higher diagnostic accuracy (area under receiver operating characteristic curve), specificity, and positive predictive value than anti-dGp IgA and anti-nGlia IgA. All of the diagnostic parameters corresponding to anti-dGp IgG reached the same values as anti-tTG IgA in children 7 years or younger. In older patients, both anti-dGp isotypes showed an inverse behavior, IgG having a higher specificity and positive predictive value but a lower sensitivity and negative predictive value than IgA. Anti-dGp levels were associated with the severity of intestinal lesions, and an inverse association was found regarding age at diagnosis. Both anti-dGp IgG and IgA were found to be positive in the 9 patients with minimal intestinal changes included in the study. All of the patients with CD with IgA deficiency were positive for anti-dGp IgG. CONCLUSIONS: The diagnostic performance of anti-dGp depends on the antibody isotype and on the age at CD diagnosis, anti-dGp IgG being a serological marker at least as useful as anti-tTG IgA for detecting CD in children ages 7 years or younger. Our data also indicate that anti-dGp IgG can improve the diagnosis of IgA-deficient patients. PMID- 22197935 TI - Th17 cell cytokine secretion profile in host defense and autoimmunity. AB - OBJECTIVE AND DESIGN: The goal of this review is to examine the effector functions of Th17 cells in host defense and autoimmunity. MATERIAL: Published literature on Th17 cells was reviewed with a focus on the secreted products that mediate effector activities of these cells. RESULTS: Th17 cells secrete an array of cytokines that contribute to host defense and that bridge the innate and adaptive arms of the immune response. When this subset of T cells is dysregulated, autoimmune phenomena develop that contribute to the manifestations of many autoimmune diseases. CONCLUSIONS: Th17 cells are positioned at a crossroads between innate and adaptive immunity and provide mediators that are essential for host defense. Current interest in harnessing this system for treatment of autoimmune disease will be challenged by the need to avoid abrogating these many protective functions. PMID- 22197937 TI - Congenital hepatic fibrosis and autosomal recessive polycystic kidney disease. AB - OBJECTIVES: The published natural history of congenital hepatic fibrosis (CHF) was examined to inform clinical decision making in autosomal recessive polycystic kidney disease (ARPKD). METHODS: A systematic literature search of the data on CHF, ARPKD, Caroli disease, Caroli syndrome, and type V choledochal cyst was performed to extract data related to portal hypertension, infection, malignancy, mortality, and transplantation. RESULTS: Information related to 1230 patients with CHF was extracted from 155 articles. Median and mean age at diagnosis were 2 and 11.2 years, respectively. Median and mean time followed after diagnosis were 5.0 and 7.5 years, respectively (range 0-38 years). Sequelae of portal hypertension (n = 409), cholangitis (n = 152), and malignancy (n = 21) were noted. The nature of the portal hypertension was similar to that in other pediatric conditions (164 with varices, 74 bleeding varices, 81 underwent portosystemic shunting). Documented cholangitis was fatal in 3 of 23 children who were infected after renal transplantation. Twenty-one patients developed hepatobiliary cancer, with the majority having cholangiocarcinoma (n = 19). Cholangiocarcinoma (CCA) was predominant in individuals older than 40 years with either Caroli syndrome or isolated CHF, not ARPKD (median and mean age at CCA diagnosis were 70.3 and 60.1 years, respectively; range 33-75 years). There was a relative paucity of data on combined liver-kidney transplantation. CONCLUSIONS: Clinical decision making in ARPKD should reflect an understanding of the potential issues emanating from CHF. Accepted pediatric specific approaches to portal hypertension are warranted but must take into consideration the stage of renal insufficiency and potential plans for renal transplantation. Cholangitis is a major issue and necessitates anticipatory guidance and awareness. CCA, although a dreaded complication, does not appear to be a major issue during childhood. The indications for liver and combined liver-kidney transplantation are controversial and warrant further analysis. PMID- 22197938 TI - Methotrexate modulates tight junctions through NF-kappaB, MEK, and JNK pathways. AB - OBJECTIVES: Chemotherapy often induces intestinal mucositis, which is associated with an increase in intestinal permeability; however, underlying mechanisms remain incompletely understood. Thus, we aimed to study the regulation of 3 tight junction (TJ) proteins, claudin-1, occludin, and zonula occludens-1, after anticancer treatment. METHODS: Methotrexate (MTX) was subcutaneously injected for 3 consecutive days in Sprague-Dawley rats to induce intestinal mucositis and was applied on Caco-2 cell monolayers. TJ protein expression and cellular distribution were studied by Western blot and microscopy, respectively. In Caco-2 cells, the paracellular permeability was evaluated by both transepithelial electrical resistance and flux of fluorescein isothiocyanate-dextran marker. Cytokine production and signaling pathways were also assessed. RESULTS: In MTX treated rats, the cellular distribution of the 3 TJ proteins was altered and claudin-1 and occludin expression was reduced during the acute phase of mucositis compared with controls. During the recovery phase, these parameters were restored. In vitro, MTX treatment led to an increase in proinflammatory cytokine production at the apical side but did not affect Caco-2 cell apoptosis and necrosis. Increase in paracellular permeability was associated with altered occludin and zonula occludens-1 expression and cellular distribution. All of these alterations were prevented by MEK1 and 2, JNK, and NF-kappaB inhibitors. CONCLUSIONS: MTX treatment induced an increase in intestinal permeability partially related to alteration of TJs protein expression and cellular distribution that may be mediated by MAPK and NF-kappaB pathways. These are potential targets to limit the adverse effects of chemotherapy. PMID- 22197939 TI - Taste perception and food choices. AB - OBJECTIVES: The extent to which variation in taste perception influences food preferences is, to date, controversial. Bitterness in food triggers an innate aversion that is responsible for dietary restriction in children. We investigated the association among genetic variations in bitter receptor TAS2R38 and food choices in healthy children in the Mediterranean area, to develop appropriate tools to evaluate the relation among genetic predisposition, dietary habits, and feeding disorders. The aims of the study were to get a first baseline picture of taste sensitivity in healthy adults and their children and to explore taste sensitivity in a preliminary sample of obese children and in samples affected by functional gastrointestinal diseases. METHODS: Individuals (98 children, 87 parents, 120 adults) were recruited from the general population in southern Italy. Bitterness sensitivity was assessed by means of a suprathreshold method with 6-propyl-2-thiouracil. Genomic DNA from saliva was used to genotype individuals for 3 polymorphisms of TAS2R38 receptor, A49P, A262 V, and V296I. Food intake was assessed by a food frequency questionnaire. RESULTS: Children's taste sensation differed from that of adults: we observed a higher frequency of supertasters among children even in the mother-child dyads with the same diplotypes. Among adults, supertaster status was related with proline-alanine valine (taster allele) homozygous haplotype, whereas supertaster children were mainly heterozygous. Regarding the food choices, we found that a higher percentage of taster children avoided bitter vegetables or greens altogether compared with taster adults. Taster status was also associated with body mass index in boys. CONCLUSIONS: Greater sensitivity to 6-propyl-2-thiouracil predicts lower preferences for vegetables in children, showing an appreciable effect of the genetic predisposition on food choices. None of the obese boys was a supertaster. PMID- 22197940 TI - Parenteral plant sterols and intestinal failure-associated liver disease in neonates. AB - OBJECTIVES: We prospectively evaluated incidence of prolonged (>28 days) parenteral nutrition (PN), associated complications, and significance of parenteral plant sterols (PS) in neonatal intestinal failure-associated liver disease (IFALD) compared with children. METHODS: We recruited 28 neonates (mean age 50 days, range 28-126) and 11 children (6.9 y, 2.1-16.6) in all of Finland. Patients underwent repeated measurements of serum cholesterol, noncholesterol sterols, including PS, cholestanol and cholesterol precursors, and liver biochemistry during and 1 month after discontinuation of PN. Healthy matched neonates (n=10) and children (n=22) served as controls. RESULTS: IFALD occurred more frequently among neonates (63%) than children (27%; P<0.05). Ratios of serum PS, including stigmasterol, sitosterol, avenasterol, and campesterol, and total PS were increased among neonates compared with healthy controls and children on PN by 2- to 22- and 2- to 5-fold (P<0.005), respectively. Neonates with IFALD had significantly higher ratios of serum PS and cholestanol compared with neonates without IFALD (P<0.05). Total duration of PN associated with serum cholestanol, stigmasterol, avenasterol, alanine aminotransferase, and aspartate aminotransferase (r=0.472-0.636, P<0.05). Cholestanol and individual serum PS, excluding campesterol, reflected direct bilirubin (r=0.529-0.688, P<0.05). IFALD persisted after discontinuation of PN in 25% of neonates with 4.2- and 2.2-times higher ratios of serum stigmasterol and cholestanol compared with neonates without IFALD (P<0.05). CONCLUSIONS: Frequent occurrence of IFALD among neonates on PN displays an association to duration of PN and markedly increased serum PS, especially stigmasterol, in comparison to healthy neonates and children on PN. Striking accumulation of parenteral PS may contribute to IFALD among neonates. PMID- 22197941 TI - Microvillus inclusion disease: antenatal ultrasound and phenotypic severity. PMID- 22197942 TI - Factors associated with nonadherence to thiopurines in adolescent and adult patients with inflammatory bowel disease. AB - OBJECTIVES: We hypothesised that nonadherence to thiopurines is more common in adolescents than in adults with inflammatory bowel disease. METHODS: We sought factors associated with thiopurine nonadherence defined by thiopurine metabolite levels. RESULTS: Multivariate logistic regression confirmed that adolescents (odds ratio [OR] 4.6 [95% confidence interval [CI] 1.9-11.5]; P < 0.01) compared with adults, patients with Crohn disease (OR 3.3 [CI 1.1-10.5] P = 0.04) compared with ulcerative colitis, and patients living in more socially deprived areas (OR 1.03 [CI 1.0-1.1] P = 0.02) were more likely to be nonadherent to thiopurines. CONCLUSIONS: Adolescents are more frequently nonadherent than adults: prospective studies are required to determine the reasons for nonadherence in adolescents. PMID- 22197943 TI - Drugs and tight junctions: adverse effects and opportunities for new therapeutic approaches. PMID- 22197945 TI - Severe erosive hemorrhagic gastritis in a pediatric patient. PMID- 22197944 TI - STAT3 genotypic variation and cellular STAT3 activation and colon leukocyte recruitment in pediatric Crohn disease. AB - OBJECTIVES: Genotypic variation in signal transducer and activator of transcription 3 (STAT3) increases risk for inflammatory bowel disease (IBD), and STAT3-dependent inflammatory networks are induced in the colon in these patients. We hypothesized that STAT3 "A" risk allele carriage would be associated with increased cellular STAT3 activation and colon leukocyte recruitment. METHODS: Colonic expression of genes regulating STAT3 signaling and leukocyte recruitment and function was measured in pediatric patients with Crohn disease (CD) stratified by STAT3 genotype. The frequency of colonic pSTAT3* and CXCR2* neutrophils was determined using immunohistochemistry. STAT3 tyrosine phosphorylation (pSTAT3) was measured in circulating leukocytes by flow cytometry, and mechanisms regulating STAT3 activation were tested in IBD Epstein Barr virus (EBV)-transformed lymphocytes (EBL). RESULTS: Colonic expression of interleukin 6 (IL-6), the STAT3 target gene SOCS3, the neutrophil chemoattractants IL-8, CXCL1, and CXCL3, and the neutrophil products S100A8, S100A9, and S100A12 were increased in patients carrying the STAT3 "A" risk allele. The frequency of neutrophils expressing the cognate receptor for IL-8, CXCR2, was increased in colonic biopsies from patients carrying the risk allele, and the frequency of pSTAT3* or CXCR2* neutrophils correlated with histologic severity. The frequency of CD4 lymphocytes and granulocytes expressing pSTAT3 was increased in patients carrying the STAT3 "A" risk allele. EBLs from patients carrying the STAT3 "A" risk allele exhibited increased basal and IL-6-stimulated STAT3 tyrosine phosphorylation, increased transcription of STAT3 and SOCS3 after IL-6 stimulation, and increased membrane localization of the IL-6 receptor, GP130, and Janus-associated kinase 2. CONCLUSIONS: The STAT3 "A" risk allele is associated with increased cellular STAT3 activation and upregulation of pathways that promote recruitment of CXCR2* neutrophils to the gut. PMID- 22197947 TI - Intestinal rehabilitation and bowel reconstructive surgery: improved outcomes in children with short bowel syndrome? PMID- 22197946 TI - Correlation between IgA tissue transglutaminase antibody ratio and histological finding in celiac disease. AB - OBJECTIVES: Positivity of both immunoglobulin A anti-tissue transglutaminase (TTG) and anti-endomysium antibodies (EMA) has a positive predictive value of nearly 100% for celiac disease (CD). The objective of the present study was to evaluate whether patients of any age, with high pretest probability of CD and high titre of anti-TTG and EMA positivity, have a high probability of intestinal damage and may not require the biopsy for final diagnosis. METHODS: A retrospective analysis of 412 consecutively referred patients, age range 10 months to 72 years, who underwent small-bowel biopsy for suspicion of CD and positivity to both anti-TTG and EMA, was performed at 4 Italian centers. Biopsies were evaluated independently by 2 pathologists using Marsh modified classification; in cases of dissimilar results, a third pathologist examined the biopsy. The final histological finding diagnosis was expressed as the prevalent or highest score assigned by the pathologist board. RESULTS: Three hundred ninety six patients (96.1%) had histological findings consistent with CD (grade 2 and 3a, 3b, or 3c of modified Marsh classification). An anti-TTG ratio >= 7 was able to identify with the 3 assays used (Celikey, anti-TTG immunoglobulin A, EuTTG) all of the patients with significant mucosal damage (Marsh >= 2) independent of age and sex; specificity and positive predictive value were 100%. An anti-TTG ratio >20 was more specific (99.8%) for identification of patients with villous atrophy (Marsh 3 a, b, or c). CONCLUSIONS: Patients with positivity of anti-TTG >= 7-fold cutoff, confirmed by positivity to EMA, have a high-degree probability of duodenal damage. In selected conditions, a duodenal biopsy may be avoided and a confirmed greatly positive anti-TTG result could be the basis to prescribe a gluten-free diet. PMID- 22197950 TI - First episode of axillary acne inversa in a teenager on infliximab therapy for Crohn disease. PMID- 22197949 TI - Socioenvironmental factors associated with constipation in Hong Kong children and Rome III criteria. AB - OBJECTIVE: Data regarding the prevalence of constipation in the general population of Asian children using internationally standardized definitions are scarce. Environmental factors surrounding a child's day to day living may trigger or perpetuate constipation and encourage postponement of defecation. METHODS: A territory-wide cross-sectional questionnaire survey was conducted in 2318 Hong Kong Chinese elementary school students. Constipation was defined by pediatric Rome III criteria. RESULTS: The mean age of the children was 9 +/- 1.9 years; 51% were boys. Two hundred eighty-two children (12.2%, 95% confidence interval [CI] 10.9%-13.5%) were found to have constipation. Children ages 6 to 7 years had the highest prevalence (16.8%, 95% CI 13.8%-19.8%). There was no difference in prevalence between boys and girls (11.6% vs 12.3%; P > 0.05) and between obese and nonobese children (11.5% vs 11.1%; P > 0.05). In univariate analysis, constipation was found to be significantly more prevalent among those children who lived with neither parent, had inadequate company of parents at home, refused to pass bowel movements in school, spent long hours doing homework, had inadequate sleep, and had decreased fiber intake and frequent consumption of fast food (P < 0.05). Multivariate analysis identified refusal to pass bowel movements in school toilets (odds ratio [OR] 1.97, 95% CI 1.42%-2.74%), having dinner with one/both parents <50% of time (OR 1.52, 95% CI 1.01%-2.31%), nighttime sleep <7 hours (OR 1.87, 95% CI 1.04%-3.33%), and frequent consumption of fast food (OR 1.14, 95% CI 1.03%-1.26%) to be independent factors associated with constipation. CONCLUSIONS: Socioenvironmental factors are associated with childhood constipation, and bringing them to the awareness of the public may help prevent or stop the progression of childhood constipation at its early stages. PMID- 22197951 TI - Anaerobic bacteria in upper respiratory tract and head and neck infections: microbiology and treatment. AB - Anaerobes are the predominant components of oropharyngeal mucous membranes bacterial flora, and are therefore a common cause of bacterial infections of endogenous origin of upper respiratory tract and head and neck. This review summarizes the aerobic and anaerobic microbiology and antimicrobials therapy of these infections. These include acute and chronic otitis media, mastoiditis and sinusitis, pharyngo-tonsillitis, peritonsillar, retropharyngeal and parapharyngeal abscesses, suppurative thyroiditis, cervical lymphadenitis, parotitis, siliadenitis, and deep neck infections including Lemierre Syndrome. The recovery from these infections depends on prompt and proper medical and when indicated also surgical management. PMID- 22197952 TI - Chronic Clostridium botulinum infections in farmers. AB - Although botulism is usually an acute, often lethal disease that is caused by the ingestion of botulinum neurotoxin, there are also recognized forms like infant botulism, wound botulism, or "botulism of undefined origin" that are characterized by the fact that Clostridium botulinum colonizes the host and produces its toxin in the host. Evidence is presented here that a disease in cattle and in human care takers of diseased animals that has evolved over the past two decades, may be a chronic, visceral form of C. botulinum infection. PMID- 22197953 TI - Corticoreticular pathway in the human brain: diffusion tensor tractography study. AB - The corticoreticular pathway (CRP) is involved in postural control and locomotor function. No study has been conducted for identification of the CRP in the human brain. In the current study, we attempted to identify the CRP in the human brain, using diffusion tensor tractography (DTT). We recruited 24 healthy volunteers for this study. Diffusion tensor images were scanned using 1.5-T. For reconstruction of the CRP, a seed region of interest (ROI) was placed on the reticular formation of the medulla. The first target ROI was placed on the midbrain tegmentum and the second target ROI was placed on the premotor cortex (Brodmann area 6). Values of fractional anisotropy, mean diffusivity, and tract volume of the CRP were measured. The CRP, which originated from the premotor cortex, descended through the corona radiata and the posterior limb of the internal capsule anterior to the corticospinal tract. In the midbrain and pons, it passed through the tegmentum and terminated at the pontomedullary reticular formation. No differences in terms of fractional anisotropy, mean diffusivity, and tract volume were observed between hemispheres (P>0.05). We identified the CRP in the human brain using DTT. These methods and results would be helpful to both clinicians and researchers in the neuroscience field. PMID- 22197954 TI - Age-related changes of body composition structure based on differences in morphological qualities of Japanese preschool children. AB - This study aims to clarify age-related changes of body composition structure in terms of the percentages of body fat and muscle (muscle mass/weight*100) in preschool children by using BMI. The subjects were 533 preschool children, comprising 260 boys and 273 girls. Regression analysis for BMI was performed and a regression polynomial of a proper order was determined. After examining the validity of the order in a regression polynomial for %Fat and muscle percentages for BMI, a regression polynomial evaluation chart was made up. After judging the degree of fat or muscle accumulation from BMI and the fat or muscle percentages for each age group of the boys and girls, a frequency distribution map of excessive development and underdevelopment of fat and muscle was drawn up and its age-related changes were examined. As a result, a complementary relationship was confirmed to exist between BMI and %Fat in preschool children. In contrast, an opposite relationship was found for BMI and muscle percentages. These results suggest that BMI can be used as an index of muscle percentages as well as %Fat. As a final result, the distribution composition map of fat and muscle percentages for BMI does not show changes with age from infancy in preschool boys as a whole, but it does show such changes in girls. It is inferred that preschool girls show, due to early maturity, earlier changes (fat decrease) toward an integrated child's body than do boys. PMID- 22197955 TI - Effects of modern eating patterns on the cardiac autonomic nervous system in young Japanese males. AB - The aim of this study was to determine the effects of the single intake of a high energy and high-fat meal, of that of a moderate-energy and high-carbohydrate meal, and of fasting, which are major global eating patterns involving the combination of various levels of energy and nutrients, on heart rate variability in healthy young males. Participants were assigned to three groups: the high energy and high-fat meal group, the moderate-energy and high-carbohydrate meal group, and the fasting group (no meal) in a randomized crossover design. The R-R intervals were continuously recorded before and after meals. Physiological and psychological data were obtained before and 30, 60, 90, and 120 min after meal intake. The main results were: (1) decreased sympathetic modulation of the heart and increased parasympathetic modulation of the heart in the fasting group, indicated by an unchanged heart rate, a decreased lowfrequency/high-frequency ratio, and increased high-frequency power of heart rate variability in the fasting group; (2) cardiac sympathetic activation or parasympathetic withdrawal after the intake of either a high-energy and high-fat meal or a moderate-energy and high-carbohydrate meal, indicated by increases in the heart rate and the low frequency/high-frequency ratio of heart rate variability, and a decrease in the high-frequency power of heart rate variability in both the high-energy and high fat meal group and the moderate-energy and high-carbohydrate meal group; and (3) the high-energy and high-fat meal group and the moderate-energy and high carbohydrate meal group showed similar movement in physiological and psychological measurements after the meal intake. In conclusion, the intake of the high-energy and high-fat meal and the moderate-energy and high-carbohydrate meal similarly activated sympathetic modulation of the heart, whereas fasting suppressed sympathetic modulation of the heart compared with the other two eating groups in healthy young males. PMID- 22197956 TI - Low-frequency force steadiness practice in plantar flexor muscle reduces postural sway during quiet standing. AB - The purpose of this study was to assess the effect of low-frequency force steadiness practice in the plantar flexor muscles on postural sway during quiet standing. Healthy young 21 men (21+/-1 yrs) were randomly assigned to a practice group (n=14) and a nonexercising control group (n=7). Practice groups were divided by frequency of practice: 7 participants practiced once a week, and the other 7 twice a week, for 4 weeks. Steadiness practice required practice group to 5 sets of 60-s contraction at levels corresponding to 10% and 20% maximal voluntary contraction (MVC) in the plantar flexor muscles. The 4-week-long practice period reduced the force fluctuations (assessed as the standard deviation (SD) of the outputted force during steady isometric plantar flexion) and postural sway (assessed as SD of the center of mass velocity during quiet standing). However, these practice effects were not significantly affected by the practice frequencies (1 vs. 2 sessions per week) examined in this study. Further, a linear regression analysis revealed the association between prepractice postural sway and the relative change in postural sway by the practice (r=-0.904) in the practice group. These results suggest that the steadiness practice in plantar flexor muscles improves postural stability during quiet standing, even though the practice is low-frequency (once a week) and low-intensity (within 20% MVC). These practice effects are dependent on prepractice postural stability. Further, the present results have provided the functional significance of force fluctuation in lower limb muscles. PMID- 22197957 TI - An approach to remote monitoring of heart rate variability (HRV) using microwave radar during a calculation task. AB - Recently, nonrestrictive and noninvasive sensing techniques to measure vital signs have been actively researched and developed. This study aimed to develop a prototype system to monitor cardiac activity using microwave radar without making contact with the body and without removing clothing--namely, a completely noncontact, remote monitoring system. In addition, heart rate and changes in heart rate variability (HRV) during simple mental arithmetic tasks were observed with the prototype system. The prototype system has a microwave Doppler radar antenna with 24 GHz frequency and approximately 7 mW output power. The experiments were conducted with seven subjects (23.00+/-0.82 years). We found that the prototype system captured heart rate and HRV precisely. The strong relationship between the heart rates during tasks (r=0.96), LF (cross correlation=0.76), and LF/HF (cross-correlation=0.73) of HRV calculated from the prototype system and from electrocardiograph (ECG) measurements were confirmed. The proposed completely noncontact, remote method appears promising for future monitoring of cardiac activity as an indicator of changes in mental workload in workplaces. PMID- 22197958 TI - Effectiveness of a red-visor cap for preventing light-induced melatonin suppression during simulated night work. AB - Bright light at night improves the alertness of night workers. Melatonin suppression induced by light at night is, however, reported to be a possible risk factor for breast cancer. Short-wavelength light has a strong impact on melatonin suppression. A red-visor cap can cut the short-wavelength light from the upper visual field selectively with no adverse effects on visibility. The purpose of this study was to investigate the effects of a red-visor cap on light-induced melatonin suppression, performance, and sleepiness at night. Eleven healthy young male adults (mean age: 21.2+/-0.9 yr) volunteered to participate in this study. On the first day, the subjects spent time in dim light (<15 lx) from 20:00 to 03:00 to measure baseline data of nocturnal salivary melatonin concentration. On the second day, the subjects were exposed to light for four hours from 23:00 to 03:00 with a nonvisor cap (500 lx), red-visor cap (approx. 160 lx) and blue-visor cap (approx. 160 lx). Subjective sleepiness and performance of a psychomotor vigilance task (PVT) were also measured on the second day. Compared to salivary melatonin concentration under dim light, the decrease in melatonin concentration was significant in a nonvisor cap condition but was not significant in a red visor cap condition. The percentages of melatonin suppression in the nonvisor cap and red-visor cap conditions at 4 hours after exposure to light were 52.6+/-22.4% and 7.7+/-3.3%, respectively. The red-visor cap had no adverse effect on performance of the PVT, brightness and visual comfort, though it tended to increase subjective sleepiness. These results suggest that a red-visor cap is effective in preventing melatonin suppression with no adverse effects on vigilance performance, brightness and visibility. PMID- 22197959 TI - One operational definition by population: the need for local evaluations of frailty. AB - Frailty is a health problem that increases the probability of developing adverse health outcomes in the elderly. A frequently used way to operationalize frailty is the construction of a frailty index, which is built from the addition of several health deficits that describe biological aging. However, there is no consensus about the number of health deficits for building a frailty index and about which deficits must be chosen. This lack of a standardized frailty index is assumed to be an obstacle for the advancement of research on frailty. The focus of the present article is to propose a theoretically plausible alternative way of operationalizing frailty by means of frailty indexes composed of deficits selected at a local level. These deficits would therefore be different for each given population. This "anthropological approach" is on the opposite side from current trends in frailty research, which is characterized by the search for a standardized operational definition of frailty. The anthropological approach would generate more reliable data by taking into account the specificity of the population to be studied for selecting frailty deficits. In this approach, emotions, motives, and beliefs are as important to determine individuals' health vulnerability as chronic diseases and physical function. Physiological anthropologists are well positioned to contribute to research on frailty by carrying out studies on the selection of the best deficits to operationalize frailty in different populations, with different socio-cultural determinants of health, and living in different environmental life spaces. PMID- 22197960 TI - Trail user demographics, physical activity behaviors, and perceptions of a newly constructed greenway trail. AB - To better understand and promote physical activity on a newly constructed trail, the present study examined the demographic characteristics and physical activity behaviors of trail users; the demographic characteristics of trail users compared to the demographic profile Greenville County, South Carolina residents; trail users' purpose for using the trail; the distance trail users traveled to access the trail from their homes; channels through which trail users learned about the trail; and trail characteristics liked by trail users. Using a valid and reliable intercept survey, 1,148 trail users were interviewed. Trail users were mostly white (93.1%), male (59.1%) adults (84.2%) who reported using the trail for exercise (91%). Significant associations were identified between trail user demographic characteristics and how trail users learned about the trail and trail characteristics liked by trail users. The findings may contribute to the development of targeted health promotion efforts to promote physical activity on this and similar trails. PMID- 22197961 TI - Tobacco advertising and sales practices in licensed retail outlets after the Food and Drug Administration regulations. AB - To assess retailer compliance with Food and Drug Administration (FDA) regulations on tobacco sales and advertising practices, including point-of-sale advertisements, in two distinct Columbus, Ohio neighborhood groups by income. Data were gathered from a random sample of 129 licensed tobacco retailers, which included data on both exterior and interior advertisements as well as sales practices. Descriptive analyses compared retail outlets by high and low income neighborhood locations. Compliance with FDA regulations was high in the random sample of urban tobacco retail outlets. None of the retail outlets sold loose cigarettes or offered free items with purchase. Less than 10% of the outlets surveyed offered self-service access to cigarettes or smokeless tobacco products. From all surveyed retail outlets 95% had cigarette, 57% had smokeless, and 57% had cigar advertisements at the point-of-sale. There were no significant differences in compliance by income, but the mean number of advertisements on the building and self-service access to cigars was significantly different by neighborhood income. There was a high degree of compliance with the new FDA regulation on tobacco marketing and sales practices in urban retail tobacco outlets in Columbus, Ohio. Tobacco advertising and marketing remain highly prevalent in retail outlets, with some significant differences between high and low income neighborhoods. PMID- 22197962 TI - A cloning vector for creation of Escherichia coli lacZ translational fusions and generation of linear template for chromosomal integration. AB - A novel cloning vector to aid in the construction of single copy beta galactosidase reporter systems for gene expression studies in lactose metabolizing Escherichia coli strains, including STEC, is described. The plasmid allows construction of translational fusions of cloned gene promoters to a short segment of E. coli lacZ. A selectable spectinomycin resistance marker flanked by a short lacI segment is positioned 5' to the cloning site. PCR amplification using opposing primers complementary to the upstream lacI fragment and the downstream lacZ fragment generates a linear template suitable for integration using pRedET recombination. Integration of linear template derived from the recombinant plasmid into host strains replaces the entire native lacZ promoter and fuses the promoter of interest in-frame with the lacZ gene, thus simultaneously producing a single-copy, chromosomal reporter system and eliminating background lacZ expression. Studies comparing ahpC expression from a chromosomal fusion in the lac open with that on a plasmid in E. coli strain EDL933 are shown. PMID- 22197963 TI - Simultaneous quantification of hemagglutinin and neuraminidase of influenza virus using isotope dilution mass spectrometry. AB - Influenza vaccination is the primary method for preventing influenza and its severe complications. Licensed inactivated vaccines for seasonal or pandemic influenza are formulated to contain a preset amount of hemagglutinin (HA), the critical antigen to elicit protection. There is currently no regulatory method that quantifies neuraminidase (NA), the other major membrane-bound protein thought to have protective capability. This is primarily due to the limitations both in sensitivity and in selectivity of current means to quantify these antigens. Current methods to establish the HA concentration of vaccines rely on indirect measurements that are subject to considerable experimental variability. We present a liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for the absolute quantification of viral proteins in a complex mixture. Through use of an isotope dilution approach, HA and NA from viral subtypes H1N1, H3N2, and B were determined both directly and rapidly. Three peptides of each subtype were used in the analysis of HA to ensure complete digestion of the protein and accuracy of the measurement. This method has been applied to purified virus preparations, to monovalent bulk concentrates, to trivalent inactivated influenza vaccines, and even crude allantoic fluid with improved speed, sensitivity, precision, and accuracy. Detection of 1 MUg/mL of protein is easily obtained using this method. The sensitivity of the method covers the range expected in vaccine preparations, including adjuvant-based vaccine. This LC/MS/MS approach substantially increases the selectivity, accuracy and precision used to quantify the amount of viral proteins in seasonal and pandemic influenza vaccines and reduce the time and effort to deliver influenza vaccines for public health use during the next influenza pandemic. PMID- 22197965 TI - The phylogeny of yellow fever virus 17D vaccines. AB - In recent years the safety of the yellow fever live vaccine 17D came under scrutiny. The focus was on serious adverse events after vaccinations that resemble a wild type infection with yellow fever and whose reasons are still not known. Also the exact mechanism of attenuation of the vaccine remains unknown to this day. In this context, the standards of safety and surveillance in vaccine production and administration have been discussed. Therein embodied was the demand for improved documentation of the derivation of the seed virus used for yellow fever vaccine production. So far, there was just a historical genealogy available that is based on source area and passage level. However, there is a need for a documentation based on molecular information to get better insights into the mechanisms of pathology. In this work we sequenced the whole genome of different passages of the YFV-17D strain used by Crucell Switzerland AG for vaccine production. Using all other publically available 17D full genome sequences we compared the sequence variance of all vaccine strains and oppose a phylogenetic tree based on full genome sequences to the historical genealogy. PMID- 22197964 TI - Plant-based expression of a partially humanized neutralizing monoclonal IgG directed against an immunodominant epitope on the ricin toxin A subunit. AB - GD12 is a murine monoclonal IgG(1) (mAb) that recognizes an immunodominant linear neutralizing epitope (163-TLARSFIICIQM-174) on the A subunit (RTA) of ricin toxin. With the long-term goal of using GD12 as a potential countermeasure against ricin intoxication, we have produced a chimeric derivative of GD12 (cGD12) in which the murine heavy and light chain variable regions were fused to a human IgG(1) framework. The chimeric mAb, expressed and purified using a Nicotiana-based system demonstrated epitope specificity and ricin neutralizing activity similar to the parental murine mAb. Passive administration of cGD12 (10MUg) to mice by intraperitoneal injection protected the animals against a systemic ricin challenge. In a post-exposure setting, the murine and chimeric mAbs administered as much as 6h after toxin challenge were each capable of rescuing mice from toxin-induced death, revealing the potential of GD12 to serve as both a prophylactic and therapeutic for ricin intoxication. PMID- 22197966 TI - Identification of two new serotypes within serogroup B of Dichelobacter nodosus. AB - The present study records the strain-specific molecular typing system for Dichelobacter nodosus (D. nodosus) based on genetic analysis of fimA locus. Based on the study two new serotypes B5 and B6 are reported within the serogroup B. Out of 200 swab samples collected randomly from foot lesions of footrot affected sheep from all the districts of Kashmir, India, 122 (61.0%) detected positive for D. nodosus. Serogroup B was predominantly prevalent in 83.60% of positive samples. Restriction fragment length polymorphism (RFLP) of polymerase chain reaction (PCR) amplified fimA gene of D. nodosus serogroup B revealed only two fingerprint patterns (FP) designated as FP1 and FP2. The FP1 was most prevalent and depicted by 82.35% of the samples with serogroup B while, FP2 was depicted by rest (17.65%) of the samples. Though the FP1 fimA sequence had the homology of 95% to D. nodosus fimA of serotype B4 isolate VRS 54, but there were 14 nucleotide differences and four nucleotide insertions/deletions in the coding sequence between these two strains resulting in eight amino acid substitutions in the fimbrial subunit. Similarly the FP2 fimA showed the sequence homology of 97% with D. nodosus fimA of serotype B2 isolate 183, with 10 nucleotide differences and three nucleotide insertions/deletions between these two sequences. This resulted in six amino acid substitutions, plus an amino acid length variation in the subunit protein. Thus it was presumed that these FP1 and FP2 strains represented new serotypes (B5 and B6, correspondingly) within the B serogroup as the degree of amino acid sequence difference with their nearest homologous strains was much greater than that within a serotype (0-5 amino acid differences), but comparable to that between serotypes (8-15 amino acid differences). This presumption was confirmed by cross tube agglutination test. PMID- 22197967 TI - Plasma cytokine levels in children with autistic disorder and unrelated siblings. AB - BACKGROUND: The pathogenesis of autistic disorder (AD) is not clearly understood but genetic factors and the immune system have been implicated. Disturbed immunoglobulin levels and autoantibodies to neuronal elements have been reported in AD including cytokines encoded by genes involved with cell proliferation, migration and adhesion but there is a paucity of data comparing cytokine levels in children with AD and unrelated siblings without AD. METHODS: We analyzed 39 plasma cytokines in 99 well-characterized children with AD between 5 and 10 years of age and 40 age and gender matched healthy unrelated siblings without AD under the same clinical assessments, specimen processing and laboratory conditions. Multiplex sandwich immunoassays were used with the Luminex fluorescent-bead based platform. Log-transformed values of the 29 cytokines meeting laboratory criteria for inclusion were analyzed by analysis of covariance with a general linear model adjusting for diagnosis, gender, diagnosis by gender interaction effects, age and days of specimen handling. The Tukey-Kramer post hoc test was used to control for multiple comparisons. RESULTS: Eight of 29 cytokine levels analyzed were significantly lower in children with AD compared with unrelated siblings without the diagnosis of AD. Three of the cytokines are known to be involved with hematopoiesis and five with attraction of T-cells, natural killer cells and monocytes. CONCLUSIONS: Plasma cytokine levels representing chemokines involved in the T-helper cell immune system and hematopoiesis were lower in the children with AD compared with unrelated siblings without AD necessitating further studies to confirm immunological disturbances influencing hematopiesis and antibody production in the children with AD. Linking genes that encode immune related proteins and cytokines are important to study for their impact on critical periods of brain development and function. PMID- 22197968 TI - Secretome analysis of atherosclerotic and non-atherosclerotic arteries reveals dynamic extracellular remodeling during pathogenesis. AB - AIMS: Early detection of cardiovascular diseases and knowledge of underlying mechanisms is essential. Tissue secretome studies resemble more closely to the in vivo situation, showing a much narrower protein concentrations dynamic range than plasma. This study was aimed to the analysis of human arterial tissue secretome and to the quantitative comparison of healthy and atherosclerotic secretome to discover proteins with key roles in atherosclerosis development. METHODS AND RESULTS: Secretomes from three biological replicates of human atherosclerotic coronary arteries (APC), preatherosclerotic coronaries (PC) and mammaries (M) were analyzed by LC-MS/MS. The identified proteins were submitted to Ingenuity Pathway Analysis (IPA) tool. Label-free MS/MS based quantification was performed and validated by immunohistochemistry. 64 proteins were identified in the 3 replicates of at least one of the 3 groups and 15 secreted proteins have not been previously reported in plasma. Four proteins were significantly released in higher amounts by mammary tissue: gelsolin, vinculin, lamin A/C and phosphoglucomutase 5. CONCLUSION: The study of tissue secretome reveals key proteins involved in atherosclerosis which have not been previously reported in plasma. Novel proteins are here highlighted which could be potential therapeutic targets in clinical practice. This article is part of a Special Issue entitled: Proteomics: The clinical link. PMID- 22197969 TI - Nanocapsulated curcumin: oral chemopreventive formulation against diethylnitrosamine induced hepatocellular carcinoma in rat. AB - Toxic outcome of chemical therapeutics as well as multidrug resistance are two serious phenomena for their inacceptance in cancer chemotherapy. Antioxidants like curcumin (Cur) have gained immense importance for their excellent anticarcinogenic activities and minimum toxic manifestations in biological system. However, Cur is lipophilic and thus following oral administration hardly appears in blood indicating its potential therapeutic challenge in cancer therapy. Nanocapsulated Cur has been used as a drug delivery vector to focus the effectiveness of these vesicles against hepatocellular carcinoma. The theme of work was to evaluate effectiveness in oral route of polylactide co-glycolide (PLGA) Nanocapsulated curcumin (Nano Cur) against diethylnitrosamine (DEN) induced hepatocellular carcinoma (HCC) in rat. Nano Cur of average diameter 14nm and encapsulation efficiency of 78% were prepared. Fourier Transform Infra Red (FTIR) analysis revealed that there is no chemical interaction between drug and the polymer. Three i.p. injections of the chemical hepatocarcinogen DEN at 15days interval causes hepatotoxicity, the generation of reactive oxygen species (ROS), lipid peroxidation, decrease in plasma membrane microviscosity and depletion of antioxidant enzyme levels in liver. Nano Cur (weekly oral treatment for 16weeks at 20mg/kg b.wt) in DEN induced HCC rats exerted significant protection against HCC and restored redox homeostasis in liver cells. Nanocapsulated Cur caused cancer cell apoptosis as visualized by ApoBrdU analysis. Histopathological analysis confirmed the pathological improvement in the liver. Nano Cur was found to be a potential formulation in oral route in combating the oxidative damage of hepatic cells and eliminating DEN induced hepatocellular cancer cells in rat whereas identical amount of free Cur treatment was found almost ineffective. PMID- 22197970 TI - Quercetin modulates Nrf2 and glutathione-related defenses in HepG2 cells: Involvement of p38. AB - Dietary flavonoid quercetin has been suggested as a cancer chemopreventive agent, but the mechanisms of action remain unclear. This study investigated the influence of quercetin on p38-MAPK and the potential regulation of the nuclear transcription factor erythroid-2p45-related factor (Nrf2) and the cellular antioxidant/detoxifying defense system related to glutathione (GSH) by p38 in HepG2 cells. Incubation of HepG2 cells with quercetin at a range of concentrations (5-50MUM) for 4 or 18h induced a differential effect on the modulation of p38 and Nrf2 in HepG2 cells, 50MUM quercetin showed the highest activation of p38 at 4h of treatment and values of p38 similar to those of control cells after 18 h of incubation, together with the inhibition of Nrf2 at both incubation times. Quercetin (50MUM) induced a time-dependent activation of p38, which was in concert with a transient stimulation of Nrf2 to provoke its inhibition afterward. Quercetin also increased GSH content, mRNA levels of glutamylcysteine-synthetase (GCS) and expression and/or activity of glutathione peroxidase, glutathione-reductase and GCS after 4h of incubation, and glutathione S-transferase after 18h of exposure. Further studies with the p38 specific inhibitor SB203580 showed that the p38 blockage restored the inhibited Nrf2 transcription factor and the enzymatic expression and activity of antioxidant/detoxificant enzymes after 4h exposure. In conclusion, p38-MAPK is involved in the mechanisms of the cell response to quercetin through the modulation of Nrf2 and glutathione-related enzymes in HepG2 cells. PMID- 22197971 TI - Depression in children and adolescents in the first 6 months after traumatic brain injury. AB - The objective was to assess the nature, rate, predictive factors, and neuroimaging correlates of novel (new-onset) depressive disorders, both definite and subclinical, after traumatic brain injury (TBI). Children with TBI from consecutive admissions were enrolled and studied with psychiatric interviews soon after injury (baseline), and again 6 months post-injury. Novel definite/subclinical depressive disorders at 6-month follow up occurred in 11% (n=15) of the children and subsets of children with non-anxious depression (n=9) and anxious depression (n=6) were identified. Novel definite/subclinical depressive disorder was significantly associated with older age at the time of injury, family history of anxiety disorder, left inferior frontal gyrus (IFG) lesions, and right frontal white matter lesions. Non-anxious depressions were associated with older age at injury, left IFG and left temporal pole lesions. Anxious depressions were associated with family history of anxiety disorder, Personality Change due to TBI, right frontal white matter lesions, and left parietal lesions. These findings, which are similar to those reported after adult TBI, identify both similarities and differences in non-anxious and anxious depression following childhood TBI with respect to lesion laterality, genetic factors (in the form of family psychiatric history of anxiety disorder), age at injury, and more generalized affective dysregulation. PMID- 22197972 TI - Differential long term effects of early diisopropylfluorophosphate exposure in Balb/C and C57Bl/J6 mice. AB - The long-term effect of postnatal administration of a sub-toxic dose of the irreversible acetylcholinesterase inhibitor diisopropylfluorophosphate (DFP) on depression and anxiety behavior was compared in two strains of inbred mice. C57BL/6J and Balb/C mice were injected for 7 consecutive days with either 1 mg/kg DFP or saline on postnatal days 14-20. Mice were tested at age 3-4 months for initial and learned anxiety using double-exposure elevated plus maze and to a novel enclosed environment. Depression was assayed using the sweet preference model of anhedonia and the forced swim test for despair. Postnatal DFP pretreatment led to less activity and more immobility in the elevated plus maze in both mouse strains in the first session. The effect was attenuated in the second session in the C57BL/6J strain but not the Balb/C strain. DFP did not affect the sweet preference or forced swim tests, suggesting a dissociation between the long-term effects of DFP on immobility in the context of approach avoidance conflict (elevated plus maze) versus despair (forced swim). PMID- 22197973 TI - Induction of neural differentiation by the transcription factor neuroD2. AB - Pro-neural basic helix loop helix (bHLH) transcription factors are involved in many aspects of normal neuronal development, and over-expression of genes for several of these factors has been shown to induce aspects of neuronal differentiation in cell lines and stem cells. Here we show that over-expression of NeuroD2 (ND2), Neurogenin1 and 2 leads to morphological differentiation of N18 RE-105 neuroblastoma cells and increased expression of synaptic proteins. Particularly ND2 induced neurite formation and increases in the expression of synaptic proteins such as synaptotagmin, that is not expressed normally in this cell type, as well as the redistribution of another synaptic protein, SNAP25, to a cell membrane location. Infection of human neural progenitor cells using adeno associated viral (AAV) vectors also promoted neuronal differentiation. Over expressing cells demonstrated a significant increase in the neuron specific form of tubulin as well as increased expression of synaptotagmin. Genetic modification of neural progenitor cell with bHLH factors such as ND2 may be a viable strategy to enhance differentiation of these cells into replacement neurons for human disease. PMID- 22197974 TI - Validation and long term performance characteristics of a quantitative enzyme linked immunosorbent assay (ELISA) for human anti-PA IgG. AB - Accurate, reliable and standardized quantification of anti-protective antigen (PA) IgG antibody levels is essential for comparative analyses of anti-toxin immune responses in anthrax cases, recipients of PA-based anthrax vaccines and for evaluation of anti-PA based immunotherapies. We have previously reported the early performance characteristics and application of a quantitative anti-PA IgG enzyme linked immunosorbent assay. The principal application of this assay was in a Phase 4 human clinical trial of anthrax vaccine adsorbed (AVA, BioThrax), the central component of the CDC Anthrax Vaccine Research Program (AVRP) and in humans following bioterrorism associated Bacillus anthracis infection (Quinn et al., 2002; Quinn et al., 2004; Marano et al., 2008). The objective of the AVRP was to determine the feasibility of reducing the number of priming series and booster doses of the licensed Anthrax Vaccine Adsorbed (AVA) (BioThrax(r); Emergent BioSolutions, Lansing, MI) and changing the route of administration from subcutaneous (SC) to intramuscular (IM) (Marano et al., 2008). In this paper we report the validation and long term performance characteristics of the assay during its six year application in the AVRP (2002-2008). The critical features are 1) extensive validation of the assay using two standard reference sera; 2) long term stability and 3) consistency of the data for quantitative analysis of human long term anti-PA IgG responses. The reportable value (RV) of the assay was expressed as anti-PA IgG concentration (MUg/ml). Accuracy of the assay was high with a percent error (%ER) range of 1.6-11.4%. Overall intra-operator and intermediate precision were high with Coefficients of Variation (%CVs) of 2.5 15.4% and 6.3-13.2%, respectively. The assay demonstrated excellent dilutional linearity for human sera using log(10) transformed data with the slope=0.95 to 0.99, intercept=0.02 to 0.06 and r(2)=0.980-0.987. The assay was robust, tolerating changes in serum incubation temperatures from 35 to 39 degrees C, serum incubation times from 55 to 65min and changes in key reagents. The long term assay stability over 6years using consecutive reference sera AVR414 and AVR801 demonstrated sustained high accuracy and precision for the assay, confirming its suitability for long term studies of PA protein-based anthrax vaccines. PMID- 22197975 TI - The transatlantic divide over brain death determination and the debate. AB - In 1976, the Royal College of Physicians published neurological criteria of death. The memorandum stated that-after preconditions and exclusion criteria were met-the absence of brainstem function, including apnoea testing, would suffice. In the USA, many experts felt that brain death could be only determined by demonstrating death of the entire brain. In the history of further refinement of UK and USA brain death criteria, one particular period stands out that would bring about an apparent transatlantic divide. On 13 October 1980, the British Broadcasting Corporation aired a programme entitled 'Transplants: Are the Donors Really Dead?' Several United States experts not only disagreed with the United Kingdom criteria, but claimed that patients diagnosed with brain death using United Kingdom criteria could recover. The fallout of this television programme was substantial, as indicated by a media frenzy and a 6-month period of heated correspondence within The Lancet and The British Medical Journal. Members of the Parliament questioned the potential long-term effect on the public's trust in organ transplantation. Given the concerns raised, the British Broadcasting Corporation commissioned a second programme, which was broadcast on 19 February 1981 entitled 'A Question of Life or Death: The Brain Death Debate.' Two panels debated the issues on the accuracy of the electroencephalogram and its place, the absolute need for assessing preconditions before an examination, the problems with recognition of toxins and the feasibility of doing a new prospective study in the United Kingdom, which would follow patients' examination assessed with United Kingdom criteria until cardiac standstill. The positions of the United States and United Kingdom remained diametrically opposed to each other. This article revisits this landmark moment and places it in a wider historical context. In the USA, the focus was not on the brainstem, and the definition of brain death became rapidly infused with terms such as whole brain death (all intracranial structures above the foramen magnum), cerebral death (all supratentorial structures) or higher brain death (cortical structures) virtually synonymous with persistent vegetative state. This review also identifies the fortitude of neurosurgeon Bryan Jennett and neurologist Christopher Pallis by introducing new corroborative data on the diagnosis of brain death and clarifying the United Kingdom position. Both understood that brainstem death was the infratentorial consequence of a supratentorial catastrophe. With the 1995 American Academy of Neurology practice parameters, the differences between the UK and USA brain death determination would become much less apparent. PMID- 22197977 TI - Mice completely lacking immunoproteasomes show major changes in antigen presentation. AB - The importance of immunoproteasomes to antigen presentation has been unclear because animals totally lacking immunoproteasomes had not been available. Having now developed mice lacking the three immunoproteasome catalytic subunits, we found that the dendritic cells of these mice had defects in presenting several major histocompatibility complex (MHC) class I epitopes. During viral infection in vivo, the presentation of a majority of MHC class I epitopes was markedly reduced in immunoproteasome-deficient animals compared with wild-type animals, whereas presentation of MHC class II peptides was unaffected. According to mass spectrometry, the repertoire of MHC class I-presented peptides was ~50% different from that in wild-type mice, and these differences were sufficient to stimulate robust transplant rejection of wild-type cells in mutant mice. These results indicated that immunoproteasomes were more important in antigen presentation than previously thought. PMID- 22197976 TI - B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. AB - Neutrophils use immunoglobulins to clear antigen, but their role in immunoglobulin production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T cell-independent immunoglobulin responses to circulating antigen. Neutrophils colonized peri-MZ areas after postnatal mucosal colonization by microbes and enhanced their B cell helper function after receiving reprogramming signals, including interleukin 10 (IL-10), from splenic sinusoidal endothelial cells. Splenic neutrophils induced immunoglobulin class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism that involved the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and a lower abundance of preimmune immunoglobulins to T cell-independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial immunoglobulin defense by interacting with MZ B cells. PMID- 22197978 TI - Scheduled out-patient endoscopy and lack of compliance in a minority serving tertiary institution. AB - INTRODUCTION: Lack of adherence to appointments wastes resources and portends a poorer outcome for patients. The authors sought to determine whether the type of scheduled endoscopic procedures affect compliance. METHODS: The authors reviewed the final endoscopy schedule from January 2010 to August 2010 in an inner city teaching hospital that serves a predominantly African American population. The final schedule only includes patients who did not cancel, reschedule or notify the facility of their inability to adhere to their care plan up to 24 hours before their procedures. All patients had face to face consultation with gastroenterologists or surgeons before scheduling. The authors identified patients who did not show up for their procedures. They used Poisson regression models to calculate relative risks (RR) and 95% confidence intervals (CI). RESULTS: Of 2183 patients who were scheduled for outpatient endoscopy, 400 (18.3%) patients were scheduled for Esophago-gastro-duodenoscopy (EGD), 1,335 (61.2%) for colonoscopy and 448 (20.5%) for both EGD and colonoscopy. The rate of noncompliance was 17.5%, 22.8% and 22.1%, respectively. When compared with those scheduled for only EGD, patients scheduled for colonoscopy alone (RR = 1.47; 95% CI: 1.13-1.92) and patients scheduled for both EGD and colonoscopy (RR = 1.36; 95% CI: 1.01-1.84) were less likely to show up for their procedures. CONCLUSIONS: This study suggests a high rate of noncompliance with scheduled out-patient endoscopy, particularly for colonoscopy. Because this may be a contributing factor to colorectal cancer disparities, increased community outreach on colorectal cancer education is needed and may help to reduce noncompliance. PMID- 22197979 TI - A 72-year-old woman with several months of weight loss and generalized weakness. PMID- 22197980 TI - Preoperative probiotics decrease postoperative infectious complications of colorectal cancer. AB - BACKGROUND: The objective is to elucidate the effects of oral bifid triple viable probiotics among patients with colorectal cancer. METHODS: Sixty patients undergoing radical colorectal resection were randomly assigned to 3-day (days -5 to -3) preoperative probiotics (group A, n = 30) or placebo (group B, n = 30) treatment. The alteration of intestinal flora was evaluated by fecal cultures of Escherichia coli, Bifidobacterium longum and intestinal fungi; the gut barrier function by serum endotoxins and D-lactic acids and the immune and stress responses by peripheral blood immunoglobins, interleukin-6 and C-reactive protein. Postoperative infections were documented physically, radiologically and microbiologically. RESULTS: Inverted Bifidobacterium/Escherichia ratios were preoperatively and postoperatively present in group B (both P < 0.05). Bifidobacterium counts increased significantly, whereas Escherichia counts decreased significantly on postoperative days 3 to 5 (P < 0.05), along with reversing the Bifidobacterium/Escherichia ratio inversion until postoperative days 3 to 5 in group A. Group A also had lower levels of endotoxins, D-lactic acids, serum interleukin-6 and C-reactive protein but higher levels of serum IgG and sIgA (all P < 0.05) than group B. The incidences of postoperative infectious complications were 3.3% to 6.7% and 3.3% to 30% in groups A and B (overall, 10.0% versus 33.3%, P < 0.05), respectively. CONCLUSION: The preoperative oral bifid triple viable probiotics minimize the postoperative occurrence of infectious complications, with possible mechanisms attributed to the maintenance of the intestinal flora and restriction of bacterial translocation from the intestine. It was representative of the enhancement of systemic/localized immunity and concurrent attenuation of systemic stress response. PMID- 22197981 TI - Cerebrotendinous xanthomatosis revealed in drug-resistant epilepsy diagnostic workup. AB - Cerebrotendinous xanthomatosis (CTX) is a treatable disorder of bile acid production caused by mutations in the mitochondrial enzyme sterol 27-hydroxilase. This inborn error of bile acid metabolism results in lipid pathologic accumulation in multiple tissues. Progressive neuropsychiatric disturbances are a frequent manifestation of this disease. Although seizures have been frequently noticed as part of CTX manifestations, there have not been reports of CTX being diagnosed in drug-resistant epilepsy diagnostic workup nor of seizure response to chenodeoxycholic acid treatment. Here, the authors present a case of a drug resistant epilepsy patient with a complex phenotype where a diagnosis of CTX was done and showed a significant reduction in seizure frequency after chenodeoxycholic acid supplementation. This report illustrates the importance of considering treatable neurometabolic disorders in epileptic patients showing complex phenotypes. PMID- 22197982 TI - Glycyrrhizin administration ameliorates coxsackievirus B3-induced myocarditis in mice. AB - In this study, the authors explored the therapeutic effect of glycyrrhizin (GL) on Coxsackievirus B3 (CVB3)-induced myocarditis and its possible mechanisms involved. The results of this study showed that GL exhibited a profound amelioration of CVB3-induced myocarditis, as evidenced by improved weight loss profile, less increased serological levels of cardiac enzymes, less myocardial inflammation and increased survival rate. Further study showed that this effect was not due to the viral clearance but ascribed to weakened proinflammatory responses, as evidenced by significantly reduced expression of proinflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1beta and interleukin-6. Moreover, the authors demonstrated that GL administration inhibited CVB3-induced nuclear factor-kappaB activity efficiently by blocking the degradation of nuclear factor -kappaB inhibitor IkappaBkappa. These data suggest that GL can effectively attenuate the severity of CVB3-induced myocarditis and may present as a new therapeutic approach for the treatment of viral myocarditis. PMID- 22197991 TI - Effects of 17alpha-ethinylestradiol on individual life-history parameters and estimated population growth rates of the freshwater gastropods Radix balthica and Bithynia tentaculata. AB - Studies of aquatic environments exposed to 17alpha-ethinylestradiol (EE2) have demonstrated detrimental effects on fish communities. However, much less is known about effects on macro-invertebrates and especially how long-term exposure may affect critical life stages and ultimately population dynamics. We studied the effects of EE2 on relevant endpoints for population growth in two common freshwater gastropods, Radix balthica and Bithynia tentaculata, that differ in reproductive, foraging and anti-predator strategies and endocrine systems. We quantified critical life-history parameters (mortality, somatic growth rate, days to and size at first reproduction, egg production and hatching success) in a concentration-response, life cycle experiment. The two species responded to EE2 exposure in different ways, B. tentaculata showing a significantly lower somatic growth rate and R. balthica a higher somatic growth rate. However, the magnitudes of the effects were small and EE2 exposure did not have any significant effect on estimated population growth rates for the two snail species. The significant effects of EE2 on individual endpoints, but not on population growth rate for both species, emphasise the importance of evaluating higher level effects from long-term exposure studies. PMID- 22197992 TI - Alternative strategies in arrhythmia therapy: evaluation of Na/Ca exchange as an anti-arrhythmic target. AB - The search for alternative anti-arrhythmic strategies is fueled by an unmet medical need as well as by the opportunities arising from identification of novel targets and novel drugs. Na/Ca exchange is a potential target involved in several types of arrhythmias, such as those related to ischemia-reperfusion, heart failure and also some forms of genetic arrhythmias. Inhibition of Na/Ca exchange is theoretically not only anti-arrhythmic but also increases cellular Ca(2+) content. This could be an advantage in conditions of low inotropy, such as in heart failure, but may also worsen conditions such as the recovery from ischemia or relaxation abnormalities. With the available drugs such as KB-R7943 and SEA 0400 these theories have now been tested in a number of cellular and in vivo models. Experience is overall rather positive and seems less hampered by the potential drawbacks than expected. This may be because the currently available drugs are not highly selective, with additional benefit derived from concurrent effects. While this precludes a definite answer regarding the benefit of a pure NCX inhibitor, they indicate that Na/Ca exchange inhibition as part of a multi target strategy is an avenue to be considered. Such studies will need further 'bench' work and testing in relevant preclinical models, including chronic disease. PMID- 22197993 TI - Targeting DNA damage and repair: embracing the pharmacological era for successful cancer therapy. AB - DNA is under constant assault from genotoxic agents which creates different kinds of DNA damage. The precise replication of the genome and the continuous surveillance of its integrity are critical for survival and the avoidance of carcinogenesis. Cells have evolved an arsenal of repair pathways and cell cycle checkpoints to detect and repair DNA damage. When repair fails, typically cell cycle progression is halted and apoptosis is initiated. Here, we review the different sources and types of DNA damage including DNA replication stress and oxidative stress, the repair pathways that cells utilize to repair damaged DNA, and discuss their biological significance, especially with reference to cancer induction and cancer therapy. We also describe the main methodologies currently used for the detection of DNA damage with their strengths and limitations. We conclude with an outline as to how this information can be used to identify novel pharmacological targets for DNA repair pathways or enhancers of DNA damage to develop improved treatment strategies that will benefit cancer patients. PMID- 22197994 TI - Tonsil amyloidosis revealing a Waldenstrom macroglobulinemia. AB - Localized amyloidosis of the tonsil is rare and its management depends on the etiology. We report a case of tonsil amyloidosis and review the characteristics of this exceptional pathology. A 74-year-old man consulted for odynophagia, upper dysphagia and deteriorated general health status, which have been evolving for 1 year. Clinical examination found a smooth swelling of the right palatine tonsil. No further abnormalities were noted. The biopsy findings were consistent with amyloidosis. Etiological assessment pointed to Waldenstrom macroglobulinemia. Tonsillectomy was performed. The patient was managed by chemotherapy associating chlorambucil, vincristine and prednisone. The progress after chemotherapy was good. Localized amyloidosis is a rare lesion of the superior aerodigestive tract, predominating in the larynx and tonsil involvement is exceptional. Its diagnosis is histological and its management depends on the etiology. Continued regular follow-up is necessary to look for recurrence. PMID- 22197995 TI - The cadherin-catenin complex in laryngeal squamous cell carcinoma. AB - Abnormal Wnt signaling and impaired cell-cell adhesion due to abnormal E-cadherin and beta-catenin function have been implicated in many cancers, but have not been fully explored in laryngeal squamous cell carcinoma. In this study, beta-catenin cellular location and E-cadherin expression levels were analyzed in 16 laryngeal squamous cell carcinomas (LSCCs) (9 glottic and 7 supraglottic) and 11 samples of non-tumoral inflammatory larynx tissue, using immunohistochemical methods. All non-tumoral tissues showed equally strong membranous expression of beta-catenin, while cytoplasmic expression was found in only 3 of the 11 samples. By contrast, whereas 8/9 glottic LSCCs exhibited only membranous expression of beta-catenin, 6/7 supraglottic LSCCs displayed both membranous and cytoplasmic expression (p = 0.003). Strong E-cadherin staining was observed in 9/11 non-tumoral tissues and 7/9 glottic LSCCs, whereas 4/7 supraglottic LSCCs exhibited weak expression. Reduced membrane expression of E-cadherin and cytoplasmic retention of beta catenin in supraglottic LSCC seems to be related with more aggressive biological behavior which has been described in clinical studies. Further research is required to clarify the involvement of beta-catenin in the mechanism associated with malignant transformation in laryngeal tissues. PMID- 22197996 TI - Is the spinal motion segment a diarthrodial polyaxial joint: what a nice nucleus like you doing in a joint like this? AB - This review challenges an earlier view that the intervertebral joint could not be classified as a diarthrodial joint and should remain as an amphiarthrosis. However, a careful analysis of the relevant literature and in light of more recent studies, it is clear that while some differences exist between the spinal articulation and the generic synovial joint, there are clear structural, functional and developmental similarities between the joints that in sum outweigh the differences. Further, since the intervertebral motion segment displays movement in three dimensions and the whole spine itself provides integrated rotatory movements, it is proposed that it should be classified not as an amphiarthrose, "a slightly moveable joint" but as a complex polyaxial joint. Hopefully, reclassification will encourage further analysis of the structure and function of the two types of overlapping joints and provide common new insights into diseases that afflict the many joints of the human skeleton. PMID- 22197998 TI - The role of chain rigidity in lipid self-association: comparative study of dihexanoyl- and disorbyl-phosphatidylcholines. AB - In the course of structure-function investigations of lipids a phosphatidylcholine molecule with short and rigid tails, di-2,4 hexadienoylphosphatidylcholine (DiSorbPC), was synthesized and studied in comparison with its saturated analog, dihexanoylphosphatidylcholine (DHPC). Conjugated double bonds in the acyl chains in DiSorbPC reduce considerably the number of possible conformers of the lipid within an aggregate. This leads to impaired packing of unsaturated acyl chains and thus, to a surprisingly high (115 A(2)) area per molecule for DiSorbPC at the air-water interface and failure to form micelles of regular size and shape. Details on DiSorbPC aggregation and packing provided by a set of experimental techniques combined with molecular dynamics simulations are presented. PMID- 22197997 TI - Elevated cross-talk between subchondral bone and cartilage in osteoarthritic joints. AB - Osteoarthritis (OA) is a degenerative joint disease and one of the leading causes of disability in the United States and across the world. As a disease of the whole joint, OA exhibits a complicated etiology with risk factors including, but not limited to, ageing, altered joint loading, and injury. Subchondral bone is hypothesized to be involved in OA development. However, direct evidence supporting this is lacking. We previously detected measurable transport of solute across the mineralized calcified cartilage in normal joints, suggesting a potential cross-talk between subchondral bone and cartilage. Whether this cross talk exists in OA has not been established yet. Using two models that induced OA by either ageing or surgery (destabilization of medial meniscus, DMM), we tested the hypothesis that increased cross-talk occurs in OA. We quantified the diffusivity of sodium fluorescein (mol. wt. 376Da), a marker of small-sized signaling molecules, within calcified joint matrix using our newly developed fluorescence loss induced by photobleaching (FLIP) method. Tracer diffusivity was found to be 0.30+/-0.17 and 0.33+/-0.20MUm(2)/s within the calcified cartilage and 0.12+/-0.04 and 0.07+/-0.03MUm(2)/s across the osteochondral interface in the aged (20-24-month-old, n=4) and DMM OA joints (5-month-old, n=5), respectively, which were comparable to the control values for the contralateral non-operated joints in the DMM mice (0.48+/-0.13 and 0.12+/-0.06MUm(2)/s). Although we did not detect significant changes in tissue matrix permeability in OA joints, we found i) an increased number of vessels invading the calcified cartilage (and sometimes approaching the tidemark) in the aged (+100%) and DMM (+50%) joints relative to the normal age controls; and ii) a 60% thinning of the subchondral bone and calcified cartilage layers in the aged joints (with no significant changes detected in the DMM joints). These results suggested that the capacity for cross talk between subchondral bone and articular cartilage could be elevated in OA. Further studies are needed to identify the direction of the cross-talk, the signaling molecules involved, and to test whether subchondral bone initiates OA development and could serve as a pharmaceutical target for OA treatment. This article is part of a Special Issue entitled "Osteoarthritis". PMID- 22197999 TI - Enterohaemorrhagic Escherichia coli requires the spectrin cytoskeleton for efficient attachment and pedestal formation on host cells. AB - Recent work has demonstrated that the spectrin cytoskeleton is a host cell target, exploited during intestinal bacterial disease. Here we show that the highly virulent intestinal pathogen enterohaemorrhagic Escherichia coli (EHEC) is also reliant upon the spectrin cytoskeleton during key pathogenic events. Immunofluorescent microscopy demonstrated that the core components of the spectrin cytoskeleton (spectrin, adducin, and protein 4.1 [p4.1]) are recruited to sites of EHEC attachment and localized at pedestal structures along with the EHEC pedestal specific proteins IRSp53 and IRTKS. Further studies involving siRNA mediated knockdowns of spectrin, adducin, or p4.1 revealed that those proteins are needed for efficient docking of EHEC to host cells, are involved in recruiting IRSp53 to the pedestal and are necessary for pedestal formation. These findings identify the spectrin cytoskeleton as a major host cell cytoskeletal network involved in critical EHEC pathogenic events. PMID- 22198000 TI - The Aeromonas dsbA mutation decreased their virulence by triggering type III secretion system but not flagella production. AB - Pathogenesis of Aeromonas species have been reported to be associated with virulence factors such as lipopolysaccharides (LPS), bacterial toxins, bacterial secretion systems, flagella, and other surface molecules. Dsb (Disulfide bond) proteins play an important role in catalyzing disulfide bond formation in proteins within the periplasmic space. An A. hydrophila dsbA mutant with attenuated virulence using Dictyostelium amoebae as an alternative host model was identified. The attenuated virulence was tested in other animal models (by intraperitoneal injection in fish and mice) and was correlated with the presence of a defective type III secretion system for the first time in non enteric bacteria. The dsbA mutation was shown in several enteric bacteria to involve the outer membrane secretin. The defect in Aeromonas also seems to involve the outer membrane secretin homologue named AscC. However, unlike what happen in Escherichia coli, no changes in motility or flagella expression were observed for A. hydrophila dsbA mutants. The loss of E. coli motility caused by deletion of dsbA is likely due to defective disulfide bond formation in FlgI, a component of the flagella. No disulfide bond formation in FlgI homologues in Aeromonas flagella biogenesis, either polar or lateral, could be expected according to their amino acid residues sequences. PMID- 22198001 TI - Distinct regulation of nNOS and iNOS by CB2 receptor in remote delayed neurodegeneration. AB - Hemicerebellectomy results in remote delayed degeneration of precerebellar neurons. We have reported that such a lesion induces type 2 cannabinoid receptor (CB(2)) expression in precerebellar neurons and that stimulation of CB(2), but not CB(1), has neuroprotective effects. In this study, we found that in the same model, the CB(2) agonist JWH-015 enhances neuronal nitric oxide synthase (nNOS) expression in axotomized neurons and that CB(2)-mediated neuroprotection is abrogated by pharmacological inhibition of nNOS. JWH-015 prevented the axotomy induced upregulation of inducible NOS (iNOS) in astrocytes but had no effect on endothelial NOS (eNOS). In addition, we observed that JWH-015 significantly reduces hemicerebellectomy-induced neuroinflammatory responses and oxidative/nitrative stress. With regard to the signaling pathways of CB(2)/nNOS mediated neuroprotection, we noted nNOS-dependent modulation of the expression of anti-oxidative (Hsp70) and anti-apoptotic (Bcl-2) proteins. These findings shed light on the interactions between the endocannabinoid and nitrergic systems after focal brain injury, implicating distinct functions of nNOS activation and iNOS inhibition in CB(2) signaling, which protect neurons from axotomy-induced cell death. PMID- 22198002 TI - In vivo genotoxicity study of titanium dioxide nanoparticles using comet assay following intratracheal instillation in rats. AB - Titanium dioxide (TiO2) is widely used as a white pigment in paints, plastics, inks, paper, creams, cosmetics, drugs and foods. In the present study, the genotoxicity of anatase TiO2 nanoparticles was evaluated in vivo using the comet assay after a single or repeated intratracheal instillation in rats. The nanoparticles were instilled intratracheally at a dosage of 1.0 or 5.0 mg/kg body weight (single instillation group) and 0.2 or 1.0 mg/kg body weight once a week for 5 weeks (repeated instillation group) into male Sprague-Dawley rats. A positive control, ethyl methanesulfonate (EMS) at 500 mg/kg, was administered orally 3 h prior to dissection. Histopathologically, macrophages and neutrophils were detected in the alveolus of the lung in the 1.0 and 5.0 mg/kg TiO2 groups. In the comet assay, there was no increase in % tail DNA in any of the TiO2 groups. In the EMS group, there was a significant increase in % tail DNA compared with the negative control group. TiO2 nanoparticles in the anatase crystal phase are not genotoxic following intratracheal instillation in rats. PMID- 22198003 TI - Knowledge, attitudes and practices of barbers regarding hepatitis B and C viral infection in Sana'a city, Yemen. AB - There is strong evidence that razors, barber's scissors, nail files and body piercing instruments are risk factors for transmission of hepatitis B and C. to investigate the knowledge, attitudes and practices regarding hepatitis B and C virus among barbers in Sana'a city. KAP study was conducted from July-September 2011. Two hundred and thirty four barbershops were surveyed. Out of 234 barber shops, 73.1% heard about viral hepatitis B and C. The awareness of modes of transmission of hepatitis and the different sources/risk factors were moderate, ranging from 51.6% who knew that hepatitis can be transmitted through sexual transmitted to 82.1% who knew that hepatitis can be transmitted through blood transfusion. 54.9% of barbers did not agree that it was essential to have periodic tests for HBV and HCV; however, 67.5%would themselves like to be tested for these infections. 32% washed their hands before attending each client, 59% cleaned instruments with disinfectant between clients, 96.1% washed razors with tap water before use on a new client, 92.6% also washed their razors with an antiseptic solution after every use, 87% used a new blade on new clients and 55% used disinfectants for skin cuts. In Yemen, a large number of barbers are shaving clients with an old style razor with a permanent blade. There is moderate awareness about the various modes of transmission of hepatitis among the barbers. PMID- 22198004 TI - Discussing death with pediatric patients: implications for nurses. AB - Communicating about end-of-life issues with a pediatric patient and their families can be difficult and uncomfortable for many nurses. The purposes of this article are to provide nurses a foundational overview of the child's understanding of death through the lens of awareness, development, and experience and to provide effective ways for nurses to implement this knowledge as they approach the topic of death with patients and their families. PMID- 22198005 TI - Neurotoxin A2NTX blocks fast inhibitory and excitatory transmitter release from presynaptic terminals. AB - Our recent study showed a possibility that newly developed A2 type botulinum toxin (A2NTX) inhibits both spontaneous and evoked transmitter release from inhibitory (glycinergic or GABAergic) and excitatory (glutamatergic) nerve terminals using rat spinal sacral dorsal commissural nucleus neurons. In the present study, to determine the modulatory effect of A2NTX on glycinergic and glutamatergic release probabilities, we tested the effects of A2NTX on a single inhibitory or excitatory nerve ending adherent to a dissociated neuron that was activated by paired-pulse stimuli by using the focal electrical stimulation technique. The results of the present paired-pulse experiments showed clearly that A2NTX enhanced paired-pulse facilitation of evoked glycinergic inhibitory postsynaptic currents and glutamatergic excitatory postsynaptic currents and increased the failure rate (Rf) of the first postsynaptic currents (P(1)) and both the responses. These effects of A2NTX on the amplitude and Rf of the P(1) and the second postsynaptic currents (P(2)) and paired-pulse ratio were rescued by application of 4-aminophthalimide. In summary, the present results showed that A2NTX acts purely presynaptically and inhibits the release machinery of transmitters such as glycine and glutamate, and the transmitter release machinery became less sensitive to intracellular free-Ca(2+) in A2NTX poisoned nerve terminals. PMID- 22198007 TI - Ameliorating effect of hypothalamic brain-derived neurotrophic factor against impaired glucose metabolism after cerebral ischemic stress in mice. AB - Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has potent neuroprotective effects against brain injury. We recently reported that glucose intolerance/hyperglycemia could be induced by ischemic stress (i.e., post-ischemic glucose intolerance) following ischemic neuronal damage. Therefore, the aim of this study was to determine the effects of BDNF on the development of post-ischemic glucose intolerance and ischemic neuronal damage. Male ddY mice were subjected to middle cerebral artery occlusion (MCAO) for 2 h. On day 1, the expression levels of BDNF were significantly decreased in the cortex, hypothalamus, liver, skeletal muscle, and pancreas. The expression levels of tyrosine kinase B receptor, a BDNF receptor, decreased in the hypothalamus and liver and increased in the skeletal muscle and pancreas, but remained unchanged in the cortex. Intrahypothalamic administration of BDNF (50 ng/mouse) suppressed the development of post-ischemic glucose intolerance on day 1 and neuronal damage on day 3 after MCAO. In the liver and skeletal muscle, the expression levels of insulin receptors decreased, while gluconeogenic enzyme levels increased on day 1 after MCAO. These changes completely recovered to normal levels in the presence of BDNF. These results indicate that regulation of post-ischemic glucose intolerance by BDNF may suppress ischemic neuronal damage. PMID- 22198006 TI - Dragon's blood inhibits chronic inflammatory and neuropathic pain responses by blocking the synthesis and release of substance P in rats. AB - As a traditional Chinese medicine, dragon's blood (DB) is widely used in treating various pains for thousands of years due to its potent anti-inflammatory and analgesic effects. In the present study, we observed that intragastric administration of DB at dosages of 0.14, 0.56, and 1.12 g/kg potently inhibited paw edema, hyperalgesia, cyclooxygenase-2 (COX-2) protein expression, or preprotachykinin-A mRNA expression in carrageenan-inflamed or sciatic nerve injured (chronic constriction injury) rats, respectively. A short-term (15 s or 10 min) pre-exposure of cultured rat dorsal root ganglion (DRG) neurons to DB (0.3, 3, and 30 ug/ml) or its component cochinchinenin B (CB; 0.1, 1, and 10 uM) blocked capsaicin-evoked increases in both the intracellular calcium ion concentration and the substance P release. Moreover, a long-term (180 min) exposure of cultured rat DRG neurons to DB or CB significantly attenuated bradykinin-induced substance P release. These findings indicate that DB exerts anti-inflammatory and analgesic effects by blocking the synthesis and release of substance P through inhibition of COX-2 protein induction and intracellular calcium ion concentration. Therefore, DB may serve as a promising potent therapeutic agent for treatment of chronic pain, and its effective component CB might partly contribute to anti-inflammatory and analgesic effects. PMID- 22198008 TI - Allograft pathology in patients transplanted for idiopathic dilated cardiomyopathy. AB - There are few morphologic studies on idiopathic dilated cardiomyopathy (CM) treated with transplant. We prospectively correlated gross, histologic, and clinical findings pertaining to hearts explanted in a 5-year period from patients with a clinical diagnosis of nonischemic CM and also correlated left ventricular diameter with preoperative echocardiographic reports. Of 64 patients with a clinical diagnosis of dilated cardiomyopathy (DC), 42 were men (age, 51 +/- 13 y) and 22 were women (age, 42 +/- 18 y). The pathologic diagnosis was idiopathic (dilated) cardiomyopathy (DC) in 55 patients (86%) and features of specific CM in 9 patients (14%). Specific diagnoses were fibrofatty change consistent with arrhythmogenic right ventricular cardiomyopathy (n=6), amyloidosis (n=2), and sarcoidosis (n=1), none of which were suspected clinically. The 55 hearts with idiopathic DC had a mean heart weight of 508 (range, 220 to 980) g. Pathologic subsets of the DC group included 4 hearts without enlargement, cavity dilatation, or significant histologic findings (minimal DC); 3 hearts with histologic evidence of healed myocarditis; and 5 hearts with mildly noncompacted left ventricle with hypertrabeculation. Five patients had prior mitral or tricuspid valve replacement/repairs to manage heart failure. There were 7 postpartum DC cases, 1 with a histologic pattern of healed myocarditis and 1 alcoholism associated DC. Familial DC comprised 16% (9 of 55) of patients. In patients without prior assist device placement, pathologic left ventricular cavity diameter correlated with echocardiographic end-diastolic volume (r , 0.8, P<0.0001). Morphologically, DC is a heterogeneous group. Areas of fibrofatty change and features of noncompaction are not uncommon. Left ventricular measurement at explant correlates well with echocardiographic findings, with a relatively consistent underestimation of the diameter. PMID- 22198009 TI - A word of caution regarding napsin A expression in squamous cell carcinomas of the lung. AB - Napsin A is a novel peripheral airway epithelial marker that, because it is commonly expressed in lung adenocarcinomas but absent in squamous cell carcinomas, is considered to be useful in distinguishing between these 2 types of tumors. Recent immunohistochemical studies, however, have reported napsin A expression in up to 26% of squamous cell carcinomas of the lung, a finding that indicates that this marker may not be as specific for lung adenocarcinomas as is generally believed. To determine the causes of the discrepancies between some recent immunohistochemical studies and previous reports on napsin A expression in squamous cell carcinomas of the lung, 90 pulmonary and 64 nonpulmonary squamous cell carcinomas (20 skin, 10 esophagus, 7 uterine cervix, and 27 from the head and neck region) were investigated by immunohistochemistry for this marker. None of the 90 squamous cell carcinomas of the lung exhibited napsin A positivity in the neoplastic cells; however, because strong napsin A reactivity was observed in hyperplastic type II pneumocytes and in intra-alveolar macrophages, both of which were sometimes seen entrapped within the tumor, it has been concluded that the presence of these entrapped cells was the most likely cause of the discrepancies. Pathologists should be aware of this potential pitfall in the interpretation of the immunostaining for napsin A, especially when small lung biopsy specimens, tissue microarrays, or cytology specimens are being evaluated. PMID- 22198010 TI - Adenocarcinomas with prominent lepidic spread: retrospective review applying new classification of the American Thoracic Society. AB - BACKGROUND: Recently, a new classification of lung adenocarcinomas has been proposed for tumors with lepidic spread. The greatest diameter of the invasive component determines minimally invasive cancers, and the term bronchioloalveolar carcinoma is no longer used. METHODS: We retrospectively reviewed 87 resected adenocarcinomas of the lung; 30 tumors with lepidic growth and without high-grade invasive areas were identified, and the invasive component was measured morphometrically and categorized. A dimension of 5 mm was the cutoff for invasion. Regional lymph node involvement and short-term follow-up were compared among subtypes of these well-differentiated and moderately differentiated adenocarcinomas. RESULTS: There were 11 well-differentiated adenocarcinomas with lepidic growth: 3 adenocarcinomas in situ (nonmucinous) and 8 minimally invasive adenocarcinomas (MIAs) (4 mucinous and 4 nonmucinous). There were 19 invasive moderately differentiated adenocarcinomas with a prominent lepidic growth pattern (LPAs). The mean size of the 3 adenocarcinomas in situ cases was 0.9+/-0.7 mm; the total size of the 8 MIA cases was 1.4+/-1.8 cm and that of the 19 LPA cases was 3.2+/-2.1 cm. The invasive size of the MIA was 0.3+/-0.6 and that of the LPA was 2.2+/-0.3. The invasive pattern of the LPAs was papillary and acinar without desmoplasia (n=3) and acinar with desmoplasia (n=16). Seven of the invasive desmoplastic tumors showed complex single-cell invasion or lymphatic invasion. Identification of the transition from lepidic to invasive acinar was straightforward because of the presence of elastotic desmoplasia. The transition between complex acinar papillary invasion and lepidic growth was often difficult to discern. Lymph node metastases were present in 5 cases (26%), all in tumors with an acinar, desmoplastic invasive component of >1 cm, with areas of single cell invasion. With follow-up, progressive nodal involvement or distant metastases occurred in 4 patients, all with complex invasive patterns; 3 with invasion >1 cm and 1 with lymphatic invasion in smaller invasive tumors. Recurrent lung nodules occurred in 5 patients, including 1 patient with MIA, 1 with nondesmoplastic invasion, 2 with desmoplastic invasion, and 1 with complex desmoplastic invasion. CONCLUSIONS: Approximately one third of lung adenocarcinomas have significant lepidic spread, and of these nearly one third are minimally invasive. Measurement of the invasive component may be difficult without elastotic desmoplasia. In this small series, lymph node and distant metastases occurred only in those with complex invasive patterns, but lung recurrence occurred in all subtypes, including MIAs. PMID- 22198011 TI - Editorial: Uniform conflict of interest disclosure and publication efficiencies at Ear and Hearing. PMID- 22198012 TI - Splenic neurohormonal modulation of mesenteric vascular tone. AB - In portal hypertension, development of a hyperdynamic circulation is preceded by transient mesenteric vasoconstriction. Portal hypertension increases splenic venous outflow pressure. We hypothesized that this causes direct reflex activation of mesenteric vasoconstrictor nerves and splenorenal reflex-mediated activation of the renin-angiotensin system. In anaesthetized male rats, we measured mesenteric efferent nerve activity and mesenteric vascular conductance (MVC) after selectively elevating splenic venous pressure. Partial splenic vein occlusion raised splenic venous pressure (from 4.8 +/- 0.4 to 24.1 +/- 0.3 mmHg; n = 18) and induced a significant increase in mesenteric efferent nerve activity (from 23.2 +/- 3.3 to 31.6 +/- 3.5 spikes s(-1); n = 11); this response was abolished by prior splenic denervation (from 32.4 +/- 2.4 to 31.2 +/- 1.6 spikes s(-1); n = 7). Mesenteric vascular conductance, the ratio of superior mesenteric artery blood flow to mean arterial pressure, fell upon splenic vein occlusion (DeltaMVC = -0.0120 +/- 0.0014 ml min(-1)mmHg(-1); P < 0.05, n = 10). This was attenuated by splenic denervation (DeltaMVC = -0.0044 +/- 0.0018 ml min(-1)mmHg( 1); P < 0.05, n = 8), but unaffected by mesenteric denervation (DeltaMVC = 0.0145 +/- 0.0020 ml min(-1)mmHg(-1); n = 6) or bilateral renal denervation (DeltaMVC = -0.0106 +/- 0.0021 ml min(-1)mmHg(-1); n = 5). Localized blockade of mesenteric vascular angiotensin II type 1 (AT(1)) receptors significantly attenuated the response (DeltaMVC = -0.0058 +/- 0.0017 ml min(-1)mmHg(-1); P < 0.05, n = 5), whereas blockade of both AT(1) and alpha(1)-adrenergic receptors caused a significant increase in mesenteric conductance (DeltaMVC = +0.0033 +/- 0.0010 ml min(-1)mmHg(-1); P < 0.05, n = 6). Our evidence suggests that increased splenic venous outflow pressure reflexly activates adrenergic/angiotensinergic mesenteric nerves, vasodilator mesenteric nerves and the renin-angiotensin system. We propose that obstruction to splenic venous outflow, such as would normally accompany portal hypertension, induces reflex mesenteric vasoconstriction independently of the increase in portal venous pressure. PMID- 22198013 TI - Enhanced insulin secretion and glucose tolerance in rats exhibiting low plasma free fatty acid levels and hypertriglyceridaemia due to congenital albumin deficiency. AB - Congenitally analbuminaemic individuals and rats (NARs) exhibit several metabolic abnormalities, including hypertriglyceridaemia and plasma free fatty acid deficiency. Our aim was to study glucose homeostasis and insulin secretion in NARs. Plasma concentrations of lipids, glucose and insulin and secretion of insulin from the pancreatic islets were measured in female NARs and control animals (Sprague-Dawley rats; SDRs). Glucose homeostasis tests were also performed. Plasma glucose levels were similar between NARs and SDRs, irrespective of feeding status. However, fed insulinaemia was ~37% higher (P 0.05) in NARs than in SDRs. The NARs displayed a markedly increased glucose tolerance, i.e. the integrated glycaemic response was one-third that of the control animals. Enhanced glucose tolerance was associated with threefold higher insulinaemia at peak glycaemia after a glucose load than in the control animals. Similar peripheral insulin sensitivity was observed between groups. Isolated pancreatic islets from NARs secreted significantly more insulin than islets from SDRs in response to a wide range of glucose concentrations (2.8-33.3 mm). Despite having similar liver glycogen contents in the fully fed state, NARs had ~40% (P 0.05) lower glycogen contents than SDRs after 6 h fasting. The injection of a gluconeogenic substrate, pyruvate, elicited a faster rise in glycaemia in NARs compared with SDRs. Overall, NARs displayed enhanced glucose tolerance, insulin secretion and gluconeogenic flux. The higher glucose tolerance in NARs compared with SDRs is attributed to enhanced islet responsiveness to secretagogues, while peripheral insulin sensitivity seems not to be involved in this alteration. We propose that the enhanced glucose metabolism is a chronic compensatory adaptation to decreased free fatty acid availability in NARs. PMID- 22198014 TI - Co-ordination of cough and swallow in vivo and in silico. AB - Coughing and swallowing are airway-protective behaviours. The pharyngeal phase of swallowing prevents aspiration of oral material (saliva, food and liquid) by epiglottal movement, laryngeal adduction and clearing of the mouth and pharynx. Coughing is an aspiration-response behaviour that removes material from the airway. Co-ordination of these behaviours is vital to protect the airway from further aspiration-promoting events, such as a swallowing during the inspiratory phase of coughing. The operational characteristics, primary strategies and peripheral inputs that co-ordinate coughing and swallowing are unknown. This lack of knowledge impedes understanding and treatment of deficits in airway protection, such as the co-occurrence of dystussia and dysphagia common in Parkinson's and Alzheimer's diseases, as well as stroke. PMID- 22198015 TI - Endurance training decreases the non-linearity in the oxygen uptake-power output relationship in humans. AB - In this study, we hypothesized that 5 weeks of cycling endurance training can decrease the magnitude of the non-proportional increase in oxygen uptake (V(O(2))) to power output relationship (V(O(2)) 'excess') at exercise intensities exceeding the lactate threshold (LT). Ten untrained, physically active men performed a bout of incremental cycling exercise until exhaustion before and after training. The mitochondrial DNA copy number, myosin heavy chain composition and content of uncoupling protein 3 and sarcoplasmic reticulum Ca(2+)-ATPases (SERCAs) were analysed in muscle biopsies taken from vastus lateralis before and after training. The training resulted in an enhancement of the power-generating capabilities at maximal oxygen uptake (V(O(2)max)) by ~7% (P = 0.002) despite there being no changes in V(O(2)max) (P = 0.49). This effect was due to a considerable reduction in the magnitude of the V(O(2)) 'excess' (P < 0.05) above the LT. A decrease in plasma ammonia concentration was found during exercise after training (P < 0.05). A downregulation of SERCA2 in vastus lateralis (P = 0.006) was observed after training. No changes in myosin heavy chain composition, selected electron transport chain proteins, uncoupling protein 3 or the mitochondrial DNA copy number (P > 0.05) were found after training. We conclude that the training-induced increase in power-generating capabilities at V(O(2)max) was due to attenuation of the V(O(2)) 'excess' above the LT. This adaptive response seems to be related to the improvement of muscle metabolic stability, as judged by a lowering of plasma ammonia concentration. The enhancement of muscle metabolic stability after training could be caused by a decrease in ATP usage at a given power output owing to downregulation of SERCA2 pumps. PMID- 22198016 TI - Chronic kidney disease: cardiac and renal angiotensin-converting enzyme (ACE) 2 expression in rats after subtotal nephrectomy and the effect of ACE inhibition. AB - Renin-angiotensin system blockade slows but does not prevent the cardiovascular complications of chronic kidney disease (CKD). Angiotensin-converting enzyme (ACE) 2 is differentially regulated in acute kidney injury, with increased cardiac ACE2 but decreased kidney ACE2 levels. This study investigated the effect of long-term ACE inhibition on cardiac and renal ACE2 in rats with CKD induced by subtotal nephrectomy (STNx). Sprague-Dawley rats had sham (control) or STNx surgery. Control rats received vehicle (n = 9) and STNx rats ramipril (1 mg kg( 1) day(-1); n = 10) or vehicle (n = 10) for 28 days. Subtotal nephrectomy resulted in impaired creatinine clearance (P < 0.05), proteinuria (P < 0.05), renal fibrosis (P < 0.05) and reduced renal cortical ACE2 mRNA (P < 0.05) and activity (P < 0.05). In rats with CKD, ramipril improved creatinine clearance (P < 0.05) and was associated with an increase in cortical but not medullary ACE2 activity (P < 0.05). Compared with control rats, STNx rats were hypertensive (P < 0.01), with increased left ventricular end-diastolic pressure (LVEDP; P < 0.01), left ventricular hypertrophy (LVH; P < 0.05) and interstitial (P < 0.05) and perivascular fibrosis (P < 0.01). In rats with CKD, ramipril decreased blood pressure (P < 0.001) and reduced LVEDP (P < 0.01), LVH (P < 0.01) and perivascular fibrosis (P < 0.05) but did not significantly reduce interstitial fibrosis. There was no change in cardiac ACE2 in rats with CKD compared with control rats. In rats with CKD, ACE inhibition had major benefits to reduce blood pressure and cardiac hypertrophy and to improve creatinine clearance, but did not significantly impact on cardiac ACE2, cardiac interstitial fibrosis, renal fibrosis or proteinuria. Thus, in rats with CKD, renal ACE2 deficiency and lack of activation of cardiac ACE2 may contribute to the progression of cardiac and renal tissue injury. As long-term ACE inhibition only partly ameliorated the adverse cardio-renal effects of CKD, adjunctive therapies that lead to further increases in ACE2 activity may be needed to combat the cardio-renal complications of CKD. PMID- 22198017 TI - Expression of doublecortin, a neuronal migration protein, in unipolar brush cells of the vestibulocerebellum and dorsal cochlear nucleus of the adult rat. AB - Doublecortin (DCX) is a microtubule-associated protein that is critical for neuronal migration and the development of the cerebral cortex. In the adult, it is expressed in newborn neurons in the subventricular and subgranular zones, but not in the mature neurons of the cerebral cortex. By contrast, neurogenesis and neuronal migration of cells in the cerebellum continue into early postnatal life; migration of one class of cerebellar interneuron, unipolar brush cells (UBCs), may continue into adulthood. To explore the possibility of continued neuronal migration in the adult cerebellum, closely spaced sections through the brainstem and cerebellum of adult (3-16 months old) Sprague-Dawley rats were immunolabeled for DCX. Neurons immunoreactive (ir) to DCX were present in the granular cell layer of the vestibulocerebellum, most densely in the transition zone (tz), the region between the flocculus (FL) and ventral paraflocculus (PFL), as well as in the dorsal cochlear nucleus (DCN). These DCX-ir cells had the morphological appearance of UBCs with oval somata and a single dendrite ending in a brush. There were many examples of colocalization of DCX with Eps8 or calretinin, UBC markers. We also identified DCX-ir elements along the fourth ventricle and its lateral recess that had labeled somata but lacked the dendritic structure characteristic of UBCs. Labeled UBCs were seen in nearby white matter. These results suggest that there may be continued neurogenesis and/or migration of UBCs in the adult. Another possibility is that UBCs maintain DCX expression even after migration and maturation, reflecting a role of DCX in adult neuronal plasticity in addition to a developmental role in migration. PMID- 22198018 TI - Thyrotropin-releasing hormone causes a tonic excitatory postsynaptic current and inhibits the phasic inspiratory inhibitory inputs in inspiratory-inhibited airway vagal preganglionic neurons. AB - The airway vagal preganglionic neurons (AVPNs) in the external formation of the nucleus ambiguus (eNA), which include the inspiratory-activated AVPNs (IA-AVPNs) and inspiratory-inhibited AVPNs (II-AVPNs), predominate in the control of the trachea and bronchia. The AVPNs receive particularly dense inputs from terminals containing thyrotropin-releasing hormone (TRH). TRH microinjection into the nucleus ambiguus (NA) caused constriction of the tracheal smooth muscles. However, it is unknown whether TRH affects all subtypes of the AVPNs in the eNA, and as a result affects the control of all types of target tissues in the airway (smooth muscles, submucosal glands, and blood vessels). It is also unknown how TRH affects the AVPNs at neuronal and synaptic levels. In this study, the AVPNs in the eNA were retrogradely labeled from the extrathoracic trachea, the II-AVPNs were identified in rhythmically firing brainstem slices, and the effects of TRH were examined using patch-clamp. TRH (100 nmol L(-1)) enhanced both the rhythm and the intensity of the hypoglossal bursts, and caused a tonic excitatory inward current in the II-AVPNs at a holding voltage of -80 mV. The frequency of the spontaneous excitatory postsynaptic currents (EPSCs) in the II-AVPNs, which showed no respiratory-related change in a respiratory cycle, was not significantly changed by TRH. At a holding voltage of -50 mV, the II-AVPNs showed both spontaneous and phasic inspiratory (outward) inhibitory postsynaptic currents (IPSCs). TRH had no effect on the spontaneous IPSCs but significantly attenuated the phasic inspiratory outward currents, in both the amplitude and area. After focal application of strychnine, an antagonist of glycine receptors, to the II-AVPNs, the spontaneous IPSCs were extremely scarce and the phasic inspiratory inhibitory currents were abolished; and further application of TRH had no effect on these currents. Under current clamp configuration, TRH caused a depolarization and increased the firing rate of the II-AVPNs during inspiratory intervals. These results demonstrate that TRH affects the II-AVPNs both postsynaptically via a direct excitatory current and presynaptically via attenuation of the phasic glycinergic synaptic inputs. PMID- 22198019 TI - The increased expression of metabotropic glutamate receptor 5 in subventricular zone neural progenitor cells and enhanced neurogenesis in a rat model of intracerebral hemorrhage. AB - The metabotropic glutamate receptor 5 (mGluR5) is closely relative to the proliferation, survival, and differentiation of neural progenitor cells (NPCs). This study primarily examined the mGluR5 expression of NPCs in subventricular zone (SVZ) and the effects of mGluR5 on neurogenesis to intracerebral hemorrhage (ICH) rat. The experiment was designated as the following: (1) The ICH model was established by collagenase infusion into the right striatum of the rats, and the brain tissue was collected to assess the expression of mGluR5 in SVZ NPCs. (2) The rat brains were sampled for immunostaining of doublecortin (DCX) and 5-bromo 2'-deoxyuridine (BrdU) to examine the effects of the (R,S)-2-chloro-5 hydroxyphenylglycine (CHPG) on neurogenesis. (3) Behavioral testing was carried out to evaluate the effects of CHPG on neurofunctional recovery. The results of Western blot analysis showed that mGluR5 levels in the ipsilateral SVZ increased as early as at 3 days after ICH, peaked at 14 days. The change of mGluR5 mRNA level in the ipsilateral SVZ was generally similar to the pattern of Western blot analysis. The immunostaining also demonstrated that some nestin-positive cells were co-expressed with mGluR5. The injection of CHPG into ipsilateral ventricle increased DCX levels both in the ipsilateral striatum (STR) and the peri-lesion area of the striatum (PLA). Meanwhile, a significant difference in behavioral score was presented at 28 days after ICH between the CHPG-treated rats and the vehicle-treated or the non-treated rats. Our results demonstrated for the first time that the increased expression of mGluR5 in SVZ NPCs occurred in ICH rat. The CHPG promoted the neurogenesis and improved neurofunctional symptom induced by ICH. These results suggested that the increased expression of mGluR5 on NPCs in SVZ may play an important role in neurogenesis in ICH rat. PMID- 22198020 TI - Development and characterisation of a novel rat model of Parkinson's disease induced by sequential intranigral administration of AAV-alpha-synuclein and the pesticide, rotenone. AB - Modeling Parkinson's disease remains a major challenge for preclinical researchers, as existing models fail to reliably recapitulate all of the classic features of the disease, namely, the progressive emergence of a bradykinetic motor syndrome with underlying nigrostriatal alpha-synuclein protein accumulation and nigrostriatal neurodegeneration. One limitation of the existing models is that they are normally induced by a single neuropathological insult, whereas the human disease is thought to be multifactorial with genetic and environmental factors contributing to the disease pathogenesis. Thus, in order to develop a more relevant model, we sought to determine if administration of the Parkinson's disease-associated pesticide, rotenone, into the substantia nigra of rats overexpressing the Parkinson's disease-associated protein, alpha-synuclein, could reliably model the triad of classic features of the human disease. To do so, rats underwent stereotaxic surgery for unilateral delivery of the adeno-associated virus (AAV)-alpha-synuclein into the substantia nigra. This was followed 13 weeks later by delivery of rotenone into the same site. The effect of the genetic and environmental insults alone or in combination on lateralised motor performance (Corridor, Stepping, and Whisker Tests), nigrostriatal integrity (tyrosine hydroxylase immunohistochemistry), and alpha-synucleinopathy (alpha-synuclein immunohistochemistry) was assessed. We found that rats treated with either AAV alpha-synuclein or rotenone developed significant motor dysfunction with underlying nigrostriatal neurodegeneration. However, when the genetic and environmental insults were sequentially administered, the detrimental impact of the combined insults on motor performance and nigrostriatal integrity was significantly greater than the impact of either insult alone. This indicates that sequential exposure to relevant genetic and environmental insults is a valid approach to modeling human Parkinson's disease in the rat. PMID- 22198021 TI - Transsynaptic tracing of conditioned eyeblink circuits in the mouse cerebellum. AB - The eyeblink has long served as a model for motor learning and modulation. However, cerebellar pathways underlying conditioned blinks remain poorly studied in the mouse, and the location of blink-related neurons has never been transsynaptically mapped in the cerebellar cortex. This study aims to rectify this gap in our knowledge. By injecting GFP-expressing Pseudorabies virus (PRV 152) into the mouse orbicularis oculi muscle, neurons in the mouse eyeblink motor control circuit are transsynaptically labeled. In the facial nucleus, labeling was strictly ipsilateral to the injection site and restricted to the dorsolateral rim, consistent with previous studies. The red nucleus is bilaterally labeled at the lateral rim with clear contralateral preference. Previously unreported labeling was found in the ventrolateral red nucleus. Single-step tracing confirmed this area receives projections from eyeblink-related portions of the anterior interpositus and sends projections to eyelid-controlling portions of the facial nucleus. In the deep cerebellar nuclei, blink-related neurons were labeled both in areas associated with blink conditioning and in areas associated with other blink modulation. Finally, novel maps of the cerebellar cortex revealed a characteristic spatiotemporal pattern of labeling. Posterior vermal Purkinje cells were labeled first, followed by anterior vermal cells, then by hemispheric cells. PMID- 22198036 TI - On the paradoxical determinations of the lacuno-canalicular permeability of bone. AB - The lacuno-canalicular permeability has been shown to play a key role in the behavior of bone tissue. The aim of this study is, by giving an overview of the determinations of this parameter, to question the paradoxical values provided by theoretical predictions and recent experimental measurements. We propose therefore a Kozeny-like law obtained by a numerical method which relates the permeability to the textural parameters of cortical bone microstructure. Moreover, we suggest possible explanations for this paradox considering the empirical difficulties and possible multiphysical effects. PMID- 22198037 TI - Looking different, feeling different: women's reactions to risk-reducing breast and ovarian surgery. AB - Most studies of quality of life following risk-reducing bilateral salpingo oophorectomy (RRSO) and mastectomy (RRM) for inherited breast and ovarian cancer susceptibility were conducted before counseling protocols were established and included women at varying times since surgery. This study aimed to overcome these deficiencies and to provide current data on outcomes for this growing group of women. Semi-structured interviews were used to explore the experiences of an Australian cohort of 40 high-risk women 3 years after they underwent RRM and/or RRSO. Data were analyzed using the method of constant comparison. 19/40 women underwent RRSO, 8/40 RRM and 13/40 both procedures. Two themes-looking different and feeling different-captured the psychosocial impact of surgery upon interviewees. All regarded RR surgery as a positive experience and were relieved at having their risks of cancer substantially reduced; however, reducing risk by removing these body parts is not without costs. In addition to relief interviewees also reported experiencing a range of negative emotions and a range of unexpected bodily sensations following surgery and reflected upon both positive and negative changes in their appearance. Women said they had been unprepared for the lack of sensation in reconstructed breasts and/or the severity of menopausal symptoms, which often had a negative impact upon sexuality. At-risk women regard RR surgery as a positive way to manage cancer risk. However, although women who currently undergo RR surgery are informed about its sequelae, few are entirely prepared for the reality of undergoing this procedure. We recommend that women who undergo these procedures should be provided with information supported by psychosocial input before and after RR surgery. PMID- 22198048 TI - Patients with atypical hyperplasia of the endometrium should be treated in oncological centers. AB - OBJECTIVES: To examine the prevalence of undiagnosed endometrial carcinoma (EC) among women with a preoperative diagnosis of atypical endometrial hyperplasia (AEH) in correlation to age, BMI and menopause. METHODS: Data extracted from the Danish Gynecological Cancer Database (DGCD) covering women diagnosed with AEH between January 1, 2005 and November 1, 2010 undergoing surgery. DGCD is a multidisciplinary, nationwide, clinical database of all cases of gynecological cancer and AEH in Denmark diagnosed after January 1, 2005. Registration is mandatory. Primary outcome was preoperative- and postoperative diagnoses. Secondary outcomes were relationship to BMI, age and menopause. RESULTS: The preoperative diagnosis of AEH was retained in 41% of 773 cases and 59% had endometrial cancer. Of the cancer cases, 18% had more than Stage I disease and 3% were non-endometrioid. Cancer risk was significantly related to age (p<0.0001) and menopause (p<0.0001). The 80% who were postmenopausal had a significantly higher risk of a postoperative cancer diagnosis compared with the premenopausal group (OR 2.8). There was no significant difference regarding BMI (p=0.25). CONCLUSION: More than half of the 773 Danish women primarily diagnosed with AEH had undiagnosed cancer. Failure to diagnose endometrial carcinoma preoperatively can lead to inadequate staging and potentially suboptimal treatment. We recommend that atypical endometrial hyperplasia should be treated as carcinoma in specialized gynecological-oncology centers. PMID- 22198047 TI - Effect of inhibition of angiotensin converting enzyme and/or neutral endopeptidase on vascular and neural complications in high fat fed/low dose streptozotocin-diabetic rats. AB - Treating high fat fed/low dose streptozotocin-diabetic rats; model of type 2 diabetes, with ilepatril (vasopeptidase inhibitor, blocks neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE)) improved vascular and neural functions. Next, studies were performed to determine the individual effect of inhibition of NEP and ACE on diabetes-induced vascular and neural dysfunctions. High fat fed rats (8 weeks) were treated with 30 mg/kg streptozotocin (i.p.) and after 4 additional weeks, were treated for 12 weeks with ilepatril, enalapril (ACE inhibitor) or candoxatril (NEP inhibitor) followed by analysis of vascular and neural functions. Glucose clearance was impaired in diabetic rats and was not improved with treatment although treatment with ilepatril or candoxatril partially improved insulin stimulated glucose uptake by isolated soleus muscle. Diabetes caused slowing of motor and sensory nerve conduction, thermal hypoalgesia, reduction in intraepidermal nerve fiber (IENF) profiles and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide (CGRP) in epineurial arterioles of the sciatic nerve. Inhibition of NEP improved nerve conduction velocity and inhibition of NEP or ACE improved thermal sensitivity and protected IENF density. Ilepatril and candoxatril treatments of diabetic rats were efficacious in improving vascular responsiveness to acetylcholine in epineurial arterioles; whereas all three treatments improved vascular response to CGRP. These studies suggest that inhibition of NEP and ACE activity is an effective approach for treatment of type 2 diabetes neural and vascular complications. PMID- 22198049 TI - A randomized phase III clinical trial of a combined treatment for cachexia in patients with gynecological cancers: evaluating the impact on metabolic and inflammatory profiles and quality of life. AB - OBJECTIVES: Gynecological neoplastic disease progression is characterized by specific energy metabolism alterations and by symptoms including fatigue, anorexia, nausea, anemia, and immunodepression, which result in a cachexia syndrome and a marked decrease in patient quality of life (QoL). Therapeutic protocols associated with appropriate and effective psychological and social support systems are essential to counteract the symptoms of neoplastic disease in incurable patients. METHODS: A phase III randomized study was performed to establish the most effective and safest treatment to improve the key symptoms in advanced gynecological cancer patients, i.e., lean body mass (LBM), resting energy expenditure (REE), fatigue, and QoL. In addition, the impact of the treatment arms on the main metabolic and inflammatory parameters, including C reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, leptin, reactive oxygen species (ROS), and glutathione peroxidase, was evaluated. The change in the Glasgow Prognostic Score (GPS) during treatment was also assessed. A total of 104 advanced-stage gynecological cancer patients were enrolled and randomly assigned to receive either megestrol acetate (MA) plus l carnitine, celecoxib, and antioxidants (arm 1) or MA alone (arm 2). The treatment duration was 4 months. RESULTS: The combination arm was more effective than arm 2 with respect to LBM, REE, fatigue, and global QoL. As for the secondary efficacy endpoints, patient appetite increased, and ECOG PS decreased significantly in both arms. The inflammation and oxidative stress parameters IL-6, TNF-alpha, CRP, and ROS decreased significantly in arm 1, while no significant change was observed in arm 2. CONCLUSIONS: The combined treatment improved both immunometabolic alterations and patient QoL. Multimodality therapies for cachexia ideally should be introduced within a context of "best supportive care" that includes optimal symptom management and careful psychosocial counseling. PMID- 22198050 TI - Evaluation of apoptosis induced by nanoparticles and fine particles in RAW 264.7 macrophages: facts and artefacts. AB - Current hazard characterisation of nanoparticles (NP) is predominantly based on in vitro test systems, being established for small molecules of drugs and chemicals. However, specific physicochemical properties of NP may result in interference with assay components, biomarkers, or detection systems. In the present study, six types of (nano)particles were screened in RAW 264.7 macrophages by common cytotoxicity methods (WST-1, LDH). Our specific focus was on the investigation of apoptosis (analysis of hypodiploid DNA, phosphatidylserine exposure, caspase 3/7 activation, and Cell Death Detection ELISA). Assays were validated by the well-known apoptosis inducer staurosporine. Our results show that ZnO, DQ12 quartz and amorphous silica are cytotoxic with strong indications for apoptotic effects in RAW 264.7 macrophages, whereas toxicity was absent for MgO. For fine as well as ultrafine TiO(2), no apoptotic effects could be detected except for induction of DNA fragmentation. The results of our study demonstrate the necessity to control on a case-by-case basis for assay interference to avoid misinterpretation of specific in vitro test findings. To obtain valid statements on the potential induction of apoptosis by specific NP the measurement of multiple endpoints is a prerequisite. PMID- 22198051 TI - Comparative in vitro cytotoxicity study of silver nanoparticle on two mammalian cell lines. AB - In this study the cytotoxic effect of commercially available silver (Ag) nanoparticle was evaluated using human dermal and cervical cancer cell lines. Prior to the cellular studies a full particle size characterisation was carried out using Dynamic Light Scattering (DLS), Transmission Electron Microscopy and Scanning Electron Microscopy in distilled water and cell culture media. The Zeta Potential (ZP) associated with the Ag nanoparticle was also determined in order to assess its stability in the solutions and its possible interaction with the media. The DLS and ZP study have suggested interaction of Ag nanoparticles with the media, which can lead to secondary toxicity. The toxic effects of Ag nanoparticles were then evaluated using different cytotoxic endpoints namely the lysosomal activity, mitochondrial metabolism, basic cellular metabolism, cellular protein content and cellular proliferative capacity. The cytotoxic effect of Ag nanoparticle was dependant on dose, exposure time and on the cell line tested. Further investigation was carried out on HeLa and HaCaT cell lines to elucidate the mechanism of its cytotoxicity. The Ag nanoparticle was noted to induce elevated levels of oxidative stress, glutathione depletion and damage to the cell membrane as found from the adenylate kinase assay and that leads to the apoptosis. Overall, significant differences were observed between the sensitivity of the two cell lines which can be understood in terms of their natural antioxidant levels. PMID- 22198052 TI - A novel method of selecting human embryonic stem cell-derived cardiomyocyte clusters for assessment of potential to influence QT interval. AB - Physiologically relevant assessment of delayed repolarization is necessary in drug development. In our preliminary experiments on the evaluation using a multielectrode recording system, we had found that the responsiveness of field potential duration (FPD), as QT-like intervals, to hERG channel blockers differed greatly from non-responders to excessive responders in human embryonic stem cell derived cardiomyocyte clusters. Thus, we report a novel method of selecting clusters suitable for evaluating compounds for the assessment. Clusters were treated with cisapride, a hERG channel blocker, at 100nM, and selected with criteria of 5-20% of corrected FPD (FPDc) prolongation. Then, selected clusters were treated with reference compounds. FPDc was prolonged by blockade of the hERG channel (E-4031 and dl-sotalol) and KvLQT1 channel (chromanol 293B and HMR1556), and by activation of the sodium channel (veratridine) and calcium channel (Bay K8644). FPDc was shortened by calcium channel blockage (verapamil, nifedipine and diltiazem) and by K(ATP) channel activation (pinacidil). Class Ia antiarrhythmic drugs, quinidine and disopyramide, prolonged FPDc. Selected clusters are appropriate for assessing the effects of compounds on ion channels affecting QT intervals. This is the first report of the establishment of an assessment system of potential to influence QT interval, using pharmacologically selected clusters. PMID- 22198053 TI - Possible mechanism of superoxide formation through redox cycling of plumbagin in pig heart. AB - The purpose of this study is to elucidate the possible mechanism of superoxide formation through redox cycling of plumbagin (PLG) in pig heart. Of four 1,4 naphthoquinones tested in this study, PLG was most efficiently reduced in the cytosolic fraction of pig heart. On the other hand, lawsone (LAS) was little reduced. Thus, whether or not PLG and LAS induce the formation of superoxide anion radical in pig heart cytosol was examined, by using the methods of cytochrome c reduction and chemiluminescence. PLG significantly induced the formation of superoxide anion radical, even though LAS had no ability to mediate superoxide formation. PLG was a significant inhibitor for the stereoselective reduction of 4-benzoylpyridine (4-BP) catalyzed by tetrameric carbonyl reductase (TCBR) in pig heart cytosol. Furthermore, PLG was confirmed to competitively inhibit the 4-BP reduction, and the optimal pH for the PLG reduction was around 6.0 similar to that for the 4-BP reduction. These results suggest that PLG mediates superoxide formation through its redox cycling involved in the two electron reduction catalyzed by TCBR, and induces oxidative stress in pig heart. PMID- 22198054 TI - Beneficial effects of benzodiazepine diazepam on chronic stress-induced impairment of hippocampal structural plasticity and depression-like behavior in mice. AB - Whether benzodiazepines (BZDs) have beneficial effects on the progress of chronic stress-induced impairment of hippocampal structural plasticity and major depression is uncertain. The present study designed four preclinical experiments to determine the effects of BZDs using chronic unpredictable stress model. In Experiment 1, several time course studies on behavior and hippocampus response to stress were conducted using the forced swim and tail suspension tests (FST and TST) as well as hippocampal structural plasticity markers. Chronic stress induced depression-like behavior in the FST and TST as well as decreased hippocampal structural plasticity that returned to normal within 3 wk. In Experiment 2, mice received p.o. administration of three diazepam dosages prior to each variate stress session for 4 wk. This treatment significantly antagonized the elevation of stress-induced corticosterone levels. Only low- (0.5mg/kg) and medium-dose (1mg/kg) diazepam blocked the detrimental effects of chronic stress. In Experiment 3, after 7 wk of stress sessions, daily p.o. diazepam administration during 1 wk recovery phase dose-dependently accelerated the recovery of stressed mice. In Experiment 4, 1 wk diazepam administration to control mice enhanced significantly hippocampal structural plasticity and induced an antidepressant like behavioral effect, whereas 4 wk diazepam administration produced opposite effects. Hence, diazepam can slow the progress of chronic stress-induced detrimental consequences by normalizing glucocorticoid hormones. Considering the adverse effect of long-term diazepam administration on hippocampal plasticity, the preventive effects of diazepam may depend on the proper dose. Short-term diazepam treatment enhances hippocampal structural plasticity and is beneficial to recovery following chronic stress. PMID- 22198055 TI - Cross regulation between Candida albicans catalytic and regulatory subunits of protein kinase A. AB - In the pathogen Candida albicans protein kinase A (PKA) catalytic subunit is encoded by two genes TPK1 and TPK2 and the regulatory subunit by one gene, BCY1. PKA mediates several cellular processes such as cell cycle regulation and the yeast to hyphae transition, a key factor for C. albicans virulence. The catalytic isoforms Tpk1p and Tpk2p share redundant functions in vegetative growth and hyphal development, though they differentially regulate glycogen metabolism, the stress response pathway and pseudohyphal formation. In Saccharomyces cerevisiae it was earlier reported that BCY1 overexpression not only increased the amount of TPK3 mRNA but also its catalytic activity. In C. albicans a significant decrease in Bcy1p expression levels was already observed in tpk2Delta null strains. In this work we showed that the upregulation in Bcy1p expression was observed in a set of strains having a TPK1 or TPK2 allele reintegrated in its own locus, as well as in strains expressing the TPKs under the control of the constitutive ACT1 promoter. To confirm the cross regulation event between Bcy1p and Tpkp expression we generated a mutant strain with the lowest PKA activity carrying one TPK1 and a unique BCY1 allele with the aim to obtain two derived strains in which BCY1 or TPK1 were placed under their own promoters inserted in the RPS10 neutral locus. We found that placing one copy of BCY1 upregulated the levels of Tpk1p and its catalytic activity; while TPK1 insertion led to an increase in BCY1 mRNA, Bcy1p and in a high cAMP binding activity. Our results suggest that C. albicans cells were able to compensate for the increased levels of either Tpk1p or Tpk2p subunits with a corresponding elevation of Bcy1 protein levels and vice versa, implying a tightly regulated mechanism to balance holoenzyme formation. PMID- 22198056 TI - Oxidative stress due to anesthesia and surgical trauma and comparison of the effects of propofol and thiopental in dogs. AB - The present study aimed to evaluate the effect of propofol and thiopental on the plasma oxidant-antioxidant profile in dogs undergoing surgery at doses used to induce anesthesia. The plasma total oxidant status (TOS) and oxidative stress index (OSI) levels increased significantly with time in both groups, whereas the plasma total antioxidant status (TAS) levels decreased with time in both groups. The OSI was significantly higher at the end of surgery than before induction of anesthesia in both groups. The TOS and OSI change ratio of propofol group were significantly lower than that of thiopental group. In conclusion, our findings show that propofol has antioxidant effects in dogs. Further studies need to be conducted to demonstrate the exact mechanism of oxidative stress due to anesthesia and surgery in dogs. PMID- 22198057 TI - Hypertrophic osteopathy associated with pulmonary adenosquamous carcinoma in a dog. AB - A six-year-old intact female Maltese dog weighing 3.8 kg presented with a history of mild lameness and swelling on both forelimbs. Radiographic and computed tomographic views revealed an extensive periosteal reaction in all four limbs and a large round mass on the right middle lung lobe. A total lobectomy was performed and pulmonary adenosquamous carcinoma was histologically confirmed. A diagnosis of hypertrophic osteopathy (HO) secondary to a lung tumor was made. Periosteal proliferation decreased significantly after surgery; however, there was evidence of dyspnea, mass recurrence, and periosteal reaction three months post operatively. This is the first case report of pulmonary adenosquamous carcinoma with HO in a dog in which we describe clinical, imaging, surgical, and histological findings. PMID- 22198058 TI - Spontaneous nephroblastoma in a Japanese giant salamander (Andrias japonicus). AB - An adult male Japanese giant salamander (Andrias japonicus) died accidentally, and necropsy showed a white mass (23 * 15 mm) in the left kidney and hepatorrhexis with hemoperitoneum. Histologically, the renal mass was mainly composed of immature nephroblastic tumor cells. In the tumor tissue, a trabecular pattern lined by oval to polygonal tumor cells with a rich interstitium, solid growth and a few tubular structures was observed. Nephroblastic tumor cells were strongly positive for vimentin and weakly positive, and epithelium-like tumor cells were strongly positive for cytokeratin. However, antibody for Wilms' tumor protein 1 did not react with the salamander's cells. On electron microscopy, a desmosome junction was observed between tumor cells. This is the first report of nephroblastoma in a Japanese giant salamander. PMID- 22198059 TI - Therapeutic potential of canine bone marrow stromal cells (BMSCs) in the carbon tetrachloride (CCl4) induced chronic liver dysfunction mouse model. AB - Regenerative medicine using bone marrow cells is an attractive therapy for the cure of patients with severe liver disease. Here, we show the therapeutic potential of canine bone marrow stromal cells (BMSCs) in mouse models of CCl(4) induced chronic liver dysfunction. We used two different models for xenotransplantation, nude mice and cyclosporine A (CSA) immunosuppressed mice. Serum parameters from a standard liver panel were not improved following transplantation. However, fibrotic liver lesions with severe inflammation were decreased in CCl(4)-treated CSA mice following BMSC transplantation. Effective migration of transplanted canine BMSCs was limited to persistently injured liver in CCl(4)-treated CSA mice, where they may be effective in resolving inflammatory fibrotic lesions. These results suggest that canine BMSCs are an effective cell source for liver regeneration. PMID- 22198060 TI - Primary care physician's knowledge of ethnicity-specific guidelines for obesity diagnosis and readiness for obesity intervention among South Asian Indians. AB - Many primary care physicians lack sufficient knowledge on current guidelines for overweight/obesity diagnosis among minority groups. We assessed physician knowledge and awareness on modified guidelines for identifying obesity among South Asian Indians (SAIs). Cross sectional survey of 183 physicians practicing in Houston, who reported on their knowledge on guidelines for obesity among SAIs, frequency of measurement of surrogate markers, self-reported competency in management of obesity, and readiness to seek training on obesity diagnosis among SAIs. 65% of physicians agree obesity is a growing problem among SAIs with only 9% of physicians reporting measuring waist circumference. Only 21% of physicians were aware of the recommended WHO modified BMI criteria and 41% the IDF criteria for waist circumference. SAI physicians had significantly higher knowledge compared to other physicians. 78% were ready to seek training on the modified guidelines across ethnicity and training. There is a low level of knowledge on ethnicity-specific guidelines for obesity diagnosis among physicians. There is however a readiness to learn, indicating the need for a physician awareness training on current obesity guidelines, for various ethnic populations. PMID- 22198061 TI - Coping strategies in Aymara caregivers of patients with schizophrenia. AB - Deinstitutionalization has forced families of patients with schizophrenia to take responsibility of informal care, without having the tools to exert their role properly. The aim of this study was to evaluate the coping strategies of caregivers of patients with schizophrenia, belonging to the Aymara ethnic group, (aborigines who are located on the highlands of Northern Chile). The studied sample comprised 45 caregivers of patients with schizophrenia users of the Mental Health Service of Arica, Chile. The results from the Family Coping Questionnaire (FCQ) show that both, Aymara and non-Aymara caregivers use the same coping strategies except for spiritual help which is more likely to be used by Aymara. This strategy might be related with the worldview they possess, thus the relation with the deities has a meaningful importance in the way of explaining and coping with different phenomena. PMID- 22198062 TI - Role of epithelial mucins during airway infection. AB - Airway surface fluid contains two layers of mucins consisting mainly of 5 different mucin gene products. While the outer layer contains two gel-forming mucins (MUC5AC and MUC5B) that are tightly associated with various biologically active, defensive molecules, the inner layer contains three membrane-tethered mucins (MUC1, MUC4 and MUC16) shed from the apical cell surface. During airway infection, all of these mucins serve as a major protective barrier against pathogens. MUC1 mucin produced by virtually all the surface columnar epithelial cells in the respiratory tract as well as Type II pneumocytes in the alveoli plays an additional, perhaps more critical role during respiratory infection by controlling the resolution of inflammation that is essential to prevent the development of inflammatory lung disease. PMID- 22198063 TI - Efficacy of Morus nigra L. on reproduction in female Wistar rats. AB - Morus nigra L. is a plant employed as a substitute for the conventional hormonal replacement therapy. This work analyzes the estrogenic effect of M. nigra on the reproductive system and embryonic development of Wistar rats. Female rats were orally treated with M. nigra hydroalcoholic extract (MnHE) at the dose levels of 25, 50, 75, 350 and 700 mg/kg of body weight over 15 days, and continued through mating until the 14th day of gestation. Vaginal smears were performed daily and the body weight of the females was recorded at 5 days intervals. On day 15 of gestation, the females were killed and their kidneys, liver, spleen and ovaries were removed and weighed. The number of implants, resorptions, and live and dead fetuses were evaluated. Histological sections of ovaries, measurement of the height of the uterine epithelium and vaginal smears were performed to assess the estrogenic activity. The results showed that the administration of MnHE did not significantly alter the analyzed variables. Therefore, considering the experimental model used in this study, the data obtained indicate that M. nigra did not exhibit any estrogenic activity nor did exert a toxic effect on the female reproductive system and on the embryonic development of rats. PMID- 22198064 TI - Fisetin prevents fluoride- and dexamethasone-induced oxidative damage in osteoblast and hippocampal cells. AB - Fluoride intoxication and dexamethasone treatment produce deleterious effects in bone and brain. The aim of this study was to evaluate the effect of fluoride (F) and dexamethasone (Dex) co-exposure on oxidative stress and apoptosis in osteoblast-like MC3T3-E1 and hippocampal HT22 cell lines. Co-exposure to F and Dex resulted in a concentration-dependent decrease in cell viability, induction of apoptosis and increased generation of reactive oxygen species (ROS) and nitric oxide (NO) following 72 h of incubation. Fluoride-induced apoptosis in MC3T3-E1 and HT22 cells was attenuated by catalase and L-NNMA, indicating a role for H2O2 and NO as mediators of cytotoxicity. Dexamethasone-induced apoptosis was associated with H2O2 generation in both cell lines and it was attenuated during co-incubation with catalase. These data indicate that co-exposure to F and Dex amplifies their respective cytotoxicity in H2O2- and NO-dependent manner. As flavonoid fisetin prevented F- and Dex-induced cytotoxicity the potential role of this product in pharmacology and diet may be considered. PMID- 22198065 TI - H295R cells as a model for steroidogenic disruption: a broader perspective using simultaneous chemical analysis of 7 key steroid hormones. AB - The effects of three model endocrine disruptors, prochloraz, ketoconazole and genistein on steroidogenesis were tested in the adrenocortical H295R cell line to demonstrate that a broader mechanistic understanding can be achieved in one assay by applying chemical analysis to the H295R assay. Seven key steroid hormones (pregnenolone, progesterone, dehydroepiandrosterone, androstenedione, testosterone, estrone and 17beta-estradiol) were analyzed using a novel and thoroughly validated GC-MS/MS method. In addition to the simultaneous quantification of 7 steroid hormones, the present method also negates the potential problems of cross-reactivity that can be encountered in some immunoassays. Although all 3 test compounds decrease the concentrations of the main sex steroids, the chemicals exerted different effects upstream in the pathway. Exposure to prochloraz resulted in increased hormone levels upstream of steroid 17 alpha-hydroxylase/17,20 lyase (P450c17) and decreases downstream. Ketoconazole inhibited the entire pathway, while exposure to genistein resulted in increased hormone levels upstream of 3-beta-hydroxysteroid dehydrogenase (3beta-HSD) and decreases downstream. The results demonstrate that chemical analysis combined with the H295R cell assay is an useful tool for studying the mechanisms by which endocrine disruptors interfere with the steroidogenic pathway. PMID- 22198066 TI - Agnathia-otocephaly complex: a case report and examination of the OTX2 and PRRX1 genes. AB - Agnathia-otocephaly is a rare, often lethal malformation characterized by absence or hypoplasia of the mandible, microstomia, hypoglossia/aglossia, and variable anterior midline fusion of the ears (melotia, synotia). Etiologies have been linked to both genetic and teratogenic factors and to date, a definitive, commonly identifiable cause has not been recognized. Mouse and human genetic studies have implicated OTX2 and PRRX1 as potential candidate genes for agnathia otocephaly. In this study we report a sporadic case of agnathia-otocephaly complex with associated features of maldevelopment and examine the roles of OTX2 and PRRX1. The proband, a male born at 31 weeks, displayed severe micrognathia, microstomia, posteriorly-rotated and low set ears, and downward slanting palpebral fissures. Mutation analysis was performed after sequencing the entire coding regions of OTX2 and PRRX1 genes isolated from the proband and his parents. After thorough analysis, no DNA variations were detected. This suggests that mutations in different genes or environmental causes are responsible. PMID- 22198067 TI - Congenital hypothyroidism as the initial presentation that led to the diagnosis of Williams syndrome. PMID- 22198068 TI - The management of neuropathic pain with a focus upon older adults. AB - By the year 2030, it is projected that the US population over the age of 65 years will be 70 million (one-fifth of the US population). Pain of various etiologies initiates about 50% of yearly physician visits and is the most frequent reason for health care consultation in the United States identified commonly by the older patient. The negative impact on the patient coupled with less than optimal treatments often presented to the patient elicit patient and prescriber frustration with inadequate outcomes. This article is focused at pharmacotherapeutic selections to be utilized in a polymodal fashion for the older adult presenting with neuropathic pain. The pharmacotherapies are to be titrated in a patient-specific patient centered-patient focused-personalized pharmacotherapeutic care. The classes of agents discussed include antidepressants, mood stabilizers/antiseizure agents, opioids, anesthetics, and miscellaneous agents. PMID- 22198069 TI - Septic thrombophlebitis: percutaneous mechanical thrombectomy and thrombolytic therapies. AB - Suppurative thrombophlebitis (Lemierre's syndrome) of the internal jugular vein is a rare and sometimes fatal complication. It commonly occurs from oropharyngeal infections, peripheral lines, complications from dental procedures, gingivitis, or central venous catheterizations. Empiric antibiotics are the initial treatment of choice followed by thrombolytics or surgical thrombectomy in refractory cases. We present a case of septic thrombophlebitis of the right internal jugular vein from a peripherally inserted central venous catheter. We also review the current percutaneous mechanical thrombectomy and thrombolytics therapies for such a rare disorder. Mechanical thrombectomy includes rotational thrombectomy or rheolytic therapies. Devices include the Amplatz thrombectomy device (Microvena), the Arrow Trerotola Percutaneous thrombolytic device (Arrow), and the Cragg-Casteneda thrombolytic brush (Microtherapeutics). Rheolytic therapies include Angiojet, the Hydrolyzer, and the Oasis Thrombectomy System. Percutaneous mechanical thrombectomy techniques include rotational fragmentation, aspiration or suction thrombectomy, and hydrodynamic thrombectomy. AngioJet catheters may be used for percutaneous embolectomy in conjunction with pulse spray techniques, which instill thrombolytics locally. Thrombolytics include streptokinase, urokinase, and recombinant-tissue plasminogen activator. Mechanical thrombectomy combined with thrombolytics provide optimal treatment results secondary to their complementary effects. Therefore, patients who are refractory to standard medical therapy and considered poor surgical candidates may benefit from combined percutaneous mechanical thrombectomy with thrombolytics to achieve superior results if no contraindications exist for thrombolytics. PMID- 22198071 TI - Study of warfarin patients investigating attitudes toward therapy change (SWITCH Survey). AB - Although the oral anticoagulant warfarin has undoubtedly saved lives and reduced the number of strokes in patients with atrial fibrillation, it is a cumbersome medication to manage and take. Novel oral anticoagulants, such as dabigatran, offer therapeutic anticoagulation without requisite blood testing or dietary restrictions. We conducted a survey of the attitudes of patients enrolled in a warfarin clinic toward switching to a novel anticoagulant. From September to December 2010, a written survey was offered to 180 patients in the Warfarin Clinic of the Rush University Medical Center and 155 patients filled out the survey (86% response rate). Inclusion criteria included being 18 years of age or older, on warfarin for 2 months. Fifty-eight percent of patients were willing to switch anticoagulants. Women were significantly less willing to switch from warfarin than men (31 of 71, 44% vs. 54 of 78, 69%; P = 0.003). Patients older than 70 years were significantly more willing to switch anticoagulants than those younger than 70 years (48 of 68, 71% vs. 38 of 75, 51%; P = 0.017). There are significant differences across age and gender in the initial willingness of patients to accept novel anticoagulants. These differences may have important implications in the prevention and treatment of thromboembolic events. PMID- 22198072 TI - Nephrotoxicity of once-daily cyclosporine A in minimal change nephrotic syndrome. AB - BACKGROUND: Although once-daily cyclosporine (CsA) therapy may have greater nephrotoxic-sparing effects than standard twice-daily therapy, little information is available in children with steroid-dependent minimal change nephrotic syndrome (MCNS) regarding histological analysis after long-term once-daily administration. CASE-DIAGNOSIS/TREATMENT: A prospective study of the clinical efficacy and comparison between pre- and post-treatment renal biopsy findings in ten children (mean age, 8.8 years) with steroid-dependent MCNS who were administered once daily CsA therapy for more than 24 months (mean +/- SD, 30 +/- 3.7) was performed in Saitama Children's Medical Center. Administration of once-daily CsA therapy (mean dose, 2.8 +/- 0.6 mg/kg/day; mean C2 levels, 670 +/- 64 ng/ml) resulted in a significant reduction in the median relapse rate from 4.6 to 0.2 times per year, and five patients did not experience a relapse of NS. Furthermore, mean threshold of prednisolone dose significantly reduced from 1.2 to 0.02 mg/kg on alternate days. However, two patients showed evidence of chronic CsA nephrotoxicity (CsAN). CONCLUSIONS: Once-daily CsA therapy appears to be effective in children with steroid-dependent MCNS. However, follow-up renal biopsies should be performed to investigate the presence of CsAN after more than 24 months of treatment with once-daily regimen as well as with the conventional twice-daily regimen. PMID- 22198073 TI - Differential effects of acyclic nucleoside phosphonates on nitric oxide and cytokines in rat hepatocytes and macrophages. AB - Acyclic nucleoside phosphonates (ANP) are virostatics effective against viruses like hepatitis B virus and human immunodeficiency virus. Our previous reports indicated immunomodulatory activities of ANP in mouse and human innate immune cells. Recently, evidence has increased that hepatocytes may play an active role in immune regulation of the liver homeostasis or injury. In this study we investigated possible immunomodulatory effects of ANP on rat hepatocytes and macrophages. Nitric oxide (NO) production and secretion of cytokines (IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-13, IL-18, IFN-gamma, TNF-alpha and GM-CSF) were analyzed under in vitro conditions. Test compounds included: 9-[2 (phosphonomethoxy)ethyl]adenine (PMEA; adefovir); 9-[2-(phosphonomethoxy)ethyl] 2,6-diaminopurine (PMEDAP); (R)- and (S)-enantiomers of 9-[2 (phosphonomethoxy)propyl]adenine [(R)-PMPA; tenofovir] and [(S)-PMPA]; 9-[2 (phosphonomethoxy)propyl]-2,6-diaminopurine [(R)-PMPDAP] and [(S)-PMPDAP]. The group of test compounds also included their N(6)-substituted derivatives. Some of ANP which are able to induce NO production and cytokine secretion in cultured macrophages possess the same immunobiological activity in isolated hepatocytes. The extent of responses is in range of LPS/IFN-gamma stimulation in both types of cells. The effects of active ANP on NO expression and cytokine secretion are dose and time-dependent. Interestingly, the spectrum of detected cytokines induced by ANP is broader in hepatocytes. The results also confirm immunomodulatory effects of some ANP on rodent macrophages. Moreover, we demonstrate for the first time immunobiological reactivity of primary rat hepatocytes induced by exogenous ANP compounds. The potential of hepatocytes to synthesize cytokines can contribute to better understanding of liver immune function and can serve for pharmacological intervention in liver diseases. PMID- 22198086 TI - FISH-based analysis of 10- and 25-kV soft X-ray-induced DNA damage in 184A1 human mammary epithelial cells. AB - Over the past years, several in vitro studies have been performed on DNA damage induced by soft X-rays, especially in the energy range below 50 keV. Radiation effects originating from such low-energy photons are relevant in the context of medical diagnostics, for example, mammography, or of accidental exposure to scattered radiation. The present study was initiated to investigate the X-ray energy-dependent induction of stable and unstable chromosomal aberrations in the human mammary epithelial cell line 184A1. Three colour fluorescence in situ hybridisation was applied to identify chromosomal damage in chromosomes 1, 8 and 17, induced by 10-kV or 25-kV soft X-rays as well as by 200-kV X-rays as a reference quality. The overall results confirm the X-ray energy dependencies published for human lymphocytes showing increasing chromosomal aberration frequencies and higher aberration complexity with decreasing X-ray energy and increasing dose. Comparing the obtained dose dependencies, ratios of 0.84 +/- 0.09 and 1.22 +/- 0.18 were revealed for stable translocations induced by 25- and 10-kV X-rays, respectively, using 200-kV X-rays as reference. Moreover, the analysis of the minimum number of breaks required to form the visible chromosomal damage resulted in similar ratios of 0.93 +/- 0.07 for 25-kV X-rays and 1.25 +/- 0.10 for 10-kV X-rays relative to 200-kV X-rays. In addition, non-DNA proportional contributions of chromosomes 8 and 17 to the whole DNA damage and deviations from the expected 1:1 ratio of translocations and dicentrics were observed for cell line 184A1. PMID- 22198087 TI - The axonal repellent Slit2 inhibits pericyte migration: potential implications in angiogenesis. AB - The Slit family of secreted proteins acts through the Roundabout (Robo) receptors to repel axonal migration during central nervous system development. Emerging evidence shows that Slit/Robo interactions also play a role in angiogenesis. The effect of Robo signaling on endothelial cells has been shown to be context dependent. However, the role of Slit/Robo in pericytes has been largely unexplored. The aim of this study was to determine the effect of Slit2 on primary human pericytes and to address the underlying mechanisms, including the receptors potentially implicated. We demonstrate that both Robo1 and Robo4 are expressed by human pericytes. In the presence of their ligand Slit2, spontaneous and PDGF induced migration of pericytes was impaired. This antimigratory activity of Slit 2 correlated with the inhibition of actin-based protrusive structures. Interestingly, human pericyte interaction with immobilized Slit2 was inhibited in the presence of anti-Robo1 and anti-Robo4 blocking antibodies, suggesting the implication of both receptors. These results add new insights into the role of Slit proteins during the angiogenic process that relies on the directional migration not only of endothelial cells but also of pericytes. PMID- 22198088 TI - The significance of the host inflammatory response on the therapeutic efficacy of cell therapies utilising human adult stem cells. AB - Controlling the fate of implanted hMSCs is one of the major drawbacks to be overcome to realize tissue engineering strategies. In particular, the effect of the inflammatory environment on hMSCs behaviour is poorly understood. Studying and mimicking the inflammatory process in vitro is a very complex and challenging task that involves multiple variables. This research addressed the questions using in vitro co-cultures of primary derived hMSCs together with human peripheral blood mononucleated cells (PBMCs); the latter are key agents in the inflammatory process. This work explored the in vitro phenotypic changes of hMSCs in co-culture direct contact with monocytes and lymphocytes isolated from blood using both basal and osteogenic medium. Our findings indicated that hMSCs maintained their undifferentiated phenotype and pluripotency despite the contact with PBMCs. Moreover, hMSCs demonstrated increased proliferation and were able to differentiate specifically down the osteogenic lineage pathway. Providing significant crucial evidence to support the hypothesis that inflammation and host defence mechanisms could be utilised rather than avoided and combated to provide for the successful therapeutic application of stem cell therapies. PMID- 22198089 TI - Analysis of the miR-34a locus in 62 patients with familial cutaneous melanoma negative for CDKN2A/CDK4 screening. AB - MicroRNAs are small non-coding RNAs, which inhibit expression of specific target genes at the post-transcriptional level and are often misregulated in human cancer. Among them, miR-34a is considered a tumor suppressor with a hypothetical role in melanoma tumorigenesis. In this work, 62 Italian index patients with familial melanoma and negative for CDKN2A/CDK4 screening were investigated for miR-34a germline mutations. Eight novel miR-34a sequence variants were identified at both the heterozygous (c.+259G>A, c.+424G>A, c.+1465C>T, c.+1769C>T, c.+2456T>G, c.+2603C>T, c.+2972T>A, c.+3069T>C) and homozygous (c.+424G>A, c.+1465C>T, c.+1769C>T) states. Molecular screening identified all nucleotide changes in a healthy population of 150 controls and demonstrated that they are common polymorphisms. However, statistically significant differences of allele and genotype frequencies were detected for c.+1465C>T and c.+1769C>T, and borderline values for c.+2456T>G. By stratifying patients by relevant clinical features (presence/absence of multiple primary melanoma, Breslow's thickness, phototype and number of nevi), no significant findings were noted except for an association between the c.+424G>A (heterozygous individual GA) and multiple primary melanoma and phototype III-IV. Our preliminary study suggests that miR 34a, although having a role in late tumorigenesis, does not contribute to the inherited susceptibility to cutaneous melanoma. A function as phenotypic modulator in familial melanoma cannot be excluded. PMID- 22198090 TI - First indications of a highland specialist among mouse lemurs (Microcebus spp.) and evidence for a new mouse lemur species from eastern Madagascar. AB - The factors that limit the distribution of the highly diverse lemur fauna of Madagascar are still debated. We visited an understudied region of eastern Madagascar, a lowland rainforest site (Sahafina, 29-230 m a.s.l.) close to the Mantadia National Park, in order to conduct a survey and collect further distributional data on mouse lemurs. We captured, measured, photographed, and sampled mouse lemurs from the Sahafina forest, performed standard phylogenetic methods based on three mitochondrial DNA genes, and conducted morphometric comparisons in order to clarify their phylogenetic position and taxonomic status. The mouse lemurs from the Sahafina forest could not be assigned to any of the known mouse lemur species and were highly divergent in all molecular analyses from all previously described species. Since they also differed morphometrically from their sister species and from their geographic neighbors, we propose species status and include a species description at the end. This study suggests that M. lehilahytsara may be the first highland specialist among all mouse lemurs. The distribution of the newly described mouse lemur is not fully known, but seems to be rather restricted and highly fragmented, which raises serious conservation concerns. PMID- 22198091 TI - The simplest device for confirmation of tracheal intubation. PMID- 22198092 TI - Suppression of the cardiopulmonary resuscitation artefacts using the instantaneous chest compression rate extracted from the thoracic impedance. AB - AIM: To demonstrate that the instantaneous chest compression rate can be accurately estimated from the transthoracic impedance (TTI), and that this estimated rate can be used in a method to suppress cardiopulmonary resuscitation (CPR) artefacts. METHODS: A database of 372 records, 87 shockable and 285 non shockable, from out-of-hospital cardiac arrest episodes, corrupted by CPR artefacts, was analysed. Each record contained the ECG and TTI obtained from the defibrillation pads and the compression depth (CD) obtained from a sternal CPR pad. The chest compression rates estimated using TTI and CD were compared. The CPR artefacts were then filtered using the instantaneous chest compression rates estimated from the TTI or CD signals. The filtering results were assessed in terms of the sensitivity and specificity of the shock advice algorithm of a commercial automated external defibrillator. RESULTS: The correlation between the mean chest compression rates estimated using TTI or CD was r=0.98 (95% confidence interval, 0.97-0.98). The sensitivity and specificity after filtering using CD were 95.4% (88.4-98.6%) and 87.0% (82.6-90.5%), respectively. The sensitivity and specificity after filtering using TTI were 95.4% (88.4-98.6%) and 86.3% (81.8 89.9%), respectively. CONCLUSIONS: The instantaneous chest compression rate can be accurately estimated from TTI. The sensitivity and specificity after filtering are similar to those obtained using the CD signal. Our CPR suppression method based exclusively on signals acquired through the defibrillation pads is as accurate as methods based on signals obtained from CPR feedback devices. PMID- 22198093 TI - Sublingual immunization with an engineered Bacillus subtilis strain expressing tetanus toxin fragment C induces systemic and mucosal immune responses in piglets. AB - Sublingual (SL) and intranasal (IN) administration of a Bacillus subtilis-based tetanus vaccine was tested in piglets, which more closely mimic the human immune system than mice. Piglets were immunized by the SL, IN or oral routes with vaccine expressing tetanus toxin fragment C, or commercial tetanus vaccine given by intramuscular injection as a control. Tetanus toxoid specific ELISA and passive neutralization tests were used to measure IgG and IgA levels in serum and mucosal secretions, and assess protective serum antibodies, respectively. The nature of the immune response was explored by MHC Class II, TGF-beta1 expression, and ELISA assays for multiple cytokines. SL or IN immunization of piglets induced neutralizing tetanus toxoid specific serum antibody and local salivary and vaginal IgA responses. Standard tetanus vaccine resulted in systemic antibodies, whereas oral administration of the Bacillus-based vaccine was ineffective. Further analyses indicated a balanced Th1/Th2 response to SL or IN immunization. CONCLUSION: This study demonstrates for the first time that SL or IN administration is effective for inducing both systemic and mucosal responses in a piglet model, indicating that SL or IN delivery of a B. subtilis-based tetanus vaccine can be a simple, non-invasive, low cost strategy to induce immunity to tetanus. PMID- 22198094 TI - Design of an enhanced fuzzy k-nearest neighbor classifier based computer aided diagnostic system for thyroid disease. AB - In this paper, we present an enhanced fuzzy k-nearest neighbor (FKNN) classifier based computer aided diagnostic (CAD) system for thyroid disease. The neighborhood size k and the fuzzy strength parameter m in FKNN classifier are adaptively specified by the particle swarm optimization (PSO) approach. The adaptive control parameters including time-varying acceleration coefficients (TVAC) and time-varying inertia weight (TVIW) are employed to efficiently control the local and global search ability of PSO algorithm. In addition, we have validated the effectiveness of the principle component analysis (PCA) in constructing a more discriminative subspace for classification. The effectiveness of the resultant CAD system, termed as PCA-PSO-FKNN, has been rigorously evaluated against the thyroid disease dataset, which is commonly used among researchers who use machine learning methods for thyroid disease diagnosis. Compared to the existing methods in previous studies, the proposed system has achieved the highest classification accuracy reported so far via 10-fold cross validation (CV) analysis, with the mean accuracy of 98.82% and with the maximum accuracy of 99.09%. Promisingly, the proposed CAD system might serve as a new candidate of powerful tools for diagnosing thyroid disease with excellent performance. PMID- 22198095 TI - Operational problems of Haniwa net as a form of social capital: interdependence between human networks of physicians and information networks. AB - In August 2009, Miyazaki Health and Welfare Network (Haniwa Net, hereafter referred to as "the Net"), centrally led by University of Miyazaki Hospital (UMH), adopted a center hospital-based system offering a unilateral linkage that enables the viewing of UMH's medical records through a web-based browser (electronic medical records (EMR)). By the end of December 2010, the network had developed into a system of 79 collaborating physicians from within the prefecture. Beginning in August 2010, physicians in 12 medical institutions were visited and asked to speak freely on the operational issues concerning the Net. Recordings and written accounts were coded using the text analysis software MAXQDA 10 to understand the actual state of operations. Analysis of calculations of Kendall's rank correlation confirmed that the interdependency between human networks and information networks is significant. At the same time, while the negative opinions concerning the functions of the Net were somewhat conspicuous, the results showed a correlation between requests and proposals for operational improvements of the Net, clearly indicating the need for a more user-friendly system and a better viewer. PMID- 22198096 TI - Analysis of the EHR systems in Spanish Primary Public Health System: the lack of interoperability. AB - This paper presents the impact of the Electronic Health Records (EHRs) systems jointly in the Spanish Primary Public Health System. Different EHRs that exist in each of the Spanish regions are discussed. Moreover, other purpose of this analysis is to identify the current state of knowledge about health information systems adoption in primary care in Spain. For the analysis and study of EHRs systems in Spain we have relied on the use of different sources, mostly items related to the study of EHRs systems in different areas. We will analyze some technical aspects of these and some of their major implications, both positive and negative. Moreover, we have resorted to make direct contact with the organizations that have implemented the EHRs systems. The result of this study leads to a main idea, the need for interoperability between different systems. We will delve into how we have reached this conclusion and that is the key to EHRs systems homogenization of Spanish territory. EHR systems used in different regions of Spain offer the access to medical information as well as provide a clinical analysis of each patient more quickly. The adoption of health information systems is seen world wide as one method to mitigate the widening health care demand and supply gap. PMID- 22198097 TI - Angiopoietin-1 but not angiopoietin-2 promotes neutrophil viability: Role of interleukin-8 and platelet-activating factor. AB - We previously reported the expression of angiopoietin receptor Tie2 on human neutrophils. Both angiopoietins (Ang1 and Ang2) induce platelet activating factor (PAF) synthesis from endothelial cells (ECs) and neutrophils. Both angiopoietins can also modulate EC viability and since PAF can promote pro-survival activity on neutrophils, we addressed whether Ang1 and/or Ang2 could modulate neutrophil viability. Neutrophils were isolated from venous blood of healthy volunteers and neutrophil viability was assessed by flow cytometry using apoptotic and necrotic markers (annexin-V and propidium iodide (P.I.), respectively). Basal neutrophil viability from 0 to 24 h post-isolation decreased from 98% to ~45%. Treatment with anti-apoptotic mediators such as interleukin-8 (IL-8; 25 nM) and PAF (100 nM) increased neutrophil basal viability by 34 and 26% (raising it from 43 to 58 and 55%) respectively. Treatment with Ang1 (0.001-50 nM) increased neutrophil viability by up to 41%, while Ang2 had no significant effect. Combination of IL-8 (25 nM) or PAF (100 nM) with Ang1 (10 nM) further increased neutrophil viability by 56 and 60% respectively. We also observed that Ang1, but not Ang2 can promote IL-8 release and that a pretreatment of the neutrophils with blocking anti-IL-8 antibodies inhibited the anti-apoptotic effect of IL-8 and Ang1 by 92 and 81% respectively. Pretreatment with a selective PAF receptor antagonist (BN 52021), did abrogate PAF pro-survival activity, without affecting Ang1-induced neutrophil viability. Our data are the first ones to report Ang1 pro-survival activity on neutrophils, which is mainly driven through IL-8 release. PMID- 22198098 TI - Heat shock protein 90 from neglected protozoan parasites. AB - Significant advances have been made in our understanding of heat shock protein 90 (Hsp90) in terms of its structure, biochemical characteristics, post translational modifications, interactomes, regulation and functions. In addition to yeast as a model several new systems have now been examined including flies, worms, plants as well as mammalian cells. This review discusses themes emerging out of studies reported on Hsp90 from infectious disease causing protozoa. A common theme of sensing and responding to host cell microenvironment emerges out of analysis of Hsp90 in Malaria, Trypanosmiasis as well as Leishmaniasis. In addition to their functional roles, the potential of Hsp90 from these infectious disease causing organisms to serve as drug targets and the current status of this drug development endeavor are discussed. Finally, a unique and the only known example of a split Hsp90 gene from another disease causing protozoan Giardia lamblia and its evolutionary significance are discussed. Clearly studies on Hsp90 from protozoan parasites promise to reveal important new paradigms in Hsp90 biology while exploring its potential as an anti-infective drug target. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90). PMID- 22198099 TI - Acute ethanol exposure affects spermatogonial stem cell homeostasis in pre pubertal mice. AB - Ethanol is a known modulator of neural stem cell development, but the consequences of ethanol toxicity on the cell fate decisions of spermatogonial stem cells (SSCs) is poorly understood. Using an in vivo treatment and stem cell transplantation approach, we investigated the effects of acute ethanol exposure on formation of the growing adult SSC population in neonatal and pre-pubertal mice. Treatment with a single dose of ethanol disrupted SSC homeostasis in vivo evidenced by a significant reduction (7-fold) of stem cell colonization efficiency in the testes of recipient mice following transplantation. Ethanol treatment also increased the rate of apoptosis in adult differentiating germ cells in situ. Gene expression analysis indicates that ethanol exposure has transient and long-term effects on the expression of GDNF and VEGF family molecules and supports the hypothesis that the niche microenvironment for SSCs is sensitive to ethanol toxicity during pre-pubertaland adult life. PMID- 22198100 TI - Comparative in vitro study of the inhibition of human and hen esterases by methamidophos enantiomers. AB - The current Organisation for Economic Co-operation and Development (OECD) guidelines for evaluating organophosphorus-induced delayed neuropathy (OPIDN) require the observation of dosed animals over several days and the sacrifice of 48 hens. Adhering to these protocols in tests with enantiomers is difficult because large quantities of the compound are needed and many animals must be utilized. Thus, developing an in vitro screening protocol to evaluate chiral organophosphorus pesticides (OPs) that can induce delayed neuropathy is important. This work aimed to evaluate, in blood and brain samples from hens, human blood, and human cell culture samples, the potential of the enantiomeric forms of methamidophos to induce acetylcholinesterase (AChE) inhibition and/or delayed neurotoxicity. Calpain activation was also evaluated in the hen brain and SH-SY5Y human neuroblastoma cells. The ratio between the inhibition of neuropathy target esterase (NTE) and AChE activities by the methamidophos enantiomers was evaluated as a possible indicator of the enantiomers' abilities to induce OPIDN. The (-)-methamidophos exhibited an IC(50) value approximately 6 times greater than that of the (+)-methamidophos for the lymphocyte NTE (LNTE) of hens, and (+) methamidophos exhibited an IC(50) value approximately 7 times larger than that of the (-)-methamidophos for the hen brain AChE. The IC(50) values were 7 times higher for the human erythrocyte AChE and 5 times higher for AChE in the SH-SY5Y human neuroblastoma cells. Considering the esterases inhibition and calpain results, (+)-methamidophos would be expected to have a greater ability to induce OPIDN than the (-)-methamidophos in humans and in hens. PMID- 22198101 TI - Long-term outcome of angioplasty or stent placement for stenosis of the cavernous or petrous portion of the internal carotid artery. AB - Percutaneous transluminal angioplasty (PTA) and stent placement are effective in patients with stenosis of the cavernous or petrous portion of the internal carotid artery (ICA), but the long-term outcomes remain unclear. The present study evaluated long-term outcomes in 54 patients treated by PTA or stent placement for stenotic lesions involving more than 50% of the cavernous or petrous portion of the ICA with ischemic symptoms or without ischemic symptoms if cerebral blood flow on single photon emission computed tomography images was decreased by 20% compared with the contralateral side. Follow-up magnetic resonance, three-dimensional computed tomography, and conventional angiography were performed. Patient condition in the follow-up period was investigated using telephone interviews or questionnaires. PTA was used to treat 13 lesions and stent placement for 41 lesions. Permanent and transient complications occurred in 2 and 5 patients, respectively. The morbidity rate was 13% (7 of 54 patients). The follow-up period ranged from 3 to 80 months (mean 29.9 months), and restenosis and occlusion were recognized in 4 patients (7.4%). Five patients died (2 of malignancy and 3 of myocardial infarction) during the follow-up period. PTA and stent placement are safe and effective in patients with stenosis of the cavernous or petrous portion of the ICA, and result in low long-term rates of restenosis. PMID- 22198102 TI - Pilot study of the safety of starting administration of low-dose aspirin and cilostazol in acute ischemic stroke. AB - Progressive stroke is a serious problem due to the associated morbidity and mortality. Aspirin is recommended for acute ischemic stroke, but does not reduce the frequency of stroke progression. No standard treatment has been approved for the prevention of stroke progression. Cilostazol, which reduces platelet aggregation about 3 hours after single administration, does not increase the frequency of bleeding events when compared with aspirin or a placebo. Moreover, the combination of 100 mg aspirin and 200 mg cilostazol does not increase the frequency of bleeding events compared with only 100 mg aspirin, and thus is expected to prevent stroke progression with a high degree of safety. The present study investigated the safety of this combination of two drugs administered at the above concentrations in 54 patients with acute ischemic stroke within 48 hours of stroke onset. Modified National Institutes of Health Stroke Scale (NIHSS) measurements were performed at baseline and again on day 4 to 7. Progressive stroke was defined as an increase greater than or equal to 1 point on NIHSS. Patient scores on the modified Rankin Scale (mRS) were evaluated at baseline and 3 months after enrollment. Stroke progression occurred in 11.1% of the patients. The percentages of patients with mRS score from 0 to 2 were 42.6% and 75% at baseline and 3 months, respectively. No symptomatic intracranial hemorrhage or major extracranial hemorrhage occurred. These results suggest that administration of aspirin and cilostazol is safe for acute ischemic stroke. PMID- 22198103 TI - Acute subdural hematoma in patients with medication associated with risk of hemorrhage. AB - The characteristics of 90 cases of acute subdural hematoma were analyzed in 25 patients taking medication related to bleeding tendency, the bleeding tendency group, and 65 patients without such medication, the control group. Acute subdural hematoma was significantly associated with over-turning or without accident in the bleeding tendency group (92%) compared with the control group (56.9%). The time from trauma to admission was significantly longer in the bleeding tendency group (32.7 hours) compared with the control group (9.7 hours). The mean Glasgow Coma Scale score on admission was 13.0 points in the bleeding tendency group and was significantly better than 10.9 points in the control group. The international normalized ratio of prothrombin time on admission was 3.59 in the patients treated with warfarin. All patients taking warfarin received reversal agents and this value decreased significantly to 1.38. In the bleeding tendency group, hematoma size increased in 20% after the operation, almost the same as in the control group (25%). Although good recovery tended to be observed less frequently in the bleeding tendency group than in the control group, the mean age of the bleeding tendency group was significantly higher than that of the control group, so the prognosis might be affected by this age-related factor. Cautious diagnosis, follow-up imaging, and strict management are mandatory in patients with bleeding tendency. PMID- 22198104 TI - Clinical outcomes and adverse events following transforaminal interbody fusion for lumbar degenerative spondylolisthesis in elderly patients. AB - Transforaminal lumbar interbody fusion (TLIF) procedure is widely used, but the surgical indications for TLIF in elderly patients remain controversial because of potential risks such as inferior bone quality and higher rate of postoperative complications. Clinical efficacy and operative risk of TLIF in elderly patients are unclear. This study investigated the clinical effect and safety of TLIF for lumbar degenerative spondylolisthesis with radiculopathy or neurogenic claudication in patients aged 70 years or older. The clinical records were retrospectively reviewed of 35 consecutive patients aged 70-86 years (mean 74.8 years) who underwent one or two-level TLIF. The preoperative diagnosis included degenerative spondylolisthesis with segmental instability. Clinical outcomes were assessed by the Japanese Orthopaedic Association score, visual analogue scale, Oswestry Disability Index. Radiological fusion rate was also investigated. Clinical and radiological results were compared with those of 43 younger patients. Clinical outcome measures were significantly improved after operation in the elderly patients, but improvement rates were significantly lower than those of younger patients. Fusion rate was similar in both groups. Overall postoperative complications were increased in aged patients, although the prevalence of complications directly related to surgical technique was not significantly increased. Postoperative complications not related to the surgical procedure were factors affecting poor results. TLIF is acceptable for achieving clinical recovery and lumbar fusion with high radiographic fusion success even in elderly patients, although clinical benefits were limited compared with those of younger patients. Postoperative morbidity was mainly related to general or non operative site complications. PMID- 22198105 TI - Subarachnoid hemorrhage due to ruptured posterior cerebral artery aneurysm simultaneously associated with multiple remote intracerebral hemorrhages--case report. AB - A 61-year-old woman presented with aneurysmal subarachnoid hemorrhage (SAH) associated with multiple remote intracerebral hemorrhages (ICHs). She had undergone microsurgical neck clipping for ruptured right middle cerebral artery aneurysm and ventriculo-peritoneal shunting 16 years previously. Computed tomography revealed SAH predominantly in the basal cistern and ambient cistern, in association with multiple ICHs in the bilateral tegmentum of the brain stem and right caudate nucleus. Digital subtraction angiography revealed an aneurysm at the P(1) segment of the left posterior cerebral artery. The ruptured aneurysm was microsurgically clipped via a left subtemporal approach without complications. Simultaneous occurrence of aneurysmal SAH and multiple remote ICHs is rare. The spatial pattern of the ICHs in the present case is apparently unique. PMID- 22198106 TI - Ruptured distal accessory anterior cerebral artery aneurysm--case report. AB - A 48-year-old man presented with an extremely rare aneurysm arising from an accessory anterior cerebral artery (ACA) manifesting as sudden onset of headache lasting for 5 days. Neurological examination on admission revealed no abnormalities. Computed tomography showed subarachnoid hemorrhage of the interhemispheric fissure and intraparenchymal hematoma of the left cingulate gyrus. Magnetic resonance and cerebral angiography revealed a saccular aneurysm of the distal portion of the accessory ACA classified as the bihemispheric type. Neck clipping of the aneurysm was performed via an interhemispheric approach 17 days after symptom onset. The patient made a good postoperative recovery without neurological deficit. Distal accessory ACA aneurysms tend to arise from the first bifurcation and supply parietal branches. The aneurysms tend to occur on the bihemispheric type of distal accessory ACA. Hemodynamic stress may contribute to formation or development of these aneurysms. PMID- 22198107 TI - Neurogenic stress cardiomyopathy following aneurysmal subarachnoid hemorrhage in a very elderly patient--case report. AB - A 90-year-old woman presented with aneurysmal subarachnoid hemorrhage (SAH) corresponding to Hunt and Hess grade II. Acute congestive heart failure and pulmonary edema developed following uneventful surgical clipping. Serial electrocardiography and echocardiography led to a diagnosis of neurogenic stress cardiomyopathy (NSC), also known as tako-tsubo cardiomyopathy. The outcome was favorable after supportive therapy with respiratory management and diuretic administration. Neurosurgeons treating SAH must take into account the various general treatment strategy options on a case by case basis after prompt recognition of NSC. PMID- 22198108 TI - Paraspinal arteriovenous fistula presenting with subarachnoid hemorrhage and acute progressive myelopathy--case report. AB - A 60-year-old man presented with paraspinal arteriovenous fistula (AVF) manifesting as subarachnoid hemorrhage (SAH) and acute progressive myelopathy. The patient presented with sudden onset of low back pain and paraparesis. Spinal magnetic resonance imaging revealed a vascular malformation on the lumbar spinal canal. Three-dimensional computed tomography angiography demonstrated a paraspinal AVF in the sacral ventral pelvis. The clinical symptoms were progressing rapidly, so transarterial embolization and surgical drainage ligation were performed. Paraspinal AVF may present with SAH and cause acute progressive myelopathy. Prompt examination and treatment are necessary. PMID- 22198109 TI - Isolated recurrence of intracranial and temporal bone myeloid sarcoma--case report. AB - A 52-year-old man presented with a rare case of isolated recurrence of myeloid sarcoma (MS) manifesting as rapidly growing intracranial and temporal bone masses 5 years after complete remission (CR) of acute myeloid leukemia (AML) (M2 in the French-American-British classification). Magnetic resonance imaging and computed tomography of the head revealed enhanced mass lesions on the superior aspect of the right petrous bone and within the right mastoid air cells, extending into the right middle ear cavity without bone destruction. Peripheral blood testing found no evidence of relapse. As the right temporal bone mass showed significant growth into the right temporal lobe over one month and diagnostic tissue was not available, he was admitted to our department for biopsy. On admission, blood testing showed relapse of AML and tumoral hemorrhage in the right temporal lobe. Emergent evacuation of the hematoma and biopsy of the right temporal lobe tumor was performed, resulting in a diagnosis of MS. Chromosomal analysis of the peripheral blood identified t(8;21)(q22;q22) abnormality. Before initiation of anti-AML chemotherapy, tumoral bleeding occurred again and he died 12 days after the operation of brain herniation. Autopsy revealed leukemia cell infiltrations in the perivascular region of the peritumoral brain parenchyma associated with hemorrhage, indicating vascular damage caused by leukemic cell infiltration from MS induced cerebral hemorrhage. Although relapse after 5 years of CR is uncommon in patients with AML, the possibility of MS recurrence must be considered. PMID- 22198110 TI - Spontaneous slow drainage of epidural hematoma into the subgaleal space through a skull fracture in an infant--case report. AB - A 4-month-old girl fell off a table onto the floor. Computed tomography performed 4 hours after the trauma showed a left parietal epidural hematoma (EDH) with an omega-shaped fracture line in the left parietal region. The EDH was enlarged after another 4 hours. However, the EDH showed drainage into the subgaleal space through the skull fracture 2 days after the trauma and was almost completely discharged into the subgaleal space by 5 days after trauma. Both the EDH and the subgaleal hematoma had resolved completely by 12 days after the trauma. No symptoms or signs were observed during the course. This case suggests that EDH can drain slowly and spontaneously into the subgaleal space through a skull fracture in an infant. PMID- 22198111 TI - Long-term outcome of fibrous dysplasia: reconstruction with dysplastic bone--case report. AB - A 10-year-old girl presented with facial asymmetry associated with bulging of the right fronto-orbital region with no symptoms. Computed tomography demonstrated enlargement of the right zygomatic, frontal, ethmoid, and sphenoid bones. Abnormal proliferation of the bone had obliterated the sphenoid, right frontal sinus, and right ethmoid sinuses. These radiological findings suggested right optic nerve compression due to fibrous dysplasia. Right optic canal decompression was performed. In preparation for recurrence, the resulting bone defect in the right orbital roof was reconstructed using the outer table of the split lesion bone. The removed frontal bone was divided into intact and lesioned parts, and the intact part was returned. The lesioned part was split and the outer table graft used to reconstruct the frontal region. A temporal musculopericranial flap was used to form a barrier between the opened ethmoid sinus and cranial cavity. A protrusion appeared on the left forehead 10 years later, and was shaved to improve the aesthetic appearance. The patient was followed up for a total of 23 years. The use of dysplastic bone involves the risk of recurrence, but the period of recurrence is delayed and the progression stops after adolescence, so the second operation involved only shaving for aesthetic appearance. This procedure is one of the treatments of choice because of easy reconstruction, easy revision, and good results. PMID- 22198112 TI - Scrotal migration of lumboperitoneal shunt catheter in an adult--case report. AB - A 57-year-old man presented with recurrent parasagittal anaplastic meningioma of frontoparietal region. The tumor was extensively removed, and the dura was repaired with Gore-Tex surgical membrane. After the operation, subcutaneous cerebrospinal fluid (CSF) collection was observed in the fronto-parietal area and a lumboperitoneal shunt was placed. Four weeks after the shunt procedure, he complained of right scrotal swelling and recurrence of the CSF collection. Radiography revealed the coiled catheter in the scrotum. The catheter was surgically removed through a small incision in the skin of the scrotum under local anesthesia. Lumboperitoneal shunt is a simple and useful procedure to control CSF pressure, but catheter migration has been reported in infants and children. Shunt catheter can migrate into the scrotum even in an adult, as the vaginal process, through which the catheter seemed to have entered the scrotum, is patent in 5% of the adult population. In these cases, direct removal through a small incision is appropriate to remove the catheter. PMID- 22198113 TI - Ventral intradural endodermal cyst in the cervical spine treated with anterior corpectomy--case report. AB - A 14-year-old girl who presented with an endodermal cyst manifesting as severe neck and shoulder pain along with vesicorectal disturbances. Cervical magnetic resonance imaging showed a slightly enhanced intradural cyst at the C6-7 level in the ventral side of the spinal canal, with significant dorsal shortening and thinning of the spinal cord. Anterior corpectomy was chosen because of the dorsal effacement of the spinal cord. The cyst wall was subtotally removed to avoid damage to the normal spinal cord. After cyst removal, the iliac bone and an anterior cervical plate were used for anterior fusion. Postoperatively, her pain subsided without neurological deficits. The histological diagnosis was endodermal cyst. The cyst did not recur during a follow-up period of 18 months. Endodermal cysts are rare congenital lesions of the spine lined by endodermal epithelium. The natural history of this lesion is unclear, and the surgical strategy for the approach route and the extent of removal of the cyst wall remain controversial. We suggest that the anterior approach may allow a safer and more effective surgical route for the treatment of ventrally located endodermal cyst compared to the posterior approach. PMID- 22198114 TI - Surgical treatment of sacral perineural cyst--case report. AB - A 67-year-old man presented with persistent penis and scrotum pain due to S-2 and S-3 radiculopathy caused by a sacral perineural cyst. The cyst was treated with microsurgical partial cyst removal and cyst wall imbrication, together with closure of the point through which cerebrospinal fluid (CSF) flowed from the subarachnoid space into the cyst cavity. His pain resolved without recurrence of the cyst or complications. Symptomatic perineural cysts are quite rare. Surgical closure of the point through which CSF flows from the subarachnoid space into the cyst cavity is the most important intervention for symptomatic perineural cysts. If the source of CSF leakage cannot be detected, placement of a cyst-subarachnoid shunt should be considered in addition to partial cyst removal and cyst wall imbrication. PMID- 22198115 TI - Higher magnification microsurgical repair of donor artery dissection in superficial temporal artery to middle cerebral artery anastomosis--technical note. AB - Donor artery dissection is a known cause of technical failure in microvascular anastomosis. A method for detection and direct repair of donor artery dissection before superficial temporal artery (STA) to middle cerebral artery (MCA) anastomosis is described using a high magnification operating microscope (maximum 50.4* magnification). Before STA-MCA anastomosis, the stump of the STA is stained using methylrosaniline chloride (pyoctaninum blue) and is observed under higher magnifications. Microsurgical suturing of the arterial dissection is performed before the anastomosis procedure under the high magnification microscope. This method was used in two patients with symptomatic hemodynamic cerebrovascular occlusive disease. Postoperative angiography revealed good patency and no complications occurred. This method may be useful for detection and direct repair of arterial dissection in small vessel walls before STA-MCA anastomosis. PMID- 22198117 TI - Loss of body hair as a side effect of albendazole. PMID- 22198116 TI - Anthraquinone antitumour agents, doxorubicin, pirarubicin and benzoperimidine BP1, trigger caspase-3/caspase-8-dependent apoptosis of leukaemia sensitive HL60 and resistant HL60/VINC and HL60/DOX cells. AB - We examined the effect of selected anthraquinone antitumour agents - doxorubicin (DOX), pirarubicin (PIRA) and benzoperimidine BP1 - on inducing apoptosis of the sensitive leukaemia HL60 cell line and its multidrug resistance sublines overexpressing P-glycoprotein (HL60/VINC) and multidrug resistance-associated protein 1 (HL60/DOX). All agents used at IC50 and IC90 were able to influence the cell cycle of sensitive HL60 and resistant cells and induce apoptosis. Interestingly, it was seen that HL60/VINC cells were more susceptible to undergo caspase-3/caspase-8-dependent apoptosis induced by the studied anthraquinone compounds compared with HL60 and HL60/DOX cells. However, the examined agents did not change the expression of Fas receptors on the surface of HL60-sensitive and resistant cells. PMID- 22198118 TI - Bilateral retinal detachment in reactive arthritis: coincidence or association? AB - Retinal lesions are not typically found in reactive arthritis. However, a previous case report documented co-existing retinal detachment and reactive arthritis. We report here a similar case of a 32-year-old male patient with concurrent non-traumatic bilateral retinal detachment and HLA-B27 associated reactive arthritis after urogenital and gastrointestinal infections. Our report substantiates a potential rare association of retinal detachment and reactive arthritis. PMID- 22198119 TI - Prenatal lipopolysaccharide exposure increases anxiety-like behaviors and enhances stress-induced corticosterone responses in adult rats. AB - Maternal infection during pregnancy may affect fetal brain development and lead to neurological and mental disorders. Previously, we used lipopolysaccharide [LPS, 33 MUg/kg, intraperitoneal injection] exposure on gestation day 10.5 to mimic maternal bacterial infection in rats and found reduced dopaminergic and serotoninergic neurons in the offspring. In the present study, we examined the anxiety and stress responses of the affected offspring and the neurophysiological changes in their brains. Our results show that LPS rats displayed more anxiety like behaviors and heightened stress responses. Dopamine (DA) in the nucleus accumbens and serotonin (5-HT) in the medial prefrontal cortex and the hippocampus were significantly reduced in LPS rats. Their glucocorticoid receptors in the dorsal hippocampus and the 5-HT(1A) receptors in the dorsal and ventral hippocampus were also reduced. In addition, chronic but not acute fluoxetine treatment reversed the behavioral changes and increased hippocampal 5 HT(1A) receptor expression. This study demonstrates that LPS exposure during a critical time of embryonic development could produce long-term reduction of DA and 5-HT and other neurophysiological changes; such alterations may be associated with the increases in stress response and anxiety-like behaviors in the offspring. PMID- 22198120 TI - Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity. AB - Microglia, the brain immune cell, express several neurotransmitter receptors which modulate microglial functions. In this project we studied the impact of serotonin receptor activation on distinct microglial properties as serotonin deficiency not only has been linked to a number of psychiatric disease like depression and anxiety but may also permeate from the periphery through blood brain barrier openings seen in neurodegenerative disease. First, we tested the impact of serotonin on the microglial response to an insult caused by a laser lesion in the cortex of acute slices from Cx3Cr1-GFP-/+ mice. In the presence of serotonin the microglial processes moved more rapidly towards the laser lesion which is considered to be a chemotactic response to ATP. Similarly, the chemotactic response of cultured microglia to ATP was also enhanced by serotonin. Quantification of phagocytic activity by determining the uptake of microspheres showed that the amoeboid microglia in slices from early postnatal animals or microglia in culture respond to serotonin application with a decreased phagocytic activity whereas we could not detect any significant change in ramified microglia in situ. The presence of microglial serotonin receptors was confirmed by patch clamp experiments in culture and amoeboid microglia and by qPCR analysis of RNA isolated from primary cultured and acutely isolated adult microglia. These data suggest that microglia express functional serotonin receptors linked to distinct microglial properties. PMID- 22198121 TI - The shell matrix of the pulmonate land snail Helix aspersa maxima. AB - In mollusks, the shell mineralization process is controlled by an array of proteins, glycoproteins and polysaccharides that collectively constitute the shell matrix. In spite of numerous researches, the shell protein content of a limited number of model species has been investigated. This paper presents biochemical data on the common edible land snail Helix aspersa maxima, a model organism for ecotoxicological purposes, which has however been poorly investigated from a biomineralization viewpoint. The shell matrix of this species was extracted and analyzed biochemically for functional in vitro inhibition assay, for amino acid and monosaccharides compositions. The matrix was further analyzed on 1 and 2D gels and short partial protein sequences were obtained from 2D gel spots. Serological comparisons were established with a set of heterologous antibodies, two of which were subsequently used for subsequent immunogold localization of matrix components. Our data suggest that the shell matrix of Helix aspersa maxima may differ widely from the shell secretory repertoire of the marine mollusks studied so far, such as the gastropod Haliotis or the pearl oyster Pinctada. In particular, most of the biochemical properties generally attributed to soluble shell matrices, such as calcium-binding capability, or the capacity to interfere in vitro with the precipitation of calcium carbonate or to inhibit the precipitation of calcium carbonate, were not recorded with this matrix. This drastic change in the biochemical properties of the landsnail shell matrix puts into question the existence of a unique molecular model for molluscan shell formation, and may be related to terrestrialisation. PMID- 22198122 TI - Kinetics and thiol requirements of iodothyronine 5'-deiodination are tissue specific in common carp (Cyprinus carpio L.). AB - Iodothyronine deiodinases determine the biological activity of thyroid hormones. Despite the homology of the catalytic sites of mammalian and teleostean deiodinases, in-vitro requirements for the putative thiol co-substrate dithiothreitol (DTT) vary considerably between vertebrate species. To further our insights in the interactions between the deiodinase protein and its substrates: thyroid hormone and DTT, we measured enzymatic iodothyronine 5'-deiodination, Dio1 and Dio2 mRNA expression, and Dio1 affinity probe binding in liver and kidney preparations from a freshwater teleost, the common carp (Cyprinus carpio L.). Deiodination rates, using reverse T3 (rT3, 3,3',5'-triiodothyronine) as the substrate, were analysed as a function of the iodothyronine and DTT concentrations. In kidney rT3 5'-deiodinase activity measured at rT3 concentrations up to 10 MUM and in the absence of DTT does not saturate appreciably. In the presence of 1mM DTT, renal rT3 deiodination rates are 20-fold lower. In contrast, rT3 5'-deiodination in liver is potently stimulated by 1mM DTT. The marked biochemical differences between 5'-deiodination in liver and kidney are not associated with the expression of either Dio1 or Dio2 mRNA since both organs express both deiodinase types. In liver and kidney, DTT stimulates the incorporation of N-bromoacetylated affinity labels in proteins with estimated molecular masses of 57 and 55, and 31 and 28 kDa, respectively. Although primary structures are highly homologous, the biochemistry of carp deiodinases differs markedly from their mammalian counterparts. PMID- 22198123 TI - Transcriptomic analyses of intestinal gene expression of juvenile Atlantic cod (Gadus morhua) fed diets with Camelina oil as replacement for fish oil. AB - For aquaculture of marine species to continue to expand, dietary fish oil (FO) must be replaced with more sustainable vegetable oil (VO) alternatives. Most VO are rich in n-6 polyunsaturated fatty acids (PUFA) and few are rich in n-3 PUFA but Camelina oil (CO) is unique in that, besides high 18:3n-3 and n-3/n-6 PUFA ratio, it also contains substantial long-chain monoenes, commonly found in FO. Cod (initial mass ~1.4 g) were fed for 12 weeks diets in which FO was replaced with CO. Growth performance, feed efficiency and biometric indices were not affected but lipid levels in liver and intestine tended to increase and those of flesh, decrease, with increasing dietary CO although only significantly for intestine. Reflecting diet, tissue n-3 long-chain PUFA levels decreased whereas 18:3n-3 and 18:2n-6 increased with inclusion of dietary CO. Dietary replacement of FO by CO did not induce major metabolic changes in intestine, but affected genes with potential to alter cellular proliferation and death as well as change structural properties of intestinal muscle. Although the biological effects of these changes are unclear, given the important role of intestine in nutrient absorption and health, further attention should be given to this organ in future. PMID- 22198124 TI - Expression of adhesion molecules, monocyte interactions and oxidative stress in human endothelial cells exposed to wood smoke and diesel exhaust particulate matter. AB - Toxicological effects of wood smoke particles are less investigated than traffic related combustion particles. We investigated the effect of wood smoke particles, generated by smouldering combustion conditions, on human umbilical endothelial cells (HUVECs) co-cultured with or without monocytic THP-1 cells. Standard reference material (SRM) 2975 diesel exhaust particles were used as benchmark particles. Wood smoke particles at 50 MUg/ml or 100 MUg/ml caused adhesion of THP 1 monocytes onto HUVECs in co-cultures, whereas SRM2975 had no such effect. Both types of particles from 1 MUg/ml increased VCAM-1 expression on HUVECs in mono cultures. However, only the exposure to wood smoke particles was associated with increased expression of TNF and IL8 mRNA in THP-1 cells. We found no effect on the intracellular production of reactive oxygen species by the fluorescent probe DCFH-DA, whereas especially the wood smoke particles caused increased level of DNA strand breaks and oxidised guanines at concentrations with low cytotoxicity. In conclusion, our results indicate that the adherence of monocytes on endothelial cells in wood smoke particle exposed cultures depend on activation of both cell types. PMID- 22198135 TI - Aortic valve repair via neo-chordae technique: mechanistic insight through numerical modelling. AB - Recently, the neo-chordae technique (NCT) was proposed to stabilize the surgical correction of isolated aortic valve (AV) prolapse. Neo-chordae are inserted into the corrected leaflet to drive its closure by minimal tensions and prevent relapses. In a previous in vitro study we analysed the NCT effects on healthy aortic roots (ARs). Here we extend that analysis via finite element models (FEMs). After successfully replicating the experimental conditions for validation purposes, we modified our AR FEM, obtaining a continent AV with minor isolated prolapse, thus representing a realistic clinical scenario. We then simulated the NCT, and systematically assessed the acute effects of changing neo-chordae length, opening angle, asymmetry and insertion on the aorta. In the baseline configuration the NCT restored physiological AV dynamics and coaptation, without inducing abnormal leaflet stresses. This outcome was notably sensitive only to neo-chordae length, suggesting that the NCT is a potentially easy-to-standardize technique. However, this parameter is crucial: major shortenings (6 mm) prevent coaptation and increase leaflet stresses by 359 kPa, beyond the yield limit. Minor shortenings (2-4 mm) only induce a negligible stress increase and mild leaflet tethering, which however may hamper the long-term surgical outcome. PMID- 22198136 TI - Adult neural progenitor cells reactivate superbursting in mature neural networks. AB - Behavioral recovery in animal models of human CNS syndromes suggests that transplanted stem cell derivatives can augment damaged neural networks but the mechanisms behind potentiated recovery remain elusive. Here we use microelectrode array (MEA) technology to document neural activity and network integration as rat primary neurons and rat hippocampal neural progenitor cells (NPCs) differentiate and mature. The natural transition from neuroblast to functional excitatory neuron consists of intermediate phases of differentiation characterized by coupled activity. High-frequency network-wide bursting or "superbursting" is a hallmark of early plasticity that is ultimately refined into mature stable neural network activity. Microelectrode array (MEA)-plated neurons transition through this stage of coupled superbursting before establishing mature neuronal phenotypes in vitro. When plated alone, adult rat hippocampal NPC-derived neurons fail to establish the synchronized bursting activity that neurons in primary and embryonic stem cell-derived cultures readily form. However, adult rat hippocampal NPCs evoke re-emergent superbursting in electrophysiologically mature rat primary neural cultures. Developmental superbursting is thought to accompany transient states of heightened plasticity both in culture preparations and across brain regions. Future work exploring whether NPCs can re-stimulate developmental states in injury models would be an interesting test of their regenerative potential. PMID- 22198137 TI - Effect of surface chemistry on gene transfer efficiency mediated by surface induced DNA-doped nanocomposites. AB - Surface-induced biomineralization represents an effective way of immobilizing DNA molecules on biomaterial surfaces to introduce DNA into cells in contact with or at an approximate distance from the biomaterial surfaces. Previous studies have investigated how the composition of mineralizing solutions affects the composition and pH responsiveness of nanocomposites and thus gene transfer efficiency in different cell types. This study investigates how the functional groups of a biomaterial surface affect the induction and crystallographic properties of nanocomposites and thus the gene transfer efficiency. Self assembled monolayers with different termini were used to control the functional groups of a surface. It is demonstrated that the induction of DNA-doped nanocomposites depends on the surface functional groups, which is consistent with previous studies. The crystallographic properties did not vary significantly with the functional groups. DNA-doped nanocomposites induced by different surface functional groups resulted in different cellular uptake of DNA and thus gene transfer efficiency. The differential cellular uptake may be attributed to the interactions between nanocomposites and functional groups. The weaker inducer resulted in higher cellular uptake, and thus higher gene transfer efficiency. Together with other previous studies, the current results suggest that surface mediated gene transfer by DNA-doped nanocomposites can be modulated through both mineralizing solutions and surface chemistries. PMID- 22198138 TI - The effect of an octacalcium phosphate co-precipitated gelatin composite on the repair of critical-sized rat calvarial defects. AB - This study was designed to investigate the extent to which an octacalcium phosphate/gelatin (OCP/Gel) composite can repair rat calvarial critical-sized defects (CSD). OCP crystals were grown with various concentrations of gelatin molecules and the OCP/Gel composites were characterized by chemical analysis, X ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), selected area electron diffraction (SAED) and mercury intrusion porosimetry. The OCP/Gel composite disks received vacuum dehydrothermal treatment, were implanted in Wistar rat calvarial CSD for 4, 8 and 16 weeks, and then subjected to radiologic, histologic, histomorphometric and histochemical assessment. The attachment of mouse bone marrow stromal ST-2 cells on the disks of the OCP/Gel composites was also examined after 1 day of incubation. OCP/Gel composites containing 24 wt.%, 31 wt.% and 40 wt.% of OCP and with approximate pore sizes of 10-500 MUm were obtained. Plate-like crystals were observed closely associated with the Gel matrices. TEM, XRD, FTIR and SAED confirmed that the plate-like crystals were identical to those of the OCP phase, but contained a small amount of sphere-like amorphous material adjacent to the OCP crystals. The OCP (40 wt.%)/Gel composite repaired 71% of the CSD in conjunction with material degradation by osteoclastic cells, which reduced the percentage of the remaining implant to less than 3% within 16 weeks. Of the seeded ST-2 cells, 60-70% were able to migrate and attach to the OCP/Gel composites after 1 day of incubation, regardless of the OCP content. These results indicate that an OCP/Gel composite can repair rat calvarial CSD very efficiently and has favorable biodegradation characteristics. Therefore, it is hypothesized that host osteoblastic cells can easily migrate into an OCP/Gel composite. PMID- 22198139 TI - Involvement of extracellular Hsp72 in wear particle-mediated osteolysis. AB - Wear particle-mediated osteolysis is one of the major problems affecting long term survival of orthopaedic prostheses, frequently progressing to failure of fixation and revision surgery. Upon challenging with wear particles, macrophages and various other types of cells release soluble factors that stimulate the resorptive activity of osteoclasts and impair the function and activity of osteoblasts. Extracellular Hsp72 has been reported to activate macrophages and up regulate pro-inflammatory cytokine production, although its role in osteolysis has not been established yet. The purpose of our study was to evaluate the involvement of this protein in the inflammatory response to wear particles that leads to periprosthetic osteolysis. To this end, we used interfacial tissues and blood samples from patients undergoing revision surgery due to aseptic loosening of cementless acetabular cups. Confocal microscopy indicated that Hsp72 co localises with CD14(+) cells of interfacial tissues. Levels of Hsp72 in the culture media from periprosthetic membranes cultured ex vivo decreased along culture time and Hsp72 levels in sera from patients were lower and under the assay detection limit compared with those from age-matched control subjects. This suggests that interfacial tissues are not actively producing the protein but likely recruit it from peripheral circulation. Incubation of human macrophages with titanium (Ti) particles decreased the release of Hsp72 into culture media. Treatment with recombinant human Hsp72 enhanced considerably IL-6 levels in culture media which were not modified after macrophage co-stimulation with Ti particles, while pre-incubation with Hsp72 increased the Ti particle-induced TNF alpha and IL-1beta production. Altogether, these data indicate that extracellular Hsp72 amplifies the inflammatory response to wear debris by interacting with resident macrophages in periprosthetic tissues. PMID- 22198140 TI - [Spinal tumours]. PMID- 22198141 TI - [Extradural tumors]. AB - Approximately 50-60% of spinal tumors are extradural and depending on the origin and location are classified into tumors of the vertebrae, tumors of the epidural space and primarily extraspinal tumors growing into the spine. Presenting complaints include back pain and weakness as well as myelopathy and radiculopathy due to compression of the spinal cord or the nerve roots, respectively. Imaging of extradural tumors mostly requires both magnetic resonance imaging (MRI) and computed tomography (CT). Extradural masses and infiltration of the cord can be depicted by MRI and CT depicts osteolytic and osteosclerotic lesions and the extent of osseous involvement. Bone scintigraphy is often helpful in detecting metastases and characterizing osteoid osteomas. PMID- 22198142 TI - [Extramedullary intradural spinal tumors]. AB - The category of extramedullary intradural tumors includes a variety of lesions ranging from meningiomas originating from meningeal cells and nerve sheath tumors (neurofibromas, schwannomas) to less common primary tumors, such as lipomas, ependymomas, hemangiopericytomas, epidermoid cysts and dermoid cysts. Extramedullary metastases can occur as transcoelomic metastases in tumors of the central nervous system (CNS) or metastasization from other tumors. Magnetic resonance imaging (MRI) is the method of choice for localization and characterization of these lesions before treatment. PMID- 22198143 TI - [Principles of multidetector-row computed tomography. Part 2: determinants of radiation exposure and current technical developments]. AB - In the field of multidetector-row computed tomography (MDCT) technical improvements have constantly extended the range of clinical applications and made new radiodiagnostic indications accessible. Whereas previous technical improvements were primarily aimed at the imaging of anatomy with high spatial and temporal resolution, nowadays a trend towards quantitative and functional imaging using computed tomography (CT) beyond the pure depiction of morphology is on the horizon: Currently the focus of technical developments is in the domain of spectral (energy-resolved) CT imaging and in the introduction of very wide multi row detectors with large z-coverage. In addition, there is great interest in technical approaches for reducing radiation exposure of the patients caused by (spiral) MDCT, as the increasing range of its clinical applications as well as some of the recent technical advances involve the risk of increased radiation exposure. The use of iterative image reconstruction techniques in MDCT represents a particularly promising technical approach for the reduction of radiation exposure. PMID- 22198145 TI - Mutability and mutational spectrum of chromosome transmission fidelity genes. AB - It has been more than two decades since the original chromosome transmission fidelity (Ctf) screen of Saccharomyces cerevisiae was published. Since that time the spectrum of mutations known to cause Ctf and, more generally, chromosome instability (CIN) has expanded dramatically as a result of systematic screens across yeast mutant arrays. Here we describe a comprehensive summary of the original Ctf genetic screen and the cloning of the remaining complementation groups as efforts to expand our knowledge of the CIN gene repertoire and its mutability in a model eukaryote. At the time of the original screen, it was impossible to predict either the genes and processes that would be overrepresented in a pool of random mutants displaying a Ctf phenotype or what the entire set of genes potentially mutable to Ctf would be. We show that in a collection of 136 randomly selected Ctf mutants, >65% of mutants map to 13 genes, 12 of which are involved in sister chromatid cohesion and/or kinetochore function. Extensive screening of systematic mutant collections has shown that ~350 genes with functions as diverse as RNA processing and proteasomal activity mutate to cause a Ctf phenotype and at least 692 genes are required for faithful chromosome segregation. The enrichment of random Ctf alleles in only 13 of ~350 possible Ctf genes suggests that these genes are more easily mutable to cause genome instability than the others. These observations inform our understanding of recurring CIN mutations in human cancers where presumably random mutations are responsible for initiating the frequently observed CIN phenotype of tumors. PMID- 22198147 TI - Parent-of-origin effects on gene expression and DNA methylation in the maize endosperm. AB - Imprinting describes the differential expression of alleles based on their parent of origin. Deep sequencing of RNAs from maize (Zea mays) endosperm and embryo tissue 14 d after pollination was used to identify imprinted genes among a set of ~12,000 genes that were expressed and contained sequence polymorphisms between the B73 and Mo17 genotypes. The analysis of parent-of-origin patterns of expression resulted in the identification of 100 putative imprinted genes in maize endosperm, including 54 maternally expressed genes (MEGs) and 46 paternally expressed genes (PEGs). Three of these genes have been previously identified as imprinted, while the remaining 97 genes represent novel imprinted maize genes. A genome-wide analysis of DNA methylation identified regions with reduced endosperm DNA methylation in, or near, 19 of the 100 imprinted genes. The reduced levels of DNA methylation in endosperm are caused by hypomethylation of the maternal allele for both MEGs and PEGs in all cases tested. Many of the imprinted genes with reduced DNA methylation levels also show endosperm-specific expression patterns. The imprinted maize genes were compared with imprinted genes identified in genome wide screens of rice (Oryza sativa) and Arabidopsis thaliana, and at least 10 examples of conserved imprinting between maize and each of the other species were identified. PMID- 22198148 TI - Phloem ultrastructure and pressure flow: Sieve-Element-Occlusion-Related agglomerations do not affect translocation. AB - Since the first ultrastructural investigations of sieve tubes in the early 1960s, their structure has been a matter of debate. Because sieve tube structure defines frictional interactions in the tube system, the presence of P protein obstructions shown in many transmission electron micrographs led to a discussion about the mode of phloem transport. At present, it is generally agreed that P protein agglomerations are preparation artifacts due to injury, the lumen of sieve tubes is free of obstructions, and phloem flow is driven by an osmotically generated pressure differential according to Munch's classical hypothesis. Here, we show that the phloem contains a distinctive network of protein filaments. Stable transgenic lines expressing Arabidopsis thaliana Sieve-Element-Occlusion Related1 (SEOR1)-yellow fluorescent protein fusions show that At SEOR1 meshworks at the margins and clots in the lumen are a general feature of living sieve tubes. Live imaging of phloem flow and flow velocity measurements in individual tubes indicate that At SEOR1 agglomerations do not markedly affect or alter flow. A transmission electron microscopy preparation protocol has been generated showing sieve tube ultrastructure of unprecedented quality. A reconstruction of sieve tube ultrastructure served as basis for tube resistance calculations. The impact of agglomerations on phloem flow is discussed. PMID- 22198150 TI - A data-driven integrative model of sepal primordium polarity in Arabidopsis. AB - Flower patterning is determined by a complex molecular network but how this network functions remains to be elucidated. Here, we develop an integrative modeling approach that assembles heterogeneous data into a biologically coherent model to allow predictions to be made and inconsistencies among the data to be found. We use this approach to study the network underlying sepal development in the young flower of Arabidopsis thaliana. We constructed a digital atlas of gene expression and used it to build a dynamical molecular regulatory network model of sepal primordium development. This led to the construction of a coherent molecular network model for lateral organ polarity that fully recapitulates expression and interaction data. Our model predicts the existence of three novel pathways involving the HD-ZIP III genes and both cytokinin and ARGONAUTE family members. In addition, our model provides predictions on molecular interactions. In a broader context, this approach allows the extraction of biological knowledge from diverse types of data and can be used to study developmental processes in any multicellular organism. PMID- 22198151 TI - A synthetic double-stranded RNA, poly I:C, induces a rapid apoptosis of human CD34(+) cells. AB - Toll-like receptor 3 (TLR3), retinoic acid-inducible gene I, and melanoma differentiation-associated antigen 5 (RIG-I/MDA-5) helicases are known to sense double-stranded RNA (dsRNA) virus and initiate antiviral responses, such as production of type-I interferons (IFNs). Recognition of dsRNA by TLR3 or RIG I/MDA-5 is cell-type-dependent and recent studies have shown a direct link between TLRs and hematopoiesis. We hypothesized that viral dsRNA recognized by either TLR3 or RIG-I/MDA-5, affects the growth of human hematopoietic stem/progenitor cells. Here we show that polyinosinic polycytidylic acid (poly I:C)-mediated very rapid apoptosis occurs within 1 hour in CD34(+) cells in a dose-dependent manner. Polyadenylic-polyuridylic acid, another synthetic dsRNA that signals only through TLR3, had no effect. Poly I:C-LMW/LyoVec, a complex between low molecular-weight poly I:C and the transfection reagent LyoVec, which signals only through RIG-I/MDA-5, induces apoptosis of CD34(+) cells. A strong and sustained upregulation of messenger RNA and protein levels of Noxa, a proapoptotic BH3-only protein that can be induced by RIG-I/MDA-5 pathway, is found in CD34(+) cells treated by poly I:C. Although poly I:C upregulates type-I IFNs in CD34(+) cells, neither exogenous IFN-alpha nor IFN-beta induces rapid apoptosis in CD34(+) cells and neutralization or blocking of type-I IFN receptor does not rescue CD34(+) cells, whereas Z-VAD, a pan-caspase inhibitor, rescues the cells from apoptosis. These results suggest that RIG-I/MDA-5, but not TLR3, signaling triggers poly I:C-induced rapid apoptosis of human CD34(+) cells, which will provide an insight into the mechanisms of dsRNA virus-mediated hematopoietic disorders. PMID- 22198152 TI - Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment. AB - Strategies that increase homing to the bone marrow and engraftment efficacy of ex vivo expended CD34(+) cells are expected to enhance their clinical utility. Here we report that nicotinamide (NAM), a form of vitamin B-3, delayed differentiation and increased engraftment efficacy of cord blood-derived human CD34(+) cells cultured with cytokines. In the presence of NAM, the fraction of CD34(+)CD38(-) cells increased and the fraction of differentiated cells (CD14(+), CD11b(+), and CD11c(+)) decreased. CD34(+) cells cultured with NAM displayed increased migration toward stromal cell derived factor-1 and homed to the bone marrow with higher efficacy, thus contributing to their increased engraftment efficacy, which was maintained in competitive transplants with noncultured competitor cells. NAM is a known potent inhibitor of several classes of ribosylase enzymes that require NAD for their activity, as well as sirtuin (SIRT1), class III NAD(+)-dependent histone-deacetylase. We demonstrated that EX-527, a specific inhibitor of SIRT1 catalytic activity, inhibited differentiation of CD34(+) cells similar to NAM, while specific inhibitors of NAD-ribosylase enzymes did not inhibit differentiation, suggesting that the NAM effect is SIRT1-specific. Our findings suggest a critical function of SIRT1 in the regulation of hematopoietic stem cell activity and imply the clinical utility of NAM for ex vivo expansion of functional CD34(+) cells. PMID- 22198153 TI - Aldehyde dehydrogenases are regulators of hematopoietic stem cell numbers and B cell development. AB - High levels of the aldehyde dehydrogenase isoform ALDH1A1 are expressed in hematopoietic stem cells (HSCs); however, its importance in these cells remains unclear. Consistent with an earlier report, we find that loss of ALDH1A1 does not affect HSCs. Intriguingly, however, we find that ALDH1A1 deficiency is associated with increased expression of the ALDH3A1 isoform, suggesting its potential to compensate for ALDH1A1. Mice deficient in ALDH3A1 have a block in B-cell development as well as abnormalities in cell cycling, intracellular signaling, and gene expression. Early B cells from these mice exhibit excess reactive oxygen species and reduced metabolism of reactive aldehydes. Mice deficient in both ALDH3A1 and ALDH1A1 have reduced numbers of HSCs as well as aberrant cell cycle distribution, increased reactive oxygen species levels, p38 mitogen-activated protein kinase activity and sensitivity to DNA damage. These findings demonstrate that ALDH3A1 can compensate for ALDH1A1 in bone marrow and is important in B-cell development, both ALDH1A1 and 3A1 are important in HSC biology; and these effects may be due, in part, to changes in metabolism of reactive oxygen species and reactive aldehydes. PMID- 22198154 TI - Mice heterozygous for CREB binding protein are hypersensitive to gamma-radiation and invariably develop myelodysplastic/myeloproliferative neoplasm. AB - Myelodysplastic syndrome is a complex family of preleukemic diseases in which hematopoietic stem cell defects lead to abnormal differentiation in one or more blood lineages. Disease progression is associated with increasing genomic instability and a large proportion of patients go on to develop acute myeloid leukemia. Primarily a disease of the elderly, it can also develop after chemotherapy. We have previously reported that CREB binding protein (Crebbp) heterozygous mice have an increased incidence of hematological malignancies, and others have shown that CREBBP is one of the genes altered by chromosomal translocations found in patients suffering from therapy-related myelodysplastic syndrome. This led us to investigate whether hematopoietic tumor development in Crebbp(+/-) mice is preceded by a myelodysplastic phase and whether we could uncover molecular mechanisms that might contribute to its development. We report here that Crebbp(+/-) mice invariably develop myelodysplastic/myeloproliferative neoplasm within 9 to 12 months of age. They are also hypersensitive to ionizing radiation and show a marked decrease in poly(ADP-ribose) polymerase-1 activity after irradiation. In addition, protein levels of XRCC1 and APEX1, key components of base excision repair machinery, are reduced in unirradiated Crebbp(+/-) cells or upon targeted knockdown of CREBBP levels. Our results provide validation of a novel myelodysplastic/myeloproliferative neoplasm mouse model and, more importantly, point to defective repair of DNA damage as a contributing factor to the pathogenesis of this currently incurable disease. PMID- 22198155 TI - Establishing Rps6 hemizygous mice as a model for studying how ribosomal protein haploinsufficiency impairs erythropoiesis. AB - Diamond-Blackfan anemia is a congenital hypoproliferative macrocytic anemia and 5q- syndrome myelodysplastic syndrome is an acquired hypoproliferative macrocytic anemia. Their common erythroid phenotype reflects a shared pathophysiology haploinsufficiency of one of many ribosomal proteins and somatic deletion of one allele of the ribosomal protein S14 gene, respectively. Although these abnormalities lead to defective ribosome biogenesis, why ribosomal protein hemizygosity results in anemia is not certain. Here, we characterize the hematopoietic phenotype of mice lacking one allele of the ribosomal protein S6 gene. The mice have an erythroid phenotype similar to both Diamond-Blackfan anemia and the 5q- syndrome and lenalidomide therapy improves their anemia. PMID- 22198156 TI - The pivotal role of adolescent autonomy in secondary school classrooms. AB - Student engagement is an important contributor to school success, yet high school students routinely describe themselves as disengaged. Identifying factors that alter (increase) engagement is a key aspect of improving support for student achievement. This study investigated students' perceptions of autonomy, teacher connection, and academic competence as predictors of changes in student engagement within the classroom from the start to the end of a course. Participants were 578 (58% female) diverse (67.8% White, 25.2% African American, 5.1% Hispanic, 1.2% Asian American) high school students from 34 classrooms who provided questionnaire data both at the start and the end of a single course. Novel results from a cross-lagged model demonstrated that students who perceived their classrooms as allowing and encouraging their own autonomy in the first few weeks increased their engagement throughout the course, rather than the typical decline in engagement that was demonstrated by students in other classrooms. This finding is unique in that it extended to both students' perceptions of engagement and observations of student engagement, suggesting a fairly robust pattern. The pertinence of this finding to adolescent developmental needs and its relationship to educational practice is discussed. PMID- 22198157 TI - Review of aeromedical intra-aortic balloon pump retrieval in New South Wales. AB - OBJECTIVES: The intra-aortic balloon pump (IABP) was first introduced in 1968 to augment cardiac output in the haemodynamically unstable patient and serve as a bridge to treatment options such as coronary artery bypass grafting and cardiac transplantation. Transfer of IABP-dependent patients for upgrade of clinical care is increasingly common and safe. In Australia, percutaneous coronary intervention centres can be located outside cardiothoracic surgical centres. This study reviews IABP medical retrieval by a doctor/paramedic team after implementation of a standardized protocol. METHODS: This was a retrospective case series review, using descriptive statistics. RESULTS: Greater Sydney Area Helicopter Emergency Service carried out 22 cases from 1 May 2007 to 31 December 2009. Median age was 62 years [interquartile range (IQR) 51-83], 67% were male. In all, 63% of patients were retrieved on inotropic support, 29% overall received invasive ventilation. Highest frequency indications were myocardial infarction, cardiogenic shock and bridge to coronary artery bypass grafts. There were complications during 18% of all retrievals and no adverse outcomes. Of the patients, 67% (14/21) were retrieved by road and 33% (7/21) by helicopter (longest distance 500 km). Median stabilization time by a retrieval team was 1 h 15 min (IQR 50 min to 3 h 30 min). Median mission time was 4 h 55 min (IQR 3 h 50 min to 8 h 54 min). CONCLUSION: Our system offers a safe method of IABP medical retrieval. The doctor and paramedic combination complements strengths in logistics and critical care. This serves as a guide to other systems looking to put in place a similar model of care. PMID- 22198158 TI - How accurate are vital signs in predicting clinical outcomes in critically ill emergency department patients. AB - OBJECTIVES: We aimed to evaluate the predictive value of pulse rate (PR), systolic blood pressure (SBP), diastolic blood pressure, respiratory rate (RR), oxygen saturation (SaO2), and the Glasgow Coma Scale (GCS) for cardiac arrest and death in critically ill patients. METHODS: In total, 1025 patients had vital signs recorded at triage at our Emergency Department and were followed up for three clinical outcomes: cardiac arrest in 72 h, admission to ICU, and death within 30 days. Vital signs were used in univariate and multivariate analyses for outcomes. Age was added in multivariate analysis. RESULTS: PR, SBP, RR, SaO2, and GCS were significantly associated with cardiac arrest within 72 h, whereas PR, SBP, RR, SaO2, and GCS were associated with death within 30 days. Only PR and GCS were associated with ICU admission. In the multivariate analysis, age, PR (>100) [odds ratio (OR) 1.65; 95% confidence interval (CI) 1.00-2.71], SBP (>140; OR 0.41; 95% CI: 0.21-0.79), RR (>20; OR 2.90; 95% CI: 1.67-5.03), and GCS (<15; OR 5.71; 95% CI: 3.40-9.57) were significantly associated with death. Vital signs with age have low sensitivity (cardiac arrest 11.54%, death 22.73%, ICU 12.50%) and high specificity (cardiac arrest 99.28%, death 97.22%, ICU 93.80%). Age and GCS were found to be independent predictors of all three outcomes. CONCLUSION: Not all vital signs are useful in the prediction of clinical outcomes. Vital signs had high specificity but very low sensitivity as predictors of clinical outcomes. Clinicians should always remember to treat patients and not numbers. PMID- 22198159 TI - Medical errors and complaints in emergency department care in Sweden as reported by care providers, healthcare staff, and patients - a national review. AB - OBJECTIVE: Despite an increase in research, there is still a lack of knowledge about patient safety in emergency departments (EDs) in many European countries. The aim of this study was therefore to describe the incidence and types of reported medical errors and complaints in ED care in Sweden. METHODS: Data reported in 2009 were gathered from national authorities, including the National Board of Health and Welfare, the Medical Responsibility Board, the Patients Advisory Committees, and local incident-reporting systems. Data were analyzed by content analysis. RESULTS: Among 428 cases reported by care providers to the National Board of Health and Welfare, 64 (15.0%) were related to ED care. As several cases contained more than one medical error, 92 errors were identified, out of which 39 (42.4%) were related to diagnostic procedures. Among the 4628 cases of complaints reported by patients to the Medical Responsibility Board, 306 (6.6%) were related to ED care. In total, 437 complaints regarding perceived medical errors were identified (several cases contained more than one error), with 189 (43.2%) pertaining to diagnostic procedures. A total of 1341 complaints about ED care were made by patients to the Patients Advisory Committees (n=21), of which 655 (48.8%) were related to care and treatment. There were 7434 medical errors reported to local incident-reporting systems at the EDs (n=45). Of these, 1450 (19.5%) referred to care and treatment. CONCLUSION: Medical errors and complaints at Swedish EDs, as reported by both patients and care providers, were related mainly to diagnostic procedures and treatments. PMID- 22198160 TI - Ventilation-associated pneumonia after intubation in the prehospital or the emergency unit. AB - The aim of the study was to evaluate the prevalence and the risk factors of ventilation-associated pneumonia (VAP) for out-of-hospital or in the emergency department intubated patients. This was a retrospective descriptive study. All intubated adults subsequently admitted to the ICU over 1-year period were included. Among 75 patients, 15 patients developed VAP (20%; 95% CI 12-31%). A multivariate analysis revealed three variables independently associated with VAP: cardiorespiratory arrest as the reason of intubation (P=0.001), out-of-hospital as the location of intubation (P=0.011), and clinical macroaspiration as clinical characteristic at the time of intubation (P=0.024). Death rate was 17% and was not significantly higher for patients with VAP (P=0.9; 95% CI 0.32-4.95%). Emergency care workers should be aware of the potential 20% occurrence of VAP when they intubate and ventilate a patient. Preventive strategies, which have been proven effective in ICUs, should be implemented in the emergency setting. PMID- 22198161 TI - Physiological and behavioral responses to an electrical stimulus in Mozambique tilapia (Oreochromis mossambicus). AB - Consumer awareness of the need to improve fish welfare is increasing. Electrostunning is a clean and potentially efficient procedure more and more used to provoke loss of consciousness prior to killing or slaughtering (reviewed by Van de Vis et al. in Aquac Res 34:211-220, 2003). Little is known how (powerful) electrical stimuli, which do not stun immediately, are perceived by fish. We investigated responses of hand-held Mozambique tilapia (Oreochromis mossambicus) to a standardized electric shock applied to the tailfin. The handling with the resulting unavoidable acute stress response was carefully controlled for. Fish responses were analyzed up to 24 h following the shock. Electric shock resulted in slightly higher levels in plasma cortisol, lactate, ionic levels, and osmolality, than handling alone. Plasma glucose had significantly increased 6 h after shock compared to handling, indicative of enhanced adrenergic activity. Mucus release from the gills, branchial Na+/K+ ATPase activity, and chloride cell migration and proliferation, parameters that will change with strong adrenergic activation, were not affected. Decreased swimming activity and delay in resumption of chafing behavior indicated a stronger and differential response toward the electric shock. Responses to handling lasted shorter compared to those to an electric shock. The differential and stronger responses to the electric shock suggest that fish perceived the shock potentially as painful. PMID- 22198162 TI - Effects of dietary administration of Echinacea purpurea on growth indices and biochemical and hematological indices in rainbow trout (Oncorhynchus mykiss) fingerlings. AB - This study was conducted to evaluate the effects of Echinacea purpurea (EP) on growth and some hematological and blood biochemical indices of rainbow trout fingerlings. A basal diet was supplemented with 0 (control), 0.25, 0.5, 1, and 2 g EP kg-1 to formulate five experimental diets. Each diet was randomly allocated to triplicate groups of fish with an initial average weight of approximately 8 g. After 8 weeks of feeding trial, fish fed diets with 0.25 and 0.5 g EP kg-1 showed highest final weight and SGR and fish fed with the control diet indicated the lowest final weight and SGR. There was a significant (P < 0.05) decrease in FCR between the control group and the groups fed with diets of 0.25 and 0.5 g EP kg 1. Biochemical parameters such as serum total protein content, albumin content, globulin content, and albumin/globulin ratio in the fish were evaluated. There were significant differences between hematological parameters including RBC, WBC, HB, lymphocyte, and neutrophil percentage in fish fed with dietary nucleotide compared with control treatment (P < 0.05). The results suggest that EP administration at 0.25 and 0.5 g EP kg-1 exerted positive effects on growth and biochemical and hematological indices in rainbow trout. PMID- 22198163 TI - The effect of cognitive reappraisal on physiological reactivity and emotional memory. AB - We investigated the effect of cognitive reappraisal on emotional arousal, facial expressivity and subsequent memory. Men and women viewed emotionally negative pictures while they attempted to either increase or decrease negative emotions elicited by the pictures, or to simply view the pictures. Neutral pictures were also presented with instructions to simply view the pictures. Concurrent changes in emotional arousal and valence were assessed with skin conductance responses (SCRs) and facial corrugator electromyographic responses (EMG), respectively. Picture memory was assessed with an immediate recall test and a delayed recognition test. Relative to simply viewing pictures, voluntary reappraisal to increase negative emotion generated greater facial corrugator EMG and SCR responses, and reappraisal to decrease negative emotion generated decreased corrugator EMG responses. Men showed enhanced recognition for pictures presented during the increase and decrease conditions, whereas women showed comparable recognition performance across all regulation conditions. The modulation of subsequent recognition memory associated with decreasing emotion was inversely associated with changes in physiological responses. Our results suggest that sex is an important factor to consider in determining how reappraisal-induced physiological changes are associated with subsequent changes in memory. These findings contribute to our understanding of how reappraising emotion exerts both immediate and enduring influences on physiological responses and subsequent memory. PMID- 22198164 TI - Abiraterone acetate: redefining hormone treatment for advanced prostate cancer. AB - Prostate cancer has long since been recognised as being hormonally driven via androgen receptor signalling. Abiraterone acetate (AA) is a rationally designed CYP17 inhibitor that blocks the conversion of androgens from non-gonadal precursors effectively, thus reducing testosterone to undetectable levels. AA has recently been proved to extend survival for men with metastatic castration resistant prostate cancer who have progressive disease after first-line chemotherapy treatment. In addition, it is currently being tested in a Phase III trial in the pre-chemotherapy setting. This paper will review the preclinical discovery and clinical development of AA and will outline the strategy of parallel translational research. PMID- 22198165 TI - Virotherapy--cancer targeted pharmacology. AB - Building on their success in vaccination, many groups are now exploring the use of viruses as anticancer agents. In general, viral therapeutics provide the possibility to express anticancer proteins directly at the tumour site, decreasing exposure to normal tissue during delivery and maximising therapeutic index. Some viruses are also 'oncolytic', either naturally or by design, and these agents function to kill cancer cells selectively before spreading to infect adjacent cells and repeat the process. This whole field of cancer 'virotherapy' is moving forward rapidly at the moment, with notable clinical successes demonstrated with a range of oncolytic agents developed as directly oncolytic and also as oncolytic cancer vaccines. Given the versatility of oncolytic viruses to express therapeutic proteins we anticipate this approach will provide the platform for useful application of a broad range of innovative biological therapies. PMID- 22198166 TI - Anticancer therapies in specialized palliative care--a multicenter survey. AB - INTRODUCTION: Anticancer therapies gain increasing attention and discussion in specialized palliative care institutions. Frequency, indication, attitude of team members, and modes of these therapies implemented in specialized palliative care settings are still under investigation. METHODS: Descriptive analysis of the nationwide Hospice and Palliative Care Evaluation 2007 that collected data from palliative medicine, hospice care, and oncology institutions concerning the use of anticancer therapies. RESULTS: Three thousand one hundred eighty-four patients from 67 palliative care units, eight oncology wards, and other in- and outpatient institutions were registered. Two hundred eleven therapeutic interventions, mostly i.v. chemotherapy (28.9%), have been documented in all institutions except from inpatient hospices. Although all institutions were asked to keep records from "palliative patients", those patients treated in oncology services differed from patients on palliative care units with respect to prognosis, therapeutic intention (symptom control versus tumor remission), and team attitude. DISCUSSION: Anticancer therapies are incorporated into palliative care concepts. The described differences in palliative patients that are treated in specialized palliative care as compared to oncology services will have to be discussed with regard to selection of patients for specialized palliative care and the range of suitable treatment modalities in palliative care concepts. PMID- 22198167 TI - Validation of the Chinese version of Multidimensional Fatigue Inventory-20 in Chinese patients with cancer. AB - GOALS OF WORK: The purpose of this research is to study the validation of the Chinese version of Multidimensional Fatigue Inventory-20 in measuring fatigue status of the patients with cancer in China. MATERIALS AND METHODS: The original English version of the Multidimensional Fatigue Inventory-20 was translated into a Chinese version, which was applied to measure the fatigue status of cancer patients prior to commencing chemotherapy and during the last week of chemotherapy, respectively. The reliability and criterion-related validity of the Chinese version of the Multidimensional Fatigue Inventory-20 were assessed by calculating Cronbach's alpha and Pearson correlation coefficients. The construct validity was analyzed by employing factor analysis. MAIN RESULTS: There were three dimensions in the Chinese version of the MFI-20, which measures the physical, mental, and spiritual fatigue of patients with cancer. All of the correlation coefficients between EORTC QLQ-C30V3.0 and MFI-20 were statistically significant (P < 0.0001). The Cronbach's alpha coefficient was more than 0.8 and 0.7 for total MFI-20 and for the three dimensions of the Chinese version of the MFI-20, respectively. CONCLUSIONS: The Chinese version of the MFI-20 is a reliable and valid instrument to assess fatigue in Chinese patients with cancer. PMID- 22198168 TI - Defective calcium inactivation causes long QT in obese insulin-resistant rat. AB - The majority of diabetic patients who are overweight or obese die of heart disease. We suspect that the obesity-induced insulin resistance may lead to abnormal cardiac electrophysiology. We tested this hypothesis by studying an obese insulin-resistant rat model, the obese Zucker rat (OZR). Compared with the age-matched control, lean Zucker rat (LZR), OZR of 16-17 wk old exhibited an increase in QTc interval, action potential duration, and cell capacitance. Furthermore, the L-type calcium current (I(CaL)) in OZR exhibited defective inactivation and lost the complete inactivation back to the closed state, leading to increased Ca(2+) influx. The current density of I(CaL) was reduced in OZR, whereas the threshold activation and the current-voltage relationship of I(CaL) were not significantly altered. L-type Ba(2+) current (I(BaL)) in OZR also exhibited defective inactivation, and steady-state inactivation was not significantly altered. However, the current-voltage relationship and activation threshold of I(BaL) in OZR exhibited a depolarized shift compared with LZR. The total and membrane protein expression levels of Cav1.2 [pore-forming subunit of L type calcium channels (LTCC)], but not the insulin receptors, were decreased in OZR. The insulin receptor was found to be associated with the Cav1.2, which was weakened in OZR. The total protein expression of calmodulin was reduced, but that of Cavbeta2 subunit was not altered in OZR. Together, these results suggested that the 16- to 17-wk-old OZR has 1) developed cardiac hypertrophy, 2) exhibited altered electrophysiology manifested by the prolonged QTc interval, 3) increased duration of action potential in isolated ventricular myocytes, 4) defective inactivation of I(CaL) and I(BaL), 5) weakened the association of LTCC with the insulin receptor, and 6) decreased protein expression of Cav1.2 and calmodulin. These results also provided mechanistic insights into a remodeled cardiac electrophysiology under the condition of insulin resistance, enhancing our understanding of long QT associated with obese type 2 diabetic patients. PMID- 22198169 TI - Calsequestrin 2 and arrhythmias. AB - Calsequestrin is the most abundant Ca-binding protein of the specialized endoplasmic reticulum found in muscle, the sarcoplasmic reticulum (SR). Calsequestrin binds Ca with high capacity and low affinity and importantly contributes to the mobilization of Ca during each contraction both in skeletal and cardiac muscle. Surprisingly, mutations in the gene encoding the cardiac isoform of calsequestrin (Casq2) have been associated with an inherited form of ventricular arrhythmia triggered by emotional or physical stress termed catecholaminergic polymorphic ventricular tachycardia (CPVT). Despite normal cardiac contractility and normal resting ECG, CPVT patients present with a high risk of sudden death at a young age. Here, we review recent new insights regarding the role of calsequestrin in genetic and acquired arrhythmia disorders. Mouse models of CPVT have shed light on the pathophysiological mechanism underlying CPVT. Casq2 is not only a Ca-storing protein as initially hypothesized, but it has a far more complex function in Ca handling and regulating SR Ca release channels. The functional importance of Casq2 interactions with other SR proteins and the importance of alterations in Casq2 trafficking are also being investigated. Reports of altered Casq2 trafficking in animal models of acquired heart diseases such as heart failure suggest that Casq2 may contribute to arrhythmia risk beyond genetic forms of Casq2 dysfunction. PMID- 22198170 TI - Fructose diet treatment in mice induces fundamental disturbance of cardiomyocyte Ca2+ handling and myofilament responsiveness. AB - High fructose intake has been linked to insulin resistance and cardiac pathology. Dietary fructose-induced myocardial signaling and morphological alterations have been described, but whether cardiomyocyte function is influenced by chronic high fructose intake is yet to be elucidated. The goal of this study was to evaluate the cardiomyocyte excitation-contraction coupling effects of high dietary fructose and determine the capacity for murine cardiomyocyte fructose transport. Male C57Bl/6J mice were fed a high fructose diet for 12 wk. Fructose- and control fed mouse cardiomyocytes were isolated and loaded with the fura 2 Ca(2+) fluorescent dye for analysis of twitch and Ca(2+) transient characteristics (4 Hz stimulation, 37 degrees C, 2 mM Ca(2+)). Myocardial Ca(2+)-handling protein expression was determined by Western blot. Gene expression of the fructose specific transporter, GLUT5, in adult mouse cardiomyocytes was detected by real time and conventional RT-PCR techniques. Diastolic Ca(2+) and Ca(2+) transient amplitude were decreased in isolated cardiomyocytes from fructose-fed mice relative to control (16 and 42%, respectively), coincident with an increase in the time constant of Ca(2+) transient decay (24%). Dietary fructose increased the myofilament response to Ca(2+) (as evidenced by a left shift in the shortening Ca(2+) phase loop). Protein expression of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a), phosphorylated (P) phospholamban (Ser(16)), and P-phospholamban (Thr(17)) was reduced, and protein phosphatase 2A expression increased, in fructose-fed mouse hearts. Hypertension and cardiac hypertrophy were not evident. These findings demonstrate that fructose diet-associated myocardial insulin resistance induces profound disturbance of cardiomyocyte Ca(2+) handling and responsiveness in the absence of altered systemic loading conditions. PMID- 22198171 TI - Angiotensin-(1-7) attenuates the chronotropic response to angiotensin II via stimulation of PTEN in the spontaneously hypertensive rat neurons. AB - Several studies have focused on the beneficial effects of peripheral angiotensin (1-7) [Ang-(1-7)] in the regulation of cardiovascular function, showing its counterregulatory effect against the actions of angiotensin II (ANG II). However, its actions in the central nervous system are not completely understood. In the present study, we investigated the intracellular mechanisms underlying the action of ANG-(1-7) using the patch-clamp technique in neurons cultured from the hypothalamus of neonatal spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Superfusion of neurons with ANG II (100 nM) significantly increased neuronal firing in both strains of rats, and this chronotropic effect of ANG II was significantly enhanced in prehypertensive SHR neurons compared with WKY rat neurons. The enhanced chronotropic effect of ANG II was attenuated by a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, LY 294002 (10 MUM). Superfusion of neurons with ANG-(1-7) (100 nM) did not alter the neuronal firing rate in either SHR or WKY neurons; however, it significantly attenuated the chronotropic action of ANG II exclusively in prehypertensive SHR neurons. This counterregulatory effect of ANG-(1-7) on ANG II action in prehypertensive SHR neurons was attenuated by cotreatment with either A-779, a Mas receptor antagonist, or bisperoxovanadium, a phosphatase and tensin homologue deleted on chromosome ten (PTEN) inhibitor. In addition, incubation of WKY and prehypertensive SHR neurons with ANG-(1-7) significantly increased PTEN activity. The data demonstrate that ANG-(1-7) counterregulates the chronotropic action of ANG II via a PTEN-dependent signaling pathway in prehypertensive SHR neurons. PMID- 22198172 TI - Mineralocorticoids participate in the reduced vascular reactivity of pregnant rats. AB - The renin-angiotensin-aldosterone (RAA) system is markedly activated in pregnancy. We evaluated if mineralocorticoid receptors (MR), a major component of the RAA system, are involved in the reduced vascular reactivity associated with pregnancy. Canrenoate (MR antagonist; 20 mg.kg(-1).day(-1)) was administered to nonpregnant (NP) rats for 7 days and to pregnant rats from day 15 to 22 of gestation. These were killed on day 17, 19, or 22 of gestation and, for NP rats, after 7 days treatment. Constrictor responses to phenylephrine (PhE) and KCl were measured in endothelium-denuded thoracic aortic rings under the influence of modulators of potassium (activators) and calcium (blocker) channels. Responses to the constrictors were blunted from days 17 to 22 of gestation. Although canrenoate increased responses to PhE and KCl, it did not reverse their blunted responses in gestation. NS-1619 and cromakalim (respectively, high-conductance calcium-activated potassium channels and ATP-sensitive potassium channel activators) diminished responses to both PhE and KCl. Inhibition by NS-1619 on responses to both agonists was decreased under canrenoate treatment in NP, but the reduced influence of NS-1619 during gestation was reversed by the mineralocorticoid antagonist. Cromakalim reduced the response to PhE significantly in the pregnant groups; this effect was enhanced by canrenoate. Finally, nifedipine (calcium channel blocker) markedly reduced KCl responses but to a lesser extent at the end of pregnancy, an inhibiting effect that was increased with canrenoate treatment. These data demonstrate that treating rats with a MR antagonist increased vascular reactivity but that it differentially affected potassium and calcium channel activity in aortas of NP and pregnant animals. This suggests that aldosterone is one of the components involved in vascular adaptations to pregnancy. PMID- 22198173 TI - Longitudinal displacement and intramural shear strain of the porcine carotid artery undergo profound changes in response to catecholamines. AB - The effects of catecholamines on longitudinal displacements and intramural shear strain of the arterial wall are unexplored. Therefore, the common carotid artery of five anaesthetized pigs was investigated using an in-house developed noninvasive ultrasonic technique. The study protocol included intravenous infusion of low-dose epinephrine (beta-adrenoceptor activation), as well as intravenous boluses of norepinephrine (alpha-adrenoceptor activation). Further, the effects of beta-blockade (metoprolol) were studied. There were significant positive correlations between pulse pressure and longitudinal displacement of the intima-media complex (r = 0.72; P < 0.001), as well as between pulse pressure and intramural shear strain (r = 0.48; P < 0.001). Following administration of norepinephrine, the longitudinal displacement of the intima-media complex and intramural shear strain profoundly increased (median 190%, range 102-296%, and median 141%, range 101-182%, respectively, compared with baseline), also when given during beta-blockade (median 228%, range 133-266%, and median 158%, range 152-235%, respectively). During infusion of low-dose epinephrine, the longitudinal displacement of the intima-media complex and intramural shear strain decreased (median 88%, range 69-122%, and median 69%, range 47-117%, respectively, compared with baseline). In conclusion, the present study shows, for the first time, that the longitudinal displacement and intramural shear strain of the porcine carotid artery undergo profound changes in response to catecholamines. Increase in longitudinal displacements seems to be strongly related to alpha-adrenoceptor activation. Thus metoprolol is insufficient to counteract a profound increase in longitudinal displacement and intramural shear strain following a surge of norepinephrine. PMID- 22198175 TI - An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment. AB - Cell lines expressing ion channels (IC) and the advent of plate-based electrophysiology device have enabled a molecular understanding of the action potential (AP) as a means of early QT assessment. We sought to develop an in silico AP (isAP) model that provides an assessment of the effect of a compound on the myocyte AP duration (APD) using concentration-effect curve data from a panel of five ICs (hNav1.5, hCav1.2, hKv4.3/hKChIP2.2, hKv7.1/hminK, hKv11.1). A test set of 53 compounds was selected to cover a range of selective and mixed IC modulators that were tested for their effects on optically measured APD. A threshold of >10% change in APD at 90% repolarization (APD(90)) was used to signify an effect at the top test concentration. To capture the variations observed in left ventricular midmyocardial myocyte APD data from 19 different dogs, the isAP model was calibrated to produce an ensemble of 19 model variants that could capture the shape and form of the APs and also quantitatively replicate dofetilide- and diltiazem-induced APD(90) changes. Provided with IC panel data only, the isAP model was then used, blinded, to predict APD(90) changes greater than 10%. At a simulated concentration of 30 MUM and based on a criterion that six of the variants had to agree, isAP prediction was scored as showing greater than 80% predictivity of compound activity. Thus, early in drug discovery, the isAP model allows integrating separate IC data and is amenable to the throughput required for use as a virtual screen. PMID- 22198174 TI - The Na+/K+ pump is an important modulator of refractoriness and rotor dynamics in human atrial tissue. AB - Pharmacological treatment of atrial fibrillation (AF) exhibits limited efficacy. Further developments require a comprehensive characterization of ionic modulators of electrophysiology in human atria. Our aim is to systematically investigate the relative importance of ionic properties in modulating excitability, refractoriness, and rotor dynamics in human atria before and after AF-related electrical remodeling (AFER). Computer simulations of single cell and tissue atrial electrophysiology were conducted using two human atrial action potential (AP) models. Changes in AP, refractory period (RP), conduction velocity (CV), and rotor dynamics caused by alterations in key properties of all atrial ionic currents were characterized before and after AFER. Results show that the investigated human atrial electrophysiological properties are primarily modulated by maximal value of Na(+)/K(+) pump current (G(NaK)) as well as conductances of inward rectifier potassium current (G(K1)) and fast inward sodium current (G(Na)). G(NaK) plays a fundamental role through both electrogenic and homeostatic modulation of AP duration (APD), APD restitution, RP, and reentrant dominant frequency (DF). G(K1) controls DF through modulation of AP, APD restitution, RP, and CV. G(Na) is key in determining DF through alteration of CV and RP, particularly in AFER. Changes in ionic currents have qualitatively similar effects in control and AFER, but effects are smaller in AFER. The systematic analysis conducted in this study unravels the important role of the Na(+)/K(+) pump current in determining human atrial electrophysiology. PMID- 22198176 TI - Relative contribution of cyclooxygenases, epoxyeicosatrienoic acids, and pH to the cerebral blood flow response to vibrissal stimulation. AB - The increase in cerebral blood flow (CBF) during neuronal activation can be only partially attenuated by individual inhibitors of epoxyeicosatrienoic acids (EETs), cyclooxgenase-2, group I metabotropic glutamate receptors (mGluR), neuronal nitric oxide synthase (nNOS), N-methyl-D-aspartate receptors, or adenosine receptors. Some studies that used a high concentration (500 MUM) of the cyclooxygenase-1 inhibitor SC-560 have implicated cyclooxygenase-1 in gliovascular coupling in certain model systems in the mouse. Here, we found that increasing the concentration of SC-560 from 25 MUM to 500 MUM over whisker barrel cortex in anesthetized rats attenuated the CBF response to whisker stimulation. However, exogenous prostaglandin E(2) restored the response in the presence of 500 MUM SC-560 but not in the presence of a cyclooxygenase-2 inhibitor, thereby suggesting a limited permissive role for cyclooxygenase-1. Furthermore, inhibition of the CBF response to whisker stimulation by an EET antagonist persisted in the presence of SC-560 or a cyclooxygenase-2 inhibitor, thereby indicating that the EET-dependent component of vasodilation did not require cyclooxygenase-1 or -2 activity. With combined inhibition of cyclooxygenase-1 and -2, mGluR, nNOS, EETs, N-methyl-D-aspartate receptors, and adenosine 2B receptors, the CBF response was reduced by 60%. We postulated that the inability to completely block the CBF response was due to tissue acidosis resulting from impaired clearance of metabolically produced CO2. We tested this idea by increasing the concentration of superfused bicarbonate from 25 to 60 mM and found a markedly reduced CBF response to hypercapnia. However, increasing bicarbonate had no effect on the initial or steady-state CBF response to whisker stimulation with or without combined inhibition. We conclude that the residual response after inhibition of several known vasodilatory mechanisms is not due to acidosis arising from impaired CO2 clearance when the CBF response is reduced. An unidentified mechanism apparently is responsible for the rapid, residual cortical vasodilation during vibrissal stimulation. PMID- 22198177 TI - Intracellular Ca2+ release underlies the development of phase 2 in mouse ventricular action potentials. AB - The ventricular action potential (AP) is characterized by a fast depolarizing phase followed by a repolarization that displays a second upstroke known as phase 2. This phase is generally not present in mouse ventricular myocytes. Thus we performed colocalized electrophysiological and optical recordings of APs in Langendorff-perfused mouse hearts founding a noticeable phase 2. Ryanodine as well as nifedipine reduced phase 2. Our hypothesis is that a depolarizing current activated by Ca(2+) released from the sarcoplasmic reticulum (SR) rather than the "electrogenicity" of the L-type Ca(2+) current is crucial in the generation of mouse ventricular phase 2. When Na(+) was partially replaced by Li(+) in the extracellular perfusate or the organ was cooled down, phase 2 was reduced. These results suggest that the Na(+)/Ca(2+) exchanger functioning in the forward mode is driving the depolarizing current that defines phase 2. Phase 2 appears to be an intrinsic characteristic of single isolated myocytes and not an emergent property of the tissue. As in whole heart experiments, ventricular myocytes impaled with microelectrodes displayed a large phase 2 that significantly increases when temperature was raised from 22 to 37 degrees C. We conclude that mouse ventricular APs display a phase 2; however, changes in Ca(2+) dynamics and thermodynamic parameters also diminish phase 2, mostly by impairing the Na(+)/Ca(2+) exchanger. In summary, these results provide important insights about the role of Ca(2+) release in AP ventricular repolarization under physiological and pathological conditions. PMID- 22198179 TI - DESTAF: a database of text-mined associations for reproductive toxins potentially affecting human fertility. AB - The Dragon Exploration System for Toxicants and Fertility (DESTAF) is a publicly available resource which enables researchers to efficiently explore both known and potentially novel information and associations in the field of reproductive toxicology. To create DESTAF we used data from the literature (including over 10500 PubMed abstracts), several publicly available biomedical repositories, and specialized, curated dictionaries. DESTAF has an interface designed to facilitate rapid assessment of the key associations between relevant concepts, allowing for a more in-depth exploration of information based on different gene/protein-, enzyme/metabolite-, toxin/chemical-, disease- or anatomically centric perspectives. As a special feature, DESTAF allows for the creation and initial testing of potentially new association hypotheses that suggest links between biological entities identified through the database. DESTAF, along with a PDF manual, can be found at http://cbrc.kaust.edu.sa/destaf. It is free to academic and non-commercial users and will be updated quarterly. PMID- 22198178 TI - A theory for water and macromolecular transport in the pulmonary artery wall with a detailed comparison to the aorta. AB - The pulmonary artery (PA) wall, which has much higher hydraulic conductivity and albumin void space and approximately one-sixth the normal transmural pressure of systemic arteries (e.g, aorta, carotid arteries), is rarely atherosclerotic, except under pulmonary hypertension. This study constructs a detailed, two dimensional, wall-structure-based filtration and macromolecular transport model for the PA to investigate differences in prelesion transport processes between the disease-susceptible aorta and the relatively resistant PA. The PA and aorta models are similar in wall structure, but very different in parameter values, many of which have been measured (and therefore modified) since the original aorta model of Huang et al. (23). Both PA and aortic model simulations fit experimental data on transwall LDL concentration profiles and on the growth of isolated endothelial (horseradish peroxidase) tracer spots with circulation time very well. They reveal that lipid entering the aorta attains a much higher intima than media concentration but distributes better between these regions in the PA than aorta and that tracer in both regions contributes to observed tracer spots. Solutions show why both the overall transmural water flow and spot growth rates are similar in these vessels despite very different material transport parameters. Since early lipid accumulation occurs in the subendothelial intima and since (matrix binding) reaction kinetics depend on reactant concentrations, the lower intima lipid concentrations in the PA vs. aorta likely lead to slower accumulation of bound lipid in the PA. These findings may be relevant to understanding the different atherosusceptibilities of these vessels. PMID- 22198180 TI - Neonatal exposure to low doses of endosulfan disrupts the expression of proteins regulating uterine development and differentiation. AB - This study investigates the effects of neonatal exposure to low doses of endosulfan on the expression of proteins regulating uterine development and differentiation. Female pups received vehicle, endosulfan (Endo6: 6 MUg/kg, Endo600: 600 MUg/kg) or diethylstilbestrol (DES: 0.2 MUg/kg) from postnatal day 1 (PND1) to PND7. The uterine expression of estrogen receptor alpha (ERalpha), progesterone receptor (PR), Hoxa10 and alpha smooth muscle actin (alpha-SMA) was detected by immunohistochemistry on PND8 (neonatal period) and PND21 (prepubertal period), to evaluate acute and short-term responses. ERalpha, Hoxa10 and alpha SMA were induced in the Endo600 group in both ages, while a striking decrease in PR expression was detected in the prepubertal rats following each dose of endosulfan. DES treatment deregulated ERalpha and Hoxa10 uterine expression at each age. Studies are currently underway to investigate whether the dysregulation of steroid receptors, Hoxa10 and alpha-SMA observed following neonatal exposure to endosulfan affect uterine functions in adulthood. PMID- 22198181 TI - Birth outcomes related to informal e-waste recycling in Guiyu, China. AB - To assess the impact of exposure to informal e-waste recycling on birth outcomes. We compared record-based birth outcomes (n=24,493) and levels of cord blood lead (CBPb) (n=531) in Guiyu and a control area in Xiamen. Guiyu births showed significantly higher rates of adverse birth outcomes including stillbirth (4.72% vs. 1.03%), low birth weight (6.12% vs. 4.12%), term low birth weight (3.40% vs. 1.57%), and lower Apgar scores (9.6 vs. 9.9) and mean birth weight (3168 g vs. 3258 g) than did births from the control site, all P<0.01. Regression analysis showed Guiyu had about four times higher risk of stillbirth compared with Xiamen. The median level of CBPb was much higher in neonates of Guiyu than those in the control group (10.78 MUg/dL vs. 2.25 MUg/dL). Prenatal exposure to informal e waste recycling related to high rate of adverse birth outcomes, lower Apgar scores and unsafe lead level in cord blood. PMID- 22198182 TI - Biochemical identification of a hydroperoxide derivative of the free 8-oxo-7,8 dihydroguanine base. AB - 8-Oxo-7,8-dihydroguanine is one the most abundant base lesions in pro- and eukaryotic DNA. In mammalian cells, it is excised by the 8-oxoguanine DNA glycosylase (OGG1) during DNA base-excision repair, and the generated free 8-oxoG base is one of the DNA-derived biomarkers of oxidative stress in biological samples. The modification of 8-oxoG in the context of nucleoside and DNA has been the subject of many studies; however, the oxidative transformation of the free 8 oxoG base has not been described. By using biochemical and cell biological assays, we show that in the presence of molecular oxygen, the free 8-oxoG base transforms to a highly reactive hydroperoxide (8-oxoG*). Specifically, 8-oxoG* oxidizes Amplex red to resorufin, H(2)DCF to DCF, Fe(2+) to Fe(3+), and GSH to GSSG. This property of 8-oxoG* was diminished by treatment with catalase and glutathione peroxidase, but not superoxide dismutase. 8-OxoG* formation was prevented by reducing agents or nitrogen atmosphere. Its addition to CM-H(2)DCF DA-loaded cells rapidly increased intracellular DCF fluorescence. There were no such properties observed for 8-oxodeoxyguanosine, 2,6-diamino-4-hydroxy-5 formamidopyrimidine, 2'-deoxyguanosine, guanine, adenine, guanosine, and 8 hydroxyadenine. These data imply that a free 8-oxoG base is more susceptible to oxidation than is its nucleoside form and, consequently, it stands as unique among intact and oxidatively modified purines. PMID- 22198183 TI - ERK/GSK3beta/Snail signaling mediates radiation-induced alveolar epithelial-to mesenchymal transition. AB - Radiotherapy is one of the major treatment regimes for thoracic malignancies, but can lead to severe lung complications including pneumonitis and fibrosis. Recent studies suggest that epithelial-to-mesenchymal transition (EMT) plays an important role in tissue injury leading to organ fibrosis. To investigate whether radiation can induce EMT in lung epithelial cells and also to understand the potential mechanism(s) associated with this change, rat alveolar type II lung epithelial RLE-6TN cells were irradiated with 8 Gy of (137)Cs gamma-rays. Western blot and immunofluorescence analyses revealed a time-dependent decrease in E cadherin with a concomitant increase in alpha-smooth muscle actin (alpha-SMA) and vimentin after radiation, suggesting that the epithelial cells acquired a mesenchymal-like morphology. Protein levels and nuclear translocation of Snail, the key inducer of EMT, were significantly elevated in the irradiated cells. Radiation also induced a time-dependent inactivation of glycogen synthase kinase 3beta (GSK3beta), an endogenous inhibitor of Snail. A marked increase in phosphorylation of ERK1/2, but not JNK or p38, was observed in irradiated RLE-6TN cells. Silencing ERK1/2 using siRNAs and the MEK/ERK inhibitor U0126 attenuated the radiation-induced phosphorylation of GSK3beta and altered the protein levels of Snail, alpha-SMA, and E-cadherin in RLE-6TN cells. Preincubating RLE-6TN cells with N-acetylcysteine, an antioxidant, abolished the radiation-induced phosphorylation of ERK and altered protein levels of Snail, E-cadherin, and alpha SMA. These findings reveal, for the first time, that radiation-induced EMT in alveolar type II epithelial cells is mediated by the ERK/GSK3beta/Snail pathway. PMID- 22198184 TI - Activation of stress signaling pathways by electrophilic oxidized and nitrated lipids. AB - Unsaturated fatty acids are prone to radical reactions that occur in biological situations where extensive formation of reactive oxygen and nitrogen species (ROS and RNS) takes place. These reactions are frequent in inflammatory conditions such as atherosclerosis, and yield a variety of biologically active species, many of which are electrophilic in nature. Electrophilic lipid oxidation and nitration products can influence redox cell signaling via S-alkylation of protein thiols, and moderate exposure to these species evokes protective cell signaling responses through this mechanism. Herein, we review the stress signaling pathways elicited by electrophiles derived from unsaturated fatty acids, focusing on the Keap1-Nrf2 pathway, the heat shock response pathway (HSR), and the unfolded protein response pathway (UPR). PMID- 22198185 TI - Higher infused CD34+ cell dose and overall survival in patients undergoing in vivo T-cell depleted, but not t-cell repleted, allogeneic peripheral blood hematopoietic cell transplantation. AB - BACKGROUND AND OBJECTIVES: Understanding the effect of cellular graft composition on allogeneic hematopoietic cell transplantation (AHCT) outcomes is an area of great interest. The objective of the study was to analyze the correlation between transplant-related outcomes and administered CD34+, CD3+, CD4+ and CD8+ cell doses in patients who had undergone peripheral blood, AHCT and received either in vivo T-cell depleted or T-cell replete allografts. DESIGN AND SETTING: Comparison of consecutive patients who underwent peripheral blood AHCT in our institution between January 2003 and December 2009. PATIENTS AND METHODS: The cohort of 149 patients was divided into two groups; non T-cell depleted (NTCD) (n=54) and T cell depleted (TCD) (n=95). Study endpoints were overall survival (OS), progression free survival (PFS), engraftment kinetics (neutrophil and platelet recovery), incidence of acute graft versus host disease (acute GVHD), chronic GVHD, nonrelapse mortality (NRM) and disease relapse. RESULTS: Multivariate analysis showed that higher infused CD34+ cell dose improved OS (relative risk 0.58, 95% CI 0.34-0.98, P=.04), PFS (relative risk 0.59, 95% CI 0.35-1.00, P=.05) and NRM (relative risk 0.49, 95% CI 0.24-0.99, P=.048) in the TCD group. By multivariate analysis, there was no difference in engraftment, grades II-IV acute GVHD, extensive chronic GVHD and relapse in the two groups relative to the infused cell doses. There was a trend towards improved OS (relative risk 0.54, 95% CI 0.29-1.01, P=.05) with higher CD3+ cell dose in the TCD group. CONCLUSION: Our findings suggest that higher CD34+ cell dose imparts survival benefit only to in vivo TCD peripheral blood AHCT recipients. PMID- 22198186 TI - Preliminary experience with the use of bendamustine: a peculiar skin rash as the commonest side effect. AB - BACKGROUND AND OBJECTIVES: Bendamustine has been recently approved for the treatment of low-grade lymphoproliferative disorders. There is little data on the effectiveness or toxicity of this drug outside the trial setting. This is the first report on the use of bendamustine from the Indian subcontinent. SETTINGS AND DESIGN: Retrospective descriptive analysis of response and side effects of bendamustine in eight patients with chronic lymphocytic leukemia and eight patients with follicular lymphoma. METHODS: Data was collated from a review of case records. We examined any association between side effects and clinical parameters. RESULTS: The median age of patients was 52 years and three-quarters had received prior treatment with alkylators or fludarabine. Three different protocols of bendamustine were used (single agent, in combination with rituximab or in combination with vincristine and prednisolone). The overall response rate was 80% (47% complete response, 33% partial response, and 20% progressive disease). The drug was well tolerated with very few grade 3/4 toxicities. More than half the patients (9/16) developed a characteristic erythematous, papular skin rash that resolved after completion of chemotherapy. CONCLUSION: Bendamustine is a safe and useful addition to the drug arsenal against lymphoproliferative disorders. A peculiar skin rash was the commonest side effect noted in Indian patients treated with this drug. PMID- 22198187 TI - A population-based study of the epidemiology and clinical features of adults with acute myeloid leukemia in Algeria: report on behalf of the Algerian Acute Leukemia Study Group. AB - BACKGROUND AND OBJECTIVES: In Algeria, the incidence of hematologic malignancies has been difficult to estimate for many years. Today, many hematological centers, including 14 university hospitals, have been developed in the entire north and have useful epidemiological data pertinent to acute myeloid leukemia (AML). We studied the incidence of AML and its subtypes, age distribution, geographic distribution and trends in the rate of diagnosis over the last 5 years in Algeria. Secondary goals were to study trends of referral of AML cases from various regions to specific centers to assess the needs for health infrastructure and change of current practices. DESIGN AND SETTING: Retrospective analysis of nationwide survey of all adult cases of AML (>16 years) diagnosed between 1 January 2006 and 31 December 2010. PATIENTS AND METHODS: A survey form was distributed to all departments of hematology at the 15 participating centers. RESULTS: The 1426 cases of AML diagnosed during the study period represented an annual incidence of 0.91/100000 persons with a male to female (M/F) ratio of 1:16 and a median age of 45 years (range, 16-82 years). Nationally, 20% of cases AML were diagnosed in the whole western region of the country, 47% in the central and 33% in the east. There was a trend of continuous increase in the rate with age and in the rate of diagnosis over the last 5 years. The most common subtype was M2, followed by M4 and M5. CONCLUSION: An overall increase in the number of AML patients diagnosed nationwide over the last five years indicates a need for additional health care resources including curative and therapy-intense strategies, such as stem cell transplant facilities to optimize outcome. The relatively younger age of patients compared to the Western countries may be due to the demographic composition of our population. PMID- 22198188 TI - Evidence for the use PET for radiation therapy planning in patients with cervical cancer: a systematic review. AB - BACKGROUND AND OBJECTIVE: In recent years, the role of positron emission tomography (PET) in the staging and management of gynecological cancers has been increasing. The aim of this study was to systematically review the role of PET in radiotherapy planning and brachytherapy treatment optimization in patients with cervical cancer. DESIGN AND SETTING: Systematic literature review. METHODS: Systematic review of relevant literature addressing the utilization of PET and/or PET-computed tomography (CT) in external-beam radiotherapy planning and brachytherapy treatment optimization. We performed an extensive PubMed database search on 20 April 2011. Nineteen studies, including 759 patients, formed the basis of this systematic review. RESULTS: PET/ PET-CT is the most sensitive imaging modality for detecting nodal metastases in patients with cervical cancer and has been shown to impact external-beam radiotherapy planning by modifying the treatment field and customizing the radiation dose. This particularly applies to detection of previously uncovered para-aortic and inguinal nodal metastases. Furthermore, PET/ PET-CT guided intensity-modulated radiation therapy (IMRT) allows delivery of higher doses of radiation to the primary tumor, if brachytherapy is unsuitable, and to grossly involved nodal disease while minimizing treatment-related toxicity. PET/ PET-CT based brachytherapy optimization allows improved tumor-volume dose distribution and detailed 3D dosimetric evaluation of risk organs. Sequential PET/ PET-CT imaging performed during the course of brachytherapy form the basis of a??adaptivea?? brachytherapy in cervical cancer. CONCLUSIONS: This review demonstrates the effectiveness of pretreatment PET/ PET-CT in cervical cancer patients treated by radiotherapy. Further prospective studies are required to define the group of patients who would benefit the most from this procedure. PMID- 22198189 TI - Durable complete response induced by paclitaxel-nimotuzumab-methotrexate chemotherapy in a patient with metastatic head and neck squamous cell carcinoma. AB - A 61-year-old male patient with metastatic poorly differentiated squamous cell carcinoma of the larynx to lymph nodes and lung was treated with a third-line chemotherapy regimen of paclitaxel, nimotuzumab and low-dose methotrexate, receiving a total of 30 cycles. The response was complete and maintained at 16 months. Nimotuzumab is a humanized monoclonal antibody used to treat squamous cell carcinomas of the head and neck. This third-line chemotherapy combination with paclitaxel-nimotuzumab-methotrexate seems to be an active combination and needs further evaluation in clinical trials to validate its use in heavily treated patients. PMID- 22198190 TI - Eight primary malignancies: case report and review of literature. AB - The incidence of multiple primary malignancies has increased over the past years secondary to the long-term survival of cancer patients due to improvements in the early detection and adequate treatment of cancer. We present a patient with eight primary malignant tumors and review the relevant literature. Our patient was a 59 year-old female with Crohn disease with an otherwise non-contributory medical history. Risk factors for multiple primary tumors were not detected in our patient. At a follow-up of 108 months from the time of diagnosis of the first malignancy, our patient was still alive. Similar long-term survival has been reported in the literature. Due to the realistic potential for long-term survival, we recommend aggressive treatment of these patients. PMID- 22198191 TI - Intensity-modulated radiotherapy in head and neck cancer: how safe is safe? PMID- 22198192 TI - An approach to finding indications and contraindications for nephrectomy in post transplant renal graft lymphomas: PTLD.Int survey. AB - BACKGROUND AND OBJECTIVES: Allograft involvement can occur in some renal transplant recipients who develop post-transplant lymphoproliferative disorders (PTLD). We aimed to find indications and/or contraindications for nephrectomy in renal allograft PTLD based on an outcome analysis of previous reports. DESIGN AND SETTING: A comprehensive search of Pubmed and Google scholar was performed to find reports of different treatment strategies addressing PTLD occurring within the allograft after renal transplantation. PATIENTS AND METHODS: Patients who underwent nephrectomy due to kidney allograft localization by PTLD were categorized as the case group, and renal recipients with kidney PTLD for whom nonsurgical treatment modalities were used served as controls. RESULTS: Survival analysis demonstrated that patients with renal allograft involvement who underwent allograft nephrectomy had a significantly better outcome compared to patients for whom a non-surgical approach was used (P=.03). In patients with disseminated PTLD, nephrectomy was not useful (P>.1). Patients with simultaneous kidney and lung complications by PTLD benefitted from nephrectomy. CONCLUSIONS: We found that patients with renal graft complication with disseminated PTLD do not benefit from nephrectomy, which can be considered the only contraindication. However, some particular PTLD co-localizations were not as likely to adversely affect the benefit of nephrectomy in these patients, and these can be considered indications for the procedure. Future multicenter studies are needed to confirm our results. PMID- 22198193 TI - Primary anaplastic large cell lymphoma of trachea with subcutaneous emphysema and progressive dyspnea. AB - Primary anaplastic large cell lymphoma of the trachea is a rare tumor. Common complaints are dyspnea and cough that could mimic a partially refractory asthma in some cases. We report a 16-year-old female with an anaplastic large cell lymphoma (null cell type) in which tracheal involvement was presented with life threatening airway obstruction and subcutaneous emphysema. After debulking the tumor by endobronchial curettage, the patient was treated with chemotherapy followed by local radiotherapy. She had no evidence of local or distant recurrence after 25 months. Primary anaplastic large cell lymphoma of the trachea is a rare life-threatening disease. Nevertheless, this condition has a good prognosis if diagnosed immediately and treated with chemotherapy and radiotherapy. PMID- 22198194 TI - Mesothelioma in Cyprus: a case series (1997-2007). PMID- 22198195 TI - Fracture resistance and marginal discrepancy of porcelain laminate veneers influenced by preparation design and restorative material in vitro. AB - OBJECTIVES: The purpose of this investigation is to evaluate marginal discrepancy and fracture resistance of two veneering materials using two preparation designs. METHODS: Two veneer preparation designs (full and traditional) were restored with leucite-reinforced ceramic (ProCAD, Ivoclar Vivadent, Amherst, NY) milled by CAD/CAM (Cerec 3D milling system, Serona Dental Systems), and conventional sintered feldspathic porcelain (Noritake Super Porcelain EX3, Noritake Dental Supply Co). Forty-eight specimens were analysed with a sample size of n=12 per group. The thickness of each veneer was measured on four specific surfaces. Marginal discrepancy was evaluated with a replica technique and cross-sectional view using a digital microscope. The fracture resistance of veneers cemented on standardised composite resin dies was evaluated using a universal testing machine. Results were analysed with ANOVA, Tukey-Kramer post hoc testing, and linear regression. RESULTS: The results of this investigation revealed no correlation between the thickness and marginal discrepancy of the veneers. The full preparation design with ProCAD and the traditional preparation design with feldspathic porcelain manifested smaller gap. Fracture resistance was decreased for the full preparation design with feldspathic porcelain. CONCLUSIONS: In terms of marginal discrepancy and fracture resistance, the most favourable combination was a traditional veneer preparation design with conventional sintered feldspathic porcelain. For the full veneer preparation, a stronger ceramic material such as ProCAD is suggested. PMID- 22198196 TI - AFM study of the effects of collagenase and its inhibitors on dentine collagen fibrils. AB - OBJECTIVE: This study evaluated the effects of exogenous collagenase and two collagenase inhibitors on the variation in microstructure of human collagen fibrils. METHODS: Dentine specimens which were sectioned from 6 freshly extracted human caries-free third molars were wet polished. Each specimen was divided into 4 parts which were treated as experimental groups (group 1, group 2, group 3) and the control group, respectively. All the specimens were etched and further treated with NaClOaq. Subsequently, the topography of each specimen was observed using atomic force microscopy (AFM) in tapping mode in air. Group 1 was then treated with a solution of collagenase II. Group 2 was treated with a solution of collagenase II and chlorhexidine (saturated solution). Group 3 was treated with a solution of collagenase II and captopril (0.3%). The control group was treated with a buffer solution. After 3h and 6h of treatment, the topography of the collagen fibrils was measured with AFM in air, respectively. RESULTS: AFM images of the dentine collagen fibrils were obtained after treatment with NaOClaq. Following further treatment with collagenase II, the topography of the collagen fibrils changed. Most reticular collagen fibrils disappeared after 6h. After treatment with collagenase II in the presence of chlorhexidine or captopril for 3h and 6h, the morphology of the collagen fibres was not changed obviously. CONCLUSIONS: Exogenous collagenase II effectively degraded human dentine collagen fibrils, and its collagenolytic activity was inhibited by the exogenous collagenase inhibitors, chlorhexidine and captopril. PMID- 22198197 TI - Optimization of 13C isotopic tracers for metabolic flux analysis in mammalian cells. AB - Mammalian cells consume and metabolize various substrates from their surroundings for energy generation and biomass synthesis. Glucose and glutamine, in particular, are the primary carbon sources for proliferating cancer cells. While this combination of substrates generates static labeling patterns for use in (13)C metabolic flux analysis (MFA), the inability of single tracers to effectively label all pathways poses an obstacle for comprehensive flux determination within a given experiment. To address this issue we applied a genetic algorithm to optimize mixtures of (13)C-labeled glucose and glutamine for use in MFA. We identified tracer combinations that minimized confidence intervals in an experimentally determined flux network describing central carbon metabolism in tumor cells. Additional simulations were used to determine the robustness of the [1,2-(13)C(2)]glucose/[U-(13)C(5)]glutamine tracer combination with respect to perturbations in the network. Finally, we experimentally validated the improved performance of this tracer set relative to glucose tracers alone in a cancer cell line. This versatile method allows researchers to determine the optimal tracer combination to use for a specific metabolic network, and our findings applied to cancer cells significantly enhance the ability of MFA experiments to precisely quantify fluxes in higher organisms. PMID- 22198198 TI - In vivo laser speckle imaging reveals microvascular remodeling and hemodynamic changes during wound healing angiogenesis. AB - Laser speckle contrast imaging (LSCI) is a high-resolution and high contrast optical imaging technique often used to characterize hemodynamic changes in short term physiological experiments. In this study, we demonstrate the utility of LSCI for characterizing microvascular remodeling and hemodynamic changes during wound healing angiogenesis in vivo. A 2 mm diameter hole was made in the mouse ear and the periphery of the wound imaged in vivo using LSCI over 12 days. We were able to visualize and quantify the vascular and perfusion changes that accompanied wound healing in the microenvironment proximal to the wound, and validated these changes with histology. We found that consistent with the stages of wound healing, microvessel density increased during the initial inflammatory phase (i.e., day 0-3), stayed elevated through the tissue formation phase (i.e., until day 7) and returned to baseline during the tissue remodeling phase (i.e., by day 12). Concomitant "wide area mapping" of blood flow revealed that tissue perfusion in the wound periphery initially decreased, gradually increased from day 3-7, and subsided as healing completed. Interestingly, some regions exhibited a reestablishment of tissue perfusion approximately 6 days earlier than the ~18 days usually reported for the long term remodeling phase. The results from this study demonstrate that LSCI is an ideal platform for elucidating in vivo changes in microvascular hemodynamics and angiogenesis, and has the potential to offer invaluable insights in a range of disease models involving abnormal hemodynamics, such as diabetes and tumors. PMID- 22198199 TI - The cytosolic domain of human Tom22 modulates human Bax mitochondrial translocation and conformation in yeast. AB - The role of the mitochondrial protein receptor Tom22p in the interaction of pro apoptotic protein Bax with yeast mitochondria was investigated. Co immunoprecipitation assays showed that human Bax interacted with different TOM subunits, including Tom22p. Expression of the cytosolic receptor domain of human Tom22 increased Bax mitochondrial localization, but decreased the proportion of active Bax. BN-PAGE showed that the cytosolic domain of Tom22 interfered with the oligomerization of Bax. These data suggest that the interaction with the cytosolic domain of Tom22 helps Bax to acquire a conformation able to interact with the outer mitochondrial membrane. PMID- 22198201 TI - 1.5 Mb microdeletion in 15q24 in a patient with mild OAVS phenotype. AB - We report on a boy presenting with features of OAVS (Oculoauriculovertebral spectrum) and carrying a 1.5 Mb microdeletion in 15q24.1q24.2. This recurrent deletion usually leads to a broad clinical spectrum but has never been found associated with features of OAVS such as ear agenesis. This observation is in accordance with OAVS being a genetically heterogeneous disorder, and points out the importance of array-CGH screening in this disorder. PMID- 22198200 TI - Comparing the temperature dependence of FMN to heme electron transfer in full length and truncated inducible nitric oxide synthase proteins. AB - The FMN-heme interdomain (intraprotein) electron transfer (IET) kinetics in full length and oxygenase/FMN (oxyFMN) construct of human iNOS were determined by laser flash photolysis over the temperature range from 283 to 304K. An appreciable increase in the rate constant value was observed with an increase in the temperature. Our previous viscosity study indicated that the IET process is conformationally gated, and Eyring equation was thus used to analyze the temperature dependence data. The obtained magnitude of activation entropy for the IET in the oxyFMN construct is only one-fifth of that for the holoenzyme. This indicates that the FMN domain in the holoenzyme needs to sample more conformations before the IET takes place, and that the FMN domain in the oxyFMN construct is better poised for efficient IET. PMID- 22198202 TI - Improvement of stress tolerance in plants by genetic manipulation of mitogen activated protein kinases. AB - Plant stress tolerance depends on many factors among which signaling by mitogen activated protein-kinase (MAPK) modules plays a crucial role. Reversible phosphorylation of MAPKs, their upstream activators and downstream targets such as transcription factors can trigger a myriad of transcriptomic, cellular and physiological responses. Genetic manipulation of abundance and/or activity of some of these modular MAPK components can lead to better stress tolerance in Arabidopsis and crop plant species such as tobacco and cereals. The main focus of this review is devoted to the MAPK-related signaling components which show the most promising biotechnological potential. Additionally, recent studies identified MAPK components to be involved both in plant development as well as in stress responses, suggesting that these processes are tightly linked in plants. PMID- 22198203 TI - Genetic engineering of cytokinin metabolism: prospective way to improve agricultural traits of crop plants. AB - Cytokinins (CKs) are ubiquitous phytohormones that participate in development, morphogenesis and many physiological processes throughout plant kingdom. In higher plants, mutants and transgenic cells and tissues with altered activity of CK metabolic enzymes or perception machinery, have highlighted their crucial involvement in different agriculturally important traits, such as productivity, increased tolerance to various stresses and overall plant morphology. Furthermore, recent precise metabolomic analyses have elucidated the specific occurrence and distinct functions of different CK types in various plant species. Thus, smooth manipulation of active CK levels in a spatial and temporal way could be a very potent tool for plant biotechnology in the future. This review summarises recent advances in cytokinin research ranging from transgenic alteration of CK biosynthetic, degradation and glucosylation activities and CK perception to detailed elucidation of molecular processes, in which CKs work as a trigger in model plants. The first attempts to improve the quality of crop plants, focused on cereals are discussed, together with proposed mechanism of action of the responses involved. PMID- 22198204 TI - A mutation screening platform for rapeseed (Brassica napus L.) and the detection of sinapine biosynthesis mutants. AB - We developed two mutant populations of oilseed rape (Brassica napus L.) using EMS (ethylmethanesulfonate) as a mutagen. The populations were derived from the spring type line YN01-429 and the winter type cultivar Express 617 encompassing 5,361 and 3,488 M(2) plants, respectively. A high-throughput screening protocol was established based on a two-dimensional 8* pooling strategy. Genes of the sinapine biosynthesis pathway were chosen for determining the mutation frequencies and for creating novel genetic variation for rapeseed breeding. The extraction meal of oilseed rape is a rich protein source containing about 40% protein. Its use as an animal feed or human food, however, is limited by antinutritive compounds like sinapine. The targeting-induced local lesions in genomes (TILLING) strategy was applied to identify mutations of major genes of the sinapine biosynthesis pathway. We constructed locus-specific primers for several TILLING amplicons of two sinapine synthesis genes, BnaX.SGT and BnaX.REF1, covering 80-90% of the coding sequences. Screening of both populations revealed 229 and 341 mutations within the BnaX.SGT sequences (135 missense and 13 nonsense mutations) and the BnaX.REF1 sequences (162 missense, 3 nonsense, 8 splice site mutations), respectively. These mutants provide a new resource for breeding low-sinapine oilseed rape. The frequencies of missense and nonsense mutations corresponded to the frequencies of the target codons. Mutation frequencies ranged from 1/12 to 1/22 kb for the Express 617 population and from 1/27 to 1/60 kb for the YN01-429 population. Our TILLING resource is publicly available. Due to the high mutation frequencies in combination with an 8* pooling strategy, mutants can be routinely identified in a cost-efficient manner. However, primers have to be carefully designed to amplify single sequences from the polyploid rapeseed genome. PMID- 22198205 TI - Identification and mapping of two powdery mildew resistance genes in Triticum boeoticum L. AB - Powdery mildew (PM) caused by Blumeria graminis f. sp. tritici (Bgt), is one of the important foliar diseases of wheat that can cause serious yield losses. Breeding for cultivars with diverse resources of resistance is the most promising approach for combating this disease. The diploid A genome progenitor species of wheat are an important resource for new variability for disease resistance genes. An accession of Triticum boeoticum (A(b)A(b)) showed resistance against a number of Bgt isolates, when tested using detached leaf segments. Inheritance studies in a recombinant inbred line population (RIL), developed from crosses of PM resistant T. boeoticum acc. pau5088 with a PM susceptible T. monococcum acc. pau14087, indicated the presence of two powdery mildew resistance genes in T. boeoticum acc. pau5088. Analysis of powdery mildew infection and molecular marker data of the RIL population revealed that both powdery mildew resistance genes are located on the long arm of chromosome 7A. Mapping was conducted using an integrated linkage map of 7A consisting of SSR, RFLP, STS, and DArT markers. These powdery mildew resistance genes are tentatively designated as PmTb7A.1 and PmTb7A.2. The PmTb7A.2 is closely linked to STS markers MAG2185 and MAG1759 derived from RFLP probes which are linked to powdery mildew resistance gene Pm1. This indicated that PmTb7A.2 might be allelic to Pm1. The PmTb7A.1, flanked by a DArT marker wPt4553 and an SSR marker Xcfa2019 in a 4.3 cM interval, maps proximal to PmT7A.2. PmTb7A.1 is putatively a new powdery mildew resistance gene. The powdery mildew resistance genes from T. boeoticum are currently being transferred to cultivated wheat background through marker-assisted backcrossing, using T. durum as bridging species. PMID- 22198206 TI - Solution NMR structures reveal a distinct architecture and provide first structures for protein domain family PF04536. AB - The protein family (Pfam) PF04536 is a broadly conserved domain family of unknown function (DUF477), with more than 1,350 members in prokaryotic and eukaryotic proteins. High-quality NMR structures of the N-terminal domain comprising residues 41-180 of the 684-residue protein CG2496 from Corynebacterium glutamicum and the N-terminal domain comprising residues 35-182 of the 435-residue protein PG0361 from Porphyromonas gingivalis both exhibit an alpha/beta fold comprised of a four-stranded beta-sheet, three alpha-helices packed against one side of the sheet, and a fourth alpha-helix attached to the other side. In spite of low sequence similarity (18%) assessed by structure-based sequence alignment, the two structures are globally quite similar. However, moderate structural differences are observed for the relative orientation of two of the four helices. Comparison with known protein structures reveals that the alpha/beta architecture of CG2496(41-180) and PG0361(35-182) has previously not been characterized. Moreover, calculation of surface charge potential and identification of surface clefts indicate that the two domains very likely have different functions. PMID- 22198207 TI - Resistance of leukemic stem-like cells in AML cell line KG1a to natural killer cell-mediated cytotoxicity. AB - Leukemic stem cells (LSCs) play the central role in the relapse and refractory of acute myeloid leukemia (AML) and highlight the critical need for the new therapeutic strategies to directly target the LSC population. However, relatively little is known about the unique molecular mechanisms of drug and natural killer cells (NK)-killing resistance of LSCs because of very small number of LSCs in bone marrow. In this study, we investigated whether established leukemia cell line contains LSCs. We showed that KG1a leukemia cell line contained leukemic stem-like cells, which have been phenotypically restricted within the CD34(+)CD38(-) fractions. CD34(+)CD38(-) cells could generate CD34(+)CD38(+) cells in culture medium and had renewal function. Moreover, CD34(+)CD38(-) cells had self-renewal potential. We found that leukemic stem-like cells from KG1a cells were resistant to chemotherapy and NK-mediated cytotoxicity. NKG2D ligands involve in protecting LSCs from NK-mediated attack. Taken together, our studies provide a novel cell model for leukemic stem cells research. Our data also shed light on mechanism of double resistant to chemotherapy and NK cell immunotherapy, which was helpful for developing novel effective strategies for LSCs. PMID- 22198208 TI - Use of the gamma-H2AX assay to monitor DNA damage and repair in translational cancer research. AB - Formation of gamma-H2AX in response to DNA double stranded breaks (DSBs) provides the basis for a sensitive assay of DNA damage in human biopsies. The review focuses on the application of gamma-H2AX-based methods to translational studies to monitor the clinical response to DNA targeted therapies such as some forms of chemotherapy, external beam radiotherapy, radionuclide therapy or combinations thereof. The escalating attention on radiation biodosimetry has also highlighted the potential of the assay including renewed efforts to assess the radiosensitivity of prospective radiotherapy patients. Finally the gamma-H2AX response has been suggested as a basis for an in vivo imaging modality. PMID- 22198210 TI - A review of transcriptome studies combined with data mining reveals novel potential markers of malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM), a cancer of the serosal pleural cavities, is one of the most aggressive human tumors. In order to identify genes crucial for the onset and progression of MPM, we performed an extensive literature review focused on transcriptome studies (RTS). In this kind of studies a great number of transcripts are analyzed without formulating any a priori hypothesis, thus preventing any bias coming from previously established knowledge that could lead to an over-representation of specific genes. Each study was thoroughly analyzed paying particular attention to: (i) the employed microarray platform, (ii) the number and type of samples, (iii) the fold-change, and (iv) the statistical significance of deregulated genes. We also performed data mining (DM) on MPM using three different tools (Coremine, SNPs3D, and GeneProspector). Results from RTS and DM were compared in order to restrict the number of genes potentially deregulated in MPM. Our main requirement for a gene to be a "mesothelioma gene" (MG) is to be reproducibly deregulated among independent studies and confirmed by DM. A list of MGs was thus produced, including PTGS2, BIRC5, ASS1, JUNB, MCM2, AURKA, FGF2, MKI67, CAV1, SFRP1, CCNB1, CDK4, and MSLN that might represent potential novel biomarkers or therapeutic targets for MPM. Moreover, it was found a sub-group of MGs including ASS1, JUNB, PTGS2, EEF2, SULF1, TOP2A, AURKA, BIRC5, CAV1, IFITM1, PCNA, and PKM2 that could explain, at least in part, the mechanisms of resistance to cisplatin, one first-line chemotherapeutic drug used for the disease. Finally, the pathway analysis showed that co-regulation networks related to the cross-talk between MPM and its micro-environment, in particular involving the adhesion molecules, integrins, and cytokines, might have an important role in MPM. Future studies are warranted to better characterize the role played by these genes in MPM. PMID- 22198209 TI - Mechanistic considerations for human relevance of cancer hazard of di(2 ethylhexyl) phthalate. AB - Di(2-ethylhexyl) phthalate (DEHP) is a peroxisome proliferator agent that is widely used as a plasticizer to soften polyvinylchloride plastics and non polymers. Both occupational (e.g., by inhalation during its manufacture and use as a plasticizer of polyvinylchloride) and environmental (medical devices, contamination of food, or intake from air, water and soil) routes of exposure to DEHP are of concern for human health. There is sufficient evidence for carcinogenicity of DEHP in the liver in both rats and mice; however, there is little epidemiological evidence on possible associations between exposure to DEHP and liver cancer in humans. Data are available to suggest that liver is not the only target tissue for DEHP-associated toxicity and carcinogenicity in both humans and rodents. The debate regarding human relevance of the findings in rats or mice has been informed by studies on the mechanisms of carcinogenesis of the peroxisome proliferator class of chemicals, including DEHP. Important additional mechanistic information became available in the past decade, including, but not limited to, sub-acute, sub-chronic and chronic studies with DEHP in peroxisome proliferator-activated receptor (PPAR) alpha-null mice, as well as experiments utilizing several transgenic mouse lines. Activation of PPARalpha and the subsequent downstream events mediated by this transcription factor represent an important mechanism of action for DEHP in rats and mice. However, additional data from animal models and studies in humans exposed to DEHP from the environment suggest that multiple molecular signals and pathways in several cell types in the liver, rather than a single molecular event, contribute to the cancer in rats and mice. In addition, the toxic and carcinogenic effects of DEHP are not limited to liver. The International Agency for Research on Cancer working group concluded that the human relevance of the molecular events leading to cancer elicited by DEHP in several target tissues (e.g., liver and testis) in rats and mice can not be ruled out and DEHP was classified as possibly carcinogenic to humans (Group 2B). PMID- 22198213 TI - MicroRNA-34a inhibits migration and invasion of colon cancer cells via targeting to Fra-1. AB - MicroRNA-34a (miR-34a), a transcriptional target of p53, is a well-known tumor suppressor gene. Here, we identified Fra-1 as a new target of miR-34a and demonstrated that miR-34a inhibits Fra-1 expression at both protein and messenger RNA levels. In addition, we found that p53 indirectly regulates Fra-1 expression via a miR-34a-dependant manner in colon cancer cells. Overexpression of miR-34a strongly inhibited colon cancer cell migration and invasion, which can be partially rescued by forced expression of the Fra-1 transcript lacking the 3' untranslated region. The expression of matrix metalloproteinase (MMP)-1 and MMP 9, two enzymes involved in cell migration and invasion, was decreased in miR-34a transfected cells, and this can be rescued by Fra-1 overexpression. Moreover, we found that miR-34a was downregulated in 25 of 40 (62.5%) colon cancer tissues, as compared with the adjacent normal colon tissues and that the expression of miR 34a was correlated with the DNA-binding activity of p53. Unexpectedly, the DNA binding activity of p53 was not inversely correlated with Fra-1 expression, and a significant statistical inverse correlation between miR-34a and Fra-1 expression was only observed in 14 of 40 (35%) colon cancer tissues. Taken together, our in vitro data suggest that p53 regulates Fra-1 expression, and eventually cell migration/invasion, via a miR-34a-dependent manner. However, in vivo data indicate that the p53-miR-34a pathway is not the major regulator of Fra-1 expression in human colon cancer tissues. PMID- 22198212 TI - Oral infusion of pomegranate fruit extract inhibits prostate carcinogenesis in the TRAMP model. AB - We earlier provided evidence that oral consumption of pomegranate fruit extract (PFE) inhibits prostate cancer (PCa) cell growth in nude mice. To ascertain convincing evidence of chemopreventive effects of PFE against PCa, its efficacy requires to be evaluated in animal models that closely emulate human disease. Here, we provide evidence of remarkable tumor growth inhibitory effects of PFE using the TRAMP model. Mice received 0.1 and 0.2% PFE, equivalent to 250 and 500 ml of pomegranate juice, in drinking water, starting at 6 weeks and examined at 12, 20 and 34 weeks of age. In water-fed group, 100% mice developed palpable tumors by 20 weeks compared with only 30 and 20% in the 0.1 and 0.2% PFE supplemented groups, respectively. At 34 weeks, palpable tumors were observed in 70 of 0.1% and only 50 of 0.2% PFE-supplemented mice. Compared with median survival of 43 weeks in water-fed mice, 0.1 and 0.2% PFE-supplemented mice exhibited median life expectancy of 73 and 92 weeks, respectively. Compared with respective water-fed groups, none of the mice in PFE-supplemented groups exhibited metastases to any of the distant organs at 20 weeks and only 20% mice exhibited metastasis at 34 weeks of age. Many of the PFE-supplemented animals had multiple foci of well-differentiated carcinoma but no evidence of poorly differentiated carcinoma. PFE supplementation resulted in simultaneous and significant inhibition of IGF-I/Akt/mTOR pathways in the prostate tissues and tumors. We suggest that pomegranate juice be evaluated in clinical trials in patients at high risk for developing PCa. PMID- 22198211 TI - Modulation of Wnt/beta-catenin signaling pathway by bioactive food components. AB - The Wnt/beta-catenin signaling pathway, one of the most conserved intercellular signaling cascade, is a known regulator of cellular functions related to tumor initiation and progression, cell proliferation, differentiation, survival and adhesion. Because aberrant Wnt/beta-catenin signaling has been observed in a variety of human cancers including a majority of colorectal cancers, about half of prostate cancers and a third of melanomas, inhibitors of its complex signaling pathways are being investigated for therapy as well as chemoprevention of these cancers. During the last decade, several naturally occurring dietary agents have been shown to target intermediates in the Wnt/beta-catenin signaling pathway. In this review, we highlight the current understanding of the Wnt/beta-catenin signaling pathway and present an analysis of the key findings from laboratory studies on the effects of a panel of dietary agents against a variety of cancers. Promise of these agents for treating and preventing human cancer is then discussed. PMID- 22198215 TI - The influence of 5-aminosalicylic acid on the progression of colorectal adenomas via the beta-catenin signaling pathway. AB - Surveillance colonoscopy is an important strategy for prevention of colorectal cancer. 5-aminosalicylate (ASA) (mesalazine) is discussed as a chemopreventive agent as it reduces the cancer risk in ulcerative colitis patients. The current study analyses the effect of 5-ASA on Wnt/beta-catenin signaling in vitro and in vivo in colon epithelial cells. The effect of 5-ASA was determined using a beta catenin/T-cell factor (TCF)-reporter assay and by western blotting in cultured colon cancer cells. Formalin fixed paraffin embedded material from 227 polyps removed from a subgroup of 56 patients, who participated in a randomized placebo controlled 3-year prevention trial with 5-ASA was evaluated according to histomorphological characteristics and expression of beta-catenin and target genes Cox2, cyclin D1 and E-cadherin as well as ornithine decarboxylase (ODC). Patients were grouped into a low-risk and a high-risk group according to the number of adenomas at initial colonoscopy. beta-catenin/TCF signaling activity was significantly reduced by 5-ASA treatment possibly through a reduction in beta catenin levels. Moreover, 5-ASA significantly reduced beta-catenin levels and nuclear localization in patients' adenomas. In addition, 5-ASA also significantly changed expression of the downstream targets Cox2, cyclin D1 and E-cadherin, correlating with beta-catenin status. Moreover, 5-ASA significantly reduced levels of ODC in vivo. Expression of p53 was unaltered by the 5-ASA treatment. Our study shows a significant in vitro and long-term in vivo effect of 5-ASA on beta-catenin signaling as a key signaling pathway in the development of colorectal adenoma. Therefore, we suggest the use of 5-ASA as a promising drug for prevention of sporadic colorectal carcinoma. PMID- 22198214 TI - Asthma and lung cancer risk: a systematic investigation by the International Lung Cancer Consortium. AB - Asthma has been hypothesized to be associated with lung cancer (LC) risk. We conducted a pooled analysis of 16 studies in the International Lung Cancer Consortium (ILCCO) to quantitatively assess this association and compared the results with 36 previously published studies. In total, information from 585 444 individuals was used. Study-specific measures were combined using random effects models. A meta-regression and subgroup meta-analyses were performed to identify sources of heterogeneity. The overall LC relative risk (RR) associated with asthma was 1.28 [95% confidence intervals (CIs) = 1.16-1.41] but with large heterogeneity (I(2) = 73%, P < 0.001) between studies. Among ILCCO studies, an increased risk was found for squamous cell (RR = 1.69, 95%, CI = 1.26-2.26) and for small-cell carcinoma (RR = 1.71, 95% CI = 0.99-2.95) but was weaker for adenocarcinoma (RR = 1.09, 95% CI = 0.88-1.36). The increased LC risk was strongest in the 2 years after asthma diagnosis (RR = 2.13, 95% CI = 1.09-4.17) but subjects diagnosed with asthma over 10 years prior had no or little increased LC risk (RR = 1.10, 95% CI = 0.94-1.30). Because the increased incidence of LC was chiefly observed in small cell and squamous cell lung carcinomas, primarily within 2 years of asthma diagnosis and because the association was weak among never smokers, we conclude that the association may not reflect a causal effect of asthma on the risk of LC. PMID- 22198216 TI - Fluorescein and indocyanine-green angiography in ocular syphilis: an exploratory study. AB - BACKGROUND: Fluorescein (FA) and indocyanine-green angiography (ICGA) may offer valuable information concerning disease severity and prognosis in ocular syphilis. The aim of the present study is to describe angiographic patterns encountered in the context of ocular syphilis, and to explore the associations between specific angiographic manifestations and severity of disease presentation, as well as disease evolution after treatment. METHODS: We performed a retrospective institutional study with the inclusion of 23 patients with ocular syphilis presenting to the uveitis clinic of the Jules-Gonin Eye Hospital in a 10 year period. FA and ICGA were performed following a standard protocol for posterior uveitis. Patterns of fluorescence were noted, and statistical associations between each angiographic pattern and any demographic, clinical, or laboratory parameter at baseline and after treatment were sought. RESULTS: The presence of any dark dots in ICGA was significantly associated with anterior uveitis (p = 0.031). The presence of hot spots in ICGA was significantly associated with longer duration of symptoms prior to initial visit (p = 0.032) and with male gender (p = 0.012). Weak non-significant trends were found associating vascular staining in FA with anterior uveitis (p = 0.066), vitritis (p = 0.069), and younger age (p = 0.061), as well as disc hyperfluorescence in FA with seropositivity for HIV (p = 0.089) and macular edema in FA with longer disease duration (p = 0.061). The presence of any dark dots in ICGA exhibited a weak trend of association with anterior uveitis and/or vitritis (p = 0.079). CONCLUSIONS: Out of the several associations identified implicating specific angiographic features, we underline the possible role of the presence of dark dots in ICGA for identifying active inflammation, and the role of hot spots in ICGA as markers of long-standing disease. Vascular staining in FA appears to be more common in patients with severe ocular inflammation with presence of anterior uveitis and/or vitritis. PMID- 22198217 TI - Genetic variation of porcine circovirus type 2 (PCV2) and its relevance to vaccination, pathogenesis and diagnosis. AB - Porcine circovirus-associated disease (PCVAD) encompasses a group of complex, multi-factorial syndromes, which are dependent on infection with porcine circovirus type 2 (PCV2). Current strains of PCV2 circulating in the field are classified into two groups, termed PCV2a and PCV2b. Outbreaks of severe PCVAD in North America and other countries are often linked to a shift from PCV2a to PCV2b as the predominant genotype. Therefore, genotype-specific differences in pathogenesis and antigenicity have been suggested. Overall, evidence suggests that virulence is a function of the specific PCV2 isolate, regardless of genotype. In addition, only minor antigenic differences have been reported. In terms of immunopathogenesis, a conserved decoy epitope, located in the C-terminal region of the capsid protein, provides an explanation for the inability to identify pathogenic differences between genotypes. Finally, genetic variation in PCV2 and the resulting consequences with respect to vaccination and diagnostics are discussed. PMID- 22198218 TI - Anesthetic management of Prader-Willi syndrome: what if neuromuscular relaxants could not be avoided? PMID- 22198219 TI - Reversal of neuromuscular blockade with sugammadex in a patient with spinal muscular atrophy type III (Kugelberg-Welander syndrome). PMID- 22198220 TI - A high dose of dexmedetomidine using the BIS monitorTM for diagnostic and interventional cardiac catheterization in a toddler with congenital heart disease. AB - Dexmedetomidine (DEX) for sedation in diagnostic and interventional cardiac catheterization (DICC) has been reported to require other drugs or rescue drugs because of its insufficient sedative effect when used alone. We administered DEX and adjusted its dose according to the bispectral index (BIS) monitorTM for DICC in a toddler; consequently, a high dose of DEX had to be administered. The patient was a 1-year and 4-month-old boy who was scheduled to undergo DICC after intracardiac repair. We used DEX alone as the sedative because this was expected to avoid oxygen supply and mechanical ventilation and to produce a safe situation for procedures around the neck. DEX was administered at the dose of 1-15 MUg/kg/h according to BIS monitorTM; administration of cardiovascular drugs or oxygen supply or assist ventilation, except chin lift, were not needed. The maximum predicted plasma concentration (pCp) of DEX and mean pCp were calculated as 6.1 and 4.1 ng/mL, respectively. A high dose of DEX may be required for DICC sedation, as for MRI sedation, in many cases. Although further studies should be conducted to reveal the merits and demerits of DEX in cardiac catheterization, a high dose of DEX may be useful in some cases. PMID- 22198222 TI - The diagnostic utility of narrow band imaging magnifying endoscopy in clinical practice in a population with intermediate gastric cancer risk. AB - OBJECTIVE: Narrow band imaging (NBI) and NBI-magnifying endoscopy (ME) have been reported to facilitate the diagnosis of intestinal metaplasia (IM) and early gastric cancer (EGC) in high-risk populations. This study aimed at comparing the detection rate of focal gastric lesions by NBI against white light endoscopy (WLE), and examined the utility of NBI-ME in differentiating gastric mucosal pathology in a population with intermediate gastric cancer risk. METHODS: Chinese patients aged 35-70 years undergoing diagnostic gastroscopy (GIF FQ260Z) by six experienced endoscopists were enrolled prospectively. The sequence of endoscopic evaluation was WLE followed by NBI. Focal lesions were re-examined by NBI-ME. The incremental diagnostic yield of NBI over WLE and ability of NBI-ME to differentiate gastric mucosal pathology were analyzed. RESULTS: Over a 30-month period, 458 patients (mean age: 52 years; men: 53.7%; Helicobacter pylori positive: 20.1%) were recruited. WLE detected a focal gastric lesion in 43.7% (200/458). WLE made a definitive diagnosis in 148 out of 200 patients (147 benign lesions and one gastric cancer), whereas NBI-ME correctly clarified the nature of the remaining 52 lesions (benign: 51; EGC: one). NBI detected an additional 69 out of 458 lesions (type 0_IIa: 91.3%; type 0_IIb: 8.7%) missed by WLE; the diagnoses based on NBI-ME were IM (67/69), EGC (1/69), and benign lesion (1/69). Interobserver agreement study revealed a kappa statistic of 0.71. CONCLUSION: NBI detected IM missed by WLE. NBI-ME was useful in differentiating the pathology of focal gastric mucosal lesions. PMID- 22198221 TI - Propofol neurotoxicity is mediated by p75 neurotrophin receptor activation. AB - BACKGROUND: Propofol exposure to neurons during synaptogenesis results in apoptosis, leading to cognitive dysfunction in adulthood. Previous work from our laboratory showed that isoflurane neurotoxicity occurs through p75 neurotrophin receptor (p75(NTR)) and subsequent cytoskeleton depolymerization. Given that isoflurane and propofol both suppress neuronal activity, we hypothesized that propofol also induces apoptosis in developing neurons through p75(NTR). METHODS: Days in vitro 5-7 neurons were exposed to propofol (3 MUM) for 6 h and apoptosis was assessed by cleaved caspase-3 (Cl-Csp3) immunoblot and immunofluorescence microscopy. Primary neurons from p75(NTR-/-) mice or wild-type neurons were treated with propofol, with or without pretreatment with TAT-Pep5 (10 MUM, 15 min), a specific p75(NTR) inhibitor. P75(NTR-/-) neurons were transfected for 72 h with a lentiviral vector containing the synapsin-driven p75(NTR) gene (Syn p75(NTR)) or control vector (Syn-green fluorescent protein) before propofol. To confirm our in vitro findings, wild-type mice and p75(NTR-/-) mice (PND5) were pretreated with either TAT-Pep5 or TAT-ctrl followed by propofol for 6 h. RESULTS: Neurons exposed to propofol showed a significant increase in Cl-Csp3, an effect attenuated by TAT-Pep5 and hydroxyfasudil. Apoptosis was significantly attenuated in p75(NTR-/-) neurons. In p75(NTR-/-) neurons transfected with Syn p75(NTR), propofol significantly increased Cl-Csp3 in comparison with Syn-green fluorescent protein-transfected p75(NTR-/-) neurons. Wild-type mice exposed to propofol exhibited increased Cl-Csp3 in the hippocampus, an effect attenuated by TAT-Pep5. By contrast, propofol did not induce apoptosis in p75(NTR-/-) mice. CONCLUSION: These results demonstrate that propofol induces apoptosis in developing neurons in vivo and in vitro and implicate a role for p75(NTR) and the downstream effector RhoA kinase. PMID- 22198223 TI - Variation in enkephalin immunoreactivity in the social behavior network and song control system of male European starlings (Sturnus vulgaris) is dependent on breeding state and gonadal condition. AB - Many temperate zone songbird species exhibit marked seasonal variation in song quality as well as in the motivation to sing. Two brain systems are known to mediate such annual variation in song quality and motivation: (1) the song control system (SCS), and (2) the social behavior network (SBN), respectively. How these two circuits interact to produce changes in singing behavior is not well understood. The opioid enkephalin is expressed in both the SCS and SBN and may function to modulate song quality in a socially relevant manner. Using immunocytochemistry, we examined variation in enkephalin immunoreactivity (ENK ir) in male European starlings (Sturnus vulgaris) that were in breeding conditions (i.e. photostimulated) or non-breeding conditions (i.e. photorefractory). We also included a group of castrated photostimulated males to investigate the relationship between gonadal steroids and ENK-ir. ENK-ir in the preoptic area (POA) and lateral septum (LS) was greater in photostimulated intact birds as compared to photorefractory males, but not in other regions within the SBN. There was a significant difference in ENK-ir in two forebrain song nuclei, HVC and the lateral nucleus of the anterior medial nidopallium (lMAN), with lower expression in photostimulated intact as compared to photorefractory birds. ENK-ir did not change across breeding conditions in the Nucleus Interface (NIf). After accounting for the volumetric change in HVC and lMAN, the pattern of ENK-ir remained greater in photorefractory compared to intact photostimulated starlings. We propose that the observed regulation of ENK-ir in the POA and LS may be related to seasonal changes in the motivation to engage in singing behavior, while the change in ENK-ir in the song system are associated with the quality of the song produced. Thus seasonal changes in a single neuromodulatory system can have very different functional effects based on the neuroanatomical specificity of its expression. PMID- 22198224 TI - Evaluation of the internal transcribed spacer 2 (ITS2) as a molecular marker for phylogenetic inference using sequence and secondary structure information in blow flies (Diptera: Calliphoridae). AB - The internal transcribed spacer 2 (ITS2) is a small non-coding region located inside the nuclear ribosomal DNA cluster. ITS2 sequence variability is thought to be appropriate to differentiate species and for phylogenetic reconstructions analyses, which can be further improved if structural information is considered. We evaluated the potential of ITS2 as a molecular marker for phylogenetic inference in Calliphoridae (Diptera: Brachycera) using a broad range of inference methods and different substitution models, accounting or not for structural information. Sequence analyses revealed a hierarchically organized pattern of sequence variation and a small level of nucleotide substitution saturation. Intragenomic variation due to small sequence repeats was found mainly in the most variable domain (IV), but it has no significant impact on the phylogenetic signal at the species level. Inferred secondary structures revealed that GC pairs are more frequently found flanking bulges and loops regions in more conserved domains, thus ensuring structure stability. In the phylogenetic analyses, the use of substitution models accounting for structural information significantly improves phylogenetic inference in both neighbour-joining and Bayesian analyses, although the former provides limited resolution for dealing with highly divergent sequences. For Bayesian analyses, a significant improvement in likelihood was observed when considering structure information, although with small changes in topology and overall support, probably reflecting better evolutionary rates estimates. Based on these findings, ITS2 is a suitable molecular marker for phylogenetic analyses in Calliphoridae, at both species and generic level. PMID- 22198226 TI - Molecular pathogenesis of a new glycogenosis caused by a glycogenin-1 mutation. AB - Glycogenin-1 initiates the glycogen synthesis in skeletal muscle by the autocatalytic formation of a short oligosaccharide at tyrosine 195. Glycogenin-1 catalyzes both the glucose-O-tyrosine linkage and the alpha1,4 glucosidic bonds linking the glucose molecules in the oligosaccharide. We recently described a patient with glycogen depletion in skeletal muscle as a result of a non functional glycogenin-1. The patient carried a Thr83Met substitution in glycogenin-1. In this study we have investigated the importance of threonine 83 for the catalytic activity of glycogenin-1. Non-glucosylated glycogenin-1 constructs, with various amino acid substitutions in position 83 and 195, were expressed in a cell-free expression system and autoglucosylated in vitro. The autoglucosylation was analyzed by gel-shift on western blot, incorporation of radiolabeled UDP-(14)C-glucose and nano-liquid chromatography with tandem mass spectrometry (LC/MS/MS). We demonstrate that glycogenin-1 with the Thr83Met substitution is unable to form the glucose-O-tyrosine linkage at tyrosine 195 unless co-expressed with the catalytically active Tyr195Phe glycogenin-1. Our results explain the glycogen depletion in the patient expressing only Thr83Met glycogenin-1 and why heterozygous carriers without clinical symptoms show a small proportion of unglucosylated glycogenin-1. PMID- 22198227 TI - [Inflammatory bowel diseases and inflammasome]. AB - Inflammatory bowel disease (IBD), the most important entities being ulcerative colitis and Crohn's disease, are chronic, relapsing and remitting inflammatory conditions that result from chronic dysregulation of the mucosal immune system in the intestinal tract. Although the precise pathogenesis of IBD is still incompletely understood, increased levels of proinflammatory cytokines, including interleukin (IL)-1b, IL-18 and tumor necrosis factor-a, are detected in active IBD and correlate with the severity of inflammation, indicating that these cytokines may play a key role in the development of IBD. Recently, the intracellular nucleotide-binding oligomerization domain-like receptor (NLR) family members, including NLRP1, NLRP3, NLRC4 and NLRP6, are emerging as important regulators of intestinal homeostasis. Together, one of those aforementioned molecules or the DNA sensor absent in melanoma 2 (AIM2), apoptosis associated speck-like protein containing 'a caspase recruitment domain (CARD)' (ASC) and caspase-1 form a large (> 700 kDa) multi-protein complex called the inflammasome. Stimulation with specific microbial and endogenous molecules triggers inflammasome assembly and caspase-1 activation. Activated caspase-1 leads to the secretion of proinflammatory cytokines, including IL-1b and IL-18, and the promotion of pyroptosis, a form of phagocyte cell death induced by bacterial pathogens, in an inflamed tissue. Therefore, inflammasomes are assumed to mediate host defense against microbial pathogens and gut homeostasis, so that their dysregulation might contribute to IBD pathogenesis. This review focuses on recent advances of the role of NLRP3 inflammasome signaling in IBD pathogenesis. Improving knowledge of the inflammasome could provide insights into potential therapeutic targets for patients with IBD. PMID- 22198225 TI - Manganese superoxide dismutase, MnSOD and its mimics. AB - Increased understanding of the role of mitochondria under physiological and pathological conditions parallels increased exploration of synthetic and natural compounds able to mimic MnSOD - endogenous mitochondrial antioxidant defense essential for the existence of virtually all aerobic organisms from bacteria to humans. This review describes most successful mitochondrially-targeted redox active compounds, Mn porphyrins and MitoQ(10) in detail, and briefly addresses several other compounds that are either catalysts of O(2)(-) dismutation, or its non-catalytic scavengers, and that reportedly attenuate mitochondrial dysfunction. While not a true catalyst (SOD mimic) of O(2)(-) dismutation, MitoQ(10) oxidizes O(2)(-) to O(2) with a high rate constant. In vivo it is readily reduced to quinol, MitoQH(2), which in turn reduces ONOO(-) to NO(2), producing semiquinone radical that subsequently dismutes to MitoQ(10) and MitoQH(2), completing the "catalytic" cycle. In MitoQ(10), the redox-active unit was coupled via 10-carbon atom alkyl chain to monocationic triphenylphosphonium ion in order to reach the mitochondria. Mn porphyrin-based SOD mimics, however, were designed so that their multiple cationic charge and alkyl chains determine both their remarkable SOD potency and carry them into the mitochondria. Several animal efficacy studies such as skin carcinogenesis and UVB-mediated mtDNA damage, and subcellular distribution studies of Saccharomyces cerevisiae and mouse heart provided unambiguous evidence that Mn porphyrins mimic the site and action of MnSOD, which in turn contributes to their efficacy in numerous in vitro and in vivo models of oxidative stress. Within a class of Mn porphyrins, lipophilic analogs are particularly effective for treating central nervous system injuries where mitochondria play key role. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. PMID- 22198228 TI - [Comparison of the toxicities and efficacies of the combination chemotherapy regimens in advanced gastric cancer patients who achieved complete response after chemotherapy]. AB - BACKGROUND/AIMS: We retrospectively analyzed comparative toxicities and efficacies of chemotherapy regimens in advanced gastric cancer (AGC) patients who achieved complete response (CR) after chemotherapy. METHODS: We reviewed the medical records of 1,203 patients, who were pathologically diagnosed as AGC in a single center between January 2001 and October 2007. On the basis of the Response Evaluation Criteria in Solid Tumors, CR was evaluated with abdominal computed tomography. Toxicities were evaluated using the National Cancer Institute's common toxicity criteria before each chemotherapy cycle. RESULTS: Among the 1,203 AGC patients enrolled in this study, 568 received chemotherapy and 635 received best supportive care. The major chemotherapy regimens were 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX), docetaxel, cisplatin and 5-fluorouracil (DCF) and 5-fluorouracil, leucovorin and irinotecan (FOLFIRI). Among the 568 patients, 51 (9.0%) achieved CR (49 [8.6%] with FOLFOX [n=12], DCF [n=26], or FOLFIRI [n=11] and 2 [0.3%] with etoposide, leucovorin and 5-fluorouracil). For patients administered FOLFOX, DCF, and FOLFIRI, the median time to disease progression was 4 months (range, 1.8-59.5), 15 months (range, 2.9-31.2) and 10 months (range, 2.0-39.5), and the median survival times were 48 months (range, 5.9-74.0), 37 months (range, 14.0-86.0), and 30 months (range, 6.0-50.0), respectively. Grades 3-4 mucositis occurred mostly in patients administered DCF (n=8, 30.8%). Grades 3-4 leucopenia were observed in 1 (8.3%), 11 (42.3%), and 4 (36.4%) patients administered FOLFOX, DCF and FOLFIRI, respectively. No statistically significant differences were observed in the 3 regimens. CONCLUSIONS: All 3 regimens (FOLFOX, DCF and FOLFIRI) were active and tolerable. Their efficacies and toxicities were not significantly different. PMID- 22198229 TI - [The safety of early enteral feeding after emergency gastrointestinal surgery]. AB - BACKGROUND/AIMS: Postoperative early feeding has many advantages, and current guidelines recommend the early diet or enteral feeding after gastrointestinal surgery. However, there are controversies in emergency situation. The aim of this study was to assess the safety of early enteral feeding in patients underwent emergency gastrointestinal (GI) surgery. METHODS: We reviewed the patients underwent emergency GI surgery by single surgeon from March 2008 to December 2010, retrospectively. The early feeding was defined when feeding was started within 72 hours after operation. RESULTS: Fifty-three patients were enrolled. Men were 31, with mean 60.6 (+/-18.5) years old age. Thirty-three patients were treated in the intensive-care unit after operation. The most common cause of operation was bowel perforation, and followed by intestinal obstruction. Segmental resection with primary anastomosis of small bowel is the most common operation. Thirty-two of them started the diet within 48 hours postoperatively. Twenty-nine patients had post-operative complications. Wound complications were the most common, and followed by the abdominal pain, and ileus. Wound complications were developed in 18 patients, and the post-feeding abdominal pain was in 7 patients. Anastomotic leakage and intraabdominal abscess were developed in 2 patients, and 1 patient required reoperation to treat the anastomotic disruption. One patient developed pneumonia and sepsis, and resolved under conservative treatment. There was no mortality in these patients. CONCLUSIONS: Early enteral feeding may be safe in cases of emergency GI surgery. However, it may require further studies to confirm the safety and feasibility of the early feeding in emergency situations. PMID- 22198230 TI - [Health care costs of digestive diseases in Korea]. AB - BACKGROUND/AIMS: Gastrointestinal (GI) diseases impose a heavy economic burden. We aimed to provide the first report on the health care utilization and costs of GI diseases in Korea. METHODS: We collected the data from all insurance claims database of National Health Insurance Corporation in Korea and the cause of death database in 2007 of Korea National Statistical Office. We compiled information about all digestive disease as a primary diagnosis on clinic visits, hospitalization, and cause of death from these databases. RESULTS: Seventeen million people (35.6%) had a diagnosis of GI diseases during the year 2007. Among them, the proportion of patients with upper GI diseases was prevalent in 54.9% (9.5 million patients/year). The 1/4 patients in out-patients clinic had any one of gastroesophageal reflux disease, irritable bowel syndrome and constipation. Thirteen percent of the total direct cost in 2007 was attributed to all GI diseases, which was 3,649 billion won (0.4% of GDP). The patients with hospitalization occupied by 5% of all patients with GI diseases, however, attributed to 58.9% of GI-related direct costs. GI malignancy was the major cause of medical expenses in hospitalization. Stomach cancer continues to be the leading cause of GI-related death in Korea. CONCLUSIONS: GI diseases causes a heavy socioeconomic burden with high morbidity of functional GI disorders in outpatients care and high mortality of GI malignancy in inpatient care. This report highlights the healthcare utilization burden of GI diseases for researchers and public health policy maker to create new directions of integrated researches and health care plan. PMID- 22198231 TI - [Endoscopic findings and clinical significance of portal hypertensive colopathy]. AB - BACKGROUND/AIMS: The endoscopic findings and clinical relevance of portal hypertensive colopathy are not well described in Korea. We aimed to do a retrospective study of mucosal changes in the colon of patients with liver cirrhosis and to find their association with clinical characteristics. METHODS: We reviewed the clinical data and endoscopic findings of 48 patients with liver cirrhosis and 48 patients, matched for age and sex, with irritable bowel disease (IBS) who underwent colonoscopy over a 5 year span. RESULTS: Patients with liver cirrhosis were more likely to have colitis-like lesions and vascular abnormalities than IBS patients. Low platelet count (p=0.005) and severe esophageal varices (p=0.011) were associated with portal hypertensive colopathy, whereas the etiologies and severity of cirrhosis were not associated with these findings. CONCLUSIONS: Portal hypertensive colopathy can be defined with colitis like lesions or vascular lesions. These lesions are more frequently present in patients with more severe esophageal varices and thrombocytopenia. PMID- 22198232 TI - [The variation of hepatic duct confluence and asymptomatic common bile duct stone with routine intraoperative cholangiogram during laparoscopic cholecystectomy]. AB - BACKGROUND/AIMS: Intraoperative cholangiogram (IOC) during laparoscopic cholecystectomy (LC) has been used to evaluate bile duct stone. But, the routine use of IOC remains controversial. With routine IOC during LC, we reviewed the variation of hepatic duct confluence and try to suggest the diagnostic criteria of asymptomatic common bile duct (CBD) stone. METHODS: We reviewed the medical record of 970 consecutive patients who underwent LC with IOC from January 1999 to December 2009, retrospectively. RESULTS: Nine hundered seventy patients were enrolled. IOC were successful in 957 (98.7%) and unsuccessful in 13 (1.3%). Eighty two of 957 patients (8.2%) were excluded because of no or poor radiologic image. According to Couinaud's classification, 492 patients (56.2%) had type A hepatic duct confluence, 227 patients (26.1%) type B, 15 patients (17%) type C1, 43 patients (4.9%) type C2, 72 patients (8.2%) type D1, 21 patients (2.4%) type D2, 1 patient (0.1%) type E1, 1 patient (0.1%) type E2, 2 patients (0.2%) type F, and 1 patient (0.1%) no classified type. The CBD stone was found in 116 of 970 (12.2%) patients. In 281 patients, preoperative serologic and radiologic tests did not show abnormality. When preoperative findings were not remarkable, there was no difference of clinical features between patients with or without CBD stones. CONCLUSIONS: Although IOC during LC has some demerits, it is a safe and accurate method for the detection of CBD stone and the anatomic variation of intrahepatic duct. PMID- 22198233 TI - Gastric duplication cyst removed by endoscopic submucosal dissection. AB - Duplication cysts are uncommon congenital malformations that may occur anywhere throughout the alimentary tract. The stomach is an extremely rare site of occurrence. Here, we report a case of gastric duplication cyst initially presenting with a gastric submucosal tumor. A 28-year-old man complained of dyspepsia lasting 1 year and upper endoscopy revealed an ellipsoid submucosal tumor at the greater curvature of the antrum. We intended to use the injection and-cut technique: however, after saline injection, the lesion was dented and impossible to grasp with a snare. Therefore, we decided to perform endoscopic submucosal dissection and removed the tumor without complication. Histopathology revealed a 0.6*0.6 cm-sized duplication cyst, and there has been no recurrence in 2 years. PMID- 22198234 TI - [A case of liver abscess and bacteremia caused by Vibrio cholerae non-O1]. AB - Vibrio cholerae non-O1 have caused several well-studied food-borne outbreaks of gastroenteritis and also have been responsible for sporadic cases of otitis media, wound infection, and bacteremia. Few cases of liver abscess caused by Vibrio cholerae non-O1 have been reported. A 73-year-old man with underlying diabetes mellitus was admitted with nausea, vomiting, dyspepsia and febrile sensation. We identified Vibrio cholerae non-O1 in his blood cultures and multiple hepatic microabscess on abdominal computed tomography. He was treated with systemic antibiotics and fluid therapy, but died due to septic shock on sixth day. We report here, a case of liver abscess with bacteremia due to Vibrio cholerae non-O1 in a patient with diabetes mellitus. PMID- 22198235 TI - [A case of cholesterol granuloma in pancreas]. AB - Cholesterol granuloma is a histological term used for the description of a tissue response to a foreign body such as cholesterol crystals. Cholesterol granuloma is histologically characterized as fibrous granulation tissue containing cholesterol crystals within surrounding giant cells. Cases of cholesterol granuloma of the pancreas are very rare. We report a case of a 47-year old male who had a cholesterol granuloma of the pancreas. Abdominal CT showed 24 mm-sized cyst in the pancreas and peri-pancreatic regional mass infiltrating to the stomach. PET CT revealed increased 18F-FDG uptake at the cyst and peri-pancreatic mass. Thus, Whipple's operation was done. The disease was confirmed by surgical pathologic examination of the tissue. Pathologic examination of resected specimen showed numerous cholesterol crystals surrounded by multinucleated foreign body giant cells. We report on this case and give a brief review of the literature. PMID- 22198236 TI - A case of intrapancreatic accessory spleen mistaken as a pancreatic mass due to different enhancing pattern from normal spleen. AB - Most cases of accessory spleen show similar features as normal spleen in imaging studies. However, some accessory spleen has unusual scan feature which can be misdiagnosed. We present a case of intrapancreatic accessory spleen that was discovered incidentally during a workup for abdominal pain in a 47-year-old woman. CT and MRI revealed a different enhancing pattern from that of the spleen. Further evaluation with endoscopic ultrasonography failed to identify the pancreatic mass. Therefore, it was surgically removed and diagnosed pathologically as an accessory spleen. PMID- 22198237 TI - MG624, an alpha7-nAChR antagonist, inhibits angiogenesis via the Egr-1/FGF2 pathway. AB - Small cell lung cancer (SCLC) demonstrates a strong etiological association with smoking. Although cigarette smoke is a mixture of about 4,000 compounds, nicotine is the addictive component of cigarette smoke. Several convergent studies have shown that nicotine promotes angiogenesis in lung cancers via the alpha7 nicotinic acetylcholine receptor (alpha7-nAChR) on endothelial cells. Therefore, we conjectured that alpha7-nAChR antagonists may attenuate nicotine-induced angiogenesis and be useful for the treatment of human SCLC. For the first time, our study explores the anti-angiogenic activity of MG624, a small-molecule alpha7 nAChR antagonist, in several experimental models of angiogenesis. We observed that MG624 potently suppressed the proliferation of primary human microvascular endothelial cells of the lung (HMEC-Ls). Furthermore, MG624 displayed robust anti angiogenic activity in the Matrigel, rat aortic ring and rat retinal explant assays. The anti-angiogenic activity of MG624 was assessed by two in vivo models, namely the chicken chorioallantoic membrane model and the nude mice model. In both of these experimental models, MG624 inhibited angiogenesis of human SCLC tumors. Most importantly, the administration of MG624 was not associated with any toxic side effects, lethargy or discomfort in the mice. The anti-angiogenic activity of MG624 was mediated via the suppression of nicotine-induced FGF2 levels in HMEC-Ls. MG624 decreased nicotine-induced early growth response gene 1 (Egr-1) levels in HMEC-Ls, and reduced the levels of Egr-1 on the FGF2 promoter. Consequently, this process decreased FGF2 levels and angiogenesis. Our findings suggest that the anti-angiogenic effects of MG624 could be useful in anti angiogenic therapy of human SCLCs. PMID- 22198238 TI - Inhibition of hemangioma development in a syngeneic mouse model correlates with bcl-2 suppression and the inhibition of Akt kinase activity. AB - BACKGROUND: Hemangiomas are benign vascular tumors that are characterised by excessive angiogenesis. While there is no definitive treatment for these tumors, several angiogenesis inhibitors, including bleomycin, have been employed. To better understand the mechanism of bleomycin in accelerating haemangioma regression, we investigated the effects of the drug on hemangiomagenesis using a previously described mouse hemangioma model. MATERIALS AND METHODS: The effects of bleomycin were tested in mice injected with endothelioma cells to induce hemangioma development. At termination, tissue samples from bleomycin-treated and control mice were stained with hematoxylin and eosin for histological examination. Bcl-2, flk-1 and vWF expression were studied by immunofluorescence microscopy. Hematological analysis was undertaken using a hemocounter. Akt activity was analyzed in tissue homogenates and endothelioma cells using ELISA. Also, caspase activity was analysed in endothelioma cells by ELISA. RESULTS: Bleomycin inhibited tumor growth in vivo in a dose-dependant manner. Our findings also revealed that bleomycin inhibited Akt activation and suppressed bcl-2. In vitro bleomycin increased caspase activation. CONCLUSION: Our observations reveal possible mechanisms for the inhibitory effects of bleomycin on hemangiomagenesis, and raise the possibility that bcl-2 might be an important therapeutic target in the treatment of hemangiomas. PMID- 22198239 TI - Structure of Dioclea virgata lectin: Relations between carbohydrate binding site and nitric oxide production. AB - The lectin of Dioclea virgata (DvirL), both native and complexed with X-man, was submitted to X-ray diffraction analysis and the crystal structure was compared to that of other Diocleinae lectins in order to better understand differences in biological properties, especially with regard to the ability of lectins to induce nitric oxide (NO) production. An association was observed between the volume of the carbohydrate recognition domain (CRD), the ability to induce NO production and the relative positions of Tyr12, Arg228 and Leu99. Thus, differences in biological activity induced by Diocleinae lectins are related to the configuration of amino acid residues in the carbohydrate binding site and to the structural conformation of subsequent regions capable of influencing site-ligand interactions. In conclusion, the ability of Diocleinae lectins to induce NO production depends on CRD configuration. PMID- 22198240 TI - Relationship between leaf litter identity, expression of cytochrome P450 genes and life history traits of Aedes aegypti and Aedes albopictus. AB - The role of toxic component of leaf litter in mediating the outcome of mosquito species interactions is not well documented. To examine the effect of leaf litter toxins on mosquito performance and interspecific interactions, we reared monospecific and heterospecific cultures of Aedes aegypti L. and Aedes albopictus Skuse larvae in microcosms with one of five leaf species and measured the expression of five cytochrome P450 genes and life history traits of the two mosquito species. For both mosquito species, survival to adulthood was significantly higher in black alder, black walnut, and cypress infusion compared to sugar maple and eastern white pine infusion. In pine but not in other leaf treatments, the presence of A. albopictus had significant positive effects on A. aegypti wing length and development time to adulthood. A. albopictus from heterospecific cultures were larger than those from monospecific cultures and were smaller and took longer to develop in pine and sugar maple infusions than in the other infusions. Up regulation of CYP6Z6 and CYP9M9 in A. aegypti and A. albopictus respectively appeared to be closely associated with the deleterious effects of sugar maple infusion on mosquito performance as was the down regulation of CYP6N12 (in A. aegypti) and lack of induction of CYP6Z6 and CYP9M9 (in A. aegypti and A. albopictus respectively) in pine infusion. Results suggest that metabolic capabilities that enable the two species to tolerate natural xenobiotics are associated with a fitness cost. PMID- 22198241 TI - Reproductive success in Anopheles arabiensis and the M and S molecular forms of Anopheles gambiae: do natural sporozoite infection and body size matter? AB - Malaria parasites stages prior to sporozoite formation are known to affect the fecundity of several species of mosquitoes in the laboratory, but little is known about this phenomenon in natural conditions especially with sporozoite-infected anophelines. The reproductive success of wild-caught Anopheles arabiensis and the M and S molecular forms of Anopheles gambiae was investigated by comparing females infected with Plasmodium falciparum sporozoites to females free of sporozoites. Association between sporozoite-infected females' body size and their egg batch size was also measured. There was no significant reduction in egg production due to sporozoite infection among wild females An. arabiensis and the M and S form of An. gambiae. The infected groups and the controls laid similar numbers of eggs. A positive association was found between body size of females infected with P. falciparum and mean egg production. Infected females of the molecular forms of An. gambiae and their sibling species An. arabiensis invest similarly in egg batch size regardless of their body size although the expected egg batch size may differ among them because of differences in their mean body size. A reduction of egg production related to infection status was not observed among females harboring sporozoites. Therefore for the gonotrophic cycles that occur once sporozoites are present, natural infection of all three vectors we studied has no or minimal effect on their densities or their reproductive outputs. PMID- 22198242 TI - Longitudinal evaluation of cancer-associated biomarkers before and after weight loss in RENEW study participants: implications for cancer risk reduction. AB - INTRODUCTION: Obesity is a major risk factor for the development of endometrial cancer (EC). An improved understanding of biologic mechanisms associated with weight loss, including alteration in inflammation, hormonal balance, and cancer antigens expression may lead to the development of effective cancer prevention strategies. The goal of this study was to explore longitudinal biomarker changes in obese women who underwent weight loss intervention, testing the hypothesis biomarker levels can be altered through intentional weight loss. METHODS: Serum samples from 89 participants with Class II and Class III obesity and 43 non morbidly obese comparisons were obtained in Re-Energize with Nutrition, Exercise and Weight Loss (RENEW) study as previously reported. Twenty-one bead-based xMAP immunoassays were utilized, including cancer-associated antigens, cytokines, chemokines, and hormones. One-way repeated measures ANOVA was used to examine the association between changes in biomarker expression levels over time (baseline, 6 months and 12 months). Linear mixed effects models were used to examine longitudinal relationships between biomarker expression levels. RESULTS: Mean levels of VEGF, soluble E-selectin, GH, adiponectin, IL-6, IL-7, CA-125, and IGFBP-1 significantly differed between time periods. In adjusted mixed linear models, decreasing BMI was significantly associated with lower levels of soluble E-selectin and IL-6 and increases in GH, adiponectin, and IGFBP-1. CONCLUSIONS: This is one of the first efforts to explore changes in cancer-associated biomarkers in a cohort of weight loss research participants at high risk for EC development. Our findings demonstrate that changes in the expression of markers can be achieved with weight loss intervention. PMID- 22198243 TI - Longitudinal evaluation of CA-125 velocity and prediction of ovarian cancer. AB - OBJECTIVE: To determine whether CA-125 velocity is a statistically significant predictor of ovarian cancer and develop a classification rule to screen for ovarian cancer. METHODS: In the ovarian component of the PLCO cancer screening trial, 28,038 women aged 55-74 had at least two CA-125 screening tests. Ovarian cancer was diagnosed in 72 (0.26%) women. A multiple logistic regression model was developed to evaluate CA-125 velocity and other related covariates as predictors of ovarian cancer. Predictive accuracy was assessed by the concordance index and measures of discrimination and calibration while the fit of the model was assessed by the Hosmer and Lemeshow's goodness-of-fit chi(2)test. RESULTS: CA 125 velocity decreased as the number of CA-125 measurements increased but was unaffected by age at baseline screen and family history of ovarian cancer. The average velocity (19.749U/ml per month) of the cancer group was more than 500 times the average velocity (0.035U/ml per month) of the non-cancer group. CONCLUSION: Among six covariates used in the model, CA-125 velocity and time intervals between baseline and second to last screening test and between last two screening tests were statistically significant predictors of ovarian cancer. The chance of having ovarian cancer increased as velocity increased, and the chance decreased when the time intervals between baseline and the second to last screening test and between last two screening tests of an individual increased. PMID- 22198244 TI - Minimally-aggressive gestational trophoblastic neoplasms. AB - INTRODUCTION: We have previously defined a new syndrome "Minimally-aggressive gestational trophoblastic neoplasms" in which choriocarcinoma or persistent hydatidiform mole has a minimal growth rate and becomes chemorefractory. Previously we described a new treatment protocol, waiting for hCG rise to >3000 mIU/ml and disease becomes more advanced, then using combination chemotherapy. Initially we found this treatment successful in 8 of 8 cases, here we find this protocol appropriate in a further 16 cases. Initially we used hyperglycosylated hCG, a limited availability test, to identify this syndrome. Here we propose also using hCG doubling rate to detect this syndrome. METHODS: Minimally aggressive gestational trophoblastic disease can be detected by chemotherapy resistance or low hyperglycosylated hCG, <40% of total hCG. It can also be identified by hCG doubling rate, with doubling time greater than 2 weeks. RESULTS: Nineteen new cases were identified as having minimally aggressive gestational trophoblastic disease by hyperglycosylated hCG and by hCG doubling test. All were recommended to hold off further chemotherapy until hCG >3000mIU/ml. One case died prior to the start of the study, one case withdrew because of a lung nodule and one withdrew refusing the suggested combination chemotherapy. The remaining 16 women were all successfully treated. DISCUSSION: A total of 8 plus 16 or 24 of 24 women were successfully treated using the proposed protocol, holding back on chemotherapy until hCG >3000mIU/ml. PMID- 22198245 TI - Brain metastases from epithelial ovarian carcinoma: evaluation of prognosis and managements - a Taiwanese Gynecologic Oncology Group (TGOG) study. AB - OBJECTIVE: To evaluate the characteristics and outcome of patients with brain metastases from epithelial ovarian carcinoma. METHODS: The clinical and pathologic characteristics, treatment and outcome of patients with brain metastases from epithelial ovarian carcinoma were analyzed from eight medical centers in Taiwan under the TGOG (Taiwanese Gynecologic Oncology Group). RESULTS: A total of 64 patients were recruited in this study. The incidence of brain metastases from epithelial ovarian carcinoma seemed to be increasing in recent years. The median survival from the diagnosis of brain metastases was 8 months (range: 0-72). Prior cancer relapse before the diagnosis of brain metastases, number of brain metastases and multimodal treatment were related to the duration of survival. CONCLUSIONS: The prognosis for patients with brain metastases from epithelial ovarian carcinoma is generally poor. However, clinicians should keep alert to the neurological complaints of ovarian cancer patients and the patients might benefit from aggressive multimodal treatments. PMID- 22198246 TI - Outcomes among living liver donors. PMID- 22198247 TI - Large tumor of the liver and hypoglycemic shock in an 85-year-old patient. PMID- 22198248 TI - Bleeding polyps? PMID- 22198249 TI - The N-terminal extension is essential for the formation of the active dimeric structure of liver peroxisomal alanine:glyoxylate aminotransferase. AB - Alanine:glyoxylate aminotransferase (AGT) is a pyridoxal-phosphate (PLP) dependent enzyme. Its deficiency causes the hereditary kidney stone disease primary hyperoxaluria type 1. AGT is a highly stable compact dimer and the first 21 residues of each subunit form an extension which wraps over the surface of the neighboring subunit. Naturally occurring and artificial amino acid replacements in this extension create changes in the functional properties of AGT in mammalian cells, including relocation of the enzyme from peroxisomes to mitochondria. In order to elucidate the structural and functional role of this N-terminal extension, we have analyzed the consequences of its removal using a variety of biochemical and cell biological methods. When expressed in Escherichia coli, the N-terminal deleted form of AGT showed the presence of the protein but in an insoluble form resulting in only a 10% soluble yield as compared to the full length version. The purified soluble fraction showed reduced affinity for PLP and greatly reduced catalytic activity. Although maintaining a dimer form, it was highly prone to self-aggregation. When expressed in a mammalian cell line, the truncated construct was normally targeted to peroxisomes, where it formed large stable but catalytically inactive aggregates. These results suggest that the N terminal extension plays an essential role in allowing AGT to attain its correct conformation and functional activity. The precise mechanism of this effect is still under investigation. PMID- 22198250 TI - Utility of B-type natriuretic peptides and cardiac troponins for population screening regarding cardiac abnormalities. AB - AIMS: The increasing importance of cardiac disease has generated an interest in improved screening strategies regarding preclinical cardiac abnormalities and employing measurement of circulating biomarkers. This review focuses on the utility of the B-type natriuretic peptides (NP) and the cardiac troponins (cTns) for this purpose. RESULTS: Both the NPs and the cTns are closely related to cardiac structural and functional abnormalities that may progress to symptomatic heart disease, e.g., left ventricular (LV) hypertrophy, LV systolic and diastolic dysfunction. Both biomarkers provide incremental information to each other. However, biomarker results may be confounded by several non-cardiac conditions, and decision thresholds and recommendations on further clinical work-up are as yet not specified. Furthermore, cost issues will probably preclude widespread biomarker screening in general populations. CONCLUSIONS: Measurement of the NPs or cTns is an attractive option for screening for cardiac abnormalities. This may be particularly effective in patients at higher risk for developing overt heart disease. Nevertheless, appropriate diagnostic and therapeutic responses to biomarker results need to be defined before routine screening can be recommended in the community setting. PMID- 22198251 TI - Should we screen for iron deficiency anaemia? A review of the evidence and recent recommendations. AB - Worldwide, over 1.6 billion people are anaemic. The prevalence of anaemia and contribution of iron deficiency to this burden is heterogeneous between different populations. Iron deficiency anaemia (IDA) is associated with impaired development in children, adverse effects on cognitive and physical performance in adults, and poorer maternal and infant outcomes in pregnancy. Causes of anaemia other than iron deficiency are important in developed countries and where malaria, thalassaemia or haemoglobinopathy are prevalent. Haemoglobin is the most commonly used screening test for iron deficiency, but may have inadequate sensitivity and specificity to determine iron status in many settings. Screening for anaemia during pregnancy is widely recommended. In children, studies evaluating screening programs have found problems with implementation, acceptability and follow-up of testing, and most international authorities do not support this practice. Nevertheless, certain groups with a particularly high pre test probability of IDA may benefit from testing following clinical evaluation. Further research is required to define the role of screening and improve available tests for IDA in both developed and developing settings. In this review, the rationale, evidence, experience and expert guidelines regarding screening for IDA, especially among pregnant and paediatric populations, will be evaluated. PMID- 22198252 TI - Screening for disease in the newborn: the evidence base for blood-spot screening. AB - This paper reviews the evidence of benefit resulting from newborn screening in Australia as well as for some of those disorders not yet included in the Australian panels, and discusses briefly disorders under active consideration for inclusion in the screening panels.There is solid evidence of benefit from newborn screening for phenylketonuria, congenital hypothyroidism, cystic fibrosis, and overall for the disorders included in tandem mass spectrometry screening. There is also some evidence of benefit for several disorders not screened for in Australia, including congenital adrenal hyperplasia. Harms resulting from screening include anxiety related to false positive results; adverse effects of unwarranted treatment for mild variants; unwanted genetic information; and the costs (opportunity costs) of screening. For well-run programs these harms are relatively small.Screening could become more effective with the development of good systems for rational consideration of disorders to be included, with the extended use of second tier testing to reduce the false positive rate, and with research on the most effective way to deal with mild variants. The most important aspect of increasing effectiveness is the full integration of the screening program, diagnostic laboratories, and the clinical service. This is already in place in Australasia. PMID- 22198253 TI - Screening for hereditary haemochromatosis. AB - Hereditary haemochromatosis (HH) is a common autosomal recessive disorder of iron overload in Caucasian populations. Clinical manifestations usually occur in individuals homozygous for the C282Y mutation in the HFE gene product and who have developed significant iron loading. Current screening methods can detect affected individuals either prior to or early during disease evolution, enabling early introduction of phlebotomy treatment that can normalise life expectancy. Evaluation of possible iron overload, via measurement of serum transferrin saturation and ferritin level, is the most appropriate initial test for those subjects presenting clinically for evaluation. HFE genotyping, when combined with serum biochemical measurements, defines the presence of likely iron overload and the underlying genetic disorder and is the preferred initial screening modality for families of an affected individual. Definitive proof of iron overload requires measurement of hepatic iron concentration or total iron burden via therapeutic phlebotomy; elevated serum ferritin level alone is not adequate. We now recognise that the natural history of HH is not as discrete as previously believed, because genetic and environmental modifiers of disease penetrance are increasingly identified as influencing the clinical expression of HH. In fact, a minority of C282Y homozygotes develop classical 'iron overload disease', although it has recently emerged that the disorder may predispose to breast and colorectal cancer. Uncertainties as to the true clinical impact of the condition at a population level lead to current recommendations of cascade screening of families of affected patients, case-finding in high-risk groups, such as patients with clinical manifestations consistent with the diagnosis, and a high level of clinical awareness in the community to facilitate early diagnosis. Generalised population screening is not presently recommended. PMID- 22198254 TI - The ethics of screening for disease. AB - Screening can identify individuals at increased risk of or in the early stage of a disease at a time when intervention can reduce the risk of morbidity and mortality. There are many ethical issues that have arisen as a result of screening. These can relate to the process of screening in general or to specific screening programs. Examples of the former include issues related to consent for screening, the utility of the screening tests employed and issues of funding of screening programs and equity of access to screening. Ethical issues related to three specific areas of screening are explored in more detail: reproductive screening, screening for disease with onset in adulthood and newborn screening. It is critical that ethical issues are considered in planning screening programs so as to ensure that the main focus of screening, preventing morbidity, is maximised. There are many lessons to be learnt from the many screening programs that have been conducted worldwide. No doubt new ethical issues will arise as new technologies and new treatments are developed, enabling screening for more conditions at lower relative costs. PMID- 22198255 TI - Prenatal assessment of fetal chromosomal and genetic disorders through maternal plasma DNA analysis. AB - The existence of cell free DNA derived from the fetus in the plasma of pregnant women was first demonstrated in 1997. This discovery offered the possibility of non-invasive sampling of fetal genetic material simply through the collection of a maternal blood sample. Such cell free fetal DNA molecules in the maternal circulation have subsequently been shown to originate from the placenta and could be detected from about 7 weeks of gestation. It has been shown that cell free fetal DNA analysis could offer highly accurate assessment of fetal genotype and chromosomal makeup for some applications. Thus, cell free fetal DNA analysis has been incorporated as a part of prenatal screening programs for the prenatal management of sex-linked and sex-associated diseases, rhesus D incompatibility as well as the prenatal detection of Down's syndrome.Cell free fetal DNA analysis may lead to a change in the way prenatal assessments are made. PMID- 22198256 TI - Using tumour pathology to identify people at high genetic risk of breast and colorectal cancers. AB - Genes have been identified for which germline mutations are associated with high lifetime risks of breast, colorectal and other cancers. Identification of mutation carriers through genetic testing is important as it could help lower cancer incidence and mortality. The translation of genetic information into better health outcomes is expensive because of the costs of genetic counselling as well as laboratory testing. Approaches to triage for mutation screening of known genes which rely on cancer family history are not necessarily sensitive and specific or the most cost-effective. Recent population-based research has shown that the cancers and precancerous lesions arising in mutation carriers have specific molecular and morphological characteristics. People with colorectal cancer, especially those diagnosed at a young age, whose tumours exhibit microsatellite instability and some specific pathology and immunohistochemically defined features are more likely to carry a germline mutation in one of four mismatch repair genes. Some morphological and immunohistochemically-defined features are associated with breast cancers arising in women who carry BRCA1 or BRCA2 germline mutations, especially if at a young age. Screening paradigms based on molecular and morphological features that predict mutation status, especially if focused on early-onset disease, have the potential to identify mutation carriers with greater sensitivity and specificity, and in a more cost-effective way, than those based on family history alone. Genetic testing results could help inform treatment if those affected are tested soon after diagnosis using pathology-led selection strategies to identify cases most likely to carry germline mutations. We propose how this new approach could be undertaken by having genetic testing and counselling prioritised to those with the greatest probability of carrying a germline mutation in these known cancer predisposition genes. PMID- 22198257 TI - Screening for lipid disorders. AB - Lipid disorders, also known as dyslipidaemias, are abnormalities of lipoprotein metabolism and include elevations of total cholesterol, low density lipoprotein (LDL) cholesterol, and triglyceride, and reductions in high density lipoprotein (HDL) cholesterol, and can be acquired or familial in nature. Dyslipidaemia is a major risk factor for coronary heart disease and cardiovascular disease (CVD), which is the leading cause of morbidity and mortality in Australia. Dyslipidaemia is defined by laboratory testing and using statistically determined criteria. Although the benefits of detecting and treating dyslipidaemia in patients with known CVD is clear, controversy remains regarding screening asymptomatic individuals who are not known to be at increased cardiovascular risk. This review examines the role of screening in the detection and treatment of individuals with lipid disorders. PMID- 22198258 TI - Prostate cancer screening. AB - Prostate cancer is a slowly progressing but potentially lethal disease. In order to cure it we must detect it while it remains organ confined. Because of the slow course of the disease, prostate cancer screening trials take a long time to show any benefit and in that time the measurement and interpretation of prostate specific antigen (PSA) concentrations have changed, and biopsy and treatment protocols have also developed. Nevertheless, measuring PSA in the blood remains the main tool we have at hand and improvements have been made but not fully utilised. Improvements in the specificity of PSA include age-related PSA reference limits, free to total PSA ratio and PSA dynamics such as doubling time. Improvements in sensitivity have progressed to defining that we should focus on the 50% of men with PSA concentrations above their population median, as men with PSA below the median are very unlikely to develop or suffer from prostate cancer. Like any medical procedure, men should be informed of the risks and benefits but this should ideally be done in a manner that encourages informed choice based on their own understanding and feelings, rather than informed compliance based on the views of others. PMID- 22198259 TI - Stool DNA screening for colorectal neoplasia: biological and technical basis for high detection rates. AB - Colorectal cancer (CRC), the second most common cause of cancer-related mortality worldwide, is preventable with effective screening and removal of precursor lesions. Yet, screening efforts have been hampered by low participation rates and by performance limitations of the screening tools themselves. Stool DNA testing has emerged as a biologically rational and user-friendly strategy for the non invasive detection of both CRC and critical precursor lesions. Unlike most conventional screening tools, stool DNA testing detects proximal and distal colorectal neoplasms equally well. Several key technical advances have led to increasingly accurate approaches for stool DNA testing including use of a DNA preservative buffer with stool collection, efficient target capture and amplification methods, broadly informative marker panels, and automated assay components. Based on recent studies, advanced multi-marker stool DNA tests including methylated markers, mutation markers and an assessment of faecal haemoglobin have been shown to detect CRC at sensitivities of 85% and higher and adenomas >1 cm at 60% and higher in a case-control environment. If the high accuracy of multi-marker stool tests is corroborated in multicentre screening studies on average-risk persons currently underway, then these stool tests could influence our CRC screening paradigm.This review discusses the biological basis, key technical advances, and recent clinical performance validation of stool DNA testing. PMID- 22198260 TI - Missed opportunities: a national survey of obstetricians about attitudes on maternal and infant immunization. AB - The recent reoccurrence of several vaccine-preventable diseases demonstrates the need for new techniques to promote childhood vaccination. Many mothers make decisions regarding vaccination of their children during pregnancy. As a result, obstetricians have a unique opportunity to influence maternal decisions on this crucial component of child health. Our objective was to understand OB/GYNs' attitudes, beliefs, and current practices toward providing vaccinations to pregnant patients and providing information about routine childhood immunizations during standard prenatal care. We surveyed OB/GYNs in the United States about their vaccination practices and perceptions during the 2009 H1N1 outbreak. Most (84%) respondents indicated their practice would be administering H1N1 vaccines to pregnant patients. While a majority (98%) of responding providers felt childhood vaccination is important, relatively few (47%) felt that they could influence mothers' vaccination choices for their children. Discussion of routine childhood immunization between obstetricians and their patients is an area for future improvements in childhood vaccination. PMID- 22198261 TI - The course of depressive symptoms in primary care patients with type 2 diabetes: results from the Diabetes, Depression, Type D Personality Zuidoost-Brabant (DiaDDZoB) Study. AB - AIMS/HYPOTHESIS: The aim of the study was to examine the course (incidence, recurrence/persistence) of depressive symptoms in primary care patients with type 2 diabetes and to identify significant predictors of these different course patterns. METHODS: A cohort of 2,460 primary care patients with type 2 diabetes was assessed for demographic, clinical and psychological factors in 2005 and followed-up in 2007 and 2008. Depression was defined as a score of >= 12 on the Edinburgh Depression Scale. Multivariate logistic regression analyses were used to determine whether several depression-course patterns could be predicted by means of demographics, medical co-morbidities and psychological factors. RESULTS: A total of 630 patients (26%) met the criterion for depression at one or more assessments. In the subgroup with no baseline depression, incident depression at follow-up was present in 14% (n = 310), while recurrence/persistence in those with baseline depression was found in 66% (n = 212).The presence of any depression was associated with being female, low education, non-cardiovascular chronic diseases, stressful life events and a self-reported history of depression. Incident depression was predicted by female sex, low education and depression history, while patients with a history of depression had a 2.5-fold increased odds of recurrent/persistent depression. CONCLUSIONS/INTERPRETATION: Depression is common in primary care patients with type 2 diabetes, with one in seven patients reporting incident depression during a 2.5 year period. Once present, depression often becomes a chronic/recurrent condition in this group. In order to identify patients who are vulnerable to depression, clinicians can use questionnaire data and/or information about the history of depression. PMID- 22198262 TI - Novel versus traditional risk markers for diabetic retinopathy. AB - AIMS/HYPOTHESIS: To explore the relative contribution of novel and traditional risk markers for diabetic retinopathy (DR). METHODS: A clinic-based study of 224 diabetic patients (85 type 1, 139 type 2) from a diabetes clinic was performed. DR was graded from fundus photographs according to the Airlie House Classification system and classified as absent or present (at least ETDRS level 14). Novel risk markers assessed included serum apolipoprotein (Apo) AI and B, skin microvascular responses to acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) iontophoresis, flicker-light-induced retinal vasodilation and retinal vascular tortuosity. Relative contribution was determined by semi-partial correlation coefficient generated from a logistic regression model containing all traditional and novel risk markers simultaneously. RESULTS: There were 144 (64.3%) participants with DR. Of the novel markers, ApoAI, flicker-light-induced vasodilation and retinal arteriolar tortuosity were significantly associated with DR, independently of traditional measures (all p < 0.03). Diabetes duration contributed most (51%) to the risk of DR, followed by ApoAI (16%), systolic blood pressure (13%), retinal arteriolar tortuosity (8%) and flicker-light-induced venular and arteriolar dilation (3% and 0.5%, respectively). CONCLUSIONS/INTERPRETATION: ApoAI and retinal arteriolar tortuosity made considerable contributions to DR risk, independently of traditional risk markers. Findings from this study suggest that serum ApoAI and retinal arteriolar tortuosity may be novel and independent risk markers of DR. PMID- 22198263 TI - RETRACTED: NAD(P)H:quinone oxidoreductase 1 protects lungs from oxidant-induced emphysema in mice. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).This article has been retracted at the request of the Authors.Since learning of potential discrepancies between the raw data from the animal pulmonary physiology laboratory at Duke that were used to calculate the in vivo pulmonary mechanics and the re-exported machine-generated raw data, some studies published elsewhere have been replicated successfully. However it is not possible to replicate this study as the NQO1-deficient mice on the C57BL/6 background are no longer available from the NCI. The authors recognize that previous work to identify differences in alveolar size can vary dependent on background strain when comparing inbred mouse strains (Soutiere SE et al Resp Physiol Neurobiol 2004;140(3)183-91 doi: 10.1016/j.resp.2004.02.003). Because of the prolonged period of time required to successfully backcross NQO1-deficient animals onto C57BL/6J background and the time required to repeat studies presented in this manuscript the authors think it does not seem feasible to conduct replicate studies in a reasonable timeline.Therefore, the most appropriate course of action is to retract the report as it is the authors' goal to maintain accuracy of the scientific record to the best of their ability.The authors offer sincere apologies to the scientific community. PMID- 22198264 TI - Pycnogenol attenuates the inflammatory and nitrosative stress on joint inflammation induced by urate crystals. AB - Acute gouty arthritis results from monosodium urate (MSU) crystal deposition in joint tissues. Deposited MSU crystals induce an acute inflammatory response which leads to damage of joint tissue. Pycnogenol (PYC), an extract from the bark of Pinus maritime, has documented antiinflammatory and antioxidant properties. The present study aimed to investigate whether PYC had protective effects on MSU induced inflammatory and nitrosative stress in joint tissues both in vitro and in vivo. MSU crystals upregulated cyclooxygenase 2 (COX-2), interleukin 8 (IL-8) and inducible nitric oxide synthase (iNOS) gene expression in human articular chondrocytes, but only COX-2 and IL-8 in synovial fibroblasts. PYC inhibited the up-regulation of COX-2, and IL-8 in both articular chondrocytes and synovial fibroblasts. PYC attenuated MSU crystal induced iNOS gene expression and NO production in chondrocytes. Activation of NF-kappaB and SAPK/JNK, ERK1/2 and p38 MAP kinases by MSU crystals in articular chondrocytes and synovial fibroblasts in vitro was attenuated by treatment with PYC. The acute inflammatory cell infiltration and increased expression of COX-2 and iNOS in synovial tissue and articular cartilage following intra-articular injection of MSU crystals in a rat model was inhibited by coadministration of PYC. Collectively, this study demonstrates that PYC may be of value in treatment of MSU crystal-induced arthritis through its anti-inflammatory and anti-nitrosative activities. PMID- 22198265 TI - Mercury and selenium interaction in vivo: effects on thioredoxin reductase and glutathione peroxidase. AB - Mercury compounds exert toxic effects via interaction with many vital enzymes involved in antioxidant regulation, such as selenoenzymes thioredoxin reductase (TrxR) and glutathione peroxidase (GPx). Selenium supplementation can reactivate the mercury-inhibited TrxR and recover the cell viability in vitro. To gain an insight on how selenium supplementation affects mercury toxicity in vertebrates, we investigated the effects of selenium on the mercury accumulation and TrxR and GPx activities in a fish model. Juvenile zebra-seabreams were exposed either to methylmercury (MeHg) or inorganic mercury (Hg(2+)) in the presence or absence of sodium selenite (Se) for 28 days followed by 14 days of depuration. Mercury accumulation was found to be 10-fold higher under MeHg exposure than under Hg(2+) exposure. Selenium supplementation caused a half decrease of the accumulation of MeHg but did not influence Hg(2+) accumulation. Exposure to both mercurials led to a decrease of the activity of TrxR (<50% of control) in all organs. Se supplementation coincident with Hg(2+) exposure protected the thioredoxin system in fish liver. However, supplementation of Se during the depuration phase had no effects. The activity of GPx was only affected in the brain of fishes upon the exposure to MeHg and coexposure to MeHg and Se. Selenium supplementation has a limited capacity to prevent mercury effects in brain and kidney. These results demonstrate that Se supplementation plays a protective role in a tissue-specific manner and also highlight the importance of TrxR as a main target for mercurials in vivo. PMID- 22198267 TI - Activation of the cAMP cascade in human fibroblast cultures rescues the activity of oxidatively damaged complex I. AB - A study of the relationship between cAMP/PKA-dependent phosphorylation and oxidative damage of subunits of complex I of the mitochondrial respiratory chain is presented. It is shown that, in fibroblast cultures, PKA-mediated phosphorylation of the NDUFS4 subunit of complex I rescues the activity of the oxidatively damaged complex. Evidence is presented showing that this effect is mediated by phosphorylation-dependent exchange of carbonylated NDUFS4 subunit in the assembled complex with the de novo synthesized subunit. These results indicate a potential use for beta-adrenoceptor agonists in preventing/reversing the detrimental effects of oxidative stress in the mitochondrial respiratory system. PMID- 22198266 TI - Hepatocyte DNA replication in growing liver requires either glutathione or a single allele of txnrd1. AB - Ribonucleotide reductase (RNR) activity requires an electron donor, which in bacteria, yeast, and plants is usually either reduced thioredoxin (Trx) or reduced glutaredoxin. Mice lacking glutathione reductase are viable and, although mice lacking thioredoxin reductase 1 (TrxR1) are embryonic-lethal, several studies have shown that mouse cells lacking the txnrd1 gene, encoding TrxR1, can proliferate normally. To better understand the in vivo electron donor requirements for mammalian RNR, we here investigated whether replication of TrxR1 deficient hepatocytes in mouse livers either employed an alternative source of Trx-reducing activity or, instead, solely relied upon the glutathione (GSH) pathway. Neither normal nor genetically TrxR1-deficient livers expressed substantial levels of mRNA splice forms encoding cytosolic variants of TrxR2, and the TrxR1-deficient livers showed severely diminished total TrxR activity, making it unlikely that any alternative TrxR enzyme activities complemented the genetic TrxR1 deficiency. To test whether the GSH pathway was required for replication, GSH levels were depleted by administration of buthionine sulfoximine (BSO) to juvenile mice. In controls not receiving BSO, replicative indexes were similar in hepatocytes having two, one, or no functional alleles of txnrd1. After BSO treatment, hepatocytes containing either two or one copies of this gene were also normal. However, hepatocytes completely lacking a functional txnrd1 gene exhibited severely reduced replicative indexes after GSH depletion. We conclude that hepatocyte proliferation in vivo requires either GSH or at least one functional allele of txnrd1, demonstrating that either the GSH- or the TrxR1 dependent redox pathway can independently support hepatocyte proliferation during liver growth. PMID- 22198268 TI - Laparoscopic extraperitoneal para-aortic lymphadenectomy in the staging of locally advanced cervical cancer: is it a feasible procedure at a peripheral center? AB - OBJECTIVE: The study's aim was to evaluate the feasibility of laparoscopic extraperitoneal para-aortic lymphadenectomy at a peripheral center for the staging of patients with locally advanced cervical cancer (LACC). METHODS: From March 2009 to January 2011, 30 patients with LACC underwent laparoscopic extraperitoneal para-aortic lymphadenectomy. All patients were treated with definitive radiotherapy tailored according to the staging results. Data on demographics, pathologic findings, surgery, complications, and disease status at follow-up are presented. RESULTS: Patients' mean age was 47.6 years (range, 28-67 years). The mean body mass index was 26.3 (range, 19.1-35.6). Mean operative time was 118.7 minutes (range, 77-195 minutes) with an average of 14.2 lymph nodes removed (range, 5-34). Intraoperative complications were a lumbar artery injury and a bowel injury. No postoperative complications occurred. Mean postoperative hospital stay was 1.9 days (range, 1-6 days). Pathological examination revealed that 26.7% (8/30) of patients had metastatic disease in para-aortic lymph nodes. Two patients with disease at the para-aortic level died 5 and 12 months after diagnosis; both of them developed pulmonary and hepatic metastases. The rest of the patients were free of disease, after completion of the treatment, during a mean follow-up time of 15.6 months (range, 5-27 months). CONCLUSIONS: Laparoscopic extraperitoneal aortic lymphadenectomy is a feasible procedure, even at peripheral centers, that is useful to identify patients with LACC and para aortic disease and to tailor their treatment. Gynecologic oncologists are encouraged to learn this procedure and offer it to their patients. PMID- 22198269 TI - Critical roles of Asp270 and Trp273 in the alpha-repeat of the carbohydrate binding module of endo-1,3-beta-glucanase for laminarin-binding avidity. AB - A carbohydrate-binding module from family 13 (CBM13), appended to the catalytic domain of endo-1,3-beta-glucanase from Cellulosimicrobium cellulans, was overexpressed in E. coli, and its interactions with beta-glucans, laminarin and laminarioligosaccharides, were analyzed using surface plasmon resonance biosensor and isothermal titration calorimetry. The association constants for laminarin and laminarioligosaccharides were determined to be approximately 10(6) M(-1) and 10(4) M(-1), respectively, indicating that 2 or 3 binding sites in the alpha-, beta-, and gamma-repeats of CBM13 are involved in laminarin binding in a cooperative manner. The binding avidity is approximately 2-orders higher than the monovalent binding affinity. Mutational analysis of the conserved Asp residues in the respective repeats showed that the alpha-repeat primarily contributes to beta glucan binding. A Trp residue is predicted to be exposed to the solvent only in the alpha-repeat and would contribute to beta-glucan binding. The alpha-repeat bound beta-glucan with an affinity of approximately 10(4) M(-1), and the other repeats additionally bound laminarin, resulting in the increased binding avidity. This binding is unique compared to the recognition mode of another CBM13 from Streptomyces lividans xylanase. PMID- 22198270 TI - Controlled delivery of nanosuspensions from osmotic pumps: zero order and non zero order kinetics. AB - Nanosuspensions have gained great interest in the last decade as a formulation tool for poorly soluble drugs. By decreasing particle sizes nanosuspensions enhance dissolution rate and bioavailability of the active pharmaceutical ingredient. Micro-osmotic pumps are widely used in experimental pharmacology and offer a tool of interest for the sustained release of nanosuspensions via the intraperitoneal or subcutaneous application site. The purpose of the present study was to investigate in-vitro the influence of (1) nanosuspension viscosity, (2) pump orifice position and (3) formulation osmolality on the delivery behavior of formulations in implantable osmotic systems. Therefore fenofibrate nanosuspension, methylene blue and fluorescein sodium solutions were chosen as model formulations. They were released in water or isotonic saline solution and drug/dye concentrations were determined by HPLC/UV. Release of nanosuspension particles in low viscous formulations resulted in a burst whereas increasing the viscosity led to the expected zero order delivery. Pumps with upward-positioned orifices released the nanosuspension in a zero order manner. Within the release of dyes, constant delivery could be ensured up to an osmolality of 486 mO sm/kg; above this value premature release of formulation was observed. The results indicate the requirement of in-vitro experiments prior to in-vivo animal testing for determining the release profiles of osmotic pumps. PMID- 22198271 TI - Femoral segment graft is a suitable alternative to stabilize pelvic osteotomies in developmental dysplasia of the hip: a comparative study. AB - The aim of this study was to compare bone healing in pelvic osteotomy patients with osteotomy gaps filled with a femoral segment resected (FSR) graft with bone healing in patients with an iliac tricortical autograft (ITA) in treatment of developmental dysplasia of the hip. Sixty-three hips were treated using FSR grafts. Sixty-one hips were treated using ITA. The mean operation time and blood loss were significantly reduced in the FSR graft group, but graft union time was extended in the FSR graft group compared with that in the ITA group. The FSR graft was found to be safe and effective in treatment of developmental dysplasia of the hip and serves as an advantageous alternative to ITA. PMID- 22198272 TI - Selective inhibition of clade A phosphatases type 2C by PYR/PYL/RCAR abscisic acid receptors. AB - Clade A protein phosphatases type 2C (PP2Cs) are negative regulators of abscisic acid (ABA) signaling that are inhibited in an ABA-dependent manner by PYRABACTIN RESISTANCE1 (PYR1)/PYR1-LIKE (PYL)/REGULATORY COMPONENTS OF ABA RECEPTORS (RCAR) intracellular receptors. We provide genetic evidence that a previously uncharacterized member of this PP2C family in Arabidopsis (Arabidopsis thaliana), At5g59220, is a negative regulator of osmotic stress and ABA signaling and that this function was only apparent when double loss-of-function mutants with pp2ca 1/ahg3 were generated. At5g59220-green fluorescent protein and its close relative PP2CA-green fluorescent protein showed a predominant nuclear localization; however, hemagglutinin-tagged versions were also localized to cytosol and microsomal pellets. At5g59220 was selectively inhibited by some PYR/PYL ABA receptors, and close relatives of this PP2C, such as PP2CA/ABA-HYPERSENSITIVE GERMINATION3 (AHG3) and AHG1, showed a contrasting sensitivity to PYR/PYL inhibition. Interestingly, AHG1 was resistant to inhibition by the PYR/PYL receptors tested, which suggests that this seed-specific phosphatase is still able to regulate ABA signaling in the presence of ABA and PYR/PYL receptors and therefore to control the highly active ABA signaling pathway that operates during seed development. Moreover, the differential sensitivity of the phosphatases At5g59220 and PP2CA to inhibition by ABA receptors reveals a functional specialization of PYR/PYL ABA receptors to preferentially inhibit certain PP2Cs. PMID- 22198273 TI - Dissecting plant genomes with the PLAZA comparative genomics platform. AB - With the arrival of low-cost, next-generation sequencing, a multitude of new plant genomes are being publicly released, providing unseen opportunities and challenges for comparative genomics studies. Here, we present PLAZA 2.5, a user friendly online research environment to explore genomic information from different plants. This new release features updates to previous genome annotations and a substantial number of newly available plant genomes as well as various new interactive tools and visualizations. Currently, PLAZA hosts 25 organisms covering a broad taxonomic range, including 13 eudicots, five monocots, one lycopod, one moss, and five algae. The available data consist of structural and functional gene annotations, homologous gene families, multiple sequence alignments, phylogenetic trees, and colinear regions within and between species. A new Integrative Orthology Viewer, combining information from different orthology prediction methodologies, was developed to efficiently investigate complex orthology relationships. Cross-species expression analysis revealed that the integration of complementary data types extended the scope of complex orthology relationships, especially between more distantly related species. Finally, based on phylogenetic profiling, we propose a set of core gene families within the green plant lineage that will be instrumental to assess the gene space of draft or newly sequenced plant genomes during the assembly or annotation phase. PMID- 22198274 TI - Lumbar muscle fatigue and subjective health measurements in patients with lumbar disc herniation 2 years after surgery. AB - INTRODUCTION: In this prospective study the purpose was to evaluate patients with lumbar-disc herniation regarding changes in back-muscle fatigue and subjective health measurements 2 years after surgery. METHODS: Endurance time, EMG median frequency and ratings of lumbar-muscle fatigue and pain were measured before surgery, 4 weeks after and 2 years after surgery in 26 patients (19 men and 7 women) with lumbar-disc herniation. A modified Sorensen test was performed with concurrent recordings of electromyography from the lumbar muscles at four recording sites. The questionnaires Oswestry disability index, Roland-Morris disability questionnaire, Self-efficacy scale, SF-36, Back beliefs questionnaire, Odom and a 6-grade physical activity scale were used. RESULTS: Two years after surgery the patients had longer endurance times (increase from 178 s to 231 s, p < 0.001), a non-significant tendency for flatter L5 slopes (decrease from -0.20 to -0.16 Hz/s, p < 0.066), higher initial median frequency (L1 increase from 58 to 64 Hz p < 0.001, L5 increase from 76 to 84 Hz p = 0.001) and improved questionnaire scores. The questionnaires Oswestry, Roland-Morris and SF-36 physical functioning correlated with the endurance time 0.69-0.93 and with L5 slope 0.01-0.93 and the highest correlations were found in women. CONCLUSION: Both EMG and endurance time measurements are needed for evaluating fatigue in lumbar-disc herniation. PMID- 22198275 TI - Cigarette smoke and the terminal ileum: increased autophagy in murine follicle associated epithelium and Peyer's patches. AB - Cigarette smoke (CS) exposure is associated with increased autophagy in several cell types, such as bronchial epithelial cells. Smoking is also an environmental risk factor in Crohn's disease, in which impairment of the autophagy-mediated anti-bacterial pathway has been implicated. So far, it is unknown whether CS induces autophagy in the gut. Here, we examined the effect of chronic CS exposure on autophagy in the follicle-associated epithelium (FAE) of murine Peyer's patches. Transmission electron microscopy revealed that the proportion of cell area occupied by autophagic vesicles significantly increased in the FAE after CS exposure. An increased number of autophagic vesicles was observed in the FAE, whereas the vesicle size remained unaltered. Besides enterocytes, also M-cells contain more autophagic vesicles upon CS exposure. In addition, the mRNA level of the autophagy-related protein Atg7 in the underlying Peyer's patches is increased after CS exposure, which indicates that the autophagy-inducing effect of CS is not limited to the FAE. In conclusion, our results demonstrate that CS exposure induces autophagy in murine FAE and in the underlying immune cells of Peyer's patches, suggesting that CS exposure increases the risk for Crohn's disease by causing epithelial oxidative damage, which needs to be repaired by autophagy. PMID- 22198276 TI - Effects of maternal screening and universal immunization to prevent mother-to infant transmission of HBV. AB - BACKGROUND & AIMS: Mother-to-infant transmission is the major cause of hepatitis B virus (HBV) infection among immunized children. There has been much debate about screening pregnant women and administering hepatitis B immunoglobulin (HBIG) to newborns. We analyzed the rate of HBV infection among children born to hepatitis B surface antigen (HBsAg)-positive mothers and whether HBIG administration reduces transmission. METHODS: We analyzed data from 2356 children born to HBsAg-positive mothers, identified through prenatal maternal screens. In addition to HBV vaccines, HBIG was given to all 583 children with hepatitis B e antigen (HBeAg)-positive mothers and to 723 of 1773 children with HBeAg-negative mothers. Serology tests for HBV were performed from 2007 to 2009, when children were 0.5-10 years old. RESULTS: A significantly greater percentage of children with HBeAg-positive mothers tested positive for antibodies against the hepatitis B core protein (16.76%) and HBsAg (9.26%) than children with HBeAg-negative mothers (1.58% and 0.29%, respectively; P < .0001 and <.001). Among the HBV infected children, the rate of chronicity also was higher among children with HBeAg-positive mothers than children with HBeAg-negative mothers (54% vs 17%; P = .002). Similar rates of antibodies against the hepatitis B core protein (0.99% and 1.88%; P = .19) and HBsAg (0.14% and 0.29%; P = .65) were noted in children born to HBeAg-negative mothers who were or were not given HBIG. Infantile fulminant hepatitis developed in 1 of 1050 children who did not receive HBIG (.095%). CONCLUSIONS: Children born to HBeAg-positive mothers are at greatest risk for chronic HBV infection (9.26%), despite immunization. Administration of HBIG to infants born to HBeAg-negative mothers did not appear to reduce the rate of chronic HBV infection, but might prevent infantile fulminant hepatitis. Screening pregnant women for HBsAg and HBeAg might control mother-to-infant transmission of HBV. PMID- 22198277 TI - Three-dimensional imaging of the unsectioned adult spinal cord to assess axon regeneration and glial responses after injury. AB - Studying regeneration in the central nervous system (CNS) is hampered by current histological and imaging techniques because they provide only partial information about axonal and glial reactions. Here we developed a tetrahydrofuran-based clearing procedure that renders fixed and unsectioned adult CNS tissue transparent and fully penetrable for optical imaging. In large spinal cord segments, we imaged fluorescently labeled cells by 'ultramicroscopy' and two photon microscopy without the need for histological sectioning. We found that more than a year after injury growth-competent axons regenerated abundantly through the injury site. A few growth-incompetent axons could also regenerate when they bypassed the lesion. Moreover, we accurately determined quantitative changes of glial cells after spinal cord injury. Thus, clearing CNS tissue enables an unambiguous evaluation of axon regeneration and glial reactions. Our clearing procedure also renders other organs transparent, which makes this approach useful for a large number of preclinical paradigms. PMID- 22198278 TI - Antibodies targeting the catalytic zinc complex of activated matrix metalloproteinases show therapeutic potential. AB - Endogenous tissue inhibitors of metalloproteinases (TIMPs) have key roles in regulating physiological and pathological cellular processes. Imitating the inhibitory molecular mechanisms of TIMPs while increasing selectivity has been a challenging but desired approach for antibody-based therapy. TIMPs use hybrid protein-protein interactions to form an energetic bond with the catalytic metal ion, as well as with enzyme surface residues. We used an innovative immunization strategy that exploits aspects of molecular mimicry to produce inhibitory antibodies that show TIMP-like binding mechanisms toward the activated forms of gelatinases (matrix metalloproteinases 2 and 9). Specifically, we immunized mice with a synthetic molecule that mimics the conserved structure of the metalloenzyme catalytic zinc-histidine complex residing within the enzyme active site. This immunization procedure yielded selective function-blocking monoclonal antibodies directed against the catalytic zinc-protein complex and enzyme surface conformational epitopes of endogenous gelatinases. The therapeutic potential of these antibodies has been demonstrated with relevant mouse models of inflammatory bowel disease. Here we propose a general experimental strategy for generating inhibitory antibodies that effectively target the in vivo activity of dysregulated metalloproteinases by mimicking the mechanism employed by TIMPs. PMID- 22198279 TI - NMR insights into protein allostery. AB - Allosterism is one of nature's principal methods for regulating protein function. Allosterism utilizes ligand binding at one site to regulate the function of the protein by modulating the structure and dynamics of a distant binding site. In this review, we first survey solution NMR techniques and how they may be applied to the study of allostery. Subsequently, we describe several examples of application of NMR to protein allostery and highlight the unique insight provided by this experimental technique. PMID- 22198280 TI - PPARalpha activation inhibits endothelin-1-induced cardiomyocyte hypertrophy by prevention of NFATc4 binding to GATA-4. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) has been implicated in the pathogenesis of cardiac hypertrophy, although its mechanism of action remains largely unknown. To determine the effect of PPARalpha activation on endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy and explore its molecular mechanisms, we evaluated the interaction of PPARalpha with nuclear factor of activated T-cells c4 (NFATc4) in nuclei of cardiomyocytes from neonatal rats in primary culture. In ET-1-stimulated cardiomyocytes, data from electrophoretic mobility-shift assays (EMSA) and co-immunoprecipitation (co-IP) revealed that fenofibrate (Fen), a PPARalpha activator, in a concentration-dependent manner, enhanced the association of NFATc4 with PPARalpha and decreased its interaction with GATA-4, in promoter complexes involved in activation of the rat brain natriuretic peptide (rBNP) gene. Effects of PPARalpha overexpression were similar to those of its activation by Fen. PPARalpha depletion by small interfering RNA abolished inhibitory effects of Fen on NFATc4 binding to GATA-4 and the rBNP DNA. Quantitative RT-PCR and confocal microscopy confirmed inhibitory effects of PPARalpha activation on elevation of rBNP mRNA levels and ET-1-induced cardiomyocyte hypertrophy. Our results suggest that activated PPARalpha can compete with GATA-4 binding to NFATc4, thereby decreasing transactivation of NFATc4, and interfering with ET-1 induced cardiomyocyte hypertrophy. PMID- 22198281 TI - Naringin ameliorates metabolic syndrome by activating AMP-activated protein kinase in mice fed a high-fat diet. AB - Metabolic syndrome is a low-grade inflammatory state in which oxidative stress is involved. Naringin, isolated from the Citrussinensis, is a phenolic compound with anti-oxidative and anti-inflammatory activities. The aim of this study was to explore the effects of naringin on metabolic syndrome in mice. The animal models, induced by high-fat diet in C57BL/6 mice, developed obesity, dyslipidemia, fatty liver, liver dysfunction and insulin resistance. These changes were attenuated by naringin. Further investigations revealed that the inhibitory effect on inflammation and insulin resistance was mediated by blocking activation of the MAPKs pathways and by activating IRS1; the lipid-lowering effect was attributed to inhibiting the synthesis way and increasing fatty acid oxidation; the hypoglycemic effect was due to the regulation of PEPCK and G6pase. The anti oxidative stress of naringin also participated in the improvement of insulin resistance and lipogenesis. All of these depended on the AMPK activation. To confirm the results of the animal experiment, we tested primary hepatocytes exposed to high glucose system. Naringin was protective by phosphorylating AMPKalpha and IRS1. Taken together, these results suggested that naringin protected mice exposed to a high-fat diet from metabolic syndrome through an AMPK dependent mechanism involving multiple types of intracellular signaling and reduction of oxidative damage. PMID- 22198282 TI - 1alpha,25-Dihydroxyvitamin D(3) and its analog, 2-methylene-19-nor-(20S) 1alpha,25-dihydroxyvitamin D(3) (2MD), suppress intraocular pressure in non-human primates. AB - Ocular hypertension is the greatest known risk factor for glaucoma that affects an estimated 70 million people worldwide. Lowering intraocular pressure (IOP) remains the mainstay of therapy in the management of glaucoma. By means of microarray analysis, we have discovered that 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) regulates genes that are known to be involved in the determination of intraocular pressure (IOP). Topical administration of 1alpha,25 (OH)(2)D(3) or its analog, 2-methylene-19-nor-(20S)-1alpha,25-dihydroxyvitamin D(3) (2MD), markedly reduces IOP in non-human primates. The reduction in IOP is not the result of reduced aqueous humor formation, while a 35% increase in aqueous humor drainage by 1alpha,25-(OH)(2)D(3) was found but this increase did not achieve significance. Nevertheless, our results suggest that 1alpha,25 (OH)(2)D(3), or an analog thereof, may present a new approach to the treatment of glaucoma. PMID- 22198283 TI - Allostery and cooperativity in Escherichia coli aspartate transcarbamoylase. AB - The allosteric enzyme aspartate transcarbamoylase (ATCase) from Escherichia coli has been the subject of investigations for approximately 50 years. This enzyme controls the rate of pyrimidine nucleotide biosynthesis by feedback inhibition, and helps to balance the pyrimidine and purine pools by competitive allosteric activation by ATP. The catalytic and regulatory components of the dodecameric enzyme can be separated and studied independently. Many of the properties of the enzyme follow the Monod, Wyman Changeux model of allosteric control thus E. coli ATCase has become the textbook example. This review will highlight kinetic, biophysical, and structural studies which have provided a molecular level understanding of how the allosteric nature of this enzyme regulates pyrimidine nucleotide biosynthesis. PMID- 22198284 TI - p53 mutants induce transcription of NF-kappaB2 in H1299 cells through CBP and STAT binding on the NF-kappaB2 promoter and gain of function activity. AB - Cancer cells with p53 mutations, in general, grow more aggressively than those with wild-type p53 and show "gain of function" (GOF) phenotypes such as increased growth rate, enhanced resistance to chemotherapeutic drugs, increased cell motility and tumorigenicity; although the mechanism for this function remains unknown. In this communication we report that p53-mediated NF-kappaB2 up regulation significantly contributes to the aggressive oncogenic behavior of cancer cells. Lowering the level of mutant p53 in a number of cancer cell lines resulted in a loss of GOF phenotypes directly implicating p53 mutants in the process. RNAi against NF-kappaB2 in naturally occurring cancer cell lines also lowers GOF activities. In H1299 cells expressing mutant p53, chromatin immunoprecipitation (ChIP) assays indicate that mutant p53 induces histone acetylation at specific sites on the regulatory regions of its target genes. ChIP assays using antibodies against transcription factors putatively capable of interacting with the NF-kappaB2 promoter show increased interaction of CBP and STAT2 in the presence of mutant p53. Thus, we propose that in H1299 cells, mutant p53 elevates expression of genes capable of enhancing cell proliferation, motility, and tumorigenicity by inducing acetylation of histones via recruitment of CBP and STAT2 on the promoters causing CBP-mediated histone acetylation. PMID- 22198285 TI - Non-heme manganese catalase--the 'other' catalase. AB - Non-heme manganese catalases are widely distributed over microbial life and represent an environmentally important alternative to heme-containing catalases in antioxidant defense. Manganese catalases contain a binuclear manganese complex as their catalytic active site rather than a heme, and cycle between Mn(2)(II,II) and Mn(2)(III,III) states during turnover. X-ray crystallography has revealed the key structural elements of the binuclear manganese active site complex that can serve as the starting point for computational studies on the protein. Four manganese catalase enzymes have been isolated and characterized, and the enzyme appears to have a broad phylogenetic distribution including both bacteria and archae. More than 100 manganese catalase genes have been annotated in genomic databases, although the assignment of many of these putative manganese catalases needs to be experimentally verified. Iron limitation, exposure to low levels of peroxide stress, thermostability and cyanide resistance may provide the biological and environmental context for the occurrence of manganese catalases. PMID- 22198286 TI - Allosteric regulation in Acetohydroxyacid Synthases (AHASs)--different structures and kinetic behavior in isozymes in the same organisms. AB - Acetohydroxyacid Synthases (AHASs) have separate small regulatory subunits which specifically activate the catalytic subunits with which they are associated. The binding sites for the inhibitory amino acid(s) (valine or leucine) are in the interface between two ACT (small ligand binding) domains, and are apparently found in all AHAS regulatory subunits. However, the structures and the kinetic mechanisms of the different enzymes are very heterogeneous. Among the three isozymes encoded in the enterobacteria, the regulatory patterns are different, and their different responses to the inhibitory end product valine can be rationalized, at least in part, on the basis of the regulatory subunit structures and differences in catalytic mechanisms. The regulatory subunits in "typical" single AHASs found in other bacteria are similar to that of Escherichia coli isozyme AHAS III. Eukaryotic AHASs have more complex regulatory mechanisms and larger regulatory subunits. Such AHASs have two separate ACT sequence domains on the same regulatory polypeptide and can simultaneously bind two amino acids with synergistic effects. Yeast and fungal AHASs have ATP-binding sequence inserts in their regulatory subunits and are activated by MgATP in addition to being inhibited by valine. PMID- 22198287 TI - Effects of hypoxia on osteogenic differentiation of rat bone marrow mesenchymal stem cells. AB - Bone reconstruction is essential in orthodontic treatment that caters to the correction of malocclusion by bone reconstruction. Mesenchymal stem cells (MSCs) have been demonstrated a great potency of osteogenesis. The aim of this study was to investigate the effect of hypoxia on the rat bone marrow MSCs (rBMSCs) in vitro during osteogenesis. In this study, we found that temporary exposure of rBMSCs after osteogenic induction for 7 days to hypoxia (2% oxygen) led to a marked decrease in ALPase activity and the expression of osteocalcin and Runt related transcription factor 2/core binding factor a1 (Runx2/Cbfa1). Meanwhile, we found that exposure to hypoxia led to an early and transient increase in the level of phosphorylated ERK1/2 but had no obvious effects on mitogen-activated protein kinase (p38 MAPK) level. Based on these results, we concluded that hypoxia could inhibit osteogenic differentiation of rBMSCs possibly through MEK ERK 1/2, while p38 MAPK may not participate in this regulation. Further exploration into the mechanisms of hypoxia on osteogenesis would surely provide reliable evidence for clinical practice. PMID- 22198288 TI - Protective effects of 7-difluoromethyl-5,4'-dimethoxygenistein against human aorta endothelial injury caused by lysophosphatidyl choline. AB - 7-Difluoromethyl-5,4'-dimethoxygenistein (DFMG) is an active new derivative of genistein (GEN). It has shown effective protection in vascular endothelial injury. To further investigate its potential protective effects and its mechanism probably related to atherosclerosis, in present study, human aorta endothelial cells (HAECs) were chosen and treated with various concentrations of lysophosphatidyl choline (LPC) to establish an experimental model. Results showed that 10.0 MUmol/l of LPC was optimal for inducing HAEC injury. DFMG pretreatment was able to prevent HAEC injury induced by LPC and restore cell viability in a concentration-dependent manner. The protective efficacy of DFMG (10.0 MUmol/l) was significantly greater than that of GEN (10.0 MUmol/l) and vitamin E (50.0 MUmol/l). The mechanisms underlying the protective effects of DFMG are related to the activation of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase and to the clearance of intracellular reactive oxygen species. DFMG inhibits the apoptosis of HAECs mediated by LPC involving the blockage of the mitochondrial apoptotic pathway. PMID- 22198289 TI - Apoptotic signaling in endothelial cells with neutrophil activation. AB - As is the case for tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), degranulated substances (DS) released from polymorphonuclear leukocytes (PMN) and H(2)O(2) cause endothelial cell apoptosis through the phosphorylation of members of the mitogen-activated protein kinase (MAPK) family. Stimulation of human umbilical vein endothelial cells (HUVEC) with IL-1beta or TNF-alpha/cycloheximide (CHX) was found to enhance the phosphorylation of p38 and Jun-N-terminal kinase (JNK) in a time-dependent fashion, but did not affect the time-dependent phosphorylation of extracellular signal-regulated kinase. In addition, IL-1beta and TNF-alpha/CHX induced the phosphorylation of activating transcription factor-2 (ATF-2), but not c-Jun. Moreover, the p38 in HUVEC was phosphorylated by DS released from PMN and also by H(2)O(2), but not by *O(2) (-) induced by myeloperoxidase (MPO) of PMN. On the other hand, caspase 8 in HUVEC was activated by DS, but not by H(2)O(2) and/or *O(2) (-). In addition, caspases 3 and 7 were cleaved by the treatment of DS and turned into active forms. DS was concentrated, analyzed by electrophoresis, and revealed to contain precursor and subunits of MPO (90, 60, and 14 kDa) and another peptide with a molecular weight of about 28 kDa. Because SB203580 that was an inhibitor of p38 MAPK did not repress phosphorylation of ATF-2 in HUVEC, it was suggested that JNK was more important than p38 in a series of signaling courses. These results suggest the possibility that not only TNF-alpha/CHX and IL-1beta but also DS released from PMN and the cell-permeable reactive oxygen species H(2)O(2) induce blood vessel injury through endothelial apoptosis. PMID- 22198290 TI - 14-aminotetradecanoic acid exhibits antioxidant activity and ameliorates xenobiotics-induced cytotoxicity. AB - Natural compounds with free-radical scavenging activity have potential role in maintaining human health and preventing diseases. In this study, we report the antioxidant and cytoprotective properties of 14-aminotetradecanoic acid (ATDA) isolated from the Decalepis hamiltonii roots. ATDA is a potent scavenger of superoxide (O(2) (*-)), hydroxyl ((*)OH), nitric oxide ((*)NO), and lipid peroxide (LOO(*)) physiologically relevant free radicals with IC(50) values in nM (36-323) range. ATDA also exhibits concentration-dependent secondary antioxidant activities like reducing power, metal-chelating activity, and inhibition of protein carbonylation. Further, ATDA at nM concentration prevented CuSO(4) induced human LDL oxidation. ATDA demonstrated cytoprotective activity in primary hepatocytes and Ehrlich ascites tumor cells against oxidative stress inducing xenobiotics apart from the in vitro free-radical scavenging activity. The mechanism of cytoprotective action involved maintaining the intracellular glutathione, scavenging of reactive oxygen species, and inhibition of lipid peroxidation. It is suggested that ATDA is a novel bioactive molecule with potential health implications. PMID- 22198291 TI - Agglomerate behaviour of fluticasone propionate within dry powder inhaler formulations. AB - Due to their small size, the respirable drug particles tend to form agglomerates which prevent flowing and aerosolisation. A carrier is used to be mixed with drug in one hand to facilitate the powder flow during manufacturing, in other hand to help the fluidisation upon patient inhalation. Depending on drug concentration, drug agglomerates can be formed in the mixture. The aim of this work was to study the agglomeration behaviour of fluticasone propionate (FP) within interactive mixtures for inhalation. The agglomerate phenomenon of fluticasone propionate after mixing with different fractions of lactose without fine particles of lactose (smaller than 32 MUm) was demonstrated by the optical microscopy observation. A technique measuring the FP size in the mixture was developed, based on laser diffraction method. The FP agglomerate sizes were found to be in a linear correlation with the pore size of the carrier powder bed (R(2)=0.9382). The latter depends on the particle size distribution of carrier. This founding can explain the role of carrier size in de-agglomeration of drug particles in the mixture. Furthermore, it gives more structural information of interactive mixture for inhalation that can be used in the investigation of aerosolisation mechanism of powder. According to the manufacturing history, different batches of FP show different agglomeration intensities which can be detected by Spraytec, a new laser diffraction method for measuring aerodynamic size. After mixing with a carrier, Lactohale LH200, the most cohesive batch of FP, generates a lower fine particle fraction. It can be explained by the fact that agglomerates of fluticasone propionate with very large size was detected in the mixtures. By using silica-gel beads as ball-milling agent during the mixing process, the FP agglomerate size decreases accordingly to the quantity of mixing aid. The homogeneity and the aerodynamic performance of the mixtures are improved. The mixing aid based on ball-milling effect could be used to ameliorate the quality of inhalation mixture of cohesive drug, such as fluticasone propionate. However, there is a threshold where an optimal amount of mixing aids should be used. Not only the drug des-aggregation reaches its peak but the increase in drug-carrier adhesion due to high energy input should balance the de-agglomeration capacity of mixing process. This approach provides a potential alternative in DPI formulation processing. PMID- 22198292 TI - Dissection of the network of interactions that links RNA processing with glycolysis in the Bacillus subtilis degradosome. AB - The RNA degradosome is a multiprotein macromolecular complex that is involved in the degradation of messenger RNA in bacteria. The composition of this complex has been found to display a high degree of evolutionary divergence, which may reflect the adaptation of species to different environments. Recently, a degradosome-like complex identified in Bacillus subtilis was found to be distinct from those found in proteobacteria, the degradosomes of which are assembled around the unstructured C-terminus of ribonuclease E, a protein not present in B. subtilis. In this report, we have investigated in vitro the binary interactions between degradosome components and have characterized interactions between glycolytic enzymes, RNA-degrading enzymes, and those that appear to link these two cellular processes. The crystal structures of the glycolytic enzymes phosphofructokinase and enolase are presented and discussed in relation to their roles in the mediation of complex protein assemblies. Taken together, these data provide valuable insights into the structure and dynamics of the RNA degradosome, a fascinating and complex macromolecular assembly that links RNA degradation with central carbon metabolism. PMID- 22198293 TI - Modulating protein-protein interactions with small molecules: the importance of binding hotspots. AB - The modulation of protein-protein interactions (PPIs) by small drug-like molecules is a relatively new area of research and has opened up new opportunities in drug discovery. However, the progress made in this area is limited to a handful of known cases of small molecules that target specific diseases. With the increasing availability of protein structure complexes, it is highly important to devise strategies exploiting homologous structure space on a large scale for discovering putative PPIs that could be attractive drug targets. Here, we propose a scheme that allows performing large-scale screening of all protein complexes and finding putative small-molecule and/or peptide binding sites overlapping with protein-protein binding sites (so-called "multibinding sites"). We find more than 600 nonredundant proteins from 60 protein families with multibinding sites. Moreover, we show that the multibinding sites are mostly observed in transient complexes, largely overlap with the binding hotspots and are more evolutionarily conserved than other interface sites. We investigate possible mechanisms of how small molecules may modulate protein-protein binding and discuss examples of new candidates for drug design. PMID- 22198294 TI - (phi,psi)2 motifs: a purely conformation-based fine-grained enumeration of protein parts at the two-residue level. AB - A deep understanding of protein structure benefits from the use of a variety of classification strategies that enhance our ability to effectively describe local patterns of conformation. Here, we use a clustering algorithm to analyze 76,533 all-trans segments from protein structures solved at 1.2 A resolution or better to create a purely phi,psi-based comprehensive empirical categorization of common conformations adopted by two adjacent phi,psi pairs (i.e., (phi,psi)(2) motifs). The clustering algorithm works in an origin-shifted four-dimensional space based on the two phi,psi pairs to yield a parameter-dependent list of (phi,psi)(2) motifs, in order of their prominence. The results are remarkably distinct from and complementary to the standard hydrogen-bond-centered view of secondary structure. New insights include an unprecedented level of precision in describing the phi,psi angles of both previously known and novel motifs, ordering of these motifs by their population density, a data-driven recommendation that the standard C(alpha(i))...C(alpha(i+3))<7 A criteria for defining turns be changed to 6.5 A, identification of beta-strand and turn capping motifs, and identification of conformational capping by residues in polypeptide II conformation. We further document that the conformational preferences of a residue are substantially influenced by the conformation of its neighbors, and we suggest that accounting for these dependencies will improve protein modeling accuracy. Although the CUEVAS-4D(r(10)e(14)) 'parts list' presented here is only an initial exploration of the complex (phi,psi)(2) landscape of proteins, it shows that there is value to be had from this approach, and it opens the door to more in-depth characterizations at the (phi,psi)(2) level and at higher dimensions. PMID- 22198295 TI - p53 and DNA-dependent protein kinase catalytic subunit independently function in regulating actin damage-induced tetraploid G1 arrest. AB - We previously reported that the p53 tumor suppressor protein plays an essential role in the induction of tetraploid G1 arrest in response to perturbation of the actin cytoskeleton, termed actin damage. In this study, we investigated the role of p53, ataxia telangiectasia mutated protein (ATM), and catalytic subunit of DNA dependent protein kinase (DNA-PKcs) in tetraploid G1 arrest induced by actin damage. Treatment with actin- damaging agents including pectenotoxin-2 (PTX-2) increases phosphorylation of Ser-15 and Ser-37 residues of p53, but not Ser-20 residue. Knockdown of ATM and DNA-PKcs do not affect p53 phosphorylation induced by actin damage. However, while ATM knockdown does not affect tetraploid G1 arrest, knockdown of DNA-PKcs not only perturbs tetraploid G1 arrest, but also results in formation of polyploidy and induction of apoptosis. These results indicate that DNA-PKcs is essential for the maintenance of actin damage induced- tetraploid G1 arrest in a p53-independent manner. Furthermore, actin damage induced p53 expression is not observed in cells synchronized at G1/S of the cell cycle, implying that p53 induction is due to actin damage-induced tetraploidy rather than perturbation of actin cytoskeleton. Therefore, these results suggest that p53 and DNA- PKcs independently function for tetraploid G1 arrest and preventing polyploidy formation. PMID- 22198296 TI - Adenovirus adenine nucleotide translocator-2 shRNA effectively induces apoptosis and enhances chemosensitivity by the down-regulation of ABCG2 in breast cancer stem-like cells. AB - Cancer stem cells (CSCs) are resistant to chemo- and radio-therapy, and can survive to regenerate new tumors. This is an important reason why various anti- cancer therapies often fail to completely control tumors, although they kill and eliminate the bulk of cancer cells. In this study, we determined whether or not adenine nucleotide translocator-2 (ANT2) suppression could also be effective in inducing cell death of breast cancer stem-like cells. A sub-population (SP; CD44+/ CD24-) of breast cancer cells has been reported to have stem/progenitor cell properties. We utilized the adeno- ANT2 shRNA virus to inhibit ANT2 expression and then observed the treatment effect in a SP of breast cancer cell line. In this study, MCF7, MDA-MB-231 cells, and breast epithelial cells (MCF10A) mesenchymally-transdifferentiated through E-cadherin knockdown were used. ANT2 expression was high in both stem-like cells and non-stem-like cells of MCF7 and MDA-MB-231 cells, and was induced and up-regulated by mesenchymal transdifferentiation in MCF10A cells (MCF10A(EMT)). Knockdown of ANT2 by adeno shRNA virus efficiently induced apoptotic cell death in the stem-like cells of MCF7 and MDA-MB-231 cells, and MCF10A(EMT). Stem-like cells of MCF7 and MDA-MB 231, and MCF10A(EMT) cells exhibited increased drug (doxorubicin) resistance, and expressed a multi-drug resistant related molecule, ABCG2, at a high level. Adeno ANT2 shRNA virus markedly sensitized the stem-like cells of MCF7 and MDA-MB-231, and the MCF10A(EMT) cells to doxorubicin, which was accompanied by down regulation of ABCG2. Our results suggest that ANT2 suppression by adeno-shRNA virus is an effective strategy to induce cell death and increase the chemosensitivity of stem-like cells in breast cancer. PMID- 22198297 TI - Gene mapping study for constitutive skin color in an isolated Mongolian population. AB - To elucidate the genes responsible for constitutive human skin color, we measured the extent of skin pigmentation in the buttock, representative of lifelong non sun-exposed skin, and conducted a gene mapping study on skin color in an isolated Mongolian population composed of 344 individuals from 59 families who lived in Dashbalbar, Mongolia. The heritability of constitutive skin color was 0.82, indicating significant genetic association on this trait. Through the linkage analysis using 1,039 short tandem repeat (STR) microsatellite markers, we identified a novel genomic region regulating constitutive skin color on 11q24.2 with an logarithm of odds (LOD) score of 3.39. In addition, we also found other candidate regions on 17q23.2, 6q25.1, and 13q33.2 (LOD >= 2). Family-based association tests on these regions with suggestive linkage peaks revealed ten and two significant single nucleotide polymorphisms (SNPs) on the linkage regions of chromosome 11 and 17, respectively. We were able to discover four possible candidate genes that would be implicated to regulate human skin color: ETS1, UBASH3B, ASAM, and CLTC. PMID- 22198299 TI - [Sentinel node procedure and endometrial cancer: senti-endo results]. AB - Based on two randomized trials and a meta-analysis, the recommendations of the National Cancer Institute (INCa) have validated the absence of systematic pelvic lymphadenectomy for patients with endometrial cancer at low risk (type 1 histology stage IA grade 1-2) and intermediate (type 1 histology stage IA grade 3 and IB grade 1-2) but without taking into account the contribution of the sentinel node (SN) procedure. The senti-endo trial assessing the role of the SN procedure in patients with early stages endometrial cancer showed that the detection rate by hemi-pelvis right and left were 77 and 76%, respectively. The detection rate per patient was 89%. Among patients with at least a SN detected, the detection was unilateral in 34 cases (31%) and bilateral in 77 cases (69%). Of the 111 patients with at least a SN detected, 19 had lymph node metastases (17%). Considering the hemi-pelvis right and left as a unit, no false negative case was observed, hence the sensitivity and NPV was 100%. Considering the NPV per patient, three false negative cases were observed. Among the 57 patients at low risk, six (11%) had lymph node metastases on SN with negative non sentinel nodes. Of the 33 patients at intermediate risk, five (15%) had lymph node metastases on SN with negative non sentinel nodes. Senti-endo results emphasize the contribution of the SN procedure to assess the nodal status in patients with low or intermediate risk group raising the issue on new definition of the recommendations of INCa. PMID- 22198298 TI - Understanding latent tuberculosis: the key to improved diagnostic and novel treatment strategies. AB - Treatment of latent tuberculosis (LTBI) is a vital component of tuberculosis (TB) elimination but is not efficiently implemented with currently available diagnostics and therapeutics. The tuberculin skin test and interferon-gamma release assays can inform that infection has occurred, but do not prove that it persists. Treatment of LTBI with isoniazid targets actively replicating bacilli but not non-replicating populations, prolonging treatment duration. Developing more predictive diagnostic tests and treatments of shorter duration requires a greater understanding of the biology of LTBI, from both host and bacillary perspectives. In this article, we discuss the basis of current diagnosis and treatment of LTBI and review recent developments in understanding the biology of latency that might enable future improved diagnostic and treatment strategies. PMID- 22198300 TI - Surgery for retinal detachment: does experience matter? PMID- 22198301 TI - Does surgical experience have an effect on the success of retinal detachment surgery? AB - PURPOSE: To examine the relationship between surgeon experience and success rates in retinal detachment surgery. METHODS: Success rates during a follow-up of 11 months of 8 surgeons who performed in total 375 retinal detachment procedures ranging from 14 to 115 cases between December 1997 and January 2002 were correlated to the total number of vitreoretinal procedures ranging between 176 and 2,587. All patients received either scleral buckling or vitrectomy, and complicated cases were excluded. RESULTS: Mean primary anatomical success rates were 0.69 +/- 0.14 for scleral buckling and 0.9 +/- 0.05 for primary vitrectomy (P < 0.05). The primary anatomical success rates did not correlate to the number of vitreoretinal procedures. Seven of the eight surgeons showed an intraindividual learning effect with better success rates in the second versus the first half of the observed procedures. The learning effect was correlated to the total number of procedures with a higher effect in inexperienced surgeons. CONCLUSION: An intraindividual learning effect that was higher in inexperienced surgeons could be demonstrated. The learning effect was reduced by half after 500 vitreoretinal procedures while the primary anatomical success rates were not correlated to the number of vitreoretinal procedures. PMID- 22198302 TI - Improved intraoperative fundus visualization in corneal edema: the Viscoat trick. PMID- 22198303 TI - Re: Ranibizumab monotherapy versus single-session verteporfin photodynamic therapy combined with as-needed ranibizumab treatment for the management of neovascular age-related macular degeneration. PMID- 22198307 TI - Sensation seeking in fathers: the impact on testosterone and paternal investment. AB - Paternal care is associated with a reduced likelihood of engaging in competitive or mating behavior and an increased likelihood of providing protection when necessary. Over recent years, there has been increasing evidence to assume that the steroid testosterone (T) in men might reflect the degree of mating effort. In line with this, decreased T levels were shown in fathers compared to non-fathers and it was suggested that paternal care, and most behavior positively associated with T, might be incompatible with each other. Independently, the personality trait sensation seeking (SS) has been related to mating behavior and also to elevated T in men. Aiming to integrate these different lines of research in a longitudinal approach, we explored the impact of SS on T levels in the context of the transition to fatherhood. Thirty-seven fathers and 38 men without children but in committed, romantic relationships (controls) were recruited. At two time points (for fathers: four weeks prior to (t1) and eight weeks after birth (t2)), all subjects repeatedly collected saliva samples for T measurement, filled in a protocol of activities during the course of these days and completed an online questionnaire. In line with our hypotheses, the results show significantly lower aggregated (AUC-T) T levels in fathers compared with non-fathers. Furthermore, moderation analyses revealed a significant interaction between group and SS at t2, with the lowest T levels in low SS fathers. These data suggest that adaptation processes of the transition to fatherhood are influenced by individual differences in personality traits. PMID- 22198308 TI - Breaking the loop: oxytocin as a potential treatment for drug addiction. AB - Drug use typically occurs within a social context, and social factors play an important role in the initiation, maintenance and recovery from addictions. There is now accumulating evidence of an interaction between the neural substrates of affiliative behavior and those of drug reward, with a role for brain oxytocin systems in modulating acute and long-term drug effects. Early research in this field indicated that exogenous oxytocin administration can prevent development of tolerance to ethanol and opiates, the induction of stereotyped, hyperactive behavior by stimulants, and the withdrawal symptoms associated with sudden abstinence from drugs and alcohol. Additionally, stimulation of endogenous oxytocin systems is a key neurochemical substrate underlying the prosocial and empathogenic effects of party drugs such as MDMA (Ecstasy) and GHB (Fantasy). Brain oxytocin systems exhibit profound neuroplasticity and undergo major neuroadaptations as a result of drug exposure. Many drugs, including cocaine, opiates, alcohol, cannabis, MDMA and GHB cause long-term changes in markers of oxytocin function and this may be linked to enduring deficits in social behavior that are commonly observed in laboratory animals repeatedly exposed to these drugs. Very recent preclinical studies have illustrated a remarkable ability of exogenously delivered oxytocin to inhibit stimulant and alcohol self administration, to alter associated drug-induced changes in dopamine, glutamate and Fos expression in cortical and basal ganglia sites, and to prevent stress and priming-induced relapse to drug seeking. Oxytocin therefore has fascinating potential to reverse the corrosive effects of long-term drugs abuse on social behavior and to perhaps inoculate against future vulnerability to addictive disorders. The results of clinical studies examining intranasal oxytocin effects in humans with drug use disorders are eagerly awaited. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID- 22198309 TI - Exploiting antitumor immunity to overcome relapse and improve remission duration. AB - Cancer survivors often relapse due to evolving drug-resistant clones and repopulating tumor stem cells. Our preclinical study demonstrated that terminal cancer patient's lymphocytes can be converted from tolerant bystanders in vivo into effective cytotoxic T-lymphocytes in vitro killing patient's own tumor cells containing drug-resistant clones and tumor stem cells. We designed a clinical trial combining peginterferon alpha-2b with imatinib for treatment of stage III/IV gastrointestinal stromal tumor (GIST) with the rational that peginterferon alpha-2b serves as danger signals to promote antitumor immunity while imatinib's effective tumor killing undermines tumor-induced tolerance and supply tumor specific antigens in vivo without leukopenia, thus allowing for proper dendritic cell and cytotoxic T-lymphocyte differentiation toward Th1 response. Interim analysis of eight patients demonstrated significant induction of IFN-gamma producing-CD8(+), -CD4(+), -NK cell, and IFN-gamma-producing-tumor-infiltrating lymphocytes, signifying significant Th1 response and NK cell activation. After a median follow-up of 3.6 years, complete response (CR) + partial response (PR) = 100%, overall survival = 100%, one patient died of unrelated illness while in remission, six of seven evaluable patients are either in continuing PR/CR (5 patients) or have progression-free survival (PFS, 1 patient) exceeding the upper limit of the 95% confidence level of the genotype-specific-PFS of the phase III imatinib-monotherapy (CALGB150105/SWOGS0033), demonstrating highly promising clinical outcomes. The current trial is closed in preparation for a larger future trial. We conclude that combination of targeted therapy and immunotherapy is safe and induced significant Th1 response and NK cell activation and demonstrated highly promising clinical efficacy in GIST, thus warranting development in other tumor types. PMID- 22198311 TI - Excretion of the dipeptidyl peptidase-4 inhibitor linagliptin in rats is primarily by biliary excretion and P-gp-mediated efflux. AB - Linagliptin is a selective, competitive dipeptidyl peptidase-4 (DPP-4) inhibitor, recently approved in the USA, Japan and Europe for the treatment of type 2 diabetes. It has non-linear pharmacokinetics and, unlike other DPP-4 inhibitors, a largely non-renal excretion route. It was hypothesised that P-glycoprotein (P gp)-mediated intestinal transport could influence linagliptin bioavailability, and might contribute to its elimination. Two studies evaluated the role of P-gp mediated transport in the bioavailability and intestinal secretion of linagliptin in rats. In the bioavailability study, male Wistar rats received single oral doses of linagliptin, 1 or 15 mg/kg, plus either the P-gp inhibitor, zosuquidar trihydrochloride, or vehicle. For the intestinal secretion study, rats underwent bile duct cannulation, and urine, faeces, and bile were collected. At the end of the study, gut content was sampled. Inhibition of intestinal P-gp increased the bioavailability of orally administered linagliptin, indicating that this transport system plays a role in limiting the uptake of linagliptin from the intestine. This effect was dependent on linagliptin dose, and could play a role in its non-linear pharmacokinetics after oral dosing. Systemically available linagliptin was mainly excreted unchanged via bile (49% of i.v. dose), but some (12%) was also excreted directly into the gut independently of biliary excretion. Thus, direct excretion of linagliptin into the gut may be an alternative excretion route in the presence of liver and renal impairment. The primarily non renal route of excretion is likely to be of benefit to patients with type 2 diabetes, who have a high prevalence of renal insufficiency. PMID- 22198310 TI - Lymphodepletion is permissive to the development of spontaneous T-cell responses to the self-antigen PR1 early after allogeneic stem cell transplantation and in patients with acute myeloid leukemia undergoing WT1 peptide vaccination following chemotherapy. AB - PR1, an HLA-A*0201 epitope shared by proteinase-3 (PR3) and elastase (ELA2) proteins, is expressed in normal neutrophils and overexpressed in myeloid leukemias. PR1-specific T cells have been linked to graft-versus-leukemia (GVL) effect. We hypothesized that lymphopenia induced by chemo-radiotherapy can enhance weak autoimmune responses to self-antigens such as PR1. We measured PR1 specific responses in 27 patients 30-120 days following allogeneic stem cell transplant (SCT) and correlated these with ELA2 and PR3 expression and minimal residual disease (MRD). Post-SCT 10/13 CML, 6/9 ALL, and 4/5 solid tumor patients had PR1 responses correlating with PR3 and ELA2 expression. At day 180 post-SCT, 8/8 CML patients with PR1 responses were BCR-ABL-negative compared with 2/5 BCR ABL-positive patients (P = 0.025). In contrast, PR1 responses were detected in 2/4 MRD-negative compared with 4/5 MRD-positive ALL patients (P = 0.76). To assess whether the lymphopenic milieu also exaggerates weak T-cell responses in the autologous setting, we measured spontaneous induction of PR1 responses in 3 AML patients vaccinated with WT1-126 peptide following lymphodepletion. In addition to WT1-specific T cells, we detected PR1-specific T cells in 2 patients during hematopoietic recovery. Our findings suggest that lymphopenia induced by chemo-radiotherapy enhances weak autoimmune responses to self-antigens, which may result in GVL if the leukemia expresses the relevant self-antigen. PMID- 22198312 TI - A venue-based approach to reaching MSM, IDUs and the general population with VCT: a three study site in Kenya. AB - A venue-based HIV prevention study which included Voluntary Counseling and Testing (VCT) was conducted in three diverse areas of Kenya-Malindi, Nanyuki and Rachounyo. Aims of the study were to: (1) assess the acceptability of VCT for the general population, men who have sex with men (MSM), and injecting drug users (IDUs) within the context of a venue-based approach; (2) determine if there were differences between those agreeing and not agreeing to testing; and (3) study factors associated with being HIV positive. Approximately 98% of IDUs and 97% of MSM agreed to VCT, providing evidence that populations with little access to services and whose behaviors are stigmatized and often considered illegal in their countries can be reached with needed HIV prevention services. Acceptability of VCT in the general population ranged from 60% in Malindi to 48% in Nanyuki. There were a few significant differences between those accepting and declining testing. Notably in Rachuonyo and Malindi those reporting multiple partners were more likely to accept testing. There was also evidence that riskier sexual behavior was associated with being HIV positive for both men in Rachounyo and women in Malindi. Overall HIV prevalence was higher among the individuals in this study compared to individuals sampled in the 2008-2009 Kenya Demographic and Health Survey, indicating the method is an appropriate means to reach the highest risk individuals including stigmatized populations. PMID- 22198313 TI - HIV disclosure and sexual transmission behaviors among an Internet sample of HIV positive men who have sex with men in Asia: implications for prevention with positives. AB - The relationship between HIV disclosure and sexual transmission behaviors, and factors that influence disclosure are unknown among HIV-positive men who have sex with men (MSM) in Asia. We describe disclosure practices and sexual transmission behaviors, and correlates of disclosure among this group of MSM in Asia. A cross sectional multi-country online survey was conducted among 416 HIV-positive MSM. Data on disclosure status, HIV-related risk behaviors, disease status, and other characteristics were collected. Multivariable logistic regression was used to identify significant correlates of disclosure. Only 7.0% reported having disclosed their HIV status to all partners while 67.3% did not disclose to any. The majority (86.5%) of non-disclosing participants had multiple partners and unprotected insertive or receptive anal intercourse with their partners (67.5%). Non-disclosure was significantly associated with non-disclosure from partners (AOR = 37.13, 95% CI: 17.22, 80.07), having casual partners only (AOR = 1.91, 95% CI: 1.03, 3.53), drug use before sex on a weekly basis (AOR: 6.48, 95% CI: 0.99, 42.50), being diagnosed with HIV between 1 and 5 years ago (AOR = 2.23, 95% CI: 1.05, 4.74), and not knowing one's viral load (AOR = 2.80, 95% CI: 1.00, 7.83). Given the high HIV prevalence and incidence among MSM in Asia, it is imperative to include Prevention with Positives for MSM. Interventions on disclosure should not solely focus on HIV-positive men but also need to include their sexual partners and HIV-negative men. PMID- 22198314 TI - HIV and syphilis prevalence and associated factors among young men who have sex with men in 4 cities in China. AB - To know the status of HIV and syphilis infection, and the correlates for HIV and syphilis prevalence among YMSM in China. 150 YMSM were recruited in Beijing, Harbin, Zhengzhou and Chengdu respectively and investigated with questionnaire, HIV and syphilis testing. The prevalence of HIV infection, syphilis infection and concurrent infection of HIV and syphilis was 6.7, 8.3, 1.5% respectively. HIV infection was associated with numerous factors including education level of high school, not being student, etc. Syphilis infection was associated with not being student and having had vaginal intercourse. The prevalence of HIV and Syphilis are high among YMSM in cities in China. Preventive interventions should be developed for controlling HIV spreading among YMSM urgently. PMID- 22198315 TI - HIV stigma and depressive symptoms are related to adherence and virological response to antiretroviral treatment among immigrant and indigenous HIV infected patients. AB - We compared adherence to cART and virological response between indigenous and immigrant HIV-infected patients in the Netherlands, and investigated if a possible difference was related to a difference in the psychosocial variables: HIV-stigma, quality-of-life, depression and beliefs about medications. Psychosocial variables were assessed using validated questionnaires administered during a face-to-face interview. Adherence was assessed trough pharmacy-refill monitoring. We assessed associations between psychosocial variables and non adherence and having detectable plasma viral load using logistic regression analyses. Two-hundred-two patients participated of whom 112 (55%) were immigrants. Viral load was detectable in 6% of indigenous patients and in 15% of the immigrants (P < 0.01). In multivariate analyses, higher HIV-stigma and prior virological failure were associated with non-adherence, and depressive symptoms, prior virological failure and non-adherence with detectable viral load. Our findings suggest that HIV-stigma and depressive symptoms may be targets for interventions aimed at improving adherence and virological response among indigenous and immigrant HIV-infected patients. PMID- 22198316 TI - The role of trust in delayed HIV diagnosis in a diverse, urban population. AB - Delayed diagnosis of HIV infection is a common problem. We hypothesized that persons with less trust in physicians and in the healthcare system would be diagnosed with lower CD4 cell counts than persons with more trust because they would delay seeking healthcare. From January 2006 to October 2007, 171 newly diagnosed HIV-infected persons, not yet in HIV primary care, were recruited from HIV testing sites in Houston, Texas, that primarily serve the under- and un insured. The participants completed instruments measuring trust in physicians and trust in the healthcare system. Initial CD4 cell counts were obtained from medical record review. Mean trust scores for participants with CD4 cell counts >=200 cells/mm(3) were compared with scores from participants with CD4 cell counts <200 cells/mm(3). We found that 51% of the cohort was diagnosed with a CD4 cell count <200 cells/mm(3). Neither trust in physicians nor trust in the healthcare system was an independent predictor of delayed diagnosis of HIV infection. In multivariate analysis, men who have sex with men and injection drug users were more likely to have early HIV diagnosis. Race/ethnicity was the only variable statistically significantly predictive of trust in physicians and in the healthcare system. Hispanics had the highest trust scores, followed by Blacks and Whites. Low trust is likely not a barrier to timely diagnosis of HIV infection. PMID- 22198317 TI - Analyzing continuous measures in HIV prevention research using semiparametric regression and parametric regression models: how to use data to get the (right) answer? AB - Semiparametric regression models based on smoothing splines were used to examine the associations between the risk of HIV seropositivity and a continuous covariate. For example, in the fully parametric logistic regression model, age was associated with a decreased risk of HIV seropositivity [Odds ratio (OR): 0.94 per 5 year increase, 95% Confidence Interval (CI): 0.90-0.98]. This association was not evident when the age was dichotomized at the median [i.e. >26 years vs. <=26 years (reference)] (OR: 1.06, 95% CI: 0.92-1.21). Understanding the relationship between a continuous covariate and an outcome variable of interest involves determining the shape and strength of that relationship. The choice of the most appropriate approach depends on the specific problem and available data. We showed that using semiparametric regression techniques may be helpful in understanding the best way to do the categorization when it is desired. PMID- 22198318 TI - Influence of label information on dark chocolate acceptability. AB - The aim of the present work was to study how the information on product labels influences consumer expectations and their acceptance and purchase intention of dark chocolate. Six samples of dark chocolate, varying in brand (premium and store brand) and in type of product (regular dark chocolate, single cocoa origin dark chocolate and high percentage of cocoa dark chocolate), were evaluated by 109 consumers who scored their liking and purchase intention under three conditions: blind (only tasting the products), expected (observing product label information) and informed (tasting the products together with provision of the label information). In the expected condition, consumer liking was mainly affected by the brand. In the blind condition, differences in liking were due to the type of product; the samples with a high percentage of cocoa were those less preferred by consumers. Under the informed condition, liking of dark chocolates varied depending on both brand and type of product. Premium brand chocolates generated high consumer expectations of chocolate acceptability, which were fulfilled by the sensory characteristics of the products. Store brand chocolates created lower expectations, but when they were tasted they were as acceptable as premium chocolates. Claims of a high percentage of cocoa and single cocoa origin on labels did not generate higher expectations than regular dark chocolates. PMID- 22198320 TI - St. John's Wort inhibits insulin signaling in murine and human adipocytes. AB - Adipocytes are insulin-sensitive cells that play a major role in energy homeostasis. Obesity is the primary disease of fat cells and a major risk factor for the development of Type 2 diabetes, cardiovascular disease, and metabolic syndrome. The use of botanicals in the treatment of metabolic diseases is an emerging area of research. In previous studies, we screened over 425 botanical extracts for their ability to modulate adipogenesis and insulin sensitivity. We identified St. John's Wort (SJW) extracts as inhibitors of adipogenesis of 3T3-L1 cells and demonstrated that these extracts also inhibited insulin-sensitive glucose uptake in mature fat cells. In these follow-up studies we have further characterized the effects of SJW on insulin action in both murine and human fat cells. We have shown that SJW also attenuates insulin-sensitive glucose uptake in human adipocytes. Moreover, SJW inhibits IRS-1 tyrosine phosphorylation in both murine and human fat cells. Botanical extracts are complex mixtures. Many bioactive compounds have been identified in SJW, including hypericin (HI) and hyperforin (HF). We have examined the ability of HI and HF, purified from SJW, to modulate adipocyte development and insulin action in mature adipocytes. Our novel studies indicate that the profound effects of SJW on adipogenesis, IRS-1 activation, and insulin-stimulated glucose uptake are not mediated by HI and/or HF. Nonetheless, we propose that extracts of SJW may contribute to adipocyte related diseases by limiting differentiation of preadipocytes and significantly inducing insulin resistance in mature fat cells. PMID- 22198319 TI - Adiponectin deficiency: role in chronic inflammation induced colon cancer. AB - Adiponectin (APN), an adipokine, exerts an anti-inflammatory and anti-cancerous activity with its role in glucose and lipid metabolism and its absence related to several obesity related malignancies including colorectal cancer. The aim of this study is to determine the effect of APN deficiency on the chronic inflammation induced colon cancer. This was achieved by inducing inflammation and colon cancer in both APN knockout (KO) and C57B1/6 wild type (WT) mice. They were divided into four treatment groups (n=6): 1) control (no treatment); 2) treatment with three cycles of dextran sodium sulfate (DSS); 3) weekly doses of 1,2-dimethylhydrazine (DMH) (20mg/kg of mouse body weight) for twelve weeks; 4) a single dose of DMH followed by 3 cycles of DSS (DMH+DSS). Mice were observed for diarrhea, stool hemoccult, and weight loss and were sacrificed on day 153. Tumor area and number were counted. Colonic tissues were collected for Western blot and immunohistochemistry analyses. APNKO mice were more protected than WT mice from DSS induced colitis during first DSS cycle, but lost this protection during the second and the third DSS cycles. APNKO mice had significantly severe symptoms and showed greater number and larger area of tumors with higher immune cell infiltration and inflammation than WT mice. This result was further confirmed by proteomic study including pSTAT3, pAMPK and Cox-2 by western blot and Immunohistochemistry. Conclusively, APN deficiency contributes to inflammation induced colon cancer. Hence, APN may play an important role in colorectal cancer prevention by modulating genes involved in chronic inflammation and tumorigenesis. PMID- 22198321 TI - Hypoxic preconditioning increases iron transport rate in astrocytes. AB - The mechanisms involved in the neuroprotection induced by hypoxic preconditioning (HP) have not been fully elucidated. The involvement of hypoxia-inducible factor 1 alpha (HIF-1alpha) in such neuroprotection has been confirmed. There is also evidence showing that a series of genes with important functions in iron metabolism, including transferrin receptor (TfR1) and divalent metal transporter 1 (DMT1), are regulated by HIF-1alpha in response to hypoxia in extra-neural organs or cells. We therefore hypothesized that HP is able to affect the expression of iron metabolism proteins in the brain and that changes in these proteins induced by HP might be associated with the HP-induced neuroprotection. We herein demonstrated for the first time that HP could induce a significant increase in the expression of HIF-1alpha as well as iron uptake (TfR1 and DMT1) and release (ferroportin1) proteins, and thus increase tansferrin-bound iron (Tf Fe) and non-transferrin-bound iron (NTBI) uptake and iron release in astrocytes. Moreover, HP could lead to a progressive increase in cellular iron content. We concluded that HP has the ability to increase iron transport speed in astrocytes. Based on our findings and the importance of astrocytes in neuronal survival in hypoxic/ischemic preconditioning, we proposed that the increase in iron transport rate and cellular iron in astocytes might be one of the mechanisms associated with the HP-induced neuroprotection. We also demonstrated that ferroportin1 expression was significantly affected by HIF-1alpha in astrocytes, implying that the gene encoding this iron efflux protein might be a hypoxia-inducible one. PMID- 22198322 TI - Vitamin C attenuates the physiological and behavioural changes induced by long term exposure to noise. AB - Persistent, high-intensity noise is an environmental pollutant that plays a destructive role in daily life, especially in industrialized communities. Its effects may be reduced by Vitamin C supplementation. This study examined the possibility that pretreatment with vitamin C (100 mg or 200 mg/kg) could attenuate behavioural and anxiogenic effects of prolonged exposure to noise (100 dB for 2 months, 5 days/week, 4 h daily) on male laboratory mice, by using open field and plus maze tests of emotionality, and by measuring the neutrophils-to lymphocytes ratio, a physiological stress measure. The effects seen on behaviour in the open field and plus maze were consistent with the hypothesis that noise could be considered as a stressor as it significantly affected six measures of behaviour in the predicted directions. The neutrophil-to-lymphocyte ratio was also increased as a result of noise exposure. Furthermore, there was good evidence from all three procedures that vitamin C supplementation can attenuate the effects of noise. We conclude that vitamin C supplementation can attenuate or prevent the psychological and physiological damage induced by prolonged noise exposure in mice. PMID- 22198323 TI - Failure of porous tantalum cervical interbody fusion devices: two-year results from a prospective, randomized, multicenter clinical study. AB - OBJECTIVE: The objective of this study was to assess the safety and efficacy of 2 novel cervical interbody fusion devices in the treatment of single-level degenerative cervical disk disease. Both devices were fabricated from a porous tantalum material. The high overall porosity of the devices was intended to facilitate anterior cervical interbody fusion. METHODS: A prospective, randomized, 3-armed, clinical study was initiated with the following treatment groups: porous tantalum ring device packed with autograft, porous tantalum block device, and iliac crest autograft control. All the patients had single-level symptomatic cervical disk disease that had failed to respond to nonoperative therapy. Clinical and radiographic data were collected preoperatively, during surgery, before hospital discharge, and at 6 weeks, 3 months, 6 months, 12 months, and 24 months postoperatively. RESULTS: Six investigators participated in the clinical study at 6 investigational centers in the United States. Enrollment into the study was terminated after 39 patients had been accrued because of concerns over delayed fusion in the porous tantalum treatment groups. Of the 39 patients enrolled into the clinical study, 11 patients received the control treatment of iliac autograft fusion, 13 patients received the porous tantalum ring device with the center cavity packed with cancellous iliac crest autograft, and 15 patients received the porous tantalum block device. These patients were evaluated for 24 months as per the study protocol. There were no significant differences in any of the patient demographic variables collected. The mean operative times for both the ring and block device groups were slightly lower than the control treatment. Two patients in the block treatment group were determined to be nonunion between the 6- and 12-month time points and underwent additional surgery. Five patients with porous tantalum devices showed radiographic evidence of device fragmentation, and one patient in addition had radiographic evidence of erosion of the involved vertebral bodies by the device. One patient in the ring treatment group died from a myocardial infarction and kidney failure subsequent to the 12-month follow-up visit, which was unrelated to the device or the spinal fusion procedure. Fusion rate at 2 years for the tantalum device was very low as compared with the control arm (44% vs. 100%). Patient Neck Disability Index scores, Short Form-36 scores, and neurological status scores were similar between the 3 treatment groups. CONCLUSIONS: This study demonstrates that stand-alone porous tantalum material is not ideal for a cervical spine interbody fusion because of the low rate of arthrodesis and the risk of device fragmentation in patients who fail to fuse. PMID- 22198324 TI - Do multilevel Ponte osteotomies in thoracic idiopathic scoliosis surgery improve curve correction and restore thoracic kyphosis? AB - BACKGROUND: To compare the routine use of posterior-based (Ponte) osteotomies to complete inferior facetectomies in thoracic idiopathic scoliosis. Hypokyphosis is common in thoracic adolescent idiopathic scoliosis. The use of pedicle screw fixation in deformity correction can exacerbate this hypokyphosis. We hypothesized that by utilizing posterior-based Ponte osteotomies rather than facetectomies, we could improve coronal plane correction and decrease the loss of kyphosis during curve correction. METHODS: The radiographs and clinical charts of patients with idiopathic scoliosis (Lenke types I, II) who underwent isolated thoracic posterior spinal fusion utilizing primarily pedicle screw constructs from January 2008 to August 2010 were reviewed. Maximum preoperative Cobb angle, thoracic kyphosis (T5-T12), levels instrumented, number of posterior-based osteotomies, operative time, estimated blood loss, and postoperative residual coronal Cobb angle and kyphosis were recorded. Operative time per level, blood loss per level, percent main curve correction, and change in thoracic kyphosis was calculated. Patients having undergone complete inferior facetectomies and those with multilevel Ponte osteotomies were then compared. RESULTS: Eighteen patients underwent posterior spinal fusion with osteotomies and 19 patients had complete inferior facetectomies during this time period. The osteotomy cohort had a larger preoperative Cobb angle [59+/-10 vs. 52+/-8 (mean+/-SD); P=0.03]. No difference was observed in the preoperative kyphosis (22+/-15 vs. 25+/-12) or in levels fused (9+/-1 vs. 8+/-1). Patients with routine osteotomies had them performed at 76% of the levels instrumented. No significant difference was found in terms of percentage of coronal plane correction (84% in both groups), average postoperative kyphosis 28+/-8 versus 25+/-7, or the change in kyphosis 6+/-14 versus 0+/-2 degrees, in the osteotomy and the facetectomy groups, respectively. Estimated blood loss per level was significantly higher in the osteotomy group (97+/-42 mL vs. 66+/-25 mL; P=0.01) as was time per level 31+/-5 versus 23+/-3 minutes/level (P<0.001). CONCLUSIONS: This study shows a significantly higher blood loss and operative time associated with the use of routine posterior osteotomies in the thoracic spine without a significant improvement in coronal or sagittal correction. PMID- 22198326 TI - Heterogeneous vascular responses to hypoxic forearm exercise in young and older adults. AB - We aimed to assess age-related differences in compensatory hypoxic vasodilation during moderate-to-high dynamic exercise at absolute workloads. We hypothesized healthy older adults (n = 12, 61 +/- 1 years) would exhibit impaired hypoxic vasodilation at a moderate absolute workload, and this effect would be exaggerated at a higher workload when compared to young adults (n = 17, 27 +/- 2 years). Forearm blood flow (FBF) was measured with Doppler ultrasound. Dynamic forearm exercise (20 contractions/min) was completed at two absolute workloads (8 and 12 kg) under normoxic (0.21 FiO2, ~98% SpO2) and isocapnic hypoxic (~0.10 FiO2, 80% SpO2) conditions performed in random order. FBF was normalized as forearm vascular conductance (FBF / mean arterial blood pressure = FVC) to control for differences in blood pressure and to assess vasodilation. FVC increased with exercise and hypoxia (main effects, p < 0.05); vascular responses were not different between young and older adults (interaction effect exercise * group p = 0.37 and hypoxia * group p = 0.96). Results were confirmed when analyzed as either an absolute or relative change in FVC (DeltaFVC and %DeltaFVC, respectively). Although group responses to hypoxia were not different, individual results were highly variable (i.e., some adults constricted and others dilated to hypoxia). These data suggest (1) compensatory hypoxic vasodilation in older adults is not impaired during forearm exercise at both moderate and higher absolute exercise intensities, and (2) vascular responses to hypoxia are heterogeneous in both young and older adults. Results suggest unique individual differences exist in factors regulating vascular responses to hypoxia. PMID- 22198327 TI - Complications of delayed cranial repair after decompressive craniectomy in children less than 1 year old. AB - BACKGROUND: Decompressive craniectomy is an effective treatment option in case of refractory intracranial hypertension after severe head injury. The incidence of complications following cranial repair after decompressive craniectomy for traumatic brain injury is not negligible, particularly in infants and young toddlers. However, only a few dedicated papers can be found in the literature. METHOD: We describe the complications observed in two boys and one girl under 1 year of age that were treated in the last decade by hemicranial decompressive craniotomy and enlarging hemispheric duraplasty, and subsequent cranial repair by means of autologous bone-flap replacement. FINDINGS: Despite good clinical and neurological outcome, the postoperative clinical course was complicated in all cases by early or late evidence of subdural fluid collections associated to the occurrence of hydrocephalus and causing recurrent dislocation and progressive resorption of the autologous bone flap. CONCLUSIONS: Infants less than 1 year old, undergoing decompressive craniectomy after traumatic brain injury, experience a high rate of complications following subsequent cranial repair. Subdural collections and resorption of the autologous bone flap are to be considered as extremely common complications. PMID- 22198325 TI - Genetic diversity in Treponema pallidum: implications for pathogenesis, evolution and molecular diagnostics of syphilis and yaws. AB - Pathogenic uncultivable treponemes, similar to syphilis-causing Treponema pallidum subspecies pallidum, include T. pallidum ssp. pertenue, T. pallidum ssp. endemicum and Treponema carateum, which cause yaws, bejel and pinta, respectively. Genetic analyses of these pathogens revealed striking similarity among these bacteria and also a high degree of similarity to the rabbit pathogen, Treponema paraluiscuniculi, a treponeme not infectious to humans. Genome comparisons between pallidum and non-pallidum treponemes revealed genes with potential involvement in human infectivity, whereas comparisons between pallidum and pertenue treponemes identified genes possibly involved in the high invasivity of syphilis treponemes. Genetic variability within syphilis strains is considered as the basis of syphilis molecular epidemiology with potential to detect more virulent strains, whereas genetic variability within a single strain is related to its ability to elude the immune system of the host. Genome analyses also shed light on treponemal evolution and on chromosomal targets for molecular diagnostics of treponemal infections. PMID- 22198328 TI - Recommended protocol for the Syrian hamster embryo (SHE) cell transformation assay. AB - The Syrian hamster embryo (SHE) cell transformation assay (CTA) is a short-term in vitro assay recommended as an alternative method for testing the carcinogenic potential of chemicals. SHE cells are "normal" cells since they are diploid, genetically stable, non-tumourigenic, and have metabolic capabilities for the activation of some classes of carcinogens. The CTA, first developed in the 1960s by Berwald and Sachs (1963,1964) [3,4], is based on the change of the phenotypic feature of cell colonies expressing the first steps of the conversion of normal to neoplastic-like cells with oncogenic properties. Pienta et al. (1977) [22] developed a protocol using cryopreserved cells to enhance practicality of the assay and limit sources of variability. Several variants of the assay are currently in use, which mainly differ by the pH at which the assay is performed. We present here the common version of the SHE pH 6.7 CTA and SHE pH 7.0 CTA protocols used in the ECVAM (European Centre for the Validation of Alternative Methods) prevalidation study on CTA reported in this issue. It is recommended that this protocol, in combination with the photo catalogues presented in this issue, should be used in the future and serve as a basis for the development of the OECD test guideline. PMID- 22198329 TI - Induction of oxidative stress, DNA damage and apoptosis in mouse liver after sub acute oral exposure to zinc oxide nanoparticles. AB - Zinc oxide (ZnO) nanoparticles are finding applications in a wide range of products including cosmetics, food packaging, imaging, etc. This increases the likelihood of human exposure to these nanoparticles through dermal, inhalation and oral routes. Presently, the majority of the studies concerning ZnO nanoparticle toxicity have been conducted using in vitro systems which lack the complex cell-cell, cell-matrix interactions and hormonal effects found in the in vivo scenario. The present in vivo study in mice was aimed at investigating the oral toxicity of ZnO nanoparticles. Our results showed a significant accumulation of nanoparticles in the liver leading to cellular injury after sub-acute oral exposure of ZnO nanoparticles (300 mg/kg) for 14 consecutive days. This was evident by the elevated alanine aminotransferase (ALT) and alkaline phosphatase (ALP) serum levels and pathological lesions in the liver. ZnO nanoparticles were also found to induce oxidative stress indicated by an increase in lipid peroxidation. The DNA damage in the liver and kidney cells of mice was evaluated by the Fpg-modified Comet assay which revealed a significant (p<0.05) increase in the Fpg-specific DNA lesions in liver indicating oxidative stress as the cause of DNA damage. The TUNEL assay revealed an induction of apoptosis in the liver of mice exposed to ZnO nanoparticles compared to the control. Our results conclusively demonstrate that sub-acute oral exposure to ZnO nanoparticles in mice leads to an accumulation of nanoparticles in the liver causing oxidative stress mediated DNA damage and apoptosis. These results also suggest the need for a complete risk assessment of any new engineered nanoparticle before its arrival into the consumer market. PMID- 22198330 TI - Environmental polycyclic aromatic hydrocarbon (PAH) exposure and DNA damage in Mexican children. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants presenting a public health risk, particularly to children, a vulnerable population. PAHs have genotoxic and carcinogenic properties, which depend on their metabolism. Many enzymes involved in PAH metabolism, including CYP1A1, CYP1B1, GSTM and GSTT are polymorphic, which may modulate the activation/deactivation of these compounds. We evaluated PAH exposure and DNA damage in children living in the vicinity of the main petrochemical complex located in the Gulf of Mexico, and explored the modulation by genetic polymorphisms of PAH excretion and related DNA damage. The participants (n=82) were children aged 6-10y attending schools near the industrial area. Urinary 1-hydroxypyrene (1-OHP; a biomarker of PAH exposure) was determined by reverse-phase-HPLC; DNA damage by the comet assay (Olive Tail Moment (OTM) parameter); CYP1A1*2C and CYP1B1*3 polymorphisms by real time-PCR; and GSTM1*0 and GSTT1*0 by multiplex PCR. The median value of 1-OHP was 0.37MUmol/mol creatinine; 59% of children had higher 1-OHP concentrations than those reported in environmentally exposed adults (0.24MUmol/mol creatinine). A stratified analysis showed increased DNA damage in children with 1-OHP concentrations greater than the median value. We observed higher 1-OHP concentrations in children with CYP1A1*2C or GSTM1*0 polymorphisms, and a positive influence of CYP1A1*2C on OTM values in children with the highest PAH exposure. The data indicate that children living in the surroundings of petrochemical industrial areas are exposed to high PAH levels, contributing to DNA damage and suggesting an increased health risk; furthermore, data suggest that polymorphisms affecting activation enzymes may modulate PAH metabolism and toxicity. PMID- 22198331 TI - Prevalidation study of the BALB/c 3T3 cell transformation assay for assessment of carcinogenic potential of chemicals. AB - The cell transformation assays (CTAs) have attracted attention within the field of alternative methods due to their potential to reduce the number of animal experiments in the field of carcinogenicity. The CTA using BALB/c 3T3 cells has proved to be able to respond to chemical carcinogens by inducing morphologically transformed foci. Although a considerable amount of data on the performance of the assay has been collected, a formal evaluation focusing particularly on reproducibility, and a standardised protocol were considered important. Therefore the European Centre for the Validation of Alternative Methods (ECVAM) decided to coordinate a prevalidation study of the BALB/c 3T3 CTA. Three different laboratories from Japan and Europe participated. In the study the following modules were assessed stepwise: test definition (Module 1) consisted of the standardisation of the protocol, the selection of the cell lineage, and the preparation of a photo catalogue on the transformed foci. The within-laboratory reproducibility (Module 2) and the transferability (Module 3) were assessed using non-coded and coded 3-methylcholanthrene. Then, five coded chemicals were tested for the assessment of between-laboratory reproducibility (Module 4). All three laboratories obtained positive results with benzo[a]pyrene, phenanthrene and o toluidine HCl. 2-Acetylaminofluorene was positive in two laboratories and equivocal in one laboratory. Anthracene was negative in all three laboratories. The chemicals except phenanthrene, which is classified by IARC (http://monographs.iarc.fr) as group 3 "not classifiable as to its carcinogenicity to human", were correctly predicted as carcinogens. Further studies on phenanthrene will clarify this discrepancy. Thus, although only a few chemicals were tested, it can be seen that the predictive capacity of the BALB/c 3T3 CTA is satisfactory. On the basis of the outcome of this study, an improved protocol, incorporating some changes related to data interpretation, has been developed. It is recommended that this protocol be used in the future to provide more data that may confirm the robustness of this protocol and the performance of the assay itself. During the study it became clear that selecting the most appropriate concentrations for the transformation assay is crucial. PMID- 22198332 TI - Functional analysis of two lebocin-related proteins from Manduca sexta. AB - Insects produce a group of antimicrobial peptides (AMPs) in response to microbial infections. Most AMPs are synthesized as inactive precursors/pro-proteins and require proteolytic processing to generate small active peptides. Here we report identification and functional analysis of two lebocin-related proteins (Leb-B and Leb-C) from the tobacco hornworm, Manduca sexta. The mRNA levels of Leb-B and Leb C increased significantly in larval fat body and hemocytes after injection of Escherichia coli, Micrococcus luteus and Saccharomyces cerevisiae. Western blotting using rabbit polyclonal antibody to Leb-B showed accumulation of large protein(s) and small peptide(s) in larval hemolymph after microbial injection. This result and the presence of RXXR motifs in the deduced amino acid sequences led to our postulation that Leb-B/C may be inactive precursors that are processed in larval hemolymph to generate short active peptides. To test this hypothesis, we expressed and purified full-length and various fragments of Leb-B and Leb-C as thioredoxin (TRX) fusion proteins. We found that fusion proteins could be cleaved by induced larval plasma, and the cleavage sites were determined by protein sequencing. Antibacterial activity of peptide fragments was also verified using synthetic peptides, and active M. sexta lebocin peptides were located at the N termini of Leb-B/C, which are different from Bombyx mori lebocins 1-4 that are located close to the C-termini. In addition, we found that synthetic Leb-B(22-48) peptide not only had higher antibacterial activity but also caused agglutination of E. coli cells. Our results provide valuable information for studying processing of lebocin precursors in lepidopteran insects. PMID- 22198333 TI - The entomopathogenic fungus Beauveria bassiana activate toll and JAK-STAT pathway controlled effector genes and anti-dengue activity in Aedes aegypti. AB - Here we investigated the effect of Beauveria bassiana infection on the survival of Aedes aegypti mosquitoes and the modulation of their susceptibility to dengue virus infection. Application of B. bassiana caused a reduction in the life span of A. aegypti and hindered dengue virus replication in the mosquito midgut. Fungus infection induced the expression a variety anti-microbial and dengue virus restriction factor genes. Transient reverse genetic analyses showed that the JAK STAT pathway is implicated anti-fungal defense of Aedes mosquitoes. Our data suggest that this B. bassiana-mediated anti-dengue activity is likely to be at least partly indirectly mediated through the activation of the mosquito's anti dengue Toll and JAK-STAT pathways. PMID- 22198334 TI - Enhanced expression of stress-responsive cytokine-like gene retards insect larval growth. AB - Growth rates of immature animals are governed by their feeding activities. A reduction in feeding sometimes causes serious growth retardation in insects; a typical case is often seen in host insects parasitized by a solitary endoparasitoid wasp. However, understanding of the mechanisms underlying the physiological repression of parasitized insects is fragmentary. Here we analyzed brain gene expression of the host common cutworm, Spodoptera litura, parasitized by a solitary endoparasitoid, Microplitis manilae, and identified a novel gene whose expression was significantly enhanced by parasitization. The gene encoded a pre-pro-peptide of a cytokine-like molecule and its expression was observed mainly in nervous tissues, hemocytes, and integuments. The 25 amino acid cytokine like peptide encoded by the C-terminus of this gene was demonstrated to exist in the hemolymph of S. litura larvae and to change hemocytes from non-adhesive to adhesive in vitro. Further, injection of the active peptide reduced feeding activities of test larvae and consequently delayed their growth. The enhanced gene expression was also observed in larvae under severe stress conditions: abdominal ligature, proleg cutting, mechanical vibration, low temperature, and heat shock at 45 degrees C. Elevated gene expression was maintained only in seriously growth-retarded larvae but not in recovered larvae at 24h or 48h after heat treatment. Thus, it is reasonable to conclude that stress-induced elevation of the peptide gene expression highly correlates with reduced feeding activities and growth retardation of the host larvae parasitized by M. manilae. Based on the conclusion, we named this peptide stress-responsive peptide (SRP). PMID- 22198335 TI - Minimally modified LDL upregulates endothelin type B receptors in rat basilar artery. AB - Minimally modified low density lipoprotein (mmLDL) is a well-known risk factor for cerebral vascular diseases and upregulation of endothelin type B (ET(B)) receptors plays key roles in the pathogenesis. The present study was designed to examine if mmLDL upregulated endothelin ET(B) receptors in basilar artery and its possible intracellular signaling molecular mechanisms. Rat basilar arteries were cultured for 24h in the presence of mmLDL with specific inhibitors. The artery contractile responses and receptor expressions of mRNA and protein were investigated using myograph system, real-time PCR and Western blot techniques, respectively. Results showed that ET(B) receptor agonist, sarafotoxin 6c induced a weak contraction in fresh basilar artery segments. After organ culture the contraction curve mediated by ET(B) receptor was shifted towards the left with an increased E(max) of 88 +/- 6%. The mmLDL 10 MUg/mL further shifted the concentration-contractile curves towards the left with an increased E(max) of 116 +/- 12%. The organ culture significantly increased ET(B) receptor mRNA and protein levels from fresh arteries, which was further enhanced by mmLDL. The staurosporine (PKC inhibitor), both SB386023 and U0126 (extracellular signal related kinases 1 and 2 inhibitor), and wedelolactone (NF-kappaB inhibitor) almost totally abolished organ culture-increased and mmLDL-increased contraction and expressions of endothelin ET(B) receptor. SP600125 (C-jun terminal kinase inhibitor) and SB203580 (p38 inhibitor) attenuated both organ cultured-induced and mmLDL-induced upregulation of endothelin ET(B) receptors. In conclusion, mmLDL upregulates ET(B) receptors of cerebral basilar artery via the PKC, MAPK and NF-kappaB signal pathways. PMID- 22198336 TI - Effects of SCR-3 on the immunosuppression accompanied with the systemic inflammatory response syndrome. AB - Steroid receptor coactivator-3 (SRC-3) is a multifunctional protein that plays an important role in mammary gland growth, development, and tumorigenesis. In this study, SCR-3 gene knockout mice were used to study the effects of SCR-3 on the immunosuppression accompanied with systemic inflammatory response syndrome (SIRS). Bacterial clearance assay was performed by blood culture and frozen sections, and the results showed that the absence of SCR-3 protein serious damaged the innate immune system and the body's ability to inactivate or phagocytosis of bacteria was significantly decreased, and the absence of SCR-3 protein also weakened phagocytes' ability to degrade bacteria and their metabolites. Furthermore, animal model of inflammatory reaction was established and the immune function was determined, and the results revealed that SRC-3 protein may play an important role in maintenance of T-cells' immune function, and severe T-cell immune function disorder would be resulted once SRC-3 protein is missing. In addition, the results of our study showed the steady-state of lymphocyte subsets was destroyed after SIRS, leading the suppression of cellular immune function, and the absence of SCR-3 protein may aggravate the suppression of T-lymphocyte function. Therefore, the present study demonstrated that the absence of SCR-3 protein would aggravate immunosuppression. In addition, SRC-3 protein is a significant regulator of infection and inflammation, and SRC-3 protein play an essential role in the development of immunosuppression accompanied with SIRS. PMID- 22198337 TI - De novo characterization of the antler tip of Chinese Sika deer transcriptome and analysis of gene expression related to rapid growth. AB - Deer antlers are well known for their regeneration and rapid growth. However, little is known about the genes that are involved in their development, especially the molecular mechanisms responsible for rapid growth. In the present study, we produced more than 41 million sequencing reads using the Illumina sequencing platform. These reads were assembled into 89,001 unique sequences (mean size: 450 bp), representing more than 58 times as many Sika deer sequences previously available in the NCBI database (as of Sep 15, 2011). Based on a similarity search with known proteins, we identified 40,088 sequences with a cut off E value of 10(-5). Assembled sequences were then annotated using Gene ontology terms, Clusters of Orthologous Groups classifications, and Kyoto Encyclopedia of Genes and Genomes pathways. In addition, we found a number of highly expressed genes involved in the regulation of Sika deer antler rapid growth, including transcription factors, signaling molecules, and extracellular matrix proteins. Our data represent the most comprehensive sequence resource available for the deer antler and provide a basis for new research on deer antler molecular genetics and functional genomics. PMID- 22198338 TI - A phase I study of concurrent weekly topotecan and cisplatin chemotherapy with whole pelvic radiation therapy in locally advanced cervical cancer: a gynecologic oncology group study. AB - PURPOSE: To determine the maximum tolerated dose (MTD) and acute dose-limiting toxicities (DLT) of intravenous topotecan administered with weekly cisplatin during pelvic radiation therapy in patients with locally advanced cervical cancer. METHODS: Patients were treated at one of two dose levels receiving intravenous topotecan at 0.5mg/m(2) and cisplatin at either 30 or 40 mg/m(2) given weekly for 6 weeks concurrently with pelvic radiation and intracavitary brachytherapy. The primary endpoint for the escalation study was acute dose limiting toxicities occurring within 30 days of completing radiation therapy. RESULTS: Eleven patients were enrolled. Dose-limiting toxicity consisting of Grade 3 nausea and vomiting lasting >24h in one patient and grade 3 febrile neutropenia in another patient occurred at the first dose level of weekly topotecan 0.5mg/m(2) and cisplatin 40 mg/m(2). This necessitated de-escalation to weekly cisplatin 30 mg/m(2) in combination with topotecan 0.5mg/m(2) and pelvic radiation. This dose level was tolerable in 6 evaluable patients with only one DLT consisting of grade 4 thrombocytopenia, grade 3 abdominal pain and grade 3 elevated gamma glutamyl transpeptidase (GGT). CONCLUSIONS: In women with locally advanced cervical cancer, intravenous topotecan 0.5mg/m(2) and cisplatin 30 mg/m(2) given weekly for 6 weeks with concurrent pelvic radiation and intracavitary brachytherapy were tolerable. Further expansion of the feasibility cohort of this study was suspended based on the results of a phase 3 trial comparing the efficacy of platinum combinations in advanced and recurrent cervical cancer. PMID- 22198339 TI - Intensity-modulated radiation therapy for advanced cervical cancer: a comparison of dosimetric and clinical outcomes with conventional radiotherapy. AB - OBJECTIVE: The aim of this study is to evaluate the dosimetry, efficacy and toxicity of reduced field intensity-modulated radiation therapy (RF-IMRT) for patients with advanced cervical cancer. METHODS: From August 2005 to August 2010, 60 patients with stage IIB-IIIB cervical cancer underwent reduced field IMRT (RF IMRT group) and 62 patients treated with conventional radiotherapy (c-RT group) were enrolled. The RF-IMRT plans were as follows: whole pelvic IMRT plan was performed to deliver a dose of 30Gy firstly, then the irradiated volume was reduced to lymphatic drainage region as well as paracervix and parametrium for an additional 30Gy boost. Intracavitary brachytherapy and concurrent chemotherapy were performed during external irradiation. The tumor coverage and normal tissue avoidance were evaluated. Treatment response, toxicities and survival were assessed. RESULTS: The mean dose delivered to the planning target volume was significantly higher in RF-IMRT group than in c-RT group (61.5 vs. 50.8Gy, P=0.046). IMRT plans yielded better dose conformity to the target and better sparing of the rectal, bladder and small intestine. The RF-IMRT patients experienced significantly lower acute and chronic toxicities with comparable short-term effects than did those treated with conventional RT (CR: 87.7% vs. 88.3%, P=0.496; PR: 7.0% vs. 6.7%, P=0.440). No significant differences were found between treatment groups for 1year, 3year, and 5year overall survival (OS) levels, although the latter approached statistical significance in favor of IMRT, while a significantly higher progression-free survival (PFS; P=0.031) was seen for IMRT. CONCLUSIONS: RF-IMRT yields improved dose distributions, with lower toxicities, while providing comparable clinical outcomes. The increased PFS may be an advantage. PMID- 22198340 TI - Tumor budding and E-Cadherin expression in endometrial carcinoma: are they prognostic factors in endometrial cancer? AB - OBJECTIVE: To evaluate the prognostic value of tumor budding (TB) in endometrioid (EEC) and non-endometrioid endometrial cancers (NEEC) and to determine its correlation with expression of E-cadherin. METHODS: Ninety-five patients with primary endometrial carcinoma were examined statistically. All patients were diagnosed, treated, and given follow-up care at Dokuz Eylul University Faculty of Medicine. Tumor budding detected by either H&E-stained sections and anticytokeratin-staining C11. The tissue block with the largest invasive front was chosen for budding counting and immunostaining. E-cadherin expression was examined by immunohistochemistry using the primary antibodies against to it. RESULTS: Tumor budding was low-grade in 73 and high-grade in 22 cases. E-cadherin expression loss was identified in 48 patients. The high-grade TB was significantly higher in patients with advanced stage and deep myometrial invasion (p=0.032 and 0.018, respectively). E-Cadherin expression was significantly lower in NEECs than EECs (p=0.032). The negative expression of E-cadherin was associated with advanced stage and poor differentiation (p=0.001 and p=0.024, respectively). We determined that tumor budding adversely correlated with the presence of E-cadherin expression but not statistically significant. Based on the results of multivariate analysis, TB has an independent impact on cumulative overall survival. We found no statistically significant difference between E cadherin expression and survival. CONCLUSIONS: TB is associated with undifferentiated tumor, advanced stage and decreased postoperative survival in endometrial cancer. It might be a valuable prognostic clinicopathologic factor which can be applicable in routine examination. PMID- 22198341 TI - HHblits: lightning-fast iterative protein sequence searching by HMM-HMM alignment. AB - Sequence-based protein function and structure prediction depends crucially on sequence-search sensitivity and accuracy of the resulting sequence alignments. We present an open-source, general-purpose tool that represents both query and database sequences by profile hidden Markov models (HMMs): 'HMM-HMM-based lightning-fast iterative sequence search' (HHblits; http://toolkit.genzentrum.lmu.de/hhblits/). Compared to the sequence-search tool PSI-BLAST, HHblits is faster owing to its discretized-profile prefilter, has 50 100% higher sensitivity and generates more accurate alignments. PMID- 22198342 TI - Visualizing adenosine-to-inosine RNA editing in the Drosophila nervous system. AB - Informational recoding by adenosine-to-inosine RNA editing diversifies neuronal proteomes by chemically modifying structured mRNAs. However, techniques for analyzing editing activity on substrates in defined neurons in vivo are lacking. Guided by comparative genomics, here we reverse-engineered a fluorescent reporter sensitive to Drosophila melanogaster adenosine deaminase that acts on RNA (dADAR) activity and alterations in dADAR autoregulation. Using this artificial dADAR substrate, we visualized variable patterns of RNA-editing activity in the Drosophila nervous system between individuals. Our results demonstrate the feasibility of structurally mimicking ADAR substrates as a method to regulate protein expression and, potentially, therapeutically repair mutant mRNAs. Our data suggest variable RNA editing as a credible molecular mechanism for mediating individual-to-individual variation in neuronal physiology and behavior. PMID- 22198343 TI - Silencing of nicotinamide nucleotide transhydrogenase impairs cellular redox homeostasis and energy metabolism in PC12 cells. AB - Mitochondrial NADPH generation is largely dependent on the inner-membrane nicotinamide nucleotide transhydrogenase (NNT), which catalyzes the reduction of NADP(+) to NADPH utilizing the proton gradient as the driving force and NADH as the electron donor. Small interfering RNA (siRNA) silencing of NNT in PC12 cells results in decreased cellular NADPH levels, altered redox status of the cell in terms of decreased GSH/GSSG ratios and increased H(2)O(2) levels, thus leading to an increased redox potential (a more oxidized redox state). NNT knockdown results in a decrease of oxidative phosphorylation while anaerobic glycolysis levels remain unchanged. Decreased oxidative phosphorylation was associated with a) inhibition of mitochondrial pyruvate dehydrogenase (PDH) and succinyl-CoA:3 oxoacid CoA transferase (SCOT) activity; b) reduction of NADH availability, c) decline of mitochondrial membrane potential, and d) decrease of ATP levels. Moreover, the alteration of redox status actually precedes the impairment of mitochondrial bioenergetics. A possible mechanism could be that the activation of the redox-sensitive c-Jun N-terminal kinase (JNK) and its translocation to the mitochondrion leads to the inhibition of PDH (upon phosphorylation) and induction of intrinsic apoptosis, resulting in decreased cell viability. This study supports the notion that oxidized cellular redox state and decline in cellular bioenergetics - as a consequence of NNT knockdown - cannot be viewed as independent events, but rather as an interdependent relationship coordinated by the mitochondrial energy-redox axis. Disruption of electron flux from fuel substrates to redox components due to NNT suppression induces not only mitochondrial dysfunction but also cellular disorders through redox-sensitive signaling. PMID- 22198345 TI - Synergism between fentanyl and tramadol in tonic inflammatory pain: the orofacial formalin test. AB - Opioids have been used for long time to management of pain, the coadministration of two opioids may induce synergism. The present study was conducted to determine the antinociceptive interaction between the dual mechanism of action of tramadol compared to the main of fentanyl antinociception in the orofacial formalin which represents a model of persistent cutaneous nociception in the region innervated by the trigeminal nerve. The i.p. administration of tramadol and fentanyl induced a dose-dependent antinociception with an ED(50) of 2.97 +/- 0.32 mg/kg for phase I and 1.79 +/- 0.30 mg/kg for phase II and 0.062 +/- 0.0040 mg/kg in phase I and 0.041 +/- 0.0039 mg/kg in phase II, respectively. The coadministration of fentanyl with tramadol induced synergism in both phases of the test with an interaction index of 0.343 and 0.163 for phase I and phase II, respectively. This finding could be explained by the more complex pharmacology of tramadol compared to fentanyl. PMID- 22198344 TI - Pathophysiology of the cardiac late Na current and its potential as a drug target. AB - A pathological increase in the late component of the cardiac Na(+) current, I(NaL), has been linked to disease manifestation in inherited and acquired cardiac diseases including the long QT variant 3 (LQT3) syndrome and heart failure. Disruption in I(NaL) leads to action potential prolongation, disruption of normal cellular repolarization, development of arrhythmia triggers, and propensity to ventricular arrhythmia. Attempts to treat arrhythmogenic sequelae from inherited and acquired syndromes pharmacologically with common Na(+) channel blockers (e.g. flecainide, lidocaine, and amiodarone) have been largely unsuccessful. This is due to drug toxicity and the failure of most current drugs to discriminate between the peak current component, chiefly responsible for single cell excitability and propagation in coupled tissue, and the late component (I(NaL)) of the Na(+) current. Although small in magnitude as compared to the peak Na(+) current (~1-3%), I(NaL) alters action potential properties and increases Na(+) loading in cardiac cells. With the increasing recognition that multiple cardiac pathological conditions share phenotypic manifestations of I(NaL) upregulation, there has been renewed interest in specific pharmacological inhibition of I(Na). The novel antianginal agent ranolazine, which shows a marked selectivity for late versus peak Na(+) current, may represent a novel drug archetype for targeted reduction of I(NaL). This article aims to review common pathophysiological mechanisms leading to enhanced I(NaL) in LQT3 and heart failure as prototypical disease conditions. Also reviewed are promising therapeutic strategies tailored to alter the molecular mechanisms underlying I(Na) mediated arrhythmia triggers. PMID- 22198346 TI - [Advanced endometrial carcinoma: primary debulking surgery or neoadjuvant chemotherapy?]. AB - Endometrial cancers with peritoneal spread are stage IVB of FIGO classification. Their pattern is similar to that of ovarian cancer. Optimal debulking surgery and chemotherapy are predictor of better overall and disease free survival. Despite the poor outcome, there is a need for new treatment options. Recommended management for this group of patients should consist of surgical cytoreduction followed by chemotherapy. There may be a role for neoadjuvant chemotherapy followed by interval surgery in selected subgroups of patients. PMID- 22198347 TI - Isolation and functional characterization of polyunsaturated fatty acid elongase (AsELOVL5) gene from black seabream (Acanthopagrus schlegelii). AB - To identify the genes encoding fatty acid elongases for the biosynthesis of polyunsaturated fatty acids (PUFAs), we isolated a cDNA via degenerate PCR and RACE-PCR from Acanthopagrus schlegelii with a high similarity to the ELOVL5-like elongases of mammals and fishes. This gene is termed AsELOVL5 and encodes a 294 amino acid protein. When AsELOVL5 was expressed in Saccharomyces cerevisiae, it conferred an ability to elongate gamma-linolenic acid (18:3 n-6) to di-homo-gamma linolenic acid (20:3 n-6). In addition, the transformed cells converted arachidonic acid (20:4 n-6) and eicosapentaenpic acid (20:5 n-3) to docosatetraenoic acid (22:4 n-6) and docosapentaenoic acid (22:5 n-3), respectively. These results indicate that the AsELOVL5 gene encodes a long-chain fatty acid elongase capable of elongating C(18)Delta6/C(20)Delta5 but not C(22) PUFA substrates. PMID- 22198348 TI - Wound healing by a 3.2 kDa recombinant polypeptide from velvet antler of Cervus nippon Temminck. AB - Velvet antler (VA) is used in traditional Chinese medicine to treat a wide range of ailments including the enhancement of wound healing. A 3.2 kDa recombinant polypeptide of VA from sika deer was purified and compared to native polypeptides stimulation growth of NIH3T3 cells. Both stimulated growth in a dose-dependent manner (10-100 MUg/ml). To study its wound healing properties, burn-wounded rats were topically administered with recombinant VA polypeptide or native polypeptide. Rats treated with 0.05 and 0.1% (w/w) polypeptides exhibited significant wound healing. As the yield of recombinant polypeptide was 40-fold higher than that of the native polypeptide, it may therefore be a useful biopharmaceutical. PMID- 22198349 TI - Re: Christian H, Eik V, Juergen M, et al. Actual and predicted survival time of patients with spinal metastases of lung cancer: evaluation of the robustness of the Tokuhashi score. Spine 2011;36:983-9. PMID- 22198350 TI - Measurements of surgeons' exposure to ionizing radiation dose during intraoperative use of C-arm fluoroscopy. AB - STUDY DESIGN: Measurement of radiation dose from C-arm fluoroscopy during a simulated intraoperative use in spine surgery. OBJECTIVE.: To investigate scatter radiation doses to specific organs of surgeons during intraoperative use of C-arm fluoroscopy in spine surgery and to provide practical intraoperative guidelines. SUMMARY OF BACKGROUND DATA: There have been studies that reported the radiation dose of C-arm fluoroscopy in various procedures. However, radiation doses to surgeons' specific organs during spine surgery have not been sufficiently examined, and the practical intraoperative radioprotective guidelines have not been suggested. METHODS: Scatter radiation dose (air kerma rate) was measured during the use of a C-arm on an anthropomorphic chest phantom on an operating table. Then, a whole body anthropomorphic phantom was located besides the chest phantom to simulate a surgeon, and scatter radiation doses to specific organs (eye, thyroid, breast, and gonads) and direct radiation dose to the surgeon's hand were measured using 4 C-arm configurations (standard, inverted, translateral, and tube translateral). The effects of rotating the surgeon's head away from the patient and of a thyroid shield were also evaluated. RESULTS: Scatter radiation doses decreased as distance from the patient increased during C arm fluoroscopy use. The standard and translateral C-arm configurations caused lower scatter doses to sensitive organs than inverted and tube translateral configurations. Scatter doses were highest for breast and lowest for gonads. The use of a thyroid shield and rotating the surgeon's head away from the patient reduced scatter radiation dose to the surgeon's thyroid and eyes. The direct radiation dose was at least 20 times greater than scatter doses to sensitive organs. CONCLUSION: The following factors could reduce radiation exposure during intraoperative use of C-arm; (1) distance from the patient, (2) C-arm configuration, (3) radioprotective equipments, (4) rotating the surgeons' eyes away from the patient, and (5) avoiding direct exposure of surgeons' hands. PMID- 22198351 TI - To the Editor, Spine. PMID- 22198353 TI - Effect of graded facetectomy on biomechanics of Dynesys dynamic stabilization system. AB - STUDY DESIGN: Finite element (FE) method was used to compare the biomechanics of L3-S1 lumbar spine with graded facetectomy before and after placement of Dynesys. OBJECTIVE: To evaluate the biomechanics of Dynesys as a function of graded bilateral facetectomies. SUMMARY OF BACKGROUND DATA: Spinal fusion or posterior dynamic stabilization systems are used to restore stability after facetectomies. METHODS: The intact FE spine was modified to simulate decompression at L4-L5 with 50% and 75% and total facetectomy with/without dynamic stabilization with Dynesys. Biomechanics of the implanted level was investigated under different physiological loadings. RESULTS: Total facetectomy increased the motion in extension (8.7 degrees vs. 2.7 degrees for intact) and axial rotation (8.4 degrees vs. 2.4 degrees for intact). However the decrease in motion in the Dynesys model ranged from 65% in axial rotation to 80% in flexion for all facetectomies, except in the total facetectomy axial rotation case (motion higher than intact). The center of rotation of dynamic stabilized segment moved inferior/posterior in partial facetectomy and superior/posterior in total facetectomy with respect to the intact and destabilized cases. The Dynesys screws observed peak stresses up to 28% higher than those of a rigid fixation system in certain loadings, such as lateral bending and extension. The critical loosening torque applied to the screws in total facetectomy case was 6 times the partial facetectomy case in axial rotation. CONCLUSION: Partial facetectomy had a minimal effect on range of motion on the Dynesys-implanted segment. However, in the case of total facetectomy the motion increased by almost 40% in flexion and by 200% in axial rotation. The higher stresses applied to the screws in Dynesys in specific loadings may lead to higher risk of screw failure in Dynesys than in a generic rigid fixation construct. PMID- 22198354 TI - The overexpression of acetylcholinesterase compensates for the reduced catalytic activity caused by resistance-conferring mutations in Tetranychus urticae. AB - The mutations (G228S, A391T and F439W) and duplication of the acetylcholinesterase (AChE) gene (Tuace) are involved in monocrotophos resistance in the two-spotted spider mites, Tetranychus urticae (Kwon et al., 2010a, b). The overexpression of T. urticae AChE (TuAChE) as a result of Tuace duplication was confirmed in several field-collected populations by Western blotting using an AChE-specific antibody. To investigate the effects of each mutation on the insensitivity and fitness cost of AChE, eight variants of TuAChE were expressed in vitro using the baculovirus expression system. Kinetic analysis revealed that the G228S and F439W mutations confer approximately 26-fold and 99-fold increases in the insensitivity to monocrotophos, respectively, whereas the insensitivity increased over 1165-fold in the AChE with double mutations. Nevertheless, the presence of these mutations reduced the catalytic efficiency of AChE significantly. In particular, the TuAChE having both mutations together exhibited a 17.8~27.1-fold reduced catalytic efficiency, suggesting an apparent fitness cost in the monocrotophos-resistant mites. The A391T mutation did not change the kinetic properties of either the substrate or inhibitor when present alone but mitigated the negative impacts of the F439 mutation. To simulate the catalytic activity of the overexpressed TuAChE in two T. urticae strains (approximately 6 copies for AD strain vs. 2 copies for PyriF strain), appropriate TuAChE variants were combined to make up the desired AChE copies and mutation frequencies, and their enzyme kinetics were determined. The reconstituted 6-copy and 2-copy TuAChEs exhibited catalytic efficiency levels comparable to those of a single copy wildtype TuAChE, suggesting that, if mutations are present, multiple copies of AChE are required to restore a normal level of catalytic activity in the monocrotophos-resistant mites. In summary, the present study provides clear evidence that Tuace duplication resulted in the proportional overexpression of AChE, which was necessary to compensate for the reduced catalytic activity of AChE caused by mutations. PMID- 22198356 TI - The knee adduction moment in hamstring and patellar tendon anterior cruciate ligament reconstructed knees. AB - PURPOSE: The external knee adduction moment during gait has previously been associated with knee osteoarthritis, and although it has been shown to be greater following anterior cruciate ligament (ACL) reconstruction surgery compared to a control group, it has not been compared between different graft types. Given that the incidence of radiographic knee osteoarthritis appears to be greater following patellar tendon compared to hamstring tendon ACL reconstruction, this study tested the hypothesis that the knee adduction moment would also be increased following patellar tendon ACL reconstruction. METHODS: In 48 male participants (16 patellar tendon graft, 16 hamstring graft and 16 controls), the external knee adduction moment was measured during level walking in a gait laboratory at mean of 10 months after surgery. RESULTS: There was no difference in the knee adduction moment between the hamstring and patellar tendon groups, and both patient groups had a significantly reduced knee adduction moment compared to the control group. In the hamstring group, the smaller adduction moment was associated with the patients walking with less knee varus whereas in the patellar tendon group, the smaller moment was associated with the patients walking with a decreased vertical ground reaction force. CONCLUSIONS: These results indicate that in male patients during the early stages of recovery from ACL reconstruction, the knee adduction moment is not greater than controls for either hamstring or patellar tendon graft types. Although the knee adduction moment was similar between the two graft types, the overall magnitude of the moment was influenced by different biomechanical factors. LEVEL OF EVIDENCE: III. PMID- 22198355 TI - Kinetic properties of alternatively spliced isoforms of laccase-2 from Tribolium castaneum and Anopheles gambiae. AB - Laccase-2 is a highly conserved multicopper oxidase that functions in insect cuticle pigmentation and tanning. In many species, alternative splicing gives rise to two laccase-2 isoforms. A comparison of laccase-2 sequences from three orders of insects revealed eleven positions at which there are conserved differences between the A and B isoforms. Homology modeling suggested that these eleven residues are not part of the substrate binding pocket. To determine whether the isoforms have different kinetic properties, we compared the activity of laccase-2 isoforms from Tribolium castaneum and Anopheles gambiae. We partially purified the four laccases as recombinant enzymes and analyzed their ability to oxidize a range of laccase substrates. The predicted endogenous substrates tested were dopamine, N-acetyldopamine (NADA), N-beta-alanyldopamine (NBAD) and dopa, which were detected in T. castaneum previously and in A. gambiae as part of this study. Two additional diphenols (catechol and hydroquinone) and one non-phenolic substrate (2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)) were also tested. We observed no major differences in substrate specificity between the A and B isoforms. Dopamine, NADA and NBAD were oxidized with catalytic efficiencies ranging from 51 to 550 min-1 mM-1. These results support the hypothesis that dopamine, NADA and NBAD are endogenous substrates for both isoforms of laccase-2. Catalytic efficiencies associated with dopa oxidation were low, ranging from 8 to 30 min-1 mM-1; in comparison, insect tyrosinase oxidized dopa with a catalytic efficiency of 201 min-1 mM-1. We found that dopa had the highest redox potential of the four endogenous substrates, and this property of dopa may explain its poor oxidation by laccase-2. We conclude that laccase-2 splice isoforms are likely to oxidize the same substrates in vivo, and additional experiments will be required to discover any isoform-specific functions. PMID- 22198357 TI - Trevor's disease: mimicking anterior ankle impingement syndrome: case report. AB - This report concerns an unusual cause of anterior ankle impingement. The case of a young male with Trevor's disease mimicking an anterior spur of the ankle that resulted in anterior impingement and treated with ankle arthroscopy is presented. The aim of this study is to explain the different diagnostic properties of Trevor's disease from a classic anterior spur. Level of evidence IV. PMID- 22198358 TI - Intraoperative assessment of resected condyle thickness in total knee arthroplasty. AB - PURPOSE: The purpose of this study was to assess the use of resected condyle thickness measurement, obtained with caliper, when verifying the accuracy of distal femoral bone resection in total knee arthroplasty. METHODS: Fifty-two total knee arthroplasties were performed to treat osteoarthritis with varus knee. The difference of caliper-measured thickness of resected medial and lateral femoral condyles after removal of cartilage from the lateral condyle was compared with radiographically measured values. The preoperative planned valgus cut angles and the postoperative femoral component valgus angles were compared. RESULTS: The difference of radiograph-measured thickness averaged 2.4 +/- 2.2 mm and the difference of caliper-measured thickness averaged 2.0 +/- 2.1 mm (r = 0.735, P < 0.001). The postoperative femoral component valgus angle averaged 4.8 degrees +/ 1.6 degrees (range, 2.0 degrees -7.6 degrees ). The difference between the valgus cut angle and femoral component valgus angle averaged -0.3 degrees +/- 1.5 degrees . CONCLUSIONS: The confirmation of correspondence between the caliper measured and radiographically measured thickness of resected condyles could verify the accuracy of distal femoral bone resection in total knee arthroplasty. LEVEL OF EVIDENCE: III. PMID- 22198359 TI - Rotatory knee laxity and the pivot shift. PMID- 22198360 TI - The relevance of the anatomical basis of fracture for the subsequent treatment of the anterior humeral circumflex artery and the axillary nerve. AB - PURPOSE: The purpose of this study was to determine the location of the anterior humeral circumflex artery and axillary nerve based on bony landmarks, and to provide anatomical information that enables a safe approach when treating a proximal humeral fractures. METHODS: Thirty cadavers were included. The distances of both the anterior humeral circumflex artery and the axillary nerve from body landmarks were measured using Vernier calipers. RESULTS: The mean distance between the inferior border of the medial acromion and the superior border of the anterior humeral circumflex artery was 5.1 +/- 0.2 cm (range, 4.6-5.5 cm); the mean distance between the prominence of the lesser tuberosity and the superior border of the anterior humeral circumflex artery was 2.5 +/- 0.2 cm (range, 2.0 3.0 cm); the mean distance between the anterior-inferior border of the acromion and the superior border of the axillary nerve was 6.3 +/- 0.5 cm (range, 5.2-7.0 cm). CONCLUSIONS: The artery is located approximately 5.1 cm below the inferior border of the medial acromion and 2.5 cm below the prominence of the lesser tuberosity, and the nerve was located approximately 6.3 cm below the anterio inferior border of the acromion and 3.5 cm below the prominence of the greater tuberosity. The reduction manoeuvres should be conducted with extreme care in this region. PMID- 22198361 TI - Infection and revision strategies in total disc arthroplasty. AB - PURPOSE: Our aim was to revise the different strategies for treating an infected disc arthroplasty. METHODS: Despite recognition that disc replacement may reduce the incidence of adjacent-segment disease, the risk of potential complications associated with primary and revision total disc arthroplasty has diminished surgeon enthusiasm for the procedure. We performed a literature review of the different revision strategies for an infected disc arthroplasty. RESULTS: The need for revision of lumbar total disc arthroplasty has been reported in a number of prospective, randomised trials (level I or II evidence). Suboptimal patient selection and/or surgical technique accounted for the majority of failed disc arthroplasties. Revision procedures include posterior stabilisation or anterior extraction and conversion to arthrodesis. The risk of injury to the great vessels and retroperitoneal structures is greater during revision than primary procedures. The use of a distant lateral, or transpsoas, approach to the anterior column may reduce these adverse events. Also, the use of adhesion barriers has been shown to reduce adhesions in abdominal and pelvic surgery and may be of benefit in revision disc arthroplasty. CONCLUSION: This review article provides an update on the various treatments for infected lumbar disc prosthesis and the different surgical approaches used in these difficult cases. It also describes potential options to avoid complications associated with the revision surgical approach. PMID- 22198362 TI - Steps in the undertaking of a systematic review in orthopaedic surgery. AB - In the last decades of the twentieth century it became obvious that modern medical care is replete with data and information, but in need of reliable evidence. This has led to an increased effort to systematically synthesise medical research and make it more useful for practitioners. Systematic reviews use an approach to research synthesis that minimises the risk of misinterpreting a body of evidence due to incomprehensive search or subjective opinion. Carrying out a systematic review is a rigorous procedure which corresponds to standard methodological steps in primary research studies. It involves posing a well defined question, developing a robust search strategy, screening for relevant primary studies, critical appraisal of included studies, data extraction and processing, analysis and interpretation of results. In some, but not all systematic reviews it is appropriate to conduct a meta-analysis, which is a statistical procedure that integrates the results of several independent studies. Results of meta-analysis are graphically presented in forest plots, with pooled point estimate and its confidence interval represented as a rhombus, usually called a "diamond". Methodological quality of systematic reviews should not be judged by the quality of primary studies included, but by a distinct set of criteria specified in assessment tools such as AMSTAR. Systematic reviews and meta-analyses should be reported according to the PRISMA checklist. A major contribution to the development of methodological standards has been given by The Cochrane Collaboration, whose Handbook of Systematic Reviews of Interventions is the primary reference for all authors and referees of systematic reviews in health care. PMID- 22198363 TI - Canonical Wnt signaling in the visceral muscle is required for left-right asymmetric development of the Drosophila midgut. AB - Many animals develop left-right (LR) asymmetry in their internal organs. The mechanisms of LR asymmetric development are evolutionarily divergent, and are poorly understood in invertebrates. Therefore, we studied the genetic pathway of LR asymmetric development in Drosophila. Drosophila has several organs that show directional and stereotypic LR asymmetry, including the embryonic gut, which is the first organ to develop LR asymmetry during Drosophila development. In this study, we found that genes encoding components of the Wnt-signaling pathway are required for LR asymmetric development of the anterior part of the embryonic midgut (AMG). frizzled 2 (fz2) and Wnt4, which encode a receptor and ligand of Wnt signaling, respectively, were required for the LR asymmetric development of the AMG. arrow (arr), an ortholog of the mammalian gene encoding low-density lipoprotein receptor-related protein 5/6, which is a co-receptor of the Wnt signaling pathway, was also essential for LR asymmetric development of the AMG. These results are the first demonstration that Wnt signaling contributes to LR asymmetric development in invertebrates, as it does in vertebrates. The AMG consists of visceral muscle and an epithelial tube. Our genetic analyses revealed that Wnt signaling in the visceral muscle but not the epithelium of the midgut is required for the AMG to develop its normal laterality. Furthermore, fz2 and Wnt4 were expressed in the visceral muscles of the midgut. Consistent with these results, we observed that the LR asymmetric rearrangement of the visceral muscle cells, the first visible asymmetry of the developing AMG, did not occur in embryos lacking Wnt4 expression. Our results also suggest that canonical Wnt/beta catenin signaling, but not non-canonical Wnt signaling, is responsible for the LR asymmetric development of the AMG. Canonical Wnt/beta-catenin signaling is reported to have important roles in LR asymmetric development in zebrafish. Thus, the contribution of canonical Wnt/beta-catenin signaling to LR asymmetric development may be an evolutionarily conserved feature between vertebrates and invertebrates. PMID- 22198364 TI - The association of inherited thrombophilia and intrauterine fetal death: a case control study. AB - Inherited thrombophilias are probably associated with placenta-mediated pregnancy complications, but the strength of the association between inherited thrombophilias and intrauterine fetal death after 22 gestational weeks varies due to small sample size and different methodologies used across studies. The objective of the present study was to investigate the association of inherited thrombophilia and intrauterine fetal death in a case-control design. We studied 105 women with a history of intrauterine fetal death after 22 gestational weeks and 262 controls with live births. We investigated the prevalence of the factor V Leiden (F5 rs6025) and prothrombin gene G20210A (F2 rs1799963) polymorphisms, and antithrombin, protein C and protein S deficiencies, and their association with intrauterine fetal death. Results were presented as percentages and odds ratios (ORs) with 95% confidence intervals (CIs). A total of 18.4% of cases and 11.8% of controls were positive for at least one inherited thrombophilia (OR 1.7; 95% CI 0.9-3.1). The prothrombin gene G20210A polymorphism (OR 4.0; 95% CI 1.1-14.4), but not the factor V Leiden polymorphism, or antithrombin, protein C or protein S deficiencies, was associated with intrauterine fetal death after 22 weeks of gestation. Compared with women with live births only, women with a history of intrauterine fetal death after 22 gestational weeks were significantly more often carriers of the prothrombin gene G20210A polymorphism. PMID- 22198365 TI - The use of extended perioperative low molecular weight heparin (tinzaparin) to improve disease-free survival following surgical resection of colon cancer: a pilot randomized controlled trial. PMID- 22198366 TI - Thrombotic thrombocytopenic purpura associated with statin therapy. PMID- 22198368 TI - Imaging of left ventricular device complications. AB - Left ventricular assist devices have become an increasingly common life-extending therapy for patients with end-stage heart failure. These devices may be used as a bridge to transplant, destination therapy, or to recovery, providing either pulsatile or nonpulsatile support. Because of the increasing frequency of left ventricular assist device utilization and the improved short-term and long-term survival after placement, there has been a parallel increase in the radiologic imaging of patients with these devices, mandating radiologists' awareness of the manifestations of common complications, including infection, thrombosis and embolism, cannula obstruction, hemorrhage, and complications of adjacent vessels and viscera, all of which will be discussed in this pictorial essay. PMID- 22198367 TI - Peptidotriazoles with antimicrobial activity against bacterial and fungal plant pathogens. AB - We designed and prepared peptidotriazoles based on the antimicrobial peptide BP100 (LysLysLeuPheLysLysIleLeuLysTyrLeu-NH(2)) by introducing a triazole ring in the peptide backbone or onto the side chain of a selected residue. These compounds were screened for their in vitro growth inhibition of bacterial and fungal phytopathogens, and for their cytotoxic effects on eukaryotic cells and tobacco leaves. Their proteolytic susceptibility was also analyzed. The antibacterial activity and the hemolysis were influenced by the amino acid that was modified with the triazole as well as by the absence of presence of a substituent in this heterocyclic ring. We identified sequences active against the bacteria Xanthomonas axonopodis pv. vesicatoria, Erwinia amylovora, Pseudomonas syringae pv. syringae (MIC of 1.6-12.5 MUM), and against the fungi Fusarium oxysporum (MIC<6.2-12.5 MUM) with low hemolytic activity (0-23% at 50 MUM), high stability to protease digestion and no phytotoxicity. These peptidotriazoles constitute good candidates to design new antimicrobial agents. PMID- 22198369 TI - Birds and longevity: does flight driven aerobicity provide an oxidative sink? AB - Birds generally age slower and live longer than similar sized mammals. For birds this occurs despite elevated blood glucose levels that for mammals would in part define them as diabetic. However these data were acquired in respiration states that have little resemblance to conditions in healthy tissues and mitochondrial RS production is probably minimal in healthy animals. Indeed mitochondria probably act as net consumers rather than producers of RS. Here we propose that (1) if mitochondria are antioxidant systems, the greater mitochondrial mass in athletic species, such as birds, is advantageous as it should provide a substantial sink for RS. (2) The intense drive for aerobic performance and decreased body density to facilitate flight may explain the relative insensitivity of birds to insulin, as well as depressed insulin levels and apparent sensitization to glucagon. Glucagon also associates with the sirtuin protein family, most of which are associated with caloric restriction regulated pathways, mitochondrial biogenesis and life span extension. (3) We note that telomeres, which appear to be unusually long in birds, bind Sirtuins 2 and 4 and therefore may stabilize and protect nuclear DNA. Ultimately these flight driven responses may suppress somatic growth and protect DNA from oxidative damage that would otherwise lead to ageing and non-viral cancers. PMID- 22198371 TI - Recommendations for managing patients with diabetes mellitus in cardiopulmonary rehabilitation: an American Association of Cardiovascular and Pulmonary Rehabilitation statement. AB - Diabetes mellitus is a highly prevalent condition in patients participating in cardiopulmonary rehabilitation. However, research and subsequent guidelines specifically applicable to patients with diabetes, participating in cardiopulmonary rehabilitation, are limited. Recognizing this limitation, the American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) initiated this statement, with the goal of developing a template that incorporated recommendations provided in the AACVPR Core Components and the American Association of Diabetes Educators 7 Self-Care Behaviors. This statement describes key processes regarding evaluation, interventions, and expected outcomes in each of the core components for the management of patients with diabetes in a cardiopulmonary rehabilitation program. PMID- 22198370 TI - Safety of hepatic resection for colorectal metastases in the era of neo-adjuvant chemotherapy. AB - PURPOSE: The relationship between neo-adjuvant chemotherapy prior to hepatectomy in patients with resectable colorectal liver metastases and post-operative morbidity still has to be clarified. METHODS: Data from 242 patients undergoing hepatectomy for colorectal liver metastases, judged resectable at first observation, were reviewed and their clinical outcome was related to neo-adjuvant chemotherapy (125 patients). Selection biases were outlined and properly handled by means of propensity score analysis. RESULTS: Post-operative death was 1.2% and morbidity 40.9%. Pre-operative chemotherapy was only apparently related to higher morbidity (P = 0.021): multivariate analysis identified extension of hepatectomy and intra-operative blood loss as independent prognostic variables (P < 0.05). Patients receiving and not receiving neo-adjuvant chemotherapy were significantly different for several covariates, including extension of hepatectomy (P = 0.049). After propensity score adjustment, 94 patients were identified as having similar covariate distribution (standardized differences <|0.1|) except for neo-adjuvant treatment (47 patients for each group). In this matched sample, mortality was similar and post-operative complications were only slightly higher (hazard ratio = 1.38) in treated patients. A significantly higher need for fluid replacement was only observed in patients receiving neo-adjuvant chemotherapy (P = 0.038). CONCLUSIONS: Neo-adjuvant chemotherapy showed a limited role in determining post operative morbidity after hepatic resection and did not modify mortality. PMID- 22198372 TI - WITHDRAWN: H-reflex up-conditioning after sciatic nerve transection and regeneration may increase VGLUT-1 terminals and GluR2/3 immunoreactivity in spinal motoneurons. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22198373 TI - Possible influence of CREB1, CREBBP and CREM variants on diagnosis and treatment outcome in patients with schizophrenia. AB - The present study explores whether some single nucleotide polymorphisms (SNPs) within CREB1 (rs2709377 and rs6740584), CREBBP (rs2239317, rs2239316, rs3025702, rs130021, rs130005, rs129974 and rs9392) and CREM (rs1148247, rs4934735, rs12775799, rs6481941 and rs16935888) could be associated with schizophrenia (SKZ) and whether they could predict clinical outcomes in Korean in-patients treated with antipsychotics. Two-hundred twenty one in-patients suffering from SKZ and 170 psychiatrically healthy controls were genotyped for 10 SNPs within CREB1, CREBBP and CREM. All patients were assessed for the severity of illness at baseline and at discharge by means of the Positive and Negative Symptoms Scale (PANSS). Our findings suggest the lack of influence of SNPs under investigation in the present study on the susceptibility to SKZ and on the response to antipsychotics. However, taking into account the several limitations of our study, further research is needed to draw more definitive conclusions. PMID- 22198375 TI - The impact of increasing sleep restriction on cortisol and daytime sleepiness in adolescents. AB - Sleep restriction is a widespread phenomenon, specifically in adolescents. This study investigated the impact of increasing sleep restriction in adolescents on cortisol levels and daytime sleepiness. Eighty-eight healthy adolescents were randomized to five sleep restriction protocols (four consecutive nights with 9, 8, 7, 6, or 5 h time in bed). Polysomnography (baseline and last experimental night) and multiple sleep latency test (day 6) data were obtained. Saliva cortisol levels were assessed half-hourly in the evening before and in the morning after the baseline and the last experimental night. Four nights of sleep restriction in healthy adolescents lead to a linear increase of objective sleepiness, but had no significant effect on evening or morning cortisol levels. The lack of detrimental effects of sleep restriction on cortisol levels might be due to compensation mechanisms during sleep. PMID- 22198374 TI - Prostaglandin E2 receptor 1 activity regulates cell survival following hypoxia in cultured rat cortical neurons. AB - The clinical side-effects of increased cyclooxygenase (COX) activity induced by pathologic conditions have raised concerns recently. However, a better understanding of the mechanisms underlying the subsequent neurotoxicity requires knowledge of pathways downstream of COX, especially prostaglandin E2 (PGE2) and its receptors. Therefore, this study was performed to investigate the effects of PGE2 receptor 1 (EP1) activity on neuronal cell death resulting from hypoxia/reoxygenation (Hyp). As cyclinD1 activity has been shown to regulate neuronal apoptosis as well, the role of cyclinD1 was investigated, as well. Cortical neural cells isolated from fetal Wistar rats were cultured for 12 d and exposed to Hyp conditions to establish an in vitro Hyp model. To determine the effects of EP1 activity on Hyp-induced neurotoxicity, cells were treated with 17 phenyl trinor-PGE2 (17-pt), a synthetic EP1 agonist, or sc-51089, an EP1 antagonist, then exposed to hypoxic conditions for 3h and reoxygenated for 21 h. Following Hyp, cell viability was quantified by MTT assays, and apoptosis was assessed by flow cytometry. Protein expression levels of caspase-3 and cyclinD1 were examined by Western blot analysis. Treatment of cultured cortical neurons with 17-pt significantly decreased the survival rate of Hyp-treated neurons (p<0.05), while treatment with sc-51089 increased the survival rate. Treatment with 17-pt also led to increased expression levels of caspase-3, further supporting a role for EP1 in the observed neurotoxicity. However, cyclinD1 expression levels were unchanged following treatment with either 17-pt or sc 51089. Therefore, EP1 may play an important role in Hyp-induced neuronal apoptosis, but this neurotoxic activity is unlikely to involve cyclinD1. PMID- 22198376 TI - Retinal dysfunction, photoreceptor protein dysregulation and neuronal remodelling in the R6/1 mouse model of Huntington's disease. AB - Huntington's disease (HD) is a progressive neurological disease characterised by motor dysfunction, cognitive impairment and personality changes. Previous work in HD patients and animal models of the disease has also highlighted retinal involvement. This study characterised the changes in retinal structure and function early within the progression of disease using the R6/1 mouse model of HD. The retinal phenotype was observed to occur at the same time in the disease process as other neurological deficits such as motor dysfunction (by 13 weeks of age). There was a specific functional deficit in cone response to the electroretinogram and using immunocytochemical techniques, this dysfunction was found to be likely due to a progressive and complete loss of cone opsin and transducin protein expression by 20 weeks of age. In addition, there was an increase in Muller cell gliosis and the presence of ectopic rod photoreceptor terminals. This retinal remodelling is also observed in downstream neurons, namely the rod and cone bipolar cells. While R6/1 mice exhibit significant retinal pathology simultaneously with other more classical HD alterations, this doesn't lead to extensive cell loss. These findings suggest that in HD, cone photoreceptors are initially targeted, possibly via dysregulation of protein expression or trafficking and that this process is subsequently accompanied by increased retinal stress and neuronal remodelling also involving the rod pathway. As retinal structure and connectivity are well characterised, the retina may provide a useful model tissue in which to characterise the mechanisms important in the development of neuronal pathology in HD. PMID- 22198377 TI - Transplantation of bone marrow mononuclear cells decreases seizure incidence, mitigates neuronal loss and modulates pro-inflammatory cytokine production in epileptic rats. AB - Approximately 30% of patients with mesial temporal lobe epilepsy do not respond to treatment with antiepileptic drugs. We have previously shown that transplantation of mononuclear bone marrow cells (BMC) has an anticonvulsant effect in acute epilepsy. Here, we used pilocarpine to induce epilepsy in rats and studied the effects of BMC injected intravenously either at the onset of seizures or after 10 months of recurrent seizures. BMC effectively decreased seizure frequency and duration. In addition, decreased levels of proinflammatory cytokines (TNF-alpha, IL-1beta and IL-6) and increased levels of anti inflammatory cytokine (IL-10) were observed in the brain and serum of BMC-treated rats. Transplants performed at seizure-onset protected against pilocarpine induced neuronal loss and gliosis and stimulated the proliferation of new neurons in epileptic rats. Our data demonstrate that BMC transplantation has potent therapeutic effects and could be a potential therapy for clinically intractable epilepsies. PMID- 22198378 TI - ATP13A2 regulates mitochondrial bioenergetics through macroautophagy. AB - Mitochondrial dysfunction and autophagy are centrally implicated in Parkinson's disease (PD). Mutations in ATP13A2, which encodes a lysosomal P-type ATPase of unknown function, cause a rare, autosomal recessive parkinsonian syndrome. Lysosomes are essential for autophagy, and autophagic clearance of dysfunctional mitochondria represents an important element of mitochondrial quality control. In this study, we tested the hypothesis that loss of ATP13A2 function will affect mitochondrial function. Knockdown of ATP13A2 led to an increase in mitochondrial mass in primary mouse cortical neurons and in SH-SY5Y cells forced into mitochondrial dependence. ATP13A2-deficient cells exhibited increased oxygen consumption without a significant change in steady-state levels of ATP. Mitochondria in knockdown cells exhibited increased fragmentation and increased production of reactive oxygen species (ROS). Basal levels of the autophagosome marker LC3-II were not significantly changed, however, ATP13A2 knockdown cells exhibited decreased autophagic flux, associated with increased levels of phospho mTOR, and resistance to autophagy induction by rapamycin. The effects of ATP13A2 siRNA on oxygen consumption, mitochondrial mass and ROS production could be mimicked by inhibiting autophagy induction using siRNA to Atg7. We propose that decreased autophagy associated with ATP13A2 deficiency affects mitochondrial quality control, resulting in increased ROS production. These data are the first to implicate loss of ATP13A2 function in mitochondrial maintenance and oxidative stress, lending further support to converging genetic and environmental evidence for mitochondrial dysregulation in PD pathogenesis. PMID- 22198379 TI - Complete transglutaminase 2 ablation results in reduced stroke volumes and astrocytes that exhibit increased survival in response to ischemia. AB - Transglutaminase 2 (TG2) is a very multifunctional protein that is ubiquitously expressed in the body. It is a Ca(2+)-dependent transamidating enzyme, a GTPase, as well as a scaffolding protein. TG2 is the predominant form of transglutaminase expressed in the mammalian nervous system. Previously, it was shown that TG2 can affect both cell death and cell survival mechanisms depending on the cell type and the stressor. In the case of ischemic stress, TG2 was previously shown to play a protective role in the models used. For example in hTG2 transgenic mice, where TG2 is overexpressed only in neurons, middle cerebral artery ligation (MCAL) resulted in smaller infarct volumes compared to wild type mice. In this study TG2 knock out mice were used to determine how endogenous TG2 affected stroke volumes. Intriguingly, infarct volumes in TG2 knock out mice were significantly smaller compared to wild type mice. As expected, primary neurons isolated from TG2 knock out mice showed decreased viability in response to oxygen glucose deprivation. However, primary astrocytes that were isolated from TG2 knock out mice were resistant to oxygen-glucose deprivation in situ. Both wild type and knock out neurons were protected against oxygen glucose deprivation when they were co-cultured with astrocytes from TG2 knockout mice. Therefore, the decreased stroke volumes observed in TG2 knock out mice after MCAL, can be correlated with the protective effects of TG2 knock out in astrocytes in response to oxygen glucose deprivation in situ. These findings suggest that neuron astrocyte crosstalk plays a significant role in mediating ischemic cell death and that TG2 differentially impacts cell survival depending on cell context. PMID- 22198381 TI - Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1. AB - Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). This study investigates the role of intercellular adhesion molecule-1 (ICAM-1) within this action. In the lung cancer cell lines A549, H358, and H460, cannabidiol (CBD; 0.001-3 MUM) elicited concentration-dependent ICAM-1 up-regulation compared to vehicle via cannabinoid receptors, transient receptor potential vanilloid 1, and p42/44 mitogen-activated protein kinase. Up-regulation of ICAM-1 mRNA by CBD in A549 was 4-fold at 3 MUM, with significant effects already evident at 0.01 MUM. ICAM-1 induction became significant after 2 h, whereas significant TIMP-1 mRNA increases were observed only after 48 h. Inhibition of ICAM-1 by antibody or siRNA approaches reversed the anti-invasive and TIMP-1-upregulating action of CBD and the likewise ICAM-1 inducing cannabinoids Delta(9)-tetrahydrocannabinol and R(+)-methanandamide when compared to isotype or nonsilencing siRNA controls. ICAM-1-dependent anti invasive cannabinoid effects were confirmed in primary tumor cells from a lung cancer patient. In athymic nude mice, CBD elicited a 2.6- and 3.0-fold increase of ICAM-1 and TIMP-1 protein in A549 xenografts, as compared to vehicle-treated animals, and an antimetastatic effect that was fully reversed by a neutralizing antibody against ICAM-1 [% metastatic lung nodules vs. isotype control (100%): 47.7% for CBD + isotype antibody and 106.6% for CBD + ICAM-1 antibody]. Overall, our data indicate that cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness. PMID- 22198383 TI - The guidance receptor neogenin promotes pulmonary inflammation during lung injury. AB - Lung injury is marked by a persistent self-propagating inflammation within the pulmonary tissue that is initiated by the migration of leukocytes into the alveolar space. Recent work has demonstrated that neuronal guidance proteins are involved into the orchestration of leukocyte migration. Neogenin is a crucial guidance receptor for axonal migration, yet its role during leukocyte migration and acute inflammation is to date unknown. Here, we report that neogenin influences neutrophil migration across endothelial HMEC-1 and alveolar A549 monolayers in vitro. In vivo, Neo1(-/-) mice demonstrated 59% reduced cell count, 41% reduced TNF-alpha, and 76% reduced IL-6 levels within the alveolar space during lung injury. In studies employing chimeric animals, the presence of Neo1( /-) bone marrow was associated with a 42% reduction of cell count and reduced inflammatory changes within pulmonary tissue during lung injury. The functional inhibition of neogenin through antibody injection confirmed these results and the role of neogenin for the inflammatory changes within the alveolar space. Previously unappreciated, the guidance receptor neogenin has a significant effect on the orchestration of leukocyte migration and the control of acute inflammation. PMID- 22198380 TI - The abolishment of anesthesia-induced cognitive impairment by timely protection of mitochondria in the developing rat brain: the importance of free oxygen radicals and mitochondrial integrity. AB - Early exposure to general anesthesia (GA) causes developmental neuroapoptosis in the mammalian brain and long-term cognitive impairment. Recent evidence suggests that GA also causes functional and morphological impairment of the immature neuronal mitochondria. Injured mitochondria could be a significant source of reactive oxygen species (ROS), which, if not scavenged in timely fashion, may cause excessive lipid peroxidation and damage of cellular membranes. We examined whether early exposure to GA results in ROS upregulation and whether mitochondrial protection and ROS scavenging prevent GA-induced pathomorphological and behavioral impairments. We exposed 7-day-old rats to GA with or without either EUK-134, a synthetic ROS scavenger, or R(+) pramipexole (PPX), a synthetic aminobenzothiazol derivative that restores mitochondrial integrity. We found that GA causes extensive ROS upregulation and lipid peroxidation, as well as mitochondrial injury and neuronal loss in the subiculum. As compared to rats given only GA, those also given PPX or EUK-134 had significantly downregulated lipid peroxidation, preserved mitochondrial integrity, and significantly less neuronal loss. The subiculum is highly intertwined with the hippocampal CA1 region, anterior thalamic nuclei, and both entorhinal and cingulate cortices; hence, it is important in cognitive development. We found that PPX or EUK-134 co treatment completely prevented GA-induced cognitive impairment. Because mitochondria are vulnerable to GA-induced developmental neurotoxicity, they could be an important therapeutic target for adjuvant therapy aimed at improving the safety of commonly used GAs. PMID- 22198382 TI - Redox modification of Akt mediated by the dopaminergic neurotoxin MPTP, in mouse midbrain, leads to down-regulation of pAkt. AB - Impairment of Akt phosphorylation, a critical survival signal, has been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. However, the mechanism underlying pAkt loss is unclear. In the current study, we demonstrate pAkt loss in ventral midbrain of mice treated with dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), when compared to ventral midbrain of control mice treated with vehicle alone. Thiol residues of the critical cysteines in Akt are oxidized to a greater degree in mice treated with MPTP, which is reflected as a 40% loss of reduced Akt. Association of oxidatively modified Akt with the phosphatase PP2A, which can lead to enhanced dephosphorylation of pAkt, was significantly stronger after MPTP treatment. Maintaining the protein thiol homeostasis by thiol antioxidants prevented loss of reduced Akt, decreased association with PP2A, and maintained pAkt levels. Overexpression of glutaredoxin, a protein disulfide oxidoreductase, in human primary neurons helped sustain reduced state of Akt and abolished MPP(+)-mediated pAkt loss. We demonstrate for the first time the selective loss of Akt activity, in vivo, due to oxidative modification of Akt and provide mechanistic insight into oxidative stress-induced down-regulation of cell survival pathway in mouse midbrain following exposure to MPTP. PMID- 22198384 TI - Differences in the enzymatic efficiency of human and bony fish AID are mediated by a single residue in the C terminus modulating single-stranded DNA binding. AB - Activation-induced cytidine deaminase (AID) mediates antibody diversification by deaminating deoxycytidines to deoxyuridine within immunoglobulin genes. However, it also generates genome-wide DNA lesions, leading to transformation. Though the biochemical properties of AID have been described, its 3-dimensional structure has not been determined. Hence, to investigate the relationship between the primary structure and biochemical characteristics of AID, we compared the properties of human and bony fish AID, since these are most divergent in amino acid sequence. We show that AIDs of various species have different catalytic rates that are thermosensitive and optimal at native physiological temperatures. Zebrafish AID is severalfold more catalytically robust than human AID, while catfish AID is least active. This disparity is mediated by a single amino acid difference in the C terminus. Using functional assays supported by models of AID core and surface structure, we show that this residue modulates activity by affecting ssDNA binding. Furthermore, the cold-adapted catalytic rates of fish AID result from increased ssDNA binding affinity at lower temperatures. Our work suggests that AID may generate DNA damage with variable efficiencies in different organisms, identifies residues critical in regulating AID activity, and provides insights into the evolution of the APOBEC family of enzymes. PMID- 22198385 TI - Orai1-mediated calcium entry plays a critical role in osteoclast differentiation and function by regulating activation of the transcription factor NFATc1. AB - Bone diseases such as postmenopausal osteoporosis are primarily caused by excessive formation and activity of osteoclasts (OCLs). Receptor activator of nuclear factor-kappaB ligand (RANKL) is a key initiating cytokine for OCL differentiation and function. RANKL induces calcium (Ca(2+)) oscillations, resulting in selective and robust induction of nuclear factor of activated T cells c1 (NFATc1), a Ca(2+)-responsive transcription factor that drives osteoclastogenesis. Store-operated Ca(2+) entry (SOCE) is a major Ca(2+) influx pathway in most nonexcitable cell types and is activated by any stimulus that depletes Ca(2+) stores in the endoplasmic reticulum. Although the role of Orai1, a SOCE channel in the plasma membrane, in maintaining Ca(2+) oscillations and transactivation of NFAT in other cell types is well known, its contribution to osteoclastogenesis remains unclear. We show here that silencing of the Orai1 gene with viral delivery of shRNA reduces SOCE and inhibits RANKL-induced osteoclastogenesis of RAW264.7 cells, a murine monocyte/macrophage cell line, by suppressing the induction of NFATc1. This was accompanied by defective induction of OCL-specific genes, such as tartrate-resistant acid phosphatase and immunoreceptor OCL-associated receptor, which are known to be direct transcriptional targets of NFATc1 during osteoclastogenesis. In addition, maturation of OCLs was abrogated by defective cell fusion of pre-OCLs depleted of Orai1, consistent with defective RANKL-mediated induction of d2 isoform of vacuolar ATPase V(o) domain that is involved in cell fusion of pre-OCLs. We found that the functional bone resorbing capacity was severely impaired in OCLs depleted of Orai1, potentially related to the observed decrease in the induction of cathepsin K, a major bone matrix degrading protease. Our results indicate that Orai1 plays a critical role in the differentiation and function of OCLs, suggesting that Orai1 might be a potential therapeutic target for the treatment or prevention of bone loss caused by OCLs. PMID- 22198386 TI - EGR1 and the ERK-ERF axis drive mammary cell migration in response to EGF. AB - The signaling pathways that commit cells to migration are incompletely understood. We employed human mammary cells and two stimuli: epidermal growth factor (EGF), which induced cellular migration, and serum factors, which stimulated cell growth. In addition to strong activation of ERK by EGF, and AKT by serum, early transcription remarkably differed: while EGF induced early growth response-1 (EGR1), and this was required for migration, serum induced c-Fos and FosB to enhance proliferation. We demonstrate that induction of EGR1 involves ERK mediated down-regulation of microRNA-191 and phosphorylation of the ETS2 repressor factor (ERF) repressor, which subsequently leaves the nucleus. Unexpectedly, knockdown of ERF inhibited migration, which implies migratory roles for exported ERF molecules. On the other hand, chromatin immunoprecipitation identified a subset of direct EGR1 targets, including EGR1 autostimulation and SERPINB2, whose transcription is essential for EGF-induced cell migration. In summary, EGR1 and the EGF-ERK-ERF axis emerge from our study as major drivers of growth factor-induced mammary cell migration. PMID- 22198387 TI - Seizure suppression and neuroprotection by targeting the purinergic P2X7 receptor during status epilepticus in mice. AB - Prolonged seizures [status epilepticus (SE)] constitute a neurological emergency that can permanently damage the brain. SE results from a failure of the normal mechanisms to terminate seizures; in particular, gamma-amino butyric acid mediated inhibition, and benzodiazepine anticonvulsants are often incompletely effective. ATP acts as a fast neurotransmitter via ionotropic ligand-gated P2X receptors. Here we report that SE induced by intra-amygdala kainic acid in mice selectively increased hippocampal levels of P2X7 receptors relative to other P2X receptors. Using transgenic P2X7 reporter mice expressing enhanced green fluorescent protein, we identify dentate granule neurons as the major cell population transcribing the P2X7 receptor after SE. Pretreatment of mice with an intracerebroventricular microinjection of 1.75 nmol A438079, a P2X7 receptor antagonist, reduced seizure duration by 58% and reduced seizure-induced neuronal death by 61%. Injection of brilliant blue G (1 pmol), another selective antagonist, reduced seizure duration by 48% and was also neuroprotective. A438079 was seizure-suppressive when injected shortly after induction of SE, and coinjection of A438079 with lorazepam 60 min after triggering SE, when electrographic seizure-responsiveness to lorazepam had decreased, also terminated SE. Our results suggest that P2X7 receptor antagonists may be a promising class of drug for seizure abrogation and neuroprotection in SE. PMID- 22198389 TI - Fusion of bone marrow-derived cells with renal tubules contributes to renal dysfunction in diabetic nephropathy. AB - Although diabetic nephropathy (DN) is a major cause of end-stage renal disease, the mechanism of dysfunction has not yet been clarified. We previously reported that in diabetes proinsulin-producing bone marrow-derived cells (BMDCs) fuse with hepatocytes and neurons. Fusion cells are polyploidy and produce tumor necrosis factor (TNF)-alpha, ultimately causing diabetic complications. In this study, we assessed whether the same mechanism is involved in DN. We performed bone marrow transplantation from male GFP-Tg mice to female C57BL/6J mice and produced diabetes by streptozotocin (STZ) or a high-fat diet. In diabetic kidneys, massive infiltration of BMDCs and tubulointerstitial injury were prominent. BMDCs and damaged tubular epithelial cells were positively stained with proinsulin and TNF alpha. Cell fusion between BMDCs and renal tubules was confirmed by the presence of Y chromosome. Of tubular epithelial cells, 15.4% contain Y chromosomes in STZ diabetic mice, 8.6% in HFD-diabetic mice, but only 1.5% in nondiabetic mice. Fusion cells primarily expressed TNF-alpha and caspase-3 in diabetic kidney. These in vivo findings were confirmed by in vitro coculture experiments between isolated renal tubular cells and BMDCs. It was concluded that cell fusion between BMDCs and renal tubular epithelial cells plays a crucial role in DN. PMID- 22198388 TI - Noninvasive detection of neural progenitor cells in living brains by MRI. AB - The presence of pericytes in brain regions undergoing repair is evident of the recruitment of bone marrow-derived multipotent regenerative cells to the neurovascular unit during angiogenesis. At present, post mortem sampling is the only way to identify them. Therefore, such cell typing is inadequate for preserving neural progenitor cells for any meaningful stem cell therapy. We aimed to target cerebral pericytes in vivo using dual gene transcript-targeted MRI (GT tMRI) in male C57black6 mice after a 60-min bilateral carotid artery occlusion (BCAO). We attached superparamagnetic iron oxide nanoparticles (SPIONs) to phosphorothioate-modified micro-DNA that targets actin or nestin mRNA. Because BCAO compromises the blood-brain barrier (BBB) and induces expression of alpha smooth muscle (alphaSM)-actin and nestin antigens by pericytes in new vessels, we delivered pericyte-specific magnetic resonance contrast agents (SPION-actin or SPION-nestin at 4 mg Fe/kg) by i.p. injection to C57black6 mice that had experienced BCAO. We demonstrated that the surge in cerebral iron content by inductively coupled plasma-mass spectrometry matched the increase in the frequency of relaxivity. We also found that SPION-nestin was colocalized in alphaSM- actin- and nestin-expressing pericytes in BCAO-treated C57black6 or transgenic mice [B6.Cg-Tg(CAG-mRFP1) 1F1Hadj/J, expressing red fluorescent protein by actin promoter]. We identified pericytes in the repair patch in living brains after BCAO with a voxel size of 0.03 mm(3). The presence of electron-dense nanoparticles in vascular pericytes in the region of BBB injury led us to draw the conclusion that GT-tMRI can noninvasively reveal neural progenitor cells during vascularization. PMID- 22198390 TI - Functional interactions between voltage-gated Ca(2+) channels and Rab3 interacting molecules (RIMs): new insights into stimulus-secretion coupling. AB - Stimulus-secretion coupling is a complex set of intracellular reactions initiated by an external stimulus that result in the release of hormones and neurotransmitters. Under physiological conditions this signaling process takes a few milliseconds, and to minimize delays cells have developed a formidable integrated network, in which the relevant molecules are tightly packed on the nanometer scale. Active zones, the sites of release, are composed of several different proteins including voltage-gated Ca(2+) (Ca(V)) channels. It is well acknowledged that hormone and neurotransmitter release is initiated by the activation of these channels located close to docked vesicles, though the mechanisms that enrich channels at release sites are largely unknown. Interestingly, Rab3 binding proteins (RIMs), a diverse multidomain family of proteins that operate as effectors of the small G protein Rab3 involved in secretory vesicle trafficking, have recently identified as binding partners of Ca(V) channels, placing both proteins in the center of an interaction network in the molecular anatomy of the active zones that influence different aspects of secretion. Here, we review recent evidences providing support for the notion that RIMs directly bind to the pore-forming and auxiliary beta subunits of Ca(V) channels and with RIM-binding protein, another interactor of the channels. Through these interactions, RIMs regulate the biophysical properties of the channels and their anchoring relative to active zones, significantly influencing hormone and neurotransmitter release. PMID- 22198391 TI - FtsZ polymers bound to lipid bilayers through ZipA form dynamic two dimensional networks. AB - Bacteria divide by forming a contractile ring around their midcell region. FtsZ, a cytoskeletal soluble protein structurally related to tubulin, is the main component of this division machinery. It forms filaments that bundle at the inner side of the cytoplasmic membrane. These FtsZ bundles do not attach to bare lipid surfaces. In Escherichia coli they remain near the membrane surface by attaching to the membrane protein ZipA and FtsA. In order to study the structure and dynamics of the ZipA-FtsZ bundles formed on a lipid surface, we have oriented a soluble form of ZipA (sZipA), with its transmembrane domain substituted by a histidine tag, on supported lipid membranes. Atomic force microscopy has been used to visualize the polymers formed on top of this biomimetic surface. In the presence of GTP, when sZipA is present, FtsZ polymers restructure forming higher order structures. The lipid composition of the underlying membrane affects the aggregation kinetics and the shape of the structures formed. On the negatively charged E. coli lipid membranes, filaments condense from initially disperse material to form a network that is more dynamic and flexible than the one formed on phosphatidyl choline bilayers. These FtsZ-ZipA filament bundles are interconnected, retain their capacity to dynamically restructure, to fragment, to anneal and to condense laterally. PMID- 22198392 TI - Stroke: Could statin treatment during hospitalization improve survival after ischemic stroke? PMID- 22198394 TI - Alzheimer disease: Arterial spin-labeled MRI for diagnosis and monitoring of AD. PMID- 22198402 TI - Neurodegenerative disease: Pridopidine for Huntington disease falls short of primary efficacy end point in phase III trial. PMID- 22198403 TI - Neural repair and rehabilitation: the effect of therapeutic hypothermia on prognostication. PMID- 22198404 TI - Parkinson disease: the controversy of levodopa toxicity in Parkinson disease. PMID- 22198406 TI - [Ovarian preservation during treatment of early stage endometrial cancer]. AB - Endometrial cancer staging is based on surgery. No matter the age of the patient, the surgical staging includes at least a total hysterectomy with bilateral salpingo-oophorectomy. Twenty to 25% of the patients diagnosed with endometrial cancer are younger than 45 years. Although some discrepancies among series may be observed, in this population, endometrial cancers are mainly of lower grade, confined to the uterus (without ovarian involvement) and of better prognosis compared to older patients. The impact of premature menopause on the quality of life, cardiovascular and bone systems should not be neglected. This raises the issue of the systematic bilateral oophorectomy legitimacy while staging endometrial cancer staging in young patient. Considering the literature, eligibility criteria to ovarian preservation in endometrial cancer would be: young patients, low-grade endometrioid tumor, disease limited to the uterus (absence of any extrauterine disease). The risk of occult ovarian lesions, either synchronous or metastatic, would than be close to 1%. The effects of residual hormonal stimulation are considered low. Nevertheless, bilateral oophorectomy should remain the standard. Oophorectomy preservation in endometrial cancer should be considered as an exception, and proposed as an individualized plan of care for patients with strict eligibility criteria. PMID- 22198407 TI - Central carbon metabolism influences fidelity of DNA replication in Escherichia coli. AB - Recent studies indicated that there is a direct link between central carbon metabolism (CCM) and initiation and elongation of DNA replication in Eschericha coli. Namely, effects of certain mutations in genes coding for replication proteins (dnaA, dnaB, dnaE, dnaG, and dnaN) could be specifically suppressed by deletions of some genes, whose products are involved in CCM reactions (pta, ackA, pgi, tktB, and gpmA). Here, we demonstrate that the link between CCM and DNA synthesis can be extended to the DNA replication fidelity, as we report changes of the mutator phenotypes of E. coli dnaQ49 and dnaX36 mutants (either suppression or enhancement) by dysfunctions of zwf, pta, ackA, acnB, and icdA genes. Overexpression of appropriate wild-type CCM genes in double mutants resulted in reversions to the initial mutator phenotypes, indicating that the effects were specific. Moreover, the observed suppression and enhancement effects were not caused by changes in bacterial growth rates. These results suggest that there is a genetic correlation between CCM and DNA replication fidelity in E. coli, apart from the already documented link between CCM and DNA replication initiation control and elongation efficiency. PMID- 22198405 TI - Depression in Parkinson disease--epidemiology, mechanisms and management. AB - Depression occurs in around 35% of patients with Parkinson disease (PD) and is often persistent. Symptoms of depression can be evident in individuals at the time of diagnosis and might develop in the premotor stage of the disease. The underlying mechanisms of depression in PD are not known in detail, but changes in brain structure, signaling by neurotransmitters, and levels of inflammatory and neurotrophic factors are all suggested to contribute to its development. Psychosocial factors and pain could also have roles in depression. Changes in dopaminergic, noradrenergic and serotonergic systems in patients with PD might help to explain the incidence of depression in these individuals. Antidepressants that have dual serotonergic and noradrenergic effects are the drugs of choice for treating depression in PD. However, antiparkinsonian drugs might have beneficial effects not only on the motor symptoms of disease, but also on a patient's mood. Deep brain stimulation can worsen depression in some patients, but a preliminary study has suggested that transcranial magnetic stimulation could improve symptoms of depression. This Review describes the frequency and course of depression in patients with PD. The mechanisms that underlie depression in this disease are also discussed, and the management strategies for these patients are highlighted. PMID- 22198409 TI - Noncore residues influence the kinetics of functional TTR(105-115)-based amyloid fibril assembly. AB - Mutations in the polypeptide sequence that forms the core structure of amyloid fibrils are known to impact on fibril assembly and stability but the effect of changes on noncore residues, particularly relating to functionalized fibrils where the fibril core is preserved, has not been systematically examined. In this study, the short peptide sequence TTR(105-115) (also known as TTR1) and the functionalized variants TTR1-RGD and TTR1-RAD are used as a model system to investigate the effect of noncore residues on the kinetics of fibril assembly. The noncore residues in TTR1-RGD and TTR1-RAD influence the rate of fibril assembly in non-seeded samples with the glycine residue at position 15 increasing the rate of aggregation compared to alanine. Mature TTR1-RGD fibrils were also found to fragment more readily, indicating possible differences in mechanical properties. Fragments of each type of fibril are capable of self- and cross seeding, generating fibrils with a highly similar cross-beta core structure. The similar rates of assembly observed for self-seeded samples reflect the similar free energy of elongation calculated for these peptides, while the morphology of cross-seeded fibrils is determined by the properties of the monomeric peptide and its macromolecular arrangement within the protofilaments and fibrils. These findings illustrate that noncore residues impact on fibril formation and fibril properties and demonstrate that the influence of noncore residues should be considered when designing sequences for the production of self-assembling functional fibrillar materials. PMID- 22198408 TI - Teaching an old scaffold new tricks: monobodies constructed using alternative surfaces of the FN3 scaffold. AB - The fibronectin type III domain (FN3) has become one of the most widely used non antibody scaffolds for generating new binding proteins. Because of its structural homology to the immunoglobulin domain, combinatorial libraries of FN3 designed to date have primarily focused on introducing amino acid diversity into three loops that are equivalent to antibody complementarity-determining regions. Here, we report an FN3 library that utilizes alternative positions for presenting amino acid diversity. We diversified positions on a beta-sheet and surface loops that together form a concave surface. The new library produced binding proteins (termed "monobodies") to multiple target proteins, generally with similar efficacy as the original, loop-focused library. The crystal structure of a monobody generated from the new library in complex with its target, the Abl SH2 domain, revealed that a concave surface of the monobody, as intended in our design, bound to a convex surface of the target with the interface area being among the largest of published structures of monobody-target complexes. This mode of interaction differs from a common binding mode for single-domain antibodies and antibody mimics in which recognition loops recognize clefts in targets. Together, this work illustrates the utilization of different surfaces of a single immunoglobulin-like scaffold to generate binding proteins with distinct characteristics. PMID- 22198410 TI - Emergence of novel reassortant H3N2 swine influenza viruses with the 2009 pandemic H1N1 genes in the United States. AB - Reassortant H1 swine influenza viruses (SIVs) carrying 2009 pandemic H1N1 virus (pH1N1) genes have been isolated from pigs worldwide. Seven novel reassortant H3N2 SIVs were identified from diseased pigs in the USA from winter 2010 to spring 2011. These novel viruses contain three or five internal genes from pH1N1 and continue to circulate in swine herds. The emergence of novel reassortant H3N2 SIVs demonstrates reassortment between pH1N1 and endemic SIVs in pigs and justifies continuous surveillance. PMID- 22198411 TI - Serotype and genotype diversity of infectious bronchitis viruses isolated during 1985-2008 in Guangxi, China. AB - The genetic diversity of the hypervariable region I of S1 gene (HVR I) of infectious bronchitis (IB) vaccine strains H120, Ma5 and 4/91 was compared to that of 26 infectious bronchitis virus (IBV) strains isolated from the field in Guangxi province of China during the years 1985-2008, and the field isolates were classified into five major genotypes. Monovalent antisera against three vaccine strains and seven field isolates of different genotypes were prepared by immunizing rabbits with mineral oil adjuvant preparations containing viruses propagated in chicken embryos. Virus neutralization (VN) tests were performed in tracheal organ cultures (TOCs) using these 10 strains with the antisera, and a one-way VN test was then used to compare the relationship of 10 monovalent antisera to the other 19 field isolates. As a result, seven different serotypes were classified based on the results of VN tests with the 26 isolates plus the three vaccine strains. We found that different serotypes were prevalent during different time periods, that more new serotypes have been prevalent in more recent years, and the prevalence of the original dominant serotype has been in constant decline since 2004. In addition, the concordance rate of the 26 field isolates between the S1 genotypes and serotypes was 57.7%. PMID- 22198413 TI - Limits on risks for healthy volunteers in biomedical research. AB - Healthy volunteers in biomedical research often face significant risks in studies that offer them no medical benefits. The U.S. federal research regulations and laws adopted by other countries place no limits on the risks that these participants face. In this essay, I argue that there should be some limits on the risks for biomedical research involving healthy volunteers. Limits on risk are necessary to protect human participants, institutions, and the scientific community from harm. With the exception of self-experimentation, limits on research risks faced by healthy volunteers constitute a type of soft, impure paternalism because participants usually do not fully understand the risks they are taking. I consider some approaches to limiting research risks and propose that healthy volunteers in biomedical research should not be exposed to greater than a 1% chance of serious harm, such as death, permanent disability, or severe illness or injury. While this guideline would restrict research risks, the limits would not be so low that they would prevent investigators from conducting valuable research. They would, however, set a clear upper boundary for investigators and signal to the scientific community and the public that there are limits on the risks that healthy participants may face in research. This standard provides guidance for decisions made by oversight bodies, but it is not an absolute rule. Investigators can enroll healthy volunteers in studies involving a greater than 1% chance of serious harm if they show that the research addresses a compelling public health or social problem and that the risk of serious harm is only slightly more than 1%. The committee reviewing the research should use outside experts to assess these risks. PMID- 22198412 TI - A phase II study of lapatinib and bevacizumab as treatment for HER2 overexpressing metastatic breast cancer. AB - Preclinical data have demonstrated that the combination of antihuman epidermal growth factor receptor-2 (anti-HER2) and antivascular endothelial growth factor (anti-VEGF)--targeted agents has antitumor activity; these data indicate certain patients with HER2-overexpressing breast cancer may derive clinical benefit from this combination. The purpose of this single-arm phase II study was to determine the efficacy and safety of the dual-targeting combination of lapatinib and bevacizumab. Women with HER2-overexpressing advanced breast cancer received 1,500 mg oral lapatinib daily plus 10 mg/kg IV bevacizumab every 2 weeks. The primary endpoint was progression-free survival (PFS) at week 12; secondary endpoints included overall tumor response rate (ORR), clinical benefit rate (CBR), duration of response, time-to-response, PFS, and safety. Circulating tumor cells (CTC) and circulating endothelial cells (CEC) were measured at baseline and during study treatment as potential response markers. Fifty-two patients with stage IV disease were enrolled. The 12-week investigator-assessed PFS rate was 69.2% (95% confidence interval [CI]: 54.9, 81.3). Median PFS was 24.7 weeks (95% CI: 20.4, 35.1), and the CBR was 30.8% (95% CI: 18.7, 45.1). Of 45 patients with measurable disease, 6 were determined to have a partial response per Response Evaluation Criteria in Solid Tumors (ORR: 13.3%; 95% CI: 5.1, 26.8). The most common adverse events (AEs) included diarrhea, rash, and fatigue; most of these were either grade 1 or 2. Clinical responses were correlated with decreases in CTC and CEC. Lapatinib plus bevacizumab was active in patients with HER2-overexpressing breast cancer. The AE profile of the combination was consistent with the known profiles for these agents. PMID- 22198414 TI - The Hastings Center and the early years of bioethics. AB - The Hastings Center was founded in 1969 to study ethical problems in medicine and biology. The Center arose from a confluence of three social currents: the increased public scrutiny of medicine and its practices, the concern about the moral problems being generated by technological developments, and the desire of one of its founders (Callahan) to make use of his philosophical training in a more applied way. The early years of the Center were devoted to raising money, developing an early agenda of issues, and identifying a cadre of people around the country interested in the issues. Various stresses and strains in the Center and the field are identified, and some final reflections are offered on the nature and value of the contributions made by bioethics as an academic field. PMID- 22198415 TI - The complete mitochondrial genome sequence of Oncicola luehei (Acanthocephala: Archiacanthocephala) and its phylogenetic position within Syndermata. AB - In the present study, we determined the complete mitochondrial genome sequence of Oncicola luehei (14,281bp), the first archiacanthocephalan representative and the second complete sequence from the phylum Acanthocephala. The complete genome contains 36 genes including 12 protein coding genes, 22 transfer RNA (tRNA) genes and 2 ribosomal RNA genes (rrnL and rrnS) as reported for other syndermatan species. All genes are encoded on the same strand. The overall nucleotide composition of O. luehei mtDNA is 37.7% T, 29.6% G, 22.5% A, and 10.2% C. The overall A+T content (60.2%) is much lower, compared to other syndermatan species reported so far, due to the high frequency (18.3%) of valine encoded by GTN in its protein-coding genes. Results from phylogenetic analyses of amino acid sequences for 10 protein-coding genes from 41 representatives of major metazoan groups including O. luehei supported monophyly of the phylum Acanthocephala and of the clade Syndermata (Acanthocephala+Rotifera), and the paraphyly of the clade Eurotatoria (classes Bdelloidea+Monogononta from phylum Rotifera). Considering the position of the acanthocephalan species within Syndermata, it is inferred that obligatory parasitism characteristic of acanthocephalans was acquired after the common ancestor of acanthocephalans diverged from its sister group, Bdelloidea. Additional comparison of complete mtDNA sequences from unsampled acanthocephalan lineages, especially classes Polyacanthocephala and Eoacanthocephala, is required to test if mtDNA provides reliable information for the evolutionary relationships and pattern of life history diversification found in the syndermatan groups. PMID- 22198416 TI - Treatment of lung cancer via telomerase inhibition: self-assembled nanoplexes versus polymeric nanoparticles as vectors for 2'-O-Methyl-RNA. AB - Antisense oligonucleotide, 2'-O-Methyl-RNA (OMR), is known as potent telomerase inhibitor for the treatment of lung cancer but limited by poor intracellular uptake. Chitosan-coated polymeric nanoparticles were compared to chitosan solution as non-viral vectors for OMR. The study investigated the role of chitosan properties and concentration in improving the efficiency of the nanocarriers in terms of loading, viability, cellular uptake, and telomerase inhibition in human lung cancer cell lines. Certain concentration of chitosan on nanoparticle surface is necessary to significantly increase the cellular uptake. However, excessive chitosan negatively affected the transfection efficiency. Self assembled nanoplexes with chitosan polymer are preferentially adsorbed to the cell membrane rather than being internalized. Thus, polymeric nanoparticles proved to be superior to cationic polymers as carrier for antisense oligonucleotides. Charge cannot be considered the principle factor behind improved transfection. Uptake studies carried out on air-interface cell cultures to mimic in vivo conditions supported the results on normal cultures showing enhanced uptake of nanoplexes over naked oligonucleotides. OMR nanoplexes reduced telomerase activity by ~50% in A549 cells concluding the potential of the system as a safe, non-invasive, and efficient treatment for lung carcinoma. These data are prerequisites for the ongoing studies on lung perfusion model and in vivo experiments. PMID- 22198417 TI - Can the health insurance reforms stop an increase in medical expenditures for middle- and old-aged persons in Japan? AB - Using two-period panel data from the Nippon Life Insurance Research Institute, this paper tests the hypothesis that an increase in the self-pay ratio of medical expenditures associated with the Japanese health insurance reforms of April 2003 reduced household medical expenditures. We find that the increase in the self-pay ratio had a positive but insignificant effect on the share of medical expenses in household expenditure. However, when we employ the data as repeated cross sectional observations to increase the sample size, the increase in the self-pay ratio has a significantly positive effect on the share of medical expenditures. This provides corroborating evidence that middle- and old-aged persons were unable to reduce their demand for medical services with the increase in the self pay ratio. An additional finding is that medical services are a necessary good, particularly for those aged 61 years or older and those with medical expenditures accounting for a relatively high share of medical expenditures in high household expenditure. PMID- 22198418 TI - Anatomic variations of the renal vessels: focus on the precaval right renal artery. AB - The aim of this study was to determine the prevalence of precaval right renal artery and to investigate the distribution of renal arteries and veins. We discuss a theory of development of renal vascular variants. We retrospectively reviewed 120 arterial phase contrast material-enhanced spiral computerized tomography scans of the abdomen (1- to 2-mm section thickness) performed during a two-month period. Forty percent of the study group (48 patients) had one artery and one vein on each side, with typical course. There was a 9.17% prevalence of precaval right renal artery: 10 patients had a lower pole accessory artery in precaval position and one patient had the main and the accessory arteries that pass anterior to the inferior vena cava. In these cases, associated variations of renal vessels were higher than in the patients without precaval artery variant. There were multiple arteries in 28.3% of the right kidneys and in 26.7% of the left ones. Variants of the right renal vein consisted in multiple veins in 20% (24 cases). We detected no case of multiple left renal veins, but we described variations of its course (circum- or retroaortic vein) in 9.17% (11 cases). Twenty-six patients (21.7%) had associated variations of the renal pedicle. The current technical support allows for a minimally invasive study of vessels anatomy. In our study the prevalence of a precaval right renal artery appears to be higher than previously reported (9.17%). Knowledge on anatomical variations of right renal artery and associated renal vessels variations has major clinical implications. PMID- 22198419 TI - Treatment of isolated chondral and osteochondral defects in the knee by autologous matrix-induced chondrogenesis (AMIC). AB - PURPOSE: The purpose of this study is to evaluate clinical and radiological outcomes of patients treated with autologous matrix-induced chondrogenesis (AMIC) for full-thickness chondral and osteochondral defects of the femoral condyles and patella. METHOD: A retrospective evaluation of clinical and radiographic outcomes of patients treated with AMIC for chondral and osteochondral full-thickness cartilage defects of the knee was performed with a mean follow-up of 28.8 +/- 1.5 months (range, 13-51 months). RESULTS: Significant improvements in clinical outcome scores (IKDC, Lysholm, Tegner, and VAS pain score) were noted. The largest improvements were seen in the osteochondral subgroup (mean age 25.9 years), whereas patients treated for chondral defects in the patellofemoral joint and on the femoral condyles improved less. Patients in all groups were generally satisfied with their results. MRI evaluation showed that tissue filling was present but generally not complete or homogenous. CONCLUSIONS: AMIC is a safe procedure and leads to clinical improvement of symptomatic full-thickness chondral and osteochondral defects and to regenerative defect filling. The value of AMIC relative to other cartilage repair procedures and to the natural course remains undefined. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 22198420 TI - Comparison of defibrillation efficacy between two pads placements in a pediatric porcine model of cardiac arrest. AB - OBJECTIVE: The placement of defibrillation pads at ideal anatomical sites is one of the major determinants of transthoracic defibrillation success. However, the optimal pads position for ventricular defibrillation is still undetermined. In the present study, we compared the effects of two different pads positions on defibrillation success rate in a pediatric porcine model of cardiac arrest. METHODS: Eight domestic male pigs weighing 12-15 kg were randomized to receive shocks using either the anterior-posterior (AP) or the anterior-lateral (AL) position with pediatric pads. Ventricular fibrillation (VF) was electrically induced and untreated for 30 s. A sequence of randomized biphasic electrical shocks ranging from 10 to 100 J was attempted. If the defibrillation failed to terminate VF, a 100 J rescuer shock was then delivered. After a recovery interval of 5 min, the sequence was repeated for a total of approximately 30 test shocks were attempted for each animal. The dose response curves were constructed and the defibrillation thresholds were compared between groups. RESULTS: The aggregated success rate was 65.6% for AP placement and 43.0% for AL one (p=0.0005) when shock energy was between 10 and 70 J. A significantly lower 50% defibrillation threshold was obtained for AP pads placement compared with traditional AL pads position (2.1+/-0.4 J/kg vs. 3.6+/-0.9 J/kg, p=0.041). CONCLUSION: In this pediatric porcine model of cardiac arrest, the anterior-posterior placement of pediatric pads yielded a higher success rate by lowering defibrillation threshold compared to the anterior-lateral position. PMID- 22198421 TI - Application of the Sequential Organ Failure Assessment score for predicting mortality in patients with acute myocardial infarction. AB - BACKGROUND: Thrombolysis in Myocardial Infarction (TIMI) score and Global Registry of Acute Coronary Events (GRACE) score have been validated as predictors of death in patients with acute myocardial infarction (AMI). This study was undertaken to determine whether the Sequential Organ Failure Assessment (SOFA) score had good accuracy for predicting mortality in AMI patients, and to compare the discriminatory performance of the 3 risk scores (RSs). METHODS: This was a retrospective study. We calculated the TIMI RS, GRACE RS, and SOFA score for 726 consecutive AMI patients. The study endpoint was all-cause mortality. All patients were followed up for at least 3 years or until the occurrence of death. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive ability of each score at different time points. RESULTS: For in-hospital death, the AUC were 0.67 for TIMI RS, 0.73 for GRACE RS, and 0.79 for SOFA score (P<0.001, respectively). However, the SOFA score and GRACE RS were significantly better for predicting the 1-year (P<0.001, respectively) and 3-year (P<0.001, respectively) mortality than the TIMI RS was. Multivariate Cox regression analysis revealed that the SOFA score was an independent predictor of long-term mortality in AMI patients [hazard ratio (HR), 1.313; 95% CI, 1.191 1.447]. CONCLUSIONS: The SOFA score provides potentially valuable prognostic information on clinical outcome when applied to patients with AMI. Compared with TIMI RS, both SOFA score and GRACE RS provide better discrimination for long-term mortality in patients presenting with AMI. PMID- 22198422 TI - The Simulation Team Assessment Tool (STAT): development, reliability and validation. AB - INTRODUCTION: Simulation sessions prepare medical professionals for pediatric emergencies. No validated tools exist to evaluate overall team performance. Our objective was to develop and evaluate the inter-rater reliability and validity of a team performance assessment tool during simulated pediatric resuscitations. METHODS: We developed the Simulation Team Assessment Tool (STAT) which evaluated 4 domains: basic assessment skills, airway/breathing, circulation, and human factors. Scoring of each element was behaviorally anchored from 0 to 2 points. Two teams of resuscitation experts and two teams of pediatric residents performed the same simulated pediatric resuscitation. Each team was scored by six raters using the STAT. Intraclass correlation coefficients (ICC) were calculated to assess inter-rater reliability. Overall performance and domain scores between expert and resident teams were compared using repeated measures of analysis of variance to assess construct validity. RESULTS: ICCs for overall performance were 0.81. Domain ICCs were: basic skills 0.73, airway/breathing skills 0.30, circulation skills 0.76, human factors 0.68. Expert versus resident average scores were: overall performance 84% vs. 66% (p=0.02), basic skills 73% vs. 55% (p<0.01); airway 80% vs. 75% (p=0.25), circulation 90% vs. 69% (p=0.02), human factors 89% vs. 66% (p=0.02). CONCLUSIONS: The STAT's overall performance, basic skills, circulation, and human factors domains had good to excellent inter-rater reliability, discriminating well between expert and resident teams. Similar performance in the airway/breathing domain among all teams magnified the impact of a small number of rater disagreements on the ICC. Additional study is needed to better assess the airway/breathing domain. PMID- 22198423 TI - Early initiation of basic resuscitation interventions including face mask ventilation may reduce birth asphyxia related mortality in low-income countries: a prospective descriptive observational study. AB - AIM OF THE STUDY: Early initiation of basic resuscitation interventions within 60 s in apneic newborn infants is thought to be essential in preventing progression to circulatory collapse based on experimental cardio-respiratory responses to asphyxia. The objectives were to describe normal transitional respiratory adaption at birth and to assess the importance of initiating basic resuscitation within the first minutes after birth as it relates to neonatal outcome. METHODS: This is an observational study of neonatal respiratory adaptation at birth in a rural hospital in Tanzania. Research assistants (n=14) monitored every newborn infant delivery and the response of birth attendants to a depressed baby. Time to initiation of spontaneous respirations or time to onset of breathing following stimulation/suctioning, or face mask ventilation (FMV) in apneic infants, and duration of FMV were recorded. RESULTS: 5845 infants were born; 5689 were liveborn, among these 4769(84%) initiated spontaneous respirations; 93% in <=30 s and 99% in <=60 s. Basic resuscitation (stimulation, suction, and/or FMV) was attempted in 920/5689(16.0%); of these 459(49.9%) received FMV. Outcomes included normal n=5613(96.0%), neonatal deaths n=56(1.0%), admitted neonatal area n=20(0.3%), and stillbirths n=156(2.7%). The risk for death or prolonged admission increases 16% for every 30 s delay in initiating FMV up to six minutes (p=0.045) and 6% for every minute of applied FMV (p=0.001). CONCLUSIONS: The majority of lifeless babies were in primary apnea and responded to stimulation/suctioning and/or FMV. Infants who required FMV were more likely to die particularly when ventilation was delayed or prolonged. PMID- 22198424 TI - Mannose-binding lectin deficiency is not associated with increased risk for polyomavirus nephropathy. AB - BACKGROUND: Polyomavirus associated nephropathy (PVAN) affects up to 10% of kidney transplant recipients and is a major risk factor for graft loss. Mannose binding lectin (MBL) is an important recognition molecule of the innate immune system, and its deficiency has been associated with susceptibility to various infections. In transplantation, on the other hand, high MBL levels have been associated with increased tissue damage in ischemia-reperfusion models and poorer graft and patient survival in solid organ transplant patients. To investigate the relation between MBL and BK virus infection, post-transplant (post-Tx) MBL levels were determined in a cohort of de novo kidney transplant patients with and without BK viremia. PATIENTS AND METHODS: 41 de novo kidney transplant patients with high (n=16, group 1) or low level BK viremia (n=25, group 2) and 64 patients without BK viremia (group 3) were included. In every patient, functional MBL levels were determined at 1-3 time points (days 30, 90 or 180) post-Tx using an MBL oligomer ELISA. RESULTS: MBL levels remained unchanged between days 30 and 180 post-Tx independent of BKV viremia. Frequencies of MBL deficiency (<500 ng/mL) and MBL levels were not significantly different between the 3 groups. However, group 2 patients showed a trend towards lower MBL serum levels compared to group 1 patients, notably in patients without acute rejection (p=0.076). CONCLUSION: MBL deficiency was not associated with higher risk for BK viremia. In contrast, we hypothesize that BK virus replication in patients with low MBL levels might imply lower risk for progression towards PVAN compared to patients with high MBL levels. This view is supported by recent data demonstrating local complement activation in BK nephropathy. PMID- 22198425 TI - A phase II study of halichondrin B analog eribulin mesylate (E7389) in patients with advanced non-small cell lung cancer previously treated with a taxane: a California cancer consortium trial. AB - INTRODUCTION: Eribulin mesylate (E7389) is an analog of halichondrin B with a unique mechanism of microtubule binding. The activity and toxicity of eribulin were assessed in patients with advanced non-small cell lung cancer (NSCLC) previously treated with a taxane. METHODS: An open-label phase II study included patients with NSCLC previously treated with platinum and taxane-based therapy, with up to two prior cytotoxic regimens, given for metastatic disease or as adjuvant therapy. Patients were stratified by taxane-sensitivity: taxane sensitive (TS, progression >90 days after taxane) or taxane-resistant (TR, progression <=90 days after taxane). Patients received an intravenous infusion of eribulin at 1.4 mg/m on days 1 and 8 every 21 days. The primary end point was objective response rate and secondary end points included progression-free survival and overall survival. RESULTS: Sixty-six patients were accrued. The objective response rate was 5% with a median duration of response of 7.8 months. In the TS arm, 3 of 45 patients (7%) achieved a partial response and another 11 of 45 (24%) achieved stable disease for at least 3 months, whereas in the TR arm, no patients achieved a partial response and 4 of 21 (19%) achieved stable disease for at least 3 months. Median progression-free survival was 2.9 months in the TS subgroup and 1.2 months in the TR subgroup. The median overall survival was 12.6 months in the TS subgroup and 8.9 months in the TR subgroup. Toxicities were primarily hematologic; only two patients developed grade 3 neuropathy. CONCLUSIONS: Eribulin mesylate is well tolerated and demonstrates activity in pretreated, TS NSCLC. PMID- 22198426 TI - Phase I/II trial of custirsen (OGX-011), an inhibitor of clusterin, in combination with a gemcitabine and platinum regimen in patients with previously untreated advanced non-small cell lung cancer. AB - PURPOSE: Clusterin (CLU), an antiapoptotic, stress-associated protein, confers resistance to therapy when overexpressed. This trial tested custirsen (OGX-011), an inhibitor of CLU protein production, combined with gemcitabine/platinum in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This was a single-arm, multicenter, phase I/II study in chemotherapy-naive stage IIIB/IV NSCLC. Custirsen was infused during a loading dose period and weekly in combination with gemcitabine (1250 mg/m) on days 1 and 8 and with cisplatin (75 mg/m) or carboplatin (area under the curve 5) on day 1 of each 21-day cycle. Ten patients were treated in a phase I lead-in and 71 in the phase II component. The primary efficacy endpoint was response rate, with exploratory analyses of other efficacy outcomes and biomarker relationships. RESULTS: Eighty-one patients received custirsen and were included in the primary analysis. The median age was 61 years; 82% had stage IV disease. Overall response was 25 of 81 (31%; 95% confidence interval 21-42). The 1- and 2-year survivals were 54 and 30%, respectively. Toxicity of the combination was not appreciably different from what is reported for gemcitabine/platinum combinations. Custirsen treatment decreased serum CLU levels in 95% of patients evaluated. Patients who achieved a minimum median CLU level for the population of <=38 MUg/ml during treatment had a median survival of 27.1 compared with 16.1 months for patients who did not (p = 0.02). CONCLUSION: Based on the above results, a randomized phase 3 trial to evaluate the survival benefit of custirsen in patients with NSCLC is warranted. PMID- 22198427 TI - Randomized study of endobronchial ultrasound-guided transbronchial biopsy: thin bronchoscopic method versus guide sheath method. AB - INTRODUCTION: In endobronchial ultrasound-guided transbronchial biopsy (EBUS TBB), techniques using a thin bronchoscope or a guide sheath have been proposed for accurate biopsy instrument reinsertion into the bronchial route indicated by a radial ultrasonic probe. The purpose of this study was to compare the diagnostic yields of these techniques for peripheral pulmonary lesions. METHODS: Patients with suspected peripheral pulmonary lesions were included in this prospective, randomized, noninferiority study and assigned to undergo EBUS-TBB under fluoroscopic guidance using a prototype 3.4-mm thin bronchoscope or a 4.0 mm bronchoscope with a guide sheath. RESULTS: A total of 205 patients were enrolled and randomized, of whom 203 patients (101 thin bronchoscopic method; 102 guide sheath method) were included in the analysis. Diagnostic histologic specimens were obtained in 65% (41% for benign and 75% for malignant lesions) of the thin bronchoscopy group and 62% (25% for benign and 71% for malignant lesions) of the guide sheath group. Diagnostic performance of the thin bronchoscopic method was confirmed to be noninferior to the guide sheath method (difference in diagnostic yields, 3.6%; 90% confidence interval, -7.5 to 14.7%). Mean procedure time was significantly shorter in the thin bronchoscopy group than the guide sheath group (27 versus 33 minutes; p = 0.002). Complications including pneumothorax, moderate bleeding, and pneumonia occurred in 5% and 2% in the respective groups (p = 0.28). CONCLUSIONS: EBUS-TBB using the thin bronchoscope was noninferior to the guide sheath method for the diagnosis of peripheral pulmonary lesions and was associated with shorter procedural time. PMID- 22198428 TI - Number of circulating endothelial progenitor cells and intratumoral microvessel density in non-small cell lung cancer patients: differences in angiogenic status between adenocarcinoma histologic subtypes. AB - INTRODUCTION: Angiogenesis plays a significant role in tumor progression. This study examined the association between the number of circulating endothelial progenitor cells (EPCs), intratumoral microvessel density (MVD) (both of which may be markers for neovascularization), and lung cancer histological types, particularly adenocarcinoma histological subtypes. METHODS: A total of 83 stage I non-small cell lung cancer (NSCLC) patients underwent complete tumor resection between November 2009 and July 2010. The number of EPCs from the pulmonary artery of the resected lungs was measured by assaying CD34/vascular endothelial growth factor receptor 2 positive cells, and the MVD was assessed immunohistochemically in tumor specimens by staining for CD34. RESULTS: A statistically significant correlation between the number of EPCs from pulmonary artery and intratumoral MVD was found (p < 0.001). No statistically significant differences in the number of EPCs and the MVD were observed between the adenocarcinomas and the squamous cell carcinomas. Among the adenocarcinoma histological subtypes, a higher number of EPCs and MVD were found significantly more frequently in solid adenocarcinomas than in nonsolid adenocarcinomas (p < 0.001 and p = 0.011, respectively). In addition, solid adenocarcinomas showed higher levels of vascular endothelial growth factor using quantitative real-time polymerase chain reaction in the tumor tissue samples than in the nonsolid adenocarcinomas (p = 0.005). CONCLUSION: The higher number of circulating EPCs and the MVD of solid adenocarcinoma may indicate the presence of differences in the tumor angiogenic status between early stage adenocarcinoma histological subtypes. Among adenocarcinoma patients, patients with solid adenocarcinoma may be the best candidates for antiangiogenic therapies. PMID- 22198429 TI - Hypofractionated image-guided radiation therapy for patients with limited volume metastatic non-small cell lung cancer. AB - INTRODUCTION: Outcomes data treating patients with oligometastatic (<= 5 metastases) non-small cell lung carcinoma (NSCLC) with hypofractionated image guided radiotherapy (HIGRT) are limited. METHODS: Consecutive oligometastatic NSCLC patients were reviewed from a prospective database. Patients were included if all active diseases were treated with HIGRT. Lesions that had received prior radiation or had radiographic/metabolic resolution after chemotherapy were not treated with HIGRT. Local control of all treated lesions, distant control, progression-free survival (PFS), overall survival (OS), and control of individual lesions (LeC) were calculated. RESULTS: Twenty-five patients with median of 2 treated oligometastatic lesions were included. Median follow-up was 14 months. Median age was 66 years. Nineteen patients received systemic therapy before HIGRT and 11 had progressive disease after their most recent systemic therapy before HIGRT. Median OS and PFS were 22.7 and 7.6 months. The 18 months local control, distant control, OS, and PFS were 66.1%, 31.7%, 52.9%, and 28.0%. Greater than two sites treated with HIGRT, nonadenocarcinoma histology, prior systemic therapy, and progression after systemic therapy were associated with worse PFS. Sixty-two individual lesions of median size 2.7 cm were treated. For extracranial lesions, median total and fraction dose were 50 and 5 Gy. Median standard equivalent dose in 2 Gy fractions for extracranial lesions was 64.6 Gy yielding 18 months LeC of 70.7%. Standard equivalent dose >=64.6 Gy increased LeC (p = 0.04). Two patients experienced grade 3 toxicity. CONCLUSIONS: HIGRT for oligometastatic NSCLC provides durable LeC and may provide long-term PFS in some patients. Future HIGRT studies should optimize patient selection and integration with systemic therapy. PMID- 22198430 TI - c-MET/phospho-MET protein expression and MET gene copy number in non-small cell lung carcinomas. AB - INTRODUCTION: The hepatocyte growth factor/MET pathway has been shown to cause tumor progression in several types of carcinomas. The aim of this study was to examine the correlations between c-MET/phospho-MET expression as well as MET gene copy number alterations and overall survival (OS) in non-small cell lung carcinomas (NSCLCs). METHODS: We analyzed 906 NSCLCs including 704 adenocarcinomas (ADCs), 150 squamous cell carcinomas (SCCs), 43 sarcomatoid carcinomas, and 9 large cell carcinomas. The mutational status of epidermal growth factor receptor and K-ras and anaplastic lymphoma kinase rearrangements were retrospectively examined. We performed immunohistochemistry to detect c MET/phospho-MET expression and MET gene copy number using bright-field in situ hybridization (BISH). RESULTS: c-MET/phospho-MET expression and MET BISH positivity were observed in 22.2%, 5.6%, and 10.9% of NSCLCs, respectively; they were more prevalent in ADCs (27.3%, 6.9%, and 11.5%, respectively) and sarcomatoid carcinomas (20.9%, 9.3%, and 36.6%, respectively) than in SCCs and large cell carcinomas. Among ADCs, poorly differentiated cases exhibited c-MET expression and MET BISH positivity more commonly than well-differentiated ones. An analysis of all patients revealed that c-MET/phospho-MET expression and MET BISH positivity were not correlated with OS. However, when SCC cases were excluded, both univariate (p=0.019) and multivariate (p=0.020) analyses revealed a significant correlation between MET BISH positivity and OS. CONCLUSIONS: c MET/phospho-MET expression and MET BISH positivity differed according to histological type. Among ADCs, c-MET expression and MET BISH positivity were more common in poorly differentiated cases. MET BISH positivity was an independent prognostic factor in nonsquamous NSCLCs. PMID- 22198431 TI - Fetal outcome in autoimmune diseases. AB - The impact on fetal outcome in women with autoimmune diseases is a result of a several conditions. Fetal success depends on early immunological changes in the mother, which rely in modifications of the innate and adaptative immune system, inducing tolerance to the semi-allogenic fetus. Others crucial factors are maternal disease activity, severity of organ damage, circulating antibodies, and drug treatment. Although fetal outcome is becoming better still it has a worse prognosis in comparison with healthy women. Diseases like antiphospholipid syndrome, systemic lupus erythematosus and vasculitis have the higher risk while rheumatoid arthritis and spondiloarthopaties the least. In the majority of the diseases the risk of poor fetal outcome directly correlates with the activity of disease. While there are no pathognomonic autoantibodies for fetal outcome, antiphospholipid and anti-thyroid antibodies have been implicated in unsuccessful pregnancies and anti-Ro and, to a lesser extent, anti-La antibodies may result in neonatal lupus syndrome congenital heart block. There is increasingly the hope that fetal outcome will be good if the disease is well controlled prior to pregnancy, and with a specialized interdisciplinary support. PMID- 22198432 TI - Renal organogenesis: what can it tell us about renal repair and regeneration? AB - The increasing prevalence of chronic kidney disease in the absence of new treatment modalities has become a strong driver for innovation in nephrology. An increasing understanding of stem cell biology has kindled the prospects of regenerative options for kidney disease. However, the kidney itself is not a regenerative organ, as all the nephrons are formed during embryonic development. Here, we will investigate advances in the molecular genetics of renal organogenesis, including what this can tell us about lineage relationships, and discuss how this may serve to inform us about both the normal processes of renal repair and options for regenerative therapies. PMID- 22198433 TI - Wnt/planar cell polarity signaling: an important mechanism to coordinate growth and patterning in the limb. AB - The limb is one of the premier models for studying how a simple embryonic anlage develops into complex three-dimensional form. One of the key issues in the limb field has been to determine how the limb becomes patterned along its proximal (shoulder/hip) to distal (digits) axis. For decades it has been known that the apical ectodermal ridge (AER) plays a crucial role in distal outgrowth and patterning of the vertebrate embryonic limb. Most studies have explored the relationship between the AER and the progressive assignment of cell fates to mesenchyme along the proximal to distal (PD) axis. Comparatively few, however, have examined the additional role of the AER to regulate distal outgrowth of the limb and how this growth may also influence pattern along the PD axis. Here, I will review key studies that explore the role of growth in limb development. In particular, I will focus on a recent flurry of papers that examine the role of the Wnt/planar cell polarity (PCP) pathway in regulating directed growth of the limb mesenchyme. Finally, I will discuss a potential mechanism that relates the AER to the Wnt/PCP pathway and how directed growth can play a role in shaping the limb along the PD axis. PMID- 22198435 TI - Structural differences in the osteocyte network between the calvaria and long bone revealed by three-dimensional fluorescence morphometry, possibly reflecting distinct mechano-adaptations and sensitivities. AB - The structural features of osteocytes and their cellular process network are thought to allow for mechanotransduction from the bone tissue to these cells. This study applied three-dimensional fluorescence microscopy to fixed and decalcified bone specimens to quantitatively compare the osteocytes and their networks between mouse parietal bone and tibia that are physiologically enforced by distinct mechanical loads. The subsequent morphometric analysis by the surface rendering of osteocyte cell bodies revealed the tibia to have relatively enriched cytoplasm in the osteocyte cell body in comparison to the parietal bone. Furthermore, quantitative tracing of the cellular processes in silico demonstrated that the numbers of the cellular processes and their bifurcation points per osteocyte in the tibia were significantly higher than those in the parietal bone. Though the total length of the processes per osteocyte in the tibia was two times longer, its total surface area and total volume were smaller than those in the parietal bone, due to its thinner diameter. These architectural differences in the osteocytes and their networks are thus implicated in the adaptation to physiologically different loading, and may also induce distinct mechanosensitivities. PMID- 22198434 TI - Transition from organogenesis to stem cell maintenance in the mouse adrenal cortex. AB - Mice showing mosaic expression of an appropriate marker gene that is activated during development provide simple tools for investigating cell lineages. We used the mosaic beta-galactosidase staining patterns in adrenal cortices of 21OH/ LacZ transgenic mice to study both organogenesis and maintenance of the adult tissue. Randomly orientated mosaic patterns present in embryonic day 14.5 (E14.5) adrenals changed progressively during the perinatal period from discrete spots, via patches and radial arrays, to radial stripes, which first emerged between postnatal days 0 and 7 (P0 and P7). The mosaic radial stripe pattern was fully established by P21 and remained unchanged throughout the adult period (8-52 weeks). The mouse adrenal gland grew continuously between E14.5 and P21, including the period during which stripes emerge. Ki67-positive, proliferative cells in the adrenal cortex were mainly localized to the outer cell layers between E18.5 and P3. By P10, cell proliferation had increased, and the proliferative region had expanded but was still mainly confined to the outer cortex. Correlation of changes in mosaic patterns in 21OH/LacZ adrenal cortices with the locations of adrenocortical cell proliferation suggest that the radial stripes arise by edge-biased growth during the perinatal period, even if they are maintained by stem cells in adults. The stability of the adult stripe pattern suggests that stem cell function is unchanged between 8 and 52 weeks. PMID- 22198436 TI - In vitro glycation of human serum albumin by dihydroxyacetone and dihydroxyacetone phosphate. AB - Amino groups in proteins can non-enzymatically react with reducing sugars to generate a structurally diverse group of compounds referred to as advanced glycation end products (AGEs). The in vivo formation of AGEs contributes to some of the complications of diabetes including atherosclerosis, cataract formation, and renal failure. The formation of AGEs is dependent on both sugar and protein concentrations. Increases in temperature, pH, and exposure time of sugars to the proteins also play a significant role in the rate of AGE formation. This study focuses on the use of a combination of analytical techniques to study the in vitro AGE formation of HSA with dihydroxyacetone phosphate (DHAP), a ketose generated during glycolysis, and its dephosphorylated analog, dihydroxy acetone (DHA), commonly used as a browning reagent in skin tanning preparations. The extent of AGE formation was affected by DHAP and DHA concentrations and by the duration of HSA exposure to these glycating agents. Increases in temperature and pH sped the glycation process and enhanced the formation of the AGEs of HSA. MALDI-TOF mass spectroscopic data provided a reliable result to evaluate the extent of the AGE formation. PMID- 22198437 TI - Rat glucagon receptor mRNA is directly regulated by glucose through transactivation of the carbohydrate response element binding protein. AB - The glucagon receptor (Gcgr) is essential for maintaining glucose homeostasis in the liver and for stimulating insulin secretion in pancreatic beta-cells. Glucose induces rat Gcgr mRNA expression; however, the precise mechanism remains unknown. We previously have studied the role of the carbohydrate response element binding protein (ChREBP), a glucose-activated transcription factor, in the regulation of glucose-stimulated gene expression. The G-box has previously been reported to be responsible for glucose regulation of Gcgr mRNA expression. The G-box comprises two E-boxes separated by 3bp, which distinguishes it from the carbohydrate response element (ChoRE), which has 5-bp spacing between the two E-boxes. In the rat Gcgr promoter, a putative ChoRE (-554bp/-538bp) is localized near the G-box ( 543bp/-529bp). In rat INS-1E insulinoma cells, deletion studies of the rat Gcgr promoter show that ChoRE is a minimal glucose response element. Moreover, reporter assays using a pGL3 promoter vector, which harbors ChoRE and chromatin immunoprecipitation assays reveal that ChoRE is a functional glucose response element in the rat Gcgr promoter. Furthermore, In contrast, glucagon partly suppresses glucose-induced expression of Gcgr mRNA. Thus, ChREBP directly regulates rat Gcgr expression in INS-1E cells. In addition, negative feedback looping between ChREBP and GCGR may further contribute to the regulation of glucose-induced gene expression. PMID- 22198438 TI - Neuropathology of acute liver failure. AB - Cerebral edema has been identified in all forms of liver disease and is closely related to the development of hepatic encephalopathy. Cerebral edema is most readily recognized in acute liver failure (ALF), while the main cause of death in patients with ALF is multi-organ failure; brain herniation as a result of intracranial hypertension does remain a major cause of mortality. The mechanisms responsible for cerebral edema in ALF suggest both cytotoxic and vasogenic injury. This article reviews the gross and ultrastructural changes associated with cerebral edema in ALF. The primary cause of cerebral edema is associated with astrocyte swelling, mainly perivascular edema and ammonia still remains the primary neurotoxin involved in its pathogenesis. The astrocytic changes were confined to the gray matter. The other organelles involved in the pathogenesis of ALF include mitochondria, basement membrane, pericytes, microglial cells, blood brain barrier (BBB) etc. Discrete neuronal changes have recently been reported. Recent studies in animal and humans have demonstrated the microglial changes which have the potential to cause neuronal dysfunction in ALF. The alterations in BBB still remain unclear though few studies have showed disruption of tight junction proteins indicating the involvement of BBB in cellular swelling. PMID- 22198439 TI - Sema4D as an inhibitory regulator in oligodendrocyte development. AB - The specific functions of intrinsic regulators of OL differentiation are poorly understood. Sema4D, originally found as a negative regulator of axon guidance, is mainly expressed by oligodendrocytes in the postnatal brain, and our previous study revealed that the lack of Sema4D induced an increase in the number of oligodendrocytes in the cerebral cortex, suggesting that Sema4D may function as an intrinsic regulator of oligodendrocyte development. In this study, we assessed the effects of Sema4D deficiency and of the exogenous addition of Sema4D on oligodendrocyte differentiation. Sema4D deficiency induced an increase in the number of oligodendrocytes in the cerebral cortex at postnatal day 14 and later, without increase in the number of oligodendrocyte progenitor cells. This increase was also observed in cultured oligodendrocytes obtained from Sema4D-deficient mice. Then we investigated whether Sema4D deficiency can increase the proliferation of the progenitor cells or influence the apoptosis. Apoptotic oligodendrocytes were markedly reduced in number in the developing cerebral cortex and in cultured oligodendrocytes obtained from Sema4D-deficient mice, although no significant change was found in proliferation of oligodendrocyte progenitor cells. Exogenous addition of Sema4D prevented the oligodendrocytes from this reduction of apoptosis, and further enhanced apoptosis in oligodendrocytes. Thus, Sema4D may act as an intrinsic inhibitory regulator of oligodendrocyte differentiation by promoting apoptosis. PMID- 22198440 TI - Comparison of academic and nonacademic sites in multi-center clinical trials. AB - The selection of appropriate subjects is a critical element of successful clinical trials. Failure to properly identify, select, and retain subjects in clinical trials of antidepressant medications may affect the ability to show separation from placebo. Little is known about which type of site, academic or nonacademic, is superior in selecting and retaining appropriate subjects. In the present investigation, the authors conducted a retrospective analysis comparing the performance of academic and nonacademic sites in selecting and retaining appropriate subjects in a recently completed multi-site clinical study of aripiprazole augmentation. The authors used a set of operationalized criteria called the SAFER to identify appropriate study subjects. No significant differences were found in rates of SAFER interview passing, study completion, and clinical outcomes between academic and nonacademic sites. Our findings suggest that academic and nonacademic sites are equally effective in their ability to identify and retain appropriate study participants. PMID- 22198441 TI - Omega-3 fatty acid augmentation of citalopram treatment for patients with major depressive disorder. AB - OBJECTIVE: The objective of this study was to explore the efficacy of combination therapy with citalopram plus omega-3 fatty acids versus citalopram plus placebo (olive oil) in the initial treatment of individuals with major depressive disorder (MDD). We hypothesized that combination therapy would lead not only to greater efficacy but also to a more rapid onset of therapeutic response. METHODS: Forty-two subjects participated in this 9-week randomized, masked, placebo controlled study of combination therapy (two 1 g capsules containing a blend of 900 mg of eicosapentaenoic acid, 200 mg of and docosahexaenoic acid, and 100 mg of other omega-3 fatty acids twice daily plus citalopram) versus monotherapy (two 1 g capsules of olive oil per day plus citalopram) treatment of MDD. RESULTS: The combination therapy demonstrated significantly greater improvement in Hamilton Depression Rating scale scores over time (F = 7.32; df 1,177; P = 0.008) beginning at week 4 (t = -2.48; df 177; P = 0.014). CONCLUSIONS: Combination therapy was more effective than monotherapy in decreasing signs and symptoms of MDD during the 8 weeks of active treatment; however, combination therapy did not seem to enhance the speed of the initial antidepressant response. These findings suggest that there may be an advantage to combining omega-3 fatty acids with a selective serotonin uptake inhibitor in the initial treatment of individuals with MDD. A larger definitive study is warranted. PMID- 22198442 TI - All-cause mortality and medication risk factors in schizophrenia: a prospective cohort study. AB - BACKGROUND: It is well established that persons with schizophrenia have high mortality rates. There is conflicting evidence that antipsychotic and perhaps other medications routinely used to treat schizophrenia contribute to mortality risk. METHODS: A health insurer database was used to examine schizophrenia diagnosis and mortality in 2008. Information from the period 2006-2008 was used to analyze demographics and medication prescriptions. The risk set composed of patients with schizophrenia using an antipsychotic (n = 7415) and a group of randomly chosen control subjects (n = 97,726). RESULTS: The mortality risk for having a diagnosis of schizophrenia and using an antipsychotic versus the random control group was a hazard ratio (HR) of 2.6; 95% CI, 2.0-3.2. Over the 3-year period, age, receiving a first-generation antipsychotic, and the use of a mood stabilizer were associated with a higher risk of mortality: HR, 1.06; 95% CI, 1.04-1.08; HR, 2.36; 95% CI, 1.38-4.04; and HR, 8.42; 95% CI, 3.06-24.07, respectively. CONCLUSION: Patients with schizophrenia have higher mortality rates than normal controls. The type of antipsychotic and concomitant medication can affect mortality rates in schizophrenia. PMID- 22198443 TI - Does the medication pattern reflect the CYP2D6 genotype in patients with diagnoses within the schizophrenic spectrum? AB - BACKGROUND: Cytochrome P450 2D6 enzyme (CYP2D6) is an important metabolic pathway for many antipsychotics. Its genetic polymorphism causes pharmacokinetic variability that might lead to adverse drug reactions or treatment failure unless countered by appropriate dose adjustments or shift to CYP2D6-independent antipsychotics. PURPOSE: To investigate the clinical impact of CYP2D6 genotype in patients with a diagnosis within the schizophrenic spectrum using medication pattern as proxy for therapeutic and side effect. METHODS: The study was conducted in patients genotyped during an inpatient stay (N = 576). Continuous antipsychotic, adjuvant, and anticholinergic drug regimens were registered retrospectively in a cross-sectional manner before genotyping. Antipsychotics were divided into CYP2D6 dependent and independent, and dose equivalents were calculated as chlorpromazine equivalents (CPZEq). RESULTS: Poor metabolizers and ultrarapid metabolizers were treated with significantly higher median CPZEq doses (625.8; inter quartile range [IQR], 460.4-926.7; and 550; IQR, 199.8-1049) than extensive metabolizers (EMs) and intermediate metabolizers (IMs) (384; IQR, 150 698; and 446; IQR, 150-800) (P = 0.018). Logistic regression showed no association between anticholinergic treatment and CYP2D6 genotype or concomitant treatment with CYP2D6 inhibitors (P = 0.79 and P = 0.46, respectively). CONCLUSIONS: Our results indicate that CYP2D6 genotype has no sufficient clinical impact that poor metabolizers and ultrarapid metabolizers are easily clinically identified with. PMID- 22198444 TI - The effectiveness and safety of adjunctive aripiprazole in Taiwanese patients with antidepressant-refractory major depressive disorder: a prospective, open label trial. AB - There is currently no published clinical trial on the safety and effectiveness of aripiprazole in Taiwanese patients with treatment-refractory major depressive disorder. We were interested in determining the applicability of current recommended doses of aripiprazole as an adjunct to antidepressant therapy in this population. We conducted a prospective, open-label nonrandomized, 4-week flexibly dosed (2.5-5 mg/d) trial with aripiprazole augmentation in 9 Taiwanese patients who had a history of nonresponse to at least 2 adequate courses of antidepressant therapy with different types of antidepressants. The primary end point for clinical effectiveness was mean change in the 17-item Hamilton Rating Scale for Depression at the end of the 4-week trial. Secondary end points for clinical effectiveness included mean change in Beck Depression Inventory and Beck Anxiety Inventory scores. The Systematic Assessment of Treatment Emergent Events-General Inquiry was used to assess adverse effects. All patients completed the trial and responded to treatment; the remission rate was 77.8%. The mean daily dose of adjunctive aripiprazole was 4.2 mg. Common treatment-emergent adverse events included insomnia and sedation (33.3%) and akathisia (22.2%). We found high effectiveness despite a lower mean daily dose of adjunctive aripiprazole (4.2 mg) when compared with previously reported findings; however, we also observed a higher frequency of treatment-emergent adverse effects. Additional studies are required to ascertain whether there are ethnic differences in the pharmacokinetics and/or pharmacodynamics of aripiprazole in treatment-refractory depression. PMID- 22198445 TI - Increased risk of antipsychotic-related QT prolongation during nighttime: a 24 hour holter electrocardiogram recording study. AB - Most antipsychotic agents can cause QT prolongation, which causes torsades de pointes. The QT interval in healthy subjects is longer during nighttime than during daytime. The QT interval of patients treated with antipsychotics may be prolonged during nighttime, and the effects of antipsychotics on the QT interval may differ between antipsychotics. This study investigated the circadian dynamics of the QT interval in patients treated with antipsychotics and healthy controls, using a 24-hour Holter electrocardiogram in a clinical setting. Sixty-six patients with a diagnosis of schizophrenia that were treated with risperidone or olanzapine and 40 healthy volunteers were enrolled. The QT intervals were corrected using the Fridericia formula (QTcF = QT / RR). Mean +/- SD nighttime QTcFs were 411.6 +/- 29.0, 395.9 +/- 21.2, and 387.8 +/- 19.0 milliseconds (ms) in the risperidone, olanzapine, and control groups, respectively. The mean daytime QTcFs were 397.7 +/- 23.4, 392.4 +/- 18.9, and 382.6 +/- 17.3 ms, respectively. The mean nighttime QTcF of the risperidone group was significantly longer than that of the olanzapine and control groups, although there was no significant difference in the mean daytime QTcF between the risperidone and olanzapine groups. The current study used 24-hour Holter electrocardiograms to reveal significantly longer QT intervals in the risperidone group especially during nighttime. In clinical practices, evaluations of the QT interval have been conducted over short periods in the daytime, but it is believed that such methods may not be able to fully elucidate the effects of antipsychotics on the QT interval. PMID- 22198446 TI - Variation in antipsychotic treatment choice across US nursing homes. AB - OBJECTIVE: Despite serious safety concerns, antipsychotic medications continue to be used widely in US nursing homes. The objective of this study was to quantify the variation in antipsychotic treatment choice across US nursing homes, and to characterize its correlates. METHODS: Prescribing practices were assessed in a cohort of 65,618 patients 65 years or older in 45 states who initiated treatment with an antipsychotic medication after nursing home admission between 2001 and 2005, using merged Medicaid; Medicare; Minimum Data Set; and Online Survey, Certification, and Reporting data. We fit mixed-effects logistic regression models to examine how antipsychotic treatment choice at the patient-level depends on patient and nursing home fixed and random effects. RESULTS: Among antipsychotic medication users, 9% of patients initiated treatment with a conventional agent. After adjustment for case-mix and facility characteristics, 95% of nursing homes had a predicted conventional antipsychotic prescribing rate between 2% and 20%. Individually, patient characteristics accounted for 36% of the explained variation, facility characteristics for 23%, and nursing home prescribing tendency for 81%. Results were consistent in the subgroup of nursing home patients with a diagnosis of dementia. The prescribing physician was not considered as a determinant of treatment choice owing to data limitations. CONCLUSION: These findings indicate that antipsychotic treatment choice is to some extent influenced by a nursing home's underling prescribing "culture." This culture may reveal strategies for targeting quality improvement interventions. In addition, these findings suggest that a nursing home's tendency for specific antipsychotics merits further exploration as an instrumental variable for improved confounding adjustment in comparative effectiveness studies. PMID- 22198447 TI - Treating depression after initial treatment failure: directly comparing switch and augmenting strategies in STAR*D. AB - OBJECTIVE: Augmenting and switching antidepressant medications are the 2 most common next-step strategies for depressed patients failing initial medication treatment. These approaches have not been directly compared; thus, our objectives are to compare outcomes for medication augmentation versus switching for patients with major depressive disorder in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial. METHODS: We conducted a retrospective analysis of participants aged 18 to 75 years with DSM-IV nonpsychotic depression who failed to remit with initial treatment in the STAR*D clinical trial (N = 1292). We compared depressive symptom remission, response, and quality of life among participants in each study arm using propensity score matching to minimize selection bias. RESULTS: The propensity-score-matched augment (N = 269) and switch (N = 269) groups were well balanced on measured characteristics. Neither the likelihood of remission (risk ratio, 1.14; 95% confidence level, 0.82-1.58) or response (risk ratio, 1.14; 95% confidence level, 0.82-1.58), nor the time to remission (log-rank test, P = 0.946) or response (log-rank test, P = 0.243) differed by treatment strategy. Similarly, quality of life did not differ. Post hoc analyses suggested that augmentation improved outcomes for patients tolerating 12 or more weeks of initial treatment and those with partial initial treatment response. CONCLUSIONS: For patients receiving and tolerating aggressive initial antidepressant trials, there is no clear preference for next-step augmentation versus switching. Findings tentatively suggest that those who complete an initial treatment of 12 weeks or more and have a partial response with residual mild depressive severity may benefit more from augmentation relative to switching. PMID- 22198449 TI - The psychopharmacology of aggressive behavior: a translational approach: part 1: neurobiology. AB - Patients with mental disorders are at an elevated risk for developing aggressive behavior. In the last 19 years, the psychopharmacological treatment of aggression has changed dramatically because of the introduction of atypical antipsychotics into the market and the increased use of anticonvulsants and lithium in the treatment of aggressive patients.Using a translational medicine approach, this review (part 1 of 2) examines the neurobiology of aggression, discussing the major neurotransmitter systems implicated in its pathogenesis, namely, serotonin, glutamate, norepinephrine, dopamine, and gamma-aminobutyric acid, and also their respective receptors. The preclinical and clinical pharmacological studies concerning the role of these neurotransmitters have been reviewed, as well as research using transgenic animal models. The complex interaction among these neurotransmitters occurs at the level of brain areas and neural circuits such as the orbitoprefrontal cortex, anterior cortex, amygdala, hippocampus, periaqueductal gray, and septal nuclei, where the receptors of these neurotransmitters are expressed. The neurobiological mechanism of aggression is important to understand the rationale for using atypical antipsychotics, anticonvulsants, and lithium in treating aggressive behavior. Further research is necessary to establish how these neurotransmitter systems interact with brain circuits to control aggressive behavior at the intracellular level. PMID- 22198448 TI - Asenapine as adjunctive treatment for acute mania associated with bipolar disorder: results of a 12-week core study and 40-week extension. AB - In a 12-week randomized, placebo-controlled study evaluating the efficacy and safety of adjunctive asenapine, bipolar I disorder patients experiencing manic or mixed episodes despite pretreatment with lithium or valproate monotherapy were treated with flexible-dose, twice-daily asenapine 5 or 10 mg (n = 158) or placebo (n = 166). The primary efficacy end point was change from baseline Young Mania Rating Scale (YMRS) total score at week 3. Secondary outcomes included YMRS response and remission and Clinical Global Impression for Bipolar Disorder and Montgomery-Asberg Depression Rating Scale score changes. Patients completing the core study were eligible for a 40-week double-blind extension assessing safety and tolerability. Adjunctive asenapine significantly improved mania versus placebo at week 3 (primary end point) and weeks 2 to 12. The YMRS response rates were similar at week 3 but significantly better with asenapine at week 12. The YMRS remission rates and changes from baseline on Clinical Global Impression for Bipolar Disorder for mania and overall illness were significantly better with asenapine at weeks 3 and 12. No other statistically significant differences on secondary outcomes were observed. Only a small number of patients entered the extension, making firm statistical conclusions on efficacy difficult. Treatment emergent adverse events reported by 5% or more of asenapine patients and at twice the incidence of placebo were sedation, somnolence, depression/depressive symptoms, oral hypoesthesia, and increased weight in the 12-week core study. Adjunctive asenapine to lithium or valproate was more effective than mood stabilizer monotherapy in the core study and was well tolerated for up to 52 weeks. PMID- 22198450 TI - Effects of aripiprazole and the Taq1A polymorphism in the dopamine D2 receptor gene on the clinical response and plasma monoamine metabolites level during the acute phase of schizophrenia. AB - The Taq1A polymorphism in the dopamine D2 receptor (DRD2) gene could be related to the response to antipsychotics. We examined the effects of the Taq1A polymorphism on the plasma monoamine metabolites during the treatment of schizophrenia with aripiprazole, a DRD2 partial agonist. Thirty Japanese patients with schizophrenia were treated with aripiprazole for 6 weeks. We measured plasma levels of homovanillic acid (pHVA) and 3-methoxy-4hydroxyphenylglycol (pMHPG) before and after treatment. The Taq1A polymorphism was genotyped with polymerase chain reaction. Aripiprazole improved the acute symptoms of schizophrenia and decreased pHVA in responders (P = 0.023) but not in nonresponders (P = 0.28). Although A1 allele carriers showed a tendency to respond to aripiprazole (61.5%) compared to A1 allele noncarriers (29.4%) (P = 0.078), there was not statistically significant difference in the response between the 2 genotype groups. There were significant effect for response (P = 0.013) and genotype * response interaction (P = 0.043) on the change of pHVA. The changes of pHVA differ between responders and nonresponders in A1 allele carriers but not in A1 allele noncarriers. There were no genotype or response effects or genotype * response interaction on the changes of the plasma levels of 3-methoxy 4hydroxyphenylglycol. Our preliminary results suggest that Taq1A polymorphism may be partly associated with changes in pHVA during acute schizophrenia. PMID- 22198452 TI - Tetrabenazine augmentation in treatment-resistant schizophrenia: a 12-week, double-blind, placebo-controlled trial. AB - Evidence linking schizophrenia to alterations in presynaptic dopamine (DA) grows, although treatments to date have largely focused on postsynaptic D2 receptor blockade. This study examined augmenting response in treatment-resistant schizophrenia through the addition of tetrabenazine (TBZ), a presynaptic vesicular monoamine transporter (VMAT2) inhibitor. Participants included 41 outpatients (mean age, 43.5 years) with treatment-refractory schizophrenia, stabilized on their present antipsychotic treatment (clozapine, 73%) for more than 3 months. Individuals were randomly assigned to TBZ augmentation (12.5-75 mg/d), titrated according to a fixed, flexible schedule, or placebo over 12 weeks. Twenty subjects received TBZ, and 21 received placebo; doses of 18 of the 20 TBZ-treated individuals were titrated up to the maximum of 75 mg/d, and 16 (80%) of them completed the trial. Tetrabenazine was well tolerated and not linked to increased adverse effects, including those that have been reported more frequently (eg, parkinsonism, depression, and sedation) with higher doses (>100 mg/d) used in the treatment of hyperkinetic movement disorders. However, there was no indication of clinical improvement as measured using the Brief Psychiatric Rating Scale, the Clinical Global Impression scale, and the Global Assessment of Functioning scale. In examining those receiving TBZ-clozapine specifically, there was no indication of drug-drug interactions or difference in response compared to the overall sample. Tetrabenazine was not effective, as used here, in augmenting clinical response in treatment-resistant schizophrenia. It may be premature, however, to discount the potential benefits of VMAT2 inhibitors in treating psychosis in light of what is presently understood regarding presynaptic DA's role and evidence that "endogenous sensitization" may occur over the course of the illness. PMID- 22198451 TI - Asenapine versus olanzapine in people with persistent negative symptoms of schizophrenia. AB - Two randomized, double-blind, 26-week core studies (Eastern [EH] and Western Hemisphere [WH]) tested the hypothesis that asenapine is superior to olanzapine for persistent negative symptoms of schizophrenia; 26-week extension studies assessed the comparative long-term efficacy and safety of these agents. In the core studies, 949 people were randomized to asenapine (n = 241 and 244) or olanzapine (n = 240 and 224); 26-week completion rates with asenapine were 64.7% and 49.6% (olanzapine, 80.4% and 63.8%) in the EH and WH, respectively. In the EH and WH extensions, respectively (asenapine, n = 134 and 86; olanzapine, n = 172 and 110), 52-week completion rates were 84.3% and 66.3% with asenapine (olanzapine, 89.0% and 80.9%). Asenapine was not superior to olanzapine in change in the 16-item Negative Symptom Assessment Scale total score in either core study, but asenapine was superior to olanzapine at week 52 in the WH extension study. Olanzapine was associated with modest, but significantly greater, changes in PANSS positive subscale score at various assessment times in both core studies and the WH extension study. Incidence of treatment-emergent adverse events was comparable between treatments across studies. Weight gain was consistently lower with asenapine. Extrapyramidal symptom-related adverse event incidence was higher with asenapine (EH: 8.3%; 95% confidence interval [CI], 5.1%-12.5%; WH: 16.4%; 95% CI, 11.9%-21.6%) than olanzapine (EH: 3.3%; 95% CI, 1.4%-6.4%; WH: 12.1%; 95% CI, 8.1%-17.0%), but Extrapyramidal Symptom Rating Scale-Abbreviated total score changes did not significantly differ between treatments. In conclusion, asenapine superiority over olanzapine was not observed in the core studies. Both treatments improved persistent negative symptoms, but discontinuation rates were higher with asenapine. PMID- 22198453 TI - Actigraphic measurements in opioid detoxification with methadone or buprenorphine. AB - The objective of the present naturalistic study was to assess the differential effects of opioid detoxification with methadone or buprenorphine on activity, circadian rhythm, and sleep. Forty-two consecutive inpatients with opiate addiction were switched to either methadone or buprenorphine and gradually tapered down over the course of 2 to 3 weeks. There were no significant differences in comedication (lofexidine, quetiapine, and valproic acid) between the methadone and buprenorphine groups. Patients in the methadone group showed 11% lower activity and were 24 minutes phase delayed as compared with buprenorphine-treated patients, whereas the latter had 2.5% lower sleep efficiency and 9% shorter actual sleep time. These significant group differences were most pronounced for the lowest doses (<=20% of maximum individual daily dose, ie, at the end of withdrawal representing late withdrawal effects). Furthermore, for the total sample, we found a significant decrease in the relative amplitude of the sleep-wake cycle and worsening of all actigraphic sleep parameters from the higher (100% to 20%) to the lowest doses (20% to 0%). The acrophase of the circadian rhythm displayed a phase advance (-88 minutes) from the highest (100% to 80%) to the lower doses (80% to 0%) in methadone-treated patients. Opioid tapering with methadone or buprenorphine leads to characteristic changes of the rest-activity cycle, but further study is required to validate these results. PMID- 22198454 TI - Treatment with duloxetine in adults and the incidence of cardiovascular events. AB - BACKGROUND: Cardiovascular events are inconclusively associated with duloxetine use in clinical trials and spontaneous reports. This analysis of cardiovascular events in relation to duloxetine use within a large health insurance database provides further data on the association. METHODS: This cohort study was conducted within a population with commercial health insurance. Adults with depression who initiated duloxetine were matched to separate cohorts of initiators of venlafaxine, selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants (TCAs), along with untreated patients with depression, and enrollees without depression. The cohorts were followed for cardiovascular events (acute myocardial infarction, sudden death, hypertensive crisis, arrhythmia, and coronary revascularization), which were identified through health insurance claims and confirmed upon review of underlying medical records. Proportional hazards and Poisson regression models were used for comparisons. RESULTS: There were approximately 64,000 person-years of follow-up among all cohorts (including 17,386 person-years among 21,457 duloxetine initiators), yielding 279 cardiovascular events. Relative to duloxetine initiators, those without depression had lower rates of combined events (incidence rate ratio [IRR], 0.51; 95% confidence interval [CI], 0.32-0.81) and coronary revascularizations (IRR, 0.51; 95% CI 0.29-0.89). The IR of each of the cardiovascular outcomes did not differ across the other cohorts, even accounting for time since last duloxetine dispensing. CONCLUSION: The incidence of cardiovascular events did not differ among duloxetine initiators relative to other antidepressant comparators or those with untreated depression but was higher than those without depression, suggesting that depression itself (or associated morbidities) may affect the risk of cardiovascular events. PMID- 22198455 TI - Medicare part D's impact on antipsychotic drug use and costs among elderly patients without prior drug insurance. AB - Medicare part D's implementation improved access to and affordability of prescription drugs for the elderly without prior drug insurance. Effects for specific drugs and drug classes are less well understood. We assessed part D's impact on antipsychotic medication (APM) utilization and out-of-pocket costs among elderly without prior drug insurance. Retail pharmacy claims from 3 nationwide pharmacy chains were used to analyze 2 time-series designs: (1) a policy model, to obtain a policymaker's perspective: what was the overall impact of part D on APM use and costs among elderly without drug insurance in 2005 with the opportunity to enroll? And (2) a clinical model, to obtain a clinician's perspective: what would happen to elderly without drug insurance in 2005 who did enroll in part D--would they be able to get APMs? At what cost? Subgroup analyses among part D enrollees evaluated potentially different effects for patients who received a subsidy and patients who used antidementia drugs. In the policy model, part D implementation was associated with a 5% increase in APM use and a 37% reduction in out-of-pocket costs, suggesting a modest need for APMs among all previously uninsured elderly. Patients who did enroll in part D (clinical model) had a 97% increase in APM use and a 62% decrease in out-of-pocket costs, suggesting that patients who needed APMs were able to access them at low cost through the part D program. Part D implementation was associated with increased use and affordability of APMs for the elderly without prior drug insurance. PMID- 22198456 TI - A randomized, naturalistic, parallel-group study for the long-term treatment of panic disorder with clonazepam or paroxetine. AB - This long-term extension of an 8-week randomized, naturalistic study in patients with panic disorder with or without agoraphobia compared the efficacy and safety of clonazepam (n = 47) and paroxetine (n = 37) over a 3-year total treatment duration. Target doses for all patients were 2 mg/d clonazepam and 40 mg/d paroxetine (both taken at bedtime). This study reports data from the long-term period (34 months), following the initial 8-week treatment phase. Thus, total treatment duration was 36 months. Patients with a good primary outcome during acute treatment continued monotherapy with clonazepam or paroxetine, but patients with partial primary treatment success were switched to the combination therapy. At initiation of the long-term study, the mean doses of clonazepam and paroxetine were 1.9 (SD, 0.30) and 38.4 (SD, 3.74) mg/d, respectively. These doses were maintained until month 36 (clonazepam 1.9 [SD, 0.29] mg/d and paroxetine 38.2 [SD, 3.87] mg/d). Long-term treatment with clonazepam led to a small but significantly better Clinical Global Impression (CGI)-Improvement rating than treatment with paroxetine (mean difference: CGI-Severity scale -3.48 vs -3.24, respectively, P = 0.02; CGI-Improvement scale 1.06 vs 1.11, respectively, P = 0.04). Both treatments similarly reduced the number of panic attacks and severity of anxiety. Patients treated with clonazepam had significantly fewer adverse events than those treated with paroxetine (28.9% vs 70.6%, P < 0.001). The efficacy of clonazepam and paroxetine for the treatment of panic disorder was maintained over the long-term course. There was a significant advantage with clonazepam over paroxetine with respect to the frequency and nature of adverse events. PMID- 22198457 TI - Satisfaction with methadone as a medication: psychometric properties of the Spanish version of the treatment satisfaction questionnaire for medication. AB - There is a manifest lack of psychometrically sound instruments designed for specific and multidimensional assessment of satisfaction with methadone as a medication within the context of methadone maintenance treatment. Therefore, it may be worthwhile to assess the pertinence and utility of using a generic and multidimensional medication satisfaction instrument that has not been specifically developed for use in methadone maintenance treatment.The aim of this study was thus to explore the psychometric properties of the Spanish version of the Treatment Satisfaction Questionnaire for Medication (TSQM version 1.4 [Health Qual Life Outcomes. 2004;2:12]) in a sample of methadone-maintained heroin dependent patients.Two hundred three methadone-maintained patients filled out the TSQM and other several measures related to the construct of patient satisfaction (eg, Verona Service Satisfaction Scale for methadone treatment). Dimensionality of the TSQM was assessed by means of a confirmatory factor analysis. Internal consistency was examined using the ordinal coefficient alpha. Spearman correlations were used to explore the relationship between the TSQM and the measures conceptually related to patient satisfaction.Regarding the dimensionality of the TSQM, its original factor structure adequately fitted the data (Satorra-Bentler chi58, 72.14 [P = 0.100]; root-mean-square error of approximation, 0.045; comparative fit index, 0.978). All but 1 of the 4 TSQM subscales showed acceptable to good internal consistency values (0.78-0.89). The dimensions of the TSQM were differentially and congruently correlated with related measures.The results strongly suggest the TSQM value as a brief, generic, and psychometrically sound instrument to assess satisfaction with methadone as a medication in a multidimensional manner. Notwithstanding, more research is needed not only to assess the generalizability of these findings but also to provide pieces of evidence for other psychometric properties, especially the TSQM predictive validity. PMID- 22198458 TI - Ketoconazole-associated preferential increase in dopamine D2 receptor occupancy in striatum compared to pituitary in vivo: role for drug transporters? AB - Membrane transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are efflux pumps that remove drugs from the brain back to the peripheral blood compartment, serving as a functional component of the blood brain barrier (BBB). We report here that coadministration of the P-gp and BCRP inhibitor ketoconazole with risperidone may preferentially increase D2 receptor occupancy in the striatum compared to pituitary. Four male patients with schizophrenia or schizoaffective disorder who had received at least 4 prior injections of the long-acting risperidone at a stable dose of 25 to 50 mg participated in this positron emission tomography study. Multiple-dose ketoconazole coadministration reduced the P-gp activity as shown by fexofenadine oral challenge. Importantly, we found a strong statistical trend in this sample of 4 subjects who consistently showed a decrease in striatal fluorine 18 (F) fallypride binding (an indication of increased D2 receptor occupancy) after ketoconazole coadministration (P = 0.057), whereas the pituitary (a region that lies outside the BBB) F-fallypride binding did not change (P = 0.99). These observations warrant further research with selective drug transporter inhibitors. We suggest that in neuroimaging studies, the pituitary drug occupancy can serve as a useful new "positive control" to evaluate whether drug occupancy is preferentially increased in brain regions that fall inside the BBB after cotreatment with P-gp and BCRP inhibitors. This is a noteworthy study design consideration regarding the future clinical testing of novel adjunct interventions aimed at modulating membrane transporter function at the BBB, with the goal of augmenting drug access into the brain compartment, particularly in treatment-resistant psychiatric illness. PMID- 22198459 TI - The case for basic research on the psychopharmacology of aggression. PMID- 22198460 TI - Flower and early fruit development in a diploid strawberry, Fragaria vesca. AB - The diploid woodland strawberry, Fragaria vesca, is being recognized as a model for the more complex octoploid commercial strawberry, Fragaria * ananassa. F. vesca exhibits a short seed to seed cycle, can be easily transformed by Agrobacteria, and a draft genome sequence has been published. These features, together with its similar flower structure, potentially make F. vesca a good model for studying the flower development of other members of the Rosaceae family, which contains many economically important fruit trees and ornamental plants. To propel F. vesca's role in genetic and genomic research and to facilitate the study of its reproductive development, we have investigated in detail F. vesca flower and early fruit development using a seventh generation inbred diploid line, Yellow Wonder 5AF7. We present here standardized developmental staging and detailed descriptions of morphological changes associated with flower and early fruit development based on images of hand dissected flowers, histological sections, and scanning electron microscopy. In situ hybridization with the F. vesca AGAMOUS homolog, FvAG, showed expression in young stamen and carpel primordia. This work lays the essential groundwork and standardization for future molecular, genetic, and genomic studies of F. vesca. PMID- 22198461 TI - The relationship between circadian blood pressure pattern and ventricular repolarization dynamics assessed by QT dynamicity. AB - OBJECTIVE: The aim of the present cross-sectional study was to evaluate ventricular repolarization dynamics by QT dynamicity in normotensive and hypertensive individuals with either a non-dipper-type or a dipper-type circadian rhythm of blood pressure (BP). METHODS: A total of 103 patients were allocated into four groups as follows: (i) normotensive/dipper, n=28; (ii) normotensive/nondipper, n=26; (iii) hypertensive/dipper, n=25; and (iv) hypertensive/nondipper, n=24. The linear regression slopes of the QT interval measured to the apex and to the end of the T wave plotted against R-R intervals (QTapex/R-R and QTend/R-R slopes, respectively) were calculated from 24-h ambulatory ECG recordings using a dedicated algorithm. RESULTS: QTapex/R-R and QTend/R-R slopes were higher in the nondipper subgroup of normotensive cases with respect to the dipper subgroup of normotensive cases (QTapex/R-R=0.171+/-0.017 vs. 0.127+/-0.023, P=0.001; QTend/R-R=0.159+/-0.015 vs. 0.133+/-0.025, P=0.001). QTapex/R-R and QTend/R-R slopes were higher in the nondipper subgroup of hypertensive cases with respect to the dipper subgroup of hypertensive cases (QTapex/R-R=0.187+/-0.019 vs. 0.133+/-0.019, P=0.001; QTend/R-R=0.183+/-0.018 vs. 0.147+/-0.022, P=0.001). Pearson's correlation analyses revealed a higher negative correlation between night-time decline in BP and QTapex/R-R (r=-0.638, P=0.001). There was also a moderate negative correlation between night-time decline in BP and QTend/R-R (r=-0.504, P=0.001). The correlation coefficients for degree of night-time dipping and QT dynamicity indices were higher in hypertensive groups than in the normotensive groups. CONCLUSION: Blunting of the nocturnal fall in BP associates with impaired QT dynamicity indices in both normotensive and hypertensive groups. PMID- 22198462 TI - Aequorin-based genetic approaches to visualize Ca2+ signaling in developing animal systems. AB - BACKGROUND: In recent years, as our understanding of the various roles played by Ca2+ signaling in development and differentiation has expanded, the challenge of imaging Ca2+ dynamics within living cells, tissues, and whole animal systems has been extended to include specific signaling activity in organelles and non membrane bound sub-cellular domains. SCOPE OF REVIEW: In this review we outline how recent advances in genetics and molecular biology have contributed to improving and developing current bioluminescence-based Ca2+ imaging techniques. Reporters can now be targeted to specific cell types, or indeed organelles or domains within a particular cell. MAJOR CONCLUSIONS: These advances have contributed to our current understanding of the specificity and heterogeneity of developmental Ca2+ signaling. The improvement in the spatial resolution that results from specifically targeting a Ca2+ reporter has helped to reveal how a ubiquitous signaling messenger like Ca2+ can regulate coincidental but different signaling events within an individual cell; a Ca2+ signaling paradox that until now has been hard to explain. GENERAL SIGNIFICANCE: Techniques used to target specific reporters via genetic means will have applications beyond those of the Ca2+ signaling field, and these will, therefore, make a significant contribution in extending our understanding of the signaling networks that regulate animal development. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signalling. PMID- 22198463 TI - A cis-antisense RNA acts in trans in Staphylococcus aureus to control translation of a human cytolytic peptide. AB - Antisense RNAs (asRNAs) pair to RNAs expressed from the complementary strand, and their functions are thought to depend on nucleotide overlap with genes on the opposite strand. There is little information on the roles and mechanisms of asRNAs. We show that a cis asRNA acts in trans, using a domain outside its target complementary sequence. SprA1 small regulatory RNA (sRNA) and SprA1(AS) asRNA are concomitantly expressed in S. aureus. SprA1(AS) forms a complex with SprA1, preventing translation of the SprA1-encoded open reading frame by occluding translation initiation signals through pairing interactions. The SprA1 peptide sequence is within two RNA pseudoknots. SprA1(AS) represses production of the SprA1-encoded cytolytic peptide in trans, as its overlapping region is dispensable for regulation. These findings demonstrate that sometimes asRNA functional domains are not their gene-target complementary sequences, suggesting there is a need for mechanistic re-evaluation of asRNAs expressed in prokaryotes and eukaryotes. PMID- 22198465 TI - [Endometrial cancers and predisposition]. AB - As nearly 5% of all endometrial cancers occur because of a predisposition, this possibility has systematically to be explored. The hallmarks of predisposition, a young age at diagnosis, a personal or a familial history of cancer, have to be searched systematically. The identification of a predisposition in a family has a major impact on the management of the proband or his relatives. The endometrial cancer main predisposition is Lynch's syndrome. In this review, we will focus on this condition and describe its clinical manifestations, the underlying molecular mechanisms, the cancer risks and the management guidelines. We will also get onto some far less frequent other predispositions. PMID- 22198464 TI - A metal switch for controlling the activity of molecular motor proteins. AB - Kinesins are molecular motors that require a divalent metal ion (for example, Mg(2+)) to convert the energy of ATP hydrolysis into directed force production along microtubules. Here we present the crystal structure of a recombinant kinesin motor domain bound to Mn(2+) and ADP and report on a serine-to-cysteine substitution in the switch 1 motif of kinesin that allows its ATP hydrolysis activity to be controlled by adjusting the ratio of Mn(2+) to Mg(2+). This mutant kinesin binds ATP similarly in the presence of either metal ion, but its ATP hydrolysis activity is greatly diminished in the presence of Mg(2+). In human kinesin-1 and kinesin-5 as well as Drosophila melanogaster kinesin-10 and kinesin 14, this defect is rescued by Mn(2+), providing a way to control both the enzymatic activity and force-generating ability of these nanomachines. PMID- 22198466 TI - ERalpha36, a new variant of the ERalpha is expressed in triple negative breast carcinomas and has a specific transcriptomic signature in breast cancer cell lines. AB - Triple negative breast cancer is deprived of estrogen receptor alpha (ERalpha), progesterone receptor (PR) and HER-2 protein. It constitutes the most heterogeneous and aggressive group of breast carcinomas, for which identification of novel characteristics and characterization of putative targets becomes very demanding. In the present work we have assayed the expression of ERalpha36, a recently identified ERalpha variant of 36kDa, in a series of triple negative breast cancers, in relation to the clinical behavior and other clinico pathological features of the tumors. While widely expressed within the cytoplasm in almost all tumors, we found that exclusively the membrane/submembrane expression of the receptor exhibits a correlation with patient's survival. Moreover, membrane ERalpha36 correlates in an inverse manner with the expression of miRNA210, a pro-angiogenic miR, with high prognostic relevance in triple negative carcinomas. A thorough transcriptomic, pharmacological-based approach in breast cancer cell lines, revealed an early (direct) transcriptional signature of the receptor activation, related to immune system processes and T-cell differentiation, RNA biosynthesis, regulation of metabolism, VEGF signaling and regulation of the cell cycle, with a down-regulation of CREB, NFkappaB and STATs transcription factors. Finally, ERalpha36 expression is not limited within breast cancer epithelial linen, but is equally identified in tumor vasculature, peritumoral fat tissue, lymphocytic infiltrate and stromal fibroblasts. In light of the above, ERalpha36 could represent a major counterpart in triple negative breast cancer. PMID- 22198467 TI - Chances and risks of SGLT2 inhibitors. PMID- 22198469 TI - Effect of baseline serum vitamin D levels on aromatase inhibitors induced musculoskeletal symptoms: results from the IBIS-II, chemoprevention study using anastrozole. AB - Severe deficiency of vitamin D in adults can cause musculoskeletal pain, stiffness, and joint discomfort. Musculoskeletal symptoms similar to those associated with vitamin D deficiency are frequently seen in breast cancer patients receiving adjuvant aromatase inhibitors (AIs). This is presumably due to oestrogen deficiency caused by AIs. However, no data are available on serum levels of vitamin D and their relation to developing musculoskeletal symptoms/arthralgia in women receiving an AI. IBIS-II is a multicentre randomized placebo controlled trial of the AI, anastrozole, in postmenopausal women aged 40 70 years, who are at increased risk of breast cancer. Serum vitamin D levels were measured for 416 participants. The samples were sent for assays in three batches: the first two batches (n = 250) included paired serum samples and the third batch (n = 166) included paired samples and samples from women who had arthralgia within the first year of follow-up. At entry, 56 (13%) women had adequate (>= 30 ng/ml), 173 (41%) had inadequate (>= 20-< 30 ng/mL), 167 (40%) were deficient (> 10-< 20 ng/mL), and 24 (6%) were severely deficient (< 10 ng/mL). At the time of analysis, 225 out of 834 (27%) women had reported arthralgia within the first year of follow-up. Baseline serum vitamin D levels did not significantly predict arthralgia within the first year of follow-up either in the overall group (OR 0.87 (95% CI: 0.67, 1.13; P = 0.30) or separately in the anastrozole (P = 0.60) or placebo groups (P = 0.38). Absolute serum levels of vitamin D increased significantly at one year in the anastrozole group (2.88 ng/ml, [1.71, 4.06; P < 0.0001]) but not in the placebo group (0.75 ng/ml [-0.35, 1.85; P = 0.18]). Only a small and a nonsignificant effect of baseline vitamin D levels were seen on the risk of musculoskeletal symptoms. This does not appear to be a major determinant of risk for these symptoms. PMID- 22198468 TI - Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). AB - Neoadjuvant chemotherapy for breast cancer allows individual tumor response to be assessed depending on molecular subtype, and to judge the impact of response to therapy on recurrence-free survival (RFS). The multicenter I-SPY 1 TRIAL evaluated patients with >= 3 cm tumors by using early imaging and molecular signatures, with outcomes of pathologic complete response (pCR) and RFS. The current analysis was performed using data from patients who had molecular profiles and did not receive trastuzumab. The various molecular classifiers tested were highly correlated. Categorization of breast cancer by molecular signatures enhanced the ability of pCR to predict improvement in RFS compared to the population as a whole. In multivariate analysis, the molecular signatures that added to the ability of HR and HER2 receptors, clinical stage, and pCR in predicting RFS included 70-gene signature, wound healing signature, p53 mutation signature, and PAM50 risk of recurrence. The low risk signatures were associated with significantly better prognosis, and also identified additional patients with a good prognosis within the no pCR group, primarily in the hormone receptor positive, HER-2 negative subgroup. The I-SPY 1 population is enriched for tumors with a poor prognosis but is still heterogeneous in terms of rates of pCR and RFS. The ability of pCR to predict RFS is better by subset than it is for the whole group. Molecular markers improve prediction of RFS by identifying additional patients with excellent prognosis within the no pCR group. PMID- 22198470 TI - Outcomes of a weight loss intervention among rural breast cancer survivors. AB - Obese breast cancer survivors have increased risk of recurrence and death compared to their normal weight counterparts. Rural women have significantly higher obesity rates, thus weight control intervention may be a key strategy for prevention of breast cancer recurrence in this population. This one-arm treatment study examined the impact of a group-based weight control intervention delivered through conference call technology to obese breast cancer survivors living in remote rural locations. The intervention included a reduced calorie diet incorporating prepackaged entrees and shakes, physical activity gradually increased to 225 min/week of moderate intensity exercise, and weekly group phone sessions. Outcomes included anthropomorphic, diet, physical activity, serum biomarker, and quality of life changes. Ninety-one percent of participants (31 of 34) attended >75% of intervention sessions and completed post-treatment data collection visits. At 6 months, significant changes were observed for weight ( 12.5 +/- 5.8 kg, 13.9% of baseline weight), waist circumference (-9.4 +/- 6.3 cm), daily energy intake (-349 +/- 550 kcal/day), fruits, and vegetables (+3.7 +/ 4.3 servings/day), percent kcal from fat (-12.6 +/- 8.6%), physical activity (+1235 +/- 832 kcal/week; all P values <0.001), as well as significant reductions in fasting insulin (16.7% reduction, P = 0.006), and leptin (37.1% reduction, P < 0.001). Significant improvements were also seen for quality of life domains including mood, body image, and sexuality. In conclusion, the intervention produced >10% weight loss as well as significant improvements across multiple endpoints. The group phone-based treatment delivery approach may help disseminate effective weight control intervention to hard-to-reach breast cancer survivors. PMID- 22198471 TI - Genetic variants at chromosome 9p21, 10p15 and 10q22 and breast cancer susceptibility in a Chinese population. AB - A recent genome-wide association study (GWAS) has identified a new subset of breast cancer susceptibility loci on chromosomes 9, 10, and 11 in populations of European descent. However, because of the genetic heterogeneity, the role of these loci in non-European descent populations is still unclear. To evaluate the relationships between genetic variants in these regions identified by GWAS and breast cancer risk in Chinese women, we genotyped four common SNPs at 9p21(rs1011970 and rs10757278), 10p15 (rs2380205), and 10q22 (rs1250009) in a two stage case-control study with a total of 1792 breast cancer cases and 1,867 controls. We found that rs1250009 at 10q22 was consistently associated with risk of breast cancer in stage 1 and stage 2, with a per-allele OR of 1.13 (95% CI 1.02-1.25) after two stages combined (P = 0.023). However, no significant associations were observed between the other three SNPs and breast cancer risk. Our results suggest that the genetic variants at 10q22 may play an important role in breast cancer development in Chinese women, and rs1250009 may be a candidate marker for breast cancer susceptibility. PMID- 22198472 TI - Functional fat body proteomics and gene targeting reveal in vivo functions of Drosophila melanogaster alpha-Esterase-7. AB - Carboxylesterases constitute a large enzyme family in insects, which is involved in diverse functions such as xenobiotic detoxification, lipid metabolism and reproduction. Phylogenetically, many insect carboxylesterases are represented by multienzyme clades, which are encoded by evolutionarily ancient gene clusters such as the alpha-Esterase cluster. Much in contrast to the vital importance attributed to carboxylesterases in general, the in vivo function of individual alpha-Esterase genes is largely unknown. This study employs a functional proteomics approach to identify esterolytic enzymes of the vinegar fly Drosophila melanogaster fat body. One of the fat body carboxylesterases, alpha-Esterase-7, was selected for mutational analysis by gene targeting to generate a deletion mutant fly. Phenotypic characterization of alpha-Esterase-7 null mutants and transgenic flies, which overexpress a chimeric alpha-Esterase-7:EGFP gene, reveals important functions of alpha-Esterase-7 in insecticide tolerance, lipid metabolism and lifespan control. The presented first deletion mutant of any alpha Esterase in the model insect D. melanogaster generated by gene targeting not only provides experimental evidence for the endogenous functions of this gene family. It also offers an entry point for in vivo structure-function analyses of alpha Esterase-7, which is of central importance for naturally occurring insecticide resistance in wild populations of various dipteran insect species. PMID- 22198473 TI - Class 2 integrons dissemination among multidrug resistance (MDR) clones of Acinetobacter baumannii. AB - Acinetobacter baumannii has emerged as a serious problem in the hospital environment at a global scale. Previous results from our laboratory showed a high frequency of class 2 integrons in A. baumannii strains from Argentina regarding the low rate of this element in A. baumannii isolates from the rest of the world. To reveal the current epidemiology of class 2 integrons, a molecular surveillance analyzing 78 multidrug resistant (MDR) A. baumannii isolates from Argentina and Uruguay was performed, exposing the presence of class 2 integron in the 36.61% of the isolates. Class 2 integron characterization showed that the typical Tn7::In2 7 array was present in 26 out of 27 intI2 positive isolates. All intI2 positive isolates contained at least one of the Tn7 transposition genes. In addition, we identified that 18 intI2 positive isolates possessed the Tn7::In2-7 within the attTn7 site. The molecular typing evidenced that clones I and IV that do not belong to widespread European clones I and II were found among the intI2 positive isolates. Our results exposed the widely dissemination of class 2 integron among MDR A. baumannii isolates from Argentina and Uruguay, also showing the persistence of two novel clones in our region, which could explain in part the high frequency of class 2 integron found in our region. PMID- 22198474 TI - Predicting binding affinities of host-guest systems in the SAMPL3 blind challenge: the performance of relative free energy calculations. AB - Relative free energy calculations based on molecular dynamics simulations are combined with available experimental binding free energies to predict unknown binding affinities of acyclic Cucurbituril complexes in the blind SAMPL3 competition. The predictions yield root mean square errors between 2.6 and 3.2 kcal/mol for seven host-guest systems. Those deviations are comparable to results for solvation free energies of small organic molecules. However, the standard deviations found in our simulations range from 0.4 to 2.4 kcal/mol, which indicates the need for better sampling. Three different approaches are compared. Bennett's Acceptance Ratio Method and thermodynamic integration based on the trapezoidal rule with 12 lambda-points exhibit a root mean square error of 2.6 kcal/mol, while thermodynamic integration with Simpson's rule and 11 lambda points leads to a root mean square error of 3.2 kcal/mol. In terms of absolute median errors, Bennett's Acceptance Ratio Method performs better than thermodynamic integration with the trapezoidal rule (1.7 vs. 2.9 kcal/mol). Simulations of the deprotonated forms of the guest molecules exhibit a poorer correspondence to experimental results with a root mean square error of 5.2 kcal/mol. In addition, a decrease of the buffer concentration by approximately 20 mM in the simulations raises the root mean square error to 3.8 kcal/mol. PMID- 22198475 TI - Alchemical prediction of hydration free energies for SAMPL. AB - Hydration free energy calculations have become important tests of force fields. Alchemical free energy calculations based on molecular dynamics simulations provide a rigorous way to calculate these free energies for a particular force field, given sufficient sampling. Here, we report results of alchemical hydration free energy calculations for the set of small molecules comprising the 2011 Statistical Assessment of Modeling of Proteins and Ligands challenge. Our calculations are largely based on the Generalized Amber Force Field with several different charge models, and we achieved RMS errors in the 1.4-2.2 kcal/mol range depending on charge model, marginally higher than what we typically observed in previous studies (Mobley et al. in J Phys Chem B 111(9):2242-2254, 2007, J Chem Theory Comput 5(2):350-358, 2009, J Phys Chem B 115:1329-1332, 2011; Nicholls et al. in J Med Chem 51:769-779, 2008; Klimovich and Mobley in J Comput Aided Mol Design 24(4):307-316, 2010). The test set consists of ethane, biphenyl, and a dibenzyl dioxin, as well as a series of chlorinated derivatives of each. We found that, for this set, using high-quality partial charges from MP2/cc-PVTZ SCRF RESP fits provided marginally improved agreement with experiment over using AM1-BCC partial charges as we have more typically done, in keeping with our recent findings (Mobley et al. in J Phys Chem B 115:1329-1332, 2011). Switching to OPLS Lennard-Jones parameters with AM1-BCC charges also improves agreement with experiment. We also find a number of chemical trends within each molecular series which we can explain, but there are also some surprises, including some that are captured by the calculations and some that are not. PMID- 22198476 TI - An improved theoretical approach to the empirical corrections of density functional theory. AB - An empirical correction to density functional theory (DFT) has been developed in this study. The approach, called correlation corrected atomization-dispersion (CCAZD), involves short- and long-range terms. Short-range correction consists of bond (1,2-) and angle (1,3-) interactions, which remedies the deficiency of DFT in describing the proto-branching stabilization effects. Long-range correction includes a Buckingham potential function aiming to account for the dispersion interactions. The empirical corrections of DFT were parameterized to reproduce reported DeltaH ( f ) values of the training set containing alkane, alcohol and ether molecules. The DeltaH ( f ) of the training set molecules predicted by the CCAZD method combined with two different DFT methods, B3LYP and MPWB1K, with a 6 31G* basis set agreed well with the experimental data. For 106 alkane, alcohol and ether compounds, the average absolute deviations (AADs) in DeltaH ( f ) were 0.45 and 0.51 kcal/mol for B3LYP- and MPWB1K-CCAZD, respectively. Calculations of isomerization energies, rotational barriers and conformational energies further validated the CCAZD approach. The isomerization energies improved significantly with the CCAZD treatment. The AADs for 22 energies of isomerization reactions were decreased from 3.55 and 2.44 to 0.55 and 0.82 kcal/mol for B3LYP and MPWB1K, respectively. This study also provided predictions of MM4, G3, CBS-QB3 and B2PLYP D for comparison. The final test of the CCAZD approach on the calculation of the cellobiose analog potential surface also showed promising results. This study demonstrated that DFT calculations with CCAZD empirical corrections achieved very good agreement with reported values for various chemical reactions with a small basis set as 6-31G*. PMID- 22198477 TI - Frozen out: molecular modeling in the age of cryocrystallography. AB - As molecular modellers we need to remember that the flexibility of a protein is necessary for it to function. Unfortunately, this flexibility is not readily apparent from the seductive molecular graphics rendering of cryocrystallographic results. PMID- 22198478 TI - Role of PGE-type receptor 4 in auditory function and noise-induced hearing loss in mice. AB - This study explored the physiological roles of PGE-type receptor 4 (EP4) in auditory function. EP4-deficient mice exhibited slight hearing loss and a reduction of distortion-product otoacoustic emissions (DPOAEs) with loss of outer hair cells (OHCs) in cochleae. After exposure to intense noise, these mice showed significantly larger threshold shifts of auditory brain-stem responses (ABRs) and greater reductions of DPOAEs than wild-type mice. A significant increase of OHC loss was confirmed morphologically in the cochleae of EP4-deficient mice. Pharmacological inhibition of EP4 had a similar effect to genetic deletion, causing loss of both hearing and OHCs in C57BL/6 mice, indicating a critical role for EP4 signaling in the maintenance of auditory function. Pharmacological activation of EP4 significantly protected OHCs against noise trauma, and attenuated noise-induced hearing loss in C57BL/6 mice. These findings suggest that EP4 signaling is necessary for the maintenance of cochlear physiological function and for cochlear protection against noise-induced damage, in particular OHCs. EP4 might therefore be an effective target for cochlear disease therapeutics. PMID- 22198479 TI - Effect of inspired CO2 on the ventilatory response to high intensity exercise. AB - We tested the hypothesis that preventing the poikilocapnic response to high intensity exercise would increase the ventilatory response to exercise. We measured ventilatory variables in 10 healthy men during incremental cycling with and without inspired CO(2) (randomised order). Inspired CO(2) elevated resting ventilation (V(E)), tidal volume (V(T)), PETCO2 and PETO2 by 5 +/- 5 L/min, 0.3 +/- 0.2 L, 6 +/- 3 mm Hg and 11 +/- 7 mm Hg, respectively (P<0.05); resting breathing frequency (f), expired CO(2) (VCO2) and O(2) consumption (VO2) remained similar (P>0.05). During high intensity exercise, inspired CO(2) elevated PETCO2 by 7 +/- 2, 10 +/- 4 and 11 +/- 4 mm Hg at 80%, 90% and 100% VO2 max, respectively (P<0.01), while PETCO2 remained unchanged (P>0.05). During high intensity exercise, inspired CO(2) elevated VT by 0.2 +/- 0.3 L at 80%, 90% and 100% VO2 max, respectively (P<0.05), while no differences were observed in V(E), f, VO2, or power output (P>0.05). These data suggest a progressively diminishing role of CO(2) chemoreception in the control of ventilation during maximal incremental exercise. PMID- 22198480 TI - NICE technology appraisals: working with multiple levels of uncertainty and the potential for bias. AB - One of the key roles of the English National Institute for Health and Clinical Excellence (NICE) is technology appraisal. This essentially involves evaluating the cost effectiveness of pharmaceutical products and other technologies for use within the National Health Service. Based on a content analysis of key documents which shed light on the nature of appraisals, this paper draws attention to the multiple layers of uncertainty and complexity which are latent within the appraisal process, and the often socially constructed mechanisms for tackling these. Epistemic assumptions, bounded rationality and more explicitly relational forms of managing knowledge are applied to this end. These findings are discussed in the context of the literature highlighting the inherently social process of regulation. A framework is developed which posits the various forms of uncertainty, and responses to these, as potential conduits of regulatory bias-in need of further research. That NICE's authority is itself regulated by other actors within the regulatory regime, particularly the pharmaceutical industry, exposes it to the threat of regulatory capture. Following Lehoux, it is concluded that a more transparent and reflexive format for technological appraisals is necessary. This would enable a more robust, defensible form of decision-making and moreover enable NICE to preserve its legitimacy in the midst of pressures which threaten this. PMID- 22198481 TI - Dysregulation of overexpressed IL-32alpha in hepatocellular carcinoma suppresses cell growth and induces apoptosis through inactivation of NF-kappaB and Bcl-2. AB - IL-32 is a newly discovered cytokine. Recently, various reports suggest that it plays a role as a proinflammatory mediator and may be involved in several cancer carcinogenesis. However, IL-32 expression in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated the expression and role of IL 32alpha in hepatocellular carcinoma, because IL-32 was identified as an upregulated gene in hepatocellular carcinoma tissues compared to nontumorous regions using DNA microarray. IL-32alpha was overexpressed in tissue and serum from patients with HCC and localized in the cytoplasm and nucleus of hepatocellular carcinoma tumor cells. Moreover, secreted IL-32alpha concentration in the serum of patients with hepatocellular carcinoma was elevated as compared with those in the normal serum using a developed sandwich ELISA. Furthermore, IL 32alpha suppression in hepatocellular carcinoma decreased expression of phospho p38 MAPK, NF-kappaB, and antiapoptotic protein Bcl-2 and induced expression of proapoptotic proteins as well as p53 and PUMA resulting in the suppression of cell growth and induction of intrinsic apoptosis. Based on our results, we suggest that IL-32alpha is involved in the progression of hepatocellular carcinoma and may be a useful biomarker for diagnosis and therapeutic target of hepatocellular carcinoma. PMID- 22198482 TI - Epigenetic biomarkers in urological tumors: A systematic review. AB - Prostate, bladder, kidney and testis cancers, the most common genitourinary (GU) neoplasms, are generally clinically silent at their earliest stages when curative treatment is most likely successful. However, there are no consensual guidelines for GU cancer screening and available methods are characterized by suboptimal sensitivity and specificity. Moreover, standard clinical and pathological parameters meet with important limitations in the assessment of prognosis in an individual basis. Herein, we focus on the development of epigenetic-based GU cancer biomarkers, which have emerged from exploratory studies in recent years and that hold the promise to revolutionize the clinical management of GU cancer patients. PMID- 22198483 TI - Methyl jasmonate reduces the survival of cervical cancer cells and downregulates HPV E6 and E7, and survivin. AB - The present study further investigated the mode of action of methyl jasmonate (MJ) in different cervical cancer cell lines. We show that in addition to the short term cytotoxicity, MJ effectively reduced the survival of cervical cancer cells (clonogenicity assays). MJ induced apoptosis in all cervical cancer cells. In some cell lines, MJ caused elevation of the mitochondrial superoxide anion, notably, in HeLa and CaSki. Changes in the expression of p53 and bax were variable, yet, downregulation of survivin was common to all cervical cancer cells. MJ significantly reduced the levels of the human papillomavirus (HPV) E6 and E7 proteins without alteration of the mRNA levels. Moreover, ectopic expression of E6, E7 or both in cervical cancer cells that lack HPV (C33A), did not alter significantly their response to MJ. Our studies point to MJ as an effective anticancer agent against a variety of cervical cancer cells acting through shared and different pathways to induce cell death regardless of the presence of HPV. PMID- 22198484 TI - Cardioprotection by Hepc1 in cTnT(R141W) transgenic mice. AB - Hepcidin 1 (Hepc1) is a peptide hormone secreted by the liver in response to iron loading. It is expressed in the heart and is thought to play a role in the regulation of iron homeostasis in an autocrine and paracrine fashion. We have shown that expression of Hepc1 is strongly down-regulated in the heart of the cTnT(R141W) transgenic mouse model of dilated cardiomyopathy (DCM) at 3 months of age. Transgenic mice with heart tissue-specific Hepc1 expression alone or in combination with the cTnT(R141W) mutation were produced to study the effects of Hepc1 on DCM. Transgenic expression of Hepc1 was found to be nonlethal and resulted in decreased mortality in cTnT(R141W) transgenic mice, from 29.6 to 7.4%(n = 27; P < 0.05), through 7 months of age. Expression of Hepc1 also brought about increases in the left ventricular wall, as well as ejection fraction and fractional shortening. In addition, the expression of Hepc1 inhibited the fibrosis and ultra-structural alterations seen in cTnT(R141W) transgenic mice. Furthermore, transgenic expression of Hepc1 restored the iron level and phosphorylation level of extracellular signal-regulated kinases 1/2 (ERK1/2) in the heart tissues of cTnT(R141W) transgenic mice. It was concluded that transgenic expression of Hepc1 compensated for the loss of Hepc1 expression and the release of iron and brought about a marked improvement in the pathologic phenotype of DCM, in which the ERK1/2 signal pathway might play an important role. PMID- 22198486 TI - Polydactyly in a patient with a cardiovascular anomaly. PMID- 22198485 TI - Cellular bioenergetics is regulated by PARP1 under resting conditions and during oxidative stress. AB - PURPOSE: The goal of the current studies was to elucidate the role of the principal poly(ADP-ribose)polymerase isoform, PARP1 in the regulation of cellular energetics in endothelial cells under resting conditions and during oxidative stress. METHODS: We utilized bEnd.3 endothelial cells and A549 human transformed epithelial cells. PARP1 was inhibited either by pharmacological inhibitors or by siRNA silencing. The Seahorse XF24 Extracellular Flux Analyzer was used to measure indices of mitochondrial respiration (oxygen consumption rate) and of glycolysis (extracellular acidification rate). Cell viability, cellular and mitochondrial NAD(+) levels and mitochondrial biogenesis were also measured. RESULTS: Silencing of PARP1 increased basal cellular parameters of oxidative phosphorylation, providing direct evidence that PARP1 is a regulator of mitochondrial function in resting cells. Pharmacological inhibitors of PARP1 and siRNA silencing of PARP1 protected against the development of mitochondrial dysfunction and elevated the respiratory reserve capacity in endothelial and epithelial cells exposed to oxidative stress. The observed effects were unrelated to an effect on mitochondrial biogenesis. Isolated mitochondria of A549 human transformed epithelial cells exhibited an improved resting bioenergetic status after stable lentiviral silencing of PARP1; these effects were associated with elevated resting mitochondrial NAD+ levels in PARP1 silenced cells. CONCLUSIONS: PARP1 is a regulator of basal cellular energetics in resting endothelial and epithelial cells. Furthermore, endothelial cells respond with a decrease in their mitochondrial reserve capacity during low-level oxidative stress, an effect, which is attenuated by PARP1 inhibition. While PARP1 is a regulator of oxidative phosphorylation in resting and oxidatively stressed cells, it only exerts a minor effect on glycolysis. PMID- 22198487 TI - Still bizarre. PMID- 22198488 TI - Calcinosis universalis in a patient with overlap of scleroderma/dermatomyositis. PMID- 22198490 TI - Visceral leishmaniasis in a rheumatoid arthritis patient treated with methotrexate. PMID- 22198491 TI - Chilling-induced ultrastructural changes to mesophyll cells of Arabidopsis grown under short days are almost completely reversible by plant re-warming. AB - Exposure of plants to chilling (low temperatures above freezing) limits growth and development in all environments outside the lowest latitudes. Cell ultrastructure and morphometric studies may allow associations to be made between chilling-induced changes at the ultrastructural level, molecular events and their physiological consequences. We examined changes in the shape, size and membrane organization of the organelles of mesophyll cells in Arabidopsis thaliana (Col 0), a cold-resistant species, after subjecting 6-week-old plants grown at normal growth temperatures to chilling (2.5-4 degrees C; 14-h dark/10-h light cycle) for 6, 24 and 72 h and after a re-warming period of 50 h. No ultrastructural differences were seen in the first 6 h of chilling but after 24 h we observed swollen and rounded chloroplasts with larger starch grains and dilated thylakoids compared to control plants. By 72 h, chilling had resulted in a large accumulation of starch in chloroplasts, an apparent crowding of the cytosol and a lower abundance of peripheral reticulum than in the controls. The average area per chloroplast in cell sections increased after 72-h chilling while the number of chloroplasts remained the same. Ring-shaped and other morphologically aberrant mitochondria were present in significantly higher abundance in plants given 72 h chilling than in the controls. Plant re-warming for 50 h reduced chloroplast size to those of the controls and returned mitochondria to standard morphology, but peripheral reticulum remained less abundant than in plants never given a cold treatment. The near full return to normal ultrastructure upon plant re-warming indicates that the morphological changes may be part of acclimation to cold. PMID- 22198492 TI - Nanospace biophysics. Editorial. PMID- 22198493 TI - Occurrence of calreticulin during the exchange of nucleohistones into protamine type proteins in Chara vulgaris spermiogenesis. AB - During spermiogenesis of an alga Chara vulgaris, which resembles that of animals, nucleohistones are replaced by protamine-type proteins. This exchange takes place in a spermatid nucleus during the key V spermiogenesis stage, in which rough endoplasmic reticulum is the site of protamine-type protein synthesis and is also the pathway guiding the proteins to their destination, nucleus. In the present work, it was shown that a chaperon protein, calreticulin (CRT), abundantly present at this significant V stage of spermiogenesis in a few cellular compartments, i.e., a nucleus, lumen of cisternae, and vesicles of significantly swollen ER as well as outside these structures, e.g., in Golgi apparatus, could have taken part in the process of exchange of nuclear proteins. Colocalization of two proteins, protamine-type proteins, crucial for reproduction, and CRT, was especially visible in a nucleus, mainly on its peripheries where condensed chromatin was present. Localization of protamine-type proteins and CRT in nucleus is in agreement with our previous results showing that protamine-type proteins were twofold more labelled in the peripheral area in comparison to the nucleus center occupied by noncondensed chromatin. The role of CRT in the reproduction of both plants and animals is also discussed. PMID- 22198494 TI - Ischemic postconditioning protects liver from ischemia-reperfusion injury by modulating mitochondrial permeability transition. AB - BACKGROUND: We tested the effectiveness of ischemic postconditioning (iPoC) in mitigating ischemia-reperfusion (I/R) injury of liver and the mechanism involves inhibiting the opening of the mitochondrial permeability transition pore (mPTP). METHODS: iPoC, performed by three cycles of 1 min I/R of the liver, was tested on a partial liver I/R model on rats. The serum alanine transaminase levels, terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, cytochrome c release, the formation of 4-hydroxy-2-nonnenal-modified proteins, and mitochondrial membrane potential (Deltapsim) were measured. Atractyloside (ATR) and NIM811, which modify the opening of mPTP, were administered in selected groups. RESULTS: iPoC, and NIM811, diminished the elevation of serum alanine transaminase level after I/R injury (174.0+/-28.3 U/L for iPoC; 94.3+/-25.4 U/L for control+NIM811) when compared with others (416.3+/-16.7 U/L for control, 557.0+/-86.7 U/L for iPoC+ATR, P<0.05). The expressions of cytosolic cytochrome c after I/R injury were decreased in iPoC and control+NIM811 groups when compared with others. After I/R, the apoptosis and the 4-hydroxy-2-nonnenal-modified proteins were attenuated in iPoC group when compared (apoptotic counts/50 HPF: 723.3+/-98.7 for iPoC, 1274+/-201.2 for control, 1057.6+/-39 for iPoC+ATR, P<0.05). The Deltapsim measured by flow cytometry was better preserved in iPoC and NIM811 groups. CONCLUSIONS: iPoC attenuated cell deaths after I/R injury of liver. The protective effects were negated by the addition of ATR--a mPTP opener- and mimicked by injection of NIM811--a mPTP opening inhibitor. The study indicated iPoC conferred protection by modulating mPTP. PMID- 22198495 TI - Preservation of pancreas graft function after complete venous thrombosis: report of four cases treated conservatively. AB - BACKGROUND: Pancreas graft thrombosis is the most common cause of technical graft failure, with an incidence of up to 20% is some series. In most instances, vascular thrombosis of the graft will require immediate removal to avoid further abdominal complications. We present a total of four cases of complete venous thrombosis with preservation of function that were managed conservatively, resulting in long-term graft function. METHODS: Retrospective analysis of our case series over 10 years was carried out, obtaining patients with complete graft thrombosis by Doppler ultrasound. We included in the study only those patients who remained asymptomatic with preserved graft function. The clinical status of the patients, radiological findings, and therapeutic approach are evaluated. Patient and graft outcomes are analyzed. RESULTS: Retrospective evaluation of 227 transplants, a total of four patients were found to have complete thrombosis of the graft, remaining asymptomatic and preserving function without complications. Graft thrombosis was found on routine Doppler ultrasound evaluation of the transplanted organs at a median time of 19 days (range, 11-28 days), angiographic confirmation was obtained in all cases. The clinical condition and the presence of collateral flow allowed for conservative treatment. Median hospital stay was 29 days (range, 16-38 days), with a median follow-up of 106 months (range, 24-110 months), all patients are alive with a functioning graft. CONCLUSIONS: In rare instances with complete thrombosis of the pancreas transplant in absence of clinical manifestations, the grafts can be closely monitored and treated with systemic anticoagulation, allowing long-term patient and graft survival. PMID- 22198496 TI - Use of 12-month renal function and baseline clinical factors to predict long-term graft survival: application to BENEFIT and BENEFIT-EXT trials. AB - BACKGROUND: Innovation in renal transplant management would benefit from identification of early markers that accurately predict long-term graft survival. METHODS: Data from the United States Renal Data System for kidney transplant recipients (1995-2004) were analyzed to develop prediction models for all-cause graft survival based on estimated glomerular filtration rate (eGFR), the presence or absence of acute rejection within 1 year, and recipient and donor demographic characteristics. The prediction models were applied to participants in the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial and Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial--EXTended criteria donors trials comparing belatacept with cyclosporine in standard criteria donor (SCD) and expanded criteria donor (ECD) graft recipients, respectively, as an external validation of the model predictions in a diverse population. RESULTS: Compared with eGFR 60 mL/min/1.73 m(2), the relative hazard for all-cause graft loss increased in an accelerating pattern with lower GFR to approximately eight and seven times, respectively, among SCD and ECD recipients with eGFR less than 15 mL/min/1.73 m(2). When applied to the clinical trial samples, the predicted differences in all-cause graft survival of less intensive belatacept versus cyclosporine at the second transplant anniversary (SCD: 3.9%, 95% confidence interval [CI]: 3.6% to 4.2%; ECD: 4.1%, 95% CI: 3.5% to 4.7%) were similar to observed differences (SCD: 4.2%, 97.3% CI: -1.3% to 10.1%; ECD: 1.4%, 97.3% CI: 7.5% to 10.2%). CONCLUSIONS: Accurate models of long-term graft survival can be developed using eGFR, donor, and recipient characteristics. Long-term survival prediction models may provide an efficient method for assessing the impact of novel pharmaceutical agents and clinical management protocols. PMID- 22198497 TI - Prognosis and outcome of non-Hodgkin lymphoma in primary Sjogren syndrome. AB - Sjogren syndrome (SS) has been associated with the development of non-Hodgkin lymphoma (NHL). From a cohort of 584 SS patients followed in our department from 1980 to 2010, we retrospectively analyzed 53 consecutive NHL cases. Considerations included histologic type, clinical manifestation and NHL staging, treatment, response rate and overall survival (OS), event-free survival (EFS), and standardized mortality ratio (SMR).Mucosa-associated lymphoid tissue (MALT) lymphomas constituted the majority (59%) of NHL subtypes, followed by nodal marginal zone lymphomas (NMZLs) (15%) and diffuse large B-cell lymphomas (DLBCLs) (15%). Six lymphoma patients died during the median follow-up of 40.8 months. The corresponding age/sex-adjusted SMR of SS with and without NHLs versus the general population was 3.25 (95% confidence interval [CI] 1.32-6.76) and 1.08 (95% CI, 0.79-1.45), respectively. A "watch and wait" policy was adopted for 9 patients with asymptomatic localized salivary MALT lymphomas. Eight patients with limited stage MALT lymphomas and extraglandular manifestations were treated with rituximab. Ten MALT lymphoma patients with disseminated disease received chemotherapy with or without rituximab. The 3-year OS and EFS in patients with MALT lymphomas was 97% and 78%, respectively. Rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) was the chosen therapeutic intervention for patients with DLBCLs. A successful outcome was recorded for this group, with 100% OS and EFS at 3 years. Patients with NMZLs had a less favorable outcome, with a 3-year OS of 80% and EFS of 53%. Our results describe the course and prognosis of SS-associated NHL and highlight the need for a risk-stratified treatment approach. PMID- 22198498 TI - Long-term outcome of arterial lesions in Behcet disease: a series of 101 patients. AB - The vasculitis of Behcet disease (BD) is distinctive because of involvement of both arteries and veins of all sizes. The concept of vasculo-Behcet disease has been adopted for cases in which vascular manifestations are present and often dominate the clinical features. While venous manifestations are frequent and have been reported in many publications, data regarding arterial lesions in patients with BD are rare and often isolated. In this study, we report the main characteristics, treatment, and long-term outcome of 101 patients with arterial lesions among a cohort of 820 (12.3%) BD patients. Factors that affect prognosis were assessed by multivariate analysis. There were 93 (91.2%) male patients; the median (Q1-Q3) age at diagnosis of BD was 33 (27-41) years. Arterial lesions included aneurysms (47.3%), occlusions (36.5%), stenosis (13.5%), and aortitis (2.7%). Lesions mainly involved the aorta (n = 25) and femoral (n = 23) and pulmonary (n = 21) arteries. Patients with arterial lesions were more frequently male (91.2% vs. 62.4%, respectively; p = 0.017) and had higher rates of venous involvement (80.4% vs. 29.8%, respectively; p < 0.001) compared to patients without arterial manifestations. Thirty-nine (38.6%) patients achieved complete remission. In multivariate analysis, the presence of venous involvement (odds ratio [OR], 0.29; 95% confidence interval [CI], 0.08-1.11) and arterial occlusive lesions (OR, 0.13; 95% CI, 0.01-1.25) were negatively associated with complete remission. The use of immunosuppressants (OR, 3.38; 95% CI, 0.87-13.23) was associated with the occurrence of complete remission. The 20-year survival rate was significantly lower in BD patients with arterial involvement than in those without arterial lesions (73% vs. 89%, respectively; p < 0.0001). In conclusion, the long-term outcome of arterial lesions in BD is poor, especially in the case of occlusive lesions and associated venous involvement. The use of immunosuppressants improved the prognosis. PMID- 22198499 TI - Methicillin-resistant Staphylococcus aureus meningitis in adults: a multicenter study of 86 cases. AB - Methicillin-resistant Staphylococcus aureus (MRSA) meningitis is an uncommon disease, and little is known about its epidemiology, clinical features, therapy, and outcome. We performed a multicenter retrospective study of MRSA meningitis in adults. Eighty-six adult patients were included and the following data were obtained: underlying diseases, clinical presentation, analytical and microbiologic data, response to therapy, and outcome.There were 56 men (65%) and the mean age was 51.5 years; 54 of them (63%) had severe comorbidities. There were 78 cases of postoperative meningitis and 8 of spontaneous meningitis. The infection was nosocomial in 93% (80/86) of the cases. Among the 78 patients with postoperative meningitis, the most common predisposing conditions were cerebrospinal fluid (CSF) devices (74%), neurosurgery (45%), CSF leakage (17%), and head trauma (12%). Most patients had fever (89%), altered mental status (68%), headache (40%), and meningeal signs (29%). The most common CSF findings were pleocytosis (90%), elevated protein level (77%), and hypoglycorrhachia (30%). CSF Gram stain and blood cultures were positive in 49% (32/65) and 36% (16/45) of cases, respectively. An associated MRSA infection and polymicrobial meningitis appeared in 33% (28/86) and 23% (20/86) of cases, respectively. Antimicrobial therapy was given to 84 patients. Most of them received vancomycin (92%) either as monotherapy (64%) or in combination with other antibiotics (28%), for a median of 18 days. Overall 30-day mortality was 31% (27/86). Multivariate study identified 2 independent factors associated with mortality: spontaneous meningitis (odds ratio [OR], 21.4; 95% confidence interval [CI], 2.3-195.4; p = 0.007), and coma (OR, 9.7; 95% CI, 2.2-42.3; p = 0.002).In conclusion, MRSA is a relatively uncommon but serious disease. Although most cases are nosocomial infections appearing in neurosurgical patients, spontaneous meningitis may present as a community-onset infection in patients with severe comorbidities requiring frequent contact with the health care system. Most patients have a favorable response to vancomycin, but the beneficial effect of combined and intraventricular therapy, or alternative drugs, remains unclear. MRSA meningitis is associated with a high mortality, and the presence of spontaneous infection and coma are the most important prognostic factors. PMID- 22198500 TI - Spectrum of cardiac lesions in Behcet disease: a series of 52 patients and review of the literature. AB - Cardiac abnormalities in patients with Behcet disease (BD) include pericarditis, myocarditis, endocarditis with valvular regurgitation, intracardiac thrombosis, endomyocardial fibrosis, coronary arteritis with or without myocardial infarction, and aneurysms of the coronary arteries or sinus of Valsalva. Data regarding the clinical spectrum, prevalence, and outcome of cardiac lesions in BD are lacking. In this study, we report the main characteristics, treatment, and long-term outcomes of 52 patients with cardiac lesions from a cohort of 807 (6%) BD patients. Forty-five (86.5%) patients were male, with a mean (+/-SD) age at BD diagnosis of 29.3 +/- 10.3 years.Cardiac involvement was the first feature of BD in 17 (32.7%) patients. Cardiac lesions included pericarditis (n = 20; 38.5%), endocarditis (mostly aortic insufficiency) (n = 14; 26.9%), intracardiac thrombosis (n = 10; 19.2%), myocardial infarction (n = 9; 17.3%), endomyocardial fibrosis (n = 4; 7.7%) and myocardial aneurysm (n = 1; 1.9%). Patients with cardiac involvement were more frequently male (86.5% vs. 64.9%; p < 0.01) and had more arterial (42.3% vs. 11.1%; p < 0.01) and venous lesions (59.6% vs. 35.8%; p < 0.01) compared to those without cardiac manifestations. Factors associated with complete remission of cardiac involvement were treatment regimens with oral anticoagulants, immunosuppressants, and colchicine. The 5-year survival rate was 83.6% and 95.8% (p = 0.03) in BD patients with and without cardiac involvement, respectively. After a median (Q1-Q3) follow-up of 3.0 (1.75-4.2) years, 8 patients had died, in 3 cases directly related to cardiac involvement.In conclusion, cardiac lesions affected 6% of our large cohort of BD patients. The prognosis of cardiac involvement in BD is poor and improves with oral anticoagulation, immunosuppressive therapy, and colchicine. PMID- 22198501 TI - IgG4-related systemic disease: features and treatment response in a French cohort: results of a multicenter registry. AB - IgG4-related systemic disease is now recognized as a systemic disease that may affect various organs. The diagnosis is usually made in patients who present with elevated IgG4 in serum and tissue infiltration of diseased organs by numerous IgG4+ plasma cells, in the absence of validated diagnosis criteria. We report the clinical, laboratory, and histologic characteristics of 25 patients from a French nationwide cohort. We also report the treatment outcome and show that despite the efficacy of corticosteroids, a second-line treatment is frequently necessary. The clinical findings in our patients are not different from the results of previous reports from Eastern countries. Our laboratory and histologic findings, however, suggest, at least in some patients, a more broad polyclonal B cell activation than the skewed IgG4 switch previously reported. These observations strongly suggest the implication of a T-cell dependent B-cell polyclonal activation in IgG4-related systemic disease, probably at least in part under the control of T helper follicular cells. PMID- 22198502 TI - P38 MAPK is involved in enhanced NMDA receptor-dependent excitotoxicity in YAC transgenic mouse model of Huntington disease. AB - Huntington disease (HD) is a dominantly inherited neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the protein huntingtin (htt). Previous studies have shown enhanced N-methyl-d-aspartate (NMDA)-induced excitotoxicity in neuronal models of HD, mediated in part by increased NMDA receptor (NMDAR) GluN2B subunit binding with the postsynaptic density protein-95 (PSD-95). In cultured hippocampal neurons, the NMDAR-activated p38 Mitogen activated Protein Kinase (MAPK) death pathway is disrupted by a peptide (Tat NR2B9c) that uncouples GluN2B from PSD-95, whereas NMDAR-mediated activation of c Jun N-terminal Kinase (JNK) MAPK is PSD-95-independent. To investigate the mechanism by which Tat-NR2B9c protects striatal medium spiny neurons (MSNs) from mutant htt (mhtt)-enhanced NMDAR toxicity, we compared striatal tissue and cultured MSNs from presymptomatic yeast artificial chromosome (YAC) mice expressing htt with 128 polyQ (YAC128) to those from YAC18 and/or WT mice as controls. Similar to the previously published shift of GluN2B-containing NMDARs to extrasynaptic sites, we found increased PSD-95 localization as well as elevated PSD-95-GluN2B interactions in the striatal non-PSD (extrasynaptic) fraction from YAC128 mice. Notably, basal levels of both activated p38 and JNK MAPKs were elevated in the YAC128 striatum. NMDA stimulation of acute slices increased activation of p38 and JNK in WT and YAC128 striatum, but Tat-NR2B9c pretreatment reduced only the p38 activation in YAC128. In cultured MSNs, p38 MAPK inhibition reduced YAC128 NMDAR-mediated cell death to WT levels, and occluded the Tat-NR2B9c peptide protective effect; in contrast, inhibition of JNK had a similar protective effect in cultured MSNs from both WT and YAC128 mice. Our results suggest that altered activation of p38 MAPK contributes to mhtt enhancement of GluN2B/PSD-95 toxic signaling. PMID- 22198503 TI - Social enrichment attenuates nigrostriatal lesioning and reverses motor impairment in a progressive 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. AB - Environmental enrichment has been shown to be both neuroprotective and neurorestorative in 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models of Parkinson's disease (PD). However, whether social interaction or novel physical stimulation is responsible for this recovery is controversial. In the current study, we have investigated the effects of only social enrichment (SocE) in progressively MPTP-lesioned mice. After mice were lesioned using a progressively increased dose (4 mg/kg, 8 mg/kg, 16 mg/kg and 32 mg/kg; each dose daily for 5 days), the MPTP-induced behavioral deficits, after the 32 mg/kg dose, were reversed with acute L-DOPA. This acute behavioral recovery suggests that this progressive MPTP-induced neurodegeneration is an appropriate murine model of PD. Mice were housed four per cage for the first 2 weeks of progressive lesioning or vehicle treatment. After the 8 mg/kg MPTP dose (prior to SocE intervention) mice showed a significant decrease in rearing and foot fault behaviors (FF/BB) compared to the vehicle group. Additionally, there was a 38% decrease in mean number of tyrosine hydroxylase immunoreactive (TH-ir) substantia nigra pars compacta (SNpc) neurons/section, and a 50% decrease in the optical density of TH ir dorsolateral caudate putamen (CPu) terminals compared to the vehicle group. Mice were then housed either two (socially limited environment; SLE) or twelve (SocE) mice per cage during continued MPTP lesioning for the next 2 weeks at 16 mg/kg and 32 mg/kg MPTP. MPTP treatment was then discontinued, while mice remained in the SLE or SocE cages for an additional week. Rearing behavior was further impaired in SLE-MPTP mice following progressive MPTP, accompanied by additional decreases in the mean number of TH-ir SNpc neurons/section and CPu TH ir terminals. CPu TH and dopamine transporter (DAT) protein expression, as well as dopamine tissue and TH protein levels was significantly decreased compared to either vehicle group. However, the deficit in rearing behavior in SLE-MPTP mice was reversed with acute L-DOPA following the intervention period. SocE-MPTP mice showed rearing and FF/BB behaviors similar to vehicle levels, although FF/BB was not significantly different from pre-intervention levels. The reversal from pre intervention rearing deficits was correlated with an attenuated decrease in the mean number of SNpc TH-ir neurons/section and CPu TH and DAT protein, and with a blocked decrease in CPu TH-ir terminals compared to pre-intervention levels. Our findings show that SocE mice not only resist further nigrostriatal lesioning and FF/BB deficit, but rearing behavior is recovered to the level of the vehicle group despite continued MPTP treatment. In contrast, SLE mice showed continued loss of nigrostriatal TH-ir and decline of motor behaviors with progressive MPTP. The data suggest that non-pharmacological intervention that started at an early stage of dopamine loss is effective at slowing or blocking further nigrostriatal degeneration. PMID- 22198504 TI - NOX2-derived reactive oxygen species are crucial for CD29-induced pro-survival signalling in cardiomyocytes. AB - AIMS: The highly expressed cell adhesion receptor CD29 (beta(1)-integrin) is essential for cardiomyocyte growth and survival, and its loss of function causes severe heart disease. However, CD29-induced signalling in cardiomyocytes is ill defined and may involve reactive oxygen species (ROS). A decisive source of cardiac ROS is the abundant NADPH oxidase (NOX) isoform NOX2. Because understanding of NOX-derived ROS in the heart is still poor, we sought to test the role of ROS and NOX in CD29-induced survival signalling in cardiomyocytes. METHODS AND RESULTS: In neonatal rat ventricular myocytes, CD29 activation induced intracellular ROS formation (oxidative burst) as assessed by flow cytometry using the redox-sensitive fluorescent dye dichlorodihydrofluorescein diacetate. This burst was inhibited by apocynin and diphenylene iodonium. Further, activation of CD29 enhanced NOX activity (lucigenin-enhanced chemiluminescence) and activated the MEK/ERK and PI3K/Akt survival pathways. CD29 also induced phosphorylation of the inhibitory Ser9 on the pro-apoptotic kinase glycogen synthase kinase-3beta in a PI3K/Akt- and MEK-dependent manner, and improved cardiomyocyte viability under conditions of oxidative stress. The ROS scavenger MnTMPyP or adenoviral co-overexpression of the antioxidant enzymes superoxide dismutase and catalase inhibited CD29-induced pro-survival signalling. Further, CD29-induced protective pathways were lost in mouse cardiomyocytes deficient for NOX2 or functional p47(phox), a regulatory subunit of NOX. CONCLUSION: p47(phox)-dependent, NOX2-derived ROS are mandatory for CD29-induced pro-survival signalling in cardiomyocytes. These findings go in line with a growing body of evidence suggesting that ROS can be beneficial to the cell and support a crucial role for NOX2-derived ROS in cell survival in the heart. PMID- 22198505 TI - In vivo natriuretic peptide reporter assay identifies chemical modifiers of hypertrophic cardiomyopathy signalling. AB - AIMS: Despite increased understanding of the fundamental biology regulating cardiomyocyte hypertrophy and heart failure, it has been challenging to find novel chemical or genetic modifiers of these pathways. Traditional cell-based methods do not model the complexity of an intact cardiovascular system and mammalian models are not readily adaptable to chemical or genetic screens. Our objective was to create an in vivo model suitable for chemical and genetic screens for hypertrophy and heart failure modifiers. METHODS AND RESULTS: Using the developing zebrafish, we established that the cardiac natriuretic peptide genes (nppa and nppb), known markers of cardiomyocyte hypertrophy and heart failure, were induced in the embryonic heart by pathological cardiac stimuli. This pathological induction was distinct from the developmental regulation of these genes. We created a luciferase-based transgenic reporter line that accurately modelled the pathological induction patterns of the zebrafish nppb gene. Utilizing this reporter line, we were able to show remarkable conservation of pharmacological responses between the larval zebrafish heart and adult mammalian models. CONCLUSION: By performing a focused screen of chemical agents, we were able to show a distinct response of a genetic model of hypertrophic cardiomyopathy to the histone deacetylase inhibitor, Trichostatin A, and the mitogen-activated protein kinase kinase 1/2 inhibitor, U0126. We believe this in vivo reporter line will offer a unique approach to the identification of novel chemical or genetic regulators of myocardial hypertrophy and heart failure. PMID- 22198507 TI - Slow calcium waves and redox changes precede mitochondrial permeability transition pore opening in the intact heart during hypoxia and reoxygenation. AB - AIMS: Opening of the mitochondrial permeability transition pore (mPTP) is an important step on the pathway towards cardiomyocyte death, defining the extent of injury following cardiac ischaemia and reperfusion. In isolated mitochondria, mPTP opening is triggered by calcium overload facilitated by oxidative stress. In isolated cells, however, it has been suggested that mPTP opening occurs before calcium overload and is stimulated by oxidative stress. Our objective was to establish the events that cause mPTP opening in the intact heart. METHODS AND RESULTS: We performed multiphoton imaging of Langendorff-perfused mouse hearts expressing an inducible, Ca(2+)-sensitive reporter (circularly Permuted GFP and calmodulin (CaM), version 2), to examine the spatiotemporal relationship between [Ca(2+)](c), redox state, and mPTP opening in the intact heart during hypoxia and reoxygenation at sub-myocyte resolution. We found that during reperfusion, calcium waves propagated across multiple cells at 3.3 um/s. mPTP opening caused an abrupt loss of mitochondrial membrane potential, measured using a potentiometric dye, which was invariably preceded by a rise in [Ca(2+)](c). The probability that localized [Ca(2+)](c) waves led to mPTP opening was greater early during reoxygenation. During reoxygenation, coordinated redox changes also occurred across large regions and preceded mPTP opening on average by 122 +/- 38 s. Fewer [Ca(2+)] waves led to mPTP opening in the presence of mPTP inhibitor cyclosporin A or mitochondrial-targeted scavenger of reactive oxygen species, MitoQ. CONCLUSION: These experiments define the spatiotemporal relationship between changes in [Ca(2+)](c), redox state and mPTP opening during reoxygenation in the intact heart. Tissue oxidation coincident with localized calcium waves together conspire to cause mPTP opening and subsequent cell death. PMID- 22198506 TI - Mitogen-activated protein kinase phosphatase-1 inhibits myocardial TNF-alpha expression and improves cardiac function during endotoxemia. AB - AIMS: Myocardial tumour necrosis factor-alpha (TNF-alpha) expression induces cardiac dysfunction in endotoxemia. The aim of this study was to investigate the role of mitogen-activated protein kinase phosphatase-1 (MKP1) pathway in myocardial TNF-alpha expression and cardiac function during endotoxemia. METHODS AND RESULTS: Lipopolysaccharide (LPS) increased MKP1 expression in the myocardium in vivo and in cultured neonatal cardiomyocytes in vitro. LPS-induced extracellular signal-regulated kinase (ERK) 1/2 and p38 phosphorylation in the myocardium was prolonged in MKP1(-/-) mice. Myocardial TNF-alpha mRNA and protein levels were enhanced in MKP1(-/-) compared with wild-type (WT) mice in endotoxemia, leading to a further decrease in cardiac function. To study if Rac1/p21-activated kinase 1 (PAK1) signalling regulates MKP1 expression, cardiomyocytes were treated with LPS. Inhibition of Rac1 and PAK1 by a dominant negative Rac1 adenovirus (Ad-Rac1N17) and PAK1 siRNA, respectively, blocked LPS induced MKP1 expression in cardiomyocytes. PAK1 siRNA also decreased p38 and c Jun N-terminal kinase (JNK) activation, and TNF-alpha expression induced by LPS. Furthermore, deficiency in either Rac1 or JNK1 decreased myocardial MKP1 expression in endotoxemic mice. CONCLUSION: LPS activates the Rac1/PAK1 pathway, which increases myocardial MKP1 expression via JNK1. MKP1 attenuates ERK1/2 and p38 activation, inhibits myocardial TNF-alpha expression, and improves cardiac function in endotoxemia. Thus, MKP1 represents an important negative feedback mechanism limiting pro-inflammatory response in the heart during sepsis. PMID- 22198508 TI - Modulation of human cardiac transient outward potassium current by EGFR tyrosine kinase and Src-family kinases. AB - AIMS: The human cardiac transient outward K(+) current I(to) (encoded by Kv4.3 or KCND3) plays an important role in phase 1 rapid repolarization of cardiac action potentials in the heart. However, modulation of I(to) by intracellular signal transduction is not fully understood. The present study was therefore designed to determine whether/how human atrial I(to) and hKv4.3 channels stably expressed in HEK 293 cells are regulated by protein tyrosine kinases (PTKs). METHODS AND RESULTS: Whole-cell patch voltage-clamp, immunoprecipitation, western blotting, and site-directed mutagenesis approaches were employed in the present study. We found that human atrial I(to) was inhibited by the broad-spectrum PTK inhibitor genistein, the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556, and the Src-family kinases inhibitor PP2. The inhibitory effect was countered by the protein tyrosine phosphatase inhibitor orthovanadate. In HEK 293 cells stably expressing human KCND3, genistein, AG556, and PP2 significantly reduced the hKv4.3 current, and the reduction was antagonized by orthovanadate. Interestingly, orthovanadate also reversed the reduced tyrosine phosphorylation level of hKv4.3 channels by genistein, AG556, or PP2. Mutagenesis revealed that the hKv4.3 mutant Y136F lost the inhibitory response to AG556, while Y108F lost response to PP2. The double-mutant Y108F-Y136F hKv4.3 channels showed no response to either AG556 or PP2. CONCLUSION: Our results demonstrate that human atrial I(to) and cloned hKv4.3 channels are modulated by EGFR kinase via phosphorylation of the Y136 residue and by Src-family kinases via phosphorylation of the Y108 residue; tyrosine phosphorylation of the channel may be involved in regulating cardiac electrophysiology. PMID- 22198509 TI - Connexin43 silencing in myofibroblasts prevents arrhythmias in myocardial cultures: role of maximal diastolic potential. AB - AIMS: Arrhythmogenesis in cardiac fibrosis remains incompletely understood. Therefore, this study aims to investigate how heterocellular coupling between cardiomyocytes (CMCs) and myofibroblasts (MFBs) affects arrhythmogeneity of fibrotic myocardial cultures. Potentially, this may lead to the identification of novel anti-arrhythmic strategies. METHODS AND RESULTS: Co-cultures of neonatal rat CMCs and MFBs in a 1:1 ratio were used as a model of cardiac fibrosis, with purified CMC cultures as control. Arrhythmogeneity was studied at day 9 of culture by voltage-sensitive dye mapping. Heterocellular coupling was reduced by transducing MFBs with lentiviral vectors encoding shRNA targeting connexin43 (Cx43) or luciferase (pLuc) as control. In fibrotic cultures, conduction velocity (CV) was lowered (11.2 +/- 1.6 cm/s vs. 23.9 +/- 2.1 cm/s; P < 0.0001), while action potential duration and ectopic activity were increased. Maximal diastolic membrane potential (MDP) of CMCs was less negative in fibrotic cultures. In fibrotic cultures, (n = 30) 30.0% showed spontaneous re-entrant tachyarrhythmias compared with 5% in controls (n = 60). Cx43 silencing in MFBs made the MDP in CMCs more negative, increased excitability and CV by 51% (P < 0.001), and reduced action potential duration and ectopic activity (P < 0.01), thereby reducing re entry incidence by 40% compared with pLuc-silenced controls. Anti-arrhythmic effects of Cx43 down-regulation in MFBs was reversed by depolarization of CMCs through I(k1) inhibition or increasing extracellular [K(+)]. CONCLUSION: Arrhythmogeneity of fibrotic myocardial cultures is mediated by Cx43 expression in MFBs. Reduced expression of Cx43 causes a more negative MDP of CMCs. This preserves CMC excitability, limits prolongation of repolarization and thereby strongly reduces the incidence of spontaneous re-entrant tachyarrhythmias. PMID- 22198510 TI - Gap junctional communication controls the overall endothelial calcium response to vasoactive agonists. AB - AIMS: A cytosolic calcium (Ca(2+)(i)) increase is an important activation signal for the endothelium. We investigated whether interendothelial spreading of the Ca(2+) signal via gap junctions (GJs) plays a role for the overall Ca(2+)(i) increase in response to vasoactive agonists. METHODS AND RESULTS: In human umbilical vein endothelial cells (HUVECs), a Ca(2+)(i) increase (Fura2) in response to histamine or ATP occurred initially only in about 30% of the cells (initially responding cells) reflecting the cell fraction expressing H(1) or purinergic receptors (FACS/immunohistochemistry). In the remaining adjacent cells, Ca(2+)(i) increases occurred only after a delay of up to 5 s. Blockade of GJ communication (meclofenamic acid and heptanol, or H(2)O(2); verified by dye injection) did not affect responses in the initially responding cells but abolished the delayed Ca(2+)(i) response of the remaining adjacent cells. The resulting reduction in the global endothelial Ca(2+)(i) response significantly reduced the nitric oxide synthesis (assessed as cGMP levels). Similar Ca(2+)(i) results were obtained in the endothelium of freshly isolated mouse (C57BL/6) aortas stimulated with ATP. The receptor-independent Ca(2+)(i) response to ionomycin occurred simultaneously in all cells, regardless of GJ inhibition. In separate experiments, inhibition of the IP(3) receptor (xestospongin-C; 40, umol/L) but not of the ryanodine receptor (ryanodine, 250 umol/L) reduced the spread of the Ca(2+)(i) signal into adjacent cells over longer distances. CONCLUSION: The global Ca(2+)(i) response of the endothelium to agonists is determined decisively by the functionality of GJs, thus establishing a new role for GJs in controlling endothelial activity and vasomotor function. PMID- 22198512 TI - Association of soluble receptor for advanced glycation end-product with increasing central aortic stiffness in hypertensive patients. AB - OBJECTIVES: In humans, a secreted isoform of (soluble) receptor for advanced glycation end-products (sRAGE) may act as a decoy receptor of advanced glycation end-product. The level of sRAGE may reflect the activity of cell surface receptor for advanced glycation end-product. But there has been no study that has demonstrated the association of sRAGE with central aortic stiffness. Here, we studied the relation of plasma sRAGE level and arterial pulse wave velocity in hypertensive patients. MATERIALS AND METHODS: A total of 415 patients were enrolled (men; 57.6%, mean age; 53.2+/-10.8 years), with 25.8% (n=107) of these being diabetic. All patients underwent pulse wave velocity (PWV) and blood sampling of sRAGE, high-sensitive C-reactive protein, and other serologic markers. RESULTS: The log-transformed sRAGE was significantly correlated with the marker of central aortic stiffness heart to femoral PWV (hfPWV; r=0.165, P=0.001). It also showed a significant correlation with hfPWV in patients with diabetes (r=0.301, P=0.002), but not in patients without diabetes (r=0.115, P=0.055). By multiple linear regression analysis, the log-transformed sRAGE was independently correlated with hfPWV (beta=0.13, P=0.004) when controlled for other variables. CONCLUSIONS: This study has demonstrated, for the first time, that serum sRAGE level was independently correlated with a marker of central aortic stiffness. This result suggests the potential role of RAGE in the pathogenesis of aortic stiffness. PMID- 22198511 TI - Representing others' actions: the role of expertise in the aging mind. AB - A large body of evidence suggests that action execution and action observation share a common representational domain. To date, little is known about age related changes in these action representations that are assumed to support various abilities such as the prediction of observed actions. The purpose of the present study was to investigate (a) how age affects the ability to predict the time course of observed actions; and (b) whether and to what extent sensorimotor expertise attenuates age-related declines in prediction performance. In a first experiment, older adults predicted the time course of familiar everyday actions less precisely than younger adults. In a second experiment, younger and older figure skating experts as well as age-matched novices were asked to predict the time course of figure skating elements and simple movement exercises. Both young age and sensorimotor expertise had a positive influence on prediction performance of figure skating elements. The expertise-related benefit did not show a transfer to movement exercises. Together, the results suggest a specific decline of action representations in the aging mind. However, extensive sensorimotor experience seems to enable experts to represent actions from their domain of expertise more precisely even in older age. PMID- 22198513 TI - Cloning and functional expression of novel cholesterol transporters ABCG1 and ABCG4 in gonadotropin-releasing hormone neurons of the tilapia. AB - In addition to reproduction, gonadotropin-releasing hormone (GnRH) has been postulated to control cholesterol metabolism via cholesterol transport, which is carried out partly by the members of ATP-binding cassette (ABC) transporters G1 (ABCG1) and G4 (ABCG4). However, there is yet to be evidence demonstrating the relationship between these transporters with reference to GnRH neurons. In the present study, we cloned two ABCG1 messenger RNA (mRNA) variants and one ABCG4 mRNA and examined their expression in the brain including GnRH neurons (GnRH1, GnRH2, and GnRH3) in the cichlid tilapia (Oreochromis niloticus). Comparison of nucleotide sequences of the tilapia ABCG1 and ABCG4 with that of other fish species showed that both of these genes are evolutionarily conserved among fishes. ABCG1 and ABCG4 were shown to have high mRNA expressions in the CNS, pituitary, and gonads. In the brain, real-time polymerase chain reaction (PCR) showed that ABCG4 mRNA was higher than ABCG1a in all brain regions including the olfactory bulb (ABCG1=13.34, ABCG4=6796.35; P<0.001), dorsal telencephalon (ABCG1=8.64, ABCG4=10149.13; P=0.001), optic tectum (ABCG1=22.12, ABCG4=13931.04; P<0.01), cerebellum (ABCG1=8.68, ABCG4=12382.90; P<0.01), and preoptic area midbrain-hypothalamus (ABCG1=21.36, ABCG4=13255.41; P=0.001). Similarly, although ABCG1 mRNA level is much higher in the pituitary compared with the brain, it was still significantly lower compared with ABCG4 (ABCG1=337.73, ABCG4=1157.87; P=0.01). The differential pattern of expression of ABCG1 and ABCG4 in the brain versus pituitary suggests that the two transporters are regulated by different mechanisms. Furthermore, ABCG1 and ABCG4 mRNA expressions were found in all three types of laser-captured GnRH neurons with highly similar percentage of expressions, suggesting that cholesterol efflux from GnRH neurons may require heterodimerization of both ABCG1 and ABCG4. PMID- 22198514 TI - Minimally modified LDL upregulates endothelin type B receptors in rat coronary artery via ERK1/2 MAPK and NF-kappaB pathways. AB - Minimally modified low density lipoprotein (mmLDL) is a well-known risk factor for coronary artery disease. Upregulation of vascular endothelin type B (ET(B)) receptors on the vascular smooth muscle cells is predicted to be the molecular mechanism that leads to cardiovascular pathogenesis. The objective of the present study was to examine the hypothesis that mmLDL upregulates ET(B) receptors in rat coronary artery. The contractile responses to sarafotoxin 6c (ET(B) receptor agonist) were studied using a sensitive myograph. ET(B) receptor mRNA and protein expression was determined using real-time PCR and Western blot analysis. The results showed that organ culture increased the contractile responses induced by sarafotoxin 6c and the levels of ET(B) receptor mRNA and protein. This increase was further enhanced by the addition of mmLDL (10MUg/mL). Specific ERK1/2 inhibitors (SB386023 and U0126) and an NF-kappaB inhibitor (wedelolactone) attenuated the mmLDL-increased ET(B) receptor-mediated contraction and ET(B) receptor mRNA and protein levels. Wedelolactone significantly attenuated the mmLDL-decreased IkappaB(alpha) protein expression. Consistent with this result, IkappaB(alpha) protein expression was significantly decreased by culture with mmLDL compared to the level of expression in the organ culture group. However, the JNK inhibitor, SP600125 or p38 pathway inhibitor, SB203580 did not inhibit mmLDL-enhanced effects. The PKC inhibitor, staurosporine attenuated only culture alone-increased effects. In conclusion, mmLDL upregulates the ET(B) receptors in rat coronary arterial smooth muscle cells, mainly via activation of the ERK1/2 MAPK and the downstream transcriptional factor NF-kappaB. PMID- 22198515 TI - Nicolau syndrome may be caused by intravascular vaccine injection. PMID- 22198516 TI - The implications of metapopulation dynamics on the design of vaccination campaigns. AB - Control programmes for vaccine preventable diseases typically operate under logistic constraints such as limited resources and in spatially structured populations where the assumption of homogeneous mixing is invalid. It is unclear, therefore, how to maximise the effectiveness of campaigns in such populations. We investigate how to deploy vaccine in metapopulations by comparing the effectiveness of alternative vaccination strategies on reducing disease occurrence (presence/absence), using canine rabies as a model system, and a domestic dog population within a Tanzanian district divided into sub-populations corresponding to villages. We use patch-occupancy models to quantify the contribution of sub-populations to disease occurrence ("risk") and model allocation strategies for a limited number of vaccine doses that prioritize villages based on their size, risk, or the reduction in risk for the entire population that would result from vaccination. We assume that a maximum of 70% of susceptible individuals in a village could be vaccinated, and that only susceptible dogs are vaccinated. The most effective strategy maximised the reduction in risk of the entire population, and was up to 62% more effective than the other strategies. Large, single-pulse campaigns provided the greatest short term protection, but higher frequencies of smaller pulses were more effective at reducing long-term disease occurrence. Vaccine allocation on a per-dose basis was substantially more effective than a per-village strategy, indicating that operational constraints can reduce control effectiveness. The spatial distribution and abundance of hosts have an important influence on disease dynamics and these results demonstrate that metapopulation models can be used to substantially improve the effectiveness of vaccination campaigns and optimize the allocation of limited control resources. PMID- 22198517 TI - Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine given with routine pediatric vaccines in Taiwan. AB - Immunogenicity and safety of 13-valent and 7-valent pneumococcal conjugate vaccines (PCV13; PCV7) were compared in Taiwanese children. In this double-blind, multicenter study, healthy children were randomly assigned to receive PCV13 (n=84) or PCV7 (n=84) at 2, 4, 6 and 15 months with routine pediatric vaccines. For the 7 PCV13/PCV7 common serotypes, serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) were high 1 month postinfant series, with >=95.0% in both groups achieving IgG levels >=0.35 MUg/mL, with a trend to lower IgG GMCs for PCV13 compared with PCV7 (PCV13:PCV7 GMC ratios 0.59-0.91). For the 6 additional serotypes unique to PCV13, GMCs were notably higher after PCV13 than PCV7 (PCV13:PCV7 GMC ratios 1.50-202.58). Immune responses generally increased posttoddler dose. Safety was similar between groups. PCV13 was safe and immunogenic in this Taiwanese population. PCV13 should offer broader protection than PCV7 against pneumococcal disease. CLINICAL TRIALS REGISTRATION NUMBER: NCT00688870. PMID- 22198518 TI - Binding affinities in the SAMPL3 trypsin and host-guest blind tests estimated with the MM/PBSA and LIE methods. AB - We have estimated affinities for the binding of 34 ligands to trypsin and nine guest molecules to three different hosts in the SAMPL3 blind challenge, using the MM/PBSA, MM/GBSA, LIE, continuum LIE, and Glide score methods. For the trypsin challenge, none of the methods were able to accurately predict the experimental results. For the MM/GB(PB)SA and LIE methods, the rankings were essentially random and the mean absolute deviations were much worse than a null hypothesis giving the same affinity to all ligand. Glide scoring gave a Kendall's tau index better than random, but the ranking is still only mediocre, tau = 0.2. However, the range of affinities is small and most of the pairs of ligands have an experimental affinity difference that is not statistically significant. Removing those pairs improves the ranking metric to 0.4-1.0 for all methods except CLIE. Half of the trypsin ligands were non-binders according to the binding assay. The LIE methods could not separate the inactive ligands from the active ones better than a random guess, whereas MM/GBSA and MM/PBSA were slightly better than random (area under the receiver-operating-characteristic curve, AUC = 0.65-0.68), and Glide scoring was even better (AUC = 0.79). For the first host, MM/GBSA and MM/PBSA reproduce the experimental ranking fairly good, with tau = 0.6 and 0.5, respectively, whereas the Glide scoring was considerably worse, with a tau = 0.4, highlighting that the success of the methods is system-dependent. PMID- 22198520 TI - Positive lymph nodes do not metastasize. AB - Our understanding of the role of lymph nodes (LN) in the metastasization process (MET) is marginal. Positive LNs (pLN) are the most important prognostic factor and lymph node dissection (LND) is still standard practice in primary treatment. However, up to now, there is almost no evidence that elective LND has a survival benefit. Based on many clinical and experimental findings, we propose that tumor foci in regional LN are incapable of metastasization and can therefore not infiltrate further LN and organs. Available data demonstrate a very early infiltration of MET capable tumor cells from the primary tumor into regional LN, and thereafter an increased probability of subsequent LN infiltrations. Disparate growth rates of the first versus subsequent infiltrating tumors as well as the asymptotic growth and prognosis of large tumor foci in LN explain many clinical observations for solid tumors. The consequence of the hypothesis "pLN do not metastasize" would impact clinical treatment and research and contribute to understanding the mounting evidence against LND. PMID- 22198519 TI - Exhaustive search and solvated interaction energy (SIE) for virtual screening and affinity prediction. AB - We carried out a prospective evaluation of the utility of the SIE (solvation interaction energy) scoring function for virtual screening and binding affinity prediction. Since experimental structures of the complexes were not provided, this was an exercise in virtual docking as well. We used our exhaustive docking program, Wilma, to provide high-quality poses that were rescored using SIE to provide binding affinity predictions. We also tested the combination of SIE with our latest solvation model, first shell of hydration (FiSH), which captures some of the discrete properties of water within a continuum model. We achieved good enrichment in virtual screening of fragments against trypsin, with an area under the curve of about 0.7 for the receiver operating characteristic curve. Moreover, the early enrichment performance was quite good with 50% of true actives recovered with a 15% false positive rate in a prospective calculation and with a 3% false positive rate in a retrospective application of SIE with FiSH. Binding affinity predictions for both trypsin and host-guest complexes were generally within 2 kcal/mol of the experimental values. However, the rank ordering of affinities differing by 2 kcal/mol or less was not well predicted. On the other hand, it was encouraging that the incorporation of a more sophisticated solvation model into SIE resulted in better discrimination of true binders from binders. This suggests that the inclusion of proper Physics in our models is a fruitful strategy for improving the reliability of our binding affinity predictions. PMID- 22198522 TI - Characterization of human B cells in umbilical cord blood-transplanted NOD/SCID mice. AB - Humanized mice are crucially important for preclinical studies. However, the development and potential function of human B cells in chimeras remain unclear. Here, we describe the study of human B cells in NOD/LtSzPrkdcscid/J (NOD/SCID) mice. In this study, we transplanted 1.0*10(5) human CD34(+) cells from umbilical cord blood (UCB) into NOD/SCID mice after pretreatment with anti-asialo GM1 antiserum and sublethal irradiation. Human CD45(+) cells were detected in the peripheral blood of the recipient mice from 6 weeks after transplantation. CD19(+) B cells accounted for the greater part of the CD45(+) cells in the human UCB-chimeric mice, but their maturational stages differed in different organs. Most of the bone marrow (BM) CD19(+) cells were immature IgM(-)IgD( )CD24(hi)CD38(hi) B cells, whereas the mature CD5(+)IgM(+)IgD(+)CD24(int)CD38(int)CD19(+) B cells were predominantly present in the spleen and peripheral blood. Human immunoglobulin (Ig) M was detected in mouse plasma. The human B cells also secreted human interleukin-10 after stimulation with LPS in vitro. These results show that human CD34(+) cells can differentiate into human B cells in NOD/SCID mice, with development and functions that are similar to those of B cell subsets in humans. The transplantation of human CD34(+) cells into NOD/SCID mice may provide a useful tool to study the development and function of human B cells. PMID- 22198521 TI - The structure of allelic diversity in the presence of purifying selection. AB - In the absence of selection, the structure of equilibrium allelic diversity is described by the elegant sampling formula of Ewens. This formula has helped to shape our expectations of empirical patterns of molecular variation. Along with coalescent theory, it provides statistical techniques for rejecting the null model of neutrality. However, we still do not fully understand the statistics of the allelic diversity expected in the presence of natural selection. Earlier work has described the effects of strongly deleterious mutations linked to many neutral sites, and allelic variation in models where offspring fitness is unrelated to parental fitness, but it has proven difficult to understand allelic diversity in the presence of purifying selection at many linked sites. Here, we study the population genetics of infinitely many perfectly linked sites, some neutral and some deleterious. Our approach is based on studying the lineage structure within each class of individuals of similar fitness in the deleterious mutation-selection balance. Consistent with previous observations, we find that for moderate and weak selection pressures, the patterns of allelic diversity cannot be described by a neutral model for any choice of the effective population site. We compute precisely how purifying selection at many linked sites distorts the patterns of allelic diversity, by developing expressions for the likelihood of any configuration of allelic types in a sample analogous to the Ewens sampling formula. PMID- 22198523 TI - A novel genetic tool for clonal analysis of fourth chromosome mutations. AB - The fourth chromosome of Drosophila remains one of the most intractable regions of the fly genome to genetic analysis. The main difficulty posed to the genetic analyses of mutations on this chromosome arises from the fact that it does not undergo meiotic recombination, which makes recombination mapping impossible, and also prevents clonal analysis of mutations, a technique which relies on recombination to introduce the prerequisite recessive markers and FLP-recombinase recognition targets (FRT). Here we introduce a method that overcomes these limitations and allows for the generation of single Minute haplo-4 clones of any fourth chromosome mutant gene in tissues of developing and adult flies. PMID- 22198524 TI - The length scale of selection in protein evolution. AB - Central to the study of molecular evolution, and an area of long-standing debate, is the appropriate model for the fitness landscape of proteins. Much of this debate has focused on the strength and frequency of positive and purifying selection, but the form and frequency of selective correlations is also a vital element. The constituent amino acids within a protein generically interact and share selective pressures in predictable ways, which conflicts with the selective independence assumed by common caricatures of the fitness landscape. Here, I discuss a recent study by myself and coauthors that used whole-genome comparisons of orthologous molecular sequences from closely related Drosophilids to explore the form of the selective correlations and selective interactions (epistasis) between the amino acids within a protein. I outline our results and highlight our finding of a selective length scale of ten amino acids within which individual amino acids are substantially and generically more likely to share selective pressures and interact epistatically. I then focus on the evidence presented in our study supporting a substantial role for epistasis in the process of molecular evolution, and discuss further the implications of this widespread epistasis on the overdispersion of the molecular clock and the efficacy of common tests for positive selection. PMID- 22198525 TI - The role of magnesium in type 2 diabetes: a brief based-clinical review. AB - A growing body of evidence from experimental studies that shows the essential role that magnesium exerts on glucose metabolism has been developed in last years, strongly suggesting that magnesium could plays an important roles in the reduction of the risk of developing type 2 diabetes. In the clinical setting, large epidemiological studies show that low dietary magnesium intake is associated with the increased risk of developing type 2 diabetes; however, results from randomized controlled clinical trials that have evaluated the beneficial effects of magnesium supplementation on glucose metabolism and insulin sensitivity are controversial. In this article we searched (in the electronic databases of Medline, Embase, and the Cochrane Controlled Trials Register up to June 2011) the evidence derived from epidemiological studies and clinical trials, about the relationship between magnesium and type 2 diabetes. The body of evidence from epidemiological studies consistently shows a strong inverse relationship between dietary magnesium intake and the risk of developing T2D; however, results from clinical trials are scarce and controversial. PMID- 22198526 TI - Transetherification-mediated E-ring opening and stereoselective "Red-Ox" modification of furostan. AB - We have developed a novel E-ring opening method for furostan, and applied it to prepare D-ring modified steroids, which can be used to synthesize cephalostatin analogs. PMID- 22198527 TI - A comparative study of the effect of 17beta-estradiol and estriol on peripheral pain behavior in rats. AB - Although estradiol has been reported to influence pain sensitivity, the role of estriol (an estradiol metabolite and another widely used female sex hormone) remains unclear. In this study, pain behavior tests, whole-cell patch clamp recording and Western blotting were used to determine whether estriol plays a role in pain signal transduction and transmission. Either systemic or local administration of 17beta-estradiol produced a significant rise of mechanical pain threshold, while estriol lacked this effect in normal and ovariectomized (OVX) rats following estriol replacement. Local administration of 17beta-estradiol or estriol significantly decreased ATP-induced spontaneous hind-paw withdrawal duration (PWD), which was blocked by an estrogen receptor antagonist, ICI 182, 780. However, systemic application of estriol in normal or OVX rats lacked this similar effect. In cultured dorsal root ganglion neurons, estriol attenuated alpha,beta-methylene ATP-induced transient currents which were blocked by ICI 182, 780. In complete Freund's adjuvant treated (CFA) rats, systemic application of 17beta-estradiol or estriol decreased the mechanical pain threshold significantly, but did not change the inflammatory process. Similar effects were observed after estriol replacement in OVX rats. The expression of c-fos in lumbosacral spinal cord dorsal horn (SCDH) was increased significantly by administration of 17beta-estradiol but not estriol, and not by estriol replacement in OVX rats. These results suggest that 17beta-estradiol but not estriol plays an anti-hyperalgesic role in physiological pain. However, both peripheral 17beta-estradiol and estriol play anti-hyperalgesic roles in ATP induced inflammatory pain. Systemic application of estriol as well as 17beta estradiol plays hyperalgesic roles in CFA-induced chronic pain. PMID- 22198528 TI - High prevalence of radiological vertebral fractures in HIV-infected males. AB - Age-related co-morbidities including osteoporosis are relevant in patients responding to combination antiretroviral therapy (cART). Vertebral fractures are common osteoporotic fractures and their diagnosis is useful for managing at-risk individuals. However, there are few data from HIV-infected patients. Therefore, the aim of this study was to determine the prevalence of and factors associated with vertebral fractures in a population of HIV-infected males. A cross-sectional study of 160 HIV-infected patients with available chest X-rays was conducted from 1998 to 2010. One hundred and sixty-three males with comparable age and with no history of HIV infection were recruited as controls. Semi-quantitative evaluation of vertebral heights in lateral chest X-rays and quantitative morphometry assessment of centrally digitized images using dedicated morphometry software were utilized to detect prevalent vertebral fractures. The result showed that the vertebral fractures were detected in 43/160 (26.9%) HIV-infected patients and in 21/163 (12.9%) controls (P = 0.002). In HIV-infected patients with fractures, 27 had two or more fractures and ten patients had severe fractures. The prevalence of any fractures and multiple fractures in HIV-infected patients receiving cART (29.6 and 20.0%) was slightly higher than in HIV-infected patients not exposed to cART (17.1 and 5.7%), but significantly higher than control subjects (12.9 and 3.7%). At multivariable analyses, body mass index and diabetes mellitus were independently correlated with vertebral fractures in HIV-infected patients. We concluded that a significant proportion of HIV-infected males receiving cART showed vertebral fractures. Furthermore, proactive diagnosis of vertebral fragility fractures is particularly relevant in patients who are overweight or suffer from diabetes. PMID- 22198529 TI - Contact points during multidigit grasping of geometric objects. AB - We investigated the choice of contact points during multidigit grasping of different objects. In Experiment 1, cylinders were grasped and lifted. Participants were either instructed as to the number of fingers they should use, ranging from a two-finger grasp to a five-finger grasp, or could grasp with their preferred number of fingers. We found a strong relationship between the position of the fingertips on the object and the number of fingers used. In general, variability in the choice of contact points was low within- as well as between participants. The virtual finger, defined as the geometric mean position of fingers opposing the thumb, was in almost perfect opposition to the thumb, suggesting the formation of a functional unit using all contributing fingers in the grasp. In Experiment 2, four more complex shapes (rectangle, hexagon, pentagon, curved object) were grasped. Although we found some moderate between participant variability in the choice of contact points, the within-participant variability was again remarkably low. In both experiments, participants showed a strong preference to use four or five fingers during grasping when left with free choice. Taken together, our findings suggest a preplanning of the grasping movement and that grasping results from a coordinated interplay between the fingers contributing to the grasp that cannot be understood as independent digit movements. PMID- 22198530 TI - Imperceptible electrical noise attenuates isometric plantar flexion force fluctuations with correlated reductions in postural sway. AB - Optimal levels of noise stimulation have been shown to enhance the detection and transmission of neural signals thereby improving the performance of sensory and motor systems. The first series of experiments in the present study aimed to investigate whether subsensory electrical noise stimulation applied over the triceps surae (TS) in seated subjects decreases torque variability during a force matching task of isometric plantar flexion and whether the same electrical noise stimulation decreases postural sway during quiet stance. Correlation tests were applied to investigate whether the noise-induced postural sway decrease is linearly predicted by the noise-induced torque variability decrease. A second series of experiments was conducted to investigate whether there are differences in torque variability between conditions in which the subsensory electrical noise is applied only to the TS, only to the tibialis anterior (TA) and to both TS and TA, during the force-matching task with seated subjects. Noise stimulation applied over the TS muscles caused a significant reduction in force variability during the maintained isometric force paradigm and also decreased postural oscillations during quiet stance. Moreover, there was a significant correlation between the reduction in force fluctuation and the decrease in postural sway with the electrical noise stimulation. This last result indicates that changes in plantar flexion force variability in response to a given subsensory random stimulation of the TS may provide an estimate of the variations in postural sway caused by the same subsensory stimulation of the TS. We suggest that the decreases in force variability and postural sway found here are due to stochastic resonance that causes an improved transmission of proprioceptive information. In the second series of experiments, the reduction in force variability found when noise was applied to the TA muscle alone did not reach statistical significance, suggesting that TS proprioception gives a better feedback to reduce force fluctuation in isometric plantar flexion conditions. PMID- 22198531 TI - Infants and adults reaching in the dark. AB - It has been shown that infants over the age of 6 months will reach for an object in complete darkness. This experiment measured the reaching movements of 9- to 16 month-old infants and adults under several different conditions of illumination to investigate the role of vision and stored visual representations in reach control. In one condition, participants reached for an object with the lights on. In a second condition, participants reached for an object glowing in the dark (glowing condition). This allowed us to measure the effects of vision of the arm and vision of the reach space. We also looked at the effect of removing vision of the object on reach control: in the final two conditions, participants reached for an object in complete darkness (0-s dark) and in complete darkness after a 4 s delay (4-s dark). We compared the kinematics of a reach (e.g. average speed, reach straightness) between the four illumination conditions. The results showed that infants reached faster and decelerated for a shorter period of time in the dark (0- and 4-s dark) than in the light. By comparison, adults reached slower and decelerated for a longer period of time in the dark (0- and 4-s dark) than in the light. We did not find any effect of the glowing condition compared to full vision on infant reaching movements. These results suggest that infant reaching movements only become compromised when the target is not visible, whereas vision of the hand and the reach space are less significant. Without online visual feedback, an infant reach in the dark appears to be driven by feedforward mechanisms and control may be affected by an immature ability to form and/or retain visual spatial memory. PMID- 22198532 TI - Proprioceptive recalibration in the right and left hands following abrupt visuomotor adaptation. AB - Previous studies have demonstrated that after reaching with misaligned visual feedback of the hand, one adapts his or her reaches and partially recalibrates proprioception, such that sense of felt hand position is shifted to match the seen hand position. However, to date, this has only been demonstrated in the right (dominant) hand following reach training with a visuomotor distortion in which the rotated cursor distortion was introduced gradually. As reach adaptation has been shown to differ depending on how the distortion is introduced (gradual vs. abrupt), we sought to examine proprioceptive recalibration following reach training with a cursor that was abruptly rotated 30 degrees clockwise relative to hand motion. Furthermore, because the left and right arms have demonstrated selective advantages when matching visual and proprioceptive targets, respectively, we assessed proprioceptive recalibration in right-handed subjects following training with either the right or the left hand. On average, we observed shifts in felt hand position of approximately 7.6 degrees following training with misaligned visual feedback of the hand, which is consistent with our previous findings in which the distortion was introduced gradually. Moreover, no difference was observed in proprioceptive recalibration across the left and right hands. These findings suggest that proprioceptive recalibration is a robust process that arises symmetrically in the two hands following visuomotor adaptation regardless of the initial magnitude of the error signal. PMID- 22198533 TI - Analysis of motoneuron responses to composite synaptic volleys (computer simulation study). AB - This paper deals with the analysis of changes in motoneuron (MN) firing evoked by repetitively applied stimuli aimed toward extracting information about the underlying synaptic volleys. Spike trains were obtained from computer simulations based on a threshold-crossing model of tonically firing MN, subjected to stimulation producing postsynaptic potentials (PSPs) of various parameters. These trains were analyzed as experimental results, using the output measures that were previously shown to be most effective for this purpose: peristimulus time histogram, raster plot and peristimulus time intervalgram. The analysis started from the effects of single excitatory and inhibitory PSPs (EPSPs and IPSPs). The conclusions drawn from this analysis allowed the explanation of the results of more complex synaptic volleys, i.e., combinations of EPSPs and IPSPs, and the formulation of directions for decoding the results of human neurophysiological experiments in which the responses of tonically firing MNs to nerve stimulation are analyzed. PMID- 22198534 TI - Medium-latency reflex response elicited from the flexor carpi radialis by radial nerve stimulation. AB - The H reflex obtained from the flexor carpi radialis muscle by median nerve stimulation is a well-known monosynaptic reflex. However, the origin of the late responses is still contentious. Radial nerve stimulation was performed through the spiral groove, and EMG recording was obtained from the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles. An M response followed by an F response was achieved from the ECR by radial nerve stimulation; the antagonistic FCR muscle elicited a late response. A total of 25 cases were included in this study. In 22 of these cases, a response with a latency of 40.97 +/- 5.35 ms was obtained from the FCR by radial nerve stimulation. When extension of the hand was restricted, the response disappeared in five of nine cases. Application of cold markedly suppressed the response and prolonged the latency of the FCR medium latency reflex response (FCR-MLR). Oral tizanidine considerably suppressed the FCR-MLR response. Two out of eight cases did not exhibit any response. No response could be recorded from a patient with complete amputation of the right hand. The FCR-MLR is the reflex caused by stretching of the FCR muscle from radial nerve stimulation, and it is greatly influenced by group II afferents. PMID- 22198536 TI - The biological response of spermidine induced by ionization radiation. AB - Globally, there are concerns over the risks associated with radiation exposure, so it is important to understand the biological effects of radiation exposure. Driven by the need to detect the presence of radiation exposure, biomarkers to monitor potential exposure after radiological accidents can be developed and would be extremely valuable for biological response. In this study, the behavior of spermidine as a biomarker was investigated in a C57BL/6 mouse model exposed to an acute whole-body sublethal dose of 6 Gy. The spermidine content values in serum increased for up to two days after 6 Gy irradiation. However, the enhanced spermidine content observed on day +3 in irradiated mice returned to normal levels on the subsequent five days. The result indicates that spermidine can be used as a biomarker of biological response to radiation exposure. PMID- 22198535 TI - Like a bolt from the blue: phthalocyanines in biomedical optics. AB - The purpose of this review is to compile preclinical and clinical results on phthalocyanines (Pcs) as photosensitizers (PS) for Photodynamic Therapy (PDT) and contrast agents for fluorescence imaging. Indeed, Pcs are excellent candidates in these fields due to their strong absorbance in the NIR region and high chemical and photo-stability. In particular, this is mostly relevant for their in vivo activation in deeper tissular regions. However, most Pcs present two major limitations, i.e., a strong tendency to aggregate and a low water-solubility. In order to overcome these issues, both chemical tuning and pharmaceutical formulation combined with tumor targeting strategies were applied. These aspects will be developed in this review for the most extensively studied Pcs during the last 25 years, i.e., aluminium-, zinc- and silicon-based Pcs. PMID- 22198537 TI - Atherogenic alterations in hypertriglyceridemic patients would not depend on insulin resistance. AB - BACKGROUND AND AIMS: Several studies have been carried out to characterize the different alterations associated with hypertriglyceridemia (HTG) and to identify this dyslipemia as an independent risk factor for cardiovascular disease (CVD). HTG is frequently, but not always, associated with insulin resistance (IR). The present study was aimed to evaluate if the alterations observed in biomarkers of CVD were similar in HTG states independently of IR. METHODS: HTG was defined as triglycerides >=1.69 mmol/l and IR as HOMA-IR >=3.1. HTG-IR patients (n=15) were compared with HTG subjects without IR (WIR) (n=15) and with normotriglyceridemic (NTG)-WIR individuals (n=30). RESULTS: Both HTG groups shared the increment in VLDL-C and non-HDL-C, HDL enrichment in triglycerides and depletion in phospholipids, the decrease in adiponectin concentration, and the increase in CETP activity. HDL-C and VCAM-1 levels were altered only in HTG-IR patients in comparison with the other groups, while oxidized LDL was only higher in HTG-IR than the control group. Multiple regression analysis identified triglycerides as the independent predictor of HDL-C, CETP activity and oxidized LDL levels. CONCLUSION: The increase in triglycerides is the major determinant factor of the atherogenic modifications observed, while IR would be an amplifier factor. PMID- 22198538 TI - Serological evaluation of relationship between viral pathogens (BHV-1, BVDV, BRSV, PI-3V, and Adeno3) and dairy calf pneumonia by indirect ELISA. AB - In this study, viral pathogens associated with nine outbreaks of naturally occurring dairy calf pneumonia in Mashhad area of Khorasan Razavi province from September 2008 to May 2009 were assessed. Five diseased calves from each farm were chosen for examination. Acute and convalescent serum samples were taken from calves with signs of respiratory disease. Sera were analyzed for antibodies to bovine viral diarrhea virus (BVDV), bovine herpesvirus type 1 (BHV-1), bovine respiratory syncytial virus (BRSV), parainfluenza virus type 3 (PI-3V), and bovine adenovirus-3 (BAV-3) by indirect ELISA kits. Among 42 serum samples collected at sample 1, seroprevalence values for viruses BHV-1, BVDV, BRSV, PI 3V, and BAV-3 were 61.9% (26), 57.1% (24), 64.2% (27), 90% (38), and 61.9% (26), respectively. Seroconversion to BVDV, BRSV, PI-3V, and BAV-3 occurred in 11.9% (5), 16.6% (7), 26.1% (11), and 21.4% (9) of animals, and 52.3% (22) had generated antibodies against one or more viral infections at sample 2. In addition, no significant relationship between seroprevalence of BHV-1, BVDV, BRSV, PI-3V, and BAV-3 and dairy herd size was observed (P > 0.05). According to serological findings, BHV-1, BVDV, BRSV, PI-3V, and BAV-3 are common pathogens of the dairy calf pneumonia in dairy herds in Mashhad area of Khorasan Razavi province, Iran. PMID- 22198540 TI - Maximally tolerated busulfan systemic exposure in combination with fludarabine as conditioning before allogeneic hematopoietic cell transplantation. AB - Systemic exposure to high-dose busulfan has been correlated with efficacy and toxicity after hematopoietic cell transplantation for malignancy. We used the area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to i.v. busulfan when given once daily after fludarabine administered at 40 mg/m(2) for 4 days. Three target AUC levels were planned: 6,000, 7,500, and 9,000 MUM-min. Included were patients 16 to 65 years old, with a hematologic malignancy, an HLA A, B, or C, DRB1 8/8 or 7/8 matched donor, Karnofsky performance status >=70%, and adequate organ function. For level 1 patients, i.v. busulfan doses 1 and 2 were 170 mg/m(2)/day, then doses 3 and 4 were adjusted based on first-dose pharmacokinetic modeling to achieve an average daily AUC of 6,000 MUM-min. Doses 1 and 2 for the subsequent cohorts were based on the level 1 data: 180 mg/m(2)/day for AUC 7,500 MUM-min (level 2) and 220 mg/m(2)/day for AUC 9,000 MUM-min (level 3), with pharmacokinetic targeting for doses 3 and 4. Pharmacokinetic analysis after the last dose showed that 88% of the patients had been exposed to a mean AUC within 10% of the target. Forty patients were treated at level 1, 29 patients at level 2, and three patients at level 3. DLT was veno-occlusive disease of the liver, which occurred in none of 40 patients (0%) at level 1, two of 29 patients (7%) at level 2, and three of three patients (100%) at level 3. Dermatitis (P < .01) and pulmonary toxicity (P = .01) were also increased at higher AUC levels. Level 2 (7,500 MUM-min * 4 days) was the maximally tolerated AUC. Within the confines of the trial's small sample size, there was no suggestion that escalating busulfan AUC from 6,000 to 7,500 MUM-min * 4 days increased nonrelapse mortality. Assessment of the higher busulfan AUC on relapse prevention requires trials in patients with a homogeneous risk of relapse. PMID- 22198539 TI - Examination of mesenchymal stem cell-mediated RNAi transfer to Huntington's disease affected neuronal cells for reduction of huntingtin. AB - Huntington's disease (HD) is a fatal, autosomal dominant neurodegenerative disorder caused by an expanded trinucleotide (CAG) repeat in exon 1 of the huntingtin gene (Htt). This expansion creates a toxic polyglutamine tract in the huntingtin protein (HTT). Currently, there is no treatment for either the progression or prevention of the disease. RNA interference (RNAi) technology has shown promise in transgenic mouse models of HD by reducing expression of mutant HTT and slowing disease progression. The advancement of RNAi therapies to human clinical trials is hampered by problems delivering RNAi to affected neurons in a robust and sustainable manner. Mesenchymal stem cells (MSC) have demonstrated a strong safety profile in both completed and numerous ongoing clinical trials. MSC exhibit a number of innate therapeutic effects, such as immune system modulation, homing to injury, and cytokine release into damaged microenvironments. The ability of MSC to transfer larger molecules and even organelles suggested their potential usefulness as delivery vehicles for therapeutic RNA inhibition. In a series of model systems we have found evidence that MSC can transfer RNAi targeting both reporter genes and mutant huntingtin in neural cell lines. MSC expressing shRNA antisense to GFP were found to decrease expression of GFP in SH SY5Y cells after co-culture when assayed by flow cytometry. Additionally MSC expressing shRNA antisense to HTT were able to decrease levels of mutant HTT expressed in both U87 and SH-SY5Y target cells when assayed by Western blot and densitometry. These results are encouraging for expanding the therapeutic abilities of both RNAi and MSC for future treatments of Huntington's disease. PMID- 22198541 TI - High incidence of radiation-induced cavernous hemangioma in long-term survivors who underwent hematopoietic stem cell transplantation with radiation therapy during childhood or adolescence. AB - Radiation-induced cavernous hemangioma (RICH) is a late complication of cerebral radiation therapy. Long-term survivors of hematopoietic stem cell transplantation (HSCT) who underwent radiation therapy could be at increased risk for RICH. We investigated records of 68 patients who underwent HSCT during childhood or adolescence and were assessed by magnetic resonance imaging (MRI), including T2* weighted imaging of the brain, annually for 5 years over a range of 6 to 29 years after HSCT. We developed a scoring and grading system for RICH to monitor the process and the progress of radiologic changes. Among the 68 patients investigated, 28 (41.2%) were diagnosed with CH. All 28 patients had received total body irradiation as a conditioning treatment for HSCT and/or cranial radiation therapy before HSCT as part of the treatment of their primary disease. RICH was diagnosed in none of the patients who did not receive radiation (n = 19), in 46.2% of those who received 6 to 12 Gy (n = 39), and in all of those who received 18 to 36 Gy (n = 10). Total RICH scores were correlated with higher radiation doses. Careful and long-term evaluation with MRI, including T2* weighted imaging, is necessary for HSCT recipients who received radiation therapy before and/or during HSCT. PMID- 22198542 TI - Sequential bortezomib, dexamethasone, and thalidomide maintenance therapy after single autologous peripheral stem cell transplantation in patients with multiple myeloma. AB - We report feasibility and response results of a phase II study investigating prolonged weekly bortezomib and dexamethasone followed by thalidomide and dexamethasone as maintenance therapy after single autologous stem cell transplantation (ASCT) in patients with multiple myeloma. Within 4 to 8 weeks of ASCT, patients received weekly bortezomib and dexamethasone for six cycles, followed by thalidomide and dexamethasone for six more cycles. Thalidomide alone was continued until disease progression. Forty-five patients underwent ASCT. Forty patients started maintenance therapy; of these, 36 patients received four cycles, and 32 completed six cycles of maintenance bortezomib. Of these 40 patients, nine (22%) were in complete response (CR) before ASCT, 13 (32%) achieved CR after ASCT but before bortezomib maintenance therapy, and 21 (53%) achieved CR after bortezomib maintenance therapy. Nine patients not previously in CR (33%) upgraded their response to CR with bortezomib maintenance. At 1 year post-ASCT, 20 patients achieved CR, and two achieved very good partial response. Twenty-seven patients experienced peripheral neuropathy during bortezomib therapy, all grade 1 or 2. Our findings indicate that prolonged sequential weekly bortezomib, dexamethasone, and thalidomide maintenance therapy after single ASCT is feasible and well tolerated. Bortezomib maintenance treatment upgraded post ASCT CR responses with no severe grade 3/4 peripheral neuropathy. PMID- 22198543 TI - Outcome of lower-intensity allogeneic transplantation in non-Hodgkin lymphoma after autologous transplantation failure. AB - We studied the outcome of allogeneic hematopoietic stem cell transplantation after lower-intensity conditioning regimens (reduced-intensity conditioning and nonmyeloablative) in patients with non-Hodgkin lymphoma who relapsed after autologous hematopoietic stem cell transplantation. Nonrelapse mortality, lymphoma progression/relapse, progression-free survival (PFS), and overall survival were analyzed in 263 patients with non-Hodgkin lymphoma. All 263 patients had relapsed after a previous autologous hematopoietic stem cell transplantation and then had undergone allogeneic hematopoietic stem cell transplantation from a related (n = 26) or unrelated (n = 237) donor after reduced-intensity conditioning (n = 128) or nonmyeloablative (n = 135) and were reported to the Center for International Blood and Marrow Transplant Research between 1996 and 2006. The median follow-up of survivors was 68 months (range, 3 111 months). Three-year nonrelapse mortality was 44% (95% confidence interval [CI], 37%-50%). Lymphoma progression/relapse at 3 years was 35% (95% CI, 29% 41%). Three-year probabilities of PFS and overall survival were 21% (95% CI, 16% 27%) and 32% (95% CI, 27%-38%), respectively. Superior Karnofsky Performance Score, longer interval between transplantations, total body irradiation-based conditioning regimen, and lymphoma remission at transplantation were correlated with improved PFS. Allogeneic hematopoietic stem cell transplantation after lower intensity conditioning is associated with significant nonrelapse mortality but can result in long-term PFS. We describe a quantitative risk model based on pretransplantation risk factors to identify those patients likely to benefit from this approach. PMID- 22198544 TI - Molecular mechanisms of EGF signaling-dependent regulation of pipe, a gene crucial for dorsoventral axis formation in Drosophila. AB - During Drosophila oogenesis the expression of the sulfotransferase Pipe in ventral follicle cells is crucial for dorsoventral axis formation. Pipe modifies proteins that are incorporated in the ventral eggshell and activate Toll signaling which in turn initiates embryonic dorsoventral patterning. Ventral pipe expression is the result of an oocyte-derived EGF signal which down-regulates pipe in dorsal follicle cells. The analysis of mutant follicle cell clones reveals that none of the transcription factors known to act downstream of EGF signaling in Drosophila is required or sufficient for pipe regulation. However, the pipe cis-regulatory region harbors a 31-bp element which is essential for pipe repression, and ovarian extracts contain a protein that binds this element. Thus, EGF signaling does not act by down-regulating an activator of pipe as previously suggested but rather by activating a repressor. Surprisingly, this repressor acts independent of the common co-repressors Groucho or CtBP. PMID- 22198545 TI - Evolution of petaloid sepals independent of shifts in B-class MADS box gene expression. AB - Attractive petals are an integral component of animal-pollinated flowers and in many flowering plant species are restricted to the second floral whorl. Interestingly, multiple times during angiosperm evolution, petaloid characteristics have expanded to adjacent floral whorls or to extra-floral organs. Here, we investigate developmental characteristics of petaloid sepals in Rhodochiton atrosanguineum, a close relative of the model species Antirrhinum majus (snapdragon). We undertook this in two ways, first using scanning electron microscopy we investigate the micromorphology of petals and sepals, followed by expression studies of genes usually responsible for the formation of petaloid structures. From our data, we conclude that R. atrosanguineum petaloid sepals lack micromorphological characteristics of petals and that petaloid sepals did not evolve through regulatory evolution of B-class MADS box genes, which have been shown to specify second whorl petal identity in a number of model flowering plant species including snapdragon. These data, in conjunction with other studies, suggests multiple convergent pathways for the evolution of showy sepals. PMID- 22198546 TI - The role of ClpP in protein expression of Streptococcus pneumoniae. AB - Previous reports suggest that ClpP proteolytic activity is important not only for cell physiology but also for regulation of virulence properties of Streptococcus pneumoniae (S. pneumoniae). In order to get a more comprehensive picture of the role of ClpP protease on protein expression in S. pneumoniae D39 and how it relates to physiology and virulence, a clpP mutant strain was constructed in S. pneumoniae D39, and global proteome expression was studied by 2-dimensional electrophoresis and matrix-assisted laser desorption-ionization-time of flight mass spectrometry. We report here that clpP deletion affects the expression of proteins which are involved in the general stress response, nucleotide metabolism, energy metabolism, and proteins metabolism. These provide clues for understanding the role of ClpP in the physiology and pathogenesis of pneumococcus. PMID- 22198547 TI - Glycation promotes the formation of genotoxic aggregates in glucose oxidase. AB - This study investigates the effect of pentose sugars (ribose and arabinose) on the structural and chemical modifications in glucose oxidase (GOD) as well as genotoxic potential of this modified form. An intermediate state of GOD was observed on day 12 of incubation having CD minima peaks at 222 and 208 nm, characteristic of alpha-helix and a few tertiary contacts with altered tryptophan environment and high ANS binding. All these features indicate the existence of molten globule state of the GOD with ribose and arabinose on day 12. GOD on day 15 of incubation forms beta structures as revealed by CD and FTIR which may be due to its aggregation. Furthermore, GOD on day 15 showed a remarkable increase in Thioflavin T fluorescence at 485 nm. Comet assay of lymphocytes and plasmid nicking assay in presence of glycated GOD show DNA damage which confirmed the genotoxicity of advance glycated end products. Hence, our study suggests that glycated GOD results in the formation of aggregates and the advanced glycated end products, which are genotoxic in nature. PMID- 22198548 TI - DSM-5: implications for pediatric mental health care. PMID- 22198550 TI - Comparative proteomics analysis of serum proteins in ulcerative colitis patients. AB - In the present study, we investigated the differentially expressed proteins associated with ulcerative colitis (UC) using proteomic methods. Two-dimensional electrophoresis (2-DE) technology was performed to separate the total proteins of ulcerative tissues from those of the normal tissues of UC patients. PDQuest software was applied to analyze the obtained 2-DE images. Candidate protein spots between the two groups were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and bioinformatics analysis. The well resolution and reproducible 2-DE patterns of UC and normal tissues were established. Of the 12 differentially expressed proteins, 9 were successfully identified, of which 6 proteins were up-regulated including apolipoprotein C-III, haptoglobin, receptor tyrosine kinase, aldehyde reductase, pericentriolar material 1, and heat shock factor protein 2, and 3 were down regulated including keratin, filamin A-interacting protein 1, and tropomyosin 3. These identified proteins were related to hormonal modulation, immune response, oxidative stress, and signal conduction. The 2-DE protein expression profile of the UC tissues displays an obvious difference from that of the normal controls. Various proteins may be involved in the occurrence of UC. PMID- 22198549 TI - Nain-e Havandi Andrographis paniculata present yesterday, absent today: a plenary review on underutilized herb of Iran's pharmaceutical plants. AB - Nain-e Havandi (Andrographis paniculata Nees.) (AP) is an annual herbaceous plant belonging to the family Acanthacea. Only a few species of Andrographis genus out of 28 are medicinally concerned of which AP is the most important. Knowledge about the arrival of AP to Iran is extremely lacking but most probably it has been imported from India. However, evidence implies the familiarity of Iran's folkloric medicine with this plant, but it has been disappeared from contemporary medicine for unknown reasons. Presence of active ingredients from diterpenoids group such as andrographolide, neoandrographolide and 14-deoxy-11,12 didehydroandrographolide has given incredible unique medicinal properties to the plant. Traditionally, Nain-e Havandi has been used in the role of a non-farm plant as a remedy for skin problems, flu, respiratory disease, and snakebite in East and Southeast Asia for centuries. Recently, it has been utilized as a treatment for HIV, hepatitis, diabetes, cancer and kidney disorders. Intensive cultivation of the herb started only in the past decade in countries such as China, India, Thailand, Indonesia, West Indies, Mauritius and to some extent, in Malaysia. Availability of different ecological zones in Iran complies with reestablishment of AP in tropical and temperate regions of the country. This is killing two birds with one stone, supporting the conservational and economic aspects. PMID- 22198551 TI - Ethnic identity of older Chinese in Canada. AB - In Canada's multicultural society, ethnic identity is important to the elderly and can influence areas such as access to services, health promotion and care. Often, the complex nature of ethnic identity is underestimated when looking at cultural groups. This study aims to: (a) validate the factor structure of a Chinese ethnic identity measure for older Chinese in Canada, (b) examine the level of ethnic identity of the participants, and (c) examine the correlates of ethnic identity in these older individuals. Using data from a large, national research project on the elderly Chinese in Canada, this study analyzed the results gathered from a total of 2,272 participants. Principal component analysis, maximum-likelihood confirmatory factor analysis, and multiple regression analysis were performed. The results indicated that ethnic identity of the older Chinese is a multi-dimensional construct made up of three factors: (a) culture related activities, (b) community ties, (c) linkage with country of origin, and (d) cultural identification. The findings have provided a better understanding of how ethnic identity can be measured among the aging Chinese population in Canada. PMID- 22198552 TI - Pulmonary toxicity after exposure to military-relevant heavy metal tungsten alloy particles. AB - Significant controversy over the environmental and public health impact of depleted uranium use in the Gulf War and the war in the Balkans has prompted the investigation and use of other materials including heavy metal tungsten alloys (HMTAs) as nontoxic alternatives. Interest in the health effects of HMTAs has peaked since the recent discovery that rats intramuscularly implanted with pellets containing 91.1% tungsten/6% nickel/2.9% cobalt rapidly developed aggressive metastatic tumors at the implantation site. Very little is known, however, regarding the cellular and molecular mechanisms associated with the effects of inhalation exposure to HMTAs despite the recognized risk of this route of exposure to military personnel. In the current study military-relevant metal powder mixtures consisting of 92% tungsten/5% nickel/3% cobalt (WNiCo) and 92% tungsten/5% nickel/3% iron (WNiFe), pure metals, or vehicle (saline) were instilled intratracheally in rats. Pulmonary toxicity was assessed by cytologic analysis, lactate dehydrogenase activity, albumin content, and inflammatory cytokine levels in bronchoalveolar lavage fluid 24h after instillation. The expression of 84 stress and toxicity-related genes was profiled in lung tissue and bronchoalveolar lavage cells using real-time quantitative PCR arrays, and in vitro assays were performed to measure the oxidative burst response and phagocytosis by lung macrophages. Results from this study determined that exposure to WNiCo and WNiFe induces pulmonary inflammation and altered expression of genes associated with oxidative and metabolic stress and toxicity. Inhalation exposure to both HMTAs likely causes lung injury by inducing macrophage activation, neutrophilia, and the generation of toxic oxygen radicals. PMID- 22198553 TI - Cation trapping by cellular acidic compartments: beyond the concept of lysosomotropic drugs. AB - "Lysosomotropic" cationic drugs are known to concentrate in acidic cell compartments due to low retro-diffusion of the protonated molecule (ion trapping); they draw water by an osmotic mechanism, leading to a vacuolar response. Several aspects of this phenomenon were recently reexamined. (1) The proton pump vacuolar (V)-ATPase is the driving force of cationic drug uptake and ensuing vacuolization. In quantitative transport experiments, V-ATPase inhibitors, such as bafilomycin A1, greatly reduced the uptake of cationic drugs and released them in preloaded cells. (2) Pigmented or fluorescent amines are effectively present in a concentrated form in the large vacuoles. (3) Consistent with V-ATPase expression in trans-Golgi, lysosomes and endosomes, a fraction of the vacuoles is consistently labeled with trans-Golgi markers and protein secretion and endocytosis are often inhibited in vacuolar cells. (4) Macroautophagic signaling (accumulation of lipidated and membrane-bound LC3 II) and labeling of the large vacuoles by the autophagy effector LC3 were consistently observed in cells, precisely at incubation periods and amine concentrations that cause vacuolization. Vacuoles also exhibit late endosome/lysosome markers, because they may originate from such organelles or because macroautophagosomes fuse with lysosomes. Autophagosome persistence is likely due to the lack of resolution of autophagy, rather than to nutritional deprivation. (5) Increased lipophilicity decreases the threshold concentration for the vacuolar and autophagic cytopathology, because simple diffusion into cells is limiting. (6) A still unexplained mitotic arrest is consistently observed in cells loaded with amines. An extended recognition of relevant clinical situations is proposed for local or systemic drug administration. PMID- 22198554 TI - The anesthetic efficacy of eugenol and the essential oils of Lippia alba and Aloysia triphylla in post-larvae and sub-adults of Litopenaeus vannamei (Crustacea, Penaeidae). AB - The aim of this study was to evaluate the anesthesia induction and recovery times of sub-adult and post-larvae white shrimp (Litopenaeus vannamei) that were treated with eugenol and the essential oils (EOs) from Lippia alba and Aloysia triphylla. Oxidative stress parameters in the hemolymph of this species were also analyzed. The concentrations of eugenol, A. triphylla EO and L. alba EO recommended for anesthesia were 200, 300 and 750 MUL L(-1) for sub-adults and 175, 300 and 500 MUL L(-1) for post-larvae, respectively. The concentrations studied during the transport of sub-adults were between 20 and 50 MUL L(-1) eugenol, 20-30 MUL L(-1)A. triphylla EO and 50 MUL L(-1)L. alba EO. For post larvae, the optimal concentrations for transport were 20 MUL L(-1) eugenol and between 20 and 50 MUL L(-1)A. triphylla EO. The white shrimp sub-adults that were exposed to A. triphylla EO (20 MUL L(-1)) showed increases in their total antioxidant capacities (150%), catalase (70%) and glutathione-S-transferase (615%) activity after 6 h. L. alba EO (50 MUL L(-1)) and eugenol (20 MUL L(-1)) also increased GST activity (1292 and 1315%) after 6 h, and eugenol (20 MUL L( 1)) decreased the total antioxidant capacity (100%). Moreover, concentrations above 30 MUL L(-1) for the EOs of A. triphylla and L. alba and 20 MUL L(-1) eugenol were effective at inducing anesthesia and improving the antioxidant system against reactive oxygen species (ROS) after 6 h. PMID- 22198556 TI - Intracerebroventricular 4-methylcatechol (4-MC) ameliorates chronic pain associated with depression-like behavior via induction of brain-derived neurotrophic factor (BDNF). AB - Neuropathic pain concurrent with mood disorder from peripheral nerve injury is a serious clinical problem that significantly affects quality of life. Recent studies have suggested that a lack of brain-derived neurotrophic factor (BDNF) in the limbic system may cause this pain-emotion. BDNF is induced in cultured neurons by 4-methylcatechol (4-MC), but the role of 4-MC-induced BDNF in pain emotion is poorly understood. Thus, we assessed the possible involvement of BDNF in brain in depression-like behavior during chronic pain following peripheral nerve injury. In addition, we examined whether intracerebroventricular (i.c.v.) 4 MC prevents chronic pain in rats and produces an antidepressant effect. Sprague Dawley rats implanted intracerebroventricularly with a PE-10 tube were subjected to chronic constriction injury (CCI). Pain was assessed by a reduction in paw withdrawal latency (PWL) to heat stimuli after CCI. We also used a forced swimming testing (FST; time of immobility, in seconds) from day 14 to day 21 after CCI. Modulation of pain and emotional behavior was performed by injection of PD0325901 (a MEK1/2 inhibitor). 4-MC (100 nM) was continuously administered i.c.v. for 3 days during the period from day 14 to day 21 after CCI. To block analgesic and antidepressant effects, anti-BDNF antibody or K252a (a TrkB receptor inhibitor) was injected in combination with 4-MC. Naloxone was also coadministered to confirm the analgesic effect of 4-MC. During the chronic stage after CCI, the rats showed a sustained decrease in PWL (thermal hyperalgesia) associated with extension of the time of immobility (depression-like behavior). PD0325901 significantly reduced the decrease in PWL and the increased time of immobility after CCI. The decreased PWL and increased time of immobility were also reduced by 4-MC and by treatment with an ERK1/2 inhibitor. These effects of 4-MC i.c.v. were reversed by anti-BDNF and K252a. The analgesic effect of 4-MC i.c.v. was also antagonized by naloxone. Based on these results, we suggest that a lack of BDNF and activation of ERK1/2 in the pain-emotion network in the CNS may be involved in depression-like behavior during chronic pain. 4-MC i.c.v. ameliorates chronic pain and depression-like behavior by producing of BDNF and normalization of ERK1/2 activation. Therefore, enhancement of BDNF may be a new treatment strategy for chronic pain associated with depression. PMID- 22198555 TI - Current therapeutic strategies to mitigate the eNOS dysfunction in ischaemic stroke. AB - Impairment of endothelial nitric oxide synthase (eNOS) activity is implicated in the pathogenesis of endothelial dysfunction in many diseases including ischaemic stroke. The modulation of eNOS during and/or following ischaemic injury often represents a futile compensatory mechanism due to a significant decrease in nitric oxide (NO) bioavailability coupled with dramatic increases in the levels of reactive oxygen species that further neutralise NO. However, applications of a number of therapeutic agents alone or in combination have been shown to augment eNOS activity under a variety of pathological conditions by potentiating the expression and/or activity of Akt/eNOS/NO pathway components. The list of these therapeutic agents include NO donors, statins, angiotensin-converting enzyme inhibitors, calcium channel blockers, phosphodiesterase-3 inhibitors, aspirin, dipyridamole and ellagic acid. While most of these compounds exhibit anti platelet properties and are able to up-regulate eNOS expression in endothelial cells and platelets, others suppress eNOS uncoupling and tetrahydrobiopterin (an eNOS stabiliser) oxidation. As the number of therapeutic molecules that modulate the expression and activity of eNOS increases, further detailed research is required to reveal their mode of action in preventing and/or reversing the endothelial dysfunction. PMID- 22198558 TI - Stress triggered changes in expression of genes for neurosecretory granules in adrenal medulla. AB - With acute stress, the release of adrenomedullary catecholamines is important for handling the emergency situation. However, when chronic or repeated, stress alters the allostatic load and leads to a hyperadrenergic state, resulting in the development or worsening of a wide range of diseases. To help elucidate the mechanism, we examined the effects of single and repeated immobilization stress on gene expression of components of neurosecretory vesicles in the adrenal medulla. Male Sprague-Dawley rats were exposed to immobilization stress once for 2 h (1* IMO) or daily for six consecutive days (6* IMO). Compared to unstressed controls, 1* IMO elevated gene expression of vesicular monoamine transporter 2 (VMAT2). In response to 6* IMO, not only was VMAT2 mRNA still elevated, but chromogranin A (CgA) and chromogranin B (CgB) mRNAs were also increased two to three-fold above basal levels. To investigate the possible role of the hypothalamic-pituitary-adrenal axis in the induction of VMAT2, PC12 cells were treated with the synthetic glucocorticoid dexamethasone, which was found to elevate VMAT2 mRNA expression. The findings suggest that following repeated stress, elevations of various components of neurosecretory vesicles in the adrenal can facilitate more efficient utilization of the well-characterized heightened catecholamine levels. PMID- 22198557 TI - Assessing behavioural effects of chronic HPA axis activation using conditional CRH-overexpressing mice. AB - The corticotropin-releasing hormone (CRH) and its cognate receptors have been implicated in the pathophysiology of stress-related disorders. Hypersecretion of central CRH and elevated glucocorticoid levels, as a consequence of impaired feedback control, have been shown to accompany mood and anxiety disorders. However, a clear discrimination of direct effects of centrally hypersecreted CRH from those resulting from HPA axis activation has been difficult. Applying a conditional strategy, we have generated two conditional CRH-overexpressing mouse lines: CRH-COE ( Del ) mice overexpress CRH throughout the body, while CRH-COE ( APit ) mice selectively overexpress CRH in the anterior and intermediate lobe of the pituitary. Both mouse lines show increased basal plasma corticosterone levels and consequently develop signs of Cushing's syndrome. However, while mice ubiquitously overexpressing CRH exhibited increased anxiety-related behaviour, overexpression of CRH in the pituitary did not produce alterations in emotional behaviour. These results suggest that chronic hypercorticosteroidism alone is not sufficient to alter anxiety-related behaviour but rather that central CRH hyperdrive on its own or in combination with elevated glucocorticoids is responsible for the increase in anxiety-related behaviour. In conclusion, the generated mouse lines represent valuable animal models to study the consequences of chronic CRH overproduction and HPA axis activation. PMID- 22198559 TI - Pharmacological mechanisms of black cohosh in Sprague-Dawley rats. AB - BACKGROUND: Studies indicate that extracts and purified components from black cohosh inhibit the growth of human breast cancer cells, but the molecular targets and signaling pathways have not yet been defined. PURPOSE: This study examines the pharmacological mechanisms and toxicological effects in the short term of the herb black cohosh on female Sprague-Dawley rats. MATERIALS AND METHODS: To assess effects on gene activity and lipid content, we treated female Sprague-Dawley rats with an extract of black cohosh enriched in triterpene glycosides (27%) at 35.7 or 0mg/kg. Four animals for each group were sacrificed at 1, 6 and 24h after treatment; liver tissue and serum samples were obtained for gene expression and lipid analysis. RESULTS: Microarray analysis of rat liver tissue indicated that black cohosh markedly downregulated mitochondrial oxidative phosphorylation genes. Phospholipid biosynthesis and remodeling, PI3-Kinase and sphingosine signaling were upregulated, driven largely by an upregulation of several isoforms of phospholipase C. Hierarchical clustering indicated that black cohosh clustered with antiproliferative compounds, specifically tubulin binding vinca alkaloids and DNA alkylators. In support of this, black cohosh repressed the expression of cyclin D1 and ID3, and inhibited the proliferation of HepG2, p53 positive, liver cancer cells. Black cohosh reduced the level of free fatty acids at 6 and 24h and triglycerides at 6h in the serum, but increased the free fatty acid and triglyceride content of the treated livers at 24h. CONCLUSION: Our results suggest that black cohosh warrants further study for breast cancer prevention and therapy. PMID- 22198561 TI - Use of toxicokinetics to support chemical evaluation: Informing high dose selection and study interpretation. AB - Toxicokinetic (TK) information can substantially enhance the value of the data generated from toxicity testing, and is an integral part of pharmaceutical safety assessment. It is less widely used in the chemical, agrochemical and consumer products industries, but recognition of its value is growing, as reflected by increased reference to the use of TK information in new and draft OECD test guidelines. To help promote increased consideration of the important role TK can play in chemical risk assessment, we have gathered practical examples from the peer-reviewed literature, as well as in-house industry data, that highlight opportunities for the use of TK in the selection of dose levels. Use of TK can help to ensure studies are designed to be of most relevance to assessing potential risk in humans, and avoid the use of excessively high doses that could result in unnecessary suffering in experimental animals. Greater emphasis on the potential contribution of TK in guiding study design and interpretation should be incorporated in regulatory data requirements and associated guidance. PMID- 22198560 TI - Influence of single nucleotide polymorphisms in the MMP1 promoter region on cutaneous melanoma progression. AB - Recently, we reported on the associations of seven single nucleotide polymorphisms (SNPs) in the promoter region of MMP1 gene with susceptibility to cutaneous melanoma (CM). Considering the reported correlation between MMP1 expression and melanoma progression, we hypothesized that these promoter SNPs might affect CM progression and prognosis. In this study, we examined the associations of seven SNPs with overall survival, as well as six clinicopathological factors in 754 patients with CM. After adjustment for 11 covariates, we observed significant associations of the SNP -422A>T (rs475007) with ulceration status (P=0.012), primary tumor thickness (P=0.040), and anatomic site (P=0.030). We also observed significant associations of the SNP -755T>G (rs498186) with ulceration status (P=0.038) and anatomic site (P=0.003). Two SNPs, -839G>A and -519A>G, were marginally associated with primary tumor thickness, ulceration status, and anatomic site. Furthermore, the frequency of haplotype 2G-G-G-A-A-G-T was higher in patients with ulceration (odds ratio=2.18, 95% confidence interval: 1.08-4.40, P=0.030) compared with those without ulceration. However, we did not find significant associations of these SNPs with overall survival and other clinical factors. As primary tumor thickness and ulceration status are two important indicators of tumor progression and have significant associations with melanoma prognosis, our results suggested that these promoter SNPs in MMP1 might have potential effects on melanoma progression and prognosis by influencing related clinical factors. PMID- 22198562 TI - Pain and functional impairment as mediators of the link between medical symptoms and depression in type 2 diabetes. AB - BACKGROUND: Among people with diabetes, depression is more common and is associated with greater morbidity and mortality. A better understanding of mechanisms underlying the link between poor health and depression is needed. Pain and functional impairment may account for the effect of poor health on depression in diabetes. PURPOSE: The purpose of the study was to examine whether pain and functional impairment mediate the association between diabetes-related medical symptoms and depression in type 2 diabetes. METHOD: Adults diagnosed with type 2 diabetes (N = 77) completed the following measures: Patient Health Questionnaire (PHQ), Diabetes Symptom Checklist (DSC), and Medical Outcomes Study 12-item Short Form Health Survey (SF-12). Body mass index (BMI) was computed using height and weight data from medical records. Mediation and linear regression analyses were conducted. RESULTS: Pain and functional impairment made significant, independent contributions to depression. Functional impairment mediated the link between diabetes-related medical symptoms and depression. Pain mediated the association between higher BMI and depression. CONCLUSION: Pain and functional impairment appear to play important, independent roles in depression in type 2 diabetes. Mediation analyses suggest the following: 1. diabetes-related medical problems increase functional impairment, which in turn leads to greater depression; and 2. the burden of carrying greater body mass (higher BMI) increases pain, which leads to increased depression. PMID- 22198563 TI - Pontomedullary lacerations and concomitant head and neck injuries: their underlying mechanism. A prospective autopsy study. AB - It is a well-documented fact that pontomedullary lacerations (PML) occur as a result of severe craniocervical injury, but their underlying mechanism has yet to be fully clarified. The aim of this prospective study has been to give greater insight into the underlying mechanism of PML through determining the site of blunt head-impact, as well as the presence of concomitant head and neck injuries in cases of brainstem PML. A total of 56 cases with partial PML have been analysed for this study. The case group was composed of 40 men and 16 women, averaging in age 44.2 +/- 19.2 years and consisting of 7 motorcyclists, 4 bicyclists, 18 car occupants, 16 pedestrians, and 10 victims of falls from a height, as well as 1 victim of a fall from standing height. The presented study has shown that there are several possible mechanisms of PML. Impact to the chin, with or without a skull base fracture, most often leads to this fatal injury, due to the impact force transmission either through the jawbone or vertebral column; most likely in combination with a fronto-posterior hyperextension of the head. Additionally, lateral head-impacts with subsequent hinge fractures and PML may also be a possible mechanism. The jawbone and other facial bones are able to act as shock absorbers, and their fracture may diminish the energy transfer towards the skull and protect the brain and brainstem from injury. The upper cervical spine can act as damper and energy absorber as well, and may prevent any occurrence of fracture to the base of the skull. PMID- 22198564 TI - Mannose-specific lectin from the mushroom Hygrophorus russula. AB - A lectin was purified from the mushroom Hygrophorus russula by affinity chromatography on a Sephadex G-50 column and BioAssist S cation exchange chromatography and designated H. russula lectin (HRL). The results of sodium dodecyl sulfate-polyaclylamidegel electrophoresis, gel filtration and matrix assisted laser desorption ionization time-of-flight mass spectrometry of HRL indicated that it was composed of four identical 18.5 kDa subunits with no S-S linkage. Isoelectric focusing of the lectin showed bands near pI 6.40. The complete sequence of 175 amino acid residues was determined by amino acid sequencing of intact or enzyme-digested HRL. The sequence showed homology with Grifola frondosa lectin. The cDNA of HRL was cloned from RNA extracted from the mushroom. The open reading frame of the cDNA consisted of 528 bp encoding 176 amino acids. In hemagglutination inhibition assay, alpha1-6 mannobiose was the strongest inhibitor and isomaltose, Glcalpha1-6Glc, was the second strongest one, among mono- and oligosaccharides tested. Frontal affinity chromatography indicated that HRL had the highest affinity for Manalpha1-6(Manalpha1-3)Manbeta1 4GlcNAcbeta1-4GlcNAc, and non-reducing terminal Manalpha1-6 was essential for the binding of HRL to carbohydrate chains. The sugar-binding specificity of HRL was also analyzed by using BIAcore. The result from the analysis exhibited positive correlations with that of the hemagglutination inhibition assay. All the results suggested that HRL recognized the alpha1-6 linkage of mannose and glucose, especially the Manalpha1-6 bond. HRL showed a mitogenic activity against spleen lymph cells of an F344 rat. Furthermore, an enzyme-linked immunosorbent assay showed strong binding of HRL to human immunodeficiency virus type-1 gp120. PMID- 22198565 TI - Preliminary data on the effect of culture on the assessment of Alzheimer's disease-related verbal memory impairment with the International Shopping List Test. AB - The International Shopping List Test (ISLT) is a measure of verbal learning and memory, developed specifically for use in people from different cultural and linguistic backgrounds. In this report, we describe two studies that examined the ISLT's ability to detect memory impairment and memory decline in patients with mild Alzheimer's disease (AD) from a range of cultural and linguistic backgrounds. In Study 1, the performance of Australian-English-speaking adults with mild AD was compared with that of native Australian-English- and Korean speaking patients with mild AD. Compared with controls, patients with AD from both language groups showed large but equivalent impairments in total recall, delayed recall, rate of learning, and primacy and retention-weighted recall (RWR) measures on the ISLT. In Study 2, the rate of deterioration in verbal memory over 1 year was examined in groups of native Canadian-English, French, and Korean speakers with mild AD using the total recall, delayed recall, and RWR measures. Rates of change on all three measures were equivalent across the language groups, although the magnitude of deterioration was most pronounced for the total recall and RWR measures. Taken together, these results suggest that the ISLT is valid and reliable for the assessment of verbal learning and memory impairment and decline in patients with mild AD from diverse language groups. PMID- 22198567 TI - Oxidative stress induced by glutathione depletion reproduces pathological modifications of TDP-43 linked to TDP-43 proteinopathies. AB - TAR DNA-binding protein 43 (TDP-43) is a major component of ubiquitin-positive inclusion of TDP-43 proteinopathies including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinated inclusions, which is now referred to as FTLD-TDP. TDP-43 in the aberrant inclusion is known to be hyperphosphorylated at C-terminal sites, to be truncated at the N-terminal region, and to re-distribute from nucleus to cytoplasm or neurite. The pathogenic role of these modifications, however, has not been clarified. Furthermore, there is no evidence about the initial cause of these modifications. Herein we show that ethacrynic acid (EA), which is able to increase cellular oxidative stress through glutathione depletion, induces TDP-43 C-terminal phosphorylation at serine 403/404 and 409/410, insolubilization, C-terminal fragmentation, and cytoplasmic distribution in NSC34 cells and primary cortical neurons. In the investigation using a nonphosphorylable mutant of TDP-43, there was no evidence that C-terminal phosphorylation of TDP-43 contributes to its solubility or distribution under EA induction. Our findings suggest that oxidative stress induced by glutathione depletion is associated with the process of the pathological TDP-43 modifications and provide new insight for TDP-43 proteinopathies. PMID- 22198568 TI - Copper is toxic to PrP-ablated mice and exacerbates disease in a mouse model of E200K genetic prion disease. AB - The pathogenesis of the diverse forms of prion disease was attributed solely to the accumulation of the misfolded PrP forms, and not to the potential loss of normal PrP(C) function during disease propagation. In this respect, it was also not established whether mutant PrPs linked to genetic prion diseases, as is the case for E200K PrP, preserve the function of PrP(C). We now show that fibroblasts generated from both PrP-ablated mice and TgMHu2ME199K, a transgenic mouse line mimicking E200KCJD, were significantly more sensitive to copper toxicity than wt fibroblasts. Long-term administration of copper significantly accelerated the onset and progression of spontaneous prion disease in TgMHu2ME199K mice and caused marked irritability and cerebellar associated tip-toe walking in PrP(0/0) mice, while wt mice were not affected. Our results are consistent with the hypothesis that a functional PrP(C) is required to protect cells from high levels of copper, and that its substitution for a nonfunctional mutant PrP may accelerate the onset of genetic prion disease during oxidative insults. PMID- 22198566 TI - Personalized therapy in endometrial cancer: challenges and opportunities. AB - Early stage endometrial cancer is generally curable. However, progress in the treatment of advanced and recurrent endometrial cancer has been limited. This has led to a shift from the use of traditional chemotherapeutic agents and radiotherapy regimens to the promising area of targeted therapy, given the large number of druggable molecular alterations found in endometrial cancer. To maximize the effects of directed targeted therapy, careful molecular characterization of the endometrial tumor is necessary. This represents an important difference in the use of targeted therapy vs. traditional chemotherapy or radiation treatment. This review will discuss relevant pathways to target in endometrial cancer as well as the challenges that arise during development of a personalized oncology approach. PMID- 22198569 TI - Meta-analysis of genetic and environmental Parkinson's disease models reveals a common role of mitochondrial protection pathways. AB - Both genetic and environmental factors trigger risks of and protection from Parkinson's disease, the second most common neurodegenerative syndrome, but possible inter-relationships between these risk and protection processes were not yet explored. By examining gene expression changes in the brains of mice under multiple treatments that increase or attenuate PD symptoms we detected underlying disease and protection-associated genes and pathways. In search for potential links between these different genes and pathways, we conducted meta-analysis on 131 brain region transcriptomes from mice over-expressing native or mutated alpha synuclein (SNCA) with or without the protective HSP70 chaperone, or exposed to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), with or without the protective acetylcholinesterase (AChE-R) variant. All these models showed shared risk-inducible and protection-suppressible transcript modifications. Self-organized map (SOM) classification revealed risk- and protection-associated alterations in nuclear and mitochondrial metal ion regulated transcripts, respectively; Gene Ontology based analysis validated these pathways. To complement this approach, and identify potential outcome damages, we further searched for shared functional enrichments in the lists of genes detected in young SNCA mutant or in old SNCA mutants and MPTP-exposed mice. This post-hoc functional analysis identified early-onset changes in Parkinsonian, immune and alternative splicing pathways which shifted into late-onset or exposure associated NFkB-mediated neuro-inflammation. Our study suggests metal ions mediated cross-talk between nuclear and mitochondrial pathways by both environmental and genetic risk and protective factors involved in Parkinson's disease, which eventually culminates in neuro-inflammation. Together, these findings offer new insights and novel targets for therapeutic interference with the gene-environment interactions underlying sporadic PD. PMID- 22198571 TI - Characterization of a murine model of SMA. AB - Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease, which is the leading genetic cause of mortality in children. To date no effective treatment exists for SMA. The genetic basis for SMA has been well documented as a mutation in the gene for survival of motor neuron (SMN). Because there is an understanding of which gene needs to be replaced (SMN) and where it needs to be replaced (spinal motor systems), SMA is an ideal target for gene replacement via gene therapy. While a variety of animal models for SMA exist, they are either too fulminant to realistically test most gene delivery strategies, or too mild to provide a robust read out of the therapeutic effect. The field, therefore, requires a robust model with a slower symptomatic progression. A conditional knockout of SMN in neuronal cell types, giving a phenotype of functional motor defects, weight loss and reduced life expectancy partially satisfies this need (Frugier, Tiziano et al. 2000). This Cre/LoxP mediated neuron specific model presents an attractive alternative. In the present manuscript, we characterize the functional motor deficits of the model. We observed a decline in locomotor ability, as assessed by open field testing. The finer functions of motor skills such as righting reflex and grip strength were also observed to degenerate in the SMA mice. The decline in motor function that we observed here correlates with the anatomical decline in motor neurons and motor axons presented in the literature (Ferri, Melki et al. 2004). This work adds to our understanding and knowledge base of this Cre/LoxP model and provides a basis from which functional recovery, following interventions can be assessed. PMID- 22198570 TI - Early glial activation, synaptic changes and axonal pathology in the thalamocortical system of Niemann-Pick type C1 mice. AB - Niemann-Pick disease type C (NPC) is an inherited lysosomal storage disease characterised by accumulation of cholesterol and glycosphingolipids. NPC patients suffer a progressive neurodegenerative phenotype presenting with motor dysfunction, mental retardation and cognitive decline. To examine the onset and progression of neuropathological insults in NPC we have systematically examined the CNS of a mouse model of NPC1 (Npc1(-/-) mice) at different stages of the disease course. This revealed a specific spatial and temporal pattern of neuropathology in Npc1(-/-) mice, highlighting that sensory thalamic pathways are particularly vulnerable to loss of NPC1 resulting in neurodegeneration in Npc1(-/ ) mice. Examination of markers of astrocytosis and microglial activation revealed a particularly pronounced reactive gliosis in the thalamus early in the disease, which subsequently also occurred in interconnected cortical laminae at later ages. Our examination of the precise staging of events demonstrate that the relationship between glia and neurons varies between brain regions in Npc1(-/-) mice, suggesting that the cues causing glial reactivity may differ between brain regions. In addition, aggregations of pre-synaptic markers are apparent in white matter tracts and the thalamus and are likely to be formed within axonal spheroids. Our data provide a new perspective, revealing a number of events that occur prior to and alongside neuron loss and highlighting that these occur in a pathway dependent manner. PMID- 22198572 TI - Mutation of Gtf2ird1 from the Williams-Beuren syndrome critical region results in facial dysplasia, motor dysfunction, and altered vocalisations. AB - Insufficiency of the transcriptional regulator GTF2IRD1 has become a strong potential explanation for some of the major characteristic features of the neurodevelopmental disorder Williams-Beuren syndrome (WBS). Genotype/phenotype correlations in humans indicate that the hemizygous loss of the GTF2IRD1 gene and an adjacent paralogue, GTF2I, play crucial roles in the neurocognitive and craniofacial aspects of the disease. In order to explore this genetic relationship in greater detail, we have generated a targeted Gtf2ird1 mutation in mice that blocks normal GTF2IRD1 protein production. Detailed analyses of homozygous null Gtf2ird1 mice have revealed a series of phenotypes that share some intriguing parallels with WBS. These include reduced body weight, a facial deformity resulting from localised epidermal hyperplasia, a motor coordination deficit, alterations in exploratory activity and, in response to specific stress inducing stimuli; a novel audible vocalisation and increased serum corticosterone. Analysis of Gtf2ird1 expression patterns in the brain using a knock-in LacZ reporter and c-fos activity mapping illustrates the regions where these neurological abnormalities may originate. These data provide new mechanistic insight into the clinical genetic findings in WBS patients and indicate that insufficiency of GTF2IRD1 protein contributes to abnormalities of facial development, motor function and specific behavioural disorders that accompany this disease. PMID- 22198573 TI - Metabotropic glutamate receptor-dependent long-term depression is impaired due to elevated ERK signaling in the DeltaRG mouse model of tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) and fragile X syndrome (FXS) are caused by mutations in negative regulators of translation. FXS model mice exhibit enhanced metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD). Therefore, we hypothesized that a mouse model of TSC, DeltaRG transgenic mice, also would exhibit enhanced mGluR-LTD. We measured the impact of TSC2-GAP mutations on the mTORC1 and ERK signaling pathways and protein synthesis dependent hippocampal synaptic plasticity in DeltaRG transgenic mice. These mice express a dominant/negative TSC2 that binds to TSC1, but has a deletion and substitution mutation in its GAP-domain, resulting in inactivation of the complex. Consistent with previous studies of several other lines of TSC model mice, we observed elevated S6 phosphorylation in the brains of DeltaRG mice, suggesting upregulated translation. Surprisingly, mGluR-LTD was not enhanced, but rather was impaired in the DeltaRG transgenic mice, indicating that TSC and FXS have divergent synaptic plasticity phenotypes. Similar to patients with TSC, the DeltaRG transgenic mice exhibit elevated ERK signaling. Moreover, the mGluR-LTD impairment displayed by the DeltaRG transgenic mice was rescued with the MEK-ERK inhibitor U0126. Our results suggest that the mGluR-LTD impairment observed in DeltaRG mice involves aberrant TSC1/2-ERK signaling. PMID- 22198574 TI - Intracerebroventricularly delivered VEGF promotes contralesional corticorubral plasticity after focal cerebral ischemia via mechanisms involving anti inflammatory actions. AB - Vascular endothelial growth factor (VEGF) has potent angiogenic and neuroprotective effects in the ischemic brain. Its effect on axonal plasticity and neurological recovery in the post-acute stroke phase was unknown. Using behavioral tests combined with anterograde tract tracing studies and with immunohistochemical and molecular biological experiments, we examined effects of a delayed i.c.v. delivery of recombinant human VEGF(165), starting 3 days after stroke, on functional neurological recovery, corticorubral plasticity and inflammatory brain responses in mice submitted to 30 min of middle cerebral artery occlusion. We herein show that the slowly progressive functional improvements of motor grip strength and coordination, which are induced by VEGF, are accompanied by enhanced sprouting of contralesional corticorubral fibres that branched off the pyramidal tract in order to cross the midline and innervate the ipsilesional parvocellular red nucleus. Infiltrates of CD45+ leukocytes were noticed in the ischemic striatum of vehicle-treated mice that closely corresponded to areas exhibiting Iba-1+ activated microglia. VEGF attenuated the CD45+ leukocyte infiltrates at 14 but not 30 days post ischemia and diminished the microglial activation. Notably, the VEGF-induced anti-inflammatory effect of VEGF was associated with a downregulation of a broad set of inflammatory cytokines and chemokines in both brain hemispheres. These data suggest a link between VEGF's immunosuppressive and plasticity-promoting actions that may be important for successful brain remodeling. Accordingly, growth factors with anti inflammatory action may be promising therapeutics in the post-acute stroke phase. PMID- 22198575 TI - Postural control in response to an external perturbation: effect of altered proprioceptive information. AB - The purpose of the study was to investigate the role of altered proprioception on anticipatory (APAs) and compensatory (CPAs) postural adjustments and their interaction. Nine healthy adults were exposed to external perturbations induced at the shoulder level while standing with intact or altered proprioception induced by bilateral Achilles tendon vibration. Visual information was altered (eyes open or closed) in both the conditions. Electrical activity of eight trunk and leg muscles and center of pressure (COP) displacements were recorded and quantified within the time intervals typical for APAs and CPAs. The results showed that when proprioceptive information was altered in eyes-open conditions, anticipatory muscle activity was delayed. Moreover, altered proprioceptive information resulted in smaller magnitudes of compensatory muscle activity as well as smaller COP displacements after the perturbation in both eyes-open and eyes-closed conditions. The outcome of the study provides information on the interaction between APAs and CPAs in the presence of altered proprioception. PMID- 22198576 TI - Identification and characterization of Penicillium citrinum VeA and LaeA as global regulators for ML-236B production. AB - In filamentous fungi, production of multiple secondary metabolites is controlled by so-called global regulators. In this study, two genes encoding homologs of VeA and LaeA, representative fungal global regulators, were identified in ML-236B producing Penicillium citrinum. Disruption of VeA and/or LaeA and complementation clearly demonstrated that both of them played critical roles in ML-236B production by controlling the expression of mlcR, the pathway-specific activator gene for ML-236B biosynthesis. Moreover, sequence analysis revealed that laeA in a mutant strain producing high levels of ML-236B (strain S-1567) possessed a single nucleotide alteration, which resulted in 15 surplus amino acids at the carboxyl terminus of LaeA compared to the LaeA in the wild-type strain (strain SANK18767). Introduction of the mutated laeA into SANK18767 proved that the extended carboxyl region plays a crucial role in the higher production of ML 236B. These results indicated that VeA and LaeA dominantly control the biosynthesis of ML-236B, and the enhanced production in the strain S-1567 is attributable to the mutation in laeA. PMID- 22198577 TI - Hemolysis, lipaemia and icterus in specimens for arterial blood gas analysis. AB - OBJECTIVE: To assess prevalence of interference from hemolysis, lipaemia, icterus in arterial blood gas analysis (ABG). DESIGN: Serum indices (SI) were assessed in the plasma of ABG samples over a 2-month period. RESULTS: Out of a total of 478 ABG specimens, we identified 17 hemolyzed samples (4%), 52 (11%) with lipaemia, and 63 (13%) with icterus. CONCLUSION: Test results on a considerable number of ABG specimens might be unreliable due to presence of interference. PMID- 22198578 TI - Unconjugated hyperbilirubinemia in patients with non-alcoholic fatty liver disease: a favorable endogenous response. AB - The clinical significance of increased frequency of unconjugated hyperbilirubinemia in patients with non-alcoholic fatty liver disease (NAFLD) is unknown. Serum bilirubin is an endogenous anti-oxidant, and oxidative stress plays an important role in the pathogenesis of NAFLD. In this study, we have documented 25.4% prevalence of unconjugated hyperbilirubinemia in 204 consecutive NAFLD patients. These patients had a significantly less severe liver disease on histopathology and/or fibroScan which may be attributed to anti-oxidant effect of bilirubin. PMID- 22198581 TI - Grants and contracts, 60-1. PMID- 22198583 TI - Surgery for movement disorders. AB - Over past three decades, there has been a resurgence of interest in functional neurosurgery for movement disorders. Recently, thanks to the increased understanding of cellular pathophysiology and advances in technology and surgical techniques, deep brain stimulation (DBS) has essentially replaced ablative procedures for most of these conditions. Success of DBS treatment in the movement disorders depends on the recognized limitations in the medical treatment, our understanding of the anatomy and physiology of these disorders and, particularly, involvement of neurologists, neurosurgeons, clinical neurophysiologists and neuropsychiatrists in outcome studies of DBS surgery. Up to now, the exact mechanism of DBS is not fully understood. This review provides an overview of use of stereotactic neurosurgery, particularly DBS, for movement disorders, focusing mainly on the patient selection, target options, clinical outcome, adverse effects and possible mechanisms of DBS for advanced Parkinson's disease, dystonia, and essential tremor. PMID- 22198582 TI - Neurotransplantation: lux et veritas, fiction or reality? AB - Neurotransplantation remains a much-debated frontier in contemporary neurosurgery and neuroscience, with roots dating to the late 19th century. Contemporary applications are far-reaching, and ongoing laboratory research and clinical trials seek to define the mechanisms at play in neurotransplant engraftment and growth, while advancing the field forward into the 21st century. Neural transplantation therapy remains an attractive idea for treating central nervous system (CNS) and peripheral nervous system (PNS) pathologies. Phase I and phase II clinical trials assessing safety and efficacy are currently underway for various disorders. The remainder of this review will focus on ongoing clinical trials and more recent research advances involving neural transplantation therapy for neuronal death, axonal injury, peripheral nerve lesions, and cancer. The field of neural transplantation, while promising, is not without ethical and scientific dilemmas; this review will conclude with a discussion of the challenges researchers and clinicians face as the field of neural transplantation moves forward. PMID- 22198584 TI - Evidence level in the treatment of meningioma with focus on the comparison between surgery versus radiotherapy. A review. AB - In the majority of cases surgery of intracranial meningioma is the primary treatment option. If tumor regrowth occurs or a tumor remnant is left, radiotherapy or radiosurgery are performed. Purpose of this review is to clarify the question, if evidence based data exists regarding the treatment of meningiomas with special focus on the efficacy of stereotactic radiosurgery/ radiotherapy (SRS/ SRT) compared to surgery. A systematic literature search in the most relevant medical databases was done. Primary studies and systematic review with focus on epidemiologic problems and different therapeutic approaches for the treatment of meningioma were included. Standardized data extraction was performed. A total of 31 publications were included. Information and results in the data published with a surgical focus vary strongly regarding the localization of the meningiomas. No randomized clinical trials or prospective cohort studies could be identified. Comparison between surgical and radiotherapeutic success rates was not clearly possible due to different outcome scales (Simpson grading versus tumor volume reduction) used. Progression free survival was ranging from 77% to 97% (complete surgical resection) and 82% to 97% (surgical resection and additional radiotherapeutical treatment) in publications not differentiating between the location of the meningioma. Although no clear evidence exists that one treatment is better than the other, in symptomatic meningioma surgery is considered to be the primary treatment, if the surgical risk is acceptable. Stereotactic radiosurgery and radiotherapy are reserved to locations (optic sheet, cavernous sinus), where surgical risk is expected to be higher. PMID- 22198585 TI - Circulatory and vascular changes after aneurysmal subarachnoid hemorrhage. AB - Delayed cerebral ischemia (DCI) is a major complication that afflicts approximately 30% of patients who suffer an aneursymal subarachnoid hemorrhage (SAH). DCI is often associated with neurological infarction, poor outcome and mortality. Though the pathogenesis of DCI is not yet clear, it is traditionally been attributed to angiographic vasospasm. Unfortunately, clinical trials based on this premise have mostly been disappointing, predominantly unable to prevent ischemic damage and improve patient outcome despite reducing angiographic vasospasm. More recently, increasing concern that vasospasm could not fully account for DCI development has incited novel proposals as to the pathogenesis of DCI. A general theme exists among these theories (microcirculatory constriction, cortical spreading depression, blood brain barrier breakdown, microthrombosis) in that a majority seems to revolve around dysfunction and changes to the microvasculature. This purpose of this review was then to juxtapose macrovascular and microvascular changes after SAH, and provide an overview of current and prospective treatments. PMID- 22198586 TI - An update on the management of traumatic brain injury. AB - The management of traumatic brain injury (TBI) continues to evolve in a number of key areas. In the first instance there have been major advances in clinical information gathering and interpretation such that there are mow sophisticated prognostic models readily available. Secondly, technological advances have allowed the introduction of advanced multimodal monitoring which can provide real time information regarding the complex physiological and biochemical derangements that occur following TBI. Finally recent clinical trials have raised important questions regarding the efficacy or otherwise of important therapeutic options most notably hypothermia and decompressive craniectomy. The aim of this update is to highlight some of the areas where there has been advancement and controversy. PMID- 22198587 TI - Anterior approach to the spine. Role of the general surgeon, techniques and surgical complications. The 10-year experience of the Niguarda Hospitals. AB - AIM: The aim of the study was to present the incidence of early and late surgical complications in a group of patients treated with anterior approach for spine lesions. The study was also focused on technical aspects for lesions of D1-D2 and L5-S1 segments and results on a group of patients underwent adjunctive surgical procedures at the same time of spinal surgery. METHODS: This was a retrospective study based on our database from April 1998 to December 2008. The study enrolled 120 consecutive patients (M/F 73/47; mean age 43.1 years; range 15-70 years) who underwent spinal surgery for trauma (92 patients), primitive or metastatic cancer (12 patients), benign lesion (2 patients), degenerative disc disease (6 patients) and infection disease (8 patients). This work describes the anterior approach to the spine. RESULTS: No death was recorded. Thirty-two patients (26.6%) presented postoperative complications: persistent urinary tract infections in 19 (15.9%), pneumonia in 6 (5%), pleural effusion in 3 (2.5%), wound infection in 2 (1.6%), retro-peritoneal abscess in 1 (0.8%) and haemorrhage in 1 (0.8%). During the follow-up (mean 3.8 years; range 2 months-10 years) 1 patient (0.8%) required two further surgical procedures for tuberculosis abscess recurrences. CONCLUSION: Anterior approach to the spine is effective and safe. Surgical complications do not negatively affect patient survival and spine stabilization included patients with D1-D2 and L5-S1 lesion and patients who receive adjunctive surgery at the same time of spine procedure. PMID- 22198588 TI - Kyphoplasty versus percutaneous vertebroplasty using the traditional and the new side-opening cannula for osteoporotic vertebral fracture. AB - AIM: The aim of this article was to study the results of two different types of percutaneous vertebroplasty (PV) and kyphoplasty (KPs) to osteoporotic vertebral fractures (OVF). METHODS: It was prospectively analyzed a series of 47 PVs from January 2003 to February 2008, and a consecutive series 30 KPs from March 2008 to January 2010, performed for patients with painful OVFs. Twenty-five PVs were performed using the frontal-opening cannula (FOC) and 22 using the new side opening cannula (SOC), randomly distributed in the PV group. RESULTS: The incidence of cement extrusion was 16.7% with KP, comparing with PV, it was 27.3% using the SOC (P<0.05) and 68,0% with the FOC (P<0.05), but comparing SOC with FOC, the cement extrusion was significantly lower using the SOC (P<0.05), all asymptomatic. The pain control was similar for all groups (P<0.05), with good improvement of pain in most of the patients, and there were no clinical relevant complications. CONCLUSION: The cement leakage was significantly reduced with the KP (16.7%) and the SOC (27.3%) for PV, in comparison with the FOC (68.0%). The cement extrusion was slightly lower with KP, but not a significant difference, comparing with SOC, increasing the safety of the procedure using both the KP and this new SOC. PMID- 22198589 TI - Progress in restorative neurosurgery: human fetal striatal transplantation in Huntington's disease. Review. AB - The purpose of this paper was to offer a review of the rationale, methods, biological and clinical results of human fetal striatal transplantation (HFST) in the treatment of Huntington's disease (HD). HD is a heritable neurodegenerative disease in which degeneration of neurons in the striatum leads to motor, psychiatric and cognitive deficits. The disease is progressive and inexorably lethal. At present there are no curative treatments for HD. A restorative therapy based on the intrastriatal transplantation of striatal neuroblasts taken from human fetus is currently being explored as potential treatment in selected HD patients. Pilot clinical trials of HFST have been started in few neurosurgery restorative centres. Results demonstrated that HFST is feasible and safe without relevant adverse effects; grafted neuroblasts survive, grow without evidence of neoplasia or teratoma, build new tissue with striatal-like imaging features, and move into the host brain towards short and long-distance cortical and sub cortical targets. HFST delays disease progression and provides a period of improvement and stability. Even though larger-scale studies are still necessary to establish the true value of such a treatment, at this time, HFST represents a promising experimental therapy for patients with HD and one of the most interesting clinical application of restorative neurosurgery. PMID- 22198590 TI - Staphylococcus aureus brainstem abscess in a Brazilian Amazon man. Case report. AB - The brainstem is an uncommon site for a brain abscess. It accounts for less than 4% of all posterior cranial fossa abscesses, and less than 1% of all intracranial abscesses. The pons is the most common site for these abscesses. The aim of the present report was to describe the case of a Brazilian Amazon man with a brainstem abscess (BSA) managed with combined surgical drainage and systemic antibiotic therapy. This case reinforces the importance of an early suspicion of BSA in patients with unexplained fever and neurologic deficits, especially sixth and seventh cranial nerve lesions, to minimize permanent damage. PMID- 22198591 TI - Parasellar myxoid chondrosarcoma: a rare variant of cranial chondrosarcoma. AB - Primary cranial chondrosarcoma in an uncommon cartilaginous tumours of which the myxoid variant is the least reported in the literature. This tumour accounts for 0.15% of all primary intracranial lesions and 6% of all skull base tumours. Chondrosarcomas are frequently misdiagnosed as chordomas, which have a different prognosis. Differential diagnosis is very important because, when treated with similar aggressive treatment strategies, chondrosarcoma has a much better prognosis than chordoma. We describe a 54-year-old female with a 9-month history of left ophtalmoplegia and increasing headache. MR imaging of the head showed a sellar and left parasellar mass. We performed a gross total removal of the mass via a left pterional approach. The histopathologic diagnosis was of a myxoid chondrosarcoma. A post-operative contrast-enhanced computed tomography (CT) scan of the head showed a total removal of the neoplasm. After surgery, the patient showed a transitory dysphasia with right hemiparesis, but they both considerably improved before discharge. Review of the literature was identified using the Medline database: only 10 cases in the worldwide literature were identified to report on this kind of tumour. We present a case report of myxoid chondrosarcoma, a rare variant of chondrosarcoma, with sellar and left parasellar localization. This histopathological type is a low-grade variant and its total removal is effective. PMID- 22198592 TI - Thoracoscopic surgery for thoracic disc herniation. AB - Technical improvements in endoscopy have had a major effect in the practice of minimally invasive surgery, which is preferable to more invasive surgical procedures for central and hard thoracic disc herniation. Eleven patients underwent surgery between 2002 and 2008. Data was collected from self-reporting questionnaires completed by the patient at each visit before surgery and after surgery at 3,6,12 and 24 months. The questionnaires included in the study were the Oswestry Disability Questionnaire and a visual analog scale(VAS) for the evaluation of pain. In all eleven patients, the thoracoscopic approach was technically performed satisfactorily. There was a significant initial improvement in both the Oswestry score and the VAS pain score at up to nine months(P<0.05). The average relative difference in the Oswestry and VAS score was not significant at 12 and 24 months. The complication rate(pleurisy and lung contusion) in our small study was 18%, which compares favorably with the literature. Video assisted thoracic spine surgery (VATS) clearly provides a minimally invasive and effective alternative to open thoracic surgery. A surgeon must be familiar with the surgical anatomy and the endoscopic techniques to ensure an optimal surgical outcome. Hence, that is one limitation in the practice of thoracoscopic discectomy. PMID- 22198593 TI - Pontine cavernoma and intraventricular meningioma: an unusual association. PMID- 22198594 TI - Differences in integrity of white matter and changes with training in spelling impaired children: a diffusion tensor imaging study. AB - While the functional correlates of spelling impairment have been rarely investigated, to our knowledge no study exists regarding the structural characteristics of spelling impairment and potential changes with interventions. Using diffusion tensor imaging at 3.0 T, we here therefore sought to investigate (a) differences between children with poor spelling abilities (training group and waiting group) and controls, and (b) the effects of a morpheme-based spelling intervention in children with poor spelling abilities on DTI parameters. A baseline comparison of white matter indices revealed significant differences between controls and spelling-impaired children, mainly located in the right hemisphere (superior corona radiata (SCR), posterior limb of internal capsule, superior longitudinal fasciculus). After 5 weeks of training, spelling ability improved in the training group, along with increases in fractional anisotropy and decreases of radial diffusivity in the right hemisphere compared to controls. In addition, significantly higher decreases of mean diffusivity in the right SCR for the spelling-impaired training group compared to the waiting group were observed. Our results suggest that spelling impairment is associated with differences in white-matter integrity in the right hemisphere. We also provide first indications that white matter changes occur during successful training, but this needs to be more specifically addressed in future research. PMID- 22198595 TI - Crystal structure of Sa239 reveals the structural basis for the activation of ribokinase by monovalent cations. AB - Ribokinase is responsible for catalyzing the reaction of d-ribose and ATP to produce ribose-5-phosphate and ADP, which can be activated by monovalent cations such as potassium, cesium and ammonium. However, the exact activation mechanism of ribokinase remains elusive. Here we report the crystal structure of Sa239, a ribokinase from Staphylococcus aureus, in the absence of monovalent ions. In addition to the dimer form similar to that observed in Escherichia coli ribokinase structure, the structure of Sa239 demonstrates that the C-terminal tail protrudes from the remaining part and interacts with the neighboring molecule, resulting in an unexpected dimerization form. By comparing the structure of Sa239 to E. coli ribokinase, we propose that binding of the monovalent cation triggers the conformational change of the large ATP loop to organize the formation of nucleotide binding pocket, thus enabling ATP binding and enhancing catalytic activity. Our study uncovers the detailed structural basis for the activation mechanism of ribokinase by monovalent cations. PMID- 22198597 TI - Nanocomposites for neurodegenerative diseases: hydrogel-nanoparticle combinations for a challenging drug delivery. AB - Neurodegenerative disorders are expected to strike social and health care systems of developed countries heavily in the coming decades. Alzheimer's and Parkinson's diseases (AD/PD) are the most prevalent neurodegenerative pathologies, and currently their available therapy is only symptomatic. However, innovative potential drugs are actively under development, though their efficacy is sometimes limited by poor brain bioavailability and/or sustained peripheral degradation. To partly overcome these constraints, the development of drug delivery devices made by biocompatible and easily administrable materials might be a great adjuvant. In particular, materials science can provide a powerful tool to design hydrogels and nanoparticles as basic components of more complex nanocomposites that might ameliorate drug or cell delivery in AD/PD. This kind of approach is particularly promising for intranasal delivery, which might increase brain targeting of neuroprotective molecules or proteins. Here we review these issues, with a focus on nanoparticles as nanocomponents able to carry and tune drug release in the central nervous system, without ignoring warnings concerning their potential toxicity. PMID- 22198596 TI - Risk indicators for the presence and extent of root caries among caries-active adults enrolled in the Xylitol for Adult Caries Trial (X-ACT). AB - OBJECTIVE: This paper uses baseline data from a randomized clinical trial to evaluate cross-sectional indicators of root caries in caries-active adults. MATERIALS AND METHODS: Adults (21-80 years) having at least 12 erupted teeth and between one and ten caries lesions were enrolled. Participants (n = 437) received caries exams by trained, calibrated examiners and responded to baseline demographic and medical-dental questionnaires. We examined associations between baseline characteristics and (1) the presence of any root caries using Mantel Haenszel hypothesis tests and odds ratio (OR) estimators and (2) the number of root surfaces with caries among study participants with exposed root surfaces (n = 349) using Mantel-Haenszel mean score tests and Mann-Whitney estimators. RESULTS/CONCLUSIONS: Adjusting for study site and age, male gender [OR, 1.72; 95% confidence interval (CI), 1.08, 2.78], white race (OR, 2.39; 95% CI, 1.43, 3.98), recent dental visit (OR, 1.98; 95% CI, 1.07, 3.66), poor self-described oral health (OR, 2.65; 95% CI, 1.10, 6.39), and recent professional fluoride treatment (OR, 1.85; 95% CI, 1.06, 3.25) were significantly associated with increased odds to have any root caries, and study participants with exposed root surfaces characterized by male gender [Mann-Whitney probability estimate (MW) = 0.57; 95% CI, 0.51, 0.63), white race (MW, 0.61; 0.55, 0.68), recent dental visit (MW, 0.58; 0.50, 0.67), poor self-described oral health (MW, 0.61; 0.53, 0.69), and flossing at least once per day (MW, 0.57; 95% CI, 0.51, 0.62) were significantly more likely to have a greater number of root surfaces with caries than a randomly selected study participant from their respective complementary subgroups (female gender, non-white, etc.). CLINICAL RELEVANCE: Our findings may help identify individuals at higher root caries risk. PMID- 22198598 TI - AICAR, a small chemical molecule, primes osteogenic differentiation of adult mesenchymal stem cells. AB - The chemical approach to controlling stem cell fates is emerging as a powerful tool, holding great promise in tissue engineering and regenerative medicine. Various small molecules have been demonstrated capable of modulating stem cell differentiation. In this paper, we studied the effects of 5-aminoimidazole-4 carboxamide-1-beta-riboside (AICAR), an activator of AMP-activated protein kinase (AMPK), on mesenchymal stem cells (MSCs). AICAR at high concentrations (1.0-2.0 mM) significantly inhibited proliferation of both human amnion-derived MSCs (hAMSCs) and rabbit bone marrow-derived MSCs (BM-MSCs). Most importantly, AICAR efficiently promoted the osteogenic differentiation of hAMSCs and BM-MSCs in both growth medium and osteogenic medium. However, Metformin, another AMPK activator, showed no such effects. Meanwhile, AICAR significantly inhibited adipogenic differentiation of hAMSCs and BM-MSCs. Our data suggests that AICAR represents a potent molecule, which can be applied in bone tissue regeneration. PMID- 22198599 TI - Tissue engineering of bladder using vascular endothelial growth factor gene modified endothelial progenitor cells. AB - PURPOSE: This study assessed the use of vascular endothelial growth factor (VEGF) gene-modified endothelial progenitor cells (EPCs) seeded onto bladder acellular matrix grafts (BAMGs), to enhance the blood supply in tissue-engineered bladders in a porcine model. METHODS: Autologous porcine peripheral EPCs were isolated, cultured, expanded, characterized, and modified with the VEGF gene using an adenovirus vector. The expression of VEGF was examined using reverse transcriptase polymerase chain reaction (RT-PCR) and an enzyme-linked immunosorbent assay (ELISA). VEGF gene modified EPCs were seeded onto BAMG and cultured for 3 days before implantation into pigs for bladder tissue engineering. A partial bladder cystectomy was performed in 12 pigs. The experimental group (6 pigs) received VEGF gene-modified EPC-seeded BAMG. The control group (6 pigs) received BAMG without seeded EPCs. The resulting tissue-engineered bladders were subject to a general and histological analysis. Microvessel density (MVD) was assessed using immunohistochemistry. RESULTS: The ex vivo transfection efficiency of EPCs was greater than 60%-70% when concentrated adenovirus was used. The genetically modified cells expressed both VEGF and green fluorescent protein (GFP). Scanning electron microscopy (SEM) and Masson's trichrome staining of cross sections of the cultured cells seeded to BAMG showed cell attachment and proliferation on the surface of the BAMG. Histological examination revealed bladder regeneration in a time-dependent fashion. Significant increases in MVD were observed in the experimental group, in comparison with the control group. CONCLUSIONS: VEGF-modified EPCs significantly enhanced neovascularization, compared with BAMG alone. These results indicate that EPCs, combined with VEGF gene therapy, may be a suitable approach for increasing blood supply in the tissue engineering of bladders. Thus, a useful strategy to achieve a tissue engineered bladder is indicated. PMID- 22198600 TI - Investigation of bladder deformability within the development process of the artificial urinary diversion system - a pilot study. AB - PURPOSE: The purpose of this pilot study was to investigate changes in the dimensions of human bladders in different body positions to determine the required deformability of an artificial urinary diversion system (AUDS). This entirely artificial organ is comparable in size to the maximum capacity of natural bladders and is a replacement for diseased bladders, such those damaged by cancer. METHODS: The full bladders (determined by the individual's perception) of 5 healthy adult volunteers were imaged using a fully opened magnetic resonance imaging (MRI) device in different body positions: standing, maximum flexion, and seated. Dimensional changes were measured in four directions (ventral, dorsal, cranial and caudal) using a custom graphical method based on midsagittal images; the standing position was used as the reference position. RESULTS: The maximum flexed position was compared to the reference position, and the largest change was found in the cranial extension of the bladders: 6+/-4.2 mm (mean+/-SD). The seated and reference positions were compared; the maximum change was in the cranial extension and was measured to be 18+/-2.8 mm. CONCLUSIONS: The results indicate the requirement for a highly deformable artificial bladder in specific directions, such as the cranial and dorsal directions, which influences the positions of the technical components within the artificial organ. In a future development stage, artificial bladders will be designed using a computer-aided design system based on the results from this study and possibly a subsequent similar study. PMID- 22198601 TI - Wear of metal-on-metal hip bearings: metallurgical considerations after hip simulator studies. AB - Metal-on-metal hip-bearing components with different percentages of carbon content (low and high carbon) were tested in 6 different configurations using a hip joint simulator. The aim of this study was to characterize metallurgical and tribological events occurring at the articulating surfaces of these articulations. Also, ion release was evaluated and correlated with wear. After the test, for the high-carbon components, carbides were observed below the matrix surface. In the low-carbon content components, most carbides were "carbide-free", while a minority were worn below the matrix surface with increased test cycles. In the cast alloy components, some carbides were pulled out resulting in micropits. Scanning microscope electron characterization of the tested specimens showed scratches and holes. The surface showed a dominant severe wear mechanism due to third-body particles. A greater amount of ions was released in the lubricant used during the wear test for the smaller diameter compared with the bigger one. This study showed that the metallurgical and tribological events taking place at the articulating surfaces of metal-metal hip implants are numerous and complex. The surface morphology after the test showed the effect of more critical working conditions with smaller diameters. PMID- 22198602 TI - Hemodialysis without heparin: a randomized, controlled, crossover study of two dialysis membranes (AN69ST and polysulfone F60). AB - PURPOSE: It has been suggested that clotting of the extracorporeal circuit during hemodialysis (HD) without heparin could be reduced by using the polyacrylonitrile AN69ST membrane. However, this has never been demonstrated in a controlled study. The objective of this study was to compare the AN69ST with a polysulfone membrane during HD without heparin in a controlled study. METHODS: This was a prospective, randomized, crossover study. Each patient had two 3-h test sessions without heparin, one with polysulfone F60 (Fresenius Medical Care, Bad Homburg, Germany), and the other with AN69ST (Hospal-Gambro, Meyzieu, France). The extracorporeal circuit was pre-rinsed with saline containing unfractionated heparin. The order of the test sessions was randomized. The test sessions were performed one week apart, during the midweek day. The participants were stable HD patients without bleeding risk. The measurements were the number of sessions with partial or complete circuit clotting. RESULTS: Fifty-four patients were included in the study. The number of sessions interrupted for circuit clotting was 8 (15%) with AN69ST, and 10 (19%) with polysulfone (p=0.60). Complete circuit clotting occurred in 3 (6%) sessions with the two dialyzers. Partial circuit clotting manifested by a persistent increase in venous pressure occurred in 5 (9%) sessions with AN69ST, and in 7 (13%) sessions with polysulfone (p=0.54). Mean urea reduction ratio was 62+/-7% for AN69ST, and 63+/-7% for polysulfone (p=0.62). CONCLUSIONS: The AN69ST membrane did not decrease the rate of circuit clotting during HD without heparin compared to the polysulfone F60 membrane. PMID- 22198603 TI - Prevalence and clinical significance of heparin induced antibodies in chronic hemodialysis patients and cardiac surgery patients. AB - INTRODUCTION: The prevalence of heparin-induced antibodies (HIA) varies widely among reported series, but is generally higher in cardiac surgery than hemodialysis patients. This study was designed to explore the reasons behind the different prevalence of HIA in these two populations. METHODS: Blood samples from all hemodialysis and cardiac surgery patients in our hospital were examined for HIA. Heparin-induced thrombocytopenia (HIT) was suspected when platelet count was <150,000 in the hemodialysis group, and >50% decline in platelet count in the cardiac surgery group. RESULTS: 79 hemodialysis and 40 cardiac surgery patients were studied. HIA prevalence was significantly higher in cardiac surgery than in hemodialysis patients (65% v 10.1%, respectively, P<0.00001). Conversely, the prevalence of suspected clinical HIT was 37.5% in the hemodialysis and 11.5% in the cardiac surgery group. Prevalence of HIA was higher in patients who were tested during the first 90 days of hemodialysis than in those tested at later times. One-year mortality was 37% in HIA positive and 19% in HIA negative hemodialysis patients. CONCLUSIONS: Prevalence of HIA was significantly lower in hemodialysis as compared with cardiac surgery patients. Our data suggest that the observed difference in HIA prevalence was either population dependent, or due to different timing of heparin administration in the two groups. PMID- 22198604 TI - Oscillabolastic model, a new model for oscillatory dynamics, applied to the analysis of Hes1 gene expression and Ehrlich ascites tumor growth. AB - This paper introduces a new dynamical model, called the oscillabolastic model, to analyze the dynamical behavior of biomedical data when one observes oscillatory behavior. The proposed oscillabolastic model is sufficiently flexible to represent various types of oscillatory behavior. The oscillabolastic model is applied to two sets of data. The first data set deals with the oscillabolastic modeling of Ehrlich ascites tumor cells and the second one is the oscillabolastic modeling of the mean signal intensity of Hes1 gene expression in response to serum stimulation. A generalized oscillabolastic model is also suggested to accommodate cases in which predictor variables other than time are also involved. PMID- 22198605 TI - Suppressive effects of aluminum trichloride on the T lymphocyte immune function of rats. AB - Aluminum (Al) has increasingly been used in the daily life, and could cause the change of human health because it can accumulate in the organs. A rat model was thus used to examine potential effect of Al on the immune function. Forty male Wistar rats (5 weeks old) weighed 110-120 g were randomly allocated into four groups and were orally exposed to 0, 64.18, 128.36, and 256.72 mg/kg body weight aluminum trichloride (AlCl3) in drinking water for 120 days. The levels of CD3+, CD4+, CD8+ T lymphocyte, acid non-specific activity esterase (ANAE+) in blood, and interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha) in serum were determined at the end of experiment. The results showed that the proportions of CD3+, CD4+ T lymphocyte, the ratio of CD4+/CD8+, and the levels of ANAE+, IL 2, and TNF-alpha were significantly reduced in AlCl3-treated rats, while the proportion of CD8+ T lymphocyte was increased in an AlCl3-dose dependent manner. Our findings indicate that a long term exposure of AlCl3 could suppress the T lymphocyte immune function of rats. PMID- 22198606 TI - Hepatoprotective effects of total saponins isolated from Taraphochlamys affinis against carbon tetrachloride induced liver injury in rats. AB - In this study, rats were orally treated with the total saponins of Taraphochlamys affinis (TSTA) daily with administration of CCl4 twice a week for 8 weeks. Compared to the normal control, CCl4 induced liver damage significantly increased the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in serum and decreased the activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GSH-Px), and glutathione reductase (GSH-Rd) in liver. Meanwhile content of hepatic malondialdehyde (MDA), which was oxidative stress marker, was increased. Histological finding also confirmed the hepatotoxic characterization in rats. Furthermore, proinflammatory mediators including tumor necrosis factor-alpha(TNF alpha) in serum, prostaglandin E2 (PGE2), inducible enitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in liver were detected with elevated contents, while expression of xenobiotic metabolizing enzyme--cytochrome P4502E1 (CYP2E1) was inhibited. The results revealed that TSTA not only significantly reversed CCl4 originated changes in serum toxicity and hepatotoxic characterization, but also altered expression of hepatic oxidative stress markers and proinflammatory mediators, combined with restoring liver CYP2E1 level. The results indicated that protective effect of TSTA against CCl4-induced hepatic injury may rely on its effect on reducing oxidative stress, suppressing inflammatory responses and improving drug-metabolizing enzyme activity in liver. PMID- 22198607 TI - Antioxidant and anti-inflammatory activities of aqueous extracts of Schizonepeta tenuifolia Briq. AB - This study investigated the antioxidative and anti-inflammatory activities of aqueous extracts of Schizonepeta tenuifolia Briq. (STE). The results showed that STE displayed radical scavenging and reducing activity, as well as liposome protection activity. In addition, the implementation of an HPLC with a photodiode array detector helped to identify polyphenolic components including hesperidin, luteolin, and diosmetin. STE administration in the range of 125-500 mg/kg showed concentration dependent inhibition on carrageenan induced inflammatory response in mice. The anti-inflammatory effects of STE could be related to tissue NO and tumor necrosis factor a (TNF-alpha) suppression, and associated with the reduction of lipid peroxidation and an increase in antioxidant enzyme activities including catalase, superoxide dismutase, and glutathione peroxidase in vivo. Overall, the results showed that STE might serve as a natural inhibitor of oxidation and inflammation. PMID- 22198608 TI - Antimicrobial properties, antioxidant activity and cytotoxicity of ethanol soluble acidic components from Ganoderma atrum. AB - The aim of this study was to investigate the possibility of ethanol-soluble acidic components (ESAC) from Ganoderma atrum as a novel source against bacteria and oxidation in food industry. The qualitative analysis of ESAC was based on liquid chromatography-mass spectrometry (LC/MS) and eight ganoderic acids were identified in ESAC. Its total phenolic content of ESAC was 75.80+/-5.67 mg/g. ESAC exhibited antimicrobial activity against all of the tested bacteria (Staphylococcus aureus subsp. Aureus, Escherichia coli, Bacillus subtilis and Proteusbacillus vulgaris), and exerted antioxidant activities by 2,2-diphenyl-1 picrylhydrazyl (DPPH) radical scavenging, total reducing power and beta-carotene bleaching assays. Moreover, ESAC (at concentrations of 0-100 MUg/mL) did not show any cytotoxic effects in RAW264.7 murine macrophage cells. Our findings suggested that ESAC has the potential as a novel natural source for food industry, ganoderic acids and phenolic compounds may be related to its antimicrobial properties as well as antioxidant activities. PMID- 22198609 TI - Analysis of combined effects of nonylphenol and Monobutyl phthalate on rat Sertoli cells applying two mathematical models. AB - Nonylphenol (NP) and Monobutyl phthalate (MBP) are two environmental endocrine disruptors (EEDs) which are widespread occurrence in our life. In present study, our purpose is to analyze style of combined effects of NP and MBP on rat testicular Sertoli cell in vitro using two mathematical models based on the Loewe additivity (LA) theory and the Bliss independence (BI) theory. Sertoli cells were administrated by NP (range 0.01-50 MUM) and MBP (range 10-20000 MUM) in single and combined forms. Cell viability and lactate dehydrogenase (LDH) leakage rate were employed as endpoints. Using the two models, a significant antagonist effect was observed both in the viability assay and in the LDH assay (at concentrations provoked LDH leakage rate>20%), but at the lower concentrations which induced LDH leakage rate<20%, the combined effect was synergism. Considering the environmental contaminants are frequently encountered simultaneously, the result indicated that the combined effect of chemical mixture needed to be set a high value in EEDs risk assessment. PMID- 22198610 TI - Effects of smoking regimens and test material format on the cytotoxicity of mainstream cigarette smoke. AB - The purpose of this study was to evaluate the effects of test material format and smoking regimens on comparative toxicity testing of cigarette smoke. Total particulate matter (TPM) or whole smoke (WS) generated from three test cigarettes under International Organization for Standardization (ISO) or Health Canada Intensive (HCI) regimens were assessed for cytotoxicity using the neutral red uptake (NRU) cytotoxicity assay. Under both ISO and HCI regimens, the relative differences of cytotoxicity among the test cigarettes indicated by the EC50 values in WS were significantly higher than those in TPM. For TPM testing, cytotoxicity was decreased going from ISO regimen to HCI regimen, consistent with the reported reductions of toxicant output on a per unit of TPM basis under the HCI regimen. For WS, cytotoxicity increased for the two lower TPM cigarettes, and decreased for the higher TPM cigarette going from HCI regimen to ISO regimen. Results from this study demonstrated WS should be the preferable test material format for smoke toxicity testing whenever possible. Intensive smoking regimens, such as HCI, are less likely to underestimate smoke toxicant intakes by smokers, and should be included in the comparative toxicological testing strategy. PMID- 22198611 TI - Isolation and phylogenetic analysis of avian-origin European H1N1 swine influenza viruses in Jiangsu, China. AB - Isolates of the A(H1N1)pdm2009 virus were first identified in asymptomatic swine in Jiangsu province, China in January 2010, indicating that the virus has retro infected swine after circulating through humans in mainland China. The purpose of this study was to determine whether the avian-origin European H1N1 swine influenza virus (SIV) and the A(H1N1)pdm2009 virus are cocirculating in swine in Jiangsu province of China. From May 2010 to May 2011, 1,030 nasal swab samples were collected from healthy swine in Jiangsu province of China and were tested for influenza A H1N1 using reverse transcription-PCR. Fragments of the complete genomes of viruses from the samples that were positive for influenza A H1N1 were sequenced and analysed. A total of 32 avian-origin European H1N1 SIVs were isolated, and no A(H1N1)pdm2009 viruses were identified; full-length genomes of 18 strains were sequenced. The eight gene segments of some of the isolated H1N1 viruses have 99.1-99.8% sequence identity with the human A/Jiangsu/ALS1/2011(H1N1) isolates in the same region. Our study indicates that the avian-origin European H1N1 SIVs remain endemic in swine and have retro infected humans after circulating through swine, which may present a risk factor for public health. PMID- 22198612 TI - [Onychomycosis: multicentre epidemiological, clinical and mycological study]. AB - BACKGROUND: Onychomycosis accounts for up to 50% of all nail disorders. They can be caused by: yeasts, dermatophytes and non-dermatophyte moulds. OBJECTIVES AND METHODS: A multicentre study designed to determine the prevalence, mycological test results, aetiological agents, and clinical presentation of onychomycosis was carried out. All fingernail and toenail samples taken during a one year period at 9 diagnostic centres were included. RESULTS: A total of 5,961 samples were analysed, of which 82.3% were from toenails and 17.7% from fingernails. The mean age of the patients was 49.7 years, and 66% were females. Direct microscopic examination was positive in 61% of the samples. In adults, 61.2% of toenails were positive using potassium hydroxide (KOH), and 43.7% were positive in cultures. The prevailing aetiological agents belong to the dermatophyte group (82.8%), and distal subungual was the most common clinical form. In fingernails, direct examination showed 59.8% positive samples, and cultures were positive in 52.9%. The prevailing agents were yeasts belonging to Candida species, and onycholysis was the most common lesion. CONCLUSIONS: Direct mycological examinations were positive in 61%, a higher value than that found in other series. Dermatophytes were prevalent in toenails of both sexes, and in finger nails yeast were prevalent in females, and dermatophytes in males. Non-dermatophyte moulds corresponded to 4.8% of toenail and 2.05% of fingernails isolates. PMID- 22198613 TI - The Y chromosome of the Okinawa spiny rat, Tokudaia muenninki, was rescued through fusion with an autosome. AB - The genus Tokudaia comprises three species, two of which have lost their Y chromosome and have an XO/XO sex chromosome constitution. Although Tokudaia muenninki (Okinawa spiny rat) retains the Y chromosome, both sex chromosomes are unusually large. We conducted a molecular cytogenetic analysis to characterize the sex chromosomes of T. muenninki. Using cross-species fluorescence in situ hybridization (Zoo-FISH), we found that both short arms of the T. muenninki sex chromosomes were painted by probes from mouse chromosomes 11 and 16. Comparative genomic hybridization analysis was unable to detect sex-specific regions in the sex chromosomes because both sex probes highlighted the large heterochromatic blocks on the Y chromosome as well as five autosomal pairs. We then performed comparative FISH mapping using 29 mouse complementary DNA (cDNA) clones of the 22 X-linked genes and the seven genes linked to mouse chromosome 11 (whose homologue had fused to the sex chromosomes), and FISH mapping using two T. muenninki cDNA clones of the Y-linked genes. This analysis revealed that the ancestral gene order on the long arm of the X chromosome and the centromeric region of the short arm of the Y chromosome were conserved. Whereas six of the mouse chromosome 11 genes were also mapped to Xp and Yp, in addition, one gene, CBX2, was also mapped to Xp, Yp, and chromosome 14 in T. muenninki. CBX2 is the candidate gene for the novel sex determination system in the two other species of Tokudaia, which lack a Y chromosome and SRY gene. Overall, these results indicated that the Y chromosome of T. muenninki avoided a loss event, which occurred in an ancestral lineage of T. osimensis and T. tokunoshimensis, through fusion with an autosome. Despite retaining the Y chromosome, sex determination in T. muenninki might not follow the usual mammalian pattern and deserves further investigation. PMID- 22198614 TI - [Leishmaniasis in Constantine (Algeria): review of five years (2006-2010) at the University Hospital]. AB - In Algeria, leishmaniasis evolves in an endemoepidemic way. A peak of 30,227 cases of alert was reached in 2005. Our retrospective study was conducted over a period of five years (2006 to 2010), during which we examined 352 skin samples and 892 marrow aspirate smears. The distribution of cutaneous leishmaniasis cases by age shows that all ages are affected with extremes of 10 months and 95 years. The model class is between 20 and 30 years with 67 cases. Lesions are usually single, reaching the face; the most common is seen in 53% of cases. About visceral leishmaniasis, the child pays the heaviest price. A rate of 87% of visceral leishmaniasis is listed under 14 years. The youngest is an infant of 8 months, which shows a high incidence of the disease. The evolution of the disease in these five years shows a real regression of visceral leishmaniasis cases, from 13 cases in 2006 to 5 cases in 2010. This leishmaniasis is clearly declining in Algeria, but the prevalence remains high, mainly in rural areas. PMID- 22198615 TI - EMMPRIN silencing inhibits proliferation and perineural invasion of human salivary adenoid cystic carcinoma cells in vitro and in vivo. AB - Salivary adenoid cystic carcinoma (SACC) is a frequent subtype of salivary gland malignancy, and it has an important biological behavior for perineural invasion (PNI). Extracellular matrix metalloproteinase inducer (EMMPRIN) is a transmembrane glycoprotein that is involved in the invasive property of many malignancies by stimulating matrix metalloproteinase (MMP) expression. The present study was designed to investigate the role and possible mechanism of EMMPRIN in the PNI of SACC using RNA interference (RNAi) technology. We found that silencing of EMMPRIN expression in the human SACC cell line (SACC-83) suppressed the cell proliferation, adhesion, MMP-2 and MMP-9 secretion, and PNI activity in vitro. EMMPRIN silencing also inhibited the tumor growth and Ki-67 labeled proliferation index in vivo. Using tumor PNI models in nude mice, EMMPRIN silencing inhibited the infiltration, swelling and functional loss of the affected sciatic nerves, as well as the expression of MMP-2 and MMP-9. These results demonstrate that EMMPRIN participates in the PNI of SACC cells by mediating the expression of MMP-2 and MMP-9. Our findings suggest that EMMPRIN is a potential target for anti-PNI treatment in SACC. PMID- 22198616 TI - Increased Helicobacter felis colonization in male 129/Sv mice fails to suppress gastritis. AB - Development of the pathologies associated with Helicobacter pylori infection, most seriously gastric adenocarcinoma, are a consequence of chronic inflammation, which both host and pathogen go to some lengths to minimize. Recently, we presented evidence that H. pylori can suppress the development of inflammation in its immediate microenvironment in the gastric mucosa of 129/Sv mice. We have now extended this study by showing that H. felis, a gastric colonizing Helicobacter closely related to H. pylori, does not possess the same ability to suppress Helicobacter-induced gastritis in mice. Differences between these bacterial species may provide clues as to the mechanism behind the inflammation-regulating ability of H. pylori. Moreover, our demonstration that H. pylori but not H. felis can locally suppress inflammation in vivo may explain why H. felis infection induces superior levels of gastritis as compared with H. pylori infection of mice. PMID- 22198617 TI - Cefoperazone-treated mice as an experimental platform to assess differential virulence of Clostridium difficile strains. AB - The toxin-producing bacterium C. difficile is the leading cause of antibiotic associated colitis, with an estimated 500,000 cases C. difficile infection (CDI) each year in the US with a cost approaching 3 billion dollars. Despite the significance of CDI, the pathogenesis of this infection is still being defined. The recent development of tractable murine models of CDI will help define the determinants of C. difficile pathogenesis in vivo. To determine if cefoperazone treated mice could be utilized to reveal differential pathogenicity of C. difficile strains, 5-8 week old C57BL/6 mice were pretreated with a 10 d course of cefoperazone administered in the drinking water. Following a 2-d recovery period without antibiotics, the animals were orally challenged with C. difficile strains chosen to represent the potential range of virulence of this organism from rapidly fatal to nonpathogenic. Animals were monitored for loss of weight and clinical signs of colitis. At the time of harvest, C. difficile strains were isolated from cecal contents and the severity of colitis was determined by histopathologic examination of the cecum and colon. Cefoperazone treated mice challenged with C. difficile strains VPI 10463 and BI1 exhibited signs of severe colitis while infection with 630 and F200 was subclinical. This increased clinical severity was correlated with more severe histopathology with significantly more edema, inflammation and epithelial damage encountered in the colons of animals infected with VPI 10463 and BI1. Disease severity also correlated with levels of C. difficile cytotoxic activity in intestinal tissues and elevated blood neutrophil counts. Cefoperazone treated mice represent a useful model of C. difficile infection that will help us better understand the pathogenesis and virulence of this re-emerging pathogen. PMID- 22198619 TI - The Yin and Yang of host-commensal mutualism. AB - The human body is populated by an extremely diverse group of microbes that live in a symbiotic relationship with their host. Among these, intestinal commensals are the most abundant, induce homeostatic mucosal immune responses, and fulfill physiologic functions that benefit the host. In some cases, gut symbionts, including Escherichia coli, may contribute to the pathogenesis of chronic intestinal inflammation by causing dysregulated immune activation in genetically susceptible hosts. Although immune responses to bacterial products are well characterized, the impact of intestinal inflammation on the function of commensal luminal microbes is only beginning to be elucidated. We recently reported that chronic intestinal inflammation induces commensal E. coli to upregulate stress response genes that paradoxically limit their growth in vivo. Herein, we discuss our findings in the context of host-microbial interactions in health and disease and a developing paradigm that may distinguish pathogens from commensals. PMID- 22198618 TI - Innate immune response to Salmonella typhimurium, a model enteric pathogen. AB - The innate immune system provides the first line of defense against invading microorganisms by inducing a variety of inflammatory and antimicrobial responses. These responses are particularly important in the gastrointestinal tract, where the needs for efficient nutrient uptake and host defense collide. Many pathogens have evolved to specifically colonize the intestine, causing millions of cases of enteric infections a year. A paradigm of an enteric pathogen is Salmonella enterica, a gram-negative bacterium that causes a wide range of gastrointestinal and systemic diseases. Infections with Salmonella enterica serovar Typhimurium (S. typhimurium) lead to an acute intestinal inflammation in human and animal hosts, as a result of the bacterium invading the mucosa. A distinctive feature of Salmonella is that it has not only adapted to survive in a strong inflammatory environment, but it also uses this adaptation as a strategy to gain a growth advantage over the intestinal microbiota. We will use the model organism S. typhimurium to discuss the innate immune mechanisms employed by the mammalian gastrointestinal system and how the pathogen responds and subverts these mechanisms. In particular, we focus on the recognition of extra- and intra cellular Salmonellae by germline-encoded pattern recognition receptors of the TLR and NLR families, and how Salmonella might profit from the activation of these receptors. PMID- 22198620 TI - "I don't see many adults on a bicycle"--Is it time to despair for the human race? Reflections on the gap between the numbers of bicycles owned and the numbers of cyclists. AB - OBJECTIVE: This commentary offers a discussion of the paper by Bauman et al. (2011) published in Preventive Medicine. METHODS: We discuss the explanations for the findings of the manuscript by Bauman et al. (2011). RESULTS: We argue that there are social, commercial and environmental drivers of cycling rates and agree that there is an urgent need to take action to promote both cycling and build environments to support cycling. CONCLUSION: The paper by Bauman et al. provides context to help build a better global cycle cultures, involving new partnerships, in a concerted effort to tackle physical inactivity at a worldwide level. PMID- 22198621 TI - The effect of black tea on risk factors of cardiovascular disease in a normal population. AB - OBJECTIVES: A prospective randomized controlled clinical trial determined the effect of Mauritian black tea consumption on fasting blood plasma levels of glucose, lipid profiles and antioxidant status in a normal population. METHODS: The study group (71%) consumed 3 x 200 ml of black tea infusate/day for 12 weeks without additives followed by a 3 week wash-out. The control group (29%) consumed equivalent volume of hot water for same intervention period. RESULTS: The tea used had high levels of gallic acid derivatives (50 +/- 0.4 mg/L), flavan-3-ols (42 +/- 2 mg/L), flavonols (32 +/- 1 mg/L) and theaflavins (90 +/- 1 mg/L). Daily 9 g supplementation of black tea infusate induced, in a normal population, a highly significant decrease of fasting serum glucose (18.4%; p<0.001) and triglyceride levels (35.8%; p<0.01), a significant decrease in LDL/HDL plasma cholesterol ratio (16.6%; p<0.05) and a non significant increase in HDL plasma cholesterol levels (20.3%), while a highly significant rise in plasma antioxidant propensity (FRAP: 418%; p<0.001) was noted . CONCLUSION: Black tea consumed within a normal diet contributes to a decrease of independent cardiovascular risk factors and improves the overall antioxidant status in humans. PMID- 22198622 TI - Neural systems underlying motivated behavior in adolescence: implications for preventive medicine. AB - OBJECTIVE: Although a time of increased independence and autonomy, adolescence is also a time of vulnerabilities, through increased risk-taking and the emergence of psychopathology. Neurodevelopmental changes during this period may provide a neurobiological basis for this normative rise in deleterious behaviors. Thus, the objective of this review was to identify neurodevelopmental processes underlying the emergence of risk-taking and psychopathology in adolescence, and discuss implications of these findings for prevention. METHOD: This article reviews literature examining developmental and contextual factors influencing neural functioning in systems mediating threat, reward, and cognitive control. This literature is discussed from the perspective of the Triadic Neural Systems Model of motivated behavior. RESULTS: Neuroimaging research suggests that neurodevelopmental and contextual factors both contribute to a shift in the functional equilibrium among the Triadic nodes. This equilibrium shift may contribute to negative outcomes of adolescent risk behavior. Most importantly, the balance of this equilibrium and its sensitivity to social and appetitive contexts may be exploited to facilitate prevention of deleterious outcomes. CONCLUSION: Understanding developmental and contextual factors that influence functioning in motivational neural circuits can inform research on adolescent risk-taking, and may provide targets for novel preventions, for example through the use of incentives to reduce deleterious outcomes. PMID- 22198626 TI - The investigation of genetic polymorphisms in the carbonic anhydrase VI gene exon 2 and salivary parameters in type 2 diabetic patients and healthy adults. AB - The aim of this study was to investigate carbonic anhydrase (CA) VI Exon 2 single nucleotide polymorphism (SNP) and its possible association with salivary parameters in type 2 diabetic patients compared to healthy adults. Caries status was measured by using the DMFT (number of decayed, missing, and filled teeth) index. Unstimulated whole saliva and blood samples were taken. SNPs of CA gene exon 2 were determined by PCR and DNA sequencing. Salivary CA activity and buffering capacity were determined by the method of Verpoorte and Ericson, respectively. Furthermore, salivary pH was measured with pH paper and salivary flow rate was calculated. Salivary buffering capacity and pH were significantly lower in diabetic patients than those of healthy subjects (P < 0.05). Salivary flow rate, CA activity and DMFT levels did not differ between groups (P > 0.05). Four SNPs were detected; their pubmed database number are rs2274327 (C/T), rs2274328 (A/C), rs2274329 (G/C) and rs2274330. While first three of those were responsible for amino acid changes, the last one was not. The frequencies of SNPs were not significant between groups (P > 0.05). Positive significant correlation was found between CA activity and the frequency of SNPs. There was no correlation between the SNPs frequencies and pH or buffering capacity. SNPs found in this study may be related to salivary CA activity in diabetics. PMID- 22198627 TI - Use of a ura5+-lys7+ cassette to construct unmarked gene knock-ins in Schizosaccharomyces pombe. AB - While the counterselectable Schizosaccharomyces pombe ura4(+) gene can be used to prepare a site in the S. pombe genome to receive an unmarked mutant allele (loss of ura4(+) confers 5FOA-resistant (5FOA(R)) growth), the desired unmarked knock in strains are generally outnumbered by spontaneously arising 5FOA(R) mutants. Relative to the same approach using the homologous URA3(+) gene in Saccharomyces cerevisiae, knock-ins in S. pombe are harder to identify due to a lower efficiency of homologous recombination and a relatively high background of spontaneous 5FOA(R) colonies. To develop an improved method for identifying cells receiving unmarked mutant alleles, we first determined that 5FOA(R) strains carry mutations in either of two genes; ura4(+) and ura5(+). We then cloned the S. pombe ura5(+) orotate phosphoribosyltransferase gene and constructed a 2.1 kb cassette containing ura5(+) together with the S. pombe lys7(+) gene. Using this doubly marked cassette to disrupt the sck1(+) kinase gene, we can distinguish between strains created by homologous knock-in of unmarked wild-type or kinase dead alleles and spontaneously arising ura4(-) and ura5(-) mutants by screening 5FOA(R) colonies for the loss of the lys7(+) marker. The utility of this system, especially when the phenotype for the strain carrying the knock-in allele is indistinguishable from that of the disruption strain, is borne out by the fact that ~95% of 5FOA(R) colonies in our studies arose from background ura4(-) and ura5(-) mutations. PMID- 22198628 TI - Does kidney transplantation onto the external iliac artery affect the haemodynamic parameters of the cavernosal arteries? AB - Reduced cavernosal arterial inflow has been hypothesized to be the likely cause of erectile dysfunction after kidney transplants in recipients revascularized through end-to-end anastomosis to the internal iliac artery, suggesting that end to-side anastomosis at the external iliac artery is preferable. The aim of this study was to prospectively evaluate the effect of the use of the external iliac artery on erectile function, hormone profiles and penile blood flow by evaluating changes in penile colour Doppler ultrasound parameters in a consecutive series of 22 recipients before and after end-to-side external iliac artery transplantation. The mean International Index of Erectile Function-Erectile Function (IIEF-EF) domain score decreased significantly 3 months after transplant (18.09+/-6.33 vs. 22.50+/-7.09, P=0.01). The reduction in peak systolic velocity (PSV) was significant for the cavernous artery homolateral to the side of transplant (42.60+/-18.77 vs. 52.01+/-19.91, P=0.01). The mean postoperative end diastolic velocity (EDV) did not differ significantly from the preoperative value (P=0.74). No statistical differences were found in the serum levels of testosterone or prolactin. Kidney grafts anastomosed at the external iliac artery produced significant (P=0.01) reductions in arterial inflow at the homolateral cavernosal artery that remained above the normal threshold. Whether these haemodynamic changes can explain the worsening of postoperative erectile function remains to be proven. PMID- 22198629 TI - The importance of combined radiation and endocrine therapy in locally advanced prostate cancer. PMID- 22198630 TI - Tales of the tail and sperm head aches: changing concepts on the prognostic significance of sperm pathologies affecting the head, neck and tail. AB - This article presents an update on the variable prognostic significance of different sperm pathologies in patients with severe male factor infertility due to morphology and motility disorders. Severe asthenozoospermia is one of the leading causes of male infertility as spermatozoa cannot reach the oocyte and/or penetrate normally. Identifying structural causes of sperm immotility was of great concern before the advent of intracytoplasmic sperm injection (ICSI), because immotility was the limiting factor in the treatment of these patients. In these cases, in vitro methods are used to identify live spermatozoa or stimulate sperm motility to avoid selection of non-viable cells. With these advances, fertilization and pregnancy results have improved dramatically. The identification of genetic phenotypes in asthenozoospermia is important to adequately inform patients of treatment outcomes and risks. The one sperm characteristic that seriously affects fertility prognosis is teratozoospermia, primarily sperm head and neck anomalies. Defects of chromatin condensation and acrosomal hypoplasia are the two most common abnormalities in severe teratozoospermia. The introduction of microscopic methods to select spermatozoa and the development of new ones to evaluate sperm quality before ICSI will assure that ultrastructural identification of sperm pathologies will not only be of academic interest, but will also be an essential tool to inform treatment choice. Herein, we review the differential roles played by sperm components in normal fertilization and early embryo development and explore how assisted reproductive technologies have modified our concepts on the prognostic significance of sperm pathologies affecting the head, neck, mid-piece and tail. PMID- 22198631 TI - Biological effect of human serum collected before and after oral intake of Pygeum africanum on various benign prostate cell cultures. AB - Pygeum africanum (Tadenan) is a popular phytotherapeutic agent used in the treatment of symptomatic benign prostatic hyperplasia. The active compounds of the drug have not been identified, and determining the plasma concentration of the drug is, therefore, not possible. Because there are conflicting results on the efficacy of this drug, we aimed to investigate its effect on prostate cell growth in vitro using human serum collected before and after Pygeum africanum intake. We used primary and organotypic cultures of human prostatic stromal myofibroblast cell line WPMY and prostatic epithelial cell line PNT2. We also used fresh benign prostatic tissue. The serum of a treated man induced decreases in the proliferation of primary cells, organotypic cells and WPMY cells but not PNT2 cells. We also analysed the effect of treated serum on the gene expression profile of WPMY cells. The transcriptome analysis revealed an upregulation of genes involved in multiple tumour suppression pathways and a downregulation of genes involved in inflammation and oxidative-stress pathways. The oral intake of Pygeum africanum resulted in serum levels of active substances that were sufficient to inhibit the proliferation of cultured myofibroblasts prostatic cells. This inhibition was associated with changes in the transcriptome. PMID- 22198632 TI - Heart healthy=prostate healthy: SELECT, the symbolic end of preventing prostate cancer via heart unhealthy and over anti-oxidation mechanisms? PMID- 22198633 TI - Intimate partner violence: not just a concern of the reproductive ages. PMID- 22198634 TI - A persistent problem. PMID- 22198635 TI - Cromoglycate, reproterol, or both--what's best for exercise-induced asthma? AB - OBJECTIVE: International guidelines recommend short- (SABA) or long-acting b agonists for the prevention of bronchoconstriction after exercise (EIB) in patients with exercise-induced asthma (EIA). However, other drugs are still in discussion for the prevention of EIB. We investigated the efficacy of a combination of inhaled sodium cromoglycate and the beta-mimetic drug reproterol versus inhaled reproterol alone and both versus inhaled placebo in subjects with exercise-induced asthma (EIA). METHODS: The study aimed to prove the preventive effect of a combination of 1-mg reproterol and 2-mg disodium cromoglycate (DSCG) and its single components vs. placebo, measuring the decrease of FEV1 after a standardized treadmill test in 11 patients with recorded EIA. The study medication was twice as high as those of drugs which are commercially available (e.g., Allergospasmin(r), Aarane(r)). RESULTS: The results revealed that the combination of reproterol and DSCG was significantly effective against a decrease of FEV1 after a standardized exercise challenge test (ECT) compared to placebo. The short-acting b-agonist reproterol alone had almost the same effectiveness as the combination of reproterol and DNCG. The difference between the combination with DNCG and reproterol alone was less than 10% and insignificant (p 0.48). DNCG alone did not show a difference in the effectiveness compared to placebo. CONCLUSION: Prevention of EIA with the combination of reproterol and DSCG or with reproterol only is effective. An exclusive recommendation in favor of the combination cannot be given due to the low difference in the effectiveness versus reproterol alone. Due to the limited number of subjects and some probands showing protection under DSCG, it cannot be completely excluded that there is some preventive power of DSCG in individual cases. PMID- 22198638 TI - Primary Non-Hodgkin's Lymphoma of the Extrahepatic Bile Duct. PMID- 22198637 TI - ARNTL2 and SERPINE1: potential biomarkers for tumor aggressiveness in colorectal cancer. AB - PURPOSE: Cathepsin and plasmin may favor cancer cell invasion degrading extracellular matrix. Plasmin formation from plasminogen is regulated by plasminogen activator inhibitor type-1 (PAI-1). ARNTL2 activates the promoters of the PAI-1 gene, officially called SERPINE1, driving the circadian variation in circulating PAI-1 levels. METHODS: We evaluated ARNTL2 and SERPINE1 expression in 50 colorectal cancer specimens and adjacent normal tissue and in colon cancer cell lines. RESULTS: We found up-regulation of ARNTL2 (P = 0.004) and SERPINE1 (P = 0.002) in tumor tissue. A statistically significant association was found between high ARNTL2 mRNA levels and vascular invasion (P < 0.0001), and between high SERPINE1 mRNA levels and microsatellite instability (MSI-H and MSI-L, P = 0.025). Sorting the subjects into quartile groups, a statistically significant association was found between high ARNTL2 expression and lymph node involvement (P < 0.001), between high SERPINE1 expression and grading (P < 0.001) and between high SERPINE1 expression and MSI H-L (P < 0.0001). In SW480 cells, a more proliferative model compared to CaCo2 cells, there were higher mRNA levels of ARNTL2 (P < 0.001) and SERPINE1 (P = 0.001). CONCLUSION: ARNTL2 and SERPINE1 expression is increased in colorectal cancer and in a highly proliferative colon cancer cell line and is related to tumor invasiveness and aggressiveness. PMID- 22198639 TI - Prolonged strength training in older patients after hip fracture: a randomised controlled trial. AB - OBJECTIVE: the aim of this study was to assess the effect of a 12-week once-a week prolonged strength-training programme in a group of home-dwelling older hip fracture patients. DESIGN: randomised, controlled; single-blind parallel-group trial. SETTING: intervention at outpatient's clinic. SUBJECTS: 95 patients with surgical fixation for a hip fracture completed a preceding 3-month progressive strength-training programme twice a week. METHODS: the programme comprised four exercises, performed at 80% of maximum capacity. Measurements were taken after 12 weeks of intervention. Outcome measurements were Berg Balance Scale (BBS), the sit-to-stand test, timed up-and-go test, maximal gait speed, 6-min walk test, Nottingham Extended Activities of Daily Living scale and the Short Form-12 questionnaire. RESULTS: we found no statistically significant difference between groups in the primary outcome BBS, presumably because of a ceiling effect. The intervention group showed significant improvements in strength, gait speed and gait distance, instrumental activities of daily living and self-rated health. CONCLUSIONS: twelve weeks of progressive strength training performed once a week, as a follow-up to a more intensive training period, seemed to improve strength and endurance and resulted in better self-reported NEADL and self-rated health after hip fracture. Hip fracture patients seem to constitute a group that needs long-term follow-up to achieve the improvements necessary for independent functioning. PMID- 22198640 TI - Molecular phylogeny of the phylum Gastrotricha: new data brings together molecules and morphology. AB - Gastrotricha is a species-rich phylum of microscopical animals that contains two main orders, Chaetonotida and Macrodasyida. Gastrotrichs are important members of the aquatic environment and significant players in the study of animal evolution. In spite of their ecological and evolutionary importance, their internal relationships are not yet well understood. We have produced new sequences for the 18S rDNA gene to improve both the quality and quantity of taxon sampling for the gastrotrichs. Our phylogeny recovers the monophyly of the two main Gastrotricha clades, in contrast to recent studies with similar sampling, but in agreement with morphology based analyses. However, our topology is not able to resolve the first branches of the macrodasyidans or settle the position of the puzzling Neodasys, a controversial genus classified as a chaetonotidan on morphological grounds but placed within macrodasyidans by molecular studies. This analysis is the most exhaustive molecular phylogeny of the phylum to date, and significantly increases our knowledge of gastrotrich evolution. PMID- 22198641 TI - Comparison of the prognostic value of various preoperative inflammation-based factors in patients with stage III gastric cancer. AB - The aim of present study was to examine whether the C-reactive protein (CRP) based systemic inflammatory response such as the Glasgow Prognostic Score (GPS; a combination of CRP and albumin) offers prognostic value that is superior to the circulating white cellular components as neutrophil/lymphocyte ratio (NLR) or platelet/lymphocyte ratio (PLR) in patients undergoing resection for stage III gastric cancer. The medical records of 324 patients with stage III gastric adenocarcinoma were reviewed. Potential prognosis factors were evaluated with the Kaplan-Meier methodology and multivariable Cox hazards model. An increase of GPS was associated with an increase weight loss, higher NLR, higher PLR, and larger tumor size. On multivariate analysis, only the GPS, tumor-nodes-metastasis staging, and adjuvant chemotherapy were associated independently with disease free and overall survival. However, the NLR and PLR were not. In subgroup analysis, patients with a GPS of 2 had a significantly poorer median survival (13.70 months) when compared with patients with a GPS of 1 (27.4 months) or 0 (median survival had not been reached) in patients who had received adjuvant chemotherapy. Our study demonstrated that elevated preoperative GPS is superior to circulating white cellular components and was associated with reduced overall and disease-free survival for patients with stage III gastric cancer. PMID- 22198642 TI - Early adolescent depressive mood: direct and indirect effects of attributional styles and coping. AB - The present study used a cross-sectional survey design to examine how adolescent depressive mood was related to attributional styles and coping strategies with a sample of 326 youths (aged 8-14 years). With the cutting point adopted in the West, 20.9% of the current sample reported depressive symptoms. Regression analysis results show that, with the asymptomatic group, seeking social support strategy mediated the effects of positive-global and positive-stable attribution, and internalization strategy mediated the effects of negative-global attribution on depression mood. In the dysphoric adolescents, attributing positive events to global factors and seeking social support strategy predicted depressive mood in the negative direction whereas attributing negative events to global factors, problem solving strategy and internalization strategy, the positive direction. The current study confirmed that both attributional styles and coping strategies were significant predictors of depressive mood but different dimensions of attribution related to depressive symptoms in different magnitude. PMID- 22198643 TI - Biomarkers of inflammation and endothelial function: the holy grail of experimental and clinical medicine? AB - Drug induced vasculitides in humans are relatively rare diseases, resembling drug induced vasculitis in rodents and primary idiopathic vasculitis. Because of their exquisite inflammatory nature, vascular lesions in these conditions release a large amount of bioactive molecules and activate multiple cell types, including endothelial cells, neutrophils, monocytes and T-lymphocytes, all of which might be in principle used as biomarkers of the underlying disease. Although each vasculitis may have specific features, the potential biomarkers released remain largely non-specific, raising the question of whether they represent a useful clinical tool. Low specificity, short half-lives and analytical weaknesses are all issues that must be resolved before such biomarkers can be routinely used as diagnostic tools in vasculitis. Further investigation of biomarkers in animal models may be key to a better understanding of their potential usefulness (graphical abstract figure). PMID- 22198644 TI - Tenocyte proliferation on collagen scaffolds protects against degradation and improves scaffold properties. AB - Tissue engineering scaffolds encourage cell proliferation whilst degrading to facilitate tissue regeneration. Their mechanical properties therefore change, decreasing due to scaffold degradation and increasing due to extracellular matrix deposition. This work compares the changing properties of collagen scaffolds incubated in culture medium, with and without human tenocytes, in order to investigate the relationship between degradation and tenocyte proliferation. The material properties of scaffolds are compared over 26 days using mechanical testing, differential scanning calorimetry, infra-red spectroscopy, and histology and biochemical assays. For medium-only scaffolds, the mechanical properties decrease rapidly, while culture medium sulfhydryl content increases significantly, with no significant changes in the denaturation temperature of scaffold collagen content. Conversely, the mechanical properties and collagen content of tenocyte-seeded scaffolds increase significantly while culture medium sulfhydryl content decreases and denaturation temperature remains the same. These results indicate that tenocytes proliferation both reduces the degradation of collagen scaffolds incubated in culture medium and produces scaffolds with improved properties. PMID- 22198645 TI - A case report and DSA findings of cerebral hemorrhage caused by syphilitic vasculitis. AB - Syphilis is now rare and easily misdiagnosed because of the wide use of antibiotics in the clinical. We report a case of cerebral hemorrhage in a patient with hypertension who was first diagnosed as hypertensive cerebral hemorrhage. However, treponema pallidum particle agglutination and rapid plasma regain tests of cerebrospinal fluid revealed the existence of neurosyphilis. Interestingly, digital subtraction angiography (DSA) showed severe stenosis in both middle cerebral arteries and right anterior cerebral artery. The case reminded us to pay attention to syphilitic vasculitis in patients with cryptogenic stroke. DSA sometimes may play a critical role in differential diagnosis of neurosyphilis. PMID- 22198646 TI - A novel adult case of juvenile-onset Alexander disease: complete remission of neurological symptoms for over 12 years, despite insidiously progressive cervicomedullary atrophy. AB - We present here a 25-year-old woman with genetically confirmed (p.R276L mutation in the GFAP gene) juvenile-onset AxD. Episodic vomiting appeared at age nine, causing anorexia and insufficient growth. Brain MRI at age 11 showed a small nodular lesion with contrast enhancement in the left dorsal portion of the cervicomedullary junction. Her episodic vomiting improved spontaneously at age 13, and she became neurologically asymptomatic. The enhancement of the lesion disappeared simultaneously, although the plaque remained. Longitudinal MRI observations, however, revealed insidiously progressive cervicomedullary atrophy without a signal change. This case broadens our knowledge of AxD: (1) molecular analysis of the GFAP gene is warranted in patients with MRI evidence of tumor like lesions in the brainstem, particularly if they present with isolated episodic vomiting and/or anorexia; (2) the disease can be self-remitting for at least 12 years; (3) cervicomedullary atrophy, characteristic of the adult form, can be insidiously progressive without a signal change before the clinical symptoms appear. PMID- 22198648 TI - Carpal tunnel syndrome diagnosed by general practitioners: an observational study. AB - The aim of this study was to investigate the results of both clinical testing and standardised nerve conduction studies performed on patients with Carpal tunnel syndrome (CTS) complaints, who had been referred to the neurologist by their general practitioners. Analysis of the data of neurological examination and electrodiagnostic tests (EDX) were performed on patients that had been referred by general practitioners. A total of 232 patients with clinically defined CTS, who had been referred by general practitioners, were seen by a neurologist and subsequently underwent electrodiagnostic testing. The diagnosis of CTS made by general practitioners was clinically confirmed by the neurologist in 187 of 232 (81%) patients. In these 187 patients, EDX confirmed CTS clinical diagnosis in 180. In 40 (17%), the neurologists disagreed with the clinical diagnosis of CTS because signs and symptoms were not those of clinical CTS. We showed that general practitioners are very well capable of making a clinical diagnosis of CTS. Therefore, direct referral of patients by general practitioners for nerve conduction studies to have their diagnosis of CTS confirmed is a desirable and time-saving procedure. PMID- 22198647 TI - Do ACE (rs4646994) and alphaADDUCIN (rs4961) gene polymorphisms predict the recurrence of hypertensive intracerebral hemorrhage? AB - This study was undertaken to evaluate the role of ACE and alphaADDUCIN polymorphisms in patients with recurrent and nonrecurrent hypertensive intracerebral hemorrhage (ICH). A total of 101 nonrecurrent and 33 recurrent hypertensive ICH patients underwent an ACE (rs4646994) and alphaADDUCIN (rs4961) gene polymorphism study. The risk factors, clinical findings, CT scan abnormalities and functional outcome of recurrent and nonrecurrent ICH were compared. ACE (rs4646994) and alphaADDUCIN (rs4961) gene polymorphisms were also compared in the two groups and with 198 controls. The patients with recurrent ICH were older compared to those with nonrecurrent ICH and the other stroke risk factors were found in the two groups. Ganglionic-ganglionic pattern of recurrence was the commonest (75.6%) and all had at least one ICH in the location of hypertensive ICH. ACE DD genotype (OR6.18, 95%CI 2.93-13.02) and D allele (OR 2.43, 95%CI 1.70-3.47) were associated with nonrecurrent ICH compared to controls. In patients with recurrent ICH, DD genotype (OR 7.46, 95%CI 2.8-19.4) and D allele (OR 3.16, 95%CI 1.83-5.46) of ACE, and GW (OR 3.49, 95%CI 1.47 8.28), WW (OR 2.9, 95%CI 1.40-4.30) genotypes and W allele (OR 7.46, 95%CI 2.80 19.40) of alphaADDUCIN were more frequent compared to controls. Recurrent ICH also had higher frequency of WW genotype (OR 9.43, 95%CI 1.49-59.50) and W allele (OR 2.19, 95%CI 1.11-4.03) compared to nonrecurrent ICH. The frequency of DD + WW (P = 0.008) and DD/WW + ID/GW (P = 0.0001) genotypes in the recurrent ICH was higher than in the nonrecurrent ICH and the controls. Variant genotype combinations of ACE and alphaADDUCIN render the hypertensive patient more vulnerable to recurrent ICH. PMID- 22198649 TI - Bedside cognitive assessments and falls risk in Parkinson's disease. AB - Cognitive deficits may contribute to falls in Parkinson's disease (PD) and these deficits may be risk factors for falls. However, their association with falls has been generally studied in patients with continuous gait problems. There have been few studies in PD patients without postural instability. In addition, the effectiveness of various simple bedside cognitive tests in predicting falls has not been established. In this study, we investigated the effectiveness of three bedside cognitive tests in consecutive patients with PD without postural instability. Of the 119 patients, 39 experienced falls during the follow-up period. Of the bedside cognitive assessment methods examined, only the Montreal Cognitive Assessment (MoCA) score was significantly lower in the group of fallers than in the group of non-fallers. This result suggests that the MoCA is effective as a bedside test for evaluating the risk of falls. PMID- 22198650 TI - Two polymorphic residues account for the differences in DNA binding and transcriptional activation by NF-kappaB proteins encoded by naturally occurring alleles in Nematostella vectensis. AB - The NF-kappaB family of transcription factors is activated in response to many environmental and biological stresses, and plays a key role in innate immunity across a broad evolutionary expanse of animals. A simple NF-kappaB pathway is present in the sea anemone Nematostella vectensis, an important model organism in the phylum Cnidaria. Nematostella has previously been shown to have two naturally occurring NF-kappaB alleles (Nv-NF-kappaB-C and Nv-NF-kappaB-S) that encode proteins with different DNA-binding and transactivation abilities. We show here that polymorphic residues 67 (Cys vs. Ser) and 269 (Ala vs. Glu) play complementary roles in determining the DNA-binding activity of the NF-kappaB proteins encoded by these two alleles and that residue 67 is primarily responsible for the difference in their transactivation ability. Phylogenetic analysis indicates that Nv-NF-kappaB-S is the derived allele, consistent with its restricted geographic distribution. These results define polymorphic residues that are important for the DNA-binding and transactivating activities of two naturally occurring variants of Nv-NF-kappaB. The implications for the appearance of the two Nv-NF-kappaB alleles in natural populations of sea anemones are discussed. PMID- 22198651 TI - Functional outcomes in elderly patients with acetabular fractures treated with minimally invasive reduction and percutaneous fixation. AB - OBJECTIVES: To present the functional outcomes of elderly patients treated with percutaneous acetabular surgery and compare them with those treated with traditional open reduction and internal fixation in previously published series. DESIGN: Retrospective. SETTING: University level I trauma center. PATIENTS: All patients aged 60 and older treated with percutaneous screw fixation for acetabular fractures from 1994 to 2007 were included. Seventy-nine consecutive patients were identified. Thirty-six patients died before functional outcomes were obtained, leaving 43 patients and fractures in our study group. Functional outcomes were obtained in 35 of 43 (81.3%) patients at an average of 6.8 years after the index surgery. INTERVENTION: Minimally invasive reduction and percutaneous fixation of acetabular fractures. MAIN OUTCOME MEASUREMENT: Short musculoskeletal functional assessment and Harris Hip Score. RESULTS: One-year mortality was 13.9% (11 of 79). Average short musculoskeletal functional assessment dysfunction and bother indices were 23.3 and 21.3, respectively, in 24 patients who maintained their native hip. When compared with Short Musculoskeletal Functional Assessment data from 2 other series of patients treated with formal open reduction and internal fixation, no differences existed in the dysfunction (P = 0.49) or bother (P = 0.55) indices. Conversion to total hip arthroplasty occurred in 11 of 36 patients (30.6%). Average Harris Hip Scores in patients with their native hip was 77 (range, 33-100). In the 11 patients converted to total hip arthroplasty, average Short Musculoskeletal Functional Assessment dysfunction and bother indices were 24.3 and 23.9, respectively. No differences were found in the dysfunction (P = 0.93) or bother (P = 0.16) indices when compared with patients converted from open reduction and internal fixation to total hip arthroplasty. Average Harris Hip Score in patients converted to total hip arthroplasty was 83 (range, 68-92), and this was not significantly different from the best scores reported with acute total hip arthroplasty. CONCLUSIONS: Functional outcomes and rates of conversion to total hip arthroplasty of acetabular fractures in elderly patients treated with percutaneous reduction and fixation show no significant differences when compared with published series of patients treated with formal open reduction and internal fixation. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22198652 TI - Cemented versus uncemented hemiarthroplasty for displaced femoral neck fractures: a prospective randomized trial with early follow-up. AB - OBJECTIVE: To prospectively compare the functional outcome associated with cemented and uncemented hemiarthroplasty. DESIGN: Prospective randomized control trial. SETTING: University-affiliated level 1 trauma center. PATIENTS/PARTICIPANTS: All individuals designated for hemiarthroplasty, older than 55 years, with a nonpathologic displaced femoral neck fracture and the ability to ambulate 10 feet independently before injury [269 patients (274 hips) presented with displaced femoral neck fracture, 130 patients (48.3%) enrolled, and 5 patients (3.8%) withdrew]. INTERVENTION: Hip hemiarthroplasty with a cemented femoral prosthesis (VerSys LD/Fx; Zimmer, Warsaw, IN) or an uncemented component (VerSys Beaded FullCoat; Zimmer, Warsaw, IN). MAIN OUTCOME MEASURES: Instrumental Activities of Daily Living and Physical Activities of Daily Living scales (Older Americans Resources and Services Instrument) and the Energy/Fatigue Scale. RESULTS: No statistically significant differences were present in the groups' preoperative or intraoperative characteristics, including American Society of Anesthesiologists grade, operative time, anesthesia time, use of perioperative beta-blockers, estimated blood loss, or the rate of intraoperative fracture. Postoperatively, no difference was found in hemoglobin level, transfusion rate, discharge disposition, or acute complication rate. At 30-day, 60-day, and 1-year follow-ups, no clinically or statistically significant differences were found in mortality, disposition, need for assistance with ambulation, Older Americans Resources and Services Activities of Daily Living subscales, or the Energy/Fatigue Scale. CONCLUSIONS: In the treatment of nonpathologic displaced femoral neck fractures, the use of cemented and uncemented femoral components is associated with similar functional outcome at 1 year. Practitioners may inform their clinical decisions using these equally good results. LEVEL OF EVIDENCE: Therapeutic Level II. See page 128 for a complete description of levels of evidence. PMID- 22198653 TI - Factors influencing functional outcomes after distal tibia shaft fractures. AB - OBJECTIVES: Surgical treatment of displaced distal tibia fractures yields reliable results with either plate or nail fixation. Comparative studies suggest more malalignment and nonunions with nails. Some studies have reported knee pain after tibial nailing. However, plates may be associated with soft tissue complications, such as infections or wound-healing problems. The purpose of this study was to assess functional outcomes after distal tibia shaft fractures treated with a plate or a nail. We hypothesized that tibial nails would be associated with more knee pain and that plates would be associated with pain from implant prominence, each of which would adversely affect functional outcome scores. DESIGN: Randomized prospective study. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: One hundred four patients with extra-articular distal tibia shaft fractures (OTA 42), mean age of 38 years (range, 18-95), and mean Injury Severity Score of 14.3 (range, 9-50). INTERVENTION: Patients were randomized to treatment with a reamed intramedullary nail (n = 56) or standard large fragment medial plate (n = 48). MAIN OUTCOME MEASUREMENTS: Ability to work was evaluated after a minimum of 12 months, with mean of 22 months. Foot Function Index (FFI) and Musculoskeletal Function Assessment (MFA) questionnaires were completed. RESULTS: Mean MFA was 27.5, and mean total FFI was 0.26; P < 0.0001 versus an uninjured reference population. Sixty-one of 64 patients (95%) employed at the time of injury had returned to work, although 31% had modified their work duties because of injury. Three patients were unable to find work. None reported unemployment secondary to their tibial fracture. Forty percent of all patients described some persistent ankle pain, and 31% had knee pain after nailing, versus 32% and 22%, respectively after plating. Both knee and ankle pain were present in 27% with nails and 15% with plates (P = 0.08), and rates of implant removal were similar after nails versus plates. Patients with malunion >=5 degrees were more likely to report knee or ankle pain (36% vs 20%, P < 0.05). Except 1 patient with knee pain when kneeling, none reported modifying activity because of persistent knee or ankle pain, although knee and ankle pain were more frequent in the unemployed (P = 0.03). Unemployed patients requested implant removal more frequently (24% vs 9.2%, P = 0.07) and continued to report pain afterward. Although FFI and MFA scores were not related to plate or nail fixation, open fracture, fracture pattern, multiple injuries, Injury Severity Score, or age, both MFA and FFI scores were worse when knee pain or ankle pain was present (all Ps < 0.004) and in patients who remained unemployed (P < 0.0001). All 4 patients with work-related injuries had returned to employment but had worse FFI scores (P = 0.01). CONCLUSIONS: Mean MFA and FFI scores suggest substantial residual dysfunction after distal tibia fractures when compared with an uninjured population. Mild ankle or knee pain was reported frequently after plate or nail fixation but was not limiting to activity in most. Angular malunion was associated with both knee and ankle pain, and there was a trend toward more patients with knee and ankle pain after tibial nailing. No patients reported unemployment because of their tibia fracture, but unemployed people described knee and ankle pain more frequently and had the worst functional outcome scores. PMID- 22198654 TI - Twenty-one-year follow-up of supination-external rotation type II-IV (OTA type B) ankle fractures: a retrospective cohort study. AB - OBJECTIVE: To evaluate long-term results after protocoled treatment of supination external rotation (SER) Type II-IV ankle injuries. DESIGN: Retrospective cohort study. SETTING: Level I trauma center. PATIENTS: Two hundred seventy-six adult patients with an SER Type II-IV ankle fracture between January 1, 1985, and January 1, 1990. All patients were approached to participate in this study. INTERVENTION: Fractures with tibiotalar congruity were treated nonoperative and unstable fractures with joint incongruity were treated operatively. MEAN OUTCOME MEASUREMENTS: 1) a functional outcome questionnaire (Olerud score); 2) range of motion; 3) functional impairment (American Medical Association guidelines); and 4) radiologic anatomic result (medial clear space widening; osteoarthritis; Cedell score). RESULTS: After a median of 21 years in 54% (n = 148) of patients, follow-up was achieved. Seventy-six patients (51%) had a SER Type II injury, four patients (3%) a SER Type III injury, and 68 (46%) had sustained a SER Type IV. Excellent or good results were found in 92% (Olerud score), 97% (loaded dorsal range of motion), 92% (medial clear space widening), 97% (osteoarthritis), and 76% (Cedell score) of patients. Functional impairment expressed as percentage of whole person impairment varied between 0% and 16%. The various fracture types performed statistically equal on all outcome parameters. There was no difference between operative and nonoperative treatment. There was no correlation between the Olerud score and other parameters. CONCLUSIONS: The very long-term overall results of the stratified surgical treatment of SER Type II-IV ankle fractures is 'excellent' or 'good' in the majority of patients and therefore seems justified. Although additional soft tissue damage is unavoidable in case of operative treatment, it does not negatively affect outcome in the long term. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22198655 TI - Twenty-two-year follow-up of pronation external rotation type III-IV (OTA type C) ankle fractures: a retrospective cohort study. AB - OBJECTIVE: Long-term evaluation protocolled treatment of pronation external rotation (PER) type III-IV (OTA type C) ankle fractures. DESIGN: Level III retrospective cohort study. SETTING: Level I trauma center. PATIENTS: A consecutive series of 98 patients with PER III-IV ankle fractures between 1985 and 1990. INTERVENTION: Stable fractures with tibiotalar congruity were treated conservatively, whereas osteosynthesis was performed in unstable and displaced fractures to restore tibiotalar congruity. MAIN OUTCOME MEASUREMENTS: Outcome parameters were (1) functional outcome questionnaire (Olerud score), (2) physical evaluation (loaded dorsal range of motion), (3) functional impairment (AMA Guides, 5th ed.), and (4) radiographic evaluation (Cedell score, medial clear space widening, and osteoarthritis). RESULTS: After a median of 22 years, follow up was achieved in 95% (n = 60) of living patients. Four patients had a true PER III injury, 5 patients had an unclear injury (between PER III and IV), and 51 patients (85%) sustained a PER IV injury. Excellent or good results were found in 90% of patients (Olerud score). Functional impairment, expressed as percentage of Whole Person Impairment, varied between 0% and 3%. Patients treated operatively and conservatively had statistically equivalent scores. CONCLUSIONS: The long term result of surgical treatment of PER ankle fractures is "good" or "excellent" in the majority of patients. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22198656 TI - Fabrication of silk sericin nanofibers from a silk sericin-hope cocoon with electrospinning method. AB - In this study, silk sericin nanofibers from sericin hope-silkworm, whose cocoons consist almost exclusively of sericin were successfully prepared by electrospinning method. Scanning electron microscopy (SEM) was used to observe the morphology of the fibers. The effect of spinning conditions, including the concentration of sericin cocoon solution, acceleration voltage, spinning distance and flow rate on the fiber morphologies and the size distribution of sericin nanofibers were examined. The structure and physical properties were also observed by Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TG). The optimum conditions for producing finely thinner fibrous sericin nanofibers without beads were the concentration of sericin solution above 6-8 wt%, acceleration voltage ranging from 25 to 32 kV, spinning distance above 9 cm, and flow rate above 0.06 cm min(-1). The mean diameter of as spun sericin fibers varied from 114 to 430 nm at the different spinning conditions. In the as-spun fibers, silk sericin was present in a random coil conformation, while after methanol treatment, the molecular structure of silk sericin was transformed into a beta-sheet containing structure. Sericin hope nanofiber demonstrated thermal degradation at lower temperature than the sericin hope cocoon, which probably due to the randomly coiled rich structure of the sericin hope nanofiber. PMID- 22198657 TI - Trans fatty acids enhanced beta-amyloid induced oxidative stress in nerve growth factor differentiated PC12 cells. AB - The effects of trans fatty acids, elaidic acid (trans-9, C18:1) and linoelaidic acid (trans-9, trans-12 C18:2), at 20 or 40 MUM in nerve growth factor differentiated PC12 cells with or without beta-amyloid peptide (Abeta) were examined. Elaidic acid treatment alone did not affect cell viability and oxidative injury associated markers (P > 0.05). However, co-treatments of elaidic acid and Abeta led to more reduction in mitochondrial membrane potential (MMP) and Na+-K+-ATPase activity, and more increase in DNA fragmentation and 8 hydroxydeoxyguanosine (8-OHdG) production than Abeta treatment alone (P < 0.05). Linoelaidic acid alone exhibited apoptotic and oxidative effects in cells via decreasing MMP and Na+-K+-ATPase activity, increasing reactive oxygen species (ROS) level, lowering glutathione content and glutathione peroxidase (GPX) activity (P < 0.05). The co-treatments of linoelaidic acid with Abeta further enhanced oxidative damage via enhancing the generation of ROS, nitrite oxide and 8-OHdG, elevating caspase-3, caspase-8 and nitric oxide synthase activities, as well as declining GPX, catalase and superoxide dismutase activities (P < 0.05). These results suggested that the interaction of linoelaidic acid and Abeta promoted oxidative stress and impaired mitochondrial functions in neuronal cells. PMID- 22198658 TI - Using longitudinal profiles to characterize women's symptoms through midlife: results from a large prospective study. AB - OBJECTIVE: The aims of this study were to identify groups of symptoms experienced by women during midlife and to determine the main profiles or trajectories for each of these symptom groups through the menopausal transition. METHODS: The study uses data from the middle-aged cohort of women from a large community-based longitudinal study. Groups or patterns of symptoms are determined using factor analysis. Latent class analysis based on age and age at menopause is used to identify profiles for each of the symptom patterns. RESULTS: Of the four symptom patterns identified, "somatic," "urogynecological," and "physical" symptoms have a constant profile through midlife. Vasomotor symptoms vary through menopause: 11% of women have the "early severe" profile of symptoms that begin at premenopause, whereas 29% have the "late severe" profile, with symptoms peaking during postmenopause and persisting more than a decade after menopause. The remaining women with the "moderate" or "mild" profiles report occasional symptoms that tend to peak around menopause. CONCLUSIONS: Identifying the profile of vasomotor symptoms could help health professionals to tailor their advice to women going through menopause. PMID- 22198659 TI - Serum ghrelin in female patients with rheumatoid arthritis during treatment with infliximab. AB - Ghrelin is a gastric hormone that posses multiple functions, including induction of growth hormone release, regulation of proinflammatory cytokines and control of food intake and energy homeostasis. A few reports on serum ghrelin level in chronic inflammatory states revealed contradictory results. The study was undertaken to determine ghrelin in patients with rheumatoid arthritis receiving infliximab, a TNF-alpha blocking agent. Serum ghrelin was determined in 18 female rheumatoid patients before the treatment with infliximab, 1 week after the first infusion and after 53 weeks of medication and compared with 15 age-matched healthy women. Serum ghrelin level was shown to be increased in the patients. A decrease in serum ghrelin level was found after the first infusion of infliximab and similarly decreased ghrelin level but still higher than in the control was shown in the 53rd week of medication. The obtained results suggest that ghrelin level is related to inflammation, and its serum level in patients with severe rheumatoid arthritis behaves similarly to acute-phase reactants. PMID- 22198660 TI - Arachnoid ossificans of thoracolumbosacral spine in the advanced ankylosing spondylitis: a case report. AB - Arachnoid ossificans is a rare type of chronic arachnoiditis characterised by the presence of calcification or ossification of the dura and arachnoid. There are a few reports of these findings in relation to various disease entities, but only one case has been reported in relation to ankylosing spondylitis. We describe a 76-year-old man of ankylosing spondylitis with arachnoiditis ossificans, who has suffered from low back pain and neuropathic leg pain. PMID- 22198661 TI - Retrospective study on the effects of immunosuppressive therapy in uveitis associated with rheumatic diseases in Korea. AB - This retrospective study of 432 patients was conducted between 2000 and 2009 to compare immunosuppressive therapy responses in uveitis accompanied or unaccompanied by rheumatic diseases. We divided patients into two groups: uveitis related or unrelated to rheumatic diseases. The clinical improvement after treatment was measured at the end of the observation period. Of the 432 patients with uveitis, 33 (7.6%) patients suffered from associated rheumatic diseases and 399 (92.4%) patients did not. The groups showed similar clinical features, but the mean age at onset of uveitis was lower in the rheumatic disease group (44.06 +/- 2.13 years vs. 48.23 +/- 0.81 years). The rheumatic diseases included spondyloarthropathy (31%), Behcet's disease (27%), rheumatoid arthritis (18%), systemic lupus erythematosus (15%), Sjogren's syndrome (6%), and mixed connective tissue disease (3%). Erythrocyte sedimentation rate and C-reactive protein level were increased in uveitis associated with rheumatic diseases, whereas ocular complications were not. The response to immunosuppressive therapy was significantly increased in cases of uveitis associated with rheumatic diseases (P < 0.05). Therefore, during early treatment, uveitis accompanied by rheumatic diseases showed better response to immunosuppressive therapy and less frequent complications. PMID- 22198662 TI - Paraneoplastic necrotizing myopathy and dermatomyositis in a patient with rectosigmoid carcinoma. AB - An 81-year-old woman with adenocarcinoma of the rectosigmoid presented with progressive muscle weakness and difficulty swallowing, with symptoms worsening following successful resection of the tumor. On examination, she had weakness primarily of lower limb proximal muscles, with no other abnormal findings. Laboratory tests showed significant elevation of creatine kinase, and EMG findings indicated myositis of the proximal muscles. While MRI showed increased signal intensity on T2-weighted images of the leg muscles, indicating inflammation, muscle biopsy found widespread necrosis with only weak and focal lymphocytic infiltration. A diagnosis of paraneoplastic necrotizing myopathy (PNM) was made, and immunomodulatory treatment initiated, with little response. Four months later she returned with exacerbation of symptoms, this time with skin changes pathognomonic of dermatomyositis (DM). A repeat MRI showed progression of inflammation, as well as necrotic foci. It is important to distinguish between paraneoplastic myopathies such as DM and PNM, with implications regarding treatment and prognosis. PMID- 22198663 TI - Typical Jaccoud's arthropathy in a patient with sarcoidosis. AB - Jaccoud's arthropathy (JA) is a deforming, non-erosive form of arthritis initially described in rheumatic fever but recently observed more frequently in patients with systemic lupus erythematosus. However, cases of JA have been described in association with other diffuse connective tissue diseases, neoplasias, and infection. We describe a rare case of sarcoidosis in a female subject who developed JA in her hands later in the course of the disease. PMID- 22198664 TI - Anti-MDA5 antibody is associated with A/SIP and decreased T cells in peripheral blood and predicts poor prognosis of ILD in Chinese patients with dermatomyositis. AB - The aim of this study is to determine serum anti-melanoma differentiation associated gene 5 prevalence and their clinical associations in Chinese patients with polymyositis and dermatomyositis (PM/DM). Serum anti-MDA5 antibody was detected by ELISA in 113 adult PM/DM patients and in various controls. Flow cytometry was applied to analyze the subgroups of lymphocytes in the peripheral blood of PM/DM patients. The serum anti-MDA5-positive rate in the DM patients (22.6%) was significantly higher compared with that in PM patients (0%, P < 0.005), patients with SLE (3.3%, P < 0.05), RA (3.3%, P < 0.05), pSS (0%, P < 0.05), pulmonary infection (0%, P < 0.05) and healthy controls (0%, P < 0.001). The percentage of decreased CD4(+), CD8(+) T cell counts, raised CD4(+)/CD8(+) ratio in peripheral blood and the incidence of acute/subacute interstitial pneumonia (A/SIP) were significantly higher in anti-MDA5-positive DM group than negative group (all P < 0.05). Additionally, logistic multivariate analysis showed that anti-MDA5 is an independent risk factor for death of ILD in DM (OR = 8.46, 95% CI 1.77-40.36, P = 0.007). In conclusion, in Chinese PM/DM patients, serum anti-MDA5 antibody is mainly presented in DM patients and can be a useful marker for A/SIP in patients with DM. It can predict unfavorable prognosis in DM patients with ILD. Further studies are needed to identify how the abnormal T cells in peripheral blood participated in the generation of the anti-MDA5 antibody. PMID- 22198665 TI - A comparative study on the diversity of clinical features between the sero negative and sero-positive rheumatoid arthritis patients. AB - To investigate the similarities and differences in clinical features between the sero-negative and sero-positive rheumatoid arthritis (RA) patients. Two hundred and sixty-two RA patients who fulfilled the 1987 ACR RA Classification Criteria were enrolled into this study. They were divided into sero-negative and sero positive group depending on the presence or absence of rheumatoid factor (RF) and anti-cyclic citrullinate peptide (anti-CCP). The clinical features were compared between these two groups. Forty-six (17.6%) RA patients were classified as sero negative group. The disease onset of sero-negative RA patients was later than that of sero-positive RA patients (52.4 +/- 15.9 vs. 47.4 +/- 15.5 years, P < 0.05). At the end of the first 2 years after disease onset, bone erosion shown in the hand X-ray occurred in 4 out of 24 (16.7%) patients with sero-negative RA. However, only 5.2% (5/97) patients with sero-positive RA developed bone erosion (P < 0.05). In the sero-positive RA patients, the titer of RF was correlated with swollen joint counts (SJC), tender joint counts (TJC), erythrocyte sedimentation rate (ESR), and disease activity score in 28 joints (DAS28) (P < 0.05), but anti CCP was not. Sero-negative and sero-positive RA are probably two distinct disease subtypes driven by different mechanisms. PMID- 22198666 TI - Cutaneous manifestations associated with adult-onset Still's disease: important diagnostic values. AB - Adult-onset Still's disease (AOSD) is a systemic inflammatory condition, characterized by a high spiking fever, leukocytosis with neutrophilia, arthralgia, and skin rash. Typical skin rash is an evanescent, salmon-pink erythema predominantly involving extremities, which is included as one of the diagnostic criteria; however, recent findings show that not only typical evanescent rash but also various skin lesions are associated with AOSD. The representative characteristic skin lesion among the non-classical skin rash is called persistent pruritic papules and plaques, which presents erythematous, slightly scaly papules with linear configuration on the trunk. Interestingly, persistent pruritic papules and plaques show unique histological features such as peculiar, distinctive distribution of dyskeratotic keratinocytes in the cornified layers as well as in the epidermis. Other non-classical skin lesions include urticaria. Current insights suggest that several inflammatory cytokines such as interleukin-1 (IL-1), IL-6, IL-18, interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) play a pathogenic role in AOSD. In particular, IL-18 is suggested to play a crucial role in activating macrophages, favoring Th1 type cytokine production. IL-18 induces IFN-gamma, IL-17, and TNF-alpha, which may play an important pathogenic role in AOSD. It is important to recognize the common and/or uncommon skin conditions of AOSD for early correct diagnosis. In this review, various skin lesions are introduced, and the complication with histiocytic necrotizing lymphadenitis (Kikuchi disease) is further discussed. PMID- 22198667 TI - Cool cuisine-feed your body, mind, and planet. AB - INTRODUCTION: This paper combines information from the book, Cool Cuisine-Taking the Bite Out of Global Warming (Gibbs Smith, 2008) with notes from the World of Healthy Flavors Conference (Culinary Institute of America, St. Helena, CA, USA, 2011). Cool Cuisine reports on connections between food choices and global warming, (what we termed the Global Warming Diet), both from a culinary and science point of view. METHOD: World of Healthy Flavors brought food industry professionals together to discuss ways the industry can collaborate on solutions to some of the most pressing health problems in the USA. RESULTS AND DISCUSSION: Science now supports the fact that dietary choices that adversely effect human health have an equally detrimental effect on the health of the environment and our livestock. Therefore, eating a more diverse, plant-based, whole grain, and sodium-reduced diet not only improves human health, but also the health of the environment. What is good for humans to eat is the same food that is best for the environment to grow and manufacture. Understanding and then teaching the connection between the two is one more tool toward effective behavior change, especially in children. Easy suggestions on ways to cook healthfully and "fight the global warming diet with a cool cuisine" close out this work. PMID- 22198668 TI - Malignant epithelioid gastric GIST resembling small cell carcinoma: a pitfall in punch biopsy diagnosis. PMID- 22198669 TI - Ars2 maintains neural stem-cell identity through direct transcriptional activation of Sox2. AB - Fundamental questions remain unanswered about the transcriptional networks that control the identity and self-renewal of neural stem cells (NSCs), a specialized subset of astroglial cells that are endowed with stem properties and neurogenic capacity. Here we report that the zinc finger protein Ars2 (arsenite-resistance protein 2; also known as Srrt) is expressed by adult NSCs from the subventricular zone (SVZ) of mice, and that selective knockdown of Ars2 in cells expressing glial fibrillary acidic protein within the adult SVZ depletes the number of NSCs and their neurogenic capacity. These phenotypes are recapitulated in the postnatal SVZ of hGFAP-cre::Ars2(fl/fl) conditional knockout mice, but are more severe. Ex vivo assays show that Ars2 is necessary and sufficient to promote NSC self-renewal, and that it does so by positively regulating the expression of Sox2. Although plant and animal orthologues of Ars2 are known for their conserved roles in microRNA biogenesis, we unexpectedly observed that Ars2 retains its capacity to promote self-renewal in Drosha and Dicer1 knockout NSCs. Instead, chromatin immunoprecipitation revealed that Ars2 binds a specific region within the 6-kilobase NSC enhancer of Sox2. This association is RNA-independent, and the region that is bound is required for Ars2-mediated activation of Sox2. We used gel-shift analysis to refine the Sox2 region bound by Ars2 to a specific conserved DNA sequence. The importance of Sox2 as a critical downstream effector is shown by its ability to restore the self-renewal and multipotency defects of Ars2 knockout NSCs. Our findings reveal Ars2 as a new transcription factor that controls the multipotent progenitor state of NSCs through direct activation of the pluripotency factor Sox2. PMID- 22198670 TI - Purkinje neuron synchrony elicits time-locked spiking in the cerebellar nuclei. AB - An unusual feature of the cerebellar cortex is that its output neurons, Purkinje cells, release GABA (gamma-aminobutyric acid). Their high intrinsic firing rates (50 Hz) and extensive convergence predict that their target neurons in the cerebellar nuclei would be largely inhibited unless Purkinje cells pause their spiking, yet Purkinje and nuclear neuron firing rates do not always vary inversely. One indication of how these synapses transmit information is that populations of Purkinje neurons synchronize their spikes during cerebellar behaviours. If nuclear neurons respond to Purkinje synchrony, they may encode signals from subsets of inhibitory inputs. Here we show in weanling and adult mice that nuclear neurons transmit the timing of synchronous Purkinje afferent spikes, owing to modest Purkinje-to-nuclear convergence ratios (~40:1), fast inhibitory postsynaptic current kinetics (tau(decay) = 2.5 ms) and high intrinsic firing rates (~90 Hz). In vitro, dynamically clamped asynchronous inhibitory postsynaptic potentials mimicking Purkinje afferents suppress nuclear cell spiking, whereas synchronous inhibitory postsynaptic potentials entrain nuclear cell spiking. With partial synchrony, nuclear neurons time-lock their spikes to the synchronous subpopulation of inputs, even when only 2 out of 40 afferents synchronize. In vivo, nuclear neurons reliably phase-lock to regular trains of molecular layer stimulation. Thus, cerebellar nuclear neurons can preferentially relay the spike timing of synchronized Purkinje cells to downstream premotor areas. PMID- 22198671 TI - Recovery rates reflect distance to a tipping point in a living system. AB - Tipping points, at which complex systems can shift abruptly from one state to another, are notoriously difficult to predict. Theory proposes that early warning signals may be based on the phenomenon that recovery rates from small perturbations should tend to zero when approaching a tipping point; however, evidence that this happens in living systems is lacking. Here we test such 'critical slowing down' using a microcosm in which photo-inhibition drives a cyanobacterial population to a classical tipping point when a critical light level is exceeded. We show that over a large range of conditions, recovery from small perturbations becomes slower as the system comes closer to the critical point. In addition, autocorrelation in the subtle fluctuations of the system's state rose towards the tipping point, supporting the idea that this metric can be used as an indirect indicator of slowing down. Although stochasticity prohibits prediction of the timing of critical transitions, our results suggest that indicators of slowing down may be used to rank complex systems on a broad scale from resilient to fragile. PMID- 22198673 TI - Effect of Bcl-2 rs956572 SNP on regional gray matter volumes and cognitive function in elderly males without dementia. AB - The Bcl-2 gene is a major regulator of neural plasticity and cellular resilience. A single-nucleotide polymorphism (SNP) in the Bcl-2 gene, Bcl-2 rs956572, significantly modulates the expression of Bcl-2 protein and cellular vulnerability to apoptosis. This study investigated the association between the Bcl-2 rs956572 SNP and brain structural abnormalities in non-demented elders, and to test the relationship between neuropsychological performance and regional gray matter (GM) volumes. Our sample comprised 97 non-demented elderly men with a mean age of 80.6 +/- 5.6 years (range, 65 to 92 years). Cognitive test results, magnetic resonance imaging, and genotyping of Bcl-2 rs956572 were examined for each subject. The differences in regional GM volumes between G homozygotes and A allele carriers were tested using optimized voxel-based morphometry. Subjects with G homozygotes exhibited significantly worse performance in the language domain of the Cognitive Abilities Screening Instrument (CASI; p = 0.009). They also showed significantly smaller GM volumes in the right middle temporal gyrus (MTG) (BA 21), but larger GM volumes in the left precuneus (BA 31), right lingual gyrus (BA 18), and left superior occipital gyrus (BA 19) relative to A-allele carriers (p < 0.001). A trend toward a positive correlation between right MTG GM volumes and the language domain of CASI was also evident (r = 0.181; p = 0.081). The findings suggest that Bcl-2 rs956572 SNP may modulate cognitive function and regional GM volume in non-demented elderly men, and that this polymorphism may affect language performance through its effect on the right MTG. PMID- 22198672 TI - Age-related changes in neuroendocrine rhythmic function in the rhesus macaque. AB - Many environmental conditions show rhythmic changes across the 24-h day; these include changes in light intensity, ambient temperature, food availability, and presence or absence of predators. Consequently, many organisms have developed corresponding adaptations, which ensure that specific physiological and behavioral events occur at an appropriate time of the day. In mammals, the underlying mechanism responsible for synchronizing internal biochemical processes with circadian environmental cues has been well studied and is thought to comprise three major components: (1) photoreception by the retina and transmission of neural signals along the retinohypothalamic tract, (2) integration of photoperiodic information with an internal reference circadian pacemaker located in the suprachiasmatic nucleus, and (3) dissemination of circadian information to target organs, via the autonomic nervous system and through humoral pathways. Given the importance that neuroendocrine rhythms play in coordinating normal circadian physiology and behavior, it is plausible that their perturbation during aging contributes to the etiology of age-related pathologies. This mini-review highlights some of the most dramatic rhythmic neuroendocrine changes that occur in primates during aging, focusing primarily on data from the male rhesus macaques (Macaca mulatta). In addition to the age associated attenuation of hormone levels and reduction of humoral circadian signaling, there are also significant age-related changes in intracrine processing enzymes and hormone receptors which may further affect the functional efficacy of these hormones. Rhesus macaques, like humans, are large diurnal primates and show many of the same physiological and behavioral circadian changes during aging. Consequently, they represent an ideal translational animal model in which to study the causes and consequences of age-associated internal circadian disruption and in which to evaluate novel therapies. PMID- 22198674 TI - Generation and characterization of orthotopic murine models for endometrial cancer. AB - We describe the generation of two orthotopic murine models for endometrial cancer (EC).The first model is generated from endometrial Hec-1A cancer cells transfected with luciferase and injected directly into the uterus of female mice. This model allows a follow-up with bioluminescence imaging (BLI) along the experiment and generates abdominal dissemination and lymphatic and hematogenous metastases in high percentages, also detectables with BLI. The dissemination pattern of this model imitates the advanced stages of EC in patients, and its molecular profile corresponds to aggressive type 2 EC (p53 positive, hormone receptors negative, high percentage of Ki67 positive cells). The second model is derived from endometrioid human tissue collected from surgical pieces. By injecting this tissue inside the uterine cavity of a mouse we obtain orthotopic growth with pelvic dissemination and lymph node metastasis. The molecular pattern observed in human type 1 endometrioid EC (p53 negative, low Ki67 index, presence of hormone receptors) is conserved after the murine growth in orthotopic tumor and metastases. This model supposes a singular pre-clinical tool to study therapeutic agents, though it mimics clinical and molecular behavior of endometrioid EC, which is the most common histology in the patient. PMID- 22198675 TI - Early versus late administration of pegfilgrastim after high-dose chemotherapy and autologous hematopoietic stem cell transplantation. AB - PURPOSE: Single-dose pegylated filgrastim (pegfilgrastim) after autologous hematopoietic stem cell transplantation (AHSCT) showed similar efficacy compared to daily lenograstim. To address the question of the optimal application time, we randomly assigned patients (pts) to pegfilgrastim on day + 1 (Peg1) or day + 4 (Peg4) after AHSCT. METHOD: Fifty-three pts with different hematological malignancies were included in this prospective randomized multicenter study. Primary endpoint of this study was time to neutrophil recovery (>500 Gpt/l), and secondary endpoint was time to neutrophil recovery (>1,000 Gpt/l), platelet recovery (>20,000 Gpt/l), number and duration of febrile episodes, i.v. antibiotics, and number of transfusions. Time to engraftment endpoints were estimated according to Kaplan-Meier. RESULTS: Median time to neutrophil recovery (>500 Gpt/l) was 10 days (95% CI: 10-11) in Peg1 versus 10 days (95% CI: 10-11) in Peg4 (P = 0.68, logrank test; hazard ratio: 0.93). The corresponding mean values were 10.2 and 10.4 days. Median time to platelet recovery (>20,000 Gpt/l) was 10 (95% CI: 10-11) in Peg1 versus 10 (95% CI: 9-11) in Peg4, again not significantly different (P = 0.54). There was no difference regarding the incidence (67% vs. 60%, P = 0.77, Fisher's exact test) or duration of febrile neutropenia episodes in both groups (median: 1 vs. 1; mean: 2.8 vs. 2.4 days; P = 0.73, Wilcoxon test). CONCLUSION: In terms of neutrophil or platelet recovery after AHSCT, number and duration of febrile episodes, the use of i.v. antibiotics, early and late administration of pegfilgrastim are equally effective. PMID- 22198676 TI - Expressions of MAGE-A10 and MAGE-A11 in breast cancers and their prognostic significance: a retrospective clinical study. AB - PURPOSE: Melanoma-associated antigens-A (MAGE-A) family is a group of well characterized cancer/testis antigens (CTA), because they are strictly tumor specific and are shared by many kinds of tumors. However, the expression pattern of MAGE-A10 and MAGE-A11 in breast cancer patients is still unclear. The purpose of our study is to investigate the expression pattern and prognostic significance of MAGE-A10 and MAGE-A11 in breast cancer patients. METHODS: Formalin-fixed and paraffin-embedded tissues and the clinicopathological parameters from 75 primary breast cancer patients were collected. The expressions of MAGE-A10 and MAGE-A11 proteins were immunohistochemically detected, and the association of MAGE-A10 and MAGE-A11 expressions with the clinicopathological parameters and the survival of breast cancer patients were analyzed. RESULTS: The expression rates of MAGE-A10 and MAGE-A11 in breast cancer specimens were 73.3 and 52.0%, respectively. MAGE A11 expression was more frequent in estrogen-receptor (ER)-positive breast carcinomas compared with ER-negative breast carcinomas (P = 0.004). MAGE-A11 expression was positively associated with HER-2 expression (P = 0.003). Overall survival of patients with MAGE-A11-negative expression was significantly longer than those patients with positive MAGE-A11 expression (P = 0.030), but no difference of overall survival was found between patients with MAGE-A10-negative and -positive expression (P = 0.881). CONCLUSIONS: MAGE-A10 and MAGE-A11 are tumor-specific antigens, and MAGE-A11 expression probably is a potential poor prognostic factor for breast cancer patients. PMID- 22198678 TI - Functional neuroimaging studies in addiction: multisensory drug stimuli and neural cue reactivity. AB - Neuroimaging studies on cue reactivity have substantially contributed to the understanding of addiction. In the majority of studies drug cues were presented in the visual modality. However, exposure to conditioned cues in real life occurs often simultaneously in more than one sensory modality. Therefore, multisensory cues should elicit cue reactivity more consistently than unisensory stimuli and increase the ecological validity and the reliability of brain activation measurements. This review includes the data from 44 whole-brain functional neuroimaging studies with a total of 1168 subjects (812 patients and 356 controls). Correlations between neural cue reactivity and clinical covariates such as craving have been reported significantly more often for multisensory than unisensory cues in the motor cortex, insula and posterior cingulate cortex. Thus, multisensory drug cues are particularly effective in revealing brain-behavior relationships in neurocircuits of addiction responsible for motivation, craving awareness and self-related processing. PMID- 22198677 TI - Bridging a yawning chasm: EEG investigations into the debate concerning the role of the human mirror neuron system in contagious yawning. AB - Ongoing debate in the literature concerns whether there is a link between contagious yawning and the human mirror neuron system (hMNS). One way of examining this issue is with the use of the electroencephalogram (EEG) to measure changes in mu activation during the observation of yawns. Mu oscillations are seen in the alpha bandwidth of the EEG (8-12 Hz) over sensorimotor areas. Previous work has shown that mu suppression is a useful index of hMNS activation and is sensitive to individual differences in empathy. In two experiments, we presented participants with videos of either people yawning or control stimuli. We found greater mu suppression for yawns than for controls over right motor and premotor areas, particularly for those scoring higher on traits of empathy. In a third experiment, auditory recordings of yawns were compared against electronically scrambled versions of the same yawns. We observed greater mu suppression for yawns than for the controls over right lateral premotor areas. Again, these findings were driven by those scoring highly on empathy. The results from these experiments support the notion that the hMNS is involved in contagious yawning, emphasise the link between contagious yawning and empathy, and stress the importance of good control stimuli. PMID- 22198679 TI - Aerosolized amikacin in patients with difficult-to-treat pulmonary nontuberculous mycobacteriosis. AB - Patients with pulmonary nontuberculous mycobacteriosis (pNTM) may have suboptimum response to conventional antimicrobial therapy. Aerosolized amikacin (aeAmk) was given to nine patients who had failed standard combination oral antimycobacterial drugs. A favorable toxicity profile, even in patients given aeAmk for an extended duration, median 75 +/- 85 (range, 18-277) days and total cumulative dose 35,400 +/- 30,568 (range, 7,600-95,400) mg, was encouraging, as was the clinical response and resolution of symptoms in 8 of 9 patients. The patient who failed therapy died due to complications arising from prior hematopoietic transplantation. The feasibility and efficacy of aeAmk in combination with oral anti-NTM drug(s) for treatment-refractory disease and, importantly, in primary therapy for pNTM requires validation randomized trials. PMID- 22198680 TI - Characterizing the pregnancy immune phenotype: results of the viral immunity and pregnancy (VIP) study. AB - PURPOSE: The increased risk of morbidity and mortality from certain microbial infections and the demonstrated improvements in the clinical course of some autoimmune diseases support the existence of pregnancy-related alterations in immune status. Elucidating the changes in innate and adaptive immunity during gestation may improve pregnancy outcomes and facilitate the development of targeted therapies for autoimmune diseases. METHOD: The Viral Immunity and Pregnancy (VIP) study evaluated over 50 subjects longitudinally at three time points during pregnancy and at two time points post-delivery. Leukocyte enumeration was performed; functional responses of NK cells and CD4 T cells were analyzed, and soluble factors such as cytokines, defensins, and steroid hormones were measured in maternal blood. RESULTS: In comparison to the post-partum period, the latter part of pregnancy was characterized by significant increases in blood phagocytes and pDCs and decreases in the number and activity of NK and T cells. Alterations were found in antimicrobial proteins and serum cytokines. CONCLUSIONS: These data show that pregnancy is not a period of immunosuppression but an alteration in immune priorities characterized by a strengthening of innate immune barriers and a concomitant reduction in adaptive/inflammatory immunity in the later stages of pregnancy. PMID- 22198681 TI - PI3K-gamma inhibition ameliorates acute lung injury through regulation of IkappaBalpha/NF-kappaB pathway and innate immune responses. AB - BACKGROUND: Acute lung injury (ALI) is a devastating disorder of the lung by various causes and its cardinal features are tissue inflammation, pulmonary edema, low lung compliance, and widespread capillary leakage. Among phosphoinositide 3-kinases (PI3Ks), PI3K-gamma isoform has been shown to play an important role in a number of immune/inflammatory responses. METHODS: We investigated the role of PI3K-gamma and its molecular basis in lipopolysaccharide (LPS)-induced ALI using a selective inhibitor for PI3K-gamma, AS 605240, and LPS treated C57BL/6 mice. RESULTS: Treatment of mice with LPS showed an increase of lung inflammation and vascular leakage. Production of reactive oxygen species (ROS), interleukin (IL)-1beta, tumor necrosis factor-alpha, and IL-4, adhesion molecule, and vascular endothelial growth factor (VEGF) was also increased. Administration of AS 605240 to LPS-treated mice markedly reduced the pathophysiological features of ALI and the increased production of ROS, cytokines, adhesion molecule, and VEGF in the lung. Our results also showed that treatment of mice with LPS activates nuclear factor-kappaB (NF-kappaB) and degradation of inhibitory kappaBalpha (IkappaBalpha) through PI3K-gamma. Additionally, infiltration of dendritic cells (DCs) and expression of toll-like receptor 4 (TLR4) were significantly increased in the lung of LPS-treated mice, and inhibition of PI3K-gamma reduced the infiltration of DCs and TLR4 expression in the lung. CONCLUSIONS: These results indicate that PI3K-gamma is critically involved in LPS-induced ALI by regulating IkappaBalpha/NF-kappaB pathway and innate immune responses. Based on our data, we suggest that PI3K-gamma isoform is a promising target for the treatment of ALI. PMID- 22198682 TI - Hox in space: gene cluster regulation linked to folding of chromatin. AB - The spatial folding of chromatin has been proposed to be involved in the regulation and coordination of gene expression. The mammalian Hox gene clusters form a particularly interesting case of coordinated gene regulation. Within each Hox cluster, the linear order of the genes closely reflects their temporal and anatomical expression pattern. This striking phenomenon suggests that the overall structure of the Hox clusters is important for their regulation. Recent studies employing chromatin conformation capture techniques indicate that Hox clusters adopt a remarkable spatial configuration, in which active and inactive genes are segregated into two distinct chromatin compartments. Here we discuss the possible underlying mechanisms and regulatory roles of this spatial compartmentalization. PMID- 22198683 TI - The liquid drop nature of nucleoli. AB - Nucleoli are prominent subnuclear organelles, and are known to be hubs of ribosome synthesis. A recent study of Brangwynne et al. reports that the nucleoli of Xenopus oocytes display "liquid drop" behavior, suggesting that nucleolar structure may be driven by rather simple physical principles. PMID- 22198685 TI - An explicit solution for progress curve analysis in systems characterized by endogenous substrate production. AB - The Lambert W function was used to explicitly relate substrate concentration S, to time t, and the kinetic parameters V (m), K (m), and R in the modified Michaelis-Menten equation that accounts for endogenous substrate production. The applicability of this explicit formulation for kinetic parameter estimation by progress curve analysis was demonstrated using a combination of synthetic and experimental substrate depletion data. Synthetic substrate depletion data were generated using S (0) values of 1, 2, and 3 MUM and V (m), K (m), and R values of 1.0 MUM h(-1), 1.0 MUM, and 0.1 MUM h(-1), respectively, and contained 5% normally distributed error. Experimental data were obtained from two previously published studies on hydrogen depletion in four experimental systems. In all instances, experimental data were well described by the explicit solution presented in this study. Differential equation solution and iterative S estimation are eliminated with the explicit solution approach, thereby simplifying progress curve analysis in systems characterized by endogenous substrate production. PMID- 22198684 TI - The nuclear envelope protein Nesprin-2 has roles in cell proliferation and differentiation during wound healing. AB - Nesprin-2, a type II transmembrane protein of the nuclear envelope, is a component of the LINC complex that connects the nuclear lamina with the actin cytoskeleton. To elucidate its physiological role we studied wound healing in Nesprin-2 Giant deficient mice and found that a loss of the protein affected wound healing particularly at later stages during fibroblast differentiation and keratinocyte proliferation leading to delayed wound closure. We identified altered expression and localization of transcription factors as one of the underlying mechanisms. Furthermore, the actin cytoskeleton which surrounds the nucleus was altered and keratinocyte migration was slowed down and focal adhesion formation enhanced. We also uncovered a new activity of Nesprin-2. When we probed for an interaction of Nesprin-2 Giant with chromatin we observed in ChIP Seq experiments an association of the protein with heterochromatic and centromeric DNA. Through this activity Nesprin-2 can affect the nuclear landscape and gene regulation. Our findings suggest functions for Nesprin-2 at the nuclear envelope (NE) in gene regulation and in regulation of the actin cytoskeleton which impact on wound healing. PMID- 22198686 TI - Expression of brain-derived neurotrophic factor is regulated by the Wnt signaling pathway. AB - Brain-derived neurotrophic factor (BDNF) is a well characterized neurotrophin that mediates a wide variety of activities in the central nervous system, including neuronal differentiation, neuroprotection, and synaptic plasticity. The canonical Wnt signaling pathway is a critical regulator of embryonic development and homeostasis in adult tissues. Our group and others recently demonstrated that Wnt signaling induces BDNF expression in neurons and glia. However, the precise relationship between BDNF and Wnt signaling pathways is not understood. Here, we investigated Wnt signaling regulation of BDNF at the transcriptional level using a combination of bioinformatics and molecular analyses. Analysis of the BDNF gene promoter identified seven binding motifs for Wnt-dependent TCF/LEF transcription factors. Furthermore, specific BDNF promoters were induced by the Wnt3a ligand using chloramphenicol acetyl transferase reporter assays and a dominant-negative TCF4 gene reduced Wnt3a-mediated induction. Finally, Wnt3a induced expression of BDNF and other members of the BDNF signaling pathway in glia cells. Therefore, these data indicate that BDNF is a direct target of Wnt signaling, which provides a new insight into the interaction between two essential signaling pathways. PMID- 22198687 TI - High-frequency pallidal stimulation eliminates tic-related neuronal activity in a nonhuman primate model of Tourette syndrome. AB - High-frequency deep brain stimulation targeting the output nucleus of the basal ganglia, the globus pallidus internus, has been suggested as a treatment modality for intractable Tourette syndrome and basal-ganglia-mediated motor tics. Recent studies on the modeling of motor tics induced by focal injections of bicuculline to the striatum, a putative model of Tourette syndrome, have shown that tics induce a widespread modulation within both segments of the globus pallidus. The purpose of this study was to investigate, using the bicuculline-induced Tourette syndrome model, whether and how high-frequency deep brain stimulation targeted to the globus pallidus internus could modulate tic-related activity in the pallidum. The perievent rate changes coinciding with tic expression under the on stimulation and off-stimulation conditions were examined to determine the effect of high-frequency stimulation on pallidal activity. The results showed that the stimulation blocked tic-related phasic changes in the firing pattern of pallidal cells in parallel with a reduction of the peak amplitude of tic events in the electromyography record. This finding supports the premise that deep brain stimulation targeted to the globus pallidus internus could be a viable treatment option for Tourette syndrome, and the use of pallidal stimulation for motor tics warrants further study. PMID- 22198688 TI - Decrease in doublecortin expression without neuronal cell death in rat retrosplenial cortex after stress exposure. AB - Exposure to acute stress by forced swim impairs spatial learning and memory in rats. The retrosplenial cortex plays an important role in spatial learning and memory. A cell population that expresses immature neuronal markers, including doublecortin (DCX), plays a key role in plasticity of the adult brain through formation of new neurons. Here, we aimed to determine whether rats exposed to acute stress showed changes in DCX expression in retrosplenial cortex cells. Twelve male Sprague-Dawley rats were used. Six were subjected to acute stress by forced swim (group S), and the remaining six served as controls (group C). Immunohistochemical staining was performed for DCX, neuron-specific nuclear protein, parvalbumin, calbindin, calretinin, and somatostatin. Newly generated cells were immunohistochemically detected by daily administration of 5-bromo-2' deoxyuridine for 1 week. Fluoro-Jade B staining was performed to detect cell death. Group S showed lower number of DCX-expressing cells than group C (P<0.001). The proportion of DCX-expressing cells showing neuron-specific nuclear protein co-localization (24% in group S; 27% in group C) or parvalbumin co localization (65% in group S; 61% in group C) remained unchanged after acute stress exposure. Neither 5-bromo-2'-deoxyuridine-positive nor Fluoro-Jade B positive cells were found in the retrosplenial cortex of groups S and C. DCX expressing cells in the retrosplenial cortex decreases markedly without cell death after acute stress exposure. Neuronal differentiation of these cells toward gamma aminobutyric acidergic interneurons appears to be unaltered. The decrease in DCX expression may reduce plasticity potential within the retrosplenial cortex and attenuate spatial learning and memory function. PMID- 22198689 TI - The discrepancy between clinical and ultrasonographic remission in rheumatoid arthritis is not related to therapy or autoantibody status. AB - To evaluate the clinical remission by means of power Doppler ultrasonographic (PDUS) monitoring in a group of patients with rheumatoid arthritis (RA) in clinical remission (DAS28 < 2.6). The study included 54 patients with RA in therapy with DMARDS, anti-TNF, or no therapy in clinical remission according to ACR criteria and DAS 28 < 2.6 for at least 6 months. All patients had active wrist or hand inflammation in the past. US examination evaluated the presence of active synovitis, power Doppler signal, and synovial hypertrophy on the following bilateral joints: metacarpophalangeal-proximal interphalangeal joints-flexor tendons (on 2 degrees -3 degrees fingers) and wrist (radiocarpal and midcarpal joints). In 19 patients, there was an agreement between clinical and US parameters. However, 35 patients with clinical remission showed a positive ultrasonographic assessment and at least an active parameter. No statistic correlation was found between US examination and antibody assessment (anti-CCP and/or RF). Patients in therapy with anti-TNF or other therapies showed similar US assessment without significant statistical differences. Among eleven patients that presented swollen and tender joints at the latest physical examination, which preceded US exam, just 5 patients had an US confirmation too. In the other patients, the PDUS did not confirm the presence of inflammation in the corresponding swollen and tender joints or showed a positive ultrasonographic assessment in other locations. The remission state is a great therapy target and not only through the biological therapy. Synovial inflammation could persist independently from type of therapy or autoantibody status. PMID- 22198690 TI - Baseline HAQ and SF-36 questionnaire scores cannot predict clinical remission, radiographic progression or the need for biological therapy in a three-year prospective study of a Brazilian early rheumatoid arthritis cohort. AB - This study evaluates prospectively whether baseline scores [Health Assessment Questionnaire (HAQ) and SF-36] can predict clinical and radiographic evolution in a cohort of early rheumatoid arthritis (RA) during a 3-year follow-up. Forty consecutive early RA patients were followed for 3 years, while receiving standardized treatment according to a pre-established protocol. HAQ and SF-36 were administered at the initial evaluation and at 3, 6, 12, 18, 24 and 36 months. Hands and feet radiographs were obtained at the initial evaluation and at 12, 24 and 36 months. Preselected outcomes were the occurrence of radiographic erosions, the achievement of an EULAR remission, low disease activity status and the need for biological therapy. The mean age at onset was 45 years with a 90% female predominance. Erosions were found in 42% of patients at T0 and in 70% after 3 years (P < 0.001). At T0, the proportion of patients in remission, low, moderate or high disease activity was 0, 0, 7.5 and 92.5% and 22.5, 7.5, 32.5 and 37.5%, respectively, at 3 years. The mean baseline HAQ score was 1.89 and 0.77 by the third year (P < 0.0001). Most SF-36 domains showed significant improvement except for general state and vitality. Biological therapy was deemed necessary in 22.5% of patients. The initial HAQ and SF-36 scores were not associated with clinical remission, bone erosions or the need for biological therapy at 36 months. The HAQ and SF-36 scores measured at baseline could not predict at 3 years, the preselected outcomes in a Brazilian cohort. PMID- 22198691 TI - Shock wave therapy for systemic sclerosis. PMID- 22198692 TI - 25-hydroxyvitamin D levels and juvenile idiopathic arthritis: is there an association with disease activity? AB - The aims of this study were to examine the association between serum levels of 25 hydroxyvitamin D [25(OH)D] and disease activity in juvenile idiopathic arthritis (JIA), to determine the prevalence of vitamin D (VD) deficiency [25(OH)D <= 19 ng/ml] and insufficiency [25(OH)D 20-29 ng/ml], and to determine factors associated with lower serum levels of 25(OH)D in this population. In this cross sectional study, disease activity was measured using JADAS-27, as well as its individual components (physician global assessment of disease activity, parent global assessment of child's well-being, count of joints with active disease, and erythrocyte sedimentation rate). Linear regression models were developed to analyze the association between serum 25(OH)D levels and JADAS-27 and to determine variables associated with serum 25(OH)D levels. A total of 154 patients (61% girls, 88% whites) were included. Mean age was 10.6. VD deficiency was detected in 13% and insufficiency in 42%. In univariate and multivariate analyses, 25(OH)D levels were not associated with JADAS-27, neither with its individual components. However, in a subset analysis including all new-onset JIA patients (n = 27), there was a nonsignificant negative correlation between serum 25(OH)D levels and JADAS-27 (r = -0.29, P = 0.14). In the univariate and multivariate analyses, age, ethnicity, BMI, and season were significantly associated with serum 25(OH)D levels, but not total VD intake. More than 1/2 of JIA patients had serum 25(OH)D levels below 29 ng/ml; however, there was no association between serum 25(OH)D levels and disease activity. Future larger, long-term studies with new-onset JIA patients are needed to further explore the association between serum 25(OH)D levels and disease activity. PMID- 22198693 TI - Optic neuritis after infliximab therapy. AB - Demyelinating diseases were described in patients receiving anti-TNF agents. Optic neuritis (ON) induced by TNF blockers was already described in 22 cases in the literature. In this article, the authors report a 53-year-old woman with refractory rheumatoid arthritis that developed neuritis optica after the fourth dose of infliximab and had a good outcome after anti-TNF withdrawal, associated with glucocorticoid treatment. In addition, the previous cases of ON induced by anti-TNF agents were reviewed. PMID- 22198694 TI - Improvement in pain intensity, spine stiffness, and mobility during a controlled individualized physiotherapy program in ankylosing spondylitis. AB - Physical therapy in ankylosing spondylitis (AS) is important for maintaining or improving mobility, fitness, functioning, and global health. It also plays a role in the prevention and management of structural deformities. In this study we assessed the functional status of AS patients in relation to disease duration and activity. Furthermore, in volunteering patients we analyzed the efficacy of a controlled, individualized physiotherapeutic program. Altogether, clinical data of 75 AS patients were retrospectively analyzed. Anthropometrical data, duration since diagnosis and disease activity, pain intensity, tender points, sacroiliac joint involvement determined by X-ray, functional condition, and physical activity level were recorded. Subjective, functional, and physical tests were performed. Out of the 75 patients, 10 volunteered to undergo a complex physical exercise program twice a week for 3 months. The program included 1.5 h of general posture reeducation, manual mobilization of the spine, and pelvic-, upper-, and lower-extremity exercises, stretching with joint prevention strategies and functional exercises. In AS, pain intensity recorded on a 10-cm visual analog scale (VAS), BASFI, BASDAI, modified Schober index, chest expansion and occiput to-wall distance values showed significant correlation with disease activity. The 3-month physical therapy improved several subjective and functional parameters, and markedly reduced pain intensity and spine stiffness. A complex, individualized physical therapy program may be useful and should be introduced to AS patients in order to maintain and increase spine mobility, preserve functional capacity, decrease the pain and stiffness. PMID- 22198695 TI - High expression of tumor-infiltrating macrophages correlates with poor prognosis in patients with diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is characterized by its clinical and biological heterogeneity. Although the International Prognostic Index (IPI) provides a clinical model for risk stratification of patients with DLBCL, notable variability in outcome is still observed within the same IPI category. Tumor infiltrating macrophages (also called Tumor-associated macrophages) are the major component in the microenvironment of DLBCL. Their correlation with the prognosis of DLBCL remains controversial. Using a CD68 antibody in immunohistochemical analysis, we studied the expression of CD68 in 112 Chinese patients with DLBCL, with 65 patients (58%) categorized as low CD68 expression and 47 patients (42%) as high CD68 expression. The complete response (CR) rate of patients with low CD68 expression was higher than that with high CD68 expression (66.1% vs. 51.6%), but there was no statistical significance (P=0.060). The median survival time of patients with low CD68 expression was not achieved and that of high expression was 41 months (P=0.029). The results suggest that higher expression of CD68 tended to yield poor treatment outcome of DLBCL. PMID- 22198696 TI - Anti-Sp17 monoclonal antibody with antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity activities against human ovarian cancer cells. AB - Sperm protein 17 (Sp17) is a cancer testis antigen that has been shown to be overexpressed in a variety of gynecologic malignancies, in particular ovarian cancer. Emerging evidences indicate that Sp17 is involved in tumorigenesis and in the migration of malignant cells. It has been proposed as a useful target for tumor-vaccine strategies and a novel marker to define tumor subsets and predict drug response. However, the antitumor activity of anti-Sp17 monoclonal antibody (anti-Sp17 mAb) has not been investigated. In this study, the in vitro cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) activities of anti-Sp17 mAb were evaluated using Sp17-positive ovarian cancer cells as targets, Sp17-negative ovarian cancer cells as the control, and healthy human peripheral blood monocytes and healthy human serum as effectors. Our preliminary results indicate that the direct cytotoxicity of anti-Sp17 mAb against the investigated ovarian cancer cells was very weak. However, the cytotoxicity of anti-Sp17 mAb, mediated by peripheral blood mononuclear cells (PBMCs), as ADCC, or by human serum, as CDC, was relatively strong in the Sp17-positive ovarian cancer cells. This finding suggested that anti-Sp17 mAb could be a useful tool against ovarian cancer and may provide insight into the development of low side-effect targeting therapy for this malignant disease. PMID- 22198697 TI - Amelioration of age associated neuroinflammation on long term bacosides treatment. AB - Bacopa monnieri (L.) is a revered medicinal plant of traditional Indian system of medicine effective against cognitive impairment in ageing and SDAT. In our previous study, long term administration of bacosides was found to exhibit remarkable anti ageing effect, ameliorate age associated neurochemical and neurobehavioral deficits and prevent hippocampal neuronal degeneration in middle aged and aged rat brain cortex. In continuation to the previous study, the present study aims to investigate the neuroprotective effect of bacosides against age related chronic neuroinflammation in Wistar rat brain on 3 months treatment. Recently, neuroinflammation has gained considerable interest in age associated neurodegeneration and pathologies like SDAT due to its slow onset and chronic nature. The results of the present study demonstrated the significant attenuation of age dependant elevation of pro inflammatory cytokines, iNOS protein expression, total nitrite and lipofuscin content in middle aged and aged rat brain cortex on long term oral administration of bacosides. Thus, the present results suggest that bacosides possess immense potential to act as a neuroprotective agent due to its pleiotropic action for the prevention of ageing complications and SDAT progression. PMID- 22198698 TI - Chronological age impacts immunotherapy and monocyte uptake independent of amyloid load. AB - One vexing issue in biomedical research is the failure of many therapies to translate from success in animal models to effective treatment of human disease. One significant difference between the animal models and the human disease is the age of the subject. Cancer, stroke and Alzheimer's occur mainly in humans beyond the 75% mean survival age, while most mouse models use juvenile or young adult animals. Here we compare two mouse models of amyloid deposition, the Tg2576 APP model and the more aggressive APP+PS1 model in which a mutant presenilin1 gene is overexpressed with Tg2576. Middle-aged APP+PS1 mice and aged APP mice have similar degrees of amyloid pathology with a few differences that may partially explain some of the differences between the two age cohorts. The first study evaluated production of microhemorrhage by a monoclonal anti-Abeta antibody. We found that in spite of greater amyloid clearance in middle-aged APP+PS1 mice than aged APP mice, the microhemorrhage only developed in old animals. This argues that preclinical studies of immunotherapy in young or middle-aged mice may not predict this potential liability in clinical trials. A second study evaluated the infiltration of systemically injected GFP labeled monocytes into the CNS. Here we find that infiltration is greater in aged mice than middle-aged mice, in spite of greater total Abeta staining in the middle-aged animals. We conclude that preclinical studies should be conducted in aged animal models as well as young mice to better prepare for unintended consequences in the human trial. PMID- 22198699 TI - Early minocycline treatment prevents a decrease in striatal dopamine in an SIV model of HIV-associated neurological disease. AB - HIV-infected individuals, even with antiretroviral therapy, often display cognitive, behavioral and motor abnormalities and have decreased dopamine (DA) levels. Minocycline prevents encephalitis and neurodegeneration in SIV models, suggesting that it might also protect against nigrostriatal dopaminergic system dysfunction. Using an SIV/macaque model of HIV-associated CNS disease, we demonstrated that striatal levels of DA were significantly lower in macaques late in infection and that levels of the metabolite DOPAC also tended to be lower. DA levels declined more than its metabolites, indicating a dysregulation of DA production or catabolism. Minocycline treatment beginning at 12 but not 21 days postinoculation prevented striatal DA loss. DA decline was not due to direct loss of dopaminergic projections to the basal ganglia as there was no difference in tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter 2 or synaptophysin between minocycline-treated and untreated macaques. SIV-infected macaques had significantly higher monoamine oxidase (MAO) activity than uninfected macaques, although MAO activity was not affected by minocycline. Oxidative/nitrosative stress was examined by nitrotyrosine staining in the deep white matter and was lower in SIV-infected, minocycline-treated macaques compared with untreated macaques. These data suggest that minocycline, which has antioxidant activity, has a protective effect on DA homeostasis when administered at an appropriate time in SIV neuropathogenesis. PMID- 22198700 TI - Genome architectures revealed by tethered chromosome conformation capture and population-based modeling. AB - We describe tethered conformation capture (TCC), a method for genome-wide mapping of chromatin interactions. By performing ligations on solid substrates rather than in solution, TCC substantially enhances the signal-to-noise ratio, thereby facilitating a detailed analysis of interactions within and between chromosomes. We identified a group of regions in each chromosome in human cells that account for the majority of interchromosomal interactions. These regions are marked by high transcriptional activity, suggesting that their interactions are mediated by transcriptional machinery. Each of these regions interacts with numerous other such regions throughout the genome in an indiscriminate fashion, partly driven by the accessibility of the partners. As a different combination of interactions is likely present in different cells, we developed a computational method to translate the TCC data into physical chromatin contacts in a population of three dimensional genome structures. Statistical analysis of the resulting population demonstrates that the indiscriminate properties of interchromosomal interactions are consistent with the well-known architectural features of the human genome. PMID- 22198701 TI - Identification of suitable reference genes for qPCR analysis of serum microRNA in gastric cancer patients. AB - BACKGROUND: Circulating microRNA expression profiles may be promising biomarkers for diagnosis and assessment of the prognosis of cancer patients. Quantitative polymerase chain reaction (qPCR) is a sensitive technique for estimating expression levels of circulating microRNAs. However, there is no current consensus on the reference genes for qPCR analysis of circulating microRNAs. AIMS: In this study we tried to identify suitable reference genes for qPCR analysis of serum microRNA in gastric cancer patients and healthy individuals. METHODS: Six microRNAs (let-7a, miR-16, miR-93, miR-103, miR-192, and miR-451) and RNU6B were chosen as candidate reference genes on the basis of the literature. Expression levels of these candidates were analyzed by qPCR in serum samples from 40 gastric cancer patients and 20 healthy volunteers. The geNorm, Normfinder, bestkeeper, and comparative delta-Ct method algorithms were used to select the most suitable reference gene from the seven candidates. This was then validated by normalizing the expression levels of serum miR-21 across all gastric cancer patients and healthy volunteers. RESULTS: The algorithms revealed miR-16 and miR-93 were the most stably expressed reference genes, with stability values of 1.778 and 2.213, respectively, for serum microRNA analysis across all the patients and healthy controls. The effect of different normalization strategies was compared; when normalized to the serum volume there were no significant differences between patients and controls. However, when the data were normalized to miR-93, miR-16, or miR-93 and miR-16 combined, significant differences were detected. CONCLUSIONS: Our results demonstrated that reference gene choice for qPCR data analysis has a great effect on the study outcome, and that it is necessary to choose a suitable reference for reliable expression data. We recommend miR-16 and miR-93 as suitable reference genes for serum miRNA analysis for gastric cancer patients and healthy controls. PMID- 22198702 TI - Spiral assisted ERCP is equivalent to single balloon assisted ERCP in patients with Roux-en-Y anatomy. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is often unsuccessful in patients with Roux-en-Y anatomy. Augmented enteroscopy allows deep insertion into the small bowel and can be useful in patients with Roux-en-Y anatomy. The aim of this study was to compare single balloon assisted ERCP (SBE ERCP) and spiral assisted ERCP (SE-ERCP) in patients with Roux-en-Y anatomy in terms of diagnostic and therapeutic yield, procedure time, and complications. METHODS: This is a retrospective cohort study of consecutive patients with Roux en-Y anatomy who underwent SBE-ERCP or SE-ERCP between October 2007 and March 2011. Diagnostic yield was defined as successful duct cannulation. Therapeutic yield was defined as the ability to successfully carry out endoscopic therapy in those cannulated. Procedure time and complications were assessed. RESULTS: Thirty four consecutive patients with Roux-en-Y anatomy underwent 54 ERCP procedures. The overall diagnostic yield was 44.4% with no significant difference between the diagnostic yield of SBE-ERCP (48.3%) and SE-ERCP (40%). The diagnostic yield was lower in patients with gastric by-pass (38.9%) compared with other types of Roux en-Y anatomy (47.2%) but this was not statistically significant (P = 0.772). The overall therapeutic yield was 93.8%, with a therapeutic yield of 100% for SBE ERCP and 87.5% for SE-ERCP (P = 1.0). There was one perforation during SBE-ERCP, giving a complication rate of 3.5%. The mean procedure time did not differ between the two techniques. CONCLUSION: Diagnostic and therapeutic yields are similar with SBE-ERCP and SE-ERCP in patients with Roux-en-Y anatomy with no significant difference in procedure time or complication rates. PMID- 22198703 TI - Lack of significant interactions between clopidogrel and proton pump inhibitor therapy: meta-analysis of existing literature. AB - BACKGROUND: Published data regarding the effect of concomitant clopidogrel and proton pump inhibitor (PPI) therapy on cardiovascular outcomes have been conflicting. AIM: To perform an updated meta-analysis in order to determine changes in risk differences (RD) between primary and secondary outcome analyses. METHODS: Primary analysis was based on definite vascular outcomes, including all cause mortality, cardiac death, myocardial infarction, and/or stroke. Secondary analysis also incorporated probable cardiac events, which included re hospitalization for cardiac symptoms or revascularization procedures. RD were combined using a random-effects model. RESULTS: We reviewed 1,204 publications of which 26 studies (16 published articles, 10 abstracts) met inclusion criteria. The meta-analysis of outcomes from the two randomized controlled trials did not show an increased risk (RD 0.0, 95% CI -0.01, 0.01) for adverse outcomes. The meta-analysis of primary outcomes showed a RD of 0.02 (95% CI 0.01, 0.03) for all studies. The meta-analysis for secondary outcomes yielded a RD of 0.02 (95% CI 0.01-0.04) based on 19 published papers and abstracts. When primary and secondary outcomes were combined, the meta-analysis for published papers yielded an overall RD of 0.05 (95% CI 0.03-0.06). CONCLUSIONS: In patients using concomitant clopidogrel and PPI therapy, the risk of adverse cardiac outcomes was 0% based on data from well-controlled randomized trials. Data from retrospective studies and the addition of probable vascular events significantly increased the RD estimates, likely due to lack of adjustment for potential confounders. PMID- 22198705 TI - Optimal duration of proton pump inhibitor for healing artificial ulcers after endoscopic submucosal dissection for early gastric cancer. PMID- 22198704 TI - Use of nucleoside (tide) analogues in patients with hepatitis B-related acute liver failure. AB - BACKGROUND AND AIMS: The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remains controversial. We determined retrospectively the impact of NAs in a large cohort of patients with HBV-ALF. METHODS: The US Acute Liver Failure Study Group, a 23 site registry, prospectively enrolled 1,413 patients with ALF with different etiologies between 1998 and 2008. Of those, 105 patients were identified as HBV ALF patients, of whom we excluded those without data on NA use or with co infection with hepatitis C, leaving 85 patients, 43 of whom had received NA treatment. HBV-DNA on admission was quantified by real time polymerase chain reaction. RESULTS: The treated and untreated groups were similar in most respects but differed significantly in regard to higher aminotransferase and bilirubin levels and hepatic coma grades, all being observed in the untreated group. Median duration of NA treatment was 6 days (range, 1-21 days). Overall survival in the NA treated and untreated groups were 61 and 64%, respectively (P = 0.72). Rates of transplant-free survival were 21 and 36% in the treated and untreated groups, respectively (P = 0.42). Multivariate analysis revealed that not using a NA [odds ratio (OR) 4.4, 95% CI 1.1-18.1, P = 0.041], hepatic coma grade I or II [OR 14.4, 95% CI 3.3-62.8, P < 0.001] and prothrombin time (PT) [OR 0.59, 95% CI 0.39-0.89, P = 0.012] were predictors of improved transplant-free survival. CONCLUSIONS: Patients who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analogues presumably because of rapid disease evolution and short treatment duration. Despite the lack of benefit, NAs should still be given to transplantation candidates since viral suppression prevents recurrence after grafting. PMID- 22198706 TI - The complex intratumoral heterogeneity of colon cancer highlighted by laser microdissection. AB - AIMS: To evaluate the utility of laser microdissection in the comparison of phenotypes and genetic alterations between colon cancer and corresponding liver metastasis in the context of intratumoral heterogeneity. METHODS: Immunohistochemistry was performed on a series of 11 patients surgically treated for colon adenocarcinoma with liver metastases, using antibodies directed against six mucins. Immunohistochemistry was completed by laser microdissection of tumor zones with particular phenotype, luminal zone and invasion front of colon tumors. Microdissected samples were compared on the basis of microsatellite instability and alterations of CTNNB1, KRAS, and TP53. RESULTS: Our study demonstrated varying mucin expression within tumors, suggesting the existence of phenotypic intratumoral heterogeneity. A common immunohistochemical profile was observed in individual tumors between tumoral subpopulations and corresponding metastases. Nevertheless, the phenotypic characteristics were distinct from one patient to another. Laser microdissection underlined that phenotypic heterogeneity could rely on genotypic heterogeneity, and that some genetic alterations were common to microdissected samples from primary colon tumors and liver metastases. CONCLUSION: We illustrated intratumoral heterogeneity of colon cancer using laser microdissection, in combination with immunohistochemical and genotypic tools. This intratumoral heterogeneity could represent a major issue in the search of prognostic biomarkers. PMID- 22198707 TI - The neurotoxic potential of engineered nanomaterials. AB - The expanding development and production of engineered nanomaterials (ENMs) have diverse and far-reaching potential benefits in consumer products, food, drugs, medical devices and for enhancing environmental cleanup and remediation. The knowledge of potential implications of ENMs, including the potential for inadvertent exposures and adverse neurotoxic consequences, is lagging behind their development. A potential risk for neurotoxicity arises if exposure leads to systemic absorption and distribution to the nervous system. This paper is the summary of a symposium entitled Neurotoxicity Potential of Engineered Nanomaterials presented at the 2011 Xi'an International Neurotoxicology Conference held June 5-9 in Xi'an China. The following topics were featured in the symposium: the toxicokinetics of engineered nanomaterials; differential uptake of nanoceria in brain and peripheral organs; translocation into the brain and potential damage following nanoparticle exposure; and the retina as a potential site of nanomaterial phototoxicity. Each of these topics is discussed fully in sections of the manuscript. The promising benefits of ENM technology can be best realized if the potential risks are first understood and then minimized in product and system designs. PMID- 22198708 TI - Barriers in the developing brain and Neurotoxicology. AB - The brain develops and grows within a well-controlled internal environment that is provided by cellular exchange mechanisms in the interfaces between blood, cerebrospinal fluid and brain. These are generally referred to by the term "brain barriers": blood-brain barrier across the cerebral endothelial cells and blood CSF barrier across the choroid plexus epithelial cells. An essential component of barrier mechanisms is the presence of tight junctions between the endothelial and epithelial cells of these interfaces. This review outlines historical evidence for the presence of effective barrier mechanisms in the embryo and newborn and provides an up to date description of recent morphological, biochemical and molecular data for the functional effectiveness of these barriers. Intercellular tight junctions between cerebral endothelial cells and between choroid plexus epithelial cells are functionally effective as soon as they differentiate. Many of the influx and efflux mechanisms are not only present from early in development, but the genes for some are expressed at much higher levels in the embryo than in the adult and there is physiological evidence that these transport systems are functionally more active in the developing brain. This substantial body of evidence supporting the concept of well developed barrier mechanisms in the developing brain is contrasted with the widespread belief amongst neurotoxicologists that "the" blood-brain barrier is immature or even absent in the embryo and newborn. A proper understanding of the functional capacity of the barrier mechanisms to restrict the entry of harmful substances or administered therapeutics into the developing brain is critical. This knowledge would assist the clinical management of pregnant mothers and newborn infants and development of protocols for evaluation of risks of drugs used in pregnancy and the neonatal period prior to their introduction into clinical practice. PMID- 22198709 TI - Analysis of shade, temperature and hydrogen peroxide concentration during dental bleaching: in vitro study with the KTP and diode lasers. AB - Many dental bleaching techniques are now available, several of them using a laser source. However, the literature on the exact role of coherent light in the biochemical reaction of the whitening process is very discordant. The aims of this in vitro study were: (1) to compare two different laser sources, a KTP laser with a wavelength of 532 nm and a diode laser with a wavelength of 808 nm, during dental bleaching, and (2) to investigate the relationships among changes in gel temperature, tooth shade and hydrogen peroxide (HP) concentration during laser irradiation. Altogether, 116 bovine teeth were bleached using a 30% HP gel, some of them with gel only and others with gel plus one of the two lasers (532 or 808 nm) at two different powers (2 and 4 W). The KTP laser produced a significant shade variation with a minimal temperature increase. The diode laser led to a higher temperature increase with a greater reduction in HP concentration, but the change in shade was only statistically significant with a power of 4 W. At a power of 2 W, the KTP laser caused a greater change in shade than the diode laser. No significant correlations were found among temperature, HP concentration and shade variation. The KTP laser appears to provide better results with less dangerous thermal increases than the diode laser. This might call into question most of the literature affirming that the action of laser bleaching is by increasing the gel temperature and, consequently, the speed of the redox reaction. Further study is required to investigate the correlations between the parameters investigated and efficacy of the bleaching process. PMID- 22198710 TI - Respiratory and non-respiratory sinus arrhythmia: implications for heart rate variability. AB - The quantity of blood arriving at the left side of the heart oscillates throughout the breathing cycle due to the mechanics of breathing. Neurally regulated fluctuations in the length of the heart period act to dampen oscillations of the left ventricular stroke volume entering the aorta. We have reported that stroke volume oscillations but not spectral frequency variability stroke volume measures can be used to estimate the breathing frequency. This study investigated with the same recordings whether heart period oscillations or spectral heart rate variability measures could function as estimators of breathing frequency. Continuous 270 s cardiovascular recordings were obtained from 22 healthy adult volunteers in the supine and upright postures. Breathing was recorded simultaneously. Breathing frequency and heart period oscillation frequency were calculated manually, while heart rate variability spectral maximums were obtained using heart rate variability software. These estimates were compared to the breathing frequency using the Bland-Altman agreement procedure. Estimates were required to be < +/-10% (95% levels of agreement). The 95% levels of agreement measures for the heart period oscillation frequency (supine: -27.7 to 52.0%, upright: -37.8 to 45.9%) and the heart rate variability spectral maximum estimates (supine: -48.7 to 26.5% and -56.4 to 62.7%, upright: 37.8 to 39.3%) exceeded 10%. Multiple heart period oscillations were observed to occur during breathing cycles. Both respiratory and non-respiratory sinus arrhythmia was observed amongst healthy adults. This observation at least partly explains why heart period parameters and heart rate variability parameters are not reliable estimators of breathing frequency. In determining the validity of spectral heart rate variability measurements we suggest that it is the position of the spectral peaks and not the breathing frequency that should be the basis of decision making. PMID- 22198712 TI - Acute upper gastrointestinal bleeding: identifying low risk patients. PMID- 22198711 TI - Spasmolytic polypeptide-expressing metaplasia (SPEM) in the gastric oxyntic mucosa does not arise from Lgr5-expressing cells. AB - OBJECTIVE: Metaplastic lineages in the oxyntic mucosa of the stomach are critical preneoplastic precursors of gastric cancer. Recent studies have demonstrated that spasmolytic polypeptide-expressing metaplasia (SPEM) in the mouse oxyntic mucosa arises from transdifferentiation of mature gastric chief cells. Other investigations of intestinal progenitor cells have shown that cells demonstrating transcriptional activity for leucine-rich repeat containing G-protein-coupled receptor 5 (Lgr5) in the intestine, colon and gastric antrum function as adult stem cells. We have now investigated whether cells demonstrating Lgr5 transcriptional activity in the oxyntic mucosa of mice might be responsible for development of metaplasia. DESIGN: Lgr5-EGFP-IRES-Cre(ERT2/+);Rosa26R mice were used to examine the distribution of Lgr5 transcriptionally active cells in the normal oxyntic mucosa as well as after treatment with DMP-777 or L-635 to induce acute SPEM. Lineage mapping was performed to determine if Lgr5-expressing cells gave rise to SPEM. RESULTS: Cells expressing transcriptional activity for Lgr5 in the oxyntic mucosa were present as scattered rare cells only along the lesser curvature of the stomach. These cells also stained for markers of chief cells (intrinsic factor and pepsinogen) but never showed any staining for proliferative markers (Ki-67). In Lgr5-EGFP-IRES-Cre(ERT2/+);Rosa26R mice induced with tamoxifen, treatment with either DMP-777 or L-635 to induce acute oxyntic atrophy caused induction of SPEM, but no lineage mapping into SPEM from Lgr5-expressing cells was observed. CONCLUSION: The results indicate that, while chief cells with Lgr5 transcriptional activity are present along the lesser curvature of the gastric oxyntic mucosa, they are not responsible for production of metaplasia. PMID- 22198713 TI - Hepatic cell-to-cell transmission of small silencing RNA can extend the therapeutic reach of RNA interference (RNAi). AB - BACKGROUND/AIMS: RNA interference (RNAi), a sequence-specific gene silencing technology triggered by small interfering RNA (siRNA), represents promising new avenues for treatment of various liver diseases including hepatitis C virus (HCV) infection. In plants and invertebrates, RNAi provides an important mechanism of cellular defence against viral pathogens and is dependent on the spread of siRNA to neighbouring cells. A study was undertaken to investigate whether vector delivered RNAi can transfer between hepatic cells in vitro and in mice, and whether this exchange could extend the therapeutic effect of RNAi against HCV infection. METHODS: Transmission of RNAi was investigated in culture by assessing silencing of HCV replication and expression of viral entry receptor CD81 using a human hepatic cell line and primary B lymphocytes transduced with siRNA expressing vectors. In vivo transmission between hepatic cells was investigated in NOD/SCID mice. Involvement of exosomes was demonstrated by purification, uptake and mass spectrometric analysis. RESULTS: Human and mouse liver cells, as well as primary human B cells, were found to have the ability to exchange small RNAs, including cellular endogenous microRNA and delivered siRNA targeting HCV or CD81. The transmission of RNAi was largely independent of cell contact and partially mediated by exosomes. Evidence of RNAi transmission in vivo was observed in NOD/SCID mice engrafted with human hepatoma cells producing CD81 siRNA, causing suppression of CD81 expression in mouse hepatocytes. CONCLUSION: Both human and mouse hepatic cells exchange small silencing RNAs, partially mediated by shuttling of exosomes. Transmission of siRNA potentially extends the therapeutic reach of RNAi-based therapies against HCV as well as other liver diseases. PMID- 22198714 TI - Burden of colonoscopy compared to non-cathartic CT-colonography in a colorectal cancer screening programme: randomised controlled trial. AB - OBJECTIVE: CT-colonography has been suggested to be less burdensome for primary colorectal cancer (CRC) screening than colonoscopy. To compare the expected and perceived burden of both in a randomised trial. DESIGN: 8844 Dutch citizens aged 50-74 years were randomly invited for CRC screening with colonoscopy (n=5924) or CT-colonography (n=2920). Colonoscopy was performed after full colon lavage, or CT-colonography after limited bowel preparation (non-cathartic). All invitees were asked to complete the expected burden questionnaire before the procedure. All participants were invited to complete the perceived burden questionnaire 14 days later. Mean scores were calculated on 5-point scales. RESULTS: Expected burden: 2111 (36%) colonoscopy and 1199 (41%) CT-colonography invitees completed the expected burden questionnaire. Colonoscopy invitees expected the bowel preparation and screening procedure to be more burdensome than CT-colonography invitees: mean scores 3.0+/-1.1 vs 2.3+/-0.9 (p<0.001) and 3.1+/-1.1 vs 2.2+/-0.9 (p<0.001). Perceived burden: 1009/1276 (79%) colonoscopy and 801/982 (82%) CT colonography participants completed the perceived burden questionnaire. The full screening procedure was reported as more burdensome in CT-colonography than in colonoscopy: 1.8+/-0.9 vs 2.0+/-0.9 (p<0.001). Drinking the bowel preparation resulted in a higher burden score in colonoscopy (3.0+/-1.3 vs 1.7+/-1.0, p<0.001) while related bowel movements were scored more burdensome in CT colonography (2.0+/-1.0 vs 2.2+/-1.1, p<0.001). Most participants would probably or definitely take part in a next screening round: 96% for colonoscopy and 93% for CT-colonography (p=0.99). CONCLUSION: In a CRC screening programme, colonoscopy invitees expected the screening procedure and bowel preparation to be more burdensome than CT-colonography invitees. In participants, CT-colonography was scored as more burdensome than colonoscopy. Intended participation in a next screening round was comparable. PMID- 22198715 TI - NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis. AB - BACKGROUND: Liver fibrosis, which involves activation of hepatic stellate cells (HSC), is a major health problem and is the end outcome of all chronic liver diseases. The liver is populated with lymphocytes, among which are natural killer (NK) cells, whose activity is controlled by inhibitory and activating receptors. NKp46, one of the major NK activating receptors expressed by NK cells, is also a specific NK marker that discriminates NK cells from all other lymphocyte subsets. It recognises viral haemagglutinins and unknown cellular ligands. METHODS: The anti-fibrotic activity of the NKp46 receptor was assessed in vivo and in vitro using NKp46-deficient mice (NCR1(gfp/gfp)), the carbon tetrachloride model and in vitro NK killing assays. Primary murine and human HSC were stained for the expression of the NKp46 ligand using fusion proteins composed of the extracellular portions of the murine and human NKp46 receptors fused to human IgG1. RESULTS: It was shown that murine HSC express a ligand for the murine orthologue of the NKp46 receptor, NCR1. NCR1 inhibited liver fibrosis in vivo; in vitro, murine HSC were killed in an NCR1-dependent manner. In humans it was shown that human HSC also express a ligand for the human NKp46 receptor and that the killing of human HSC is NKp46 dependent. CONCLUSIONS: In addition to NKG2D, NKp46/NCR1 play an important role in inhibition of liver fibrosis. This suggests that fibrosis can be better controlled through the manipulation of NKp46 activity. PMID- 22198716 TI - MALDI-TOF MS in microbiological diagnostics-identification of microorganisms and beyond (mini review). AB - Few developments in microbiological diagnostics have had such a rapid impact on species level identification of microorganisms as matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). Conventional differentiation methods rely on biochemical criteria and require additional pre-testing and lengthy incubation procedures. In comparison, MALDI TOF MS can identify bacteria and yeast within minutes directly from colonies grown on culture plates. This radically new, methodically simple approach profoundly reduces the cost of consumables and time spent on diagnostics. The reliability and accuracy of the method have been demonstrated in numerous studies and different systems are already commercially available. Novel applications of the system besides microbial species level identification are also being explored. This includes identification of pathogens from positive blood cultures or directly from patient samples, such as urine. Currently, intriguing MALDI-TOF MS developments are being made regarding the phenotypic detection of certain antibiotic resistance mechanisms, e.g., beta-lactamases and carbapenemases. This mini review provides an overview of the literature in the field and also includes our own data and experiences gathered from over 4 years of routine MALDI-TOF MS use in a university hospital's microbiological diagnostics facility. PMID- 22198717 TI - In search of sustainable chemical processes: cloning, recombinant expression, and functional characterization of the 7alpha- and 7beta-hydroxysteroid dehydrogenases from Clostridium absonum. AB - Nicotinamide adenine dinucleotide phosphate-dependent 7alpha-hydroxysteroid dehydrogenase (7alpha-HSDH) and 7beta-hydroxysteroid dehydrogenases (7beta-HSDH) from Clostridium absonum catalyze the epimerization of primary bile acids through 7-keto bile acid intermediates and may be suitable as biocatalysts for the synthesis of bile acids derivatives of pharmacological interest. C. absonum 7alpha-HSDH has been purified to homogeneity and the N-terminal sequence has been determined by Edman sequencing. After PCR amplifications of a gene fragment with degenerate primers, cloning of the complete gene (786 nt) has been achieved by sequencing of C. absonum genomic DNA. The sequence coding for the 7beta-HSDH (783 nt) has been obtained by sequencing of the genomic DNA region flanking the 5' termini of 7alpha-HSDH gene, the two genes being contiguous and presumably part of the same operon. After insertion in suitable expression vectors, both HSDHs have been successfully produced in recombinant form in Escherichia coli, purified by affinity chromatography and submitted to kinetic analysis for determination of Michaelis constants (K (m)) and specificity constants (k (cat)/K (m)) in the presence of various bile acids derivatives. Both enzymes showed a very strong substrate inhibition with all the tested substrates. The lowest K (S) values were observed with chenodeoxycholic acid and 12-ketochenodeoxycholic acid as substrates in the case of 7alpha-HSDH, whereas ursocholic acid was the most effective inhibitor of 7beta-HSDH activity. PMID- 22198718 TI - Characterization of a thermostable beta-glucuronidase from Thermotoga maritima expressed in Arabidopsis thaliana. AB - TmGUSI, a gene identical to that encoding a thermostable beta-glucuronidase in the hyperthermophilic anaerobe Thermotoga maritima, has been synthesized using a PCR-based two-step DNA synthesis and codon optimization for plants, and expressed in both Escherichia coli and Arabidopsis thaliana. TmGUSI expressed in transformed E. coli cells exhibited maximum hydrolytic activity at 65 degrees C and pH 6.5 and retained more than 80% activity after incubation at 85 degrees C for 30 min. TmGUSI activity in transgenic A. thaliana plants containing TmGUSI was also stable over the temperature range 65-80 degrees C. Our data suggest that beta-glucuronidase from T. maritima can serve as a useful thermostable marker in higher plants. PMID- 22198719 TI - Synthesis of heparosan oligosaccharides by Pasteurella multocida PmHS2 single action transferases. AB - Pasteurella multocida heparosan synthase PmHS2 is a dual action glycosyltransferase that catalyzes the polymerization of heparosan polymers in a non-processive manner. The two PmHS2 single-action transferases, obtained previously by site-directed mutagenesis, have been immobilized on Ni(II) nitrilotriacetic acid agarose during the purification step. A detailed study of the polymerization process in the presence of non-equal amounts of PmHS2 single action transferases revealed that the glucuronyl transferase (PmHS2-GlcUA(+)) is the limiting catalyst in the polymerization process. Using experimental design, it was determined that the N-acetylglucosaminyl transferase (PmHS2-GlcNAc(+)) plays an important role in the control of heparosan chain elongation depending on the number of heparosan chains and the UDP-sugar concentrations present in the reaction mixture. Furthermore, for the first time, the synthesis of heparosan oligosaccharides alternately using PmHS2-GlcUA(+) and PmHS2-GlcNAc(+) is reported. It was shown that the synthesis of heparosan oligosaccharides by PmHS2 single-action transferases do not require the presence of template molecules in the reaction mixture. PMID- 22198720 TI - Effects of MAOA promoter methylation on susceptibility to paranoid schizophrenia. AB - This study was undertaken to analyze DNA methylation profiling at the monoamine oxidase A (MAOA) locus, in order to determine whether abnormal DNA methylation is involved in the development of schizophrenia. We recruited a total of 371 patients with paranoid schizophrenia (199 males and 172 females) and 288 unrelated control subjects (123 males and 165 females) for analysis of DNA methylation. Diagnosis was made based on the Structured Clinical Interview for DSM-VI. Genomic DNA extracted from peripheral blood was chemically modified using bisulfite, and DNA methylation profiles of the MAOA promoter were determined by BSP-sequencing. DNA methylation ratios of individual CpG residues and overall methylation ratios were measured on each subject. The results showed that there was no significant difference in overall DNA methylation ratios between patients and controls either in the female group (P = 0.42) or in the male group (P = 0.24). Of 15 CpG residues that showed significant differences in DNA methylation status between the patient group and the control group in females, eight of which had an increased level and seven, a decreased level, with a combined P value of 1 (df = 160). In male subjects, however, six individual CpG residues showed an increased methylation level with a combined P value of 5.80E-35 (df = 158). In conclusion, abnormalities of DNA methylation at the MAOA promoter may be associated with schizophrenia in males. PMID- 22198721 TI - GWAS-linked GAK locus in Parkinson's disease in Han Chinese and meta-analysis. AB - Genome-wide association studies of Parkinson's disease (PD) have recently identified a new susceptibility locus GAK (PARK17) (rs1564282 variant) in subjects of European ancestry. Its role in other races is still unclear. The potential differences of the clinical characteristics between carriers and non carriers have not been examined in detail. Using a case-control methodology, we analyzed the GAK rs1564282 variant in an ethnic Han Chinese population and conducted a meta-analysis combining our result and available published data. A total of 1,574 ethnic Han Chinese study subjects comprising 812 sporadic PD patients and 762 control individuals were included. The minor allele frequency was significantly different at SNP rs1564282 between the cases and the controls (OR = 1.59, 95% CI = 1.09, 1.69, P = 0.007) in the overall PD population. Subjects with CT + TT genotypes have an increased risk (OR = 1.34, 95% CI = 1.05, 1.72, P = 0.017) compared to those with CC genotype. A meta-analysis revealed that the frequency of carrier's genotypes was significantly higher in PD than in control subjects (OR = 1.31, 95% CI = 1.19, 1.44, P < 0.00001). The gender, age of onset, Hoehn-Yahr stage and UPDRS scores and clinical features were similar between carriers and non-carriers. In conclusion, we demonstrated that the rs1564282 variant in GAK (PARK17) increases the risk of PD in Han Chinese patients from mainland China and the meta-analysis with European populations revealed a similar finding. However, carriers cannot be distinguished from non carriers based on their clinical features or motor severity. Functional studies of GAK to unravel its role in the pathophysiologic pathway of PD will be useful. PMID- 22198722 TI - OPRM1 and EGFR contribute to skin pigmentation differences between Indigenous Americans and Europeans. AB - Contemporary variation in skin pigmentation is the result of hundreds of thousands years of human evolution in new and changing environments. Previous studies have identified several genes involved in skin pigmentation differences among African, Asian, and European populations. However, none have examined skin pigmentation variation among Indigenous American populations, creating a critical gap in our understanding of skin pigmentation variation. This study investigates signatures of selection at 76 pigmentation candidate genes that may contribute to skin pigmentation differences between Indigenous Americans and Europeans. Analysis was performed on two samples of Indigenous Americans genotyped on genome wide SNP arrays. Using four tests for natural selection--locus-specific branch length (LSBL), ratio of heterozygosities (lnRH), Tajima's D difference, and extended haplotype homozygosity (EHH)--we identified 14 selection-nominated candidate genes (SNCGs). SNPs in each of the SNCGs were tested for association with skin pigmentation in 515 admixed Indigenous American and European individuals from regions of the Americas with high ground-level ultraviolet radiation. In addition to SLC24A5 and SLC45A2, genes previously associated with European/non-European differences in skin pigmentation, OPRM1 and EGFR were associated with variation in skin pigmentation in New World populations for the first time. PMID- 22198723 TI - The role of dual-phase Tc-99m MIBI in the evaluation of potentially operable lesions detected by bone scanning in fibrous dysplasia: a long-term prospective follow-up study. AB - PURPOSE: The aim of this study was to determine the role of whole-body Tc-99m MDP bone scintigraphy (BSc) with dual-phase Tc-99m MIBI scintigraphy (DPMSc) in the assessment of fibrous dysplasia (FD) and the value of DPMSc in the detection of potentially operable lesions for guiding surgical treatment. METHODS: Twelve patients with histopathologically confirmed FD were evaluated with BSc and DPMSc. The patients were clinically followed up for a mean duration of 75 months. BSc images have been used as a guide to identify the site and the extent of the skeletal involvement. The symptomatic lesions were evaluated with DPMSc. RESULTS: Forty-three lesions were evaluated in 12 patients. BSc showed increased uptake in all of the lesions, whereas DPMSc findings correlated more accurately with the symptoms. Fifteen symptomatic lesions showed increased Tc-99m MIBI uptake on DPMSc, especially in the early phase of DPMSc. The sensitivity, specificity and accuracy values for the early phase in detecting the symptomatic lesions were 100 and 93%, and for delayed phase were 100 and 98%, respectively. CONCLUSION: BSc is useful in determining the site and extent of the skeletal involvement, especially in polyostotic FD. It seems that the potentially operable symptomatic lesions may be evaluated more accurately with DPMSc as compared with BSc. In addition, it seems that DPMSc findings correlate with the symptoms of FD, and this relationship may have a role in improving the preoperative assessment for guiding surgical treatment. DPMSc could be useful in the work-up of symptomatic patients if our results are validated in a larger patient series. PMID- 22198725 TI - Athermal nerve sparing robot-assisted radical prostatectomy: initial experience with microporous polysaccharide hemospheres as a topical hemostatic agent. AB - PURPOSE: Microporous polysaccharide hemospheres (MPH) are hemostatic beads engineered from plant starch to accelerate the natural clotting cascade. The purpose of this report is to detail our initial experience with MPH as a topical hemostatic agent during robot-assisted radical prostatectomy (RARP). METHODS: We examined a single surgeon series of 30 consecutive RARP's dividing patients into MPH or non-MPH groups. The last ten procedures utilized the MPH, which were matched 1:2 to non-MPH procedures for comparison. Nerve-sparing procedures were performed when clinically indicated and all done athermally. All demographic data, length of operation, margin status, blood loss, change in hemoglobin, and need for blood transfusion were prospectively collected and analyzed. RESULTS: The baseline characteristics were the same. The post-operative decrease in hemoglobin was less in the MPH group (1.8 g/dL MPH group vs. 3.2 g/dL non-MPH). One patient in each group required a blood transfusion. CONCLUSIONS: These preliminary findings support the role for MPH as a potential hemostatic agent during athermal nerve-sparing RARP. PMID- 22198724 TI - Potential for prostate cancer prevention through physical activity. AB - OBJECTIVES: Review the most recent literature investigating exercise in the prevention of prostate cancer to determine whether or not exercise might play a role preventing the disease. METHODS: A review of the published literature available on the Medline, PubMed, and Ovid literature databases and search of relevant publications through September 2011 was conducted to identify studies that investigated the role of physical activity in the prevention of prostate cancer. RESULTS: Summarizing the findings from 40 epidemiological studies, 22 suggested that physical activity reduced the risk of prostate cancer, 14 found no association between physical activity and risk of prostate cancer, and four showed an increased risk of prostate cancer. In the 22 studies reporting a protective effect, the effect sizes were predominantly small or moderate. In the four studies reporting that physical activity increased a man's risk for prostate cancer, the effect size was also predominantly small. CONCLUSIONS: There is a growing body of epidemiological research suggesting that physical activity is protective against the development of prostate cancer. This paper reviewed 22 studies published in the past 12 years updating an earlier review finding that although some studies show no benefit and a very few show increased risk for prostate cancer, the majority of studies document a significant, albeit small, protective effect of physical activity. PMID- 22198726 TI - Staging of muscle-invasive bladder cancer: can computerized tomography help us to decide on local treatment? AB - OBJECTIVES: To assess the power of multi-detector row computerized tomography (MDCT) in daily routine as a basic staging procedure for the decision on local treatment of patients with bladder cancer. PATIENTS AND METHODS: We retrospectively analysed 276 patients who had undergone radical cystectomy between 2004 and 2008 and correlated the MDCT findings with pathological findings, number of removed lymph nodes and type of urinary diversion. RESULTS: Accuracy of MDCT in predicting pathological tumour stage was 49% (kappa coefficient, 0.23; P < 0.001). Overstaging occurred in 23.4%, and understaging occurred in 24.7%. Accuracy in predicting lymph node metastases was 54% (kappa coefficient, 0.04; P = 0.297). Overstaging and understaging occurred in 8.3 and 29.4%, respectively. Significantly more ileal conduits were performed in patients with high postoperative pathological tumour stages (P = 0.04) and positive lymph nodes (P = 0.013). In contrast, there was no correlation between preoperative CT tumour/nodal stage and the number of removed lymph nodes (P = 0.44 and P = 0.732, respectively), and between preoperative tumour stage and type of urinary diversion (P = 0.126). CONCLUSIONS: MDCT as a preoperative staging procedure has a low accuracy in predicting the correct tumour and nodal stage, and therefore, it has little impact on decision-making for local treatment of muscle-invasive bladder cancer during radical cystectomy. PMID- 22198727 TI - Mapping QTLs for plant phenology and production traits using indica rice (Oryza sativa L.) lines adapted to rainfed environment. AB - Drought is a major abiotic stress limiting rice production and yield stability in rainfed ecosystems. Identifying quantitative trait loci (QTL) for rice yield and yield components under water limited environments will help to develop drought resilient cultivars using marker assisted breeding (MAB) strategy. A total of 232 recombinant inbred lines of IR62266/Norungan were used to map QTLs for plant phenology and production traits under rainfed condition in target population of environments. A total of 79 QTLs for plant phenology and production traits with phenotypic variation ranging from 4.4 to 72.8% were detected under non-stress and drought stress conditions across two locations. Consistent QTLs for phenology and production traits were detected across experiments and water regimes. The QTL region, RM204-RM197-RM217 on chromosome 6 was linked to days to 50% flowering and grain yield per plant under both rainfed and irrigated conditions. The same genomic region, RM585-RM204-RM197 was also linked to harvest index under rainfed condition with positive alleles from Norungan, a local landrace. QTLs for plant production and drought resistance traits co-located near RM585-RM204-RM197-RM217 region on chromosome 6 in several rice genotypes. Thus with further fine mapping, this region may be useful as a candidate QTL for MAB, map-based cloning of genes and functional genomics studies for rainfed rice improvement. PMID- 22198728 TI - Evidence for leaf fold to remedy the deficiency of physiological photoprotection for photosystem II. AB - An interesting phenomenon is that some light-demanding plants fold their leaves when exposed to high light. Since high light could induce selective photodamage to photosystem II (PSII), we suggest that the leaves fold themselves to diminish the absorption of light energy and remedy the deficiency of physiological photoprotection for PSII. To test this hypothesis, we determined light responses of non-photochemical quenching (NPQ) and cyclic electron flow (CEF) and the effect of high light on PSII activity in Microcos paniculata (non-foldable species) and Bauhinia tenuiflora (foldable species). Under high light B. tenuiflora showed much lower NPQ and CEF than M. paniculata. Meanwhile, the excess light energy that cannot be harmlessly dissipated in B. tenuiflora was more compared with that in M. paniculata. After exposure to a high light of 1,900 MUmol photons m(-2) s(-1) for 2 h, the maximum quantum yield of PSII, as estimated by variable to maximal fluorescence (F (v) /F (m)) decreased from 0.7 to 0.52 in the foldable species B. tenuiflora but was stable at 0.7 in the nonfoldable species M. paniculata. These results indicate that the foldable species B. tenuiflora has more sensitivity of PSII to high light stress than the nonfoldable species M. paniculata, partly as a result of less CEF and NPQ in B. tenuiflora. Our results suggest that sun leaves fold themselves under high light to remedy the deficiency of physiological photoprotection for PSII. PMID- 22198729 TI - Towards determining soft tissue properties for modelling spine surgery: current progress and challenges. AB - Current complication rates for adolescent scoliosis surgery necessitate the development of better surgical planning tools to improve outcomes. Here we present our approach to developing finite element models of the thoracolumbar spine for deformity surgery simulation, with patient-specific model anatomy based on low-dose pre-operative computed tomography scans. In a first step towards defining patient-specific tissue properties, an initial 'benchmark' set of properties were used to simulate a clinically performed pre-operative spinal flexibility assessment, the fulcrum bending radiograph. Clinical data for ten patients were compared with the simulated results for this assessment and in cases where these data differed by more than 10%, soft tissue properties for the costo-vertebral joint (CVJt) were altered to achieve better agreement. Results from these analyses showed that changing the CVJt stiffness resulted in acceptable agreement between clinical and simulated flexibility in two of the six cases. In light of these results and those of our previous studies in this area, it is suggested that spinal flexibility in the fulcrum bending test is not governed by any single soft tissue structure acting in isolation. More detailed biomechanical characterisation of the fulcrum bending test is required to provide better data for determination of patient-specific soft tissue properties. PMID- 22198730 TI - Primary amines protect against retinal degeneration in mouse models of retinopathies. AB - Vertebrate vision is initiated by photoisomerization of the visual pigment chromophore 11-cis-retinal and is maintained by continuous regeneration of this retinoid through a series of reactions termed the retinoid cycle. However, toxic side reaction products, especially those involving reactive aldehyde groups of the photoisomerized product, all-trans-retinal, can cause severe retinal pathology. Here we lowered peak concentrations of free all-trans-retinal with primary amine-containing Food and Drug Administration (FDA)-approved drugs that did not inhibit chromophore regeneration in mouse models of retinal degeneration. Schiff base adducts between all-trans-retinal and these amines were identified by MS. Adducts were observed in mouse eyes only when an experimental drug protected the retina from degeneration in both short-term and long-term treatment experiments. This study demonstrates a molecular basis of all-trans-retinal induced retinal pathology and identifies an assemblage of FDA-approved compounds with protective effects against this pathology in a mouse model that shows features of Stargardt's disease and age-related retinal degeneration. PMID- 22198731 TI - Natural product-inspired cascade synthesis yields modulators of centrosome integrity. AB - In biology-oriented synthesis, the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is, in particular, met by the scaffolds of natural products selected in evolution. The synthesis of natural product-inspired compound collections calls for efficient reaction sequences that preferably combine multiple individual transformations in one operation. Here we report the development of a one-pot, twelve-step cascade reaction sequence that includes nine different reactions and two opposing kinds of organocatalysis. The cascade sequence proceeds within 10-30 min and transforms readily available substrates into complex indoloquinolizines that resemble the core tetracyclic scaffold of numerous polycyclic indole alkaloids. Biological investigation of a corresponding focused compound collection revealed modulators of centrosome integrity, termed centrocountins, which caused fragmented and supernumerary centrosomes, chromosome congression defects, multipolar mitotic spindles, acentrosomal spindle poles and multipolar cell division by targeting the centrosome-associated proteins nucleophosmin and Crm1. PMID- 22198732 TI - Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor. AB - Until now, a lack of inhibitors with high potency and selectivity in vivo has hampered investigation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. We describe the design of skepinone-L, which is, to our knowledge, the first ATP-competitive p38 MAPK inhibitor with excellent in vivo efficacy and selectivity. Therefore, skepinone-L is a valuable probe for chemical biology research, and it may foster the development of a unique class of kinase inhibitors. PMID- 22198734 TI - Electroretinography in healthy subjects in relation to systemic glucocorticoid intake. AB - This study examined electroretinographic function in healthy subjects before and after prednisolone intake. To separate the effect of prednisolone on the retina from the potentially confounding hyperglycemia-inducing effect of prednisolone, electroretinography was made while fasting and at a pre-specified level of clamped hyperglycemia. The study included 10 eyes in 10 healthy lean men aged 25 +/- 3 years (mean +/- SD). The subjects were examined before and after oral intake of prednisolone 37.5 mg/day for 9.1 +/- 1.4 days. The diabetogenic potential of prednisolone was reinforced by the intake of a high-caloric diet and by the reduction of physical activity. Full-field electroretinography (ffERG) demonstrated no significant change (P < 0.05) in amplitudes or implicit times in relation to prednisolone intake, neither at fasting glycemia levels, which were 4.9 +/- 0.2 mM before and 5.0 +/- 0.3 mM (P = 0.467) after the intervention, nor at 10 mM clamped hyperglycemia. Specifically, the fasting b-wave amplitude of the combined rod-cone response was 432 +/- 84 mV before and 463 +/- 71 mV (P = 0.13) after prednisolone intake. Furthermore, the ffERG could not be shown to be influenced by the doubling of glycemia from fasting to clamped hyperglycemia, neither before, nor after prednisolone (P > 0.05). The stability of ffERG performance in the face of shifting glycemia levels, which differs from what has been found in diabetes, was not influenced by the mild diabetogenic effect of the intervention on insulin resistance (P = 0.011) and post-prandial glycemia (P = 0.023). We conclude that prednisolone had no detectable effect on the ffERG in healthy lean men in this study. Retinal function may be less sensitive to changes in glycemia in healthy subjects than in people with diabetes, a characteristic that was unchanged by a short course of prednisolone. PMID- 22198733 TI - Small-molecule proteostasis regulators for protein conformational diseases. AB - Protein homeostasis (proteostasis) is essential for cellular and organismal health. Stress, aging and the chronic expression of misfolded proteins, however, challenge the proteostasis machinery and the vitality of the cell. Enhanced expression of molecular chaperones, regulated by heat shock transcription factor 1 (HSF-1), has been shown to restore proteostasis in a variety of conformational disease models, suggesting this mechanism as a promising therapeutic approach. We describe the results of a screen comprised of ~900,000 small molecules that identified new classes of small-molecule proteostasis regulators that induce HSF 1-dependent chaperone expression and restore protein folding in multiple conformational disease models. These beneficial effects to proteome stability are mediated by HSF-1, FOXO, Nrf-2 and the chaperone machinery through mechanisms that are distinct from current known small-molecule activators of the heat shock response. We suggest that modulation of the proteostasis network by proteostasis regulators may be a promising therapeutic approach for the treatment of a variety of protein conformational diseases. PMID- 22198735 TI - Mating disruption of Guatemalan potato moth Tecia solanivora by attractive and non-attractive pheromone blends. AB - The behavioral mechanisms of mating disruption in Guatemalan potato moth Tecia solanivora were studied using the sex pheromone components, (E)-3-dodecenyl acetate, (Z)-3-dodecenyl acetate, and dodecyl acetate, formulated in a 100:1:20 ratio mimicking the female-produced blend, and in a 100:56:100 off-blend ratio. The mode of action of these two blends was tested in mating disruption experiments in the field and in a greenhouse, as well as in a laboratory wind tunnel. Field treatments with both blends at 80 g pheromone per ha reduced male attraction to trap lures baited with 100 MUg of female sex pheromone. In mesh house treatments, these two blends were equally effective at reducing male attraction to traps baited with live females and mating of caged females. Subsequent flight tunnel tests corroborated that both blends reduced attraction of naive males to calling females, and pre-exposure of males with either dispenser blend for 24 hr resulted in a strongly reduced response to calling females. The pre-exposure effect was reversible, with males again responsive after 24 hr in clean air. The two dispenser formulations produced a similar effect on male behavior, despite the differences in blend composition. One mating disruption dispenser formulated with either the female-blend or off-blend elicited the same rate of male upwind attraction in a wind-tunnel bioassay. Sensory overload and camouflage, therefore, are contributing mechanisms to mating disruption using either blend. The off-blend, which is more economical to synthesize, is a valuable tool for further development of mating disruption against this major pest of potatoes in Latin America. PMID- 22198736 TI - Will they fit? Development of a measurement device to assess body habitus compatibility with MRI bore diameter for emergency trauma imaging. AB - Excessive obesity poses a significant limitation to radiographic magnetic resonance imaging (MRI), particularly related to aperture or bore diameter due to the patient's girth. Determination of whether a patient will fit into the bore of the MRI scanner is currently accomplished using patient height, weight, and MRI technician experience. These simple methods have proven unreliable. We sought to develop a device and method which could accurately determine whether a patient would fit into the MRI scanner. We developed an MRI template prototype which was tested against the standard radiology methods in a pilot study (n = 6). We then performed a prospective validation study in adult human volunteers (n = 100) to assess the accuracy of the MRI template. We collected height, weight, shoulder and pelvis girth/diameter for each study participant to evaluate the body dimension measurements that would assist in determination of whether a patient would fit into the MRI scanner. Using the MRI template, we determined that 11 of the 100 study participants would not fit in the MRI scanner and 10 were confirmed to not fit into the MRI aperture [positive predictive value (PPV) 0.91 (0.58 0.99); negative predictive value (NPV) 1.00 (0.95-1.00), sensitivity 1.00 (0.69 1.00), specificity 0.99 (0.93-0.99), likelihood ratio positive test 90 (12.81 632), likelihood ratio negative test 0, accuracy 99%]. In comparison, the body measurement method did not perform as well [PPV 0.66 (0.34-0.90), NPV 0.97 (0.92 0.99), sensitivity 0.80 (0.44-0.97), specificity 0.95 (0.89-0.98), likelihood ratio positive test 17.97 (6.56-49.2), likelihood ratio negative test 0.209 (0.06 0.72), accuracy 94%]. This study confirmed that the use of an MRI template is an accurate tool in determining whether an obese patient can fit through the MRI bore and be accommodated in the MRI scanner. PMID- 22198737 TI - Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis: evidence from the International Consortium for Prostate Cancer Genetics (ICPCG). AB - Multiple prostate cancer (PCa) risk-related loci have been discovered by genome wide association studies (GWAS) based on case-control designs. However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer (HPC). The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1,979 hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics, with a total of 5,730 affected men. The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 (regions 1, 2 and 3), 10q11, 11q13, 17q12 (region 1), 17q24 and Xp11. In subgroup analyses, three loci, at 8q24 (regions 1 and 2) plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 (region 2), 11q13, 17q12 (region 1), 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65 years or less. Our results indicate that at least a subset of PCa risk-related loci identified by case-control GWAS are also associated with disease risk in HPC families. PMID- 22198738 TI - Multidrug-resistant gram-negative bacterial infections after liver transplantation - spectrum and risk factors. AB - OBJECTIVES: Gram-negative bacilli infections, especially multidrug-resistant gram negative bacilli infections, are the leading cause of high mortality after liver transplantation. This study sought to investigate the type of infection, infection rate, pathogenic spectrum, antibiotic-resistance profile, risk factors, and epidemiology of multidrug-resistant gram-negative bacterial infection. METHODS: A retrospective cohort study was conducted and data of 217 liver transplant patients receiving cadaveric livers between January 2007 and April 2010 were analyzed. Antibiotic susceptibility was determined by minimum inhibitory concentration test. Extended-spectrum and metallo-beta-lactamase assays were used to analyze beta-lactamase-produced isolates, and repetitive sequence polymerase chain reaction was used to differentiate bacterium subspecies. RESULTS: Sixty-seven isolates of multidrug-resistant gram-negative bacteria were isolated from 66 infected liver transplant patients. Stenotrophomonas maltophilia (100%, 8/8), Klebsiella pneumoniae (61.5%, 8/13), Enterobacter cloacae (75%, 3/4) and Escherichia coli (81.3%, 13/16) were the most common extended-spectrum beta-lactamase-producing bacilli. Metallo-beta-lactamase expressing isolates were identified as S. maltophilia (100%, 8/8), Pseudomonas aeruginosa (83.3%, 5/6), Acinetobacter baumannii (95%, 19/20). Significant independent risk factors for multidrug-resistant gram-negative infection were extended use of pre-transplant broad-spectrum antibiotics (OR 9.027, P=0.001) and prolonged (?72h) endotracheal intubation (OR 3.537, P=0.033). CONCLUSIONS: To reduce the risk of acquiring MDR gram-negative bacillus infections after liver transplant, control measures are required to limit the use of prophylactic antibiotic in preventing infection during liver transplant and to shorten endotracheal intubation time. PMID- 22198739 TI - Attitudes towards mandatory vaccination and vaccination coverage against vaccine preventable diseases among health-care workers in tertiary-care hospitals. AB - OBJECTIVE: To assess the attitudes about mandatory vaccination and vaccination coverage against vaccine-preventable diseases among health-care workers (HCWs) working in tertiary-care hospitals in Greece. METHODS: A questionnaire was distributed to HCWs working in four tertiary-care hospitals. RESULTS: In total, 505 HCWs participated in the survey. Self-reported completed vaccination rates were 18.8% against measles, 18.8% against mumps, 22.2% against rubella, 1.9% against varicella, 3.6% against hepatitis A, 56.5% against hepatitis B, and 35.7% against tetanus-diphtheria. Younger age groups had higher completed vaccination rates against measles, mumps, rubella, varicella, and hepatitis B compared with older HCWs (p-value < 0.001). Self-reported susceptibility rates were 12.7% for measles, 18.9% for mumps, 15.8% for rubella, 15.2% for varicella, 89.9% for hepatitis A, 34.2% for hepatitis B, and 64.3% for tetanus-diphtheria. Sixty three percent of 451 HCWs who answered this question supported mandatory vaccinations for HCWs, with significant differences per target disease. Physicians more frequently supported a mandatory vaccination policy compared to nurses and other professions (72.1% versus 61.9% and 54.2%, respectively; p-value = 0.028). CONCLUSIONS: Approximately two thirds of HCWs working in tertiary-care hospitals in Greece support mandatory vaccinations for HCWs, however suboptimal vaccination rates against vaccine-preventable diseases were recorded. PMID- 22198740 TI - High yield of human monoclonal antibody produced by stably transfected Drosophila schneider 2 cells in perfusion culture using wave bioreactor. AB - Since it was first introduced in late 1990s Wave bioreactor has been used for protein production by mammalian and insect cell lines. However, using Wave bioreactor to produce human monoclonal antibody by stable Drosophila Schneider 2 (S2) cell transfectants has not been reported before. In this study, S2 cells were co-transfected with an inducible vector expressing human monoclonal antibody heavy and light chains, respectively, specific for hemagglutinin (HA) of H5N1 influenza virus. Stable S2 transfectant clone was selected by limiting dilution assay. Stable S2 transfectant clone that produce the highest amount of human monoclonal antibody was inoculated into two 2-l disposable cellbags, where cell growth and antibody production were compared between batch and perfusion cultures using Wave bioreactor. Here, we report that maximum viable cell density reached 1.06 * 10(7) cells/ml in batch culture; whereas 1.04 * 10(8) cells/ml was achieved in perfusion culture. The maximum volumetric antibody productivity in batch culture was 52 mg/l/day; while perfusion culture yielded 1,437 mg/l/day. As a result, the total antibody production was 201 mg in batch culture and 8,212 mg in perfusion culture. The antibody produced by both cultures displays full neutralizing activity. Thus, our results provide strong support for using Wave bioreactor in perfusion culture for a large-scale production of human monoclonal antibody by stable S2 cell transfectants. PMID- 22198741 TI - Measuring quality of life in rural Uganda: reliability and validity of summary scores from the medical outcomes study HIV health survey (MOS-HIV). AB - PURPOSE: Summary scores derived from the medical outcomes study HIV health survey (MOS-HIV) are used to assess treatment impacts among HIV-infected patients in Western settings, but have yet to be validated in rural, African settings. We examined the reliability, validity and responsiveness of scores among a prospective cohort of 947 HIV-1-infected adults initiating antiretroviral therapy between May 2003 and May 2004 in rural Uganda. METHODS: Physical (PHS) and mental health (MHS) summary scores were developed from baseline MOS-HIV sub-domains using exploratory factor analysis. Construct and discriminant validity were established by comparing mean summary scores across known groups of sociodemographic, clinical and health status characteristics. Effect sizes were calculated to assess responsiveness to therapy. RESULTS: Reliability of the PHS and MHS scores was 0.79 and 0.85, respectively. Mean baseline PHS and MHS scores varied significantly by CD4 cell count, HIV viral load, WHO stage of disease and Karnofsky performance status scores. By 12 months on antiretroviral therapy, PHS and MHS scores improved by 14.6 points (P < 0.001) and 13.9 points (P < 0.001), respectively. CONCLUSIONS: PHS and MHS scores can be derived from the MOS-HIV and used to assess health status among cohorts of patients taking antiretroviral therapy in rural Uganda. PMID- 22198742 TI - Particle motion is broadly represented in the vestibular medulla of the bullfrog across larval development. AB - In their shallow-water habitats, bullfrog (Rana catesbeiana) tadpoles are exposed to both underwater and airborne sources of acoustic stimulation. We probed the representation of underwater particle motion throughout the tadpole's dorsal medulla to determine its spatial extent over larval life. Using neurobiotin filled micropipettes, we recorded neural activity to z-axis particle motion (frequencies of 40-200 Hz) in the medial vestibular nucleus, lateral vestibular nucleus, dorsal medullary nucleus (DMN), and along the dorsal arcuate pathway. Sensitivity was comparable in the medial and lateral vestibular nuclei, with estimated thresholds between 0.016 and 12.5 MUm displacement. Neither best responding frequency nor estimated threshold varied significantly over larval stage. Transport of neurobiotin from active recording sites was also stable over development. The DMN responded poorly to z-axis particle motion, but did respond to low-frequency pressure stimulation. These data suggest that particle motion is represented widely and stably in the tadpole's vestibular medulla. This is in marked contrast to the representation of pressure stimulation in the auditory midbrain, where a transient "deaf period" of non-responsiveness and decreased connectivity occurs immediately prior to metamorphic climax. We suggest that, in bullfrogs, sensitivity to particle motion and to pressure follows different developmental trajectories. PMID- 22198743 TI - Dendritic cell vaccines in cancer immunotherapy: from biology to translational medicine. PMID- 22198744 TI - Overcoming the challenges of conducting translational research in cell therapy. AB - Cell therapy holds promise in addressing a number of unmet medical needs but despite its considerable impetus, faces numerous challenges including support for translational research in this area. Here, we examine the challenges confronting cell therapy research including the limited funding available for translational research partly due to the uncompetitive nature of required validation studies in cell therapy that of necessity are not hypothesis-driven. Other issues include lack of standardization of definitions of cell products, uncertainty regarding optimum preclinical animal models, duplication of efforts to secure regulatory approval and a lack of uniformity of nomenclature for some cell products. Nonetheless, several initiatives to address all of these issues are underway. PMID- 22198745 TI - Endostatin specifically targets both tumor blood vessels and lymphatic vessels. AB - Endostatin, a 20 kDa C-terminal fragment of collagen XVIII, was first identified as a potent angiogenic inhibitor. The anti-angiogenic function of endostatin has been well documented during the past decade. Recently, several studies demonstrated that endostatin also inhibits tumor lymphangiogenesis and lymphatic metastasis. However, the exact mechanism that endostatin executes its anti angiogenic and anti-lymphangiogenic functions remains elusive. In the current mini-review, we briefly summarize recent novel findings, including the functions of endostatin targeting not only angiogenesis but also lymphangiogenesis, and the underlying mechanism by which endostatin internalization regulates its biological functions. PMID- 22198746 TI - Current treatment strategy of acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). The prognosis of APL has changed from the worst among the AMLs to currently the best. The application of all-trans retinoic acid (ATRA) in the induction therapy of APL decreases the high mortality of newly diagnosed patients, thereby significantly improving the response rate. ATRA combined with anthracycline-based chemotherapy is the current standard treatment, and for high risk patients, high doses cytarabine have a beneficial effect on relapse prevention. In recent years, the indications of arsenic trioxide (ATO) therapy for APL have been extended from the salvage therapy for relapse patients to the first-line treatment of de novo APL. The introduction of both ATRA and ATO represents great achievements in translational medicine. In this review article, we discuss the therapeutic strategies for this disease, including the initial approaches to newly diagnosed patients, prevention, and treatment of side effects and relapse to ensure the best and timely treatment for each newly diagnosed APL patient. PMID- 22198748 TI - Mesenchymal stem cells hold promise for regenerative medicine. AB - Regenerative medicine is an emerging interdisciplinary field of research that uses several technological approaches including stem cells to repair tissues. Mesenchymal stem cells (MSCs), a type of adult stem cell, have generated a great amount of interest over the past decade in this field. Numerous studies have explored the role of MSCs in tissue repair and modulation of allogeneic immune responses. The mechanisms through which MSCs exert their therapeutic potential rely on some key properties of the cells as follows: the capacity to differentiate into osteoblasts, chondrocytes, adipocytes, cardiomyocytes, hepatocytes, endothelial, and neuronal cells; the ability to secrete multiple bioactive molecules capable of stimulating the recovery of injured cells and inhibiting inflammation; the lack of immunogenicity; and the ability to perform immunomodulatory functions. In the present review, we focus on these three aspects upon which the therapeutic effects of MSCs are mainly based. Furthermore, some pathological conditions under which the application of MSCs should be done with caution are also mentioned. PMID- 22198747 TI - Stem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity. AB - Virus-based vectors are widely used in hematopoietic stem cell (HSC) gene therapy, and have the ability to integrate permanently into genomic DNA, thus driving long-term expression of corrective genes in all hematopoietic lineages. To date, HSC gene therapy has been successfully employed in the clinic for improving clinical outcomes in small numbers of patients with X-linked severe combined immunodeficiency (SCID-X1), adenosine deaminase deficiency (ADA-SCID), adrenoleukodystrophy (ALD), thalassemia, chronic granulomatous disease (CGD), and Wiskott-Aldrich syndrome (WAS). However, adverse events were observed during some of these HSC gene therapy clinical trials, linked to insertional activation of proto-oncogenes by integrated proviral vectors leading to clonal expansion and eventual development of leukemia. Numerous studies have been performed to understand the molecular basis of vector-mediated genotoxicity, with the aim of developing safer vectors and lower-risk gene therapy protocols. This review will summarize current information on the mechanisms of insertional mutagenesis in hematopoietic stem and progenitor cells due to integrating gene transfer vectors, discuss the available assays for predicting genotoxicity and mapping vector integration sites, and introduce newly-developed approaches for minimizing genotoxicity as a way to further move HSC gene therapy forward into broader clinical application. PMID- 22198749 TI - Synthesis and application of superparamagnetic iron oxide nanoparticles in targeted therapy and imaging of cancer. AB - Superparamagnetic iron oxide (SPIO) nanoparticles have become a popular strategy of cancer treatment and molecular imaging because of their versatile properties and biocompatibility. A variety of studies have shown the exciting potential of functionalized SPIO nanoparticles, such as surface-coated, targeted ligandconjugated, and/or drug-loaded SPIO nanoparticles, as powerful tools for targeted imaging and therapy. Moreover, the applications of SPIO nanoparticles that integrate diagnosis and therapy in SPIO nanoparticles facilitate the monitoring of therapeutic efficacy during treatment. In the present review, we primarily concentrate on the recent advancements in the field of SPIO nanoparticles in terms of synthesis, targeted therapy, and cancer imaging. PMID- 22198750 TI - Laparoscopic treatment of liver diseases in children. AB - Laparoscopic liver surgery has been increasingly used for the treatment of pediatric liver diseases over the past decade due to the development of special laparoscopic instruments and improvements in the technique. A number of factors are considered when electing to undergo the surgical process, including age, type of liver disease, and so on. Especially in children with liver masses, the number of trocars used and the position of their placement must be carefully designed to achieve successful outcomes. In the current review, the application of various laparoscopic instruments and the methods used for the laparoscopic treatment of liver diseases in children over the past decade are summarized. PMID- 22198751 TI - Translational research on novel drug-eluting stents in percutaneous coronary intervention. AB - Although first-generation drug-eluting stents (DES) have markedly reduced restenosis, complications of late and very late in-stent thrombosis have emerged as prime limitations to this technology. The development of new DES is a key process to prevent these complications. Translational research plays a very important role in experiments which determine the safety and efficacy of DES before human clinical trials. The present review focuses on translational research of novel DES, including drug discovery, creation of preclinical research models, planning and conducting of first-in-man studies, and developing next generation DES systems. PMID- 22198752 TI - Bone regeneration by stem cell and tissue engineering in oral and maxillofacial region. AB - Clinical imperatives for the reconstruction of jaw bone defects or resorbed alveolar ridge require new therapies or procedures instead of autologous/allogeneic bone grafts. Regenerative medicine, based on stem cell science and tissue engineering technology, is considered as an ideal alternative strategy for bone regeneration. In this paper, we review the current choices of cell source and strategies on directing the osteogenic differentiation of stem cells. The preclinical animal models for bone regeneration and the key translational points to clinical success in oral and maxillofacial region are also discussed. We propose comprehensive strategies based on stem cell and tissue engineering researches, allowing for clinical application in oral and maxillofacial region. PMID- 22198753 TI - MicroRNAs and their roles in osteoclast differentiation. AB - Osteoclasts, which are derived from monocyte-macrophage precursors, are exclusive bone resorption cells. Limited evidence indicates that a class of small non coding single-stranded RNAs known as "microRNAs" (miRNAs) is also involved in bone resorption. Although various miRNAs regulate cell proliferation and differentiation, few miRNAs have been reported to play a key role in the regulation of osteoclast differentiation. In this short review, the biology and functional mechanisms of miRNAs in osteoclastogenesis are summarized. The profiling, function, and target prediction of miRNAs are discussed as well. PMID- 22198754 TI - Arsenic geochemistry of groundwater in Southeast Asia. AB - The occurrence of high concentrations of arsenic in the groundwater of the Southeast Asia region has received much attention in the past decade. This study presents an overview of the arsenic contamination problems in Vietnam, Cambodia, Lao People's Democratic Republic and Thailand. Most groundwater used as a source of drinking water in rural areas has been found to be contaminated with arsenic exceeding the WHO drinking water guideline of 10 MUg.L(-1). With the exception of Thailand, groundwater was found to be contaminated with naturally occurring arsenic in the region. Interestingly, high arsenic concentrations (> 10 MUg.L( 1)) were generally found in the floodplain areas located along the Mekong River. The source of elevated arsenic concentrations in groundwater is thought to be the release of arsenic from river sediments under highly reducing conditions. In Thailand, arsenic has never been found naturally in groundwater, but originates from tin mining activities. More than 10 million residents in Southeast Asia are estimated to be at risk from consuming arsenic-contaminated groundwater. In Southeast Asia, groundwater has been found to be a significant source of daily inorganic arsenic intake in humans. A positive correlation between groundwater arsenic concentration and arsenic concentration in human hair has been observed in Cambodia and Vietnam. A substantial knowledge gap exists between the epidemiology of arsenicosis and its impact on human health. More collaborative studies particularly on the scope of public health and its epidemiology are needed to conduct to fulfill the knowledge gaps of As as well as to enhance the operational responses to As issue in Southeast Asian countries. PMID- 22198755 TI - Pyogenic liver abscess as initial presentation in locally advanced right colon cancer invading the liver, gallbladder, and duodenum. AB - Locally advanced colorectal cancer complicated with adjacent organic invasion may remain confined to the local area with minimal metastasis. In the present paper, we report on a patient with advanced right colon cancer, including liver, gallbladder, and duodenal invasion behind the scene of liver abscess. En bloc resection was performed on the patient, with right-hemicolectomy, cholecystectomy, partial duodental resection, and hepatectomy. Postoperative management was administered, including nutritional support in the early postoperative period, effective anti-infection treatment, and adjuvant chemotherapy (FOLFOX4). The patient survived for 16 months after the operation. Common clinical manifestations of colorectal cancer were digestive symptoms and changes in defecation. However, the clinical manifestation of locally advanced colon cancer was extremely complicated. Extended or multivisceral resection may offer patients a chance to survive an acute crisis and allow for treatment with adjuvant therapy. PMID- 22198756 TI - Changing state structures: outside in. AB - In explaining the development of institutional structures within states, social science analysis has focused on autochthonous factors and paid less attention to the way in which external factors, especially purposive agent-directed as opposed to more general environmental factors, can influence domestic authority structures. For international relations scholarship, this lacunae is particularly troubling or perhaps, just weird. If the international system is anarchical, then political leaders can pursue any policy option. In some cases, the most attractive option would be conventional state to state interactions, diplomacy, or war. In other instances, however, changing the domestic authority structures of other states might be more appealing. In some cases, domestic authority structures have been influenced through bargaining, and in others through power. Power may reflect either explicit agent-oriented decisions or social processes that reflect the practices, values, and norms of more powerful entities. PMID- 22198757 TI - Development, social norms, and assignment to task. AB - Economic development involves a structural transformation in the way people are allocated to tasks. There is a shift from self-provision to market exchange, facilitating specialization. There is also a shift from self-employment to wage employment in large firms and organizations, driven by innovation and increasing returns to scale. Changes in allocation mechanisms require changes in norms and attitudes. Because different labor assignment domains coexist, conflicts arise among norms that apply to different domains, possibly resulting in dysfunctional outcomes. I argue that religion, humanism, and schools have all played an important historical role in fostering the changes in social norms and attitudes that are needed to accompany structural changes in the way economies allocate workers to tasks. PMID- 22198758 TI - Toward a theory of leadership and state building. AB - We present a theory of the state based on political leadership and reputational equilibria. A political leader first needs a reputation for reliably rewarding loyal supporters. Reputational expectations between political leaders and their supporters become the fundamental political laws on which the enforcement of all other constitutional laws may be based. Successful democratic development requires a plentiful supply of leaders who have good reputations for using public funds responsibly to serve the public at large and not just giving jobs to their active supporters. It is argued that decentralized democracy may be the best way to improve the chances for successful democracy. PMID- 22198759 TI - Individualism, innovation, and long-run growth. AB - Countries having a more individualist culture have enjoyed higher long-run growth than countries with a more collectivist culture. Individualist culture attaches social status rewards to personal achievements and thus, provides not only monetary incentives for innovation but also social status rewards, leading to higher rates of innovation and economic growth. PMID- 22198760 TI - Political model of social evolution. AB - Almost all democratic societies evolved socially and politically out of authoritarian and nondemocratic regimes. These changes not only altered the allocation of economic resources in society but also the structure of political power. In this paper, we develop a framework for studying the dynamics of political and social change. The society consists of agents that care about current and future social arrangements and economic allocations; allocation of political power determines who has the capacity to implement changes in economic allocations and future allocations of power. The set of available social rules and allocations at any point in time is stochastic. We show that political and social change may happen without any stochastic shocks or as a result of a shock destabilizing an otherwise stable social arrangement. Crucially, the process of social change is contingent (and history-dependent): the timing and sequence of stochastic events determine the long-run equilibrium social arrangements. For example, the extent of democratization may depend on how early uncertainty about the set of feasible reforms in the future is resolved. PMID- 22198761 TI - Legal reform in the presence of a living custom: an economic approach. AB - Empowerment of disadvantaged groups of population is a key issue in development. One major difficulty in implementing progressive legal reforms arises from the persistent and contrary influence of custom. In this paper, we present a simple theoretical framework that analyzes how customary rules evolve under the impact of a change in formal law. This evolution is ultimately caused by a modification of relative costs and benefits of exiting the community by members of the disadvantaged groups as a result of change in the law. We also describe how the welfare of these groups is affected and provide illustrative evidence. PMID- 22198762 TI - The dynamics of social innovation. AB - Social norms and institutions are mechanisms that facilitate coordination between individuals. A social innovation is a novel mechanism that increases the welfare of the individuals who adopt it compared with the status quo. We model the dynamics of social innovation as a coordination game played on a network. Individuals experiment with a novel strategy that would increase their payoffs provided that it is also adopted by their neighbors. The rate at which a social innovation spreads depends on three factors: the topology of the network and in particular the extent to which agents interact in small local clusters, the payoff gain of the innovation relative to the status quo, and the amount of noise in the best response process. The analysis shows that local clustering greatly enhances the speed with which social innovations spread. It also suggests that the welfare gains from innovation are more likely to occur in large jumps than in a series of small incremental improvements. PMID- 22198763 TI - Stabilizing brokerage. AB - A variety of social and economic arrangements exist to facilitate the exchange of goods, services, and information over gaps in social structure. Each of these arrangements bears some relationship to the idea of brokerage, but this brokerage is rarely like the pure and formal economic intermediation seen in some modern markets. Indeed, for reasons illuminated by existing sociological and economic models, brokerage is a fragile relationship. In this paper, we review the causes of instability in brokerage and identify three social mechanisms that can stabilize fragile brokerage relationships: social isolation, broker capture, and organizational grafting. Each of these mechanisms rests on the emergence or existence of supporting institutions. We suggest that organizational grafting may be the most stable and effective resolution to the tensions inherent in brokerage, but it is also the most institutionally demanding. PMID- 22198764 TI - Brassinosteroids modulate plant immunity at multiple levels. PMID- 22198765 TI - On the scent of pleiotropy. PMID- 22198766 TI - Bayesian analysis of the astrobiological implications of life's early emergence on Earth. AB - Life arose on Earth sometime in the first few hundred million years after the young planet had cooled to the point that it could support water-based organisms on its surface. The early emergence of life on Earth has been taken as evidence that the probability of abiogenesis is high, if starting from young Earth-like conditions. We revisit this argument quantitatively in a bayesian statistical framework. By constructing a simple model of the probability of abiogenesis, we calculate a bayesian estimate of its posterior probability, given the data that life emerged fairly early in Earth's history and that, billions of years later, curious creatures noted this fact and considered its implications. We find that, given only this very limited empirical information, the choice of bayesian prior for the abiogenesis probability parameter has a dominant influence on the computed posterior probability. Although terrestrial life's early emergence provides evidence that life might be abundant in the universe if early-Earth-like conditions are common, the evidence is inconclusive and indeed is consistent with an arbitrarily low intrinsic probability of abiogenesis for plausible uninformative priors. Finding a single case of life arising independently of our lineage (on Earth, elsewhere in the solar system, or on an extrasolar planet) would provide much stronger evidence that abiogenesis is not extremely rare in the universe. PMID- 22198767 TI - A single conformational transglutaminase 2 epitope contributed by three domains is critical for celiac antibody binding and effects. AB - The multifunctional, protein cross-linking transglutaminase 2 (TG2) is the main autoantigen in celiac disease, an autoimmune disorder with defined etiology. Glutamine-rich gliadin peptides from ingested cereals, after their deamidation by TG2, induce T-lymphocyte activation accompanied by autoantibody production against TG2 in 1-2% of the population. The pathogenic role and exact binding properties of these antibodies to TG2 are still unclear. Here we show that antibodies from different celiac patients target the same conformational TG2 epitope formed by spatially close amino acids of adjacent domains. Glu153 and 154 on the first alpha-helix of the core domain and Arg19 on first alpha-helix of the N-terminal domain determine the celiac epitope that is accessible both in the closed and open conformation of TG2 and dependent on the relative position of these helices. Met659 on the C-terminal domain also can cooperate in antibody binding. This composite epitope is disease-specific, recognized by antibodies derived from celiac tissues and associated with biological effects when passively transferred from celiac mothers into their newborns. These findings suggest that celiac antibodies are produced in a surface-specific way for which certain homology of the central glutamic acid residues of the TG2 epitope with deamidated gliadin peptides could be a structural basis. Monoclonal mouse antibodies with partially overlapping epitope specificity released celiac antibodies from patient tissues and antagonized their harmful effects in cell culture experiments. Such antibodies or similar specific competitors will be useful in further functional studies and in exploring whether interference with celiac antibody actions leads to therapeutic benefits. PMID- 22198768 TI - Database independent proteomics analysis of the ostrich and human proteome. AB - Mass spectrometry (MS)-based proteome analysis relies heavily on the presence of complete protein databases. Such a strategy is extremely powerful, albeit not adequate in the analysis of unpredicted postgenome events, such as posttranslational modifications, which exponentially increase the search space. Therefore, it is of interest to explore "database-free" approaches. Here, we sampled the ostrich and human proteomes with a method facilitating de novo sequencing, utilizing the protease Lys-N in combination with electron transfer dissociation. By implementing several validation steps, including the combined use of collision-induced dissociation/electron transfer dissociation data and a cross-validation with conventional database search strategies, we identified approximately 2,500 unique de novo peptide sequences from the ostrich sample with over 900 peptides generating full backbone sequence coverage. This dataset allowed the appropriate positioning of ostrich in the evolutionary tree. The described database-free sequencing approach is generically applicable and has great potential in important proteomics applications such as in the analysis of variable parts of endogenous antibodies or proteins modified by a plethora of complex posttranslational modifications. PMID- 22198769 TI - Low temperature formation of naphthalene and its role in the synthesis of PAHs (polycyclic aromatic hydrocarbons) in the interstellar medium. AB - Polycyclic aromatic hydrocarbons (PAHs) are regarded as key molecules in the astrochemical evolution of the interstellar medium, but the formation mechanism of even their simplest prototype-naphthalene (C(10)H(8))-has remained an open question. Here, we show in a combined crossed beam and theoretical study that naphthalene can be formed in the gas phase via a barrierless and exoergic reaction between the phenyl radical (C(6)H(5)) and vinylacetylene (CH(2) = CH-C = CH) involving a van-der-Waals complex and submerged barrier in the entrance channel. Our finding challenges conventional wisdom that PAH-formation only occurs at high temperatures such as in combustion systems and implies that low temperature chemistry can initiate the synthesis of the very first PAH in the interstellar medium. In cold molecular clouds, barrierless phenyl-type radical reactions could propagate the vinylacetylene-mediated formation of PAHs leading to more complex structures like phenanthrene and anthracene at temperatures down to 10 K. PMID- 22198770 TI - Incorporating microorganisms into polymer layers provides bioinspired functional living materials. AB - Artificial two-dimensional biological habitats were prepared from porous polymer layers and inoculated with the fungus Penicillium roqueforti to provide a living material. Such composites of classical industrial ingredients and living microorganisms can provide a novel form of functional or smart materials with capability for evolutionary adaptation. This allows realization of most complex responses to environmental stimuli. As a conceptual design, we prepared a material surface with self-cleaning capability when subjected to standardized food spill. Fungal growth and reproduction were observed in between two specifically adapted polymer layers. Gas exchange for breathing and transport of nutrient through a nano-porous top layer allowed selective intake of food whilst limiting the microorganism to dwell exclusively in between a confined, well enclosed area of the material. We demonstrated a design of such living materials and showed both active (eating) and waiting (dormant, hibernation) states with additional recovery for reinitiation of a new active state by observing the metabolic activity over two full nutrition cycles of the living material (active, hibernation, reactivation). This novel class of living materials can be expected to provide nonclassical solutions in consumer goods such as packaging, indoor surfaces, and in biotechnology. PMID- 22198771 TI - Cyanobacterial metallochaperone inhibits deleterious side reactions of copper. AB - Copper metallochaperones supply copper to cupro-proteins through copper-mediated protein-protein-interactions and it has been hypothesized that metallochaperones thereby inhibit copper from causing damage en route. Evidence is presented in support of this latter role for cyanobacterial metallochaperone, Atx1. In cyanobacteria Atx1 contributes towards the supply of copper to plastocyanin inside thylakoids but it is shown here that in copper-replete medium, copper can reach plastocyanin without Atx1. Unlike metallochaperone-independent copper supply to superoxide dismutase in eukaryotes, glutathione is not essential for Atx1-independent supply to plastocyanin: Double mutants missing atx1 and gshB (encoding glutathione synthetase) accumulate the same number of atoms of copper per cell in the plastocyanin pool as wild type. Critically, Deltaatx1DeltagshB are hypersensitive to elevated copper relative to wild type cells and also relative to DeltagshB single mutants with evidence that hypersensitivity arises due to the mislocation of copper to sites for other metals including iron and zinc. The zinc site on the amino-terminal domain (ZiaA(N)) of the P(1)-type zinc transporting ATPase is especially similar to the copper site of the Atx1 target PacS(N), and ZiaA(N) will bind Cu(I) more tightly than zinc. An NMR model of a substituted-ZiaA(N)-Cu(I)-Atx1 heterodimer has been generated making it possible to visualize a juxtaposition of residues surrounding the ZiaA(N) zinc site, including Asp(18), which normally repulse Atx1. Equivalent repulsion between bacterial copper metallochaperones and the amino-terminal regions of P(1)-type ATPases for metals other than Cu(I) is conserved, again consistent with a role for copper metallochaperones to withhold copper from binding sites for other metals. PMID- 22198772 TI - The rational design of a synthetic polymer nanoparticle that neutralizes a toxic peptide in vivo. AB - Synthetic polymer nanoparticles (NPs) that bind venomous molecules and neutralize their function in vivo are of significant interest as "plastic antidotes." Recently, procedures to synthesize polymer NPs with affinity for target peptides have been reported. However, the performance of synthetic materials in vivo is a far greater challenge. Particle size, surface charge, and hydrophobicity affect not only the binding affinity and capacity to the target toxin but also the toxicity of NPs and the creation of a "corona" of proteins around NPs that can alter and or suppress the intended performance. Here, we report the design rationale of a plastic antidote for in vivo applications. Optimizing the choice and ratio of functional monomers incorporated in the NP maximized the binding affinity and capacity toward a target peptide. Biocompatibility tests of the NPs in vitro and in vivo revealed the importance of tuning surface charge and hydrophobicity to minimize NP toxicity and prevent aggregation induced by nonspecific interactions with plasma proteins. The toxin neutralization capacity of NPs in vivo showed a strong correlation with binding affinity and capacity in vitro. Furthermore, in vivo imaging experiments established the NPs accelerate clearance of the toxic peptide and eventually accumulate in macrophages in the liver. These results provide a platform to design plastic antidotes and reveal the potential and possible limitations of using synthetic polymer nanoparticles as plastic antidotes. PMID- 22198774 TI - Test sequence in the management of gastrointestinal bleeding. AB - BACKGROUND AND STUDY AIM: A large variety of test procedures is available to diagnose and treat patients with suspected gastrointestinal bleeding. The aim of the study was to investigate which test sequence should be utilized in managing gastrointestinal bleeding. METHODS: For each endoscopic, radiologic, or laboratory test procedure, professional fees and facility costs were estimated based on payments allowed by the US Centers for Medicare and Medicaid Services during the fiscal year 2010. A threshold analysis was used to compare the costs associated with different test sequences of varying clinical scenarios. RESULTS: A threshold represents the lowest expected probability of success, for which a test would still be indicated. In a work-up including all possible management options, the threshold associated with laboratory tests and gastric lavage was 1 %, esophagogastroduodenoscopy (EGD) 8 %, colonoscopy 9 %, nuclear scan 9 %, enteroscopy 11 %, computed tomography (CT) angiography 14 %, capsule endoscopy 23 %, and angiography with transcatheter embolization 25 %. Varying sets of thresholds were calculated for different clinical scenarios. The thresholds of EGD and colonoscopy remained low in most scenarios. In sensitivity analysis, rising risk of complications or costs of a procedure also lead to rising threshold values for it, potentially rendering the particular procedure untenable. CONCLUSIONS: A low threshold indicated a preferred management option that should be used early rather than late in a sequence of multiple possible test procedures to work up instances of gastrointestinal bleeding. PMID- 22198775 TI - Measurement of IgG4 in bile: a new approach for the diagnosis of IgG4-associated cholangiopathy. AB - BACKGROUND AND STUDY AIMS: Immunoglobulin G4 (IgG4)-associated cholangitis (IAC) is difficult to diagnose because on cholangiography the associated biliary tract strictures cannot be differentiated from cholangiocarcinoma or primary sclerosing cholangitis (PSC). Serum IgG4 levels show a low sensitivity and specificity and are unreliable, particularly in patients with related diseases such as PSC. As IAC takes place at the biliary epithelium, we hypothesized that IgG4 measurement in bile may have higher sensitivity compared with serum. METHODS: Bile and serum samples were collected during cholangiography in 67 patients, including 23 patients with PSC, 25 with cholangiocarcinoma, 14 with choledocholithiasis, and five with IAC. IgG4 was measured in both bile and serum. RESULTS: Bile IgG4 levels were markedly elevated in patients with IAC compared with patients with other biliary disorders. Whereas elevated serum IgG4 levels were found both in patients with PSC and IAC, biliary IgG4 levels were only increased in patients with IAC. CONCLUSIONS: The study demonstrates that bile IgG4 measurement is possible and may help to distinguish IAC from other diseases. PMID- 22198776 TI - Combination of diclofenac plus somatostatin in the prevention of post-ERCP pancreatitis: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND AND STUDY AIMS: Pancreatitis is the most common complication of therapeutic endoscopic retrograde cholangiopancreatography (ERCP), and many pharmacoprophylactic approaches have been suggested, though not without controversy. The aim was to investigate the impact of combined therapy with diclofenac plus somatostatin on reducing the frequency and severity of post-ERCP pancreatitis (PEP). PATIENTS AND METHODS: A prospective, double-blind, placebo controlled trial was conducted in two tertiary referral centers, with 540 eligible patients randomized to receive either combined therapy with diclofenac 100 mg rectally 30 to 60 minutes before ERCP plus somatostatin 0.25 mg/h for 6 hours (group A), or a placebo suppository identical in appearance to the diclofenac along with saline solution (group B). Patients were clinically evaluated and serum amylase levels were determined before ERCP and at 6 and 24 hours post-procedure. Standardized criteria were used to diagnose and grade the severity of PEP. Adverse events were recorded prospectively. RESULTS: There were no statistical differences between the groups regarding demographic data, ERCP findings, and procedure risk factors for PEP. The overall incidence of acute pancreatitis was 7.2 %. The PEP rate was significantly lower in the patients who received the combination therapy than in controls (4.7 % vs. 10.4 %, P = 0.015). Previous history of acute pancreatitis (P = 0.001), pancreatic opacification of first-class branches and beyond (P = 0.008), and absence of pharmacoprophylaxis (P = 0.023) were identified as independent risk factors for PEP in multivariate analysis. CONCLUSION: Although combined prophylactic therapy with diclofenac plus somatostatin was promising in reducing frequency of PEP, further comparative large-scale studies are needed to confirm our findings before definitive conclusions can be drawn. PMID- 22198777 TI - What an endoscopist should know about immunoglobulin-G4-associated disease of the pancreas and biliary tree. AB - Autoimmune pancreatitis (AIP) and IgG4-associated cholangitis (IAC) are the recently recognized pancreatobiliary manifestations of IgG4-associated systemic disease (ISD). Clinically, ISD of the pancreas and/or biliary tree may mimic pancreatic cancer, sclerosing cholangitis, or cholangiocarcinoma. Patients often present with abdominal pain, weight loss, jaundice, itch, and biochemical signs of pancreatitis and cholestasis. Tomography may reveal enlargement of the pancreas or may mimic malignant pancreatic lesions, and cholangiopancreatography may disclose irregularities of the pancreatic duct and stenoses of the distal and/or proximal common bile duct and intrahepatic bile ductules. Serum immunoglobulin G4 (IgG4) is elevated in most patients but, unlike tissue IgG4 loaded plasma cell infiltrates, is not diagnostic of the disease. The application of consensus diagnostic criteria for laboratory investigations, imaging, and histologic findings can identify patients who qualify for corticosteroid treatment. The excellent response to immunosuppressive therapy suggests an immune mediated etiology of the disease, but the exact pathophysiological mechanisms are still under investigation. Relapse may occur after tapering down of corticosteroids, which supports the rationale of maintenance immunosuppression after remission has been induced. PMID- 22198779 TI - Long term follow-up of appendiceal and distal right-sided colonic inflammation. AB - The aim of this study was to investigate the possibility of appendiceal orifice inflammation (AOI) as a preceding lesion in the development of ulcerative colitis. A total of 20 patients were identified (mean age 41.2 years; 11 males) who had ulcerative colitis-like inflammatory lesions at the appendiceal orifice without concomitant typical features of ulcerative colitis, such as rectal involvement. A total of 19 patients were followed up endoscopically for a mean duration of 18.4 months (range 2 - 84 months). Typical ulcerative colitis developed in five patients (25 %; four proctitis, one pancolitis) in a mean time of 18.4 months (range 2 - 36 months). Negative conversion of all inflammatory lesions occurred in seven patients (35 %) after a mean follow-up of 20 months (range 3 - 84 months). In the remaining seven patients (35 %), initial lesions did not progress to ulcerative colitis and did not go into remission during a mean follow-up of 16.9 months (range 2 - 42 months). These results suggest that, at least in some cases, AOI precedes development of ulcerative colitis. PMID- 22198780 TI - Endoscopic ultrasound-guided fine needle aspiration in cystic pancreatic lesions: is it still controversial? PMID- 22198782 TI - Endoscopic ultrasound features of mediastinal tuberculosis. PMID- 22198785 TI - Where we are with community-associated Staphylococcus aureus prevention--and in the meantime, what do we tell our patients? PMID- 22198786 TI - beta-Glucan antigenemia assay for the diagnosis of invasive fungal infections in patients with hematological malignancies: a systematic review and meta-analysis of cohort studies from the Third European Conference on Infections in Leukemia (ECIL-3). AB - BACKGROUND: Invasive fungal infections (IFIs) are life-threatening complications in patients with hemato-oncological malignancies, and early diagnosis is crucial for outcome. The compound 1,3-beta-D-glucan (BG), a cell wall component of most fungal species, can be detected in blood during IFI. Four commercial BG antigenemia assays are available (Fungitell, Fungitec-G, Wako, and Maruha). This meta-analysis from the Third European Conference on Infections in Leukemia (ECIL 3) assessed the performance of BG assays for the diagnosis of IFI in hemato oncological patients. METHODS: Studies reporting the performance of BG antigenemia assays for the diagnosis of IFI (European Organization for Research and Treatment of Cancer and Mycoses Study Group criteria) in hemato-oncological patients were identified. The analysis was focused on high-quality cohort studies with exclusion of case-control studies. Meta-analysis was performed by conventional meta-analytical pooling and bivariate analysis. RESULTS: Six cohort studies were included (1771 adult patients with 414 IFIs of which 215 were proven or probable). Similar performance was observed among the different BG assays. For the cutoff recommended by the manufacturer, the diagnostic performance of the BG assay in proven or probable IFI was better with 2 consecutive positive test results (diagnostic odds ratio for 2 consecutive vs one single positive results, 111.8 [95% confidence interval {CI}, 38.6-324.1] vs 16.3 [95% CI, 6.5-40.8], respectively; heterogeneity index for 2 consecutive vs one single positive results, 0% vs 72.6%, respectively). For 2 consecutive tests, sensitivity and specificity were 49.6% (95% CI, 34.0%-65.3%) and 98.9% (95% CI, 97.4%-99.5%), respectively. Estimated positive and negative predictive values for an IFI prevalence of 10% were 83.5% and 94.6%, respectively. CONCLUSIONS: Different BG assays have similar accuracy for the diagnosis of IFI in hemato-oncological patients. Two consecutive positive antigenemia assays have very high specificity, positive predictive value, and negative predictive value. Because sensitivity is low, the test needs to be combined with clinical, radiological, and microbiological findings. PMID- 22198787 TI - Rapid diagnostic test-based management of malaria: an effectiveness study in Papua New Guinean infants with Plasmodium falciparum and Plasmodium vivax malaria. AB - BACKGROUND: In malaria-endemic areas it is recommended that febrile children be tested for malaria by rapid diagnostic test (RDT) or blood slide (BS) and receive effective malaria treatment only if results are positive. However, RDTs are known to perform less well for Plasmodium vivax. We evaluated the safety of withholding antimalarial drugs from young Papua New Guinean children with negative RDT results in areas with high levels of both Plasmodium falciparum and P. vivax infections. METHODS: Longitudinal prospective study of children aged 3-27 months visiting outpatient clinics for fever. RDT was administered at first visit. RDT and microscopy were performed if children returned because of persistent symptoms. Outcomes were rates of reattendance and occurrence of severe illnesses. RESULTS: Of 5670 febrile episodes, 3942 (70%) involved a negative RDT result. In 133 cases (3.4%), the children reattended the clinic within 7 days for fever, of whom 29 (0.7%) were parasitemic by RDT or microscopy. Of children who reattended, 24 (0.7%) presented with a severe illness: 2 had lower respiratory tract infections (LRTIs) with low-density P. vivax on BS; 2 received a diagnosis of P. vivax malaria on the basis of RDT but BSs were negative; 16 had LRTIs; 3 had alternative diagnoses. Of these 24, 22 were cured at day 28. Two children died of illnesses other than malaria and were RDT and BS negative at the initial and subsequent visits. CONCLUSION: Treatment for malaria based on RDT results is safe and feasible even in infants living in areas with moderate to high endemicity for both P. falciparum and P. vivax infections. PMID- 22198788 TI - Short- and long-term immunological and virological outcome in HIV-infected infants according to the age at antiretroviral treatment initiation. AB - The clinical benefit of antiretroviral therapy in infants is established. In this cohort collaboration, we compare immunological and virological response to treatment started before or after 3 months of age. Early initiation provides a better short-term response, although evolution after 12 months of age is similar in both groups. PMID- 22198778 TI - Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED). AB - Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy (ESGE), the European Helicobacter Study Group (EHSG), the European Society of Pathology (ESP) and the Sociedade Portuguesa de Endoscopia Digestiva (SPED) have therefore combined efforts to develop evidence based guidelines on the management of patients with precancerous conditions and lesions of the stomach (termed MAPS). A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia, and the need for adequate staging in the case of high grade dysplasia, and they focus on treatment and surveillance indications and methods. PMID- 22198789 TI - Sulfur mustard: a liquid, not a gas. PMID- 22198790 TI - Additional drug resistance in Mycobacterium tuberculosis isolates from resected cavities among patients with multidrug-resistant or extensively drug-resistant pulmonary tuberculosis. AB - The pathogenesis of increasing drug resistance among patients with multidrug resistant or extensively drug-resistant tuberculosis undergoing treatment is poorly understood. Increasing drug resistance found among Mycobacterium tuberculosis recovered from cavitary isolates compared with paired sputum isolates suggests pulmonary cavities may play a role in the development of worsening tuberculosis drug resistance. PMID- 22198791 TI - High prevalence of cryptococcal infection among HIV-infected patients hospitalized with pneumonia in Thailand. AB - BACKGROUND: Cryptococcal meningitis (CM) is a major cause of death among HIV infected patients. Cryptococcal antigenemia (CrAg+) in the absence of CM can represent early-stage cryptococcosis during which antifungal treatment might improve outcomes. However, patients without meningitis are rarely tested for cryptococcal infection. We evaluated Cryptococcus species as a cause of acute respiratory infection in hospitalized patients in Thailand and evaluated clinical characteristics associated with CrAg+. METHODS: We tested banked serum samples from 704 human immunodeficiency virus (HIV)-infected and 730 HIV-uninfected patients hospitalized with acute respiratory infection from 2004 through 2009 in 2 rural provinces in Thailand for the presence of CrAg+. Retrospective chart reviews were conducted for CrAg+ patients to distinguish meningeal and nonmeningeal cryptococcosis and to identify clinical characteristics associated with CrAg+ in patients with and without evidence of CM. RESULTS: CrAg+ was found in 92 HIV-infected patients (13.1%); only tuberculosis (19.3%) and rhinovirus (16.5%) were identified more frequently. No HIV-uninfected patients were CrAg+. Of 70 CrAg+ patients with medical charts available, 37 (52.9%) had no evidence of past or existing CM at hospitalization; 30 of those patients (42.9% of all CrAg+) had neither past nor existing CM, nor any alternate etiology of infection identified. Dyspnea was more frequent among CrAg+ patients without CM than among CrAg- patients (P = .0002). CONCLUSIONS: Cryptococcus species were the most common pathogens detected in HIV-infected patients hospitalized with acute respiratory infection in Thailand. Few clinical differences were found between antigenemic and nonantigenemic HIV-infected patients. Health care providers in Thailand should evaluate HIV-infected patients hospitalized with acute respiratory infection for cryptococcal antigenemia, even in the absence of meningitis. PMID- 22198792 TI - Staphylococcus aureus: is it a pathogen of acute bacterial sinusitis in children and adults? AB - Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the etiologic agents of acute bacterial sinusitis (ABS). Staphylococcus aureus has been an uncommon cause of ABS despite its frequent occupancy within the anterior nares. A quantitative culture of a maxillary sinus aspirate is the gold standard for determining etiology of ABS. Cultures of the middle meatus cannot be used as a surrogate for a maxillary sinus aspirate in children with ABS, although they may be used in adults if interpretation is confined to usual sinus pathogens. Recent studies highlighting S. aureus as a major pathogen in ABS should be interpreted cautiously. Most isolates in recent pediatric studies were derived from cultures of the middle meatus. The range of reported results for the incidence of S. aureus as a cause of ABS in adults is similar to the results reported for staphylococcal colonization of the middle meatus in healthy adults. PMID- 22198794 TI - Low vision rehabilitation plans comparing two intake methods. AB - PURPOSE: This qualitative study investigates possible differences in identified rehabilitation needs indicated by the usual intake procedures at a Multidisciplinary Rehabilitation Center (MRC) for visually impaired persons compared with those indicated by the use of a structured Dutch version [based on the International Classification of the Disability, Functioning and Health (ICF)] of the Activity Inventory (D-AI). METHODS: Twenty patients who enrolled at the MRC received a D-AI assessment by telephone, in addition to the usual intake. All patients received usual care, based on rehabilitation needs identified by the usual intake procedure at the MRC. Rehabilitation needs identified at the MRC were obtained from patient files retrospectively and were compared with rehabilitation needs identified by the D-AI. RESULTS: The mean number of rehabilitation needs reported in the patient files was 6.9 (+/- 5.1) vs. 24.0 (+/ 11.2) using the D-AI. Only 22.6% (+/- 14.3) of the rehabilitation needs identified by the D-AI were present in the patient files; 79.3% (+/- 28.2) of the rehabilitation needs reported in the patient files were identified by the D-AI. Overall agreement corrected for chance between both intake methods revealed a fair Cohen kappa of 0.27. CONCLUSIONS: At the MRC, more needs were revealed using the D-AI compared with the usual intake procedure. The systematic character of the D-AI prevents important topics being overlooked. In the usual intake, it was not clear whether needs were investigated from the patient's perspective. This may hamper (medical) communication and shared decision making about the rehabilitation program that needs to be followed. Moreover, using the unstructured information from the patient files makes it difficult to evaluate rehabilitation outcomes. With the D-AI, although an extensive overview of rehabilitation needs is produced, it remains difficult to focus on the most relevant needs. However, after assessment with the D-AI, all aspects of the ICF, Disability, and Health scheme can be discussed in a process of shared decision making, which leads to the final determination of rehabilitation goals. PMID- 22198795 TI - Impaired face processing in early monocular deprivation from enucleation. AB - PURPOSE: We investigated the effects of early monocular enucleation (ME) (surgical removal of one eye) on a high-level spatial visual ability, namely face perception. Early monocular deprivation of pattern vision from disorders such as strabismus, amblyopia, or cataract is associated with impairments in low-level spatial vision. This is inconsistent with studies of early ME that show either equivalent or enhanced low-level spatial vision compared with controls. Impairments on some aspects of face perception (i.e., feature-spacing and holistic face processing, both of which mature later in life) have been found with early pattern deprivation from congenital cataract. It is not clear whether the intact low-level spatial vision with ME will also persist with high-level face perception or whether deficits similar to those found with cataract will emerge. METHODS: We tested individuals who have experienced early ME and controls on a series of high-level spatial visual tasks that measure feature-spacing, feature, and holistic face processing. RESULTS: The ME group were slower for feature spacing and feature tasks. Furthermore, the ME group did not exhibit the normal pattern of poorer performance on the aligned compared with misaligned composite face discrimination tasks, demonstrating a lack of the composite face effect. However, they did show the normal pattern of poorer performance on same vs. different trials on the aligned tasks. CONCLUSIONS: These results indicate an impairment in the feature spacing and feature aspects of face perception with ME. They also suggest a present yet, incomplete, development of holistic face processing in this group. Although the complete removal of inhibitory binocular interactions and/or the absence of binocular competition in early ME may result in cortical reorganization of the visual system and preserve low- to mid-level spatial vision, it may be insufficient for the maturation of high-level face perception. PMID- 22198793 TI - Household versus individual approaches to eradication of community-associated Staphylococcus aureus in children: a randomized trial. AB - BACKGROUND: Community-associated Staphylococcus aureus infections often affect multiple members of a household. We compared 2 approaches to S. aureus eradication: decolonizing the entire household versus decolonizing the index case alone. METHODS: An open-label, randomized trial enrolled 183 pediatric patients (cases) with community-onset S. aureus skin abscesses and colonization of anterior nares, axillae, or inguinal folds from 2008 to 2009 at primary and tertiary centers. Participants were randomized to decolonization of the case alone (index group) or of all household members (household group). The 5-day regimen included hygiene education, twice-daily intranasal mupirocin, and daily chlorhexidine body washes. Colonization of cases and subsequent skin and soft tissue infection (SSTI) in cases and household contacts were ascertained at 1, 3, 6, and 12 months. RESULTS: Among 147 cases with 1-month colonization data, modified intention-to-treat analysis revealed S. aureus eradication in 50% of cases in the index group and 51% in the household group (P = 1.00). Among 126 cases completing 12-month follow-up, S. aureus was eradicated from 54% of the index group versus 66% of the household group (P = .28). Over 12 months, recurrent SSTI was reported in 72% of cases in the index group and 52% in the household group (P = .02). SSTI incidence in household contacts was significantly lower in the household versus index group during the first 6 months; this trend continued at 12 months. CONCLUSIONS: Household decolonization was not more effective than individual decolonization in eradicating community-associated S. aureus carriage from cases. However, household decolonization reduced the incidence of subsequent SSTI in cases and their household contacts. CLINICAL TRIALS REGISTRATION: NCT00731783. PMID- 22198796 TI - Objective and subjective refractive error measurements in monkeys. AB - PURPOSE: To better understand the functional significance of refractive-error measures obtained using common objective methods in laboratory animals, we compared objective and subjective measures of refractive error in adolescent rhesus monkeys. METHODS: The subjects were 20 adolescent monkeys. Spherical equivalent spectacle-plane refractive corrections were measured by retinoscopy and autorefraction while the animals were cyclopleged and anesthetized. The eye's axial dimensions were measured by A-Scan ultrasonography. Subjective measures of the eye's refractive state, with and without cycloplegia, were obtained using psychophysical methods. Specifically, we measured spatial contrast sensitivity as a function of spectacle lens power for relatively high spatial frequency gratings. The lens power that produced the highest contrast sensitivity was taken as the subjective refraction. RESULTS: Retinoscopy and autorefraction consistently yielded higher amounts of hyperopia relative to subjective measurements obtained with or without cycloplegia. The subjective refractions were not affected by cycloplegia and on average were 1.42 +/- 0.61 D and 1.24 +/- 0.62 D less hyperopic than the retinoscopy and autorefraction measurements, respectively. Repeating the retinoscopy and subjective measurements through 3 mm artificial pupils produced similar differences. CONCLUSIONS: The results show that commonly used objective methods for assessing refractive errors in monkeys significantly overestimate the degree of hyperopia. It is likely that multiple factors contributed to the hyperopic bias associated with these objective measurements. However, the magnitude of the hyperopic bias was in general agreement with the "small-eye artifact" of retinoscopy. PMID- 22198797 TI - Assessing corneal hysteresis using the Ocular Response Analyzer. AB - PURPOSE: An examination of studies that have assessed corneal biomechanical performance using the Ocular Response Analyzer (ORA: Reichert Ophthalmic Instruments, Depew, NY) raises some questions regarding the influence of measurement variables and the interpretation of the findings obtained with this instrument. This analysis of those questions describes additional factors which do or may contribute to the assessment of corneal hysteresis (CH). METHODS: Using key words CH and ORA, English language articles relevant to this analysis were selected after a PubMed search with the addition of some articles referenced in the selected publications. RESULTS: Corneal thickness, the level of edema, intraocular pressure, and corneal temperature as well as the area, location, rate, duration, and sequence of corneal unloading and loading may need to be considered as significant variables when assessing CH. CONCLUSIONS: CH values may be specific to measurement method and conditions rather than representing an unequivocal corneal property. Consideration of the uncontrolled variables involved may help explain some of the findings obtained with the ORA. That a CH measurement might vary with the sequence of unloading and loading suggests that the ORA CH finding may not represent the CH, but instead represents a hysteresis value better described as central, applanation-derived hysteresis, which is based on a very short unloading/loading sequence. The potential for the ORA to contribute to improved clinical management appears to be considerable but so does the need for better understanding and further development of its functions and applications. PMID- 22198798 TI - Grassland plant species diversity decreases invasion by increasing resource use. AB - Species richness of plant communities has been demonstrated to provide resistance to invasion by unsown species, though the relationship with resource availability varies between studies. The present work involved five grassland species grown in monocultures and in four-species mixtures sown in accordance with a simplex design. The species used represented different functional groups (i.e. grasses, legumes and non-N(2)-fixing species), each of which differed internally in terms of competitiveness. I hypothesized that sown diversity would negatively affect invader performance by decreasing the availability of light and soil nitrogen (N) for invading species, and that functional composition of the sown diversity would affect the functional composition of the invading flora. The experimental plots were harvested for two years, and were fertilized with 100 kg N ha(-1) each year. The number of unsown species (classified into four functional groups) invading each plot and their proportion of the biomass harvested were recorded. The penetration of incoming light through the canopy, the apparent N uptake by the sown species from the soil, and the mineral N content in the soil were measured. I found that diverse communities captured more resources both above- and belowground, and the number of invading species and their biomass production were smaller in mixed than in monoculture plots. However, the sampling effect of one grass was also strong. These results suggest that increased resource use in diverse communities can reduce invasion. PMID- 22198799 TI - Carboplatin-gemcitabine combination chemotherapy upregulates AKR1B10 expression in bladder cancer. AB - BACKGROUND: AKR1B10 is considered to contribute to cell proliferation and chemoresistance. In the present study, we examined whether AKR1B10 expression is associated with disease-free survival in bladder cancer patients. METHODS: We obtained bladder cancer specimens from 10 patients before and after chemotherapy and measured AKR1B10 mRNA levels using real-time PCR. In addition, we conducted an immunohistochemical examination of AKR1B10 expression in 57 patients with bladder cancer before and after chemotherapy. RESULTS: AKR1B10 mRNA expression was significantly higher in the post-chemotherapy group than in the pre chemotherapy group (p < 0.001). The average immunohistochemical intensity score in the pre-chemotherapy group was 0.83 +/- 1.08, compared with the significantly higher score of 2.03 +/- 1.03 in the post-chemotherapy group (p < 0.001). The disease-free survival rate of post-chemotherapy AKR1B10(+) patients (61.2%) was significantly lower than that of AKR1B10(-) patients (100%) (log-rank test, p = 0.039). CONCLUSIONS: Although the present study is small and preliminary, our data suggest that post-chemotherapy AKR1B10 expression may be associated with a poor prognosis in patients who received carboplatin-gemcitabine combination chemotherapy and underwent cystectomy. Further study is warranted to elucidate its clinical significance. PMID- 22198800 TI - Health-related quality of life in Japanese patients with metastatic renal cell carcinoma treated with sunitinib. AB - BACKGROUND: To analyze the impact of sunitinib treatment on health-related quality of life (HRQOL) in Japanese patients with metastatic renal cell carcinoma (mRCC). METHODS: This study prospectively included 90 consecutive patients with mRCC treated with sunitinib for at least 3 months. HRQOL in these patients was assessed using the Medical Outcomes Study 36-Item Short Form (SF-36) consisting of 8 multi-item scales measuring health status. RESULTS: There were no significant differences in any of the 8 scores in these 90 patients between surveys conducted before and 3 months after sunitinib treatment. Three months after treatment, all 8 scores in patients who had some degree of tumor shrinkage were more favorable than those in the remaining patients, and there were significant differences in 2 of the 8 scale scores (role limitations because of emotional problems, mental health) between these two groups. However, there were no significant differences in any scale scores except one (social function) between patients with and without severe adverse events (AEs). Furthermore, a significant time-dependent improvement was observed in one score (body pain), while there were no significant differences in the remaining 7 scores 3, 6 and 12 months after sunitinib treatment in 29 patients who could be followed for at least 12 months. CONCLUSIONS: Although this was a non-randomized study including a comparatively small number of patients, these findings suggest that efficacy rather than AE is likely to be associated with HRQOL in Japanese mRCC patients treated with sunitinib. PMID- 22198801 TI - Pharmacotherapies for Alzheimer's disease: beyond cholinesterase inhibitors. AB - Alzheimer's disease (AD) is the most common cause of memory impairment and dementia in the elderly. AD is pathologically characterized by extracellular deposits of beta-amyloid (Abeta) peptide, neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, neuronal loss, and neurotransmitter dysfunction. Clinically, AD is characterized by progressive cognitive decline that usually starts with memory impairment and progresses to cause a more generalized cognitive dysfunction, behavioral dysregulation, and neuropsychiatric symptoms. These symptoms collectively lead to a progressive and relentless decline in the ability to perform functions of daily living, eventually leading to total incapacitation. The incidence and prevalence of AD are expected to exponentially increase with the aging of the population. Currently approved treatments, including the acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine and rivastigmine, and the N-methyl-D-aspartate (NMDA) antagonist memantine, do not halt the progression of the disease, and have provided marginal therapeutic benefits. Accordingly, there is an urgent need to develop novel and effective medications for AD that go beyond AChEIs and NMDA antagonists. Modern research has focused on discovering effective disease-modifying therapies, which specifically target the pathophysiologic cascade, hoping to delay the onset of the disease and slow its progression. In this review, different pharmacological drugs and therapeutic approaches will be discussed, with an emphasis on novel therapies that are currently being investigated in clinical trials. PMID- 22198802 TI - Immature platelet fraction (IPF) determined with an automated method predicts clopidogrel hyporesponsiveness. AB - The mechanisms for the variability in antiplatelet effects of clopidogrel are not elucidated entirely. Immature (reticulated) platelets may modulate the antiplatelet effects of clopidogrel but must be measured using flow cytometry. Whether new automated detection techniques yield similar results is not known. The objectives of the study to evaluate the role of immature platelets assessed by an automated method in response to the antiplatelet effects of clopidogrel. Twenty-nine healthy volunteers had platelet studies performed before and 1 week after 75 mg daily dosing of clopidogrel. Immature platelet fraction (IPF) was determined using an automated particle counter. Subjects were stratified into tertiles based on the IPF. Platelet studies included light transmission aggregometry (LTA), and vasodilator stimulated phosphoprotein phosphorylation (VASP-P) determined by platelet reactivity index (PRI). Baseline platelet aggregation responses to 2, 5 and 20 MUM ADP, were similar in all three tertiles, however they were greater in the upper than in the lower tertile of immature platelets after clopidogrel in response to 5 MUM ADP (54% vs. 23%, P = 0.02), with concordant trends for the other two concentrations. PRI was also greater in the upper tertile after clopidogrel (71.2% vs. 57.8%, P = 0.04). The frequency of clopidogrel hyporesponsiveness (aggregation >50% in response to 5 MUM of ADP) was also higher in the upper tertile when compared to lower tertile, (60%) versus (10%) respectively (P = 0.02). [corrected]. Immature platelets measured using an automated method, are associated with impaired response to antiplatelet effects of clopidogrel. PMID- 22198805 TI - Seasonal leptin resistance is associated with impaired signalling via JAK2-STAT3 but not ERK, possibly mediated by reduced hypothalamic GRB2 protein. AB - The Siberian hamster, Phodopus sungorus, undergoes a striking seasonal cycle of leptin sensitivity and body weight regulation, but the molecular mechanism and relevance to human leptin insensitivity are unknown. Here we show that nuclear translocation of phospho-STAT3 in the hypothalamus is rapidly stimulated by leptin to a greater extent in hamsters held in short-day length (SD) as compared to long-day length (LD). Intriguingly, effects of leptin on STAT3 appeared to be in part limited to nuclear translocation of phospho-STAT3 associated with the cell surface rather than phosphorylation of STAT3. The number of phospho-ERK cells within the hypothalamus was unaffected by either photoperiod or leptin. However, proximal to ERK phosphorylation, hypothalamic SH2-containing tyrosine phosphatase (SHP2) and the small growth factor receptor-binding protein (GRB2), which act as competitive negative modulators on binding of SOCS3 to leptin receptor (LRb)-associated Tyr985, were increased in SD compared to LD. Our findings suggest that activation of STAT3 by leptin may be dependent on interaction of stimulatory SHP2/GRB2 as well as inhibitory SOCS3 on the level of competitive binding to LRb-associated Tyr985. This hypothetical mechanism may represent the molecular identity of seasonally induced adjustments in leptin sensitivity and may be applied to investigating leptin sensitivity in other rodent models. PMID- 22198804 TI - Melatonin as a neuroprotective agent in the rodent models of Parkinson's disease: is it all set to irrefutable clinical translation? AB - Parkinson's disease (PD), a neurodegenerative disorder, is characterized by the selective degeneration of the nigrostriatal dopaminergic neurons, continuing or permanent deficiency of dopamine, accretion of an abnormal form of alpha synuclein in the adjacent neurons, and dysregulation of ubiquitin proteasomal system, mitochondrial metabolism, permeability and integrity, and cellular apoptosis resulting in rigidity, bradykinesia, resting tremor, and postural instability. Melatonin, an indoleamine produced almost in all the organisms, has anti-inflammatory, anti-apoptotic, and anti-oxidant nature. Experimental studies employing 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine (MPTP), 6 hydroxydopamine (6-OHDA), methamphetamine, rotenone, and maneb and paraquat models have shown an enormous potential of melatonin in amelioration of the symptomatic features of PD. Although a few reviews published previously have described the multifaceted efficacy of melatonin against MPTP and 6-OHDA rodent models, due to development and validation of the newer models as well as the extensive studies on the usage of melatonin in entrenched PD models, it is worthwhile to bring up to date note on the usage of melatonin as a neuroprotective agent in PD. This article presents an update on the usage and applications of melatonin in PD models along with incongruous observations. The impending implications in the clinics, success, limitations, and future prospective have also been discussed in this article. PMID- 22198806 TI - Twenty-five years later--what do we know about religion/spirituality and psychological well-being among breast cancer survivors? A systematic review. AB - INTRODUCTION: A diagnosis of cancer is a life-changing event for most people. The trauma and uncertainties of a breast cancer diagnosis can affect survivors' psychological well-being. Religion and/or spirituality can provide a means of support for many women as they live with the realities of a diagnosis of cancer. The purpose of this focused review is to critically analyze and synthesize relationships among psychological well-being, religion, and spirituality among women with breast cancer. METHODS: MEDLINE, CINAHL, Web of Science, Cambridge Scientific Abstracts, Cochrane CENTRAL, and PsycINFO databases were searched: January 1985-March 2010. The search terms religi*(religious/religion), spiritu*(spiritual/spirituality), breast cancer, psychological adjustment, psychological outcomes, psychological distress, psychological well-being, and outcomes were searched for separately and in combination. RESULTS: Eighteen quantitative studies were analyzed in order to examine associations among religion, spirituality, and psychological well-being for women diagnosed with breast cancer. These three variables were operationally defined as follows: (a) religious practice, religious coping, and perception of God; (b) spiritual distress, spiritual reframing, spiritual well-being, and spiritual integration; and (c) combined measure of both the religion and spirituality constructs. DISCUSSION/CONCLUSIONS: Results of this review suggest that within this population, limited relationships exist among religion, spirituality, and psychological well-being. Given the various definitions used for the three variables, the strength and clarity of relationships are not clear. In addition, the time of assessment along the course of the disease varies greatly and in some instances is not reported. Diagnosis and/or prognosis, factors that could influence psychological well-being, are frequently not factored into results. There does, however, appear to be sufficient evidence to include a brief, clinically focused assessment of women diagnosed with breast cancer regarding the importance of a given belief system as they face the diagnosis and treatment of their disease. IMPLICATIONS FOR CANCER SURVIVORS: The implications for cancer survivors are as follows: (a) Psychological well-being of women diagnosed with breast cancer may depend to some extent on their belief system. (b) Coping through "turning to God" for women without a significant prior relationship with God, or minimal spiritual behaviors, may experience diminished well-being. (c) Longitudinal studies suggest that struggling with, or questioning, one's belief system in early survivorship may also be associated with lower levels of well being. This diminished well-being often resolves over time. PMID- 22198807 TI - Prune belly syndrome. AB - The majority of paediatric surgeons will encounter a patient with prune belly syndrome (PBS) only a few times in their clinical practice. There have been many opposing views in the literature regarding the pathogenesis and management of this complex condition. A detailed review was conducted using PubMed to identify key publications involving PBS. This article discusses the evolution of our understanding of the pathogenesis and diagnosis of PBS, including its typical characteristics. We describe the management options available for bilateral intra abdominal testes, the deficient abdominal wall, the dilated urinary system and examine the evidence base used to support the current approaches employed. PMID- 22198808 TI - Neuroendocrine pancreatic tumors: guidelines for management and update. AB - Pancreatic neuroendocrine tumors (PanNETs) are a diverse group of rare neoplasms. Commonly referred to as islet cell tumors, PanNETs are classified as functional or nonfunctional depending on their production of specific pancreatic endocrine hormones (e.g. insulin, gastrin, glucagon, and others) and association with the resultant clinical syndromes. While most PanNETs are sporadic, syndromic patients, in particular those with multiple endocrine neoplasia type 1 (MEN-1) and von Hippel Lindau (VHL), are at increased risk of developing these tumors. Recent investigations of patients with sporadic and syndromic PanNETs have elucidated critical pathways in tumor development, such as mammalian target of rapamycin (mTOR) signaling and its downstream growth factors such as vascular endothelial growth factor (VEGF). Prognosis ranges from favorable for localized, low-grade neoplasms to poor for advanced, high-grade tumors. Regardless of the stage at presentation, surgery is the first-line therapy for patients with disease amenable to surgical resection. We favor formal pancreatectomy with conventional lymph node sampling for the vast majority of patients, either through open or laparoscopic techniques. Those with insulinomas, however, may be candidates for enucleation. Cytoreductive surgery is also recommended for patients with locoregional recurrences or hepatic metastases. Regional adjuvants such as radiofrequency ablation (RFA), transarterial chemoembolization (TACE), and others are often employed in an attempt to palliate symptoms and prolong survival. Unfortunately, cytotoxic chemotherapy has been largely ineffective in treating patients with PanNETs. The somatostatin analogue octreotide, however, has been effective in palliating symptoms and slowing the progression of disease. Other promising systemic agents, including sunitinib and everolimus, have targeted critical PanNET signaling pathways. In summary, surgery remains the principal therapeutic strategy for patients with PanNETs, but continued research may identify more robust systemic therapies for those with advanced disease. PMID- 22198809 TI - The role of passive leg raising to predict fluid responsiveness in pediatric intensive care unit patients. AB - OBJECTIVE: Fluid challenge is often used to predict fluid responsiveness in critically ill patients. Inappropriate fluid expansion can lead to some unwanted side effects; therefore, we need a noninvasive predictive parameter to assess fluid responsiveness. We want to assess the hemodynamic parameter changes after passive leg raising, which can mimic fluid expansion, to predict fluid responsiveness in pediatric intensive care unit patients and to get a cutoff value of cardiac index in predicting fluid responsiveness in pediatric patients. DESIGN: Nonrandomized experimental study. SETTING: Tertiary academic pediatric intensive care. PATIENTS: Children admitted to pediatric intensive care. INTERVENTION: Hemodynamic parameters were assessed at baseline, after passive leg raising, at second baseline, and after volume expansion (10 mL/kg normal saline infusion over 15 mins). MEASUREMENTS AND MAIN RESULTS: We measured the heart rate, systolic blood pressure, and stroke volume and cardiac index using Doppler echocardiography. The hemodynamic parameter changes induced by passive leg raising were monitored. Among 40 patients included in the study, 20 patients had a cardiac index increase of >=10% after volume expansion (responders). Changes in heart rate, systolic blood pressure, and stroke volume after passive leg raising did not significantly relate to the response to volume expansion. There was significant relation between changes in cardiac index to predict fluid responsiveness (p = .012, r(2) = .22, 95% confidence interval 1.529 to 31.37). A cardiac index increase by >=10% induced by passive leg raising predicted preload dependent status with sensitivity of 55% and specificity of 85% (area under the curve 0.71 +/- 0.084, 95% confidence interval 0.546-0.874). CONCLUSION: The concomitant measurements in cardiac index changes after the passive leg raising maneuver can be helpful in predicting who might have an increase in cardiac index with subsequent fluid resuscitation. PMID- 22198810 TI - Spinal muscular atrophy type 1: are proactive respiratory interventions associated with longer survival? AB - CONTEXT: Spinal muscular atrophy type 1, an autosomal recessive motor neuron disease, is a leading genetic cause of death in infancy and early childhood. OBJECTIVE: To determine whether the early initiation of noninvasive respiratory interventions is associated with longer survival. DESIGN: Single-institution retrospective cohort study identified children with spinal muscular atrophy type 1 from January 1, 2002 to May 1, 2009 who were followed for 2.3 mean yrs. SETTING: Tertiary care children's hospital and outpatient clinics in a vertically integrated healthcare system. PATIENTS OR OTHER PARTICIPANTS: Forty-nine children with spinal muscular atrophy type 1 were grouped according to the level of respiratory support their caregivers chose within the first 3 months after diagnosis: proactive respiratory care (n = 26) and supportive care (n = 23). INTERVENTIONS: Proactive respiratory care included bilevel noninvasive ventilation during sleep and twice a day cough assist while supportive respiratory care included suctioning, with or without supplemental oxygen. MEASUREMENTS AND MAIN RESULTS: Kaplan-Meier survival curves were assessed based on intention to treat. Children treated with early proactive respiratory support had statistically longer survival compared to supportive care (log rank 0.047); however, the adjusted hazard ratio for survival was not statistically different (2.44 [95% confidence interval 0.84-7.1]). Children in the proactive group were more likely to be hospitalized for respiratory insufficiency (83% vs. 46%) and had shortened time after diagnosis until first hospital admission for respiratory insufficiency (median 118 vs. 979 days). CONCLUSION: Longer survival time with spinal muscular atrophy type 1 is associated with early, noninvasive respiratory care interventions after diagnosis. PMID- 22198811 TI - Comparing the clinical severity of the first versus second wave of 2009 Influenza A (H1N1) in a New York City pediatric healthcare facility. AB - OBJECTIVE: We previously reported the epidemiology of 2009 Influenza A (H1N1) in our pediatric healthcare facility in New York City during the first wave of illness (May-July 2009). We hypothesized that compared with the first wave, the second wave would be characterized by increased severity of illness and mortality. DESIGN: : Case series conducted from May 2009 to April 2010. SETTING: Pediatric emergency departments and inpatient facilities of New York-Presbyterian Hospital. PATIENTS: All hospitalized patients / 18 yrs of age with positive laboratory tests for influenza A. MEASUREMENTS AND MAIN RESULTS: We compared severity of illness during the first and second wave assessed by the number of hospitalized children, including those in the pediatric intensive care unit, bacterial superinfections, and mortality rate. Compared to the first wave, fewer children were hospitalized during the second wave (n = 115 vs. 76), but a comparable portion were admitted to the pediatric intensive care unit (30.4% vs. 19.7%; p = .10). Pediatric Risk of Mortality III scores, length of hospitalization in the pediatric intensive care unit, incidence of respiratory failure and pneumonia, and peak oxygenation indices were similar during both waves. Bacterial superinfections were comparable in the first vs. second wave (3.5% vs. 1.3%). During the first wave, no child received extracorporeal membrane oxygenation and one died, while during the second wave, one child received extracorporeal membrane oxygenation and there were no deaths. CONCLUSIONS: At our pediatric healthcare facility in New York City, fewer children were hospitalized with 2009 Influenza A (H1N1) during the second wave, but both waves had a similar spectrum of illness severity and low mortality rate. PMID- 22198812 TI - Thrombosis risk factor assessment and implications for prevention in critically ill children. AB - OBJECTIVES: To describe nursing compliance with a computer-based pediatric thrombosis risk assessment tool; to generate an estimate of risk factors present in our population; and to explore relationships between risk factors and confirmed thrombotic events. DESIGN: Institutional review board-approved prospective, observational cohort study. SETTING: Pediatric intensive care unit within a tertiary care children's hospital. PATIENTS: All infants and children admitted to the pediatric intensive care unit during a 6-month study period (January 1, 2010-June 30, 2010). MEASUREMENTS AND MAIN RESULTS: Eight hundred admissions were enrolled, representing 742 patients. Thrombosis risk assessment scores were recorded for 707 admissions (88% of total). Mean age = 6.95 +/- 6 yrs, mean weight = 28 +/- 23 kg, 45% female. A total of 32 thrombi (14 prehospital and 18 in-hospital) were present in the study group. This translated to an overall occurrence rate of 4.3% (1.9% for prehospital and 2.4% for in hospital). Logistic regression identified that for every 1-point increase in total thrombosis score, the risk of developing a symptomatic thrombus increased by 1.57-fold (95% confidence interval 0.192-5.5) to 2.12-fold (95% confidence interval 0.175-18.34), for prehospital and in-hospital thrombi, respectively (p < .05). The most important risk factors identified for development of any thrombus were thrombophilia (acquired or inherited) (p < .001), presence of a central catheter (p = .01), and age <1 or >14 yrs (p = .052). CONCLUSIONS: Incorporation of a scoring system into the bedside nursing assessment flow sheet was successful and identified children at risk for in-hospital thrombosis. The overall score appears to be most indicative of thrombus risk. These data may serve as a platform for future development of routine screening and possible interventional trials in critically ill children. PMID- 22198813 TI - An assessment of the psychometric performance of the Health Utilities Index 2 and 3 in children following discharge from a U.K. pediatric intensive care unit. AB - OBJECTIVE: Our objective was to assess the psychometric performance of the Health Utilities Index 2 and 3 in a pediatric population following admission to a pediatric intensive care unit. DESIGN: As part of a larger study of pediatric intensive care outcomes, children were followed up at 6 and 12 months post admission from pediatric intensive care using the Health Utilities Index 2 and 3. We evaluated and compared the psychometric performance of the Health Utilities Index 2 and 3 in this population by assessing their practicality, reliability, and limited information regarding validity. SETTING: Twenty-two pediatric intensive care units in the United Kingdom. PATIENTS: A total of 685 children aged 5 yrs and over. INTERVENTIONS: The Health Utilities Index 2 and 3, which are both generic preference-based measures of health-related quality of life, were completed by proxy and children over 11 yrs of age were invited to self-complete. MEASUREMENT AND MAIN RESULTS: Both Health Utilities Index 2 and 3 demonstrated good practicality, with excellent completion rates (>97%) and a mean time to complete of around 8 mins. Both Health Utilities Index 2 and 3 demonstrated very good inter-rater reliability and evidence of sensitivity to change. At 6 months after admission, mean scores of the Health Utilities Index 2 and 3 were different in some groups of children with different degrees of in-hospital severity of illness, but those differences were not found at 12 months of follow-up. CONCLUSIONS: The Health Utilities Index 2 and 3 both perform well in a pediatric intensive care setting whether by self-complete or proxy complete. Evidence of good inter-rater reliability gives confidence that the measures can be reliably used with a proxy completer, such as parent or caregiver. Additional research is important to investigate their construct validity further in this population, ideally using baseline data collected at the time of hospital stay in pediatric intensive care and other measures of health status at the times of follow-up. PMID- 22198814 TI - Neuron-specific deletion of a single copy of the insulin-like growth factor-1 receptor gene reduces fat accumulation during aging. AB - Insulin, insulin-like growth factor-1 (IGF-1), and leptin signaling have been proposed to play an important role in regulating energy homeostasis. In order to specifically address the role of neuronal IGF-1 receptor (IGF-1R) signaling for energy expenditure and metabolism we used conditional mutagenesis. Deletion of one copy of the IGF-1R specifically in post-mitotic neurons (nIGF-1R(+/-) ) does not result in growth retardation or skeletal abnormalities. Interestingly, male nIGF-1R(+/-) mice accumulate less fat mass during aging accompanied with decreased leptin levels compared to wild-type littermates. Furthermore, male nIGF 1R(+/-) mice present with increased locomotor activity and energy expenditure. In contrast, female nIGF-1R(+/-) mice remained nearly unaffected. Circadian pattern of locomotor activity and energy expenditure as well as food and water intake did not change. Consistent with increased locomotor activity, the respiratory quotient was shifted to increased fat oxidation in nIGF-1R(+/-) mice. Surprisingly, serum IGF-1 and IGF-1 binding protein 3 (IGF-BP3) concentrations were decreased in nIGF-1R(+/-) mice despite the presence of normal pituitaries suggesting a functional feedback mechanism via neuronal IGF 1Rs, which regulate serum IGF-1 levels. Thus, we show that neuron-specific IGF-1R deletion in male mice decreases body fat accumulation and increases energy expenditure during aging. PMID- 22198815 TI - Oral salmon calcitonin improves fasting and postprandial glycemic control in lean healthy rats. AB - A novel oral form of salmon calcitonin (sCT) was recently demonstrated to improve both fasting and postprandial glycemic control and induce weight loss in diet induced obese and insulin-resistant rats. To further explore the glucoregulatory efficacy of oral sCT, irrespective of obesity and metabolic dysfunction, the present study investigated the effect of chronic oral sCT treatment on fasting and postprandial glycemic control in male lean healthy rats. 20 male rats were divided equally into a control group receiving oral vehicle or an oral sCT (2 mg/kg) group. All rats were treated twice daily for 5 weeks. Body weight and food intake were monitored during the study period and fasting blood glucose, plasma insulin and insulin sensitivity were determined and an oral glucose tolerance test (OGTT) performed at study end. Compared with the vehicle group, rats receiving oral sCT had improved fasting glucose homeostasis and insulin resistance, as measured by homeostatic model assessment of insulin resistance index (HOMA-IR), with no change in body weight or fasting plasma insulin. In addition, the rats receiving oral sCT had markedly reduced glycemia and insulinemia during OGTT. This is the first report showing that chronic oral sCT treatment exerts a glucoregulatory action in lean healthy rats, irrespective of influencing body weight. Importantly, oral sCT seems to exert a dual treatment effect by improving fasting and postprandial glycemic control and insulin sensitivity. This and previous studies suggest oral sCT is a promising agent for the treatment of obesity-related insulin resistance and type 2 diabetes. PMID- 22198816 TI - Increased GLP-1 response after gavage-administration of glucose in UCP2-deficient mice. AB - Although it has been widely reported that endogenous level of GLP-1 can be enhanced by various secretagogues, the mechanism of GLP-1 secretion in vivo is still not fully understood. In the present study, we assessed the possible effect of uncoupling protein 2 (UCP2) on GLP-1 secretion in gut. The levels of plasma GLP-1(7-36) amide/(7-37) in UCP2-deficient mice and wild-type mice were measured by applying ELISA technique. UCP2 mRNA and protein levels were detected in the gastrointestinal tract by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analysis, respectively. The plasma GLP-1 levels in C57BL/6J mice had significantly increased to 6.9 pM (n=8, p<0.001) at 15 min after gavage-administration of glucose (2 g glucose/kg body weight), approximately 2-fold, compared with control group. Plasma GLP-1 levels were also significantly elevated at 30 min (p<0.001), but nearly returned to baseline levels at 60 min. UCP2-deficient mice had higher level of GLP-1 at various time points after administration of glucose (UCP2-deficient mice vs. wild type littermates, 15 min, 9.3+/-0.9 vs. 6.9+/-0.3, p<0.001; 30 min, 7.9+/-0.3 vs. 5.6+/-0.4, p<0.001; 60 min, 4.9+/-0.1 vs. 3.3+/-0.1, p<0.01). UCP2-deficient mice increased GLP-1 response to gavage-administration of glucose. Plasma GLP-1 level was not significantly altered after gavage-administration of saline. This study showed that plasma GLP-1 level increased after gastric glucose challenge, and UCP2 maybe serve as a negative regulator in glucose-induced GLP-1 secretion in mouse gut tract. PMID- 22198817 TI - NMR assignments of the FKBP-type PPIase domain of FKBP42 from Arabidopsis thaliana. AB - The Atfkbp42 gene is associated with reduced and disoriented growth of Arabidopsis thaliana. Resonance assignments are reported for the FKBP-type PPIase domain of AtFKBP42. Signal intensities reveal an additional structure element that is atypical for such FKBP domains. PMID- 22198818 TI - Dietary intake of energy and nutrients in relation to resting energy expenditure and anthropometric parameters of Czech pregnant women. AB - PURPOSE: The aim of this study was to evaluate the dietary intake of energy and nutrients (DIEN) of Czech pregnant women and to assess relationships with body size variables during pregnancy. METHODS: One hundred and fifty-two randomly recruited healthy pregnant Czech women, who were normoglycemic, euthyroid, nonsmokers, not anemic, and not users of chronic medications or abusers of alcohol or drugs from countryside and city with different education, were recruited for the study. Anthropometric parameters were measured and resting energy expenditure obtained by indirect calorimetry after 12 h of fasting during four phases of pregnancy. DIEN was evaluated from self-reported dietary intake records over 7 days. RESULTS: Positive correlations were demonstrated between measured resting energy expenditure and intake of energy, substrates and some minerals and vitamins, and negative correlations between DIEN and anthropometric parameters. Lower dietary intake of energy and differences between dietary intake of nutrients and recommended daily allowances during pregnancy of Czech women were documented. CONCLUSIONS: The difference between pregnancy body weight and ideal body weight was shown to be a determinant of DIEN. From recent knowledge on prevention of various pathological states, the supplementation or modification of nutritional intake of food with folate, iron, vitamin D, zinc, iodine and fiber for Czech pregnant women is recommended. PMID- 22198820 TI - Integrating interacting drugs and genetic variations to improve the predictability of warfarin maintenance dose in Chinese patients. AB - OBJECTIVE: Compared with genetic factors, drug interactions are largely unexplored in pharmacogenetic studies. This study sought to systematically investigate the effects of VKORC1, STX4A, CYP2C9, CYP4F2, CYP3A4, and GGCX gene polymorphisms and interacting drugs on warfarin maintenance dose. METHODS: A retrospective study of 845 Chinese patients after heart valve replacement receiving long-term warfarin maintenance therapy was conducted. Thirteen polymorphisms in the six genes were genotyped, and 36 drugs that may interact with warfarin were investigated. RESULTS: Single-nucleotide polymorphism association analysis showed that VKORC1, CYP2C9 and CYP4F2 variations were highly associated with the warfarin maintenance dose. Among 36 drugs that may interact with warfarin, fluconazole, amiodarone, and omeprazole were associated with the requirement for 45.8, 16.7, and 16.7% lower median warfarin dose (all P<0.05 with a false discovery rate <0.05). The final pharmacogenetic equation explained 43.65% of interindividual variation of warfarin maintenance dose with age, body surface area, VKORC1 g.3588G>A, CYP2C9*3, CYP4F2 c.1297G>A, amiodarone, fluconazole, and diltiazem accounting for 1.97, 2.74, 24.12, 3.94, 1.64, 5.92, 2.47, and 0.84% of variation. CONCLUSION: The present study indicated that VKORC1, CYP4F2, and CYP2C9 genotypes and interacting drugs had a significant impact on the warfarin maintenance dose in Chinese patients with heart valve replacement and demonstrated that integrating interacting drugs can largely improve the predictability of the dose algorithm. PMID- 22198819 TI - Role of PD-1 in HIV pathogenesis and as target for therapy. AB - Major advances in Antiretroviral Therapy (ART) have resulted in a dramatic decline in HIV-related deaths. However, no current treatment regimen leads to viral eradication or restoration of HIV-specific immune responses capable of durable viral control after cessation of ART. Thus, there is a need for novel interventions that could complement ART in order to eliminate virus or reach a state of "functional cure." It has been shown in murine models and humans that the negative co-signaling molecule programmed-death 1 (PD-1) plays an active and reversible role in mediating T-cell exhaustion in chronic infections. This review summarizes recent advances in our understanding of the PD-1 pathway in HIV infection, and the lessons learned from studies in the SIV model and cancer. We discuss the potential of immunotherapeutic interventions targeting PD-1 in order to augment immune responses or facilitate viral eradication. We also present the challenges to therapies targeting immunoregulatory networks. PMID- 22198821 TI - Anti-hyperglycemic and anti-hypercholesterolemic effects of Aloe vera leaf gel in hyperlipidemic type 2 diabetic patients: a randomized double-blind placebo controlled clinical trial. AB - Diabetes mellitus type 2 with dyslipidemia is a common disease. Previous studies suggest that aloe (Aloe vera L.) leaf gel may positively affect the blood glucose and lipid levels in dyslipidemic type 2 diabetic patients. Thus, in this randomized double-blind placebo-controlled clinical trial with hyperlipidemic (hypercholesterolemic and/or hypertriglyceridemic) type 2 diabetic patients aged 40 to 60 years not using other anti-hyperlipidemic agents and resistant to daily intake of two 5 mg glyburide tablets and two 500 mg metformin tablets, the efficacy and safety of taking aloe gel (one 300 mg capsule every 12 hours for 2 months) combined with the aforementioned drugs in treatment of 30 patients were evaluated and compared with the placebo group (n = 30). The aloe gel lowered the fasting blood glucose, HbA1c, total cholesterol, and LDL levels significantly (p = 0.036, p = 0.036, p = 0.006, and p = 0.004, respectively) without any significant effects on the other blood lipid levels and liver/kidney function tests (p > 0.05) compared with the placebo at the endpoint. No adverse effects were reported. The results suggest that aloe gel may be a safe anti-hyperglycemic and anti-hypercholesterolemic agent for hyperlipidemic type 2 diabetic patients. PMID- 22198823 TI - Kinetics of neuronal contribution during the development of a contact allergic reaction. AB - The nervous system contributes to allergic contact dermatitis (ACD). Elucidation of the implication of the nervous system during different stages of ACD could be of therapeutic value. Our aim was to study the kinetics and contribution of the nervous system to ACD by investigating innervation and expression of neuropeptides in skin biopsies obtained at 0, 6, 24, 48 and 72 h post-challenge. Biopsies were stained using antisera against protein gene product (PGP) 9.5, growth associated protein (GAP)-43, substance P and its receptor (R) neurokinin (NK)-1, NKA and NK-2R, and calcitonin gene-related peptide (CGRP). GAP-43 immunoreactive (ir) nerves revealed a time-dependent increase that was more pronounced at 48 and 72 h, while PGP 9.5-ir nerves remained unaltered. Substance P-, NKA- and CGRP-ir nerves at 0 and 6 h were significantly higher compared to later time points, whereas NKA-, NK-1R- and NK-2R-ir cells were lower. A dramatic rise in cell numbers was noted at 24 h. Our findings demonstrate the implication of nerves and sensory neuropeptides during the kinetics of ACD and suggest a possibility to target this system at an early time point for therapy. PMID- 22198822 TI - Solitary langerhans histiocytosis of the thyroid gland: a case report and literature review. AB - Langerhans cell histiocytosis (LCH) is a rare disease of antigen presenting cells, with an incidence rate of 4.0-5.4 per 1 million individuals. The most common endocrinological manifestation of classical LCH is associated with the posterior pituitary, presenting as Diabetes Insipidus. However, LCH can affect multiple organs and classification is based on the body system involvement. The disease is confirmed by electron microscopy or immunohistochemical reactivity of histiocytes to CD1a and/or S100. LCH rarely involves the thyroid gland, and management of such disease is controversial. Current literature documents 65 English language reported cases of LCH involving the thyroid gland. We present an unusual case of LCH of the thyroid gland, with variable diagnoses on fine needle aspiration (FNA) cytology, and literature review of all English reported cases. PMID- 22198824 TI - Gene-environment interaction in major depression and antidepressant treatment response. AB - Response to antidepressants is interindividually variable. It has been suggested that this variability is a direct consequence of etiological heterogeneity. Therefore, the same genes, environments, and gene-environment interactions implicated in different etiological pathways to depression may also predict response to treatment. This article reviews the evidence relevant to this hypothesis by first outlining the roles of genes, environments, and gene environment interplay in the etiology of depression, and then considering the same factors in treatment response. Environmental exposures, such as childhood maltreatment, are potent predictors of both depression and treatment response. Although alone genetic factors have failed to consistently predict either phenotype, several polymorphisms have been shown to moderate the effects of environmental adversity on the development of depression and treatment response. These findings suggest that the dissection of etiological pathways to depression may provide the key to understanding and predicting response to antidepressants. PMID- 22198825 TI - Clinical significance of serum S100A12 in acute otitis media in young children. AB - BACKGROUND: S100A12 is a calcium-binding protein predominantly expressed in neutrophil granulocytes in response to infections or inflammation. Acute otitis media (AOM) is a local infection mainly caused by Streptococcus pneumoniae (Spn), nontypeable Haemophilus influenzae (NTHi), and/or Moraxella catarrhalis (Mcat). METHODS: To study if S100A12 values could serve as a diagnostic marker, serum S100A12 concentrations were tested in young children before, at onset, and after recovery from AOM. RESULTS: Among 116 children with AOM, we found that serum S100A12 concentrations were significantly increased at onset of AOM compared with before infection (P = 0.0001), and returned to normal levels when the children recovered from the infection (P = 0.01). Elevation of S100A12 correlated with the presence of Spn (P = 0.004) or NTHi (P = 0.04) in the middle ear, but not with Mcat or upper respiratory viral infection. Change in serum value of S100A12 at onset of AOM was not related to the frequency of occurrence of AOM or the age of the child. CONCLUSION: S100A12 may be a useful biomarker for onset of AOM due to Spn and NTHi, and for following children with AOM. PMID- 22198826 TI - Pasteurella multocida Infection in a neonate: evidence for a human-to-human horizontal transmission. AB - Pasteurella multocida is usually transmitted by animal contact; however, in a significant proportion of cases, no animal exposure can be identified. Although vertical transmission has been identified in neonates, horizontal human-to-human spread has not been documented. A case of neonatal sepsis and meningitis resulting from horizontal transmission of P. multocida is described. PMID- 22198827 TI - Pharmacokinetic profile of valganciclovir in pediatric transplant recipients. AB - We evaluated the pharmacokinetic profile of intravenous ganciclovir and oral valganciclovir in transplant children. Median AUC0-24 concentrations obtained after intravenous and oral formulations were 22.9 ug*h/mL (range, 17-65.2) and 34.55 ug*h/mL (range, 20.8-84.2), respectively. After normalization on a 20 mg/kg/d valganciclovir dosage, the median AUC0-24 concentration was 37.6 ug*h/mL (range, 23.6-68). PMID- 22198828 TI - [Thoracic aortic interventions]. AB - The treatment of thoracic aortic diseases has undergone a paradigm shift due to the introduction and further development of interventional techniques in recent years. Thoracic endovascular aortic repair (TEVAR) of the descending aorta has significantly lower mortality and complication rates compared to open repair. Meanwhile this endovascular approach is the first option for the treatment of the majority of thoracic aortic diseases. PMID- 22198829 TI - Interstitial pneumonitis associated with the immunomodulatory drugs thalidomide and lenalidomide. PMID- 22198830 TI - Outcomes of pregnancies complicated by hyperemesis gravidarum. AB - OBJECTIVES: To evaluate maternal and fetal outcomes among women with hyperemesis gravidarum (HG). METHODS: In a university hospital and a research and training hospital, a retrospective cohort study was conducted among women with singleton deliveries between 2003 and 2011. Maternal outcomes evaluated included gestational diabetes, pregnancy-induced hypertension, cesarean delivery. Neonatal outcomes also determined were 5-min Apgar score of less than 7, low birth weight, small for gestational age (SGA), preterm delivery, fetal sex, and stillbirth. RESULTS: There were no statistical differences in the mean of age, parity, the number of artificial pregnancy, and smoking between two groups. Infants from HG pregnancies manifested similar birth weight (3,121.5 +/- 595.4 vs. 3,164 +/- 664.5 g) and gestational age (38.1 +/- 2.3 vs. 38.1 +/- 2.6 weeks), relative to infants from the control group (p = 0.67 and 0.91, respectively). In addition, no statistical significant differences were found in the rates of SGA birth, preterm birth, gestational diabetes, pregnancy-induced hypertension, and adverse fetal outcome between two groups (p > 0.05). Cesarean delivery rates were similar in two groups (31.9% in hyperemesis group vs. 27% in control group, p = 0.49). Comparing the gender of the newborn baby and Apgar scores less than 7 at 5 min, there were no statistically significant differences between two groups (p = 0.16 and 0.42, respectively). CONCLUSION: Hyperemesis gravidarum is not associated with adverse pregnancy outcomes. PMID- 22198831 TI - The patient's experience of gout: new insights to optimize management. AB - Despite the high prevalence of disease, gout management is frequently poor, with low patient adherence to urate-lowering therapy and attainment of recommended serum urate targets. Recent research has explored the patient's experience of gout, providing new understanding of the impact of disease. Pain is central to the patient's experience of gout. Poorly controlled gout leads to limitation of activities, reduced participation, and poor health-related quality of life. Although effective gout management with urate-lowering therapy improves many patient-reported outcomes in clinical trials, major gaps exist in patient understanding of disease and adherence to long-term urate-lowering therapy. Furthermore, a large mismatch in the perceptions of gout and its therapy exists between patients and health care practitioners. These issues may contribute to progressive and poorly controlled disease despite the availability of effective treatment. These findings provide potential pathways to improved clinical care of patients with gout. Work is now required to identify the optimal models of care for patients with gout that can be tested in clinical trials using outcome measures of relevance to individuals with this disease. PMID- 22198832 TI - Genetics and mechanisms of crystal deposition in calcium pyrophosphate deposition disease. AB - Calcium pyrophosphate deposition (CPPD) disease (common in older adults) can be asymptomatic, associated with osteoarthritis, or can present as acute/chronic inflammatory arthritis. Due to the phenotypic complexity of CPPD, the European League Against Rheumatism (EULAR) recently made recommendations on terminology, diagnosis, and management based on available research evidence and expert consensus. There are no disease-modifying treatments for CPPD disease, and therapy remains nonspecific with the use of anti-inflammatory and analgesic drugs. For years, it has been known that inorganic phosphate and pyrophosphate regulate the formation of CPP or hydroxyapatite crystals. The discovery of ANKH (human homologue of progressive ankylosis) mutations in familial CPPD disease confirmed the importance of phosphate/pyrophosphate homeostasis in CPPD, with ANKH being a regulator of inorganic pyrophosphate transport. Despite progress in our understanding of the function of ANKH, much remains to be investigated. This review summarizes the genetic basis of this disease and focuses on the challenges of research in this area. PMID- 22198833 TI - Update on the phenotypic spectrum of Lesch-Nyhan disease and its attenuated variants. AB - Congenital deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) results in a spectrum of clinical phenotypes. All of these phenotypes are associated with marked overproduction of uric acid and related problems such as hyperuricemia, urate nephrolithiasis, tophi, and gout. The mildest phenotypes include only problems related to overproduction of uric acid. The most severe phenotype is known as Lesch-Nyhan disease, in which the phenotype also includes severe motor handicap, intellectual disability, and self-injurious behavior. In between these two extremes is a continuous spectrum of phenotypes with varying degrees of motor and cognitive handicap but no self injurious behavior. The pathogenesis of overproduction of uric acid in HPRT deficiency is well-understood, and treatments are available to control it. The pathogenesis of the neurobehavioral problems is less well-understood, and effective treatments for them are lacking. PMID- 22198834 TI - [State-of-the-art imaging of peritoneal carcinomatosis]. AB - Imaging studies are essential in the evaluation of patients with suspected or known peritoneal malignancy. Despite major advances in imaging technology in the last few years, the early and adequate detection of a peritoneal dissemination remains challenging because of the great variety in size, morphology and location of the peritoneal lesions. New therapeutic approaches in peritoneal-based neoplasms combining cytoreductive surgery and peritonectomy with hyperthermic intraoperative chemotherapy (HIPEC) suggest improved long-term survival, provided that a complete (macroscopic) cytoreduction is achieved. The preoperative radiological assessment of the extent and distribution of peritoneal involvement plays a vital role in the patient selection process. Despite its known limited accuracy in detecting small peritoneal lesions and the involvement of the small bowel/mesentery, contrast-enhanced MDCT remains the standard imaging modality in the assessment of peritoneal carcinomatosis. MRI, especially with diffusion weighted images, and FDG-PET/CT are promising methods for the evaluation of peritoneal carcinomatosis with superior results in recent studies, but still have a limited role in selected cases because of high costs and limited availability. Generally, to obtain the most precise readings of peritoneal carcinomatosis, an optimized examination protocol and dedicated radiologists with a deep knowledge of peritoneal pathways and variable morphologies of peritoneal disease are required. PMID- 22198835 TI - Upgrade to iterative image reconstruction (IR) in abdominal MDCT imaging: a clinical study for detailed parameter optimization beyond vendor recommendations using the adaptive statistical iterative reconstruction environment (ASIR). AB - PURPOSE: To compare the image quality of dose-reduced 64-row abdominal CT reconstructed at different levels of adaptive statistical iterative reconstruction (ASIR) to full-dose baseline examinations reconstructed with filtered back-projection (FBP) in a clinical setting and upgrade situation. MATERIALS AND METHODS: Abdominal baseline examinations (noise index NI = 29; LightSpeed VCT XT, GE) were intra-individually compared to follow-up studies on a CT with an ASIR option (NI = 43; Discovery HD750, GE), n = 42. Standard-kernel images were calculated with ASIR blendings of 0 - 100 % in slice and volume mode, respectively. Three experienced radiologists compared the image quality of these 567 sets to their corresponding full-dose baseline examination (- 2: diagnostically inferior, - 1: inferior, 0: equal, + 1: superior, + 2: diagnostically superior). Furthermore, a phantom was scanned. Statistical analysis used the Wilcoxon - the Mann-Whitney U-test and the intra-class correlation (ICC). RESULTS: The mean CTDIvol decreased from 19.7 +/- 5.5 to 12.2 +/- 4.7 mGy (p < 0.001). The ICC was 0.861. The total image quality of the dose reduced ASIR studies was comparable to the baseline at ASIR 50 % in slice (p = 0.18) and ASIR 50 - 100 % in volume mode (p > 0.10). Volume mode performed 73 % slower than slice mode (p < 0.01). CONCLUSION: After the system upgrade, the vendor recommendation of ASIR 50 % in slice mode allowed for a dose reduction of 38 % in abdominal CT with comparable image quality and time expenditure. However, there is still further dose reduction potential for more complex reconstruction settings. PMID- 22198836 TI - [Magnetic particle imaging (MPI)]. AB - Magnetic particle imaging (MPI) displays the spatial distribution and concentration of superparamagnetic iron oxides (SPIOs). It is a quantitative, tomographic imaging method with high temporal and spatial resolution and allows work with high sensitivity yet without ionizing radiation. Thus, it may be a very promising tool for medical imaging. In this review, we describe the physical and technical basics and various concepts for clinical scanners. Furthermore, clinical applications such as cardiovascular imaging, interventional procedures, imaging and therapy of malignancies as well as molecular imaging are presented. PMID- 22198838 TI - Stabilized G protein binding site in the structure of constitutively active metarhodopsin-II. AB - G protein-coupled receptors (GPCR) are seven transmembrane helix proteins that couple binding of extracellular ligands to conformational changes and activation of intracellular G proteins, GPCR kinases, and arrestins. Constitutively active mutants are ubiquitously found among GPCRs and increase the inherent basal activity of the receptor, which often correlates with a pathological outcome. Here, we have used the M257Y(6.40) constitutively active mutant of the photoreceptor rhodopsin in combination with the specific binding of a C-terminal fragment from the G protein alpha subunit (GalphaCT) to trap a light activated state for crystallization. The structure of the M257Y/GalphaCT complex contains the agonist all-trans-retinal covalently bound to the native binding pocket and resembles the G protein binding metarhodopsin-II conformation obtained by the natural activation mechanism; i.e., illumination of the prebound chromophore 11 cis-retinal. The structure further suggests a molecular basis for the constitutive activity of 6.40 substitutions and the strong effect of the introduced tyrosine based on specific interactions with Y223(5.58) in helix 5, Y306(7.53) of the NPxxY motif and R135(3.50) of the E(D)RY motif, highly conserved residues of the G protein binding site. PMID- 22198837 TI - Two surfaces on the histone chaperone Rtt106 mediate histone binding, replication, and silencing. AB - The histone chaperone Rtt106 binds histone H3 acetylated at lysine 56 (H3K56ac) and facilitates nucleosome assembly during several molecular processes. Both the structural basis of this modification-specific recognition and how this recognition informs Rtt106 function are presently unclear. Guided by our crystal structure of Rtt106, we identified two regions on its double-pleckstrin homology domain architecture that mediated histone binding. When histone binding was compromised, Rtt106 localized properly to chromatin but failed to deliver H3K56ac, leading to replication and silencing defects. By mutating analogous regions in the structurally homologous chromatin-reorganizer Pob3, we revealed a conserved histone-binding function for a basic patch found on both proteins. In contrast, a loop connecting two beta-strands was required for histone binding by Rtt106 but was dispensable for Pob3 function. Unlike Rtt106, Pob3 histone binding was modification-independent, implicating the loop of Rtt106 in H3K56ac-specific recognition in vivo. Our studies described the structural origins of Rtt106 function, identified a conserved histone-binding surface, and defined a critical role for Rtt106:H3K56ac-binding specificity in silencing and replication-coupled nucleosome turnover. PMID- 22198839 TI - Assembly of vorticity-aligned hard-sphere colloidal strings in a simple shear flow. AB - Colloidal suspensions self-assemble into equilibrium structures ranging from face and body-centered cubic crystals to binary ionic crystals, and even kagome lattices. When driven out of equilibrium by hydrodynamic interactions, even more diverse structures can be accessed. However, mechanisms underlying out-of equilibrium assembly are much less understood, though such processes are clearly relevant in many natural and industrial systems. Even in the simple case of hard sphere colloidal particles under shear, there are conflicting predictions about whether particles link up into string-like structures along the shear flow direction. Here, using confocal microscopy, we measure the shear-induced suspension structure. Surprisingly, rather than flow-aligned strings, we observe log-rolling strings of particles normal to the plane of shear. By employing Stokesian dynamics simulations, we address the mechanism leading to this out-of equilibrium structure and show that it emerges from a delicate balance between hydrodynamic and interparticle interactions. These results demonstrate a method for assembling large-scale particle structures using shear flows. PMID- 22198840 TI - Nonplanar peptide bonds in proteins are common and conserved but not biased toward active sites. AB - The planarity of peptide bonds is an assumption that underlies decades of theoretical modeling of proteins. Peptide bonds strongly deviating from planarity are considered very rare features of protein structure that occur for functional reasons. Here, empirical analyses of atomic-resolution protein structures reveal that trans peptide groups can vary by more than 25 degrees from planarity and that the true extent of nonplanarity is underestimated even in 1.2 A resolution structures. Analyses as a function of the phi,psi-backbone dihedral angles show that the expected value deviates by +/- 8 degrees from planar as a systematic function of conformation, but that the large majority of variation in planarity depends on tertiary effects. Furthermore, we show that those peptide bonds in proteins that are most nonplanar, deviating by over 20 degrees from planarity, are not strongly associated with active sites. Instead, highly nonplanar peptides are simply integral components of protein structure related to local and tertiary structural features that tend to be conserved among homologs. To account for the systematic phi,psi-dependent component of nonplanarity, we present a conformation dependent library that can be used in crystallographic refinement and predictive protein modeling. PMID- 22198841 TI - Formation of buckminsterfullerene (C60) in interstellar space. AB - Buckminsterfullerene (C(60)) was recently confirmed as the largest molecule identified in space. However, it remains unclear how and where this molecule is formed. It is generally believed that C(60) is formed from the buildup of small carbonaceous compounds in the hot and dense envelopes of evolved stars. Analyzing infrared observations, obtained by Spitzer and Herschel, we found that C(60) is efficiently formed in the tenuous and cold environment of an interstellar cloud illuminated by strong ultraviolet (UV) radiation fields. This implies that another formation pathway, efficient at low densities, must exist. Based on recent laboratory and theoretical studies, we argue that polycyclic aromatic hydrocarbons are converted into graphene, and subsequently C(60), under UV irradiation from massive stars. This shows that alternative--top-down--routes are key to understanding the organic inventory in space. PMID- 22198842 TI - Reexamination of magnetic isotope and field effects on adenosine triphosphate production by creatine kinase. AB - The influence of isotopically enriched magnesium on the creatine kinase catalyzed phosphorylation of adenosine diphosphate is examined in two independent series of experiments where adenosine triphosphate (ATP) concentrations were determined by a luciferase-linked luminescence end-point assay or a real-time spectrophotometric assay. No increase was observed between the rates of ATP production with natural Mg, (24)Mg, and (25)Mg, nor was any significant magnetic field effect observed in magnetic fields from 3 to 1,000 mT. Our results are in conflict with those reported by Buchachenko et al. [J Am Chem Soc 130:12868-12869 (2008)], and they challenge these authors' general claims that a large (two- to threefold) magnetic isotope effect is "universally observable" for ATP-producing enzymes [Her Russ Acad Sci 80:22-28 (2010)] and that "enzymatic phosphorylation is an ion-radical, electron-spin-selective process" [Proc Natl Acad Sci USA 101:10793-10796 (2005)]. PMID- 22198843 TI - Influence of quorum sensing signal molecules on biofilm formation in Proteus mirabilis O18. AB - The influence of basis of quorum sensing molecules on Proteus strains is much less known as compared to Pseudomonas or Escherichia. We have previously shown that a series of acylated homoserine lactones (acyl-HSL) does not influence the ureolytic, proteolytic, or hemolytic abilities, and that the swarming motility of Proteus mirabilis rods is strain specific. The aim of the presented study was to find out if the presence of a series of acyl-HSL influences biofilm formation of P. mirabilis laboratory strain belonging to O18 serogroup. This serogroup is characterized by the presence of a unique non-carbohydrate component, namely phosphocholine. Escherichia coli and P. mirabilis O18 strains used in this work contains cloned plasmids encoding fluorescent protein genes with constitutive gene expression. In mixed biofilms in stationary and continuous flow conditions, P. mirabilis O18 overgrow whole culture. P. mirabilis O18 strain has genetically proved a presence of AI-2 quorum sensing system. Differences in biofilm structure were observed depending on the biofilm type and culture methods. From tested acylated homoserine lactones (BHL, HHL, OHL, DHL, dDHL, tDHL), a significant influence had BHL on thickness, structure, and the amount of exopolysaccharides produced by biofilms formed by P. mirabilis O18 pDsRed(2). PMID- 22198844 TI - Sonographic cervical length as a predictor of type of delivery after induced labor. AB - PURPOSE: This study was undertaken to evaluate the comparative value of sonographic cervical length and the Bishop score in predicting the type of delivery after induced labor. METHODS: The Bishop score was determined by digital examination and cervical length by transvaginal sonography in 177 women. RESULTS: The best cut-off points for predicting type of delivery found with ROC curves were 25.2 mm for cervical length and 5 for the Bishop score. The Bishop score was not predictive of type of delivery. Cervical length was related to type of delivery in women with Bishop score <=5. A logistic regression model showed that only cervical length >=25.2 mm, parity, and body mass index significantly predicted the likelihood of cesarean delivery. CONCLUSIONS: Our study suggests that both Bishop score and sonographic cervical length can contribute to predicting type of delivery after labor induction, but cervical length is a better predictor of the risk of cesarean delivery. PMID- 22198845 TI - Clinicopathological features and immunoprofile of 30 cases of Brenner ovarian tumors. AB - AIM: The aim of this study was to investigate the clinicopathological and immunopathological features of Brenner ovarian tumors. MATERIALS AND METHODS: Thirty cases of Brenner ovarian tumors were examined in our laboratory among 1,680 cases of ovarian tumors, representing 1.5% of all tumors examined. Blocks of paraffin-embedded tumor tissue for all cases were available for additional immunohistochemical stain by a Ventana autoimmunostainer. Moreover, antibodies for Uroplakine III (cellmarque AU-1 clone, 1:25) Chromogen (monosan clone 5H7,1:25) WT1 (novocastra, clone 3F-H2, 1:25) NSE (DAKO, clone BB5/NC/V1-H14, 1:50), CK20 (DAKO, clone Ks20.8, 1:50),CK7 (Zymed 1:25, clone V-TL12/30)were used. RESULTS: The mean age of the patients was 51.4 years ranging from 16 to 82 years. The tumor was unilateral in 28 cases (16/28 in the right ovary and 12/28 in the left ovary) and bilateral in two cases. Twenty-eight cases (93%) were benign and two (7%) were proliferating (borderline) tumors. Seventeen cases (56%) were pure Brenner tumors, measuring from 0.5 to 2.5 cm and 13 cases (44%) were mixed tumors consisting of a Brenner tumor element and a mucinous ovarian tumor (10/13 cases, 53.8%) and a germ cell tumor in 3/13 cases. The largest diameter of the mixed tumors ranged from 7 to 22 cm. The largest area consisting of Brenner elements measured 7 cm. The immunoprofile of Brenner tumor cell was cytokeratine 7 positive (30/30 cases) cytokeratine-20 negative in the Brenner cell element but positive in the mucinous component in 5/7 cases of mixed Brenner tumors, focally WT-1 positive (5/30 cases), NSE negative (0/30 cases) and focally chromogranine positive (6/30 cases), Uroplakin-III positive in 23/30 cases, with faint cytoplasmatic or luminal distribution. In conclusion, Brenner ovarian tumors are unilateral, small and benign neoplasms in their majority and present specific histopathological and immunopathological characteristics and mixed forms with other epithelial and germ cell neoplasms. This could be explained as a form of metaplasia or a diverse histogenesis from surface epithelium and/or the germ cell ovarian component. PMID- 22198846 TI - Nitric Oxide concentration in endometrial washing throughout the menstrual cycle. AB - PURPOSE: Nitric oxide (NO) intrauterine production has been shown to have an important role in the reproductive system in females. The objective of the present study was to evaluate NO concentration in endometrial washing throughout the menstrual cycle. METHODS: Observational study at Institute of Obstetrics and Gynecology, Mother-Infant Department, University Hospital. The study included 40 healthy fertile women, aged 21-40, with regular menstrual cycle, undergoing endometrial washing by hydrosonography for the assessment of NO concentration. RESULTS: Nitric oxide concentration in endometrial washing were low in early to mid proliferative phase (4.73 +/- 1.57 mcM/L), but significantly higher (p < 0.05) in late proliferative phase (7.30 +/- 3.37 mcM/L) early secretory phase (8.05 +/- 1.97 mcM/L) and late secretory phase (8.69 +/- 4.12 mcM/L) of menstrual cycle. CONCLUSIONS: Endometrial washing by hydrosonography is a simple, minimally invasive, and effective tool to use in the evaluation of cyclical NO intrauterine production. Nitric oxide concentrations increased during the late proliferative and secretory phase of menstrual cycle. PMID- 22198847 TI - Right endometrioma is related with more extensive obliteration of the Douglas pouch. AB - OBJECTIVE: To investigate that endometrioma is an asymmetric disease with left lateral predisposition as compared to other benign ovarian cyst and also, whether endometrioma side is related with endometriosis severity. METHODS: Operative and histopathologic findings of 340 women who underwent cystectomy for treatment of endometriotic (n = 239) and nonendometriotic ovarian cysts (n = 101) by laparoscopy (n = 268) or laparotomy (n = 72) between January 2005 and August 2009 were evaluated retrospectively. We compared left and right sided distribution of endometriotic and nonendometriotic ovarian cysts, and we also investigated the extent of endometriotic foci, obliteration of pouch of Douglas and endometriosis stage according to the revised American Fertility Society classification of endometriosis to assess whether endometrioma side is related with the severity of endometriosis. RESULTS: Of 239 women with endometriosis, endometrioma was found in the left ovary (n = 109), right ovary (n = 58) and bilaterally (n = 72). Of 101 control group women functional and dermoid cysts were found in the left ovary (n = 48), right ovary (n = 43) and bilaterally (n = 10). Among women with unilateral ovarian endometrioma (n = 167) a left cyst (63.3%) was found more frequently than a right cyst (34.7%) (P < 0.0001). In women with a left ovarian endometrioma pouch of Douglas was open in 99 (90.8%) cases. However, it was partially obliterated in 3 (2.8%) and completely obliterated in 7 (6.4%) cases. On the other hand, in women with a right endometrioma it was open in 44 (75.9%) cases and partially obliterated in 2 (3.4%) and completely obliterated in 12 (20.7%) cases. In women with a right endometrioma, the possibility of the pouch of Douglas obliteration is significantly higher than the women with a left endometrioma (P = 0.006). CONCLUSION: Moreover, we also showed that in women with a right endometrioma, incidence of the pouch of Douglas obliteration is higher and the endometriosis tends to be more severe compared to women with a left endometrioma. Our most relevant observation is obliteration of Douglas pouch which was found to be more extensive in women with right ovarian endometrioma. Our results showing left lateral predisposition of endometriomas are in agreement with the previous reports and highlight the retrograde menstruation theory for the pathogenesis of this enigmatic disorder. PMID- 22198848 TI - Prevention and management of contrast-induced acute kidney injury. AB - OPINION STATEMENT: Contrast-induced acute kidney injury (AKI) is an important complication associated with coronary angiography, percutaneous coronary intervention, and computed tomography studies. The increasing utilization of contrast agents for imaging makes the importance of this complication even greater. Patients can be risk stratified for the risk of contrast-induced AKI by several clinical factors including hypotension, renal function, age, advanced heart failure, anemia, and diabetes mellitus. Contrast volume is also an important and modifiable risk factor for AKI. For the prevention of contrast induced AKI, multiple approaches have been tried. The most effective prevention strategy is hydration. Normal saline has been the standard, but other options such as sodium bicarbonate may be a reasonable alternative. Further studies will be required to clarify the best preventive strategies. PMID- 22198849 TI - Coagulopathies and thrombosis: usual and unusual causes and associations. Part V. PMID- 22198850 TI - Seminars in Thrombosis & Hemostasis 2010: impact factor and highest-cited articles from 2008 to 2009. PMID- 22198851 TI - Holiday thrombosis. AB - The pathogenesis of acute thrombosis, either arterial or venous, is typically multifactorial and involves a variety of factors that may be considered relatively "innocuous" when present alone. When someone is unlucky enough to accumulate several risk factors, compounded in many cases by one or more acute triggers, that person may be propelled over a threshold that precipitates the development of an acute episode of thrombosis. There is now reliable evidence that acute thromboses (both venous thromboembolism and acute coronary syndrome) follow a typical seasonal pattern and particularly display a characteristic spike during holiday periods. Overindulgence and abrupt changes of several lifestyle habits have been described as potential precipitating factors during such periods. Long travels, unhealthy diet, excessive or binge drinking and eating, decreased or increased physical activity, emotional and psychological stress, might all variably contribute to trigger an acute thrombotic event. Although the real causes of this "holiday phenomenon" remain speculative as yet, there is a widespread perception that they might represent preventable events like several other risk factors of both venous and arterial thrombosis. Beside drastic and unrealistic measures, such as canceling such holidays from the calendar, it seems reasonable to at least provide advice to patients about these "dangers," especially those individuals believed to be carrying a higher risk. Many (if not all) patients may ignore such advice and carry on regardless, but they should be given the benefit of informed choice. PMID- 22198852 TI - Alcohol dosing and the heart: updating clinical evidence. AB - The consequences of heavy or irregular alcohol drinking have long been known. Recently, consistent information has been provided in support of an association between light/moderate alcohol consumption and protection from vascular and all cause mortality, ischemic stroke, peripheral arterial disease, congestive heart failure, and recurrence of ischemic events. After reviewing the information with respect to major aspects of cardiovascular pathophysiology, to potential confounders and to underlying mechanisms, several concepts emerge. First, the recommended amounts of "safe alcohol drinking" in healthy individuals are up to two standard drinks (~20 g/d) for a man and up to one drink (10 g/d) for a nonpregnant woman. The overall balance for young premenopausal women, but not for older women, would be unfavorable for drinking. The risk of cancer would not outweigh potential benefits of alcohol on heart disease. Second, within the frame of a balanced pattern of dietary energy intake, patients with cardiovascular disease who drink alcohol should not exceed one or two standard drinks per day for women or up to two or three drinks per day for men. Third, the low rates of coronary heart disease among the Mediterranean people may be related to their pattern of drinking wine every day during meals. Regular drinking is associated with better outcomes than occasional (binge)/weekly drinking. Fourth, wine (ethanol with antioxidants) exhibits significantly higher anti-inflammatory effects than gin (ethanol without polyphenols), and thus in general wine should be preferred to liquor or beer. PMID- 22198853 TI - Relationship between venous and arterial thrombosis: a review of the literature from a causal perspective. AB - Venous thrombosis and arterial thrombosis are traditionally regarded as two different diseases with respect to pathophysiology, epidemiology, and treatment strategies. Research findings of the past few years suggest that this categorical distinction may be too strict. However, whether the described relationship between venous and arterial thrombosis is real or a result of other factors such as confounding, chance, or bias is still unclear. In this review, we discuss the current literature while using causal diagrams to better understand possible causal relations between cardiovascular risk factors, atherosclerosis, arterial thrombosis, and venous thrombosis. Furthermore, we propose study designs to investigate the causal link between venous and arterial thrombosis. In addition, we comment on the effect of statin use on the occurrence of both arterial and venous thrombosis. The possible clinical implications of these findings are discussed. PMID- 22198854 TI - Dyslipidemia, statins, and venous thromboembolism. AB - Venous thromboembolism (VTE) is one of the most frequent and serious vascular diseases. Although the major risk factors of VTE are well recognized, the pathology often develops in subjects without any obvious precipitating factor. Recent evidence suggests a link between arterial and venous thrombosis, particularly in patients with idiopathic venous thrombosis. Therefore, similar or identical risk factors may play a role in the development of both diseases. A positive association between classical risk factors of atherosclerosis, including dyslipidemia, and VTE has been reported. Recent studies demonstrated an association between hypercholesterolemia and objectively verified VTE. Circulating lipids have been shown to have both prothrombotic- and endothelium deteriorating properties. Studies suggested a greater generation of thrombin, endothelial dysfunction, and higher platelet activity in hyperlipidemic blood. By impeding these mechanisms, statins may protect against VTE. Observational, controlled studies and two meta-analyses showed that statins significantly reduced VTE risk, most likely in a process independent from cholesterol lowering, through mechanisms related to the pleiotropic effects of these drugs. Currently, it is unknown whether VTE prevention is a class-effect of statins, or if statins differ in their antithrombotic efficacy, and it is also unknown if statin benefit is dose-dependent. However, there are also opposite findings about the efficacy of statins in prevention of VTE. Therefore, the use of statins for prophylaxis of VTE cannot be generally recommended at this stage. Further studies are needed to identify those patients who could eventually benefit maximally from treatment with statins for prevention of VTE. PMID- 22198856 TI - The challenge of diagnosing pulmonary embolism in children, pregnant women, and elderly patients: a descriptive review of the literature. AB - The prompt and accurate diagnosis of pulmonary embolism (PE) greatly influences patient outcomes. However, diagnosing PE is one of the most difficult challenges confronting physicians, even more so when the clinical suspicion is addressed in children, during pregnancy, or in elderly patients. In these patient groups, symptoms and signs from concomitant conditions or diseases may mimic PE and make difficult defining clinical probability categories for PE as usually applied to general adult patients. Moreover, the diagnostic techniques show wider, specific limitations in these settings. PE is considered rare in children. The diagnostic management of a child with suspected PE is largely extrapolated from the knowledge achieved in adult patients. An increased risk of venous thromboembolism is reported in all trimesters of pregnancy and in the puerperium. An accurate diagnosis of PE in pregnancy has important implications, including the need for prolonged anticoagulation, delivery planning, and prophylaxis during future pregnancies, as well as concerns about future oral contraceptive use and estrogen therapy. Although incidence, morbidity, and mortality increase steadily with age, PE remains an underdiagnosed disease in elderly patients. About 40% of PE found at necropsy were not suspected antemortem. In the present article, challenges in diagnosing PE in children, during pregnancy, and in the elderly will be discussed, reviewing the available clinical, laboratory, and instrumental diagnostic strategies. PMID- 22198855 TI - Obesity and venous thrombosis: a review. AB - The world is experiencing an obesity pandemic, with rates of obesity rising for more than two decades. Obesity is defined as a body mass index (BMI) of 30 kg/m (2) or greater. Of particular concern are the risks that millions of obese people are likely to develop chronic diseases and at earlier ages than their parents might have. The risk of venous thrombosis increases with obesity, so that the incidence of this pathology is also expected to rise significantly. There is remarkable and consistent evidence from a systematic review, as well as cohort and case-control studies that obesity might predispose to venous thromboembolism (VTE). The risk appears to be at least double that for normal weight subjects (BMI 20 to 24.9 kg/m (2)). Plausible mechanisms exist to explain this relationship, including the physical effects of body fat limiting venous return and a proinflammatory, prothrombotic, and hypofibrinolytic milieu. Loss of body weight has been shown to reduce the concentrations of coagulation factors and plasminogen activator inhibitor-1 toward the normal range. Whether weight loss would prevent secondary occurrence of VTE in the absence of anticoagulant therapy could not be discerned from this literature search. PMID- 22198857 TI - Doping and thrombosis in sports. AB - Historically, humans have long sought to enhance their "athletic" performance to increase body weight, aggressiveness, mental concentration and physical strength, contextually reducing fatigue, pain, and improving recovery. Although regular training is the mainstay for achieving these targets, the ancillary use of ergogenic aids has become commonplace in all sports. The demarcation between ergogenic aids and doping substances or practices is continuously challenging and mostly based on perceptions regarding the corruption of the fairness of competition and the potential side effects or adverse events arising from the use of otherwise unnecessary ergogenic substances. A kaleidoscope of side effects has been associated with the use of doping agents, including behavioral, skeletal, endocrinologic, metabolic, hemodynamic, and cardiovascular imbalances. Among the various doping substances, the most striking association with thrombotic complications has been reported for androgenic anabolic steroids (i.e., cardiomyopathy, fatal and nonfatal arrhythmias, myocardial infarction [MI], intracardiac thrombosis, stroke, venous thromboembolism [VTE], limb arterial thrombosis, branch retinal vein occlusion, cerebral venous sinus thrombosis) and blood boosting (i.e., VTE and MI, especially for epoetin and analogs). The potential thrombotic complication arising from misuse of other doping agents such as the administration of cortisol, growth hormone, prolactin, cocaine, and platelet-derived preparations is instead speculative or anecdotal at best. The present article provides an overview on the epidemiological association as well as the underlying biochemical and biological mechanisms linking the practice of doping in sports with the development of thrombosis. PMID- 22198858 TI - Bleeding and thrombosis in multiple myeloma and related plasma cell disorders. AB - A variety of disease- and treatment-related factors affect the coagulation system and the risk of bleeding and thrombotic complications in patients with multiple myeloma (MM) and related plasma cell disorders (PCD). As commonly observed in other cancer settings, the malignant clone induces a cytokine environment responsible for a hypercoagulable state. The increase of blood viscosity and impairment of platelet and coagulation function due to circulating monoclonal proteins are considered key mechanisms in the hemostatic abnormalities frequently detected in patients with PCD. However, clinically significant bleeding is relatively rare and poorly correlated with these abnormalities. Management is often challenging because of the multifactorial pathogenesis and underestimation or misdiagnosis of acquired bleeding disorders, particularly acquired von Willebrand syndrome. In recent years, growing interest in thromboembolic risk has emerged after the introduction of novel and more effective antimyeloma agents (thalidomide and lenalidomide), which was associated with increased risk of venous thromboembolism, particularly when associated with dexamethasone and multiagent chemotherapy in newly diagnosed patients. The clinical impact of bleeding and thrombotic complications in patients with PCD, with emphasis on MM, will be discussed in this review, reporting the current knowledge about pathophysiologic mechanisms and implications for management. PMID- 22198859 TI - Thrombosis and occlusion of vascular access in hemodialyzed patients. AB - Patients undergoing chronic hemodialysis have a high risk of arterial thrombotic events as well as vascular access thrombosis (VAT). The latter complication has been consistently associated with inherited (i.e., the prothrombin 20210 polymorphism, and polymorphisms in the genes encoding for transforming growth factor-beta1, nitric oxide synthase, plasminogen activator inhibitor-1, angiotensin converting enzyme, and methylene tetrahydrofolate reductase), and acquired thrombotic risk factors (i.e., diabetes, obesity, atrial fibrillation, hypertension, hyperhomocysteinemia, hyperlipoproteinemia(a), low serum albumin, antiphospholipid antibodies, autoantibodies against protein C and S, erythropoietin administration, malnutrition, and cytomegalovirus infection). The three main factors involved in the pathogenesis of VAT overlap those of venous thrombosis and therefore include endothelial cell injury, blood stasis, and hypercoagulability. These changes are characteristic of patients affected by end stage renal disease and might be further aggravated during and after hemodialysis. The aim of this review is to describe the epidemiology and pathogenesis of thrombosis of dialysis vascular access and to discuss the application of therapeutic interventions in prevention and treatment of this clinical problem. PMID- 22198860 TI - Factor v Leiden mutation in severe infection and sepsis. AB - In severe infection and sepsis, activation of coagulation frequently occurs, which contributes to the development of multiple organ dysfunction. Factor V Leiden is a relatively common mutation resulting in a mild prohemostatic state and consequently with an increased tendency to develop thrombosis. Hypothetically, patients with factor V Leiden may suffer from more severe coagulopathy in cases of severe infection or sepsis. Aggravation of the procoagulant state in sepsis may subsequently result in more severe organ dysfunction and an increased risk of death. In this article we review the experimental and clinical evidence regarding the relationship between the presence of a factor V Leiden mutation and the incidence and outcome of sepsis. PMID- 22198861 TI - Microvascular thrombosis: a serious and deadly pathologic process in multiple diseases. AB - Much of our understanding of the pathogenesis of thrombosis has long been based on observations made on large blood vessels. Nevertheless, there has been a recent shift in our attention to the microvasculature and to how microcirculatory occlusion affects function of various organs in diseases. This article provides an overview of microthrombosis in small blood vessels, with discussion of the progressive stages of its development. The initial event is triggered by a variety of diseases, followed by a second phase when multiple contributory factors amplify the process with the final phase of microvascular occlusion and microvascular thrombosis. The outcome is either recovery or injury to the affected organ. If the process is generalized, it is often associated with catastrophic or fatal outcomes. Our current knowledge of the major role of contributory factors leads to a new paradigm. A therapeutic approach limited to a single target of the underlying pathogenic factor, such as the use of anticoagulants, is insufficient and too often unsuccessful. Simultaneous management of all the contributory factors should therefore be considered. PMID- 22198862 TI - Molecular profiling of parathyroid hyperplasia, adenoma and carcinoma. AB - The objective of the study was to examine proliferation and apoptosis associated gene expression in the whole sequence parathyroid lesions to reveal specific features of carcinoma. This study was based on surgically removed parathyroid tissues, gene expression analysis was performed both at gene and protein level. First, mRNA isolation was performed from deep-frozen tissue samples, and further apoptosis pathway-specific cDNA macroarray analysis was carried out. The results were validated with real-time PCR. Subsequently, protein expression was analyzed with immunhistochemistry on Tissue Micro Array multi-blocks derived from several paraffin-embedded samples. cDNA macroarrays revealed elevated expression of both pro-apoptotic (FAS receptor, TRAIL ligand, CASPASE8, and -4) and anti-apoptotic (cIAP1, APOLLON) genes in benign proliferative lesions compared to that in normal gland. TMA studies showed overexpression of KI67, P53, SURVIVIN and APOLLON protein and failure of expression of P27, BCL2, BAX, CHROMOGRANIN-A, SYNAPTOPHYSIN, CYCLIND1, FLIP, TRAIL, CK8, CK18, CK19 in parathyroid carcinoma was detected. These alterations in gene expression of the investigated products could be used in differentiation between beningn and malignant proliferative processes of the parathyroid gland. Authors conclude that a series of alterations in gene expression such as overexpression of APOLLON, P53, KI67 and suppression of P27, BCL2, BAX lead to uncontrolled cell proliferation, but still not leading to increased apoptotic activity in parathyroid carcinoma. PMID- 22198863 TI - Integrated perspective for effective bioremediation. AB - Identification of factors which can influence the natural attenuation process with available microbial genetic capacities can support the bioremediation which has been viewed as the safest procedure to combat with anthropogenic compounds in ecosystems. With the advent of molecular techniques, assimilatory capacity of an ecosystem can be defined with changing community dynamics, and if required, the essential genetic potential can be met through bioaugmentation. At the same time, intensification of microbial processes with nutrient balancing, expressing and enhancing the degradative capacities, could reduce the time frame of restoration of the ecosystem. The new concept of ecosystems biology has added greatly to conceptualize the networking of the evolving microbiota of the niche that helps in effective application of bioremediation tools to manage pollutants as additional carbon source. PMID- 22198864 TI - A thermophilic cellulase complex from Phialophora sp. G5 showing high capacity in cellulose hydrolysis. AB - A cellulase-producing mesophilic fungal strain, named G5, was isolated from the acidic wastewater and mud of a tin mine and identified as Phialophora sp. based on the internal transcribed spacer sequence. The volumetric activities and specific activities of cellulase induced by different carbon sources (Avicel, corn cob, wheat bran and corn stover) were compared. The cellulase complex of Phialophora sp. G5 exhibited the optimal activities at 60-65 degrees C and pH 4.0-5.0, and had good long-term thermostability at 50 degrees C. Compared with the commercial cellulase (Accellerase 1500, Genencor), the enzyme under study showed 60% and 80% of the capacity to hydrolyze pure cellulose and natural cellulose, respectively. This is the first study to report that a cellulytic enzymes complex from Phialophora genus, and the superior properties of this enzyme complex make strain G5 a potential microbial source to produce cellulase for industrial applications, and the production ability could be improved by mutagenesis. PMID- 22198865 TI - Solid-state fermentation of Mortierella isabellina for lipid production from soybean hull. AB - Soybean hull, generated from soybean processing, is a lignocellulosic material with limited industrial applications and little market value. This research is exploring a new application of soybean hull to be converted to fungal lipids for biodiesel production through solid-state fermentation. Mortierella isabellina was selected as the oil producer because of its high lipid content at low C/N ratio. Several cultivation factors were investigated, including moisture content, inoculums size, fungal spore age, and nutrient supplements, in an attempt to enhance the lipid production of the solid-state fermentation process. The results showed that lipid production with the increase of the moisture content and the spore age, while decreased as the size of inoculums increased. Nutrients addition (KH2PO4 1.2 mg and MgSO4 0.6 mg/g soybean hull) improved the lipid production. The total final lipid reached 47.9 mg lipid from 1 g soybean hull after the conversion, 3.3-fold higher than initial lipid reserve in the soybean hull. The fatty acid profile analysis indicated that fatty acid content consisted of 30.0% of total lipid, and 80.4% of total fatty acid was C16 and C18. Therefore, lipid production from soybean hull is a possible option to enable soybean hull as a new resource for biodiesel production and to enhance the overall oil production from soybeans. PMID- 22198866 TI - Cloning, differential expression, and association analysis with fat traits of porcine IDH3gamma gene. AB - Mitochondrial NAD+-dependent isocitrate dehydrogenase (IDH3) catalyzes the allosterically regulated rate-limiting step of the tricarboxylic acid cycle activated. In pigs, very little is known about this gene. Here, we cloned 1,346 bp full-length cDNA and 8,778 bp genomic sequence of porcine gamma subunit of IDH3 (IDH3gamma). IDH3gamma contains 12 exons separated by 11 introns. Real-time PCR revealed that IDH3gamma mRNA were upregulated in backfat of Large White compared with Meishan and F1 hybrids, and most abundant in small intestine via tissue distribution profile. A microsatellite ("GT" repeats) in second intron was found. The selected pigs were genotyped at this microsatellite. The IDH3gamma genotypes showed a significant effect on backfat thickness at thorax-waist (P < 0.05), backfat thickness at sixth to seventh thorax (P < 0.01), and average backfat thickness (P < 0.05). This site seemed to be significantly dominant in action (P < 0.05 for backfat thickness at sixth to seventh thorax, backfat thickness at thorax-waist, and average backfat thickness), and allele B was associated with increase of thickness values of these traits. This locus is possibly considered as a marker for adipose deposition traits. PMID- 22198867 TI - Synthesis, characterization, and oil recovery application of biosurfactant produced by indigenous pseudomonas aeruginosa WJ-1 using waste vegetable oils. AB - A bacterial strain was isolated and cultured from the oil excavation areas in tropical zone in northern China. The biochemical characteristics and partial sequenced 16S rRNA gene of isolate, WJ-1, was identical to those of cultured representatives of the species Pseudomonas aeruginosa. This bacterium was able to produce a type of biosurfactant. Compositional analysis revealed that the extracted biosurfactant was composed of high percentage lipid (~74%, w/w) and carbohydrate (~20%, w/w) in addition to a minor fraction of protein (~6%, w/w). The best production of 50.2 g/l was obtained when the cells were grown on minimal salt medium containing 6.0% (w/v) glucose and 0.75% (w/v) sodium nitrate supplemented with 0.1% (v/v) element solution at 37 degrees C and 180 rpm after 96 h. The optimum biosurfactant production pH value was found to be 6.0-8.0. The biosurfactant of WJ-1, with the critical micelle concentration of 0.014 g/L, could reduce surface tension to 24.5 mN/m and emulsified kerosene up to EI(24) ~95. The results obtained from time course study indicated that the surface tension reduction and emulsification potential was increased in the same way to cell growth. However, maximum biosurfactant production occurred and established in the stationary growth phase (after 90 h). Thin layer chromatography, Fourier transform infrared spectrum, and mass spectrum analysis indicate the extracted biosurfactant was affiliated with rhamnolipid. The core holder flooding experiments demonstrated that the oil recovery efficiency of strain and its biosurfactant was 23.02% residual oil. PMID- 22198869 TI - Circadian rhythm in serum iron levels. AB - This study was aimed at assessing the circadian rhythm of serum iron levels in Chinese healthy subjects. The project was conducted in 19 healthy, Chinese male subjects following a 4-day diet equilibration. Blood samples were collected on day 5 at 0800, 1000, 1200, 1400, 1600, 1800, 2000, and 2400 hours to determine endogenous serum iron concentrations. Iron concentrations were determined using an inductively coupled plasma mass spectrometry. Iron concentration was decreased from morning to afternoon. The minimum value of iron level was 1,987 MUg/L at 2000 hours while the maximum was 2,229 MUg/L at 1000 hours, and 2,278 MUg/L at 1400 hours, respectively, the amplitude was 291 MUg/L. This study indicates that when assessing the bioequivalence of iron formulations, baseline levels of iron (obtained before dosing) should not be subtracted simply from the amount obtained on the drug dosing day to yield the net effect of iron formulation administration. More valid methods to optimize the design of such bioequivalence studies should be taken into consideration. PMID- 22198871 TI - Pathoanatomy of cerebellar degeneration in spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3). AB - The cerebellum is one of the well-known targets of the pathological processes underlying spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3). Despite its pivotal role for the clinical pictures of these polyglutamine ataxias, no pathoanatomical studies of serial tissue sections through the cerebellum have been performed in SCA2 and SCA3 so far. Detailed pathoanatomical data are an important prerequisite for the identification of the initial events of the underlying disease processes of SCA2 and SCA3 and the reconstruction of its spread through the brain. In the present study, we performed a pathoanatomical investigation of serial thick tissue sections through the cerebellum of clinically diagnosed and genetically confirmed SCA2 and SCA3 patients. This study demonstrates that the cerebellar Purkinje cell layer and all four deep cerebellar nuclei consistently undergo considerable neuronal loss in SCA2 and SCA3. These cerebellar findings contribute substantially to the pathogenesis of clinical symptoms (i.e., dysarthria, intention tremor, oculomotor dysfunctions) of SCA2 and SCA3 patients and may facilitate the identification of the initial pathological alterations of the pathological processes of SCA2 and SCA3 and reconstruction of its spread through the brain. PMID- 22198870 TI - 3D morphometric analysis of human fetal cerebellar development. AB - To date, growth of the human fetal cerebellum has been estimated primarily from linear measurements from ultrasound and 2D magnetic resonance imaging (MRI). In this study, we use 3D analytical methods to develop normative growth trajectories for the cerebellum in utero. We measured cerebellar volume, linear dimensions, and local surface curvature from 3D reconstructed MRI of the human fetal brain (N = 46). We found that cerebellar volume increased approximately 7-fold from 20 to 31 gestational weeks. The better fit of the exponential curve (R (2) = 0.96) compared to the linear curve (R (2) = 0.92) indicated acceleration in growth. Within-subject cerebellar and cerebral volumes were highly correlated (R (2) = 0.94), though the cerebellar percentage of total brain volume increased from approximately 2.4% to 3.7% (R (2) = 0.63). Right and left hemispheric volumes did not significantly differ. Transcerebellar diameter, vermal height, and vermal anterior to posterior diameter increased significantly at constant rates. From the local curvature analysis, we found that expansion along the inferior and superior aspects of the hemispheres resulted in decreased convexity, which is likely due to the physical constraints of the dura surrounding the cerebellum and the adjacent brainstem. The paired decrease in convexity along the inferior vermis and increased convexity of the medial hemisphere represents development of the paravermian fissure, which becomes more visible during this period. In this 3D morphometric analysis of the human fetal cerebellum, we have shown that cerebellar growth is accelerating at a greater pace than the cerebrum and described how cerebellar growth impacts the shape of the structure. PMID- 22198872 TI - Neurosteroid biosynthesis and action during cerebellar development. AB - The formation of the mammalian cerebellar cortex becomes complete in the neonate through the processes of migration of external granule cells, neuronal and glial growth, and synaptogenesis. In the middle 1990s, we identified the Purkinje cell, a principal cerebellar neuron, as a major site for neurosteroid formation in mammals. This discovery has provided the opportunity to understand neuronal neurosteroidogenesis and neurosteroid actions on neuronal growth and synaptic formation in the cerebellum. Based on extensive studies on mammals over the past decade, we now know that the Purkinje cell actively synthesizes progesterone and estradiol de novo from cholesterol during neonatal life, when cerebellar neuronal circuit formation occurs. Both progesterone and estradiol promote dendritic growth, spinogenesis, and synaptogenesis via each cognate nuclear receptor in the developing Purkinje cell. Such neurosteroid actions that may be mediated by neurotrophic factors contribute to the formation of cerebellar neuronal circuit during neonatal life. Allopregnanolone, a progesterone metabolite, is also synthesized in the cerebellum and acts on Purkinje cell survival in the neonate. This paper highlights the biosynthesis and biological actions of neurosteroids in the Purkinje cell during cerebellar development. PMID- 22198873 TI - Estradiol promotes purkinje dendritic growth, spinogenesis, and synaptogenesis during neonatal life by inducing the expression of BDNF. AB - Neurosteroids are synthesized de novo from cholesterol in the brain. In rodents, the Purkinje cell actively produces several kinds of neurosteroids including estradiol during neonatal life, when cerebellar neuronal circuit formation occurs. Estradiol may be involved in cerebellar neuronal circuit formation through promoting neuronal growth and synaptic contact, because the Purkinje cell expresses estrogen receptor-beta. To test this hypothesis, in this study we examined the effect of estradiol on dendritic growth, spinogenesis, and synaptogenesis in the Purkinje cell using neonatal wild-type (WT) mice or cytochrome P450 aromatase knock-out (ArKO) mice. Administration of estradiol to neonatal WT or ArKO mice increased dendritic growth, spinogenesis, and synaptogenesis in the Purkinje cell. In contrast, WT mice treated with tamoxifen, an ER antagonist, or ArKO mice exhibited decreased Purkinje dendritic growth, spinogenesis, and synaptogenesis at the same neonatal period. Estrogen administration to neonatal WT or ArKO mice increased the expression of brain derived neurotrophic factor (BDNF) in the cerebellum, whereas tamoxifen decreased the BDNF level in WT mice similar to ArKO mice. BDNF administration to tamoxifen treated WT mice increased Purkinje dendritic growth. These results indicate that estradiol induces dendritic growth, spinogenesis, and synaptogenesis in the developing Purkinje cell via BDNF action during neonatal life. PMID- 22198874 TI - [Medical training reform: what's the situation?]. PMID- 22198876 TI - Inflammatory pseudotumor of the pancreas head in children. PMID- 22198877 TI - [Intravascular leiomyomatosis of the uterus]. PMID- 22198878 TI - [Primitive small cell carcinoma of the urinary bladder]. PMID- 22198879 TI - [Inverted papilloma of the renal pelvis]. PMID- 22198880 TI - [Cutaneous symptoms revealing acute myeloid leukemia]. PMID- 22198881 TI - [Chronic viral B hepatitis associated with primary biliary cirrhosis]. PMID- 22198882 TI - [A new case of cystic nephroma in adults]. PMID- 22198883 TI - [Epidermoid cyst mimicking a hydatid cyst of abdominal wall]. PMID- 22198884 TI - [Pregnancy and delivery in a patient with Glanzmann's thrombasthenia]. PMID- 22198885 TI - [Mazabraud's syndrome]. PMID- 22198886 TI - Visceral leishmaniasis in renal transplant patient. PMID- 22198887 TI - [Hepatorenal syndrome]. AB - BACKGROUND: Hepatorenal syndrome (HRS) is a particular form of functional renal failure which may develop in patients with liver cirrhosis. Recent advances in the understanding of the biology of vasoactive mediators and the physiology of microcirculation have allowed to better anticipate its pathophysiological mechanisms. AIM: To review new advances in the knowledge of epidemiology, diagnosis criteria, pathophysiological mechanisms and treatment of HRS. METHODS: Review of literature using medical data bases (Medline) with the following key words: hepatorenal syndrome, pathophysiology, medical treatment, MARS, liver transplantation. RESULTS: During the course of cirrhosis, portal hypertension leads to splanchnic and systemic vasodilation, responsible for a reduction of effective arteriel blood volume. As a result, a state of intense renal vasoconstriction develops, leading to renal failure in the absence of any organic renal disease. At this stage, liver transplantation is the only definitive therapy able to reverse renal dysfunction. Pharmacologic and radiologic therapy is aimed at improving renal function to enable patients to survive until transplantation is possible. These therapies are based on vasoconstrictor drugs associated with intravenous albumin infusion and transjugular intrahepatic portosystemic shunt (TIPS). They improve circulatory function, normalize serum creatinine and may improve survival. CONCLUSION: Simple measures have been shown to reduce the risk of HRS in cirrhotic patients including the plasma volume expansion with albumin in patients with spontaneous bacterial peritonitis and optimal fluid management in patients undergoing large volume paracentesis. PMID- 22198888 TI - [Rheumatic manifestations of genetic hemochromatosis]. AB - BACKGROUND: Rheumatic manifestations of genetic hemochromatosis are frequent with axial or peripheral arthropathies (mono-, oligo- or polyarticular). These manifestations are characterized by articular damage and osteoporosis. AIM: To review the rheumatic manifestations of genetic hemochromatosis. METHODS: A narrative review of literature. RESULTS: The diagnosis should be brought to mind when we discover arthropathy resembling degenerative joint disease with involvement of unusual articular sites, almost identical to the arthropathy in calcium pyrophosphate dihydrate crystals deposition disease (chondrocalcinosis). CONCLUSION: There is a significant bone loss in HC that cannot solely be explained by hypogonadism or cirrhosis and must lead to measure bone mass density to each patient with HC. PMID- 22198889 TI - [Anatomic and functional results after surgical treatment of uro genital prolapse: prospective study about 93 cases]. AB - BACKGROUND: genital polapse is a frequent olisease several techniques were described. AIM: To evaluate the anatomical and functional results of surgery for genital prolapse by vaginal and abdominal approach. METHODS: Prospective study on 93 patients operated for urogenital prolapse (50 by high and 43 vaginal approach) in the department of obstetrics and gynecology of Sfax. Anatomic results and postoperative patient satisfaction was assessed. Quality of life was assessed using the French versions of the questionnaires Pelvic Floor Distress Inventory (PFDI 20), Pelvic Floor Impact Questionnaire (PISQ 7). RESULTS: The mean age of patients was 59 years. 85.9% of our population consisted of postmenopausal women. The results of the postoperative visit, after a mean of 28.7 months, showed about the anatomical level, a success rate for the treatment of prolapse by high 82% against 72.1% for vaginal delivery, but the difference is not significant (P = 0.45). For prolapse of grades 1 and 2, surgical treatment by high and low has corrected all the elements of prolapse. For prolapse of grades 3 and 4, high surgery has resulted in a satisfactory anatomical result in 86%, while the lower channel yielded a significant result in 76.5%, and recurrence were interested mainly the anterior stage. The questionnaire PFDI 20, showed an improvement in the quality of life after surgery significantly in both groups (p<0.003). The improvement was more significant PFDI 20 after surgery by high versus vaginal surgery (p <0.002). Regarding PFIQ 7, improved quality of life was observed after surgery without significant differences between the two groups. CONCLUSION: The treatment of urogenital prolapse is mainly based on surgical and reconstructive surgery to restore anatomical and functional surgery also in order to improve the quality of life of patients. PMID- 22198890 TI - [Cutaneous schwannoma: study of 26 cases]. AB - BACKGROUND: Schwannoma is generally a benign tumour developing from Schwann cells. AIM: To study epidemiological, clinical and pathological features of scwannoma. METHODS: Retrospective study about 26 cases of cutaneous schwannoma collected in our department over 24 years. RESULTS: Our patients were 12 females and 14 males. Mean age was 30 years. Clinically, schwannoma was a subcutaneous tumour which was painful in 11 cases. Individual tumours were located on the limbs (10 cases), on the head (9 cases) and the trunk (5 cases). Multiple tumours were seen in two patients. Histopathological examination confirmed the diagnosis of schwannoma in all cases. Treatment was complete surgical excision in all cases. CONCLUSION: Cutaneous location of schwannoma is not rare. Usually, and contrarily to our series, there is no sex predominance. Clinically, schwannoma is located on the limbs and head. The diagnosis is confirmed by histopathological examination. Malignant epitheloid schwannoma diagnosed in one of our patients is a rare tumour. Schwannomas usually grow slowly and are poorly invasive. Malignant degeneration is exceptional. Treatment is complete surgical excision. PMID- 22198891 TI - Trends in hospital morbidity among adults in the region of Monastir (Tunisia) between 1996 and 2007. AB - AIM: To study trends of hospital morbidity among adults in the region of Monastir during a period of 12 years (1996 - 2007). METHODS: We analyzed data from the morbidity database of the university hospital of Monastir (Tunisia) between 01/01/1996 and 31/12/2007. Data were drawn from the register of hospital morbidity implemented in the Department of Preventive Medicine and Epidemiology since 1995. The International Classification of Diseases (tenth revision) was used to identify and classify morbid conditions. RESULTS: During the study period, we collected 150749 admissions with male tendency (sex-ratio = 1.27). Among these admissions 24.4% were over than 64 years. Morbid conditions were dominated by Ischemic Heart diseases (4.24%) followed by cancers and diabetes mellitus (3.3% and 2.52% respectively). Chronological trends, using Spearman correlation rank test, showed that overall rate of chronic conditions increased significantly from 4.4% in 1996 to 9.1% in 2007 (r'= |0.88|, p-value < 0.001). In contrast, the rate of infectious and parasitic diseases decreased from 4.3% to 2.9% (r'= |0.98|, p-value < 0.001). CONCLUSION: Morbidity trends reflect the epidemiological transition of our country and call to a backing of the ambulatory system and the development of specific services able to decrease the needs of hospitalizations. PMID- 22198892 TI - [Gastric MALT lymphoma: anatomo-clinical data and outcome of early stage H. pylori-associated gastric MALT-lymphoma resistant to treatment]. AB - AIM: To describe the clinical, endoscopic and histological particularities of early stage HP associated gastric MALT lymphoma resistant to anti Hp treatment and identify predicting factors of resistance. METHODS: We retrospectively studied 12 patients with primary low grade gastric localized MALT lymphoma treated with anti HP treatment and diagnosed at La Rabta Hospital from 1999 to 2009. RESULTS: The ultrasonography was normal in 5 patients between the 6 responding patients. Perigastric lymph nodes were found in non responders (33.3%). Hp eradication was achieved in 66% of patients not responding while Hp was eradicated in 100% of responders. The two non-responding patients with failure of eradication of Hp had a strain resistant to Clarithromycin Hp. CONCLUSION: Predicting factors of failure of anti HP: HP resistance to antibiotics, the proximal head, and the presence of perigastric lymph nodes. Recently, chromosomal aberrations and immune-histochemical markers have been implicated as factors of non response to anti Hp. PMID- 22198893 TI - [Is there a place for the Glasgow-Blatchford score in the management of upper gastrointestinal bleeding?]. AB - BACKGROUND: Upper gastrointestinal bleeding is a frequent cause for emergency hospital admission. Most severity scores include in their computation the endoscopic findings. The Glasgow-Blatchford score is a validated score that is easy to calculate based on simple clinical and biological variables that can identify patients with a low or a high risk of needing a therapeutic (interventional endoscopy, surgery and/ or transfusions). AIM: To validate retrospectively the Glasgow-Blatchford Score (GBS). METHODS: The study examined all patients admitted in both the general surgery department as of Anesthesiology of the Regional Hospital of Sidi Bouzid. There were 50 patients, which the mean age was 58 years and divided into 35 men and 15 women. In all these patients, we calculated the GBS. Series were divided into 2 groups, 26 cases received only medical treatment and 24 cases required transfusion and / or surgery. Univariate analysis was performed for comparison of these two groups then the ROC curve was used to identify the 'Cut off point' of GBS. Sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) with confidence interval 95% were calculated. RESULTS: The SGB was significantly different between the two groups (p <0.0001). Using the ROC curve, it was determined that for the threshold of GBS 3 7, Se = 96% (88-100%), Sp = 69% (51 87%), PPV = 74% (59 -90%) and NPV = 95% (85-100%). This threshold is interesting as to its VPN. Indeed, if GBS <7, we must opt for medical treatment to the risk of being wrong in only 5% of cases. CONCLUSION: The Glasgow-Blatchford score is based on simple clinical and laboratory variables. It can recognize in the emergency department the cases that require medical treatment and those whose support could need blood transfusions and / or surgical treatment. PMID- 22198894 TI - [Urinary tract infections in elderly]. AB - BACKGROUND: Urinary tract infections (UTI) in elderly are frequent and polymorphic clinical symptoms. This is a public health problem both in support and cost they generate. AIM: To study the epidemiological, clinical, paraclinical and therapeutic aspects of UTI in the elderly. METHODS: We conducted a retrospective study of 50 cases of UTI in the elderly collected in the Internal Medicine Department at Habib Thameur Hospital between January 2002 and December 2006 (Group I). We compared this group to another group of patients aged below 60 years also explored for UTI in the same service and during the same period (Group II). RESULTS: They were 37 women and 13 men in group I and 41 women and 9 men in the group II. In group I, the average age was 74.10 +/- 6.7 years, in group II 43.58 +/- 11.26 years. In group I, 35 patients (70%) showed no evidence of suspicion of a UTI on admission. 15 patients (30%) were admitted for suspected UTI. In group II, 36 patients (72%) showed no evidence of suspicion of a UTI on admission. 14 patients (28%) were admitted for suspected UTI. Urological abnormalities underlying the UTI, detected by ultrasound, were more frequent in Group I (40%) than in Group II (12%). Second-line antibiotics, due to the likely resistance of the microorganism, had to be prescribed in 16% cases in Group I vs. 4% of cases in Group II. The evolution under antibiotic treatment was marked by the occurrence of 3 deaths and transition to renal failure in 4 cases for Group I. In Group II, the outcome was favorable in all cases. CONCLUSION: Urinary tract infection is a significant factor in morbidity and mortality in the elderly. Female is much more concerned than male. Clinical manifestations of UTI are often crude and misleading in a pathological and poly polymedicated patient. The preventive arm accounts for most of the management of urinary tract infection in the elderly. PMID- 22198895 TI - [Prevalence and risk factors of thromboembolic complications in inflammatory bowel disease]. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk of thromboembolic complications (TEC), which represent an important cause of morbidity and mortality. AIM: To assess the prevalence and risk factors of TEC in patients with IBD. METHODS: We conducted a retrospective study including all the IBD patients in the gastroenterological department of Charles Nicolle hospital between 2000 and 2010. Only thromboembolic events that had been diagnosed by an imaging procedure were counted. RESULTS: A total of 266 patients with IBD were consecutively included. TE events occurred in nine patients (3.4%); six men and three women. Their mean age was 31 years [15-64 years]. Five patients had Crohn's disease and four had ulcerative colitis. The types of TEC were deep venous thrombosis of the leg in five cases with pulmonary embolism in one of them, cerebral venous thrombosis in two cases, portal thrombosis in one case and jugular vein thrombosis in one case. Active disease was present in all cases at the time TEC occurred. CONCLUSIONS: In our study, the prevalence of TEC is 3.4% in patients with IBD. Deep venous thromboses of the leg are the most common TEC and all our cases occurs during the active phase of IBD. PMID- 22198896 TI - [Treatment of idiopathic varicocele: comparative study of three techniques about 128 cases]. AB - BACKGROUND: Several modalities of varicocele treatment are available, however, no therapeutic technique showed its superiority with regard to the other one. AIM: To compare the results of three techniques of varicocelecomy. METHODS: Retrospective Analytical and comparative study of 128 patients treated by of three techniques of varicocelectomy: the open surgery by retro peritoneal way for 42 patients (GI), the varicocelectomie coelioscopique for 41 patients (GII) and the antegrade scrotal sclerotherapy done for 45 patients (GIII), between march 2001 and January 2009.The mean age was 28 years. The main motive for consultation was represented by the painful varicocele in 67 % of the cases, followed by the hypofertility in 20.3 % of the cases and the association both in 12,5 % of the cases. The varicocele was in leftsider in 71.1 % of the cases, to the right side in 5.4 % of the cases and was bilateral in 23.43 % of the cases. Varicocele was infra-clinical at 6 patients, grade 1 in 16 sides, grade 2 in 105 sides and grade 3 in 31 sides. The numeration, the mobility as well as the morphology of sperm cells were comparable between the three groups Results: The global rate success was 81.2 %, with the highest rate found in the group III which was treated by antegrade scrotal sclerotherapy (84.4 %). The improvement of the parameters of the spermogramme was noted in the three groups, however a statistically significant difference was found only in patients treated by antegrade scrotal sclerotherapy; it mainly concerned numeration and the mobility of spermatozoides. The highest rate of pregnancy was recorded in patients treated by antegrade scrotal sclerotherapy (13.3%). The main postoperative complications were hydrocele (16%) followed by testicular hypotrophy (3 patients). CONCLUSION: Three techniques of varicocele treatment, offer either a similar success rate, and improvement of parameters of the sperm cells. However, antegrade scrotal sclerotherpy seem to be the best treatment of first intention in proposed, regarding its efficiency, of the ease of its realization, its moderate cost and its feasibility in case of recurrence if varicocele was treated with open way'GIII). PMID- 22198897 TI - [Gastric heterotopia: clinical and histological study of 12 cases]. AB - BACKGROUND: Gastric heterotopia is a rare congenital lesion, described everywhere in the body, but involves predominantly the digestive tract. Diagnosis is based on histologic examination and requires the presence of gastric mucosa, especially fundic. This diagnosis is usually easy, but sometimes it can be misinterpreted as gastric metapalsia . This latter is an acquired and frequent lesion of the gastrointestinal tract. AIMS: To determine the relationship between this affection and the other digestive malformations, to describe the clinical characteristics and the evolution of this lesion and to discuss the differential diagnosis particularly the gastric metaplasia. METHODS: Twelve cases of gastric heterotopia were diagnosed over a 12-year period at Habib Thameur Hospital. Clinical data was obtained and all the slides were reviewed. RESULTS: Nine cases were found in Meckel's diverticulum (75%), one case in intestinal duplication, one case in the esophagus and another in the gallbladder. The mean age of patients at diagnosis was 16 years with a peak of incidence at the first decade of life. Intestinal obstruction and digestive bleeding were the most presenting features. Heterotopic gastric mucosa complicates other congenital anomalies such as common mesentery, vestigial polyp of the liver, appendiceal agenesis and heterotopic pancreas. Differential diagnosis consists in gastric metaplasia was found extensively in a patient with Crohn's disease associated with Meckel's diverticulum. CONCLUSION: Gastric heterotopia is frequently associated with congenital anomalies especially with Meckel's diverticulum and digestive duplication. Diagnosis relies on histology, mainly on finding heterotopic fundic glands in normal organizational structure. Sometimes, differentiating between gastric heterotopia and gastric metaplasia requires clinical confrontation. PMID- 22198898 TI - A case study of a patient with gliosarcoma with an extended survival and spinal cord metastases. AB - Gliosarcoma is a rare brain tumor consisting of both glial and mesenchymal components. Metastatic gliosarcoma is rare; however, here we report a 31-year-old Chinese woman with cranial gliosarcoma metastatic to the liver, lymph nodes and the spinal cord. Initially, the patient presented with dizziness, headache and vomiting and after surgery and histological examination, was diagnosed with cranial gliosarcoma. The patient was treated with surgical resection followed by chemotherapy and radiotherapy. Three years after completing treatment, the patient again presented with similar symptoms with the addition of a seizure. Test revealed recurrence of the gliosarcoma, and the same treatment was prescribed. Three years after treatment completion, the patient again presented with dizziness and headache. Masses at the right temple and in the right side of the neck were found. Tumors were surgically removed from the brain, skull, scalp and neck, the latter three diagnosed as metastatic gliosarcomas. The patient received both chemotherapy and radiotherapy following resection. One month after treatment, bone scans revealed possible metastasis in the right skull, lumbar and left ileum, soft neck tissue, lungs, collarbone, humeri, vertebrae, liver and abdominal lymph nodes. No further therapy was recommended due to the poor condition of the patient. The patient died 5 months later. PMID- 22198899 TI - Knowledge implementation in healthcare practice: a view from The Netherlands. AB - In this contribution we discuss some pertinent issues regarding knowledge implementation in the Netherlands, focusing on the largest public funding agency for health research in the Netherlands (ZonMw). The commentary is based on a report, which includes a structured analysis of 79 projects funded by ZonMW, a survey of published implementation research covering 141 systematic reviews, and qualitative study of the implementation infrastructure in the Netherlands. Five themes were identified. First, the term 'knowledge implementation' may be better replaced by more specific terms in some situations. Second, contextual factors need to be taken more systematically into account when planning and evaluating implementation programs. Third, knowledge may change when implemented and this needs to be considered in projects. Fourth, we observed that implementation has developed into a specific world, separated from both healthcare practice and scientific research. It is important to guard against the risk of isolation from the practical and societal needs that the field is meant to address. Finally, we suggest that the strong focus on 'doing projects' and limited opportunities for structural funding may reduce substantial improvement in the field. Many good activities are underway, but the policies regarding knowledge implementation appear to need some adjustment. In its policy plan for the coming years, ZonMW has partly taken up the lessons from our advisory report. PMID- 22198900 TI - Quality of in-hospital cardiac arrest calls: a prospective observational study. AB - OBJECTIVE: To determine the quality and diagnostic accuracy of in-hospital adult clinical emergency calls. DESIGN: Prospective observational study. SETTING: Three National Health Service acute hospitals in England. PARTICIPANTS: Adult patients sustaining an in-hospital cardiac arrest (CA) or medical emergency (ME) which required activation of the hospital resuscitation team between 1 December 2009 and 30 April 2010. MAIN OUTCOME MEASURES: Emergency call duration, emergency team dispatch time, diagnostic accuracy of emergency call (sensitivity/specificity), thematic analysis of emergency call, patient outcomes (return of spontaneous circulation and survival to hospital discharge). RESULTS: There were 426 adult resuscitation team activations. There was variability in emergency call duration ranging from 6 to 92 s (median 15 s; IQR 12-19). The sensitivity and specificity of calls for a CA was 91% (86.4-94.6%) and 62% (55.5-68.7%), respectively. Sensitivity did not change with call duration but specificity increased from 38% (25.8-51.0%) for the shortest calls to 82% (69.5-89.6%) for longer calls; p=0.03. The return of spontaneous circulation rate was 38% for calls when the patient was confirmed as in CA upon arrival of the resuscitation team. Survival to hospital discharge rates was higher in patients with shorter call durations (26%) than calls with longer call duration (12%); p=0.028. Five themes emerged identifying reasons for the increased call delay. CONCLUSION: There is variability in duration and diagnostic accuracy of in-hospital emergency calls. This is associated with delayed activation of the emergency response. The attempt to differentiate between ME and CA is a source of confusion. A single clinical emergency response for CA and ME calls may provide a more focused and timely emergency response. PMID- 22198901 TI - 'Wading through treacle': quality improvement lessons from the frontline. AB - In a time of financial uncertainty and structural reform, the National Health Service (NHS) in England needs clinical leadership to help improve the quality of patient care. Increasingly, leadership development is being targeted at doctors in postgraduate training to help prepare them for their future leadership roles as consultants and general practitioners. However, there is a risk that we are missing an opportunity here by failing to recognise the role that doctors in training can play now, during their training. As our frontline clinicians they have a unique view of the health service and the inefficiencies therein. The London Deanery has been running an educational programme called Beyond Audit to provide doctors in training with quality improvement skills. During this programme we have been given a unique insight into NHS systems as viewed by junior doctors. They have identified a wide range of small system problems that, when combined, result in large-scale inefficiency and prevent the delivery of high quality patient care. These problems they identify have implications for cost, efficiency, patient safety, team-working and patient experience. Any attempt to improve the quality of care delivered in the NHS needs to look at the system from the point of view of those delivering the care, including our doctors in postgraduate training. By empowering them to make improvements to the systems that they see, there is the potential to make significant improvement in the quality of patient care that they deliver. PMID- 22198902 TI - Comparison of Microlife BP A200 Plus and Omron M6 blood pressure monitors to detect atrial fibrillation in hypertensive patients. AB - INTRODUCTION: Self-monitoring home blood pressure (BP) devices are currently recommended for long-term follow-up of hypertension and its management. Some of these devices are integrated with algorithms aimed at detecting atrial fibrillation (AF), which is common essential hypertension. This study was designed to compare the diagnostic accuracy of two widely diffused home BP monitoring devices in detecting AF in an unselected population of outpatients referred to a hypertension clinic because of high BP. METHODS: In 503 consecutive patients the authors simultaneously compared the accuracy of the Microlife((r)) BP A200 Plus (Microlife) and the OMRON((r)) M6 (OMRON) home BP devices, in detecting AF. RESULTS: Systolic and diastolic BP as well as heart rate (HR) values detected by the two devices were not significantly different. Pulse irregularity was detected in 124 and 112 patients with the OMRON M6 and Microlife BP A200 Plus devices, respectively. Simultaneous electrocardiogram (ECG) recording revealed that pulse irregularity was due to AF in 101 patients. Pulse irregularity detected by the OMRON M6 device corresponded to AF in 101, to supraventricular premature beats in 18, and to frequent premature ventricular beat in five patients, respectively. Pulse irregularity detected by the Microlife BP A200 Plus device corresponded to AF in 93, to supraventricular premature beats in 14, and to ventricular premature beats in five patients. The sensitivity for detecting AF was 100%, the specificity was 92%, and diagnostic accuracy 95% for the OMRON M6 and 100%, 92%, and 95 for the Microlife BP A200 Plus, respectively. AF was newly diagnosed by ECG recordings in 47 patients, and was detected in all patients by the OMRON device, and in 42 patients by the Microlife device. CONCLUSION: These results indicate that OMRON M6 is more accurate than Microlife BP A200 Plus in detecting AF in patients with essential hypertension. Widespread use of these devices in hypertensive patients could be of clinical benefit for the early diagnosis and treatment of this arrhythmia and related consequences. PMID- 22198906 TI - Loss-of-function thrombospondin-1 mutations in familial pulmonary hypertension. AB - Most patients with familial pulmonary arterial hypertension (FPAH) carry mutations in the bone morphogenic protein receptor 2 gene (BMPR2). Yet carriers have only a 20% risk of disease, suggesting that other factors influence penetrance. Thrombospondin-1 (TSP1) regulates activation of TGF-beta and inhibits endothelial and smooth muscle cell proliferation, pathways coincidentally altered in pulmonary arterial hypertension (PAH). To determine whether a subset of FPAH patients also have mutations in the TSP1 gene (THBS1) we resequenced the type I repeats of THBS1 encoding the TGF-beta regulation and cell growth inhibition domains in 60 FPAH probands, 70 nonfamilial PAH subjects, and in large control groups. We identified THBS1 mutations in three families: a novel missense mutation in two (Asp362Asn), and an intronic mutation in a third (IVS8+255 G/A). Neither mutation was detected in population controls. Mutant 362Asn TSP1 had less than half of the ability of wild-type TSP1 to activate TGF-beta. Mutant 362Asn TSP1 also lost the ability to inhibit growth of pulmonary arterial smooth muscle cells and was over threefold less effective at inhibiting endothelial cell growth. The IVS8+255 G/A mutation decreased and/or eliminated local binding of the transcription factors SP1 and MAZ but did not affect RNA splicing. These novel mutations implicate THBS1 as a modifier gene in FPAH. These THBS1 mutations have implications in the genetic evaluation of FPAH patients. However, since FPAH is rare, these data are most relevant as evidence for the importance of TSP1 in pulmonary vascular homeostasis. Further examination of THBS1 in the pathogenesis of PAH is warranted. PMID- 22198908 TI - Apocynin improves oxygenation and increases eNOS in persistent pulmonary hypertension of the newborn. AB - NADPH oxidase is a major source of superoxide anions in the pulmonary arteries (PA). We previously reported that intratracheal SOD improves oxygenation and restores endothelial nitric oxide (NO) synthase (eNOS) function in lambs with persistent pulmonary hypertension of the newborn (PPHN). In this study, we determined the effects of the NADPH oxidase inhibitor apocynin on oxygenation, reactive oxygen species (ROS) levels, and NO signaling in PPHN lambs. PPHN was induced in lambs by antenatal ligation of the ductus arteriosus 9 days prior to delivery. Lambs were treated with vehicle or apocynin (3 mg/kg intratracheally) at birth and then ventilated with 100% O(2) for 24 h. A significant improvement in oxygenation was observed in apocynin-treated lambs after 24 h of ventilation. Contractility of isolated fifth-generation PA to norepinephrine was attenuated in apocynin-treated lambs. PA constrictions to NO synthase (NOS) inhibition with N nitro-l-arginine were blunted in PPHN lambs; apocynin restored contractility to N nitro-l-arginine, suggesting increased NOS activity. Intratracheal apocynin also enhanced PA relaxations to the eNOS activator A-23187 and to the NO donor S nitrosyl-N-acetyl-penicillamine. Apocynin decreased the interaction between NADPH oxidase subunits p22(phox) and p47(phox) and decreased the expression of Nox2 and p22(phox) in ventilated PPHN lungs. These findings were associated with decreased superoxide and 3-nitrotyrosine levels in the PA of apocynin-treated PPHN lambs. eNOS protein expression, endothelial NO levels, and tetrahydrobiopterin-to dihydrobiopterin ratios were significantly increased in PA from apocynin-treated lambs, although cGMP levels did not significantly increase and phosphodiesterase 5 activity did not significantly decrease. NADPH oxidase inhibition with apocynin may improve oxygenation, in part, by attenuating ROS-mediated vasoconstriction and by increasing NOS activity. PMID- 22198909 TI - Hydrocortisone normalizes oxygenation and cGMP regulation in lambs with persistent pulmonary hypertension of the newborn. AB - In the pulmonary vasculature, cGMP levels are regulated by soluble guanylate cyclase (sGC) and phosphodiesterase 5 (PDE5). We previously reported that lambs with persistent pulmonary hypertension of the newborn (PPHN) demonstrate increased reactive oxygen species (ROS) and altered sGC and PDE5 activity, with resultant decreased cGMP. The objective of this study was to evaluate the effects of hydrocortisone on pulmonary vascular function, ROS, and cGMP in the ovine ductal ligation model of PPHN. PPHN lambs were ventilated with 100% O(2) for 24 h. Six lambs received 5 mg/kg hydrocortisone every 8 h times three doses (PPHN hiHC), five lambs received 3 mg/kg hydrocortisone followed by 1 mg.kg(-1).dose( 1) times two doses (PPHN-loHC), and six lambs were ventilated with O(2) alone (PPHN). All groups were compared with healthy 1-day spontaneously breathing lambs (1DSB). O(2) ventilation of PPHN lambs decreased sGC activity, increased PDE5 activity, and increased ROS vs. 1DSB lambs. Both hydrocortisone doses significantly improved arterial-to-alveolar ratios relative to PPHN lambs, decreased PDE5 activity, and increased cGMP relative to PPHN lambs. High-dose hydrocortisone also increased sGC activity, decreased PDE5 expression, decreased ROS, and increased total vascular SOD activity vs. PPHN lambs. These data suggest that hydrocortisone treatment in clinically relevant doses improves oxygenation and decreases hyperoxia-induced changes in sGC and PDE5 activity, increasing cGMP levels. Hydrocortisone reduces ROS levels in part by increasing SOD activity in PPHN lambs ventilated with 100% O(2.) We speculate that hydrocortisone increases cGMP by direct effects on sGC and PDE5 expression and by attenuating abnormalities induced by oxidant stress. PMID- 22198910 TI - Applications of PET-CT in patients with esophageal cancer. AB - Although esophageal cancer is not among the common cancers as prostate, lung, breast, or colon malignancies, it has an exceedingly high mortality rate, with its incidence close to the cancer-specific mortality. Currently, the only potentially curative treatment is surgery. Unfortunately, surgical treatment is extensive and may have significant morbidity and mortality related with it. Given these facts, selection of patients who are amenable to surgical treatment is of utmost importance. Conventional morphology based cross-sectional imaging modalities are extremely helpful for pre-surgical evaluation and follow-up of these patients, however, they have very wellknown limitations. Positron emission tomography-computed tomography (PET-CT) is a relatively new, highly promising molecular imaging technique which may overcome some of the fundemental limitations of these conventional cross-sectional modalities in the pre-surgical evaluation and follow-up of these patients. In this review, we evaluated the applications of PET-CT in patients with esophageal cancer. PMID- 22198907 TI - Genetically manipulated mouse models of lung disease: potential and pitfalls. AB - Gene targeting in mice (transgenic and knockout) has provided investigators with an unparalleled armamentarium in recent decades to dissect the cellular and molecular basis of critical pathophysiological states. Fruitful information has been derived from studies using these genetically engineered mice with significant impact on our understanding, not only of specific biological processes spanning cell proliferation to cell death, but also of critical molecular events involved in the pathogenesis of human disease. This review will focus on the use of gene-targeted mice to study various models of lung disease including airways diseases such as asthma and chronic obstructive pulmonary disease, and parenchymal lung diseases including idiopathic pulmonary fibrosis, pulmonary hypertension, pneumonia, and acute lung injury. We will attempt to review the current technological approaches of generating gene-targeted mice and the enormous dataset derived from these studies, providing a template for lung investigators. PMID- 22198911 TI - US-guided percutaneous thrombin injection of postcatheterization pseudoaneurysms. AB - PURPOSE: This study retrospectively evaluated ultrasonography-guided (US-guided) percutaneous thrombin injection for the treatment of postcatheterization femoral and brachial artery pseudoaneurysms. MATERIALS AND METHODS: Fifty-five patients with postcatheterization femoral artery (n = 53) or brachial artery (n = 2) pseudoaneurysms were treated using US-guided human thrombin (500 IU/mL) injection. Pseudoaneurysm size, thrombin dose, therapy outcome, and complications were documented. Follow-up color Doppler US was performed 7 and 30 days after treatment. Short-duration supplemental compression was applied to six patients at the first week follow-up examination after a reinjection of thrombin had failed. RESULTS: Mean pseudoaneurysm volume was 20.3 +/- 18.7 cm(3). The mean injected thrombin dose was 478 +/- 238 IU. Thirty-eight (69.1%) of the 55 pseudoaneurysms were thrombosed with a single injection, and 11 of 17 pseudoaneurysms were thrombosed after a second injection. All (100%) of the 41 pseudoaneurysms that were diagnosed within the first two weeks of postcatheterization were successfully treated. The overall primary success rate was 89.1% (49 of 55 pseudoaneurysms). Supplemental compression promoted thrombosis in four of the six patients who had treatment failure with thrombin injection. The secondary success rate was 96.4% (53 of 55 pseudoaneurysms). There were no complications. CONCLUSION: US-guided thrombin injection was most successful within the first two weeks, and the supplemental compression might aid in the closure of partially thrombosed pseudoaneurysms. PMID- 22198913 TI - Cytomegalovirus: recent progress in understanding pathogenesis and control. AB - Cytomegalovirus continues to be an important pathogen in a variety of patient groups especially the neonate and the transplant recipient, and has implicated in a range of pathologies including inflammatory disease and in contributing to early death in ageing populations. This review will focus on advances in understanding the virus-host interaction and options for the new therapeutic control measures. PMID- 22198912 TI - The association of low bone mineral density with systemic inflammation in clinically stable COPD. AB - Chronic obstructive pulmonary disease (COPD) is known to be a systemic inflammatory disease which affects the function of many organs, and the low bone mineral density (BMD) may be the result of systemic inflammation. The aim of the present study was to explore the association of BMD with systemic inflammation in patients with clinically stable COPD. BMD and inflammatory markers, including C reactive protein, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL 6), were determined in all the recruited patients with clinically stable COPD. The patients were classified according to T scores, and the relationship between BMD with markers of systemic inflammation and that with other osteoporosis risk factors was assessed. There were no differences in age, female sex, body composition, tobacco exposure, and the use of respiratory medications among these groups. As the abnormality of BMD went severer, COPD patients with osteoporosis had significantly higher levels of systemic inflammation than those with either normal BMD or osteopenia. The presence of systemic inflammation was associated with a greater likelihood of low BMD, and multivariate logistic regression analysis showed that TNF-alpha and IL-6 were independent predictors of low BMD. It can be concluded that systemic inflammation is a significantly independent predictor of low BMD in patients with clinically stable COPD. PMID- 22198914 TI - [Investigation of Toxoplasma gondii seropositivity in pregnant women attending the Antalya Training and Research Hospital for the last four years]. AB - OBJECTIVE: The aim of this study was to determine the seropositivity of Toxoplasma gondii in female patients admitted to the outpatient clinic of Antalya Training and Research Hospital, Department of Obstetrics and Gynecology. METHODS: The seropositivity of Toxoplasma gondii was investigated with the "chemiluminescence immunoassay" method from August 2008 to May 2011. RESULTS: Toxoplasma seropositivity was 33.4% and the rate of seropositivity increased with age (p < 0.05). There has been a statistically significant gradual increase in Toxoplasma gondii IgM seropositivity between 2008 to 2011. CONCLUSION: Toxoplasmosis seropositivity in pregnant women is increasing in our area. In order to avoid congenital toxoplasmosis and the possible complications of pregnancy Toxoplasma gondii surveilans studies should be planned. PMID- 22198915 TI - [Seasonal distribution and economic importance of cystic echinococcosis in cattle slaughtered at Kars Municipal Abattoir, Turkey]. AB - OBJECTIVE: Cystic echinococcosis is a very important zoonotic disease both for the World and Turkey. This study was performed to determine the prevalence, seasonal distribution and economic importance of Cystic echinococcosis by using the data provided from the 2010 records of the Kars Municipal Abattoir. METHODS: In this retrospective study, the records of 3.846 cattle slaughtered at the Kars Municipal Abattoir between January and December 2010 were investigated. RESULTS: In this study, 3.846 cattle were examined. CE was found in 203 (5.3%) out of 3846 cattle in that Abattoir. It was also found that the incidence rate of this infection in female cattle is higher than the rates in the males (p < 0.001). It was also determined that this infection is mostly prevalent in Spring (37.4%), while it is less prevalent in Autumn (15.8%). The total annual economic loss due to hydatidosis in cattle slaughtered at Kars municipal abattoir was estimated to be to 12.180 TL (7.708 $) per year. CONCLUSION: As a result, obtained prevalence values indicate that cystic echinococcosis causes potential risks for public health besides causing significant economic losses in the Kars province. PMID- 22198916 TI - [Histopathologically diagnosed pulmonary complicated hydatid cyst cases]. AB - OBJECTIVE: Hydatid cyst disease is caused by the metacestod form of Echinococcosis granulosus from cestods. Pulmonary hydatid cyst is the second most frequent form of the disease after the liver involvement and may open into the bronchial or pleural space by perforation and may cause complications. The aim of the study was to evaluate the clinical features and the frequency of the complicated pulmonary hydatid cyst disease. METHODS: Fifteen hydatid cyst patients were evaluated according to socio-demographical, clinical and radiological findings between 2009 and 2011 retrospectively. Hydatid cyst diseases were diagnosed histopathologically after chest surgery. Diagnostic difficulties and clinical features were analysed in four complicated pulmonary hydatid cyst cases. RESULTS: Pneumothorax, pleural effusion, lung abscess, and hemoptysis were observed in four complicated cases. The complicated cases were diagnosed after surgery. Eleven of lung cysts were intact, radiological and histopathological features were typical for images of hydatid cyst disease and reported as compatible with the clinical diagnosis. A synchronized liver and pulmonary hydatid cyst was evaluated as a morbidity factor. CONCLUSION: Hydatid cyst should be considered in the differential diagnosis of uncertain chest pathologies, especially in rural areas where the disease is endemic. PMID- 22198917 TI - [The distribution of intestinal parasites detected in the Uludag University Medical School Hospital between 2005 and 2008]. AB - OBJECTIVE: Intestinal parasite infection is still an important public health problem. In this study, patients (outpatients and in-patients) with various gastrointestinal system complaints presenting at various clinics of the Uludag University Medical Faculty, from January 2009-December 2010 were investigated retrospectively for intestinal parasites. METHODS: Parasitological examinations were done with native-lugol, cellophane-tape methods and trichrome staining in ambiguous cases. Also modified Erlich-Ziehl-Nielsen staining was used to identify Cryptosporidium spp. RESULTS: In a total of 5,624 cases examined 10.25% were found infected with at least one or more parasite, without difference between genders. Enterobius vermicularis eggs (9.3%) was detected in 227 of 1,971 cellophane tape preparations. The distribution of identified parasites was as follows: Giardia intestinalis, 199 (34.48%); 29 Blastocystis hominis, 136 (23.57%); Entamoeba coli, 83 (14.38%); Enterobius vermicularis, 227 (9.3%). The prevalence of parasite infections in stool samples examined was highest among the age group of 10-29 years old (36.8%), followed by the age group 0-9 years, in which rate was 18.6%. Parasites such as helminth detected in 225 (32.09%) and protozoon in 476 (67.91%) of the patients were included in this study. CONCLUSION: This study re-emphasises the fact that intestinal parasitic infection is still an important public health problem. PMID- 22198918 TI - [Prevalence of head lice in some primary schools in Igdir province]. AB - OBJECTIVE: This study was carried out to detect the prevalence and evaluate risk factors of Pediculus capitis infestation in four primary schools in Igdir in April and May, 2010. METHODS: The study was performed on 2222 students (6-15 years old), 1116 female and 1106 male. The hair of the students, especially from the neck and back of the head, were examined for egg, nymph and imago of P. capitis. The samples taken from the students were brought to the Medical Laboratory of Health Services Vocational School of Igdir University for examination. Each student answered a questionnaire containing some questions related to the infestation. RESULTS: The imago, nymph or eggs of the parasite were encountered in 22.9% of females and in 3.2% of males. Prevalence of infestation in all students was 13.1%. CONCLUSION: It was determined that there was a significant relation between head louse infestation and gender, socioeconomic status of the schools, hair length, number of people living in the home and the number of rooms in the house. In most comparisons, relations between prevalence of pediculosis capitis and education level, income level and job of the children's father and education level of the children's mother were found significant at different levels. PMID- 22198919 TI - [Parasites observed in a zebra in Izmir]. AB - This work consists of a case report on a zebra presented to our institute for the determination of the cause of death. The animal was subjected to necropsy before it was presented to our institute. During examination, ascarids in the intestines and myasis agents in the stomach were observed. The parasites seen in the stomach and the intestines were identified according to the identification key and afterwards counted. In this work, the ascarids were identified as Parascaris equorum, myasis agents in the stomach were determined to be the third stage larvae of Gasterophilus intestinalis. In the intestines, 344 P. equorum were counted, while in the stomach there were 20 third stage larvae of G. intestinalis. As a result, it is concluded that these parasites should not be overlooked in zebras that start vomiting without any prior symptoms, aspirate the stomach contents and show signs of colic. PMID- 22198920 TI - [A report of ectoparasite Piscicola geometra (Linnaeus, 1761) (Hirudinea: Rhynchobdellida) on roach (Rutilus rutilus (Linnaeus, 1758)) from Uluabat Lake]. AB - An ectoparasite leech Piscicola geometra were found on female roach (Rutilus rutilus) between the anus and lateral line during the biometric measurements for the purpose of monitoring the fish population in Uluabat Lake. P. geometra was previously reported on Carassius gibelio and Tinca tinca from Lake Uluabat. It was understood with this case report that R. rutilus also is a host fish for P. geometra in Uluabat Lake. PMID- 22198921 TI - Endoscopic diagnosis in Ascaris lumbricoides case with pyloric obstruction. AB - Ascaris lumbricoides is the largest and most prevalent helminth seen in the human body. Ascariasis having high morbidity and mortality causes a unique type of intestinal obstruction with specific problems. This is probably due to reduced intestinal absorption and luminal obstruction, which can lead to anorexia and blockage of the absorbing surface. It affects humans especially in developing countries. This essay presented a 78-year-old female case had severe abdominal pain, nausea and constipation for seven days and the pylorus was obstructed by A. lumbricoides and diagnosis was obtained by endoscopy. During endoscopy in the treatment, the ascariasis that could be removed was. Afterwards, 100 mg mebendazole was given for 3 days once in two months.The purpose of the presentation of this case is that it is seen in advanced ages and it sets us thinking of stomach tumor due to its obstruction and anemia clinic. PMID- 22198923 TI - Primary cyst hydatid in the neck; report of one case. AB - Hydatid cyst is a parasitic disease that has been recognized endemically in many countries. Although the liver and lung are the most common organs involved by the disease, it may appear rarely in other tissues as a primary disease. In the ultrasonography of the neck taken from a 17 year old case who attended with a complaint of swelling in the neck, a partly regular, bounded cystic lesion of 33x28 mm in size was reported. When the cyst was thought to be hydatid during surgical exploration, this diagnosis was confirmed by histopathological verification of the specimen obtained. Whole abdomen ultrasonography and PA Chest Radiography were taken in order to determine whether there was another focus during the postoperative period. The Echinococcus ELISA test was performed as an immunological parameter. Treatment with Albendazole began after diagnosis during the postoperative period. Although hydatid cyst most commonly involves the liver and lung, it may be detected in all body tissues. Therefore hydatid cyst must be considered in the differential diagnosis in cystic lesions that are rarely encountered in body localizations in human, living in endemic regions. PMID- 22198922 TI - [Primary pancreatic hydatid cyst resembling a pseudocyst]. AB - Hydatid cyst is a parasitic disease that is commonly seen in certain areas. It may localize in many organs in the body. Pancreas is a rarely involved organ. A 48 years old patient who could not be diagnosed before surgery was then diagnosed with hydatid cyst localized in the uncinate process of the pancreas post operatively. Albendazole treatment was begun after the operation. No problem was observed in the follow-up ultrasonography. This rare case may be mistaken for cystic malignancies and pseudocysts of pancreas. PMID- 22198924 TI - Calcified intracranial hydatid cyst: case report. AB - We present a 26-year-old patient who did farming related work had an asymptomatic intracranial hydatid cyst. A calcified intracranial cystic mass was found on radiological investigations and the patient underwent surgery. The mass was totally excised. The histopathology result reported a hydatid cyst. There were no postoperative complications. Calcification is quite rare in cerebral hydatid cyst. The computed tomography and magnetic resonance imaging provide information that is especially useful for preoperative diagnosis. Observing membrane detachment and daughter cysts during these investigations is pathognomonic. The presence of calcification in the cyst wall and intracystic membranes indicated hydatid cyst. PMID- 22198925 TI - [External ophthalmomyiasis: case reports]. AB - We report two cases with external ophthalmomyiasis due to infestation with the larvae of Oestrus ovis. During an ophthalmologic examination, motile larvae were seen on the conjunctiva, which were removed and sent to the Department of Parasitology for identification. Microscopic examination of the specimens revealed that both patients were infested with the first stage larvae of O. ovis. The patients were treated with topical antibiotics and steroids and recovered without any complications. O. ovis larvae are the most common cause of ophthalmomyiasis worldwide. They are usually seen in underdeveloped, agricultural areas with high numbers of livestock, especially during Spring and Summer. These kind of infestations should be kept in mind in cases of conjunctivitis in the warm months of the year. PMID- 22198926 TI - [Case report: Infestation of lower extremities by Phthirus pubis, Linnaeus 1758 after contact with second-hand furniture]. AB - This case has been filed as a 21-year old male patient who was diagnosed with P. pubis present in his tibial hair. The agent was not found in body parts of the patient other than both lower extremities. The infestation is thought to stem from using second-hand furniture which had been bought the day before the case developed; as other possible ways of infection such as transmission through the rest of the residents of the house were ruled out in our medical investigation. It is understood that second-hand furniture pieces such as mattresses, quilts, carpets, and sofas might be a source of infection of P. pubis including tibial hair areas. The conclusion is that, in infested people or those who are exposed to such a risk, this possibility should be taken into account. PMID- 22198927 TI - [Primary disseminated pulmonary hydatid cyst manifesting with right-side cardiac failure: case report]. AB - Hydatid disease is a parasitic infection caused by a tapeworm of the genus Echinococcus. There are three known species of Echinococcus that lead to the disease among humans. E. granulosus is the most common of the three. A 26-year old man admitted to emergency room with a cough, dyspnea, tachycardia, and chest pain was hospitalized with suspected pneumonia. The patient was in poor general condition and was conscious. On physical examination, fever: 37.3 degrees C/axillary, blood pressure: 165/100 mmHg, cardiac pulse: 114/min, remarkable bilateral pretibial edema, peripheral cyanosis, and disseminated rales and rhonchi were found. Chest radiography showed the multiple disseminated cystic formations, and thorax computed tomography showed remarkable dilatation in the ring of pulmonary artery, and multiple cystic formations in the lung area. The disseminated pulmonary hydatid cyst disease was diagnosed according to clinical and laboratory findings. Albendazole 800 mg/kg daily was administered to the patient for three months. The patient recovered markedly after this treatment. To our knowledge, this is the first case of primary disseminated pulmonary hydatid cyst to manifest with right-side cardiac failure. In endemic areas, the morbidity and mortality due to hydatid cyst may be decreased if hydatid cyst is considered among patients with suspected radiologic findings. PMID- 22198928 TI - [Medicinal leeches and hirudotherapy]. AB - Leeches have been used in the treatment of certain diseases since ancient times. There are a few species of medicinal leeches. However, H. medicinalis and H. verbana are known in Turkey. Currently, Turkey is one of the world's most important leech-exporting countries. Secretion of the salivary glands of medical leeches contains more than 100 bioactive substances. These secretions include vasodilators, bacteriostatic, analgesic, anti-inflammatory and anticoagulants, anti-edematous, which eliminate microcirculatory disorders, restore the damaged vascular permeability of tissues and organs, eliminate hypoxia, reduce blood pressure, increase immune system activity, resolving the cause of pain and improve the bioenergetic status of the organism. U.S. Food and Drug Administration (Food and Drug Authority of USA-FDA) have allowed the sale of leeches in this country, the use for plastic surgery, the general purposes and microsurgery in 2004. Turkey is the richest source in terms of the medical leech. Better evaluation of this valuable commodity and more effective use of hirudotherapy in modern medical practice as supportive treatment is very important. PMID- 22198929 TI - Two mechanisms of human contingency learning. AB - How do humans learn contingencies between events? Both pathway-strengthening and inference-based process models have been proposed to explain contingency learning. We propose that each of these processes is used in different conditions. Participants viewed displays that contained single or paired objects and learned which displays were usually followed by the appearance of a dot. Some participants predicted whether the dot would appear before seeing the outcome, whereas other participants were required to respond quickly if the dot appeared shortly after the display. In the prediction task, instructions guiding participants to infer which objects caused the dot to appear were necessary in order for contingencies associated with one object to influence participants' predictions about the object with which it had been paired. In the response task, contingencies associated with one object affected responses to its pair mate irrespective of whether or not participants were given causal instructions. Our results challenge single-mechanism accounts of contingency learning and suggest that the mechanisms underlying performance in the two tasks are distinct. PMID- 22198930 TI - [High-quality hospital discharge summaries - general practitioners expectations]. AB - Hospital discharge summaries ensure treatment continuity after hospital discharge. In Switzerland discharge letters are a celebrated custom and a tool for training young colleagues. The primary purpose is to guarantee high-quality care of patients treated by hospital staff and general practitioners. From the perspective of the patient's general practitioner discharge summaries should convey current and accurate medically important patient data to the physician responsible for follow-up care. In the era of highly developed electronic data transfer and introduction of diagnose related groups (DRGs), it will be necessary to transmit hospital discharge information selectively to different target groups. Nevertheless data protection and medical secret must be complied with. PMID- 22198931 TI - [Fast Track Surgery - conditions and challenges in post-surgical treatment]. AB - In the last 15 years the Fast Track Concept or Enhanced Recovery after Surgery (ERAS) as a clinical pathway for improving perioperative care, maintaining physiological functions, reducing intraoperative stress and shortening the length of hospital stay, has become more common in colorectal surgery. After first promising results in prospective studies an expert group developed recommendations of a modified, multimodal Fast Track Concept in 2009. Main elements in this concept are laparoscopy, no nasogastric tubes, perioperative peridural anaesthesia and quick mobilisation of the patient after surgery. A metaanalysis in 2011 based on the Cochrane database showed, that in most studies regarding Fast Track Surgery, the authors have not strictly followed the recommendations of the expert group. Further studies with better quality and strict adaption on the multimodal principles of Fast Track Surgery are needed to gain more evidence. Furthermore the Fast Track Concept constitutes a challenge for the interdisciplinary collaboration of all involved treatment groups. Especially the postoperative outpatient treatment remains a problem due to unavailable rehabilitation capacities or ambulant care. Therefore a proper preoperative planning of the Fast Track Concept and the outpatient care should be performed interdisciplinary by the surgeons and the general practitioners. PMID- 22198932 TI - [Length of hospital stay due to DRG reimbursement]. AB - The introduction of DRG systems causes a paradigm shift in consideration of length of hospital stay. A daily rate for a hospital bed is an inventive to lengthen hospital stay as long as possible. In a DRG system it would be lucrative to release a patient from hospital as soon as possible and tenable. If DRGs are calculated properly, based on a valid statistical analysis of average length of stay, hospital reimbursement will be ensured in the average of one year. Not cost effective cases will be compensated with profitable patients. There is no economic need to release or transfer patients from hospital earlier than necessary or tenable. To have sufficient control over the economic situation in each individual patient it is necessary and recommended to build up a cost unit accounting. PMID- 22198933 TI - [Simple and complicated surgical wounds]. AB - Aiming at primary wound healing, the majority of surgical interventions end with a wound closure. The wound edges are brought together and secured using sutures, staples or glue, respectively. A common surgical wound therefore tends to undergo an orderly and timely repair process with the result of sustained restored anatomic and functional integrity. In case of surgical wound infection, dehiscence, seroma or hematoma tissue repair is impaired and the healing process becomes delayed. Here, a simple wound becomes more complex or even chronic. Delayed wound healing continues to be a problem with associated significant morbidity and impaired quality of life that take up substantial health care resources. In situations of complicated or chronic wound setting the aim of wound healing will be by secondary intention referring to an open wound. Wound dressings, usually applied after wound closure, provide physical support and protection from bacterial contamination. In open wound, dressings not only have the protective intention but also clean the wound and induce the healing process. Further measurements of wound dressings in complicated wounds are pain relief, ease of use and removal on an outpatient basis, cost-effectiveness and patient satisfaction. Advances in the basic science of wound healing and its clinical application have led to numerous new therapies, products, and modalities that are constantly changing the approach to wound management. In the last two decades, negative-pressure wound therapy has been one of the major innovations in wound care. In addition to acting as an occlusive dressing, it may increase blood flow to the wound site, decrease edema, decrease bacterial contamination, and promote wound contraction. Further strategies to enhance wound healing or scar formation still under investigation include growth factors or regenerative cell therapy. PMID- 22198934 TI - [Current recommendations for aftercare in patients following hernia repair]. AB - Abdominal wall hernias, in particular inguinal hernias are the most frequently encountered entity in general surgery. Consequently, the socio-economic burden results from the in-hospital phase itself and to a considerable extent from the convalescence period. In addition to the surgical procedure and the occupation of the patient there are two factors of particular significance influencing the aftercare: the post-operative pain and the given recommendations for postoperative strain. Next to patient-factor adapted operative procedures it is therefore essential, to offer a standardized pain management and recommendations for postoperative strain. Currently there is no conclusion, whether the minimally invasive techniques will be established as the "Gold-standard", particularly from an economic point of view and the introduction of the DRG in Switzerland. PMID- 22198935 TI - [Management of the post-bariatric surgery patient]. AB - Worldwide the obesity epidemic is becoming one of the leading causes of mortality and morbidity. The rates of bariatric surgery procedures are sharply increasing. Today it is the only treatment option for a substantial and durable long-term weight loss. However, bariatric surgery is not a guarantee of successful weight loss and maintenance. For all patients undergoing bariatric surgery, education and clinical management to prevent and detect nutritional deficiencies are recommended. Particularly for patients undergoing malabsorptive procedures, the management of potential nutritional deficiencies is important. Strategies should be employed to compensate for food intolerance aiming at risk reduction for nutritional deficiencies. All patients should receive care from a multidisciplinary team and be considered for comprehensive perioperative program for nutrition and lifestyle management. PMID- 22198936 TI - [Functional syndromes after surgery of the upper gastrointestinal tract]. AB - Functional and metabolic syndromes after surgery of the upper gastrointestinal tract (including the pancreas) are frequent. Resections of organs mandate the reconstruction with a change of anatomy. Predominantly, the reconstruction using a Y-en-Roux jejunal loop is used. The surgical alteration of the anatomy may lead to a different physiology. Patients after esophagectomy or gastrectomy may suffer from dysphagia, dumping syndromes, reflux and anaemia. Pancreatic resections or drainage operations may cause an exocrine or endocrine insufficiency. Patients after surgery for gastroesophageal reflux or achalasia may have gas-related symptoms such as bloating and flatulence. The treatment options of these syndromes include physical measures, drugs, interventional procedures and even revisional surgery. Detailed preoperative information of the procedure and multidisciplinary postoperative treatment (general practitioner, surgeon, gastroenterologist etc.) of evolving functional syndromes is mandatory to achieve a high standard of care. PMID- 22198937 TI - [Surveillance after curative surgery for colorectal and breast cancer]. AB - Surveillance programs have been recommended for colorectal and breast cancer patients in several countries, and appropriate surveillance guidelines have been issued by various societies. The Swiss Society of Gastroenterology consensus paper recommends a surveillance program for patients after curative resection of colorectal cancer (CRC), and the respective guidelines are updated regularly. Early detection of recurrent disease from CRC allows treatment with intention to cure. Five year survival rates after treatment for recurrent CRC can reach up to 50 % or more. Therefore tumor surveillance in CRC is important, and there is compelling evidence that patients benefit from intensive surveillance. In addition to clinical controls, measurements of carcinoembryonal antigen, colonoscopies and thoraco-abdominal CT scans should be performed on a regular basis. For surveillance of breast cancer (BC) patients, a regular schedule is recommended as well. However, this surveillance program is more focussing on the detection of possible loco-regional tumor relapse, as curative therapy of BC metastases is much less frequently possible than in CRC patients. Irrespective of the underlying tumor entity, surveillance is an important and challenging process that should be coordinated by one single physician. It is crucial that all involved physicians are aware of their responsibility and that they are informed about the respective surveillance program and its benefit to the patient. PMID- 22198938 TI - [Postoperative care following vascular surgery - control of risk factors and guide-lines for physicians in charge of vascular patients]. AB - Patients after major vascular surgery operations present with different problems. Therefore dedicated physicians and good communication between surgeon and physician are required. One of the main goals should be control of cardiovascular risk factors. The following article presents an overview of common vascular operations and proposes guide-lines for postoperative care. PMID- 22198939 TI - [Postoperative course following open reduction and internal fixation of fractures]. AB - The postoperative management after open reduction and internal fixation (ORIF) of fractures is addressed with this article. The topics selected focus on topics that are of relevance for the family practitioner. Because of large differences in the treatment of adult - and geriatric fracture patients these two groups are separately looked at in Part 1 and Part 2 of the article. Fractures in children or fractures of the growing skeleton are not addressed. In the early postoperative phase, the fracture patient might seek for advice in case of complications, such as wound infection or complex regional pain syndrome (CRPS). After fracture healing, the decision on implant removal has to be made. Geriatric fracture patients mostly cannot return back home directly from the hospital. Instead they are transferred to a rehabilitation center. In these patients secondary fracture prevention should be in the focus of the family practitioner. This means osteoporosis diagnostics and treatment shall be initiated, if not done before. Another important task is to guarantee for compliance with the therapy once it is initiated. PMID- 22198941 TI - Granulomatous interstitial nephritis causing acute renal failure: a rare presenting feature of sarcoidosis. PMID- 22198942 TI - Eosinophilic meningoencephalitis caused by Angiostrongylus cantonesis. PMID- 22198943 TI - Recent advances in management of gout. AB - Incidence and prevalence of gout have markedly increased over the last few decades in keeping with the rise in prevalence of obesity and metabolic syndrome. Until recently, management of gout in patients with associated metabolic syndrome and comorbid illnesses such as renal impairment was difficult because of limited treatment options. However, significant progress has been made in the last few years, with introduction of new treatments such as interleukin-1 antagonists for management of acute gout, and febuxostat and pegloticase for chronic gout. The association of gout with alcohol, dietary purines and fructose ingestion has been confirmed in large prospective studies, thus enabling the clinician to now provide evidence-based advice to patients. Recent efficacy and safety data favour lower over higher doses of colchicine, and oral corticosteroids over non steroidal anti-inflammatory drugs for patients with acute gout. Local ice therapy might help to differentiate gout from other forms of inflammatory arthritis, and supplementation with vitamin C help to reduce risk of gout. Several other drugs with rational mechanisms of action are in the pipeline, and likely to be introduced over the next few years. A new era has thus begun in the field of gout. PMID- 22198944 TI - Contraceptive ring-induced intestinal obstruction. PMID- 22198945 TI - The complete control of murine pregnancy from embryo implantation to parturition. AB - The ovary is the main secretory source of progestin and estrogen and is indispensable to the maintenance of all events of pregnancy in mice. The purpose of this study was to control all processes of pregnancy in mice, from embryo implantation to parturition, without ovaries. The ovaries were removed before embryo implantation, and a single injection of medroxyprogesterone acetate (MPA) was given. Embryo implantation was induced by leukemia inhibitory factor, which can substitute 17beta-estradiol (E(2)). Continuous exposure to E(2) was necessary at mid-pregnancy, when placentation was completed. All mice sustained pregnancy without ovaries before parturition, which was initiated by the removal of E(2) and MPA. Murine pregnancy is a complicated process involving embryo implantation, placentation, and parturition. Complete control of pregnancy was achieved with the simple treatment of MPA and E(2) after induction of embryo implantation. Here, time-dependent events in the uterus during pregnancy could be realized without the ovaries, because the initiation of each event could be stringently controlled by hormonal treatments. PMID- 22198946 TI - Statistical issues in drug development. PMID- 22198947 TI - Intestinal epithelial cell-derived semaphorin 7A negatively regulates development of colitis via alphavbeta1 integrin. AB - The intestinal immune system is constantly challenged by commensal bacteria; therefore, it must maintain quiescence via several regulatory mechanisms. Although intestinal macrophages (Ms) have been implicated in repression of excessive inflammation, it remains unclear how their functions are regulated during inflammation. In this study, we report that semaphorin 7A (Sema7A), a GPI anchored semaphorin expressed in intestinal epithelial cells (IECs), induces IL 10 production by intestinal Mphis to regulate intestinal inflammation. Sema7A deficient mice showed severe signs of dextran sodium sulfate-induced colitis due to reduced intestinal IL-10 levels. We further identified CX3CR1(+)MHC class II(int)F4/80(hi)CD11b(hi) Mphis as the main producers of IL-10 via alphavbeta1 integrin in response to Sema7A. Notably, Sema7A was predominantly expressed on the basolateral side of IECs, and its expression pattern was responsible for protective effects against dextran sodium sulfate-induced colitis and IL-10 production by Mphis during interactions between IECs and Mphis. Furthermore, we determined that the administration of recombinant Sema7A proteins ameliorated the severity of colitis, and these effects were diminished by IL-10-blocking Abs. Therefore, our findings not only indicate that Sema7A plays crucial roles in suppressing intestinal inflammation through alphavbeta1 integrin, but also provide a novel mode of IL-10 induction via interactions between IECs and Mphis. PMID- 22198948 TI - IL-33-responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. AB - Innate immunity provides the first line of response to invading pathogens and a variety of environmental insults. Recent studies identified novel subsets of innate lymphoid cells that are capable of mediating immune responses in mucosal organs. In this paper, we describe a subset of lymphoid cells that is involved in innate type 2 immunity in the lungs. Airway exposure of naive BALB/c or C57BL/6J mice to IL-33 results in a rapid (<12 h) production of IL-5 and IL-13 and marked airway eosinophilia independently of adaptive immunity. In the lungs of nonsensitized naive mice, IL-33-responsive cells were identified that have a lymphoid morphology, lack lineage markers, highly express CD25, CD44, Thy1.2, ICOS, Sca-1, and IL-7Ralpha (i.e., Lin(-)CD25(+)CD44(hi) lymphoid cells), and require IL-7Ralpha for their development. Airway exposure of naive mice to a clinically relevant ubiquitous fungal allergen, Alternaria alternata, increases bronchoalveolar lavage levels of IL-33, followed by IL-5 and IL-13 production and airway eosinophilia without T or B cells. This innate type 2 response to the allergen is nearly abolished in mice deficient in IL-33R (i.e., ST2), and the Lin(-)CD25(+)CD44(hi) lymphoid cells in the lungs are required and sufficient to mediate the response. Thus, a subset of innate immune cells that responds to IL 33 and vigorously produces Th2-type cytokines is present in mouse lungs. These cells may provide a novel mechanism for type 2 immunity in the airways and induction of allergic airway diseases such as asthma. PMID- 22198949 TI - TLR2 is a primary receptor for Alzheimer's amyloid beta peptide to trigger neuroinflammatory activation. AB - Microglia activated by extracellularly deposited amyloid beta peptide (Abeta) act as a two-edged sword in Alzheimer's disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering anti inflammatory/neurotrophic M2 activation and by clearing Abeta via phagocytosis. TLRs are associated with Abeta-induced microglial inflammatory activation and Abeta internalization, but the mechanisms remain unclear. In this study, we used real-time surface plasmon resonance spectroscopy and conventional biochemical pull-down assays to demonstrate a direct interaction between TLR2 and the aggregated 42-aa form of human Abeta (Abeta42). TLR2 deficiency reduced Abeta42 triggered inflammatory activation but enhanced Abeta phagocytosis in cultured microglia and macrophages. By expressing TLR2 in HEK293 cells that do not endogenously express TLR2, we observed that TLR2 expression enabled HEK293 cells to respond to Abeta42. Through site-directed mutagenesis of tlr2 gene, we identified the amino acids EKKA (741-744) as a critical cytoplasmic domain for transduction of inflammatory signals. By coexpressing TLR1 or TLR6 in TLR2 transgenic HEK293 cells or silencing tlrs genes in RAW264.7 macrophages, we observed that TLR2-mediated Abeta42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6. Using bone marrow chimeric Alzheimer's amyloid precursor transgenic mice, we observed that TLR2 deficiency in microglia shifts M1- to M2-inflammatory activation in vivo, which was associated with improved neuronal function. Our study demonstrated that TLR2 is a primary receptor for Abeta to trigger neuroinflammatory activation and suggested that inhibition of TLR2 in microglia could be beneficial in Alzheimer's disease pathogenesis. PMID- 22198950 TI - Pathogenic natural antibodies propagate cerebral injury following ischemic stroke in mice. AB - Self-reactive natural Abs initiate injury following ischemia and reperfusion of certain tissues, but their role in ischemic stroke is unknown. We investigated neoepitope expression in the postischemic brain and the role of natural Abs in recognizing these epitopes and mediating complement-dependent injury. A novel IgM mAb recognizing a subset of phospholipids (C2) and a previously characterized anti-annexin IV mAb (B4) were used to reconstitute and characterize injury in Ab deficient Rag1(-/-) mice after 60 min of middle cerebral artery occlusion and reperfusion. Reconstitution with C2 or B4 mAb in otherwise protected Rag1(-/-) mice restored injury to that seen in wild-type (wt) mice, as demonstrated by infarct volume, demyelination, and neurologic scoring. IgM deposition was demonstrated in both wt mice and reconstituted Rag1(-/-) mice, and IgM colocalized with the complement activation fragment C3d following B4 mAb reconstitution. Further, recombinant annexin IV significantly reduced infarct volumes in wt mice and in Rag1(-/-) mice administered normal mouse serum, demonstrating that a single Ab reactivity is sufficient to develop cerebral ischemia reperfusion injury in the context of an entire natural Ab repertoire. Finally, C2 and B4 mAbs bound to hypoxic, but not normoxic, human endothelial cells in vitro. Thus, the binding of pathogenic natural IgM to postischemic neoepitopes initiates complement-dependent injury following murine cerebral ischemia and reperfusion, and, based also on previous data investigating IgM reactivity in human serum, there appears to be a similar recognition system in both mouse and man. PMID- 22198951 TI - Phenotypic variation in IgG receptors by nonclassical FCGR2C alleles. AB - The balance between activating and inhibitory signals from the different FcgammaRs for IgG ensures homeostasis of many inflammatory responses. FCGR2C is the product of an unequal crossover of the FCGR2A and FCGR2B genes encoding the activating FcgammaRIIa (CD32a) and inhibitory FcgammaRIIb (CD32b), respectively. A single nucleotide polymorphism (SNP) in exon 3 of FCGR2C results in either expression of the activating FcgammaRIIc (CD32c) (FCGR2C-open reading frame [ORF]) or its absence because of a stop codon (FCGR2C-Stop). Two additional variations in FcgammaRIIb/c expression on leukocytes have now been identified. In case of "nonclassical" FCGR2C-ORF alleles, FcgammaRIIc expression was unexpectedly absent, because of novel splice site mutations near exon 7 leading to another stop codon. In some individuals with FCGR2C-Stop alleles FcgammaRIIb was detected on NK cells, which normally are devoid of this protein. Individuals with these nonclassical FCGR2C-Stop alleles carried a deletion of FCGR2C-FCGR3B that extends into the promoter region of the adjacent FCGR2B gene and probably deletes a negative regulatory element in the FCGR2B promoter in NK cells. FcgammaRIIb expression on NK cells effectively inhibited killing mediated by FcgammaRIIIa (CD16a) in Ab-dependent cytotoxicity tests. Our findings demonstrate a more extensive and previously unnoticed variation in FcgammaR expression with relevance to immunity and inflammation. PMID- 22198953 TI - Expression of Helios in peripherally induced Foxp3+ regulatory T cells. AB - The transcription factor Helios has been reported to be a marker of regulatory T cells (Treg) of thymic origin, distinguishing them from Treg induced in the periphery (iTreg). In this study, we demonstrate Helios expression in Foxp3(+) iTreg, both in vitro and in vivo. Following i.v. peptide injection, in vivo Helios expression in adoptively transferred TCR transgenic T cells was more rapid than Foxp3 induction but less stable at later time points without a second injection of peptide. Our in vitro data suggest that APC influence Helios expression in a manner distinct from stimuli required for Foxp3 induction. Thus, Helios expression in iTreg may reflect the context of stimulation during Foxp3 induction. In summary, the robust Helios expression we observe in iTreg precludes its use as a marker of thymic Treg. PMID- 22198954 TI - Organ-specific cellular requirements for in vivo dendritic cell generation. AB - Bone marrow-derived dendritic cell (DC) precursors seed peripheral organs, where they encounter diverse cellular environments during their final differentiation into DCs. Flt3 ligand (Flt3-L) is critical for instructing DC generation throughout different organs. However, it remains unknown which cells produce Flt3 L and, importantly, which cellular source drives DC development in such a variety of organs. Using a novel BAC transgenic Flt3-L reporter mouse strain coexpressing enhanced GFP and luciferase, we show ubiquitous Flt3-L expression in organs and cell types. These results were further confirmed at the protein level. Although Flt3-L was produced by immune and nonimmune cells, the source required for development of the DC compartment clearly differed among organs. In lymphoid organs such as the spleen and bone marrow, Flt3-L production by hemopoietic cells was critical for generation of normal DC numbers. This was unexpected for the spleen because both immune and nonimmune cells equally contributed to the Flt3-L content in that organ. Thus, localized production rather than the total tissue content of Flt3-L in spleen dictated normal splenic DC development. No differences were observed in the number of DC precursors, suggesting that the immune source of Flt3-L promoted pre-cDC differentiation in spleen. In contrast, DC generation in the lung, kidney, and pancreas was mostly driven by nonhematopoietic cells producing Flt3-L, with little contribution by immune cells. These findings demonstrate a high degree of flexibility in Flt3-L dependent DC generation to adapt this process to organ-specific cellular environments encountered by DC precursors during their final differentiation. PMID- 22198952 TI - Regulatory B10 cells differentiate into antibody-secreting cells after transient IL-10 production in vivo. AB - Regulatory B cells that are functionally defined by their capacity to express IL 10 (B10 cells) downregulate inflammation and autoimmunity. In studies using well defined IL-10 reporter mice, this rare B10 cell subset was also found to maintain a capacity for plasma cell differentiation. During a transient period of il10 transcription, the blimp1 and irf4 transcription factors were induced in B10 cells, whereas pax5 and bcl6 were downregulated as a significant fraction of B10 cells completed the genetic and phenotypic program leading to Ab-secreting cell differentiation in vitro and in vivo. B10 cell-derived IgM reacted with both self and foreign Ags, whereas B10 cells generated Ag-specific IgG in response to immunizations. Moreover, B10 cells represented a significant source of serum IgM and IgG during adoptive-transfer experiments and produced Ag-specific, polyreactive and autoreactive Ab specificities that were consistent with their expression of a diverse AgR repertoire. Thereby, B10 cells limit inflammation and immune responses by the transient production of IL-10, and may facilitate clearance of their eliciting Ags through an inherent capacity to quickly generate polyreactive and/or Ag-specific Abs during humoral immune responses. PMID- 22198956 TI - Implementation of an education and skills programme in a teledermatology project for rural veterans. AB - In July 2009 we implemented a store-and-forward teledermatology project to provide dermatology care to veterans living in underserved rural areas of the Pacific Northwest region of the US. We also developed an educational programme for rural primary care providers and imaging technicians. Participants were tested and their competencies were assessed at baseline and during a two-year project. Participation in a comprehensive education programme improved the knowledge of dermatology diagnosis and treatment care plans. All of the providers were performing dermatology procedures (e.g. biopsies, excisions, cauteries) after two years and more patients were being seen at their rural clinics than when the teledermatology project began (85% vs 39%). After two years, 71% of the providers and 56% of the imaging technicians had completed surgical training sessions and all passed their competency assessments. The educational component of the teledermatology project created teams of primary care health-care providers and imaging technicians with improved dermatology educational levels and new dermatology skills. PMID- 22198955 TI - Importance of antibody in virus infection and vaccine-mediated protection by a latency-deficient recombinant murine gamma-herpesvirus-68. AB - The human gamma-herpesviruses EBV and Kaposi's sarcoma-associated herpesvirus establish lifelong latent infections, can reactivate in immunocompromised individuals, and are associated with the development of malignancies. Murine gamma-herpesvirus-68 (gammaHV68), a rodent pathogen related to EBV and Kaposi's sarcoma-associated herpesvirus, provides an important model to dissect mechanisms of immune control and investigate vaccine strategies. Infection of mice with gammaHV68 elicits robust antiviral immunity, and long-term protection from gammaHV68 reactivation requires both cellular and humoral immune responses. Vaccination of mice with AC-replication and transcription activator (RTA), a highly lytic latency-null recombinant gammaHV68, results in complete protection from wild-type gammaHV68 infection that lasts for at least 10 mo. In this report, we examine the immune correlates of AC-RTA-mediated protection and show that sterilizing immunity requires both T cells and Ab. Importantly, Ab was also critical for mitigating viral infection in the brain, and in the absence of Ab mediated control, amplification of the AC-RTA virus in the brain resulted in fatality. Our results highlight important considerations in the development of vaccination strategies based on live-attenuated viruses. PMID- 22198957 TI - Who shall coordinate the coordinators? Facilitating the work of telemedicine networks which provide humanitarian services. AB - Telemedicine networks for humanitarian purposes have evolved over the last decade or so in a largely autonomous way. Communication between them has been informal and relatively limited in scope. This situation could be improved by developing a comprehensive approach to the collection and dissemination of information. We propose the formation of a central 'clearing house' which would allow networks to exchange information and cases where appropriate. In order for a network to belong to the clearing house, it would need to conform to certain guidelines, which would ensure that safe and satisfactory standards would be maintained. We propose that a coordinators' conference should be held to discuss who would operate the clearing house and how it would be resourced. The creation of a central clearing house would facilitate the operation of the networks, particularly during periods of heavy workload, and lead to improved sustainability, thereby benefiting individual patients. We believe that more can be achieved by the networks acting together than by them acting independently. PMID- 22198958 TI - Guidelines for designing wireless communications for rural telemedicine in developing countries. PMID- 22198959 TI - Organizational factors associated with the use of telehospice. AB - We investigated organizational factors associated with the use of telehospice (defined as the use of video technology by hospices). The investigation was based on the 2007 National Home and Hospice Care Survey. There were 695 hospice agencies, of which 6% used telehospice. Logistic regression was used to examine the relation between use of hospice and a number of organizational factors. The dependent variable was the use/non-use of video technology in patient monitoring or consultations with professionals. Most of the variables that were significantly associated with the use of telehospice were related to characteristics of the agency director. If the director had at least a Masters degree or had a longer tenure as director of the agency, there was a higher likelihood that the agency used telehospice. If the director was a nurse, the likelihood that telehospice was used was considerably lower. Organizations with inter-agency contracts were less likely to use telehospice. Providing financial, training and organizational support to agencies that recognize the potential benefits of telehospice would probably assist in its future introduction. PMID- 22198960 TI - A comparison of tele-education versus conventional lectures in wound care knowledge and skill acquisition. AB - We conducted a randomized controlled study to compare conventional lectures with tele-education for delivering wound care education. Education was delivered by the two methods simultaneously to two classes. Forty-eight paramedics received a live didactic presentation and 41 paramedics received the same lecture via videoconferencing. The participants were evaluated by a multiple-choice examination and a practical test of their wound closure skills. There were no significant differences in any category of the practical skills test, and no difference in the results of the written examination: the mean total score was was 109.0 (95% CI 105.7-112.4) in the conventional lecture group and 110.3 (95% CI 106.2-114.3) in the video group (P = 0.63). In a survey at the end of the study the live lecture group rated the overall effectiveness of teaching significantly higher than the video-based group: the median scores for effectiveness of teaching were 6.0 (IQR 5.5-6.0) in the live lecture group and 4.0 (IQR 3.0-5.0) in the video group (P < 0.001). Videoconferencing was at least as effective as live didactic presentation. PMID- 22198961 TI - Telehealth in cystic fibrosis: a systematic review. AB - We conducted a systematic review of the use of telehealth in people with Cystic Fibrosis (CF). The studies reviewed were of adults and children with CF, and incorporated telehealth for monitoring symptoms, assessing adherence to prescribed therapies or providing a therapeutic intervention. Searches of four electronic databases returned 293 references. Eight studies met the inclusion criteria. Variability in study design and outcome measures precluded meta analysis. Seven studies assessed telemonitoring feasibility for patient usability and acceptance, or for physiological monitoring. Two studies were randomised controlled trials, although only one showed differences in outcome between the intervention and usual care with improved spirometry stability and significantly increased antibiotic use in the intervention group. In four studies participants were asked to transmit data on spirometry (FEV(1)) or symptoms. Participant non compliance with data reporting ranged from 43-63%. Generally, participants reported being able to use the required technology. There is insufficient evidence to reach a firm conclusion about the benefits of telehealth in people with CF, but it remains a promising area for future investigation. PMID- 22198962 TI - Mouse model of necrotic tuberculosis granulomas develops hypoxic lesions. AB - BACKGROUND: Preclinical evaluation of tuberculosis drugs is generally limited to mice. However, necrosis and hypoxia, key features of human tuberculosis lesions, are lacking in conventional mouse strains. METHODS: We used C3HeB/FeJ mice, which develop necrotic lesions in response to Mycobacterium tuberculosis infection. Positron emission tomography in live infected animals, postmortem pimonidazole immunohistochemistry, and bacterial gene expression analyses were used to assess whether tuberculosis lesions in C3HeB/FeJ are hypoxic. Efficacy of combination drug treatment, including PA-824, active against M. tuberculosis under hypoxic conditions, was also evaluated. RESULTS: Tuberculosis lesions in C3HeB/FeJ (but not BALB/c) were found to be hypoxic and associated with up-regulation of known hypoxia-associated bacterial genes (P < .001). Contrary to sustained activity reported elsewhere in BALB/c mice, moxifloxacin and pyrazinamide (MZ) combination was not bactericidal beyond 3 weeks in C3HeB/FeJ. Although PA-824 added significant activity, the novel combination of PA-824 and MZ was less effective than the standard first-line regimen in C3HeB/FeJ. CONCLUSIONS: We demonstrate that tuberculosis lesions in C3HeB/FeJ are hypoxic. Activities of some key tuberculosis drug regimens in development are represented differently in C3HeB/FeJ versus BALB/c mice. Because C3HeB/FeJ display key features of human tuberculosis, this strain warrants evaluation as a more pathologically relevant model for preclinical studies. PMID- 22198963 TI - Validation of self-swab for virologic confirmation of influenza virus infections in a community setting. AB - Few studies have investigated the validity of self-collected nose and throat swabs for influenza confirmation in community settings. We followed outpatients with confirmed influenza with sequential measurement of viral loads and applied log-linear regression models to the viral shedding patterns. Among 176 outpatients with confirmed influenza, the detection of virus and quantitative viral loads obtained from self-swabs was consistent with statistical predictions based on earlier and later measurements, suggesting that self-collected nose and throat swabs can be a valid alternative for virologic confirmation of influenza A or B infection in a community setting. PMID- 22198965 TI - Health perceptions in Latin America. AB - The influence of cultural patterns and economic conditions on health perceptions in Latin America is studied using the results of the 2007 Gallup World Poll. The differences in health satisfaction between countries around the world have a robust association with variables that may reflect cultural differences rather than with aggregate economic variables or traditional health indicators. Simple health self-rating indicators reveal huge cultural differences in health perceptions in Latin America. However, within each country, differences correlate strongly with individuals' economic and health conditions. Lower-income groups recognize more health problems, but are less tolerant of some of them than the rich. PMID- 22198964 TI - Reoxygenation of glioblastoma multiforme treated with fractionated radiotherapy concomitant with temozolomide: changes defined by 18F-fluoromisonidazole positron emission tomography: two case reports. AB - Two glioblastoma multiforme patients underwent (18)F-FMISO (fluoromisonidazole) positron emission tomography study to access the tumor oxygenation status before and immediately after fractionated radiotherapy concomitant with temozolomide chemotherapy. In both cases, a prominent (18)F-FMISO tumor accumulation observed in the first study was notably decreased in the second study, which was supposed to be a reoxygenation of the tumor. As far as we investigated, this is the first report of the changes of oxygenation status in glioblastoma multiforme treated through radiation therapy with temozolomide. PMID- 22198966 TI - Managing scientific uncertainty in medical decision making: the case of the advisory committee on immunization practices. AB - This article explores the question of how scientific uncertainty can be managed in medical decision making using the Advisory Committee on Immunization Practices as a case study. It concludes that where a high degree of technical consensus exists about the evidence and data, decision makers act according to a clear decision rule. If a high degree of technical consensus does not exist and uncertainty abounds, the decision will be based on a variety of criteria, including readily available resources, decision-process constraints, and the available knowledge base, among other things. Decision makers employ a variety of heuristic devices and techniques, thereby employing a pragmatic approach to uncertainty in medical decision making. The article concludes with recommendations for managing scientific uncertainty in medical decision making. PMID- 22198967 TI - Neural correlates of wishful thinking. AB - Wishful thinking (WT) implies the overestimation of the likelihood of desirable events. It occurs for outcomes of personal interest, but also for events of interest to others we like. We investigated whether WT is grounded on low-level selective attention or on higher level cognitive processes including differential weighting of evidence or response formation. Participants in our MRI study predicted the likelihood that their favorite or least favorite team would win a football game. Consistent with expectations, favorite team trials were characterized by higher winning odds. Our data demonstrated activity in a cluster comprising parts of the left inferior occipital and fusiform gyri to distinguish between favorite and least favorite team trials. More importantly, functional connectivities of this cluster with the human reward system were specifically involved in the type of WT investigated in our study, thus supporting the idea of an attention bias generating WT. Prefrontal cortex activity also distinguished between the two teams. However, activity in this region and its functional connectivities with the human reward system were altogether unrelated to the degree of WT reflected in the participants' behavior and may rather be related to social identification, ensuring the affective context necessary for WT to arise. PMID- 22198968 TI - Great expectations: neural computations underlying the use of social norms in decision-making. AB - Social expectations play a critical role in everyday decision-making. However, their precise neuro-computational role in the decision process remains unknown. Here we adopt a decision neuroscience framework by combining methods and theories from psychology, economics and neuroscience to outline a novel, expectation based, computational model of social preferences. Results demonstrate that this model outperforms the standard inequity-aversion model in explaining decision behavior in a social interactive bargaining task. This is supported by fMRI findings showing that the tracking of social expectation violations is processed by anterior cingulate cortex, extending previous computational conceptualizations of this region to the social domain. This study demonstrates the usefulness of this interdisciplinary approach in better characterizing the psychological processes that underlie social interactive decision-making. PMID- 22198969 TI - What lies beneath the face of aggression? AB - Recent evidence indicates that a sexually dimorphic feature of humans, the facial width-to-height ratio (FWHR), is positively correlated with reactive aggression, particularly in men. Also, predictions about the aggressive tendencies of others faithfully map onto FWHR in the absence of explicit awareness of this metric. Here, we provide the first evidence that amygdala reactivity to social signals of interpersonal challenge may underlie the link between aggression and the FWHR. Specifically, amygdala reactivity to angry faces was positively correlated with aggression, but only among men with relatively large FWHRs. The patterns of association were specific to angry facial expressions and unique to men. These links may reflect the common influence of pubertal testosterone on craniofacial growth and development of neural circuitry underlying aggression. Amygdala reactivity may also represent a plausible pathway through which FWHR may have evolved to represent an honest indicator of conspecific threat, namely by reflecting the responsiveness of neural circuitry mediating aggressive behavior. PMID- 22198970 TI - Social anxiety modulates amygdala activation during social conditioning. AB - Aversive social learning experiences might play a significant role in the aetiology of social anxiety disorder. Therefore, we investigated emotional learning and unlearning processes in healthy humans using a social conditioning paradigm. Forty-nine healthy subjects participated in a 2-day fMRI differential conditioning protocol. Acquisition and extinction were conducted on Day 1 and extinction recall on Day 2. BOLD responses, ratings and skin conductance responses were collected. Our data indicate successful conditioning and extinction on the neural and subjective level. As a main result, we observed a positive correlation of social anxiety and conditioning responses on the subjective level (valence and fear) as well as on the neural level with significant CS(+)/CS(-) differentiation in the left amygdala and the left hippocampus. Further, significant CS(+)/CS(-) differentiation in the left amygdala was found during extinction and was associated with lower scores in social anxiety. During extinction recall, we found a tendentially negative correlation of social anxiety and CS(+)/CS(-) differentiation in the vmPFC. In sum, we were able to show that social anxiety is related to conditionability with socially threatening stimuli. This could point to an important aspect in the aetiology of social anxiety disorder. PMID- 22198971 TI - Religion priming differentially increases prosocial behavior among variants of the dopamine D4 receptor (DRD4) gene. AB - Building on gene-environment interaction (G * E) research, this study examines how the dopamine D4 receptor (DRD4) gene interacts with a situational prime of religion to influence prosocial behavior. Some DRD4 variants tend to be more susceptible to environmental influences, whereas other variants are less susceptible. Thus, certain life environments may be associated with acts of prosociality for some DRD4 variants but not others. Given that religion can act as an environmental influence that increases prosocial behavior, environmental input in the form of religion priming may have G * E effects. Results showed that participants with DRD4 susceptibility variants were more prosocial when implicitly primed with religion than not primed with religion, whereas participants without DRD4 susceptibility variants were not impacted by priming. This research has implications for understanding why different people may behave prosocially for different reasons and also integrates G * E research with experimental psychology. PMID- 22198972 TI - A reward prediction error for charitable donations reveals outcome orientation of donators. AB - The motives underlying prosocial behavior, like charitable donations, can be related either to actions or to outcomes. To address the neural basis of outcome orientation in charitable giving, we asked 33 subjects to make choices affecting their own payoffs and payoffs to a charity organization, while being scanned by functional magnetic resonance imaging (fMRI). We experimentally induced a reward prediction error (RPE) by subsequently discarding some of the chosen outcomes. Co localized to a nucleus accumbens BOLD signal corresponding to the RPE for the subject's own payoff, we observed an equivalent RPE signal for the charity's payoff in those subjects who were willing to donate. This unique demonstration of a neuronal RPE signal for outcomes exclusively affecting unrelated others indicates common brain processes during outcome evaluation for selfish, individual and nonselfish, social rewards and strongly suggests the effectiveness of outcome-oriented motives in charitable giving. PMID- 22198973 TI - A comparison between two strategies for monitoring hepatic function during antituberculous therapy. AB - RATIONALE: The optimum strategy for monitoring liver function during antituberculous therapy is unclear. OBJECTIVES: To assess the value of the American Thoracic Society risk-factor approach for predicting drug-induced liver injury and to compare with a uniform policy of liver function testing in all patients at 2 weeks. METHODS: We conducted an observational study of adult patients undergoing therapy for active tuberculosis at a tertiary center. All patients had alanine transferase measurement at baseline and 2 weeks following commencement of therapy. Sensitivity, specificity, and positive and negative predictive values were used to assess strategies. MEASUREMENTS AND MAIN RESULTS: There were 288 patients included, and 21 (7.3%) developed drug-induced liver injury (57.1% "early" at 2 wk and 42.9% "late," after 2 wk). There were increased rates of individuals with HIV infection in the early drug-induced liver injury group compared with no drug-induced liver injury and late drug-induced liver injury groups (33% vs. 7.1% vs. 0%; P = 0.004). The American Thoracic Society algorithm had a sensitivity and specificity of 66.7 and 65.6%, respectively, for prediction of early and 22.2% and 63.7% for late drug-induced liver injury. The uniform monitoring policy had poor sensitivity but better specificity (22.2 and 82.1%) for prediction of late drug-induced liver injury. CONCLUSIONS: In our urban, ethnically diverse population, a risk-factor approach is neither sensitive nor specific for prediction of drug-induced liver injury. A uniform policy of liver function testing at 2 weeks is useful for prompt identification of a subgroup who develop early drug-induced liver injury and may offer better specificity in ruling out late drug-induced liver injury. PMID- 22198975 TI - Inhaled glucocorticoids during pregnancy and offspring pediatric diseases: a national cohort study. AB - RATIONALE: Glucocorticoid inhalation is the preferred asthma treatment during pregnancy. Previous studies on its safety focused on obstetric outcomes and offspring malformations. OBJECTIVES: To determine whether glucocorticoid inhalation during pregnancy is a risk factor for offspring pediatric diseases. METHODS: We studied offspring (live singletons) of pregnant women suffering from asthma during pregnancy (prevalence = 6.3%; n = 4,083 mother-child pairs) from the Danish National Birth Cohort (births, 1996-2002; prospective data). We estimated the associations between use of inhaled glucocorticoids for asthma treatment during pregnancy (n = 1231; 79.9% budesonide, 17.6% fluticasone, 5.4% beclomethasone, and 0.9% other or unspecified glucocorticoids) and offspring diseases (International Classification of Diseases-10th Revision, diagnoses) during childhood. We conducted Cox or logistic regression analyses for each International Classification of Diseases-10th Revision category, controlling for use of non-glucocorticoid-containing inhalants, and confirmed results by addressing confounding by treatment indication using propensity score. MEASUREMENTS AND MAIN RESULTS: Offspring median age at end of follow-up was 6.1 (range, 3.6-8.9) years. Glucocorticoid inhalation was not associated with offspring disease risk in most categories, except for offspring endocrine, metabolic, and nutritional disorders (hazard ratio, 1.84; 95% confidence interval, 1.13-2.99). When repeating analyses with the major subgroup that used budesonide only, association estimates were of similar magnitude. CONCLUSIONS: Regarding most disease categories, data are reassuring, supporting the use of inhaled glucocorticoids during pregnancy. In line with animal data, glucocorticoid inhalation during pregnancy may be a risk factor for offspring endocrine and metabolic disturbances, which should be considered further. PMID- 22198974 TI - Long-term inhaled dry powder mannitol in cystic fibrosis: an international randomized study. AB - RATIONALE: New treatment strategies are needed to improve airway clearance and reduce the morbidity and the time burden associated with cystic fibrosis (CF). OBJECTIVES: To determine whether long-term treatment with inhaled mannitol, an osmotic agent, improves lung function and morbidity. METHODS: Double-blind, randomized, controlled trial of inhaled mannitol, 400 mg twice a day (n = 192, "treated" group) or 50 mg twice a day (n = 126, "control" group) for 26 weeks, followed by 26 weeks of open-label treatment. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was absolute change in FEV(1) from baseline in treated versus control groups, averaged over the study period. Secondary endpoints included other spirometric measurements, pulmonary exacerbations, and hospitalization. Clinical, microbiologic, and laboratory safety were assessed. The treated group had a mean improvement in FEV(1) of 105 ml (8.2% above baseline). The treated group had a relative improvement in FEV(1) of 3.75% (P = 0.029) versus the control group. Adverse events and sputum microbiology were similar in both treatment groups. Exacerbation rates were low, but there were fewer in the treated group (hazard ratio, 0.74; 95% confidence interval, 0.42-1.32; P = 0.31), although this was not statistically significant. In the 26-week open-label extension study, FEV(1) was maintained in the original treated group, and improved in the original control group to the same degree. CONCLUSIONS: Inhaled mannitol, 400 mg twice a day, resulted in improved lung function over 26 weeks, which was sustained after an additional 26 weeks of treatment. The safety profile was also acceptable, demonstrating the potential role for this chronic therapy for CF. Clinical trial registered with www.clinicaltrials.gov (NCT 00630812). PMID- 22198977 TI - Improving outcome after stroke: time to treat new targets. PMID- 22198976 TI - Surfactant protein-D regulates effector cell function and fibrotic lung remodeling in response to bleomycin injury. AB - RATIONALE: Surfactant protein (SP)-D and SP-A have been implicated in immunomodulation in the lung. It has been reported that patients with idiopathic pulmonary fibrosis (IPF) often have elevated serum levels of SP-A and SP-D, although their role in the disease is not known. OBJECTIVES: The goal of this study was to test the hypothesis that SP-D plays an important role in lung fibrosis using a mouse model of fibrosis induced by bleomycin (BLM). METHODS: Triple transgenic inducible SP-D mice (iSP-D mice), in which rat SP-D is expressed in response to doxycycline (Dox) treatment, were administered BLM (100 U/kg) or saline subcutaneously using miniosmotic pumps. MEASUREMENTS AND MAIN RESULTS: BLM-treated iSP-D mice off Dox (SP-D off) had increased lung fibrosis compared with mice on Dox (SP-D on). SP-D deficiency also increased macrophage dominant cell infiltration and the expression of profibrotic cytokines (transforming growth factor [TGF]-beta1, platelet-derived growth factor-AA). Alveolar macrophages isolated from BLM-treated iSP-D mice off Dox (SP-D off) secreted more TGF-beta1. Fibrocytes, which are bone marrow-derived mesenchymal progenitor cells, were increased to a greater extent in the lungs of the BLM treated iSP-D mice off Dox (SP-D off). Fibrocytes isolated from BLM-treated iSP-D mice off Dox (SP-D off) expressed more of the profibrotic cytokine TGF-beta1 and more CXCR4, a chemokine receptor that is important in fibrocyte migration into the lungs. Exogenous SP-D administered intratracheally attenuated BLM-induced lung fibrosis in SP-D(-/-) mice. CONCLUSIONS: These data suggest that alveolar SP D regulates numbers of macrophages and fibrocytes in the lungs, profibrotic cytokine expression, and fibrotic lung remodeling in response to BLM injury. PMID- 22198978 TI - Hospitalization costs for acute ischemic stroke patients treated with intravenous thrombolysis in the United States are substantially higher than medicare payments. AB - BACKGROUND AND PURPOSE: It is important to know the costs for hospitalization for ischemic stroke patients treated with intravenous thrombolysis so that comparisons can be made with payments to hospitals. METHODS: Using the National Inpatient Sample, we evaluated hospitalization costs for patients treated with intravenous thrombolysis for acute ischemic stroke in the United States from 2001 to 2008. Cost data were correlated with demographics and clinical outcome. RESULTS: Intravenous thrombolysis for acute ischemic stroke was received by 63 472 patients; 24 094 patients were younger than age 65 years and 40 780 patients were 65 years or older. Median hospital costs in 2008 dollars were $14 102 (interquartile range, $9987-$20 819) for patients with good outcome, $18 856 (interquartile range, $13 145-$30 423) for patients with severe disability, and $19 129 (interquartile range, $11 966-$30 781) for patients with in-hospital mortality. Average 2008 Medicare payments were $10 098 for intravenous thrombolysis without complication and $13 835 for intravenous thrombolysis with major complication. CONCLUSIONS: Hospitalization costs for patients treated with intravenous thrombolysis are substantially higher than Medicare payments. PMID- 22198979 TI - Continuous positive airway pressure ventilation for acute ischemic stroke: a randomized feasibility study. AB - BACKGROUND AND PURPOSE: Sleep-related breathing disorders occur frequently after stroke. We assessed the feasibility of continuous positive airway pressure (CPAP) treatment initiated in the first night after stroke. METHODS: In this open-label, parallel-group trial, 50 patients were randomly assigned to the CPAP therapy or to the control group. All patients underwent polysomnography in the fourth night. Intervention patients received CPAP therapy for 3 nights starting the first night after stroke onset and for an additional 4 nights when polysomnography revealed an apnea-hypopnea index >10/hour. The primary end point was feasibility defined as apnea-hypopnea index reduction under CPAP treatment, nursing workload, and CPAP adherence. RESULTS: The apnea-hypopnea index under CPAP treatment was significantly reduced (32.2+/-25.3-9.8+/-6.6, P=0.0001). Nursing workload did not significantly differ between the CPAP (n=25) and the control group (n=25; P=0.741). Ten patients (40.0%) had excellent CPAP use, 14 patients (56.0%) had some use, and 1 patient (4.0%) had no use. There was a trend toward greater National Institutes of Health Stroke Scale score improvement until Day 8 in patients on CPAP (2.00 versus 1.40, P=0.092) and a significantly greater National Institutes of Health Stroke Scale score improvement in patients with excellent CPAP use when compared with control patients (2.30 versus 1.40, P=0.022). CONCLUSIONS: CPAP therapy initiated in the first night after stroke seems to be feasible and was not associated with neurological deterioration. Clinical Trial Registration- URL: www.clinicaltrials.gov. Unique identifier: NCT00151177. PMID- 22198980 TI - Perfusion CT in patients with spontaneous lobar intracerebral hemorrhage: effect of surgery on perihemorrhagic perfusion. AB - BACKGROUND AND PURPOSE: The aim of the present study was to investigate cerebral hemodynamics in patients requiring surgical treatment for lobar intracerebral hemorrhage. METHODS: Twenty patients who underwent surgery to remove a lobar spontaneous intracerebral hemorrhage were scanned before and after surgery using perfusion CT mapping. Mean transit time, time to peak of the residue function, cerebral blood volume, and cerebral blood flow were measured in 4 defined regions of interest. RESULTS: Preoperatively, time to peak of the residue function, cerebral blood volume, and cerebral blood flow were significantly impaired in the perihemorrhagic zone as compared with the ipsilateral and contralateral hemisphere. Perihematomal perfusion improved significantly after clot evacuation and there was no difference in time to peak of the residue function, cerebral blood flow, and cerebral blood volume values between the perihemorrhagic zone and ipsilateral as well as contralateral hemisphere after surgical treatment. CONCLUSIONS: Our findings illustrate distinct perihemorrhagic perfusion impairments in a selected patient population with lobar intracerebral hemorrhage as evident by impaired time to peak of the residue function, cerebral blood flow, and cerebral blood volume and their improvement after early surgical treatment. Whether these early improvements in hemodynamic measurements may influence secondary neuronal injury and ultimately clinical outcome, as opposed to the natural course of spontaneous intracerebral hemorrhage remains unclear. PMID- 22198981 TI - Adiponectin and carotid intima-media thickness in the northern Manhattan study. AB - BACKGROUND AND PURPOSE: Adiponectin is an insulin-sensitizing plasma protein expressed in adipose tissue and suggested to play a role in atherosclerosis and cardiovascular disease. Data are lacking on the relationship between adiponectin and carotid intima-media thickness (IMT) in ethnically heterogeneous populations. We examined the relationship between adiponectin and IMT, a marker of atherosclerosis, in a multiethnic cohort study of stroke risk factors. METHODS: Participants were from the Northern Manhattan Study (N=1522, mean age 66+/-9 years, 60% female, 20% black, 18% white, 60% Hispanic). Adiponectin was measured from baseline plasma samples and IMT was assessed by high-resolution B-mode carotid ultrasound. Regression models were used to examine the association between adiponectin, assessed continuously and in quartiles, and IMT controlling for demographics and vascular risk factors. RESULTS: The mean adiponectin level was 10.3+/-5.2 MUg/mL (median, 9.2 MUg/mL; range, 2.3-53.3 MUg/mL), and the mean IMT was 0.91+/-0.08 mm. Adiponectin was inversely associated with IMT, even after controlling for demographics and vascular risk factors. Individuals in the first quartile of adiponectin had mean IMT that was on average 0.02 mm greater than those in the top quartile. The relationship between adiponectin and IMT appeared to be stronger among those with diabetes. CONCLUSIONS: Our findings suggest that low adiponectin is associated with increased IMT in a multiethnic cohort and support a protective role for adiponectin in atherosclerosis. PMID- 22198982 TI - Thinning of the arterial media layer as a possible preclinical stage in HIV vasculopathy: a pilot study. AB - BACKGROUND AND PURPOSE: The purpose of this study was to determine if postmortem intracranial arteries from donors with HIV without stroke have thinner media layers compared with patients without HIV and without stroke. METHODS: Cross sectional cuts from intracranial arteries were stained with van Gieson and hematoxylin and eosin. Arteries were examined for thickness of each arterial layer. Univariable and multivariable models were used for statistical analyses with probability values <0.05 considered significant. RESULTS: A total of 18 brains were analyzed, 5 with HIV and 13 without. Fifty-five arteries were collected, 15 from HIV brains and 40 from unaffected controls. In univariable analysis, in arteries from HIV-infected brains, the media to wall thickness ratio was smaller than in donors without HIV (0.496 versus 0.563, P=0.017). In multivariable analysis, HIV infection was the only independent predictor of smaller media ratios compared with the same-aged control subjects (P=0.049) but not with aged control subjects (P=0.081). CONCLUSIONS: In patients with HIV without clinical stroke, the media arterial layer is thinner than in patients without HIV. This suggests that a thinner media layer might be a preclinical stage in the development of HIV-related vasculopathy. PMID- 22198983 TI - Granulocyte-colony stimulating factor for mobilizing bone marrow stem cells in subacute stroke: the stem cell trial of recovery enhancement after stroke 2 randomized controlled trial. AB - BACKGROUND AND PURPOSE: Granulocyte-colony stimulating factor (G-CSF) is neuroprotective in experimental stroke and mobilizes CD34(+) peripheral blood stem cells into the circulation. We assessed the safety of G-CSF in recent stroke in a phase IIb single-center randomized, controlled trial. METHODS: G-CSF (10 MUg/kg) or placebo (ratio 2:1) was given SC for 5 days to 60 patients 3 to 30 days after ischemic or hemorrhagic stroke. The primary outcome was the frequency of serious adverse events. Peripheral blood counts, CD34(+) count, and functional outcome were measured. MRI assessed lesion volume, atrophy, and the presence of iron-labeled CD34(+) cells reinjected on day 6. RESULTS: Sixty patients were recruited at mean of 8 days (SD +/- 5) post ictus, with mean age 71 years (+/- 12 years) and 53% men. The groups were well matched for baseline minimization/prognostic factors. There were no significant differences between groups in the number of participants with serious adverse events: G-CSF 15 (37.5%) of 40 versus placebo 7 (35%) of 20, death or dependency (modified Rankin Score: G-CSF 3.3 +/- 1.3, placebo 3.0 +/- 1.3) at 90 days, or the number of injections received. G-CSF increased CD34(+) and total white cell counts of 9.5- and 4.2-fold, respectively. There was a trend toward reduction in MRI ischemic lesion volume with respect to change from baseline in G-CSF-treated patients (P=0.06). In 1 participant, there was suggestion that labeled CD34(+) cells had migrated to the ischemic lesion. CONCLUSIONS: This randomized, double-blind, placebo-controlled trial suggests that G-CSF is safe when administered subacutely. It is feasible to label and readminister iron-labeled CD34(+) cells in patients with ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: www.controlled-trials.com. Unique identifier: ISRCTN63336619. PMID- 22198984 TI - Near infrared spectroscopy for the detection of desaturations in vulnerable ischemic brain tissue: a pilot study at the stroke unit bedside. AB - BACKGROUND AND PURPOSE: There is uncertainty whether bilateral near infrared spectroscopy (NIRS) can be used for monitoring of patients with acute stroke. METHODS: The NIRS responsiveness to systemic and stroke-related changes was studied overnight by assessing the effects of brief peripheral arterial oxygenation and mean arterial pressure alterations in the affected versus nonaffected hemisphere in 9 patients with acute stroke. RESULTS: Significantly more NIRS drops were registered in the affected compared with the nonaffected hemisphere (477 drops versus 184, P<0.001). In the affected hemispheres, nearly all peripheral arterial oxygenation drops (n=128; 96%) were detected by NIRS; in the nonaffected hemispheres only 23% (n=30; P=0.17). Only a few mean arterial pressure drops were followed by a significant NIRS drop. This was however significantly different between both hemispheres (32% versus 13%, P=0.01). CONCLUSIONS: This pilot study found good responsiveness of NIRS signal to systemic and stroke-related changes at the bedside but requires confirmation in a larger sample. PMID- 22198985 TI - Mechanical thrombolysis and stenting in acute ischemic stroke. PMID- 22198986 TI - Arterial stiffness and stroke in sickle cell disease. AB - BACKGROUND AND PURPOSE: Large vessels are also affected in sickle cell disease. The aim of this study was to assess several parameters in adult patients with sickle cell disease compared with control subjects and in patients with sickle cell disease with stroke. METHODS: Carotid arterial stiffness, intima-media thickness, and transcranial Doppler ultrasonography were measured. RESULTS: Arterial stiffness and transcranial Doppler velocity were significantly increased in 49 patients with sickle cell disease compared with 47 control subjects (P<0.05) and especially in patients with stroke (P<0.05). CONCLUSIONS: These data suggest that transcranial Doppler and arterial stiffness might be associated to stroke in adult patients with sickle cell disease. PMID- 22198987 TI - Predicting the lack of development of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: Patients with aneurysmal subarachnoid hemorrhage are typically kept in the intensive care unit to be monitored for signs of delayed cerebral ischemia (DCI). Identifying patients at lower risk for DCI could have a positive financial impact by allowing earlier transfer from the intensive care unit. METHODS: We analyzed 307 consecutive patients admitted to the intensive care unit. Demographic, clinical, and neuroimaging data were recorded. The relationship with absent DCI was analyzed using univariate and multivariate logistic regression models. RESULTS: DCI did not develop in 169 patients (57.9%). Among factors at admission, age 68 years or older (P=0.0003; OR, 3.16; 95% CI, 1.66-6.39), World Federation of Neurological Surgeons (WFNS) I to III at presentation (P=0.0003; OR, 2.73; 95% CI, 1.57-4.79), WFNS I to III at worst (P=0.0003; OR, 2.39; 95% CI, 1.48-3.87), WFNS I to III after resuscitation (P=0.0006; OR, 2.85; 95% CI, 1.56-5.32), modified Fisher grade 1 to 2 (P=0.0021; OR, 2.43; 95% CI, 1.37-4.47), absence of intracranial hematoma (P=0.0042; OR, 2.26; 95% CI, 1.29-4.01), and aneurysm in the posterior circulation (P=0.025; OR, 1.74; 95% CI, 1.07-2.87) were associated with absence of DCI. On multivariate analysis, a model including age 68 years or older, WFNS I to III at presentation and a modified Fisher grade 1 to 2 were independently predictive of the absence of DCI, with a specificity of 100% and a positive predictive value of 100%. CONCLUSIONS: We propose a new model that can reliably identify patients with aneurysmal subarachnoid hemorrhage who are at very low risk for DCI. These patients could be candidates for early transfer to the general ward. PMID- 22198988 TI - Stroke occurrence and patterns are not influenced by the degree of stenosis in cervical artery dissection. AB - BACKGROUND AND PURPOSE: In stroke attributable to spontaneous dissection of the cervical artery, it is unclear whether the occurrence and pattern of stroke depend on the degree of stenosis. METHODS: In 147 consecutive dissection of the cervical artery patients with (n=88) and without stroke (n=59), we compared the number, volume, and patterns of cerebral diffusion-weighted imaging stroke lesions among patients with <70% stenosis (Group 1), >=70% stenosis (Group 2), and occlusion (Group 3). RESULTS: The presence (26 of 45 in Group 1, 32 of 59 in Group 2, 30 of 43 in Group 3; P=0.27) and the number of diffusion-weighted imaging lesions (mean+/-SD [interquartile range], 3.5+/-3.9 [1-4] in Group 1; 4.2+/-4.1 [1-5] in Group 2; 3.3+/-4.0 [1-3] in Group 3; P=0.85) were independent of lumen patency, whereas volume of diffusion-weighted imaging lesions was larger in occlusive dissection of the cervical artery (82+/-90 mm [17-91] versus 34+/-54 [2-48]; P=0.03). There were no differences in the breakdown of diffusion-weighted imaging lesion patterns according to degree of stenosis. CONCLUSIONS: The occurrence and diffusion-weighted imaging lesion patterns in dissection of the cervical artery patients may not be influenced by the degree of stenosis of the dissected artery. Occlusive dissection of the cervical artery was associated with larger infarcts. PMID- 22198989 TI - Relationship between Mycobacterium tuberculosis phylogenetic lineage and clinical site of tuberculosis. AB - BACKGROUND: Genotyping of Mycobacterium tuberculosis has revealed 4 major phylogenetic lineages with differential distribution worldwide. It is not clear whether different lineages are associated with different sites of infection (eg, pulmonary tuberculosis versus extrapulmonary tuberculosis). We sought to determine whether M. tuberculosis lineage is associated with the site of tuberculosis disease. METHODS: We conducted a cross-sectional analysis of all culture-confirmed cases of tuberculosis with routinely determined M. tuberculosis spoligotype-defined lineage reported to the US National Tuberculosis Surveillance System from 2004 through 2008. Odds ratios (ORs) were used to assess the relation between disease site and M. tuberculosis lineage, after adjustment for age, sex, human immunodeficiency virus infection status, region of birth, and race/ethnicity. RESULTS: Of 53972 reported culture-positive tuberculosis cases, 32000 (59.3%) were cases of M. tuberculosis that included complete spoligotype based data on lineage. Of these, 23844 (74.5%) were exclusively pulmonary, 5085 (15.9%) were exclusively extrapulmonary, and 3071 (9.6%) were combined pulmonary and extrapulmonary. The percentages of tuberculosis cases that were exclusively extrapulmonary differed by lineage: East Asian, 13.0%; Euro-American, 13.8%; Indo Oceanic, 22.6%; and East-African Indian, 34.3%. Compared with East Asian lineage, the odds of exclusively extrapulmonary tuberculosis relative to exclusively pulmonary tuberculosis were greater for Euro-American (adjusted OR, 1.3; 95% confidence interval [CI], 1.1-1.4), Indo-Oceanic (adjusted OR, 1.7; 95% CI, 1.5 1.9), and East-African Indian (adjusted OR, 1.6; 95% CI, 1.4-1.9) lineages. CONCLUSIONS: Phylogenetic lineage of M. tuberculosis is associated with the site of tuberculosis disease. PMID- 22198990 TI - Mycobacterium tuberculosis lineage--what's in your lungs? PMID- 22198991 TI - Photo quiz. Multiloculated liver abscess. PMID- 22198994 TI - Zoster in monasteries: some clarification needed. PMID- 22198992 TI - Forgotten antibiotics: an inventory in Europe, the United States, Canada, and Australia. AB - In view of the alarming spread of antimicrobial resistance in the absence of new antibiotics, this study aimed at assessing the availability of potentially useful older antibiotics. A survey was performed in 38 countries among experts including hospital pharmacists, microbiologists, and infectious disease specialists in Europe, the United States, Canada, and Australia. An international expert panel selected systemic antibacterial drugs for their potential to treat infections caused by resistant bacteria or their unique value for specific criteria. Twenty two of the 33 selected antibiotics were available in fewer than 20 of 38 countries. Economic motives were the major cause for discontinuation of marketing of these antibiotics. Fourteen of 33 antibiotics are potentially active against either resistant Gram-positive or Gram-negative bacteria. Urgent measures are then needed to ensure better availability of these antibiotics on a global scale. PMID- 22199005 TI - Prognostic factors of 634 HIV-negative patients with Mycobacterium avium complex lung disease. AB - RATIONALE: The prognostic factors of Mycobacterium avium complex lung disease (MAC-LD) are not clearly defined. OBJECTIVES: To assess the prognostic factors of all-cause and MAC-specific mortality in patients with MAC-LD, especially in accordance with radiographic features, first-line treatment, and host predisposition. METHODS: Medical records of 634 HIV-negative patients with MAC-LD treated at our institution in Saitama, Japan were retrospectively analyzed. MEASUREMENTS AND MAIN RESULTS: Patients' mean age was 68.9 years, and median follow-up period was 4.7 years. Radiographic features included nodular/bronchiectatic (NB) disease: 482 patients (76.0%); fibrocavitary (FC) disease: 105 patients (16.6%); FC+NB disease: 30 patients (4.7%); and other types: 17 patients (3.0%). First-line treatments were observation or one drug: 479 patients (75.6%); 2 to 5 drugs: 131 patients (20.7%); and unknown: 24 patients (3.8%). A multivariate Cox proportional hazard model showed male sex, older age, presence of systemic and/or respiratory comorbidity, non-NB radiographic features, body mass index (BMI) less than 18.5 kg/m(2), anemia, hypoalbuminemia, and erythrocyte sedimentation rate greater than or equal to 50 mm/h to be negative prognostic factors for all-cause mortality, and FC or FC+NB radiographic features, BMI less than 18.5 kg/m(2), anemia, and C-reactive protein greater than or equal to 1.0 mg/dl to be negative prognostic factors for MAC specific mortality. CONCLUSIONS: The first-line treatment regimen was not associated with all-cause mortality. FC or FC+NB disease, BMI less than 18.5 kg/m(2), and anemia were negative prognostic factors for both all-cause and MAC specific mortality. PMID- 22199006 TI - Differentiation and recruitment of IL-22-producing helper T cells stimulated by pleural mesothelial cells in tuberculous pleurisy. AB - RATIONALE: IL-22-producing helper T cells (Th22 cells) have been reported to be involved in tuberculosis infection. However, differentiation and immune regulation of Th22 cells in tuberculous pleural effusion (TPE) remain unknown. OBJECTIVES: To elucidate the mechanism by which Th22 cells differentiate and recruit into the pleural space. METHODS: The distribution and phenotypic features of Th22 cells in both TPE and blood were determined. The impacts of proinflammatory cytokines and antigen presentation by pleural mesothelial cells (PMCs) on Th22-cell differentiation were explored. The chemoattractant activity of chemokines produced by PMCs for Th22 cells was observed. MEASUREMENTS AND MAIN RESULTS: Th22 cells were significantly higher in TPE than in blood. IL-1beta, IL 6, and/or tumor necrosis factor-alpha promoted Th22-cell differentiation from CD4(+) T cells. It was found that PMCs expressed CCL20, CCL22, and CCL27, and that TPE and PMC supernatants were chemotactic for Th22 cells. This activity was partly blocked by anti-CCL20, anti-CCL22, and anti-CCL27 antibodies. IL-22 and IL 17 significantly improved PMC wound healing. Moreover, PMCs were able to stimulate CD4(+) T-cell proliferation and Th22-cell differentiation by presenting tuberculosis-specific antigen. CONCLUSIONS: The overrepresentation of Th22 cells in TPE may be due to pleural cytokines and to PMC-produced chemokines. Our data suggest a collaborative loop between PMCs and Th22 cells in TPE. In particular, PMCs were able to function as antigen-presenting cells to stimulate CD4(+) T-cell proliferation and Th22-cell differentiation. PMID- 22199008 TI - A new global palaeobiogeographical model for the late Mesozoic and early Tertiary. AB - Late Mesozoic palaeobiogeography has been characterized by a distinction between the northern territories of Laurasia and the southern landmasses of Gondwana. The repeated discovery of Gondwanan lineages in Laurasia has led to the proposal of alternative scenarios to explain these anomalous occurrences. A new biogeographical model for late Mesozoic terrestrial ecosystems is here proposed in which Europe and "Gondwanan" territories possessed a common Eurogondwanan fauna during the earliest Cretaceous. Subsequently, following the Hauterivian, the European territories severed from Africa and then connected to Asiamerica resulting in a faunal interchange. This model explains the presence of Gondwanan taxa in Laurasia and the absence of Laurasian forms in the southern territories during the Cretaceous. In order to test this new palaeobiogeographical model, tree reconciliation analyses (TRAs) were performed based on biogeographical signals provided by a supertree of late Mesozoic archosaurs. The TRAs found significant evidence for the presence of an earliest Cretaceous Eurogondwanan fauna followed by a relatively short-term Gondwana-Laurasia dichotomy. The analysis recovered evidence for a biogeographical reconnection of the European territories with Africa and South America-Antarctica during the Campanian to Maastrichtian time-slice. This biogeographical scenario appears to continue through the early Tertiary and sheds light on the trans-Atlantic disjunct distributions of several extant plant and animal groups. PMID- 22199009 TI - Disparity in left ventricular stimulation among different pacing configurations in cardiac resynchronization therapy. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) demands high energy utilization due to continuous biventricular pacing. Current technology allows 6 pacing configurations for a bipolar left ventricular (LV) lead. Understanding the energy requirements for each configuration will allow optimization of pacing output. METHODS AND RESULTS: Pacing impedance, LV voltage threshold at 1.5 ms (rheobase) and 0.4 ms and chronaxie were obtained in 6 LV configurations in 49 consecutive patients undergoing CRT implantation or replacement. Strength duration curves were derived using the Lapicque formula. Pacing impedances and voltage thresholds at 1.5 and 0.4 ms, calculated minimum threshold energy at chronaxie, current drain, energy thresholds at 0.4 ms, and strength-duration curves were statistically different between LV configurations (P<0.05). The lowest threshold energy requirements were found in Tip->right ventricular (RV) coil and Tip->Can configuration. Energy strength-duration curves involving the ring as the cathode (Ring->RV, Ring->Can, and Ring->Tip) had the highest LV thresholds. The pacing configuration with the lowest energy threshold correlated 89% of the time with the lowest voltage threshold at 0.4 ms. The probability to reach LV thresholds <1.5 V at 0.4 ms was increased from 51% with 2 LV configurations to 67% with 6 LV configurations. CONCLUSIONS: Pacing impedance, LV thresholds, minimum threshold energy at chronaxie, current drain, voltage, and energy strength-duration curves were statistically different between LV pacing configurations. LV pacing configuration with the lowest voltage threshold does not always reflects the lowest energy threshold, particularly in the presence of a low impedance configuration. The availability of 6 LV configurations increases the probability of optimizing LV pacing output. PMID- 22199010 TI - Spontaneous ventricular fibrillation in right ventricular failure secondary to chronic pulmonary hypertension. AB - BACKGROUND: Right ventricular failure (RVF) in pulmonary hypertension (PH) is associated with increased incidence of sudden death by a poorly explored mechanism. We test the hypothesis that PH promotes spontaneous ventricular fibrillation (VF) during a critical post-PH onset period characterized by a sudden increase in mortality. METHODS AND RESULTS: Rats received either a single subcutaneous dose of monocrotaline (MCT, 60 mg/kg) to induce PH-associated RVF (PH, n=24) or saline (control, n=17). Activation pattern of the RV-epicardial surface was mapped using voltage-sensitive dye in isolated Langendorff-perfused hearts along with single glass-microelectrode and ECG-recordings. MCT-injected rats developed severe PH by day 21 and progressed to RVF by approximately day 30. Rats manifested increased mortality, and ~30% rats died suddenly and precipitously during 23-32 days after MCT. This fatal period was associated with the initiation of spontaneous VF by a focal mechanism in the RV, which was subsequently maintained by both focal and incomplete reentrant wave fronts. Microelectrode recordings from the RV-epicardium at the onset of focal activity showed early afterdepolarization-mediated triggered activity that led to VF. The onset of the RV cellular triggered beats preceded left ventricular depolarizations by 23+/-8 ms. The RV but not the left ventricular cardiomyocytes isolated during this fatal period manifested significant action potential duration prolongation, dispersion, and an increased susceptibility to depolarization-induced repetitive activity. No spontaneous VF was observed in any of the control hearts. RVF was associated with significantly reduced RV ejection fraction (P<0.001), RV hypertrophy (P<0.001), and RV fibrosis (P<0.01). The hemodynamic function of the LV and its structure were preserved. CONCLUSIONS: PH induced RVF is associated with a distinct phase of increased mortality characterized by spontaneous VF arising from the RV by an early afterdepolarization-mediated triggered activity. PMID- 22199012 TI - When a tax increase fails as a tobacco control policy: the ITC China project evaluation of the 2009 cigarette tax increase in China. PMID- 22199013 TI - Local Nordic tobacco interests collaborated with multinational companies to maintain a united front and undermine tobacco control policies. AB - OBJECTIVE: To analyse how local tobacco companies in the Nordic countries, individually and through National Manufacturers' Associations, cooperated with British American Tobacco and Philip Morris in denying the health hazards of smoking and undermining tobacco control. METHODS: Analysis of tobacco control policies in the Nordic countries and tobacco industry documents. RESULTS: Nordic countries were early adopters of tobacco control policies. The multinational tobacco companies recognised this fact and mobilised to oppose these policies, in part because of fear that they would set unfavourable precedents. Since at least 1972, the Nordic tobacco companies were well informed about and willing to participate in the multinational companies activities to obscure the health dangers of smoking and secondhand smoke and to oppose tobacco control policies. Cooperation between multinational companies, Nordic national manufacturer associations and local companies ensured a united front on smoking and health issues in the Nordic area that was consistent with the positions that the multinational companies were taking. This cooperation delayed smoke-free laws and undermined other tobacco control measures. CONCLUSIONS: Local tobacco companies worked with multinational companies to undermine tobacco control in distant and small Nordic markets because of concern that pioneering policies initiated in Nordic countries would spread to bigger market areas. Claims by the local Nordic companies that they were not actively involved with the multinationals are not supported by the facts. These results also demonstrate that the industry appreciates the global importance of both positive and negative public health precedents in tobacco control. PMID- 22199014 TI - Stomatal response of an anisohydric grapevine cultivar to evaporative demand, available soil moisture and abscisic acid. AB - Stomatal responsiveness to evaporative demand (air vapour pressure deficit (VPD)) ranges widely between species and cultivars, and mechanisms for stomatal control in response to VPD remain obscure. The interaction of irrigation and soil moisture with VPD on stomatal conductance is particularly difficult to predict, but nevertheless is critical to instantaneous transpiration and vulnerability to desiccation. Stomatal sensitivity to VPD and soil moisture was investigated in Semillon, an anisohydric Vitis vinifera L. variety whose leaf water potential (Psi(l)) is frequently lower than that of other grapevine varieties grown under similar conditions in the warm grape-growing regions of Australia. A survey of Semillon vines across seven vineyards revealed that, regardless of irrigation treatment, midday Psi(l) was dependent on not only soil moisture but VPD at the time of measurement. Predawn Psi(l) was more closely correlated to not only soil moisture in dry vineyards but to night-time VPD in drip-irrigated vineyards, with incomplete rehydration during high night-time VPD. Daytime stomatal conductance was low only under severe plant water deficits, induced by extremes in dry soil. Stomatal response to VPD was inconsistent across irrigation regime; however, in an unirrigated vineyard, stomatal sensitivity to VPD-the magnitude of stomatal response to VPD-was heightened under dry soils. It was also found that stomatal sensitivity was proportional to the magnitude of stomatal conductance at a reference VPD of 1kPa. Exogenous abscisic acid (ABA) applied to roots of Semillon vines growing in a hydroponic system induced stomatal closure and, in field vines, petiole xylem sap ABA concentrations rose throughout the morning and were higher in vines with low Psi(l). These data indicate that despite high stomatal conductance of this anisohydric variety when grown in medium to high soil moisture, increased concentrations of ABA as a result of very limited soil moisture may augment stomatal responsiveness to low VPD. PMID- 22199015 TI - Long-term cardiovascular mortality after procedure-related or spontaneous myocardial infarction in patients with non-ST-segment elevation acute coronary syndrome: a collaborative analysis of individual patient data from the FRISC II, ICTUS, and RITA-3 trials (FIR). AB - BACKGROUND: The present study was designed to investigate the long-term prognostic impact of procedure-related and spontaneous myocardial infarction (MI) on cardiovascular mortality in patients with non-ST-elevation acute coronary syndrome. METHODS AND RESULTS: Five-year follow-up after procedure-related or spontaneous MI was investigated in the individual patient pooled data set of the FRISC-II (Fast Revascularization During Instability in Coronary Artery Disease), ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes), and RITA-3 (Randomized Intervention Trial of Unstable Angina 3) non-ST-elevation acute coronary syndrome trials. The principal outcome was cardiovascular death up to 5 years of follow-up. Cumulative event rates were estimated by the Kaplan Meier method; hazard ratios were calculated with time-dependent Cox proportional hazards models. Adjustments were made for the variables associated with long-term outcomes. Among the 5467 patients, 212 experienced a procedure-related MI within 6 months after enrollment. A spontaneous MI occurred in 236 patients within 6 months. The cumulative cardiovascular death rate was 5.2% in patients who had a procedure-related MI, comparable to that for patients without a procedure-related MI (hazard ratio 0.66; 95% confidence interval, 0.36-1.20, P=0.17). In patients who had a spontaneous MI within 6 months, the cumulative cardiovascular death rate was 22.2%, higher than for patients without a spontaneous MI (hazard ratio 4.52; 95% confidence interval, 3.37-6.06, P<0.001). These hazard ratios did not change materially after risk adjustments. CONCLUSIONS: Five-year follow-up of patients with non-ST-elevation acute coronary syndrome from the 3 trials showed no association between a procedure-related MI and long-term cardiovascular mortality. In contrast, there was a substantial increase in long-term mortality after a spontaneous MI. PMID- 22199016 TI - American College of Cardiology/American Heart Association/European Society of Cardiology/World Heart Federation universal definition of myocardial infarction classification system and the risk of cardiovascular death: observations from the TRITON-TIMI 38 trial (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38). AB - BACKGROUND: The availability of more sensitive biomarkers of myonecrosis and a new classification system from the universal definition of myocardial infarction (MI) have led to evolution of the classification of MI. The prognostic implications of MI defined in the current era have not been well described. METHODS AND RESULTS: We investigated the association between new or recurrent MI by subtype according to the European Society of Cardiology/American College of Cardiology/American Heart Association/World Health Federation Task Force for the Redefinition of MI Classification System and the risk of cardiovascular death among 13 608 patients with acute coronary syndrome in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38). The adjusted risk of cardiovascular death was evaluated by landmark analysis starting at the time of the MI through 180 days after the event. Patients who experienced an MI during follow-up had a higher risk of cardiovascular death at 6 months than patients without an MI (6.5% versus 1.3%, P<0.001). This higher risk was present across all subtypes of MI, including type 4a (peri-percutaneous coronary intervention, 3.2%; P<0.001) and type 4b (stent thrombosis, 15.4%; P<0.001). After adjustment for important clinical covariates, the occurrence of any MI was associated with a 5-fold higher risk of death at 6 months (95% confidence interval 3.8-7.1), with similarly increased risk across subtypes. CONCLUSIONS: MI is associated with a significantly increased risk of cardiovascular death, with a consistent relationship across all types as defined by the universal classification system. These findings underscore the clinical relevance of these events and the importance of therapies aimed at preventing MI. PMID- 22199018 TI - N-acetylcysteine in children with dengue-associated liver failure: a case report. AB - There is no specific treatment for dengue-associated fulminant liver failure. We report a child with dengue-associated fulminant liver failure who was treated successfully with intravenous N-acetylcysteine. A 6-year-old boy was diagnosed with dengue-associated fulminant liver failure. After administration of intravenous N-acetylcysteine, a rapid decrease in liver transaminases and normalization of coagulation profile was observed followed by clinical improvement and favourable outcome despite factors associated with poor prognosis. The use of intravenous N-acetylcysteine is safe and efficient in the treatment of dengue-associated fulminant liver failure, especially in centres when liver transplantation is not readily available. PMID- 22199017 TI - Are physicians' perceptions of healthcare quality and practice satisfaction affected by errors associated with electronic health record use? AB - BACKGROUND: Electronic health record (EHR) adoption is a national priority in the USA, and well-designed EHRs have the potential to improve quality and safety. However, physicians are reluctant to implement EHRs due to financial constraints, usability concerns, and apprehension about unintended consequences, including the introduction of medical errors related to EHR use. The goal of this study was to characterize and describe physicians' attitudes towards three consequences of EHR implementation: (1) the potential for EHRs to introduce new errors; (2) improvements in healthcare quality; and (3) changes in overall physician satisfaction. METHODS: Using data from a 2007 statewide survey of Massachusetts physicians, we conducted multivariate regression analysis to examine relationships between practice characteristics, perceptions of EHR-related errors, perceptions of healthcare quality, and overall physician satisfaction. RESULTS: 30% of physicians agreed that EHRs create new opportunities for error, but only 2% believed their EHR has created more errors than it prevented. With respect to perceptions of quality, there was no significant association between perceptions of EHR-associated errors and perceptions of EHR-associated changes in healthcare quality. Finally, physicians who believed that EHRs created new opportunities for error were less likely be satisfied with their practice situation (adjusted OR 0.49, p=0.001). CONCLUSIONS: Almost one third of physicians perceived that EHRs create new opportunities for error. This perception was associated with lower levels of physician satisfaction. PMID- 22199019 TI - Future applications of contrast echocardiography. PMID- 22199011 TI - Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies. AB - BACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome wide association study data from 21 population-based cohorts. METHODS AND RESULTS: Continuous ABI and PAD (ABI <=0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ~2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (~60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (beta=-0.006, P=2.46*10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65*10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6*10(-5)), CYBA (rs3794624, P=6.3*10(-5)), and rs1122608 (LDLR, P=0.0026). CONCLUSIONS: Genome wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI. PMID- 22199020 TI - Resistant hypertension. PMID- 22199022 TI - Robust nuclear lamina-based cell classification of aging and senescent cells. AB - Changes in the shape of the nuclear lamina are exhibited in senescent cells, as well as in cells expressing mutations in lamina genes. To identify cells with defects in the nuclear lamina we developed an imaging method that quantifies the intensity and curvature of the nuclear lamina. We show that this method accurately describes changes in the nuclear lamina. Spatial changes in nuclear lamina coincide with redistribution of lamin A proteins and local reduction in protein mobility in senescent cell. We suggest that local accumulation of lamin A in the nuclear envelope leads to bending of the structure. A quantitative distinction of the nuclear lamina shape in cell populations was found between fresh and senescent cells, and between primary myoblasts from young and old donors. Moreover, with this method mutations in lamina genes were significantly distinct from cells with wild-type genes. We suggest that this method can be applied to identify abnormal cells during aging, in in vitro propagation, and in lamina disorders. PMID- 22199023 TI - Myofibrillar myopathy caused by a mutation in the motor domain of mouse MyHC IIb. AB - Ariel is a mouse mutant that suffers from skeletal muscle myofibrillar degeneration due to the rapid accumulation of large intracellular protein aggregates. This fulminant disease is caused by an ENU-induced recessive mutation resulting in an L342Q change within the motor domain of the skeletal muscle myosin protein MYH4 (MyHC IIb). Although normal at birth, homozygous mice develop hindlimb paralysis from Day 13, consistent with the timing of the switch from developmental to adult myosin isoforms in mice. The mutated myosin (MYH4(L342Q)) is an aggregate-prone protein. Notwithstanding the speed of the process, biochemical analysis of purified aggregates showed the presence of proteins typically found in human myofibrillar myopathies, suggesting that the genesis of ariel aggregates follows a pathogenic pathway shared with other conformational protein diseases of skeletal muscle. In contrast, heterozygous mice are overtly and histologically indistinguishable from control mice. MYH4(L342Q) is present in muscles from heterozygous mice at only 7% of the levels of the wild-type protein, resulting in a small but significant increase in force production in isolated single fibres and indicating that elimination of the mutant protein in heterozygotes prevents the pathological changes observed in homozygotes. Recapitulation of the L342Q change in the functional equivalent of mouse MYH4 in human muscles, MYH1, results in a more aggregate-prone protein. PMID- 22199021 TI - Vesicular and plasma membrane transporters for neurotransmitters. AB - The regulated exocytosis that mediates chemical signaling at synapses requires mechanisms to coordinate the immediate response to stimulation with the recycling needed to sustain release. Two general classes of transporter contribute to release, one located on synaptic vesicles that loads them with transmitter, and a second at the plasma membrane that both terminates signaling and serves to recycle transmitter for subsequent rounds of release. Originally identified as the target of psychoactive drugs, these transport systems have important roles in transmitter release, but we are only beginning to understand their contribution to synaptic transmission, plasticity, behavior, and disease. Recent work has started to provide a structural basis for their activity, to characterize their trafficking and potential for regulation. The results indicate that far from the passive target of psychoactive drugs, neurotransmitter transporters undergo regulation that contributes to synaptic plasticity. PMID- 22199024 TI - Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls. AB - Recurrent rearrangements of chromosome 1q21.1 that occur via non-allelic homologous recombination have been associated with variable phenotypes exhibiting incomplete penetrance, including congenital heart disease (CHD). However, the gene or genes within the ~1 Mb critical region responsible for each of the associated phenotypes remains unknown. We examined the 1q21.1 locus in 948 patients with tetralogy of Fallot (TOF), 1488 patients with other forms of CHD and 6760 ethnically matched controls using single nucleotide polymorphism genotyping arrays (Illumina 660W and Affymetrix 6.0) and multiplex ligation dependent probe amplification. We found that duplication of 1q21.1 was more common in cases of TOF than in controls [odds ratio (OR) 30.9, 95% confidence interval (CI) 8.9-107.6); P = 2.2 * 10(-7)], but deletion was not. In contrast, deletion of 1q21.1 was more common in cases of non-TOF CHD than in controls [OR 5.5 (95% CI 1.4-22.0); P = 0.04] while duplication was not. We also detected rare (n = 3) 100-200 kb duplications within the critical region of 1q21.1 in cases of TOF. These small duplications encompassed a single gene in common, GJA5, and were enriched in cases of TOF in comparison to controls [OR = 10.7 (95% CI 1.8-64.3), P = 0.01]. These findings show that duplication and deletion at chromosome 1q21.1 exhibit a degree of phenotypic specificity in CHD, and implicate GJA5 as the gene responsible for the CHD phenotypes observed with copy number imbalances at this locus. PMID- 22199025 TI - Exceptional longevity is associated with decreased reproduction. AB - A number of leading theories of aging, namely The Antagonistic Pleiotropy Theory (Williams, 1957), The Disposable Soma Theory (Kirkwood, 1977) and most recently The Reproductive-Cell Cycle Theory (Bowen and Atwood, 2004, 2010) suggest a tradeoff between longevity and reproduction. While there has been an abundance of data linking longevity with reduced fertility in lower life forms, human data have been conflicting. We assessed this tradeoff in a cohort of genetically and socially homogenous Ashkenazi Jewish centenarians (average age ~100 years). As compared with an Ashkenazi cohort without exceptional longevity, our centenarians had fewer children (2.01 vs 2.53, p<0.0001), were older at first childbirth (28.0 vs 25.6, p<0.0001), and at last childbirth (32.4 vs 30.3, p<0.0001). The smaller number of children was observed for male and female centenarians alike. The lower number of children in both genders together with the pattern of delayed reproductive maturity is suggestive of constitutional factors that might enhance human life span at the expense of reduced reproductive ability. PMID- 22199026 TI - Gene-environment interactions in genome-wide association studies: a comparative study of tests applied to empirical studies of type 2 diabetes. AB - The question of which statistical approach is the most effective for investigating gene-environment (G-E) interactions in the context of genome-wide association studies (GWAS) remains unresolved. By using 2 case-control GWAS (the Nurses' Health Study, 1976-2006, and the Health Professionals Follow-up Study, 1986-2006) of type 2 diabetes, the authors compared 5 tests for interactions: standard logistic regression-based case-control; case-only; semiparametric maximum-likelihood estimation of an empirical-Bayes shrinkage estimator; and 2 stage tests. The authors also compared 2 joint tests of genetic main effects and G-E interaction. Elevated body mass index was the exposure of interest and was modeled as a binary trait to avoid an inflated type I error rate that the authors observed when the main effect of continuous body mass index was misspecified. Although both the case-only and the semiparametric maximum-likelihood estimation approaches assume that the tested markers are independent of exposure in the general population, the authors did not observe any evidence of inflated type I error for these tests in their studies with 2,199 cases and 3,044 controls. Both joint tests detected markers with known marginal effects. Loci with the most significant G-E interactions using the standard, empirical-Bayes, and 2-stage tests were strongly correlated with the exposure among controls. Study findings suggest that methods exploiting G-E independence can be efficient and valid options for investigating G-E interactions in GWAS. PMID- 22199027 TI - Testing gene-environment interaction in large-scale case-control association studies: possible choices and comparisons. AB - Several methods for screening gene-environment interaction have recently been proposed that address the issue of using gene-environment independence in a data adaptive way. In this report, the authors present a comparative simulation study of power and type I error properties of 3 classes of procedures: 1) the standard 1-step case-control method; 2) the case-only method that requires an assumption of gene-environment independence for the underlying population; and 3) a variety of hybrid methods, including empirical-Bayes, 2-step, and model averaging, that aim at gaining power by exploiting the assumption of gene-environment independence and yet can protect against false positives when the independence assumption is violated. These studies suggest that, although the case-only method generally has maximum power, it has the potential to create substantial false positives in large-scale studies even when a small fraction of markers are associated with the exposure under study in the underlying population. All the hybrid methods perform well in protecting against such false positives and yet can retain substantial power advantages over standard case-control tests. The authors conclude that, for future genome-wide scans for gene-environment interactions, major power gain is possible by using alternatives to standard case control analysis. Whether a case-only type scan or one of the hybrid methods should be used depends on the strength and direction of gene-environment interaction and association, the level of tolerance for false positives, and the nature of replication strategies. PMID- 22199030 TI - The naked mole rat genome: understanding aging through genome analysis. PMID- 22199029 TI - Invited commentary: GE-Whiz! Ratcheting gene-environment studies up to the whole genome and the whole exposome. AB - One goal in the post-genome-wide association study era is characterizing gene environment interactions, including scanning for interactions with all available polymorphisms, not just those showing significant main effects. In recent years, several approaches to such "gene-environment-wide interaction studies" have been proposed. Two contributions in this issue of the American Journal of Epidemiology provide systematic comparisons of the performance of these various approaches, one based on simulation and one based on application to 2 real genome-wide association study scans for type 2 diabetes. The authors discuss some of the broader issues raised by these contributions, including the plausibility of the gene-environment independence assumption that some of these approaches rely upon, the need for replication, and various generalizations of these approaches. PMID- 22199032 TI - Perturbation and candidate analysis to combat overfitting of gene expression microarray data. AB - Analysis of gene expression microarray datasets presents the high risk of over fitting (spurious patterns) because of their feature-rich but case-poor nature. This paper describes our ongoing efforts to develop a method to combat over fitting and determine the strongest signal in the dataset. A GA-SVM hybrid along with Gaussian noise (manual noise gain) is used to discover feature sets of minimal size that accurately classifies the cases under cross-validation. Initial results on a colorectal cancer dataset shows that the strongest signal (modest number of candidates) can be found by a binary search. PMID- 22199031 TI - Integrating multiple disturbance aspects: management of an invasive thistle, Carduus nutans. AB - BACKGROUND AND AIMS: Disturbances occur in most ecological systems, and play an important role in biological invasions. We delimit five key disturbance aspects: intensity, frequency, timing, duration and extent. Few studies address more than one of these aspects, yet interactions and interdependence between aspects may lead to complex outcomes. METHODS: In a two-cohort experimental study, we examined how multiple aspects (intensity, frequency and timing) of a mowing disturbance regime affect the survival, phenology, growth and reproduction of an invasive thistle Carduus nutans (musk thistle). KEY RESULTS: Our results show that high intensity and late timing strongly delay flowering phenology and reduce plant survival, capitulum production and plant height. A significant interaction between intensity and timing further magnifies the main effects. Unexpectedly, high frequency alone did not effectively reduce reproduction. However, a study examining only frequency and intensity, and not timing, would have erroneously attributed the importance of timing to frequency. CONCLUSIONS: We used management of an invasive species as an example to demonstrate the importance of a multiple aspect disturbance framework. Failure to consider possible interactions, and the inherent interdependence of certain aspects, could result in misinterpretation and inappropriate management efforts. This framework can be broadly applied to improve our understanding of disturbance effects on individual responses, population dynamics and community composition. PMID- 22199033 TI - Prioritisation of candidate Single Amino Acid Polymorphisms using one-class learning machines. AB - Recent advancements of the next-generation sequencing technology have enabled the direct sequencing of rare genetic variants in both case and control individuals. Although there have been a few statistical methods for uncovering potential associations between multiple rare variants and human inherited diseases, most of these methods require computational approaches to filter out non-functional variants for the purpose of maximising the statistical power. To tackle this problem, we formulate the detection of genetic variants that are associated with a specific type of disease from the perspective of one-class novelty learning. We focus on a typical type of genetic variants called Single Amino Acid Polymorphisms (SAAPs), and we take advantages of a feature selection mechanism and two one-class learning methods to prioritise candidate SAAPs. Systematic validation demonstrates that the proposed model is effective in recovering disease-associated SAAPs. PMID- 22199034 TI - In silico analysis of enzyme involved in enrichment of citronella oil. AB - Citronella oil is one of the essential oils obtained from Cymbopogon sp. having medicinally important aromatic chemicals (like citronellal, citronellol, hydroxy citronellol and geraniol) exhibiting insecticidal, anti-oxidant and anti inflammatory effects. Geraniol Dehydrogenase (GDH) is responsible for the degradation of Citronella oil. Therefore, we aimed to generate 3D structure of GDH and a potent specific GDH inhibitor by homology modelling, virtual screening of ligand database and molecular docking. Inhibitor model indicated strong binding affinity to the binding pocket of GDH and varying affinity for different ligands. Obtained structures will open the possibility of testing new inhibitor families, in addition to new substituent for the already known lead structures. PMID- 22199035 TI - Identification of cortical landmarks based on structural connectivity to subcortical regions. AB - Quantitative assessment of structural connectivities between cortical and subcortical regions has been of increasing interest in recent years. This paper proposes an algorithmic pipeline for identification of reliable cortical landmarks based on the consistent structural connectivity patterns between cortical and subcortical regions. Our experimental results of eight healthy subjects show that reliable and meaningful cortical landmarks can be extracted by using our approaches. Furthermore, subcortical regions can serve as reliable reference points for the identification of consistent corresponding cortical regions across individuals. PMID- 22199036 TI - Integrated cellular and gene interaction modelling of pattern formation. AB - Cellular behaviour depends on and also modifies protein concentration and activity. An integrated cellular and gene interaction model is proposed to reveal this relationship. In this model, protein activity varies spatiotemporally with cellular location, gene interaction, and diffusion. In the meanwhile, cellular behaviour can vary spatially, driven by cell-cell signalling and inhomogeneous protein distribution across cells. This model integrates two components. The first component adopts a variation of the reaction-diffusion mechanism at the gene expression level. The second component is a lattice cellular model based on the Differential Adhesion Hypothesis (DAH) for cell sorting at the cellular level. Cell sorting and tumour invasion were simulated to illustrate the model. This model approximates cellular pattern formation more closely than existing models based on cell density. PMID- 22199037 TI - Discovering a potent small molecule inhibitor for gankyrin using de novo drug design approach. AB - Gankyrin is an oncoprotein composed of six ankyrin repeats, over-expressed in the Hepatocellular Carcinoma (HCC), and directly involved in the cell cycle regulation. Therefore, it is a potential drug target to restrict the growth of cancer cell and activation of apoptosis. We have successfully designed a potent ligand to inhibit the activity of gankyrin. Using docking approach we designed a potential ligand, which is exactly fitting in the cavity of gankyrin and forming many close interactions to protein atoms including its active site residues. This molecule shows minimum energy and good binding affinity for gankyrin. PMID- 22199038 TI - Using protein abundance to indicate underlying mRNA expression levels in E.coli: an SEM modelling approach. AB - Do steady-state protein levels accurately predict mRNA levels? Based on the central dogma (DNA RNA protein) current protein levels are representative of mRNA present at an earlier time. However, most cellular mRNA protein comparative studies try to relate steady-state protein levels to current mRNA levels in cells. Protein steady-states are more correctly related to protein production, protein degradation and other complex cellular conditions. Using Structural Equation Modelling (SEM) we relate linear protein measurements to latent mRNA in E.coli. This method can be used to find the optimal protein measurements that explain underlying mRNA expression, and better understand the proteomic and transcriptomic relationship in E.coli gene expression. PMID- 22199039 TI - On the safety of diagnostic ultrasound in pregnancy: have we handled the available data correctly? AB - Robust evidence of the bioeffects of ultrasound is available from animal studies but human studies are less convincing. Nevertheless, it is disturbing that the only response to safety issues is a twenty-year old principle known as ALARA (As Low As Reasonably Applicable). Using experience from obstetrics and toxicology, and drawing information mainly from two recent systematic reviews and meta analysis that extensively covered the subject of ultrasound safety, this review captures the current knowledge of ultrasound bioeffects and suggests that it may be time for an international, multidisciplinary meeting on ultrasound safety to decide how to provide the evidence (available data) to patients and sonographers in a succinct manner. PMID- 22199040 TI - Acute occlusive mesenteric ischemia in high altitude of southwestern region of Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: Mesenteric ischemia which can be acute or chronic depending on the rapidity of compromised blood flow produces bowel ischemia, infarction, bacterial transmigration, endotoxemia, multisystem organ failure and death. High altitude can precipitate thrombosis because of hypobaric hypoxia and its effect on coagulation system. The objectives of this study are to determine the risk factors, clinical presentation, type and pattern of acute occlusive mesenteric ischemia in high-altitude of southwestern region of Saudi Arabia. MATERIALS AND METHODS: We reviewed the records of all the patients with acute occlusive mesenteric ischemia admitted to the Armed Forces Hospital, southern region, Kingdom of Saudi Arabia during the period of 2005 to 2010, and compiled data including demographics, clinical presentation, risk factors, preoperative investigations, management, histopathological examination, and complications. The cases of mesenteric ischemia resulting from conditions such as volvulus and strangulated hernias were excluded. RESULTS: Our study included 21 patients, 10 (48%) men and 11 (52%) women with a mean age of 56 years (SD 14). Abdominal pain was the most common presenting symptoms. CT angiography depicted occlusive arterial disease in 8 patients (38%) and venous thrombosis in 13 patients (62%). Diabetes mellitus was the most frequent risk factor for arterial mesenteric ischemia. Chronic liver disease particularly liver cirrhosis was the most prominent risk factor for venous mesenteric thrombosis. Intestinal ischemia was confirmed by histopathological examination. CONCLUSION: Acute occlusive mesenteric ischemia can mimic other more common intra-abdominal diseases clinically; therefore a high index of suspicion is required particularly for patients with relevant risk factors to prompt early diagnosis and intervention. Venous mesenteric thrombosis was more common than arterial mesenteric ischemia in our region. PMID- 22199041 TI - Mesenteric ischemia, high altitude and Hill's criteria. PMID- 22199042 TI - Social network as a determinant of pathway to mental health service utilization among psychotic patients in a Nigerian hospital. AB - OBJECTIVE: The main objectives of the study were to determine the relationship between social network and pathway to service utilization among psychotic patients. MATERIALS AND METHODS: This descriptive study was carried out in a psychiatric unit in a general hospital in South West Nigeria. Using structured questionnaires, primary data were collected from 652 psychotic patients on their social network, health behaviors and pathway to current service use. Logistic regression analysis was used to assess the effect of social network on patients' use of services, controlling for sociodemographics, health and functional status. RESULTS: Mean age of the respondents was 29.0 +/- 7.5 years, range 14-58 years, males constituted 52.6%. Regarding pathway to services, alternative sources of care such as priests, spiritualists, natural therapists, herbalists, was the first port of call for 78.9% of respondents. Family dominated the social network in 51.1% of patients. The presence of some social network and social support structures were significantly associated with the use of general medical and specialty psychiatric services for patients with schizophrenia (P = 0.03), schizoaffective disorder (P = 0.02), bipolar I disorder (P = 0.01), but not with major depression and symptoms of psychological distress. CONCLUSIONS: Findings indicate that social support and social network enhanced utilization of mental health services for psychiatric patients except for those with psychotic depression or those with symptoms of psychological distress. In addition, alternative sources of care are still relevant in mental health service delivery in South West Nigeria. PMID- 22199043 TI - Electrocardiographic abnormalities among dialysis naive chronic kidney disease patients in Ilorin Nigeria. AB - BACKGROUND: Chronic kidney disease (CKD) has an increased risk of not only end stage renal disease (ESRD), but majority of moderate CKD patients do die from cardiovascular disease (CVD) before reaching ESRD. The prognosis of these patients is very poor in most developing countries because of late presentation, inadequate diagnostic facilities, and inability to pay for treatment. Knowledge about CVD in CKD is crucial because of unpredictable progressive nature of the disease and increased risk of premature death from cardiovascular events. We sought to determine prevalence and pattern of electrocardiographic abnormalities in dialysis naive CKD patients. MATERIALS AND METHODS: This is a 10-year prospective cross-sectional study carried out at the University of Ilorin Teaching Hospital, Ilorin. Patients were recruited from the nephrology clinic and renal wards and all who met diagnostic criteria for stages 4 and 5 CKD were included. All had their standard 12-lead electrocardiogram (ECG) recorded and various findings were critically studied and interpreted independently by two consultant physician including a cardiologist. Data analysis was done using SPSS version 16. RESULTS: Overall, 86% of the patients had at least one form of ECG abnormality, with hypertension (HTN) and anemia being the main contributory factors. These include left ventricular hypertrophy (LVH) (27.6%), left atrial enlargement (LAE) (21.6%), combination of LVH and LAE (17.2%), and ventricular premature contractions (6%). Etiology of CKD appears to have influence on ECG changes as prevalence of LVH and LAE were high among hypertensive renal disease, chronic glomerulonephritis (CGN), and diabetic nephropathy patients. CONCLUSION: LVH and LAE were very common ECG abnormalities in our dialysis naive CKD patients. HTN, CGN, anemia, late presentation, and male gender appear to be the main risk factors for the ECG abnormalities. There is need for gender-specific intervention strategies directed at early detection and treatment of HTN, anemia, and underlying kidney disease, especially in resource poor nations where the burden of CKD is assuming epidemic proportion. PMID- 22199045 TI - An observational study of road safety around selected primary schools in Ibadan municipality, Oyo State, Southwestern Nigeria. AB - BACKGROUND/OBJECTIVE: Child pedestrians have been identified as vulnerable road users. Although walking as a means of transport has health and other benefits, it exposes children to the risk of road traffic injuries. This study was conducted to assess the availability of road safety features around government-owned primary schools in Ibadan municipality. MATERIALS AND METHODS: A multistage sampling technique was used to select 46 of the 74 schools in the study area. Some (11) of the selected schools were sited within the same premises and shared a common entrance; thus a total of 35 school premises were eventually observed. Trained research assistants observed the school environment around the selected schools for road safety features such as location of schools, presence of "school", "child crossing" and "speed limit" road signs, and presence of traffic calming devices (road bumps or zebra crossing). RESULTS: Five (14%) of the schools were located on major roads and eight (23%) had road signs indicating that a school was nearby. Seven (20%) had road bumps close to the school, 15 (43%) had a warden who assisted children to cross, and none had a zebra crossing. Five (14%) schools had pedestrian sidewalks. CONCLUSIONS: The study revealed that the environment around a number of the observed schools in the municipality compromised the pupils' road safety. The local government, school authorities, parents, and road safety professionals need to institute definite measures to enhance the road safety environment around schools in the municipality. PMID- 22199044 TI - Progestogen-only injectable contraceptive: experience of women in Osogbo, southwestern Nigeria. AB - BACKGROUND: Progestogen-only injectable contraceptive is a long-acting contraceptive given intramuscularly to give protection against unwanted pregnancy for a period of 2 or 3 months, depending on the type. Alterations in menstrual pattern are a well known side effect of this effective contraceptive method. OBJECTIVES: To determine the characteristics of women accepting the method, complications and indications for discontinuation. MATERIALS AND METHODS: This was a retrospective review of clients using progestogen-only injectable contraceptive between 1 st January, 2001 and 31 st December, 2009. Relevant information extracted from the case notes was analyzed. Survival analysis was carried out using Log-Rank Chi-square test to measure association over 12-month period of usage. Level of significance was set at P value less than 0.05. RESULTS: A total of 1,967 women used contraception during the study period and 433 (22.1%) made progestogen-only injectable their method of choice. 199(45.96%) used NET-EN, while DMPA was used by234 (54.04%) women. Many of the women (197, 45.5%) used the method for terminal fertility control. Menstrual abnormality was the commonest (264, 71.4%) complaint about progestogen-only injectable contraceptive, of which amenorrhea was experienced by constituted 176(66.7%). Eighty-three (22.4%) women had discontinued the contraceptive, and menstrual abnormality was the commonest reason for the discontinuation (68, 81.9%). No pregnancy was reported among the women that came for follow up while on the method. CONCLUSION: Short duration of POIC use that is within 12 months is still high. However the main reason for discontinuation was found to be due to menstrual irregularities, hence the need for effective education of the women about this side effect, thus increasing the acceptance and continuation rate of the contraceptive method. PMID- 22199046 TI - Injection safety practices among nursing staff of mission hospitals in Benin City, Nigeria. AB - BACKGROUND/OBJECTIVE OF THE STUDY: Injection safety has over the years become important in view of the many diseases that are transmitted through unsafe injection practice. The objective was to assess the knowledge and practice of injection safety by nurses in mission hospitals in Benin City, Nigeria. MATERIALS AND METHODS: A descriptive cross-sectional study was carried out. A structured interviewer-administered questionnaire was the tool for data collection. All the nurses (122) who gave their consent in the mission hospitals were studied. Data were analyzed using SPSS version 13. RESULTS: The mean age of the respondents was 32.0 +/- 8.9 years. The knowledge of injection safety among the respondents was poor (55.7%) while their practice of it was found to be good (48.4%) and excellent (47.5%). Knowledge was significantly influenced by the age, sex, and years of experience of the nurses. Twenty-eight (23.0%) and 40 (32.8%) respondents recap used needles regularly and sometimes respectively. Majority (71 [58.2%]) of the respondents had sustained needle stick injuries but only 4 (0.6%) respondents had a postexposure prophylaxis. CONCLUSION: This study showed that the knowledge of injection safety was poor among the nurses in mission hospitals in Benin City but their practice of injection safety was encouraging. There is need for the mission hospitals to organize regular training workshops on injection safety to improve the knowledge and practice of injection safety among their nurses. PMID- 22199047 TI - An audit of basic practical skills acquisition of final year medical students in a Nigerian medical school. AB - BACKGROUND/OBJECTIVE: Young medical graduates undertaking their housemanship are naturally expected to demonstrate reasonable competence in basic practical skills. Failure to do this may not only be a source of anxiety to the doctor but also potentially dangerous to the patient. The objective was to assess the level of exposure of final year medical students of a Nigerian medical school to basic practical skills. MATERIALS AND METHODS: This is a descriptive cross-sectional study. Structured questionnaires were distributed to a set (all) of 86 final year medical students of the University of Port Harcourt immediately after their last lecture in their final posting in medicine and surgery. The questionnaires listed some selected basic practical skills (e.g. phlebotomy, male urethral catheter insertion, etc.) that house officers are expected to be competent in. The students were asked to anonymously fill them and return same before leaving the lecture hall. RESULTS: Of the 86 students, 84 completed and returned the questionnaires, giving a 97.7% response rate. No student had performed an arterial puncture for an arterial blood sample. Seventy-six students (90.5%) had not inserted a naso-gastric tube. Only 14 (16.7%) students had successfully inserted more than 10 intravenous canulae. A significant number, 38 (45.2%), had never inserted a urinary catheter (for male patients) nor had any experience with bag/mask skills. Majority, 59 (70.2%) had had some experience with intravenous antibiotics administration. Forty-one (48.7%) students had had 6 or more successful attempts at venous blood sampling. CONCLUSION: The exposure level of final year medical students to basic practical skills was low. PMID- 22199048 TI - Teaching technical skills to medical students: beyond 'see one, do one, teach one'. PMID- 22199049 TI - Transurethral prostatectomy in human immunodeficiency virus-infected patients, morbidity and surgical risks in a developing economy. AB - Human immunodeficiency virus (HIV) infection is increasing world-wide and highly active antiretroviral treatment (HAAT) is allowing afflicted individuals to live near normal life span and acquire surgical diseases of the aged as in the unaffected population. This pose occupational hazards to operating surgeons especially in tropical Africa where the seroprevalence is so high that seroconversion in the medical staff contaminated with the virus is estimated to be as much as 15 times (per annum) more than what obtains in developed. A 63-year old man was admitted to our Hospital with urethral catheter in situ and having failed medical therapy, he opted for transurethral prostatectomy (TURP) which was done without any post-operative complication. He was known to be afflicted with human immunodeficiency virus and on treatment for 3 years. He also had a large but reducible inguinoscrotal hernia for 4 years attributed to lower urinary tract obstruction. He had a Lichtenstein repair of right inguinoscrotal hernia which was complicated by small hematoma that was evacuated. The risk of transmission and surgical morbidity during transurethral prostatectomy could be minimized by adequate universal precaution, pre-testing of all consented patients and wise selection of patients that would benefit from such surgical therapy. PMID- 22199050 TI - Editorial on transurethral prostatectomy in human immunodeficiency virus infected. PMID- 22199051 TI - Functional outcome of diaphyseal fractures of femur managed by closed intramedullary interlocking nailing in adults. AB - OBJECTIVE: To study the effectiveness, advantages, disadvantages and failure rates of closed intramedullary interlocking nailing of daiphyseal fractures of the femur in adults. MATERIALS AND METHODS: A total of 30 cases of diaphyseal femur fractures in adults, who have been treated with closed intramedullary interlocking nailing were studied from 2008 - 2010. Data was analyzed both with regards to the clinical and radiological outcome to evaluate the effectiveness, functional outcome and morbidity associated with the procedure. RESULTS: Average age of the patient was 27.4 years with male preponderance. Road traffic accidents were the most common mode of injury; middle third shaft fractures were most commonly seen (56.66%); comminuted and transverse fractures (63.33%) were the commonest fracture pattern. The union rate was 96.6%. Five patients had superficial infection, four had shortening of limb, and in two cases union was delayed. Excellent to good results were seen in 86.6% cases as per modified Klaus and Klemm criteria. CONCLUSION: Closed intramedullary interlocking nailing has now become the treatment of choice for closed diaphyseal fractures of femur in adults, especially those with high comminution, long spiral, and segmental fractures. Interlocking nail offers the added advantages of early joint mobilization, early weight bearing, early muscle rehabilitation, shortened hospital stay, and most importantly early return to work and prefracture state. PMID- 22199052 TI - The intricacies of impact factor and mid-term review of editorship. PMID- 22199053 TI - Measuring the severity of vitiligo. PMID- 22199055 TI - Vitiligo: Emerging paradigms. PMID- 22199054 TI - Camouflage for patients with vitiligo. AB - Vitiligo is known to be associated with social stigma and a decreased quality of life, especially when lesions are located over the face. While there are numerous treatment options for vitiligo, most of these need a long time to produce good cosmetic results. Camouflaging the skin lesions can be a useful option in such patients. The proper use of camouflage has been shown to improve the quality of life in patients with vitiligo. In this article, we discuss the different camouflage options available in vitiligo - products and techniques with their relative advantages and disadvantages. PMID- 22199056 TI - Melanocytorrhagy and apoptosis in vitiligo: connecting jigsaw pieces. AB - Vitiligo is an acquired depigmenting disorder characterized by a chronic and progressive loss of melanocytes from the epidermis and follicular reservoir. The mechanism of melanocyte disappearance has never been clearly understood. This review discussed the data supporting the theory of melanocytorrhagy and apoptosis as one of the primary defects underlying melanocyte loss. Theory of melanocytorrhagy proposes that non-segmental vitiligo is a primary melanocytorrhagic disorder with altered melanocyte responses to friction and possibly other types of stress, inducing their detachment and subsequent transepidermal loss. Melanocytes detachment induces apoptosis whereas adherence to basement membrane suppresses apoptosis. The study of apoptosis, mechanisms of its induction, and the ways to block apoptosis is one possible way to find both the causes of depigmentation and medications to prevent its progression. PMID- 22199057 TI - On the pathophysiology of vitiligo: possible treatment options. AB - Vitiligo is an acquired depigmenting disorder usually classified as non-segmental and segmental types with a higher incidence of the non-segmental ones. The cause of non-segmental vitiligo is still unknown. Currently, it is a dogma that there are several genes affecting the immune system and the pigment system that predisposes someone to develop vitiligo. A precipitating factor must then ellicit an interaction between the immune system and the melanocyte, resulting in destruction of the melanocyte population in discrete areas of the skin. Starting from the overlapping but distinct pathomechanisms, treatment should be finalized to the cellular targets and possibly related to the disease phase. PMID- 22199058 TI - Childhood vitiligo. AB - Childhood vitiligo is often encountered in dermatological practice. When present in infancy or early childhood, various nevoid and hereditary disorders are to be differentiated. In many cases, familial aggregation of the disease is seen and other autoimmune disorders may be associated. Segmental presentation is more common, and limited body surface area involvement is usual in this age group. Children with vitiligo often suffer from anxiety and depression because of their unusual appearance. Management of vitiligo in children is difficult as therapeutic options are restricted when compared to that in adult patients. Selection of treatment should be careful in these patients with the aim to achieve best results with minimal side effects as well as relieving patients' and parents' anxiety. PMID- 22199059 TI - Ultraviolet-based therapy for vitiligo: what's new? AB - Vitiligo is an ancient disease in which depigmented and hypopigmented macules appear on the skin. It is a disfiguring condition that may lead to severe psychological trauma. Among the many treatment modalities available for use in vitiligo, those using light therapy, and in particular ultraviolet (UV) light, are some of the most effective treatments. UV-based therapy includes phototherapy (narrowband UVB), photochemotherapy (psoralens with UVA), and targeted phototherapy (excimer laser and excimer lamp). It is important for any practitioner of UV-based therapy to understand the efficacy of each treatment type, as well as their respective adverse effects. In order to take full advantage of UV-based therapy, location, dosing, and photoadaptation must also be taken into account. This review discusses the various UV-based therapeutic options, adjuvant therapies, optimal dosing guidelines, appropriate patient selection, future treatment options, and recommendations based upon the current evidence and the authors' experience with vitiligo. PMID- 22199060 TI - Depigmentation therapies in vitiligo. AB - Depigmentation therapy in vitiligo is an option in those with extensive vitiligo who have failed to respond to medical therapy and have obvious cosmetic disfigurement due to intervening patchy pigmented areas. Various aspects of this therapy such as the cost, treatment time, course, permanency of depigmentation, side effects, and the possibility of repigmentation should first be discussed with the patient. At present, there is no ideal depigmenting therapy available, but many agents in the market have been in use for many years. Monobenzyl ether of hydroquinone (MBEH) is the mainstay and Food and Drug Administration (FDA) approved in USA but takes many months to depigment and is associated with local side effects and risk of repigmentation. Other agents which are also used are 4 methoxy phenol and 88% phenol. Physical therapies for depigmentation include Q switched ruby and alexandrite lasers and cryotherapy. Second-line agents which can be explored for depigmentation include imatinib mesylate, imiquimod, and diphencyprone. Many possible experimental agents are being explored like various phenol derivatives, melanoma vaccines, interferon gamma, busulfan, etc. A major lacuna still exists in this area and a lot more research is desirable to give satisfactory cosmesis to these patients with extensive vitiligo. PMID- 22199061 TI - Non-cultured epidermal suspension in vitiligo: from laboratory to clinic. AB - BACKGROUND: Medical treatments are ineffective in many patients and surgical methods have therefore been developed. OBJECTIVE: A review of autologous non cultured melanocyte grafting techniques is proposed to obtain a successful repigmentation of vitiligo macules. METHODS: Initially in 1992, we had developed a simplified grafting method which was carried out in the following two steps: production of blisters on the depigmented lesions by freezing with liquid nitrogen and injection in each blister of a non-cultured suspension of epidermal cells. The cellular suspension was obtained from samples of skin of the hair scalp after trypsinization. This very simple technique could be used at the dermatologist's clinic. Since 1998 (Olsson MJ, Juhlin L), quite comparable but improved and more sophisticated techniques have been proposed for the surgical treatment of vitiligo. These techniques require a laboratory set up to perform the melanocyte transplantation. The donor zone was usually taken on the gluteal region. The time of trypsinization was reduced to 60 minutes at 37 degrees C and the centrifuged cellular suspension added with hyaluronic acid (Van Geel) was directly applied on a dermabraded or laser abraded vitiligo lesions. RESULTS: Whatever the technique chosen, repigmentation was evident within 25 to 30 days. Coalescence of the pigmented areas was spontaneously observed or obtained after UVB radiation. It is obvious that the complete repigmentation occurred more rapidly with the recent techniques compared with the initial method, but the efficiency was quite similar. CONCLUSION: The use of non-cultured epidermal suspension appears to be an effective, safe, and simple method for treating patients with achromic areas lacking melanocytes. PMID- 22199062 TI - The effect of H1 and H2 receptor antagonists on melanogenesis. AB - BACKGROUND: Histamine was found to stimulate melanogenesis in cultured human melanocytes specifically mediated by histamine H 2 receptors via protein kinase A activation. Based on this finding, the effect of topically applied H 2 antagonist on UVB-irradiated Guinea pigs' skin was examined and found to be suppressive on the post-irradiation melanogenesis. AIMS: In this study, we tried to explore the role of topically applied H 1 and H 2 receptor antagonists, in inhibition of UVB induced melanization. METHODS: The effect of topically applied H 1 and H 2 receptor antagonists in inhibition of melanization was done clinically and histochemically using Fontana Masson and DOPA reactions compared with placebo. RESULTS: The post-irradiation pigmentation was found to be brownish/black instead of the original light brown color. This color change occurred below the shaved orange-red fur suggesting a switch of melanogenesis from pheomelanin to eumelanin. The induced pigmentation was suppressed by topically applied H 2 antagonist while both H 1 antagonist and vehicle had no effect. The microscopic examination showed that the keratinocytes in the H 2 antagonist-treated areas contained few melanosomes while the nearby dendrites are full of them. CONCLUSION: H 2 antagonists' inhibition of UVB-induced pigmentation is not only due to suppression of melanization but also due to a specific action on melanosomes' transfer. PMID- 22199064 TI - Survey of dermatologists' phototherapy practices for vitiligo. AB - BACKGROUND: The details of phototherapy practices for vitiligo have been rarely studied. OBJECTIVE: To explore the details of phototherapy practices for vitiligo among dermatologists. METHODS: A self-administered questionnaire about the details of phototherapy practices for vitiligo was distributed to all dermatologists attending a national general dermatology conference in Riyadh, Saudi Arabia, in 2008. RESULTS: Questionnaires were returned by 121 of 140 participants (response rate = 86.4%). The mean age of the respondents was 39.34 +/- 9.7 years, and 65% were males. One hundred eight of 110 (98.2%) respondents provided phototherapy to their vitiligo patients. The mean number of vitiligo patients who underwent phototherapy each week per dermatologist's office was 18 +/- 2.26. Narrowband ultraviolet B (NB-UVB) was the most common modality chosen to treat generalized vitiligo (84%). Excimer laser was the most common modality used to treat focal and segmental vitiligo (53% and 39%, respectively). Sixty eight percent of dermatologists administered a fixed starting dose of NB-UVB to all patients, whereas 31% used the minimal erythema dose as a guide. Fifty percent reported that NB-UVB resulted in better color matching with the surrounding skin. Thirty-seven percent favored NB-UVB over psoralen + ultraviolet A for a faster response, and 31% preferred NB-UVB for a pigmentation that is more durable. Forty-seven percent (50/106) of the respondents limited the number of phototherapy sessions to reduce the risks of skin cancer. However, no respondent reported any skin cancer incidence in phototherapy-treated vitiligo patients. CONCLUSION: There is a need for phototherapy guidelines for the treatment of vitiligo in patients with skin of color. PMID- 22199063 TI - Segmental vitiligo: a randomized controlled trial to evaluate efficacy and safety of 0.1% tacrolimus ointment vs 0.05% fluticasone propionate cream. AB - BACKGROUND: Segmental vitiligo is a small subset of vitiligo which responds very well to surgical therapy, but the role of medical treatment is not very well defined. AIM: To compare the efficacy and safety of 0.1% tacrolimus ointment versus 0.05% fluticasone propionate cream in patients of segmental vitiligo. METHODS: A randomized control trial was conducted in a tertiary care hospital on 60 consecutive patients with segmental vitiligo. Patients with segmental vitiligo exclusively or along with focal vitiligo, untreated or had not taken any topical treatment in previous 1 month or systemic treatment in previous 2 months, from May 2005 to January 2007, were block randomized into two groups. Children <5 years, pregnant and lactating women, and patients with known hypersensitivity to either drug and with associated multiple lesions of vitiligo were excluded. Group A (n = 29) patients were treated with tacrolimus 0.1% ointment twice daily and group B (n = 31) patients were treated with 0.05% of fluticasone cream once daily for 6 months. Response and side effects were recorded clinically and by photographic comparison. RESULTS: Nineteen patients treated with tacrolimus and 21 patients treated with fluticasone completed the treatment with median repigmentation of 15% and 5%, respectively, at 6 months (P = 0.38). Transient side effects limited to the application site were observed. CONCLUSIONS: Both tacrolimus and fluticasone propionate produce variable but overall unsatisfactory repigmentation in segmental vitiligo. PMID- 22199065 TI - Granulomatous and eccrinotropic lymphomatoid papulosis. AB - Lymphomatoid papulosis has been classically described as a chronic, recurrent and self-healing papulonecrotic or papulonodular skin eruption, which is clinically benign and histopathologically malignant. The histologic characteristics of lymphomatoid papulosis are suggestive of a cluster of differentiation 30+ (CD30+) malignant lymphoma, and it is best regarded as a low grade cutaneous T cell lymphoma (CTCL). We hereby report a case of granulomatous and eccrinotropic lymphomatoid papulosis in a 40- year-old male. There was no systemic involvement. The patient was treated with low dose oral methotrexate with good response. PMID- 22199066 TI - Unilateral linear punctate palmoplantar keratoderma. AB - Punctate palmoplantar keratoderma (Brauer-Buschke-Fischer syndrome) is a rare entity. Among punctate keratoderma, the linear presentation is much rarer, and exact incidence is not known. Unilateral linear punctate palmoplantar keratoderma is not yet reported in the literature. Here we report a case 12-year-old child presented with asymptomatic linear punctate plaque on the left sole and hand; histology revealed hyperkeratotic epidermis without columns of parakeratosis or cornoid lamella. PMID- 22199067 TI - Primary extramammary Paget's disease with extensive skeletal metastases. AB - Extramammary Paget's disease (EMPD) is an uncommon malignancy that is most commonly seen in the vulval area in postmenopausal women. Pruritus is the predominant symptom. The clinical presentation can be so nonspecific that it can be misdiagnosed as an inflammatory or infective condition. We report an elderly male patient with EMPD over the pubic area, which remained asymptomatic for 5 years; he presented with severe low backache of 5 months' duration. Skin biopsy and immunohistochemistry showed the typical epidermal changes and deep dermal invasion. Positron emission tomography scan revealed involvement of regional lymph nodes as well as extensive skeletal metastases. PMID- 22199068 TI - Neurocutaneous spectrum of multiple endocrine neoplasia-1. AB - Multiple endocrine neoplasia type I or Wermer syndrome is characterized by primary hyperparathyroidism, enteropancreatic endocrine tumor, and a pituitary pathology. A 35-year-old male presented with visual field defects, hyperprolactinemia, and hypogonadism. He also had multiple infraumbilical skin colored nodules. A syndromal association of Wermer syndrome was derived using the dermal, pituitary, parathyroid, and gastrointestinal hormonal manifestations of the tumor. The radiological and histological findings of lesion which underwent biopsy are discussed. The presence of collagenomas, lipomas, and hypopigmented macules in a patient with neuroendocrine symptoms should raise the suspicion of an underlying multiple endocrine neoplasia. PMID- 22199069 TI - Hyperhidrosis, vesicles, and papules over the nose: granulosis rubra nasi. PMID- 22199070 TI - Comparative study of dietary habits between acne patients and a healthy cohort. PMID- 22199071 TI - Can highly active antiretroviral therapy unmask leprosy? A case of type 1 lepra reaction in a HIV-seropositive patient. PMID- 22199072 TI - Epidermal inclusion cyst or giant milium of the nipple. PMID- 22199073 TI - A case of Parry-Romberg syndrome with congenital heart disease. PMID- 22199074 TI - Idiopathic acquired persistent true partial to total leukonychia. PMID- 22199075 TI - Bone marrow transplantation improves symptoms of congenital erythropoietic porphyria even when done post puberty. PMID- 22199076 TI - Colocalization of mucosal vitiligo and oral pemphigus vulgaris. PMID- 22199078 TI - Excellent response of infantile hemangioma associated with PHACES syndrome to propranolol. PMID- 22199077 TI - Majocchi's granuloma over the face. PMID- 22199079 TI - In vivo antinuclear antibodies of the skin. PMID- 22199080 TI - A solitary facial tumor with erosion on an 81-year-old oriental woman. Atypical fibroxanthoma. PMID- 22199081 TI - Acute hemorrhagic edema of infancy: a report of two cases. AB - Acute hemorrhagic edema of infancy is one of the clinical forms of leukocytoclastic vasculitis seen in children. The condition runs a benign course. We report two male children who presented with upper respiratory tract infection followed by limb swelling and purpuric and ecchymotic lesions on the skin. Skin biopsy revealed leukocytoclastic vasculitis in both patients. In both cases, the lesions resolved completely without any sequelae. PMID- 22199082 TI - A case of bacillary angiomatosis developed at a burn site. AB - Bacillary Angiomatosis (BA) is frequently seen in patients with human immunodeficiency virus (HIV)-induced immunodeficiency. Our patient was a case that developed granuloma-like lesions in the area of a burn, 8 days after being burnt on the upper right arm by scalding water. No indication of immune deficiency was observed and no history of direct contact with cats was evident. By the sixth day of the patient's admission to our clinic, some of the lesions had reached a diameter of 2.5 cm. An excision biopsy was carried out from the lesions present on the patient. Electron microscopy revealed solitary bacilli located close to the capillary wall. Oral erythromycin treatment was implemented at 250 mg, 4 times a day for 2.5 months. Within this period of treatment, the lesions regressed completely, and a complete cure was achieved. This case demonstrates that BA must be considered in the differential diagnosis of both HIV infected and immunocompetent patients. PMID- 22199083 TI - Lymphangioma circumscriptum-like presentation of breast carcinoma. PMID- 22199084 TI - Coexistence of acquired hypertrichosis and scalp alopecia in a patient with infiltrating ductal carcinoma. PMID- 22199085 TI - Lymphangiectasia of the vulva, treatment with CO2 laser. PMID- 22199086 TI - Erythema gyratum repens and rheumatoid arthritis: an unrecognized association? PMID- 22199087 TI - A new site of milia en plaque. PMID- 22199088 TI - Zinc responsive acrodermatitis in nephrotic syndrome: a rare presentation. PMID- 22199089 TI - Giant linear syringocystadenoma papilliferum of the back. PMID- 22199090 TI - Asymptomatic nodule over the shin. Cutaneous focal mucinosis (CFM). PMID- 22199091 TI - Cognitive neuroscience test reliability and clinical applications for schizophrenia. PMID- 22199092 TI - Optimization of a goal maintenance task for use in clinical applications. AB - BACKGROUND: We sought to develop a Dot Pattern Expectancy task (DPX) to assess goal maintenance for use in clinical trials. Altering the standard task created 5 versions of the DPX to compare-a standard version and 4 others. Alterations in the interstimulus interval (ISI) length and the strength of a learned prepotent response distinguished the different tasks. These adjustments were designed to decrease administration time and/or improve reliability of the data. METHODS: We determined participant eligibility in an initial session (the first of 3) using clinical interviewing tools. The initial session also included a demographic assessment and assessments of community functioning and symptom severity. All versions of the DPX were administered, across 3 sessions. Specific deficits on the context processing compared with difficulty control condition were evaluated using mixed-effects logistic regression within a hierarchical linear model. RESULTS: We analyzed the data from 136 control participants and 138 participants with schizophrenia. Relative to a difficulty control condition, patients performed worse than controls on context processing conditions that required goal maintenance. ISI did not predict errors. Stronger prepotency was associated with increased errors in the difficulty control relative to context processing condition for controls, which improved the interpretability of findings for patients. Reliability was acceptable for a version of the task with a 10-minute running time. CONCLUSIONS: The best compromise between task duration and interpretability occurred on a version with a short ISI and a strong prepotency. PMID- 22199093 TI - Diabetes prevention: a call to action. PMID- 22199094 TI - Commercial serological tests for the diagnosis of active tuberculosis in India: time for introspection. PMID- 22199095 TI - The hunt for genetic risk among Mysore, south India patent ductus arteriosus patients. PMID- 22199096 TI - The challenge of building rural health services. PMID- 22199097 TI - Relationship between metabolic syndrome & obstructive sleep apnoea in a hospital based urban population. PMID- 22199099 TI - Hand hygiene: back to the basics of infection control. AB - Health care associated infections are drawing increasing attention from patients, insurers, governments and regulatory bodies. This is not only because of the magnitude of the problem in terms of the associated morbidity, mortality and cost of treatment, but also due to the growing recognition that most of these are preventable. The medical community is witnessing in tandem unprecedented advancements in the understanding of pathophysiology of infectious diseases and the global spread of multi-drug resistant infections in health care set-ups. These factors, compounded by the paucity of availability of new antimicrobials have necessitated a re-look into the role of basic practices of infection prevention in modern day health care. There is now undisputed evidence that strict adherence to hand hygiene reduces the risk of cross-transmission of infections. With "Clean Care is Safer Care" as a prime agenda of the global initiative of WHO on patient safety programmes, it is time for developing countries to formulate the much-needed policies for implementation of basic infection prevention practices in health care set-ups. This review focuses on one of the simplest, low cost but least accepted from infection prevention: hand hygiene. PMID- 22199098 TI - Sickle cell disease in Middle East Arab countries. AB - The sickle cell (HbS) gene occurs at a variable frequency in the Middle Eastern Arab countries, with characteristic distribution patterns and representing an overall picture of blood genetic disorders in the region. The origin of the gene has been debated, but studies using beta-globin gene haplotypes have ascertained that there were multiple origins for HbS. In some regions the HbS gene is common and exhibits polymorphism, while the reverse is true in others. A common causative factor for the high prevalence and maintenance of HbS and thalassaemia genes is malaria endemicity. The HbS gene also co-exists with other haemoglobin variants and thalassaemia genes and the resulting clinical state is referred to as sickle cell disease (SCD). In the Middle Eastern Arab countries, the clinical picture of SCD expresses two distinct forms, the benign and the severe forms, which are related to two distinct beta-globin gene haplotypes. These are referred to as the Saudi-Indian and the Benin haplotypes, respectively. In a majority of the Middle Eastern Arab countries the HbS is linked to the Saudi-Indian haplotype, while in others it is linked to the Benin haplotype. This review outlines the frequency, distribution, clinical feature, management and prevention as well as gene interactions of the HbS genes with other haemoglobin disorders in the Middle Eastern Arab countries. PMID- 22199100 TI - Mutations of TFAP2B in congenital heart disease patients in Mysore, South India. AB - BACKGROUND & OBJECTIVES: Cardiac malformations in the young constitute a major portion of clinically significant birth defects. Congenital heart disease (CHD) is a common congenital cardiac birth defect, affecting nearly 1 per cent of all live births. Patent ductus arteriosus (PDA) is clinically significant foetal circulation anomaly, second most common form of CHD which constitutes approximately 10 per cent of total CHDs. The study aimed to screen for TFAP2B mutations in CHD patients of Mysore. METHODS: With informed consent, 100 clinically diagnosed CHD patients and 50 healthy controls in Mysore, south India, were recruited for the analysis of screening of mutations. MassARRAY analysis of 5 prominent mutations of TFAP2B was performed. RESULTS: The analysis did not show any of the five mutations of TFAP2B screened by massARRAY in patients and controls, indicating that these mutations were not involved in the manifestation of CHD in the patients at Mysore, south India. INTERPRETATION & CONCLUSIONS: The findings suggest the lack of involvement of known mutations of TFAP2B with syndromic or nonsyndromic CHDs in Mysore patients. PMID- 22199101 TI - 'First we go to the small doctor': first contact for curative health care sought by rural communities in Andhra Pradesh & Orissa, India. AB - BACKGROUND & OBJECTIVES: Against the backdrop of insufficient public supply of primary care and reports of informal providers, the present study sought to collect descriptive evidence on 1 st contact curative health care seeking choices among rural communities in two States of India - Andhra Pradesh (AP) and Orissa. METHODS: The cross-sectional study design combined a Household Survey (1,810 households in AP; 5,342 in Orissa), 48 Focus Group Discussions (19 in AP; 29 in Orissa), and 61 Key Informant Interviews with healthcare providers (22 in AP; 39 in Orissa). RESULTS: In AP, 69.5 per cent of respondents accessed non-degree allopathic practitioners (NDAPs) practicing in or near their village; in Orissa, 40.2 per cent chose first curative contact with NDAPs and 36.2 per cent with traditional healers. In AP, all NDAPs were private practitioners, in Orissa some pharmacists and nurses employed in health facilities, also practiced privately. Respondents explained their choice by proximity and providers' readiness to make house-calls when needed. Less than a quarter of respondents chose qualified doctors as their first point of call: mostly private practitioners in AP, and public practitioners in Orissa. Amongst those who chose a qualified practitioner, the most frequent reason was doctors' quality rather than proximity. INTERPRETATION & CONCLUSIONS: The results of this study show that most rural persons seek first level of curative healthcare close to home, and pay for a composite convenient service of consulting-cum-dispensing of medicines. NDAPs fill a huge demand for primary curative care which the public system does not satisfy, and are the de facto first level access in most cases. PMID- 22199102 TI - Prevalence of metabolic syndrome in a north Indian hospital-based population with obstructive sleep apnoea. AB - BACKGROUND & OBJECTIVES: Obstructive sleep apnoea (OSA) is known to be associated with cardiovascular risk factors and metabolic syndrome (MS). The burden of MS in patients with OSA in India is unknown. We investigated the prevalence of MS and its components in a cross-sectional study in patients with and without OSA in a hospital-based population of a tertiary health care centre in New Delhi, India. METHODS: Consecutive patients undergoing overnight polysomnography in the Sleep Laboratory of the Department of Internal Medicine of All India Institute of Medical Sciences (AIIMS) hospital, New Delhi, were studied. Anthropometry and body composition analysis, blood pressure (BP), fasting blood glucose, insulin resistance by homeostasis model assessment (HOMA-IR) and fasting blood lipid profile were measured. MS was defined using the National Cholesterol Education Program Adult treatment panel III criteria, with Asian cut-off values for abdominal obesity. RESULTS: Of the 272 subjects recruited, 187 (82%) had OSA [apnoea-hypopnoea index (AHI)>5 events/h] while 40 (18%) had a normal sleep study. Prevalence of MS in OSA patients was 79 per cent compared to 48 per cent in non-OSA individuals [OR 4.15, (2.05-8.56), P<0.001]. Prevalence of OSA in mild, moderate and severe OSA was 66, 72 and 86 per cent, respectively (P<0.001). Patients with OSA were more likely to have higher BP [OR: 1.06 (1.02-1.11)], fasting insulin [OR: 1.18 (1.05-1.32)], HOMA-IR [OR: 1.61 (1.11-2.33)] and waist circumference [OR: 1.20 (1.13-1.27)]. INTERPRETATION & CONCLUSIONS: Our findings suggest that OSA is associated with a 4-fold higher occurrence of MS than patients without OSA. The prevalence of MS increases with increasing severity of OSA, therefore, early detection will be beneficial. PMID- 22199103 TI - Study of sense of coherence health promoting behavior in north Indian students. AB - BACKGROUND & OBJECTIVES: With advances in knowledge about health promotion, public health professionals are in search for the determinants of personal health behaviours. This study was carried out to explore the level of engagement of north Indian students in health promoting behaviours; to determine their sense of coherence scores; and to ascertain the determinants of health promoting behaviours of these students. METHODS: A cross-sectional study was done in four randomly selected colleges of Chandigarh during 2007-2008 in 200 students (100 male, 100 female). Their health promoting lifestyle profile (HPLP) and sense of coherence (SOC) scores were estimated using interviews. The data were analyzed using Pearson's product moment correlation, and also stepwise linear regression analysis. RESULTS: Mean HPLP and SOC scores of the students were 138.69 and 130.87, respectively. Females cared more about their health than males. Male students were more involved in physical activities. There was a linear correlation between the total SOC and HPLP scores (r=0.3). Female students (63%) consulted doctors more than males (50%) and washed their hands more regularly (P<0.05). Only 13 per cent students practiced yoga regularly. Female students had more meaningful relationships with friends and had more faith in God. Regression equation revealed that the two independent variables (SOC and age) accounted for 10.8 per cent of the variance in HPLP. INTERPRETATION & CONCLUSION: Students with higher SOC scores had higher HPLP scores. Female students were more health conscious than male students. In general, college students in Chandigarh had a good health promoting lifestyle and good sense of coherence. PMID- 22199104 TI - Pulmonary function studies in young healthy Malaysians of Kelantan, Malaysia. AB - BACKGROUND & OBJECTIVES: Pulmonary function tests have been evolved as clinical tools in diagnosis, management and follow up of respiratory diseases as it provides objective information about the status of an individual's respiratory system. The present study was aimed to evaluate pulmonary function among the male and female young Kelantanese Malaysians of Kota Bharu, Malaysia, and to compare the data with other populations. METHODS: A total of 128 (64 males, 64 females) non-smoking healthy young subjects were randomly sampled for the study from the Kelantanese students' population of the University Sains Malaysia, Kota Bharu Campus, Kelantan, Malaysia. The study population (20-25 yr age group) had similar socio-economic background. Each subject filled up the ATS (1978) questionnaire to record their personal demographic data, health status and consent to participate in the study. Subjects with any history of pulmonary diseases were excluded from the study. RESULTS: The pulmonary function measurements exhibited significantly higher values among males than the females. FEV 1% did not show any significant inter-group variation probably because the parameter expresses FEV 1 as a percentage of FVC. FVC and FEV 1 exhibited significant correlations with body height and body mass among males whereas in the females exhibited significant correlation with body mass, body weight and also with age. FEV 1% exhibited significant correlation with body height and body mass among males and with body height in females. FEF 25-75% did not show any significant correlation except with body height among females. However, PEFR exhibited significant positive correlation with all the physical parameters except with age among the females. On the basis of the existence of significant correlation between different physical parameters and pulmonary function variables, simple and multiple regression norms have been computed. INTERPRETATION & CONCLUSIONS: From the present investigation it can be concluded that Kelantanese Malaysian youths have normal range of pulmonary function in both the sexes and the computed regression norms may be used to predict the pulmonary function values in the studied population. PMID- 22199105 TI - A pilot study on the effect of telmisartan & ramipril on 24 h blood pressure profile & dipping pattern in type 1 diabetes patients with nephropathy. AB - BACKGROUND & OBJECTIVES: Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) have been used to normalize the blood pressure and the dipping pattern in patients with type 1 diabetes mellitus (T1DM) and nephropathy. However, there are no data on the effect of the dual blockade on the dipping pattern in these subjects. We therefore, carried out this study to evaluate the effect of administrating an ACEI followed by ARB in the optimum doses in T1DM patients with nephropathy on 24 h blood pressure (BP) profile and nocturnal dipping pattern. METHODS: An open label interventional pilot study was done during a one year period involving 30 consecutive patients who were treated with telmisartan 80 mg (0800-1000 h) for eight weeks followed by addition of ramipril 10 mg (1200-1400 h) for the next eight weeks. Ambulatory BP, dipping pattern and albumin excretion rate were studied after each phase. Twenty patients were hypertensive and 10 patients had macro- and 20 patients had microalbuminuria. RESULTS: Telmisartan produced a fall in the clinic BP by 4/1.3 mm Hg (P<0.05 and P<0.362, respectively), 2/1.9 mm Hg in the mean 24 h BP, 1.4/1.1 mm Hg in the day BP and 3.7/3 mm Hg in the trough BP. Addition of ramipril to telmisartan produced a further reduction of 6.3/5.9 mm Hg in the clinic BP (P<0.001 for both), 4.3/4.2 mm Hg in the mean 24 h BP (P<0.01 and P<0.0001, respectively), 5.8/3.9 mm Hg in the day BP (P<0.01 for both), 4.2/2.5 mm Hg in the trough BP, with a reduction of clinic SBP and DBP of 10.3/7.2 mm Hg from the baseline. Telmisartan restored normal systolic dipping pattern in 33.3 per cent of the nondippers (P<0.01) but addition of ramipril was not complimentary. Hyperkalamia (>5.5 mmol/l) was observed only in 2 patients towards the end of the study. INTERPRETATION & CONCLUSIONS: The dual blockade with telmisartan and ramipril had complimentary effect on lowering of the BP, however, similar beneficial effect on the nocturnal dipping was not observed. Further studies with large number of subjects with longer duration of follow-up are required to validate these observations. PMID- 22199106 TI - Assessing the adhesion of putative indigenous probiotic lactobacilli to human colonic epithelial cells. AB - BACKGROUND & OBJECTIVES: Adherence of bacteria to epithelial cells and mucosal surfaces is a key criterion for selection of probiotic. We assessed the adhesion property of selected indigenous probiotic Lactobacillus strains based on their hydrophobicity and ability to adhere to human epithelial cells. METHODS: Five human faecal Lactobacillus isolates, one from buffalo milk and one from cheese were assessed for hydrophobicity following the microbial adhesion to hydrocarbons (MATH) method and colonization potentials based on their adherence to Caco2 and HT-29 colonic adenocarcinomal human intestinal epithelial cell lines. Lactobacillus strains that adhered to Caco2 and HT-29 cell lines were quantified by plating after trypsinization and simultaneously the adhered bacteria were also examined microscopically after staining with Geimsa stain and counted in different fields. RESULTS: Among the tested faecal isolates, L. plantarum Lp91 showed maximum percentage hydrophobicity (35.73+/-0.40 for n-hexadecane and 34.26+/-0.63 for toluene) closely followed by L. plantarum Lp9 (35.53+/-0.29 for n-hexadecane and 33.00+/-0.57 for toluene). Based on direct adhesion to epithelial cells, L. plantarum Lp91 was the most adhesive strain to HT-29 and Caco2 cell lines with per cent adhesion values of 12.8 +/- 1.56 and 10.2 +/- 1.09, respectively. L. delbrukeii CH4, was the least adhesive with corresponding figures of 2.5 +/- 0.37 and 2.6 +/- 0.20 per cent on HT-29 and Caco2 cell lines. Adhesion of the six isolated Lactobacillus strain to HT-29 cell and Caco2 lines as recorded under microscope varied between 131.0 +/- 13.9 (Lp75) to 342.7 +/- 50.52 (Lp91) and 44.7 +/- 9.29 (CH4) to 315.7+/- 35.4 (Lp91), respectively. INTERPRETATION & CONCLUSIONS: Two Indigenous probiotic Lactobacillus strains (Lp9, Lp91) demonstrated their ability to adhere to epithelial cell and exhibited strong hydrophobicity under in vitro conditions, and thus could have better prospects to colonize the gut with extended transit. PMID- 22199107 TI - Prolonged expression of MHC class I - peptide expression in bone marrow derived retrovirus transfected matured dendritic cells by continuous centrifugation in the presence of IL-4. AB - BACKGROUND & OBJECTIVES: Dendritic cells (DCs) are potent antigen presenting cells which proceed from immature to a mature stage during their differentiation. There are several methods of obtaining long lasting mature antigen expressing DCs and different methods show different levels of antigen expressions. We investigated bone marrow derived DCs for the degree of maturation and genetically engineered antigen presentation in the presence of interleukin-4 (IL-4) as a maturity enhancer. METHODS: DCs and transfected retrovirus were cultured together in the presence of granulocyte-macrophage colony stimulating factor (GMCSF)-IL4, GMCSF +IL4, lipopolysaccharide (LPS). B 7.1, B7.2 and CD11c were measured by the degree of immune fluorescence using enhanced green fluorescent protein (EGFP) shuttled retrovirus transfected antigen. Degree of MHC class I molecule with antigen presentation of antigen was also evaluated by fluorescence activated cell sorting. The antigen presenting capacity of transfected DCs was investigated. Bone marrow DCs were generated in the presence of GMCSF and IL-4 in vitro. Dividing bone marrow cells were infected with EGFP shuttled retrovirus expressing SSP2 by prolonged centrifugation for three consecutive days from day 5, 6 and 7 and continued to culture in the presence of GMSCF and IL-4 until day 8. RESULTS: IL-4 as a cytokine increased the maturation of retrovirus transfected DCs by high expression of B 7-1 and B 7-2. Also, IL-4 induced DC enhanced by the prolonged centrifugation and it was shown by increased antigen presentation of these dendric cells as antigen presenting cell (APC). Cytolytic effects were significantly higher in cytotoxic T cell response (CTLs) mixed with transfected DCs than CTLs mixed with pulsed DCs. INTERPRETATION & CONCLUSIONS: There was an enhanced antigen presentation by prolonged expression of antigen loaded MHC class I receptors in DCs in the presence of IL-4 by prolonged centrifugation. PMID- 22199108 TI - Characterization of low molecular weight antimicrobial peptide from human female reproductive tract. AB - BACKGROUND & OBJECTIVES: The mechanisms that protect female upper genital tract from ascending infection by microbes present in vagina are only partially understood. It is expected that epithelial cells in mucosal surfaces and their secretions directly interfere with microbial colonization and invasion. This study was aimed to demonstrate the expression of 2 kDa antimicrobial peptide which was identified and purified from female genital tract tissues using chromatographic techniques. METHODS: Low molecular weight proteins were isolated from human female reproductive tract tissues obtained from premenopausal women. Antimicrobial activity of these LMW proteins was assessed against different reproductive tract pathogens viz., Neisseria gonorrhoeae, Group B streptococcus, Gardnerella vaginalis, Escherechia coli and Candida albicans. The expression of these peptides were also documented in reproductive tract tissues with the help of hyperimmune sera raised against the rabbits. The purified peptide was characterized by N-terminal sequencing. RESULTS: Immunohistochemical and immunofluorescence studies demonstrated that 2 kDa peptide was expressed in the stratified squamous epithelial cells of the ectocervix while it was absent in columnar epithelial cells of upper genital tract. Upregulation of the expression of this peptide was observed in patients of chronic non-specific cervicitis and acute on chronic cervicitis. This purified antimicrobial peptide also showed broad spectrum antimicrobial activity against different reproductive tract pathogens. INTERPRETATION & CONCLUSIONS: Considering the emerging bacterial resistance against conventional antibiotics, isolation and understanding of the expression of antimicrobial peptides from female reproductive tissue extracts may provide some leads towards the development of strategies for the treatment of reproductive tract infections. PMID- 22199109 TI - Non invasive real-time monitoring of bacterial infection & therapeutic effect of anti-microbials in five mouse models. AB - BACKGROUND & OBJECTIVES: In vivo imaging system has contributed significantly to the understanding of bacterial infection and efficacy of drugs in animal model. We report five rapid, reproducible, and non invasive murine pulmonary infection, skin and soft tissue infection, sepsis, and meningitis models using Xenogen bioluminescent strains and specialized in vivo imaging system (IVIS). METHODS: The progression of bacterial infection in different target organs was evaluated by the photon intensity and target organ bacterial counts. Genetically engineered bioluminescent bacterial strains viz. Staphylococcus aureus Xen 8.1, 29 and 31; Streptococcus pneumoniae Xen 9 and 10 and Pseudomonas aeruginosa Xen-5 were used to induce different target organs infection and were validated with commercially available antibiotics. RESULTS: The lower limit of detection of colony forming unit (cfu) was 1.7-log10 whereas the lower limit of detection of relative light unit (RLU) was 4.2-log10 . Recovery of live bacteria from different target organs showed that the bioluminescent signal correlated to the live bacterial count. INTERPRETATION & CONCLUSIONS: This study demonstrated the real time monitoring and non-invasive analysis of progression of infection and pharmacological efficacy of drugs. These models may be useful for pre-clinical discovery of new antibiotics. PMID- 22199110 TI - Mycobacterium indicus pranii as stand-alone or adjunct immunotherapeutic in treatment of experimental animal tuberculosis. AB - BACKGROUND & OBJECTIVES: Mycobacterium w (M.w) is a saprophytic cultivable mycobacterium and shares several antigens with M. tuberculosis. It has shown good immunomodulation in leprosy patients. Hence in the present study, the efficacy of M.w immunotherapy, alone or in combination with multi drug chemotherapeutic regimens was investigated against drug sensitive M. tuberculosis H37Rv and three clinical isolates with variable degree of drug resistance in mice. METHODS: BALB/c mice were infected with M. tuberculosis H37Rv (susceptible to all first and second line drugs) and three clinical isolates taken from the epository of the Institute. The dose of 200 bacilli was used for infection via respiratory route in an aerosol chamber. Chemotherapy (5 days/wk) was given one month after infection and the vaccinated group was given a dose of 1x107 bacilli by subcutaneous route. Bacterial load was measured at 4 and 6 wk after initiation of chemotherapy. RESULTS: M.w when given along with chemotherapy (4 and 6 wk) led to a greater reduction in the bacterial load in lungs and other organs of TB infected animals compared to. However, the reduction was significantly (P<0.05) more in terms of colony forming units (cfu) in both organs (lungs and spleen). CONCLUSION: M.w (as immunomodulator) has beneficial therapeutic effect as an adjunct to chemotherapy. PMID- 22199111 TI - Vancomycin resistance among methicillin resistant Staphylococcus aureus isolates from intensive care units of tertiary care hospitals in Hyderabad. AB - BACKGROUND & OBJECTIVES: Multidrug resistant methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of nosocomial and community acquired infections and is on the rise. The glycopeptide vancomycin has been proposed as the drug of choice for treating such infections. The present study aimed at identifying the vancomycin resistance both phenotypically and genotypically among the MRSA isolates from two tertiary care hospitals in Hyderabad, south India. METHODS: MRSA were isolated and identified from different clinical samples collected from ICUs of tertiary care hospitals in Hyderabad using conventional methods. Antibiogram of the isolates and vancomycin MIC were determined following CLSI guidelines. vanA was amplified by PCR using standard primers. RESULTS: All vancomycin resistant S. aureus (VRSA) isolates were MRSA. The VRSA isolates were positive for vanA gene, except one which was negative. All VRSA had a vancomycin MIC in the range of 16-64 mg/l. INTERPRETATION & CONCLUSIONS: The increase in vancomycin resistance among MRSA and excessive use of antimicrobial agents have worsened the sensitivity. Larger studies need to be done in various geographical regions of the country to better define the epidemiology, mechanism of vancomycin resistance in S. aureus and its clinical implications. PMID- 22199112 TI - Antiparasitic activity of plumericin & isoplumericin isolated from Plumeria bicolor against Leishmania donovani. AB - BACKGROUND & OBJECTIVES: The severe toxicity, exorbitant cost and emerging resistance of Leishmania species against most of the currently used drugs underscores the urgent need for the alternative drugs. The present study evaluates in vitro anti-leishmanial activity of Plumeria bicolor and its isolated compounds. METHODS: The in vitro anti-parasitic activity of chloroform extract of Plumeria bicolor, plumericin and isoplumericin were tested alongwith appropriate controls against promastigote and amastigote forms of Leishmania donovani using 96 well microtiter plate. The concentration used for assessing the anti leishmanial activity of extract of Plumeria bicolor and both isolated compounds were 100 MUg/ml and 15 MUM, respectively. The viability of the cells was assessed by MTT assay. The cytotoxicity of these compounds was performed against J774G8 murine macrophage cells lines at the concentration of 30 MUM. RESULTS: The Plumeria bicolor extract showed activity with the IC 50 of 21+/-2.2 and 14+/-1.6 MUg/ml against promastigote and amastigote forms of L. donovani, respectively. Plumericin consistently showed high activity with the IC 50 of 3.17+/-0.12 and 1.41+/-0.03 MUM whereas isoplumericin showed the IC50 of 7.2+/-0.08 MUM and 4.1+/ 0.02 MUM against promastigote and amastigote forms, respectively. Cytotoxic effect of the chloroform extract of P. bicolor, plumericin and isoplumericin was evaluated in murine macrophage (J774G8) model with CC50 value of 75+/-5.3 MUg/ml, 20.6+/-0.5 and 24+/-0.7 MUM, respectively. INTERPRETATION & CONCLUSIONS: Our results indicated that plumericin showed more potent activity than isoplumericin and might be a promising anti-leishmanial agent against L. donovani. PMID- 22199113 TI - Preventive action of curcumin in experimental acute pancreatitis in mouse. AB - BACKGROUND & OBJECTIVES: Curcuma longa (turmeric) has a long history of use in Ayurvedic medicine as a treatment for inflammatory conditions. The purpose of the present study was to investigate the preventive effects of curcumin against acute pancreatitis (AP) induced by caerulein in mouse and to elucidate possible mechanism of curcumin action. METHODS: Curcumin (50 mg/kg/day) was intraperitoneally injected to Kun Ming male mice for 6 days, followed by injection of caerulein to induce AP. GW9662 (0.3 mg/kg), a specific peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist, was intravenously injected along with curcumin. Murine macrophage RAW264.7 cells were treated with 100 MUmol/l curcumin for 2 h, and then stimulated with 0.1 MU g/ml lipopolysaccharide (LPS). Serum amylase and transaminase levels were measured at 10 h after AP. TNF-alpha level in mouse serum and cell culture medium were detected by ELISA. Expression of PPARgamma and NF-kappaB were analyzed by RT-PCR and Western blot. RESULTS: Curcumin significantly decreased the pancreas injury and reversed the elevation of serum amylase, ALT and AST activities and TNF-alpha level in mice with AP. Curcumin treatment inhibited the elevation of NF-kappaB p65 in the nucleus of mouse pancreas AP group and RAW264.7 cells, but significantly increased the expression of PPARgamma. GW9662 could abolish the effects of curcumin on serum levels of amylase, ALT, AST, TNF-alpha, and NF kappaB level. INTERPRETATION & CONCLUSIONS: Our results suggest that curcumin could attenuate pancreas tissue and other organ injury by inhibiting the release of inflammatory cytokine TNF-alpha. These effects may involve upregulation of PPARgamma and subsequent downregulation of NF-kappaB. PMID- 22199114 TI - Framework for estimating tumour parameters using thermal imaging. AB - BACKGROUND & OBJECTIVES: Non-invasive and non-ionizing medical imaging techniques are safe as these can be repeatedly used on as individual and are applicable across all age groups. Breast thermography is a non-invasive and non-ionizing medical imaging that can be potentially used in breast cancer detection and diagnosis. In this study, we used breast thermography to estimate the tumour contour from the breast skin surface temperature. METHODS: We proposed a framework called infrared thermography based image construction (ITBIC) to estimate tumour parameters such as size and depth from cancerous breast skin surface temperature data. Markov Chain Monte Carlo method was used to enhance the accuracy of estimation in order to reflect clearly realistic situation. RESULTS: We validated our method experimentally using Watermelon and Agar models. For the Watermelon experiment error in estimation of size and depth parameters was 1.5 and 3.8 per cent respectively. For the Agar model it was 0 and 8 per cent respectively. Further, thermal breast screening was done on female volunteers and compared it with the magnetic resonance imaging. The results were positive and encouraging. INTERPRETATION & CONCLUSIONS: ITBIC is computationally fast thermal imaging system and is perhaps affordable. Such a system will be useful for doctors or radiologists for breast cancer diagnosis. PMID- 22199115 TI - Long-term follow up of clients from a community-based opioid substitution therapy programme in Manipur. PMID- 22199116 TI - Variants in the 3' untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner. AB - AIMS: Heterozygous mutations in KCNQ1 cause type 1 long QT syndrome (LQT1), a disease characterized by prolonged heart rate-corrected QT interval (QTc) and life-threatening arrhythmias. It is unknown why disease penetrance and expressivity is so variable between individuals hosting identical mutations. We aimed to study whether this can be explained by single nucleotide polymorphisms (SNPs) in KCNQ1's 3' untranslated region (3'UTR). METHODS AND RESULTS: This study was performed in 84 LQT1 patients from the Academic Medical Center in Amsterdam and validated in 84 LQT1 patients from the Mayo Clinic in Rochester. All patients were genotyped for SNPs in KCNQ1's 3'UTR, and six SNPs were found. Single nucleotide polymorphisms rs2519184, rs8234, and rs10798 were associated in an allele-specific manner with QTc and symptom occurrence. Patients with the derived SNP variants on their mutated KCNQ1 allele had shorter QTc and fewer symptoms, while the opposite was also true: patients with the derived SNP variants on their normal KCNQ1 allele had significantly longer QTc and more symptoms. Luciferase reporter assays showed that the expression of KCNQ1's 3'UTR with the derived SNP variants was lower than the expression of the 3'UTR with the ancestral SNP variants. CONCLUSION: Our data indicate that 3'UTR SNPs potently modify disease severity in LQT1. The allele-specific effects of the SNPs on disease severity and gene expression strongly suggest that they are functional variants that directly alter the expression of the allele on which they reside, and thereby influence the balance between proteins stemming from either the normal or the mutant KCNQ1 allele. PMID- 22199117 TI - Increased short-term risk of thrombo-embolism or death after interruption of warfarin treatment in patients with atrial fibrillation. AB - AIMS: It is presently unknown whether patients with atrial fibrillation (AF) are at increased risk of thrombo-embolic adverse events after interruption of warfarin treatment. The purpose of this study was to assess the risk and timing of thrombo-embolism after warfarin treatment interruption. METHODS AND RESULTS: A retrospective, nationwide cohort study of all patients in Denmark treated with warfarin after a first hospitalization with AF in the period 1997-2008. Incidence rate ratios (IRRs) of thrombo-embolic events and all-cause mortality were calculated using the Poisson regression analyses. In total, 48 989 AF patients receiving warfarin treatment were included. Of these, 35 396 patients had at least one episode of warfarin treatment interruption. In all, 8255 deaths or thrombo-embolic events occurred during treatment interruption showing an initial clustering of events with 2717, 835, 500, and 427 events occurring during 0-90, 91-180, 181-270, and 271-360 days after treatment interruption, respectively. Correspondingly, the crude incidence rates were 31.6, 17.7, 12.3, and 11.4 events per 100 patient-years. In a multivariable analysis, the first 90-day interval of treatment interruption was associated with a markedly higher risk of death or thrombo-embolism (IRR 2.5; 95% confidence interval 2.3-2.8) vs. the interval of 271-360 days. CONCLUSION: In patients with AF, an interruption of warfarin treatment is associated with a significantly increased short-term risk of death or thrombo-embolic events within the first 90 days of treatment interruption. PMID- 22199118 TI - Protein kinase G type I in cardiac myocytes: unmasked at last? PMID- 22199119 TI - Reference values for exercise limitations among adults with congenital heart disease. Relation to activities of daily life--single centre experience and review of published data. AB - AIMS: We aimed to investigate the distribution of exercise capacity across the spectrum of adult congenital heart disease (ACHD) using own data and the published experience and to provide diagnosis, gender-, and age- specific reference values. METHODS AND RESULTS: Publications describing exercise capacity in ACHD patients using cardiopulmonary exercise testing (CPET) were identified (n = 2286 patients in 23 papers). In addition, we included 2129 patients who underwent CPET at our own institution. The majority of patients (80%) had reduced peak oxygen uptake (peak VO(2)) compared with normal values (defined as <90% of predicted peak VO(2)). There were significant differences in peak VO(2) between subgroups of patients, with the lowest values seen in patients with Eisenmenger syndrome and complex heart disease. However, even in patients with simple lesions, peak VO(2) was on average significantly reduced compared with normal values. Based on a large number of observations we herewith provide gender- and age-specific peak VO(2) centile plots for the most common lesions (Tetralogy of Fallot, systemic right ventricle, Ebstein anomaly and Fontan-palliation) and relate disease-specific exercise capacity to that required for specific activities of daily life, sports, and occupations. CONCLUSION: We provide age-, gender-, and diagnosis-specific data on peak VO(2) levels across the spectrum of ACHD allowing to compare the exercise capacity of individual patients with that of their peer patients. These data should be helpful in interpreting CPET results, guiding therapy, and advising patients on activities of daily life, sports participation, and choice of occupation. PMID- 22199120 TI - Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I. AB - AIMS: Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Elevation of myocyte cyclic GMP levels by local actions of endogenous atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) or by pharmacological inhibition of phosphodiesterase-5 was shown to counter regulate pathological hypertrophy. It was suggested that cGMP-dependent protein kinase I (cGKI) mediates this protective effect, although the role in vivo is under debate. Here, we investigated whether cGKI modulates myocyte growth and/or function in the intact organism. METHODS AND RESULTS: To circumvent the systemic phenotype associated with germline ablation of cGKI, we inactivated the murine cGKI gene selectively in cardiomyocytes by Cre/loxP-mediated recombination. Mice with cardiomyocyte-restricted cGKI deletion exhibited unaltered cardiac morphology and function under resting conditions. Also, cardiac hypertrophic and contractile responses to beta-adrenoreceptor stimulation by isoprenaline (at 40 mg/kg/day during 1 week) were unaltered. However, angiotensin II (Ang II, at 1000 ng/kg/min for 2 weeks) or transverse aortic constriction (for 3 weeks) provoked dilated cardiomyopathy with marked deterioration of cardiac function. This was accompanied by diminished expression of the [Ca(2+)]i-regulating proteins SERCA2a and phospholamban (PLB) and a reduction in PLB phosphorylation at Ser16, the specific target site for cGKI, resulting in altered myocyte Ca(2+)i homeostasis. In isolated adult myocytes, CNP, but not ANP, stimulated PLB phosphorylation, Ca(2+)i-handling, and contractility via cGKI. CONCLUSION: These results indicate that the loss of cGKI in cardiac myocytes compromises the hypertrophic program to pathological stimulation, rendering the heart more susceptible to dysfunction. In particular, cGKI mediates stimulatory effects of CNP on myocyte Ca(2+)i handling and contractility. PMID- 22199122 TI - Wnt signalling: a mediator of the heart-bone marrow axis after myocardial injury? PMID- 22199123 TI - Catheterization laboratories open 24 hours a day, every day: does stable non-ST elevation acute coronary syndrome need the offer? PMID- 22199121 TI - Adjustment of the GRACE score by growth differentiation factor 15 enables a more accurate appreciation of risk in non-ST-elevation acute coronary syndrome. AB - AIMS: The aim of the study was to evaluate whether knowledge of the circulating concentration of growth differentiation factor 15 (GDF-15) adds predictive information to the Global Registry of Acute Coronary Events (GRACE) score, a validated scoring system for risk assessment in non-ST-elevation acute coronary syndrome (NSTE-ACS). We also evaluated whether GDF-15 adds predictive information to a model containing the GRACE score and N-terminal pro-B-type natriuretic peptide (NT-proBNP), a prognostic biomarker already in clinical use. METHODS AND RESULTS: The GRACE score, GDF-15, and NT-proBNP levels were determined on admission in 1122 contemporary patients with NSTE-ACS. Six-month all-cause mortality or non-fatal myocardial infarction (MI) was the primary endpoint of the study. To obtain GDF-15- and NT-proBNP-adjusted 6-month estimated probabilities of death or non-fatal MI, statistical algorithms were developed in a derivation cohort (n = 754; n = 66 reached the primary endpoint) and applied to a validation cohort (n = 368; n = 33). Adjustment of the GRACE risk estimate by GDF-15 increased the area under the receiver-operating characteristic curve (AUC) from 0.79 to 0.85 (P < 0.001) in the validation cohort. Discrimination improvement was confirmed by an integrated discrimination improvement (IDI) of 0.055 (P = 0.005). A net 31% of the patients without events were reclassified into lower risk, and a net 27% of the patients with events were reclassified into higher risk, resulting in a total continuous net reclassification improvement [NRI(>0)] of 0.58 (P = 0.002). Addition of NT-proBNP to the GRACE score led to a similar improvement in discrimination and reclassification. Addition of GDF-15 to a model containing GRACE and NT-proBNP led to a further improvement in model performance [increase in AUC from 0.84 for GRACE plus NT-proBNP to 0.86 for GRACE plus NT-proBNP plus GDF-15, P = 0.010; IDI = 0.024, P = 0.063; NRI(>0) = 0.42, P = 0.022]. CONCLUSION: We show that a single measurement of GDF-15 on admission markedly enhances the predictive value of the GRACE score and provides moderate incremental information to a model including the GRACE score and NT-proBNP. Our study is the first to provide simple algorithms that can be used by the practicing clinician to more precisely estimate risk in individual patients based on the GRACE score and a single biomarker measurement on admission. The rigorous statistical approach taken in the present study may serve as a blueprint for future studies exploring the added value of biomarkers beyond clinical risk scores. PMID- 22199124 TI - Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy. AB - AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease predominantly caused by mutations in desmosomal protein genes. Lamin A/C gene (LMNA) mutations are associated with dilated cardiomyopathy, conduction abnormalities and high incidence of sudden cardiac death. In this study, we screened a large cohort of ARVC patients for LMNA mutations. METHODS AND RESULTS: One hundred and eight patients from unrelated families with borderline (n = 27) or definite (n = 81) diagnosis of ARVC were genetically tested for five desmosomal genes and LMNA. Sixty-one (56.5%) were positive for desmosomal gene mutations. Standard polymerase chain reaction (PCR) amplification of the 12 protein-coding LMNA exons was performed and mutational screening performed by direct sequencing. Four patients (4%) without desmosomal gene mutations carried LMNA variants. Three had severe right ventricular involvement, and during follow-up three died (two suddenly and one from congestive heart failure); all three had conduction abnormalities on resting 12 lead electrocardiogram (ECG). Myocardial tissue from two patients showed myocyte loss and fibro-fatty replacement. In one of these, immunohistochemical staining with antibody to plakoglobin showed reduced/absent staining of the intercalated discs in the myocardium. CONCLUSION: Lamin A/C gene mutations can be found in severe forms of ARVC. Lamin A/C gene should be added to desmosomal genes when genetically testing patients with suspected ARVC, particularly when they also have ECG evidence for conduction disease. PMID- 22199126 TI - Suppression of UVB-induced HIF-1alpha up-regulation by hyperoxia does not prevent wrinkle formation associated with increased MMPs activity in mouse skin. AB - This study investigated whether the suppression of hypoxia-inducible factor (HIF) 1alpha up-regulation prevents high-dose and long-term UVB-induced wrinkle formation and angiogenesis associated with increased matrix metalloproteinase (MMP)-2 and MMP-9 activities. Twenty-four hairless mice were assigned to three groups: 1) control, 2) UVB-irradiation (UVB), and 3) UVB-irradiation followed by hyperoxia (UVB+HO). The backs of the mice were exposed to UVB irradiation three times a week for 10 weeks. To suppress UVB-induced cutaneous HIF-1alpha up regulation, the mice were exposed to hyperoxia (90% oxygen) for 2 h immediately after each UVB irradiation. The UVB and UVB+HO groups had significantly increased degrees of wrinkle formation, dermal blood vessel density, and MMP-2 and MMP-9 activities compared with the control group. HIF-1alpha expression levels were significantly higher in the UVB group than in the control group whereas these levels remained unchanged in the UVB+HO groups. The activity of type 1 collagenase which digests collagen type 1 (a main component of the dermis), was similar in all groups; furthermore, the dermal soluble collagen content was similar in all groups. These results suggest that the suppression of increases in HIF-1alpha levels alone is insufficient to restrain wrinkle formation caused by higher doses and longer periods of the UVB irradiation that led to the up regulation of MMP-2 and MMP-9 activities. PMID- 22199125 TI - Effects of kale ingestion on pharmacokinetics of acetaminophen in rats. AB - Kale is a cruciferous vegetable (Brassicaceae) that contains a large amount of health-promoting phytochemicals. The chronic ingestion of cabbage of the same family is known to accelerate conjugating acetaminophen (AA) and decrease the plasma AA level. Therefore, we examined to clarify the effects of kale on the pharmacokinetics of AA, its glucuronide (AA-G) and sulfate (AA-S). AA was orally administered to rats pre-treated with kale or cabbage (2000 mg/kg/day) for one week. Blood samples were collected from the jugular vein, and the concentrations of AA, AA-G and AA-S were determined. In results, kale ingestion induced an increase in the area under the concentration-time curve (AUC) and a decrease in the clearance of AA, whereas cabbage had almost no influence. In addition, there were significant differences in the AUC of AA-G between the control and kale groups. mRNA expression levels of UDP-glucuronosyltransferases, the enzymes involved in glucuronidation, in the kale group were significantly higher than those in the control group. In conclusion, kale ingestion increased the plasma concentrations of both AA and AA-G. The results suggest that kale ingestion accelerates the glucuronidation of AA, but an increase of plasma AA levels has a different cause than the cause of glucuronidation. PMID- 22199127 TI - Altered expression pattern of testican-1 mRNA after brain injury. AB - Testican, a chondroitin/heparan sulfate proteoglycan, is primarily expressed in neurons of the adult and embryonic mouse brain, suggesting its role in normal and/or proliferation and differentiation processes of neurons. However, the role of testican in injured brain remains unclear. In the present study we investigated testican-1 mRNA expression pattern after cryo-injury of the brain. In situ hybridization histochemistry revealed that testican-1 mRNA is induced in the region surrounding the necrotic tissue. Time course study of testican-1 mRNA showed the highest level of signal intensity at 7 days after the injury. To determine which cell types express testican-1 mRNA, we performed in situ hybridization histochemistry combined with immunohistochemistry of several cell markers. Testican-1 mRNA signals were detected in the proximal reactive astrocytes, whereas the distribution pattern of testican-1 mRNA positive cells was different from those of mature oligodendrocytes and activated microglia. In addition, signals for testican-1 mRNA overlapped with those of FGF-2 mRNA, showing that these molecules are coexpressed in reactive astrocytes. These results suggest a possibility that testican-1 plays a permissive role for regenerating axons in reactive astrocytes after injury. PMID- 22199128 TI - Immunohistochemical analysis of cell death pathways in gastrointestinal adenocarcinoma. AB - Caspase-8 and caspase-9 play crucial roles in the extrinsic and intrinsic apoptotic pathways, respectively. The nuclear translocation of apoptosis-inducing factor (AIF) is involved in caspase-independent apoptosis. Microtubule-associated protein 1 light chain 3 (LC3) plays a pivotal role in autophagy. In the present study, we analyzed the expression of cleaved caspase-8 (CC8), cleaved caspase-9 (CC9), AIF, and LC3 in 160 gastrointestinal adenocarcinomas. The nuclear expression of AIF was rare. The expression of CC8 in gastric and colorectal adenocarcinomas did not differ, whereas the percentage of CC9-positive tumors in gastric adenocarcinomas was significantly higher than in colorectal adenocarcinomas. In contrast, the percentage of LC3-positive tumors in gastric adenocarcinomas was significantly lower than in colorectal adenocarcinomas. CC8 and CC9 occasionally co-existed in the same tumor cells in gastric adenocarcinoma. However, LC3-positive tumor cells in colorectal adenocarcinomas were constantly negative for CC8. No correlation was identified between the expression of any markers and clinicopathological parameters. These results suggest that different cell death pathways are activated in a manner that depends upon the primary site and cell type. The extrinsic and intrinsic apoptotic pathways may be mutually regulated in gastric adenocarcinomas. Also, autophagy may function as a cellular guardian to avoid apoptosis in colorectal adenocarcinomas. PMID- 22199129 TI - Effects of dietary supplementation with a combination of fish oil, bilberry extract, and lutein on subjective symptoms of asthenopia in humans. AB - The aim of this study was to determine the effects of dietary supplementation with a combination of fish oil, bilberry extract, and lutein on subjective symptoms of asthenopia in humans by a double- blind, randomized, parallel-group, and placebo-controlled trial. In the Active group, eleven subjects ingested a supplement containing omega-3 fatty acid-rich fish oil (docosahexaenoic acid 783 mg/day, eicosapentaenoic acid 162 mg/day), bilberry extract (anthocyanidin 59 mg/day), and lutein (17.5 mg/day) in soft gel capsule form, every day for 4 weeks. In the Placebo group, nine subjects ingested placebo capsules. Before and after supplementation, subjects completed a questionnaire to determine their asthenopia symptoms and were also assessed for mental fatigue symptom by the visual analog scale (VAS) test. Asthenopia symptoms such as "stiff shoulder, low back pain", "frustration", "dry-eye", and "stuffy head" were improved in the Active group. Furthermore, a score of mental fatigue was improved after 4 weeks of supplementation, and no side effects were observed after the 4-week supplementation and a 2-week washout period in the Active group. These results suggest that dietary supplementation with the combination of omega-3 fatty acid rich fish oil, bilberry extract, and lutein may safely improve subjective symptoms of asthenopia and mental fatigue in humans. PMID- 22199130 TI - Association between sleep bruxism and stress sensitivity in an experimental psychological stress task. AB - The objective of this study was to examine the association between sleep bruxism and psychological stress. The subjects consisted of 76 volunteers, who were divided into those with and without bruxism according to the diagnostic criteria for sleep bruxism outlined by the American Academy of Sleep Medicine (AASM). Stress sensitivity was evaluated before and after an experimental stress task, which involved simple mathematical calculations. It was assessed objectively by measuring the subjects' salivary chromogranin A (CgA) levels and subjectively using a ten-division visual analog scale (VAS). Compared with those observed before the stress task, the mean salivary CgA levels of the non-bruxism group (n = 54) were not significantly increased after the stress task. Conversely, the mean salivary CgA levels of the bruxism group (n = 22) were significantly increased after the stress task (P < 0.01). The mean VAS scores of the groups without (n = 54) and with (n = 22) bruxism were significantly (P < 0.01) increased after the stress task compared with those observed before the stress task, but no differences were detected between the two groups in the stress task. These findings suggest that there is an association between sleep bruxism and psychological stress sensitivity. PMID- 22199131 TI - Administration of ursodeoxycholate failed to prevent sludge and/or gallstone formation in cholecystokinin-1(A) receptor-deficient mice. AB - Gallstone disease is one of the most prevalent digestive diseases. The frequency of gallstone disease is about 10% in middle-age persons and 20% in aged persons. Gallbladder dysmotility and stasis of bile flow promote sludge and/or gallstone formation. Gallbladder contraction depends on cholecystokinin (CCK) via CCK-1 receptors (R)s. Previously, we raised CCK-1R deficient (-/-) mice and observed sludge and/or gallstone formation in more than 30% at 12-24 months of age. As ursodeoxycholate (UDCA) is commonly used for patients with gallstone disease, we expected that continuous administration of UDCA could prevent sludge and/or gallstone formation in CCK- 1R(-/-) mice. A diet containing 0.1% UDCA was administered in age-matched CCK-1R(-/-) and wild-type male and female mice for 8 months. Administration of UDCA decreased the frequency of sludge and/or gallstone formation compared with the control (CRF-1) diet (39%->26% in male, 35%->25% in female mice); however, these effects did not attain a level of statistical significance. Although the body weight was significantly higher in UDCA-fed than CRF-1-fed male mice regardless of genotypes, the plasma lipid concentrations did not differ between the two diets. In conclusion, administration of UDCA was less effective than expected at preventing sludge and/or gallstone formation in CCK 1R(-/-) mice. PMID- 22199132 TI - Novel internally quenched fluorogenic substrates for angiotensin I-converting enzyme and carboxypeptidase Y. AB - Angiotensin I-converting enzyme (ACE, EC 3.4.15.1) is one of the most important enzymes in the renin-angiotensin system, a major blood pressure control system in mammals. We synthesized novel internally quenched fluorogenic (IQF) substrates for ACE based on the cleavage site of an angiotensin I, introducing N-methyl anthranic acid (Nma) and N(epsilon)-2,4-dinitrophenyl-lysine (Lys(Dnp))at the N- and C-terminal regions. Kinetic parameters of the synthesized IQF substrates Nma Phe-His-Lys(Dnp) and Nma-His-Pro-Phe-Lys(Dnp)-Pro were compared with those of a common peptide substrate for ACE, hippuryl (Hip)-His-Leu. The k(cat)/K(m) values of Nma-Phe-His-Lys(Dnp), Nma-His-Pro-Phe-Lys(Dnp)-Pro, and Hip-His-Leu were 5.12, 1.90, and 0.80 uM(-1) s(-1) for rabbit lung ACE, and 16.0, 7.36, and 0.30 uM(-1) s(-1) for recombinant human (rh)-ACE, respectively. These results indicate that Nma-Phe-His-Lys(Dnp) is an excellent substrate for rh-ACE. Carboxypeptidase Y also hydrolyzed Nma-Phe-His-Lys(Dnp) efficiently with K(m), k(cat), and k(cat)/K(m) values of 60.2 uM, 105 s(-1), and 1.74 uM(-1) s(-1), respectively. On the other hand, carboxypeptidase B did not hydrolyze IQF substrates. The newly developed IQF substrate, Nma-Phe-His-Lys(Dnp), is a valuable tool for ACE and carboxypeptidase studies. PMID- 22199133 TI - Building the bypass--implications of improved access to sexual healthcare: evidence from surveys of patients attending contrasting genitourinary medicine clinics across England in 2004/2005 and 2009. AB - OBJECTIVE: The objective of this study was to examine changes in patient routes into genitourinary medicine (GUM) clinics since policy changes in England sought to improve access to sexual healthcare. METHODS: Cross-sectional patient surveys at contrasting GUM clinics in England in 2004/2005 (seven clinics, 4600 patients) and 2009 (four clinics, 1504 patients). Patients completed a short pen-and-paper questionnaire that was then linked to an extract of their clinical data. RESULTS: Symptoms remained the most common reason patients cited for attending GUM (46% in both surveys), yet the proportion of patients having sexually transmitted infection (STI) diagnosis/es declined between 2004/2005 and 2009: 38%-29% of men and 28%-17% of women. Patients in 2009 waited less time before seeking care: median 7 days (2004/2005) versus 3 days (2009), in line with shorter GUM waiting times (median 7 vs 0 days, respectively). Fewer GUM patients in 2009 first sought care elsewhere (23% vs 39% in 2004/2005), largely from general practice, extending their time to attending GUM by a median of 2 days in 2009 (vs 5 days in 2004/2005). Patients with symptoms in 2009 were less likely than patients in 2004/2005 to report sex since recognising a need to seek care, but this was still reported by 25% of men and 38% of women (vs 44% and 58%, respectively, in 2004/2005). CONCLUSIONS: Patient routes to GUM shortened between 2004/2005 and 2009. While GUM patients in 2009 were less likely overall to have STIs diagnosed, perhaps reflecting lower risk behaviour, there remains a substantial proportion of high-risk individuals requiring comprehensive care. Behavioural surveillance across all STI services is therefore essential to monitor and maximise their public health impact. PMID- 22199134 TI - Testing the fathers: carrying out HIV and STI tests on partners of pregnant women. AB - OBJECTIVES: Opt out antenatal HIV testing has significantly reduced mother to child transmission of HIV, but seroconversion during pregnancy from undiagnosed HIV positive male partners remains a risk. The authors report on a pilot initiative for sexual health and HIV screening for male partners of women attending antenatal ultrasound examination at Homerton Hospital, London. METHODS: Men attending with their female partners for routine ultrasound examination between 1 August 2010 and 31 January 2011 were offered on-site serology for HIV, syphilis, hepatitis B and hepatitis C and urine testing for Neiserria gonorrhoeae and Chlamydia trachomatis. RESULTS: were followed up through the genitourinary medicine service. Referral pathways were established for men with positive results. RESULTS: 1243 male partners of 2400 women attended ultrasound examinations, of whom 430 accepted testing (acceptance rate 35% and coverage rate 18%). Median age was 32 years (range 19-52). 112/430 (26%) male partners were of black ethnicity. 41% had previously had a HIV test. There was no difference in prior HIV testing between whites and non-whites. 16 infections were diagnosed, including two cases of hepatitis C, eight cases of hepatitis B and six cases of C trachomatis. No HIV diagnoses were made. CONCLUSIONS: The authors have shown that it is acceptable and feasible to engage heterosexual men for testing in this setting. Of those men who accepted HIV testing, more than half had never been previously tested. 4% of men tested had an infection, which had the potential to affect the outcome of the pregnancy. PMID- 22199135 TI - Chlamydia trachomatis re-infections in a population-based cohort of women. AB - OBJECTIVES: Re-infection with chlamydia may increase subsequent reproductive morbidity in women. The authors sought to identify characteristics associated with re-infection. METHODS: A cohort of all women aged 10-49 years with a notification of genital chlamydia in the Australian state of New South Wales during 1999-2008 was defined. Probabilistic linkage was used to identify women with repeat notifications in the same period. The risk of repeat notification was examined according to age and other characteristics using proportional hazards regression. RESULTS: Among 40 936 women in the cohort, 3236 had at least one repeat chlamydia notification over an average of 3.5 years of follow-up. The incidence of repeat notification was greatest in the first year after index notification (4.5 per 100 person-years) and decreased thereafter. The RR of repeat notification increased by 8% (95% CI 7% to 9%) for each year decrease in age. Compared with women aged 20-21 years at index chlamydia notification, women aged <16 years were twice as likely to have a repeat notification (adjusted HR 2.12, 95% CI 1.75 to 2.56), while women aged 26-27 years were half as likely (adjusted HR 0.53, 95% CI 0.43 to 0.66). Year of index notification, parity and concurrent or past gonorrhoeal infection were also significantly associated with the risk of repeat notification, but socioeconomic status and area of residence were not. CONCLUSIONS: Younger age is a strong predictor of chlamydia re infection in women. The results support targeting interventions to prevent re infections to very young women. PMID- 22199136 TI - Effect of adaptive servo-ventilation on 1-year prognosis in heart failure patients. AB - BACKGROUND: Adaptive servo-ventilation (ASV) has been used as therapy for heart failure (HF). The objective of the present study was to estimate the effect of ASV on 1-year prognosis in HF patients. METHODS AND RESULTS: After optimizing medical therapy, a 1-year follow-up study was conducted of 85 HF patients (mean age, 72 +/- 10 years; 46 men), categorized as New York Heart Association class II IV. The patients were classified into 2 groups based on adherence to ASV therapy. Use of ASV for >= 4h/night was designated as good adherence, and use of ASV for <4h/night was designated as poor adherence. The incidence of fatal cardiovascular events including death from progression of HF, cardioembolic stroke, and fatal cardiac arrhythmias was tracked. Fifty-seven patients were classified into the good adherence group. After 1-year follow-up, the survival rate calculated using Kaplan-Meier analysis was significantly higher in the good adherence group than in the poor adherence group (P=0.0046, log-rank test). In a Cox proportional hazards model, the odds ratio (95% confidence interval) of fatal cardiovascular events was 0.53 (0.27-0.99) for the good ASV adherence group (P=0.046). CONCLUSIONS: ASV prevents fatal cardiovascular events and improves survival in HF patients. PMID- 22199137 TI - Evaluation of transplacental treatment for fetal congenital bradyarrhythmia: - nationwide survey in Japan -. AB - BACKGROUND: There are few large studies of fetal congenital bradyarrhythmia. The aim of the present study was to investigate the effects and risks of transplacental treatment for this condition. METHODS AND RESULTS: Using questionnaires, 128 cases of fetal bradyarrhythmia were identified at 52 Japanese institutions from 2002 to 2008. Of the 128 fetuses, 90 had structurally normal hearts. Among these 90 fetuses, 61 had complete atrioventricular block (CAVB), 16 had second-degree AVB, 8 had sinus bradycardia, and 5 had other conditions. The 61 CAVB fetuses were divided into those who did (n = 38) and those who did not (n = 23) receive transplacental medication. Monotherapy with beta-sympathomimetics, steroid monotherapy, and combination therapy with these agents was given in 11, 5 and 22 cases, respectively. Beta-sympathomimetics improved bradycardia (P<0.001), but no medication could significantly improve the survival rate. Fetal hydrops was associated with a 14-fold increased risk of perinatal death (P = 0.001), and myocardial dysfunction was a significant risk factor for poor prognosis (P = 0.034). Many adverse effects were observed with steroid treatment, with fetal growth restriction increasing significantly after >10 weeks on steroids (P = 0.043). CONCLUSIONS: Treatment with beta-sympathomimetics improved bradycardia, but survival rate did not differ significantly in fetuses with and without transplacental medication. It is recommended that steroid use should be limited to <10 weeks to avoid maternal and fetal adverse effects, especially fetal growth restriction and oligohydramnios. PMID- 22199138 TI - Cautions and strategy for treating chronic heart failure by using adaptive servo ventilation. PMID- 22199139 TI - Can acute myocardial infarction sneak out from Takotsubo? PMID- 22199140 TI - The less embraces the greater in detecting multiple coronary artery disease. PMID- 22199141 TI - Natural course of untreated microalbuminuria in children and adolescents with type 1 diabetes and the importance of diabetes duration and immigrant status: longitudinal analysis from the prospective nationwide German and Austrian diabetes survey DPV. AB - OBJECTIVE: To identify risk factors for the development and progression of untreated persistent microalbuminuria in children and adolescents with type 1 diabetes. DESIGN AND METHODS: A total number of 683 children and adolescents with type 1 diabetes recruited from the prospective nationwide German and Austrian diabetes survey (DPV) were included in the analysis. Inclusion criteria were onset of type 1 diabetes under the age of 11 years, diabetes duration of more than 1 year and continuous follow-up over 5 years with at least two documented urine analyses per year. Subjects treated with angiotensin-converting enzyme inhibitors were excluded. Risk factors such as sex, body mass index SDS, diabetes duration, HbA1c, total cholesterol, HDL-cholesterol, LDL-cholesterol, systolic and diastolic blood pressure, and immigrant status were analysed by logistic regression. RESULTS: At baseline (age 10.5 +/- 0.1 years, diabetes duration 4.6 +/- 2.4 years and HbA1c 7.4 +/- 1.1%), 75.6% of children had normoalbuminuria, 15.7% had intermittent microalbuminuria, 8.6% had persistent microalbuminuria and 0.1% had macroalbuminuria. After a follow-up of 5 years, 59.4% of adolescents continued to have normoalbuminuria, 18.4% had progression, 15.2% had regression of microalbuminuria, and in 6.9% of the subjects, microalbuminuria remained unchanged. We found significant associations between persistent microalbuminuria at baseline and during each year of follow-up (P < 0.0001). Logistic regression analysis identified diabetes duration and immigrant status as significant factors for microalbuminuria (P = 0.009 and P = 0.009). CONCLUSIONS: The survey in a real world setting shows that diabetes duration and immigrant status are risk factors for the development and progression of untreated microalbuminuria in children and adolescents with type 1 diabetes. PMID- 22199142 TI - Emergency department crowding: prioritising quantified crowding measures using a Delphi study. AB - AIMS: Emergency department (ED) crowding has been associated with a number of negative health outcomes, including unnecessary deaths, increased waiting times and a decrease in care quality. Despite the seriousness of this issue, there is little agreement on appropriate crowding measures to assess crowding effects on ED operations. The objective of this study was to prioritise a list of quantified crowding measures that would assess the current state of a department. METHODS: A three round Delphi study was conducted via email and an Internet based survey tool. The panel consisted of 40 professionals who had exposure to and expertise in crowding. Participants submitted quantified crowding measures which, through three rounds, were evaluated and ranked to assess participant agreement for inclusion. RESULTS: The panel identified 27 measures of which eight (29.6%) reached consensus at the end of the study. These measures comprised: (1) ability of ambulances to offload; (2) patients who leave without being seen or treated; (3) time until triage; (4) ED occupancy rate; (5) patients' total length of stay in the ED; (6) time to see a physician; (7) ED boarding time; and (8) number of patients boarding in the ED. CONCLUSIONS: This study resulted in the identification of eight quantified crowding measures, which present a comprehensive view of how crowding is affecting ED operations, and highlighted areas of concern. These quantified measures have the potential to make a considerable contribution to decision making by ED management and to provide a basis for learning across different departments. PMID- 22199143 TI - Association of serum sex steroid receptor bioactivity and sex steroid hormones with breast cancer risk in postmenopausal women. AB - Postmenopausal women with elevated serum sex steroids have an increased risk of breast cancer. Most of this risk is believed to be exerted through binding of the sex steroids to their receptors. For the first time, we investigate the association of estrogen receptor (ER) and androgen receptor (AR) serum bioactivity (SB) in addition to hormone levels in samples from women with breast cancer collected before diagnosis. Two hundred postmenopausal women participating in the UK Collaborative Trial of Ovarian Cancer Screening who developed ER positive breast cancer 0.6-5 years after sample donation were identified and matched to 400 controls. ER and AR bioassays were used to measure ERalpha, ERbeta, and AR SB. Androgen and estrogen levels were measured with immunoassays. Subjects were classified according to quintiles of the respective marker among controls and the associations between SB and hormones with breast cancer risk were determined by logistic regression analysis. ERalpha and ERbeta SB were significantly higher before diagnosis compared with controls, while estrogens showed no difference. Women had a twofold increased breast cancer risk if ERalpha SB (odds ratio (OR), 2.114; 95% confidence interval (CI), 1.050-4.425; P=0.040) was in the top quintile >2 years before diagnosis or estrone (OR, 2.205; 95% CI, 1.104-4.586; P=0.029) was in the top quintile <2 years before diagnosis. AR showed no significant association with breast cancer while androstenedione (OR, 3.187; 95% CI, 1.738-6.044; P=0.0003) and testosterone (OR, 2.145; 95% CI, 1.256 3.712; P=0.006) were significantly higher compared with controls and showed a strong association with an almost threefold increased breast cancer risk independent of time to diagnosis. This study provides further evidence on the association of androgens and estrogens with breast cancer. In addition, it reports that high ER but not AR SB is associated with increased breast risk >2 years before diagnosis. PMID- 22199144 TI - PIT1 upregulation by HMGA proteins has a role in pituitary tumorigenesis. AB - We have previously demonstrated that HMGA1B and HMGA2 overexpression in mice induces the development of GH and prolactin (PRL) pituitary adenomas mainly by increasing E2F1 transcriptional activity. Interestingly, these adenomas showed very high expression levels of PIT1, a transcriptional factor that regulates the gene expression of Gh, Prl, Ghrhr and Pit1 itself, playing a key role in pituitary gland development and physiology. Therefore, the aim of our study was to identify the role of Pit1 overexpression in pituitary tumour development induced by HMGA1B and HMGA2. First, we demonstrated that HMGA1B and HMGA2 directly interact with both PIT1 and its gene promoter in vivo, and that these proteins positively regulate Pit1 promoter activity, also co-operating with PIT1 itself. Subsequently, we showed, by colony-forming assays on two different pituitary adenoma cell lines, GH3 and alphaT3, that Pit1 overexpression increases pituitary cell proliferation. Finally, the expression analysis of HMGA1, HMGA2 and PIT1 in human pituitary adenomas of different histological types revealed a direct correlation between PIT1 and HMGA expression levels. Taken together, our data indicate a role of Pit1 upregulation by HMGA proteins in pituitary tumours. PMID- 22199145 TI - Considerations on a new left ventricular multi-polar lead. PMID- 22199146 TI - Recording of low-amplitude diastolic electrograms through the coronary veins: a guide for epicardial ventricular tachycardia ablation. AB - AIMS: The purpose of the study was to evaluate the role of coronary venous mapping to identify epicardial ventricular tachycardia (VT) in patients with structural heart disease. METHODS AND RESULTS: Epicardial mapping of the electrophysiological substrate through the coronary vein branches using a 2.2F, 16-pole microelectrode catheter was performed in 33 consecutive patients undergoing VT ablation. Twenty-six patients had a history of myocardial infarction and seven had a non-ischaemic cardiomyopathy. Endocardial ablation was successful in 19 of the 33 patients (58%). Low-amplitude fractionated diastolic electrograms with an electrogram-QRS interval amounting to 30-70% of the VT cycle length were recorded during the VT in the coronary vein branches in eight patients (24%). Endocardial ablation failed in seven of the eight patients with diastolic electrograms in the coronary veins, suggesting an epicardial involvement of the VT re-entry circuit. Among the patients with a suspected epicardial VT origin, four patients underwent epicardial ablation using a pericardial access after unsuccessful endocardial ablation which eliminated mappable VTs in all. CONCLUSION: Recording of low-amplitude fractionated diastolic electrograms through the coronary veins facilitates the identification of VTs with an epicardial origin requiring mapping and ablation through a pericardial access. PMID- 22199147 TI - Demonstration of reversible complete left bundle branch block following tachycardia-induced cardiomyopathy. AB - A 56-year-old man with atrial fibrillation and complete left bundle branch block (CLBBB) developed heart failure refractory to the initial medical treatment. Both the CLBBB and cardiac dysfunction completely recovered only with an advanced medical regimen for rate control and heart failure. This report describes a case with reversible CLBBB following tachycardia-induced cardiomyopathy, who was not a candidate for cardiac resynchronization therapy. PMID- 22199148 TI - Overweight/Obesity and related factors among thai medical students. AB - This study was conducted to assess the prevalence of overweight/obesity and the related demographic data and health behaviors of Thai medical students. A cross sectional study of 5441 medical students from all the 13 medical schools in Thailand was conducted in 2006 by means of a self-administered questionnaire. Demographic data, health behaviors, and self-reported body weight and height were recorded. The results revealed that Thai medical students have a lower prevalence of overweight/obesity than the general population of the same age group. The multiple logistic regression analysis showed that higher academic year was associated with being overweight or obesity in males, having improper dietary habits were associated with being overweight or obesity in both genders, whereas alcohol consumption was associated with being overweight in male only. Therefore, medical curricula should place an emphasis not only on knowledge but also on attitudes and behaviors for healthy lifestyles. PMID- 22199149 TI - Home and other nontraffic injuries among children and youth in a high-income Middle Eastern country: a trauma registry study. AB - A trauma registry in the United Arab Emirates was used to ascertain nontraffic injuries of 0- to 19-year-olds. The registry's value for prevention was assessed. A total of 292 children and youth with nontraffic injuries were admitted for >24 hours at surgical wards of the main trauma hospital in Al Ain region during 36 months in 2003-2006. Injuries were analyzed by external cause, location, body part, and severity. Nontraffic represented 60% (n = 292) of child and youth injuries. Incidence/100 000 person-years was 91 for males, 43 for females. Unintentional included falls 65% (n = 191), burns 17% (n = 49), animal-related (mainly camel) 3% (n = 10), and others 10% (n = 29). Intentional accounted for 4% (n = 13). Falls affected all ages, burns mainly 1- to 4-year-olds. Of the injuries, 70% occurred at home. Most frequent and severe injuries measured by the Injury Severity Score and Abbreviated Injury Scale involved extremities. Prevention of home falls for all ages and burns of 1- to 4-year-olds are priorities. Registries should cover pediatric wards and include data on fall locations and hazardous products. PMID- 22199150 TI - Does change in perception following counseling result in improved quitting outcome among Malaysian smokers? AB - OBJECTIVE: The authors examined the effects that change in perception about the advantages and disadvantages of smoking and quitting had on quitting outcome among smokers enrolled in a program for smoking cessation. METHODS: A total of 185 smokers from 2 public universities who were interested in quitting received smoking cessation counseling on understanding the risks and benefits of quitting (or smoking) in addition to a course of free nicotine replacement therapy (NRT). A decisional balance questionnaire (DBQ) was administered at baseline and at 2 months postcounseling to determine and assess changes in smoking perception. RESULTS: After counseling, 72.3% of smokers had reduced their perceptions about the advantages of smoking, and 66.4% had increased perceptions of disadvantages of smoking. At the eighth week, 51 participants (27%) had quit. Smokers who had reduced perceptions of the advantages of smoking had significantly higher quit rates compared with those with no improvement in perception (82.6% vs 17.4%; odds ratio = 2.47; 95% confidence interval = 1.00-6.10). CONCLUSION: After counseling, smokers did change their perception of the advantages and disadvantages of smoking during the quitting process. These changes are associated with a higher likelihood of smoking cessation. PMID- 22199151 TI - Knowledge and perceptions of HIV-infected patients regarding HIV transmission and treatment in Ho Chi Minh City, Vietnam. AB - Patient education concerning HIV and antiretroviral (ARV) medications is important for optimal outcomes. The authors assessed the knowledge and perceptions of HIV-infected patients in an ARV education program in Ho Chi Minh City, Vietnam. Of 185 patients, 64 (35%) receiving ARV medications, nearly 80% correctly answered questions regarding HIV. Correct responses were associated with higher education (P < .05) and longer duration of HIV diagnosis (P < .05). A lack of knowledge was observed in 40% of respondents who believed HIV and AIDS were the same and 70% of respondents who believed ARV medications cured HIV. Greater embarrassment of living with HIV was associated with female gender (P < .05) and lower education (P < .05). Patients were concerned over ARV medication use (27%) and its side effects (38%). The study population's knowledge of HIV/AIDS and ARV medications, perceived stigmatization, and areas of knowledge deficits underscore the need for effective patient education programs addressing poorly understood issues around HIV/AIDS. PMID- 22199152 TI - Measuring subnational under-5 mortality: lessons from a survey in the eastern Indonesian district of Ende. AB - There is an urgent need for measurements of the magnitude and determinants of under-5 mortality at the district level in Indonesia. This article describes a sample household survey conducted in Ende District, East Nusa Tenggara province. Complete birth histories were recorded from all women residing in a sample of 32 villages (7454 households) of Ende. The survey was conducted in early 2010, deriving measures for the period 2000-2009. The survey instrument also included key variables required to measure determinants of under-5 mortality. The results showed that there are significant differentials in under-5 mortality risk within Ende, ranging from 27 to 85 per 1000. This information will assist the district health office to implement maternal and child health programs to meet national targets for United Nations Millennium Development Goal 4. The findings provide robust mortality measures at the district level and demonstrate the feasibility of conducting such a study using local resources, in a short time, and with low costs. PMID- 22199153 TI - Self-reported functional and general health status among older respondents in China: the impact of age, gender, and place of residence. AB - This study made comparisons of self-reported functional and general health status between Chinese women and men in different age-groups in rural and urban settings and examined multiple factors relating to these health statuses in older adults. This study included a sample of 4017 respondents, aged 55 years and older, from the Hubei subsample of the Chinese National Health Service Survey III in 2003. The results illustrate that the differences in self-rated functional and general health status between genders and between urban and rural areas diminished with age. Access to health care was strongly associated with health status. The quality of the local environment, measured by access to tap water, was a significant factor for rural residents. Our study suggests that improving access to health care services and reducing environmental health risks are critical for improving physical functioning, psychological functioning, and self-rated general health for older adults in China. PMID- 22199154 TI - Risk factors associated with death in a 12-month cohort analysis of tuberculosis patients: 12-month follow-up after registration. AB - The aim of the study was to investigate the risk of death for 12 months follow-up after registration of tuberculosis (TB), using a nationwide population-based retrospective cohort study. A total of 33851 new TB cases were enrolled from 2006 to 2008. Of these, 5584 (16.5%) patients died during the follow-up period because of TB, and 4224 (12.5%) patients died because of other causes. Multivariate survival analysis revealed that age, HIV, chronic kidney disease, stroke, cancer, and chronic liver disease and cirrhosis were significant risk factors associated with death. Patients of age 0 to 64 years with HIV, chronic kidney disease, cancer, stroke, chronic liver disease and cirrhosis, or diabetes had a higher risk of death than those without these comorbidities. The majority of the TB patients in Taiwan died because of causes other than TB, and death often occurred in the first 2 months after TB registration. Therefore, medical care and case management for those with comorbidities are advised to prevent death during TB treatment. PMID- 22199155 TI - Gender-dependent association of a beta(2)-adrenergic gene variant with obesity parameters in Malaysian Malays. AB - Recent findings have shown that the rs1042714 (Gln27Glu) single-nucleotide polymorphism (SNP) on the beta2-adrenoceptor gene may predispose to obesity. The findings from other studies carried on different populations, however, have been inconsistent. The authors investigated the association between the rs1042714 SNP with obesity-related parameters. DNA of 672 Malaysian Malays was analyzed using real-time polymerase chain reaction. Univariate and multivariate linear regression analyses revealed significant associations between rs1042714 and diastolic blood pressure in the pooled Malaysian Malay subjects under additive and recessive models. After gender stratification, however, a significant association was found between the rs1042714 and triglyceride and the rs1042714 and log-transformed high-density lipoprotein cholesterol levels in Malaysian Malay men. No significant association was found between the SNP and log transformed body mass index. This polymorphism may have an important role in the development of obesity-related traits in Malaysian Malays. Gender is an effect modifier for the effect of the rs1042714 polymorphism on obesity-related traits in Malaysian Malays. PMID- 22199156 TI - Impulsivity, self-regulation,and pathological video gaming among youth: testing a mediation model. AB - Given the potential negative mental health consequences of pathological video gaming, understanding its etiology may lead to useful treatment developments. The purpose of the study was to examine the influence of impulsive and regulatory processes on pathological video gaming. Study 1 involved 2154 students from 6 primary and 4 secondary schools in Singapore. Study 2 involved 191 students from 2 secondary schools. The results of study 1 and study 2 supported the hypothesis that self-regulation is a mediator between impulsivity and pathological video gaming. Specifically, higher levels of impulsivity was related to lower levels of self-regulation, which in turn was related to higher levels of pathological video gaming. The use of impulsivity and self-regulation in predicting pathological video gaming supports the dual-system model of incorporating both impulsive and reflective systems in the prediction of self-control outcomes. The study highlights the development of self-regulatory resources as a possible avenue for future prevention and treatment research. PMID- 22199157 TI - Developing a measure to evaluate a positive youth development program for Native Hawaiians: the Hui Malama o ke Kai rubrics of Hawaiian values. AB - OBJECTIVE: This study introduces the rubrics of Native Hawaiian values developed to measure youth knowledge and understanding of indigenous values along with 8 other tools to evaluate Hui Malama o ke Kai (HMK), a culturally relevant, positive youth development, after-school program in a Native Hawaiian community. Findings from our efforts to validate the rubrics tool, as an evaluation measure, using triangulation are presented. METHODS: Evaluation tools were modified through community input and measured youth risk and protective factors, including knowledge and practice of Hawaiian values. Validity and reliability of the tools were tested by analyzing internal consistency, intraclass correlations, and triangulating data sources. RESULTS: Corroboration of results from the different data sources indicated convergent validity of measures to evaluate youth understanding and practice of Hawaiian values. CONCLUSIONS: This community focused approach to evaluation demonstrates how multiple evaluation instruments may reliably evaluate a program. PMID- 22199158 TI - Hand, foot and mouth disease in Yunnan Province, China, 2008-2010. AB - This study was done to assess the epidemic features of hand, foot and mouth disease in Yunnan Province. Surveillance data from the beginning of 2008 through the end of 2010 were analyzed to conduct the demographic data of patients and morbidity as well as the estimation between possible risk factors for severe or fatal cases. Of the 75109 cases reported, laboratory tests confirmed 3691 cases. Thus, the average annual incidence proportion was 55 per 100000 population with a total case fatality rate of 0.04%. A seasonal peak was observed in May, along with a smaller winter peak in 2010. Most severe and fatal cases were caused by enterovirus 71. It is demonstrated that most of the severe and fatal cases occurred in very young children and that delayed access to health care led to the higher likelihood of serious illness. PMID- 22199159 TI - Social support and glycemic control in adult patients with type 2 diabetes mellitus. AB - INTRODUCTION: The purpose of this study is to examine the prevalence of social support and its association with glycemic control in patients with type 2 diabetes mellitus (T2D) in an urban primary care center within an academic institution. Social support is important in the management of chronic diseases. However, its association with glycemic control has been controversial. METHODS: This was part of a study examining religiosity in T2D patients. Nonsmoking patients with T2D for at least 3 years and aged 30 years and above were recruited. Social support was measured using The Social Support Survey-Medical Outcomes Study (SS), a self-administered questionnaire; the scores range from 19 to 95, and a high score indicates better social support. Glycemic control was measured using the 3 most recent glycosylated hemoglobin (HbA1c) levels within the past 3 years. RESULTS: A total of 175 participants completed the SS survey (response rate 79.0%). The mean age was 62.7 (standard deviation [SD] = 10.8) years, and the mean duration of diabetes was 11.74 (SD = 6.7) years. The mean HbA1c level was 8.15 (SD = 1.44). The mean SS score was 68.1. The prevalence of high and low social support were 29.7% and 24.0 %, respectively. A significant correlation was found between SS score and number of social supporters (n = 167). No significant correlation was found between the self-reported number of social supporters or the SS score and the mean HbA1c level. CONCLUSIONS: Social support was not associated with glycemic control in adult patients with T2D in this primary care setting. PMID- 22199160 TI - Economic crisis, austerity and the Greek public health system. PMID- 22199161 TI - Human Papillomavirus awareness, knowledge and vaccine acceptance: a survey among 18-25 year old male and female vocational school students in Berlin, Germany. AB - BACKGROUND: Human Papillomavirus (HPV) is a common sexually transmitted infection and is aetiologically linked with a number of health problems. In Germany, HPV vaccination for cervical cancer prevention is recommended for girls aged 12-17 years since 2007; however, a coordinated national immunization programme does not exist. We assessed whether socio-demographic factors and sexual history are associated with awareness of HPV and the HPV vaccine, vaccine uptake and HPV related knowledge among young women and men. METHODS: In 2010, a survey was conducted with 18- to 25-year-old students from six vocational schools in Berlin. A total of 259 women and 245 men completed the questionnaire that included socio demographic and sexual behaviour characteristics, questions about HPV awareness, vaccine status, reasons for not wanting to get vaccinated and HPV-related knowledge. RESULTS: Among women aged 18-20 years (those eligible for reimbursed vaccination), 67% were vaccinated. At trend level, women with low education and those without past sexual intercourse were less likely to be vaccinated. Ninety five per cent of the women and 80% of the men were aware of the 'vaccine against cervical cancer', but only half of the women and 25% of the men had heard of HPV. Knowledge was poor (M = 2.8; SD = 2.10 for women and M = 1.5; SD = 1.49 for men; possible range 0-11). Fifty-one per cent of the women and 42% of the men thought that only women can be infected with HPV and the majority did not know that HPV is sexually transmitted. CONCLUSION: Results indicate a need for better education about HPV that should extend beyond its link with cervical cancer. PMID- 22199162 TI - Spikes, BOLD, attention, and awareness: a comparison of electrophysiological and fMRI signals in V1. AB - Early fMRI studies comparing results from fMRI and electrophysiological experiments support the notion that the blood oxygen level-dependent (BOLD) signal reliably follows the spiking activity of an underlying neuronal population averaged across a small region in space and a brief period in time. However, more recent studies focusing on higher level cognitive factors such as attention and visual awareness report striking discrepancies between the fMRI response in humans and electrophysiological signals in macaque early visual areas. Four hypotheses are discussed that can explain the discrepancies between the two methods: (1) the BOLD signal follows local field potential (LFP) signals closer than spikes, and only the LFP is modulated by top-down factors, (2) the BOLD signal is reflecting electrophysiological signals that are occurring later in time due to feedback delay, (3) the BOLD signal is more sensitive than traditional electrophysiological methods due to massive pooling by the hemodynamic coupling process, and finally (4) there is no real discrepancy, and instead, weak but reliable effects on firing rates may be obscured by differences in experimental design and interpretation of results across methods. PMID- 22199163 TI - Resistance training alters skeletal muscle structure and function in human heart failure: effects at the tissue, cellular and molecular levels. AB - Reduced skeletal muscle function in heart failure (HF) patients may be partially explained by altered myofilament protein content and function. Resistance training increases muscle function, although whether these improvements are achieved by correction of myofilament deficits is not known. To address this question, we examined 10 HF patients and 14 controls prior to and following an 18 week high-intensity resistance training programme. Evaluations of whole muscle size and strength, single muscle fibre size, ultrastructure and tension and myosin-actin cross-bridge mechanics and kinetics were performed. Training improved whole muscle isometric torque in both groups, although there were no alterations in whole muscle size or single fibre cross-sectional area or isometric tension.Unexpectedly, training reduced the myofibril fractional area of muscle fibres in both groups. This structural change manifested functionally as a reduction in the number of strongly bound myosin-actin cross-bridges during Ca2+ activation. When post-training single fibre tension data were corrected for the loss of myofibril fractional area, we observed an increase in tension with resistance training. Additionally, training corrected alterations in cross-bridge kinetics (e.g. myosin attachment time) in HF patients back to levels observed in untrained controls. Collectively, our results indicate that improvements in myofilament function in sedentary elderly with and without HF may contribute to increased whole muscle function with resistance training. More broadly, these data highlight novel cellular and molecular adaptations in muscle structure and function that contribute to the resistance-trained phenotype. PMID- 22199164 TI - Basket cell dichotomy in microcircuit function. AB - A diversity of GABAergic cell types exist within each brain area, and each cell type is thought to play a unique role in the modulation of principal cell output. Basket cells, whose axon terminals surround principal cell somata and proximal dendrites, have a privileged and influential position for regulating the firing of principal cells. This review explores the dichotomy of the two basket cell classes, cholecystokinin- (CCK) and parvalbumin (PV)-containing basket cells, beginning with differences at the level of the individual cell and subsequently focusing on two ways in which this intrinsic dichotomy is enhanced by extrinsic factors. Neuromodulatory influences, exemplified by the effects of the peptide CCK, dynamically enhance the differential functions of the two cell types. Specifications at the level of the postsynaptic principal cell, including input specific differences in chloride handling and differences in long-range projection patterns of the principal cell targets, also enhance the distinct network function of basket cells. In this review, new findings will be highlighted concerning the roles of neuromodulatory control and postsynaptic long range projection pattern in the definition of basket cell function. PMID- 22199165 TI - Positive allosteric modulation reveals a specific role for mGlu2 receptors in sensory processing in the thalamus. AB - Group II metabotropic glutamate receptor (mGlu) modulation of sensory processing in the rat ventrobasal thalamic nucleus (VB) has been extensively studied in vivo. However, it is not yet known what the relative contributions are of the Group II mGlu receptor subtypes (mGlu2 and mGlu3) to this modulation, nor to what extent these receptors may be activated under physiological conditions during this process. Using single-neurone recording in the rat VB in vivo with local application of the selective Group II agonist LY354740 and the subtype selective mGlu2 positive allosteric modulator (PAM) LY487379, our findings were twofold. Firstly, we found that there is an mGlu2 component to the effects of LY354740 on sensory responses in the VB. Secondly, we have demonstrated that application of the PAM alone can modulate sensory responses of single neurones in vivo. This indicates that mGlu2 receptors can be activated by endogenous agonist following physiological sensory stimulation. We speculate that the mGlu2 subtype could be activated under physiological stimulus-evoked conditions by 'glutamate spillover' from synapses between excitatory sensory afferents and VB neurones that can lead to a reduction in sensory-evoked inhibition arising from the thalamic reticular nucleus (TRN). We propose that this potential mGlu2 receptor modulation of inhibition could play an important role in discerning relevant information from background activity upon physiological sensory stimulation. Furthermore, this could be a site of action for mGlu2 PAMs to modulate cognitive processes. PMID- 22199167 TI - Non-invasive long-term and real-time analysis of endocrine cells on micro electrode arrays. AB - Non-invasive high-throughput and long-term monitoring of endocrine cells is important for drug research, phenotyping, tissue engineering and pre transplantation quality control. Here we report a novel approach to obtain simultaneous long-term electrical recordings of different islet cell types using multi-electrode arrays. We implemented wavelet transforms to resolve the low signal/noise ratio inherent to these measurements and extracted on-line a signature specific of cell activity. The architecture employed allows multiplexing a large number of electrodes for high-throughput screening. This method should be of considerable advantage in endocrine research and may be extended to other excitable cells previously not accessible to the technique. PMID- 22199166 TI - Regulation of glucose and glycogen metabolism during and after exercise. AB - Utilization of carbohydrate in the form of intramuscular glycogen stores and glucose delivered from plasma becomes an increasingly important energy substrate to the working muscle with increasing exercise intensity. This review gives an update on the molecular signals by which glucose transport is increased in the contracting muscle followed by a discussion of glycogen mobilization and synthesis by the action of glycogen phosphorylase and glycogen synthase, respectively. Finally, this review deals with the signalling relaying the well described increased sensitivity of glucose transport to insulin in the post exercise period which can result in an overshoot of intramuscular glycogen resynthesis post exercise (glycogen supercompensation). PMID- 22199168 TI - An update on cholinergic regulation of cholecystokinin-expressing basket cells. AB - Information processing and transfer within cortical circuits requires precise spatiotemporal coordination of excitatory principal cell activity by a relatively small population of inhibitory interneurons that exhibit remarkable anatomical, molecular and electrophysiological diversity. One subtype of interneuron, the cholecystokinin-expressing basket cell (CCKBC), is particularly well suited to integrate and impart emotional features of an animal's physiological state to principal cell entrainment through the inhibitory network as CCKBCs are highly susceptible to neuromodulation by local and subcortically generated signals commonly associated with 'mood' such as cannabinoids, serotonin and acetylcholine. Here we briefly review recent studies that have elucidated the cellular mechanisms underlying cholinergic regulation of CCKBCs. PMID- 22199169 TI - Acute stress induces down-regulation of large-conductance Ca2+-activated potassium channels in the lateral amygdala. AB - Large-conductance Ca2+-activated potassium channels (BKCa) are highly expressed in the lateral amygdala (LA), which is closely involved in assigning stress disorders, but data on their role in the neuronal circuits of stress disorders are limited. In the present study, a significant reduction in BKCa channel expression in the amygdala of mice accompanied anxiety-like behaviour induced by acute stress. Whole-cell patch-clamp recordings from LA neurons of the anxious animals revealed a pronounced reduction in the fast after-hyperpolarization (fAHP) of action potentials mediated by BKCa channels that led to hyperexcitability of the LA neurons. Activation of BKCa channels in the LA reversed stress-induced anxiety-like behaviour after stress. Furthermore, down regulated BKCa channels notably increased the evoked NMDA receptor-mediated excitatory postsynaptic potentials at the thalamo-LA synapses. These data demonstrate, for the first time, that restraint stress-induced anxiety-like behaviour could at least partly be explained by alterations in the functional BKCa channels in the LA. PMID- 22199170 TI - An integrated in vitro and in situ study of kinetics of myosin II from frog skeletal muscle. AB - A new efficient protocol for extraction and conservation of myosin II from frog skeletal muscle made it possible to preserve the myosin functionality for a week and apply single molecule techniques to the molecular motor that has been best characterized for its mechanical, structural and energetic parameters in situ.With the in vitro motility assay, we estimated the sliding velocity of actin on frog myosin II (VF) and its modulation by pH, myosin density, temperature (range 4-30?C) and substrate concentration. VF was 8.88 +/- 0.26 MUms-1 at 30.6?C and decreased to 1.60 +/- 0.09 MUms-1 at 4.5?C. The in vitro mechanical and kinetic parameters were integrated with the in situ parameters of frog muscle myosin working in arrays in each half-sarcomere. By comparing VF with the shortening velocities determined in intact frog muscle fibres under different loads and their dependence on temperature, we found that VF is 40-50% less than the fibre unloaded shortening velocity (V0) at the same temperature and we determined the load that explains the reduced value of VF. With this integrated approach we could define fundamental kinetic steps of the acto-myosin ATPase cycle in situ and their relation with mechanical steps. In particular we found that at 5?C the rate of ADP release calculated using the step size estimated from in situ experiments accounts for the rate of detachment of motors during steady shortening under low loads. PMID- 22199171 TI - Cerebellar theta burst stimulation impairs eyeblink classical conditioning. AB - Theta burst stimulation (TBS) protocols of repetitive transcranial magnetic stimulation (rTMS) have after-effects on excitability of motor areas thought to be due to LTP- and LTD-like processes at cortical synapses. The present experiments ask whether, despite the low intensities of stimulation used and the anatomy of the posterior fossa, TBS can also influence the cerebellum. Acquisition and retention of eyeblink classical conditioning (EBCC) was examined in 30 healthy volunteers after continuous theta burst stimulation (cTBS) over the right cerebellar hemisphere. In subjects who received cerebellar cTBS, conditioned responses were fewer and their onsets were earlier (in the last half of the acquisition blocks) than those from control subjects. There was, however, no effect of cerebellar cTBS on the re-acquisition of EBCC in another session of EBCC 7-10 days later. There was also no effect of cerebellar cTBS on the re acquisition of EBCC in subjects not naive to EBCC when the stimulation was delivered immediately before a re-acquisition session. Control experiments verified that suppressive effects of cTBS on EBCC were not due to changes in motor cortical excitability or sensory disturbance caused by cTBS. Based on previous EBCC studies in various cerebellar pathologies, our data are compatible with the hypothesis that cerebellar cTBS has a focal cerebellar cortical effect, and are broadly in line with data from studies of EBCC in various animal models. These results confirm that cerebellar TBS has measurable effects on the function of the cerebellum, and indicate it is a useful non-invasive technique with which to explore cerebellar physiology and function in humans. PMID- 22199172 TI - FUNdamentally important: humour and fun as caring and practice. PMID- 22199173 TI - Understanding the private worlds of physicians, nurses, and parents: a study of life-sustaining treatment decisions in Italian paediatric critical care. AB - This study's aim was to describe: (a) How life-sustaining treatment (LST) decisions are made for critically ill children in Italy; and (b) How these decisional processes are experienced by physicians, nurses and parents. Focus groups with 16 physicians and 26 nurses, and individual interviews with 9 parents were conducted. Findings uncovered the 'private worlds' of paediatric intensive care unit (PICU) physicians, nurses and parents; they all suffer tremendously and privately. Physicians struggle with the weight of responsibility and solitude in making LST decisions. Nurses struggle with feelings of exclusion from decisions regarding patients and families that they care for. Physicians and nurses are distressed by legal barriers to LST withdrawal. Parents struggle with their dependence on physicians and nurses to provide care for their child and strive to understand what is happening to their child. Features of helpful and unhelpful communication with parents are highlighted, which should be considered in educational and practice changes. PMID- 22199174 TI - Children's weight status and maternal and paternal feeding practices. AB - Child obesity has become a major concern of health researchers. This study explores the association between parental feeding practices and children's weight status. The study also examines whether maternal and paternal feeding practices lead to significantly different children's weight outcomes. By analyzing samples of 312 children (aged 9-11 and 13-15) and their parents, randomly selected from the Houston Metropolitan Statistical Area, the results show that parental feeding practices are linked to children's weight status. The finding that maternal and paternal feeding practices do not have significantly different effects on children's weight highlights an equivalent role of maternal and paternal feeding practices in shaping children's weight status. PMID- 22199175 TI - Food insecurity among Australian children: potential determinants, health and developmental consequences. AB - Children in food-insecure households may be at risk of poor health, developmental or behavioural problems. This study investigated the associations between food insecurity, potential determinants and health and developmental outcomes among children. Data on household food security, socio-demographic characteristics and children's weight, health and behaviour were collected from households with children aged 3-17 years in socioeconomically disadvantaged suburbs by mail survey using proxy-parental reports (185 households). Data were analysed using logistic regression. Approximately one-in-three households (34%) were food insecure. Low household income was associated with an increased risk of food insecurity [odds ratio (OR), 16.20; 95% confidence interval (CI), 3.52-74.47]. Children with a parent born outside of Australia were less likely to experience food insecurity (OR, 0.42; 95% CI, 0.19-0.93). Children in food-insecure households were more likely to miss days from school or activities (OR, 3.52; 95% CI, 1.46-8.54) and were more likely to have borderline or atypical emotional symptoms (OR, 2.44; 95% CI, 1.11-5.38) or behavioural difficulties (OR, 2.35; 95% CI, 1.04-5.33). Food insecurity may be prevalent among socioeconomically disadvantaged households with children. The potential developmental consequences of food insecurity during childhood may result in serious adverse health and social implications. PMID- 22199176 TI - Pediatric eye injuries treated in US emergency departments, 1990-2009. AB - This study investigates activity- and consumer product-related eye injuries treated in US hospital emergency departments among children <18 years old using National Electronic Injury Surveillance System data from 1990 through 2009. An estimated 1,406,200 (95% confidence interval = 1,223,409-1,588,992) activity- and consumer product-related pediatric eye injuries occurred during the study period, averaging 70,310 annually. The annual number of injuries declined significantly by 17%. Patients <= 4 years of age accounted for 32% of all injuries and had the highest mean annual eye injury rate (11.31 per 10,000 population). Eye injuries associated with sports and recreation (24%) and chemicals (17%) occurred most frequently. The majority (69%) of eye injuries occurred at home. Opportunities exist to further decrease these injuries. Pediatricians should educate child caregivers and children about risks for eye injuries in the home and about use of appropriate protective eyewear during sports. PMID- 22199177 TI - Utilization of umbilical cord blood for the evaluation of group B streptococcal sepsis screening. AB - OBJECTIVE: To evaluate reliability of umbilical cord blood (UCB) for complete blood count (CBC) and blood cultures compared with the infant's blood from peripheral site for group B streptococcal (GBS) sepsis screening. METHODS: A total of 200 neonates, at risk for GBS infection, were studied prospectively. After birth, UCB sample was obtained for CBC and blood cultures from umbilical vein. Peripheral arterial/venous blood was obtained from the neonate. RESULTS: In 200 neonates, CBC counts were similar for clinical significance except for leukopenia (6% in UCB vs 1.2% in peripheral blood, P = .02). One UCB sample grew GBS and another grew microaerophilic streptococcus, a contaminant. A neonatal sample grew Escherichia coli, a pathogen and another neonatal sample grew Staphylococcus auricularis, a contaminant. CONCLUSION: CBC results were similar from UCB and the infant for the purpose of GBS screening. Contamination of UCB sample for culture is uncommon. Hence, UCB may be used for GBS sepsis screen. PMID- 22199178 TI - Endovascular repair of ascending aortic pseudoaneurysm in a high-risk patient. AB - Mycotic ascending aortic pseudoaneurysm (AAP) is an uncommon but surgically challenging problem with high morbidity and mortality rates. We describe endovascular repair of an acute mycotic AAP in a high-risk patient. A 45-year old man, HIV serum positive, chronic hepatitis HBV and HCV related, presented, after two sternotomies, with a fast growing 11 6 cm AAP that was sealed with two Gore Exluder aortic cuffs, inserted from the left axillary artery. Nine months control CT continued to show no endoleak with shrinking of the AAP. PMID- 22199179 TI - Social comparison processes, narrative mapping and their shaping of the cancer experience: a case study of an elite athlete. AB - Drawing on data generated by life history interviews and fieldwork observations we illuminate the ways in which a young elite athlete named David (a pseudonym) gave meaning to his experiences of cancer that eventually led to his death. Central to this process were the ways in which David utilized both social comparisons and a narrative map provided by the published autobiography of Lance Armstrong (2000). Our analysis reveals the selective manner in which social comparison processes operated around the following key dimensions: mental attitude to treatment; the sporting body; the ageing body; and physical appearance. The manner in which different comparison targets were chosen, the ways in which these were framed by Armstrong's autobiography, and the work that the restitution narrative as an actor did in this process are also examined. Some reflections are offered regarding the experiential consequences of the social comparison processes utilized by David when these are shaped by specific forms of embodiment and selective narrative maps of cancer survival. PMID- 22199180 TI - The symbolic constitution of addiction: language, alienation, ambivalence. AB - The author offers an articulation of addiction, via existential-phenomenology and Lacanian psychoanalysis, where it is argued that the addicted subject is constituted via a symbolic structuring evolving from societal practices, laws and the effects of language. Language carries a heritage, which bears on the knowledge and practices of designated subjects and practitioners of that discourse. Addiction, as one particular form of embodied existence and knowledgeable practice, finds expression through the speech and habits of the addict. Addiction, it is argued, is symbolically saturated with ambivalence and alienation. Also the addict is described as the complete modern technocratic subject, consumed by the ideology of consumption. The clinical implications are briefly explored where it is noted that two major approaches to addiction, namely 12-step fellowships and motivational interviewing, both attend to language as a critical component of their treatment approach. PMID- 22199181 TI - Comparing identification of standardized and regionally valid vowels. AB - PURPOSE: In perception studies, it is common to use vowel stimuli from standardized recordings or synthetic stimuli created using values from well-known published research. Although the use of standardized stimuli is convenient, unconsidered dialect and regional accent differences may introduce confounding effects. The goal of this study was to examine the effect of regional accent variation on vowel identification. METHOD: The authors analyzed formant values of 8 monophthong vowels produced by 12 talkers from the region where the research took place and compared them with standardized vowels. Fifteen listeners with normal hearing identified synthesized vowels presented in varying levels of noise and at varying spectral distances from the local-dialect values. RESULTS: Acoustically, local vowels differed from standardized vowels, and distance varied across vowels. Perceptually, there was a robust effect of accent similarity such that identification was reduced for vowels at greater distances from local values. CONCLUSIONS: Researchers and clinicians should take care in choosing stimuli for perception experiments. It is recommended that regionally validated vowels be used instead of relying on standardized vowels in vowel perception tasks. PMID- 22199182 TI - Episodic long-term memory of spoken discourse masked by speech: what is the role for working memory capacity? AB - PURPOSE: To investigate whether working memory capacity (WMC) modulates the effects of to-be-ignored speech on the memory of materials conveyed by to-be attended speech. METHOD: Two tasks (reading span, Daneman & Carpenter, 1980; Ronnberg et al., 2008; and size-comparison span, Sorqvist, Ljungberg, & Ljung, 2010) were used to measure individual differences in WMC. Episodic long-term memory of spoken discourse was measured by requesting participants to listen to stories masked either by normal speech or by a rotated version of that speech and to subsequently answer questions on the content of the stories. RESULTS: Normal speech impaired performance on the episodic long-term memory test, and both WMC tasks were negatively related to this effect, indicating that individuals with high WMC are less susceptible to disruption. Moreover, further analyses revealed that size-comparison span (a task that requires resolution of semantic confusion by inhibition processes) is a stronger predictor of the effect than is reading span. CONCLUSIONS: Cognitive control processes support listening in adverse conditions. In particular, inhibition processes acting to resolve semantic confusion seem to underlie the relationship between WMC and susceptibility to distraction from masking speech. PMID- 22199183 TI - Speech recognition and acoustic features in combined electric and acoustic stimulation. AB - PURPOSE: In this study, the authors aimed to identify speech information processed by a hearing aid (HA) that is additive to information processed by a cochlear implant (CI) as a function of signal-to-noise ratio (SNR). METHOD: Speech recognition was measured with CI alone, HA alone, and CI + HA. Ten participants were separated into 2 groups; good (aided pure-tone average [PTA] < 55 dB) and poor (aided PTA >= 55 dB) at audiometric frequencies <= 1 kHz in HA. RESULTS: Results showed that the good-aided PTA group derived a clear bimodal benefit (performance difference between CI + HA and CI alone) for vowel and sentence recognition in noise, whereas the poor-aided PTA group received little benefit across speech tests and SNRs. Results also showed that a better aided PTA helped in processing cues embedded in both low and high frequencies; none of these cues was significantly perceived by the poor-aided PTA group. CONCLUSIONS: The aided PTA is an important indicator for bimodal advantage in speech perception. The lack of bimodal benefits in the poor group may be attributed to the nonoptimal HA fitting. Bimodal listening provides a synergistic effect for cues in both low- and high-frequency components in speech. PMID- 22199184 TI - Relationship between consonant recognition in noise and hearing threshold. AB - PURPOSE: Although poorer understanding of speech in noise by listeners who are hearing-impaired (HI) is known not to be directly related to audiometric hearing threshold, HT (f), grouping HI listeners with HT (f) is widely practiced. In this article, the relationship between consonant recognition and HT (f) is considered over a range of signal-to-noise ratios (SNRs). METHOD: Confusion matrices (CMs) from 25 HI ears were generated in response to 16 consonant-vowel syllables presented at 6 different SNRs. Individual differences scaling (INDSCAL) was applied to both feature-based matrices and CMs in order to evaluate the relationship between HT (f) and consonant recognition among HI listeners. RESULTS: The results showed no predictive relationship between the percent error scores (Pe) and HT (f) across SNRs. The multiple regression models showed that the HT (f) accounted for 39% of the total variance of the slopes of the Pe. Feature-based INDSCAL analysis showed consistent grouping of listeners across SNRs, but not in terms of HT (f). Systematic relationship between measures was also not defined by CM-based INDSCAL analysis across SNRs. CONCLUSIONS: HT (f) did not account for the majority of the variance (39%) in consonant recognition in noise when the complete body of the CM was considered. PMID- 22199185 TI - Perceptual learning of dysarthric speech: a review of experimental studies. AB - PURPOSE: This review article provides a theoretical overview of the characteristics of perceptual learning, reviews perceptual learning studies that pertain to dysarthric populations, and identifies directions for future research that consider the application of perceptual learning to the management of dysarthria. METHOD: A critical review of the literature was conducted that summarized and synthesized previously published research in the area of perceptual learning with atypical speech. Literature related to perceptual learning of neurologically degraded speech was emphasized with the aim of identifying key directions for future research with this population. CONCLUSIONS: Familiarization with unfamiliar or ambiguous speech signals can facilitate perceptual learning of that same speech signal. There is a small but growing body of evidence that perceptual learning also occurs for listeners familiarized with dysarthric speech. Perceptual learning of the dysarthric signal is both theoretically and clinically significant. In order to establish the efficacy of exploiting perceptual learning paradigms for rehabilitative gain in dysarthria management, research is required to build on existing empirical evidence and develop a theoretical framework for learning to better recognize neurologically degraded speech. PMID- 22199186 TI - The influence of stimulus taste and chemesthesis on tongue movement timing in swallowing. AB - PURPOSE: To explore the influence of taste and trigeminal irritation (chemesthesis) on durational aspects of tongue movement in liquid swallowing, controlling for the influence of perceived taste intensity. METHOD: Electromagnetic midsagittal articulography was used to trace tongue movements during discrete liquid swallowing with 5 liquids: water, 3 moderate concentration tastants without odor (sweet, sour, sweet-sour), and a high concentration of citric acid (sour taste plus chemesthesis). Participants were 33 healthy adults in 2 gender-balanced, age-stratified groups (under/over 50). Perceived taste intensity was measured using the Generalized Labeled Magnitude Scale (Bartoshuk, 2000; Bartoshuk et al., 2004). Tongue movement sequencing and durations of the composite tongue movement envelope and component events (rise phase, location of first movement peak, release phase) were calculated. RESULTS: No obligate sequence of tongue segment movement was observed. Overall durations and the timing of the first movement peak were significantly longer with water than with the moderate concentration of sweet-sour liquid. Perceived taste intensity did not modulate stimulus effects in a significant way. The expected pattern of shorter movement durations with the high concentration of citric acid was not seen. CONCLUSIONS: A chemesthetic-taste stimulus of high citric acid did not influence the durations of tongue movements compared with those seen during the swallowing of moderate concentration tastants and water. PMID- 22199187 TI - Effect of onset and rhyme primes in preschoolers with typical development and specific language impairment. AB - PURPOSE: In this study, the authors used cued shadowing to examine children's phonological word-form representations by studying the effects of onset and rhyme primes on lexical access. METHOD: Twenty-five preschoolers with specific language impairment (SLI; hereafter known as the SLI group), 24 age- and gender-matched children (AM group), and 20 vocabulary- and gender-matched children (VM group) participated. Children listened to pairs of words and repeated the second word as quickly as they could. Primes included words with overlapping onsets, words with overlapping rimes, and identical or unrelated words. RESULTS: As expected, unrelated words inhibited production in the AM and VM groups. Overlapping rimes primed production in the AM group. No inhibitory or priming effects were found for the SLI group. CONCLUSION: Phonological priming may be used to study the phonological representations of preschool-age children. Results suggest that none of the groups accessed words incrementally. Priming for overlapping rimes by the AM but not the VM or SLI groups may indicate that the AM group benefited from lexical organization favoring nucleus + rime organization that has not yet developed for the VM or SLI groups. The lack of inhibition in the SLI group suggests that their phonological representations were not detailed enough to prime words in their lexicon or that they did not process the prime or target words. PMID- 22199188 TI - Vocabulary and working memory in children fit with hearing aids. AB - PURPOSE: To determine whether children with mild-to-moderately severe sensorineural hearing loss (CHL) present with disturbances in working memory and whether these disturbances relate to the size of their receptive vocabularies. METHOD: Children 6 to 9 years of age participated. Aspects of working memory were tapped by articulation rate, forward and backward digit span in the auditory and visual modalities, Corsi span, parent surveys, and a sequential encoding task. Articulation rate, digit spans, and Corsi spans were also administered in low level broadband noise. RESULTS: CHL and children with normal hearing (CNH) demonstrated auditory advantage in forward serial recall. CHL demonstrated slower articulation rates than CNH, but similar memory spans. CHL with poor executive function presented with poorer performance on the Corsi span task. The presence of background noise had no effect on performance in either group. CHL presented with significantly smaller receptive vocabularies than their CNH peers. Across groups, receptive vocabulary size was positively correlated with digit span in quiet, Corsi span in noise, and articulation rate. CONCLUSIONS: In the presence of mild-to-moderately severe hearing loss, children demonstrated resilient working memory systems. For all children, working memory and vocabulary were related; that is, children with poorer working memory had smaller vocabulary sizes. PMID- 22199189 TI - Effects of the menstrual cycle and oral contraception on singers' pitch control. AB - PURPOSE: Difficulties with intonation and vibrato control during the menstrual cycle have been reported by singers; however, this phenomenon has not yet been systematically investigated. METHOD: A double-blind randomized placebo-controlled trial assessing effects of the menstrual cycle and use of a combined oral contraceptive pill (OCP) on pitch control in singing is presented. Audio electrolaryngograph recordings were made and blood samples were taken from 9 singers in each of the 3 phases of the menstrual cycle both under the placebo and the OCP conditions for a total of 6 months. Participants sang an exercise consisting of an ascending octave followed by a descending major triad, starting on pitches F4 and B4. Pitch control was assessed in terms of the octave's deviations from pure intonation and of the vibrato rate and extent. RESULTS: Significant differences were found between the 3 phases of the cycle regarding octave size only for pitch F5 during OCP use. Significant vibrato rate differences between placebo and OCP conditions were found only for pitch F5. CONCLUSION: OCP use may have an effect on pitch control in singers. Possible explanations point to a complex interaction between hormonal milieu and pitch control, enhancing the need for longitudinal studies. PMID- 22199190 TI - How children with autism extend new words. AB - PURPOSE: How do children with autism spectrum disorders (ASD) extend a noun to the category of objects it labels? Given their tendency to perceive locally, their extensions might be too narrow. Given their social-communicative deficits and a context in which the knowledge of a social-communicative partner promotes narrow extensions, their extensions might be too broad. METHOD: We tested these predictions by comparing 25 high-functioning school-aged children with ASD to 29 age-matched peers with typical development (TD) in a task that required extraction of commonalities of object referents and use of social-communicative context to support the category inference. RESULTS: The children with ASD readily extended a given noun to multiple exemplars, thereby demonstrating tacit knowledge that words label categories and the ability to override local perceptual biases they might have. However, unlike their peers with TD, those who had concomitant weaknesses in semantic and syntactic language ability formed broad categories when their social partner's behavior suggested narrow categories. CONCLUSIONS: Some, but not all, people with ASD fail to use social context to support inferences about word extension. The direction of any causal relationship between failure to use social contextual cues and language deficits awaits determination. PMID- 22199191 TI - New measures of masked text recognition in relation to speech-in-noise perception and their associations with age and cognitive abilities. AB - PURPOSE: In this research, the authors aimed to increase the analogy between Text Reception Threshold (TRT; Zekveld, George, Kramer, Goverts, & Houtgast, 2007) and Speech Reception Threshold (SRT; Plomp & Mimpen, 1979) and to examine the TRT's value in estimating cognitive abilities that are important for speech comprehension in noise. METHOD: The authors administered 5 TRT versions, SRT tests in stationary (SRT(STAT)) and modulated (SRT(MOD)) noise, and 2 cognitive tests: a reading span (RSpan) test for working memory capacity and a letter-digit substitution test for information-processing speed. Fifty-five adults with normal hearing (18-78 years, M = 44 years) participated. The authors examined mutual associations of the tests and their predictive value for the SRTs with correlation and linear regression analyses. RESULTS: SRTs and TRTs were well associated, also when controlling for age. Correlations for the SRT(STAT) were generally lower than for the SRT(MOD.) The cognitive tests were correlated to the SRTs only when age was not controlled for. Age and the TRTs were the only significant predictors of SRT(MOD). SRT(STAT) was predicted by level of education and some of the TRT versions. CONCLUSIONS: TRTs and SRTs are robustly associated, nearly independent of age. The association between SRTs and RSpan is largely age dependent. The TRT test and the RSpan test measure different nonauditory components of linguistic processing relevant for speech perception in noise. PMID- 22199192 TI - Auditory long latency responses to tonal and speech stimuli. AB - PURPOSE: The effects of type of stimuli (i.e., nonspeech vs. speech), speech (i.e., natural vs. synthetic), gender of speaker and listener, speaker (i.e., self vs. other), and frequency alteration in self-produced speech on the late auditory cortical evoked potential were examined. METHOD: Young adult men (n = 15) and women (n = 15), all with normal hearing, participated. P1-N1-P2 components were evoked with the following stimuli: 723-Hz tone bursts; naturally produced male and female /a/ tokens; synthetic male and female /a/ tokens; an /a/ token self-produced by each participant; and the same /a/ token produced by the participant but with a shift in frequency. RESULTS: In general, P1-N1-P2 component latencies were significantly shorter when evoked with the tonal stimulus versus speech stimuli and natural versus synthetic speech (p < .05). Women had significantly shorter latencies for only the P2 component (p < .05). For the tonal versus speech stimuli, P1 amplitudes were significantly smaller, and N1 and P2 amplitudes were significantly larger (p < .05). There was no significant effect of gender on the P1, N1, or P2 amplitude (p > .05). CONCLUSION: These findings are consistent with the notion that spectrotemporal characteristics of nonspeech and speech stimuli affect P1-N1-P2 latency and amplitude components. PMID- 22199193 TI - Phonology and language development in Italian children: an analysis of production and accuracy. AB - PURPOSE: The principal aims of this study were to detect phonetic measures (consonant inventory, intelligibility, frequency, and types of phonological errors) associated with lexical and morphosyntactic ability and to analyze the types of phonological processes in children with different language skills. METHOD: The sample was composed of 30 children between the ages of 36 and 42 months. Two tests were administered, one investigating phonological ability and one investigating general linguistic ability. RESULTS: A strong relationship between phonetic measures and language performance was found. The proportion of unintelligible productions and simplified words correlated with all the linguistic measures considered. A comparison of the phonological processes used by children with low, average, and high linguistic performance showed that phonotactic structure errors discriminated better than did system errors between the three groups. In particular, the less competent talkers were more likely to delete weak syllables, omit consonants and vowels, reduce diphthongs, and make consonant harmony errors. CONCLUSIONS: The results emphasize the importance of phonetic measures in explaining differences in language performance and suggest the possibility of identifying children with low linguistic competence on the basis of phonetic measures, such as the level of intelligibility and the type of errors committed. PMID- 22199194 TI - Lack of generalization of auditory learning in typically developing children. AB - PURPOSE: To understand the components of auditory learning in typically developing children by assessing generalization across stimuli, across modalities (i.e., hearing, vision), and to higher level language tasks. METHOD: Eighty-six 8 to 10-year-old typically developing children were quasi-randomly assigned to 4 groups. Three of the groups received twelve 30-min training sessions on multiple standards using either an auditory frequency discrimination task (AFD group), auditory phonetic discrimination task (PD group), or visual frequency discrimination task (VFD group) over 4 weeks. The 4th group, which was the no intervention control (NI) group, did not receive any training. Thresholds on all tasks (AFD, PD, and VFD) were assessed immediately before and after training, along with performance on a battery of language assessments. RESULTS: Relative to the other groups, both the AFD group and the PD group, but not the VFD group, showed significant learning on the stimuli upon which they were trained. However, in those instances where learning was observed, it did not generalize to the nontrained stimuli or to the language assessments. CONCLUSIONS: Nonspeech (AFD) or speech (PD) discrimination training can lead to auditory learning in typically developing children of this age range. However, this learning does not always generalize across stimuli or tasks, across modalities, or to higher level measures of language ability. PMID- 22199195 TI - Perception of speech features by French-speaking children with cochlear implants. AB - PURPOSE: The present study investigates the perception of phonological features in French-speaking children with cochlear implants (CIs) compared with normal hearing (NH) children matched for listening age. METHOD: Scores for discrimination and identification of minimal pairs for all features defining consonants (e.g., place, voicing, manner, nasality) and vowels (e.g., frontness, nasality, aperture) were measured in each listener. RESULTS: The results indicated no differences in "categorical perception," specified as a similar difference between discrimination and identification between CI children and controls. However, CI children demonstrated a lower level of "categorical precision," that is, lesser accuracy in both feature identification and discrimination, than NH children, with the magnitude of the deficit depending on the feature. CONCLUSIONS: If sensitive periods of language development extend well beyond the moment of implantation, the consequences of hearing deprivation for the acquisition of categorical perception should be fairly important in comparison to categorical precision because categorical precision develops more slowly than categorical perception in NH children. These results do not support the idea that the sensitive period for development of categorical perception is restricted to the first 1-2 years of life. The sensitive period may be significantly longer. Differences in precision may reflect the acoustic limitations of the cochlear implant, such as coding for temporal fine structure and frequency resolution. PMID- 22199196 TI - Semantic deficits in Spanish-English bilingual children with language impairment. AB - PURPOSE: To examine the nature and extent of semantic deficits in bilingual children with language impairment (LI). METHOD: Thirty-seven Spanish-English bilingual children with LI (ranging from age 7;0 [years;months] to 9;10) and 37 typically developing (TD) age-matched peers generated 3 associations to 12 pairs of translation equivalents in English and Spanish. Responses were coded as paradigmatic (e.g., dinner-lunch, cena-desayuno [dinner-breakfast]), syntagmatic (e.g., delicious-pizza, delicioso-frijoles [delicious-beans]), and errors (e.g., wearing-where, vestirse-mal [to get dressed-bad]). A semantic depth score was derived in each language and conceptually by combining children's performance in both languages. RESULTS: The LI group achieved significantly lower semantic depth scores than the TD group after controlling for group differences in vocabulary size. Children showed higher conceptual scores than single-language scores. Both groups showed decreases in semantic depth scores across multiple elicitations. Analyses of individual performances indicated that semantic deficits (1 SD below the TD mean semantic depth score) were manifested in 65% of the children with LI and in 14% of the TD children. CONCLUSION: School-age bilingual children with and without LI demonstrated spreading activation of semantic networks. Consistent with the literature on monolingual children with LI, sparsely linked semantic networks characterize a considerable proportion of bilingual children with LI. PMID- 22199197 TI - Bilingual listeners' perception of temporally manipulated English passages. AB - PURPOSE: The current study measured, objectively and subjectively, how changes in speech rate affect recognition of English passages in bilingual listeners. METHOD: Ten native monolingual, 20 English-dominant bilingual, and 20 non-English dominant bilingual listeners repeated target words in English passages at five speech rates (unprocessed, two expanded, and two compressed), in quiet and in noise. For noise conditions, performance was measured at a signal-to-noise ratio that was determined through an adaptive procedure to avoid ceiling and floor effects. Listeners also made subjective judgments of speech rate, speech clarity, and performance confidence. RESULTS: In noise, stepwise improvement was observed as rate slowed down. A similar effect was not found in quiet. This pattern in performance was largely comparable across listener groups but was most robust in English-dominant listeners. Changes in speech rate and presence of noise significantly affected listeners' subjective ratings; however, no intergroup differences were observed for any of the subjective ratings. CONCLUSIONS: Bilingual listeners benefited from slow speech rates, more evidently so in noise than in quiet. Their performance, however, did not reach a monolingual level, even at the most favorable rate. Nonetheless, all listeners reported comparable confidence when processing temporally manipulated English passages. PMID- 22199198 TI - Sentence comprehension in postinstitutionalized school-age children. AB - PURPOSE: In this study, the authors investigated sentence comprehension and spatial working memory abilities in a sample of internationally adopted, postinstitutionalized (PI) children. The authors compared the performance of these PI children with that of an age-matched group of children living with their birth families. They hypothesized that PI children would perform below clinical threshold on tasks of sentence comprehension and that poor sentence comprehension would be associated with poor performance in working memory. METHOD: Twenty-three PI children and 36 comparison children were administered sentence comprehension and spatial memory tasks from standardized assessments. RESULTS: Some oral sentence comprehension skills and the spatial working memory skills were weaker in the school-age PI children than in the age-matched comparison children. A mediational analysis demonstrated that poor spatial working memory performance partially explains the sentence comprehension differences between the 2 groups. CONCLUSION: These findings provide valuable information to better plan early intervention and special education for PI children. PMID- 22199199 TI - Selective auditory attention in adults: effects of rhythmic structure of the competing language. AB - PURPOSE: The authors assessed adult selective auditory attention to determine effects of (a) differences between the vocal/speaking characteristics of different mixed-gender pairs of masking talkers and (b) the rhythmic structure of the language of the competing speech. METHOD: Reception thresholds for English sentences were measured for 50 monolingual English-speaking adults in conditions with 2-talker (male-female) competing speech spoken in a stress-based (English, German), syllable-based (Spanish, French), or mora-based (Japanese) language. Two different masking signals were created for each language (i.e., 2 different 2 talker pairs). All subjects were tested in 10 competing conditions (2 conditions for each of the 5 languages). RESULTS: A significant difference was noted between the 2 masking signals within each language. Across languages, significantly greater listening difficulty was observed in conditions where competing speech was spoken in English, German, or Japanese, as compared with Spanish or French. CONCLUSIONS: Results suggest that (a) for a particular language, masking effectiveness can vary between different male-female 2-talker maskers and (b) for stress-based vs. syllable-based languages, competing speech is more difficult to ignore when spoken in a language from the native rhythmic class as compared with a nonnative rhythmic class, regardless of whether the language is familiar or unfamiliar to the listener. PMID- 22199200 TI - Contribution of linguistic variables to bilingual listeners' perception of degraded English sentences. AB - PURPOSE: The present study was designed to investigate what linguistic variables best predict bilingual recognition of acoustically degraded sentences and how to identify bilingual individuals who might have more difficulty than their monolingual counterparts on such tasks. METHOD: Four hundred English speech perception-in-noise (SPIN) sentences with high and low context were presented in combinations of noise (signal-to-noise ratio: +6 and 0 dB) and reverberation (reverberation time: 1.2 and 3.6 s) to 10 monolingual and 50 bilingual listeners. A detailed linguistic profile was obtained for bilingual listeners using the Language Experience and Proficiency Questionnaire. RESULTS: Variables per reading in English (age of fluency, proficiency, and preference) emerged as strong predictors of performance across noise, reverberation, and context effects. Via discriminant analyses, bilingual listeners who rated their accent to be perceptible and reported shorter length of immersion in an English-spoken country or school tended to score significantly lower on the SPIN test than monolingual listeners. CONCLUSIONS: Bilingual listeners' linguistic background plays a major role in their use of context in degraded English sentences. Rather than conventional variables such as age of acquisition, variables pertaining to reading, proficiency, immersion, and accent severity may be obtained for improved prediction of bilingual performance on the task. PMID- 22199201 TI - Are syllabification and resyllabification strategies phonotactically directed in French children with dyslexia? A preliminary report. AB - PURPOSE: In this study, the authors queried whether French-speaking children with dyslexia were sensitive to consonant sonority and position within syllable boundaries to influence a phonological syllable-based segmentation in silent reading. METHOD: Participants included 15 French-speaking children with dyslexia, compared with 30 chronological age-matched and reading level-matched controls. Children were tested with an audiovisual recognition task. A target pseudoword (TOLPUDE) was simultaneously presented visually and auditorily and then was compared with a printed test pseudoword that either was identical or differed after the coda deletion (TOPUDE) or the onset deletion (TOLUDE). The intervocalic consonant sequences had either a sonorant coda-sonorant onset (TOR.LADE), sonorant coda-obstruent onset (TOL.PUDE), obstruent coda-sonorant onset (DOT.LIRE), or obstruent coda-obstruent onset (BIC.TADE) sonority profile. RESULTS: All children processed identity better than they processed deletion, especially with the optimal sonorant coda-obstruent onset sonority profile. However, children preserved syllabification (coda deletion; TO.PUDE) rather than resyllabification (onset deletion; TO.LUDE) with intervocalic consonant sequence reductions, especially when sonorant codas were deleted but the optimal intersyllable contact was respected. CONCLUSIONS: It was surprising to find that although children with dyslexia generally exhibit phonological and acoustic phonetic impairments (voicing), they showed sensitivity to the optimal sonority profile and a preference for preserved syllabification. The authors proposed a sonority-modulated explanation to account for phonological syllable-based processing. Educational implications are discussed. PMID- 22199202 TI - Is tongue strength an important influence on rate of articulation in diadochokinetic and reading tasks? AB - PURPOSE: The purpose of this study was to assess the relationship between tongue strength and rate of articulation in 2 speech tasks, diadochokinetic rates and reading aloud, in healthy men and women between 20 and 78 years of age. METHOD: Diadochokinetic rates were measured for the syllables /p/, /t/, /k/, and /ptk/, and articulation rates were calculated for a reading of the Rainbow Passage for 57 adult volunteers. The Iowa Oral Performance Instrument (LLC Northwest) was used to obtain maximum tongue pressure, tongue pressure exerted during production of /t/, and tongue endurance. Correlation analyses were performed to determine the relation among articulation rate and tongue pressure and endurance measures. RESULTS: Maximum tongue pressure, the pressure used to produce /t/, the proportion of maximum pressure used to produce /t/, and tongue endurance were poor predictors of diadochokinetic rates and articulation rate in reading for healthy speakers. Discussion Focus must remain on factors beyond strength, such as movement precision and coordination, to improve researchers' understanding of normal and disordered speech production in adults. PMID- 22199203 TI - Dialect variation and reading: is change in nonmainstream American English use related to reading achievement in first and second grades? AB - PURPOSE: In this study, we examined (a) whether children who spoke Nonmainstream American English (NMAE) frequently in school at the beginning of 1st grade increased their use of Mainstream American English (MAE) through the end of 2nd grade, and whether increasing MAE use was associated with (b) language and reading skills and school context and (c) greater gains in reading skills. METHOD: A longitudinal design was implemented with 49 children who spoke NMAE moderately to strongly. Spoken production of NMAE forms, word reading, and reading comprehension were measured at the beginning, middle, and end of 1st and 2nd grades. Various oral language skills were also measured at the beginning of 1st grade. RESULTS: Results indicate that most children increased their MAE production during 1st grade and maintained these levels in 2nd grade. Increasing MAE use was predicted by children's expressive vocabulary and nonword repetition skills at the beginning of 1st grade. Finally, the more children increased their MAE production, the greater were their reading gains from 1st grade through 2nd grade. CONCLUSIONS: The findings extend previous reports of a significant association between NMAE use and specific reading skills among young children and have implications for theory, educational practice, and future research. PMID- 22199204 TI - Examining success of communication strategies used by formal caregivers assisting individuals with Alzheimer's disease during an activity of daily living. AB - PURPOSE: To examine how formal (i.e., employed) caregivers' use verbal and nonverbal communication strategies while assisting individuals with moderate to severe Alzheimer's disease (AD) during the successful completion of an activity of daily living (ADL). Based on the literature, the authors hypothesized that caregivers' use of 1 proposition, closed-ended questions, and repetition would be of most benefit. METHOD: Twelve caregiver-AD dyads participated in this observational study. Each dyad was videorecorded on 6 separate occasions while completing handwashing. Handwashing sessions were transcribed and systematically coded for the use of communication strategies during completion of the ADL. RESULTS: Caregiver-AD dyads successfully completed 90% of all handwashing sessions, and caregivers employed a variety of communication strategies. Consistent with our hypotheses, during successful task completion, caregivers most frequently provided individuals with AD with 1 direction or idea (i.e., proposition) at a time, closed-ended questions, and paraphrased repetition. Caregivers also frequently used encouraging comments and the resident's name during the task; however, use of these strategies was not correlated to task success rate. CONCLUSION: This study adds to the limited body of evidence supporting the use of specific communication strategies by caregivers assisting individuals with moderate to severe AD during successful completion of ADLs. PMID- 22199205 TI - General and specific effects of lexicon in grammar: determiner and object pronoun omissions in child Spanish. AB - PURPOSE: This study explores the hypothesis that vocabulary growth can have 2 types of effects in morphosyntactic development. One is a general effect, where vocabulary growth globally determines utterance complexity, defined in terms of sentence length and rates of subordination. There are also specific effects, where vocabulary size has a selective impact on the acquisition of grammatical markers and where lexicon is a prerequisite for typological convergence. The study compares the differential effects of vocabulary in 2 measures of morphosyntactic development: omissions of object clitic pronouns and definite articles. METHOD: Correlation analysis and structural equation models were used to analyze the statistical effects of measures of vocabulary and grammatical development in 110 Spanish-speaking monolingual children ages 3-5 years. RESULTS: The data revealed general effects of vocabulary growth on utterance length and subordination rates and on the use of definite determiners and object pronouns. Specific effects of vocabulary growth were identified for object pronouns but not for determiners. CONCLUSIONS: The study found support for a 2-dimensional model separating lexicon and syntax and for 2 types of relationships. Vocabulary development generally determines sentence complexity and further evidence for specific effects in object pronoun use. PMID- 22199206 TI - Genetic and environmental effects on vocal symptoms and their intercorrelations. AB - PURPOSE: Recently, Simberg et al. (2009) found genetic effects on a composite variable consisting of 6 vocal symptom items measuring dysphonia. The purpose of the present study was to determine genetic and environmental effects on the individual vocal symptoms in a population-based sample of Finnish twins. METHOD: The sample comprised 1,728 twins (125 monozygotic and 108 dizygotic twin pairs) born between 1961 and 1989, who completed a questionnaire concerning 6 vocal symptoms. Values for additive genetic, dominant genetic, shared environmental, and nonshared environmental components were computed separately for all symptoms. Multivariate analyses to determine genetic and environmental associations between the vocal symptoms were also performed. RESULTS: Variance was explained by significant additive genetic effects (27%) in only one of the vocal symptoms, namely, voice gets low or hoarse, whereas the variance of one of the vocal symptoms, voice gets strained or tires, could be explained by nonshared environmental influence alone. Multivariate analyses showed that the correlations for most of the symptom combinations were significant. CONCLUSIONS: Both genetic and environmental components influence vocal symptoms. Genetic and environmental influences seem to be differently balanced in different vocal symptoms. Genetic effects are moderate, whereas environmental effects seem to be the most important factor contributing to the presence of vocal symptoms. PMID- 22199207 TI - Reclassification of Xylanibacter oryzae Ueki et al. 2006 as Prevotella oryzae comb. nov., with an emended description of the genus Prevotella. AB - 16S rRNA gene sequence information has indicated that Xylanibacter oryzae has a close relationship with the genus Prevotella. To clarify the taxonomic position of X. oryzae, we determined the sequence of hsp60 as it represents an alternative phylogenetic marker for identification and classification of Gram-negative anaerobic rods. On the basis of hsp60 sequences, X. oryzae was located within the genus Prevotella, indicating that the species does not represent a distinct taxon at the genus level. Statistical tests (the Shimodaira-Hasegawa test and the approximately unbiased test) supported the finding that X. oryzae is monophyletic with members of the genus Prevotella and thus belongs to the genus. On the basis of the phylogenetic findings, we propose that X. oryzae should be reclassified as Prevotella oryzae comb. nov.; the type strain is KB3(T) (=JCM 13648(T) =DSM 17970(T)). An emended description of the genus Prevotella is also provided. PMID- 22199208 TI - Imtechella halotolerans gen. nov., sp. nov., a member of the family Flavobacteriaceae isolated from estuarine water. AB - A novel Gram-negative, rod-shaped, non-motile, non-sporulating bacterium, designated strain K1(T), was isolated from an estuarine water sample collected from Kochi, Kerala, India. Colonies on marine agar were circular, 2.0-2.5 mm in diameter, shiny, yellow, translucent and convex with entire margins. Strain K1(T) was negative for ornithine decarboxylase, lysine decarboxylase, nitrate reduction and H(2)S production. The fatty acids were dominated by iso-branched components with a high abundance of iso-C(15:0), iso-C(15:1) G and iso-C(17:0) 3-OH; MK-6 (64%) and MK-7 (34%) were found as major respiratory quinones; and phosphatidylethanolamine, two unidentified aminolipids, four unidentified phospholipids and two unidentified lipids were major polar lipids. The DNA G+C content of strain K1(T) was 46.1 mol%. 16S rRNA gene sequence analysis indicated that strain K1(T) was related most closely to the type strain of Zhouia amylolytica (pairwise sequence similarity of 93.0%). Phylogenetic analysis showed that strain K1(T) formed a distinct branch within the family Flavobacteriaceae and clustered with the clade comprising species of the genera Zhouia, Coenonia and Capnocytophaga, being phylogenetically most closely related to the type strain of Zhouia amylolytica at a distance of 9.2% (90.8% similarity). Other species of the genera within the same clade were related to strain K1(T) at distances of 15.0-23.1%. Based on phenotypic and chemotaxonomic characteristics and on phylogenetic inference, strain K1(T) is considered to represent a novel species of a new genus in the family Flavobacteriaceae, for which the name Imtechella halotolerans gen. nov., sp. nov. is proposed. The type strain of Imtechella halotolerans is K1(T) (=MTCC 11055(T)=JCM 17677(T)). PMID- 22199209 TI - Lactobacillus delbrueckii subsp. sunkii subsp. nov., isolated from sunki, a traditional Japanese pickle. AB - Although four strains of bacteria isolated from sunki, a traditional Japanese, non-salted pickle, were initially identified as Lactobacillus delbrueckii, the molecular and phenotypic characteristics of the strains did not match those of any of the four recognized subspecies of L. delbrueckii. Together, the results of phenotypic characterization, DNA-DNA hybridizations (in which the relatedness values between the novel strains and type strains of the recognized subspecies of L. delbrueckii were all >88.7%) and 16S rRNA gene sequence, amplified fragment length polymorphism (AFLP) and whole-cell MALDI-TOF/MS spectral pattern analyses indicated that the four novel strains represented a single, novel subspecies, for which the name Lactobacillus delbrueckii subsp. sunkii subsp. nov. is proposed. The type strain is YIT 11221(T) (=JCM 17838(T) =DSM 24966(T)). PMID- 22199210 TI - Microvirga lupini sp. nov., Microvirga lotononidis sp. nov. and Microvirga zambiensis sp. nov. are alphaproteobacterial root-nodule bacteria that specifically nodulate and fix nitrogen with geographically and taxonomically separate legume hosts. AB - Strains of Gram-negative, rod-shaped, non-spore-forming bacteria were isolated from nitrogen-fixing nodules of the native legumes Listia angolensis (from Zambia) and Lupinus texensis (from Texas, USA). Phylogenetic analysis of the 16S rRNA gene showed that the novel strains belong to the genus Microvirga, with >= 96.1% sequence similarity with type strains of this genus. The closest relative of the representative strains Lut6(T) and WSM3557(T) was Microvirga flocculans TFB(T), with 97.6-98.0% similarity, while WSM3693(T) was most closely related to Microvirga aerilata 5420S-16(T), with 98.8% similarity. Analysis of the concatenated sequences of four housekeeping gene loci (dnaK, gyrB, recA and rpoB) and cellular fatty acid profiles confirmed the placement of Lut6(T), WSM3557(T) and WSM3693(T) within the genus Microvirga. DNA-DNA relatedness values, and physiological and biochemical tests allowed genotypic and phenotypic differentiation of Lut6(T), WSM3557(T) and WSM3693(T) from each other and from other Microvirga species with validly published names. The nodA sequence of Lut6(T) was placed in a clade that contained strains of Rhizobium, Mesorhizobium and Sinorhizobium, while the 100% identical nodA sequences of WSM3557(T) and WSM3693(T) clustered with Bradyrhizobium, Burkholderia and Methylobacterium strains. Concatenated sequences for nifD and nifH show that the sequences of Lut6(T), WSM3557(T) and WSM3693(T) were most closely related to that of Rhizobium etli CFN42(T) nifDH. On the basis of genotypic, phenotypic and DNA relatedness data, three novel species of Microvirga are proposed: Microvirga lupini sp. nov. (type strain Lut6(T) =LMG 26460(T) =HAMBI 3236(T)), Microvirga lotononidis sp. nov. (type strain WSM3557(T) =LMG 26455(T) =HAMBI 3237(T)) and Microvirga zambiensis sp. nov. (type strain WSM3693(T) =LMG 26454(T) =HAMBI 3238(T)). PMID- 22199211 TI - Otariodibacter oris gen. nov., sp. nov., a member of the family Pasteurellaceae isolated from the oral cavity of pinnipeds. AB - A total of 27 bacterial isolates from California sea lions and a walrus tentatively classified within the family Pasteurellaceae was further characterized by genotypic and phenotypic tests. Phylogenetic analysis of partial 16S rRNA and rpoB gene sequences showed that the isolates investigated formed a monophyletic group, tentatively designated Bisgaard taxon 57. According to 16S rRNA gene sequences, the most closely related species with a validly published name was Bisgaardia hudsonensis and the most closely related species based on rpoB sequence comparison was Pasteurella multocida subsp. multocida; highest similarities between the isolates and the type strains of B. hudsonensis and P. multocida subsp. multocida were 95.0 and 88.2%. respectively. All isolates of Bisgaard taxon 57 exhibit the phenotypic characters of the family Pasteurellaceae. Members of Bisgaard taxon 57 can be separated from existing genera of the Pasteurellaceae by the following tests: positive reactions for catalase, oxidase, Voges-Proskauer and indole; no X- or V-factor dependency; and acid production from L-arabinose (slow), L-fucose, maltose and trehalose, but not from dulcitol, D-mannitol, D-mannose or sucrose. The main fatty acids of Bisgaard taxon 57 (CCUG 59994(T)) are C(14:0), C(16:0), C(16:1)omega7c and the summed feature C(14:0) 3-OH/iso-C(16:1) I. This fatty acid profile is characteristic of members of the Pasteurellaceae. The quinone profile of Bisgaard taxon 57 (DSM 23800(T)) was similar to that of other genera in the Pasteurellaceae. The DNA G+C content of strain Baika1(T) is 36.2 mol%, which is at the lower end of the range for members of the family Pasteurellaceae. On the basis of both phylogenetic and phenotypic evidence, it is proposed that members of Bisgaard taxon 57 should be classified as representatives of a novel species in a new genus, Otariodibacter oris gen. nov., sp. nov. The type strain of Otariodibacter oris is Baika1(T) (=CCUG 59994(T)=DSM 23800(T)), which was isolated from the oral cavity of a healthy California sea lion in Copenhagen Zoo, Denmark, in 2007. PMID- 22199212 TI - Pseudomonas zeshuii sp. nov., isolated from herbicide-contaminated soil. AB - A Gram-stain-negative, rod-shaped, non-motile, non-spore-forming bacterium, designated strain BY-1(T), was isolated from a soil sample from the city of Qiqihar in Heilongjiang Province, PR China. Strain BY-1(T) grew optimally at pH 7.0 and 30-35 degrees C in the presence of 0.5% (w/v) NaCl. Analysis of 16S rRNA gene sequences revealed that strain BY-1(T) fell within the radiation of the genus Pseudomonas, and showed highest 16S rRNA gene sequence similarities to Pseudomonas luteola IAM 13000(T) (99.5%) and Pseudomonas duriflava HR2(T) (97.3%); the levels of sequence similarity with respect to other recognized species of the genus Pseudomonas were <96.7%. Strain BY-1(T) showed low DNA-DNA relatedness values with Pseudomonas luteola IAM 13000(T) (29 +/- 3.1%) and Pseudomonas duriflava HR2(T) (21 +/- 1.5 %). The G+C content of the genomic DNA of strain BY-1(T) was 55.3 mol%. The major fatty acids were C(18:1), C(16:0) and summed feature 3 (C(16:1)omega6c and/or C(16:1)omega7c). Major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine, and the major ubiquinone was Q-9. Data obtained in this study indicated that this isolate represents a novel species of the genus Pseudomonas, for which the name Pseudomonas zeshuii sp. nov. is proposed. The type strain is BY-1(T) (=KACC 15471(T)=ACCC 05688(T)). PMID- 22199213 TI - Isolates belonging to CDC group II-i belong predominantly to Sphingobacterium mizutaii Yabuuchi et al. 1983: emended descriptions of S. mizutaii and of the genus Sphingobacterium. AB - Two clinical strains, NF 296 and NF 931, present in our collection, were identified biochemically as members of CDC group II-i. Determination of the 16S rRNA gene sequence revealed highest similarity with strains of Sphingobacterium mizutaii. Because these strains produced indole, whereas S. mizutaii has been described as indole-negative, we also investigated the type strain and a reference strain of S. mizutaii, LMG 8340(T) (=CCUG 15907(T)) and LMG 8341 (=CCUG 15908), and found both strains also to be positive for indole production. These data warrant inclusion of some of the CDC group II-i strains into S. mizutaii and emended descriptions of Sphingobacterium mizutaii as indole-production-positive and of the genus Sphingobacterium as variable for indole production. PMID- 22199214 TI - Jannaschia aquimarina sp. nov., isolated from seawater. AB - A Gram-negative, aerobic, non-motile rod, designated GSW-M26(T), was isolated from seawater from the southern coast of Korea. Strain GSW-M26(T) grew optimally at pH 7.0-8.0, at 30 degrees C and with 2 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain GSW-M26(T) fell within the cluster comprising the genus Jannaschia and clustered with Jannaschia seosinensis CL-SP26(T). The isolate exhibited the highest 16S rRNA gene sequence similarity (96.9%) with J. seosinensis CL-SP26(T) and 93.7-95.5% 16S rRNA gene sequence similarity with the other members of the genus Jannaschia. Strain GSW-M26(T) contained Q-10 as the predominant ubiquinone and C(18:1)omega7c and 11-methyl C(18:1)omega7c as the major fatty acids. The major polar lipids were phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol and one unidentified aminolipid. The DNA G+C content was 66.4 mol%. Phenotypic characteristics demonstrated that strain GSW-M26(T) could be differentiated from recognized members of the genus Jannaschia. On the basis of the data presented, strain GSW-M26(T) is considered to represent a novel species of the genus Jannaschia, for which the name Jannaschia aquimarina sp. nov. is proposed. The type strain is GSW-M26(T) (=KCTC 23555(T) =CCUG 60899(T)). PMID- 22199215 TI - Parabacteroides chartae sp. nov., an obligately anaerobic species from wastewater of a paper mill. AB - A bacterial strain, designated NS31-3(T), was isolated from the wastewater of a paper mill. Cells of the isolate were obligately anaerobic, non-pigmented, non motile, Gram-negative, short rods (0.7-1.0 * 1.4-2.5 um). The isolate was able to grow on media containing 20% bile salts. API 20A tests showed that acid was produced from glucose, lactose, sucrose, maltose, D-xylose, L-arabinose, cellobiose, D-mannose, D-melezitose, D-raffinose, D-trehalose, D-mannitol, salicin and D-sorbitol. The main fermentation products from PYG broth were lactic acid, propionic acid, formic acid and acetic acid. Chemotaxonomic analysis showed that the major fatty acids were anteiso-C(15:0), C(15:0) and iso-C(17:0) 3-OH and the predominant respiratory quinones were MK-9 and MK-10. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain NS31-3(T) was related to members of genus Parabacteroides (91.2-93.2% sequence similarity); the isolate had the closest affinity with Parabacteroides merdae JCM 9497(T). The G+C content of the genomic DNA was 37.2 mol%. On the basis of phenotypic, chemotaxonomic and phylogenetic analysis, strain NS31-3(T) represents a novel species of the genus Parabacteroides, for which the name Parabacteroides chartae sp. nov. is proposed. The type strain is NS31-3(T) (=JCM 17797(T) =DSM 24967(T)). PMID- 22199216 TI - Methylobacterium gnaphalii sp. nov., isolated from leaves of Gnaphalium spicatum. AB - A pink-pigmented, facultatively methylotrophic bacterium, strain 23e(T), was isolated from the leaves of Gnaphalium spicatum (cudweed). The cells of strain 23e(T) were Gram-reaction negative, motile and non-spore-forming rods. On the basis of 16S rRNA gene sequence similarities, strain 23e(T) was related to Methylobacterium organophilum ATCC 27886(T) (97.1%) and Methylobacterium marchantiae JT1(T) (97%), and the phylogenetic similarities to all other Methylobacterium species with validly published names were less than 97%. Major cellular fatty acids were C(18:1)omega7c, C(16:00) and C(18:0). The results of DNA-DNA hybridization, phylogenetic analyses based on 16S rRNA and cpn60 gene sequences, fatty acid profiles, whole-cell matrix-assisted laser desorption/ionization time of flight/MS analysis, physiological and biochemical tests allowed genotypic and phenotypic differentiation of strain 23e(T) from the phylogenetically closest relatives. We propose that strain 23e(T) represents a novel species within the genus Methylobacterium, for which the name Methylobacterium gnaphalii sp. nov. is proposed. The type strain is 23e(T) (=DSM 24027(T)=NBRC 107716(T)). PMID- 22199217 TI - Catenulispora graminis sp. nov., a rhizobacterium from bamboo (Phyllostachys nigro var. henonis) rhizosphere soil. AB - A novel actinobacterium, designated strain BR-34(T), was isolated from rhizosphere soil of bamboo (Phyllostachys nigro var. henonis) sampled in Damyang, Korea. The strain was found to have morphological and chemotaxonomic characteristics typical of the genus Catenulispora. The strain contained iso-C(16 : 0) as the major fatty acid and MK-9(H(4)), MK-9(H(6)) and MK-9(H(8)) as major isoprenoid quinones. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain BR-34(T) formed a cluster separate from members of the genus Catenulispora and was related most closely to Catenulispora acidiphila ID139908(T) (97.4% similarity), Catenulispora rubra Aac-30(T) (97.3%), Catenulispora yoronensis TT N02-20(T) (97.3%) and Catenulispora subtropica TT 99 48(T) (97%). However, the level of DNA-DNA relatedness between strain BR-34(T) and C. acidiphila ID139908(T) was only 45.32%. Based on DNA-DNA relatedness, morphological and phenotypic data, strain BR-34(T) could be distinguished from the type strains of phylogenetically related species. It is therefore considered to represent a novel species of the genus Catenulispora, for which the name Catenulispora graminis sp. nov. is proposed. The type strain is BR-34(T) (=KACC 15070(T)=NBRC 107755(T)). PMID- 22199218 TI - Thermosulfurimonas dismutans gen. nov., sp. nov., an extremely thermophilic sulfur-disproportionating bacterium from a deep-sea hydrothermal vent. AB - An extremely thermophilic, anaerobic, chemolithoautotrophic bacterium (strain S95(T)) was isolated from a deep-sea hydrothermal vent chimney located on the Eastern Lau Spreading Center, Pacific Ocean, at a depth of 1910 m. Cells of strain S95(T) were oval to short Gram-negative rods, 0.5-0.6 um in diameter and 1.0-1.5 um in length, growing singly or in pairs. Cells were motile with a single polar flagellum. The temperature range for growth was 50-92 degrees C, with an optimum at 74 degrees C. The pH range for growth was 5.5-8.0, with an optimum at pH 7.0. Growth of strain S95(T) was observed at NaCl concentrations ranging from 1.5 to 3.5% (w/v). Strain S95(T) grew anaerobically with elemental sulfur as an energy source and bicarbonate/CO(2) as a carbon source. Elemental sulfur was disproportionated to sulfide and sulfate. Growth was enhanced in the presence of poorly crystalline iron(III) oxide (ferrihydrite) as a sulfide-scavenging agent. Strain S95(T) was also able to grow by disproportionation of thiosulfate and sulfite. Sulfate was not used as an electron acceptor. Analysis of the 16S rRNA gene sequence revealed that the isolate belongs to the phylum Thermodesulfobacteria. On the basis of its physiological properties and results of phylogenetic analyses, it is proposed that the isolate represents the sole species of a new genus, Thermosulfurimonas dismutans gen. nov., sp. nov.; S95(T) (=DSM 24515(T)=VKM B-2683(T)) is the type strain of the type species. This is the first description of a thermophilic micro-organism that disproportionates elemental sulfur. PMID- 22199219 TI - Alkalitalea saponilacus gen. nov., sp. nov., an obligately anaerobic, alkaliphilic, xylanolytic bacterium from a meromictic soda lake. AB - A Gram-positive, obligately anaerobic, motile, slender, flexible rod, designated SC/BZ-SP2(T), was isolated from mixed alkaline water and sediment of Soap Lake, Washington State, USA. Strain SC/BZ-SP2(T) formed salmon to pink colonies and was alkaliphilic. The isolate grew at pH(35 degrees C) 7.5-10.5 (optimum pH(35 degrees C) 9.7), at 8-40 degrees C (optimum 35-37 degrees C) and with 0.35-1.38 M Na(+) (optimum 0.44-0.69 M Na(+)). The isolate utilized L-arabinose, D-ribose, D-xylose, D-fructose, D-mannose, D-galactose, cellobiose, maltose, sucrose, trehalose, sorbitol, xylan, malate and yeast extract as carbon and energy sources; best growth was observed with L-arabinose, cellobiose, maltose and trehalose. The major fermentation products from beechwood xylan were propionate and acetate. The dominant fatty acids were iso-C(15:0), anteiso-C(15:0), iso C(17:0) 3-OH, C(17:0) 3-OH and C(15:0) 3-OH. The cell-wall sugars were ribose, xylose, galactose and glucose. Thiosulfate and sulfite could be reduced to sulfide. The genomic DNA G+C content was 39.5 +/- 0.9 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain SC/BZ-SP2(T) belonged to the family Marinilabiliaceae of the order Bacteroidales, class Bacteroidia. The most closely related strains were Alkaliflexus imshenetskii Z-7010(T) (91.8% 16S rRNA gene sequence similarity), Marinilabilia salmonicolor Cy s1(T) (91.0%) and Anaerophaga thermohalophila Fru22(T) (90.4%). On the basis of phenotypic, chemotaxonomic and phylogenetic features, strain SC/BZ-SP2(T) represents a novel species in a new genus of the family Marinilabiliaceae, for which the name Alkalitalea saponilacus gen. nov., sp. nov. is proposed. The type strain of Alkalitalea saponilacus is SC/BZ-SP2(T) (=ATCC BAA-2172(T) =DSM 24412(T)). PMID- 22199220 TI - Amycolatopsis dongchuanensis sp. nov., an actinobacterium isolated from soil. AB - A novel actinomycete strain, designated YIM 75904(T), was isolated from a soil sample that had been collected from a dry and hot river valley in Dongchuan county, Yunnan province, south-western China. The taxonomic position of the novel strain was investigated by a polyphasic approach. In phylogenetic analyses based on 16S rRNA gene sequences, strain YIM 75904(T) formed a distinct clade within the genus Amycolatopsis and appeared to be closely related to Amycolatopsis sacchari K24(T) (99.3% sequence similarity). Strain YIM 75904(T) had a type-IV cell wall, with no detectable mycolic acids, and had MK-9(H(4)) as its predominant menaquonine. Its cell wall contained meso-diaminopimelic acid, galactose, glucose and arabinose, and its major cellular fatty acids were iso C(16:0), iso-C(15:0), anteiso-C(17:0) and anteiso-C(15:0). The genomic DNA G+C content of the novel strain was 68.5 mol%. Based on the results of physiological and biochemical tests and DNA-DNA hybridizations, strain YIM 75904(T) represents a novel species of the genus Amycolatopsis for which the name Amycolatopsis dongchuanensis sp. nov. is proposed. The type strain is YIM 75904(T) (=CCTCC AA 2011016(T) =JCM 18054(T)). PMID- 22199221 TI - Neptunomonas concharum sp. nov., isolated from a dead ark clam, and emended description of the genus Neptunomonas. AB - A novel Gram-staining-negative, facultatively anaerobic, motile and rod-shaped bacterium, designated strain LHW37(T), was isolated from a dead ark clam collected on the south coast of Korea. The novel strain grew optimally at 37 degrees C, at pH 7.0-8.0 and with 2% (w/v) NaCl. The predominant cellular fatty acids were C(18:1)omega7c and summed feature 3 (C(16:1)omega7c and/or iso-C(15:0) 2-OH). The major isoprenoid quinone was ubiquinone-8 (Q-8) and the predominant polar lipids were phosphatidylethanolamine and phosphatidylglycerol. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the novel strain was most closely related to Neptunomonas japonica JAMM 0745(T) (97.1% sequence similarity). The genomic DNA G+C content of strain LHW37(T) was 48.2 mol%. The DNA-DNA relatedness values recorded in hybridization experiments between the novel strain and its closest known relative were <= 18%. Based on the phenotypic, genotypic and phylogenetic data, strain LHW37(T) represents a novel species belonging to the genus Neptunomonas for which the name Neptunomonas concharum sp. nov. is proposed. The type strain is LHW37(T) (=KACC 15543(T) =JCM 17730(T)). An emended description of the genus Neptunomonas is also provided. PMID- 22199222 TI - Polaromonas glacialis sp. nov. and Polaromonas cryoconiti sp. nov., isolated from alpine glacier cryoconite. AB - The taxonomic positions of two Gram-staining-negative, psychrophilic bacteria, which were isolated from alpine glacier cryoconite and designated strains Cr4 12(T) and Cr4-35(T), were investigated using a polyphasic approach. Both novel strains contained ubiquinone Q-8 as the sole quinone, summed feature 3 (C(16:1)omega7c and/or C(16:1)omega6c) and C(16:0) as the dominant cellular fatty acids, putrescine and 2-hydroxyputrescine as the major polyamines, and diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine as the major polar lipids. The genomic DNA G+C contents of strains Cr4-12(T) and Cr4 35(T) were 61.3 mol% and 60.7 mol%, respectively. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the two strains belonged to the genus Polaromonas. Although the 16S rRNA gene sequences of strains Cr4-12(T) and Cr4 35(T) were very similar (98.7% sequence similarity), hybridizations indicated a DNA-DNA relatedness value of only 26.9% between the two novel strains. In pairwise comparisons with the type strains of recognized Polaromonas species, strains Cr4-12(T) and Cr4-35(T) showed 16S rRNA gene sequence similarities of 96.4-98.5% and 96.5-98.4%, respectively. Based on the phenotypic and phylogenetic evidence and DNA-DNA relatedness data, strains Cr4-12(T) and Cr4-35(T) represent two novel species within the genus Polaromonas, for which the names Polaromonas glacialis sp. nov. and Polaromonas cryoconiti sp. nov., respectively, are proposed. The type strain of Polaromonas glacialis sp. nov. is Cr4-12(T) (=DSM 24062(T) =LMG 26049(T) =KACC 15089(T)) and that of Polaromonas cryoconiti sp. nov. is Cr4-35(T) (=DSM 24248(T) =LMG 26050(T) =KACC 15090(T)). PMID- 22199223 TI - Terrimonas rubra sp. nov., isolated from a polluted farmland soil and emended description of the genus Terrimonas. AB - A salmon-red-pigmented bacterial strain, designated M-8(T), was isolated from a polluted farmland soil sample in China and was characterized in a taxonomic study using a polyphasic approach. Strain M-8(T) was Gram-stain-negative, rod-shaped, non-motile and non-spore-forming. Growth occurred at 20-37 degrees C, at pH 5.0 10.0 and with 0-2% (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain M-8(T) belonged to the genus Terrimonas.16S rRNA gene sequence similarity values between strain M-8(T) and the type strains of the three recognized species of the genus Terrimonas, Terrimonas ferruginea KACC 11310(T), Terrimonas aquatica LMG 24825(T) and Terrimonas lutea KACC 13047(T), were 97.1, 96.3 and 95.3%, respectively. The predominant respiratory quinone was menaquinone-7 (MK-7) and the major fatty acids were iso-C(15:0), iso-C(17:0) 3-OH and summed feature 3 (comprising C(16:1)omega7c and/or C(16:1)omega6c). The DNA G+C content of strain M-8(T) was 47.0 mol%. On the basis of genotypic and phenotypic data, strain M-8(T) is considered to represent a novel species of the genus Terrimonas, for which the name Terrimonas rubra sp. nov. is proposed. The type strain is M-8(T) (=CCTCC AB 2010401(T)=KCTC 23299(T)). An emended description of the genus Terrimonas is also presented. PMID- 22199224 TI - Microbacterium murale sp. nov., isolated from an indoor wall. AB - A Gram-positive rod, designated 01-Gi-001(T), was isolated from a wall colonized with moulds. The 16S rRNA gene sequence analysis clearly showed that the isolate belonged to the genus Microbacterium. On the basis of pairwise comparisons of 16S rRNA gene sequences, strain 01-Gi-001(T) was most closely related to Microbacterium hydrocarbonoxydans DSM 16089(T) (98.9% sequence similarity), Microbacterium profundi Shh49(T) (98.7%), Microbacterium phyllosphaerae DSM 13468(T) (98.3%) and Microbacterium foliorum DSM 12966(T) (98.1%). The diagnostic diamino acid of the peptidoglycan was ornithine. The major menaquinones detected were MK-13 and MK-12. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, one unknown phospholipid and one unknown glycolipid. The major fatty acids were anteiso-C(15:0), iso-C(16:0) and anteiso-C(17:0), which were in agreement with those reported for other members of the genus Microbacterium. Physiological and biochemical characteristics and DNA-DNA relatedness between strain 01-Gi-001(T) and the type strains of its closest phylogenetic neighbours showed clear differences. For this reason, strain 01-Gi 001(T) (=DSM 22178(T)=CCM 7640(T)) is proposed as the type strain of a novel species, Microbacterium murale sp. nov. PMID- 22199225 TI - Flavobacterium ummariense sp. nov., isolated from hexachlorocyclohexane contaminated soil, and emended description of Flavobacterium ceti Vela et al. 2007. AB - A Gram-negative, strictly aerobic, yellow bacterial strain, designated DS-12(T), was isolated from hexachlorocyclohexane-contaminated soil in Lucknow, Uttar Pradesh, India. Strain DS-12(T) showed the highest 16S rRNA gene sequence similarity with Flavobacterium ceti 454-2(T) (94.2%). Phylogenetic analysis based on 16S rRNA gene sequences showed that strain DS-12(T) belonged to the genus Flavobacterium. Strain DS-12(T) produced flexirubin-type pigments. Gliding motility was not observed. The major fatty acids of strain DS-12(T) were iso C(15:0) (48.0%), summed feature 9 (comprising iso-C(17:1)omega9c and/or C(16:0) 10-methyl; 19.3%), iso-C(17:0) 3-OH (8.5%) and summed feature 3 (comprising one or more of C(16:1)omega7c, C(16:1)omega6c and iso-C(15:0) 2-OH; 7.2%). The only respiratory quinone was menaquinone-6 and the major polyamine was homospermidine. Strain DS-12(T) contained phosphatidyldimethylethanolamine, phosphatidylserine, phosphatidylethanolamine, one unknown phospholipid and one unknown aminolipid. The DNA G+C content was 37.4 mol%. Phylogenetic inference and phenotypic properties indicated that strain DS-12(T) represents a novel species of the genus Flavobacterium, for which the name Flavobacterium ummariense sp. nov. is proposed. The type strain is DS-12(T) (=CCM 7847(T) =MTCC 10766(T)). An emended description of Flavobacterium ceti is also given. PMID- 22199226 TI - Streptomyces atacamensis sp. nov., isolated from an extreme hyper-arid soil of the Atacama Desert, Chile. AB - The taxonomic position of a Streptomyces strain isolated from an extreme hyper arid soil sample collected from the Atacama Desert was determined using a polyphasic approach. The strain, isolate C60(T), had chemical and morphological features typical of members of the genus Streptomyces and formed a distinct phyletic line in the Streptomyces 16S rRNA gene tree, together with the type strain of Streptomyces radiopugnans. The two strains were distinguished readily using a combination of phenotypic properties and by a DNA-DNA relatedness value of 23.17 (+/- 0.95)%. On the basis of these genotypic and phenotypic data, it is proposed that isolate C60(T) (=CGMCC 4.7018(T)=KACC 15492(T)) be classified in the genus Streptomyces as Streptomyces atacamensis sp. nov. PMID- 22199227 TI - Combination of chemical genetics and phosphoproteomics for kinase signaling analysis enables confident identification of cellular downstream targets. AB - Delineation of phosphorylation-based signaling networks requires reliable data about the underlying cellular kinase-substrate interactions. We report a chemical genetics and quantitative phosphoproteomics approach that encompasses cellular kinase activation in combination with comparative replicate mass spectrometry analyses of cells expressing either inhibitor-sensitive or resistant kinase variant. We applied this workflow to Plk1 (Polo-like kinase 1) in mitotic cells and induced cellular Plk1 activity by wash-out of the bulky kinase inhibitor 3-MB PP1, which targets a mutant kinase version with an enlarged catalytic pocket while not interfering with wild-type Plk1. We quantified more than 20,000 distinct phosphorylation sites by SILAC, approximately half of which were measured in at least two independent experiments in cells expressing mutant and wild-type Plk1. Based on replicate phosphorylation site quantifications in both mutant and wild-type Plk1 cells, our chemical genetic proteomics concept enabled stringent comparative statistics by significance analysis of microarrays, which unveiled more than 350 cellular downstream targets of Plk1 validated by full concordance of both statistical and experimental data. Our data point to hitherto poorly characterized aspects in Plk1-controlled mitotic progression and provide a largely extended resource for functional studies. We anticipate the described strategies to be of general utility for systematic and confident identification of cellular protein kinase substrates. PMID- 22199228 TI - Interlaboratory evaluation of automated, multiplexed peptide immunoaffinity enrichment coupled to multiple reaction monitoring mass spectrometry for quantifying proteins in plasma. AB - The inability to quantify large numbers of proteins in tissues and biofluids with high precision, sensitivity, and throughput is a major bottleneck in biomarker studies. We previously demonstrated that coupling immunoaffinity enrichment using anti-peptide antibodies (SISCAPA) to multiple reaction monitoring mass spectrometry (MRM-MS) produces Immunoprecipitation MRM-MS (immuno-MRM-MS) assays that can be multiplexed to quantify proteins in plasma with high sensitivity, specificity, and precision. Here we report the first systematic evaluation of the interlaboratory performance of multiplexed (8-plex) immuno-MRM-MS in three independent labs. A staged study was carried out in which the effect of each processing and analysis step on assay coefficient of variance, limit of detection, limit of quantification, and recovery was evaluated. Limits of detection were at or below 1 ng/ml for the assayed proteins in 30 MUl of plasma. Assay reproducibility was acceptable for verification studies, with median intra- and interlaboratory coefficients of variance above the limit of quantification of 11% and <14%, respectively, for the entire immuno-MRM-MS assay process, including enzymatic digestion of plasma. Trypsin digestion and its requisite sample handling contributed the most to assay variability and reduced the recovery of target peptides from digested proteins. Using a stable isotope-labeled protein as an internal standard instead of stable isotope-labeled peptides to account for losses in the digestion process nearly doubled assay accuracy for this while improving assay precision 5%. Our results demonstrate that multiplexed immuno-MRM MS can be made reproducible across independent laboratories and has the potential to be adopted widely for assaying proteins in matrices as complex as plasma. PMID- 22199229 TI - Characterization of a highly conserved histone related protein, Ydl156w, and its functional associations using quantitative proteomic analyses. AB - A significant challenge in biology is to functionally annotate novel and uncharacterized proteins. Several approaches are available for deducing the function of proteins in silico based upon sequence homology and physical or genetic interaction, yet this approach is limited to proteins with well characterized domains, paralogs and/or orthologs in other species, as well as on the availability of suitable large-scale data sets. Here, we present a quantitative proteomics approach extending the protein network of core histones H2A, H2B, H3, and H4 in Saccharomyces cerevisiae, among which a novel associated protein, the previously uncharacterized Ydl156w, was identified. In order to predict the role of Ydl156w, we designed and applied integrative bioinformatics, quantitative proteomics and biochemistry approaches aiming to infer its function. Reciprocal analysis of Ydl156w protein interactions demonstrated a strong association with all four histones and also to proteins strongly associated with histones including Rim1, Rfa2 and 3, Yku70, and Yku80. Through a subsequent combination of the focused quantitative proteomics experiments with available large-scale genetic interaction data and Gene Ontology functional associations, we provided sufficient evidence to associate Ydl156w with multiple processes including chromatin remodeling, transcription and DNA repair/replication. To gain deeper insights into the role of Ydl156w in histone biology we investigated the effect of the genetic deletion of ydl156w on H4 associated proteins, which lead to a dramatic decrease in the association of H4 with RNA polymerase III proteins. The implication of a role for Ydl156w in RNA Polymerase III mediated transcription was consequently verified by RNA-Seq experiments. Finally, using these approaches we generated a refined network of Ydl156w-associated proteins. PMID- 22199230 TI - Surface interactome in Streptococcus pyogenes. AB - Very few studies have so far been dedicated to the systematic analysis of protein interactions occurring between surface and/or secreted proteins in bacteria. Such interactions are expected to play pivotal biological roles that deserve investigation. Taking advantage of the availability of a detailed map of surface and secreted proteins in Streptococcus pyogenes (group A Streptococcus (GAS)), we used protein array technology to define the "surface interactome" in this important human pathogen. Eighty-three proteins were spotted on glass slides in high density format, and each of the spotted proteins was probed for its capacity to interact with any of the immobilized proteins. A total of 146 interactions were identified, 25 of which classified as "reciprocal," namely, interactions that occur irrespective of which of the two partners was immobilized on the chip or in solution. Several of these interactions were validated by surface plasmon resonance and supported by confocal microscopy analysis of whole bacterial cells. By this approach, a number of interesting interactions have been discovered, including those occurring between OppA, DppA, PrsA, and TlpA, proteins known to be involved in protein folding and transport. These proteins, all localizing at the septum, might be part, together with HtrA, of the recently described ExPortal complex of GAS. Furthermore, SpeI was found to strongly interact with the metal transporters AdcA and Lmb. Because SpeI strictly requires zinc to exert its function, this finding provides evidence on how this superantigen, a major player in GAS pathogenesis, can acquire the metal in the host environment, where it is largely sequestered by carrier proteins. We believe that the approach proposed herein can lead to a deeper knowledge of the mechanisms underlying bacterial invasion, colonization, and pathogenesis. PMID- 22199232 TI - E3Net: a system for exploring E3-mediated regulatory networks of cellular functions. AB - Ubiquitin-protein ligase (E3) is a key enzyme targeting specific substrates in diverse cellular processes for ubiquitination and degradation. The existing findings of substrate specificity of E3 are, however, scattered over a number of resources, making it difficult to study them together with an integrative view. Here we present E3Net, a web-based system that provides a comprehensive collection of available E3-substrate specificities and a systematic framework for the analysis of E3-mediated regulatory networks of diverse cellular functions. Currently, E3Net contains 2201 E3s and 4896 substrates in 427 organisms and 1671 E3-substrate specific relations between 493 E3s and 1277 substrates in 42 organisms, extracted mainly from MEDLINE abstracts and UniProt comments with an automatic text mining method and additional manual inspection and partly from high throughput experiment data and public ubiquitination databases. The significant functions and pathways of the extracted E3-specific substrate groups were identified from a functional enrichment analysis with 12 functional category resources for molecular functions, protein families, protein complexes, pathways, cellular processes, cellular localization, and diseases. E3Net includes interactive analysis and navigation tools that make it possible to build an integrative view of E3-substrate networks and their correlated functions with graphical illustrations and summarized descriptions. As a result, E3Net provides a comprehensive resource of E3s, substrates, and their functional implications summarized from the regulatory network structures of E3-specific substrate groups and their correlated functions. This resource will facilitate further in-depth investigation of ubiquitination-dependent regulatory mechanisms. E3Net is freely available online at http://pnet.kaist.ac.kr/e3net. PMID- 22199231 TI - Proteomic analysis of mitotic RNA polymerase II reveals novel interactors and association with proteins dysfunctional in disease. AB - RNA polymerase II (RNAPII) transcribes protein-coding genes in eukaryotes and interacts with factors involved in chromatin remodeling, transcriptional activation, elongation, and RNA processing. Here, we present the isolation of native RNAPII complexes using mild extraction conditions and immunoaffinity purification. RNAPII complexes were extracted from mitotic cells, where they exist dissociated from chromatin. The proteomic content of native complexes in total and size-fractionated extracts was determined using highly sensitive LC MS/MS. Protein associations with RNAPII were validated by high-resolution immunolocalization experiments in both mitotic cells and in interphase nuclei. Functional assays of transcriptional activity were performed after siRNA-mediated knockdown. We identify >400 RNAPII associated proteins in mitosis, among these previously uncharacterized proteins for which we show roles in transcriptional elongation. We also identify, as novel functional RNAPII interactors, two proteins involved in human disease, ALMS1 and TFG, emphasizing the importance of gene regulation for normal development and physiology. PMID- 22199233 TI - Proteome expression and carbonylation changes during Trypanosoma cruzi infection and Chagas disease in rats. AB - Inflammation and oxidative stress, elicited by Trypanosoma cruzi infection, are important pathologic events during progressive Chagasic cardiomyopathy. In this study, we infected Sprague-Dawley rats with T. cruzi, and treated with phenyl alpha-tert-butylnitrone (PBN-antioxidant) and/or benznidazole (BZ-anti-parasite). We employed two-dimensional gel electrophoresis/mass spectrometry to investigate (a) the plasma proteomic changes associated with infection and disease development, and (b) the beneficial effects of PBN and BZ in controlling the disease-associated plasma profile. Matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) tandem MS (MS/MS) analysis of differentially expressed (total 146) and oxidized (total 48) protein spots yielded 92 unique proteins. Our data showed that treatment with PBN and BZ restored the differential expression of 65% and 30% of the disease-associated proteins to normal level, respectively, and PBN prevented development of oxidative adducts on plasma proteins. Western blotting to detect dinitrophenyl derivatized carbonyl-proteins revealed plasma proteins were maximally oxidized during acute infection. Functional and disease/disorder analyses allocated a majority of the differentially expressed and oxidized proteins into inflammation/immunity and lipid metabolism categories and to molecular pathways associated with heart disease (e.g. cardiac infarction, contractile dysfunction, hypertrophy, and hypertension) in chagasic rats, and to curative pathways (e.g. ROS scavenging capacity, immune regulation) in infected rats treated with PBN and/or BZ. We validated the two-dimensional gel electrophoresis results by Western blotting, and demonstrated that the disease-associated increased expression of gelsolin and vimentin and release of cardiac MYL2 in the plasma of chagasic rats was returned to control level by PBN/BZ treatment. Increased plasma levels of gelsolin, MYL2 and vimentin were directly correlated with the severity of cardiac disease in human chagasic patients. Together, these results demonstrate the plasma oxidative and inflammatory response profile, and plasma detection of cardiac proteins parallels the pathologic events contributing to Chagas disease development, and is of potential utility in diagnosing disease severity and designing suitable therapy for management of human chagasic patients. PMID- 22199234 TI - Role of 9-lipoxygenase and alpha-dioxygenase oxylipin pathways as modulators of local and systemic defense. AB - Plant 9-lipoxygenases (9-LOX) and alpha-dioxygenases (alpha-DOX) initiate the synthesis of oxylipins after bacterial infection. Here, the role of these enzymes in plants' defense was investigated using individual Arabidopsis thaliana lox1 and dox1 mutants and a double lox1 dox1 mutant. Studies with Pseudomonas syringae pv. tomato (Pst) revealed the enhanced susceptibility of lox1 to the virulent strain Pst DC3000 and the partial impairment of lox1 and dox1 mutants to activate systemic acquired resistance. Notably, both defects were enhanced in the lox1 dox1 plants as compared with individual mutants. We found that pre-treatment with 9-LOX- and alpha-DOX-generated oxylipins protected plant tissues against bacterial infection. The strongest effect in this respect was exerted by 9 ketooctadecatrienoic acid (9-KOT), which is produced from linolenic acid by 9 LOX. Quantification of 9-KOT revealed its accumulation after bacterial infection. The levels were reduced in lox1 and lox1 dox1 plants but strongly increased in the dox1 mutant due to metabolic interaction of the two pathways. Transcriptional analyses indicated that 9-KOT pre-treatment modifies hormone homeostasis during bacterial infection. The nature of the changes detected suggested that 9-KOT interferes with the hormonal changes caused by bacterial effectors. This notion was substantiated by the finding that 9-KOT failed to reduce the growth of PstDC3000hrpA, a mutant compromised in effector secretion, and of the avirulent strain Pst DC3000 avrRpm1. Further support for the action of the 9-LOX- and alpha DOX-oxylipin pathways as modulators of hormone homeostasis was the observation that lox1 dox1 seedlings are hypersensitive to the growth-inhibitory effect of ABA and showed enhanced activation of ABA-inducible marker genes as compared with wild-type plants. PMID- 22199235 TI - Studies on differential nuclear translocation mechanism and assembly of the three subunits of the Arabidopsis thaliana transcription factor NF-Y. AB - The eukaryotic transcription factor NF-Y consists of three subunits (A, B, and C), which are encoded in Arabidopsis thaliana in multigene families consisting of 10, 13, and 13 genes, respectively. In principle, all potential combinations of the subunits are possible for the assembly of the heterotrimeric complex. We aimed at assessing the probability of each subunit to participate in the assembly of NF-Y. The evaluation of physical interactions among all members of the NF-Y subunit families indicate a strong requirement for NF-YB/NF-YC heterodimerization before the entire complex can be accomplished. By means of a modified yeast two hybrid system assembly of all three subunits to a heterotrimeric complex was demonstrated. Using GFP fusion constructs, NF-YA and NF-YC localization in the nucleus was demonstrated, while NF-YB is solely imported into the nucleus as a NF YC-associated heterodimer NF-YC. This piggyback transport of the two Arabidopsis subunits differs from the import of the NF-Y heterotrimer of heterotrophic organisms. Based on a peptide structure model of the histone-fold-motifs, disulfide bonding among intramolecular conserved cysteine residues of NF-YB, which is responsible for the redox-regulated assembly of NF-YB and NF-YC in human and Aspergillus nidulans, can be excluded for Arabidopsis NF-YB. PMID- 22199236 TI - Cellular auxin homeostasis: gatekeeping is housekeeping. AB - The phytohormone auxin is essential for plant development and contributes to nearly every aspect of the plant life cycle. The spatio-temporal distribution of auxin depends on a complex interplay between auxin metabolism and cell-to-cell auxin transport. Auxin metabolism and transport are both crucial for plant development; however, it largely remains to be seen how these processes are integrated to ensure defined cellular auxin levels or even gradients within tissues or organs. In this review, we provide a glance at very diverse topics of auxin biology, such as biosynthesis, conjugation, oxidation, and transport of auxin. This broad, but certainly superficial, overview highlights the mutual importance of auxin metabolism and transport. Moreover, it allows pinpointing how auxin metabolism and transport get integrated to jointly regulate cellular auxin homeostasis. Even though these processes have been so far only separately studied, we assume that the phytohormonal crosstalk integrates and coordinates auxin metabolism and transport. Besides the integrative power of the global hormone signaling, we additionally introduce the hypothetical concept considering auxin transport components as gatekeepers for auxin responses. PMID- 22199237 TI - Catabolism of branched chain amino acids supports respiration but not volatile synthesis in tomato fruits. AB - The branched-chain amino acid transaminases (BCATs) have a crucial role in metabolism of the branched-chain amino acids leucine, isoleucine, and valine. These enzymes catalyze the last step of synthesis and the initial step of degradation of these amino acids. Although the biosynthetic pathways of branched chain amino acids in plants have been extensively investigated and a number of genes have been characterized, their catabolism in plants is not yet completely understood. We previously characterized the branched chain amino acid transaminase gene family in tomato, revealing both the subcellular localization and kinetic properties of the enzymes encoded by six genes. Here, we examined possible functions of the enzymes during fruit development. We further characterized transgenic plants differing in the expression of branched chain amino acid transaminases 1 and 3, evaluating the rates of respiration in fruits deficient in BCAT1 and the levels of volatiles in lines overexpressing either BCAT1 or BCAT3. We quantitatively tested, via precursor and isotope feeding experiments, the importance of the branched chain amino acids and their corresponding keto acids in the formation of fruit volatiles. Our results not only demonstrate for the first time the importance of branched chain amino acids in fruit respiration, but also reveal that keto acids, rather than amino acids, are the likely precursors for the branched chain flavor volatiles. PMID- 22199238 TI - Conservation of IRE1-regulated bZIP74 mRNA unconventional splicing in rice (Oryza sativa L.) involved in ER stress responses. AB - Protein folding in the endoplasmic reticulum (ER) is a fundamental process in plant cells that is vulnerable to many environmental stresses. When unfolded or misfolded proteins accumulate in the ER, the well-conserved unfolded protein response (UPR) is initiated to mitigate the ER stress by enhancing the protein folding capability and/or accelerating the ER-associated protein degradation. Here, we report the conservation of the activation mechanism of OsbZIP74 (also known as OsbZIP50), an important ER stress regulator in monocot plant rice (Oryza sativa L.). Under normal conditions, OsbZIP74 mRNA encodes a basic leucine-zipper transcription factor with a putative transmembrane domain. When treating with ER stress-inducing agents such as tunicamycin and DTT, the conserved double stem loop structures of OsbZIP74 mRNA are spliced out. Thereafter, the resulting new OsbZIP74 mRNA produces the nucleus-localized form of OsbZIP74 protein, eliminating the hydrophobic region. The activated form of OsbZIP74 has transcriptional activation activity in both yeast cells and Arabidopsis leaf protoplasts. The induction of OsbZIP74 splicing is much suppressed in the OsIRE1 knock-down rice plants, indicating the involvement of OsIRE1 in OsbZIP74 splicing. We also demonstrate that the unconventional splicing of OsbZIP74 mRNA is associated with heat stress and salicylic acid, which is an important plant hormone in systemic acquired resistance against pathogen or parasite. PMID- 22199240 TI - Crystalline lens power and refractive error. AB - PURPOSE: To study the relationships between the refractive power of the crystalline lens, overall refractive error of the eye, and degree of nuclear cataract. METHODS: All phakic participants of the population-based Central India Eye and Medical Study with an age of 50+ years were included. Calculation of the refractive lens power was based on distance noncycloplegic refractive error, corneal refractive power, anterior chamber depth, lens thickness, and axial length according to Bennett's formula. RESULTS: The study included 1885 subjects. Mean refractive lens power was 25.5 +/- 3.0 D (range, 13.9-36.6). After adjustment for age and sex, the standardized correlation coefficients (beta) of the association with the ocular refractive error were highest for crystalline lens power (beta = -0.41; P < 0.001) and nuclear lens opacity grade (beta = 0.42; P < 0.001), followed by axial length (beta = -0.35; P < 0.001). They were lowest for corneal refractive power (beta = -0.08; P = 0.001) and anterior chamber depth (beta = -0.05; P = 0.04). In multivariate analysis, refractive error was significantly (P < 0.001) associated with shorter axial length (beta = 1.26), lower refractive lens power (beta = -0.95), lower corneal refractive power (beta = -0.76), higher lens thickness (beta = 0.30), deeper anterior chamber (beta = 0.28), and less marked nuclear lens opacity (beta = -0.05). Lens thickness was significantly lower in eyes with greater nuclear opacity. CONCLUSIONS: Variations in refractive error in adults aged 50+ years were mostly influenced by variations in axial length and in crystalline lens refractive power, followed by variations in corneal refractive power, and, to a minor degree, by variations in lens thickness and anterior chamber depth. PMID- 22199239 TI - Coordination of plastid and light signaling pathways upon development of Arabidopsis leaves under various photoperiods. AB - Plants synchronize their cellular and physiological functions according to the photoperiod (the length of the light period) in the cycle of 24 h. Photoperiod adjusts several traits in the plant life cycle, including flowering and senescence in annuals and seasonal growth cessation in perennials. Photoperiodic development is controlled by the coordinated action of photoreceptors and the circadian clock. During the past 10 years, remarkable progress has been made in understanding the molecular mechanism of the circadian clock, especially with regard to the transition of Arabidopsis from the vegetative growth to the reproductive phase. Besides flowering photoperiod also modifies plant photosynthetic structures and traits. Light signals controlling biogenesis of chloroplasts and development of leaf photosynthetic structures are perceived both by photoreceptors and in chloroplasts. In this review, we provide evidence suggesting that the photoperiodic development of Arabidopsis leaves mimics the acclimation of plant to various light intensities. Furthermore, the chloroplast to-nucleus retrograde signals that adjust acclimation to light intensity are proposed to contribute also to the signaling pathways that control photoperiodic acclimation of leaves. PMID- 22199241 TI - Differential gene expression in eyecup and retina of a mouse model of Stargardt like macular dystrophy (STGD3). AB - PURPOSE: To investigate differentially expressed genes in eyecup and retina of the ELOVL4 transgenic mouse, a model of Stargardt-like macular dystrophy (STGD3). METHODS: We examined gene and protein expression in known pathways relevant to retinal degeneration using PCR arrays, Western blotting, and immunohistochemistry. Investigations were performed on ELOVL4 transgenic mice at 9 months, when 50% of rod (but no cone) photoreceptors had degenerated. Age matched wild-type littermates served as controls. RESULTS: Significant expression level changes were found in only 17 of the 252 genes examined. Nine were upregulated (Fgf2, Fgfr1, Ntf5, Cbln1, Ngfr, Ntrk1, Trp53, Tlr6, and Herpud1), and eight were downregulated (Ccl22, Ccr3, Il18rap, Nf1, Ccl11, Atf6beta, Rpn1, and Serp1). Overexpression of FGF2 was detected at 1 month, before rod loss onset, and was maintained at high levels until cone loss (18 months). By 9 months, FGF2 overexpression was seen in photoreceptor cell bodies. Increased glial fibrillary acidic protein (GFAP) expression due to glial cell reactivity followed the same time course. Levels of NGFR/p75NTR remained invariant. Although present in rod outer segments at 1 month, the macrophage chemoattracting chemokine CCL22 became undetectable by 9 months, a likely consequence of progressive rod outer segment truncation. CONCLUSIONS: At a mid-degeneration stage, major changes in gene expression in the ELOVL4 transgenic mouse retina included upregulation of Fgf2 and Fgfr1 and downregulation of Ccl22. Modulation of FGF2 occurred very early, concomitant with an increase in GFAP expression. Future studies will address which factors upstream of Fgf2 could provide potential therapeutic targets to slow photoreceptor degeneration in STGD3. PMID- 22199242 TI - Analysis of the role of ZEB1 in the pathogenesis of posterior polymorphous corneal dystrophy. AB - PURPOSE: To determine how nonsense mutations in the transcription factor ZEB1 lead to the development of posterior polymorphous corneal dystrophy type 3 (PPCD3). METHODS: Whole-cell extracts were obtained from cultured human corneal epithelial cells (HCEpCs) as a source of ZEB1 protein. DNA-binding assays were performed using the whole-cell extract and oligonucleotide probes consisting of the two conserved E2-box motifs and surrounding nucleotides upstream of COL4A3. ZEB1 and COL4A3 mRNA expression in primary human corneal endothelial cells (HCEnCs) was assayed in both PPCD3 and control corneas by RT-PCR. Immunohistochemistry was used to localize ZEB1 and COL4A3 expression in normal human cornea. RESULTS: Electromobility shift assays (EMSAs) and competition EMSAs demonstrated binding of protein(s) in the cultured HCEpCs to the E2-box motifs in the probes. The supershift EMSA confirmed that ZEB1, demonstrated to be present in the whole-cell extracts, binds to both the proximal and distal E2-box motifs in the COL4A3 promoter region. Both COL4A3 and ZEB1 are expressed in normal HCEnCs, although in PPCD3, ZEB1 expression is decreased and COL4A3 expression is increased compared with levels of both genes in healthy control corneas. CONCLUSIONS: Inversely related HCEnC expression levels of ZEB1 and COL4A3 in PPCD3 indicate that ZEB1-mediated alterations in COL4A3 expression are most likely associated with the pathogenesis of this corneal endothelial dystrophy. However, the demonstration of COL4A3 expression in healthy adult primary HCEnCs suggests that PPCD3 is more likely to involve an alteration in the timing and/or degree of COL4A3 expression than to result from the dichotomous change implied by the previously proposed ectopic expression model. PMID- 22199244 TI - Nonsense-mediated decay as the molecular cause for autosomal recessive bestrophinopathy in two unrelated families. AB - PURPOSE: To characterize the molecular basis of two novel BEST1 mutations causing autosomal recessive bestrophinopathy (ARB). Strong evidence argues in favor of the dominant negative effects of most autosomal dominantly inherited mutations, whereas there is only weak support for the molecular basis of the ARB phenotype. METHODS: Patients underwent ophthalmic examination, color and autofluorescence fundus imaging, optical coherence tomography (OCT), electrooculogram, and full field electroretinogram (ERG). BEST1 was directly screened for mutations in two ARB unrelated patients. The pathogenicity of the new BEST1 variants was assessed in silico and in vivo. RESULTS: Two unrelated patients with diagnoses of ARB showed retinal pigment epithelial disturbances and abnormal ERGs. Each patient was homozygous for a novel BEST1 mutation, c.521_522del and c.1100+1G>A. A carrier sibling (WT/c.521_522del) was unaffected. Both mutations generate a frameshift and a premature stop codon that, if translated, would seriously compromise bestrophin-1 function. However, the in vivo quantitative RT-PCR assays showed that most of the mutated transcripts were eliminated before translation because the mRNA-BEST1 levels were dramatically diminished the controls. CONCLUSIONS: In truncating BEST1 mutations, the null phenotype associated with ARB is attributed to a substantial decrease of BEST1 expression promoted by the nonsense-mediated decay (NMD) surveillance mechanism. Moreover, the severity of the phenotype increases with the preserved amount of altered transcript, suggesting that the clinical outcome reflects the combined null and dominant negative effects of the two mutations over the patient's genetic background. PMID- 22199243 TI - alphabeta TCR+ T cells, but not B cells, promote autoimmune keratitis in b10 mice lacking gammadelta T cells. AB - PURPOSE: To investigate additional factors in the spontaneous development of keratitis previously reported in B10.TCRdelta-/- female mice. METHODS: The study tested whether susceptible B10.TCRdelta-/- mice have dry eyes compared with resistant B6.TCRdelta-/- females and also rederived the B10.TCRdelta-/- strain to test for the role of an infectious agent. Also assessed was whether adoptive transfer of alphabeta T cells from autoimmune mice induced keratitis in resistant mice. In addition, a potential role was examined for B cells or autoantibodies by B-cell inactivation, and the role of female hormones was tested by ovariectomy. Finally, the study investigated whether adoptive transfer of Vgamma1+ gammadelta T cells confers protection. RESULTS: Tear production in B10.TCRdelta-/- females was actually higher than in B6.TCRdelta-/- controls. Rederived B10.TCRdelta-/- mice still developed keratitis. Keratitis was induced in resistant mice after adoptive transfer of alphabeta T cells from keratitic donors. Inactivation of B cells from susceptible mice had no effect on the development of keratitis. Ovariectomy did not significantly reduce disease in B10.TCRdelta-/- females. Adoptive transfer of Vgamma1+ cells from wild-type donors reduced keratitis in B10.TCRdelta-/- females. CONCLUSIONS: Neither low tear levels nor ovarian hormones contribute to spontaneous keratitis in B10.TCRdelta-/- female mice, nor does it appear to depend on an infectious agent carried vertically in this strain. However, alphabeta T cells from keratitic hosts are sufficient to induce disease in the resistant B10.TCRbeta-/-delta-/- strain. Autoaggressive alphabeta T cells in the absence of Vgamma1+ T cells in B10.TCRdelta-/- mice may be insufficiently checked to prevent disease. PMID- 22199245 TI - The cross-linked biopolymer hyaluronic acid as an artificial vitreous substitute. AB - PURPOSE: Biopolymers are promising substances in the development of a new vitreous substitute to overcome the drawbacks associated with current hydrophobic tamponade materials. METHODS: Different hydrogels were assembled by cross-linking hyaluronic acid either with adipic dihydrazide (ADH) by carboxylation with N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) after hydrazation or by photocrosslinking with UV-light and N-vinyl-pyrrolidinone. The refractive index and rheologic properties of the obtained gels were investigated. To quantify the degradation of the hydrogels over time, free hyaluronic acid was measured photometrically by means of the degradation product uronic acid. For biocompatibility testing, the hydrogels were applied on top of cultured retinal pigment epithelial (RPE) cells and analyzed by the cell viability, MTT, and alamar blue viability cytotoxicity assays and flow cytometry, with Annexin V-FITC and propidium iodide co-staining. The in vivo biocompatibility of the hydrogels was tested in vitrectomized rabbit eyes for up to 6 weeks. RESULTS: The synthesized hydrogels were all clear and transparent and had a refractive index similar to human vitreous. The rheologic measurements suggested sufficient viscosity and elasticity for intraocular use. Quantification of the degradation products revealed only a small decay of the gels over 1 month. However, the ADH cross-linked hydrogels induced mild cytotoxicity in the RPE cells. The UV cross linked hydrogels showed no toxicity or induction of apoptosis. In vivo the UV cross-linked biogels remained in place for 6 weeks, and electrophysiology and histology showed excellent tissue biocompatibility. CONCLUSIONS: Biopolymers based on UV cross-linked hyaluronic acid may be promising vitreous substitutes. PMID- 22199246 TI - Effect of nifedipine on choroidal blood flow regulation during isometric exercise. AB - PURPOSE: To determine whether nifedipine, an L-type calcium channel blocker, alters choroidal blood flow (ChBF) regulation during isometric exercise in healthy subjects. METHODS: The study was carried out in a randomized, placebo controlled, double-masked, two-way crossover design. Fifteen healthy male subjects were randomly assigned to receive either placebo or nifedipine on two different study days. Subfoveal ChBF was measured with laser Doppler flowmetry while the study participants performed isometric exercise (squatting). This was performed before drug administration and during infusion of nifedipine and placebo, respectively. Mean arterial pressure (MAP) and intraocular pressure (IOP) were measured noninvasively, and ocular perfusion pressure (OPP) was calculated as ⅔ MAP-IOP. RESULTS: MAP and OPP increased significantly during all squatting periods (P < 0.01). The increase in ChBF was less pronounced than the increase in OPP during isometric exercise. Nifedipine did not alter the OPP increase in response to isometric exercise, but it significantly augmented the exercise-induced increase in ChBF (P < 0.001 vs. placebo). Although ChBF increased by a maximum of 14.2% +/- 9.2% during the squatting period when placebo was administered, the maximum increase during administration of nifedipine was 23.2% +/- 7.2%. CONCLUSIONS: In conclusion, the data of the present study suggest that nifedipine augments the ChBF response to an experimental increase in OPP. In addition, it confirms that the choroidal vasculature has a significant regulatory capacity over wide ranges of OPPs during isometric exercise. (ClinicalTrials.gov number, NCT00280462.). PMID- 22199247 TI - Characterization of ocular surface epithelial and progenitor cell markers in human adipose stromal cells derived from lipoaspirates. AB - PURPOSE: The goal of this study was to characterize and compare mesenchymal stem cells from adult human adipose tissue (ADS cells) with progenitor cell lines from the human corneoscleral limbus and to analyze their potential for the expression of epithelial markers. METHODS: Stem cell markers (CD34, CD90, p63, and ABCG2) and epithelial cell markers (CK3/76, CK12, CK76, CK19, and CK1/5/10/14) were analyzed by immunostaining, flow cytometry, Western blot analysis, and PCR methods. The authors assayed adhesion and proliferation on different extracellular matrix proteins. RESULTS: ADS cells expressed a set of progenitor cell markers, including p63 and ABCG2. CK12 expression in ADS cell cultures increased spontaneously and progressively by differential adhesion, which demonstrates the cells' potential and capability to acquire epithelial-like cell characteristics. The authors observed an increase in the adhesion and proliferation of ADS cells seeded onto different basement membrane extracellular matrix proteins. Laminin substrates reduced the proliferative state of ADS cells. CONCLUSIONS: The expression of putative stem cell markers (CD90, ABCG2, and p63) and cytokeratins (CK12 and CK76) supports the hypothesis that ADS cells have self renewal capacity and intrinsic plasticity that enables them to acquire some epithelial-like characteristics. Therefore, adult ADS cells could be a potential source for cell therapy in ocular surface regeneration. PMID- 22199248 TI - Transduction of PTEN proteins using the tat domain modulates TGF-beta1-mediated signaling pathways and transdifferentiation in subconjunctival fibroblasts. AB - PURPOSE: This study investigated the effects of the tumor suppressor protein PTEN (phosphatase and tensin homolog) on transforming growth factor (TGF)-beta1 mediated signaling pathways and the transdifferentiation of human subconjunctival fibroblasts (SCFs) after the transduction of this protein containing a transactivator of transcription (Tat) domain. METHODS: The Tat-PTEN expression vector was constructed to express the Tat domain of HIV-1 fused to PTEN. After transduction of the fusion protein and TGF-beta1 stimulation, the dose-dependent effect of the transduced Tat-PTEN fusion protein on Akt phosphorylation and the stability of the Tat-PTEN fusion protein in SCF cells were evaluated by Western blot analysis. The effect of the Tat-PTEN fusion protein on the TGF-beta1 stimulated expression of alpha-SMA and fibronectin was also evaluated by Western blot analysis and immunocytochemistry. RESULTS: To increase the efficiency of enzyme activity and to successfully deliver this protein to cells, the authors used a PTEN fusion protein that contained the transduction domain of the Tat protein from HIV-1. By Western blot analysis, the transduced Tat-PTEN fusion protein was found to modulate TGF-beta1 signaling in SCF cells and result in the suppression of Akt phosphorylation. Furthermore, the transduction of the Tat-PTEN fusion protein was found to suppress the TGF-beta1-stimulated expression of alpha SMA and fibronectin by Western blot analysis and immunocytochemical staining, and the effects of the transduced fusion protein could be controlled in a dose dependent manner. CONCLUSIONS: The Tat-PTEN fusion proteins were successfully transduced into the SCF cells and induced the suppression of transdifferentiation and fibrosis through the regulation of TGF-beta-mediated signaling. The ability of the Tat-PTEN fusion protein to regulate cell survival could potentially be applied to protein therapy to counteract postoperative scarring in glaucoma surgery. PMID- 22199249 TI - Refractive error and presbyopia in timor-leste: the impact of 5 years of a national spectacle program. AB - PURPOSE: To characterize refractive error, presbyopia, and spectacle correction among adults aged >=40 years in Timor-Leste in 2010 and examine the impact of the National Spectacle Program by comparing results to those obtained 5 years earlier. METHODS: A population-based, cross-sectional survey sampled 50 clusters of 45 people each. Participants with uncorrected and undercorrected refractive error (presenting visual acuity <6/18, but >=6/18 in the better eye with pinhole), uncorrected and undercorrected presbyopia (=6/18 in the better eye with presenting spectacles), and corrected presbyopia (binocular >=N8 with presenting spectacles) were identified. Willingness to wear and to pay for spectacles was elicited. Data were adjusted for sex, age, and urban/rural domicile, to compare results from 2005 and 2010. RESULTS: A participation rate of 89.5% (n = 2014) was achieved. The 2010 sex-age domicile-adjusted parameters were as follows: 3.7% (95% confidence interval [CI], 2.8%-4.5%) met refractive error need; 9.6% (95% CI, 8.3%-10.9%) unmet refractive error need; 27.6% (95% CI, 22.2%-32.9%) refractive error correction coverage; 8.6% (95% CI, 7.4%-9.8%) met presbyopia need; 41.8% (95% CI, 39.7%-44.0%) unmet presbyopia need; and, 17.0% (95% CI, 14.7%-19.3%) presbyopia correction coverage. Refractive error correction coverage was significantly higher in 2010 than in 2005 (8.0%; 95% CI, 4.5%-11.6%), but presbyopia correction coverage was unchanged. Almost all the 2010 sample (99.5%) were willing to wear spectacles if needed. Sex-age-domicile-adjusted willingness to pay at least US$1.00 for spectacles was 56.9% (95% CI, 54.7%-59.1%) in 2010, significantly greater than in 2005 (47.2%; 95% CI, 44.5%-49.9%). CONCLUSIONS: The National Spectacle Program has not produced uniform improvement across all service indicators. Evidence based enhancements may now be initiated. PMID- 22199250 TI - Vitreal IgM autoantibodies target neurofilament medium in a spontaneous model of autoimmune uveitis. AB - PURPOSE: Although the presence of IgG autoantibodies in the vitreous of spontaneous cases of equine recurrent uveitis (ERU) has been demonstrated, the potential role of IgM reactivities during ERU pathogenesis remains unexplored. The purpose of this study was to examine the presence of IgM autoantibodies in vitreous specimens of ERU-affected horses and to test their binding specificity to intraocularly expressed proteins. METHODS: To test IgM autoantibody responses to retinal tissue, vitreous samples of eye-healthy controls and ERU patients were analyzed via two-dimensional Western blot analysis with equine retinal tissue as an antigen source. A candidate protein, the peptide neurofilament medium (NF-M), was identified via mass spectrometry and validated via enzyme-linked immunosorbent assay. Immunohistochemistry for NF-M expression was performed on healthy and ERU-affected retinal sections. RESULTS: Whereas autoreactivity was never detected in the healthy vitreous samples, NF-M was specifically targeted by vitreal IgM autoantibodies in 44% of the ERU cases. Vitreal anti-NF-M IgG was detected in only 8% of the ERU samples, pointing to a persistent IgM response. In healthy horse retina, NF-M was located in the retinal ganglion cells and their processes, with additional staining in the outer plexiform layer. NF-M expression in ERU-affected retinas decreased considerably, and the remaining expression was limited to the nerve fiber layer. CONCLUSIONS: Intraocular anti NF-M IgM autoantibodies occur with high prevalence in vitreous of spontaneous autoimmune uveitis cases. The IgM dominated response may indicate a thymus-independent response to NF-M and merits further investigation in ERU, as well as in its human counterpart, autoimmune uveitis. PMID- 22199251 TI - Vascular endothelial growth factor receptor 1 morpholino decreases angiogenesis in a murine corneal suture model. AB - PURPOSE: This study sought to determine whether a vascular endothelial growth factor receptor 1 (VEGFR1)-specific morpholino could induce the alternative splicing of Flt-1 pre-mRNA to downregulate membrane-bound Flt-1 (mFlt-1) and increase the production of soluble Flt-1 (sFlt-1), thereby limiting angiogenesis and inflammation in a mouse corneal suture injury model. METHODS: A murine corneal suture model was used to investigate the effects of a VEGFR1-specific morpholino in vivo. Western blot analysis and RT-PCR were used to compare the impact of the Flt morpholino on mFlt-1 and sFlt-1 levels. For vascular regression modeling, two corneal sutures were placed and injected with Flt morpholino, standard morpholino, and PBS on days 8 and 10. Corneas were harvested on day 14. The grade of neovascularization (graded 0-5; 0, no neovascularization; 5, thick tortuous new vessel growth over the suture and toward the center of the cornea) was compared on days 8, 10, and 14. Immunohistochemistry, fluorescent microscopy, and confocal microscopy were used to digitally quantify the area and volume of neovascularization and inflammatory infiltration. RESULTS: Western blot analysis revealed that the Flt morpholino decreased mFlt-1 levels while increasing sFlt-1 levels. An increased sFlt-1/mFlt-1 ratio in the Flt morpholino group was seen with RT-PCR. Based on the neovascularization grading, there was a decrease in neovascularization area in the Flt morpholino group (3.29 +/- 0.19 to 2.92 +/- 0.13) from day 8 to 14 (P < 0.05) compared with that in both the standard morpholino (2.68 +/- 0.19 to 3.14 +/- 0.22) and in the PBS (2.96 +/- 0.14 to 3.42 +/- 0.19) groups, both of which showed an increase in neovascularization (P < 0.05). The Flt morpholino group also showed reduced neovascularization volume compared with that of the PBS (P = 0.001) and STD morpholino groups (P = 0.000). CONCLUSIONS: Flt morpholinos decrease mFlt-1 and increase sFlt-1 levels, resulting in decreased neovascularization in a murine corneal suture model. PMID- 22199252 TI - Rad26p regulates the occupancy of histone H2A-H2B dimer at the active genes in vivo. AB - Recently, we have demonstrated a predominant association of Rad26p with the coding sequences but not promoters of several GAL genes following transcriptional induction. Here, we show that the occupancy of histone H2A-H2B dimer at the coding sequences of these genes is not altered following transcriptional induction in the absence of Rad26p. A histone H2A-H2B dimer-enriched chromatin in Deltarad26 is correlated to decreased association of RNA polymerase II with the active coding sequences (and hence transcription). However, the reduced association of RNA polymerase II with the active coding sequence in the absence of Rad26p is not due to the defect in formation of transcription complex at the promoter. Thus, Rad26p regulates the occupancy of histone H2A-H2B dimer, which is correlated to the association of elongating RNA polymerase II with active GAL genes. Similar results are also found at other inducible non-GAL genes. Collectively, our results define a new role of Rad26p in orchestrating chromatin structure and hence transcription in vivo. PMID- 22199253 TI - Human box C/D snoRNA processing conservation across multiple cell types. AB - Small nucleolar RNAs (snoRNAs) function mainly as guides for the post transcriptional modification of ribosomal RNAs (rRNAs). In recent years, several studies have identified a wealth of small fragments (<35 nt) derived from snoRNAs (termed sdRNAs) that stably accumulate in the cell, some of which may regulate splicing or translation. A comparison of human small RNA deep sequencing data sets reveals that box C/D sdRNA accumulation patterns are conserved across multiple cell types although the ratio of the abundance of different sdRNAs from a given snoRNA varies. sdRNA profiles of many snoRNAs are specific and resemble the cleavage profiles of miRNAs. Many do not show characteristics of general RNA degradation, as seen for the accumulation of small fragments derived from snRNA or rRNA. While 53% of the sdRNAs contain an snoRNA box C motif and boxes D and D' are also common in sdRNAs (54%), relatively few (12%) contain a full snoRNA guide region. One box C/D snoRNA, HBII-180C, was analysed in greater detail, revealing the presence of C' box-containing sdRNAs complementary to several pre-messenger RNAs (pre-mRNAs) including FGFR3. Functional analyses demonstrated that this region of HBII-180C can influence the alternative splicing of FGFR3 pre-mRNA, supporting a role for some snoRNAs in the regulation of splicing. PMID- 22199254 TI - Hobbes: optimized gram-based methods for efficient read alignment. AB - Recent advances in sequencing technology have enabled the rapid generation of billions of bases at relatively low cost. A crucial first step in many sequencing applications is to map those reads to a reference genome. However, when the reference genome is large, finding accurate mappings poses a significant computational challenge due to the sheer amount of reads, and because many reads map to the reference sequence approximately but not exactly. We introduce Hobbes, a new gram-based program for aligning short reads, supporting Hamming and edit distance. Hobbes implements two novel techniques, which yield substantial performance improvements: an optimized gram-selection procedure for reads, and a cache-efficient filter for pruning candidate mappings. We systematically tested the performance of Hobbes on both real and simulated data with read lengths varying from 35 to 100 bp, and compared its performance with several state-of-the art read-mapping programs, including Bowtie, BWA, mrsFast and RazerS. Hobbes is faster than all other read mapping programs we have tested while maintaining high mapping quality. Hobbes is about five times faster than Bowtie and about 2-10 times faster than BWA, depending on read length and error rate, when asked to find all mapping locations of a read in the human genome within a given Hamming or edit distance, respectively. Hobbes supports the SAM output format and is publicly available at http://hobbes.ics.uci.edu. PMID- 22199255 TI - Dissecting the protein-RNA interface: the role of protein surface shapes and RNA secondary structures in protein-RNA recognition. AB - Protein-RNA interactions are essential for many biological processes. However, the structural mechanisms underlying these interactions are not fully understood. Here, we analyzed the protein surface shape (dented, intermediate or protruded) and the RNA base pairing properties (paired or unpaired nucleotides) at the interfaces of 91 protein-RNA complexes derived from the Protein Data Bank. Dented protein surfaces prefer unpaired nucleotides to paired ones at the interface, and hydrogen bonds frequently occur between the protein backbone and RNA bases. In contrast, protruded protein surfaces do not show such a preference, rather, electrostatic interactions initiate the formation of hydrogen bonds between positively charged amino acids and RNA phosphate groups. Interestingly, in many protein-RNA complexes that interact via an RNA loop, an aspartic acid is favored at the interface. Moreover, in most of these complexes, nucleotide bases in the RNA loop are flipped out and form hydrogen bonds with the protein, which suggests that aspartic acid is important for RNA loop recognition through a base-flipping process. This study provides fundamental insights into the role of the shape of the protein surface and RNA secondary structures in mediating protein-RNA interactions. PMID- 22199256 TI - Gli2 and MEF2C activate each other's expression and function synergistically during cardiomyogenesis in vitro. AB - The transcription factors Gli2 (glioma-associated factor 2), which is a transactivator of Sonic Hedgehog (Shh) signalling, and myocyte enhancer factor 2C (MEF2C) play important roles in the development of embryonic heart muscle and enhance cardiomyogenesis in stem cells. Although the physiological importance of Shh signalling and MEF2 factors in heart development is well known, the mechanistic understanding of their roles is unclear. Here, we demonstrate that Gli2 and MEF2C activated each other's expression while enhancing cardiomyogenesis in differentiating P19 EC cells. Furthermore, dominant-negative mutant proteins of either Gli2 or MEF2C repressed each other's expression, while impairing cardiomyogenesis in P19 EC cells. In addition, chromatin immunoprecipitation (ChIP) revealed association of Gli2 to the Mef2c gene, and of MEF2C to the Gli2 gene in differentiating P19 cells. Finally, co-immunoprecipitation studies showed that Gli2 and MEF2C proteins formed a complex, capable of synergizing on cardiomyogenesis-related promoters containing both Gli- and MEF2-binding elements. We propose a model whereby Gli2 and MEF2C bind each other's regulatory elements, activate each other's expression and form a protein complex that synergistically activates transcription, enhancing cardiac muscle development. This model links Shh signalling to MEF2C function during cardiomyogenesis and offers mechanistic insight into their in vivo functions. PMID- 22199257 TI - RNASEQR--a streamlined and accurate RNA-seq sequence analysis program. AB - Next-generation sequencing (NGS) technologies-based transcriptomic profiling method often called RNA-seq has been widely used to study global gene expression, alternative exon usage, new exon discovery, novel transcriptional isoforms and genomic sequence variations. However, this technique also poses many biological and informatics challenges to extracting meaningful biological information. The RNA-seq data analysis is built on the foundation of high quality initial genome localization and alignment information for RNA-seq sequences. Toward this goal, we have developed RNASEQR to accurately and effectively map millions of RNA-seq sequences. We have systematically compared RNASEQR with four of the most widely used tools using a simulated data set created from the Consensus CDS project and two experimental RNA-seq data sets generated from a human glioblastoma patient. Our results showed that RNASEQR yields more accurate estimates for gene expression, complete gene structures and new transcript isoforms, as well as more accurate detection of single nucleotide variants (SNVs). RNASEQR analyzes raw data from RNA-seq experiments effectively and outputs results in a manner that is compatible with a wide variety of specialized downstream analyses on desktop computers. PMID- 22199258 TI - Normalized Affymetrix expression data are biased by G-quadruplex formation. AB - Probes with runs of four or more guanines (G-stacks) in their sequences can exhibit a level of hybridization that is unrelated to the expression levels of the mRNA that they are intended to measure. This is most likely caused by the formation of G-quadruplexes, where inter-probe guanines form Hoogsteen hydrogen bonds, which probes with G-stacks are capable of forming. We demonstrate that for a specific microarray data set using the Human HG_U133A Affymetrix GeneChip and RMA normalization there is significant bias in the expression levels, the fold change and the correlations between expression levels. These effects grow more pronounced as the number of G-stack probes in a probe set increases. Approximately 14% of the probe sets are directly affected. The analysis was repeated for a number of other normalization pipelines and two, FARMS and PLIER, minimized the bias to some extent. We estimate that ~15% of the data sets deposited in the GEO database are susceptible to the effect. The inclusion of G stack probes in the affected data sets can bias key parameters used in the selection and clustering of genes. The elimination of these probes from any analysis in such affected data sets outweighs the increase of noise in the signal. PMID- 22199259 TI - Structuring the bacterial genome: Y1-transposases associated with REP-BIME sequences. AB - REPs are highly repeated intergenic palindromic sequences often clustered into structures called BIMEs including two individual REPs separated by short linker of variable length. They play a variety of key roles in the cell. REPs also resemble the sub-terminal hairpins of the atypical IS200/605 family of insertion sequences which encode Y1 transposases (TnpA(IS200/IS605)). These belong to the HUH endonuclease family, carry a single catalytic tyrosine (Y) and promote single strand transposition. Recently, a new clade of Y1 transposases (TnpA(REP)) was found associated with REP/BIME in structures called REPtrons. It has been suggested that TnpA(REP) is responsible for REP/BIME proliferation over genomes. We analysed and compared REP distribution and REPtron structure in numerous available E. coli and Shigella strains. Phylogenetic analysis clearly indicated that tnpA(REP) was acquired early in the species radiation and was lost later in some strains. To understand REP/BIME behaviour within the host genome, we also studied E. coli K12 TnpA(REP) activity in vitro and demonstrated that it catalyses cleavage and recombination of BIMEs. While TnpA(REP) shared the same general organization and similar catalytic characteristics with TnpA(IS200/IS605) transposases, it exhibited distinct properties potentially important in the creation of BIME variability and in their amplification. TnpA(REP) may therefore be one of the first examples of transposase domestication in prokaryotes. PMID- 22199261 TI - Quantification of angiogenesis in breast cancer by automated vessel identification in CD34 immunohistochemical sections. AB - BACKGROUND/AIM: Tumor growth is dependent upon angiogenesis. Tumor vascularity, as measured by microvessel density or Chalkley counts, has been shown to predict treatment outcome. However, many issues related to reproducibility and methodology have prevented its clinical application. We present a method of automatic vessel identification applied to CD34 immunohistochemical sections which facilitates increased reproducibility. MATERIALS AND METHODS: Pixel colour information was used to identify CD34 stain. In order to reduce the effects of noise and background, stained areas smaller than 3.5 MUm were ignored. RESULTS: Comparing automatic and manual vessel counts in 50 randomly selected breast cancer cases, the method achieved an intraclass correlation coefficient of r(a)(2)=0.96 and a 95% confidence interval for the percentage difference between the counts from -26.1% to 10.8%. The method was also found to have a sensitivity approaching 100%. CONCLUSION: The method can reliably be used on colour photographs of staining for CD34 to quantify angiogenesis. PMID- 22199260 TI - Type III restriction endonuclease EcoP15I is a heterotrimeric complex containing one Res subunit with several DNA-binding regions and ATPase activity. AB - For efficient DNA cleavage, the Type III restriction endonuclease EcoP15I communicates with two inversely oriented recognition sites in an ATP-dependent process. EcoP15I consists of methylation (Mod) and restriction (Res) subunits forming a multifunctional enzyme complex able to methylate or to cleave DNA. In this study, we determined by different analytical methods that EcoP15I contains a single Res subunit in a Mod(2)Res stoichiometry. The Res subunit comprises a translocase (Tr) domain carrying functional motifs of superfamily 2 helicases and an endonuclease domain with a PD..D/EXK motif. We show that the isolated Tr domain retains ATP-hydrolyzing activity and binds single- and double-stranded DNA in a sequence-independent manner. To localize the regions of DNA binding, we screened peptide arrays representing the entire Res sequence for their ability to interact with DNA. We discovered four DNA-binding regions in the Tr domain and two DNA-binding regions in the endonuclease domain. Modelling of the Tr domain shows that these multiple DNA-binding regions are located on the surface, free to interact with DNA. Interestingly, the positions of the DNA-binding regions are conserved among other Type III restriction endonucleases. PMID- 22199262 TI - Establishing efficient xenograft models with intrinsic vascularisation for growing primary human low-grade sarcomas. AB - BACKGROUND: There are no xenograft models of low-grade soft tissue sarcoma. Transplant survival remains an obstacle in sarcoma xenograft models and is attributed to post-transplantation hypoxia. Models with an intrinsic tissue - engineered vascular supply may overcome this obstacle. The aim of this study was to establish a novel xenograft model of primary human low grade soft tissue sarcoma. MATERIALS AND METHODS: Primary low-grade liposarcoma fragments were transplanted into a silicon chamber, placed around the superficial epigastric vessels in athymic nude mice. Xenograft samples were assessed histologically (light/electron microscopy and immunohistochemistry for S100). RESULTS: All xenotransplants of low grade primary soft tissue liposarcoma (n=4) engrafted, led to the development of solid tumours in mice. Histological and immunohistochemical staining confirmed the xenografts as being well-differentiated liposarcomas identical to the original tumor tissue. CONCLUSION: Successful transplantation of human low-grade liposarcoma tissue in mice was established for the first time using a model with an intrinsic vascular supply. PMID- 22199263 TI - Inhibition of human tumor xenograft growth in nude mice by a novel monoclonal anti-HSPG isolated from human liver. AB - Heparan sulfate proteoglycans (HSPGs) were isolated from normal human liver and alpha monoclonal antibody (MAb) was raised against them. Preliminary studies showed that MAb clone 1E4-1C2 was able to react with many cell lines tested, including hematopoietic cells and solid tumors. MAb1E4-1C2 was used to study whether HSPG was involved in growth and proliferation of human liver cancer using hepatocellular carcinoma (HCC) cell line (HepG2) as a model. Inhibition by MAb1E4 1C2 of HepG2 cell proliferation was studied in vitro by MTT assay. For in vivo assay, xenograft induction in athymic mice was performed. The results showed that MAb1E4-1C2 inhibited proliferation of HepG2 cells significantly, compared to isotype and medium control. MAb1E4-1C2 also suppressed the growth of tumor, resulting in smaller tumor size and weight. The investigation also showed that MAb1E4-1C2 inhibited proliferation and restricted tumor growth through the induction of apoptosis. The results suggest that HSPG might be involved in liver cancer cell proliferation. Therefore, a specific MAb that was raised against liver HSPG might be an alternative therapeutic agent for the treatment of human liver cancer. PMID- 22199264 TI - L-type amino acid transporter 1 (LAT1) expression in malignant pleural mesothelioma. AB - L-Type amino acid transporter 1 (LAT1) is known to be highly expressed in various human neoplasms. However, little is known about how LAT1 is expressed in malignant pleural mesothelioma (MPM). Twenty-one patients were included in this study. Tumor sections were stained by immunohistochemistry for LAT1, glucose transporter 1 (GLUT1), GLUT3, hypoxia inducible factor-1alpha (HIF-1alpha), hexokinase I, vascular endothelial growth factor (VEGF), microvessel density (MVD) by determination of CD34, epidermal growth factor receptor (EGFR), phosphatase and tensin analog (PTEN), p-AKT, p-manmalian target of rapamycin (mTOR), p-S6K, p53 and BCL-2. LAT1 was overexpressed in approximately 50% of the patients with MPM. LAT1 expression was closely correlated with CD98, hypoxic markers, the mTOR pathway, Ki-67 and p53. The overexpression of LAT1 was closely associated with poor outcome in patients with MPM. LAT1 is closely associated with tumor development and progression in patients with MPM. PMID- 22199265 TI - Electrotransfer of RNAi-based oligonucleotides for oncology. AB - For more than a decade, there has been tremendous growth in our understanding of RNA interference (RNAi). The potent ability that small oligonucleotides have in gene silencing makes them desirable as novel cancer therapeutics, but many biological barriers exist for their efficient delivery into target cells or tissues. Electropulsation (EP) appears to be a promising method for cancer associated gene therapy. EP is the direct application of electric pulses to cells or tissues that transiently permeabilize the plasma membranes, allowing efficient in vitro and in vivo cytoplasmic delivery of exogenous molecules. The present review reports on the type of therapeutic RNAi-based oligonucleotides that can be electrotransferred, the mechanism of their electrotransfer and the technical settings for pre-clinical purposes. PMID- 22199266 TI - The novel vitamin D analog ZK191784 inhibits prostate cancer cell invasion. AB - BACKGROUND: Low serum levels of 1,25(OH)(2)D(3) (1,25D), have been associated with aggressive biologic behavior of prostate cancer (PCa). In the present study, we examined the effects of 1,25D and its novel, low-calcemic analog ZK191784 (ZK) on matrix metalloproteinases (MMPs), as well as on intercellular adhesion molecule-1 (ICAM-1) protein levels in human PCa cell lines LNCaP and DU-145. MATERIALS AND METHODS: Cells were incubated with either vehicle (control), 1,25D or ZK. MMP-2 and MMP-9 activity was determined by gelatin zymography, while ICAM 1 levels were assessed by Western blot analysis and immunocytochemistry. RESULTS: Compared to the controls, 1,25D and ZK caused a marked dose-dependent decrease in the gelatinolytic activity of the MMPs under study, particularly when ZK was used. Likewise, ICAM-1 was down-regulated in the cells incubated with 1,25D or ZK. CONCLUSION: Vitamin D analogs appear to be involved in the regulation of extracellular MMP activity and membrane adhesion molecule expression. Further studies, both in vitro and in vivo, are needed to define their role as potential therapeutic tools. PMID- 22199267 TI - Characterization of T-cell memory phenotype after in vitro expansion of tumor infiltrating lymphocytes from melanoma patients. AB - Memory T-cell populations in human antitumor tumor-infiltrating lymphocytes (TILs) for adoptive cell transfer have not been fully characterized. Our studies demonstrated that CD62L, CD27 and CD28 positive effector memory T-cells were present in the TIL samples from the tumor tissues of melanoma patients and T-cell expansion led to the significant loss of memory T-cells. CD27- and CD28-positive T-cells had high levels of CD44 expression. T-Cell expansion resulted in significant down-regulation of CD44 expression. Interleukin-2 (IL-2) and anti-CD3 antibody stimulation may be responsible for CD44 down-regulation on CD8(+) T cells during expansion. Furthermore, CD44 down-regulation using small interfering RNA (siRNA) on TILs dramatically reduced interferon-gamma and IL-2 release upon tumor stimulation. These results suggest that the regulation of CD44 expression in TILs may play an important role in memory T-cell maintenance and antitumor immune response. PMID- 22199268 TI - Effects of artemisinin dimers on rat breast cancer cells in vitro and in vivo. AB - Artemisinin has been shown to be an effective antimalarial and anticancer compound. Dimers of artemisinin have been synthesized and shown to be potent antimalarials compared with monomers. In the present study, we investigated the effect of two artemisinin dimers (dimer-alcohol and dimer-hydrazone) on rat mammary adenocarcinoma cells (MTLn3) in vitro and in vivo compared with that of the artemisinin monomer dihydroartemisinin (DHA). We found that the dimers are considerably more potent than DHA in killing MTLn3 cells in vitro and suppressing the growth of MTLn3 breast tumors in vivo. PMID- 22199269 TI - Histone-modifier gene expression profiles are associated with pathological and clinical outcomes in human breast cancer. AB - BACKGROUND: Epigenetic regulation of gene expression is under normal circumstances tightly controlled by the specific methylation of cytosine residues in CpG dinucleotides and coordinated by adjustments in the histone-dependent configuration of chromatin. Following our original report, providing the first description of potential tumor suppressor function associated with the histone methyltransferase SET domain containing 2 (SETD2) in breast cancer, the objective of this study was to determine the expression profiles of 16 further histone modifier genes in a well annotated cohort of patients with primary operable breast cancer. MATERIALS AND METHODS: Breast cancer tissues (n=127) and normal tissues (n=33) underwent RNA extraction and reverse transcription, and histone modifier gene transcript levels were determined using real-time quantitative PCR. The histone-modifier genes included: histone acetyltransferases (cAMP response element-binding protein-binding protein (CREBBP)); class I (histone deacetylase 1 (HDAC1) and histone deacetylase 2 (HDAC2)), II (histone deacetylase 5 (HDAC5)) and III (sirtuin 1 (SIRT1)) histone deacetylases; and histone methyltransferases (SET domain containing suppressor of variegation 3-9 homolog 1 (SUV39H1) and suppressor of variegation 3-9 homolog 2 (SUV39H2)) amongst others. Expression levels were analysed against tumor size, grade, nodal involvement, histological subtype, receptor status, TNM stage, Nottingham Prognostic Index, and disease free and overall survival over a 10-year follow-up period. RESULTS: Expression of histone-modifier genes in breast cancer differed significantly from those in normal tissue (HDAC5, HDAC1, lysine (K)-specific demethylase 4A (KDM4A) and lysine (K)-specific demethylase 6A (KDM6A)). Differences in expression profiles were also found to exist between individual breast tumors and, in some cases, were significantly associated with conventional pathological parameters and prognostic indices: tumor grade (K (lysine) acetyltransferase 5 (KAT5), HDAC1, KDM4A, SUV39H1 and KDM6A)); TNM stage (SUV39H1, K (lysine) acetyltransferase 2B (KAT2B), lysine (K)-specific demethylase 1A (KDM1A), KDM4A, lysine (K)-specific demethylase 5C (KDM5C), K (lysine) acetyltransferase 8 (KAT8), HDAC5 and KAT5)); Nottingham Prognostic Index (KDM5C, myeloid/lymphoid or mixed-lineage leukemia (MLL), KAT8 and SET and MYND domain containing 3 (SMYD3)); receptor status (KAT5, SMYD3 and KDM1A); histological type (KAT5, KDM5C, KAT8, KDM4A and MLL); disease free survival (SUV39H1, SMYD3, HDAC5, KDM6A, HDAC1, KDM1A, KDM4A, KAT8, KDM5C, KAT5 and MLL) and overall survival (KAT8). Significant correlations were identified between the differential expression profiles of particular histone modifying genes. CONCLUSION: Expression levels of histone-modifier genes in breast cancer differ significantly from normal tissue. Differences in expression profiles exist between breast tumors and are significantly associated with conventional pathological parameters and clinical outcomes. Further study is warranted to determine the consequences of altered expression for each specific histone-modifier gene and the biological and clinical implications of combinatorial variations in expression profiles. Histone-modifier enzymes offer utility as biomarkers and potential for targeted therapeutic strategies. PMID- 22199270 TI - PINCH mRNA overexpression in colorectal carcinomas correlated with VEGF and FAS mRNA expression. AB - BACKGROUND: Particularly interesting new cysteine-histidine-rich protein (PINCH) was found to be up-regulated in the stroma of colorectal carcinomas (CRCs) in our previous studies and was involved in angiogenesis through activation of fibroblasts in extracellular matrix (ECM) in response to tumors. Here, we examined PINCH mRNA expression in colorectal cancer and investigated its relationship with the clinicopathological features and proliferation cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF) and FAS. MATERIALS AND METHODS: The primary cancer tissues, adjacent noncancerous tissues and the proximal and distant margins of normal mucosa were collected from 81 colorectal cancer patients during surgery. PINCH, PCNA, VEGF and FAS mRNA expression was examined by reverse transcriptional PCR (RT-PCR). RESULTS: PINCH mRNA expression was significantly increased in primary tumors compared with that in adjacent noncancerous tissues, and the proximal and distant margins of normal mucosa (p<0.0001). Expression of PINCH mRNA in colon cancer tended to be higher than expression in rectal cancer (p=0.051). Tumors which had infiltrated through the wall of the colorectum trended to have higher PINCH mRNA expression (p=0.073). PINCH mRNA expression in primary tumors was positively related to the expression of PCNA mRNA (r=0.534, p=0.010), VEGF mRNA (r=0.431, p=0.022) and FAS mRNA (r=0.542, p=0.012). CONCLUSION: PINCH mRNA was overexpressed in colorectal cancer and associated with PCNA mRNA, VEGF mRNA and FAS mRNA expression. PINCH mRNA was involved in the development of colorectal cancer and might play a role in the epithelial mesenchymal transition in the rectum differently than in the colon, through the adenomatous polyposis coli (APC)/catenin pathway. PMID- 22199271 TI - ERCC1 expression and outcomes in head and neck cancer treated with concurrent cisplatin and radiation. AB - BACKGROUND: Overexpression of excision repair cross complementing group 1 (ERCC1), a DNA repair enzyme, is associated with resistance to cisplatin. MATERIALS AND METHODS: Tissues from 73 patients with squamous cell carcinoma of the head and neck (HNSCC) who received concurrent cisplatin and radiation was analyzed immunohistochemically to determine if ERCC1 expression predicted for survival and response. Expression was scored as follows: 0=0% tumor nuclei positive, 1+=<50%, 2+=50-75% and 3+=>75%. RESULTS: ERCC1 expression was 0 in 0%, 1+ (14%), 2+ (42%) and 3+ (44%). In uni- and multivariate analyses, 3+ ERCC1 expression was not a significant predictor of survival or response. Median survival for the ERCC1 3+ patients was 2.9 years versus 2.1 years for the ERCC1 <3+ group (p=0.44). CONCLUSION: In this retrospective review of HNSCC patients receiving concurrent cisplatin and radiation, ERCC1 expression was not a significant predictor of survival or response. PMID- 22199272 TI - Treatment of bone metastasis in prostate cancer: efficacy of a novel polybisphosphonate. AB - AIM: To investigate the in vivo efficacy of a novel polybisphosphonate (ODX) in the treatment of bone metastasis from prostate cancer. MATERIAL AND METHODS: A rat prostatic carcinoma model was used. Forty-two rats (21 control, 21 treatment) had induction of bone lesions through injection of AT6.1 cells into the distal medullar cavity of long bones (right femur). At day 21 post injection, radiographs were taken and tumor score (severity of lesions, 0-4) and tumor incidence (score >0) were determined. Treatment started at day 23 and lasted until day 49 (four i.v. administrations of ODX during four weeks). RESULTS: ODX reduced the severity of the lesions compared to the control group. Forty-seven percent of the treated rats had regression of their lesions at the study end, including four rats showing disappearance of the lesions i.e. score 0. Osteocondensation at the growth plate was only observed in the treatment group, indicating osteoclast inhibition. CONCLUSION: In spite of a relatively short treatment period with only four administrations, ODX showed significant efficacy (p=0.0023), with inhibition of tumor progression and osteolysis. The results are encouraging, confirming previous in vitro studies. Clinical research is pending on patients with bone metastasis from castration-resistant prostate cancer. PMID- 22199273 TI - REG4, NEIL2, and BIRC5 gene expression correlates with gamma-radiation sensitivity in patients with rectal cancer receiving radiotherapy. AB - AIM: The present study aimed to identify genes that influence the susceptibility of cancer cells to radiation. MATERIALS AND METHODS: The sensitivities of eight colorectal cancer cell lines to gamma radiation were tested. Microarray data and cells with stable overexpression were used to identify candidate genes. Candidate genes correlating with radioresistance were validated with the use of 22 clinical specimens obtained before preoperative radiotherapy from patients with rectal cancer. RESULTS: Regenerating islet-derived protein 4 (REG4) gene expression was 12-fold higher in radioresistant cells. REG4-overexpressing cells had higher survival rates and fewer DNA strand breaks after gamma irradiation. Expression of the antiapoptotic gene baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) and base excision-repair pathway gene nei endonuclease VIII-like 2 (NEIL2) in REG4-overexpressing cells, was also three to four times higher than that of the parental cell lines. REG4, BIRC5 and NEIL2 expression levels were significantly higher in non-responding patients (n=14) than in responders (n=8). CONCLUSION: The REG4, BIRC5 and NEIL2 genes might be useful predictors of the sensitivity of cancer patients to radiotherapy. PMID- 22199274 TI - Overexpressed HER2 in NSCLC is a possible therapeutic target of EGFR inhibitors. AB - BACKGROUND: "Oncogene addiction" is a concept in which tumor cells exhibit dependence on certain oncogene(s) for their sustained proliferation and survival, thus providing the rationale for molecular targeted therapies. Cancer cells addicted to epidermal growth factor receptor (EGFR) bear activated mutations in the EGFR gene, and these mutations are used as the markers for predicting carcinomas susceptible to EGFR inhibitors such as gefitinib and erlotinib. However, other unknown mechanisms underlying susceptibility to EGFR inhibitors have also been suggested. MATERIALS AND METHODS: The susceptibility of non-small cell lung cancer (NSCLC) cell lines to EGFR inhibitors and the pattern of their oncogene addiction was examined. The effect of EGFR inhibitors on the activation of the oncogene was analyzed. The possible use of the oncogene protein expression as a biomarker was assessed. RESULTS: HER2 addicted, non-EGFR expressing NSCLC cell line NCI-H2170 was susceptible to EGFR inhibitors. EGFR inhibitor treatment led to markedly decreased phosphorylation levels of activated HER2 and its downstream effector AKT. Furthermore, the soluble form of HER2 was secreted by NCI-H2170 cells and was positively detected in the blood of xenografted mice. CONCLUSION: HER2 seems to be a valid therapeutic target of EGFR inhibitors in HER2-addicted lung carcinomas, and soluble HER2 may be an effective biomarker to guide the appropriate treatment of such cancer cells. PMID- 22199275 TI - Acridine orange inhibits pulmonary metastasis of mouse osteosarcoma. AB - Although the survival of patients with osteosarcoma has improved following development of chemotherapy and surgery, the presence of pulmonary metastases indicate a poor prognosis. We developed photodynamic and radiodynamic therapies with acridine orange (AO-PDT and AO-RDT) for minimally invasive surgery to treat musculoskeletal sarcomas and reported a good clinical outcome of local control and limb function. We investigated the effect of AO-PDT using flash-wave light (FWL) on pulmonary metastasis of mouse osteosarcoma. In in vitro and in vivo studies, AO alone and AO-PDT significantly inhibited cell invasion and the growth of pulmonary metastases from primary mouse osteosarcoma. AO may have a specific metastasis-inhibitory effect, different from the effect of AO-PDT. The fluorovisualization effect on pulmonary metastases following intravenous AO administration showed that pulmonary metastases localized on the lung surface were recognized as brilliant green lesions. In conclusion, AO-PDT using FWL inhibited cell invasion and pulmonary metastases in mouse osteosarcoma; therefore, this treatment modality might be applicable for treating pulmonary metastasis from malignant musculoskeletal tumors in humans. PMID- 22199276 TI - Effects of inorganic and organic arsenic compounds on growth and apoptosis of human T-lymphoblastoid leukemia cells. AB - BACKGROUND/AIM: To investigate the effects of inorganic and organic arsenic compounds on human T-lymphoblastoid leukemia cells. MATERIALS AND METHODS: Cell proliferation was analyzed by 3-(4,5-dimethylthiazol-2-yl) 2,5!diphenyltetrazolium bromide (MTT) assay. Apoptotic cell morphology was examined by cell staining with Hoechst 33342. Cellular caspase-3/7 activities were measured after arsenic treatment. RESULTS: The inhibitory concentration by 50% (IC(50)) values of As(2)O(3) towards MOLT-4 and daunorubicin- resistant MOLT 4/DNR cell proliferation were 0.87 and 0.92 MUM, while the values for arsenic acid were 69.1 and 116.6 MUM, respectively. These arsenic compounds also inhibited mitogen-induced proliferation of human peripheral blood mononuclear cells. Six organic arsenic compounds did not inhibit leukemia cell proliferation. As(2)O(3) and arsenic acid induced apoptotic cell morphology and increased caspase-3/7 activity in the leukemia cells. Ascorbic acid and buthionine sulfoxide enhanced, while N-acetyl-L-cysteine abated, the suppressive effects of inorganic arsenic compounds on leukemia cell proliferation. CONCLUSION: As(2)O(3) and arsenic acid inhibit proliferation and induce apoptosis in MOLT-4 and daunorubicine-resistant MOLT-4/DNR cells via glutathione-depletion and subsequent caspase-3/7 activation. Organic arsenic compounds have no inhibitory activity on the leukemia cell proliferation. Inorganic arsenic compounds are suggested as useful agents for treatment of T-lymphoblastoid leukemia. PMID- 22199278 TI - Inactivated orf virus (Parapoxvirus ovis) induces antitumoral activity in transplantable tumor models. AB - Orf virus (ORFV, Parapoxvirus ovis) possesses strong immunomodulating activity including the induction of interferon gamma (IFN-gamma) and interleukin-12 (IL 12) expression. Antiviral effects have been described which appeared to be facilitated by an ORFV-induced Type 1 helper T-cell (Th1-type) immune response. In this study, we investigated the potential antitumoral activity of inactivated ORFV in transplantable tumor models. We show that parenteral administration of inactivated ORFV mediates antitumor effects in various models including the murine syngenic B16 F10 melanoma and MDA-MB-231 human breast cancer xenograft. Inhibition of natural killer (NK) and NKT cell activity through administration of an anti-mouse NK-1.1 antibody led to a reduction of ORFV-mediated antitumoral effects. However, residual antitumoral activity was observed. This observation was confirmed in MDA-MB-231 tumor-bearing NOD/LtSz-scid/j mice which not only lack functional T and B lymphocytes but, in addition, have virtually no cells positive for the NK 1.1 cell surface marker. Thus, administration of inactivated ORFV induced inhibitory effects on the growth of transplantable tumors even under conditions of severe immunosuppression. PMID- 22199277 TI - Mutational screening of RET, HRAS, KRAS, NRAS, BRAF, AKT1, and CTNNB1 in medullary thyroid carcinoma. AB - BACKGROUND: Screening medullary thyroid carcinomas (MTCs) for rearranged during transfection (RET) mutations becomes increasingly important for clinical assessment of the disease. The role of mutations in other genes including RAS (i.e. HRAS, KRAS, and NRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), v-akt murine thymoma viral oncogene homolog 1 (AKT1), and CTNNB1 (beta catenin) is unknown or not fully explored yet for this disease. MATERIALS AND METHODS: Formalin-fixed and paraffin-embedded (FFPE) material was the primary source for screening 13 sporadic and inherited MTCs and matched non-tumor specimens. Multiplex PCR was included in the PCR protocol. Sequence analysis encompassed mutational hotspot regions in RET exons 5, 8, 10, 11, and 13 to 16; HRAS exons 1 and 2; KRAS exons 1 and 2; NRAS exons 1 and 2; BRAF exon 15; AKT1 exon 2, and CTNNB1 exon 3. RESULTS: We identified RET mutations in seven of 13 MTCs: five RET-positive cases revealed a mutation in exon 16 (M918T) and two a mutation in exon 10 (C618S and C620S). In four of the RET-positive cases, the mutation was inherited, out of which three were reportedly associated with a multiple endocrine neoplasia type 2 (MEN2) syndrome, i.e. MEN2A (C618S), MEN2A/familial MTC (FMTC) (C620S), and MEN2B (M918T). These cases reflect the known MEN2 genotype-phenotype correlation. Three of the five stage IVc MTCs were inherited RET-positive cases. Mutational screening in HRAS, KRAS, NRAS, BRAF, AKT1, and CTNNB1 disclosed one sporadic RET-negative MTC (stage III) with mutation in HRAS codon 13 (G13R). CONCLUSION: Our study supports the clinical relevance of screening MTC patients for RET mutations. The role of RAS mutations, in particular HRAS mutations, in sporadic RET-negative MTC has not been fully explored yet. Mutations in BRAF, AKT1, and CTNNB1 are likely not to play a role in MTC. PMID- 22199279 TI - Expression of the apoptosis-related genes Bcl-2 and p53 in clinical samples from endometrial carcinoma patients. AB - BACKGROUND: Although alterations in the mechanisms of apoptosis are an integral part of the tumor phenotype, their precise role in endometrial carcinoma is still obscure. The aim was to determine whether Bcl-2 plays a similar biological role in endometrial cancer as in breast cancer, endometrial cancer being also a hormone-dependent tumor. MATERIALS AND METHODS: The expression of the apoptosis related Bcl-2 and p53 genes, together with Ki67, E-cadherin, c-erb-B2 and estrogen and progesterone receptors were studied in 136 formalin-fixed, paraffin embedded endometrial carcinoma samples by means of immunohistochemistry. RESULTS: Bcl-2 expression correlated directly and significantly with E-cadherin (r=0.22, p=0.011) estrogen receptor (r=0.18, p=0.04) and progesterone receptor expression (r=0.30, p=0.0006), and inversely with surgical stage (r=-0.20, p=0.024). Mutant p53 expression was directly and significantly associated with increasing patient age (r=0.25, p=0.007), tumor grade (r=0.37, p<0.001), Ki67 (r=0.47, p<0.0001), c erb-B2 expression (r=0.21, p=0.012) and with E-cadherin expression (r=0.19, p=0.026). CONCLUSION: Bcl-2 and p53 are independently and significantly co expressed with E-cadherin in endometrial carcinoma. Furthermore, the expression of Bcl-2 is also significantly associated with the expression of both progesterone and estrogen receptors, in that order, suggesting that, analogously to breast cancer, apoptosis is hormonally regulated to some degree also in endometrial cancer. PMID- 22199280 TI - Yeast-derived beta-(1-3),(1-6)-D-glucan induces up-regulation of CD86 on dectin-1 positive human B-lymphoma cell lines. AB - BACKGROUND: The knowledge of direct effects of beta-glucans on tumor cells is limited. This study evaluated the impact of a soluble yeast-derived beta-(1-3),(1 6)-d-glucan, containing a fraction of aggregated sugar polymers, on viability, proliferation and expression of CD86 of the human B-cell lymphoma cell lines Daudi and Raji. MATERIALS AND METHODS: Proliferation of carboxyfluorescein diacetate succinimidyl ester (CFSE)-stained cell lines was determined by measuring depletion of the dye and cell death was quantified by staining with propidium iodide, both by flow cytometry. Surface expression of CD86 and the beta glucan receptors dectin-1 and complement receptor 3 (CR3) was assessed by flow cytometry. RESULTS: Exposure to the carbohydrate increased the expression of CD86 on both dectin-1(+)CR3(-) cell lines, whereas proliferation and viability of the cells were not affected. CONCLUSION: Yeast-derived beta-glucan lacks cytotoxic effects towards B-lymphoma cells but up-regulation of CD86 suggests maturation of the cells via dectin-1 by the carbohydrate. PMID- 22199281 TI - Thioridazine induces apoptosis of multidrug-resistant mouse lymphoma cells transfected with the human ABCB1 and inhibits the expression of P-glycoprotein. AB - AIM: Chlorpromazine has activity against a large variety of cancer types. However, this phenothiazine produces a plethora of serious side-effects. We have studied thioridazine (TZ), a phenothiazine neuroleptic that is much milder, for activity against multidrug-resistant (MDR) cancer cells, as well as against the overexpressed ABCB1 transporter (P-glycoprotein) that is the cause for the MDR phenotype of these cancer cells. MATERIALS AND METHODS: MDR mouse T-lymphoma cells, transfected with the human gene ABCB1 that codes for the transporter ABCB1, were incubated with TZ for various periods of time and examined for evidence of apoptosis. Concentrations of TZ were evaluated for activity against the ABCB1 transporter with the aid of an automated ethidium bromide (EB) method. RESULTS: TZ induces apoptosis of MDR cancer cell line, as well as inhibits the activity of the overexpressed ABCB1 transporter of these cells. CONCLUSION: Because thioridazine has been in moderately safe use for over 40 years for the therapy of psychosis, it has the potential to serve as an adjuvant with anticancer agents, rendering the a priori MDR cancer cells susceptible to the anticancer agent. PMID- 22199282 TI - Reliability of direct sequencing of EGFR: comparison between cytological and histological samples from the same patient. AB - The results of a recent study have shown the superiority of treatment with gefitinib or erlotinib in lung tumors positive for epidermal growth factor receptor (EGFR) mutation. As a consequence, the complete diagnosis of lung cancer cannot be limited to histotype classification, but should include a series of molecular biology analyses. In most cases, the diagnosis of lung cancer is performed on cytological specimens; therefore, there is a need to obtain a complete and reliable molecular diagnosis on cytologic specimens. Brushing, transbronchial needle aspiration (TBNA) and broncho alveolar lavage during fibro bronchoscopy allow the sampling of the lung and the mediastinal lymph node. The aim of this study was to demonstrate that direct sequencing of exons 19 and 21 of EGFR in lung tumors, carried out on the cytological samples obtained through fibro-bronchoscopy, is as reliable as the same analysis carried out on a histological surgical sample obtained from the same individual. We considered 50 patients with a histological diagnosis of lung adenocarcinoma whose cytological samples, obtained by fibro-bronchoscopy and histological samples, obtained by surgical resection were available. A comparison of the sensitivity and reliability of the molecular biology analyses carried out on histological and cytological samples of the same patient was carried out. The combined mutation percentage of exons 19 and 21 of EGFR was 10%. The results of the analyses carried out on cytological samples matched those obtained from the histological samples. The feasibility of EGFR analysis on cytological samples has already been demonstrated in previous studies, however these studies referred to the method of fluorescence in situ hybridization, or did not perform any comparison between histological samples from the same patient; our work, on the other hand, shows that direct sequencing of exons 19 and 21 of the EGFR gene is feasible on fibro bronchoscopy cytological samples with the same reliability offered by the histological samples obtained from the same patient. PMID- 22199283 TI - Prognostic significance of N-Cadherin expression in oral squamous cell carcinoma. AB - BACKGROUND: N-Cadherin (CDH2) is a calcium-dependent adhesion protein, whose de novo expression, re-expression, up-regulation and down-regulation in human tumors has been demonstrated. The aim of the present work was to define the prognostic role of N-Cadherin in a large series of oral squamous cell carcinomas (OSCCs). MATERIALS AND METHODS: A total of 94 selected OSCCs were quantitatively and qualitatively analyzed by immunohistochemistry for N-Cadherin. The association between protein expression and clinico-pathological parameters was assessed by statistical analysis. RESULTS: In neoplastic tissue, N-Cadherin levels were more evident than in normal peritumoral epithelium (p<0.05). Protein staining was mainly detected in the neoplastic cells, and only focal nuclear positivity was observed. Expression of cytoplasmic N-Cadherin correlated significantly with poor histological differentiation (p<0.05). Furthermore, we have observed significant a statistical trend for stage and a correlation with worst patient outcome, also confirmed by Kaplan-Meier estimates. CONCLUSION: Our work has underlined the key role of N-Cadherin in oral carcinogenesis and in the prognostic stratification of patients. PMID- 22199284 TI - Circulating tumor cells and "suspicious objects" evaluated through CellSearch(r) in metastatic renal cell carcinoma. AB - BACKGROUND: Recent evidence supports the hypothesis that the CellSearch assay, used in the enumeration of circulating tumor cells (CTCs), may underestimate the number of CTCs, especially in tumors, such as renal cell carcinoma, frequently lacking cytokeratin expression. According to the CellSearch guidelines, all objects with no clear cytokeratin staining are defined as "suspicious objects", and are not counted as CTCs. The aim of this study was to investigate the presence of CTCs and "suspicious objects" in 25 patients affected by metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Twenty-five patients were enrolled in the study, all with a diagnosis of metastatic clear cell RCC. The CellSearchTM system was used to count the CTC in 7.5 mL of whole blood. A further 10 ml blood obtained from each patient was used to isolate CTCs through CELLectionTM Dynabeads(r). The expression of cytokeratin (CK) 8, 18, 19 and CD44 were evaluated by RT-PCR. RESULTS: Standard CTCs and suspicious objects were found in 16% and 60% of the patients, respectively. CK-8/18/19 transcripts were found in 15% and CD44 in 68% of the 19 patients with evidence of classical CTC or "suspicious objects" as assessed by Cellsearch. CONCLUSION: The low number of CTCs detected through CellSearch in renal cell carcinoma may be due to the presence of a CTC population with atypical characteristics and a peculiar gene expression profile, characterized by lack of cytokeratin expression and gain of CD44. PMID- 22199286 TI - Quantitative structure-activity relationship (QSAR) analysis of tumor-specificity of 1,2,3,4-tetrahydroisoquinoline derivatives. AB - BACKGROUND: We have previously reported on the relative cytotoxicity of a total of 38 1,2,3,4-tetrahydroisoquinoline derivatives against human oral squamous cell carcinoma cell lines and human normal oral cells, and the correlation between the cytotoxicity and 17 chemical descriptors. However, the correlation between the tumor-specificity of these compounds and the chemical descriptors has never been investigated so far. Using these previous data, we investigated various parameters for their applicability in predicting tumor specificity. MATERIALS AND METHODS: Original data of 50% cytotoxic concentration (CC(50)) values exceeding the maximum concentration in experimental conditions were corrected by the introduction of a harmonic mean, reducing the number of compounds analyzed to 30. The mean pCC(50) (=-log CC(50)) values for normal and tumor cells were defined as N and T, respectively. Tumor specificity was defined as the ratio of the difference of these values to their sum: (T-N)/(T+N). The chemical descriptors were obtained by quantum chemical calculations using semi-empirical (AM1, PM3, and PM6) and density functional theory methods. The relationship between the chemical descriptors and tumor specificity was analyzed by linear regression and artificial neural networks. RESULTS: Out of 17 chemical descriptors, water accessible surface area showed the highest correlation coefficient with tumor specificity, regardless of the method of calculation. Furthermore, neural network analysis demonstrated the importance of quantum chemical calculations in predicting the specificity of tetrahydroisoquinoline derivatives. CONCLUSION: The present study suggests the applicability of quantum chemical descriptor in the estimation of tumor specificity of related compounds. PMID- 22199285 TI - Resveratrol reduces TNF-alpha-induced U373MG human glioma cell invasion through regulating NF-kappaB activation and uPA/uPAR expression. AB - BACKGROUND: High invasiveness of glioma cells is one of the reasons that patients with malignant glioma have a poor prognosis. Resveratrol, a plant compound abundant in the peel of grapes, has been suggested as a potential cancer chemopreventive agent. Therefore, we investigated the effect of resveratrol on glioma cell invasion. MATERIALS AND METHODS: The effect of resveratrol on U373MG human glioma cell invasion was assessed by Matrigel assay and methylthiazoltetrazolium assay. Western blotting and reverse transcription polymerase chain reaction were performed to elucidate the action mechanism of resveratrol. RESULTS: Resveratrol reduced tumor necrosis factor (TNF)-alpha induced U373MG human glioma cell invasion. In addition, resveratrol repressed nuclear factor kappa B (NF-kappaB) activation and down-regulated mRNA expression of urokinase plasminogen activator (uPA) and its receptor in TNF-alpha-treated glioma cells. CONCLUSION: These findings suggest that resveratrol could prevent glioma cell invasion via inhibiting proteolysis of extracellular matrix. PMID- 22199287 TI - Cytoskeleton network and cellular migration modulated by nuclear-localized receptor tyrosine kinase ROR1. AB - Biological functions of receptor tyrosine kinase-like orphan receptor 1 (ROR1) remain to be elucidated due to the lack of identified genuine ligands. Previously, transiently expressed ROR1 was unexpectedly found to exhibit nuclear localization, the functions of which are unknown. MATERIALS AND METHODS: We constructed nuclear-homing peptidyl-prolyl cis-trans isomerases (FKBP) domain fusion ROR1-expressing cells and used a synthetic dimerizer to specifically activate FKBP-fused ROR1 proteins for subsequent functional characterization. RESULTS: Activation of nuclear-homing ROR1 by treating cells with AP20187 dimerizer led to significant increase in actin stress fibers and increased cellular migration. Following gene expression microarray analysis, we demonstrated that activated ROR1 affects several genes involved in the regulation of the actin cytoskeleton (radixin (RDX), ezrin (EZR), son of sevenless homolog 2 (SOS2) and caldesmon 1 (CALD1)). CONCLUSION: Our data indicate that nuclear localized ROR1 may play an important role in cell migration and cytoskeleton remodeling. This might explain the critical roles of ROR1 in neuron development. PMID- 22199288 TI - Novel cytotoxic isolated from Jamaican Hyptis verticillata jacq induces apoptosis and overcomes multidrug resistance. AB - BACKGROUND: Adult T-cell leukemia is an aggressive hematological malignancy with a poor clinical prognosis, and a rapid resistance to chemotherapy is rapid. MATERIALS AND METHODS: Cytotoxicity assay-directed fractionation identified a novel lignan-related agent, 4-methoxy-9-(3,4,5-trimethoxyphenyl)-8, 9 - dihydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5H)-one (4-MTDND) from the Jamaican plant Hyptis verticillata jacq, and its effects on apoptosis, cell cycle and drug resistance were elucidated. RESULTS: The novel agent, 4-MTDND, exhibited cytotoxicity against myriad cancer types, with a wide therapeutic index of 30- to 40-fold, promoted G(2)/M arrest and up-regulated expression of pro-apoptotic proteins p53 and BAX, as well as enhanced activation of caspase-3, caspase-9 and poly (ADP ribose) polymerase, consistent with apoptosis induction. Multidrug resistant cancer cells were as susceptible to 4-MTDND as their non-resistant control counterparts, with 4-MTDND having greater efficacy compared to standard chemotherapy agents etoposide and mitoxantrone. CONCLUSION: The novel cytotoxic agent 4-MTDND induces G(2)/M arrest and apoptosis in cancer cells possibly due to direct DNA damage or interference with topoisomerase II. PMID- 22199289 TI - IGF1Ec expression in MG-63 human osteoblast-like osteosarcoma cells. AB - AIM: The insulin-like growth factor 1 (IGF1) gene gives rise to multiple transcripts, using an elaborate alternative splicing mechanism. The aim of this study was to shed light on the expression and role of the IGF1 system in human MG 63 osteoblast-like osteosarcoma cells. MATERIALS AND METHODS: The expression of the IGF1Ea, IGF1Eb and IGF1Ec isoforms was characterized using reverse transcription polymerase chain reaction (RT-PCR), quantitative real time-PCR (qRT PCR) and western blot analysis. Using trypan blue exclusion assays, we also examined the mitogenic effects of IGF1 and of a synthetic peptide related to the E domain of IGF1Ec (synthetic E peptide) on MG-63 cells, as well as on MG-63 cells which had been molecularly modified to restrain the expression of type I IGF receptor (IGF1R) and of insulin receptor (INSR) by siRNA techniques (IGF1R KO or INSR KO MG-63 cells). RESULTS: MG-63 cells express only the IGF1Ea and IGF1Ec transcripts. Exogenous administration of dihydrotestosterone (DHT) significantly increased the expression of IGF1Ea and IGF1Ec mRNA and it induced the previously undetectable expression of IGF1Eb transcript. Exogenous administration of IGF1, insulin and the synthetic E peptide stimulated the growth of MG-63 cells, while only E peptide stimulated the growth of IGF1R KO and INSR KO MG-63 cells. CONCLUSION: These data suggest that the expression of all IGF1 isoforms is hormonally regulated in MG-63 cells and that the expression of IGF1Ec may be involved in osteosarcoma biology by generating the Ec peptide which acts via an IGF1R-independent and INSR-independent mechanism. PMID- 22199290 TI - Mutations of mitochondrial DNA as potential biomarkers in breast cancer. AB - BACKGROUND: Alterations of mitochondrial DNA (mtDNA) have been found in cancer patients, therefore informative mtDNA mutations could serve as biomarkers for the disease. MATERIALS AND METHODS: The two hypervariable regions HVR1 and HVR2 in the D-Loop region were sequenced in ten paired tissue and plasma samples from breast cancer patients. RESULTS: MtDNA mutations were found in all patients' samples, suggesting a 100% detection rate. Examining germline mtDNA mutations, a total of 85 mutations in the D-loop region were found; 31 of these mutations were detected in both tissues and matched plasma samples, the other 54 germline mtDNA mutations were found only in the plasma samples. Regarding somatic mtDNA mutations, a total of 42 mutations in the D-loop region were found in breast cancer tissues. CONCLUSION: Somatic mtDNA mutations in the D-loop region were detected in breast cancer tissues but not in the matched plasma samples, suggesting that more sensitive methods will be needed for such detection to be of clinical utility. PMID- 22199291 TI - Differential CD133 expression pattern during mouse colon tumorigenesis. AB - BACKGROUND/AIM: The cancer stem cell model suggests that only a rare subpopulation, known as cancer stem cells (CSC) are responsible for tumor initiation. CSC from several human carcinomas are characterized by specific cell surface markers, such as CD133. The CD133 role in colon tumorigenesis remains controversial. MATERIALS AND METHODS: CD133 was evaluated by immunohistochemistry in a mouse model of colitis-related colon tumorigenesis induced by a combined treatment with azoxymethane (AOM) and dextran sodium sulphate (DSS). RESULTS: In normal tissue rare scattered positive cells were detectable at the bottom of the crypts. The percentage of positive cells significantly increased in dysplastic lesions and appeared to progressively decrease in the passage from dysplasia to adenoma and then to cancer, although always remaining greater in number than in the normal tissue. CONCLUSION: An increased CD133 expression occurs at early stages of colon tumorigenesis in the mouse. CD133-expressing cells might play an important role from the earlier phase and throughout the entire process of colon cancer development. PMID- 22199292 TI - The expression of Ki-67, but not proliferating cell nuclear antigen, predicts poor disease free survival in patients with adenocarcinoma of the lung. AB - BACKGROUND: Ki-67 expression has been established as a predictive marker for recurrence in breast cancer, and proliferating cell nuclear antigen (PCNA) which is also a proliferation marker, is also herein discussed regarding its role in the prognosis of various types of cancer. However, no useful data are presently available regarding the biological significance of both molecules in lung cancer. PATIENTS AND METHODS: Tumor specimens were collected from 183 consecutive patients who underwent a complete resection for lung adenocarcinoma from 2003 to 2007 in our Department. We analyzed the Ki-67 and PCNA expression levels in primary lung adenocarcinoma by immunohistochemistry. RESULTS: Positive expression of Ki-67 and PCNA was identified in 41 (22.4%) and 149 (81.4%) patients, respectively. The positive expression of Ki-67 was identified in 14 (50.0%) out of 28 patients and 27 (18.1%) out of 155 patients with and without recurrence, respectively (p<0.001). PCNA expression was not correlated with recurrence. Positive expression of Ki-67 was associated with a poorer disease-free survival according to the survival analysis. A multivariate analysis also demonstrated that Ki-67 expression was independently associated with an increased risk of poor disease-free survival. CONCLUSION: Ki-67 may be a useful marker for predicting postoperative recurrence in patients with non-small cell lung cancer following complete resection. PMID- 22199293 TI - Synergism from the combination of oxaliplatin with selected phytochemicals in human ovarian cancer cell lines. AB - Oxaliplatin (Oxa) is a third generation platinum drug currently in clinical use for the treatment against colorectal cancer. Although it has a somewhat different spectrum of activity than cisplatin (Cis), it too has two major limitations, namely problems of side-effects and drug resistance. In this study, combined drug action from the combination of Oxa with the phytochemicals andrographolide (Andro), epigallocatechin-3-gallate (EGCG), chlorophyllin (Chl), colchicines (Col), curcumin (Cur) and paclitaxel (Tax) was evaluated in the human ovarian cancer cell lines A2780 and A2780(cisR). The combination index (CI) was used as a measure of synergism (CI<1), addictiveness (CI=1) and antagonism (CI>1). Generally, all the combinations showed greater synergism at a lower concentration (ED(50)) than at higher concentrations (ED(75) and ED(90)). Oxa in binary combination with Col and Tax showed the highest synergism in both the cancer cell lines, when administered 4 h after the phytochemical, with CI at ED(50) ranging from 0.004 to 0.1. The combination of Oxa with the other phytochemicals generally showed greater synergism when Oxa was administered 4 h before the phytochemical. Appropriately sequenced combination of Oxa with tumor active phytochemicals produces marked synergistic effects in cisplatin resistant as well as non resistant ovarian cancer cell lines and may offer the means of overcoming drug resistance in ovarian cancer. PMID- 22199294 TI - Investigation of cell death induced by N-methyl-N-nitrosourea in cell lines of human origin and implication of RNA binding protein alterations. AB - Methylating agents, a widely used class of anticancer drugs, induce DNA methylation adducts, the most biologically significant being O(6)-methylguanine. The efficacy of these drugs depends on the interplay of three DNA repair systems: base excision repair (BER), methyl-directed mismatch repair (MMR) and direct damage reversal by O(6)-methylguanine-DNA methyltransferase (MGMT). An MGMT inducible, MMR- and BER-proficient HeLa cell line was treated with different concentrations of N-methyl-N-nitrosourea (MNU), a model S(N)1 methylating agent, analogous to widely used methylating cancer chemotherapeutic drugs, under different expression levels of the repair enzyme (MGMT). MNU induced MGMT dependent apoptotic cell death. In this particular cellular context, the induction of apoptosis was accompanied by modifications of the RNA binding protein poly(A)polymerase and significant down-regulation of the heterogeneous nuclear ribonucleoprotein (hnRNP) C1/C2. These results implicate alterations of the above mentioned RNA binding proteins in S(N)1 methylating agent-induced cell death and apoptosis, providing a possible perspective regarding their use as biomarkers of tumor resistance/sensitivity to chemotherapy. PMID- 22199295 TI - Association of p53 and CDKN1A genotypes with endometriosis. AB - BACKGROUND: The tumor suppressor p53 protein plays a critical role in different cellular processes in response to DNA damage and it is responsible for transcriptional induction of the p21 (CDKN1A/WAF1/CIP1) gene. Both p53 and p21 are thought to play major roles in the development of human malignancy. Polymorphic variants of p53 at codon 72, and CDKN1A at codon 31, have been found to be associated with cancer susceptibility, but few studies have investigated their effect on endometriosis risk. MATERIALS AND METHODS: In this hospital-based case-control study, we investigated the association of p53 codon 72 and CDKN1A codon 31 polymorphisms with endometriosis susceptibility in a Taiwanese population. In total, 180 patients with endometriosis, and 330 age-matched controls in Central Taiwan were recruited and genotyped. RESULTS: We found a significant difference in the distribution of the p53 genotype, but not the CDKN1A genotype, between the endometriosis and control groups. Individuals with the C (Pro) allele at p53 codon 72 had a 1.6-fold increased odds ratio of endometriosis, and those with Arg/Pro and Pro/Pro genotypes for p53 codon 72 had a 1.84- and 2.74-fold (95% confidence interval=1.17-2.92 and 1.58-4.74) increased risk of endometriosis compared to those with Arg/Arg, respectively. The distribution of haplotype combinations of p53 codon 72 and CDKN1A codon 31 was statistically different in the endometriosis and control groups. The percentages of the three subgroups with p53 CC homozygote were all higher in the endometriosis group than in the control group. CONCLUSION: Our findings suggest that the C (Pro) allele of p53 codon 72 may be associated with the development of endometriosis, and could serve as a potential biomarker for early prediction of this disease. PMID- 22199296 TI - Human brain endothelial cell-derived COX-2 facilitates extravasation of breast cancer cells across the blood-brain barrier. AB - With improvements in systemic control, metastasis to the brain has been more frequently found in patients with breast cancer. In order to gain access to the brain, breast cancer cells must overcome the blood-brain barrier (BBB), a highly selective filter against cellular and soluble substances. Human brain endothelial cells (HBECs) comprise a major element of the BBB, and breast cancer cells first encounter and pass through them for extravasation. To date, however, the precise role of HBECs in metastasis to the brain is unknown. In this study, we examined how HBECs take part in the extravasation process. In an established in vitro model of the BBB, unexpectedly, the transmigration of breast cancer cells was markedly enhanced in the presence of HBECs than in their absence, suggesting that HBECs facilitate the transmigration of breast cancer cells rather than acting as a barrier against them. We then showed that cyclooxygenase (COX-2) induced from HBECs rather than that from breast cancer cells plays a key role in the transmigration. Moreover, expression of matrix metalloproteinase (MMP-2) mediating the transmigration was induced in HBECs by COX-2 after co-culture with breast cancer cells. Taken together, our results suggest that COX-2 and MMP-2 produced from HBECs facilitate the extravasation of breast cancer cells across the BBB. PMID- 22199297 TI - Differential cytotoxic effects of sodium meta-arsenite on human cancer cells, dental papilla stem cells and somatic cells correlate with telomeric properties and gene expression. AB - We investigated the effects of sodium meta-arsenite (NaAsO(2)) on human cancer cells (MDA-MB-231, MCF-7 and U-87 MG), dental papilla tissue stem cells (DPSCs) and somatic cells [MRC-5 fetal fibroblasts and adult muscle cells (MCs)] by examining telomeric properties, endogenous reverse transcriptase (RT) activity and the expression of tumorigenesis-linked genes. Half maximal inhibitory concentration (IC(50)) values were higher in DPSCs and MCs, possessing longer telomere lengths when compared to cancer cells. Levels of telomerase and RT activity, and the expression of protein 53 (p53), B-cell lymphoma 2 (BCL2), nuclear factor kappa-light-chain-enhancer of activated B-cells (NFkappaB), transforming growth factor beta (TGFbeta) and vascular endothelial growth factor (VEGF) were significantly lower in cancer cells following sodium meta-arsenite treatment, whereas the effect was absent or marginally detected in DPSCs and somatic cells. Collectively, sodium meta-arsenite effectively induced cellular cytotoxicity by inhibiting telomerase and RT activity, and down-regulating transcript levels in cancer cells with shorter telomere lengths, whereas more tolerance was evident in DPSCs and somatic cells possessing longer telomere lengths. PMID- 22199298 TI - Genome-wide identification of chemosensitive single nucleotide polymorphism markers in gastric cancer. AB - A chemosensitive single nucleotide polymorphism (SNP) discovery schema is presented that utilizes (i) genome-wide SNP screening, with a human SNP array and an in vitro chemosensitivity assay, in 93 patients with gastric cancer (GC), and (ii) biological utility assessment using cell viability assays of transfected GC cells. Cytotoxicity analysis showed that most of the MKN1 and SNU638 clones transfected with the G allele of Deoxyribonuclease II beta (DNASE2B) rs3738573 were more sensitive to docetaxel than those with the C allele (p<=0.001-0.029) and most of the AGS and SNU638 clones transfected with the T allele of 5 hydroxytryptamine receptor IE (HTRIE) rs3828741 were more sensitive to paclitaxel than those with the C allele (p<=0.001-0.019). Our findings show that the two novel markers, DNASE2B rs3738573 and HTR1E rs3828741, have potential for improving the prediction of chemosensitivity of GC patients. PMID- 22199299 TI - De-alcoholization of paclitaxel injection for clinical application. AB - A generic drug of Taxol(r) Injection, Paclitaxel Injection NK (PTX injection), cannot be used for patients with severe hypersensitivity or overwhelming intolerance to alcohol because it contains ethanol as a dissolving agent. Therefore, we evaluated the suitability of de-alcoholized PTX injection for clinical application. De-alcoholization was carried out using inactive N2 gas under sterile conditions. The pharmacokinetic properties of the de-alcoholized PTX injection were evaluated in rats after intravenous injection. Finally, the de alcoholized PTX injection was administered to a patient with alcohol intolerance to evaluate its suitability for clinical application. The ethanol included in the supplied PTX injection was almost completely removed (>99.9%). PTX, the major component of the de-alcoholized PTX injection, was stable with no decomposed compounds or bacterial contamination, although its viscosity was increased by 29 fold compared with untreated PTX injection. No significant differences in the pharmacokinetic parameters of PTX were observed between the de-alcoholized and untreated PTX injections. No drunkenness was observed in the patient with severe alcohol intolerance after injection of de-alcoholized PTX injection. Adverse events such as nausea, muscle pain, joint pain, neuropathy and myelosuppression were observed at similar degrees to those after injection of untreated PTX injection. The plasma concentrations of PTX after injection of the de-alcoholized PTX injection were similar to those after injection of untreated PTX injection. The present findings suggest that almost complete de-alcoholization of PTX can be achieved easily under sterile conditions and that the resulting product can be used safely for patients with severe alcohol intolerance. PMID- 22199300 TI - Modulation of PGE2-induced EP4 expression on snail signaling and the impact on epithelial-mesenchymal transition: significance of EP4 antagonism. AB - BACKGROUND: Although significant accumulation of prostaglandin E(2) (PGE(2)) in the human prostate cancer tissues has been reported, there is lack of substantial evidence regarding the key role of PGE(2)-induced E-prostanoid-4 receptor (EP4) on Snail, a master regulator of epithelial mesenchymal transition (EMT). In this study, we investigated a novel connection between PGE(2)-induced EP4 and Snail (encodes DNA binding zinc finger protein that acts as transcriptional repressor) signaling in prostate cancer. MATERIALS AND METHODS: To investigate the key role of serum PGE(2), EP4, p-Akt and Snail in prostate cancer progression, we used prostate-specific phosphatase and tensin homolog (PTEN)-knockout (PTEN-KO) mice of different age groups from 4 to 28 weeks. To determine the EP4-specific interaction with Snail in prostate cancer, we used cell-based assays, including siRNA knockdown, and treatment with EP4 antagonist. RESULTS: An interaction between EP4 with Snail was evident in prostate-specific PTEN-KO mice that showed an elevated level of PGE(2) in the serum and of EP4, p-Akt and Snail in the tissues. Prostate cancer cells transfected with EP4-siRNA and treatments with EP4 antagonist suggest a link between EP4, and Snail activation, potentially via p Akt. Cells treated with EP4 antagonist exhibited a significant decrease in Snail, mesenchymal markers and cell migration, and cell cycle arrest with a gain in E cadherin levels. CONCLUSION: Our findings provide key evidence that support there being a role of PGE(2)/EP4/p-Akt in Snail signaling and conferring cell survival advantage. Cancer progression via EMT can be reversed by an EP4 antagonist in this model of prostate cancer. PMID- 22199301 TI - Impact of cyclooxygenase-2 in breast cancer. AB - Prostaglandin metabolism plays a pivotal role in inflammatory processes and has also been demonstrated to have a role in carcinogenesis, tumor differentiation and tumor growth in breast cancer. Cyclooxygenase-2 (COX-2) is the key involved enzyme, as it triggers prostaglandin synthesis. We reviewed the current literature regarding the impact of prostaglandin metabolism on breast cancer and illustrated the current evidence of the COX-2 influence on breast cancer, delineating possible future prophylactic and therapeutic strategies. PMID- 22199302 TI - Estrogen pathway polymorphisms and mammographic density. AB - Elevated mammographic density (MD) is strongly associated with breast cancer risk and the estrogen pathway has been proposed as a potential mechanism for this association. It has been repeatedly observed that several established estrogen related factors associated with breast cancer risk, such as parity and hormone replacement therapy, are also associated with MD. However, the association of circulating estrogen levels (known to be strongly positively associated with breast cancer risk) with MD has so far been inconsistent. Since MD is highly heritable, single nucleotide polymorphisms (SNPs) in genes involved in the estrogen pathway and their relation with MD could provide information that would help understand the link between MD and breast cancer risk. This review of 18 studies describes the relation of SNPs located in genes of the estrogen pathway (genes coding for hydroxysteroid dehydrogenases (HSD3B1, HSD17B1), cytochrome P450 (CYP1A1, CYP1A2, CYP17A1, CYP19A1 and CYP1B1), catechol-O-methyltransferase (COMT), uridine diphospho-glucuronosyltransferase (UGT1A1), sulfotransferases (SULT1A1, SULT1E1) and for estrogen receptors alpha and beta (ESR1, ESR2)) with MD. Most of the SNPs evaluated showed no association with MD when analyses were performed on overall study population. However, when this relation was assessed within strata based on estrogen-related factors, a few SNPs (HSD17B1 (rs2010750, rs598126 and rs676387), COMT (rs4680), UGT1A1 (rs8175347) and ESR1 (rs9340799)) seemed to be related to MD in the same direction of their associations with breast cancer risk. Since such data are very limited, additional research including stratified analyses by factors related to estrogen are needed to validate these findings. PMID- 22199303 TI - Targeting AKT protein kinase in gastric cancer. AB - Gastric cancer is a highly lethal malignancy with more than 700,000 deaths every year worldwide. Despite significant improvements in our understanding of disease biology, the 5-year survival rates remain low. With the exception of trastuzumab, targeted agents have failed to add any meaningful benefit for this patient population, despite promising pre-clinical data. Protein kinase B (AKT) is essential for cell growth, proliferation, and survival. Aberrant activation of AKT is one of the most common molecular findings in human malignancies including gastric cancer, and it is believed to play an important role in cancer cell survival and chemotherapy resistance. Combining phosphatidylinositol 3-kinase (PI3K)/AKT pathway inhibitors with chemotherapy has successfully attenuated chemotherapeutic resistance in gastric cancer cell lines. Drugs designed to specifically target AKT are now being developed for clinical use. In this article, we will review the current knowledge on AKT signaling in the pathogenesis of gastric cancer and the evolving therapeutic implications of targeting this pathway. PMID- 22199304 TI - Feasibility of image-guided radiotherapy based on tomotherapy for the treatment of locally advanced anal carcinoma. AB - BACKGROUND: The standard of care for locally advanced anal cancer has been concurrent chemoradiation. However, conventional treatment with 3-dimensional radiotherapy is associated with significant toxicity. The feasibility of new radiotherapy techniques such as image-guided radiotherapy (IGRT) in combination with chemotherapy for the treatment of this malignancy was assessed. PATIENTS AND METHODS: A retrospective review of five patients with locally advanced anal carcinoma treated with Tomotherapy-based IGRT was conducted. All the patients received concurrent chemotherapy. RESULTS: Gastrointestinal toxicity remained the limiting factor as four patients experienced grade 3-4 enteritis requiring a break during treatment. No patient experienced grade 3-4 hematological toxicity. Despite the large tumor size, three patients achieved local control at a median follow-up of 19 months. CONCLUSION: Tomotherapy-based IGRT may be a promising treatment for locally advanced anal cancer and needs to be investigated in further prospective trials. PMID- 22199305 TI - Primary peritoneal carcinoma in complete remission: a case report. AB - Primary peritoneal carcinoma (PPCa) is a relatively uncommonly diagnosed tumor. It has a similar presentation to ovarian cancer. PPCa has a poor prognosis with survival ranging from 12-18 months. PPCa spreads mainly transperitoneally, but lymphatic and hematological metastases have also been reported. It is a diagnosis of exclusion made after pathological report. Here, a case of a 71-year-old female who presented with early satiety, fatigue, weight loss and left cervical lymphadenopathy and was diagnosed with metastatic PPCa, is reported. The patient was treated with chemotherapy and achieved a complete remission. The management of this rare tumor is discussed herein. PMID- 22199306 TI - Loss of p27KIP1 expression in fully-staged node-negative breast cancer: association with lack of hormone receptors in T1a/b, but not T1c infiltrative ductal carcinoma. AB - Nuclear expression of the cell cycle inhibitor p27(KIP1) is reduced in a variety of human malignancies, including breast cancer. Loss of nuclear p27(KIP1) during tumor progression, documented by immunohistochemistry (IHC), has been studied for its potential prognostic implication. We examined by IHC the association between nuclear p27(KIP1) expression and hormone receptor status in T1N0M0 breast cancer. PATIENTS AND METHODS: The correlation between nuclear p27(KIP1) expression and estrogen (ER) and progesterone (PR) hormone receptor status was analyzed in 122 human T1N0M0 (68 T1a/b, 54 T1c) breast cancer specimens. All patients were staged as N0 by axillary node dissection. RESULTS: A statistically significant reduction in p27(KIP1) expression was observed as tumor size increased from T1a/b (7%) to T1c (22%). The proportion of tumors with low nuclear p27(KIP1) expression was higher in the ER-negative/PR-negative group compared to the ER-positive/PR positive group, but this difference was only statistically significant in the T1a/b subgroup (p=0.0007). CONCLUSION: Further investigations into causes of p27(KIP1) deregulation and their relationship to hormone receptor expression in T1N0M0 breast ductal carcinomas are warranted. Such studies may help identify prognostic, as well as predictive, markers of therapy resistance. PMID- 22199307 TI - Triple induction chemotherapy and chemoradiotherapy for locally advanced esophageal cancer. A phase II study. AB - BACKGROUND: This phase II trial assessed the feasibility and safety of induction chemotherapy with cisplatin (25 mg/m(2) d1-5, d29-34)/docetaxel (75 mg/m(2) d1, d29)/5-fluorouracil (5-FU, 750 mg/m(2) d1-5, d 29-34) followed by external beam radiotherapy concurrent with docetaxel (15 mg/m(2) d1,8,15,22) and 5-FU (300 mg/m(2) continuous infusion on the days of radiotherapy). PATIENTS AND METHODS: Twenty-four patients with locally advanced carcinoma of the esophagus were included. Following chemotherapy and chemoradiation eligible patients underwent esophagectomy. If surgery could not be performed patients received definitive radiation. RESULTS: Sixteen patients underwent resection. Pathologic complete remission was achieved in 5 of those 16 patients, 13 patients had downstaging of disease. R0 resection was feasible in all 16 patients. Main grade 3 and 4 toxicities were neutropenia in 10 patients, diarrhea in 4 and postoperative morbidity in 9 patients. At a median follow-up of 16.5 months 15 patients are alive; median survival has not yet been reached. CONCLUSION: Neoadjuvant treatment with cisplatin/docetaxel/5-fluorouracil followed by chemoradiation with docetaxel/5-fluorouracil is safe, feasible, and effective. PMID- 22199308 TI - Intraepidermal nerve fibre density in cancer patients receiving adjuvant chemotherapy. AB - BACKGROUND: Chemotherapy-induced neuropathy is a common adverse event in patients receiving vinca alcaloids, platinum derivatives and taxanes. However, the underlying pathogenetic mechanisms have not been completely elucidated. We set up a prospective pilot study on skin biopsies in newly diagnosed cancer patients receiving neurotoxic chemotherapeutic agents as adjuvant treatment in order to study the occurrence of small-fibre pathology and its relationship to clinical symptoms. PATIENTS AND METHODS: Skin biopsies from distal leg were performed in 12 patients before, during and after chemotherapy. Using light microscopy, the intraepidermal nerve fibre (IENF) density was determined from the skin biopsies by counting morphometrically the immunopositive nerves per epidermal area. RESULTS: Reduced IENF density was observed in eight patients at baseline. During the follow-up, the IENF density increased significantly in six patients and remained unchanged in two. In four patients, the IENF density was normal both at baseline and at the end of the follow-up period. Neuropathic symptoms were manifested in nine patients, but no association with the IENF count was found. CONCLUSION: During chemotherapy, results from patients revealed different evolutionary patterns of IENF density, but symptoms and IENF density were not related. PMID- 22199309 TI - First study of oral Artenimol-R in advanced cervical cancer: clinical benefit, tolerability and tumor markers. AB - BACKGROUND/AIM: Artenimol-R is cytotoxic in transformed cervical cells and safety in humans is yet to be established. The present study investigates the clinical benefits, safety and the tumor marker effect of orally administered Artenimol-R in patients with advanced cervix carcinoma. PATIENTS AND METHODS: Ten patients were treated with Artenimol-R for 28 days. Clinical symptoms, vaginal discharge and pain were followed-up. Adverse events were recorded. Biopsy samples were analyzed by immunohistochemistry for the expression of relevant tumor markers. RESULTS: Artenimol-R treatment induced clinical remission with a median time for the disappearance of the symptoms being 7 days. No adverse events of grade 3 or 4 occurred. The expression of p53, Epidermal growth factor receptor (EGFR), and antigen Ki-67 as a cellular marker of proliferation, as well as the number of blood vessels stained by the CD31 antibody decreased, whereas the expression of transferrin receptor protein 1 (CD71) increased. CONCLUSION: The current pilot study provides evidence on the improvement of the clinical symptoms and the good tolerability of Artenimol-R in patients with advanced carcinoma of the cervix uteri. A survival trial with Artenimol-R in advanced patients is warranted. PMID- 22199310 TI - Impaired bone microenvironment: correlation between bone density and presence of disseminated tumor cells. AB - BACKGROUND: Disseminated tumor cells (DTCs) in bone marrow (BM) occur in 30-40% of primary breast cancer patients. An impaired bone microenvironment may lead to reduced bone density and osteoporosis affecting the BM as a homing site for DTCs. The bone mineral density (BMD) and its correlation to DTC in BM was evaluated. MATERIALS AND METHODS: One hundred and eighty-one women (70 premenopausal, 111 postmenopausal) underwent quantitative ultrasonometry before adjuvant chemotherapy. BM aspirates were analyzed by immunocytochemistry using the ACIS system (Chromavision) based on immunostaining. RESULTS: DTCs were detected in 39% of the patients. Positive BM status correlated significantly with the nodal status. BMD was significantly reduced in the postmenopausal patients (p=0.003). Smaller tumors and higher BMD correlated significantly (p<0.014). Fifty percent of the patients with preclinical osteoporosis were BM positive, whereas 37% with normal or osteopenic BMD had DTCs. CONCLUSION: An impaired bone micro-environment as found in preclinical osteoporosis might be a homing site for DTCs. PMID- 22199311 TI - Immunohistochemical study of VEGF expression in oral squamous cell carcinomas: correlation with the mTOR-HIF-1alpha pathway. AB - The aim of this study was to clarify the relationship between vascular endothelial growth factor (VEGF) expression and clinicopathological factors in oral squamous cell carcinoma (OSCC). We also examined the correlation between the VEGF expression and the mammalian target of rapamycin (mTOR)-hypoxia inducible factor-1alpha (HIF-1alpha) pathway. Formalin-fixed paraffin-embedded tissues from 120 OSCC cases and 10 samples of normal mucosa were stained immunohistochemically for VEGF-A, VEGF-C, p-mTOR and HIF-1alpha proteins. VEGF-A and VEGF-C protein expression was detected in 76 out of 120 (63%) and 81 of 120 (67.5%) OSCCs, respectively, and their expression was significantly higher in primary OSCC than in normal oral mucosa. VEGF-A expression was significantly associated with the tumor stage and age. VEGF-C expression was significantly associated with the cancer cell invasion. The cases with combined p-mTOR+/HIF-1alpha(+)/VEGF-A(+) expression had a significantly higher tumor stage and invasion grade, and combined p-mTOR+/HIF-1alpha(+)/VEGF-C(+) expression was significantly associated with tumor stage, regional lymph node metastasis and invasion grade. In a survival analysis, no obvious correlation was observed with any of the immunohistochemical results. This study indicated that the mTOR-HIF-1alpha-VEGF pathway affects the progression of OSCC, and inhibition of this pathway may be useful for the treatment of OSCC. PMID- 22199312 TI - Oxaliplatin, irinotecan and cetuximab in advanced gastric cancer. A multicenter phase II trial (Gastric-2) of the Arbeitsgemeinschaft Medikamentose Tumortherapie (AGMT). AB - BACKGROUND: Patients suffering from advanced gastric cancer still have a poor prognosis and treatment options are limited. In our previous phase II trial (AGMT Gastric-1), we showed that the combination of oxaliplatin and irinotecan was well tolerated and effective. The same chemotherapy regimen was now tested in combination with cetuximab in a multicenter phase II trial. PATIENTS AND METHODS: Oxaliplatin at 85 mg/m(2) biweekly and irinotecan at 125 mg/m(2) biweekly were combined with cetuximab at 400 mg/m(2) loading dose and subsequent weekly infusions of 250 mg/m(2). Fifty-one patients with histologically proven unresectable and/or metastatic gastric adenocarcinoma were treated in the first line setting. The median age was 62 years. A single metastatic site was found in 24 patients, 27 patients had multiple metastatic sites. RESULTS: Frequently reported adverse events (in more than 20% of patients) were predominantly grade 1 or 2 and included neutropenia (35%), thrombocytopenia (33%), anemia (73%), nausea (45%), diarrhea (57%), alopecia (22%), and fatigue (37%). Grade 3/4 toxicities included neutropenia in 9/1 patients., thrombocytopenia in 1/0 patients, anemia in 3/1 patients, nausea in 2/0 patients, and diarrhea in 7/2 patients. Sensory neuropathy occurred mostly as grade 1 and 2 in 37% of patients, grade 3 neurotoxicity was observed in 7 patients. Acne-like rash grades 1/2/3/4 were reported in 31%/20%/6%/2% of patients respectively. Thirteen patients discontinued the study due to neutropenia (n=5), nausea/vomiting (n=1), diarrhea (n=1), toxic colon (n=2), and allergic reaction to cetuximab at first (n=2), second (n=1) or third infusion (n=1). Thirty-five patients were assessable for response, with 1 patient (3%) showing a complete response, 21 patients (60%) a partial response, 7 patients (20%) a stable disease, and 6 patients (17%) a progressive disease respectively. The median time to progression was 24.8 weeks, median overall survival was 38.1 weeks. All patients tested had a wild type KRAS status. CONCLUSION: The combination of oxaliplatin and irinotecan with cetuximab is safe and its action established in advanced gastric cancer. PMID- 22199313 TI - PCA3 score vs PSA free/total accuracy in prostate cancer diagnosis at repeat saturation biopsy. AB - AIM: PCA3 score and PSA free/total (F/T) accuracy in PCa diagnosis at repeat saturation prostate biopsy (SPBx) in patients with PSA between 4 and 10 ng/mL was evaluated. MATERIALS AND METHODS: From October 2009 to September 2011 74 men (median 64 years) with persistent high or increasing PSA values, negative DRE, median PSA values of 8.9 ng/mL and primary negative extended biopsy underwent a SPBx (median 28 cores) for persistent suspicion for PCa. RESULTS: PCA3 >20 and >35, PSA F/T <=15%, <=20% and <=25% identified 25, 21, 18, 23 and 26 out 27 cancer, respectively. PCA3 cut-off of 20 demonstrated the best accuracy with an AUC-ROC curve of 0.73. CONCLUSION: The NPV equal to 88.9% suggests to use PCA3 cut-off 20 as an exclusion tool; moreover, PCA3 cut-off of 35 combined with PSA F/T <=15% allows to spare 32.4% of unnecessary repeat biopsies. PMID- 22199314 TI - The EMT status in the primary tumor does not predict postoperative recurrence or disease-free survival in lung adenocarcinoma. AB - BACKGROUND: The epithelial to mesenchymal transition (EMT) is an important contributor to the invasion and metastasis of epithelial cell-derived cancer. However, whether or not the expression of EMT-related molecules can be used as a biomarker for the prognosis of lung cancer has yet to be fully determined. PATIENTS AND METHODS: Tumor specimens were collected from 183 consecutive patients who underwent a complete resection for lung adenocarcinoma. We analyzed the E-cadherin, gamma-catenin, vimentin, and fibronectin expression levels in the primary lung adenocarcinoma by immunohistochemical analysis. RESULTS: A positive expression of E-cadherin, gamma-catenin, vimentin, and fibronectin was observed in 94 (51.4%), 82 (40.4%), 32 (17.5%) and 1 (0.5%) patient, respectively. A significant association between E-cadherin expression and the pathological stage, T status, N status, tumor grade, and carcinoembryonic antigen was identified. The rate of gamma-catenin positivity was higher in patients with a smoking history than in never smokers. Moreover, a significant correlation was observed between vimentin expression and the pathological stage, N status, and tumor grade. However, an association between EMT-related molecules and postoperative recurrence of lung adenocarcinoma is lacking. Based on a Kaplan-Meier analysis, the expression of EMT-related molecules is not associated with the survival of lung adenocarcinoma patients. CONCLUSION: The EMT status in the primary tumor does not predict postoperative recurrence or disease-free survival in lung cancer patients. Our findings indicate that immunocytochemical markers related to EMT do not provide relevant prognostic information about lung adenocarcinoma. Future research is therefore expected to clarify the clinical usefulness of EMT-related molecules. PMID- 22199315 TI - Correlation between IDH1 gene mutation status and survival of patients treated for recurrent glioma. AB - Somatic mutations in the isocitrate dehydrogenase 1 (IDH1) gene have been frequently found in low-grade glioma and secondary glioblastoma and are associated with a significantly younger age at diagnosis and a superior overall survival. We investigated the IDH1 gene mutation status by nested PCR and denaturing gradient gel electrophoresis (DGGE) on DNA extracted from archival tumor blocks of 63 glioma patients who were treated following recurrence with the epidermal growth factor receptor (EGFR)-targeted blocking monoclonal antibody cetuximab, or the vascular endothelial growth factor (receptor) (VEGF(R)) targeted agents sunitinib malate and bevacizumab. In our study population, IDH1 mutation was significantly correlated with a longer overall survival (OS) from the time of initial diagnosis. Patients with IDH1 mutation also had a superior OS from the time of recurrence when treated with sunitinib or bevacizumab but a worse OS when treated with cetuximab. Our observations support the hypothesis that IDH1 mutation may correlate with the benefit from VEGF(R)- versus EGFR targeted therapy at the time of recurrence in glioma patients. PMID- 22199316 TI - Effect of maintenance chemotherapy with gemcitabine and paclitaxel on recurrent squamous cell carcinoma of the bladder: a case report. AB - Squamous cell carcinoma (SCC) of the bladder is a relatively rare malignancy and the standard treatment is surgical resection. Prognosis of unresectable and recurrent SCC of the bladder is poor because no effective treatment is available at present. Here, we describe the response of one patient with this cancer to combination chemotherapy of gemcitabine and paclitaxel. A 47-year-old man with recurrent bladder SCC underwent radical cystectomy, but initially refused any adjuvant therapy. The pathological diagnosis was pT3. The patient was treated with three cycles of methotrexate, vinblastin, epirubicin, and cisplatin but with no response (no decrease in tumor volume). Subsequently, he received the combination chemotherapy of gemcitabine (GEM, 700 mg/m(2) on days 1 and 8) and paclitaxel (PTX, 700 mg/m(2) on days 1 and 8) per each 28-day cycle. After five cycles, the tumor volume had decreased from 562 to 101 cm(3) (18.0%). The combination therapy was reduced to GEM monotherapy, but the tumor volume increased to 573 cm(3). GEM+PTX administration was re-instituted; however, the patient died 21 months after recurrence. The combination GEM+PTX chemotherapy was applied at the outpatient treatment and caused no severe side-effects. Although the maintenance chemotherapy of GEM+PTX did not induce complete remission, it improved quality of life and had no serious side-effects, making it a promising combination chemotherapy for recurrent SCC of the bladder. Although further studies are necessary to determine its therapeutic efficacy, we suggest that this combined therapy is a useful option in the treatment of this disease including recurrent cases. PMID- 22199317 TI - External validation of a laparoscopic-based score to evaluate resectability for patients with advanced ovarian cancer undergoing interval debulking surgery. AB - AIM: To evaluate the relevance of laparoscopic index of Fagotti et al during staging laparoscopy (S-LPS) to predict optimal cytoreduction during interval debulking surgery (IDS) after neoadjuvant chemotherapy for ovarian cancer. PATIENTS AND METHODS: Fifty-two patients with stage III-IV ovarian cancer were retrospectively analyzed. We evaluated discrimination with a receiver operating characteristic (ROC) curve analysis and calibration of Fagotti et al's model among our population and compared this performance with their data. RESULTS: A score >4 was associated with optimal resection with sensitivity and positive predictive value (PPV) of 95% and 82% respectively. The ROC curve analysis gave an area under the curve (AUC) of 0.72 (95% confidence interval (CI) 0.65-0.80) for our population compared to 0.88 (95% CI 0.84-0.91) in Fagotti et al's population. Percentages predicted in our population were unsatisfactory (p<0.01), illustrating the different rates of optimal cytoreduction between the centers (average error of 25%). CONCLUSION: The laparoscopic index of Fagotti et al is relevant in prediction of optimal cytoreduction among women undergoing IDS. PMID- 22199318 TI - Anaplastic oligodendroglial tumors harboring 1p/19q deletion can be successfully treated without radiotherapy. AB - Although anaplastic oligodendroglial tumors are known to be chemosensitive, patients under this diagnosis have been traditionally treated with radiotherapy. To avoid possible neurotoxicity, we prospectively treated patients with anaplastic oligodendroglial tumors harboring 1p/19q deletion, with exclusive procarbazine, ACNU, and vincristine chemotherapy without radiotherapy. Twenty five patients were enrolled in the study (12 with 1p/19q co-deletion, 2 with 1p mono-deletion, 2 with 19q mono-deletion, and 9 without 1p/19q deletion). The median progression-free survival (PFS) was 50 months for all the patients, and those with tumors harboring 1p/19q deletion were progression free for a significantly longer period than those without the deletion (p=0.0391). The median overall survival (OS) time was not reached in both patient groups with and without 1p/19q deletion (p=0.230), and the 5-year OS rate was 62.2% for all patients. The excellent treatment results warrant a large-scale clinical study to confirm the efficacy of upfront chemotherapy omitting radiotherapy as initial therapy for anaplastic oligodendroglial tumors with 1p/19q deletion. PMID- 22199319 TI - Synchronous double tumor of breast cancer and gastrointestinal stromal tumor in a patient with neurofibromatosis type 1: report of a case. AB - We report a rare case of synchronous double tumor formation of breast cancer and gastrointestinal stromal tumor (GIST) in a patient with neurofibromatosis type 1(NF-1). A 76-year-old woman with a history of NF-1 who had undergone left modified mastectomy for breast cancer seven years previously was admitted to our hospital because of a right breast tumor and abdominal discomfort. Computed tomography revealed an enhanced irregular tumor in the right breast and peripheral enhanced tumors in the abdomen. The patient underwent right modified mastectomy and laparoscopic tumor resection combined with small intestine surgery. Histopathological examination revealed the presence of invasive lobular carcinoma in the right breast and GIST in the abdomen. The synchronous development of breast cancer and GIST in a patient with NF-1 is extremely rare, with this being the second case ever reported. PMID- 22199320 TI - Clinical and histopathological profile of primary or secondary osteosarcoma of the jaws. AB - Osteosarcoma of the jaw is a rare disease; we report two cases, one in which the primary osteosarcoma had occurred in the sacrum and ileum, the second at the mandible. Dissemination of osteosarcoma to other organs, especially early dissemination to the lung, is common, but metastasis to the jaw has only rarely been reported. About 10% of osteosarcomas occur in the head and neck, most in the mandible or maxilla. Clinically, both patients presented swelling, and pain at the jaw in the premolar-molar region. At radiography, extensive bone erosion and soft-tissue swelling were apparent. A biopsy was taken and a diagnosis of osteosarcoma rendered in both cases. Histological examination revealed a proliferation of atypical osteoblast-like cells with hyperchromatic nuclei and formation of scattered neoplastic osteoid tissue. Immunohistochemistry for a panel of antibodies showed strong positivity for CD99, weak positivity for S-100, but was negative for desmin, vimentin, and cytokeratins. The diagnosis for both cases was of osteogenic osteosarcoma, chondroblastic subtype. Unfortunately, both patients died, one before the planned chemotherapy regime could begin, the second during the chemotherapy course. Our report aims to highlight the importance of the diagnostic profile in formulating a diagnosis of osteosarcoma, and that this tumor, although very rare, may be primary or may metastasize to the jaws. PMID- 22199321 TI - The cancer stem cell antigens CD133, BCRP1/ABCG2 and CD117/c-KIT are not associated with prognosis in resected early-stage non-small cell lung cancer. AB - BACKGROUND: In various tumor entities, expression of cancer stem cell (CSC) antigens has been proven to be prognostically unfavorable. However, for lung cancer, the data are scant and conflicting. PATIENTS AND METHODS: The CSC antigens CD117/c-KIT, CD133 and breast cancer resistance protein-1 (BCRP1/ABCG2) were immunohistochemically analyzed in tissues from a total of 133 completely resected stage I/II non-small cell lung cancer (NSCLC) patients with a median follow-up time of 53.8 months. Their expression was related to clinicopathological characteristics, angiogenic features and prognosis. RESULTS: Cox proportional hazards regression analysis revealed no association between CSC antigens, disease-free survival or overall survival (OS). However, in the subgroup of patients with relapse and tumors >3 cm, there was a trend towards worse OS upon expression of CD117 (hazard ratio=2.6, 95%, confidence interval=0.8 8.3, p=0.080). Except for CD133, which was overrepresented in T1 tumors (p=0.001), the CSC antigens were not linked to clinico-pathological characteristics or angiogenic features. CONCLUSION: In resected early-stage NSCLC, CSC antigens show no association with prognosis. However, in patients with relapse and tumors >3 cm, expression of CD117 might predict worse OS. PMID- 22199322 TI - Evidence for acute vascular toxicity of cisplatin-based chemotherapy in patients with germ cell tumour. AB - BACKGROUND: Acute early vascular toxicity of chemotherapy for germ cell tumour (GCT) is poorly understood. To explore the pathogenesis of this complication we evaluated laboratory parameters associated with vascular disease. PATIENTS AND METHODS: In 33 GCT patients the following parameters were investigated with routine laboratory methods before and after chemotherapy: von Willebrand factor antigen (vWF:AG), collagen binding capacity (vWF:CB), lipoprotein (a), homocysteine, plasminogen activator inhibitor I, total cholesterol, high density lipoprotein, low density lipoprotein, troponine I. Statistical evaluation involved descriptive analysis and the Wilcoxon signed rank test. RESULTS: Levels of vWF:AG and vWF:CB increased significantly upon therapy (p=0.002). All other parameters remained unchanged. Upon late measurement, vWF:AG and vWF:CB were normalised. CONCLUSION: As von Willebrand factor is released from endothelial cells upon damage, we postulate that early vascular toxicity of chemotherapy is caused by direct damage of the vascular endothelium. Long-term vascular complications of chemotherapy appear to be different, pathogenetically. PMID- 22199323 TI - Circulating CD95-ligand as a potential prognostic marker for recurrence in patients with synchronous colorectal liver metastases. AB - AIM: To assess whether circulating soluble CD95 ligand (sCD95L) levels are associated with recurrence-free survival (RFS) in patients with synchronous colorectal liver metastases. PATIENTS AND METHODS: Blood samples were obtained from 62 patients with synchronous colorectal liver metastases before and after liver surgery. Serum sCD95L levels were determined using enzyme-linked immunosorbent assay (ELISA). Cox regression analysis was performed to determine the correlation between sCD95L levels and RFS and overall survival (OS). RESULTS: Median follow-up was 33 months. High pre-operative sCD95L levels were associated with poor RFS and OS in univariable (p=0.019 and p=0.020) and multivariable analyses (p=0.020 and p=0.003). CONCLUSION: Preoperatives CD95L is a potential prognostic factor for RFS and OS of patients undergoing surgery for synchronous colorectal liver metastases. Low preoperatives CD95L levels may help identify a subgroup of patients with synchronous liver metastases that are likely to benefit from liver surgery. PMID- 22199324 TI - Dissection of unsuspicious para-aortic lymph nodes does not improve prognosis of advanced endometrial carcinoma with intra- or extra-abdominal metastasis. AB - BACKGROUND: The aim of this study was to analyze the significance of dissection of unsuspicious para-aortic lymph nodes (PAN) in patients with advanced endometrial carcinomas with intra- or extra-abdominal metastasis. PATIENTS AND METHODS: We conducted a retrospective comparison of the results of PAN dissection versus non-dissection for endometrial carcinomas with macroscopic metastatic lesions beyond the uterus (without significant swelling of the regional lymph nodes, including PAN), whose lesions were completely resected. RESULTS: Disease free survival and overall survival did not exhibit a significant difference between the two groups. Multivariate Cox proportional hazards analysis demonstrated that PAN dissection was not an independent prognostic factor for survival. The frequency of PAN involvement at the first recurrence did not differ between the two groups. CONCLUSION: For advanced endometrial carcinomas with macroscopic metastatic lesions beyond the uterus, without significant swelling of regional lymph nodes, PAN dissection may be omitted without a significant adverse effect on prognosis and survival. PMID- 22199325 TI - Continuous administration of EGFR-TKIs following radiotherapy after disease progression in bone lesions for non-small cell lung cancer. AB - BACKGROUND: There have been reports suggesting that continuous administration of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is advantageous for patients in which disease progression was observed after the establishment of clinical benefit from EGFR-TKIs. We retrospectively evaluated the clinical course of patients who received continuous administration of EGFR TKIs after disease progression was detected solely in bone lesions. PATIENTS AND METHODS: The medical records of patients administered gefitinib or erlotinib between 2002 and 2010 were reviewed. We evaluated the progression-free survival (PFS) and overall survival (OS) in patients who had bone metastases after the establishment of clinical benefit from EGFR-TKI and who received radiation therapy for the bone lesion and continuous treatment with EGFR-TKI. RESULTS: Ten patients were enrolled in this study. The median PFS and OS were 88 days and 330 days, respectively. Furthermore, a longer duration from the start of first EGFR TKI to detection of bone metastases (p=0.0049) was identified as being significantly associated with a longer PFS. CONCLUSION: Our data suggest that continuous administration of EGFR-TKI is a treatment option for patients with bone metastases who previously benefited from therapy with EGFR-TKI. PMID- 22199326 TI - Hypersensitivity reactions associated with platinum-containing antineoplastic agents for thoracic malignancies. AB - Recently, the use of platinum-containing antineoplastic agents for extended periods has increased. In this study, we determined the relationship between the hypersensitivity reactions to cisplatin or carboplatin and the frequency of administration among patients with thoracic malignancies. The study included 255 patients with thoracic malignancies who were treated with chemotherapy containing cisplatin or carboplatin in our institution between April 2007 and October 2008. A total of 89 patients received a median of 3 courses of cisplatin and 140 patients a median of 4 courses of carboplatin. A median of 6 courses of cisplatin plus carboplatin was administered to a further 26 patients. The total incidence of hypersensitivity reactions was 1.96%. Patients who were treated with <6 courses of platinum-containing antineoplastic agent did not experience any hypersensitivity reaction, but one patient, who was administered with 6 courses of platinum-containing antineoplastic agent experienced a hypersensitivity reaction (0.44%), as did four patients who were administered >=7 courses (13.8%). Univariate and multivariate analyses indicated that the number of courses of platinum-containing antineoplastic agents was significantly correlated to the incidence of hypersensitivity reactions to these agents. PMID- 22199327 TI - Carbonic anhydrase IX, hypoxia-inducible factor-1alpha, ezrin and glucose transporter-1 as predictors of disease outcome in rectal cancer: multivariate Cox survival models following data reduction by principal component analysis of the clinicopathological predictors. AB - Strong expression of carbonic anhydrase IX (CAIX), hypoxia-inducible factor 1alpha (HIF-1alpha), ezrin and glucose transporter-1 (GLUT-1) was previously shown to be related to adverse disease outcome in rectal cancer. In this study, operative samples of 178 rectal cancer patients 77 treated with short-course and 47 with long-course preoperative radiotherapy (RT), and 54 with no preoperative treatment, as well as 80 preoperative biopsies from the RT group patients were analyzed for these markers. For data reduction, principal component analysis (PCA) was used to extract a set of factors from the original clinicopathological variables that would explain as much as possible of their variance. After extraction and promax rotation, this set of five first-order factors (F1-F5) was used in multivariate (Cox) modeling together with the four biomarkers. In model 1 (biomarkers in operative samples), F1 was the only independent determinant of disease-free (DFS) (p=0.043) and disease-specific survival (DSS) (p=0.029). In model 2 (biomarkers in preoperative biopsies), none of the five factors or biomarkers were significantly associated with DFS. However, HIF-1alpha (p=0.024), ezrin (p=0.034), F1 (p=0.011), and F3 (p=0.001) were significant independent predictors of DSS. Similarly, in model 3 (ezrin in preoperative biopsies and others in operative samples), none of the factors or biomarkers were significant predictors of DFS. However, CAIX (p=0.028), and F1 (p= 0.017) were significantly associated with DSS. Preoperative RT markedly modifies the expression of these four biomarkers and also interferes with the original clinicopathological prognosticators (loaded to F1-F5), emphasizing the complexity of prognostication in rectal cancer. PMID- 22199328 TI - Retrospective study of patients with brain metastases from melanoma receiving concurrent whole-brain radiation and temozolomide. AB - BACKGROUND: Metastatic melanoma is the second most common cancer to metastasize to the brain. It is typically treated using stereotactic radiosurgery with or without whole-brain radiation (WBR) therapy. Recently, the alkylating agent temozolomide, which has demonstrated activity in patients with brain metastasis and primary tumors, was used alongside WBR to delay brain metastasis recurrence, increase survival, and improve quality-of-life in patients with brain metastases. PATIENTS AND METHODS: In this retrospective study, we reviewed outcomes of 29 patients treated from 2005-2009 at the Moffitt Cancer Center with brain metastases of melanoma. Results were narrowed via retrospective chart analysis to a cohort with brain metastasis receiving concomitant temozolomide and WBR. RESULTS: Median progression-free survival was 20.4 weeks and overall survival was 44.4 weeks compared to 16 week survival of patients treated with WBR alone. CONCLUSION: A prospective trial evaluating this combined regimen may be considered. PMID- 22199329 TI - Perioperative non-tumorous factors associated with survival in HCC patients who underwent hepatectomy. AB - AIM: To clarify perioperative factors associated with poor survival following hepatectomy. PATIENTS AND METHODS: Clinical parameters and stress score, including surgical stress score (SSS) and comprehensive risk score (CRS) were examined from 183 hepatocellular carcinoma patients who underwent hepatectomy. RESULTS: Factors associated with tumor relapse were increased blood loss/weight, uncontrolled ascites and grade B liver damage (p<0.05). Ascites was identified as an independent risk factor by multivariate logistic regression analysis. Increased blood loss/weight, transfusion, high SSS, high CRS, ascites, and grade B liver damage were associated with poor disease-free survival (p<0.05). Increased blood loss/weight, transfusion, ascites, and grade B liver damage were associated with poor overall survival (p<0.05), and ascites, transfusion, male sex and grade B liver damage were identified as independent risk factors. CONCLUSION: Reducing blood loss and avoiding transfusion appear important for improving prognosis. Maintenance of liver function is necessary in cases showing poor liver function and uncontrolled ascites. PMID- 22199330 TI - Initial experience with hepatic intraarterial fotemustine and interferon alpha 2b combination for treatment of liver tumors. AB - BACKGROUND: Locoregional treatments represent a good option for patients suffering from hepatocellular carcinoma (HCC) not eligible for resection or transplantation. Locoregional approaches include a wide spectrum of therapeutic methods and hepatic intra-arterial drug infusion is also considered. Fotemustine is a chemotherapy drug usually administered intravenously according to standard administration schedules. Interferon alpha 2b (IFNalpha2b), a biological response modifier conventionally administered by a systemic route, has been employed in the treatment of both virus-related hepatitis and HCC. Nonetheless, both drugs can also be infused into the hepatic artery. PATIENTS AND METHODS: We report on five patients with liver cancer, not suitable for conventional therapies, treated with hepatic intra-arterial administration of fotemustine in combination with IFNalpha2b. They received fotemustine at a dose of 30 mg/m(2) and IFNalpha2b at a starting dose of 2,000,000 IU (increasing up to 3,000,000 IU for subsequent administrations) weekly for three consecutive weeks, followed by two weeks of rest. RESULTS: Among the patients suffering from HCC, the first patient showed a partial response, two patients had almost stable disease and one patient was not assessable. A patient with an intrahepatic biliary tract cancer experienced disease progression. CONCLUSION: The therapeutic regimen used showed acceptable tolerability profiles and lack of life-threatening side-effects. Further evaluation with a larger patient cohort will be required to clarify if fotemustine and IFNalpha2b administered into the hepatic artery could be beneficial in treating patients with HCC. PMID- 22199331 TI - Prospective study evaluating the plasma concentrations of twenty-six cytokines and response to morphine treatment in cancer patients. AB - Cytokine signaling is involved in pain and opioid-receptor signaling. In this prospective study, we studied the plasma cytokine levels in order to identify candidate biomarkers for predicting resistance to morphine treatment in a cohort of opioid-treatment-naive cancer patients. We analyzed pain rating and the plasma concentrations of 26 cytokines at baseline and after morphine treatment using a multiplex immunoassay system for the following cytokines: eotaxin, colony stimulating factor, granulocyte (G-CSF), colony stimulating factor granulocyte macrophage (GM-CSF), interferon alpha2 (IFN-alpha2), IFN-gamma, interleukin 1alpha (IL-1alpha), IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL 12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IP-10, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, tumor necrosis factor-alpha (TNF-alpha) and TNF-beta. No correlation was observed between the clinical characteristics and the numerical rating scale for pain at baseline or among patients who developed resistance to morphine treatment. Interestingly, the plasma concentration of MIP-1alpha significantly decreased during morphine treatment (day 8 vs. baseline, p=0.03). Regarding the baseline plasma cytokine concentrations, none of the cytokine levels were correlated with the numerical rating scale for pain at baseline; however, the baseline plasma concentrations of eotaxin, IL-8, IL-12 (p40), IL-12 (p70), MIP-1alpha and MIP 1beta were significantly lower in patients who required a high dose of morphine or who developed resistance to morphine treatment. In conclusion, this is the first report revealing that the plasma concentrations of several cytokines were significantly modulated during treatment and were correlated with treatment outcome of morphine. Our results suggest that plasma cytokine levels may be promising biomarkers for morphine treatment and that they warrant further study. PMID- 22199332 TI - Impact of chemotherapy for colorectal cancer on regulatory T-cells and tumor immunity. AB - BACKGROUND: Regulatory T-cells (Tregs) actively engage in the maintenance of immunological self-tolerance and immune homeostasis. The purpose of the present study was to determine how oxaliplatin plus infusional 5-fluorouracil and leucovorin (FOLFOX) and irinotecan plus infusional 5-fluorouracil and leucovorin (FOLFIRI) affect Tregs and other immune effectors. PATIENTS AND METHODS: A total of 27 patients with metastatic colorectal cancer received the FOLFOX (n=17) or FOLFIRI (n=10) chemotherapeutic regimen. Blood samples were collected from patients before and 7 days after chemotherapy. The prevalence of Tregs co expressing CD4(+)FoxP3(+) was analyzed with flow cytometry. RESULTS: The percentage and the number of CD4(+)FoxP3(+) Tregs were significantly reduced after FOLFOX and FOLFIRI in the patients who had high levels of Tregs before chemotherapy. On the other hand, the total number of lymphocytes and the population of CD4(+) T lymphocytes were unchanged. CONCLUSION: FOLFOX and FOLFIRI may enhance antitumor immunity via suppression of Tregs. PMID- 22199333 TI - Radiofrequency ablation for intrahepatic cholangiocarcinoma: retrospective analysis of a single centre experience. AB - PURPOSE: To evaluate the usefulness and safety of radiofrequency ablation for primary and recurrent intrahepatic cholangiocarcinoma (ICC) in our single centre experience. MATERIALS AND METHODS: Ten patients with ICC refusing or not eligible for surgery underwent radiofrequency ablation for their tumor. The ICC was primary in 9 cases and recurrent, after 2 previous resections, in 1 patient. Radiofrequency ablation was performed percutaneously under ultrasound guidance using a 15G perfused electrode. Technical success of the procedure was assessed by contrast-enhanced ultrasound (CEUS). Technical effectiveness was evaluated by CEUS and contrast enhanced CT 1 month after the last course of a defined ablation protocol. Follow-up contrast enhanced CT or MRI were performed every 3-6 months. RESULTS: RFA was always technically successful and effective for ICC lesions <=3.4 cm and ineffective for lesion >=4 cm. After a median follow-up of 19.5 months (range 9-64 months), 8 patients were still alive while 2 had died due to tumor progression. The 1-, 3- and 5-year overall survival rate of all patients with ICC of our series were 100%, 83.3% and 83.3%. No major complication was observed. CONCLUSION: Radiofrequency ablation seems to be a safe and effective option for small (<=3.4 cm) ICC nodules. In addition it may be considered as a palliative treatment for larger tumors. PMID- 22199334 TI - Trans-arterial chemoembolization of metastatic colorectal carcinoma to the liver adopting DC Bead(r), drug-eluting bead loaded with irinotecan: results of a phase II clinical study. AB - Trans-arterial chemoembolization (TACE) is a promising locoregional therapy for the treatment of primary hepatic tumors and liver metastases. The aim of the study was to define the activity and outcome of using DC Bead, drug-eluting bead, a spherical embolic device capable of being loaded with irinotecan. PATIENTS AND METHODS: We conducted a double institutional, single arm, phase II clinical study to evaluate TACE adopting this device in 82 patients presenting with metastatic colorectal carcinoma to the liver after failing chemotherapy. The primary endpoints were tumor shrinkage, safety, feasibility, compliance, and overall survival. RECIST criteria were used to assess responses. Quality of life (QoL) was addressed using Edmonton SAS improvement scale. RESULTS: Out of 103 patients considered, 82 were enrolled and underwent a total of 185 treatments of TACE. The median number of TACE was 2.2 (1-4). A post-embolization syndrome was frequently observed. Adverse observed effects were: right upper quadrant pain (40%), fever (80%), nausea (27%) and increased transaminases (70%). The median follow-up was 29 months. Within one month after treatment, each patient received a computed tomograpic scan. It showed reduction of metastatic contrast enhancement in all patients. Responses were 78% at 3 months. After the first treatment, 75 out 82 patients declared an improvement of their well being lasting more than 18 weeks. The median duration of response was 6 (range 3-10) months; the median follow up was 29 (range 7-48) months. The median survival was 25 (range 6-34) months, with progression free survival at 8 (range 4-16) months. CONCLUSION: We suggest that TACE adopting DC Bead(r), drug-eluting bead loaded with irinotecan could be proposed as palliative therapy for unresectable and chemotherapy resistant liver metastases from CRC. PMID- 22199335 TI - Docetaxel, nedaplatin, and S-1 (DGS) chemotherapy for advanced esophageal carcinoma: a phase I dose-escalation study. AB - AIM: More effective regimens are urgently needed for treatment of esophageal carcinoma; therefore, we conducted a phase I trial of a combination of docetaxel, nedaplatin, and S-1 (DGS) to determine the optimal dose in patients with advanced esophageal carcinoma. PATIENTS AND METHODS: We studied 14 patients with previously untreated advanced cervical esophageal carcinoma with T3-4 tumors and/or M1 staging and esophageal carcinoma with cervical lymph node metastasis. The patients received an infusion of docetaxel at different dose levels (levels 1, 2, 3, 4: 25, 30, 35, 40 mg/m(2), respectively) and an infusion of nedaplatin (40 mg/m(2)) on day 8 plus oral administration of S1 (80 mg/m(2)/day) for two consecutive weeks at two-week intervals. RESULTS: Dose-limiting toxicities (DLTs) included febrile neutropenia and leukopenia. DLTs occurred in 2 out of 5 patients at level 4. The response rate was 78.6 (11/14)%, including a complete response rate of 35.7(5/14)%. CONCLUSION: The DGS regimen reported here was well tolerated and toxicities were manageable. The maximum tolerated dose was level 4, and the recommended dose was determined to be docetaxel at 35 mg/m(2) with nedaplatin at 40 mg/m(2) plus S1 at 80 mg/m(2). We found that our regimen, administered on an outpatient basis, showed high activity and tolerance. A phase II study has been started. PMID- 22199336 TI - Long-term survival following resection of brain metastases from pancreatic cancer. AB - Brain metastases originating from pancreatic cancer are associated with a dismal prognosis and, generally, therapeutic options remain palliative. We present the cases of two patients that developed brain metastases after resection of a pancreatic ductal adenocarcinoma. Brain metastases were resected successfully and neither patients developed any further tumor recurrence. These cases demonstrate that resection of brain metastatic lesions originating from pancreatic ductal adenocarcinoma is a reasonable therapeutic option with a chance for complete cure in some cases. PMID- 22199337 TI - Comparison of lymphangiogenesis between primary colorectal cancer and corresponding liver metastases. AB - BACKGROUND: Liver metastasis (LM) is the determining factor of poor prognosis in colorectal cancer (CRC). Peripheral lymphatico-venous communications have been discussed as a potential pathway of tumor cell dissemination for the development of LMs. In the current study, we investigated the clinical impact of the lymphangiogenic activity in CRCs and their corresponding LMs. PATIENTS AND METHODS: In 47 patients with CRC, the primary tumors and the corresponding LMs were investigated. Lymphangiogenesis (LMVD), lymphovascular invasion (LVI), lymphatic vascular endothelial growth factor C expression (VEGF-C) were investigated RESULTS: A significant correlation was observed between LMVD and LVI in CRCs (p=0.001) as well as in LMs (p=0.0001). LMVD in CRC correlated significantly with that in LMVD-LMs (p=0.026) and LVI in LMs (p=0.036). Survival analysis reveilled a significant difference in disease free and overall survival between patients with and without VEGF-C expression in LMs (p=0.0019 and p=0.0101, respectively). CONCLUSION: Our data provide evidence for an important role of lymphangiogenesis in liver metastasis of CRC and provide further support for a possible role of a lymphatico-venous metastatic pathway. PMID- 22199338 TI - Salvage chemotherapy for ovarian carcinoma recurring during or after consolidation chemotherapy with paclitaxel. AB - BACKGROUND: The aim of the study was to analyze the effectiveness of salvage chemotherapy for recurring ovarian carcinoma during or after consolidation chemotherapy. PATIENTS AND METHODS: During the study period, 12 patients received salvage chemotherapy for recurrence during or after consolidation chemotherapy. These cases were retrospectively reviewed. RESULTS: The response rate for salvage chemotherapy was 67% and was significantly associated with treatment-free interval (TFI) after consolidation (p=0.038). Progression-free survival was also significantly related to TFI (p=0.032). Combination chemotherapy of cisplatin plus irinotecan was effective in all five cases with TFI>=6 months and in three out of seven cases with TFI<6 months. CONCLUSION: Our study provides, for the first time, evidence that effectiveness of salvage chemotherapy for recurrent ovarian carcinoma occurring during or after consolidation chemotherapy can be predicted by TFI, and that combination chemotherapy of cisplatin plus irinotecan is potentially useful for these cases. PMID- 22199339 TI - Clinical significance of BRAF gene mutations in patients with non-small cell lung cancer. AB - BACKGROUND: V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations are attractive molecular targets for cancer treatment. Detection of BRAF gene mutation and analyses in non-small cell lung cancer (NSCLC) are of great scientific interest. PATIENTS AND METHODS: The study included 581 NSCLC patients (377 males, 204 female) undergoing pulmonary resection. BRAF gene mutations were screened using the PCR-SSCP method and were confirmed by direct DNA sequencing. Mutations of epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2), and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene were also analyzed. RESULTS: Five patients (0.8%) had BRAF mutations within exon 15. In 581 NSCLC patients, EGFR gene mutations within exons 18 to 21 were detected in 191 (32.8%) patients, KRAS codon 12 mutations in 56 (9.6%) patients, and ERBB2 codon 20 mutations in 11 (1.8%) patients. All mutations were mutually exclusive. The NSCLC patients with BRAF mutations were proved to be men who were heavy smokers. CONCLUSIONS: PCR-SSCP analysis of BRAF exon 15 in NSCLC patients without other gene mutations may be sufficient to identify candidates for treatment. PMID- 22199340 TI - Weekly paclitaxel in combination with doxifluridine for peritoneally disseminated gastric cancer with malignant ascites. AB - BACKGROUND: The efficacy of systemic chemotherapy for peritoneal dissemination of gastric cancer remains unclear. The efficacy of weekly paclitaxel in combination with doxifluridine (5'-DFUR) in gastric cancer patients with malignant ascites was evaluated. PATIENTS AND METHODS: Patients with histologically confirmed gastric cancer with ascites were eligible. The treatment consisted of paclitaxel intravenously (i.v.) administered at 80 mg/m(2) on days 1, 8 and 15 every 4 weeks, and doxifluridine administered orally at 533 mg/m(2) on days 1-5 every week. The response rate for patients with ascites was determined based on the Japanese Classification of Gastric Carcinoma. Also, the concentration of paclitaxel in the ascites was measured. RESULTS: Twenty-four patients were investigated. The response rate (RR) was 41.7%, including complete remission (CR) and partial remission (PR) in 4 and 6 patients, respectively. The concentration of paclitaxel in the ascites was maintained between 0.01 MUM and 0.05 MUM until 72 hours. The median overall survival (OS) was 215 days, and 1-year survival rate was 29.2%. No severe toxicity was noted. CONCLUSION: Weekly paclitaxel in combination with doxifluridine is effective for gastric cancer patients with malignant ascites with an acceptable toxicity profile. PMID- 22199341 TI - The prognostic significance of HER2 overexpression in non-small cell lung cancer. AB - AIM: The human epidermal growth factor receptor HER-2/neu (HER2) gene is a proto oncogene involved in the signal transduction pathways leading to cell growth and differentiation. The present study focused on the clinical significance of the expression of HER2 in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Consecutive specimens of 159 adenocarcinomas and 77 squamous cell carcinomas, from patients who had been treated by complete resection of NSCLC in our department between 2003 and 2005, were studied. The HER2 expression was evaluated by immunohistochemical staining with score of membranous staining being 0=none, 1=weak, 2=10-30% cells, 3>=30% cells stained. RESULTS: The staining scores in adenocarcinoma were 0 in 121 patients (76.1%), 1 in 16 (10.0%), 2 in 17 (10.7%), and 3 in 5 patients (3.1%). The HER2 expression scores in squamous cell carcinoma were 0 in 74 patients (96.1%), 1 in 1 (1.2%), 2 in 1 (1.2%), and 3 in 1 patient (1.2%). The postoperative 5-year survival rate of patients with adenocarcinoma according to the expression of HER2 scores 0, 1, 2 and 3 was 75.3%, 77.8%, 76.5% and 20.0%, respectively. Patients with adenocarcinoma with score 3 staining had a significantly unfavorable prognosis compared to those with staining scores of 0-2 (p=0.0216). CONCLUSION: HER2 overexpression (score 3) in adenocaricinoma was a significantly unfavorable prognostic factor. Since the number of NSCLC patients with HER2 overexpression was small, further investigations will be necessary to clarify the efficacy of molecular targeted therapy for this subgroup. PMID- 22199342 TI - Single-agent paclitaxel in advanced anal cancer after failure of cisplatin and 5 fluorouracil chemotherapy. AB - Squamous cell cancer of the anal canal (anal cancer) is a rare disease but with worldwide increasing incidence. While combined therapy of 5-fluorouracil (5-FU), mitomycin, and radiation is the treatment of choice for locoregional anal cancer, the treatment of metastatic disease is less established. 5-FU and cisplatin combination has been adopted as the first-line treatment of choice for metastatic disease based on several phase II studies. However, no standard therapy has been established for stage IV anal cancer after the failure of this combination. Paclitaxel, a microtubule-stabilizing chemotherapeutic agent, has established clinical activity in squamous cell cancer of the head and neck. One prior report described the activity of paclitaxel in five patients with anal cancer. In this report, we describe our experience using this agent in seven patients suffering from metastatic anal cancer with prior progression on cisplatin and 5-FU. Four patients had an objective response and one patient experienced stable disease. Our results confirm activity of weekly-paclitaxel in patients with 5-FU and cisplatin-resistant metastatic anal cancer. PMID- 22199343 TI - Clinical characteristics and treatment outcomes of hepatocellular carcinoma with inferior vena cava/heart invasion. AB - BACKGROUND: The prognosis and treatment outcomes of hepatocellular carcinoma (HCC) with inferior vena cava (IVC)/heart invasion have not been established. This study aimed to investigate the clinical characteristics and treatment outcomes of patients with HCC extending to IVC/heart and ascertained whether active treatment beyond best supportive care (BSC) can prolong overall survival. PATIENTS AND METHODS: We retrospectively reviewed 50 patients with HCC extending to IVC/heart who were admitted from November 1987 to November 2010. They were stratified into a control group with BSC alone (n=18) and a treated group with active treatment more than BSC (n=32). RESULTS: The mean age was 56.5 years and male gender predominated (n=39, 78.0%). Treatment modalities in the treated group included systemic chemotherapy using 5-fluorouracil with/without cisplatin (n=10, 31.3%), transarterial chemoembolization (n=8, 25.0%), intra-arterial chemotherapy (n=3, 9.4%), concurrent chemoradiation therapy (n=3, 9.4%), radiation (n=2, 6.2%), surgery (n=1, 3.1%), and of the combination above (n=5, 15.6%). Active treatment more than BSC was the only independent predictor of overall survival and the overall survival of the treated group was significantly better than that of the control group (median 4.0 vs. 2.0 months, p=0.003). CONCLUSION: The prognosis of HCC with IVC/heart invasion is poor. However, if patients are cautiously selected, active treatment beyond BSC might provide a survival benefit in patients with HCC extending to IVC/heart. PMID- 22199344 TI - Clinical significance of hypermethylation status in NSCLC: evaluation of a 30 gene panel in patients with advanced disease. AB - BACKGROUND: DNA methylation is one of major factors in cancer progression. We observed multiple genes involved in cancer-related signaling and focused on patients with advanced non-small cell lung cancer (NSCLC) and evaluated methylation in relation to various clinical parameters. PATIENTS AND METHODS: Thirty genes were examined in 121 NSCLC patients using the methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) method. Correlations to gender, smoking status, tumor subtype, disease stage and EGFR/KRAS mutation status were performed by chi-square test. RESULTS: 90% of tumors exhibited methylation of at least one gene. Most frequently methylated were cadherin-13 (CDH13), Ras associated domain-containing protein (RASSF1A), Wilms' tumor protein (WT1), adenomatous polyposis coli protein (APC), paired box protein Pax-5 (PAX5), estrogen receptor (ESR1), an inhibitor of cyclin-dependent kinase p15 (CDKN2B), paired box protein Pax-6 (PAX6), transcription factor GATA-5 (GATA5) and cell adhesion molecule 4 (IGSF4). Overall methylation (any gene) was increased in adenocarcinomas (p=0.0329), unrelated to gender or disease stage. Several genes exhibited variable methylation with gender (CDH13, p<0.001; GATA5, p=0.02; PAX6, p=0.01 and ESR1, p=0.03), smoking (CDH13, p=0.002), or epidermal growth factor receptor (EGFR) mutation status [Von Hippel-Lindau disease tumor supresor (VHL), p=0.001; CDKN2B, p=0.02; CDH13, p=0.02; APC, p=0.04 and ESR1, p=0.04]. CONCLUSION: Differences in gene methylation associated with gender, smoking and EGFR mutation suggest potential for prediction in relation to management of tyrosine kinase inhibitor therapy. PMID- 22199345 TI - Growth factors and breast tumors, comparison of selected growth factors with traditional tumor markers. AB - BACKGROUND: The first aim of this project was to study new possibilities for distinguishing benign from malignant tumors using growth factors and to compare them with the traditional tumor markers Carcinoembryonic antigen (CEA) and Cancer antigen 15-3 (CA15-3) for breast tumors. The second aim was to make a comparison of CEA, CA 15-3, Insulin-like growth factor I (IGF1), Insulin-like growth factor binding protein 3 (IGFBP3), Hepatocyte growth factor (HGF) and Epidermal growth factor (EGF) for individual stages of cancer. PATIENTS AND METHODS: Our group of patients consisted of 110 females, 89 with breast cancer and 21 with benign breast tumors (fibroadenomas). Serum levels of CEA and CA 15-3 were measured using a DxI instrument. Serum levels of IGF1 and IGFBP3 were measured using IRMA radioisotope assay kits. HGF and EGF were measured using an xMAP Luminex multiplex panel. Serum samples were collected prior to surgery and those of the two groups of patients were compared (malign vs. benign). Patients with diabetes mellitus were excluded from this project. RESULTS AND DISCUSSION: Comparing the individual parameters of serum levels between the two groups of patients (malignant vs. benign) only HGF was found to show a statistically significant difference. The mean of HGF in patients with malignant diseases prior to surgery was 3370 pg/ml compared to 1799 pg/ml in benign tumors with p=0.0016. We found significantly lower serum values of IGF1 at stage III in comparison to stages I and II: mean values: at stage I=181 ng/ml, at stage II=182 ng/ml and at stage III=70 ng/ml; stage III vs. stage II, p=0.0167. CONCLUSION: Tumor markers are currently used for therapy monitoring in cancer patients as one of the indicators of successful therapy. Our findings correspond to existing literature. IGF1 and its binding protein IGFBP3 cannot be used to distinguish between malignant and benign tumor. HGF is considered to be a marker of progression and of the aggressiveness of breast cancer; our data fully corresponds to this. Based on our data, this marker could potentially be used as an additional tool for the differentiation between benign and malignant tumor. PMID- 22199346 TI - Multi-center phase II study of FLOX for advanced colorectal cancer patients in Japan: SWIFT 3 study. AB - AIM: This is a multicenter phase II study to assess the efficacy and toxicity of the 5-FU, leucovorin, and oxaliplatin (FLOX) (SWIFT 3) regimen in Japanese patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: Fifty-two patients were enrolled and evaluated from 12 institutions. The median age was 66 years, with 40.4% of patients with colon cancer and 59.6% with rectal cancer. RESULTS: Forty-one patients underwent chemotherapy for first-line therapy and 11 patients for second-line. The response rate for first-line was 46.3% and that for second-line was 9.1%. The response rates categorized by metastatic sites were 59.4% for liver, 33.3% for lung, and 22.2% for lymph nodes. Grade 3/4 neutropenia occurred in 21.2% and Grade 3/4 non-hematologic toxicity in 46.1%. There were no deaths within 60 days following the administration. CONCLUSION: Standard FLOX regimen can be administered for Japanese patients. It is suggested that FLOX is an appropriate option for adjuvant therapy in CRC. PMID- 22199347 TI - Low dihydropyrimidine dehydrogenase correlates with prolonged survival in patients with lung adenocarcinoma treated with 5-fluorouracil. AB - BACKGROUND: The enzyme dihydropyrimidine dehydrogenase (DPD) is involved in the metabolism of 5-fluorouracil (5-FU). The aim of this study was to clarify the correlation between the expression of DPD and the efficacy of 5-FU therapy in patients with lung adenocarcinoma (AD). PATIENTS AND METHODS: We examined surgically resected specimens from 90 stage I to IIIA patients with lung ADs to determine the level of intra-tumoral DPD mRNA. RESULTS: Administration of 5-FU improved the prognosis of patients with low DPD-expressing tumors, whereas it did not do so for patients with high DPD expressing tumors. Patients with low DPD expressing tumors administered with 5-FU had a significantly better prognosis than those who underwent surgery alone. A Cox proportional hazards regression model revealed that administration of 5-FU was an independent variable to predict prognosis in patients with low DPD-expressing tumors. CONCLUSION: Quantification of DPD mRNA levels is useful for determining the subgroup of lung AD patients who would benefit most from 5-FU after surgery. PMID- 22199349 TI - Protein arginine methyltransferase 5 (PRMT5) signaling suppresses protein kinase Cdelta- and p38delta-dependent signaling and keratinocyte differentiation. AB - PKCdelta is a key regulator of keratinocyte differentiation that activates p38delta phosphorylation leading to increased differentiation as measured by an increased expression of the structural protein involucrin. Our previous studies suggest that p38delta exists in association with protein partners. A major goal is to identify these partners and understand their role in regulating keratinocyte differentiation. In this study we use affinity purification and mass spectrometry to identify protein arginine methyltransferase 5 (PRMT5) as part of the p38delta signaling complex. PRMT5 is an arginine methyltransferase that symmetrically dimethylates arginine residues on target proteins to alter target protein function. We show that PRMT5 knockdown is associated with increased p38delta phosphorylation, suggesting that PRMT5 impacts the p38delta signaling complex. At a functional level we show that PRMT5 inhibits the PKCdelta- or 12-O tetradecanoylphorbol-13-acetate-dependent increase in human involucrin expression, and PRMT5 dimethylates proteins in the p38delta complex. Moreover, PKCdelta expression reduces the PRMT5 level, suggesting that PKCdelta activates differentiation in part by reducing PRMT5 level. These studies indicate antagonism between the PKCdelta and PRMT5 signaling in control of keratinocyte differentiation. PMID- 22199350 TI - Angiogenesis induced by signal transducer and activator of transcription 5A (STAT5A) is dependent on autocrine activity of proliferin. AB - Multiple secreted factors induce the formation of new blood vessels (angiogenesis). The signal transduction events that orchestrate the numerous cellular activities required for angiogenesis remain incompletely understood. We have shown previously that STAT5 plays a pivotal role in angiogenesis induced by FGF2 and FGF8b. To delineate the signaling pathway downstream of STAT5, we expressed constitutively active (CA) or dominant-negative (DN) mutant STAT5A in mouse brain endothelial cells (EC). We found that the conditioned medium from CA STAT5A but not from dominant-negative STAT5A overexpressing EC is sufficient to induce EC invasion and tube formation, indicating that STAT5A regulates the secretion of autocrine proangiogenic factors. Conversely, CA-STAT5A-induced conditioned medium had no effect on EC proliferation. Using a comparative genome wide transcription array screen, we identified the prolactin family member proliferin (PLF1 and PLF4) as a candidate autocrine factor. The CA-STAT5A dependent transcription and secretion of PLF by EC was confirmed by quantitative RT-PCR and Western blotting, respectively. CA-STAT5A binds to the PLF1 promoter region, suggesting a direct transcriptional regulation. Knockdown of PLF expression by shRNA or by blocking of PLF activity with neutralizing antibodies removed the CA-STAT5A-dependent proangiogenic activity from the conditioned medium of EC. Similarly, the ability of concentrated conditioned medium from CA STAT5A transfected EC to induce angiogenesis in Matrigel plugs in vivo was abolished when PLF was depleted from the medium. These observations demonstrate a FGF/STAT5/PLF signaling cascade in EC and implicate PLF as autocrine regulator of EC invasion and tube formation. PMID- 22199351 TI - Different requirements for proteolytic processing of bone morphogenetic protein 5/6/7/8 ligands in Drosophila melanogaster. AB - Bone morphogenetic proteins (BMPs) are synthesized as proproteins that undergo proteolytic processing by furin/subtilisin proprotein convertases to release the active ligand. Here we study processing of BMP5/6/7/8 proteins, including the Drosophila orthologs Glass Bottom Boat (Gbb) and Screw (Scw) and human BMP7. Gbb and Scw have three functional furin/subtilisin proprotein convertase cleavage sites; two between the prodomain and ligand domain, which we call the Main and Shadow sites, and one within the prodomain, which we call the Pro site. In Gbb each site can be cleaved independently, although efficient cleavage at the Shadow site requires cleavage at the Main site, and remarkably, none of the sites is essential for Gbb function. Rather, Gbb must be processed at either the Pro or Main site to produce a functional ligand. Like Gbb, the Pro and Main sites in Scw can be cleaved independently, but cleavage at the Shadow site is dependent on cleavage at the Main site. However, both Pro and Main sites are essential for Scw function. Thus, Gbb and Scw have different processing requirements. The BMP7 ligand rescues gbb mutants in Drosophila, but full-length BMP7 cannot, showing that functional differences in the prodomain limit the BMP7 activity in flies. Furthermore, unlike Gbb, cleavage-resistant BMP7, although non-functional in rescue assays, activates the downstream signaling cascade and thus retains some functionality. Our data show that cleavage requirements evolve rapidly, supporting the notion that changes in post-translational processing are used to create functional diversity between BMPs within and between species. PMID- 22199352 TI - Primary role for endoplasmic reticulum-bound ribosomes in cellular translation identified by ribosome profiling. AB - In eukaryotic cells, the spatial regulation of protein expression is frequently conferred through the coupling of mRNA localization and the local control of translation. mRNA localization to the endoplasmic reticulum (ER) is a prominent example of such regulation and serves a ubiquitous role in segregating the synthesis of secretory and integral membrane proteins to the ER. Recent genomic and biochemical studies have now expanded this view to suggest a more substantial role for the ER cellular protein synthesis. We have utilized cell fractionation and ribosome profiling to obtain a genomic survey of the subcellular organization of mRNA translation and report that ribosomal loading of mRNAs, a proxy for mRNA translation, is biased to the ER. Notably, ER-associated mRNAs encoding both cytosolic and topogenic signal-encoding proteins display similar ribosome loading densities, suggesting that ER-associated ribosomes serve a global role in mRNA translation. We propose that the partitioning of mRNAs and their translation between the cytosol and ER compartments may represent a novel mechanism for the post-transcriptional regulation of gene expression. PMID- 22199353 TI - Dual regulation of notch1 signaling pathway by adaptor protein fe65. AB - Notch1 receptor functions as a critical controller of cell fate decisions and also as a key regulator of cell growth, differentiation, and proliferation in invertebrates and vertebrates. In this study, we have demonstrated that the adaptor protein Fe65 attenuates Notch1 signaling via the accelerated degradation of the membrane-tethered Notch1 in the cytoplasm. Fe65 also suppresses Notch1 transcriptional activity via the dissociation of the Notch1-IC-recombining binding protein suppressor of hairless (RBP)-Jk complex within the nucleus. Fe65 is capable of forming a trimeric complex with Itch and membrane-tethered Notch1, and Fe65 enhances the protein degradation of membrane-tethered Notch1 via an Itch dependent proteasomal pathway. Collectively, our results demonstrate that Fe65 carries out different functions depending on its location in the regulation of Notch1 signaling. PMID- 22199354 TI - Toxin-antitoxin systems of Mycobacterium smegmatis are essential for cell survival. AB - The role of chromosomal toxin-antitoxin (TA) modules in bacterial physiology remains enigmatic despite their abundance in the genomes of many bacteria. Mycobacterium smegmatis contains three putative TA systems, VapBC, MazEF, and Phd/Doc, and previous work from our group has shown VapBC to be a bona fide TA system. In this study, we show that MazEF and Phd/Doc are also TA systems that are constitutively expressed, transcribed as leaderless transcripts, and subject to autoregulation, and expression of the toxin component leads to growth inhibition that can be rescued by the cognate antitoxin. No phenotype was identified for deletions of the individual TA systems, but a triple deletion strain (DeltavapBC, mazEF, phd/doc), designated DeltaTA(triple), exhibited a survival defect in complex growth medium demonstrating an essential role for these TA modules in mycobacterial survival. Transcriptomic analysis revealed no significant differences in gene expression between wild type and the DeltaTA(triple) mutant under these conditions suggesting that the growth defect was not at a transcriptional level. Metabolomic analysis demonstrated that in response to starvation in complex medium, both the wild type and DeltaTA(triple) mutant consumed a wide range of amino acids from the external milieu. Analysis of intracellular metabolites revealed a significant difference in the levels of branched-chain amino acids between the wild type and DeltaTA(triple) mutant, which are proposed to play essential roles in monitoring the nutritional supply and physiological state of the cell and linking catabolic with anabolic reactions. Disruption of this balance in the DeltaTA(triple) mutant may explain the survival defect in complex growth medium. PMID- 22199355 TI - Cdc37/Hsp90 protein-mediated regulation of IRE1alpha protein activity in endoplasmic reticulum stress response and insulin synthesis in INS-1 cells. AB - IRE1alpha is an endoplasmic reticulum (ER) localized signaling molecule critical for unfolded protein response. During ER stress, IRE1alpha activation is induced by oligomerization and autophosphorylation in its cytosolic domain, a process triggered by dissociation of an ER luminal chaperone, binding immunoglobulin protein (BiP), from IRE1alpha. In addition, inhibition of a cytosolic chaperone protein Hsp90 also induces IRE1alpha oligomerization and activation in the absence of an ER stressor. Here, we report that the Hsp90 cochaperone Cdc37 directly interacts with IRE1alpha through a highly conserved cytosolic motif of IRE1alpha. Cdc37 knockdown or disruption of Cdc37 interaction with IRE1alpha significantly increased basal IRE1alpha activity. In INS-1 cells, Hsp90 inhibition and disruption of IRE1alpha-Cdc37 interaction both induced an ER stress response and impaired insulin synthesis and secretion. These data suggest that Cdc37-mediated direct interaction between Hsp90/Cdc37 and an IRE1alpha cytosolic motif is important to maintain basal IRE1alpha activity and contributes to normal protein homeostasis and unfolded protein response under physiological stimulation. PMID- 22199356 TI - c-Abl tyrosine kinase regulates serum-induced nuclear export of diacylglycerol kinase alpha by phosphorylation at Tyr-218. AB - c-Abl is a tyrosine kinase involved in many cellular processes, including cell cycle control and proliferation. However, little is known about its substrates. Here, we show that c-Abl directly phosphorylates diacylglycerol kinase alpha (DGKalpha), an important regulator of many cellular events through its conversion of diacylglycerol to phosphatidic acid. We found that DGKalpha was transported from the cytoplasm to the nucleus in response to serum starvation, and serum restoration induced the nuclear export of the enzyme to the cytoplasm. This serum induced export involves two tyrosine kinases, c-Src and c-Abl. The latter, c-Abl, is activated by c-Src, phosphorylates DGKalpha, and shuttles between the nucleus and the cytoplasm in a direction opposite to that of DGKalpha in response to serum restoration. Moreover, an in vitro phosphorylation assay using purified mutants of DGKalpha identified Tyr-218 as a site of phosphorylation by c-Abl. We confirmed these results for endogenous DGKalpha using an antibody specific for phospho-Tyr-218, and this phosphorylation was necessary for the serum-induced export of DGKalpha. These results demonstrate that the nucleo-cytoplasmic shuttling of DGKalpha is orchestrated by tyrosine phosphorylation by the Src activated tyrosine kinase c-Abl and that this phosphorylation is important for regulating the function of cytoplasmic and/or nuclear DGKalpha. PMID- 22199357 TI - Cytoplasmic Metadherin (MTDH) provides survival advantage under conditions of stress by acting as RNA-binding protein. AB - Overexpression of metadherin (MTDH) has been documented in many solid tumors and is implicated in metastasis and chemoresistance. MTDH has been detected at the plasma membrane as well as in the cytoplasm and nucleus, and the function of MTDH in these locales remains under investigation. In the nucleus, MTDH acts as a transcription co-factor to induce expression of chemoresistance-associated genes. However, MTDH is predominantly cytoplasmic in prostate tumors, and this localization correlates with poor prognosis. Herein, we used endometrial cancer cells as a model system to define a new role for MTDH in the cytoplasm. First, MTDH was primarily localized to the cytoplasm in endometrial cancer cells, and the N-terminal region of MTDH was required to maintain cytoplasmic localization. Next, we identified novel binding partners for cytoplasmic MTDH, including RNA binding proteins and components of the RNA-induced silencing complex. Nucleic acids were required for the association of MTDH with these cytoplasmic proteins. Furthermore, MTDH interacted with and regulated protein expression of multiple mRNAs, such as PDCD10 and KDM6A. Depletion of cytoplasmic MTDH was associated with increased stress granule formation, reduced survival in response to chemotherapy and the tyrosine kinase inhibitor BIBF1120, Rad51 nuclear accumulation, and cell cycle arrest at G(2)/M. Finally, in vivo tumor formation was abrogated with knockdown of cytoplasmic MTDH. Taken together, our data identify a novel function for cytoplasmic MTDH as an RNA-binding protein. Our findings implicate cytoplasmic MTDH in cell survival and broad drug resistance via association with RNA and RNA-binding proteins. PMID- 22199358 TI - Tissue inhibitor of metalloproteinases (TIMP-1), genetic markers of insulin resistance and cardiomyopathy in patients with kidney failure. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is a major cardiovascular (CV) complication in patients with kidney failure, and an association between polymorphisms in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene, a genetic marker of insulin resistance, and LVH and Left ventricular (LV) concentric remodelling has been recently documented in these patients. Aims. Since myocardial fibrosis is a prominent feature in LVH induced by insulin resistance, we tested the hypothesis that the interaction between ENPP1 rs1974201 and rs9402349 polymorphisms and the tissue inhibitor of metalloproteinases (TIMP 1)--a pro-fibrotic protein which inhibits extracellular matrix degradation--is implicated in concentric LVH and diastolic dysfunction in a cohort of 223 dialysis patients. RESULTS: Both ENPP1 polymorphisms rs1974201 and rs9402349 were in Hardy-Weinberg equilibrium in dialysis patients. In an analysis stratified by ENPP1, rs1974201 polymorphism, circulating levels of TIMP-1 in GG patients were coherently associated with two markers of concentric remodelling [relative wall thickness (RWT) and LV mass-to-volume ratio] as well as with a marker of diastolic dysfunction (E/A ratio) (P ranging from 0.005 to 0.02), whereas no such associations existed in CC or CG patients. These observations suggest that the rs1974201 modifies the relationship between TIMP-1 and LV geometry and diastolic dysfunction. Accordingly, in a multiple regression model, an identical increase of TIMP-1 (100 ng/mL) was associated with an increase of 22% in RWT, 14% in LV mass-to-volume ratio and 29% in E/A ratio in GG patients but with almost no change (from -0.22 to -3.78%) in these echocardiographic indices in the remaining patients (P for the effect modification <= 0.024). The rs9402349 did not modify the relationship between TIMP-1 and LV geometry and function. CONCLUSIONS: In dialysis patients, the ENPP1 rs1974201 polymorphism modifies the association between TIMP-1 and LV geometry and diastolic function. These results are consistent with the hypothesis that insulin resistance is involved not only in LVH but also in myocardial fibrosis, an alteration of primary importance in the high risk of this population. PMID- 22199359 TI - Complete remission in severe lupus nephritis: assessing the rate of loss in proteinuria. AB - BACKGROUND: The prognosis of severe lupus nephritis (SLN) is improved in patients attaining a complete remission (CR). The time to remission ranges from 10 to 16 months with many patients not attaining a CR until after 12 months. We assessed whether the rate of loss in proteinuria (UPro) is predictive of a CR in SLN patients. METHODS: We studied 85 adult patients in the prospective controlled trial of plasmapheresis in SLN (New England Journal of Medicine 1992). All patients had International Society of Nephrology/Renal Pathology Society Class IV+/-Class V lesions. All patients received prednisone and oral cyclophosphamide and 39 patients received plasmapheresis. A CR was defined by a serum creatinine (SCr) of <=1.4 mg/dL and UPro of <=0.33 g/day. The change in UPro in gram per day per week was determined at 3 and 6 months from entry to the study. RESULTS: A CR was attained in 37 patients (44%) by 16+/-14 months. The level of UPro at baseline was similar in CR and no remission (NR) patients (5.5 versus 6.4 g/day), but CR patients had a lower SCr (1.2 versus 2.4, P<0.0001). At 6 months, the rate of change of UPro was higher at (-)0.224 g/day/week in CR patients and (-)0.107 g/day/week in NR patients (P=0.01) and a 50% reduction in UPro was seen in 78% of CR patients but only 42% of NR patients (P=0.009). The time to a CR was <=12 months in 19 patients and >12 months in 18 patients. The baseline SCr was similar among the two groups. However, UPro at baseline was lower in patients with CR in <=12 months (3.9+/-2.7 versus 7.2+/-3.0 g/day, P=0.001) but the proportion of patients with membranous glomerulonephritis was similar (16 versus 22%). The rate of change in UPro at 6 months was similar at (-)0.214 g/day/week in patients with CR <=12 months and (-)0.235 g/day/week in those with CR>12 months (P=0.6). At 6 months, a 50% reduction in UPro was also similar in the two groups (84 versus 72%, P=0.4). Additionally, the rate of change in UPro at 3 and 6 months was similar within each group. CONCLUSIONS: The rate of change in proteinuria at 6 months is significantly greater in patients attaining a CR relative to NR patients but similar in patients with a CR in <=12 months or >12 months. Thus, the rate of loss of UPro at 6 months may help in predicting which patients will attain a CR. PMID- 22199360 TI - Decreased prevalence and incidence of HCV markers in haemodialysis units. PMID- 22199361 TI - Death-associated protein 6 (Daxx) mediates cAMP-dependent stimulation of Cyp11a1 (P450scc) transcription. AB - SF-1 is a key transcription factor for all steroidogenic genes. It up-regulates the expression of the steroidogenic Cyp11a1 gene in the adrenal in a pathway stimulated by cAMP through HIPK3-mediated JNK/c-Jun phosphorylation. In the present study, we have investigated the factors mediating cAMP-dependent HIPK3 action to potentiate the activity of SF-1 for Cyp11a1 transcription in mouse adrenocortical Y1 cells. We found Daxx, a HIPK kinase substrate in the apoptosis pathway, was phosphorylated by HIPK3 at Ser-669 in response to cAMP stimulation. Daxx participated in SF-1-dependent Cyp11a1 expression as shown by experiments involving both overexpression and down-regulation via a dominant negative Daxx mutant. The S669A mutant of Daxx, which could not be phosphorylated by HIPK3, lost the ability to potentiate SF-1 activity for Cyp11a1 expression. The enhancement of SF-1 activity by Daxx required JNK and c-Jun phosphorylation. Thus, Daxx functioned as a signal transducer linking cAMP-stimulated HIPK3 activity with JNK/c-Jun phosphorylation and SF-1-dependent Cyp11a1 transcription for steroid synthesis. PMID- 22199363 TI - Assessment of three conventional automated external defibrillators in seafaring telemedicine. AB - BACKGROUND: Germany was the first country worldwide to issue a directive regulating the provision of automated external defibrillators (AEDs) on board merchant ships. AIMS: To test the applicability and suitability for telemedicine in seafaring, including long-term electrocardiogram (ECG) monitoring, of three currently available AEDs. METHODS: Sixty nautical officers were asked to record and transmit a one-lead ECG with one of three AEDs under test. Subsequently, they evaluated the user-friendliness of the devices. RESULTS: The number of steps required for ECG transmission (as a pdf file) varied from three to six between the various AEDs. Correspondingly, differences were found in the subjects' understanding of the AED software. After theoretical instruction in the use of the AEDs, 55 officers (92%) succeeded in telemedical transmission of the pdf file without any help. At the time of our investigation, long-term ECG monitoring was possible with only one of the AEDs. CONCLUSIONS: The study results suggest that most trained lay rescuers can use conventional AEDs effectively for ECG transmission. PMID- 22199362 TI - Essential role of ELOVL4 protein in very long chain fatty acid synthesis and retinal function. AB - Very long chain polyunsaturated fatty acid (VLC-PUFA)-containing glycerophospholipids are highly enriched in the retina; however, details regarding the specific synthesis and function of these highly unusual retinal glycerophospholipids are lacking. Elongation of very long chain fatty acids-4 (ELOVL4) has been identified as a fatty acid elongase protein involved in the synthesis of VLC-PUFAs. Mutations in ELOVL4 have also been implicated in an autosomal dominant form of Stargardt disease (STGD3), a type of juvenile macular degeneration. We have generated photoreceptor-specific conditional knock-out mice and used high performance liquid chromatography-mass spectrometry (HPLC-MS) to examine and analyze the fatty acid composition of retinal membrane glycerophosphatidylcholine and glycerophosphatidylethanolamine species. We also used immunofluorescent staining and histology coupled with electrophysiological data to assess retinal morphology and visual response. The conditional knock-out mice showed a significant decrease in retinal glycerophospholipids containing VLC PUFAs, specifically contained in the sn-1 position of glycerophosphatidylcholine, implicating the role of Elovl4 in their synthesis. Conditional knock-out mice were also found to have abnormal accumulation of lipid droplets and lipofuscin like granules while demonstrating photoreceptor-specific abnormalities in visual response, indicating the critical role of Elovl4 for proper rod or cone photoreceptor function. Altogether, this study demonstrates the essential role of ELOVL4 in VLC-PUFA synthesis and retinal function. PMID- 22199364 TI - Cardiorespiratory fitness selection standard and occupational outcomes in trainee firefighters. AB - BACKGROUND: UK fire services have differing practices relating to the use of a cardiorespiratory fitness standard as a selection criterion for recruits. AIMS: To establish whether a reduction in, or elimination of, a defined cardiorespiratory standard for firefighter recruitment impacted on a number of occupational and health-related outcomes. METHODS: Data were collected on firefighter recruits from services which applied either a minimum recruit cardiorespiratory fitness standard of 42 ml O(2)/kg/min (398 full-time and 48 part-time recruits) or no such direct standard (198 full-time and 206 part-time subjects). VO(2) max estimated, where available, was also recorded and the impact of a reduction in the standard from 45 to 42 ml O(2)/kg/min assessed. RESULTS: Twenty-five per cent of all recruits reported injury during training. Injury related restrictions were more likely where no cardiorespiratory standard was applied for full-time recruits. For part-time recruits, higher VO(2) max (est.) predicted a lower incidence of injuries. Further adverse health-related outcomes were found for full-time and part-time recruits. Multiple regression analyses suggest that eliminating the 42 ml O(2)/kg/min cardiorespiratory standard at recruitment for full-time firefighters was associated with an 8% (95% CI 7.16 8.84) increase in subsequent injuries reported during training. For part-time firefighters, VO(2) max (est.) was inversely associated with 5% of the variation in injuries (95% CI 4.66-5.34). CONCLUSIONS: Removal of a cardiorespiratory fitness standard was associated with adverse health and employment outcomes. Older age and gender were not associated with adverse outcomes. No reliable evidence of adverse outcomes from a reduction in a cardiorespiratory standard from 45 to 42 ml O(2)/kg/min was found. PMID- 22199365 TI - Sensitization and irritant-induced occupational asthma with latency are clinically indistinguishable. AB - BACKGROUND: Acute irritant exposures at work are well-recognized causes of asthma. In the occupational setting, low-dose exposure to the same agent does not provoke asthma. Occupational asthma (OA) with latency due to irritants is not widely accepted. AIMS: To compare workers with OA with latency likely to be due to irritant exposures with workers with the more usual sensitization-induced OA. METHODS: Following identification of a worker who fulfils all the criteria for irritant-induced OA with latency whose investigation documented lime dust as a cause for his OA, we searched the Shield reporting scheme database between 1989 and 2010 for entries where the OA was more likely to be due to irritant than allergic mechanisms and compared these with the remainder where allergic mechanisms were likely. Outcome measures were latent interval from first exposure to first work-related symptom, non-specific bronchial reactivity, smoking, atopy and the presence of pre-existing asthma. RESULTS: A previously fit lecturer teaching bricklaying had irritant-induced OA with latency without unusual exposures with an immediate asthmatic reaction following exposure to a sand/lime mixture (pH 8). The Shield database identified 127 workers with likely irritant induced asthma with latency and 1646 with hypersensitivity-induced OA. The two groups were indistinguishable in terms of pre-existing asthma, atopy, age, latent interval, non-specific reactivity and smoking. CONCLUSIONS: Irritant exposure is a cause of OA with latency currently clinically indistinguishable from OA due to sensitization. PMID- 22199366 TI - Evaluation of direct workers' compensation costs for musculoskeletal injuries surrounding interventions to reduce patient lifting. AB - OBJECTIVES: We evaluated costs for workers' compensation (WC) injuries of a musculoskeletal (MS) nature in a large tertiary care hospital and an affiliated community hospital in the 13 years surrounding an institution-wide shift to a 'minimal manual patient-lifting environment' supported with inpatient mechanical lift equipment. METHODS: Negative binomial regression was used to model adjusted and discounted payment rates based on full-time equivalents (FTEs), and payment ratios. The risk of higher cost was assessed based on type of injury (patient handling vs non-patient-handling), hospital, job, age, gender, institutional tenure and time since the implementation of lift equipment. Lagging was used to evaluate the latency of the intervention effect. RESULTS: Patient-handling injuries (n=1543) were responsible for 72% of MS injuries and 53% of compensation costs among patient care staff. Mean costs per claim were 5 times higher for those over age 45 than those <25 years of age. Physical and occupational therapy aides had the highest cost rates ($578/FTE) followed by nursing aides ($347/FTE) and patient transporters ($185/FTE). There was an immediate, marked decline in mean costs per claim and costs per FTE following the policy change and delivery of lift equipment. CONCLUSIONS: The observed patterns of changes in cost likely reflect the effects of activities other than use of lift equipment, including targeted efforts to close WC claims and an almost simultaneous policy that shifted cost responsibility to the budgets of managers on individual units. Inference was facilitated through the use of longitudinal data on the workgroups and an internal injury comparison. PMID- 22199368 TI - Vascular incorporation of endothelial colony-forming cells is essential for functional recovery of murine ischemic tissue following cell therapy. AB - OBJECTIVE: Cord blood-derived human endothelial colony-forming cells (ECFCs) bear a high proliferative capacity and potently enhance tissue neovascularization in vivo. Here, we investigated whether the leading mechanism for the functional improvement relates to their physical vascular incorporation or perivascular paracrine effects and whether the effects can be further enhanced by dual-cell based therapy, including mesenchymal stem cells (MSCs). METHODS AND RESULTS: ECFCs or MSCs were lentivirally transduced with thymidine kinase suicide gene driven by the endothelial-specific vascular endothelial growth factor 2 (kinase insert domain receptor) promoter and evaluated in a hindlimb ischemia model. ECFCs and MSCs enhanced neovascularization after ischemic events to a similar extent. Dual therapy using ECFCs and MSCs further enhanced neovascularization. Mechanistically, 3 weeks after induction of ischemia followed by cell therapy, ganciclovir-mediated elimination of kinase insert domain receptor(+) cells completely reversed the therapeutic effect of ECFCs but not that of MSCs. Histological analysis revealed that ganciclovir effectively eliminated ECFCs incorporated into the vasculature. CONCLUSIONS: Endothelial-specific suicide gene technology demonstrates distinct mechanisms for ECFCs and MSCs, with complete abolishment of ECFC-mediated effects, whereas MSC-mediated effects remained unaffected. These data strengthen the notion that a dual-cell-based therapy represents a promising approach for vascular regeneration of ischemic tissue. PMID- 22199367 TI - Mitochondrial oxidative stress in aortic stiffening with age: the role of smooth muscle cell function. AB - OBJECTIVE: Age-related aortic stiffness is an independent risk factor for cardiovascular diseases. Although oxidative stress is implicated in aortic stiffness, the underlying molecular mechanisms remain unelucidated. Here, we examined the source of oxidative stress in aging and its effect on smooth muscle cell (SMC) function and aortic compliance using mutant mouse models. METHODS AND RESULTS: Pulse wave velocity, determined using Doppler, increased with age in superoxide dismutase 2 (SOD2)+/- but not in wild-type, p47phox-/- and SOD1+/- mice. Echocardiography showed impaired cardiac function in these mice. Increased collagen I expression, impaired elastic lamellae integrity, and increased medial SMC apoptosis were observed in the aortic wall of aged SOD2+/- versus wild-type (16-month-old) mice. Aortic SMCs from aged SOD2+/- mice showed increased collagen I and decreased elastin expression, increased matrix metalloproteinase-2 expression and activity, and increased sensitivity to staurosporine-induced apoptosis versus aged wild-type and young (4-month-old) SOD2+/- mice. Smooth muscle alpha-actin levels were increased with age in SOD2+/- versus wild-type SMCs. Aged SOD2+/- SMCs had attenuated insulin-like growth factor-1-induced Akt and Forkhead box O3a phosphorylation and prolonged tumor necrosis factor-alpha induced Jun N-terminal kinase 1 activation. Aged SOD2+/- SMCs had increased mitochondrial superoxide but decreased hydrogen peroxide levels. Finally, dominant-negative Forkhead box O3a overexpression attenuated staurosporine induced apoptosis in aged SOD2+/- SMCs. CONCLUSION: Mitochondrial oxidative stress over a lifetime causes aortic stiffening, in part by inducing vascular wall remodeling, intrinsic changes in SMC stiffness, and aortic SMC apoptosis. PMID- 22199369 TI - Short telomere length, myocardial infarction, ischemic heart disease, and early death. AB - OBJECTIVE: We tested the hypothesis that short telomere length is associated with increased risk of myocardial infarction, ischemic heart disease, and early death. METHODS AND RESULTS: We measured leukocyte telomere length in 2 prospective studies of 19 838 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 19 years for incident myocardial infarction (n=929), ischemic heart disease (n=2038), and death (n=4342). Follow-up was 100% complete. Telomere length decreased linearly with increasing age in women and men in both studies (P=7*10(-74) to P=3*10(-125)). Multifactorially adjusted hazard ratios were 1.10 (95% CI 1.01-1.19) for myocardial infarction, 1.06 (1.00-1.11) for ischemic heart disease, and 1.09 (1.05-1.13) for early death per 1000-base pair decrease in telomere length. The multifactorially adjusted hazard ratios for the shortest versus the longest decile of telomere length were 1.49 (1.07-2.07) for myocardial infarction, 1.24 (1.01-1.53) for ischemic heart disease, and 1.25 (1.07-1.46) for early death. CONCLUSION: Short telomere length is associated with only modestly increased risk of myocardial infarction, ischemic heart disease, and early death. PMID- 22199370 TI - Matrix metalloproteinase-2 proteolysis of calponin-1 contributes to vascular hypocontractility in endotoxemic rats. AB - OBJECTIVE: Matrix metalloproteinase (MMP)-2 is activated in aorta during endotoxemia and plays a role in the hypocontractility to vasoconstrictors. Calponin-1 is a regulator of vascular smooth muscle tone with similarities to troponin, a cardiac myocyte protein that is cleaved by MMP-2 in myocardial oxidative stress injuries. We hypothesized that calponin-1 may be proteolyzed by MMP-2 in endotoxemia-induced vascular hypocontractility. METHODS AND RESULTS: Rats were given a nonlethal dose of bacterial lipopolysaccharide (LPS) or vehicle. Some rats were given the MMP inhibitors ONO-4817 or doxycycline. Six hours later, plasma nitrate+nitrite increased >15-fold in LPS-treated rats, an effect unchanged by doxycycline. Both ONO-4817 and doxycycline prevented LPS induced aortic hypocontractility to phenylephrine. LPS activated MMP-2 in the aorta by S-glutathiolation. Calponin-1 levels decreased by 25% in endotoxemic aortae, which was prevented by doxycycline. Calponin-1 and MMP-2 coimmunoprecipitated and both exhibited uniform cytosolic staining in medial vascular smooth muscle cells. In vitro incubation of calponin-1 with MMP-2 led to calponin-1 degradation and appearance of its cleavage product. CONCLUSION: Calponin-1 is a target of MMP-2, which contributes to endotoxemia-induced vascular hypocontractility. PMID- 22199372 TI - Insights into Maize LEA proteins: from proteomics to functional approaches. AB - LEA (late embryogenesis abundant) proteins participate in plant stress tolerance responses, but the mechanisms by which protection occurs are not fully understood. In the present work the unfolded proteins from maize dry embryos were analyzed by mass spectrometry. Twenty embryo proteins were identified, and among them 13 corresponded to LEA-type proteins. We selected three major LEA proteins, Emb564, Rab17 and Mlg3, belonging to groups 1, 2 and 3, respectively, and we undertook a comparative study in order to highlight differences among them. The post-translational modifications of native proteins were analyzed and the anti aggregation properties of recombinant Emb564, Rab17 and Mgl3 proteins were evaluated in vitro. In addition, the protective effects of the LEA proteins were assessed in living cells under stress in Escherichia coli cells and in Nicotiana bentamiana leaves agroinfiltrated with fluorescent LEA-green fluorescent protein (GFP) fusions. Protein visualization by confocal microscopy indicated that cells expressing Mg3-GFP showed reduced cell shrinkage effects during dehydration and that Rab17-GFP co-localized to leaf oil bodies after heat shock. Overall, the results highlight differences and suggest functional diversity among maize LEA groups. PMID- 22199371 TI - Accelerated atherosclerosis in Apoe-/- mice heterozygous for the insulin receptor and the insulin receptor substrate-1. AB - OBJECTIVE: Prediabetic states are associated with accelerated atherosclerosis, but the availability of mouse models to study connections between these diseases has been limited. The aim of this study was to test the selective role of impaired insulin receptor/insulin receptor substrate-1 signaling on atherogenesis. METHODS AND RESULTS: To address the effects of impaired insulin signaling associated with hyperinsulinemia on atherosclerosis in the absence of obesity and hyperglycemia, we generated insulin receptor (Insr)/insulin receptor substrate-1 (Insr1) double heterozygous apolipoprotein (Apoe)-knockout mice (Insr(+/-)Irs1(+/-)Apoe(-/-)) mice. Insr(+/-)Irs1(+/-)Apoe(-/-) mice fed a Western diet for 15 weeks showed elevated levels of fasting insulin compared to Insr(+/+)Irs1(+/+)Apoe(-/-) mice. There were no significant differences in glucose, triglyceride, HDL, VLDL, cholesterol levels or free fatty acid in the plasma of Insr(+/-)Irs1(+/-)Apoe(-/-) and Insr(+/+)Irs1(+/+)Apoe(-/-) mice. Atherosclerotic lesions were increased in male (brachiocephalic artery) and female (aortic tree) Insr(+/-)Irs1(+/-)Apoe(-/-) compared to Insr(+/+)Irs1(+/+)Apoe(-/-) mice. Bone marrow transfer experiments demonstrated that nonhematopoietic cells have to be Insr(+/-)Irs1(+/-) to accelerate atherosclerosis. Impaired insulin signaling resulted in decreased levels of vascular phospho-eNOS, attenuated endothelium-dependent vasorelaxation and elevated VCAM-1 expression in aortas of Insr(+/-)Irs1(+/-)Apoe(-/-) mice. In addition, phospho-ERK and vascular smooth muscle cell proliferation were significantly elevated in aortas of Insr(+/-)Irs1(+/-)Apoe(-/-) mice. CONCLUSIONS: These results demonstrate that defective insulin signaling is involved in accelerated atherosclerosis in Insr(+/-)Irs1(+/-)Apoe(-/-) mice by promoting vascular dysfunction and inflammation. PMID- 22199373 TI - Structural and functional studies of casein kinase I-like protein from rice. AB - Casein kinase I (CKI) is a protein serine/threonine kinase that is highly conserved from plants to animals. It performs various functions in both the cytoplasm and nucleus, such as DNA repair, cell cycle, cytokinesis, vesicular trafficking, morphogenesis and circadian rhythm. CKI proteins contain a highly conserved kinase domain responsible for catalytic activity at the N-terminus and a highly diverse regulatory domain responsible for determining substrate specificity at the C-terminus. CKI-like protein has been identified in plants, including in rice, but its function and structure have not been reported. Here, we report the 2.0 A crystal structure of the kinase domain of CKI-like protein from rice. Although the structure adopts the typical bi-lobal kinase architecture, the length and orientation of the glycine-rich ATP-binding motif are dynamic within the CKI family. A loop between alpha5 and alpha6 (the alpha5 alpha6 loop), which was previously not detected in the CKI family because of flexibility, was clearly detected in our structure. In addition, we identified a lipase as a substrate of CKI-like protein from rice. Phosphorylation of the lipase dramatically reduced its catalytic activity, suggesting that CKI may play a role in the regulation of lipase activity. PMID- 22199374 TI - Ethylene's role in phosphate starvation signaling: more than just a root growth regulator. AB - Phosphate (Pi) is a common limiter of plant growth due to its low availability in most soils. Plants have evolved elaborate mechanisms for sensing Pi deficiency and for initiating adaptive responses to low Pi conditions. Pi signaling pathways are modulated by both local and long-distance, or systemic, sensing mechanisms. Local sensing of low Pi initiates major root developmental changes aimed at enhancing Pi acquisition, whereas systemic sensing governs pathways that modulate expression of numerous genes encoding factors involved in Pi transport and distribution. The gaseous phytohormone ethylene has been shown to play an integral role in regulating local, root developmental responses to Pi deficiency. Comparatively, a role for ethylene in systemic Pi signaling has been more circumstantial. However, recent studies have revealed that ethylene acts to modulate a number of systemically controlled Pi starvation responses. Herein we highlight the findings from these studies and offer a model for how ethylene biosynthesis and responsiveness are integrated into both local and systemic Pi signaling pathways. PMID- 22199375 TI - Graduate training in immunology. PMID- 22199376 TI - Pathogen comparative genomics in the next-generation sequencing era: genome alignments, pangenomics and metagenomics. AB - As soon as whole-genome sequencing entered the scene in the mid-1990s and demonstrated its use in revealing the entire genetic potential of any given microbial organism, this technique immediately revolutionized the way pathogen (and many other fields of) research was carried out. The ability to perform whole genome comparisons further transformed the field and allowed scientists to obtain information linking phenotypic dissimilarities among closely related organisms and their underlying genetic mechanisms. Such comparisons have become commonplace in examining strain-to-strain variability, as well as comparing pathogens to less, or nonpathogenic near neighbors. In recent years, a bloom in novel sequencing technologies along with continuous increases in throughput has occurred, inundating the field with various types of massively parallel sequencing data and further transforming comparative genomics research. Here, we review the evolution of comparative genomics, its impact in understanding pathogen evolution and physiology and the opportunities and challenges presented by next-generation sequencing as applied to pathogen genome comparisons. PMID- 22199377 TI - Applications of system-level models of metabolism for analysis of bacterial physiology and identification of new drug targets. AB - For nearly all of the 20th century, biologists gained considerable insights into the fundamental principles of cellular dynamics by examining select modules of biochemical processes. This form of analysis provides detailed information about the workings of the examined pathways. However, any attempt to alter the normal function of bacteria (perhaps for industrial or medicinal goals) requires a detailed global understanding of cellular mechanisms. The reductionist mode of analysis cannot provide the required information for developing the needed perspective on the complex interactions of biochemical pathways. Thankfully, the increasing availability of microbial genomic, transcriptomic, proteomic and other high-throughput data permits system-level analyses of microbiology. During the past two decades, systems biologists have developed constraint-based genome-scale models (GSM) of metabolism for a variety of pathogens. These models are important tools for assessing the metabolic capabilities of various genotypes. Simultaneously, new computational methods have been developed that use these network reconstructions to answer an array of important immunological questions. The objective of this article is to briefly review some of the uses of GSMs for studying bacterial metabolism under different conditions and to discuss how the calculated solutions can be used for rational design of drugs. PMID- 22199378 TI - Generic framework for high-dimensional fixed-effects ANOVA. AB - In functional genomics it is more rule than exception that experimental designs are used to generate the data. The samples of the resulting data sets are thus organized according to this design and for each sample many biochemical compounds are measured, e.g. typically thousands of gene-expressions or hundreds of metabolites. This results in high-dimensional data sets with an underlying experimental design. Several methods have recently become available for analyzing such data while utilizing the underlying design. We review these methods by putting them in a unifying and general framework to facilitate understanding the (dis-)similarities between the methods. The biological question dictates which method to use and the framework allows for building new methods to accommodate a range of such biological questions. The framework is built on well known fixed effect ANOVA models and subsequent dimension reduction. We present the framework both in matrix algebra as well as in more insightful geometrical terms. We show the workings of the different special cases of our framework with a real-life metabolomics example from nutritional research and a gene-expression example from the field of virology. PMID- 22199379 TI - Hawkeye and AMOS: visualizing and assessing the quality of genome assemblies. AB - Since its launch in 2004, the open-source AMOS project has released several innovative DNA sequence analysis applications including: Hawkeye, a visual analytics tool for inspecting the structure of genome assemblies; the Assembly Forensics and FRCurve pipelines for systematically evaluating the quality of a genome assembly; and AMOScmp, the first comparative genome assembler. These applications have been used to assemble and analyze dozens of genomes ranging in complexity from simple microbial species through mammalian genomes. Recent efforts have been focused on enhancing support for new data characteristics brought on by second- and now third-generation sequencing. This review describes the major components of AMOS in light of these challenges, with an emphasis on methods for assessing assembly quality and the visual analytics capabilities of Hawkeye. These interactive graphical aspects are essential for navigating and understanding the complexities of a genome assembly, from the overall genome structure down to individual bases. Hawkeye and AMOS are available open source at http://amos.sourceforge.net. PMID- 22199380 TI - Probe mapping across multiple microarray platforms. AB - Access to gene expression data has become increasingly common in recent years; however, analysis has become more difficult as it is often desirable to integrate data from different platforms. Probe mapping across microarray platforms is the first and most crucial step for data integration. In this article, we systematically review and compare different approaches to map probes across seven platforms from different vendors: U95A, U133A and U133 Plus 2.0 from Affymetrix, Inc.; HT-12 v1, HT-12v2 and HT-12v3 from Illumina, Inc.; and 4112A from Agilent, Inc. We use a unique data set, which contains 56 lung cancer cell line samples each of which has been measured by two different microarray platforms-to evaluate the consistency of expression measurement across platforms using different approaches. Based on the evaluation from the empirical data set, the BLAST alignment of the probe sequences to a recent revision of the Transcriptome generated better results than using annotations provided by Vendors or from Bioconductor's Annotate package. However, a combination of all three methods (deemed the 'Consensus Annotation') yielded the most consistent expression measurement across platforms. To facilitate data integration across microarray platforms for the research community, we develop a user-friendly web-based tool, an API and an R package to map data across different microarray platforms from Affymetrix, Illumina and Agilent. Information on all three can be found at http://qbrc.swmed.edu/software/probemapper/. PMID- 22199381 TI - htSeqTools: high-throughput sequencing quality control, processing and visualization in R. AB - We provide a Bioconductor package with quality assessment, processing and visualization tools for high-throughput sequencing data, with emphasis in ChIP seq and RNA-seq studies. It includes detection of outliers and biases, inefficient immuno-precipitation and overamplification artifacts, de novo identification of read-rich genomic regions and visualization of the location and coverage of genomic region lists. AVAILABILITY: www.bioconductor.org. PMID- 22199382 TI - Modeling mechanistic biological networks: an advanced Boolean approach. AB - MOTIVATION: The understanding of the molecular sources for diseases like cancer can be significantly improved by computational models. Recently, Boolean networks have become very popular for modeling signaling and regulatory networks. However, such models rely on a set of Boolean functions that are in general not known. Unfortunately, while detailed information on the molecular interactions becomes available in large scale through electronic databases, the information on the Boolean functions does not become available simultaneously and has to be included manually into the models, if at all known. RESULTS: We propose a new Boolean approach which can directly utilize the mechanistic network information available through modern databases. The Boolean function is implicitly defined by the reaction mechanisms. Special care has been taken for the treatment of kinetic features like inhibition. The method has been applied to a signaling model combining the Wnt and MAPK pathway. AVAILABILITY: A sample C++ implementation of the proposed method is available for Linux and compatible systems through http://code.google.com/p/libscopes/wiki/Paper2011. PMID- 22199383 TI - Fast large-scale clustering of protein structures using Gauss integrals. AB - MOTIVATION: Clustering protein structures is an important task in structural bioinformatics. De novo structure prediction, for example, often involves a clustering step for finding the best prediction. Other applications include assigning proteins to fold families and analyzing molecular dynamics trajectories. RESULTS: We present Pleiades, a novel approach to clustering protein structures with a rigorous mathematical underpinning. The method approximates clustering based on the root mean square deviation by first mapping structures to Gauss integral vectors--which were introduced by Rogen and co workers--and subsequently performing K-means clustering. CONCLUSIONS: Compared to current methods, Pleiades dramatically improves on the time needed to perform clustering, and can cluster a significantly larger number of structures, while providing state-of-the-art results. The number of low energy structures generated in a typical folding study, which is in the order of 50,000 structures, can be clustered within seconds to minutes. PMID- 22199384 TI - MeQA: a pipeline for MeDIP-seq data quality assessment and analysis. AB - MOTIVATION: We present a pipeline for the pre-processing, quality assessment, read distribution and methylation estimation for methylated DNA immunoprecipitation (MeDIP)-sequence datasets. This is the first MeDIP-seq specific analytic pipeline that starts at the output of the sequencers. This pipeline will reduce the data analysis load on staff and allows the easy and straightforward analysis of sequencing data for DNA methylation. The pipeline integrates customized scripting and several existing tools, which can deal with both paired and single end data. AVAILABILITY: The package and extensive documentation, and comparison to public data is available at http://life.tongji.edu.cn/meqa/. PMID- 22199385 TI - LaTcOm: a web server for visualizing rare codon clusters in coding sequences. AB - We present LaTcOm, a new web tool, which offers several alternative methods for 'rare codon cluster' (RCC) identification from a single and simple graphical user interface. In the current version, three RCC detection schemes are implemented: the recently described %MinMax algorithm and a simplified sliding window approach, along with a novel modification of a linear-time algorithm for the detection of maximally scoring subsequences tailored to the RCC detection problem. Among a number of user tunable parameters, several codon-based scales relevant for RCC detection are available, including tRNA abundance values from Escherichia coli and several codon usage tables from a selection of genomes. Furthermore, useful scale transformations may be performed upon user request (e.g. linear, sigmoid). Users may choose to visualize RCC positions within the submitted sequences either with graphical representations or in textual form for further processing. AVAILABILITY: LaTcOm is freely available online at the URL http://troodos.biol.ucy.ac.cy/latcom.html. PMID- 22199386 TI - Optimal structural inference of signaling pathways from unordered and overlapping gene sets. AB - MOTIVATION: A plethora of bioinformatics analysis has led to the discovery of numerous gene sets, which can be interpreted as discrete measurements emitted from latent signaling pathways. Their potential to infer signaling pathway structures, however, has not been sufficiently exploited. Existing methods accommodating discrete data do not explicitly consider signal cascading mechanisms that characterize a signaling pathway. Novel computational methods are thus needed to fully utilize gene sets and broaden the scope from focusing only on pairwise interactions to the more general cascading events in the inference of signaling pathway structures. RESULTS: We propose a gene set based simulated annealing (SA) algorithm for the reconstruction of signaling pathway structures. A signaling pathway structure is a directed graph containing up to a few hundred nodes and many overlapping signal cascades, where each cascade represents a chain of molecular interactions from the cell surface to the nucleus. Gene sets in our context refer to discrete sets of genes participating in signal cascades, the basic building blocks of a signaling pathway, with no prior information about gene orderings in the cascades. From a compendium of gene sets related to a pathway, SA aims to search for signal cascades that characterize the optimal signaling pathway structure. In the search process, the extent of overlap among signal cascades is used to measure the optimality of a structure. Throughout, we treat gene sets as random samples from a first-order Markov chain model. We evaluated the performance of SA in three case studies. In the first study conducted on 83 KEGG pathways, SA demonstrated a significantly better performance than Bayesian network methods. Since both SA and Bayesian network methods accommodate discrete data, use a 'search and score' network learning strategy and output a directed network, they can be compared in terms of performance and computational time. In the second study, we compared SA and Bayesian network methods using four benchmark datasets from DREAM. In our final study, we showcased two context-specific signaling pathways activated in breast cancer. AVAILABILITY: Source codes are available from http://dl.dropbox.com/u/16000775/sa_sc.zip. PMID- 22199387 TI - CLARE: Cracking the LAnguage of Regulatory Elements. AB - CLARE is a computational method designed to reveal sequence encryption of tissue specific regulatory elements. Starting with a set of regulatory elements known to be active in a particular tissue/process, it learns the sequence code of the input set and builds a predictive model from features specific to those elements. The resulting model can then be applied to user-supplied genomic regions to identify novel candidate regulatory elements. CLARE's model also provides a detailed analysis of transcription factors that most likely bind to the elements, making it an invaluable tool for understanding mechanisms of tissue-specific gene regulation. AVAILABILITY: CLARE is freely accessible at http://clare.dcode.org/. PMID- 22199388 TI - Artemis: an integrated platform for visualization and analysis of high-throughput sequence-based experimental data. AB - MOTIVATION: High-throughput sequencing (HTS) technologies have made low-cost sequencing of large numbers of samples commonplace. An explosion in the type, not just number, of sequencing experiments has also taken place including genome re sequencing, population-scale variation detection, whole transcriptome sequencing and genome-wide analysis of protein-bound nucleic acids. RESULTS: We present Artemis as a tool for integrated visualization and computational analysis of different types of HTS datasets in the context of a reference genome and its corresponding annotation. AVAILABILITY: Artemis is freely available (under a GPL licence) for download (for MacOSX, UNIX and Windows) at the Wellcome Trust Sanger Institute websites: http://www.sanger.ac.uk/resources/software/artemis/. PMID- 22199389 TI - PathVisio-Validator: a rule-based validation plugin for graphical pathway notations. AB - PURPOSE: The PathVisio-Validator plugin aims to simplify the task of producing biological pathway diagrams that follow graphical standardized notations, such as Molecular Interaction Maps or the Systems Biology Graphical Notation. This plugin assists in the creation of pathway diagrams by ensuring correct usage of a notation, and thereby reducing ambiguity when diagrams are shared among biologists. Rulesets, needed in the validation process, can be generated for any graphical notation that a developer desires, using either Schematron or Groovy. The plugin also provides support for filtering validation results, validating on a subset of rules, and distinguishing errors and warnings. PMID- 22199390 TI - PIE the search: searching PubMed literature for protein interaction information. AB - MOTIVATION: Finding protein-protein interaction (PPI) information from literature is challenging but an important issue. However, keyword search in PubMed((r)) is often time consuming because it requires a series of actions that refine keywords and browse search results until it reaches a goal. Due to the rapid growth of biomedical literature, it has become more difficult for biologists and curators to locate PPI information quickly. Therefore, a tool for prioritizing PPI informative articles can be a useful assistant for finding this PPI-relevant information. RESULTS: PIE (Protein Interaction information Extraction) the search is a web service implementing a competition-winning approach utilizing word and syntactic analyses by machine learning techniques. For easy user access, PIE the search provides a PubMed-like search environment, but the output is the list of articles prioritized by PPI confidence scores. By obtaining PPI-related articles at high rank, researchers can more easily find the up-to-date PPI information, which cannot be found in manually curated PPI databases. AVAILABILITY: http://www.ncbi.nlm.nih.gov/IRET/PIE/. PMID- 22199391 TI - Measuring the distance between multiple sequence alignments. AB - MOTIVATION: Multiple sequence alignment (MSA) is a core method in bioinformatics. The accuracy of such alignments may influence the success of downstream analyses such as phylogenetic inference, protein structure prediction, and functional prediction. The importance of MSA has lead to the proliferation of MSA methods, with different objective functions and heuristics to search for the optimal MSA. Different methods of inferring MSAs produce different results in all but the most trivial cases. By measuring the differences between inferred alignments, we may be able to develop an understanding of how these differences (i) relate to the objective functions and heuristics used in MSA methods, and (ii) affect downstream analyses. RESULTS: We introduce four metrics to compare MSAs, which include the position in a sequence where a gap occurs or the location on a phylogenetic tree where an insertion or deletion (indel) event occurs. We use both real and synthetic data to explore the information given by these metrics and demonstrate how the different metrics in combination can yield more information about MSA methods and the differences between them. AVAILABILITY: MetAl is a free software implementation of these metrics in Haskell. Source and binaries for Windows, Linux and Mac OS X are available from http://kumiho.smith.man.ac.uk/whelan/software/metal/. PMID- 22199392 TI - ART: a next-generation sequencing read simulator. AB - ART is a set of simulation tools that generate synthetic next-generation sequencing reads. This functionality is essential for testing and benchmarking tools for next-generation sequencing data analysis including read alignment, de novo assembly and genetic variation discovery. ART generates simulated sequencing reads by emulating the sequencing process with built-in, technology-specific read error models and base quality value profiles parameterized empirically in large sequencing datasets. We currently support all three major commercial next generation sequencing platforms: Roche's 454, Illumina's Solexa and Applied Biosystems' SOLiD. ART also allows the flexibility to use customized read error model parameters and quality profiles. AVAILABILITY: Both source and binary software packages are available at http://www.niehs.nih.gov/research/resources/software/art. PMID- 22199393 TI - Read count approach for DNA copy number variants detection. AB - MOTIVATION: The advent of high-throughput sequencing technologies is revolutionizing our ability in discovering and genotyping DNA copy number variants (CNVs). Read count-based approaches are able to detect CNV regions with an unprecedented resolution. Although this computational strategy has been recently introduced in literature, much work has been already done for the preparation, normalization and analysis of this kind of data. RESULTS: Here we face the many aspects that cover the detection of CNVs by using read count approach. We first study the characteristics and systematic biases of read count distributions, focusing on the normalization methods designed for removing these biases. Subsequently, we compare the algorithms designed to detect the boundaries of CNVs and we investigate the ability of read count data to predict the exact number of DNA copy. Finally, we review the tools publicly available for analysing read count data. To better understand the state of the art of read count approaches, we compare the performance of the three most widely used sequencing technologies (Illumina Genome Analyzer, Roche 454 and Life Technologies SOLiD) in all the analyses that we perform. PMID- 22199394 TI - Axenfeld-Rieger syndrome: new perspectives. AB - Axenfeld-Rieger syndrome is a genetic disease affecting multiple organ systems. In the eye, this condition manifests with varying degrees of anterior segment dysgenesis and carries a high risk of glaucoma. Other associated systemic issues include cardiovascular outflow tract malformations, craniofacial abnormalities and pituitary abnormalities, which can result in severe endocrinological sequelae. Recent advances in molecular genetics have identified two major genes, PITX2 and FOXC1, demonstrating a wide spectrum of mutations, which aids in the molecular diagnosis of the disease, although evidence exists to implicate other loci in this condition. The management of individuals affected by Axenfeld-Rieger syndrome requires a multidisciplinary approach and would include dedicated surveillance and management of glaucoma, sensorineural hearing loss, and cardiac, endocrinological, craniofacial and orthopaedic abnormalities. PMID- 22199395 TI - Teasing out the role of ATP in immune responses. See referenced article, J. Biol. Chem. 2011, 286, 44776-44787. Real-time imaging reveals that P2Y2 and P2Y12 receptor agonists are not chemoattractants and macrophage chemotaxis to complement C5a is phosphatidylinositol 3-kinase (PI3K)- and p38 mitogen-activated protein kinase (MAPK)-independent. PMID- 22199396 TI - Discovering environmental causes of disease. AB - Although chronic diseases are primarily environmental (ie, not genetic) in origin, the particular environmental causes of these diseases are poorly understood. A WHO study of worldwide cancer mortality identified nine diverse environmental factors, including pollution, diet, lifestyle factors and infections. However, the joint effect of these nine factors accounted for only about one-third of cancer mortality, indicating that about two-thirds are of unknown aetiology. One problem relates to the community of epidemiologists, which sorts environmental factors into marginally overlapping domains, thereby creating gaps in coverage. Also, information about environmental exposures in epidemiologic studies is generally derived from questionnaires that are ill suited for assessing thousands of potentially causative exposures. Finally, the few studies that rigorously estimate exposure levels focus upon a handful of pollutants of regulatory importance and thus are unsuited for finding hitherto unrecognised exposures from both exogenous and endogenous sources. The concept of the 'exposome'-representing the totality of exposures from gestation onwards-has recently been introduced as a complement to the genome in studies of disease aetiology. The exposome concept promotes environmental analogues of genome-wide association studies, which employ untargeted omic methods to compare biospecimens from diseased and healthy subjects. The goal of such investigations is to discover key biomarkers of exposure that enable follow-up hypotheses to be explored regarding sources of exposure, dose-response relationships, mechanisms of action, disease causality and public health interventions. Examples of this approach are cited from recent metabolomic studies of several complex chronic diseases. PMID- 22199397 TI - THE NEW U. S. IMMIGRANTS: HOW DO THEY AFFECT OUR UNDERSTANDING OF THE AFRICAN AMERICAN EXPERIENCE? AB - The implications of recent immigration for race relations in the United States depend importantly on family cultural orientations among Mexican Americans and how this group is culturally perceived by Anglos. Because Moynihan's 1965 work (in)famously emphasized the need to change black family culture in order to ameliorate black poverty, his work still holds implications for understanding how cultural orientations affect changing color lines. Unfortunately, his partially insightful analyses inadequately foresaw that policies designed to alleviate poverty through the modification of family cultural patterns are likely to fail without parallel changes in structural opportunities. Similar limitations also often emerge from mis-characterizations of Mexican origin family cultural situations, which all too often are incongruously reified as either being unduly familistic (thus falsely implying Mexican origin families foster self sufficiency) or largely governed by culture of poverty tendencies (thus inaccurately suggesting Mexican origin families depend on welfare). Here we review research suggesting that Mexican origin families are neither substantially familistic nor disproportionately susceptible to moral hazard, thus indicating that future Mexican origin economic advancement is likely to turn on the availability of structural opportunities. In-depth interviews with Anglos further suggest that Mexicans are not culturally viewed with the same degree of prejudice and discrimination as blacks, implying that the integration of Mexicans into American society, contingent on adequate economic opportunity, will probably progress more steadily than often feared, while that of blacks may proceed more slowly than often expected. PMID- 22199398 TI - Nonmarital Childbearing, Union History, and Women's Health at Midlife. AB - Despite high rates of nonmarital childbearing in the U.S., little is known about the health of women who have nonmarital births. We use data from the NLSY79 to examine differences in age 40 self-assessed health between women who had a premarital birth and those whose first birth occurred within marriage. We then differentiate women with a premarital first birth according to their subsequent union histories and estimate the effect of marrying or cohabiting versus remaining never-married on midlife self-assessed health, paying particular attention to the paternity status of the mother's partner and the stability of marital unions. To partially address selection bias, we employ multivariate propensity score techniques. Results suggest that premarital childbearing is negatively associated with midlife health for white and black (but not Hispanic) women. We find no evidence that these negative health consequences of nonmarital childbearing are mitigated by either marriage or cohabitation for black women. For other women, only enduring marriage to the biological father is associated with better health than remaining unpartnered. PMID- 22199399 TI - Social Environmental Variation, Plasticity Genes, and Aggression: Evidence for the Differential Susceptibility Hypothesis. AB - Although G*E studies are typically based on the assumption that some individuals possess genetic variants that enhance their vulnerability to environmental adversity, the differential susceptibility perspective posits that these individuals are simply more susceptible to environmental influence than others. An important implication of this model is that those persons most vulnerable to adverse social environments are the same ones who reap the most benefit from environmental support. The present study tested several implications of this proposition. Using longitudinal data from a sample of several hundred African Americans, we found that relatively common variants of the dopamine receptor gene and the serotonin transporter gene interact with social environmental conditions to predict aggression in a manner consonant with differential susceptibility. When the social environment was adverse, individuals with these genetic variants manifested more aggression than other genotypes, whereas when the environment was supportive they demonstrated less aggression than other genotypes. Further, we found that these genetic variants interact with environmental conditions to foster various cognitive schemas and emotions in a manner consistent with differential susceptibility and that a latent construct formed by these schemas and emotions mediated the effect of gene by environment interaction on aggression. PMID- 22199400 TI - The LaueUtil toolkit for Laue photocrystallography. I. Rapid orientation matrix determination for intermediate-size-unit-cell Laue data. AB - A new method for determination of the orientation matrix of Laue X-ray data is presented. The method is based on matching of the experimental patterns of central reciprocal lattice rows projected on a unit sphere centered on the origin of the reciprocal lattice with the corresponding pattern of a monochromatic data set on the same material. This technique is applied to the complete data set and thus eliminates problems often encountered when single frames with a limited number of peaks are to be used for orientation matrix determination. Application of the method to a series of Laue data sets on organometallic crystals is described. The corresponding program is available under a Mozilla Public License like open-source license. PMID- 22199401 TI - iotbx.cif: a comprehensive CIF toolbox. AB - iotbx.cif is a new software module for the development of applications that make use of the CIF format. Comprehensive tools are provided for input, output and validation of CIFs, as well as for interconversion with high-level cctbx [Grosse Kunstleve, Sauter, Moriarty & Adams (2002). J. Appl. Cryst.35, 126-136] crystallographic objects. The interface to the library is written in Python, whilst parsing is carried out using a compiled parser, combining the performance of a compiled language (C++) with the benefits of using an interpreted language. PMID- 22199402 TI - Who Lacks Support and Why? An Examination of Mothers' Personal Safety Nets. AB - We use data from the Fragile Families and Child Wellbeing Study (N = 12,140 person-waves) to identify characteristics associated with mothers' having or lacking "personal safety net" support from family and friends. We focus on characteristics that are likely to increase the importance of having support available but may also interfere with the maintenance of supportive ties: poverty, poor physical and mental health, and challenging child rearing responsibilities. By capitalizing on distinctions among these types of personal disadvantages and among types of personal safety nets (financial, housing, child care, and emotional), we help to explain why personal disadvantages are associated with weaker support. Our paper contributes to the literature emphasizing the importance of reciprocity in support relationships and introduces the idea that families that are more difficult to help will have less support available. PMID- 22199403 TI - TOO MANY MEN? SEX RATIOS AND WOMEN'S PARTNERING BEHAVIOR IN CHINA. AB - The relative numbers of women and men are changing dramatically in China, but the consequences of these imbalanced sex ratios have received little attention. We merge data from the Chinese Health and Family Life Survey with community-level data from Chinese censuses to examine the relationship between cohort- and community-specific sex ratios and women's partnering behavior. Consistent with demographic-opportunity theory and sociocultural theory, we find that high sex ratios (indicating more men relative to women) are associated with an increased likelihood that women marry before age 25. However, high sex ratios are also associated with an increased likelihood that women engage in premarital and extramarital sexual relationships and have had more than one sexual partner, findings consistent with demographic-opportunity theory but inconsistent with sociocultural theory. PMID- 22199404 TI - Double Couplings of Dibromothiophenes using Boronic Acids and Boronates. AB - One-pot double couplings of dibromothiophenes have been investigated. Standard Suzuki couplings work well for 2,4-dibromothiophene, but are much more sensitive to steric effects in the case of 2,3-dibromothiophene. By using the recently reported potassium borates, though, good yields for both dibromothiophene isomers can be achieved. PMID- 22199405 TI - Design and synthesis of a potential SH2 domain inhibitor bearing a stereodiversified 1,4-cis-enediol scaffold. AB - Synthesis of a potential Src family SH2 domain inhibitor incorporating a 1,4-cis enediol scaffold is reported. The synthetic route offers straightforward and highly selective access to the enediol and its associated chiral centers. Key steps include stereocontrolled syn-aldol coupling, amide alkynylation, and asymmetric ketone reduction. PMID- 22199406 TI - Design, synthesis, and biological evaluation of estrone-derived hedgehog signaling inhibitors. AB - The design, synthesis and biological evaluation of new analogs of the naturally occurring compound cyclopamine, a Hedgehog signaling inhibitor, are described. Stucture-activity relationship studies lead to an evolving model for the pharmacophore of this medically promising compound class of anti-cancer chemotherapeutic agents. PMID- 22199407 TI - Synthesis of the C21-C34 fragment of antascomicin B. AB - The C21-C34 fragment of the potent FKBP12-binding macrolide antascomicin B was prepared using Ireland-Claisen and allylic diazene rearrangements to establish the C26/C27 and the C23 stereocenters, respectively. Directed hydrogenation installed the C29 beta-configuration. The fragment possesses 7 of the 11 fixed stereocenters contained in the natural product. PMID- 22199408 TI - Parallel Solid-Phase Synthesis of disubstituted 3-(1H-benzo[d]imidazol-2 yl)imidazolidine-2,4-diones and 3-(1H-benzo[d]imidazol-2-yl)-2-thioxoimidazolidin 4-ones. AB - A multistep approach to construct novel 3-(1H-benzo[d]imidazol-2-yl)imidazolidine 2,4-diones and 3-(1H-benzo[d]imidazol-2-yl)-2-thioxoimidazolidin-4-ones from commercially available amino acids, amines, and carboxylic acids is described. Coupling of Fmoc-amino acid to resin-bound aminobenzimidazole provided following Fmoc elimination free amine. Treatment of the free amine with 1,1' carbonyldiimidazole or 1,1'-thiocarbonyldiimidazole furnished the corresponding hydantoins and thiohydantoins via intramolecular cyclization. The desired aminobenzimidazole tethered hydantoin or thiohydantoins were isolated in good yields. PMID- 22199409 TI - Implementation of the Communities That Care Prevention System by Coalitions in the Community Youth Development Study. AB - While advances in prevention science over the past 2 decades have produced a growing list of tested and effective programs and policies for preventing adolescent delinquency and drug use, widespread dissemination and high-quality implementation of effective programs and policies in communities has not been achieved. The Community Youth Development Study (CYDS) is a randomized, community level trial of the Communities That Care (CTC) system for promoting science-based prevention in communities. This paper compares 12 community prevention coalitions implementing the CTC system in 12 intervention communities as part of the CYDS to prevention coalitions located in the 12 control communities. As hypothesized, the CYDS coalitions implemented significantly more of the CTC core intervention elements, and also implemented significantly greater numbers of tested, effective prevention programs than the prevention coalitions in the control communities. Implications of the findings for efforts to achieve widespread dissemination of effective prevention programs, policies, and practices are discussed. PMID- 22199410 TI - Effect of Immigrant Nurses on Labor Market Outcomes of US Nurses. AB - We study the effect of immigration of foreign-trained, registered nurses (RNs) on the employment and wages of US-trained RNs. We use the "area" approach and study effects of immigration in labor markets defined by the state. We find substantial evidence that immigration by foreign-trained nurses increases the supply of nurses and that this increase in supply is associated with a decrease in annual earnings. Estimates suggest that a 10 percent increase in supply due to immigration is associated with a one to four percent decrease in annual earnings. PMID- 22199411 TI - The North Atlantic Population Project: Progress and Prospects. AB - The North Atlantic Population Project (NAPP) is a massive database of historical census microdata from European and North American countries. The backbone of the project is the unique collection of completely digitized censuses providing information on the entire enumerated populations of each country. In addition, for some countries, the NAPP includes sample data from surrounding census years. In this article, the authors provide a brief history of the project, describe their progress to data and plans for the future, and discuss some potential implications of this unique data resource for social and economic research. PMID- 22199412 TI - Hierarchical spatio-temporal extraction of models for moving rigid parts. AB - This paper presents a method to extract a part-based model of an observed scene from a video sequence. Independent motion is a strong cue that two points belong to different "rigid" entities. Conversely, things that move together throughout the whole video belong together and define a "rigid" object or part. Successfully tracked features indicate trajectories of salient points in the scene. A triangulated graph connects the salient points and encodes their local neighborhood in the first frame. The length variation of the triangle edges is used to label them as relevant (on an object) or separating (connecting different objects). A following grouping process uses the motion of the triangles marked as relevant as a cue to identify the "rigid" parts of the foreground or the background. The choice of the motion-based grouping criterion depends on the type of motion: in the image plane or out of the image plane. The result is a hierarchical description (graph pyramid) of the scene, where each vertex in the top level of the pyramid represents a "rigid" part of the foreground or the background, and encloses to the salient features used to describe it. Promising experimental results show the potential of the approach. PMID- 22199413 TI - A matching algorithm for the distribution of human pancreatic islets. AB - The success of human pancreatic islet transplantation in a subset of type 1 diabetic patients has led to an increased demand for this tissue in both clinical and basic research, yet the availability of such preparations is limited and the quality highly variable. Under the current process of islet distribution for basic science experimentation nationwide, specialized laboratories attempt to distribute islets to one or more scientists based on a list of known investigators. This Local Decision Making (LDM) process has been found to be ineffective and suboptimal. To alleviate these problems, a computerized Matching Algorithm for Islet Distribution (MAID) was developed to better match the functional, morphological, and quality characteristics of islet preparations to the criteria desired by basic research laboratories, i.e. requesters. The algorithm searches for an optimal combination of requesters using detailed screening, sorting, and search procedures. When applied to a data set of 68 human islet preparations distributed by the Islet Cell Resource (ICR) Center Consortium, MAID reduced the number of requesters that a) did not receive any islets, and b) received mis-matched shipments. These results suggest that MAID is an improved more efficient approach to the centralized distribution of human islets within a consortium setting. PMID- 22199414 TI - 3D printing in X-ray and Gamma-Ray Imaging: A novel method for fabricating high density imaging apertures. AB - Advances in 3D rapid-prototyping printers, 3D modeling software, and casting techniques allow for cost-effective fabrication of custom components in gamma-ray and X-ray imaging systems. Applications extend to new fabrication methods for custom collimators, pinholes, calibration and resolution phantoms, mounting and shielding components, and imaging apertures. Details of the fabrication process for these components, specifically the 3D printing process, cold casting with a tungsten epoxy, and lost-wax casting in platinum are presented. PMID- 22199415 TI - Electrophysiological Evidence for Use of the Animacy Hierarchy, but not Thematic Role Assignment, During Verb Argument Processing. AB - Animacy is known to play an important role in language processing and production, but debate remains as to how it exerts its effects: 1) through links to syntactic ordering, 2) through inherent differences between animate and inanimate entities in their salience/lexico-semantic accessibility, 3) through links to specific thematic roles. We contrasted these three accounts in two event related potential (ERP) experiments examining the processing of direct object arguments in simple English sentences. In Experiment 1, we found a larger N400 to animate than inanimate direct object arguments assigned the Patient role, ruling out the second account. In Experiment 2 we found no difference in the N400 evoked by animate direct object arguments assigned the Patient role (prototypically inanimate) and those assigned the Experiencer role (prototypically animate), ruling out the third account. We therefore suggest that animacy may impact processing through a direct link to syntactic linear ordering, at least on post verbal arguments in English. We also examined processing on direct object arguments that violated the animacy-based selection restriction constraints of their preceding verbs. These violations evoked a robust P600, which was not modulated by thematic role assignment or reversibility, suggesting that the so called semantic P600 is driven by overall propositional impossibility, rather than thematic role reanalysis. PMID- 22199416 TI - Positive Traits Linked to Less Pain through Lower Pain Catastrophizing. AB - The present study examined the association between positive traits, pain catastrophizing, and pain perceptions. We hypothesized that pain catastrophizing would mediate the relationship between positive traits and pain. First, participants (n = 114) completed the Trait Hope Scale, the Life Orientation Test- Revised, and the Pain Catastrophizing Scale. Participants then completed the experimental pain stimulus, a cold pressor task, by submerging their hand in a circulating water bath (0o Celsius) for as long as tolerable. Immediately following the task, participants completed the Short-Form McGill Pain Questionnaire (MPQ-SF). Pearson correlation found associations between hope and pain catastrophizing (r = -.41, p < .01) and MPQ-SF scores (r = -.20, p < .05). Optimism was significantly associated with pain catastrophizing (r = -.44, p < .01) and MPQ-SF scores (r = -.19, p < .05). Bootstrapping, a non-parametric resampling procedure, tested for mediation and supported our hypothesis that pain catastrophizing mediated the relationship between positive traits and MPQ-SF pain report. To our knowledge, this investigation is the first to establish that the protective link between positive traits and experimental pain operates through lower pain catastrophizing. PMID- 22199417 TI - Dissociations Between Fluency And Agrammatism In Primary Progressive Aphasia. AB - BACKGROUND: Classical aphasiology, based on the study of stroke sequelae, fuses speech fluency and grammatical ability. Nonfluent (Broca's) aphasia often is accompanied by agrammatism; whereas in the fluent aphasias grammatical deficits are not typical. The assumption that a similar relationship exists in primary progressive aphasia (PPA) has led to the dichotomization of this syndrome into fluent and nonfluent subtypes. AIMS: This study compared elements of fluency and grammatical production in the narrative speech of individuals with PPA to determine if they can be dissociated from one another. METHOD: Speech samples from 37 individuals with PPA, clinically assigned to agrammatic (N=11), logopenic (N=20) and semantic (N=6) subtypes, and 13 cognitively healthy control participants telling the "Cinderella Story" were analyzed for fluency (i.e., words per minute (WPM) and mean length of utterance in words (MLU-W)) and grammaticality (i.e., the proportion of grammatically correct sentences, open-to closed-class word ratio, noun-to-verb ratio, and correct production of verb inflection, noun morphology, and verb argument structure.) Between group differences were analyzed for each variable. Correlational analyses examined the relation between WPM and each grammatical variable, and an off-line measure of sentence production. OUTCOMES AND RESULTS: Agrammatic and logopenic groups both had lower scores on the fluency measures and produced significantly fewer grammatical sentences than did semantic and control groups. However, only the agrammatic group evinced significantly impaired production of verb inflection and verb argument structure. In addition, some semantic participants showed abnormal open-to-closed and noun-to-verb ratios in narrative speech. When the sample was divided on the basis of fluency, all the agrammatic participants fell in the nonfluent category. The logopenic participants varied in fluency but those with low fluency showed variable performance on measures of grammaticality. Correlational analyses and scatter plots comparing fluency and each grammatical variable revealed dissociations within PPA participants, with some nonfluent participants showing normal grammatical skill. CONCLUSIONS: Grammatical production is a complex construct comprised of correct usage of several language components, each of which can be selectively affected by disease. This study demonstrates that individuals with PPA show dissociations between fluency and grammatical production in narrative speech. Grammatical ability, and its relationship to fluency, varies from individual to individual, and from one variant of PPA to another, and can even be found in individuals with semantic PPA in whom a fluent aphasia is usually thought to accompany preserved ability to produce grammatical utterances. PMID- 22199418 TI - Behavioral Parent Training: Is There an "App" for That? PMID- 22199419 TI - Little things can be big diagnostic clues: 6 illustrative cases. PMID- 22199420 TI - Don't blame the patient! PMID- 22199421 TI - Heterogeneity of left ventricular signal characteristics in response to acute vagal stimulation during ventricular fibrillation in dogs. AB - Studies have shown that long-term vagal stimulation is protective against ventricular fibrillation; however, the effects of acute vagal stimulation during ventricular fibrillation in the normal heart have not been investigated. We examined the effects of acute vagal stimulation on ventricular fibrillation in a canine model. In 4 dogs, we induced 30-second periods of ventricular fibrillation by means of intraventricular pacing. During 2 of the 4 periods of fibrillation that we analyzed, vagal stimulation was delivered through electrodes in the caudal ends of the vagus nerves. Noncontact unipolar electrograms were recorded from 3 ventricular regions: the basal septum, apical septum, and lateral free wall. We then computed the most frequent cycle length, mean organization index, and mean electrogram amplitude for each region. During fibrillation, vagal stimulation shortened the most frequent cycle lengths in the basal septum (P=0.02) and apical septum (P=0.0001), but not in the lateral wall (P=0.46). In addition, vagal stimulation significantly reduced the mean organization indices in the apical septum (P <0.001) and lateral wall (P <0.001), but not in the basal septum (P=0.19). Furthermore, vagal stimulation raised the mean electrogram amplitude in the basal septum (P <0.01) but lowered it substantially in the apical septum (P=0.00005) and lateral wall (P=0.00003). We conclude that vagal stimulation acutely affects the characteristics of ventricular fibrillation in canine myocardium in a spatially heterogeneous manner. This nonuniformity of response may have implications with regard to manipulating the autonomic system as a means of modifying the substrate for ventricular dysrhythmias. PMID- 22199422 TI - Central venous pressure and pulmonary capillary wedge pressure: fresh clinical perspectives from a new model of discordant and concordant heart failure. AB - Heart-failure phenotypes include pulmonary and systemic venous congestion. Traditional heart-failure classification systems include the Forrester hemodynamic subsets, which use 2 indices: pulmonary capillary wedge pressure (PCWP) and cardiac index. We hypothesized that changes in PCWP and central venous pressure (CVP), and in the phenotypes of heart failure, might be better evaluated by cardiovascular modeling. Therefore, we developed a lumped-parameter cardiovascular model and analyzed forms of heart failure in which the right and left ventricles failed disproportionately (discordant ventricular failure) versus equally (concordant failure). At least 10 modeling analyses were carried out to the equilibrium state. Acute discordant pump failure was characterized by a "passive" volume movement, with fluid accumulation and pressure elevation in the circuit upstream of the failed pump. In biventricular failure, less volume was mobilized. These findings negate the prevalent teaching that pulmonary congestion in left ventricular failure results primarily from the "backing up" of elevated left ventricular filling pressure. They also reveal a limitation of the Forrester classification: that PCWP and cardiac index are not independent indices of circulation. Herein, we propose a system for classifying heart-failure phenotypes on the basis of discordant or concordant heart failure. A surrogate marker, PCWP CVP separation, in a simplified situation without complex valvular or pulmonary disease, shows that discordant left and right ventricular failures are characterized by differences of >= 4 and <= 0 mmHg, respectively. We validated the proposed model and classification system by using published data on patients with acute and chronic heart failure. PMID- 22199423 TI - Surgical treatment of isolated right-sided infective endocarditis. AB - We reviewed our department's experience with the perioperative features and surgical treatment of isolated right-sided infective endocarditis. From January 2000 through July 2010, 35 patients underwent surgery for isolated right-sided infective endocarditis in our department. The mean pathologic course was 3.6 months. Preoperative transthoracic echocardiography had revealed intracardiac vegetations in all 35 patients: the tricuspid valve was involved in 28, and preoperative cultures were positive in 31. The median follow-up time was 5.8 years, and the follow-up rate was 85.3%. All the operations were performed with the patients on cardiopulmonary bypass, with or without cardiac arrest. All concomitant congenital heart defects were repaired, and vegetations and foreign materials were removed as part of intensive debridement of the infected area. After vegetation removal, 4 tricuspid valve replacements with tissue valves and 24 tricuspid valve reconstructions were performed. One patient who underwent tricuspid valve replacement died of uncontrollable infection and multiple-organ failure. Two patients required mechanical ventilation for more than 1 week, and 3 needed dialysis for acute renal failure. Of the excised vegetations, 31.4% were positive for microorganisms. Of the patients who underwent tricuspid valvuloplasty, 23 had no valvular incompetence and 11 had mild or moderate regurgitation before discharge from the hospital. During follow-up, no patient needed reoperation because of reinfection, and 1 underwent reoperation for severe tricuspid regurgitation. We conclude that surgery can yield satisfactory immediate and midterm results in the treatment of isolated right-sided infective endocarditis. PMID- 22199426 TI - Endovascular repair of aortoesophageal and aortobronchial fistulae. PMID- 22199424 TI - Prehypertension: a meta-analysis of the epidemiology, risk factors, and predictors of progression. AB - We investigated the prevalence and risk factors of prehypertension, as well as the predictors of progression from prehypertension to hypertension. To do this, we performed a systematic review and meta-analysis of cross-sectional and longitudinal studies, after unrestricted searches of PubMed and The Cochrane Library through September 2010. In addition, we reviewed references, major textbooks, and review articles. Pooled prevalence, standardized mean differences, and odds ratios were estimated by using a random-effects model. Twenty-six articles met our inclusion criteria; these included 20 cross-sectional and 6 longitudinal studies, with a total sample of 250,741 individuals. The overall pooled prevalence of prehypertension was 36%. The pooled prevalence among males was higher than that among females (40% vs 33%). The pooled standardized mean difference for body mass index was 1.37 (95% confidence interval [CI], 1.20 1.55); for total cholesterol, 8.08 (95% CI, 6.71-9.46); for low-density lipoprotein cholesterol, 5.14 (95% CI, 3.09-7.18); and for fasting plasma glucose, 4.23 (95% CI, 3.28-5.18); all of which showed more significant results in females. The pooled odds ratio was 1.13 (95% CI, 0.93-1.37) for smoking and 0.98 (95% CI, 0.69-1.39) for drinking. In addition, factors such as older age at baseline, male sex, Mongolian race, and being overweight or obese were predictors of progression to hypertension, according to descriptive analysis. The prevalence of prehypertension was relatively high, especially for males. There were many modifiable risk factors associated with prehypertension, to which healthcare providers should pay more attention. PMID- 22199427 TI - When stent-grafts fail: extraction and open surgical repair of the thoracic aorta. PMID- 22199428 TI - Valve-sparing root replacement: where are the limits? PMID- 22199429 TI - Aggressive aortic replacement for Loeys-Dietz syndrome. PMID- 22199430 TI - Surgical treatment of endocarditis: current status. PMID- 22199431 TI - Reoperative cardiac surgery: challenges and outcomes. PMID- 22199432 TI - Replacement of the proximal arch: should it be routine in patients with bicuspid aortic valve and ascending aneurysms? AB - Multiple lines of evidence establish a relationship between BAV and proximal aortic aneurysms. Emerging indications and techniques are leading to a more standardized surgical approach to these patients. In the individual patient, however, one must use judgment to determine the best approach on the basis of several factors, including age, comorbidities, extent of concomitant surgery, and the expected risk of subsequent complications. PMID- 22199433 TI - Cerebral perfusion in aortic arch surgery: antegrade, retrograde, or both? PMID- 22199434 TI - Future perspectives in minimally invasive cardiac surgery. PMID- 22199435 TI - Reoperative repair of the aortic root and ascending aorta. PMID- 22199436 TI - Intraoperative conversion after surgical failure: an overlooked complication of aortic root replacement in Marfan patients? PMID- 22199437 TI - Hybrid repair of aortic aneurysms and dissections: the European perspective. PMID- 22199438 TI - Robotic cardiac surgery by 2031. PMID- 22199439 TI - Aortic dissection: a 250-year perspective. AB - Two hundred fifty years have passed since Frank Nicholls' history-making, accurate observations on the anatomic findings and cause of death of King George II were published. Several decades later, the disease was named, using--for the first time--the terms dissection and dissecting attached to an aortic disease process. Another century went by before effective surgical treatment was developed. In sharp contrast, the evolution of the last 20 years has been nothing short of amazing. Our understanding of AD, while not yet complete, has improved dramatically. In addition, the introduction of nonsurgical endovascular therapy has had a profoundly transformative impact--and we are just at the beginning! It would not be unreasonable to predict that stent-graft repair will likely replace (or nearly replace) open surgery in the treatment of complicated type B dissection in the near future, especially as technologies continue to improve and indication-specific designs are developed and tested in the clinical setting. Moreover, it is predictable that endovascular solutions for some patients with type A aortic dissection will become available in the years to come as surgical results continue to be suboptimal. Finally, and amidst this plethora of "good news," it is appropriate to reflect on the formidable challenge that endovascular therapies face as they gear to "compete" with optimal medical therapy in the management of patients with acute uncomplicated type B dissection, because it will obviously be difficult (if not impossible) to improve on the already achieved 30-day mortality rate of less than 10%. Long-term gains may well become the winning card when and if the late results of TEVAR can be shown to improve on the rather compromised outlook of medically treated dissection patients. Stay tuned. PMID- 22199440 TI - Minimally invasive mitral valve surgery without aortic cross-clamping. PMID- 22199441 TI - Can we predict mitral valve repair rates by individual surgeons' mitral volume? PMID- 22199442 TI - Adult congenital heart disease: past, present, and future. PMID- 22199443 TI - Update on lung cancer screening: it works? PMID- 22199445 TI - Inflammatory pseudothrombus on a patent foramen ovale occluder device. AB - Herein, we describe late complications after the transcatheter device closure of a patent foramen ovale in a patient with migraine headaches. The clinical presentation included acute neurologic symptoms and new-onset atrial fibrillation. A mass on the left atrial side of the occluder was surgically removed. Histologic results showed an inflammatory lesion that consisted predominantly of lymphocytes, plasma cells, and macrophages. Despite complete surgical closure and the termination of atrial fibrillation, the patient continued to experience neurologic events. Although transcatheter patent foramen ovale closure is associated with low complication rates, a careful risk-benefit evaluation is warranted in view of the potentially severe complications and the current lack of robust pathophysiologic and clinical trial data to support this therapy in the treatment of migraine headaches. PMID- 22199446 TI - Hypertension, tachycardia, and reversible cardiomyopathy temporally associated with milnacipran use. AB - Elevated catecholamine levels are a well-recognized cause of various types of cardiomyopathy. Causes of catecholamine elevation include tumors, toxins, drugs, emotional stress, and sepsis. Milnacipran is a dual and equipotent inhibitor of norepinephrine and serotonin uptake. It is frequently prescribed as therapy for fibromyalgia, and the drug has a good safety profile. Herein, we report the case of a 42-year-old woman with undefined connective-tissue disease and fibromyalgia who developed a severe and reversible cardiomyopathy while taking recommended doses of milnacipran. The cardiomyopathy was associated with a hyperadrenergic state manifested by tachycardia, hypertension, and elevated plasma catecholamine levels. The discontinuation of milnacipran and the initiation of anti-failure therapy resulted in complete resolution of the cardiomyopathy in 6 months. To our knowledge, this is the first report of milnacipran as a possible cause of catecholamine-induced cardiomyopathy. PMID- 22199448 TI - Hypotension due to dynamic left ventricular outflow tract obstruction after percutaneous coronary intervention. AB - Persistent hypotension subsequent to percutaneous coronary intervention is attributed to access-site bleeding, re-infarction, or mechanical complications either of myocardial infarction or of the procedure itself (for example, pericardial tamponade). Dynamic left ventricular outflow tract obstruction after an uncomplicated percutaneous coronary intervention is an unusual, and to our knowledge not previously reported, complication that manifests itself as hypotension refractory to the usual therapy with inotropic agents. We discuss the clinical course, pathophysiology, diagnosis, and management of hypotension due to left ventricular outflow tract obstruction after percutaneous coronary intervention. Early recognition and accurate diagnosis that determines appropriate therapy will improve the patient's prospects. PMID- 22199447 TI - Large cardiac hydatid cyst in the interventricular septum. AB - Cystic hydatid disease results from infection with the larval or adult form of the Echinococcus granulosus tapeworm. Cardiac involvement is seen in 0.5% to 2% of patients with hydatid disease, and involvement of the interventricular septum is even rarer. Herein, we report our surgical treatment of a large cardiac hydatid cyst in the interventricular septum. A 39-year-old woman presented with dyspnea. Transthoracic echocardiography revealed a large cyst in the apical part of the interventricular septum. Thoracic computed tomography showed a cystic lesion in that site, and magnetic resonance imaging confirmed the presence of a 50 * 55-mm mass. The patient was placed on cardiopulmonary bypass. Hypertonic saline solution-soaked sponges were distributed within the pericardial cavity to prevent local invasion of the parasite intraoperatively. Through an incision parallel to the left anterior descending coronary artery, and without opening adjacent cardiac chambers, we aspirated the entire contents of the cyst, removed its germinative membrane, and washed the cavity with 20% hypertonic saline solution. The patient recovered uneventfully. She had begun taking albendazole 5 days preoperatively, and this therapy was continued for 12 weeks postoperatively. In cases of an interventricular cardiac hydatid cyst, the combination of surgical resection, washout of the remaining cavity with hypertonic saline solution, and albendazole therapy typically yields excellent results. PMID- 22199449 TI - Hemodynamic manifestation of hypertrophic obstructive cardiomyopathy. PMID- 22199450 TI - Aorto-right ventricular fistula after percutaneous aortic valve implantation of a CoreValve prosthesis. PMID- 22199451 TI - Coronary arteriovenous fistula with giant aneurysm treated with surgical removal and coronary artery bypass grafting. PMID- 22199452 TI - Bronchoalveolar lung carcinoma manifesting itself as a swinging heart. PMID- 22199453 TI - Giant primary B-cell lymphoma invading the superior vena cava and right lung. PMID- 22199455 TI - Re: Cardiac surgery: a century of progress. PMID- 22199456 TI - Obstacles to medical professionalism: it's not just Generation X's problem. PMID- 22199458 TI - 1-D ELECTRO-OPTIC BEAM STEERING DEVICE. AB - In this paper, we present the design and fabrication of a 1D beam steering device based on planar electro-optic thermal-plastic prisms and a collimator lens array. With the elimination of moving parts, the proposed device is able to overcome the mechanical limitations of present scanning devices, such as fatigue and low operating frequency, while maintaining a small system footprint (~0.5mm*0.5mm). From experimental data, our prototype device is able to achieve a maximum deflection angle of 5.6 degrees for a single stage prism design and 29.2 degrees for a cascaded three prisms stage design. The lens array shows a 4um collimated beam diameter. PMID- 22199459 TI - Collagen Structural Hierarchy and Susceptibility to Degradation by Ultraviolet Radiation. AB - Collagen type I is the most abundant extracellular matrix protein in the human body, providing the basis for tissue structure and directing cellular functions. Collagen has complex structural hierarchy, organized at different length scales, including the characteristic triple helical feature. In the present study, the relationship between collagen structure (native vs. denatured) and sensitivity to UV radiation was assessed, with a focus on changes in primary structure, changes in conformation, microstructure and material properties. A brief review of free radical reactions involved in collagen degradation is also provided as a mechanistic basis for the changes observed in the study. Structural and functional changes in the collagens were related to the initial conformation (native vs. denatured) and the energy of irradiation. These changes were tracked using SDS-PAGE to assess molecular weight, Fourier transform infrared (FTIR) spectroscopy to study changes in the secondary structure, and atomic force microscopy (AFM) to characterize changes in mechanical properties. The results correlate differences in sensitivity to irradiation with initial collagen structural state: collagen in native conformation vs. heat-treated (denatured) collagen. Changes in collagen were found at all levels of the hierarchical structural organization. In general, the native collagen triple helix is most sensitive to UV-254nm radiation. The triple helix delays single chain degradation. The loss of the triple helix in collagen is accompanied by hydrogen abstraction through free radical mechanisms. The results received suggest that the effects of electromagnetic radiation on biologically relevant extracellular matrices (collagen in the present study) are important to assess in the context of the state of collagen structure. The results have implications in tissue remodeling, wound repair and disease progression. PMID- 22199460 TI - Statistical Inference for Regression Models with Covariate Measurement Error and Auxiliary Information. AB - We consider statistical inference on a regression model in which some covariables are measured with errors together with an auxiliary variable. The proposed estimation for the regression coefficients is based on some estimating equations. This new method alleates some drawbacks of previously proposed estimations. This includes the requirment of undersmoothing the regressor functions over the auxiliary variable, the restriction on other covariables which can be observed exactly, among others. The large sample properties of the proposed estimator are established. We further propose a jackknife estimation, which consists of deleting one estimating equation (instead of one obervation) at a time. We show that the jackknife estimator of the regression coefficients and the estimating equations based estimator are asymptotically equivalent. Simulations show that the jackknife estimator has smaller biases when sample size is small or moderate. In addition, the jackknife estimation can also provide a consistent estimator of the asymptotic covariance matrix, which is robust to the heteroscedasticity. We illustrate these methods by applying them to a real data set from marketing science. PMID- 22199461 TI - ARV Treatment and Time Allocation to Household Tasks: Evidence from Kenya. AB - Using longitudinal survey data collected over a period of two years, this paper examines the impact of antiretroviral (ARV) treatment on the time allocated to various household tasks by treated HIV-positive patients and their household members. We study outcomes such as time devoted to housework, firewood and water collection, as well as care-giving and care-seeking. As treatment improves the health and productivity of patients, we find that female patients in particular are able to increase the amount of time they devote to water and firewood collection. This increased productivity of patients coupled with large decreases in the amount of time they spend seeking medical care leads to a reduced burden on children and other household members. We find evidence that boys and girls in treated patients' households devote less time to housework and other chores. These results suggest that the provision of ARV treatment generates a wide variety of benefits to households in resource-poor settings. PMID- 22199462 TI - ESTIMATING TREATMENT EFFECTS ON HEALTHCARE COSTS UNDER EXOGENEITY: IS THERE A 'MAGIC BULLET'? AB - Methods for estimating average treatment effects, under the assumption of no unmeasured confounders, include regression models; propensity score adjustments using stratification, weighting, or matching; and doubly robust estimators (a combination of both). Researchers continue to debate about the best estimator for outcomes such as health care cost data, as they are usually characterized by an asymmetric distribution and heterogeneous treatment effects,. Challenges in finding the right specifications for regression models are well documented in the literature. Propensity score estimators are proposed as alternatives to overcoming these challenges. Using simulations, we find that in moderate size samples (n= 5000), balancing on propensity scores that are estimated from saturated specifications can balance the covariate means across treatment arms but fails to balance higher-order moments and covariances amongst covariates. Therefore, unlike regression model, even if a formal model for outcomes is not required, propensity score estimators can be inefficient at best and biased at worst for health care cost data. Our simulation study, designed to take a 'proof by contradiction' approach, proves that no one estimator can be considered the best under all data generating processes for outcomes such as costs. The inverse propensity weighted estimator is most likely to be unbiased under alternate data generating processes but is prone to bias under misspecification of the propensity score model and is inefficient compared to an unbiased regression estimator. Our results show that there are no 'magic bullets' when it comes to estimating treatment effects in health care costs. Care should be taken before naively applying any one estimator to estimate average treatment effects in these data. We illustrate the performance of alternative methods in a cost dataset on breast cancer treatment. PMID- 22199463 TI - Neonatal Informatics: Information Technology to Support Handoffs in Neonatal Care. AB - Communication failures during physician handoffs represent a significant source of preventable adverse events. Computerized sign-out tools linked to hospital electronic medical record systems and customized for neonatal care can facilitate standardization of the handoff process and access to clinical information, thereby improving communication and reducing adverse events. It is important to note, however, that adoption of technological tools alone is not sufficient to remedy flawed communication processes. OBJECTIVES: After completing this article, readers should be able to: Identify key elements of a computerized sign-out tool.Describe how an electronic tool might be customized for neonatal care.Appreciate that technological tools are only one component of the handoff process they are designed to facilitate. PMID- 22199464 TI - Spoken Language Derived Measures for Detecting Mild Cognitive Impairment. AB - Spoken responses produced by subjects during neuropsychological exams can provide diagnostic markers beyond exam performance. In particular, characteristics of the spoken language itself can discriminate between subject groups. We present results on the utility of such markers in discriminating between healthy elderly subjects and subjects with mild cognitive impairment (MCI). Given the audio and transcript of a spoken narrative recall task, a range of markers are automatically derived. These markers include speech features such as pause frequency and duration, and many linguistic complexity measures. We examine measures calculated from manually annotated time alignments (of the transcript with the audio) and syntactic parse trees, as well as the same measures calculated from automatic (forced) time alignments and automatic parses. We show statistically significant differences between clinical subject groups for a number of measures. These differences are largely preserved with automation. We then present classification results, and demonstrate a statistically significant improvement in the area under the ROC curve (AUC) when using automatic spoken language derived features in addition to the neuropsychological test scores. Our results indicate that using multiple, complementary measures can aid in automatic detection of MCI. PMID- 22199465 TI - Erratum: N-tert-Butyl-2-methyl-propanamide. Corrigendum. AB - The name of one of the authors in the paper by Kluge et al. [Acta Cryst. (2011), E67, o2143] is corrected.[This corrects the article DOI: 10.1107/S1600536811028947.]. PMID- 22199466 TI - Redetermination of eveite, Mn(2)AsO(4)(OH), based on single-crystal X-ray diffraction data. AB - The crystal structure of eveite, ideally Mn(2)(AsO(4))(OH) [dimanganese(II) arsenate(V) hydroxide], was refined from a single crystal selected from a co-type sample from Langban, Filipstad, Varmland, Sweden. Eveite, dimorphic with sarkinite, is structurally analogous with the important rock-forming mineral andalusite, Al(2)OSiO(4), and belongs to the libethenite group. Its structure consists of chains of edge-sharing distorted [MnO(4)(OH)(2)] octa-hedra (..2 symmetry) extending parallel to [001]. These chains are cross-linked by isolated AsO(4) tetra-hedra (..m symmetry) through corner-sharing, forming channels in which dimers of edge-sharing [MnO(4)(OH)] trigonal bipyramids (..m symmetry) are located. In contrast to the previous refinement from Weissenberg photographic data [Moore & Smyth (1968 ?). Am. Mineral.53, 1841-1845], all non-H atoms were refined with anisotropic displacement param-eters and the H atom was located. The distance of the donor and acceptor O atoms involved in hydrogen bonding is in agreement with Raman spectroscopic data. Examination of the Raman spectra for arsenate minerals in the libethenite group reveals that the position of the peak originating from the O-H stretching vibration shifts to lower wavenumbers from eveite, to adamite, zincolivenite, and olivenite. PMID- 22199467 TI - A sodium calcium arsenate, NaCa(AsO(4)). AB - The title compound, NaCa(AsO(4)), was synthesized using a hydro-thermal method at 633-643 K. It has a dense structure composed of alternating layers of distorted [CaO(6)] octa-hedra and layers of [AsO(4)] tetra-hedra and distorted [NaO(6)] octa-hedra, stacked along the a axis. The As, Ca and two O atoms lie on the mirror plane at y = 1/4 (i.e. 4c), while the Na atom lies on an inversion centre (1/2, 1/2, 0) (i.e. 4b). Each distorted [CaO(6)] octa-hedron shares four equatorial common O vertices with four neighboring octa-hedra, forming a layer parallel to (100), whereas each distorted [NaO(6)] octa-hedron shares two opposite edges with two neighboring ones, forming a chain running along [010]. Each isolated [AsO(4)] tetra-hedron shares two edges with two different [NaO(6)] octa-hedra in one [NaO(6)] chain and a vertex with another chain. Simultaneously the above [AsO(4)] tetra-hedron located in a four-membered [CaO(6)] ring shares one edge of its base facet with one [CaO(6)] octa-hedron and three corners with three other [CaO(6)] octa-hedra of one [CaO(6)] layer, and the remaining apex is shared with another [CaO(6)] layer. [NaO(6)] octa-hedra and [CaO(6)] octa-hedra are linked to each other by sharing edges and vertices. PMID- 22199468 TI - Zirconium(IV) dilanthanum(III) penta-sulfide. AB - Zirconium(IV) dilanthanum(III) penta-sulfide, ZrLa(2)S(5), crystallizes with four formula units in the space group Pnma in the U(3)S(5) structure type. The asymmetric unit comprises one Zr, one La and four S atoms. The Zr and three S atoms are situated on mirror planes. The structure consists of LaS(8) face sharing bicapped distorted trigonal prisms and ZrS(7) edge-sharing monocapped octa-hedra. PMID- 22199469 TI - Scheelite-type sodium neodymium(III) ortho-oxidomolybdate(VI), NaNd[MoO(4)](2). AB - Scheelite-type NaNd[MoO(4)](2) contains one crystallographic position (site symmetry [Formula: see text]) for the large cations, which is mixed-occupied by Na(+) and Nd(3+) cations in a 1:1 molar ratio. Thus, both are surrounded by eight O atoms in the shape of a trigonal dodeca-hedron. Furthermore, the structure consists of crystallographically unique [MoO(4)](2-) units (site symmetry [Formula: see text]) surrounded by eight sodium and neodymium cations, which are all vertex-attached. The polyhedra around the Na(+)/Nd(3+) cations are connected to four others via common edges, building up a three-dimensional network in whose tetra-hedral voids of O atoms the Mo(6+) cations reside. PMID- 22199470 TI - Barium manganese(II) selenostannate(IV), BaMnSnSe(4). AB - The title compound, BaMnSnSe(4), was obtained by reaction of the elements at 1123 K in an evacuated silica tube. It adopts the BaCdSnS(4) structure type, which is a variant of the SrIn(2)Se(4) structure type. Its structure consists of distorted edge-sharing tetra-hedra, alternating with Mn and Sn atoms as central atom. These [MnSnSe(6)] units display corner sharing, forming stacked infinite layers in the ac plane. The three different Ba(2+) atoms are located between the [MnSnSe(6)] layers, two on twofold rotation axes, and exhibit distorted square-antiprismatic coordinations. PMID- 22199471 TI - Lithio-marsturite, LiCa(2)Mn(2)Si(5)O(14)(OH). AB - Lithio-marsturite, ideally LiCa(2)Mn(2)Si(5)O(14)(OH), is a member of the pectolite-pyroxene series of pyroxenoids (hydro-pyroxenoids) and belongs to the rhodonite group. A previous structure determination of this mineral based on triclinic symmetry in space group P[Formula: see text] by Peacor et al. [Am. Mineral. (1990), 75, 409-414] converged with R = 0.18 without reporting any information on atomic coordinates and displacement param-eters. The current study redetermines its structure from a natural specimen from the type locality (Foote mine, North Carolina) based on single-crystal X-ray diffraction data. The crystal structure of lithio-marsturite is characterized by ribbons of edge-sharing CaO(6) and two types of MnO(6) octa-hedra as well as chains of corner-sharing SiO(4) tetra-hedra, both extending along [110]. The octa-hedral ribbons are inter connected by the rather irregular CaO(8) and LiO(6) polyhedra through sharing corners and edges, forming layers parallel to ([Formula: see text]1[Formula: see text]), which are linked together by the silicate chains. Whereas the coordination environments of the Mn and Li cations can be compared to those of the corresponding cations in nambulite, the bonding situations of the Ca cations are more similar to those in babingtonite. In contrast to the hydrogen-bonding scheme in babingtonite, which has one O atom as the hydrogen-bond donor and a second O atom as the hydrogen-bond acceptor, our study shows that the situation is reversed in lithio-marsturite for the same two O atoms, as a consequence of the differences in the bonding environments around O atoms in the two minerals. PMID- 22199472 TI - The matlockite-type praseodymium(III) oxide bromide PrOBr. AB - The crystal structure of the praseodymium(III) oxide bromide, PrOBr, can be best described with layers of agglomerated square anti-prisms [PrO(4)Br(4)](9-). These slabs are stacked along the c axis and linked via two different secondary contacts between Pr(3+) and Br(-). The Pr(3+) cations occupy the Wyckoff site 2c with 4mm symmetry and carry four O(2-) anions as well as four primary Br(-) anions, yielding a coordination number of 8. While the Br(-) anions exhibit the same site symmetry as the Pr(3+) cations, the oxide anions are located at the Wyckoff position 2a with site symmetry [Formula: see text]m2 and have four Pr(3+) cations as neighbours, defining a tetra-hedron. PMID- 22199473 TI - The beta-polymorph of uranium phosphide selenide. AB - beta-UPSe was synthesized from the reaction of U(2)Se(3), P and Se in a CsCl flux in a fused-silica tube. It crystallizes with four formula units in the tetra gonal space group I4/mmm in the UGeTe structure type. The asymmetric unit comprises one U (site symmetry 4mm), one Se (4mm), and one P (mmm.) atom. The U atom is coordinated in a monocapped square-anti-prismatic arrangement, where the square face is formed by P atoms and the other five vertices are Se atoms. The P site is disordered about a mirror plane, showing half-ocupancy for each of the two resulting P atoms. The title structure is related to that of alpha-UPSe, which crystallizes with two formula units in the tetra-gonal space group P4/nmm in the PbFCl structure type. PMID- 22199474 TI - Bis(MU(2)-eta:eta-2,4,6-trimethyl-benzonitrile)-bis-[(N-isopropyl-3,5-dimethyl anilido)molybdenum(III)](Mo-Mo). AB - The title compound, [Mo(2)(C(11)H(16)N)(4)(C(10)H(11)N)(2)], is a dinuclear molybdenum complex with a formal metal-metal bond [Mo?Mo separation = 2.5946 (8) A], four anilide-type ligands and two bridging mesityl nitrile groups. There are two inversion symmetric mol-ecules in the unit cell (an inversion center is localized at the mid-point of the Mo-Mo bond), each with approximate non crystallographic C(2h) symmetry. The mol-ecules contain disordered isopropyl and 3,5-C(6)H(3)Me(2) groups on different anilido ligands; the major component having an occupancy of 0.683 (7). The complex was obtained in low yield as the product from the reaction between the bridging pyrazine adduct of molybdenum tris- anilide ([MU(2)-(C(4)H(4)N(2)){Mo(C(11)H(16)N)(3)}(2)]) and mesityl nitrile with a loss of one anilido ligand. PMID- 22199475 TI - Diaqua-bis-{5-carb-oxy-2-[(1H-1,2,4-triazol-1-yl)meth-yl]-1H-imidazole-4-carboxyl ato}zinc. AB - In the title compound, [Zn(C(8)H(6)N(5)O(4))(2)(H(2)O)(2)], the six-coordinate Zn(II) ion, which is located on an inversion center, has a distorted octa-hedral configuration. Each 5-carb-oxy-2-[(1H-1,2,4-triazol-1-yl)meth-yl]-1H-imidazole-4 carboxyl-ate ligand chelates to the Zn(II) ion through a triazole N atom and a carboxyl-ate O atom in the equatorial plane. The coordination sphere is completed by two water mol-ecules in axial positions. There is an intra-molecular O-H?O hydrogen bond in the ligand. In the crystal, mol-ecules are linked via inter molecular O-H?O, O-H?N and N-H?N hydrogen bonds, forming a three-dimensional structure. PMID- 22199476 TI - Poly[tetra-kis-(MU-benzene-1,2-dicarboxyl-ato)di-MU-formato-penta-strontium(II)]. AB - The asymmetric unit of the title complex, [Sr(5)(C(8)H(4)O(4))(4)(HCO(2))(2)](n), contains three independent Sr(II) ions, one of which is located on an inversion center. In the crystal, the Sr(II) ions (coordination numbers 8, 9 and 12) are connected by two crystallographically distinct benzene-1,2-dicarboxyl-ate ligands and one formate ligand, forming a two-dimensional polymer parallel to (001). PMID- 22199477 TI - 4-Amino-pyridinium trans-diaqua-dioxalatochromate(III) monohydrate. AB - In the non-centrosymmetric structure of the title compound, (C(5)H(7)N(2))[Cr(C(2)O(4))(2)(H(2)O)(2)].H(2)O, the Cr(III) ion has a slightly distorted octa-hedral coordination environment defined by two chelating oxalato ligands in equatorial positions and two water mol-ecules in axial positions. An extensive three-dimensional network of hydrogen bonds involving all the water mol ecules, the 4-amino-pyridinium cation and some of the oxalate O atoms contributes to the stabilization of the structure. pi-pi inter-actions between adjacent pyridine rings provide additional stability of the crystal packing, with a closest distance between pyridine mean planes of 3.613 (1) A. PMID- 22199478 TI - (2,9-Dimethyl-1,10-phenanthroline-kappaN,N')diiodidocadmium. AB - In the title compound, [CdI(2)(C(14)H(12)N(2))], the mol-ecule sits on a crystallographic twofold axis. The coordination sphere of the Cd(II) atom is built of two symmetry-equivalent N atoms of one 2,9-dimethyl-1,10-phenanthroline (dmphen) ligand and two symmetry-equivalent I atoms, thus forming a distorted tetra-hedral geometry. Inversion-related mol-ecules inter-act along the c-axis direction by pi-pi stacking inter-actions between the phenanthroline ring systems, with centroid-centroid distances of 3.707 (9) and 3.597 (10) A. PMID- 22199479 TI - Bis[bis-(2,2'-bipyridine-kappaN,N')chloridocopper(II)] bis-(MU-2,6-pyridine dicarboxyl-ato)-kappaO,N,O:O;kappaO:O,N,O-bis-[aqua-dichloridobismuthate(III)] penta-hydrate. AB - In the title compound, [CuCl(C(10)H(8)N(2))(2)](2)[Bi(2)Cl(4)(C(7)H(3)NO(4))(2)(H(2)O)(2)].5H(2)O, the dianion [Bi(2)Cl(4)(C(7)H(3)NO(4))(2)(H(2)O)(2)](2-) is located about an inversion center. The Cu(II) atom of the cation is coordinated by four N atoms of the two chelating 2,2'-bypyridine ligands and one Cl(-) ion, completing a distorted trigonal-bipyramidal coordination environment. In the anion, each Bi(III) atom is seven-coordinate and is bonded to a tridentate pyridine-2,6 dicarboxyl-ate ligand, a water mol-ecule, two chloride ions and a bridging carboxyl-ate O atom of another carboxyl-ate ligand. The coordination geometry of Bi(III) is distorted penta-gonal-bipyramidal with the Cl(-) ions located in axial positions. The structure of the dianion is additionally stabilized by an intra molecular O-H?O hydrogen bond between the coordinated water mol-ecule and carboxyl-ate O atom. In the crystal, O-H?O hydrogen bonds occur . The H atoms of the solvent water mol-ecules could not be located. PMID- 22199480 TI - trans-Tetra-carbonyl-bis-[tris-(3-fluoro-phen-yl)phosphane]chromium(0). AB - In the title compound, [Cr(C(18)H(12)F(3)P)(2)(CO)(4)], the Cr atom is octa hedrally coordinated by four carbonyl ligands and the two tertiary phosphanes, which are trans to each other. The three benzene rings in one phosphane ligand make dihedral angles of 53.50 (9), 75.51 (10) and 80.63 (10) degrees with each other, while in the other ligand these angles are 51.92 (10), 78.56 (11) and 86.80 (10) degrees . C-H?O and C-H?F inter-actions link the mol-ecules into a three-dimensional network. Each of the F atoms is disordered over two positions with refined occupancies of 0.944 (3):0.056 (3), 0.702 (4):0.298 (4), 0.829 (4):0.171 (4), 0.567 (4):0.433 (4), 0.545 (4):0.455 (4) and 0.920 (4):0.080 (4). PMID- 22199481 TI - 1-(2,4-Dichloro-benz-yl)pyridinium bis-(2-sulfanyl-idene-1,3-dithiole-4,5-dithiol ato-kappaS,S')nickelate(III). AB - In the title compound, (C(12)H(10)Cl(2)N)[Ni(C(3)S(5))(2)], the Ni(III) atom is chelated by two bidentate 2-sulfanyl-idene-1,3-dithiole-4,5-dithiol-ate (dmit) dianions and shows a distorted square-planar geometry. The two dmit ligands are twisted with respect to each other by 3.21 (2) degrees . In the cation, the two aromatic groups linked by the methyl-ene bridging group form a dihedral angle of 68.09 (2) degrees . S?S [3.6212 (11) and 3.5573 (9) A] and Ni?S [3.566 (2)A] inter-actions influence the arrangement of the anions in the crystal. PMID- 22199482 TI - Dibromido(2,4,6-tri-2-pyridyl-1,3,5-triazine-kappaN,N,N)manganese(II). AB - The Mn(II) ion in the title complex, [MnBr(2)(C(18)H(12)N(6))], is five coordinated in a distorted square-pyramidal geometry by three N atoms of the tridentate 2,4,6-tri-2-pyridyl-1,3,5-triazine (tptz) ligand and two bromide anions. In the crystal, the pyridyl rings coordinated to the Mn atom are inclined slightly to their carrier triazine ring [dihedral angles = 8.0 (3) and 7.5 (3) degrees ], whereas the uncoordinated pyridyl ring is located approximately parallel to the triazine ring [dihedral angle = 3.7 (3) degrees ]. The complexes are stacked in columns along the a axis and linked by inter-molecular C-H?Br hydrogen bonds, forming chains. In the column, inter-molecular pi-pi inter actions between the six-membered rings are present, the shortest centroid centroid distance being 3.750 (4) A. PMID- 22199483 TI - Bis[tris-(1H-pyrazol-1-yl-kappaN)methane]-nickel(II) bis-{[tris-(1H-pyrazol-1-yl kappaN)methane]-tris-(thio-cyanato-kappaN)nickelate(II)} methanol disolvate. AB - Attempts to prepare the mononuclear [(tpm)Ni(II)L(3)](-1) [tpm = tris-(1H-pyrazol 1-yl)methane and L = thio-cyanate] anion yielded the methanol-solvated salt, [(tpm)(2)Ni(II)][(tpm)Ni(II)(NCS)(3)](2).2CH(3)OH or [Ni(C(10)H(10)N(6))(2)][Ni(NCS)(3)(C(10)H(10)N(6))](2).2CH(3)OH. The asymmetric unit consists of half a centrosymmetric bis-[tris-(1H-pyrazol-1-yl)methane] nickel(II) cation and an octa-hedral nickelate(II) anion bound to one tpm and three L ligands, and a methanol solvent mol-ecule. One of the L ligands is disordered over two positions with occupancy factors of 0.650 (3) and 0.350 (3). There are O-H?S inter-actions between the methanol and the disordered thio cyanate anion, and a weak C-H?O hydrogen bond between the cation and the methanol O atom. PMID- 22199484 TI - catena-Poly[[diaqua-lithium]-MU-[rac-cis-(2-carb-oxy-cyclo-hexane-1-carboxyl-ato kappaO:O]]. AB - In the structure of the title compound, [Li(C(8)H(11)O(4))(H(2)O)(2)](n), the distorted tetra-hadral LiO(4) coordination sphere comprises two water mol-ecules and two carboxyl O-atom donors from separate bridging cis-2-carb-oxy-cyclo-hexane 1-carboxyl-ate monoanions [Li-O = 1.887 (4)-1.946 (3) A], giving chain substructures which extend along [010]. Water-water and water-carboxyl O-H?O hydrogen bonds stabilize these chain structures and provide inter-chain links, resulting in a two-dimensional layered structure extending parallel to (100). PMID- 22199485 TI - (Acetato-kappaO)(2,5,5,7,9,12,12,14-octa-methyl-1,4,8,11-tetra-aza-cyclo-tetra decane-kappaN,N',N'',N''')zinc perchlorate. AB - The Zn(II) atom in the cation of the title salt, [Zn(C(2)H(3)O(2))(C(18)H(40)N(4))]ClO(4), is five-coordinated by the four N atoms of the macrocycle and the O atom of the monodentate acetate ligand. The N(4)O donor set is based on a trigonal bipyramid with two N atoms occupying axial positions [N-Zn-N = 170.89 (16) degrees ]. The perchlorate anions are associated with the cations via N-H?O hydrogen bonds; intra-molecular N-H?O(acetate) inter actions are also observed. The neutral aggregates are connected into an helical chain along the b axis via N-H?O(acetate) hydrogen bonds. The perchlorate anion was found to be disordered about a pseudo-threefold axis: the major component of the disorder had a site occupancy factor of 0.692 (11). PMID- 22199486 TI - Bis(8-hy-droxy-1-methyl-quinolin-1-ium) bis-(1,2-dicyano-ethene-1,2-dithiol ato)nickelate(II) dihydrate. AB - In the title ion-pair complex, (C(10)H(10)NO)(2)[Ni(C(4)N(2)S(2))(2)].2H(2)O, the anion has crystallographically imposed centre of symmetry. The Ni(II) atom exhibits a slightly distorted square-planar coordination geometry. In the crystal, the water mol-ecule links anions and cations into a three-dimensional network via O-H?N, O-H?S and O-H?O hydrogen bonds. The structure is further stabilized by weak S?pi contacts [S?centroid = 3.8047 (9) A] and pi-pi stacking inter-actions [centriod-centroid distance = 3.8653 (7) A]. PMID- 22199487 TI - cis-Dichloridobis[diphen-yl(4-vinyl-phenyl)phosphane-kappaP]platinum(II). AB - The title compound, [PtCl(2)(C(20)H(17)P)(2)], forms a monomeric cis-square planar geometry. The Pt-P bond lengths are 2.2489 (9) and 2.2627 (9) A, whereas the Pt-Cl bond lengths are 2.3566 (9) and 2.3336 (9) A. PMID- 22199488 TI - trans-Dichloridobis[diphen-yl(4-vinyl-phen-yl)phosphane-kappaP]palladium(II). AB - In the title compound, [PdCl(2)(C(20)H(17)P)(2)], the Pd(II) atom lies on a center of symmetry, resulting in a distorted trans-square-planar geometry. The Pd P and Pd-Cl bond lengths are 2.3366 (7) and 2.2966 (7) A, respectively. The vinyl group is disordered over two sets of sites in a 0.696 (15):0.304 (15) ratio. PMID- 22199489 TI - Di-MU-acetato-1:2kappaO:O';2:3kappaO:O,O'-bis-(5,5,7,12,12,14-hexa-methyl 1,4,8,11-tetra-aza-cyclo-tetra-deca-ne)-1kappaN,3kappaN-bis-(perchlorato 2kappaO,O')-2-sodium-1,3-dizinc perchlorate. AB - In the title salt, [NaZn(2)(CH(3)COO)(2)(ClO(4))(2)(C(16)H(36)N(4))(2)]ClO(4), the macrocyclic ligand binds to the Zn(2+) cations through their four amino N atoms; the Zn(2+) cations are also each covalently bonded to an acetate ion. For one zinc atom, the acetate group is monodentate, and the geometry is a distorted ZnN(4)O trigonal bipyramid; for the other, the acetate group is anisobidentate and the geometry is a distorted ZnN(4)O(2) octa-hedron. The two macrocycle-zinc acetate units are bridged through a diperchloratosodium unit. In the crystal, the complex cations and uncoordinated perchlorate anions are linked by N-H?O hydrogen bonds. PMID- 22199490 TI - Bis(dimethyl sulfoxide-kappaO)bis(saccharinato-kappaN)-zinc(II). AB - The title compound, [Zn(C(7)H(4)N(2)O(3)S)(2)(C(2)H(6)OS)(2)], is a neutral four coordinate complex with a tetra-hedral geometry. The metal atom is surrounded by the two dimethyl sulfoxide (DMSO) ligands, each coordinating through the O atom, and two anionic saccharinate (1,1,3-trioxo-2,3-dihydro-1lambda(6),2-benzo-thia zol-2-ide) ligands coordinating through the N atom. The tetra-hedral geometry is slightly distorted as is evident from the N-Zn-N bond angle of 113.85 (6) degrees , the O-Zn-O bond angle of 98.92 (6) degrees and O-Zn-N bond angles of 116.96 (6) and 103.93 (6) degrees . The Zn-N bond lengths are 1.9742 (15) and 2.0025 (16) A. The Zn-O bond lengths are 1.9806 (14) A and 1.9468 (14) A. The DMSO ligand coordinates through the lone pair of electrons on the O atom, as can be seen from the Zn-O-S bond angle of 131.30 (8) degrees . PMID- 22199491 TI - trans-Carbonyl-chloridobis(tri-o-tolyl-phosphane-kappaP)rhodium(I). AB - In the title compound, [RhCl(C(21)H(21)P)(2)(CO)], the coordination geometry around the Rh(I) atom is slightly distorted square-planar with the phosphane ligands in trans positions with respect to each other. The chloride and carbonyl ligands show positional disorder, and the Rh(I) atom lies on a center of inversion. The effective cone angle Theta(E) for the title compound is 169.0 (3) degrees . There are no significant inter-molecular inter-actions. PMID- 22199492 TI - Diaqua-bis-(dimethyl sulfoxide-kappaO)bis(saccharinato-kappaN)cobalt(II). AB - The title complex, [Co(C(7)H(4)NO(3)S)(2)(C(2)H(6)OS)(2)(H(2)O)(2)], contains a Co(2+) cation in an octa-hedral coordination environment. The metal atom is surrounded by two different neutral ligands, namely dimethyl-sulfoxide (DMSO) and water, each coordinating through the O atom. The anionic saccharinate (sac; 1,1,3 trioxo-2,3-dihydro-1lambda(6),2-benzothia-zol-2-ide) ligand coordinates through the N atom. Each of the three similar ligand pairs is in a trans configuration with respect to each other. The Co atom lies on a crystallographic center of symmetry and the octa-hedral geometry is not significantly distorted. A short O H?O hydrogen bond is present between a water H atom and the ketone O atom; two longer hydrogen bonds (intra- and inter-molecular) are also present between a water H and a sulfonic O atom, forming a supramolecular assembly through head-to tail aggregation between adjacent complexes. PMID- 22199493 TI - cyclo-Tetra-MU-oxido-tetra-kis-[(acetyl-acetonato-kappaO,O')bis-(ethano-lato kappaO)niobium(V)]. AB - The asymmetric unit of the title tetra-nuclear niobium(V) compound, [Nb(4)(C(2)H(5)O)(8)(C(5)H(7)O(2))(4)O(4)], contains two Nb(V) atoms, two bridging O atoms, two acetyl-acetonate and four ethano-late ligands. Each Nb(V) atom is six-coordinated by the bridging O atoms, two ethano-late and one chelating acetyl-acetonate ligands. The Nb-O distances vary between 1.817 (2) and 2.201 (2) A and the O-Nb-O angles vary between 78.88 (8) and 102.78 (9) degrees , illustrating the significant distortion from ideal ocahedral geometry. The rest of the tetra-nuclear unit is generated through an inversion centre. The C atoms of two of the ethano-late mol-ecules are disordered over two sites [occupancy ratio 0.601 (12):0.399 (12)]. PMID- 22199494 TI - [1,1'-Bis(diphenyl-phosphan-yl)cobalto-cenium]carbonyl-chloridohydrido(triphenyl phosphane)ruthenium(II) hexa-fluoridophosphate dichloro-methane disolvate. AB - In the title compound, [CoRu(C(17)H(14)P)(2)ClH(C(18)H(15)P)(CO)]PF(6).2CH(2)Cl(2), the Ru(II) atom is coordinated by three P atoms from a chelating 1,1'-bis-(diphenyl-phosphan yl)cobaltocenium ligand and a triphenyl-phosphine ligand, one CO ligand, one Cl atom and one H atom in a distorted octa-hedral geometry. In the cobaltocenium unit, the two cyclo-penta-dienyl rings are almost parallel, making a dihedral angle of 1.2 (3) degrees . The F atoms of the hexa-fluoridophosphate anion are disordered over two sets of sites, with an occupancy ratio of 0.849 (11):0.151 (11). Intra-molecular C-H?Cl hydrogen bonds occur in the complex cation. The complex cations, hexa-fluoridophosphate anions and dichloro-methane solvent mol ecules are linked by inter-molecular C-H?F hydrogen bonds. PMID- 22199495 TI - {5,10,15,20-Tetra-kis[4-(oct-yloxy)phen-yl]porphyrinato}copper(II). AB - In the title compound, [Cu(C(76)H(92)N(4)O(4))], the central Cu(II) ion is situated on an inversion centre. The porphyrinate core exhibits a nearly planar conformation [maximum deviation = 0.027 (3) A], with Cu-N distances of 1.997 (2) and 2.001 (2) A. The benzene rings of the 4-octyloxyphenyl groups are rotated at angles of 84.02 (8) and 77.02 (6) degrees with respect to the mean plane of the porphyrin fragment. The two terminal C atoms in the octyl group are disordered over two positions of equal occupancy. PMID- 22199496 TI - catena-Poly[[triphenyl-tin(IV)]-MU-phenyl-phosphinato-kappaO:O']. AB - In the structure of the title coordination polymer, [Sn(C(6)H(5))(3)(C(6)H(6)O(2)P)](n) or [PhP(H)O(2)Sn(IV)(Ph)(3)](n), the Sn(IV) atom is five-coordinate, with the SnC(3)O(2) framework in a trans trigonal bipyramidal arrangement having the PhP(H)O(2) (-) anions in apical positions. In the crystal, neighbouring polymer chains are linked via C-H?pi inter-actions, forming a two-dimensional network lying parallel to (001). PMID- 22199497 TI - {4,6-Bis[(E)-1-methyl-2-(pyridin-2-yl-methyl-idene)hydrazinyl]pyrimidine kappaN,N',N''}dichloridomanganese(II). AB - In the title compound, [MnCl(2)(C(18)H(18)N(8))], the geometry around the Mn(II) centre is distorted square-pyramidal. In the crystal structure, mol-ecules pack via weak C-H?N and C-H?Cl inter-actions. PMID- 22199498 TI - Bis[MU(2)-bis-(diphenyl-phosphan-yl)methane-kappaP:P']bis-(MU(4)-diphenyl phosphinato-kappaO:O:O':O')bis-(MU(2)-trifluoro-acetato-kappaO:O')tetra-silver(I) acetonitrile disolvate. AB - In the cation of the title compound, [Ag(4)(C(2)F(3)O(2))(2)(C(12)H(10)O(2)P)(2)(C(25)H(22)P(2))(2)].2CH(3)CN, the two independent Ag(+) cations are four-coordinated in a distorted tetra-hedral geometry by one P atom from a bis-(diphenyl-phosphan-yl)methane (dppm) ligand, one O atom from a trifluoro-acetate anion and two O atoms from two diphenyl phosphinate (dpp) ligands. Two dppm ligands, two dpp ligands and two trifluoro acetate anions bridge four metal atoms, forming a centrosymmetric tetra-nuclear complex. Intra-molecular C-H?O hydrogen bonds and a weak pi-pi inter-action [centroid-centroid distance = 3.9804 (13) A] are also observed. PMID- 22199499 TI - cis-Diaqua-bis-(2,2'-bipyrimidine-kappaN,N)manganese(II) bis-(perchlorate) nitro methane disolvate monohydrate. AB - The asymmetric unit of the title compound, [Mn(C(8)H(6)N(4))(2)(H(2)O)(2)](ClO(4))(2).2CH(3)NO(2).H(2)O, contains one half of a cationic Mn(II) complex, a ClO(4) (-) anion, a nitro-methane solvent mol ecule and one half-mol-ecule of water. The complex mol-ecule and the solvent water mol-ecule are located on a twofold rotation axis. In the complex, the Mn(II) ion has a distorted cis-N(4)O(2) octa-hedral coordination geometry defined by four N atoms of the two chelating 2,2'-bipyrimidine ligands and two O atoms of water mol-ecules. In the crystal, the complex cations, anions and solvent mol ecules are linked by inter-molecular O-H?N, O-H?O and weak C-H?O hydrogen bonds. The ClO(4) (-) anion is disordered over two sites with a site-occupancy factor of 0.512 (12) for the major component. PMID- 22199500 TI - Poly[[tetra-aqua-bis-(MU(3)-imidazole-4,5-dicarboxyl-ato)tetra-kis-(MU(2) imidazole-4,5-dicarboxyl-ato)tricobalt(II)dilutetium(III)] dihydrate]. AB - In the title compound, {[Co(3)Lu(2)(C(5)H(2)N(2)O(4))(6)(H(2)O)(4)].2H(2)O}(n), the Lu(III) ions are seven-coordinated in a monocapped trigonal prismatic coordination geometry by six O atoms from three imidazole-4,5-dicarboxyl-ate ligands and one water O atom. The Co(II) ions are six-coordinated in a slightly distorted octa-hedral geometry and exhibit two types of coordination environments. One Co(II) ion, located on an inversion center, is coordinated by two water O atoms as well as two O atoms and two N atoms from two imidazole-4,5 dicarboxyl-ate ligands. The other Co(II) ion is bonded to four O atoms and two N atoms from four imidazole-4,5-dicarboxyl-ate ligands. These metal coordination units are connected by bridging imidazole-4,5-dicarboxyl-ate ligands, generating a three-dimensional network. The crystal structure is further stabilized by N H?O, O-H?O, and C-H?O hydrogen-bonding inter-actions between the water mol-ecules and the imidazole-4,5-dicarboxyl-ate ligands. PMID- 22199501 TI - Poly[diaqua-bis-(MU(3)-1H-imidazole-4,5-dicarboxyl-ato)(MU(2)-sulfato) diytterbium(III)]. AB - In the title compound, [Yb(2)(C(5)H(2)N(2)O(4))(2)(SO(4))(H(2)O)(2)](n), the Yb(III) ion is eight-coordinated by four O atoms and one N atom from three imidazole-4,5-dicarboxyl-ate ligands, two O atoms from one SO(4) (2-) anion (site symmetry 2), as well as one O atom of a water mol-ecule, giving a bicapped trigonal-prismatic coordination geometry. The metal coordination units are connected by bridging imidazole-4,5-dicarboxyl-ate and sulfate ligands, generating a heterometallic layer. The layers are stacked along the a axis via N H?O, O-H?O, and C-H?O hydrogen-bonding inter-actions, generating a three dimensional framework. PMID- 22199502 TI - Poly[[(4,4'-bipyridine-kappaN)[MU(3)-(S)-2-hy-droxy-butane-dioato kappaO,O:O:O]zinc] dihydrate]. AB - In the title compound, {[Zn(C(4)H(4)O(5))(C(10)H(8)N(2))].2H(2)O}(n), the Zn(II) ion displays a distorted tetra-gonal-pyramidal coordination environment with one hy-droxy O and three carboxyl-ate O atoms from three malate anions, and the one remaining position occupied by an N atom from a 4,4'-bipyridine ligand. The pyridine rings of the 4,4'-bipyridine ligand are twisted with respect to each other by a dihedral angle of 35.8 (2) degrees . The uncoordinated water mol ecules are linked to the complex mol-ecules by O-H?O hydrogen bonds. Each malate anion forms four coordination bonds with three Zn atoms, establishing a layer structure parallel to the ac plane. Adjacent layers are further linked via O-H?N hydrogen bonding. pi-pi stacking between the pyridine rings [face-to-face distance = 3.651 (3) A] occurs in the crystal structure. PMID- 22199503 TI - Tetra-aqua-bis-(2-methyl-1H-imidazole-kappaN)cobalt(II) naphthalene-1,5 disulfonate. AB - In the title complex, [Co(C(4)H(6)N(2))(2)(H(2)O)(4)](C(10)H(6)O(6)S(2)), the cation and anion both reside on crystallographic inversion centers, such that the asymmetric unit comprises one half cation and one half anion. The central Co(II) ion is coordinated by four water mol-ecules and two 2-methyl-imidazole ligands, resulting in a trans-octa-hedral coordination geometry. The existence of strong N H?O and O-H?O hydrogen-bonding inter-actions gives rise to a three-dimensional structure. PMID- 22199505 TI - Bis(piperazine-1,4-diium) hexa-chlorido-bismuthate(III) chloride monohydrate. AB - The crystal structure of the title compound, (C(4)H(12)N(2))(2)[BiCl(6)]Cl.H(2)O, consists of piperazinediium cations, [BiCl(6)](3-) anions, Cl(-) anions and uncoordinated water mol-ecules. The Bi(III) cation is coordinated by six Cl(-) anions in a slightly distorted octa-hedral geometry. The diprotonated piperazine ring adopts a chair conformation. In the crystal, extensive inter-molecular N H?Cl, N-H?O and O-H?Cl hydrogen bonds occur. PMID- 22199504 TI - Bis(2,2'-bipyridine)(pyridin-2-olato)ruthenium(II) hexa-fluorido-phosphate benzene hemisolvate. AB - In the title compound, [Ru(C(5)H(4)NO)(C(10)H(8)N(2))(2)]PF(6).0.5C(6)H(6), the Ru(2+) cation has a distorted octa-hedral RuN(5)O coordination environment. This complex is more distorted than the closely related ruthenium complex containing a pyridine-2-thiol-ate ligand [Santra et al. (1997 ?). J. Chem. Soc. Dalton Trans. pp. 1387-1393]. The distortion is caused by the difference in size between the O and S atoms. The benzene solvent mol-ecule is situated on a twofold rotation axis. PMID- 22199506 TI - Tetra-aqua-bis-{3-carb-oxy-5-[(4-carb-oxy-phen-yl)diazen-yl]benzoato kappaO}cobalt(II) dihydrate. AB - In the title complex, [Co(C(15)H(9)N(2)O(6))(2)(H(2)O)(4)].2H(2)O, the Co(II) ion is located on an inversion center and is coordinated by two monodentate 3-carb oxy-5-[(4-carb-oxy-phen-yl)diazen-yl]benzo-ate ligands and four water mol-ecules in a distorted octa-hedral geometry. In the crystal, inter-molecular O-H?O hydrogen bonds link the mol-ecules into a three-dimensional supra-molecular network. PMID- 22199507 TI - Diaqua-bis-[5-(pyrazin-2-yl-kappaN)-3-(pyridin-3-yl)-1,2,4-triazolido kappaN]cadmium. AB - In the title compound, [Cd(C(11)H(7)N(6))(2)(H(2)O)(2)], the Cd(II) cation is located on an inversion center and is coordinated by four N atoms from two 5 (pyrazin-2-yl)-3-(pyridin-3-yl)-1,2,4-triazol-ide anions and two water mol-ecules in a distorted octa-hedral geometry. The triazolide ligand is nearly planar: the central triazole ring is oriented at dihedral angles of 4.63 (13) and 8.41 (13) degrees with respect to the pyrazine and pyridine rings. Inter-molecular O-H?N hydrogen bonds link the mol-ecules into a two-dimensional supra-molecular network parallel to (001). PMID- 22199508 TI - Bis{2-[bis-(3,5-dimethyl-1H-pyrazol-1-yl-kappaN)meth-yl]pyridine kappaN}copper(II) dinitrate. AB - In the mononuclear title complex, [Cu(C(16)H(19)N(5))(2)](NO(3))(2), the Cu(II) ion is located on a twofold rotation axis and is six-coordinated by six N atoms from two 2-[bis-(3,5-dimethyl-1H-pyrazol-1-yl)meth-yl]pyridine ligands, forming a distorted octa-hedral geometry. In the crystal, mol-ecules are linked by weak C H?O inter-actions. PMID- 22199509 TI - Bis[methyl 3-(propyl-amino)-but-2-eno-ato]zinc. AB - The title compound, [Zn(C(8)H(14)NO(2))(2)], represents a zinc complex with the Zn(2+) cation coordinated by two O and two N atoms in a distorted tetrahedral geometry. PMID- 22199510 TI - [eta-1,3-Bis(trimethyl-sil-yl)cyclo-penta-dien-yl]dichlorido[eta-(trimethyl-sil yl)cyclo-penta-dien-yl]titanium(IV). AB - In the title compound, [Ti(C(8)H(13)Si)(C(11)H(21)Si(2))Cl(2)], the Ti(IV) atom is bonded to two Cl atoms, one 1,3-bis-(trimethyl-sil-yl)cyclo-penta-dienyl (Si(2)Cp) and one (trimethyl-sil-yl)cyclo-penta-dienyl ring (SiCp). The Si(2)Cp centroid-titanium distance is 2.0763 (10) A and the SiCp centroid-titanium distance is 2.0793 (10) A. The angle subtended at the Ti atom by the centroids of both cyclo-penta-dienyl rings is 131.22 (4) degrees and the Cl-Ti-Cl angle is 94.14 (2) degrees . PMID- 22199511 TI - Diaqua-bis-(dihydrogen 3-aza-niumyl-1-hy-droxy-propyl-idene-1,1-di-phos-phon-ato kappaO,O')cobalt(II). AB - The asymmetric unit of title compound, [Co(C(3)H(10)NO(7)P(2))(2)(H(2)O)(2)], contains one half-mol-ecule of the complex. The Co(II) atom is located on an inversion centre and displays a distorted octa-hedral coordination geometry defined by four O atoms of two 3-aza-niumyl-1-hy-droxy-propyl-idene-1,1-bis phospho-nato ligands in the equatorial plane and two water mol-ecules located in axial positions. The ligand mol-ecules, which exist in a zwitterionic state, form two six-membered chelate rings with chair conformations. In the crystal, mol ecules are inter-linked by O-H?O and N-H?O hydrogen bonds, forming a three dimensional supra-molecular structure. PMID- 22199512 TI - trans-Carbonyl-chloridobis[tris-(4-meth-oxy-phen-yl)phosphane-kappaP]rhodium(I). AB - The title complex, [RhCl(C(21)H(21)O(3)P)(2)(CO)], is a rhodium analogue to Vaska's complex with para-meth-oxy substituents on the six phosphan-yl-aryl units. Two independent mol-ecules are present in the unit cell, with their metal atoms both located on an inversion centre. This causes the chloride and carbonyl ligands to exhibit a positional disorder in a 0.5:0.5 ratio. The two Rh(I) atoms exhibit a distorted square-planar geometry. There are a few weak intra-molecular C-H?X inter-actions (X = O, Cl). Inter-estingly, no significant inter-molecular inter-actions are found between the two independent mol-ecules. PMID- 22199513 TI - Bis(pentane-2,4-dionato-kappaO,O')(1,10-phenanthroline-kappaN,N')cobalt(II). AB - In the title compound, [Co(C(5)H(7)O(2))(2)(C(12)H(8)N(2))], the Co(II) cation lies on a twofold rotation axis and is coordinated by four O atoms from two acetyl-acetonate (acac) ligands and two N atoms from a 1,10-phenanthroline (phen) ligand in a slightly distorted octa-hedral environment, with Co-O bond lengths of 2.0565 (11) and 2.0641 (11) A and Co-N bond lengths of 2.1630 (12) A. In the crystal, there are no significant hydrogen-bonding or pi-pi inter-actions. PMID- 22199514 TI - Bis(1H-benzotriazole-7-sulfonato-kappaO)bis-(1,10-phenanthroline kappaN,N')cadmium dihydrate. AB - In the title complex, [Cd(C(6)H(4)N(3)O(3)S)(2)(C(12)H(8)N(2))(2)].2H(2)O, the Cd(2+) cation is located on an inversion center and is coordinated by four N atoms from two symmetry-related 1,10-phenanthroline ligands and two sulfonate O atoms from two benzotriazole-7-sulfonate anions, displaying a distorted CdN(4)O(2) octa-hedral geometry. In the crystal, O-H?N, O-H?O, N-H?O, C-H?N and C H?O hydrogen bonds occur. The lattice water mol-ecules and sulfonate O atoms as donor or acceptor atoms play important roles in the formation of these inter actions. PMID- 22199515 TI - Bis(1H-benzotriazole-4-sulfonato-kappaN,O)(2,2'-bipyridyl-kappaN,N')cadmium. AB - In the title complex, [Cd(C(6)H(4)N(3)O(3)S)(2)(C(10)H(8)N(2))], the Cd(2+) cation is located on a twofold rotation axis and is coordinated by two N and two O atoms from two symmetry-related benzotriazole-4-sulfonate anions and two N atoms from a 2,2-bipyridyl ligand, displaying a distorted CdN(4)O(2) octa-hedral geometry. The crystal structure is stabilized by N-H?O and C-H?O hydrogen-bonding inter-actions. PMID- 22199516 TI - Poly[tetra-aqua-(MU(8)-butane-1,2,3,4-tetra-carboxyl-ato)distrontium]. AB - In the title compound, [Sr(2)(C(8)H(6)O(8))(H(2)O)(4))](n), the Sr(II) ion is coordinated by six O atoms of four symmetry-related ligands and two water mol ecules in a distorted bicapped trigonal-prismatic environment. The butane-1,2,3,4 tetra-carboxyl-ate ligands lie on inversion centers and bridge Sr(II) ions, forming a three-dimensional network. Within the three-dimensional structure, there are O-H?O hydrogen bonds involving the water mol-ecules and carboxyl-ate O atoms. PMID- 22199517 TI - Tetra-aqua-bis-[1-(3-carb-oxy-phen-yl)-4,4'-bipyridin-1-ium-kappaN]zinc bis-(4,5 carb-oxy-benzene-1,2-dicarboxyl-ate) 2.5-hydrate. AB - In the complex cation of the title compound, [Zn(C(17)H(13)N(2)O(2))(2)(H(2)O)(4)](C(10)H(4)O(8))(2).2.5H(2)O, the Zn(II) atom, lying on an inversion center, is coordinated by two N atoms from two N-(3 carb-oxy-phen-yl)-4,4'-bipyridin-1-ium ligands and four water mol-ecules in a distorted octa-hedral geometry. The pyromellitate anion is double deprotonated. O H?O and C-H?O hydrogen bonds connect the cations, anions and uncoordinated water mol-ecules into a three-dimensional supra-molecular network. One of the two lattice water molecules shows an occupancy of 0.25. An intra-molecular O-H?O hydrogen bond is present in the anion. PMID- 22199518 TI - Di-MU-azido-kappaN:N-bis-{aqua-[bis-(1H-benzimidazol-2-ylmeth-yl)amine] copper(II)} dinitrate. AB - In the centrosymmetric dinuclear title complex, [Cu(2)(N(3))(2)(C(16)H(15)N(5))(2)(H(2)O)(2)](NO(3))(2), the Cu(II) ion is in a distorted octa-hedral coordination environment with long axial Cu-N(azide) [2.821 (6) A] and Cu-O(water) [2.747 (5) A] bonds as a result of the Jahn-Teller effect. Two symmetry-related azide ligands bridge in MU(2)-modes giving a Cu?Cu distance of 3.533 (2) A. In the crystal, N-H?O and O-H?O hydrogen bonds link the components into a three-dimensional network. In addition, there are weak inter molecular C-H?N hydrogen bonds and pi-pi stacking inter-actions with centroid centroid distances ranging from 3.562 (2) to 3.974 (2) A. PMID- 22199519 TI - catena-Poly[[bis-(2,4-dichloro-benzoato)bis-(methanol-kappaO)cobalt(II)]-MU-4,4' bipyridine-kappaN:N']. AB - In the title compound, [Co(C(7)H(3)Cl(2)O(2))(2)(C(10)H(8)N(2))(CH(3)OH)(2)](n), the Co(II) ion lies on a twofold rotation axis and is in a slightly distorted octa-hedral CdO(4)N(2) environment, formed by two O atoms from monodentate dichloro-benzoate ligands, two O atoms from methanol ligands, and two N atoms from trans-related 4,4'-bipyridine ligands. The bipyridine ligands also lies on a twofold rotation axis and bridge the Co(II) ions, forming chains extending along [010]. An intra-chain O-H?O hydrogen bond is observed. PMID- 22199520 TI - Poly[penta-kis-(MU-cyanido-kappaN:C)tris-(5-phenyl-2,2'-bipyridine kappaN,N')penta-copper(I)]. AB - The hydro-thermal reaction of Cu(acetate)(2) and K(3)[Fe(CN)(6)] with 5-phenyl 2,2'-bipyridine (5-ph-2,2'-bpy) in water yields the polymeric title complex, [Cu(5)(CN)(5)(C(16)H(12)N(2))(3)](n), which consists of ribbons along the a axis, constructed from 26-membered {Cu(10)(CN)(8)} rings. In these rings, the metal atoms are bridged by cyanide groups, except for one close Cu?Cu contact [2.7535 (12) A], which can be considered as ligand-unsupported. Within the rings, one Cu atom has a distorted tetra-hedral geometry through the coordination to two N atoms from 5-ph-2,2'-bpy and two N/C atoms from two cyanide groups. Two Cu atoms have a trigonal planar environment being coordinated by three cyanide groups and two other Cu atoms have a distorted square planar geometry through coordination to two N atoms from 5-ph-2,2'-bpy and two N/C atoms from two cyanide groups. PMID- 22199521 TI - catena-Poly[[(6-carb-oxy-pyrazine-2-carboxyl-ato)lithium]-MU-aqua]. AB - The asymmetric unit of the title compound, [Li(C(6)H(3)N(2)O(4))(H(2)O)](n), contains an Li(I) ion with a distorted trigonal-bipyramidal coordination environment. It is chelated by a singly protonated ligand mol-ecule via its heterocyclic N atom, by two O aoms, each donated by an adjacent carboxyl-ate group, and is further coordinated by a water O atom which acts as a bridge, forming a mol-ecular ribbon. A proton attached to one of the carboxyl-ate O atoms is situated on an inversion centre and forms a short centrosymmetric hydrogen bond, generating mol-ecular layers parallel to the ac plane. These layers are held together by weak O-H?O hydrogen bonds in which the coordinated water mol ecules act as donors, whereas carboxyl-ate O atoms are acceptors. PMID- 22199522 TI - catena-Poly[[[triaqua-copper(II)]-MU-2,2'-bipyridine-3,3'-dicarboxyl-ato kappaN,N':O] monohydrate]. AB - The title compound, {[Cu(C(12)H(6)N(2)O(4))(H(2)O)(3)].H(2)O}(n), was synthesized under hydro-thermal conditions. The Cu(2+) ion is six-coordinated by three water O atoms, and two N atoms and one O atom of the 2,2'-bipyridine-3,3'-dicarboxyl ate bridging ligand in a sligthly distorted octa-hedral environment. The 2,2 bipyridine-3,3'-dicarboxyl-ate bridges link the Cu(2+) ions into chains along the b-axis direction. These chains are further linked by O-H?O hydrogen bonds involving the water solvent mol-ecules, forming a three-dimensional framework. PMID- 22199523 TI - Tris(tetra-hydro-furan-kappaO)tris-[tris-(thio-phen-2-yl)methano-lato kappaO]terbium(III) tetra-hydro-furan monosolvate. AB - In the mononuclear title compound, [Tb(C(13)H(9)OS(3))(3)(C(4)H(8)O)(3)].C(4)H(8)O, the lanthanide cation is located on a threefold rotation axis and is surrounded by electron-rich ligands in an approximately octa-hedral geometry. One of the thienyl groups and the bound THF are disordered with 0.5:0.5 occupancy. The free THF is disordered around the threefold axis. PMID- 22199524 TI - [1,3-Bis(diphenyl-phosphan-yl)propane-kappaP,P'](1,10-phenanthroline kappaN,N')copper(I) perchlorate. AB - The title compound, [Cu(C(12)H(8)N(2))(C(27)H(26)P(2))]ClO(4), crystallizes with two Cu(I) complex cations and two perchlorate anions in the asymmetric unit. Each Cu(I) cation is four-coordinated by two P atoms of a 1,3-bis-(diphenyl-phosphan yl)propane mol-ecule and two N atoms of a 1,10-phenanthroline ligand, with a coordination geometry that can be considered as distorted tetra-hedral. The crystal studied was twinned with a twin ratio of 0.786 (2):0.214 (2). PMID- 22199525 TI - {1,2-Bis[(3,5-dimethyl-1H-pyrazol-1-yl-kappaN)meth-yl]benzene} dichloridozinc(II). AB - The title zinc complex, [ZnCl(2)(C(18)H(22)N(4))], contains a bidentate 1,2 bis(3,5-dimethyl-1H-pyrazol-1-ylmeth-yl)benz-ene ligand that binds to the zinc atom, forming a nine-membered metallocyclic ring. The geometry about the Zn atom is distorted tetra-hedral, with the largest deviation observed in the magnitude of the Cl-Zn-Cl angle. Similar distortions are observed in the cobalt analogue and related zinc compounds containing metallocyclic rings with more than six members. The copper analogue exhibits a more severe distortion of the metal coordination sphere than is observed in the title compound. PMID- 22199526 TI - Poly[[tetra-aqua-MU(4)-fumarato-di-MU(3)-fumarato-dineodymium(III)] trihydrate]. AB - The title coordination polymer, {[Nd(2)(C(4)H(2)O(4))(3)(H(2)O)(4)].3H(2)O}, was synthesized by the reaction of neodymium(III) nitrate hexa-hydrate with fumaric acid in a water-methanol (7:3) solution. The asymmetric unit comprises two Nd(3+) cations, three fumarate dianions (L(2-)), four aqua ligands and three uncoordinated water mol-ecules. The carboxyl-ate groups of the fumarate dianions exhibit different coordination modes. In one fumarate dianion, two carboxyl-ate groups chelate two Nd(3+) cations, while one of the O atoms is coordinated to another Nd(3+) cation. Another fumarate dianion bridges three Nd(3+) cations: one of the carboxyl-ate groups chelates one Nd(3+) cation, while the other carboxyl ate group bridges two Nd(3+) cations in a monodentate mode. The third fumarate dianion bridges four Nd(3+) cations, where one of the carboxyl-ate groups chelates one Nd(3+) cation and coordinates in a monodentate mode to a second Nd(3+), while the second carboxyl-ate groups bridges two Nd(3+) cations in a monodentate mode and one O atom is coordinated to one Nd(3+) cation. The Nd(3+) cations are in a distorted tricapped-trigonal prismatic environment and coordinated by seven O atoms from the fumarate ligands and two O atoms from water mol-ecules. The Nd(3+) cations are linked by two carboxyl-ate O atoms and two carboxyl-ate groups, generating infinite Nd-O chains to form a three-dimensional framework. There are O-H?O and C-H?O hydrogen-bonding interactions between the coordin-ated and uncoordinated water mol-ecules and carboxyl-ate O atoms. PMID- 22199527 TI - Poly[tetra-aquadi-MU(4)-oxalato-potassium-ytterbium(III)]. AB - In the title compound, [KYb(C(2)O(4))(2)(H(2)O)(4)](n), the Yb(III) ion lies on a site of [Formula: see text] symmetry in a dodeca-hedral environment defined by eight O atoms from four oxalate ligands. The K atom lies on a different [Formula: see text] axis and is coordinated by four O atoms from four oxalate ligands and four water O atoms. The oxalate ligand has an inversion center at the mid-point of the C-C bond. The metal ions are linked by the oxalate ligands into a three dimensional framework. O-H?O hydrogen bonding is present in the crystal structure. PMID- 22199528 TI - catena-Poly[[[(pyridine-kappaN)copper(II)]-MU-3-{1-[(2-amino-eth-yl)imino]-eth yl}-6-methyl-2-oxo-2H-pyran-4-olato-kappaN,N,O:O] perchlorate]. AB - In the title compound, {[Cu(C(10)H(13)N(2)O(3))(C(5)H(5)N)]ClO(4)}(n), the Cu(II) atom has an N(3)O(2) coordination sphere. The complex contains two different ligands, viz. a pyridine mol-ecule and a Schiff base mol-ecule, resulting from the condensation of ethyl-enodiamine with dehydro-acetic acid. The Cu(II) atom exhibits a square-pyramidal geometry: three of the four donors of the pyramid base belong to the Schiff base ligand (an N atom from the amine group, a second N atom from the imine group and the O atom of the pyran-one residue) and the fourth donor is the pyridine N atom. The coordination around the metal ion is completed by a longer axial bond to the pyran-one O atom of an adjacent Schiff base, so forming a one-dimensional polymer. The complex has a +1 charge that is compensated by a perchlorate ion. The crystal packing, which can be described as alternating chains of cations and tetra-hedral perchlorate anions along the a axis, is stabilized by inter-molecular N-H?O, C-H?O and C-H?N hydrogen-bonding interactions. PMID- 22199529 TI - Dichlorido[(4E,11E)-5,7,12,14-tetra-benzyl-7,14-dimethyl-1,4,8,11-tetra-aza-cyclo tetra-deca-4,11-diene]cobalt(III) perchlorate. AB - The Co(III) atom in the title complex, [CoCl(2)(C(40)H(48)N(4))]ClO(4), is octa hedrally coordinated within a trans-Cl(2)N(4) donor set provided by the tetra dentate macrocylic ligand and two chloride ions. The N-H atoms, which are orientated to one side of the N(4) plane, form hydrogen bonds with chloride ions and perchlorate-O atoms. These along with C-H?O inter-actions consolidate the three-dimensional crystal structure. One of the benzene rings was disordered. This was resolved over two positions with the major component of the disorder having a site-occupancy factor of 0.672 (4). PMID- 22199530 TI - catena-Poly[[tetra-kis-(hexa-methyl-phospho-ramide-kappaO)bis-(nitrato kappaO,O')holmium(III)] [silver(I)-di-MU-sulfido-tungstate(VI)-di-MU-sulfido]]. AB - In the title salt, {[Ho(NO(3))(2)(C(6)H(18)N(3)OP)(4)][AgWS(4)]}(n), the anion forms a W/S/Ag polymeric chain along the a axis. The holmium atom in the cation is coordinated by eight O atoms from two nitrate and four hexa-methyl-phospho ramide ligands in a distorted square-anti-prismatic geometry. Together with the two nitrate ligands, the complex cation in the title compound is univalent, which leads the anion to be univalent as well. The polymeric anionic chain with W-Ag-W and Ag-W-Ag angles of 161.429 (17) and 153.608 (10) degrees , respectively, presents a distorted linear configuration. The title complex is isotypic with the corresponding Y, Yb, Eu, Nd, La and Dy analogues. PMID- 22199531 TI - 3-Butyl-1-methyl-1H-imidazol-3-ium bis-(1,2-dicyano-ethene-1,2-dithiol-ato kappaS,S')nickel(III). AB - In the title compound, (C(8)H(15)N(2))[Ni(C(4)N(2)S(2))(2)], the Ni(III) atom is coordinated by four S atoms of two maleonitrile-dithiol-ate ligands and exhibits a distorted square-planar geometry. In the crystal, the cations and anions are connected alternately by weak inter-molecular C-H?N hydrogen bonds, forming a zigzag chain along [201]. PMID- 22199532 TI - catena-Poly[[lead(II)-MU-N'-[1-(pyridin-2-yl-kappaN)ethyl-idene]isonicotino hydrazidato-kappaN',O:N] perchlorate]. AB - The Pb(II) atom in the polymeric title compound, {[Pb(C(13)H(11)N(4)O)]ClO(4)}(n), is coordinated by the N'-[1-(pyridin-2-yl kappaN)ethyl-idene]isonicotinohydrazidate ligand via its O,N,N'-donors and simultaneously bridged by a neighbouring ligand via the pyridin-2-yl N atom. The resultant supra-molecular chain is a zigzag along the a axis. The stereochemistry of the Pb(II) atom is defined by an N(3)OE donor set (E = lone pair of electrons), which results in a Psi-trigonal-bipyramidal coordination with the O and pyridin-2-yl N atoms in axial positions. The dihedral angle between the pyridine rings of the ligand is 6.3 (3) degrees . The supra-molecular cationic chains are linked into a three-dimensional array via secondary Pb?O [3.133 (6) and 3.28 (7) A] and Pb?N [3.028 (4) A] inter-actions. Weak C-H?O inter-actions and aromatic pi-pi stacking [centroid-centroid separation = 3.693 (2) A] also occur in the crystal. PMID- 22199533 TI - catena-Poly[[[bis-(methanol-kappaO)lead(II)]-MU-N'-[1-(pyridin-2-yl-kappaN)ethyl idene]isonicotinohydrazidato-kappaN',O:N] perchlorate]. AB - The Pb(II) atom in the polymeric title compound, {[Pb(C(13)H(11)N(4)O)(CH(3)OH)(2)]ClO(4)}(n), is coordinated by an N'-[1-(pyridin 2-yl-kappaN)ethyl-idene]isonicotinohydrazidate ligand via O,N,N'-donors and simultaneously bridged by a neighbouring ligand via the isonicotinoyl N atom; two additional sites are occupied by methanol O atoms. The resultant supra-molecular chain is a zigzag along the c axis. The Pb(II) atom is seven-coordinated within an N(3)O(3) donor set and a lone pair of electrons, which defines a Psi pentagonal-bipyramidal coordination geometry with the pyridine N and lone pair in axial positions. The supra-molecular chains are linked into the two-dimensional array via inter-molecular Pb?N [3.020 (4) A] inter-actions. Layers stack along the a axis, being connected by O-H?O hydrogen bonds formed between the coordinated methanol mol-ecules and perchlorate anions. PMID- 22199534 TI - Poly[[hexa-aqua-(MU(2)-oxalato-kappaO,O:O,O)bis-(MU(3)-pyridine-2,4-dicarboxyl ato-kappaN,O:O:O)dilanthanum(III)] monohydrate]. AB - In the polymeric title compound, {[La(2)(C(7)H(3)NO(4))(2)(C(2)O(4))(H(2)O)(6)].H(2)O}(n), the La(3+) cation is nine-coordinated in a distorted LaNO(8) tricapped trigonal-prismatic geometry formed by three pyridinedicarboxylate anions, one oxalate anion and three water mol-ecules. The oxalate anion is located on an inversion center. The oxalate and pyridine-dicarboxyl-ate anions bridge the La(3+) cations, forming a two dimensional polymeric complex parallel to (010). Inter-molecular O-H?O hydrogen bonding and weak C-H?O hydrogen bonding is present in the crystal structure and pi-pi stacking [centroid-centroid distance = 3.571 (3) A] is observed between parallel pyridine rings of adjacent mol-ecules. The uncoordinated water molecule shows an occupancy of 0.5. PMID- 22199535 TI - Hexaaqua-cobalt(II) bis-(5-acetyl-2-hy-droxy-benzoate) dihydrate. AB - In the title compound, [Co(H(2)O)(6)](C(9)H(7)O(4))(2).2H(2)O, the Co(2+) cation lies on a twofold rotation axis and is coordinated by six water mol-ecules in a distorted octa-hedral geometry. In the 5-acetyl-2-hy-droxy-benzoate anion, the hy droxy group links with the carboxyl-ate group via an intra-molecular O-H?O hydrogen bond and the acetyl group is twisted to the benzene ring at a dihedral angle of 16.99 (12) degrees . In the crystal structure, the cations, anions and water mol-ecules are linked by extensive O-H?O hydrogen bonding. PMID- 22199536 TI - Bis[N-(pyridin-2-ylcarbon-yl)pyridine-2-carboximidato-kappaN,N',N'']iron(III) tris-(cyanido-kappaC)[N-(pyridin-2-ylcarbon-yl)pyridine-2-carboximidato kappaN,N',N'']ferrate(III) monohydrate. AB - In the title compound, [Fe(C(12)H(8)N(3)O(2))(2)][Fe(C(12)H(8)N(3)O(2))(CN)(3)].H(2)O, the Fe(3+) ions in the cation and anion each lie in a slightly distorted octa-hedral coordination environment. The solvent water mol-ecule is disordered over three positions with occupancies of 0.401 (7), 0.322 (7) and 0.277 (6). The water content was confirmed by thermogravimetric data. PMID- 22199537 TI - Bis(4-fluoro-benz-yl-kappaC)bis-(3-methyl-sulfanyl-1,2,4-thia-diazole-5-thiol-ato kappaN,S)tin(IV). AB - The mononuclear title molecule, [Sn(C(7)H(6)F)(2)(C(3)H(3)N(2)S(3))(2)], has 2 symmetry. The Sn(IV) atom, located on a twofold rotation axis, is in a skew trapezoidal-bipyramidal geometry, with the basal plane defined by two S,N chelating 3-methyl-sulfanyl-1,2,4-thia-diazole-5-thiol-ate ligands. The apical positions are occupied by the C atoms of two 4-fluoro-benzyl groups. PMID- 22199538 TI - Calcium acamprosate: a triclinic polymorph. AB - The title compound, poly[bis-(MU(3)-4-acetamido-propane-sulfon-ato)-calcium], [Ca(C(5)H(10)NO(4)S)(2)](n), is a triclinic polymorph of the previously reported monoclinic structure [Toffoli et al. (1988 ?). Acta Cryst. C44, 1493-1494]. The triclinic modification was found to have an all-trans configuration of the acetamido-propane chain, in contrast with the monoclinic polymorph which shows an angle of 74.66 (8) degrees between the S-C-C-C chain plane and that of the amide group. The Ca(2+) cation is situated on an inversion centre and is hexa coordinated by six O atoms belonging to different anions in a distorted octa hedral geometry. This arrangement leads to a layered structure parallel to (011). The layers are held together by N-H?O hydrogen bonds and by short C-H?O inter actions, both involving the sulfonate O atoms not coordinated to the Ca(2+) cations. The structure was determined from a crystal twinned by non-merohedry [twin law ([Formula: see text]00, 0[Formula: see text]0, -0.335 -0.85 1), with a fractional contribution of the minor twin domain of 46.7 (1)%]. PMID- 22199539 TI - MU-Oxido-bis-[chlorido(4,4'-di-tert-butyl-2,2'-bipyridine-kappaN,N')dioxido molybdenum(VI)] 0.2-hydrate. AB - The title hydrate, [Mo(2)Cl(2)O(5)(C(18)H(24)N(2))(2)].0.2H(2)O, has been isolated as the oxidation product of [Mo(eta(3)-C(3)H(5))Cl(CO)(2)(di-t-Bu-bipy)] (where di-t-Bu-bipy is 4,4'-di-tert-butyl-2,2'-bipyridine). A MU-oxide ligand bridges two similar MoCl(di-t-Bu-bipy)O(2) units, having the terminal oxide ligands mutually cis, and the chloride and MU-oxide trans to each other. In the binuclear complex, the coordination geometries of the metal atoms can be described as highly distorted octa-hedra. Individual complexes co-crystallize with a partially occupied water mol-ecule of crystallization (occupancy factor = 0.20; H atoms not located), with the crystal packing being mediated by the need to effectively fill the available space. A number of weak C-H?O and C-H?Cl inter actions are present. PMID- 22199540 TI - catena-Poly[[[(acetato-kappaO,O')cadmium]-MU-acetato-kappaO,O':O'-MU-{1,2-bis-[4 (pyridin-3-yl)pyrimidin-2-ylsulfan-yl]ethane}-kappaN,N] trihydrate]. AB - The title compound, {[Cd(CH(3)COO)(2)(C(20)H(16)N(6)S(2))].3H(2)O}(n), exists as a one-dimensional zigzag polymer in which the Cd(II) ion shows a seven-coordinate [CdO(5)N(2)] distorted penta-gonal-bipyramidal geometry with the N atoms in axial positions and an N-Cd-N angle of 176.94 (13) degrees . The metal atoms are bridged by 1,2-bis-[4-(pyridin-3-yl)pyrimidin-2-ylsulfan-yl]ethane ligands, giving a polymeric chain extending along the b axis. Adjacent chains related by an inversion center are further bridged by Cd-O bonds formed between the O atom of one of the acetate ligands and the metal atom. The five Cd-O bond lengths are in the range 2.329 (3)-2.485 (3) A. There are pi-pi stacking inter-actions between the aromatic rings of adjacent polymeric chains, the centroid-centroid distances being 3.556 (3) and 3.698 (3) A, organizing the chains into a three dimensional framework. This framework is additionally stabilized by extensive O H?O and O-H?N hydrogen bonding between water mol-ecules and the ligands. PMID- 22199541 TI - Poly[[tetra-aqua-(MU(4)-imidazole-4,5-dicarboxyl-ato)(MU(3)-imidazole-4,5 dicarboxyl-ato)-MU(3)-sulfato-MU(2)-sulfato-cobalt(II)digadolinium(III)] monohydrate]. AB - The asymmetric unit of the title compound, {[CoGd(2)(C(5)H(2)N(2)O(4))(2)(SO(4))(2)(H(2)O)(4)].H(2)O}(n), contains one Co(II) ion, two Gd(III) ions, two imidazole-4,5-dicarboxyl-ate ligands, two SO(4) (2-) anions, four coordinated water mol-ecules and one uncoordinated water mol ecule. The Co(II) ion is six-coordinated by two O atoms from two coordinated water mol-ecules, as well as two O atoms and two N atoms from two imidazole-4,5 dicarboxyl-ate ligands, giving a slightly distorted octa-hedral geometry. Both Gd(III) ions are eight-coordinated in a distorted bicapped trigonal-prismatic geometry. One Gd(III) ion is coordinated by four O atoms from two imidazole-4,5 dicarboxyl-ate ligands, three O atoms from three SO(4) (2-) anions and a water O atom; the other Gd(III) ion is bonded to five O atoms from three imidazole-4,5 dicarboxyl-ate ligands, two O atoms from two SO(4) (2-) anions as well as a water O atom. These metal coordination units are connected by bridging imidazole-4,5 dicarboxyl-ate and sulfate ligands, generating a heterometallic layer parallel to the ac plane. The layers are stacked along the b axis via N-H?O, O-H?O, and C-H?O hydrogen-bonding inter-actions, generating a three-dimensional framework. PMID- 22199542 TI - Tetra-aqua-bis-[3-(pyridin-4-yl)benzoato-kappaN]cobalt(II). AB - In the title compound, [Co(C(12)H(8)NO(2))(2)(H(2)O)(4)], the Co atom lies on a twofold rotation axis and has an N(2)O(4) octa-hedral coordination environment formed by four O atoms of water mol-ecules in the equatorial plane and two apical N atoms of pyridine groups. An intricate three-dimensional supra-molecular network is formed by multiple O-H?O hydrogen bonds between the coordinated water mol-ecules and the uncoordinated carboxyl-ate groups. PMID- 22199543 TI - 1-[(Ferrocen-1-yl)meth-yl]-3-(naphthalen-1-yl)thio-urea. AB - In the title compound, [Fe(C(5)H(5))(C(17)H(15)N(2)S)], the cyclo-penta-dienyl (Cp) rings are almost parallel and essentially eclipsed, with a dihedral angle between the Cp ring planes of 0.807 (11) degrees . The Fe atom is slightly closer to the substituted cyclo-penta-dienyl ring, with an Fe-centroid distance of 1.6510 (8) A, compared with 1.6597 (8) A for the unsubstituted ring. The bridging unit between the substituted Cp ring and the naphthyl ring system is planar within 0.0174 A and makes dihedral angles of 59.032 (10) and 66.02 (2) degrees , respectively, with these two rings. The angle between the substituted Cp ring and the naphthyl ring system is 72.094 (18) degrees . The H atoms of the NH groups of the thio-urea moiety are positioned anti with respect to each other. In the crystal, mol-ecules form centrosymmetric dimers via pairs of N-H?S hydrogen bonds. PMID- 22199544 TI - Poly[aqua-(MU(11)-4,6-dihy-droxy-benzene-1,3-disulfonato)-dipotassium]. AB - In the title salt, [K(2)(C(6)H(4)O(8)S(2))(H(2)O)](n), both K(+) ions exhibit a seven-coordination with K-O bond lengths in the range 2.6600 (14) to 3.0522 (16) A. One K(+) ion is coordinated by seven O atoms from the sulfonate and phenolic hy-droxy groups of six 4,6-dihy-droxy-benzene-1,3-disulfonate (L(2-)) anions while the other K(+) ion is coordinated by six O atoms from the sulfonate and phenolic hy-droxy groups of five L(2-) anions and one water O atom. The L(2-) anion exhibits chelating-bridging multidentate coordination to potassium, resulting in the formation of a cross-linked three-dimensional network. PMID- 22199545 TI - Tetra-aqua-bis-(2-{[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]sulfan-yl}acetato) cobalt(II) monohydrate. AB - In the title compound, [Co(C(9)H(6)N(3)O(3)S)(2)(H(2)O)(4)].H(2)O, the two 2-{[5 (pyridin-4-yl)-1,3,4-oxadiazol-2-yl]sulfan-yl}acetate ligands are monodentate. One coordinates the metal atom via the pyridyl N atom whereas the other coordinates via the carboxyl-ate O atom. The Co(II) atom adopts a slightly distorted octa-hedral coordination geometry with four O atoms of the coordinated water mol-ecules located in the equatorial plane and the N and O atoms of the two POA ligands in axial positions. In the crystal, the components are connected through O-H?O and O-H?N hydrogen bonds into a three-dimensional framework. PMID- 22199546 TI - [(Z)-1-({3-[(3-Amino-prop-yl)(2-nitro-benz-yl)amino]-prop-yl}imino-meth yl)naphthalen-2-olato]copper(II) perchlorate. AB - In the title compound, [Cu(C(24)H(27)N(4)O(3))]ClO(4), the Cu(II) atom has a distorted square-planar coordination geometry and is surrounded by an N(3)O donor set composed of a secondary amine N, a primary amine H, an imino N and a naphthalen-2-olate O atom. An intra-molecular N-H?O hydrogen bond occurs. In the crystal, mol-ecules are held together by inter-molecular N-H?O hydrogen bonds, leading to the formation of a three-dimensional network. PMID- 22199547 TI - Bis[5-(pyridin-2-yl)pyrazine-2-carbo-nitrile-kappaN,N]silver(I) perchlorate. AB - In the mononuclear title complex, [Ag(C(10)H(6)N(4))(2)]ClO(4), the Ag(I) ion is surrounded by two 5-(pyridin-2-yl)pyrazine-2-carbonitrile ligands, forming a considerably distorted square-planar N(4)-coordination geometry, with two short and two long Ag-N distances. Each perchlorate anion links two mononuclear coordination units through C-H?O(perchlorate) hydrogen bonding, forming an infinite tape structure along [110]. Inter-molecular pi-pi stacking inter-actions between adjacent pyridine and pyrazine rings [centroid-centroid distances of 3.777 (3) and 3.879 (2) A] further assemble the tape motifs into a three dimensional supra-molecular structure. PMID- 22199548 TI - Penta-carbonyl-1kappaC,2kappaC-(MU-pyrazine-2,3-dithiol-ato 1:2kappaS,S':S,S')(trimethyl-phosphane-1kappaP)diiron(I)(Fe-Fe). AB - In the title compound, [Fe(2)(C(4)H(2)N(2)S(2))(C(3)H(9)P)(CO)(5)], the Fe(2)S(2) core adopts a butterfly conformation. The PMe(3) ligand is coordinated in the basal position, roughly cis to the Fe-Fe bond. The Fe-Fe distance of 2.4970 (6) A is relatively short compared to those (ca 2.53 A) found in another monosubstituted diiron compound. A rigid planar dithiol-ate bridge is featured, with an angle of 2.78 (1) degrees between the Fe-Fe bond and the normal to the pyrazine-2,3-dithiol-ate plane. PMID- 22199549 TI - cis-Aqua-bis-(di-2-pyridyl-amine-kappaN,N')iodidomanganese(II) iodide. AB - The asymmetric unit of the title compound, [MnI(C(10)H(9)N(3))(2)(H(2)O)]I, contains a cationic Mn(II) complex and an I(-) anion. In the complex, the Mn(II) ion is six-coordinated in a considerably distorted cis-N(4)IO octa-hedral environment defined by four N atoms of the two chelating di-2-pyridyl-amine (dpa) ligands, one I(-) anion and one O atom of a water ligand. As a result of the different trans effects of the I, N and O atoms, the Mn-N bond trans to the I atom is slightly longer than the Mn-N bond trans to the N or O atoms. The dpa ligands are not planar, with dihedral angles between the two pyridine rings of 26.2 (4) and 26.5 (4) degrees . The complex cations are stacked in columns along the a axis and are linked to the anions by inter-molecular O-H?I and N-H?I hydrogen bonds. PMID- 22199550 TI - Tetra-aqua-bis-[N,N'-bis-(pyridin-3-yl-methyl-idene)benzene-1,4-diamine]-zinc dinitrate 1.49-hydrate. AB - In the title compound, [Zn(C(18)H(14)N(4))(2)(H(2)O)(4)](NO(3))(2).1.49H(2)O, the Zn(II) atom, lying on an inversion center, is coordinated by two N atoms from two N,N'-bis-(pyridin-3-yl-methyl-idene)benzene-1,4-diamine ligands and four water mol-ecules in a distorted octa-hedral geometry. The nitrate anion is disordered over two sets of sites, with an occupancy ratio of 0.744 (4):0.256 (4). The uncoordinated water mol-ecule is also disordered with an occupancy factor of 0.744 (4). O-H?O and O-H?N hydrogen bonds link the complex cations, nitrate anions and uncoordinated water mol-ecules into a supra-molecular layer parallel to (102). PMID- 22199551 TI - Penta-carbonyl-1kappaC,2kappaC-(4-iodo-phenyl isocyanide-1kappaC)(MU-propane-1,3 dithiol-ato-1:2kappaS,S':S,S')iron(I)(Fe-Fe). AB - In the title compound, [Fe(2)(C(7)H(4)IN)(C(3)H(6)S(2))(CO)(5)], the Fe-Fe distance of 2.5156 (11) A compares well with that in related model structures. The phenyl isocyanide ligand is in the basal position and trans to the S atoms of the propane-dithiol-ate ligand due to steric hindrance. The crystal structure features C-H?O inter-actions. PMID- 22199552 TI - Aqua-{tris-[(1H-benzimidazol-2-yl-kappaN)meth-yl]amine}-zinc 5-(dimethyl-amino) naphthalene-1-sulfonate perchlorate 2.5-hydrate. AB - In the title compound, [Zn(C(24)H(21)N(7))(H(2)O)](C(12)H(12)NO(3)S)(ClO(4)).2.5H(2)O, the Zn(II) ion is in a distorted trigonal-bipyramidal coordination geometry. In the crystal, N-H?O and O-H?O hydrogen bonds connect the components into a two-dimensional network parallel to (001). In addition, there are weak C-H?O hydrogen bonds. PMID- 22199553 TI - 1,1'-[(Biphenyl-4,4'-di-yl)bis-(methyl-ene)]di-1H-imidazol-3-ium tetra-chlorido mercurate(II). AB - In the title compound, (C(20)H(20)N(4))[HgCl(4)], the Hg(II) ion is four coordinated in a tetra-hedral environment defined by four chloride ions. The dihedral angle between the two phenyl rings is 32.83 (15) degrees . The protonated 1,1'-[(biphenyl-4,4'-di-yl)bis-(meth-yl-ene)]di-1H-imidazol-3-ium cations, showing a cis conformation, link the [HgCl(4)](2-) anions into an R(4) (4)(42) motif via N-H?Cl hydrogen bonds. PMID- 22199554 TI - Tetra-aqua-bis-{5-[4-(imidazol-1-yl-kappaN)phen-yl]tetra-zolido}manganese(II). AB - In the title complex, [Mn(C(10)H(7)N(6))(2)(H(2)O)(4)], the Mn(2+) cation is located on a twofold rotation axis and is coordinated by two N atoms from two 5 [4-(imidazol-1-yl)phen-yl]tetra-zolide ligands and four O atoms from four water mol-ecules, displaying a distorted MnN(2)O(4) octa-hedral geometry. The crystal structure is stabilized by intermolecular O-H?N hydrogen bonds involving the coordinated water mol-ecules and the N atoms of the tetra-zolide group. PMID- 22199555 TI - catena-Poly[[(1,10-phenanthroline-kappaN,N')zinc]-MU-4-sulfonato-benzo-triazolido kappaN,O:N]. AB - In the title complex, [Zn(C(6)H(3)N(3)O(3)S)(C(12)H(8)N(2))](n), the Zn(2+) cation is coordinated by two N atoms from two 4-sulfonato-benzotriazolide dianions, two N atoms from a 1,10-phenanthroline mol-ecule and a sulfonate O atom from a 4-sulfonato-benzotriazolide anion, displaying a distorted ZnN(4)O trigonal bipyramidal geometry. Each 1,10-phenanthroline ligand displays a bidentate chelating coordinating mode and the 4-sulfonato-benzotriazolide ions act as MU(2) bridges, linking different Zn(2+) cations into a chain along the b axis. The crystal structure is consolidated by C-H?O hydrogen-bonding inter-actions. PMID- 22199556 TI - 4-[3-(Isonicotino-yloxy)propoxycarbon-yl]pyridinium diiodidoargentate(I). AB - The structure of the title compound, (C(15)H(15)N(2)O(4))[AgI(2)], consists of an organic 4-[3-(isonicotino-yloxy)propoxycarbon-yl]pyridinium cation which has a gauche-gauche (O/C/C/C-O/C/C/C or GG') conformation and lies on a twofold rotation axis, which passes through the central C atom of the aliphatic chain, and an inorganic [AgI(2)](-) anion. In the complex anion, the Ag(+) cation is bound to two I(-) anions in a linear geometry. The anion was modelled assuming disorder around a crystallographic inversion centre near the location of the Ag(+) cation. The crystal packing is stabilized by a strong inter-molecular N-H?N hydrogen bond, which links the cations into zigzag chains with graph-set notation C(16) running along the face diagonal of the ac plane. The N-bound H atom is disordered over two equally occupied symmetry-equivalent sites, so that the mol ecule has a pyridinium ring at one end and a pyridine ring at the other. PMID- 22199557 TI - Ethyl (Z)-4-ferrocenyl-2-(4-hy-droxy-anilino)-4-oxobutenoate. AB - In the title compound, [Fe(C(5)H(5))(C(17)H(16)NO(4))], the O=C-C=C-N mean plane is twisted with respect to the mean planes of the benzene and substituted cyclo penta-dienyl rings by 44.2 (2) and 13.8 (3) degrees , respectively. Furthermore, the O=C-C=C-N mean plane and the O=C-O(ester) plane make a dihedral angle of 55.5 (6) degrees . Consistent with this large dihedral angle, the linking C-C bond [1.507 (6) A] does not show any (delocalized) double-bond character. PMID- 22199558 TI - Monoclinic form of (Z)-1-ferrocenyl-3-(3-hy-droxy-anilino)but-2-en-1-one. AB - The title compound, [Fe(C(5)H(5))(C(15)H(14)NO(2))], is a monoclinic polymorph of the previously reported triclinic form [Shi et al. (2006 ?). Acta Cryst. C62, m407-m410]. The polymorphs feature the same strong intra-molecular N-H?O=C hydrogen bonds, but show different packing modes. The mol-ecules in the monoclinic form associate into double chains via O-H?O=C and (Cp)C-H?O-H inter actions. PMID- 22199559 TI - Undeca-carbonyl-MU(2)-methane-thiol-ato-MU(2)-[(pyridin-2-yl)methane-thiol-ato] MU(4)-sulfido-tetra-iron(II)(2 Fe-Fe). AB - The title compound, [Fe(4)(C(6)H(6)NS)(CH(3)S)S(CO)(11)], com-prises two butterfly-shaped sub-cluster cores, Fe(2)S(2)N and Fe(2)S(2), joined together by a spiro-type MU(4)-S atom. The (pyridin-2-yl)methane-thiol-ate ligand is attached to the Fe(2)(CO)(5) unit in a MU-kappaN:kappa(2)S mode, and the methane-thiol-ate ligand is coordinated to the Fe(2)(CO)(6) unit in a MU-kappa(2)S fashion. PMID- 22199560 TI - catena-Poly[(dichloridozinc)-MU-bis-(pyridin-3-yl)methanone-kappaN:N']. AB - In the title polymer, [ZnCl(2)(C(11)H(8)N(2)O)](n), the Zn(II) atom lies on a twofold rotation axis and has a distorted tetra-hedral ZnCl(2)N(2) geometry involving two chloride donors and two N-atom donors from MU(2)-bridging bis (pyridin-3-yl)methanone ligands, which also have twofold symmetry. A zigzag chain structure is formed, extending along (001). Each chain is surrounded by three others which are inter-connected through weak C=O?pi(pyrid-yl) [O?centroid = 2.999 (3) A] and pi(pyrid-yl)-pi(pyrid-yl) inter-actions [minimum ring centroid separation = 4.014 (2) A], giving a three-dimensional framework. PMID- 22199561 TI - Bis[N-(pyridin-2-ylcarbon-yl)pyridine-2-carboxamidato]iron(III) perchlorate monohydrate. AB - The structure of the title salt complex, [Fe(C(12)H(8)N(3)O(2))(2)]ClO(4).H(2)O, contains one Fe(III) cation, two N-(pyridin-2-ylcarbon-yl)pyridine-2 carboxamidate (bpca(-)) anions, one perchlorate anion and one water mol-ecule. The Fe(III) cation has an approximate octa-hedral geometry, defined by six N atoms from two bpca(-) anions. The nearly parallel [dihedral angle = 1.50 (1) degrees ] bpca(-) anions form two-dimensional supermolecules along the a axis by the way of weak pi-pi stacking inteactirons [centroid-centroid distances = 3.948 (2), 4.000 (2), 3.948 (2), 3.911 (2), 3.897 (2), 3.984 (2) and 3.929 (2) A]. Intra- and inter-molecular C-H?O hydrogen bonding occurs. The water mol-ecule [occupancies 0.520 (5) and 0.480 (5)], two carbonyl O atoms [occupancies 0.622 (7) and 0.378 (7)] and the four perchlorate O atoms [occupancies 0.887 (4) and 0.113 (4)] are each disordered over two positions. PMID- 22199562 TI - Poly[[tetra-aqua-(MU(3)-naphthalene-1,6-disulfonato-kappaO:O,O:O)strontium(II)] monohydrate]. AB - In the crystal structure of the polymeric title compound, {[Sr(C(10)H(6)O(6)S(2))(H(2)O)(4)].H(2)O}(n), the naphthalene-1,6-disulfonate dianion uses one -SO(3) unit to O,O'-chelate to an Sr(II) cation and its third O atom to bind to another Sr(II) cation. The other -SO(3) unit binds to yet another Sr(II) atom. The four coordinated water mol-ecules are monodentate but one is disordered over two positions in a 1:1 ratio. The MU(3)-bonding mode of the dianion generates a polymeric three-dimensional network; the network is consolidated by O-H?O hydrogen bonds. The Sr(II) cation exists in an undefined eight-coordinate environment. PMID- 22199563 TI - Bis[MU-N-(pyridin-2-ylmeth-yl)pyridin-2-amine-kappaN:N']disilver(I) bis(trifluoro methane-sulfonate). AB - In the binuclear title compound, [Ag(2)(C(11)H(11)N(3))(2)](CF(3)O(3)S)(2), the complex cation is centrosymmetric, with the unique Ag(+) cation coordinated by two pyridine N atoms from two symmetry-related N-(pyridin-2-ylmeth-yl)pyridin-2 amine ligands in a geometry slightly distorted from linear [N-Ag-N 161.02 (7) degrees ]. This set-up leads to the formation of a 14-membered cyclic dimer. The two pyridine rings coordinated to the Ag(+) cation are tilted by 80.19 (7) degrees with respect to each other. Inter-molecular N-H?O hydrogen-bonding inter actions between the cyclic dimer and the anion exist. A two-dimensional network parallel to the ac plane is constructed by three weak Ag?(O,N) inter-actions as well as an F?F contact of 2.890 (4) A. PMID- 22199564 TI - catena-Poly[[(triaqua-cadmium)-MU-1,4-phenyl-enediacetato-kappaO,O':O'',O'''] dihydrate]. AB - In the title compound, {[Cd(C(10)H(8)O(4))(H(2)O)(3)].2H(2)O}(n), penta-gonal bipyramidally coordinated Cd(II) ions on a twofold rotation axis are linked by tethering 1,4-phenyl-enediacetate (1,4-phda) ligands into [Cd(1,4 phda)(H(2)O)(3)](n) coordination polymer chains. The chain motifs are oriented parallel to the c-axis direction. Individual chains are connected into a supra molecular network via O-H?O hydrogen bonding involving the aqua ligands. PMID- 22199565 TI - Bis-(2-methyl-1H-imidazole-kappaN)bis[2-(naphthalen-2-yl)acetato kappaO]copper(II). AB - In the crystal structure of the title compound, [Cu(C(12)H(9)O(2))(2)(C(4)H(6)N(2))(2)], the Cu(II) cations are square-planar coordinated by two 1-naphthyl-acetate anions and two 2-methyl-imidazole ligands into discrete complexes that are located on centres of inversion. These complexes are linked into chains parallel to [010] by inter-molecular N-H?O hydrogen bonding between the N-H H atom of the 2-methyl-imidazole ligands and the carboxyl ate O atoms that are not involved in metal coordination. PMID- 22199566 TI - cis-Aqua-bromidobis(di-2-pyridyl-amine-kappaN,N')manganese(II) bromide. AB - In the title compound, [MnBr(C(10)H(9)N(3))(2)(H(2)O)]Br, the Mn(II) ion is six coordinated in a considerably distorted cis-N(4)BrO octa-hedral environment defined by four N atoms of two chelating di-2-pyridyl-amine (dpa) ligands, one Br(-) anion and one O atom of a water ligand. As a result of the different trans effects of Br, N and O atoms, the Mn-N bond trans to the Br atom is slightly longer than the Mn-N bond trans to the N or O atoms. In the crystal, the dpa ligands are not planar, the dihedral angles between the two pyridine rings being 29.2 (4) and 28.2 (3) degrees . The complex cations and the Br(-) anions are linked by inter-molecular O-H?Br and N-H?Br hydrogen bonds. Inter-molecular pi-pi inter-actions are present between the pyridine rings, with a centroid-centroid distance of 3.793 (4) A. PMID- 22199567 TI - cis-Bis(2,2'-bipyridine-kappaN,N')bis-(dimethyl sulfoxide-kappaO)zinc bis-(tetra phenyl-borate) dimethyl sulfoxide monosolvate. AB - In the mononuclear title complex, [Zn(C(10)H(8)N(2))(2)(C(2)H(6)OS)(2)](C(24)H(20)B)(2).C(2)H(6)OS, the Zn(II) ion is coordinated by four N atoms of two bidentate 2,2'-bipyridine mol-ecules and by the O atoms of two cis-disposed dimethyl sulfoxide mol-ecules in a distorted octa hedral geometry. The S atom and the methyl groups of one of the coordinated dimethyl sulfoxide mol-ecules are disordered in a 0.509 (2):0.491 (2) ratio. The crystal packing is stabilized by C-H?O hydrogen bonds between the dimethyl sulfoxide solvent mol-ecules and tetra-phenyl-borate anions. PMID- 22199568 TI - Bis[tris-(ethyl-enediamine-kappaN,N')cobalt(III)] octa-kis-MU-(3)-oxido-hexa-deca MU(2)-oxido-tetra-deca-oxido-MU(12)-tetra-oxo-silicato-octa-molybdenum(VI)hexa vanadium(IV,V) hexa-hydrate. AB - The title compound, [Co(C(2)H(8)N(2))(3)](2)[SiMo(8)V(4)O(40)(VO)(2)].6H(2)O, was prepared under hydro-thermal conditions. The asymmetric unit consists of a transition metal complex [Co(en)(3)](3+) cation (en is ethyl-enediamine), one half of an [SiMo(8)V(4)O(40)(VO)(2)](6-) heteropolyanion, two solvent water mol ecules in general positions and two half-mol-ecules of water located on a mirror plane. In the complex cation, the Co(3+) ion is in a distorted octa-hedral coordination environment formed by six N atoms of the three chelating en ligands. One of the en ligands exhibits disorder of its aliphatic chain over two sets of sites of equal occupancy. The [SiMo(8)V(4)O(40)(VO)(2)](6-) heteropolyanion is a four-electron reduced bivanadyl-capped alpha-Keggin-type molybdenum-vanadium oxide cluster. In the crystal, it is located on a mirror plane, which results in disorder of the central tetra-hedral SiO(4) group: the O atoms of this group occupy two sets of sites related by a mirror plane. Furthermore, all of the eight MU(2)-oxide groups are also disordered over two sets of sites with equal occupancy. There are extensive inter-molecular N-H?O hydrogen bonds between the complex cations and inorganic polyoxidoanions, leading to a three-dimensional supra-molecular network. PMID- 22199569 TI - MU(3)-Dodeca-tungsto(V,VI)aluminato-kappaO:O':O''-tris-[aqua-bis-(ethyl-ene diamine-kappaN,N')copper(II)]. AB - The title compound, [AlCu(3)W(12)O(40)(C(2)H(8)N(2))(6)(H(2)O)(3)], was prepared under hydro-thermal conditions. The Cu(2+) ion displays an elongated octa-hedral geometry defined by one bridging O atom from the polyoxidoanion and a coordinated water mol-ecule in axial positions and four N atoms of the two chelating ethyl enediamine (en) ligands in equatorial positions. The one-electron reduced [AlW(12)O(40)](6-) anion coordinates three [Cu(en)(H(2)O)](2+) fragments, generating a neutral tri-supported Keggin-type polyoxidometalate (POM). This tri supported POM is located in a special position of [Formula: see text] symmetry and therefore O atoms from the central AlO(4) tetra-hedron are disordered over two sets of sites. Disorder is also observed for three other bridging O atoms of the POM. In the crystal, mol-ecules are connected via N-H?O and O-H?O hydrogen bonds, forming a three-dimensional framework. PMID- 22199570 TI - Tetra-kis[diamminesilver(I)] bis-(2-hy-droxy-5-methyl-benzene-1,3-disulfonate) monohydrate. AB - In the crystal structure of the title salt, [Ag(NH(3))(2)](4)(C(7)H(6)O(7)S(2))(2).H(2)O, the four independent Ag(I) complex cations all lie on special positions of m site symmetry, as do the two independent 2-hy-droxy-5-methyl-benzene-1,3-disulfonate anions. The Ag(I) cations exist in an almost linear coordination geometry [N-Ag-N = 175.2 (2), 178.08 (16), 175.8 (2) and 178.20 (19) degrees ]. The water mol-ecule is disordered about a mirror plane. Two independent complex cations are linked by an Ag?Ag inter-action of 3.3151 (1) A, furnishing a linear [Ag(NH(3))(2)](n) polycationic chain running along b. The free complex cations, polycationic chain and 2-hy-droxy-5-methyl benzene-1,3-disulfonate anions inter-act via N-H?O and O-H?O hydrogen bonds, forming a three-dimensional network. PMID- 22199571 TI - Diaqua-bis-(pyridine-2-sulfonato-kappaN,O)cobalt(II). AB - The title complex, [Co(C(5)H(4)NO(3)S)(2)(H(2)O)(2)], lies on a twofold rotation axis that relates the two water mol-ecules and the two pyridine-2-sulfonate ions. The Co(II) atom exists in an slightly distorted octa-hedral environment. The N donor atoms are cis to each other. In the crystal, adjacent mol-ecules are linked by O-H?O hydrogen bonds into a layer motif extending along (001). PMID- 22199572 TI - Poly[di-MU(2)-aqua-MU(5)-(pyridine-2,6-dicarboxyl-ato)-MU(3)-(pyridine-2,6 dicarboxyl-ato)-cobalt(II)disodium]. AB - In the title compound, [CoNa(2)(C(7)H(3)NO(4))(2)(H(2)O)(2)](n), the Co(II) atom is coordinated by two pyridine N atoms and four carboxyl-ate O atoms from two doubly deprotonated pyridine-2,6-dicarboxyl-ate ligands in a distorted octa hedral geometry. One Na(+) cation is coordinated by three carboxyl-ate O atoms and two water mol-ecules and the other is coordinated by five carboxyl-ate O atoms and two water mol-ecules in an irregular geometry. The bis-(pyridine-2,6 dicarboxyl-ato)cobalt complex units are connected by Na(+) cations and bridging water mol-ecules into a three-dimensional coordination network. O-H?O hydrogen bonds are formed between the water mol-ecules and the carboxyl-ate O atoms. PMID- 22199574 TI - Acetonitrile-trichloridobis(cyclo-hexyl-diphenyl-phosphane)rhodium(III) acetonitrile disolvate. AB - In the title compound, [RhCl(3)(CH(3)CN)(C(18)H(21)P)(2)].2CH(3)CN, the complex mol-ecule lies on a twofold rotation axis that passes through the Rh(III) atom, one Cl atom, and the C and N atoms of the coordinated acetonitrile mol-ecule. The Rh(III) atom is coordinated by two P atoms in trans positions, three Cl atoms and an acetonitrile mol-ecule in a distorted octa-hedral geometry. Intra-molecular C H?Cl inter-actions are observed. The uncoordinated acetonitrile mol-ecule is disordered over two sites with occupancies of 0.588 (4) and 0.412 (4). PMID- 22199573 TI - catena-Poly[[diacetonitrile-copper(I)]-MU-dicyanamido]. AB - The crystal structure of the title compound, [Cu(C(2)N(3))(C(2)H(3)N)(2)](n), features zigzag chains along the a axis that consist of alternating [Cu(MeCN)(2)] and dicyanamide units, the latter acting as bidentate ligands via both terminal N atoms. The Cu atom shows a slightly distorted tetra-hedral coordination sphere. The anionic and neutral ligands lie on different mirror planes (perpendicular to the b and a axis, respectively), while the Cu atom is situated on their inter section. The asymmetric unit comprises one fourth of the formula unit. PMID- 22199575 TI - Poly[MU(2)-aqua-aqua-MU(5)-naphthalene-2,7-disulfonato-strontium]. AB - In the crystal structure of the polymeric title compound, [Sr(C(10)H(6)O(6)S(2))(H(2)O)(2)](n), the naphthalene-2,7-disulfonate dianion uses one -SO(3) unit to bind to two Sr(II) cations and the other -SO(3) unit to bind to three Sr(II) cations; of the two coordinated water mol-ecules, one is monodentate to one Sr(II) cation, whereas the other bridges two Sr(II) cations. The MU(5)-bridging mode of the dianon and the MU(2)-bridging mode of the water mol-ecule generate a polymeric three-dimensional network which is consolidated by O-H?O hydrogen bonds. The Sr(II) cation exists in an undefined eight-coordinate environment. PMID- 22199576 TI - A new Ag complex based on 1-[(1H-benzimidazol-1-yl)meth-yl]-1H-1,2,4-triazole. AB - In the title complex, bis-{MU-1-[(1H-benzimidazol-1-yl)meth-yl]-1H-1,2,4 triazole}disilver(I) dinitrate, [Ag(2)(C(10)H(9)N(5))(2)](NO(3))(2), the Ag(I) ion is nearly linearly coordinated [N-Ag-N angle is 155.72 (14) degrees ] by two 1-[(1H-benzimidazole-1-yl)meth-yl]-1H-1,2,4-triazole (bmt) ligands. In addition, two bmt ligands link two Ag(I) ions, forming a dinuclear unit with an Ag?Ag distance of 5.0179 (15) A. The whole complex is generated by an inversion centre. The dinuclear units and the NO(3) (-) counter-ions are connected by N-H?O hydrogen bonds and weak Ag?O inter-actions [2.831 (5), 2.887 (5) and 2.908 (5) A], leading to a three-dimensional structure. PMID- 22199577 TI - catena-Poly[[chlorido(1,10-phenanthro-line)copper(II)]-MU-{2-[(1S,3S)-3-acetyl 2,2-dimethyl-cyclo-but-yl]acetato}]. AB - The title compound, [Cu(C(10)H(15)O(3))Cl(C(12)H(8)N(2))](n), is a one dimensional coordination polymer. The Cu(II) atom is coordin-ated by a chloride ion, two N atoms from the 1,10-phenanthroline ligand, and a monodentate carboxyl ate O atom from the pinononate anion, forming a CuN(2)ClO approximate square plane. A symmetry-generated pinononate O atom completes a square-based pyramidal geometry for the copper ion. The bridging 2-(3-acetyl-2,2-dimethyl-cyclo-but yl)acetate anion leads to chains in the crystal propagating in [001]. Adjacent 1,10-phenanthroline rings form a dihedral angle of 39.4 (2) degrees . PMID- 22199578 TI - Dicarbon-yl(pyrazine-1,3-dithiol-ato-kappaS,S')bis-(trimethyl-phosphane kappaP)iron(II). AB - The title compound, [Fe(C(4)H(2)N(2)S(2))(C(3)H(9)P)(2)(CO)(2)], was obtained as a mononuclear by-product during the treatment of [Fe(2)(MU S(2)C(4)N(2)H(2))(CO)(6)] in excess trimethyl-phosphane. The Fe atom is six coordinated by two thiol-ate S atoms, two phosphane P atoms and two carbonyl C atoms in a distorted octa-hedral geometry. The average Fe-C(O) distance (1.771 A) is relatively shorter than that of its parent hexa-carbonyl-diiron compound, and differs by 0.511 A from the average Fe-P(Me)(3) distance. The five-membered FeC(2)S(2) chelate ring plane is close to being perpendicular to the P/Fe/P plane [86.5 (2) degrees ]. PMID- 22199579 TI - (Tris{2-[(5-hy-droxy-pyridin-2-yl-kappaN)methyl-idene-imino-kappaN]eth-yl}amine) zinc dinitrate. AB - In the complex cation of the title compound, [Zn(C(24)H(27)N(7)O(3))](NO(3))(2), the tripodal tris-{[2-(5-hy-droxy-pyridin-2-yl)methyl-idene-imino]-eth-yl}amine ligand is coordin-ated to the Zn atom through the three pyridine and three imino N atoms. The coordination sphere of the Zn atom is based on an octahedron with a significant distortion towards trigonal prismatic, the twist angle being 45.58 (9) degrees . The crystal packing is formed by L and D anti-podes arranged in layers disposed parallel to the b axis. Strong O-H?O hydrogen bonding exists between the hy-droxy groups of the ligand and the nitrate anion. PMID- 22199580 TI - Benzyl-triethyl-ammonium aqua-trichlorido-zincate. AB - In the crystal structure of the title mol-ecular salt, (C(13)H(22)N)[ZnCl(3)(H(2)O)], the distorted tetrahedral anions are linked by O H?Cl hydrogen bonds, generating [100] chains. Weak cation-to-anion C-H?Cl inter actions generate a three-dimensional network. PMID- 22199581 TI - Tris(1,10-phenanthroline-kappaN,N')nickel(II) dinitrate tetra-hydrate. AB - In the title complex, [Ni(C(12)H(8)N(2))(3)](NO(3))(2).4H(2)O, the Ni(II) ion is octa-hedrally coordinated by three bidentate 1,10-phenanthroline ligands, each forming a five-membered chelate ring. In the crystal, O-H?O and C-H?O hydrogen bonds are present between the complex cations, nitrate anions and water mol ecules. O-H?O hydrogen bonds between the uncoord-inated water mol-ecules lead to the formation of a four-membered ring water cluster, with a planar configuration. There were an additional five grossly disordered water mol-ecules in the asymmetric unit, which were removed by the subroutine SQUEEZE; these were were excluded in the calculation of the molecular weight, etc. pi-pi stacking inter actions between the aromatic rings are also observed [centroid-centroid distances = 3.697 (2), 3.728 (2) and 3.761 (2) A]. PMID- 22199582 TI - Aqua-(1,10-phenanthroline-kappaN,N')(valinato-kappaN,O)copper(II) nitrate dihydrate. AB - In the title compound, [Cu(C(5)H(10)NO(2))(C(12)H(8)N(2))(H(2)O)]NO(3).2H(2)O, the Cu(II) atom displays a distorted square-pyramidal coordination (tau = 0.03) where the water mol-ecule occupies the apical position and the base is defined by the N atom, one of the O atoms from the valinate ligand, and both phenanthroline N atoms. The phenanthroline chelate ring plane is slightly distorted from planarity (r.m.s. deviation = 0.0057 A), whereas the five-membered ring formed by the valinate ligand presents an envelope conformation with the N atom being the flap atom. The crystal packing is stabilized by O-H?O and N-H?O hydrogen-bonding inter-actions, creating a three-dimensional network superstructure. PMID- 22199583 TI - catena-Poly[[[cis-aqua-dibromido-cobalt(II)]-MU-(pyrazine-2-carb-oxy-lic acid) kappaN,O:N] monohydrate]. AB - The title compound, {[CoBr(2)(C(5)H(4)N(2)O(2))(H(2)O)].H(2)O}(n), is a one dimensional coordination polymer which crystallizes as a monohydrate. The asymmetric unit contains one Co(II) atom in a distorted octa-hedral geometry, forming a chain parallel to [010] with the pyrazine carb-oxy-lic acid ligands coordinating on one side in a bidentate fashion through one N and one O atom, and in a monodentate fashion through a N atom, with N atoms trans, and with both ligands lying in the same plane. The bromide atoms are cis to each other, while a water mol-ecule occupies the final octa-hedral coordination site. The chains are linked together though an O-H?Br hydrogen bonding network, and are further stabilized by an O-H?Br and O-H?O hydrogen-bonding framework with the solvent water mol-ecule. PMID- 22199584 TI - cis-Bis(benzyl-diphenyl-phosphane-kappaP)dichloridoplatinum(II) dichloro-methane sesquisolvate. AB - The asymmetric unit of the title compound, [PtCl(2)(C(19)H(17)P)(2)](2).3CH(2)Cl(2), contains two complex mol-ecules and three dichloro-methane solvent mol-ecules, two of which are disordered over various positions. The Pt(II) complexes reveal a slightly distorted square-planar geometry with average Pt-P and Pt-Cl bond lengthss of 2.252 (8) and 2.363 (8) A, respectively, and average P-Pt-P and Cl-Pt-Cl angles of 99.17 (8) and 87.1 (7) degrees , respectively. PMID- 22199585 TI - Anhydrous penta-guanidinium dihydrogen nona-vanado(IV)platinate(IV). AB - The title compound, (CH(6)N(3))(5)[H(2)PtV(9)O(28)], containing the nona vanadoplatinate(IV) polyanion, was obtained by hydro-thermal reaction. The polyanion has approximate C(2v) symmetry. The two Pt-bound MU(2)-O atoms are protonated in the polyanion. The heteropolyanions form inversion-generated dimers, {[H(2)PtV(9)O(28)](2)}(10-), held together by each of the two MU(2)-O H?MU(2)-O and MU(2)-O-H?MU(3)-O hydrogen bonds. The guanidinium cations are hydrogen bonded with the MU(2)- and terminal O atoms of the polyanion, connecting the polyanions into a three-dimensional network. PMID- 22199586 TI - Bis[MU(2)-1-(2-carb-oxy-benzo-yl)thio-semi-carbazide(3-)]hexa-pyridine trinickel(II) pyridine monosolvate monohydrate. AB - The reaction of Ni(OAc)(2).4H(2)O with 1-(2-carb-oxy-benzo-yl)thio-semicarbazide (H(3)L) produces the title complex, [Ni(3)(C(9)H(6)N(3)O(3)S)(2)(C(5)H(5)N)(6)].C(5)H(5)N.2H(2)O, which contains an linear array of three Ni(II) atoms. The asymmetric unit contains half of the complex mol-ecule, a water mol-ecule and a half-mol-ecule of pyridine. The central Ni(II) atom, located on a crystallographic inversion centre, has an octa hedral N(4)O(2) environment. The other two Ni(II) atoms have a square-pyramidal N(3)OS environment, each bridged to the central Ni(II) atom via the L(3-) group. The carboxyl-ate groups coordinate to the metal atoms in a monodentate fashion. The water mol-ecule is linked to the complex mol-ecule via O-H?O hydrogen bonds. The mol-ecules further assemble into a one-dimensional network parallel to [001] via inter-molecular N-H?O hydrogen bonds. PMID- 22199587 TI - [1,5-Bis(2-meth-oxy-phen-yl)thio-carbazo-nato-kappaN,S]phenyl-mercury(II). AB - The title compound, [Hg(C(6)H(5))(C(15)H(15)N(4)O(2)S)], shows the metal-phenyl moiety coordinated out of plane with the thio-carbazo-nate ligand by 43.84 (6) degrees . Important geometrical parameters include Hg-S = 2.3653 (10) A, Hg-C = 2.058 (4) A and S-Hg-C = 179.06 (11) degrees . There is a weak coordination of an N atom of the ligand to Hg [Hg-N = 2.725 (3) A]. S?Hg inter-actions[3.2928 (10) A] form chains along [001], stabilizing the crystal structure. PMID- 22199588 TI - catena-Poly[[chloridodimethyl-tin(IV)]-MU-chloro-acetato-kappaO:O']. AB - In the title polymeric coordination compound, [Sn(CH(3))(2)(C(2)H(2)ClO(2))Cl](n), the Sn atom has a distorted trigonal bipyramidal geometry, with two O atoms of the ligands in axial positions and two methyl groups and one Cl atom in equatorial positions. Adjacent Sn atoms are bridged by the two O atoms of the carboxylate ligand, forming a chain structure along the a-axis direction. PMID- 22199589 TI - {(R,S(Fc),S(Fc))-2''-Bromo-2-[1-(dimethyl-amino)-ethyl-kappaN]-1,1'' biferrocene}trihydridoboron. AB - The title structure, [Fe(2)(C(5)H(5))(2)(C(14)H(19)BBrN)], contains a chiral and asymmetrically 2,2''-disubstituted biferrocene designed as precursor for enanti oselective non-C(2)-symmetric biferrocenyldiphosphine catalysts. The mean bond lengths in the biferrocene unit are Fe-C = 2.048 (10) A and C-C = 1.427 (8) A within the cyclo-penta-dienyl rings. The B-N bond lengths of the BH(3) protected amine is 1.631 (3) A. The inter-planar angle between the two connected cyclo penta-dienyl rings is 54.29 (8) degrees and the corresponding Fe-Cg-Cg-Fe torsion angle is -52.5 degrees . The conformation of the mol-ecule is stabilized by an intra-molecular C-H?Br inter-action. PMID- 22199590 TI - Bis{1,2-bis-[bis-(3-meth-oxy-prop-yl)phosphan-yl]ethane-kappaP,P'}dichlorido osmium(II). AB - In the centrosymmetric title compound, [OsCl(2)(C(18)H(40)O(4)P(2))(2)], the Os(II) atom adopts a trans-OsCl(2)P(4) geometry, arising from its coordination by two chelating diphosphane ligands and two chloride ions. One of the meth-oxy side chains of the ligand is disordered over two orientations in a 0.700 (6):0.300 (6) ratio. PMID- 22199591 TI - catena-Poly[[triphenyl-tin(IV)]-MU-3-methyl-phenyl-seleninato-kappaO:O']. AB - In the polymeric title coordination compound, [Sn(C(6)H(5))(3)(C(7)H(7)O(2)Se)](n), the Sn(IV) atom has a distorted trigonal bipyramidal geometry, with two O atoms from two symmetry-related bridging seleninate ligands in axial positions and three phenyl groups in the equatorial plane. In the crystal, the complex exhibits a zigzag chain structure running parallel to the c axis. An intra-chain C-H?O hydrogen bond is observed. PMID- 22199592 TI - Chlorido[1-(pyridin-2-yl)ethanone oximato-kappaN,N'][1-(2-pyrid-yl)ethanone oxime kappaN,N']copper(II) trihydrate. AB - In the title compound, [Cu(C(7)H(7)N(2)O)Cl(C(7)H(8)N(2)O)].3H(2)O, the metal ion is five-coordinated by the N atoms from the 1-(pyridin-2-yl)ethanone oximate and 1-(pyridin-2-yl)ethanone oxime ligands and by the chloride anion in a distorted square-pyramidal geometry. The distortion parameter is 0.192. The two organic ligands are linked by an intra-molecular O-H?O hydrogen bond. In the crystal, mol ecules are linked by O-H?O and O-H?Cl hydrogen bonds. The title compound is the hydrated form of a previously reported structure [Wu & Wu (2008 ?). Acta Cryst. E64, m828]. There are only slight variations in the mol-ecular geometries of the two compounds. PMID- 22199593 TI - Tris(3-methyl-anilinium) penta-chlorido-anti-monate(III) chloride. AB - In the title compound, (C(7)H(10)N)(3)[SbCl(5)]Cl, the Sb(III) cation is coordinated by five Cl(-) anions in a distorted square-pyramidal geometry, in which the longest Sb-Cl distance of 3.0319 (14) A indicates a weak coordination bond. In the crystal, the 3-methyl-anilinium cations link with the complex antimonate anions and Cl(-) anions via N-H?Cl hydrogen bonds. PMID- 22199594 TI - Bis{3-[2-(methyl-sulfon-yl)pyrimidin-4-yl]pyridinium} tetra-chloridocadmium. AB - In the title compound, (C(10)H(10)N(3)O(2)S)(2)[CdCl(4)], the Cd(II) ion lies on a twofold axis and is coordinated by four chloride anions, with bond distances of 2.4787 (10) and 2.4410 (10) A. A chain along the c axis is formed by C-H?N hydrogen-bonding inter-actions and a weak pi-pi inter-action is observed between the pyrimidine rings of two adjacent parallel chains [centroid-centroid distance = 3.722 (2) A]. N-H?Cl, CN-H?Cl and N-H?O interactions also occur. PMID- 22199595 TI - Tris(1,10-phenanthroline-kappaN,N')nickel(II) bis-(2,4,5-tricarb-oxy-benzo-ate) monohydrate. AB - In the title compound, [Ni(C(12)H(8)N(2))(3)](C(10)H(5)O(8))(2).H(2)O, the Ni(II) cation is coordinated by six N atoms of the three bidentate chelating 1,10 phenanthroline ligands in a slightly distorted octa-hedral coordination geometry. The Ni-N bond lengths range from 2.074 (2) to 2.094 (2) A. The dihedral angles between the three chelating NCCN groups to each other are 85.71 (3), 73.75 (2) and 85.71 (3) degrees , respectively. The Ni cation, the phenyl ring of the 1,10 phenanthroline ligand and the lattice water molecule are located on special positions (site symmetry 2). In the crystal, the uncoordinated 2,4,5-tricarb-oxy benzeno-ate anions join with each other through O-H?O hydrogen bonds, forming a two-dimensional hydrogen-bonded layer structure along the bc plane. The layers are further linked via additional O-H?O inter-actions between water and carboxyl groups, resulting in a three-dimensional supra-molecular network. PMID- 22199596 TI - [MU-Bis(diphenyl-phosphan-yl-kappaP)methane]-deca-carbonyl-tri-MU-hydrido trirhenium(I)(3 Re-Re) dichloromethane solvate. AB - In the title compound, [Re(3)(MU-H)(3)(C(25)H(22)P(2))(CO)(10)].CH(2)Cl(2), the three Re atoms form a triangle bearing ten terminal carbonyl groups and three edge-bridging hydrides. The bis-(diphenyl-phosphan-yl)methane ligand bridges two Re atoms. Neglecting the Re-Re inter-actions, each Re atom is in a slightly distorted octa-hedral coordination environment. The dichloro-methane solvent mol ecule is disordered over two sets of sites with fixed occupancies of 0.6 and 0.4. PMID- 22199597 TI - Tris(ethyl-enediamine-kappaN,N')nickel(II) naphthalene-2,7-disulfonate. AB - The Ni(II) atom in the title salt, [Ni(C(2)H(8)N(2))(3)](C(10)H(6)O(6)S(2)), is chelated by three ethyl-enediamine ligands in an octa-hedral geometry. The cation and anion are linked by N-H?O hydrogen bonds into a three-dimensional network. One of the two -SO(3) groups is disordered over two positions in a 1:1 ratio. PMID- 22199598 TI - Poly[[MU-aqua-triaqua-[MU(6)-1,3,4,6-tetra-kis-(carboxyl-atometh-yl)-7,8-diphenyl glycoluril]dizinc] monohydrate]. AB - In the crystal structure of the title coordination polymer, {[Zn(2)(C(24)H(18)N(4)O(10))(H(2)O)(4)].H(2)O}(n), the mol-ecular building block (MBB), viz [Zn(2)(CO(2))(4)(H(2)O)(4)], comprises two Zn(II) cations, each bridged by three carboxyl-ate groups from different ligand mol-ecules. These two Zn(II) cations exhibit different coordination environments: a distorted trigonal pyramidal coordination, as an inter-mediate, is formed by the two coordinated water mol-ecules and three carboxyl-ate groups, and a distorted octa-hedral geometry defined by three water mol-ecules and three carboxyl-ate groups, in which two carboxyl-ate groups from the same side of the clip glycoluril ring and one water mol-ecule are bidentate bridging, whereas others are monodentate units. Every ligand mol-ecule connects four MBBs, thus forming a three-dimensional structure. Extensive intra- and inter-molecular O-H?O hydrogen bonding is observed. PMID- 22199599 TI - trans-Bromido(pyrimidinyl-kappaC)bis-(triphenyl-phosphane-kappaP)palladium(II). AB - In the title complex, [PdBr(C(4)H(3)N(2))(C(18)H(15)P)(2)], the geometry around the Pd atom is distorted square-planar with the Pd atom displaced by 0.0334 (14) A from the BrP(2)C plane. The two Ph(3)P ligands are in trans positions, defining a P-Pd-P angle of 171.78 (5) degrees , while the pyrimidinyl and bromide ligands are trans to each other [C-Pd-Br = 174.63 (14) degrees ]. PMID- 22199600 TI - Bis(1-methyl-1H-imidazole-kappaN)bis-[2-(naphthalen-1-yl)acetato kappaO]copper(II) monohydrate. AB - In the crystal structure of the title compound, [Cu(C(12)H(9)O(2))(2)(C(4)H(6)N(2))(2)].H(2)O, the Cu(II) atom is coordinated by two 2-(naphthalen-1-yl)acetate anions and two 1-methyl-imidazole ligands, giving monomeric complexes with a square-planar coordination environment. Two complex mol-ecules and two water mol-ecules form a centrosymmetric ring system via O-H?O hydrogen bonds. PMID- 22199601 TI - Di-MU-hydroxido-bis-[tris-(4,4,4-trifluoro-1-phenyl-acetyl-acetonato kappaO,O')hafnium(IV)] dimethyl-formamide disolvate. AB - The binuclear molecule of the title compound, [Hf(2)(C(10)H(6)F(3)O(2))(6)(OH)(2)].2C(3)H(7)NO, lies across an inversion centre and contains a Hf(IV) atom which is eight-coordinated and surrounded by three chelating beta-diketonato tris-(4,4,4-trifluoro-1-phenyl-acetyl-acetonate (tfba( )) ligands and two bridging OH(-) groups in a distorted square-anti-prismatic geometry. The Hf-O bond lengths vary from 2.073 (2) to 2.244 (2) A and the O-Hf-O bite angles vary from 73.49 (9) to 75.60 (9) degrees . Weak O-H?O hydrogen bonding inter-actions are observed between the bridging hy-droxy groups and the dimethylformamide solvent mol-ecules. The unit cell contains solvent-accessible voids of 131 A(3), but the residual electron density in the difference Fourier map suggests no solvent mol-ecule occupies this void. PMID- 22199602 TI - [S-Allyl-4-(4-hy-droxy-2-oxidobenzyl-idene-kappaO)-1-(2-oxidobenzyl-idene kappaO)isothio-semicarbazidato-kappaN,N](ethanol-kappaO)dioxido-uranium(VI) ethanol monosolvate. AB - In the title compound, [U(C(18)H(15)N(3)O(3)S)O(2)(C(2)H(5)OH)].C(2)H(5)OH, the U(VI) ion is in a distorted penta-gonal-bipyramidal coordination geometry, with two oxide O atoms in axial sites. Two N and two O atoms of the tetra-dentate ligand and an O atom of an ethanol ligand form the equatorial plane. The dihedral angle between the mean planes of the two benzene rings is 34.8 (3) degrees . In the crystal, relatively strong O-H?O hydrogen bonds connect the complex and ethanol solvent mol-ecules into alternating centrosymmetric R(2) (2)(8) and R(4) (4)(16) ring motifs, forming chains along [100]. Weak inter-molecular C-H?O hydrogen bonds are also present. PMID- 22199603 TI - Diaqua-bis-(4,4'-bipyridine-kappaN)bis-(2,4,5-trifluoro-3-hy-droxy-benzoato kappaO)manganese(II). AB - In the title compound, [Mn(C(7)H(2)F(3)O(3))(2)(C(10)H(8)N(2))(2)(H(2)O)(2)], the Mn(II) ion, situated on a centre of inversion, has a distorted octa-hedral coordination geometry and is coordinated by two N atoms from two 4,4'-bipyridine ligands, two O atoms from two 2,4,5-trifluoro-3-hy-droxy-benzoate ligands and two water mol-ecules. Inter-molecular O-H?N hydrogen bonds link the mol-ecules into a chain along the a axis. Inter-actions between neighboring chains occur through O H?O hydrogen bonds, which link the chains into a two-dimensional supra-molecular network parallel to the ac plane. In addition, O-H?O hydrogen bonds between the water mol-ecules and carboxyl-ate groups also exist in the the crystal structure. PMID- 22199604 TI - Octa-kis(3-methyl-anilinium) hexa-chlorido-cadmate tetra-chloride. AB - The asymmetric unit of the title compound, (C(7)H(10)N)(8)[CdCl(6)]Cl(4), contains four 3-methyl-anilinium cations, two chloride anions and half an octa hedral hexa-chloridocadmate(II) anion, which lies on an inversion centre. In the crystal, numerous N-H?Cl and bifurcated N-H?(Cl,Cl) hydrogen bonds link the components. PMID- 22199605 TI - Tris(4,4'-di-tert-butyl-2,2'-bipyridine-kappaN,N')molybdenum(II) MU(6)-oxido dodeca-MU(2)-oxido-hexa-oxidohexa-molybdate(VI) acetonitrile tetra-solvate. AB - The asymmetric unit of the title compound, [Mo(C(18)H(24)N(2))(3)][Mo(6)O(19)].4CH(3)CN, comprises an [Mo(di-t-Bu bipy)(3)](2+) cation (di-t-Bu-bipy is 4,4'-di-tert-butyl-2,2'-bipyridine), two halves of Lindqvist-type [Mo(6)O(19)](2-) anions (with each anion completed by the application of a center of inversion) and four acetonitrile solvent mol ecules. The geometry around the metal atom of the cation resembles a distorted octa-hedron, with each of the three di-t-Bu-bipy ligands being almost planar [deviation from planarity < 6.3 (2) degrees ]. Supra-molecular inter-actions, namely Mo=O?pi, C N?pi, C-H?O and C-H?N, along with electrostatic forces, mediate the crystal packing. Two of the tert-butyl groups are affected by rotational disorder which was modeled over two distinct positions with major site occupancies of 0.707 (9) and 0.769 (8). PMID- 22199606 TI - [2,2'-Bis(diphenyl-phosphan-yl)-1,1'-binaphthyl-kappaP,P']chlorido(4-methyl phenyl-sulfon-yl-kappaS)palladium(II) dichloro-methane tris-olvate monohydrate. AB - In the title compound, [Pd(C(7)H(7)O(2)S)Cl(C(44)H(32)P(2))].3CH(2)Cl(2).H(2)O, the geometry around the metal atom is distorted square planar, with a twist angle between the P-Pd-P and S-Pd-Cl planes of 28.11 (2) degrees . The two Pd-P bond lengths differ by about 0.04 A and the biphosphane bite angle is slightly obtuse [92.92 (2) degrees ]. There are three dichloro-methane and one water mol-ecule co crystallized with the palladium mol-ecule, all with atoms in general positions. Alternating water and palladium mol-ecules form four-membered cyclic units through O-H?Cl and O-H?O hydrogen bonding. One of the dichloromethane solvent molecules is disordered over two positions in a 0.55:0.45 ratio. PMID- 22199607 TI - Bis[2-(2H-benzotriazol-2-yl)-4-methyl-6-(phenyl-imino-methyl-kappaN)phenolato kappaO]palladium(II). AB - In the title complex, [Pd(C(20)H(15)N(4)O)(2)], the Pd(II) atom is tetra coordinated by two N atoms and two O atoms from two bidentate imine-benzotriazole phenolate ligands, forming a square-planar environment. The asymmetric unit contains two half-mol-ecules in both of which the Pd(II) atom lies on a centre of symmetry. The average distances between the Pd(II) atom and the coordinated O and N atoms are 1.9831 (12) and 2.012 (2) A, respectively. PMID- 22199608 TI - catena-Poly[[bis-[3-(1H-imidazol-1-yl)-1-phenyl-propan-1-one-kappaN]nickel(II)] MU-oxalato-kappaO,O:O,O]. AB - In the title compound, [Ni(C(2)O(4))(C(12)H(12)N(2)O)(2)](n), the Ni(II) atom, lying on a twofold rotation axis, is coordinated by two N atoms from two monodentate 3-(1H-imidazol-1-yl)-1-phenyl-propan-1-one (L) ligands and four O atoms from two oxalate anions in a distorted octa-hedral geometry. The oxalate anion has a twofold rotation axis through the mid-point of the C-C bond and acts as a bridging ligand, linking the Ni(II) atoms into a polymeric chain along [010]. Weak inter-molecular C-H?O hydrogen bonds connect the chains, resulting in a three-dimensional supra-molecular structure. > PMID- 22199609 TI - Poly[(MU(4)-benzene-1,3,5-tricarboxyl-ato)bis-(dimethyl sulfoxide-kappaO) neodymium(III)]. AB - The asymmetric unit of the title compound, [Nd(C(9)H(3)O(6))(C(2)H(6)OS)(2)](n), contains one Nd(3+) ion, one benzene-1,3,5-tricarb-oxy-lic ligand and two coordinating dimethyl sulfoxide mol-ecules. The Nd(3+) ion is coordinated by six O atoms from four carboxyl-ate groups of the benzene-1,3,5-tricarboxyl-ate ligands and two O atoms from two dimethyl sulfoxide mol-ecules. The metal-organic cluster formed upon symmetry expansion of the asymmetric unit consists of two metal atoms and four benzene-1,3,5-tricarboxyl-ate groups, creating a paddle wheel-type building block arrangement. The remaining coordination sites are occupied by additional benzene-1,3,5-tricarboxyl-ate groups and dimethyl sulfoxide mol-ecules, forming a three-dimensional polymeric rare earth metal organic framework structure. PMID- 22199610 TI - catena-Poly[[trimethyl-tin(IV)]-MU-5-methyl-thio-phene-2-carboxyl-ato-kappaO:O']. AB - In the title polymeric coordination compound, [Sn(CH(3))(3)(C(6)H(5)O(2)S)](n), which contains two formula units in the asymmetric unit, the Sn(IV) atom has a distorted trigonal-bipyramidal geometry, with two O atoms of the ligands in axial positions and three methyl groups in equatorial positions. Adjacent Sn(IV) atoms are bridged by the ligands, thereby forming a chain propagating in [010]. PMID- 22199611 TI - Poly[[(MU(3)-5-amino-isophthalato-kappaO:O:N)(1H-imidazole-kappaN)zinc] 0.25 hydrate]. AB - In the title coordination polymer, {[Zn(C(8)H(5)NO(4))(C(3)H(4)N(2))].0.25H(2)O}(n), the Zn(2+) cation has an N(2)O(2) donor set involving two carboxyl-ate O atoms from two 5-amino isophthalate anions, one N atom from a 5-amino-isophthalate anion, and one imidazole N atom displaying a slightly distorted tetra-hedral geometry with two additional O-atom neighbours, with Zn-to-ligand distances of 2.711 (2) and 2.717 (2) A, respectively. Each 5-amino-isophthalate anion acts as a MU(3)-bridge linking symmetry-related Zn(II) ions into a layered polymeric structure parallel to (100). The asymmetric unit also comprises a disordered crystal water molecule located on an inversion centre with 0.25 occupancy. In the crystal, N-H?O hydrogen bonds form a three-dimensional network. PMID- 22199612 TI - {4-Dimethyl-amino-N'-[1-(2-oxidophen-yl)ethyl-idene]benzohydrazidato}(methano lato)oxidovanadium(V). AB - The title oxidovanadium(V) complex, [V(C(17)H(17)N(3)O(2))(CH(3)O)O], was obtained by the reaction of 2-acetyl-phenol, 4-dimethyl-amino-benzohydrazide and vanadyl sulfate in methanol. The V(V) atom is five-coordinated by N,O,O'-donor atoms of the Schiff base ligand, one meth-oxy O atom and one oxide O atom, forming a square-pyramidal geometry. PMID- 22199613 TI - (Acetonitrile-kappaN)chloridobis[2-(pyridin-2-yl)phenyl-kappaC,N]iridium(III). AB - The Ir(III) atom of the title compound, [Ir(C(11)H(8)N)(2)Cl(CH(3)CN)], displays a distorted octa-hedral coordination. The pyridyl groups are in trans positions [N-Ir-N = 173.07 (10) degrees ], while the phenyl groups are trans with respect to the acetonitrile and chloride groups [C-Ir-N = 178.13 (11) and C-Ir-Cl = 176.22 (9) degrees ]. The pyridyl-phenyl groups only show a small deviation from planarity, with the dihedral angle between the planes of the two six-membered rings in each pyridyl-phenyl group being 5.6 (2) and 5.8 (1) degrees . The crystal packing shows inter-molecular C-H?Cl, C-H?pi(acetonitrile) and C H?pi(pyridyl-phen-yl) contacts. PMID- 22199614 TI - 4,5-Dihydro-3a,5a-diazo-niapyrene triiodidocuprate(I). AB - In the dianion of the title salt, (C(14)H(12)N(2))[CuI(3)], the Cu(I) atom is coordinated by three I(-) ions that define a nearly trigonal-planar geometry; the Cu(I) atom lies 0.1407 (6) A out of the plane. With the exception of the methyl ene C atoms, the dication is essentially planar (r.m.s deviation = 0.067 A). The most significant inter-action between the ions is a C-H?I contact. PMID- 22199615 TI - Tetra-kis(MU(2)-ferrocene-carboxyl-ato-kappaO:O')bis-[(methanol kappaO)copper(II)] methanol disolvate. AB - The complex mol-ecule of the title compound, [Cu(2)Fe(4)(C(5)H(5))(4)(C(6)H(4)O(2))(4)(CH(3)OH)(2)].2CH(3)OH, lies about an inversion centre and contains two centrosymetrically related Cu(II) atoms bridged by four O:O'-bidentante ferrocene-carboxyl-ate anions, leading to a dimeric tetra bridged unit with a paddle-wheel geometry. The Cu(II) atom has a distorted square pyramidal coordination environment with four O atoms from four ferrocene-carboxyl ate ligands in basal positions and an O atom from a methanol mol-ecule in an apical position. One of the two crystallographically independent ferrocenyl groups has a staggered conformation, while the other is eclipsed. The mol-ecules are connected into a chain along the b axis by O-H?O hydrogen bonds involving coordinated and uncoordinated methanol mol-ecules and the O atom from a ferrocene carboxyl-ate unit. PMID- 22199616 TI - Tris(acetonitrile-kappaN){2,6-bis-[(diphenyl-phosphan-yl)amino]-4-eth-oxy-1,3,5 triazine-kappaP,N,P'}iron(II) bis-(tetra-fluorido-borate) acetonitrile disolvate. AB - In the title compound, [Fe(CH(3)CN)(3)(C(29)H(27)N(5)OP(2))](BF(4))(2).2CH(3)CN, the Fe(II) ion is octa-hedrally coordinated by a meridionally chelating tridentate pincer-type PNP ligand derived from 2,6-diamino-4-eth-oxy-1,3,5 triazine and by three acetonitrile mol-ecules. The four Fe-N bond lengths range from 1.9142 (12) to 1.9579 (11) A, while the Fe-P bonds are 2.2452 (4) and 2.2506 (4) A [P-Fe-P = 165.523 (14) degrees ], consistent with Fe(II) in a low-spin state. Unlike related Fe PNP complexes based on 2,6-diamino-pyridine, the BF(4) anions are not hydrogen bonded to the two NH groups of the pincer ligand but show instead anion-pi inter-actions with the triazine ring and acetonitrile mol-ecules in addition to ten C-H?F inter-actions. Most remarkable among these is an anion pi(triazine) inter-action with a short distance of 2.788 (2) A between one F and the centroid of the pi-acidic triazine ring. The corresponding shortest distance between this F atom and a triazine carbon atom is 2.750 (2) A. The two NH groups of the pincer ligand donate N-H?N hydrogen bonds to the triazine N atom of a neighbouring complex and to an uncoordinated acetonitrile mol-ecule. This last mol-ecule is in a side-on head-to-tail association with the second uncoordinated acetonitrile at C?N distances of 3.467 (2) and 3.569 (2) A. In contrast to several related compounds with diamino-pyridine- instead of diamino-triazine based PNP ligands, the title crystal structure is remarkably well ordered. This suggests that the diamino-triazine moiety exerts notable crystal structure stabilizing effects. PMID- 22199617 TI - [2,2'-(1,1'-Binaphthyl-2,2'-diyldiimino)-diethanol kappaN,N',O]dichloridocopper(II). AB - In the title complex, [CuCl(2)(C(24)H(24)N(2)O(2))], the Cu(II) cation is N,N',O chelated by a 2,2'-(1,1'-binaphthyl-2,2'-diyldiimino)-diethanol ligand and coordinated by two chloride anions in a distorted square-pyramidal geometry. In the diethanol ligand, the two naphthalene ring systems are twisted with respect to each other at a dihedral angle of 68.30 (9) degrees . The uncoord-inated hy droxy group links with a coordinated chloride anion via an intra-molecular O-H?Cl hydrogen bond. Inter-molecular N-H?O and N-H?Cl hydrogen bonds occur in the crystal structure. PMID- 22199618 TI - Bis[(1-vinyl-1H-imidazol-2-yl-kappaN)methanamine-kappaN]copper(II) bis-(hexa fluoridophosphate). AB - In the title compound, [Cu(C(6)H(9)N(3))(2)](PF(6))(2), the Cu atom is located on a crystallographic center of inversion. The coordination environment of the Cu atom is square-planar with two amino and two imidazole N atoms bonded to the metal in a trans configuration. PMID- 22199619 TI - Dibromido(2,9-dimethyl-1,10-phenanthroline-kappaN,N')cadmium. AB - In the title complex, [CdBr(2)(C(14)H(12)N(2))], the Cd(II) ion is tetra coordinated by two N atoms of the bidentate 2,9-dimethyl-1,10-phenanthroline ligand and two bromide ions in a substanti-ally distorted CdN(2)Br(2) tetra hedral geometry. In the crystal, inversion dimers linked by pairs of weak C-H?Br bonds generate R(2) (2)(14) loops. Aromatic pi-pi stacking [shortest centroid centroid separation = 3.633 (2) A] inter-actions occur within, and also link, the dimers into chains propagating parallel to [100]. PMID- 22199620 TI - catena-Poly[[[dibromidomanganese(II)]-MU-2,2'-bipyrimidine kappaN,N:N,N]dihydrate]. AB - The asymmetric unit of the title compound, {[MnBr(2)(C(8)H(6)N(4))].2H(2)O}(n), contains one half of a repeat unit of the neutral linear coordination polymer and a solvent water mol-ecule, with the Mn(II) ion on a crystallographic twofold axis. In the polymer, inversion-related Mn(II) ions are bridged by the bis chelating 2,2'-bipyrimidine (bpym) ligands, thereby forming a chain structure along the c-axis direction, and are six-coordinated in a distorted cis-N(4)Br(2) octa-hedral environment by four N atoms of twofold-related bpym ligands and twofold-related bromide anions. In the crystal, the complex polymers and solvent water mol-ecules are linked by inter-molecular O-H?Br and C-H?O hydrogen bonds, forming a two-dimensional layered structure extending parallel to the ac plane. PMID- 22199621 TI - Dibromidobis{1-[4-(pyridin-4-yl)phen-yl]ethanone-kappaN}mercury(II). AB - In the title compound, [HgBr(2)(C(13)H(11)NO)(2)], the Hg(II) atom adopts a four coordinated HgN(2)Br(2) geometry, formed by two pyridine N atoms from two ligands and two bromide anions. The complex is located on a twofold axis. The coordination geometry is close to forming a see-saw (SS-4) polyhedron, the symmetry-related organic ligands being almost perpendicular; the dihedral angles between the two pyridine rings and between the two benzene rings are 85.5 (4) and 87.7 (4) degrees , respectively. Within the organic ligand, the pyridine ring is nearly coplanar with the benzene ring [dihedral angle = 13.1 (8) degrees ]. In the crystal, the mol-ecular complexes are connected through weak inter-molecular C-H?Br contacts. PMID- 22199622 TI - catena-Poly[[bis-(1-ethyl-1H-imidazole-kappaN)cadmium]-di-MU-chlorido-[(1-ethyl 1H-imidazole-kappaN)cadmium]-di-MU-chlorido-[(1-ethyl-1H-imidazole kappaN)cadmium]-di-MU-chlorido-[bis-(1-ethyl-1H-imidazole-kappaN)cadmium]]. AB - The asymmetric unit of the crystal structure of the title compound, [Cd(2)Cl(4)(C(5)H(8)N(2))(3)](n), contains two Cd(II) cations, three 1-ethyl-1H imidazole ligands, and four Cl(-) anions. The two Cd(II) atoms have quite different coordination environments: one is octa-hedrally coordinated by four Cl atoms and two N atoms from two 1-ethyl-1H-imidazole ligands, and the second is in a severely distorted fivefold coordination by four Cl atoms and one N atom from a 1-ethyl-1H-imidazole ligand. Adjacent Cd(II) cations are inter-connected alternately by pairs of chloride bridges, generating an infinite step-like chain along the a axis. One ethyl group of the 1-ethyl-1H-imidazole ligand is disordered over two sets of sites with a 0.668 (13):0.332 (13) site-occupancy ratio. PMID- 22199623 TI - Dichlorido{N'-[(pyridin-2-yl)methyl-idene-kappaN]acetohydrazide kappaN',O}copper(II). AB - In the title compound, [CuCl(2)(C(8)H(9)N(3)O)], the Cu(II) atom has a distorted square-pyramidal CuCl(2)N(2)O coordination geometry. The tridentate acetohydrazide ligand occupies three basal positions, the fourth basal position being defined by a chloride anion at a distance of 2.2116 (6) A. The second chloride anion is in the apical position and forms a longer Cu-Cl distance of 2.4655 (7) A. Inter-molecular N-H?Cl hydrogen bonds are present in the crystal, leading to the formation of chains along [10[Formula: see text]]. PMID- 22199624 TI - Aqua-(4-fluoro-benzoato-kappaO)bis-(1,10-phenanthroline-kappaN,N')manganese(II) 4 fluoro-benzoate trihydrate. AB - In the title compound, [Mn(C(7)H(4)FO(2))(C(12)H(8)N(2))(2)(H(2)O)](C(7)H(4)FO(2)).3H(2)O, the Mn(II) atom is coordinated by four N atoms from two chelating 1,10-phenanthroline ligands and two O atoms from one monodentate 4-fluoro-benzoate ion and one water mol-ecule, forming a distorted octa-hedral geometry. In the crystal, the three components are assembled into a tape structure along the a axis by O-H?O and C H?O hydrogen bonds. Between the tapes, a pi-pi inter-action with a centroid centroid distance of 3.569 (3) A and a weak C-H?F hydrogen bond are observed. PMID- 22199625 TI - (Nitrato-kappaO){N,N,N',N'-tetra-kis-[(1H-benzimidazol-2-yl-kappaN)meth-yl]cyclo hexane-1,2-diamine}-lead(II) hemiaqua-{N,N,N',N'-tetra-kis-[(1H-benzimidazol-2-yl kappaN)meth-yl]cyclo-hexane-1,2-diamine}-lead(II) trinitrate dihydrate. AB - In the title compound, [Pb(NO(3))(C(38)H(38)N(10))][Pb(C(38)H(38)N(10))(H(2)O)(0.5)](NO(3))(3).2H(2)O, both Pb(II) ions are coordinated in a distorted trigonal-prismatic environment by a hexa-dentate N,N,N',N'-tetra-kis-[(1H-benzimidazol-2-yl)meth-yl]cyclo-hex-ane 1,2-diamine ligand. A nitrate and a half-occupancy water ligand form long coordination bonds to the Pb(II) ions capping the trigonal-prismatic environment. In the crystal, the components are linked by N-H?O and O-H?O hydrogen bonds, forming a three-dimensional network. C-H?O inter-actions also occur. PMID- 22199626 TI - Hexaaqua-magnesium 5-[1-(carboxyl-ato-meth-yl)pyridin-1-ium-4-yl]tetra-zol-2-ide chloride dihydrate. AB - In the title compound, [Mg(H(2)O)(6)](C(8)H(6)N(5)O(2))Cl.2H(2)O, the Mg(II) ion is surrounded by six water mol-ecules, exhibiting a slightly distorted octa hedral coordination. The pyridine and tetra-zole rings are nearly coplanar, forming a dihedral angle of 4.63 (3) degrees . The complex cations, zwitterionic organic anions, Cl(-) anions and uncoordinated water mol-ecules are connected by O-H?O, O-H?N and O-H?Cl hydrogen bonds, leading to the formation of a three dimensional network. PMID- 22199627 TI - Poly[(aqua-calcium)-MU(4)-pyrazine-2,3-di-carboxyl-ato]. AB - The polymeric title compound, [Ca(C(6)H(2)N(2)O(4))(H(2)O)](n), was synthesized from pyrazine-2,3-dicarb-oxy-lic acid and calcium dichloride under hydro-thermal conditions. The Ca(2+) cation is seven-coordinated by five O atoms and one N atom of four pyrazine-2,3-dicarboxyl-ate anions, and one water mol-ecule. The complete deprotonated pyrazine-2,3-dicarboxyl-ate anion adopts a MU(4)-coordination mode, resulting in the formation of a three-dimensional structure. PMID- 22199628 TI - [1,5-Bis(4-fluoro-phen-yl)thio-carbazo-nato-kappaN,S]phenyl-mercury(II) dichloro methane hemisolvate. AB - In the title compound, [Hg(C(6)H(5))(C(13)H(9)F(2)N(4)S)].0.5CH(2)Cl(2), the Hg(C(6)H(5)) units are twisted out of the planes of the thio-carbazo-nate ligands by 61.49 (10) and 67.79 (11) degrees in the two complex mol-ecules comprising the asymmetric unit. Important geometrical parameters include Hg-C = 2.079 (4) and 2.087 (4) A, Hg-S = 2.3869 (10) and 2.3889 (11) A, and C-Hg-S = 166.42 (12) and 168.09 (13) degrees . Weak intramolecular Hg-N bonding inter-actions of 2.589 (4) and 2.626 (4) A are observed. In the crystal, C-H?Cl, C-H?F, C-H?N, C-H?pi and pi-pi [centroid-centroid distances = 3.648 (3) and 3.641 (3) A] inter actions, create parallel planes along [101]. PMID- 22199629 TI - [(1,2,5,6-eta)-Cyclo-octa-1,5-diene]bis-(1-isopropyl-3-methyl-imidazolin-2-yl idene)rhodium(I) tetra-fluorido-borate. AB - In the title compound, [Rh(C(8)H(12))(C(7)H(12)N(2))(2)]BF(4), the square-planar Rh complex cation and the BF(4) (-) anion are both bis-ected by a crystallographic twofold rotation axis. The Rh and B atoms lie on this axis and all others are in general positions. In the crystal, two unique C-H?F hydrogen bonding inter-actions are present, which involve both imidazolin-2-yl-idene H atoms. They form two separate C(5) motifs, the combination of which is a rippled hydrogen-bonded sheet structure in the ab plane. PMID- 22199630 TI - Poly[aqua-{MU(3)-5-[(pyridin-2-ylmeth-yl)amino]-isophthalato kappaN,N':O,O:O}cobalt(II)]. AB - In the title polymer, {[Co(C(14)H(10)N(2)O(4))(H(2)O)].3.5H(2)O}(n), the Co(2+) ion is coordinated by three carboxyl-ate O atoms from two 5-[(pyridin-2-ylmeth yl)amino]-isophthalate anions, two N atoms from a (pyridin-2-ylmeth-yl)amino group and an O atom from a water mol-ecule, furnishing a distorted CoO(4)N(2) octa-hedral geometry. Each anion acts as a MU(3)-bridge, linking cobalt ions into a two-dimensional layer parallel to (100). The asymmetric unit also contains three and a half solvent water mol-ecules, which could not be modeled. Therefore, the diffraction contribution of the solvent water mol-ecules was removed by the subroutine SQUEEZE in PLATON [Spek (2009). Acta Cryst. D65, 148-155]. The crystal structure is stabilized by O-H?O hydrogen bonds in which the coordinated water mol-ecule acts as donor and the carboxyl-ate O atoms as acceptors. PMID- 22199631 TI - (Nitrato-kappaO)bis-[5-(pyridin-2-yl)pyrazine-2-carbonitrile-kappaN,N]silver(I). AB - In the mononuclear title complex, [Ag(NO(3))(C(10)H(6)N(4))(2)], two kappa(2)N:N' chelating 5-(pyridin-2-yl)pyrazine-2-carbonitrile ligands surround the Ag(I) atom, forming an N(4)O square-pyramidal coordination geometry with one nitrate anion bonding at the apical site. The two heterocyclic rings of the 5-(2-pyridin 2--yl)pyrazine-2-carbonitrile ligand are almost coplanar [dihedral angle = 5.63 (8) degrees ], and the two chelating ligands are in an anti relationship. The mononuclear units are inter-connected along [010] through C-H?O(nitrate) and C H?N(cyano) inter-actions, forming an infinite chain. The mononuclear units are stacked along the a axis and inter-connected via inter-molecular pi-pi stacking inter-actions between adjacent pyridine and pyrazine rings [centroid-centroid distances = 3.984 (2) and 3.595 (3) A], thus forming a three-dimensional supra molecular structure. PMID- 22199632 TI - Bis{MU(2)-2-[(2-hy-droxy-eth-yl)(meth-yl)amino]-ethano-lato}bis-(MU(3)-N-methyl 2,2'-aza-nediyldiethano-lato)tetra-kis-(thio-cyan-atato kappaN)dichromium(III)dimanganese(II) dimethyl-formamide tetra-solvate. AB - The heterometallic title complex, [Cr(2)Mn(2)(C(5)H(11)NO(2))(2)(C(5)H(12)NO(2))(2)(NCS)(4)].4C(3)H(7)NO, was prepared using manganese powder, Reineckes salt, ammonium thio-cyanate and a non aqueous solution of N-methyl-diethano-lamine in air. The centrosymmetric mol ecular structure of the complex is based on a tetra-nuclear {Mn(2)Cr(2)(MU-O)(6)} core. The tetra-nuclear complex mol-ecule and the two uncoordinated dimethyl formamide mol-ecules are linked by O-H?O hydrogen bonds, while the two other mol ecules of dimethyl-formamide do not participate in hydrogen bonding. PMID- 22199633 TI - Aqua-(4,4'-dimethyl-2,2'-bipyridine-kappaN,N')(nitrato-kappaO)(nitrato kappaO,O')zinc. AB - In the title compound, [Zn(NO(3))(2)(C(12)H(12)N(2))(H(2)O)], the Zn(II) atom is six-coordinated in a distorted octa-hedral geometry by two N atoms from a chelating 4,4'-dimethyl-2,2'-bipyridine ligand, one water O atom, one O atom from a monodentate nitrate anion and two O atoms from a chelating nitrate anion. In the crystal, there are aromatic pi-pi contacts between the pyridine rings [centroid-centroid distances = 3.9577 (13) A] and inter-molecular O-H?O and C-H?O hydrogen bonds. PMID- 22199634 TI - Bis(di-2-pyridyl-amine-kappaN,N')bis-(thio-cyanato-kappaN)nickel(II). AB - The mononuclear neutral title complex, [Ni(NCS)(2)(C(10)H(9)N(3))(2)], shows a cis-octa-hedral geometry around the Ni(II) ion, formed by two chelating di-2 pyridyl-amine (Hdpa) ligands and two thio-cyanate anions. Both amine H atoms are involved in N-H?S hydrogen bonding, resulting in the formation of layers of inter linked mol-ecules parallel to the ab plane, which are further held together by weak pi-pi inter-actions between adjacent complexes, involving one ring of each dipyridyl-amine unit [centroid-centroid distance = 3.777 (4) A], forming a three dimensional assembly. PMID- 22199635 TI - Diaqua-bis-(5-carb-oxy-2-propyl-1H-imidazole-4-carboxyl-ato-kappaN,O)cadmium N,N dimethyl-formamide disolvate. AB - In the title complex, [Cd(C(8)H(9)N(2)O(4))(2)(H(2)O)(2)].2C(3)H(7)NO, the six coordinate Cd(II) ion is in a slightly distorted octa-hedral environment, defined by two O atoms from two coordinated water mol-ecules and two carboxyl-ate O atoms and two N atoms from two N,O-bidentate 5-carb-oxy-2-propyl-1H-imidazole-4 carboxyl-ate ligands. In the crystal, complex mol-ecules and dimethyl-formamide solvent mol-ecules are linked by O-H?O and N-H?O hydrogen bonds into a two dimensional supra-molecular structure. The propyl groups of the ligands are disordered over two conformations with refined occupancies of 0.680 (7) and 0.320 (7). PMID- 22199636 TI - Dicyclo-hexyl-ammonium trimethyl-bis-(hydrogen phenyl-phospho-nato)stannate(IV). AB - In the title compound, (C(12)H(24)N)[Sn(CH(3))(3)(C(6)H(6)O(3)P)(2)], the SnMe(3) residues are axially coordinated by two monodentate [PhPO(3)H](-) anions, leading to a trigonal-bipyramidal geometry for the Sn(IV) atom. The two [SnMe(3)(PhPO(3)H)(2)](-) anions in the unit cell are associated into infinite chains along the a axis by O-H?O hydrogen bonds involving the hy-droxy group of the hydrogen phenyl-phospho-nate ion. The chains inter-act with one another via O H?O hydrogen bonds along the c axis. These networks of anions assemble with the dicyclo-hexyl-ammonium ion through N-H?O hydrogen bonds, forming a three dimensional network. PMID- 22199637 TI - (Acetyl-acetonato-kappaO,O')carbon-yl{dicyclo-hex-yl[4-(dimethyl-amino)-phen yl]phosphane-kappaP}rhodium(I). AB - The title compound, [Rh(C(5)H(7)O(2))(C(20)H(32)NP)(CO)], features an acetyl acetonate-chelated Rh(I) cation coordinated by one P [Rh-P = 2.2525 (7) A], one carbonyl C [Rh-C = 1.792 (3) A] and two O [Rh-O = 2.0582 (17) and 2.0912 (18) A] atoms in a slightly distorted square-planar geometry. Mol-ecules are packed in positions of least steric hindrance, with the phosphane ligands positioned above and below the Rh-acetyl-acetonate backbone. PMID- 22199638 TI - (2-Bromo-acet-yl)ferrocene. AB - In the title mol-ecule, [Fe(C(5)H(5))(C(7)H(6)BrO)], the C atoms of the substituted ring have disparate Fe-C bond lengths compared with the unsubstituted ring. In the bromo-acetyl residue, the Br and O atoms are co-planar [the O-C-C-Br torsion angle is 5.7 (4) degrees ] and are syn to each other. Helical supra molecular chains along the b axis are formed in the crystal structure mediated by C-H?O contacts; the carbonyl-O atom is bifurcated. The chains are linked into layers by C-H?pi(unsubstituted ring) inter-actions that stack along the a-axis direction. PMID- 22199639 TI - Bis[3-dimethyl-amino-1-(pyridin-2-yl)prop-2-en-1-one-kappaN,O]tris-(nitrato kappaO,O)gadolinium(III) ethanol disolvate. AB - In the title compound, [Gd(NO(3))(3)(C(10)H(12)N(2)O)(2)].2C(2)H(5)OH, the Gd(III) ion and one nitrate anion are located on a twofold rotation axis. The Gd(III) ion is ten-coordinated by two N and two O atoms from two bidentate 3-(N,N dimethyl-amino)-1-(2-pyrid-yl)prop-2-en-1-one) ligands and six O atoms from three nitrate anions in a distorted bicapped square-anti-prismatic geometry. In the crystal, the components are linked by O-H?O hydrogen bonds. The ethanol solvent mol-ecule is disordered over two positions in a ratio 0.615 (16):0.385 (16). PMID- 22199640 TI - catena-Poly[bis(dimethylazanium) [[chloridocopper(II)]-di-MU-chlorido [chloridocopper(II)]-di-MU-azido-kappaN:N]]. AB - The crystal structure of the title complex, {(C(2)H(8)N)[CuCl(2)(N(3))]}(n), exhibits inorganic chains consisting of Cu(II) cations as well azide and chloride anions. The chains, made up from Cu-Cl-Cu-N-Cu linkages, are aligned parallel to the c axis. This architecture is further stabilized by a number of N-H?Cl hydrogen bonds involving the protonated charge-compensating dimethyl-amine cations and chloride atoms. PMID- 22199641 TI - Tetra-n-butyl-ammonium tricyanido[N-(2-pyridyl-carbon-yl)pyridine-2-carbox imidato]ferrate(III) dihydrate. AB - In the title compound, (C(16)H(36)N)[Fe(C(12)H(8)N(3)O(2))(CN)(3)].2H(2)O, the tetra-n-butyl-ammonium ion has a tetra-hedral configuration around the N atom, while the Fe(III) atom of the tricyanido[N-(2-pyridyl-carbon-yl)pyridine-2 carboximidato]iron(III) anion adopts a distorted octa-hedral geometry. O-H?O and O-H?N hydrogen bonds link the components in the crystal structure. PMID- 22199642 TI - Tetra-MU(2)-acetato-tetraaquadi-MU(3)-oxido-octaoxidotetrauranium(VI) methanol disolvate tetrahydrate. AB - The centrosymmetric title tetra-mer, [U(4)(C(2)H(3)O(2))(4)O(10)(H(2)O)(4)].2CH(4)O, has a near planar core [maximum deviation from the least squares plane of 0.294 (6) A]. It consists of two hexa gonal-bipyramidally coordinated U(VI) atoms connected via MU(2)-O (acetate) and MU(3)-O (oxide) bridges in the equatorial plane to two penta-gonal-bipyramidally coordinated U(VI) atoms. The equatorial plane of each U(VI) atom is completed by a bound water mol-ecule, while the axial positions are occupied by uranyl (UO(2))(2+) O atoms. Multiple O-H?O hydrogen bonds are present, including a lattice methanol mol-ecule bound to one of the penta-gonal bipyramidal uranyl O atoms, as well as two different C(1) (1)(6) chains orginating from a donor water mol-ecule, via a uranyl oxygen acceptor and an acetate acceptor on different, adjacent tetra-mers. Finally, the unit cell contains four U(VI) tetra-mers, all connected by hydrogen bonding, forming a supra-molecular R(4) (4)(24) ring. PMID- 22199643 TI - (1,2,3,4-Tetra-hydro-isoquinoline-2-carbo-dithio-ato-kappaS,S')(thio-cyanato kappaN)(tri-phenyl-phosphane)nickel(II). AB - The Ni(II) atom in the mononuclear title compound, [Ni(C(10)H(10)NS(2))(NCS)(C(18)H(15)P)], exists within a S(2)PN donor set that defines a distorted square-planar geometry. A significant asymmetry in the Ni-S bond lengths support the less effective trans effect of SCN(-) over PPh(3). PMID- 22199644 TI - catena-Poly[[trimeth-yl(4-sulfanylphen-yl)aza-nium] [(chloridocadmate)-di-MU chlorido]]. AB - The title compound, {(C(9)H(14)NS)[CdCl(3)]}(n), consists of a linear [CdCl(3)](n) (n) (-) polyanion and a trimeth-yl(4-sulfanylphen-yl)aza-nium cation. The Cd(II) atom is penta-coordinated by four MU(2)-Cl atoms and one terminal Cl atom in a trigonal-bipyramidal geometry. The trigonal-bipyramidal units are linked by two opposite shared faces, giving rise to infinite [CdCl(3)](n) chains parallel to the a axis. The cations surround the chain and are linked to them by S-H?Cl and C-H?Cl hydrogen bonds, forming a three dimensional network. PMID- 22199645 TI - Di-MU-acetato-kappaO:O-bis-{(acetato-kappaO,O')bis-[3-(1H-imidazol-1-yl-kappaN)-1 phenyl-propan-1-one]cadmium} tetra-hydrate. AB - In the mol-ecular structure of the title neutral binuclear complex, [Cd(2)(C(2)H(3)O(2))(4)(C(12)H(12)N(2)O)(4)].4H(2)O, each Cd(II) atom is six coordinated and exhibits a distorted octa-hedral geometry. Three O atoms from two acetate ions and one monodentate 3-(1H-imidazol-1-yl-kappaN(3))-1-phenyl-propan-1 one (L) ligand form the equatorial plane, while the bridging-O atom forming the longer Cd-O distance,and the N atom of the second L ligand, forming the longer Cd N distance, occupy axial positions with an N-Cd-O angle of 170.77 (7) degrees . Inter-molecular O-H?O hydrogen bonds exist between the lattice water mol-ecules and the acetate ions of adjacent mol-ecules, resulting in a two-dimensional supra molecular structure. PMID- 22199646 TI - Bis(2,4-dioxo-5,5-diphenyl-imidazol-idin-ido-kappaN)bis-(propane-1,3-diamine kappaN,N')cobalt(II). AB - The complex mol-ecule of the title compound, [Co(C(15)H(11)N(2)O(2))(2)(C(3)H(10)N(2))(2)], has crystallographically imposed inversion symmetry. The Co(II) atom displays a distorted octa-hedral coordination geometry. In the phenytoin anion, the two phenyl rings form dihedral angles of 62.26 (8) and 57.47 (9) degrees with the central imidazole ring. Intra-molecular N-H?O and C-H?O hydrogen bonds occur. In the crystal, N-H?O and C-H?O hydrogen bonds forming a three-dimensional network. PMID- 22199647 TI - Bis{MU-4-chloro-N'-[(E)-1-(5-chloro-2-oxidophen-yl)ethyl idene]benzohydrazidato}bis-[pyridine-copper(II)]. AB - The crystal structure of the title complex, [Cu(2)(C(15)H(10)Cl(2)N(2)O(2))(2)(C(5)H(5)N)(2)], features centrosymmetric dimers. The Cu(II) ion is penta-coordinated in a quadratic pyramidal mode. The quadratic plane is formed by the O,O',N-tridentate ligand and a pyridine mol ecule. The fifth coordination site is occupied by the O atom of another ligand showing a significantly longer Cu-O bond. PMID- 22199648 TI - N,N,N',N'-Tetra-methyl-N,N'-dipropyl-ethane-1,2-diaminium tetra-chlorido cobaltate(II). AB - The crystal structure of the title compound, (C(12)H(30)N(2))[CoCl(4)], is composed of discrete (C(12)H(30)N(2))(2+) cations and [CoCl(4)](2-) anions. The asymmetric unit contains a half-cation and a half-anion. The atoms of the cation occupy general positions about an inversion centre, which is located at the midpoint of the central C-C bond. The Co atoms lie on a twofold rotation axis. The slightly distorted tetra-hedral coordination environment around the metal atom consists of two Cl atoms and their symmetry-related pairs. PMID- 22199649 TI - catena-Poly[[copper(II)-bis-[MU-bis-(pyridin-3-yl)methanone-kappaN:N']] bis (tetra-fluorido-borate)]. AB - In the title complex, {[Cu(C(11)H(8)N(2)O)(2)](BF(4))(2)}(n), the Cu(II) ion is situated on an inversion centre and adopts an N(4)F(2) octa-hedral coordination geometry with four N atoms from four different bis-(pyridin-3-yl)methanone ligands at the equatorial sites and two independent tetra-fluoridoborate anions weakly bonded at the axial sites via two F atoms [Cu?F = 2.613 (3) A]. Chains with the bridging ligands are formed along the a axis. C-H?F inter-actions stabilize the structure. C-O?pi inter-actions also occur. PMID- 22199650 TI - Dichloridobis{2-[(dimethyl-amino)-meth-yl]phen-yl}bis-{2-[(dimethyl-aza-nium yl)meth-yl]phen-yl}di-MU-hydroxido-di-MU(3)-oxido-tetra-phenyl-tetra-tin(IV) dichloride deuterochloro-form deca-solvate. AB - The ladder-like structure of the tetranuclear title compound, [Sn(4)(C(6)H(5))(4)Cl(2)O(2)(OH)(2)(C(9)H(13)N)(2)(C(9)H(12)N)(2)]Cl(2).10CDCl(3) consists of two five- and two six-coordinated Sn(IV) atoms bridged by oxide or hydroxide groups. The chelating ligands reveal rather strong Sn-N bonds [2.517 (4) A], but the protonated dimethylamino groups in the periphery of the complex show no interaction with the metal atoms. The complex cation is located on an inversion centre. The chloride anion is linked to the complex mol-ecule by strong intra-molecular O-H?Cl and N-H?Cl hydrogen bonds. Five independent deuterochloroform accompany the complex, two of them are disordered [occupancy ratios 0.63 (2):0.27 (2) and 0.60 (2):0.40 (2)]. PMID- 22199651 TI - Tetra-MU-acetato-kappaO:O'-bis-{[2,2-dimeth-yl-N-(pyridin-2-yl)propanamide kappaN]copper(II)}(Cu-Cu). AB - The crystal structure of the title compound, [Cu(2)(C(2)H(3)O(2))(4)(C(10)H(14)N(2)O)(2)], reveals a dinuclear Cu(II) complex located about a center of inversion. The coordination environment of each Cu(II) cation is distorted octa-hedral, composed of four bridging acetate ligands, an apical pyridine donor and is completed by a Cu-Cu bond. The amide H atom forms intra-molecular hydrogen bonds to two carboxyl O atoms. In the crystal, weak inter-molecular pyridine-amide C-H?O inter-actions are also present. PMID- 22199652 TI - Dichloridobis(4-methyl-3,5-diphenyl-1H-pyrazole-kappaN)copper(II). AB - The asymmetric unit of the title compound, [CuCl(2)(C(16)H(14)N(2))(2)], comprises half of the complex. The Cu(II) atom lies on a crystallographic twofold rotation axis and shows a significantly distorted tetra-hedral coordination geometry. The dihedral angle between the phenyl rings is 74.3 (2) degrees . The crystal structure is stabilized by inter-molecular pi-pi inter-actions [centroid centroid distances = 3.635 (2)-3.803 (3) A]. PMID- 22199653 TI - trans-Dichloridobis(4-phenyl-pyridine-kappaN)palladium(II). AB - The asymmetric unit of the title complex, [PdCl(2)(C(11)H(9)N)(2)], contains one half of a neutral Pd(II) complex, with the complete mol-ecule generated by the application of a twofold rotation axis; the N-Pd-N atoms lie on the axis. The Pd(II) ion has a trans-Cl(2)N(2) square-planar coordination geometry defined by two N atoms from two 4-phenyl-pyridine ligands and two Cl(-) anions. In the refinement, the pyridine ring and the phenyl ring were found to be disordered over two sites with the site-occupancy factors being 0.53 (2) and 0.51 (1), respectively, for the major components. PMID- 22199654 TI - Dibromido(2,3-di-2-pyridyl-pyrazine-kappaN,N)palladium(II). AB - The Pd(II) ion in the title complex, [PdBr(2)(C(14)H(10)N(4))], is four coordinated in a slightly distorted square-planar environment by the two pyridine N atoms of the chelating 2,3-di-2-pyridyl-pyrazine (dpp) ligand and two bromide anions. The pyridine rings are considerably inclined to the least-squares plane of the PdBr(2)N(2) unit [maximum deviation = 0.080 (2) A], making dihedral angles of 64.9 (1) and 66.4 (1) degrees . The pyrazine ring is perpendicular to the unit plane, with a dihedral angle of 89.0 (1) degrees . In the crystal, the complex mol-ecules are stacked in columns along the a axis and connected by C-H?Br hydrogen bonds, forming a helical chain along the b axis. PMID- 22199655 TI - 1,3-Bis(2,4,6-trimethyl-phen-yl)-3H-imidazol-1-ium tetra-oxidorhenate(VII). AB - The title compound, (C(21)H(25)N(2))[ReO(4)], was formed as the unexpected product in an attempted synthesis of a rhenium(I)-N-heterocyclic carbene (NHC) complex. The compound has crystallographic mirror symmetry with both the cation and the tetrahedral anion located across a mirror plane. The cation and anion are linked by a C-H?O hydrogen bond. PMID- 22199656 TI - Tetra-kis(3-cyano-pyridine-kappaN)bis-(thio-cyanato-kappaN)cobalt(II) 1,4-dioxane disolvate. AB - In the crystal structure of the title compound, {[Co(NCS)(2)(C(6)H(4)N(2))(4)].2C(4)H(8)O(2)}, the Co(II) cations are octa hedrally coordinated by two terminal N-bonded thio-cyanate anions and four N bonded 3-cyano-pyridine ligands. The asymmetric unit consists of one Co(II) cation, which is located on a special position with site symmetry 2/m, one thio cyanate anion and one dioxane mol-ecule, located on a crystallographic mirror plane, as well as one 3-cyano-pyridine ligand in a general position. The crystal structure consists of discrete complexes of [Co(NCS)(2)(3-cyano-pyridine)(4)], as well as two non-coordinating 1,4-dioxane solvent mol-ecules which are disordered due to symmetry. PMID- 22199657 TI - Poly[[aqua-(MU(5)-3,4,5,6-tetra-carb-oxy-cyclo-hexane-1,2-dicarboxyl ato)strontium] monohydrate]. AB - In the title compound, {[Sr(C(12)H(10)O(12))(H(2)O)].H(2)O}(n), the Sr(II) ion is coordinated by six O atoms of five symmetry-related 3,4,5,6-tetra-carb-oxy-cyclo hexane-1,2-dicarboxyl-ate ligands and one water mol-ecule in a slightly distorted monocapped trigonal-prismatic environment. The ligands bridge the Sr(II) ions, forming a two-dimensional structure. In the crystal, O-H?O hydrogen bonds further connect the structure into a three-dimensional network. The H atoms of two of the carboxyl groups were refined as half-occupancy. PMID- 22199658 TI - catena-Poly[[(diiodidocadmium)-MU-{1-[(1H-benzimidazol-2-yl)meth-yl]-1H-imidazole kappaN:N'}] N,N-dimethyl-formamide monosolvate]. AB - In the title complex, {[CdI(2)(C(11)H(10)N(4))].C(3)H(7)NO}(n), the Cd(II) ion is four-coordinated by two N atoms from two 1-[(1H-benzimidazol-1-yl)meth-yl]-1H imidazole (bmi) ligands and by two terminal I(-) anions in a distorted tetra hedral geometry. One of the two I(-) anions is disordered over two sets of sites, with refined occupancies of 0.66 (5) and 0.34 (5). The Cd(II) ions are bridged by bmi ligands, leading to the formation of a chain along [001]. Dimethyl-formamide solvent mol-ecules are located between these chains. Classical N-H?O hydrogen bonding between the bmi ligands and the solvent mol-ecules leads to a consolidation of the structure. PMID- 22199659 TI - (meso-5,5,7,12,12,14-Hexamethyl-1,4,8,11-tetra-aza-cyclo-tetra-deca-ne)nickel(II) bis-[O,O'-(1,2-phenyl-ene) dithio-phosphate]. AB - In the crystal structure of the title compound, [Ni(C(16)H(36)N(4))](C(6)H(4)O(2)PS(2))(2), the Ni(II) cation is located on a center of inversion and is chelated by the folded tetra-amine macrocycle ligand in a slightly distorted NiN(4) square-planar geometry. Two symmetry-related O,O' (1,2-phenyl-ene)dithio-phosphate anions are located on either side of the Ni(II) cation, with Ni?S of 3.9558 (5) A, and link to the tetra-amine macrocycle ligand via N-H?S hydrogen bonding. PMID- 22199660 TI - Chlorido(12,17-dieth-oxy-carbonyl-11,18-dimethyl-2:3,6:7-dibutano-corrphycenato kappaN)iron(III). AB - The title complex, [Fe(C(36)H(36)N(4)O(4))Cl], shows a domed structure with a slightly distorted trapezoidpyramidal core, in which the perpendicular displacements of the Fe(III) atom from the mean pyrrole N(4) plane are 0.418 (3) and 0.465 (3) A for the two crystallographically independent mol-ecules. PMID- 22199661 TI - Bis(chloro-acetato-kappaO,O')bis-(2-fluoro-benzyl-kappaC)tin(IV). AB - In the title complex, [Sn(C(2)H(2)ClO(2))(2)(C(7)H(6)F)(2)], the Sn(IV) atom is located on a twofold rotation axis and forms a strongly distorted trans-octa hedral geometry. The equatorial plane is defined by two chelating chloro-acetate ligands with asymmetrical Sn-O bond lengths, while the axial positions are occupied by the C atoms of two 2-fluoro-benzyl groups. In the crystal, infinite chains in the [010] direction are formed through inter-molecular Sn?O inter actions [Sn?O separation = 3.682 (3) A]. PMID- 22199662 TI - Bromidotetra-kis-(1H-2-ethyl-5-methyl-imidazole-kappaN)copper(II) bromide. AB - The Cu(II) ion in the title compound, [CuBr(C(6)H(10)N(2))(4)]Br, is coordinated in a square-based-pyramidal geometry by the N atoms of four imidazole ligands and a bromide anion in the apical site. Both the Cu(II) and Br(-) atoms lie on a crystallographic fourfold axis. In the crystal, the [CuBr(C(6)H(10)N(2))(4)](+) complex cations are linked to the uncoordinated Br(-) anions (site symmetry [Formula: see text]) by N-H?Br hydrogen bonds, generating a three-dimensional network. The ethyl group of the imidazole ligand was modelled as disordered over two orientations with occupancies of 0.620 (8) and 0.380 (8). PMID- 22199663 TI - Tetrakis[MU-3-(3-hy-droxy-phen-yl)propenoato]bis-{aqua-(2,2'-bipyridine)-[3-(3-hy droxy-phen-yl)propenoato]neodymium(III)} 2,2'-bipyridine disolvate dihydrate. AB - The dinuclear title compound, [Nd(2)(C(9)H(7)O(3))(6)(C(10)H(8)N(2))(2)].2C(10)H(8)N(2).2H(2)O, was synthesized under hydro-thermal conditions. The centrosymmetric complex consists of two nine coordinated Nd(3+) cations, six 3-hy-droxy-cinnamate anions and two chelating 2,2'-bipyridine mol-ecules. The coordination geometry around the cations can be best described as distorted tricapped trigonal-prismatic. The carboxyl-ate groups show different coordination and bridging modes. Two of them chelate to one Nd(3+) cation, two bridge the two cations in a bis-monodentate fashion, and two chelate to one and bridge monodentately to the symmetry-related Nd(3+) cation. The dinuclear mol-ecule is surrounded by two 2,2'-bipyridine solvent and two water mol-ecules. Extensive O-H?O and O-H?N hydrogen-bonding inter-actions between the components lead to the formation of a three-dimensional network. PMID- 22199664 TI - Bis(2,2'-bipyridine-kappaN,N')bis-[3-(3-hy-droxyphenyl)propenoato kappaO,O]cadmium. AB - The title compound, [Cd(C(9)H(7)O(3))(2)(C(10)H(8)N(2))(2)], was synthesized under mild hydro-thermal conditions. The structure of the complex mol-ecule consists of four approximately planar fragments: two 3-(3-hy droxyphenyl)propenoate residues and two 2,2'-bipyridine ligands [largest deviation from the least-squares planes is 0.240 (1) A for one of 3-(3-hy-droxy phenyl)propenoate residues]. The dihedral angles formed by the least-squares planes of the 2,2'-bipyridine ligands and the opposite 3-(3-hy droxyphenyl)propenoate residues are 22.68 (7) and 26.47 (6) degrees . The CdN(4)O(4) coordination polyhedron can be described as distorted dodecahedral. Inter-molecular O-H?O hydrogen bonds between carboxyl-ate O atoms and hy-droxy groups lead to the formation of chains along the a-axis direction. PMID- 22199665 TI - 4-Methyl-N'-(2,2,2-trichloro-ethanimido-yl)benzene-1-carboximidamide. AB - The title compound, C(10)H(10)Cl(3)N(3), features a delocalized unsaturated N C N C N chain and strong intra-molecular N-H?N hydrogen bonding across the chelate ring and also intra-molecular N-H?Cl contacts to a CCl(3)-group Cl atom. The only inter-molecular contacts in the lattice are non-classical hydrogen bonds between methyl and CCl(3) groups. The pseudo-six-membered ring is distinctly non-planar by virtue of rotation about the N-C bond between the carboximidamide and imine components [C-N-C-N torsion angle = -23.6 (2) degrees ]. PMID- 22199666 TI - Diethyl 2,5-bis-[(2,3-dihydro-thieno[3,4-b][1,4]dioxin-5-yl)methyl-idene-amino] thio-phene-3,4-dicarboxyl-ate acetone monosolvate. AB - The unique 3,4-ethyl-ene-dioxy-thio-phene (EDOT) unit of the title compound, C(24)H(22)N(2)O(8)S(3).C(3)H(6)O, is twisted by 1.9 (3) degrees relative to the central thio-phene ring. The three heterocyclic units are anti-periplanar. In the crystal, inversion dimers linked by pairs of C-H?O hydrogen bonds connect the heterocycles. pi-pi interactions occur between the central thiophene and the imine bond of the molecule [distance between the ring centroid of the ring and the azomethine bond = 3.413 (3) A. PMID- 22199667 TI - Methyl 5-chloro-2-nitro-benzoate. AB - In the title compound, C(8)H(6)ClNO(4), the nitro and acet-oxy groups attached to the benzene ring at neighbouring positions are twisted from its plane by 29.4 (1) and 49.7 (1) degrees , respectively. In the crystal, weak C-H?O hydrogen bonds link mol-ecules into layers parallel to (101). The crystal packing exhibits short inter-molecular C?O distances of 2.925 (3) A. PMID- 22199668 TI - 1,1'-{[1,4-Phenyl-enebis(methyl-ene)]bis-(-oxy)bis-(3,1-phenyl-ene)}diethanone. AB - In the title compound, C(24)H(22)O(4), the centroid of the central benzene ring lies on a special position of 2/m site symmetry, while the terminal aromatic rings are located on a mirror plane. The central and terminal benzene rings are perpendic-ular to each other. In the crystal, the mol-ecules are connected via C H?O hydrogen bonds into a three-dimensional polymeric structure. The network is further consolidated by a C-H?pi inter-action. PMID- 22199669 TI - (Z)-2-(5-Chloro-2-oxoindolin-3-yl-idene)-N-phenyl-hydrazinecarbothio-amide. AB - In the title compound, C(15)H(11)ClN(4)OS, the dihedral angle between the nine membered 5-chloro-indolin-2-one ring system and the benzene ring is 10.00 (6) degrees . Intra-molecular cyclic N-H?O and C-H?S hydrogen-bonding inter-actions [graph set S(6)] are present in the N-N-C-N chain between the ring systems. In the crystal, mol-ecules form centrosymmetric cyclic dimers through inter molecular N-H?O hydrogen bonds [graph-set R(2) (2)(8)] and are extended by C-H?Cl inter-actions into infinite chains which propagate along [100]. PMID- 22199670 TI - Redetermination of 2,4'-methyl-ene-diphenol. AB - In the previous determination [Finn & Musti (1950 ?). J. Soc. Chem. Ind. (London), 69, S849] of the title compound, C(13)H(12)O(2), the three-dimensional coordinates and displacement parameters were not reported. This redetermination at room temperature reveals that the dihedral angle between the benzene rings is 79.73 (6) degrees . In the crystal, inter-molecular O-H?O hydrogen bonds between adjacent mol-ecules result in two-dimensional wave-like supra-molecular motifs parallel to the ab plane. PMID- 22199671 TI - 4,4'-Bis(trimethyl-sil-yl)-2,2'-bipyridine. AB - In the mol-ecule of title compound, C(16)H(24)N(2)Si(2), the pyridine rings are nearly planar (r.m.s. deviation = 0.002 A). PMID- 22199673 TI - N-(3,5-Dimethyl-phen-yl)-4-methyl-benzamide. AB - In the title compound, C(16)H(17)NO, the dihedral angle between the two benzene rings is 16.6 (1) degrees . The crystal structure is stabilized by inter molecular N-H?O hydrogen bonds, which link the mol-ecules into chains running along the c axis. PMID- 22199672 TI - Talatisamine, a C(19)-diterpenoid alkaloid from Chinese traditional herbal 'Chuanwu'. AB - THE TITLE COMPOUND [SYSTEMATIC NAME: (1S,4S,5R,7S,8S,9R,10R,11S,13S,14S,16S,17R) N-methyl-8,14-dihy-droxy-1,16-tri-meth-oxy-4-(meth-oxy-methyl-ene)aconitane], C(24)H(39)NO(5), was isolated from the roots of Aconitum carmichaelii Debx., which is known as 'Chuanwu' in Chinese traditional herbal medicine. The mol-ecule has an aconitane carbon skeleton with four six-membered rings and two five membered rings, including a six-membered N-containing heterocyclic ring. Both five-membered rings adopt envelope conformations. The four six-membered adopt chair conformations. Two intra-molecular O-H?O hydrogen bonds occur. PMID- 22199674 TI - Tetra-ethyl-ammonium 2-[bis-(4-hy-droxy-phen-yl)meth-yl]benzoate. AB - In the title compound, C(8)H(20)N(+).C(20)H(15)O(4) (-), the benzoate anions are connected by multiple inter-molecular O-H?O hydrogen bonds, forming columns propagating along [1[Formula: see text]0]. The hydrogen bonding can be described by two rings with R(2) (2)(22) and R(4) (2)(28) motifs. In the crystal, the tetra ethyl-ammonium cations are situated between these columns and are linked to them via C-H?O inter-actions. PMID- 22199675 TI - Isopropyl-triphenyl-phospho-nium bromide monohydrate. AB - In the title water-solvated salt, C(21)H(22)P(+).Br(-).H(2)O, the ionic components are linked by short C-H?Br contacts along the a-axis direction. The two half occupied water mol-ecules are connected to each other by strong O-H?O hydrogen bonds and they are also linked to the bromide anion by short O-H?Br contacts. PMID- 22199676 TI - 2-Bromo-4-chloro-6-(cyclo-hexyl-imino-meth-yl)phenol. AB - The title compound, C(13)H(15)BrClNO, was prepared by the condensation of equimolar quanti-ties of 3-bromo-5-chloro-salicyl-aldehyde with cyclo-hexyl-amine in methanol. There is an intra-molecular O-H?N hydrogen bond in the mol-ecule. The cyclo-hexyl ring adopts a chair conformation. PMID- 22199677 TI - 6-[(4-Hy-droxy-phen-yl)diazenyl]-1,10-phenanthrolin-1-ium chloride monohydrate. AB - In the cation of the title mol-ecular salt, C(18)H(13)N(4)O(+).Cl(-).H(2)O, the dihedral angle between the mean planes of the 1,10-phenanthroline system and the phenol ring is 14.40 (19) degrees . The crystal packing is stabilized by O-H?O hydrogen bonds, weak N-H?Cl and O-H?Cl inter-molecular inter-actions and pi-pi stacking inter-actions [centroid-centroid distance = 3.6944 (13) and 3.9702 (12) A]. PMID- 22199678 TI - 2-(2-Chloro-phen-yl)-2-oxo-N-phenyl-acetamide. AB - In the title compound, C(14)H(10)ClNO(2), the dihedral angle between the two rings is 59.4 (2) degrees . The two carbonyl groups are oriented almost anti periplanar to each other, with a torsion angle of -160.43 (2) degrees . In the crystal, mol-ecules are linked into inversion dimers by pairs of N-H?O hydrogen bonds. PMID- 22199679 TI - (E)-2,2'-[3-(2-Nitro-phen-yl)prop-2-ene-1,1-di-yl]bis-(3-hy-droxy-5,5-dimethyl cyclo-hex-2-en-1-one). AB - In the title compound, C(25)H(29)NO(6), each of the cyclo-hexenone rings adopts a half-chair conformation. Each of the pairs of hy-droxy and carbonyl O atoms are oriented to allow for the formation of intra-molecular O-H?O hydrogen bonds, which are typical of xanthene derivatives. The nitro group is rotationally disordered over two orientations in a 0.544 (6):0.456 (6) ratio. In the crystal, weak inter-molecualr C-H?O hydrogen bonds link mol-ecules into layers parallel to the ab plane. PMID- 22199680 TI - 2-(4-Bromo-phen-yl)-2-oxoethyl 4-methyl-benzoate. AB - The title compound, C(16)H(13)BrO(3), consists of a toluene ring and a bromo benzene ring which are linked together by a 2-oxopropyl acetate group. The dihedral angle formed between the toluene and bromo-benzene rings is 80.70 (7) degrees . In the crystal, inter-molecular C-H?O hydrogen bonds link the mol ecules into a three-dimensional network. PMID- 22199681 TI - 1,1,1,5,5,5-Hexafluoro-2,4-dimeth-oxy-pentane-2,4-diol. AB - The title compound, C(7)H(10)F(6)O(4), was isolated as an unexpected product from a reaction of tantalum(V) methoxide with hexa-fluoro-acetyl-acetone in a methanol solution. The asymmetric unit consists of one half-mol-ecule with the middle C atom lying on a twofold axis. The crystal structure is stabilized by O-H?O and an array of C-H?F hydrogen-bonding inter-actions. These inter-actions link the mol ecules into a stable supra-molecular three-dimensional network. The mol-ecules pack in a ribbon-like form in the ac plane as a result of these inter-actions. PMID- 22199682 TI - 2-Phenyl-imidazolium hemi(benzene-1,4-dicarboxyl-ate) trihydrate. AB - The asymmetric unit of the title compound, C(9)H(9)N(2) (+.)0.5C(8)H(4)O(4) ( ).3H(2)O, contains one 2-phenyl-imidazolium cation, half a benzene-1,4-dicarboxyl ate anion and three water mol-ecules, which are connected by O-H?O and N-H?O hydrogen bonds into a three-dimensional network. PMID- 22199683 TI - 5,10,15,20-Tetra-kis(1-methyl-pyridinium-4-yl)porphyrin tetra-iodide tetra hydrate. AB - The asymmetric unit of the title compound, C(44)H(38)N(8) (2+).4I(-).4H(2)O, comprises two halves of non-equivalent cations of 5,10,15,20-tetra-kis-(1-methyl pyridinium)porphyrin (with the full mol-ecule of each completed by the application of inversion symmetry), four charge balancing iodide anions and four water mol-ecules of crystallization (two water mol-ecules are fully occupied and four mol-ecules have a site occupancy of 50%). The porphyrin cations are arranged into supramolecular columns parallel to the b axis, mediated by pi-pi [centroid centroid distance = 3.762 (4) A] and C-H?pi supra-molecular inter-actions [C?centroid distance = 3.522 (7) A, C-H?centroid = 128 degrees ], leading to the formation of columns parallel to the b axis. The close packing leads to the presence of a one-dimensional channel filled with partially occupied water mol ecules engaged in O-H?O and O-H?I hydrogen bonds. PMID- 22199684 TI - (E)-1-(4,4''-Difluoro-5'-meth-oxy-1,1':3',1''-terphenyl-4'-yl)-3-phenyl-prop-2-en 1-one. AB - The title compound, C(28)H(20)F(2)O(2), is a polysubstituted terphenyl derivative bearing a Michael system. The C=C double bond is E configured. In the crystal, C H?O and C-H?F contacts connect the mol-ecules, forming undulating sheets that lie perpendicular to the crystallographic a axis. The shortest pi-pi inter-action [centroid-centroid distance = 3.7163 (7) A] involves the para-fluoro-phenyl ring in the para position to the Michael system, and its symmetry-generated equivalent. PMID- 22199685 TI - 2-Amino-4,5,6,7-tetra-hydro-benzo[b]thio-phene-3-carbonitrile. AB - The title compound, C(9)H(10)N(2)S, was synthesized according to Gewald procedures by the reaction of cyclo-hexa-none with malonitrile and sulfur in the presence morpholine. The cyclo-hexane ring adopts a half-chair conformation and the thio-phene ring is essentially planar (r.m.s. deviation = 0.05 A). The crystal packing is stabilized by two inter-molecular N-H?N hydrogen bonds, which link the mol-ecules into centrosymmetric rings with graph-set motif R(2) (2)(12). PMID- 22199686 TI - N-(2-Fluoro-phen-yl)-5-[(4-meth-oxy-phen-yl)amino-meth-yl]-6-methyl-2-phenyl pyrimidin-4-amine. AB - The conformation of the title mol-ecule, C(25)H(23)FN(4)O, is mainly determined by an intra-molecular N-H?N hydrogen bond closing a six-membered ring and the dihedral angles between the pyrimidine ring and the three benzene rings which are 12.8 (2), 12.0 (2) and 86.1 (2) degrees . An intra-molecular N-H?F inter-action also occurs. The crystal stucture is stabilized by weak C-H?O and C-H?pi inter actions. An inter-molecular N-H?N inter-action is also observed. PMID- 22199687 TI - 2-(4-Chloro-phen-yl)chromen-4-one. AB - The title compound, C(15)H(9)ClO(2), is a synthetic flavonoid obtained by the cyclization of 3-(4-chloro-phen-yl)-1-(2-hy-droxy-phen-yl)prop-2-en-1-one. The 4 chloro-phenyl ring is twisted at an angle of 11.54 degrees with respect to the chromen-4-one skeleton. In the crystal, pairs of mol-ecules are inter-connected by weak Cl?Cl inter-actions [3.3089 (10) A] forming dimmers which are further peripherally connected through inter-molecular C-H?O hydrogen bonds. PMID- 22199688 TI - 1,1'-{[1,4-Phenyl-enebis(methyl-ene)]bis-(-oxy)bis-(4,1-phenyl-ene)}diethanone. AB - The centroid of the central aromatic ring of the title mol-ecule, C(24)H(22)O(4), is located on an inversion center. The dihedral angle between the central and terminal benzene rings is 75.00 (7) degrees . In the crystal, mol-ecules are linked through C-H?O hydrogen bonds into chains along [121]. The chains are connected into layers via C-H?pi inter-actions. PMID- 22199689 TI - 2-[(E)-(2-Hy-droxy-naphthalen-1-yl)methyl-idene-amino]-isoindoline-1,3-dione. AB - The title compound, C(19)H(12)N(2)O(3), has two independent mol-ecules (A and B) in the asymmetric unit. There is an intra-molecular O-H?N hydrogen bond in each mol-ecule. The mean planes of the naphthalene [maximum deviations = 0.024 (3) and 0.030 (3) A in A and B, respectively] and the isoindoline units [maximum deviations 0.009 (3) and 0.008 (3) A in A and B, respectively] are almostly coplanar, with dihedral angles of 4.25 (9) ad 3.84 (9) degrees in mol-ecules A and B, respectively. The two independent mol-ecules are connected by pi-pi inter actions [centroid-centroid distances 3.5527 (19) and 3.5627 (19) A]. In the crystal, the A+B pairs are further connected via pi-pi inter-actions [centroid centroid distances = 3.693 (2)-3.831 (2) A], leading to the formation of columns propagating along the a-axis direction. The columns are linked via C-H?O inter actions, leading to the formation of a three-dimensional network. PMID- 22199690 TI - 4-(4-Bromo-phen-yl)-3-methyl-1-phenyl-6,7-dihydro-1H-pyrazolo-[3,4-b]thieno[2,3 e]pyridine 5,5-dioxide. AB - In the title compound, C(21)H(16)BrN(3)O(2)S, the pyrazole and pyridine rings are nearly coplanar, the dihedral angle between their planes being 3.17 (14) degrees . The 2,3-dihydro-thio-phene ring adopts an envelope conformation. The 4-bromo phen-yl/pyridine ring and phen-yl/pyrazole rings form dihedral angles of 60.06 (9) and 33.49 (11) degrees , respectively. There is an intra-molecular C-H?N hydrogen bond. The crystal packing is stabilized by inter-molecular C-H?O hydrogen bonding and C-H?pi inter-actions. PMID- 22199691 TI - 1-[2-(1H-Benzimidazol-2-yl)eth-yl]-1H-1,2,3-benzotriazole. AB - In the title compound, C(15)H(13)N(5), the N-containing heterocycles are linked by an ethyl-ene spacer in a gauche conformation, the N-C-C-C torsion angle along the linker being 60.1 (3) degrees . The dihedral angle between the terminal benzotriazole and benzimidazole rings is 39.02 (6) degrees . In the crystal, adjacent mol-ecules are connected by N-H?N hydrogen bonds, forming an infinite chain along the c axis. pi-pi stacking inter-actions [centroid-centroid distance = 3.8772 (7) A] between the benzotriazole rings of neighbouring chains extend these chains into a supra-molecular sheet in the bc plane. Weak inter-molecular C H?N inter-actions further stabilize the crystal structure. PMID- 22199692 TI - 4-Hy-droxy-3-meth-oxy-benzaldehyde-nicotinamide (1/1). AB - In the title compound, C(6)H(6)N(2)O.C(8)H(8)O(3), an equimolar co-crystal of nicotinamide and vanillin, the aromatic ring and the amide fragment of the nicotinamide mol-ecule make a dihedral angle of 32.6 (2) degrees . The vanillin mol-ecule is almost planar, with an r.m.s. deviation for all non-H atoms of 0.0094 A. The vaniline and nicotinamide aromatic rings are nearly coplanar, the dihedral angle between them being 3.20 (9) degrees . In the crystal, the two components are linked through N-H?O and O-H?N hydrogen bonds into chains along the a axis. The chains are connected via C-H?O inter-actions, forming a three dimensional polymeric structure. PMID- 22199693 TI - N,N-Diethynyl-N,N-diphenyl-benzene-1,4-diamine. AB - The title compound, C(22)H(16)N(2), is the first example of an ynamine with H atoms bonded to the terminal C atoms. The environment around each N atom is almost planar. The distances of the N atoms from a least squares plane fitted through each N atom and the surrounding three C atoms, are 0.087 (3) and 0.041 (4) A. The dihedral angles between these two planes and the central phenyl-ene ring are 23.34 (14) and 34.57 (14) degrees . The two acetyl-ene groups have an anti conformation, keeping a conjugation through the central benzene ring. The freely refined lengths of C(sp)-H are 1.00 (5) and 0.93 (4) A, consistent with those of reported acetyl-enes. The H atoms bound to terminal C atoms have short contacts with the neighboring acetyl-enic C and N atoms. The closest contacts are an H?N distance of 2.67 (5) A and an H?C distance of 2.74 (5) A. PMID- 22199694 TI - 1-(4-Fluoro-phen-yl)-2-(1H-1,2,4-triazol-1-yl)ethanone hemihydrate. AB - In the title compound, C(10)H(8)FN(3)O.0.5H(2)O, the dihedral angle between the mean planes of the rings is 99.80 (4) degrees . The water mol-ecule lies on a twofold axis. Weak inter-molecular O-H?N and C-H?O hydrogen bonds link one water mol-ecule with four phenyl-ethanone mol-ecules, while inter-molecular C-H?O hydrogen bonds involving the ketone group link phenyl-ethanone mol-ecules into layers parallel to (100). PMID- 22199695 TI - 4-Chloro-N-phenyl-benzamide. AB - In the title compound, C(13)H(10)ClNO, the dihedral angle between the two benzene rings is 59.6 (1) degrees . The crystal structure features N-H?O hydrogen bonds, which link the mol-ecules into C(4) chains running along the a axis. PMID- 22199696 TI - Bis(3-methyl-anilinium) sulfate. AB - In the crystal structure of the title salt, 2C(7)H(7)NH(3) (+).SO(4) (2-), the cations inter-act with the oxyanions through strong charge-assisted N-H?O hydrogen bonds. PMID- 22199697 TI - 2,7-Bis(2,6-diisopropyl-phen-yl)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H) tetra-one. AB - In the title compound, C(38)H(38)N(2)O(4), the 16 atoms comprising the four six membered rings that are fused together are approximately coplanar (maximum r.m.s. deviation = 0.033 A). The benzene rings at either ends are nearly perpendicular to the mean plane of the fused-ring system; one is aligned at 80.4 (1) degrees and the other at 82.2 (1) degrees . PMID- 22199698 TI - 2-(2-Meth-oxy-phen-oxy)-3-nitro-pyridine. AB - In the title compound, C(12)H(10)N(2)O(4), the pyridine and benzene rings are almost orthogonal, forming a dihedral angle of 86.63 (6) degrees . Each of the nitro [O-N-C-C torsion angle = -6.45 (19) degrees ] and meth-oxy [C-O-C-C torsion angle = 179.69 (11) degrees ] groups is almost coplanar with the ring to which it is connected. Mol-ecules are consolidated in the crystal structure via C-H?O inter-actions, forming a three-dimensional network. PMID- 22199699 TI - N-(4-Chloro-phen-yl)quinolin-2-amine. AB - There is a twist in the title mol-ecule, C(15)H(11)ClN(2), as seen in the dihedral angle of 18.85 (9) degrees between the quinoline and benzene rings. A short C-H?N contact arises from this conformation and the amine H and quinoline N atoms are directed towards opposite sides of the mol-ecule. In the crystal, supra molecular layers in the ab plane are mediated by C-H?pi inter-actions. PMID- 22199700 TI - N-(4-Chloro-phen-yl)-3-nitro-pyridin-2-amine. AB - In the title compound, C(11)H(8)ClN(3)O(2), the presence of intra-molecular N-H?O and C-H?N inter-actions help to establish an almost planar mol-ecule [dihedral angle between the pyridine and benzene rings = 9.89 (8) degrees and r.m.s. deviation for all 17 non-H atoms = 0.120 A]. Supra-molecular tapes feature in the crystal packing whereby dimeric aggregates sustained by pairs of C-H?O inter actions are connected by pi-pi inter-actions occurring between translationally related pyridine rings and between translationally related benzene rings along the b axis [centroid-centroid distance = length of b axis = 3.8032 (4) A]. PMID- 22199701 TI - 1-[2-(2,5-Dichloro-benz-yloxy)-2-phenyl-eth-yl]-1H-benzotriazole. AB - In the title mol-ecule, C(21)H(17)Cl(2)N(3)O, the benzotriazole ring is oriented at dihedral angles of 48.72 (6) and 62.94 (5) degrees , respectively, to the phenyl and benzene rings and the dihedral angle between the phenyl and benzene rings is 88.95 (6) degrees . In the crystal, weak C-H?N hydrogen bonds link the mol-ecules into chains. pi-pi contacts between the triazole and benzene rings [centroid-centroid distance = 3.678 (1) A] and a weak C-H?pi inter-action are also observed. PMID- 22199702 TI - (E)-1-(4,4''-Difluoro-5'-meth-oxy-1,1':3',1''-terphenyl-4'-yl)-3-(4-nitro-phen yl)prop-2-en-1-one. AB - In the title compound, C(28)H(19)F(2)NO(4), a polysubstituted terphenyl derivative bearing a Michael system, the C=C double bond has an E configuration. Two C-H?F contacts connect mol-ecules into inversion dimers. In addition, a C H?pi as well as a C-F?pi contact can be identified. The shortest centroid centroid distance between two aromatic rings is 3.9535 (8) A, between one of the para-fluoro-benzene rings and its symmetry-generated equivalent. PMID- 22199703 TI - (E)-1-(4,4''-Difluoro-5'-meth-oxy-1,1':3',1''-terphenyl-4'-yl)-3-(4-methyl-phen yl)prop-2-en-1-one. AB - In the meta-terphenyl fragment of the title mol-ecule, C(29)H(22)F(2)O(2), the two fluoro-phenyl rings are twisted from the central benzene ring by 46.72 (6) and 41.70 (6) degrees , respectively. In the crystal, weak C-H?O and C-H?F hydrogen bonds link the mol-ecules into layers parallel to the ab plane. The crystal packing exhibits pi-pi inter-actions, the shortest distance between the centroids of aromatic rings being 3.6364 (7) A. PMID- 22199704 TI - 3,5-Dibromo-2-[2,5-dibut-oxy-4-(3,5-dibromo-thio-phen-2-yl)phen-yl]thio-phene. AB - The title mol-ecule, C(22)H(22)Br(4)O(2)S(2), is centrosymmetric with an inversion centre located at the centre of the benzene ring. The 3,5-dibromo-thio phene groups are twisted relative to the benzene ring, making a dihedral angle of 41.43 (9) degrees . PMID- 22199705 TI - (E)-2-[(2-Chloro-benzyl-idene)amino]-isoindoline-1,3-dione. AB - The title compound, C(15)H(9)ClN(2)O(2), adopts an E configuration about the C=N double bond. The mean plane of the isoindoline ring system [maximum deviation = 0.011 (2) A] is inclined to the chloro-benzene ring by 22.62 (8) degrees . In the crystal, mol-ecules are connected by C-H?O hydrogen bonds, forming chains that propagate along [010]. PMID- 22199706 TI - (E)-3-(Furan-2-yl)-1-(4-meth-oxy-phen-yl)prop-2-en-1-one. AB - In the title mol-ecule, C(14)H(12)O(3), the prop-2-en-1-one unit forms dihedral angles of 12.96 (5) and 7.89 (7) degrees with the 4-meth-oxy-phenyl group and the furan ring, respectively. The furan and benzene rings form a dihedral angle of 8.56 (5) degrees . In the crystal, C-H?pi and pi-pi inter-actions are observed between the benzene and heterocyclic rings [centroid-centroid distance = 3.760 (1) A]. PMID- 22199707 TI - 2-[(1RS,3RS,3aRS,6aSR)-5-Benzyl-4,6-dioxo-3-phenyl-octa-hydro-pyrrolo-[3,4 c]pyrrol-1-yl]acetamide. AB - In the title compound, C(21)H(21)N(3)O(3), the relative stereochemistry of the four stereogenic C atoms has been determined. The dihedral angle between the phenyl rings is 77.63 (7) degrees . In the crystal, ribbons spread along the a axis are formed by N-H?O hydrogen bonds. C-H?pi inter-actions also occur. PMID- 22199708 TI - 1-Benzoyl-3-(naphthalen-1-yl)thio-urea. AB - In the title compound, C(18)H(14)N(2)OS, the dihedral angle between the mean planes of the 3-naphthyl and 1-benzoyl rings is 20.7 (1) degrees . The crystal packing is stabilized by weak N-H?S inter-actions. Intra-molecular N-H?O and C H?O hydrogen bonding is also observed. PMID- 22199709 TI - 4-[2-(4-Meth-oxy-phen-yl)eth-yl]-3-(thio-phen-2-ylmeth-yl)-1H-1,2,4-triazol-5(4H) one monohydrate. AB - In the title compound, C(16)H(17)N(3)O(2)S.H(2)O, the triazole ring makes a dihedral angle of 34.63 (6) degrees with the benzene ring. The thio-phene ring is disordered over two orientations [occupancy ratio = 0.634 (4):0.366 (4)] which make dihedral angles of 54.61 (16) and 54.57 (31) degrees with the triazole ring. Inter-molecular N-H?O and O-H?O hydrogen bonds stabilize the crystal structure. PMID- 22199710 TI - A second monoclinic polymorph of 2,4-dimethyl-anilinium chloride. AB - A second monoclinic polymorph of 2,4-dimethyl-anilinium chloride, C(8)H(12)N(+).Cl(-), (I), is reported. The unit-cell dimensions differ from those of the first reported monoclinic form, (II) [Yao (2010 ?). Acta Cryst. E66, o1563]. Nevertheless, both compounds crystallize in the monoclinic space group P2(1)/n. As in (II), the protonated amine group in (I) acts as a hydrogen-bond donor to the chloride ion, forming three N-H?Cl hydrogen bonds. The result is a two-dimensional network in the ac plane. The difference in the hydrogen-bond pattern is that in (I) only 12-membered rings are formed whereas in (II), eight membered and 16-membered rings are formed. PMID- 22199711 TI - 4-{4-[(4-Oxoquinazolin-3-yl)meth-yl]-1H-1,2,3-triazol-1-yl}butyl acetate. AB - In the heterocyclic title compound, C(17)H(19)N(5)O(3), the quinazolinone ring system forms a dihedral angle of 67.22 (7) degrees with the triazole ring. The butyl acetate group has a non-linear conformation, with an alternation of synclinal and anti-periplanar torsion angles [N-C-C-C = 58.5 (2) degrees , C-C-C C = 170.72 (19) degrees and C-C-C-O = -65.9 (3) degrees ]. The crystal structure features inter-molecular C-H?N and C-H?O non-classical hydrogen bonds, building an infinite one-dimensional network along the [100] direction. PMID- 22199712 TI - (4aS,4bR,7R,10aS)-3,7-Dimethyl-10a-(propan-2-yl)-1,4,4a,4b,5,6,7,8,10,10a-deca hydro-phenanthrene-1,4-dione. AB - In the title compound, C(19)H(26)O(2), the A ring adopts a chair conformation, whereas the B and C rings both adopt distorted half-chair conformations with the quaternary C atom common to both rings lying 0.577 (3) and 0.648 (3) A out of the approximate plane defined by the remaining five C atoms (r.m.s. deviations = 0.1386 and 0.1156 A) for the B and C rings, respectively. Mol-ecules are assembled in the crystal through C-H?O inter-actions involving both carbonyl O atoms, which lead to supra-molecular chains aligned along the b axis. PMID- 22199713 TI - Bis{2,6-bis-[(2-hy-droxy-5-methyl-phen-yl)imino-meth-yl]pyridine} monohydrate. AB - The title compound, 2C(21)H(19)N(3)O(2).H(2)O, was synthesized by a Schiff base condensation of 2,6-diformyl-pyridine with 2-amino-4-methyl-phenol in ethanol. In the crystal, two mol-ecules of 2,6-bis-[(2-hy-droxy-5-methyl-phen-yl)imino-meth yl]pyridine dimer-ize via hydrogen bonding to a water mol-ecule, which lies on a twofold axis. There are also intra-molecular phenol-imine hydrogen bonds. The dimers are further linked via pi-pi (phen-yl-pyridine) [centroid-centroid distance = 3.707 (2) A] and pi-pi edge-to-edge [3.392 (2) A] inter-actions. The dihedral angles between the central ring and the two pendant rings are 11.46 (8) and 2.06 (8) degrees while the pendant rings make a dihedral angle of 10.14 (8) degrees . PMID- 22199714 TI - 5-(2,4-Dichloro-phen-oxy)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde. AB - In the title mol-ecule, C(12)H(10)Cl(2)N(2)O(2), the benzene and pyrazole rings form a dihedral angle of 72.8 (3) degrees . In the crystal, weak inter-molecular C-H?O hydrogen bonds link the mol-ecules into chains along [01[Formula: see text]]. PMID- 22199715 TI - (Z)-N,N-Dimethyl-2-[phen-yl(pyridin-2-yl)methyl-idene]hydrazinecarbothio-amide. AB - The title compound, C(15)H(16)N(4)S, exists in the Z conformation with the thionyl S atom lying cis to the azomethine N atom. The shortening of the N-N distance [1.3697 (17) A] is due to extensive delocalization with the pyridine ring. The hydrazine-carbothio-amide unit is almost planar, with a maximum deviation of 0.013 (2) A for the amide N atom. The stability of this conformation is favoured by the formation of an intra-molecular N-H?N hydrogen bond. The packing of the mol-ecules involves no classical inter-molecular hydrogen-bonding inter-actions; however, a C-H?pi inter-action occurs. PMID- 22199716 TI - 5-Meth-oxy-3-[(5-meth-oxy-1H-indol-3-yl)(phen-yl)meth-yl]-1H-indole. AB - In the title compound, C(25)H(22)N(2)O(2), the indole rings are individually almost planar [with maximum deviations of 0.0116 (19) and 0.0113 (18) A] and are almost orthogonal to each other, making a dihedral angle of 84.49 (6) degrees . The benzene ring is inclined at 72.83 (9) and 80.85 (9) degrees with respect to the indole rings. In the crystal, mol-ecules are linked by N-H?O inter-actions into chains running parallel to the c axis. The crystal structure is further stabilized by C-H?pi inter-actions. PMID- 22199717 TI - N,N,N',N'-Tetra-ethyl-pyridine-2,6-dicarboxamide. AB - The title compound, C(15)H(23)N(3)O(2), crystallizes with two mol-ecules in the asymmetric unit which are linked by a C-H?N hydrogen bond. In the crystal, mol ecules are connected via weak C-H?O and C-H?N hydrogen bonds between the amide O atoms and ethyl chains and between pyridine N atoms and aromatic H atoms in para positions. C-H?pi inter-actions also occur. PMID- 22199718 TI - (1-Adamant-yl)(3-amino-phen-yl)methanone. AB - In the crystal sructure of the title compound, C(17)H(21)NO, the mol-ecular packing is stabilized by inter-molecular N-H?O hydrogen bonds and additional weak N-H?pi inter-actions, forming chains that propagate along the b axis. Conjugation of the carbonyl group and the benzene ring is rather attenuated due to a twisting of the carbonyl group from the plane of the benzene ring [torsion angle = 27.1 (2) degrees ]. PMID- 22199719 TI - 4-Benzyl-3,5-dimethyl-1H-pyrazole. AB - In the title mol-ecule, C(12)H(14)N(2), the dihedral angle between the pyrazole and phenyl ring mean planes is 78.65 (19) degrees . In the crystal, mol-ecules are linked by N-H?N hydrogen bonds into chains along [010]. PMID- 22199720 TI - (E)-1-(4-Benzhydrylpiperazin-1-yl)-3-(2-eth-oxy-phen-yl)prop-2-en-1-one. AB - In the title mol-ecule, C(28)H(30)N(2)O(2), the piperazine ring adopts a chair conformation and the C=C bond exhibits an E conformation. The dihedral angle between the terminal phenyl rings is 71.4 (2). In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming [010] chains. PMID- 22199721 TI - N-(2-Aza-niumyleth-yl)carbamate monohydrate. AB - In the crystal structure of the title compound, C(3)H(8)N(2)O(2).H(2)O, the organic mol-ecule exists as zwitterion with the carboxyl group deprotonated and the amino group protonated. In the crystal, the components are linked by O-H?O and N-H?O hydrogen bonds. PMID- 22199722 TI - (E)-1-(2,4-Dinitro-phen-yl)-2-[1-(2-meth-oxy-phen-yl)ethyl-idene]hydrazine. AB - The mol-ecule of the title compound, C(15)H(14)N(4)O(5), is in an E conformation with respect to the C=N double bond and the dihedral angle between the two benzene rings is 37.83 (7) degrees . The ethyl-idenehydrazine plane makes dihedral angles of 4.93 (9) and 42.38 (9) degrees with the two benzene rings. An intra-molecular N-H?O hydrogen bond generates an S(6) ring motif. In the crystal, mol-ecules are linked by weak C-H?O inter-actions into chains along the c axis which are stacked along the b axis by aromatic pi-pi inter-actions with a centroid-centroid distance of 3.5927 (10) A. PMID- 22199723 TI - N-(Naphthalen-1-yl)benzamide. AB - In the title compound, C(17)H(13)NO, the N-H and C=O bonds are anti with respect to each other. The dihedral angle between the naphthalene ring system and the phenyl ring is 86.63 (5) degrees . In the crystal, N-H?O hydrogen bonds link mol ecules into chains along [010]. PMID- 22199724 TI - 9-(2,5-Dimethyl-phen-oxy-carbon-yl)-10-methyl-acridinium trifluoro-methane sulfonate. AB - In the title compound, C(23)H(20)NO(2) (+).CF(3)SO(3) (-), the acridine ring system is oriented at a dihedral angle of 23.1 (1) degrees with respect to the benzene ring and the carboxyl group is twisted at an angle of 74.1 (1) degrees relative to the acridine skeleton. In the crystal, adjacent cations are linked through C-H?pi inter-actions and neighboring cations and anions via weak C-H?O hydrogen bonds. The mean planes of adjacent acridine units are either parallel or inclined at angles of 15.0 (1), 26.9 (1) and 48.1 (1) degrees in the crystal structure. PMID- 22199725 TI - N-(2,6-Dichloro-phen-yl)-5-methyl-1,2-oxazole-4-carboxamide monohydrate. AB - In the title compound, C(11)H(8)Cl(2)N(2)O(2).H(2)O, the dihedral angle between the benzene and isoxazole rings is 59.10 (7) degrees . In the crystal, the components are linked by N-H?O and O-H?O hydrogen bonds into a three-dimensional network. The crystal structure is further stabilized by pi-pi stacking inter actions [centroid-centroid distance = 3.804 (2) A]. PMID- 22199726 TI - Second monoclinic polymorph of 4-[(1H-benzimidazol-1-yl)meth-yl]benzoic acid. AB - Recently, we reported the first monoclinic [Kuai & Cheng (2011). Acta Cryst., E67, o2787] and the ortho-rhom-bic polymorph [Kuai & Cheng (2011). Acta Cryst., E67, o3014] of the title compound, C(15)H(12)N(2)O(2). Another monoclinic polymorph was obtained accidentally by the hydro-thermal reaction of the title compound with manganese chloride in the presence of potassium hydroxide at 413 K. The asymmetric unit consists of four independent mol-ecules. In the crystal, O H?N hydrogen bonds link the independent mol-ecules into four separate chains parallel to the b axis. PMID- 22199727 TI - Dibenzo[a,e]penta-cyclo-[12.2.1.1.0.0]octa-deca-2(13),5(10)-diene. AB - In the title compound, C(26)H(24), the central cyclo-octa-tetra-ene ring has a boat conformation, and the mol-ecule is saddle shaped. The seat is defined by the mean plane of the four-atom attachment points (r.m.s. deviation = 0.014 A) of the two bicyclo-heptane substituents. These substituents comprise the pommel and cantle, with each mean plane defined by four atoms proximate to the seat (r.m.s. deviations = 0.001 and 0.000 A). Relative to the seat, the pommel and cantle bend up 33.36 (5) and 34.22 (4) degrees , while the benzo units (flaps, r.m.s. deviations = 0.008 and 0.013 A) bend down 33.48 (4) and 36.58 (4) degrees . PMID- 22199728 TI - 5''-(4-Meth-oxy-benzyl-idene)-7'-(4-meth-oxy-phen-yl)-1''-methyl-5',6',7',7a' tetra-hydro-dispiro-[acenaphthene-1,5'-pyrrolo-[1,2-c][1,3]thia-zole-6',3'' piperidine]-2,4''-dione. AB - In the title compound, C(37)H(34)N(2)O(4)S, the piperidine ring adopts a half chair conformation. The thia-zole ring adopts a slightly twisted envelope conformation and the pyrrole ring adopts an envelope conformation; in each case, the C atom linking the rings is the flap atom. An intra-molecular C-H?O inter action is noted. The crystal structure is stabilized by C-H?O and C-H?pi inter actions. PMID- 22199729 TI - N-[7-Eth-oxy-2-(prop-2-en-1-yl)-2H-indazol-6-yl]-4-methyl-benzene-sulfonamide. AB - In the title compound, C(19)H(21)N(3)O(3)S, the C-SO(2)-NH-C torsion angle is 66.20 (9) degrees . The dihedral angle between the benzene ring and the essentially planar indazole ring system [r.m.s. deviation = 0.0361 (1) A] is 72.97 (6) degrees . The S atom has a distorted tetra-hedral geometry [maximum deviation = O-S-O = 119.30 (6) degrees ]. The crystal structure features inversion-related dimers linked by pairs of N-H?O hydrogen bonds. In addition, weak C-H?O inter-actions may stabilize the crystal packing. PMID- 22199730 TI - 3-(4-Hy-droxy-phen-yl)-7-meth-oxy-chroman-4-one monohydrate. AB - In the title compound, C(16)H(14)O(4).H(2)O, the dihedral angle betwen the benzene rings is 71.4 (6) degrees . The pyran ring is in a sofa conformation. In the crystal, O-H?O hydrogen bonds connect the components into a two-dimensional network parallel to (010), incorporating C(2) (2)(4) and C(2) (2)(11) chains. In addition, weak C-H?O, C-H?pi and pi-pi stacking inter-actions [centroid-centroid distance = 3.768 (2) A] are present. PMID- 22199731 TI - 1-Prop-2-ynyl-1H-benzimidazol-2-amine. AB - In the title compound, C(10)H(9)N(3), the benzimidazol-2-amine and CH(2)-C CH units are not coplanar, with a dihedral angle of 60.36 degrees between their mean planes. The crystal structure is stabilized by inter-molecular N-H?N hydrogen bonding and pi-pi inter-actions [centroid-centroid distances 3.677 (1) and 3.580 (1) A], assembling the mol-ecules into a supra-molecular structure with a three-dimensional network. PMID- 22199732 TI - {5-Chloro-2-[(4-nitro-benzyl-idene)amino]-phen-yl}(phen-yl)methanone. AB - The mol-ecule of the title Schiff base compound, C(20)H(13)ClN(2)O(3), assumes an E configuration about the C=N bond. The aromatic rings of the nitro-benzene and chloro-benzene groups are twisted by 13.89 (13) degrees and form dihedral angles of 76.38 (13) and 84.64 (13) degrees , respectively, with the phenyl ring. In the crystal, mol-ecules are linked into chains parallel to the b axis by C-H?pi inter actions. PMID- 22199733 TI - Tris(2-amino-1,3-thia-zolium) hydrogen sulfate sulfate monohydrate. AB - The centrosymmetric crystal structure of the novel semi-organic compound, 3C(3)H(5)N(2)S(+).HSO(4) (-).SO(4) (2-).H(2)O, is based on chains of alternating anions and water mol-ecules (formed by O-H?O hydrogen bonds). The chains are inter-connected with the 2-amino-1,3-thia-zolium cations via strong N-H?O and weak C-H?O hydrogen-bonding inter-actions into a three-dimensional network. PMID- 22199734 TI - 7'-Phenyl-5',6',7',7a'-tetra-hydro-dipiro[indan-2,5'-pyrrolo-[1,2-c][1,3]thia zole-6',2''-indan]-1,3,1''-trione. AB - The asymmetric unit of the title compound, C(28)H(21)NO(3)S, contains two mol ecules with similar geometries. The thia-zolidine rings adopt half-chair conformations while the pyrrolidine and the diketo-substituted five-membered carbocyclic rings are in envelope conformations with the spiro C atoms at the flaps. In one mol-ecule, the phenyl ring forms dihedral angles of 57.76 (12) and 71.79 (12) degrees with the fused benzene rings and the fused benzene rings form a dihedral angle of 57.75 (13) degrees . The corresponding dihedral angles in the other mol-ecule are 60.04 (12), 72.93 (12) and 54.51 (13) degrees . The mol ecular structure is stabilized by intra-molecular C-H?O hydrogen bonds, which generate S(6) ring motifs. In the crystal, mol-ecules are linked via C-H?O and C H?N hydrogen bonds into layers lying parallel to the ab plane. PMID- 22199735 TI - N,N-Dimethyl-N',N''-diphenyl-phospho-ric triamide. AB - In the title compound, C(14)H(18)N(3)OP, a crystallographic mirror plane bis-ects the mol-ecule (the C,N,C atoms of the dimethyl-amido moiety and the P=O unit lie on the mirror plane). The P atom has a distorted tetra-hedral geometry; the bond angles at P are in the range 98.98 (11)-115.28 (7) degrees . In the crystal, the O atom of the P=O group acts as a double hydrogen-bond acceptor for two symmetry equivalent N-H?O hydrogen bonds, building [001] chains containing R(2) (1)(6) loops. PMID- 22199736 TI - N,N'-Dibenzyl-N,N'-dimethyl-N''-(p-tol-yl)phospho-ric triamide. AB - The asymmetric unit of the title compound, C(23)H(28)N(3)OP, contains two independent mol-ecules with significant conformational differences. For example, the torsion angles N-C-C-C involving the N-benzyl moieties are 57.3 (7) and 11.6 (8) degrees in one mol-ecule and 76.5 (7) and 97.4 (7) degrees in the other. In each mol-ecule, the P atom exhibits a distorted tetra-hedral conformation [the bond angles at P are in the ranges 104.7 (2)-115.2 (2) and 105.1 (2)-115.1 (2) degrees in the two molecules], and the phosphoryl group and the N-H group adopt an anti orientation with respect to one another. In the crystal, mol-ecules are linked via N-H?O(P) hydrogen bonds, forming a chain parallel to the a axis. PMID- 22199737 TI - 4-Chloro-2-nitro-benzoic acid-pyrazine (2/1). AB - In the title co-crystal, 2C(7)H(4)ClNO(4).C(4)H(4)N(2), the pyrazine mol-ecule is located on an inversion centre, so that the asymmetric unit consists of one mol ecule of 4-chloro-2-nitro-benzoic acid and a half-mol-ecule of pyrazine. The components are connected by O-H?N and C-H?O hydrogen bonds, forming a 2:1 unit. In the hydrogen-bonded unit, the dihedral angle between the pyrazine ring and the benzene ring of the benzoic acid is 16.55 (4) degrees . The units are linked by inter-molecular C-H?O hydrogen bonds, forming a sheet structure parallel to ([Formula: see text]04). A C-H?O hydrogen-bond linkage is also observed between these sheets. PMID- 22199738 TI - (E)-1-([1,1'-Biphen-yl]-4-yl)-2-(1,3,3-tri-methylindolin-2-yl-idene)ethanone. AB - The title compound, C(25)H(23)NO, consists of a biphenyl-4-carbonyl unit attached to an exocyclic double bond group at position 2 of an indole unit, which presents methyl groups as substituents at positions 1 and 3. The mol-ecular conformation is s-cis with an E configuration, supported by weak intra-molecular C-H?O contacts involving the methyl groups and the carbonyl function. The rings of the biphenyl group are twisted by 37.13 (5) degrees . In the crystal, C-H?O and C H?pi inter-actions link the molecules. PMID- 22199739 TI - (E)-N'-(2,3-Dihy-droxy-benzyl-idene)-4-meth-oxy-benzohydrazide. AB - The mol-ecule of the title benzohydrazide derivative, C(15)H(14)N(2)O(4), is twisted and exists in a trans conformation with respect to the C=N double bond. The dihedral angle between the benzene rings is 56.86 (9) degrees and the C atom of the meth-oxy group deviates slightly [C-O-C-C = -10.4 (3) degrees ] from its attached benzene ring. An intra-molecular O-H?N hydrogen bond generates an S(6) ring. In the crystal, mol-ecules are linked by N-H?O and bifurcated N-H?(O,O) hydrogen bonds, as well as weak C-H?O inter-actions, into two-dimensional networks lying parallel to the bc plane. A weak C-H?pi inter-action also occurs. PMID- 22199740 TI - 1-(4-Benz-yloxy-2-hy-droxy-phen-yl)ethanone. AB - The title compound, C(15)H(14)O(3), has been obtained from the reaction of 2,4 dihy-droxy-acetophenone, potassium carbonate and benzyl bromide. The remaining hy droxy group is involved in an intra-molecular O-H?O hydrogen bond. In the crystal, inter-molecular C-H?O contacts occur. PMID- 22199741 TI - N,N'-Dimethyl-N,N'-bis-(pyridin-2-yl)methane-diamine. AB - The title compound, C(13)H(16)N(4), consists of two pyridine rings which are linked by an N,N'-dimethyl-methane-amine chain. The pyridine rings adopt a twist conformation and the dihedral angle between them is 60.85 (5) degrees . The crystal packing is stabilized by weak C-H?pi inter-actions. PMID- 22199742 TI - rac-N,N'-Dimethyl-N,N'-(1,1'-binaphthyl-2,2'-di-yl)diformamide. AB - The mol-ecule of the title compound, C(24)H(20)N(2)O(2), lies on a twofold rotation axis that relates one 2-(N-methyl-formamido)-naphthyl unit to the other. The N-methyl-formamido substituent is twisted by 54.9 (1) degrees with respect to the naphthalene fused-ring system; the two fused-ring systems are themselves twisted by 70.3 (1) degrees . PMID- 22199743 TI - 2-Hy-droxy-2-methyl-1-phenyl-indolin-3-one. AB - In the title compound, C(15)H(13)NO(2), the indole and benzene rings make a dihedral angle of 60.61 (4) degrees . In the crystal, dimeric pairs (twofold symmetry) are formed via O-H?O hydrogen bonds. PMID- 22199744 TI - 3-Benzyl-amino-2-cyano-N-[N-(2-fluoro-phenyl)-carbamo-yl]-3-(methyl sulfanyl)acryl-amide. AB - In the crystal structure of the title compound, C(19)H(17)FN(4)O(2)S, mol-ecules are linked via pairs of N-H?N inter-actions, forming centrosymmetric dimers. Two intra-molecular N-H?O hydrogen bonds stabilize the mol-ecular conformation. PMID- 22199745 TI - Ethyl 1-(butan-2-yl)-2-(2-meth-oxy-phen-yl)-1H-benzimidazole-5-carboxyl-ate. AB - In the title compound, C(21)H(24)N(2)O(3), the mean planes of the benzene ring and the benzimidazole ring system form a dihedral angle of 69.94 (7) degrees . The ethyl group atoms of the ethano-ate fragment are disordered over two sets of sites, with refined occupancies of 0.742 (6) and 0.258 (6). In the crystal, there are weak C-H?N hydrogen bonds which connect mol-ecules into chains along the b axis. A weak inter-molecular C-H?pi inter-action is also observed. PMID- 22199746 TI - Isopropyl 3,4-dihy-droxy-benzoate. AB - In the crystal structure of the title compound, C(10)H(12)O(4), O-H?O hydrogen bonds incorporating R(2) (2)(10) and R(2) (2)(14) motifs link mol-ecules into chains along [1[Formula: see text]0]. An intra-molecular O-H?O hydrogen bond is also observed. PMID- 22199747 TI - 1,3-Dibenzyl-1H-benzimidazol-2(3H)-one. AB - In the mol-ecular structure of the title compound, C(21)H(18)N(2)O, the fused ring system is essentially planar, the largest deviation from the mean plane being 0.0121 (9) A. The O atom and adjacent C atom are located in Wyckoff position 4e on a twofold axis (0, y, 1/4). The two benzyl groups are almost perpendicular to the benzimidazole plane, but point in opposite directions. The dihedral angle between the benzimidazole mean plane and the phenyl ring is 81.95 (5) degrees , whereas that between the two benzyl groups is 60.96 (7) degrees . PMID- 22199748 TI - N,N'-Bis(2-amino-benz-yl)ethane-1,2-diaminium bis-(4-methyl-benzene-sulfonate). AB - The title salt, C(16)H(24)N(4) (2+).2C(7)H(7)O(3)S(-), crystallizes with the dication situated on an inversion center and the anion in a general position. The cation contains two ammonium and two free amine groups, and the observed conformation for the chain linking the benzene rings is different from that found in the free tetra-amine and in the fully protonated tetra-amine. All amine and ammonium H atoms of the cation form hydrogen bonds with eight symmetry-related anions, using the sulfonate O atoms as acceptors. This arrangement for the ions precludes any pi-pi contacts between benzene rings in the crystal. PMID- 22199749 TI - N,N'-Bis(2-aza-niumylbenz-yl)ethane-1,2-diaminium tetra-chloride. AB - The title compound, C(16)H(26)N(4) (4+).4Cl(-), is based on a fully protonated tetra-amine. In the cation, both benzene rings are connected by an all-trans chain, and the rings are almost parallel, with an angle between the mean planes of 8.34 (12) degrees . The benzene rings are arranged in such a way that the NH(3) (+) substituents are oriented cis with respect to the central chain. This arrangement is a consequence of multiple N-H?Cl hydrogen bonds, involving all N-H groups in the cation and the four independent Cl(-) anions. These contacts have strengths ranging from weak to strong (based on H?Cl separations), and generate a complex three-dimensional crystal structure with no preferential crystallographic orientation for the contacts. PMID- 22199750 TI - 5-tert-Butyl 3-ethyl 1-isopropyl-4,5,6,7-tetra-hydro-1H-pyrazolo-[4,3-c]pyridine 3,5-dicarboxyl-ate. AB - In the title compound, C(17)H(27)N(3)O(4), the six-membered ring adopts a half chair conformation with the N atom and the adjacent methyl-ene C atom displaced by -0.391 (2) and 0.358 (2) A, respectively, from the plane of the other four atoms. In the crystal, mol-ecules are linked by weak C-H?O inter-actions. PMID- 22199751 TI - 2-{[4-(Dimethyl-amino)-benzyl-idene]amino}-phenyl disulfide. AB - In the title mol-ecule, C(30)H(30)N(4)S(2), the two benzene rings connected through the disulfide chain form a dihedral angle of 88.7 (1) degrees , and the two benzene rings in the benzyl-ideneaniline fragments form dihedral angles of 34.0 (1) and 35.4 (1) degrees . The crystal packing exhibits no significantly short inter-molecular contacts. PMID- 22199752 TI - 2-Amino-4,6-dimethyl-pyrimidin-1-ium 2,3,5-triiodo-benzoate 2,3,5-triiodo-benzoic acid monosolvate. AB - In the crystal structure of the title compound, C(6)H(10)N(3) (+).C(7)H(2)I(3)O(2) (-).C(7)H(3)I(3)O(2), two R(2) (2)(8) motifs are observed. One is generated by the inter-action of the 2-amino-4,6-dimethyl-pyrimidin-1-ium cation with the carboxyl-ate group of the 2,3,5-triiodo-benzoate anion via N-H?O hydrogen bonds. The other R(2) (2)(8) motif is formed by the inter-action of two centrosymmentrically related pyrimidine moieties through N-H?N hydrogen bonds. The two motifs combine to form a linear heterotetra-meric unit. Heterotetra-meric units are linked by a carbox-yl-carboxyl-ate O-H?O hydrogen bond (involving the O H group of neutral 2,3,5-triiodo-benzoic acid and an O atom of the anion), forming a supra-molecular chain along the a axis. In addition, components are held by weak I?O interactions in the range 3.023 (5) to 3.382 (5) A and I?I inter actions in the range 3.6327 (7) to 4.0025 (8) A. PMID- 22199753 TI - 1,3-Dicyclo-hexyl-imidazolidine-2,4,5-trione. AB - The title compound, C(15)H(22)N(2)O(3), has been isolated as a by-product of an oxidative cleavage of the C-C bond linking two five-membered rings of 1,3-dicyclo hexyl-5-(3-oxo-2,3-dihydro-benzofuran-2-yl)imidazolidine-2,4-dione. Individual mol-ecular units are engaged in weak C=O?C=O inter-actions [O?C = 2.814 (10) and 2.871 (11) A], leading to the formation of supra-molecular chains which close pack, mediated by van der Waals contacts, in the bc plane. PMID- 22199754 TI - Bis{5-[(2-propyn-1-yl-oxy)meth-yl]-1,3-phenyl-ene}-32-crown-10. AB - The mol-ecule of the title compound {systematic name: 17,35-bis-[(2-propyn-1-yl oxy)meth-yl]-2,5,8,11,14,20,23,26,29,32-deca-oxatricyclo-[31.3.1.1(15,19)]octa triaconta-1(37),15,17,19 (38),33,35-hex-a--ene}, C(36)H(48)O(12), has crystallographic inversion symmetry and adopts a chair-like conformation. The polyether bridges of the macrocycle adopt gauche conformations and the cavity of the macrocycle is collapsed. In the crystal structure, there are weak inter molecular C-H?O hydrogen bonds driven in part by the elevated acidity of acetylenyl H atoms. PMID- 22199755 TI - (Z)-Methyl 2-[(2-eth-oxy-6-formyl-phen-oxy)meth-yl]-3-(4-ethyl-phen-yl)acrylate. AB - The title compound, C(22)H(24)O(5), consists of two substituted benzene rings linked by an ethyl acrylate group. The dihedral angle between the two benzene rings is 58.39 (7) degrees . The crystal packing is governed by two C-H?O inter actions, one of which forms centrosymmetric dimers with a graph-set descriptor of R(2) (2)(18). PMID- 22199756 TI - 5-(4-Chloro-phen-oxy)-1-methyl-3-tri-fluoro-methyl-1H-pyrazole-4-carbaldehyde O [(2-chloro-pyridin-5-yl)meth-yl]oxime. AB - In the title mol-ecule, C(18)H(13)Cl(2)F(3)N(4)O(2), the intra-molecular distance between the centroids of the benzene and pyridine rings is 3.953 (3) A, and the trifluoro-methyl group is rotationally disordered over two orientations in a 0.678 (19):0.322 (19) ratio. The crystal packing exhibits weak inter-molecular C H?F inter-actions. PMID- 22199757 TI - 4-Carb-oxy-anilinium chloride. AB - In the title salt, C(7)H(8)NO(2) (+).Cl(-), the cation and anion are linked by an O-H?Cl hydrogen bond. The three-dimensional crystal structure is stabilized by N H?O and N-H?Cl hydrogen bonds. PMID- 22199758 TI - 2-Phenyl-1H-imidazole. AB - In the title compound, C(9)H(8)N(2), a mirror plane lies perpendicular to the phenyl and imidazole rings and passes through the bridging C-C bond, so that the imidazole ring is disordered over two sites about the mirror plane with the equal site occupancy; the asymmetric unit contains one half-mol-ecule. In the crystal, adjacent mol-ecules are linked via N-H?N hydrogen bonds. PMID- 22199759 TI - N,N-Dimethyl-N,N-diphenyl-pyrimidine-4,5,6-triamine. AB - In the title compound, C(18)H(19)N(5), the pyrimidine ring makes dihedral angles of 56.49 (9) and 70.88 (9) degrees with the phenyl rings. The dihedral angle between the two phenyl rings is 72.45 (9) degrees . No significant inter molecular inter-actions are observed in the crystal structure. PMID- 22199760 TI - An ortho-rhom-bic polymorph of pyrazino-[2,3-f][1,10]phenanthroline-2,3 dicarbonitrile. AB - The title compound, C(16)H(6)N(6), is a polymorph of the previously reported structure [Kozlov & Goldberg (2008 ?). Acta Cryst. C64, o498-o501]. Unlike the previously reported monoclinic polymorph (space group P2(1)/c, Z = 8), the title compound reveals ortho-rhom-bic symmetry (space group Pnma, Z = 4). The mol-ecule shows crystallographic mirror symmetry, while the previously reported structure exhibits two independent mol-ecules per asymmetric unit. In the title compound, adjacent mol-ecules are essentially parallel along the c axis and tend to be vertical along the b axis with dihedral angles of 72.02 (6) degrees . However, in the reported polymorph, the entire crystal structure shows an anti-parallel arrangement of adjacent columns related by inversion centers and the two independent mol-ecules are nearly parallel with a dihedral angle of 2.48 (6) degrees . PMID- 22199761 TI - 2-{[(4-{[(2-Hy-droxy-phen-yl)(phen-yl)methyl-idene]amino}-phen-yl)imino](phen yl)meth-yl}phenol. AB - The title mol-ecule, C(32)H(24)N(2)O(2), has a crystallographically imposed inversion centre and exists in the crystal as an enol-imine tautomer. The mol ecular structure is stabilized by two strong intra-molecular O-H?N hydrogen bonds. The dihedral angles between the central benzene ring and the mean planes of the phenyl substituents are 59.99 (1) and 62.79 (2) degrees . In the crystal, the mol-ecules are arranged into (010) layers via C-H?pi inter-actions. PMID- 22199762 TI - 7-Hy-droxy-4-methyl-8-(3-methyl-benzo-yl)-2H-chromen-2-one ethanol monosolvate. AB - In the title compound, C(18)H(14)O(4).C(2)H(6)O, the coumarin ring system is approximately planar with a maximum deviation of 0.037 (3) A and is nearly perpendicular to the benzene ring, making a dihedral angle of 86.55 (9) degrees . In the crystal, mol-ecules are linked by classical O-H?O hydrogen bonds and weak C-H?O inter-actions. PMID- 22199763 TI - N,N'-Bis(pyridin-2-yl)benzene-1,4-diamine-quinoxaline (2/1). AB - The asymmetric unit of the title compound, 2C(16)H(14)N(4).C(8)H(6)N(2), consits of one mol-ecule of N,N'-bis-(pyridin-2-yl)benzene-1,4-diamine (PDAB) and one half-mol-ecule of quinoxaline (QX) that is located around an inversion centre and disordered over two overlapping positions. The PDAB mol-ecule adopts a non-planar conformation with an E configuration at the two partially double exo C N bonds of the 2-pyridyl-amine units. In the crystal, these self-complementary units are N H?N hydrogen bonded via a cyclic R(2) (2)(8) motif, creating tapes of PDAB mol ecules extending along [010]. Inversion-related tapes are arranged into pairs through pi-pi stacking inter-actions between the benzene rings [centroid-centroid distance = 3.818 (1) A] and the two symmetry-independent pyridine groups [centroid-centroid distance = 3.760 (1) A]. The QX mol-ecules are enclosed in a cavity formed between six PDAB tapes. PMID- 22199764 TI - 2-(3,4-Dimeth-oxy-phen-yl)-1H-benzimidazole. AB - In title compound, C(15)H(14)N(2)O(2), the dihedral angle between the 3,4-dimeth oxy-phenyl group and the benzimidazole system is 26.47 (6) degrees . In the crystal, neighbouring mol-ecules are linked by N-H?N hydrogen bonds into C(4) chains propagating along the c-axis direction. The crystal structure also features weak C-H?O inter-actions. PMID- 22199765 TI - 4-Methyl-N'-(2-oxoindolin-3-yl-idene)benzene-1-sulfono-hydrazide. AB - In the title compound, C(15)H(13)N(3)O(3)S, the C-S-N(H)-N linkage is non-planar, the torsion angle being -65.12 (13) degrees and the S atom showing a tetra hedral environment. The compound has two almost planar fragments linked to the S atom: the isatin-derivative fragment [(C(8)H(5)NO)N-N(H)-] and the tolyl fragment [C(7)H(7)-] have maximum deviations from the mean plane through the non-H atoms of 0.0813 (13) and 0.0094 (16) A, respectively, and make an inter-planar angle of 80.48 (3) degrees . In the crystal, mol-ecules are connected into inversion dimers via pairs of N-H?O hydrogen bonds. Additionally, the mol-ecular structure is stabilized by an intra-molecular N-H?O hydrogen bond. PMID- 22199766 TI - Guanidinium 2-(myristoylsulfanyl)ethane-sulfonate. AB - In the title compound, CH(6)N(3) (+).C(16)H(31)O(4)S(2) (-) [systematic name: guanidinium 2-(tetra-deca-noylsulfan-yl)ethane-sulfon-ate], each 2-(myristoyl thio)-ethane-sulfonate ion displays hydrogen bonding to three guanidinium counter ions, which themselves display hydrogen bonding to two symmetry-related 2 (myristoylthio)ethanesulfonate ions. Thus each cation forms six N-H?O bonds to neighboring anions, thereby self-assembling an extended ladder-type network. The average hydrogen-bond donor-acceptor distance is 2.931 (5) A. The alkyl chains form the rungs of a ladder with hydrogen-bonding inter-actions forming the side rails. PMID- 22199767 TI - 2-[(Pyrimidin-2-yl-amino)-meth-yl]phenol. AB - In the title compound, C(11)H(11)N(3)O, the aromatic rings at either ends of the CH(2)-NH- link are twisted by 72.58 (8) degrees ; the hy-droxy substituent is a hydrogen-bond donor to an N atom of the pyrimidine ring. The other N atom of the pyrimidine ring is a hydrogen-bond acceptor to the amino group of an inversion related mol-ecule. PMID- 22199768 TI - 2-[(Pyridin-3-yl-amino)-meth-yl]phenol. AB - In the title compound, C(12)H(12)N(2)O, the aromatic rings at either ends of the CH(2)-NH- link are twisted by 68.79 (7) degrees . In the crystal, the hy-droxy substituent is a hydrogen-bond donor to the N atom of the pyridine ring of an adjacent mol-ecule, and the hydrogen bond generates a chain along the b axis; it is also a hydrogen-bond acceptor to the amino group of another adjacent mol ecule. The two hydrogen bonds lead to the formation of a layer structure. PMID- 22199769 TI - 3-Bromo-6-nitro-1-(prop-2-yn-yl)-1H-indazole. AB - In the title compound, C(10)H(6)BrN(3)O(2), the indazole fused-ring system is nearly planar (r.m.s. deviation = 0.008 A); its nitro substituent is nearly coplanar with the fused ring [dihedral angle = 4.5 (2) degrees ]. In the crystal, adjacent mol-ecules are linked by weak acetyl-ene-nitro C-H?O hydrogen bonds, generating a helical chain running along the b axis. PMID- 22199770 TI - 2-(4-Chloro-phen-yl)acetamide. AB - In the title compound, C(8)H(8)ClNO, the acetamide group is twisted out the benzene plane with a dihedral angle of 83.08 (1) degrees . In the crystal, mol ecules are linked by N-H?O hydrogen bonds, forming layers parallel to the ab plane. PMID- 22199771 TI - 3,5-Dibromo-4-oxo-2,2,6,6-tetra-methyl-piperidin-1-yl oxide. AB - In the title compound, C(9)H(14)Br(2)NO(2), the substituted ring exhibits a chair conformation. A crystallographic mirror plane, passing through the N atom, the O atoms and the C atom in the 4-position, bis-ects the mol-ecule. PMID- 22199772 TI - 2,6-Dibromo-4-(2-hy-droxy-eth-yl)phenol. AB - The title compound, C(8)H(8)Br(2)O(2), crystallized with two independent mol ecules (A and B) in the asymmetric unit. They differ in the conformation of the 2 hy-droxy-ethyl chain with the C-C-C-O torsion angle being -68.0 (12) degrees in mol-ecule A and 172.2 (9) degrees in mol-ecule B. In the crystal, the A mol ecules are linked via pairs of O-H?O hydrogen bonds, forming inversion dimers, while the B mol-ecules are linked via an O-H?O hydrogen bond, forming a polymeric chain propagating in [010]. In addition, there are O-H?O and O-H?Br hydrogen bonds, and Br?Br [3.599 (2) A] and pi-pi inter-actions [centroid-centroid distances = 3.581 (6) and 3.931 (6) A], leading to the formation of a two dimensional network parallel to (001). PMID- 22199773 TI - 6-Fluoro-2-(4-meth-oxy-phen-yl)imidazo[2,1-b][1,3]benzothia-zole. AB - The asymmetric unit of the title compound, C(16)H(11)FN(2)OS, comprises two independent mol-ecules in which the benzothia-zole rings are essentially planar, with maximum deviations of 0.038 (2) and 0.045 (3) A. The central benzothia-zole ring makes dihedral angles of 4.87 (13) and 0.64 (12) degrees and 4.04 (12) and 3.67 (12) degrees with the two terminal phenyl rings in the two independent mol ecules. In the crystal, mol-ecules are connected via weak inter-molecular C-H?O hydrogen bonds forming supra-molecular chains along the c axis. PMID- 22199774 TI - N'-[(E)-Furan-2-yl-methyl-idene]pyridine-3-carbohydrazide. AB - The title compound, C(11)H(9)N(3)O(2), exists in the E conformation with respect to the azomethane C=N bond, and has the keto form. There are two independent mol ecules in the asymmetric unit and each of these features a slight slanting of the pyridine and furan rings, which form a dihedral angle of 14.96 (10) degrees in one of the mol-ecules and 5.53 (10) degrees in the other. The crystal structure is stabilized by N-H?O and N-H?N hydrogen bonds, weak C-H?O and C-H?N hydrogen bonds and C-H?pi inter-actions and pi-pi inter-actions [shortest centroid centroid distance = 3.7864 (15) A]. PMID- 22199775 TI - 2-(6-Chloro-2,3,4,9-tetra-hydro-1H-carbazol-1-yl-idene)propane-dinitrile. AB - The mol-ecular conformation of the title compound, C(15)H(10)ClN(3), is stabilized by an intra-molecular N-H?N hydrogen bond with an S(7) ring motif. The crystal packing is controlled by N-H?N and C-H?N inter-molecular inter-actions. One of the methyl-ene groups of the cyclo-hexene ring is disordered over two positions with refined occupancies of 0.457 (12) and 0.543 (12). PMID- 22199776 TI - 6-Bromo-2-(3-phenyl-allyl-idene)-2,3,4,9-tetra-hydro-1H-carbazol-1-one. AB - Mol-ecules of the title compound, C(21)H(16)BrNO, are linked through pairs of N H?O inter-molecular hydrogen bonds into centrosymmetric R(2) (2)(10) dimers. One of the C atoms of the cyclohex-2-enone ring is disordered with refined occupancies of 0.61 (2) and 0.39 (2). PMID- 22199777 TI - 2-(6-Methyl-2,3,4,9-tetra-hydro-1H-carbazol-1-yl-idene)propane-dinitrile. AB - In the title compound, C(16)H(13)N(3), the cyclo-hexene ring adopts a sofa conformation. An intra-molecular N-H?N hydrogen bond generates an S(7) ring motif. In the crystal, the mol-ecules are linked by pairs of N-H?N inter-actions, forming centrosymmetric dimers with an R(2) (2)(14) motif. PMID- 22199778 TI - 6-Bromo-2-[(E)-thio-phen-2-yl-methyl-idene]-2,3,4,9-tetra-hydro-1H-carbazol-1 one. AB - In the title compound, C(17)H(12)BrNOS, the cyclo-hexene ring deviates only slightly from planarity (r.m.s. deviation for non-H atoms = 0.047 A). In the crystal, the mol-ecules are linked into centro-symmetric R(2) (2)(10) dimers via pairs of N-H?O hydrogen bonds. The thio-phene ring is disordered over two positions rotated by 180 degrees and with a site-occupation factor of 0.843 (4) for the major occupied site. PMID- 22199779 TI - Low-temperature superstructure of [(N,N-diisobutyl-carbamo-yl)meth-yl]oct-yl(phen yl)phosphine oxide (CMPO). AB - At 120 K, the title compound, C(24)H(42)NO(2)P, crystallizes in a unit cell with a doubled a parameter compared with the room-temperature structure. There are four mol-ecules in the asymmetric unit, one of which shows extensive disorder in a 0.588 (3):0.412 (3) ratio. In the crystal, numerous C-H?O inter-actions link the mol-ecules. PMID- 22199780 TI - 7'-(4-Bromo-phen-yl)-5',6',7',7a'-tetra-hydro-dispiro-[indan-2,5'-pyrrolo-[1,2 c][1,3]thia-zole-6',2''-indan]-1,3,1''-trione. AB - In the title compound, C(28)H(20)BrNO(3)S, the thia-zolidine, pyrrolidine and two five-membered carbocyclic rings are in envelope conformations. The bromo-bound phenyl ring forms dihedral angles of 61.97 (18) and 88.30 (17) degrees with the other two benzene rings. The two benzene rings form a dihedral angle of 30.3 (2) degrees . The mol-ecular structure features an intra-molecular C-H?O hydrogen bond, which generates an S(6) ring motif. In the crystal, mol-ecules are linked into inversion dimers by pairs of C-H?O hydrogen bonds. PMID- 22199781 TI - 3-Hy-droxy-2-(4-meth-oxy-benzene-sulfonamido)-butanoic acid. AB - The title compound, C(11)H(15)NO(6)S, features a distorted tetra-hedral geometry for the S atom. One of the sulfonamide O atoms is approximately coplanar with the benzene ring [C-C-S-O torsion angle = -160.81 (7) degrees ], whereas the other lies well below the plane [C-C-S-O = -29.66 (8) degrees ]. In the crystal, O-H?O and C-H?O hydrogen bonds link the mol-ecules into chains parallel to the b axis. PMID- 22199782 TI - (Biphenyl-4-yl)[2-(4-methyl-benzo-yl)phen-yl]methanone. AB - In the title compound, C(27)H(20)O(2), the central benzene ring makes dihedral angles of 64.86 (7) and 70.35 (7) degrees with the methyl-substituted ring and the biphenyl ring system, respectively. The crystal packing is stabilized by inter-molecular C-H?O inter-actions, which link the mol-ecules into chains parallel to the b axis. PMID- 22199783 TI - 3-Chloro-N-(3-methyl-phen-yl)benzamide. AB - In the mol-ecular structure of the title compound, C(14)H(12)ClNO, the meta-Cl atom in the benzoyl ring is positioned syn to the C=O bond, while the meta-methyl group in the aniline ring is positioned anti to the N-H bond. The two aromatic rings make a dihedral angle of 77.4 (1) degrees . In the crystal, the molecules are linked by N-H?O hydrogen bonds, forming C(4) chains propagating in [010]. PMID- 22199784 TI - N'-[(2-Hy-droxy-naphthalen-1-yl)methyl-idene]-4-nitro-benzohydrazide. AB - In the title mol-ecule, C(18)H(13)N(3)O(4), the hy-droxy group is involved in the formation of an intra-molecular O-H?N hydrogen bond. The dihedral angle between the planes of the benzene ring and the naphthyl ring system is 9.0 (2) degrees . In the crystal, mol-ecules are linked through N-H?O hydrogen bonds into chains along the c axis. PMID- 22199785 TI - 4-(2,4-Dichloro-phen-yl)-5,5-dimethyl-2-(3-silatranyl-propyl-mino)-1,3,2-dioxa phospho-rinane 2-oxide. AB - In the title compound, C(20)H(31)Cl(2)N(2)O(6)PSi, the dioxaphospho-rinane ring adopts a cis conformation. The silatrane fragment forms a cage-like structure in which there exists an intra-molecular Si-N donor-acceptor bond. In the crystal, centrosymmetrically related mol-ecules are linked by pairs of N-H?O hydrogen bonds into inversion dimers, generating rings with graph-set motif R(2) (2)(8). The dimers are further connected into ribbons parallel to the a axis by inter molecular C-H?O hydrogen bonds. PMID- 22199786 TI - N,N'-Diallyl-2,2',5,5'-tetra-chloro-N,N'-[1,3-phenyl-enebis(methyl-ene)]dibenzene sulfonamide. AB - In the title compound, C(26)H(24)Cl(4)N(2)O(4)S(2), the dihedral angles between the central benzene ring and the pendant rings are 70.07 (12) and 59.07 (12) degrees . The equivalent angle between the pendant rings is 79.24 (12) degrees . Both sulfonamide groups lie to the same side of the central ring but the pendant chains have very different conformations, as indicated by their C-S-N-C torsion angles [104.66 (17) and -76.35 (19) degrees ] and S-N-C-C torsion angles [129.61 (17) and 147.10 (17) degrees ]. Both N atoms are close to planar (bond angle sums = 359.0 and 354.8 degrees ). In the crystal, inversion dimers are formed via a pair of weak C-H?O inter-actions which generate R(2) (2)(22) loops. PMID- 22199787 TI - N,N'-Bis(3-methylbut-2-enyl)-N,N'-(1,4-phenylene)dibenzenesulfonamide. AB - The complete mol-ecule of the title compound, C(28)H(32)N(2)O(4)S(2), is generated by a crystallographic inversion centre. The dihedral angle between the central and pendant aromatic rings is 46.78 (7) degrees . The C(ar)-S-N-C(ar) (ar = aromatic) torsion angle is 73.64 (15) degrees and the bond-angle sum for the N atom is 350.4 degrees . In the crystal, weak C-H?O inter-actions link the mol ecules, forming a two-dimensional network lying parallel to the bc plane. PMID- 22199788 TI - N'-(2-Hy-droxy-benzyl-idene)-2-(hy-droxy-imino)-propano-hydrazide. AB - The mol-ecule of the title compound, C(10)H(11)N(3)O(3), adopts an all-trans conformation and is approxomately planar, the largest deviation from the least squares plane through all non-H atoms being 0.261 (1) A. An intra-molecular O-H?N hydrogen bond occurs. In the crystal, the mol-ecules are packed into layers lying parallel to the ab plane by pi-stacking inter-actions between the benzene ring of one molecule and the C-N bond of the oxime group of another molecule; the shortest inter-molecular C?C separation within the layer is 3.412 (1) A. The layers are connected by O-H?O and N-H?O hydrogen bonds. PMID- 22199789 TI - 3-Nitro-4-(propyl-amino)-benzonitrile. AB - In the title compound, C(10)H(11)N(3)O(2), the nitro group is essentially coplanar with the aromatic ring [dihedral angle = 1.3 (3) degrees ] and forms an intra-molecular amine-nitro N-H?O hydrogen bond. In the crystal, weak inter molecular aromatic C-H?O(nitro) hydrogen bonds link the mol-ecules. Weak aromatic ring pi-pi inter-actions [minimum ring centroid separation = 3.7744 (13) A] are also present. PMID- 22199790 TI - (S)-Methyl 3-(3,4-dimeth-oxy-phen-yl)-2-[2-(diphenyl-phosphan-yl)benzamido] propano-ate. AB - Mol-ecules of the title compound, C(31)H(30)NO(5)P, show a sttagered conformation about the C-C bond joining the dimeth-oxy-benzene group to the chiral centre, with the dimeth-oxy-benzene ring gauche to the amide group and anti to the ester group. In the crystal, weak inter-molecular N-H?O and C-H?O hydrogen bonds form layers parallel to (110). PMID- 22199791 TI - (7aR*,12bS*)-8,12b-Dihydro-7aH-indeno-[1',2':5,6][1,4]selenazino[2,3,4 ij]quinolin-13-ium hydrogen sulfate. AB - In the title compound, C(18)H(14)NSe(+).HSO(4) (-), the cyclo-pentene ring in the cation has an envelope conformation while the central six-membered 1,4-selenazine ring adopts a sofa conformation. The dihedral angle between the planes of the terminal benzene rings is 68.08 (11) degrees . In the crystal, the anions form chains along the c axis through O-H?O hydrogen bonds. Weak C-H?O and C-H?pi hydrogen bonds, as well as attractive Se?Se [3.5608 (8) A] inter-actions, further consolidate the crystal structure. PMID- 22199792 TI - 4-Chloro-anilinium 4-methyl-benzene-sulfonate. AB - In the crystal structure of the title salt, C(6)H(7)ClN(+).C(7)H(7)O(3)S(-), the cations and anions are linked via N-H?O hydrogen bonds into double chains in [101]. Weak inter-molecular C-H?pi-ring inter-actions link these chains into layers parallel to the ac plane. PMID- 22199793 TI - (E)-Methyl 3-(1H-indol-3-yl)acrylate. AB - In the title compound, C(12)H(11)NO(2), the indole and methyl acrylate mean planes are inclined at an angle of 10.6 (1) degrees . In the crystal, N-H?pi inter-actions link mol-ecules into chains along [010] and weak inter-molecular C H?O hydrogen bonds further consolidate the crystal packing. PMID- 22199794 TI - N,N-Bis(quinolin-8-yl)-2,2'-[(1,3,4-thia-diazole-2,5-di-yl)bis-(sulfanedi yl)]diacetamide monohydrate. AB - In the title compound, C(24)H(18)N(6)O(2)S(3).H(2)O, the thia-diazole ring makes dihedral angles of 78.00 (13) and 77.27 (13) degrees with the quinoline ring systems. In the crystal, mol-ecules are linked into a two-dimensional network by O-H?O and C-H?O hydrogen bonds. PMID- 22199795 TI - Piperazine-1,4-diium diacetate. AB - In the title salt, C(4)H(12)N(2) (2+).2C(2)H(3)O(2) (-), the piperazine-1,4-diium cation has 2/m symmetry with the NH(2) unit located on a mirror plane and the acetate anion has m symmetry with all non-H atoms and one H atom located on a mirror plane. The piperazine ring adopts a chair conformation. In the crystal, the cations are linked with the anions via N-H?O hydrogen bonding into chains parallel to the c axis. PMID- 22199796 TI - 7'-[4-(Trifluoro-meth-yl)phen-yl]-5',6',7',7a'-tetra-hydrodispiro-[indan-2,5' pyrrolo-[1,2-c][1,3]thia-zole-6',2''-indan]-1,3,1''-trione. AB - In the title compound, C(29)H(20)F(3)NO(3)S, the thia-zolidine ringadopts a half chair conformation. The pyrrolidine and two five-membered carbocyclic rings are in envelope conformations with the spiro C atoms at the flaps. The trifluoro methyl-substituted benzene ring forms dihedral angles of 62.37 (14) and 87.40 (14) degrees with the benzene rings of the dihydro-1H-indene units. The two benzene rings form a dihedral angle of 36.94 (15) degrees . The mol-ecular structure is stabilized by intra-molecular C-H?O hydrogen bonds, which generate S(6) ring motifs. In the crystal, mol-ecules are linked into inversion dimers by pairs of inter-molecular C-H?O hydrogen bonds, generating R(2) (2)(10) ring motifs. PMID- 22199797 TI - 2-(3-Oxo-2,3-dihydro-1,2-benzothia-zol-2-yl)acetic acid. AB - In the title compound, C(9)H(7)NO(3)S, the benzoisothia-zolone ring system is essentially planar, with a maximum deviation of 0.013 (2) A. In the crystal, mol ecules are linked via O-H?O hydrogen bonds, forming chains along [010]. In addition, weak inter-molecular C-H?O hydrogen bonds are present. PMID- 22199798 TI - (20S*,24S*)-25-Hy-droxy-20,24-ep-oxy-A-homo-4-oxadammaran-3-one (Chrysura) isolated from the leaves of Walsura chrysogyne. AB - The title dammarane triterpenoid, C(30)H(50)O(4), assigned the name chrysura, was isolated from an ethyl acetate extract of Walsura chrysogyne leaves (Meliaceae). It has 20S*,24S* relative stereochemistry and an oxepanone ring with two methyl groups at position 4. The two cyclo-hexane rings adopt chair conformations. The cyclo-pentane and tetra-hydro-furan rings have envelope conformations; their mean planes make a dihedral angle of 13.1 (3) degrees , indicating that the rings are only slightly tilted with respect to each other. There is an intra-molecular C H?O hydrogen bond in the mol-ecule, which forms S(6) and S(7) ring motifs. In the crystal, mol-ecules are linked via O-H?O and C-H?O hydrogen bonds, forming chains propagating along [001] which stack along the b-axis direction. PMID- 22199799 TI - (1R*,5S*)-8-(2-Fluoro-4-nitro-phen-yl)-8-aza-bicyclo-[3.2.1]octan-3-one. AB - In the title compound, C(13)H(13)FN(2)O(3), the fused piperidine ring is in a chair conformation. The fused pyrrolidine ring shows an envelope conformation with the N atom displaced by 0.661 (3) A out of the plane formed by the four C atoms of the pyrrolidine ring. The dihedral angle between this plane and the plane formed by the four attached C atoms of the piperidine ring (not including the carbonyl C atom) is 67.63 (10) degrees . The F atom is disordered and was refined using a split model with an occupancy ratio of 0.910 (3): 0.080 (3). PMID- 22199800 TI - 5-Chloro-2-(phenyl-diazen-yl)pyridine. AB - In the title compound, C(11)H(8)ClN(3), the azo group adopts a trans conformation and the dihedral angle between the six-membered rings is 15.47 (8) degrees . PMID- 22199801 TI - 5-[(1H-Benzimidazol-1-yl)meth-yl]benzene-1,3-dicarb-oxy-lic acid. AB - Crystals of the title compound, C(16)H(12)N(2)O(4), were obtained accidentally from a hydro-thermal reaction of 5-[(1H-benzimidazol-1-yl)meth-yl]isophthalic acid with manganese bromide in the presence of N,N'-dimethyl-formamide. In the title mol-ecule, the benzimidazole ring system is almost planar, with a maximum deviation from the mean plane of 0.010 (2) A. The benzimidazole and central benzene rings are inclined at a dihedral angle of 71.7 (6) degrees . The crystal structure is stabilized by O-H?N and O-H?O hydrogen bonds. PMID- 22199802 TI - N,N'-Bis(pyridin-2-yl)benzene-1,4-diamine-naphthalene (2/1). AB - The asymmetric unit of the title compound, C(10)H(8).2C(16)H(14)N(4), consists of one mol-ecule of N,N'-bis-(pyridin-2-yl)benzene-1,4-diamine (PDAB) and one half of the centrosymmetric naphthalene mol-ecule. The PDAB mol-ecule adopts a non planar conformation with an E configuration at the two partially double exo C N bonds of the 2-pyridyl-amine units. In the crystal, N-H?N hydrogen bonds between the PDAB mol-ecules generate a cyclic R(2) (2)(8) motif, leading to the formation of PDAB tapes extending along [100]. The tapes are arranged into (010) layers and the naphthalene mol-ecules are enclosed in cavities formed between the PDAB layers. PMID- 22199803 TI - 1-(2-Aza-niumyleth-yl)piperazine-1,4-diium trinitrate. AB - In the title salt, C(6)H(18)N(3) (3+).3NO(3) (-), the piperazine ring adopts a chair conformation and the ethyl-ammonium group is equatorial relative to the piperazine ring, and in an all-trans conformation. In the crystal, strong charge assisted N-H?O hydrogen bonds link the piperazinediium trications and the nitrate anions into a three-dimensional network. PMID- 22199804 TI - 2-(2-Benzyl-phen-yl)propan-2-ol. AB - There are two mol-ecules in the asymmetric unit of the title compound, C(16)H(18)O, a tertiary alcohol featuring a 2-benzyl-phenyl substituent. Co operative O-H?O hydrogen bonds connect the mol-ecules into tetra-mers. PMID- 22199805 TI - (Z)-N-{3-[(2-Chloro-1,3-thia-zol-5-yl)meth-yl]-1,3-thia-zolidin-2-yl idene}cyanamide. AB - In the title compound, C(8)H(7)ClN(4)S(2), the thia-zole ring is essentially planar [r.m.s. deviation = 0.0011 (2) A] and conformation of the thia-zolidine ring is twisted on the C-C bond. The C=N bond has a Z configuration. PMID- 22199806 TI - N-(2-Formyl-phen-yl)-4-meth-oxy-N-(4-meth-oxy-phenyl-sulfon-yl)benzene sulfonamide. AB - In the title compound, C(21)H(19)NO(7)S(2), the dihedral angles between the formyl-phenyl ring and the two meth-oxy-phenyl rings are 33.87 (9) and 41.00 (10) degrees . The S atoms have a distorted tetra-hedral geometry and the N atom shows a trigonally planar [r.m.s. deviation = 0.0437 (13) A] coordination. The crystal structure is stabilized by inter-molecular C-H?O hydrogen bonds. PMID- 22199807 TI - 4,5,6,10,11,12,16,17,18,22,23,24-Dodeca-kis-[(meth-oxy-carbon-yl)meth-oxy] 2,8,14,20-tetra-pentyl-resorcin[4]arene. AB - The title compound, C(84)H(112)O(36), has a macrocyclic structure. It has 12 (meth-oxy-carbon-yl)meth-oxy 'head groups' in the upper rim and exhibits a flattened boat geometry. Intra-molecular C-H?O hydrogen bonds occur. In the crystal, inter-molecular C-H?O contacts occur. The 'head groups' and the pentyl 'feet' contain disordered (0.5:0.5 occupancy ratio) atoms. PMID- 22199808 TI - 9-(4-Bromo-phen-yl)-3,6-di-tert-butyl-9H-carbazole. AB - The asymmetric unit of the title compound, C(26)H(28)BrN, contains two independent mol-ecules in which the carbazole rings are almost planar, with r.m.s. deviations of 0.0212 (1) and 0.0229 (1) A. The dihedral angles between the carbazole ring system and the pendent benzene ring are 60.5 (1) and 56.3 (1) degrees in the two mol-ecules. In the crystal, mol-ecules are linked into chains along the b axis by C-H?pi inter-actions. PMID- 22199809 TI - Prop-2-yn-1-yl 4,6-di-O-acetyl-2,3-dide-oxy-alpha-d-erythro-hex-2-enopyran-o side. AB - The absolute structure of the title compound, C(13)H(16)O(6), was determined. The pyranosyl ring adopting an envelope conformation. The acetyl groups are located in equatorial positions. The crystal structure features weak C-H?O inter-actions. PMID- 22199810 TI - 1-Amino-5-(4-methyl-benzo-yl)-4-(4-methyl-phen-yl)pyrimidin-2(1H)-one. AB - In the title compound, C(19)H(17)N(3)O(2), the dihedral angles between the pyrimidine ring and the two benzene rings are 34.87 (12) (for the directly-bonded ring) and 69.57 (12) degrees . An intra-molecular N-H?O hydrogen bond occurs. The crystal packing features inter-molecular N-H?O hydrogen bonds. PMID- 22199811 TI - 1,1'-Binaphthyl-2,2'-diyl benzyl-phos-phoramidate. AB - In the title compound, C(27)H(20)NO(3)P, the P atom exhibits a somewhat distorted PNO(3) tetra-hedral geometry, with the O-P-O angle for the binaphthyl fragment being 102.82 (6) degrees . The dihedral angle between the naphthyl ring systems is 59.00 (2) degrees . In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R(2) (2)(8) loops. PMID- 22199812 TI - (E)-5-[(2-Hy-droxy-5-meth-oxy-benzyl-idene)amino]-1,3,4-thia-diazole-2(3H) thione. AB - In the title thione-Schiff base compound, C(10)H(9)N(3)O(2)S(2), the dihedral angle between the benzene ring and the five-membered ring is 6.69 (8) degrees . An intra-molecular O-H?N hydrogen bond forms an S(2) (2)(6) ring. In the crystal, inversion dimers linked by pairs of N-H?S inter-actions occur, generating R(2) (2)(8) ring motifs. The crystal structure features a S?S contact [3.3776 (7) A], which is significantly shorter than the sum of the van der Waals radii (3.7 A). The crystal structure also features C-H?O and pi-pi inter-actions [centroid centroid distances = 3.4636 (9)-3.808 (1) A]. PMID- 22199813 TI - rac-1,2,3,4-Tetra-hydro-1,4-methano-anthracene-6,7-dicarbonitrile. AB - The title compound, C(17)H(12)N(2), comprises a norbornane unit having a dicyanona-phthalene ring fused on one side. Both cyano groups are twisted slightly out of the plane of the naphthalene ring system [C-C-C-C torsion angle = 1.9 (2) degrees ]. In the crystal, inversion-related mol-ecules are linked by pairs of weak C-H?N hydrogen bonds, forming dimers. PMID- 22199814 TI - Benzyl 2-{[2,8-bis-(trifluoro-meth-yl)quinolin-4-yl](hy-droxy)meth-yl}piperidine 1-carboxyl-ate. AB - The title mol-ecule, C(25)H(22)F(6)N(2)O(3), adopts an open conformation whereby the quinoline and carboxyl-ate ester groups are orientated in opposite directions but to the same side of the piperidine ring so that the mol-ecule has an approximate U-shape. The piperidine ring adopts a distorted boat conformation. In the crystal, inversion dimers linked by pairs of O-H?O hydrogen bonds generate R(2) (2)(14) loops. PMID- 22199815 TI - tert-Butyl 2-{[2,8-bis-(trifluoro-meth-yl)quinolin-4-yl](hy-droxy)meth yl}piperidine-1-carboxyl-ate. AB - The title mol-ecule, C(22)H(24)F(6)N(2)O(3), adopts a folded conformation whereby the carboxyl-ate residue lies over the quinolinyl residue, with the dihedral angle between the carbamate and quinoline planes being 41.64 (7) degrees . Helical supra-molecular C(7) chains sustained by O-H?O hydrogen bonds propagating along the a-axis direction feature in the crystal packing. The F atoms of one of the CF(3) groups are disordered over two orientations; the major component has a site occupancy of 0.824 (7). PMID- 22199816 TI - N-(4-Chloro-2-methyl-phen-yl)maleamic acid. AB - In the mol-ecular structure of the title compound, C(11)H(10)ClNO(3), the conformation of the N-H bond in the amide segment is syn to the ortho-methyl group in the phenyl ring. The C=O and O-H bonds of the acid group are in the relatively rare anti position with respect to each other. This is an obvious consequence of the hydrogen bond donated to the amide carbonyl group. The central oxobutenoic acid core C(=O)-C=C-C-OH is twisted by 31.65 (6) degrees out of the plane of the 4-chloro-2-methyl-phenyl ring. An intra-molecular O-H?O hydrogen bond occurs. In the crystal, N-H?O hydrogen bonds link the mol-ecules into infinite chains running along the a axis. PMID- 22199817 TI - 3-Oxo-5-(piperidin-1-yl)-2,3-dihydro-1H-pyrazole-4-carbonitrile. AB - In the title compound, C(9)H(12)N(4)O, the piperidine ring adopts a chair conformation and makes a dihedral angle of 42.49 (11) degrees with the approximately planar pyrazole moiety [maximum deviation = 0.038 (2) A]. In the crystal, N-H?O and N-H?N hydrogen bonds and a weak C-H?O inter-action link the mol-ecules into sheets lying parallel to (110). PMID- 22199818 TI - 4,6-Bis(diphenyl-phosphan-yl)dibenzo[b,d]furan. AB - The asymmetric unit of the title compound, C(36)H(26)OP(2), comprises two mol ecules which have slightly different conformations of the phenyl ring substituents. In both mol-ecules, the dibenzofuran unit is close to being planar, with dihedral angles of 3.20 (3) and 1.86 (2) degrees for the two mol-ecules. Its planarity affects the intra-molecular distances between P atoms, with P?P distances of 5.574 (2) and 5.485 (2) A for the two mol-ecules. PMID- 22199819 TI - N,N'-Bis(1,3-thia-zol-2-yl)methyl-ene-diamine. AB - In the title compound, C(7)H(8)N(4)S(2), the dihedral angle between the thia zoline rings is 71.25 (13) degrees . In the crystal, inter-molecular N-H?N hydrogen bonds connect the mol-ecules into zigzag chains parallel to the ab plane. PMID- 22199820 TI - 1-[((E)-{2-[(2-Nitro-benz-yl)(2-{[(E)-(2-oxidonaphthalen-1-yl)methyl-idene]aza nium-yl}eth-yl)amino]-eth-yl}aza-niumyl-idene)meth-yl]naphthalen-2-olate monohydrate. AB - The title Schiff base compound, C(33)H(30)N(4)O(4).H(2)O, adopts an E configuration with respect to each C=N double bond. In the mol-ecule, there are naphthoxide anions and the protonated imino N atoms. Intra-molecular N-H?O hydrogen bonds lead to the formation of approximately planar (maximum deviation 0.029 A for H atom) six-membered rings.. In the crystal, mol-ecules are linked by O-H?O and N-H?O hydrogen bonds as well as C-H?O contacts, leading to the formation of a three-dimensional network. PMID- 22199821 TI - (E)-Methyl 2-[(4-bromo-2-formyl-phen-oxy)meth-yl]-3-phenyl-acrylate. AB - The C=C double bond in the title compound, C(18)H(15)BrO(4), adopts an E configuration. The two rings are almost orthogonal to each other, making a dihedral angle of 82.8 (1) degrees . An intra-molecular C-H?O hydrogen bond occurs. The crystal structure is stabilized by inter-molecular C-H?O hydrogen bonds. PMID- 22199822 TI - (E)-1-(4,4''-Difluoro-5'-meth-oxy-1,1':3',1''-terphenyl-4'-yl)-3-(4-meth-oxy-phen yl)prop-2-en-1-one. AB - The title compound, C(29)H(22)F(2)O(3), is a meta-terphenyl derivative featuring a Michael-system-derived substituent with an E-configured C=C function. In the crystal, C-H?O and C-H?F contacts connect the mol-ecules into planes parallel to (101). The shortest centroid-centroid distance between two aromatic systems is 3.7169 (7) A and is apparent between the terminal benzene ring of the Michael system-derived substituent and its symmetry-generated equivalent. PMID- 22199823 TI - 2,3-Diamino-pyridinium 6-carb-oxy-pyridine-2-carboxyl-ate. AB - The asymmetric unit of the title proton-transfer compound, C(5)H(8)N(3) (+).C(7)H(4)NO(4) (-), consists of one mono-deprotonated pyridine-2,6-dicarb-oxy lic acid as anion and one protonated 2,3-diamino-pyridine as cation. The crystal packing shows extensive O-H?O, N-H?O and N-H?N hydrogen bonds. Thre are also several pi-pi inter-actions between the anions and also between the cations [centriod-centroid distances = 3.6634 (7), 3.7269 (7), 3.6705 (7) and 3.4164 (7) A]. PMID- 22199824 TI - 6-Benzyl-3-[(6-chloro-pyridin-3-yl)meth-yl]-6,7-dihydro-3H-1,2,3-triazolo[4,5 d]pyrimidin-7-imine. AB - The title compound, C(17)H(14)ClN(7), crystallizes with two independent mol ecules in the asymmetric unit. Inter-molecular N-H?N and C-H?N hydrogen bonds contribute to the stability of the crystal structure. In addition, weak C-H?pi and pi-pi stacking [centroid-centroid distances of 3.699 (8) and 3.699 (6) A] interactions are observed. PMID- 22199825 TI - (E)-1-(4,4''-Difluoro-5'-meth-oxy-1,1':3',1''-terphenyl-4'-yl)-3-(6-meth-oxy naphthalen-2-yl)prop-2-en-1-one. AB - In the title compound, C(33)H(24)F(2)O(3), the central benzene ring makes dihedral angles of 44.71 (10), 47.80 (10) and 63.68 (9) degrees with the two fluoro-substituted benzene rings and the naphthalene ring system, respectively. In the crystal, mol-ecules are connected via inter-molecular C-H?F and C-H?O hydrogen bonds. Furthermore, the crystal structure is stabilized by weak C-H?pi and pi-pi inter-actions [centroid-centroid distance = 3.6816 (13) A]. PMID- 22199826 TI - 3-Chloro-N-phenyl-benzamide. AB - In the title compound, C(13)H(10)ClNO, the meta-chloro group on the benzoyl ring is positioned syn to the C=O bond. The two aromatic rings make a dihedral angle of 88.5 (3) degrees . In the crystal, N-H?O hydrogen bonds link the mol-ecules into C(4) chains propagating in [010]. PMID- 22199827 TI - [3-({(E)-2-[(4-Fluorophenyl)carbamo-thioyl]hydrazinylidene}methyl)-4-hy-droxy benzyl]methyl-triphenyl-phos-phonium chloride. AB - The cation in the title salt, C(33)H(28)FN(3)OPS(+).Cl(-), is highly twisted with the phospho-nium group occupying a position almost normal to the central hydroxyl benzene ring [P-C-C-C tosrsion angle = -100.9 (3) degrees ], and with the hydrazone substituent twisted out of the plane [C-C-C-N torsion angle = 13.1 (4) degrees ]. The fluoro-benzene ring is twisted out of the plane of the adjacent thio-urea residue, forming a dihedral angle of 51.69 (10) degrees . The configuration about the C=N bond [1.281 (4) A] is E, the O-H and N-H hydrogen atoms are syn, and in the thio-urea residue, the N-H hydrogen atoms are anti, allowing for the formation of an intra-molecular N-H?N hydrogen bond. In the crystal, dimeric aggregates mediated by N-H?S bonds are formed, which are linked to the Cl(-) anions by O-H?Cl hydrogen bonds. The four-component aggregates are linked into a three-dimensional structure by C-H?Cl inter-actions. PMID- 22199828 TI - N-(4-Chloro-2-nitro-phen-yl)-5-methyl-isoxazole-4-carboxamide. AB - In the title compound, C(11)H(8)ClN(3)O(4), the dihedral angle between benzene and isoxazole rings is 9.92 (1) degrees . The nitro group is almost coplanar with the benzene ring with an O-N-C-C torsion angle of 8.4 (3) degrees . The mol ecular conformation is stabilized by an intra-molecular N-H?O hydrogen bond, closing a six-membered ring. PMID- 22199829 TI - (2E)-1-(2,5-Dimethyl-thio-phen-3-yl)-3-(3-nitro-phen-yl)prop-2-en-1-one. AB - In the title compound, C(15)H(13)NO(3)S, the benzene ring and the five-membered heterocyclic ring are oriented at a dihedral angle of 12.00 (6) degrees . In the crystal, C-H?O inter-actions generate two types of cyclic motifs, R(2) (2)(14) and R(2) (2)(26), connecting the mol-ecules into tapes extending along [101]. In addition, there are pi-pi stacking inter-actions between the benzene and thio phene rings with centroid-centroid distances of 3.7263 (14) and 3.7487 (14) A. PMID- 22199830 TI - 1,3-Bis(propan-2-yl)naphthalene. AB - In the title compound, C(16)H(20), one of the isopropyl groups shows almost equal displacements [1.252 (1) and -1.270 (1) A] of its methyl-C atoms from the mean plane of the naphthalene ring system, while the other shows asymmetric displacements [1.586 (2) and -0.315 (1) A]. In the crystal, the mol-ecules are linked into sheets lying in the ab plane by three C-H?pi contacts, two involving donors belonging to the isopropyl groups and the third a donor atom from the naphthalene ring system. The different orientations of the isopropyl groups might be attributed to the fact that the C-H?pi inter-action involving one of them is enhanced by the C-H?pi inter-action involving the aromatic ring. PMID- 22199831 TI - Morpholinium hydrogen chloranilate methanol monosolvate. AB - In the crystal structure of the title compound, C(4)H(10)NO(+).C(6)HCl(2)O(4) ( ).CH(4)O, the components are held together by bifurcated O-H?(O,O), O-H?(O,Cl) and N-H?(O,O) hydrogen bonds into a centrosymmetric 2+2+2 aggregate. The aggregates are further connected by another bifurcated N-H?(O, O) hydrogen bond, forming a double-tape structure along the b axis. A weak C-H?O inter-action is observed between the tapes. PMID- 22199832 TI - 4-Diethyl-amino-3,5-diisopropyl-benzalde-hyde. AB - The title benzaldehyde, C(17)H(27)NO, was prepared via lithia-tion of bromoaniline and reaction with DMF. In the crystal, the molecule adopts a C2 symmetrical conformation; nevertheless, two modes of disorder are present: the orientation of the aldehyde group (occupancy ratio 0.5:0.5) and of symmetry equivalent ethyl groups [occupancy ratio 0.595 (7):0.405 (7)]. The phenyl-ene ring and the carbonyl group are essentially coplanar [C-C-C-O torsion angle = 179.0 (4) degrees ] but the dihedral angle between the mean planes of the phenyl ene ring and the amino group = 67.5 (2) degrees . This and the long [1.414 (3) A] aniline C-N bond indicate electronic decoupling between the carbonyl and amino groups. The angle sum of 359.9 (2) degrees around the N atom results from steric compression-induced rehybridization. PMID- 22199833 TI - 5-Acetyl-3-hy-droxy-4-phenyl-4,5-dihydro-1H-1,5-benzodiazepin-2(3H)-one. AB - In the title compound, C(17)H(16)N(2)O(3), the seven-membered diazepine ring adopts a boat conformation with the hy-droxy-substituted C atom at the prow and fused benzene ring C atoms at the stern. The phenyl substituent occupies an equatorial position. The amino group of the ring system is a hydrogen-bond donor to the oxo O atom of an inversion-related mol-ecule, and the hy-droxy group is a hydrogen-bond donor to the acetyl O atom of another inversion-related mol-ecule. The two hydrogen bonds generate a ribbon motif parallel to [10[Formula: see text]] in the crystal structure. PMID- 22199834 TI - (4R*,4aS*,4bS*,5R*,10aR*)-4-Hy-droxy-4a,5-dimethyl-2-(propan-2-yl) 1,4,4a,4b,5,6,7,8,10,10a-deca-hydro-phenan-thren-1-one. AB - In the title compound, C(19)H(28)O(2), the A ring adopts a chair conformation. Both the B and C rings adopt envelope conformations with the C atoms common to both rings and adjacent to the carbonyl and hydroxyl groups, respectively, lying 0.604 (3) and 0.634 (3) A out of the mean planes defined by the remaining five C atoms of rings B and C, respectively (r.m.s. deviations = 0.0100 and 0.0157 A, respectively). The formation of linear supra-molecular C(7) chains along the a axis mediated by hy-droxy-O-H?O(carbon-yl) hydrogen bonds is the most prominent feature of the crystal packing. PMID- 22199835 TI - N'-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetra-zin-3-yl]butano-hydrazide. AB - In the title compound, C(11)H(16)N(8)O, the tetra-zine and pyrazole rings form a dihedral angle of 48.75 (2) degrees . In the crystal, N-H?O and N-H?N hydrogen bonds link the mol-ecules into layers parallel to (101). PMID- 22199836 TI - 5-Chloro-1-nonyl-1H-benzimidazol-2(3H)-one. AB - The asymmetric unit of the title compound, C(16)H(23)ClN(2)O, comtains two independent mol-ecules in which the fused-ring systems are essentially planar, the largest deviation from the mean plane of each mol-ecule being 0.011 (2) A and 0.016 (2) A. The benzimidazole rings of the two mol-ecules make a dihedral angle of 66.65 (7) degrees . The nonyl substituents are almost perpendicular to the benzimidazole planes [C-N-C-C tosrsion angles = 96.0 (3) and 81.0 (2) degrees ]. In the crystal, each independent molecule forms an inversion dimer via a pair of N-H?O hydrogen bonds. In one of the independent molecules, the terminal -CH(2) CH(3) group of the alkyl chain is disordered over two sets of sites with a refined occupancy ratio of 0.746 (7):0.254 (7). PMID- 22199837 TI - (E)-1-{4-[Bis(4-fluoro-phen-yl)meth-yl]piperazin-1-yl}-3-(4-eth-oxy-phen-yl)prop 2-en-1-one. AB - In the title mol-ecule, C(28)H(28)F(2)N(2)O(2), the ethene bond exhibits an E conformation and the piperazine ring adopts a chair conformation. The amide-N atom of the piperazine ring is almost planar (bond-angle sum = 358.8 degrees ) whereas the other N atom is clearly pyramidal (bond-angle sum = 330.5 degrees ). The dihedral angle between the fluoro-benzene rings is 76.36 (17) degrees . In the crystal, inversion dimers linked by pairs of C-H?O hydrogen bonds generate R(2) (2)(22) loops. PMID- 22199838 TI - 1-Methyl-3-trifluoro-methyl-5-[(3-chloro-phen-yl)sulfanyl]-1H-pyrazole-4 carbaldehyde O-(4-chloro-benzo-yl)oxime. AB - In the title compound, C(19)H(12)Cl(2)F(3)N(3)O(2)S, the 3-chloro-phenyl and 4 chloro-phenyl rings form dihedral angles 89.5 (2) and 11.4 (2) degrees , respectively, with the pyrazole ring. In the crystal, mol-ecules related by translation along the a axis are linked into chains via C-H?N hydrogen bonds. PMID- 22199839 TI - 10-Ethyl-10H-phenothia-zine-3-carbaldehyde. AB - In the title mol-ecule, C(15)H(13)NOS, the two benzene rings of the tricyclic fused-ring system are inclined at 21.1 (1) degrees . In the crystal, weak C-H?O hydrogen bonds link the mol-ecules into chains along [001]. The crystal packing also exhibits pi-pi inter-actions with a distance of 3.801 (5) A between the centroids of the benzene rings of neighbouring mol-ecules. PMID- 22199840 TI - 2-n-Butyl-6-chloro-1-(2,4-dimethyl-phenyl-sulfon-yl)-1H-benzimidazole-2-n-butyl-5 chloro-1-(2,4-dimethyl-phenyl-sulfon-yl)-1H-benzimidazole (0.759/0.241). AB - The title compound, 0.759C(19)H(21)ClN(2)O(2)S.0.241C(19)H(21)ClN(2)O(2)S, was synthesized by aryl-sulfonyl-ation of 2-n-butyl-5-chloro-1H-benzimidazole in the presence of triethyl-amine. The crystal structure is composed of two mol-ecules, 2-n-butyl-6-chloro-1-(2,4-dimethylphenyl-sulfon-yl)-1H-benzimidazole and 1-(2,4 dimethylphenyl-sulfon-yl)-2-n-butyl-5-chloro-1H-benz-imidazole, in the refined ratio of 0.759 (4):0.241 (4) disordered at the same position in the unit cell. The mol-ecule has three essentially planar fragments viz. benzimidazole, dimethyl benzene and n-butyl (r.m.s. deviations of 0.009, 0.024 and 0.003 A, respectively). The angle between the benzimidazole and dimethyl-benzene fragments is 86.0 (1) degrees . In the crystal, pairs of inter-molecular C-H?pi inter actions form centrosymmetrical dimers, which are linked by weak inter-molecular C H?O hydrogen bonds. PMID- 22199841 TI - 1-(4,6-Dimethyl-pyrimidin-2-yl)thio-urea. AB - In the crystal structure of the title compound, C(7)H(10)N(4)S, weak inter molecular N-H?S inter-actions form a two-dimensional network parallel to the ab plane. An intra-molecular N-H?N hydrogen bond occurs. PMID- 22199843 TI - 4-[(4-Chloro-phen-yl)(hy-droxy)methyl-idene]isochromane-1,3-dione. AB - In the title compound, C(16)H(9)ClO(4), the six-membered heterocyclic ring adopts a screw-boat conformation. The benzene rings are oriented to each other at a dihedral angle of 59.26 (9) degrees . The mol-ecular structure exhibits a ring motif, viz. S(6), owing to an intra-molecular O-H?O hydrogen bond. The presence of C-H?O contacts generates an infinite chain along [001]. Also present are pi-pi stacking inter-actions between neighbouring isochromanedione benzene rings [centroid-centroid distance = 3.746 (1) A], and C-O?pi inter-actions [O?centroid = 3.934 (2) A]. PMID- 22199842 TI - 2-[4-(2-Hy-droxy-eth-oxy)phenyl]-4,4,5,5-tetra-methyl-2-imidazoline-1-oxyl 3 oxide. AB - In the title compound, C(15)H(21)N(2)O(4), the imidazoline ring displays a twisted conformation. The dihedral angle between the mean plane of the imidazoline ring and the benzene ring is 33.50 (12) degrees . In the crystal, mol ecules are connected by O-H?O hydrogen bonds, forming a zigzag chain along the c axis. The chains are linked by C-H?O and C-H?pi inter-actions. PMID- 22199844 TI - Ethyl 2-[N-(tert-butyl-sulfin-yl)carbamo-yl]benzoate. AB - The title compound, C(14)H(19)NO(4)S, was obtained in quanti-tative yield by Lewis acid-catalysed alcoholysis of a phtalimide precursor. An intra-molecular C H?O hydrogen bond occurs. In the crystal, centrosymmetric dimers are formed by pairs of N-H?O hydrogen bonds between the sulfinyl O atoms and the carbamoyl N-H group of a neighboring mol-ecule. C-H?O inter-actions feature in the crystal structure. PMID- 22199845 TI - 2-(4-Chloro-phen-yl)-2-oxoethyl 3,4-dimeth-oxy-benzoate. AB - In the title compound, C(17)H(15)ClO(5), the benzene rings forms a dihedral angle of 74.45 (10) degrees . In the crystal, mol-ecules are linked into C(13) chains along [011] via C-H?O hydrogen bonds. The crystal packing also features short Cl?Cl contacts of 3.1253 (10) A. PMID- 22199846 TI - 3-({[(1-Phenyl-eth-yl)sulfan-yl]methane-thio-yl}sulfan-yl)propanoic acid. AB - In the title compound, C(12)H(14)O(2)S(3), a chain transfer agent (CTA) used in polymerization, the dihedral angle between the aromatic ring and the CS(3) grouping is 84.20 (10) degrees . In the crystal, carb-oxy-lic acid inversion dimers linked by pairs of O-H?O hydrogen bonds generate R(2) (2)(8) loops. PMID- 22199847 TI - 2-Nitro-N'-[1-(pyridin-2-yl)ethyl-idene]benzohydrazide. AB - In the title compound, C(14)H(12)N(4)O(3), the dihedral angle between the benzene ring and the pyridine ring is 60.9 (2) degrees . The major twist in the mol-ecule occurs about the (NH)-(CO)-C(ar)-C(ar) (ar = aromatic) bond, the relevant torsion angle being 63.97 (12) degrees . In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R(2) (2)(8) loops. PMID- 22199848 TI - [8-(4-But-oxy-benzo-yl)-2,7-dimeth-oxy-naphthalen-1-yl](4-but-oxy-phen yl)methanone. AB - The mol-ecule of the title compound, C(34)H(36)O(6), is located on a twofold rotation axis. The two 4-but-oxy-benzoyl groups at the 1- and 8-positions of the naphthalene ring system are aligned almost anti-parallel. The dihedral angles between the benzene rings and the naphthalene ring system are 71.70 (4) degrees . In the crystal, the mol-ecules are connected via C-H?pi inter-actions into a layer parallel to (010). PMID- 22199849 TI - 3beta,11alpha-Dihy-droxy-12-ursen-3-yl palmitate. AB - In the title compound, C(46)H(80)O(3), a natural ursane-type triperpenoid, four of the five six-membered rings adopt chair conformations; the fifth, which has a C=C double bond, adopts an approximate half-boat conformation. In the crystal, mol-ecules are linked by O-H?O hydrogen bonds, forming chains along [010]. PMID- 22199850 TI - 4,6-Di-tert-butyl-2,8-dimeth-oxy-dibenzo[b,d]furan. AB - In the title compound, C(22)H(28)O(3), the dihedral angle between the benzene rings is 3.47 (13) degrees and the five-membered furan ring is essentially planar with a largest deviation of 0.0052 (14) A. The Csp(2)-Csp(2) bond length between the two benzene rings [1.443 (3) A] is considerably shorter than those between the benzene and tertiary C atoms [1.538 (3) and 1.530 (3) A], which are sp(2)-sp(3) hybridized. C-H?pi inter-actions involving the furan and benzene rings are found in the crystal structure. PMID- 22199851 TI - A monoclinic polymorph of theophylline. AB - A monoclinic polymorph of theophylline, C(7)H(8)N(4)O(2), has been obtained from a chloro-form/methanol mixture by evaporation under ambient conditions. The new polymorph crystallizes with two mol-ecules in the asymmetric unit. The structure features inter-molecular N-H?O hydrogen bonds, resulting in the formation of dimers between two crystallographically different mol-ecules; each mol-ecule acts as both donor and acceptor. PMID- 22199852 TI - (E)-1-{4-[Bis(4-bromo-phen-yl)meth-yl]piperazin-1-yl}-3-(4-bromo-phen-yl)prop-2 en-1-one. AB - In the title mol-ecule, C(26)H(23)Br(3)N(2)O, the piperazine ring adopts a chair conformation and the C=C double bond has an E configuration. In the crystal, mol ecules are linked through weak inter-molecular C-H?O hydrogen bonds. PMID- 22199853 TI - 3-(3-Fluoro-phenyl-sulfon-yl)-2,5,7-trimethyl-1-benzofuran. AB - In the title compound, C(17)H(15)FO(3)S, the 3-fluoro-phenyl ring makes a dihedral angle of 73.39 (4) degrees with the mean plane of the benzofuran fragment. In the crystal, mol-ecules are linked by weak inter-molecular C-H?O hydrogen bonds. The crystal structure also exhibits a slipped pi-pi inter-action between the furan and benzene rings of neighboring mol-ecules [centroid-centroid distance = 3.743 (2) A, inter-planar distance = 3.543 (2) A and slippage = 1.207 (2) A]. PMID- 22199854 TI - 5,5'-Bis(naphthalen-2-yl)-2,2'-bi(1,3,4-oxadiazole). AB - The title mol-ecule, C(24)H(14)N(4)O(2), lies on an inversion centre and the asymmetric unit containg one half-mol-ecule. The naphthalene ring systems are twisted slightly with respect to the oxadiazole rings, making a dihedral angle of 1.36 (6) degrees . These mol-ecules are pi-stacked along the crystallographic a axis, with an inter-planar distance of 3.337 (1) A. Adjacent mol-ecules are slipped from the 'ideal' cofacial pi-stack in both the long and short mol-ecular axis (the long mol-ecular axis is defined as the line through the naphthalene C atom in the 6-position and the mol-ecular center, the short mol-ecular axis is in the mol-ecular plane perpendicular to it). The slip distance along the long mol ecular axis (S(1)) is 7.064 (1) A, nearly a two-ring-length displacement. The side slip (S(2), along the short mol-ecular axis) is 1.159 (8) A. PMID- 22199855 TI - 2-Amino-benzoic acid-4-(pyridin-4-yl-disulfan-yl)pyridine (1/1). AB - The title 1:1 co-crystal, C(7)H(7)NO(2).C(10)H(8)N(2)S(2), features a highly twisted 4-(pyridin-4-yldisulfan-yl)pyridine mol-ecule [dihedral angle between the pyridine rings = 89.06 (10) degrees ]. A small twist is evident in the 2-amino benzoic acid mol-ecule, with the C-C-C-O torsion angle being -7.7 (3) degrees . An N-H?O hydrogen bond occurs in the 2-amino-benzoic acid mol-ecule. In the crystal, mol-ecules are linked by O-H?N and N-H?N hydrogen bonds into a supra molecular chain along the b axis. These are connected into layers by pi-pi inter actions occurring between pyridine rings [centroid-centroid distance = 3.8489 (15) A]. The layers are connected along the a axis by C-H?O contacts. The crystal studied was a racemic twin. PMID- 22199856 TI - 1,3-Bis(2-anilino-2-oxoeth-yl)-1H-imidazol-3-ium chloride acetonitrile monosolvate. AB - In the title compound, C(19)H(19)N(4)O(2) (+).Cl(-).C(2)H(3)N, the dihedral angle between the two phenyl rings is 69.57 (8) degrees while the dihedral angles between the imidazole ring and the phenyl rings are 70.61 (7) and 82.11 (7) degrees . In the crystal, N-H?Cl, C-H?O, C-H?Cl and C-H?N hydrogen bonds link the imidazolium cations, chloride anions and acetonitrile solvent mol-ecules into a two-dimensional hydrogen-bonded network parallel to (001); an intra-molecular C H?O hydrogen bond is also observed. PMID- 22199857 TI - [3-Bromo-meth-yl-1-(4-methyl-phenyl-sulfon-yl)azetidin-3-yl]methanol. AB - The asymmetric unit of the title compound, C(12)H(16)BrNO(3)S, contains two independent mol-ecules. In each mol-ecule, the azetidine four-membered ring adopts a nearly planar conformation, the maximum deviations being 0.087 (3) and 0.079 (3) A. The mean azetidine plane is twisted by 75.2 (2) and 73.6 (2) degrees with respect to the plane of the benzene ring in the two independent mol-ecules. The crystal packing is stabilized by O-H?O hydrogen bonds. PMID- 22199858 TI - Bis[2-(benzyl-idene-amino)-phen-yl] disulfide. AB - In the title mol-ecule, C(26)H(20)N(2)S(2), the two benzene rings connected by a disulfide chain form a dihedral angle of 84.9 (1) degrees , and the two benzene rings in the two benzyl-idene-amino-phenyl fragments form dihedral angles of 34.4 (1) and 32.8 (1) degrees . The crystal structure exhibits weak inter-molecular C H?S hydrogen bonds, which link the mol-ecules into chains along [101]. PMID- 22199859 TI - N'-[(E)-1-(5-Bromo-2-hy-droxy-phen-yl)ethyl-idene]-2-chloro-benzohydrazide. AB - The title compound, C(15)H(12)BrClN(2)O(2), was synthesized by the condensation of 1-(5-bromo-2-hy-droxy-phen-yl)ethanone with 2-chloro-benzohydrazide in anhydrous ethanol. The Schiff base mol-ecule displays a trans configuration with respect to the C=N double bond. The dihedral angle between the two benzene rings is 13.74 (3) degrees . The mol-ecular conformation is stabilized by an intra molecular O-H?N and the crystal structure by inter-molecular N-H?O hydrogen bonds. PMID- 22199860 TI - Bis[(2R,6S)-4-(5-amino-3-carb-oxy-1-cyclo-propyl-6,8-difluoro-4-oxo-1,4-dihydro quinolin-7-yl)-2,6-dimethyl-piperazin-1-ium] sulfate penta-hydrate. AB - The title compound, C(19)H(23)F(2)N(4)O(3) (+).0.5SO(4) (2-).2.5H(2)O, an anti bacterial fluoro-quinolone, crystallized as a racemic twin (major twin component = 0.633) in the chiral space group P1. The asymmetric unit contains two sparfloxacinium cations, one sulfate anion and five mol-ecules of water of solvation. The bond lengths and angles of both cations are almost identical. The quinoline ring systems in the cations are essentially planar, the mean deviations from the best plane being 0.045 (2) and 0.054 (2) A and make pi-pi inter-actions with each other [centroid-centroid distances of 3.692 (4) A and 3.744 (4) A]. The crystal structure features inter-molecular O-H?O, O-H?S, N(+)-H?O, N(+)-H?S and N H?O hydrogen bonds together with intra-molecular O-H?O and N-H?O hydrogen bonds. As a result, a three-dimensional supra-molecular structure is observed. PMID- 22199861 TI - 5,8-Dibromo-15-nitro-2,11-dithia-[3.3]paracyclo-phane. AB - IN THE TITLE COMPOUND [SYSTEMATIC NAME: 13,15-dibromo-6-nitro-3,10-dithia tricyclo-[10.2.2.2(5,8)]octa-deca-1(14),5,7,12,15,17-hexa-ene], C(16)H(13)Br(2)NO(2)S(2), the dihedral angle between the two benzene rings is 0.93 (2) degrees . The crystal structure is stabilized by weak pi-pi inter molecular inter-actions [centroid-centroid distance = 3.286 (5) A]. One S atom and the H atoms on neighboring C atoms are disordered over two sets of sites (occupancy ratios: S = 0.91:0.09 and H = 0.93:0.07). PMID- 22199862 TI - (Z)-1-[2-(Trifluoro-meth-yl)benzyl-idene]thio-semicarbazide. AB - In the crystal structure of the title compound, C(9)H(8)F(3)N(3)S, all atoms except for two of the F atoms are located on a mirror plane. In the crystal, the molecules are connected by N-H?S hydrogen bonds, forming a mol-ecular tape along the a axis. PMID- 22199863 TI - (E)-N'-(3-Hy-droxy-4-meth-oxy-benzyl-idene)-4-meth-oxy-benzohydrazide. AB - The title mol-ecule, a benzohydrazide derivative, C(16)H(16)N(2)O(4), is twisted with a dihedral angle of 69.97 (5) degrees between the two benzene rings. An intra-molecular O-H?O hydrogen bond generates an S(5) ring motif. In the crystal, mol-ecules are linked by N-H?O and weak C-H?O hydrogen bonds into a chain along the c axis. C-H?pi inter-actions are also present. PMID- 22199864 TI - 5-(4,4''-Difluoro-5'-hy-droxy-1,1':3',1''-terphenyl-4'-yl)-3-(morpholin-4-ylmeth yl)-1,3,4-oxadiazole-2(3H)-thione. AB - In the title compound, C(25)H(21)F(2)N(3)O(3)S, the morpholine ring adopts a chair conformation. The 1,3,4-oxadiazole-2(3H)-thione group makes dihedral angles of 78.69 (8), 53.56 (7) and 55.30 (9) degrees with the benzene rings. In the crystal, O-H?O, C-H?S and C-H?F hydrogen bonds linked the mol-ecules into layers lying parallel to the ab plane. Weak C-H?pi inter-actions also occur. PMID- 22199865 TI - 2-(4-Chloro-anilino)-1-(4-chloro-phen-yl)ethanone. AB - In the title compound, C(14)H(11)Cl(2)NO, the benzene rings form a dihedral angle of 3.14 (6) degrees . Overall, the mol-ecule is close to being planar (r.m.s. deviation for all the non-H atoms = 0.054 A). No significant directional inter molecular inter-actions are observed in the crystal structure. PMID- 22199866 TI - 5,8-Bis(3-hy-droxy-3-methyl-but-1-yn-1-yl)-2,11-dithia-[3.3]paracyclo-phane. AB - IN THE CRYSTAL STRUCTURE OF THE TITLE COMPOUND [SYSTEMATIC NAME: 2,2'-dimethyl 4,4'-(3,10-dithia-tricyclo-[10.2.2.2(5,8)]octa-deca-1(14),5,7,12,15,17-hexaen 6,17-di-yl)dibut-3-yn-2-ol], C(26)H(28)O(2)S(2), mol-ecules are linked by O-H?O hydrogen bonds, forming a tubular chain which runs parallel to the b axis. The tubular structure is reinforced by pi-pi stacking inter-actions [centroid centroid distance = 3.6332(16A]. PMID- 22199867 TI - 3-Bromo-5-tert-butyl-2-hy-droxy-benz-alde-hyde. AB - The mol-ecular conformation of the title compound, C(11)H(13)BrO(2), is stabilized by an intra-molecular O-H?O hydrogen bond. All non-H atoms except the methyl groups lie approximately in a common plane (r.m.s. deviation = 0.011 A). PMID- 22199868 TI - (1R*,3'S*,4'R*)-4'-(4-Chloro-phen-yl)-3'-[(4-hy-droxy-2-oxo-1,2-dihydro-quinolin 3-yl)carbon-yl]-1'-methyl-spiro-[ace-naphthyl-ene-1,2'-pyrrolidin]-2-one. AB - The title compound, C(32)H(23)ClN(2)O(4), has a quinoline, a chloro-phenyl and an acenaphthalene ring system attached to a central pyrrolidine ring, which has three stereogenic centers. Nevertheless, the compound crystallizes as a racemate with two mol-ecules of identical chirality in the asymmetric unit. They differ in the conformation of the five-membered pyrrolidine ring; in one molecule it has an envelope conformation, while in the other molecule it has a twisted conformation. In each molecule there is an intra-molecular O-H?O hydrogen bond making an S(6) ring motif. In the crystal, pairs of N-H?O hydrogen bonds produce inversion dimers with R(2) (2)(8) motifs. There are also C-H?O interactions present. The crystal structure contains voids (60 A(3)) within which there is no evidence of solvent mol-ecules. PMID- 22199869 TI - 1-Methyl-hydrazinium picrate. AB - In the title salt, CH(7)N(2) (+).C(6)H(2)N(3)O(7) (-), the dihedral angles between the three nitro groups and the plane of the benzene ring are 22.4 (2), 35.3 (2) and 2.8 (2) degrees . In the crystal, the components are linked by N-H?O and N-H?N hydrogen bonds into a two-dimensional network parallel to (10[Formula: see text]). PMID- 22199870 TI - 2-(2,4-Dichloro-phen-yl)-2-oxoethyl 4-meth-oxy-benzoate. AB - In the title compound, C(16)H(12)Cl(2)O(4), the dihedral angle between the benzene rings is 70.11 (6) degrees . In the crystal, mol-ecules are linked by C H?O hydrogen bonds into a three-dimensional network. A C-H?pi inter-action is also observed. PMID- 22199871 TI - 2,4-Dibromo-6-[(quinolin-8-yl-amino)-methyl-idene]cyclo-hexa-2,4-dien-1-one monohydrate. AB - In the title compound, C(16)H(10)Br(2)N(2)O.H(2)O, bifurcated intra-molecular N H?(N,O) hydrogen bonding defines the essential planarity of the main mol-ecule: the dihedral angle between the quinoline and benzene rings is 7.53 (8) degrees . Inter-molecular O-H?O and weak C-H?O hydrogen bonds consolidate the crystal packing, which exhibits pi-pi inter-actions with a distance of 3.588 (1) A between the centroids of the aromatic rings and short Br?Br contacts of 3.5757 (6) A. PMID- 22199872 TI - 3-Chloro-N-(2-methyl-phen-yl)benzamide. AB - In the mol-ecular structure of the title compound, C(14)H(12)ClNO, the meta-Cl atom in the benzoyl ring is positioned anti to the C=O bond, while the ortho methyl group in the aniline ring is positioned syn to the N-H bond. The two benzene rings are nearly coplanar [dihedral angle = 3.48 (5) degrees ]. The crystal structure is stabilized by N-H?O hydrogen bonds, which link the mol ecules into chains along the b axis. PMID- 22199873 TI - 8-Acetyl-4-methyl-2-oxo-2H-chromen-7-yl acetate. AB - In the title compound, C(14)H(12)O(5), the benzopyran-2-one ring system is approximately planar [maximum deviation = 0.018 (1) A]; the mean plane is oriented at dihedral angles of 52.26 (11) and 72.92 (7) degrees , respectively, to the acetyl and acet-oxy groups. In the crystal, pi-pi stacking is observed between parallel benzene rings of adjacent mol-ecules, the centroid-centroid distance being 3.6774 (17) A. Inter-molecular weak C-H?O hydrogen bonding, and C=O?C=O [O?C = 3.058 (3) A] and C=O?pi [O?centroid = 3.328 (2) A] inter-actions occur in the crystal structure. PMID- 22199874 TI - N-(2-Hy-droxy-benz-yl)adamantan-1-aminium 4-methyl-benzene-sulfonate. AB - In the crystal structure of the title salt, C(17)H(24)NO(+).C(7)H(7)O(3)S(-), the N-(2-hy-droxy-benz-yl)adamantan-1-aminium cations and 4-methyl-benzene-sulfonate anions are linked by O-H?O and N-H?O hydrogen bonds. C-H?pi inter-actions are also observed between the cation and the anion. PMID- 22199875 TI - Propyl-ammonium 4,4,4-trifluoro-1-(naphthalen-2-yl)butane-1,3-dionate. AB - The title salt, C(3)H(10)N(+).C(14)H(8)F(3)O(2) (-), constitutes the first organic crystal containing a residue of 4,4,4-trifluoro-1-(naphthalen-2-yl)butane 1,3-dione. The terminal -CF(3) group is disordered over two locations [occupancy ratio = 0.830 (7):0.170 (7)]. Bond delocalization involving the two carbonyl groups and the alpha-carbon was observed. The crystal packing is mediated by several supra-molecular inter-actions, namely charged-assisted N-H?O hydrogen bonds, C-H?F and C-F?F short contacts and C-H?pi inter-actions. PMID- 22199876 TI - (2R)-4-[(9H-Fluoren-9-ylmeth-oxy)carbon-yl]-2-methyl-piperazin-1-ium chloride. AB - The synthesis of the title salt, C(20)H(23)N(2)O(2) (+).Cl(-), was carried out with a precursor of known absolute configuration (R) and the X-ray analysis confirmed that the product retained the absolute configuration. In the crystal, the dominant packing motif is a chain running along [010] generated by N-H?Cl hydrogen bonding. C-H?O and C-H?Cl inter-actions are also observed. PMID- 22199877 TI - 2-Benzyl-6-chloro-1-(4-methyl-phen-yl)-1H-indole-3-carbonitrile. AB - In the title compound, C(23)H(17)ClN(2), the dihedral angle between the indole ring and the attached tolyl ring is 86.97 (8) degrees . Weak C-H?N(nitrile) hydrogen bonding, and C-H?pi(aromatic) and short Cl?pi(aromatic) [3.628 (1) A] inter-actions consolidate the crystal packing. PMID- 22199878 TI - 6',7'-Dimeth-oxy-1',2'-dihydro-spiro-[cyclo-hexane-1,2'-quinazolin]-4'(3'H)-one. AB - In the title compound, C(15)H(20)N(2)O(3), prepared from the reaction of 2-amino 4,5-dimeth-oxy-benzonitrile and cyclo-hexa-none, the six-membered diaza ring assumes an envelope conformation. In the crystal, inversion dimers are formed by pairs of N-H?O hydrogen bonds. Futher N-H?O hydrogen bonds link the dimers into a two-dimensional structure parallel to (001). PMID- 22199879 TI - Methyl 4,4''-difluoro-5'-meth-oxy-1,1':3',1''-terphenyl-4'-carboxyl-ate. AB - In the title compound, C(21)H(16)F(2)O(3), the pendant fluoro-benzene rings form dihedral angles of 22.22 (12) and 50.74 (11) degrees with the central benzene ring. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds into chains along the a axis. The crystal structure also features C-H?pi inter-actions. PMID- 22199880 TI - [1,4-Phenyl-enebis(methyl-ene)]bis-(tri-phenyl-phospho-nium) bis-(tetra-fluoro borate). AB - The crystal structure of the title salt, C(44)H(38)P(2) (2+)2BF(4) (-), consists of discrete dications inter-laced with the BF(4) (-) counter-ions. In each cation, both phospho-nium groups lie on the same side of the plane of the central benzene ring. The tetra-fluoro-borate anions are involved in intensive thermal motion, thus some B-F bond lengths [range 1.329 (6) to 1.391 (6) A] deviate significantly from their standard values. PMID- 22199881 TI - N-Benzyl-P-(2-ethyl-phen-yl)-P-phenyl-phosphinic amide. AB - In the crystal structure of the title compound, C(21)H(22)NOP, the amine H atom is involved in N-H?O hydrogen-bonding inter-actions, resulting in chains along the c axis. The crystal lattice is consolidated by weak inter-molecular C-H?pi inter-actions. PMID- 22199882 TI - 4-[(tert-Butyl-dimethyl-sil-yl)-oxy]-6-meth-oxy-7-methyl-5-(oxiran-2-ylmeth-yl)-2 benzofuran-3(1H)-one. AB - The title compound, C(19)H(28)O(5)Si, was obtained in the reaction of 1,3-dihydro 4-[(tert-butyl-dimethyl-sil-yl)-oxy]-6-meth-oxy-7-methyl-3-oxo-5-(prop-2-en yl)isobenzofuran with meta-chloro-perbenzoic acid. This reaction is one of the stages of the total synthesis of mycophenolic acid, which we attempted to modify. The title compound forms crystals with only weak inter-molecular inter-actions. The strongest stacking inter-action is found between the benzene and furan rings of inversion-related mol-ecules with a distance of 3.8773 (13) A between the ring centroids. PMID- 22199883 TI - A new polymorph of 2,6-dimeth-oxy-benzoic acid. AB - A new crystalline form of 2,6-dimeth-oxy-benzoic acid, C(9)H(10)O(4), crystallizing in a tetra-gonal unit cell has been identified during screening for co-crystals. The asymmetric unit comprises a non-planar independent mol-ecule with a synplanar conformation of the carb-oxy group. The sterically bulky o-meth oxy substituents force the carb-oxy group to be twisted away from the plane of the benzene ring by 65.72 (15) degrees . The carb-oxy group is disordered over two sites about the C-C bond [as indicated by the almost equal C-O distances of 1.254 (3) and 1.250 (3) A], the occupancies of the disordered carboxym H atoms being 0.53 (5) and 0.47 (5). In the known ortho-rhom-bic form reported by Swaminathan et al. [Acta Cryst. (1976), B32, 1897-1900], due to the anti-planar conformation adopted by the OH group, the mol-ecular components are associated in the crystal in chains stabilized by linear O-H?O hydrogen bonds. However, in the new tetra-gonal polymorph, mol-ecules form dimeric units via pairs of O-H?O hydrogen bonds between the carb-oxy groups. PMID- 22199884 TI - 4-[(4-Bromo-phen-yl)diazen-yl]-2-eth-oxy-aniline. AB - The title compound, C(14)H(14)BrN(3)O, exhibits a trans geometry about the -N=N- double bond. The dihedral angle between the benzene rings is 24.01 (5) degrees . An intra-molecular N-H?O hydrogen bond occurs. In the crystal, inter-molecular N H?N hydrogen bonds between the amine groups lead to the formation of a C(8) polymeric chain along [101]. PMID- 22199885 TI - (E,E)-N-(2,3,4,5,6-Penta-fluoro-benzyl-idene)-N-(3,4,5-trimeth-oxy-benzyl idene)benzene-1,4-diamine. AB - The title compound, C(23)H(17)F(5)N(2)O(3), forms a layered centrosymmetric crystal structure in which C-H?F inter-actions are responsible for the formation of planar ribbons along [110], meth-oxy-meth-oxy (C-H?O) inter-actions for the formation of layers parallel to [[Formula: see text]13], and OCH(3)?pi and C-F?pi inter-actions for the stacking of these layers. PMID- 22199886 TI - cis-N,N-Bis(2-hy-droxy-benzyl-idene)cyclo-hexane-1,2-diamine. AB - In the title compound, C(20)H(22)N(2)O(2), the cyclo-hexane ring adopts a chair conformation and the two N atoms bonded to salicyl-idene groups are in cis positions. Both hy-droxy groups are involved in intra-molecular O-H?N hydrogen bonding and the two benzene rings form a dihedral angle of 60.5 (1) degrees . PMID- 22199887 TI - 4-Chloro-anilinium perchlorate-18-crown-16 (1/1). AB - In the title compound, C(6)H(7)ClN(+).ClO(4) (-).C(12)H(24)O(6), the cation forms a 1:1 complex with the crown ether, viz [C(6)H(7)ClN-(18-crown-6)](+), in which the -NH(3) (+) unit nests in the crown and inter-acts with it through bifurcated N-H?O hydrogen bonding. All constituents of the structure have crystallographically imposed mirror symmetry except for the H atoms of the -NH(3) (+) group which are disordered across the mirror. PMID- 22199888 TI - N,N'-Dicyclo-pentyl-N'',N''-dimethyl-phospho-ric triamide. AB - The P atom in the title mol-ecule, C(12)H(26)N(3)OP, has a distorted tetra-hedral configuration: its bond angles lie in the range 101.1 (2)-119.1 (2) degrees . The P-N bonds to the two cyclo-pentyl-amido moieties are significantly different [1.619 (4) and 1.643 (4) A], with the shorter bond related to an anti orientation of the lone electron pair of the corresponding N atom relative to the P=O bond. The O atom of the P=O group acts as a double hydrogen-bond acceptor and is involved in two different inter-molecular N-H?O(P) hydrogen bonds, building R(2) (2)(8) rings that are further linked into chains along [001]. PMID- 22199889 TI - 5-Bromo-N-[(E)-(6-bromo-pyridin-2-yl)methyl-idene]pyridine-3,4-diamine. AB - The title compound, C(11)H(8)Br(2)N(4), is a Schiff base obtained from 6-bromo picolinaldehyde and 5-bromo-pyridine-3,4-diamine. The mol-ecule has an E configuration about the C=N bond and the dihedral angle between the two pyridine rings is 14.02 (1) degrees . The observed conformation is stabilised by an intramolecular N-H?N hydrogen bond. In the crystal, mol-ecules are stacked along the b axis and are linked through N-H?N hydrogen bonds into chains along the c axis. PMID- 22199890 TI - 2-Fluoro-6-[(E)-(pyridin-2-yl)imino-meth-yl]phenol. AB - The title compound, C(12)H(9)FN(2)O, is almost planar (r.m.s. deviation for the 16 non-H atoms = 0.019 A), a conformation stabilized by an intra-molecular O-H?N hydrogen bond, which generates an S(6) ring. In the crystal, inversion dimers linked by pairs of C-H?O hydrogen bonds generate R(2) (2)(16) loops. PMID- 22199891 TI - 4-(4-Chloro-benzo-yl)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-chloro-benzoate. AB - In the title compound, C(24)H(16)Cl(2)N(2)O(3), the three benzene rings are twisted with respect to the central pyrazole ring, making dihedral angles of 71.56 (9) (4-chloro-benzo-yloxy), 57.55 (8) (4-chloro-benzo-yl) and 39.33 (1) degrees (phen-yl). PMID- 22199892 TI - O-Phenyl (tert-butyl-amido)(p-tolyl-amido)-phosphinate. AB - In the title mol-ecule, C(17)H(23)N(2)O(2)P, the P atom has a distorted tetra hedral environment. The P-N bond to the tolyl-amido fragment is 1.642 (4) A while that to the butyl-amido fragment is 1.629 (3) A. The dihedral angle between the two benzene rings is 82.3 (2) degrees . In the crystal, adjacent mol-ecules are linked via weak N-H?(O)P and N-H?N hydrogen-bonding inter-actions into an extended chain parallel to the b axis. The three methyl groups of the tert-butyl amido substituent are disordered over two sets of sites with equal occupancies. The crystal studied was found to be a non-merohedral twin with the minor twin component = 23.1 (1)%. PMID- 22199893 TI - 2,2-[(E)-3,3-Diphenyl-prop-2-ene-1,1-di-yl]bis-(3-hy-droxy-cyclo-hex-2-en-1-one). AB - In the title compound, C(27)H(26)O(4), each of the cyclo-hexenone rings adopts a half-chair conformation. The dihedral angle between the two phenyl rings is 89.53 (5) degrees . The hy-droxy and carbonyl O atoms face each other and are orientated to allow the formation of two intra-molecular O-H?O hydrogen bonds, which are typical of xanthene derivatives. PMID- 22199894 TI - 2-[2-(2-Carb-oxy-phen-yl)hydrazinyl-idene]-3-oxo-N-phenyl-butyramide. AB - In the title compound, C(17)H(15)N(3)O(4), the mol-ecule is in the keto-hydrazone form. Intra-molecular N-H?O hydrogen bonds ensure that the mol-ecule is nearly planar (r.m.s. deviation of non-H atoms is 0.098 A), with the two benzene rings forming a dihedral angle of 10.04 (2) degrees . In the crystal, inversion dimers are formed via pairs of O-H?O hydrogen bonds involving the -CO(2)H groups. PMID- 22199895 TI - Butyl 3-oxo-2,3-dihydro-benzo[d][1,2]thia-zole-2-carboxyl-ate. AB - The title compound, C(12)H(13)NO(3)S, was synthesised by the reaction of benzo[d]isothia-zol-3(2H)-one with butyl alcohol in toluene. The benzoisothia zolone ring system is almost planar with a mean deviation of 0.041 (1) A. In the crystal, mol-ecules are linked by weak inter-molecular C-H?O hydrogen bonds. PMID- 22199896 TI - 2-Amino-1,3-thia-zolium dihydrogen phosphate. AB - In the title compound, C(3)H(5)N(2)S(+).H(2)PO(4) (-), the dihydrogen phosphate anions form infinite chains along [001] via short O-H?O hydrogen bonds. The 2 amino-thia-zolium cations inter-connect these chains into a three-dimensional network by short linear or bifurcated N-H?O and weak C-H?O hydrogen bonds. PMID- 22199897 TI - 1-(5,7-Dihy-droxy-2,2-dimethylchroman-6-yl)ethanone. AB - In the title mol-ecule, C(13)H(16)O(4), the pyran ring is in a half-chair conformation. There is an intra-molecular hydrogen bond involving the ketone O atom and an H atom of a phenol group which forms an S(6) ring. The ketone O atom is also involved in an inter-molecular hydrogen bond with a different phenolic H atom of a symmetry-related mol-ecule, forming C(6) chains along the c-axis direction. PMID- 22199898 TI - 5,8-Dibromo-15-cyano-2,11-dithia-[3.3]paracyclo-phane. AB - IN THE TITLE COMPOUND [SYSTEMATIC NAME: 13,15-dibromo-3,10-dithia-tricyclo [10.2.2.2(5,8)]octa-deca-1(14),5,7,12,15,17-hexa-ene-6-carbonitrile], C(17)H(13)Br(2)NS(2), the mean planes of the benzene rings are almost parallel, making a dihedral angle of 1.1 (2) degrees , and the distance between the ring centroids is 3.294 (3) A, which is shorter than the normal packing distance of aromatic rings (about 3.4 A), indicating a strong pi-pi inter-action. The S atom of one bridging chain is disorderd over two positions with site occupancies of 0.605 (4) and 0.395 (4) for the major and minor components, respectively. PMID- 22199899 TI - 1,1-Diethyl-3-(4-meth-oxy-benzo-yl)thio-urea. AB - In the title compound, C(13)H(18)N(2)O(2)S, the 4-meth-oxy-benzoyl fragment is approximately planar [maximum deviation = 0.057 (2) A] and twisted relative to the thio-amide fragment, forming a dihedral angle of 86.62 (6) degrees . The two Csp(2)-Nsp(2) bonds in the thio-urea unit differ significantly in length [1.327 (2) and 1.431 (2) A]. In the crystal, N-H?O hydrogen bonds link the mol-ecules into chains parallel to [010]. PMID- 22199900 TI - Ethyl 7-pivaloyl-amino-1,8-naphthyridine-2-carboxyl-ate sesquihydrate. AB - In the title hydrate, C(16)H(19)N(3)O(3).1.5H(2)O, both water mol-ecules are disordered: one over two adjacent sites in a 0.498 (5):0.502 (5) ratio and one lying near a crystallographic twofold axis. The dihedral angle between the pyridine rings of the organic moleucle is 1.47 (6) degrees . In the crystal, the components are linked by N-H?O, O-H?N and C-H?O hydrogen bonds, forming sheets lying parallel to the ac plane. PMID- 22199901 TI - 1,5-Bis(thio-phen-2-yl)-3-(2,4,5-trimeth-oxy-phen-yl)pentane-1,5-dione. AB - In the title 1,5-diketone compound, C(22)H(22)O(5)S(2), the benzene ring makes dihedral angles of 41.51 (6) and 25.83 (6) degrees with the two thio-phene rings, while the dihedral angle between the thio-phene rings is 26.67 (7) degrees . An intra-molecular C-H?O inter-action generates an S(9) ring motif. In the crystal, mol-ecules are linked into a three-dimensional network by weak C-H?O and C-H?pi inter-actions, and a pi-pi inter-action with a centroid-centroid distance of 3.6527 (8) A. PMID- 22199902 TI - Ethyl 4-acetamido-3-acet-oxy-2-benzyl-3-methyl-butano-ate. AB - The crystal structure of the title compound, C(18)H(25)NO(5), is stabilized by inter-molecular N-H?O hydrogen bonds, which form inversion dimers. The ethyl group is disordered over two positions in a 0.651 (12):0.349 (12) ratio. PMID- 22199903 TI - 2-[(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl-idene]indan-1,3-dione. AB - In the title compound, C(21)H(16)N(2)O(2), the five-membered heterocyclic ring makes a dihedral angle of 47.06 (6) degrees with the attached benzene ring, whereas the indan-1,3-dione ring system and the benzene ring are oriented at a dihedral angle of 21.92 (7) degrees . In the crystal, inversion dimers linked by pairs of C-H?O hydrogen bonds generate R(2) (2)(22) loops. Aromatic pi-pi stacking inter-actions [centroid-centroid distances = 3.8325 (12)-3.8600 (12) A] also occur. PMID- 22199904 TI - (E)-2-(4-Benz-yloxy-2-hy-droxy-benzyl-idene)-N-phenyl-hydrazinecarbothio-amide. AB - The title compound, C(21)H(19)N(3)O(2)S, exists in the thione form. The configuration about the C=N bond is E. The hydrazinecarbothio-amide unit adopts an almost planar arrangement, with maximum deviations of 0.016 (3) and -0.016 (2) A for the two thio-urea N atoms. An intra-molecular O-H?N hydrogen bond occurs. Weak inter-molecular N-H?S, C-H?O and C-H?pi inter-actions are observed in the crystal structure. PMID- 22199905 TI - Tris{2-[(2,6-dimethyl-phen-yl)amino]-eth-yl}amine. AB - The title compound, C(30)H(42)N(4), is an aryl-ated tris-(amino-eth-yl)amine derivative which was obtained by reducing the corresponding tris-amide with AlH(3). The asymmetric unit consists of one third of a C(3v)-symmetric mol-ecule with the tertiary N atom lying on a crystallographic threefold axis. PMID- 22199906 TI - 4-(3-Chloro-phen-yl)-3-[(2,6-difluoro-benz-yl)sulfan-yl]-5-(3,4,5-trimeth-oxy phen-yl)-4H-1,2,4-triazole. AB - In the title compound, C(24)H(20)ClF(2)N(3)O(3)S, the essentially planar triazole ring (r.m.s. deviation = 0.001 A) forms dihedral angles of 22.35 (10), 68.17 (10) and 42.01 (10) degrees with the mean planes of the trimeth-oxy-phenyl, chloro phenyl and difluoro-phenyl rings, respectively. A weak intra-molecular C-H?pi inter-action occurs. In the crystal, mol-ecules are linked into sheets lying parallel to the bc plane by C-H?O and C-H?N hydrogen bonds. The crystal packing also features weak C-H?pi inter-actions. PMID- 22199907 TI - (1E,2E)-1,2-Bis[1-(3-chloro-phen-yl)ethyl-idene]hydrazine. AB - The title mol-ecule, C(16)H(14)Cl(2)N(2), lies on an inversion center. The dihedral angle between the symmetry-related benzene rings is 0.02 (11) degrees . The mean plane of the central C(meth-yl)-C=N-N=C-C(meth-yl) unit forms a dihedral angle of 5.57 (12) degrees with the symmetry-unique benzene ring. PMID- 22199908 TI - N,N'-Dibenzyl-N,N'-dimethyl-N''-(2-phenyl-acet-yl)phospho-ric triamide. AB - The P atom in the title mol-ecule, C(24)H(28)N(3)O(2)P, is in a distorted tetra hedral P(=O)(N)(N)(2) environment. The phosphoryl group and the NH unit adopt a syn orientation with respect to each other and the N atoms have sp(2) character. The P-N bonds in the P(O)[N(CH(3))(CH(2)C(6)H(5))](2) unit are shorter than the P N bond in the C(=O)NHP(=O) fragment. An intra-molecular C-H?O hydrogen bond occurs. In the crystal, pairs of P=O?H-N hydrogen bonds form centrosymmetric dimers. C-H?O contacts are also observed. Four C atoms of two benzene rings are disordered over two alternative sites with an occupancy ratio of 0.523 (12):0.427 (12). PMID- 22199909 TI - 1-Benzyl-6-chloro-indoline-2,3-dione. AB - In the title compound, C(15)H(10)ClNO(2),the dihedral angle between the mean planes of the benzene and 6-chloro-indoline-2,3-dione ring systems, linked through a methyl-ene group, is 81.68 (10) degrees . In the crystal, mol-ecules are connected by C-H?O hydrogen bonds, generating C(6) chains propagating in [010]. PMID- 22199910 TI - 3-(2-Chloro-phen-yl)-4-hy-droxy-furan-2(5H)-one. AB - In the title mol-ecule, C(10)H(7)ClO(3), the butyrolactone core, a furan-2(5H) one, forms a dihedral angle of 59.21 (5) degrees with the benzene ring. In the crystal, two types of hydrogen bonds (O-H?O and C-H?Cl) link mol-ecules into infinite chains along the b axis. pi-pi contacts [centroid-centroid distances = 3.6359 (10) and 3.8776 (11) A] link the chains into a three-dimensional network. PMID- 22199911 TI - N,N,N,N-Tetra-kis(2,3,4,5,6-penta-fluoro-benzo-yl)pyridine-2,6-diamine. AB - The title compound, C(33)H(3)F(20)N(3)O(4), is a highly fluorinated organic imide that was isolated as an unexpected product from the reaction of 2,6-diamino pyridine with 2,3,4,5,6-penta-fluoro-benzoyl chloride in a 1:2 molar ratio. The mol-ecule is located on a twofold axis and one of its symmetry-independent 2,3,4,5,6-penta-fluoro-benzoyl groups is disordered over two sets of sites, the occupancy of the major component being 0.773 (3). In the major component, the dihedral angle between the perfluoro-phenyl groups is 63.64 (10) degrees , and these groups form dihedral angles of 67.14 (7) and 21.1 (2) degrees with the pyridine core. Short inter-molecular C-H?O and C-H?N contacts are found in the crystal structure. PMID- 22199912 TI - Bis[(4-cyano-benz-yl)ammonium] bis-(perchlorate) monohydrate. AB - The asymmetric unit of the title compound, 2C(8)H(9)N(2) (+).2ClO(4) (-).H(2)O, consists of two (4-cyano-benz-yl)>ammonium cations, two disordered ClO(4) (-) anions and one water mol-ecule. The differences in the two cations are reflected in the N-C-C-C torsion angles [-94.7 (3) and -115.9 (3) degrees ]. In addition, the cations show different hydrogen-bonding patterns as one N atom bonds to two O atoms of ClO(4) (-) ions, while the other N atom is involved in hydrogen bonding with the O atoms of the ClO(4) (-) ions and water mol-ecules. In the crystal, N H?O and O-H?O hydrogen bonds result in a three-dimensional network. An O atom in each of the anions is disordered over two positions of equal occupancy. PMID- 22199913 TI - N-[4-(4-Fluoro-phen-yl)-5-hy-droxy-methyl-6-isopropyl-pyrimidin-2-yl]-N-methyl methane-sulfonamide. AB - In the title compound, C(16)H(20)FN(3)O(3)S, the pyrimidine and benzene rings are oriented at a dihedral angle of 38.8 (3) degrees . An intra-molecular C-H?O hydrogen bond occurs. The crystal structure is stabilized by O-H?N hydrogen bonds. In addition, C-H?O inter-actions are also present. PMID- 22199914 TI - Ethyl 4-[(4-chloro-phen-oxy)meth-yl]-2-(4-nitro-phen-yl)-1,3-thia-zole-5-carboxyl ate. AB - The title compound, C(19)H(15)ClN(2)O(5)S, contains two mol-ecules (A and B) in the asymmetric unit. In mol-ecule A, the dihedral angles between the thia-zole ring and the pendant chloro-benzene and nitro-benzene rings are 72.14 (15) and 3.03 (15) degrees , respectively. The corresponding angles for mol-ecule B are 45.56 (16) and 1.51 (14) degrees , respectively. In the crystal, both mol-ecules form inversion dimers linked by pairs of weak C-H?O inter-actions. PMID- 22199915 TI - A monoclinic polymorph with Z = 4 of (E)-2,4-dihy-droxy-acetophenone 2,4-dinitro phenyl-hydrazone N,N-dimethyl-formamide monosolvate. AB - The title compound, C(14)H(12)N(4)O(6).C(3)H(7)NO, is a monoclinic polymorph of an already published structure [Baughman et al. (2004 ?). Acta Cryst. C60, 103 106]. In the previously reported structure, the compound crystallized in the triclinic space group P[Formula: see text] (Z = 2), whereas the structure reported here is monoclinic (P2(1)/n, Z = 4). In both forms, two intra-molecular hydrogen bonds result in the formation of a fairly planar hydrazone skeleton (r.m.s. deviations for all non-H atoms = 0.127 A for the monoclinic from and 0.131 A for the triclinic form) and each mol-ecule is hydrogen bonded to one solvent mol-ecule. The principal difference between the two forms lies in the different orientation of the two mol-ecules. In the monoclinic form, the two mol ecules are almost coplanar [dihedral angle = 3.27 (2) degrees ], whereas in the triclinic form the two mol-ecules are almost mutulally perpendicular (dihedral angle = 85.3 degrees ). PMID- 22199916 TI - rac-4-{(E)-[1-Cyano-1-cyclo-hexyl-2-(1H-indol-3-yl)eth-yl]imino-meth yl}benzonitrile. AB - A phosphine-catalysed addition of gramine to an alkyl-idene-amino-nitrile gives the title compound, C(25)H(24)N(4), in good yield. In the crystal, pairs of mol ecules are connected via N-H?N hydrogen bonds into inversion dimers. The mol ecules are characterized by a planar indole moiety [maximum deviation = 0.012 (1) A], a chair conformation of the cyclo-hexane ring and an anti-periplanar conformation of the H atom on the cyclo-hexane and the adjacent cyano group. PMID- 22199917 TI - 5-[(E)-(5-Bromo-2-hy-droxy-benzyl-idene)amino]-1,3,4-thia-diazole-2(3H)-thione. AB - In the title mol-ecule, C(9)H(6)BrN(3)OS(2), the dihedral angle between the benzene ring and the five-membered ring is 5.5 (3) degrees . An intra-molecular O H?N hydrogen bond forms an S(6) ring motif. In the crystal, N-H?S hydrogen bonds link mol-ecules into centrosymmetric dimers creating R(2) (2)(8) ring motifs. In addition, there are inter-molecular S?S [3.430 (2) A] contacts. The crystal used was a non-merohedral twin with a ratio of 0.113 (3):0.887 (3) for the components. PMID- 22199918 TI - (E)-5-[(3-Eth-oxy-2-hy-droxy-benzyl-idene)amino]-1,3,4-thia-diazole-2(3H)-thione. AB - In the title compound, C(11)H(11)N(3)O(2)S(2), the dihedral angle between the benzene ring and the five-membered ring is 6.85 (9) degrees . An intra-molecular O-H?N hydrogen bond makes an S(6) ring motif. In the crystal, mol-ecules are linked through bifurcated N-H?(O,O) hydrogen bonds with R(1) (2)(5) ring motifs, forming chains along the b axis. A short C?S contact [3.3189 (19) A], which is shorter than the sum of the van der Waals radii of these atoms (3.50 A), occurs in the structure. The crystal structure is further stabilized by C-H?N hydrogen bonding and pi-pi inter-actions [centroid-centroid distance = 3.7649 (12) A]. PMID- 22199919 TI - N'-(4-Meth-oxy-benzyl-idene)-4-methyl-benzohydrazide. AB - The title compound, C(16)H(16)N(2)O(2), is the product of the reaction of 4-meth oxy-benzaldehyde and 4-methyl-benzo-hydrazide. The dihedral angle between the substituted benzene rings is 17.6 (3) degrees and the meth-oxy C atom is almost coplanar with its attached ring [deviation = 0.019 (4) A]. In the crystal, mol ecules are linked by N-H?O hydrogen bonds, forming C(4) chains propagating along the b-axis direction. PMID- 22199920 TI - N'-(2-Hy-droxy-benzyl-idene)-3-methyl-benzohydrazide. AB - The title compound, C(15)H(14)N(2)O(2), is the product of the reaction of 2-hy droxy-benzaldehyde and 3-methyl-benzo-hydrazide. The dihedral angle between the substituted benzene rings is 19.5 (3) degrees and an intra-molecular O-H?N hydrogen bond generates an S(6) ring motif. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds to generate C(4) chains propagating in [001] and C-H?O inter-actions to the same O-atom acceptor reinforce the chains. PMID- 22199921 TI - Isonicotinamide-2-naphthoic acid (1/1). AB - In the title 1:1 adduct, C(6)H(6)N(2)O.C(11)H(8)O(2), the amide group is slightly twisted out of the plane of the aromatic ring, with a C-C-C-N torsion angle of 25.11 (19) degrees , whereas the carb-oxy-lic acid group is approximately coplanar with the bicylic ring system, with a C-C-C-O torsion angle of 10.9 (2) degrees . The amide groups from two isonicotinamide mol-ecules form a dimer via N H?O hydrogen bonds. In addition, the 2-naphthanoic acid mol-ecule is hydrogen bonded to the pyridine unit of an isonicotinamide mol-ecule via an O-H?N hydrogen bond. This gives rise to a centrosymmetric four-mol-ecule chain, which is cross linked by further N-H?O hydrogen bonds from the amide group. PMID- 22199922 TI - (1R,3S)-N-Benzhydryl-2-benzyl-6,7-dimeth-oxy-1-phenyl-1,2,3,4-tetra-hydro isoquinoline-3-carbothio-amide. AB - The title compound, C(38)H(36)N(2)O(2)S, has a heterocyclic ring that assumes a half-chair conformation. The phenyl rings of neighbouring mol-ecules align forming alternating chains parallel to [100] within the crystal packing. The absolute stereochemistry of the crystal was confirmed to be R,S at the 1- and 3 positions, respectively, by proton NMR spectroscopy. A single intra-molecular N H?N hydrogen bond is observed. PMID- 22199923 TI - {5-Chloro-2-[(2-hy-droxy-benzyl-idene)amino]-phen-yl}(phen-yl)methanone. AB - The title Schiff base compound, C(20)H(14)ClNO(2), adopts an E configuration about the azomethine bond. The phenol and chloro-benzene rings form dihedral angles of 84.71 (9) and 80.70 (8) degrees , respectively, with the phenyl ring and are twisted by 15.32 (8) degrees with respect to one another. The mol-ecular conformation is stabilized by an intra-molecular O-H?N hydrogen bond, which forms an S(6) ring motif. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming columns parallel to the a axis. PMID- 22199924 TI - Methyl 5-(4-hy-droxy-3-meth-oxy-phen-yl)-2-(4-meth-oxy-benzyl-idene)-7-methyl-3 oxo-2,3-dihydro-5H-thia-zolo[3,2-a]pyrimidine-6-carboxyl-ate. AB - In the title compound, C(24)H(22)N(2)O(6)S, a pyrimidine ring substituted with 4 hy-droxy-3-meth-oxy-phenyl is fused with a thia-zole ring. The 4-hy-droxy-3-meth oxy-phenyl group is positioned axially to the pyrimidine ring, making a dihedral angle 85.36 (7) degrees . The pyrimidine ring adopts a twist boat conformation. In the crystal, O-H?N inter-actions result in a chain running along the b axis. The carbonyl O atom bonded to the thia-zole ring is involved in two C-H?O hydrogen-bond inter-actions forming centrosymmetric dimers; the ten- and six membered rings resulting from these inter-actions have R(2) (2)(10) and R(1) (2)(6) motifs, respectively. PMID- 22199925 TI - Methyl 4-hy-droxy-1,1-dioxo-2-(2-phenyl-eth-yl)-2H-1lambda,2-benzothia-zine-3 carboxyl-ate. AB - In the title compound, C(18)H(17)NO(5)S, the thia-zine ring adopts a half-chair conformation and the dihedral angle between the aromatic rings is 79.41 (6) degrees . An intra-molecular O-H?O hydrogen bond generates an S(6) ring. In the crystal, mol-ecules are linked by weak C-H?O inter-actions resulting in infinite sheets along the b and c axes. PMID- 22199926 TI - 6-Bromo-2-methyl-sulfanyl-1,3-benzo-thia-zole. AB - The title mol-ecule, C(8)H(6)BrNS(2), is almost planar with a dihedral angle of 0.9 (1) degrees between the benzene and thia-zole rings. The values of the geometry-based index of aromaticity (HOMA) and the nucleus-independent chemical shift (NICS) for the two cyclic fragments of the title mol-ecule are 0.95 and 9.61, respectively, for the benzene ring, and 0.69 and -7.71, respectively, for the thia-zole ring. They show that the benzene ring exhibits substanti-ally higher cyclic pi-electron delocalization than the thia-zole ring. Comparison with other similar benzothia-zole fragments reveals a similar trend. PMID- 22199927 TI - Ethyl 4-[(E)-(2-hy-droxy-benzyl-idene)amino]-piperidine-1-carboxyl-ate. AB - In the title compound, C(15)H(20)N(2)O(3), the piperidine ring adopts a chair conformation, although the amide N atom is almost planar (bond angle sum = 359.7 degrees ). The mol-ecule adopts an E conformation about the C=N bond, which allows for the formation of an intra-molecular O-H?N hydrogen bond. In the crystal, mol-ecules are linked by C-H?O inter-ations, resulting in C(6) chains propagating in [010]. PMID- 22199928 TI - 2,2'-(9,9-Dioctyl-9H-fluorene-2,7-di-yl)bis-(4,4,5,5-tetra-methyl-1,3,2 dioxaborolane). AB - In the title compound, C(41)H(64)B(2)O(4), one of the five-membered rings has an envelope conformation, while the other, which may be affected by disorder, is nearly coplanar with the fluorene ring. The dihedral angle between the fluorene and dioxaborolane rings is 2.29 (1) degrees . Two of the methyl groups are disordered over two orientations in 0.67 (3):0.33 (3) and 0.568 (10):0.432 (10) ratios. PMID- 22199929 TI - Bis[2-(4-amino-phen-yl)-4,5-dihydro-1H-imidazol-3-ium] dichloride monohydrate. AB - The asymmetric unit of the title compound, 2C(9)H(12)N(3) (+).2Cl(-).H(2)O, comprises two mol-ecules, two chloride anions and one mol-ecule of crystal water. In the imidazolinium ring, the protonation contributes to delocalization of the positive charge over the two C-N bonds. Both chloride anions are acceptors of four hydrogen bonds in a flattened tetra-hedron environment. The donors are NH(2) groups, the NH groups of the imidazolinium rings and the water mol-ecule. These hydrogen bonds and N-H?O(H(2)O) hydrogen bonds form a three-dimensional network. PMID- 22199930 TI - N,N-Diethyl-anilinium 2,4-dioxo-5-(2,4,6-trinitro-phen-yl)-1,2,3,4-tetra-hydro pyrimi-din-6-olate. AB - In the crystal structure of the title mol-ecular salt, C(10)H(16)N(+).C(10)H(4)N(5)O(9) (-), the components are linked through a N-H?O hydrogen bonds. R(2) (2)(8) ring motifs are formed between inversion-related barbiturate residues. Two intra-moleculer N-H?O hydrogen bonds are observed in the anion. The dihedral angle between 2,4,6-trinitro-phenyl and barbiturate rings is 53.6 (2) degrees . The N,N-diethyl-amine substituent is disordered and was modeled as two geometrically equivalent conformers with occupancies of 0.737 (2) and 0.273 (2). PMID- 22199931 TI - Ethyl 2-(4-bromo-phen-yl)-1-sec-butyl-1H-benzimidazole-5-carboxyl-ate. AB - In the title compound, C(20)H(21)BrN(2)O(2), the bromo-phenyl ring is twisted by 40.13 (8) degrees from the benzimidazole mean plane and the Br atom deviates by 0.753 (1) A from that plane. The sec-butyl group is disordered over two conformations in a 0.898 (5):0.102 (5) ratio. In the crystal, mol-ecules related by translation along [[Formula: see text]10] are linked into chains via weak C H?Br hydrogen bonds. PMID- 22199932 TI - 4-Eth-oxy-carbonyl-N,N,N-trimethyl-anilinium iodide. AB - In the title molecular salt, C(12)H(18)NO(2) (+).I(-), the C atoms of the ethyl group are disordered over two sets of sites [occupancies of 0.76 (4) and 0.24 (4)]. In the crystal, ion pairs linked by weak C-H?I interactions occur. PMID- 22199933 TI - (2,4-Dipropoxyphen-yl)boronic acid. AB - In the crystal, the title compound, C(12)H(19)BO(4), exists as a centrosymmetric O-H?O hydrogen-bonded dimer. Dimers are linked via C-H?O hydrogen bonds, generating an infinite zigzag chain oriented parallel to [1[Formula: see text]1]. The chains are assembled, giving sheets aligned parallel to (21[Formula: see text]) and inter-connected by weak C-H?pi inter-actions, producing a three dimensional network. PMID- 22199934 TI - 2-(4-Fluoro-phen-yl)-2-oxoethyl 4-meth-oxy-benzoate. AB - In the title compound, C(16)H(13)FO(4), the dihedral angle between the benzene rings is 84.28 (8) degrees . In the crystal, C-H?F and C-H?O hydrogen bonds link the mol-ecules to form a three-dimensional network. The crystal structure is consolidated by C-H?pi inter-actions and short F?F contacts [2.7748 (14) A] also occur. PMID- 22199935 TI - 4-Methyl-2-oxo-2H-chromen-7-yl 4-meth-oxy-benzene-sulfonate. AB - In the title compound, C(17)H(14)O(6)S, the 2H-chromene ring is essentially planar, with a maximum deviation of 0.016 (1) A. The dihedral angle between the 2H-chromene and the benzene rings is 54.61 (5) degrees . The C atom of the meth oxy group is close to coplanar with its attached ring [deviation = 0.082 (2) A]. In the crystal, mol-ecules are connected via C-H?O hydrogen bonds, forming sheets lying parallel to the bc plane. Weak C-H?pi inter-actions are also observed. PMID- 22199936 TI - 1-(6-Fluoro-1,3-benzothia-zol-2-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde. AB - The asymmetric unit of the title compound, C(17)H(10)FN(3)OS, consists of two crystallographically independent mol-ecules. In one mol-ecule, the pyrazole ring makes dihedral angles of 6.51 (7) and 34.02 (9) degrees , respectively, with the terminal 1,3-benzothia-zole ring system and the phenyl ring, while in the other mol-ecule these values are 6.41 (8) and 23.06 (9) degrees . In the crystal, the molecules are linked by weak pi-pi [centroid-centroid distance = 3.7069 (10) A] and C-H?pi inter-actions. PMID- 22199937 TI - Ethyl 1-cyclo-hexyl-5-(4-meth-oxy-phen-yl)-1H-pyrazole-4-carboxyl-ate. AB - In the title compound, C(19)H(24)N(2)O(3), the benzene ring forms a dihedral angle of 65.34 (7) degrees with the pyrazole ring. The cyclo-hexane ring adopts a chair conformation. In the crystal, mol-ecules are linked into a inversion dimers by pairs of C-H?O hydrogen bonds, generating R(2) (2)(22) ring motifs. PMID- 22199938 TI - 1,3-Bis(2-cyano-benz-yl)imidazolium bromide. AB - In the title salt, C(19)H(15)N(4) (+).Br(-), the central imidazole ring makes dihedral angles of 83.1 (2) and 87.6 (2) degrees with the terminal benzene rings. The dihedral angle between the terminal benzene rings is 6.77 (19) degrees ; the cyanide substituents have an anti orientation. In the crystal, the cations and anions are linked via C-H?N and C-H?Br hydrogen bonds, forming sheets lying parallel to the ac plane. PMID- 22199939 TI - Glutaric acid-2-(pyridin-4-yl)-1H-benzimidazole (1/1). AB - The crystal structure of the title co-crystal, C(12)H(9)N(3).C(5)H(8)O(4), N-H?O and O-H?N hydrogen bonds link the components. There are also pi-pi stacking inter actions between the imidazole rings, between the imidazole and pyridine rings and between the pyridine and benzene rings [centroid-centroid distances = 3.643 (2), 3.573 (2) and 3.740 (1)A, respectively]. PMID- 22199940 TI - 3,3'-Bis(3-meth-oxy-benz-yl)-1,1'-(ethane-1,2-diyl)-diimidazolium dibromide dihydrate. AB - In the title compound, C(24)H(28)N(4)O(2) (2+).2Br(-).2H(2)O, the diimid-azo-lium cation is located on an inversion center. The imidazole and the benzene rings make a dihedral angle of 68.08 (04) degrees . In the crystal, O-H?Br, C-H?O and C H?Br hydrogen bonds link the diimidazolium cations, the bromide anions and the water mol-ecules into a two-dimensional network. PMID- 22199941 TI - 3-[4-(10H-Indolo[3,2-b]quinolin-11-yl)piperazin-1-yl]propan-1-ol. AB - In the title compound, C(22)H(24)N(4)O, the aromatic moiety is essentially planar (r.m.s. deviation of a least-squares plane fitted through all non-H atoms = 0.0386 A) and is rotated by 89.98 (4) degrees from the piperazine ring, which adopts the expected chair conformation. The propanol chain is not fully extended away from the piperazine ring. In the crystal, there are two unique hydrogen bonding inter-actions. One is an O-H?N inter-action which, together with an inversion-related symmetry equivalent, forms a ring motif. The second is an N-H?N inter-action which links adjacent mol-ecules by means of a chain motif which propagates in the c-axis direction. Overall, a two-dimensional hydrogen-bonded structure is formed. PMID- 22199942 TI - N,N',N''-Tricyclo-hexyl-guanidinium iodide. AB - In the title compound, C(19)H(36)N(3) (+).I(-), the orientation of the cyclo hexyl rings around the planar (sum of N-C-N angles = 360 degrees ) CN(3) (+) unit produces steric hindrance around the N-H groups. As a consequence of this particular orientation of the tricyclo-hexyl-guanidinium cation (hereafter denoted CHGH(+)), hydrogen bonding is restricted to classical N-H?I and non clasical (cyclo-hex-yl)C-H?I hydrogen bonds. The propeller CHGH(+) cation and the oriented hydrogen-bonding interactions lead to a three-dimensional supra molecular structure. PMID- 22199943 TI - (Z)-1-(2,4-Difluoro-phen-yl)-2-(1H-1,2,4-triazol-1-yl)ethanone oxime. AB - In the title compound, C(10)H(8)F(2)N(4)O, the dihedral angle between the rings is 65.4 (1) degrees . In the crystal, inter-molecular O-H?N and C-H?F hydrogen bonds link the mol-ecules in a stacked arrangement along the a and c axes, respectively. PMID- 22199944 TI - 2-[(6-Nitro-1,3-benzodioxol-5-yl)methyl-idene]malononitrile. AB - In the title compound, C(11)H(5)N(3)O(4), the nitro group is rotated by 29.91 (16) degrees out of the plane of the adjacent aryl ring. The 1,3-benzodioxole ring is nearly planar, with a maximium deviation of 0.0562 (10) A. The dioxolene ring adopts an envelope conformation on the O-C-O C atom. In the crystal, mol ecules are linked via C-H?O inter-actions, resulting in R(2) (2)(6) and R(2) (2)(12) graph-set motifs. PMID- 22199945 TI - Dehydro-leucodin: a guaiane-type sesquiterpene lactone. AB - Dehydro-leucodin [systematic name: (1S,6S,2R)-9,13-dimeth-yl-5-methyl-ene-3 oxatricyclo-[8.3.0.0(2,6)]trideca-9,12-diene-4,11-dione], C(15)H(16)O(3), is a guanolide isolated from Artemisia douglasiana. The fused-ring system contains a seven-membered ring that adopts a chair conformation, a fused planar cyclo pentenone ring and a five-membered lactone ring fused in envelope conformation. The absolute structure determined by X-ray analysis agrees with that previously assigned to this compound by NMR studies [Bohlmann & Zdero (1972 ?). Tetra-hedron Lett.13, 621-624] and also with that of leucodine, a closely related guaianolide [Martinez et al. (1988 ?). J. Nat. Prod.51, 221-228]. PMID- 22199946 TI - N'-[(E)-(3-Phenyl-1H-pyrazol-4-yl)methyl-idene]naphtho-[2,1-b]furan-2 carbohydrazide monohydrate. AB - In the title hydrate, C(23)H(16)N(4)O(2).H(2)O, the pyrazole ring is approximately planar, with a maximum deviation of 0.023 (1) A, and makes dihedral angles of 28.63 (6) and 46.44 (7) degrees with the naphtho-[2,1-b]furan ring system and the benzene ring, respectively, In the crystal, O-H?N, O-H?O, N-H?O, N H?N, C-H?O and C-H?N hydrogen bonds link the mol-ecules, forming sheets lying parallel to the ab plane. The crystal structure also features C-H?pi inter actions involving the centroids of the pyrazole and benzene rings. PMID- 22199947 TI - 2-Trifluoro-methyl-1H-benzimidazol-3-ium hydrogen sulfate. AB - In the crystal of the title mol-ecular salt, C(8)H(6)F(3)N(2) (+).HSO(4) (-), cation-to-anion N-H?O hydrogen bonds generate [100] chains. Anion-to-anion O-H?O hydrogen bonds generate [001] helices and cross-link the chains into a three dimensional network. PMID- 22199948 TI - (E)-1-(5-Bromo-thio-phen-2-yl)-3-(3,4,5-trimeth-oxy-phen-yl)prop-2-en-1-one. AB - In the title compound, C(16)H(15)BrO(4)S, the dihedral angle between the thio phene and benzene rings is 13.08 (16) degrees . The C atoms of the meta meth-oxy groups of the substituted benzene ring lie close to the plane of the ring [displacements = 0.049 (5) and -0.022 (4) A], whereas the para-C atom is significantly displaced [-1.052 (4) A]. In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds, forming C(11) chains propagating in [100]. PMID- 22199949 TI - 2-Amino-pyridinium 5-(5-chloro-2,4-dinitro-phen-yl)-1,3-dimethyl-2,4-dioxo 1,2,3,4-tetra-hydro-pyrimidin-6-olate. AB - In the title mol-ecular salt, C(5)H(7)N(2) (+).C(12)H(8)ClN(4)O(7) (-), the dihedral angle between the aromatic rings of the anion is 51.88 (6) degrees . One of the nitro groups is disordered over two orientations in a 0.710 (6):0.290 (6) ratio. In the crystal, the cations and anions are linked by N-H?O hydrogen bonds, generating infinite ribbons extending along [100] which incorporate R(4) (4)(22) ring motifs. Weak C-H?O inter-actions also occur. PMID- 22199950 TI - (Z)-2-(5-Methyl-2-oxoindolin-3-yl-idene)-N-phenyl-hydrazinecarbothio-amide. AB - In the title compound, C(16)H(14)N(4)OS, the dihedral angle between the nine membered 5-methyl-indolin-2-one ring system and the benzene ring is 10.21 (7) degrees . Intra-molecular cyclic N-H?O and C-H?S hydrogen-bonding inter-actions [graph set S(6)] are present within the N-N-C-N chain between the ring systems. In the crystal, mol-ecules form centrosymmetric cyclic dimers through pairs of N H?O hydrogen bonds [graph set R(2) (2)(8)]. PMID- 22199951 TI - 1,4-Bis[(2,2':6',2''-terpyridin-4'-yl)-oxy]butane. AB - The title compound, C(34)H(28)N(6)O(2), has an inversion centre located at the mid-point of the central C-C bond of the diether bridging unit. The central pyridine rings of the terpyridyl units and the diether chain are co-planar: the maximum deviation from the 18-atom mean plane defined by the bridging unit and the central pyridyl ring is for the pyridyl N atom which sits 0.055 (1) A above the plane. The dihedral angles between the terminal pyridine rings with this plane are 10.3 (1) and 37.6 (1) degrees , repectively. In the crystal, weak C-H?N inter-actions link the mol-ecules into infinite chains parallel to the a axis. PMID- 22199952 TI - 5-Methyl-12-phenyl-sulfonyl-12H-naphtho-[1,2-b]carbazole. AB - In the title compound, C(27)H(19)NO(2)S, the naphtho-carbazole unit is approximately planar (r.m.s. deviation = 0.002 A) except for the N atom, which is displaced by 0.122 (1) A out of the mean plane. The dihedral angle between the naphtho-carbazole mean plane and the phenyl ring of the phenyl-sulfonyl substituent is 83.16 (3) degrees . An inter-molecular C-H?pi inter-action involving the phenyl group and the pyrrole ring is observed in the crystal structure. PMID- 22199953 TI - Dimethyl 2,6-dimethyl-4-phenyl-pyridine-3,5-dicarboxyl-ate. AB - In the title compound, C(17)H(17)NO(4), the dihedral angle between the benzene and pyridine rings is 75.51 (4) degrees . The benzene and pyridine rings are both approximately planar (r.m.s. deviations of 0.0040 and 0.0083 A, respectively), indicating that the pyridine N atom is not protonated. The crystal structure is stabilized by weak inter-molecular C-H?O and C-H?N inter-actions. PMID- 22199954 TI - 2-Meth-oxy-N-[(S)-3-methyl-butan-2-yl]-6-{[(S)-3-methyl-butan-2-yl]amino}-3,5 dinitro-benzamide. AB - The title compound, C(18)H(28)N(4)O(6), crystallizes with two mol-ecules in the asymmetric unit which differ slightly in conformation. The dihedral angle between the amide plane and the benzene ring are 72.6 (2) and 66.8 (2) degrees in the two mol-ecules. A strong intra-molecular N-H?O hydrogen bond between the amino and nitro groups occurs in each mol-ecule. The crystal structure features two symmetry-independent polymeric chains along [010] generated by N-H?O hydrogen bonds between the amide groups. PMID- 22199955 TI - 2-Bromo-4-tert-butyl-6-[(pyridin-2-yl-imino)-meth-yl]phenol. AB - In the title compound, C(16)H(17)BrN(2)O, the pyridine and benzene rings are almost coplanar [dihedral angle = 1.3 (2) degrees ]. An intra-molecular O-H?Br inter-action forms an S(5) ring motif. PMID- 22199956 TI - 4-[(2-Hy-droxy-naphthalen-1-yl)(morpholin-4-yl)meth-yl]benzonitrile. AB - The title compound, C(22)H(20)N(2)O(2), was synthesized via a multicomponent reaction using naphthalen-2-ol, morpholine and 4-formyl-benzonitrile. The dihedral angle between the naphthalene ring system and the benzene ring is 81.25 (10) degrees . The morpholine ring adopts a chair conformation. The mol-ecular conformation is stabilized by intra-molecular O-H?N and C-H?O hydrogen bonds. In the crystal, inter-molecular C-H?N hydrogen bonds link mol-ecules into helical chains running parallel to the c axis. PMID- 22199957 TI - 3-(2-Eth-oxy-phen-yl)-1-(3-nitro-phen-yl)triaz-1-ene. AB - The title compound, C(14)H(14)N(4)O(3), exhibits a trans geometry about the N=N double bond in the triazene unit. The mol-ecule is approximately planar (r.m.s. deviation = 0.044 A for all non-H atoms). An intra-molecular N-H?O hydrogen bond occurs. In the crystal, C-H?N hydrogen bonds lead to the formation of dimers which are, in turn, connected to each other by C-H?O hydrogen bonds, forming infinite chains of R(2) (2)(8) graph-set motif. PMID- 22199958 TI - Methyl 2-(4-chloro-3,5-dinitro-benz-amido)-acetate. AB - The title mol-ecule, C(10)H(8)ClN(3)O(7), is twisted with the dihedral angle between the amide and benzene ring being 38.75 (11) degrees . The C-N-C-C torsion angle between the amide and acetyl groups is -150.1 (2) degrees . Finally, each nitro group is twisted out of the plane of the benzene ring to which it is connected [O-N-C-C torsion angles = 34.0 (3) and -64.5 (3) degrees ]. Linear supra-molecular chains along [010] and mediated by N-H?O hydrogen bonds between successive amide groups dominate the crystal packing. The chains are consolidated into the three-dimensional structure by C-H?O contacts. PMID- 22199959 TI - N-[(E)-Anthracen-9-yl-methyl-idene]-3,4-dimethyl-1,2-oxazol-5-amine. AB - In the title compound, C(20)H(16)N(2)O, an intra-molecular C-H?N forms an S(6) ring motif. In the crystal, the mol-ecules are stacked with their anthracene ring planes in sheets along [100]. PMID- 22199960 TI - Benzyl 5-phenyl-pyrazolo-[5,1-a]isoquino-line-1-carboxyl-ate. AB - In the title compound, C(25)H(18)N(2)O(2), the pyrazolo-[5,1-a]iso-quin-oline ring system is approximately planar [maximum deviation = 0.027 (2) A] and is oriented at dihedral angles of 57.22 (6) and 71.36 (7) degrees with respect to the two phenyl rings. The phenyl rings are twisted to each other by a dihedral angle of 66.33 (8) degrees . A weak intra-molecular C-H?O hydrogen bond occurs. In the crystal, weak C-H?pi inter-actions are present. PMID- 22199961 TI - N-(3-Chloro-benzo-yl)-2-methyl-benzene-sulfonamide. AB - In the title compound, C(14)H(12)ClNO(3)S, the N-H bond in the C-SO(2)-NH-C(O) segment is anti to the C=O bond. Further, the C=O bond and the meta-Cl atom in the benzoyl ring are also anti to each other. The dihedral angle between the sulfonyl and the benzoyl benzene rings is 72.4 (1) degrees . In the crystal, mol ecules are linked by pairs of N-H?O hydrogen bonds, forming inversion dimers. PMID- 22199962 TI - 2-Chloro-5-({[5-(4-meth-oxy-phen-yl)-1,3,4-oxadiazol-2-yl]-sulfanyl}-meth yl)pyridine. AB - In the title compound, C(15)H(12)ClN(3)O(2)S, the central oxadiazole ring forms dihedral angles of 7.72 (14) and 69.86 (12) degrees with the benzene and pyridine rings, respectively. The crystal packing is governed only by van der Waals inter-actions. PMID- 22199963 TI - N-(Phenyl-sulfon-yl)naphtho-[2,1-b]furan-1-carboxamide. AB - In the title compound, C(19)H(13)NO(4)S, the mol-ecule is twisted at the S atom with a C-S-N-C torsion angle of -65.2 (2) degrees between the benzene ring and the -SO(2)-NH-C=O segment. The dihedral angle between the benzene and the naphtho furan ring system is 83.3 (1) degrees . In the crystal, mol-ecules are linked by N-H?O hydrogen bonds into chains running along the c axis. An intra-molecular N H?O(furan) inter-action is also observed. PMID- 22199964 TI - tert-Butyl 6-oxo-2,7-diaza-spiro[4.4]nonane-2-carboxyl-ate. AB - In the title mol-ecule, C(12)H(20)N(2)O(3), both five-membered rings are in envelope conformations. In the crystal, N-H?O hydrogen bonds link the mol-ecules into chains along [010]. PMID- 22199965 TI - 2,9,16,23-Tetra-kis(1-methyl-eth-yl)-5,6,11,12,13,14,19,20,25,26,27,28 dodecadehydro-tetra-benzo[a,e,k,o]cyclo-eicosene. AB - The title compound, C(48)H(40), is a tetra-isopropyl-substituted polyannulenoenyne. The unsubstituted polyannulenoenyne, C(36)H(16) (CSD: RICVEE; CAS: 186494-87-1), has quasi-D(2) (222) symmetry, as determined by least-squares fit (excluding H atoms) to a model optimized in D(2) symmetry by mol-ecular mechanics (r.m.s. deviation = 0.239 A). The least-squares fits of 36 common C atoms of the title compound (at 90 K) to the parent (at 295 K) and to the optimized model show r.m.s. deviations of 0.419 and 0.426 A, respectively. PMID- 22199966 TI - (5RS,10SR,15RS)-Trimethyl-truxene. AB - The title mol-ecule, C(30)H(24), was prepared as a possible precursor to buckminsterfullerene cages. The two enanti-omers adopt the anti configuration, with one S/R and two R/S methyl groups, one anti to the other two. The truxene framework is slightly non-planar: with respect to the central six-ring mean plane, the three methyl C atoms are 1.377 (3), -1.475 (3) and 1.515 (3) A distant, whereas the respective proximate peripheral six-ring mean planes make dihedral angles of 6.27 (6), 3.45 (7) and -7.37 (7) degrees . PMID- 22199967 TI - (2R,3R)-1-(4-Chloro-phen-yl)-2-[(S)-2-nitro-1-phenyl-eth-yl]-3-phenyl-pentan-1 one. AB - The title compound, C(25)H(24)ClNO(3), has three contiguous chiral centres. The absolute structure was determined by anomalous dispersion. The chloro-benzene ring is inclined to the two phenyl rings by 14.98 (9) and 59.05 (9) degrees . The two phenyl rings are inclined to one another by 49.51 (10) degrees . In the crystal, neighbouring mol-ecules are linked via C-H?O hydrogen bonds, forming chains propagating along [010]. There is also a C-H?pi inter-action present that leads to the formation of a three-dimensional network. PMID- 22199968 TI - N-(2,3-Dimethyl-phen-yl)-2-methyl-benzamide. AB - In the title compound, C(16)H(17)NO, the two aromatic rings make a dihedral angle of 5.9 (2) degrees , while the central amide core -NH-C(=O)- is twisted by 44.0 (3) and 47.1 (3) degrees out of the planes of the 2,3-dimethyl-phenyl and 2 methyl-phenyl rings, respectively. In the crystal, N-H?O hydrogen bonds link the mol-ecules into infinite chains running along the b axis. PMID- 22199969 TI - 1-Benzoyl-4-(4-methyl-phen-yl)phthal-azine. AB - In the title mol-ecule, C(22)H(16)N(2)O, the tolyl and benzoyl rings make dihedral angles 50.2 (5) and 56.4 (5) degrees , respectively, with the phthalazine ring system while the dihedral angle between the tolyl and benzoyl rings is 0.70 (4) degrees . The crystal structure is stabilized by inter molecular C-H?O and C-H?N hydrogen bonds, as well as weak C-H?pi inter-actions. PMID- 22199970 TI - 2,3-Diamino-pyridinium 3-chloro-benzo-ate-3-chloro-benzoic acid (1/1). AB - The asymmetric unit of the title compound, C(5)H(8)N(3) (+).C(7)H(4)ClO(2) ( ).C(7)H(5)ClO(2), contains an ion pair and a 3-chloro-benzoic acid mol-ecule. In the cation, the pyridine N atom is protonated. In the crystal, the components are connected via N-H?O, O-H?O and C-H?O hydrogen bonds, thereby forming sheets lying parallel to (100). PMID- 22199971 TI - (E)-1-[1-(2-Chloro-phen-yl)ethyl-idene]-2-(2,4-dinitro-phen-yl)hydrazine. AB - The title mol-ecule, C(14)H(11)ClN(4)O(4), is in an E configuration and is twisted with the dihedral angle between the two benzene rings being 38.48 (8) degrees . The ethyl-idenehydrazine plane makes dihedral angles of 6.03 (10) and 44.04 (11) degrees , respectively, with the dinitro- and chloro-substituted benzene rings. The two nitro groups are essentially coplanar with the bound benzene ring, making dihedral angles of 0.9 (2) and 1.65 (18) degrees . An intra molecular N-H?O hydrogen bond generates an S(6) ring motif. In the crystal, mol ecules are linked by a weak C-H?O inter-action into a chain along the c axis. The chains are further stacked along the b axis by a pi-pi inter-action with a centroid-centroid distance of 3.6088 (10) A. PMID- 22199972 TI - 5-(4-Meth-oxy-phen-yl)-3-(pyridin-2-yl)-4,5-dihydro-1H-pyrazole-1-carbothio amide. AB - In the title compound, C(16)H(16)N(4)OS, the dihedral angle between the pyridine and benzene rings is 81.08 (6) degrees . The pyrazole ring makes dihedral angles of 12.36 (7) and 87.96 (6) degrees , respectively, with the pyridine and benzene rings. In the crystal, mol-ecules are linked by N-H?O and N-H?S hydrogen bonds and a weak C-H?S inter-action into a layer parallel to the ab plane. Weak C-H?pi and pi-pi inter-actions [centroid-centroid distances = 3.7043 (9) and 3.8120 (7) A] are also observed. PMID- 22199973 TI - 2-[2-(2-Hy-droxy-eth-oxy)phen-yl]-4,4,5,5-tetra-methyl-2-imidazoline-1-oxyl 3 oxide. AB - In the title compound, C(15)H(21)N(2)O(4), the nitronyl nitroxide unit displays a twisted conformation. The crystal structure is stabilized by non-classical C-H?O and C-H?pi hydrogen bonds, which build up a three-dimensional network. PMID- 22199974 TI - 2-(4-Fluoro-phen-yl)-3-isopropyl-sulfinyl-5,6-methyl-enedi-oxy-1-benzofuran. AB - In the title compound, C(18)H(15)FO(4)S, the fluoro-benzene ring makes a dihedral angle of 4.3 (1) degrees with the mean plane of the benzofuran fragment. In the crystal, mol-ecules are linked by weak inter-molecular C-H?O hydrogen bonds. The O atom of the sulfinyl group is disordered over two orientations, with site occupancy factors of 0.940 (3) and 0.060 (3). PMID- 22199975 TI - 1-Bromo-2-[(E)-2-nitro-ethen-yl]benzene. AB - In the title compound, C(8)H(6)BrNO(2), the dihedral angle between the planes of the benzene ring and the nitro group is 22.99 (12) degrees . In the crystal, inversion dimers associated by pairs of short Br?O contacts [3.2319 (17) A] occur. PMID- 22199976 TI - 2-Methyl-12H-benzimidazo[2,1-b][1,3]benzothia-zin-12-one. AB - In the title compound, C(15)H(10)N(2)OS, prepared by the reaction of 2-iodo-5 methyl-benzoyl chloride with 2-mercaptobenzimidazole, the four-membered fused ring system is essentially planar [maximum deviation from the least-squares plane = 0.137 (6) A]. The crystal packing is stabilized by weak inter-molecular pi-pi inter-actions [minimum ring centroid separation = 3.536 (4) A] and weak C-H?pi inter-actions. PMID- 22199977 TI - N,N'-Bis(3,3-dimethyl-all-yl)-N,N'-(prop-ane-1,3-diyl)dibenzene-sulfonamide. AB - In the title compound, C(25)H(34)N(2)O(4)S(2), the conformation of the linking N C-C-C-N chain is gauche-anti [torsion angles = -68.49 (19) and 167.95 (14) degrees ]. The dihedral angle between the aromatic rings is 89.64 (6) degrees . PMID- 22199978 TI - (E)-2-Cyano-3-(2,3-dimeth-oxy-phen-yl)acrylic acid. AB - The asymmetric unit of the title compound, C(12)H(11)NO(4), contains two mol ecules. In the crystal, neighbouring mol-ecules are linked together by O-H?O hydrogen bonds into dimers. The dimers are arranged into columns parallel to the a axis, meditated by pi-pi inter-actions [centroid-centroid distances = 3.856 (3) and 3.857 (3) A]. The crystal structure is further stabilized by weak inter molecular C-H?O inter-actions. The crystal studied was a non-merohedral twin with a ratio of the twin components of 0.657 (11):0.343 (11). PMID- 22199979 TI - 1,3-Dimethyl-5-(3-methyl-phen-oxy)-1H-pyrazole-4-carbaldehyde. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(13)H(14)N(2)O(2), in which the dihedral angles between the substituted phenyl ring and the pyrazole ring are 86.5 (2) and 82.3 (3) degrees . The crystal packing features weak inter-molecular C-H?O inter-actions. PMID- 22199980 TI - Methyl (Z)-2-{[N-(2-formyl-phen-yl)-4-methyl-benzene-sulfonamido]-meth-yl}-3 phenyl-prop-2-enoate. AB - In the title compound, C(25)H(23)NO(5)S, the sulfonyl-bound benzene ring forms dihedral angles of 37.2 (1) and 67.0 (1) degrees , respectively, with the formyl phenyl and phenyl rings. The mol-ecular conformation is stabilized by an intra molecular C-H?pi inter-action. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming a two-dimensional network in the (110) plane in which R(4) (4)(38) ring motifs are generated. PMID- 22199981 TI - 2,2'-(3,3'-Dihexyl-2,2'-bithio-phene-5,5'-di-yl)bis-(4,4,5,5-tetra-methyl-1,3,2 dioxaborolane). AB - In the title mol-ecule, C(32)H(52)B(2)O(4)S(2), the two thio-phene rings are twisted by 67.34 (2) degrees . In the crystal, weak C-H?O hydrogen bonds link mol ecules related by translation along the a axis into chains. PMID- 22199982 TI - 1-Cyclo-hexyl-5-(4-meth-oxy-phen-yl)-1H-pyrazole-4-carb-oxy-lic acid. AB - In the title compound, C(17)H(20)N(2)O(3), the meth-oxy-phenyl unit is disordered over two sets of sites in a 0.715 (4):0.285 (4) ratio. The pyrazole ring forms dihedral angles of 55.88 (16) and 72.6 (4) degrees with the benzene rings of its major and minor components, respectively. The cyclo-hexane ring adopts a chair conformation and its C-N bond is in an equatorial orientation. In the crystal, mol-ecules are linked into inversion dimers by pairs of O-H?O hydrogen bonds, generating R(2) (2)(8) loops. PMID- 22199983 TI - (2E)-3-(3-Bromo-4-meth-oxy-phen-yl)-1-(4,4''-difluoro-5'-meth-oxy-1,1':3',1'' terphenyl-4'-yl)prop-2-en-1-one. AB - In the title compound, C(29)H(21)BrF(2)O(3), the dihedral angles between the central anisole ring and the pendant fluoro-benzene rings are 48.86 (19) and 31.89 (18) degrees . The dihedral angle between the anisole ring and the 1-bromo 2-meth-oxy-benzene ring linked via the enone bridge is 82.95 (17) degrees . In the crystal, C-H?O hydrogen bonds link the mol-ecules into C(11) chains propagating along [010]. PMID- 22199984 TI - N-Benzoyl-3-nitro-benzene-sulfonamide. AB - In the title compound, C(13)H(10)N(2)O(5)S, the dihedral angle between the phenyl and benzene rings is 86.7 (1) degrees . In the crystal, mol-ecules are linked into zigzag C(4) chains running along the b axis via N-H?O hydrogen bonds. PMID- 22199985 TI - 1',6-Dimethyl-4'-phenyl-dispiro-[1-benzopyran-3(4H),3'-pyrrolidine-2',3'' indoline]-2,2''-dione. AB - In the title compound, C(27)H(24)N(2)O(3), the five-membered pyrroldine ring adopts an envelope conformation (with the N atom in the flap position) and the six-membered pyran-one ring of the coumarine ring system adopts a slightly distorted boat conformation. The oxindole unit makes dihedral angles of 89.7 (1) and 25.6 (1) degrees , respectively, with the pyrrolidine ring and the coumarin ring system. The mol-ecular structure is stabilized by two intra-molecular C-H?O contacts and two intra-molecular pi-pi inter-actions [centroid-centroid seperations of 3.514 (1) and 3.623 (1) A]. The crystal packing features N-H?O hydrogen bonds, which link the mol-ecules into cyclic centrosymmetric R(2) (2)(8) dimers, and C-H?pi inter-actions. PMID- 22199986 TI - (E)-5-[(2-Hy-droxy-3-meth-oxy-benzyl-idene)amino]-1,3,4-thia-diazole-2(3H) thione. AB - In the title compound, C(10)H(9)N(3)O(2)S(2), the dihedral angle between the benzene ring and the five-membered ring is 1.54 (13) degrees . An intra-molecular O-H?N hydrogen bond makes an S(6) ring. In the crystal, mol-ecules are linked together through bifurcated N-H?(O,O) hydrogen bonds having R(1) (2)(5) ring motifs, forming chains along the b axis. The crystal structure also features pi pi inter-actions, with centroid-centroid distances of 3.699 (3)-3.767 (3) A. PMID- 22199987 TI - 1-(4-Methyl-benz-yl)-2-(4-methyl-phen-yl)-1H-benzimidazole. AB - The title compound, C(22)H(20)N(2), crystallizes with two independent mol-ecules (A and B) in the asymmetric unit. The benzimidazole units are almost planar [maximum deviations = 0.0161 (8) A for A and 0.0276 (8) A for B]. The dihedral angles between the benzimidazole unit and the benzene rings of the 4-methyl benzyl and 4-methyl-phenyl groups are 76.64 (3) and 46.87 (4) degrees , respectively, in mol-ecule A. The corresponding values in mol-ecule B are 86.31 (2) and 39.14 (4) degrees . The dihedral angles between the planes of the two benzene rings are 73.73 (3) and 80.69 (4) degrees in mol-ecules A and B, respectively. Pairs of weak inter-molecular C-H?N hydrogen bonds link B mol ecules, forming centrosymmetric dimers with R(2) (2)(8) ring motifs. There are no significant corresponding inter-actions involving the A mol-ecules. PMID- 22199988 TI - (4R,6S,7S,8S,8aS)-6-Ethyl-7,8-dihy-droxy-4-methyl-1,2,3,5,6,7,8,8a-octa-hydro indolizin-4-ium iodide. AB - The title compound, C(11)H(22)NO(2) (+).I(-), is a chiral mol-ecule with five stereogenic centres. The absolute configuration was assigned from the synthesis and confirmed by the structure determination. The central six-membered ring of the indolizine system adopts a chair conformation, with two atoms displaced by 0.690 (2) and 0.550 (2) A from the plane of the other four atoms. The conformation of the pyrrolidine ring is close to that of an envelope, with the flap atom displaced by 0.563 (2) A from the plane of the remaining four atoms. In the crystal, there are two O-H?I hydrogen bonds. PMID- 22199989 TI - Design of Biomolecular Interfaces using Liquid Crystals Containing Oligomeric Ethylene Glycol. AB - We report an investigation of nematic LCs formed from miscible mixtures of 4 cyano-4'-pentylbiphenyl (5CB) and 2-(2-[2-{2-(2,3-difluoro-4-{4-(4-trans pentylcyclohexyl)-phenyl-phenoxy)ethoxy}ethoxy]ethoxy)ethanol (EG4-LC), the latter being a mesogen with a tetra(ethylene glycol) tail. Quantitative characterization of the ordering of this LC mixture at biologically-relevant aqueous interfaces revealed that addition of EG4-LC (1-5% by weight) to 5CB causes a continuous transition in the ordering of the LC from a planar (pure 5CB) to a perpendicular (homeotropic) orientation. The homeotropic ordering is also seen in aqueous dispersions of micrometer-sized droplets of the LC mixture, which exhibit enhanced stability against coalescence. These observations and others, all of which suggest partitioning of the EG4-LC from the bulk of the LC to its aqueous interface, were complemented by measurements of the adsorption of bovine serum albumin (BSA) to the aqueous-LC interface. Whereas adsorption of BSA to the interface of a LC mixture containing 1% wt/wt of EG4-LC triggered an ordering transition, higher concentrations of EG4-LC (>2% wt/wt) prevented this ordering transition, consistent with a decrease in adsorption of BSA. This conclusion is supported by epifluorescence measurements using fluorescently labeled BSA and comparisons to LC interfaces at which EG4-containing lipids are adsorbed. Overall, these results demonstrate a general and facile approach to the design of LCs with interfaces that present biologically relevant chemical functional groups, assume well-defined orientations at aqueous interfaces, and lower non specific protein adsorption. The bulk of the LC serves as a reservoir of EG4-LC, thus permitting easy preparation of these interfaces and the potential for spontaneous repair of the EG4-decorated interfaces during contact with biological systems. PMID- 22199990 TI - You never call, you never write: why return of 'omic' results to research participants is both a good idea and a moral imperative. AB - The rapid emergence of whole-genome and whole-exome sequencing of research participants has helped to revive the debate about whether genetic and other 'omic' data should be returned to research participants, and if so, which data, under what circumstances and by whom. While partial disclosure of such data has been justified in cases where participants' lives and health are threatened, full disclosure appears to remain beyond the pale for most researchers and bioethicists. I argue that it should not be and that the objections to full disclosure short-sightedly favor near-term considerations over long-term benefits. Return of genomic data to those who want it, even if a difficult undertaking and even if the meaning of the data is unclear, engages participants in science and the research enterprise, and positions them to be better stewards of their own health and wellbeing. PMID- 22199991 TI - Genomic information as a behavioral health intervention: can it work? AB - Individuals can now obtain their personal genomic information via direct-to consumer genetic testing, but what, if any, impact will this have on their lifestyle and health? A recent longitudinal cohort study of individuals who underwent consumer genome scanning found minimal impacts of testing on risk reducing lifestyle behaviors, such as diet and exercise. These results raise an important question: is personal genomic information likely to beneficially impact public health through motivation of lifestyle behavioral change? In this article, we review the literature on lifestyle behavioral change in response to genetic testing for common disease susceptibility variants. We find that only a few studies have been carried out, and that those that have been done have yielded little evidence to suggest that the mere provision of genetic information alone results in widespread changes in lifestyle health behaviors. We suggest that further study of this issue is needed, in particular studies that examine response to multiplex testing for multiple genetic markers and conditions. This will be critical as we anticipate the wide availability of whole-genome sequencing and more comprehensive phenotyping of individuals. We also note that while simple communication of genomic information and disease susceptibility may be sufficient to catalyze lifestyle changes in some highly motivated groups of individuals, for others, additional strategies may be required to prompt changes, including more sophisticated means of risk communication (e.g., in the context of social norm feedback) either alone or in combination with other promising interventions (e.g., real-time wireless health monitoring devices). PMID- 22199993 TI - Informal Taxation. AB - Informal payments are a frequently overlooked source of local public finance in developing countries. We use microdata from ten countries to establish stylized facts on the magnitude, form, and distributional implications of this "informal taxation." Informal taxation is widespread, particularly in rural areas, with substantial in-kind labor payments. The wealthy pay more, but pay less in percentage terms, and informal taxes are more regressive than formal taxes. Failing to include informal taxation underestimates household tax burdens and revenue decentralization in developing countries. We discuss various explanations for and implications of these observed stylized facts. PMID- 22199992 TI - Cardiovascular Disease Risk Factors and Cognition in the Elderly. AB - While it is relatively widely known that cardiovascular disease (CVD) can result in cognitive decline, it is becoming increasingly clearer that actual risk factors for CVD, such as high blood pressure, diabetes, and obesity are also associated with alterations to brain structure and cognition. The prevalence of CVD risk factors increase exponentially with age and are often overlooked as a source of cognitive changes that are otherwise thought to be part of the 'normal' aging process. Associated cognitive changes are observed even at levels of risk that would be considered subclinical by current diagnostic convention, and are often significant enough to interfere with daily functional abilities. More importantly, if not controlled, CVD risk can lead to further decline, including cerebrovacsular disease and dementia. Thus, it is critically important to consider these factors in the elderly and we recommend more routine cognitive screenings, particularly when CVD risk factors are involved. PMID- 22199994 TI - Genetic variability in EGFR, Src and HER2 and risk of colorectal adenoma and cancer. AB - The EGFR signaling pathway is involved in carcinogenesis at multiple sites, particularly colorectal cancer, and is a target of colorectal cancer chemotherapy. EGFR signaling is linked to pro-carcinogenic mechanisms, including cell proliferation, survival, angiogenesis, and more recently prostaglandin synthesis. Genetic variability in this pathway has not yet been studied in relation to colorectal carcinogenesis. In three case-control studies of colorectal adenoma (n=485 cases/578 controls), colon cancer (n=1424 cases/1780 controls) and rectal cancer (n=583 cases/775 controls), we investigated associations between candidate SNPs, tagSNPs and haplotypes in EGFR signaling (EGFR, Src, and HER2) and risk. We also examined associations with tumor subtypes: TP53 and KRAS2 mutations, CpG island methylator phenotype, and microsatellite instability. All three studies were genotyped using an identical Illumina GoldenGate assay, allowing thorough investigation of genetic variability across stages and locations of colorectal neoplasia. The EGFR tagSNP 142572T>C (rs3752651) CC genotype was associated with a suggested increased risk for both colon (OR: 1.40; 95% CI: 1.00-1.96; p-trend=0.04) and rectal cancer (OR: 1.39; 95% CI: 0.81-2.41; p-trend=0.65). In tumor subtype analyses, the association was limited to TP53-mutated colon tumors. Using the Chatterjee 1 df Tukey test to assess gene-gene interactions, we observed a statistically significant (p<0.01) interaction between SNPs in EGFR and Src for colorectal adenoma risk. The association with EGFR 142572 should be investigated in additional studies and the significant gene-gene interaction between EGFR and Src in relation to adenoma risk suggests that these two genes are jointly affecting early stages in colorectal carcinogenesis and requires further follow-up. PMID- 22199996 TI - Tumor necrosis factor-related genes and colon and rectal cancer. AB - Tumor necrosis factor-alpha (TNF) is a promoter of inflammation. Genes in the TNF pathway include tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), TNF receptor-associated factor 2 (TRAF2), mitogen activated protein kinase 8 (MAPK8), 14 (MAPK14), and mitogen activated protein kinase kinase kinase 7 (MAP3K7), nuclear factor of activated-T-5 (NFAT5) cells and NFAT activated protein with ITAM motif 1 {NFAM1). Data from population-based studies of colon cancer (cases=1,555; controls=1,956) and rectal cancer (cases=754; controls=959) were used. We observed that MAP3K7 rs13208824 was associated with reduced colon cancer risk (OR 0.83, 95% CI 0.71, 0.98 dominant model), TNF rs1800630 was associated with an increased colon cancer risk (OR 1.19 95% CI 1.03, 1.38 for CA/AAvsCC), and TNFRSF1A rs4149570 was associated with reduced risk (OR 0.79 95% CI 0.64, 0.96 TTvsGG). For rectal cancer MAPK8 rs10508901 was associated with increased risk (OR 1.45 95% CI 1.05, 1.99 AA vs CC/CA; NFAT5 (rs12447326 and rs16959025) was associated with a 40% reduced risk for the recessive model. Aspirin/NSAID interacted with MAP3K7 (colon cancer) and with MAPK14, NFAT5, and TRAF2 (rectal cancer); smoking cigarettes interacted with NFAM1 and NFAT2 (colon cancer) and MAPK8, NFAT5, and TNFRSF1A (rectal cancer); BMI interacted with NFAM1 and NFAT5 (colon cancer) and with MAPK8 and TNFRSF1A (rectal cancer). A genotype summary score showed a threefold increased risk of dying with higher mutational load. Although few independent associations were detected, aspirin/NSAID, cigarette smoking, and BMI influenced genes in this pathway. These data suggest pathways through which TNF-signaling operates. PMID- 22199995 TI - The causal roles of vitamin B(12) and transcobalamin in prostate cancer: can Mendelian randomization analysis provide definitive answers? AB - Circulating vitamin B(12) (cobalamin/B(12)) and total transcobalamin (tTC) have been associated with increased and reduced risk, respectively, of prostate cancer. Mendelian randomization has the potential to determine whether these are causal associations. We estimated associations of single nucleotide polymorphisms in B(12)-related genes (MTR, MTRR, FUT2, TCN2, TCN1, CUBN, and MUT) with plasma concentrations of B(12), tTC, holo-transcobalamin, holo-haptocorrin, folate, and homocysteine and with prostate cancer risk in a case-control study (913 cases, 895 controls) nested within the UK-wide population-based ProtecT study of prostate cancer in men age 45-69 years. Instrumental variable (IV) analysis was used to estimate odds ratios for effects of B(12) and tTC on prostate cancer. We observed that B(12) was lower in men with FUT2 204G>A (rs492602), CUBN 758C>T (rs1801222) and MUT 1595G>A (rs1141321) alleles (P(trend)<0.001); tTC was lower in men with the TCN2 776C>G (rs1801198) allele (P(trend)<0.001). FUT2 204G>A and CUBN 758C>T were selected as instruments for B(12); TCN2 776C>G for tTC. Conventional and IV estimates for the association of log(e)(B(12)) with prostate cancer were: OR=1.17 (95% CI 0.90-1.51), P=0.2 and OR=0.60 (0.16-2.15), P=0.4, respectively. Conventional and IV estimates for the association of loge(tTC) with prostate cancer were: OR=0.81 (0.54-1.20), P=0.3 and OR=0.41 (0.13-1.32), P=0.1, respectively. Confidence intervals around the IV estimates in our study were too wide to allow robust inference. Sample size estimates based on our data indicated that Mendelian randomization in this context requires much larger studies or multiple genetic variants that explain all of the variance in the intermediate phenotype. PMID- 22199997 TI - Epidemiologic Investigation of Extra-intestinal pathogenic E. coli (ExPEC) based on PCR phylogenetic group and fimH single nucleotide polymorphisms (SNPs) in China. AB - Using the combination method with PCR phylogrouping and fimH SNPs analysis, this study investigates the epidemiology of Extra-intestinal pathogenic E. coli in China. 116 E. coli strains including (74 from Urine, 39 from other extra intestinal sources and 3 references strains) were collected. The bacteria Genomic DNA were extracted; phylogroup and the fimH gene amplifications were determined by two-step triplex PCR-based phylogrouping and simple PCR amplification assay respectively. Finally the fimH SNPs analysis and phylogenetic analysis and construction of tree were carried out using DNAMAN Version 6.0.3.93 and MEGA4, ClustalW and CLC Bio software respectively for 50 E. coli strains isolated from clinical sample and 3 references; K-12 E. coli strain was used as reference comparison. For E. coli strains phylogroup, 25% (28/113) were observed to belong to the group A, 15% (17/113) to the group B1, 14% (16/113) to the group B2, and 46% (52/113) to the group D. 75% (85/113) were fimH positive. fimH SNPs analysis for 50 isolated from clinical sample and 3 references found 60 SNPs at 57 polymorphic sites. The number of amino-acid variants and silent SNPs were observed more in UPEC strains than in other extra-intestinal E. coli strains. Most of the UPEC strains with the same amino-acid variants were belong to the same phylogroup. This combination method could serve as a rapid, highly reproducible typing test for epidemiological studies of ExPEC. Large collection data could be compared with other clinical laboratories that the sequence data are accessible. PMID- 22199998 TI - Interaction between IGF-1 polymorphisms and overweight for the risk of pancreatic cancer in Japanese. AB - Although several reports have described a possible association between insulin like growth factors-1 (IGF-1) and pancreatic cancer (PC) risk, this association has not been evaluated in the non-Caucasian population. To assess the impact of IGF-1 polymorphisms on PC risk in Japanese, we conducted a case-control study which compared the frequency of ten single nucleotide polymorphisms (SNPs) and haplotypes of IGF-1. SNPs were investigated using the TaqMan method in 176 patients with PC and 1402 control subjects. Exposure to risk factors was assessed from the results of a self-administered questionnaire. Associations and gene environment interactions were examined using an unconditional logistic regression model. We did not observe any significant main effect of IGF-1 loci, but did find interactions between rs5742714 and past and/or current body-mass index (BMI) status. Among patients with BMI > 25 at age 20, an increased PC risk was observed with the addition of the minor allele for rs5742714 (trend P = 0.048) and rs6214 (P = 0.043). Among patients with current BMI > 25, an increased or decreased PC risk was observed with the addition of the minor allele for rs5742714 (trend P = 0.046), rs4764887 (P = 0.031) and rs5742612 (P = 0.038). Haplotype analysis of IGF-1 showed a significant association among patients who were either or both previously or currently overweight. These findings suggest that IGF-1 polymorphisms may affect the development of PC in the Japanese population in combination with obesity. Further studies to confirm these findings are warranted. PMID- 22200000 TI - Biomarkers of inflammation and hemostasis associated with left ventricular mass: The Multiethnic Study of Atherosclerosis (MESA). AB - PURPOSE: Biomarkers of inflammation and hemostasis have been associated with left ventricular (LV) mass. We studied relationships of C-reactive protein (CRP), interleukin-6 (IL6), D-dimer, soluble intercellular adhesion molecule-1 (sICAM 1), plasminogen activator inhibitor 1 (PAI-1), soluble thrombomodulin (sTM), soluble tumor necrosis factor type 1 receptor (sTNFR1), von Willebrand factor (vWF), soluble E-selectin (sE-selectin), factor VIII, fibrinogen, matrix metalloproteinase 3 (MMP3), and matrix metalloproteinase 9 (MMP9) with LV mass in an asymptomatic population. Multi-Ethnic Study of Atherosclerosis participants underwent magnetic resonance imaging to characterize LV mass; biomarkers were measured using standardized protocols (N = 763 to 4979). Adjusted models were used to associate each biomarker with LV mass while correcting for potential confounding. FINDINGS: LV mass was associated with many biomarkers after adjustment for demographic characteristics and traditional cardiovascular risk factors. Although the demographic and risk factor adjustments attenuated the association of CRP and IL6 with LV mass, further adjustment for weight changed regression coefficients from positive to negative for CRP and IL6 for LV mass. sTM, Factor VIII, and vWF were directly associated with LV mass in fully-adjusted models. For sTNFR1, sICAM-1, D-dimer, fibrinogen, and PAI-1, adjustment for risk factors and weight rendered associations with LV mass nonsignificant. CONCLUSIONS: In this large cohort free of clinical cardiovascular disease, several hemostasis and inflammation markers were associated with LV mass. The unusual finding of a negative relationship of CRP and IL6 with LV mass only after adjustment for weight suggests that the effects of inflammation on LV mass are strongly influenced by obesity. PMID- 22200001 TI - Broad consent and biorepositories for molecular epidemiology and genomics research. PMID- 22199999 TI - Superparamagnetic iron oxide nanoparticles: promises for diagnosis and treatment of cancer. AB - During the last decade, significant scientific research efforts have led to a significant growth in understanding of cancer at the genetic, molecular, and cellular levels providing great opportunities for diagnosis and treatment of cancer diseases. The hopes for fast cancer diagnosis and treatment were significantly increased by the entrance of nanoparticles to the medical sciences. Nanoparticles are attractive due to their unique opportunities together with negligible side effects not only in cancer therapy but also in the treatment of other ailments. Among all types of nanoparticles, surface-engineered superparamagnetic iron oxide nanoparticles (SPIONs) have been attracted a great attention for cancer therapy applications. This review covers the recent advances in the development of SPIONs together with their opportunities and challenges, as theranosis agents, in cancer treatment. PMID- 22200002 TI - Molecular epidemiology of beta-thalassemia in Pakistan: far reaching implications. AB - beta-thalassaemia, an autosomal recessive hemoglobinopathy, is one of the commonest genetically transmitted disorders throughout the world. Collective measures including carrier identification, genetic counseling and prenatal diagnosis are required for preventing beta-thalassemia. To achieve this objective, Identification of the spectrum of genetic mutations, especially for various ethnic backgrounds in Pakistan is necessary. Therefore, we designed a cross sectional prospective study to identify the frequency of various gene mutations in different ethnic groups of Pakistan. Over a 5-year period, DNA from 648 blood samples [including specimens of chorionic villus sampling (CVS)] were analyzed for the twelve most common beta-thalassemia mutations found in the Pakistani population by a Multiplex amplification refractory mutation system (ARMS). The most common mutation identified was Intervening Sequence 1-5 (IVS 1-5 (G-C)); accounting for 40.89% mutated alleles, and was represented in all ethnic groups. 15.7 % of the beta-thalassemia alleles were found to have Frameshift 8-9 (Fr 8-9) as the second most common mutation Other common genetic defects responsible for beta-thalassemia: IVS 1-1 (G-T) was found in 8.17%, Codon-30 (Cd 30 (G-C)) 8.02%, Codon-5(Cd-5 (-CT)) contributed 2.16% and Deletion 619 base pair (Del 619bp) affected 11.11% were found in Pakistan. This large study adds to the pre-existing data in Pakistan. Knowledge of the predominant mutation in a given ethnic group will not only help in developing a short panel of (population specific) primers of mutations thereby providing a cost-effective method for prenatal diagnosis and also help the clinicians to counsel regarding blood transfusion regimen/ pregnancy termination. PMID- 22200003 TI - The influence of tumour necrosis factor- alpha (TNF-alpha) on amyloid-beta (Abeta)-degrading enzymes in vitro. AB - Pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha), are increased in serum and CSF in Alzheimer's disease (AD). We investigated the effect of TNF-alpha on gene and protein expression levels of Abeta degrading enzymes (ACE, ECE-1, ECE- 2, IDE and NEP) in vitro. Differentiated (DC) and non differentiated (NDC) neuroblastoma cells (SH-SY5Y) were exposed to TNF-alpha for 15 minutes and 3 hours and protein and gene expression levels measured using western blotting or sandwich ELISA (ECE-2), and real time-PCR (RT-PCR). Only ECE 2 protein levels decreased significantly in NDCs in a dose-dependent manner after 15 minutes of TNF-alpha exposure but reverted to basal levels after 3 hours. Basal NEP gene expression levels were higher in control DCs compared to NDCs but TNF-alpha treatment did not significantly alter the levels of expression of any of the Abeta degrading enzymes. In conclusion, apart from a transient reduction in ECE-2 protein levels, TNF-alpha had no impact in our in vitro experimental system on transcription or translation of any of our selected mediators of Abeta degradation. PMID- 22200004 TI - Permselectivity Replication of Artificial Glomerular Basement Membranes in Nanoporous Collagen Multilayers. AB - Basement membranes (BMs) play important roles in many biological functions such as tissue regeneration, cancer proliferation, nutrient/drug delivery, breathing, and many others. While there are many theoretical models, adequate experimental analogs of BMs describing basic physicochemical properties of BM, such as diffusion and permselectivity are not available. Taking BMs found in glomerulus of kidneys as an example, adequate reproduction of their permselectivity requires biomimetic membranes with submicron thickness, high uniformity, nanoscale porosity, and size-selective permeability. Artificial kidney BMs were assembled from poly(acrylic acid) and collagen using layer-by-layer (LBL) assembly technology and display multiple structural similarities with glomerular BMs. Diffusional transport through the artificial BMs faithfully replicate cut-off parameters of kidney membranes. Their utilization in understanding of unique diffusion processes in kidneys, in vitro studies of blood clearance time of small drugs/nanoscale drug carriers and design of more complex organoids including live cells for cancer proliferation studies is anticipated. PMID- 22200005 TI - Characterization of the Structure and Dynamics of the HDV Ribozyme at Different Stages Along the Reaction Path. AB - The structure and dynamics of the hepatitis delta virus ribozyme (HDVr) are studies using molecular dynamics simulations at several stages along its catalytic reaction path, including reactant, activated precursor, transition state mimic and product states, departing from an initial structure based on the C75U mutant crystal structure (PDB: 1VC7). Results of five 350 ns molecular dynamics simulations reveal a spontaneous rotation of U-1 that leads to an in line conformation and support the role of protonated C75 as the general acid in the transition state. Our results provide rationale for the interpretation of several important experimental results, and make experimentally testable predictions regarding the roles of key active site residues that are not obvious from any available crystal structures. PMID- 22200006 TI - Five-factor model personality disorder prototypes in a community sample: self- and informant-reports predicting interview-based DSM diagnoses. AB - The need for an empirically validated, dimensional system of personality disorders is becoming increasingly apparent. While a number of systems have been investigated in this regard, the five-factor model of personality has demonstrated the ability to adequately capture personality pathology. In particular, the personality disorder prototypes developed by Lynam and Widiger (2001) have been tested in a number of samples. The goal of the present study is to extend this literature by validating the prototypes in a large, representative community sample of later middle-aged adults using both self and informant reports. We found that the prototypes largely work well in this age group. Schizoid, Borderline, Histrionic, Narcissistic, and Avoidant personality disorders demonstrate good convergent validity, with a particularly strong pattern of discriminant validity for the latter four. Informant-reported prototypes show similar patterns to self reports for all analyses. This demonstrates that informants are not succumbing to halo representations of the participants, but are rather describing participants in nuanced ways. It is important that informant reports add significant predictive validity for Schizoid, Antisocial, Borderline, Histrionic, and Narcissistic personality disorders. Implications of our results and directions for future research are discussed. PMID- 22200007 TI - Radiological apoplexy and its correlation with acute clinical presentation, angiogenesis and tumor microvascular density in pituitary adenomas. AB - OBJECTIVE: Pituitary apoplexy is life-threatening clinical syndrome caused by the rapid enlargement of a pituitary tumor due to hemorrhage and/or infarction. The pathogenesis of pituitary apoplexy is not completely understood. We analyzed the magnetic resonance imaging (MRI) of pituitary tumors and subsequently correlated the radiological findings with the clinical presentation. Additionally, immunohistochemistry was also performed to determine whether certain biomarkers are related to radiological apoplexy. METHODS: Thirty-four cases of pituitary adenoma were enrolled for retrospective analysis. In this study, the radiological apoplexy was defined as cases where hemorrhage, infarction or cysts were identified on MRI. Acute clinical presentation was defined as the presence of any of the following symptoms: severe sudden onset headache, decreased visual acuity and/or visual field deficit, and acute mental status changes. Angiogenesis was quantified by immunohistochemical expression of fetal liver kinase 1 (Flk-1), neuropilin (NRP) and vascular endothelial growth factor (VEGF) expression, while microvascular density (MVD) was assessed using Endoglin and CD31. RESULTS: Clinically, fourteen patients presented with acute symptoms and 20 for mild or none clinical symptoms. Radiologically, fifteen patients met the criteria for radiological apoplexy. Of the fifteen patients with radiologic apoplexy, 9 patients presented acute symptoms whereas of the 19 patient without radiologic apoplexy, 5 patients presented acute symptoms. Of the five biomarkers tracked, only VEGF was found to be positively correlated with both radiological and nonradiological apoplexy. CONCLUSION: While pituitary apoplexy is currently defined in cases where clinical symptoms can be histologically confirmed, we contend that cases of radiologically identified pituitary hemorrhages that present with mild or no symptoms should be designated subacute or subclinical apoplexy. VEGF is believed to have a positive correlation with pituitary hemorrhage. Considering the high rate of symptomatic or asymptomatic pituitary tumor hemorrhage, additional studies are needed to detect predictors of the pituitary hemorrhage. PMID- 22200008 TI - Activation of matrix metalloproteinases-9 after photothrombotic spinal cord injury model in rats. AB - OBJECTIVE: Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9 have been known to play an important role in secondary inflammatory reaction after spinal cord injury (SCI). The aim of this study was to investigate the expression and activity of MMP-2 and MMP-9 and to determine their relationship with disruption of endothelial blood-barrier after photochemically induced SCI in rats. METHODS: Female Sprague-Dawley rats, weighing between 250 and 300 g (aged 8 weeks) received focal spinal cord ischemia by photothrombosis using Rose Bengal. Expressions and activities of MMP-2 and MMP-9 were assessed by Western blot and gelatin zymography at various times from 6 h to 7 days. Endothelial blood-barrier integrity was assessed indirectly using spinal cord water content. RESULTS: Zymography and Western blot analysis demonstrated rapid up-regulation of MMP-9 protein levels in spinal cord after ischemic onset. Expressions and activities of MMP-9 showed a significant increased at 6 h after the photothrombotic ischemic event, and reached a maximum level at 24 h after the insult. By contrast, activated MMP-2 was not detected at any time point in either the experimental or the control groups. When compared with the control group, a significant increase in spinal cord water content was detected in rats at 24 h after photothrombotic SCI. CONCLUSION: Early up-regulation of MMP-9 might be correlated with increased water content in the spinal cord at 24 h after SCI in rats. Results of this study suggest that MMP-9 is the key factor involved in disruption of the endothelial blood-barrier of the spinal cord and subsequent secondary damage after photothrombotic SCI in rats. PMID- 22200009 TI - Polymorphisms of integrin, alpha 6 contribute to the development and neurologic symptoms of intracerebral hemorrhage in korean population. AB - OBJECTIVE: The extracellular matrix (ECM) and cell adhesion molecules play crucial roles in angiogenesis, apoptosis, thrombosis, and inflammation, and also contribute to the pathogenesis of stroke. Integrin, alpha 6 (ITGA6) is a member of ECM adhesion receptors. We investigated whether two single nucleotide polymorphisms (SNPs) (rs11895564, Ala380Thr; rs2293649, Asp694Asp) of ITGA6 were associated with the development and clinical phenotypes of intracerebral hemorrhage (ICH) and ischemic stroke (IS). METHODS: We enrolled 199 stroke (78 ICH and 121 IS) and 291 control subjects. Stroke patients were divided into subgroups according to the scores of the National Institutes of Health Stroke Survey (NIHSS, <6 and >=6) and Modified Barthel Index (MBI, <60 and >=60). SNPStats, SNPAnalyzer, and Helixtree programs were used to calculate odds ratios, 95% confidence intervals, and p values. Multiple logistic regression models were used to analyze genetic data. RESULTS: A missense SNP rs11895564 was associated with the development of ICH (p=0.026 in codominant2, p=0.013 in recessive, p=0.02 in log-additive models; p=0.041 in allele distributions). The A allele frequency of rs11895564 was higher in the ICH group (13.5%) than in the control group (8.1%). In the clinical phenotypes, rs11895564 and rs2293649 showed significant associations in the MBI scores of IS (p=0.014 in codominant1 model; p=0.02 in allele distributions) and NIHSS scores of ICH (p=0.017 in codominant2, p=0.035 in recessive, p=0.035 in log-additive models), respectively. CONCLUSION: These results suggest that ITGA6 may be associated with the development and clinical phenotypes of stroke in Korean population. PMID- 22200010 TI - Gamma knife radiosurgery for brainstem metastasis. AB - OBJECTIVE: Brainstem metastases are rarely operable and generally unresponsive to conventional radiation therapy or chemotherapy. Recently, Gamma Knife Radiosurgery (GKRS) was used as feasible treatment option for brainstem metastasis. The present study evaluated our experience of brainstem metastasis which was treated with GKRS. METHODS: Between November 1992 and June 2010, 32 patients (23 men and 9 women, mean age 56.1 years, range 39-73) were treated with GKRS for brainstem metastases. There were metastatic lesions in pons in 23, the midbrain in 6, and the medulla oblongata in 3 patients, respectively. The primary tumor site was lung in 21, breast in 3, kidney in 2 and other locations in 6 patients. The mean tumor volume was 1,517 mm(3) (range, 9-6,000), and the mean marginal dose was 15.9 Gy (range, 6-23). Magnetic Resonance Imaging (MRI) was obtained every 2-3 months following GKRS. Follow-up MRI was possible in 24 patients at a mean follow-up duration of 12.0 months (range, 1-45). Kaplan-Meier survival analysis was used to evaluate the prognostic factors. RESULTS: Follow-up MRI showed tumor disappearance in 6, tumor shrinkage in 14, no change in tumor size in 1, and tumor growth in 3 patients, which translated into a local tumor control rate of 87.5% (21 of 24 tumors). The mean progression free survival was 12.2 months (range, 2-45) after GKRS. Nine patients were alive at the completion of the study, and the overall mean survival time after GKRS was 7.7 months (range, 1-22). One patient with metastatic melanoma experienced intratumoral hemorrhage during the follow-up period. Survival was found to be associated with score of more than 70 on Karnofsky performance status and low recursive partitioning analysis class (class 1 or 2), in terms of favorable prognostic factors. CONCLUSION: GKRS was found to be safe and effective for management of brainstem metastasis. The integral clinical status of patient seems to be important in determining the overall survival time. PMID- 22200012 TI - The Comparison of Outcome between Thromboaspiration and Aggressive Mechanical Clot Disruption in Treating Hyperacute Stroke Patients. AB - OBJECTIVE: Stroke is the third leading cause of death in the Republic of Korea. Time is the most important factor in hyperacute stroke. Yet, there had been no protocol for mechanical thrombolysis. We have treated patients with hyperacute stroke by mechanical thrombolysis for 3 years. In current study, we analyzed the outcome of mechanical thrombolysis. METHODS: From March 2008 to February 2011, 36 patients were treated with mechanical thrombolysis. Initially we treated the patients by aggressive mechanical clot disruption (AMCD) who were admitted within 6 hours after the symptom onset. If revascularization was not achieved, balloon angioplasty was performed, followed by stenting or temporary endovascular bypass was performed. The result in 15 cases was not so successful. Since then, we started using the thromboaspiration method as the first line treatment of the mechanical thrombolysis. RESULTS: After using the thromboaspiration, we had better results in recanalization rate, modified Rankin Score (mRS) and reperfusion injury compared to AMCD. The recanalization rate was 80.85%, mRS is 2.85, and there was only 0.09% hemorrhagic formation. CONCLUSION: Even though thromboaspiration is not statistically significant due to the limited numbers of patients enrolled in this study, we think it is a good way in mechanical thronbolysis for hyperacute stroke. PMID- 22200011 TI - Leukoencephalopathy and disseminated necrotizing leukoencephalopathy following intrathecal methotrexate chemotherapy and radiation therapy for central nerve system lymphoma or leukemia. AB - OBJECTIVE: Intrathecal methotrexate (MTX) therapy combined with whole brain radiotherapy (WBRT) is one of the major treatment modalities for leukemia and lymphoma involving the central nervous system (CNS). The purpose of this study was to retrospectively determine the incidences of leukoencephalopathy and disseminated necrotizing leukoencephalopathy (DNL) following intrathecal MTX therapy for CNS lymphoma or leukemia and to assess the potential risk factors. METHODS: Between January 2000 and August 2009, 143 patients with CNS lymphoma or leukemia received intrathecal MTX therapy alone or in combination with WBRT at a single institution. Patients were followed up clinically and radiologically at regular two- or three-month intervals. Medical records were reviewed to obtain information regarding the patients' demographics, medical histories, radiologic characteristics, treatments, and clinical courses. RESULTS: On follow-up MR images, leukoencephalopathy was found in 95 of 143 patients (66.4%). The median time to develop leukoencephalopathy was 6.6 months. Among those with leukoencephalopathy, four patients showed seven extensive white-matter changes with strongly enhancing lesions demonstrating DNL. Histological confirmation was done in six lesions of three patients and radiological diagnosis alone in one patient. Four lesions spontaneously disappeared on MR images without any treatment, with a mean duration of 14 months before disappearance of DNL. CONCLUSION: Leukoencephalopathy is a common phenomenon that occurs following intrathecal MTX therapy; however, DNL occurs at a very low incidence. For newly developed enhancing lesions, consideration for the occurrence of DNL should be taken to avoid unnecessary invasive procedures or therapies. PMID- 22200013 TI - Accuracy and Safety of Bedside External Ventricular Drain Placement at Two Different Cranial Sites : Kocher's Point versus Forehead. AB - OBJECTIVE: External ventricular drain (EVD) is commonly performed with a freehand technique using surface anatomical landmarks at two different cranial sites, Kocher's point and the forehead. The aim of this study was to evaluate and compare the accuracy and safety of these percutaneous ventriculostomies. METHODS: A retrospectively review of medical records and head computed tomography scans were examined in 227 patients who underwent 250 freehand pass ventriculostomy catheter placements using two different methods at two institutions, between 2003 and 2009. Eighty-one patients underwent 101 ventriculostomies using Kocher's point (group 1), whereas 146 patients underwent 149 forehead ventriculostomies (group 2). RESULTS: In group 1, the catheter tip was optimally placed in either the ipsilateral frontal horn or the third ventricle, through the foramen of Monro (grade 1) in 82 (81.1%) procedures, in the contralateral lateral ventricle (grade 2) in 4 (3.9%), and into eloquent structures or non-target cerebrospinal space (grade 3) in 15 (14.8%). Intracerebral hemorrhage (ICH) >1 mL developed in 5 (5.0%) procedures. Significantly higher incidences of optimal catheter placements were observed in group 2. ICH>1 mL developed in 11 (7.4%) procedures in group 2, showing no significant difference between groups. In addition, the mean interval from the EVD to ventriculoperitoneal shunt was shorter in group 2 than in group 1, and the incidence of EVD-related infection was decreased in group 2. CONCLUSION: Accurate and safe ventriculostomies were achieved using both cranial sites, Kocher's point and the forehead. However, the forehead ventriculostomies provided more accurate ventricular punctures. PMID- 22200014 TI - Urgent recanalization with stenting for severe intracranial atherosclerosis after transient ischemic attack or minor stroke. AB - OBJECTIVE: Stenting of symptomatic intracranial stenosis has recently become an alternative treatment modality. However, urgent intracranial stenting in patients with intracranial stenosis following a transient ischemic attack (TIA) or minor stroke is open to dispute. We sought to assess the feasibility, safety, and effectiveness of urgent intracranial stenting for severe stenosis (>70%) in TIA or minor stroke patients. METHODS: Between June 2009 and October 2010, stent assisted angioplasty by using a balloon-expandable coronary stent for intracranial severe stenosis (>70%) was performed in 7 patients after TIA and 5 patients after minor stroke (14 stenotic lesions). Technical success rates, complications, angiographic findings, and clinical outcomes were retrospectively analyzed. RESULTS: Stenting was successful in all 12 patients. The mean time from symptom onset to stenting was 2.1 days (1-8 days). Post-procedural angiography showed restoration to a normal luminal diameter in all patients. In-stent thrombosis occurred in one patient (n=1, 8.3%), and was lysed with abciximab. No device-related complications, such as perforations or dissections at the target arteries or intracranial hemorrhaging, occurred in any patient. The mortality rate was 0%. No patient had an ischemic event over the mean follow-up period of 12.5 months (range, 7-21 months), and follow-up angiography (n=7) revealed no significant in-stent restenosis (>50%). CONCLUSION: Urgent recanalization with stenting is feasible, safe, and effective in patients with TIA or acute minor stroke with intracranial stenosis of >=70%. PMID- 22200015 TI - Predicting factors affecting clinical outcomes for saccular aneurysms of posterior inferior cerebellar artery with subarachnoid hemorrhage. AB - OBJECTIVE: The aim of this study is to investigate the clinical outcomes of surgery and coiling and analyze the predicting factors affecting the clinical outcomes of ruptured posterior inferior cerebellar artery (PICA) aneurysms. METHODS: During the last 15 years, 20 consecutive patients with ruptured PICA aneurysms were treated and these patients were included in this study. The Fisher's exact test was used for the statistical significance of Glasgow Outcome Scale (GOS) according to initial Hunt-Hess (H-H) grade, treatment modalities, and the presence of acute hydrocephalus. RESULTS: Eleven (55%) and nine (45%) patients were treated with surgical clipping and endovascular treatment, respectively. Among 20 patients, thirteen (65.0%) patients had good outcomes (GOS 4 or 5). There was the statistical significance between initial poor H-H grade, the presence of acute hydrocephalus and poor GOS. CONCLUSION: In our study, we suggest that initial H-H grade and the presence of acute hydrocephalus may affect the clinical outcome rather than treatment modalities in the ruptured PICA aneurysms. PMID- 22200016 TI - Laminotomy with continuous irrigation in patients with pyogenic spondylitis in thoracic and lumbar spine. AB - OBJECTIVE: Pyogenic spondylitis often results in acute neurological deterioration requiring adequate surgical intervention and appropriate antibiotic treatment. The purpose of this study was to conduct an analysis of the clinical effect of continuous irrigation via laminotomy in a series of patients with pyogenic spondylitis in thoracic and lumbar spine. METHODS: The authors conducted a retrospective investigation of 31 consecutive patients with pyogenic thoracic and lumbar spondylitis who underwent continuous irrigation through laminotomy from 2004 to 2008. The study included 22 men and 9 women, ranging in age from 38 to 78 years (mean 58.1 years). The average follow-up duration was 13.4 months (range, 8 34 months). We performed debridement and abscess removal after simple laminotomy, and then washed out epidural and disc space using a continuous irrigation system. Broad spectrum antibiotics were administered empirically and changed according to the subsequent culture result. Clinical outcomes were based on the low back outcome scale (LBOS), visual analogue scale (VAS) score, and Frankel grade at the last follow-up. Radiological assessment involved plain radiographs, including functional views. RESULTS: Common predisposing factors included local injection for pain therapy, diabetes mellitus, chronic renal failure, and liver cirrhosis. Causative microorganisms were identified in 22 cases (70.9%) : Staphylococcus aureus and Streptococcus spp. were the main organisms. After surgery, LBOS, VAS score, and Frankel grade showed significant improvement in most patients. Spinal stability was maintained during the follow-up period, making secondary reconstructive surgery unnecessary for all patients, except one. CONCLUSION: Simple laminotomy with continuous irrigation by insertion of a catheter into intervertebral disc space or epidural space was minimally invasive and effective in the treatment of pyogenic spondylitis. This procedure could be a beneficial treatment option in patients with thoracolumbar spondylitis combined with minimal or moderate destructive change of vertebrae. PMID- 22200017 TI - Inferolateral entry point for c2 pedicle screw fixation in high cervical lesions. AB - OBJECTIVE: The purpose of this retrospective study was to evaluate the efficacy and safety of atlantoaxial stabilization using a new entry point for C2 pedicle screw fixation. METHODS: Data were collected from 44 patients undergoing posterior C1 lateral mass screw and C2 screw fixation. The 20 cases were approached by the Harms entry point, 21 by the inferolateral point, and three by pars screw. The new inferolateral entry point of the C2 pedicle was located about 3-5 mm medial to the lateral border of the C2 lateral mass and 5-7 mm superior to the inferior border of the C2-3 facet joint. The screw was inserted at an angle 30 degrees to 45 degrees toward the midline in the transverse plane and 40 degrees to 50 degrees cephalad in the sagittal plane. Patients received followed-up with clinical examinations, radiographs and/or CT scans. RESULTS: There were 28 males and 16 females. No neurological deterioration or vertebral artery injuries were observed. Five cases showed malpositioned screws (2.84%), with four of the screws showing cortical breaches of the transverse foramen. There were no clinical consequences for these five patients. One screw in the C1 lateral mass had a medial cortical breach. None of the screws were malpositioned in patients treated using the new entry point. There was a significant relationship between two group (p=0.036). CONCLUSION: Posterior C1-2 screw fixation can be performed safely using the new inferolateral entry point for C2 pedicle screw fixation for the treatment of high cervical lesions. PMID- 22200018 TI - The safety and efficacy of cadaveric allografts and titanium cage as a fusion substitutes in pyogenic osteomyelitis. AB - OBJECTIVE: The safety and efficacy of various fusion substitutes in pyogenic osteomyelitis has not been investigated. We evaluated and compared the cadaveric allograft and titanium cages used to reconstruct, maintain alignment and achieve fusion in the management of pyogenic spinal infection. METHODS: There were 33 patients with pyogenic osteomyelitis underwent fusion in this study. Fifteen of the 33 patients were operated on by fusion with allografts (cadaveric patella bones) and 18 of those were operated with titanium mesh cages filled with autologous cancellous iliac bone. After the affected disc and vertebral body resection with pus drainage, cadaveric allograft or titanium cages were inserted into the resected space. Posterior transpedicular screw fixation and rod compression in resected space, where cadaveric allograft or titanium cages were inserted, was performed to prevent the malposition in all patients except in 1 case. Recurrent infection was identified by serial erythrocyte sedimentation rate and cross reactive protein follow-up. Osseous union and recurred infection available at a minimum of 2 years following operation was identified. The amount of kyphosis correction and the subsidence were measured radiographically. RESULTS: Spinal fusion was achieved in 29 of 33 patients. In the cadaveric allograft group, 93.3% of patient (14 of 15) showed the osseous union while 83.3% of patient (15 of 18) in the titanium cage group showed union. Subsidence was noted in 12 of the patients. Twelve patients (36.3%) showed unsettling amounts of subsidence postoperatively whereas 46.6% of patients in the cadaveric allograft group and 37.7% of patients in the titanium cage group showed similar subsidence, respectively. There were statistical difference in the fusion rate (p=0.397) and subsidence rate (p=0.276) between the two groups. There was significant statistical difference in the postoperative improvement of segmental kyphosis between the two groups (p=0.022), that is the improvement in sagittal alignment was greater in the titanium cage group than in the cadaveric allograft group. There was no case of recurred infection. CONCLUSION: The cadaveric allograft and titanium cages are effective and safe in restoring and maintaining sagittal plane alignment without increased incidence in infection recurrence in pyogenic osteomyelitis. The postoperative improvement of segmental kyphosis was better in the cage group. PMID- 22200019 TI - Is titanium mesh cage safe in surgical management of pyogenic spondylitis? AB - OBJECTIVE: To report our experience with pyogenic spondylitis treated with anterior radical debridement and insertion of a titanium mesh cage and to demonstrate the effectiveness and safety of the use of a titanium mesh cage in the surgical management of pyogenic spondylitis. METHODS: We retrospectively analyzed the clinical characteristics of 19 patients who underwent surgical treatment in our department between January 2004 and December 2008. The average follow-up period was 11.16 months (range, 6-64 months). We evaluated risk factors, cultured organisms, lab data, clinical outcomes, and radiographic results. Surgical techniques for patients with pyogenic spondylitis were anterior radical debridement and reconstruction with titanium mesh cage insertion and screw fixation. All patients received intravenous antibiotics for at least 6 weeks postoperatively, and some patients received oral antibiotics. RESULTS: The infections resolved in all of the patients as noted by normalization of their erythrocyte sedimentation rates and C-reactive protein levels. The mean pain score on a Visual Analog Scale was 7.8 (range, 4-10) before surgery and 2.4 (range, 1-5) after surgery. The Frankel grade was improved by one grade in seven patients. After surgery, the average difference of the angle was improved about 6.96 degrees in all patients. At the last follow-up, the mean loss of correction was 4.86 degrees . CONCLUSION: Anterior radical debridement followed by the placement of instrumentation with a titanium mesh cage may be a safe and effective treatment for selected patients with pyogenic spondylitis. This surgical therapy does not lead to recurrent pyogenic spondylitis. PMID- 22200020 TI - Comparative Study of Posterior Lumbar Interbody Fusion via Unilateral and Bilateral Approaches in Patients with Unilateral Leg Symptoms. AB - OBJECTIVE: We investigated the clinical and radiological advantages of unilateral laminectomy in posterior lumbar interbody fusion (PLIF) procedure comparing with bilateral laminectomy, under the same procedural condition including bilateral instrumentation and insertion of two cages, in patients with degenerative lumbar disease with unilateral leg symptoms. METHODS: We retrospectively reviewed 124 consecutive cases of PLIF via unilateral or bilateral approach between January 2006 and April 2010. In 80 cases (bilateral group), two cages were inserted via bilateral laminectomy, and in 44 cases (unilateral group), via unilateral laminectomy. The average follow-up duration was 29.5 months. The clinical outcomes were evaluated with the Visual Analogue Scale (VAS) and the Oswestry disability index (ODI). The fusion rates and disc space heights were determined by dynamic standing radiographs and/or computed tomography. Operative times, intra-operative and post-operative blood losses and hospitalization periods were also evaluated. RESULTS: In clinical evaluation, the VAS and ODI scores showed excellent outcomes in both groups. There were no significant differences in term of fusion rate, but the perioperative blood loss and the operative time of the unilateral group were lower than that of the bilateral group. CONCLUSION: Unilateral laminectomy can minimize the operative time and perioperative blood loss in PLIF procedure. However, the different preoperative disc height between two groups is a limitation of this study. Despite this limitation, solid fusion and satisfactory symptomatic improvement could be achieved uniquely by our surgical method. This surgical method can be an alternative surgical technique in patients with unilateral leg pain. PMID- 22200021 TI - Post-traumatic cerebral infarction : outcome after decompressive hemicraniectomy for the treatment of traumatic brain injury. AB - OBJECTIVE: Posttraumatic cerebral infarction (PTCI), an infarction in well defined arterial distributions after head trauma, is a known complication in patients with severe head trauma. The primary aims of this study were to evaluate the clinical and radiographic characteristics of PTCI, and to assess the effect on outcome of decompressive hemicraniectomy (DHC) in patients with PTCI. METHODS: We present a retrospective analysis of 20 patients with PTCI who were treated between January 2003 and August 2005. Twelve patients among them showed malignant PTCI, which is defined as PTCI including the territory of Middle Cerebral Artery (MCA). Medical records and radiologic imaging studies of patients were reviewed. RESULTS: Infarction of posterior cerebral artery distribution was the most common site of PTCI. Fourteen patients underwent DHC an average of 16 hours after trauma. The overall mortality rate was 75%. Glasgow outcome scale (GOS) of survivors showed that one patient was remained in a persistent vegetative state, two patients were severely disabled and only two patients were moderately disabled at the time of discharge. Despite aggressive treatments, all patients with malignant PTCI had died. Malignant PTCI was the indicator of poor clinical outcome. Furthermore, Glasgow coma scale (GCS) at the admission was the most valuable prognostic factor. Significant correlation was observed between a GCS less than 5 on admission and high mortality (p<0.05). CONCLUSION: In patients who developed non-malignant PTCI and GCS higher than 5 after head injury, early DHC and duroplasty should be considered, before occurrence of irreversible ischemic brain damage. High mortality rate was observed in patients with malignant PTCI or PTCI with a GCS of 3-5 at the admission. A large prospective randomized controlled study will be required to justify for aggressive treatments including DHC and medical treatment in these patients. PMID- 22200022 TI - Position Change of the Neurovascular Structures around the Carpal Tunnel with Dynamic Wrist Motion. AB - OBJECTIVE: The purpose of this study was to determine the anatomic relationships between neurovascular structures and the transverse carpal ligament so as to avoid complications during endoscopic carpal tunnel surgery. METHODS: Twenty eight patients (age range, 35-69 years) with carpal tunnel syndrome were entered into the study. We examined through wrist magnetic resonance imaging in three different positions (neutral, radial flexion, and ulnar flexion) and determined several anatomic landmark (distance from the hamate hook to the median nerve, ulnar nerve, and ulnar vessel) based on the lateral margin of the hook of the hamate. The median nerve and ulnar neurovascular structure were studied with the wrist in the neutral, ulnar, and radial flexion positions. RESULTS: The ulnar neurovascular structures usually passed just over or ulnar to the hook of the hamate. However, in 12 hands, a looped ulnar artery coursed 0.6-3.3 mm radial to the hook of the hamate and continued to the superficial palmar arch. The looped ulnar artery migrates on the ulnar side of Guyon's canal (-5.2-1.8 mm radial to the hook of the hamate) with the wrist in radial flexion. During ulnar flexion of the wrist, the ulnar artery shifts more radially beyond the hook of the hamate ( 2.5-5.7 mm). CONCLUSION: It is appropriate to transect the ligament greater than 4 mm apart from the lateral margin of the hook of the hamate without placing the edge of the scalpel toward the ulnar side. We would also recommend not transecting the transverse carpal ligament in the ulnar flexed wrist position to protect the ulnar neurovascular structure. PMID- 22200023 TI - Atypical extraventricular neurocytoma. AB - The authors report a case of atypical extraventricular neurocytoma (EVN) transformed from EVN which had been initially diagnosed as an oligodendroglioma 15 years ago. An 8-year-old boy underwent a surgical resection for a right frontal mass which was initially diagnosed as oligodendroglioma. When the tumor recurred 15 years later, a secondary operation was performed, followed by salvage gamma knife treatment. The recurrent tumor was diagnosed as an atypical EVN. The initial specimen was reviewed and immunohistochemistry revealed a strong positivity for synaptophysin. The diagnosis of the initial tumor was revised as an EVN. The patient maintained a stable disease state for 15 years after the first operation, and was followed up for one year without any complications or disease progression after the second operation. We diagnosed an atypical extraventricular neurocytoma transformed from EVN which had been initially diagnosed as an oligodendroglioma 15 years earlier. We emphasize that EVN should be included in the differential diagnosis of oligodendroglioma. PMID- 22200024 TI - Malignant ascites after subduroperitoneal shunt in a patient with leptomeningeal metastasis. AB - Leptomeningeal metastasis is a devastating complication of advanced stage cancer. It is frequently accompanied by hydrocephalus and intracranial hypertension that must be treated by ventriculoperitoneal shunts. However, there are actual risks of peritoneal seeding or accumulation of malignant ascites after the cerebrospinal fluid diversion procedure, though it has not been reported. Here, we present the case of a patient with non-small cell lung cancer with leptomeningeal metastasis in whom malignant ascites developed after a subduroperitoneal shunt. PMID- 22200025 TI - Serial magnetic resonance images of a right middle cerebral artery infarction : persistent hyperintensity on diffusion-weighted MRI over 8 months. AB - A lesion that is hyperintense on diffusion-weighted imaging (DWI) and hypointense on the apparent diffusion coefficient (ADC) map is a characteristic magnetic resonance imaging (MRI) finding in acute ischemic infarction. In some cases, however, these findings can persist for a few months after infarct onset. It is thought that these finding reflect the different evolution speeds of the infarcted tissue. We report a patient with a right middle cerebral artery territory infarction with persistent hyperintensity on DWI and hypointensity on the ADC map for over 8 months. To our knowledge, this is the most persistent case of hyperintensity lesion on DWI and the serial MRI images of this patient provide important information on the evolution of infarcted tissue. PMID- 22200026 TI - Idiopathic hypertrophic spinal pachymeningitis : report of two cases and review of the literature. AB - Idiopathic hypertrophic spinal pachymeningitis (IHSP) is a rare inflammatory disease characterized by hypertrophic inflammation of the dura mater and various clinical courses that are from myelopathy. Although many associated diseases have been suggested, the etiology of IHSP is not well understood. The ideal treatment is controversial. In the first case, a 55-year-old woman presented back pain, progressive paraparesis, both leg numbness, and voiding difficulty. Initial magnetic resonance imaging (MRI) demonstrated an anterior epidural mass lesion involving from C6 to mid-thoracic spine area with low signal intensity on T1 and T2 weighted images. We performed decompressive laminectomy and lesional biopsy. After operation, she was subsequently treated with steroid and could walk unaided. In the second case, a 45-year-old woman presented with fever and quadriplegia after a spine fusion operation due to lumbar spinal stenosis and degenerative herniated lumbar disc. Initial MRI showed anterior and posterior epidural mass lesion from foramen magnum to C4 level. She underwent decompressive laminectomy and durotomy followed by steroid therapy. However, her conditions deteriorated gradually and medical complications occurred. In our cases, etiology was not found despite through investigations. Initial MRI showed dural thickening with mixed signal intensity on T1- and T2-weighted images. Pathologic examination revealed chronic nonspecific inflammation in both patients. Although one patient developed several complications, the other showed slow improvement of neurological symptoms with decompressive surgery and steroid therapy. In case of chronic compressive myelopathy due to the dural hypertrophic change, decompressive surgery such as laminectomy or laminoplasty may be helpful as well as postoperative steroid therapy. PMID- 22200027 TI - Nocardia brain abscess in a liver transplant recipient. AB - Nocardia brain abscess is rare. We report on a unique case of N. farcinica brain abscess in a liver transplant recipient, following Aspergillus fumigatus pneumonia. A 43-year-old liver transplant recipient presented with altered mentality at 2 months after A. fumigates pneumonia. He was successfully treated with surgical removal and antibiotic therapy with trimethoprim-sulfamethoxazole and ceftriaxone. PMID- 22200029 TI - Role of polycomb group protein cbx2/m33 in meiosis onset and maintenance of chromosome stability in the Mammalian germline. AB - Polycomb group proteins (PcG) are major epigenetic regulators, essential for establishing heritable expression patterns of developmental control genes. The mouse PcG family member M33/Cbx2 (Chromobox homolog protein 2) is a component of the Polycomb-Repressive Complex 1 (PRC1). Targeted deletion of Cbx2/M33 in mice results in homeotic transformations of the axial skeleton, growth retardation and male-to-female sex reversal. In this study, we tested whether Cbx2 is involved in the control of chromatin remodeling processes during meiosis. Our analysis revealed sex reversal in 28.6% of XY(-/-) embryos, in which a hypoplastic testis and a contralateral ovary were observed in close proximity to the kidney, while the remaining male mutant fetuses exhibited bilateral testicular hypoplasia. Notably, germ cells recovered from Cbx2((XY-/-)) testes on day 18.5 of fetal development exhibited premature meiosis onset with synaptonemal complex formation suggesting a role for Cbx2 in the control of meiotic entry in male germ cells. Mutant females exhibited small ovaries with significant germ cell loss and a high proportion of oocytes with abnormal synapsis and non-homologous interactions at the pachytene stage as well as formation of univalents at diplotene. These defects were associated with failure to resolve DNA double strand breaks marked by persistent gammaH2AX and Rad51 foci at the late pachytene stage. Importantly, two factors required for meiotic silencing of asynapsed chromatin, ubiquitinated histone H2A (ubH2A) and the chromatin remodeling protein BRCA1, co-localized with fully synapsed chromosome axes in the majority of Cbx2((-/-)) oocytes. These results provide novel evidence that Cbx2 plays a critical and previously unrecognized role in germ cell viability, meiosis onset and homologous chromosome synapsis in the mammalian germline. PMID- 22200028 TI - Induction of cancer cell death by isoflavone: the role of multiple signaling pathways. AB - Soy isoflavones have been documented as dietary nutrients broadly classified as "natural agents" which plays important roles in reducing the incidence of hormone related cancers in Asian countries, and have shown inhibitory effects on cancer development and progression in vitro and in vivo, suggesting the cancer preventive or therapeutic activity of soy isoflavones against cancers. Emerging experimental evidence shows that isoflavones could induce cancer cell death by regulating multiple cellular signaling pathways including Akt, NF-kappaB, MAPK, Wnt, androgen receptor (AR), p53 and Notch signaling, all of which have been found to be deregulated in cancer cells. Therefore, homeostatic regulation of these important cellular signaling pathways by isoflavones could be useful for the activation of cell death signaling, which could result in the induction of apoptosis of both pre-cancerous and/or cancerous cells without affecting normal cells. In this article, we have attempted to summarize the current state-of-our knowledge regarding the induction of cancer cell death pathways by isoflavones, which is believed to be mediated through the regulation of multiple cellular signaling pathways. The knowledge gained from this article will provide a comprehensive view on the molecular mechanism(s) by which soy isoflavones may exert their effects on the prevention of tumor progression and/or treatment of human malignancies, which would also aid in stimulating further in-depth mechanistic research and foster the initiation of novel clinical trials. PMID- 22200030 TI - Image microarrays (IMA): Digital pathology's missing tool. AB - INTRODUCTION: The increasing availability of whole slide imaging (WSI) data sets (digital slides) from glass slides offers new opportunities for the development of computer-aided diagnostic (CAD) algorithms. With the all-digital pathology workflow that these data sets will enable in the near future, literally millions of digital slides will be generated and stored. Consequently, the field in general and pathologists, specifically, will need tools to help extract actionable information from this new and vast collective repository. METHODS: To address this limitation, we designed and implemented a tool (dCORE) to enable the systematic capture of image tiles with constrained size and resolution that contain desired histopathologic features. RESULTS: In this communication, we describe a user-friendly tool that will enable pathologists to mine digital slides archives to create image microarrays (IMAs). IMAs are to digital slides as tissue microarrays (TMAs) are to cell blocks. Thus, a single digital slide could be transformed into an array of hundreds to thousands of high quality digital images, with each containing key diagnostic morphologies and appropriate controls. Current manual digital image cut-and-paste methods that allow for the creation of a grid of images (such as an IMA) of matching resolutions are tedious. CONCLUSION: The ability to create IMAs representing hundreds to thousands of vetted morphologic features has numerous applications in education, proficiency testing, consensus case review, and research. Lastly, in a manner analogous to the way conventional TMA technology has significantly accelerated in situ studies of tissue specimens use of IMAs has similar potential to significantly accelerate CAD algorithm development. PMID- 22200031 TI - Standardization of whole slide image morphologic assessment with definition of a new application: Digital slide dynamic morphometry. AB - BACKGROUND: In histopathology, the quantitative assessment of various morphologic features is based on methods originally conceived on specific areas observed through the microscope used. Failure to reproduce the same reference field of view using a different microscope will change the score assessed. Visualization of a digital slide on a screen through a dedicated viewer allows selection of the magnification. However, the field of view is rectangular, unlike the circular field of optical microscopy. In addition, the size of the selected area is not evident, and must be calculated. MATERIALS AND METHODS: A digital slide morphometric system was conceived to reproduce the various methods published for assessing tumor budding in colorectal cancer. Eighteen international experts in colorectal cancer were invited to participate in a web-based study by assessing tumor budding with five different methods in 100 digital slides. RESULTS: The specific areas to be tested by each method were marked by colored circles. The areas were grouped in a target-like pattern and then saved as an .xml file. When a digital slide was opened, the .xml file was imported in order to perform the measurements. Since the morphometric tool is composed of layers that can be freely moved on top of the digital slide, the technique was named digital slide dynamic morphometry. Twelve investigators completed the task, the majority of them performing the multiple evaluations of each of the cases in less than 12 minutes. CONCLUSIONS: Digital slide dynamic morphometry has various potential applications and might be a useful tool for the assessment of histologic parameters originally conceived for optical microscopy that need to be quantified. PMID- 22200032 TI - High-throughput profiling of tissue and tissue model microarrays: Combined transmitted light and 3-color fluorescence digital pathology. AB - For many years pathologists have used Hematoxylin and Eosin (H&E), single marker immunohistochemistry (IHC) and in situ hybridization with manual analysis by microscopy or at best simple digital imaging. There is a growing trend to update pathology to a digital workflow to improve objectivity and productivity, as has been done in radiology. There is also a need for tissue-based multivariate biomarker assays to improve the accuracy of diagnostic, prognostic, and predictive testing. Multivariate tests are not compatible with the traditional single marker, manual analysis pathology methods but instead require a digital platform with brightfield and fluorescence imaging, quantitative image analysis, and informatics. Here we describe the use of the Hamamatsu NanoZoomer Digital Pathology slide scanner with HCImage software for combined brightfield and multiplexed fluorescence biomarker analysis and highlight its applications in biomarker research and pathology testing. This combined approach will be an important aid to pathologists in making critical diagnoses. PMID- 22200033 TI - S100/calgranulins EN-RAGEing the blood vessels: implications for inflammatory responses and atherosclerosis. AB - Atherosclerosis remains the leading cause of death in the western countries and represents a complex chronic inflammatory process whose regulation is dependent on a network of cytokine and chemokine signaling between key cells such as endothelial cells, monocytes, dendritic cells, lymphocytes and smooth muscle cells. This review focuses on the biology and function of S100 proteins and their receptor RAGE with respect to the multifactorial process leading to atherosclerosis, plaque rupture, and aortic wall remodeling. PMID- 22200034 TI - E2F and microRNA regulation of angiogenesis. AB - E2F family of transcription factors are best known for regulating genes involved in cell cycle control, cell proliferation, tumorigenesis, and apoptosis. Recent evidences have revealed their critical involvement in modulating cellular response to hypoxia and ischemia in a variety of physiological and pathological processes. Of particular interest are findings that E2Fs act as both regulators and targets of microRNAs that govern hypoxic/ischemic angiogenesis. This review focuses on the crosstalk between E2Fs and microRNAs that have been shown to participate in the regulation of angiogenesis, hypoxia response and ischemic disease. PMID- 22200036 TI - Status and prospect of workforce requirement for surgery in republic of Korea. AB - PURPOSE: In order to prepare long-term alternatives to surgical residency training and workforce policies in Korea, objective data are needed; in addition, determination of the status of surgical procedures being performed is also needed. METHODS: Cases of surgeries performed by board-certified Korean surgeons for 1 year, from July 2009 to June 2010 were reviewed and analyzed. Variation of the last five years was also investigated against the number of surgery cases of the same item and for data on status of population, medical institutions, and surgeons. RESULTS: Difficulty in distribution of a given surgery varied according to the classification of medical institution types, and performance of highly difficult surgeries occurred more in tertiary hospitals. The number of surgeries has increased over the last 5 years (28.1%). The number of surgeries among elderly patients (41.5%), high difficulty (41.8%), and tertiary hospitals (34.9%) has especially increased. There has been no increase in the number of diagnosis related group claim cases for the last 5 years (-0.8%). 43.3% of surgeons working at private clinics in Korea did not present surgery as an indicating item of their clinics. CONCLUSION: While the demand for surgeons in high risk and highly difficult surgeries is continuously increasing, stagnation is expected in the traditional area. Considering the proportion and current status of surgeons working at private clinics, the need for a realistic reduction in the quota of surgical residents and reconsideration of personnel policies is raised. PMID- 22200035 TI - The impact of local U.S. tobacco policies on youth tobacco use: A critical review. AB - Tobacco use continues to be the leading preventable cause of premature death in the United States, killing over 430,000 people annually. Tobacco initiation and use among youth remains a significant public health concern. Despite declines in U.S. youth tobacco use in recent years, state and national survey results are still cause for alarm. Although traditional school-based curricular programs are the most common strategy to prevent or reduce youth tobacco use, their effectiveness may be limited because young people are immersed in a broader social context in which tobacco is readily available. Environmental strategies change this social context by focusing on policy, enforcement, and media. A compelling body of evidence suggests that interventions at the state and federal levels can, when implemented in combination, reduce youth tobacco use. The impact of policies implemented at the local levels is less well understood and effects of environmental strategies on smokeless tobacco consumption have been largely ignored. The purpose of this paper is to review the literature on environmental strategies implemented at the local level on youth use of both cigarettes and smokeless tobacco. We highlight results of the extant literature, hypothesize possible effects where research is lacking, and suggest where future studies might be warranted. PMID- 22200037 TI - Primary thyroid mucosa-associated lymphoid tissue lymphoma; a clinicopathological study of seven cases. AB - PURPOSE: Primary thyroid mucosa-associated lymphoid tissue (MALT) lymphoma is a very rare subgroup of thyroid lymphoma, accounting for about 6 to 28% of all primary thyroid lymphomas. The purpose of this study was to evaluate its clinicopathological features and treatment outcomes. METHODS: We identified seven patients with thyroid MALT lymphoma who were treated between January 1997 and December 2007, and reviewed their clinicopathological features and follow-up outcomes. RESULTS: There were five female and two male patients, and their mean age was 73 years. All patients presented with palpable neck mass. Two patients had hoarseness and dyspnea. All patients had a history of Hashimoto's thyroiditis with a mean of 175 months. Malignant lymphoma was suspected in only three patients using core needle biopsy. Four patients underwent thyroidectomy in the absence of preoperative pathologic confirmation, and histologic diagnosis was obtained after surgery. As initial treatment, complete surgical resection was performed in five patients, radiotherapy in one, and a combination of chemotherapy and radiotherapy in one. Six patients were alive for the mean follow up period of 66 months and one patient died of unrelated causes. There were neither recurrences nor disease-specific mortalities. CONCLUSION: When primary thyroid MALT lymphoma occurs in the thyroid or is confined to the neck, it responds well to local treatment such as surgical resection and external beam radiation therapy. PMID- 22200038 TI - Is it possible to predict hypothyroidism after thyroid lobectomy through thyrotropin, thyroglobulin, anti-thyroglobulin, and anti-microsomal antibody? AB - PURPOSE: We investigated the incidence and risk factors of hypothyroidism after thyroid lobectomy, and evaluated the possibility to predict hypothyroidism preoperatively with serologic markers, such as thyrotropin (TSH), thyroglobulin (TG), anti-thyroglobulin (ATA), and anti-microsomal antibody (AMA). METHODS: We enrolled 123 consecutive patients who underwent thyroid lobectomy due to benign conditions between May 2004 and April 2008. Only preoperative euthyroid patients were included. Patients were divided into two groups by postoperative thyroid function outcomes, into hypothyroid (n = 97) and euthyroid groups (n = 26), and analyzed specially for the preoperative levels of TSH, TG, ATA, and AMA. RESULTS: Twenty-six (21.1%) patients developed hypothyroidism following thyroid lobectomy within 35.7 months of follow-up. The proportion of post-lobectomy hypothyroidism was high in patients with high-normal preoperative TSH level, and the cut-off value was 2.0 mIU/L, with 67% sensitivity and 75% specificity. The quantitative titer of preoperative TG, ATA, and AMA was not significant, but the outcome of categorical analysis of two or more positivities on these three markers was significantly higher in hypothyroid patients than in euthyroid patients (28.6% vs. 3.9%, P = 0.024). The combined positivity of preoperative TSH and two or more positivities of TG, ATA, and AMA possess 100% positive predictive value and 81% negative predictive value. CONCLUSION: The incidence of hypothyroidism following thyroid lobectomy was 21.1%. High-normal preoperative TSH and two or more positivities for TG, ATA, and AMA are good pre-operative predictive markers. Such high-risk patients need close TSH monitoring before the onset of clinical hypothyroidism. PMID- 22200039 TI - Carcinoembryonic antigen level of draining venous blood as a predictor of recurrence in colorectal cancer patient. AB - PURPOSE: We designed this study to evaluate the efficacy of carcinoembryonic antigen in draining venous blood (vCEA) as a predictor of recurrence. METHODS: Draining venous and supplying arterial bloods were collected separately during the operation of 82 colorectal cancer patients without distant metastasis from September 2004 to December 2006. Carcinoembryonic antigen was measured and assessed for the efficacy as a prognostic factor of recurrence using receiver operating characteristic (ROC) and Kaplan-Meier curves. RESULTS: vCEA is a statistically significant factor that predicts recurrence (P = 0.032) and the optimal cut-off value for vCEA from ROC curve is 8.0 ng/mL. The recurrence-free survival between patients with vCEA levels >8 ng/mL and <=8 ng/mL significantly differed (P < 0.001). The significance of vCEA as a predictor of recurrence gets higher when limited to patients without lymph node metastasis. The proper cut-off value for vCEA is 4.0 ng/mL if confined to patients without lymph node metastasis. The recurrence-free survival between the patients of vCEA levels >4 ng/mL and <=4 ng/mL significantly differed (P < 0.001). Multivariate analysis revealed vCEA is an independent prognostic factor in patients without lymph node metastasis. CONCLUSION: vCEA is an independent prognostic factor of recurrence in colorectal cancer patients especially in patients without lymph node metastases. PMID- 22200040 TI - Factors affecting long-term survival after surgical resection of pancreatic ductal adenocarcinoma. AB - PURPOSE: Some patients who undergo surgical resection of pancreatic cancer survive longer than other patients. The purpose of this study was to identify the factors that affect long-term survival after resection of histopathologically confirmed pancreatic ductal adenocarcinoma. METHODS: A single-center, retrospective study was conducted among 164 patients who underwent surgical resection of pancreatic cancer, between May 1995 and December 2004. The patient follow-up process was conducted via telephone survey and review of electronic medical records for at least 5 years or until death. RESULTS: We compared patients with long-term (>=60 months, n = 19) and short-term survival (<60 months, n = 145). Resection margin status, differentiation of the tumor, tumor stage, pre-operative serum level of albumin, total bilirubin and carbohydrate antigen (CA) 19-9 level are related with survival difference (all factors, P < 0.05). Multivariate analysis revealed that a pre-operative serum total bilirubin level <7 mg/dL and a pre-operative serum CA19-9 level <37 U/mL is a statistically significant prognostic factor for long-term survival. CONCLUSION: The preoperative serum total bilirubin and serum CA19-9 levels are associated with long-term survival after surgical resection of pancreatic cancer. PMID- 22200041 TI - Amylase, lipase, and volume of drainage fluid in gastrectomy for the early detection of complications caused by pancreatic leakage. AB - PURPOSE: Pancreatic leakage is a serious complication of gastrectomy due to stomach cancer. Therefore, we analyzed amylase and lipase concentrations in blood and drainage fluid, and evaluated the volume of drainage fluid to discern their usefulness as markers for the early detection of serious pancreatic leakage requiring reoperation after gastrectomy. METHODS: From January 2001 to December 2007, we retrospectively analyzed data from 24,072 patient samples. We divided patients into two groups; 1) complications with pancreatic leakage (CG), and 2) no complications associated with pancreatic leakage (NCG). Values of amylase and lipase in the blood and drainage fluid, volume of the drainage fluid, and relationships among the volumes, amylase values, and lipase values in the drainage fluid were evaluated, respectively in the two groups. RESULTS: The mean amylase values of CG were significantly higher than those of NCG in blood and drainage fluid (P < 0.05). For lipase, statistically significant differences were observed in drainage fluid (P < 0.05). The mean volume (standard deviation) of the drained fluid through the tube between CG (n = 22) and NCG (n = 236) on postoperative day 1 were 368.41 (266.25) and 299.26 (300.28), respectively. There were no statistically significant differences between the groups (P = 0.298). There was a correlation between the amylase and lipase values in the drainage fluid (r = 0.812, P = 0.000). CONCLUSION: Among postoperative amylase and lipase values in blood and drainage fluid, and the volume of drainage fluid, the amylase in drainage fluid was better differentiated between CG and NCG than other markers. The volume of the drainage fluid did not differ significantly between groups. PMID- 22200042 TI - Percutaneous ilioinguinal-iliohypogastric nerve block or step-by-step local infiltration anesthesia for inguinal hernia repair: what cadaveric dissection says? AB - PURPOSE: The repair of groin hernias with local anesthesia has gained popularity. Two main methods have been described for local anesthesia. This study was aimed at comparing percutaneous truncular ilioinguinal-iliohypogastric block and step by-step infiltration technique by using cadaver dissections. METHODS: The study was performed on an adult male cadaver by using blue dye injection. A percutaneous nerve block simulation was done on right side and the dye was given in between the internal oblique and transversus muscles. On the left side, a skin incision was deepened and the dye was injected under the external oblique aponeurosis. Following the injections, stained areas were investigated superficially and within the deeper tissues with dissection. RESULTS: There was a complete superficial staining covering the iliohypogastric and ilioinguinal nerves in the inguinal floor at both sides. On the right side, intraabdominal observation showed a wide and intense peritoneal staining, while almost no staining was seen on the left side. Preperitoneal dissection displayed a massive staining including testicular vascular pedicule and vas deferens on the right side. The dye solution also infiltrated the area of the femoral nerve prominently. On the contrary, a very limited staining was seen on the left. CONCLUSION: It may not always be easy to keep the percutaneous block within optimum anatomical limits without causing adverse events. A step-by-step infiltration technique under direct surgical vision seems to be safer than percutaneous inguinal block for patients undergoing inguinal hernia repair. PMID- 22200043 TI - Interstitial lung disease caused by TS-1: a case of long-term drug retention as a fatal adverse reaction. AB - TS-1 is an oral anti-cancer agent for gastric cancer with a high response rate and low toxicity. We report a case of long-term drug retention of TS-1 causing interstitial lung disease (ILD) as a fatal adverse reaction. A 65-year-old woman underwent a total gastrectomy with pathologic confirmation of gastric adenocarcinoma. She received 6 cycles of TS-1 and low-dose cisplatin for post operative adjuvant chemotherapy followed by single-agent maintenance therapy with TS-1. After 8 months, the patient complained of a productive cough with sputum and mild dyspnea. A pulmonary evaluation revealed diffuse ILD in the lung fields, bilaterally. In spite of discontinuing chemotherapy and the administration of corticosteroids, the pulmonary symptoms did not improve, and the patient died of pulmonary failure. TS-1-induced ILD can be caused by long-term drug retention that alters the lung parenchyma irreversibly, the outcome of which can be life threatening. Pulmonary evaluation for early detection of disease is recommended. PMID- 22200044 TI - Adenocarcinoma derived from gastric hamartomatous polyps. AB - Most hamartomatous polyps in the stomach occur in patients with adenomatous polyposis coli and dysplasia. The authors report a case of a 57-year-old man without prior history of polyposis coli who presented with adenocarcinomas derived from hamartomatous polyps in the stomach. The patient underwent a radical subtotal gastrectomy with Billroth I anastomosis. Pathology revealed adenocarcinomas with moderate differentiation without evidence of lymph node metastasis in 60 nodes. We report a case of gastric cancers arising from de novo gastric hamartomatous polyps. PMID- 22200045 TI - Gallbladder pseudolithiasis caused by ceftriaxone in young adult. AB - Ceftriaxone is a commonly used antibiotic due to some of its advantages. Reversible gallbladder (GB) sludge or stone has been reported after ceftriaxone therapy. Most of these patients have no symptom, but the GB sludge or stone can sometimes cause cholecystitis. We experienced two patients who had newly developed GB stones after ceftriaxone therapy for diverticulitis and pneumonia, and this resolved spontaneously 1 month after discontinuation of the drug. Awareness of this complication could help to prevent unnecessary cholecystectomy. PMID- 22200046 TI - Histologic confirmation of huge pancreatic lipoma: a case report and review of literatures. AB - Pancreatic lipomas are commonly diagnosed based on radiologic images, although the prevalence of lipomas has not been established. Histologic confirmation of pancreatic lipomas is extremely rare because surgical treatment is unnecessary in most cases. Endoscopic ultrasound-guided fine-needle aspiration cytology has been suggested to avoid unnecessary surgery to distinguish between a lipoma and a well differentiated liposarcoma; however, surgery would be needed when the tumor is associated with symptoms or difficult to distinguish from a liposarcoma. We present a case of a pancreatic lipoma in a 54-year-old male patient that was histologically-confirmed by subtotal pancreatectomy. PMID- 22200047 TI - New photoluminescence acylhydrazidate-coordinated complexes. AB - Under the hydrothermal conditions, five new acylhydrazidate-containing compounds [Cd(EPDH)(2)(H(2)O)] 1, [Cd(MPDH)(2)] 2, [Zn(MPDH)(2)(H(2)O)(2)].2H(2)O 3, [Pb(2)(ODPTH)(2)(phen)(2)(H(2)O)(2)] 4 and [Cd(2)(APTH)(4)(phen)(2)].2H(2)O 5 (EPDH = 5-ethylpyridine-2,3-dicarboxylhydrazidate, MPDH = 6-methylpyridine-2,3 dicarboxylhydrazidate, ODPTH = 4,4'-oxydiphthalhydrazidate, APTH = 3 amiophthalhydrazidate, phen = 1,10-phenanthroline) were luckily obtained. Note that MPDH, EPDH and ODPTH were derived from the hydrothermal in situ acylation reactions between organic polycarboxylic acids and N(2)H(4).H(2)O, whereas APTH originated from the hydrothermal in situ reduction reaction of NPTH (NPTH = 3 nitrophthalhydrazidate) in the presence of N(2)H(4).H(2)O. The photoluminescence analysis indicates that all of the title compounds are fluorescent materials with maximum emissions at 530 nm for 1, 540 nm for 2, 517 nm for 3, 413 nm for 4 and 563 nm for 5, respectively. The density functional theory (DFT) calculations on the excited electronic states of compound 3 indicate that the emission is associated with the ligands, corresponding to the charge transfer from the pi orbital of the acylhydrazidate ring to the pi* orbital of the pyridine ring. PMID- 22200048 TI - Environmental monitoring of radon in soil during a very seismically active period occurred in South West Greece. AB - This paper focuses on the environmental monitoring of radon in soil as a potential trace gas in the search of earthquake precursors. The paper reports the following: (a) Pre-monitoring experiments. (b) Set-up of methods and devices. (c) Active and passive monitoring results concentrating on two extremely-strong radon anomalies (~ 500 kBq m(-3)). (e) Discussion regarding the employed +/- 2sigma technique for identifying radon disturbances. (f) Application of wavelet-power spectrum fractal analysis for detecting power-law behaviour. The strong anomalies exhibited anti-persistent power-law-beta-values (b = (1.8 +/- 0.2), b = (1.8 +/- 0.3)) significantly higher than those of the baseline. Persistent b-values were also detected. The findings comply with a self-organised-critical pre-earthquake state. (h) Discussion on models that interpret the radon anomalies focusing on the recently-proposed asperity-model. (i) Application of a recent technique which showed that the two strong disturbances were proportional to the strain change. It was concluded that the strong radon disturbances may be linked to the strong earthquake of 8/6/2008, M = 6.5, occurred 29 km away from the installed instrumentation. PMID- 22200049 TI - Distribution of perfluorinated compounds in water, sediment, biota and floating plants in Baiyangdian Lake, China. AB - The distribution of perfluorinated compounds (PFCs) in Baiyangdian Lake, China, was determined in this study. Perfluorooctanoic acid (PFOA) was the dominant PFC in lake water (1.70-73.5 ng L(-1), median 9.72 ng L(-1)), while perfluorooctane sulfonate (PFOS) was the dominant PFC in sediments (0.06-0.64 ng g(-1) dry wt, median 0.19 ng g(-1) dry wt) and in aquatic animals (0.57-13.7 ng g(-1) wet wt, median 2.56 ng g(-1) wet wt). Significant differences in PFC levels were observed among various aquatic animals. We also determined, for the first time, the PFC levels in floating plants, including Ceratophyllum demersum L., Hydrocharis dubia (Bl.) Backer and Salvinia natans (L.), and we found that PFOA and PFNA were the dominant PFCs in these plants. Furthermore, floating plants were observed to have different composition profiles compared to aquatic animals. Geographical differences in PFC levels were also observed, with higher PFC levels in samples from the north part of Baiyangdian Lake than those in the south. The differences in human and industrial activities in different parts of the lake and the discharged wastewater from the Fuhe River may be the major contributors for these geographical differences. PMID- 22200050 TI - A controllable transformation in copper valence states and its applications. AB - The present study revealed a surprising valence transformation of copper (Cu) in the sintering process of mixtures of copper chloride dihydrate (CuCl(2).2H(2)O) with beta-cyclodextrin (beta-CD) in ambient atmosphere. Such a transformation in Cu valence states can be modulated by changing the initial molar ratio (IMR) of CuCl(2).2H(2)O to beta-CD in the mixtures. Firstly, as the value of IMR decreased, the content of cuprous chloride (CuCl) decreased, while the content of cupric oxide (CuO) increased gradually. That is to say, there is an unambiguous IMR-dependence of the contents of CuCl and CuO formed. However, such a controllable valence transformation from Cu(II) to Cu(I) to Cu(II) did not happen in nitrogen atmosphere. Secondly, the in situ composite of CuCl and CuO produced a highly ordered structure of self-assembled nanowires, intertwined, with a diameter of 30 to 50 nm. Furthermore, electronic structural analysis provided direct evidence that the Cu-Cl and Cu-O bonds in this composite material were simultaneously impaired by self-assembled growth. Finally, we noticed that the photoluminescence property of CuCl was regulated through the formation of composites with CuO. In addition, this in situ composite synthesis technique was used to modify the magnetic property of CuO. Furthermore, the anomalous ferromagnetic behaviour of the CuO nanocrystal was observed and explained. In short, this work not only demonstrates a flexible and easily controllable valence transformation of Cu, but also provides a novel approach for constructing inorganic nanocomposite materials. We believe that the implications of these findings are important and make significant contributions to the development of inorganic chemistry and material science. PMID- 22200051 TI - Guest dependent pressure behavior of the flexible MIL-53(Cr): a computational exploration. AB - Molecular dynamics simulations evidenced a structural transition of the flexible MIL-53(Cr) under a relatively moderate applied pressure ~50 MPa. The incorporation of CO(2) within its porosity significantly shifts the onset of such a transformation at lower pressure while it decreases the bulk modulus of this solid. PMID- 22200053 TI - Lab on a chip phased-array MR multi-platform analysis system. AB - We present a lab on a chip (LOC) compatible modular platform for magnetic resonance (MR)-based investigation of sub-millimetre samples. The platform combines the advantages offered respectively by microcoils (high resolution at the microscale) and macroscopic surface coils (large field of view) as MR detectors and consists of a phased array of microcoils (PAMs) providing a flat MR sensitive area of 18.3 mm(2) with a B(0)-field uniformity better than 0.25 ppm in the sensor centre area. We demonstrate both high-resolution magnetic resonance imaging (MRI) and NMR spectroscopy using this platform. To demonstrate the application for biological samples, we report MR imaging of fish oocytes with an in-plane resolution of 30 * 30 MUm(2) and a contrast to noise ratio of 10 for a scan time of only 13 min 39 s. We have also demonstrated high-resolution spectroscopy of a water phantom achieving 11 ppb (4.5 Hz at 400 MHz) linewidth and an SNR of 28 for only 12 s scan time. State of the art automatic wire bonding technology in conjunction with MEMS techniques has been employed to manufacture the platform with potential applications in MR-investigation of planar samples. PMID- 22200052 TI - Use of fungal derived polysaccharide-conjugated particles to probe Dectin-1 responses in innate immunity. AB - The number of life-threatening fungal infections has risen in immunocompromised patients, and identification of the rules that govern an appropriate immune response is essential to develop better diagnostics and targeted therapeutics. The outer cell wall component on pathogenic fungi consists of beta-1,3-glucan, and Dectin-1, a pattern recognition receptor present on the cell surface of innate immune cells, binds specifically to this carbohydrate. A barrier in understanding the exact immunological response to pathogen-derived carbohydrate epitopes is the presence of multiple types of carbohydrate moieties on fungal cell walls. To dissect the immunological mechanisms used to recognize pathogens, a system of "fungal like particles" was developed that consisted of polystyrene beads, which mimicked the three dimensional shape of the fungus, coated covalently with purified beta-1,3-glucan derived from Saccharomyces cerevisiae. The morphology of the beta-1,3-glucan layer was examined by immunofluorescence, flow cytometery, and immuno-transmission electron microscopy. The covalent linkages of the beta-1,3-glucan to the polystyrene surface were stable after subjecting the beads to detergents. By pre-treating beta-1,3-glucan beads with laminarinase, a specific beta-1,3-gluconase, the reactivity of the anti-beta-1,3 glucan antibody was abrogated in comparison to treatment with proteinase K indicating that the coating of these beads was predominantly beta-1,3-glucan. TNF alpha was also measured by stimulating bone-marrow derived macrophages with the beta-1,3-glucan beads, and showed a dose dependent response compared to soluble beta-glucan, insoluble beta-1,3-glucan, uncoated beads, and soluble beta-1,3 glucan mixed with uncoated beads. Finally, beta-1,3-glucan beads were incubated with GFP-Dectin-1 expressing macrophages and imaged using confocal microscopy. beta-1,3-beads were taken up within minutes and retained Dectin-1 recruitment to the phagosome as compared to uncoated beads. These data describe a unique fungal like particle system that will permit immunologists to probe the critical steps in early recognition of pathogen-derived fungal carbohydrate antigens by innate immune cells. PMID- 22200054 TI - ZnO-ZnGa2O4 core-shell nanowire array for stable photoelectrochemical water splitting. AB - A dense array of vertically aligned ZnO-ZnGa(2)O(4) core-shell nanowires was synthesized on a large scale on an a-plane sapphire substrate by a simple two step chemical vapor deposition method. The ZnO cores and ZnGa(2)O(4) shells of the nanowires are of single crystal quality and have aligned crystallographic orientations as evidenced from XRD and TEM analyses. Mott-Schottky analysis and voltage onset from the photocurrent-voltage curve confirm an n-type semiconductor property, a flat-band potential of -0.4 V (versus NHE) and a carrier density of 7 * 10(18) cm(-3) for the ZnO-ZnGa(2)O(4) core-shell nanowires. A stable and large photocurrent of 1.2 mA cm(-2) was obtained with the ZnO-ZnGa(2)O(4) core-shell nanowire array when used as a photoanode at an applied bias of +0.7 V (versus Ag/AgCl) under a 300 W xenon lamp illumination. Moreover, a low dark current of <10(-4) mA cm(-2) was obtained at an applied bias of +0.7 V (versus Ag/AgCl) without light illumination for the ZnO-ZnGa(2)O(4) nanowire array. These results suggest that the dense array of ZnO-ZnGa(2)O(4) core-shell nanowires provides enhanced electronic properties and stable anti-photocorrosion ability and, therefore, is promising as a photoanode in photoelectrochemical water splitting. PMID- 22200055 TI - Oxide nanowires for solar cell applications. AB - Oxide nanowire arrays were studied for their applications to solar cells. It was demonstrated that the nanowires could provide direct pathways for electron transport in dye-sensitized solar cells and therefore, while forming photoelectrode films, they offered better suppression of charge recombination than nanoparticles. However, the photoelectron films consisting of nanowires suffered a disadvantage in giving large surface area for dye adsorption. Such a shortcoming of nanowires had been exemplified in this paper illustrating that it could be well compensated by incorporating with nanoparticles to form a nanoparticle-nanowire array hybrid photoelectrode film. The oxide nanowires were also demonstrated to be able to enhance the performance of inverted structure polymer solar cells as a cathode buffer layer by establishing a large interface with the polymers so as to facilitate the transport of photogenerated electrons from the polymer to the electron collecting electrode. Such an enhancement effect could be further boosted while the nanowires were replaced with nanotubes; the latter may build up larger interface with the polymers than the former and therefore facilitates the electron transport more efficiently. PMID- 22200057 TI - Midwest nursing research society news. PMID- 22200056 TI - Adsorption and release of biocides with mesoporous silica nanoparticles. AB - In this proof-of-concept study, an agricultural biocide (imidacloprid) was effectively loaded into the mesoporous silica nanoparticles (MSNs) with different pore sizes, morphologies and mesoporous structures for termite control. This resulted in nanoparticles with a large surface area, tunable pore diameter and small particle size, which are ideal carriers for adsorption and controlled release of imidacloprid. The effect of pore size, surface area and mesoporous structure on uptake and release of imidacloprid was systematically studied. It was found that the adsorption amount and release profile of imidacloprid were dependent on the type of mesoporous structure and surface area of particles. Specifically, MCM-48 type mesoporous silica nanoparticles with a three dimensional (3D) open network structure and high surface area displayed the highest adsorption capacity compared to other types of silica nanoparticles. Release of imidacloprid from these nanoparticles was found to be controlled over 48 hours. Finally, in vivo laboratory testing on termite control proved the efficacy of these nanoparticles as delivery carriers for biopesticides. We believe that the present study will contribute to the design of more effective controlled and targeted delivery for other biomolecules. PMID- 22200058 TI - Potentially preventable hospitalizations among older adults with diabetes. AB - OBJECTIVES: To examine prevalence of and factors associated with different types of potentially preventable hospitalizations (PPHs) among older adults with diabetes. STUDY DESIGN: Population-based secondary analysis. METHODS: We analyzed the California State Inpatient Databases, 2005 to 2006. PPHs for 3 acute and 5 chronic ambulatory care-sensitive conditions relevant for older adults were defined by applying the Prevention Quality Indicator algorithm developed by the Agency for Health Research and Quality. Prevalence and costs of PPHs for acute conditions (acute PPHs) and chronic conditions(chronic PPHs) were examined. Associations of sociodemographic and health-related factors as well as hospitalization history with both types of PPH were estimated. RESULTS: One-fifth of 555,538 hospitalizations of adults 65 years and older with diabetes were PPHs. Of these, 43.7% were acute PPHs and 56.3%were chronic PPHs. The total hospital cost associated with these PPHs was more than$1.1 billion. Having Medi-Cal as the primary payer and hospitalization through the emergency department were positively associated with both types of PPH. Acute PPH rates were lower, but chronic PPH rates were higher, among blacks, patients with multiple chronic conditions, and those with previous admission(s) in the same year. CONCLUSIONS: PPHs for common medical conditions are costly and prevalent among older patients with diabetes, suggesting a need for more comprehensive primary care, beyond glycemic control. The groups at risk for acute and chronic PPHs may differ, which suggests that more targeted and tailored approaches are necessary to reduce the rates of each type of PPH. PMID- 22200059 TI - Medication adherence for 90-day quantities of medication dispensed through retail and mail order pharmacies. AB - OBJECTIVES: To examine relative medication adherence of patients filling 90-day supplies of maintenance medications using retail and mail order channels. It was hypothesized that adherence rates would not differ across the 2 channels. STUDY DESIGN: A cross-sectional retrospective analysis was conducted using de identified pharmacy claims data from a large pharmacy benefit manager (PBM) database over a 2-year period (January 2008 to August 2010). Patients who were continuously eligible for at least 12 months during this time frame, with benefit plan designs that allowed filling of 90-day supplies either at retail or by mail order pharmacy, were selected. METHODS: Adherence was measured by medication possession ratio (MPR) within a 1-year period. Propensity score matching was employed to minimize differences between the Retail-90 group and Mail Order-90 group. RESULTS: Overall, patients filling 90-day prescriptions for 9 therapeutic groups (antiasthmatics and bronchodilators, antidepressants, antidiabetics, antihyperlipidemics, antihypertensives, beta blockers, calcium channel blockers, diuretics, and thyroid agents) at retail pharmacies demonstrated a propensity score-matched average MPR that was statistically higher than for patients filling prescriptions via mail order (77.0% vs 76.0%). There were no significant differences in MPR (post-matching) between 90-day retail and mail order channels for individual therapeutic groups, except for antidiabetics (80.2% vs 83.1%). CONCLUSIONS: On a propensity-matched basis, patients who fill maintenance prescriptions at retail have a slightly, but statistically significantly, higher MPR than patients who fill their prescriptions by mail PMID- 22200060 TI - Preventive care for chronically ill children in medicaid managed care. AB - OBJECTIVES: To determine whether there is an association between the quality of child preventive care received and the existence of 1 or more chronic conditions. STUDY DESIGN: A retrospective study of all New York State children and adolescents enrolled in Medicaid managed care in 2008. METHODS: Using a cohort identified through mandatory annual quality reporting, a clinical algorithm was applied to administrative data to assign children to 3 health status levels: healthy/ acute, minor chronic, and significant chronic. We performed bivariate and logistic regression analyses to compare the quality of care received by these 3 groups on 10 child-relevant preventive care services. RESULTS: One-fourth of the children in our cohort were deemed to have either minor or significant chronic health conditions. Children with chronic conditions generally had a higher or equal probability of receiving recommended preventive care compared with healthy or acutely ill children, even after controlling for member characteristics. For those services where children with chronic conditions were significantly more likely to receive a preventive care service, the risk ratios ranged from 1.03 to 1.11 for minor chronic children and from 1.03 to 1.17 for significant chronic children. CONCLUSIONS: The quality of preventive health care for children with chronic conditions in New York State Medicaid managed care is equivalent to or better than that for healthy or acutely ill children. Investigating quality concerns for subpopulations of members by combining existing standardized quality measures with administrative health status data is a useful tool for informing state quality-improvement initiatives. PMID- 22200061 TI - Trends in retail clinic use among the commercially insured. AB - OBJECTIVES: To describe trends in retail clinic use among commercially insured patients and to identify which patient characteristics predict retail clinic use. STUDY DESIGN: Retrospective cohort analysis of commercial insurance claims sampled from a population of 13.3 million patients in 22 markets in 2007 to 2009. METHODS: We identified 11 simple acute conditions that can be managed at a retail clinic and described trends in retail clinic utilization for these conditions. We used multiple logistic regressions to identify predictors of retail clinic versus another care site for these conditions and assessed whether those predictors changed over time. RESULTS: Retail clinic use increased 10-fold from 2007 to 2009. By 2009, 6.9% of all visits for the 11 conditions were to a retail clinic. Proximity to a retail clinic was the strongest predictor of use. Patients living within 1 mile of a retail clinic were 7.5% more likely to use one than those living 10 to 20 miles away (P <.001). Women (+0.9%, P <.001), young adults (+1.6%, P <.001), patients without a chronic condition (+0.9%, P <.001), and patients with high incomes (+2.6%, P <.001) were more likely to use retail clinics. All these associations became stronger over time. There was no association between primary care physician availability and retail clinic use. CONCLUSIONS: If these trends continue, health plans will see a dramatic increase in retail clinic utilization. While use is increasing on average, it is particularly increasing among young, healthy, and higher income patients living close to retail clinics. PMID- 22200062 TI - US prevalence of upper gastrointestinal symptoms: a systematic literature review. AB - OBJECTIVES: To quantify the prevalence of dyspeptic and gastroesophageal symptoms and peptic ulcer disease (PUD) in the United States and to identify factors affecting their prevalence. STUDY DESIGN: Systematic search of MEDLINE and Web of Science through November 2010. METHODS: We identified studies of US patients and evaluated a general (not disease-specific) adult sample that reported the prevalence of 1 or more upper gastrointestinal (GI) outcomes of interest, including dyspeptic symptoms, gastroesophageal symptoms, dyspeptic and/or gastroesophageal symptoms, or PUD. Proportions of individuals in each study reporting each symptom were pooled to derive separate prevalence estimates. Qualitative synthesis of data depicting multivariate relationships between covariates and upper GI outcomes was undertaken. RESULTS: A total of 36 citations representing 24 studies were included: 9 studies reporting dyspeptic symptoms (n = 14,181), 14 reporting gastroesophageal symptoms (n = 58,701), 5 reporting dyspeptic and/or gastroesophageal symptoms (n = 103,175), and 7 reporting PUD prevalence (n = 269,299). The pooled prevalences of dyspeptic, gastroesophageal, and dyspeptic and/or gastroesophageal symptoms were 16.3% (95% confidence interval [CI] 9.1%-25.1%), 24.2% (95% CI 18.2%-30.5%), and 35.2% (95% CI 14.9% 58.9%). The pooled prevalence for studies asking for shorter-term PUD recall was 3.3% (95% CI 2.2%-4.6%), with lifetime PUD prevalence estimated at 13.8% (95% CI 10.7%-17.0%). The influence of covariates evaluated as part of multivariate analyses was often inconsistent. CONCLUSIONS: It appears that upper GI symptoms and disorders are common in US inhabitants. We identified patient- and study level factors that should be considered when assessing upper GI symptom prevalence and conducting future research. PMID- 22200063 TI - Retraction notice to: "The anti-inflammatory activity of 1,25-dihydroxyvitamin D3 in macrophages" [J. Steroid Biochem. Mol. Biol. 103 (2007) 558-562]. PMID- 22200064 TI - A family portrait: unravelling the complexities of palms. PMID- 22200065 TI - T-cell tolerance induced by non-Treg T-cell-derived TGF-beta1. PMID- 22200067 TI - Home care therapists: helping patients regain their lives. PMID- 22200066 TI - Treg-mediated angiogenesis and tolerance is programmed by hypoxia in the tumor microenvironment. PMID- 22200068 TI - November is Home Care & Hospice Month: celebrating the spirit of love. PMID- 22200069 TI - [Development and aging of women's bone]. PMID- 22200073 TI - Electrochemically controlled drug-mimicking protein release from iron-alginate thin-films associated with an electrode. AB - Novel biocompatible hybrid-material composed of iron-ion-cross-linked alginate with embedded protein molecules has been designed for the signal-triggered drug release. Electrochemically controlled oxidation of Fe(2+) ions in the presence of soluble natural alginate polymer and drug-mimicking protein (bovine serum albumin, BSA) results in the formation of an alginate-based thin-film cross linked by Fe(3+) ions at the electrode interface with the entrapped protein. The electrochemically generated composite thin-film was characterized by electrochemistry and atomic force microscopy (AFM). Preliminary experiments demonstrated that the electrochemically controlled deposition of the protein containing thin-film can be performed at microscale using scanning electrochemical microscopy (SECM) as the deposition tool producing polymer patterned spots potentially containing various entrapped drugs. Application of reductive potentials on the modified electrode produced Fe(2+) cations which do not keep complexation with alginate, thus resulting in the electrochemically triggered thin-film dissolution and the protein release. Different experimental parameters, such as the film-deposition time, concentrations of compounds and applied potentials, were varied in order to demonstrate that the electrodepositon and electrodissolution of the alginate composite film can be tuned to the optimum performance. A statistical modeling technique was applied to find optimal conditions for the formation of the composite thin-film for the maximal encapsulation and release of the drug-mimicking protein at the lowest possible potential. PMID- 22200075 TI - Clay and DOPA containing polyelectrolyte multilayer film for imparting anticorrosion properties to galvanized steel. AB - A facile and green approach is developed to impart remarkable protection against corrosion to galvanized steel. A protecting multilayer film is formed by alternating the deposition of a polycation bearing catechol groups, used as corrosion inhibitors, with clay that induces barrier properties. This coating does not affect the esthetical aspect of the surface and does not release any toxic molecules in the environment. PMID- 22200076 TI - Excited-state spectroscopy on an individual quantum dot using atomic force microscopy. AB - We present a new charge sensing technique for the excited-state spectroscopy of individual quantum dots, which requires no patterned electrodes. An oscillating atomic force microscope cantilever is used as a movable charge sensor as well as gate to measure the single-electron tunneling between an individual self assembled InAs quantum dot and back electrode. A set of cantilever dissipation versus bias voltage curves measured at different cantilever oscillation amplitudes forms a diagram analogous to the Coulomb diamond usually measured with transport measurements. The excited-state levels as well as the electron addition spectrum can be obtained from the diagram. In addition, a signature which can result from inelastic tunneling by phonon emission or a peak in the density of states of the electrode is also observed, which demonstrates the versatility of the technique. PMID- 22200078 TI - Government and Navy knowledge regarding health hazards of asbestos: a state of the science evaluation (1900 to 1970). AB - We evaluated dozens of published and unpublished documents describing the knowledge and awareness of both the scientific community and governmental entities, particularly the US Navy, regarding the health hazards associated with asbestos over time. We divided our analysis into specific blocks of time: 1900 1929, 1930-1959, and 1960-1970. By 1930, it was clear that high occupational exposure to asbestos caused a unique disease (asbestosis). Between about 1938 and 1965, a considerable amount of exposure and epidemiology data were collected by various scientific and government organizations. Between 1960 and 1970, mesothelioma was clearly linked to exposure to amphibole asbestos. Nonetheless, the Navy continued to require the use of asbestos-containing materials on ships, but also recommended that proper precautions be taken when handling asbestos. We concluded that the Navy was arguably one of the most knowledgeable organizations in the world regarding the health hazards of asbestos, and that it attempted to implement procedures that would minimize the opportunity for adverse effects on both servicemen and civilians. Finally, it is apparent from our research that through at least 1970, neither the military nor the private sector believed that the myriad of asbestos-containing products considered "encapsulated" (e.g. gaskets, brakes, Bakelite) posed a health hazard to those working with them. PMID- 22200079 TI - Induction by lenalidomide and dexamethasone combination increases regulatory cells of patients with previously untreated multiple myeloma. PMID- 22200080 TI - Accuracy and responsiveness of the stepwatch activity monitor and ActivPAL in patients with COPD when walking with and without a rollator. AB - PURPOSE: To evaluate the measurement properties of the StepWatch(TM) Activity Monitor (SAM) and ActivPAL in COPD. METHOD: Whilst wearing both monitors, participants performed walking tasks at two self-selected speeds, with and without a rollator. Steps obtained using the monitors were compared with that measured by direct observation. RESULTS: Twenty participants aged 73 +/- 9 years (FEV(1) = 35 +/- 13% pred; 8 males) completed the study. Average speeds for the slow and normal walking tasks were 34 +/- 7 m.min(-1)and 46 +/- 10 m.min(-1), respectively. Agreement between steps recorded by the SAM with steps counted was similar irrespective of speed or rollator use (p = 0.63) with a mean difference and limit of agreement (LOA) of 2 steps.min(-1) and 6 steps.min(-1), respectively. Agreement for the ActivPAL was worse at slow speeds (mean difference 7 steps.min(-1); LOA 10 steps.min(-1)) compared with normal speeds (mean difference 4 steps.min(-1); LOA 5 steps.min(-1)) (p = 0.03), but was unaffected by rollator use. The change in step rate between slow and normal walking via direct observation was 12 +/- 7 steps.min(-1) which was similar to that detected by the SAM (12 +/- 6 steps.min(-1)) and ActivPAL (14 +/- 7 steps.min(-1)). CONCLUSIONS: The SAM can be used to detect steps in people who walk very slowly including those who use a rollator. Both devices were sensitive to small changes. PMID- 22200082 TI - Targeted catalytic inactivation of angiotensin converting enzyme by lisinopril coupled transition-metal chelates. AB - A series of compounds that target reactive transition-metal chelates to somatic angiotensin converting enzyme (sACE-1) have been synthesized. Half-maximal inhibitory concentrations (IC(50)) and rate constants for both inactivation and cleavage of full-length sACE-1 have been determined and evaluated in terms of metal chelate size, charge, reduction potential, coordination unsaturation, and coreactant selectivity. Ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and tripeptide GGH were linked to the lysine side chain of lisinopril by 1-ethyl-3-[3 (dimethylamino)propyl]carbodiimide hydrochloride/N-hydroxysuccinimide coupling. The resulting amide-linked chelate-lisinopril (EDTA-lisinopril, NTA-lisinopril, DOTA-lisinopril, and GGH-lisinopril) conjugates were used to form coordination complexes with iron, cobalt, nickel, and copper, such that lisinopril could mediate localization of the reactive metal chelates to sACE-1. ACE activity was assayed by monitoring cleavage of the fluorogenic substrate Mca-RPPGFSAFK(Dnp) OH, a derivative of bradykinin, following preincubation with metal chelate lisinopril compounds. Concentration-dependent inhibition of sACE-1 by metal chelate-lisinopril complexes revealed IC(50) values ranging from 44 to 4500 nM for Ni-NTA-lisinopril and Ni-DOTA-lisinopril, respectively, versus 1.9 nM for lisinopril. Stronger inhibition was correlated with smaller size and lower negative charge of the attached metal chelates. Time-dependent inactivation of sACE-1 by metal chelate-lisinopril complexes revealed a remarkable range of catalytic activities, with second-order rate constants as high as 150,000 M(-1) min(-1) (Cu-GGH-lisinopril), while catalyst-mediated cleavage of sACE-1 typically occurred at much lower rates, indicating that inactivation arose primarily from side chain modification. Optimal inactivation of sACE-1 was observed when the reduction potential for the metal center was poised near 1000 mV, reflecting the difficulty of protein oxidation. This class of metal chelate-lisinopril complexes possesses a range of high-affinity binding to ACE, introduces the advantage of irreversible catalytic turnover, and marks an important step toward the development of multiple-turnover drugs for selective inactivation of sACE-1. PMID- 22200083 TI - FISH and chips: the recipe for improved prognostication and outcomes for children with medulloblastoma. AB - Rapidly evolving genomic technologies have permitted progressively detailed studies of medulloblastoma biology in recent years. These data have increased our understanding of the molecular pathogenesis of medulloblastoma, identified prognostic markers, and suggested future avenues for targeted therapy. Although current randomized trials are still stratified based largely on clinical variables, the use of molecular markers is approaching routine use in the clinic. In particular, integrated genomics has uncovered that medulloblastoma comprises four distinct molecular and clinical variants: WNT, sonic hedgehog (SHH), group 3, and group 4. Children with WNT medulloblastoma have improved survival, whereas those with group 3 medulloblastoma have a dismal prognosis. Additionally, integrated genomics has shown that adult medulloblastoma is molecularly and clinically distinct from the childhood variants. Prognostic and predictive markers identified by genomics should drive changes in stratification of treatment protocols for medulloblastoma patients on clinical trials once they can be demonstrated to be reliable, reproducible, and practical. Cases with excellent prognoses (WNT cases) should be considered for therapy de-escalation, whereas those with bleak prognoses (group 3 cases) should be prioritized for experimental therapy. In this review, we will summarize the genomic data published over the past decade and attempt to interpret its prognostic significance, relevance to the clinic, and use in upcoming clinical trials. PMID- 22200084 TI - FISH-based determination of HER2 status in circulating tumor cells isolated with the microfluidic CEETM platform. AB - Determination of HER2 status in breast cancer patients is considered standard practice for therapy selection. However, tumor biopsy in patients with recurrent and/or metastatic disease is not always feasible. Thus, circulating tumor cells (CTCs) are an alternative source of tumor cells for analysis of HER2. An antibody cocktail for recovery of variable, high- and low-, EpCAM-expressing tumor cells was developed based on FACS evaluation and then verified by CTC enumeration (based on CK and CD45 staining) with comparison to EpCAM-only and with CellSearch(r) (n=19). HER2 fluorescence in situ hybridization (FISH) on all (CK+ and CK-) captured cells was compared to HER2 status on the primary tumors (n=54) of patients with late stage metastatic/recurrent breast cancer. Capture of low EpCAM-expressing tumor cells increased from 27% to 76% when using the cocktail versus EpCAM alone, respectively. Overall, CTC detection with the OncoCEETM platform was better compared to CellSearch(r) (68% vs. 89%, respectively), and a 93% concordance in HER2 status was observed. HER2 FISH analysis of CK+ and CK- CTCs is feasible using the CEETM platform. Although larger clinical studies are warranted, the results demonstrate adequate sensitivity and specificity as needed for incorporation into laboratory testing. PMID- 22200085 TI - FOXL2 mutation and large-scale genomic imbalances in adult granulosa cell tumors of the ovary. AB - Adult granulosa cell tumors (AGCTs) are a rare class of ovarian tumors with recurrent cytogenetic abnormalities including trisomy 12, trisomy 14, monosomy 16/deletion 16q, and monosomy 22. Over 90% contain a missense point mutation (C134W) in the FOXL2 gene at 3q22.3. The relationship between FOXL2 mutation and cytogenetic abnormalities is unclear, although both are presumably early events in tumorigenesis. In addition, FOXL2 C134W mutant allele imbalance has been noted in a minority of AGCTs, but the mechanism for allelic imbalance has not yet been described. We used a microarray platform designed for formalin-fixed, paraffin embedded (FFPE) tissue specimens, the Affymetrix OncoScan FFPE Express 330K Molecular Inversion Probe (MIP) array, to explore the correlation between genomic imbalances detected by microarray and FOXL2 mutation status detected by pyrosequencing in a series of 21 archived AGCTs. Tumors were characterized by histopathologic features, stage, and alpha-inhibin expression by immunohistochemistry. All tumors were positive for inhibin, and 18/21 tumors contained a FOXL2 mutation. The most common genomic imbalances were a gain of 14q, a loss of 16q, and a loss of 22q. Three tumors showed evidence of FOXL2 mutant allele imbalance by pyrosequencing; microarray revealed a 32.5 Mb deletion encompassing FOXL2 in 1 case and a 70.9 Mb stretch of homozygosity encompassing FOXL2 in the other case. The third case, with a FOXL2 mutant allele imbalance, showed a diminished mutant allele population (32%) despite high estimated tumor content (>90%), suggesting tumor heterogeneity for the mutation. This study provides the first correlation of FOXL2 mutation status and genomic imbalances in AGCTs, and it further elucidates the mechanisms for mutant allele imbalance in cancer. PMID- 22200086 TI - Microarray-based comparative genomic hybridization of cancer targets reveals novel, recurrent genetic aberrations in the myelodysplastic syndromes. AB - The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis, cytopenias, and a risk of transformation to acute myeloid leukemia (AML). However, only approximately 50% of primary MDS patients show clonal cytogenetic aberrations. To determine whether high-resolution microarray analysis would reveal new or additional aberrations, we analyzed 35 samples derived from patients with a diagnosis or suspicion of MDS and abnormal karyotypes. We used a whole-genome oligonucleotide microarray with targeted coverage of approximately 1900 genes associated with hematologic and other cancers. Clinically relevant copy number aberrations (CNAs) were identified by microarray-based comparative genomic hybridization (aCGH) in all samples (range 1-31, median 5). In 28 of 35 samples (80%), aCGH revealed new cytogenetic aberrations not seen by karyotype or fluorescence in situ hybridization (FISH). Furthermore, 132 cryptic aberrations (<=5 Mb) were identified in 25 cases (71.4%) including deletions of NF1, RUNX1, RASSF1, CCND1, TET2, DNMT3A, HRAS, PDGFRA and FIP1L1. Additionally, aCGH clarified known complex aberrations in 17 of 35 samples (48.6%). Finally, our results using whole-genome arrays with higher density coverage targeted to cancer features demonstrate the usefulness of arrays to identify rare and cryptic recurring imbalances that may prove to be significant in disease progression or transformation to AML and may improve the suitability or efficacy of molecularly targeted therapy. PMID- 22200087 TI - A novel t(8;13)(q21;q22) translocation in a pediatric lipoma. AB - Pediatric lipomas are rare and their etiology is unknown. As in adult lipomas, a segment of 12q13-q15 has been documented as a common chromosomal rearrangement region. Here, we report a pediatric lipoma case without rearrangement of 12q13 q15 but with an apparently balanced translocation involving chromosomes 8 and 13 [t(8;13)(q21;q22)] detected by routine cytogenetic analysis, and small deletions on 5q21.1 and 8q21.11 detected by array comparative genetic hybridization. The small deletion on 8q21.11 is possibly due to chromosomal instability at the breakpoint of the translocation. PMID- 22200089 TI - Clinical consequences of increased ciprofloxacin and gentamicin resistance in patients with Escherichia coli bacteraemia in the Netherlands. AB - BACKGROUND: Escherichia coli is a common cause of bacteraemia and is increasingly resistant to ciprofloxacin and gentamicin. The primary objective of this study was to investigate how often this leads to inadequate initial antimicrobial treatment. Secondary goals were to determine factors associated with inadequate empirical therapy and to assess its impact on mortality and length of stay. METHODS: All patients with an E. coli bacteraemia hospitalized in 2008 were identified retrospectively. Initial antimicrobial therapy and clinical outcomes of all patients with an isolate resistant to gentamicin and/or ciprofloxacin (cases) were compared to those of a group of randomly selected patients in whom a gentamicin and ciprofloxacin susceptible E. coli was isolated (controls). RESULTS: One hundred and thirty-six unique patients had E. coli bacteraemia. Of these, 34 patients were identified as cases and were compared to 34 controls. Among the cases, 97% of the E. coli was resistant to ciprofloxacin and 44% to gentamicin. Resistance to amoxicillin was high in both cases (94%) and controls (65%). In 41% of the cases initial antimicrobial therapy was inadequate, compared to only 3% in the controls. The majority of inadequately treated cases had a biliary focus (64%). Infections in cases were more often healthcare-associated than infections in controls (62% vs 26%). E. coli with the same resistance pattern had been isolated before in adequately treated cases more often than in inadequately treated cases. Mortality did not differ significantly between cases and controls. CONCLUSIONS: Neither ciprofloxacin nor amoxicillin should be used as empirical therapy in patients with a presumed E. coli bacteraemia. PMID- 22200088 TI - Interleukin-1 beta and neurotrophin-3 synergistically promote neurite growth in vitro. AB - Pro-inflammatory cytokines such as interleukin-1 beta (IL-1beta) are considered to exert detrimental effects during brain trauma and in neurodegenerative disorders. Consistently, it has been demonstrated that IL-1beta suppresses neurotrophin-mediated neuronal cell survival rendering neurons vulnerable to degeneration. Since neurotrophins are also well known to strongly influence axonal plasticity, we investigated here whether IL-1beta has a similar negative impact on neurite growth. We analyzed neurite density and length of organotypic brain and spinal cord slice cultures under the influence of the neurotrophins NGF, BDNF, NT-3 and NT-4. In brain slices, only NT-3 significantly promoted neurite density and length. Surprisingly, a similar increase of neurite growth was induced by IL-1beta. Additionally, both factors increased the number of brain slices displaying maximal neurite growth. Furthermore, the co-administration of IL-1beta and NT-3 significantly increased the number of brain slices displaying maximal neurite growth compared to single treatments. These data indicate that these two factors synergistically stimulate two distinct aspects of neurite outgrowth, namely neurite density and neurite length from acute organotypic brain slices. PMID- 22200091 TI - Modulated dissolution rate from the inclusion complex of antichagasic benznidazole and cyclodextrin using hydrophilic polymer. AB - Benznidazole (BNZ) is the primary chemotherapeutic agent for treating Chagas' disease; however, its poor water solubility and irregular oral absorption lead to the treatment failure in the chronic phase. The aim of this work was to investigate the utility of the polymer hydroxypropyl methylcellulose (HPMC) in controlling the release of BNZ from solid inclusion complexes with cyclodextrin to overcome the problem of its bioavailability. Preliminary studies of solubility were conducted in solution using selected beta-cyclodextrin derivatives according to an experimental mixture design. The best cyclodextrin composition was used to produce solid-state systems by kneading in the presence or absence of HPMC. The formulations were characterized by different physico-chemical techniques, including the dissolution rate. Hydroxypropyl-beta-cyclodextrin (HPbetaCD) produced the greatest improvement in drug solubility and was selected for the development of solid systems. Assays confirmed the production of true inclusion complexes between BNZ and HPbetaCD. The dissolution rate of the BNZ-HPbetaCD system was markedly increased, while the presence of HPMC retarded drug release. An optimal formulation obtained by the combination of kneading systems developed in appropriate ratios could be a promising drug delivery system with a prolonged therapeutic effect coupled with more balanced bioavailability. The produced systems present interesting perspectives for Chagas' therapy. PMID- 22200092 TI - Health, wealth and ways of life: what can we learn from the Swedish, US and UK experience? Overview. PMID- 22200093 TI - New findings do not support the neomaterialist theory of the relation between income inequality and infant mortality. PMID- 22200094 TI - Conjunctival stromal tumor: report of 4 cases. AB - PURPOSE: To describe the clinical, histopathologic, immunohistochemical, and ultrastructural features of a case series of benign stromal tumors in the bulbar conjunctiva. DESIGN: Observational case series. PARTICIPANTS: Four patients with a conjunctival lesion that were classified histologically as low-grade stromal tumors consisting of spindle-shaped cells with occasional pseudonuclear inclusion and multinucleated cells in a partly myxoid matrix. METHODS: Four cases of low grade conjunctival stromal tumors were retrospectively identified in an ophthalmic pathology laboratory database. Patients' records were analyzed for demographic data, clinical appearance, and the postoperative course. Formalin fixed, paraffin-embedded specimens were routinely processed and stained with hematoxylin and eosin and periodic acid Schiff. Immunohistochemical stains for vimentin, S100, CD34, smooth muscle actin (SMA), CD68, and factor XIIIa were performed. Transmission electron microscopy (TEM) was performed on 3 of the cases. MAIN OUTCOME MEASURES: Histopathologic evaluation (including immunostains and TEM) and clinical correlation. RESULTS: All 4 tumors occurred in the bulbar conjunctiva of patients between 41 to 53 years of age. None of the patients developed recurrence after excisional biopsy. Histologically, all tumors exhibited spindle-shaped cells with pseudonuclear inclusions and occasional multinuclear cells. Mitotic figures were not observed. The stroma seemed to be myxoid to collagenous. Immunohistochemical stains were positive for CD34, vimentin, and focally for CD68, but were negative for S100 and SMA. CONCLUSIONS: We propose to classify these benign lesions, which share distinct histopathologic features, as "conjunctival stromal tumors." A reactive/inflammatory component needs to be considered in the pathogenesis of this lesion. PMID- 22200095 TI - Overgeneralized autobiographical memory and future thinking in combat veterans with posttraumatic stress disorder. AB - BACKGROUND: Studies show that individuals with Posttraumatic Stress Disorder (PTSD) tend to recall autobiographical memories with decreased episodic specificity. A growing body of research has demonstrated that the mechanisms involved in recalling autobiographical memories overlap considerably with those involved in imagining the future. Although shared autobiographical deficits in remembering the past and imagining the future have been observed in other clinical populations, this has yet to be examined in PTSD. This study examined whether, compared to combat trauma-exposed individuals without PTSD, those with combat-related PTSD would be more likely to generate overgeneralized autobiographical memories and imagined future events. METHOD: Operation Enduring/Iraqi Freedom (OEF/OIF) veterans with and without PTSD were presented with neutral word cues and were instructed to generate memories or imagine future autobiographical events. Responses were digitally recorded and were coded for level of episodic specificity and content related to combat trauma. RESULTS: Individuals with PTSD were more likely to generate overgeneral autobiographical memories and future events than individuals without PTSD, and were more likely to incorporate content associated with combat when remembering the past or thinking about the future. LIMITATION: Limitations of the study include a cross-sectional design, precluding causality; the lack of a non-trauma exposed group, relatively small sample, and almost all-male gender of participants, limiting the generalizability to other populations. CONCLUSION: These findings suggest that individuals with PTSD show similar deficits when generating personal past and future events, which may represent a previously unexamined mechanism involved in the maintenance of PTSD symptoms. PMID- 22200096 TI - Intention to use a combined contraceptive method and decision after counselling in Switzerland--Swiss data from the European CHOICE study. AB - BACKGROUND: Considering the advantages of parenteral routes of administration of combined hormonal contraceptives (CHCs), their low prevalence of use in Europe is surprising. The Contraceptive health research of informed choice experience (CHOICE) study involved 11 European countries. It aimed at evaluating the influence of counselling on users' choice between three modalities of CHC administration (the pill, the transdermal patch, and the vaginal ring). We report here the results for Switzerland. STUDY DESIGN: Women (N = 2629) with a need for contraception received extended counselling. Questionnaires were used to collect data about the women's preferred method before and after counselling, and the reasons for their ultimate decision. RESULTS: After counselling, 40% of the women chose a contraceptive method that was different from the one initially intended. The number of vaginal ring users (28% vs. 11% intended) and patch users (7% vs. 4% intended) increased (p < 0.0001). Of the initially undecided women, 93% chose a contraceptive method after counselling. However, although information was provided on the risks, side effects and benefits associated with the different contraceptive methods, surprisingly few women retained this knowledge. CONCLUSION: The provision of balanced information on all CHCs influenced women's decisions to a great extent. Unlike the pill, non-oral methods were significantly more often chosen. PMID- 22200100 TI - Use of InfCare HIV to identify and characterize suboptimally treated HIV patients at a Danish HIV clinic: a cross-sectional cohort study. AB - BACKGROUND: The software program InfCare HIV is a combined clinical decision support tool and database. This study investigated the usefulness of InfCare HIV for identifying and characterizing suboptimally treated HIV-infected patients at a Danish HIV clinic. METHODS: This cross-sectional cohort study included data on all HIV-infected patients treated at the Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark on a specific date. InfCare HIV was used to identify and characterize suboptimally treated patients defined as patients with virological failure (VF) or untreated patients with a CD4 + count below 350 cells/MUl. Patient characteristics were analyzed (i.e. age, sex, ethnicity, and nadir and latest CD4 + cell count). Treatment history and reasons for suboptimal treatment were also investigated. RESULTS: Among all 530 patients, 421 were receiving highly active antiretroviral therapy (HAART) and had undergone at least 48 weeks of treatment on 29 October 2010. Of these, 27 (6.4%) had ongoing VF. Four were untreated despite a CD4 + count below 350 cells/MUl. Among patients on HAART, patients with VF were younger and had lower median nadir CD4 + cell counts than patients without VF. Further, 33.3% (6/18) of African Black men but only 4.1% (10/244) of Caucasian men on HAART had VF (p < 0.001). The primary reason for VF was non-adherence. Three untreated patients had refused HAART, and 1 was not treated because of concerns of non-adherence. CONCLUSIONS: InfCare HIV was successfully used to identify patients with suboptimal treatment. A surprisingly high percentage of African Black men had VF. PMID- 22200101 TI - Osteosarcoma of the patella: a case report. AB - We present a rare case of osteosarcoma involving the patella. A 30-year-old Japanese woman first consulted our out-patient clinic with a 2-year history of knee pain. Radiographs showed an enlargement of the patella with irregular distribution of both osteolytic and sclerotic lesions. Computed tomography and magnetic resonance imaging demonstrated soft tissue extension at the anterior part of the patella. Incisional biopsy showed abundant osteoid formation by spindle-shaped malignant cells, and the histological diagnosis was conventional osteosarcoma. The patient underwent preoperative chemotherapy, but there was no response. Furthermore, she developed a pathological fracture during chemotherapy. She underwent above-the-knee amputation with postoperative chemotherapy. She developed multiple metastases in the thoracic vertebrae 20 months after the surgery. At the most recent examination, she remains alive with multiple spinal metastases without paralysis 4 years after the surgery. PMID- 22200102 TI - Determinants for a low health-related quality of life in asthmatics. AB - People with asthma suffer from impaired health-related quality of life (HRQL), but the determinants of HRQL among asthmatics are not completely understood. The aim of this investigation was to study determinants of low HRQL in asthmatics and to study whether the determinants of HRQL differ between sexes and age groups. A cohort of three age groups in Sweden was investigated in 1990 using a questionnaire with focus on respiratory symptoms. To study quality of life, the generic instrument Gothenburg Quality of Life was used. The participants were also investigated with interviews, spirometry, and allergy testing. Asthma was diagnosed in 616 subjects. Fifty-eight per cent (n = 359) of the subjects were women; and 24% were smokers, 22% ex-smokers, and 54% were non-smokers. Women were more likely than men to report poor health-related quality of life. Respiratory symptoms severity was another independent determinant of a lower quality of life as well as airway responsiveness to irritants. Current and former smokers also reported lower quality of life. Finally, absenteeism from school and work was associated with lower quality of life. Factors such as sex, smoking habits, airway responsiveness to irritants, respiratory symptom severity, allergy, and absenteeism from school and work were associated with low HRQL in asthmatics. PMID- 22200104 TI - Attitude of German gynecologists towards prescribing HRT before and after the WHI study. AB - OBJECTIVE: The publication of the Women's Health Initiative (WHI) randomized, controlled trial in 2002 resulted in a critical discussion on the risks and benefits of hormone replacement therapy (HRT). The present study aims to evaluate the attitude of German gynecologists regarding changes in the prescription of HRT over recent years. Method A questionnaire was sent to all 9589 German gynecologists in private practice in November 2010. RESULTS: The response rate was 2548 (26.6%). Whereas 82.2% of the responders stated that their advice for primary hormone therapy and alternative agents depended on the severity of symptoms, 9.1% of the responders would recommend HRT in the first place (male: 14.3%; female: 6.1%; p < 0.001). An age limit for hormone prescription was stated by 26.2%, with a mean age limit of 63 +/- 5.3 years. An increasing number of patients and becoming more critical about HRT after the WHI was mentioned by 79.8%. Of the responding doctors, 43.9% found that their patients were badly informed by the media, 44.5% stated they were moderately or well (10.1%) informed, whereas only 1% considered their patients to be very well informed. HRT was prescribed for the relief of vasomotor symptoms by 97.4% of responders, making this the primary indication. This percentage decreased slightly to 92.6% between 2003 and 2008 (p < 0.001) and increased again to a similar level at the beginning of 2010 (96.7%, p < 0.05). CONCLUSION: German gynecologists generally have a positive attitude towards HRT, but find it important to focus on the evaluation of the risk-benefit ratio. The major barriers to prescription are multiple concerns of the patients resulting from non-objective media. PMID- 22200105 TI - User satisfaction with orthotic and prosthetic devices and services of a single clinic. AB - PURPOSE: To evaluate the user satisfaction with orthotic and prosthetic (O & P) devices and services of a single clinic. METHOD: In this survey, 293 volunteer users of a private O & P facility (172 women, 121 men) in Iran were participated. User satisfaction was evaluated with the O & P Users' Survey. RESULTS: For device satisfaction, the highest satisfaction was for well fitting of device (2.6 +/- 0.8) and the lowest satisfaction was for the appearance of the device (1.6 +/- 1.4). For service satisfaction, the highest satisfaction was for being shown an appropriate level of courtesy and respect by staff (3.3 +/- 0.7), and the lowest satisfaction was for coordination between O & P staff and the users' therapists and doctors (1.2 +/- 1.3). CONCLUSIONS: Most of patients agreed that their devices were fitted well and the higher concerns were related to the appearance, durability, wear and tear of the cloths, and price of their devices. Users agreed that they were treated with a high level of courtesy and respect by O & P staff, but that the staff did not coordinate services adequately with their therapists and doctors. User participation in the decision-making process was also rated as poor. Our findings may represent valuable information which can be applied to improve O & P facilities in developing countries. PMID- 22200106 TI - Single-sided and small-scaled grasping of delicate tissues: effectiveness of indirect heat-induced attachment and detachment. AB - INTRODUCTION: Indirect heat-induced attachment and detachment (iHIAD) is a promising concept for gripping delicate tissues in microsurgery. However, the optimal settings of iHIAD are unknown. This study evaluates the effects of the instrument heating properties and initial contact force on the adhesion force, detachment success and thermal damage. MATERIAL AND METHODS: An instrument prototype was developed to test attachment and detachment for different combinations of generated energy (3.5-20.0 mJ) and pulse length (0.25-2.50 ms). The tissues tested on were kidney and eye from the pig. Thermal tissue damage was estimated with a histological analysis. RESULTS: The adhesion force F(a) depended strongly on the amount of generated energy (F(a) = 0.03-2.5 mN) and contact force (F(a) = 0.25-1.0 mN). Pulse length played a minor role. Detachment success (0 100%) was determined by generated energy (3-16 mJ). Histological analysis showed minimal damage. CONCLUSION: Adhesion forces increased with increasing contact forces. iHIAD proved sensitive to heating characteristics. Detachment success increased with generated energy. Thermal damage was minimal. iHIAD creates a potential to build better performing tissue manipulators. PMID- 22200107 TI - Advantages of single-incision laparoscopic appendectomy should not be just cosmetics. PMID- 22200108 TI - Swelling-induced delamination causes folding of surface-tethered polymer gels. AB - When a polymer film that is weakly attached to a rigid substrate is exposed to solvent, swelling-induced compressive stress nucleates buckle delamination of the film from the substrate. Surprisingly, the buckles do not have a sinusoidal profile, instead, the film near the delamination buckles slides toward the buckles causing growth of sharp folds of high aspect ratio. These folds do not result from a wrinkle-to-fold transition; instead, the film goes directly from a flat state to a folded state. The folds persist even after the solvent evaporates. We propose that patterned delamination and folding may be exploited to realize high-aspect ratio topological features on surfaces through control of a set of boundary constraints arising from the interrelation of film-surface adhesion, film thickness and degree of swellabilty. PMID- 22200109 TI - Knowledge-attitude-practice survey among Portuguese gynaecologists regarding combined hormonal contraceptives methods. AB - ABSTRACT Objectives To evaluate knowledge, attitude and practices of Portuguese gynaecologists regarding combined hormonal contraceptives. Methods A cross sectional survey was conducted among 303 gynaecologists. Results Ninety percent of the gynaecologists considered that deciding on contraceptive methods is a process wherein the woman has her say. Efficacy, safety and the woman's preference were the major factors influencing gynaecologists, while efficacy, tolerability and ease of use were the major factors perceived by the specialists to influence the women's choice. Gynaecologists believed that only 2% of women taking the pill were 100% compliant compared to 48% of those using the patch and 75% of those using the ring. The lower risk of omission was the strong point for the latter methods. Side effects were the main reason to change to another method. Vaginal manipulation was the most difficult topic to discuss. Conclusions Most gynaecologists decided with the woman on the contraceptive method. The main reasons for the gynaecologist's recommendation of a given contraceptive method and the women's choice were different. Counselling implies an open discussion and topics related to sexuality were considered difficult to discuss. Improving communication skills and understanding women's requirements are critical for contraceptive counselling. PMID- 22200110 TI - Preventive measures against sexually transmitted infections among female sex workers in Lanzhou, China. AB - BACKGROUND: We assessed the effects of preventive practices on sexually transmitted infections (STIs) and reproductive tract infections (RTIs) among female sex workers (FSWs) in Lanzhou, China. METHODS: A cross-sectional survey was conducted among 350 FSWs from November 2008 to January 2009. Demographic information and behavioural factors associated with STIs were collected from all the participants. Blood samples and cervical swabs were obtained, and genital and cervical examinations were done at the collection site. A multivariate logistic regression model was used to analyze the relationships between preventive measures and the incidences of STIs and RTIs. RESULTS: The utilization rates of vaginal douching (VD), regular intravenous infusion (RII), and prophylactic oral antibiotics (POA) among FSWs were 72.9%, 35.7%, and 36.3%, respectively. The preventive measures had no impact on diagnosed STIs. On the contrary, the use of VD + POA could increase the risk of vaginal infection by 2-fold (odds ratio (OR) 2.9, 95% credible interval (95% CI) 1.3-6.7). Moreover, the risk for cervical infection increased with the use of POA alone (OR 4.0, 95% CI 1.1-15.4), VD + POA (OR 4.2, 95% CI 1.7-10.3), and VD + RII (OR 2.5, 95% CI 1.1-5.7). CONCLUSIONS: VD, RII, and POA, which were used widely by FSWs to prevent STIs after sex with their clients, were assumed to prevent STIs. Instead, our study indicates that they could increase the risk of vaginal or cervical infections. Therefore, FSWs should be informed of proper preventive strategies to reduce the incidence. PMID- 22200112 TI - Biomolecule-coated metal nanoparticles on titanium. AB - Immobilizations of nanoparticles and biomolecules on biocompatible substrates such as titanium are two promising approaches to bringing new functionalities to Ti-based biomaterials. Herein, we used a variety of X-ray spectroscopic techniques to study and better understand metal-thiolate interactions in biofunctionalized metal nanoparticle systems supported on Ti substrates. Using a facile one-step procedure, a series of Au nanoparticle samples with varied biomolecule coatings ((2-mercatopropionyl)glycine (MPG) and bovine serum albumin (BSA)) and biomolecule concentrations are prepared. Ag and Pd systems are also studied to observe change with varying metal composition. The structure and properties of these biomolecule-coated nanoparticles are investigated with scanning electron microscopy (SEM) and element-specific X-ray techniques, including extended X-ray absorption fine structure (Au L(3)-edge), X-ray absorption near-edge structure (Au L(3), Ag L(3), Pd L(3), and S K-edge), and X ray photoelectron spectroscopy (Au 4f, Ag 3d, Pd 3d, and S 2p core level). It was found that, by comparison of SEM and X-ray spectroscopy results, the coating of metal nanoparticles with varying model biomolecule systems can have a significant effect on both surface coverage and organization. This work offers a facile chemical method for bio- and nanofunctionalization of Ti substrates as well as provides a physical picture of the structure and bonding of biocoated metal nanoparticles, which may lead to useful applications in orthopedics and biomedicine. PMID- 22200116 TI - A locus-specific database for mutations in GDAP1 allows analysis of genotype phenotype correlations in Charcot-Marie-Tooth diseases type 4A and 2K. AB - BACKGROUND: The ganglioside-induced differentiation-associated protein 1 gene (GDAP1), which is involved in the Charcot-Marie-Tooth disease (CMT), the most commonly inherited peripheral neuropathy, encodes a protein anchored to the mitochondrial outer membrane. The phenotypic presentations of patients carrying GDAP1 mutations are heterogeneous, making it difficult to determine genotype phenotype correlations, since the majority of the mutations have been found in only a few unrelated patients. Locus-specific databases (LSDB) established in the framework of the Human Variome Project provide powerful tools for the investigation of such rare diseases. METHODS AND RESULTS: We report the development of a publicly accessible LSDB for the GDAP1 gene. The GDAP1 LSDB has adopted the Leiden Open-source Variation Database (LOVD) software platform. This database, which now contains 57 unique variants reported in 179 cases of CMT, offers a detailed description of the molecular, clinical and electrophysiological data of the patients. The usefulness of the GDAP1 database is illustrated by the finding that GDAP1 mutations lead to primary axonal damage in CMT, with secondary demyelination in the more severe cases of the disease. CONCLUSION: Findings of this nature should lead to a better understanding of the pathophysiology of CMT. Finally, the GDAP1 LSDB, which is part of the mitodyn.org portal of databases of genes incriminated in disorders involving mitochondrial dynamics and bioenergetics, should yield new insights into mitochondrial diseases. PMID- 22200121 TI - Over-treatment of carbapenemase-producing Enterobacteriaceae. AB - OBJECTIVES: To describe the treatment and outcomes of patients with carbapenemase producing Enterobacteriaceae and evaluate whether these cases represented active infection requiring antibiotic therapy or colonization. METHODS: Adult inpatients with carbapenemase-producing Enterobacteriaceae were retrospectively evaluated. Cases were classified as colonization versus infection by 2 infectious diseases physicians. Multiple cultures that grew in the same patient within a 2-week period were evaluated as a single case. RESULTS: A total of 42 cases among 35 patients were identified. The mean age of the cohort was 67.7 +/- 13.7 y, mean APACHE II score was 17.9 +/- 8.6, and 77% of patients were in the intensive care unit when the carbapenem-producing Enterobacteriaceae was isolated. Klebsiella pneumoniae (84%) was the predominant organism; urine (36%), tissue/wound/drainage (25%), and blood (20%) were the most common sites of collection. Though 43% of cases were classified as colonization, 56% of these cases were treated with antibiotics. Only 1 patient characterized as colonized subsequently developed infection, 29 days later. Among infected cases, colistin (55%), meropenem (41%), aminoglycosides (32%), and tigecycline (27%) were used for treatment, and combination antimicrobial therapy was common (55%). Clinical and microbiological success was higher in patients receiving combination therapy (83% vs 60%, p = 0.35). Colistin monotherapy was only successful in urinary infections. All-cause hospital mortality was 29%. CONCLUSIONS: Nearly half of cases represented colonization, yet the majority were treated with broad-spectrum antibiotics. Determining infection versus colonization is a critical first step in managing patients with carbapenemase-producing Enterobacteriaceae. The risk of not treating apparent colonization appears low. PMID- 22200122 TI - Preparation and in vivo evaluation of spray dried matrix type controlled-release microparticles of tamsulosin hydrochloride for orally disintegrating tablet. AB - The objective of this study was to achieve an optimal formulation of spray dried matrix type controlled-release (MTCR) microparticles containing tamsulosin hydrochloride for orally disintegrating tablet. To control the release rate of tamsulosin hydrochloride, Acrylate-methacrylate copolymer (Eudragit((r)) L-100 or Eudragit((r)) S-100) and ethylcellulose were employed on the composition of MTCR microparticles. Physicochemical properties of MTCR microparticles such as particle size and SEM were characterized. Pharmacokinetic parameters of tamsulosin hydrochloride were evaluated in the rats after oral administration. MTCR microparticles were spherical microparticles of around 10 um diameter with a corrugated surface. ODTs containing MTCR microparticles were disintegrated within 30 s and MTCR microparticles were able to control the release rate of tamsulosin hydrochloride following Fickian diffusion mechanism. The in vitro release rates of tamsulosin hydrochloride from MTCR microparticles were proportional to the ratio of Acrylate-methacrylate copolymer to ethylcellulose. Moreover, MTCR microparticles retarded the in vivo release rate of tamsulosin hydrochloride without reducing the bioavailability. Our results suggest that MTCR microparticles may be potential oral dosage forms to control the release and to improve the bioavailability of tamsulosin hydrochloride. PMID- 22200123 TI - 3-Dimensional reconstruction of the venous system in patients suffering from pulsatile tinnitus. AB - CONCLUSIONS: An abrupt change in the venous caliber, producing turbulent flow, may be a cause of pulsatile tinnitus (PT). The largest area/smallest area (L/S) ratio >4.75 may be a criterion indicating abrupt caliber change and causing PT. OBJECTIVES: Contrast-enhanced CT is recommended as an initial work-up modality in PT. But, in the majority of cases, no definite pathology can be found, even after extensive work-up. In these cases, the unilateral dominant venous system may be the cause of PT. The aim of this study was to compare, through 3D-reformatted images of the intracranial venous system, the volume, cross-sectional area, and caliber changes in patients with PT and normal controls. METHODS: This was a cross-sectional study set in a tertiary referral center. Eleven patients (11 unilateral PT ears) and 12 normal control ears were enrolled. All the subjects were confirmed with normal CT angiography findings. The intracranial venous structure was three-dimensionally reconstructed. Three areas with the largest and the smallest dimension were selected for further analysis: the transverse sinus (T), isthmus (I), and the jugular bulb (B). The total volume, cross-sectional area, and cross-sectional area ratios of the three areas were compared in the PT group and the normal control group. RESULTS: The L/S ratio was significantly increased in the PT group (5.01), compared with the control group (3.42). When the threshold value of the L/S ratio was assessed by the ROC method, 4.75 seemed to be the significant dissecting point. The sensitivity of this method was 0.64 and the specificity was 0.83. PMID- 22200124 TI - Photovoltaic device performance of single-walled carbon nanotube and polyaniline films on n-Si: device structure analysis. AB - In this paper, we explore the use of two organic materials that have been touted for use as photovoltaic (PV) materials: inherently conducting polymers (ICPs) and carbon nanotubes (CNTs). Due to these materials' attractive features, such as environmental stability and tunable electrical properties, our focus here is to evaluate the use of polyaniline (PANI) and single wall carbon nanotube (SWNT) films in heterojunction diode devices. The devices are characterized by electron microscopy (film morphology), current-voltage characteristics (photovoltaic behavior), and UV/visible/NIR spectroscopy (light absorption). We have found that both PANI and SWNT can be utilized as photovoltaic materials in a simple bilayer configuration with n-type Silicon: n-Si/PANI and n-Si/SWNT. It was our aim to determine how photovoltaic performance was affected utilizing both PANI and SWNT layers in multilayer devices: n-Si/PANI/SWNT and n-Si/SWNT/PANI. The short circuit current density increased from 4.91 mA/cm(2) (n-Si/PANI) to 12.41 mA/cm(2) (n-Si/PANI/SWNT), while an increase in power conversion efficiency by ~91% was also observed. In the case of n-Si/SWNT/PANI and its corresponding device control (n-Si/SWNT), the short-circuit current density was decreased by an order of magnitude. The characteristics of the device were affected by the architecture and the findings have been attributed to the more effective transport of holes from the PANI to SWNT and less effective transport of holes from PANI to SWNT in the respective multilayer devices. PMID- 22200125 TI - Identifying factors associated with self-rated health according to age at onset of disability. AB - PURPOSE: Although later-onset disability has been associated with poor self-rated health (SRH), factors mediating differences in SRH related to age at onset of disability remain unclear. The present study was designed to identify the variables explaining poor SRH in later-onset disability. We examined chronic disease and functional status as alternatives to psychosocial adaptation as explanatory variables. METHOD: Our data were taken from the seventh National Survey for People with Disabilities among Korean individuals >=18 years of age (n =5311). RESULTS: Those with later-onset disability (onset ages 20-40, 41-64 and >=65 years) showed higher age-adjusted odds ratios (ORs) for poor SRH compared with those with earlier-onset disability (onset ages 0-19 years). The ORs for poor SRH in individuals with later-onset disability were not substantially changed after adjusting for confounding variables including alternatives to psychosocial adaptation (chronic diseases and functional status) as explanatory variables. CONCLUSIONS: Failure to explain poor SRH in later-onset disability with explanatory variables other than psychosocial adaptation indirectly supports the role of psychosocial adaptation in differences in SRH related to age at onset. Because we could not include appropriate measures of psychosocial adaptation, the use of additional instruments should be considered in future studies. PMID- 22200126 TI - Sexual health problems of adolescents attending a sexual health service. AB - OBJECTIVE: To determine whether adolescents who present at a sexual health service aged 13 have more sexual health problems in later years than those who present aged 15. METHODS: A case-note review was done in 2009 to identify sexual health problems for all 13-year-olds who registered with Sandyford sexual health service from April 2003 until December 2004 (group 1). This was compared with selected notes from adolescents who were 15 years old at the time of registration (group 2). RESULTS: Eighty-eight youths aged 13 and 632 aged 15 registered in the aforementioned period. Ninety records of 15-year-olds were selected for comparison. Twenty two of the 86 girls in group 1 and 31 of the 87 girls in group 2 had at least one pregnancy. Twenty-one adolescents in group 1 and 25 of those in group 2 had a sexually transmitted infection. Thirteen youths in group 1 and one in group 2 had suffered a sexual assault. CONCLUSION: Adolescents aged 13 at first registration with this service have more sexual health problems and warrant additional support throughout their teenage years. A very young age at first registration should prompt health professionals to provide additional clinical, emotional and social support. PMID- 22200129 TI - Brain stimulation in neuropsychiatry. PMID- 22200130 TI - The use of ECT and MST in treating depression. AB - Electroconvulsive therapy (ECT) has been used clinically since 1938. Its most common use is in the treatment of depression: first line treatment where rapid recovery is a priority, but more frequently as an effective treatment for patients who do not respond to pharmacological and psychological approaches. Whilst it is widely hailed as an effective treatment, concerns about its effect on cognition remain. The development of magnetic seizure therapy (MST) over the past decade has attempted to devise a therapy with comparable efficacy to ECT, but without the associated cognitive side effects. The rationale for this is that MST uses magnetic fields to induce seizures in the cortex, without electrical stimulation of brain structures involved with memory. MST has been used successfully in the treatment of depression, yet there is a dearth of literature in comparison with ECT. We present a systematic review of the literature on ECT (from 2009-2011) and MST (from 2001-2011). PMID- 22200131 TI - A systematic review of the neurocognitive effects of magnetic seizure therapy. AB - Magnetic seizure therapy (MST) is a novel neurotherapeutic intervention in development for the treatment of major affective disorders. Like other neurotherapeutic strategies such as electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS), a primary interest will be to monitor the associated neurocognitive effects. Thus, the purpose of this systematic review was to synthesize the available data on the neurocognitive effects of MST. The authors performed two independent literature searches with the following terms terms: MST, magnetic, magnetic seizure therapy, depression, neurocognition, cognitive, preclinical. We included in this review a total of eleven articles that mentioned MST and neurocognition in the abstract. The articles were divided into three methodological domains that included virtual computer simulations, preclinical studies, and clinical investigations. Collectively, the available evidence suggests MST has little to no adverse cognitive effects. Specifically, virtual computer simulations found the magnetic field was localized to grey matter, and preclinical studies found no neurocortical or neurocognitive sequelae. Clinical investigations found MST to be associated with rapid reorientation and intact anterograde and retrograde memory. Future investigations using translational methods are warranted to confirm these findings and to further determine the effects of MST on neurocognitive functions. PMID- 22200132 TI - Neurostimulation therapies for treatment resistant depression: a focus on vagus nerve stimulation and deep brain stimulation. AB - Antidepressant treatments, including pharmacotherapy and psychotherapy, do not result in remission for the majority of patients with major depressive disorder. The high prevalence of treatment resistant depression (TRD) poses a significant issue for patients as well as both societal and economic costs. Due to the limited efficacy of existing therapies in this sub-population, alternative somatic treatments are being explored. Both vagus nerve stimulation (VNS) and deep brain stimulation (DBS) are neurostimulation treatments for TRD. While VNS has Food Drug Administration approval as an adjunctive therapy for MDD, DBS is still in the experimental stages. This article will review the evidence supporting the clinical utility of these therapies. PMID- 22200134 TI - Applications of transcranial magnetic stimulation (TMS) in child and adolescent psychiatry. AB - Transcranial magnetic stimulation (TMS) is emerging as a new treatment and neurophysiological research tool for psychiatric disorders. Recent publications suggest that this modality will also serve as a treatment and research tool in child and adolescent psychiatry. Current reports on therapeutic trials of repetitive transcranial magnetic stimulation (rTMS) in adolescents have primarily focused on depression. However, other pilot work involves the treatment of attention-deficit/hyperactivity disorder (ADHD), autism and schizophrenia. Neurophysiological studies typically utilize single and paired-pulse TMS paradigms which index cortical excitability and inhibition. Initial studies have focused on ADHD, autism, and depression. General knowledge regarding TMS among child and adolescent psychiatrists is lacking. The aim of this review is to provide an overview of TMS in the context of child and adolescent psychiatry, discuss recent therapeutic and neurophysiological studies, and examine relevant ethical considerations. PMID- 22200135 TI - Repetitive transcranial magnetic stimulation and drug addiction. AB - Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that is now being tested for its ability to treat addiction. This review discusses current research approaches and results of studies which measured the therapeutic use of rTMS to treat tobacco, alcohol and illicit drug addiction. The research in this area is limited and therefore all studies evaluating the therapeutic use of rTMS in tobacco, alcohol or illicit drug addiction were retained including case studies through NCBI PubMed ( http://www.ncbi.nlm.nih.gov ) and manual searches. A total of eight studies were identified that examined the ability of rTMS to treat tobacco, alcohol and cocaine addiction. The results of this review indicate that rTMS is effective in reducing the level of cravings for smoking, alcohol, and cocaine when applied at high frequencies to the dorsolateral prefrontal cortex (DLPFC). Furthermore, these studies suggest that repeated sessions of high frequency rTMS over the DLPFC may be most effective in reducing the level of smoking and alcohol consumption. Although work in this area is limited, this review indicates that rTMS is a promising modality for treating drug addiction. PMID- 22200133 TI - Treatment of late-life depression: a role of non-invasive brain stimulation techniques. AB - Late-life depression (LLD) is a frequent complication of the ageing process, occurring in up to 5% of community-dwelling elderly and in a higher proportion of subjects with coexistent medical illnesses. Its presence has been consistently associated with cognitive impairment, greater disability and increased mortality. Approximately half of patients with LLD have evidence of subcortical ischaemic damage in prefrontal circuits revealed by MRI. This might constitute the biological substrate of the cardinal symptoms of depression and of executive dysfunction. An important proportion of patients with LLD do not achieve remission of their depressive symptoms in spite of adequate pharmacological and psychotherapeutic treatment. In addition, a group of LLD patients progress to further impairment and disability in the form of a dementing disorder. There is an imperative need to develop new treatment strategies for LLD. Non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are safe and efficacious interventions that might be used in combination with other therapeutic options to improve treatment outcomes. However, there are still questions regarding the optimal way in which rTMS and dTCS should be delivered as well as to the way in which we may identify the subjects who will benefit the most from these interventions. PMID- 22200136 TI - Combining functional imaging with brain stimulation in Parkinson's disease. AB - Brain stimulation techniques such as deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS) constitute promising clinical and research tools to investigate neural mechanisms underlying neurological and psychiatric diseases. They have enormous potential in modifying brain activity and subsequent function. However, it is still a matter of debate how either of these stimulation approaches operates to produce the clinical outcomes observed in patients. The combination of these techniques with functional neuroimaging is contributing significantly to disentangle the mechanisms through which brain stimulation affects neuronal activity and related networks. In the present review we outline the research done to date on the effects of DBS and TMS on motor, cognition and behaviour in Parkinson's disease (PD) with particular emphasis on neuroimaging. PMID- 22200137 TI - Transcranial magnetic stimulation, deep brain stimulation and personal identity: ethical questions, and neuroethical approaches for medical practice. AB - Neurotechnology provides means to engage micro- and macrostructural networks of the brain to both mitigate the manifestations of several neurological and psychiatric disorders, and alter cognition and motoric activity. Such capacity also generates questions of how these interventions may affect personal identity. This paper discusses the ethical implications regarding changes to personal identity that arise from the therapeutic use of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) technologies. In addition, we raise the question of whether changes in personal identity, as a side effect of these interventions, are ethically acceptable and whether such alterations of personality foster patients' sense of well-being and autonomy. First, we provide a series of case vignettes that afford an overview of the ways that various neurological interventions can affect personal identity. Second, we offer a brief working definition of personal identity in order to delineate an ethical framework that we deem necessary for the responsible use of neurostimulation technologies. In so doing, we argue that neurostimulation therapy, as a doctoring act, should be directed, and adherent to goals of restoring and/or preserving patients' personal identity. To this end, we offer an ethical framework that we believe enables sound decisions about the right and good use of TMS and DBS. PMID- 22200138 TI - Deep brain stimulation, personal identity and policy. AB - A range of implantable brain-interfacing devices (IBIDs) is currently in use and development for the treatment of movement disorders and disorders of mood, behaviour and thought. These include cochlear implants, deep brain stimulation (DBS), prosthetic limbs, and optogenetic interventions (the combined use of genetics and optics to control individual cells). While implantable non-brain devices, such as implantable cardioverter defibrillators, began receiving US Food and Drug Administration approval in 1980, the development of IBIDs is recent, with the approval of DBS for Parkinson's disease in 1997. The expansion in use of IBIDs from neurological to psychiatric conditions is even more recent, with current trials underway for a range of disorders including depression, OCD, addiction, Alzheimer's disease and Tourette's syndrome. Emerging applications of existing IBIDs and new devices in development differ from currently approved devices and applications in two potentially crucial ways: 1) They target conditions traditionally seen as psychiatric; and/or 2) They target and modify functions or traits tied closely to agency, personal identity and personhood. As such, understanding patients' and caregivers' conceptions of personal identity in the context of disease and treatment is important not only for the informed consent process, but also for questions of public policy. PMID- 22200141 TI - [Summary of the multidisciplinary guideline 'Varicella']. AB - The multidisciplinary guideline 'Varicella' provides guidelines for diagnosis, therapy, and prevention of chickenpox. At the first pregnancy check, patients should be questioned about previous chickenpox; in case of a negative or doubtful history varicella zoster virus (VZV) serology is indicated. VZV antibody determination is also indicated in patients considered for immunosuppressive therapy and for healthcare workers with a negative VZV history who are in contact with immunocompromised patients. Administration of VZV immunoglobulin within 96 hours following VZV contact can mitigate the infection in pregnant women and patients with T-cell deficiency. VZV immunoglobulin treatment should be considered for newborn infants of mothers who developed chickenpox in the period from five days before to two days after delivery. Antivirals can reduce the severity of infection and are safe during pregnancy. Varicella vaccine protects against chickenpox, but is contraindicated in immunocompromised patients and pregnant women. PMID- 22200142 TI - [Falloppius and his uterine tubes]. AB - Gabriele Falloppio (1523-1562) was initially educated as a priest in his native Modena, Italy. He subsequently became a physician and professor of anatomy in Pisa, and later in Padua on the post Vesalius (1515-1564) had occupied not long before him. In 1561, Falloppius published a collection of anatomical observations to supplement, and sometimes correct, Vesalius' great De humani corporis fabrica libri septem of 1543. Among Falloppius' observations was a description of the female 'semen-conveying ducts', as they were then called, in which he emphasized their gradual widening towards the female 'testes', to which they were only loosely attached by fringe (fimbriae) or 'shreds of worn clothes'. When this fringe was folded back, the resulting opening resembled that of a brazen trumpet (tuba). Vesalius published a courteous riposte in which he still denied the existence of such an opening. The tubes Falloppius had described were eventually named after him. PMID- 22200143 TI - [Exosomes and cancer]. AB - Exosomes are a subtype of vesicles released by cells of both healthy and neoplastic origin. Preclinical studies suggest a role for tumour-derived exosomes in tumour progression, mainly through the transfer of RNA and proteins from tumour cells to other cells. The transfer of RNA and proteins by tumour-derived exosomes seems to mediate stimulation of angiogenesis and suppression of immune cells; in contrast, exosomes from healthy cells of the immune system appear to have anti-tumour characteristics. Characterisation of the RNA or protein profile of tumour-derived exosomes could have diagnostic or prognostic value, for example, in brain tumours. Anti-tumour therapies could be based on exosomes, for example, by blocking the formation of tumour-derived exosomes or having exosomes release therapeutic agents at specific sites. The most advanced application of this is the use of exosomes from dendritic cells in tumour vaccination; the safety of this has been demonstrated in phase I studies. PMID- 22200144 TI - [Brueghel's cripples]. AB - The auction of Brueghel's 'Fight between Carnival and Lent' is the reason for a survey of a group of cripples painted by Brueghel. In the late middle ages and early modern times, cripples and the handicapped who could only move with the aid of crutches were virtually excluded from society. Begging and making music were often the only way they could make a living. Their injuries were not always genuine, often they were feigned to gain sympathy and obtain money more easily. PMID- 22200145 TI - [A young child with respiratory acidosis and hypoxia from mechanical ventilation with equipment made for adults]. AB - BACKGROUND: During mechanical ventilation of young children, problems may arise due to the additional dead space of the ventilation circuit. This may lead to respiratory acidosis and even hypoxia in the child. CASE DESCRIPTION: A 3-month old boy suffered from frequent apnoea. He was mechanically ventilated for this. Shortly after its initiation, he developed severe respiratory acidosis, hypoxemia and circulatory insufficiency. This was due to a large additional dead space caused by the use of equipment components made for adults. After he was switched to a circuit suitable for himself, he recovered rapidly. CONCLUSION: As a rule of thumb, an additional dead space of 1.5-2 ml/kg body weight is acceptable in young children. Emergency wards for young children should have specific equipment to mechanically ventilate them, and have a protocol paying explicit attention to the dead space. PMID- 22200146 TI - [The art of facial prosthetics]. AB - BACKGROUND: Anaplastology is the discipline devoted to the construction of epithesis. An epithesis is a prosthesis that replaces soft tissue. This offers a solution for patients with a facial defect. CASE DESCRIPTION: A 78-year-old woman, who had undergone ablative surgical treatment for a squamous cell carcinoma of the left ear, was left with a large defect in the mastoid region. This defect had a severe impact on her psychosocial functioning. For this patient an episthesis was constructed to replace the left ear. After this, her psychosocial problems were greatly improved. CONCLUSION: A nearly-realistic episthesis can reduce the negative psychosocial effects of facial mutilation. The construction requires multidisciplinary treatment. In order to achieve the optimal result, an anaplastologist must have well developed artistic capacities. Feeling for detail, form and colour are essential. Modern 3D technology contributes to a more precise, quicker and cosmetically high-quality result. PMID- 22200147 TI - [Dutiful, sinister and proud--doctors on the silver screen]. AB - Apart from documentaries and a few other exceptions, the history of film is not an area where one will find a realistic view of medicine. The vast majority of physicians appearing in films are insane, megalomaniac and often extremely dangerous. Even so, that leads to films which are worth watching. PMID- 22200148 TI - [Treating voice problems in professional singers]. AB - A 33-year-old male singer presented with a vocal fold polyp, a 20-year-old female singer with vocal fold submucosal bleeding, and an 18-year-old female singer with early vocal fold nodules. The vocal fold polyp was removed surgically. In the second patient vocal fold nodules were visible after resorption of the blood; they were removed surgically. The third patient was treated conservatively. A professional singer with a voice problem should be examined by an ear, nose, and throat surgeon with a special interest in disorders of the professional voice. After surgical treatment of voice problems, enough rehabilitation time should be taken for optimal recovery. Agreement about resting and rehabilitation of the voice and careful planning of the return to the stage are essential. If the singer is famous it is important that the doctor should resist the pressure exerted by management and media. PMID- 22200149 TI - [Guideline "Cancer rehabilitation"]. AB - Initiated by IKNL (Integraal Kankercentrum Nederland), a multidisciplinary guideline for cancer rehabilitation for adult oncology patients has been developed. The guideline describes the rehabilitation care of adult patients with cancer, during and after treatment. The guideline focuses on (a) prevalence of complaints either resulting from cancer or the treatment, (b) detection of these complaints and indicated referral, (c) the intake procedure before cancer rehabilitation, (d) intervention and evaluation within cancer rehabilitation and (e) the importance of patient empowerment. The guideline is directed at all professionals giving care to patients with cancer. It concerns those (such as medical specialists, general practitioners and nurses) who are responsible for detecting cancer-related complaints and for referral to cancer rehabilitation, as well as health care professionals involved in cancer rehabilitation care (such as consultants in rehabilitation medicine, physiotherapists and psychologists). The main goal of the guideline is that every cancer patient or ex-cancer patient with (residual) complaints resulting from cancer or its treatment receives timely and appropriate cancer rehabilitation. PMID- 22200150 TI - [Hendrik Wiegersma (1891-1969)--doctor for ten hours, painter for eight]. AB - Wiegersma was an eccentric general practitioner in the Catholic Dutch province of Brabant, like his father. In his home village, Deurne, he chanced to encounter a circle of painters and sculptors; through their encouragement, painting became an important part of his life after 1924. He painted in an expressionistic style, mostly portraits of human figures; also self-portraits. Up until the Second World War, expositions of his work were held in the Netherlands as well as abroad. Afterwards, he lost contact with the newly emerging artistic movement. He practised medicine until 1962. PMID- 22200151 TI - [The Dutch College of General Practitioners' practice guideline 'Parkinson's disease' in summary]. AB - Parkinson's disease is characterised by bradykinesia in combination with one or more of the following symptoms: rigidity, resting tremor and disorders of posture and balance. Refer a patient with suspected Parkinson's disease (or parkinsonism) for diagnosis and treatment preferably to a neurologist with expertise in movement disorders. The treatment of Parkinson's disease is symptomatic; to date, there is no treatment that slows disease progression. The treatment of patients with Parkinson's disease and its related disorders involves collaboration of the neurologist, Parkinson's disease nurse and general practitioner. In addition to recognizing the hypokinetic-rigid syndrome, the general practitioner has a role in diagnosing and treating associated symptoms and disorders, and in supporting and counseling the patient and their partner or caregiver. PMID- 22200152 TI - [What can art contribute to medicine?]. AB - Art is often used as a medical therapy, or in medical education for the students' all-round development. In this article we discuss whether there is a scientific basis for this use of art. We conclude that though it is true that on a number of points there does seem to be scientific evidence more research is necessary to really be able to speak of an important role for the use of art in medicine. PMID- 22200153 TI - [The facelift of the Vrolik Museum]. AB - The Vrolik Museum is the Amsterdam anatomical museum, and originates from the private collection of Gerard Vrolik (1775-1859) and his son Willem (1801-1863). Over the years the attitude towards anatomical specimens has changed and the museum changed along with it. Since 1984 the museum has been located in the Amsterdam Academic Medical Centre. It is closed at the moment until May 2012 for refurbishment and is receiving a facelift. Not only will the permanent exhibitions be expanded, new displays about the history of the museum and its collectors will be added. After the refurbishment the museum hopes to reach the general public more than has been possible in the past. PMID- 22200154 TI - [A woman with Christmas in sight]. AB - A 70-year-old woman was referred because of vision deterioration of her right eye since several months. With optimal spheric correction of +2.50 in her right eye she had a vision of 0.7. The intraocular pressure was 10 mmHg. There were no abnormalities in the anterior chamber of the eye. The right eye did show a palette of coloured needle-shaped opacities in the cortex and anterior nucleus of the lens, consistent with unilateral Christmas tree cataract. PMID- 22200155 TI - [Dance, art and top performance sport with specific injuries]. AB - Professional theatre dance has high and specific physical demands, comparable to top sport. Dance injuries are often caused by faulty technique due to compensation for physical limitations. Knowledge of these limitations and professional teaching can prevent many problems. Dance injuries mostly involve the lower limbs, especially the ankles and knees. Dance injuries require that the medical professional has knowledge of dance technique and respects the passion of the dancer. The advice to stop dancing has hardly ever to be given. Scientific, prospective dance medical research is recommended. PMID- 22200156 TI - [Good architecture exercises body and mind: on design and health care]. AB - The design of hospitals is increasingly being based on scientific research. Spaces are designed in such a way that they contribute to the healing process - the 'healing environment'. Thinking about the hospital of the future should not be purely focused on the optimal building. It is also important to develop a vision of the connection between the institution of the hospital and society as a whole. It could be asked how increasingly short treatment times affect the way the patient experiences hospital. A compact hospital located in a town centre could take part in local activities. It is possible that social interaction between patient and passer by could be beneficial. Prevention and health education could possibly reach larger sections of the population more simply and directly. This sort of integration between society and hospital may not only be beneficial to patient health but also to the society in general. PMID- 22200157 TI - [Medical mistakes in doctors novels]. AB - OBJECTIVE: To investigate whether doctors novels give a realistic picture of medical practice. DESIGN: Descriptive, qualitative analysis. METHOD: 6 items in total from two series of doctors novels (4 Dutch 'Doctors novels' and 2 'Dr. Anne Maas' publications) were examined. RESULTS: The series 'Doctors novels' was translated from English, the 'Dr. Anne' novels were written by Dutch authors. The medical situations were located mostly in hospital emergency departments and operation rooms. Medical specialisms were represented mainly by surgeons, emergency care doctors, orthopaedic specialists, cardiologists and gynaecologists. In the series 'Doctors novels' most of the patients described suffered a trauma. In the 'Dr. Anne' series the patients admitted to the emergency department had a greater range of medical conditions. In the series 'Doctors novels' 3 of the 4 main characters were pregnant. In one case, giving birth was described in detail. CONCLUSION: The doctors novels which were studied give an unbalanced and distorted view of medical practice. The medical information was sometimes incorrect, partly due to lack of knowledge by the author, partly due to incorrect translation from English. The reality of medical practice was not represented accurately in either of the series investigated, although the medical information in the 'Doctors novels' series appeared to be accurate more often than that in the 'Dr. Anne' series. PMID- 22200158 TI - [Cultural interests of doctors, accountants and lawyers; art, culture and interface with the profession]. AB - OBJECTIVE: To investigate the role of art and culture in the recreational activities of doctors, accountants and lawyers. DESIGN: Descriptive questionnaire study. METHOD: In this study, doctors, accountants and lawyers were asked to respond to an online questionnaire. They were presented with 13 questions or statements concerning their recreational activities and their active or passive involvement with art and culture. To gain an impression in which respect doctors, accountants and lawyers could be distinguished from each other, predictive models based on logistic regression with possible results 'doctor', 'accountant' or 'lawyer' were generated. On the basis of these models, a miniquiz was created, which could distinguish the typical doctor, accountant or lawyer after answering of dichotomous questions. RESULTS: Among all respondents, museum and cinema visits were popular, sports or gardening were favourite activities, and apart from newspapers, the Internet was frequently consulted for news. It was remarkable that doctors and lawyers resembled each other in most of the areas investigated, whereas the accountants differed significantly. Doctors and lawyers particularly visited museums and dance, opera or theatre performances, and two thirds themselves played music. The majority of these 2 groups also had an above average interest in art and culture, this being a significant part of the recreational activity. Therefore, we were able to differentiate between a doctor or lawyer and an accountant, but the difference between doctors and lawyers was less clear. CONCLUSION: Doctors and lawyers seemed to have comparable interests in art and culture, but accountants differed in important respects. PMID- 22200159 TI - [Death and the pop musician]. AB - Many people are inclined to believe that popular music artists are prone to die prematurely. Scientific research into this matter is scarce. There is only one epidemiological study on this subject, showing that mortality among pop stars during the first 25 years after they became famous is increased. This mortality is higher in Northern America than it is in Europe, but European pop stars die on average at an earlier age. A fairly common belief states that many pop stars die at the age of 27 years. This age has even been proclaimed as the most critical for modern musicians. However, data of several hundred deceased pop stars shows no evidence for increased mortality at the age of 27. Moreover, the data suggests that the age of death has increased over the past forty years. As far as the cause of death is concerned, overdose of drugs or alcohol rank highly next to cardiovascular disease and malignancy. PMID- 22200164 TI - Arsenic, vinyl chloride, viral hepatitis, and hepatic angiosarcoma: a hospital based study and review of literature in Taiwan. AB - BACKGROUND: Hepatic angiosarcoma (HAS) is a rare type of liver cancer that is often fatal, and arsenic and vinyl chloride monomer (VCM) are two major causal agents. Whereas Taiwan is an endemic area of liver cancer, epidemiologic data on HAS are limited. We reviewed the cases observed at a teaching hospital to evaluate the roles of VCM, arsenic, and viral hepatitis in the occurrence of HAS. METHODS: We reviewed the medical records of patients with pathological proof of HAS from January 2000 to August 2010 at a teaching hospital which is adjacent to the major VCM processing area in Taiwan and nearby an endemic area of arsenic exposure from drinking water. We also conducted a literature review and included all patients of HAS reported in Taiwan. RESULTS: Six male and three female cases aged from 56 to 83 years (64.6 +/- 8.2 years) were identified at the hospital. The differences in clinical features between men and women were not statistically significant. None of them had exposure to VCM or arsenic in drinking water. Two had evidence of hepatitis C infection, but none had evidence of hepatitis B infection. Five male and four female cases aged 30 to 82 years (58.6 +/- 15.5 years) were identified in the literature, including two with arsenic exposure and one with chronic hepatitis B infection. CONCLUSIONS: HAS is rare in Taiwan, and we found no evidence supporting a major role of VCM, arsenic in drinking water, or viral hepatitis in its occurrence. PMID- 22200165 TI - Tuberculous meningitis in Greek children. AB - BACKGROUND: Tuberculous meningitis (TBM) is the most severe form of Mycobacterium tuberculosis infection. Our aim was to analyze the epidemiology, clinical features, diagnostic approach, and outcome of tuberculous meningitis in childhood. METHODS: During a 25-y period (1984-2008), 43 children, aged 7 months to 13 y, were hospitalized in the Paediatric Department of the referral centre for infectious diseases in Thessaloniki, Greece with the diagnosis of TBM. The patients were classified according to the clinical findings on admission as per the UK Medical Research Council (MRC) staging: stage I, 16/43 (37.2%) children; stage II, 16/43 (37.2%); and stage III 11/43 (25.6%). RESULTS: Twenty-seven of the 43 patients were Greek (63%) and none had been BCG-vaccinated. A family history of tuberculosis was identified in 18 cases (42%). 35 patients (81%) had a positive tuberculin skin test. An extrameningeal site of infection was identified in 14 children (33%); pulmonary tuberculosis in 14/43 patients (5/13 miliary tuberculosis) and spondylitis in 1. All patients were treated with anti tuberculous drugs and 36 (84%) also received corticosteroids. Complications during hospitalization (coma, seizures, cranial nerve palsy, hydrocephalus) presented in 26 patients (60%). Two patients died (5%) and 6 (14%) had permanent neurological sequelae. CONCLUSION: TBM, although rare, remains a disease with significant morbidity and mortality. Early clinical diagnosis and appropriate treatment initiation are important for the prognosis. PMID- 22200167 TI - Study of interaction between croscarmellose and escitalopram during sample preparation. AB - During routine analysis of an escitalopram tablet formulation, it was seen that there was a systematic deviation between content uniformity (CU - one tablet analysis) and assay analysis (ten pooled tablets). In the presence of the excipients from the tablet, it was found that the extraction of the active pharmaceutical ingredient (API) was incomplete. It was shown that the commonly used tablet disintegrant croscarmellose sodium (crosslinked carboxy-methyl cellulose) had a significant interaction with escitalopram. This was later found to be the explanation for the lower extraction during assay testing. Under normal conditions, the extraction took place in acidic medium which caused protonation of the amine and thereby the interaction of charged species in solution. The interaction of API was studied further with pure croscarmellose and the entire tablet matrix. A range of conditions was considered, including altering extraction volumes, organic solvents, pH of the extraction solvent, and addition of competitive binder in various concentrations. It was seen that arginine was the most effective cationic competitive binder of those tested and that adding it at a suitable concentration level could significantly improve the analytical methods. In the present case, an improvement in recovery was from 98.5% to almost 100% was achieved. PMID- 22200168 TI - Implementation of standardized time limits in sickness insurance and return-to work: experiences of four actors. AB - PURPOSE: In 2008, time limits were introduced in Swedish sickness insurance, comprising a pre-defined schedule for return-to-work. The purpose of this study was to explore experienced consequences of these time limits. Sick-listed persons, physicians, insurance officials and employers were interviewed regarding the process of sick-listing, rehabilitation and return-to-work in relation to the reform. METHOD: The study comprises qualitative interviews with 11 sick-listed persons, 4 insurance officials, 5 employers and 4 physicians (n = 24). RESULTS: Physicians, employers, and sick-listed persons described insurance officials as increasingly passive, and that responsibility for the process was placed on the sick-listed. Several ethical dilemmas were identified, where officials were forced to act against their ethical principles. Insurance officials' principle of care often clashed with the standardization of the process, that is based on principles of egalitarianism and equal treatment. CONCLUSIONS: The cases reported in this study suggest that a policy for activation and early return-to-work in some cases has had the opposite effect: central actors remain passive and the responsibility is placed on the sick-listed, who lacks the strength and knowledge to understand and navigate through the system. The standardized insurance system here promoted experiences of procedural injustice, for both officials and sick listed persons. PMID- 22200169 TI - Molecular identification of larval bucephalids, Prosorhynchoides ozakii and Parabucephalopsis parasiluri , infecting the golden mussel, Limnoperna fortunei , by PCR-RFLP. AB - A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was developed for the molecular identification of 2 introduced bucephalid trematodes, Prosorhynchoides ozakii and Parabucephalopsis parasiluri . The method was applied for sporocysts and cercariae obtained from the golden mussel Limnoperna fortunei collected in the Uji River, Japan. The PCR-RFLP method showed that L. fortunei is the intermediate host of both trematode species. The present study thus recognizes the risk of L. fortunei , an invasive molluscan species, as a potential host for pathogenic trematodes. PMID- 22200170 TI - Multiple hydrogen bond interactions in the processing of functionalized multi walled carbon nanotubes. AB - In a set of unprecedented experiments combining "bottom-up" and "top-down" approaches, we report the engineering of patterned surfaces in which functionalized MWCNTs have been selectively adsorbed on polymeric matrices as obtained by microlithographic photo-cross-linking of polystyrene polymers bearing 2,6-di(acetylamino)-4-pyridyl moieties (PS1) deposited on glass or Si. All patterned surfaces have been characterized by optical, fluorescence, and SEM imaging techniques, showing the local confinement of the CNTs materials on the polymeric microgrids. These results open new possibilities toward the controlled manipulation of CNTs on surfaces, using H-bonding self-assembly as the main driving force. PMID- 22200172 TI - Acceptability of the levonorgestrel releasing-intrauterine system and etonogestrel implant: one-year results of an observational study. AB - OBJECTIVES: To analyse the acceptability and patterns of use of the levonorgestrel releasing-intrauterine system (LNG-IUS) and the etonogestrel releasing-subdermal implant (ENG implant) among young European women. METHODS: A total of 454 women aged 20-35 years opting to switch their method of contraception from oral contraception to the LNG-IUS or ENG implant, were recruited in an observational study in four different European countries (France, Ireland, Slovakia and the United Kingdom). The present paper reports the interim results of the study at 12 months of observation. RESULTS: Data from 311 subjects (211 using the LNG-IUS and 100 using the ENG implant), with at least one follow up visit after insertion, were analysed. The cumulative continuation rates at 12 months for the LNG-IUS and ENG implant were 93% and 86%, respectively. Most women were satisfied with their method of contraception after one year of follow-up (80% in the LNG-IUS group and 66% in the ENG implant group). CONCLUSIONS: Both the LNG-IUS and the ENG implant are highly acceptable contraceptive options among women with previous experience of oral contraceptive use. The highest continuation and satisfaction rates were observed with the LNG-IUS. PMID- 22200176 TI - Defining exercise prescription in lifestyle modification programs for overweight/obese polycystic ovary syndrome women. PMID- 22200174 TI - Uncoupling oxidative phosphorylation with 2,4-dinitrophenol promotes development of the adhesion phenotype. AB - OBJECTIVE: To determine the effect of uncoupling oxidative phosphorylation with 2,4-dinitrophenol (DNP) on adhesion phenotype development. DESIGN: Prospective experimental study. SETTING: Academic medical center. PATIENT(S): Women undergoing laparotomy for pelvic pain from whom normal peritoneum and adhesions were excised to create primary cultures of normal peritoneal and adhesion fibroblasts. INTERVENTION(S): Treatment of normal peritoneal and adhesion fibroblasts isolated from the same patient(s) with or without 0.2 mM DNP for 24 hours. MAIN OUTCOME MEASURE(S): Evaluation of adhesion phenotype markers type I collagen, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor (HIF)-1alpha. RESULT(S): In agreement with prior findings, adhesion fibroblasts exhibited significantly higher basal levels of type I collagen, VEGF, and HIF 1alpha compared with normal peritoneal fibroblasts. Treatment of normal peritoneal fibroblasts with DNP resulted in significant increases in type I collagen (10.2 +/- 1.4 vs. 18.4 +/- 1.9 fg/MUg RNA) and VEGF (8.2 +/- 1.1 vs. 13.7 +/- 0.4 fg/MUg RNA) over baseline. HIF-1alpha levels did not increase when normal peritoneal fibroblasts were treated with DNP. CONCLUSION(S): The adhesion phenotype, which is normally expressed in response to hypoxia, is reproduced in a normoxic environment by uncoupling oxidative phosphorylation with DNP, as evidenced by an increase in type I collagen and VEGF. Acquisition of the adhesion phenotype was via a mechanism distinct from up-regulation of HIF-1alpha. These observations are consistent with the hypothesis that the adhesion phenotype represents a state of intracellular metabolic depletion. PMID- 22200177 TI - The Malthus programme--a new tool for estimating radiotherapy demand at a local level. PMID- 22200180 TI - Nasopharyngeal adenoid cystic carcinoma: magnetic resonance imaging features in ten cases. AB - Nasopharyngeal adenoid cystic carcinoma (NACC) is a rare malignancy with high local invasiveness. To date, there is no consensus on the imaging characteristics of NACC. To address this, we retrospectively reviewed 10 cases of NACC and summarized the magnetic resonance imaging (MRI) features. MR images of 10 patients with histologically validated NACC were reviewed by two experienced radiologists. The location, shape, margin, signal intensity, lesion texture, contrast enhancement patterns, local invasion, and cervical lymphadenopathy of all tumors were evaluated. Clinical and pathologic records were also reviewed. No patients were positive for antibodies against Epstein-Barr virus (EBV). The imaging patterns of primary tumors were classified into two types as determined by location, shape, and margin. Of all patients, 7 had tumors with a type 1 imaging pattern and 3 had tumors with a type 2 imaging pattern. The 4 tubular NACCs were all homogeneous tumors, whereas 3 (60%) of 5 cribriform NACCs and the sole solid NACC were heterogeneous tumors with separations or central necrosis on MR images. Five patients had perineural infiltration and intracranial involvement, and only 2 had cervical lymphadenopathy. Based on these results, we conclude that NACC is a local, aggressive neoplasm that is often negative for EBV infection and associated with a low incidence of cervical lymphadenopathy. Furthermore, MRI features of NACC vary in locations and histological subtypes. PMID- 22200179 TI - Novel roles of Skp2 E3 ligase in cellular senescence, cancer progression, and metastasis. AB - S-phase kinase-associated protein 2 (Skp2) belongs to the F-box protein family. It is a component of the SCF E3 ubiquitin ligase complex. Skp2 has been shown to regulate cellular proliferation by targeting several cell cycle-regulated proteins for ubiquitination and degradation, including cyclin-dependent kinase inhibitor p27. Skp2 has also been demonstrated to display an oncogenic function since its overexpression has been observed in many human cancers. This review discusses the recent discoveries on the novel roles of Skp2 in regulating cellular senescence, cancer progression, and metastasis, as well as the therapeutic potential of targeting Skp2 for human cancer treatment. PMID- 22200181 TI - Tumor necrosis factor-alpha -308G/A polymorphism and risk of hepatocellular carcinoma in hepatitis C virus-infected patients. AB - Tumor necrosis factor-alpha (TNF-alpha) is an important cytokine in generating an immune response against infection with hepatitis C virus (HCV). The functions of TNF-alpha may be altered by single-nucleotide polymorphisms (SNPs) in its gene structure. We hypothesized that SNPs in TNF-alpha may be important in determining the outcome of an HCV infection. To test this hypothesis, we investigated the role of the polymorphism -308G/A, which is located in the promoter region of the TNF-alpha gene, in the progression of HCV infection in Egyptian patients using a quantitative real-time polymerase chain reaction (qRT-PCR). The distribution of this polymorphism and its impact on the serum level of TNF-alpha was compared between 90 HCV-infected patients [45 with HCV-induced cirrhosis and 45 with HCV related hepatocellular carcinoma (HCC)] and 45 healthy Egyptian volunteers without any history of liver disease. Our results showed that at the TNF-alpha 308 position, the G/G allele was most common (78.5%) in the study population, with the G/A and A/A alleles occurring less frequently (13.3% and 8.1%, respectively). Frequencies of G/G, G/A, and A/A genotypes were 87%, 7%, and 6% in patients with liver cirrhosis and were 94%, 4%, and 2% in patients with HCC, respectively. Serum levels of TNF-alpha were significantly higher in HCV-infected patients than in healthy controls, indicating that the TNF-alpha -308 polymorphism does not influence the production of TNF-alpha. The serum level of TNF-alpha was positively correlated with HCV infection. Taken together, these findings suggest that the TNF-alpha -308 polymorphism may not be a host genetic factor associated with the severity of HCV infection, but may be an independent risk factor for HCC. PMID- 22200182 TI - Nonmetabolic functions of pyruvate kinase isoform M2 in controlling cell cycle progression and tumorigenesis. AB - Pyruvate kinase catalyzes the rate-limiting final step of glycolysis, generating adenosine triphosphate (ATP) and pyruvate. The M2 tumor-specific isoform of pyruvate kinase (PKM2) promotes glucose uptake and lactate production in the presence of oxygen, known as aerobic glycolysis or the Warburg effect. As recently reported in Nature, PKM2, besides its metabolic function, has a nonmetabolic function in the direct control of cell cycle progression by activating beta-catenin and inducing expression of the beta-catenin downstream gene CCND1(encoding for cyclin D1). This nonmetabolic function of PKM2 is essential for epidermal growth factor receptor (EGFR) activation-induced tumorigenesis. PMID- 22200183 TI - Nanoscale plasmonic interferometers for multispectral, high-throughput biochemical sensing. AB - In this work, we report the design, fabrication, and characterization of novel biochemical sensors consisting of nanoscale grooves and slits milled in a metal film to form two-arm, three-beam, planar plasmonic interferometers. By integrating thousands of plasmonic interferometers per square millimeter with a microfluidic system, we demonstrate a sensor able to detect physiological concentrations of glucose in water over a broad wavelength range (400-800 nm). A wavelength sensitivity between 370 and 630 nm/RIU (RIU, refractive index units), a relative intensity change between ~10(3) and 10(6) %/RIU, and a resolution of ~3 * 10(-7) in refractive index change were experimentally measured using typical sensing volumes as low as 20 fL. These results show that multispectral plasmonic interferometry is a promising approach for the development of high-throughput, real-time, and extremely compact biochemical sensors. PMID- 22200184 TI - Early mineralocorticoid receptor blockade in primary percutaneous coronary intervention for ST-elevation myocardial infarction is associated with a reduction of life-threatening ventricular arrhythmia. AB - BACKGROUND: Aldosterone levels are high early after admission for ST elevation myocardial infarction (STEMI) concomitantly with high risk of sudden death and life-threatening ventricular arrhythmia. METHODS: We assessed the hypothesis that early aldosterone blockade on admission for primary percutaneous coronary intervention (PCI) may be associated with a reduction of life-threatening ventricular arrhythmia in a prospective cohort-nested case (n=159) versus historical control (n=623) study. All cases were treated on admission by 200mg IV bolus of potassium canrenoate, followed by 25mg PO spironolactone daily during the coronary care unit stay. The primary endpoint--in-hospital composite of death, resuscitated cardiac arrest and ventricular tachycardia--was assessed by logistic regression models adjusted on major pre-specified variables and validated by a bootstrap procedure and propensity-score based analyses. RESULTS: Aldosterone blockade was associated with lower risks of the primary endpoint (adjusted ORs 0.26, 95% CI [0.13-0.57]), resuscitated cardiac arrest (adjusted OR 0.39, 95% CI [0.16-0.94]), ventricular tachycardia or fibrillation (adjusted ORs 0.23, 95% CI [0.12-0.45]), as well as ventricular arrhythmia requiring resuscitation or anti-arrhythmic therapy (adjusted OR 0.41, 95% CI [0.19-0.88]). All findings were confirmed by the bootstrap procedure. The benefit on death or resuscitated cardiac arrest seemed sustained at 6month follow-up. CONCLUSIONS: Early aldosterone blockade in patients presenting for primary PCI for STEMI is associated with significant reductions in rates of life-threatening arrhythmia and cardiac arrest independent of the initial risk profile, heart failure or hemodynamic status. These findings support the concept of aldosterone blockade early after STEMI, warranting further confirmation by ongoing randomized trials. PMID- 22200185 TI - Atorvastatin, not rosuvastatin, improves cardiac function in heart failure: a meta-analysis of randomized trials. PMID- 22200186 TI - Ion pair pKs of some amines: extension of the computed lithium pK scale. AB - The pK of p-(methylamino)biphenyl, 1, on our Li scale, pK(Li) = 22.09, compared to the cesium scale, pK(Cs) = 28.60. For hexamethyldisilazane, HMDS, pK(Li) = 23.05, pK(Cs) = 29.26. These results are those for the monomers in THF; corrections were made for dimers present in some cases. The pK(Li) of these two amines fit well the previously found correlation with Hartree-Fock calculations at 6-31+g(d) using RLi coordinated with three dimethyl ethers as a computational model for RLi in THF. The results are also compared with earlier pK(Li)s reported from equilibria with lithium amides in which aggregation was not considered. PMID- 22200187 TI - Factors associated with catheter-associated urinary tract infections and the effects of other concomitant nosocomial infections in intensive care units. AB - BACKGROUND: Catheter-associated urinary tract infections (CAUTIs) are the most common nosocomial infections in intensive care units (ICUs). The objectives of this study were to describe the incidence, aetiology, and risk factors of CAUTIs in ICUs and to determine whether concomitant nosocomial infections alter risk factors. METHODS: Between April and October 2008, all adult catheterized patients admitted to the ICUs of Zonguldak Karaelmas University Hospital were screened daily, and clinical and microbiological data were collected for each patient. RESULTS: Two hundred and four patients were included and 85 developed a nosocomial infection. Among these patients, 22 developed a CAUTI alone, 38 developed a CAUTI with an additional nosocomial infection, either concomitantly or prior to the onset of the CAUTI, and 25 developed nosocomial infections at other sites. The CAUTI rate was 19.02 per 1000 catheter-days. A Cox proportional hazard model showed that in the presence of other site nosocomial infections, immune suppression (hazard ratio (HR) 3.73, 95% CI 1.47-9.46; p = 0.006), previous antibiotic usage (HR 2.06, 95% CI 1.11-3.83; p = 0.023), and the presence of a nosocomial infection at another site (HR 1.82, 95% CI 1.04-3.20; p = 0.037) were the factors associated with the acquisition of CAUTIs with or without a nosocomial infection at another site. When we excluded the other site nosocomial infections to determine if the risk factors differed depending on the presence of other nosocomial infections, female gender (HR 2.67, 95% CI 1.03 6.91; p = 0.043) and duration of urinary catheterization (HR 1.07 (per day), 95% CI 1.01-1.13; p = 0.019) were found to be the risk factors for the acquisition of CAUTIs alone. CONCLUSIONS: Our results showed that the presence of nosocomial infections at another site was an independent risk factor for the acquisition of a CAUTI and that their presence alters risk factors. PMID- 22200191 TI - Carbon nanotubes: from nano test tube to nano-reactor. AB - Confinement of molecules and atoms inside carbon nanotubes provides a powerful strategy for studying structures and chemical properties of individual molecules at the nanoscale. In this issue of ACS Nano, Allen et al. explore the nanotube as a template leading to the formation of unusual supramolecular and covalent structures. The potential of carbon nanotubes as reactors for synthesis on the nano- and macroscales is discussed in light of recent studies. PMID- 22200192 TI - On parallel tracks: newly home from hospital--people with stroke describe their expectations. AB - PURPOSE: This study aimed to investigate how stroke survivors describe their expectations regarding life when coming home, and how these expectations were met on discharge from the rehabilitation clinic and during their first 3 months at home. METHOD: Semistructured interviews were performed repeatedly with five people, two women and three men, during 3 months around their discharge from hospital. Fifteen interviews were performed and analyzed using content analysis. RESULTS: On discharge from the rehabilitation clinic, the informants described experience of being at a dividing line between the safety of the ward and the unknown at home. Expectations for improvement were high. A few weeks later, they described being on parallel tracks in life, waiting for improvement and adjusting to life at home. Three months after discharge, they were still waiting for improvement and had begun to realize that life might never be the same as before the stroke. CONCLUSIONS: Patients after stroke may have high, sometimes unrealistic expectations of recovery at discharge. Health care professionals need to support patients in adjusting to real life by balancing high expectations with realistic views on the prognosis, this to enhance the rehabilitation process. Practicing at home or in a home-like environment is one way to highlight capacity and personal resources. PMID- 22200193 TI - The cost-effectiveness of exercise referral schemes. AB - BACKGROUND: Exercise referral schemes (ERS) aim to identify inactive adults in the primary care setting. The primary care professional refers the patient to a third party service, with this service taking responsibility for prescribing and monitoring an exercise programme tailored to the needs of the patient. This paper examines the cost-effectiveness of ERS in promoting physical activity compared with usual care in primary care setting. METHODS: A decision analytic model was developed to estimate the cost-effectiveness of ERS from a UK NHS perspective. The costs and outcomes of ERS were modelled over the patient's lifetime. Data were derived from a systematic review of the literature on the clinical and cost effectiveness of ERS, and on parameter inputs in the modelling framework. Outcomes were expressed as incremental cost per quality-adjusted life-year (QALY). Deterministic and probabilistic sensitivity analyses investigated the impact of varying ERS cost and effectiveness assumptions. Sub-group analyses explored the cost-effectiveness of ERS in sedentary people with an underlying condition. RESULTS: Compared with usual care, the mean incremental lifetime cost per patient for ERS was L169 and the mean incremental QALY was 0.008, generating a base-case incremental cost-effectiveness ratio (ICER) for ERS at L20,876 per QALY in sedentary individuals without a diagnosed medical condition. There was a 51% probability that ERS was cost-effective at L20,000 per QALY and 88% probability that ERS was cost-effective at L30,000 per QALY. In sub-group analyses, cost per QALY for ERS in sedentary obese individuals was L14,618, and in sedentary hypertensives and sedentary individuals with depression the estimated cost per QALY was L12,834 and L8,414 respectively. Incremental lifetime costs and benefits associated with ERS were small, reflecting the preventative public health context of the intervention, with this resulting in estimates of cost-effectiveness that are sensitive to variations in the relative risk of becoming physically active and cost of ERS. CONCLUSIONS: ERS is associated with modest increase in lifetime costs and benefits. The cost-effectiveness of ERS is highly sensitive to small changes in the effectiveness and cost of ERS and is subject to some significant uncertainty mainly due to limitations in the clinical effectiveness evidence base. PMID- 22200195 TI - Preconcentration of Organic Compounds from Water across Dialysis Membranes into Micellar Media. PMID- 22200197 TI - Frequency Distributions of PM10 Chemical Components and Their Sources. PMID- 22200196 TI - Predictive model for estimating the extent of petroleum hydrocarbon biodegradation in contaminated soils. PMID- 22200198 TI - Application of a mass balance model to assess in-place arsenic pollution. PMID- 22200199 TI - Some observations on times to equilibrium for semivolatile polycyclic aromatic hydrocarbons. PMID- 22200200 TI - Long-term changes in water and soil chemistry in spruce and beech forests, solling, Germany. PMID- 22200201 TI - Speciation of EDTA in Natural Waters: Exchange Kinetics of Fe-EDTA in River Water. PMID- 22200202 TI - Distribution of industrial air emissions by income and race in the United States: an approach using the toxic release inventory. PMID- 22200203 TI - Contaminants in Used Lubricating Oils and Their Fate during Distillation/Hydrotreatment Re-Refining. PMID- 22200204 TI - Full-scale hydrotreatment of polychlorinated biphenyls in the presence of used lubricating oils. PMID- 22200206 TI - Formal reduction potentials and redox chemistry of polyhalogenated biphenyls in a bicontinuous microemulsion. PMID- 22200205 TI - A distributed reactivity model for sorption by soils and sediments. 3. Effects of diagenetic processes on sorption energetics. PMID- 22200207 TI - Sampler for measurement of alveolar carbon monoxide. PMID- 22200208 TI - In-situ biodegradation of toluene in a contaminated stream. Part 1. Field studies. PMID- 22200209 TI - In-situ biodegradation of toluene in a contaminated stream. 2. Laboratory studies. PMID- 22200210 TI - Micrometeorological gradient approach for quantifying air/surface exchange of mercury vapor: tests over contaminated soils. PMID- 22200212 TI - Acid neutralizing capacity of municipal waste incinerator bottom ash. PMID- 22200211 TI - Consequences of the Partition between Water and Molecular Aggregates on the Photodegradation Pattern and Kinetics of a Pesticide of the Coumarin Family. PMID- 22200213 TI - Analytical method for the sorption of hydrophobic organic pollutants in clay-rich materials. PMID- 22200214 TI - Trophic-level differences in the bioconcentration of chemicals: implications in assessing environmental biomagnification. PMID- 22200216 TI - Hydrocarbon vapor transport in low moisture soils. PMID- 22200215 TI - Impact of river transport characteristics on contaminant sampling error and design. PMID- 22200217 TI - Destruction of formaldehyde with dielectric barrier discharge plasmas. PMID- 22200218 TI - Impact of sediment-bound iron on redox buffering in a landfill leachate polluted aquifer (vejen, denmark). PMID- 22200219 TI - Sources and burden of lead in st. Lawrence estuary sediments: isotopic evidence. PMID- 22200220 TI - Upper Limit for the Rate Coefficient for the Reaction HO2 + NO2 .fwdarw. HONO + O2. PMID- 22200221 TI - Air-water equilibrium of hexachlorocyclohexanes and chloromethoxybenzenes in the north and South atlantic. PMID- 22200222 TI - Kinetics of acetic Acid oxidation in supercritical water. PMID- 22200224 TI - Isomerization of Alkoxy Radicals under Atmospheric Conditions. PMID- 22200223 TI - Chemical kinetic mechanism for atmospheric chromium. PMID- 22200225 TI - Biotransformation of the Cyanobacterial Hepatotoxin Microcystin-LR, as Determined by HPLC and Protein Phosphatase Bioassay. PMID- 22200226 TI - Atmospheric Chemistry of CF3OH: Is Photolysis Important? PMID- 22200227 TI - Comparison of an enzyme immunoassay and gas chromatography/mass spectrometry for the detection of atrazine in surface waters. PMID- 22200228 TI - Reduction of Cr(VI) in the Presence of Excess Soil Fulvic Acid. PMID- 22200229 TI - Sulfur hexafluoride as a gas tracer in soil venting operations. PMID- 22200230 TI - Persistent chlorinated cyclodiene compounds in ringed seal, polar bear, and human plasma from northern quebec, Canada: identification and concentrations of photoheptachlor. PMID- 22200231 TI - Changes in the PCB Concentration of United Kingdom air between 1972 and 1992. PMID- 22200232 TI - Modeling Clathrate Hydrate Formation during Carbon Dioxide Injection into the Ocean. PMID- 22200234 TI - Method detection limits in solid waste analysis. PMID- 22200233 TI - Comment on "method detection limits in solid waste analysis". PMID- 22200235 TI - Comment on "application of permeant/polymer diffusional model to the desorption of polychlorinated biphenyls from hudson river sediments". PMID- 22200236 TI - Application of permeant/polymer diffusional model to the desorption of polychlorinated biphenyls from Hudson River sediments. Reply to comments. PMID- 22200238 TI - Peroxyisobutyryl nitrate. Reply to comments. PMID- 22200237 TI - Comments on "peroxyisobutyryl nitrate". PMID- 22200239 TI - Corrections: mineralogy and surface properties of municipal solid waste ash. PMID- 22200241 TI - A comparison of activity, participation and quality of life in children with and without spastic diplegia cerebral palsy. AB - PURPOSE: To measure activity, participation and QoL in children with CP and to determine how these differ from a comparable group of typically developing (TD) children. METHOD: A total of eleven males and eight females with CP ranging in age from 5 to 12 years (mean age 7 years 10 months, SD 1 year 10 months; GMFCS level I-II) and 19 age and sex matched TD peers were recruited. Activity was measured using Paediatric Activity Card Sort (PACS), 6-Minute Walk Test and Timed Up and Go Test (TUG). Participation was measured using the assessment of Life Habits (LIFE-H) and quality of life was measured using the Cerebral Palsy Quality of Life Questionnaire (CP-QoL). RESULTS: TD children performed more activities of personal care than children with CP, as assessed via the PACS, t(40) = 3.266, p = 0.002. TD children participate in more life habits than children with CP across all the LIFE-H domains except that of relationships. Results from the CP-QoL indicate that TD children experience a greater QoL in the domains of functioning, t(40) = 2.824, p = 0.007, and participation and physical health, t(40) = 3.543, p = 0.001, than children with CP. CONCLUSIONS: These findings encourage the development of therapeutic interventions that aim to reduce these imbalances at all levels of the International Classification of Functioning, Disability and Health. PMID- 22200242 TI - Temperature-sensitive hydrogels by graft polymerization of chitosan and N isopropylacrylamide for drug release. AB - Thermo-responsive polysaccharidic hydrogels were designed and synthesized by a free radical induced grafting procedure. Chitosan was chosen as biopolymer to impart biocompatibility and biodegradability to the macromolecular systems, while N-isopropylacrylamide (NIPAAm) was selected as co-monomer responsive for the thermo-sensitive properties. Ammonium persulfate was the initiator system and different polymeric networks have been synthesized by modulating the amount of NIPAAm in the polymerization feed. The resulting hydrogels were proposed as drug delivery devices and their performance was evaluated by using Diclofenac sodium salt as a model drug. Hydrogels were carefully characterized by FT-IR spectrophotometry, calorimetric analyses and swelling behavior in a temperature range of 15-45 degrees C. Finally, to verify the suitability of these hydrogels as thermo-responsive devices, the drug release profiles were studied performing in vitro experiments around the swelling-shrinking transition temperatures of the macromolecular systems. PMID- 22200244 TI - Treatment with methotrexate of a cornual pregnancy following endometrial resection. AB - OBJECTIVES: Endometrial resection is a procedure often performed for treatment of menorrhagia. Despite the fact that amenorrhoea frequently ensues, some normal endometrium can remain present and become the implantation site of a pregnancy. Such an event is uncommon (0.7%); however, the likelihood of an ectopic pregnancy is increased. This case report calls the reader's attention to the risk of intra- and extrauterine pregnancies and the necessity for contraception after endometrial resection, even in cases where amenorrhoea supervenes. CASE: A 46 year-old woman with prior endometrial resection and subsequent amenorrhoea, was diagnosed with a cornual pregnancy. She was successfully treated with systemic methotrexate, which was given in an outpatient clinic. CONCLUSION: Clinicians should be aware of the increased likelihood of an ectopic pregnancy after endometrial resection. All women submitting to this procedure should be counselled about the need for contraception, even in cases where amenorrhoea develops. PMID- 22200245 TI - Origin of strong synergism in weakly perturbed binary solvent system: a case study of primary alcohols and chlorinated methanes. AB - A strong synergistic solvation was observed for the mixtures of hydrogen bond donating and accepting solvent pairs. The nature of the interactions between two solvent pairs was investigated with different dye molecules viz. coumarin 480, coumarin 153, 4-aminophthalimide, and p-nitroaniline. Coumarin 480 in differenet alcohols-CHCl(3) (alcohols: MeOH, EtOH, BuOH) binary mixture shows a strong synergism, which is explained in the backdrop of solvent-solvent interactions. Fluorescence quenching of C480 by 1,2-phenylenediamine in the binary solvent mixture exhibited the maximum deviation in quenching constant corresponding to ~0.45 mol fraction of MeOH in MeOH-CHCl(3) binary mixture and hence suggested the maximum extent of hydrogen-bonding interactions prevailing at this proportion of mixture. The solvation behavior of MeOH-CHCl(3) mixture shows strong probe dependence with no synergism observed in p-nitroaniline, which is ascribed to its higher ground state dipole moment (8.8 D) relative to C480 (6.3 D). Interestingly, the strong synergistic signature observed through spectrophotometric measurement of C480 in alcohol-CHCl(3) binary mixture is absent when studied by fluorescence measurement. The higher excited state dipole moment of coumarin 480 (13.1 D) is considered to be the driving force for the absence of synergism in the excited state. In such strongly perturbed systems (due to high dipole moment values) the dominant phenomenon is preferential solvation. Analysis of proton NMR of MeOH-CHCl(3) binary solvent mixture indicates the existence of MeOH-CHCl(3) clusters in the stoichiometric ratio of 1:2.15. Refractive index measurement also infers the existence of hydrogen bonded network structure between MeOH and CHCl(3). A modified Bosch solvent exchange model has been used to determine the feasibility of synergistic behavior and polarity parameter of the mixed solvent structure of MeOH-CHCl(3) binary solvent mixture. PMID- 22200246 TI - Role of comorbidities in locally advanced cervical cancer patients administered preoperative chemoradiation: impact on outcome and treatment-related complications. AB - AIMS: The study aimed at describing the prevalence, and pattern of comorbidities, as well as their clinical role in a large series of locally advanced cervical cancer (LACC) patients triaged to preoperative chemoradiation. METHODS: The Charlson index (CCI), and the ACE27 index were used to retrospectively evaluate comorbidities in 258 LACC patients: life tables were computed by the Kaplan-Meier method; multivariate analysis was performed by Cox's regression model. RESULTS: A CCI score = 0 was documented in 225 patients (87.2%), while 24 patients (9.3%) had a CCI score = 1, and only 9 patients (3.5%) had a CCI score >= 2. An ACE27 score = 0 was documented in 170 patients (65.9%), and was 1 in 59 patients (22.8%), 2 in 24 patients (9.3%) and 3 in 5 patients (2%). There was no association between the presence of comorbidities and clinico-pathological variables with the exception of a direct association with older age. There was no difference in the distribution of comorbid cases according to the extent of hysterectomy and lymphadenectomy. DFS or OS curves did not differ in patients with or without comorbidities according to both indexes. No difference in the distribution of patients with comorbidities according to presence of complications was documented. CONCLUSIONS: The role of comorbidities in the decision-making process relative to the enrollment of LACC patients into this trimodal therapeutic strategy needs to be established in specifically designed prospective trials. PMID- 22200249 TI - Long-term outcome of invasive Staphylococcus aureus infections. AB - BACKGROUND: Short-term mortality from invasive Staphylococcus aureus infections (ISA) is high. Death rates from 20% to 60% are reported. Long-term outcome has not been investigated. Studies of other critical illnesses have demonstrated incremental health effects that persist after hospital discharge. Several researchers have proposed that evaluation of mortality secondary to sepsis should take place after 1 y. METHODS: We performed an observational, prospective, population-based study of long-term mortality and recurrence in a cohort of ISA patients during 2 y. RESULTS: One hundred and fifty-seven patients were included. All-cause mortality after 1 y was 37.6% and after 3 y was 45.5%. The multivariate survival analysis explored different independent factors for short-term compared to long-term mortality. Age, comorbidity, and place of acquisition were the determinants of long-term outcome. In contrast, infection-related factors such as disease severity and systolic blood pressure determined short-term mortality. The relapse-reinfection rate was 11.2% (16 in 143 episodes in 127 patients living 4 weeks after inclusion). Predictive factors for relapse-reinfection in a univariate analysis were joint prosthesis (28.6%, p = 0.027), haemodialysis (27.8%, p = 0.017), kidney disease (22.2%, p = 0.015), and healthcare- and nosocomial-related infection (18.3%, p = 0.029). No association to length of antibiotic therapy and relapse-reinfection rate was observed, nor any sex differences. The majority of relapses-reinfections (11 of 16) occurred during the first 11 months after the initial episode. CONCLUSION: Patients with ISA infections, irrespective of age, suffer a high long-term mortality and recurrence rate. PMID- 22200250 TI - Observation of multiple vibrational modes in ultrahigh vacuum tip-enhanced Raman spectroscopy combined with molecular-resolution scanning tunneling microscopy. AB - Multiple vibrational modes have been observed for copper phthalocyanine (CuPc) adlayers on Ag(111) using ultrahigh vacuum (UHV) tip-enhanced Raman spectroscopy (TERS). Several important new experimental features are introduced in this work that significantly advance the state-of-the-art in UHV-TERS. These include (1) concurrent sub-nm molecular resolution STM imaging using Ag tips with laser illumination of the tip-sample junction, (2) laser focusing and Raman collection optics that are external to the UHV-STM that has two cryoshrouds for future low temperature experiments, and (3) all sample preparation steps are carried out in UHV to minimize contamination and maximize spatial resolution. Using this apparatus we have been able to demonstrate a TERS enhancement factor of 7.1 * 10(5). Further, density-functional theory calculations have been carried out that allow quantitative identification of eight different vibrational modes in the TER spectra. The combination of molecular-resolution UHV-STM imaging with the detailed chemical information content of UHV-TERS allows the interactions between large polyatomic molecular adsorbates and specific binding sites on solid surfaces to be probed with unprecedented spatial and spectroscopic resolution. PMID- 22200251 TI - Health, work, and personal-related predictors of time to return to work among employees with mental health problems. AB - PURPOSE: To identify health-, personal- and work-related factors predictive of return to work (RTW) in employees sick-listed due to common mental health problems, such as, stress, depression, burnout, and anxiety. METHODS: We distributed a baseline questionnaire to employees applying for sickness absence benefits at a large Danish welfare Department (n = 721). A total of 298 employees returned the questionnaire containing information on possible predictors of RTW. We followed up all baseline responders for a maximum of one year in a national registry of social transfer payments, including sickness absence benefits. RESULTS: At baseline, about 9% of respondents had quit their job, 10% were dismissed and the remaining 82% were still working for the same employer. The mean time to RTW, measured from the first day of absence, was 25 weeks (median = 21) and at the end of follow-up (52 weeks) 85% had returned to work. In the fitted Cox model we found that fulfilling the DSM-IV criteria for depression predicted a longer time to RTW (HR: 0.61, CI: 0.45-0.84), whereas a better self rated health predicted a shorter time to RTW (HR: 1.18, CI: 1.03-1.34). Employees working in the municipal (HR: 0.62, CI: 0.41-0.94) and private sector (HR: 0.65, CI: 0.44-0.96) returned to work slower compared to employees working in the governmental sector. Gender, education, cohabitation, size of workplace, low-back and upper-neck pain and employment at baseline did not predict RTW. CONCLUSION: Our results indicate that time to RTW is determined by both health- and work related factors. PMID- 22200254 TI - Essure(r) hydrosalpinx occlusion prior to IVF-ET as an alternative to laparoscopic salpingectomy. AB - OBJECTIVE: To investigate the success rate of proximal tubal occlusion with Essure((r)) devices in subfertile women with unilateral or bilateral hydrosalpinx and to observe the results of subsequent treatment with IVF-ET and/or frozen embryo transfer. STUDY DESIGN: Prospective, single-arm, clinical study in 20 women with unilateral or bilateral hydrosalpinges (all visible on transvaginal ultrasound) due to undergo IVF-ET and/or frozen embryo transfer. In all patients, laparoscopy was considered to be contraindicated due to extensive pelvic adhesions. RESULT(S): In all patients the Essure((r)) devices were placed in an ambulant setting without any complications. Proximal tubal occlusion was confirmed by hysterosalpingography in 19 out of 20 patients (95%) and in 26 of 27 treated tubes (96%). After 45 embryo transfer procedures in 19 patients, 18 pregnancies with 12 live births, 6 miscarriages and 1 immature delivery (probably related to cervical insufficiency leading to chorioamnionitis and subsequent rupture of the membranes) were observed. CONCLUSION(S): Essure((r)) devices are effective in inducing proximal tubal occlusion in subfertile patients with hydrosalpinges. After artificial reproductive treatments a cumulative live birth rate per patient of 63% and a cumulative live birth rate per transfer of 27% were achieved. The latter was related to the large proportion of patients with severe endometriosis. PMID- 22200252 TI - Unintended pregnancy and contraception among active-duty servicewomen and veterans. AB - The number of women of childbearing age who are active-duty service members or veterans of the US military is increasing. These women may seek reproductive health care at medical facilities operated by the military, in the civilian sector, or through the Department of Veterans Affairs. This article reviews the current data on unintended pregnancy and prevalence of and barriers to contraceptive use among active-duty and veteran women. Active-duty servicewomen have high rates of unintended pregnancy and low contraceptive use, which may be due to official prohibition of sexual activity in the military, logistic difficulties faced by deployed women, and limited patient and provider knowledge of available contraceptives. In comparison, little is known about rates of unintended pregnancy and contraceptive use among women veterans. Based on this review, research recommendations to address these issues are provided. PMID- 22200255 TI - Neonatal outcome and birth defects in 6623 singletons born following minimal ovarian stimulation and vitrified versus fresh single embryo transfer. AB - OBJECTIVE: To compare neonatal outcome between children born after vitrified versus fresh single-embryo transfer (SET). STUDY DESIGN: Retrospective, single centre cohort study of 6623 delivered singletons following 29,944 single-embryo transfers. Patients underwent minimal ovarian stimulation/natural cycle IVF followed by SET of fresh or vitrified-warmed (using Cryotop, Kitazato) cleavage stage embryos or blastocysts. Outcome measures were gestational age at delivery, birth weight, birth length, low birth weight (LBW), small for gestational age (SGA) and large for gestational age (LGA) infants, perinatal mortality and minor/major birth defects (evaluated by parent questionnaire). RESULTS: Gestational age (38.6 +/- 2 versus 38.7 +/- 1.9 weeks) and preterm delivery rate (6.9% versus 6.9%, aOR: 0.96 95%CI: 0.76-1.22) in singletons born after the transfer of vitrified embryos were comparable to those born after the transfer of fresh embryos. Children born after the transfer of vitrified embryos had a higher birth weight (3028 +/- 465 versus 2943 +/- 470 g, p<0.0001) and lower LBW (8.5% versus 11.9%, aOR: 0.65 95%CI: 0.53-0.79) and SGA (3.6% versus 7.6% aOR: 0.43 95%CI: 0.33-0.56) rates. Total birth defect rates (including minor anomalies) (2.4% versus 1.9%, aOR: 1.41 95%CI: 0.96-2.10) and perinatal mortality rates (0.6% versus 0.5%, aOR: 1.02 95%CI: 0.21-4.85) were comparable between the vitrified and fresh groups. CONCLUSIONS: Vitrification of embryos/blastocysts did not increase the incidence of adverse neonatal outcomes or birth defects following single embryo transfer. PMID- 22200256 TI - Metalloproteinases 2 and 9 and their tissue inhibitors 1 and 2 are increased in vulvar lichen sclerosus. AB - OBJECTIVES: To evaluate the expression of different matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in vulvar lichen sclerosus (LS), a chronic dermatosis in women, histologically characterized by a zone of collagen remodeling in the superior dermis. STUDY DESIGN: Analysis of the expression of different MMPs (MMP-1, -2, -9 and -13) and TIMPs (TIMP-1 and -2) by reverse transcriptase-polymerase chain reaction (RT-PCR) in vulvar biopsies from patients with LS (n=11), classified according to Hewitt histological criteria and compared with clinically normal vulvar tissue (n=5), and the immunohistochemistry of MMP-2 and -9 and TIMP-1 and -2 distribution in the remodeling zone of LS (n=31) and in clinically normal vulvar tissue (n=28). RESULTS: Although no statistically significant difference between LS and normal skin groups at the mRNA level of MMP and TIMP transcripts was shown, an increase in the immunodistribution of MMP-2 and -9 and TIMP-1 and -2 in LS compared to normal vulvar skin was observed. CONCLUSIONS: These results suggest that these molecules could be related to the process of cutaneous collagen remodeling in LS pathology. PMID- 22200260 TI - A polishing hybrid AER/UF membrane process for the treatment of a high DOC content surface water. AB - The efficacy of a combined AER/UF (Anion Exchange Resin/Ultrafiltration) process for the polishing treatment of a high DOC (Dissolved Organic Carbon) content (>8 mgC/L) surface water was investigated at lab-scale using a strong base AER. Both resin dose and bead size had a significant impact on the kinetic removal of DOC for short contact times (i.e. <15 min). For resin doses higher than 700 mg/L and median bead sizes below 250 MUm DOC removal remained constant after 30 min of contact time with very high removal rates (80%). Optimum AER treatment conditions were applied in combination with UF membrane filtration on water previously treated by coagulation-flocculation (i.e. 3 mgC/L). A more severe fouling was observed for each filtration run in the presence of AER. This fouling was shown to be mainly reversible and caused by the progressive attrition of the AER through the centrifugal pump leading to the production of resin particles below 50 MUm in diameter. More important, the presence of AER significantly lowered the irreversible fouling (loss of permeability recorded after backwash) and reduced the DOC content of the clarified water to l.8 mgC/L (40% removal rate), concentration that remained almost constant throughout the experiment. PMID- 22200261 TI - Wastewater quality monitoring system using sensor fusion and machine learning techniques. AB - A multi-sensor water quality monitoring system incorporating an UV/Vis spectrometer and a turbidimeter was used to monitor the Chemical Oxygen Demand (COD), Total Suspended Solids (TSS) and Oil & Grease (O&G) concentrations of the effluents from the Chinese restaurant on campus and an electrocoagulation electroflotation (EC-EF) pilot plant. In order to handle the noise and information unbalance in the fused UV/Vis spectra and turbidity measurements during the calibration model building, an improved boosting method, Boosting Iterative Predictor Weighting-Partial Least Squares (Boosting-IPW-PLS), was developed in the present study. The Boosting-IPW-PLS method incorporates IPW into boosting scheme to suppress the quality-irrelevant variables by assigning small weights, and builds up the models for the wastewater quality predictions based on the weighted variables. The monitoring system was tested in the field with satisfactory results, underlying the potential of this technique for the online monitoring of water quality. PMID- 22200257 TI - HIV/STD pattern and its associated risk factors among male STD clinic attendees in China: a foci for HIV intervention. AB - BACKGROUND: Previous studies suggested a high prevalence of STDs including HIV among female sex workers and men who have sex with men in China, but little was known about the prevalence in male patients attending public STD clinics. The aim of this study was to investigate STD patterns and HIV prevalence among male STD clinic attendees in different areas in China and the associated risk factors. The feasibility of Provider-initiated HIV testing and counseling (PITC) was evaluated as well. METHODS: A cross-sectional study was conducted at 46 public STD clinics in 4 provinces in China. Between July 2009 and September 2009, a total of 3243 eligible subjects were invited to participate in an interview with a structured questionnaire for collecting socio-demographic characteristics and sexual behavioral information. They also were asked to provide venous blood samples for serological determinations of HIV and syphilis infection, and first void urine specimens for detecting Chlamydia trachomatis and Neisseria gonorrhoeae infections, RESULTS: Out of the 3243 eligible patients, 2951(91%) men agreed to take part in the HIV and syphilis testing. The overall prevalence rate of HIV infection was 0.7% while the rates of syphilis, N. gonorrhoeae, C. trachomatis infections were 10.7%, 4.3% and 6.9%, respectively, with the highest syphilis and N. gonorrhoeae rates in Jiangsu Province. Patients from Guangxi province, homosexual/bisexual practices and intravenous drug use were significantly associated with HIV infection in multivariate logistic regression analyses. Provider-initiated HIV testing and counseling (PITC) was well accepted by attendees, with 91% of eligible attendees agreeing to undergo HIV testing and counseling. All HIV positive patients were properly managed accordingly. CONCLUSIONS: A modest prevalence of HIV infection and substantial prevalence of other STD infections were found among male patients attending public STD clinics in China. The findings further support the introduction of HIV and syphilis PITC strategy into this important setting. PMID- 22200262 TI - Immunoassays for pesticides. PMID- 22200264 TI - Comparison of three methods of estimating atmospheric mercury deposition. PMID- 22200263 TI - Partition of Pesticides of the Coumarin Family between Water and Amphiphilic Aggregates. PMID- 22200265 TI - Degradation of Octachlorodibenzofuran and Octachlorodibenzo-p-dioxin Spiked on Fly Ash: Kinetics and Mechanism. PMID- 22200266 TI - Kinetics of oxidation of selenite to selenate in the presence of oxygen, titania, and light. PMID- 22200267 TI - Metallocoenzyme-Mediated Reductive Transformation of Carbon Tetrachloride in Titanium(III) Citrate Aqueous Solution. PMID- 22200268 TI - Bioenergetics-Based Model for Accumulation of Polychlorinated Biphenyls by Nestling Tree Swallows, Tachycineta bicolor. PMID- 22200269 TI - Effects of Sublethal Exposure on Lethal Body Burdens of Narcotic Organic Chemicals in Daphnia magna. PMID- 22200270 TI - Potentiometric titrations of humic substances: do ionic strength effects depend on the molecular weight? PMID- 22200271 TI - Comprehensive Approach toward Understanding Element Speciation and Leaching Behavior in Municipal Solid Waste Incineration Electrostatic Precipitator Ash. PMID- 22200272 TI - Measurement error and spatial variability effects on characterization of volatile organics in the subsurface. PMID- 22200273 TI - Effect of Various Factors on Dehalogenation of Chlorinated Phenols and Anilines during Oxidative Coupling. PMID- 22200274 TI - Isomer and Enantioselective Degradation of Hexachlorocyclohexane Isomers in Sewage Sludge under Anaerobic Conditions. PMID- 22200275 TI - Simulated Air Levels of Volatile Organic Compounds following Different Methods of Indoor Insecticide Application. PMID- 22200276 TI - Polychlorinated Dibenzo-p-dioxin and Dibenzofuran Contamination at Metal Recovery Facilities, Open Burn Sites, and a Railroad Car Incineration Facility. PMID- 22200277 TI - Sorption of nonionic organic contaminants to single and dual organic cation bentonites from water. PMID- 22200278 TI - Analysis of environmental air samples by solid-phase microextraction and gas chromatography/ion trap mass spectrometry. PMID- 22200279 TI - Genotoxicity profiles and reaction characteristics of potassium polyethylene glycol dehalogenation of wood preserving waste. PMID- 22200280 TI - Automated HPLC Fractionation of PCDDs and PCDFs and Planar and Nonplanar PCBs on C18-Dispersed PX-21 Carbon. PMID- 22200282 TI - Surrogate parameter for the baseline toxicity content of contaminated water: simulating the bioconcentration of mixtures of pollutants and counting molecules. PMID- 22200281 TI - Reductive Dehalogenation of Aliphatic Halocarbons by Lignin Peroxidase of Phanerochaete chrysosporium. PMID- 22200283 TI - Evidence of complete retention of atmospheric lead in the soils of northern hardwood forested ecosystems. PMID- 22200284 TI - Synchronous response of hydrophobic chemicals in herring gull eggs from the great lakes. PMID- 22200285 TI - Development of a Gold Amalgam Voltammetric Microelectrode for the Determination of Dissolved Fe, Mn, O2, and S(-II) in Porewaters of Marine and Freshwater Sediments. PMID- 22200286 TI - Methanethiol in nonacclimated sewage sludge after addition of chloroform and other toxicants. PMID- 22200287 TI - Round-robin study of performance evaluation soils vapor-fortified with volatile organic compounds. PMID- 22200288 TI - Reduction of nitroaromatic compounds coupled to microbial iron reduction in laboratory aquifer columns. PMID- 22200289 TI - Sampling artifacts in the determination of particulate sulfate and SO2(g) in the desert Southwest using filter pack samplers. PMID- 22200290 TI - Persistent organochlorine residues in air, water, sediments, and soils from the lake baikal region, Russia. PMID- 22200291 TI - Factors affecting microbial 2,4,6-trinitrotoluene mineralization in contaminated soil. PMID- 22200292 TI - Facilitated transport and enhanced desorption of polycyclic aromatic hydrocarbons by natural organic matter in aquifer sediments. PMID- 22200293 TI - Rates and Mechanism of Fe(II) Oxidation at Nanomolar Total Iron Concentrations. PMID- 22200294 TI - Factors affecting methyl chloride emissions from forest biomass combustion. PMID- 22200295 TI - Formation of 2-Hydroxyethyl Hydroperoxide in an OH-Initiated Reaction of Ethylene in Air in the Absence of NO. PMID- 22200296 TI - Catalytic dechlorination of polychlorinated biphenyls. PMID- 22200297 TI - Enhanced Rates of Photocatalytic Degradation of an Azo Dye Using SnO2/TiO2 Coupled Semiconductor Thin Films. PMID- 22200299 TI - Reply to comment. PMID- 22200298 TI - Comment on "seasonal variations in air-water exchange of polychlorinated biphenyls in lake superior". PMID- 22200301 TI - Determination of polyphenolic content in beverages using laccase, gold nanoparticles and long wavelength fluorimetry. AB - An enzymatic fluorimetric method for the determination of polyphenol compounds in beverages is described, which is based on the temporal inhibition caused by these compounds on the oxidation of the long wavelength fluorophor indocyanine green (lambda(ex) 764 nm, lambda(em) 806 nm), in the presence of the enzyme laccase and positively charged gold nanoparticles (AuNPs). The oxidation of the dye gives rise to a fast decrease in its fluorescence, but it is delayed by the polyphenol, obtaining a time period directly proportional to its concentration, which has been used as the analytical parameter. The behaviour of several benzenediols and benzenetriols in the system and the modification of the activity of the enzyme by its interaction with AuNPs have been studied. The system has been optimized using gallic acid as a polyphenol model, but the dynamic ranges of the calibration graphs and the detection limits for several of the polyphenols assayed were obtained (MUmol L(-1)): gallic acid (0.13-5, 0.04), catechol (0.08-5, 0.01), hydroquinone (0.05-2, 0.01), hydroxyhydroquinone (0.09-5, 0.03), pyrogallol (0.17 5, 0.04). Most of the values of the regression coefficients were 0.999 and the precision of the method, expressed as RSD% and checked at two concentration levels of each analyte, ranged between 1.8 and 5.6%. The method has been applied to the determination of polyphenol content in several foodstuff samples and the results compared with those obtained with the standard Folin-Ciocalteu method. PMID- 22200302 TI - High resolution separation methods for the determination of intact human erythropoiesis stimulating agents. A review. AB - Human erythropoietin (hEPO), a hormone involved in the formation of red blood cells, is a 30 kDa glycoprotein with a high carbohydrate content. The production of recombinant hEPO has made possible its widespread therapeutic use and its banned use in competition sports. Methods to analyze EPO and other erythropoiesis stimulating agents (ESAs) are necessary for the characterization and quality control of these biopharmaceuticals and also for doping control. In this paper, high resolution separation methods, namely high performance liquid chromatography (HPLC) and capillary electrophoresis (CE), with special attention to CE-coupled mass spectrometry, are reviewed. The usefulness of these techniques when applied in different modes to separate the glycoprotein isoforms, aggregates or excipients are detailed. In addition, sample preparation methods that have been applied to ESA samples for subsequent determination by HPLC or CE, as well as the potential compatibility of other preparation methods, are discussed. Applications of the HPLC and CE methods regarding regulatory considerations for biopharmaceuticals analysis, with emphasis on biosimilars, and doping control are also included. Finally, limitations of the present methods and their possible solutions are considered. PMID- 22200303 TI - Development of salt-tolerance interface for an high performance liquid chromatography/inductively coupled plasma mass spectrometry system and its application to accurate quantification of DNA samples. AB - Accurate quantification of DNA is highly important in various fields. Determination of phosphorus by ICP-MS is one of the most effective methods for accurate quantification of DNA due to the fixed stoichiometry of phosphate to this molecule. In this paper, a smart and reliable method for accurate quantification of DNA fragments and oligodeoxythymidilic acids by hyphenated HPLC/ICP-MS equipped with a highly efficient interface device is presented. The interface was constructed of a home-made capillary-attached micronebulizer and temperature-controllable cyclonic spray chamber (IsoMist). As a separation column for DNA samples, home-made methacrylate-based weak anion-exchange monolith was employed. Some parameters, which include composition of mobile phase, gradient program, inner and outer diameters of capillary, temperature of spray chamber etc., were optimized to find the best performance for separation and accurate quantification of DNA samples. The proposed system could achieve many advantages, such as total consumption for small amount sample analysis, salt-tolerance for hyphenated analysis, high accuracy and precision for quantitative analysis. Using this proposed system, the samples of 20 bp DNA ladder (20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 300, 400, 500 base pairs) and oligodeoxythymidilic acids (dT(12-18)) were rapidly separated and accurately quantified. PMID- 22200304 TI - Multiple information contents derived from the chromatograms and their application to the modeling of quantitative profile-efficacy relationship. AB - Herbal medicine has been successfully applied in clinical therapeutics throughout the world. In this paper, various information contents in addition to a best first search strategy are proposed for improving prediction quality of quantitative profile-efficacy relationship (QPER). As a demonstration, a QPER model was constructed to predict the blood-clotting time increasing effect of Naodesheng prescription, a widely used herbal medicine in China. Evaluated by both the self-consistency test and the rigorous jackknife test, the predictive accuracy was increased by feeding the model with the merged information contents compared to only with the common chromatographic peak areas. The confirmation experiment exhibited that the predicted blood-clotting time were well consistent with the observed values. Furthermore, it has not escaped from our notice that the important potential application of the current QPER model is to be extended to help search active fractions, which has attracted more and more attention in the re-developments of herbal medicines based on the active compounds. PMID- 22200305 TI - Fabrication of an electrochemical sensor based on computationally designed molecularly imprinted polymers for determination of cyanazine in food samples. AB - A computational approach was used for screening functional monomers and polymerization solvent in the rational design of molecularly imprinted polymers (MIPs). It was based on the comparison of the binding energy of the complexes between the template and functional monomers. On the basis of computational results, acrylamide (AAM) and toluene were selected as functional monomer and polymerization solvent, respectively. The MIP, embedded in the carbon paste electrode, functioned as a selective recognition element and pre-concentrator agent for cyanazine determination by using cathodic stripping voltammetric method. The MIP-CP electrode showed very high recognition ability in comparison with NIP-CPE. Some parameters affecting the sensor response were optimized, and then the calibration curve was plotted. A dynamic linear range of 5.0-1000 nM was obtained. The detection limit of the sensor was calculated as 3.2 nM. This sensor was successfully used for cyanazine determination in food samples. PMID- 22200306 TI - An electrochemiluminescent assay for high sensitive detection of mercury (II) based on isothermal rolling circular amplification. AB - In this study, we firstly demonstrated that Bst DNA polymerase shows specific recognition and function on the T-Hg(2+)-T biomimetic structure. Based on this, a novel available electrochemiluminescence (ECL) sensor for Hg(2+) has been developed. In this strategy, magnet beads tagged primer was designed to complementary to the region of the circular padlock probe but with two T-T mismatches at the 3' end. The mismatched primers cannot be extended by Bst DNA polymerase in the absence of Hg(2+). Stable T-Hg(2+)-T can be formed in the presence of Hg(2+), thus induces the elongation and amplification reaction by DNA polymerase with a rolling circular amplification (RCA) mechanism. Subsequently, the resulted RCA products are hybridized with the tris (bipyridine) ruthenium (TBR)-tagged probes and detected by ECL platform. Current method shows a sub nanomolar sensitivity and excellent selectivity over a spectrum of interference metal ions. PMID- 22200307 TI - Electrochemical immunoassay of cotinine in serum based on nanoparticle probe and immunochromatographic strip. AB - A disposable sensor for the determination of cotinine in human serum was developed based on immunochromatographic test strip and quantum dot label. In this assay, cotinine linked with quantum dot competes with cotinine in sample to bind to anti-cotinine antibody in the test strip and the quantum dots serve as signal vehicles for electrochemical readout. Some parameters governing the performance of the sensor were optimized. The sensor shows a wide linear range from 1 ng mL(-1) to 100 ng mL(-1) cotinine with a detection limit of 1.0 ng mL( 1). The sensor was validated with spiked human serum samples and it was found that this method was reliable in measuring cotinine in human serum. The results demonstrate that this sensor is rapid, accurate, and less expensive and has the potential for point of care (POC) detection of cotinine and fast screening of tobacco smoke exposure. PMID- 22200308 TI - Selective determination of inorganic cobalt in nutritional supplements by ultrasound-assisted temperature-controlled ionic liquid dispersive liquid phase microextraction and electrothermal atomic absorption spectrometry. AB - In the present work, a simple and rapid analytical method based on application of ionic liquids (ILs) for inorganic Co(II) species (iCo) microextraction in a variety of nutrient supplements was developed. Inorganic Co was initially chelated with 1-nitroso-2-naphtol (1N2N) reagent followed by a modern technique named ultrasound-assisted temperature-controlled ionic liquid dispersive liquid phase microextraction (USA-TILDLME). The extraction was performed with 1-hexyl-3 methylimidazolium hexafluorophosphate [C(6)mim][PF(6)] with the aid of ultrasound to improve iCo recovery. Finally, the iCo-enriched IL phase was solubilized in methanol and directly injected into an electrothermal atomic absorption spectrometer (ETAAS). Several parameters that could influence iCo microextraction and detection were carefully studied. Since the main difficulty in these samples is caused by high concentrations of potential interfering ions, different approaches were evaluated to eliminate interferences. The limit of detection (LOD) was 5.4 ng L(-1), while the relative standard deviation (RSD) was 4.7% (at 0.5 MUg L(-1) Co level and n=10), calculated from the peak height of absorbance signals. Selective microextraction of iCo species was achieved only by controlling the pH value during the procedure. The method was thus successfully applied for determination of iCo species in nutritional supplements. PMID- 22200309 TI - Polyaniline-nylon-6 electrospun nanofibers for headspace adsorptive microextraction. AB - A headspace adsorptive microextraction technique was developed using a novel polyaniline-nylon-6 (PANI-N6) nanofiber sheet, fabricated by electrospinning. The homogeneity and the porosity of the prepared PANI-N6 sheet were studied using the scanning electron microscopy (SEM) and nanofibers diameters were found to be around 200 nm. The novel nanofiber sheet was examined as an extracting medium to isolate some selected chlorobenzenes (CBs), as model compounds, from aquatic media. The extracted analytes were desorbed using MUL-amounts of solvent and eventually an aliquot of extractant was injected into gas chromatography-mass spectrometry (GC-MS). Various parameters affecting the extraction and desorption processes were optimized. The developed method proved to be convenient and offers sufficient sensitivity and a good reproducibility. Limits of detection achieved for CBs with the developed analytical procedure ranged from 19 to 33 ng L(-1), while limits of quantification were from 50 to 60 ng L(-1). The relative standard deviations (RSD) at a concentration level of 0.1 ng mL(-1) and 1 ng mL(-1) were in the range of 8-14% and 5-11% (n=3), respectively. The calibration curves of analytes were investigated in the range of 50-1000 ng L(-1) and R(2) between 0.9739 and 0.9932 were obtained. The developed method was successfully applied to the extraction of selected CBs from tap and river water samples. The relative recovery (RR) percentage obtained for the spiked real water samples at 0.1 ng mL( 1) and 1 ng mL(-1) level were 93-103% and 95-104%, respectively. The whole procedure showed to be conveniently applicable and quite easy to handle. PMID- 22200310 TI - Development of a new dispersive liquid-liquid microextraction method in a narrow bore tube for preconcentration of triazole pesticides from aqueous samples. AB - In the present work a new, simple, rapid and environmentally friendly dispersive liquid-liquid microextraction (DLLME) method has been developed for extraction/preconcentration of some triazole pesticides in aqueous samples and in grape juice. The extract was analyzed with gas chromatography-flame ionization detection (GC-FID) or gas chromatography-mass spectrometry (GC-MS). The DLLME method was performed in a narrow-bore tube containing aqueous sample. Acetonitrile and a mixture of n-hexanol and n-hexane (75:25, v/v) were used as disperser and extraction solvents, respectively. The effect of several factors that influence performance of the method, including the chemical nature and volume of the disperser and extraction solvents, number of extraction, pH and salt addition, were investigated and optimized. Figures of merit such as linearity (r(2)>0.995), enrichment factors (EFs) (263-380), limits of detection (0.3-5 MUg L(-1)) and quantification (0.9-16.7 MUg L(-1)), and relative standard deviations (3.2-5%) of the proposed method were satisfactory for determination of the model analytes. The method was successfully applied for determination of target pesticides in grape juice and good recoveries (74-99%) were achieved for spiked samples. As compared with the conventional DLLME, the proposed DLLME method showed higher EFs and less environmental hazards with no need for centrifuging. PMID- 22200311 TI - Application of hollow fiber liquid phase microextraction for pinic acid and pinonic acid analysis from organic aerosols. AB - A method based on hollow fiber liquid phase microextraction (HF-LPME) for analysis of pinic acid and pinonic acid was developed and for the first time successfully applied to ambient aerosol samples. In this method, the aerosol samples were dissolved in 0.05 M H(2)SO(4) and the solution was extracted using three-phase HF-LPME where donor phase was 0.1 M (NH(4))(2)CO(3). Different parameters like type of organic solvent for membrane phase, extraction time and stirring speed etc. were optimized. Optimum extraction time was 4.5 h and optimum stirring speed was found to be 900 rpm. We used 6-undecanone as organic phase along with tri-n-octylphosphine oxide (optimum TOPO contents was 15% w/v), which gave an enormous enrichment for both pinic and pinonic acid. Enrichment factors of 28,050 and 27,400 times were obtained for pinonic acid and pinic acid, respectively, that are the highest ever published. The extraction efficiency for pinic acid and pinonic acid were 68.5% and 70.1%, respectively. Very low limits of detection were obtained. Values of 1.0 ng L(-1) and 0.5 ng L(-1) in aqueous solutions, corresponding to 24 pg m(-3) and 12 pg m(-3) in aerosol samples were the limits of detections for pinonic acid and pinic acid, respectively. Both pinonic acid and pinic acid were found in all aerosol samples analyzed. PMID- 22200312 TI - A novel approach for determining total titanium from titanium dioxide nanoparticles suspended in water and biosolids by digestion with ammonium persulfate. AB - Titanium dioxide (i.e. TiO(2)) in nano-form is a constituent of many nanomaterials that are used in sunscreens, cosmetics, industrial products and in biomedical applications. Quantification of TiO(2) nanoparticles in various matrixes is a topic of great interest for researchers studying the potential health and environmental impacts of nanoparticles. However, analysis of TiO(2) as Ti(4+) is difficult because current digestion techniques require use of strong acids that may be a health and safety risk in the laboratory. To overcome this problem, we developed a new method to digest TiO(2) nanoparticles using ammonium persulfate as a fusing reagent. The digestion technique requires short times to completion and optimally requires only 1 g of fusing reagent. The fusion method showed >95% recovery of Ti(4+) from 6 MUg mL(-1) aqueous suspensions prepared from 10 MUg mL(-1) suspension of different forms of TiO(2,) including anatase, rutile and mixed nanosized crystals, and amorphous particles. These recoveries were greater than open hot-plate digestion with a tri-acid solution and comparable to microwave digestion with a tri-acid solution. Cations and anions commonly found in natural waters showed no significant interferences when added to samples in amounts of 10 ng to 110 mg, which is a much broader range of these ions than expected in environmental samples. Using ICP-MS for analysis, the method detection limit (MDL) was determined to be 0.06 ng mL(-1), and the limit of quantification (LOQ) was 0.20 ng mL(-1). Analysis of samples of untreated and treated wastewater and biosolids collected from wastewater treatment plants yielded concentrations of TiO(2) of 1.8 and 1.6 ng mL(-1) for the wastewater samples, respectively, and 317.4 ng mg(-1) dry weights for the biosolids. The reactions between persulfate ions and TiO(2) were evaluated using stoichiometric methods and FTIR and XRD analysis. A formula for the fusing reaction is proposed that involves the formation of sulfate radicals. PMID- 22200313 TI - Extraction and preconcentration of trace levels of cobalt using functionalized magnetic nanoparticles in a sequential injection lab-on-valve system with detection by electrothermal atomic absorption spectrometry. AB - A new approach to performing extraction and preconcentration employing functionalized magnetic nanoparticles for the determination of trace metals is presented. Alumina-coated iron oxide nanoparticles were synthesized and used as the solid support. The nanoparticles were functionalized with sodium dodecyl sulfate and used as adsorbents for solid phase extraction of the analyte. Extraction, elution, and detection procedures were performed sequentially in the sequential injection lab-on-valve (SI-LOV) system followed by electrothermal atomic absorption spectrometry (ETAAS). Mixtures of hydrophobic analytes were successfully extracted from solution using the synthesized magnetic adsorbents. The potential use of the established scheme was demonstrated by taking cobalt as a model analyte. Under the optimal conditions, the calibration curve showed an excellent linearity in the concentration range of 0.01-5 MUg L(-1), and the relative standard deviation was 2.8% at the 0.5 MUg L(-1) level (n=11). The limit of detection was 6 ng L(-1) with a sampling frequency of 18 h(-1). The present method has been successfully applied to cobalt determination in water samples and two certified reference materials. PMID- 22200314 TI - Investigation of the efficiency of the sample pretreatment stage for the determination of the rare earth elements in rock samples by inductively coupled plasma mass spectrometry technique. AB - Different methods of rock sample digestion for final analysis by ICP-MS technique are investigated. It is shown that only basic rocks can be quantitatively digested in a microwave (MW) field with the mixture of HF and HNO(3) acids at 210 degrees C for 60 min. The addition of HCl and H(3)BO(3) provides complete digestion of andesites and some types of granites. Even at maximal temperature in the used MW oven of 210 degrees C syenites, granodiorites and albitized granites are not digested. These types of rocks are not digested in a closed Teflon autoclave for 16 h and can be digested only by fusion with lithium metaborate. The reason for such behavior is discussed. To avoid problems with the introduction of heavily acidic solutions after fusion in ICP the solutions were diluted. To compensate the loss of sensitivity due to the dilution step the REEs (Rare Earth Elements) pre-concentration using aminocarboxylic Pol-DETATA (diethyltriaminetetraacetate) sorbent was tested. The developed scheme is validated by the analysis of a wide range of reference rock materials. PMID- 22200315 TI - Direct affinity screening chromatography-mass spectrometry assay for identification of antibacterial agents from natural product sources. AB - A direct affinity screening-mass spectrometry assay, coupled to liquid chromatography, is presented as a tool for natural product drug discovery. Using the assay, fractionated extracts from a Caribbean gorgonian coral were shown to contain a new chemical entity (NCE) which binds to a mimic of the Gram positive bacterial cell wall (lysine-D-alanine-D-alanine). Conditions for observation of a specific noncovalent complex between the NCE and the target mimic using electrospray ionization-mass spectrometry were validated in a series of positive and negative control experiments, which featured flow injection analysis-based titrations. While the structural identity of the NCE could not be determined due to limited sample quantities, this work provides proof-of-principle for such an approach to potentially accelerate drug discovery from natural product sources. PMID- 22200316 TI - An efficient upconversion luminescence energy transfer system for determination of trace amounts of nitrite based on NaYF4:Yb3+, Er3+ as donor. AB - Based on NaYF(4):Yb(3+), Er(3+) upconversion nanocrystals as donor and 4-((4-(2 aminoethylamino)naphthalen-1-yl)diazenyl) benzenesulfonic acid dihydrochloride (ANDBS) as acceptor, an efficient luminescence energy transfer (LET) system was developed for selective and sensitive determination of trace amounts of nitrite. Based on Griess Reaction, ANDBS was generated by the quantitative reaction of nitrite, sulfanilamide and N-(1-naphtyl)-ethylenediamine dihydrochloride (N1NED). The degree of the overlaps between the emission spectrum of NaYF(4):Yb(3+), Er(3+) and the absorption spectrum of ANDBS were effective for luminescence energy transfer. Under the optimal condition, the upconversion luminescence quenching of NaYF(4):Yb(3+), Er(3+) was in proportion to the trace amounts of nitrite. The detection limit for nitrite achieved is 0.0046 MUg mL(-1) and the system shows high sensitivity towards nitrite at 0.008000-0.2500 MUg mL(-1) range. PMID- 22200317 TI - Simultaneous impedimetric and amperometric interrogation of renal cells exposed to a calculus-forming salt. AB - The complexity of the cellular response, induced even by the simplest experimental stimulus, requires an increased number of cellular parameters to be simultaneously monitored. An all electrochemical system allowing the simultaneous and real-time monitoring of both cell adherence and superoxide release into the extracellular space was developed to address this challenge. Cell adherence (to neighboring cells and to substrate) was monitored using non-faradaic impedance spectroscopy while the superoxide release was monitored using a cytochrome c based amperometric biosensor. The system was used to observe for the first time how these two cellular parameters are changing in real-time for renal cells exposed to calcium oxalate, a calculus-forming salt. It was discovered that calcium oxalate crystals decrease cell adherence and in the same time induce oxidative stress by an overproduction of superoxide. Subconfluent cells, without fully developed tight junctions, appear to be more vulnerable than confluent cells with tight junctions indicating the important protective role of these junctions. PMID- 22200318 TI - Comprehensive two-dimensional high performance liquid chromatography system with immobilized liposome chromatography column and monolithic column for separation of the traditional Chinese medicine Schisandra chinensis. AB - A comprehensive two-dimensional (2D) separation is one that employs two separation dimensions (columns) and draws on all of the available resolving power from each of the dimensions of separate the components in a sample. In this study, a comprehensive 2D chromatography approach was developed for the separation and identification of membrane permeable compounds in a famous traditional Chinese medicine of Schisandra chinensis. The first dimensional column was the immobilized liposome chromatography (ILC) column, which mimics the biological membranes and can be used to study drug-membrane interactions in liquid chromatography. Using an automatic ten-port switching valve equipped with two sample loops, the section of the first-dimension was introduced in the second dimension consist of a silica monolithic column. More than 40 components in Schisandra chinensis were resolved by using the developed separation system and among them 14 compounds were identified interacting with the ILC column based on their retention action, UV and mass data. With this comprehensive 2D-HPLC system, the three-dimensional chromatographic fingerprints of Schisandra chinensis were preliminarily established and processed by using principal component analysis and hierarchical clustering analysis. The obtained information can distinguish the unacceptable samples of the quality control. The result demonstrated that the 2D biochromatography system has been demonstrated to have more advantages of finding strong binding bioactive components, providing an enhanced peak capacity, good sensitivity and powerful resolution biological fingerprinting analysis of complex TCMs, which was a useful means to control the quality of and to clarify the membrane permeability of the compounds in Schisandra chinensis. PMID- 22200320 TI - Highly selective solid-phase extraction of trace Pd(II) by murexide functionalized halloysite nanotubes. AB - The originality on the high efficiency of murexide modified halloysite nanotubes as a new adsorbent of solid phase extraction has been reported to preconcentrate and separate Pd(II) in solution samples. The new adsorbent was confirmed by Fourier transformed infrared spectra, X-ray diffraction, scanning electron microscope, transmission electron microscope and N(2) adsorption-desorption isotherms. Effective preconcentration conditions of analyte were examined using column procedures prior to detection by inductively coupled plasma-optical emission spectrometry (ICP-OES). The effects of pH, the amount of adsorbent, the sample flow rate and volume, the elution condition and the interfering ions were optimized in detail. Under the optimized conditions, Pd(II) could be retained on the column at pH 1.0 and quantitatively eluted by 2.5 mL of 0.01 mol L(-1) HCl-3% thiourea solution at a flow rate of 2.0 mL min(-1). The analysis time was 5 min. An enrichment factor of 120 was accomplished. Common interfering ions did not interfere in both separation and determination. The maximum adsorption capacity of the adsorbent at optimum conditions was found to be 42.86 mg g(-1) for Pd(II). The detection limit (3sigma) of the method was 0.29 ng mL(-1), and the relative standard deviation (RSD) was 3.1% (n=11). The method was validated using certified reference material, and has been applied for the determination of trace Pd(II) in actual samples with satisfactory results. PMID- 22200319 TI - A novel evaluation method for extrapolated retention factor in determination of n octanol/water partition coefficient of halogenated organic pollutants by reversed phase high performance liquid chromatography. AB - The retention factor corresponding to pure water in reversed-phase high performance liquid chromatography (RP-HPLC), k(w), was commonly obtained by extrapolation of retention factor (k) in a mixture of organic modifier and water as mobile phase in tedious experiments. In this paper, a relationship between logk(w) and logk for directly determining k(w) has been proposed for the first time. With a satisfactory validation, the approach was confirmed to enable easy and accurate evaluation of k(w) for compounds in question with similar structure to model compounds. Eight PCB congeners with different degree of chlorination were selected as a training set for modeling the logk(w)-logk correlation on both silica-based C(8) and C(18) stationary phases to evaluate logk(w) of sample compounds including seven PCB, six PBB and eight PBDE congeners. These eight model PCBs were subsequently combined with seven structure-similar benzene derivatives possessing reliable experimental K(ow) values as a whole training set for logK(ow)-logk(w) regressions on the two stationary phases. Consequently, the evaluated logk(w) values of sample compounds were used to determine their logK(ow) by the derived logK(ow)-logk(w) models. The logK(ow) values obtained by these evaluated logk(w) were well comparable with those obtained by experimental extrapolated logk(w), demonstrating that the proposed method for logk(w) evaluation in this present study could be an effective means in lipophilicity study of environmental contaminants with numerous congeners. As a result, logK(ow) data of many PCBs, PBBs and PBDEs could be offered. These contaminants are considered to widely exist in the environment, but there have been no reliable experimental K(ow) data available yet. PMID- 22200321 TI - Insights into intrastrand cross-link lesions of DNA from QM/MM molecular dynamics simulations. AB - DNA damages induced by oxidative intrastrand cross-links have been the subject of intense research during the past decade. Yet, the currently available experimental protocols used to isolate such lesions only allow to get structural information about linked dinucleotides. The detailed structure of the damaged DNA macromolecule has remained elusive. In this study we generated in silico the most frequent oxidative intrastrand cross-link adduct, G[8,5-Me]T, embedded in a solvated DNA dodecamer by means of quantum mechanics/molecular mechanics (QM/MM) Car-Parrinello simulations. The free energy of activation required to bring the reactant close together and to form the C-C covalent-bond is estimated to be ~10 kcal/mol. We observe that the G[8,5-Me]T tandem lesion is accommodated with almost no perturbation of the Watson-Crick hydrogen-bond network and induces bend and unwinding angles of ~20 degrees and 8 degrees , respectively. This rather small structural distortion of the DNA macromolecule compared to other well characterized intrastrand cross-links, such as cyclobutane pyrimidines dimers or cisplatin-DNA complex adduct, is a probable rationale for the known lack of efficient repair of oxidative damages. PMID- 22200323 TI - Survival of Listeria innocua in dry fermented sausages and changes in the typical microbiota and volatile profile as affected by the concentration of nitrate and nitrite. AB - The involvement of nitrate and nitrite in the formation of N-nitrosamines in foods is a matter of great concern. This situation has led to revise the real amount of nitrate and nitrite needed in meat products to exert proper technological and safety activities, and also to extensive research to find alternatives to their use. The present study addresses the possibility of reducing the ingoing amounts of these additives below the legal limits established by the current European regulations. Different concentrations of nitrate and nitrite were tested on Spanish salchichon-type dry fermented sausages concerning their role in the microbiota and volatile profile. Sausages were manufactured with the maximum ingoing amounts established by the EU regulations (150 ppm NaNO(3) and 150 ppm NaNO(2)), a 25% reduction and a 50% reduction; control sausages with no nitrate/nitrite addition were also prepared. The mixtures were inoculated with 5 log cfu/g of Listeria innocua as a surrogate for Listeria monocytogenes. L. innocua numbers in the final product were approximately 1.5 log cfu/g lower in the batch with the maximum nitrate/nitrite concentration when compared to 25 and 50% reduced batches, and about 2 log cfu/g in comparison to the control sausages. The final numbers of catalase-positive cocci were 1 log cfu/g higher in the 50% nitrate/nitrite reduced batch and 2 log cfu/g higher in the control sausages, compared to products manufactured with the maximum nitrate/nitrite concentration. This increase was related to a higher amount of volatile compounds derived from carbohydrate fermentation and amino acid degradation. Sausages with no addition of nitrate/nitrite showed higher amount of volatiles from lipid oxidation. Enterobacteriaceae counts reached detectable values (1-2 log cfu/g) in both nitrate/nitrite reduced sausages and in the control batch, while these organisms were not detected in the batch with the maximum ingoing amount. Nitrate and nitrite exerted a significant effect on the typical microbiota of dry fermented sausages and effectively contributed to control Listeria. These considerations should be taken into account in view of a future restriction in the use of these curing additives. PMID- 22200324 TI - Immunotherapy targeting glioma stem cells--insights and perspectives. AB - INTRODUCTION: Glioblastoma multiforme (GBM) is the most aggressive and lethal primary malignant brain tumor. Although progress has been made in current conventional therapies for GBM patients, the effect of these advances on clinical outcomes has been disappointing. Recent research into the origin of cancers suggest that GBM cancer stem cells (GSC) are the source of initial tumor formation, resistance to current conventional therapeutics and eventual patient relapse. Currently, there are very few studies that apply immunotherapy to target GSC. AREAS COVERED: CD133, a cell surface protein, is used extensively as a surface marker to identify and isolate GSC in malignant glioma. We discuss biomarkers such as CD133, L1-cell adhesion molecule (L1-CAM), and A20 of GSC. We review developing novel treatment modalities, including immunotherapy strategies, to target GSC. EXPERT OPINION: There are very few reports of preclinical studies targeting GSC. Identification and validation of unique molecular signatures and elucidation of signaling pathways involved in survival, proliferation and differentiation of GSC will significantly advance this field and provide a framework for the rational design of a new generation of antigen-specific, anti GSC immunotherapy- and nanotechnology-based targeted therapyies. Combined with other therapeutic avenues, GSC-targeting therapies may represent a new paradigm to treat GBM patients. PMID- 22200325 TI - Pre- and perinatal risk factors in adults with attention-deficit/hyperactivity disorder. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and disabling lifespan disorder, but little is yet known about risk factors for ADHD persisting beyond adolescence. The present study investigates the association between pregnancy and birth complications and ADHD in adulthood. METHODS: We used data from the Medical Birth Registry of Norway to compare pre-and perinatal risk factors among 2323 adults approved for medical treatment for ADHD, with the remaining population born during the same years, 1967-1987, and surviving into adulthood (n = 1,170,073). Relative risks (RR) adjusted for potential confounders were calculated. RESULTS: Preterm (< 37 weeks of gestation) and extremely preterm birth (< 28 weeks of gestation) were associated with 1.3- and 5-fold increased risks of ADHD, respectively. Birth weights <2500 g and <1500 g also increased the risk of ADHD (RR: 1.5, 95% confidence interval [CI]: 1.2-1.8, and RR: 2.1, 95% CI: 1.3-3.6, respectively). Five-minute Apgar scores <4 and <7 were associated with 2.8- and 1.5-fold increased risks of persisting ADHD, respectively. Maternal epilepsy (RR: 1.7, 95% CI: 1.1-2.7) and offspring oral cleft (RR: 2.8, 95% CI: 1.6-4.9) occurred more frequently among adult ADHD patients. CONCLUSIONS: This is the first population-based study of pre-and perinatal risk factors in adults with ADHD. We show that low birth weight, preterm birth, and low Apgar scores increase the risk of ADHD, persisting up to 40 years after birth. The increased risk of ADHD related to oral cleft and to maternal epilepsy warrants further investigation to explore possible causal mechanisms. PMID- 22200326 TI - Ammonia gas-sensing characteristics of fluorescence-based poly(2 (acetoacetoxy)ethyl methacrylate) thin films. AB - Novel fluorescent poly(2-(acetoacetoxy)ethyl methacrylate)(PAAEMA) latexes have been synthesized by miniemulsion polymerization employing a polymeric costabilizer. Nanoscale aggregates of macromolecules bearing beta-dicarbonyl are formed in the prepared latex particles. Ammonia and the beta-dicarbonyl aggregates assemble a supramolecular complex, which exhibits strong visible fluorescence under UV light. The formation of the complex is confirmed by the characteristic absorption peak located at about 275 nm in UV-Vis spectra. The absorption spectrum has been found to be applicable for ammonia detection. Atomic Force Microscopy (AFM) studies of surface morphology reveal that gas-sensing properties of the PAAEMA thin films involve the reversible absorption and desorption of ammonia. PAAEMA thin films are sensitive to ammonia gas and have a short response time of 80s when exposed to 54 ppm of ammonia gas concentration. PMID- 22200327 TI - One-pot deposition of palladium on hybrid TiO2 nanoparticles and catalytic applications in hydrogenation. AB - One-pot deposition of Pd onto TiO(2) has been achieved through directly contacting palladium(II) salt with nanosized functionalized TiO(2) support initially obtained by sol-gel process using titanium isopropoxide and citric acid. Citrate groups act as functional moieties able to directly reduce the Pd salt avoiding any further reducing treatment. Various palladium salts (Na(2)PdCl(4) and Pd(NH(3))(4)Cl(2).H(2)O) and titanium to citrate (Ti/CA) ratios (20, 50, and 100) were used in order to study the effect of the nature of the precursor and of the citrate content on the final Pd particle size and catalytic properties of the as-obtained Pd/TiO(2) systems. Characterization was performed using N(2) adsorption-desorption isotherms, ICP-AES, FTIR, XRD, XPS, and TEM. The as-obtained hybrid Pd/TiO(2) catalysts were tested in the selective hydrogenation (HYD) of an alpha,beta-unsaturated aldehyde, i.e. cinnamaldehyde. Citrate-free Pd/TiO(2)-based catalysts present lower selectivity into saturated alcohol. However, citrate-functionalized Pd/TiO(2) catalyst seems to control the selectivity, the particle size and dispersion of Pd NPs leading to high intrinsic activity. PMID- 22200328 TI - Structural and mechanical properties of Laponite-PEG hybrid films. AB - Inorganic/organic hybrids were obtained by the sol-gel type organic modification reaction of Laponite sidewalls with poly(ethylene glycol) (PEG) bearing alkoxysiloxy terminal functionality. By casting an aqueous dispersion of the hybrid, the flexible and transparent hybrid films were obtained. Regardless of the inorganic/organic component ratio, the hybrid film had the ordered structure of Laponite in-plane flat arrays. The mechanical strength of hybrid films was drastically improved by the presence of cross-linking among alkoxysilyl functionalities of PEG terminals and the absence of PEG crystallines. Hybrid films, especially those that consisted of PEG with short chain, showed good mechanical properties that originate from quasi-homogeneous dispersion of components due to anchoring of PEG terminal to Laponite sidewall and interaction of PEG to Laponite surface. PMID- 22200329 TI - Direct formation of iron oxide/MCM-41 nanocomposites via single or mixed n alkyltrimethylammonium bromide surfactants. AB - Iron oxide/MCM-41 nanocomposites, Fe(2)O(3)/MCM-41, containing 5%, 10%, and 20% (w/w) iron oxide, were prepared via a direct nonhydrothermal method at room temperature. The preparations were preformed by using iron(III) nitrate, tetra ethoxysilane (TEOS), and cetyltrimethylammonium bromide (CTAB) mixed or unmixed with dodecyltrimethylammonium bromide (DTAB). The produced materials were dried and calcined at 550 degrees C for 3 h. Test materials were characterized by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), N(2) gas adsorption/desorption isotherms, small angle and wide angle X-ray diffraction (XRD). Results indicate that mixing of CTAB with DTAB does not harm the formation of blank MCM-41 structure. For the composite Fe(2)O(3)/MCM-41 materials, results showed formation of more stable MCM-41 structure with higher surface area and improved porosity in the presence of mixed (CTAB+DTAB) than in the presence of single (CTAB) surfactants for up to 10% Fe(2)O(3)/MCM-41 (w/w). This was explained in terms of the effect DTAB on contraction of the template micellar size to compensate for the expected size expansion upon the addition of ionic iron(III) nitrate precursor. Highly dispersed Fe(2)O(3) nanoparticles were formed in all cases even with the highest iron oxide percentage. Formation of the nanocomposites was postulated to be determined by fast nucleation and slow growth of iron oxide species, which facilitated formation of well dispersed iron oxide nanoparticles inside and on the wall of the MCM-41 material. PMID- 22200330 TI - Gold nanoparticles generated and stabilized by water soluble curcumin-polymer conjugate: blood compatibility evaluation and targeted drug delivery onto cancer cells. AB - Curcumin (Cur) shows low anticancer activity in vivo due to its reduced systemic bioavailability stemmed from its poor aqueous solubility and instability. Suitably functionalized nanocarriers designed to empty the drug specifically at tumor sites can potentially enhance the antitumor activity of Cur. We devised a simple method for the fabrication of water soluble Cur conjugated gold nanoparticles to target various cancer cell lines. Cur was conjugated to hyaluronic acid (HA) to get a water soluble conjugate (HA-Cur). We generated gold nanoparticles (AuNPs) by reducing chloroauric acid using HA-Cur, which played the dual role of a reducing and stabilizing agent and subsequently anchored folate conjugated PEG. These entities were probed using different analytical techniques, assayed the blood compatibility and cytotoxicity. Their interaction with cancer cell lines (HeLa cells, glyoma cells and Caco 2 cells) was followed by flow cytometry and confocal microscopy. Blood-materials interactions studies showed that the nanoparticles are highly hemocompatible. Flow cytometry and confocal microscopy results showed significant cellular uptake and internalization of the particles by cells. HA-Cur@AuNPs exhibited more cytotoxicity comparing to free Cur. The strategy, we adopted here, resulted the formation blood compatible Cur conjugated AuNPs with enhanced targeting and improved efficacy. PMID- 22200331 TI - Synthesis, characterization and visible light photocatalytic properties of Bi2WO6/rectorite composites. AB - Visible light-induced Bi(2)WO(6)/rectorite (BR) composites were prepared by a sol gel method. The as-prepared samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), UV-vis diffuse reflectance spectrum, Fourier transform infrared (FTIR) spectrum, X-ray photoelectron spectroscopy (XPS) and Brunauer-Emmet-Teller (BET). The UV absorption edges of the BR-450 catalyst showed a marked red shift as compared to that of the pure Bi(2)WO(6). The photocatalytic activities of the as prepared samples were evaluated by the photocatalytic degradation of 4BS dye in aqueous solution under visible light irradiation (>420 nm). The results showed that the BR-450 catalyst exhibited a strong adsorption capability and a higher photocatalytic degradation activity than the pure Bi(2)WO(6) for 4BS dye, which could be attributed to the synergetic effects of the adsorbability of rectorite and the photocatalytic property of Bi(2)WO(6) in it. PMID- 22200332 TI - In vitro and in vivo consideration of novel environmentally responsive ophthalmic drug delivery system. AB - In the present study, novel environmentally responsive ophthalmic drug delivery system composed of two gelling polymers with different phase transition mechanisms was developed in order to obtain sustained drug release in ocular cavity. Combination of polyacrylic acid (carbopol 934P) and xanthan gum was investigated as ophthalmic vehicle and assessed for its in vitro and in vivo performance. Different ratios of these polymers were used to prepare environmentally responsive ophthalmic drug delivery system by simple mixing procedure. Developed formulation was assessed for physical tests such as appearance/clarity, pH, gelation; and performance characteristics such as drug content, rheological measurement, in vitro release, antimicrobial efficiency, in vivo studies for eye irritation, residence time estimation. Prepared formulation showed agreeable appearance/clarity, acceptable pH and good gelation property. In vitro and in vivo studies demonstrated adequate drug content, desired rheological behavior and reasonable in vitro and in vivo drug release property. In conclusion, the optimum concentration of polymers results in increased residence time and sustained drug release. On the basis of these findings, environmentally responsive system based on combination of carbopol and xanthan gum may be considered as a promising tool for ophthalmic delivery. PMID- 22200335 TI - Evaluation of donor and steric properties of anionic ligands on high valent transition metals. AB - Synthetic protocols and characterization data for a variety of chromium(VI) nitrido compounds of the general formula NCr(NPr(i)(2))(2)X are reported, where X = NPr(i)(2) (1), I (2), Cl (3), Br (4), OTf (5), 1-adamantoxide (6), OSiPh(3) (7), O(2)CPh (8), OBu(t)(F6) (9), OPh (10), O-p-(OMe)C(6)H(4) (11), O-p (SMe)C(6)H(4) (12), O-p-(Bu(t))C(6)H(4) (13), O-p-(F)C(6)H(4) (14), O-p (Cl)C(6)H(4) (15), O-p-(CF(3))C(6)H(4) (16), OC(6)F(5) (17), kappa(O)-N-oxy phthalimide (18), SPh (19), OCH(2)Ph (20), NO(3) (21), pyrrolyl (22), 3-C(6)F(5) pyrrolyl (23), 3-[3,5-(CF(3))(2)C(6)H(3)]pyrrolyl (24), indolyl (25), carbazolyl (26), N(Me)Ph (27), kappa(N)-NCO (28), kappa(N)-NCS (29), CN (30), NMe(2) (31), F (33). Several different techniques were employed in the syntheses, including nitrogen-atom transfer for the formation of 1. A cationic chromium complex [NCr(NPr(i)(2))(2)(DMAP)]BF(4) (32) was used as an intermediate for the production of 33, which was produced by tin-catalyzed degredation of the salt. Using spin saturation transfer or line shape analysis, the free energy barriers for diisopropylamido rotation were studied. It is proposed that the estimated enthalpic barriers, Ligand Donor Parameters (LDPs), for amido rotation can be used to parametrize the donor abilities of this diverse set of anionic ligands toward transition metal centers in low d-electron counts. The new LDPs do not correlate well to the pK(a) value of X. Conversely, the LDP values of phenoxide ligands do correlate with Hammett parameters for the para-substituents. Literature data for (13)C NMR chemical shifts for a tungsten-based system with various X ligands plotted versus LDP provided a linear fit. In addition, the angular overlap model derived e(sigma) + e(pi) values for chromium(III) ammine complexes correlate with LDP values. Also discussed is the correlation with XTiCp*(2) spectroscopic data. X-ray diffraction has been used used to characterize 31 of the compounds. From the X-ray diffraction data, steric parameters for the ligands using the Percent Buried Volume and Solid Angle techniques were found. PMID- 22200334 TI - Impact of socioeconomic deprivation and area of residence on access to coronary revascularization and mortality after a first acute myocardial infarction in Quebec. AB - BACKGROUND: Socioeconomic status (SES) and area of residence are known to impact access to invasive cardiac procedures. Low SES adversely affects long-term mortality after acute myocardial infarction (AMI). Most of the data were derived from private healthcare systems. Our objectives were to evaluate the effects of SES and area of residence on access to coronary angiography, revascularization and mortality after a first AMI in a publicly-funded healthcare system with a high supply of catheterization facilities. METHODS: Quebec administrative databases were used to identify all patients with a first AMI between 1997 and 2001. The SES was determined with the population deprivation index, which has 2 dimensions: material and social. Six-month access to angiography, revascularization and 1-year mortality were considered in proportional hazards survival regression analyses measuring the effect of deprivation and the geographical area of residence, accounting for several other covariates. RESULTS: The study cohort consisted of 50,242 patients. The most materially and socially deprived patients had a 16% (95% confidence interval [CI], 1.08-1.25) and 13% (95% CI, 1.05-1.21) relative increased hazard of dying within 1 year respectively compared with the most privileged subjects. This mortality gradient could not be explained by meaningful differences in access to angiography or revascularization. Geography did not influence access to revascularization procedures. CONCLUSIONS: Despite universal healthcare system, SES measured with a material and social deprivation index, had significant adverse effect on 1-year mortality after a first AMI. Such findings were not explained by lower access to coronary angiography or revascularization. PMID- 22200336 TI - [Brain development of infant and MRI by diffusion tensor imaging]. AB - Studying how the brain develops and becomes functional is important to understand how the man has been able to develop specific cognitive abilities, and to comprehend the complexity of some developmental pathologies. Thanks to magnetic resonance imaging (MRI), it is now possible to image the baby's immature brain and to consider subtle correlations between the brain anatomical development and the early acquisition of cognitive functions. Dedicated methodologies for image acquisition and post-treatment must then be used because the size of cerebral structures and the image contrast are very different in comparison with the adult brain, and because the examination length is a major constraint. Two recent studies have evaluated the developing brain under an original perspective. The first one has focused on cortical folding in preterm newborns, from 6 to 8 months of gestational age, assessed with T2-weighted conventional MRI. The second study has mapped the organization and maturation of white matter fiber bundles in 1- to 4-month-old healthy infants with diffusion tensor imaging (DTI). Both studies have enabled to highlight spatio-temporal differences in the brain regions' maturation, as well as early anatomical asymmetries between cerebral hemispheres. These studies emphasize the potential of MRI to evaluate brain development compared with the infant's psychomotor acquisitions after birth. PMID- 22200337 TI - [Neurobiological bases and neurophysiological correlates of developmental coordination disorders]. AB - Among psychomotor disorders in children, developmental coordination disorder (DCD) is characterized by a motor skill impairment that interferes with psychomotor development, academic performance and activities of daily living, despite normal intelligence. The main behavioural phenomena (lack of postural control, coordination and motor learning) suggest involvement of cerebellum, basal ganglia and frontal and parietal lobes. Our studies on a synchronisation/syncopation task, with EEG recording (coherence analysis and evoked potential), show that DCD children (8 to 12 years old) exhibit major interindividual variability and do not improve performance with repetition. In younger DCD children, an increase of coherence between fronto-central regions was reported, and, for evoked potential, an increase of motor preparation component and a N100 latency longer than control children. These findings support the idea of a general synchronization disorder in DCD children and furnish elements allowing a better understanding of intra- and interindividual variability. PMID- 22200338 TI - fMRI and MEG in the study of typical and atypical cognitive development. AB - The tremendous changes in brain structure over childhood are critical to the development of cognitive functions. Neuroimaging provides a means of linking these brain-behaviour relations, as task protocols can be adapted for use with young children to assess the development of cognitive functions in both typical and atypical populations. This paper reviews some of our research using magnetoencephalography (MEG) and functional MRI (fMRI) in the study of cognitive development, with a focus on frontal lobe functions. Working memory for complex abstract patterns showed clear development in terms of the recruitment of frontal regions, seen with fMRI, with indications of strategy differences across the age range, from 6 to 35 years of age. Right hippocampal involvement was also evident in these n-back tasks, demonstrating its involvement in recognition in simple working memory protocols. Children born very preterm (7 to 9 years of age) showed reduced fMRI activation particularly in the precuneus and right hippocampal regions relative to control children. In a large normative n-back study (n=90) with upright and inverted faces, MEG data also showed right hippocampal activation that was present across the age range; frontal sources were evident only from 10 years of age. Other studies have investigated the development of set shifting, an executive function that is often deficit in atypical populations. fMRI showed recruitment of frontal areas, including the insula, that have significantly different patterns in children (7 to 14 years of age) with autism spectrum disorder compared to typically developing children, indicating that successful performance implicated differing strategies in these two groups of children. These types of studies will help our understanding of both normal brain behaviour development and cognitive dysfunction in atypically developing populations. PMID- 22200339 TI - Magnetoencephalography in neonatology. AB - Magnetoencephalography (MEG) is a noninvasive method to study brain activity. In the previous decade the advantages of MEG -- good temporal resolution combined with good spatial resolution allowing separation of activated brain areas -- have been successfully used in gaining new information about the neonatal brain functioning. In this review, we discuss the findings from studies of spontaneous magnetoencephalogram and evoked responses to somatosensory, auditory, and visual stimulation. Our group has shown that stimulation of the upper limb in neonates evokes a response sequence reflecting activation of both primary (S(I)) and secondary somatosensory (S(II)) cortices. Like in mature brains, the earliest cortical response to median nerve stimulation reflects the arrival of afferent information to S(I). However, source modeling of the subsequent activation from S(I)suggests immature cortical functioning in neonates. Another feature typical for neonates is that the S(II)response is prominent in quiet sleep, unlike in adults in whom it diminishes in sleep. Interestingly, in very prematurely-born infants, we found alterations of the somatosensory responses at both group and individual levels. MEG provides a novel way to look at brain activity in neonates and can be used to increase knowledge of the development of brain processing and its disturbances. PMID- 22200340 TI - Infant brain responses associated with reading-related skills before school and at school age. AB - INTRODUCTION: In Jyvaskyla Longitudinal Study of Dyslexia, we have investigated neurocognitive processes related to phonology and other risk factors of later reading problems. Here we review studies in which we have investigated whether dyslexic children with familial risk background would show atypical auditory/speech processing at birth, at six months and later before school and at school age as measured by brain event-related potentials (ERPs), and how infant ERPs are related to later pre-reading cognitive skills and literacy outcome. PATIENTS AND METHODS: One half of the children came from families with at least one dyslexic parent (the at-risk group), while the other half belonged to the control group without any familial background of dyslexia. RESULTS: Early ERPs were correlated to kindergarten age phonological processing and letter-naming skills as well as phoneme duration perception, reading and writing skills at school age. The correlations were, in general, more consistent among at-risk children. Those at-risk children who became poor readers also differed from typical readers in the infant ERP measures at the group level. ERPs measured before school and at the 3rd grade also differed between dyslexic and typical readers. Further, speech perception at behavioural level differed between dyslexic and typical readers, but not in all dyslexic readers. CONCLUSIONS: These findings suggest persisting developmental differences in the organization of the neural networks sub-serving auditory and speech perception, with cascading effects on later reading related skills, in children with familial background for dyslexia. However, atypical auditory/speech processing is not likely a sufficient reason by itself for dyslexia but rather one endophenotype or risk factor. PMID- 22200341 TI - Action and representation of action during childhood and adolescence: a functional approach. AB - Our scientific activity is focused on the field of action and representation of action from various adaptative situations during the life span, including pathology and extreme environment such as microgravity. The early action/perception matching, subserving the motor simulation network, is probably a major milestone for the building of action and representation of action during the course of ontogenesis. We have developed a functional approach of motor development based on a gradual mastering of coordination, adaptation and anticipation in postural control in the course of ontogenesis from babies to adolescents. This functional approach is recently associated with studies of brain structures involved in action and representation of action in children and adolescents with typical or atypical neurodevelopment. From our developmental studies, it was possible to put in light two turning points during motor development, such as 6/7 years of age and adolescence. The first step for children consists in building a repertoire of postural strategies. The second step consists in learning to select postural strategy depending on the characteristics of the task and the environmental requirements. An appropriate selection means to anticipate the consequence of the movement in order to maintain balance control and efficiency of the task. Taking into account the complexity of the parameters to control and the late maturation of anticipation and representation of action, it is not surprising that the development of postural control continues up to late periods during childhood and adolescence. PMID- 22200342 TI - Impact of focal interictal epileptiform discharges on behaviour and cognition in children. AB - It is hypothesised that focal interictal epileptiform discharges (IED) may exert a deleterious effect on behaviour and cognition in children. This hypothesis is supported by the abnormally high prevalence of IED in several developmental disorders, like specific language impairment, and of cognitive and behavioural deficits in epileptic children after excluding confounding factors such as underlying structural brain lesions, drug effects, or the occurrence of frequent or prolonged epileptic seizures. Neurophysiological and functional neuroimaging evidence suggests that IED may impact cognition through either transient effects on brain processing mechanisms, or through more long-lasting effects leading to prolonged inhibition of brain areas distant from but connected with the epileptic focus (i.e. remote inhibition effect). Sustained IED may also impair sleep related learning consolidation processes. Nowadays, the benefits of anti epileptic treatment aimed at reducing IED are not established except in specific situations like epileptic encephalopathies with continuous spike and waves during slow-wave sleep. Well-designed pharmacological studies are still necessary to address this issue. PMID- 22200343 TI - Knowledge matters--impact of two types of information brochure on contraceptive knowledge, attitudes and intentions. AB - OBJECTIVE: To compare the effect of two types of counselling brochure on knowledge, attitudes and intention towards combined oral contraceptives (COCs). STUDY DESIGN: Double-blind, parallel-group randomised trial conducted in Germany. Nulliparous women aged 18-24 years were randomly assigned to receive one of two comprehensive information brochures about COCs, their benefits and risks, and alternative contraceptive methods. The first brochure was based on standard recommendations for evidence-based patient information (EBPI). This was restructured and adapted according to the mental models approach (MMA) for the second brochure. The primary endpoint was the change in number of correct answers in a knowledge questionnaire administered directly after the intervention and three months later. The impact on attitudes and intention were secondary outcomes. RESULTS: Before the intervention, women answered 18.9 (standard deviation [SD] 4.2) of 39 knowledge items correctly. After the intervention, the EBPI group (n = 66; p = not significant) improved by 7.6 (SD 5.4) correct answers compared to 8.3 (SD 5.8) in the MMA group (n = 66). After three months, the MMA group (n = 60) maintained an improvement (5.0 [SD 4.8] correct answers vs. pre intervention measurement). In the EPBI group (n = 64), this value was 3.9 (SD 5.6). The change in correct answers was positively correlated with a change in attitude (r = 0.284, p = 0.001) and intention (r = 0.212, p = 0.015). CONCLUSIONS: The use of detailed evidence-based information brochures - irrespective of the underlying risk communication approach - can be recommended. PMID- 22200344 TI - Weight loss effects of quaternary salts of 5-amino-1-(chloromethyl)-1,2-dihydro 3H-benz[e]indoles; structure-activity relationships. AB - Quaternary salt analogues based on the DNA minor groove binder and adenine N3 alkylating agent 5-amino-1-(chloromethyl)-1,2-dihydro-3H-benz[e]indole (aminoCBI) show remarkable effects on the body weight of mice (a long-term failure to gain weight relative to matched controls with no loss of appetite or perceptible deterioration in health) following administration of a single (non-toxic) dose between about 0.5-5 MUmol/kg. The nature of the quaternizing group was not important, but a related hydroxyCBI analogue was much less effective. Compounds where the chloro group was replaced by a hydrogen or hydroxy group (thus abrogating DNA alkylating capability) showed no weight control activity. It is speculated, based on other studies, that the marked long-term weight control effect is due to inhibition of bile flow into the intestine and reduced absorption of triglycerides, together with accelerated cell death in spleen and white adipose tissues due to drug accumulation there. This class of compound may serve as interesting tools for further study of these phenomena. PMID- 22200345 TI - An integrated computational workflow for efficient and quantitative modeling of renin inhibitors. AB - A new integrated computational workflow that couples the strength of the molecular overlay methods to achieve rapid and automated alignments along with 3D QSAR techniques like CoMFA and CoMSIA for quantitative binding affinity prediction is presented. The results obtained from such techniques are compared with rule-based Topomer CoMFA method, where possible. The developed 3D-QSAR models were prospectively used to predict the affinities of new compounds designed through R-group deconvolution starting from the core chemical scaffold and subsequent virtual combinatorial library enumeration. The general applicability of the seamless in silico modeling workflow is demonstrated using several datasets reported for small molecule inhibitors of renin. PMID- 22200346 TI - Specific instructions for estimating unclearly reported blinding status in randomized trials were reliable and valid. AB - OBJECTIVE: To test the reliability and validity of specific instructions to classify blinding, when unclearly reported in randomized trials, as "probably done" or "probably not done." STUDY DESIGN AND SETTING: We assessed blinding of patients, health care providers, data collectors, outcome adjudicators, and data analysts in 233 randomized trials in duplicate and independently using detailed instructions. The response options were "definitely yes," "probably yes," "probably no," and "definitely no." We contacted authors for data verification (46% response). For each of the five questions, we assessed reliability by calculating the agreement between the two reviewers and validity by calculating the agreement between reviewers' consensus and verified data. RESULTS: The percentage with unclear blinding status varied between 48.5% (patients) and 84.1% (data analysts). Reliability was moderate for blinding of outcome adjudicators (kappa=0.52) and data analysts (kappa=0.42) and substantial for blinding of patients (kappa=0.71), providers (kappa=0.68), and data collectors (kappa=0.65). The raw agreement between the consensus record and the author-verified record varied from 84.1% (blinding of data analysts) to 100% (blinding of health care providers). CONCLUSION: With the possible exception of blinding of data analysts, use of "probably yes" and "probably no" instead of "unclear" may enhance the assessment of blinding in trials. PMID- 22200349 TI - Editorial: Toxicology of acid rain. PMID- 22200347 TI - Solution phase gold nanorings on a viral protein template. AB - Current studies on materials that exhibit metamaterial properties are mainly focused on lithography-generated 2D substrates. Here we report the successful fabrication of 22 nm gold nanoparticle rings with and without a central nanoparticle assembled on Tobacco Mosaic Virus coat protein disks. These structures are one of the first examples of nanorings produced independently of a substrate and represent the first steps toward the realization of a solution phase or coatings-based metamaterial. PMID- 22200350 TI - Currents. PMID- 22200352 TI - Detecting waste combustion emissions. PMID- 22200351 TI - Viruses in drinking water. PMID- 22200353 TI - Regulatory Focus: Legislative outlook for 1986. PMID- 22200354 TI - ES Views: Turning detection into protection. PMID- 22200355 TI - Environmental awards. PMID- 22200356 TI - Particle collection efficiency in a venturi scrubber: comparison of experiments with theory. PMID- 22200357 TI - Microbiological treatment of uranium mine waters. PMID- 22200358 TI - Transformation of trace organic compounds in drinking water by enzymic oxidative coupling. PMID- 22200359 TI - PCBs have declined more than the DDT group residues in Arctic ringed seals (Phoca hispida) between 1972 and 1981. PMID- 22200360 TI - Spatial variability of pesticide adsorption parameters. PMID- 22200361 TI - Photooxidation of 2,4-dinitrotoluene in aqueous solution in the presence of hydrogen peroxide. PMID- 22200362 TI - Fate of hazardous waste derived organic compounds in Lake Ontario. PMID- 22200363 TI - Snow chemistry of the Cascade-Sierra Nevada Mountains. PMID- 22200364 TI - Influence of carbonaceous particles on the interaction of coal combustion stack ash with organic matter. PMID- 22200365 TI - Solution of hydrocarbons in a hydrocarbon-water system with changing phase composition due to evaporation. PMID- 22200367 TI - Acidification of southern Appalachian lakes. Comments. PMID- 22200366 TI - Diagenetic trace-metal profiles in Arctic lake sediments. PMID- 22200368 TI - Acidification of southern Appalachian lakes. Reply to comments. PMID- 22200369 TI - Early and late outcome after aortic root replacement with a mechanical valve prosthesis in a series of 528 patients. AB - BACKGROUND: Aortic root replacement with a mechanical valve prosthesis is a widely accepted surgical technique. This study aims to evaluate short-term and long-term outcomes of this approach and to identify predictors of 30-day mortality. METHODS: We retrospectively analyzed a consecutive series of 528 patients (mean age, 54+/-13 years) who underwent aortic root replacement for aneurysm (83%), acute type A dissection (15%), or endocarditis (2%) in the period between 1974 and 2008. The mean time of follow-up was 9.0+/-7.0 years (range, 0 to 36 years). Concomitant aortic surgery was performed in 71%, coronary revascularization in 18%, and mitral valve surgery in 3%. Selective antegrade cerebral perfusion was applied in 25% and deep hypothermic circulatory arrest in 28% of patients. RESULTS: Overall 30-day mortality was 3.2% to 2.5% for elective surgery and 6.5% for urgent surgery. Morbidity included resternotomy for bleeding or tamponade (19%), pacemaker implantation (3.6%), myocardial infarction (4.0%), and neurologic damage (4.2%). Multivariate analysis revealed myocardial infarction (p<0.001) and the lack of glue use (p=0.018) as independent predictors of 30-day mortality. Subanalysis of the selective antegrade cerebral perfusion patients and the deep hypothermic circulatory arrest patients revealed infarction (p=0.005) and coronary artery disease (p=0.45) for selective antegrade cerebral perfusion and wrapping (p=0.035) for deep hypothermic circulatory arrest as independent risk factors. The survival rate was 87%, 73%, and 29% after 5, 10, and 25 years, respectively. CONCLUSIONS: Aortic root replacement with a mechanical valve prosthesis can be performed safely with low mortality and acceptable morbidity. Perioperative myocardial infarction is the strongest independent risk factor of 30-day mortality. PMID- 22200370 TI - Delirium: a cause for concern beyond the immediate postoperative period. AB - BACKGROUND: Delirium is a common neurologic complication after cardiac surgery, and may be associated with increased morbidity and mortality. Research has focused on potential causes of delirium, with little attention to its sequelae. METHODS: Perioperative data were collected prospectively on all isolated cases of coronary artery bypass grafting (CABG) performed from 1995 to 2006 at a single center. The definition of delirium used in the study was that of the Society of Thoracic Surgeons. Characteristics of patients who became delirious postoperatively were compared with those of patients who did not. The outcomes of interest were long-term all-cause mortality, hospital admission for stroke, and in-hospital mortality, examined in all three cases through multivariate analysis. RESULTS: Of 8,474 patients who underwent CABG within the defined period, 496 (5.8%) developed postoperative delirium and 229 (2.7%) died while in the hospital. At baseline, patients who developed delirium were more likely to be older and to have a greater burden of comorbid illness. Delirium was an independent predictor of perioperative stroke (odds ratio [OR]; 1.96; 95% confidence interval [CI], 1.22 to 3.16), but was not associated with in-hospital mortality (OR, 0.81; 95%CI, 0.49 to 1.34). Delirious patients had a median postoperative hospital stay of 12 days (interquartile range [IQR], 8 to 21 days) versus 6 days (IQR, 5 to 8 days) for those who were nondelirious. Delirium was identified as an independent predictor of all-cause mortality (hazard ratio [HR], 1.52; 95%CI, 1.29 to 1.78) and hospitalization for stroke (HR, 1.54; 95%CI, 1.10 to 2.17). CONCLUSIONS: There was an association between delirium and adverse outcomes after CABG that persisted beyond the immediate perioperative period. Patients with delirium after CABG appear to have an increased long-term risk of death and stroke. The advancing age and rising rates of delirium in the CABG population make it necessary to address the prevention and management of delirium in this population. PMID- 22200372 TI - Human amniotic epithelial cell feeder layers maintain human iPS cell pluripotency via inhibited endogenous microRNA-145 and increased Sox2 expression. AB - Currently, human induced pluripotent stem (iPS) cells were generated from patient or disease-specific sources and share the same key properties as embryonic stem cells. This makes them attractive for personalized medicine, drug screens or cellular therapy. Long-term cultivation and maintenance of normal iPS cells in an undifferentiated self-renewing state are a major challenge. Our previous studies have shown that human amniotic epithelial cells (HuAECs) could provide a good source of feeder cells for mouse and human embryonic stem cells, or spermatogonial stem cells, but the mechanism for this is unknown. Here, we examined the effect of endogenous microRNA-145 regulation on Sox2 expression in human iPS cells by HuAECs feeder cells regulation, and in turn on human iPS cells pluripotency. We found that human IPS cells transfected with a microRNA-145 mutant expressed Sox2 at high levels, allowing iPS to maintain a high level of AP activity in long-term culture and form teratomas in SCID mice. Expression of stem cell markers was increased in iPS transfected with the microRNA-145 mutant, compared with iPS was transfected with microRNA-145. Besides, the expression of Drosha proteins of the microRNA-processor complex, required for the generation of precursor pre-miRNA, was significantly increased in human iPS cells cultured on MEF but not on HuAECs. Taken together, these results suggest that endogenous Sox2 expression may be regulated by microRNA-145 in human iPS cells with HuAECs feeder cells, and Sox2 is a crucial component required for maintenance of them in an undifferentiated, proliferative state capable of self-renewal. PMID- 22200373 TI - Large scale surveys suggest limited mercury availability in tropical north Queensland (Australia). AB - Little is known about the threat of mercury (Hg) to consumers in food webs of Australia's wet-dry tropics. This is despite high concentrations in similar biomes elsewhere and a recent history of gold mining that could lead to a high degree of exposure for biota. We analysed Hg in water, sediments, invertebrates and fishes in rivers and estuaries of north Queensland, Australia to determine its availability and biomagnification in food webs. Concentrations in water and sediments were low relative to other regions of Hg concern, with only four of 138 water samples and five of 60 sediment samples above detection limits of 0.1MUgL( 1) and 0.1MUgg(-1), respectively. Concentrations of Hg in fishes and invertebrates from riverine and wetland food webs were well below international consumption guidelines, including those in piscivorous fishes, likely due to low baseline concentrations and limited rates of biomagnification (average slope of log Hg vs. delta(15)N=0.08). A large fish species of recreational, commercial, and cultural importance (the barramundi, Lates calcarifer), had low concentrations that were below consumption guidelines. Observed variation in Hg concentrations in this species was primarily explained by age and foraging location (floodplain vs. coastal), with floodplain feeders having higher Hg concentrations than those foraging at sea. These analyses suggest that there is a limited threat of Hg exposure for fish-eating consumers in this region. PMID- 22200374 TI - Changes in atmospheric deposition and streamwater chemistry over 25 years in undisturbed catchments in a Mediterranean mountain environment. AB - Surface water chemistry has changed in response to reduced atmospheric deposition of sulphur and acidity in many regions of Europe and North America. Most of these studies come from acidic or low-alkalinity surface waters under high acidic deposition. Mediterranean climates offer a different biogeochemical context, characterised by streamwaters of higher alkalinity and low acid inputs. In this paper, we use surveys of streamwater chemistry conducted in 1981-1984 and again in 2007 in the Montseny natural park (NE Spain) to test whether streamwaters of these well-buffered catchments respond to changes in atmospheric deposition, which has declined for S during the last decades in NE Spain while remaining about stable for nitrogen. The 23 sampled streams drained heathland, beech forests and evergreen oak forests in relatively undisturbed small catchments underlain by silicate bedrock. Bulk deposition of sulphate at Montseny decreased by 54% while nitrate bulk deposition increased (non-significantly) by 30% in this period. Total N deposition is estimated in the range 15-30 kg N ha(-1) y(-1) for NE Spain. This is well above threshold values (e.g. 10 kg N ha(-1) y(-1)) reported as starting nitrogen saturation symptoms in forest ecosystems in Europe. Baseflow sulphate concentrations decreased on average by 47 MUeq L(-1) or 29% of early 1980s concentrations. Baseflow mean nitrate concentrations increased significantly but only from 5.5 to 8.9 MUeq L(-1). Thus, despite decades of high N deposition, these ecosystems appear to be still far from N saturation. Baseflow alkalinity and base cation concentrations increased substantially, probably a combined result of decreased S deposition, enhanced silicate weathering under current higher temperatures, reduced plant cation uptake as vegetation matures, and slightly drier conditions in the survey of 2007. Overall, these well-buffered catchments have shown sizable changes in baseflow chemistry in response to changed atmospheric deposition and other environmental changes. PMID- 22200375 TI - The occurrence of hazardous volatile elements and nanoparticles in Bulgarian coal fly ashes and the effect on human health exposure. AB - Low-rank, high-mineral matter Bulgarian coals were studied using a variety of chemical, optical, and electron beam methods. The larger fly ash carbon phases include charred carbons in contrast to coked carbons present in the fly ashes of bituminous-coal-derived fly ashes. Nanoscale carbons include multi-walled carbon nanotubes (MWCNTs) encapsulating Hg, Se, and As, among other elements. In addition to the glass which dominates the fly ash, relatively coarse 'rock fragments', consisting of an unmelted to partially melted core surrounded by a glassy rim, are present in the fly ash. Nano-scale minerals can contain hazardous elements and, along with metal-bearing multiwalled nanotubes, can be a path for the entry of hazardous particles into the lungs and other organs. PMID- 22200376 TI - Increased neointimal formation in cystathionine gamma-lyase deficient mice: role of hydrogen sulfide in alpha5beta1-integrin and matrix metalloproteinase-2 expression in smooth muscle cells. AB - The physiological and pathological roles of hydrogen sulfide (H(2)S) in the regulation of cardiovacular functions have been recognized. Vascular smooth muscle cells (SMCs) express cystathionine gamma-lyase (CSE) and produce significant amount of H(2)S. Although growing evidence demonstated the anti atherosclerotic effect of H(2)S, less is known about the contribution of the endogenous CSE/H(2)S pathway to the development of vascular remodeling. This study investigated the roles of the CSE/H(2)S pathway on SMC migration and neoimtimal formation by using CSE knockout (KO) mice. SMCs and aortic explants isolated from CSE KO mice exhibited more migration and outgrowth compared with that from wild-type (WT) mice, and exogenously applied NaHS (a H(2)S donor) at 100 MUM significantly inhibited SMC migration and outgrowth. SMCs became more elongated and spread in the absence of CSE, and fibronectin significantly stimulated adhesion and migration of SMCs from CSE KO mice (KO-SMCs) in comparison with SMCs from WT mice (WT-SMCs). The expressions of alpha5- and beta1 integrins were significantly higher in KO-SMCs, and functional blocking of alpha5beta1-integrin effectively abrogated KO-SMC migration. CSE deficiency also enhanced matrix metalloproteinase-2 (MMP-2) expression, and the selective blocking of MMP-2 decreased KO-SMC migration. NaHS treatment decreased both the expressions of alpha5- and beta1-integrins and MMP-2. We further found that the expressions of alpha5- and beta1-integrins as well as MMP-2, were stimulated by fibronectin, and that the blockage of alpha5beta1-integrin reduced but overexpression of alpha5beta1-integrin induced MMP-2 expression in both WT-SMCs and KO-SMCs. We also noticed that CSE deficiency in mice led to increased neointima formation in carotid arteries 4 weeks after ligation, which were attenuated by NaHS administration. In conclusion, inhibition of SMC migration by H(2)S may be a novel target for the treatment of vascular occlusive disorder. PMID- 22200377 TI - The impact of nontechnical skills on technical performance in surgery: a systematic review. AB - BACKGROUND: Failures in nontechnical and teamwork skills frequently lie at the heart of harm and near-misses in the operating room (OR). The purpose of this systematic review was to assess the impact of nontechnical skills on technical performance in surgery. STUDY DESIGN: MEDLINE, EMBASE, PsycINFO databases were searched, and 2,041 articles were identified. After limits were applied, 341 articles were retrieved for evaluation. Of these, 28 articles were accepted for this review. Data were extracted from the articles regarding sample population, study design and setting, measures of nontechnical skills and technical performance, study findings, and limitations. RESULTS: Of the 28 articles that met inclusion criteria, 21 articles assessed the impact of surgeons' nontechnical skills on their technical performance. The evidence suggests that receiving feedback and effectively coping with stressful events in the OR has a beneficial impact on certain aspects of technical performance. Conversely, increased levels of fatigue are associated with detriments to surgical skill. One article assessed the impact of anesthesiologists' nontechnical skills on anesthetic technical performance, finding a strong positive correlation between the 2 skill sets. Finally, 6 articles assessed the impact of multiple nontechnical skills of the entire OR team on surgical performance. A strong relationship between teamwork failure and technical error was empirically demonstrated in these studies. CONCLUSIONS: Evidence suggests that certain nontechnical aspects of performance can enhance or, if lacking, contribute to deterioration of surgeons' technical performance. The precise extent of this effect remains to be elucidated. PMID- 22200379 TI - Electrochemical determination of L-methionine using the electropolymerized film of non-peripheral amine substituted Cu(II) phthalocyanine on glassy carbon electrode. AB - This paper reports the stable determination of L-methionine (L-Met) in phosphate buffer solution (pH=4.0) using the electropolymerized film of 1,8,15,22 tetraaminophthalocyanato-copper(II) (p-4alpha-Cu(II)TAPc) on glassy carbon electrode (GCE). Bare GCE shows an ill-defined oxidation wave around 1.32 (+/ 0.02) V for L-Met whereas p-4alpha-Cu(II)TAPc electrode shows a well-defined oxidation peak at 1.26 (+/-0.02) V. The modified electrode does not show any fouling effect towards the oxidation of L-Met. Further, the p-4alpha-Cu(II)TAPc modified electrode was successfully used for the selective determination of L-Met in the presence of ascorbic acid (AA) and uric acid (UA). Differential pulse voltammetry method was used to determine L-Met in the concentration range of 50 500 MUM with a detection limit of 2.7*10-8 M (S/N=3). The present modified electrode shows good recovery results for spiked L-Met in human blood serum sample. PMID- 22200378 TI - The transport of nifurtimox, an anti-trypanosomal drug, in an in vitro model of the human blood-brain barrier: evidence for involvement of breast cancer resistance protein. AB - Human African trypanosomiasis (HAT) is a parasitic disease affecting sub-Saharan Africa. The parasites are able to traverse the blood-brain barrier (BBB), which marks stage 2 (S2) of the disease. Delivery of anti-parasitic drugs across the BBB is key to treating S2 effectively and the difficulty in achieving this goal is likely to be a reason why some drugs require highly intensive treatment regimes to be effective. This study aimed to investigate not only the drug transport mechanisms utilised by nifurtimox at the BBB, but also the impact of nifurtimox-eflornithine combination therapy (NECT) and other anti-HAT drug combination therapies (CTs) on radiolabelled-nifurtimox delivery in an in vitro model of drug accumulation and the human BBB, the hCMEC/D3 cell line. We found that nifurtimox appeared to use several membrane transporters, in particular breast-cancer resistance protein (BCRP), to exit the BBB cells. The addition of eflornithine caused no change in the accumulation of nifurtimox, nor did the addition of clinically relevant doses of the other anti-HAT drugs suramin, nifurtimox or melarsoprol, but a significant increase was observed with the addition of pentamidine. The results provide evidence that anti-HAT drugs are interacting with membrane transporters at the human BBB and suggest that combination with known transport inhibitors could potentially improve their efficacy. PMID- 22200380 TI - A comparison of glucose oxidase and aldose dehydrogenase as mediated anodes in printed glucose/oxygen enzymatic fuel cells using ABTS/laccase cathodes. AB - Current generation by mediated enzyme electron transfer at electrode surfaces can be harnessed to provide biosensors and redox reactions in enzymatic fuel cells. A glucose/oxygen enzymatic fuel cell can provide power for portable and implantable electronic devices. High volume production of enzymatic fuel cell prototypes will likely require printing of electrode and catalytic materials. Here we report on preparation and performance of, completely enzymatic, printed glucose/oxygen biofuel cells. The cells are based on filter paper coated with conducting carbon inks, enzyme and mediator. A comparison of cell performance using a range of mediators for either glucose oxidase (GOx) or aldose dehydrogenase (ALDH) oxidation of glucose at the anode and ABTS and a fungal laccase, for reduction of oxygen at the cathode, is reported. Highest power output, although of limited stability, is observed for ALDH anodes mediated by an osmium complex, providing a maximum power density of 3.5 MUW cm(-2) at 0.34 V, when coupled to a laccase/ABTS cathode. The stability of cell voltage in a biobattery format, above a threshold of 200 mV under a moderate 75 kOmega load, is used to benchmark printed fuel cell performance. Highest stability is obtained for printed fuel cells using ALDH, providing cell voltages over the threshold for up to 74 h, compared to only 2 h for cells with anodes using GOx. These results provide promising directions for further development of mass-producible, completely enzymatic, printed biofuel cells. PMID- 22200381 TI - The comparative effectiveness of combined lumbrical muscle splints and stretches on symptoms and function in carpal tunnel syndrome. AB - OBJECTIVE: To compare the effectiveness of an intensive lumbrical splint/stretch combination with 3 less intensive lumbrical splint/stretch combinations on carpal tunnel symptoms and function. DESIGN: Randomized Clinical Trial. SETTING: Outpatient hand therapy clinics. PARTICIPANTS: Volunteers (N=124) with mild to moderate carpal tunnel syndrome. INTERVENTIONS: A 4-week home regimen of nocturnal splints (lumbrical splints or cock-up splints) combined with stretches (lumbrical intensive or general) performed 6 times daily. MAIN OUTCOME MEASURES: The effect of the intervention on carpal tunnel symptoms and function was examined with the Carpal Tunnel Symptom Severity and Function Questionnaire (CTQ) and Disabilities of the Arm, Shoulder, and Hand (DASH). We also evaluated whether subjects obtained surgery at 24 weeks. RESULTS: There were significant main effects over time for all outcome measures at 4, 12, and 24 weeks. There was a significant interaction effect for the CTQ-Function and DASH at 12 weeks. Post hoc analyses indicated significant differences between the lumbrical splint/general stretch and general splint/lumbrical stretch groups and the other 2 groups. At 24 weeks, a significantly greater percentage of subjects in the general splint/lumbrical stretch group achieved a clinically important improvement on the CTQ-Function. By 24 weeks, only 25.5% of subjects had elected to undergo surgery. CONCLUSIONS: A combination of a cock-up splint with lumbrical intensive stretches was the most effective combination for improvements in functional gains at 24 weeks postbaseline. Our findings support further evaluation of this combination as a method of conservative carpal tunnel syndrome treatment. PMID- 22200382 TI - A structured protocol of evidence-based conservative care compared with usual care for acute nonspecific low back pain: a randomized clinical trial. AB - OBJECTIVE: To compare a protocol of evidence-based conservative care with usual care for acute nonspecific low back pain (LBP) of less than 6 weeks' duration. DESIGN: Parallel-group randomized trial. SETTING: Three practices in the United Kingdom. PARTICIPANTS: Convenience sample of 149 eligible patients were invited to participate in the study, with 118 volunteers being consented and randomly allocated to a treatment group. INTERVENTIONS: The experimental group received evidence-based treatments for acute nonspecific LBP as prescribed in a structured protocol of care developed for this study. The control group received usual conservative care. Participants in both groups could receive up to 7 treatments over a 4-week period. MAIN OUTCOME MEASURES: Oswestry Low Back Disability Index (ODI), visual analog scale (VAS), and Patient Satisfaction Questionnaire, alongside estimation of clinically meaningful outcomes. RESULTS: Total dropout rate was 14% (n=16), with 13% of data missing. Missing data were replaced using a multiple imputation method. Participants in both groups received an average of 6 treatments. There was no statistically significant difference in disability (ODI) scores at the end of week 4 (P=.33), but there was for pain (VAS) scores (P<.001). Interestingly, there were statistically significant differences between the 2 groups for both disability and pain measures at the midpoint of the treatment period (P<.001). Patient satisfaction with care was equally high (85%) in both groups. Minimally clinically important differences in scores and number needed to treat scores (NNT<6) indicated that the experimental treatment (protocol of care) offered a clinically meaningful benefit over the control treatment (usual care), particularly at the midpoint of the treatment period. CONCLUSIONS: Overall, the 2 treatment groups were similar based on primary or secondary outcome measure scores for the full treatment period (4 weeks, with up to 7 treatments). However, there were statistically significant and clinically meaningful differences in both disability and pain scores at week 2 (midpoint) with 4 treatments, suggesting that the protocol of care had a more rapid effect than usual care. PMID- 22200383 TI - Effect of low-intensity pulsed ultrasound on the cartilage repair in people with mild to moderate knee osteoarthritis: a double-blinded, randomized, placebo controlled pilot study. AB - OBJECTIVE: To determine the feasibility of conducting a randomized controlled trial assessing the effect of low-intensity pulsed ultrasound (US) therapy on cartilage repair in patients with mild to moderate knee osteoarthritis (OA). DESIGN: Pilot, double-blinded, randomized placebo-controlled trial with 2-months follow-up. SETTING: Rehabilitation research facility. PARTICIPANTS: Adults (N=27; >=45y) with grades 1 or 2 of medial joint space narrowing (Osteoarthritis Research Society International atlas) due to knee OA were randomly allocated to receive active (n=14) or sham (n=13) US therapy. Four participants withdrew for personal reasons. INTERVENTIONS: Twenty-four sessions of active (20% duty cycle, 1MHz, average temporal intensity: 0.2W/cm(2), therapeutic dose: 112.5J/cm(2)) or sham (no sound-head crystal) US therapy. MAIN OUTCOME MEASURES: Success of recruitment and adherence rates were established by a priori criteria. Effect on cartilage repair was assessed by measuring cartilage volume and thickness and scoring cartilage injury, subchondral cyst formation, and bone marrow lesions on magnetic resonance images. RESULTS: Patient recruitment and adherence rates were successful. No significant age-adjusted differences were seen between groups in the cartilage repair outcomes. Age-adjusted analyses, including only subjects who attended 20 sessions or more, showed an increase in medial tibia cartilage thickness in the active US therapy group (90MUm; 95% confidence interval, 1-200; P=.05). CONCLUSIONS: Conducting a randomized controlled trial to assess the effects of US therapy on the cartilage repair in people with mild to moderate knee OA is feasible. However, further pilot studies are needed to determine the optimal US dose and application parameters before designing a full trial. PMID- 22200384 TI - Sacroiliac joint manipulation attenuates alpha-motoneuron activity in healthy women: a quasi-experimental study. AB - OBJECTIVE: To determine whether sacroiliac joint (SIJ) manipulation decreases alpha-motoneuron activity and increases the pressure pain threshold (PPT) over the posterior superior iliac spine (PSIS) in healthy women. DESIGN: Quasi experimental study. SETTING: A university medical center. PARTICIPANTS: Healthy young women (N=20) aged 18 to 30 years were recruited from among the students of a university medical center after a request for volunteers. INTERVENTIONS: Joint manipulation consisted of the supine rotational glide manipulation for the sacroiliac region. PPT measurements from the PSIS and Hoffman-reflex (H-reflex) amplitudes from the tibial nerve on the same side were recorded before and after joint manipulation. PPT was monitored for 15 minutes and H-reflex for 20 minutes after the procedure. MAIN OUTCOME MEASURES: Changes in tibial nerve H-reflex amplitude and PPT values after SIJ manipulation. RESULTS: SIJ manipulation attenuated alpha-motoneuronal activity significantly (P<.05) but transiently, since the decrease was seen only for 20 seconds after the intervention. There was no positive significant difference in the PPT after SIJ manipulation at any time during postintervention follow-up. CONCLUSIONS: SIJ manipulation produced a transient attenuation of alpha-motoneuron excitability in healthy women. These findings demonstrate that our manipulation technique can lead to a short-term reduction in muscle tone as a result of changes in sensory discharge, predominantly in la afferents. SIJ manipulation did not significantly affect the PPT in healthy women. PMID- 22200385 TI - Physical rehabilitation with ergonomic intervention of currently working keyboard operators with nonspecific/type II work-related upper limb disorder: a prospective study. AB - OBJECTIVE: To evaluate the effect of a physical training program in combination with ergonomic changes in a group of keyboard operators with nonspecific/type II work-related upper limb disorder (WRULD). DESIGN: Prospective study. SETTING: Hospital department. PARTICIPANTS: Pain-free controls (n=6) and currently working patients with WRULD (n=17) were included. INTERVENTIONS: Participants were taught how to self-rehabilitate according to a previously published physical exercise program, in addition the patients requested maximal ergonomic assistance from their employer according to British law. MAIN OUTCOMES MEASURES: Pain at rest and after a standardized functional typing test, before and after rehabilitation, with recording of endurance and calculation of typing speed during the tests. Statistical evaluation: Student t test, paired, and 2-tailed. RESULTS: After the rehabilitation program, the patients as a group had significantly less pain both at rest (P=.009) and after the typing test (P<.001). The typing endurance improved significantly (P=.027) and became similar to the healthy control group (P =.09). The typing speed improved significantly in the patient group after rehabilitation (P=.032) and became similar to the normal control group (P=.058). CONCLUSIONS: Currently working keyboard operators with nonspecific/type II WRULD can benefit significantly from a combination of an individualized self administered physical rehabilitation program and ergonomic work place improvements. Randomized control studies are needed to further investigate the long-term effect of this encouraging finding. PMID- 22200386 TI - Males aging with a spinal cord injury: prevalence of cardiovascular and metabolic conditions. AB - OBJECTIVE: To compare the prevalence of cardiovascular and metabolic conditions in male veterans aging with spinal cord injury (SCI) with that of older men comparison groups. DESIGN: Cross-sectional survey. SETTING: National community dwelling. PARTICIPANTS: Men 65 years and older (veterans with SCI [n=794] injured at least 20y, veterans [n=13,528], and general population [n=6105]). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Prevalence of diabetes, myocardial infarction (MI), stroke, and coronary heart disease (CHD). RESULTS: In older adult men with SCI, prevalences of diabetes, MI, stroke, and CHD were 20.30%, 18.70%, 9.84%, and 15.47%, respectively. The odds for stroke were 1.4 times higher in veterans with SCI than general veterans (P<.05), and there was a trend to higher odds for stroke in men with SCI than in the general population (P=.06). The odds for CHD were significantly lower for veterans with SCI than both comparison groups. Being a past smoker was associated with greater odds for diabetes, MI, and CHD, and being a current smoker was associated with higher odds for stroke. High blood pressure and high cholesterol levels were associated with higher odds for all conditions examined. CONCLUSIONS: Diabetes and MI were most prevalent in older adults, but the presence was similar in men with SCI (vs other men). In older adult men, SCI appeared to be protective of CHD. Stroke was most prevalent in veterans with SCI, and controlling for demographic and risk factors, SCI was associated independently with stroke. These findings may be useful for prioritizing preventive health strategies and planning long-term care for men aging with SCI. PMID- 22200387 TI - Pilot study assessing the impact of intrathecal baclofen administration mode on sleep-related respiratory parameters. AB - OBJECTIVE: To assess the impact of intrathecal baclofen (ITB) mode of administration on sleep and sleep-related breathing events in severely disabled patients with severe spasticity. DESIGN: Open prospective trial. SETTING: Physical medicine and rehabilitation department. PARTICIPANTS: Patients (N=11) treated with ITB pump for severe spasticity. INTERVENTION: Assessment of patients' sleep before and after ITB pump implantation, and comparison of polysomnography results after continuous or bolus mode of administration of ITB. MAIN OUTCOME MEASURES: Polysomnography and sleep-related breathing events. RESULTS: ITB reduced periodic limb movements and increased the respiratory disturbance index (RDI) and central apneas in our population of patients. This study showed that ITB mode of administration may affect sleep-disordered breathing. Indeed, we observed a significant increase of respiratory events in the bolus condition (RDI and central apneas). In contrast, continuous infusion did not induce a significant modification of sleep-disordered breathing. When a sleep apnea syndrome was preexisting, it was generally severely worsened by the bolus mode of administration. CONCLUSIONS: These results indicate that sleep function and sleep-related respiratory events should be assessed before ITB pump implantation. It is probably better to use a continuous mode of infusion if patients have preexisting sleep-disordered breathing. PMID- 22200388 TI - Progress assessed with the Mayo-Portland Adaptability Inventory in 604 participants in 4 types of post-inpatient rehabilitation brain injury programs. AB - OBJECTIVE: To compare progress in 4 types of post-inpatient rehabilitation brain injury programs. DESIGN: Quasiexperimental observational cohort study. SETTING: Community and residential. PARTICIPANTS: Individuals (N=604) with acquired brain injury. INTERVENTIONS: Four program types within the Pennsylvania Association of Rehabilitation Facilities were compared: intensive outpatient and community-based rehabilitation (IRC; n=235), intensive residential rehabilitation (IRR; n=78), long-term residential supported living (SLR; n=246), and long-term community based supported living (SLC; n=45). With the use of a commercial web-based data management system developed with federal grant support, progress was examined on 2 consecutive assessments. MAIN OUTCOME MEASURE: Mayo-Portland Adaptability Inventory (MPAI-4). RESULTS: Program types differed in participant age (F=10.69, P<.001), sex (chi(2)=22.38, P<.001), time from first to second assessment (F=20.71, P<.001), initial MPAI-4 score (F=6.89, P<.001), and chronicity (F=13.43, P<.001). However, only initial MPAI-4 score and chronicity were significantly associated with the second MPAI-4 rating. On average, SLR participants were 9.1 years postinjury compared with 5.1 years for IRR, 6.0 years for IRC, and 6.8 years for SLC programs. IRR participants were more severely disabled per MPAI-4 total score on admission than the other groups. Controlling for these variables, program types varied significantly on second MPAI-4 total score (F=5.14, P=.002). Both the IRR and IRC programs resulted in significant functional improvement across assessments. In contrast, both the SLR and SLC programs demonstrated relatively stable MPAI-4 scores. CONCLUSIONS: Results are consistent with stated goals of the programs; that is, intensive programs resulted in functional improvements, whereas supported living programs produced stable functioning. Further studies using data from this large, multiprovider measurement collaboration will potentially provide the foundation for developing outcome expectations for various types of postacute brain injury programs. PMID- 22200389 TI - Validation of the Reintegration to Normal Living Index for community-dwelling persons with chronic spinal cord injury. AB - OBJECTIVE: To determine the validity (construct, concurrent) of the Reintegration to Normal Living (RNL) Index for measurement of community participation in adults with chronic spinal cord injury (SCI). DESIGN: Cross-sectional telephone survey. SETTING: Rehabilitation institute. PARTICIPANTS: Community-dwelling adult men and women (N=617) with SCI who were at least 1 year postinjury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: RNL Index and Satisfaction With Life Scale (SWLS). RESULTS: Reliability of the RNL Index was determined by using Cronbach alpha, and construct validity was established through confirmatory factor analysis (CFA). In addition, general linear models to predict RNL Index scores were conducted to establish concurrent validity. The RNL Index is a reliable measure of community participation (alpha=.87). CFA analyses suggested that the RNL Index loads onto a 2-factor solution and is distinct from the SWLS. Significant predictors of RNL Index score included years post-injury, impairment, ambulatory status, employment, and poor health, which yielded R(2)=.26 (P<.001). CONCLUSIONS: The RNL Index is a valid and reliable measure of community participation for persons with chronic SCI of traumatic cause. PMID- 22200390 TI - Evaluation of a wearable body monitoring device during treadmill walking and jogging in patients with fibromyalgia syndrome. AB - OBJECTIVE: To evaluate the reliability and validity of a body monitoring device against measures obtained from indirect calorimetry (IC) in patients with fibromyalgia syndrome (FMS) during various incremental exercise intensities. DESIGN: Cross-sectional reliability and validity study. SETTING: Testing was completed in a university exercise physiology laboratory. PARTICIPANTS: Women (N=25) with FMS, with a mean age +/- SD of 48.6+/-8.4 years and a median symptom duration of 15 years (25th-75th percentiles, 10-23y), were recruited to the study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patients walked and jogged on a treadmill at 4 intensities (50m.min(-1), 0% grade [n=25]; 83.3m.min( 1), 0% grade [n=25]; 116.7m.min(-1), 0% grade [n=21]; 116.7m.min(-1), 2.5% grade [n=13]) during 2 measurement conditions, while IC and a multiple-sensor body monitor measured energy expenditure (EE). The differences between the readings (test 1 - test 2) and the SD of the differences, intraclass correlation coefficient (ICC), 95% confidence interval (CI) for the ICC, coefficient of repeatability, intrapatient SD, standard error of mean (SEM), minimal detectable change, Wilcoxon signed-rank test, and Bland-Altman graphs were used to examine reliability. The magnitude of the associations between IC and the body monitoring device, ICC, 95% CI for the ICC, paired t tests, and Bland-Altman graphs were used to examine the validity of the body monitoring device versus the IC. RESULTS: Moderate to excellent test-retest reliability was found for the 4 bouts of exercise (ICC=.73-.76). The SEM and minimal detectable change were satisfactory for the 4 bouts of exercise (.54-1.18kcal.min(-1) and 1.51 3.28kcal.min(-1), respectively). The differences mean between test and retest were lower than the SEM for the 4 bouts of exercise, varying from -.17 to .14kcal.min(-1). No significant differences were found between test and retest for any bout. The Bland-Altman plots and the coefficients of repeatability indicated that the differences between repeated tests would lie within 2 SDs in 95% of the cases for the 4 bouts of exercise. Significant associations were found between the body monitoring device and IC measurements of EE for the 4 bouts of exercise (r=.87-.99). The differences for all bouts between the 2 methods were nonsignificant, except for the second bout (P<.001). The ICCs and Bland-Altman plots of EE for the 4 bouts showed high agreement (ICCs=.84-.99) and sufficient accuracy for quantifying EE during exercise in patients with FMS. CONCLUSIONS: The body monitoring device provided a valid and reliable estimate of EE in patients with FMS during walking on horizontal and inclined surfaces in a laboratory setting across various exercise intensities. PMID- 22200391 TI - The influence of mechanically and physiologically imposed stiff-knee gait patterns on the energy cost of walking. AB - OBJECTIVE: To investigate the relative roles of mechanically imposed and physiologically imposed stiff-knee gait (SKG) patterns on energy cost. DESIGN: Repeated-measures, within-subjects design. SETTING: Research laboratory. PARTICIPANTS: Individuals (N=20) without musculoskeletal, neuromuscular, or cardiorespiratory limitations. INTERVENTIONS: Participants walked on an instrumented treadmill at their self-selected overground gait speed for 3 randomly ordered conditions: (1) control, (2) mechanically imposed stiff-knee gait (SKG-M) using a lockable knee brace, and (3) physiologically imposed stiff knee gait (SKG-P) using electrical stimulation to the quadriceps. Each condition was performed with 0% and 20% body weight support. Indirect calorimetry determined net metabolic power, and motion capture measured lower extremity joint kinematics and kinetics. MAIN OUTCOME MEASURES: Net metabolic power, knee flexion angle, circumduction, hip hiking, and hip flexion and ankle plantarflexion moments. RESULTS: Participants walked at 1.25+/-.09m/s. Net metabolic power was significantly increased by 17% in SKG-M and 37% in SKG-P compared with control (mean increase: .66+/-.60W/kg for SKG-M; 1.39+/-.79W/kg for SKG-P; both P<.001). Furthermore, SKG-P required greater net metabolic power than SKG-M (P<.001). Simulated SKG was associated with increased circumduction and hip hiking. Despite no change in ankle plantarflexion moments (P=.280), the hip flexion moment was increased during SKG-P (.43+/-.15Nm/kg.m) compared with control (.31+/ .08Nm/kg.m; P<.001). CONCLUSIONS: The increase in energy cost associated with simulated SKG was due in part to abnormal mechanical compensations, and in part to an increase in quadriceps activity. Understanding the mechanisms underlying the increase in quadriceps activity will enable a reduction in the energy cost of walking with SKG. PMID- 22200392 TI - Capability of 2 gait measures for detecting response to gait training in stroke survivors: Gait Assessment and Intervention Tool and the Tinetti Gait Scale. AB - OBJECTIVE: To characterize the performance of 2 observational gait measures, the Tinetti Gait Scale (TGS) and the Gait Assessment and Intervention Tool (G.A.I.T.), in identifying improvement in gait in response to gait training. DESIGN: In secondary analysis from a larger study of multimodal gait training for stroke survivors, we measured gait at pre-, mid-, and posttreatment according to G.A.I.T. and TGS, assessing their capability to capture recovery of coordinated gait components. SETTING: Large medical center. PARTICIPANTS: Cohort of stroke survivors (N=44) greater than 6 months after stroke. INTERVENTIONS: All subjects received 48 sessions of a multimodal gait-training protocol. Treatment consisted of 1.5 hours per session, 4 sessions per week for 12 weeks, receiving these 3 treatment aspects: (1) coordination exercise, (2) body weight-supported treadmill training, and (3) overground gait training, with 46% of subjects receiving functional electrical stimulation. MAIN OUTCOME MEASURES: All subjects were evaluated with the G.A.I.T. and TGS before and after completing the 48-session intervention. An additional evaluation was performed at midtreatment (after session 24). RESULTS: For the total subject sample, there were significant pre /post-, pre-/mid-, and mid-/posttreatment gains for both the G.A.I.T. and the TGS. According to the G.A.I.T., 40 subjects (91%) showed improved scores, 2 (4%) no change, and 2 (4%) a worsening score. According to the TGS, only 26 subjects (59%) showed improved scores, 16 (36%) no change, and 1 (2%) a worsening score. For 1 treatment group of chronic stroke survivors, the TGS failed to identify a significant treatment response to gait training, whereas the G.A.I.T. measure was successful. CONCLUSIONS: The G.A.I.T. is more sensitive than the TGS for individual patients and group treatment response in identifying recovery of volitional control of gait components in response to gait training. PMID- 22200394 TI - Occurrence and temporal evolution of upper limb spasticity in stroke patients admitted to a rehabilitation unit. AB - OBJECTIVES: To document the temporal development and evolution of upper limb spasticity, and to establish clinical correlates and predictors of upper limb spasticity in a cohort of stroke patients. DESIGN: Prospective cohort study. SETTING: A rehabilitation unit. PARTICIPANTS: Patients (N=163) with a first-ever ischemic stroke. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Ashworth Scale for measuring upper limb spasticity, Motor Assessment Scale for upper limb activity, Motricity Index for upper limb strength, and Modified Barthel Index for self-care. Upper limb spasticity was defined as an Ashworth Scale score of 1 or greater. RESULTS: Upper limb spasticity occurred in 54 patients (33%) at 3 months after stroke. Development of spasticity at later stages of the stroke was infrequent, occurring in only 28 patients (17%). In patients with mild spasticity (Ashworth Scale score 1) at 3 months after stroke, worsening of spasticity occurred in only 1 patient. On the other hand, almost half of the patients with moderate spasticity (Ashworth Scale score 2) at 3 months progressed to severe spasticity (Ashworth Scale score 3). Poor upper limb activity was the most important correlate of "moderate to severe spasticity" (Ashworth Scale score >=2) (P<.001), and poor upper limb strength on admission to rehabilitation, the most important predictor of "moderate to severe spasticity" (P<.001). CONCLUSIONS: Upper limb spasticity was relatively infrequent in this study, occurring in 33% of patients at 3 months after stroke. Selective monitoring to detect severe spasticity is recommended for patients with an Ashworth Scale score of 2 or greater at 3 months after stroke, and in patients with severe upper limb weakness on admission to rehabilitation. PMID- 22200393 TI - Psychometric evaluation of neglect assessment reveals motor-exploratory predictor of functional disability in acute-stage spatial neglect. AB - OBJECTIVE: To determine the psychometric properties of 2 neglect measures, the Behavioral Inattention Test (BIT)-conventional and the Catherine Bergego Scale (CBS), in acute spatial neglect. Spatial neglect is a failure or slowness to respond, orient, or initiate action toward contralesional stimuli, associated with functional disability that impedes stroke recovery. Early identification of specific neglect deficits may identify patients likely to experience chronic disability. However, psychometric evaluation of assessments has focused on subacute/chronic populations. DESIGN: Correlational/psychometric study. SETTING: Inpatient rehabilitation hospital. PARTICIPANTS: Screening identified 51 consecutive patients with a right-hemisphere stroke with left neglect (BIT score <129 or CBS score >11) tested an average of 22.3 days poststroke. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We obtained BIT, CBS, and Barthel Index assessments for each participant and clinical and laboratory measures of perceptual-attentional and motor-intentional deficits. RESULTS: The BIT showed good reliability and loaded onto a single factor. Consistent with our theoretical prediction, principal components analysis of the CBS identified 2 underlying factors: Where perceptual-attentional items (CBS-PA) and embodied, motor exploratory items (CBS-ME). The CBS-ME uniquely predicted deficits in activities of daily living (ADLs) assessed by using the Barthel Index, but did not predict clinical and laboratory assessments of motor-intentional bias. More severe neglect on the CBS-PA correlated with greater Where perceptual-attentional bias on clinical and laboratory tests, but did not uniquely predict deficits in ADLs. CONCLUSIONS: Our results indicate that assessments of spatial neglect may be used to detect specific motor-exploratory deficits in spatial neglect. Obtaining CBS ME scores routinely might improve the detection of acute-stage patients with spatial action deficits requiring increased assistance that may persist to the chronic stage. PMID- 22200395 TI - Responsiveness of 2 scales to evaluate lateropulsion or pusher syndrome recovery after stroke. AB - OBJECTIVES: To analyze responsiveness to change of 2 outcome measures in the lateropulsion population after stroke. Lateropulsion describes an atypical balance problem after stroke where patients actively push themselves toward their paretic side. Secondary aims were to measure the incidence of lateropulsion and evaluate the site of the brain most commonly involved in lateropulsion. DESIGN: Stroke patients were screened for lateropulsion on admission to rehabilitation. Those demonstrating lateropulsion were assessed every 2 weeks using 2 scales to measure progress. Analysis of variance and the standardized response mean (SRM) were used to analyze change for each scale. SETTING: Rehabilitation and geriatric units. PARTICIPANTS: Prospective purposive sample of stroke patients (N=43) demonstrating lateropulsion on admission from a consecutive admission sample of 160. To allow comparison, data from 43 stroke patients who did not display lateropulsion were collected retrospectively, matched on age (+/-5y) and sex. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Incidence of lateropulsion was calculated as a percentage of stroke patients admitted. Responsiveness to change was measured by using the Burke Lateropulsion Scale (BLS), to quantify severity of lateropulsion, and the Postural Assessment Scale for Stroke (PASS), which measures postural abilities. RESULTS: Of 160 stroke patients, 26.9% displayed lateropulsion (mean age, 72y; 51% men). The BLS and PASS had high levels of measurement responsiveness (BLS SRM =1.48 and 2.24; PASS SRM =1.76 and 1.87) at 4 and 8 weeks, respectively. CONCLUSIONS: The BLS and PASS are responsive scales to monitor progress and recovery during rehabilitation. As more than 25% of stroke patients admitted to rehabilitation may exhibit lateropulsion, these 2 scales could be valuable in monitoring progress and designing future intervention studies. PMID- 22200396 TI - Study on the occurrence and neural bases of hemispatial neglect with different reference frames. AB - OBJECTIVES: To study the distributions and the neural correlates of left hemispatial neglect with different reference frames. DESIGN: Data were collected from patients with right brain injury who participated in a case series. SETTING: Hospital departments of rehabilitation and neurology. PARTICIPANTS: Right brain damaged patients (N=110). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The frequency of left hemispatial neglect with different reference frames was investigated, and the respective brain lesions were displayed and analyzed. RESULTS: Not all subjects finished predesigned neglect tests because of their condition: 8 of the 55 neglect patients were unable to complete the test for classification. Thirty (63.83%) of 47 subjects with neglect displayed both allocentric and egocentric neglect, while 17 subjects showed pure egocentric neglect. The lesions in the inferior frontal gyrus, precentral gyrus, postcentral gyrus, superior temporal gyrus (STG), middle temporal gyrus (MTG), insula, and surrounding white matters were more frequent in the neglect group than in the control group. Compared with the egocentric neglect group, the lesions in the right STG, MTG, lenticular nucleus, and the surrounding white matter were damaged more frequently in the group displaying both allocentric and egocentric neglect. CONCLUSIONS: More than half of the subjects with left neglect after right brain injury have both egocentric and allocentric neglect. The right inferior frontal gyrus, precentral gyrus, postcentral gyrus, STG, MTG, insula, and the surrounding white matter are associated with left hemispatial neglect. Left allocentric neglect is associated with the right STG, MTG, and lenticular nucleus. PMID- 22200397 TI - The shuttle walk test: a new approach to functional walking capacity measurements for patients after stroke? AB - OBJECTIVE: To determine the construct validity, test-retest reliability, and measurement error of the shuttle walk test (SWT) for patients after stroke. DESIGN: Clinimetric study. SETTING: Three rehabilitation centers in the Netherlands. PARTICIPANTS: A sample of patients after stroke (N=75; mean age +/- SD, 58.8+/-9.8y) who are capable of walking without physical assistance. Patients were excluded if they had sustained a subarachnoid hemorrhage or a stroke in the cerebellum or brainstem, or had any other conditions that limited their walking capacity more than the current stroke, or had sensory aphasia. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Construct validity (6-minute walk test [6MWT]) and test-retest reliability of the SWT were assessed. Measurement error was determined with the standard error of measurement (SEM), limits of agreement, and smallest detectable differences (SDDs). RESULTS: Construct validity was confirmed by high significant correlations (r(p)>=.65, P<.01) between the SWT and 6MWT. Difference scores were significantly higher in favor of the SWT for high-speed walkers (>=0.8m/s). In the small group (n=12) of low-speed walkers (<0.8m/s), no significant correlations and differences between both tests were found except for walking distance in favor of the 6MWT. Test-retest reliability was good (intraclass correlation coefficient model 2,1 [ICC(2,1)]=.961 [.936-.977]). SEM was 6.0%, and the SDDs for individual and group were 302.0m (37%) and 38.7m (5%), respectively. CONCLUSIONS: The SWT is a valid and reliable measure and therefore a feasible instrument to determine functional walking capacity of patients after stroke, especially in high-speed walkers. PMID- 22200398 TI - Feedback device for improvement of coordination of reach-to-grasp after stroke. AB - OBJECTIVE: To describe a novel feedback device (Grasp Rehabilitation Accessory for Stroke Patients [GRASP]) that gives feedback on the time lag between the start of hand opening and the start of transport during reach-to-grasp movements, and to report the results of a preliminary series of single case studies to assess the utility of the device for improving the coordination of arm and hand at the beginning of a reach-to-grasp movement. DESIGN: A multiple baseline design across 6 subjects was used, with each subject performing 40 repetitions of reaching to grasp a jar. Two subjects each performed 10, 15, or 20 randomly assigned baseline repetitions. SETTING: Physiotherapy department or at the participant's home. PARTICIPANTS: Participants with middle cerebral artery or parietal stroke (n=6) were consecutively recruited from physiotherapy departments. Additional inclusion criteria were a Rivermead Motor Assessment score of 5 or more and time between start of hand opening and transport of more than 60ms. INTERVENTIONS: During the intervention phase, feedback on time between start of transport and start of grasp was communicated via GRASP. Participants were encouraged to reduce the time. MAIN OUTCOME MEASURE: The outcome measure was the time between start of transport and start of grasp, measured with GRASP. RESULTS: All participants decreased the mean time lag during the intervention phase compared with the baseline phase. Participants 1 to 6 showed decreases of 35, 296, 34, 34, 1212, and 114ms, respectively. Two out of 6 participants demonstrated a significant decrease in time lag in the intervention compared with the baseline phase. CONCLUSIONS: GRASP is potentially beneficial as an adjunct to physiotherapy training of reach-to-grasp coordination after stroke. PMID- 22200399 TI - Association of functional status with changes in physical activity: insights from a behavioral intervention for participants with arthritis. AB - OBJECTIVE: To analyze change over 6 months in accelerometer-measured physical activity for participants with arthritis in a physical activity promotion trial. We tested the hypothesis that participants with the highest baseline functional capacity, regardless of their intervention status, experienced the greatest increases in physical activity levels at 6-month follow-up. DESIGN: At baseline, participants were interviewed in person, completed a 5-minute timed walk, and wore a biaxial accelerometer for 1 week, with a subsequent week of accelerometer wear at 6 months. We present data on the changes in accelerometer-measured physical activity across baseline function quartiles derived from participants' walking speed. Analyses were controlled for sociodemographic, health status, and seasonal covariates as well as exposure to the study's behavioral intervention. SETTING: A Midwest academic medical center. PARTICIPANTS: Participants (N=226) with knee osteoarthritis or rheumatoid arthritis currently enrolled in the Improving Motivation for Physical Activity in Persons With Arthritis Clinical Trial. INTERVENTION: Counseling by physical activity coaches versus control group physician advice to exercise. MAIN OUTCOME MEASURE: Change in average daily counts between baseline and 6-month follow-up. RESULTS: Contrary to our hypothesis, and after controlling for other predictors of change, the lowest quartile function participants had the largest mean absolute and relative physical improvement over baseline, regardless of intervention group status. CONCLUSIONS: Participants at a higher risk of immanent mobility loss may have been more committed to improve lifestyle physical activity, reflecting the wisdom of targeting older adults at risk of mobility loss for physical activity behavior change interventions. PMID- 22200401 TI - Single-step versus stepwise two-electron reduction of polyarylpyridiniums: insights from the steric switching of redox potential compression. AB - Contrary to 4,4'-dipyridinium (i.e., archetypal methyl viologen), which is reduced by two single-electron transfers (stepwise reduction), the 4,1' dipyridinium isomer (so-called "head-to-tail" isomer) undergoes two electron transfers at apparently the same potential (single-step reduction). A combined theoretical and experimental study has been undertaken to establish that the latter electrochemical behavior, also observed for other polyarylpyridinium electrophores, is due to potential compression originating in a large structural rearrangement. Three series of branched expanded pyridiniums (EPs) were prepared: N-aryl-2,4,6-triphenylpyridiniums (Ar-TP), N-aryl-2,3,4,5,6 pentaphenylpyridiniums (Ar-XP), and N-aryl-3,5-dimethyl-2,4,6-triphenylpyridinium (Ar-DMTP). The intramolecular steric strain was tuned via N-pyridinio aryl group (Ar) phenyl (Ph), 4-pyridyl (Py), and 4-pyridylium (qPy) and their bulky 3,5 dimethyl counterparts, xylyl (Xy), lutidyl (Lu), and lutidylium (qLu), respectively. Ferrocenyl subunits as internal redox references were covalently appended to representative electrophores in order to count the electrons involved in EP-centered reduction processes. Depending on the steric constraint around the N-pyridinio site, the two-electron reduction is single-step (Ar = Ph, Py, qPy) or stepwise (Ar = Xy, Lu, qLu). This steric switching of the potential compression is accurately accounted for by ab initio modeling (Density Functional Theory, DFT) that proposes a mechanism for pyramidalization of the N(pyridinio) atom coupled with reduction. When the hybridization change of this atom is hindered (Ar = Xy, Lu, qLu), the first reduction is a one-electron process. Theory also reveals that the single-step two-electron reduction involves couples of redox isomers (electromers) displaying both the axial geometry of native EPs and the pyramidalized geometry of doubly reduced EPs. This picture is confirmed by a combined UV-vis-NIR spectroelectrochemical and time-dependent DFT study: comparison of in situ spectroelectrochemical data with the calculated electronic transitions makes it possible to both evidence the distortion and identify the predicted electromers, which play decisive roles in the electron-transfer mechanism. Last, this mechanism is further supported by in-depth analysis of the electronic structures of electrophores in their various reduction states (including electromeric forms). PMID- 22200400 TI - Esterified eicosanoids: generation, characterization and function. AB - Eicosanoids are oxidation products of C20 polyunsaturated fatty acids (e.g. arachidonic acid) that include prostaglandins, thromboxanes, leukotrienes and hydroperoxy fatty acids. They have important biological roles in vivo, including regulation of renal, cardiovascular and gastrointestinal function. Historically, eicosanoids were thought to mediate their signaling actions exclusively as free acids, however evidence is now emerging that they may also be generated attached to other functional groups including phospholipids and glycerol, and that these more complex forms are pathophysiological signaling mediators in their own right. Early studies showed that exogenously added eicosanoids could become esterified into membrane phospholipids of cells, while more recently, it was uncovered that esterified eicosanoids are formed endogenously. This review summarizes our current knowledge of this area, starting with the early discoveries documenting what is known about eicosanoid generation and their esterification, and moving on to discuss the discovery that esterified eicosanoids are generated endogenously by a number of different cell types. Recent research that is highlighting new structures and functions of these important lipid mediators will be presented. This article is part of a Special Issue entitled: Oxidized phospholipids-their properties and interactions with proteins. PMID- 22200402 TI - Design, synthesis and biological evaluation of new naphtalene diimides bearing isothiocyanate functionality. AB - The synthesis and the biological activities of new derivatives 1-3, characterized by the isothiocyanate (ITC) functionalities coming from sulforaphane (SFN), a well-known anticancer natural product, were reported. The most interesting compound of the series was 2. It was chemically characterized by two ITC functionalities mounted on the 1,4,5,8-naphthalentetracarboxylic diimide (NDI) scaffold through two polymethylene chains, each constituted by three carbon units. It demonstrated an IC(50) value in the submicromolar range, more potent than SFN, displaying also the ability to trigger apoptotic induction in the same range by eliciting both extrinsic and intrinsic apoptotic pathways. Finally, it was observed that 2 inhibited the cell growth by blocking the cell cycle in G1 phase. PMID- 22200403 TI - Analogs of pentamidine as potential anti-Pneumocystis chemotherapeutics. AB - A series of 20 pentamidine analogs were prepared using 2 general Schemes that evaluated heteroatoms, sulfobenzene and alkanediamide groups in the aliphatic linker and methoxy substituents attached to the benzene rings for efficacy against the fungal pathogen, Pneumocystis carinii in an ATP bioassay. All but one of the 20 bisamidines reduced the ATP content of the P. carinii over the 72 h of the assay period. The highest activities were associated with the lack of methoxy groups and the presence of the O, N and S heteroatoms. Activity (IC(50)) for compounds 1, 5, 6, 10 ranged from 1.1 to 2.13 MUM. The compound 11 with similar activity (1.33 MUM), bears a sulfobenzene group at a nitrogen in the aliphatic linker. The alkanediamide-linked bisbenzamidines showed a moderate inhibition of ATP. Generally, the inclusion of a heteroatom in the aliphatic linker and absence of methoxy groups at the benzene rings were associated with higher activities in this assay. Of note, most of the compounds had little to no cytotoxicity in mammalian cell cultures. Although not quite as potent as other pentamidine derivatives, these compounds hold promise for decreased side effects within the mammalian host. PMID- 22200404 TI - Synthesis and cytotoxicity of O,O'-dialkyl {[2-(substituted phenoxy)acetamido](substituted phenyl)methyl}phosphonates. AB - A series of O,O'-dialkyl {[2-(substituted phenoxy)acetamido](substituted phenyl)methyl}phosphonates was synthesized and their cytotoxic activities were tested against various human tumor cell lines. Some compounds (5q, 5r, 5s, 5w, 5x and 5y) showed relatively high cytotoxicity. Especially, compounds 5x and 5q exhibited the best cytotoxicity against KB and CNE2 cells with IC(50) 7.1 and 11.4 MUM, respectively. Their inhibitory activities against KB and CNE2 cells were even higher than that of fluorouracil. PMID- 22200405 TI - Electronic states and metal-ligand bonding of gadolinium complexes of benzene and cyclooctatetraene. AB - Gadolinium (Gd) complexes of benzene (C(6)H(6)) and (1,3,5,7-cyclooctatetraene) (C(8)H(8)) were produced in a laser-vaporization supersonic molecular beam source and studied by single-photon pulsed-field ionization zero electron kinetic energy (ZEKE) spectroscopy. Adiabatic ionization energies and metal-ligand stretching frequencies were measured for the first time from the ZEKE spectra. Metal-ligand bonding and electronic states of the neutral and cationic complexes were analyzed by combining the spectroscopic measurements with ab initio calculations. The ground states of Gd(C(6)H(6)) and [Gd(C(6)H(6))](+) were determined as (11)A(2) and (10)A(2), respectively, with C(6v) molecular symmetry. The ground states of Gd(C(8)H(8)) and [Gd(C(8)H(8))](+) were identified as (9)A(2) and (8)A(2), respectively, with C(8v) molecular symmetry. Although the metal-ligand bonding in Gd(C(6)H(6)) is dominated by the covalent interaction, the bonding in Gd(C(8)H(8)) is largely electrostatic. The bonding in the benzene complex is much weaker than that in the cyclooctatetraene species. The strong bonding in Gd(C(8)H(8)) arises from two-electron transfer from Gd to C(8)H(8), which creates a strong charge-charge interaction and converts the tub-shaped ligand into a planar form. In both systems, Gd 4f orbitals are localized and play little role in the bonding, but they contribute to the high electron spin multiplicities. PMID- 22200406 TI - Capsaicin sensitizes TRAIL-induced apoptosis through Sp1-mediated DR5 up regulation: involvement of Ca(2+) influx. AB - Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various malignant cells, several cancers including human hepatocellular carcinoma (HCC) exhibit potent resistance to TRAIL-induced cell death. The aim of this study is to evaluate the anti-cancer potential of capsaicin in TRAIL-induced cancer cell death. As indicated by assays that measure phosphatidylserine exposure, mitochondrial activity and activation of caspases, capsaicin potentiated TRAIL-resistant cells to lead to cell death. In addition, we found that capsaicin induces the cell surface expression of TRAIL receptor DR5, but not DR4 through the activation Sp1 on its promoter region. Furthermore, we investigated that capsaicin-induced DR5 expression and apoptosis are inhibited by calcium chelator or inhibitors for calmodulin-dependent protein kinase. Taken together, our data suggest that capsaicin sensitizes TRAIL-mediated HCC cell apoptosis by DR5 up-regulation via calcium influx-dependent Sp1 activation. PMID- 22200407 TI - Central estrogenic pathways protect against the depressant action of acute nicotine on reflex tachycardia in female rats. AB - We have previously shown that acute exposure of male rats to nicotine preferentially attenuates baroreceptor-mediated control of reflex tachycardia in contrast to no effect on reflex bradycardia. Here, we investigated whether female rats are as sensitive as their male counterparts to the baroreflex depressant effect of nicotine and whether this interaction is modulated by estrogen. Baroreflex curves relating reflex chronotropic responses evoked by i.v. doses (1 16 MUg/kg) of phenylephrine (PE) or sodium nitroprusside (SNP), were constructed in conscious freely moving proestrus, ovariectomized (OVX), and estrogen (50 MUg/kg/day s.c., 5 days)-replaced OVX (OVXE2) rats. Slopes of the curves were taken as a measure of baroreflex sensitivity (BRS(PE) and BRS(SNP)). Nicotine (100 MUg/kg i.v.) reduced BRS(SNP) in OVX rats but not in proestrus or OVXE2 rats. The attenuation of reflex tachycardia by nicotine was also evident in diestrus rats, which exhibited plasma estrogen levels similar to those of OVX rats. BRS(PE) was not affected by nicotine in all rat preparations. Experiments were then extended to determine whether central estrogenic receptors modulate the nicotine-BRS(SNP) interaction. Intracisteral (i.c.) treatment of OVX rats with estrogen sulfate (0.2 MUg/rat) abolished the BRS(SNP) attenuating effect of i.v. nicotine. This protective effect of estrogen disappeared when OVX rats were pretreated with i.c. ICI 182,780 (50 MUg/rat, selective estrogen receptor antagonist). Together, these findings suggest that central neural pools of estrogen receptors underlie the protection offered by E2 against nicotine-induced baroreceptor dysfunction in female rats. PMID- 22200409 TI - The 40-item Monell Extended Sniffin' Sticks Identification Test (MONEX-40). AB - BACKGROUND: Most existing olfactory identification (ID) tests have the primary aim of diagnosing clinical olfactory dysfunction, thereby rendering them sub optimal for experimental settings where the aim is to detect differences in healthy subjects' odor ID abilities. MATERIALS AND METHODS: We have developed an extended version of the olfactory ID subtest of the Sniffin' Sticks test battery to better assess the variability in ID scores and thereby olfactory abilities of healthy, adult individuals. Twenty-four odorants, corresponding cue labels, and distractor labels were added to the existing 16-item Sniffin' Sticks ID test to create the 40-item Monell Extended Sniffin' Sticks Identification Test (MONEX 40). The MONEX-40 was administered to 259 healthy young subjects, of which 72 were retested on an average of 212 days (SD 112 days) later. RESULTS: The added odor items demonstrated good validity, as shown by a significant correlation of the results with the original 16-item ID test. In addition, the MONEX-40 achieved a significant test-retest and split-half reliability. CONCLUSIONS: Taken together, these results suggest that the MONEX-40 is a reliable method for experimental assessment of odor ID ability in healthy, young individuals. Moreover, its use of a wider range of odors allows the experimenter to present subsets of the MONEX-40 within the same experiment while maintaining statistical power. PMID- 22200410 TI - Stress-induced laboratory eating behavior in obese women with binge eating disorder. AB - Aim of the study was to compare the microstructural eating behavior of obese patients with and without binge eating disorder (BED) after stress induction in laboratory. Seventy-one female subjects were investigated (mean BMI 36.9). Thirty five fulfilled criteria for BED. A 2*2 factorial design with repeated measurement (stress vs. no stress) on the second factor was applied. Stress was induced by the Trier Social Stress Test (TSST) and chocolate pudding served as laboratory food. Variables of eating behavior were measured by a universal eating monitor (UEM). Only in participants with BED stress was associated with an increase in the initial eating rate and a diminished deceleration of eating at the end of the meal. Generally, BED subjects ate with larger size of spoonfuls during the laboratory meal than non BED controls. The eating behavior of obese patients with binge eating disorder seems to be significantly affected by stress. The stress induced eating behavior of BED patients is characterized by a stronger motivation to eat (indicated by a fast initial eating rate) as well as by a lack of satiety perception (indicated by less deceleration of eating rate). PMID- 22200411 TI - Contextual control of appetite. Renewal of inhibited food-seeking behavior in sated rats after extinction. AB - Obesity and overeating have become fundamental problems in modern society. This article studies the inhibition of food-seeking behavior, and how contextual cues can control it. Rats that had free food in the home cage nevertheless learned to lever press for sucrose or high-fat pellets in a distinctive context (a Skinner box). Lever pressing was then inhibited by extinction, in which lever presses no longer produced food. After extinction, inhibited responding was "renewed" when the rats were switched to a different context: in the new context, the rats lever pressed again, and worked more for food when food was made available. These effects were observed when conditioning, extinction and testing occurred in contexts A, B, and A (respectively) or in A, A, and B. Thus, mere removal from the context in which food-seeking was inhibited initiated a return to food seeking. The contextual control of extinction may help explain why food seeking and consumption seem so persistent. PMID- 22200412 TI - Dietary resilience as described by older community-dwelling adults from the NuAge study "if there is a will -there is a way!". AB - Many older adults experience age-related changes that can have negative consequences for food intake. Some older adults continue to eat well despite these challenges showing dietary resilience. We aimed to describe the strategies used by older adults to overcome dietary obstacles and to explore the key themes of dietary resilience. The sample was drawn from the five-year Quebec Longitudinal Study "NuAge". It included 30 participants (80% female) aged 73-87 years; 10 with decreased diet quality and 20 with steady or increased diet quality; all had faced key barriers to eating well. Semi-structured interviews explored how age-related changes affected participants' experiences with eating. Thematic analysis revealed strategies used to overcome eating, shopping, and meal preparation difficulties. Key themes of dietary resilience were: prioritizing eating well, doing whatever it takes to keep eating well, being able to do it yourself, getting help when you need it. Implications for health professionals are discussed. PMID- 22200413 TI - Time spent in home meal preparation affects energy and food group intakes among midlife women. AB - Time spent in meal preparation may be indicative of the healthfulness of meals and therefore with weight status. The purpose of this study was to examine the association between amount of time spent preparing meals and meal food group and nutrient content by meal occasion (breakfast, lunch, and dinner) among 1036 midlife women. Participants completed a 1-day food record and eating occasion questionnaires for each meal occasion. ANCOVA was used to identify possible associations. Approximately half of the participants reported spending <5 min preparing breakfast and lunch, and <20 min preparing dinner. Less time spent preparing breakfast was associated with lower energy and fat intakes (p<0.0001), while less time spent preparing lunch and dinner was associated with lower vegetable and sodium intakes (p<0.0001). There were no apparent differences in the association between time spent preparing meals and meal content by weight status. Nutrition education should encourage home meal preparation while stressing the selection of healthier options. The differing associations by meal occasion suggest that interventions should be tailored according to meal type. PMID- 22200415 TI - Eliminating muscle artifacts from EEG recordings: a necessary imperative. PMID- 22200414 TI - Olmesartan attenuates the development of heart failure after experimental autoimmune myocarditis in rats through the modulation of ANG 1-7 mas receptor. AB - Angiotensin-converting enzyme 2 (ACE-2) is a membrane-associated carboxy peptidase catalyzes the conversion of the vasoconstrictor angiotensin (ANG)-II to the vasodilatory peptide ANG 1-7. In view of the expanding axis of the renin angiotensin system, we have investigated the cardioprotective effects of olmesartan (10mg/kg/day) in experimental autoimmune myocarditis. Olmesartan treatment effectively suppressed the myocardial protein expressions of inflammatory markers in comparison to the vehicle-treated rats. However, the protein and mRNA levels of ACE-2 and ANG 1-7, and its receptor Mas were upregulated in olmesartan treated group compared to vehicle-treated rats. Olmesartan medoxomil treatment significantly decreased the expression levels of phospho-p38 mitogen-activated protein kinase (MAPK), phospho-JNK, phospho-ERK and phospho-(MAPK) activated protein kinase-2 than with those of vehicle-treated rats. Moreover, vehicle-treated rats were shown to be up-regulated protein expressions of NADPH oxidase subunits (p47phox, p67phox and Nox-4), myocardial apoptotic markers and endoplasmic reticulum stress markers in comparison to those of normal and all these effects are expectedly down-regulated by an olmesartan. In addition, attenuated protein levels of phosphatidylinositol-3-kinase (PI3K) and phospho-Akt in the vehicle-treated EAM rats were prevented by olmesartan treatment. Our results suggest that beneficial effects of olmesartan treatment was more effective therapy in combating the inflammation, oxidative stress, apoptosis and signaling pathways associated with heart failure at least in part via the modulation of ANG 1-7 mas receptor. PMID- 22200416 TI - Nephrology and nutrition leaders coming to hawaii for the World Renal Nutrition Week: why is the 16th Congress in Renal Nutrition and Metabolism in Honolulu, Hawai'i, June 2012, worth attending? PMID- 22200417 TI - Call to arms.... PMID- 22200418 TI - Uremia research and toxicity. PMID- 22200419 TI - Dysregulated oxygen metabolism of the kidney by uremic toxins: review. AB - Because kidneys consume a large amount of oxygen and are relatively inefficient in oxygen uptake, they are susceptible to hypoxia, especially in patients with advanced chronic kidney disease accompanied by loss of peritubular capillaries. Accumulating evidence suggests that chronic tubulointerstitial hypoxia acts as a final common pathway leading to end-stage renal disease. Some biologically active uremic retention molecules, considered as uremic toxins, accumulate as the renal function declines, and at this moment, more than 90 bioactive uremic toxins have been identified. Uremic toxins per se have been proven to accelerate the progression of renal failure. However, the causal relationship between uremic toxin and tubulointerstitial hypoxia remains unclear. Our studies provided direct evidence that uremic toxin dysregulates oxygen metabolism in the kidney. Indoxyl sulfate (IS), a representative protein-bound uremic toxin, increased oxygen consumption in proximal renal tubules, decreased renal oxygenation, and consequently aggravated hypoxia in the remnant rat kidneys. The increase in tubular oxygen consumption by IS was dependent on sodium-potassium adenosine triphosphatase and oxidative stress. Our work also indicated a possible connection between IS and the desensitization of the oxygen-sensing mechanism in erythropoietin-producing cells, which may partly explain inadequate erythropoietin production in hypoxic kidneys of end-stage renal disease patients. Studies of uremic toxins will open a new avenue in development of novel therapeutic approaches of kidney disease. PMID- 22200420 TI - Adipokines as uremic toxins. AB - The adipose tissue has pleiotropic functions far beyond the mere storage of energy, and it secretes a number of hormones and cytokines, called adipokines, which have biological effects that impact heath and disease. Adipokines are markedly elevated in the plasma of uremic patients, mainly due to decreased renal excretion. They have pluripotent signaling effects on inflammation/oxidative stress (leptin, adiponectin, resistin), protein-energy wasting (leptin, adiponectin), insulin signaling (adiponectin, leptin, visfatin), endothelial dysfunction (visfatin), and vascular damage (adiponectin, leptin, resistin), which are prevalent in uremic patients. Obesity superimposed to uremia may further aggravate hyperadipokinemia, with the exception of adiponectinemia, which is mitigated by adiposity. Among adipokines and until more data become available, only leptin may be considered as a full uremic toxin owing to adverse effects on protein-energy wasting, cardiovascular damage, inflammation, and the immune system, which have been documented both clinically and experimentally. Resistin and visfatin display some features of uremic toxins, but more data are needed to consider these adipokines as true uremic toxins. In contrast, high levels of adiponectin and chemerin seen in uremia appear to be beneficial. Further research is needed to investigate whether selective removal of leptin, resistin, and visfatin and increments of adiponectin and chemerin levels may have clinical relevance in uremic patients. PMID- 22200421 TI - Indoxyl sulfate induces endothelial cell senescence by increasing reactive oxygen species production and p53 activity. AB - BACKGROUND/AIM: We have reported that indoxyl sulfate (IS), a uremic toxin, accelerates proximal tubular cell senescence. Asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, has been reported to induce endothelial cell senescence. This study aimed to determine whether IS induces endothelial cell senescence in comparison with ADMA, and to investigate its molecular mechanism. METHODS: Human umbilical vein endothelial cells (HUVECs) were incubated with IS (250 MUM) and/or ADMA (10 MUM). These concentrations were comparable with their mean serum levels in hemodialysis patients. Cell senescence was evaluated by measuring senescence-associated beta-galactosidase (SA-beta-gal) activity. N-acetylcysteine, an antioxidant, and pifithrin alpha p-nitro, a p53 inhibitor, were used to determine the role of reactive oxygen species (ROS) and p53 in the induction of cell senescence. RESULTS: Both IS and ADMA significantly increased SA-beta-gal activity in HUVECs. Further, some additional increase in SA beta-gal activity was observed when IS and ADMA were co-incubated. Preincubation of N-acetylcysteine or pifithrin alpha p-nitro significantly inhibited SA-beta gal activity induced by IS and ADMA in HUVECs. Thus, both IS and ADMA induced endothelial senescence through ROS and p53. CONCLUSION: IS induces endothelial cell senescence by increasing ROS production and p53 activity, like ADMA. PMID- 22200422 TI - An update on protein-bound uremic retention solutes. AB - Although protein-bound uremic retention solutes are recognized as 1 of the 3 main categories of uremic retention solutes, they only recently have been submitted to thorough analysis. In vitro and ex vivo data link both p-cresyl sulfate and indoxyl sulfate, two of the main compounds of this solute group, to negative impact on the cardiovascular system and progression of kidney failure. Recent in vivo observational data also relate concentration of these compounds to survival outcome, inflammation, and vascular disease in different, even moderate, stages of chronic kidney disease. Removal by different dialysis strategies, even high flux hemodialysis, is difficult, and only by applying convection, some improvement of removal has been obtained. The other strategy with the potential to decrease concentration is by influencing intestinal generation and/or absorption. The sorbent Kremezin (AST-120) has been shown in controlled studies to decrease protein-bound solute concentration. In pilot controlled studies, AST 120 has been shown to be superior on outcome parameters to placebo. Results from large randomized trials are awaited, before these data can be considered as solid enough to warrant the recommendation to use these compounds for overall therapeutic purposes. PMID- 22200423 TI - Cellular toxicity of nicotinamide metabolites. AB - There are almost 100 different substances called uremic toxins. Nicotinamide derivatives are known as new family of uremic toxins. These uremic compounds play a role in an increased oxidative stress and disturbances in cellular repair processes by inhibiting poly (ADP-ribose) polymerase activity. New members of this family were discovered and described. Their toxic properties were a subject of recent studies. This study evaluated the concentration of 4-pyridone-3 carboxamid-1-beta-ribonucleoside-triphosphate (4PYTP) and 4-pyridone-3-carboxamid 1-beta-ribonucleoside-monophosphate (4PYMP) in erythrocytes of patients with chronic renal failure. Serum and red blood cells were collected from chronic renal failure patients on conservative treatment, those treated with hemodialysis, and at different times from those who underwent kidney transplantation. Healthy volunteers served as a control group. Nicotinamide metabolites were determined using liquid chromatography with mass spectrometry based on originally discovered and described method. Three novel compounds were described: 4-pyridone-3-carboxamid-1-beta-ribonucleoside (4PYR), 4PYMP, and 4PYTP. 4PYR concentration was elevated in the serum, whereas 4PYMP and 4PYTP concentrations were augmented in erythrocytes of dialysis patients. Interestingly, concentrations of these compounds were less elevated during the treatment with erythropoietin-stimulating agents (ESAs). After successful kidney transplantation, concentrations of 4PYR and 4PYMP normalized according to the graft function, whereas that of 4PYTP was still elevated. During the incubation of erythrocytes in the presence of 4PYR, concentration of 4PYMP rose very rapidly while that of 4PYTP increased slowly. Therefore, we hypothesized that 4PYR, as a toxic compound, was actively absorbed by erythrocytes and metabolized to the 4PYMP and 4PYTP, which may interfere with function and life span of these cells. PMID- 22200424 TI - Role of uremic toxins and oxidative stress in the development of chronic kidney disease-mineral and bone disorder. AB - The kidney plays an important role in the regulation of mineral metabolism. As kidney function declines, there is a progressive deterioration in mineral homeostasis, along with various abnormalities, including bone disease and vascular calcification, which has recently been named as "Chronic Kidney Disease Mineral and Bone Disorder (CKD-MBD)." Although the precise mechanisms of this systemic disorder remain to be elucidated, accumulating evidence suggest that uremic toxins contribute substantially to the development of CKD-MBD, partly through evoking oxidative stress in the bone and cardiovascular systems. This brief review summarizes recent work on the role of uremic toxins and oxidative stress in the development of CKD-MBD. PMID- 22200425 TI - Indoxyl sulfate induces nephrovascular senescence. AB - Indoxyl sulfate is markedly accumulated in the serum of chronic kidney disease (CKD) patients. The oral sorbent AST-120 reduces serum levels of indoxyl sulfate in CKD patients by adsorbing indole, a precursor of indoxyl sulfate, in the intestine. Indoxyl sulfate is taken up by proximal tubular cells through organic anion transporters (OAT1, OAT3), and it induces reactive oxygen species (ROS) with impairment of cellular antioxidative system. Indoxyl sulfate stimulates progression of CKD by increasing renal expression of profibrotic cytokines such as transforming growth factor beta 1. Further, it promotes the expression of p53 by ROS-induced activation of nuclear factor kappa B, thereby accelerating senescence of proximal tubular cells with progression of CKD. Administration of indoxyl sulfate to hypertensive rats reduces renal expression of Klotho and promotes cell senescence, with expression of senescence-associated beta galactosidase, p53, p21, p16, and retinoblastoma protein, accompanied by kidney fibrosis. Indoxyl sulfate downregulates Klotho expression in the kidneys through production of ROS and activation of nuclear factor kappa B in proximal tubular cells. It promotes cell senescence, with expression of senescence-associated beta galactosidase, p53, p21, p16, and retinoblastoma protein, in the aorta of hypertensive rats. It also promotes aortic calcification and aortic wall thickening in hypertensive rats with expression of osteoblast-specific proteins, induces ROS in vascular smooth muscle cells and vascular endothelial cells, stimulates proliferation and osteoblastic transdifferentiation of vascular smooth muscle cells, and inhibits viability and nitric oxide production of vascular endothelial cells. Thus, indoxyl sulfate accelerates the progression of not only CKD but also of cardiovascular disease by inducing nephrovascular cell senescence. PMID- 22200426 TI - A nexus of progression of chronic kidney disease: tryptophan, profibrotic cytokines, and charcoal. AB - Fibrosis plays a major role in the pathogenesis of progressive chronic kidney disease (CKD). The inhibition of the renin-angiotensin system, which promotes fibrosis, has become the standard of care in the treatment of patients with CKD. The use of alternative agents capable of blocking the actions of profibrotic cytokines such as transforming growth factor-beta (TGF-beta) is also an important strategy that is in its early stages of development. An example of such a drug is AST-120, a charcoal compound that ultimately inhibits the synthesis of TGF-beta in the kidney. The inhibition is mediated by blocking the intestinal absorption of tryptophan-derived indole by AST-120. This reduces the hepatic conversion of indole to indoxyl sulfate (IS). IS stimulates the production of TGF-beta in the renal parenchyma, and lowering the level of IS with AST-120 appears to slow progression of CKD. The status of recent trials examining the safety and efficacy of AST-120 has been described, including a multicenter, randomized, placebo controlled, phase III trial of approximately 2,000 subjects being conducted to gain approval of this drug by the U.S. Food and Drug Administration. PMID- 22200427 TI - SIRTUIN 1 gene polymorphisms are associated with cholesterol metabolism and coronary artery calcification in Japanese hemodialysis patients. AB - OBJECTIVES: Sirtuin 1 (SIRT1), a longevity gene, protects cells against oxidative and genotoxic stress. This study aimed to investigate the association of SIRT 1 gene single-nucleotide polymorphisms, namely, rs7895833, rs7069102, and rs2273773 with lipid profiles and coronary artery calcification score in 219 Japanese hemodialysis (HD) patients. METHODS: Genotyping of these polymorphisms was performed using polymerase chain reaction with confronting two-pair primers assay. RESULTS: The A allele frequency of rs7895833 and G allele frequency of rs7069102 were significantly lower in HD patients (0.228 and 0.131, respectively) than those in 803 control subjects (general population) (0.289 and 0.181, respectively) (P = .010 and P = .012, respectively). However, the allele frequency of rs2273773 was not significantly different from that in the control subjects. Multivariate analysis adjusted for age and duration on HD demonstrated that the serum levels of total and low-density lipoprotein cholesterol were significantly high in G allele carriers of rs7069102 compared with CC genotype in male HD patients. Coronary artery calcification score was significantly high in C allele carriers of rs2273773 in all and male HD patients. CONCLUSIONS: SIRT 1 polymorphisms, rs7069102 and rs2273773, are associated with abnormal cholesterol metabolism and coronary artery calcification, respectively, in Japanese HD patients, especially in males. PMID- 22200428 TI - Cardiovascular biomarkers in chronic kidney disease. AB - Cardiovascular disease (CVD) is the major cause of death in patients with advanced chronic kidney disease (CKD). Recent studies have suggested that novel risk factors, uremia- or dialysis-related, are of great importance, as they act synergistically with the highly prevalent traditional risk factors for CVD in CKD patients. Whereas an ideal single biomarker, i.e., one that adds relevant prognostic information in clinical practice over and above that provided by conventional (Framingham) risk factors, has yet to be identified, combinations of several biomarkers or repeated measurements of biomarkers may increase the explanatory power of prognostic information provided by traditional risk factors to predict cardiovascular outcomes. However, because the increase of predictive power is modest, clinical assessment of patient status still remains the cornerstone tool for predicting risk for CVD. On the other hand, the search for better biomarkers may reveal novel pathways linked to CVD that need to be explored in CKD patients. This brief review summarizes some emerging and potentially clinically applicable CVD biomarkers in CKD patients, especially focusing on inflammation and vascular calcification that may provide additional information to conventional risk factors. PMID- 22200429 TI - AGEs and cardiovascular diseases in patients with end-stage renal diseases. AB - Cardiovascular disease is the major cause of death in patients with renal insufficiency, accounting for 50% of all deaths in renal replacement therapy patients. Mortality from cardiovascular diseases in these patients is approximately 9% per year, which is about 30 times the risk in the general population. So far, intensive interventions to the general risk factors, such as high levels of low-density lipoprotein -cholesterol or C-reactive protein, have not been successful in improving their cardiovascular outcomes, suggesting that the beneficial effect of risk reduction may be overwhelmed by accumulated risk memorized by long-term exposure to oxidative stress during the progression of renal failure. This irreversible memory effect may be mediated by advanced glycation end products (AGEs), the generation of which has been implicated to be deeply associated with increased oxidative stress. To examine whether circulating AGEs predict future cardiovascular events, a cohort containing 386 (243 male, 142 female) hemodialysis patients was set up. The patients were examined for plasma pentosidine at registration (December 2005) and were followed until March 2010. Patients with high tertile for plasma pentosidine exhibited significantly higher risk for cardiovascular events (hazard risk: 1.74, 95% confidence interval: 1.11 to 2.74, P = .017). Comparisons of the risk of high plasma pentosidine in key subgroups showed that the risk of the high tertile was more prominent in patients with low serum albumin levels. Thus, AGE levels could represent accumulated oxidative stress during the progression of CKD, and their measurements would be useful for stratification of the cardiovascular risks in patients with ESRD. PMID- 22200430 TI - Carbamylated low-density lipoprotein: nontraditional risk factor for cardiovascular events in patients with chronic kidney disease. AB - The high cardiovascular morbidity and mortality associated with chronic kidney disease (CKD) cannot be explained entirely by traditional risk factors. Urea spontaneously dissociates to form cyanate, which modifies proteins in a process referred to as carbamylation. Carbamylated low-density lipoprotein (cLDL) has been shown to have all of the major biological effects relevant to atherosclerosis, including endothelial cell injury, increased expression of cell adhesion molecules, and vascular smooth muscle cell proliferation. Recent studies indicate that cLDL leads to endonuclease G activation, which participates in cellular injury. In addition, cLDL has been shown to enhance generation of oxidants. Limited human data have demonstrated high levels of cLDL in hemodialysis patients, with the highest levels in patients who have atherosclerosis. In 2 separate clinical studies, plasma levels of carbamylated protein independently predicted an increased risk of coronary artery disease, future myocardial infarction, stroke, and death. Future prospective studies to examine the association and/or predictive value of cLDL and studies to establish cause-effect relationship in patients with CKD are needed. PMID- 22200431 TI - Coronary artery calcification score is associated with mortality in Japanese hemodialysis patients. AB - OBJECTIVE: Coronary artery calcification has been associated with higher mortality in coronary artery disease and chronic kidney disease. This study aimed to correlate coronary artery calcification score (CACS) with all-cause and cardiovascular mortalities in hemodialysis (HD) patients. DESIGN, SETTING, SUBJECTS: A survival analysis was conducted in 200 HD patients. CACS was assessed by multidetector-row computed tomography and stratified as tertiles: group 1 (0~105 U), group 2 (110~1067 U), and group 3 (1094~15481 U). The duration of follow-up was 7 years and 4 months. Kaplan-Meier method and Cox proportional hazard analysis adjusted for age and HD duration were performed to examine the impact of CACS on survival. MAIN OUTCOME MEASURE: All-cause and cardiovascular mortalities were measured. RESULTS: The cumulative all-cause and cardiovascular mortalities of group 1 were significantly lower than those of groups 2 and 3 (all cause mortality: 7.6% vs. 43.3% and 52.2%, respectively, cardiovascular mortality: 3.0% vs. 22.4% and 26.9%, respectively). Cox proportional hazard analysis adjusted for age and HD duration revealed that all-cause and cardiovascular mortalities of group 1 were significantly lower than those of groups 2 and 3. CONCLUSION: CACS is helpful to predict prognosis of HD patients independently of age and HD duration. PMID- 22200432 TI - Advanced oxidation protein products and advanced glycation end products in children and adolescents with chronic renal insufficiency. AB - OBJECTIVE: Advanced oxidation protein products (AOPPs) represent dityrosine containing cross-linked protein modifications formed mainly via myeloperoxidase reaction, supposed to accelerate the uremia-associated atherogenesis and renal fibrosis. DESIGN, SUBJECTS, AND MAIN OUTCOME MEASURES: In a cross-sectional study, we investigated the accumulation of AOPPs and advanced glycation end product (AGE)-specific fluorescence corrected for albumin in children and adolescents with chronic renal failure (CRF, n = 42), end-stage renal disease (ESRD, n = 12), kidney transplanted patients (Tx, n = 16), and age-matched healthy controls (n = 38). RESULTS: AOPP levels were 2.4-fold higher in the CRF and ESRD patients, and 1.6-fold higher in the transplanted subjects when compared with the controls (P < .001). In comparison with healthy controls, AGE levels rose 2-fold in the CRF, 7-fold in the ESRD, and 5-fold in the kidney transplanted children and adolescents, (P < .001). Patients with cardiovascular affliction presented with higher AGE levels than those without diagnosed cardiovascular disease (P < .02). In patients with stabilized renal function, AOPP and AGE levels did not change significantly during 12 months. CONCLUSION: Pattern of accumulation of AOPP and AGE in children and adolescents with chronic renal disease differs. Accelerated rise in AOPP levels in some children and adolescents in predialysis stage of chronic renal insufficiency, inadequate to deterioration of renal function, might require further attention. PMID- 22200433 TI - Effect of uremia on structure and function of immune system. AB - End-stage renal disease (ESRD) is simultaneously associated with immune activation, marked by systemic inflammation, and immune deficiency. Systemic inflammation contributes to atherosclerosis, cardiovascular disease, cachexia, and anemia, whereas immune deficiency leads to impaired response to vaccination, and increased incidence and severity of microbial infections. ESRD-associated inflammation and immune deficiency are associated with the following: (a) general expansion of monocytes and elevations of their basal integrin, Toll-like receptor (TLR)-2, TLR-4 expression, cytokine production, and reactive oxygen species (ROS) generation and reduced phagocytic capacity, (b) depletion and impaired inhibitory activity of regulatory T cells, (c) spontaneous activation, degranulation, increased basal ROS production, decreased phagocytic capacity, and increased apoptosis of the circulating polymorphonuclear leukocytes, (d) upregulation of ROS production machinery and chemokine expression in the cellular constituents of various tissues, highlighting participation of nonimmune cells in the prevailing inflammatory state, (e) depletion of the antigen-presenting dendritic cells, (f) reduced CD4/CD8 T cell ratio and depletion of naive and central memory T cells, (g) diffuse B cell lymphopenia leading to impaired humoral immunity, and (h) increased proinflammatory activity of low-density lipoprotein and reduced anti inflammatory capacity of high-density lipoprotein. Thus, ESRD-associated inflammation is due to activation of innate immune system, orchestrated by monocytes, macrophages, granulocytes, and cellular constituents of other organs/tissues. This is coupled with immune deficiency that is caused by depletion of dendritic cells, naive and central memory T cells and B cells, and impaired phagocytic function of polymorphonuclear leukocytes and monocytes. PMID- 22200434 TI - International evaluation of unrecognizably uglifying human faces in late and severe secondary hyperparathyroidism in chronic kidney disease. Sagliker syndrome. A unique catastrophic entity, cytogenetic studies for chromosomal abnormalities, calcium-sensing receptor gene and GNAS1 mutations. Striking and promising missense mutations on the GNAS1 gene exons 1, 4, 10, 4. AB - Hypotheses explaining pathogenesis of secondary hyperparathyroidism (SH) in late and severe CKD as a unique entity called Sagliker syndrome (SS) are still unclear. This international study contains 60 patients from Turkey, India, Malaysia, China, Romania, Egypt, Tunisia, Taiwan, Mexico, Algeria, Poland, Russia, and Iran. We examined patients and first degree relatives for cytogenetic chromosomal abnormalities, calcium sensing receptor (Ca SR) genes in exons 2 and 3 abnormalities and GNAS1 genes mutations in exons 1, 4, 5, 7, 10, 13. Our syndrome could be a new syndrome in between SH, CKD, and hereditary bone dystrophies. We could not find chromosomal abnormalities in cytogenetics and on Ca SR gene exons 2 and 3. Interestingly, we did find promising missense mutations on the GNAS1 gene exons 1, 4, 10, 4. We finally thought that those catastrophic bone diseases were severe SH and its late treatments due to monetary deficiencies and iatrogenic mistreatments not started as early as possible. This was a sine qua non humanity task. Those brand new striking GNAS1 genes missense mutations have to be considered from now on for the genesis of SS. PMID- 22200435 TI - New-onset posttransplant diabetes mellitus begins in the dialysis period. AB - OBJECTIVES: New-onset posttransplant diabetes mellitus (PTDM) affects >20% of transplant recipients at 1 year and is associated with increased risk of mortality. From the pathogenetic point of view, PTDM can be considered as the consequence of predisposing factors existing in the dialysis period, which are triggered by immunosuppressive drugs, calcineurin inhibitors, mTOR inhibitors, and steroids. DESIGN, PATIENTS, AND MAIN OUTCOME MEASURE: In our own study, the independent predictors of PTDM were recipient age, a positive family history of diabetes, and treatment by peritoneal dialysis. Other clinical investigations have added the presence of metabolic syndrome components and hepatitis C infection to this list. CONCLUSIONS: Estimation of the risk of development of PTDM should be an integral element in the qualification process for the waiting list. An intensive lifestyle modification program should be offered to candidates with impaired glucose tolerance. PMID- 22200436 TI - Muscle and fat metabolism in obesity after kidney transplantation: no effect of peritoneal dialysis or hemodialysis. AB - Our prospective study analyzed selected adipocytokines: adiponectin (ADPN), leptin, visfatin, and asymmetric dimethylarginine (ADMA) in the plasma of renal transplant recipients previously treated by peritoneal dialysis and hemodialysis. A total of 70 patients were on follow-up for 12 months after transplantation. Of these, 30 patients (group I) developed obesity, and 40 patients were nonobese (group II). All were receiving standard immunosuppressive therapy (cyclosporine A or tacrolimus and mycophenolate mofetil, with prednisone added in the early posttransplant period) and did not differ statistically in HLA typing, age, sex, duration of previous dialysis, history of cardiovascular disease, and rate of rejection episodes. At the end of the study period, there were significant differences between groups I and II (t test, analysis of variance) in plasma: ADPN, 22.30 +/- 10.2 versus 14.3 +/- 7.2 MUg/mL; visfatin, 1.7 +/- 0.1 versus 1.2 +/- 0.1 ng/mL; ADMA, 3.60 +/- 0.47 versus 2.10 +/- 0.36 MUmol/L; P < .01; leptin, 55.6 +/- 10.2 versus 25.6 +/- 8.3 ng/L; P < .01 (P < .02). In conclusion, an increase of body fat after renal transplantation was associated with an increase of ADMA and leptin, TNF-alpha, MCP-1, and visfatin and decrease of adiponectin. Our study documented there was now long-term beneficial metabolic effect of peritoneal dialysis in developing posttransplant obesity. PMID- 22200437 TI - Ghrelin and muscle metabolism in chronic uremia. AB - Patients with chronic kidney disease (CKD) are prone to nutritional complications with negative prognostic impact. In particular, protein-energy wasting is a major CKD-associated clinical burden, and emerging evidence indicates that clustered metabolic alterations, including inflammation, oxidative stress, and insulin resistance, contribute to loss of skeletal muscle mass. Ghrelin is a gastric hormone discovered in its acylated form and extensively studied for its appetite stimulating effect. Further studies have shown that ghrelin may positively modulate systemic inflammation and insulin action. In addition, a role of ghrelin in the regulation of redox state has been described in vitro. Ghrelin treatment could therefore represent a potential comprehensive therapeutic approach for CKD related metabolic and nutritional complications, and evidence supporting this hypothesis has emerged in clinical and experimental CKD. Clinical trials of ghrelin administration are needed to test the hypothesis that ghrelin may chronically improve nutritional status and outcome in CKD patients. PMID- 22200438 TI - AST-120 ameliorates epithelial-to-mesenchymal transition and interstitial fibrosis in the kidneys of chronic kidney disease rats. AB - OBJECTIVE: Indoxyl sulfate (IS), a uremic toxin, is a risk factor for progression of chronic kidney disease (CKD). AST-120 reduces serum IS and delays the progression of CKD. This study aimed to examine whether AST-120 inhibits epithelial-to-mesenchymal transition (EMT) in the kidneys of CKD rats. METHODS: CKD rats were produced by 5/6 nephrectomy and were divided into 2 groups: (1) CKD rats and (2) AST-120-treated CKD rats at a dosage of 4 g/kg body weight/day. After 10 weeks, their kidneys were excised for histological and immunohistochemical analysis. EMT was evaluated by immunohistochemistry of zonula occludens (ZO-1), an epithelial marker, and alpha-smooth muscle actin (alpha SMA), a mesenchymal marker. Interstitial fibrosis was evaluated by Masson's trichrome staining. RESULTS: CKD rats showed reduced expression of ZO-1 and enhanced expression of alpha-SMA as compared with normal rats. Administration of AST-120 to CKD rats increased expression of ZO-1 and decreased expression of alpha-SMA as compared with CKD rats. Further, CKD rats showed enhanced extent of interstitial fibrosis as compared with normal rats, and administration of AST-120 to CKD rats ameliorated interstitial fibrosis. CKD rats showed increased serum level of IS as compared with normal rats, whereas administration of AST-120 to CKD rats decreased both serum and urine levels of IS. CONCLUSION: We conclude that AST-120 ameliorated EMT and interstitial fibrosis in the kidneys of CKD rats, probably by alleviating IS overload on the kidneys. PMID- 22200439 TI - Chemical and physiological relevance of glucose degradation products in peritoneal dialysis. AB - Fibrosis and vascular sclerosis are main complications that limit the long-term application of peritoneal dialysis (PD). Low biocompatibility has been largely attributed to the presence of glucose degradation products (GDPs), which are formed during the heat sterilization of PD fluids. GDPs readily modify proteins in the peritoneum, leading to a decline of their biological function. After absorption, GDPs can also promote systemic protein glycation. Additionally, GDPs may augment DNA glycation, a process enhanced in uremia. Apart from their glycating activity, GDPs induce cytotoxicity and interfere with cell signaling in peritoneal mesothelial cells. Targeted screening revealed the nature of the 6 major GDPs with alpha-dicarbonyl structure as 3-deoxyglucosone, 3 deoxygalactosone, glucosone, glyoxal, methylglyoxal, and 3,4-dideoxyglucosone-3 ene. Valid quantification of these GDPs was achieved by ultrahigh-performance liquid chromatography/diode array detector/tandem mass spectrometry. Identification and quantification of single GDPs allow a structure-dependent risk evaluation. As a consequence, PD fluids and processes can be improved to reduce the GDP burden of patients undergoing PD. PMID- 22200440 TI - A brief review of external mass balance and internal calcium redistribution in dialysis patients--is calcium a uremic toxin? AB - Recent debates between 2 schools of thought on calcium mass balance in dialysis patients and its relevance to disease--one emphasizing external calcium mass balance, and the other, internal calcium redistribution--have created controversy. Due to decreased ability to excrete calcium and loss of endocrine function by the kidney, patients suffering from chronic kidney disease, particularly when requiring dialysis, demonstrate varying degrees of positive or negative calcium balance, vitamin D deficiency, and secondary hyperparathyroidism. Consequently, patients are prone to bone demineralization, with diminished bone strength, and are thus prone to fractures that substantially worsen morbid outcomes in this population. However, intra- and interdialytic positive calcium mass balance creates complications of a different kind, which include the occurrence of vascular and cardiac disease and reduced survival. This review aims to shed light on the mechanisms of and relationships between external calcium mass balance and internal calcium redistribution and their consequences. It also discusses the potential to improve current regimens by means of diffusive and convective calcium mass transfer for the achievement of neutral calcium mass balance. PMID- 22200441 TI - Hyperhomocysteinemia in chronic renal failure: alternative therapeutic strategies. AB - Chronic renal failure and uremia represent states wherein high blood levels of homocysteine, a cardiovascular risk factor, are largely resistant to folate therapy. Indeed, normalization of homocysteine levels through vitamin administration is rarely achieved in this population, and this fact could explain, among other causes, the negative results of intervention trials designed to lower cardiovascular risk. Dialysis itself lowers homocysteine levels, albeit transitorily. N-acetylcysteine therapy could induce an additional decrease in homocysteine removal during dialysis, thus representing an alternative approach in the attempt to lower cardiovascular risk in these patients. PMID- 22200442 TI - Dietary and synthetic activators of the antistress gene response in treatment of renal disease. AB - Renal failure is associated with increased vascular inflammation, oxidative stress and dicarbonyl stress linked to development of cardiovascular disease, and other complications. The endogenous defense to inflammatory, oxidative, and dicarbonyl challenge to vascular function is coordinated by nuclear factor E2 related factor 2 (nrf2), kelch-related erythroid cell-derived protein with CNC homology (ECH) protein 1 (keap1), and antioxidant response element-linked gene expression in the antistress gene response. Intervention trials of the synthetic nrf2 activator, bardoloxone methyl, in patients with advanced diabetic nephropathy, showing improvement of renal function and decreased inflammation, suggest that nrf2 activators may have therapeutic benefit in chronic renal failure. Activators of nrf2 are of both synthetic and dietary origin. The aim of this review is to describe the "nrf2/keap1/antioxidant response element" transcriptional system and studies of this system in renal failure, and to assess the current status and future prospects that dietary nrf2 activators may be of benefit to patients with chronic renal failure. PMID- 22200443 TI - The removal of protein-bound solutes by dialysis. AB - Protein-bound solutes that accumulate in plasma when the kidneys fail are poorly cleared by conventional dialysis. Means have been developed to reduce the levels of such solutes, either by modifying the dialysis procedure to increase their clearance or by limiting their production. A trial testing whether reducing bound solute levels clinically benefits dialysis patients is required to determine whether these measures should be adopted in routine clinical practice. PMID- 22200444 TI - Anxiety and depression in maintenance dialysis patients: preliminary data of a cross-sectional study and brief literature review. AB - BACKGROUND: Anxiety and depression affect the quality of life of maintenance dialysis (MD) patients. There is little information concerning the extent to which the experience of individual hemodialysis treatments engenders anxiety in this patient population. This preliminary study examined the prevalence and severity of anxiety and depression in MD patients and the incidence of anxiety related to dialysis treatment. METHODS: One hundred seventy patients, 155 undergoing maintenance hemodialysis and 15 undergoing chronic peritoneal dialysis, were examined. Inclusion criteria included dialysis vintage of at least 6 months. Patients completed the Beck Anxiety Inventory and Beck Depression Inventory and questionnaires that examined their feelings of anxiety related to individual hemodialysis sessions. RESULTS: Patients' mean age was 56 +/- standard deviation of 16 years; dialysis vintage, 55 +/- 48 months; 46% were female. The data confirmed a high prevalence of anxiety and depression in MD patients. Many MD patients become anxious, often severely, by merely going for routine hemodialysis treatment and also owing to such common events as being connected to the hemodialyzer by a new person or on hearing their hemodialyzer alarm sound. CONCLUSION: Anxiety and depression are common in MD patients. Many patients who are well established on MD experience anxiety during individual maintenance hemodialysis treatments. PMID- 22200445 TI - Survival is not enough. AB - Survival is not enough is a yearly international event started in 2007 in Naples, Italy, in the week of the World Kidney Day to discuss the needs of renal patients and the quality of life of a category of patients living a machine-dependent life. Renal patients and their associations, philosophers, economists, nephrologists, and health care managers are enrolled to discuss about the possibility to grant the best cures and care without reducing the quality and the quantity of the services the patients need. Various quests have arisen for (1) a new cadre of managers capable of keeping health accounts in balance without cutting expenditure but by reducing waste of resources, (2) the promotion of prevention as the only measure capable of reducing costs in the long run, and (3) the promotion of clinical and translational research. The changes occurring in the health system should be viewed as a window of opportunity, including the advent of the medical-industrial complex firstly described in 1980, an event originating in the United States of America and now spreading worldwide. PMID- 22200446 TI - Patient education. Nutrition supplementation and chronic kidney disease: what are the options? PMID- 22200447 TI - Multimodal imaging in the diagnosis of large vessel vasculitis: a pictorial review. PMID- 22200448 TI - The implications of particle energy and acidic media on gross alpha and gross beta determination using liquid scintillation. AB - The interaction of humans with radioactivity present in the environment from natural and artificial sources necessitates an evaluation of its risk on human health. Gross alpha and gross beta activities can provide a rapid evaluation of the radioactive content of a sample and can be simultaneously determined by using liquid scintillation counters. However, calibration of the liquid scintillation counter is required and is affected by many factors, such as particle energy and the acidity of the media. This study investigates what effect the particle energy used for calibration has on misclassification and how to account for this misclassification in routine measurements. The variability in measurement produced by the final pH, as well as any acids used in sample treatment, was also studied. These results showed that the most commonly used acid for these types of analyses, HNO(3), produced a high amount of misclassifications at very low pH. The results improved when HCl was used to adjust the sample to low pH. PMID- 22200450 TI - The C-terminus of PARK2 is required for its self-interaction, solubility and role in the spindle assembly checkpoint. AB - PARK2, an ubiquitin ligase closely correlated with Parkinson's disease and cancer, has been shown to accumulate at centrosomes to ubiquitinate misfolded proteins accumulated during interphase. In the present study, we demonstrated that PARK2 can also localize to centrosomes in mitosis and that the protein does not fluctuate through the S- to M-phase. A C-terminal truncation of PARK2 resulted in a spindle assembly checkpoint defect, characterized by HeLa cells able to bypass mitotic arrest induced by nocodazole and form multinucleated cells when overexpressing the C-terminal truncated PARK2 protein. The spindle assembly checkpoint defect may be due to a change in a biochemical or structural property of PARK2 caused by the C-terminal truncation, resulting in a loss of self interaction between PARK2 proteins. PMID- 22200451 TI - Probiotic properties of Weissella strains isolated from human faeces. AB - Three Weissella confusa and five Weissella cibaria strains were previously isolated from human faeces and their potential as probiotics was examined in this work. Resistance to low pHs (pH 2.0 and 3.0) and 0.3% bile salt were examined. Enzyme activities, susceptibilities to heat treatment and various antibiotics, and adhesion capacities to Caco-2 cells were also examined. All Weissella strains were killed when exposed to pH 2.0 for 2 h but survived at pH 3.0 with different survival ratios. W. confusa 31 survived best (20.2%) and W. confusa 31 was also quite resistant against 0.3% bile salt (128.8%). All strains except one grew well at temperature between 15 and 45 degrees C and all strains grew in the presence of 6.5% NaCl. W. confusa 20 showed the highest beta-galactosidase activity (527.3 +/- 23.66 unit/mg protein) and W. cibaria 31 had the highest beta-glucosidase activity (115.12 +/- 5.3 unit/mg protein) in MRS broth. All strains adhered to Caco-2 cells better than Lactobacillus rhamnosus GG and W. confusa 20 was the best adhesive strain (85 CFU/cell). These results show that some strains such as W. confusa 31 and W. confusa 20 are fully qualified as probiotics and deserve further application studies. PMID- 22200449 TI - Anti-superoxide and anti-peroxynitrite strategies in pain suppression. AB - Superoxide (SO, O(2).(-)) and its reaction product peroxynitrite (PN, ONOO(-)) have been shown to be important in the development of pain of several etiologies. While significant progress has been made in teasing out the relative contribution of SO and PN peripherally, spinally, and supraspinally during the development and maintenance of central sensitization and pain, there is still a considerable void in our understanding. Further research is required in order to develop improved therapeutic strategies for selectively eliminating SO and/or PN. Furthermore, it may be that PN is a more attractive target, in that unlike SO it has no currently known beneficial role. Our group has been at the forefront of research concerning the role of SO and PN in pain, and our current findings have led to the development of two new classes of orally active catalysts which are selective for PN decomposition while sparing SO. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. PMID- 22200452 TI - Visceral botulism at dairy farms in Schleswig Holstein, Germany: prevalence of Clostridium botulinum in feces of cows, in animal feeds, in feces of the farmers, and in house dust. AB - From 41 dairy farms in Schleswig Holstein, Germany, 196 fecal specimens of diseased cows, 77 fecal specimens of farmers and family members from 26 of these farms, 35 animal feed specimens and 7 house dust specimens were investigated for Clostridium botulinum and its antigens, respectively. Four of the humans under study (one child, 8 month, and three adults) showed symptoms of infant/visceral botulism. Specimens were cultivated in reinforced clostridial medium (RCM). C. botulinum antigens were detected by ELISA. The aim of the study was to obtain information on the relationship of detected C. botulinum toxin-types in cows, in the feces of attending humans, and in the immediate environment. The results revealed that C. botulinum toxin-types were different for cows and humans. Toxin type A was dominant in cow feces while type E was found in humans. Type E was also present in some animal feed specimens. Conversely, toxin-type A was prevalent in the house dust of farms. It may be assumed that the feeds were the source of human colonization with C. botulinum. PMID- 22200455 TI - Editorial: Peer review expertise. PMID- 22200454 TI - Editorial: Peer review expertise. PMID- 22200456 TI - Letters. PMID- 22200457 TI - Currents. PMID- 22200458 TI - Distribution of volatile organic chemicals in outdoor and indoor air: a national VOCs data base. PMID- 22200459 TI - Discharges from coal gasification plants. PMID- 22200460 TI - ES Views: Radon testing of soils. PMID- 22200461 TI - Superinsulated homes. PMID- 22200462 TI - Regulatory Focus: A scientist's valedictory. PMID- 22200464 TI - ES Meetings. PMID- 22200463 TI - ES Books: Acid Rain: Rhetoric and Reality. PMID- 22200465 TI - Enhancement of pentachlorophenol degradation in soil through induced anaerobiosis and bioaugmentation with anaerobic sewage sludge. PMID- 22200466 TI - Henry's law constants of some environmentally important aldehydes. PMID- 22200467 TI - Factors limiting success of inoculation to enhance biodegradation of low concentrations of organic chemicals. PMID- 22200468 TI - Isolation and identification of reaction products arising from the chlorination of cytosine in aqueous solution. PMID- 22200469 TI - The analysis of organophosphorus pesticide samples by high-performance liquid chromatography/mass spectrometry and high-performance liquid chromatography/mass spectrometry/mass spectrometry. PMID- 22200470 TI - PCB transport into lake sediments. Conceptual model and laboratory simulation. PMID- 22200471 TI - Characterization of polar polycyclic aromatic compounds in a heavy-duty diesel exhaust particulate by capillary column gas chromatography and high-resolution mass spectrometry. PMID- 22200472 TI - Organic photochemistry. 20. A method for estimating gas-phase rate constants for reactions of hydroxyl radicals with organic compounds from their relative rates of reaction with hydrogen peroxide under photolysis in 1,1,2 trichlorotrifluoroethane solution. PMID- 22200473 TI - The effect of fulvic acid on the kinetics of aluminum fluoride complexation in acidic waters. PMID- 22200474 TI - A method for the estimation of historical sulfate concentrations in natural freshwaters. PMID- 22200475 TI - Evaluation of an annular denuder/filter pack system to collect acidic aerosols and gases. PMID- 22200476 TI - Kinetics of trace metal complexation: role of alkaline-earth metals. PMID- 22200477 TI - Empirical relationships between the 1-octanol/water partition coefficient and nine physicochemical properties. PMID- 22200478 TI - Tributyltin contamination in bivalves from United States coastal estuaries. PMID- 22200480 TI - Electrogenerative oxidation of dissolved sulfur dioxide with packed-bed anodes. PMID- 22200479 TI - MS/MS analysis of the products of toluene photooxidation and measurement of their mutagenic activity. PMID- 22200481 TI - Effect of hydrofluoric or hydrochloric acid pretreatment on the ultrasonic extraction of organic materials from fly ash for chromatographic analysis. PMID- 22200482 TI - Stereoselective glycosylations using oxathiane spiroketal glycosyl donors. AB - Novel oxathiane spiroketal donors have been synthesised and activated via an umpolung S-arylation strategy using 1,3,5-trimethoxybenzene and 1,3 dimethoxybenzene. The comparative reactivity of the resulting 2,4,6 trimethoxyphenyl (TMP)- and 2,4-dimethoxyphenyl (DMP)-oxathiane spiroketal sulfonium ions is discussed, and their alpha-stereoselectivity in glycosylation reactions is compared to the analogous TMP- and DMP-sulfonium ions derived from an oxathiane glycosyl donor bearing a methyl ketal group. The results show that the stereoselectivity of the oxathiane glycosyl donors is dependent on the structure of the ketal group and reactivity can be tuned by varying the substituent on the sulfonium ion. PMID- 22200483 TI - The effect of amyloidogenic peptides on bacterial aging correlates with their intrinsic aggregation propensity. AB - The formation of aggregates by misfolded proteins is thought to be inherently toxic, affecting cell fitness. This observation has led to the suggestion that selection against protein aggregation might be a major constraint on protein evolution. The precise fitness cost associated with protein aggregation has been traditionally difficult to evaluate. Moreover, it is not known if the detrimental effect of aggregates on cell physiology is generic or depends on the specific structural features of the protein deposit. In bacteria, the accumulation of intracellular protein aggregates reduces cell reproductive ability, promoting cellular aging. Here, we exploit the cell division defects promoted by the intracellular aggregation of Alzheimer's-disease-related amyloid beta peptide in bacteria to demonstrate that the fitness cost associated with protein misfolding and aggregation is connected to the protein sequence, which controls both the in vivo aggregation rates and the conformational properties of the aggregates. We also show that the deleterious impact of protein aggregation on bacterial division can be buffered by molecular chaperones, likely broadening the sequential space on which natural selection can act. Overall, the results in the present work have potential implications for the evolution of proteins and provide a robust system to experimentally model and quantify the impact of protein aggregation on cell fitness. PMID- 22200485 TI - Role of the coiled-coil tip of Escherichia coli DksA in promoter control. AB - Escherichia coli DksA works in conjunction with the small-molecule ppGpp to regulate transcription initiation negatively or positively, depending on the identity of the promoter. DksA is in a class of transcription factors that do not bind directly to DNA such as classical repressors or activators but rather bind in the RNA polymerase (RNAP) secondary channel such as the transcription elongation factors GreA and GreB in E. coli and TFIIS in eukaryotes. We found that substitution for either of two residues in its coiled-coil tip, D74 or A76, eliminates DksA function without affecting its apparent affinity for RNAP. The properties of DksA-Gre factor chimeras indicated that the coiled-coil tip is responsible for the DksA-specific effects on open complex formation. A conservative substitution at position 74, D74E, resulted in a loss of DksA function in both negative and positive control, and an E44D substitution at the analogous position in GreA resulted in a gain of function in both negative and positive control. That a single methylene group has such an extraordinary effect on these transcription factors highlights the critical nature of the identity of coiled-coil tip interactions with RNAP for open complex formation. PMID- 22200484 TI - NMR characterization of monomeric and oligomeric conformations of human calcitonin and its interaction with EGCG. AB - Calcitonin is a 32-residue peptide hormone known for its hypocalcemic effect and its inhibition of bone resorption. While calcitonin has been used in therapy for osteoporosis and Paget's disease for decades, human calcitonin (hCT) forms fibrils in aqueous solution that limit its therapeutic application. The molecular mechanism of fiber formation by calcitonin is not well understood. Here, high resolution structures of hCT at concentrations of 0.3 mM and 1 mM have been investigated using NMR spectroscopy. Comparing the structures of hCT at different concentrations, we discovered that the peptide undergoes a conformational transition from an extended to a beta-hairpin structure in the process of molecular association. This conformational transition locates the aromatic side chains of Tyr12 and Phe16 in a favorable way for intermolecular pi-pi stacking, which is proposed to be a crucial interaction for peptide association and fibrillation. One-dimensional (1)H NMR experiments confirm that oligomerization of hCT accompanies the conformational transition at 1 mM concentration. The effect of the polyphenol epigallocatechin 3-gallate (EGCG) on hCT fibrillation was also investigated by NMR and electron microscopy, which show that EGCG efficiently inhibits fibril formation of hCT by preventing the initial association of hCT before fiber formation. The NMR experiments also indicate that the interaction between aromatic rings of EGCG and the aromatic side chains of the peptide may play an important role in inhibiting fibril formation of hCT. PMID- 22200486 TI - A novel co-culture model of the blood-retinal barrier based on primary retinal endothelial cells, pericytes and astrocytes. AB - Loss of blood-retinal barrier (BRB) properties is an important feature in the pathology of diabetic macular edema (DME), but cellular mechanisms underlying BRB dysfunction are poorly understood. Therefore, we developed and characterized a novel in vitro BRB model, based on primary bovine retinal endothelial cells (BRECs). These cells were shown to maintain specific in vivo BRB properties by expressing high levels of the endothelial junction proteins occludin, claudin-5, VE-cadherin and ZO-1 at cell borders, and the specific pumps glucose transporter 1 (GLUT1) and efflux transporter P-glycoprotein (MDR1). To investigate the influence of pericytes and astrocytes on BRB maintenance in vitro, we compared five different co-culture BRB models, based on BRECs, bovine retinal pericytes (BRPCs) and rat glial cells. Co-cultures of BRECs with BRPCs and glial cells showed the highest trans-endothelial resistance (TEER) as well as decreased permeability of tracers after vascular endothelial growth factor (VEGF) stimulation, suggesting a major role for these cell types in maintaining barrier properties. To mimic the in vivo situation of DME, we stimulated BRECs with VEGF, which downregulated MDR1 and GLUT1 mRNA levels, transiently reduced expression levels of endothelial junctional proteins and altered their organization, increased the number of intercellular gaps in BRECs monolayers and influence the permeability of the model to differently-sized molecular tracers. Moreover, as has been shown in vivo, expression of plasmalemma vesicle-associated protein (PLVAP) was increased in endothelial cells in the presence of VEGF. This in vitro model is the first co-culture model of the BRB that mimicks in vivo VEGF dependent changes occurring in DME. PMID- 22200487 TI - The deletion of Math5 disrupts retinal blood vessel and glial development in mice. AB - Retinal vascular development is a complex process that is not yet fully understood. The majority of research in this area has focused on astrocytes and the template they form in the inner retina, which precedes endothelial cells in the mouse retina. In humans and dogs, however, astrocyte migration follows behind development of blood vessels, suggesting that other cell types may guide this process. One such cell type is the ganglion cell, which differentiates before blood vessel formation and lies adjacent to the primary retinal vascular plexus. The present study investigated the potential role played by ganglion cells in vascular development using Math5(-/-) mice. It has previously been reported that Math5 regulates the differentiation of ganglion cells and Math5(-/-) mice have a 95% reduction in these cells. The development of blood vessels and glia was investigated using Griffonia simplicifolia isolectin B4 labeling and GFAP immunohistochemistry, respectively. JB-4 analysis demonstrated that the hyaloid vessels arose from choriovitreal vessels adjacent to the optic nerve area. As previously reported, Math5(-/-) mice had a rudimentary optic nerve. The primary retinal vessels did not develop post-natally in the Math5(-/-) mice, however, branches of the hyaloid vasculature eventually dove into the retina and formed the inner retinal capillary networks. An astrocyte template only formed in some areas of the Math5(-/-) retina. In addition, GFAP(+) Muller cells were seen throughout the retina that had long processes wrapped around the hyaloid vessels. Transmission electron microscopy confirmed Muller cell abnormalities and revealed disruptions in the inner limiting membrane. The present data demonstrates that the loss of ganglion cells in the Math5(-/-) mice is associated with a lack of retinal vascular development. PMID- 22200488 TI - Activation of the aldosterone/mineralocorticoid receptor system and protective effects of mineralocorticoid receptor antagonism in retinal ischemia-reperfusion injury. AB - The purpose of this project was to investigate the effects of the mineralocorticoid receptor antagonist against retinal ischemia-reperfusion injury and identify the aldosterone/mineralocorticoid receptor (MR) system in the rat retina. Retinal ischemia was induced by increasing intraocular pressure to 130 mmHg. Rats were treated with the angiotensin II type 1 receptor (AT1-R) antagonist (candesartan), MR antagonist (spironolactone), or aldosterone. Retinal damage was evaluated at 7 days after the ischemia by measuring the retinal thickness and the number of retinal ganglion cells. Pretreatment with candesartan, spironolactone, or candesartan and spironolactone significantly inhibited retinal ischemic injury. However, there was no protective effect against retinal ischemia-reperfusion injury provided by the combined aldosterone with candesartan treatment. Additionally, pretreatment with aldosterone alone also did not provide any neuroprotective effects against retinal ischemia reperfusion injury. When rats were treated via local administration of aldosterone in the absence of ischemia, the number of retinal ganglion cells decreased while the retinal thickness remained unchanged. The present findings demonstrated the existence of a local aldosterone/MR system in the retina. Our results also demonstrated that an MR antagonist can attenuate subsequent ischemic damage in the rat retina. PMID- 22200489 TI - Costimulatory molecule expression on human uveal melanoma cells: functional analysis of CD40 and B7-H1. AB - Costimulatory molecules play important roles in regulating T cell function in tumor immunity. In this study, we investigated costimulatory molecule expression on human uveal melanoma cells (a primary culture, and OCM-1, OMM-1 and 92-1 cell lines) and assessed the functional roles of selected costimulatory molecules. Uveal melanoma cells were incubated in the presence or absence of IFN-gamma and expression of costimulatory molecules on the cells was measured by flow cytometry. The costimulatory effect of B7-H1-expressing uveal melanoma cells on cytokine production by purified T cells was studied in uveal melanoma/T cell co culture experiments using a blocking anti-B7-H1 monoclonal antibody (mAb). The functional role of CD40-mediated interactions in modifying immune responses to uveal melanoma cells was assessed in vitro using recombinant human CD40 ligand (rhCD40L). MHC class I and B7-H1 were consistently detected and further upregulated by IFN-gamma stimulation in all human uveal melanoma cell cultures. CD40 was consistently detected and further upregulated by IFN-gamma stimulation in primary culture, OCM-1, and OMM-1 but not 92-1. IL-2 production from purified CD3(+) T cells co-stimulated with IFN-gamma-treated uveal melanoma cells was significantly enhanced by the addition of anti-B7-H1 mAb. Treatment of primary culture, OCM-1, or OMM-1 with rhCD40L induced or enhanced secretion of chemokines IL-8, MCP-1, IP-10 and RANTES. These results suggest that the expression of B7-H1 on IFN-gamma-treated uveal melanoma cells contributes to suppression of T cells by decreasing IL-2 production. In contrast, CD40 expressed on uveal melanoma cells plays an important role in augmenting anti-tumor immunity by stimulating chemokine production. The dual effects of CD40 and B7-H1 may contribute to positive or negative regulation of anti-tumor immune responses to human uveal melanoma. PMID- 22200490 TI - Role of the striatum in language: Syntactic and conceptual sequencing. AB - The basal ganglia (BG) have long been associated with cognitive control, and it is widely accepted that they also subserve an indirect, control role in language. Nevertheless, it cannot be completely ruled out that the BG may be involved in language in some domain-specific manner. The present study aimed to investigate one type of cognitive control-sequencing, a function that has long been connected with the BG-and to test whether the BG could be specifically implicated in language. Participants were required to rearrange materials sequentially based on linguistic (syntactic or conceptual) or non-linguistic (order switching) rules, or to repeat a previously ordered sequence as a control task. Functional magnetic resonance imaging (fMRI) data revealed a strongly active left-lateralized corticostriatal network, encompassing the anterior striatum, dorsolaterial and ventrolateral prefrontal cortex and presupplementary motor area, while the participants were sequencing materials using linguistic vs. non-linguistic rules. This functional network has an anatomical basis and is strikingly similar to the well-known associative loop implicated in sensorimotor sequence learning. We concluded that the anterior striatum has extended its original sequencing role and worked in concert with frontal cortical regions to subserve the function of linguistic sequencing in a domain-specific manner. PMID- 22200491 TI - Changes in mitochondrial glutathione levels and protein thiol oxidation in ?yfh1 yeast cells and the lymphoblasts of patients with Friedreich's ataxia. AB - Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by low levels of the mitochondrial protein frataxin. The main phenotypic features of frataxin deficient human and yeast cells include iron accumulation in mitochondria, iron sulfur cluster defects and high sensitivity to oxidative stress. Frataxin deficiency is also associated with severe impairment of glutathione homeostasis and changes in glutathione-dependent antioxidant defenses. The potential biological consequences of oxidative stress and changes in glutathione levels associated with frataxin deficiency include the oxidation of susceptible protein thiols and reversible binding of glutathione to the SH of proteins by S glutathionylation. In this study, we isolated mitochondria from frataxin deficient ?yfh1 yeast cells and lymphoblasts of FRDA patients, and show evidence for a severe mitochondrial glutathione-dependent oxidative stress, with a low GSH/GSSG ratio, and thiol modifications of key mitochondrial enzymes. Both yeast and human frataxin-deficient cells had abnormally high levels of mitochondrial proteins binding an anti-glutathione antibody. Moreover, proteomics and immunodetection experiments provided evidence of thiol oxidation in alpha ketoglutarate dehydrogenase (KGDH) or subunits of respiratory chain complexes III and IV. We also found dramatic changes in GSH/GSSG ratio and thiol modifications on aconitase and KGDH in the lymphoblasts of FRDA patients. Our data for yeast cells also confirm the existence of a signaling and/or regulatory process involving both iron and glutathione. PMID- 22200493 TI - Late partial failure of a free ALT flap. AB - Late failure of microsurgical flaps is a rare event and it has been reported as a consequence of compression of the vascular pedicle or late infection. We report a case of late partial failure occurring 3 weeks post-operatively which was shown by vascular imaging to be caused by a previously unidentified complete occlusion of the right external iliac artery. After successful vascular bypass surgery, the suffering flap developed granulation tissue and was skin grafted. In patients carrying multiple risk factors for peripheral vascular disease, the risk of proximal vessel occlusion as a cause of flap failure, should be kept in mind. PMID- 22200492 TI - Notch-ligand expression by NALT dendritic cells regulates mucosal Th1- and Th2 type responses. AB - Our previous studies showed that an adenovirus (Ad) serotype 5 vector expressing Flt3 ligand (Ad-FL) as nasal adjuvant activates CD11c(+) dendritic cells (DCs) for the enhancement of antigen (Ag)-specific IgA antibody (Ab) responses. In this study, we examined the molecular mechanism for activation of CD11c(+) DCs and their roles in induction of Ag-specific Th1- and Th2-cell responses. Ad-FL activated CD11c(+) DCs expressed increased levels of the Notch ligand (L) expression and specific mRNA. When CD11c(+) DCs from various mucosal and systemic lymphoid tissues of mice given nasal OVA plus Ad-FL were cultured with CD4(+) T cells isolated from non-immunized OVA TCR-transgenic (OT II) mice, significantly increased levels of T cell proliferative responses were noted. Furthermore, Ad-FL activated DCs induced IFN-gamma, IL-2 and IL-4 producing CD4(+) T cells. Of importance, these APC functions by Ad-FL activated DCs were down-regulated by blocking Notch-Notch-L pathway. These results show that Ad-FL induces CD11c(+) DCs to the express Notch-ligands and these activated DCs regulate the induction of Ag-specific Th1- and Th2-type cytokine responses. PMID- 22200495 TI - Focal nonconvulsive seizures during detoxification for benzodiazepine abuse. AB - Chronic benzodiazepine (BDZ) abuse is currently treated with detoxification using a low-dose flumazenil infusion, a relatively recently developed and promising procedure. Given the possibility reported in the literature of the occurrence of generalized seizures during therapeutic BDZ detoxification, we usually administer preventive antiepileptic drug (AED) therapy. We describe two patients with no previous history of seizures or evidence of intracerebral lesions who, during detoxification for benzodiazepine abuse, developed repetitive focal nonconvulsive seizures instead of generalized seizures, even with appropriate doses of preventive AED therapy. There are no previous reported cases of focal nonconvulsive seizures occurring during this procedure or, more generally, during abrupt BDZ discontinuation. The cases we describe suggest that during detoxification for BDZ abuse, not only generalized, but also focal nonconvulsive seizures may occur. In this context, the focal seizures probably result from a diffuse decrease in the seizure threshold (caused by a generalized excitatory rebound), which may trigger focal seizures arising from cortical regions with higher intrinsic epileptogenicity. Detoxification for benzodiazepine abuse, even if performed with adequate-dosage AED treatment, may not be as safe a procedure as previously considered, because not only convulsive, but also nonconvulsive seizures may occur and go unnoticed. It is therefore strongly advisable to perform this detoxification under close medical supervision and to maintain a low threshold for EEG monitoring in the event of sudden onset of behavioral changes. PMID- 22200496 TI - Negative-shift activation, current reduction and resurgent currents induced by beta-toxins from Centruroides scorpions in sodium channels. AB - The beta-toxins purified from the New World scorpion venoms of the Centruroides species affect several voltage-gated sodium channels (VGSCs) and thus are essential tools not only for the discrimination of different channel sub-types but also for studying the structure-function relationship between channels and toxins. This communication reports the results obtained with four different peptides purified from three species of Centruroides scorpions and assayed on seven distinct isoforms of VGSC (Na(v)1.1-Na(v)1.7) by specific functional analysis conducted through single cell electrophysiology. The toxins studied were CssII from Centruroides suffusus suffusus, Cll1 and Cll2 from Centruroides limpidus limpidus and a novel toxin from Centruroides noxius, which was characterized for the first time here. It has 67 amino acid residues and four disulfide bridges with a molecular mass of 7626 Da. Three different functional features were identified: current reduction of macroscopic conductance, left shift of the voltage-dependent activation and induction of resurgent currents at negative voltages following brief, strong depolarizations. The isoforms which revealed to be more affected resulted to be Na(v)1.6 > 1.1 > 1.2 and, for the first time, a beta-toxin is here shown to induce resurgent current also in isoforms different from Na(v)1.6. Additionally, these results were analyzed with molecular modelling. In conclusion, although the four toxins have a high degree of identity, they display tri-modal function, each of which shows selectivity among the different sub-types of Na+ -channels. Thus, they are invaluable as tools for structure-function studies of beta-toxins and offer a basis for the design of novel ion channel-specific drugs. PMID- 22200497 TI - Characterization and inhibition of norovirus proteases of genogroups I and II using a fluorescence resonance energy transfer assay. AB - Noroviruses are the major cause of food- or water-borne gastroenteritis outbreaks in humans. The norovirus protease that cleaves a large viral polyprotein to nonstructural proteins is essential for virus replication and an attractive target for antiviral drug development. Noroviruses show high genetic diversity with at least five genogroups, GI-GV, of which GI and GII are responsible for the majority of norovirus infections in humans. We cloned and expressed proteases of Norwalk virus (GI) and MD145 virus (GII) and characterized the enzymatic activities with fluorescence resonance energy transfer substrates. We demonstrated that the GI and GII proteases cleaved the substrates derived from the naturally occurring cleavage site in the open reading frame (ORF) 1 of G1 norovirus with similar efficiency, and that enzymatic activity of both proteases was inhibited by commercial protease inhibitors including chymostatin. The interaction of chymostatin to Norwalk virus protease was validated by nuclear magnetic resonance (NMR) spectroscopy. PMID- 22200498 TI - Odors from proximal species reverse the stress-decreased neurogenesis via main olfactory processing. AB - Unconditioned foot shock followed by restraint in water was used as a stress regimen to induce decreases in neurogenesis in mouse dentate gyrus (DG). Presence of conspecific odors has been known to reverse the stress-induced decrease in DG neurogenesis. In this study, we found that the conspecific odors did not produce these protective effects in mice whose MOE was impaired by nasal zinc sulfate lavage. Moreover, we observed that the presence of odors from rats, hamsters, and guinea pigs throughout the stress procedure reversed the stress-induced decrease in cell proliferation and neurogenesis in mouse dentate gyrus, while these odors alone did not affect mouse dentate cell proliferation or neurogenesis. In contrast, the presence of rabbit, sugar glider, hedgehog, beetle odors did not affect cell proliferation, neurogenesis, the stress-decreased cell proliferation or neurogenesis in DG. Finally, the presence of fox urine odors decreased mouse dentate cell proliferation and neurogenesis but did not affect the stress-induced decrease in cell proliferation or neurogenesis. Taken together, we conclude that olfactory processing via activation of sensory neurons in MOE is responsible for the conspecific odor-produced protective effect against the stress-decreased cell proliferation and neurogenesis. Phylogenetic distances of the odor-generating species and mice might contribute to the odors' protective effects against the stress-induced decreases in cell proliferation and neurogenesis. PMID- 22200499 TI - Ferulic acid prevents the cerebral ischemic injury-induced decrease of Akt and Bad phosphorylation. AB - Ferulic acid protects neuronal cells from glutamate-induced excitotoxicity and focal cerebral ischemia. This study investigated whether ferulic acid exerts a neuroprotective effect through the activation of Akt and its downstream targets, Bad and 14-3-3. Adult male rats were immediately treated with ferulic acid (100mg/kg, i.v.) after middle cerebral artery occlusion (MCAO). Brains were collected 24h after MCAO and infarct volumes were analyzed using triphenyltetrazolium chloride staining. It was found that ferulic acid treatment significantly reduced infarct volume during MCAO. Ferulic acid attenuated the MCAO injury-induced decrease of phospho-PDK1, phospho-Akt and phospho-Bad levels. However, ferulic acid did not affect the expression of 14-3-3 and Bcl-xL, which exerts an anti-apoptotic effect through interaction with phospho-Bad. Immunoprecipitation analysis demonstrated that the interaction between phospho Bad and 14-3-3 decreased during MCAO, whereas ferulic acid prevented the injury induced decrease in these interaction levels. Moreover, ferulic acid prevented the injury-induced increase in cleaved caspase-3 levels. These findings suggest that ferulic acid attenuates cell death during MCAO and that these protective effects are due to inhibition of Akt signaling pathway inactivation and maintenance of the interaction between phospho-Bad and 14-3-3. PMID- 22200500 TI - Hho1p, the linker histone of Saccharomyces cerevisiae, is important for the proper chromatin organization in vivo. AB - Despite the existence of certain differences between yeast and higher eukaryotic cells a considerable part of our knowledge on chromatin structure and function has been obtained by experimenting on Saccharomyces cerevisiae. One of the peculiarities of S. cerevisiae cells is the unusual and less abundant linker histone, Hho1p. Sparse is the information about Hho1p involvement in yeast higher order chromatin organization. In an attempt to search for possible effects of Hho1p on the global organization of chromatin, we have applied Chromatin Comet Assay (ChCA) on HHO1 knock-out yeast cells. The results showed that the mutant cells exhibited highly distorted higher-order chromatin organization. Characteristically, linker histone depleted chromatin generally exhibited longer chromatin loops than the wild-type. According to the Atomic force microscopy data the wild-type chromatin appeared well organized in structures resembling quite a lot the "30-nm" fiber in contrast to HHO1 knock-out yeast. PMID- 22200501 TI - Active surveillance for influenza vaccine adverse events: the integrated vaccine surveillance system. AB - OBJECTIVES: We conducted a pilot study of the Integrated Vaccine Surveillance System (IVSS), a novel active surveillance system for monitoring influenza vaccine adverse events that could be used in mass vaccination settings. METHODS: We recruited 605 adult vaccinees from a convenience sample of 12 influenza vaccine clinics conducted by public health departments of two U.S. metropolitan regions. Vaccinees provided daily reports on adverse reactions following immunization (AEFI) using an interactive voice response system (IVR) or the internet for 14 consecutive days following immunization. Followup with nonrespondents was conducted through computer-assisted telephone interviewing (CATI). Data on vaccinee reports were available real-time through a dedicated secure website. RESULTS: 90% (545) of vaccinees made at least one daily report and 49% (299) reported consecutively for the full 14-day period. 58% (315) used internet, 20% (110) IVR, 6% (31) CATI, and 16% (89) used a combination for daily reports. Of the 545 reporters, 339 (62%) reported one or more AEFI, for a total of 594 AEFIs reported. The majority (505 or 85%) of these AEFIs were mild symptoms. CONCLUSIONS: It is feasible to develop a system to obtain real-time data on vaccine adverse events. Vaccinees are willing to provide daily reports for a considerable time post vaccination. Offering multiple modes of reporting encourages high response rates. Study findings on AEFIs showed that the IVSS was able to exhibit the emerging safety profile of the 2008 seasonal influenza vaccine. PMID- 22200502 TI - Epitope based recombinant BCG vaccine elicits specific Th1 polarized immune responses in BALB/c mice. AB - Developing an efficacious vaccine is one of the highest priorities in tuberculosis research. A vaccine based on T cell epitopes representing multiple antigens is an ideal approach to generate effective cellular immunity against the disease. In the present study, we have selected four T cell epitopes from four well defined Mycobacterium tuberculosis antigens, Ag85C (Rv2903c), 10-kDa culture filtrate protein (CFP-10) (Rv3874), PPE68 (Rv3873) and INV (Rv1478). The epitope encoding genes were grafted into a Cpn 10 based epitope delivery system. The cpn 10-epitope chimeras were further cloned and expressed in BCG to obtain four rBCGs (BCG::CFP, BCG::FBP, BCG::PPE and BCG::INV). Both cellular and humoral immune responses induced by these r-BCG strains were evaluated in BALB/c mice after subcutaneous injection of a single dose of 1*10(6)CFU of the individual rBCGs. Compared to the parent BCG immunized animals the splenocytes derived from rBCG vaccinated groups showed greater antigen specific proliferation, characterized with higher IFN-gamma response and reduced IL-4 secretion. Also rBCG vaccination was able to induce specific humoral immune response with an enhanced IgG2a/IgG1 ratio. The rBCGs therefore favor an epitope specific Th1 type response, which is known to be important for mycobacterial immunity. Further when two of the rBCGs (BCG::CFP and BCG::FBP) were tested for their protective efficacy both the rBCGs were comparable to BCG in a H37Rv challenge study performed in guinea pigs. PMID- 22200504 TI - Differential expressions of nuclear proteomes between honeybee (Apis mellifera L.) Queen and Worker Larvae: a deep insight into caste pathway decisions. AB - Honeybees (Apis mellifera L.) possess individuals (castes) in their colonies, to which specific tasks are allocated. Owing to a difference in nutrition, the young female larvae develop into either a fertile queen or a sterile worker. Despite a series of investigations on the underlying mechanisms of honeybee caste polyphenism, information on proteins and enzymes involved in DNA and RNA regulation in the nucleus is still missing. The techniques of nuclear protein enrichment, two-dimensional electrophoresis, mass spectrometry and bioinformatics were applied to understand the nuclear proteome changes in response to changes in environmental settings (nutrition and time) during the early developmental stages at the third (72 h), fourth (96 h), and fifth (120 h) instars of the two caste intended larvae. A total of 120 differentially expressed nuclear proteins were identified in both caste intended larvae during these developmental stages. The third, fourth and fifth instars of queen prospective larvae expressed 69%, 84%, and 68% of the proteins that had altered expression, respectively. Particularly, the prospective queen larvae up-regulated most of the proteins with nuclear functions. In general, this changing nuclear proteome of the two caste intended larvae over the three developmental stages suggests variations in DNA and RNA regulating proteins and enzymes. These variations of proteins and enzymes involved in DNA and RNA regulation in response to differential nutrition between the two caste intended larvae lead the two caste larvae to pursue different developmental trajectories. Hence, this first data set of the nuclear proteome helps us to explore the innermost biological makings of queen and worker bee castes as early as before the 72 h (3rd instar). Also, it provides new insights into the honeybee's polymorphism at nuclear proteome level and paves new ways to understand mechanisms of caste decision in other eusocial insects. PMID- 22200503 TI - Adenovirus-based vaccination against Clostridium difficile toxin A allows for rapid humoral immunity and complete protection from toxin A lethal challenge in mice. AB - Clostridium difficile associated diarrhea (CDAD) is a critical public health problem worldwide with over 300,000 cases every year in the United States alone. Clearly, a potent vaccine preventing the morbidity and mortality caused by this detrimental pathogen is urgently required. However, vaccine efforts to combat C. difficile infections have been limited both in scope as well as to efficacy, as such there is not a vaccine approved for use against C. difficile to date. In this study, we have used a highly potent Adenovirus (Ad) based platform to create a vaccine against C. difficile. The Ad-based vaccine was able to generate rapid and robust humoral as well as cellular (T-cell) immune responses in mice that correlated with provision of 100% protection from lethal challenge with C. difficile toxin A. Most relevant to the clinical utility of this vaccine formulation was our result that toxin A specific IgGs were readily detected in plasma of Ad immunized mice as early as 3 days post vaccination. In addition, we found that several major immuno-dominant T cell epitopes were identified in toxin A, suggesting that the role of the cellular arm in protection from C. difficile infections may be more significant than previously appreciated. Therefore, our studies confirm that an Adenovirus based-C. difficile vaccine could be a promising candidate for prophylactic vaccination both for use in high risk patients and in high-risk environments. PMID- 22200505 TI - Chromatography approaches for early screening of the phospholipidosis-inducing potential of pharmaceuticals. AB - Drug-induced phospholipidosis (PLD) is an excessive accumulation of polar phospholipids within cells as a result of medical treatment. Even though a direct link between in vitro drug-induced PLD and toxicity in humans has not yet been firmly established, the development of PLD during preclinical testing in animals is a recognized problem in the pharmaceutical industry and can delay or abort the development process. Therefore, it is of interest to investigate the potential PLD risk of candidates at an early stage of the drug discovery process. In this work, a high throughput physicochemical approach, which is based on measuring the retention factors of the test compound within several different separation systems, was developed for screening phospholipidosis-inducing potential (PLIP) of pharmaceuticals. The measured retention factors of 36 drugs were compared with literature data on PLIP risk from three different sources. It is clearly shown that there is a statistical correlation between the chromatographic retention parameters of tested drugs and their PLIP risk. In conclusion, the retention factor (logk(AOT)) observed on a docusate sodium salt (AOT) surfactant vesicle electrokinetic chromatography (EKC) system and the logarithm of the volume of distribution (logV(d)) calculated from immobilized artificial membrane chromatography at pH 7.4 (CHI IAM(7.4)) and HSA binding value (% HSA) can provide primary profile prediction for a large number of drug candidates early in the drug discovery process with minimal resources. The observations are that the higher the value of both logk(AOT) and logV(d), the higher the PLIP risk, and we would recommend this dual approach. PMID- 22200506 TI - Granulocyte-macrophage colony-stimulating factor as an autocrine survival-growth factor in human gliomas. AB - We studied the expression of granulocyte-macrophage colony-stimulating factor (GM CSF) and its receptors (GM-CSF.R) in 20 human brain gliomas with different tumor gradings and demonstrated constitutive high levels of both mRNA gene expression and protein production exclusively in the highest-grade tumors (WHO, III-IV grade). Five astrocytic cell lines were isolated in vitro from glioma cells, which had selectively adhered to plates pre-coated with rhGM-CSF. These cells were tumorigenic when xenografted to athymic mice, and produced GM-CSF constitutively in culture. Two lines, particularly lines AS1 and PG1, each from a patient with glioblastoma multiforme, constitutively over-expressed both GM-CSF and GM-CSF.R genes and secreted into their culture media biologically active GM CSF. Different clones of the AS1 line, isolated after subsequent passages in vitro and then transplanted to athymic mice, demonstrated higher tumorigenic capacity with increasing passages in vivo. Cell proliferation was stimulated by rhGM-CSF in late-stage malignant clones, whereas apoptosis occurred at high frequency in the presence of blocking anti-GM-CSF antibodies. In contrast, rhGM CSF did not induce any apparent effect in early-stage clones expressing neither GM-CSF nor GM-CSF.R. The addition of rhGM-CSF or rhIL-1beta, to cultures induced the overproduction of both GM-CSF and its receptors and increased gene activation for several functional proteins (e.g. NGF, VEGF, VEGF.R1, G-CSF, MHC-II), indicating that these cells may undergo dynamic changes in response to environmental stimuli. These findings thus revealed: (1) that the co-expression of both autocrine GM-CSF and GM-CSF.R correlates with the advanced tumor stage; (2) that an important contribution of GM-CSF in malignant glioma cells is the prevention of apoptosis. These results imply that GM-CSF has an effective role in the evolution and pathogenesis of gliomas. PMID- 22200507 TI - Toll-like receptor 3-elicited MAPK activation induces stabilization of interferon beta mRNA. AB - Prolonged release of cytokines after activation of the innate immune system may lead to systemic infection and inflammatory diseases. Many cytokines with short half-lives contain adenine- and uridine-rich elements (AREs) in their 3' untranslated region (UTR), which mediate mRNA destabilization. The Toll-like receptors (TLRs) TLR3 and TLR4 induce immune responses via the adaptor proteins TRIF or TRIF and MyD88, respectively, leading to IFN-beta production. The 3'-UTR of IFN-beta mRNA contains an ARE sequence. We demonstrate that the TLR3 ligand dsRNA and the TLR4 ligand LPS induce stabilization of IFN-beta mRNA transcripts in monocyte-derived dendritic cells. In cells from TRIF(-/-) and MyD88(-/-) mice we found that dsRNA-induced stabilization of IFN-beta mRNA is TRIF-dependent. MAPK-activated protein 2 (MK2) has previously been found to regulate mRNA stabilization. We show that dsRNA elicits increased MK2 activation, mediated by TRIF and p38 MAPK. Chemical inhibition of p38 and MK2, and siRNA knockdown of MK2 relieved dsRNA-triggered prolongation of IFN-beta mRNA half-life. Taken together, these results suggest that TLR3 induces signaling mechanisms involving TRIF, p38 MAPK and MK2 to enhance stabilization of IFN-beta mRNA contributing to enhanced IFN-beta levels during pathogen infections. PMID- 22200508 TI - Cytokine profile, metabolic syndrome and cardiovascular disease risk in women with late-onset gestational diabetes mellitus. AB - Inflammation is an important component of the metabolic syndrome (MetS) which could be the link between the metabolic and the cardiovascular consequences of this condition. Gestational diabetes mellitus (GDM) has been recognized as a significant risk factor for MetS and an inflammation component has been described in this disease. The aim of the study was to evaluate the relationships between cytokine concentrations, components of MetS and cardiovascular risk markers in women with late-onset GDM. Women (n=63) with late-onset GDM and 63 controls were enrolled. Clinical variables, and obstetrics and perinatal outcomes were recorded. Relationships between cytokines (TNF-alpha, leptin, IL6, adiponectin) and endothelial injury markers (VCAM, ICAM and selectine) were analyzed. Control vs. patient data indicated: pre-gestational body mass index (BMI) 23.46+/-3.73 vs. 26.97+/-5.07kg/m(2) (p=0.001); TNF-alpha 2.2+/-0.8 vs. 3.1+/-1.5pg/mL (p=0.002); leptin 18714.78+/-8859.08 vs. 27365.79+/-16209.67pg/mL (p=0.001); adiponectin 162.42+/-34.19 vs. 141.54+/-41.33ng/mL (p=0.04). Multivariate analyses showed that adiponectin had a protective effect (OR=0.9; p=0.02) and BMI carried a significant risk (OR=8.4; p=0.01) for GDM. No differences were found in endothelial injury markers. In conclusion, the cytokine profile in women with late-onset GDM is characterized by high concentrations of TNF-alpha and leptin and low adiponectin. This profile is related, in large extent, to an increased pregravid BMI which, potentially, may be linked to the future development of both metabolic and cardiovascular disease. PMID- 22200509 TI - Delayed-onset interface fluid syndrome after laser in situ keratomileusis secondary to combined cataract and vitreoretinal surgery. AB - A 40-year-old man with a history of laser in situ keratomileusis (LASIK) 13 years earlier had combined cataract extraction and vitreoretinal surgery due to rhegmatogenous retinal detachment and posterior subcapsular cataract. Two weeks postoperatively, he complained of painless visual blurring. Diffuse interface haze was observed, and antiinflammatory treatment including topical steroid and cyclosporine was started. One week later, visual blurring had not improved and intraocular pressure was 27 mm Hg. Interface haze, fluid collection, and flap edema were observed and confirmed by spectral-domain anterior segment optical coherence tomography. After discontinuation of the steroid and addition of IOP lowering medication, visual acuity and interface fluid collection and haze improved. This case illustrates that interface fluid syndrome can develop more than 10 years after LASIK, triggered by ocular hypertension and inflammation after intraocular surgery. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22200510 TI - Evaluation of variables affecting intraoperative aberrometry. AB - PURPOSE: To understand some of the variable refractive changes that occur during routine cataract surgery that could affect the accuracy and effectiveness of intraoperative aberrometry as it relates to the postoperative refractive state. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Comparative case series. METHODS: Phase 1 of this study assessed the cylinder induced by 2 eyelid speculums (open wire and closed wire) with corneal topographic images from participants without cataract. Phase 2 assessed the refractive change in cylinder, its axis, and the spherical equivalent (SE) in cataract patients within 1 hour of cataract surgery compared with 1 week after surgery. These measurements were taken using wavefront aberrometry, manual refraction, and corneal topography. RESULTS: Phase 1 evaluated 99 corneal topographic images from 5 participants. The presence of a speculum induced erratic changes in cylinder and a statistically significant difference in axis when comparing the open-wire speculum and the closed-wire speculum (both P<.0001). In phase 2, which evaluated 10 patients, there was a significant change in the SE within 1 hour of cataract surgery compared with 1 week after surgery (P=.039). CONCLUSION: Cataract surgery induced changes in cylinder, its axis, and the SE. This suggests that decisions based on intraoperative aberrometry may be inaccurate. FINANCIAL DISCLOSURE: Dr. Olson has been a consultant to Abbott Medical Optics, Inc., Becton, Dickinson and Co., and Allergan, Inc., and has received grant support from Abbott Medical Optics, Inc. and Allergan, Inc. No author has a financial or proprietary interest in any material or method mentioned. PMID- 22200512 TI - Retinoic acid metabolism links the periodical differentiation of germ cells with the cycle of Sertoli cells in mouse seminiferous epithelium. AB - Homeostasis of tissues relies on the regulated differentiation of stem cells. In the epithelium of mouse seminiferous tubules, the differentiation process from undifferentiated spermatogonia (A(undiff)), which harbor the stem cell functions, to sperm occurs in a periodical manner, known as the "seminiferous epithelial cycle". To identify the mechanism underlying this periodic differentiation, we investigated the roles of Sertoli cells (the somatic supporting cells) and retinoic acid (RA) in the seminiferous epithelial cycle. Sertoli cells cyclically change their functions in a coordinated manner with germ cell differentiation and support the entire process of spermatogenesis. RA is known to play essential roles in this periodic differentiation, but its precise mode of action and its regulation remains largely obscure. We showed that an experimental increase in RA signaling was capable of both inducing A(undiff) differentiation and resetting the Sertoli cell cycle to the appropriate stage. However, these actions of exogenous RA signaling on A(undiff) and Sertoli cells were strongly interfered by the differentiating germ cells of intimate location. Based on the expression of RA metabolism-related genes among multiple cell types - including germ and Sertoli cells - and their regulation by RA signaling, we propose here that differentiating germ cells play a primary role in modulating the local RA metabolism, which results in the timed differentiation of A(undiff) and the appropriate cycling of Sertoli cells. Similar regulation by differentiating progeny through the modulation of local environment could also be involved in other stem cell systems. PMID- 22200514 TI - Reuptake inhibitors. PMID- 22200515 TI - Post-myocardial infarction depression: increased hospital admissions and reduced adoption of secondary prevention measures--a longitudinal study. AB - OBJECTIVE: Depression is prevalent in the aftermath of myocardial infarction (MI), and has been linked with mortality however few studies have investigated hospital admissions in MI survivors. Using a prospective cohort design, we examined the long-term relationship between depressive symptoms, post-MI hospital admissions and secondary prevention measures, in order to assess the burden of post-MI depression on patients and the healthcare system. METHODS: A cohort of 632 patients aged <=65 years, admitted for first-ever MI to 1 of the 8 hospitals in central Israel, was followed up for 10-13 years. Depressive symptoms were assessed at initial hospitalization using the Beck Depression Inventory. Rehospitalization and adoption of secondary prevention measures were recorded throughout follow-up. RESULTS: Depressive symptoms were significantly associated with days of hospitalization during follow-up (RR, 1.37, CI, 1.26-1.49), an association which remained significant after risk adjustment (RR, 1.14, CI, 1.04 1.26). The association appeared stronger for cardiac-related admissions than for other, non-cardiac admissions. Depressed patients were less likely to stop smoking (OR, 0.75, CI, 0.60-0.94), be physically active (OR, 0.80, CI, 0.69-0.94) and participate in cardiac rehabilitation (OR, 0.74, CI, 0.59-0.92). CONCLUSION: Post-MI depressive symptoms were shown to be associated with increased hospital admissions, particularly cardiac admissions, and with reduced adoption of secondary prevention behaviors. These findings have implications for patients' prognosis and quality of life and for healthcare costs. Depressive symptoms, even at the sub-clinical level, should be monitored in post-MI patients in order to identify those at greater risk of rehospitalization. PMID- 22200516 TI - Effects of escitalopram in prevention of depression in patients with acute coronary syndrome (DECARD). AB - OBJECTIVE: Depression is a major problem in patients after acute coronary syndrome (ACS) with negative impact on survival and quality of life. No studies have examined prevention of post-ACS depression. We examined whether treatment with escitalopram can prevent post-ACS depression. METHODS: We have conducted a randomised controlled trial. Between November 2004 and December 2007, 240 patients in 2 university hospitals in Copenhagen, Denmark, with ACS were randomised. Patients were randomised to a double-blind treatment with escitalopram or matching placebo for 1 year. Main outcome measure was the incidence of ICD-10 depressive episode. RESULTS: Of 120 patients treated with escitalopram 2 developed depression versus 10 in placebo treated group (log rank, p=0.022). In multivariate analysis treatment with placebo and high Hamilton Depression Scale score at baseline were associated with development of depression. Patients were well matched at baseline. CONCLUSION: Twelve months treatment with escitalopram prevented depression in post-ACS patients. PMID- 22200517 TI - Exhaustion predicts coronary heart disease independently of symptoms of depression and anxiety in men but not in women. AB - OBJECTIVE: Exhaustion is hypothesised to be a risk-factor for coronary heart disease (CHD), but as such its independence from emotional states, in particular depression, has not been established in previous investigations. This study aimed to explore the unique contribution of exhaustion, independent from symptoms of depression and anxiety, to CHD development. METHODS: The study sample was 5061 men and 6734 women from the Malmo Shoulder and Neck Study cohort examined in 1993 96. Exhaustion was measured by the SF-36 vitality scale. Symptoms of depression and anxiety were measured by the General Health Questionnaire. 571 first coronary events were ascertained through record linkage until 2005. Cox regression analysis was used to assess the contribution of exhaustion to CHD. RESULTS: In age-adjusted analysis exhaustion predicted coronary events in a non-linear way in both men (HR=1.49, 95% CI 1.06-2.11 in the highest exhaustion category) and women (HR=1.78, 95% CI 1.23-2.58 in the second highest exhaustion category). After adjustment for traditional risk-factors for CHD and socioeconomic status, the effect was attenuated and statistically significant only in women. However, further adjustment for symptoms of depression and anxiety strengthened the association between exhaustion and CHD in men (HR=1.62, 95% CI 1.05-2.50), whereas in women, exhaustion no longer predicted CHD. CONCLUSION: In age-adjusted analysis, exhaustion predicted CHD in both men and women, but its independence from depression and anxiety was demonstrated only in men. Further studies on the topic are required. A larger focus on potential gender differences should seem warranted in future research. PMID- 22200518 TI - Diagnostic accuracy of self-rating scales for screening of depression in coronary artery disease patients. AB - OBJECTIVE: We evaluated the internal consistency and psychometric properties of the Hospital Anxiety and Depression Scale (HADS) and the Beck Depression Inventory-II (BDI-II) for screening of major depressive episodes (MDE) in coronary artery disease (CAD) patients undergoing rehabilitation. METHODS: Five hundred and twenty-two consecutive CAD patients (72% men; mean age 58+/-9 years) attending a rehabilitation program 2 weeks after inpatient treatment for acute ischemic cardiac events completed the HADS depression subscale (HADS-D), HADS anxiety subscale (HADS-A) and the BDI-II. Interview outcome using the Mini International Neuropsychiatric Interview (MINI) for current MDE according to the DSM-IV-TR criteria was considered as the gold standard. RESULTS: Fifty-six (11%) patients had a current MDE. The HADS-D, HADS-A, HADS-total and BDI-II had high internal consistency. Area under the ROC curve was the highest for the BDI-II followed by the HADS. Optimal cut-off values for screening of MDE were >=5 for the HADS-D, >=8 for the HADS-A and >=14 for the HADS-total and for the BDI-II. At optimal cut-off values the BDI-II had slightly superior psychometric properties when compared to the HADS. However, positive predictive values were low for the HADS and for the BDI-II. CONCLUSIONS: In CAD patients undergoing rehabilitation, the HADS and BDI-II had high internal consistency. Screening for MDE at optimal cut-off values the BDI-II was slightly superior when compared to the HADS. Positive predictive values for the BDI-II and for the HADS were low indicating that a large proportion of patients with positive screening results did not meet criteria for MDE. PMID- 22200519 TI - Repeated exposure to effort-reward imbalance, increased blood pressure, and hypertension incidence among white-collar workers: effort-reward imbalance and blood pressure. AB - OBJECTIVES: To determine whether men and women with repeated ERI exposure have increased BP means or higher hypertension incidence over a 3-year follow-up. To examine the potential modifying effect of age and overcommitment. METHODS: The study cohort was composed of 1,595 white-collar workers (629 men and 966 women) assessed at baseline and 3-year follow-up. Ambulatory BP measures were taken every 15 min during a working day. ERI at work was self-reported using validated scales. BP means at follow-up and cumulative incidence of hypertension were respectively modeled with analyses of covariance (ANCOVA) and log-binomial regression. RESULTS: Among men, no association was observed between repeated ERI exposure and BP. Among women, age had a modifying effect. Women <45 years old exposed to ERI at both times had significantly higher BP means at follow-up (122.2/78.9 mmHg) than those unexposed (120.4/77.4 mmHg). In women >=45 years old, the cumulative incidence of hypertension was 2.78 (95% CI: 1.26-6.10) times higher among those exposed to ERI at both times. Men and women in the higher tertile of overcommitment had higher BP means (men: 128.9/82.2 mmHg, women: 121.9/78.0 mmHg) than those in the lower tertile (men: 127.2/81.3 mmHg, women: 120.6/77.0 mmHg). CONCLUSION: This prospective study showed that, among women, repeated ERI exposure led to a significant age-specific increase in BP means and a major age-specific increase in hypertension incidence. These results suggest that primary intervention aimed at reducing ERI may contribute to lower BP and prevent hypertension in women. PMID- 22200520 TI - Posttraumatic stress disorder and hypertension in Australian veterans of the 1991 Gulf War. AB - OBJECTIVE: Military veterans experience a high prevalence of psychopathologies such as posttraumatic stress disorder (PTSD). Relationships between physical and psychological health are increasingly recognised. This study investigated associations between PTSD and hypertension in male Australian Gulf War veterans. METHODS: In 2000-02, 1456 veterans underwent medical and psychological assessments. Medical practitioners rated self-reported medical conditions as probable diagnoses, possible, unlikely or non-medical. The Composite International Diagnostic Interview (CIDI) assessed psychological symptomatology present in the 12 months preceding evaluation, and lifetime prevalence. Odds of hypertension among those with and without PTSD were calculated for each timeframe using logistic regression. RESULTS: Analysis was restricted to the 1381 veterans for whom CIDI and medical data were available. Hypertension was considered probable in 100 subjects (7.2%). Adjusted odds ratios of hypertension were 2.90 (95% CI 1.19-7.09) amongst veterans with PTSD in the past 12 months and 2.27 (95% CI 1.01-5.10) for lifetime prevalence, compared with those without PTSD. Hypertension was over seven times more likely amongst veterans with PTSD alone than those with no mental illness in the past 12 months. CONCLUSIONS: Veterans with a history of PTSD had increased odds of having hypertension. Given the array of disabling psychosocial associations of PTSD, and the numerous potential clinical sequelae of hypertension, co-existence of these conditions may have implications for prevention and management at the individual, clinical, and public health policy and practice level. Early identification of PTSD in military samples may help to ameliorate longer-term adverse physical health outcomes. PMID- 22200521 TI - Health and distress predictors of heart rate variability in fibromyalgia and other forms of chronic pain. AB - OBJECTIVE: To examine health, psychological, and autonomic impairment differences between individuals with fibromyalgia and those with other chronic benign pain in these conditions. The possible role of the autonomic nervous system in the maintenance of chronic benign pain can be examined using heart rate variability (HRV), which measures the interplay between the excitatory sympathetic and the inhibitory parasympathetic nervous system. Predictors of HRV will also be examined. METHODS: This study examined resting HRV in a sample of 84 patients with chronic benign pain, a subgroup of whom had fibromyalgia. Participants completed a battery of self-report measures and underwent measurements of resting HRV. RESULTS: Individuals with fibromyalgia experienced higher levels of depression (t (82)=-2.27, p<.05) and significantly greater difficulty with physical functioning (t (75.8)=2.65, p<.01) than did those with other chronic benign pain, there were no significant differences in any of the HRV indices. Across all pain conditions, we found that age, gender, physical health functioning, pain anxiety, and pain sensations were all significant predictors of HRV, suggesting that each are involved in the relationship between chronic benign pain and autonomic function. CONCLUSIONS: These findings emphasize the importance of addressing psychological distress and physical functioning in chronic pain populations and specifically fibromyalgia. Future research can further examine the role of physical health functioning, psychological distress, and pain severity in the relationship between chronic pain and autonomic abnormalities. PMID- 22200522 TI - The match-mismatch model of emotion processing styles and emotion regulation strategies in fibromyalgia. AB - OBJECTIVE: Individuals differ in their style of processing emotions (e.g., experiencing affects intensely or being alexithymic) and their strategy of regulating emotions (e.g., expressing or reappraising). A match-mismatch model of emotion processing styles and emotion regulation strategies is proposed and tested. This model specifies that for people high on affect intensity, emotion expression is more adaptive than reappraisal, whereas for alexithymic people, reappraisal is more adaptive than expression. The present study tested this model in 403 women with fibromyalgia (mean age 46.5+/-12.3 years). METHODS: In a cross sectional design, we assessed affect intensity (Berkeley Expressivity Questionnaire), alexithymia (Toronto Alexithymia Scale-20), cognitive reappraisal (Emotion Regulation Questionnaire), and emotion expression (Emotional Approach Coping Scales), as well as the impact of fibromyalgia (Fibromyalgia Impact Questionnaire). RESULTS: Multiple regression analyses with interaction terms indicated that among people high on affect intensity, emotion expression - but not cognitive reappraisal - was associated with less fibromyalgia impact. No support was found for the hypothesis that among alexithymic people, cognitive reappraisal would be more adaptive than emotion expression. CONCLUSION: Findings suggest that for women with fibromyalgia who experience their emotions intensely, an emotional disclosure or expression intervention may be beneficial. This hypothesis requires verification in experimental studies. PMID- 22200523 TI - Catecholamines and heart rate in female fibromyalgia patients. AB - BACKGROUND: Fibromyalgia syndrome is a disease of unknown pathogenesis characterised by widespread chronic musculoskeletal pain. Fibromyalgia has been associated with dysregulation of the stress systems, but results are inconsistent. PURPOSE: To investigate autonomic nervous system activity (urinary noradrenaline, adrenaline, dopamine, and heart rate) of fibromyalgia patients and healthy controls. METHODS: Urinary catecholamines and heart rate were assessed for a 24-hour period in a controlled hospital setting (including relaxation, a test with prolonged mental stress, and sleep), and during daily activity in 29 female fibromyalgia patients and 29 age-matched female healthy controls. RESULTS: With repeated measures ANOVAs, catecholamine levels were lower in patients than controls (P=.035 for noradrenaline; P=.005 for adrenaline; P=.001 for dopamine). One-way ANOVAs for the single periods showed that patients compared to controls had significantly lower adrenaline levels during the night (P=.010) and the second day (P=.010), significantly lower dopamine levels during the first day (P=.008), the night (P=.001), and the second day (P=.004). However, single time point noradrenaline levels were not significantly different between the groups. Overall, heart rate was significantly higher in patients than controls (P=.014). Specifically, significant differences emerged during relaxation (P=.016) and sleep (P=.011), but not during stress provocation or daily activities. CONCLUSIONS: The results indicate an altered regulation of the autonomic nervous system in fibromyalgia patients, with attenuated activity of both the sympathetic (adrenal medulla component) and the parasympathetic branch. PMID- 22200524 TI - Cognitive and physiological dissociations in response to emotional pictures in patients with anorexia. AB - Recent studies suggest that patients with anorexia may express dissociated cognitive and physiological reactivities to emotional stimuli. The present research aimed to compare subjective and autonomic responses to pleasant, unpleasant and neutral scenes during a categorization task and an activation rating task in anorexic (AN), alexithymic (AL), depressed (DEP) and control participants (CONT). The participants first categorized pictures according to their emotional valence, followed by a rating of their activation level, concomitant with the recording of skin conductance responses (SCRs). Main findings showed that the AN patients presented major difficulty in categorizing pictures, particularly neutral ones. Contrary to the AL participants, this difficulty did not induce significant increases of SCR amplitude in the AN patients. In the second task, the AN patients rated the intensity of activation of unpleasant pictures higher than the AL participants and that of pleasant ones higher than the AL and CONT participants. In addition, no significant linear correlation was observed between the intensity of activation ratings and SCR amplitude in the AN, AL or DEP participants contrarily to what was observed for control participants. This lack of relation suggests a non-specific disconnection between physiological and cognitive self-reported responses to emotional stimuli. Our results highlight a specific form of emotional processing in the AN patients distinct from that observed in alexithymia or depression and characterized by a dissociation between cognitive and physiological responses. This kind of disconnection could be associated with emotional regulation processes and may benefit the AN patients by lowering the psychological stress response. PMID- 22200525 TI - Latent class analysis of eating and impulsive behavioral symptoms in Taiwanese women with bulimia nervosa. AB - OBJECTIVE: The implications of impulsivity in its relationship with binge-eating or purging behaviors remain unclear. This study examined the patterns of eating behaviors and co-morbid impulsive behaviors in individuals with bulimia nervosa n optimally homogeneous classes using latent class analysis (LCA). METHODS: All participants (n=180) were asked to complete a series of self-reported inventories of impulsive behaviors and other psychological measures. Information regarding the lifetime presence of symptoms of eating disorder was assessed by clinical interviews. LCA was conducted using eating disorder symptoms, impulsive behaviors, and the number of purging methods. RESULTS: Three latent classes of bulimic women were identified. These were women who exhibited relatively higher rates of purging, symptoms of impulsive behavior, and multiple purging methods (17.8%), women who used no more than one purging method with a low occurrence of impulsive behavior (41.7%), and women who showed higher rates of purging behaviors and the use of multiple purging methods with a low rate of impulsive behavior (41.7%). The impulsive sub-group had comparable severity of eating related measures, frequency of binge-eating, and higher levels of general psychopathology than that of the other two sub-groups. CONCLUSION: This study provides empirical support for the existence of an impulsive subgroup with distinctive features among a non-Western group of BN patients. This study also suggests that mechanisms other than impulse dysregulation may exist for the development of binge-eating and purging behaviors in bulimia nervosa patients, or the mechanisms contributing to binge-eating and impulsive behaviors may be different. PMID- 22200526 TI - Association between co-twin sex and eating disorders in opposite sex twin pairs: evaluations in North American, Norwegian, and Swedish samples. AB - OBJECTIVE: These three studies examined the hypothesis that prenatal exposure to sex hormones influences twins' risk for eating disorders based on co-twin sex, such that individuals with a female co-twin would be more likely than individuals with a male co-twin to meet diagnostic criteria for an eating disorder. METHODS: Male and female twins from the United States (N=2607), Norway (N=2796) and Sweden (N=16,458) with known co-twin sex and zygosity were assessed for eating disorders. RESULTS: In the U.S. and Swedish samples, sex was significantly associated with eating disorder diagnoses, and although co-twin sex was not associated with eating disorders overall, it was associated with broadly defined bulimia nervosa in the Swedish sample. The effects for bulimia were not sustained when monozygotic twins were excluded, suggesting that the effects of prenatal sex hormones play a minor role in influencing eating disorders. Sex and co-twin sex were not associated with eating disorders in the Norwegian sample. CONCLUSION: The prenatal sex hormone hypothesis, which proposes that prenatal hormone exposure is associated with later eating disorder symptomatology, was not supported in these three population-based twin samples. PMID- 22200528 TI - Randomised control trials for delirium: current evidence and statistical methods. PMID- 22200527 TI - Behavioral and characterological self-blame in chronic obstructive pulmonary disease. AB - OBJECTIVE: To assess behavioral and characterological self-blame, identify demographic and relational correlates of self-blame, and determine the association of self-blame with psychological and clinical outcomes of chronic obstructive pulmonary disease (COPD). METHODS: Data were collected via self report questionnaires completed by 398 individuals with COPD who had at least a 10 pack-year history of smoking. Behavioral and characterological self-blame were measured, and multiple regression was used to identify correlates of both types of self-blame. Multiple regression was also used to determine the association of self-blame with outcomes of COPD. RESULTS: More than one-third of participants endorsed the maximum possible score on the measure of behavioral self-blame. The perception that family members blamed the individual for having COPD (p=.001), tobacco exposure (p=.005), and general family functioning (p=.002) were associated with behavioral self-blame. Current smoking status (p=.001) and perception of blame from family (p<.001) were associated with characterological self-blame. While behavioral self-blame was associated with fewer symptoms of depression (p=.02), characterological self-blame was associated with more symptoms of depression (p=.02). CONCLUSIONS: Individuals with COPD tend to blame themselves for smoking and other behaviors that may have led to their COPD. Smoking-related variables and the perception that family members blamed the individual for having COPD were associated with self-blame. Findings support the importance of distinguishing between behavioral and characterological self-blame in COPD, as behavioral self-blame had a negative association with depression and characterological self-blame had a positive association with depression. PMID- 22200530 TI - Responses to a comment on "autonomic cardiovascular control and responses to experimental pain stimulation in fibromyalgia syndrome". PMID- 22200531 TI - Prismatic adaptation effects on spatial representation of time in neglect patients. AB - Processing of temporal information may require the use of spatial attention to represent time along a mental time line. We used prismatic adaptation (PA) to explore the contribution of spatial attention to the spatial representation of time in right brain damaged patients with and without neglect of left space and in age-matched healthy controls. Right brain damaged patients presented time underestimation deficits, that were significantly greater in patients with neglect than in patients without neglect. PA inducing leftward attentional deviation reduced time underestimation deficit in patients with neglect. The results support the hypothesis that a right hemispheric network has a role, per se, in time perception. Moreover, they suggest that right hemisphere is important in time perception for its control of spatial attention, engaged in spatial representation of time. Procedures that ameliorate left spatial deficits could also be useful for modulating temporal deficits in right brain damaged patients with neglect. PMID- 22200532 TI - Effects of cholesterol on phospholipid membranes: inhibition of the interdigitated gel phase of F-DPPC and F-DPPC/DPPC. AB - Unlike the parent phospholipid, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), the monofluorinated analog, 1-palmitoyl-2-(16-fluoropalmitoyl)sn-glycero 3-phosphocholine (F-DPPC), spontaneously forms an interdigitated gel phase (L(beta)I) below the main transition temperature (T(m)). We have examined the effects of introducing cholesterol to F-DPPC and 1:1 F-DPPC/DPPC membranes using a combination of DSC, optical density, fluorescence intensity and polarization, (31)P NMR, and X-ray diffraction techniques. Cholesterol increases the fluidity of the gel phase, broadens the main transition, and decreases the main transition enthalpy. However, these results also reveal that there is an unusually large degree of phase coexistence between the L(beta)I and non-interdigitated gel phases when cholesterol is added. Cholesterol encourages this phase segregation by partitioning into the thicker non-interdigitated domains. At higher cholesterol concentrations, the majority or all of the L(beta)I phase of F-DPPC and 1:1 F-DPPC/DPPC is eliminated and is replaced by a non-interdigitated liquid ordered (l(o)) phase with properties similar to DPPC/cholesterol. Consequently, cholesterol mitigates the influence the CF moiety has on the thermodynamic phase behavior of F-DPPC. Our findings demonstrate that there are multiple characteristics of cholesterol-rich membranes that disfavor interdigitation. PMID- 22200533 TI - Selenite-induced apoptosis and autophagy in colon cancer cells. AB - Sodium selenite (Se) is known to induce diverse stress responses in malignant cells which may lead to various types of cell death including apoptosis and/or autophagy. In colon cancer cells, Se activates several signaling pathways whose interactions and ultimate endpoints may vary in individual study models. In our previous work we showed differences in Se-dependent growth inhibition, cell cycle alterations and apoptosis in colon cancer cells with functional (HCT-116) and deleted (HCT-116-p53KO) p53. Moreover, detailed morphological and biochemical analyses revealed the presence of autophagy in Se-treated cells. Thus the aim of this study was to investigate in detail mechanisms, relationship and crosstalk between apoptosis and autophagy in Se-treated HCT-116 cancer cells differing in p53 status since p53 has been shown to play a well-known role in apoptosis but dichotomous role in autophagy. We report that the absence of p53 in malignant colonocytes changes patterns of response to Se-induced stress which include differential activation of MAP kinases (p38 - HCT-116 and JNK - HCT-116 p53KO) including their respective roles in the process of apoptosis and autophagy as well as the involvement of mTOR or PI3K signaling. Our results seem to suggest that deletion of p53 inevitably leads to a higher level of instability and delays in an individual cell decision in the face of stress whether to activate apoptosis or autophagy which may consequently occur simultaneously with mutual dichotomous relationship. PMID- 22200534 TI - A glyphosate-based herbicide induces necrosis and apoptosis in mature rat testicular cells in vitro, and testosterone decrease at lower levels. AB - The major herbicide used worldwide, Roundup, is a glyphosate-based pesticide with adjuvants. Glyphosate, its active ingredient in plants and its main metabolite (AMPA) are among the first contaminants of surface waters. Roundup is being used increasingly in particular on genetically modified plants grown for food and feed that contain its residues. Here we tested glyphosate and its formulation on mature rat fresh testicular cells from 1 to 10000ppm, thus from the range in some human urine and in environment to agricultural levels. We show that from 1 to 48h of Roundup exposure Leydig cells are damaged. Within 24-48h this formulation is also toxic on the other cells, mainly by necrosis, by contrast to glyphosate alone which is essentially toxic on Sertoli cells. Later, it also induces apoptosis at higher doses in germ cells and in Sertoli/germ cells co-cultures. At lower non toxic concentrations of Roundup and glyphosate (1ppm), the main endocrine disruption is a testosterone decrease by 35%. The pesticide has thus an endocrine impact at very low environmental doses, but only a high contamination appears to provoke an acute rat testicular toxicity. This does not anticipate the chronic toxicity which is insufficiently tested, and only with glyphosate in regulatory tests. PMID- 22200535 TI - Enhanced stability and gene silencing ability of siRNA-loaded polyion complexes formulated from polyaspartamide derivatives with a repetitive array of amino groups in the side chain. AB - The delivery of siRNA therapeutics owes its success to the development of carrier systems with high efficacy and minimum toxicity. Here, cationic polyaspartamide derivatives with a regulated number and spacing of positively charged amino groups in the side chain were prepared from a single platform polymer of poly(beta-benzyl l-aspartate) to assess their availability as siRNA carriers through polyion complex (PIC) formation. These polymers have 1,2-diaminoethane, 1,3-diaminopropane, and N,N'-bis(2-aminoethyl)-1,2-diaminoethane moieties in the side chain, and are termed as PAsp(DET), PAsp(DPT), and PAsp(TEP), respectively. siRNA-loaded PICs stable in serum-containing media were formed from PAsp(TEP) and PAsp(DPT) with two positive charges in the side chain at pH 7.4, whereas no such stable PIC was obtained from PAsp(DET) with only a single charge in the side chain, suggesting facilitated multivalent interactions with siRNA molecules to increase the PIC stability. The PAsp(DPT) and PAsp(TEP) PICs stable in the serum containing media underwent an appreciably enhanced uptake into cultured cells through endocytosis, and subsequently exerted effective endosomal escape for the significant silencing of target gene expression. Notably, PAsp(TEP) PIC displayed negligible cytotoxicity in sharp contrast to the highly toxic feature of PAsp(DPT) PIC. This cytotoxicity is apparently correlated with the minimal damage to the cytoplasmic membrane of cells exposed to PAsp(TEP) at pH 7.4 evidenced from the fluorescent dye (YO-PRO-1) permeation assay. There was, in turn, a significant increase in YO-PRO-1 permeability at endosomal pH of 5.5 for PAsp(TEP)-exposed cells, indicating that PAsp(TEP) exerts membrane damage in a pH selective manner, and eventually facilitates the translocation of siRNA-loaded PIC from the acidic endosomal compartment into the cytoplasm for effective gene silencing without any severe toxicity at physiological conditions. This acidic pH modulated enhancement in membrane damage of PAsp(TEP) may be explained by an increased protonation of the arrayed amino groups in the side chain that strongly perturb the endosomal membrane integrity. Eventually, PAsp(TEP) with a side chain array of pH-sensitive amino groups was demonstrated to be a promising component for constructing siRNA carriers exerting effective gene silencing in a less toxic context. PMID- 22200536 TI - Tumor regression following intravenous administration of a tumor-targeted p73 gene delivery system. AB - The potential of gene therapy to treat cancer is hampered by the lack of safe and efficacious gene delivery systems able to selectively deliver therapeutic genes to tumors by intravenous administration. With the long-term aim of developing an efficacious cancer-targeted gene medicine, we demonstrated that transferrin bearing polypropylenimine dendrimer complexed to a plasmid DNA encoding p73 led to an enhanced anti-proliferative activity in vitro, by up to 120-fold in A431 compared to the unmodified dendriplex. In vivo, the intravenous administration of this p73-encoding dendriplex resulted in a rapid and sustained inhibition of tumor growth over one month, with complete tumor suppression for 10% of A431 and B16-F10 tumors and long-term survival of the animals. The treatment was well tolerated by the animals, with no apparent signs of toxicity. These results suggest that the p73-encoding tumor-targeted polypropylenimine dendrimer should be further explored as a therapeutic strategy for cancer therapy. PMID- 22200537 TI - Liposomal formulations of Etoposide and Docetaxel for p53 mediated enhanced cytotoxicity in lung cancer cell lines. AB - The objective of present investigation was to develop and assess comparative enhancement in cytotoxicity of liposomal Etoposide and Docetaxel in non-small cell lung cancer cell lines after pre-treatment and co-administration of p53 tumor suppressor gene and to assess direct lung targeting of optimized formulations by dry powder inhaler technology. Cationic liposomes with and without drug were prepared and allowed to form p53-lipoplex for undertaking cytotoxicity studies in H-1299 (p53 null) and A-549 (p53 wt) cell lines. The optimized lipoplexes showed average size of 200-350 nm, zeta potential of 25-32 mV and sustained drug release up to 16-24 h. The developed liposomes and lipoplexes showed significant intracellular uptake and demonstrated enhanced cytotoxicity of 13-28 % after p53-drug co-administration and 41-63 % after p53 pre-treatment. The p53 mediated enhanced cytotoxicity by increased apoptosis and necrosis was also confirmed using Annexin V - FITC assay. The increased apoptosis suggested restored p53 function and reduced anti-apoptotic drug resistance theirby causing cell sensitization and synergism towards cytotoxicity. The studies conducted above demonstrated significant cell chemo-sensitization after p53 pre-treatment followed by Etoposide/Docetaxel liposomes administration than p53-Etoposide or p53-Docetaxel lipoplex co-administration; more significantly in Docetaxel and in H 1299 cell line. All the formulations when developed as dry powder inhalers showed significant in vitro lung deposition pattern in cascade impactor with fine particle faction of 33-37%. The study opens up a new strategy to treat lung cancer especially in cases of drug resistance. Moreover direct delivery to lung may provide an important role in complete remission of the disease due to target specificity. PMID- 22200538 TI - Hemimegalencephalic variant of epidermal nevus syndrome: case report and literature review. AB - The epidermal nevus syndrome (ENS) is an uncommon neurocutaneous disorder in which epidermal nevi are found in association with congenital abnormalities of the brain, eye, and/or skeleton. The association of epidermal nevi and neurologic abnormalities was comprehensively described by Schimmelpenning in 1957. Pavone et al. (1991) identified a homogeneous variant of ENS with hemimegalencephaly, gyral malformation, mental retardation, seizures and facial hemihypertrophy. A 13-year old boy with the neurologic variant of ENS with hemimegalencephaly, facial asymmetry, febrile seizures and mental retardation is reported. Additionally, we performed a literature review using the search terms "epidermal nevus syndrome" and "hemimegalencephaly", including secondary sources of data such as reference lists of articles reviewed. We found 57 previously reported cases with the hemimegalencephalic variant of epidermal nevus syndrome, in which the most frequent associated features are severe epilepsy, in about half of cases with neonatal onset, mental retardation/developmental delay, ocular/visual involvement, and facial abnormalities. PMID- 22200539 TI - Protein aggregates in Huntington's disease. AB - Huntington's disease (HD) is an incurable neurodegenerative disease characterized by abnormal motor movements, personality changes, and early death. HD is caused by a mutation in the IT-15 gene that expands abnormally the number of CAG nucleotide repeats. As a result, the translated protein huntingtin contains disease-causing expansions of glutamines (polyQ) that make it prone to misfold and aggregate. While the gene and mutations that cause HD are known, the mechanisms underlying HD pathogenesis are not. Here we will review the state of knowledge of HD, focusing especially on a hallmark pathological feature intracellular aggregates of mutant Htt called inclusion bodies (IBs). We will describe the role of IBs in the disease. We speculate that IB formation could be just one component of a broader coping response triggered by misfolded Htt whose efficacy may depend on the extent to which it clears toxic forms of mutant Htt. We will describe how IB formation might be regulated and which factors could determine different coping responses in different subsets of neurons. A differential regulation of IB formation as a function of the cellular context could, eventually, explain part of the neuronal vulnerability observed in HD. PMID- 22200540 TI - Neural cell adhesion molecule and its polysialic acid moiety exhibit opposing and linked effects on neuropathic hyperalgesia. AB - Spinal lamina II, where nociceptive C-fibers terminate, expresses high amounts of the polysialylated form of neural cell adhesion molecule (PSA-NCAM). While enzymatic removal of the PSA moiety from NCAM did not affect normal sensitivity to thermal stimuli, it exacerbated nerve injury-induced neuropathic hyperalgesia. The genetic removal of the NCAM core protein also did not alter thermal sensitivity. However in the presence of a peripheral nerve injury, NCAM-null mutants exhibited a complete suppression of thermal hyperalgesia. This strong NCAM mutant phenotype appears to involve the long form of NCAM's cytoplasmic domain, in that it is duplicated by selective genetic deletion of the NCAM-180 isoform. PSA appears therefore to provide a mechanism for modulation of chronic sensory overload, by means of attenuation of the activity of the NCAM-180 isoform, which reduces nociceptive transmission. PMID- 22200542 TI - Modelling the role of the basement membrane beneath a growing epithelial monolayer. AB - The role of the basement membrane is vital in maintaining the integrity and structure of an epithelial layer, acting as both a mechanical support and forming the physical interface between epithelial cells and the surrounding connective tissue. The function of this membrane is explored here in the context of a growing epithelial monolayer, defined such that the epithelial cells divide and migrate along a deformable substrate. A discrete, off-lattice cell-centre modelling approach is undertaken, which permits definition of a basement membrane component, separating the epithelial cells from the tissue stroma whilst responding to forces from both that arise due to cell division, migration and apoptosis. This model is applicable to a range of biological epithelia, including the self-renewing interfollicular epidermis, the olfactory epithelium and the intestinal crypts of Lieberkuhn, to inform response and recovery of such tissues following injury. Model simulations show that homeostasis of the growing monolayer can be achieved and sustained, and the necessary balance of interactive cell forces, cell migration and cell death is presented. This work is proposed as a novel extension to the body of discrete models of biological epithelia, permitting investigation of the growth and migration of epithelial cells in a deformable environment. PMID- 22200543 TI - Global dynamics in a stage-structured discrete-time population model with harvesting. AB - The purpose of this paper is to analyze the effect of constant effort harvesting upon global dynamics of a discrete-time population model with juvenile and adult stages. We consider different scenarios, including adult-only mortality, juvenile only mortality, and equal mortality of juveniles and adults. In addition to analytical study of equilibria of the system, we analyze global dynamics by means of an automated set-oriented rigorous numerical method. We obtain a comprehensive overview of the dynamics as the harvest rate and survival probability change. In particular, we determine the range of parameters for which the population abundance gets larger in spite of an increase in the harvest rate (so-called hydra effect), and for which subsequent increases in harvesting effort can magnify fluctuations in population abundance (destabilize it) and then stabilize it again (so-called bubble effect). PMID- 22200541 TI - Treatments to restore respiratory function after spinal cord injury and their implications for regeneration, plasticity and adaptation. AB - Spinal cord injury (SCI) often leads to impaired breathing. In most cases, such severe respiratory complications lead to morbidity and death. However, in the last few years there has been extensive work examining ways to restore this vital function after experimental spinal cord injury. In addition to finding strategies to rescue breathing activity, many of these experiments have also yielded a great deal of information about the innate plasticity and capacity for adaptation in the respiratory system and its associated circuitry in the spinal cord. This review article will highlight experimental SCI resulting in compromised breathing, the various methods of restoring function after such injury, and some recent findings from our own laboratory. Additionally, it will discuss findings about motor and CNS respiratory plasticity and adaptation with potential clinical and translational implications. PMID- 22200544 TI - An experimental investigation of the role of negative mood in worry: the role of appraisals that facilitate systematic information processing. AB - BACKGROUND AND OBJECTIVES: Negative mood is associated with increased worry levels, and also with deployment of a systematic information processing style. An experimental study assessed the potential role of systematic information processing in mediating the facilitative effect of negative mood on worry (e.g. Johnston & Davey, 1997). METHOD: Participants underwent appropriate vignette based mood inductions (negative, neutral, and cognitive priming). Participants completed visual analogue scales measuring variables that reflect a raised processing sufficiency threshold and are known to increase systematic processing (responsibility, accountability, desire for control, and need for cognition), a measure of 'as many as can' worry stop rule deployment, and two measures of worry (the catastrophising interview and the Penn State Worry Questionnaire, PSWQ, Meyer, Miller, Metzger, & Borkovec, 1990). RESULTS: Experimentally-induced negative mood facilitated the endorsement of cognitive appraisals known to increase systematic as opposed to heuristic information processing. In addition, a meditational analysis showed that the systematic processing facilitators measure together with a measure of 'as many as can' worry stop rule deployment fully mediated the relationship between negative mood and a measure of worry frequency (PSWQ). LIMITATIONS: Future studies should develop and validate direct measures of systematic processing. CONCLUSIONS: Similarities and differences between systematic processing and chronic worrying as effortful forms of information processing are discussed, and a role for systematic processing as an information processing style relevant to understanding worrisome thought is described. PMID- 22200545 TI - The relationship between cognitive control and posttraumatic stress symptoms. AB - BACKGROUND AND OBJECTIVES: Recently researchers have theorized that individual differences in cognitive control (i.e., the ability to complete goal-directed behavior by actively maintaining information while inhibiting irrelevant information) may elucidate processes involved in disorders characterized by intrusive thoughts and memories. By this account, the relationship between cognitive control and emotional disorders would be specific to symptoms associated with intrusive cognitions, such as re-experiencing symptoms of posttraumatic stress disorder (PTSD). METHODS: In the present study, 77 undergraduate participants with a self-reported history of trauma exposure were administered assessments of cognitive control (working memory capacity; WMC), PTSD symptoms, trait anxiety, and depression. PTSD symptoms from each of the three symptom clusters (re-experiencing, avoidance, and hyperarousal) were predicted from trait anxiety, depression, and WMC performance scores using separate regression models. RESULTS: After controlling for trait anxiety and depression, there was a negative, statistically significant relationship between cognitive control and re-experiencing symptoms but not avoidance or hyperarousal symptoms. LIMITATIONS: The study was completed cross-sectionally and did not include a diagnostic assessment of PTSD. CONCLUSIONS: Findings add to extant literature suggesting a relationship between cognitive control and intrusive cognitions. Moreover, the present study expands the current literature by demonstrating the specificity of this relationship within individuals with varying degrees of PTSD symptom severity. PMID- 22200547 TI - Apomorphine-evoked redistribution of neurokinin-3 receptors in dopaminergic dendrites and neuronal nuclei of the rat ventral tegmental area. AB - Mammalian neurokinin-3 (NK(3)) receptors of the tachykinin family of neuropeptides have been shown to activate dopaminergic neurons of the ventral tegmental area (VTA), a midbrain area displaying dopaminergic dysfunctional activity in schizophrenia. The recent finding of NK(3) receptors in VTA neuronal nucleus highlights a new level of neuromodulation, in addition to the traditional tachykinin-induced NK(3) receptor internalization and activation of second messenger signaling pathways. The function of nuclear NK(3) receptors is still unknown. It is also unclear how dopaminergic activation is affecting the NK(3) receptor distribution in the VTA. In the present study, trafficking of the NK(3) receptor in somatodendritic profiles of dopaminergic and non-dopaminergic neurons of the rat VTA was investigated following acute systemic administration of the dopamine D(1)/D(2) receptor agonist apomorphine. VTA sections were dual immunolabeled for the NK(3) receptor (immunogold) and the dopamine synthesizing enzyme tyrosine hydroxylase (TH, immunoperoxidase). Electron microscopic quantifications of somatic and dendritic densities of NK(3) immunogold particles with or without TH immunolabeling were compared in vehicle-injected or apomorphine-injected rats. In dopaminergic (TH) neurons, apomorphine evoked a significant increase in NK(3) receptor densities in cytoplasmic and nuclear portions of the soma. These changes were accompanied by a respective decrease and increase in plasmalemmal and cytoplamic NK(3) receptor densities in dopaminergic dendrites. In non-TH neurons, presumably GABAergic neurons of the VTA, the NK(3) receptor densities in somata and dendrites were not significantly altered by apomorphine. The results suggest that dopaminergic receptor activation is inducing a rapid mobilization of NK(3) receptors in VTA dopaminergic neurons. The apomorphine-evoked NK(3) receptors plasticity might reflect dendritic internalization and translocation of NK(3) receptors toward the soma and nucleus. This trafficking is not observed in non-dopaminergic neurons of the VTA. The selective apomorphine-evoked redistribution of VTA NK(3) receptors might have important implications in normal or pathological conditions such as schizophrenia. PMID- 22200546 TI - Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison with the neuropathy induced by paclitaxel. AB - Anti-neoplastic agents in the platinum-complex, taxane, vinca alkaloid, and proteasome-inhibitor classes induce a dose-limiting, chronic, distal, symmetrical, sensory peripheral neuropathy that is often accompanied by neuropathic pain. Clinical descriptions suggest that these conditions are very similar, but clinical data are insufficient to determine the degree of similarity and to determine if they share common pathophysiological mechanisms. Animal models do not have the limitations of clinical studies and so we have characterized a rat model of chronic painful peripheral neuropathy induced by a platinum-complex agent, oxaliplatin, in order to compare it with a previously characterized model of chronic painful peripheral neuropathy induced by a taxane agent, paclitaxel. The oxaliplatin model evokes mechano-allodynia, mechano hyperalgesia, and cold-allodynia that have a delayed onset, gradually increasing severity, a distinct delay to peak severity, and duration of about 2.5 months. There is no effect on heat sensitivity. Electron microscopy (EM) analyses found no evidence for axonal degeneration in peripheral nerve, and there is no upregulation of activating transcription factor-3 in the lumbar dorsal root ganglia. There is a statistically significant loss of intraepidermal nerve fibers in the plantar hind paw skin. Oxaliplatin treatment causes a significant increase in the incidence of swollen and vacuolated mitochondria in peripheral nerve axons, but not in their Schwann cells. Nerve conduction studies found significant slowing of sensory axons, but no change in motor axons. Single fiber recordings found an abnormal incidence of A- and C-fibers with irregular, low-frequency spontaneous discharge. Prophylactic dosing with two drugs that are known to protect mitochondria, acetyl-l-carnitine and olesoxime, significantly reduced the development of pain hypersensitivity. Our results are very similar to those obtained previously with paclitaxel, and support the hypothesis that these two agents, and perhaps other chemotherapeutics, produce very similar conditions because they have a mitotoxic effect on primary afferent neurons. PMID- 22200548 TI - Hypoxic preconditioning attenuates global cerebral ischemic injury following asphyxial cardiac arrest through regulation of delta opioid receptor system. AB - This study was designed to investigate whether delta opioid receptor (DOR) is involved in the neuroprotective effect induced by hypoxic preconditioning (HPC) in the asphyxial cardiac arrest (CA) rat model. Twenty-four hours after the end of 7-day HPC, the rats were subjected to 8-min asphyxiation and resuscitated with a standardized method. In the asphyxial CA rat model, HPC improved the neurological deficit score (NDS), inhibited neuronal apoptosis, and increased the number of viable hippocampal CA1 neurons at 24 h, 72 h, or 7 days after restoration of spontaneous circulation (ROSC); however, the above-mentioned neuroprotection of HPC was attenuated by naltrindole (a selective DOR antagonist). The expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and DOR, and the content of leucine enkephalin (L-ENK) in the brain were also investigated after the end of 7-day HPC. HPC upregulated the neuronal expression of HIF-1alpha and DOR, and synchronously elevated the content of L-ENK in the rat brain. HIF-1alpha siRNA was used to further elucidate the relationship between HIF-1alpha and DOR in the HPC-treated brain. Knockdown of HIF-1alpha by siRNA markedly abrogated the HPC induced upregulation of HIF-1alpha and DOR. The present study demonstrates that the expression of DOR in the rat brain is upregulated by HIF-1alpha following exposure to 7-day HPC, at the same time, HPC also increases the production of endogenous DOR ligand L-ENK in the brain. DOR activation after HPC results in prolonged neuroprotection against subsequent global cerebral ischemic injury, suggesting a new mechanism of HPC-induced neuroprotection on global cerebral ischemia following CA and resuscitation. PMID- 22200549 TI - Quantitative real-time PCR (qPCR) detection chemistries affect enumeration of the Dehalococcoides 16S rRNA gene in groundwater. AB - Quantitative real-time PCR (qPCR) commonly uses the fluorogenic 5' nuclease (TaqMan) and SYBR Green I (SG) detection chemistries to enumerate biomarker genes. Dehalococcoides (Dhc) are keystone bacteria for the detoxification of chlorinated ethenes, and the Dhc 16S ribosomal RNA (rRNA) gene serves as a biomarker for monitoring reductive dechlorination in contaminated aquifers. qPCR enumeration of Dhc biomarker genes using the TaqMan or SG approach with the same primer set yielded linear calibration curves over a seven orders of magnitude range with similar amplification efficiencies. The TaqMan assay discriminates specific from nonspecific amplification observed at low template concentrations with the SG assay, and had a 10-fold lower limit of detection of ~3 copies per assay. When applied to Dhc pure cultures and Dhc-containing consortia, both detection methods enumerated Dhc biomarker genes with differences not exceeding 3 fold. Greater variability was observed with groundwater samples, and the SG chemistry produced false-positive results or yielded up to 6-fold higher biomarker gene abundances compared to the TaqMan method. In most cases, the apparent error associated with SG detection resulted from quantification of nonspecific amplification products and was more pronounced with groundwater samples that had low biomarker concentrations or contained PCR inhibitors. Correction of the apparent error using post-amplification melting curve analysis produced 2 to 21-fold lower abundance estimates; however, gel electrophoretic analysis of amplicons demonstrated that melting curve analysis was insufficient to recognize all nonspecific amplification. Upon exclusion of nonspecific amplification products identified by combined melting curve and electrophoretic amplicon analyses, the SG method produced false-negative results compared to the TaqMan method. To achieve sensitive and accurate quantification of Dhc biomarker genes in environmental samples (e.g., groundwater) and avoid erroneous conclusions, the analysis should rely on TaqMan detection chemistry, unless additional analyses validate the results obtained with the SG approach. PMID- 22200550 TI - Improved biovar test for Ralstonia solanacearum. AB - Race 3, biovar 2 strains of Ralstonia solanacearum are quarantined pathogens in Europe and Canada and Select Agent pathogens in the United States. The biovar classification of R. solanacearum strains is based on their biochemical abilities to utilize a carbohydrate panel. The standard biovar test uses bromothymol blue as a pH indicator in 15 ml culture tubes containing 3 to 5 ml of test media, and takes weeks to complete at 24 or 28 degrees C. We improved the biovar test by using phenol red as a pH indicator that changes color at a higher pH when a carbohydrate is utilized. We also conducted the test at 32 degrees C in 0.2 ml of 8-tube strips that reduced the medium needed by at least 20 fold. Using the improved test, biovars of R. solanacearum strains can be determined in 4 days when a panel of seven carbohydrates is used including glucose, trehalose, mannitol, sorbitol, dulcitol, maltose and cellobiose. To differentiate biovars 1, 2, 3 and 4, the test can be further simplified and completed in 3 days using a panel of four carbohydrates containing glucose, trehalose, maltose and dulcitol, significantly saving money, space and time. PMID- 22200551 TI - Identification of molecular pathways involved in oxaliplatin-associated sinusoidal dilatation. AB - BACKGROUND & AIMS: Oxaliplatin-based chemotherapy for colorectal liver metastases (CRLM) can result in vascular liver lesions such as sinusoidal dilatations. Physiopathology remains unclear and variability between patients suggests that there is individual susceptibility. A better understanding of the molecular mechanisms of oxaliplatin liver toxicity may allow the identification of biomarkers and adaptation of chemotherapy delivery. METHODS: Between 1998 and 2009, 83 non-tumor frozen liver samples were obtained from patients operated on for CRLM after an exclusive oxaliplatin-based chemotherapy. Gene-expression profiles were first analyzed by microarray on a selected population of 19 patients: 9 patients with severe sinusoidal dilatation after a short period of chemotherapy and 10 patients without any sinusoidal dilatation after a long period of chemotherapy. These were compared with a control group of 5 patients without any chemotherapy and lesions. Twenty-two differentially-expressed (at least 1.5-fold difference in expression) genes were selected. These were validated using microfluidic quantitative RT-PCR in an independent set of 58 patients (28 with sinusoidal dilatation and 30 without sinusoidal dilatation). RESULTS: Among the 22 selected genes, 12 were validated as being up-regulated in samples from patients with sinusoidal dilatation compared to patients without sinusoidal dilatation. Genes involved in angiogenesis (VEGFD, THY-1, GPNMB) and cellular adhesion (VWF, CDH13, THBS2), and extracellular matrix components (COL1A1, COL4A1, SLCO1A2) were over-represented in patients with sinusoidal dilatation. CONCLUSIONS: This molecular signature confirms the involvement of angiogenesis and coagulation in sinusoidal injuries induced by oxaliplatin and reinforces a potential protective role of bevacizumab and aspirin, as suggested in retrospective clinical studies. PMID- 22200553 TI - Metabonomic profiles discriminate hepatocellular carcinoma from liver cirrhosis by ultraperformance liquid chromatography-mass spectrometry. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and usually develops in patients with liver cirrhosis (LC). Biomarkers that discriminate HCC from LC are important but are limited. In the present study, an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS)-based metabonomics approach was used to characterize serum profiles from HCC (n = 82), LC (n = 48), and healthy subjects (n = 90), and the accuracy of UPLC-MS profiles and alpha-fetoprotein (AFP) levels were compared for their use in HCC diagnosis. By multivariate data and receiver operating characteristic curves analysis, metabolic profiles were capable of discriminating not only patients from the controls but also HCC from LC with 100% sensitivity and specificity. Thirteen potential biomarkers were identified and suggested that there were significant disturbances of key metabolic pathways, such as organic acids, phospholipids, fatty acids, bile acids, and gut flora metabolism, in HCC patients. Canavaninosuccinate was first identified as a metabolite that exhibited a significant decrease in LC and an increase in HCC. In addition, glycochenodeoxycholic acid was suggested to be an important indicator for HCC diagnosis and disease prognosis. UPLC-MS signatures, alone or in combination with AFP levels, could be an efficient and convenient tool for early diagnosis and screening of HCC in high-risk populations. PMID- 22200554 TI - Atmospheric radionuclides from the Fukushima Dai-ichi nuclear reactor accident observed in Vietnam. AB - Radionuclides from the reactor accident at the Fukushima Dai-ichi Nuclear Power Plant were observed in the surface air at stations in Hanoi, Dalat, and Ho Chi Minh City (HCMC) in Vietnam, about 4500 km southwest of Japan, during the period from March 27 to April 22, 2011. The maximum activity concentrations in the air measured at those three sites were 193, 33, and 37 MUBq m(-3) for (131)I, (13)(4)Cs, and (13)(7)Cs, respectively. Peaks of radionuclide concentrations in the air corresponded to arrival of the air mass from Fukushima to Vietnam after traveling for 8 d over the Pacific Ocean. Cesium-134 was detected with the (134)Cs/(137)Cs activity ratio of about 0.85 in line with observations made elsewhere. The (131)I/(137)Cs activity ratio was observed to decrease exponentially with time as expected from radioactive decay. The ratio at Dalat, where is 1500 m high, was higher than those at Hanoi and HCMC in low lands, indicating the relative enrichment of the iodine in comparison to cesium at high altitudes. The time-integrated surface air concentrations of the Fukushima derived radionuclides in the Southeast Asia showed exponential decrease with distance from Fukushima. PMID- 22200556 TI - Simultaneous water desalination and electricity generation in a microbial desalination cell with electrolyte recirculation for pH control. AB - A recirculation microbial desalination cell (rMDC) was designed and operated to allow recirculation of solutions between the anode and cathode chambers. This recirculation avoided pH imbalances that could inhibit bacterial metabolism. The maximum power density was 931+/-29mW/m(2) with a 50mM phosphate buffer solution (PBS) and 776+/-30mW/m(2) with 25mM PBS. These power densities were higher than those obtained without recirculation of 698+/-10mW/m(2) (50mM PBS) and 508+/ 11mW/m(2) (25mM PBS). The salt solution (20g/L NaCl) was reduced in salinity by 34+/-1% (50mM) and 37+/-2% (25mM) with recirculation (rMDC), and by 39+/-1% (50mM) and 25+/-3% (25mM) without recirculation (MDC). These results show that electrolyte recirculation using an rMDC is an effective method to increase power and achieve efficient desalination by eliminating pH imbalances. PMID- 22200557 TI - Deactivation of individual cellulase components. AB - Deactivation extents of cellobiohydrolase, endoglucanase, and a total cellulase mixture (Spezyme CP) were studied independently as functions of incubating time and mixing intensity. It was found that the decrease in total cellulase activity was more strongly related to deactivation of cellobiohydrolase 1 (CBH1) than endoglucanase. The mass-averaged shear in orbiting flasks at 50, 150, and 250rpm was quantified by computational fluid dynamics and was two-orders smaller than shear in typical stirred tanks. Endoglucanase activity did not change significantly with mixing speed, but CBH1 and total cellulase activities were 10 25% higher at 250rpm compared to the lower speeds after a 24-h incubation. Total deactivation due to mechanical mixing (~20%) may be too low to account for all the rate reduction during cellulose hydrolysis. Thermal deactivation was independent of enzyme concentration while deactivation due to mechanical stress decreased when cellulase loading increased over 0.15 filterpaperunit/ml. PMID- 22200558 TI - Common copy number variations in fifty radiosensitive cell lines. AB - Hypersensitivity to radiation exposure is a major challenge to radiotherapy in the treatment of cancer patients. Copy number variations (CNVs) are believed to identify genomic regions of functional significance for radiosensitivity (RS) but have yet to be systematically investigated. We used Affymetrix 6.0 SNP arrays to survey common CNVs in a cohort of 50 radiosensitive lymphoblastoid cell lines (RS LCLs) derived from patients with undiagnosed diseases. A total of 317 CNVs that were present in at least 10% of the studied cell lines were identified. Three hundred and eight CNVs overlapped with polymorphic CNVs, 13 of which were significantly enriched in the RS-LCLs compared to the reference. The remaining 9 CNVs were novel. The majority of these enriched and novel CNVs were chromosomal gains. The dominance of the chromosomal gains over losses is inconsistent with the traditional concept of molecular basis of RS and suggests more complex genetic mechanisms for RS. PMID- 22200559 TI - Facial emotion triggered cerebral potentials in treatment-resistant depression and borderline personality disorder patients of both genders. AB - BACKGROUND: Processing facial expressions of emotion is deteriorated in depression, which might be more pronounced in treatment-resistant depression (TRD), especially when the latter is comorbid with borderline personality disorder (BPD). Neurophysiologically, both early perceptual and late cognitive cerebral processes of facial emotions can be illustrated by event-related potentials (ERPs). METHODS: We therefore tried the ERPs to facial expressions of Neutral, Anger, Happiness, and Sadness in 25 patients with TRD, 15 with BPD, 22 with their comorbidity (TRD+BPD), as well as in 37 healthy volunteers. The depression levels of participants were measured with the Plutchik-van Praag Depressive Inventory (PVP). RESULTS: There was no group difference regarding either N1 (N170), P2, N2, P3a or P3b latency or amplitude to the four facial emotions. Reaction times (RTs) to Anger (p<.01), Happiness (p<.01), and Sadness (p<.001) in TRD, and those to Anger (p<.01) and Happiness (p<.01) in TRD+BPD patients were longer than those in the healthy volunteers. RTs to the four facial expressions were positively correlated (p<.01) with their depressive moods in all participants. In addition, PVP was positively correlated with the P2 latency to Anger in TRD+BPD patients (Fz, p<.01; Cz, p<.01; Pz, p<.01). CONCLUSIONS: BPD contributed little to TRD or TRD+BPD regarding cerebral processing of facial emotions, however, other cognitive and behavioral data suggest a generalized impairment when responding to facial emotions in TRD and TRD+BPD patients, and a deteriorated perceptual processing of Anger in TRD+BPD patients. PMID- 22200560 TI - Melatonin: neuritogenesis and neuroprotective effects in crustacean x-organ cells. AB - Melatonin has both neuritogenic and neuroprotective effects in mammalian cell lines such as neuroblastoma cells. The mechanisms of action include receptor coupled processes, direct binding and modulation of calmodulin and protein kinase C, and direct scavenging of free radicals. While melatonin is produced in invertebrates and has influences on their physiology and behavior, little is known about its mechanisms of action. We studied the influence of melatonin on neuritogenesis in well-differentiated, extensively-arborized crustacean x-organ neurosecretory neurons. Melatonin significantly increased neurite area in the first 24h of culture. The more physiological concentrations, 1 nM and 1 pM, increased area at 48 h also, whereas the pharmacological 1 MUM concentration appeared to have desensitizing effects by this time. Luzindole, a vertebrate melatonin receptor antagonist, had surprising and significant agonist-like effects in these invertebrate cells. Melatonin receptors have not yet been studied in invertebrates. However, the presence of membrane-bound receptors in this population of crustacean neurons is indicated by this study. Melatonin also has significant neuroprotective effects, reversing the inhibition of neuritogenesis by 200 and 500 MUM hydrogen peroxide. Because this is at least in part a direct action not requiring a receptor, melatonin's protection from oxidative stress is not surprisingly phylogenetically-conserved. PMID- 22200561 TI - Relationship between thiol, tyrosine nitration and carbonyl formation as biomarkers of oxidative stress and changes of hemostatic function of plasma from breast cancer patients before surgery. AB - OBJECTIVES: In breast cancer patients dysregulation of reactive oxygen species metabolism, as detected by various indicators in plasma or various blood cells, including red blood cells and blood platelets, is observed. DESIGN AND METHODS: The aim of our study was to explain the effect of oxidative/nitrative stress on hemostatic activity of plasma from breast cancer patients. Different methods were used to analyze oxidative/nitrative stress (carbonyl groups and 3-nitrotyrosine levels - ELISA and C-ELISA method, respectively and free thiol groups was estimated with 5,5'-dithio-bis(2-nitro-benzoic acid)). We also measured total antioxidant status (TAS) in plasma. RESULTS: Our results showed the correlation between the oxidative stress and changes of hemostasis in breast cancer patients; the correlation between the increased amount of carbonylated or nitrated plasma proteins and fibrin polymerization or lysis in plasma isolated from invasive breast cancer patients. We also observed that the relationship between TAS and fibrin polymerization or lysis in plasma from invasive breast cancer exists. CONCLUSION: Considering the data presented in this study, we suggest that the oxidative/nitrative stress in breast cancer patients may induce the changes of hemostasis in these patients. PMID- 22200562 TI - beta37Trp->Cys mutation leads to multiple new hemoglobin species in red cells. AB - OBJECTIVES: To determine the cause of an unusual hemoglobin (Hb) pattern detected during HbA(1)c monitoring. DESIGN AND METHOD: Hemolysate was analysed by ESI MS, and individual components purified by reverse phase HPLC. Peptide mapping was used to pinpoint the substitution and DNA sequencing to confirm the mutation. RESULTS: ESI MS of lysate showed three novel beta chains with mass changes of 83, -51 and +222 Da. Peptide mapping and DNA sequencing indicated a beta37Trp >Cys substitution. Reverse phase chromatography showed three new beta globins eluting ahead of beta(A) CONCLUSION: The new Hbs result from an initial beta37Trp >Cys mutation (-83 Da) followed by oxidation to cysteine sulfinic acid (+32 Da) and the formation of a glutathione adduct (+305 Da). Despite the hydrophobicity change and the critical location of the side chain on the alpha1beta2 interface, there was no evidence of molecular instability or altered oxygen affinity, and no clear phenotype apart from discordant HbA(1)c. PMID- 22200563 TI - Matrix metalloproteinase 9 mRNA: an early prognostic marker for patients with acute stroke. AB - OBJECTIVES: To investigate matrix metalloproteinase 9 (MMP9) mRNA as a prognostic marker in stroke. DESIGN AND METHODS: MMP9 mRNA concentrations in 126 stroke patients were analyzed using quantitative reverse transcription-polymerase chain reaction. RESULTS: The normalized MMP9 mRNA concentration was almost 3 times higher in non-survival patients compared to survival patients (P=0.0002); and 1.9 fold higher in patients with post-stroke modified Rankin score (mRS) >2 than patients with mRS<=2 (P<0.05). CONCLUSIONS: MMP9 mRNA was a predictor of poor outcome and mortality in stroke. PMID- 22200565 TI - Deterministic schedules for robust and reproducible non-uniform sampling in multidimensional NMR. AB - We show that a simple, general, and easily reproducible method for generating non uniform sampling (NUS) schedules preserves the benefits of random sampling, including inherently reduced sampling artifacts, while removing the pitfalls associated with choosing an arbitrary seed. Sampling schedules are generated from a discrete cumulative distribution function (CDF) that closely fits the continuous CDF of the desired probability density function. We compare random and deterministic sampling using a Gaussian probability density function applied to 2D HSQC spectra. Data are processed using the previously published method of Spectroscopy by Integration of Frequency and Time domain data (SIFT). NUS spectra from deterministic sampling schedules were found to be at least as good as those from random schedules at the SIFT critical sampling density, and significantly better at half that sampling density. The method can be applied to any probability density function and generalized to greater than two dimensions. PMID- 22200566 TI - A compact high-speed mechanical sample shuttle for field-dependent high resolution solution NMR. AB - Analysis of NMR relaxation data has provided significant insight on molecular dynamic, leading to a more comprehensive understanding of macromolecular functions. However, traditional methodology allows relaxation measurements performed only at a few fixed high fields, thus severely restricting their potential for extracting more complete dynamic information. Here we report the design and performance of a compact high-speed servo-mechanical shuttle assembly adapted to a commercial 600 MHz high-field superconducting magnet. The assembly is capable of shuttling the sample in a regular NMR tube from the center of the magnet to the top (fringe field ~0.01 T) in 100 ms with no loss of sensitivity other than that due to intrinsic relaxation. The shuttle device can be installed by a single experienced user in 30 min. Excellent 2D-(15)N-HSQC spectra of (u (13)C, (15)N)-ubiquitin with relaxation at low fields (3.77 T) and detection at 14.1T were obtained to illustrate its utility in R(1) measurements of macromolecules at low fields. Field-dependent (13)C-R(1) data of (3,3,3-d) alanine at various field strengths were determined and analyzed to assess CSA and (1)H-(13)C dipolar contributions to the carboxyl (13)C-R(1). PMID- 22200564 TI - Mitochondrial oxidative stress and epilepsy in SOD2 deficient mice: attenuation by a lipophilic metalloporphyrin. AB - Epileptic seizures are a common feature associated with inherited mitochondrial diseases. This study investigated the role of mitochondrial oxidative stress in epilepsy resulting from mitochondrial dysfunction using cross-bred mutant mice lacking mitochondrial manganese superoxide dismutase (MnSOD or SOD2) and a lipophilic metalloporphyrin catalytic antioxidant. Video-EEG monitoring revealed that in the second to third week of postnatal life (P14-P21) B6D2F2 Sod2(-/-) mice exhibited frequent spontaneous motor seizures providing evidence that oxidative stress-induced mitochondrial dysfunction may contribute to epileptic seizures. To confirm the role of mitochondrial oxidative stress in epilepsy a newly developed lipophilic metalloporphyrin, AEOL 11207, with high potency for catalytic removal of endogenously generated reactive oxygen species was utilized. AEOL 11207-treated Sod2(-/-) mice showed a significant decrease in both the frequency and duration of spontaneous seizures but no effect on seizure severity. A significant increase in the average lifespan of AEOL 11207-treated Sod2(-/-) mice compared to vehicle-treated Sod2(-/-) mice was also observed. Indices of mitochondrial oxidative stress and damage (aconitase inactivation, 3 nitrotyrosine formation, and depletion of reduced coenzyme A) and ATP levels affecting neuronal excitability were significantly attenuated in the brains of AEOL 11207-treated Sod2(-/-) mice compared to vehicle-treated Sod2(-/-) mice. The occurrence of epileptic seizures in Sod2(-/-) mice and the ability of catalytic antioxidant therapy to attenuate seizure activity, mitochondrial dysfunction, and ATP levels suggest that ongoing mitochondrial oxidative stress can contribute to epilepsy associated with mitochondrial dysfunction and disease. PMID- 22200567 TI - Relationship between disability and health-related quality of life and caregiver burden in patients with upper limb poststroke spasticity. AB - OBJECTIVE: To evaluate the relationship between disability and both health related quality of life (HRQoL) and caregiver burden in patients with upper limb poststroke spasticity. DESIGN: Multicenter open-label study. SETTING: Thirty-five sites in North America. PARTICIPANTS: Patients (N = 279) with upper limb poststroke spasticity. METHODS: Post hoc analyses of data from an open-label study were performed to estimate HRQoL and caregiver burden at study baseline across levels of disability in 4 problem domains: hygiene, dressing, limb posture, and pain. Disability severity in these areas was determined by using the 4-point Disability Assessment Scale rated by the physicians. MAIN OUTCOME MEASUREMENTS: HRQoL measured by the patient-reported EuroQol 5 Dimensions questionnaire and the Stroke-Adapted Sickness Impact Profile and caregiver burden. RESULTS: At study baseline, increasing disability in the hygiene, dressing, and pain domains of the Disability Assessment Scale was associated with diminishing HRQoL scores (P < .002) measured by the EuroQol 5 Dimensions. By using the Stroke-Adapted Sickness Impact Profile, greater disability scores in all problem domains were significantly associated with higher overall dysfunction scores (P <= .05). Within the physical dimension of the Stroke-Adapted Sickness Impact Profile, significant associations also were observed in all domains. At baseline, caregiver burden was significantly related to increasing levels of hygiene and dressing domain severity (P <= .05). Caregiver assistance requirement increased from approximately 9.0-28.2 hours per week in the hygiene domain and 3.3-32.1 hours per week in the dressing domain as disability increased from "none" to "severe." CONCLUSIONS: In patients with upper limb poststroke spasticity, increasing disability in the hygiene, dressing, and pain domains of the Disability Assessment Scale were associated with diminishing HRQoL. Furthermore, these patients required caregiver assistance proportionally related to the severity of their disability in the hygiene and dressing domains. PMID- 22200568 TI - Cloning and characterization of homeologous cellulose synthase catalytic subunit 2 genes from allotetraploid cotton (Gossypium hirsutum L.). AB - Cellulose synthase catalytic subunits (CesAs) are the catalytic sites within a multisubunit complex for cellulose biosynthesis in plants. CesAs have been extensively studied in diploid plants, but are not well characterized in polyploid plants. Gossypium hirsutum is an allotetraploid cotton species producing over 90% of the world's cotton fibers. Although G. hirsutum CesAs (GhCesAs) are responsible for cellulose production in cotton fiber, very limited numbers of GhCesA genes have been identified. Here, we report isolating and characterizing a pair of homeologous CesA2 genes and their full-length cDNAs from allotetraploid cotton. The GhCesA2-A(T) gene from the A-subgenome and GhCesA2 D(T) gene from the D-subgenome were screened from a G. hirsutum BAC library. These genes shared 92% sequence similarity throughout the entire sequence. The coding sequences were nearly identical, and the deduced amino acid sequences from GhCesA2-A(T) (1,039 amino acids) and GhCesA2-D(T) (1,040 amino acids) were identical except four amino acids, whereas the noncoding sequences showed divergence. Sequence analyses showed that all exons of GhCesA2-A(T) contained consensus splice donor dinucleotides, but one exon in GhCesA2-D(T) contained nonconsensus splice donor dinucleotides. Although the nonconsensus splice donor dinucleotides were previously suggested to be involved in alternative splice or pseudogenization, our results showed that a majority of GhCesA2-A(T) and GhCesA2 D(T) transcripts consisted of functional and full-length transcripts with little evidence for alternative mRNA isoforms in developing cotton fibers. Expression analyses showed that GhCesA2-A(T) and GhCesA2-D(T) shared common temporal and spatial expression patterns, and they were highly and preferentially expressed during the cellulose biosynthesis stage in developing cotton fibers. The observations of higher expression levels of both GhCesA2-A(T) and GhCesA2-D(T) in developing fibers of one near-isogenic line (NIL) with higher fiber bundle strength over the other NIL with lower fiber bundle strength suggested that the differential expression of genes associated with secondary cell wall cellulose biosynthesis in developing fiber might affect cotton fiber properties. PMID- 22200569 TI - TLR1 polymorphisms in Europeans and spontaneous pregnancy loss. AB - Toll-like receptors (TLRs) are critical components of the pathogen recognition by the host innate immune system. Recently it has been shown that TLR1 is under evolutionary pressure in Europeans. This involves the positive selection of the nonsynonymous TLR1 1805G variant in Europeans, although this is associated with poor TLR1 response and unfavorable prognosis in various infections. In terms of natural selection, differential fertility is another mechanism, independent of infection susceptibility, that may explain the polymorphism pattern observed for TLR1. To test this hypothesis, we assessed the correlation of two TLR1 SNPs (T1805G and G239C) with spontaneous pregnancy loss in a case-control study that included 132 spontaneous pregnancy loss patients and 142 control volunteers. Similar allele frequencies of T1805G were observed between cases and controls, but GG genotype tended to be associated with pregnancy loss (OR 1.91; 95%CI 1.03, 3.53). No differences were observed for the TLR1 G239C SNP. Our findings showed slight differences in the distribution of T1805G variants in women with pregnancy loss, but these were not indicative of a protective effect of the TLR1 1805G allele for this fertility disorder. Although our hypothesis was not proven, potential effects of TLR1 polymorphisms on pregnancy outcome have been suggested, and future studies in larger cohorts are warranted. PMID- 22200570 TI - Effect of N-homocysteinylation on physicochemical and cytotoxic properties of amyloid beta-peptide. AB - Abstract Hyperhomocysteinemia has recently been identified as an important risk factor for Alzheimer's disease (AD). One of the potential mechanisms underlying harmful effects of homocysteine (Hcy) is site-specific acylation of proteins at lysine residues by homocysteine thiolactone (HCTL). The accumulation of amyloid beta-peptide (Abeta) in the brain is a neuropathological hallmark of AD. In the present study we were interested to investigate the effects of N homocysteinylation on the aggregation propensity and neurotoxicity of Abeta(1 42). By coupling several techniques, we demonstrated that the homocysteinylation of lysine residues increase the neurotoxicity of the Abeta peptide by stabilizing soluble oligomeric intermediates. PMID- 22200571 TI - Dissociation of the insulin receptor from caveolae during TNFalpha-induced insulin resistance and its recovery by D-PDMP. AB - Previously, we demonstrated that an inhibitor of ganglioside biosynthesis, d PDMP, could restore impaired insulin signaling in tumor necrosis factor alpha (TNFalpha)-treated adipocytes by blocking the increase of GM3 ganglioside. Here, we analyzed the interaction between insulin receptor (IR) and GM3 in the plasma membranes using immunoelectron microscopy. In normal adipocytes, most GM3 molecules localized at planar and non-caveolar regions. Approximately 19% of IR molecules were detected in caveolar regions. The relative ratio of IRs associated with caveolae in TNFalpha-treated adipocytes was decreased to one-fifth of that in normal adipocytes, but this decrease was restored by d-PDMP. Thus, we could obtain direct evidence that insulin resistance is a membrane microdomain disorder caused by aberrant expression of ganglioside. PMID- 22200572 TI - A novel family of toxin/antitoxin proteins in Bacillus species. AB - The C-terminal regions (CT) of Pfam PF04740 proteins share significant sequence identity with the toxic CdiA-CT effector domains of contact-dependent growth inhibition (CDI) systems. In accord with this homology, we find that several PF04740 CT domains inhibit cell growth when expressed in Escherichia coli. This growth inhibition is specifically blocked by antitoxin proteins encoded downstream of each PF04740 gene. The YobL-CT, YxiD-CT and YqcG-CT domains from Bacillus subtilis 168 have cytotoxic RNase activities, which are neutralized by the binding of cognate YobK, YxxD and YqcF antitoxin proteins, respectively. Our results show that PF04740 proteins represent a new family of toxin/antitoxin pairs that are widely distributed in Gram-positive bacteria. PMID- 22200573 TI - Formation of supramolecular structures of a native-like protein in the presence of amphiphilic peptides: Variations in aggregate morphology. AB - A striking potential of the amphiphilic dipeptides, Arg-Phe or Asp-Phe, to induce aggregation of a model protein, alcohol dehydrogenase in its native-like state, has been demonstrated under physiologically relevant conditions, using dynamic light scattering, fluorescence spectroscopy, circular dichroism, transmission electron- and atomic force microscopy. The peptide action resulted in accumulation of a variety of morphologically distinct supramolecular structures profoundly differing from those generated by the heat-induced aggregation at the early stages of the process, when amyloid fibril assemblies were not detectable. The biogenic amphiphilic agents are suggested to act as regulators of structural transformations of native-like proteins. PMID- 22200576 TI - Variation in macrophage migration inhibitory factor [MIF] immunoreactivity during bovine gestation. AB - Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in several aspects of the immune response. MIF appears to play important roles in materno-fetal immuno-tolerance during placental establishment, modulation and growth as studied in epitheliochorial porcine and hemochorial human and mouse placentae. Here we studied the bovine placenta being multiplex, villous and synepitheliochorial with a low degree of invasion, to see if MIF could be involved. Placental tissues sampled from 12 cows at 9 stages of gestation (days 18-250), and endometrial tissues from two non-pregnant animals were processed for immunohistochemistry. Bovine MIF was detected by Western blot using anti-human MIF monoclonal antibodies. An immunoreactive band of approximately 12kDa confirmed similarities between bovine and human MIFs. Compared to the non-pregnant stage with very faint staining, the caruncular epithelium during pregnancy showed stronger staining for MIF. The intercaruncular epithelium in non-pregnant endometrium showed some reaction apically with increasing intensity at uterine gland openings; in contrast, at day 18 of gestation this staining was markedly increased. During gestation both caruncular and trophoblast epithelium of the placentomes were positive with different intensity in relation to the gestational stage. In the uterine glands, some strongly stained cells were present. The mature binucleated trophoblast giant cells were negative throughout pregnancy. During reestablishment of vascularisation, the vasculature in the caruncular area showed MIF reactivity. While supporting involvement of MIF in different placental types, the spatio temporal variation in the bovine placenta suggests a regulatory role for MIF mainly in the interhemal barrier and during vascular development. PMID- 22200577 TI - Fc-mediated transport of nanoparticles across airway epithelial cell layers. AB - In a study directed towards non-invasive delivery of therapeutic biomacromolecules, we examined whether surface modification of sub-200 nm model nanoparticles with the Fc portion of IgG promotes their cell uptake and transport across the airway epithelial cells. The study initially confirms the expression of the relevant receptor, namely neonatal Fc receptor (FcRn), by Calu-3 cell layers simulating the airway epithelium and demonstrates FcRn-mediated cell association, internalization and transcellular transport of molecular IgG. Surface decoration of nanoparticles with the Fc portion of IgG enhanced both cell uptake and translocation of the particulate system across the cell layers, in a manner strongly suggesting FcRn involvement in these processes. The study further demonstrates the potential of Fc-modified nanoparticles to 'shuttle' a model therapeutic antibody fragment across the epithelial cell layers. Fc-modified nanoparticles are transported in the MUg/h/cm(2) range, presenting a substantial increase in transport capacity in comparison to molecular IgG (ng/h/cm(2) range), therefore warranting consideration of the FcRn transcytotic pathway for further investigation as a means to achieve transmucosal delivery of nanoparticulate systems that could act as carriers of a range of biotherapeutics. PMID- 22200574 TI - New stochastic carcinogenesis model with covariates: an approach involving intracellular barrier mechanisms. AB - In this paper we present a new multiple-pathway stochastic model of carcinogenesis with potential of predicting individual incidence risks on the basis of biomedical measurements. The model incorporates the concept of intracellular barrier mechanisms in which cell malignization occurs due to an inefficient operation of barrier cell mechanisms, such as antioxidant defense, repair systems, and apoptosis. Mathematical formalism combines methodological innovations of mechanistic carcinogenesis models and stochastic process models widely used in studying biodemography of aging and longevity. An advantage of the modeling approach is in the natural combining of two types of measures expressed in terms of model parameters: age-specific hazard rate and means of barrier states. Results of simulation studies allow us to conclude that the model parameters can be estimated in joint analyses of epidemiological data and newly collected data on individual biomolecular measurements of barrier states. Respective experimental designs for such measurements are suggested and discussed. An analytical solution is obtained for the simplest design when only age-specific incidence rates are observed. Detailed comparison with TSCE model reveals advantages of the approach such as the possibility to describe decline in risk at advanced ages, possibilities to describe heterogeneous system of intermediate cells, and perspectives for individual prognoses of cancer risks. Application of the results to fit the SEER data on cancer risks demonstrates a strong predictive power of the model. Further generalizations of the model, opportunities to measure barrier systems, biomedical and mathematical aspects of the new model are discussed. PMID- 22200578 TI - Novel biomarkers in diagnosing cardiac ischemia in the emergency department: a systematic review. AB - BACKGROUND: Novel biomarkers of myocardial ischemia and inflammatory processes have the potential to improve diagnostic accuracy of acute coronary syndrome (ACS) within a shorter time interval after symptom onset. OBJECTIVE: The objective was to review the recent literature and evaluate the evidence for use of novel biomarkers in diagnosing ACS in patients presenting with chest pain or symptoms suggestive of cardiac ischemia to the emergency department or chest pain unit. METHODS: A literature search was performed in MEDLINE, EMBASE, Cochrane DSR, ACP Journal Club, DARE, CCTR, CMR, HTA, and NHSEED for studies from 2004 to 2010. We used the inclusion criteria: (1) human subjects, (2) peer-reviewed articles, (3) enrolled patients with ACS, acute myocardial infarction or undifferentiated signs and symptoms suggestive of ACS, and (4) English language or translated manuscripts. Two reviewers conducted a hierarchical selection and assessment using a scale developed by the International Liaison Committee on Resuscitation. RESULTS: Out of a total 3194 citations, 58 articles evaluating 37 novel biomarkers were included for final review. Forty-one studies did not support the use of their respective biomarkers. Seventeen studies supported the use of 5 biomarkers, particularly when combined with cardiac-specific troponin: heart fatty acid-binding protein, ischemia-modified albumin, B-type natriuretic peptide, copeptin, and matrix metalloproteinase-9. CONCLUSION: In patients presenting to the emergency department with chest pain or symptoms suggestive of cardiac ischemia, there is inadequate evidence to suggest the routine testing of novel biomarkers in isolation. However, several novel biomarkers have the potential to improve the sensitivity of diagnosing ACS when combined with cardiac specific troponin. PMID- 22200579 TI - Basic life support: simulation, simplicity and survival. PMID- 22200580 TI - Differential expression of genes related to drug responsiveness between sparsely and densely granulated somatotroph adenomas. AB - There are two main subtypes of GH-producing pituitary adenoma: densely granulated (DG-type) and sparsely granulated (SG-type). Despite the difference in drug responsiveness between the two subtypes, their molecular mechanisms remain unknown. The aim of this study is to evaluate the differential expression of genes related to drug responsiveness between the two subtypes of somatotroph adenoma, and their relationship to the clinical characteristics. Eighty-two acromegaly patients (44 DG-type, 38 SG-type) were studied retrospectively. Clinical characteristics were compared between the two subtypes. Among them, 36 tumor tissue specimens (19 DG-type, 17 SG-type) were available for investigation of the expression of SSTR2, SSTR5 and D2R that are reported to be involved in drug responsiveness by realtime RT-PCR. Protein level was evaluated by immunohistochemical study. Patients with SG-type adenomas were younger in age and showed greater GH suppression by octreotide, but not by bromocriptin, and bigger in size and more invasiveness than DG-type adenomas. The mRNA expression of SSTR2 in DG-type adenomas were greater than those in SG-type adenomas and showed significantly positive correlation with GH suppression by octreotide. There was positive correlation between mRNA and protein levels of SSTR2. These data suggested that the differences of responsiveness to octreotide between DG- and SG-type adenomas are based on the expression levels of SSTR2. PMID- 22200581 TI - Prognosis and prognostic factors of patients with papillary thyroid carcinoma requiring resection of recurrent laryngeal nerve due to carcinoma extension. AB - The recurrent laryngeal nerve (RN) is one of the most common organs to which papillary thyroid carcinoma (PTC) extends. However, the prognosis and prognostic factors for patients with PTC extending to the RN remain unclear. In this study, we investigated this issue in 298 patients who underwent initial and locally curative surgery for PTC requiring RN resection due to carcinoma extension. Preoperative vocal cord paralysis was detected in 179 patients (60.1%), and directly linked to significant extension to other organs, large tumor size, and advanced age. However, it did not have a significant prognostic impact on uni- or multivariate analyses. On multivariate analysis, independent prognostic factors were large node metastasis and advanced age for lymph node recurrence, significant extension to other organs for distant recurrence, and significant extension to other organs, large node metastasis, extranodal tumor extension, and advanced age for carcinoma death, respectively. Most prognostic factors identified in the entire series of patients also had a strong prognostic impact on the subset of patients requiring RN resection, together with significant extension to other organs. Preoperative vocal cord paralysis reflected the aggressive characteristic of PTC to some extent, but did not have a significant prognostic value. PMID- 22200582 TI - Characteristics of anemia in subclinical and overt hypothyroid patients. AB - Thyroid hormones stimulate directly or indirectly growth of erythroid colonies through erythropoietin. Anemia is often the first sign of hypothyroidism. Hypothyroidism can cause a wide variety of anemic disorders. Numerous mechanisms are involved in the pathogenesis of these anemias that can be microcytic, macrocytic and normocytic. We designed this study to investigate the anemia frequency and if present, etiology of anemia in hypothyroid patients. 100 patients with overt hypothyroid, 100 patients with subclinical hypothyroid, and 200 healthy controls were enrolled in this study. Overt hypothyroidism diagnosis is done when elevated TSH and low levels of free T4 and/or free T3 have been observed. Subclinical hypothyroidism is defined as elevated serum TSH with normal free T(4) and free T(3) levels. Peripheral smears of the anemic patients were examined. Anemia prevalence was 43% in the overt hypothyroid group, 39% in the subclinical hypothyroid group, and 26% in the control group (p=0.0003 and p=0.021 respectively related to controls). Thus, the frequency of anemia in subclinical hypothyroidism is as high as that in overt hypothyroidism. There was no difference between the hypothyroid groups in terms of anemia. Vitamin B12, Fe, and folic acid were similar between these groups. According to our findings, anemia of chronic disease is the most common type of anemia in hypothyroid patients. Suspicion of hypothyroidism should be considered in anemias with uncertain etiology. PMID- 22200583 TI - Home blood pressure control is low during the critical morning hours in patients with hypertension: the SURGE observational study. AB - BACKGROUND: The morning blood pressure (BP) surge is associated with a peak increase in vascular events. OBJECTIVE: The aim of this observational study was to evaluate morning BP control in treated hypertensive patients using home BP (HBP) monitoring and to compare these findings with clinic BP control. METHODS: Clinic BP was measured twice during a 2-week period, prior to medication. Seated HBP was measured, using a BHS-validated device, three times per day over a 2-week period. Assessments included morning (06:00-11:59), lunch time (12:00-14:00) and evening (18:00-22:00) HBP control (all <135/85 mmHg) and clinic BP (<140/90 mmHg) control. RESULTS: A total of 15618 patients were assessed. At baseline (Day 1 and Week 1), clinic BP control (<140/90 mmHg) and morning HBP control (<135/85 mmHg) were low: 23.6% and 21.9%, respectively. The percentage of patients with both clinic BP and morning HBP control was extremely low (8.5%). Similar values were obtained at lunch time (11.3%) and evening (9.9%). There was a slight improvement at the end of the second week, but values remained low. At final visit (Day 4 and Week 2), morning, lunch time and evening HBP control was observed in 31.8%, 42.2% and 36.4% of patients, respectively. Clinic BP control was observed in 41.7%. CONCLUSION: Morning HBP control was low in this large hypertensive population. The improvement in BP control observed may be associated with inclusion in a study; this could indicate low medication compliance in general practices but may also be attributable to the use of agents that cannot sustain 24-hour BP control. PMID- 22200584 TI - The spectrum of renal histologies seen in HIV with outcomes, prognostic indicators and clinical correlations. AB - BACKGROUND: Two hundred and twenty-one HIV-positive renal biopsies were analysed from Groote Schuur Hospital to determine outcomes and prognostic indicators based on histology and clinical features. METHODS: The histology findings were compared with patient demographics, clinical and renal parameters, mortality, CD4 count and date of commencing combined anti-retroviral therapy (cART). Follow-up was between 1 and 3.5 years. RESULTS: We found a spectrum of renal histologies in HIV positive patients of which HIV-associated nephropathy (HIVAN) was the most common histology. cART reduced the mortality in those with any feature of HIVAN by 57% [adjusted hazard ratio (AHR) 0.43, 95% confidence interval (CI) 0.22-0.85]. Of those patients with HIVAN who died, 79% died of renal failure as registered on their death certificate. Proteinuria and microcysts were shown to be poor prognostic indicators (AHR 1.36: 1.09-1.70 and 2.04: 1.24-3.37). In patients with HIVAN alone followed for up to 2 years on cART, estimated glomerular filtration rate remained stable and there was a trend towards decreased proteinuria. cART improved survival in patients with isolated immune complex disease. CONCLUSIONS: As mortality is improved in patients with any feature of HIVAN or isolated immune complex disease, cART should be initiated once any of these histological features are established. We believe the spectrum of disease that constitutes HIVAN needs to be more specifically defined. The ultimate outcome may be determined by the histological subtype. PMID- 22200585 TI - Nucleation and aggregative growth process of platinum nanoparticles studied by in situ quick XAFS spectroscopy. AB - The early stage in the nucleation and subsequent aggregative particle growth of the colloidal platinum (Pt) dispersions produced by photoreduction in an aqueous ethanol solution of poly(N-vinyl-2-pyrrolidone) (PVP) was quantitatively investigated by means of in situ quick XAFS (QXAFS) measurements. The stages of the reduction-nucleation and the association process (aggregative particle growth and Ostwald ripening) of Pt atoms to produce Pt nanoparticles was successfully discriminated in course of the photoreduction time. The present QXAFS analysis indicated that Pt nuclei (i.e., (Pt(0))(m) nucleates approximately m = 4) were continuously produced in the reduction-nucleation process at the early time, followed by the aggregative particle growth with the autocatalytic reduction of Pt ionic species on the surface of Pt nuclei to produce Pt nanoparticles. Subsequently the particle growth proceeded via Ostwald ripening, resulting in the production of larger Pt nanoparticles at a later time. It was also found that the aggregative particle growth follows a sigmoidal profile well described either by the solid-state kinetic model or by the chemical-mechanism-based kinetic model, specifically the Avrami-Erofe'ev or Finke-Watzky models. The difference in terms of the formation mechanism was observed between the reduction of Pt(IV)Cl(6)(2-) and Pt(II)Cl(4)(2-) as a source material. Also presented is that the addition of the photoactivator such as benzoin, benzophenone, and acetophenone in the system is very effective to enhance the rate for the formation of Pt nanoparticles. PMID- 22200586 TI - A population-based randomized controlled trial of the effect of combining a pedometer with an intervention toolkit on physical activity among individuals with low levels of physical activity or fitness. AB - OBJECTIVES: To examine if receiving a pedometer along with an intervention toolkit is associated with increased physical activity, aerobic fitness and better self-rated health among individuals with low levels of physical activity or fitness. METHODS: The intervention was nested in the Danish Health Examination Survey (DANHES) and carried out in 2008. Participants were randomly assigned to either a pedometer group (n=326) or a control group (n=329). Physical activity, aerobic fitness, and self-rated health were measured at baseline and at 3-month follow-up, and differences were tested by Wilcoxons signed rank tests and Chi squared tests. RESULTS: At follow-up, no significant differences in physical activity, aerobic fitness and self-rated health were found between the groups. However, the oldest participants in the pedometer group reported significantly more walking time compared to the controls (controls=368 min/week, pedometer group=680 min/week, P=0.05). Among participants who completed the intervention, a significant effect on total walking time was observed (median difference=225 min/week, P=0.04). CONCLUSIONS: The results suggest that receiving a pedometer and along with an intervention toolkit can increase walking time in older individuals, but not in younger individuals. Thus, this type of intervention offers great potential for promoting physical activity in older individuals. TRIAL REGISTRATION NUMBER: NCT01071811. PMID- 22200587 TI - State of the art in computational modelling of cancer. PMID- 22200588 TI - Endothelial-derived neuregulin is an important mediator of ischaemia-induced angiogenesis and arteriogenesis. AB - AIMS: Neuregulins (NRG) are growth factors that are synthesized by endothelial cells (ECs) and bind to erbB receptors. We have shown previously that NRG is proangiogenic in vitro, and that NRG/erbB signalling is important for autocrine endothelial angiogenic signalling in vitro. However, the role of NRG in the angiogenic response to ischaemia is unknown. We hypothesized that endothelial NRG is required for ischaemia-induced angiogenesis in vivo and that exogenous administration of NRG will enhance angiogenic responses after ischaemic insult. METHODS AND RESULTS: An endothelial-selective inducible NRG knockout mouse was created and subjected to femoral artery ligation. Endothelial NRG deletion significantly decreased blood flow recovery (by 40%, P < 0.05), capillary density, alpha(v)beta(3) integrin activation, and arteriogenesis after ischaemic injury. Isolated ECs from knockout mice demonstrated significantly impaired cord formation in vitro, suggesting that NRG signalling performs an important cell autonomous function. Recombinant human NRG (rNRG) has not only reversed the angiogenic defect in knockout mice but also accelerated blood flow recovery in wild-type mice. CONCLUSION: Endothelial production of NRG is required for angiogenesis and arteriogenesis induced by ischaemic injury. Furthermore, exogenous administration of rNRG can enhance this process, suggesting a potential role for NRG in vascular disease. PMID- 22200590 TI - Mutagenicity of ipriflavone in vivo and in vitro. AB - Ipriflavone (7-isopropoxy-isoflavone) is a semisynthetic isoflavone derivative from daidzein and prescribed to prevent and treat osteoporosis in postmenopausal women. In the present study, ipriflavone was investigated with regard to their cytotoxic and mutagenic effects using the micronucleus assay (MN) in vivo on cells of bone marrow and peripheral blood of Swiss albino mice and the micronucleus test with the cytokinesis-blocked micronucleus assay (CBMN assay) on human peripheral blood lymphocytes. The studies were performed in mice with three dosages of the drug, 1.71, 8.57 and 42.85 mg/kg bw in single oral exposure, and for two dosages, 5 and 10 MUg/mL in the CBMN assay. Ipriflavone, in the dosages tested, did not differ from controls neither in the induction of MN nor induced cytotoxicity to cells in the in vivo test. However, in the CBMN assay, the concentration of 10 MUg/mL induced a statistically significant increase in MN formation and decreased cell proliferation, demonstrating to be mutagenic and cytotoxic at this concentration. PMID- 22200591 TI - Subliminal access to abstract face representations does not rely on attention. AB - The present study used masked repetition priming to examine whether face representations can be accessed without attention. Two experiments using a face recognition task (fame judgement) presented masked repetition and control primes in spatially unattended locations prior to target onset. Experiment 1 (n=20) used the same images as primes and as targets and Experiment 2 (n=17) used different images of the same individual as primes and targets. Repetition priming was observed across both experiments regardless of whether spatial attention was cued to the location of the prime. Priming occurred for both famous and non-famous targets in Experiment 1 but was only reliable for famous targets in Experiment 2, suggesting that priming in Experiment 1 indexed access to view-specific representations whereas priming in Experiment 2 indexed access to view-invariant, abstract representations. Overall, the results indicate that subliminal access to abstract face representations does not rely on attention. PMID- 22200592 TI - The roles of cell size and cell number in determining ovariole number in Drosophila. AB - All insect ovaries are composed of functional units called ovarioles, which contain sequentially developing egg chambers. The number of ovarioles varies between and within species. Ovariole number is an important determinant of fecundity and thus affects individual fitness. Although Drosophila oogenesis has been intensively studied, the genetic and cellular basis for determination of ovariole number remains unknown. Ovariole formation begins during larval development with the morphogenesis of terminal filament cells (TFCs) into stacks called terminal filaments (TFs). We induced changes in ovariole number in Drosophila melanogaster by genetically altering cell size and cell number in the TFC population, and analyzed TF morphogenesis in these ovaries to understand the cellular basis for the changes in ovariole number. Increasing TFC size contributed to higher ovariole number by increasing TF number. Similarly, increasing total TFC number led to higher ovariole number via an increase in TF number. By analyzing ovarian morphogenesis in another Drosophila species we showed that TFC number regulation is a target of evolutionary change that affects ovariole number. In contrast, temperature-dependent plasticity in ovariole number was due to changes in cell-cell sorting during TF morphogenesis, rather than changes in cell size or cell number. We have thus identified two distinct developmental processes that regulate ovariole number: establishment of total TFC number, and TFC sorting during TF morphogenesis. Our data suggest that the genetic changes underlying species-specific ovariole number may alter the total number of TFCs available to contribute to TF formation. This work provides for the first time specific and quantitative developmental tools to investigate the evolution of a highly conserved reproductive structure. PMID- 22200594 TI - Combinatorial coding of Drosophila muscle shape by Collier and Nautilus. AB - The diversity of Drosophila muscles correlates with the expression of combinations of identity transcription factors (iTFs) in muscle progenitors. Here, we address the question of when and how a combinatorial code is translated into muscle specific properties, by studying the roles of the Collier and Nautilus iTFs that are expressed in partly overlapping subsets of muscle progenitors. We show that the three dorso-lateral (DL) progenitors which express Nautilus and Collier are specified in a fixed temporal sequence and that each expresses additionally other, distinct iTFs. Removal of Collier leads to changes in expression of some of these iTFs and mis-orientation of several DL muscles, including the dorsal acute DA3 muscle which adopts a DA2 morphology. Detailed analysis of this transformation revealed the existence of two steps in the attachment of elongating muscles to specific tendon cells: transient attachment to alternate tendon cells, followed by a resolution step selecting the final sites. The multiple cases of triangular-shaped muscles observed in col mutant embryos indicate that transient binding of elongating muscle to exploratory sites could be a general feature of the developing musculature. In nau mutants, the DA3 muscle randomly adopts the attachment sites of the DA3 or DO5 muscles that derive from the same progenitor, resulting in a DA3, DO5-like or bifid DA3-DO5 orientation. In addition, nau mutant embryos display thinner muscle fibres. Together, our data show that the sequence of expression and combinatorial activities of Col and Nau control the pattern and morphology of DL muscles. PMID- 22200593 TI - Specification of GnRH-1 neurons by antagonistic FGF and retinoic acid signaling. AB - A small population of neuroendocrine cells in the rostral hypothalamus and basal forebrain is the key regulator of vertebrate reproduction. They secrete gonadotropin-releasing hormone (GnRH-1), communicate with many areas of the brain and integrate multiple inputs to control gonad maturation, puberty and sexual behavior. In humans, disruption of the GnRH-1 system leads to hypogonadotropic gonadism and Kallmann syndrome. Unlike other neurons in the central nervous system, GnRH-1 neurons arise in the periphery, however their embryonic origin is controversial, and the molecular mechanisms that control their initial specification are not clear. Here, we provide evidence that in chick GnRH-1 neurons originate in the olfactory placode, where they are specified shortly after olfactory sensory neurons. FGF signaling is required and sufficient to induce GnRH-1 neurons, while retinoic acid represses their formation. Both pathways regulate and antagonize each other and our results suggest that the timing of signaling is critical for normal GnRH-1 neuron formation. While Kallmann's syndrome has generally been attributed to a failure of GnRH-1 neuron migration due to impaired FGF signaling, our findings suggest that in at least some Kallmann patients these neurons may never be specified. In addition, this study highlights the intimate embryonic relationship between GnRH-1 neurons and their targets and modulators in the adult. PMID- 22200595 TI - DNA binding and anticancer activity of naphthalimides with 4-hydroxyl-alkylamine side chains at different lengths. AB - A series of novel naphthalimide derivatives modified with various hydroxyl alkylamines at 4-position have been synthesized. Their DNA binding properties were investigated by UV-Vis, fluoescence, and circular dichroism (CD) spectroscopies and thermal denaturation. The results showed that compounds 3a-e as the DNA intercalator exhibited middle binding affinities with Ct-DNA. The anticancer activities of 3a-e were preliminarily evaluated, compounds 3c and 3e exhibited potent anticancer activities against Bel-7402 cell line with IC(50) values of 5.57 and 9.17MUM, respectively. More interestingly, enhancement of the fluorescence emission was found in the complexes of 3a-e with Ct-DNA, especially for 3c. This would make these compounds as potential DNA staining agents. PMID- 22200596 TI - An alternative synthetic route for an antidiabetic drug, rosiglitazone. AB - A convenient and scalable four-step novel route has been developed for the synthesis of rosiglitazone (8), an antidiabetic drug. This multistep route requires 4-fluoro benzaldehyde (4), 2,4-thiazolidinedione (6) and 2-chloro pyridine (1) as key reactants and gives overall better yield of rosiglitazone. In addition, some steps have been accelerated, which leads to an overall time saving of 10h. PMID- 22200597 TI - Discovery and molecular docking of quinolyl-thienyl chalcones as anti-angiogenic agents targeting VEGFR-2 tyrosine kinase. AB - Vascular endothelial growth factor Receptor-2 (VEGFR-2) kinase inhibition is one of the well established strategies to promptly tackle tumor growth by suppression of angiogenesis. In the current study, structure-based virtual screening methodology of a series of quinolyl-thienyl chalcones indicated their strong potential as VEGFR-2 kinase inhibitors. In vitro VEGFR-2 kinase inhibitory activity was found to be significant (compound 19, IC(50): 73.41nM). All compounds showed significant inhibition of human umbilical vein endothelial cells (HUVEC) proliferation (compound 19, IC(50): 21.78nM). Molecular interactions of the compounds were studied using molecular docking studies. PMID- 22200598 TI - Synthesis, characterization and in vitro biological evaluation of some novel diarylsulfonylureas as potential cytotoxic and antimicrobial agents. AB - A series of novel diarylsulfonylureas (1-28) have been synthesized and characterized by FTIR, (1)H NMR, (13)C NMR and LC mass spectral analysis. All the synthesized compounds were evaluated for their in vitro cytotoxicity and antimicrobial activities. Among the tested compounds for cytotoxicity using Brine Shrimp Lethality assay, compounds 18 and 22 exhibited significant cytotoxicity at ED(50) values 3.96+/-0.21 and 4.02+/-0.19MUg/mL, respectively. This level of activity was found comparable to that of the reference drug podophyllotoxin with ED(50) value 3.61+/-0.17MUg/mL and it could be a remarkable starting point to develop new lead molecules with major cytotoxicity. Antimicrobial activity was screened using agar well diffusion assay method against selected Gram-positive, Gram-negative and fungal strains. Most of the compounds showed promising antibacterial and antifungal activity and the activity expressed as the minimum inhibitory concentration (MIC) in MUg/mL. PMID- 22200599 TI - Pathogen recognition receptors in channel catfish: I. Identification, phylogeny and expression of NOD-like receptors. AB - Innate immune system plays a significant role in all multicellular organisms. The key feature of the system is its ability to recognize and respond to invading microorganisms. Vertebrates including teleost fish have evolved an array of pathogen recognition receptors (PRRs) for detecting and responding to various pathogen-associated molecular patterns (PAMPs), including Toll-like receptors (TLRs), nucleotide-binding domain, leucine-rich repeat containing receptors (NLRs), and the retinoic acid inducible gene I (RIG-I) like receptors (RLRs). In this study, we identified 22 NLRs including six members of the NLR-A subfamily (NODs), two members of the NLR-B subfamily, 11 members of the NLR-C subfamily, and three genes that do not belong to any of these three subfamilies: Apaf1, CIITA, and NACHT-P1. Phylogenetic analysis indicated that orthologs of the mammalian NOD1, NOD2, NOD3, NOD4, and NOD5 were all identified in catfish. In addition, an additional truncated NOD3-like gene was also identified in catfish. While the identities of subfamily A NLRs could be established, the identities of the NLR-B and NLR-C subfamilies were inconclusive at present. Expression of representative NLR genes was analyzed using RT-PCR and qRT-PCR. In healthy catfish tissues, all the tested NLR genes were found to be ubiquitously expressed in all 11 tested catfish tissues. Analysis of expression of these representative NLR genes after bacterial infection with Edwardsiella ictaluri revealed a significant up-regulation of all tested genes in the spleen and liver, but a significant down-regulation in the intestine and head kidney, suggesting their involvement in the immune responses of catfish against the intracellular bacterial pathogen in a tissue-specific manner. The up-regulation and down regulation of the tested genes exhibited an amazing similarity of expression profiles after infection, suggesting the co-regulation of these genes. PMID- 22200600 TI - Glatiramer acetate reverts stress-induced alterations on adult neurogenesis and behavior. Involvement of Th1/Th2 balance. AB - Long-term exposure to stressful situations has deleterious effects on adult neurogenesis, behavior, and the immune system. We have previously shown that stressed BALB/c mice show poor learning performance, which correlates with an increase in the T helper 1/T helper 2 (Th1/Th2) cytokine balance. Glatiramer acetate (GA) can stimulate autoreactive T cells. In this work we investigated the effects of GA treatment on BALB/c mice exposed to chronic mild stress (CMS). Stressed mice exhibited a significant decline in their performance in the open field and Y-maze tasks, which was accompanied by a reduction in dentate gyrus neurogenesis and an altered Th1/Th2 balance. Interestingly, after 6 weeks of CMS exposure administration of GA reestablished normal levels of adult neurogenesis, restored the Th1/Th2 balance, and improved learning performance. These results demonstrate that GA treatment can reverse the learning impairment induced by stress through a mechanism that likely involves the regulation of the cytokine balance and adult neurogenesis. PMID- 22200601 TI - Does a causal relation between cardiovascular disease and periodontitis exist? AB - Inflammation is believed to play a central part in the pathogenesis of atherosclerosis, and much attention has been paid to the possible association between atherosclerosis and other inflammatory diseases. Periodontal disease is a common inflammatory disease affecting up to 50% of the adult population, and during the past two decades much research has focused on a possible association between periodontitis and cardiovascular disease. Here, we review the existing literature on the association between the two diseases. PMID- 22200602 TI - Experiences in reconciling risk management and restorative justice: how circles of support and accountability work restoratively in the risk society. AB - Circles of Support and Accountability (COSA) is a restorative justice-based model that originated in Canada in the mid-1990s for the postincarceration reintegration of those who have offended sexually. Although the roots of COSA are in restorative justice philosophy, the program has also found favour, to some degree, with organisations such as police services and corrections that are traditionally concerned more with protecting community safety than with the ideals of restorative justice. Informed by the author's research and personal experience as a COSA volunteer, and analysis of recent and historical representations of COSA, this article explores theoretically how the development of the COSA initiative has been influenced by the seemingly disparate concerns of both the restorative justice and community protection movements, and examines the importance of balancing these paradigms in the everyday practices of circles. PMID- 22200603 TI - On-line integration of computer controlled diagnostic devices and medical information systems in undergraduate medical physics education for physicians. AB - We designed and evaluated an innovative computer-aided-learning environment based on the on-line integration of computer controlled medical diagnostic devices and a medical information system for use in the preclinical medical physics education of medical students. Our learning system simulates the actual clinical environment in a hospital or primary care unit. It uses a commercial medical information system for on-line storage and processing of clinical type data acquired during physics laboratory classes. Every student adopts two roles, the role of 'patient' and the role of 'physician'. As a 'physician' the student operates the medical devices to clinically assess 'patient' colleagues and records all results in an electronic 'patient' record. We also introduced an innovative approach to the use of supportive education materials, based on the methods of adaptive e-learning. A survey of student feedback is included and statistically evaluated. The results from the student feedback confirm the positive response of the latter to this novel implementation of medical physics and informatics in preclinical education. This approach not only significantly improves learning of medical physics and informatics skills but has the added advantage that it facilitates students' transition from preclinical to clinical subjects. PMID- 22200604 TI - Myocardial ischemia in severe aortic regurgitation despite angiographically normal coronary arteries. AB - Patients with severe aortic regurgitation frequently present with angina pectoris. The exact pathophysiology for angina in aortic regurgitation is not clear. Left ventricular hypertrophy and myocardial blood supply-demand mismatch have been the suggested mechanisms to explain ischemia. However, no conclusive clinical study exists to define the incidence of ischemia in patients with severe aortic regurgitation and normal coronary arteries. We, therefore, investigated the frequency of myocardial ischemia in relation to left ventricular hypertrophy or dilatation in patients with severe aortic regurgitation and normal coronary arteries. We reviewed the medical records of all patients (n = 311) with aortic valve replacement due to aortic regurgitation between 2007 and 2010. We selected subjects with normal coronary arteries (n =182) for the study purpose, and we identified 35 patients who underwent myocardial perfusion scintigraphy prior to the coronary angiography (19 female and 16 male subjects; age 45.0 +/- 8.9 years). Left ventricular hypertrophy and dilatation were detected in 9 (26%) and 5 (14%) patients, respectively. Myocardial perfusion scintigraphy showed evidence of ischemia in 10 (29%) patients with normal coronary arteries. The presence of ischemia did not relate to the presence of left ventricular hypertrophy and/or dilatation. As a potential mechanism, aortic regurgitation causes backflow of blood from the aorta into the left ventricle, hence disturbs coronary flow dynamics. In conclusion, myocardial ischemia is common (nearly one third) among patients with severe aortic regurgitation even in the absence of coronary obstruction, left ventricular hypertrophy and/or dilatation. PMID- 22200605 TI - Embryonic lethality in mice lacking mismatch-specific thymine DNA glycosylase is partially prevented by DOPS, a precursor of noradrenaline. AB - Thymine DNA glycosylase (TDG) is involved in the repair of G:T and G:U mismatches caused by hydrolytic deamination of 5-methylcytosine and cytosine, respectively. Recent studies have shown that TDG not only has G-T/U glycosylase activities but also acts in the maintaining proper epigenetic status. In order to investigate the function of TDG in vivo, mice lacking Tdg, Tdg (-/-), were generated. Tdg mutant mice died in utero by 11.5 days post coitum (dpc), although there were no significant differences in the spontaneous mutant frequencies between wild type and Tdg (-/-) embryos. On the other hand, the levels of noradrenaline in 10.5 dpc whole embryos, which is necessary for normal embryogenesis, were dramatically reduced in Tdg (-/-) embryos. Consequently, we tested the effect of D, L-threo 3, 4-dihydroxyphenylserine (DOPS), a synthetic precursor of noradrenaline, on the survival of the Tdg (-/-) embryos. DOPS was given to pregnant Tdg (+/-) mice from 6.5 dpc through drinking water. Most of the Tdg (-/-) embryos were alive at 11.5 dpc, and they were partially rescued up to 14.5 dpc by the administration of DOPS. In contrast, the administration of L-3, 4-dihydroxyphenylalanine (L-DOPA) had marginal effects on Tdg (-/-) embryonic lethality. No embryo was alive without DOPS beyond 11.5 dpc, suggesting that the lethality in (-/-) embryos is partially due to the reduction of noradrenaline. These results suggest that embryonic lethality in Tdg (-/-) embryos is due, in part, to the reduction of noradrenaline levels. PMID- 22200606 TI - Antibody microarrays for label-free cell-based applications. AB - The recent advances in microtechnologies have shown the interest of developing microarrays dedicated to cell analysis. In this way, miniaturized cell analyzing platforms use several detection techniques requiring specific solid supports for microarray read-out (colorimetric, fluorescent, electrochemical, acoustic, optical...). Real-time and label-free techniques, such as Surface Plasmon Resonance imaging (SPRi), arouse increasing interest for applications in miniaturized formats. Thus, we focused our study on chemical methods for antibody based microarray fabrication dedicated to the SPRi analysis of cells or cellular activity. Three different approaches were designed and developed for specific applications. In the first case, a polypyrrole-based chemistry was used to array antibody-microarray for specific capture of whole living cells. In the second case, the polypyrrole-based chemistry was complexified in a three molecular level assembly using DNA and antibody conjugates to allow the specific release of cells after their capture. Finally, in the third case, a thiol-based chemistry was developed for long incubation times of biological samples of high complexity. This last approach was focused on the simultaneous study of both cell type characterization and secretory activity (detection of proteins secreted by cells). This paper describes three original methods allowing a rapid and efficient analysis of cellular sample on-chip using immunoaffinity-based assays. PMID- 22200608 TI - The effects of context and musical training on auditory temporal-interval discrimination. AB - Non sensory factors such as stimulus context and musical experience are known to influence auditory frequency discrimination, but whether the context effect extends to auditory temporal processing remains unknown. Whether individual experiences such as musical training alter the context effect is also unknown. The goal of the present study was therefore to investigate the effects of stimulus context and musical experience on auditory temporal-interval discrimination. In experiment 1, temporal-interval discrimination was compared between fixed context conditions in which a single base temporal interval was presented repeatedly across all trials and variable context conditions in which one of two base intervals was randomly presented on each trial. Discrimination was significantly better in the fixed than in the variable context conditions. In experiment 2 temporal discrimination thresholds of musicians and non-musicians were compared across 3 conditions: a fixed context condition in which the target interval was presented repeatedly across trials, and two variable context conditions differing in the frequencies used for the tones marking the temporal intervals. Musicians outperformed non-musicians on all 3 conditions, but the effects of context were similar for the two groups. Overall, it appears that, like frequency discrimination, temporal-interval discrimination benefits from having a fixed reference. Musical experience, while improving performance, did not alter the context effect, suggesting that improved discrimination skills among musicians are probably not an outcome of more sensitive contextual facilitation or predictive coding mechanisms. PMID- 22200609 TI - Mobilization of mesenchymal stem cells by stromal cell-derived factor-1 released from chitosan/tripolyphosphate/fucoidan nanoparticles. AB - Stromal cell-derived factor 1 (SDF-1) is an important chemokine in stem cell mobilization, and plays a critical role in the biological and physiological functions of mesenchymal stem cells (MSC). However, the use of SDF-1 in tissue regeneration is limited by two drawbacks, which are its short half-life and ready degradation by enzymes. This study investigates the release of SDF-1 from chitosan-based nanoparticles (NP) and evaluates the effect of released SDF-1 on the migration of MSC. Among the prepared chitosan-based NP a chitosan/tripolyphosphate/fucoidan (CS/TPP/F) NP is the most effective carrier for SDF-1 release. CS/TPP/F NP are spherical and effectively encapsulate SDF-1. The CS/TPP/F NP protected SDF-1 against proteolysis and heat treatment and controlled its release for up to 7 days. The concentration of released SDF-1 reached 23 ng ml(-1). According to in vitro experiments on cells the released SDF 1 retained its mitogenic activity, promoted the migration of MSC and enhanced PI3K expression. Biocompatible CS/TPP/F NP may be effective as carriers for the delivery and controlled release of SDF-1 to mobilize stem cells in tissue engineering applications. PMID- 22200611 TI - Assessing viscoelastic properties of chitosan scaffolds and validation with cyclical tests. AB - We evaluated and modeled the viscoelastic characteristics of chitosan and chitosan-gelatin scaffolds prepared using a freeze-drying technique. Chitosan and chitosan-gelatin solutions (0.5 and 2 wt.%) were frozen at -80 degrees C and freeze-dried. Using the scaffolds, uniaxial tensile properties were evaluated under physiological conditions (hydrated in phosphate buffered saline at 37 degrees C) at a cross-head speed of 0.17 mms(-1) (10 mm min(-1)). From the break strain, the limit of strain per ramp was calculated to be 5% and the samples were stretched at a strain rate of 2.5%s(-1). The ramp-and-hold type of stress relaxation test was performed for five successive stages. Chitosan and chitosan gelatin showed nearly 90% relaxation of stress after each stage. The relaxation behavior was independent of the concentration of chitosan and gelatin. Also, changes in the microstructure of the tested samples were evaluated using an inverted microscope. The micrographs acquired after relaxation experiments showed orientation of pores, suggesting the retention of the stretched state even after many hours of relaxation. Based on these observations, two models (i) containing a hyper-elastic spring (containing two parameters) and (ii) retaining pseudo components (containing three parameters) were developed in Visual Basic Applications accessed through MS Excel. The models were used to fit the experimental stress-relaxation data and the parameters obtained from modeling were used to predict their respective cyclic behaviors, which were compared with cyclical experimental results. These results showed that the model could be used to predict the cyclical behavior under the tested strain rates. The model predictions were also tested using cyclic properties at a lower strain rate of 0.0867%s(-1) (5%min(-1)) for 0.5 wt.% scaffolds but the model could not predict cyclical behavior at a very slow rate. In summary, the pseudo-component modeling approach can be used to model the sequential strain-and-hold stage and predict cyclical properties for the same strain rate. PMID- 22200610 TI - bFGF-containing electrospun gelatin scaffolds with controlled nano-architectural features for directed angiogenesis. AB - Current therapeutic angiogenesis strategies are focused on the development of biologically responsive scaffolds that can deliver multiple angiogenic cytokines and/or cells in ischemic regions. Herein, we report on a novel electrospinning approach to fabricate cytokine-containing nanofibrous scaffolds with tunable architecture to promote angiogenesis. Fiber diameter and uniformity were controlled by varying the concentration of the polymeric (i.e. gelatin) solution, the feed rate, needle to collector distance, and electric field potential between the collector plate and injection needle. Scaffold fiber orientation (random vs. aligned) was achieved by alternating the polarity of two parallel electrodes placed on the collector plate thus dictating fiber deposition patterns. Basic fibroblast growth factor (bFGF) was physically immobilized within the gelatin scaffolds at variable concentrations and human umbilical vein endothelial cells (HUVEC) were seeded on the top of the scaffolds. Cell proliferation and migration was assessed as a function of growth factor loading and scaffold architecture. HUVECs successfully adhered onto gelatin B scaffolds and cell proliferation was directly proportional to the loading concentrations of the growth factor (0-100 bFGF ng/mL). Fiber orientation had a pronounced effect on cell morphology and orientation. Cells were spread along the fibers of the electrospun scaffolds with the aligned orientation and developed a spindle-like morphology parallel to the scaffold's fibers. In contrast, cells seeded onto the scaffolds with random fiber orientation, did not demonstrate any directionality and appeared to have a rounder shape. Capillary formation (i.e. sprouts length and number of sprouts per bead), assessed in a 3-D in vitro angiogenesis assay, was a function of bFGF loading concentration (0 ng, 50 ng and 100 ng per scaffold) for both types of electrospun scaffolds (i.e. with aligned or random fiber orientation). PMID- 22200607 TI - Actin in hair cells and hearing loss. AB - Hereditary deafness is genetically heterogeneous such that mutations of many different genes can cause hearing loss. This review focuses on the evidence and implications that several of these deafness genes encode actin-interacting proteins or actin itself. There is a growing appreciation of the contribution of the actin interactome in stereocilia development, maintenance, mechanotransduction and malfunction of the auditory system. PMID- 22200612 TI - Trace element-incorporating octacalcium phosphate porous beads via polypeptide assisted nanocrystal self-assembly for potential applications in osteogenesis. AB - The promising future of calcium phosphates (CaP) as a group of biomedical materials with a wide range of functions, might ultimately depend on tuning their composition and microstructure. However, the disorderly growth and aggregation of CaP nanocrystals limit their practical application. This paper reports a strategy for designing polypeptide/trace elements (TE), dual mediating the self-assembly of octacalcium phosphate (OCP) nanocrystals, with multilayered porous cross section and TE dilute doping. Intriguing advantages such as bead morphology, mesoporous structure, tunable diameter (20-1,000 MUm) and TE contents, biodegradability and bioactivity are obtained. The microcomputerized-tomography reconstruction reveals an interconnective macroporous architecture and a void volume of over 49.02% for the nearly close-packed bead scaffolds. The specific surface area and average mesopore size are 89.73 m(2)g(-1) and 2.75 nm for the 180 MUm diameter bead group, and those of 500 MUm diameter beads are 130.17 m(2)g(-1) and 3.69 nm, respectively. It is demonstrated that the bead production mechanism is a multistep process including liquid-like precursor formation, nanocrystal nucleation and aggregation, aggregate combination and bead growth. Such a multilayer structure of TE-OCP porous beads would have adequate physical strength to maintain their shape, in contrast to the physical weakness of pure OCP hollow shell. The beads exhibit good biocompatibility and degradability and encourage bone mineralization in the early stage in vivo. This study demonstrates the feasibility of developing highly porous calcium phosphate giant beads via biomimetic self-assembly for direct application in reconstructive surgery and other widespread applications such as tissue engineering and drug delivery. PMID- 22200613 TI - Interferon Regulatory Factor 1 (IRF-1) induces p21(WAF1/CIP1) dependent cell cycle arrest and p21(WAF1/CIP1) independent modulation of survivin in cancer cells. AB - We have shown that the ectopic expression of Interferon Regulatory Factor 1 (IRF 1) results in human cancer cell death accompanied by the down-regulation of the Inhibitor of Apoptosis Protein (IAP) survivin and the induction of the cyclin dependent kinase inhibitor p21(WAF1/CIP1). In this report, we investigated the direct role of p21 in the suppression of survivin. We show that IRF-1 down regulates cyclin B1, cdc-2, cyclin E, E2F1, Cdk2, Cdk4, and results in p21 mediated G1 cell cycle arrest. Interestingly, while p21 directly mediates G1 cell cycle arrest, IRF-1 or other IRF-1 signaling pathways may directly regulate survivin in human cancer cells. PMID- 22200614 TI - Collagen VI ablation retards brain tumor progression due to deficits in assembly of the vascular basal lamina. AB - To investigate the importance of the vascular basal lamina in tumor blood vessel morphogenesis and function, we compared vessel development, vessel function, and progression of B16F10 melanoma tumors in the brains of wild-type and collagen VI null mice. In 7-day tumors in the absence of collagen VI, the width of the vascular basal lamina was reduced twofold. Although the ablation of collagen VI did not alter the abundance of blood vessels, a detailed analysis of the number of either pericytes or endothelial cells (or pericyte coverage of endothelial cells) showed that collagen VI-dependent defects during the assembly of the basal lamina have negative effects on both pericyte maturation and the sprouting and survival of endothelial cells. As a result of these deficits, vessel patency was reduced by 25%, and vessel leakiness was increased threefold, resulting in a 10 fold increase in tumor hypoxia along with a fourfold increase in hypoxia inducible factor-1alpha expression. In 12-day collagen VI-null tumors, vascular endothelial growth factor expression was increased throughout the tumor stroma, in contrast to the predominantly vascular pattern of vascular endothelial growth factor expression in wild-type tumors. Vessel size was correspondingly reduced in 12-day collagen VI-null tumors. Overall, these vascular deficits produced a twofold decrease in tumor volume in collagen VI-null mice, confirming that collagen VI-dependent basal lamina assembly is a critical aspect of vessel development. PMID- 22200615 TI - Inflammation-induced lymph node lymphangiogenesis is reversible. AB - The extent of lymph node metastasis is a prognostic indicator of disease progression in many malignancies. Current noninvasive imaging technologies for the clinical assessment of lymph node metastases are based on the detection of cancer cells and commonly suffer from a lack of sensitivity. Recent evidence has indicated that the expansion of lymphatic networks (ie, lymphangiogenesis) within tumor-draining lymph nodes might be the earliest sign of metastasis. Therefore, we recently developed a noninvasive imaging method to visualize lymph node lymphangiogenesis in mice using radiolabeled antibodies against the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) as well as positron emission tomography (PET). This technique, termed anti-LYVE-1 immuno-PET, was found to be very sensitive in the detection of metastasis to the lymph nodes. However, lymphatic vessel expansion to the lymph nodes can also be induced by inflammation, and it is currently unclear whether such vessel expansion is reversed once inflammation has resolved. Detection of residual inflammation induced lymph node lymphangiogenesis, thus, might hamper the identification of metastasized lymph nodes. In this study, we therefore used a well-established mouse model of inflammation in the skin to investigate whether lymphatic vessels in the lymph nodes regress on resolution of inflammation. Our data reveal that the lymphatic network indeed regresses on the resolution of inflammation and that we can image this process by anti-LYVE-1 immuno-PET. PMID- 22200616 TI - Promotion of lymphatic integrity by angiopoietin-1/Tie2 signaling during inflammation. AB - The cutaneous lymphatic system plays a major role in tissue fluid homeostasis and inflammation of the skin. Although several lymphangiogenic factors are known to be involved in the formation of lymphatic vessels, the molecular mechanisms that maintain lymphatic integrity and control the functional drainage of interstitial fluid and resolution of inflammation remain unknown. Here we show that angiopoietin-1 (Ang1) enhances lymphatic integrity and function during inflammation. Ang1 transgenic mice under the control of keratin-14 (K14-Ang1) showed attenuated edema formation and inflammation after UV B (UVB) exposure. After UVB irradiation, blood vascular permeability was inhibited in K14-Ang1 mice compared with wild-type (WT) mice. Moreover, lymphatic vessels of WT mice were markedly enlarged and leaky in inflamed skin, whereas K14-Ang1 mice showed relatively contracted lymphatic vessels together with enhanced lymphatic vascularization. Expression of endothelial-specific tight junction molecules claudin-5 and zonula occludens protein 1 (ZO-1) was strongly down-regulated in the inflamed lymphatic vessels of UVB-exposed WT mice, whereas down-regulation of both claudin-5 and ZO-1 was blocked in UVB-exposed K14-Ang1 mice. In vitro studies revealed that the stability of lymphatic endothelial cells was enhanced in the presence of Ang1, presumably via up-regulation of claudin-5, as well as ZO 1. Claudin-5 knockdown markedly increased the permeability of lymphatic endothelial cells. Overall, our data strongly support the idea that Ang1/Tie2 signaling promotes lymphatic integrity by modulating tight junction molecule expression during inflammation. PMID- 22200617 TI - The adipocyte as an endocrine organ in the regulation of metabolic homeostasis. AB - Over the past decade and a half it has become increasingly clear that adipose tissue is a much more complex organ than was initially considered and that its metabolic functions extend well beyond the classical actions of thermoregulation and of storage and release of fatty acids. In fact, it is now well established that adipose tissue plays a critical role in maintenance of energy homeostasis through secretion of a large number of adipokines that interact with central as well as peripheral organs such as the brain, liver, pancreas, and skeletal muscle to control diverse processes, such as food intake, energy expenditure, carbohydrate and lipid metabolism, blood pressure, blood coagulation, and inflammation. While many of these adipokines are adipocyte-derived and have a variety of endocrine functions, others are produced by resident macrophages and interact in a paracrine fashion to control adipocyte metabolism. It is also abundantly clear that the dysregulation of adipokine secretion and action that occurs in obesity plays a fundamental role in the development of a variety of cardiometabolic disorders, including the metabolic syndrome, type 2 diabetes, inflammatory disorders, and vascular disorders, that ultimately lead to coronary heart disease. Described herein are the traditional as well as endocrine roles of adipose tissue in controlling energy metabolism and their dysregulation in obesity that leads to development of cardiometabolic disorders, with a focus on what is currently known regarding the characteristics and roles in both health and disease of the adipocyte-derived adipokines, adiponectin, leptin, resistin, and retinol binding protein 4, and the resident macrophage-derived adipokines, tumor necrosis factor-alpha and interleukin-6. This article is part of a Special Issue entitled 'Central Control of Food Intake'. PMID- 22200618 TI - Zebrafish dystrophin and utrophin genes: dissecting transcriptional expression during embryonic development. AB - Some genes can encode multiple overlapping transcripts, and this can result in challenges in identifying transcript-specific developmental expression profiles where tools such as RNA in situ hybrisations are inapplicable. Given this difficulty, we have undertaken a preliminary analysis of the developmental expression profile of selected transcripts of the dystrophin and utrophin genes of the zebrafish (Danio rerio) by targeting unique and common regions of each of these transcripts. The dystrophin and utrophin genes of zebrafish were identified by bioinformatic analysis and the dystrophin gene predictions were confirmed by transcript sequencing. These data enabled primer pairs to be designed in order to determine the expression profiles of unique, but overlapping transcripts, throughout embryonic development using quantitative real time reverse transcription PCR (qRT-PCR). The data indicated the early expression of the short carboxyl-terminal dystrophin transcript, with expression of the full length muscle transcript occurring during myogenesis. Importantly, a composite of these two profiles appeared to comprise the major transcriptional load of the zebrafish dystrophin gene. In contrast, utrophin gene expression was dominated by the full length transcript throughout embryogenesis. The approach described here provided a means by which a gene's transcriptional complexity can be deconvoluted to reveal transcriptional diversity during embryogenesis. This approach, however, required the identification of unique regions for transcript-specific targeting, and an appreciation of alternative splicing events that may compromise the design of primers for qRT-PCR. PMID- 22200619 TI - The activity of the inosine triphosphate pyrophosphatase affects toxicity of 6 mercaptopurine during maintenance therapy for acute lymphoblastic leukemia in Japanese children. AB - The association between inosine triphosphate pyrophosphatase (ITPA) activity and toxicity of 6-mercaptopurine (6-MP) was retrospectively evaluated in 65 Japanese children with acute lymphoblastic leukemia (ALL). Patients with an ITPA activity of less than 126 MUmol/h/gHb presented with hepatotoxicity more frequently than those with higher ITPA activity (p<0.01). The average 6-MP dose during maintenance therapy administered to two patients with the ITPA deficiency was lower than that given to the other patients. Measuring ITPA activity is important for ensuring the safety of maintenance therapy for Asians with ALL because thiopurine S-methyl transferase mutations are rare in the Asian population. PMID- 22200620 TI - Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells. AB - The MUC1 heterodimeric protein is aberrantly overexpressed in diverse human carcinomas and contributes to the malignant phenotype. The MUC1-C transmembrane subunit contains a CQC motif in the cytoplasmic domain that has been implicated in the formation of dimers and in its oncogenic function. The present study demonstrates that MUC1-C forms dimers in human breast and lung cancer cells. MUC1 C dimerization was detectable in the cytoplasm and was independent of MUC1-N, the N-terminal mucin subunit that extends outside the cell. We show that the MUC1-C cytoplasmic domain forms dimers in vitro that are disrupted by reducing agents. Moreover, dimerization of the MUC1-C subunit in cancer cells was blocked by reducing agents and increased by oxidative stress, supporting involvement of the CQC motif in forming disulfide bonds. In support of these observations, mutation of the MUC1-C CQC motif to AQA completely blocked MUC1-C dimerization. Importantly, this study was performed with MUC1-C devoid of fluorescent proteins, such as GFP, CFP and YFP. In this regard, we show that GFP, CFP and YFP themselves form dimers that are readily detectable with cross-linking agents. The present results further demonstrate that a cell-penetrating peptide that targets the MUC1-C CQC cysteines blocks MUC1-C dimerization in cancer cells. These findings provide definitive evidence that: i) the MUC1-C cytoplasmic domain cysteines are necessary and sufficient for MUC1-C dimerization, and ii) these CQC motif cysteines represent an Achilles' heel for targeting MUC1-C function. PMID- 22200621 TI - Dihydroceramide desaturase and dihydrosphingolipids: debutant players in the sphingolipid arena. AB - Sphingolipids are a wide family of lipids that share common sphingoid backbones, including (2S,3R)-2-amino-4-octadecane-1,3-diol (dihydrosphingosine) and (2S,3R,4E)-2-amino-4-octadecene-1,3-diol (sphingosine). The metabolism and biological functions of sphingolipids derived from sphingosine have been the subject of many reviews. In contrast, dihydrosphingolipids have received poor attention, mainly due to their supposed lack of biological activity. However, the reported biological effects of active site directed dihydroceramide desaturase inhibitors and the involvement of dihydrosphingolipids in the response of cells to known therapeutic agents support that dihydrosphingolipids are not inert but are in fact biologically active and underscore the importance of elucidating further the metabolic pathways and cell signaling networks involved in the biological activities of dihydrosphingolipids. Dihydroceramide desaturase is the enzyme involved in the conversion of dihydroceramide into ceramide and it is crucial in the regulation of the balance between sphingolipids and dihydrosphingolipids. Furthermore, given the enzyme requirement for O2 and the NAD(P)H cofactor, the cellular redox balance and dihydroceramide desaturase activity may reciprocally influence each other. In this review both dihydroceramide desaturase and the biological functions of dihydrosphingolipids are addressed and perspectives on this field are discussed. PMID- 22200622 TI - Mitral annulus segmentation from four-dimensional ultrasound using a valve state predictor and constrained optical flow. AB - Measurement of the shape and motion of the mitral valve annulus has proven useful in a number of applications, including pathology diagnosis and mitral valve modeling. Current methods to delineate the annulus from four-dimensional (4D) ultrasound, however, either require extensive overhead or user-interaction, become inaccurate as they accumulate tracking error, or they do not account for annular shape or motion. This paper presents a new 4D annulus segmentation method to account for these deficiencies. The method builds on a previously published three-dimensional (3D) annulus segmentation algorithm that accurately and robustly segments the mitral annulus in a frame with a closed valve. In the 4D method, a valve state predictor determines when the valve is closed. Subsequently, the 3D annulus segmentation algorithm finds the annulus in those frames. For frames with an open valve, a constrained optical flow algorithm is used to the track the annulus. The only inputs to the algorithm are the selection of one frame with a closed valve and one user-specified point near the valve, neither of which needs to be precise. The accuracy of the tracking method is shown by comparing the tracking results to manual segmentations made by a group of experts, where an average RMS difference of 1.67+/-0.63mm was found across 30 tracked frames. PMID- 22200623 TI - Genotoxicity of furan in Big Blue rats. AB - Furan is a multispecies liver carcinogen whose cancer mode of action (MOA) is unclear. A major metabolite of furan is a direct acting mutagen; however, it is not known if genotoxicity is a key step in the tumors that result from exposure to furan. In order to address this question, transgenic Big Blue rats were treated by gavage five times a week for 8 weeks with two concentrations of furan used in cancer bioassays (2 and 8mg/kg), and with two higher concentrations (16 and 30mg/kg). Peripheral blood samples taken 24h after the 5th dose (1 week of dosing) were used to assay for micronucleus (MN) frequency in normochromatic erythrocytes (NCEs) and reticulocytes (RETs), and Pig-a gene mutation in total red blood cells (RBCs). 24h after the last dose of the 8-week treatment schedule, the rats were euthanized, and their tissues were used to perform NCE and RET MN assays, the Pig-a RBC assay, Pig-a and Hprt lymphocyte gene mutation assays, the liver cII transgene mutation assay, and the liver Comet assay. The responses in the MN assays conducted at both sampling times, and all the gene mutation assays, were uniformly negative; however, the Comet assay was positive for the induction of liver DNA damage. As the positive responses in the Comet assay were seen only with doses in excess of the cancer bioassay doses, and at least one of these doses (30mg/kg) produced toxicity in the liver, the overall findings from the study are consistent with furan having a predominantly nongenotoxic MOA for cancer. PMID- 22200624 TI - A systematic review of the fetal safety of interferon alpha. AB - BACKGROUND: Interferon alpha (IFN) is an effective treatment for a variety of conditions including essential thrombocythemia (ET), chronic myelocytic leukemia, Hepatitis B and C. Because these conditions also occur in women of childbearing age who may become pregnant, information regarding the safety of this medication in pregnancy is essential. This systematic review attempts to summarize all published data on outcome of pregnancies exposed to IFN alpha, trying to differentiate between disease effect and drug effect. METHODS: Reports on the use of IFN alpha in human pregnancy and reports on essential thrombocythemia (ET) without use of any medication in pregnancy were identified by a systematic search of the medical literature. We were able to locate only case reports of IFN alpha exposure in pregnancy, of whom 40 out of 63 were diagnosed with ET. We also collected randomly 71 cases (more cases were available in the literature) that were diagnosed with ET due to different etiologies, but who had not received any medication in pregnancy. RESULTS: Among the 63 IFN alpha exposures in pregnancy, the mean maternal age was 30+/-6 years and the mean full term babies' weight was 3096+/-463 g. Mean gestational age at delivery was 37+/-3 weeks. There were 55 single and 4 twin pregnancies. No cases of major malformations or stillbirths were reported. There was one case of spontaneous abortion and 13 preterm deliveries (20% of all exposed cases). Among the 71 cases with untreated ET in pregnancy of different etiologies, 46 (65%) had early (within the first 12 weeks of pregnancy) or late (13-20 weeks of gestation) pregnancy loss. There were also 3 cases (4%) of stillbirth and 4 cases (5.6%) of preterm delivery. Only 18 women (25%) delivered healthy term babies. CONCLUSIONS: The results of our systematic review suggest that IFN-alpha does not significantly increase the risk of major malformation, miscarriage, stillbirth or preterm delivery above general population rates. It is also possible that IFN-alpha may have a protective effect against pregnancy loss in cases of ET. PMID- 22200625 TI - Heme oxygenase-1 system, inflammation and ventilator-induced lung injury. AB - Mechanical ventilation is an indispensable supportive intervention for acute respiratory failure. However, mechanical ventilation can provoke ventilator induced lung injury, which remains one of the major causes of morbidity and mortality in critically ill patients. Excessive inflammatory response characterized by infiltration of inflammatory cells and overproduction of inflammatory mediators contributes to the pathogenesis of ventilator-induced lung injury. At present, apart from the protective ventilation strategy, no other pharmacological intervention is available to attenuate ventilator-induced lung injury. Heme oxygenase-1 (HO-1) is the inducible isoform of the first and rate limiting enzyme which degrades heme into carbon monoxide, ferritin and bilirubin. Accumulating evidence suggests that HO-1 system may function as a crucial negative regulator in the modulation of inflammatory process. This anti inflammatory action of HO-1 is mediated essentially by the regulation of the key cells involved in inflammation and restoration of the balance between pro inflammatory and anti-inflammatory mediators. Therefore, HO-1 system represents a promising therapeutic target for intervention of ventilator-induced lung injury. PMID- 22200626 TI - Hetero-oligomerization between adenosine A1 and thromboxane A2 receptors and cellular signal transduction on stimulation with high and low concentrations of agonists for both receptors. AB - Growing evidence indicates that G protein-coupled receptors can form homo- and hetero-oligomers to diversify signal transduction. However, the molecular mechanisms and physiological significance of G protein-coupled receptor-oligomers are not fully understood. Both ADOR1 (adenosine A(1) receptor) and TBXA2R (thromboxane A(2) receptor alpha; TPalpha receptor), members of the G protein coupled receptor family, act on astrocytes and renal mesangial cells, suggesting certain functional correlations. In this study, we explored the possibility that adenosine A(1) and TPalpha receptors form hetero-oligomers with novel pharmacological profiles. We showed that these receptors hetero-oligomerize by conducting coimmunoprecipitation and bioluminescence resonance energy transfer (BRET(2)) assays in adenosine A(1) receptor and TPalpha receptor-cotransfected HEK293T cells. Furthermore, coexpression of the receptors affected signal transduction including the accumulation of cyclic AMP and phosphorylation of extracellular signal-regulated kinase-1 and -2 was significantly increased by high and low concentrations of adenosine A(1) receptor agonist and TPalpha agonists, respectively. Our study provides evidence of hetero-oligomerization between adenosine A(1) and TPalpha receptors for the first time, and suggests that this oligomerization affects signal transduction responding to different concentrations of receptor agonists. PMID- 22200627 TI - Activation of alpha7 nicotinic acetylcholine receptors persistently enhances hippocampal synaptic transmission and prevents Abeta-mediated inhibition of LTP in the rat hippocampus. AB - Nicotinic acetylcholine receptors mediate fast cholinergic modulation of glutamatergic transmission and synaptic plasticity. Here we investigated the effects of subtype selective activation of the alpha7 nicotinic acetylcholine receptors on hippocampal transmission and the inhibition of synaptic long-term potentiation by the Alzheimer's disease associated amyloid beta-protein (Abeta). The alpha7 nicotinic acetylcholine receptor agonist "compound A" ((R)-N-(1 azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl))thiophene-2-carboxamide) induced a rapid onset persistent enhancement of synaptic transmission in the dentate gyrus in vitro. Consistent with a requirement for activation of alpha7 nicotinic acetylcholine receptors, the type II alpha7-selective positive allosteric modulator PheTQS ((3aR, 4S, 9bS)-4-(4-methylphenyl)-3a,4,5,9b-tetrahydro-3H cyclopenta[c]quinoline-8-sulfonamide) potentiated, and the antagonist methyllycaconitine (MLA) prevented the persistent enhancement. Systemic injection of the agonist also induced a similar MLA-sensitive persistent enhancement of synaptic transmission in the CA1 area in vivo. Remarkably, although compound A did not affect control long-term potentiation (LTP) in vitro, it prevented the inhibition of LTP by Abeta1-42 and this effect was inhibited by MLA. These findings strongly indicate that activation of alpha7 nicotinic acetylcholine receptors is sufficient to persistently enhance hippocampal synaptic transmission and to overcome the inhibition of LTP by Abeta. PMID- 22200628 TI - The anti-angiogenic and anti-tumor activity of synthetic phenylpropenone derivatives is mediated through the inhibition of receptor tyrosine kinases. AB - Abnormal angiogenesis plays a critical role in the pathogenesis of various diseases such as cancer and chronic inflammation. A variety of pro-angiogenic factors, including vascular endothelial growth factor (VEGF), exert their action through endothelial receptor tyrosine kinases (RTKs). The synthetic phenylpropenone derivatives, used in this study were the following: 1,3-diphenyl propenone (DPhP), 3-phenyl-1-thiophen-2-yl-propenone (PhT2P), 3-phenyl-1-thiophen 3-yl-propenone (PhT3P) and 1-furan-2-yl-3-phenyl-propenone (FPhP). These derivatives were screened for their inhibitory effect on VEGF-induced angiogenesis in vitro using HUVECs and in vivo using chick chorioallantoic membrane (CAM). The order of anti-angiogenic activity was DPhP>FPhP>PhT3P>PhT2P. The most effective compound DPhP, also known as chalcone, showed weak VEGF receptor tyrosine kinase activity compared with the specific inhibitor, SU4312 (3 [[4-(dimethylamino)phenyl]methylene]-1,3-dihydro-2H-indol-2-one). However, DPhP also inhibited several other receptor tyrosine kinases including Tie-2, epithermal growth factor (EGF) receptor, EphB2, fibroblast growth factor (FGF) receptor 3 and insulin-like growth factor-1 (IGF-1) receptor, as revealed by a receptor tyrosine kinase array assay. In addition, the down-stream signaling, including ERK phosphorylation and NF-kappaB activation, after receptor activation was significantly inhibited by DPhP. Furthermore, in the HT29 human colon cancer cell-inoculated CAM assay, the tumor growth and tumor-induced angiogenesis was significantly inhibited by DPhP (10MUg/ml). These results suggest that the simple flavonoid, DPhP (chalcone), has valuable potential as an antiangiogenic and anti cancer agent, and its action is mediated through the inhibition of multi-target RTKs including VEGF receptor 2. PMID- 22200629 TI - The effects of combined menthol and borneol on fluconazole permeation through the cornea ex vivo. AB - The bioavailabilities of eye drops are very low, so it is eager to find a safe and effective penetration enhancer to improve drug bioavailability. In our study, the corneas of New Zealand albino rabbit were mounted in the improved Franz diffusion cells for the measurement of fluconazole diffusion across the corneal permeation barrier. The fluconazole concentrations and the cumulative osmolalities were calculated to investigate the changes of permeation parameters of fluconazole through the ex vivo cornea in the presence of different penetration enhancers. Compared with the control group, 0.05% and 0.1% menthol, as well as menthol combined with borneol were considered as the penetration enhancer significantly promoted the permeation of fluconazole through the cornea ex vivo (P<0.05), but the same trend was not found in borneol groups. Furthermore, the combination of borneol and menthol significantly enhanced the permeation rate in the same concentration, compared with their effects when used alone (P<0.01). In order to investigate the feasibility and safety of the mixture, the corneal hydration level or wink frequency over 5 min were detected. So there were no significant differences between the mixture group and the control one. Consequently, menthol combined with borneol can highly enhance fluconazole permeation through the ex vivo cornea. Because of its low irritation, it may be a new efficient and safe penetration enhancer with a good development and application potential. PMID- 22200630 TI - Hsp70 promotes synaptic transmission in brain slices damaged by contact with blood clot. AB - Neurotrophic and neuroprotective properties of Hsp70 were studied in olfactory cortex slices of hypertensive rats under normal conditions and under influence of autologous blood (blood clot). Under normal conditions, synaptic response in slices depended on Hsp70 amount in medium. Incubation of slices with Hsp70 showed a biphasic effect on electrogenesis in tissue. Hsp70 (from 0.1 to 3.0 MUg/ml) stimulated glutamatergic and GABA-ergic receptor activity. An inhibitory action on synaptic response is detected at increased amounts of Hsp70 (>4 MUg/ml). Pretreatment with Hsp70 (1 and 10 MUg/ml) prevented the irreversible inhibition of bioelectric activity in neurons damaged by autologous blood action and interfered with swelling in slices. Our results indicate that exogenous Hsp70 may play a role in the maintenance of neuronal synaptic functions in normal conditions, and protects electrogenesis of brain tissue in strokes. PMID- 22200631 TI - Involvement of phosphatidylcholine-specific phospholipase C in thromboxane A2 receptor-mediated extracellular Ca2+ influx in rat aorta. AB - An involvement of signal transduction other than phosphatidylinositol turnover in thromboxane A(2) receptor (TP receptor)-mediated vascular contraction was investigated in rat aorta. The contraction induced by U46619, a TP receptor agonist, at low concentrations (<= 30 nM) was partially inhibited by verapamil, an inhibitor of voltage-dependent Ca(2+) channels (VDCC), and was further diminished in Ca(2+)-free solution. Twenty nanomolar of U46619 induced contraction and elevation of intracellular Ca(2+) concentration ([Ca(2+)](i)), which were consisted of two phases; slowly developing first phase followed by quickly rising second phase. The second phase was inhibited by verapamil, and all the [Ca(2+)](i) response was abolished in Ca(2+)-free solution. The contraction and [Ca(2+)](i) elevation induced by 20 nM U46619 were not inhibited by U73122, an inhibitor of phosphatidylinositol-specific phospholipase C, or GF109203X, a protein kinase C inhibitor, but were abolished by D609, an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC). However, D609 had no effect on those induced by 1 MUM phenylephrine. The U46619-induced responses were also partially inhibited by cation channel blockers, 2-APB and LOE908. The inhibition by LOE908 was abolished in the presence of verapamil, suggesting that LOE908-sensitive cation channels lead to the activation of VDCC by depolarizing plasma membrane. In contrast, 2-APB further diminished the U46619-induced [Ca(2+)](i) elevation in the presence of verapamil. In conclusion, TP receptor stimulation is suggested to be coupled with PC-PLC. Diacylglycerol produced by PC PLC seems to activate two types of cation channels independently of PKC, which in turn leads to VDCC-dependent and independent Ca(2+) influx, thereby eliciting contraction. PMID- 22200632 TI - Norcantharidin: a potential antiangiogenic agent for gallbladder cancers in vitro and in vivo. AB - Our objective was to explore the antiangiogenic activity of norcantharidin (NCTD) as an angiogenic inhibitor for gallbladder cancers. In vitro and in vivo experiments to determine the effects of NCTD on HUVECs, chicken CAM capillaries and gallbladder cancer xenograft angiogenesis in nude mice were respectively done. The MTT method was used to assay the cytotoxicity of NCTD on HUVECs. Immunofluorescence was used to evaluate HUVEC apoptosis. The scraping line method, matrigel invasion assay and tube formation assay were used to detect the migration, invasion and tube formation of HUVECs. A digital camera was used to observe chicken CAM capillaries. Experiments with NCTD in a xenograft model were used to observe the effect of NCTD on xenograft growth and survival of mice with xenografts. CD34 immunohistochemistry, flow cytometry and micro-MRA were used, respectively, to determine MVD, cell apoptosis and hemodynamic analysis of the xenografts. Immunohistochemistry and RT-PCR were used, respectively, to detect the expression of VEGF, Ang-2, TSP, TIMP-2 proteins/mRNAs of the xenografts. The xenograft MVD associated with tumor volume, the PCNA/apoptosis ratio and related protein expression was evaluated simultaneously. We found that NCTD effectively inhibited the proliferation, migration, invasion and capillary-like tube formation of HUVECs in vitro; it reduced angiogenesis and directly destroyed the formed CAM capillaries in vivo. In the experiments in mice, NCTD not only inhibited significantly xenograft proliferation and growth, prolonged survival time of mice with xenografts, decreased the xenograft MVD and vascular perfusion, but also, similarly to ES, decreased significantly the expression of VEGF or Ang 2 protein/mRNA, increased the expression of TSP or TIMP-2 protein/mRNA. Moreover, the xenograft MVD was positively related with tumor volume, PCNA/apoptosis ratio, and VEGF or Ang-2 expression, respectively (all P<0.05), but negatively correlated with TSP or TIMP-2 expression (both P<0.05). These data showed that NCTD could serve as a potential antiangiogenic agent for gallbladder cancers. PMID- 22200633 TI - Regulators of osteoclast differentiation and cell-cell fusion. AB - Osteoclasts are multinuclear giant cells derived from osteoclast/macrophage/dendritic cell common progenitor cells. The most characteristic feature of osteoclasts is multinucleation resulting from cell-cell fusion of mononuclear osteoclasts. Osteoclast cell-cell fusion is considered essential for re-organization of the cytoskeleton, such as the actin-ring and ruffled boarder to seal the resorbing area and to secret protons, respectively, to resorb bone; the fusion process is thus critical for osteoclast function. Various molecules, such as E-cadherin and macrophage fusion receptor (MFR), have been identified as regulators of osteoclast or macrophage cell-cell fusion. Laboratory production of osteoclasts used to be performed in a co-culture of osteoclast progenitors with osteoblastic cells, but recent advances in the identification of nuclear factor of kappa B ligand (RANKL) enabled the isolation of osteoclast-specific molecules involving osteoclast cell-cell fusion and differentiation regulators from purified osteoclast mRNA, since osteoclasts can be formed without osteoblasts. The essential cell-cell fusion regulator, dendritic cell-specific transmembrane protein (DC-STAMP), was isolated by a cDNA subtractive screen between mononuclear macrophages and RANKL-induced multinuclear osteoclasts. The cell-cell fusion of osteoclasts and foreign body giant cells (FBGCs) was completely abrogated in DC-STAMP-deficient mice in vivo and in vitro. Bone resorbing activity was significantly reduced but was still detected in DC STAMP-deficient osteoclasts. DC-STAMP expression is positively regulated by two transcriptional factors: nuclear factor of activated T cells 1 (NFATc1) and c Fos, both of which are essential for osteoclast differentiation. Furthermore, a novel osteoclastogenesis-regulating pathway involving two transcriptional repressors [B cell lymphoma 6 (Bcl6) and B lymphocyte-induced maturation protein 1 (Blimp1)] under RANKL stimulation has been discovered. The expression of osteoclastic genes such as DC-STAMP, NFATc1, and Cathepsin K, as well as osteoclast differentiation, was inhibited by Bcl6. Bcl6-deficient mice showed enhanced osteoclastogenesis and reduced bone mass, whereas osteoclast-specific Blimp1-conditional knockout mice showed elevated Bcl6 expression, osteoclastic gene expression, and osteoclast differentiation and increased bone mass. In this review, recent advances in our understanding of the regulators of osteoclast differentiation and cell-cell fusion are discussed. PMID- 22200634 TI - Non-coding RNAs for medical practice in oncology. AB - Alterations in microRNA (miRNA) and other short or long non-coding RNA (ncRNA) are involved in the initiation, progression, and metastasis of human cancer. The main molecular alterations result from variations in gene expression, which are usually minor but have consequences for a vast number of target protein-coding genes. The causes of the widespread differential expression of ncRNAs in malignant cells compared with normal cells can be explained by the location of these genes in genomic regions associated with cancer, by epigenetic mechanisms, and by alterations in the processing machinery. Expression profiling of human tumors based on the expression of miRNAs and other short or long ncRNAs has identified signatures associated with diagnosis, staging, progression, prognosis, and response to treatment. In addition, profiling has been exploited to identify ncRNAs that may represent downstream targets of activated oncogenic pathways or that target protein-coding genes involved in cancer. Recent studies found that miRNAs and non-coding ultraconserved genes are the main candidates for the elusive class of cancer-predisposing genes and that other types of ncRNAs participate in the genetic puzzle that gives rise to the malignant phenotype. These discoveries could be exploited for the development of useful markers for diagnosis and prognosis in cancer, as well as for the development of new RNA based cancer therapies. PMID- 22200635 TI - Modulation of event-related desynchronization during motor imagery with transcranial direct current stimulation in a patient with severe hemiparetic stroke: a case report. AB - Recently, surface electroencephalogram (EEG)-based brain-machine interfaces (BMI) have been used for people with disabilities. As a BMI signal source, event related desynchronization of alpha-band EEG (8-13 Hz) during motor imagery (mu ERD), which is interpreted as desynchronized activities of the activated neurons, is commonly used. However, it is often difficult for patients with severe hemiparesis to produce mu ERD of sufficient strength to activate BMI. Therefore, whether it is possible to modulate mu ERD during motor imagery with anodal transcranial direct-current stimulation (tDCS) was assessed in a severe left hemiparetic stroke patient. EEG was recorded over the primary motor cortex (M1), and mu ERD during finger flexion imagery was measured before and after a 5-day course of tDCS applied to M1. The ERD recorded over the affected M1 increased significantly after tDCS intervention. Anodal tDCS may increase motor cortex excitability and potentiate ERD during motor imagery in patients with severe hemiparetic stroke. PMID- 22200637 TI - Application of a public health framework to examine the characteristics of coroners' recommendations for injury prevention. AB - OBJECTIVES: Exploring the characteristics of recommendations generated from medicolegal death investigations is an important step towards improving their contribution to injury prevention. This study aimed to: (1) quantify coroners' recommendations; and (2) examine the nature of these recommendations according to public health principles of injury causation and prevention. METHODS: Deaths where coroners' recommendations were and were not made in the State of Victoria, Australia during the period 1 July 2000 to 30 June 2005 were compared by sex, age group and underlying cause of death. The nature of recommendations made was examined retrospectively using a derived model based on principles of injury causation and prevention, comprising seven elements: (1) priority population; (2) risk/contributing factors; (3) countermeasure; (4) level of intervention; (5) strategy for implementation; (6) organisation; (7) time frame for implementation. RESULTS: Coroners' recommendations were relatively rare, made in only ~6% of external-cause deaths. When coroners did make recommendations, they were statistically significantly more likely for persons aged 0-14 years and deaths resulting from transport crashes, complications of medical and surgical care, drowning and inanimate mechanical forces. Of the coroners' recommendations, ~70% included at least four of the model's seven elements. The elements 'countermeasure' and 'level of intervention' were most commonly specified by coroners (~95%) in their recommendations. CONCLUSIONS: This study shows that highly evolved medicolegal death investigation systems may not draw systematically from the scientific research evidence base to inform the formulation of coroners' public health and safety recommendations. To maximise its contribution to fatal injury prevention, the medicolegal death investigation may benefit from incorporation of a public health perspective. PMID- 22200636 TI - LTR retrotransposons contribute to genomic gigantism in plethodontid salamanders. AB - Among vertebrates, most of the largest genomes are found within the salamanders, a clade of amphibians that includes 613 species. Salamander genome sizes range from ~14 to ~120 Gb. Because genome size is correlated with nucleus and cell sizes, as well as other traits, morphological evolution in salamanders has been profoundly affected by genomic gigantism. However, the molecular mechanisms driving genomic expansion in this clade remain largely unknown. Here, we present the first comparative analysis of transposable element (TE) content in salamanders. Using high-throughput sequencing, we generated genomic shotgun data for six species from the Plethodontidae, the largest family of salamanders. We then developed a pipeline to mine TE sequences from shotgun data in taxa with limited genomic resources, such as salamanders. Our summaries of overall TE abundance and diversity for each species demonstrate that TEs make up a substantial portion of salamander genomes, and that all of the major known types of TEs are represented in salamanders. The most abundant TE superfamilies found in the genomes of our six focal species are similar, despite substantial variation in genome size. However, our results demonstrate a major difference between salamanders and other vertebrates: salamander genomes contain much larger amounts of long terminal repeat (LTR) retrotransposons, primarily Ty3/gypsy elements. Thus, the extreme increase in genome size that occurred in salamanders was likely accompanied by a shift in TE landscape. These results suggest that increased proliferation of LTR retrotransposons was a major molecular mechanism contributing to genomic expansion in salamanders. PMID- 22200639 TI - Molecular cloning and expression profiles of nitric oxide synthase (NOS) in mud crab Scylla paramamosain. AB - The importance of the nitric oxide synthase (NOS) gene family is demonstrated by many studies in vertebrates and invertebrates in recent years. However, it keeps unknown of nitric oxide (NO) system and NOS gene family in mud crab Scylla paramamosain, an important cultured commercial crustacean in China and Pacific area. In this report, the cDNA of NOS containing full-length ORF was cloned from mud crab, S. paramamosain. It was of 4424 bp, including a 5'-terminal untranslated region (UTR) of 239 bp, a 3'-terminal UTR of 540 bp, which contained two ATTTA motifs, and an open reading frame (ORF) of 3645 bp encoding a polypeptide of 1214 amino acids. Structural analysis indicated that NOS contained a typical NO synthase domain at the N-terminal, next to a flavodoxin 1 domain, a flavin adenine dinucleotide (FAD) binding domain, respectively, and a conservative nicotinamide adenine dinucleotide (NAD) binding domain structure at the C-terminal. Quantitative real-time PCR analysis revealed S. paramamosain NOS (SpNOS) to be expressed in all tissues examined, with the highest expression in midintestine and the weakest level in heart and eyestalk. The expression profiles of SpNOS indicated that the NOS expression levels were significantly induced in midintestine, hepatopancrease and hemocytes after challenged with Vibrio Parahaemolyticus, the synthetic double-stranded RNA polyinosinic polycytidylic acid (poly I:C) and lipopolysaccharides (LPS). The NOS activity in hemocytes showed significant increase during at 24 h-48 h time period after immune challenges with V. Parahaemolyticus, poly I:C and LPS. Results here may suggest that the inducible NOS play an important role in mud crab's defense against pathogenic infection. PMID- 22200638 TI - Two Kazal-type protease inhibitors from Macrobrachium nipponense and Eriocheir sinensis: comparative analysis of structure and activities. AB - Kazal-type inhibitors (KPIs) play important roles in many biological and physiological processes, such as blood clotting, the immune response and reproduction. In the present study, two male reproductive tract KPIs, termed Man KPI and Ers-KPI, were identified in Macrobrachium nipponense and Eriocheir sinensis, respectively. The inhibitory activities of recombinant Man-KPI and Ers KPI against chymotrypsin, elastase, trypsin and thrombin were determined. The results showed that both of them strongly inhibit chymotrypsin and elastase. Kinetic studies were performed to elucidate their inhibition mechanism. Furthermore, individual domains were also expressed to learn further which domain contributes to the inhibitory activities of intact KPIs. Only Man-KPI_domain3 is active in the inhibition of chymotrypsin and elastase. Meanwhile, Ers-KPI_domain2 and 3 are responsible for inhibition of chymotrypsin, and Ers-KPI_domains2, 3 and 4 are responsible for the inhibition of elastase. Meanwhile, the inhibitory activities of these two KPIs toward Macrobrachium rosenbergii, M. nipponense and E. sinensis sperm were compared with that of the Kazal-type peptidase inhibitor (MRPINK) characterized from the M. rosenbergii reproductive tract in a previous study. The results demonstrated that KPIs can completely inhibit the gelatinolytic activities of sperm proteases from their own species, while different levels of cross-inhibition were observed between KPI and proteases from different species. These results may provide new perspective to further clarify the mechanism of KPI-proteases interaction in the male reproductive system. PMID- 22200640 TI - Application of PCR-denaturing-gradient gel electrophoresis (DGGE) method to examine microbial community structure in asparagus fields with growth inhibition due to continuous cropping. AB - Growth inhibition due to continuous cropping of asparagus is a major problem; the yield of asparagus in replanted fields is low compared to that in new fields, and missing plants occur among young seedlings. Although soil-borne disease and allelochemicals are considered to be involved in this effect, this is still controversial. We aimed to develop a technique for the biological field diagnosis of growth inhibition due to continuous cropping. Therefore, in this study, fungal community structure and Fusarium community structure in continuously cropped fields of asparagus were analyzed by polymerase chain reaction/denaturing gradient gel electrophoresis (PCR-DGGE). Soil samples were collected from the Aizu region of Fukushima Prefecture, Japan. Soil samples were taken from both continuously cropped fields of asparagus with growth inhibition and healthy neighboring fields of asparagus. The soil samples were collected from the fields of 5 sets in 2008 and 4 sets in 2009. We were able to distinguish between pathogenic and non-pathogenic Fusarium by using Alfie1 and Alfie2GC as the second PCR primers and PCR-DGGE. Fungal community structure was not greatly involved in the growth inhibition of asparagus due to continuous cropping. By contrast, the band ratios of Fusarium oxysporum f. sp. asparagi in growth-inhibited fields were higher than those in neighboring healthy fields. In addition, there was a positive correlation between the band ratios of Fusarium oxysporum f. sp. asparagi and the ratios of missing asparagus plants. We showed the potential of biological field diagnosis of growth inhibition due to continuous cropping of asparagus using PCR-DGGE. PMID- 22200641 TI - Distribution of ammonia-oxidizing archaea and bacteria in the surface sediments of Matsushima Bay in relation to environmental variables. AB - Ammonia oxidization is the first and a rate-limiting step of nitrification, which is often a critical process in nitrogen removal from estuarine and coastal environments. To clarify the correlation of environmental conditions with the distribution of ammonia oxidizers in organic matter-rich coastal sediments, ammonia-oxidizing archaea (AOA) and bacteria (AOB) ammonia monooxygenase alpha subunit gene (amoA) abundance was determined in sediments of Matsushima Bay located in northeast Japan. The AOA and AOB amoA copy numbers ranged from 1.1*10(6) to 1.7*10(7) and from 7.1*10(5) to 7.6*10(6) copies g(-1) sediment, respectively. AOA and AOB amoA abundance was negatively correlated with dissolved oxygen levels in the bottom water. AOA amoA abundance was also correlated with total phosphorus levels in the sediments. On the other hand, no significant relationship was observed between the amoA abundance and ammonium, organic matter (ignition loss), or acid volatile sulfide-sulfur levels in the sediments. These results show the heterogeneous distribution of ammonia oxidizers by the difference in environmental conditions within the bay. Moreover, AOA amoA diversity was relatively low in the area of high AOA amoA abundance, suggesting the variability of AOA community composition. PMID- 22200642 TI - Vertical profiles of abundance and potential activity of methane-oxidizing bacteria in sediment of Lake Biwa, Japan. AB - Vertical profiles of the abundance, community composition, and potential activity of methane-oxidizing bacteria (MOB) were investigated in the sediment of Lake Biwa. Sediment samples were obtained from two sites at different water depths. The abundance of MOB was assessed as the copy number of the pmoA gene (encoding the alpha subunit of particulate methane monooxygenase), measured with quantitative real-time PCR. Abundance of the pmoA gene peaked in the 5-8 cm layer of the sediment from both sites. MOB community composition was investigated by denaturing gradient gel electrophoresis (DGGE) analysis of pmoA and 16S rRNA genes. The band patterns observed in DGGE did not significantly differ with sediment depths or sampling sites. Sequence analysis of the DGGE bands indicated the dominance of the genus Methylobacter. Potential activity, which was measured in the presence of sufficient amounts of methane and oxygen, decreased linearly from the sediment surface to deeper layers. These results suggest that the pmoA gene copy number cannot be regarded as an indicator of aerobic MOB that retain potential activity in sediments. PMID- 22200644 TI - Bacillus thuringiensis Cry3Aa toxin increases the susceptibility of Crioceris quatuordecimpunctata to Beauveria bassiana infection. AB - The spotted asparagus beetle, Crioceris quatuordecimpunctata (Coleoptera: Chrysomelidae), is one of the most devastating pests of asparagus in China. Sprayed synthetic pesticides have been used to control C. quatuordecimpunctata damage, but they pose problems because of residues and harm to natural enemies. Neither the microbial coleopteran-specific toxin from Bacillus thuringiensistenebrionis, Cry3Aa, nor the fungal pathogen Beauveria bassiana have sufficient activity to effectively control C. quatuordecimpunctata damage to asparagus. However, second instar C. quatuordecimpunctata larvae exposed to a sublethal dose of Cry3Aa toxin demonstrated significantly higher larval mortality when exposed to B. bassiana. Our results suggest that a combination of Cry3Aa and B. bassiana may be effective in reducing damage by C. quatuordecimpunctata larvae to asparagus. PMID- 22200645 TI - Antimicrobial activity of Amazonian oils against Paenibacillus species. AB - The Gram-positive, spore-forming bacterium Paenibacillus larvae is the primary bacterial pathogen of honeybee brood and the causative agent of American foulbrood disease (AFB). One of the feasible alternative treatments being used for their control of this disease is essential oils. In this study in vitro antimicrobial activity of Andiroba and Copaiba essential oils against Paenibacillus species, including P. larvae was evaluated. Minimal inhibitory concentration (MIC) in Mueller-Hinton broth by the microdilution method was assessed. Andiroba registered MIC values of 1.56-25%, while the MICs values obtained for Copaiba oil were of 1.56-12.5%. In order to determine the time response effect of essential oils on P. larvae, this microorganism was exposed to the oils for up to 48 h. After 24 h treatment with Andiroba oil and after 48 h treatment with Copaiba oil no viable cells of P. larvae ATCC 9545 were observed. The possible toxic effect of essential oils were assessed by the spraying application method of the same concentrations of MICs. Bee mortality was evident only in treatment with Andiroba oil and the Copaiba oil shows no toxic effects after 10 days of observation. Taking together ours results showed for the first time that these oils presented a high activity against Paenibacillus species showing that Copaiba oil may be a candidate for the treatment or prevention of AFB. PMID- 22200646 TI - RASA1 analysis: clinical and molecular findings in a series of consecutive cases. AB - RASA1 mutations have been reported to be associated with hereditary capillary malformations (CM) with or without arteriovenous malformations (AVM), arteriovenous fistulas (AVF), or Parkes Weber syndrome. But the number of cases with RASA1 mutations reported to date is relatively small and the spectrum of phenotypes caused by mutations in this gene is not well defined. Mutation results and clinical findings in thirty-five unrelated consecutive cases sent for RASA1 molecular sequencing testing at ARUP Laboratories within the last two years were evaluated. Eight individuals had a pathogenic RASA1 mutation of which six were novel. These eight individuals all had CMs (seven had multifocal CMs; one had multiple CMs), and six also had a brain or facial AVM. Two individuals with multifocal CMs including one with a fast flow lesion had a variant of uncertain significance. All other individuals, including sixteen with CMs and one with a vein of Galen aneurysm, tested negative for a RASA1 mutation. Our data suggest that multifocal CM is the key clinical finding to suggest a RASA1 mutation. The clinical diagnostic mutation detection rate among all samples sent for RASA1 testing was 29% (10/35) which increases to approximately 39% (10/26) if patients without CMs are excluded. PMID- 22200647 TI - Ibogaine and the inhibition of acetylcholinesterase. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ibogaine is a psychoactive monoterpine indole alkaloid extracted from the root bark of Tabernanthe iboga Baill. that is used globally in medical and nonmedical settings to treat drug and alcohol addiction, and is of interest as an ethnopharmacological prototype for experimental investigation and pharmaceutical development. The question of whether ibogaine inhibits acetylcholinesterase (AChE) is of pharmacological and toxicological significance. MATERIALS AND METHODS: AChE activity was evaluated utilizing reaction with Ellman's reagent with physostigmine as a control. RESULTS: Ibogaine inhibited AChE with an IC(50) of 520+/-40 MUM. CONCLUSIONS: Ibogaine's inhibition of AChE is physiologically negligible, and does not appear to account for observations of functional effects in animals and humans that might otherwise suggest the possible involvement of pathways linked to muscarinic acetylcholine transmission. PMID- 22200648 TI - Graft-versus-host disease prophylaxis: does drug dosage matter? PMID- 22200649 TI - On the choice of prior density for the Bayesian analysis of pedigree structure. AB - This article is concerned with the choice of structural prior density for use in a fully Bayesian approach to pedigree inference. It is found that the choice of prior has considerable influence on the accuracy of the estimation. To guide this choice, a scale invariance property is introduced. Under a structural prior with this property, the marginal prior distribution of the local properties of a pedigree node (number of parents, offspring, etc.) does not depend on the number of nodes in the pedigree. Such priors are found to arise naturally by an application of the Minimum Description Length (MDL) principle, under which construction of a prior becomes equivalent to the problem of determining the length of a code required to encode a pedigree, using the principles of information theory. The approach is demonstrated using simulated and actual data, and is compared to two well-known applications, CERVUS and COLONY. PMID- 22200650 TI - Lessons from innovation in drug-device combination products. AB - Drug-device combination products introduced a new dynamic on medical product development, regulatory approval, and corporate interaction that provide valuable lessons for the development of new generations of combination products. This paper examines the case studies of drug-eluting stents and transdermal patches to facilitate a detailed understanding of the challenges and opportunities introduced by combination products when compared to previous generations of traditional medical or drug delivery devices. Our analysis indicates that the largest barrier to introduce a new kind of combination products is the determination of the regulatory center that is to oversee its approval. The first product of a new class of combination products offers a learning opportunity for the regulator and the sponsor. Once that first product is approved, the leading regulatory center is determined, and the uncertainty about the entire class of combination products is drastically reduced. The sponsor pioneering a new class of combination products assumes a central role in reducing this uncertainty by advising the decision on the primary function of the combination product. Our analysis also suggests that this decision influences the nature (pharmaceutical, biotechnology, or medical devices) of the companies that will lead the introduction of these products into the market, and guide the structure of corporate interaction thereon. PMID- 22200651 TI - Label-free impedimetric aptasensor for lysozyme detection based on carbon nanotube-modified screen-printed electrodes. AB - We report on the direct electrochemical detection of aptamer-protein interactions, namely between a DNA aptamer and lysozyme (LYS) based on electrochemical impedance spectroscopy (EIS) technique. First, the affinity of the aptamer to LYS and control proteins was presented by using filter retention assay. An amino-modified version of the DNA aptamer-recognizing lysozyme was covalently immobilized on the surface of multiwalled carbon nanotube-modified screen-printed electrodes (MWCNT-SPEs), which were employed for measurements and have improved properties compared with bare SPEs. This carbon nanotube setup enabled the reliable monitoring of the interaction of lysozyme with its cognate aptamer by EIS transduction of the resistance to charge transfer (R(ct)) in the presence of 2.5 mM [Fe(CN)6]3-/4-. This assay system provides a means for the label-free, concentration-dependent, and selective detection of lysozyme with an observed detection limit of 12.09 MUg/ml (equal to 862 nM). PMID- 22200652 TI - Study on alanine aminotransferase kinetics by microchip electrophoresis. AB - Alanine aminotransferase (ALT), which catalyzes the reversible conversion between L-glutamic acid (L-Glu) and L-alanine (L-Ala), is one of the most active aminotransferases in the clinical diagnosis of liver diseases. This work displays a microanalytical method for evaluating ALT enzyme kinetics using a microchip electrophoresis laser-induced fluorescence system. Four groups of amino acid (AA) mixtures, including the substrates of ALT (L-Glu and L-Ala), were effectively separated. Under the optimized conditions, the quantitative analysis of L-Glu and L-Ala was conducted and limits of detection (signal/noise=3) for L-Glu and L-Ala were 4.0 * 10-7 and 2.0 * 10-7 M, respectively. In the reaction catalyzed by ALT, enzyme kinetic constants were determined for both the forward and reverse reactions by monitoring the concentration decrease of substrate AAs (L-Ala and L Glu), and the K(m) and V(max) values were 10.12 mM and 0.48 mM/min for forward reaction and 3.22 mM and 0.22 mM/min for reverse reaction, respectively. Furthermore, the applicability of this assay was assessed by analysis of real serum samples. The results demonstrated that the proposed method could be used for kinetic study of ALT and shows great potential in the real application. PMID- 22200653 TI - Analytical method for determination of nitric oxide in zebrafish larvae: toxicological and pharmacological applications. AB - Zebrafish are currently used at various stages of the drug discovery process and can be a useful and cost-effective alternative to some mammalian models. Nitric oxide (NO) plays an important role in physiology of zebrafish. The availability of appropriate analytical techniques to quantify the NO is crucial for studying its role in physiological and pathological conditions. This work aimed at establishing a high-performance liquid chromatography method for determination of NO levels in zebrafish larvae. Attempts were also made to assess the normal levels of NO at the first days postfertilization and the possible changes under pathological conditions. The method validation was quantitatively evaluated in terms of sensitivity, specificity, precision, accuracy, linearity, and recovery. NO levels from zebrafish larvae at the first days postfertilization and larvae challenged to N(G)-nitro-L-arginine methyl ester, sodium nitroprusside, Escherichia coli lipopolysaccharide, and copper sulfate were analyzed. The samples were derivatized with 2,3-diaminonaphthalene, and fluorescence detection was used for the indirect determination of NO. The method showed a good performance for all validation parameters evaluated and was efficient to monitor changes in NO concentration under physiological and pathophysiological conditions. This method might represent a powerful tool to be applied in NO studies with zebrafish larvae. PMID- 22200654 TI - Time course of automatic emotion regulation during a facial Go/Nogo task. AB - Neuroimaging research has determined that the neural correlates of automatic emotion regulation (AER) include the anterior cingulate cortex. However, the corresponding time course remains unknown. In the current study, we collected event-related potentials (ERPs) from 20 healthy volunteers during a judgment of the gender of emotional faces in a cued Go/Nogo task. The results indicate that Go-N2 amplitudes and latencies following positive and negative faces decreased more than those following neutral faces; Nogo-N2 amplitudes and latencies did not vary with valence. Moreover, positive and negative faces prompted higher P3 amplitudes and shorter P3 latencies than neutral faces in both Go and Nogo trials. These observations suggest that in the executive processes, Go-N2 reflects top-down attention toward emotions, while Go-P3 reflects only motivated attention; in the inhibitory processes, Nogo-N2 reflects cognitive conflict monitoring, while Nogo-P3 overlaps with the automatic response inhibition of emotions. These observations imply that AER can modulate early ERP components, and both Go-N2 and Nogo-P3 can be used as electrophysiological indices of AER. PMID- 22200655 TI - Frontal brain activity pattern predicts depression in adolescent boys. AB - Limited research has explored the relationship between frontal brain activity and depression in adolescent boys. This study examined whether frontal brain activity predicted depressive symptoms in 41 adolescent boys one year later. A step-wise hierarchical regression analysis was conducted using frontal brain activity as predictors and depressive symptoms as the dependent variable, controlling for depressive symptoms at baseline. Results revealed that greater relative right sided activity predicted depressive symptoms in adolescent boys one year later. PMID- 22200656 TI - Neuroelectric indices of goal maintenance following a single bout of physical activity. AB - Previous event-related brain potential (ERP) investigations have demonstrated that single bouts of physical activity have transient benefits to aspects of cognitive control. However, this line of research has yet to explore goal maintenance. ERPs were collected using a within-participants design with young adults following 30-min of both moderate walking and a non-exercise control session. Participants completed three conditions of an AX-continuous performance task (AX-CPT) that targeted goal maintenance processes, which were placed under greater cognitive demand when contexts were conflicting, as indexed by modulation of the N2 and P3 components. Following exercise, individuals exhibited increased accuracy for target trials, and P3 amplitude was greater at midline-parietal sites for both target trials and non-target trials. These results suggest that a single bout of aerobic exercise may facilitate goal maintenance processes and enable individuals to better inhibit extraneous neural activity to allocate greater attentional resources towards the updating and revision of goal representations. PMID- 22200657 TI - Neural reactivity tracks fear generalization gradients. AB - Recent studies on fear generalization have demonstrated that fear-potentiated startle and skin conductance responses to a conditioned stimulus (CS) generalize to similar stimuli, with the strength of the fear response linked to perceptual similarity to the CS. The aim of the present study was to extend this work by examining neural correlates of fear generalization. An initial experiment (N=8) revealed that insula reactivity tracks the conditioned fear gradient. We then replicated this effect in a larger independent sample (N=25). Activation in the insula, anterior cingulate, right supplementary motor cortex and caudate increased reactivity as generalization stimuli (GS) were more similar to the CS, consistent with participants' overall ratings of perceived shock likelihood and pupillary response to each stimulus. PMID- 22200659 TI - Necrotizing sialometaplasia within a benign mixed tumor of parotid gland. PMID- 22200658 TI - Targeting lysophosphatidic acid receptor type 1 with Debio 0719 inhibits spontaneous metastasis dissemination of breast cancer cells independently of cell proliferation and angiogenesis. AB - Metastasis is the main cause of death for cancer patients. Targeting factors that control metastasis formation is a major challenge for clinicians. Lysophosphatidic acid (LPA) is a bioactive phospholipid involved in cancer. LPA activates at least six independent G protein-coupled receptors (LPA1-6). Tumor cells frequently co-express multiple LPA receptors, puzzling the contribution of each one to cancer progression. All three receptors, LPA1, LPA2 and LPA3, act as oncogenes and prometastatic factors in the mouse mammary gland. The competitive inhibitor of LPA1 and LPA3 receptors, Ki16425, inhibits efficiently breast cancer bone metastases in animal models. We showed here that Debio 0719, which corresponds to the R-stereoisomer of Ki16425 exhibited highest antagonist activities at LPA1 (IC50=60 nM) and LPA3 (IC50=660 nM) than Ki16425 [IC50=130 nM (LPA1); IC50=2.3 uM (LPA3)]. In vitro, Debio 0719, inhibited LPA-dependent invasion of the 4T1 mouse mammary cancer cells. In vivo, early but not late administration of Debio 0719 (50 mg/kg p.o. twice daily) to BALB/c mice during the course of orthotopic 4T1 primary tumor growth reduced the number of spontaneously disseminated tumor cells to bone and lungs without affecting the growth of primary tumors and tumor-induced angiogenesis. We found that increased LPA1 mRNA expression in primary tumors of breast cancer patients correlated significantly with their positive lymph node status (p<0.001). Altogether, our results suggest that LPA1 controls early events of metastasis independently of cell proliferation and angiogenesis. Therefore, targeting this receptor with Debio 0719 has a high therapeutic potential against metastasis formation for breast cancer patients. PMID- 22200660 TI - Malignant peripheral nerve sheath tumor with primitive neuroepithelial differentiation in an adult: a case report. AB - Primitive neuroepithelial differentiation in malignant peripheral nerve sheath tumors (MPNSTs) has been reported in children but is extremely rare in adults. The authors report the case of a 70-year-old woman who presented with swelling of the right leg of 1-month duration. Fine-needle aspiration cytology was suggestive of a benign peripheral nerve sheath tumor. Histopathological examination of the excised mass revealed a MPNST with spindle-cell areas and a few round-cell areas with rosettes. The spindle cells showed positive immunoreactivity for S-100 protein and vimentin and negativity for desmin, confirming their nerve sheath origin. The round cells were immunoreactive for synaptophysin and chromogranin, indicating primitive neuroepithelial differentiation. These cells did not stain for CD99, which is consistently expressed by the cells of primitive neuroectodermal tumors (PNETs) of bone and soft tissue but not by central nervous system (CNS) PNETs or medulloblastomas. In this case, the PNET-like focus resembled a CNS-PNET. PMID- 22200661 TI - ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion. AB - ADAM17, also known as tumor necrosis factor-alpha converting enzyme (TACE), is involved in proteolytic ectodomain shedding of cell surface molecules and cytokines. Although aberrant expression of ADAM17 has been shown in various malignancies, the function of ADAM17 in prostate cancer has not been clarified. In the present study, we sought to elucidate whether ADAM17 contributes to prostate cancer cell invasion, as well as the mechanism involved in the process. The expression pattern of ADAM17 was investigated in human prostate cancer cells. The results showed that ADAM17 expression levels are correlated with the invasive ability of androgen-independent prostate cancer cell lines. Further, ADAM17 was overexpressed in cells showing high invasion characteristics, activation of the EGFR-MEK-ERK pathway, up-regulation of MMP-2, MMP-9, and an increased TGF-alpha release into the supernatant. However, AG1478, PD98059 and antibody against TGF alpha deactivating the EGFR-MEK-ERK signaling pathway, abolished up-regulation of MMP-2, MMP-9 and prevented cell invasion. In addition, cells with knockdown of ADAM17 by siRNA exhibited low invasive ability, deactivated EGFR-MEK-ERK signaling pathway, reduced TGF-alpha released and down-regulation of MMP-2, MMP 9. However, these effects could be reversed by simultaneous addition of TGF alpha. These data demonstrated that ADAM17 contributes to androgen-independent prostate cancer cell invasion by shedding of EGFR ligand TGF-alpha, which subsequently activates the EGFR-MEK-ERK signaling pathway, leading finally to overexpression of MMP-2 and MMP-9. This study suggests that the ADAM17 expression level may be a new predictive biomarker of invasion and metastasis of prostate cancer, and ADAM17 could provide a target for treating metastatic PCa. PMID- 22200662 TI - A survey of carbon fixation pathways through a quantitative lens. AB - While the reductive pentose phosphate cycle is responsible for the fixation of most of the carbon in the biosphere, it has several natural substitutes. In fact, due to the characterization of three new carbon fixation pathways in the last decade, the diversity of known metabolic solutions for autotrophic growth has doubled. In this review, the different pathways are analysed and compared according to various criteria, trying to connect each of the different metabolic alternatives to suitable environments or metabolic goals. The different roles of carbon fixation are discussed; in addition to sustaining autotrophic growth it can also be used for energy conservation and as an electron sink for the recycling of reduced electron carriers. Our main focus in this review is on thermodynamic and kinetic aspects, including thermodynamically challenging reactions, the ATP requirement of each pathway, energetic constraints on carbon fixation, and factors that are expected to limit the rate of the pathways. Finally, possible metabolic structures of yet unknown carbon fixation pathways are suggested and discussed. PMID- 22200663 TI - Effects of non-uniform root zone salinity on water use, Na+ recirculation, and Na+ and H+ flux in cotton. AB - A new split-root system was established through grafting to study cotton response to non-uniform salinity. Each root half was treated with either uniform (100/100 mM) or non-uniform NaCl concentrations (0/200 and 50/150 mM). In contrast to uniform control, non-uniform salinity treatment improved plant growth and water use, with more water absorbed from the non- and low salinity side. Non-uniform treatments decreased Na(+) concentrations in leaves. The [Na(+)] in the '0' side roots of the 0/200 treatment was significantly higher than that in either side of the 0/0 control, but greatly decreased when the '0' side phloem was girdled, suggesting that the increased [Na(+)] in the '0' side roots was possibly due to transportation of foliar Na(+) to roots through phloem. Plants under non-uniform salinity extruded more Na(+) from the root than those under uniform salinity. Root Na(+) efflux in the low salinity side was greatly enhanced by the higher salinity side. NaCl-induced Na(+) efflux and H(+) influx were inhibited by amiloride and sodium orthovanadate, suggesting that root Na(+) extrusion was probably due to active Na(+)/H(+) antiport across the plasma membrane. Improved plant growth under non-uniform salinity was thus attributed to increased water use, reduced leaf Na(+) concentration, transport of excessive foliar Na(+) to the low salinity side, and enhanced Na(+) efflux from the low salinity root. PMID- 22200664 TI - Ascorbic acid and reactive oxygen species are involved in the inhibition of seed germination by abscisic acid in rice seeds. AB - The antagonism between abscisic acid (ABA) and gibberellin (GA) plays a key role in controlling seed germination, but the mechanism of antagonism during this process is not known. The possible links among ABA, reactive oxygen species (ROS), ascorbic acid (ASC), and GA during rice seed germination were investigated. Unlike in non-seed tissues where ROS production is increased by ABA, ABA reduced ROS production in imbibed rice seeds, especially in the embryo region. Such reduced ROS also led to an inhibition of ASC production. GA accumulation was also suppressed by a reduced ROS and ASC level, which was indicated by the inhibited expression of GA biosynthesis genes, amylase genes, and enzyme activity. Application of exogenous ASC can partially rescue seed germination from ABA treatment. Production of ASC, which acts as a substrate in GA biosynthesis, was significantly inhibited by lycorine which thus suppressed the accumulation of GA. Consequently, expression of GA biosynthesis genes was suppressed by the low levels of ROS and ASC in ABA-treated seeds. It can be concluded that ABA regulates seed germination in multiple dimensions. ROS and ASC are involved in its inhibition of GA biosynthesis. PMID- 22200665 TI - Subcellular analysis of starch metabolism in developing barley seeds using a non aqueous fractionation method. AB - Compartmentation of metabolism in developing seeds is poorly understood due to the lack of data on metabolite distributions at the subcellular level. In this report, a non-aqueous fractionation method is described that allows subcellular concentrations of metabolites in developing barley endosperm to be calculated. (i) Analysis of subcellular volumes in developing endosperm using micrographs shows that plastids and cytosol occupy 50.5% and 49.9% of the total cell volume, respectively, while vacuoles and mitochondria can be neglected. (ii) By using non aqueous fractionation, subcellular distribution between the cytosol and plastid of the levels of metabolites involved in sucrose degradation, starch synthesis, and respiration were determined. With the exception of ADP and AMP which were mainly located in the plastid, most other metabolites of carbon and energy metabolism were mainly located outside the plastid in the cytosolic compartment. (iii) In developing barley endosperm, the ultimate precursor of starch, ADPglucose (ADPGlc), was mainly located in the cytosol (80-90%), which was opposite to the situation in growing potato tubers where ADPGlc was almost exclusively located in the plastid (98%). This reflects the different subcellular distribution of ADPGlc pyrophosphorylase (AGPase) in these tissues. (iv) Cytosolic concentrations of ADPGlc were found to be close to the published K(m) values of AGPase and the ADPGlc/ADP transporter at the plastid envelope. Also the concentrations of the reaction partners glucose-1-phosphate, ATP, and inorganic pyrophosphate were close to the respective K(m) values of AGPase. (v) Knock-out of cytosolic AGPase in Riso16 mutants led to a strong decrease in ADPGlc level, in both the cytosol and plastid, whereas knock-down of the ADPGlc/ADP transporter led to a large shift in the intracellular distribution of ADPGlc. (v) The thermodynamic structure of the pathway of sucrose to starch was determined by calculating the mass-action ratios of all the steps in the pathway. The data show that AGPase is close to equilibrium, in both the cytosol and plastid, whereas the ADPGlc/ADP transporter is strongly displaced from equilibrium in vivo. This is in contrast to most other tissues, including leaves and potato tubers. (vi) Results indicate transport rather than synthesis of ADPGlc to be the major regulatory site of starch synthesis in barley endosperm. The reversibility of AGPase in the plastid has important implications for the regulation of carbon partitioning between different biosynthetic pathways. PMID- 22200667 TI - Intrarectal administration of milk fat globule epidermal growth factor-8 protein ameliorates murine experimental colitis. AB - Milk fat globule epidermal growth factor-8 (MFG-E8) promotes phagocytic clearance of apoptotic cells to maintain normal tissue homeostasis. However, its functions in intestinal inflammatory disorders are unknown. Since the pathogenesis of those disorders are due to abnormal interactions between intestinal epithelial cells (IECs) and microbial pathogens, we analyzed the effects of MFG-E8 on IECs to determine its protective role in murine experimental colitis. Expression of alphavbeta3-integrin in Colon-26 cells was examined by RT-PCR and immunostaining. Colon-26 cells were pretreated with recombinant wild-type and mutant MFG-E8 proteins, following stimulation with flagellin as an inducer of innate immunity, and the effects of the recombinant proteins on inhibition of nuclear factor kappaB (NF-kappaB) and inflammatory cytokine production in flagellin-stimulated Colon-26 cells were determined using a luciferase assay and EIA, respectively. Experimental colitis was induced in mice by intrarectal administration of trinitrobenzene sulfonic acid (TNBS). Recombinant proteins were then intrarectally administered into TNBS-induced colitic mice, after which disease activity parameters (body weight, colon length, histological score), as well as interleukin (IL)-6 and MIP-2 levels were determined in inflamed tissues. Flagellin-induced inflammatory cytokine production in vitro was significantly downregulated via alphavbeta3-integrin following pretreatment with wild-type MFG E8 due to inhibition of NF-kappaB activation. In vivo, intrarectal treatment with wild-type MFG-E8, but not its mutant counterpart, significantly inhibited body weight loss, colon shortening and histological inflammation induced by TNBS administration. Our findings suggest that MFG-E8 has anti-inflammatory effects on flagellin-induced inflamed intestinal epithelial cells and may be a useful therapeutic agent for colitis. PMID- 22200668 TI - alpha-Enolase and caveolin alterations in the heart of rats having undergone gentamicin-induced toxicity. AB - Gentamicin (GM)-induced heart damage is associated with alterations in expression levels of various enzymes and proteins. The aim of the present study was to investigate GM-induced alterations in cardiac alpha-enolase and caveolin after GM administration. Male Wistar rats were randomly divided into two groups: a control group and a GM group. The GM group intraperitoneally received GM at a single dose of 7 mg/kg for 8 days, while the controls were given the same amount of saline via the same route. On Day 9, the rats were anesthetized and a thoracotomy was performed in all animals. Immunohistochemical analysis was performed to evaluate protein expression of alpha-enolase and caveolin. Sections were analyzed by digital image analysis. Our results revealed that cardiac protein expression of alpha-enolase and caveolin was altered after GM-induced toxicity in the rat. The expression of alpha-enolase and caveolin was significantly increased after GM induced toxicity, as determined by integrated optical density analysis, when compared with the control (P<0.05). The current findings indicate that such changes in protein expression may be reflected in abnormal cardiac function, and the proteins identified in this study may be useful for elucidating the mechanisms underlying GM-induced toxicity and may also provide various clues for further investigations. PMID- 22200666 TI - Plant organellar calcium signalling: an emerging field. AB - This review provides a comprehensive overview of the established and emerging roles that organelles play in calcium signalling. The function of calcium as a secondary messenger in signal transduction networks is well documented in all eukaryotic organisms, but so far existing reviews have hardly addressed the role of organelles in calcium signalling, except for the nucleus. Therefore, a brief overview on the main calcium stores in plants-the vacuole, the endoplasmic reticulum, and the apoplast-is provided and knowledge on the regulation of calcium concentrations in different cellular compartments is summarized. The main focus of the review will be the calcium handling properties of chloroplasts, mitochondria, and peroxisomes. Recently, it became clear that these organelles not only undergo calcium regulation themselves, but are able to influence the Ca(2+) signalling pathways of the cytoplasm and the entire cell. Furthermore, the relevance of recent discoveries in the animal field for the regulation of organellar calcium signals will be discussed and conclusions will be drawn regarding potential homologous mechanisms in plant cells. Finally, a short overview on bacterial calcium signalling is included to provide some ideas on the question where this typically eukaryotic signalling mechanism could have originated from during evolution. PMID- 22200669 TI - Loss of breast cancer metastasis suppressor 1 promotes ovarian cancer cell metastasis by increasing chemokine receptor 4 expression. AB - Breast cancer metastasis suppressor 1 (BRMS1) is a predominantly nuclear protein that differentially regulates the expression of multiple genes, leading to suppression of metastasis without affecting orthotopic tumor growth. It has been demonstrated that BRMS1 may be correlated with advanced ovarian cancer. The aim of this study was to investi-gate the mechanisms of BRMS1 involvement in ovarian cancer metastasis. We constructed a plasmid containing a short hairpin RNA (shRNA) against BRMS1 and transfected it into the ovarian cancer cell line OVCAR3. Real-time reverse transcription polymerase chain reaction (real-time PCR) and Western blot analyses demonstrated that BRMS1 expression was efficiently downregulated. Stable suppression of BRMS1 significantly enhanced cell adhesion, migration, invasion and angiogenesis. We also found that chemokine receptor 4 (CXCR4) was upregulated at both the mRNA and protein levels. When approaching for the mechanism, we discovered that activation of the nuclear factor-kappaB (NF kappaB) signaling pathway mediated CXCR4 upregulation, as demonstrated by the electrophoretic mobility shift assay (EMSA). Collectively, these results suggest that attenuation of BRMS1 may play a critical role in promoting migration, invasion and angiogenesis of ovarian cancer cells and BRMS1 may regulate the metastatic potential at least in part through upregulation of CXCR4 via NF-kappaB activation. Restoration of BRMS1 function is thus a potential new strategy for treating human ovarian cancer. PMID- 22200670 TI - Differential effects of calcium antagonists on ABCG2/BCRP-mediated drug resistance and transport in SN-38-resistant HeLa cells. AB - The effects of 9 calcium antagonists on ABCG2/BCRP-mediated resistance and transport were examined in HeLa and SN-38-resistant HeLa (HeLa/SN100) cells, overexpressing ABCG2/BCRP. Sensitivity to mitoxantrone, an ABCG2/BCRP substrate, in HeLa/SN100 cells was significantly reversed by the coexistence of the calcium antagonists, except for diltiazem and verapamil. The accelerated transport activity of Hoechst33342, an ABCG2/BCRP substrate, in HeLa/SN100 cells was significantly decreased by the presence of the calcium antagonists, except for diltiazem, nifedipine or verapamil, returning to the level of HeLa cells. The present study classifies the calcium antagonists into 3 categories: strong (benidipine, felodipine, nicardipine, nisoldipine and nitrendipine), moderate (amlodipine and nifedipine) and weak (diltiazem and verapamil) inhibitors of ABCG2/BCRP. PMID- 22200671 TI - Development of high-grade B-cell lymphoma concurrent with T-cell chronic lymphocytic leukemia in a dog. AB - Second malignancies are frequent complications in human patients with chronic lymphocytic leukemia (CLL). However, the clinical details and outcome of this phenomenon were unclear in their canine counterparts. Here, we report a dog with high-grade lymphoma concurrent with T-cell CLL. A 10-year-old male golden retriever presented with lymphadenopathies. The lymph nodes contained large-sized lymphocytes, raising suspicion of high-grade lymphoma. Meanwhile, small lymphocytic lymphocytosis in the peripheral blood was consistent with CLL. Interestingly, molecular biological analyses revealed that CLL cells were of the T-cell type, whereas lymphoma cells were of the B-cell type. Chemotherapy using the L-VCA short protocol was effective for 155 days, but the dog died on day 194 after diagnosis, despite rescue therapies. PMID- 22200672 TI - In vitro antibacterial susceptibility of Arcobacter butzleri isolated from different sources. AB - The objective of this study was to determine the antibiotic susceptibility of Arcobacter spp. isolated from various sources. Seventy Arcobacter spp. isolates were tested for their susceptibility to 13 antimicrobial agents. Antimicrobial susceptibility testing was performed by using the agar disc diffusion method on Mueller-Hinton agar supplemented with 5% defibrinated sheep blood. The antibiotics tested included enrofloxacin, erythromycin, streptomycin, gentamycin, rifampin, tetracycline, ampicillin, trimethoprim/sulfamethoxazole, nalidixic acid, danofloxacin, amoxycillin-clavulonic acid, cefuroxime-sodium, neomycine. Although all the arcobacters tested were susceptible to gentamycin, resistance to three or more antibacterial agents (especially, trimethoprim/sulfamethoxazole, cefuroxime-sodium and rifampin) was observed. A. butzleri isolates were found to be resistant to amoxycillin+clavulonic acid, nalidixic acid and ampicillin, at the rate of 20%, 44.28% and 78.57% respectively. In conclusion, gentamycin, streptomycin and tetracycline may be suitable antibiotics for the treatment or control of disease caused by Arcobacter spp. in veterinary and human medicine. PMID- 22200673 TI - Possible association of decreased NKG2D expression levels and suppression of the activity of natural killer cells in patients with colorectal cancer. AB - Natural-killer group 2 (NKG2), a natural killer (NK) cell receptor, plays a critical role in regulating NK cytotoxicity. In this study, we investigated the expression levels of natural killer group 2 member A (NKG2A) and natural killer group 2 member D (NKG2D) in NK cells as well as the regulatory function of NKG2D in patients with colorectal cancer (CRC). Sixty-two CRC patients and 32 healthy controls were enrolled in this study. The expression levels of NKG2A and NKG2D mRNA in peripheral blood mononuclear cells (PBMCs) were investigated using real time PCR. Flow cytometry was performed to assay the levels of NKG2A and NKG2D proteins in NK cells. The levels of NKG2D mRNA in PBMCs in the patients were significantly lower than those in the controls [mean +/- SD, 1.11 +/- 0.60 (CRC patients) vs. 1.65 +/- 0.71 (healthy controls); p < 0.01], whereas the 2 groups showed no apparent difference in the levels of NKG2A mRNA (p>0.05). In addition, the patients showed significantly lower NKG2D levels in NK cells than the controls did (71.23% +/- 8.31% [CRC patients] vs. 79.39% +/- 5.58% [healthy controls]; p < 0.01). However, we observed no distinct difference in the NKG2A expression levels in NK cells between the 2 groups (p> 0.05). Notably, blockage of NKG2D signaling with anti-NKG2D antibodies ex vivo resulted in decreased cytotoxicity and CD107a degranulation. Our data revealed that the decrease in NKG2D expression levels may have been associated with suppression of NK cell activity in CRC patients. PMID- 22200674 TI - Evaluation of the salivary proteome as a surrogate tissue for systems biology approaches to understanding appetite. AB - Current measurement of appetite depends upon tools that are either subjective (visual analogue scales), or invasive (blood). Saliva is increasingly recognised as a valuable resource for biomarker analysis. Proteomics workflows may provide alternative means for the assessment of appetitive response. The study aimed to assess the potential value of the salivary proteome to detect novel biomarkers of appetite using an iTRAQ-based workflow. Diurnal variation of salivary protein concentrations was assessed. A randomised, controlled, crossover study examined the effects on the salivary proteome of isocaloric doses of various long chain fatty acid (LCFA) oil emulsions compared to no treatment (NT). Fasted males provided saliva samples before and following NT or dosing with LCFA emulsions. The oil component of the DHA emulsion contained predominantly docosahexaenoic acid and the oil component of OA contained predominantly oleic acid. Several proteins were present in significantly (p<0.05) different quantities in saliva samples taken following treatments compared to fasting samples. DHA caused alterations in thioredoxin and serpin B4 relative to OA and NT. A further study evaluated energy intake (EI) in response to LCFA in conjunction with subjective appetite scoring. DHA was associated with significantly lower EI relative to NT and OA (p=0.039). The collective data suggest investigation of salivary proteome may be of value in appetitive response. This article is part of a Special Issue entitled: Proteomics: The clinical link. PMID- 22200675 TI - Stimulation and clustering of cytochrome b5 reductase in caveolin-rich lipid microdomains is an early event in oxidative stress-mediated apoptosis of cerebellar granule neurons. AB - The apoptosis of cerebellar granule neurons (CGN) induced by low potassium in the extracellular medium is a model of neuronal apoptosis where an overshot of reactive oxygen species (ROS) triggers the neuronal death. In this work, using dihydroethidium and L-012 as specific dyes for superoxide anion detection we show that this ROS overshot can be accounted by an increased release of superoxide anion to the extracellular medium. The amplitude and time course of the increase of superoxide anion observed early during apoptosis correlated with the increase of the content of soluble cytochrome b(5), a substrate of the NADH-dependent oxidase activity of the cytochrome b(5) reductase associated with lipid rafts in CGN. Western blotting and immunofluorescence microscopy approaches, including fluorescence energy transfer, pointed out an enhanced clustering of cytochrome b(5) reductase within caveolins-rich lipid rafts microdomains. Protein/protein docking analysis suggests that cytochrome b(5) reductase can form complexes with caveolins 1alpha, 1beta and 2, playing electrostatic interactions a major role in this association. In conclusion, our results indicate that overstimulation of cytochrome b(5) reductase associated with lipid rafts can account for the overshot of plasma membrane-focalized superoxide anion production that triggers the entry of CGN in the irreversible phase of apoptosis. This article is part of a Special Issue entitled: Proteomics: The clinical link. PMID- 22200676 TI - Carbohydrate transporting membrane proteins of the rumen bacterium, Butyrivibrio proteoclasticus. AB - The research was aimed at finding which membrane proteins of the rumen bacterium Butyrivibrio proteoclasticus are involved in the uptake of carbohydrates resulting from extracellular enzymatic degradation of hemicellulose and fructan. The proteomic analysis of cells grown with fructose or xylan as the sole substrate identified 13 membrane proteins predicted to function as carbohydrate transporters. One protein detected was the membrane component of a fructose specific phosphoenolpyruvate:sugar phosphotransferase system believed to be involved in the fructose uptake following extracellular fructan breakdown. The other 12 proteins were all ABC transport system substrate-binding proteins, nine of which belong to functional category COG1653 that includes proteins predicted to transport oligosaccharides. Four of the SBPs were significantly upregulated in xylan grown cells, and three of these were found in polysaccharide utilisation loci where they are clustered with other genes involved in hemicellulose breakdown and metabolism. It is possible that the carbon source available regulates a wider network of genes. The information on the mechanisms used by rumen bacteria to take up carbohydrates from their environment may improve our understanding of the ruminant digestion and facilitate strategies for improved pasture and stored feed utilisation. PMID- 22200677 TI - Proteomic analysis and identification of aqueous humor proteins with a pathophysiological role in diabetic retinopathy. AB - Diabetic retinopathy (DR) can cause irreversible blindness and is the severest microvascular complication in the eyes of patients with diabetic mellitus (DM). The identification of susceptibility factors contributing to development of DR is helpful for identifying predisposed patients and improving treatment efficacy. Although proteomics analysis is useful for identifying protein markers related to diseases, it has never been used to explore DR-associated susceptibility factors in the aqueous humor (AH). To better understand the pathophysiology of DR and to identify DR-associated risk factors, a gel-based proteomics analysis was performed to compare AH protein profiles of DM patients with and without development of DR. MALDI-TOF MS was then performed to identify protein spots that were differentially expressed between the two groups and western blot analysis was used to validate the expressional change of protein demonstrated by proteomics. Our proteomics and bioinformatics analysis identified 11 proteins differentially expressed between DR and control groups. These proteins are linked to biological networks associated with nutrition transport, microstructure reorganization, angiogenesis, anti-oxidation, and neuroprotection. The data may provide potential AH biomarkers and susceptibility factors for predicting DR development, and provide an insight into the underlying pathophysiological mechanisms of DR. This article is part of a Special Issue entitled: Proteomics: The clinical link. PMID- 22200678 TI - Heterodimerization of human apelin and kappa opioid receptors: roles in signal transduction. AB - Apelin receptor (APJ) and kappa opioid receptor (KOR) are members of the family A of G protein-coupled receptors (GPCRs). These two receptors are involved in the central nervous system regulation of the cardiovascular system. Here, we explore the possibility of heterodimerization between APJ and KOR and investigate their novel signal transduction characteristics. Co-immunoprecipitation (Co-IP), co localization and bioluminescence resonance energy transfer (BRET) assays confirmed the heterodimerization of APJ and KOR. In APJ and KOR stably transfected HEK293 cells, treatment with APJ ligand apelin-13 or KOR ligand dynorphinA (1-13) resulted in higher phosphorylation levels of extracellular regulated kinases 1/2 (ERK1/2) compared to HEK293 cells transfected with either APJ or KOR alone. The siRNA knockdown of either APJ or KOR receptor in human umbilical vein endothelial cells (HUVECs) resulted in significant reduction of the apelin-13 induced ERK activation. Additionally both forskolin (FSK)-induced cAMP levels and cAMP response element reporter activities were significantly reduced, whereas the serum response element luciferase (SRE-luc) reporter activity was significantly upregulated. Moreover, the ERK phosphorylation and SRE luc activity were abrogated by the protein kinase C (PKC) inhibitor. These results demonstrate for the first time that human APJ forms a heterodimer with KOR and leads to increased PKC and decreased protein kinase A activity leading to a significant increase in cell proliferation, which may translate to the regulation of diverse biological actions and offers the potential for the development of more selective and tissue specific drug therapies. PMID- 22200679 TI - MKP-1: a negative feedback effector that represses MAPK-mediated pro-inflammatory signaling pathways and cytokine secretion in human airway smooth muscle cells. AB - Airway smooth muscle (ASM) plays an important immunomodulatory role in airway inflammation in asthma. In our previous in vitro studies in ASM cells delineating the pro-inflammatory mitogen-activated protein kinase (MAPK) signaling pathways activated by tumor necrosis factor alpha (TNFalpha), we observed that TNFalpha concomitantly induces the rapid, but transient, upregulation of the anti inflammatory protein-mitogen-activated protein kinase phosphatase 1 (MKP-1). As this was suggestive of a negative feedback loop, the aim of this study was to investigate the molecular mechanisms of MKP-1 upregulation by TNFalpha and to determine whether MKP-1 is a negative feedback effector that represses MAPK mediated pro-inflammatory signaling pathways and cytokine secretion in ASM cells. Herein, we show that TNFalpha increases MKP-1 mRNA expression and protein upregulation in a p38 MAPK-dependent manner. TNFalpha does not increase MKP-1 transcription (measured by MKP-1 promoter activity); rather, we found that TNFalpha-induced MKP-1 mRNA stability is regulated by the p38 MAPK pathway. Inhibiting MKP-1 upregulation (with triptolide) demonstrated the precise temporal control exerted on MAPK signaling by MKP-1. In the absence of MKP-1, downstream phosphoprotein targets of MAPKs (such as MSK-1 and histone H3) are not turned off at the right time, allowing pro-inflammatory pathways to continue in an unrestrained manner. This is confirmed by knocking-down MKP-1 by siRNA where enhanced secretion of the neutrophil chemoattractant cytokine-interleukin 8 was detected in the absence of MKP-1. Thus, by activating p38 MAP kinase, TNFalpha concomitantly upregulates the MAPK deactivator MKP-1 to serve as an important negative feedback effector, limiting the extent and duration of pro-inflammatory MAPK signaling and cytokine secretion in ASM cells. PMID- 22200680 TI - Clinical coverage of an archetype repository over SNOMED-CT. AB - Clinical archetypes provide a means for health professionals to design what should be communicated as part of an Electronic Health Record (EHR). An ever growing number of archetype definitions follow this health information modelling approach, and this international archetype resource will eventually cover a large number of clinical concepts. On the other hand, clinical terminology systems that can be referenced by archetypes also have a wide coverage over many types of health-care information. No existing work measures the clinical content coverage of archetypes using terminology systems as a metric. Archetype authors require guidance to identify under-covered clinical areas that may need to be the focus of further modelling effort according to this paradigm. This paper develops a first map of SNOMED-CT concepts covered by archetypes in a repository by creating a so-called terminological Shadow. This is achieved by mapping appropriate SNOMED CT concepts from all nodes that contain archetype terms, finding the top two category levels of the mapped concepts in the SNOMED-CT hierarchy, and calculating the coverage of each category. A quantitative study of the results compares the coverage of different categories to identify relatively under covered as well as well-covered areas. The results show that the coverage of the well-known National Health Service (NHS) Connecting for Health (CfH) archetype repository on all categories of SNOMED-CT is not equally balanced. Categories worth investigating emerged at different points on the coverage spectrum, including well-covered categories such as Attributes, Qualifier value, under covered categories such as Microorganism, Kingdom animalia, and categories that are not covered at all such as Cardiovascular drug (product). PMID- 22200681 TI - Data driven linear algebraic methods for analysis of molecular pathways: application to disease progression in shock/trauma. AB - MOTIVATION: Although trauma is the leading cause of death for those below 45years of age, there is a dearth of information about the temporal behavior of the underlying biological mechanisms in those who survive the initial trauma only to later suffer from syndromes such as multiple organ failure. Levels of serum cytokines potentially affect the clinical outcomes of trauma; understanding how cytokine levels modulate intra-cellular signaling pathways can yield insights into molecular mechanisms of disease progression and help to identify targeted therapies. However, developing such analyses is challenging since it necessitates the integration and interpretation of large amounts of heterogeneous, quantitative and qualitative data. Here we present the Pathway Semantics Algorithm (PSA), an algebraic process of node and edge analyses of evoked biological pathways over time for in silico discovery of biomedical hypotheses, using data from a prospective controlled clinical study of the role of cytokines in multiple organ failure (MOF) at a major US trauma center. A matrix algebra approach was used in both the PSA node and PSA edge analyses with different matrix configurations and computations based on the biomedical questions to be examined. In the edge analysis, a percentage measure of crosstalk called XTALK was also developed to assess cross-pathway interference. RESULTS: In the node/molecular analysis of the first 24h from trauma, PSA uncovered seven molecules evoked computationally that differentiated outcomes of MOF or non-MOF (NMOF), of which three molecules had not been previously associated with any shock/trauma syndrome. In the edge/molecular interaction analysis, PSA examined four categories of functional molecular interaction relationships--activation, expression, inhibition, and transcription--and found that the interaction patterns and crosstalk changed over time and outcome. The PSA edge analysis suggests that a diagnosis, prognosis or therapy based on molecular interaction mechanisms may be most effective within a certain time period and for a specific functional relationship. PMID- 22200682 TI - A study of the suppressive effect on human pancreatic adenocarcinoma cell proliferation and angiogenesis by stable plasmid-based siRNA silencing of c-Src gene expression. AB - The non-receptor protein tyrosine kinase c-Src regulates diverse biological processes by associating with multiple signaling and structural molecules. Overexpression of c-Src occurs in pancreatic cancer and can be predictive of poor prognosis. The aim of this study was to investigate the inhibitory effects of plasmid-based siRNAs targeting the human c-Src gene on proliferation and angiogenesis in the human pancreatic adenocarcinoma cell line Panc-1. Three siRNAs targeting the c-Src gene were transfected into the Panc-1 pancreatic adenocarcinoma cell line mediated by Lipofectamine. Transfection efficiency was assessed by flow cytometry. Real-time quantitative PCR (RQ-PCR) was employed to detect the expression of c-Src mRNA, and the most effective siRNA was chosen to be cloned into a plasmid. Two single-strand DNA templates were designed according to the most effective siRNA sequences. The short hairpin RNA (shRNA) plasmid targeting c-Src with pGPU6/green fluorescent protein (GFP)/Neo vector psiRNA-c Src was constructed. Sequencing was performed to check whether the plasmid was constructed correctly. Panc-1 cells were transfected with psiRNA-c-Src and the negative control plasmid (psiRNA-N), respectively. Following selection with G418, the transfected monoclonal cells were chosen. GFP was evaluated by flow cytometry and fluorescence microscopy to estimate transfection efficiency. RQ-PCR and western blotting were used to detect c-Src silencing efficiency. To verify the effects of gemcitabine chemoresistance of c-Src expression, MTT assay was performed. ELISA was used to determine VEGF levels in culture supernatants. In a nude mouse model, tumor growth was studied, c-Src, VEGF expression and microvessel density in tumor tissue were measured by immunohistochemistry. The transfection efficiency of siRNA in the Panc-1 cell line was above 90%, the most effective siRNA could suppress expression of the c-Src gene with an inhibition efficiency of 86.1%. Sequencing confirmed that the c-Src siRNA plasmid was successfully constructed. MTT assay indicated that the effect of gemcitabine induced cytotoxicity was markedly increased in the psiRNA-c-Src group (P<0.05). Meanwhile, the expression of VEGF in vitro was reduced significantly (P<0.05) in the psiRNA-c-Src group. In nude mice bearing tumors, c-Src, VEGF expression and MVD were decreased in tumors produced from psiRNA-c-Src transfected cells (P<0.05). In summary, the siRNA expression constructs targeting c-Src could specifically suppress c-Src expression, inhibit VEGF expression, inhibit cell proliferation and enhance gemcitabine chemosensitivity in vitro. C-Src gene silencingwas able to inhibit angiogenesis of tumors in vivo. These findings demonstrate that the c-Src targeting gene silencing approach has the potential to serve as a novel tool for pancreatic carcinoma treatment. PMID- 22200683 TI - Celecoxib suppresses fibroblast proliferation and collagen expression by inhibiting ERK1/2 and SMAD2/3 phosphorylation. AB - This study aimed to investigate whether celecoxib suppresses fibroblast proliferation and collagen expression by inhibiting extracellular signal regulated kinase 1/2 (ERK1/2) and SMAD2/3 phosphorylation. Celecoxib was added to NIH/3T3 fibroblasts stimulated by fibroblast growth factor-2 (FGF-2) or transforming growth factor-beta1 (TGF-beta1). NIH/3T3 fibroblast proliferation and viability were assessed by MTT assays; ERK1/2 expression and SMAD2/3 expression were assessed by quantitative RT-PCR and Western blot analysis. The results indicated that celecoxib suppressed cell proliferation (IC50 FGF+ group, 75 +/- 1.9 umol/l) stimulated by FGF-2, and also inhibited cell viability (IC50 FGF- group, 252 +/- 2.3 umol/l) by inhibiting ERK1/2 phosphorylation but not ERK1/2 expression. In addition, celecoxib treatment led to the apoptosis of NIH/3T3 fibroblasts (IC50 FGF- group, 35 +/- 1.4 umol/l). Celecoxib also suppressed collagen expression (0.35-fold COL3 and 0.43-fold COL1 with 320 umol/l celecoxib relative to the untreated group following stimulation for 3 h, p<0.01) when stimulated by TGF-beta1, by inhibiting SMAD2/3 phosphorylation but not SMAD2/3 expression. Celecoxib is capable of inhibiting ERK1/2 and SMAD2/3 phosphorylation, which is responsible for NIH/3T3 fibroblast proliferation and collagen expression. PMID- 22200684 TI - Solitary liver mass in a patient with hepatitis C. PMID- 22200685 TI - Portal hypertensive enteropathy in small-bowel capsule endoscopy. PMID- 22200686 TI - The biopsy GAVE the diagnosis. PMID- 22200687 TI - Kayexalate-induced esophageal ulcer in a patient with gastroparesis. PMID- 22200688 TI - Solving the dilemma of proton pump inhibitor nonresponders: targeting the mechanism. PMID- 22200689 TI - Diagnosis and management of patients with alpha1-antitrypsin (A1AT) deficiency. AB - Alpha(1)-antitrypsin (A1AT) deficiency is an autosomal codominant disease that can cause chronic liver disease, cirrhosis, and hepatocellular carcinoma in children and adults and increases risk for emphysema in adults. The development of symptomatic disease varies; some patients have life-threatening symptoms in childhood, whereas others remain asymptomatic and healthy into old age. As a result of this variability, patients present across multiple disciplines, including pediatrics, adult medicine, hepatology, genetics, and pulmonology. This can give physicians the mistaken impression that the condition is less common than it actually is and can lead to fragmented care that omits critical interventions commonly performed by other specialists. We sought to present a rational approach for hepatologists to manage adult patients with A1AT deficiency. PMID- 22200690 TI - Expression of MMP-2, -7, -9, MT1-MMP and TIMP-1 and -2 has no prognostic relevance in patients with advanced epithelial ovarian cancer. AB - Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in tumor invasion, but their prognostic significance is still under discussion. We set out to analyze the epithelial and stromal expression of MMP-2, MMP-7, MMP 9, MT1-MMP, TIMP-1 and TIMP-2 in advanced epithelial ovarian cancers and to assess their prognostic value. A tissue microarray of malignant ovarian tumors from 69 patients was constructed. Immunostaining results were scored using the HSCORE and assessed by univariate analysis with Bonferroni correction and classical multidimensional scaling (CMDS). Kaplan-Meier survival curves calculated with regard to patient and tumor characteristics were compared by the log-rank test. Patients treated by primary surgery (n=43) had a higher tumor size and a trend toward higher epithelial MMP and TIMP expression than those treated by interval surgery (n=26). Optimal cytoreduction (residue <= 1 cm) was obtained in 27 and 18 patients, respectively. Clinical and histological characteristics were not different in patients with optimal cytoreduction and those with suboptimal cytoreduction. The expression of epithelial MMP-9 (P=0.002) and TIMP-2 (P=0.026) were higher in the latter group. CMDS failed to demonstrate any influence of MMP and TIMP expression with regard to cytoreduction outcome. MMP and TIMP expression did not influence survival. Their prognostic values were outweighed by histological type, lymph node involvement and cytoreduction. Standard statistical analysis adjusted after Bonferroni correction and CMDS reduced the relevance of MMPs and TIMPs in the prognosis of patients with advanced ovarian cancer. PMID- 22200691 TI - Changes in mechanical properties of seven light-cured composite resins after thermal cycling. AB - OBJECTIVE: To examine the changes of the mechanical properties of 7 different light-cured composite resins after thermal cycling and the correlations between these properties. METHODS: Seven different light-cured composite resins, including 2 microfilled composites (A110:AH and ESTELITE :ET), 3 microhybrid composites (AELITE:AT, Z250:ZS, and CharmFil plus:CP), and 2 nanohybrid composites (Z350:ZH and Grandio:GD), were prepared into test specimens with a diameter of 12 mm and a thickness of 1.0 mm. The specimens were stored in distilled water at 37 degrees celsius; for 24 h prior to 1 000 thermal cycles of 5 degrees celsius; for 15 s and 55 degrees celsius; for 15 s. The biaxial flexural strength (delta(f)) was tested using the ball-on-three-ball method at a crosshead speed of 0.5 mm/min (ISO4049). The fracture surface was observed under scanning electron microscope (SEM), and the remaining specimens underwent Knoop hardness test with a 50-g loading for 10 s. RESULTS: The highest and lowest Weibull modulus was observed in AH (18.752) and AT (5.290) group, respectively. The highest and lowest biaxial flexural strength was observed in ZS (158.2 MPa) and ET (54.0 MPa) groups, respectively. The delta(f) of the tested materials decreased in the order of microhybrid composite, nanohybrid composite, and microfiller composite, and the delta(f) showed no significant difference between the composites with a similar filler (P>0.05). The fracture number was positively correlated to the strength of the material. The Knoop hardness numbers (H) was the highest in GD group (110.81?14.77 kg/mm(2)) and the lowest in AH group (42.81?1.91 kg/mm(2)). SEM showed that the interface region of the matrix and the filler was vulnerable to crack formation. CONCLUSION: The nanohybrid composite resins better suit clinical applications than microhybrid composites. The applicability of Knoop hardness test in hardness measurement of the composite resins needs to be further demonstrated. PMID- 22200692 TI - Risk factors for severe retinopathy of prematurity in premature infants: a single center study. AB - OBJECTIVE: To evaluate the incidence and risk factors for severe retinopathy of prematurity (ROP) in preterm infants. METHODS: Between May, 2008 and May, 2011, a total of 957 preterm infants at 4-6 weeks of chronological age or 32 weeks of postmenstrual age underwent retinal evaluation by RetCamII in our center, and the data of infants with ROP in any stage were analyzed. RESULTS: Among the 957 preterm infants, we found 86 (8.99%) infants to have ROP in different stages, including 60 (6.27%) with mild ROP and 26 (2.72%) with severe ROP. The birth weight and gestational age of the infants with severe ROP averaged 1 420.40?328.64 g and 29.88?1.67 weeks, as compared to 1 593.28?339.30 g and 31.78?2.53 weeks in those with mild ROP, respectively, showing a significant difference between the two groups (P<0.005). The significant variables for severe ROP included gestational age (P=0.001), birth weight (P=0.035), 1 min Apgar score (P=0.001), 5 min Apgar score (P=0.005), number of blood transfusions (P=0.032), and the presence of apnea (P=0.04) and retinal hemorrhage (P=0.000). Gestational age and retinal hemorrhage were the independent risk factors for severe ROP (OR=0.353, 95%CI 0.163-0.763, P=0.008; OR=26.133, 95%CI 3.042-224.501, P=0.035). CONCLUSION: Severe ROP tends to have a decreasing incidence and occurs more often in more mature preterm infants. The affected infants have the characteristics of the first epidemics. Gestational age and retinal hemorrhage are independent predictive factors for severe ROP. PMID- 22200693 TI - [Efficacy of gadobenate dimeglumine vs gadopentetate dimeglumine in contrast- enhanced magnetic resonance imaging for diagnosis of solitary brain metastases]. AB - OBJECTIVE: To compare gadobenate dimeglumine (Gd-BOPTA) and gadopentetate dimeglumine (Gd-DTPA) for their efficacy as contrast agents in contrast-enhanced magnetic resonance imaging (MRI) for diagnosis of solitary brain metastases (SBM). METHODS: We conducted an intra-individual study of contrast-enhanced T1 weighted MRI (T(1)WI) data from 27 Chinese patients with suspected SBM to compare the enhancement findings of two different MRI contrast agents, Gd-BOPTA and Gd DTPA (at equivalent doses of 0.1 mmol/kg), for the detection of SBM. All the patients underwent two identical MRI examinations on a 3.0-T MRI scanner first with Gd-DTPA and then with Gd-BOPTA. Evaluation of the contrast enhancement was performed qualitatively (border delineation, extent, internal morphology, and contrast enhancement) and quantitatively (lesion-to-brain ratio, contrast-to noise ratio, and percent enhancement) by 3 independent, fully blinded, and highly experienced neuroradiologists. RESULTS: Qualitative assessment by readers revealed a significant overall preference (P<0.05) for Gd-BOPTA over Gd-DOTA in terms of lesion border delineation, extent, lesion internal morphology, and contrast enhancement. Quantitative assessment also revealed a significant better performance of Gd-BOPTA in light of lesion-to-brain ratio (P<0.05), contrast-to noise ratio (P<0.05), and percent enhancement (P<0.05). CONCLUSION: At an equivalent dose, Gd-BOPTA allows better contrast enhancement of SBM than Gd-DTPA in MRI. PMID- 22200694 TI - [Three-dimensional low-dose CT volume reconstruction based on non-local weights optimization and GPU acceleration]. AB - OBJECTIVE: Concerns have been raised over x-ray radiation dose associated with repeated computed tomography (CT) scans for tumor surveillance and radiotherapy planning. In this paper, we present a low-dose CT image reconstruction method for improving low-dose CT image quality. The method proposed exploited rich redundancy information from previous normal-dose scan image for optimizing the non-local weights construction in the original non-local means (NLM)-based low dose image reconstruction. The objective 3D low-dose volume and the previous 3D normal-dose volume were first registered to reduce the anatomic structural dissimilarity between the two datasets, and the optimized non-local weights were constructed based on the registered normal-dose volume. To increase the efficiency of this method, GPU was utilized to accelerate the implementation. The experimental results showed that this method obviously improved the image quality, as compared with the original NLM method, by suppressing the noise induced artifacts and preserving the edge information. PMID- 22200695 TI - [Feature analysis of superficial soft tissue interface based on wave numbers]. AB - OBJECTIVE: Based on a simple deconvolution model of multi-layer interfaces, the reasons of wave number variation of the interfacial echo signal were analyzed to explore a method for feature recognition of the superficial soft tissue interfaces. The interfacial echo signal data were decomposed and reconstructed by Mallat multisolution analysis, with the number of the reconstructed interface signal as the feature. The results showed that the deconvolution model was effective for extracting the interface echo signal features in the superficial soft tissue and allowed identification and location of tissue defects. PMID- 22200696 TI - [Comparison of two methods for establishing rat models of complex regional pain syndrome type 1]. AB - OBJECTIVE: To investigate the difference between two methods for establishing rat models of complex regional pain syndrome type 1. METHODS: Twenty-four adult SD rats were randomly allocated into control group, tibia fracture group and ischemia group (n=8), and complex regional pain syndrome type 1 was simulated in the latter two groups using different methods. The pain behaviors of the rats were observed and serum substance P level was detected with ELISA at different time points after the operations. RESULTS: Limb loss occurred in 3 rats in tibia fracture group, and the other 5 rats showed a lowered pain threshold. At 8 h after modeling, the rats in ischemia group showed more obvious reduction of pain threshold than those in tibia fracture group. Serum substance P levels in the two model groups underwent similar alterations after modeling, both significantly higher than that in the control group (P<0.01). Microcirculation changes were more serious in tibia fracture group than in ischemia group. Ulcer-like lesions were found in the skin of some rats in tibia fracture group. No obvious pathologies were observed microscopically in the sciatic nerve in the two model groups. CONCLUSION: The two methods can both be effective to simulate complex regional pain syndrome type 1, but tibia fracture results in more sustained symptoms and pathological changes in the microcirculation. PMID- 22200697 TI - [Prophylactic irradiation at the level Ib for nasopharyngeal carcinoma: should that be a routine?]. AB - OBJECTIVE: To assess the necessity of routine prophylactic irradiation at the level Ib for nasopharyngeal carcinoma (NPC). METHODS: Newly diagnosed NPC patients between January, 2001 and June, 2005 were enrolled in this study. The nodal distribution in each region was calculated from the data of transversal contrast enhance CT or magnetic resonance scan of the head and neck. RESULTS: Cervical node involvement was found in 75.1% of the 338 patients enrolled. The rates of involvement at levels Ib, IIa, IIb, III, IV, Va, Vb and in the supra clavicular region were 0.9%, 49.1%, 60.7%, 26.0%, 5.9%, 9.5%, 3.8% and 0.9%, respectively. Skip metastasis occurred only in 2.4% of the cases. The high risk region (defined by a probable risk>5%) of nodal metastases was (1) the ipsilateral levels III, IV, Va, and Vb in case of level II involvement, (2) the ipsilateral levels II, IV, Va, and Vb in case of level III involvement, (3) the ipsilateral levels II, III, Va, Vb and the supra-clavicular region in case of level IV involvement, (4) the ipsilateral levels II, III, IV, Vb and the supra clavicular region in case of level Va involvement, (5) the ipsilateral levels II, III, IV, Vb, and the supra-clavicular region in case of level Vb involvement, (6) the contralateral levels II, III, and Va in case of unilateral cervical node involvement. CONCLUSION: Nodal involvement in NPC patients rarely occurs at the level Ib, which is not a high risk region whatever the regions may be to have lymph node metastasis and therefore does not need routine prophylactic irradiation. PMID- 22200698 TI - [Effect of gemcitabine in enhancing the radiosensitivity of HepG2 hepatoma cells and the possible mechanism]. AB - OBJECTIVE: To evaluate the effect of gemcitabine in enhancing the radiosensitivity of hepatoma cell line HepG2 and explore its mechanisms. METHODS: Clonogenic survival assay is employed to calculate the ratios of L-Q model radiation biology parameters and radiosensitization after different doses of irradiation. Flow cytometry was used to detect the changes in HepG2 cell cycle and apoptosis rate after gemcitabine treatment and radiation exposure. RESULTS: The survival fraction at 2 Gy of HepG2 cells treated with gemcitabine was significantly lower, and the value of alpha was significantly higher than those of untreated cells. GEM treatment increased the percentage of radiation-induced G0/G1 phase cells and cell apoptosis. CONCLUSION: Gemcitabine can significantly enhance the radiosensitivity of HepG2 cells by enhancing radiation-induced cell cycle arrest in G0/G1 phase and cell apoptosis. PMID- 22200699 TI - [Inhibitory effect of 4-chlorobenzoyl berbamine on imatinib-resistant K562 cells in vitro and in vivo]. AB - OBJECTIVE: To observe the inhibitory effect of 4-chlorobenzoyl berbamine (BBD9) on imatinib-resistant cell line K562 (K562/IR) in vitro and in vivo and explore the mechanisms. METHODS: The IC50 of BBD9 and berbamine (BBM) was determined by MTT assay. The expressions of p210(Bcr-Abl), IKKa, cytoplasmic and nuclear NF kappaBp65 were determined using Western blotting in K562/IR cells following a 48 h exposure to 0.5 ug/ml BBD9 or 8 ug/ml BBM. Flow cytometry was used to analyze the cell viability, apoptosis and necrosis; Western blotting was employed to determine the expressions of PARP, caspase-3, caspase-9 and LC3II in K562/IR cells exposed to different concentrations of BBD9 for 48 h. In nude mouse models bearing K562/IR cell xenograft, the tumor weight, tumor regression, and body weight changes of the mice were measured after treatments with 15 mg/kg and 30 mg/kg BBD9 and 100 mg/kg imatinib. RESULTS: The IC50 of BBD9 and BBM was 0.73 ug/ml and 5.43 ug/ml, respectively. In K562/IR cell cultures, the expressions of p210(Bcr-Abl), IKKa and nuclear NF-kappaB p65 were all decreased following BBD9 and BBM treatments, but BBD9 produced more potent effect; cytoplasmic NF-kappaB p65 showed no obvious changes after the treatments. The cell apoptosis and necrosis increased with the concentrations of BBD9, which also dose-dependently increased the levels of cleaved caspase-3, csapase-9, PARP, and LC3II expression. In the tumor-bearing mouse model, BBD9 showed stronger effects than imatinib in reducing the tumor weight, promoting tumor regression, and increasing the body weight. CONCLUSION: BBD9 can effectively inhibit the growth of K562/IR cells in vitro and in vivo by activating cell apoptosis, necrosis and autophage pathways, down-regulating expressions of p210(Bcr-Abl) and IKKa and suppressing the cytoplasm-to- nucleus translocation of NF-kappaBp65. PMID- 22200700 TI - [Cloning, prokaryotic expression and antibacterial assay of Tenecin gene encoding an antibacterial peptide from Tenebrio molitor]. AB - OBJECTIVE: To clone tenecin gene, an antibacterial peptide gene, from Tenebrio molitor for its prokaryotic expression and explore the molecular mechanism for regulating the expression of antibacterial peptide in Tenebrio molitor larvae. METHODS: The antibacterial peptide was induced from the larvae of Tenebrio molitor by intraperitoneal injection of Escherichia coli DH-5alpha (1*10(8)/ml). RT-PCR was performed 72 h after the injection to clone Tenecin gene followed by sequencing and bioinformatic analysis. The recombinant expression vector pET 28a(+)-Tenecin was constructed and transformed into E. coli BL21(DE3) cells and the expression of tenecin protein was observed after IPTG induction. RESULTS: Tenecin expression was detected in transformed E.coli using SDS-PAGE after 1 mmol/L IPTG induction. Tenecin gene, which was about 255 bp in length, encoded Tenecin protein with a relative molecular mass of 9 kD. Incubation of E.coli with 80, 60, 40, and 20 ug/ml tenecin for 18 h resulted in a diameter of the inhibition zone of 25.1?0.03, 20.7?0.06, 17.2?0.11 and 9.3?0.04 mm, respectively. CONCLUSIONS: Tenecin protein possesses strong antibacterial activity against E. coli DH-5alpha, which warrants further study of this protein for its potential as an antibacterial agent in clinical application. PMID- 22200701 TI - [Assessment of the mechanical properties and biocompatibility of a new electrospun polyurethane vascular prosthesis]. AB - OBJECTIVE: To develop a small-caliber vascular grafts and study its morphologies, mechanical properties and biocompatibility. METHODS: The effects of electrospinning conditions on the microstructure and porosity of the resulting scaffolds were investigated for preparation of a small-caliber (4 mm) polyurethane vascular grafts with optimum microstructures and mechanical properties. The mechanical properties and biocompatibility of the prepared grafts were evaluated. RESULTS: The polyurethane vascular grafts showed a three dimensional reticular structure consisting of nanofibers, with an average porosity of (51.48?4.47)% and tensile strength of 5.85 ? 0.62 MPa. The grafts provided a better long-term support than e-PTFE graft for endothelial cell growth and endothelialization. CONCLUSION: The polyurethane vascular prosthesis possessed favorable microstructures, excellent mechanical properties and good biocompatibility for potential clinical application. PMID- 22200702 TI - [Relationship between single nucleotide polymorphisms in IL28B gene and response to interferon treatment in chronic hepatitis B patients]. AB - OBJECTIVE: To explore the relationship between the single nucleotide polymorphisms (SNPs) of rs12979860 and rs8099917 in IL28B gene and the response to interferon treatment in hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B patients. METHODS: Peripheral blood samples were collected from 82 HBeAg-positive patients with chronic hepatitis B receiving interferon treatment, including 38 with favorable response to the treatment and 44 without response. IL28B gene was amplified from the chromosomal DNA, and rs8099917 SNP was genotyped based on PCR-RLFP and rs12979860 SNP by sequencing. RESULTS: In the responsive patients, the distribution frequencies of TT and TG+GG genotypes and allele G in SNPrs8099917 were 81.6% (31/38), 18.4% (7/38), and 9.2% (7/76), as compared to the frequencies of 97.7% (43/44), 2.3% (1/44), and 1.1% (1/88) in nonresponsive patients, respectively. The frequencies showed significant differences between the responsive and nonresponsive patients (P=0.014 for genotypes and P=0.025 for allele G). The distribution frequencies of CT genotypes and allele T in SNPrs12979860 showed no differences between the responsive and nonresponsive patients (P<0.05). CONCLUSION: rs8099917 SNP is probably associated with the response to interferon treatment in HBeAg-positive patients with chronic hepatitis B, and Allele G may be predictive of the treatment success. PMID- 22200703 TI - [Protective effect of remifentanil preconditioning against hepatic ischemia reperfusion injury in rats: role of p38 mitogen-activated protein kinases]. AB - OBJECTIVE: To assess the role of p38 mitogen-activated protein kinases (p38MAPK) in the protective effect of remifentanil preconditioning (RPC) on hepatic ischemia-reperfusion injury in rats. METHODS: Ninety-six male SD rats were randomly assigned into sham-operated group, ischemia-reperfusion group (I/R group), RPC group, and SB (an inhibitor of p38 MAPK) +RPC group. The rats were sacrificed at the end of reperfusion, and serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-alpha), and interleukin-1beta (IL-1beta) were measured. HE staining was used to observe the hepatic histopathological changes, and Western blotting was employed to examine p38MAPK and pp38MAPK protein expression. TUNEL staining was used to examine cell apoptosis in the liver tissues. RESULTS: Compared with sham-operated group, I/R group showed significantly increased serum levels of AST, ALT, TNF-alpha and IL-1beta with obvious histopathological changes and cell apoptosis in the liver. RPC significantly decresed the elevated serum levels of AST, ALT, TNF-alpha and IL-1beta and lessened hepatic histopathological changes, and caused reduced p38MAPK phosphorylation and hepatic cell apoptosis index. The protective effects of RPC were abolished by SB 203580 pretreatment. CONCLUSION: RPC attenuates the production of inflammatory factors by activating p38MAPK signal pathway to improve hepatic ischemia-reperfusion injury, and these effects can be blocked by SB203580, a p38MAPK inhibitor. PMID- 22200704 TI - [Culture and identification of breast cancer stem cells]. AB - OBJECTIVE: To isolate breast cancer stem cells from breast cancer patients and identify their biological characteristics. METHODS: Mammospheric cells were purified and enriched from the tumor tissues of breast cancer patients using mammosphere culture. Their expressions of CD44 and CD24 were analyzed by flow cytometry, and ALDH1, ESA and Oct4 expressions were determined by Western Blotting. The primary mammospheric and adherent cells, at the density of 2*10(4), 2*10(5) or 2*10(6), were inoculated into NOD/SCID mice to observe their tumorigenic and metastatic activities. RESULTS: With mammosphere culture method, 62.36% of the mammospheric cells showed CD44(+)/CD24(-/low) phenotype. The expressions of ALDH1, ESA and Oct4 in the mammospheric cells were significantly higher than those in the adherent culture-derived breast cancer cells (P<0.05). Primary mammospheric cells were at least 100-fold more tumorigenic than the adherent cells; the mammospheric cells were associated with liver or lung metastases, but the adherent cells were not. CONCLUSION: Mammosphere culture can be employed to obtain breast cancer stem cells from the tumor tissues of breast cancer patients. PMID- 22200705 TI - [Application of spiral CT three-dimensional reconstruction in treatment planning of impacted teeth]. AB - OBJECTIVE: To assess the value of three-dimensional (3D) reconstruction in treatment planning of impacted teeth. METHODS: Thirty-two orthodontic patients with impacted teeth aged from 13 to 17 years were enrolled, including 15 with impacted maxillary canines, 8 with impacted premolars and 6 with second molar impaction and retention. All the impacted teeth were examined by spiral CT scan and 3D reconstruction to determine the 3D position of the tooth in relation to both the crown and root, and the proximity to the roots of other teeth. The data were used for treatment planning and determination of the suitable direction of the orthodontic forces, approaches of surgical exposure, and the position of the attachment to be bonded. RESULTS: Normal occlusion was achieved for 15 patients with transposition maxillary canines and 5 with lower position premolar. Three malformed premolars were extracted after traction. For 9 patients with second molar impaction and retention, normal occlusion was achieved after extraction of the third molar or moving the first molar mesial. CONCLUSION: Spiral CT scan and 3D reconstruction can accurately determine the 3D position of the impacted tooth and provide assistance in the treatment planning to achieve a higher success rate of orthodontic correction. PMID- 22200706 TI - [Effect of different dietary loads on glucose-dependent insulinotropic polypeptide in subjects with normal glucose tolerance]. AB - OBJECTIVE: To investigate the secretion patterns of glucose-dependent insulinotropic polypeptide (GIP) after different dietary loads in subjects with normal glucose tolerance (NGT) and their relation to insulin secretion and plasma glucose levels. METHODS: Fourteen subjects with normal glucose tolerance underwent 75 g glucose tolerance test(OGTT) followed by mixed meal tolerance test(MMT) one week later. Blood glucose, insulin, and GIP were measured in the fasting state and at 0, 15, 30, 60, 90 and 120 min after glucose load or mixed meal load. RESULTS: The first peak value of GIP after glucose load occurred at 15 min (45.09?4.67 pmol/L). After a brief decline, GIP continued to increase till reaching 59.66?11.73 pmol/L at 120 min after the load. After the mixed meal load, GIP secretion presented with two peaks: the first peak appeared at 15 min (71.69?14.19 pmol/L) with a level significantly higher than that at 15 min following glucose load (P<0.05), and the second occurred at 90 min (55.35?13.19 pmol/L). The area under curve of GIP showed no significant difference between the two loads (P>0.05). Compared with glucose load, mixed meal load resulted in an increase of the first GIP peak and an earlier insulin peak (30 min vs 60 min), but a significant decrease of blood glucose at 15 min (P<0.05). CONCLUSION: Compared with glucose load, mixed meal (containing fat) can strongly stimulate GIP release and cause earlier occurrence of the insulin peak, which might be an important reason for the lower blood glucose after mixed meal. PMID- 22200707 TI - [Effect of puerarin in myocardial protection in rats with acute and chronic alcoholism]. AB - OBJECTIVE: To investigate the protective effect of puerarin on the myocardium of rats with acute and chronic alcoholism. METHODS: In acute alcoholism experiment, normal male SD rats were randomly divided into the control group, alcoholism group and puerarin group (n=8), and high- and low-dose puerarin was administered. In chronic alcoholism experiment, increasing puerarin doses were given. Serum and myocardial levels of spartate aminotransferase (AST) and creatine phosphokinase (CPK) were determined using enzymatic methed, and superoxide dismutase (SOD), malondialdehyde (MDA), Ca(2+)-Mg(2+)-ATPase, and Na(+)-K(+)-ATPase in the myocardium were assayed with colorimetric method. HE staining was used to observe the microscopic changes of the myocardium. RESULTS: Compared with alcoholism group, puerarin-treated groups showed significantly lowered myocardial contents of MDA, CPK and AST and serum levels of AST and CPK (P<0.05, P<0.01) and increased myocardial SOD (P<0.05, P<0.01), Na(+)-K(+)-ATPase and Ca(2+)-Mg(2+) ATPase activity (P<0.05, P<0.01), but Na(+)-K(+)-ATPase was similar between the two groups (P>0.05). HE staining of the myocardium showed cell swelling and obscure cell boundaries in alcoholism group, especially in chronic alcoholism group. The myocardial structure in puerarin group remained clear and regular. CONCLUSION: Puerarin can protect from myocardial injuries induced by acute and chronic alcoholism in rats. PMID- 22200708 TI - [Effect of decellularization on tissue composition and immunogenicity of porcine and human aortic valves]. AB - OBJECTIVE: To study the changes of tissue composition and immunogenicity of porcine and human aortic valves after decellularization. METHODS: Three cryopreserved human aortic valves and 4 porcine valves were decellularized with trypsin, and the leaflet tissue was homogenized for SDS-PAGE protein electrophoresis and U-937 migration assay. RESULTS: Trypsin effectively removed the cells from the valve. SDS-PAGE demonstrated an obvious difference in the tissue composition between porcine and human valves. Although decellularization significantly diminished the differences between the valves, decellularized procine aortic valve stilled contained more protein components (between 26 000 and 43 000) than human valve. U-937 migration assay showed an obvious decrease of cell migration in the valves by decellularization (from 832.7*10(3) to 152.4?31.1*10(3) for porcine valves, P<0.01, and from 644.9*10(3) to 91.2*10(3) for the human valves, P<0.01). Decellularized porcine valves induced a significantly greater cell migration than decellularized human valves (P<0.05). CONCLUSION: Decellularization with trypsin can effectively decrease the immunogenicity of human or porcine heart valve, but can not completely eliminate the antigen, and decellularized porcine valve still retain strong immunogenicity. PMID- 22200709 TI - [Effect of melatonin on glial fibrillary acidic protein, nuclear factor-kB and synaptophysin expressions in aging mice]. AB - OBJECTIVE: To study the effect of melatonin on the expressions of glial fibrillary acidic protein (GFAP), nuclear factor-kappaB (NF-kappaB p65) and synaptophysin in mice of different ages. METHODS: Twenty young male B6C3F1 mice (5.5 months) and 20 aged mice (26 months) were both divided into control and melatonin treatment (daily dose of 0.04 mg/kg) groups. After 2.5 months of treatment, the brain tissues of the mice were collected to examine the expressions of GFAP, NF-kappaB and SYN by immunohistochemistry. RESULTS: In the control groups, the expression of NF-kappaB p65 in the brain tissue increased with age, whereas a reverse change was found in melatonin-treated aged rats (P<0.05). Synaptophysin expression also decreased with age, but melatonin treatment significantly enhanced its expression in aged mice (P<0.05). GFAP expression in the brain tissue increased with age regardless of melatonin treatment (P>0.05). CONCLUSION: GFAP expression is almost not affected by melatonin treatment in aged mice. Melatonin can reduce the expression levels of NF-kappaB p65 and synaptophysin in the brain tissue to protect the brain and slow down the aging process. PMID- 22200710 TI - [Expression of MMP-2 and TIMP-1 in renal tissues of patients with chronic active antibody-mediated renal graft rejection]. AB - OBJECTIVE: To investigate the expressions of matrix metalloprotein-2 (MMP-2) and tissue inhibitor of metallopeptidase inhibitor-1 (TIMP-1) in the renal allografts of patients with chronic active antibody-mediated rejection (ABMR), and explore their role in the pathogenesis of ABMR. METHODS: Immunohistochemistry and computer-assisted image analysis were used to detect the expression of MMP-2 and TIMP-1 in the renal allografts of 46 patients with interstitial fibrosis and tubular atrophy (IF/TA), with 15 normal renal tissue specimens as the control. The association of MMP-2 and TIMP-1 with the pathological grade of IF/TA in ABMR was analyzed. RESULTS: The expressions of MMP-2 and TIMP-1 significantly increased in the renal tissues of the patients as compared with the normal renal tissues (P<0.05). MMP-2 expression tended to decrease, while TIMP-1 and serum creatinine increased with the pathological grades of IF/TA (P<0.05). In IF/TA group, the expression of TIMP-1 was positively correlated to serum creatinine level (r=0.718, P=0.00<0.05). CONCLUSION: Abnormal expressions of MMP-2 and TIMP 1 can promote the development of renal fibrosis in chronic ABMR. PMID- 22200711 TI - [Protective effects of resveratrol on lipopolysaccharide-induced inflammatory toxicity in primary cortical astrocyte cultures]. AB - OBJECTIVE: To study the anti-inflammatory effect of resveratrol in primary cortical astrocyte cultures stimulated by lipopolysaccharide (LPS) and explore the underlying mechanism of this protective effect. METHODS: The astrocytes were cultured in the presence of resveratrol at different concentrations for 12 h followed by stimulation with lipopolysaccharide (LPS) for another 24 h. Lactate dehydrogenas (LDH) leakage volumes were detected, the cytotoxicity of resveratrol was examined using cell counting kit-8 (CCK-8), the release of NO was measured by Griess reaction, and the expression levels of TNF-alpha and iNOS were measured using ELISA and Western blotting respectively. RESULTS: The purity of the astrocytes cultured in vitro was (95.49?1.86)%. LPS treatment increased LDH leakage and reduced the survival rate of the astrocytes, resulting also in significantly increased NO and TNF-alpha release and iNOS protein expressions. Within the concentration range of 5-50 umol/L, resveratrol effectively improved the survival rate of the astrocytes and decreased LDH leakage with a dose response relationship. Only 25 and 50 umol/L resveratrol produced obvious inhibitory effect on NO and TNF-alpha release and iNOS expression, while 5 umol/L resveratrol had no such effects. CONCLUSION: High concentration of resveratrol can inhibit the release of inflammatory mediators and improve the inflammation injury induced by LPS in astrocytes, the mechanism of which may involve the inhibition of iNOS/NO expression pathway. PMID- 22200712 TI - [Characteristics of dark-adapted and light-adapted oscillatory potentials in human electroretinogram]. AB - OBJECTIVE: To characterize dark-adapted and light-adapted oscillatory potentials (OPs) in human electroretinogram (EGR) elicited by flashing light stimulation of the same intensity. METHODS: Dark- and light-adapted ERGs of normal eyes were studied. The frequency spectra of the extracted dark-adapted OPs and light adapted OPs were analyzed by a fast Fourier transform. The peak frequency, latency and total power of the OPs were determined. RESULTS: The averaged peak frequency, latency, and power of the dark-adapted OPs was 125.3?9.93 Hz, 41.7?3.56 ms, and 9.25?5.55 (V.s)(2), as compared with 79.5?6.79 Hz, 50.8?5.36 ms, and 3.56?2.18 (V.s)(2) for light-adapted Ops, respectively, showing significant differences in the parameters between dark- and light-adapted Ops (P<0.001). CONCLUSIONS: Compared with dark-adapted OPs, light-adapted Ops is characterized by a lower peak frequency and a lower power with a prolonged latency. PMID- 22200713 TI - [Adult-to-adult living-related donor liver transplantation: report of 2 cases]. AB - OBJECTIVE: To investigate the feasibility and safety of adult-to-adult living related donor liver transplantation using a right lobe graft. METHODS: The clinical data of 2 cases of living-related donor liver transplantation performed between July, 2010 and November, 2010 were analyzed. RESULTS: Liver transplantation was performed using a right lobe graft including the middle hepatic vein in one case and a right lobe graft without the middle hepatic vein in the other. The ratio of graft volume to standard liver volume was 46.2% and 47.3% in the two cases, with GR/WR of 0.83 and 0.80, and donor residue liver of 42.1% and 39.5%, respectively. The donor operation lasted for 6.5 h and 5 h in the two cases with blood loss of about 200-250 ml without blood transfusion. The donors recovered uneventfully without any surgical complications, whose liver function was normal 7 days after the operation, and were discharged 14 days and 16 days after the surgery, respectively. The recipient operation lasted for 8 h and 7 h with blood loss of about 800-1000 ml. The right hepatic vein, hepatic artery, portal vein and bile duct reconstruction were performed by end-to-end anastomoses in the 2 recipients. Bile duct anastomosis stricture occurred in the first recipient 2 months after transplantation and was treated with percutaneous transhepatic cholangiography and drainage. The second recipient recovered smoothly without any complications. The recipients have so far survived 9 months and 5 months, respectively. CONCLUSION: Adult-to-adult living-related donor liver transplantation is a safe and effective option for treatment of end-stage liver diseases in the context of cadaveric liver graft shortage. PMID- 22200714 TI - [Effects of hypertonic sodium chloride hydroxyethyl starch 40 on brain histopathology in rats with whole body hyperthermia]. AB - OBJECTIVE: To investigate the effects of hypertonic sodium chloride hydroxyethyl starch 40 (HSH) on brain edema and morphological changes during whole body hyperthermia (WBH) in rats. METHODS: Sixty adult male SD rats were randomized into control group, WBH group without fluid infusion (group HT), WBH group with Ringer's infusion (group RL), WBH group with HAES + Ringer's infusion (group HRL) and WBH group with HSH infusion (group HSH). WBH was induced by exposure to 36 degrees celsius; for 3 h to achieve a rectal temperature of 41-42 degrees celsius;, and the corresponding fluids were administered intravenously within 30 min at the beginning of WBH. The control rats were housed at a controlled room temperature (22?1) degrees celsius; for 4 h. After cooling at room temperature for 1 h, the rats were sacrificed and brain water content and morphological changes were evaluated. RESULTS: Compared with the control group, all the WBH groups had significantly increased brain water content (P<0.05 or 0.01), but group HSH showed a significantly lower brain water content than group HT (P<0.05). The rats in groups HT, RL and HRL showed serious to moderate structural changes of the brain tissue and nerve cells, but HSH group had only mild pathologies. CONCLUSION: HSH can reduce brain edema and ameliorate the damages to brain cells in rats exposed to WBH. PMID- 22200715 TI - [Mannatide enhances the efficacy of fractionated and unfractionated radiotherapy in mice bearing Lewis lung cancer]. AB - OBJECTIVE: To investigate the effect of mannatide injection (MI) in enhancing the efficacy of radiotherapy in two therapeutic schedules in mice bearing Lewis lung cancer. METHODS: C57BL/6 mice bearing Lewis lung cancer xenograft were assigned randomly into control group, fractionated schedule (FS) group, nonfractionated schedule (NFS) group, MI group, FS+MI group, and NFS+MI group (n=10). MI (4.5 mg/kg) or saline was given intraperitoneally for 14 consecutive days in the corresponding groups. Radiation with 8 MeV electron beam was delivered in a single 4 Gy dose in NFS and in 4 fractions (total dose 4 Gy) in FS. Tumor inhibition rate and the spleen and thymus index were calculated after the treatments. RESULTS: MI significantly enhanced the efficacy of radiotherapy with a tumor inhibition rate reaching 70% in FS+MI group (P<0.01). FS resulted in a significantly higher tumor inhibition rate than NFS (P<0.05), but the rates were comparable between FS+MI and NFS+MI groups. The spleen index and thymus indices were significantly higher in FS+MI and NFS+MI groups than in FS and NFS groups (P<0.05). CONCLUSION: MI can enhance the efficacy of radiotherapy with different therapeutic schedules in mice bear Lewis lung cancer, and MI plus fractionated radiation produces the optimal effect. PMID- 22200716 TI - [Factors associated with acute febrile reaction in elderly patients receiving intravenous zoledronic acid for osteoporosis]. AB - OBJECTIVE: To survey the incidence of acute febrile reaction in elderly patients receiving intravenous zoledronic acid for osteoporosis and identify the related factors. METHODS: Thirty-eight elderly patients with osteoporosis were hospitalized and treated with intravenous infusion of 5 mg zoledronic acid in 2010. The incidence of acute fever reaction was observed in these patients , and the time of fever onset, duration, average maximum temperature, and antipyretic drug used were recorded. The patients with and without acute febrile reaction were compared for age, duration of osteoporosis, sex ratio, use of parathyroid hormone before zoledronic acid treatment, beta-fragment of collagen breakdown, calcitonin, osteocalcin, serum calcium, and use of anti-osteoporosis drugs before the treatment. RESULTS: Acute fever reaction occurred in 12 (31.6%) of the patients. Two of the patients had fever on the day of zoledronic acid treatment, and the other patients developed fever after the first day of treatment, with a mean duration of 1 day and a maximum temperature of (38.5?0.84) degrees celsius;. The fever was treated with a mean of 3.55?1.21 pseudoephedrine tablets. The patients with fever showed significantly higher parathyroid hormone levels before treatment than those without fever (P<0.05); osteocalcin, calcitonin, beta fragment of collagen breakdown, or serum calcium showed no significant difference between the two groups. CONCLUSION: Acute febrile reaction, often moderate and transient, is common in elderly patients receiving intravenous zoledronic acid for osteoporosis, and its occurrence is possibly associated with parathyroid hormone levels before the treatment. PMID- 22200717 TI - [Percutaneous nephrolithotomy through the upper pole calix access for complicated renal calculi: report of 581 cases]. AB - OBJECTIVE: To discuss the optimal approach of percutaneous nephrolithotomy (PCNL) for treatment of complicated renal calculi. METHODS: A total of 581 patients with complicated renal calculus were treated by PCNL through the upper pole calix access. Of the 581 patients, 55 had multiple upper pole calculi, 136 had staghorn stones, 145 had partial staghorn stones, and 245 had multiple renal calculi. RESULTS: PCNL through the upper pole calix access was completed successfully in all the cases. Of these patients, 90.3% (525/581) were stone-free after a single access, with a total stone-free rate of 94.6% (550/581). Thirty-five patients needed two accesses, 10 needed 3 accesses, 2 required 4 accesses, and 1 patients had 5 accesses. The operative time ranged from 30 to 150 min (mean 45 min). The successful rate of puncture was 100% without occurrence of severe injury of the pleura, intestine, peritoneum or other adjacent organs. CONCLUSIONS: Percutaneous nephrolithotomy through the upper pole calix access allows greater stone clearance rate due to its easy access into the intrarenal collecting system and can be an ideal approach for PCNL for complicated renal calculi. PMID- 22200718 TI - [Submucosal tunneling endoscopic resection for submucosal tumor originating from the muscularis propria layer of the esophagus]. AB - OBJECTIVE: Tumors originating from the muscularis propria layer of esophagus are usually removed by thoracoscopic resection. With the introduction of new endoscopic therapeutic techniques, some of these tumors could be treated by endoscopic submucosal dissection (ESD). However, the above endoscopic methods are associated with a high risk of perforation and it is hard to close the perforation through the endoscopy. Recently we successfully resected a tumor originating from the muscularis propria layer of the esophagus by submucosal tunneling endoscopic resection (STER), which was based on peroral endoscopic myotomy (POEM) and ESD. Compared with ESD, STER is a safe, economic and less invasive treatment. Even when perforation happens, it is easier to close the tunnel with the endoscopic clips which can help stopping the leak of air and digestive fluids. In this case, we found STER wss an effective and safe endoscopic procedure to remove tumors originating from the muscularis propria layer in the esophagus. PMID- 22200719 TI - [Effect of CD40 blockade on acute renal graft rejection in rats]. AB - OBJECTIVE: To explore the effect of CD40 blockade in suppressing acute rejection of renal graft in rats. METHODS: With Wistar rats as the donor and male SD rats as the recipients, rat models of acute renal graft rejection was established. The rat models were divided into therapy group and control group, and in the former group, CD40 ligand (CD40L) monoclonal antibody was injected daily for 4 consecutive days starting on the next day following kidney transplantation. On day 5 after the transplantation, the renal graft was harvested for histological examination, and graft rejection was evaluated semiquantitatively. RESULTS: The mean semiquantitative score of the renal graft was 0.63?0.52 in the therapy group, significantly lower than that of the control group (3.72?1.48, P<0.05). CONCLUSION: CD40L monoclonal antibody can inhibit acute renal graft in rats. PMID- 22200720 TI - [Clinical significance of blood and fecal tumor M2-pyruvate kinase expression in patients with colorectal cancer]. AB - OBJECTIVE: To evaluate the clinical significance of blood and fecal expression of tumor M2-pyruvate kinase (Tumor M2-PK) in patients with colorectal cancer. METHODS: With 22 healthy subjects as controls, 44 patients with CRC were examined for tumor M2-PK in serum and fecal samples using a sandwich enzyme immunoassay. RESULTS: The sensitivity of serum and fecal tumor M2-PK for detecting CRC was 59.1% and 63.6% with a specificity of 86.4% and 81.8%, respectively. The serum and fecal levels of tumor M2-PK showed a significant correlation in CRC patients. CONCLUSION: Tumor M2-PK has good sensitivity and specificity in the diagnosis of CRC. PMID- 22200722 TI - [Synchronous primary endometrial and fallopian tube cancers: one case report]. AB - OBJECTIVE: A patient was admitted for menopause for 2 years and abnormal vaginal bleeding and abdominal pain for 2 months. Gynecological examination revealed uterine atrophy without abnormal findings in the bilateral adnexa. CA125 and CEA levels were normal. The patient underwent laparoscopically assisted vaginal hysterectomy with bilateral salpingo-oophorectomy. Pathological examination of the surgical specimens revealed synchronous primary cancers stage Ia in both the endometrium and the right fallopian tube. The patient then received 6 cycles of chemotherapy with oxaliplatin combined with docetaxel given intravenously and remained alive without evidence of recurrence. Synchronous primary endometrial and fallopian tube cancer is a rare clinical entity, and laparoscopic surgery with postoperative chemotherapy can be considered for stage I patients. PMID- 22200721 TI - [Influence of Shenfu Injection on the quality of life of lung cancer patients receiving chemotherapy]. AB - OBJECTIVE: To evaluate the influence of Shenfu Injection (SHF) on the quality of life of patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy. METHODS: A total of 133 patients with NSCLC receiving at least two cycles of chemotherapy with taxol plus cisplatin (TP)/vinorelbine plus cisplatin (NP) or gemcitabine plus cisplatin (GP) were randomized into SHF pre-treatment group (with SHF given only in the first cycle) and SHF post-treatment group (with SHF given only in the second cycle). The Quality of Life Questionnaire-Core 30 (QLQ-C30) and the Functional Living Index-Cancer (FLIC) were used to evaluate the quality of life of the patients after the treatments. RESULTS: Both of the groups showed improved quality of life after the treatments (P<0.01), but the improvements were more obvious in SHF pre-treatment group (P<0.05). SHF showed favorable effects in relieving such adverse effects as fatigue, nausea, vomiting and diarrhea associated with the chemotherapy. CONCLUSION: SHF can improve the quality of life in NSCLC patients receiving chemotherapies. PMID- 22200723 TI - Capture of lexical but not visual resources by task-irrelevant emotional words: a combined ERP and steady-state visual evoked potential study. AB - Numerous studies have found that emotionally arousing faces or scenes capture visual processing resources. Here we investigated whether emotional distractor words capture attention in an analogous way. Participants detected brief intervals of coherent motion in an array of otherwise randomly moving squares superimposed on words of positive, neutral or negative valence. Processing of the foreground task was assessed by behavioural responses and steady-state visual evoked potentials (SSVEPs) elicited by the squares flickering at 15 Hz. Although words were task-irrelevant, P2 and N400 deflections to negative words were enhanced, indicating that emotionally negative word content modulated lexico semantic processing and that emotional significance was detected. In contrast, the time course of behavioural data and SSVEP amplitudes revealed no interference with the task regardless of the emotional connotation of distractor words. This dissociation of emotion effects on early perceptual versus lexical stages of processing suggests that written emotional words do not inevitably lead to attentional modulation in early visual areas. Prior studies have shown a distraction effect of emotional pictures on a similar task. Thus, our results indicate the specificity of emotion effects on sensory processing and semantic encoding dependent on the information channel that emotional significance is derived from. PMID- 22200724 TI - Putting Humpty together and pulling him apart: accessing and unbinding the hippocampal item-context engram. AB - A remarkable act of memory entails binding different forms of information. We focus on the timeless question of how the bound engram is accessed such that its component features-item and context-are extracted. To shed light on this question, we investigate the dynamics between brain structures that together mediate the binding and extraction of item and context. Converging evidence has implicated the Parahippocampal cortex (PHc) in contextual processing, the Perirhinal cortex (PRc) in item processing, and the hippocampus in item-context binding. Effective connectivity analysis was conducted on fMRI data gathered during retrieval on tests that differ with regard to the to-be-extracted information. Results revealed that recall is initiated by context-related PHc activity, followed by hippocampal item-context engram activation, and completed with retrieval of the study-item by the PRc. The reverse path was found for recognition. We thus provide novel evidence for dissociative patterns of item context unbinding during retrieval. PMID- 22200725 TI - National cultural dimensions as drivers of inappropriate ambulatory care consumption of antibiotics in Europe and their relevance to awareness campaigns. AB - OBJECTIVES: European countries exhibit significant geographical differences in antibiotic consumption per capita within ambulatory care, especially inappropriate use for colds/flu/sore throat (CFSt). One potential explanation could be national cultural differences resulting in varying perceptions and, therefore, influences. METHODS: Publicly available data on the proportions of respondents in the 2009 Eurobarometer survey who had taken antibiotics for CFSt were tested for association against country scores derived from the Hofstede cultural dimension model. They were also correlated with knowledge of respondents about various key antibiotic facts. RESULTS: The Eurobarometer dataset incorporated 26,259 responses from all European Union (EU) countries except Cyprus. Using multiple regression, uncertainty avoidance and masculinity were identified as the two national cultural dimensions significantly associated with the use of antibiotics for CFSt (R-adjusted = 0.45; P<0.001). After controlling for these cultural influences, individuals who stated they had received information about antibiotics in the previous year were also more likely to correctly answer antibiotic-related questions (r=0.721; P<0.001). The use of antibiotics for CFSt was found to be inversely correlated with respondents' knowledge that antibiotics are ineffective against viruses (r=-0.724; P<0.001) and that misuse will render them ineffective in the longer term (r=-0.775; P<0.001). CONCLUSIONS: National cultural dimensions, especially uncertainty avoidance and masculinity, appear to have a very significant impact on inappropriate antibiotic use within European countries. Nevertheless, their influence can be reduced by making EU citizens more knowledgeable about antibiotics through appropriate messages and targeted campaigns. PMID- 22200726 TI - Apoptotic and anti-metastatic effects of the whole skin of Venenum bufonis in A549 human lung cancer cells. AB - In the present study, the effects of the whole skin of Venenum bufonis on apoptotic and anti-invasive activity in A549 human lung cancer cells were investigated. Treatment with extract of the whole skin of V. bufonis (SVB) resulted in a significant decrease in cell growth of A549 cells, depending on dosage, which was associated with apoptosis induction, as proved by chromatin condensation and accumulation of apoptotic fraction. SVB treatment induced expression of death receptor-related proteins, such as death receptor 4, which further triggered activation of caspase-8 and cleavage of Bid. In addition, the increase in apoptosis by SVB treatment was correlated with dysfunction of mitochondria, activation of caspase-9 and -3, downregulation of IAP family proteins, such as XIAP, cIAP-1 and cIAP-2, and concomitant degradation of activated caspase-3-specific target proteins, such as poly (ADP-ribose) polymerase and beta-catenin proteins. However, z-DEVD-fmk, a caspase-3-specific inhibitor, blocked SVB-induced apoptosis and increased the survival rate of SVB treated cells, indicating that activation of caspase-3 plays a key role in SVB induced apoptosis. In addition, within concentrations that were not cytotoxic to A549 cells, SVB induced marked inhibition of cell motility and invasiveness. Activities of matrix metalloproteinase (MMP)-2 and MMP-9 in AGS cells were dose dependently inhibited by treatment with SVB, and this was also correlated with a decrease in expression of their mRNA and proteins, and upregulation of tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 mRNA expression. Further studies are needed; however, the results indicated that SVB induces apoptosis of A549 cells through a signaling cascade of death receptor-mediated extrinsic as well as mitochondria-mediated intrinsic caspase pathways. Our data also demonstrated that MMPs are critical targets of SVB-induced anti-invasiveness in A549 cells. PMID- 22200727 TI - Synergistic effects of telmisartan and pyridoxamine on early renal damage in spontaneously hypertensive rats. AB - The aim of this study was to investigate the protective effects of telmisartan and/or pyridoxamine on spontaneously hypertensive rats (SHRs). Rats were treated with telmisartan (T group) or pyridoxamine (P group), or telmisartan and pyridoxamine (TP group). The serum levels of advanced glycation end products (AGEs), superoxide dismutase (SOD), malonaldehyde and the level of 24-h urinary albumin were measured. Morphological changes in renal tissues were observed under light (H&E or Masson's trichrome) and transmission electron microscopy. Expression of NF-kappaBp65 and p-ERK1/2 in renal tissue was detected by immunohistochemistry. Expression of receptors for advanced glycation end products (RAGE) and TGF-beta in the renal cortex was investigated by western blotting. We found that early renal structural and functional damage was alleviated in the three intervention groups. SOD activity was significantly elevated in the P and TP groups (P<0.05) compared to that in the T group. Of note, both the positive expression of NF-kappaBp65 (P<0.01 vs. the T and P groups) and p-ERK1/2 (P<0.05 vs. the P group) was lowest in the TP group. Our results suggest that the combined use of telmisartan and pyridoxamine is superior to the single use of either drug on renoprotection, which may result from the alleviation of oxidative stress and the reduction of NF-kappaBp65 and p-ERK1/2 activation. PMID- 22200728 TI - The endothelin receptor antagonist bosentan improves peripheral endothelial function in patients with type 2 diabetes mellitus and microalbuminuria: a randomised trial. AB - AIMS/HYPOTHESIS: Endothelial dysfunction is important in the development of vascular complications in diabetes. Patients with type 2 diabetes have increased production of the vasoconstrictor and pro-inflammatory peptide, endothelin-1. Short-term intra-arterial administration of endothelin antagonists improves endothelium-dependent vasodilatation in patients with type 2 diabetes. We tested the hypothesis that oral administration of the dual endothelin receptor antagonist, bosentan, improves peripheral endothelial function in patients with type 2 diabetes and microalbuminuria. METHODS: This placebo-controlled and double blind study was performed on 46 patients with type 2 diabetes and microalbuminuria (urine albumin/creatinine ratio >3 mg/mmol) at a medical university department. Patients were randomised to bosentan, 125 mg two times per day (n = 28), or placebo (n = 28) for 4 weeks. The computer-generated randomisation code was kept in sealed envelopes. Patients and people doing examinations or assessing outcomes were blinded. The primary endpoint was change in microvascular endothelium-dependent vasodilatation, based on change in digital reactive hyperaemia index. The secondary endpoint was change in brachial artery flow-mediated vasodilatation. RESULTS: Reactive hyperaemia index increased from 1.73 +/- 0.43 (mean +/- SD) at baseline to 2.08 +/- 0.59 at follow-up (p < 0.05) in the bosentan group (n = 22), but did not change in the placebo group (1.84 +/- 0.49 to 1.87 +/- 0.47; n = 24). The change in reactive hyperaemia index from baseline was greater in the bosentan group than in the placebo group (p < 0.05). Nitroglycerine-induced digital hyperaemia was not affected. Brachial artery flow mediated vasodilatation and blood pressure did not change during treatment. CONCLUSIONS/INTERPRETATION: Oral treatment of 4 weeks duration with the dual endothelin receptor antagonist, bosentan, improves peripheral endothelial function in patients with type 2 diabetes and microalbuminuria. PMID- 22200729 TI - Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers. AB - PURPOSE: To investigate the pharmacokinetics, metabolism and tolerability of afatinib (BIBW 2992), an oral irreversible ErbB family blocker, in healthy male volunteers. METHODS: In this open-label, single-center study, 8 healthy male volunteers received a single oral dose of 15 mg [(14)C]-radiolabeled afatinib (equivalent to 22.2 mg of the dimaleinate salt) as a solution. Blood, urine and fecal samples were collected for at least 96 hours (h) after dosing. Plasma and urine concentrations of afatinib were analyzed using high-performance liquid chromatography-tandem mass spectrometry. [(14)C]-radioactivity levels in plasma, whole blood, urine and feces were measured by liquid scintillation counting methods. Metabolite patterns were assessed by high-performance liquid chromatography. RESULTS: [(14)C]-radioactivity was mainly excreted via feces (85.4%). Overall recovery of [(14)C]-radioactivity was 89.5%, indicative of a complete mass balance. Afatinib was slowly absorbed, with maximum plasma concentrations achieved at a median of 6 h after dosing, declining thereafter in a biexponential manner. The geometric mean terminal half-life of afatinib was 33.9 h in plasma and longer for [(14)C]-radioactivity in plasma and whole blood. Apparent total body clearance for afatinib was high (geometric mean 1,530 mL/min). The high volume of distribution (4,500 L) in plasma may indicate a high tissue distribution. Afatinib was metabolized to only a minor extent, with the main metabolite afatinib covalently bound to plasma proteins. Oxidative metabolism mediated via cytochrome P-450 was of negligible importance for the elimination of afatinib. Afatinib was well tolerated. CONCLUSIONS: Afatinib displayed a complete mass balance with the main route of excretion via feces. Afatinib undergoes minimal metabolism. PMID- 22200730 TI - E-cadherin and caveolin-1 alterations in the heart of rats having undergone chlorpromazine-induced toxicity. AB - Heart damage induced by chlorpromazine (CPZ) toxicity is associated with changes in the expression of various enzymes and proteins. This study aimed to investigate CPZ-induced alterations in cardiac E-cadherin and caveolin-1 (cav-1) after CPZ administration. Male Wistar rats were randomly divided into two groups: a control group and a CPZ group. The CPZ group was administered CPZ intraperitoneally at a single dose of 10 mg/kg for 21 days; the controls were given the same amount of saline via the same route. On Day 22, the rats were anesthetized, and a thoracotomy was performed in all animals. Immunohistochemical analysis was performed to evaluate protein expression of E-cadherin and cav-1. Sections were analyzed by digital image analysis. Results of the present study revealed that cardiac protein expression of E-cadherin and cav-1 was altered after CPZ-induced toxicity in the rat. The expression of E-cadherin was significantly reduced, while expression of cav-1 was significantly increased after CPZ treatment, as supported by integrated optical density analysis, compared with the control (P<0.05). The current findings indicate that such changes in the expression of E-cadherin and cav-1 may be reflected in abnormal cardiac function, and these proteins may be useful in revealing the mechanisms underlying CPZ-induced toxicity and may also provide additional insight for further research. PMID- 22200731 TI - Response to "model averaging in the analysis of leukaemia mortality among Japanese A-bomb survivors" by Richardson and Cole. PMID- 22200732 TI - Evaluation of intra-lesional corticosteroids in the treatment of peri-ocular haemangioma of infancy: still an alternative besides propranolol. AB - PURPOSE: Haemangioma of infancy (HOI) is the most frequently occurring benign tumour of infancy. Alarming HOI require treatment. Current therapy is empirically based; corticosteroids are often administered but in recent publications propranolol was reported to be more effective. Peri-ocular HOI are highly sensitive to corticosteroids. Our goal was to evaluate the effectiveness of intra lesional corticosteroids in the treatment of peri-ocular HOI. METHODS: We selected all patients with peri-ocular HOI who had only been treated with intra lesional corticosteroids at our hospital from 1993 until 2009. Treatment was standardized according to a prospective protocol. RESULTS: A total of n = 34 patients were included. There were no complications at all after therapy. A second intra-lesional injection was necessary in five patients. At follow-up after 6 and 12 months after injection, 94 and 91% of the patients, respectively, had regression of the HOI. Astigmatism, Haemangioma Activity Score and global assessments all had improved after therapy. CONCLUSIONS: This study shows that intra-lesional therapy with corticosteroids is very safe in the treatment of peri ocular HOI. It remains a good and safe alternative besides propranolol or when propranolol therapy is not possible (e.g. asthma, PHACE syndrome, and certain cardiac diseases). PMID- 22200733 TI - Laparoscopic versus robot-assisted Nissen fundoplication in an infant pig model. AB - PURPOSE: Surgical robots are designed to facilitate dissection and suturing, although objective data on their superiority are lacking. This study compares conventional laparoscopic Nissen fundoplication (CLNF) to robot-assisted Nissen fundoplication (RANF) using computer-based workflow analysis in an infant pig model. METHODS: CLNF and RANF were performed in 12 pigs. Surgical workflow was segmented into phases. Time required to perform specific actions was compared by t test. The quality of knot-tying was evaluated by a skill scoring system. Cardia yield pressure (CYP) was determined to test the efficacy of the fundoplications, and the incidence of complications was compared. RESULTS: There was no difference in average times to complete the various phases, despite faster robotic knot tying (p = 0.001). Suturing quality was superior in CLNF (p = 0.02). CYP increased similarly in both groups. Workflow-interrupting hemorrhage and pneumothorax occurred more frequently during CLNF (p = 0.040 and 0.044, respectively), while more sutures broke during RANF (p = 0.001). CONCLUSION: The robot provides no clear temporal advantage compared to conventional laparoscopy for fundoplication, although suturing was faster in RANF. Fewer complications were noted using the robot. RANF and CLNF were equally efficient anti-reflux procedures. For robotic surgery to manifest its full potential, more complex operations may have to be evaluated. PMID- 22200735 TI - Dynein regulates cell migration depending on substrate rigidity. AB - The mechanical environment in combination with biochemical signaling is an important regulatory factor for cellular physiology including tissue development, cell motility and differentiation. Exerting a tractional force triggered by myosin-dependent cell contractility is known to be an indispensible element of cell migration in a mechanically stiff environment such as a 2D planar surface. However, a number of reports have argued that the requirement of myosin activity for cell migration is limited by cell type and the environment. In this study, we present evidence that dynein, a minus end-directed microtubule motor, plays a central role in cell migration in the absence of tractional force. Interfering with the dynein activity through a dynein-specific inhibitor, erythro-9-(2 hydroxy-3-nonyl) adenine (EHNA), dramatically inhibited 2D migration of the fibroblast when cell contractility was blocked by Rho kinase or a myosin inhibitor, although EHNA itself did not affect cell migration. Cell migration in 3D soft collagen matrices, where the cell exerts a relatively low tractional force compared to that on a 2D stiff surface, is also profoundly inhibited by dynein intermediate chain (DIC) silencing regardless of the presence of myosin activity. In addition, DIC-silenced cells on a soft acrylamide surface show decreased migration without blockade of myosin activity. Taken together, our results suggest that dynein may be a primary regulatory factor for cell migration when a cell is in a mechanically low-tension environment, such as in a 3D matrix. PMID- 22200734 TI - Management of hearing aid assembly by urban-dwelling hearing-impaired adults in a developed country: implications for a self-fitting hearing aid. AB - A self-fitting hearing aid, designed to be assembled and programmed without audiological or computer support, could bring amplification to millions of people in developing countries, who remain unaided due to the lack of a local, professional, audiological infrastructure. The ability to assemble and insert a hearing aid is fundamental to the successful use of a self-fitting device. In this study, the management of such tasks was investigated. Eighty older, urban dwelling, hearing-impaired adults in a developed country were asked to follow a set of written, illustrated instructions to assemble two slim-fit behind-the-ear hearing aids. Participants were allowed to access assistance with the task from an accompanying partner. A range of personal and audiometric variables was measured through the use of structured questionnaires and standardized tests of health literacy, cognitive function, and manual dexterity. The results showed that 99% of participants were able to complete the hearing aid assembly task, either on their own or with assistance. Health literacy, or the ability to read and understand health-related text, and gender most strongly influenced participants' ability to complete the assembly task independently and accurately. Higher levels of health literacy were associated with an increased likelihood of independent and successful task completion. Male participants were more likely to complete the task on their own, while female participants were more likely to assemble the device without errors. The results of this study will inform future work regarding development of educational material for the self-fitting hearing aid as well as candidacy for such a device. PMID- 22200737 TI - Simplified estimates of ion-activity products of calcium oxalate and calcium phosphate in mouse urine. AB - This study aimed at formulating simplified estimates of ion-activity products of calcium oxalate (AP(CaOx)) and calcium phosphate (AP(CaP)) in mouse urineto find the most important determinants in order to limit the analytical work-up. Literature data on mouse urine composition was used to determine the relative effect of each urine variable on the two ion-activity products. AP(CaOx) and AP(CaP) were calculated by iterative approximation with the EQUIL2 computerized program. The most important determinants for AP(CaOx) were calcium, oxalate and citrate and for AP(CaP) calcium, phosphate, citrate, magnesium and pH. Urine concentrations of the variables were used. A simplified estimate of AP(CaOx) (AP(CaOx)-index(MOUSE)) that numerically approximately corresponded to 10(8) * AP(CaOx) was given the following expression:[Formula: see text]For a series of urine samples with various composition the coefficient of correlation between AP(CaOx)-index(MOUSE) and 10(8) * AP(CaOx) was 0.99 (p = 0.00000). A similar estimate of AP(CaP) (AP(CaP)-index(MOUSE)) was formulated so that it approximately would correspond numerically to 10(14) * AP(CaP) taking the following form:[Formula: see text]For a series of variations in urine composition the coefficient of correlation was 0.95 (p = 0.00000). The two approximate estimates shown in this article are simplified expressions of AP(CaOx) and AP(CaP). The intention of these theoretical calculations was not to get methods for accurate information on the saturation levels in urine, but to have mathematical tools useful for rough conclusions on the outcome of different experimental situations in mice. It needs to be emphasized that the accuracy will be negatively influenced if urine variables not included in the formulas differ very much from basic concentrations. PMID- 22200738 TI - Squamous cell carcinoma must be considered in patients with long standing upper ureteral stone and pyonephrosis. PMID- 22200739 TI - Updated epidemiologic study of urolithiasis in Turkey II: role of metabolic syndrome components on urolithiasis. AB - The components of metabolic syndrome, such as obesity, hypertension, and diabetes, are thought to be associated with urolithiasis. However, there are few large-scale studies that have examined the association between metabolic syndrome and urolithiasis, which prompted us to study and evaluate the relationship between metabolic syndrome components and urolithiasis in a nationwide survey, using the cross-sectional study conducted by a professional investigation company, with 2,468 enrolled participants, aged between 18 and 70 years, from 33 provinces in Turkey. Participants were interviewed face-to-face by medical faculty students. Participants with a history of urolithiasis (Group 1) were compared with participants without a history of urolithiasis (Group 2) in terms of hypertension, diabetes, body-mass index (BMI), waist size, and trouser size using Chi-square and odds ratio tests. Of the 2,468 participants, 274 (11.1%) reported a history of urinary stone disease diagnosed by a physician. The percentage of participants with hypertension along with urolithiasis was significantly higher than that in participants without urolithiasis (16.9 and 34.3%, p 0.000, OR 3.0). The percentage of participants with diabetes in groups 1 and 2 was 14.2 and 9%, respectively (p 0.001, OR 1.83). The mean BMI was 27.2 and 25.2, respectively (p 0.01). Participants with a BMI >30 had a 2.2-fold increased risk of having urolithiasis. The mean waist size was significantly greater in participants with urolithiasis (p 0.000). Those with a waist size >100 cm had a 1.87-fold increased risk of having urolithiasis. The mean trouser size was also significantly larger in those participants who were stone formers (p 0.003). The results indicate that metabolic syndrome components are important factors in the development of urolithiasis. PMID- 22200740 TI - Resveratrol given intraperitoneally does not inhibit the growth of high-risk t(4;11) acute lymphoblastic leukemia cells in a NOD/SCID mouse model. AB - The efficacy of resveratrol as a preventive agent against the growth of t(4;11) acute lymphoblastic leukemia (ALL) was evaluated in NOD.CB17-Prkdcscid/J mice engrafted with the human t(4;11) ALL SEM cell line. SEM cells were injected into the tail vein and engraftment was monitored by flow cytometry. Once engraftment was observed, mice were injected intraperitoneally with resveratrol (10 mg/kg body weight) dissolved in dimethylsulfoxide (DMSO) or DMSO alone (control) every other day, or vincristine (0.5 mg/kg body weight) 3 times per week for 4 weeks (n=16 per group). Comparisons of the percent of human leukemia cells in blood and survival curves showed resveratrol did not inhibit progression of the disease. Liquid chromatography-tandem mass spectrometry analyses of mouse sera showed resveratrol was rapidly metabolized to glucuronidated and sulfated forms 1 h post injection, with low to no resveratrol or metabolites observed in sera by 24-48 h. These data indicate that in contrast to findings in in vitro models, parenterally administered resveratrol does not have potential as a preventive agent against high risk t(4;11) ALL. PMID- 22200741 TI - Magnetic stent hyperthermia for esophageal cancer: an in vitro investigation in the ECA-109 cell line. AB - Magnetic stent hyperthermia (MSH) is a novel approach for targeted thermotherapy for esophageal cancer, which is based on the mechanism that inductive heat can be generated by the esophageal stent upon exposure under an alternative magnetic field (AMF). A positive effect of MSH on esophageal cancer has been demonstrated, however, there is no study on the in vitro effects of heating treatment or of the effects of AMF exposure on human esophageal cancer cells. This study aimed to investigate the effect of MSH and of AMF exposure in esophageal cancer cells. Inductive heating characteristics of esophageal stents were assessed by exposing the stents under AMF. A rather rapid temperature rise of the Ni-Ti stent when subjected to AMF exposure was observed and the desired hyperthermic temperature could be controlled by adjusting the field parameter of the AMF. Human esophageal squamous carcinoma (ESCC) ECA-109 cells were divided into four groups: the control group, the water-bath heating group, the MSH group and the AMF exposure group. Hyperthermic temperatures were 43, 48 and 53C and the treatment time was in the range of 5-30 min. The MTT assay, apoptotic analysis and TUNEL staining were applied in the current investigation. Exposure of ECA-109 cells under AMF with a field intensity of 50 to 110 kA/m had negligible effect on cell viability, cell necrosis and apoptosis. Hyperthermia had a remarkable inhibitory effect on the cell viability and the effect was dependent on the thermal dose (temperature and time). The optimal thermal dose of MSH for ECA-109 cells was 48C for 20-30 min. The study also elucidated that there was a difference in the effects on cell necrosis and apoptosis between the heating mode of water bath and MSH. The data suggest that MSH may have clinical significance for esophageal cancer treatment. PMID- 22200742 TI - Genetic polymorphisms and cervical cancer development: ATM G5557A and p53bp1 C1236G. AB - Persistent infections by high-risk types of human papillomavirus (HPV) have been established as the etiological agent of cervical cancer. The integration of the HPV genome into the host genome is a crucial step in cervical carcinogenesis, although, correct activation of DNA damage repair pathways will avoid the development of cancer. Recent data indicate that several polymorphisms of key regulators from the DNA damage repair pathway (i.e. 53BP1 and ATM) are associated with cancer development susceptibility. We have developed a hospital-based retrospective study considering 429 cervical specimens from women with different cervical lesions including invasive carcinoma. This study aimed to evaluate the role of the ATM D1853N (5557G>A) and 53bp1 D353E (1236C>G) polymorphisms in the development of cervical cancer, using TaqMan SNP Genotyping Assays. Statistical analysis revealed that ATM 5557GG homozygous individuals (OR=1.94; p=0.044) are at increased risk of developing LSIL, while for the 53BP1 1236C>G polymorphism no association was found. Nevertheless, we observed a tendency for an increased risk of LSIL in 53BP1 1236C allele carriers (OR=1.63; p=0.069). Logistic regression adjusted for age revealed no significant differences from the non-adjusted analysis. This is the first study to evaluate the role of ATM G5557A and P53BP1 C1236G polymorphisms in cervical cancer susceptibility. This study reveals a possible trend of both polymorphisms for a genetic susceptibility pattern of cervical cancer development. Hence, our results may be of interest for future understanding of the progression of cervical cancer. PMID- 22200743 TI - A humanized anti-IGF-1R monoclonal antibody (R1507) and/or metformin enhance gemcitabine-induced apoptosis in pancreatic cancer cells. AB - Pancreatic cancer is a disease with a dismal prognosis and treatment options are limited. This study investigated the interaction of gemcitabine with R1507 and/or metformin and the induction of an inhibitor of apoptosis protein by this com bination. Pancreatic cancer cells were treated with gemcitabine, R1507 and metformin alone or in combination. The effects of treatments were evaluated for cell proliferation, apoptosis, and the expression of genes related to inhibition of apoptosis and chemotherapy resistance. Combination of gemcitabine with R1507 and/or metformin additively interacted with the inhibition of cell proliferation in human pancreatic ductal adenocarcinoma cell lines, SUIT-2 and MIAPaCa-2 with differential gemcitabine resistance, and assessment of apoptosis demonstrated that drug associations increased the apoptotic index in both cell lines. Treatment with gemcitabine induced the expression of survivin and XIAP in both cell lines, indicating the induction of chemoresistance. In conclusion, these data demonstrate that the combination of gemcitabine with R1507 and/or metformin has an additive effect in pancreatic cancer cell lines with differential sensitivity to gemcitabine; however, gemcitabine may induce chemotherapy resistance. PMID- 22200744 TI - [Inhibitory effect of essential oils, food additives, peracetic acid and detergents on bacterial histidine decarboxylase]. AB - The aim of this study is to examine whether various essential oils, food additives, peracetic acid and detergents inhibit bacterial histidine decarboxylase. Crude extract of Morganella morganii NBRC3848 was prepared and incubated with various agents. Histidine decarboxylase activity was significantly inhibited (p<0.05) by 26 of 45 compounds tested. Among the 26 agents, sodium hypochlorite completely decomposed both histidine and histamine, while peracetic acid caused slight decomposition. Histidine and histamine were stable in the presence of the other 24 agents. These results indicated that 25 of the agents examined were inhibitors of histidine decarboxylase. PMID- 22200745 TI - [Antibacterial activity of essential oil vapor for histamine-producing bacteria]. AB - In this study, we evaluated the antibacterial activity of essential oil vapors against histamine-producing bacteria Morganella morganii NBRC3848 and Raultella planticola NBRC3317. We measured the minimum inhibitory dose (MID) of 14 essential oils towards these two strains. Allyl isothiocyanate (AIT) and salicylaldehyde (SA) vapors showed higher antibacterial activity than the other 12 essential oil vapors. Both AIT and SA vapors suppressed growth of total aerobic bacteria and histamine-producing bacteria in bigeye tuna and mackerel meat during storage at 12 degrees C. These vapors also inhibited histamine accumulation in bigeye tuna meat and mackerel meat. Thus, application of AIT and SA vapors is effective for preventing increase of histamine-producing bacteria and histamine formation in fish meat. PMID- 22200746 TI - [Simultaneous determination of polyether antibiotics and macrolide anthelmintics in livestock products by liquid chromatography/tandem mass spectrometry]. AB - A method using liquid chromatography coupled with tandem mass spectrometry (LC MS/MS) was developed for the simultaneous determination of polyether antibiotics and macrolide anthelmintics in livestock products. The polyether antibiotics and macrolide anthelmintics were extracted from livestock products with acetonitrile and cleaned up with dispersive solid-phase extractions and a silica gel column. The quantification limits of polyether antibiotics and macrolide anthelmintics were 0.00005-0.0005 ug/g. Except for narasin and lasalocid in bovine liver and milk, the recoveries were 70 to 117%. The relative standard deviations met the required guideline. The developed method was applied to six kinds of livestock products. PMID- 22200747 TI - [Analytical method of cereulide in processed cereal-based foods and milk powder by LC-MS/MS]. AB - An LC-MS/MS method for analysis of cereulide, an emetic toxin produced by Bacillus cereus, was developed. Cereulide was extracted from samples, fried rice, pan-fried noodles, red bean paste and baby formula, with methanol and purified using Oasis HLB cartridges. LC separation was performed on a C18 column with a mixture of formic acid solution and methanol containing ammonium formate as a mobile phase, and the mass spectrometer was operated in the positive electrospray ionization mode. Performance evaluation showed that trueness was higher than 70% and repeatability and reproducibility were within 10%. The limits of quantification were lower than 1 ug/kg. PMID- 22200748 TI - [Determination of pindone in animal products, fishery products, and honey by LC MS/MS]. AB - A sensitive and selective analytical method for the determination of the rodenticide pindone in animal products, fishery products, and honey by LC-MS/MS was developed. Pindone was extracted with acidified acetone, and the crude extract was purified by liquid-liquid partitioning, followed by silica gel and ODS column chromatography. LC separation was performed on an ODS column with methanol/water containing ammonium acetate as the mobile phase, and detection was carried out using tandem mass spectrometry (MS/MS) with electrospray ionization (ESI) in the negative mode. The average recoveries from fortified bovine muscle, bovine liver, bovine fat, chicken muscle, salmon, eel, freshwater clam, egg, milk, and honey spiked at 0.001 mg/kg were in the range of 76-92%, and the relative standard deviations were 4-8%. The limit of quantitation (S/N>=10) of the developed method was 0.001 mg/kg for all the tested foods. PMID- 22200749 TI - Survival of biofilm-forming Salmonella on stainless steel bolt threads under dry conditions. AB - We examined the survival of two biofilm-forming strains and two biofilm-deficient strains of non typhoid Salmonella (NTS) on stainless steel bolt threads under dry conditions. Five uL of tryptone soya broth or egg yolke mulsion containing NTS strains at a concentration of 9 log cfu/mL was dropped onto the thread surfaces of hexagonal bolts. After inoculation, the bolts were screwed into the nuts, and then removed (Separate type) or not removed (Unit type). The two types of samples were kept in a dry environment (20.0-25.0 degrees C, 2-15% humidity) and bacteria on the surfaces were periodically counted. Biofilm-forming strains were recovered from all samples after 336 days of incubation, but biofilm-deficient strains were isolated from only two of 8 samples after 336 days. This finding demonstrates that NTS can survive for approximately one year on bolt threads, providing direct evidence of the potential risk of constructions having crevices or uneven surfaces as possible contamination sources. The risk of cross-contamination may be higher for biofilm-forming strains than for biofilm-deficient strains. PMID- 22200750 TI - [Determination of vedaprofen in livestock products and seafoods by liquid chromatography-tandem mass spectrometry]. AB - A novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the trace residue determination of vedaprofen (VPF) in livestock products and seafoods. VPF was extracted from each sample with acidified acetone, and the crude extract was re-extracted with ethyl acetate and NaCl solution. Clean-up was performed using a weak anion exchange cartridge (Bond Elut DEA). The LC separation was performed on a C18 column using acetonitrile-0.0025 mol/L formic acid (3 : 2) as the mobile phase and MS was run in the negative ion electrospray ionization mode. The calibration curve was linear in the range of 0.001-0.1 ug/mL VPF. The mean recoveries from equine muscle, cattle muscle, cattle liver, cattle fat, salmon, eel, corbicula, milk, egg and buckwheat honey were 72-94%, and the relative standard deviations (RSDs) were 1.1-2.0%. Limits of quantitation (LOQs) ranged from 0.001 to 0.007 ug/g. PMID- 22200751 TI - [Test method for 6 phthalates in polyvinyl chloride]. AB - A test method for 6 phthalates, bis(2-ethylhexyl)phthalate, dibutyl phthalate, benzyl butyl phthalate, diisononyl phthalate, diisodecyl phthalate and di-n-octyl phthalate, in polyvinyl chloride (PVC) was developed. GC/MS was used in the SIM mode for the separation and detection of phthalates. For preparation of the test solution, the extraction method with acetone-hexane mixture (3 : 7) and the dissolution method with tetrahydrofuran and ethanol were compared and it was confirmed that each method gave good recoveries. Dilution of the test solution was effective to reduce the influence of PVC. In a collaborative study with nine laboratories, the intra-laboratory variations showed good repeatability, but the measurements at some laboratories deviated widely. It appears that this method is unsuitable for the judgment of acceptability, but it may be suitable for the determination of phthalate content in PVC products. PMID- 22200752 TI - Conservative management of unilateral condylar hyperplasia. AB - OBJECTIVE: The purpose of this study was to eliminate orthodontic treatment in mild to moderate cases of condylar hyperplasia in its early stages by condylectomy. PATIENTS AND METHODS: A total of five patients (two females and three males) aged between 17 and 40 years were treated with unilateral condylectomy of the involved side without orthodontic treatment. All patients underwent standardized clinical and radiological examination at initial consultation, before surgery, immediately after surgery, and follow-up. Objective and subjective evaluation of temporomandibular joint (TMJ) included maximal incisal opening, lateral excursions, correction of facial asymmetry, occlusal harmony, TMJ pain, and jaw function. Results were recorded at 5-year follow-up. RESULTS: In all our cases, we achieved good mouth opening and near to normal occlusion. Good facial aesthetics was obtained after 3 months postoperative follow-up without secondary orthodontic treatment. CONCLUSION: Thus, we conclude that treatment of mild to moderate cases of unilateral condylar hyperplasia during the inactive phase can be treated with condylectomy without orthodontic treatment, and it significantly improves long-term surgical outcomes. PMID- 22200753 TI - Right ventricular and left atrial and left ventricular myxomas: report of a case. AB - Myxomas are common cardiac tumors, which are usually managed by complete excision. We report a case of myxomas at different stages of development found simultaneously in the left atrium and both ventricles. The patient underwent successful surgical excision of all myxomas and there has been no clinical or echocardiographic evidence of recurrence or valvular insufficiency in 6 months of follow-up. PMID- 22200754 TI - Esophageal reconstruction using the terminal ileum and right colon in esophageal cancer surgery. AB - PURPOSE: To evaluate the outcomes of colon interposition based on our surgical experience. METHODS: We reviewed data from 40 patients who underwent esophagectomy with colon interposition using the terminal ileum and right colon, to treat esophageal cancer, between January 1990 and December 2009. RESULTS: Transthoracic esophagectomy, transhiatal esophagectomy, and pharyngolaryngoesophagectomy were performed in 31 (77.5%), 8 (20.0%), and 1 (2.5%) patients, respectively. The routes of the colon interposition were posterior mediastinal in 30 (75.0%) patients, retrosternal in 5 (12.5%), and subcutaneous in 5 (12.5%). The median operative time was 450 min (range 320-760 min) and the median blood loss was 755 ml (range 180-3,000 ml). Overall postoperative morbidity involved 18 (45.0%) patients and included esophagoileostomy leakage in 7 (17.5%; minor, n = 4; major, n = 3) and necrosis of the colon conduit in 2 (5%) patients. The 30- and 90-day mortality rates were 0 and 2.5%, respectively. The 1-, 3-, and 5-year survival rates were 80, 66, and 66%, respectively. CONCLUSIONS: Our surgical outcomes were acceptable in relation to other published results and the prognosis was favorable. Thus, esophageal reconstruction using the ileum and right colon is useful for patients with esophageal cancer for whom the stomach is not available. We currently perform colon interposition with microvascular anastomoses for grafts via the subcutaneous route to increase the safety of this operation. PMID- 22200755 TI - The effects of the early administration of sivelestat sodium, a selective neutrophil elastase inhibitor, on the postoperative course after radical surgery for esophageal cancer. AB - PURPOSE: The goal of this retrospective study was to evaluate the effects of perioperative administration of sivelestat sodium hydrate, a selective neutrophil elastase inhibitor, on the clinical course after radical surgery for esophageal cancer. METHODS: The effects of sivelestat on postoperative systemic inflammatory reactions and respiratory function were examined in 53 patients who underwent radical surgery for esophageal cancer between April 2004 and March 2005 with (n = 26, sivelestat group) and without (n = 27, control group) the administration of sivelestat. RESULTS: The average age in the sivelestat group was higher than that in the control group, but there were no other differences in the background factors between the two groups. The postoperative oxygenation (PaO(2)/FiO(2) ratio) did not differ between the groups, but the decrease in oxygen saturation (SpO(2)) was significantly inhibited in the sivelestat group compared with the control group (p < 0.01). A significant inhibition of the increase in the CRP level also occurred in the sivelestat group (p < 0.01). The patients in the sivelestat group were also hospitalized for shorter periods compared to those in the control group. CONCLUSION: The early administration of sivelestat to patients receiving radical surgery for esophageal cancer can inhibit postoperative systemic inflammatory reactions and it might also have a beneficial effect on the prognosis. PMID- 22200756 TI - Tissue engineered myoblast sheets improved cardiac function sufficiently to discontinue LVAS in a patient with DCM: report of a case. AB - Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by progressive heart failure, and is a leading cause of mortality and morbidity. Recently, cellular therapy for end-stage heart failure has been emerging. We herein report a 56-year-old male who received a transplant of autologous myoblast sheets manufactured in temperature-responsive culture dishes. His clinical condition improved markedly, leaving him without any arrhythmia and able to discontinue using a left ventricular assist system and avoid cardiac transplantation. These findings suggest that cellular therapy using myoblast sheets is a promising new strategy for treating patients with end-stage DCM. This method might be an effective alternative to heart transplantation in the near future. PMID- 22200757 TI - Zero mortality in more than 300 hepatic resections: validity of preoperative volumetric analysis. AB - PURPOSE: We reviewed a series of patients who underwent hepatic resection at our institution, to investigate the risk factors for postoperative complications after hepatic resection of liver tumors and for procurement of living donor liver transplantation (LDLT) grafts. METHODS: Between April 2004 and August 2007, we performed 304 hepatic resections for liver tumors or to procure grafts for LDLT. Preoperative volumetric analysis was done using 3-dimensional computed tomography (3D-CT) prior to major hepatic resection. We compared the clinicopathological factors between patients with and without postoperative complications. RESULTS: There was no operative mortality. According to the 3D-CT volumetry, the mean error ratio between the actual and the estimated remnant liver volume was 13.4%. Postoperative complications developed in 96 (31.6%) patients. According to logistic regression analysis, histological liver cirrhosis and intraoperative blood loss >850 mL were significant risk factors of postoperative complications after hepatic resection. CONCLUSIONS: Meticulous preoperative evaluation based on volumetric analysis, together with sophisticated surgical techniques, achieved zero mortality and minimized intraoperative blood loss, which was classified as one of the most significant predictors of postoperative complications after major hepatic resection. PMID- 22200758 TI - Utility of preoperative small-bowel endoscopy for hemorrhagic lesions in the small intestine. AB - PURPOSE: We evaluated a small group of patients with hemorrhagic lesions in the small intestine diagnosed preoperatively by video capsule endoscopy (VCE) and/or double-balloon endoscopy (DBE), who underwent surgery in our hospital. METHODS: The subjects were 20 patients with hemorrhagic lesions in the small intestine diagnosed preoperatively by VCE and/or DBE, who underwent surgery between April 2004 and December 2008. RESULTS: VCE, DBE, and computed tomography were performed in 12, 17, and 20 patients, respectively. Eleven patients also had a biopsy taken during DBE, resulting in a definitive diagnosis in eight. Because of the risk of hemorrhage during DBE in five patients, a biopsy was not taken and the sites of the lesion were marked in these patients. Twenty patients underwent surgery, and the diagnoses were small-intestinal cancer in eight, gastrointestinal stromal tumor in seven, arteriovenous malformation in two, and Crohn's disease, angioectasia, and leiomyoma in one each. The interval between the onset of symptoms and surgery was less than 50 days for six patients, 50-100 days for two, 100-200 days for five, and more than 200 days for seven. CONCLUSION: Preoperative small-bowel endoscopy proved useful for diagnosing the cause of hemorrhagic lesions in the small intestine. PMID- 22200759 TI - Left sleeve pneumonectomy via a clamshell incision for lung cancer with carinal invasion: report of a case. AB - Surgery for lung cancer involving the carina is challenging as it requires special surgical techniques and airway management. We report how we successfully treated carinal invasion of primary lung cancer by performing left sleeve pneumonectomy through a clamshell incision, as bilateral thoracotomy through a transverse sternotomy. Without a cardiopulmonary assist device, adequate ventilation and oxygenation were maintained across the operative field with a spinal tube. Tracheo-bronchial anastomosis was relatively easy to perform, with an excellent surgical view. The patient had an uneventful postoperative course and was discharged from hospital without oxygen support. There was no evidence of complications at the anastomosis on chest computed tomography and no sign of recurrence during 6 months of follow-up. The clamshell incision approach provided an excellent surgical view without the need to change the position of the patient during the operation. Thus, it could prove a useful procedure for carinal surgery; especially left sleeve pneumonectomy. PMID- 22200760 TI - Microtubule associated tumor suppressor 1 deficient mice develop spontaneous heart hypertrophy and SLE-like lymphoproliferative disease. AB - The microtubule associated tumor suppressor gene 1 (MTUS1) is a recently published tumor suppressor gene, which has also been shown to act as an early component in the growth inhibitory signaling cascade of the angiotensin II type 2 receptor (AT2R). In this study we report the generation of MTUS1 knock-out (KO) mice, which develop normally but reveal higher body weights and slightly decreased blood pressure levels. Twenty-eight percent of the studied MTUS1 KO mice also developed heart hypertrophy and 12% developed nephritis, independent of blood pressure levels. Forty-three percent of the MTUS1 KO mice revealed lymphoid hyperplasia affecting spleen (20%), kidney (37%), lung (23%), lymph nodes (17%), and liver (17%) accompanied with leukocytosis, lymphocytosis, and mild anemia. One animal (3%) developed a marginal zone B-cell lymphoma affecting submandibular salivary gland and regional lymph nodes. The symptoms of all mentioned animals are consistent with a B-cell lymphoproliferative disease with features of systemic lupus erythematosus. In addition, body weight of the MTUS1 KO mice was significantly increased and isolated skin fibroblasts showed increased cell proliferation and decreased cell size, compared to wild-type (WT) fibroblasts in response to depleted FCS concentration and lack of growth factors. In conclusion we herein report the first generation of a MTUS1 KO mouse, developing spontaneous heart hypertrophy and increased cell proliferation, confirming once more the anti proliferative effect of MTUS1, and a SLE-like lymphoproliferative disease suggesting crucial role in regulation of inflammation. These MTUS1 KO mice can therefore serve as a model for further investigations in cardiovascular disease, autoimmune disease and carcinogenesis. PMID- 22200761 TI - RNAi-mediated ERBB2 gene knockdown sensitizes human colorectal cancer cells to radiation. AB - This study aimed to investigate the involvement of c-erbB-2, encoded by the receptor tyrosine kinase ERBB2 gene, in the pathogenesis of colorectal cancer and to validate its potential as an anticancer target. Immunohistochemical and histopathological analyses were applied in tissue samples derived from 80 colorectal cancer patients. ERBB2 stable small hairpin RNA (shRNA) knockdown in HT29 human colorectal cancer cells was confirmed by RT-PCR and western blotting. Cell cycle profile and apoptosis were measured using PI or Annexin V-PI dual staining. A significant correlation between ERBB2 levels and Dukes' stage of colorectal cancer, in both the primary malignancy and lymph node metastatic tissues, was observed. ERBB2-depleted HT-29 cells exhibited increased sensitivity to radiation compared to control cells, likely due to enhanced G0/G1 phase cell cycle arrest and apoptosis. ERBB2 may be involved in the malignancy and metastasis of colorectal cancer. Overexpressed ERBB2 may constitute a potential target for colorectal cancer therapy. PMID- 22200762 TI - Antiplatelet, anticoagulant and fibrinolytic effects of Litchi chinensis Sonn. extract. AB - Litchi chinensis Sonn. (lychee), which belongs to the family of Sapindaceae, is a subtropical evergreen tree that is cultivated throughout Southeast Asia, particularly in China. Litchi chinensis has been reported to have anti inflammatory, antioxidant and antidiabetic activities. However, the antiplatelet and anticoagulant effects of Litchi chinensis have not been reported previously. In this study, we investigated the effects of a 70% ethanol extract from Litchi chinensis (LCE) on platelet aggregation, coagulation and fibrinolysis. LCE dose dependently inhibited collagen- and ADP-induced platelet aggregation in rat platelet-rich plasma. LCE at 4 mg/ml had a maximal inhibitory effect on platelet aggregation. In particular, the LCE 4 mg/ml-treated group showed almost complete inhibition in the collagen-induced platelet aggregation assay. It also significantly prolonged coagulation times, such as the activated partial thromboplastin and prothrombin time, in rat platelet-poor plasma. We also investigated the fibrinolytic effects of LCE using the fibrin plate assay. LCE increased fibrinolytic activity in a dose-dependent manner. These results demonstrated the antithrombotic effects of LCE and suggest that Litchi chinensis may be a new natural source for the development of antiplatelet, anticoagulant and thrombolytic therapeutics for thrombotic and cardiovascular diseases. PMID- 22200763 TI - Combination therapy with lentinan improves outcomes in patients with esophageal carcinoma. AB - With a view to improving treatment response and the quality of life of cancer patients, this study investigated the clinical efficacy of combining lentinan, a flavonoid compound with antitumor abilities, with traditional chemotherapy in individuals with esophageal carcinoma (EC), with a particular focus on its effect on immune function. A total of 50 patients undergoing treatment for EC were evenly divided into two groups: control and experimental. Patients in the control group were treated with the chemotherapeutic agent tegafur (1,000 mg/day for 5 days); patients in the experimental group were treated with the same dosage of tegafur combined with 1 mg lentinan diluted in 250 ml normal saline. Patients were monitored for their general condition, symptoms and signs, quality of life and clinical efficacy (remission vs. progression). Additionally, the effects of lentinan on immune function were assessed through analysis of serum levels of pro inflammatory and anti-inflammatory cytokines using enzyme-linked immunosorbent assay (ELISA) prior to and following the first and second course of treatment. The results of the scores showed that the general condition (Karnofsky performance scale; KPS), the symptoms and signs (Zubrod-ECOG-WHO score; ZPS) and the quality of life (QOL scale) of the patients following the first and second course of treatment were better in both groups compared to the scores prior to treatment; however, patients in the experimental group exhibited significantly greater improvement than those in the control group (P<0.05). Clinical efficacy was not significantly different between the two groups after 1 course of treatment, but after 2 courses of treatment, clinical efficacy was significantly greater in the experimental group than in the control group (P<0.05). Additionally, serum levels of IL-2, IL-6 and IL-12 increased, while levels of IL 4, IL-5 and IL-10 decreased, in patients of both groups after 2 courses of treatment (P<0.05). These changes occurred to a greater extent in the experimental group than in the control group (P<0.05). In conclusion, the addition of lentinan to the chemotherapy regimen improves the general condition, symptoms and signs, and quality of life of patients with EC. In particular, the patient's immune function may be enhanced by the combined treatment. The generalized application of lentinan is, therefore, recommended in the clinic. PMID- 22200764 TI - Antidromic vasodilatation and the migraine mechanism. AB - Despite the fact that an unprecedented series of new discoveries in neurochemistry, neuroimaging, genetics and clinical pharmacology accumulated over the last 20 years has significantly increased our current knowledge, the underlying mechanism of the migraine headache remains elusive. The present review article addresses, from early evidence that emerged at the end of the nineteenth century, the role of 'antidromic vasodilatation' as part of the more general phenomenon, currently defined as neurogenic inflammation, in the unique type of pain reported by patients suffering from migraine headaches. The present paper describes distinctive orthodromic and antidromic properties of a subset of somatosensory neurons, the vascular- and neurobiology of peptides contained in these neurons, and the clinical-pharmacological data obtained in recent investigations using provocation tests in experimental animals and human beings. Altogether, previous and recent data underscore that antidromic vasodilatation, originating from the activation of peptidergic somatosensory neurons, cannot yet be discarded as a major contributing mechanism of the throbbing head pain and hyperalgesia of migraine. PMID- 22200765 TI - Headache prevalence and characteristics among school children as assessed by prospective paper diary recordings. AB - In the present school-based study, a convenience sample of 477 students in grades 6-9 and second year in high school from a city and a smaller town recorded daily occurrence and intensity of headaches in a standard paper diary during a 3-week period. Total headache activity (headache sum), number of headache days, intensity level and duration for weekly headaches were estimated. Approximately 85% of the adolescents had experienced headache of any intensity level during the 3-week recording period. On the average, they reported 2.5 headache days per week and a mean intensity level for headache episodes of 1.7. Our estimates for headache of any intensity level (1-5) occurring at least once a week was surprisingly high (73.8%). For the highest intensity level across the whole 3 week period, almost identical proportions of mild and moderate headaches were reported by students (22.3-22.5%), while about twice as many (40.7%) had experienced severe headaches. Girls consistently reported more headaches than boys, in particular of the moderate and severe intensity types. Students in the city also reported more frequent and intense headaches than those in the town. Peak headache activity was observed at noon and in the afternoon and in the days from the middle of the week until weekend. The use of prospective recordings in diaries will further advance our knowledge on the prevalence and characteristics of recurrent headaches among children and adolescents in community samples. PMID- 22200766 TI - The effect of pentobarbital sodium and propofol anesthesia on multifocal electroretinograms in rhesus macaques. AB - We compared the suitability of pentobarbital sodium (PB) and propofol (PF) anesthetics for multifocal electroretinograms (mfERGs) in rhesus macaques. mfERGs were collected from 4 ocularly normal rhesus macaques. All animals were pre anesthetized with intramuscular ketamine (10-15 mg/kg). Intravenous PB induction/maintenance levels were 15 mg/kg/2-10 mg/kg and for PF, 2-5 mg/kg/6-24 mg/kg/h. There were 3 testing sessions with PB anesthesia and 5-7 testing sessions with PF anesthesia. All PB sessions were carried out before PF. First order (K1) and second-order (first slice) kernels (K2.1) response density amplitude (RDA), implicit time (IT), and root mean square signal-to-noise ratios (RMS SNR) of the low-frequency (LFC) and high-frequency (HFC) components were evaluated. The use of PF or PB anesthesia resulted in robust, replicable mfERGs in rhesus macaques; however, RMS SNR of K1 LFC in ring and quadrant analyses was significantly larger for PF than for PB. Additionally, K1 RDA under PF was significantly larger than under PB for N1, P1, and P2 components (ring and quadrant) and for N2 (quadrant). PF IT was significantly prolonged (<1 ms) relative to PB IT for N1, P1 (ring), and N1 (quadrant), while PB IT was significantly prolonged (0.8-4.2 ms) relative to PF IT for N2 and P2 (ring and quadrant). K1 HFC and K2.1 LFC did not differ significantly between PB and PF in the ring or quadrant analyses. The response differences found with PB and PF anesthesia likely arise from variable relative effects of the anesthetics on retinal gamma-aminobutyric acid (GABA(A)) receptors, and in part, on glycine and on glutamate receptors. Given the advantages of a stable anesthetic plane with continuous intravenous infusion and a smoother, more rapid recovery, PF is an appealing alternative for mfERG testing in rhesus macaques. PMID- 22200768 TI - Full spectrum genetics. PMID- 22200767 TI - Genetic association between human chitinases and lung function in COPD. AB - Two primary chitinases have been identified in humans--acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host's immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case-control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV(1)) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV(1) and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV(1). Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups. PMID- 22200770 TI - Improved imputation of common and uncommon SNPs with a new reference set. PMID- 22200771 TI - Spliceosome mutations in hematopoietic malignancies. AB - Recent studies, including two in this issue, report heterozygous missense mutations in the U2AF1 and SF3B1 genes that encode spliceosome subunits. U2AF1 is frequently mutated in myeloid hematopoietic malignancies, especially in myelodysplastic syndrome (MDS), and SF3B1 is frequently mutated in both MDS and chronic lymphocytic leukemia (CLL). PMID- 22200772 TI - Following evolution of bacterial antibiotic resistance in real time. AB - A new study reports the development of the 'morbidostat', a device that allows for continuous culture of bacteria under a constant drug selection pressure using computer feedback control of antibiotic concentration. This device, together with bacterial whole-genome sequencing, allowed the authors to follow the evolution of resistance-conferring mutations in Escherichia coli populations in real time, providing support for deterministic evolution of resistance in some situations. PMID- 22200779 TI - Torulaspora indica a novel yeast species isolated from coal mine soils. AB - Four yeast strains (APSS 805, APSS 806, APSS 815 and AP-18) belonging to a novel Torulaspora species were isolated from coal mine soils of Singareni in Andhra Pradesh state, India. Another strain (PBA-22) was isolated from agricultural field soil from Gujarat state, India. The vegetative cells of all these strains were round, haploid and produced asci by conjugation between independent cells or mother cell and bud, with rough ascospores, suggesting their possible relation to ascomycetous yeast genus Torulaspora. Phylogenetic analysis of the D1/D2 domain of the large subunit (LSU) rRNA gene and Internal Transcribed Spacer (ITS) regions revealed that, among the five strains, three viz. APSS 805, APSS 806 and APSS 815 have identical sequences. The other two strains (AP-18 and PBA-22) differed from the other three strains in less than 1% nucleotide substitutions in the combined D1/D2 domain and ITS sequences, indicating that all of them (five strains) may belong to the same species. These five strains were closely related to Torulaspora globosa, but showed more than 3-7% sequence divergence from T. globosa and all other species in the genus Torulaspora in the combined sequence analysis of D1/D2 domain and ITS region of rRNA gene. In addition, these strains also showed distinct microsatellite finger-printing pattern from related species and differed in several physiological responses suggesting that these strains belong to a novel species of Torulaspora. We propose to name these strains as Torulaspora indica sp. nov., and designate APSS 805(T) = MTCC 9772 (T) = CBS 12408 (T) as the type strain of this novel species. The Mycobank number of the novel species is MB 563738. PMID- 22200773 TI - Dnmt3a silences hematopoietic stem cell self-renewal. AB - DNA methylation is an epigenetic mark stably directing gene expression throughout development. A new study uncovers a role for the DNA methyltransferase Dnmt3a in silencing self-renewal genes in hematopoietic stem cells (HSCs) to permit efficient hematopoietic differentiation. PMID- 22200780 TI - Pseudonocardia yuanmoensis sp. nov., a novel actinobacterium isolated from soil in Yunnan, south-west China. AB - A novel Gram-stain positive, aerobic, non-motile, spore-forming actinobacterium, designated YIM 75926(T), was isolated from a soil sample collected at soil forest in Yuanmo county of Yunnan province, south-west China. Its taxonomic position was investigated by a polyphasic approach. Phylogenetic analyses based on 16S rRNA gene sequences showed that the novel strain YIM 75926(T) belongs to the genus Pseudonocardia and was closely related to Pseudonocardia halophobica DSM 43089(T) (98.1% similarity). Strain YIM 75926(T) had MK-8 (H(4)) as the predominant menaquinone. The whole organism hydrolysates mainly consisted of meso diaminopimelic acid, mannose, glucose, galactose and arabinose. The major cellular fatty acids were iso-C(16:0) (37.16%) and C(16:0) (12.43%). The DNA G+C content of strain YIM 75926(T) was 70.6 mol%. The resultant phylogenetic trees further showed that strain YIM 75926(T) belong to Pseudonocardia and had a distinct subclade within the evolutionary radiation of the genus Pseudonocardia. On the basis of its comparative analysis of phenotypic and genotypic characteristics, it is proposed that strain YIM 75926(T) represent a novel species of the genus Pseudonocardia, named Pseudonocardia yuanmoensis sp. nov. The type strain is YIM 75926(T) (=CCTCC AA 2011017(T) = JCM 18055(T)). PMID- 22200781 TI - Aliidiomarina haloalkalitolerans sp. nov., a marine bacterium isolated from coastal surface seawater. AB - A novel Gram-negative, rod shaped, motile, non-sporing strictly aerobic bacterium, designated strain AK5(T), was isolated from a sea water sample collected near Visakhapatnam coast, Bay of Bengal, India. Colonies on marine agar were circular, 3-4 mm in diameter, creamish and rose with entire margin. Growth occurred at 10-40 degrees C, 0.5-12% (w/v) NaCl and pH of 7-11. Strain AK5(T) was oxidase and catalase positive. The fatty acids were dominated by iso-branched saturated and unsaturated fatty acids with a high abundance of iso-C(15:0), iso C(17:0) and summed feature 9 (as defined by MIDI). Q8 was found to be the major respiratory quinone and diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and four unidentified phospholipids as polar lipids. The DNA G+C content of strain AK5(T) was 54.7 +/- 0.2 mol%. Phylogenetic analysis revealed that strain AK5(T) was a member of the genus Aliidiomarina and closely related to Aliidiomarina taiwanensis with a phylogenetic distance of 5.3% (94.7% 16S rRNA gene sequence similarity) and clustered with the same species. Results from the polyphasic taxonomy study support the conclusion that strain AK5(T) represents a novel Aliidiomarina species, for which the name Aliidiomarina haloalkalitolerans sp. nov. is proposed. The type strain of A. haloalkalitolerans is AK5(T) (= MTCC 11064(T) = JCM 17359(T)). PMID- 22200782 TI - Cohnella boryungensis sp. nov., isolated from soil. AB - A Gram-staining positive, endospore-forming, motile and rod-shaped bacterial strain, BR-29(T), was isolated from soil from west coast of the Korean peninsula, and its taxonomic position was investigated by a polyphasic study. Strain BR 29(T) grew optimally at around pH 7.5, at 30 degrees C and in the presence of 0.5% (w/v) NaCl. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain BR-29(T) fell into a clade comprising the type strains of Cohnella species, with which it exhibited 16S rRNA gene sequence similarity values of 92.8 96.4%. Strain BR-29(T) contained a cell wall peptidoglycan based on meso diaminopimelic acid and MK-7 as the predominant menaquinone. The major fatty acids were anteiso-C(15:0), C(16:0) and iso-C(16:0). The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, lysylphosphatidylglycerol and two unidentified phospholipids; a minor amount of phosphatidylglycerol was present. The DNA G+C content was 54.9 mol%. Strain BR-29(T) could be differentiated from phylogenetically related Cohnella species by differences in phenotypic characteristics. On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain BR-29(T) represents a novel species of the genus Cohnella, for which the name Cohnella boryungensis sp. nov., is proposed. The type strain is BR-29(T) (= KCTC 13735(T) = CCUG 59598(T)). PMID- 22200784 TI - Inhibition airway remodeling and transforming growth factor-beta1/Smad signaling pathway by astragalus extract in asthmatic mice. AB - Airway remodeling is characterized by airway wall thickening, subepithelial fibrosis, increased smooth muscle mass, angiogenesis and increased mucous glands, which can lead to a chronic and obstinate asthma with pulmonary function depression. In the present study, we investigated whether the astragalus extract inhibits airway remodeling in a mouse asthma model and observed the effects of astragalus extract on the transforming growth factor-beta1 (TGF-beta1)/Smad signaling pathway in ovalbumin-sensitized mice. Mice were sensitized and challenged by ovalbumin to establish a model of asthma. Treatments included the astragalus extract and budesonide. Lung tissues were obtained for hematoxylin and eosin staining and Periodic acid-Schiff staining after the final ovalbumin challenge. Levels of TGF-beta1 were assessed by immunohistology and ELISA, levels of TGF-beta1 mRNA were measured by RT-PCR, and levels of P-Smad2/3 and T-Smad2/3 were assessed by western blotting. Astragalus extract and budesonide reduced allergen-induced increases in the thickness of bronchial airway and mucous gland hypertrophy, goblet cell hyperplasia and collagen deposition. Levels of lung TGF beta1, TGF-beta1 mRNA and P-Smad2/3 were significantly reduced in mice treated with astragalus extract and budesonide. Astragalus extract improved asthma airway remodeling by inhibiting the expression of the TGF-beta1/Smad signaling pathway, and may be a potential drug for the treatment of patients with a severe asthma airway. PMID- 22200785 TI - Feasibility study for epidemic prevention and control in a regional hospital. AB - Epidemic prevention policies in hospitals address issues such as, indoor air quality control, cleanliness of medical staff clothing and employee hand-washing procedures. Our hospital employed Bio-Kil to treat air-conditioning filters and nursing staff uniforms. We also assessed the efficacy of different detergents. Using Bio-Kil technology, the mean bacterial count in the air was reduced from 108.8 CFU/h/plate (n=420) to 68.6 CFU/h/plate (n=630). On the lower hems of the Bio-Kil-treated gowns, the mean bacterial count was 1,201 CFU/100 cm(2), markedly lower than the bacterial count of 7,753 CFU/100 cm(2), found on the parts of the gowns not treated with Bio-Kil (p=0.0401). On the cuffs of sleeves treated with Bio-Kil, the mean count was 1,165 CFU/100 cm(2), markedly lower than that of 2,131 CFU/100 cm(2), found on the cuffs not treated with Bio-Kil (p=0.0073). With regard to the mean bacterial eradication rates of antimicrobial solutions, Steridal Solution, 75% alcohol and Bio-Kil (3rd generation) were shown to be the most effective, with rates exceeding 80%. Hibiscrub with paper towels and Fresh Protect Skin were the second most effective. Bio-Kil (1st generation), tap water with paper towels, liquid hand soap with paper towels and ozone water were the least effective. One important observation was that hand-washing without the use of paper towels increased the bacterial count by as much as 84% . Bio-Kil is effective in reducing bacterial counts in the air, on nursing staff uniforms and is an effective detergent. PMID- 22200783 TI - Epiphytic pink-pigmented methylotrophic bacteria enhance germination and seedling growth of wheat (Triticum aestivum) by producing phytohormone. AB - Methylotrophic bacteria were isolated from the phyllosphere of different crop plants such as sugarcane, pigeonpea, mustard, potato and radish. The methylotrophic isolates were differentiated based on growth characteristics and colony morphology on methanol supplemented ammonium mineral salts medium. Amplification of the mxaF gene helped in the identification of the methylotrophic isolates as belonging to the genus Methylobacterium. Cell-free culture filtrates of these strains enhanced seed germination of wheat (Triticum aestivum) with highest values of 98.3% observed using Methylobacterium sp. (NC4). Highest values of seedling length and vigour were recorded with Methylobacterium sp. (NC28). HPLC analysis of production by bacterial strains ranged from 1.09 to 9.89 MUg ml( 1) of cytokinins in the culture filtrate. Such cytokinin producing beneficial methylotrophs can be useful in developing bio-inoculants through co-inoculation of pink-pigmented facultative methylotrophs with other compatible bacterial strains, for improving plant growth and productivity, in an environment-friendly manner. PMID- 22200787 TI - Downregulation of S100A4 expression by RNA interference suppresses cell growth and invasion in human colorectal cancer cells. AB - S100A4 protein, a member of the S100 superfamily of calcium-binding proteins, is frequently observed in various types of human cancers, including colorectal cancer (CRC). Our previous investigations have demonstrated that the overexpression of S100A4 is associated with lymph node metastasis and poor prognosis in CRC; however, its biological roles in CRC remain unclear. In the present study, we compared the expression of S100A4 at the mRNA and protein levels in six CRC cell lines, and found that the expression levels roughly coincided with their invasiveness. Using RNA interference, we suppressed S100A4 expression in SW620 CRC cells with highly invasive potential and S100A4 high expression. The specific knockdown of S100A4 strongly suppressed cell growth, migration and invasion activities. Furthermore, employing metastasis-related gene mRNA microarrays, we found four genes to be significantly dysregulated (more than 2-fold) after downregulation of S100A4, including three downregulated genes (MMP9, MMP10 and CDH11) and one upregulated gene (TIMP4). Our present results indicate that S100A4 may positively regulate tumor cell proliferation, invasion and metastasis associated with multiple molecules. Thus, the inhibition of S100A4 might be a potentially novel approach to treatment for CRC. PMID- 22200786 TI - Clarithromycin enhances bortezomib-induced cytotoxicity via endoplasmic reticulum stress-mediated CHOP (GADD153) induction and autophagy in breast cancer cells. AB - The specific 26S proteasome inhibitor, bortezomib (BZ) potently induces apoptosis as well as autophagy in metastatic breast cancer cell lines such as MDA-MB-231 and MDA-MB-468. The combined treatment of clarithromycin (CAM) and BZ significantly enhances cytotoxicity in these cell lines. Although treatment with up to 100 ug/ml CAM alone had little effect on cell growth inhibition, the accumulation of autophagosomes and p62 was observed after treatment with 25 ug/ml CAM. This result indicated that CAM blocked autophagy flux. However, the combined treatment of BZ and CAM resulted in more pronounced autophagy induction, as assessed by increased expression ratios of LC3B-II to LC3B-I and clearance of intracellular p62, than treatment with BZ alone. This combination further enhanced induction of the pro-apoptotic transcription factor CHOP (CADD153) and the chaperone protein GRP78. Knockdown of CHOP by siRNA attenuated the death promoting effect of BZ in MDA-MB-231 cells. A wild-type murine embryonic fibroblast (MEF) cell line also exhibited enhanced BZ-induced cytotoxicity with the addition of CAM, whereas a Chop knockout MEF cell line completely abolished this enhancement and exhibited resistance to BZ treatment. These data suggest that endoplasmic reticulum (ER)-stress mediated CHOP induction is involved in pronounced cytotoxicity by combining these reagents. Simultaneously targeting two major intracellular protein degradation pathways such as the ubiquitin-proteasome system by BZ and the autophagy-lysosome pathway by CAM may improve the therapeutic outcome in breast cancer patients via ER-stress mediated apoptosis. PMID- 22200788 TI - p53 codon 72 polymorphism as a progression index for bladder cancer. AB - The aim of this study was to calculate the positive predictive value (PPV) and negative predictive value (NPV) to determine whether p53 codon 72 can be used as a bladder cancer management index. Ninety-six patients diagnosed with bladed cancer and two control groups of 427 randomly sampled community participants and 142 non-cancerous individuals without a prior history of cancer were enrolled. After preliminary analysis, the convergent validity resulted in 96 patients from this study and 129 patients from our previous study. Results showed that these two groups were of the same population, and could be merged into one case group. Logistic regression showed that the Pro/Pro genotype was not statistically significantly associated with bladder cancer incidence using each sample set after adjustment by age and gender. Moreover, the Pro/Pro genotype was not associated with high-grade tumors (P=0.078), but was highly correlated to muscle invasive tumors (P=0.002). Pro/Pro genotype carriers were estimated to have a 3.36-fold higher risk to develop invasive tumors compared to non-carriers. The NPV of the Pro/Pro genotype for invasive tumors was 88.00%, and the PPV was 31.91%. By Cox regression analysis, high-grade tumors were associated with recurrence (P=0.020, OR=1.83), whereas invasive tumors were associated with cancer-related death (P<0.001, OR=2.87). p53 codon 72 polymorphism is associated with bladder cancer progression rather than incidence and prognosis. The Pro/Pro genotype in p53 codon 72 polymorphism shows a high NPV for bladder cancer progression, thus, it can be used clinically as a progression index in bladder cancer management. PMID- 22200789 TI - Musculoskeletal manifestation in the joints of the diabetic animal model Otsuka Long-Evans Tokushima fatty rat: a histological study. AB - Diabetes mellitus (DM) is a chronic metabolic disease and is associated with vascular complications. However, the association of musculoskeletal manifestations and DM is not clear. We investigated musculoskeletal manifestations in the diabetic animal model Otsuka Long-Evans Tokushima Fatty (OLETF) rat. OLETF rats and control LETO (Long-Evans Tokushima Otsuka) rats at two different ages (44 and 95 weeks) were used. Knee joints and ankles with interphalangeal joints were removed, dissected, stained with hematoxylin and eosin (H&E), periodic acid-Schiff, methenamine silver, and Masson-trichrome staining and examined under light microscopy. Mild degenerative changes with focal edema and mild fibrosis were noted in OLETF rats (at 95 weeks of age) and in age-matched LETO rats, particularly in the interphalangeal joints. Necrosis, phagocytosis of necrotic fibers, regeneration, mononuclear inflammatory cell infiltration, granulation tissue, calcification and cartilage erosion were not observed in either the aged diabetic or the non-diabetic group. We found no prominent musculoskeletal manifestations in the OLETF rats. The reasons may be due to the low prevalence rate of these anomalies, or the life span of rats may be too short to express these alterations. More studies are needed to elucidate the pathophysiological mechanisms by demonstrating the musculoskeletal manifestations histologically. PMID- 22200769 TI - Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry. PMID- 22200790 TI - Gene alterations in the PI3K/PTEN/AKT pathway as a mechanism of drug-resistance (review). AB - The most common therapeutic approach for many cancers is chemotherapy. However, many patients relapse after treatment due to the development of chemoresistance. Recently, targeted therapies represent novel approaches to destroy cancer cells. The PI3K/PTEN/AKT pathway is a key signaling pathway involved in the regulation of cell growth. Dysregulated signaling of this pathway may be associated with activating mutations of PI3K-related genes. Analyses of these mutations reveal that they increase the PI3K signal, stimulate downstream Akt signaling, promote growth factor-independent growth and increase cell invasion and metastasis. In this review, we summarize the PI3K/PTEN/AKT pathway genetic alterations in cancer and their potential clinical applications. PMID- 22200791 TI - Relative biological effectiveness of high linear energy transfer alpha-particles for the induction of DNA-double-strand breaks, chromosome aberrations and reproductive cell death in SW-1573 lung tumour cells. AB - Ionizing radiation-induced foci (IRIF) of DNA repair-related proteins accumulated at DNA double-strand break (DSB) sites have been suggested to be a powerful biodosimetric tool. However, the relationship between IRIF induction and biologically relevant endpoints, such as cell death and formation of chromosome rearrangements is less clear, especially for high linear energy transfer (LET) radiation. It is thus not sufficiently established whether IRIF are valid indicators of biological effectiveness of the various radiation types. This question is more significant in light of the recent advancements in light ion beam and radionuclide therapy. Dose-effect relationships were determined for the induction of DNA-DSBs, chromosome aberrations and reproductive cell death in cultured SW-1573 cells irradiated with gamma-rays from a Cs-137 source or with alpha-particles from an Am-241 source. Values of relative biological effectiveness (RBE) of the high LET alpha-particles were derived for these effects. DNA-DSB were detected by scoring of gamma-H2AX foci, chromosome aberrations by fragments and translocations using premature chromosome condensation and cell survival by colony formation. Analysis of dose-effect relations was based on the linear-quadratic model. Except for the survival curves, for other effects no significant contribution was derived of the quadratic term in the range of doses up to 2 Gy of gamma-rays. Calculated RBE values derived for the linear component of dose-effect relations for gamma-H2AX foci, cell reproductive death, chromosome fragments and colour junctions are 1.0+/-0.3, 14.7+/-5.1, 15.3+/-5.9 and 13.3+/-6.0, respectively. RBE values calculated at a certain biological effect level are 1, 4, 13 and 13, respectively. The RBE values derived from the LQ model are preferred as they are based on clinically relevant doses. The results show that with low LET radiation only a small fraction of the numerous DNA-DSBs yield chromosome damage and reproductive cell death. It is concluded that many of the chromosomal aberrations detected by premature chromosome condensation do not cause reproductive cell death. Furthermore, RBE values for DNA-DSB detectable by gamma-H2AX foci shortly after irradiation, provide no information relevant to applications of high LET radiation in radiotherapy. The RBE values of chromosome aberrations assessed by premature chromosome condensation are close to the value for reproductive cell death. This suggests possible relevance to assess RBE values for radiotherapy with high LET ions. PMID- 22200792 TI - Nanog inhibits lipopolysaccharide-induced expression of pro-inflammatory cytokines by blocking NF-kappaB transcriptional activity in rat primary microglial cells. AB - Nanog is an essential transcription factor maintaining the self-renewal and pluripotency of embryonic stem cells, which binds to nuclear factor-kappaB (NF kappaB) proteins, inhibits their transcriptional activity and represses their pro differentiation activity. The persistent and excessive activation of microglial cells, as primary immune cells in the central nervous system is associated with various nerve system diseases, such as neuropathic pain, ischemia, infection, as well as neurodegenerative diseases. However, the effects of Nanog on the activation of microglial cells have yet to be elucidated. In this study, we investigated whether Nanog inhibits the production of pro-inflammatory factors in lipopolysaccharide (LPS)-stimulated microglial cells. Nanog was shown to down regulate the mRNA and protein levels of IL-1beta, TNF-alpha and IL-6 in LPS stimulated rat primary microglial cells. Furthermore, we also found that the transcriptional activity of NF-kappaB was dramatically reduced by Nanog, which was measured using luciferase assay. The results suggest that Nanog reduces the production of pro-inflammatory cytokines and attenuates inflammatory responses in LPS-stimulated microglial cells by blocking the transcriptional activity of NF kappaB. Thus, Nanog may be a potentially useful anti-inflammatory therapy for the treatment of various nervous system diseases. PMID- 22200793 TI - Gastrointestinal quality of life after laparoscopic-assisted sigmoidectomy for diverticular disease. AB - PURPOSE: Laparoscopic-assisted sigmoidectomy is a widely applied technique in the operative treatment of diverticular disease. Treatment guidelines recommend operation of complicated diverticulitis and after recurrent attacks of uncomplicated diverticulitis. These guidelines have become subject to controversy. The objective of this study was to assess disease-related quality of life after laparoscopic sigmoidectomy. METHODS: Data were collected retrospectively. Patients filled in a form describing their quality of life. All patients undergoing elective operation for diverticular disease between 1999 and 2006 at the Department of Surgery of the Uster Hospital, a regional medical center in Switzerland were included. The measurement tool we used is the Gastrointestinal Quality of Life Index (GIQLI). Wilcoxon-Mann-Whitney test or unpaired t-tests were applied to determine statistical significance of differences observed. RESULTS: A total of 130 patients were included and 120 questionnaires were available for analysis. Mean follow-up was 40 months. Of the total, 48% reported a GIQLI >100 before the operation, which rose to 83% after the operation (p < 0.0001). Mean GIQLI was 95 before and 114 after the operation (p < 0.0001). Female patients reported lower GIQLI rates. Overall, 96% were satisfied with the operation. CONCLUSIONS: The results in this study population show that in a majority of patients who underwent elective laparoscopic-assisted sigmoidectomy for recurrent diverticulitis gastrointestinal quality of life improved with the operation. PMID- 22200794 TI - Hereditary nonpolyposis colorectal cancer (Lynch syndrome I) in a 15-year-old male. PMID- 22200795 TI - Overexpression of GLUT1 correlates with Kras mutations in lung carcinomas. AB - Glucose is the major source of energy for cells, and glucose transporter 1 (GLUT1) is the most common glucose transporter. GLUT1 has been found to be aberrantly expressed in several tumor types. From the results of the microarray and serial analysis of gene expression (SAGE), GLUT1 transcript expression was found to be higher in clones with mutant Kras alleles. We hypothesized that GLUT1 overexpression might be correlated with clinicopathological features of Japanese lung cancers. Immunohistochemistry for GLUT1 was performed in 283 surgically treated non-small cell lung cancer (NSCLC) cases from Nagoya City University Hospital. Thirty-six Kras mutant carcinoma cases were included. GLUT1 overexpression was found in 138 (48.8%) lung cancer patients. The GLUT1 overexpression status was significantly correlated with gender (women 31.9% vs. men 54.5%, P<0.0001), smoking status (never smoker 31.4% vs. smoker 59.4%, P<0.0001) and pathological subtypes (adenocarcinoma 36.4% vs. non-adenocarcinoma 74.5%, P<0.0001). In addition, the GLUT1 overexpression status was significantly correlated with gene mutation status, including EGFR (mutation-positive 23.4% vs. -negative 58.3%, P<0.0001) and Kras (mutation-positive 66.7% vs. -negative 46.6%, P=0.038). The survival of patients with GLUT1 overexpression (n=137, 50 were deceased) was significantly worse when compared to the patients with normal expression of GLUT1 (n=142, 31 were deceased) (Log-rank test, P=0.0009). Thus, GLUT-1 overexpression correlates with an aggressive phenotype of lung carcinoma. PMID- 22200797 TI - [Control of halophilic histamine-producing bacteria by using natural antimicrobials and other agents]. AB - We have investigated the control of halophilic histamine-producing bacteria, Photobacterium phosphoerum and Photobacterium damselae by using vapor of essential oils and other agents. Three of fourteen essential oils showed high antibacterial activity against histamine-producing bacteria. Among food additives and detergents, ten of twenty-one food additives and seven of nine detergents also showed antibacterial activity. Low concentrations of sodium chloride suppressed the growth of both species. We examined the resistance of these bacteria to dryness on food contact surfaces. After 0.5 hours, no viable cells were detected. So, the bacteria were sensitive to dry conditions. These results should contribute to development of the techniques to prevent histamine food poisoning. PMID- 22200796 TI - Reduction in corticospinal inhibition in the trained and untrained limb following unilateral leg strength training. AB - This study used transcranial magnetic stimulation to measure the corticospinal responses following 8 weeks of unilateral leg strength training. Eighteen healthy, non-strength trained participants (14 male, 4 female; 18-35 years of age) were matched for age, gender, and pre-training strength; and assigned to a training or control group. The trained group participated in unilateral horizontal leg press strength training, progressively overloaded and wave periodised, thrice per week for 8 weeks. Testing occurred prior to the intervention, at the end of 4 weeks and at the completion of training at 8 weeks. Participants were tested in both legs for one repetition maximum strength, muscle thickness, maximal electromyography (EMG) activity, and corticospinal excitability and inhibition. No changes were observed in muscle thickness in either leg. The trained leg showed an increase in strength of 21.2% (P = 0.001) and 29.0% (P = 0.007, compared to pre-testing) whilst the untrained contralateral leg showed 17.4% (P = 0.01) and 20.4% (P = 0.004, compared to pre-testing) increases in strength at 4 and 8 weeks, respectively. EMG and corticospinal excitability did not change; however, corticospinal inhibition was significantly reduced by 17.7 ms (P = 0.003) and 17.3 ms (P = 0.001) at 4 and 8 weeks, respectively, in the trained leg, and 25.1 ms (P = 0.001) and 20.8 ms (P = 0.001) at 4 and 8 weeks, respectively, in the contralateral untrained leg. This data support the theory of corticospinal adaptations underpinning cross-education gains in the lower limbs following unilateral strength training. PMID- 22200798 TI - Detection of irradiated food using 2-alkylcyclobutanones as markers: verification of the european committee standardization method EN1785 for the detection of irradiated food containing lipids. AB - 2-Alkylcyclobutanones (ACBs) are specific radiolytic products in irradiated lipid containing food and can be used to detect irradiation of foodstuffs. EN1785, a European Committee Standardization Method, can detect 2-dodecylcyclobutanone (DCB) and 2-tetradecylcyclobutanone (TCB), which are ACBs, using GC/MS, thereby allowing judgement as to whether foodstuffs have been irradiated. In this study, the performance of EN1785 as a qualitative test in a single laboratory was evaluated and its applicability to beef, pork, chicken and salmon was verified. In the performance evaluation test, lipids extracted from unirradiated food using the Soxhlet extraction method were used as negative samples. Further, negative samples, to which DCB and TCB were added at 0.05 ug/g lipid (equivalent to the amount generated in food when irradiated at 0.5 kGy or more), were used as positive samples. For each food type examined, 4 negative and 16 positive samples were analyzed by EN1785 to verify the method's ability to detect irradiation. All of the negative samples were judged negative and all of the positive samples were judged positive. Thus, the method should be able to detect irradiation in beef, pork chicken and salmon irradiated at 0.5 kGy or higher. Next, to confirm that this is the case, the same types of food examined above, both unirradiated and irradiated at doses of 0.5-4 kGy, were analyzed by the method. All of the unirradiated samples were judged negative and all of the irradiated samples were judged positive. In a laboratory different from the one where the aforementioned evaluation was conducted, a performance evaluation test was carried out. Blind coded samples, including unirradiated and irradiated samples, were then analyzed in the laboratory according to EN178S. Ten samples (2 unirradiated and 8 irradiated samples) were analyzed for each type of food and the verified method was found to be 100% accurate. Even after the irradiated foodstuffs had been frozen for 6-9 months, it was still possible to judge whether the foodstuffs had been irradiated or not using the EN1785 method. PMID- 22200799 TI - [Analysis of spinosad in animal and fishery products by LC-MS]. AB - We investigated the determination of spinosyn A and spinosyn D, the active ingredients of spinosad, in animal and fishery products by liquid chromatography with mass spectrometry (LC-MS). The sample was homogenized with 1 mol/L dipotassium hydrogenphosphate aqueous solution and extracted with acetone-n hexane under mildly alkaline conditions. After n-hexane-acetonitrile partitioning using an EXtrelut((r)) column, the extract was cleaned up on a tandem SAX/PSA mini-column, and examined by means of fragmenter-voltage-switching ESI-SIM mode LC-MS. Mean recoveries (n=5) of spinosyn A and spinosyn D from eleven kinds of fortified samples at the analyte concentration of 0.01 ug/g and 0.05 ug/g ranged from 76.1% to 93.8% (RSD<=8.7%) and from 75.1% to 104.1% (RSD<=8.6%), respectively. PMID- 22200800 TI - [Rapid and simultaneous determination method for analysis of minerals in infant formula using ICP-MS]. AB - A rapid and simultaneous method by using inductively coupled plasma mass spectrometry (ICP-MS) was developed for determination of 19 elements in infant formula. Fast and efficient sample digestion was achieved by a microwave-assisted nitric acid procedure. An acetic acid was added to both these treated solutions and standard solutions as a countermeasure for carbon charge transfer in As, Se elements. The observed calibration curves showed good linearity (r(2)>0.9993) and the quantification limit was low. The recoveries of elements were 95.0-108% and the relative standard deviations (RSD) of this method were 0.3-4.2%. The analyzed values were in good agreement with the certified values in a NIST standard reference material. This study showed that the ICP-MS method is useful for major to trace multi-elemental determination in infant formula. PMID- 22200801 TI - [Antibacterial effect of food additives and detergents against histamine producing bacteria on food contact material surfaces]. AB - We investigated the antibacterial activity of food additives and detergents against histamine-producing bacteria on food contact material surfaces. Based on minimum inhibitory concentration (MIC) testing with Morganella morganii NBRC3848, Raoultella planticola NBRC3317 and Enterobacter aerogenes NCTC10006, we screened nine food additives and four detergents with relatively high inhibitory potency. We prepared food contact material surfaces contaminated with histamine-producing bacteria, and dipped them into fourteen agents (100 ug/mL). Sodium hypochlorite, benzalkonium chloride, benzethonium chloride, n-hexadecyltrimethylammonium chloride and 1-n-hexadecylpyridinium chloride showed antibacterial activity against histamine-producing bacteria. We prepared low concentrations of the five agents (10 and 50 ug/mL) and tested them in the same way. Sodium hypochlorite showed high antibacterial activity at 10 ug/mL, and the other four showed activity at 50 ug/mL. So, washing the material surface with these reagents might be effective to prevent histamine food poisoning owing to bacterial contamination of food contact surfaces. PMID- 22200802 TI - DNA-based identification of fish species implicated in Puffer fish poisoning. AB - A method for identification of fish species using three different mitochondrial DNA regions, 16S rRNA, cytochrome b and cytochrome c gene fragments, was investigated. The combined use of all three regions enabled reliable species identification in not only raw fish, but also dried, seasoned and boiled fish, products. Furthermore, the method was applicable even to vomitus from a patient involved in a puffer fish poisoning incident. However, further improvement is necessary to discriminate between closely related species such as Takifugu rubripes and T. chinensis, because they showed close similarity in the nucleotide sequences in the three gene fragments analyzed in this study. PMID- 22200803 TI - Bacteriological and chemical evaluation of overseas mineral waters. AB - Overseas and imported mineral waters were subjected to visual examination, tested for standard plate count and heterotrophic bacteria, and also analyzed to determine the concentrations of several anions and cations. Some products showed turbidity or color, and several had standard plate count and/or heterotrophic bacteria. One imported natural mineral water product had a high level of standard plate count, and the levels differed with the lot. Tests for total coliform bacteria, Escherichia coli, fecal streptococci, and Pseudomonas aeruginosa were negative on additional testing of samples having standard plate counts of more than 100. The fluoride concentration of one European region sample exceeded the production standard of the Food Sanitation Act in Japan (raw water: less than 2 mg/L) and most of the products lacked the warning labels which are mandatory for fluoride concentrations over 0.8 mg/L. These results indicate that none of the raw water for mineral waters was seriously polluted, but insufficient sterilization of the bottle or cap or contamination with air-borne microbes during the production process was probably responsible for the pollution. Attention needs to be paid to fair labeling, such as no sterilization/no sterile filtration and high fluoride concentration. PMID- 22200804 TI - Study on detection of drugs in slimming health foods using GC-MS/MS. AB - The determination of five drugs, fenfluramine (FEN), N-nitrosofenfluramine (NFE), sibutramine (SIB), mazindol (MAZ) and phenolphthalein (PHP), was studied in slimming health foods using GC-MS/MS. These drugs have been detected at high rates, especially in slimming health foods. Prolonged or excessive consumption of non-approved or unauthorized pharmaceuticals may cause serious adverse health consequences. In this study, samples were extracted with methanol and ultrasonication. Analyses were performed by GC-MS/MS, using established MS/MS parameters in the electron ionization (EI) mode and chemical ionization (CI) mode. In the EI mode, the recoveries of five drugs from several types of slimming health foods such as tablets, capsules and tea-bags spiked at 1 ug/mg (except PHP, spiked at 4 ug/mg) were in the range of 85.0-110.7% and 100 ug/mg (except PHP, spiked at 200 ug/mg) were 94.9-102.9%, respectively. In the CI mode, good recoveries of 80.3-102.2% (spiked at low concentration) and 92.8-103.2% (spiked at high concentration) were also obtained. We evaluated the present method using four slimming health foods, in which drugs had previously been detected. The results were similar to the previous results. These findings indicate that the present procedure for evaluating five drugs in slimming health foods by means of GC-MS/MS is useful. PMID- 22200805 TI - Evaluation of an analytical method for cyanogenic compounds in beans and surveillance of cyanogenic compounds in beans. AB - The performance characteristics of an analytical method for cyanogenic compounds were evaluated. Specifically, we tested the trueness, repeatability and intermediate precision of the method using a spectrophotometric-based detection system for 4-pyridinecarboxylic acid and pyrazolone after steam distillation. The pH adjustment of the distillate was revealed to affect the trueness of the measurements. A pH of approximately 6 was found to be optimal. The targeted quantitation limit of the cyanide ion was set to 5 mg/kg. The performance of the method was evaluated using beans spiked with cyanide ion at one to two times the quantitation limit (5-10 mg/kg). The trueness of the method was between 78-90%, and the repeatability and intermediate precision were between RSD 1.2% to 6.0%. A surveillance of cyanogenic compounds in beans retailed in Japan was then carried out. All the results were below the quantitation limit of 5 mg/kg. PMID- 22200806 TI - Assessment of efficacy of pamidronate in undifferentiated spondyloarthropathy (uSpA): a placebo control trial in a tertiary level center. AB - Undifferentiated spondyloarthropathy (uSpA) is a nonspecific form of spondyloarthropathy where nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs are still mainstay of treatment. We evaluated the efficacy and adverse effect profile of pamidronate, in uSpA patients refractory to NSAIDs therapy. A case series of 87 patients fulfilling the modified Amor criteria for the diagnosis of uSpA, having active disease even after 3-month continuous therapy with two NSAIDs, were selected. Active disease was defined as a VAS score >50 in a scale of 0-100 in 3 out of four following parameters: patients' global assessment, pain, BASFI and BASDAI morning stiffness. Sixty-six patients among those were administered monthly pamidronate infusion (60 mg over 4 h in 500 ml of normal saline) for 6 months. Other 21 patients (placebo group) transfused with normal saline. Treatment outcome was assessed by comparing baseline and 6 months value of BASDAI, BASFI, BASMI, BAS-G, CRP and ESR in both groups and improvement by ASAS-20 and BASDAI-50. Among the 66 patients, 48 patients (72.73%) achieved ASAS-20 and 42 patients (63.64%) achieved BASDAI-50 response. Among the treatment group, mean ESR, CRP, BASDAI, BASFI, BAS G and BASAMI reduced by 54.81 mm/h (64.95%), 3.94 mg/l (43.3%), 3.74 (48.38%), 3.73 (49.40%), 4.47 (58.97%) and 4.28 (58.15%), respectively, after treatment, whereas in placebo group, increased by 5.48 mm/h (6.34%), 0.34 mg/l (3.77%), 0.24 (3.02%), 0.45 (6.03%), 0.05 (0.67%) and 0.52 (7.13%), respectively, after 6 months. Intravenous pamidronate has very good efficacy for the treatment of uSpA. PMID- 22200807 TI - PAI-1 mRNA expression and plasma level in rheumatoid arthritis: relationship with 4G/5G PAI-1 polymorphism. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the synovial membrane, cartilage and bone. PAI-1 is a key regulator of the fibrinolytic system through which plasminogen is converted to plasmin. The plasmin activates the matrix metalloproteinase system, which is closely related with the joint damage and bone destruction in RA. The aim of this study was to investigate the relationship between 4G/5G PAI-1 polymorphism with mRNA expression and PAI-1 plasma protein levels in RA patients. 113 RA patients and 123 healthy subjects (HS) were included in the study. The 4G/5G PAI-1 polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism method; the PAI-1 mRNA expression was determined by real-time PCR; and the soluble PAI-1 (sPAI-1) levels were quantified using an ELISA kit. No significant differences in the genotype and allele frequencies of 4G/5G PAI-1 polymorphism were found between RA patients and HS. However, the 5G/5G genotype was the most frequent in both studied groups: RA (42%) and HS (44%). PAI-1 mRNA expression was slightly increased (0.67 fold) in RA patients with respect to HS (P = 0.0001). In addition, in RA patients, the 4G/4G genotype carriers showed increased PAI-1 mRNA expression (3.82 fold) versus 4G/5G and 5G/5G genotypes (P = 0.0001), whereas the sPAI-1 plasma levels did not show significant differences. Our results indicate that the 4G/5G PAI-1 polymorphism is not a marker of susceptibility in the Western Mexico. However, the 4G/4G genotype is associated with high PAI-1 mRNA expression but not with the sPAI-1 levels in RA patients. PMID- 22200808 TI - Prevalence and factors affecting glucosamine use in Korea: a survey-based study. AB - Glucosamine and chondroitin are widely used as pharmaceutical and dietary supplements. However, there is a lack of information regarding consumer consumption of glucosamine and chondroitin in the Republic of Korea. We investigated the prevalence and factors affecting the use of glucosamine products in the general population aged 40 years and older in the Republic of Korea. We conducted this descriptive and exploratory study using a telephone-based survey with a structured questionnaire. We randomly selected subjects using a proportional allocation method based on age, gender, and region. We started the survey on September 19, 2009, and continued the survey until we obtained 1,000 respondents who were currently taking glucosamine or chondroitin, which occured on September 30, 2009. Among the 8,135 people approached, the response rate was 29.6%. A total of 12.2% of respondents (n = 991) were current users of glucosamine, while only 0.1% (n = 9) were current users of chondroitin. Two fifths of current glucosamine users were not diagnosed with osteoarthritis by a doctor nor did they experience arthritis pain. These participants used glucosamine to maintain and promote joint health. Information on glucosamine was mainly obtained through advertisements on television or the Internet. Seventy percent of current users indicated that they did not know the composition of the glucosamine they took. Appropriate information and guides concerning glucosamine or chondroitin usage should be provided by expert clinicians because of the accessibility of both these cartilage derivatives as supplements and medical drugs in the Republic of Korea. PMID- 22200809 TI - Thrombosis in Behcet's disease: a Behcet's disease patient with complete thrombotic obstruction of IVC and both iliac veins and decreased protein S activity. AB - Behcet's disease represents a multisystemic inflammatory disease characterized by recurrent oral ulcers, genital ulcers, and uveitis. Although vascular attack and thrombosis are not major complications in Behcet's disease, they can still pose risks that must not be overlooked. In this paper, we reported that a 25-year-old female Behcet's disease patient with complete thrombotic obstruction of the inferior vena cava that was successfully treated by aspiration thrombectomy and balloon angioplasty. The procedure produced marked symptomatic improvement. Currently, data about the treatment and the prophylaxis of thrombotic events in Behcet's disease are lacking. In this case report, we hope to discuss the future direction of such studies, how we understand the mechanism of Behcet's disease hypercoagulability, and which treatments can improve thrombotic tendencies in Behcet's disease. PMID- 22200810 TI - Unusual manifestations in two cases of necrotizing myopathy associated with SRP antibodies. PMID- 22200811 TI - Temperament and character profile of patients with fibromyalgia. AB - Personality may play an important role in the development and initiation of fibromyalgia (FM). It may also be used for individualized treatment planning. We aimed to assess personality profiles of FM patients and to evaluate the association of personality profiles with education, symptom severity, depression, anxiety, and functioning. Forty-two female patients with FM and 48 healthy female controls were enrolled in the study. We assessed personality profiles of FM patients using the Temperament and Character Inventory (TCI). Spearman's rank correlation coefficient was used to detect the correlation between the TCI and education, symptom severity, depression, anxiety, and functioning. FM patients had significantly higher harm avoidance (HA) and self-transcendence (ST) scores, and lower self-directedness (SD) scores than those in the healthy controls. High HA scores were related to impaired functioning, depression, and anxiety symptoms. A negative correlation has been found between SD scores and depression scores. The study suggests that FM patients have distinctive temperament and character profile compared with healthy controls. FM patients tend to have high HA, high ST, and low SD scores. PMID- 22200812 TI - Posterior C1-2 fusion with C1 lateral mass and C2 isthmic screws: accuracy of screw position, alignment and patient outcome. AB - BACKGROUND: Transarticular screw fixation is seen as the "gold standard" in instrumented fusion of C1 and C2. However, drawbacks are the necessity of a reduction before instrumentation and a risk of vertebral artery injury. Therefore, C1 lateral mass and C2 isthmic screws are an alternative. The present study assessed the feasibility of C1-2 stabilization with C1 lateral mass and C2 isthmic screws and evaluated quality of life. METHOD: All data of 35 consecutive patients treated from May 2006 to September 2009 were collected. Patients had C1 lateral mass and C2 isthmic screws. RESULTS: Twenty patients were operated on for traumatic instabilities, six for neoplastic instabilities, five for infectious instabilities and two each for degenerative and congenital instabilities. Sixty six of 70 C1 screws had an ideal position, while four were placed suboptimal without the need for revision. Twelve of 68 C2 screws were not ideal but acceptable; one screw needed a surgical revision. There was one non-surgery related case of neurological deterioration after multilevel instrumentation. No vascular injuries occurred. Realignment was correct in all patients. After a median follow-up of 12 months, patients showed a reduction of pain, disability and improvements in EQ-5D items. SF36 data compared with a normative population and a historical cohort showed lower levels of function in all domains. CONCLUSION: C1-C2 instrumented fusion with lateral mass and isthmic screws is a safe procedure. Sufficient screw position and alignment was possible in all cases. Therefore, at our institution transarticular screws were abandoned in favor of C1 lateral mass and C2 isthmic screws. PMID- 22200813 TI - Longitudinal ultrasound and clinical follow-up of Baker's cysts injection with steroids in knee osteoarthritis. AB - This study was conducted to assess ultrasound (US) and clinical changes of Baker's cyst (BC) of patients with knee osteoarthritis (OA) after steroid injection. Patients with knee OA complicated with symptomatic BC (40) were treated with US-guided direct (posterior) aspiration. The injection of 40 mg triamcynolone acetonide was in 20 patients direct into the BC and in other 20 subjects intra-articular (anterior). BC diameters (longitudinal, transverse, and thickness) were measured and followed up with US at baseline, 2, 4, and 8 weeks after injection. Swelling, pain, and range motion were scored at clinical examination with Rauschning and Lindgren classification (RLC, since 0 normal to 3 maximal signs). All US measures of BC and RLC significantly decreased after treatment, in comparison to baseline (p < 0.001) and during the follow-up, did not change through the time (no significant difference between 2, 4, and 8 weeks). At 4 and 8 weeks, diameters measured at US are lower when BC is directly infiltrated in comparison to intra-articular injection (p < 0.01). US steroid direct injection reduces US measures and clinics of BC in knee OA, in particular, when steroid is directly infiltrated into BC. PMID- 22200814 TI - Delineating psychological and biomedical profiles in a heterogeneous fibromyalgia population using cluster analysis. AB - The heterogeneity of patients meeting American College of Rheumatology (ACR) criteria for a diagnosis of fibromyalgia (FM) challenges our ability to understand the underlying pathogenesis and to optimize treatment of this enigmatic disorder. Our goal was to discern clinically relevant subgroups across multiple psychological and biomedical domains to better characterize the phenomenology of FM. Women meeting 1990 ACR criteria for FM (N = 107) underwent psychological (childhood trauma, mood, anxiety, and stress) and biomedical (neuroendocrine, immune, and metabolic) testing. Cluster analysis identified four distinct subgroups. Subgroups I, II, and III exhibited profiles that included high psychological distress. Subgroup I was further distinguished by a history of childhood maltreatment and hypocortisolism, and these women reported the most pain and disability. Subgroup II evinced more physiological dysregulation and also reported high levels of pain, fatigue, and disability. Subgroup III was characterized by normal biomarkers and reported intermediate pain severity with higher global functioning. Subgroup IV was distinguished by their psychological well-being, reporting less disability and pain. Our findings underscore the heterogeneity of both psychological and physiological features among FM patients presenting with nearly identical tender point counts. This subgroup categorization is compatible with hypothesized pathogenetic mechanisms of early trauma, stress system dysregulation, and pro-inflammatory bias, each prominent in some but not all FM patients. Appreciation of distinct FM subgroup features is invaluable for selecting the most appropriate treatment modalities. PMID- 22200815 TI - The Christchurch earthquake--providing a rheumatology service during a natural disaster. AB - To report on the effects of the Canterbury earthquake on rheumatology service provision and identify factors that allowed continuation of patient care. Data was collected on the number of appointments during the period after the earthquake and the effects of the earthquake on service provision. The rheumatology service faced unique challenges in continuing to provide a service and ensure ongoing care for our patients in the community after the earthquake. All outpatient services were cancelled for 2 weeks, resulting in the cancellation of 23 new patient and 145 follow-up patient appointments. Telephone consultation was attempted for all these patients. A total of 113 patients could be contacted, and 15 required acute review. Challenges included difficult access to the hospital, lack of laboratories for blood testing, limited access to clinical records, loss of power, sewerage and waste water and a contaminated drinking water supply. The impact of these on patients with rheumatic diseases was wide ranging. Despite a natural disaster and challenging logistics, the Rheumatology Department was able to provide a service with the use of remote telephone consultations and an electronic patient record backed up by an effective patient and primary practitioner education base and resource access. PMID- 22200816 TI - Sulforaphane protects against 6-hydroxydopamine-induced cytotoxicity by increasing expression of heme oxygenase-1 in a PI3K/Akt-dependent manner. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder with selective loss of dopaminergic neurons in the substantia nigra. Evidence suggests that oxidative stress is involved in the pathogenesis of PD. Sulforaphane (SF), a naturally occurring isothiocyanate, has been shown to protect against oxidative stress by inducing the expression of various NF-E2-related factor-2 (Nrf2) responsive genes. Previous studies have shown that SF protects dopaminergic neurons against PD-related neurotoxin 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. However, the molecular mechanisms by which SF protects against 6 OHDA-induced cytotoxicity are poorly elucidated. In this study, we found that pretreatment with SF significantly reduced 6-OHDA-induced caspase-3 activation and subsequent cell death. SF also increased heme oxygenase-1 (HO-1) expression, which conferred protection against 6-OHDA-induced cytotoxicity. Furthermore, SF induced the translocation of Nrf2 into the nucleus and activated PI3K/Akt, a pathway that is involved in SF-induced Nrf2 nuclear translocation, HO-1 expression and cytoprotection. These results suggest that SF inhibits 6-OHDA induced cytotoxicity through increasing HO-1 expression in a PI3K/Akt-dependent manner. PMID- 22200821 TI - Male factor infertility: coenzyme Q10 improves semen quality and pregnancy rate. PMID- 22200817 TI - Prostate cancer: does denosumab have a role in metastasis prevention? PMID- 22200823 TI - Targeted therapies: can sunitinib use be expanded to other cancers? PMID- 22200824 TI - Bladder cancer: narrow-band imaging--improving urothelial carcinoma detection. PMID- 22200825 TI - Prostate cancer: androgen deprivation causes EMT in the prostate. PMID- 22200826 TI - Bladder cancer: hematuria and point-of-care tests. PMID- 22200828 TI - Prostate cancer: assessing the surgeon. PMID- 22200832 TI - Prostate cancer: reducing IGF-1 levels unlikely to ProtecT against prostate cancer initiation. PMID- 22200833 TI - Urinary tract infections: oral FimH inhibitors effective against UTI. PMID- 22200834 TI - Radiotherapy: PSA surrogates for survival with ADT. PMID- 22200835 TI - Bladder cancer: improving the management of T1 bladder cancer. PMID- 22200836 TI - Prostate cancer: next-generation RNA sequencing identifies gene signature of neuroendocrine differentiation in prostate tumors. PMID- 22200837 TI - Geraniol induces cooperative interaction of apoptosis and autophagy to elicit cell death in PC-3 prostate cancer cells. AB - Geraniol, an acyclic dietary monoterpene, suppresses prostate cancer growth and enhances docetaxel chemosensitivity in cultured cell or xenograft tumor models. However, the mechanisms of the geraniol action against prostate cancer are largely unknown. In this study, we investigated the cellular and molecular mechanisms of geraniol-induced cell death in PC-3 prostate cancer cells. Among the examined structurally and functionally similar monoterpenes, geraniol potently induced apoptosis and autophagy. Although independent processes, apoptosis and autophagy acted as cooperative partners to elicit geraniol-induced cell death in PC-3 cells. At a molecular level, geraniol inhibited AKT signaling and activated AMPK signaling, resulting in mTOR inhibition. Combined treatment of AKT inhibitor and AMPK activator markedly suppressed cell growth compared to either treatment alone. Our findings provide insight into future investigations that are aimed at elucidating the role of apoptosis and autophagy in prostate cancer therapy and at developing anticancer strategies co-targeting AKT and AMPK. PMID- 22200838 TI - Suicidal behaviours in adolescents in Nova Scotia, Canada: protective associations with measures of social capital. AB - PURPOSE: Few studies of adolescent suicidality have examined its associations with social capital. We explored associations of measures of individual level social capital with self-reported suicide ideation and suicide attempt in adolescents in Cape Breton, Nova Scotia, Canada, controlling for other factors known to be associated with adolescent suicidality. METHODS: We surveyed 1,597 grade 10-12 students at three high schools in 2006 using self-completion questionnaires. Both sexes were combined for analysis. Outcome measures were suicidal ideation and attempt in the previous year. Measures of social capital included perceptions of trustworthiness and helpfulness of others at school, frequency of religious attendance and participation in extracurricular activities. Logistic regressions were carried out to determine associations of social capital with suicidality while controlling for other factors. RESULTS: Perceived trustworthiness and helpfulness were protective for suicidal ideation and suicide attempt in the previous year. In adjusted analyses, there were interactions of gender and social capital-females reporting more social capital were more protected from suicide attempt relative to males with similar levels of social capital. CONCLUSIONS: This study provides initial evidence of protective associations of individual level social capital with adolescent suicidality. Our findings suggest that among adolescents low social capital as measured by perceptions of trust and helpfulness of others at school may be a warning sign for suicidality, particularly for females. It may be helpful to inquire of young people how they perceive the trustworthiness and helpfulness of their school environment as a measure of how supportive that environment might be to them when they are facing challenges to their mental health. PMID- 22200839 TI - Barrett's metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor. AB - BACKGROUND: Little is known about the stem cell organisation of the normal oesophagus or Barrett's metaplastic oesophagus. Using non-pathogenic mitochondrial DNA mutations as clonal markers, the authors reveal the stem cell organisation of the human squamous oesophagus and of Barrett's metaplasia and determine the mechanism of clonal expansion of mutations. METHODS: Mutated cells were identified using enzyme histochemistry to detect activity of cytochrome c oxidase (CCO). CCO-deficient cells were laser-captured and mutations confirmed by PCR sequencing. Cell lineages were identified using immunohistochemistry. RESULTS: The normal squamous oesophagus contained CCO-deficient patches varying in size from around 30 MUm up to about 1 mm. These patches were clonal as each area within a CCO-deficient patch contained an identical mitochondrial DNA mutation. In Barrett's metaplasia partially CCO-deficient glands indicate that glands are maintained by multiple stem cells. Wholly mutated Barrett's metaplasia glands containing all the expected differentiated cell lineages were seen, demonstrating multilineage differentiation from a clonal population of Barrett's metaplasia stem cells. Patches of clonally mutated Barrett's metaplasia glands were observed, indicating glands can divide to form patches. In one patient, both the regenerating squamous epithelium and the underlying glandular tissue shared a clonal mutation, indicating that they are derived from a common progenitor cell. CONCLUSION: In normal oesophageal squamous epithelium, a single stem cell clone can populate large areas of epithelium. Barrett's metaplasia glands are clonal units, contain multiple multipotential stem cells and most likely divide by fission. Furthermore, a single cell of origin can give rise to both squamous and glandular epithelium suggesting oesophageal plasticity. PMID- 22200840 TI - Interval cancers after negative colonoscopy: population-based case-control study. AB - OBJECTIVE: The risk of colorectal cancer after a previous negative colonoscopy is very low. Nevertheless, interval cancers occur. We aimed to assess the characteristics and predictors of interval cancers after negative colonoscopy. METHODS: A population-based case-control study was conducted in Southern Germany in 2003-7. Sociodemographic and tumour characteristics were compared among 78 patients with interval cancers occurring 1-10 years after a negative colonoscopy and 433 colorectal cancers detected at screening. In addition, the indication for the preceding negative colonoscopy and its completeness were compared between patients with interval cancers and 515 controls with a preceding negative colonoscopy. RESULTS: 56.4% of interval cancers occurred among women compared with 33.7% of cases detected by screening (p=0.0001). After adjustment for covariates, female sex (OR 2.28, 95% CI 1.35 to 3.83) and location in the caecum or ascending colon (OR 1.98, 95% CI 1.17 to 3.35) were independently associated with occurrence of interval cancers. The preceding negative colonoscopy was more commonly conducted because of a positive faecal occult blood test (26.0% vs 12.9%, p=0.009) and was more often incomplete (caecum not reached: 18.1% vs 6.7%, p=0.001) among interval cancer cases than among controls. Characteristics of the preceding negative colonoscopy strongly and independently associated with occurrence of interval cancers were follow-up of a positive faecal occult blood test among men (OR 5.49, 95% CI 2.10 to 14.35) and incompleteness among women (OR 4.38, 95% CI 1.69 to 11.30). CONCLUSIONS: The observed patterns suggest that a substantial proportion of interval cancers are due to neoplasms missed at colonoscopy and are potentially preventable by enhanced performance of colonoscopy. PMID- 22200841 TI - Medical geology and environmental geochemistry are closely related disciplines. Introduction. PMID- 22200842 TI - The influence of six pharmaceuticals on freshwater sediment microbial growth incubated at different temperatures and UV exposures. AB - Pharmaceutical compounds have been detected in freshwater for several decades. Once they enter the aquatic ecosystem, they may be transformed abiotically (i.e., photolysis) or biotically (i.e., microbial activity). To assess the influence of pharmaceuticals on microbial growth, basal salt media amended with seven pharmaceutical treatments (acetaminophen, caffeine, carbamazepine, cotinine, ibuprofen, sulfamethoxazole, and a no pharmaceutical control) were inoculated with stream sediment. The seven pharmaceutical treatments were then placed in five different culture environments that included both temperature treatments of 4, 25, 37 degrees C and light treatments of continuous UV-A or UV-B exposure. Microbial growth in the basal salt media was quantified as absorbance (OD(550)) at 7, 14, 21, 31, and 48d following inoculation. Microbial growth was significantly influenced by pharmaceutical treatments (P < 0.01) and incubation treatments (P < 0.01). Colonial morphology of the microbial communities post incubation identified selection of microbial and fungal species with exposure to caffeine, cotinine, and ibuprofen at 37 degrees C; acetaminophen, caffeine, and cotinine at 25 degrees C; and carbamazepine exposed to continuous UV-A. Bacillus and coccus cellular arrangements (1000X magnification) were consistently observed across incubation treatments for each pharmaceutical treatment although carbamazepine and ibuprofen exposures incubated at 25 degrees C also selected spiral-shaped bacteria. These data indicate stream sediment microbial communities are influenced by pharmaceuticals though physiochemical characteristics of the environment may dictate microbial response. PMID- 22200843 TI - bFGF peptide combined with the pVAX-8CpG plasmid as adjuvant is a novel anticancer vaccine inducing effective immune responses against Lewis lung carcinoma. AB - Due to the poor immunogenicity of subunit protein antigens, there is a need to use adjuvants in order to generate effective immune responses. Basic fibroblast growth factor (bFGF) is one of the best characterized pro-angiogenic cytokine and is a candidate target for anticancer therapy. We used truncated bFGF (tbFGF) combined with engineered pVAX-nCpG as novel adjuvant to immunize mice in order to inhibit tumor angiogenesis and suppress tumor growth. In our study, the results demonstrated that the mice immunized with tbFGF-alum-pVAX-8CpG produced a better tumor-suppression effect compared with the other groups, apart from the group treated with tbFGF-alum-CpG. In addition, the function of immune modulation of pVAX-8CpG was similar to CpG ODNs. The vaccine composed of tbFGF, alum and pVAX 8CpG effectively inhibited tumor angiogenesis and induced strong antitumor immune responses. The antitumor activity induced by the vaccine tbFGF-alum-pVAX-8CpG was not only associated with the antigen-specific antibody, but also with the killing activity of cytotoxic cells. This indicates that alum-pVAX-8CpG may be an innovative adjuvant for cancer vaccines. PMID- 22200844 TI - Endogenous technological change in medicine and its impact on healthcare costs: evidence from the pharmaceutical market in Taiwan. AB - Although the technological change in medicine has been recognized widely as the major driver of rising healthcare costs, there is very little research that estimates this effect directly. This paper uses both a single-equation and a simultaneous equations approach to investigate empirically the interactive relationship between technological innovation and the growth of health expenditure in the context of the pharmaceutical market in Taiwan. Based on observing 182 therapeutic groups between 1997 and 2006, we find evidence to support the argument that technological innovation and health expenditure are determined simultaneously as technological innovation, and that the growth of health expenditure are endogenous rather than exogenous. Specifically, we find that therapeutic groups associated with higher pharmaceutical expenditure are likely to attract more new products to the market. Meanwhile, therapeutic groups with more new products are associated with higher pharmaceutical expenditures. An important implication of the paper is that cost containment policies will affect not only the growth of health expenditure, but also the progress of technological innovation in the health sector. PMID- 22200845 TI - Autophagy induced by baicalin involves downregulation of CD147 in SMMC-7721 cells in vitro. AB - Baicalin has been demonstrated to exert anticancer effects mainly through induction of tumor cell apoptosis and cell cycle arrest. However, the precise mechanisms underlying its anticancer role remain to be elucidated. In the present study, we investigated whether autophagy was involved in the anticancer activity of baicalin in the human hepatocellular carcinoma (HCC) cell line SMMC-7721 and the possible molecular mechanisms. Our data showed that the viability of SMMC 7721 cells was significantly inhibited by baicalin in a dose- and time-dependent manner. Alongside apoptosis, autophagy was also induced by baicalin dose- and time-dependently with the involvement of the autophagy-associated protein Betaeclin 1. Moreover, we demonstrated that cell death induced by baicalin was significantly inhibited by the apoptosis inhibitor z-DEVD-fmk or the autophagy inhibitor 3-MA, respectively. In addition, we found that CD147, a key molecule related both to apoptosis and autophagy, was markedly downregulated at the protein level in SMMC-7721 cells treated with baicalin. Collectively, this is the first study to suggest that baicalin induces autophagic cell death in SMMC-7721 cells, which involves the downregulation of CD147. Our study reveals a new mechanism for the anticancer effects of baicalin and puts forward a potential crucial role of CD147 in baicalin-induced cancer cell death. PMID- 22200846 TI - Diethyldithiocarbamate induces apoptosis in HHV-8-infected primary effusion lymphoma cells via inhibition of the NF-kappaB pathway. AB - Primary effusion lymphoma (PEL) is a subtype of B-cell lymphoma caused by human herpes virus 8/Kaposi sarcoma-associated herpes virus (HHV-8/KSHV), which is mostly found in patients with AIDS and has poor prognosis. Nuclear factor (NF) kappaB pathway is constitutively activated in HHV-8-infected PEL cells and plays a crucial role in tumorigenesis. Recently, it has been shown that diethyldithiocarbamate (DDTC), an active metabolite of disulfiram, has apoptotic activity in cancer cells. Here, we investigated the effect of DDTC on PEL using a PEL mouse model generated by intraperitoneal injection of BC-3 cells, a PEL cell line. DDTC ameliorated the symptoms of PEL in these mice, such as development of ascites, splenomegaly and increase of body weight, in comparison with PBS-treated controls. Moreover, we determined in vitro that DDTC suppressed the constitutively activated NF-kappaB pathway in BC-3 cells. Methylthiotetrazole assay revealed that the cell proliferation of various PEL cell lines was significantly suppressed by the treatment of DDTC. DDTC also induced the expression of cleaved caspase-3, an apoptosis marker, whereas the addition of Q VD-OPh, a pan-caspase inhibitor, inhibited cell apoptosis induced by DDTC treatment. Together, our results indicated that DDTC induces apoptosis via inhibition of the NF-kappaB signaling pathway in HHV-8-infected PEL cells. This study suggests the potential use of DDTC as a therapeutic approach for PEL. PMID- 22200847 TI - Fibroblast growth factor 2 inhibits the expression of stromal cell-derived factor 1alpha in periodontal ligament cells derived from human permanent teeth in vitro. AB - Although cells derived from periodontal ligament (PDL) tissue are reported to have stem cell-like activity and are speculated to play a crucial role for tissue healing and regeneration after injury or orthodontic treatment, mechanisms regulating their recruitment and activation remain unknown. Recently, stromal cell-derived factor 1alpha (SDF-1alpha) has been reported to be important for stem cell homing and recruitment to injured sites. The aim of this study was to evaluate whether fibroblast growth factor 2 (FGF-2) affects the expression of SDF 1alpha in PDL cells derived from human permanent teeth in vitro. Using real-time PCR, the expression of SDF-1alpha mRNA in PDL cells was inhibited by treatment with 10 ng/ml FGF-2. When PDL cells were treated with SU5402 (an inhibitor of FGF receptor 1) in combination with FGF-2, the FGF-2-reduced expression of SDF-1alpha was inhibited. In the presence of the JNK inhibitor SP600125, SDF-1alpha mRNA in PDL cells was not suppressed by the FGF-2 treatment. Western blot analysis also showed that SDF-1alpha production was suppressed by treatment with FGF-2, but it recovered with treatment by FGF-2 + SU5402. These findings suggest that SDF 1alpha from PDL cells plays an important role in the regeneration and homeostasis of periodontal tissues via the recruitment of stem cells. PMID- 22200849 TI - Activation of MAP kinase family members triggered by TPA or ionomycin occurs via the protein phosphatase 4 pathway in Jurkat leukemia T cells. AB - Protein phosphatase 4 (PP4) is a protein phosphatase 2A (PP2A)-related, okadaic acid-sensitive, serine/threonine protein phosphatase that shares 65% amino acid identity with PP2A. Numerous studies have shown that protein phosphatase is involved in the regulation of T cell signaling and activation. In this study, we investigated the effect of overexpression of PP4 on the expression of members of the MAP kinase family in Jurkat leukemia T cells, which had previously been stimulated with UV, 12-O-tetradecanoylphorbol-13-acetate (TPA), ionomycin and okadaic acid. We found that the overexpression of PP4 expressed relatively low activity in the absence of any kind of stimulation. However, TPA, UV or ionomycin treatment strongly increased the activity of PP4. In addition, Jurkat T cells, transfected with various expression plasmids and/or stimulated with TPA, UV or ionomycin strongly induced the c-Jun N-terminal kinase (JNK) and p38, whereas the extracellular signal-regulated kinase (ERK)-1/2 kinase pathway was weekly activated. Treatment of Jurkat T cells with okadaic acid, an inhibitor of PP2, also inhibited the increase of JNK and p38 activity induced by PP4. The effect of okadaic acid on the activity of PP4 was similar to that observed in Jurkat T cells treated with a dominant negative c-Jun (dn-jun). These results indicate that the activation of JNK and p38, but not ERKs, is a target for the PP4 activity in Jurkat leukemia T cells. PMID- 22200848 TI - miRNAs in breast cancer tumorigenesis (Review). AB - miRNAs are small, endogenous, non-coding RNAs that negatively regulate protein coding mRNAs at the post-transcriptional level. It is estimated that in humans thousands of miRNAs are expressed and more than 700 miRNAs have been described to date. About 50% of annotated human miRNAs are detected in regions of fragile sites, which are associated with cancer. The available evidence has shown that miRNAs widely participate in the development or progression of many types of cancers, including breast cancer. The role of miRNAs in breast cancer has been widely investigated; here, we will focus on what is known about the working mechanism of miRNAs in different stages of breast cancer development. PMID- 22200850 TI - Dietary salt modulates the sodium chloride cotransporter expression likely through an aldosterone-mediated WNK4-ERK1/2 signaling pathway. AB - WNK is a serine/threonine kinase. Mutation in WNK1 or WNK4 kinase results in pseudohypoaldosteronism type II (PHA II) featuring hypertension, hyperkalemia and metabolic acidosis. Sodium chloride cotransporter (NCC) is known to be regulated by phosphorylation and trafficking. Dietary salt and hormonal stimulation, such as aldosterone, also affect the regulation of NCC. We have previously reported that WNK4 inhibits NCC protein expression. To determine whether dietary salt affects NCC abundance through WNK4-mediated mechanism, we investigated the effects of dietary salt change with or without aldosterone infusion (1 mg/kg/day) on NCC and WNK4 expression in rats. We found that high-salt (HS, 4% NaCl) diet significantly inhibits NCC mRNA expression and protein abundance while enhancing WNK4 mRNA and protein expression, whereas low-salt (LS, 0.07% NaCl) diet increases NCC mRNA expression and protein abundance while reducing WNK4 expression. We also found that aldosterone infusion in HS-fed rats increases NCC mRNA expression and protein abundance, but decreases WNK4 expression. Administration with spironolactone (0.1 g/kg/day) in LS-fed rats decreases NCC mRNA expression and protein abundance while increasing WNK4 expression. We further showed that ERK1/2 phosphorylation was increased in HS-fed rats, but decreased in LS-fed rats. In HEK293 cells, over-expressed WNK4 increases ERK1/2 phosphorylation, whereas knockdown of WNK4 expression decreases ERK1/2 phosphorylation. Aldosterone treatment for 3 h decreases ERK1/2 phosphorylation. These data suggest that dietary salt change affects NCC protein abundance in an aldosterone-dependent mechanism likely via the WNK4-ERK1/2-mediated pathway. PMID- 22200851 TI - Detecting predators and locating competitors while foraging: an experimental study of a medium-sized herbivore in an African savanna. AB - Vigilance allows individuals to escape from predators, but it also reduces time for other activities which determine fitness, in particular resource acquisition. The principles determining how prey trade time between the detection of predators and food acquisition are not fully understood, particularly in herbivores because of many potential confounding factors (such as group size), and the ability of these animals to be vigilant while handling food. We designed a fertilization experiment to manipulate the quality of resources, and compared awareness (distinguishing apprehensive foraging and vigilance) of wild impalas (Aepyceros melampus) foraging on patches of different grass height and quality in a wilderness area with a full community of predators. While handling food, these animals can allocate time to other functions. The impalas were aware of their environment less often when on good food patches and when the grass was short. The animals spent more time in apprehensive foraging when grass was tall, and no other variable affected apprehensive behavior. The probability of exhibiting a vigilance posture decreased with group size. The interaction between grass height and patch enrichment also affected the time spent in vigilance, suggesting that resource quality was the main driver when visibility is good, and the risk of predation the main driver when the risk is high. We discuss various possible mechanisms underlying the perception of predation risk: foraging strategy, opportunities for scrounging, and inter-individual interference. Overall, this experiment shows that improving patch quality modifies the trade-off between vigilance and foraging in favor of feeding, but vigilance remains ultimately driven by the visibility of predators by foragers within their feeding patches. PMID- 22200852 TI - Complementary ecophysiological strategies combine to facilitate survival in the hostile conditions of a deep chlorophyll maximum. AB - In the deep, cooler layers of clear, nutrient-poor, stratified water bodies, phytoplankton often accumulate to form a thin band or "deep chlorophyll maximum" (DCM) of ecological importance. Under such conditions, these photosynthetic microorganisms may be close to their physiological compensation points and to the boundaries of their ecological tolerance. To grow and survive any resulting energy limitation, DCM species are thought to exhibit highly specialised or flexible acclimation strategies. In this study, we investigated several of the adaptable ecophysiological strategies potentially employed by one such species, Chlamydomonas acidophila: a motile, unicellular, phytoplanktonic flagellate that often dominates the DCM in stratified, acidic lakes. Physiological and behavioural responses were measured in laboratory experiments and were subsequently related to field observations. Results showed moderate light compensation points for photosynthesis and growth at 22 degrees C, relatively low maintenance costs, a behavioural preference for low to moderate light, and a decreased compensation point for photosynthesis at 8 degrees C. Even though this flagellated alga exhibited a physiologically mediated diel vertical migration in the field, migrating upwards slightly during the day, the ambient light reaching the DCM was below compensation points, and so calculations of daily net photosynthetic gain showed that survival by purely autotrophic means was not possible. Results suggested that strategies such as low-light acclimation, small scale directed movements towards light, a capacity for mixotrophic growth, acclimation to low temperature, in situ exposure to low O(2), high CO(2) and high P concentrations, and an avoidance of predation, could combine to help overcome this energetic dilemma and explain the occurrence of the DCM. Therefore, corroborating the deceptive ecophysiological complexity of this and similar organisms, only a suite of complementary strategies can facilitate the survival of C. acidophila in this DCM. PMID- 22200853 TI - Determinants of extinction in fragmented plant populations: Crepis sancta (Asteraceae) in urban environments. AB - Local populations are subject to recurrent extinctions, and small populations are particularly prone to extinction. Both demographic (stochasticity and the Allee effect) and genetic factors (drift load and inbreeding depression) potentially affect extinction. In fragmented populations, regular dispersal may boost population sizes (demographic rescue effect) or/and reduce the local inbreeding level and genetic drift (genetic rescue effect), which can affect extinction risks. We studied extinction processes in highly fragmented populations of the common species Crepis sancta (Asteraceae) in urban habitats exhibiting a rapid turnover of patches. A four-year demographic monitoring survey and microsatellite genotyping of individuals allowed us to study the determinants of extinction. We documented a low genetic structure and an absence of inbreeding (estimated by multilocus heterozygosity), which suggest that genetic factors were not a major cause of patch extinction. On the contrary, local population size was the main factor in extinction, whereas connectivity was shown to decrease patch extinction, which we interpreted as a demographic rescue effect that was likely due to better pollination services for reproduction. This coupling of demographic and genetic tools highlighted the importance of dispersal in local patch extinctions of small fragmented populations connected by gene flow. PMID- 22200854 TI - Microgeographical, inter-individual, and intra-individual variation in the flower characters of Iberian pear Pyrus bourgaeana (Rosaceae). AB - Flower characteristics have been traditionally considered relatively constant within species. However, there are an increasing number of examples of variation in flower characteristics. In this study, we examined the variation in attracting and rewarding flower characters at several ecological levels in a metapopulation of Pyrus bourgaeana in the Donana area (SW Spain). We answered the following questions: what are the variances of morphological and nectar characters of flowers? How important are intra-individual and inter-individual variance in flower characters? Are there microgeographical differences in flower characters? And if so, are they consistent between years? In 2008 and 2009, we sampled flowers of 72 trees from five localities. For six flower morphological and two nectar characteristics, we calculated coefficients of variation (CV). The partitioning of total variation among-localities, among-individuals, and within individuals was estimated. To analyze differences among localities and their consistency between years, we conducted generalized linear mixed models. The CVs of nectar characters were always higher than those of morphological characters. As expected, inter-individual variation was the main source of variation of flower morphology, but nectar characters had significant variation at both intra- and inter-individual levels. For most floral traits, there were no differences among localities. Our study documents that variation is a scale-dependent phenomenon and that it is essential to consider intra- and inter-individual variance when investigating the causes and consequences of variation. It also shows that single year studies of floral characters should be viewed with caution. PMID- 22200855 TI - Contributions of algae to GPP and DOC production in an Alaskan fen: effects of historical water table manipulations on ecosystem responses to a natural flood. AB - The role of algae in the metabolism of northern peatlands is largely unknown, as is how algae will respond to the rapid climate change being experienced in this region. In this study, we examined patterns in algal productivity, nutrients, and dissolved organic carbon (DOC) during an uncharacteristically wet summer in an Alaskan rich fen. Our sampling was conducted in three large-scale experimental plots where water table position had been manipulated (including both drying and wetting plots and a control) for the previous 4 years. This study allowed us to explore how much ecosystem memory of the antecedent water table manipulations governed algal responses to natural flooding. Despite no differences in water table position between the manipulated plots at the time of sampling, algal primary productivity was consistently higher in the lowered water table plot compared to the control or raised water table plots. In all plots, algal productivity peaked immediately following seasonal maxima in nutrient concentrations. We found a positive relationship between algal productivity and water-column DOC concentrations (r (2) = 0.85, P < 0.001). Using these data, we estimate that algae released approximately 19% of fixed carbon into the water column. Algal exudates were extremely labile in biodegradability assays, decreasing by more than 55% within the first 24 h of incubation. We suggest that algae can be an important component of the photosynthetic community in boreal peatlands and may become increasingly important for energy flow in a more variable climate with more intense droughts and flooding. PMID- 22200856 TI - Expression of caveolin-1 is correlated with disease stage and survival in lung adenocarcinomas. AB - Caveolin-1 (cav-1) has been implicated in the development of human cancers. However, the distribution of cav-1 in non-small cell lung cancer (NSCLC) and its significance require further study. Real-time PCR and Western blot assays were performed to detect cav-1 mRNA and protein levels in tumor tissues (TT) and matched tumor-free tissues (TF). The protein expression in 115 paraffin-embedded blocks was examined by immunohistochemical staining (IHC). Correlations between cav-1 mRNA and protein expression by IHC and clinicopathological features were statistically evaluated. For the 136 patients examined, the levels of cav-1 mRNA and protein expression were significantly lower in lung TT compared to matched TF (P<0.05). High cav-1 expression was detected in 60 of 115 (52.2%) NSCLC tissues and this level was significantly lower than cav-1 expression in non-cancerous lung tissues (15 of 19, 78.9%, P<0.05). Up-regulation of cav-1 mRNA expression in lung adenocarcinoma (AC) (29.7%) was higher than that observed in lung squamous cell carcinoma (SCC) (15.8%). Statistical analysis of the correlation between cav 1 protein expression and clinical features showed a statistical association with poorer N-stage (P=0.032) and higher pathological TNM stage (P=0.012) in lung AC patients, that was not found in lung SCC patients. Moreover, lung AC patients with higher cav-1 expression showed significantly shorter life-spans than those with lower cav-1 expression (P=0.032, log-rank test). The levels of cav-1 mRNA and protein expression were significantly lower in lung cancers when compared to matched TF or non-cancerous lung tissues. The higher protein expression correlated with the advanced pathological stage and shorter survival rates in lung AC patients. PMID- 22200857 TI - Ketogenic diet increases concentrations of kynurenic acid in discrete brain structures of young and adult rats. AB - Targeting mechanisms that result in increased concentrations of kynurenic acid (KYNA) in the brain has been considered as a therapeutic approach for the treatment of epilepsy and certain neurodegenerative disorders. Recently, KYNA has been implicated in the effects produced by the high-fat and low protein/carbohydrate ketogenic diet (KD) in a report demonstrating an increased production of KYNA in vitro by one of the ketone bodies, beta-hydroxybutyrate, elevated by the KD. To further explore this association, brain concentrations of KYNA were compared in young (3 weeks old) and adult (8-10 weeks old) rats that were chronically exposed to the KD and regular diet. Exposure to the KD resulted in the anticipated elevations of beta-hydroxybutyrate with accompanying decreases in glucose concentrations. In comparison to rats fed the regular diet, KYNA concentrations were significantly (p < 0.05) increased in the hippocampus (256 and 363% increase in young and adult rats, respectively) and in the striatum (381 and 191% increase in young and adult rats, respectively) in KD-fed rats. KD induced increases in KYNA concentrations in young versus adult rats in the hippocampus and striatum were comparable (p > 0.05). Exposure to the KD had no effect on KYNA concentrations in the cortex of young and adult rats (p > 0.05). In summary, chronic exposure to the KD resulted in several-fold increases in KYNA concentrations in discrete brain structures in the rats. Thus, the relevant clinical question for further exploration is whether KD-induced increases in KYNA concentrations can translate into clinically significant improvements in neuropsychiatric diseases associated with KYNA hypofunction. PMID- 22200858 TI - Neuromelanin enhances the toxicity of alpha-synuclein in SK-N-SH cells. AB - The key pathological feature of Parkinson's disease (PD) is selective degeneration of the neuromelanin (NM)-pigmented dopaminergic neurons in the substantia nigra (SN). NM, like other risk factors, such as oxidative stress (OS) and alpha-synuclein (alpha-syn), is involved in the pathogenesis of PD. But whether or not NM synergizes with alpha-syn or OS in the pathogenesis of PD remains unexplored. In the present study, we examined the effects of NM on cellular viability, apoptosis and free radical production in alpha-syn over expressing human neuroblastoma cell line (SK-N-SH) in the presence or absence of the oxidizer Fenton's Reagent (FR). We showed that NM synergized with FR in suppressing cell viability, and in inducing apoptosis and hydroxyl radical production in all SK-N-SH cell lines. alpha-Syn over-expressing cells exhibited more pronounced effect, especially the A53T mutation. Our findings suggest that NM synergizes with both OS and alpha-syn in conferring dopaminergic vulnerability, adding to our understanding of the pathogenesis of PD. PMID- 22200859 TI - Methanol poisoning: two case studies of blindness in Indonesia. AB - We report two recent cases of methanol intoxication in French patients living in Bali. These intoxications were secondary to the consumption of adulterated liquor. Both patients presented acute bilateral loss of vision a few days after methanol ingestion with no sign of recovery. The fundus showed bilateral optic atrophy that was well correlated with retinal nerve fibre layer thickness measured with spectral-domain optical coherence tomography and compatible with toxic optic neuropathy. In one of the patients, macular swelling in one eye was observed. Electroretinograms were normal contrasting with abolished visual evoked potentials. Methanol was isolated from a sample of the beverage with gas chromatography. Methanol intoxication may occur in Asia and therefore adequate information for tourists and the local population is required. PMID- 22200860 TI - Trabeculectomy for advanced glaucoma. AB - The objective of this study is to evaluate the visual prognosis and postoperative course in advanced glaucoma patients who underwent trabeculectomy. The records of 30 patients with advanced visual field (VF) defects undergoing trabeculectomy were retrospectively reviewed. Severe VF defects were defined as those with a sensitivity of <=5 dB either in more than 85% of test points, excluding the central four points, or in >75% of test points, including three of the central four points with threshold automated perimetry. Main outcome measures were intraocular pressure (IOP), corrected visual acuity (VA) and mean deviation (MD) of VF tests. Mean preoperative IOP, VA and MD values were compared with their respective postoperative values. The latest examination of each patient was used to determine postoperative outcome measures. In addition, any complications encountered were recorded. A total of 34 trabeculectomies were performed. The mean age was 59.3 years (13-80 years). The mean follow-up time was 41.1 months (3 120 months). Preoperatively the mean IOP was 28.4 +/- 13.1 mmHg, and the mean postoperative IOP was 14.8 +/- 5.0 mmHg (P = 0.001). Preoperatively the mean VA was 0.87 +/- 80, and the mean value of the MD was -24.5 +/- 6.7 dB. At the latest follow-up there was no significant difference in VA (0.89 +/- 79, P = 0.699) and MD (-23.9 +/- 6.7, P = 0.244) values. Transient hypotony occured in five eyes while one eye with mitomycin C trabeculectomy experienced extended hypotony. Ten eyes showed reduction of VA between 1 and 5 lines due to cataracts and five eyes had late bleb failure with uncontrolled IOP. One patient had late endophthalmitis and one patient presented with blebitis, both of which were successfully treated. No patients experienced wipe-out phenomenon. In conclusion, our study of advanced glaucoma patients undergoing trabeculectomy, vision was preserved with no cases of unexplained loss of central vision. IOP was largely controllable, with cataract being the leading factor decreasing VA at late term. PMID- 22200861 TI - Effects of lithium on oxidative stress parameters in healthy subjects. AB - Increased neuronal oxidative stress (OxS) induces deleterious effects on signal transduction, structural plasticity and cellular resilience, mainly by inducing lipid peroxidation in membranes, proteins and genes. Major markers of OxS levels include the thiobarbituric acid reactive substances (TBARS) and the enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase. Lithium has been shown to prevent and/or reverse DNA damage, free-radical formation and lipid peroxidation in diverse models. This study evaluates OxS parameters in healthy volunteers prior to and following lithium treatment. Healthy volunteers were treated with lithium in therapeutic doses for 2-4 weeks. Treatment with lithium in healthy volunteers selectively altered SOD levels in all subjects. Furthermore, a significant decrease in the SOD/CAT ratio was observed following lithium treatment, which was associated with decreased OxS by lowering hydrogen peroxide levels. This reduction in the SOD/CAT ratio may lead to lower OxS, indicated primarily by a decrease in the concentration of cell hydrogen peroxide. Overall, the present findings indicate a potential role for the antioxidant effects of lithium in healthy subjects, supporting its neuroprotective profile in bipolar disorder (BD) and, possibly, in neurodegenerative processes. PMID- 22200862 TI - Magnetic resonance imaging in children with sickle cell disease--detecting alterations in the apparent diffusion coefficient in hips with avascular necrosis. AB - BACKGROUND: Avascular necrosis (AVN) is a common morbidity in children with sickle cell disease (SCD) that leads to pain and joint immobility. However, the diagnosis is often uncertain or delayed. OBJECTIVE: To examine the ability of apparent diffusion coefficient (ADC) measurements on diffusion-weighted imaging to detect AVN in children with SCD. MATERIALS AND METHODS: ADC values were calculated at the hips of normal children (n = 19) and children with SCD who were either asymptomatic with no known previous hip disease (n = 13) or presented for the first time with clinical symptoms of hip pathology (n = 12). ADC values were compared for differences among groups with and without AVN using non-parametric statistical methods. RESULTS: The ADC values were elevated in the hips of children with AVN (median ADC = 1.57 * 10(-3) mm(2)/s [95% confidence interval = 0.86-2.10]) and differed significantly in pairwise comparisons (all P < 0.05) from normal children (0.74 [0.46-0.98]), asymptomatic children with SCD (0.55 [0.25-0.85]), and SCD children who had symptoms referable to their hips but did not show findings of hip AVN on conventional MRI or radiographs (0.46 [0.18 0.72]). CONCLUSION: Children with sickle cell disease have elevated apparent diffusion coefficient values in their affected hips on initial diagnosis of avascular necrosis. PMID- 22200863 TI - Comparative analysis of a cryptic thienamycin-like gene cluster identified in Streptomyces flavogriseus by genome mining. AB - In silico database searches allowed the identification in the S. flavogriseus ATCC 33331 genome of a carbapenem gene cluster highly related to the S. cattleya thienamycin one. This is the second cluster found for a complex highly substituted carbapenem. Comparative analysis revealed that both gene clusters display a high degree of synteny in gene organization and in protein conservation. Although the cluster appears to be silent under our laboratory conditions, the putative metabolic product was predicted from bioinformatics analyses using sequence comparison tools. These data, together with previous reports concerning epithienamycins production by S. flavogriseus strains, suggest that the cluster metabolic product might be a thienamycin-like carbapenem, possibly the epimeric epithienamycin. This finding might help in understanding the biosynthetic pathway to thienamycin and other highly substituted carbapenems. It also provides another example of genome mining in Streptomyces sequenced genomes as a powerful approach for novel antibiotic discovery. PMID- 22200864 TI - A TASH experience: post-infarction myocardial oedema necessitating the support of ECMO and occurrence of significant mitral regurgitation. PMID- 22200865 TI - Callose deposition at plasmodesmata is a critical factor in restricting the cell to-cell movement of Soybean mosaic virus. AB - Callose is a beta-l,3-glucan with diverse roles in the viral pathogenesis of plants. It is widely believed that the deposition of callose and hypersensitive reaction (HR) are critical defence responses of host plants against viral infection. However, the sequence of these two events and their resistance mechanisms are unclear. By exploiting a point inoculation approach combined with aniline blue staining, immuno-electron microscopy and external sphincters staining with tannic acid, we systematically investigated the possible roles of callose deposition during viral infection in soybean. In the incompatible combination, callose deposition at the plasmodesmata (PD) was clearly visible at the sites of inoculation but viral RNA of coat protein (CP-RNA) was not detected by RT-PCR in the leaf above the inoculated one (the upper leaf). In the compatible combination, however, callose deposition at PD was not detected at the site of infection but the viral CP-RNA was detected by RT-PCR in the upper leaf. We also found that in the incompatible combination the fluorescence due to callose formation at the inoculation point disappeared following the injection of 2-deoxy-D-glucose (DDG, an inhibitor of callose synthesis). At same time, in the incompatible combination, necrosis was observed and the viral CP-RNA was detected by RT-PCR in the upper leaf and HR characteristics were evident at the inoculation sites. These results show that, during the defensive response of soybean to viral infection, callose deposition at PD is mainly responsible for restricting the movement of the virus between cells and it occurs prior to the HR response. PMID- 22200866 TI - Isolated parachute tricuspid valve in an asymptomatic adult patient detected by three-dimensional echocardiography. PMID- 22200867 TI - A cost-benefit analysis of bevacizumab in combination with paclitaxel in the first-line treatment of patients with metastatic breast cancer. AB - Bevacizumab in combination with chemotherapy increases progression-free survival (PFS), but not overall survival when compared to chemotherapy alone in the treatment of metastatic breast cancer (MBC). Recently in November, 2011 the Food and drug administration revoked approval of bevacizumab in combination with paclitaxel for the treatment of MBC. The European Medicines Agency, in contrast, maintained its approval of bevacizumab in MBC. While neither agency considers health economics in their decision-making process, one of the greatest challenges in oncology practice today is to reconcile hard-won small incremental clinical benefits with exponentially rising costs. To inform policy-makers in the US, this study aimed to assess the cost-effectiveness of bevacizumab/paclitaxel in MBC, from a payer perspective. We created a decision analytical model using efficacy and adverse events data from the ECOG 2100 trial. Health utilities were derived from available literature. Costs were obtained from the Center for Medicare Services Drug Payment Table and Physician Fee Schedule and are represented in 2010 US dollars. Quality-adjusted life-years (QALY) and incremental cost effectiveness ratio (ICER) were calculated. Sensitivity analyses were performed. Bevacizumab added 0.49 years of PFS and 0.135 QALY with an incremental cost of $100,300, and therefore a cost of $204,000 per year of PFS gained and an ICER of $745,000 per QALY. The main drivers of the model were drug acquisition cost, PFS, and health utility values. Using a threshold of $150,000/QALY, drug price would have to be reduced by nearly 80% or alternatively PFS increased by 10 months to make bevacizumab cost-effective. The results of the model were robust in sensitivity analyses. Bevacizumab plus paclitaxel is not cost-effective in treating MBC. Value-based pricing and the development of biomarkers to improve patient selection are needed to better define the role of the drug in this population. PMID- 22200868 TI - Optimal outcomes for liver-dominant metastatic breast cancer with transarterial chemoembolization with drug-eluting beads loaded with doxorubicin. AB - The purpose of this study was to evaluate the efficacy of image-guided delivery of locoregional chemotherapy to breast cancer hepatic metastases using doxorubicin-loaded drug-eluting beads (DEBDOX). An IRB-approved multi-center, prospective, open, non-controlled repeat treatment registry to investigate the safety and efficacy of doxorubicin microspheres in the treatment of patients with unresectable liver metastasis from breast cancer was reviewed. Statistical analysis was performed with differences of P < 0.05 considered significant. About 40 patients with metastatic breast cancer (MBC) to the liver underwent a total of 75 image-guided procedures with hepatic arterial drug-eluting beads loaded with doxorubicin (DEBDOX). Treatment was well tolerated with a total of eight patients sustaining 13 adverse events within the 30 days of each treatment session. All adverse events were either a grade I or grade II in toxicity. After a median follow-up of 12 months in all patients, the hepatic progression-free survival was a median of 26 months and overall survival was a median of 47 months. The treatment of hepatic metastasis from MBC using DEBDOX is an effective local therapy with very high response rates and a very safe toxicity profile. In comparison to chemotherapy alone, consideration of hepatic-directed therapy is warranted in patients with liver-dominant metastatic disease. PMID- 22200869 TI - Phase I-II study of vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer: evidence for vorinostat-induced tubulin acetylation and Hsp90 inhibition in vivo. AB - In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulin-polymerizing agents and to anti-vascular endothelial growth factor-directed therapies. We sought to determine the safety and efficacy of vorinostat plus paclitaxel and bevacizumab as first-line therapy in metastatic breast cancer (MBC), and the biological effects of vorinostat in vivo. For this purpose of this study, 54 patients with measurable disease and no prior chemotherapy for MBC received vorinostat (200 or 300 mg PO BID) on days 1 3, 8-10, and 15-17, plus paclitaxel (90 mg/m(2)) on days 2, 9, 16, and bevacizumab (10 mg/kg) on days 2 and 16 every 28 days. The primary objective of the phase I study was to determine the recommended phase II dose (RPTD) of vorinostat, and for the phase II to detect an improvement of response rate from 40 to 60% (alpha = 0.10, beta = 0.10). No dose limiting toxicities were observed, and the RPTD of vorinostat was 300 mg BID. For the primary efficacy analysis in 44 patients at the RPTD, we observed 24 objective responses (55%, 95% confidence intervals (C.I) 39%, 70%). The adverse event profile was consistent with paclitaxel-bevacizumab, with the exception of increased diarrhea with the addition of vorinostat. Analysis of serial tumor biopsies in seven patients showed increased acetylation of Hsp90 and alpha-tubulin following vorinostat. Vorinostat induces histone and alpha tubulin acetylation and functional inhibition of Hsp90 in breast cancer in vivo and can be safely combined with paclitaxel and bevacizumab. PMID- 22200870 TI - Cancer incidence among priests: 45 years of follow-up in four Nordic countries. AB - Previously published studies on the risk of cancer among male priests have been based on cancer mortality with the exception of one case-control study. The aim of this study was to present estimates of cancer incidence among Nordic male priests. The study cohort for our analyses consisted of 6.5 million men aged 30 64 years old who had participated in any computerised population census in four Nordic countries in 1990 or earlier. Follow-up was done by drawing linkages with the national population and cancer registries. 13,491 priests were identified by their job title codes. We estimated the standardised incidence ratio (SIR) and 95% confidence intervals (95% CI) for the priests using the male population as a reference. Priests had a lower cancer incidence than the general population (overall SIR 0.85, 95% CI: 0.82-0.88). The majority of smoking- and alcohol related cancers were associated with decreased SIR estimates. Increased risks were observed for skin melanoma (SIR 1.34, 95% CI: 1.11-1.62), acute myeloid leukemia (SIR 1.75, 95% CI: 1.20-2.47) and thyroid cancer (SIR 1.86, 95% CI: 1.22 2.73). This is the first cohort study regarding the incidence of cancer among priests. The lower incidence of smoking and alcohol-related cancers among Nordic male priests can be explained by their lower exposure to cigarettes and alcohol when compared to the general population. A greater risk of melanoma is typical of highly-educated people, but it is unclear why priests should have an increased risk of acute myeloid leukemia or thyroid cancer. PMID- 22200872 TI - Immuno-flow cytometry for the rapid identification of Staphylococcus aureus and the detection of methicillin resistance. AB - Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) can be reliably differentiated by flow cytometry when labeled with nucleic acid dyes. The purpose of this study was to determine if this differentiation can be achieved while labeling with a S. aureus-specific anti staphylococcal protein A antibody instead of nucleic acid dyes. A total of 103 S. aureus isolates were incubated for 4 h at 37 degrees C in Mueller Hinton broth with and without oxacillin, then stained with anti-staphylococcal protein A antibody, and analyzed by flow cytometry using the Micro PROTM instrument. Dot plots (side scatter vs. fluorescence intensity) of isolates exposed to oxacillin were examined to define two gates encompassing the majority of MSSA and MRSA signal events, respectively. The ratio of signal event counts in the two gates was called the gate signal count ratio (GSCR), and its performance was evaluated using receiver operating characteristic (ROC) curves. The GSCR could differentiate MRSA from MSSA with 98% sensitivity and 100% specificity using a cut-off of 0.6868 when the two gates were defined as follows: gate 1, fluorescence intensity 2-10, side scatter 5-70; gate 2, fluorescence intensity 7 700, side scatter 70-500. MRSA and MSSA can be accurately detected and differentiated by flow cytometry after 4 h of oxacillin exposure when labeled with anti-staphylococcal protein A antibody. PMID- 22200873 TI - Programmed cell death 4 inhibits leptin-induced breast cancer cell invasion. AB - Obesity is a significant risk factor for post-menopausal women to develop and die from breast cancer. Leptin, an adipokine is produced in high levels in obese individuals, and its receptor is overexpressed in breast tumors and lymph node metastases. Previously, we demonstrated that leptin stimulates breast cancer cell invasion, which is correlated with breast cancer metastasis. Programmed cell death 4 (PDCD4) has been shown to block cancer cell invasion. However, whether PDCD4 blocks leptin-induced breast cancer cell invasion is not known. Here, we report the novel findings that leptin failed to induce invasion in MCF-7 breast cancer cells overexpressing PDCD4 (MCF-7/PDCD4). Tissue inhibitor of metalloproteinase-2 (TIMP-2) was essential to the anti-invasive effect of PDCD4, as leptin stimulated the invasion of MCF-7/PDCD4 cells pretreated with TIMP-2 siRNA. Furthermore, TIMP-2 knockdown allowed leptin to augment phosphorylation of extracellular signal-regulated kinases 1,2 and signal transducer and activator of transcription 3, but not that of Jun N-terminal kinases. These data indicate that PDCD4 utilizes TIMP-2 to exert its anti-invasive effect by suppressing leptin induced activation of extracellular signal-regulated kinases 1,2 and signal transducer and activator of transcription 3. Novel therapeutic strategies aiming at enhancing PDCD4 expression in breast tumors may be able to stop obesity related breast tumor progression and prolong the life of patients. PMID- 22200874 TI - Anticancer effect and apoptosis induction by quercetin in the human lung cancer cell line A-549. AB - The aim of the present study was to investigate the anticancer effect of quercetin (QC) in the human lung cancer cell line A-549 and further study the mechanism of apoptosis induction by QC. Low differentiation potential A-549 human lung cancer cells were treated with QC at different doses and for different times, and the growth inhibitory rates were detected by MTT assay. Apoptosis induced by QC in A-549 cells was observed by Annexin V/PI double staining and flow cytometric assay. The relative tumor growth ratio of the treated/control tumors (T/C) (%) was chosen to represent the tumor growth inhibition of A-549 cell nude mouse xenografts by QC. Apoptosis of the nude mouse xenografts was observed by Annexin V/PI double staining and flow cytometric assay and DNA fragmentation assay. To further determine the molecular mechanism of apoptosis induced by QC, changes in the expression of bcl-2 and bax genes were detected by RT-PCR. Following incubation with QC, the cell growth of the low differentiation potential A-549 human lung cancer cells was dramatically inhibited in a dose dependent manner. After the cells were exposed to QC for 24, 48 and 72 h, the IC50 value was 1.02 +/- 0.05, 1.41 +/- 0.20 and 1.14 +/- 0.19 umol/l, respectively. Apoptosis in the A-549 cells induced by QC was noted. The apoptotic subpopulation of A-549 cells was approximately 12.96 and 24.58%, respectively, when cells were incubated with 1.2 umol/l QC for 48 and 72 h. T/C (%) of A-549 nude mouse xenografts was 44.3, when the nude mice were treated with QC (8 mg/kg). Meanwhile, apoptosis induced by QC was observed in the A-549 nude mouse xenografts. Increased expression of the bax gene and decreased expression of the bc1-2 gene were noted using RT-PCR. Our results provide further evidence of the growth inhibition of the A-549 human lung adenocarcinoma cancer cell line by QC. This effect is associated with the induction of apoptosis in A-549 cells and the molecular mechanism may be related to the reduction in expression of the apoptosis-regulating gene bcl-2, and increase in expression of the apoptosis regulating gene bax. These results were also confirmed in vivo. PMID- 22200875 TI - Accreditation and the use of validated/recognised methods to analyse human semen. AB - Accreditation of laboratories who perform diagnostic semen analysis in Australia and New Zealand is a requirement of the healthcare system. Within the accreditation process laboratories are required to set ISO standards within their policies and procedures. In order to achieve their aims, laboratories need to be able to measure a number of defined semen parameters both accurately and repetitively, especially around the lower limit of the reference intervals. The methods documented in the WHO-manual are used almost universal as the laboratory standard. Some laboratories incorporate minor method variations into their procedures. As part of the ISO requirements all variations require validation using internally approved processes that are documented and that incorporate appropriate statistical analysis and comparison of results. Validation is an ongoing process and regular review is essential. Evidence of the validation must be available for review by external auditors during accreditation. Where any validated variant method returns results that are significantly different to any method within the WHO-manual, the laboratory needs to develop its own, in-house reference interval for that method. PMID- 22200876 TI - Some foundations of contemporary methods for culturing preimplantation embryos; a personal account. AB - This article traces the history of the work on mammalian embryos carried out by the author, his students and related scientists. It traces the work from the initial experiments at the King Ranch Laboratories, University of Pennsylvania in 1966, the set up of an embryo culture laboratory at the Department of Veterinary Physiology, University of Sydney and the work within that laboratory from 1967 to 1974. This is followed by an account of the author's subsequent work at Murdoch University from 1975 till his retirement in 1996. The significant role of some of the author's graduate students in human IVF is also documented. PMID- 22200877 TI - A clinician's personal view of assisted reproductive technology over 35 years. AB - This invited presentation is intended to cover clinical developments in the evolution of assisted reproductive technology (ART), a process which was attempted during the 1940's and 50's and culminated in the first fruition in 1978. The first in vitro fertilisation (IVF) child ensued following the partnership by a scientist with a focussed ambition (Nobel laureate Robert Edwards) joining with the gynaecologist who introduced laparoscopy to Britain in the late 60's (Patrick Steptoe). My journey commenced in 1976 as a clinician who became immersed in the embryological and endocrinological science, whence most progress in ART emanates, and continued into a medical directorship position from which this personal view is documented. Several clinical advances have been important developments in the understanding and management of sub-fertile patients. However evolution of the various laboratory sciences has been the major key essential to meeting both the immediate as well as the long-term needs for human reproduction. The future requires a much better understanding and control over gametogenesis and a laboratory process which much more closely duplicates intrinsic reproductive physiology, avoiding gamete and embryo exposure to the atmosphere.This invited presentation is intended to cover clinical developments in the evolution of assisted reproductive technology (ART), a process which was attempted during the 1940's and 50's and culminated in the first fruition in 1978. The first in vitro fertilisation (IVF) child ensued following the partnership by a scientist with a focussed ambition (Nobel laureate Robert Edwards) joining with the gynaecologist who introduced laparoscopy to Britain in the late 60's (Patrick Steptoe). My journey commenced in 1976 as a clinician who became immersed in the embryological and endocrinological science, whence most progress in ART emanates, and continued into a medical directorship position from which this personal view is documented. Several clinical advances have been important developments in the understanding and management of sub-fertile patients. However evolution of the various laboratory sciences has been the major key essential to meeting both the immediate as well as the long-term needs for human reproduction. The future requires a much better understanding and control over gametogenesis and a laboratory process which much more closely duplicates intrinsic reproductive physiology, avoiding gamete and embryo exposure to the atmosphere. PMID- 22200878 TI - Artificial insemination technology for the emu--improving sperm survival. AB - For the emu, where monogamous mating is normal, artificial insemination (AI) promises much faster genetic improvement and a considerable reduction in production costs by reducing the number of male birds needed for mating. Semen collection is now a routine procedure so the next step is to develop successful protocols for sperm storage. In this paper, we briefly overview our recent progress on the development of protocols for liquid storage and cryopreservation of emu spermatozoa. We have shown that emu semen can be stored at 10 degrees C for up to 48 h with a minimal loss of viability, and that cryopreservation with dimethylacetamide (DMA) as a cryoprotectant is feasible because we have observed no adverse effects of this cryoprotectant on the emu sperm membrane integrity, morphology and motility. We now need to establish the predictability of the various tests in vivo, but the proportions of live normal and motile sperm with good egg membrane penetration potential suggest that acceptable numbers of competent sperm are preserved and that this will be sufficient for AI. PMID- 22200879 TI - The genetic screening of preimplantation embryos by comparative genomic hybridisation. AB - Comparative genomic hybridization (CGH) is an indirect DNA-based test which allows for the accurate analysis of aneuploidy involving any of the 24 types of chromosomes present (22 autosomes and the X and Y sex chromosomes). Traditionally, embryos have been screened using fluorescence in situ hybridization (FISH)--a technique that was limited in the number of chromosomes able to be identified in any one sample. Early CGH reports on aneuploidy in preimplantation embryos showed that any of the 24 chromosomes could be involved and so FISH methods were going to be ineffective in screening out abnormal embryos. Our results from routine clinical application of array CGH in preimplantation genetic diagnosis (PGD) patients confirm previous reports on patterns of chromosomal contribution to aneuploidy. The pregnancy outcomes following embryo transfer also indicate that despite the requirement to freeze embryos, rates are encouraging, and successful ongoing pregnancies can be achieved. PMID- 22200880 TI - External and internal modulators of sheep reproduction. AB - Several factors such as season, genetics, social interaction and metabolic status control or modulate the reproductive capacity of sheep. In addition to these well studied factors in sheep, the influence of emotional reactivity on the reproductive success of sheep has started to be investigated over the last two decades. In this paper, after briefly reviewing the impact of classical factors affecting reproduction in sheep, we define emotional reactivity and the expression of its inter-individual variability, named temperament. Then, following a description of the protocol to measure temperament in sheep and discussion on the heritability of temperament traits, we illustrate how this selection affects the reproductive biology of sheep. We will be mainly using results obtained from a unique flock of sheep selected for low or high emotional reactivity. In conclusion, we propose that energy partitioning could be one of the mechanisms by which selection for temperament in sheep affects the different steps of the reproductive cycle. PMID- 22200881 TI - Effects of bpV(pic) and bpV(phen) on H9c2 cardiomyoblasts during both hypoxia/reoxygenation and H2O2-induced injuries. AB - Reactive oxygen species (ROS) are involved in myocardial injury. ROS are known to inactivate lipid phosphatase and tension homolog on chromosome 10 (PTEN), an enzyme that increases apoptosis in neonatal cardiomyocytes. BpV(pic) and bpV(phen), two bisperoxovanadium molecules and PTEN inhibitors, may be involved in limiting myocardial infarction. To compare the protective effects of bpV(pic) and bpV(phen) on ROS-induced cardiomyocyte injury and their possible mechanisms, we selected two popular models of hypoxia/reoxygenation (H/R) and H2O2-induced injury in H9c2 cardiomyoblasts to investigate their effects against injury. We found that pre-treatment with bpV(pic) and bpV(phen) increased the viability and protected the morphology of H9c2 cells under the conditions of H/R and H2O2 by inhibiting LDH release, apoptosis and caspases 3/8/9 activities. However, their respective inhibitory abilities in the two models were different, suggesting that the quantity of ROS from the two models might be different. However, the conflict between ROS and PTEN may affect the action of bpV(pic) and bpV(phen). Taken together, the results demonstrate that bpV(pic) and bpV(phen) have inhibitory effects on oxidative stress-induced cardiomyocyte injury that may be partially modulated by the action of ROS on PTEN. PMID- 22200882 TI - Frontal terminations for the inferior fronto-occipital fascicle: anatomical dissection, DTI study and functional considerations on a multi-component bundle. AB - The anatomy and functional role of the inferior fronto-occipital fascicle (IFOF) remain poorly known. We accurately analyze its course and the anatomical distribution of its frontal terminations. We propose a classification of the IFOF in different subcomponents. Ten hemispheres (5 left, 5 right) were dissected with Klingler's technique. In addition to the IFOF dissection, we performed a 4-T diffusion tensor imaging study on a single healthy subject. We identified two layers of IFOF. The first one is superficial and antero-superiorly directed, terminating in the inferior frontal gyrus. The second is deeper and consists of three portions: posterior, middle and anterior. The posterior component terminates in the middle frontal gyrus (MFG) and dorso-lateral prefrontal cortex. The middle component terminates in the MFG and lateral orbito-frontal cortex. The anterior one is directed to the orbito-frontal cortex and frontal pole. In vivo tractography study confirmed these anatomical findings. We suggest that the distribution of IFOF fibers within the frontal lobe corresponds to a fine functional segmentation. IFOF can be considered as a "multi-function" bundle, with each anatomical subcomponent subserving different brain processing. The superficial layer and the posterior component of the deep layer, which connects the occipital extrastriate, temporo-basal and inferior frontal cortices, might subserve semantic processing. The middle component of the deep layer could play a role in a multimodal sensory-motor integration. Finally, the anterior component of the deep layer might be involved in emotional and behavioral aspects. PMID- 22200883 TI - The visual cortex in schizophrenia: alterations of gyrification rather than cortical thickness--a combined cortical shape analysis. AB - In light of bottom-up models of disrupted cognition in schizophrenia, visual processing deficits became a key feature for the pathophysiology of schizophrenia. However, morphometric studies focusing on the visual cortex are limited. Thus, the present study sought to provide a combined cortical shape analysis (cortical thickness, folding) of visual areas, which were implicated to be involved in disturbed visual processing in schizophrenia. A group of 72 patients with schizophrenia according to DSM-IV and 72 age- and gender-matched healthy control subjects were included. All participants underwent high resolution T1-weighted MRI scans on a 1.5-T scanner. Cortical thickness and mean curvature of the V1, V2 and V5/MT+ visual cortex were estimated using an automated computerized algorithm (Freesurfer Software). A GLM controlling for the effect of age was used to estimate differences of cortical shape parameters between the study groups. Significantly increased gyrification of the V1, V2 and the V5/MT+ visual area bilaterally was detected. Conversely, cortical thickness was reduced in patients with schizophrenia only for the V5/MT+ area. This study is the first providing direct in vivo evidence for a disturbed cortical shape of central visual areas in schizophrenia. The present findings of hypergyria are highly indicative for a disrupted corticogenesis of these visual key regions and might constitute a relevant anatomical basis for visual processing deficits in schizophrenia. PMID- 22200884 TI - Carboxyl-terminal modulator protein induces apoptosis by regulating mitochondrial function in lung cancer cells. AB - Serine/threonine protein kinase B (PKB/Akt) is involved in cell survival and growth. Carboxyl-terminal modulator protein (CTMP), a novel Akt binding partner, prevents Akt activation at the plasma membrane in response to various stimuli, and thus possesses a tumor suppressor-like function. In a previous study, we have demonstrated that CTMP inhibits tumor progression by facilitating apoptosis in a mouse lung cancer model. However, the precise mechanism of CTMP-induced apoptosis remains to be elucidated. The present study was performed to examine the role of CTMP in mitochondrial-mediated apoptosis and regulation of mitochondrial function in human lung carcinoma cells. Our results showed that CTMP altered mitochondrial morphology and caused the release of cytochrome c by inhibiting OPA1 expression. Additionally, CTMP facilitated mitochondrial-mediated apoptosis by inhibiting heat-shock protein 27 and preventing cytochrome c interaction with Apaf-1. Our data suggest that CTMP may therefore play a critical role in mitochondrial mediated apoptosis in lung cancer cells. PMID- 22200885 TI - Protein interactions with HER-family receptors can have different characteristics depending on the hosting cell line. AB - Cell lines are common model systems in the development of therapeutic proteins and in the research on cellular functions and dysfunctions. In this field, the protein interaction assay is a frequently used tool for assessing the adequacy of a protein for diagnostic and therapeutic purposes. In this study, we investigated the extent to which the interaction characteristics depend on the choice of cell line for HER-family receptors. The interaction characteristics of two therapeutic antibodies (trastuzumab and cetuximab) and one Affibody molecule (ZHER2:342), interacting with the intended receptor were characterized with high precision using an automated real-time interaction method, in different cell lines (HaCaT, A431, HEP-G2, SKOV3, PC3, DU-145). Clear differences in binding affinity and kinetics, up to one order of magnitude, were found for the interaction of the same protein binding to the same receptor on different cells for all three proteins. For HER-family receptors, it is therefore important to refer to the measured affinity for a protein-receptor interaction together with the hosting cell line. The ability to accurately measure affinity and kinetics of a protein receptor interaction on cell lines of different origins may increase the understanding of underlying receptor biology, and impact the selection of candidates in the development of therapeutic or diagnostic agents. PMID- 22200886 TI - A perturbation solution of the mechanical bidomain model. AB - This research focuses on finding analytical solutions to the mechanical bidomain model for cardiac tissue. In particular, a perturbation expansion is used to analyze the equations, with the perturbation parameter being inversely proportional to the spring constant coupling the intracellular and extracellular spaces. The results indicate that the intracellular and extracellular pressures are not equal and that the two spaces can move relative to each other. This calculation is complicated enough to illustrate the implications of the mechanical bidomain model but is nevertheless simple enough to solve analytically. One application of the calculation is to the mechanical behavior of active cardiac tissue surrounding an ischemic region. PMID- 22200887 TI - High-resolution NMR field-cycling device for full-range relaxation and structural studies of biopolymers on a shared commercial instrument. AB - Improvements are described in a shuttling field-cycling device (Redfield in Magn Reson Chem 41:753-768, 2003), designed to allow widespread access to this useful technique by configuring it as a removable module to a commercial 500 MHz NMR instrument. The main improvements described here, leading to greater versatility, high reliability and simple construction, include: shuttling provided by a linear motor driven by an integrated-control servomotor; provision of automated bucking magnets to allow fast two-stage cycling to nearly zero field; and overall control by a microprocessor. A brief review of history and publications that have used the system is followed by a discussion of topics related to such a device including discussion of some future applications. A description of new aspects of the shuttling device follows. The minimum round trip time to 1T and above is less than 0.25 s and to 0.002 T is 0.36 s. Commercial probes are used and sensitivity is that of the host spectrometer reduced only by relaxation during travel. A key element is development of a linkage that prevents vibration of the linear motor from reaching the probe. PMID- 22200888 TI - Tetramethylpyrazine attenuates PPAR-gamma antagonist-deteriorated oxazolone induced colitis in mice. AB - Tetramethylpyrazine (TMP) is suggested to have anti-inflammatory activity. The aim of this study was to determine the role of peroxisome proliferator activated receptor gamma (PPAR-gamma) signaling in the pharmacologic effect of TMP on oxazolone (OXZ)-induced colitis. TMP (80 mg/kg/day i.p.) was administered daily 48 h after intrarectal instillation of OXZ, with or without PPAR-gamma inhibitor [bisphenol A diglycidyl ether (BADGE) 30 mg/kg] during the 4 days before sacrifice. The inflammatory response was assessed by the disease activity index, macroscopy, histology and myeloperoxidase (MPO) activity. Expression levels of PPAR-gamma, NF-kappaB p65, COX-2, iNOS and TNF-alpha mRNA in colon mucosa were determined by FQ-PCR, levels of PPAR-gamma and NF-kappaB p65 protein were analyzed by immunohistochemistry, and the total and phosphorylated levels of p38 MAPK were assessed by western blotting. TMP significantly attenuated the damage caused by OXZ and substantially reduced the rise in MPO activity, TNF-alpha, iNOS, NF-kappaB p65 and COX-2 expression, as well as the increase in PPAR-gamma production; however, no changes in the activation of p38 MAPK were observed. Inhibition of PPAR-gamma signaling aggravated inflammation of colon mucosa, and increased p38 phosphrylation. TMP counteracted the effect of inhibition of PPAR gamma. We suggest that the effect of TMP treatment in ulcerative colitis may be related to PPAR-gamma signaling, but is independent of PPAR-gamma. PMID- 22200889 TI - Optimised cord blood sample selection for small-scale CD34+ cell immunomagnetic isolation. AB - Haematopoietic stem cells (HSCs) are defined as multipotential cells, capable of self-renewal and reconstituting in vivo the haematopoietic compartment. The CD34 antigen is considered an important HSCs marker in humans. Immunomagnetic isolation, by targeting CD34 antigen, is widely used for human HSC separation. This method allows the enrichment of human HSCs that are present at low frequencies in umbilical cord blood (CB). Immunomagnetic CD34+-cell isolation reproducibility, regarding cell yield and purity, is affected by the CD34+ cell frequency and total cell numbers present in a given sample; CB HSC purification may thus yield variable results, which also depend on the volume and density fractionation-derived cell loss of a CB sample. The uncertainty of such an outcome and associated technical costs call for a cost-effective sample screening strategy. A correlation analysis using clinical and laboratory data from 59 CB samples was performed to establish predictive variables for CD34+-immunomagnetic HSCs isolation. This study described the positive association of CD34+-cell isolation with white and red cell numbers present after cell fractionation. Furthermore, purity has been correlated with lymphocyte percentages. Predictive variable cut-off values, which are particularly useful in situations involving low CB volumes being collected (such as prevalent late umbilical cord clamping clinical practice), were proposed for HSC isolation sampling. Using the simple and cost-effective CB sample screening criteria described here would lead to avoiding costly inefficient sample purification, thereby ensuring that pure CD34+ cells are obtained in the desired numbers following CD34 immunomagnetic isolation. PMID- 22200890 TI - Protective effects of the antioxidant sulforaphane on behavioral changes and neurotoxicity in mice after the administration of methamphetamine. AB - RATIONALE: Methamphetamine (METH) is a powerfully addictive stimulant associated with serious health conditions. Accumulating evidence suggests a role of oxidative stress in METH-induced behavioral abnormalities. Sulforaphane (SFN), found in cruciferous vegetables, is a potent antioxidant. It is of interest to determine whether SFN can attenuate behavioral and neuropathological changes associated with METH exposure. OBJECTIVES: This study was undertaken to examine the effects of SFN on behavioral changes and dopaminergic neurotoxicity in mice exposed to METH. METHODS: The effects of SFN on acute hyperlocomotion and the development of behavioral sensitization induced by the administration of METH were examined. Levels of dopamine (DA) and its major metabolite 3,4 dihydroxyphenyl acetic acid (DOPAC) in the striatum were measured. In addition, DA transporter (DAT) immunoreactivity was also performed. RESULTS: Pretreatment with SFN at 1, 3, and 10 mg/kg elicited a dose-dependent attenuation of acute hyperlocomotion in mice, after a single administration of METH (3 mg/kg). The development of behavioral sensitization after repeated administrations of METH (3 mg/kg/day, once daily for 5 days) was significantly reduced by pretreatment with SFN (10 mg/kg). In addition, the lowering of DA levels and DOPAC as well as DAT immunoreactivity in the striatum, usually seen after repeated administration of METH, was significantly attenuated by both pretreatment and the subsequent administration of SFN. Furthermore, SFN significantly reduced microglial activation in the striatum after repeated exposure to METH. CONCLUSION: It is therefore likely that SFN can be a useful drug for the treatment of signs associated with METH abuse in humans. PMID- 22200891 TI - Expressed antibody repertoires in human cord blood cells: 454 sequencing and IMGT/HighV-QUEST analysis of germline gene usage, junctional diversity, and somatic mutations. AB - Human cord blood cell-derived IgM antibodies are important for the neonate immune responses and construction of germline-based immunoglobulin libraries. Several previous studies of a relatively small number of sequences found that they exhibit restrictions in the usage of germline genes and in the diversity of the variable heavy chain complementarity determining region 3 compared to adults. To further characterize such restrictions on a larger scale and to compare the early B-cell diversity to adult IgM repertoires, we performed 454 sequencing and IMGT/HighV-QUEST analysis of cord blood IG libraries from two babies and determined germline gene usage, V-D-J rearrangement, VHCDR3 diversity, and somatic mutations to characterize human neonate repertoire. Most of the germline subgroups were identified with frequencies comparable to those present in the adult IgM repertoire except for the IGHV1-2 gene that was preferentially expressed in the cord blood cells. The gene usage diversity contributed to 1,430 unique IGH V-D-J rearrangement patterns while the exonuclease trimming and N region addition at the V-D-J junctions along with gene diversity created a wide range of VHCDR3 with different lengths and sequence variability. We observed a lower degree of somatic mutations in the CDR and framework regions of antibodies from cord blood cells compared to adults. These results provide insights into the characteristics of human cord blood antibody repertoires, which have gene usage diversity and VHCDR3 lengths similar to that of the adult IgM repertoire but differ significantly in some of the gene usages, V-D-J rearrangements, junctional diversity, and somatic mutations. PMID- 22200892 TI - UVC irradiation suppresses platelet-derived growth factor-BB-induced migration in human pancreatic cancer cells. AB - We have recently reported that short wavelength ultraviolet-C (UVC) irradiation inhibits cell growth and induces apoptosis in human pancreatic cancer cells. In this study, we investigated the effect of UVC on platelet-derived growth factor (PDGF)-BB-induced migration in pancreatic cancer cells, AsPC1 and BxPC3. In cell migration assays using a Boyden chamber Transwell, PDGF-BB exerted a maximum effect on migration of these cells at a dose of 70 ng/ml after 36 h of treatment. PDGF-BB also caused phosphorylation of p44/p42 mitogen-activated protein kinase (MAPK), stress-activated protein kinase/c-Jun-N-terminal kinase (SAPK/JNK) and Akt, but not of p38 MAPK in these cells. Pretreatment of these cells with UVC at a dose over 10 J markedly suppressed PDGF-BB-induced migration. Since UVC significantly inhibited PDGF-BB-induced phosphorylation of Akt, and subsequent glycogen synthase kinase (GSK) 3beta, but not p44/p42 MAPK and SAPK/JNK, it is likely that UVC inhibits PDGF-BB-induced migration by suppressing the Akt GSK3beta pathway in pancreatic cancer cells. Taken together with our previous findings, UVC could be a useful tool for the treatment of patients with pancreatic cancer. PMID- 22200893 TI - A multi-domain model of risk factors for ODD symptoms in a community sample of 4 year-olds. AB - Few studies have been designed to assess the pathways by which risk factors are associated with symptoms of psychopathology across multiple domains, including contextual factors, parental depression, parenting, and child characteristics. The present study examines a cross-sectional model of risk factors for symptoms of Oppositional Defiant Disorder (ODD) in a diverse community sample of 796 four year-old children. In the best-fitting model: (a) SES had indirect effects on contextual factors of stress and conflict, parental depression, and parenting factors including hostility, support, and scaffolding; (b) stress and conflict had both direct effects on ODD symptoms, and indirect effects via parental depression and parenting; (c) parenting had direct effects on ODD symptoms and indirect effects via child effortful control (EC), negative affect (NA) and sensory regulation (SR); (c) NA, EC, and SR had direct effects on symptom frequency, and attachment had indirect effects via EC, and SR. These results highlight the importance of using a multi-domain model to examine risk factors for symptoms of ODD, and also provide information about areas to target in treatment. PMID- 22200894 TI - Human metapneumovirus strains circulating in Latin America. AB - The human metapneumovirus (HMPV) is responsible for acute respiratory tract infections in young children, elderly patients, and immunocompromised hosts. In this study, we genetically analyzed the circulating HMPV in Central and South America from July 2008 to June 2009 and characterized the strains present in this region. Samples were collected during an international collaborative influenza like illness surveillance study and then sequenced with specific primers for the HMPV G gene. Our results show that two distinct clusters of HMPV circulated in Central and South America, subtypes A2 and B2 being the predominant strains. PMID- 22200895 TI - NGAL distinguishes steroid sensitivity in idiopathic nephrotic syndrome. AB - BACKGROUND: Idiopathic nephrotic syndrome (NS) is the most common glomerular disorder of childhood. Invasive biopsy remains the diagnostic method of choice for NS. Prognosis correlates with steroid responsiveness, from sensitive (SSNS) to resistant (SRNS). Neutrophil gelatinase-associated lipocalin (NGAL) has been demonstrated to be a powerful risk marker of chronic kidney disease progression. We set out to determine if urine NGAL can distinguish between patients with SRNS, SSNS, and healthy controls. METHODS: Urine and clinical data were collected from patients at Cincinnati Children's Hospital who were recently diagnosed with active nephrotic syndrome as well as healthy controls. Participants included SRNS (n = 15), SSNS (n = 14), and healthy controls (n = 10). Urinary NGAL was measured by ELISA and normalized to creatinine. RESULTS: Median NGAL was significantly (p < 0.001) higher in SRNS (172.3 ng/ml, IQR 18.8-789) than both SSNS (6.3 ng/ml, IQR 4.9-9.9) and healthy controls (6.5 ng/ml, IQR 4.2-9.1). The area under the curve (AUC) for NGAL to distinguish SRNS from SSNS was 0.91 (p < 0.0001). NGAL levels demonstrated a significant negative correlation with glomerular filtration rate (r = -0.5, p < 0.001). Results did not change with NGAL corrected for urine creatinine and were independent of the degree of proteinuria. CONCLUSIONS: NGAL levels differentiate SSNS from SRNS and correlate with disease severity in SRNS. PMID- 22200896 TI - Job autonomy, its predispositions and its relation to work outcomes in community health centers in Taiwan. AB - It has been debated that employees in a government or public ownership agency may perceive less need for growth opportunities or high-powered incentives than is the case for employees in private organizations. This study examined employees' job autonomy in government-run community health centers, its predispositions and its relation to their work outcomes. A cross-sectional study was conducted in Taiwan. From 230 responding community health centers, 1380 staff members responded to the self-completed, structured questionnaire. Structural equation modeling revealed that employees' job autonomy has positive work outcomes: greater work satisfaction, and less intent to transfer and intentions to leave. In addition, job autonomy was related to employees' higher education levels, medical profession, permanent employment and serving smaller populations. Moreover, employees' age, educational levels, medical profession and employment status were found to be related to their work satisfaction, intent to transfer and intent to leave. PMID- 22200897 TI - EMMPRIN contributes to the in vitro invasion of human salivary adenoid cystic carcinoma cells. AB - Extracellular matrix metalloproteinase inducer (EMMPRIN) is a transmembrane glycoprotein that is involved in tumor invasion by stimulating matrix metalloproteinase (MMP) expression. Our previous immunohistochemical study found that the expression of EMMPRIN in salivary adenoid cystic carcinoma (SACC) was positively correlated with tumor perineural and perivascular invasion. The present study was designed to further investigate the role of EMMPRIN in the invasion of SACC. Western blot results showed that EMMPRIN was upregulated in the highly metastatic SACC cell line SACC-LM, compared to SACC-83, a SACC cell line with low metastatic ability. Blocking of EMMPRIN by its antibody significantly decreased the adhesion, secretion of MMP-2 and MMP-9, and invasion activity of SACC-LM cells in vitro (P<0.01). Co-cultures of SACC-LM cells with fibroblasts significantly produced elevated levels of MMP-2 and MMP-9, and promoted the in vitro invasion activity of SACC-LM cells, compared with cultures of SACC-LM cells alone (P<0.01). These results indicate that EMMPRIN may play an important role in the invasion of SACC by stimulating the expression of MMP-2 and MMP-9 in tumor and stromal cells. PMID- 22200898 TI - Maternal smoking during pregnancy, genetic polymorphisms of metabolic enzymes, and childhood acute leukemia: the ESCALE study (SFCE). AB - PURPOSE: This study explored interactions between prenatal exposure to maternal smoking and polymorphisms in metabolic genes in the risk of childhood acute leukemia (AL). METHODS: The data were generated by the ESCALE study, which included 764 AL cases and 1,681 controls in 2003-2004. The data on maternal smoking during pregnancy were obtained by standardized telephone interview of the cases' and controls' mothers. The genotypes CYP1A1*2A/2B (rs4646903), CYP2E1*5 (rs2031920, rs3813867), NQO1*2 (rs1800566), NAT2*5 (rs1801280), and EPHX1 exon 3 (rs1051740) and exon 4 (rs2234922) were obtained using a high-throughput platform and imputation for untyped polymorphisms. The analyses were restricted to the 493 cases (433 cases of lymphoblastic (ALL) and 51 of myeloblastic (AML) leukemia) and 441 controls with at least 2 grandparents born in Europe, who were genotyped with individual call rates greater than 95%. Odds ratios were estimated by logistic regression in case-control analyses and, for gene-gene and gene environment interactions, by case-only analyses. RESULTS: ALL and AML were not associated with either maternal smoking during pregnancy or candidate polymorphisms in CYP1A1, CYP2E1, EPHX1, and NQO1. Carrying two NAT2*5 alleles was significantly associated with ALL (OR = 1.8 [1.3-2.5]). The analyses also suggested an interaction between three genes involved in benzene metabolism CYP2E1, NQO1, and EPHX1. There was no interaction between maternal smoking and any of the polymorphisms under study. CONCLUSIONS: The ESCALE study did not evidence the interaction between CYP1A1*2A/2B and maternal smoking suggested previously. The association with NAT2*5 and the gene-gene interactions need to be replicated. PMID- 22200899 TI - Proportional incidence and radiological review of large (T2+) breast cancers as surrogate indicators of screening programme performance. AB - OBJECTIVES: Surrogate measures of screening performance [e.g. interval cancer (IC) proportional incidence] allow timely monitoring of sensitivity and quality. This study explored measures using large (T2+) breast cancers as potential indicators of screening performance. METHODS: The proportional incidence of T2+ cancers (observed/expected cases) in a population-based screening programme (Trento, 2001-2009) was estimated. A parallel review of 'negative' preceding mammograms for screen-detected T2+ and for all ICs, using 'blinded' independent readings and case-mixes (54 T2+, 50 ICs, 170 controls) was also performed. RESULTS: T2+ cancers were observed in 168 screening participants: 48 at first screen, 67 at repeat screening and 53 ICs. The T2+ estimated proportional incidence was 68% (observed/expected = 168/247), corresponding to an estimated 32% reduction in the rate of T2+ cancers in screening participants relative to that expected without screening. Majority review classified 27.8% (15/54) of T2+ and 28% (14/50) of ICs as screening error (P = 0.84), with variable recall rates amongst radiologists (8.8-15.2%). CONCLUSIONS: T2+ review could be integrated as part of quality monitoring and potentially prove more feasible than IC review for some screening services. KEY POINTS: * Interval breast cancers, assumed as screening failures, are monitored to estimate screening performance * Large (T2+) cancers at screening may also represent failed prior screening detection * Analysis of T2+ lesions may be more feasible than assessing interval cancers * Analysis of T2+ cancers is a potential further measure of screening performance. PMID- 22200900 TI - Effect of hybrid iterative reconstruction technique on quantitative and qualitative image analysis at 256-slice prospective gating cardiac CT. AB - OBJECTIVES: To evaluate the effect of hybrid iterative reconstruction on qualitative and quantitative parameters at 256-slice cardiac CT. METHODS: Prospective cardiac CT images from 20 patients were analysed. Paired image sets were created using 3 reconstructions, i.e. filtered back projection (FBP) and moderate- and high-level iterative reconstructions. Quantitative parameters including CT-attenuation, noise, and contrast-to-noise ratio (CNR) were determined in both proximal- and distal coronary segments. Image quality was graded on a 4-point scale. RESULTS: Coronary CT attenuation values were similar for FBP, moderate- and high-level iterative reconstruction at 293 +/- 74-, 290 +/ 75-, and 283 +/- 78 Hounsfield units (HU), respectively. CNR was significantly higher with moderate- and high-level iterative reconstructions (10.9 +/- 3.5 and 18.4 +/- 6.2, respectively) than FBP (8.2 +/- 2.5) as was the visual grading of proximal vessels. Visualisation of distal vessels was better with high-level iterative reconstruction than FBP. The mean number of assessable segments among 289 segments was 245, 260, and 267 for FBP, moderate- and high-level iterative reconstruction, respectively; the difference between FBP and high-level iterative reconstruction was significant. Interobserver agreement was significantly higher for moderate- and high-level iterative reconstruction than FBP. CONCLUSIONS: Cardiac CT using hybrid iterative reconstruction yields higher CNR and better image quality than FBP. KEY POINTS: * Cardiac CT helps clinicians to assess patients with coronary artery disease * Hybrid iterative reconstruction provides improved cardiac CT image quality * Hybrid iterative reconstruction improves the number of assessable coronary segments * Hybrid iterative reconstruction improves interobserver agreement on cardiac CT. PMID- 22200901 TI - Shear wave elastography of focal salivary gland lesions: preliminary experience in a routine head and neck US clinic. AB - OBJECTIVES: To evaluate shear wave elastography (SWE) for focal lesions in major salivary glands. METHODS: Sixty lesions (49 parotid, 11 submandibular) undergoing routine ultrasound (grey scale and Doppler) also underwent SWE before US-guided needle aspiration for cytology. Quantitative indices of the shear elastic modulus (stiffness) were compared with cytological results. RESULTS: Fifty-five lesions were benign (21 pleomorphic adenomas, 18 Warthin's tumours; 16 others) and 5 malignant (2 mucoepidermoid carcinomas, 1 myoepithelial carcinoma, 1 B-cell lymphoma, 1 nodal metastasis). Shear modulus of benign lesions, median 18.3 kPa, overlapped appreciably with malignant lesions, median 13.5 kPa. However, 2 mucoepidermoid carcinomas had the highest stiffness values (81.9 kPa, 132.0 kPa). Stiffness of pleomorphic adenomas (median 22.5 kPa) was higher than Warthin's tumours (16.9 kPa) (P = 0.05 Mann-Whitney U-test). The standard deviation of stiffness values within a lesion, used as an indicator of spatial heterogeneity, was highest in mucoepidermoid cancers (median 44.2 kPa), followed by pleomorphic adenomas (median 12.4 kPa) and remaining lesions (medians 1.4-10.3 kPa). CONCLUSION: This study shows a degree of clustering of SWE indices according to pathology although it appears that SWE has suboptimal performance for ruling out malignancy, thus limiting its use in routine practice. KEY POINTS: * Shear wave elastography is a feasible technique for focal salivary gland lesions. * Elastographic artefacts aggravated by the regional anatomy may hinder this technique. * Elastographic indices vary according to pathology but there is appreciable overlap. * Overlapping indices for malignant and benign lesions limit its utility. * Pleomorphic adenomas have higher elasticity indices, i.e. are stiffer, than Warthin's tumours. PMID- 22200902 TI - Influence of trabecular microstructure and cortical index on the complexity of proximal humeral fractures. AB - OBJECTIVES: Poor bone quality increases the susceptibility to fractures of the proximal humerus. It is unclear whether local trabecular and cortical measures influence the severity of fracture patterns. The goal of this study was to assess parameters of trabecular and cortical bone properties and to compare these parameters with the severity of fractures and biomechanical testing. METHODS: Twenty patients with displaced proximal humeral fractures planned for osteosynthesis were included. Fractures were classified as either 2-part fractures or complex fractures. Bone after core drilling was harvested during surgery from the humeral head in each patient. Twenty bone cores obtained from nonpaired cadaver humeral heads served as nonfractured controls. Micro-CT (MUCT) was performed and bone volume/total volume (BV/TV), connectivity density (CD), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular spacing (Tb.Sp), and bone mineral density (BMD) were assessed. The cortical index (CI) was determined from AP plain films. Biomechanical testing was done after MUCT scanning by axially loading until failure, and ultimate strength and E modulus were recorded. RESULTS: BV/TV, BMD and CD showed moderate to strong correlations with biomechanical testing (r = 0.45-0.76, all p < 0.05). No significant differences were detected between the 2-part and complex fracture groups and controls regarding MUCT and biomechanical parameters. CI was not significantly different between the 2-part and complex fracture groups. CONCLUSIONS: In our study population local trabecular bone structure and cortical index could not predict the severity of proximal humeral fractures in the elderly. Complex fractures do not necessarily imply lower bone quality compared to simple fractures. PMID- 22200903 TI - Accuracy of measurement of femoral anteversion in femoral shaft fractures using a computer imaging software: a cadaveric study. AB - INTRODUCTION: Rotational malalignment after intramedullary nailing of femoral fractures remains an unresolved problem. Various techniques have been described to address this problem, with limited success. In this cadaveric study, we describe the determination of the femoral anteversion (FAV) angle utilizing a new imaging software program which allows us to generate and manipulate reformatted virtual images from standard DICOM (Digital Imaging and Communications in Medicine) images. MATERIALS AND METHODS: Eleven intact femoral specimens were scanned by CT before and after fracture induction in standardized fashion. The obtained DICOM image datasets were uploaded to the new software tool. From this, we obtained reformatted virtual fracture fragment images, which enabled us to reconstruct the femoral anatomy and determine FAV measurements. We then compared FAV measurements before and after fracture induction to determine if there were any statistically significant differences. RESULTS: Fracture induction generated 5 AO type A and 6 AO type B fractures. In the specimens prior to fracture induction, we were able to determine the mean FAV to be 17.94 degrees +/- 4.48 degrees . Additionally, analysis of the fractured femoral specimens revealed the new mean FAV to be 16.26 degrees +/- 4.83 degrees . Statistical analysis of these two measurement groups did not demonstrate statistical significance. When a sub-analysis was performed of the FAV measurements between the two different AO fracture types, there also were no statistically significant differences. DISCUSSION: Through new imaging software that allows us to reformat standard DICOM images and generate virtual fracture fragments, we were able to determine the appropriate FAV. We feel that this technique can potentially be integrated into the imaging algorithm for femoral shaft fractures in the future, and can potentially optimize clinical outcomes by allowing the orthopaedic surgeon to determine precisely the appropriate native FAV. PMID- 22200904 TI - Using an exon microarray to identify a global profile of gene expression and alternative splicing in K562 cells exposed to sodium valproate. AB - To investigate the effect of valproate treatment on the K562 cell line, a model for chronic myelogenous leukaemia, the growth and survival of the K562 cell line were investigated using the Annexin-V/PI dual staining method, and global profiles of gene expression and alternative splicing in K562 cells were assessed using exon microarrays. A significant increase in cell apoptosis was observed in valproate-exposed K562 cells using flow cytometry. A total of 628 transcripts were identified as being significantly differentially expressed. The number of genes demonstrating increased expression levels was greater than the number of genes demonstrating decreased expression levels (445 genes vs. 183 genes, respectively). The significant enrichment analysis of GO terms for the differentially expressed genes revealed that these genes are involved in many important biological processes such as apoptosis. Six of the genes observed to be differentially expressed that might be involved in apoptosis were selected to undergo qRT-PCR validation. In total, 198 candidates of alternative splicing variants were identified. Among them, three alternative splicing events were selected for validation, and CBLC and TBX1 were confirmed to be alternatively spliced by semi-nested PCR. In conclusion, valproate exposure facilitated cell apoptosis, altered mRNA expression and alternative splicing events in the K562 cell line. PMID- 22200906 TI - E-cadherin and 5-HT alterations in the heart of rats having undergone atropine induced toxicity. AB - Atropine-induced heart damage is associated with changes in the expression of various enzymes and proteins. The purpose of this study was to investigate atropine-induced alterations in cardiac E-cadherin and 5-hydroxytryptamine (5-HT) after atropine administration. Male Wistar rats were randomly divided into two groups: a control group and an atropine group. The atropine group intraperitoneally received atropine at a single dose of 15 mg/kg for 7 days; the controls received the same amount of saline via the same route. On Day 8, the rats were anesthetized, and a thoracotomy was performed in all animals. Immunohistochemical analysis was performed to evaluate protein expression of E cadherin and 5-HT. Sections were analyzed by digital image analysis. Cardiac protein expression of E-cadherin and 5-HT was altered after atropine-induced toxicity in the rat. The expression levels of E-cadherin and 5-HT were significantly decreased after atropine treatment, supported by IOD analysis, when compared with the control (P<0.05). The current findings indicate that such changes would be reflected in abnormal cardiac function, and these proteins may be useful for revealing the mechanisms underlying atropine-induced toxicity and may also provide various clues for further research. PMID- 22200905 TI - Molecular evolution of aminoacyl tRNA synthetase proteins in the early history of life. AB - Aminoacyl-tRNA synthetases (aaRS) consist of several families of functionally conserved proteins essential for translation and protein synthesis. Like nearly all components of the translation machinery, most aaRS families are universally distributed across cellular life, being inherited from the time of the Last Universal Common Ancestor (LUCA). However, unlike the rest of the translation machinery, aaRS have undergone numerous ancient horizontal gene transfers, with several independent events detected between domains, and some possibly involving lineages diverging before the time of LUCA. These transfers reveal the complexity of molecular evolution at this early time, and the chimeric nature of genomes within cells that gave rise to the major domains. Additionally, given the role of these protein families in defining the amino acids used for protein synthesis, sequence reconstruction of their pre-LUCA ancestors can reveal the evolutionary processes at work in the origin of the genetic code. In particular, sequence reconstructions of the paralog ancestors of isoleucyl- and valyl- RS provide strong empirical evidence that at least for this divergence, the genetic code did not co-evolve with the aaRSs; rather, both amino acids were already part of the genetic code before their cognate aaRSs diverged from their common ancestor. The implications of this observation for the early evolution of RNA-directed protein biosynthesis are discussed. PMID- 22200907 TI - Control of M184V HIV-1 mutants by CD8 T-cell responses. AB - Antiretroviral treatment directed against HIV is highly effective, yet limited by drug resistance mutations. We hypothesized that CD8 T cells targeting drug resistant HIV mutants are able to inhibit viral replication in the setting of a failing therapeutic regimen. We evaluated CD8 T-cell responses and mapped epitopes in HIV-infected patients by interferon-gamma Elispot and intracellular cytokine staining. Autologous virus was sequenced by RT-PCR. Viral replication inhibition assays were performed using M184V mutant virus and CD8 T cell lines. CD8 T-cell responses toward the regions of viral drug resistance mutations in Pol are frequent. Focusing on the M184V mutation, A*02:01-YQYVDDLYV and A*02:01 VIYQYVDDLYV were identified as optimal epitopes for the majority of study subjects. Viral replication of M184V HIV mutants was inhibited by CD8 T cell lines in vitro. In case of a failing lamivudine/emtricitabine containing regimen, individuals with a CD8 T-cell response toward M184V had a significant lower viral load than those without a CD8 response (p = 0.005). Two study subjects even achieved an undetectable viral load. Our data suggest that control of M184V mutant virus by CD8 T-cell responses is possible in vitro and in vivo. This control has important implications for therapeutic vaccination strategies. PMID- 22200908 TI - Mutational patterns in the frameshift-regulating site of HIV-1 selected by protease inhibitors. AB - Sustained suppression of viral replication in HIV-1 infected patients is especially hampered by the emergence of HIV-1 drug resistance. The mechanisms of drug resistance mainly involve mutations directly altering the interaction of viral enzymes and inhibitors. However, protease inhibitors do not only select for mutations in the protease but also for mutations in the precursor Gag and Pol proteins. In this study, we analysed the frameshift-regulating site of HIV-1 subtype B isolates, which also encodes for Gag and Pol proteins, classified as either treatment-naive (TN) or protease inhibitor resistant (PI-R). HIV-1 Gag cleavage site mutations (G435E, K436N, I437V, L449F/V) especially correlated with protease inhibitor resistance mutations, but also Pol cleavage site mutations (D05G, D05S) could be assigned to specific protease resistance profiles. Additionally, two Gag non-cleavage site mutations (S440F, H441P) were observed more often in HIV-1 isolates carrying protease resistance mutations. However, in dual luciferase assays, the frameshift efficiencies of specific clones did not reveal any effect from these mutations. Nevertheless, two patterns of mutations modestly increased the frameshift rates in vitro, but were not specifically accumulating in PI-resistant HIV-1 isolates. In summary, HIV-1 Gag cleavage site mutations were dominantly selected in PI-resistant HIV-1 isolates but also Pol cleavage site mutations influenced resistance profiles in the protease. Additionally, Gag non-cleavage site mutations accumulated in PI-resistant HIV-1 isolates, but were not related to an increased frameshift efficiency. PMID- 22200909 TI - Does Apolipoprotein E genotype affect cardiovascular risk in subjects with acromegaly? AB - Acromegaly is a syndrome that results when the pituitary gland produces excess growth hormone after epiphyseal closure at puberty. Usually, subjects with acromegaly exhibit a 2- to 3-fold higher mortality rate from diseases that are associated with cardiovascular complications when compared to the normal population. In this study, we therefore aimed to evaluate whether a well established cardiovascular risk factor, the Apolipoprotein E (Apo E) genotype, contributes to increased risk of cardiovascular complications in subjects with acromegaly. A total of 102 unrelated acromegaly subjects were prospectively included into this case-control association study and constituted our study group. The study group was comparable by age and gender with 200 unrelated healthy subjects constituting our control group. Genomic DNA was isolated from the peripheral blood leukocytes of all subjects and Apo E genotype (codon 112/158) was assessed by melting temperature analyses after using a real-time PCR protocol. The Apolipoprotein E4 allele was found at a significantly higher frequency in the study group when compared with the control group (P = 0.032). Subjects with the E2 allele, on the other hand, had significantly increased values in body mass index (P = 0.004), waist circumference (P = 0.001), C reactive protein (CRP) (P < 0.001), and left-side carotid intima media thickness (P = 0.025). The Apolipoprotein E2 genotype might contribute to increased risk of cardiovascular complications in subjects with acromegaly since it is concurrently present with other cardiovascular risk factors such as the left-side carotid intima media thickness and CRP. PMID- 22200910 TI - A hypothesis on the origin of genetic heterozygosity in diploids and triploids in Japanese Cayratia japonica species complex (Vitaceae). AB - We previously reported the occurrence of triploid strains in Japanese populations of Cayratia japonica (Thunb.) Gagnep. Interestingly, the triploid and most diploid strains had variably reduced pollen fertility. Two questions emerged from this earlier work: (1) How do triploids arise, and are they allotriploids or autotriploids? and (2) Why is there low pollen fertility in some diploid plants? We used a molecular genetic approach to determine the phylogenetic origins of triploids in C. japonica and the closely related species Cayratia tenuifolia (Wight & Arn.) Gagnep. In our analysis, we compared the sequences of the nuclear single-copy genes LEAFY and ASYMMETRIC LEAVES1. As a result, most triploids and diploids were heterozygous for the loci examined; the triploid genome shared an allele with the diploid genome, but other alleles differed between the ploidies. Therefore, Japanese populations of C. japonica and C. tenuifolia almost certainly arose from repeated hybridization events among genetically differentiated strains. Using our sequence data, we discuss possible scenarios accounting for the occurrence of triploids in the two species of Cayratia. PMID- 22200911 TI - Stroke aetiology and predictors of outcome in patients with heart failure and acute stroke: a 10-year follow-up study. AB - AIMS: The aim of this study was to investigate stroke aetiology and assess the predictors of early and late outcome in patients with heart failure (HF) and acute stroke. METHODS AND RESULTS: A total of 2904 patients, admitted between 1993 and 2010, were regularly followed up at months 1, 3, and 6, and yearly thereafter up to 10 years. There were 283 (9.7%) stroke patients with HF; atrial fibrillation (AF) was present in 144 (50.9%) of them. Stroke aetiology in patients with HF and AF was mainly cardioembolism (82%) regardless of HF aetiology. In contrast, in the 139 non-AF patients with HF, the stroke mechanism was associated with the aetiology of HF: valvular heart disease and dilated cardiomyopathy were related to cardioembolism in 60% and 66.7% of patients, respectively, whereas HF due to coronary artery disease or hypertension was associated with atherosclerotic and lacunar stroke in 40.8% and 61.5%, respectively. In the overall population, HF was an independent predictor of 10 year mortality [hazard ratio = 1.54, 95% confidence interval (CI) 1.29-1.83; P < 0.001]. Probability of 10-year survival was 19.4% (95% CI 14.5-23.5) for HF patients and 44.1% (95% CI 41.4-46.8) for non-HF patients (P < 0.0001). Ten-year mortality in HF patients was associated with functional class of HF, age, diabetes, stroke severity, and in-hospital aspirin use. The presence of AF in HF stroke patients did not influence 10-year survival and composite cardiovascular events (P = 0.429 and P = 0.406, respectively). CONCLUSIONS: In patients with HF, stroke aetiology is influenced by the presence of AF and the underlying cause of HF. Early and late stroke outcome is associated with HF severity but not with the presence of AF. PMID- 22200912 TI - Distractor strength and selective attention in picture-naming performance. AB - Whereas it has long been assumed that competition plays a role in lexical selection in word production (e.g., Levelt, Roelofs, & Meyer, 1999), recently Finkbeiner and Caramazza (2006) argued against the competition assumption on the basis of their observation that visible distractors yield semantic interference in picture naming, whereas masked distractors yield semantic facilitation. We examined an alternative account of these findings that preserves the competition assumption. According to this account, the interference and facilitation effects of distractor words reflect whether or not distractors are strong enough to exceed a threshold for entering the competition process. We report two experiments in which distractor strength was manipulated by means of coactivation and visibility. Naming performance was assessed in terms of mean response time (RT) and RT distributions. In Experiment 1, with low coactivation, semantic facilitation was obtained from clearly visible distractors, whereas poorly visible distractors yielded no semantic effect. In Experiment 2, with high coactivation, semantic interference was obtained from both clearly and poorly visible distractors. These findings support the competition threshold account of the polarity of semantic effects in naming. PMID- 22200913 TI - Synergistic antitumor interactions between gemcitabine and clofarabine in human pancreatic cancer cell lines. AB - Pancreatic cancer is a highly malignant disease, with a 5-year survival rate of less than 4%. Thus, new therapies for this deadly disease are urgently required. In this study, we sought to investigate whether combination treatments with gemcitabine and clofarabine result in synergistic cytotoxic effects against human pancreatic cancer cells. The type and extent of cytotoxic interactions between gemcitabine and clofarabine in three human pancreatic cancer cell lines were determined by MTT assays and standard isobologram analysis. The effects of the two agents on cell cycle distribution and apoptosis were determined by flow cytometry. Clofarabine significantly and synergistically enhanced gemcitabine cytotoxicities in all of the cell lines tested. This was accompanied by a nearly complete S phase arrest and synergistic induction of apoptosis (cooperativity index = 0.67). Combined treatment of gemcitabine and clofarabine resulted in synergistic cytotoxicities in vitro. Our results strongly suggest potential clinical benefits for using this drug combination to treat pancreatic cancer patients. PMID- 22200914 TI - Presumed occult globe rupture resulting in sympathetic ophthalmia. AB - INTRODUCTION: Sympathetic ophthalmia (SO) is an uncommon bilateral granulomatous panuveitis following uveal trauma to one eye. We present an unusual case of SO which resulted from presumed occult globe rupture following blunt trauma; and highlight the association of trauma and acquired external ocular pigmentation as a possible predictor for SO. CASE REPORT: Five weeks following blunt trauma to the left eye (OS), a 30-year-old patient presented complaining of spontaneous blurred vision (4/60) in the right eye (OD). In the OD, there was anterior chamber and vitreous inflammation (3+), multiple areas of serous retinal detachments, Dalen Fuchs spots, and optic disk swelling. In the OS, there was iridodialysis, post-traumatic acquired external ocular pigmentation suggestive of occult globe rupture. This was diagnosed as SO and treated with systemic steroids and a steroid sparing agent; which resulted in resolution of the inflammation with improvement in the visual acuity. CONCLUSION: Sympathetic ophthalmia has been reported to occur following penetrating eye injury secondary to trauma and surgery, and also secondary to non-penetrating eye trauma. This case reports SO occurring after presumed occult globe rupture; and reinforces the association between acquired external ocular pigmentation and SO in the context of trauma. PMID- 22200915 TI - Distribution of estimated glomerular filtration rate (eGFR) values in patients receiving contrast-enhanced magnetic resonance imaging. AB - PURPOSE: The aim of this study was to elucidate the distribution of estimated glomerular filtration rate (eGFR) values in patients who underwent gadolinium based contrast agent (GBCA)-enhanced magnetic resonance imaging (MRI) at different types of hospitals. MATERIALS AND METHODS: We retrospectively studied 2,550 patients who underwent MRI at five institutions. We recorded the date and value of each patient's eGFR test. The distribution of eGFR values was compared with that in the general Japanese population. RESULTS: A total of 84.3% of patients had their eGFRs evaluated before GBCA-enhanced MRI. Of these, 84.7% were evaluated within 3 months before the GBCA-enhanced MRI, and 1.3% were evaluated on the day of the GBCA-enhanced MRI. A total of 87.2% of patients tested had an eGFR of >=60 ml/min/1.73 m(2); 12.8% had an eGFR of <60 and >=30 ml/min/1.73 m(2), and no patients had an eGFR of <30 ml/min/1.73 m(2). CONCLUSION: The rate of renal function evaluation differed among hospitals. The prevalence of low eGFR values was greater in Juntendo Tokyo Koto Geriatric Medical Center than in the other hospitals, and the prevalence of low eGFR values was greater in patients who underwent GBCA-enhanced MRI than in the general Japanese population. PMID- 22200916 TI - Radiographic and CT features of radiation-induced organizing pneumonia syndrome after breast-conserving therapy. AB - PURPOSE: To investigate radiographic and computed tomography features of radiation-induced organizing pneumonia syndrome after breast-conserving surgery. MATERIALS AND METHODS: The appearances and distribution of lung parenchymal abnormalities were retrospectively analyzed on chest radiographs (n = 12) and computed tomography scan images (n = 10) of 12 women (range 37-78 years, mean 55.8 years) with radiation-induced organizing pneumonia syndrome after breast conserving surgery. RESULTS: The principal radiographic feature was an airspace filling pattern in all patients that involved the middle and lower lung zones in 10 of the 12 patients. Multi-focal lesions manifesting airspace consolidation surrounded by ground-glass opacities were the predominant CT finding in all 10 of these patients. The main lesion was predominantly located in the lung periphery in nine patients and contiguously extended to the central portion of the lung in seven patients. Frequent ancillary findings were airway dilation within the consolidation and lobar volume loss in nine and eight patients, respectively. All had solitary (6/10) or multifocal (4/10) distant lung opacities, mostly consistent with the finding of ground-glass opacities (9/10). Migration of the lung disease was observed in ten patients on subsequent radiographs. CONCLUSION: The cardinal radiologic feature of this syndrome is airspace consolidation surrounded by ground-glass opacification with airway dilation and volume loss, involving primarily the irradiated, subpleural area, along with distant opacities. PMID- 22200917 TI - Comparison of CT findings of biliary tract changes with autoimmune pancreatitis and extrahepatic bile duct cholangiocarcinoma. AB - PURPOSE: To retrospectively evaluate criteria for differentiating biliary tract changes in autoimmune pancreatitis (AIP-BTC) from extrahepatic cholangiocarcinoma (ECCA) based on CT findings and to determine predictors for differentiation between the two disorders. MATERIALS AND METHODS: CT findings of 22 patients with AIP-BTC and 45 patients with ECCA, both with positive CT findings in the biliary system, were retrospectively assessed. The images were assessed for presence of biliary obstruction, diameter of the maximally dilated biliary duct, maximum thickness of the involved duct, presence of masses inside or around the involved ducts, lengths of the biliary lesions, concentricity of wall thickening, multifocality of the lesion, and degree of lesion enhancement. RESULTS: Compared with AIP-BTC, ECCA was significantly more frequently associated with biliary obstruction (p = 0.0037), shorter lengths of the biliary lesions (p = 0.0036), and masses (p < 0.001). No significant differences were found for other items. CONCLUSION: Presence of obstructive dilatation of the bile ducts and intraluminal or peri-ductal masses and length of the thickened wall may help differentiate between AIP-BTC and ECCA. PMID- 22200918 TI - Molecular detection, quantification, and diversity evaluation of microalgae. AB - This study reviews the available molecular methods and new high-throughput technologies for their practical use in the molecular detection, quantification, and diversity assessment of microalgae. Molecular methods applied to other groups of organisms can be adopted for microalgal studies because they generally detect universal biomolecules, such as nucleic acids or proteins. These methods are primarily related to species detection and discrimination among various microalgae. Among current molecular methods, some molecular tools are highly valuable for small-scale detection [e.g., single-cell polymerase chain reaction (PCR), quantitative real-time PCR (qPCR), and biosensors], whereas others are more useful for large-scale, high-throughput detection [e.g., terminal restriction length polymorphism, isothermal nucleic acid sequence-based amplification, loop-mediated isothermal amplification, microarray, and next generation sequencing (NGS) techniques]. Each molecular technique has its own strengths in detecting microalgae, but they may sometimes have limitations in terms of detection of other organisms. Among current technologies, qPCR may be considered the best method for molecular quantification of microalgae. Metagenomic microalgal diversity can easily be achieved by 454 pyrosequencing rather than by the clone library method. Current NGS, third and fourth generation technologies pave the way for the high-throughput detection and quantification of microalgal diversity, and have significant potential for future use in field monitoring. PMID- 22200919 TI - Recombination suppression at the dominant Rhg1/Rfs2 locus underlying soybean resistance to the cyst nematode. AB - Host resistance to "yellow dwarf" or "moonlight" disease cause by any population (Hg type) of Heterodera glycines I., the soybean cyst nematode (SCN), requires a functional allele at rhg1. The host resistance encoded appears to mimic an apoptotic response in the giant cells formed at the nematode feeding site about 24-48 h after nematode feeding commences. Little is known about how the host response to infection is mediated but a linked set of 3 genes has been identified within the rhg1 locus. This study aimed to identify the role of the genes within the locus that includes a receptor-like kinase (RLK), a laccase and an ion antiporter. Used were near isogeneic lines (NILs) that contrasted at their rhg1 alleles, gene-based markers, and a new Hg type 0 and new recombination events. A syntenic gene cluster on Lg B1 was found. The effectiveness of SNP probes from the RLK for distinguishing homolog sequence variants on LgB1 from alleles at the rhg1 locus on LgG was shown. The resistant allele of the rhg1 locus was shown to be dominant in NILs. None of the recombination events were within the cluster of the three candidate genes. Finally, rhg1 was shown to reduce the plant root development. A model for rhg1 as a dominant multi-gene resistance locus based on the developmental control was inferred. PMID- 22200920 TI - Carbohydrate-protein interactions and their biosensing applications. AB - Carbohydrate recognition is clearly present throughout nature, playing a major role in the initial attachment of one biological entity to another. The important question is whether these prevalent interactions could provide a real suitable alternative to the use of antibodies or nucleic acid for detection and identification. Currently, examples of carbohydrates being employed in biological detection systems are limited. The challenges of using carbohydrate recognition for detection mainly come from the weak affinity of carbohydrate-protein interactions, the lack of versatile carbohydrate scaffolds with well-defined structures, and the less developed high-information-content, real-time, and label free assay technology. In this review, we focus on discussing the characteristics of carbohydrate-protein interactions in nature and the methods for carbohydrate immobilization based on surface coupling chemistry in terms of their general applicability for developing carbohydrate- and lectin-based label-free sensors. Furthermore, examples of innovative design of multivalent carbohydrate-protein interactions for sensor applications are given. We limit our review to show the feasibility of carbohydrate and lectin as recognition elements for label-free sensor development in several representative cases to formulate a flexible platform for their use as recognition elements for real-world biosensor applications. PMID- 22200922 TI - DESI-MS2: a rapid and innovative method for trace analysis of six cytostatic drugs in health care setting. AB - With the aim of establishing exposure levels for hospital personnel preparing and administering cytostatic drugs (CDs), here, we present an innovative screening method based on the use of the desorption electrospray ionization (DESI) interface coupled with a hybrid quadrupole linear ion trap mass spectrometer. A rapid, simple, and sensitive procedure was developed for the simultaneous surface monitoring of cyclophosphamide, dacarbazine, methotrexate, vincristine, gemcitabine, and cytarabine. Since analytes were in the solid state, a novel approach based on the use of passive samplers was combined with the direct analysis of wipes. A PTFE-printed glass slide was used as a passive sampler, while hydrophobic centers of Swiffer(r) cloths were judged extremely efficient as wipe samplers. After the sampling period, the CD collectors were directly processed with the DESI-MS system without any further treatment. MS/MS confirmatory analysis was conducted using selected reaction monitoring in the positive ion mode and detection limits were evaluated. Values were at the picograms per square millimeter levels on the passive collector and at the picograms per square centimeter levels for the wipe ones. Direct determination on solid-state samples combined with mass spectrometry selectivity provided a powerful tool so far unapplied to occupational hygiene. PMID- 22200921 TI - Functional characterisation of metal(loid) processes in planta through the integration of synchrotron techniques and plant molecular biology. AB - Functional characterisation of the genes regulating metal(loid) homeostasis in plants is a major focus for phytoremediation, crop biofortification and food security research. Recent advances in X-ray focussing optics and fluorescence detection have greatly improved the potential to use synchrotron techniques in plant science research. With use of methods such as micro X-ray fluorescence mapping, micro computed tomography and micro X-ray absorption near edge spectroscopy, metal(loids) can be imaged in vivo in hydrated plant tissues at submicron resolution, and laterally resolved metal(loid) speciation can also be determined under physiologically relevant conditions. This article focuses on the benefits of combining molecular biology and synchrotron-based techniques. By using molecular techniques to probe the location of gene expression and protein production in combination with laterally resolved synchrotron techniques, one can effectively and efficiently assign functional information to specific genes. A review of the state of the art in this field is presented, together with examples as to how synchrotron-based methods can be combined with molecular techniques to facilitate functional characterisation of genes in planta. The article concludes with a summary of the technical challenges still remaining for synchrotron-based hard X-ray plant science research, particularly those relating to subcellular level research. PMID- 22200923 TI - Lactosylated casein phosphopeptides as specific indicators of heated milks. AB - Casein phosphopeptides (CPP) were identified in small amounts in milks heated at various intensities by using matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry. CPP selectively concentrated on hydroxyapatite (HA) were regenerated using phosphoric acid mixed in the matrix. Unphosphorylated peptides not retained by HA were removed by buffer washing. This procedure enhanced the MALDI signals of CPP that are ordinarily suppressed by the co occurrence of unphosphorylated peptides. CPP, belonging to the beta-casein (CN) family, i.e., (f1-29) 4P, (f1-28) 4P, and (f1-27) 4P, and the alpha(s2)-CN family, i.e., (f1-21) 4P and (f1-24) 4P, were observed in liquid and powder milk. The lactosylated counterparts were specific to intensely heated milks, but absent in raw and thermized/pasteurized milk. Most CPP with C-terminal lysines probably arose from the activity of plasmin; an enzyme most active in casein hydrolysis. A CPP analogue was used as the internal standard. The raw milk signature peptide beta-CN (f1-28) 4P constituted ~4.3% of the total beta-CN. Small amounts of lactosylated peptides, which varied with heat treatment intensity, were detected in the milk samples. The limit of detection of ultra-high-temperature milk adjunction in raw or pasteurized milk was ~10%. PMID- 22200924 TI - Connecting simulated, bioanalytical, and molecular docking data on the stereoselective binding of (+/-)-catechin to human serum albumin. AB - The stereoselective binding of the frequently ingested nutraceutical (+/-) catechin, with demonstrated differential biological activity between enantiomers, to human serum albumin (HSA), with the largest complexation and enantioselectivity potential among the plasmatic proteins, is studied by combining simulations to optimize the experimental design, robust in vitro electrokinetic chromatographic data, and molecular docking-chiral recognition estimates. Methodological and mathematical drawbacks in previous reports on (+/-) catechin-HSA are detected and eliminated. Recent and novel direct equations extracted from the classical interaction model allows advantageous univariate mathematical data treatment, providing the first evidence of quantitative (+/-) catechin-HSA enantioselectivity. Also, the binding site in HSA of the enantiomers is approached, and both the experimental enantioselectivity and the main binding site information are contrasted with a molecular docking approach. PMID- 22200925 TI - De novo analysis of protein N-terminal sequence utilizing MALDI signal enhancing derivatization with Br signature. AB - De novo analysis of protein N-terminal sequence is important for identification of N-terminal proteolytic processing such as N-terminal methionine or signal peptide removal, or for the genome annotation of uncharacterized proteins. We introduce a de novo sequencing method of protein N terminus utilizing matrix assisted laser desorption/ionization (MALDI) signal enhancing picolinamidination with bromine isotopic tag incorporated to the N terminus. The doublet signature of bromine in the tandem mass (MS/MS) spectrum distinguished N-terminal ion series from C-terminal ion series, facilitating de novo N-terminal sequencing of protein. The dual advantage of MALDI signal enhancement by the basic picolinamidine and b-ion selection aided by Br signature is demonstrated using a variety of peptides. The N-terminal sequences of myoglobin and hemoglobin as model proteins were determined by incorporating the Br tag to the N terminus of the proteins and obtaining a series of b-ions with Br signature by MS/MS analysis after chymotryptic digestion of the tagged proteins. The N-terminal peptide was selected for MS/MS analysis from the chymotryptic digest based on the Br signature in the mass spectrum. Identification of phosphorylation site as well as N-terminal sequencing of a phosphopeptide was straightforward. PMID- 22200926 TI - TOF-SIMS imaging of halide/thiocyanate anions and hydrogen sulfide in mouse kidney sections using silver-deposited plates. AB - In vivo imaging of reactive small molecule metabolites with high spatial resolution and specificity could give clues to understanding pathophysiology of various diseases. We herein applied time of flight-secondary ion mass spectrometry (TOF-SIMS) to newly developed silver-deposited plates that were stamped on mouse tissues, and succeeded in visualization of halide (Cl(-), Br(-), and I(-)) and pseudohalide thiocyanate (SCN(-)) anions, a class of substrates for neutrophils/eosinophil peroxidases to produce hypohalous acids (HOX/OX(-) mixture; X: (pseudo)halides), as well as hydrogen sulfide (H(2)S). Forty micrometer frozen mouse kidney sections on cover glasses were attached to 37 degrees C preheated silver-deposited plates and incubated at -10 degrees C for 1 h. After sputter cleaning to remove surface contaminants, the plates were analyzed by TOF-SIMS to identify distribution of Br(-), AgBr(2)(-), I(-), AgI(2)( ), SCN(-), as well as S(2-) and AgS(-) as products of tissue-derived H(2)S. Br( ), AgBr(2)(-), I(-), and SCN(-) anions were mainly distributed in core regions including the inner medulla and inner stripe of the outer medulla (except for I( )), rather than outer regions such as the cortex and outer stripe of the outer medulla. AgI(2)(-) anion was spread over the whole kidney, although its levels were relatively low. In contrast, S(2-) and AgS(-) anions were mainly present in the outer regions. To our knowledge, this is the first imaging study to reveal the distribution of (pseudo)halides and H(2)S in animal tissue sections. PMID- 22200927 TI - A new methodology for simultaneous quantification of total-Abeta, Abetax-38, Abetax-40, and Abetax-42 by column-switching LC/MS/MS. AB - This article details the development of a novel method that overcomes the drawbacks of sandwich ELISA (sELISA) and allows reliable evaluation of simultaneous quantification of the amyloid (Abeta)-peptides, total-Abeta, Abetax 38, Abetax-40, and Abetax-42, in rat brain by optimized sample purification and column-switching liquid chromatographic-tandem mass spectrometry (LC/MS/MS). This method provides accurate analyses of total-Abeta, Abetax-38, Abetax-40, and Abetax-42 with a linear calibration range between 0.05 and 45 ng/mL. Verification for accuracy and precision of biological samples were determined by a standard addition and recovery test, spiked with synthetic Abeta1-38, Abeta1-40, and Abeta1-42 into the rat brain homogenate. This method showed <20% relative error and relative standard deviation, indicating high reproducibility and reliability. The brain concentrations of total-Abeta, Abetax-38, Abetax-40, and Abetax-42 after oral administration of flurbiprofen in rats were measured by this method. Abetax-42 concentrations (4.57 +/- 0.69 ng/g) in rats administered flurbiprofen were lower than those in untreated rats (6.48 +/- 0.93 ng/g). This was consistent with several reports demonstrating that NSAIDs reduced the generation of Abeta. We report here a method that allows not only the quantification of specific molecular species of Abeta but also simultaneous quantification of total-Abeta, Abetax-38, Abetax-40, and Abetax-42, thus overcoming the drawbacks of sELISA. PMID- 22200928 TI - Highly sensitive detection of microRNA by chemiluminescence based on enzymatic polymerization. AB - We have developed a new methodology for miRNA assay using chemiluminescence imaging by poly(U) polymerase catalyzed miRNA polymerization. This method is very sensitive with a 50 fM limit of detection, which is comparable to or better than current assay methods. Multiplex detection for miRNA can be easily realized by introducing different capture probes onto the biosensor array, which will make it highly versatile for various research purposes. PMID- 22200929 TI - Rapid identification of microorganisms by mass spectrometry: improved performance by incorporation of in-house spectral data into a commercial database. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is increasingly used as a microbial diagnostic method for species identification of pathogens. However, MALDI-TOF identification of bacteria at the species level remains unsatisfactory, with the major problem being an incomplete database that still needs refinement and expansion. Augmentation of the original MALDI BioTyper 2.0 (Bruker) database by incorporating mass spectra obtained in house from clinical isolates may increase the identification rate at the species level. We conducted a prospective study to assess whether the augmented database can improve the performance of MALDI-TOF MS for routine identification of species. Cluster analyses revealed distinct differences in MS spectral profiles of clinical isolates obtained in our hospital and those of ATCC strains in the Bruker database. In the first part of the study, which was performed over 3 weeks, 259 bacterial isolates were subjected to analysis by MALDI-TOF MS, and MS spectra of 229 successfully identified isolates (49 species) were incorporated into the original database to give the augmented Bruker-Chiba database. In a second separate analysis, the concordance of identification of 498 clinical isolates of the 49 species with conventional methods was 87.1% (434/498) with the commercial Bruker database and 98.0% (488/498) using the Bruker-Chiba database. These results indicate that refinement of a commercial database can be achieved relatively easy and effectively by incorporating MS spectra of clinical isolates obtained in a clinical laboratory. PMID- 22200930 TI - Advances in cellular therapy: 6th International Symposium on the clinical use of cellular products, March 24 and 25, 2011, Erlangen, Germany. PMID- 22200931 TI - Hemodynamic response, arrhythmic risk, and overall safety of regadenoson as a pharmacologic stress agent for myocardial perfusion imaging in chronic obstructive pulmonary disease and bronchial asthma patients. AB - Regadenoson (REG) is a A2a receptor selective pharmacologic SPECT imaging agent. Its safety in unselected chronic obstructive pulmonary disease (COPD) or asthma (AM) undergoing SPECT imaging has not been well evaluated. We retrospectively identified 228 patients (COPD n = 126 and AM n = 102, Grp 1) undergoing REG SPECT from Jan to Nov 2009 and compared to 1,142 patients without COPD and AM (control, Grp 2). A standard 400 MUg REG bolus was used and gated Tc-99 m tetrofosmin SPECT done. Patient demographics, REG SPECT data, side effects, arrhythmia occurrences, and any exacerbation of COPD or AM leading to treatment, hospitalization or death were evaluated. The side effect profile of Grp 1 was also compared to a historical cohort who underwent intravenous dipyridamole thallium-201 imaging and adenosine SPECT. Both groups were comparable with regards to baseline characteristics. There was 0% incidence of clinical exacerbation of COPD or AM after REG. COPD patients had more non-significant arrhythmias (58.3% vs. Grp 2, 43%, P = 0.004). There was 0% incidence of any atrio-ventricular block and only 2 instances of brief supraventricular tachycardia. When compared to the historical cohort of COPD who underwent IV dipyridamole thallium imaging, COPD in Grp 1, had more dyspnea and flushing and when compared to COPD/AM patients who underwent adenosine SPECT, Grp 1 pts had more of flushing and headache (24.9% vs. 2.8%, P = <0.001) but less of bronchospasm (1.3% vs. 6.9%, P = 0.022) and AV block (0% vs. 4.2%, P = 0.014). REG SPECT can be safely performed in COPD and AM population. PMID- 22200932 TI - Determination of acute vascular injury and edema in porcine carotid arteries by T2 weighted cardiovascular magnetic resonance. AB - Inflammation plays an essential role for destabilization and rupture of carotid atherosclerotic plaques causing embolic ischemic stroke. Inflammation of the vessel wall may result in the formation of edema. This study investigated whether edema in the carotid artery wall induced by acute balloon injury could be detected by cardiovascular magnetic resonance (CMR) using a T2-weighted short-tau inversion recovery sequence (T2-STIR). Edema was induced unilaterally by balloon injury in the carotid artery of six pigs. Four to nine days (average six) post injury, the carotid arteries were assessed by T2-STIR and multi-contrast weighted sequences. CMR images were matched to histopathology, validated against Evans blue, and correlated with the amount of fibrinogen in the arterial wall used as an edema marker. T2-STIR images showed that the carotid signal intensity (SI) divided by the sternocleid muscle SI of the injured carotid artery was on average 223% (P = 0.03) higher than that of the uninjured carotid artery. Using a threshold value of 4SD, T2-STIR detected edema in the vessel wall (i.e., hyperintense signal intensity) with a sensitivity of 100% and a specificity of 75%. Agreement was observed between carotid artery wall hyperintense signal intensity and Evans blue uptake (X(2) = 17.1, P < 0.001). The relative signal intensity correlated in a linear fashion with the amount of fibrinogen detected by histopathology (rho = 0.9, P < 0.001). None of the multi-contrast weighted sequences detected edema in the carotid artery with reasonable sensitivity or specificity. T2-STIR CMR allowed carotid artery wall edema detection and may therefore be a useful non-invasive diagnostic tool for determination of inflammatory activity in the carotid artery wall. PMID- 22200933 TI - L-Arginine improves multiple physiological parameters in mice exposed to diet induced metabolic disturbances. AB - L-Arginine (L-Arg) is a conditionally essential amino acid and a natural constituent of dietary proteins. Studies in obese rats and type 2 diabetic humans have indicated that dietary supplementation with L-Arg can diminish gain in white adipose tissue (WAT) and improve insulin sensitivity. However, the effects of L Arg on glucose homeostasis, body composition and energy metabolism remain unclear. In addition, no studies have, to our knowledge, examined whether L-Arg has beneficial effects as a dietary supplement in the mouse model. In the present study, we investigated the effects of L-Arg supplementation to male C57BL/6 mice on an array of physiological parameters. L-Arg supplemented mice were maintained on a low-protein diet and body composition, appetite regulation, glucose tolerance, insulin sensitivity and energy expenditure were evaluated. A significant reduction in epididymal WAT was observed in L-Arg supplemented mice compared with mice fed an isocaloric control diet. Surprisingly, the L-Arg supplemented animals were hyperphagic corresponding to a highly significant decrease in feed efficiency, as body weight developed in a similar pattern in both experimental groups. Glucose homeostasis experiments revealed a major effect of L-Arg supplementation on glucose tolerance and insulin sensitivity, interestingly, independent of a parallel regulation in whole-body adiposity. Increased L-Arg ingestion also raised energy expenditure; however, no concurrent effect on locomotor activity, substrate metabolism or expression of uncoupling proteins (UCP1 and UCP2) in adipose tissues was displayed. In conclusion, dietary L-Arg supplementation substantially affects an array of metabolic-associated parameters including a reduction in WAT, hyperphagia, improved insulin sensitivity and increased energy expenditure in mice fed a low-protein diet. PMID- 22200934 TI - The association between walking ability and falls in elderly Japanese living in the community using a path analysis. AB - The aim of this study is to investigate the association between falls and physiological factors primarilly the toe-gap force and the Good Walker's Index using a path analysis. Three hundred and sixty-two (362) elderly people, over 65 years of age, undertook five types of walking ability and physiological tests, The Toe-gap Force and the Good Walker's Index, which consists of 10-m walking time, Maximal Step Length (MSL), 40/20 cm step test, and tandem gait. Questions concerning demographic characteristics, instrumental activities of daily living (IADL), subjective well-being, long-term care needs, and characteristics of falls were asked. Ninety participants (24.9%) reported one or more falls within the past year. The results showed that a lower toe-gap force and a lower good walker's Index score were significantly associated with falls. Fallers scored worse on Toe-gap force R, 10-m walking time, and Maximal Step strength. The Good Walker's Index was significantly associated with all test measures. The path analysis model revealed the association between the Good Walker's Index and falls. Toe-gap force and the Good Walker's Index can serve as an effective predictive factor for older people who are living independently in the community. This study provided a model of the inter-relationships among physiological factors such as the Good walker's Index, Toe-gap force and falls, as well as vision and falls. PMID- 22200935 TI - Evaluation of bladder capacity in Korean children younger than 24 months: a nationwide multicenter study. AB - PURPOSE: Bladder capacity is an important factor in the diagnosis and treatment of children with voiding dysfunction. The purpose of this study was to define the normal maximal voided volume formula in Korean children younger than 2 years. METHODS: We measured the bladder capacities of 151 Korean children between 0 and 24 months of age (83 boys and 68 girls) who did not have clinical voiding dysfunction. The maximal voided volume was determined in all subjects using a 2 day frequency volume chart with a four-hour voiding observation. The largest voided volume for each patient was considered to be the maximal voided volume. Statistical analyses were carried out using linear regression analysis. RESULTS: The maximal voided volume increased with age and weight (P = 0.0001). There was no significant difference between males and females (P = 0.771). A formula that approximates bladder capacity with respect to age is the following: bladder capacity (ml) = [1.6 * age (months)] + 45 (t = 8.757, P = 0.0001). A formula that approximates bladder capacity with respect to weight is the following: bladder capacity (ml) = [4.1 * weight (kg)] + 28 (t = 10.152, P = 0.0001). CONCLUSIONS: These formulas may be useful for the diagnosis of abnormal bladder capacity and the evaluation of voiding dysfunction in Korean children younger than 24 months. PMID- 22200936 TI - Accuracy of multi-detector computed tomography (MDCT) in staging of renal cell carcinoma (RCC): analysis of risk factors for mis-staging and its impact on surgical intervention. AB - OBJECTIVES: To assess the accuracy of multi-detector computed tomography (MDCT) in preoperative staging of renal cell carcinoma (RCC) and to detect the possible risk factors for mis-staging. In addition, the impact of radiological mis-staging on surgical decision and operative procedures was evaluated. MATERIALS AND METHODS: Data files of 693 patients, who underwent either radical or partial nephrectomy after preoperative staging by MDCT between January 2003 and December 2010, were retrospectively reviewed. Radiological data were compared to surgical and histopathological findings. Patients were classified according to 2009 TNM staging classification. Diagnostic accuracy per stage and its impact on surgical intervention were evaluated. RESULTS: The overall accuracy was 64.5%, and over stage was detected in 29.5% and under-stage in 6%. Sensitivity and specificity were highest in stage T3b (85 and 99.5%, respectively), while T4 showed the lowest sensitivity and PPV (57 and 45%). Degree of agreement with pathological staging was substantial in T1 (kappa = 0.7), fair in T2 (kappa = 0. 4), perfect in T3b (kappa = 0.81), and slight for the other stages (kappa = <0.1). On multivariate analysis, conventional RCC and tumor size > 7 cm represent the significant risk factors (RR: 1.6, 95% CI: 1.1-2.3, P < 0.004 and RR: 2.4, 95% CI: 1.7-3.5, P < 0.001, respectively). Mis-staging was seen to have no negative impact on surgical decision. CONCLUSIONS: MDCT is an accepted tool for renal tumor staging. Tumor mis-staging after MDCT is of little clinical importance. Large tumor size >7 cm and conventional RCC are risk factors for tumor mis staging. PMID- 22200937 TI - The development of facial gender categorization in individuals with and without autism: the impact of typicality. AB - While much research has examined the development of facial recognition abilities, less is known about the ability of individuals with and without autism to categorize facial gender. The current study tested gender categorization abilities in high-functioning children (5-7 and 8-12 years), adolescents (13-17 years), and adults (18-53 years) with autism and matched controls. Naturalistic videos depicted faces that were either typical or less typical of each gender. Both groups improved in their performance across development. However, control children reached expertise that was similar to control adults by 8-12 years; whereas, adults with autism never reached this level of expertise, particularly with less typical gender faces. Results suggest that individuals with autism employ different face processing mechanisms than typically developing individuals. PMID- 22200938 TI - A five-year prospective study of quality of life after colorectal cancer. AB - PURPOSE: Long-term (>=5 years) quality of life after colorectal cancer is not well described. The present study assessed quality of life (QOL) and psychological distress in colorectal cancer survivors more than 5 years to describe changes over time and antecedents of long-term outcomes. METHOD: A prospective survey of a population-based sample of 763 colorectal cancer patients assessed socio-demographic variables, health behaviors, optimism, threat appraisal, and perceived social support at 5 months post-diagnosis as predictors of QOL and psychological distress 5 years post-diagnosis. RESULTS: QOL improved over time (P < 0.01 for each measure); however, measures of psychological distress remained stable (P > 0.07 for each measure). Risk factors for poorer QOL and/or greater psychological distress included: later stage disease, having a permanent stoma, rectal cancer, fatigue, smoking, being single, low social support, low optimism, and a more negative cancer threat appraisal. Being women, having a pet, having a private health insurance, and receiving both surgery and adjuvant treatment were protective. CONCLUSION: Consistent with response shift theory, the antecedents of QOL after colorectal cancer are multifactorial and include predisposing socio-demographic, medical, and psychological variables. Psychosocial interventions that target both social support and threat appraisal may be effective for this patient group. Additional stepped-up support may be needed for people from a poorer social environment who have multiple risk factors for poorer adjustment. Health system effects require further investigation. PMID- 22200939 TI - Adaptation and cognitive testing of physical activity measures for use with young, school-aged children and their parents. AB - BACKGROUND: Increasing physical activity is one way to address the public health concern of childhood obesity. Physical activity measures for use with young, school-aged children are limited. METHODS: This study adapted two existing activity measures for young children, specifically self-efficacy and 7-day recall of physical activity. RESULTS: Through expert review and cognitive testing, the scales were adapted for use with young, school-aged children (ages 7-9). This article describes how the measures were adapted to insure comprehension of the child self-report measures. Reliability analyses provide support for their use in this population [Cronbach's alpha = 0.76 for the self-efficacy scale; moderate correlation between parent report and child report of child physical activity over the past week (rho = 0.52, P < 0.01]. CONCLUSIONS: Suggestions are offered for researchers interested in using similar methods when designing and adapting physical activity measures for new populations. PMID- 22200940 TI - Value of post-vascular phase (Kupffer imaging) by contrast-enhanced ultrasonography using Sonazoid in the detection of hepatocellular carcinoma. AB - BACKGROUND: We evaluated the sensitivity and specificity of post-vascular phase (Kupffer imaging) by contrast-enhanced ultrasonography (CEUS) using perflubutane microbubbles (Sonazoid) in comparison with conventional B-mode ultrasonography (US) for the detection of hepatocellular carcinoma (HCC) nodules. METHODS: A total of 100 treatment-naive HCC patients admitted at our hospital between December 2007 and June 2009 were consecutively enrolled. The sensitivity and specificity of conventional and contrast-enhanced US were evaluated on a liver segment basis using dynamic CT as a reference standard. Movie files of conventional and enhanced US were stored separately for each segment (e.g., lateral, medial, anterior, and posterior) and reviewed randomly by two blinded readers. RESULTS: A total of 138 HCC nodules (mean diameter 20.3 mm) were detected in 123 of 400 segments. Detection sensitivity of B-mode US was 0.837 for reader A and 0.846 for reader B, and that of CEUS was 0.732 for reader A and 0.831 for reader B. Specificity of B-mode US was 0.902 for reader A and 0.949 for reader B, and that of CEUS was 0.986 for reader A and 0.978 for reader B. CEUS false positives were mainly due to misidentification of hepatic cysts. A significant proportion of false-negative nodules are hyperechoic in B-mode US, likely because echogenicity hampers visualization of the defect in Kupffer imaging. CONCLUSIONS: Kupffer imaging by CEUS with Sonazoid showed very high specificity but rather mediocre sensitivity for HCC detection. CEUS is highly suitable for confirmatory diagnosis of HCC; however, caution should be exercised in reaching a diagnosis based only on CEUS. PMID- 22200941 TI - Oral symptoms including dental erosion in gastroesophageal reflux disease are associated with decreased salivary flow volume and swallowing function. AB - BACKGROUND: This preliminary clinical study aimed to evaluate the effects of salivary flow volume and swallowing function on oral symptoms including dental erosion in gastroesophageal reflux disease (GERD). METHODS: The subjects were 40 GERD patients and 30 (15 younger, 15 older) healthy controls. Detailed medical, dietary, and dental histories were obtained to identify individual behavioral habits potentially associated with dental erosion. Oral examination evaluated dental erosion and determined scores for the decayed, missing, filled (DMF) index, the papillary, marginal, attached (PMA) index for gingivitis, and the Simplified Oral Hygiene Index (OHI-S). Salivary flow volume and swallowing function were evaluated by the Saxon test and repetitive saliva swallowing test, respectively. RESULTS: The DMF index and OHI-S scores differed significantly between all 3 groups. The PMA index was significantly different between the GERD group and the two control groups. The prevalence of dental erosion was 24.3% in the GERD group (0% in the control groups). No specific relationship was found between the incidence of dental erosion and dietary history or behavioral habits. The Saxon test results were significantly lower in the GERD group than in both the control groups. Frequency of swallowing was significantly lower and time to first swallow was significantly longer in the GERD group than in the two control groups. CONCLUSIONS: Oral symptoms in GERD are likely to be associated with impaired salivary flow volume or swallowing function. Treatment for the oral dryness induced by reduced salivary flow volume and rehabilitation for swallowing function could be indicated in patients with GERD. PMID- 22200942 TI - Neutrophil gelatinase-associated lipocalin (NGAL) in inflammatory bowel disease: association with pathophysiology of inflammation, established markers, and disease activity. AB - BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a multi-potent 25-kDa protein mainly secreted by neutrophils. In inflammatory bowel disease (IBD), overexpression of NGAL in colon epithelium has been previously shown. This is the first study analyzing serum and urinary NGAL levels in IBD patients, with regard to specific characteristics of patients and disease. METHODS: Serum and urinary NGAL levels were determined in 181 patients with IBD, 93 with ulcerative colitis (UC), and 88 with Crohn's disease (CD), 82 healthy controls (HC), and 41 patients with irritable bowel syndrome (IBS). RESULTS: Serum NGAL levels were elevated in IBD patients (88.19 +/- 40.75 ng/mL) compared with either HC (60.06 +/- 24.18 ng/mL) or IBS patients (60.80 +/- 20.30 ng/mL), P < 0.0001. No significant difference was shown between UC (86.62 +/- 35.40 ng/mL) and CD (89.92 +/- 46.05 ng/mL). Significantly higher levels of serum NGAL were observed in patients with active (120.1 +/- 38.46) versus inactive IBD (61.58 +/- 15.98), P < 0.0001. Serum NGAL displayed a strong ability to distinguish active IBD from inactive disease, healthy controls, or IBS patients with a sensitivity of 100, 95, and 95% and a specificity of 68, 83, and 79%, respectively, performing better than erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in the assessment of disease activity in both UC and CD. Urinary NGAL levels showed neither significant difference among patients and controls nor correlation with disease activity. CONCLUSIONS: Serum NGAL is elevated particularly in active IBD and correlates with established markers of inflammation and disease activity, implicating its role in the pathophysiology of IBD. PMID- 22200943 TI - Trends in benthic macroinvertebrate community biomass and energy budgets in Lake Sevan, 1928-2004. AB - Water levels of Lake Sevan (Armenia) were artificially lowered by nearly 20 m between 1949 and 1997. Lowered water levels, combined with increased eutrophication, were associated with seasonally anoxic conditions (lasting 1-4 months) near the bottom of the profundal zone each year during 1976-2004. In addition, the extents of the macrophyte zone and of certain substrate types were severely reduced following drawdown. Maximal depth of occurrence decreased by 2 44 m for at least for 50 species of benthic macroinvertebrates between 1982 and 2004 compared to 1937-1961. Species richness of benthic macroinvertebrates declined from 25 to three species at depths where seasonal anoxia occurred. Total biomass increased by a factor of 10 from the period 1928-1948 to 1976-1979 then declined by a factor of 3 to 4 between 1987 and 2004. Energy flow through detritivores was more than tripled during 1976-2004 compared to 1928-1971, a result of increased plankton primary production. In contrast, energy flow through herbivorous benthic macroinvertebrates decreased by a factor of nearly 5, due to reduced areal coverage of macrophytes. Energy flow through filter feeders did not change over the time period examined, but energy flow through the entire zoobenthos community was nearly tripled. The biomasses of Oligochaeta, Chironomidae, and total zoobenthos showed a delayed response to changes in primary production of 7-9, 2, and 2-4 years, respectively. These patterns may provide a basis to predict results of restoration efforts based on the abundance of the zoobenthos in future years as the level of the lake is restored and water quality improves. PMID- 22200944 TI - Analysis of agricultural drought using vegetation temperature condition index (VTCI) from Terra/MODIS satellite data. AB - The most commonly used normalized difference vegetation index (NDVI) from remote sensing often fall short in real-time drought monitoring due to a lagged vegetation response to drought. Therefore, research recently emphasized on the use of combination of surface temperature and NDVI which provides vegetation and moisture conditions simultaneously. Since drought stress effects on agriculture are closely linked to actual evapotranspiration, we used a vegetation temperature condition index (VTCI) which is more closely related to crop water status and holds a key place in real-time drought monitoring and assessment. In this study, NDVI and land surface temperature (T (s)) from MODIS 8-day composite data during cloud-free period (September-October) were adopted to construct an NDVI-T (s) space, from which the VTCI was computed. The crop moisture index (based on estimates of potential evapotranspiration and soil moisture depletion) was calculated to represent soil moisture stress on weekly basis for 20 weather monitoring stations. Correlation and regression analysis were attempted to relate VTCI with crop moisture status and crop performance. VTCI was found to accurately access the degree and spatial extent of drought stress in all years (2000, 2002, and 2004). The temporal variation of VTCI also provides drought pattern changes over space and time. Results showed significant and positive relations between CMI (crop moisture index) and VTCI observed particularly during prominent drought periods which proved VTCI as an ideal index to monitor terminal drought at regional scale. VTCI had significant positive relationship with yield but weakly related to crop anomalies. Duration of terminal drought stress derived from VTCI has a significant negative relationship with yields of major grain and oilseeds crops, particularly, groundnut. PMID- 22200945 TI - The relative role of climate change and human activities in the desertification process in Yulin region of northwest China. AB - To overcome the shortcoming of existing studies, this paper put forward a statistical vegetation-climate relationship model with integrated temporal and spatial characteristics. Based on this model, we quantitatively discriminated on the grid scale the relative role of climate change and human activities in the desertification dynamics from 1986 to 2000 in Yulin region. Yulin region's desertification development occurred mainly in the southern hilly and gully area and its reverse in the northwest sand and marsh area. This spatial pattern was especially evident and has never changed thoroughly. From the first time section (1986-1990) to the second (1991-1995), the desertification was developing as a whole, and either in the desertification development district or in the reverse district human activities' role was always occupying an overwhelmingly dominant position (they were 98.7% and 101.4%, respectively), the role of climate change was extremely slight. From the second time section (1991-1995) to the third (1996 2000), the desertification process was reaching a state of stability, in the desertification development district the role of climate change was nearly equivalent to that of human activities (they were 46.2% and 53.8% separately), and yet in the desertification reverse district, the role of human activities came up to 119.0%, the role of climate change amounted to -19.0%. In addition, the relative role of climate change and human activities possessed great spatial heterogeneity. The above conclusion rather coincides with the qualitative analysis in many literatures, which indicates that this method has certain rationality and can be utilized as a reference for the monitoring and studying of desertification in other areas. PMID- 22200946 TI - The light-sensitive conductance of melanopsin-expressing Joseph and Hesse cells in amphioxus. AB - Two types of microvillar photoreceptors in the neural tube of amphioxus, an early chordate, sense light via melanopsin, the same photopigment as in "circadian" light detectors of higher vertebrates. Because in amphioxus melanopsin activates a G(q)/phospholipase C cascade, like phototransduction in arthropods and mollusks, possible commonalities in the photoconductance were investigated. Unlike other microvillar photoreceptors, reversal of the photocurrent can only be attained upon replacement of extracellular Na(+). In addition to Na(+), Ca(2+) is also permeant, as indicated by the fact that (a) in normal ionic conditions the photocurrent remains inward at V(m) > E(Na); (b) in Na-free solution a small residual inward photocurrent persists at V(m) near resting level, provided that Ca is present; and (c) V(rev) exhibits a modest shift with [Ca](o) manipulations. The unusual reversal is accounted for by an uncommonly low permeability of the light-dependent channels to K(+), as [K](o) only marginally affects the photocurrent amplitude and its reversal. Lanthanum and ruthenium red (RuR), two TRP channel antagonists, reversibly suppress the response to photostimulation of moderate intensity; therefore, the melanopsin-initiated cascade may recruit ion channels of the same family as those of rhabdomeric photoreceptors. With brighter lights, blockage declines, so that both La(3+) and RuR induce a right shift in the sensitivity curve without a reduction of its asymptote. Nonetheless, an effect on the transduction cascade, rather than the channels, was ruled out on the basis of the voltage dependency of the blockade and the lack of effects of intracellular application of the same substances. The mechanisms of action of these antagonists thus entail a state-dependent blockade, with a higher affinity for the channel in the closed conformation. Collectively, the results indicate a kinship of the light-sensitive channels of amphioxus with those of invertebrate rhabdomeric visual cells and support the representation of this lineage of photoreceptors among chordates. PMID- 22200947 TI - Speed, adaptation, and stability of the response to light in cone photoreceptors: the functional role of Ca-dependent modulation of ligand sensitivity in cGMP gated ion channels. AB - The response of cone photoreceptors to light is stable and reproducible because of the exceptional regulation of the cascade of enzymatic reactions that link visual pigment (VP) excitation to the gating of cyclic GMP (cGMP)-gated ion channels (cyclic nucleotide-gated [CNG]) in the outer segment plasma membrane. Regulation is achieved in part through negative feedback control of some of these reactions by cytoplasmic free Ca(2+). As part of the control process, Ca(2+) regulates the phosphorylation of excited VP, the activity of guanylate cyclase, and the ligand sensitivity of the CNG ion channels. We measured photocurrents elicited by stimuli in the form of flashes, steps, and flashes superimposed on steps in voltage-clamped single bass cones isolated from striped bass retina. We also developed a computational model that comprises all the known molecular events of cone phototransduction, including all Ca-dependent controls. Constrained by available experimental data in bass cones and cone transduction biochemistry, we achieved an excellent match between experimental photocurrents and those simulated by the model. We used the model to explore the physiological role of CNG ion channel modulation. Control of CNG channel activity by both cGMP and Ca(2+) causes the time course of the light-dependent currents to be faster than if only cGMP controlled their activity. Channel modulation also plays a critical role in the regulation of the light sensitivity and light adaptation of the cone photoresponse. In the absence of ion channel modulation, cone photocurrents would be unstable, oscillating during and at the offset of light stimuli. PMID- 22200948 TI - Mechanism of inhibition of connexin channels by the quinine derivative N benzylquininium. AB - The anti-malarial drug quinine and its quaternary derivative N-benzylquininium (BQ(+)) have been shown to inhibit gap junction (GJ) channels with specificity for Cx50 over its closely related homologue Cx46. Here, we examined the mechanism of BQ(+) action using undocked Cx46 and Cx50 hemichannels, which are more amenable to analyses at the single-channel level. We found that BQ(+) (300 uM-1 mM) robustly inhibited Cx50, but not Cx46, hemichannel currents, indicating that the Cx selectivity of BQ(+) is preserved in both hemichannel and GJ channel configurations. BQ(+) reduced Cx50 hemichannel open probability (P(o)) without appreciably altering unitary conductance of the fully open state and was effective when added from either extracellular or cytoplasmic sides. The reductions in P(o) were dependent on BQ(+) concentration with a Hill coefficient of 1.8, suggesting binding of at least two BQ(+) molecules. Inhibition by BQ(+) was voltage dependent, promoted by hyperpolarization from the extracellular side and conversely by depolarization from the cytoplasmic side. These results are consistent with binding of BQ(+) in the pore. Substitution of the N-terminal (NT) domain of Cx46 into Cx50 significantly impaired inhibition by BQ(+). The NT domain contributes to the formation of the wide cytoplasmic vestibule of the pore and, thus, may contribute to the binding of BQ(+). Single-channel analyses showed that BQ(+) induced transitions that did not resemble pore block, but rather transitions indistinguishable from the intrinsic gating events ascribed to loop gating, one of two mechanisms that gate Cx channels. Moreover, BQ(+) decreased mean open time and increased mean closed time, indicating that inhibition consists of an increase in hemichannel closing rate as well as a stabilization of the closed state. Collectively, these data suggest a mechanism of action for BQ(+) that involves modulation loop gating rather than channel block as a result of binding in the NT domain. PMID- 22200949 TI - Light inactivation of water transport and protein-protein interactions of aquaporin-Killer Red chimeras. AB - Aquaporins (AQPs) have a broad range of cellular and organ functions; however, nontoxic inhibitors of AQP water transport are not available. Here, we applied chromophore-assisted light inactivation (CALI) to inhibit the water permeability of AQP1, and of two AQP4 isoforms (M1 and M23), one of which (M23) forms aggregates at the cell plasma membrane. Chimeras containing Killer Red (KR) and AQPs were generated with linkers of different lengths. Osmotic water permeability of cells expressing KR/AQP chimeras was measured from osmotic swelling-induced dilution of cytoplasmic chloride, which was detected using a genetically encoded chloride-sensing fluorescent protein. KR-AQP1 red fluorescence was bleached rapidly (~10% per second) by wide-field epifluorescence microscopy. After KR bleaching, KR-AQP1 water permeability was reduced by up to 80% for the chimera with the shortest linker. Remarkably, CALI-induced reduction in AQP4-KR water permeability was approximately twice as efficient for the aggregate-forming M23 isoform; this suggests intermolecular CALI, which was confirmed by native gel electrophoresis on cells coexpressing M23-AQP4-KR and myc-tagged M23-AQP4. CALI also disrupted the interaction of AQP4 with a neuromyelitis optica autoantibody directed against an extracellular epitope on AQP4. CALI thus permits rapid, spatially targeted and irreversible reduction in AQP water permeability and interactions in live cells. Our data also support the utility of CALI to study protein-protein interactions as well as other membrane transporters and receptors. PMID- 22200950 TI - Co-transmission of dopamine and glutamate. PMID- 22200951 TI - Total endoscopic robotic atrial septal defect repair in a patient with dextrocardia and situs inversus totalis. AB - Situs inversus with mirror-image of the heart is a rare condition. The present report describes a case of a patient with dextrocardia with situs inversus who had atrial septal defect with multiple holes in the fossa ovalis. The patient underwent total endoscopic atrial septal defect repair using the da Vinci surgical system. This procedure was achieved safely with good clinical and excellent cosmetic results. PMID- 22200952 TI - Effects of low pseudoallergen diet on urticarial activity and leukotriene levels in chronic urticaria. AB - Pseudoallergens and leukotrienes (LTs) may have a role in chronic urticaria (CU). The aim of our study is to evaluate the response to the low pseudoallergen diet therapy in patients with CU and the change in LT levels in diet responsive and non-responsive patients. 34 patients with CU were put on diet for 4 weeks. All patients kept a daily score sheet of pruritus and whealing symptoms. The urticarial activity score (UAS) of each patient was calculated with the sum of pruritus and wheal score. The sum score of the first 7 consecutive days (UAS7 first week) and last 7 days (UAS7-fourth week) were used to compare the clinical outcome of the diet. A reduction of >=50% in UAS7-fourth week compared to UAS7 first week was considered as "response". Urinary LTE4 (uLTE4) level of each patient was measured at baseline and after the 4 week of diet therapy. 14 of the patients (41.2%) were responsive to diet therapy. Baseline uLTE4 levels were similar between responsive and non-responsive patients (P = 0.540). Second uLTE4 levels (after the 4 week of diet therapy) were significantly lower in responsives than in non-responsive patients (P < 0.001). Second uLTE4 levels of responsives were significantly lower than the baseline values (P = 0.019), whereas this was not significant for non-responsives (P = 0.070). There was a significant correlation between the change in uLTE4 levels and the change in mean urticarial activity scores (r = 0.554, P = 0.001) in the whole study population. In conclusion, low pseudoallergen diet helps to reduce the urticarial activity in CU. The change in urticarial activity correlates with the change in LT levels. PMID- 22200953 TI - Assessment of stanniocalcin-1 as a prognostic marker in human esophageal squamous cell carcinoma. AB - Stanniocalcin-1 (STC1) is a secreted glycoprotein hormone and highly expressed in various types of human malignancies. Although evidence points to the role of STC1 in human cancers, the clinical significance of STC1 expression in esophageal cancer has not been well established. Quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry were performed to assess the expression of STC1 in the cancer cell line TE8 and esophageal cancer tissues from 229 esophageal squamous cell carcinomas (ESCC). Surgically-resected tissue sections were immunostained for potential regulators of STC1 expression, hypoxia inducible factor-1alpha (HIF-1alpha) and p53. Marked increase in STC1 mRNA and protein expression was noted in TE8 cells cultured under hypoxic conditions. Overexpression of STC1 mRNA was noted in ESCC tumors compared to normal counterparts. Positive immunohistochemical staining for STC1 protein was observed in 38.9% of patients, and correlated significantly with advanced pT status (p=0.019), poor prognosis [overall survival (p<0.0006) and disease-free survival (p<0.0002) of ESCC patients who had undergone curative surgery]. Positive staining for HIF-1alpha and p53 proteins in ESCC did not correlate with STC1 expression. The results showed marked induction of STC1 expression under hypoxia in cultured cells and in esophageal cancer cells and that overexpression of STC1 was an independent prognostic factor in patients with esophageal cancer who had undergone curative surgery. STC1 is a potentially useful biomarker for ESCC treatment. PMID- 22200954 TI - Biolarvicidal and pupicidal activity of Acalypha alnifolia Klein ex Willd. (Family: Euphorbiaceae) leaf extract and Microbial insecticide, Metarhizium anisopliae (Metsch.) against malaria fever mosquito, Anopheles stephensi Liston. (Diptera: Culicidae). AB - The present study was to establish of Acalypha alnifolia leaf extract and microbial insecticide, Metarizhium anisopliae on larvicidal and pupicidal properties of against the malaria fever mosquito, Anopheles stephensi. The leaf extract showed larvicidal and pupicidal effects after 24 h of exposure; however, the highest larval and pupal mortality was found in the leaf extract of ethanol A. alnifolia against the 1st to 4th instar larvae and pupae of values LC(50) value of 1st instar was 5.388%, 2nd instar was 6.233%, 3rd instar was 6.884%, 4th instar was 8.594%, and pupae was 10.073%, respectively, and microbial insecticide, M. anisopliae against the 1st to 4th instar larvae and pupae of values LC(50) value of 1st instar was 7.917%, 2nd instar was 10.734%, 3rd instar was 17.624%, 4th instar was 26.590%, and pupae was 37.908%, respectively. Moreover, combined treatment of values of LC(50) value of 1st instar was 3.557%, 2nd instar was 4.373%, 3rd instar was 5.559%, 4th instar was 7.223%, and pupae was 8.542%, respectively. No mortality was observed in the control. The results that the leaves extract of A. alnifolia and microbial insecticide, M. anisopliae is promising as good larvicidal and pupicidal properties of against malaria fever mosquito, A. stephensi. This is an ideal eco-friendly approach for the control of malarial vector, A. stephensi as a vector control programs. Therefore, this study provides first report on the combined effect of mosquitocidal efficacy of this plant extract and fungal pathogen of M. anisopliae against A. stephensi from Southern India. PMID- 22200955 TI - Multi-epitope recombinant vaccine induces immunoprotection against mixed infection of Eimeria spp. AB - Immunity to Eimeria is species-specific, and chickens with immunity to one species of Eimeria remain susceptible to other Eimeria species. This presents a major challenge in the development of effective vaccines against multiple Eimeria species. In this study, we cloned the antigenic epitope of a tachyzoite surface protein gene of Eimeria tenella, a tachyzoite surface protein gene of Eimeria acervulina and the gametocyte protein gene of Eimeria maxima, and constructed prokaryotic and eukaryotic plasmids carrying the multi-epitope antigenic gene. Immunization of chickens with the multivalent DNA and protein conferred partial protection against infection by the three Eimeria species, as shown by increased CD4+ T lymphocytes in the intestinal mucosa, decreased oocyst excretion and intestinal lesions, and increased body weight gain compared with non-immunized controls. The DNA prime-protein boost immunization schedule induced greater cellular immunity and protection from Eimeria infection than immunization with DNA or protein alone. Our findings demonstrated that DNA prime-protein boost immunization with a multivalent vaccine could stimulate protective immunity against challenge infection of multiple Eimeria species. This work provides a promising step towards DNA-protein vaccination against multiple species of pathogens. PMID- 22200956 TI - Effectiveness of synthetic trioxolane OZ78 against Schistosoma japonicum in mice and rabbits. AB - Antischistosomal activities of a synthetic peroxide OZ78 (an ozonide carboxylic acid) against Schistosoma japonicum have been studied in mice and rabbits. Among 132 mice used, 30 of them were infected with 80-100 S. japonicum cercariae for collection of juvenile and adult schistosomes applied in in vitro tests. The remaining 102 mice were infected with 40 schistosome cercariae used for experimental treatment. Other 13 rabbits infected each with 200 schistosome cercariae were treated orally with OZ78 42 days post-infection. Most treated mice and rabbits were sacrificed 4 weeks post-treatment to collect residual schistosomes for evaluation of the drug efficacy. OZ78 and its sodium salt (OZ78 Na salt) 10-60 MUg/mL alone exhibited no in vitro effect against day 14, day 21 schistosomula, and day 35 adult schistosomes. But OZ78 and OZ78-Na salt 10 and 20 MUg/mL together with hemin 80 MUg/mL showed decrease in worm motor activity and severe damage to the worm tegument and intestine, and all worms died within 3 days post-incubation. After infected mice were treated orally with OZ78 at a single dose of 400 mg/kg for 1 day, 34.9% of the worms shifted to the liver. Three and 7 days post-treatment, 100% of the worms were recovered from the liver. Fourteen days post-treatment, 92.3% of the worms still remained in the liver and 7.7% of the worms returned back to the mesenteric veins. Male and female worms shifted to the liver revealed in apparent shrinkage, degeneration of worm body, depigmentation in gut, and disappearance of ova in the uterus of some female worms. Meanwhile, dead worm and dead worm fragments were found in the liver tissues. In mice infected with various stages of schistosomes and treated orally with single OZ78 400 mg/kg, moderate or potential effect of the drug against day 0 (3-h-old worm), day 7, day 14, and day 21 juvenile worms and day 28, day 35 as well as day 42 adult worms were observed, the differences of total or female worm burdens between each treated group and control group were statistically significant (P < 0.01 or P < 0.05). Among the various stages of juveniles, day 7 worms were more susceptible to OZ78 with worm reduction of 83.8%, while the effect of OZ78 against day 28 to day 42 adult worms were similar. Finally, rabbits infected with adult schistosomes and treated with OZ78 at a single dose of 45 mg/kg or a daily dose of 35 mg/kg for three consecutive days resulted in significantly lower total and female worm burdens in comparison with that of control (P < 0.05) with total and female worm reductions of 84.1% and 84.7% as well as 74.3% and 77.4%, respectively. The results demonstrate that OZ78 possesses effect against both juvenile and adult S. japonicum in mouse model, and also shows effect against adult schistosomes in rabbits. PMID- 22200957 TI - Gene cloning, expression, and localization of antigen 5 in the life cycle of Echinococcus granulosus. AB - Antigen 5 (Ag5) has been identified as a dominant component of cyst fluid of Echinococcus granulosus and is considered as a member of serine proteases family, which in other helminth, plays an important role in the egg hatch and larva invasion. However, whether Ag5 is expressed and secreted in all life stages is unknown. In this study, according to the sequence in GenBank, we cloned and sequenced the open reading frame (ORF) of Ag5 gene from the protoscolices of E. granulosus isolated from the sheep in Qinhai Province of China, and found several substitutions and a base insert and deletion in a short region near the stop code, leading to a frameshift mutation which is conserved with the homologue of other cestode. The ORF is 1,455 bp in length, encoding 484 amino acids with a secretory signal peptide. Bioinformatics analysis predicted several phosphorylation and myristoylation sites and a N-glycosylation site and a species specific linear B epitope in the protein. The ORF was cloned into the plasmid pET28a(+) vector and expressed in Escherichia coli . The recombinant protein was purified by affinity chromatography. Anti-rEgAg5 antiserum was prepared in rats and used to analyze the localization of Ag5 in protoscolex and adult worm by immunofluorescence technique. Results demonstrated that the Ag5 is strongly expressed in the tegument of protoscolex and the embryonic membrane of egg and surface of oncosphere; meanwhile, it is also weakly expressed in tegument of the adult. This study showed that Ag5 is expressed in all stages of life cycle, secreted from the surface of the worm and may be anchored in membrane by its myristoylation sites; these characteristics make it a candidate antigen for diagnosis and vaccine for both intermediate and definitive hosts. PMID- 22200958 TI - Morphology and histopathology of Calyptospora sp. (Apicomplexa: Calyptosporidae) in speckled peacock bass, Cichla temensis Humboldt, 1821 (Perciformes: Cichlidae), from the Marajo-Acu River, Marajo Island, Brazil. AB - Several species of coccidia are protozoan parasites that cause infection in a wide variety of animal groups. Calyptospora is an important genus of protozoan, which infests both freshwater and marine fish. The hepatopancreases of 150 speckled peacock bass captured on Marajo Island, Brazil were studied macro- and microscopically. Oocysts were found in 84 (56%) of the specimens in both the examination of the fresh material by compression and the analysis of histological sections stained with hematoxylin-eosin. Small, circular, homogeneous forms in negative contrast had a mean diameter of 21.2 MUm, frequently with pyriform sporocysts, with a mean length of 9.2 MUm and width of 3.1 MUm, and a thin-walled capsule, were observed in both the hepatic and the pancreatic parenchyma, but were completely devoid of any inflammatory reaction. Calyptospora infections are documented for the first time in the Marajo-Acu River. PMID- 22200959 TI - Anthelmintic activity of medicinal plants used in Cote d'Ivoire for treating parasitic diseases. AB - Natural products play an important role in the discovery and development of new pharmaceuticals. In the present study, we assessed the anthelmintic properties of medicinal plants used in Cote d'Ivoire. Ethanolic extracts from 50 medicinal plants were tested in vitro against trematodes (Echinostoma caproni, Schistosoma mansoni) and nematodes (Ancylostoma ceylanicum, Heligmosomoides bakeri, Trichuris muris). Active extracts were evaluated for their cytotoxicity and followed up in vivo in mice harbouring adult S. mansoni, E. caproni and T. muris at single oral doses of 400 or 800 mg/kg. All extracts tested were active against at least one helminths species. Ten of the 65 extracts tested (15.4%) in vitro revealed activity against all helminths tested. Of 65 extracts tested in vitro at a concentration of 2 mg/ml, all caused death of schistosomula and 34.4% and 39.1% were lethal against adult S. mansoni and E. caproni 72 h post-incubation, respectively. The highest activity against A. ceylanicum in vitro was observed with Sclerocarya birrea at 2 mg/ml, which resulted in death of adult worms and inhibition of activity of third-stage larvae (L3). Of the extracts, 41.5% completely inhibited movement of H. bakeri L3 at minimal lethal concentration (MLC) values of 20-200 MUg/ml 48 h post-incubation, and 15.4% paralysed adult H. bakeri at 200 MUg/ml 72 h after incubation. Of the extracts, 19% resulted in death of adult T. muris at MLC values of 10-100 MUg/ml. In vivo, none of the extracts tested revealed activity against E. caproni. Olax subscorpioidea achieved total and female worm burden reductions of 60% and 84%, respectively in S. mansoni-infected mice. Combretum mucronatum was the most active extracts in vivo against T. muris with a worm burden reduction of 85.3%. In conclusion, several of the medicinal plants used in Cote d'Ivoire are active against different helminths, hence might play a role in the treatment of helminthiases. Further studies are necessary to isolate the active components from these extracts. PMID- 22200960 TI - Identification and characterization of one novel type of Triactinospomyxon with short spore axis. AB - This study identifies and characterizes one novel type of triactinospomyxon in oligochaete specimen of Branchiura sowerbyi Beddard collected from a fish pond used for rearing gibel carp located in Caidian Experimental Station of the Institute of Hydrobiology. It is nominated as Triactinospomyxon caidianensis type. The spore is of characteristic triactinomyxon "anchor" shape and possesses a spore body with sporoplasm containing 32 germ cells, 3 polar capsules, and 3 caudal processes. Compared with other triactinomyxon spores described previously, T. caidianensis type has a short spore axis with 76.5 MUm in length and a very short style with 38.9 MUm in length. Molecular analyses on 18S rDNA sequences indicate that the novel T. caidianensis type is most closely related to Triactinomyxon sp SA-2005, Antonactinomyxon sp KAB-2001, and Synactinomyxon sp KAB-2001 with 80.33% to 81.92% identities. On the basis of spore morphology and genetic data, the T. caidianensis type presented in this paper differs from those already known and described in the literatures. PMID- 22200961 TI - Confocal laser scanning microscopic observation on adult Schistosoma japonicum harbored in mice following treatment with single-dose mefloquine. AB - The aim of the present study is to assess the mefloquine-induced alteration of adult Schistosoma japonicum using confocal laser scanning microscopy (CLSM). Eight out of ten mice infected with 60-80 S. japonicum cercariae for 35 days were treated orally with mefloquine at a single dose of 400 mg/kg. Four groups of two mice were killed at 24 h and 3, 7, and 14 days post-treatment, and schistosomes were collected by perfusion from the liver and mesenteric veins, fixed in 70% alcohol, stained with acid carmine, and examined by CLSM. Worms obtained from untreated mice served as controls. Twenty-four hours post-treatment, focal tegument of adult male and female worms, which composed of fine and short villus like materials, became thicker and longer, or disorder arrangement, while the musculatures beneath the tegument revealed in focal and irregular swelling with various degrees. In the gut of male and female schistosomes, severe dilatation accompanied by swelling, collapse, and peeling of gut mucosa was universal. In the reproductive organs, no apparent alteration in the testis structure of male worms was seen, while in female worms, slight damage to the ovary included loose arrangement of mature ovary cells accompanied by some of them degenerated and collapsed. As to vitelline glands, severe damage, such as swelling, indistinction, fusion or collapse of vitelline cells, and apparent swelling of parenchymal tissues in vitelline gland lobules, was seen. Meanwhile, abnormal ova emerged in the uterus at this time point. Three to 7 days post-treatment, the damage to the worms aggravated either in extent or in severity along with time. In some focally swollen worm body, the parenchymal tissues revealed in severe swelling. In addition, a large piece of degenerated and necrotic parenchymal tissues emerged closed to the severe destructed oral or ventral sucker. In the gut of male and female worms, the major alterations manifested by focal collapse or peeling of mucosa, and desquamation of gut epithelial cells. As to the reproductive organs, the testes of male worms revealed in reduction of size, decrease in number of germinative cells, and some of them showed degeneration and collapse, or destruction of the capsule around the testis. In female worms, some ovaries only showed degenerated and collapsed cells accompanied with many cell fragments. Meanwhile, almost all of the vitelline cells lost their definition, which revealed in indistinct cell structure, fusion of some cells, and formation of many cell fragments due to their collapse. Fourteen days post-treatment, only some male worms survived the treatment were collected. Their tegument and musculature showed prominent recovery, but severe damage to the gut and testes was still observed. Our results confirm that under the observation by CLSM, mefloquine exhibits destructive effect on adult S. japonicum, particularly the morphological structure of digestive system and reproductive system of the worms. PMID- 22200962 TI - Molecular test for vivax malaria with loop-mediated isothermal amplification method in central China. AB - Vivax malaria has the highest incidence in central China. High-throughput and cost-effective testing methods are essential for vivax malaria diagnosis in this area. Loop-mediated isothermal amplification (LAMP) is an established nucleic acid amplification method, which provides a promising platform for the molecular detection of malaria parasites in development countries. This study was performed to compare the LAMP method, the nested PCR-based method, and microscopic examinations in diagnosing vivax malaria. LAMP detected vivax malaria parasites in 160 of 164 microscopically positive samples (sensitivity, 97.6%), whereas nested PCR detected Plasmodium vivax in 162 of 164 samples (sensitivity, 98.8%). No false-positive results were obtained by LAMP or nested PCR among fever positive and healthy samples. The sensitivities and specificities of the two molecular tests were consistently high. In addition, the reproducibility of the LAMP assays using water bath, which reduced the cost substantially. LAMP method is an accurate, rapid, simple, and cost-effective method that may be useful for diagnosis in field diagnoses instead of nested PCR. This method is feasible to diagnose vivax malaria parasite in endemic areas of central China. PMID- 22200963 TI - Inhibition of mammalian muscle differentiation by excretory secretory products of muscle larvae of Trichinella spiralis in vitro. AB - The excretory-secretory products (ESP) released by muscle stage of Trichinella spiralis have been suggested to be involved in nurse cell formation. However, the molecular mechanisms by which ESP modulate nurse cell formation remain unclear. In the present study, the ability of ESP of muscle larvae of T. spiralis (ML-ESP) to influence the proliferation and differentiation of murine myoblasts and the mechanisms were evaluated in vitro using C2C12 myoblast cell line, which were incubated for various times under grow or differentiation culture medium containing various concentrations of ML-ESP. The results indicated that ML-ESP promoted myoblast proliferation in a dose-dependent manner and increased the expression of the cell-cycle regulator cyclin D1 as well as that of proliferating cell nuclear antigen (PCNA). Conversely, ML-ESP inhibited the differentiation of these cells, which was evidenced by a reduction in the levels of MHC and MRFs expression (MyoD and myogenin) as well as that of p21. In addition, ML-ESP also inhibited the phosphorylation of p38 MAPK in differentiating C2C12 myoblast. Taken together, these results imply that certain critical mediators contained in ML-ESP inhibit myogenesis through enhancing skeletal myoblasts proliferation and down-regulating the expression of MRFs as well as involving p38 MAPK signalling pathway, which provides insight into the mechanisms utilised by T. spiralis to interfere normal wound repair in infected muscle cells and affect nurse cell formation. PMID- 22200964 TI - Feasibility of pseudocontinuous arterial spin labeling at 7 T with whole-brain coverage. AB - OBJECT: We studied the feasibility of pseudocontinuous arterial spin labeling (pCASL) at 7 T. MATERIALS AND METHODS: Simulations were performed to find the optimal labeling parameters for pCASL, with particular attention to the maximum allowed specific absorption rate (SAR). Subsequently, pCASL experiments (four volunteers) were performed to find the B1 efficiency at the labeling position with and without high-permittivity pads placed around the head, and to study the optimal labeling duration (four separate volunteers). Finally, feasibility of whole-brain pCASL imaging was tested. RESULTS: Simulations showed that a lower B1 efficiency should be compensated by a lower effective flip angle of the labeling, a moderately shorter labeling duration, and a longer repetition time. B1 efficiency in the internal carotid arteries just below the carotid siphon was approximately 55% and 35% with and without high-permittivity pads, respectively. In vivo experiments showed an optimal labeling duration of 1,500 ms, although longer labeling durations up to 2,500 ms resulted in similar signal-to-noise efficiency. Whole-brain pCASL imaging was demonstrated in a single volunteer. CONCLUSION: Despite decreased B1 efficiency, sufficient labeling efficiency can be achieved for whole-brain pCASL at 7 T with high-permittivity pads. However, image quality is still limited compared with 3 T, probably due to imaging instabilities, and further research is needed to elucidate this. PMID- 22200966 TI - A Gastrointestinal Stromal Tumor Presenting as an Emergency: a Case Report. PMID- 22200965 TI - Intussusception in adults: what radiologists should know. AB - Adult intussusception (AI) is a rare entity with an organic lesion within the intussusception in 70-90% of the cases. Intussusception is classified according to location, etiology, and to the presence or not of a lead point. We illustrate several causes of AI with a variety of radiological findings on plain film, ultrasonography, computed tomography, magnetic resonance, and endoscopy seen at our institution. Imaging plays a major role in their diagnosis and in determining the appropriate treatment. PMID- 22200967 TI - Case-control study on the survival of abutment teeth of partially dentate patients. AB - OBJECTIVES: Due to the scarce amount of data available, a retrospective analysis of patients treated with removable dental prostheses (RDPs) was performed. The aim of the trial was to evaluate the rate of repairs and failures of attachment retained RDPs (AR-RDPs) compared to clasp-retained RDPs (CR-RDPs) with respect to cofactors (e.g., type of loading). In this respect, two hypotheses were proposed: AR-RDPs are more prone to repairs than CR-RDPs, and AR-RDPs are more prone to fail than CR-RDPs. MATERIALS AND METHOD: Two hundred three patients treated with 135 AR-RDPs and 68 CR-RDPs between 1994 and 2006 were evaluated in this trial. The dental treatment was carried out in the clinical training course of senior students. Kaplan-Meier estimates were calculated for the primary end point (repairs) and for the secondary end point (failures). RESULTS: The survival of CR RDPs and AR-RDPs did show significant differences regarding repairs (p = 0.034) but not with regard to failures (p = 0.169). Prostheses of the non-axially loaded group showed no significant differences in the frequency of repairs and failures. CONCLUSIONS: Technical complications occurred more frequently in the CR-RDP group. Taking the higher observation time in the AR-RDP group into account, CR RDPs are more prone to repairs, especially to those with technical background (e.g., fracture of the metal framework). CLINICAL RELEVANCE: The use of crowns with rod attachments on tilted teeth seems to be an appropriate treatment approach in order to simplify removable dental prosthesis design. PMID- 22200968 TI - The quality of information on three common ENT procedures on the Internet. AB - BACKGROUND: The Internet hosts a large number of high-quality medical resources and poses seemingly endless opportunities to inform, teach, and connect professionals and patients alike. However, it is difficult for the lay person to distinguish accurate from inaccurate information. AIM: This study was undertaken in an attempt to assess the quality of information on otolaryngology available on the Internet. METHODS: Sixty appropriate websites, using search engines Yahoo and Google, were evaluated for completeness and accuracy using three commonly performed ENT operations: tonsillectomy (T), septoplasty (S), and myringoplasty (M). RESULTS: A total of 60 websites were evaluated (NT = 20, NM = 20, NS = 20). A total of 86.7% targeted lay population and 13.3% targeted the medical professionals. 35% of the sites included all critical information that patients should know prior to undergoing surgery and over 94% of these were found to contain no inaccuracies. Negative bias towards medical profession was detected in 3% of websites. CONCLUSIONS: In the current climate, with informed consent being of profound importance, the Internet represents a useful tool for both patients and surgeons. PMID- 22200969 TI - The effects of cyclooxygenase-2 gene silencing by siRNA on cell proliferation, cell apoptosis, cell cycle and tumorigenicity of Capan-2 human pancreatic cancer cells. AB - The prognosis of pancreatic cancer is still very poor. No specific effective gene therapy for pancreatic cancer has been found. As a key enzyme of the metabolic process of arachidonic acid, cyclooxygenase-2 (COX-2) has been found to be closely related to the tumorigenesis of epithelial cancers. However, the antitumor effect of small interfering RNA (siRNA) targeting COX-2 in pancreatic cancer has not yet been verified. Therefore, the aim of this study was to investigate the effects of COX-2 gene silencing by siRNA on cell proliferation, cell apoptosis, cell cycle and tumorigenicity of pancreatic cancer cells. COX-2 mRNA was detected by RT-PCR and real-time PCR. COX-2 protein was detected by Western blotting. The cell proliferation was measured by cell counting using microscopy. The cell apoptosis and cell cycle were measured by flow cytometry. The tumorigenicity of Capan-2 pancreatic cancer cells transfected with COX-2 siRNA was evaluated using a nude mouse xenograft model. The expression of COX-2 mRNA as well as COX-2 protein were downregulated after COX-2 siRNA transfection. COX-2 siRNA could inhibit the growth of Capan-2 cells significantly by decreasing the cell proliferation, increasing cell apoptosis and regulating cell cycle as well. In vivo experiments demonstrated that the mean volume and weight of subcutaneous xenografts in nude mice derived from Capan-2 cells transfected with COX-2 siRNA were significantly decreased. COX-2 siRNA could inhibit the growth of Capan-2 pancreatic cancer cells and also decrease the tumorigenicity of Capan-2 cells, implicating a new potential therapeutic target in pancreatic cancer. PMID- 22200970 TI - Banking of fresh-frozen prostate tissue using the alternate mirror image protocol: methods, validation, and impact on the pathological prognostic parameters in radical prostatectomy. AB - We evaluated the value of the 'alternative slices mirror image method' used in prostate tissue banking in terms of predicting the sampling of cancerous tissue while preserving the pathological prognostic information. The concordance of diagnosis between banked sections and their mirror image paraffin- sections was studied using 50 cases corresponding to 400 H&E sections taken from 400 banked frozen blocks (two presumed benign and two presumed cancer for each case). The mean number of paraffin blocks in each case was 21. On average 29% of the prostate gland was banked and banked tissue contained cancer in 47 cases (94%). There was no difference between the concordant and discordant groups in terms of the final Gleason score, pathological stage, prostate size, number of banked blocks and the percentage of the prostate submitted for banking. However, concordant cases had larger foci of cancer in the mirror image paraffin block (P = 0.0088). In addition, the surgical margins sections which are not banked using this method provided important information about the pathological stage, surgical margins status and the final Gleason score in 2.6, 2.6, and 1.3% of cases, respectively. The 'alternative slices mirror image method' is a straightforward method that is highly efficient in banking prostatic cancerous tissue. Overall, tumor volume and especially size of tumor foci in the image paraffin block are the most important factors in dictating the success rate of banking frozen cancerous tissue. Including 'surgical margins' sections for histology provides additional important prognostic information in a minority of cases. PMID- 22200971 TI - The in vitro elution of BMP-7 from demineralized bone matrix. AB - Demineralized bone matrix (DBM) grafts induce new bone formation by locally releasing matrix-associated growth factors, such as bone morphogenetic proteins (BMPs), to the surrounding tissue after implantation. However, the release kinetics of BMPs from DBM lack characterization. Such information can potentially help to improve processing techniques to maximize graft osteoinductive potential, as well as increase understanding of the osteoinductive process itself. We produced DBM with three particle size ranges from bovine cortical bone, i.e., <106, 106-300, and 300-710 MUm and extracted 1.5 g of each size range in 40 ml of Sorensen's buffer at room temperature for up to 168 h. The BMP-7 concentration of the DBM and the buffer were measured at each time point using enzyme-linked immunosorbant assay. Based on measurement of the concentration of BMP-7 in the buffer, the 0-8 h elution rate was high, i.e., 3.3, 2.9, and 2.2 ng BMP-7/g DBM h, and for the 8-168 h interval was much lower, at 0.039, 0.15, and 0.11 ng BMP 7/g DBM h for the three size ranges, respectively. By 168 h, there was no indication that elution was nearing completion. Measurement of the residual BMP-7 remaining in the DBM as a function of time yielded unexpected results, i.e., after the BMP-7 content of the DBM declined for the first 4-6 h, it paradoxically increased for the remaining interval. We propose a two-compartment model to help explain these results in terms of the possible distribution of BMP-7 in bone matrix. PMID- 22200972 TI - Treatment of B cell lymphoma with chemotherapy plus rituximab: a survival benefit can be demonstrated in the routine data of a regional cancer registry. AB - Combination of standard chemotherapy with rituximab led to improved disease control in patients with B cell lymphoma in clinical trials. We wanted to know if a similar benefit could be demonstrated in the routine data of a regional population-based cancer registry. We searched the registry of the Regensburg Tumor Center for B cell non-Hodgkin lymphomas diagnosed between 1998 and 2006 and compared overall survival of patients receiving any first-line chemotherapy with or without rituximab. Comparing registry data to death certificates, an 86% coverage within the registry was estimated. In the aggressive lymphoma group, 133 patients received rituximab-containing chemotherapy resulting in a 5-year survival of 69.6%, whereas 205 patients received chemotherapy alone with a significantly inferior 5-year survival of 56.8%. First-line chemotherapy with rituximab in 81 patients with indolent lymphoma also led to improved 5-year survival compared to 134 patients without rituximab (69.7% vs. 51.8%), primarily observed among patients with follicular lymphoma (84.7% vs. 52.0%). These data confirm the standard use of rituximab as first-line therapy in diffuse large B cell lymphomas as well as in indolent lymphoma. Furthermore, they support the collection of treatment data including detailed information on systemic therapy in cancer registries to be used for outcomes research. PMID- 22200973 TI - Subjective social status: construct validity and associations with psychosocial vulnerability and self-rated health. AB - BACKGROUND: Subjective social status (SSS) predicts health outcomes independently of traditional, objective indicators of socioeconomic status (SES). However, the potential confounding and mediating effects of negative affect and similar psychosocial risk and resilience factors have not been adequately addressed through formal studies of convergent and discriminant validity of SSS measures. PURPOSE: The current study provides such a test of construct validity and subsequently examines whether psychosocial factors mediate the relationship between SSS and self-rated health. METHODS: We examined the convergent and discriminant validity of the MacArthur scales of SSS relative to measures of psychosocial risk and resilience (i.e., neuroticism, depressive symptoms, optimism, and marital quality) as well as SES (i.e., income) in 300 middle-aged and older married US couples. We also tested a factor of psychosocial vulnerability as a mediator of the relationship between SSS and self-rated health. RESULTS: Findings indicated clear convergent and discriminant validity of the MacArthur scales. Further, controlling age and income, both the US and community measures of SSS predicted psychosocial factors for men, however, only the community measure was independently predictive for women. Psychosocial vulnerability significantly mediated the pathway between SSS and self-rated health for men and women after controlling age and income. CONCLUSIONS: These results provide strong support for the construct validity of the MacArthur scales and provide additional evidence of the role of psychosocial risk and resilience factors as mediators of the effects of SSS on health. PMID- 22200974 TI - MRI and associated clinical characteristics of EV71-induced brainstem encephalitis in children with hand-foot-mouth disease. AB - INTRODUCTION: This study was conducted to investigate MRI and associated clinical characteristics of brainstem encephalitis induced by enterovirus 71 (EV71) in children with hand-foot-mouth disease (HFMD). METHODS: We analyzed clinical and imaging data from 42 HFMD cases with EV71-induced brainstem encephalitis. All patients underwent plain and enhanced MRI cranial scans and were placed into one of two groups according to MRI enhancement results, an enhanced group or a nonenhanced group. RESULTS: Thirty-two cases were positive on MRI exam. The primary location of the lesion for brainstem encephalitis was the dorsal pons and medulla oblongata (32 cases), followed by the cerebellar dentate nucleus (8 cases), midbrain (5 cases), and thalamus (2 cases). Plain T1-weighted images showed isointense or hypointense signals, and T2-weighted images showed isointense and hyperintense signals. Enhanced MRI scans showed that 12 cases had slight to moderate enhancement; 4 of these were normal on plain scan. The time from MRI examination to disease onset was statistically different between the enhanced (n = 12) and nonenhanced (n = 21) groups with a mean of 7.67 days (SD = 1.07) vs 11.95 days (SD = 5.33), respectively. The most common neurological symptoms for brainstem encephalitis were myoclonus and tremor. The greater the area of affected brain, the more severe the clinical symptoms were. CONCLUSION: The locations of EV71-induced HFMD-associated brainstem encephalitis lesions are relatively specific. Enhanced MRI scans could also identify the lesions missed by early plain scans. MRI scans can provide important information for clinical evaluation and treatment. PMID- 22200975 TI - Taste-mediated behavioral and electrophysiological responses by the predatory fish Ariopsis felis to deterrent pigments from Aplysia californica ink. AB - Chemical defenses are used by many organisms to avoid predation, and these defenses may function by stimulating predators' chemosensory systems. Our study examined detection mechanisms for components of defensive ink of sea hares, Aplysia californica, by predatory sea catfish, Ariopsis felis. Behavioral analyses show aplysioviolin and phycoerythrobilin are detected intra-orally and by barbels and are deterrent at concentrations as low as 0.1% full strength. We performed electrophysiological recordings from the facial-trigeminal nerve complex innervating the maxillary barbel and tested aplysioviolin, phycoerythrobilin, amino acids, and bile salts in cross-adaptation experiments. Amino acids and bile salts are known stimulatory compounds for teleost taste systems. Our results show aplysioviolin and phycoerythrobilin are equally stimulatory and completely cross-adapt to each other's responses. Adaptation to aplysioviolin or phycoerythrobilin reduced but did not eliminate responses to amino acids or bile salts. Adaptation to amino acids or bile salts incompletely reduced responses to aplysioviolin or phycoerythrobilin. The fact that cross adaptations with aplysioviolin and phycoerythrobilin were not completely reciprocal indicates there are amino acid and bile salt sensitive fibers insensitive to aplysioviolin and phycoerythrobilin. These results indicate two gustatory pathways for aplysioviolin and phycoerythrobilin: one independent of amino acids and bile salts and another shared with some amino acids. PMID- 22200976 TI - Lowered nudix type 5 (NUDT5) expression leads to cell cycle retardation in HeLa cells. AB - The molecule 8-oxo-7,8-dihydroguanine (8-oxoGua), an oxidized form of guanine, can pair with adenine or cytosine during nucleic acid synthesis. Moreover, RNA containing 8-oxoGua causes translational errors, thus leading to the production of abnormal proteins. Human NUDT5, a MutT-related protein, catalyzes the hydrolysis of 8-oxoGDP to 8-oxoGMP, thereby preventing misincorporation of 8 oxoGua into RNA. To investigate the biological roles of NUDT5 in mammalian cells, we established cell lines with decreased level of NUDT5 expression. In NUDT5 inhibited cells, the RNA oxidation was not significantly higher than that of normal cells. However, the cell cycle G1 phase was significantly delayed, and cell numbers in both S and G2/M phases were reduced, indicating that cell proliferation was hampered by NUDT5 suppression. Key proteins for preventing the G1-S transition, including p53, p16, and Rb were increased, while the Rb phosphorylation was decreased. These results suggested that the NUDT5 protein may play significant roles in regulating the G1-S transition in mammalian cells. PMID- 22200977 TI - Upon the tightrope in prostate cancer: two acrobats on the same tightrope to cross the finishline. AB - Prostate cancer is a multifactorial, multistep progressive disorder that is undruggable to date because of stumbling blocks in the standardization of therapy. It is triggered by a broad range of proteins, signaling networks and DNA damage response modulators. It is becoming increasingly apparent that DNA repair mediators have split personalities, as they are instrumental in suppressing and promoting carcinogenesis. In this article, we discuss on post-transcriptional processing of regulators of DNA damage response, and how DNA repair proteins trigger shuttling of androgen receptor. Substantial fraction of information has been added into the existing literature of ATM biology; however, the particular area of post-transcriptional processing errors and gene therapy for reprogramming of ATM has been left unaddressed in prostate cancer. It is therefore noteworthy that the facet of targeting strategy, antisense morpholino oligonucleotides chemistry, and systematic delivery of AOs has promising outlook in splice targeted antisense-mediated therapy. PMID- 22200978 TI - RNA interference against MDM2 suppresses tumor growth and metastasis in pancreatic carcinoma SW1990HM cells. AB - In our previous study, the mouse double minute 2 (MDM2) was identified as one of the leading genes that promote the metastasis of pancreatic cancer (PC). However, the mechanism by which MDM2 promotes metastasis of PC is not understood. In this study, we show that down-regulation of MDM2 through lentivirus-mediated RNA interference could also suppress in vitro proliferation and in vivo tumor growth, and led to an obvious inhibition of both in vitro invasion and in vivo live metastases of SW1990HM cells which had an over-expression of MDM2 and a higher metastatic potential. Moreover, we also show that the down-regulation of MDM2 induced a significant decrease in MMP9, Ki-67 and increase in P53, E-Cadherin expression, and results in an altered expression of genes involved in metastasis, apoptosis, and cell proliferation. Our results suggest that MDM2 plays an important role in metastasis as well as tumor growth of PC. MDM2 could be a hopeful target for the control of PC. PMID- 22200979 TI - The great descriptor melting pot: mixing descriptors for the common good of QSAR models. AB - The usefulness and utility of QSAR modeling depends heavily on the ability to estimate the values of molecular descriptors relevant to the endpoints of interest followed by an optimized selection of descriptors to form the best QSAR models from a representative set of the endpoints of interest. The performance of a QSAR model is directly related to its molecular descriptors. QSAR modeling, specifically model construction and optimization, has benefited from its ability to borrow from other unrelated fields, yet the molecular descriptors that form QSAR models have remained basically unchanged in both form and preferred usage. There are many types of endpoints that require multiple classes of descriptors (descriptors that encode 1D through multi-dimensional, 4D and above, content) needed to most fully capture the molecular features and interactions that contribute to the endpoint. The advantages of QSAR models constructed from multiple, and different, descriptor classes have been demonstrated in the exploration of markedly different, and principally biological systems and endpoints. Multiple examples of such QSAR applications using different descriptor sets are described and that examined. The take-home-message is that a major part of the future of QSAR analysis, and its application to modeling biological potency, ADME-Tox properties, general use in virtual screening applications, as well as its expanding use into new fields for building QSPR models, lies in developing strategies that combine and use 1D through nD molecular descriptors. PMID- 22200980 TI - A Simple Route for Synthesis of 4-Phospho-D-Erythronate. AB - 4-Phospho-D-erythronate is an intermediate in synthesis of pyridoxal 5'-phosphate in some bacteria and an inhibitor of ribose 5-phosphate isomerase. Previous synthetic schemes for the preparation of 4-phospho-D-erythronate required expensive precursors and typically gave low yields. We report a straightforward synthesis of 4-phospho-D-erythronate from the inexpensive precursor D erythronolactone in 5 steps with a preparatively useful yield of 22%. PMID- 22200981 TI - Use of GlideScope in airway management of a patient with osteogenesis imperfecta. PMID- 22200982 TI - Changes of motor evoked potentials during descending thoracic and thoracoabdominal aortic surgery with deep hypothermic circulatory arrest. AB - BACKGROUND: Paraplegia is a serious complication of descending and thoracoabdominal aortic aneurysms (dTAAs and TAAAs) surgery. Motor evoked potentials (MEPs) enable monitoring the functional integrity of motor pathways during dTAA and TAAA surgery. Although MEPs are sensitive to temperature changes, there are few human data on changes of MEPs during mild and deep hypothermia. Therefore, we investigated changes of MEPs in deep hypothermic circulatory arrest (DHCA) in dTAA and TAAA surgery. METHODS: Fifteen consecutive patients undergoing dTAA and TAAA surgery using DHCA were enrolled. MEPs were elicited and recorded during each degree Celsius change in nasopharyngeal temperature during both the cooling and rewarming phases. Hand and leg skin temperature were also recorded simultaneously. RESULTS: In the cooling phase MEP amplitude decreased lineally in both the hand and leg. The MEP disappeared at ~16 degrees C in both the hand and leg in 10 of 15 patients, but was still elicited in 5 patients. In the rewarming phase MEP in the hand recovered before the temperature reached 20 degrees C for eight patients and 25 degrees C for the other seven patients. In contrast, MEP in the leg recovered below 20 degrees C for two patients and 30 degrees C for three patients. For the other eight patients MEP waves did not recover during the rewarming phase. CONCLUSION: In the cooling phase of DHCA, MEP disappeared at ~16 degrees C in some patients but was still elicited in others. MEP recovered below 25 degrees C in the hand. Recovery of MEP in the leg was, however, extremely variable. PMID- 22200983 TI - Mast-cell-releasing tryptase triggers acute lung injury induced by small intestinal ischemia-reperfusion by activating PAR-2 in rats. AB - Mast cell has been demonstrated to be involved in the small intestinal ischemia reperfusion (IIR) injury, however, the precise role of tryptase released from mast cell on acute lung injury(ALI) induced by IIR remains to be elucidated, our study aimed to observe the roles of tryptase on ALI triggered by IIR and its underlying mechanism. Adult SD rats were randomized into sham-operated group, sole IIR group in which rats were subjected to 75 min superior mesenteric artery occlusion followed by 4 h reperfusion, or IIR being respectively treated with cromolyn sodium, protamine, and compound 48/80. The above agents were, respectively, administrated intravenously 5 min before reperfusion. At the end of experiment, lung tissue was obtained for assays for protein expressions of tryptase and mast cell protease 7 (MCP7) and protease-activated receptor 2 (PAR 2). Pulmonary mast cell number and levels of IL-8 were quantified. Lung histologic injury scores and lung water content were measured. IIR resulted in lung injury evidenced as significant increases in lung histological scores and lung water contents, accompanied with concomitant increases of expressions of tryptase and MCP7, and elevations in PAR-2 expressions and IL-8 levels in lungs. Stabilizing mast cell with cromolyn sodium and inhibiting tryptase with protamine significantly reduced IIR-mediated ALI and the above biochemical changes while activating mast cell with compound 48/80 further aggravated IIR-mediated ALI and the increases of above parameters. Tryptase released from mast cells mediates ALI induced by intestinal ischemia-reperfusion by activating PAR-2 to produce IL-8. PMID- 22200984 TI - Field testing, gene flow assessment and pre-commercial studies on transgenic Solanum tuberosum spp. tuberosum (cv. Spunta) selected for PVY resistance in Argentina. AB - Solanum tuberosum ssp. tuberosum (cv. Spunta) was transformed with a chimeric transgene containing the Potato virus Y (PVY) coat protein (CP) sequence. Screening for PVY resistance under greenhouse conditions yielded over 100 independent candidate lines. Successive field testing of selected lines allowed the identification of two genetically stable PVY-resistant lines, SY230 and SY233, which were further evaluated in field trials at different potato-producing regions in Argentina. In total, more than 2,000 individuals from each line were tested along a 6-year period. While no or negligible PVY infection was observed in the transgenic lines, infection rates of control plants were consistently high and reached levels of up to 70-80%. Parallel field studies were performed in virus-free environments to assess the agronomical performance of the selected lines. Tubers collected from these assays exhibited agronomical traits and biochemical compositions indistinguishable from those of the non-transformed Spunta cultivar. In addition, an interspecific out-crossing trial to determine the magnitude of possible natural gene flow between transgenic line SY233 and its wild relative Solanum chacoense was performed. This trial yielded negative results, suggesting an extremely low probability for such an event to occur. PMID- 22200985 TI - Personality, choice of coping and T stage predict level of distress in head and neck cancer patients during follow-up. AB - The aim of the present study was to investigate to what extent TNM stage, treatment level, personality, choice of coping, mood and health-related quality of life (HRQoL) scores predicted distress as measured by general health questionnaire (GHQ) in successfully treated head and neck squamous cell carcinoma (HNSCC) patients. All patients younger than 80 years who had been diagnosed with HNSCC in western Norway in the period from 1992 to 1997, and who had survived until 1999, were sampled. Ninety-six patients (90% response rate) were included 48 +/- 2 months after diagnosis. We determined personality by the Eysenck personality inventory, coping by the COPE questionnaire; HRQoL by EORTC QLQ questionnaire; and mood by Beck depression inventory (BDI). Fifty-five of 58 eligible patients were interviewed a second time 47 +/- 1 months after the first interview where neuroticism and GHQ-30 questionnaires were answered. Both HRQoL [explained variance (EV), 9-40%] and BDI (EV 26-30%) scores predicted the GHQ scores. Numerical T stage was inversely associated with GHQ scores (EV ~10%). High neuroticism generally predicted high GHQ scores (EV 16-28%). Avoidance focused, problem focused, drinking to cope predicted GHQ scores (EV 8-14%) and high alcohol consumption (EV ~8%) predicted GHQ scores. The present association pattern could still be shown when adjusted for gender, age and educational level when studied by multiple regression analyses. In conclusion, lowered HRQoL, low mood, a high T stage, high alcohol consumption, high neuroticism, coping by avoidance and coping by problem solving directly predicted worse distress as measured by high GHQ scores, whereas neuroticism was also associated with GHQ through choice of coping. PMID- 22200987 TI - In memoriam, Dr. Abhijit Guha, 1957-2011. PMID- 22200989 TI - Defining species: a multi-level approach. AB - Different concepts define species at the pattern-level grouping of organisms into discrete clusters, the level of the processes operating within and between populations leading to the formation and maintenance of these clusters, or the level of the inner-organismic genetic and molecular mechanisms that contribute to species cohesion or promote speciation. I argue that, unlike single-level approaches, a multi-level framework takes into account the complex sequences of cause-effect reinforcements leading to the formation and maintenance of various patterns, and allows for revisions and refinements of pattern-based characterizations in light of the gradual elucidation of the causes and mechanisms contributing to pattern formation and maintenance. PMID- 22200990 TI - Detection of hepatocellular carcinomas with near-infrared fluorescence imaging using indocyanine green: its usefulness and limitation. AB - BACKGROUND: Indocyanine green (ICG), an agent for measuring liver function, becomes fluorescent under near-infrared (NIR) light after binding to serum proteins. Hepatocellular carcinoma (HCC) with a deposit of preoperatively administered ICG becomes clearly detectable under ICG fluorography; however, it remains unclear whether this detection method is always reliable. This case series study was designed to clarify the reliability of this method. METHODS: ICG (0.5 mg/kg) was injected from the 3rd to 28th preoperative day to evaluate hepatic function in 58 patients with HCCs. Preoperative imaging modalities identified 76 HCC foci. The operative fields and resected specimens were observed with an NIR camera system. Preoperatively detected lesions and lesions newly detected by the ICG fluorography were histologically investigated. RESULTS: ICG fluorography identified 73 of 76 preoperatively diagnosed HCC lesions. Intraoperative ICG fluorography visualized 47 lesions in 40 patients. The other 26 lesions showing emission were found in the sectioned specimens under NIR observation. Other than preoperatively diagnosed foci, ICG fluorography visualized 35 new lesions, including 6 HCCs, 2 dysplastic nodules and 27 non neoplastic lesions, such as bile plugs and cysts. The sensitivity of ICG fluorography for HCCs was 96% and its positive predictive value was 71.5%. CONCLUSIONS: Indocyanine green fluorography is useful to detect HCCs; however, attention should be paid to the fact that HCCs may be occasionally overlooked by this imaging method and that lesions detected by this method are not always neoplastic lesions. PMID- 22200988 TI - Advances in Gene Delivery Systems. AB - The transfer of genes into cells, both in vitro and in vivo, is critical for studying gene function and conducting gene therapy. Methods that utilize viral and nonviral vectors, as well as physical approaches, have been explored. Viral vector-mediated gene transfer employs replication-deficient viruses such as retro virus, adenovirus, adeno-associated virus and herpes simplex virus. A major advantage of viral vectors is their high gene delivery efficiency. The nonviral vectors developed so far include cationic liposomes, cationic polymers, synthetic peptides and naturally occurring compounds. These nonviral vectors appear to be highly effective in gene delivery to cultured cells in vitro but are significantly less effective in vivo. Physical methods utilize mechanical pressure, electric shock or hydrodynamic force to transiently permeate the cell membrane to transfer DNA into target cells. They are simpler than viral- and nonviral-based systems and highly effective for localized gene delivery. The past decade has seen significant efforts to establish the most desirable method for safe, effective and target-specific gene delivery, and good progress has been made. The objectives of this review are to (i) explain the rationale for the design of viral, nonviral and physical methods for gene delivery; (ii) provide a summary on recent advances in gene transfer technology; (iii) discuss advantages and disadvantages of each of the most commonly used gene delivery methods; and (iv) provide future perspectives. PMID- 22200991 TI - The relationship of the active and latent forms of TGF-beta1 with marrow fibrosis in essential thrombocythemia and primary myelofibrosis. AB - The aim of this study was to perform an immunohistochemical analysis from 100 megakaryocytes per sample, analyzing positivity and intensity levels of anti-LAP human TGF-beta1 (or Latent TGF-beta1) and anti-TGF-beta1 (or Active TGF-beta1) antibodies from 18 essential thrombocythemia (ET) and 38 primary myelofibrosis (PMF) patients (being 19 pre-fibrotic and 19 fibrotic). Six bone marrow donor biopsies were used as controls. Fibrosis in bone marrow biopsies (BMB) was evaluated according to the European Consensus. The average fibrosis grade differed between each group (P=0.001 or P=0.003). Latent TGF-beta1 values differed significantly between pre-fibrotic (P=0.018) and fibrotic (P=0.031) groups when compared with the control group. The high immunoexpression level of Latent TGF-beta1 in the megakaryocytes from patients with myelofibrosis, which was not observed in patients with essential thrombocythemia, may be associated with the development of bone marrow fibrosis. PMID- 22200992 TI - Transarterial chemoembolization compared with conservative treatment for advanced hepatocellular carcinoma with portal vein tumor thrombus: using a new classification. AB - We aimed to compare the survival benefit of transarterial chemoembolization (TACE) with conservative treatment for patients with advanced hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT), furthermore, to reveal which PVTT types benefit from TACE treatment. From August 2007 to January 2010, a prospective controlled study was performed on consecutive patients with advanced HCC and PVTT. Of a total of 150 patients, 115 were treated with TACE (lipiodol and anticancer agents +/- gelatin sponge embolization), and 35 who refused to accept the procedure were treated with conservative treatment. We performed survival analysis of the two treatment groups and then stratified by a new classification of PVTT that was divided into four types. Overall survival was significantly better in the TACE group than in the conservative group (8.67 months vs. 1.4 months, P<0.001). The overall median survival for types I-IV PVTT were 12.0, 8.3, 5.0, and 2.43 months (P<0.01). On subgroup analysis of PVTT, the median survival in the TACE group compared with conservative group for type I, II, III, and IV PVTT was 19.0 months versus 4.0 months, 11.0 months versus 1.43 months, 7.1 months versus 1.3 months, and 4.0 months versus 1.0 months, respectively (P<0.01). The TACE group had significantly better survival than the conservative group for different extent of PVTT. TACE is an effective treatment mode compared with conservative treatment for HCC and PVTT and may provide a significantly better survival benefit for different extent of PVTT. PMID- 22200993 TI - A Large Chondroitin Sulfate Proteoglycan, Versican, in Porcine Predentin. AB - Proteoglycans and their constituent glycosaminoglycan (GAG) have been proposed to be involved in the inhibition of mineralization in unmineralized tissue, predentin. Among the proteoglycans secreted by odontoblasts, we focused on the large chondroitin sulfate proteoglycan, versican, for its large binding capacity for calcium ions. The aims of this study were the determination of the full length sequence and splicing variants of the porcine versican, and the detection of versican in the porcine predentin. The complete coding sequence of the porcine versican mRNA was cloned to be 11,775 nucleotides long and encode 3,924 amino acids, and four splicing variants, V0, V1, V2 and V3, were characterized in the isolated porcine cartilage cells. The number of potential GAG attachment sites was 15 in the V0 variant, 13 in the V1 variant, 2 in the V2 variant and 0 in the V3 variant. They were deposited in DDBJ. The V1 variant was determined by RT-PCR in the odontoblasts, dental papilla cells, dental follicle cells, periodontal ligament cells, dental pulp cells, and gingival cells of pigs, although a small amount of the V0 valiant was found in the dental papilla cells. The predentin was prepared from developing porcine permanent incisor tooth germs and its soluble proteins were extracted in order to be partially characterized by protein and proteinase profiles. The versican V1 cleavage products were detected in the predentin extract by Western blotting analysis. These results suggested that the versican splice variant V1 implicates both the control of the mineralization and the activities of the predentin metalloproteinases, because it has 13 GAG chains that bind a large amount of calcium. PMID- 22200994 TI - Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9. AB - BACKGROUND: Mitochondrial complex I deficiency is the most common cause of mitochondrial disease in childhood. Identification of the molecular basis is difficult given the clinical and genetic heterogeneity. Most patients lack a molecular definition in routine diagnostics. METHODS: A large-scale mutation screen of 75 candidate genes in 152 patients with complex I deficiency was performed by high-resolution melting curve analysis and Sanger sequencing. The causal role of a new disease allele was confirmed by functional complementation assays. The clinical phenotype of patients carrying mutations was documented using a standardised questionnaire. RESULTS: Causative mutations were detected in 16 genes, 15 of which had previously been associated with complex I deficiency: three mitochondrial DNA genes encoding complex I subunits, two mitochondrial tRNA genes and nuclear DNA genes encoding six complex I subunits and four assembly factors. For the first time, a causal mutation is described in NDUFB9, coding for a complex I subunit, resulting in reduction in NDUFB9 protein and both amount and activity of complex I. These features were rescued by expression of wild-type NDUFB9 in patient-derived fibroblasts. CONCLUSION: Mutant NDUFB9 is a new cause of complex I deficiency. A molecular diagnosis related to complex I deficiency was established in 18% of patients. However, most patients are likely to carry mutations in genes so far not associated with complex I function. The authors conclude that the high degree of genetic heterogeneity in complex I disorders warrants the implementation of unbiased genome-wide strategies for the complete molecular dissection of mitochondrial complex I deficiency. PMID- 22200995 TI - Porcine Amelogenin : Alternative Splicing, Proteolytic Processing, Protein - Protein Interactions, and Possible Functions. AB - Amelogenin is the major secretory product of ameloblasts and is critical for proper tooth enamel formation. Amelogenin isoforms and their cleavage products comprise over 80% of total secretory stage enamel protein. We have isolated and characterized four secreted amelogenin isoforms from developing porcine enamel : P190 (27-kDa), P173 (25-kDa), P132 (18-kDa) and P56 (6.5-kDa ; leucine rich amelogenin polypeptide or LRAP). P190 and P132 are low abundance amelogenins that contain a novel exon 4-encoded segment of lack the exon 3-encoded segment, respectively. P173 is the most abundant (major) amelogenin isoform. Cleavage of P173 by matrix metalloproteinase 20 (Mmp20) occurs at specific sites that generates a set of N-terminal cleavage products : P162 (23-kDa), P148 (20-kDa), P62/P63 (11-kDa), and Trp(45) (6-kDa, tyrosine rich amelogenin polypeptide or TRAP). P148 is the most abundant protein in developing enamel and influences the conversion of amorphous calcium phosphate into hydroxyapatite in vitro. Mmp20 cleaves LRAP, the second abundant amelogenin isoform after Pro(45) and Pro(40). Processing by Mmp20 allows amelogenin cleavage products to serve separate functions. Over time, Mmp20 catalyzes additional cleavages that facilitate the progressive replacement of amelogenin by mineral, so enamel crystals thicken and widen with depth. Besides proteolytic processing, amelogenin protein-protein interactions are critical for function. Far-Western analyses demonstrate that the larger amelogenins (P173, P162, and P148) are only able to interact with larger amelogenins. No amelogenin-amelogenin interactions are observed for the smaller amelogenin cleavage products, TRAP or LRAP Amelogenin doesn't interact with the 32-kDa glycosylated enamelin cleavage product, unless it it partially deglycosylated. PMID- 22200997 TI - Mornitoring is often seen as the poor relative to research. PMID- 22200996 TI - Role of TET2 mutations in myeloproliferative neoplasms. AB - Recently, 5-hydroxymethylcytosine (5-hmC), the 6th base of DNA, was discovered as the product of the hydroxylation of 5-methylcytosine (5-mC) by the ten-eleven translocation (TET) oncogene family members. One of them, TET oncogene family member 2 (TET2), is mutated in a variety of myeloid malignancies, including in 15% of myeloproliferative neoplasms (MPNs). Recent studies tried to go further into the biological and epigenetic function of TET2 protein and 5-hmC marks in the pathogenesis of myeloid malignancies. Although its precise function remains partially unknown, TET2 appears to be an important regulator of hematopoietic stem cell biology. In both mouse and human cells, its inactivation leads to a dramatic deregulation of hematopoiesis that ultimately triggers blood malignancies. Understanding this leukemogenic process will provide tools to develop new epigenetic therapies against blood cancers. PMID- 22200998 TI - Insight in impacts of atmospheric emissions of population on air, soil and water quality, and thereby on terrestrial and aquatic ecosystems. PMID- 22200999 TI - Regular monitoring of ecosystems was initiated in Sweden during the 1970's. PMID- 22201000 TI - Recovery of soil water, groundwater, and streamwater from acidification at the Swedish integrated monitoring catchments. AB - Recovery from anthropogenic acidification in streams and lakes is well documented across the northern hemisphere. In this study, we use 1996-2009 data from the four Swedish Integrated Monitoring catchments to evaluate how the declining sulfur deposition has affected sulfate, pH, acid neutralizing capacity, ionic strength, aluminum, and dissolved organic carbon in soil water, groundwater and runoff. Differences in recovery rates between catchments, between recharge and discharge areas and between soil water and groundwater are assessed. At the IM sites, atmospheric deposition is the main human impact. The chemical trends were weakly correlated to the sulfur deposition decline. Other factors, such as marine influence and catchment features, seem to be as important. Except for pH and DOC, soil water and groundwater showed similar trends. Discharge areas acted as buffers, dampening the trends in streamwater. Further monitoring and modeling of these hydraulically active sites should be encouraged. PMID- 22201001 TI - Epiphytic algae and lichen cover in boreal forests-a long-term study along a N and S deposition gradient in Sweden. AB - The aim was to describe spatiotemporal patterns of colonization of spruce branches by algae and lichens and the relationship with decreasing deposition of N and S. Coverage was estimated annually over 10 years for four Swedish Integrated Monitoring catchments with varying deposition levels. Initial hypotheses were that algal coverage would be positively correlated with deposition and that lichen coverage would be negatively correlated with S and positively with N deposition. Data were analyzed using regression, ANOVA, and partial least square regression. The results showed a temporal decrease in the coverage of algae but an increase in colonization rates, while lichens showed less uniform patterns. Within catchments, algae and lichen coverages were positively correlated with mainly S deposition. Across catchments, coverage of algae increased, while the coverage of lichens decreased with increasing N and S deposition. Colonization rates of both algae and lichens showed weak correlations with both spatial and temporal trends in N and S deposition. Thus, while N and S deposition had an effect on the colonization and coverage of algae and lichens, other factors are also important. PMID- 22201002 TI - Understorey vegetation stability and dynamics in unmanaged boreal forests along a deposition gradient in Sweden. AB - The aims of this study were to investigate spatial patterns and temporal changes in understorey vegetation at four forest catchments forming a depositional gradient. Inventories of the bottom and field layers were carried out in the 1990s and repeated after 5-14 years, depending on catchment. It was hypothesized that changes and patterns in ground vegetation would be related to changes and patterns in N and S deposition. The data were analyzed using Ellenberg indices and multivariate methods. All catchments showed temporal changes in species composition. Analyses of the bottom layer were confounded by a change of field staff, but after accounting for this observer effect, differences in species composition between the catchments remained. Within catchments, the changes in species composition were unrelated to N or S deposition. Relationships between environmental factors, expressed as Ellenberg indices, and compositional patterns differed between catchments although Ellenberg indices showed small temporal changes. PMID- 22201003 TI - Long-term monitoring of scots pine litter decomposition rates throughout Sweden indicates formation of a more recalcitrant litter in the South. AB - Decomposition studies were carried out at sites throughout Sweden, including the four Integrated Monitoring sites. Scots pine needle litterbag weight loss measurements over 3 or 5 years were determined at 26 sites and repeated up to 27 times, depending on the site. Humus layer respiration rates were determined for 20 sites in 1987-1989 and repeated in 2007-2008. Partial Least Squares (PLS) regression was used to elucidate the relative importance of climatic and soil factors. Annual needle weight losses decreased only slowly (20-10%) over 3-5 years for all northern (>60 degrees N) sites but decreased sharply from 30 to 10% in the third year in southern (<60 degrees N) sites. Respiration rates of southern sites were less (40% on average) than those of northern sites. Humus layer N was positively correlated to needle weight loss during the first and the second years, but negatively correlated in the third year and to respiration rates. The results indicated that litter formed in southern Sweden became more recalcitrant in later stages of decomposition compared to litter produced in northern Sweden. PMID- 22201004 TI - Assessment of uncertainty in long-term mass balances for acidification assessments: a MAGIC model exercise. AB - Long-term (1860-2010) catchment mass balance calculations rely on models and assumptions which are sources of uncertainty in acidification assessments. In this article, we report on an application of MAGIC to model acidification at the four Swedish IM forested catchments that have been subject to differing degrees of acidification stress. Uncertainties in the modeled mass balances were mainly associated with the deposition scenario and assumptions about sulfate adsorption and soil mass. Estimated base cation (BC) release rates (weathering) varied in a relatively narrow range of 47-62 or 42-47 meq m(-2) year(-1), depending on assumptions made about soil cation exchange capacity and base saturation. By varying aluminum solubility or introducing a dynamic weathering feedback that allowed BC release to increase at more acidic pHs, a systematic effect on predicted changes in acid neutralizing capacity (DeltaANC ca. 10-41 MUeq l(-1)) and pH (ca. DeltapH = 0.1-0.6) at all sites was observed. More robust projections of future changes in pH and ANC are dependent on reducing uncertainties in BC release rates, the timing, and extent of natural acidification through BC uptake by plants, temporal changes in soil element pools, and fluxes of Al between compartments. PMID- 22201005 TI - Simulating dissolved organic carbon dynamics at the swedish integrated monitoring sites with the integrated catchments model for carbon, INCA-C. AB - Surface water concentrations of dissolved organic carbon ([DOC]) are changing throughout the northern hemisphere due to changes in climate, land use and acid deposition. However, the relative importance of these drivers is unclear. Here, we use the Integrated Catchments model for Carbon (INCA-C) to simulate long-term (1996-2008) streamwater [DOC] at the four Swedish integrated monitoring (IM) sites. These are unmanaged headwater catchments with old-growth forests and no major changes in land use. Daily, seasonal and long-term variations in streamwater [DOC] driven by runoff, seasonal temperature and atmospheric sulfate (SO4(2-)) deposition were observed at all sites. Using INCA-C, it was possible to reproduce observed patterns of variability in streamwater [DOC] at the four IM sites. Runoff was found to be the main short-term control on [DOC]. Seasonal patterns in [DOC] were controlled primarily by soil temperature. Measured SO4(2-) deposition explained some of the long-term [DOC] variability at all sites. PMID- 22201006 TI - Riparian zone influence on stream water dissolved organic carbon concentrations at the Swedish integrated monitoring sites. AB - Short-term variability in stream water dissolved organic carbon (DOC) concentrations is controlled by hydrology, climate and atmospheric deposition. Using the Riparian flow-concentration Integration Model (RIM), we evaluated factors controlling stream water DOC in the Swedish Integrated Monitoring (IM) catchments by separating out hydrological effects on stream DOC dynamics. Model residuals were correlated with climate and deposition-related drivers. DOC was most strongly correlated to water flow in the northern catchment (Gammtratten). The southern Aneboda and Kindla catchments had pronounced seasonal DOC signals, which correlated weakly to flow. DOC concentrations at Gardsjon increased, potentially in response to declining acid deposition. Soil temperature correlated strongly with model residuals at all sites. Incorporating soil temperature in RIM improved model performance substantially (20-62% lower median absolute error). According to the simulations, the RIM conceptualization of riparian processes explains between 36% (Kindla) and 61% (Aneboda) of the DOC dynamics at the IM sites. PMID- 22201008 TI - Anglo-Indian residential care homes: accounts from Kolkata and Melbourne. AB - Research was conducted in four Anglo-Indian residential care facilities (one in Melbourne and three in Kolkata) which identified the distinctly Anglo-Indian characteristics of the institutions and sought to ascertain residents' attitudes towards and reasons for living in them. The methods used were ethnographic: participant observation fieldwork combined with semi-structured informal interviews over the course of multiple research visits. The histories of the institutions were examined, including the purpose of their establishment. All four institutions are unique, but share common characteristics such as distinctly Anglo-Indian food, religious observance, and hospitality. Residents' values and background, accents, and their (and their children's) migration experiences are also shared. This article looks closely at what makes these homes distinctly Anglo-Indian, and compares residents' narratives about why they chose to live in the ethnic-specific residential facilities in the two cities. This forms the basis for the argument presented here that in an increasingly globalised world the need for ethnic-specific homes for residents to spend their last years in a culturally familiar environment is growing rapidly. In conjunction with this is a need for published research on such homes to provide models for these types of facilities. PMID- 22201010 TI - Development of percutaneously insertable/removable interspinous process spacer for treatment of posture-dependent lumbar spinal-canal stenosis: preclinical feasibility study using porcine model. AB - PURPOSE: A procedure using an interspinous process spacer (IPS) was recently developed for the treatment of posture-dependent lumbar spinal-canal stenosis (LSS) patients. We developed a novel IPS which can be inserted with simpler procedures and removed percutaneously. The objectives of this study were: (1) to evaluate the feasibility and safety of this novel technique, and (2) to assess the effectiveness of this spacer in terms of preventing an increase of epidural pressure in lumbar extension using a porcine model. METHODS: Eight young pigs were used. Under general anesthesia and image guidance, the spacers were inserted. Three months after operation, MR images were taken and all spacers were removed. Blood samples were obtained before and 1, 3, 7 days after surgery. After killing the animals, the lumbar spines were observed macroscopically. Another six animals were used. Under general anesthesia and image guidance, a flexible pressure transducer was inserted into the epidural space and epidural pressure was measured in neutral and at maximum extension with and without spacer insertion. RESULTS: Percutaneous insertion and removal of the spacer was successful for all animals through small skin incisions. MR images showed minimal damage to the muscle. No significant up-regulation of Interleukin-6 (IL-6) and CRP was detected. Macroscopic observation of the lumbar spine 3 months after the operation revealed that the area of the interspinous process contacting with the inserted spacer showed some bone erosion/remodeling. Insertion of the spacer did not affect the epidural pressure in neutral but significantly prevented an increase of epidural pressure in lumber extension. CONCLUSIONS: This study demonstrated that the percutaneous insertion and removal of a novel IPS was feasible and safe using a simple technique. Furthermore, this procedure can be recognized as minimally invasive surgery from the viewpoint of skin incision, short insertion track, inflammatory mediators, and muscle damage. Improvements should be attempted in future studies using softer or more elastic materials for the spacer to lessen bone erosion/remodeling at contacting area of the inserted spacer. PMID- 22201009 TI - Transmembrane mucins as novel therapeutic targets. AB - Membrane-tethered mucin glycoproteins are abundantly expressed at the apical surfaces of simple epithelia, where they play important roles in lubricating and protecting tissues from pathogens and enzymatic attack. Notable examples of these mucins are MUC1, MUC4 and MUC16 (also known as cancer antigen 125). In adenocarcinomas, apical mucin restriction is lost and overall expression is often highly increased. High-level mucin expression protects tumors from killing by the host immune system, as well as by chemotherapeutic agents, and affords protection from apoptosis. Mucin expression can increase as the result of gene duplication and/or in response to hormones, cytokines and growth factors prevalent in the tumor milieu. Rises in the normally low levels of mucin fragments in serum have been used as markers of disease, such as tumor burden, for many years. Currently, several approaches are being examined that target mucins for immunization or nanomedicine using mucin-specific antibodies. PMID- 22201011 TI - Effect of dietary monensin inclusion on performance, nutrient utilisation, rumen volatile fatty acid concentration and blood status of West African dwarf bucks fed with basal diets of forages. AB - This experiment investigated the effect of dietary monensin on performance, nutrient utilisation, rumen volatile fatty acid and blood status in West African dwarf (WAD) goats fed with basal diets of forages. Four concentrate supplements were formulated to include 0 (MO), 15 (M15), 30 (M30) and 45 (M45) mg monensin/kg dry matter. Twenty-four WAD bucks (7.3 +/- 1.20 kg initial body weight, aged 9-12 months) were randomly allotted to four experimental diets in a completely randomised design for 90 days, six animals per diet. Results indicated that animals fed M15, M30 and M45 diets had lower (P < 0.01) dry matter and water intake than those fed M0 diet. Crude protein and neutral detergent fibre intakes by the bucks followed similar trend. Animals on M15, M30 and M45 had better (P < 0.001) feed and protein efficiency ratio than those fed M0 diet. Rumen pH and total volatile fatty acid concentration were maintained (P > 0.05) while monensin decreased (P < 0.001) acetate/propionate ratio. Blood glucose increased (P < 0.001) from 59.1 mg/dl in animals on M0 diet to 67.8, 66.0 and 66.3 mg/dl in animals on M15, M30 and M45 diets. Overall, there were no variations among animals on M15, M30 and M45 diets. It is concluded that feeding monensin at 15 to 45 mg/kg DM of supplemental concentrate diets to West African dwarf bucks could be effective in improving feed and protein efficiency, manipulating the rumen for increased propionate production and increasing blood glucose levels. PMID- 22201012 TI - Limitations and potentials of dual-purpose cow herds in Central Coastal Veracruz, Mexico. AB - Feed chemical and kinetic composition and animal performance information was used to evaluate productivity limitations and potentials of dual-purpose member herds of the Genesis farmer organization of central coastal Veracruz, Mexico. The Cornell Net Carbohydrate and Protein System model (Version 6.0) was systematically applied to specific groups of cows in structured simulations to establish probable input-output relationships for typical management, and to estimate probable outcomes from alternative management based on forage-based dietary improvements. Key herd vulnerabilities were pinpointed: chronic energy deficits among dry cows of all ages in late gestation and impeded growth for immature cows. Regardless of the forage season of calving, most cows, if not all, incur energy deficits in the final trimester of gestation; thus reducing the pool of tissue energy and constraining milking performance. Under typical management, cows are smaller and underweight for their age, which limits feed intake capacity, milk production and the probability of early postpartum return to ovarian cyclicity. The substitution of good-quality harvested forage for grazing increased predicted yields by about one-third over typical scenarios for underweight cows. When diets from first parturition properly supported growth and tissue repletion, milk production in second and third lactations was predicted to improve about 60%. Judiciously supplemented diets based on good quality grass and legume forages from first calving were predicted to further increase productivity by about 80% across a three-lactation cow lifetime. These dual-purpose herd owners have large incentives to increase sales income by implementing nutritional strategies like those considered in this study. PMID- 22201013 TI - Comparison of conventional and non-conventional techniques for the diagnosis of bovine brucellosis in Sudan. AB - The objective of the present study was to detect brucellosis in suspected dairy cattle in Khartoum State, Sudan using the conventional serological tests and tests done on milk in comparison to a PCR-based technique. Milk and blood samples collected simultaneously from suspected brucellosis cows (n = 147) in 12 different dairy farms around Khartoum State were used in the study. Overall, 54 (36.7%) of the total milk samples were positive according to the milk ring test (MRT), while 29 (19.7%) of the serum samples were positive according to the Rose Bengal test (RBT); microscopy on modified Ziehl-Neelsen-stained slides detected 13.6% of the cases, and recovery of Brucella species on both Brucella medium and tryptic soya agar was 7.5%. Thirty-three (22.4%) samples were found positive on PCR-amplified IS711 which were then taken as positive brucellosis cases. The differences of RBT and PCR-IS711 from MRT were highly significant (P < 0.05). MRT detected more cases of bovine brucellosis compared to RBT, PCR, microscopy, and culture. MRT is recommended as a noninvasive test compared to RBT, and it is less expensive compared to PCR and culture. PMID- 22201014 TI - Advances in stroke therapy. AB - Stroke is a leading cause of death, long-term disability, and socioeconomic costs, highlighting the urgent need for more effective treatments. Intravenous administration of tissue plasminogen activator (t-PA) is the only FDA-approved therapy to re-establish cerebral blood flow. However, because of increased risk of hemorrhage beyond 3 h post stroke, few stroke patients (1-2%) benefit from t PA; t-PA, which has neurotoxic effects, can also aggravate the extent of reperfusion injury by increasing blood-brain barrier permeability. An alternative strategy is needed to extend the window of intervention, minimize damage from reperfusion injury, and promote brain repair leading to neurological recovery. Reactive oxygen species (ROS), generated soon after ischemia and during reperfusion and thereafter, are considered the main mediators of ischemic injury. Antioxidant enzymes such as catalase, superoxide dismutase, etc. can neutralize ROS-mediated injury but their effective delivery to the brain remains a challenge. In this article, we review various therapeutic approaches including surgical interventions, and discuss the potential of nanoparticle-mediated delivery of antioxidants for stroke therapy. PMID- 22201016 TI - Single-lead VDD pacing--a serious alternative for atrioventricular synchronous pacing in patients with atrioventricular block? PMID- 22201015 TI - Neuroimaging results impose new views on Alzheimer's disease--the role of amyloid revised. AB - Huge progress has been made in unraveling the mysteries of Alzheimer's disease (AD), but we still do not understand the basic mechanisms that set off the cascade of pathological events. In May 2011, the National Institute on Aging Alzheimer's Association published new diagnostic guidelines, expected to have huge impact on AD research and clinical practice. However, the new guidelines are already criticized for being biased in favor of a specific theory of the pathophysiological origins of AD-the amyloid cascade hypothesis. Shortly before publication of the guidelines, a hypothetical model of the dynamic biomarkers of the Alzheimer's pathological cascade was published, taking as starting point that biomarkers reflecting brain levels of amyloid become deviant long before brain atrophy, cognitive dysfunction, or clinical symptoms are manifest. This model has already attracted substantial interest and arguably represents a dominating view within human research on AD. Here we critically review the evidence for the view of amyloid as an initiating event in the pathological cascade and discuss how central assumptions of this hypothesis affect how results from contemporary human AD research are understood. Interpretations of new results are greatly impacted by researchers' view on the role of amyloid, and identical observations are sometimes taken to support radically opposing views on the amyloid hypothesis. We argue that the canonical view of the role of amyloid as the main causal factor in AD may not be correct and that evidence from recent neuroimaging studies indicates that amyloid is neither necessary nor sufficient, for the manifestation of AD-like brain atrophy. PMID- 22201017 TI - Sinus nodal response to adenosine relates to the severity of sinus node dysfunction. AB - AIMS: It is unknown as to whether the result of adenosine testing for the diagnosis of sinus node dysfunction (SND) depends on the clinical presentation. We investigated whether syncope or presyncope are associated with a more pronounced sinus nodal inhibition by adenosine in SND. METHODS AND RESULTS: We studied 46 patients with SND, 33 with syncope or presyncope and 13 without such history. Controls were 30 subjects undergoing electrophysiological studies for supraventricular tachycardia or unexplained syncope. We calculated the corrected sinus node recovery time after intravenous adenosine 0.15 mg/kg (ADSNRT) as well as after atrial pacing (CSNRT). Corrected sinus node recovery time values >525 ms were considered abnormal. Corrected sinus node recovery time after adenosine injection was more prolonged in SND patients with syncope or presyncope as compared with those without such history [median: 4900 inter-quartile range (IQR): 920-8560 ms vs. median: 280 IQR: 5-908 ms; P< 0.005]. In SND patients with syncope or presyncope ADSNRT was more prolonged than CSNRT (median: 4900 IQR: 920 8560 ms vs. median: 680 IQR: 359-1650 ms, P< 0.01). In SND patients without syncope or presyncope no statistical difference was noted between ADSNRT and CSNRT (median: 280 IQR: 5-908 ms vs. median: 396 IQR: 270-600 ms, P = 0.80). The sensitivity of CSNRT for SND diagnosis was 57% and the specificity was 100%. A cut-off of 1029 ms for ADSRNT yields the same sensitivity with a specificity of 96.6%. CONCLUSION: In patients with SND syncope or presyncope relate to an exaggerated sinus nodal suppression by adenosine. Prolonged ADSNRT can diagnose cases with severe underlying SND where a more aggressive management strategy is probably warranted. PMID- 22201018 TI - Comparison of tools and techniques for implanting pacemaker leads on the ventricular mid-septum. AB - INTRODUCTION: Many physicians target the interventricular septum for pacemaker implantation, but the lead may inadvertently end up in an anterior position. AIMS: We sought to compare two stylet shapes to achieve mid-septal lead placement, as well as the utility of a novel right anterior oblique (RAO) fluoroscopic landmark. METHODS AND RESULTS: Patients undergoing pacemaker implantation were enrolled into four consecutive groups according to stylet shape: a standard curve [two-dimensional (2D) stylet] or with an additional distal posterior curve [three-dimensional (3D) stylet], and whether RAO fluoroscopy was used. Left oblique anterior (LAO) and postero-anterior (PA) fluoroscopic views were used in all cases. After implantation, validation of right ventricular lead position (septal vs. anterior) was performed by echocardiography. A total of 113 patients were included, of whom lead position could be validated in 106 patients. Septal position was achieved in only 10 of 22 (45%) patients in the 2D stylet group and in 17 of 23 (74%) patients in the 3D stylet group (P = 0.07) when only PA and LAO fluoroscopy were used. Results were significantly improved by additional use of RAO fluoroscopy, with successful septal placement in 25 of 28 (89%) patients in the 2D stylet + RAO group (P = 0.001) and 32 of 33 (97%) patients in the 3D stylet + RAO group (P = 0.015). CONCLUSIONS: A septal lead position was obtained in only about half of the patients when a 2D stylet was used with only LAO and PA fluoroscopic views. A 3D stylet was useful to attain the target position, and additional RAO fluoroscopy significantly improved success rate with both stylet shapes. PMID- 22201019 TI - Effect of dose and dosage interval on the oral bioavailability of docetaxel in combination with a curcumin self-emulsifying drug delivery system (SEDDS). AB - The present study investigated the effects of a curcumin self-emulsifying drug delivery systems (SEDDS) on the pharmacokinetics of orally administered docetaxel in rats. A single dose of docetaxel was orally administered (30 mg/kg) alone or after oral curcumin SEDDS (25, 50, 100 and 150 mg/kg) administration with time intervals of 0, 15 and 30 min, respectively. After oral administration, the C (max) and the area under the plasma concentration-time curve (AUC) of docetaxel were significantly increased (0 min, p < 0.05; 15 and 30 min, p < 0.01) by 2.2, 4.7 and 4.6 times and 2.0, 3.8 and 4.1 times compared to that of control group, respectively, after treatment with curcumin SEDDS (100 mg/kg) for each interval. Moreover, The C (max) of docetaxel was increased by 2.6 and 4.4 times in response to 25 and 50 mg/kg curcumin SEDDS treatment, respectively, the corresponding AUC was increased by about 2.4 and 3.1 times, and consequently the absolute bioavailabilities of docetaxel in these two treatment groups were 7.9 and 10.4%, respectively, which showed a significant increase of about 2.4- and 3.2-fold in comparison to the control value (3.3%). However, no further increase in either AUC or C (max) values of docetaxel was observed as the curcumin SEDDS dose was increased from 50 to 150 mg/kg. It is worth noting that the presence of curcumin SEDDS did not significantly decrease the systemic clearance, which was shown by the almost unchanged terminal half-life (t (1/2)) of docetaxel in all treatment groups. Thus, the enhanced bioavailability of oral docetaxel by curcumin SEDDS seemed to be likely due to an inhibition function of cytochrome P450 (CYP) 3A and P-glycoprotein (Pgp) in the intestines of the rats. However, further in vivo studies are needed to verify these hypotheses. PMID- 22201020 TI - PDIA3 mRNA expression and IL-2, IL-4, IL-6, and CRP levels of acute kidney allograft rejection in rat. AB - Kidney transplantation to treat end-stage renal disease has evolved rapidly from the first successful transplantations to the current widespread use of grafts from both cadaveric and living donors. But acute rejection is still a strong risk factor for chronic rejection in recipients of renal grafts. To investigate possible mechanisms, we describe a comparison between differentially proteins expression and immune markers profile (IL-2, IL-4, IL-6, and CRP) of acute rejection and the controls. Through quantitative real-time RT-PCR confirmation, PDIA3 mRNA and protein expression levels in serum and transplanted kidney in experiment group was significantly (P < 0.05) higher than that in control group. Immunity analysis showed that plasma IL-2, IL-4, IL-6, and CRP levels were higher in experimental rats than those in control rats. Our data thus indicate that PDIA3 might be potentially involve into the occurence and development of acute rejection response in renal transplantation and increased plasma IL-2, IL-4, IL 6, and CRP levels play an important role to prevent acute kidney allograft rejection in rats. PMID- 22201021 TI - Analysis of the bacterial diversity in the fecal material of the endangered Yangtze finless porpoise, Neophocaena phocaenoides asiaeorientalis. AB - The aim of this study was to determine the bacteria present in the fecal material of the endangered Yangtze finless porpoise, Neophocaena phocaenoides asiaeorientalis. Fecal samples were collected from 12 Yangtze finless porpoises living in the wild at Poyang Lake, located in Jiangxi Province, China. To determine the bacterial diversity, a 16S rRNA gene clone library using the bacterial PCR primers fD1 and rP2, was prepared. A total of 138 near-full-length sequences were analyzed and 39 operational taxonomic units (OTUs) were identified. Sequences showing >=97% similarity were grouped together as an OTU. Six different phyla were identified in which 38 OTUs were classified. Most of the OTUs contained sequences belonged to the phylum Firmicutes (51.3%), followed by Tenericutes (17.9%), Proteobacteria (15.4%), Actinobacteria (7.7%), Deinococcus Thermus (2.6%) and Cyanobacteria (2.6%). A phylum could not be assigned for one clone within one OTU (2.6%). It appears that the Yangtze finless porpoise has a more diverse range of bacteria compared to other aquatic mammals, such as seals. PMID- 22201022 TI - Constitutive expression of barley alpha-amylase in Pichia pastoris by high density cell culture. AB - alpha-amy gene amplified from barley genome was cloned into MCS of pGAP9K to generate pGAP9K-alpha-amy which was then transformed into Pichia pastoris GS115 by electroporation. Transformants with multi-copies and high expression for the foreign gene were selected on G418 containing plate and expression analysis. The fermentation was carried out in a 50 l bioreactor with 20 l working volume, using a high-density cell culture method by continuously feeding with 50% glycerol-0.8% PTM4 to the growing culture for 54 h at 30 degrees C. Under the control of GAP promoter (pGAP), alpha-amy gene was constitutively expressed. At the end of the fermentation, the alpha-AMY expression reached 125 mg/l, while the biomass growth was 186 as measured by absorption of 600 nm. The secreted alpha-AMY was purified to 97.5% by SP-Sepharose FF ion-exchange chromatography and affinity purification. The recombinant alpha-AMY showed activity on hydrolysis of starch. PMID- 22201023 TI - Molecular cloning and characterization of OsUPS, a U-box containing E3 ligase gene that respond to phosphate starvation in rice (Oryza sativa). AB - The ubiquitin-26S proteasome system is important in the quality control of intracellular proteins. The ubiquitin-26S proteasome system includes the E1 (ubiquitin activating), E2 (ubiquitin conjugating), and E3 (ubiquitin ligase) enzymes. U-box proteins are a derived version of RING-finger domains, which have E3 enzyme activity. Here, we present the isolation of a novel U-box protein, U box containing E3 ligase induced by phosphate starvation (OsUPS), from rice (Oryza sativa). The cDNA encoding the O. sativa U-box protein (OsUPS) comprises 1338 bp, with an open reading frame of 445 amino acids. The amino acid sequence of OsUPS cDNA shows 41-79% identity with other plant U-box homologous genes. The open reading frame of the OsUPS protein is comprised of notable domains: a single ~70-amino acid domain and a GKL domain that contains conserved glycine, lysine/arginine residues and leucine-rich feature. We found that full-length expression of OsUPS was up-regulated in both rice plants and cell culture in the absence of inorganic phosphate (P(i)). A self-ubiquitination assay indicated that the bacterially expressed OsUPS protein had E3 ligase activity, and subcellular localization results showed that OsUPS was located in the chloroplast. These results support the notion that OsUPS plays an important role in the P(i) signaling pathway through the ubiquitin-26S proteasome system. PMID- 22201024 TI - Characterization of reference genes for quantitative real-time PCR analysis in various tissues of Anoectochilus roxburghii. AB - Accurate quantification of transcript profiling with quantitative real time polymerase chain reaction (qRT-PCR) relies on the reliable normalization of an appropriate reference gene. This study reported the identification and validation of nine reference genes, including beta-tubulin (beta-TUB), elongation factor 1 alpha (EF-1alpha), elongation factor 1 beta (EF-1beta), glyceraldehyde-3 phosphate dehydrogenase (GAPDH), ubiquitin (UBQ), actin 1/2(ACT-1 and ACT-2), 18S rRNA, and 26S rRNA, from Anoectochilus roxburghii (Wall.) Lindl., a valuable herb remedy widely used for various diseases treatment in traditional Chinese medicine. Transcriptional levels of the candidate reference genes were examined using qRT-PCR analysis and revealed differential expression of the genes in the leaf, stem, root, flower, and peduncle tissues. The relative quantities data were subjected to geNorm software for ranking the expression stability of the reference genes and the results showed that EF-1beta and ACT-2 were the two best stable genes whereas GAPDH and 26S rRNA did not favor normalization of qRT-PCR in these tissues. The expression pattern of a squalene synthase encoding gene (SS) was also determined in parallel. The analyses were in great consistency when the qRT-PCR data was normalized to the expression of each or both of EF-1beta and ACT 2 as the internal control, further confirming the reliability of EF-1beta and ACT 2 as the best internal control. The present study provided the first important clues for accurate data normalization in transcript profiling in A. roxburghii, which will be essential to further functional genomics study in the valuable medicinal plant. PMID- 22201025 TI - Genetic variations in KIFC1 and the risk of aspirin exacerbated respiratory disease in a Korean population: an association analysis. AB - Modest effects of genes in various pathways are significant in the etiology of complex human diseases, including aspirin exacerbated respiratory disease (AERD). By functioning as a relevant component of respiratory processes, the human kinesin family member C1 (KIFC1) is hypothesized to play a role in AERD pathogenesis. A case-control analysis was carried out by comparing the genotype distribution of six KIFC1 single-nucleotide polymorphisms between 93 AERD cases and 96 aspirin-tolerant asthma controls in a Korean population. After controlling for confounds, logistic and regression models via various modes of genetic inheritance facilitated the association analysis. Initial results revealed significant association at 0.05 level of significance between several KIFC1 variations and AERD (P = 0.01-0.05, OR = 1.81-1.90) as well as fall rate of forced expiratory volume in the 1st second, an important diagnostic marker of airways constriction (P = 0.04-0.05). However, the signals were not deemed significant after multiple testing corrections (P (corr) > 0.05). Although the results do not support a major role of KIFC1 in AERD pathogenesis in a Korean asthma cohort, further replication and validation studies are required to clarify the current findings. PMID- 22201026 TI - Genome-wide pathway analysis of a genome-wide association study on psoriasis and Behcet's disease. AB - The aim of this study was to identify candidate causal single nucleotide polymorphisms (SNPs) and candidate causal mechanisms of psoriasis and Behcets's disease (BD) and to generate an SNP -> gene -> pathway hypothesis. A psoriasis genome-wide association study (GWAS) dataset that included 436,192 SNPs in 1,409 psoriasis cases and 1,436 controls of European descent and a BD GWAS dataset that contained 310,324 SNPs in 1,215 BD cases and 1,278 controls were used in this study. Identify candidate causal SNPs and pathways (ICSNPathway) analysis was applied to the GWAS datasets. ICSNPathway analysis identified 15 candidate causal SNPs and 28 candidate causal pathways. The top five candidate causal SNPs were rs1063478 (P = 1.45E-10), rs8084 (P = 2.20E-08), rs7192 (P = 5.18E-08), rs20541 (P = 5.30E-06), and rs1130838 (P = 5.65E-06), which with the exception of rs20541 [interleukin (IL)-13] are at human leukocyte antigen (HLA) loci. These candidate causal SNPs and pathways provided ten hypothetical biological mechanisms. The most strongly associated pathway concerned HLA. When HLA loci were excluded, ICSNPathway analysis provided one hypothetical biological mechanism. rs20541 (non_synonymous_coding) -> IL-13 -> dendritic cell involvement in the regulation of Th1 and Th2 development, and the GATA3 pathway. ICSNPathway analysis identified four candidate causal SNPs, eleven candidate causal pathways, and three hypothetical biological mechanisms. One of them was as follows: rs2072895 (non_synonymous_coding & splice-site) and rs2735059 (non_synonymous_coding) -> HLA-F -> type I diabetes mellitus, antigen processing and presentation, and autoimmune thyroid disease. The application of ICSNPathway analysis to GWAS dataset of psoriasis and BD resulted in the identification of candidate causal SNPs and candidate pathways that might contribute to psoriasis susceptibility. PMID- 22201027 TI - Variant allele of CHEK2 is associated with a decreased risk of esophageal cancer lymph node metastasis in a Chinese population. AB - Growing evidence suggests that the checkpoint kinase 2 (CHEK2) signaling pathway occupies a central position in the signaling networks of DNA-damage signaling. Many functional and molecular epidemiological studies have evaluated the association between genetic variants of CHEK2 and various cancers. To evaluate the relationship between CHEK2 functional genetic variants and esophageal cancer risk and the risk of lymph node metastasis among a Chinese population. We genotyped CHEK2 rs738722, rs2236141 and rs2236142 single nucleotide polymorphisms (SNPs) using the matrix assisted laser desorption/ionization time-of-flight mass spectrometry assay in a case-controlled study, including 380 esophageal cancer cases and 380 healthy controls in a Chinese population. We found that none of the three polymorphisms achieved significant difference in their distributions between esophageal cancer cases and controls. Multiple logistic regression analyses revealed that esophageal cancer risk was not associated significantly with the variant genotypes of the three CHEK2 polymorphisms as compared with their wild-type genotypes. However, we found that functional variant rs738722 and rs2236142 in CHEK2 might contribute to susceptibility to lymph node metastasis. Our data did not support a significant association between CHEK2 SNPs and the risk of esophageal cancer. Functional variant CHEK2 rs738722 and rs2236142 might contribute to lymph node metastasis susceptibility. The CT allele of SNP rs738722 and the GC allele of SNP rs2236142 might be a protective factor of the risk for lymph node metastasis of esophageal cancer. PMID- 22201028 TI - In vitro release kinetics and physical, chemical and mechanical characterization of a POVIAC(r)/CaCO3/HAP-200 composite. AB - Coralline calcium-hydroxyapatite and calcium carbonate from Porites Porites coral were added to a polymeric matrix based on polyvinyl acetate (POVIAC((r))), to obtain a novel bone substitute composite as well as a system for the controlled drug (cephalexin) release. Composite samples with different compositions were characterized by physical-chemical and mechanical methods. Furthermore, the in vitro release profile of cephalexin and the kinetic behavior of its release from these composites were analyzed by appropriate mathematical models. It was shown that there is no chemical interaction between the inorganic filler and the polymer matrix, each conserving the original properties of the raw materials. The compressive mechanical strength and Young modulus of the composite with 17.5% of POVIAC((r)), has better mechanical properties than those of cancellous bone. The variation of POVIAC((r)) content can affect the cephalexin release kinetic in the composite. The cephalexin release mechanism from the composites can be considered as the result of the joint contribution of a prevailing Fickian diffusion and of polymer chain relaxation. It was also demonstrated that cephalexin is occluded inside the composites and not on their surface. PMID- 22201029 TI - The association of human primary bone cells with biphasic calcium phosphate (betaTCP/HA 70:30) granules increases bone repair. AB - This work evaluates the suitability of biphasic calcium phosphate (BCP) granules (beta-TCP/HA 70:30) as potential carriers for cell-guided bone therapy. The BCP granules were obtained by synthesis in the presence of wax, thermal treatment, crushing and sieving and characterized by scanning electron microscopy (SEM), X ray diffraction and Fourier transform infrared spectroscopy. The cytocompatibility of the BCP granules was confirmed by a multiparametric cytotoxicity assay. SEM analysis showed human bone cell adhesion and migration after seeding onto the material. Rat subcutaneous xenogeneic grafting of granules associated to human bone cells revealed a more accentuated moderate chronic inflammatory infiltrate, without signs of a strong xenoreactivity. Histomorphometrical analysis of bone repair of defects in rat skulls (? = 5 mm) has shown that bone cell associated-BCP and autograft promoted a two- and threefold increase, respectively, on new bone formation after 45 days, as compared to BCP alone and blood clot. The increase in bone repair supports the suitability the biocompatible (70:30) BCP granules as injectable and mouldable scaffolds for human cells in bone bioengineering. PMID- 22201030 TI - Effect of topological cues on material-driven fibronectin fibrillogenesis and cell differentiation. AB - Fibronectin (FN) assembles into fibrillar networks by cells through an integrin dependent mechanism. We have recently shown that simple FN adsorption onto poly(ethyl acrylate) surfaces (PEA), but not control polymer (poly(methyl acrylate), PMA), also triggered FN organization into a physiological fibrillar network. FN fibrils exhibited enhanced biological activities in terms of myogenic differentiation compared to individual FN molecules. In the present study, we investigate the influence of topological cues on the material-driven FN assembly and the myogenic differentiation process. Aligned and random electrospun fibers were prepared. While FN fibrils assembled on the PEA fibers as they do on the smooth surface, the characteristic distribution of globular FN molecules observed on flat PMA transformed into non-connected FN fibrils on electrospun PMA, which significantly enhanced cell differentiation. The direct relationship between the fibrillar organization of FN at the material interface and the myogenic process was further assessed by preparing FN gradients on smooth PEA and PMA films. Isolated FN molecules observed at one edge of the substrate gradually interconnected with each other, eventually forming a fully developed network of FN fibrils on PEA. In contrast, FN adopted a globular-like conformation along the entire length of the PMA surface, and the FN gradient consisted only of increased density of adsorbed FN. Correspondingly, the percentage of differentiated cells increased monotonically along the FN gradient on PEA but not on PMA. This work demonstrates an interplay between material chemistry and topology in modulating material-driven FN fibrillogenesis and cell differentiation. PMID- 22201033 TI - Behavioral disorders: the new public health crisis. AB - Behavioral health has become a public health crisis. No other public health crises are as widespread or contribute as much to the burden of illness in the U.S. as do behavioral health disorders. By 2020, mental and substance use disorders will surpass all physical diseases worldwide as major causes of disability. Yet state and federal governments continue to make steep cuts to funding for public behavioral health services. We cannot afford to wait for the next national tragedy to recognize that behavioral health disorders are a public health crisis deserving of our nation's attention and support. PMID- 22201032 TI - Prevention and management of cataracts in children with juvenile idiopathic arthritis-associated uveitis. AB - Juvenile idiopathic arthritis (JIA)-associated uveitis can be associated with vision-compromising complications such as cataracts, glaucoma, synechiae, and band keratopathy. Of these, cataracts are one of the most common sequelae of JIA associated uveitis and can result in significant visual disability. Risk factors for cataracts include posterior synechiae and longstanding ocular inflammation. Prevention of cataract development is crucial through appropriate control of uveitis. However, not all preventive measures are successful, and further management consisting of medical and surgical techniques is often necessary. Various factors should be taken into consideration when deciding on cataract management, including timing of surgery and placement of an intraocular lens. Continued partnership between pediatric rheumatologists and pediatric ophthalmologists can help ensure favorable visual outcomes. PMID- 22201031 TI - The use of calcium phosphate-based biomaterials in implant dentistry. AB - Since calcium phosphates (CaPs) were first proposed, a wide variety of formulations have been developed and continuously optimized, some of which (e.g. calcium phosphate cements, CPCs) have been successfully commercialized for clinical applications. These CaP-based biomaterials have been shown to be very attractive bone substitutes and efficient drug delivery vehicles across diverse biomedical applications. In this article, CaP biomaterials, principally CPCs, are addressed as alternatives/complements to autogenous bone for grafting in implant dentistry and as coating materials for enhancing the osteoinductivity of titanium implants, highlighting their performance benefits simultaneously as carriers for growth factors and as scaffolds for cell proliferation, differentiation and penetration. Different strategies for employing CaP biomaterials in dental implantology aim to ultimately reach the same goal, namely to enhance the osseointegration process for dental implants in the context of immediate loading and to augment the formation of surrounding bone to guarantee long-term success. PMID- 22201034 TI - Assessing the knowledge of the potential harm to others caused by second-hand smoke and its impact on protective behaviours at home. AB - BACKGROUND: Smokers' knowledge of the risks of second-hand smoke (SHS) and the role this plays in implementing behaviours to reduce the SHS exposure of others have not been thoroughly explored. Mass media health promotion is used to promote behaviour change partly by providing information on the consequences of behaviour. In England, between 2003 and 2006, frequent mass media campaigns highlighted the toxicity of SHS. OBJECTIVES: To examine peoples' knowledge of SHS related illnesses in England over time, identify the determinants of good knowledge and to assess its importance in predicting SHS-protective behaviours. METHODS: Statistical analysis of repeat cross-sectional data (1996-2008) from the Omnibus Survey to explore the trends and determinants of knowledge of SHS-related illnesses and the determinants of SHS-protective behaviours. RESULTS: Only 40% of smokers had 'good' knowledge of SHS-related illnesses compared with 65% of never smokers. Knowledge increased markedly when frequent SHS-related mass media campaigns (2003-06) ran, compared with earlier years (1996-2002). Smokers with better knowledge were more likely to have smoke-free homes [odds ratio (OR): 1.10, 1.04-1.16] and abstain from smoking in a room with children (OR: 1.11, 1.09 1.14). CONCLUSIONS: The low levels of knowledge of some SHS-related conditions, especially among smokers, and the relationship between knowledge and SHS protective behaviours, suggest that greater efforts to educate smokers about the risks associated with SHS are worthwhile. PMID- 22201036 TI - 1H, 13C and 15N resonance assignments of the kinetochore localisation domain of BUBR1, a central component of the spindle assembly checkpoint. AB - Human BUBR1 is a 120 kDa protein that plays a central role in the spindle assembly checkpoint (SAC), the evolutionary conserved and self-regulatory system of higher organisms that monitors and repairs defects in chromosome segregation in mitotic cells. BUBR1 is organised into several domains, with an N-terminal region responsible for its localisation into the kinetochore, the multi-component proteinaceous network that assembles onto chromosomes upon mitotic entry. We have expressed and purified uniformly-(15)N/(13)C N-terminal BUBR1 and assigned backbone and side-chain resonances bound to an unlabelled peptide from the protein Blinkin, an element essential for recruitment of BUBR1 to the kinetochore. These assignments provide insights on the Blinkin interaction interface and form the basis of the three-dimensional structure determination of a BUBR1-Blinkin complex. PMID- 22201035 TI - 1H, 15N and 13C chemical shift assignments of the BA42 protein of the psychrophilic bacteria Bizionia argentinensis sp. nov. AB - BA42 is a protein belonging to the psychrophilic bacteria Bizionia argentinensis sp. nov. Bioinformatics analysis showed that it presents significant sequence identity with a Pfam A family, DUF 477, found both in eukarya and eubacteria but of unknown function in all these organisms. Here, we report the NMR spectra assignment of this 145 amino acid protein. These data will allow performing NMR structural studies with the aim of using the three-dimensional structure as relevant information in order to determine the function of this family of proteins. PMID- 22201037 TI - Enhanced corticospinal response to observed pain in pain synesthetes. AB - Observing noxious injury to another's hand is known to induce corticospinal inhibition that can be measured in the observer's corresponding muscle. Here, we investigated whether acquired pain synesthetes, individuals who experience actual pain when observing injury to another, demonstrate less corticospinal inhibition than do controls during pain observation, as a potential mechanism for the experience of vicarious pain. We recorded motor-evoked potentials (MEPs) induced at two time points through transcranial magnetic stimulation while participants observed videos of a hand at rest, a hypodermic needle penetrating the skin, a Q tip touching the skin, and a hypodermic needle penetrating an apple. We compared MEPs in three groups: 7 amputees who experience pain synesthesia, 11 nonsynesthete amputees who experience phantom limb pain, and 10 healthy controls. Results indicated that the pain synesthete group demonstrated significantly enhanced MEP response to the needle penetrating the hand, relative to the needle not having yet penetrated the hand, as compared with controls. This effect was not observed exclusively in the same muscle where noxious stimulation was applied. We speculate that our findings reflect a generalized response to pain observation arising from hyperactivity of motor mirror neurons not involved in direct one-to-one simulation but, rather, in the representation of another's experience. PMID- 22201038 TI - The interaction between intrathecal administration of low doses of palmitoylethanolamide and AM251 in formalin-induced pain related behavior and spinal cord IL1-beta expression in rats. AB - Most of the modulating effects of cannabinoids on pain are through putative cannabinoid CB1 and CB2 receptors. However, the involvement of other receptors is also suggested. Cannabinoid compounds with analgesic activity such as palmitoylethanolamide (PEA) show low affinity to CB1 and CB2 receptors, yet selectively activate GPR55 receptors. The objective of the present study was to evaluate the possible role of spinal CB1 and GPR55 receptors on antinociceptive activity of PEA in formalin test as well as in the spinal expression of IL1-beta in rat. Intrathecal (i.t.) administration of PEA (1, 10 MUg) significantly decreased both pain-related scores in formalin test and IL1-beta expression in rat spinal cord. Pretreatment of rats with low doses of CB1 receptor antagonist/GPR55 receptor agonist AM251 (10, 100 ng; i.t.), did not attenuated the effect of PEA, yet even significantly increased the effect of PEA on IL1-beta expression in rat spinal cord. Interestingly, i.t. administration of low doses of AM251 per se significantly decreased both pain related behavior and spinal IL1 beta expression in formalin test. These findings suggest the possible involvement of receptors other than CB1 receptors in spinal pain pathways, such as GPR55, in pain modulating activity of cannabinoids. PMID- 22201039 TI - Role of secondary mediators in caffeine-mediated neuroprotection in maneb- and paraquat-induced Parkinson's disease phenotype in the mouse. AB - Maneb and paraquat are known to induce Parkinson's disease (PD) phenotype, however, caffeine offers neuroprotection. Nitric oxide (NO) acts an important mediator in PD phenotype and tyrosine kinase (TK), nuclear factor kappa B (NF kB), p38 mitogen activated protein kinase (p38 MAPK) are known to regulate its production. The present study aimed to elucidate the role of caffeine in the regulation of NO production and microglial activation and their subsequent contribution in dopaminergic neuroprotection. The animals were treated with caffeine and/or maneb and paraquat along with controls. In a few sets of experiments, the animals were also treated with aminoguanidine, an inhibitor of inducible NO synthase, pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kB, genistein, an inhibitor of TK or SB202190, an inhibitor of p38 MAPK. Tyrosine hydroxylase (TH)-immunoreactivity and anti-integrin alphaM (OX-42) staining were performed to assess the number of dopaminergic neurons and activation of microglia, respectively. NO was measured in terms of nitrite, however, the expressions of p38 MAPK, interleukin (IL)-1beta, NF-kB and TK were checked by western blot analyses. Maneb and paraquat induced the number of degenerating dopaminergic neurons, microglial cells, nitrite content, expressions of IL-1beta, p38 MAPK, NF-kB and TK and caffeine co-treatment reduced the level of such alterations. Reductions were more pronounced in the animals co-treated with aminoguanidine, PDTC, genistein or SB202190. The results obtained thus demonstrate that caffeine down-regulates NO production, neuroinflammation and microglial activation, which possibly contribute to neuroprotection. PMID- 22201040 TI - The analysis of forces needed for the suturing of elliptical skin wounds. AB - There is a lack of information regarding the forces required for suturing human wounds. The knowledge of suturing forces serves as complementary information for setting up the limiting geometry when using tissue adhesives and it might also be used in robot-assisted surgery. The main purpose of this paper was to evaluate the forces required for suturing selected skin wounds. An elliptical wound was chosen for our study. In this study a numerical analysis and in vivo experiments were performed. Regarding the numerical models, the maximum forces occurred in the middle of the elliptical wound in all cases. In the case of highest pre stress used in these analyses the maximal force varied from 0.5 N for the smallest wound (30 * 5 mm) to 1.5 N for the largest wound (30 * 15 mm). The maximum peak force for the wound with a size of 46 * 13 mm was 3.2 N. The minimum peak force for the wound with a size of 36 * 5 mm was 1.1 N. PMID- 22201041 TI - Treating cardiac arrhythmias detected with an implantable cardiac monitor in patients after an acute myocardial infarction. AB - OPINION STATEMENT: Using an implantable cardiac monitor (ICM) in patients with acute myocardial infarction (MI) allows continuous electrocardiogram monitoring and provides a much more detailed picture of the incidence of brady- and tachyarrhythmias than conventional follow-up. The CARISMA study was the first to use the ICM in post-MI patients with moderate to severe left ventricular systolic dysfunction. Atrial fibrillation (AF) events lasting longer than 30 s were associated with an almost threefold increase in the risk of major cardiac events. This confirms the current definition of clinically significant AF episodes, as patients with episodes of shorter duration were not at increased risk. The association of AF to progressive heart failure, reinfarction, and cardiovascular death underlines the need for an intensive follow-up of post-MI patients with new onset AF in order to reveal underlying causes of AF such as progressive left ventricular dysfunction or myocardial ischemia. Asymptomatic, especially nightly, bradycardia episodes including high-degree 2 degrees -3 degrees atrioventricular (AV) block, sinus bradycardia, and sinus arrest were frequently documented by ICM in the CARISMA study. Ten percent of patients experienced high-degree 2 degrees 3 degrees AV block, of which the main part was nightly and asymptomatic, and 50% of all cardiovascular deaths occurred in this group, most from severe heart failure. Therefore, in post-MI patients with paroxysmal high-degree AV block, pacemaker implantation should be done, and in the case of left ventricular dysfunction (LVEF <= 35%), an implantable cardioverter defibrillator/cardiac resynchronization therapy defibrillator (ICD/CRT-D) may be indicated. Nonsustained ventricular tachycardia (VT) is very frequent in post-MI patients, and in the CARISMA study, high-risk patients with nonsustained VT were implanted with an ICD. Furthermore, in 10% of the patients, the ICM recorded nonsustained VT episodes of >= 16 beats per minute, resulting in a twofold increase in the risk for cardiac death. Thus, patients with nonsustained VT should undergo careful investigation, and we recommend a repeat echocardiography and electrophysiological stimulation in these patients. Patients with sustained VT or VF should receive an ICD. PMID- 22201042 TI - Shwachman-Diamond syndrome. AB - Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder with exocrine pancreatic insufficiency, bone marrow failure and skeletal abnormalities. Patients frequently present failure to thrive, susceptibility to infections and short stature. A persistent or intermittent neutropenia occurs in 88-100% of patients. Bone marrow biopsy usually reveals a hypoplastic specimen with varying degrees of hypoplasia and fat infiltration. Some patients may develop myeloblastic syndrome and acute myeloblastic leukemia. The genetic defect in SDS has been identified in 2002. The osteoporosis is increased in patients with SDS, and also, bone malformations are included among the primary characteristics of the syndrome. The severity and location change with age and sexes. The typical characteristics include the following: secondary ossification centers delayed appearance, metaphysis enlargement and irregularity (very common in childhood, particularly in coastal and femur), growth cartilage progressive thinning and irregularity (possibly asymmetric growth), generalized osteopenia with cortical thinning. We describe a clinical case regarding an SDS patient with severe bone abnormalities and treated surgically for corrective osteotomy. The persistent or intermittent neutropenia that characterized this disease and the consequent risk of infection is a contraindication for short stature correction and limbs lengthening. PMID- 22201043 TI - A common error term regulates acquisition but not extinction of causal judgments in people. AB - In three experiments, we used the allergist task to examine the role of error correction mechanisms in the acquisition and extinction of causal judgments in people. Consistent with existing human and animal studies, acquisition of causal judgments was influenced by the discrepancy between the allergenic outcome and that predicted by all of the cues present on a trial (the "common error" term). However, in the present experiments, we failed to detect any evidence for the use of a common error term in extinction learning: Judgments of the allergenic properties of a cue were unaffected by the predictive value of the other cues present on a trial. This asymmetry in the use of a common error term in acquisition and extinction learning is inconsistent with previous animal studies and also with most models of associative learning. However, approaches that allow learning to be specific to a particular arrangement of elemental cues (context specific and state based) offer some explanation of the observed asymmetry. PMID- 22201044 TI - Heavy metals in hair of wild canids from the Brazilian Cerrado. AB - In this study, we aimed to assess whether free-ranging wild canids are exposed to heavy metals in one of the most developed and populated regions of Brazil. Hair of 26 wild canids (maned wolves Chrysocyon brachyurus, crab-eating foxes Cerdocyon thous, and hoary foxes Lycalopex vetulus) from the Cerrado biome in Southeast Brazil were analyzed by spectrophotometry to detect cadmium, chromium, and lead, and also the essential copper, iron, manganese, and zinc traces. All samples showed traces of copper, iron, manganese, and zinc. Non-essential lead was detected in 57% (2.35 +/- 0.99 mg/kg), and chromium in 88% (2.98 +/- 1.56 mg/kg) of samples. Cadmium traces (detection limit 0.8 mg/kg) were not found. Crab-eating foxes had more copper, iron, and manganese in hair than maned wolves. Correlations among element levels differed between maned wolves and crab-eating foxes. Concentrations of chromium and lead were outstandingly higher than in wild canids from other areas. Addressing the causes of such levels and the impacts of the heavy metal pollution in Neotropical ecosystems is urgent for animal health and conservation purposes. We argue that heavy metal pollution should be considered as dangerous threats to wildlife health in Brazil and recommend hair sampling as a biomonitoring tool for heavy metals in Neotropical terrestrial mammals. PMID- 22201045 TI - The retention of cadmium and selenium influence in fowl and chickens of F1 generation. AB - The retention of cadmium and selenium influence on Cd retention in the muscle, liver and kidneys of hens, chickens and in eggs was studied. Cadmium (Cd) as cadmium chloride (CdCl(2)) and selenium (Se) as sodium selenite (Na(2)SeO(3)) were added to feed at dosages: group 0-control, group 1-20 mg/kg Cd, group 2-30 mg/kg Cd + 4 mg/kg Se. The birds were exposed to Cd for 8 weeks. Cadmium level in hens and cocks was found highest in the kidneys, followed by the liver and muscle. Se supplementation resulted in Cd increase in the muscle tissue and in the reduction of Cd content in the liver and in significant decrease in the kidneys (p < 0.05). A higher Cd level in the yolk and lower in the white was noted in both experimental groups. Nonsignificant increase of Cd in eggs was noted in experimental groups with Se supplementation. Level of cadmium in organs of 7-day-old chicks hatched from Cd-treated hens in both experimental groups was low but the tendency to accumulate preferentially the Cd in the liver and kidneys was recorded. Supplementation of selenium in hens and cocks was not reflected in the decrease of Cd in these two organs of F(1) chickens but was reflected in increase in the muscle. In spite of relatively high Cd levels in the organs of layers no layer-egg-chickens transfer was observed. It was confirm that kidneys and liver are organs more attacked by dietary cadmium than muscle. Supplementation of low dose of Se resulted in decrease of cadmium deposition in analyzed organs. PMID- 22201046 TI - Prediction of type-2 diabetes based on several element levels in blood and chemometrics. AB - The present study was designed to evaluate the levels of eight elements including lithium, zinc, chromium, copper, iron, manganese, nickel and vanadium in whole blood of type-2 diabetes patients, to compare them with age-matched healthy controls and to investigate the feasibility of combining them with an ensemble model for diagnosing purpose. A dataset involving 158 samples, among which 105 were taken from healthy adults and the remaining 53 from patients with type-2 diabetes, was collected. All samples were split into the training set and the test set with the equal size. Based on a simple variable selection, two elements, i.e., chromium and iron, are also picked out as the most important elements. Three kinds of algorithms, i.e., fisher linear discriminate analysis (FLDA), support vector machine (SVM) and decision tree (DT), were used for constructing member models. The best ensemble classifiers constructed on the training set were validated on the independent test set, and the prediction results were compared with those from clinical diagnostics on the same subjects. The results reveal that almost all ensemble classifiers exhibit similar performance, implying that these elements coupled with an appropriate ensemble classifier can serve as a valuable tool of diagnosing diabetes type-2. PMID- 22201047 TI - Arabidopsis TT19 functions as a carrier to transport anthocyanin from the cytosol to tonoplasts. AB - Anthocyanins are synthesized in the cytosolic surface of the endoplasmic reticulum (ER) but dominantly accumulate in the vacuole. Little is known about how anthocyanins are transported from the ER to the vacuole. Here, we provide evidence supporting that Transparent Testa 19 (TT19), a glutathione S-transferase (GST), functions as a carrier to transport cyanidin and/or anthocyanins to the tonoplast. We identified a novel tt19 mutant (tt19-7), which barely accumulates anthocyanins but produces a 36% higher level of flavonol than the wild-type (WT), from ethyl methanesulfonate mutagenized seeds. Expressing TT19-fused green fluorescence protein (GFP) in tt19-7 rescues the mutant phenotype in defective anthocyanin biosynthesis, indicating that TT19-GFP is functional. We further showed that TT19-GFP is localized not only in the cytoplasm and nuclei, but also on the tonoplast. The membrane localization of TT19-GFP was further ascertained by immunoblot analysis. In vitro assay showed that the purified recombinant TT19 increases water solubility of cyanidin (Cya) and cyanidin-3-O-glycoside (C3G). Compared with C3G, Cya can dramatically quench the intrinsic tryptophan fluorescence of TT19 to much lower levels, indicating a higher affinity of TT19 to Cya than to C3G. Isothermal titration calorimetry analysis also confirmed physical interaction between TT19 and C3G. Taken together, our data reveal molecular mechanism underlying TT19-mediated anthocyanin transportation. PMID- 22201049 TI - Cross-domain multicue fusion for concept-based video indexing. AB - The success of query-by-concept, proposed recently to cater to video retrieval needs, depends greatly on the accuracy of concept-based video indexing. Unfortunately, it remains a challenge to recognize the presence of concepts in a video segment or to extract an objective linguistic description from it because of the semantic gap, that is, the lack of correspondence between machine extracted low-level features and human high-level conceptual interpretation. This paper studies three issues with the aim to reduce such a gap: 1) how to explore cues beyond low-level features, 2) how to combine diverse cues to improve performance, and 3) how to utilize the learned knowledge when applying it to a new domain. To solve these problems, we propose a framework that jointly exploits multiple cues across multiple video domains. First, recursive algorithms are proposed to learn both interconcept and intershot relationships from annotations. Second, all concept labels for all shots are simultaneously refined in a single fusion model. Additionally, unseen shots are assigned pseudolabels according to their initial prediction scores so that contextual and temporal relationships can be learned, thus requiring no additional human effort. Integration of cues embedded within training and testing video sets accommodates domain change. Experiments on popular benchmarks show that our framework is effective, achieving significant improvements over popular baselines. PMID- 22201048 TI - Interplay between Heat Shock Protein 90 and HY5 controls PhANG expression in response to the GUN5 plastid signal. AB - The presence of genes encoding organellar proteins in different cellular compartments necessitates a tight coordination of expression by the different genomes of the eukaryotic cell. This coordination of gene expression is achieved by organelle-to-nucleus or retrograde communication. Stress-induced perturbations of the tetrapyrrole pathway trigger large changes in nuclear gene expression in plants. Recently, we identified HSP90 proteins as ligands of the putative plastid signal Mg-ProtoIX. In order to investigate whether the interaction between HSP90 and Mg-ProtoIX is biologically relevant, we produced transgenic lines with reduced levels of cytosolic HSP90 in wild-type and gun5 backgrounds. Our work reveals that HSP90 proteins respond to the tetrapyrrole-mediated plastid signal to control expression of photosynthesis-associated nuclear genes (PhANG) during the response to oxidative stress. We also show that the hy5 mutant is insensitive to tetrapyrrole accumulation and that Mg-ProtoIX, cytosolic HSP90, and HY5 are all part of the same signaling pathway. These findings suggest that a regulatory complex controlling gene expression that includes HSP90 proteins and a transcription factor that is modified by tetrapyrroles in response to changes in the environment is evolutionarily conserved between yeast and plants. PMID- 22201050 TI - Unsupervised learning of categorical segments in image collections. AB - Which one comes first: segmentation or recognition? We propose a unified framework for carrying out the two simultaneously and without supervision. The framework combines a flexible probabilistic model, for representing the shape and appearance of each segment, with the popular "bag of visual words" model for recognition. If applied to a collection of images, our framework can simultaneously discover the segments of each image and the correspondence between such segments, without supervision. Such recurring segments may be thought of as the "parts" of corresponding objects that appear multiple times in the image collection. Thus, the model may be used for learning new categories, detecting/classifying objects, and segmenting images, without using expensive human annotation. PMID- 22201051 TI - Reflection symmetry-integrated image segmentation. AB - This paper presents a new symmetry-integrated region-based image segmentation method. The method is developed to obtain improved image segmentation by exploiting image symmetry. It is realized by constructing a symmetry token that can be flexibly embedded into segmentation cues. Interesting points are initially extracted from an image by the SIFT operator and they are further refined for detecting the global bilateral symmetry. A symmetry affinity matrix is then computed using the symmetry axis and it is used explicitly as a constraint in a region growing algorithm in order to refine the symmetry of the segmented regions. A multi-objective genetic search finds the segmentation result with the highest performance for both segmentation and symmetry, which is close to the global optimum. The method has been investigated experimentally in challenging natural images and images containing man-made objects. It is shown that the proposed method outperforms current segmentation methods both with and without exploiting symmetry. A thorough experimental analysis indicates that symmetry plays an important role as a segmentation cue, in conjunction with other attributes like color and texture. PMID- 22201052 TI - Handwritten Chinese text recognition by integrating multiple contexts. AB - This paper presents an effective approach for the offline recognition of unconstrained handwritten Chinese texts. Under the general integrated segmentation-and-recognition framework with character oversegmentation, we investigate three important issues: candidate path evaluation, path search, and parameter estimation. For path evaluation, we combine multiple contexts (character recognition scores, geometric and linguistic contexts) from the Bayesian decision view, and convert the classifier outputs to posterior probabilities via confidence transformation. In path search, we use a refined beam search algorithm to improve the search efficiency and, meanwhile, use a candidate character augmentation strategy to improve the recognition accuracy. The combining weights of the path evaluation function are optimized by supervised learning using a Maximum Character Accuracy criterion. We evaluated the recognition performance on a Chinese handwriting database CASIA-HWDB, which contains nearly four million character samples of 7,356 classes and 5,091 pages of unconstrained handwritten texts. The experimental results show that confidence transformation and combining multiple contexts improve the text line recognition performance significantly. On a test set of 1,015 handwritten pages, the proposed approach achieved character-level accurate rate of 90.75 percent and correct rate of 91.39 percent, which are superior by far to the best results reported in the literature. PMID- 22201053 TI - Human identification using temporal information preserving gait template. AB - Gait Energy Image (GEI) is an efficient template for human identification by gait. However, such a template loses temporal information in a gait sequence, which is critical to the performance of gait recognition. To address this issue, we develop a novel temporal template, named Chrono-Gait Image (CGI), in this paper. The proposed CGI template first extracts the contour in each gait frame, followed by encoding each of the gait contour images in the same gait sequence with a multichannel mapping function and compositing them to a single CGI. To make the templates robust to a complex surrounding environment, we also propose CGI-based real and synthetic temporal information preserving templates by using different gait periods and contour distortion techniques. Extensive experiments on three benchmark gait databases indicate that, compared with the recently published gait recognition approaches, our CGI-based temporal information preserving approach achieves competitive performance in gait recognition with robustness and efficiency. PMID- 22201054 TI - Detecting curves with unknown endpoints and arbitrary topology using minimal paths. AB - Existing state-of-the-art minimal path techniques work well to extract simple open curves in images when both endpoints of the curve are given as user input or when one input is given and the total length of the curve is known in advance. Curves which branch require even further prior input from the user, namely, each branch endpoint. In this work, we present a novel minimal path-based algorithm which works on much more general curve topologies with far fewer demands on the user for initial input compared to prior minimal path-based algorithms. The two key novelties and benefits of this new approach are that 1) it may be used to detect both open and closed curves, including more complex topologies containing both multiple branch points and multiple closed cycles without requiring a priori knowledge about which of these types is to be extracted, and 2) it requires only a single input point which, in contrast to existing methods, is no longer constrained to be an endpoint of the desired curve but may in fact be ANY point along the desired curve (even an internal point). We perform quantitative evaluation of the algorithm on 48 images (44 pavement crack images, 1 catheter tube image, and 3 retinal images) against human supplied ground truth. The results demonstrate that the algorithm is indeed able to extract curve-like objects accurately from images with far less prior knowledge and less user interaction compared to existing state-of-the-art minimal path-based image processing algorithms. In the future, the algorithm can be applied to other 2D curve-like objects and it can be extended to detect 3D curves. PMID- 22201055 TI - Fast rotation invariant 3D feature computation utilizing efficient local neighborhood operators. AB - We present a method for densely computing local rotation invariant image descriptors in volumetric images. The descriptors are based on a transformation to the harmonic domain, which we compute very efficiently via differential operators. We show that this fast voxelwise computation is restricted to a family of basis functions that have certain differential relationships. Building upon this finding, we propose local descriptors based on the Gaussian Laguerre and spherical Gabor basis functions and show how the coefficients can be computed efficiently by recursive differentiation. We exemplarily demonstrate the effectiveness of such dense descriptors in a detection and classification task on biological 3D images. In a direct comparison to existing volumetric features, among them 3D SIFT, our descriptors reveal superior performance. PMID- 22201056 TI - Context-aware saliency detection. AB - We propose a new type of saliency-context-aware saliency-which aims at detecting the image regions that represent the scene. This definition differs from previous definitions whose goal is to either identify fixation points or detect the dominant object. In accordance with our saliency definition, we present a detection algorithm which is based on four principles observed in the psychological literature. The benefits of the proposed approach are evaluated in two applications where the context of the dominant objects is just as essential as the objects themselves. In image retargeting, we demonstrate that using our saliency prevents distortions in the important regions. In summarization, we show that our saliency helps to produce compact, appealing, and informative summaries. PMID- 22201057 TI - Visual event recognition in videos by learning from Web data. AB - We propose a visual event recognition framework for consumer videos by leveraging a large amount of loosely labeled web videos (e.g., from YouTube). Observing that consumer videos generally contain large intraclass variations within the same type of events, we first propose a new method, called Aligned Space-Time Pyramid Matching (ASTPM), to measure the distance between any two video clips. Second, we propose a new transfer learning method, referred to as Adaptive Multiple Kernel Learning (A-MKL), in order to 1) fuse the information from multiple pyramid levels and features (i.e., space-time features and static SIFT features) and 2) cope with the considerable variation in feature distributions between videos from two domains (i.e., web video domain and consumer video domain). For each pyramid level and each type of local features, we first train a set of SVM classifiers based on the combined training set from two domains by using multiple base kernels from different kernel types and parameters, which are then fused with equal weights to obtain a prelearned average classifier. In A-MKL, for each event class we learn an adapted target classifier based on multiple base kernels and the prelearned average classifiers from this event class or all the event classes by minimizing both the structural risk functional and the mismatch between data distributions of two domains. Extensive experiments demonstrate the effectiveness of our proposed framework that requires only a small number of labeled consumer videos by leveraging web data. We also conduct an in-depth investigation on various aspects of the proposed method A-MKL, such as the analysis on the combination coefficients on the prelearned classifiers, the convergence of the learning algorithm, and the performance variation by using different proportions of labeled consumer videos. Moreover, we show that A-MKL using the prelearned classifiers from all the event classes leads to better performance when compared with A-MK- using the prelearned classifiers only from each individual event class. PMID- 22201058 TI - Combining scale-space and similarity-based aspect graphs for fast 3D object recognition. AB - This paper describes an approach for recognizing instances of a 3D object in a single camera image and for determining their 3D poses. A hierarchical model is generated solely based on the geometry information of a 3D CAD model of the object. The approach does not rely on texture or reflectance information of the object's surface, making it useful for a wide range of industrial and robotic applications, e.g., bin-picking. A hierarchical view-based approach that addresses typical problems of previous methods is applied: It handles true perspective, is robust to noise, occlusions, and clutter to an extent that is sufficient for many practical applications, and is invariant to contrast changes. For the generation of this hierarchical model, a new model image generation technique by which scale-space effects can be taken into account is presented. The necessary object views are derived using a similarity-based aspect graph. The high robustness of an exhaustive search is combined with an efficient hierarchical search. The 3D pose is refined by using a least-squares adjustment that minimizes geometric distances in the image, yielding a position accuracy of up to 0.12 percent with respect to the object distance, and an orientation accuracy of up to 0.35 degree in our tests. The recognition time is largely independent of the complexity of the object, but depends mainly on the range of poses within which the object may appear in front of the camera. For efficiency reasons, the approach allows the restriction of the pose range depending on the application. Typical runtimes are in the range of a few hundred ms. PMID- 22201059 TI - Online kernel principal component analysis: a reduced-order model. AB - Kernel principal component analysis (kernel-PCA) is an elegant nonlinear extension of one of the most used data analysis and dimensionality reduction techniques, the principal component analysis. In this paper, we propose an online algorithm for kernel-PCA. To this end, we examine a kernel-based version of Oja's rule, initially put forward to extract a linear principal axe. As with most kernel-based machines, the model order equals the number of available observations. To provide an online scheme, we propose to control the model order. We discuss theoretical results, such as an upper bound on the error of approximating the principal functions with the reduced-order model. We derive a recursive algorithm to discover the first principal axis, and extend it to multiple axes. Experimental results demonstrate the effectiveness of the proposed approach, both on synthetic data set and on images of handwritten digits, with comparison to classical kernel-PCA and iterative kernel-PCA. PMID- 22201060 TI - A Tangent Bundle Theory for Visual Curve Completion. AB - Visual curve completion is a fundamental perceptual mechanism that completes the missing parts (e.g., due to occlusion) between observed contour fragments. Previous research into the shape of completed curves has generally followed an "axiomatic" approach, where desired perceptual/geometrical properties are first defined as axioms, followed by mathematical investigation into curves that satisfy them. However, determining psychophysically such desired properties is difficult and researchers still debate what they should be in the first place. Instead, here we exploit the observation that curve completion is an early visual process to formalize the problem in the unit tangent bundle R(2) * S(1), which abstracts the primary visual cortex (V1) and facilitates exploration of basic principles from which perceptual properties are later derived rather than imposed. Exploring here the elementary principle of least action in V1, we show how the problem becomes one of finding minimum-length admissible curves in R(2) * S(1). We formalize the problem in variational terms, we analyze it theoretically, and we formulate practical algorithms for the reconstruction of these completed curves. We then explore their induced visual properties vis-a-vis popular perceptual axioms and show how our theory predicts many perceptual properties reported in the corresponding perceptual literature. Finally, we demonstrate a variety of curve completions and report comparisons to psychophysical data and other completion models. PMID- 22201061 TI - Edge structure preserving 3D image denoising by local surface approximation. AB - In various applications, including magnetic resonance imaging (MRI) and functional MRI (fMRI), 3D images are becoming increasingly popular. To improve the reliability of subsequent image analyses, 3D image denoising is often a necessary preprocessing step, which is the focus of the current paper. In the literature, most existing image denoising procedures are for 2D images. Their direct extensions to 3D cases generally cannot handle 3D images efficiently because the structure of a typical 3D image is substantially more complicated than that of a typical 2D image. For instance, edge locations are surfaces in 3D cases which would be much more challenging to handle compared to edge curves in 2D cases. We propose a novel 3D image denoising procedure in this paper, based on local approximation of the edge surfaces using a set of surface templates. An important property of this method is that it can preserve edges and major edge structures (e.g., intersections of two edge surfaces and pointed corners). Numerical studies show that it works well in various applications. PMID- 22201062 TI - Gender and ethnicity specific generic elastic models from a single 2D image for novel 2D pose face synthesis and recognition. AB - In this paper, we propose a novel method for generating a realistic 3D human face from a single 2D face image for the purpose of synthesizing new 2D face images at arbitrary poses using gender and ethnicity specific models. We employ the Generic Elastic Model (GEM) approach, which elastically deforms a generic 3D depth-map based on the sparse observations of an input face image in order to estimate the depth of the face image. Particularly, we show that Gender and Ethnicity specific GEMs (GE-GEMs) can approximate the 3D shape of the input face image more accurately, achieving a better generalization of 3D face modeling and reconstruction compared to the original GEM approach. We qualitatively validate our method using publicly available databases by showing each reconstructed 3D shape generated from a single image and new synthesized poses of the same person at arbitrary angles. For quantitative comparisons, we compare our synthesized results against 3D scanned data and also perform face recognition using synthesized images generated from a single enrollment frontal image. We obtain promising results for handling pose and expression changes based on the proposed method. PMID- 22201063 TI - Rotationally invariant descriptors using intensity order pooling. AB - This paper proposes a novel method for interest region description which pools local features based on their intensity orders in multiple support regions. Pooling by intensity orders is not only invariant to rotation and monotonic intensity changes, but also encodes ordinal information into a descriptor. Two kinds of local features are used in this paper, one based on gradients and the other on intensities; hence, two descriptors are obtained: the Multisupport Region Order-Based Gradient Histogram (MROGH) and the Multisupport Region Rotation and Intensity Monotonic Invariant Descriptor (MRRID). Thanks to the intensity order pooling scheme, the two descriptors are rotation invariant without estimating a reference orientation, which appears to be a major error source for most of the existing methods, such as Scale Invariant Feature Transform (SIFT), SURF, and DAISY. Promising experimental results on image matching and object recognition demonstrate the effectiveness of the proposed descriptors compared to state-of-the-art descriptors. PMID- 22201065 TI - Detachable object detection: segmentation and depth ordering from short-baseline video. AB - We describe an approach for segmenting a moving image into regions that correspond to surfaces in the scene that are partially surrounded by the medium. It integrates both appearance and motion statistics into a cost functional that is seeded with occluded regions and minimized efficiently by solving a linear programming problem. Where a short observation time is insufficient to determine whether the object is detachable, the results of the minimization can be used to seed a more costly optimization based on a longer sequence of video data. The result is an entirely unsupervised scheme to detect and segment an arbitrary and unknown number of objects. We test our scheme to highlight the potential, as well as limitations, of our approach. PMID- 22201066 TI - Exploring tiny images: the roles of appearance and contextual information for machine and human object recognition. AB - Typically, object recognition is performed based solely on the appearance of the object. However, relevant information also exists in the scene surrounding the object. In this paper, we explore the roles that appearance and contextual information play in object recognition. Through machine experiments and human studies, we show that the importance of contextual information varies with the quality of the appearance information, such as an image's resolution. Our machine experiments explicitly model context between object categories through the use of relative location and relative scale, in addition to co-occurrence. With the use of our context model, our algorithm achieves state-of-the-art performance on the MSRC and Corel data sets. We perform recognition tests for machines and human subjects on low and high resolution images, which vary significantly in the amount of appearance information present, using just the object appearance information, the combination of appearance and context, as well as just context without object appearance information (blind recognition). We also explore the impact of the different sources of context (co-occurrence, relative-location, and relative-scale). We find that the importance of different types of contextual information varies significantly across data sets such as MSRC and PASCAL. PMID- 22201067 TI - Multidimensional scaling for matching low-resolution face images. AB - Face recognition performance degrades considerably when the input images are of Low Resolution (LR), as is often the case for images taken by surveillance cameras or from a large distance. In this paper, we propose a novel approach for matching low-resolution probe images with higher resolution gallery images, which are often available during enrollment, using Multidimensional Scaling (MDS). The ideal scenario is when both the probe and gallery images are of high enough resolution to discriminate across different subjects. The proposed method simultaneously embeds the low-resolution probe images and the high-resolution gallery images in a common space such that the distance between them in the transformed space approximates the distance had both the images been of high resolution. The two mappings are learned simultaneously from high-resolution training images using an iterative majorization algorithm. Extensive evaluation of the proposed approach on the Multi-PIE data set with probe image resolution as low as 8 6 pixels illustrates the usefulness of the method. We show that the proposed approach improves the matching performance significantly as compared to performing matching in the low-resolution domain or using super-resolution techniques to obtain a higher resolution test image prior to recognition. Experiments on low-resolution surveillance images from the Surveillance Cameras Face Database further highlight the effectiveness of the approach. PMID- 22201068 TI - Design of 2D time-varying vector fields. AB - Design of time-varying vector fields, i.e., vector fields that can change over time, has a wide variety of important applications in computer graphics. Existing vector field design techniques do not address time-varying vector fields. In this paper, we present a framework for the design of time-varying vector fields, both for planar domains as well as manifold surfaces. Our system supports the creation and modification of various time-varying vector fields with desired spatial and temporal characteristics through several design metaphors, including streamlines, pathlines, singularity paths, and bifurcations. These design metaphors are integrated into an element-based design to generate the time-varying vector fields via a sequence of basis field summations or spatial constrained optimizations at the sampled times. The key-frame design and field deformation are also introduced to support other user design scenarios. Accordingly, a spatial-temporal constrained optimization and the time-varying transformation are employed to generate the desired fields for these two design scenarios, respectively. We apply the time-varying vector fields generated using our design system to a number of important computer graphics applications that require controllable dynamic effects, such as evolving surface appearance, dynamic scene design, steerable crowd movement, and painterly animation. Many of these are difficult or impossible to achieve via prior simulation-based methods. In these applications, the time-varying vector fields have been applied as either orientation fields or advection fields to control the instantaneous appearance or evolving trajectories of the dynamic effects. PMID- 22201069 TI - A coclustering approach for mining large protein-protein interaction networks. AB - Several approaches have been presented in the literature to cluster Protein Protein Interaction (PPI) networks. They can be grouped in two main categories: those allowing a protein to participate in different clusters and those generating only nonoverlapping clusters. In both cases, a challenging task is to find a suitable compromise between the biological relevance of the results and a comprehensive coverage of the analyzed networks. Indeed, methods returning high accurate results are often able to cover only small parts of the input PPI network, especially when low-characterized networks are considered. We present a coclustering-based technique able to generate both overlapping and nonoverlapping clusters. The density of the clusters to search for can also be set by the user. We tested our method on the two networks of yeast and human, and compared it to other five well-known techniques on the same interaction data sets. The results showed that, for all the examples considered, our approach always reaches a good compromise between accuracy and network coverage. Furthermore, the behavior of our algorithm is not influenced by the structure of the input network, different from all the techniques considered in the comparison, which returned very good results on the yeast network, while on the human network their outcomes are rather poor. PMID- 22201070 TI - Exploiting intrastructure information for secondary structure prediction with multifaceted pipelines. AB - Predicting the secondary structure of proteins is still a typical step in several bioinformatic tasks, in particular, for tertiary structure prediction. Notwithstanding the impressive results obtained so far, mostly due to the advent of sequence encoding schemes based on multiple alignment, in our view the problem should be studied from a novel perspective, in which understanding how available information sources are dealt with plays a central role. After revisiting a well known secondary structure predictor viewed from this perspective (with the goal of identifying which sources of information have been considered and which have not), we propose a generic software architecture designed to account for all relevant information sources. To demonstrate the validity of the approach, a predictor compliant with the proposed generic architecture has been implemented and compared with several state-of-the-art secondary structure predictors. Experiments have been carried out on standard data sets, and the corresponding results confirm the validity of the approach. The predictor is available at http://iasc.diee.unica.it/ssp2/ through the corresponding web application or as downloadable stand-alone portable unpack-and-run bundle. PMID- 22201071 TI - Relationship of spindle assembly checkpoint fidelity to species body mass, lifespan, and developmental rate. AB - We have examined the tolerance of the spindle assembly checkpoint (SAC), as measured by the appearance of tetraploid cells in the presence of a microtubule inhibitor, in a series of primary cell strains derived from species with diverse lifespan and body size. We find that the integrity of the SAC varies among these species. There is a robust correlation between the integrity of the SAC and body size, but poor correlation with longevity and parameters of species development (i.e., time of female fertility, gestation length, and postnatal growth rate). The results suggest that fidelity of the SAC co-evolved more closely with the number of mitoses needed to reach adulthood than with species lifespan. PMID- 22201072 TI - [Rare types of aneurysms-aneurysms of the hand and fingers: case reports]. AB - Case reports of two patients with aneurysms, description of clinical sings, steps of diagnostic protocols and surgical techniques are presented in this article. The first case - false aneurysm of the proper lateral artery of the IV finger of the right hand; second case - false aneurysm of the right hand. In both cases operation of aneurismal sac resection with ligation of aneurysma forming vessels were performed. After surgical interventions compensation of blood circulation and full restoration of the function of operated segments were found. IN CONCLUSION: early verification of correct clinical diagnosis and nomination of the patient to the specialized department of hand microsurgery is of crucial importance in achievement of good results after surgical treatment of aneurysms of the hand and fingers. PMID- 22201073 TI - The quality of life analysis in renal transplant recipients and dialysis patients. AB - Health-related quality of life (HRQoL) is becoming an important outcome measure in evaluation of various forms of renal replacement therapy (RRT). The Short Form 36 (SF-36), Giessen Subjective Complaints List (GBB-24) and Zerssen's Mood-Scale (Bf-S) are internationally validated questionnaires for the assessment of HRQoL. The goal of the current study was to evaluate and compare the HRQoL of patients on different forms of the RRT. The study population consisted of: 1) 120 patients on hemodialysis (HD); 2) 43 patients on peritoneal dialysis (PD); 3) 9 recipients who lost their grafts and went back to dialysis (PT); 4) 120 age- and sex matched healthy individuals (Controls); and 5) 48 renal transplant recipients (T). The SF 36, GBB-24 and Bf-S questionnaires have been used for the assessment of HRQoL. The mean SF-36 scores were not significantly different between: a) control group and transplant recipients; b) hemo- and peritoneal dialysis patients including previously transplanted patients. The dialysis patients scored significantly worse in all eight SF-36 domains as compared with the transplant recipients and healthy subjects. In all GBB-24 components the transplant recipients scored significantly higher than HD and PD patients. In the following components: "Fatigue tendency", "Limb pain" and "Cardiac complaints", recipients scored significantly higher than the control group subjects. The mood analysis (Bf-S) has shown that the scores of transplant recipients and controls did not differ and were significantly higher than that of the dialysis patients. The HRQoL of patients on hemo- and peritoneal dialysis is similar and lower than that of the general population. Renal transplantation significantly improves HRQoL at least to the level of the healthy individuals. The graft loss is associated with the significant worsening of HRQoL. PMID- 22201074 TI - [Relationship of acute urinary retention, bladder ischemia and metabolic changes in bladder wall and urine during infravesical obstruction due to benign prostatic hyperplasia]. AB - Decrease of enzyme activity in the bladder wall in combination with increase of enzyme activity in the urine, affirm that exactly the bladder is the source of enzymuria increase and it is related with marked damage. Taking into consideration, that from the bladder wall not only cytoplazmatic enzymes come out but also enzymes connected with cell membranes, it is expected that high enzymuria is not only because of increase permeability of cytoplazmatic membrane for large molecules but also is connected with cell parts distruction. Similarity of changes during acute urinary retention and bladder wall ischemia let us assume vital value of the factor of changes of bladder wall blood supply during acute urinary retention and its role in the development of metabolic and functional changes. PMID- 22201075 TI - [Intramural blood flow and neurogenic regulation changes of the bladder wall of rats with infravesical obstruction based on harmonic analysis of bioimpedans]. AB - During high pressure in the bladder, particularly during delay of urination because of infravesical obstruction, raisings of blood pressure were marked with simultaneous increase of renal and spleen sympathetic nerves activity. During urination the activity of sympathetic nervous system decreases while the activity of parasympathetic system which is responsible for detrusor contraction increase. All these data testify to changes of vegetative regulation of hypertrophic bladder during inftavesical obstruction, but on the other hand mechanism of those changes and their functional consequences require further studies. PMID- 22201076 TI - Effectiveness of different diagnostic methods for assessment of hyperandrogenism in young women with hirsutism. AB - Free testosterone is the most common marker of hyperandrogenism in women. Its measurement by equilibrium dialysis and liquid chromatography-tandem mass spectroscopy is the "gold standard", but determination of free testosterone routinely not feasible in all laboratories. In some cases the level of free testosterone may be elevated when the total testosterone level is normal. Low level of sex-hormone binding globulin determines the fraction of plasma testosterone that is free or bound to albumin. Recently, some models for calculating free testosterone and bioavailable testosterone from total testosterone, sex hormone binding globulin and albumin have been developed. The aim of this study was to compare effectiveness of diagnostic methods, such as serum free testosterone measured by ELISA-method and free androgen index and calculated androgen parameters for assessment of hyperandrogenism in young women with hirsutism. In 35 patients with hirsutism and different diagnosis free androgen index, free and bioavailable testosterone were calculated from total testosterone, sex hormone binding globulin and albumin. Free testosterone was measured by Elisa- method. Receiver operating characteristics (ROC) curves were drawn to assess diagnostic power of androgen parametres for different hirsutism degree. Significant positive correlation between free testosterone (FT) measured by ELISA -method and free androgen index (FAI) in patients with hirsutism was detected. The diagnostic power of cFT (calculated free testosterone) was greater than diagnostic power of FT and FAI in the group with severe hirsutism (for severe hirsutism (n=14) auROC (FT) =0,446; auROC (cFT)= 0,507; auROC (FAI)=0,461). FAI, cFT and cBio-T may be more adequate and alternative methods for assessment hyperandrogenism in women with hirsutism, than only free testosterone measured by ELISA-method. Furthermore, the calculated androgen parameters may be important to determinate the mechanisms of hyperandrogenism development. PMID- 22201077 TI - [Correlations between clinical signs and hormonal parameters in young women with hirsutism]. AB - Hyperandrogenism is the pathological condition, which clinical signs are "androgendependent dermopathies" (seborrhea, acne, hirsutism, alopecia) and not in every cases evidence with hyperandrogenemia. Free testosterone is the most frequent marker of hyperandrogenism, but its determination routinely not feasible in all laboratories. Therefore, some models for calculating free and bioavailable testosterone have been developed. In women the testosterone sources are not only ovaries and adrenal glands, but also abdominal and peripheral fat. There are many investigations to definite correlations between body mass index, androgens and sex hormone binding globulin. The aim of this study was to define the correlations between clinical, biochemical markers of hyperandrogenism and body mass index, with regard of abdominal obesity in young women with hirsutism. 83 female adolescents (14-20 year) with hirsutism and 20 female adolescents in control group were included. C-peptide, estradiol, total testosterone, sex hormone binding globulin (SHBG) were measured. Free androgen index (FAI), free (cFT) and bioavailable (Bio-T) testosterone were calculated. The levels of C peptide and glucose were used to compute Homa-IR (homeostasis model assessment for insulin resistance). There were detected significant high levels by all hormonal parameters of hyperandrogenism in women with hirsutism, than in control group. In patients with abdominal obesity were also found significant high levels by all calculated parameters of hyperandrogenism and significant low level of steroid-bind globulin, than in patients with central obesity. In two groups by hirsutism degree were not detected any differences between androgen markers. The findigs of this research suggest, that android obesity in female adolescents with hirsutism can cause harder hyperandrogenism and elevate free androgen index, free and bioavailable testosterone levels. The prophylactic reduction of body mass index may prevent complications. PMID- 22201078 TI - The role of multislice spiral computed tomography in the diagnosis and management of acute facial trauma in patients with multiple injuries. AB - Using of mutislice spiral CT as first line examination for the diagnosis of Acute Facial trauma in the setting of Polytrauma reduces both: valuable time and cost of patient treatment. After a brief clinical examination, MDCT was performed depending on the area of injury, using a slice thickness of 0.65 mm. The obtained data were analyzed using 3D, MIP and Standard axial with Bone reconstruction protocols. 64 polytrauma patients were evaluated with both Anterior and Lateral craniography (plain skull X ray: AP and Lateral) and Multi Slice CT. Craniography detected only 18 cases of traumatic injuries of facial bones, but exact range of dislocation and accurate management plan could not be established. In the same 64 cases, Multislice CT revealed localization of all existed fractures, range of fragment dislocation, soft tissue damage and status of Paranasal sinus in 62 cases (96.8%). In two cases MS CT missed the facial fracture, in one case the examination was complicated because of bone thinness and numerous fracture fragments, in another multiple foreign body artifacts complicated the investigation. The study results show that, CT investigation based on our MDCT polytrauma protocol, detects all more or less serious facial bone injuries. PMID- 22201079 TI - [Role of multislice spiral computed tomography in diagnosis of spinal injuries in polytrauma patients]. AB - Spinal injury in poly trauma patients is serious problem, because they cause high mortality and morbidity. According to WHO statistics, there are registered 30 million cases of spinal injuries annually, 50% of them die before reaching the hospital. In last 5 years incidence of spinal traumas has increased 2.6 fold and is about one third of all spinal diseases. That is why spinal injuries remain a challenge. The purpose of our study is to assess diagnostic efficiency of multislice spiral CT in diagnosis of spinal injuries in poly trauma patients. We randomly assessed data from 200 poly trauma patients, who underwent multislice spiral CT in poly trauma mode. In 92 (46%) patients different types of spinal fractures and injuries were detected. Age distribution was 16-72 (mean age 52 years). Out of 92 patients, 9 (4.5%) had isolated trauma, 83 (41.5%) had multiple trauma. Solitary injury of spinal column was detected in 30 (32.6%) patients, 54 (58.6%) had combined spinal injuries. In spinal injury patients the most common trauma mechanism was MVC - 56 patients (60.86%), fall from height 27 (29.36%) patients, diving 5 (5.43%) patients, gun shot wound 3 (3.26%) patients, industrial injury 1 (1.08%) patients. The most common location of the injury was lumbar vertebra (55 patients), thoracic vertebra (39 patients), cervical vertebra (28 patients). After assessing MDCT and MRI results 37 patients were operated, 6 of them underwent surgical intervention urgently, 31 had delayed surgery, that was performed after treating other life threatening injuries. Indications for surgical intervention were spinal cord compression and non stable vertebral fractures. According to our study results, MDCT is the study of choice for the diagnosis of spinal injuries in poly trauma patients. It helps to detect type and extension of the bony injury and visualize fragments in the spinal canal. It is superior to other radiological studies. 3D, MIP and MPR reconstruction gives information about spatial location of the fracture and helps to timely plan correct management. PMID- 22201080 TI - Correspondence of treatment of acute diarrhea to who recommendations in georgia. AB - The aim of this study was to analyze Georgian health care practitioners' knowledge on management of acute diarrhea and its adherence to WHO treatment guidelines. A questionnaire-based, cross-sectional survey was carried out in hospitals and out-patient clinics of Georgia. 350 anonymously filled questionnaires were analyzed (27% - hospitals, 73% - out-patient clinics). Majority (65%) of interviewees defined diarrhea correctly, 74% correctly named main signs of dehydrations and classified severity of dehydration, 26% mixed up signs of moderate and severe dehydration. About 90% uses ORS during diarrhea, but only 51% follow WHO recommendations about fast rehydration. The most of responding staff (78%) don't know the benefits of low osmolarity ORS. 42% pediatricians who work at the hospital use IV rehydration in case of moderate dehydration. 78% of medical staff named recommended IV fluids either Ringer lactate solution or Normal saline, but 22% still choose 5-10% Dextrose solution. Almost all doctors (94%) use probiotics, either as monotherapy (22%) or in combination (78%). 35% of physicians prescribe antiemetics, 27% antidiarrheals, 45% antimicrobial drugs, from those 65% uses antibiotics only in case of presence of blood in stool. The majority of medical staff don't use Zinc. Study revealed that most respondents advise continuation of breastfeeding, in case of bottle feeding 32% prescribe lactose free formula, while others continue normal diet. In elder children some restrictions in diet is still in practice. The study revealed that primary level health care representatives adhered to the WHO recommendations better, than hospital doctors, that was statistically significant. The findings show a moderate adherence to standard treatment guidelines of diarrhea. The recommendations on using ORS and continuation of breast-feeding are most followed. The most problematic issues are excessive use of antibiotics and IV fluids, no use of zinc, unnecessary use of antidiarheals and antiemetics. To improve case management of acute diarrhea, continuing professional development program targeting the practitioners is necessary. PMID- 22201081 TI - [The importance of risk factors in emergence and development of ishemic heart deasease]. AB - The prognostic value of some risk factors in emergence of ishemic heart disease and insult were analyzed. 1500 healthy men from 40 to 59 years old were under investigation. Reinvestigation of 71% responses was conducted after 10 years. The prognostic role of different risk factors of ishemic heart disease was revealed. Multifactorial prophylaxis carried out for 5 years among men aged 40 to 59 years brought about a significant decrease in the total death rate (by 22,2%), Mainly because of the lowering of the death rate due to cardiovascular diseases (by 41,3%), determined by a reduction of these indicators among persons who initially had coronary heart disease. The data indicate that in order to reach a positive effect, the primary care should be exercised for a longer time. At the same time, the prophylactic measures are to be multifactorial and include not only correction of risk factors but also the screening and treatment of patients suffering from coronary heart disease. PMID- 22201082 TI - [A programe of multifactorial prophylaxis of coronary heart disease: study of the death rate]. AB - Multifactorial prophylaxis carried out for 5 years among men aged 40 to 59 years brought about a significant decrease in the total death rate (by 22,2%), mainly because of the lowering of the death rate due to cardiovascular diseases (by 41,3%), determined by a reduction of these indicators among persons who initially had coronary heart disease. The data indicate that in order to reach a positive effect, the primary care should be exercised for a longer time. At the same time, the prophylactic measures are to be multifactorial and include not only correction of risk factors but also the screening and treatment of patients suffering from coronary heart disease. PMID- 22201083 TI - [Anxiety, depression, panic disorder and bronchial asthma]. AB - The Research purpose was studying anxiety and depression, and also the disturbing attacks in bronchial asthma (BA) patients. Research problems included: specification of prevalence of anxiety, depression, and also panic frustration of BA patients; an establishment of psychosomatic parities between anxiety, depression, panic frustration and BA. The study included the analysis of a mental condition, subjective and objective anamnestic information and medical documentation. 50 patients with BA are examined - 32 women, 18 men (average age of the patients was 38,7 +/- 2,1). In 40% of cases the anxiety and depression is revealed. Subclinical expressed anxiety and depression is observed in 15 (39%) cases. Clinically expressed anxiety and depression is observed in 25 (50%) patients. During emotional and physical activities the phenomena of hypersthenic weaknesses is revealed in 45% of patients, short-term disturbance of falling asleep in 53%, propensity to revealing of polymorphic pathological corporal sensations (cephalgia, cardialgia, abdominalgia) is found out in 85% of cases. In all observation the beginning of mental frustration concerns to the second decade of life. In intervals between panic attacks are registered anxiety of expectation (fear of development of repeated panic attacks) and nosophobia (fear of development of myocardial heart attack, a stroke etc.). In all observation the beginning of mental frustration was revealed at the second decade of life. Symptoms of type "behavioral apnea (wind)" (breath dissatisfaction, feeling short of breath, arrhythmias and respiratory regularity of cycles) developed long before the manifestation of asthma (BA) and persist in its remission. The clinical manifestation of BA is extended by signs of panic attacks. Symptoms of anxiety and recurrent panic attacks worsen duration and outcome of BA. Hence, psychological and psychopharmacological therapy for anxiety disorders in addition to standard anti-asthma therapy could be suggested as one of the affective methods for treatment of BA patients with symptoms of anxiety and depression. PMID- 22201084 TI - [Effects of combined administration of ripronat and rotavit royal on the working capacity of the young football players]. AB - The goal of the study was evaluation of the impact of the pharmaceutical preparations Ripronat and Rotavit Royal on the physical working capacity and psychomotor performance of the young football players during their basic preparatory period of physical conditioning. Blinded placebo controlled study was performed on 50 male football players (mean age 19,8 +/- 3,2 years). The football players were divided into three groups: study group (n=30), placebo group (n=10) and control group (n=10). Study group in turn were divided in two subgroups: subgroup A (n=15, receiving ripronat and rotavit royal) and subgroup B (n=15, receiving only ripronat). In all groups following tests were performed before and after four weeks of the medical administration: 1.Watt max bicycle test. 2. Wingate cykletest. 3. Psychomotor performance including reaction time and relaxation abilities. Results of our study allow us to conclude that ripronat increase the aerobic capacity and psychomotor performance of football players, and it would be recommended for administration during early stages of training, when main emphasis is made on aerobic performance. PMID- 22201085 TI - Does McCollough effect provide evidence for implicit change perception? AB - The possibility of implicit change detection in the visual scene is one of the central issues of a change detection process. The present work was aimed at studying the possibility of implicit perception of color changes. With this end, we have acquired the McCollough effect (MCE) with no possibility of explicit perception of the inducing stimulus color. The experiments were conducted on 40 male and female subjects with normal color vision. The MCE acquisition occurred using only one inducing stimulus - a vertical black-green grating. In the adaptation period the grating was presented as short expositions, with an instant substitution of the stimulus by so-called "deleting" image, whose presentation played simultaneously a role of an interstimulus interval. Owing to the fact that the time of exposition was selected so as to allow for the subjects perceive explicitly but the form of an inducing stimulus (in this case the grating's orientation) and not the color of chromatic stripes between the black ones, the subjects couldn't, in the adaptation period, perceive explicitly either the color per se or its appearance-disappearance. In spite of this, in a definite part of subjects (approximately in 20%) the effect was acquired indicating that in the adaptation period perception of not only color but also of its appearance disappearance did occur, i.e. there took place implicit perception of color change. This result can be viewed as a confirmation of the visual system's ability of implicit change perception. PMID- 22201086 TI - Color naming and color visual searching in the Georgian-speaking population: the comparative age-specific study. AB - When verbally sequencing colors, Georgian-speaking individuals name approximately forty colors, starting with the basic colors mainly primarily with red. When viewing a collage composed of familiar colors, four year old children initially name the basic colors, in most cases starting with red, without giving preference to any specific strategy. However, school-aged children and adults name colors in a sequence that coincides with the eye movement during the color viewing process; specifically, from left to right and top to bottom. This fact indicates that the color searching strategy of a visual scene is determined by the eye movement direction, which is worked out as a result of reading and writing abilities and habits. This does not permit an individual to use any other strategy or give priority to any color. PMID- 22201087 TI - Factors that determin color appearance and color classification. AB - The purpose of this work was to consider the objective and subjective factors involved in color perception and on their basis offer a color classification that would allow for determining which of these factors are significant for each particular class of colors. In the first part of the article it is considered that physical correlates of subjective sensation of color have mainly a dual nature and sometimes correlate with spectral-power content of light coming from a given area of visual scene to retina, and sometimes with surface reflectance of the given area. Other objective and subjective factors which participate in the formation of color appearance are also considered. According to the characteristics of the visual stimulus, viewing conditions and functional state of visual system, composition of objective and subjective factors participating in the formation of color appearance, as well as the share of each factor in this process are changeable. In the second part of the article one of the possible version of color classification according to which it is possible to distinguish nine different classes of colors is proposed. Among differences between these classes, the most noticeable is that in the case of all classes of color except constant colors, the physical parameter that determines the color category of a given area is the spectral-power distribution of the light coming from this area to the retina. However, in the case of constant colors, the physical parameter that determines the color category of a given area is its reflectance. In the case of considered different classes of colors, composition of objective and subjective factors participating in the formation of color appearance is different. The proposed classification allows determining which of these factors are significant in the case of each specific class of color. PMID- 22201088 TI - [Two possible modes of memory trace reproduction]. AB - The current study tested spatial memory in 8 adult domestic cats using a spatial delayed response ("DR") memory task. Two existing different variants of that task were used by us in 8 adult domestic cats. One group of 4 cats was tested in the direct variant ("DDR"), while other group of 4 cats was trained to perform indirect variant ("IDDR"). DDR was based on the visual perception of baited food wells located in different places of large room which was rich of distal landmarks; testing of DDR proceeded initially with short delay intervals (minutes) followed after attainment of correct performance criterion (80% of correct responses during two consecutive days, each encompassing 20 trials of DDR), by long delays including one hour. In parallel other four cats were tested in NDDR situation. In that case before memory testing in cats was established quite strong (100% correct) visual discrimination of two different visual stimuli of the "go left - go right" type. Afterwards actual testing of IDDR was issued just with the same program of different delay presentations as was used in preceding DDR situation. Results obtained convinced us, that results of two different methods of DR testing might be explained by different modes of trace retrieval (reproduction) from the visuospatial memory stores - one working in DDR is based on the "cue recall" aided by distal landmarks, presented in DDR situations, and the other working in NDDR based on the "cue recognition" aided by visual discrimination of visual conditioned stimuli. PMID- 22201089 TI - [Effect of short-term manganese chloride intoxicatuion on anxiety and fear of young rats]. AB - Manganese is an essential trace element for all living organisms. Though some neurological dysfunction take place during intoxication caused by excessive exposure of this metal. The goal of this research was to elucidate the emotional state, in particular anxiety and fear in three groups of young male rats. Two groups of 30 day old rat pups were given drinking water with MnCl(2).4H(2)O dissolved in, the doses were 1mg/ml (I group) and 10 mg/ml (II group), and the third group was control animals. Before starting and a day after of termination manganese consumption the animals were tested in the "open field" and "elevated plus maze". In two month old rat pups compared to one month ones the elevation of anxiety was observed that led to increase of fear. 30 day intoxication of one month old rat pups with both doses of manganese (1 and 10 mg/ml) induces: strengthening of motor and orienting-explorative activity, decrease in the level of anxiety and fear. During the intoxication of animals with above mentioned doses of manganese chloride the dose-dependant effect is not observed. PMID- 22201090 TI - Changes of open field behavior in animal model of depression. AB - Animal model of depression was developed by means of chronic exposure of rat pups to anticholinergic drugs (Atropine, Scopolamine) during the early life period from postnatal day 7 (P7) and/or 14 (P14) to P21 and/or P28, respectively. Such procedure resulted in lasting behavioral changes that were evident long after drug discontinuation and persisted at mature age (2-3 month period). Behavioral changes included most indices of open field behavior. Modeled animals exhibited significant depression of locomotor activity certified by sharp reduction of the number of crossed squares, rising of a head and vertical standings. Grooming behavior was also significantly decreased. Frequency of center entrance and the time of staying in the center of open field were sharply shortened. Modeled animals exhibited complete loss of exploratory motivation which wasn't related to the enhancement of fear emotion so far as values of incidence of urination and defecation remained unchangeable. These findings indicate that postnatal exposure of rat pups to Atropine and/or Scopolamine induces lasting behavioral "despai"' or "refractory loss of interest" at mature age. In sum animal model of depression which are characterized by super sensitivity of brain muscarinic cholinergic system exhibit more depressed behavioral items in open field than other types of animal models of depression. These data imply the preference of muscarinic cholinergic super sensitivity for the development of depressive state and therefore they are very significant for both basic science and clinical research issues. PMID- 22201091 TI - Development of solid, dosage forms of medicinal drugs from indoline group alkaloids. AB - According to biopharmaceutical investigations, the regimen of the tablets of alkaloid containing new galenic preparation of indoline and indole group - Vinkabral, Vingerbin has been developed. Also, the preparation technology was worked out and it has been defined that optimal method of tabletting new galenic formulations, such as Vincabral and Vingerbin is direct pressing by using polifunctional additional formulations - Proslov SMCC (siliced methylceluslose) and Glikonat Sodium of Starch. Their influence on the technological characteristics are studied, so as the proportion of additional compounds are defined. The influence of technological parameters on technological characteristics of the tablets Vinkabral, Vingerbin were investigated and optimal conditions were selected: optimal humidity was 1.5-3.0%, Optimal compression power-105-120 mpa. The kinetics of the release of active substance - alkaloids from the tablets of Vinkabral and Vingerbin was studied using the methods of "rotary basket" in sour, neutral and alkaline area during the mix time 50 rt/min and 100 rt/min. The 90% of active substance releases in sour area during 75 minutes in 100 rt/min mix up condition. PMID- 22201092 TI - Investigation and record of the apricot trees' gums raw resources of flora of the Republic of Armenia. AB - Considering the fact that the recent resourceological researches referring to the local flora apricot trees' gums held in different regions of the RA were encountered in 1999-2000, there was a problem of serious approach necessity regarding gums in the RA (for a process of their resources record in the RA), as their need increase is anticipated not just in the medical industry, but also in the other industrial aspects. According to the got value, the possible annual provision volume all over the Republic made up 49.52-55.69 tons. Meanwhile raw productivity is approximately 53.6 +/- 6.67 g/m(2). Thus, the gums' raw sources provided by the widely-cultivating in the RA apricot gum-trees can fully meet the needs of those industrial aspects, where use of the polysaccharides of natural origin is inevitable. PMID- 22201093 TI - Cytologic, colposcopic and histopathologic correlations of hyperkeratosis in reproductive women. AB - The significance of leucoplakia/hyperkeratosis in colposposcopy or hyperkeratotic cells in Pap smear, is not fully understood. It is considered that hyperkeratosis itself is a benign change, but it may mask other pathologies, including invasive carcinoma. We studied 123 woman with colposcopically identified hyperkeratosis and its' possible relationship with dysplastic lesions of uterine cervix, based on correlation with cytopathological and histopathological data. The results of our study showed that 1) cervical dysplastic lesions are identified 2 times less frequently in conventional Pap smears from patients with thick leukoplakia, than in patients with thin leukoplakia and 2) histopathologically identified cervical dysplasias are 1,5 times more common in patients with thick leukoplakia. Pathologists and gynecologists in practice should be aware of this difference. PMID- 22201095 TI - [Odontoclasts and calcitonin]. AB - Although it is believed that odontoclasts, which mediated root resorption of deciduous teeth, possess common properties to osteoclasts, these regulatory mechanisms differ from osteoclastic bone resorption. It is well established that calcitonin receptor is an important osteoclast marker and that calcitonin is a potent inhibitory hormone of osteoclastic bone resorption. However, the presence and function of calcitonin receptors in human odontoclasts are still controversial. We summarize the physiological properties and differentiation mechanisms of odontoclasts, and the effects of calcitonin on root resorption, including our recent results using human odontoclasts and periodontal ligament cells freshly isolated from deciduous tooth roots. PMID- 22201094 TI - [Bone and tooth in calcium and phosphate metabolism]. AB - Tight regulation of serum concentrations of calcium and phosphate is indispensable for maintaining normal physiological condition. Imbalance of this regulation leads to pathophysiological disorders including heart disease, chronic kidney disease, and ectopic calcification. Formation and mineralization of bone and tooth are greatly influenced by calcium and phosphate metabolism since both organs are mainly consist of calcium-phosphate. Calcium and phosphate homeostasis is under hormonal control on its target organs such as kidney, bone and intestine. Calcium and phosphate are absorbed in intestine and reabsorbed and excreted in kidney. Bone store and release them in response to changing physiological demand by osteoblastic bone formation and osteoclastic bone resorption. Bone is also important as an endocrine organ that releases FGF23 from osteocytes, a novel hormone that targets the kidney to inhibit phosphate reabsorption and 1alpha, 25 (OH) (2)D(3) production. PMID- 22201096 TI - [Tooth and bone research using genetically modified mice]. AB - Teeth and bone are both hard tissues and composed of hydroxyapatite. Tooth development initiates with the invasination of oral epithelium, followed by aggregation of supporting ectomesenchymal cells. From mouse study, numbers of molecules have been discovered to relate tooth development. These discoveries have helped to clarify the responsible genes of human genetic disorders with abnormal tooth number and structure. During tooth development, teeth erupt into the outer environment, oral cavity. From this point, teeth are completely different from bone which is always covered by soft tissues. Tooth eruption is composed of two different processes, that is, eruption pathway formation and vertical tooth movement. In this review, mutant mice with abnormal tooth development and eruption are introduced, and molecular mechanism required for this process is discussed. PMID- 22201097 TI - [Molecular mechanisms for the improvement of wound healing ability of periodontal ligament in Marfan's syndrome]. AB - Marfan's syndrome (MFS) is a systemic disorder of the connective tissues caused by insufficient fibrillin-1 microfibril formation and can cause cardiac complications, emphysema, ocular lens dislocation and severe periodontal disease. ADAMTSL6beta, a microfibril-associated extracellular matrix protein that has been implicated in fibrillin-1 microfibril assembly is able to improve microfibril insufficiency in MFS mice model. These findings suggest a new therapeutic strategy for the treatment of MFS through ADAMTSL6beta-mediated fibrillin-1 microfibril assembly. We here review effect on ADAMTSL6beta to the improvement of microfibril insufficiency in periodontal tissue as a model. PMID- 22201098 TI - [Cardiovascular diseases and periodontal diseases]. AB - Accumulated evidence has strongly suggested that the long-term effects of periodontal diseases can be linked to more serious systemic conditions such as cardiovascular diseases, diabetes, and complications of pregnancy. Especially, a prevalence of coronary heart disease was found to be significantly increased in patients with periodontitis after adjusting for risk factors such as smoking, diabetes, alcohol intake, obesity, and blood pressure. Furthermore, various studies have shown that Porphyromonas gingivalis, a major periodontal pathogen, is able to exacerbate atherosclerosis following oral-hematogenous spread due to the bacteremia. By P. gingivalis, endothelial cells activate and upregulate various adhesion molecules, thus increasing the likelihood of macrophage diapedesis and subsequent conversion to foam cells thus furthering athroma progression. These findings likely indicate the tight relationship between periodontitis/periodontal pathogens and cardiovascular diseases. PMID- 22201099 TI - [Diabetes and oral disease]. AB - Periodontal disease is one of the complications in diabetes. We mention about relationship between diabetes and periodontitis from the view of epidemiology, mechanism and effect of intervention treatment. Excellent glycemic control is essential to improve periodontal disease in diabetic patients, and periodontal treatment not only prevents development and progression of diabetes but also prevents its complications. We need to focus on the treatment for both diabetes and periodontal disease, as the disease to affect each other. PMID- 22201100 TI - [Xerostomia and dysphagia]. AB - Xerostomia is a general term used to refer to dryness of oral mucosa, and is distinguished from a sense of thirst. Causes of xerostomia with a decrease in saliva which bears calcium metabolism such as recalcification of enamel canes include ; age-related atrophy of salivary gland, Sjogren's syndrome, salivary gland disorder due to radiation therapy, side effect of medication, and autonomic nervous system imbalance, dehydration. Xerostomia without decrease in saliva production but shows excessive evaporation of saliva could be due to mouth breathing. Symptoms of xerostomia include ; burning sensation in the mouth, poor oral hygiene, inflammatory change of oral mucosa, high incidence of periodontal disease or caries, and impairment of oral function (dysphagia, dysgeusia, and speech disorder) . This article discusses about xerostomia and dysphagia. PMID- 22201101 TI - [iPS cells in dentistry]. AB - The discovery of the induced pluripotent stem (iPS) cell technology, which enables us to produce pluripotent stem cells by introducing a few genetic factors, commands considerable attention in the field of dentistry. These iPS cells may be of particular importance for developing innovative technologies to regenerate missing jaw bones and lost teeth, and there are expectations that several types of tissue stem cells and mucosal cells in the oral area can be used as an ideal iPS cell source. We previously reported that the gingiva, which is often resected during general dental treatments and treated as biomedical waste, is a promising source of iPS cells. In this review, the current trends in iPS cell research in dentistry are outlined, and future aspects of potential applications of the iPS cell technologies to dental treatments will be discussed. PMID- 22201102 TI - [Potential use of parathyroid hormone (PTH) in the treatments for oral diseases]. AB - Bone formation is the key for successful dental treatments including periodontal tissue regeneration osseointegration of implant placement in which new alveolar bone formation is mandatory. Parathyroid hormone (PTH) is a peptide hormone containing 84 amino acids. Accumulated results show that intermittent PTH administration increases bone mass. Accordingly, recombinant N-terminal fragment of human PTH (1-34) , Teriparatide, is used for the treatments of osteoporosis worldwide. It is, therefore, expected that PTH has the potential to be a new therapeutic intervention for oral diseases that require increased bone remodeling and new bone formation. PMID- 22201103 TI - [Vitamin D and bisphosphonate-related osteonecrosis of the jaw (BRONJ) ]. AB - Bisphosphonate have been widely used for the treatment of osteoporosis and malignant hypercalcemia or bone metastasis of solid cancers. Recently bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been reported. However the pathogenesis of BRONJ has been unclear. This article reviews the various hypotheses of the pathogenesis of BRONJ including our hypothesis for its pathogenesis. PMID- 22201104 TI - [Orthodontic tooth movement and expression of calcium regulating hormone]. AB - Nociception by orthodontic tooth movement stimulate Trigeminal nerve free endings in periodontal ligament (PDL) , and neuropeptides such as substance P and CGRP are synthesized in Trigeminal ganglion sensory cells and released both centrally and peripherally around blood vessels in PDL and pulp. Neuropeptides such as CGRP and substance P are the signal transmitter of pain and might modulate vascular enlargement, blood flow or vascular permeability. CGRP receptor for its subunit, receptor activity modifying protein 1 (RAMP 1) distributed on osteoclasts and osteoblasts in PDL. CGRP may have effects on bone remodeling due to not only inhibiting bone resorption like calcitonin but also directly stimulating bone formation in the luxated PDL and during experimental tooth movement. PMID- 22201105 TI - [Present status of periodontal regeneration - FGF-2 and Teriparatide - ]. AB - Periodontal regenerative therapy is required to regain the tooth function and oral health for patients with periodontal diseases. We reported that topical application of basic fibroblast growth factor (FGF-2) into alveolar bone defects stimulated significant periodontal regeneration in periodontitis patients. On the other hand, subcutaneous administration of Teriparatide, a drug composed of the first 34 amino acids of parathyroid hormone that has anabolic effects for osteoporosis, has been reported to induce periodontal regeneration in the clinical trial. Both of the therapies have been expected to be the periodontal regeneration therapy of the next generation. In this review, we introduce the present status of these new periodontal regenerative therapies. PMID- 22201106 TI - [ASBMR 2011 report. Meeting report on the ASBMR. Topics for basic research in ASBMR 2011]. AB - This is the report from ASBMR2011 held in San Diego, CA, USA focusing on basic research. This year's key words seem to be "Muscle" and "Osteocytes" . In this brief report, I would like to introduce a part of current basic researches presented at ASBMR 2011. PMID- 22201107 TI - [ASBMR 2011 report. Meeting report on the ASBMR. Clinical topics in ASBMR 2011 at San Diego - vitamin D and calcium -]. AB - The 33rd meeting of ASBMR was held in San Diego, California, from Sep 16th to 20th, 2011. Some of the clinical topics such as ASBMR/ECTS Clinical debate, IOM vitamin D report from the meeting are summarized. PMID- 22201108 TI - [ASBMR 2010 report. Meeting report on the ASBMR. Present and future of the treatment of osteoporosis]. AB - ASBMR meeting 2011 had been held in San Diego, CA from September 16th to 20th 2011. Identification of new risk factors for osteoporosis or the long-term result of novel medicine in clinical trials was presented. Also the hot discussion as to the updated recommendations of the US Institute of Medicine (IOM) on the intake of vitamin D was done. PMID- 22201109 TI - [Calcium pros and cons. Is QUS available for clinical use? QUS should be used as fracture-risk assessment tool, not as diagnostic tool for osteoporosis]. AB - The large prospective studies of osteoporotic fracture in Europe and the United States have confirmed the utility of calcaneal QUS to predict fracture risk in elderly people. The other side, QUS has unfortunately only a few evidence concerning about usefulness as osteoporosis diagnostic tool in recent reports. For the present, QUS should be used as risk assessment tool of osteoporotic fracture. Because various ultrasound parameters depending on the manufacture are defined, the standardization of these values should be achieved. A large number of normative data have been collect to re-calculate to standardize SOS by the committee of Japan Osteoporosis Society, and age-related change of the standardized Speed of Sound (S-SOS) has been already reported. In this report, the peak value of S-SOS is seen in teenager, and mean of S-SOS in each age are gradually decrease in life. This age related change indicates that fracture risk would be gradually increase in life. PMID- 22201110 TI - [Calcium pros and cons. Is QUS available for clinical use? Quantitative ultrasound has not been established as a method for diagnosing osteoporosis and monitoring the effectiveness of therapy]. AB - Quantitative ultrasound (QUS) is a convenient method for bone mass measurement and provides an index of bone strength reflecting bone structure as well as bone density. It applies to the peripheral skeleton such as calcaneus and is not applicable to vertebra and hip. The sensitivity for interval change is not so high. Thus, QUS is preferred for assessing fracture risk, and has not been established as a method for diagnosing osteoporosis and monitoring the effectiveness of therapy. PMID- 22201111 TI - Memory after silent stroke: hippocampus and infarcts both matter. AB - OBJECTIVE: Memory decline commonly occurs among elderly individuals. This observation is often attributed to early neurodegenerative changes in the hippocampus and related brain regions. However, the contribution of vascular lesions, such as brain infarcts, to hippocampal integrity and age-associated memory decline remains unclear. METHODS: We studied 658 elderly participants without dementia from a prospective, community-based study on aging and dementia who received high-resolution structural MRI. Cortical and subcortical infarcts were identified, and hippocampal and relative brain volumes were calculated following standard protocols. Summary scores reflecting performance on tasks of memory, language, processing speed, and visuospatial function were derived from a comprehensive neuropsychological battery. We used multiple regression analyses to relate cortical and subcortical infarcts, hippocampal and relative brain volume, to measures of cognitive performance in domains of memory, language, processing speed, and visuospatial ability. RESULTS: Presence of brain infarcts was associated with a smaller hippocampus. Smaller hippocampus volume was associated with poorer memory specifically. Brain infarcts were associated with poorer memory and cognitive performance in all other domains, which was independent of hippocampus volume. CONCLUSIONS: Both hippocampal volume and brain infarcts independently contribute to memory performance in elderly individuals without dementia. Given that age-associated neurodegenerative conditions, such as Alzheimer disease, are defined primarily by impairment in memory, these findings have clinical implications for prevention and for identification of pathogenic factors associated with disease symptomatology. PMID- 22201112 TI - Giant head neurofibroma. PMID- 22201113 TI - An unusual cause of isolated vomiting. PMID- 22201114 TI - Immune reconstitution inflammatory syndrome in natalizumab-associated PML. PMID- 22201115 TI - Progressive multifocal leukoencephalopathy in a patient without immunodeficiency. PMID- 22201117 TI - Teaching neuroimages: neuroradiologic findings in pontine and extrapontine myelinolysis: clue for the pathogenesis? PMID- 22201118 TI - Teaching neuroimages: sequential MRI of the pituitary in Sheehan syndrome. PMID- 22201119 TI - An artifact derived from a pseudogene led to the discovery of microRNA binding site polymorphism in the 3'-untranslated region of the human dihydrofolate reductase gene. AB - A novel single-nucleotide polymorphism (SNP) in the 3'-untranslated region of the human dihydrofolate reductase (DHFR) gene with enhanced expression was identified in 2001. In 2007, it was reported that this SNP, DHFR C829T, was located close to a microRNA binding site and contributed to the stability of mRNA. Many researchers have analyzed this SNP in several races including Asians and Caucasians. However, the mutation allele is not yet confirmed in most populations. In this study, we reinvestigated the frequency of this SNP using three methods. First, this SNP in genomic DNA was analyzed by a PCR-restriction fragment length polymorphism method. Second, this SNP in mRNA was analyzed by a single nucleotide extension method following a reverse transcription reaction. Third, the mRNA expression level was analyzed by a real-time PCR method. The findings in our study, regarding the discovery of this SNP, suggest that the SNP is an artifact caused by contamination by the genomic DNA of the pseudogene DHFRP1. This study is a reinvestigation of a newly discovered genetic polymorphism. PMID- 22201120 TI - Association of ABCC2 genotype with efficacy of first-line FOLFIRI in Japanese patients with advanced colorectal cancer. AB - This exploratory retrospective study examined the effects of polymorphisms in transporter genes related to irinotecan pharmacokinetics and those in genes related to irinotecan pharmacodynamics on the efficacy of first-line combination chemotherapy with irinotecan, 5-fluorouracil, and folinic acid (leucovorin) (FOLFIRI) in Japanese patients with advanced colorectal cancer. All patients harbored UDP-glucuronosyltransferase (UGT) 1A1*1/*1, *1/*6, or *1/*28 genotypes, which are associated with similar irinotecan pharmacokinetics and responses to FOLFIRI. Genetic polymorphisms were analyzed by direct sequencing. Overall response rate and median progression-free survival in a total of 61 patients were 43% and 7.5 months, respectively. The overall response rate was higher in patients with the CC genotype at -24 in ATP-binding cassette, subfamily C, and member 2 (ABCC2) than in the others (p = 0.0313). Median progression-free survival was the longest in patients with CC at -24 in ABCC2, followed by those with CT and TT (p = 0.00910). A clear gene-dose effect was seen between -24C>T and median progression-free survival. No other polymorphisms tested were related to the efficacy of FOLFIRI. We thus found that the -24C>T polymorphism in the ABCC2 gene was significantly associated with the efficacy of first-line FOLFIRI in Japanese patients with advanced colorectal cancer. PMID- 22201121 TI - Similarities and differences between US and Japan as to pharmacogenomic biomarker information in drug labels. AB - Pharmacogenomics (PGx) has been utilized as a tool to improve a drug's benefit/risk ratio and the efficiency of drug developments. In order to examine what factors are involved to determine the level of contexts (contents and descriptions) of drug-PGx biomarker information, we graded sections of Japanese package inserts and US drug labels into six levels according to the importance of cautions in regards to clinical practice and compared similarities and differences of the contexts between the two countries. Out of 54 contexts identified, 33 (61%) were graded differently between Japan and the US. The different contexts were mainly related to metabolizing enzymes used in terms of safety, therapeutic areas other than oncology, outcome before 1993, Japan-based companies having marketing authorization and no PGx data on the Japanese population. We describe the potential reasons that could lead to the differences between the two countries such as genetic differences and quantitative evidence in the Japanese population, and also discuss future perspectives to improve PGx utilization in clinical practices in Japan. PMID- 22201122 TI - Functional pleiotropy of organic anion transporting polypeptide OATP2B1 due to multiple binding sites. AB - The purpose of this study was to examine whether the presence of multiple binding sites can explain the pleiotropy of substrate recognition by OATP2B1, using Xenopus oocytes expressing OATP2B1. OATP2B1-mediated uptake of estrone-3-sulfate apparently exhibited biphasic saturation kinetics, with Km values of 0.10 +/- 0.05 and 29.9 +/- 12.1 uM and Vmax values of 14.1 +/- 6.4 and 995 +/- 273 fmol/min/oocyte for high- and low-affinity sites, respectively. Contribution analysis revealed that transport of estrone-3-sulfate mediated by high- and low affinity sites on OATP2B1 could be evaluated at the concentrations of 0.005 and 50 uM, respectively. pH-dependence study of OATP2B1-mediated estrone-3-sulfate uptake suggested that high- and low-affinity sites show different pH sensitivity. When the inhibitory effect of 12 compounds on estrone-3-sulfate uptake by high- and low-affinity sites on OATP2B1 was examined, 4 compounds appeared to be inhibitors of the high-affinity site on OATP2B1. Two other compounds appeared to be inhibitors for the low-affinity site and four others were inhibitory at both sites. These results indicated the presence of multiple binding sites on OATP2B1 with different affinity for drugs. Accordingly, it is likely that drug-drug and drug-beverage interactions occur only when two drugs share the same binding site on OATP2B1. PMID- 22201123 TI - Rong Li: tipping the balance in cell biology. Interview by Caitlin Sedwick. PMID- 22201124 TI - Cdc6 expression represses E-cadherin transcription and activates adjacent replication origins. AB - E-cadherin (CDH1) loss occurs frequently in carcinogenesis, contributing to invasion and metastasis. We observed that mouse and human epithelial cell lines overexpressing the replication licensing factor Cdc6 underwent phenotypic changes with mesenchymal features and loss of E-cadherin. Analysis in various types of human cancer revealed a strong correlation between increased Cdc6 expression and reduced E-cadherin levels. Prompted by these findings, we discovered that Cdc6 repressed CDH1 transcription by binding to the E-boxes of its promoter, leading to dissociation of the chromosomal insulator CTCF, displacement of the histone variant H2A.Z, and promoter heterochromatinization. Mutational analysis identified the Walker B motif and C-terminal region of Cdc6 as essential for CDH1 transcriptional suppression. Strikingly, CTCF displacement resulted in activation of adjacent origins of replication. These data demonstrate that Cdc6 acts as a molecular switch at the E-cadherin locus, linking transcriptional repression to activation of replication, and provide a telling example of how replication licensing factors could usurp alternative programs to fulfill distinct cellular functions. PMID- 22201126 TI - ZBTB1 is a determinant of lymphoid development. AB - In this study, we describe a chemically induced mouse mutation that caused a complete and cell-intrinsic T cell deficiency. Development of other lymphoid lineages was also partially impaired and was severely compromised under competitive conditions. Positional cloning, retroviral transduction, and a somatic reversion event revealed that the causative mutation lay within Zbtb1 (zinc finger and BTB domain containing 1), a gene conserved throughout vertebrate evolution. Our data establish ZBTB1 as a critical determinant of T cell development and lymphopoiesis in general, most likely by acting as a transcriptional regulator. PMID- 22201125 TI - Smaug1 mRNA-silencing foci respond to NMDA and modulate synapse formation. AB - Mammalian Smaug1/Samd4A is a translational repressor. Here we show that Smaug1 forms mRNA-silencing foci located at postsynapses of hippocampal neurons. These structures, which we have named S-foci, are distinct from P-bodies, stress granules, or other neuronal RNA granules hitherto described, and are the first described mRNA-silencing foci specific to neurons. RNA binding was not required for aggregation, which indicates that S-foci formation is not a consequence of mRNA silencing. N-methyl-D-aspartic acid (NMDA) receptor stimulation provoked a rapid and reversible disassembly of S-foci, transiently releasing transcripts (the CaMKIIalpha mRNA among others) to allow their translation. Simultaneously, NMDA triggered global translational silencing, which suggests the specific activation of Smaug1-repressed transcripts. Smaug1 is expressed during synaptogenesis, and Smaug1 knockdown affected the number and size of synapses, and also provoked an impaired response to repetitive depolarizing stimuli, as indicated by a reduced induction of Arc/Arg3.1. Our results suggest that S-foci control local translation, specifically responding to NMDA receptor stimulation and affecting synaptic plasticity. PMID- 22201127 TI - Gfi1b negatively regulates Rag expression directly and via the repression of FoxO1. AB - Precise regulation of Rag (recombination-activating gene) expression is crucial to prevent genomic instability caused by the generation of Rag-mediated DNA breaks. Although mechanisms of Rag activation have been well characterized, the mechanism by which Rag expression is down-regulated in early B cell development has not been fully elucidated. Using a complementary DNA library screen, we identified the transcriptional repressor Gfi1b as negative regulator of the Rag locus. Expression of Gfi1b causes repression of Rag1 and Rag2 in cell lines and primary mouse cells. Conversely, Gfi1b-deficient cell lines exhibit increased Rag expression, double-strand breaks and recombination, and cell cycle defects. In primary cells, transcription of Gfi1b inversely correlates with Rag transcription, and simultaneous inactivation of Gfi1 and Gfi1b leads to an increase in Rag transcription early in B cell development. In addition, deletion of Gfi1 and Gfi1b in vivo results in a severe block in B cell development. Gfi1b orchestrates Rag repression via a dual mechanism. Direct binding of Gfi1b to a site 5' of the B cell-specific Erag enhancer results in epigenetic changes in the Rag locus, whereas indirect inhibition is achieved through repression of the trans-activator Foxo1. Together, our experiments show that Gfi family members are essential for normal B cell development and play an important role in modulating expression of the V(D)J recombinase. PMID- 22201130 TI - Gustave Caillebotte the house painters 1877. PMID- 22201128 TI - RAG-induced DNA double-strand breaks signal through Pim2 to promote pre-B cell survival and limit proliferation. AB - Interleukin 7 (IL-7) promotes pre-B cell survival and proliferation by activating the Pim1 and Akt kinases. These signals must be attenuated to induce G1 cell cycle arrest and expression of the RAG endonuclease, which are both required for IgL chain gene rearrangement. As lost IL-7 signals would limit pre-B cell survival, how cells survive during IgL chain gene rearrangement remains unclear. We show that RAG-induced DNA double-strand breaks (DSBs) generated during IgL chain gene assembly paradoxically promote pre-B cell survival. This occurs through the ATM-dependent induction of Pim2 kinase expression. Similar to Pim1, Pim2 phosphorylates BAD, which antagonizes the pro-apoptotic function of BAX. However, unlike IL-7 induction of Pim1, RAG DSB-mediated induction of Pim2 does not drive proliferation. Rather, Pim2 has antiproliferative functions that prevent the transit of pre-B cells harboring RAG DSBs from G1 into S phase, where these DNA breaks could be aberrantly repaired. Thus, signals from IL-7 and RAG DSBs activate distinct Pim kinase family members that have context-dependent activities in regulating pre-B cell proliferation and survival. PMID- 22201132 TI - In search of the black stuff. PMID- 22201131 TI - Health and safety of the older worker. AB - BACKGROUND: In the UK, increasing numbers of paid employees are over 60 years with further increases expected as the state pension age rises. Some concern surrounds possible increased work-related illness and accidents for people working beyond the age of 60. AIMS: To identify the available evidence for health and safety risks of workers over age 60 years with respect to factors associated with injuries and accidents. METHODS: Databases searched included PUBMED, OSHUpdate, National Institute for Occupational Safety and Health (NIOSHTIC-2), SafetyLit, the UK The Health and Safety Executive (HSELINE) and the Canadian Centre for Occupational Health and Safety until December 2009. Inclusion criteria were workers aged over 60 years. Findings were grouped into occupational accidents and injuries and individual and workplace factors that may have influenced risk of injury to the over-60s. RESULTS: Very little direct evidence was found concerning safety practices and health risks of workers over age 60. Some safety risks were associated with specific physical declines such as age related hearing loss. Overall, these workers had fewer accidents and injuries but these were more likely to be serious or fatal when they occurred. There was no strong evidence that work patterns, including shift work or overtime, affected safety. Protective, compensatory strategies or experience may maintain safe working practices. CONCLUSIONS: Implications for health and safety risks cannot be assessed without longitudinal research on workforces with substantial numbers of workers over age 60 in order to address the healthy worker effect. PMID- 22201134 TI - Why I now watch my step as an occupational physician ... PMID- 22201135 TI - Dusting down older technologies. PMID- 22201136 TI - Respiratory symptoms in insect breeders. PMID- 22201137 TI - Response to: managing black when in the red, challenges for general practice. PMID- 22201140 TI - How I use it: iGoogle, RSS feeds and aggregators. PMID- 22201143 TI - Endorsement of Health and Human Services recommendation for pulse oximetry screening for critical congenital heart disease. AB - Incorporation of pulse oximetry to the assessment of the newborn infant can enhance detection of critical congenital heart disease (CCHD). Recently, the Secretary of Health and Human Services (HHS) recommended that screening for CCHD be added to the uniform screening panel. The American Academy of Pediatrics (AAP) has been a strong advocate of early detection of CCHD and fully supports the decision of the Secretary of HHS. The AAP has published strategies for the implementation of pulse oximetry screening, which addressed critical issues such as necessary equipment, personnel, and training, and also provided specific recommendations for assessment of saturation by using pulse oximetry as well as appropriate management of a positive screening result. The AAP is committed to the safe and effective implementation of pulse oximetry screening and is working with other advocacy groups and governmental agencies to promote pulse oximetry and to support widespread surveillance for CCHD. Going forward, AAP chapters will partner with state health departments to implement the new screening strategy for CCHD and will work to ensure that there is an adequate system for referral for echocardiographic/pediatric cardiac evaluation after a positive screening result. It is imperative that AAP members engage their respective policy makers in adopting and funding the recommendations made by the Secretary of HHS. PMID- 22201144 TI - Quality of early maternal-child relationship and risk of adolescent obesity. AB - OBJECTIVE: The goal of this study was to determine whether obesity in adolescence is related to the quality of the early maternal-child relationship. METHODS: We analyzed data from 977 of 1364 participants in the Study of Early Child Care and Youth Development. Child attachment security and maternal sensitivity were assessed by observing mother-child interaction at 15, 24, and 36 months of age. A maternal-child relationship quality score was constructed as the number of times across the 3 ages that the child was either insecurely attached or experienced low maternal sensitivity. Adolescent obesity was defined as a measured BMI >=95th percentile at age 15 years. RESULTS: Poor-quality maternal-child relationships (score: >=3) were experienced by 24.7% of children compared with 22.0% who, at all 3 ages, were neither insecurely attached nor exposed to low maternal sensitivity (score: 0). The prevalence of adolescent obesity was 26.1%, 15.5%, 12.1%, and 13.0% for those with risk scores of >=3, 2, 1, and 0, respectively. After adjustment for gender and birth weight, the odds (95% confidence interval) of adolescent obesity was 2.45 (1.49-4.04) times higher in those with the poorest quality early maternal-child relationships (score: >=3) compared with those with the highest quality (score: 0). Low maternal sensitivity was more strongly associated with obesity than insecure attachment. CONCLUSIONS: Poor quality of the early maternal-child relationship was associated with a higher prevalence of adolescent obesity. Interventions aimed at improving the quality of maternal child interactions should consider assessing effects on children's weight and examining potential mechanisms involving stress response and emotion regulation. PMID- 22201145 TI - Plasmapheresis to treat hypertriglyceridemia in a child with diabetic ketoacidosis and pancreatitis. AB - A 10-year-old girl presented with diabetic ketoacidosis, shock, and severe abdominal pain. She was found to have acute pancreatitis and acute kidney injury after shock resuscitation and severe persistent hypertriglyceridemia. The severe hypertriglyceridemia was treated with 1 course of plasmapheresis, which corrected the triglyceride level and was temporally associated with improvement of the abdominal pain and renal dysfunction. Diabetes is known to contribute to an elevated triglyceride level, especially in the setting of an underlying lipid disorder. However, no such disorders were found in this patient. To the best of our knowledge, this is the first report of a pediatric patient presenting with the triad of severe hypertriglyceridemia, diabetic ketoacidosis, and pancreatitis treated successfully with plasmapheresis. PMID- 22201146 TI - Allergy testing in childhood: using allergen-specific IgE tests. AB - A variety of triggers can induce common pediatric allergic diseases which include asthma, allergic rhinitis, atopic dermatitis, food allergy, and anaphylaxis. Allergy testing serves to confirm an allergic trigger suspected on the basis of history. Tests for allergen-specific immunoglobulin E (IgE) are performed by in vitro assays or skin tests. The tests are excellent for identifying a sensitized state in which allergen-specific IgE is present, and may identify triggers to be eliminated and help guide immunotherapy treatment. However, a positive test result does not always equate with clinical allergy. Newer enzymatic assays based on anti-IgE antibodies have supplanted the radioallergosorbent test (RAST). This clinical report focuses on allergen-specific IgE testing, emphasizing that the medical history and knowledge of disease characteristics are crucial for rational test selection and interpretation. PMID- 22201147 TI - Children and secondhand smoke: clear evidence for action. PMID- 22201148 TI - Early childhood adversity, toxic stress, and the role of the pediatrician: translating developmental science into lifelong health. AB - Advances in a wide range of biological, behavioral, and social sciences are expanding our understanding of how early environmental influences (the ecology) and genetic predispositions (the biologic program) affect learning capacities, adaptive behaviors, lifelong physical and mental health, and adult productivity. A supporting technical report from the American Academy of Pediatrics (AAP) presents an integrated ecobiodevelopmental framework to assist in translating these dramatic advances in developmental science into improved health across the life span. Pediatricians are now armed with new information about the adverse effects of toxic stress on brain development, as well as a deeper understanding of the early life origins of many adult diseases. As trusted authorities in child health and development, pediatric providers must now complement the early identification of developmental concerns with a greater focus on those interventions and community investments that reduce external threats to healthy brain growth. To this end, AAP endorses a developing leadership role for the entire pediatric community-one that mobilizes the scientific expertise of both basic and clinical researchers, the family-centered care of the pediatric medical home, and the public influence of AAP and its state chapters-to catalyze fundamental change in early childhood policy and services. AAP is committed to leveraging science to inform the development of innovative strategies to reduce the precipitants of toxic stress in young children and to mitigate their negative effects on the course of development and health across the life span. PMID- 22201149 TI - The importance of play in promoting healthy child development and maintaining strong parent-child bond: focus on children in poverty. AB - Play is essential to the social, emotional, cognitive, and physical well-being of children beginning in early childhood. It is a natural tool for children to develop resiliency as they learn to cooperate, overcome challenges, and negotiate with others. Play also allows children to be creative. It provides time for parents to be fully engaged with their children, to bond with their children, and to see the world from the perspective of their child. However, children who live in poverty often face socioeconomic obstacles that impede their rights to have playtime, thus affecting their healthy social-emotional development. For children who are underresourced to reach their highest potential, it is essential that parents, educators, and pediatricians recognize the importance of lifelong benefits that children gain from play. PMID- 22201150 TI - Parental smoking and vascular damage in their 5-year-old children. AB - BACKGROUND: The relation between smoke exposure in early life, the prenatal period in particular, and the vascular development of young children is largely unknown. METHODS: Data from the birth cohort participating in the WHISTLER-Cardio study were used to relate the smoking of parents during pregnancy to subsequent vascular properties in their children. In 259 participating children who turned 5 years of age, parental smoking data were updated and children's carotid artery intima-media thickness (CIMT) and arterial wall distensibility were measured by using ultrasonography. RESULTS: Children of mothers who had smoked throughout pregnancy had 18.8 MUm thicker CIMT (95% confidence interval [CI] 1.1, 36.5, P = .04) and 15% lower distensibility (95% CI -0.3, -0.02, P = .02) after adjustment for child's age, maternal age, gender, and breastfeeding. The associations were not found in children of mothers who had not smoked in pregnancy but had smoked thereafter. The associations were strongest if both parents had smoked during pregnancy, with 27.7 MUm thicker CIMT (95% CI 0.2, 55.3) and 21% lower distensibility (95% CI -0.4, -0.03). CONCLUSION: Exposure of children to parental tobacco smoke during pregnancy affects their arterial structure and function in early life. PMID- 22201151 TI - Comprehensive health evaluation of the newly adopted child. AB - Children who join families through the process of adoption often have multiple health care needs. After placement in an adoptive home, it is essential that these children have a timely comprehensive health evaluation. This evaluation should include a review of all available medical records and a complete physical examination. Evaluation should also include diagnostic testing based on the findings from the history and physical examination as well as the risks presented by the child's previous living conditions. Age-appropriate screens should be performed, including, for example, newborn screening panels, hearing, vision, dental, and formal behavioral/developmental screens. The comprehensive assessment can occur at the time of the initial visit to the physician after adoptive placement or can take place over several visits. Adopted children should be referred to other medical specialists as deemed appropriate. The Section on Adoption and Foster Care is a resource within the American Academy of Pediatrics for physicians providing care for children who are being adopted. PMID- 22201152 TI - Parental smoking cessation to protect young children: a systematic review and meta-analysis. AB - BACKGROUND: Young children can be protected from much of the harm from tobacco smoke exposure if their parents quit smoking. Some researchers encourage parents to quit for their children's benefit, but the evidence for effectiveness of such approaches is mixed. OBJECTIVE: To perform a systematic review and meta-analysis to quantify the effects of interventions that encourage parental cessation. METHODS: We searched PubMed, the Cochrane Library, Web of Science, and PsycINFO. Controlled trials published before April 2011 that targeted smoking parents of infants or young children, encouraged parents to quit smoking for their children's benefit, and measured parental quit rates were included. Study quality was assessed. Relative risks and risk differences were calculated by using the DerSimonian and Laird random-effects model. RESULTS: Eighteen trials were included. Interventions took place in hospitals, pediatric clinical settings, well-baby clinics, and family homes. Quit rates averaged 23.1% in the intervention group and 18.4% in the control group. The interventions successfully increased the parental quit rate. Subgroups with significant intervention benefits were children aged 4 to 17 years, interventions whose primary goal was cessation, interventions that offered medications, and interventions with high follow-up rates (>80%). CONCLUSIONS: Interventions to achieve cessation among parents, for the sake of the children, provide a worthwhile addition to the arsenal of cessation approaches, and can help protect vulnerable children from harm due to tobacco smoke exposure. However, most parents do not quit, and additional strategies to protect children are needed. PMID- 22201154 TI - Aerobic capacity and exercise performance in young people born extremely preterm. AB - OBJECTIVES: The goal of this study was to compare aerobic capacity and exercise performance of children and adolescents born extremely preterm and at term, and to relate findings to medical history and lifestyle factors. Potential cohort effects were assessed by studying subjects born in different decades. METHODS: Two area-based cohorts of subjects born with gestational age <=28 weeks or birth weight <=1000 g in 1982-1985 and 1991-1992 and matched control subjects born at term were compared by using standardized maximal treadmill exercise and pulmonary function tests. Background data were collected from questionnaires and medical records. RESULTS: Seventy-five of 86 eligible preterm subjects (87%) and 75 control subjects were assessed at mean ages of 17.6 years (n = 40 + 40) and 10.6 years (n = 35 + 35). At average, measures of aerobic capacity for subjects born preterm and at term were in the same range, whereas average running distance was modestly reduced for those born preterm. Leisure-time physical activity was similarly and positively associated with exercise capacity in preterm and term born adolescents alike, although participation was lower among those born preterm. Neonatal bronchopulmonary dysplasia and current forced expiratory vol in 1 second was unrelated to exercise capacity. Differences between subjects born preterm and at term had not changed over the 2 decades studied. CONCLUSION: Despite their high-risk start to life and a series of potential shortcomings, subjects born preterm may achieve normal exercise capacity, and their response to physical training seems comparable to peers born at term. PMID- 22201153 TI - Human rhinoviruses in severe respiratory disease in very low birth weight infants. AB - OBJECTIVES: To assess incidence, burden of illness, and risk factors for human rhinoviruses (HRVs) in a cohort of very low birth weight (VLBW) infants. METHODS: A 2-year prospective cohort study was conducted among VLBW premature infants in Buenos Aires, Argentina. Infants were enrolled in the NICU from June 1, 2003, to May 31, 2005, and managed monthly and with every acute respiratory illness (ARI) during the first year of life. Nasal wash samples were obtained during every respiratory episode and tested for HRV, respiratory syncytial virus (RSV), human parainfluenza viruses, influenza viruses, and human metapneumovirus using reverse transcriptase-polymerase chain reaction. RESULTS: Of 119 patients, 66 (55%) had HRV-associated ARIs. The incidence of HRV-associated ARI was 123 events per 100 child-years of follow-up. Of those infants experiencing an episode of bronchiolitis, 40% had HRV versus 7% with RSV. The incidence of HRV-associated bronchiolitis was 75 per 100 infant-years of follow-up. HRV was associated with 12 of 36 hospitalizations (33%), and RSV was associated with 9 of 36 hospitalizations (25%). The incidence of HRV-associated hospitalization was 12 per 100 infant-years of follow-up. The risk of HRV-associated hospitalization was higher for infants with bronchopulmonary dysplasia and those who were not breastfed. CONCLUSIONS: HRV is an important and frequent pathogen associated with severe respiratory infections in VLBW infants. Bronchopulmonary dysplasia and the absence of breastfeeding are risk factors for hospitalization. The results of our study reveal that HRV is the predominant pathogen of respiratory infections in premature infants. PMID- 22201155 TI - Factors affecting health care utilization for children in Japan. AB - BACKGROUND AND OBJECTIVE: Studies on the ecology of medical care for children have been reported only from the United States. Our objective was to describe proportions of children receiving care in 6 types of health care utilization seeking behaviors in Japan on a monthly basis and to identify care characteristics. METHODS: A population-weighted random sample from a nationally representative panel of households was used to estimate the number of health related symptoms, over-the-counter medicine doses, and health care utilizations per 1000 Japanese children per month. Variations in terms of age, gender, socioeconomic status, and residence location were also examined. RESULTS: Based on 1286 households (3477 persons including 1024 children) surveyed, on average per 1000 children, 872 had at least 1 symptom, 335 visited a physician's office, 82 a hospital-based outpatient clinic, 21 a hospital emergency department, and 2 a university-based outpatient clinic. Two were hospitalized, and 4 received professional health care in their home. Children had 2 times more physician visits and 3 times more emergency visits than adults in Japan, and Japanese children had 2.5 times more physician visits and 11 times more hospital-based outpatient clinic visits than US children. Pediatric health care utilization is influenced significantly by age but not affected by income or residence location in Japan. CONCLUSIONS: Compared with the data from the United States, more children in Japan visit community physicians and hospital-based outpatient clinics. Results of this study would be useful for further delineation of health care utilization of children in the context of a health care system unique to Japan. PMID- 22201156 TI - The lifelong effects of early childhood adversity and toxic stress. AB - Advances in fields of inquiry as diverse as neuroscience, molecular biology, genomics, developmental psychology, epidemiology, sociology, and economics are catalyzing an important paradigm shift in our understanding of health and disease across the lifespan. This converging, multidisciplinary science of human development has profound implications for our ability to enhance the life prospects of children and to strengthen the social and economic fabric of society. Drawing on these multiple streams of investigation, this report presents an ecobiodevelopmental framework that illustrates how early experiences and environmental influences can leave a lasting signature on the genetic predispositions that affect emerging brain architecture and long-term health. The report also examines extensive evidence of the disruptive impacts of toxic stress, offering intriguing insights into causal mechanisms that link early adversity to later impairments in learning, behavior, and both physical and mental well-being. The implications of this framework for the practice of medicine, in general, and pediatrics, specifically, are potentially transformational. They suggest that many adult diseases should be viewed as developmental disorders that begin early in life and that persistent health disparities associated with poverty, discrimination, or maltreatment could be reduced by the alleviation of toxic stress in childhood. An ecobiodevelopmental framework also underscores the need for new thinking about the focus and boundaries of pediatric practice. It calls for pediatricians to serve as both front-line guardians of healthy child development and strategically positioned, community leaders to inform new science-based strategies that build strong foundations for educational achievement, economic productivity, responsible citizenship, and lifelong health. PMID- 22201157 TI - Immunizing parents and other close family contacts in the pediatric office setting. AB - Additional strategies are needed to protect children from vaccine-preventable diseases. In particular, very young infants, as well as children who are immunocompromised, are at especially high risk for developing the serious consequences of vaccine-preventable diseases and cannot be immunized completely. There is some evidence that children who become infected with these diseases are exposed to pathogens through household contacts, particularly from parents or other close family contacts. Such infections likely are attributable to adults who are not fully protected from these diseases, either because their immunity to vaccine-preventable diseases has waned over time or because they have not received a vaccine. There are many challenges that have added to low adult immunization rates in the United States. One option to increase immunization coverage for parents and close family contacts of infants and vulnerable children is to provide alternative locations for these adults to be immunized, such as the pediatric office setting. Ideally, adults should receive immunizations in their medical homes; however, to provide greater protection to these adults and reduce the exposure of children to pathogens, immunizing parents or other adult family contacts in the pediatric office setting could increase immunization coverage for this population to protect themselves as well as children to whom they provide care. PMID- 22201158 TI - Testing the impact of calibration on molecular divergence times using a fossil rich group: the case of Nothofagus (Fagales). AB - Although temporal calibration is widely recognized as critical for obtaining accurate divergence-time estimates using molecular dating methods, few studies have evaluated the variation resulting from different calibration strategies. Depending on the information available, researchers have often used primary calibrations from the fossil record or secondary calibrations from previous molecular dating studies. In analyses of flowering plants, primary calibration data can be obtained from macro- and mesofossils (e.g., leaves, flowers, and fruits) or microfossils (e.g., pollen). Fossil data can vary substantially in accuracy and precision, presenting a difficult choice when selecting appropriate calibrations. Here, we test the impact of eight plausible calibration scenarios for Nothofagus (Nothofagaceae, Fagales), a plant genus with a particularly rich and well-studied fossil record. To do so, we reviewed the phylogenetic placement and geochronology of 38 fossil taxa of Nothofagus and other Fagales, and we identified minimum age constraints for up to 18 nodes of the phylogeny of Fagales. Molecular dating analyses were conducted for each scenario using maximum likelihood (RAxML + r8s) and Bayesian (BEAST) approaches on sequence data from six regions of the chloroplast and nuclear genomes. Using either ingroup or outgroup constraints, or both, led to similar age estimates, except near strongly influential calibration nodes. Using "early but risky" fossil constraints in addition to "safe but late" constraints, or using assumptions of vicariance instead of fossil constraints, led to older age estimates. In contrast, using secondary calibration points yielded drastically younger age estimates. This empirical study highlights the critical influence of calibration on molecular dating analyses. Even in a best-case situation, with many thoroughly vetted fossils available, substantial uncertainties can remain in the estimates of divergence times. For example, our estimates for the crown group age of Nothofagus varied from 13 to 113 Ma across our full range of calibration scenarios. We suggest that increased background research should be made at all stages of the calibration process to reduce errors wherever possible, from verifying the geochronological data on the fossils to critical reassessment of their phylogenetic position. PMID- 22201160 TI - The poverty of the phylocode: a reply to de Queiroz and Donoghue. PMID- 22201159 TI - Recurrent introgression of mitochondrial DNA among hares (Lepus spp.) revealed by species-tree inference and coalescent simulations. AB - Understanding recent speciation history requires merging phylogenetic and population genetics approaches, taking into account the persistence of ancestral polymorphism and possible introgression. The emergence of a clear phylogeny of hares (genus Lepus) has been hampered by poor genomic sampling and possible occurrence of mitochondrial DNA (mtDNA) introgression from the arctic/boreal Lepus timidus into several European temperate and possibly American boreal species. However, no formal test of introgression, taking also incomplete lineage sorting into account, has been done. Here, to clarify the yet poorly resolved species phylogeny of hares and test hypotheses of mtDNA introgression, we sequenced 14 nuclear DNA and 2 mtDNA fragments (8205 and 1113 bp, respectively) in 50 specimens from 11 hare species from Eurasia, North America, and Africa. By applying an isolation-with-migration model to the nuclear data on subsets of species, we find evidence for very limited gene flow from L. timidus into most temperate European species, and not into the American boreal ones. Using a multilocus coalescent-based method, we infer the species phylogeny, which we find highly incongruent with mtDNA phylogeny using parametric bootstrap. Simulations of mtDNA evolution under the speciation history inferred from nuclear genes did not support the hypothesis of mtDNA introgression from L. timidus into the American L. townsendii but did suggest introgression from L. timidus into 4 temperate European species. One such event likely resulted in the complete replacement of the aboriginal mtDNA of L. castroviejoi and of its sister species L. corsicanus. It is remarkable that mtDNA introgression in hares is frequent, extensive, and always from the same donor arctic species. We discuss possible explanations for the phenomenon in relation to the dynamics of range expansions and species replacements during the climatic oscillations of the Pleistocene. PMID- 22201161 TI - Progression of early structural lung disease in young children with cystic fibrosis assessed using CT. AB - BACKGROUND: Cross-sectional studies implicate neutrophilic inflammation and pulmonary infection as risk factors for early structural lung disease in infants and young children with cystic fibrosis (CF). However, the longitudinal progression in a newborn screened population has not been investigated. AIM: To determine whether early CF structural lung disease persists and progresses over 1 year and to identify factors associated with radiological persistence and progression. METHODS: 143 children aged 0.2-6.5 years with CF from a newborn screened population contributed 444 limited slice annual chest CT scans for analysis that were scored for bronchiectasis and air trapping and analysed as paired scans 1 year apart. Logistic and linear regression models, using generalised estimating equations to account for multiple measures, determined associations between persistence and progression over 1 year and age, sex, severe cystic fibrosis transmembrane regulator (CFTR) genotype, pancreatic sufficiency, current respiratory symptoms, and neutrophilic inflammation and infection measured by bronchoalveolar lavage. RESULTS: Once detected, bronchiectasis persisted in 98/133 paired scans (74%) and air trapping in 178/220 (81%). The extent of bronchiectasis increased in 139/227 (63%) of paired scans and air trapping in 121/264 (47%). Radiological progression of bronchiectasis and air trapping was associated with severe CFTR genotype, worsening neutrophilic inflammation and pulmonary infection. DISCUSSION: CT-detected structural lung disease identified in infants and young children with CF persists and progresses over 1 year in most cases, with deteriorating structural lung disease associated with worsening inflammation and pulmonary infection. Early intervention is required to prevent or arrest the progression of structural lung disease in young children with CF. PMID- 22201162 TI - Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a commonly fatal pulmonary vascular disease that is often diagnosed late and is characterised by a progressive rise in pulmonary vascular resistance resulting from typical vascular remodelling. Recent data suggest that vascular damage plays an important role in the development of radiation-induced pulmonary toxicity. Therefore, the authors investigated whether irradiation of the lung also induces pulmonary hypertension. METHODS: Different sub-volumes of the rat lung were irradiated with protons known to induce different levels of pulmonary vascular damage. RESULTS: Early loss of endothelial cells and vascular oedema were observed in the irradiation field and in shielded parts of the lung, even before the onset of clinical symptoms. 8 weeks after irradiation, irradiated volume-dependent vascular remodelling was observed, correlating perfectly with pulmonary artery pressure, right ventricle hypertrophy and pulmonary dysfunction. CONCLUSIONS: The findings indicate that partial lung irradiation induces pulmonary vascular remodelling resulting from acute pulmonary endothelial cell loss and consequential pulmonary hypertension. Moreover, the close resemblance of the observed vascular remodelling with vascular lesions in PAH makes partial lung irradiation a promising new model for studying PAH. PMID- 22201163 TI - Genomic divergence during speciation: causes and consequences. AB - Speciation is a fundamental process responsible for the diversity of life. Progress has been made in detecting individual 'speciation genes' that cause reproductive isolation. In contrast, until recently, less attention has been given to genome-wide patterns of divergence during speciation. Thus, major questions remain concerning how individual speciation genes are arrayed within the genome, and how this affects speciation. This theme issue is dedicated to exploring this genomic perspective of speciation. Given recent sequencing and computational advances that now allow genomic analyses in most organisms, the goal is to help move the field towards a more integrative approach. This issue draws upon empirical studies in plants and animals, and theoretical work, to review and further document patterns of genomic divergence. In turn, these studies begin to disentangle the role that different processes, such as natural selection, gene flow and recombination rate, play in generating observed patterns. These factors are considered in the context of how genomes diverge as speciation unfolds, from beginning to end. The collective results point to how experimental work is now required, in conjunction with theory and sequencing studies, to move the field from descriptive studies of patterns of divergence towards a predictive framework that tackles the causes and consequences of genome wide patterns. PMID- 22201164 TI - Genomic islands of divergence in hybridizing Heliconius butterflies identified by large-scale targeted sequencing. AB - Heliconius butterflies represent a recent radiation of species, in which wing pattern divergence has been implicated in speciation. Several loci that control wing pattern phenotypes have been mapped and two were identified through sequencing. These same gene regions play a role in adaptation across the whole Heliconius radiation. Previous studies of population genetic patterns at these regions have sequenced small amplicons. Here, we use targeted next-generation sequence capture to survey patterns of divergence across these entire regions in divergent geographical races and species of Heliconius. This technique was successful both within and between species for obtaining high coverage of almost all coding regions and sufficient coverage of non-coding regions to perform population genetic analyses. We find major peaks of elevated population differentiation between races across hybrid zones, which indicate regions under strong divergent selection. These 'islands' of divergence appear to be more extensive between closely related species, but there is less clear evidence for such islands between more distantly related species at two further points along the 'speciation continuum'. We also sequence fosmid clones across these regions in different Heliconius melpomene races. We find no major structural rearrangements but many relatively large (greater than 1 kb) insertion/deletion events (including gain/loss of transposable elements) that are variable between races. PMID- 22201165 TI - Genome-wide patterns of divergence during speciation: the lake whitefish case study. AB - The nature, size and distribution of the genomic regions underlying divergence and promoting reproductive isolation remain largely unknown. Here, we summarize ongoing efforts using young (12 000 yr BP) species pairs of lake whitefish (Coregonus clupeaformis) to expand our understanding of the initial genomic patterns of divergence observed during speciation. Our results confirmed the predictions that: (i) on average, phenotypic quantitative trait loci (pQTL) show higher F(ST) values and are more likely to be outliers (and therefore candidates for being targets of divergent selection) than non-pQTL markers; (ii) large islands of divergence rather than small independent regions under selection characterize the early stages of adaptive divergence of lake whitefish; and (iii) there is a general trend towards an increase in terms of numbers and size of genomic regions of divergence from the least (East L.) to the most differentiated species pair (Cliff L.). This is consistent with previous estimates of reproductive isolation between these species pairs being driven by the same selective forces responsible for environment specialization. Altogether, dwarf and normal whitefish species pairs represent a continuum of both morphological and genomic differentiation contributing to ecological speciation. Admittedly, much progress is still required to more finely map and circumscribe genomic islands of speciation. This will be achieved through the use of next generation sequencing data but also through a better quantification of phenotypic traits moulded by selection as organisms adapt to new environmental conditions. PMID- 22201166 TI - What can patterns of differentiation across plant genomes tell us about adaptation and speciation? AB - Genome scans have become a common approach to identify genomic signatures of natural selection and reproductive isolation, as well as the genomic bases of ecologically relevant phenotypes, based on patterns of polymorphism and differentiation among populations or species. Here, we review the results of studies taking genome scan approaches in plants, consider the patterns of genomic differentiation documented and their possible causes, discuss the results in light of recent models of genomic differentiation during divergent adaptation and speciation, and consider assumptions and caveats in their interpretation. We find that genomic regions of high divergence generally appear quite small in comparisons of both closely and more distantly related populations, and for the most part, these differentiated regions are spread throughout the genome rather than strongly clustered. Thus, the genome scan approach appears well-suited for identifying genomic regions or even candidate genes that underlie adaptive divergence and/or reproductive barriers. We consider other methodologies that may be used in conjunction with genome scan approaches, and suggest further developments that would be valuable. These include broader use of sequence-based markers of known genomic location, greater attention to sampling strategies to make use of parallel environmental or phenotypic transitions, more integration with approaches such as quantitative trait loci mapping and measures of gene flow across the genome, and additional theoretical and simulation work on processes related to divergent adaptation and speciation. PMID- 22201167 TI - No evidence for biased co-transmission of speciation islands in Anopheles gambiae. AB - Genome-scale scans have revealed highly heterogeneous levels of divergence between closely related taxa in many systems. Generally, a small number of regions show high differentiation, with the rest of the genome showing no or only low levels of divergence. These patterns have been interpreted as evidence for ongoing speciation-with-gene-flow, with introgression homogenizing the whole genome except loci involved in reproductive isolation. However, as the number of selected loci increases, the probability of introgression at unselected loci decreases unless there is a transmission ratio distortion causing an over representation of specific combinations of alleles. Here we examine the transmission of three 'speciation islands' that contain fixed differences between the M and S forms of the mosquito, Anopheles gambiae. We made reciprocal crosses between M and S parents and genotyped over 2000 F(2) individuals, developing a hierarchical likelihood model to identify specific genotypes that are under- or over-represented among the recombinant offspring. Though our overall results did not match the expected number of F(2) genotypes, we found no biased co transmission among M or S alleles in the three islands. Our likelihood model did identify transmission ratio distortion at two of the three islands, but this distortion was small (approx. 3%) and in opposite directions for the two islands. We discuss how our results impinge on hypotheses of current gene flow between M and S and ongoing speciation-with-gene-flow in this system. PMID- 22201168 TI - Genomics of adaptation and speciation in cichlid fishes: recent advances and analyses in African and Neotropical lineages. AB - Cichlid fishes are remarkably phenotypically diverse and species-rich. Therefore, they provide an exciting opportunity for the study of the genetics of adaptation and speciation by natural and sexual selection. Here, we review advances in the genomics and transcriptomics of cichlids, particularly regarding ecologically relevant differences in body shape, trophic apparatus, coloration and patterning, and sex determination. Research conducted so far has focused almost exclusively on African cichlids. To analyse genomic diversity and selection in a Neotropical radiation, we conducted a comparative transcriptomic analysis between sympatric, ecologically divergent crater-lake Midas cichlids (Lake Xiloa Amphilophus amarillo and Amphilophus sagittae). We pyrosequenced (Roche 454) expressed sequence tag (EST) libraries and generated more than 178 000 000 ESTs and identified nine ESTs under positive selection between these sister species (Ka/Ks > 1). None of these ESTs were found to be under selection in African cichlids. Of 11 candidate genes for ecomorphological differentiation in African cichlids, none showed signs of selection between A. amarillo and A. sagittae. Although more population-level studies are now needed to thoroughly document patterns of divergence during speciation of cichlids, available information so far suggests that adaptive phenotypic diversification in Neotropical and African cichlids may be evolving through non-parallel genetic bases. PMID- 22201169 TI - Extensive linkage disequilibrium and parallel adaptive divergence across threespine stickleback genomes. AB - Population genomic studies are beginning to provide a more comprehensive view of dynamic genome-scale processes in evolution. Patterns of genomic architecture, such as genomic islands of increased divergence, may be important for adaptive population differentiation and speciation. We used next-generation sequencing data to examine the patterns of local and long-distance linkage disequilibrium (LD) across oceanic and freshwater populations of threespine stickleback, a useful model for studies of evolution and speciation. We looked for associations between LD and signatures of divergent selection, and assessed the role of recombination rate variation in generating LD patterns. As predicted under the traditional biogeographic model of unidirectional gene flow from ancestral oceanic to derived freshwater stickleback populations, we found extensive local and long-distance LD in fresh water. Surprisingly, oceanic populations showed similar patterns of elevated LD, notably between large genomic regions previously implicated in adaptation to fresh water. These results support an alternative biogeographic model for the stickleback radiation, one of a metapopulation with appreciable bi-directional gene flow combined with strong divergent selection between oceanic and freshwater populations. As predicted by theory, these processes can maintain LD within and among genomic islands of divergence. These findings suggest that the genomic architecture in oceanic stickleback populations may provide a mechanism for the rapid re-assembly and evolution of multi-locus genotypes in newly colonized freshwater habitats, and may help explain genetic mapping of parallel phenotypic variation to similar loci across independent freshwater populations. PMID- 22201170 TI - Recombination rate variation and speciation: theoretical predictions and empirical results from rabbits and mice. AB - Recently diverged taxa may continue to exchange genes. A number of models of speciation with gene flow propose that the frequency of gene exchange will be lower in genomic regions of low recombination and that these regions will therefore be more differentiated. However, several population-genetic models that focus on selection at linked sites also predict greater differentiation in regions of low recombination simply as a result of faster sorting of ancestral alleles even in the absence of gene flow. Moreover, identifying the actual amount of gene flow from patterns of genetic variation is tricky, because both ancestral polymorphism and migration lead to shared variation between recently diverged taxa. New analytic methods have been developed to help distinguish ancestral polymorphism from migration. Along with a growing number of datasets of multi locus DNA sequence variation, these methods have spawned a renewed interest in speciation models with gene flow. Here, we review both speciation and population genetic models that make explicit predictions about how the rate of recombination influences patterns of genetic variation within and between species. We then compare those predictions with empirical data of DNA sequence variation in rabbits and mice. We find strong support for the prediction that genomic regions experiencing low levels of recombination are more differentiated. In most cases, reduced gene flow appears to contribute to the pattern, although disentangling the relative contribution of reduced gene flow and selection at linked sites remains a challenge. We suggest fruitful areas of research that might help distinguish between different models. PMID- 22201171 TI - Genomic impacts of chromosomal inversions in parapatric Drosophila species. AB - Chromosomal inversions impact genetic variation and facilitate speciation in part by reducing recombination in heterokaryotypes. We generated multiple whole-genome shotgun sequences of the parapatric species pair Drosophila pseudoobscura and Drosophila persimilis and their sympatric outgroup (Drosophila miranda) and compared the average pairwise differences for neutral sites within, just outside and far outside of the three large inversions. Divergence between D. pseudoobscura and D. persimilis is high inside the inversions and in the suppressed recombination regions extending 2.5 Mb outside of inversions, but significantly lower in collinear regions further from the inversions. We observe little evidence of decreased divergence predicted to exist in the centre of inversions, suggesting that gene flow through double crossovers or gene conversion is limited within the inversion, or selection is acting within the inversion to maintain divergence in the face of gene flow. In combination with past studies, we provide evidence that inversions in this system maintain areas of high divergence in the face of hybridization, and have done so for a substantial period of time. The left arm of the X chromosome and chromosome 2 inversions appear to have arisen in the lineage leading to D. persimilis approximately 2 Ma, near the time of the split of D. persimilis-D. pseudoobscura D. miranda, but likely fixed within D. persimilis much more recently, as diversity within D. persimilis is substantially reduced inside and near these two inversions. We also hypothesize that the inversions in D. persimilis may provide an empirical example of the 'mixed geographical mode' theory of inversion origin and fixation, whereby allopatry and secondary contact both play a role. PMID- 22201172 TI - Coalescent patterns for chromosomal inversions in divergent populations. AB - Chromosomal inversions allow genetic divergence of locally adapted populations by reducing recombination between chromosomes with different arrangements. Divergence between populations (or hybridization between species) is expected to leave signatures in the neutral genetic diversity of the inverted region. Quantitative expectations for these patterns, however, have not been obtained. Here, we develop coalescent models of neutral sites linked to an inversion polymorphism in two locally adapted populations. We consider two scenarios of local adaptation: selection on the inversion breakpoints and selection on alleles inside the inversion. We find that ancient inversion polymorphisms cause genetic diversity to depart dramatically from neutral expectations. Other situations, however, lead to patterns that may be difficult to detect; important determinants are the age of the inversion and the rate of gene flux between arrangements. We also study inversions under genetic drift, finding that they produce patterns similar to locally adapted inversions of intermediate age. Our results are consistent with empirical observations, and provide the foundation for quantitative analyses of the roles that inversions have played in speciation. PMID- 22201173 TI - Genomics of isolation in hybrids. AB - Hybrid zones are common in nature and can offer critical insights into the dynamics and components of reproductive isolation. Hybrids between diverged lineages are particularly informative about the genetic architecture of reproductive isolation, because introgression in an admixed population is a direct measure of isolation. In this paper, we combine simulations and a new statistical model to determine the extent to which different genetic architectures of isolation leave different signatures on genome-level patterns of introgression. We found that reproductive isolation caused by one or several loci of large effect caused greater heterogeneity in patterns of introgression than architectures involving many loci with small fitness effects, particularly when isolating factors were closely linked. The same conditions that led to heterogeneous introgression often resulted in a reasonable correspondence between outlier loci and the genetic loci that contributed to isolation. However, demographic conditions affected both of these results, highlighting potential limitations to the study of the speciation genomics. Further progress in understanding the genomics of speciation will require large-scale empirical studies of introgression in hybrid zones and model-based analyses, as well as more comprehensive modelling of the expected levels of isolation with different demographies and genetic architectures of isolation. PMID- 22201174 TI - Divergence hitchhiking and the spread of genomic isolation during ecological speciation-with-gene-flow. AB - In allopatric populations, geographical separation simultaneously isolates the entire genome, allowing genetic divergence to accumulate virtually anywhere in the genome. In sympatric populations, however, the strong divergent selection required to overcome migration produces a genetic mosaic of divergent and non divergent genomic regions. In some recent genome scans, each divergent genomic region has been interpreted as an independent incidence of migration/selection balance, such that the reduction of gene exchange is restricted to a few kilobases around each divergently selected gene. I propose an alternative mechanism, 'divergence hitchhiking' (DH), in which divergent selection can reduce gene exchange for several megabases around a gene under strong divergent selection. Not all genes/markers within a DH region are divergently selected, yet the entire region is protected to some degree from gene exchange, permitting genetic divergence from mechanisms other than divergent selection to accumulate secondarily. After contrasting DH and multilocus migration/selection balance (MM/SB), I outline a model in which genomic isolation at a given genomic location is jointly determined by DH and genome-wide effects of the progressive reduction in realized migration, then illustrate DH using data from several pairs of incipient species in the wild. PMID- 22201176 TI - Letter to the editor: "Left ventricular mechanical limitations to stroke volume in healthy humans during incremental exercise". PMID- 22201175 TI - Establishment of new mutations under divergence and genome hitchhiking. AB - Theoretical models addressing genome-wide patterns of divergence during speciation are needed to help us understand the evolutionary processes generating empirical patterns. Here, we examine a critical issue concerning speciation-with gene flow: to what degree does physical linkage (r < 0.5) of new mutations to already diverged genes aid the build-up of genomic islands of differentiation? We used simulation and analytical approaches to partition the probability of establishment for a new divergently selected mutation when the mutation (i) is the first to arise in an undifferentiated genome (the direct effect of selection), (ii) arises unlinked to any selected loci (r = 0.5), but within a genome that has some already diverged genes (the effect of genome-wide reductions in gene flow for facilitating divergence, which we term 'genome hitchhiking'), and (iii) arises in physical linkage to a diverged locus (divergence hitchhiking). We find that the strength of selection acting directly on a new mutation is generally the most important predictor for establishment, with divergence and genomic hitchhiking having smaller effects. We outline the specific conditions under which divergence and genome hitchhiking can aid mutation establishment. The results generate predictions about genome divergence at different points in the speciation process and avenues for further work. PMID- 22201178 TI - MDHS 25 revisited: part 2, modified sampling and analytical procedures applied to HDI-based isocyanates. AB - The method that is probably the most commonly used worldwide for the determination of total organic isocyanates (NCO) in air is the Health and Safety Executive method, MDHS 25/3, Organic Isocyanates in Air, and its variants. This paper summarizes some of the research and development work carried out by Health and Safety Laboratory on this method since its publication in 1999 with the eventual aim of incorporating this work in an updated version of MDHS 25 (i.e. MDHS 25/4). The work falls into two main areas: use of liquid chromatography/mass spectrometry (LC/MS) as an alternative to liquid chromatography with electrochemical and ultraviolet/visible detection (LC/EC/UV) and evaluation of 'solid-phase' sampling techniques as an alternative to the impinger-filter combination stated in MDHS 25/3. This paper deals primarily with HDI-based NCO but some comments regarding aromatic NCO (MDI and TDI) are included for completeness. An LC/MS/MS version of MDHS 25/3 has been developed that gives improved performance to the 'classical' version of MDHS 25/3 using EC/UV detection. The LC/MS/MS offers significant advantages over the EC/UV version of MDHS 25/3 in that it is more sensitive, provides improved identification, and has been found to be easier to use. The solid-phase samplers evaluated were a double thickness glass-fibre (GF/B) filter coated with 1-(2-methoxyphenyl)piperazine (MP) reagent in an IOM (Institute of Occupational Medicine) sampling head ('FIN MP' sampler) and an MP-impregnated polyurethane foam sponge (PUF) with an MP coated glass-fibre (GF/A) backup filter also in an IOM sampling head ('Rudzinski' sampler). Both samplers were found to give acceptable performance for the sampling of oligomeric HDI in workplace air and in laboratory simulations when compared to the impinger-filter combination at levels corresponding to the UK short-term limit (70 MUg m(-3)). For practical reasons, the FIN-MP sampler was the preferred alternative. PMID- 22201179 TI - Tensile properties and integrity of clean room and low-modulus disposable nitrile gloves: a comparison of two dissimilar glove types. AB - BACKGROUND: The selection of disposable nitrile exam gloves is complicated by (i) the availability of several types or formulations, (ii) product variability, and (iii) an inability of common quality control tests to detect small holes in the fingers. Differences in polymer formulation (e.g. filler and plasticizer/oil content) and tensile properties are expected to account for much of the observed variability in performance. OBJECTIVES: This study evaluated the tensile properties and integrity (leak failure rates) of two glove choices assumed to contain different amounts of plasticizers/oils. The primary aims were to determine if the tensile properties and integrity differed and if associations existed among these factors. Additional physical and chemical properties were evaluated. METHODS: Six clean room and five low-modulus products were evaluated using the American Society for Testing and Materials Method D412 and a modified water-leak test to detect holes capable of passing a virus or chemical agent. RESULTS: Significant differences in the leak failure rates and tensile properties existed between the two glove types (P <= 0.05). The clean room gloves were about three times more likely to have leak failures (chi-square; P = 0.001). No correlation was observed between leak failures and tensile properties. Solvent extract, an indication of added plasticizer/oil, was not associated with leak failures. However, gloves with a maximum modulus <4 MPa or area density (AD) <11 g cm(-2) were about four times less likely to leak. CONCLUSIONS: On average, the low-modulus gloves were a better choice for protection against aqueous chemical or biological penetration. The observed variability between glove products indicated that glove selection cannot rely solely on glove type or manufacturer labeling. Measures of modulus and AD may aid in the selection process, in contrast with common measures of tensile strength and elongation at break. PMID- 22201180 TI - Pulmonary nodules in patients with melanoma--assume nothing. PMID- 22201181 TI - Anaesthesia and postoperative analgesia in surgical neonates with or without Down's syndrome: is it really different? AB - BACKGROUND: Reports conflict on optimal postoperative analgesic treatment in children with intellectual disability. We retrospectively compared postoperative analgesics consumption between neonates with and without Down's syndrome in relation to anaesthesia requirements and pain scores. METHODS: We analysed hypnotic and analgesic drug administration, pain scores [COMFORT-Behaviour (COMFORT-B) scale], and duration of mechanical ventilation during the first 48 h after surgical repair of congenital duodenal obstruction in neonates, between 1999 and 2011. Data of 15 children with Down's syndrome were compared with data of 30 children without Down's syndrome. RESULTS: General anaesthesia requirements did not differ. The median (inter-quartile range) maintenance dose of morphine during the first 24 h after operation was 9.5 (7.8-10.1) ug kg(-1) h(-1) in the Down's syndrome group vs 7.7 (5.0-10.0) ug kg(-1) h(-1) in the control group (P=0.46). Morphine doses at postoperative day 2 and COMFORT-B scores at day 1 did not significantly differ between the two groups. COMFORT-B scores at day two were lower in children with Down's syndrome (P=0.04). The duration of postoperative mechanical ventilation did not statistically differ between the two groups (P=0.89). CONCLUSIONS: In this study, neonates with and without Down's syndrome received adequate postoperative analgesia, as judged from comparable analgesic consumption and pain scores. We recommend prospective studies in children of different age groups with Down's syndrome and in other groups of intellectually disabled children to provide further investigation of the hypothesis that intellectual disability predisposes to different analgesic requirements. PMID- 22201182 TI - New method for quantitative assessment of airway calibre using a stereovision fibreoptic bronchoscope. AB - BACKGROUND: We have developed a new bronchoscopy system with two independent lenses at the tip of the device. This enables measurement of object size using the principle of triangulation. This study was performed to assess the accuracy of this system. METHODS: The accuracy of the bronchoscopy system was confirmed by measuring the diameters of four plastic tubes and 36 airway calibres in 12 surgical patients under general anaesthesia. The measured diameters of the tubes and airway tracts were compared with the manufactured diameters of tubes and those measured by high-resolution computed tomography (HRCT)-based virtual bronchoscopy, respectively. RESULTS: Using the new bronchoscope system, tube diameters, 9, 12, 15, and 19 mm, were measured as 9.9 (0.7), 12.8 (1.4), 16.3 (1.6), and 20.1 (2.0) mm, respectively. Airway calibres obtained by a stereovision bronchoscopy and HRCT-based virtual bronchoscopy were 8.66 (4.31) and 9.38 (5.09) mm, respectively. There is a significant correlation between airway calibres with the two measurement methods (r=0.975, P<0.01). CONCLUSIONS: We have confirmed that this new bronchoscopy system could provide relatively accurate quantitative data. This new system may be useful in the clinic to measure airway dimension and lesion sizes such as tumours. PMID- 22201183 TI - Sex-related differences in the relationship between acceleromyographic adductor pollicis train-of-four ratio and clinical manifestations of residual neuromuscular block: a study in healthy volunteers during near steady-state infusion of mivacurium. AB - BACKGROUND: Studies in volunteers suggest that train-of-four (TOF) ratios >0.9 are needed to retain normal function of muscles involved in upper airway patency, swallowing, and vital capacity breathing. We determined if sex-related differences exist in the relationship between adductor pollicis (AP) TOF ratio and measures of neuromuscular function commonly used to assess recovery from neuromuscular block. METHODS: In 10 males and 10 females, three steady-state levels of neuromuscular block were achieved with mivacurium infusions. TOF ratio was measured with acceleromyography at the AP. Hand grip strength and the ability to clench the teeth, raise the head >5 s, swallow, protrude the tongue, and open the eyes were tested at each stable block level and reconciled to uncorrected and normalized (pre-paralysis values) TOF measures. These relationships were compared between sexes. RESULTS: The ability to clench teeth and head raise >5 s was lost at a significantly greater TOF ratio in males than females. The percentage decrease in handgrip strength with decreasing TOF ratio was proportionally greater in males than females. Forty per cent of the males were unable to clench the teeth at an uncorrected TOF ratio >0.9. When TOF ratios were normalized, clinical functions showed no decrement at TOF ratio >0.9 in any volunteer. CONCLUSIONS: Sex-related differences exist in the relationship between AP TOF ratio and clinical measures of muscle function used to assess recovery from neuromuscular block. Normalization of AP TOF ratios is recommended because a non normalized TOF ratio of 0.9 does not guarantee adequate reversal of neuromuscular block. PMID- 22201184 TI - Oxycodone clearance is markedly reduced with advancing age: a population pharmacokinetic study. AB - BACKGROUND: Oxycodone is a u-opioid receptor agonist, the global use of which has increased vigorously during the past decade. The pharmacokinetic data of oxycodone available for elderly are limited, and there appear to be only little data on the population pharmacokinetics of oxycodone. METHODS: We analysed 1272 plasma oxycodone samples of 77 individuals (range of age 19-89 yr) with non linear mixed effect modelling. Inter- and intra-individual variability of the model was estimated for clearances and distribution volumes. The effect of covariates was studied with simulations. RESULTS: Data were best described with a two-compartment linear model. Lean body mass and age were found to be significant covariates for elimination clearance and the volume of the central compartment. The population estimates of elimination clearance, volume of the central compartment, and the volume of distribution at steady state for a reference individual (male 35 yr, 70 kg, 170 cm) were 51.0 litre h(-1), 134, and 258 litres, respectively. The elimination half-life of oxycodone showed an age dependent increase. The context-sensitive half-time at steady state increased from 3.8 to 4.6 h between the age of 25 and 85 yr, respectively. Simulations of repetitive bolus dosing showed a 20% increase in oxycodone concentration in the elderly. CONCLUSIONS: Age was found to be a significant covariate for oxycodone pharmacokinetics. In elderly patients, dosing should therefore be reduced and carefully titrated to avoid considerable accumulation of oxycodone and potentially hazardous side-effects. PMID- 22201185 TI - Alveolar recruitment improves ventilation during thoracic surgery: a randomized controlled trial. AB - BACKGROUND: This study was conducted to determine whether an alveolar recruitment strategy (ARS) applied during two-lung ventilation (TLV) just before starting one lung ventilation (OLV) improves ventilatory efficiency. METHODS: Subjects were randomly allocated to two groups: (i) control group: ventilation with tidal volume (VT) of 8 or 6 ml kg(-1) for TLV and OLV, respectively, and (ii) ARS group: same ventilatory pattern with ARS consisting of 10 consecutive breaths at a plateau pressure of 40 and 20 cm H(2)O PEEP applied immediately before and after OLV. Volumetric capnography and arterial blood samples were recorded 5 min (baseline) and 20 min into TLV, at 20 and 40 min during OLV, and finally 10 min after re-establishing TLV. RESULTS: Twenty subjects were included in each group. In all subjects, the airway component of dead space remained constant during the study. Compared with baseline, the alveolar dead space ratio (VD(alv)/VT(alv)) increased throughout the protocol in the control but decreased in the ARS group. Differences in VD(alv)/VT(alv) between groups were significant (P<0.001). Except for baseline, all values in kPa (sd) were higher in the ARS than in the control group (P<0.001), respectively [70 (7) and 55 (9); 33 (9) and 24 (10); 33 (8) and 22 (10); 70 (7) and 55 (10)]. CONCLUSIONS: Recruitment of both lungs before instituting OLV not only decreased alveolar dead space but also improved arterial oxygenation and the efficiency of ventilation. PMID- 22201186 TI - Inhibition of glycogen synthase kinase-3 activity triggers an apoptotic response in pancreatic cancer cells through JNK-dependent mechanisms. AB - Recent evidences suggest that the activity of glycogen synthase kinase-3 (GSK3) contributes to the tumorigenic potential of pancreatic cancer cells through modulation of cell proliferation and survival. However, further investigations are needed to identify GSK3-dependent mechanisms involved in the control of pancreatic cancer cell proliferation and survival. This study was undertaken to provide further support for a role of GSK3 in pancreatic cancer cell growth as well as to identify new cellular and molecular mechanisms involved. Herein, we demonstrate that prolonged inhibition of GSK3 triggers an apoptotic response only in human pancreatic cancer cells but not in human non-transformed pancreatic epithelial cells. We show that prolonged inhibition of GSK3 activity increases Bim messenger RNA and protein expressions. Moreover, we provide evidence that activation of the c-jun N-terminal kinase (JNK) pathway is necessary for the GSK3 inhibition-mediated increase in Bim expression and apoptotic response. Finally, we demonstrate that concomitant inhibition of GSK3 potentiates the death ligand induced apoptotic response in pancreatic cancer cells but not in non-transformed pancreatic epithelial cells and that this effect also requires JNK activity. Considering that different approaches leading to stimulation of death receptor signaling are under clinical trials for treatment of unresectable or metastatic pancreatic cancer, inhibition of GSK3 could represent an attractive new avenue to improve their effectiveness. PMID- 22201187 TI - Comment on 'a German storm affecting Britain: childhood leukaemia and nuclear power plants'. PMID- 22201188 TI - Comment on 'a German storm affecting Britain: childhood leukaemia and nuclear power plants'. PMID- 22201189 TI - Compact fluorescent lights. PMID- 22201190 TI - Immunolocalization of endocan during the endothelial-mesenchymal transition process. AB - Endocan is a dermatan sulfate proteoglycan (DSPG) that has been observed in the cytoplasm of endothelial cells of small and large vessels in lung, kidney, liver, colon, ovary and brain tumors. This DSPG has been implicated in the regulation of cellular activities such as adhesion, migration, and proliferation. Given the important roles played by endocan in such processes, we sought to determine whether this DSPG is present in the chicken embryo aortic wall in embryonic days 12 and 14, when intimal thickening and endothelial transformation are notorious. Immunolabeling of serial paraffin cross-sections revealed endocan immunoreactivity at the endothelium and some mesenchymal cells constituting the intimal thickening but not in the cells arranged in lamellar layers. We also investigated whether endocan was present in monolayers of primary embryonic aortic endothelial cells attached to fibronectin when they were deprived of serum and stimulated with epidermal growth factor. Immunofluorescence determined that in the epidermal growth factor (EGF) condition where separating, detaching, and migrating cells were observed, endocan appeared organized in arrays typical of focal complexes in the leading edge of these cells. In serum-free medium condition in which the endothelial cells displayed a cobblestone appearance, endocan appeared mainly delineating the margin of many cells. This study demonstrates for the first time the presence of endocan during the aortic wall remodeling, and provides evidence that suggests a possible contribution of this DSPG in the endothelial-mesenchymal transition (EndoMT) process. PMID- 22201191 TI - ASHP statement on leadership as a professional obligation. PMID- 22201192 TI - [Low publishing of articles presented in the congress of the Gastroenterology Society of Peru]. PMID- 22201193 TI - [Great Earthquake of Eastern Japan and the Society of Biological Psychiatry]. PMID- 22201194 TI - [On surgical strategy for ischemic cardiomyopathy]. PMID- 22201195 TI - [Key points in lymph node dissection during surgery of esophageal cancer]. PMID- 22201196 TI - Healthcare delivery. PMID- 22201197 TI - Interview with Sandra Bruce, FACHE, President and CEO, Resurrection Health Care and Provena Health. Interview by Stephen J. O'Connor. PMID- 22201198 TI - Innovation or stagnation? Crossing the creativity gap in healthcare. PMID- 22201199 TI - End-of-life care: the time for a meaningful discussion is now. PMID- 22201200 TI - Leading for quality in healthcare: development and validation of a competency model. AB - Increased attention to healthcare quality and impending changes due to health reform are calling for healthcare leaders at all levels to strengthen their skills in leading quality improvement initiatives. To address this need, the National Association for Healthcare Quality spearheaded the development and validation of a competency model to support healthcare leaders in assessing their strengths and planning appropriate steps for development. Initial development took place over the course of several days of meetings by an advisory panel of quality professionals. The draft model was then validated via electronic survey of a national sample of 883 quality professionals. Follow-up analyses indicated that the model was content valid for each of the target samples and also distinguished differing levels of job scope and experience. The resulting model contains six domains spanning three organizational levels. PMID- 22201201 TI - A roadmap for improving healthcare service quality. AB - A data-driven, comprehensive model for improving service and creating long-term value was developed and implemented at Mayo Clinic Arizona (MCA). Healthcare organizations can use this model to prepare for value-based purchasing, a payment system in which quality and patient experience measures will influence reimbursement. Surviving and thriving in such a system will require a comprehensive approach to sustaining excellent service performance from physicians and allied health staff (e.g., nurses, technicians, nonclinical staff). The seven prongs in MCA's service quality improvement model are (1) multiple data sources to drive improvement, (2) accountability for service quality, (3) service consultation and improvement tools, (4) service values and behaviors, (5) education and training, (6) ongoing monitoring and control, and (7) recognition and reward. The model was fully implemented and tested in five departments in which patient perception of provider-specific service attributes and/or overall quality of care were below the 90th percentile for patient satisfaction in the vendor's database. Extent of the implementation was at the discretion of department leadership. Perception data rating various service attributes were collected from randomly selected patients and monitored over a 24 month period. The largest increases in patient perception of excellence over the pilot period were realized when all seven prongs of the model were implemented as a comprehensive improvement approach. The results of this pilot may help other healthcare organizations prepare for value-based purchasing. PMID- 22201202 TI - Language services in hospitals: discordance in availability and staff use. AB - Despite efforts to advance effective patient-provider communication, many patients' language needs continue to be unmet or inappropriately addressed by healthcare providers (Wielawski 2010; Patek et al. 2009; Wilson-Stronks and Galvez 2007). This study presents a picture of the language resources currently provided by hospitals and those resources practitioners actually use. Questionnaire data were collected from 14 hospitals in Florida's Palm Beach, St. Lucie, and Martin counties on availability, staff awareness, and staff use of linguistic resources and services. Inconsistencies were identified between the language tools, services, and resources hospitals provide and those staff use. In addition, a large majority of staff respondents still rely upon someone accompanying the patient for communication with patients who have limited English proficiency, despite evidence that this practice contributes to miscommunication and serious medical errors (Flores et al. 2003; Flores 2005; HHS OMH 2001; Patek et al. 2009). Hospitals that use bilingual staff as interpreters often do not test the competency of these staff, nor do they assess the utilization or effectiveness of the tools and resources they provide. Hospitals can improve the cultural and linguistic care they provide if they (1) address the practice of using ad hoc interpreters, (2) effectively disseminate information to hospital staff regarding how and when to access available resources, and (3) collect patient population data and use it to plan for and evaluate the language services they provide to their patients. PMID- 22201203 TI - Occupational stress and job burnout in mental health. PMID- 22201204 TI - Psychosocial safety climate: a multilevel theory of work stress in the health and community service sector. AB - Work stress is widely thought to be a significant problem in the health and community services sector. We reviewed evidence from a range of different data sources that confirms this belief. High levels of psychosocial risk factors, psychological health problems and workers compensation claims for stress are found in the sector. We propose a multilevel theoretical model of work stress to account for the results. Psychosocial safety climate (PSC) refers to a climate for psychological health and safety. It reflects the balance of concern by management about psychological health v. productivity. By extending the health erosion and motivational paths of the Job Demands-Resources model we propose that PSC within work organisations predicts work conditions and in turn psychological health and engagement. Over and above this, however, we expect that the external environment of the sector particularly government policies, driven by economic rationalist ideology, is increasing work pressure and exhaustion. These conditions are likely to lead to a reduced quality of service, errors and mistakes. PMID- 22201205 TI - Burnout and psychiatrists: what do we know and where to from here? AB - Medicine in most parts of the world is becoming a stressful profession. Psychiatrists represent a high-risk group among doctors for experiencing burnout, alcohol and drug use, posing suicide risk and other forms of work-related stress. There are reports that entrants in the profession of psychiatrists are decreasing globally. Conceptual issues related to burnout are explored and factors contributing to burnout in psychiatrists are reviewed. Methodologically sound studies are needed to help us understand positive aspects of psychiatry as a profession and the environment psychiatrists work in. Effective treatment programmes for burnout are also needed not only to reduce suffering but also to retain psychiatrists in the profession. PMID- 22201206 TI - Fired up, not burnt out--focusing on the rewards of working in psychiatry. PMID- 22201207 TI - Cluster randomised trials. AB - Although randomised controlled trials are the reference methodology to assess the effects of therapeutic interventions, for interventions that naturally occur in groups of individuals random allocation of participants may be inappropriate. In these cases, the unit of random allocation may be the group or cluster, rather than the individual. Clinical trials that randomly allocate groups or clusters of individuals are called cluster randomised trials. This article briefly presents the main implications of cluster randomisation with respect to the following methodological aspects: generalisability, concealment of allocation, comparability at baseline, blindness, loss of clusters and intra-class correlation. PMID- 22201208 TI - Language disturbances in ADHD. AB - This article aims to review the studies exploring language abilities in attention deficit hyperactivity disorder (ADHD; with or without comorbid language impairment) focusing on oral speech discrimination, listening comprehension, verbal and spatial working memory as well as on discourse analysis and pragmatic aspects of communication and language comprehension. PMID- 22201209 TI - Beyond the facts in schizophrenia: closing the gaps in diagnosis, pathophysiology, and treatment. AB - BACKGROUND: Although schizophrenia has been considered a distinct disease entity for the past century, its precise definition and etio-pathophysiology remain obscure and its treatment remains unsatisfactory. In this review, we summarize our state of knowledge about the etiology, pathophysiology, clinical features, and treatment of schizophrenia. METHODOLOGICAL ISSUES: The inadequacy of the major conceptual models of schizophrenia is a major roadblock in providing a coherent explanation for the known facts of this illness, despite these limitations and its changing definitions, the construct of schizophrenia does convey useful information: (i) patients diagnosed as having schizophrenia do have a real disease--they experience both suffering and disability; (ii) a diagnosis of schizophrenia does suggest a distinctive clinical profile--a characteristic long-term course; an admixture of positive, negative, and cognitive symptoms; (iii) a diagnosis of schizophrenia has clear treatment and prognostic implications--likelihood of benefit from antipsychotic treatment and likelihood of incomplete recovery; and (iv) schizophrenia satisfies criteria for a valid diagnostic entity better than almost any other psychiatric diagnosis. DISCUSSION: On the other hand, the concept of schizophrenia has serious shortcomings. First, it is not a single disease entity--it has multiple etiological factors and pathophysiological mechanisms but common phenotypic features. Second, its clinical manifestations are so diverse that its extreme variability has been considered by some to be a core feature. Third, its boundaries remain ill defined and not clearly demarcated from other clinical entities. CONCLUSIONS: A necessary next step is to deconstruct schizophrenia as an entity into component dimensions- endophenotypes linked to unique etiological and pathophysiological processes that may yield unique treatment targets. Innovative approaches are needed to elucidate the biological substrates of these entities because such clarity is vital for replicable research. We conclude by identifying the critical gaps in our knowledge, and unmet needs in our approaches to care, and outline steps that can move the field forward. PMID- 22201210 TI - The CBCL 1.5-5 and the identification of preschoolers with autism in Italy. AB - AIMS: To study the potential use of child behaviour checklist (CBCL) 1.5-5 scales for the early identification of preschoolers at risk of autism. METHODS: CBCL scores of three groups of preschoolers were compared: (1) an experimental group of 101 preschoolers with autism spectrum disorder (ASD); (2) a control group of 95 preschoolers with other psychiatric disorders (OPD); (3) a control group of 117 preschoolers with typical development (TD). One-way analysis of variance (ANOVA), logistic regression with odds ratio (OR) and receiver operating characteristic (ROC) analyses were performed. RESULTS: ANOVA revealed that ASD and OPD had significantly higher scores in almost all CBCL scales than TD. ASD presented significantly higher scores than OPD on Withdrawn, Attention Problems and Pervasive Developmental Problems (PDP) scales. Logistic regression analysis demonstrated that these same CBCL scales have validity in predicting the presence of an ASD towards both TD and OPD. ROC analysis indicated high sensitivity and specificity for PDP (0.85 and 0.90) and Withdrawn (0.89 and 0.92) scales when ASD is compared to TD. Specificity (0.60 for PDP and 0.65 for Withdrawn) decreases when comparing ASD and OPD CONCLUSIONS: The PDP and Withdrawn scales have a good predictive validity so that they could be proposed as a first-level tool to identify preschoolers at risk of autism in primary care settings. Problems regarding the lower specificity when comparing ASD v. OPD are discussed. PMID- 22201211 TI - Bullying behaviours among students in Pavia, Italy: prevalence and association with stress and cannabis use. AB - BACKGROUND: This study examined the prevalence of students' reported experiences of bullying and victimization in primary and secondary schools and their association with levels of perceived stress and cannabis use. METHODS: We consecutively enrolled 407 students attending three secondary schools in Pavia (Italy). Bullying and victimization were measured using the retrospective bullying questionnaire (RQB). The 10-item perceived stress scale (PSS-10) was used to assess the degree to which situations in life were perceived as stressful. Data on demographic characteristics and cannabis use in the previous 6 months were also collected. RESULTS: There were 328 victims (80.6%) and 221 bullies (52.1%). The results of the stepwise regression analysis with bullying as the dependent variable were significant with either male sex (R2 = 0.030, p = 0.024) or PSS-10 scores (R2 0.056, p = 0.036) in the model. With victimization as the dependent variable, only the PSS-10 scores were retained in the model as an independent predictor variable (R2 = 0.048, p<0.001). CONCLUSIONS: The results from this study indicate that the level of perceived stress has an independent association with both bullying and victimization. Further studies are needed to clarify the psychobiological links between stress, cannabis use and bullying behaviours. PMID- 22201212 TI - The trauma symptom inventory: Italian validation of an instrument for the assessment of post-traumatic symptoms. AB - AIM: The trauma symptom inventory (TSI; Briere, 1995) is a useful instrument for the assessment of post-traumatic and common trauma-related mental health symptoms. The purpose of the study was to validate the Italian version of the original TSI. METHODS: Participants from non-clinical (n = 285), clinical (n = 110) and post-traumatic (n = 30) samples completed the TSI as part of a battery that included self-report measures of trauma exposure [MMPI-2 PK scale and Impact of Event Scale-Revised (IES-R)] and of psychological symptoms [brief symptom inventory (BSI) and symptom questionnaire (SQ)]. TSI validity scales were compared with MMPI-2 validity scales in order to assess convergent validity. RESULTS: The TSI Italian version showed adequate internal consistency reliability and a good convergent validity. Discriminant function analysis indicates a classification accuracy of TSI scales of 90% for true-positive and 91.4% for true negative post-traumatic stress disorder (PTSD) cases. A revised three-factor structural model, which demonstrated an adequate and the best fit for the data, was proposed. CONCLUSIONS: The study extended the generalization and validity of TSI and provided some suggestions for eventually revisiting factorial structure of the questionnaire. PMID- 22201213 TI - Prevalence of psychosocial problems in Dutch children aged 8-12 years and its association with risk factors and quality of life. AB - AIMS: To determine the prevalence of psychosocial problems among Dutch children aged 8-12 years and studying its association with risk factors and quality of life. METHODS: This study was conducted within the framework of a community-based health study in the north-west region of the Netherlands. The cross-sectional study sample consisted of 2703 children (1392 boys and 1311 girls). Psychosocial problems and quality of life were measured with the extended version of the Strengths and Difficulties Questionnaire (SDQ) and KIDSCREEN-10, respectively. Questionnaires and data about risk factors (parental education level, ethnicity, family structure, income, chronic diseases and life events) were completed by the parents or caregivers. RESULTS: The prevalence of psychosocial problems (SDQ score > or =14) in the total sample was 10.4%. The prevalence was higher in boys compared with girls (13.9% v. 6.6%, OR= 2.28; 95% CI = 1.75-2.97). Boys had significantly more hyperactivity/inattention, conduct, peer relationship and prosocial behaviour problems compared with girls. Risk factors associated with psychosocial problems were: one or more chronic disease(s), life event(s), a low parental educational level (for boys only) and an income under a modal level. Psychosocial problems were significantly inverse related with quality of life in the total sample (rho = -0.47). CONCLUSIONS: Psychosocial problems are common in children, especially among boys, and are inversely related with children's quality of life. The identified risk factors in this study can be useful for developing targeted prevention strategies aimed at children at high risk for psychosocial problems. PMID- 22201214 TI - Maternal and paternal psychopathology increases risk of offspring ADHD equally. AB - BACKGROUND: Parental psychopathology may increase the risk of attention-deficit hyperactivity disorder (ADHD) in the offspring. The aim of this study was to analyze if/how gender influences the association between parental psychiatric/addictive disorders and ADHD medication in the offspring. METHODS: Register study in national birth cohorts of 1.1 million 6-19-year-olds. In this population, 7960 individuals with ADHD medication were identified in the Swedish Prescribed Drug Register during 2006. Data on parental psychiatric/addictive disorders and suicide death were obtained through linkages to national registers. Logistic regression was used for analyses with multiple adjustments for socio economic, regional and demographic confounders. RESULTS: Parental diagnosis related to illicit drugs was associated with the highest odds ratios (ORs) of ADHD medication (OR: -3.5-4), followed by suicide attempt/death (OR: -3-3.5), alcohol (OR: -2.5-3), affective disorder (OR: -2.5) and psychosis (OR: -2-2.5). The ORs were of similar magnitudes for maternal and paternal psychopathology and did not vary by the gender of the offspring. Adjusting for social characteristics decreased the ORs substantially and in the same way regarding fathers' and mothers' possible influence on the risk of ADHD in children. CONCLUSIONS: Neither parental nor offspring gender seems to influence the link between parental addictive/psychiatric disorder and offspring ADHD. PMID- 22201215 TI - Test performance of the Cantonese Chinese Mood Disorder Questionnaire for detecting bipolar spectrum disorder in the community of Hong Kong. PMID- 22201216 TI - Effects of polybrominated diphenyl ethers (PBDEs) and their derivatives on protein disulfide isomerase activity and growth hormone release of GH3 cells. AB - Polybrominated diphenyl ethers (PBDEs) have been used in a variety of consumer products such as flame retardants and recently have been known to be widespread environmental pollutants, which probably affect biological functions of mammalian cells. However, the risk posed by PBDE metabolites has not been clarified. Our previous study suggested that bisphenol A (BPA), an endocrine-disrupting chemical, binds to protein disulfide isomerase (PDI) and inhibits its activity. PDI is an isomerase enzyme in the endoplasmic reticulum and facilitates the formation or cleavage of disulfide bonds. PDI consists of a, b, b', and a' domains and the c region, with the a and a' domains having isomerase active sites. In the present study, we tested the effects of 10 kinds of PBDE compounds and their metabolites on PDI. OH-PBDEs specifically inhibited the isomerase activity of PDI, with 4'-OH-PBDE more effective than 2' (or 2)-OH-PBDEs. 4'-OH PBDE inhibited the isomerase activity of the b'a'c fragment but not that of ab and a'c, suggesting that the b' domain of PDI is essential for the inhibition by 4'-OH-PBDE. We also investigated the effects of these chemicals on the production of growth hormone (GH) in GH3 cells. In GH3 cells, levels of mRNA and protein of GH stimulated by T(3) were reduced by 4'-OH-PBDE and 4'-MeO-PBDE. The reduction in GH expression caused by these compounds was not changed by the overexpression or knockdown of PDI in GH3 cells, while these manipulations of PDI levels significantly suppressed the expression of GH. These results suggest that the biological effects of PBDEs differed depending on their brominated and hydroxylated positions. PMID- 22201217 TI - Controlling bandgap of rippled hexagonal boron nitride membranes via plasma treatment. AB - Few-layer rippled hexagonal boron nitride (h-BN) membranes were processed with hydrogen plasma, which exhibit distinct and pronounced changes in its electronic properties after the plasma treatment. The bandgaps of the h-BN membrane reduced from ~5.6 eV at 0 s to ~4.25 eV at 250 s, which is a signature of transition from the insulating to the semiconductive regime. It typically required 250 s of plasma treatment to reach the saturation. It illustrates that two-dimensional material with engineered electronic properties can be created by attaching other atoms or molecules. PMID- 22201218 TI - Proton transfers along hydrogen bonds in the tautomerization of purine. AB - Tautomerization of purine in the water cluster was investigated by the use of DFT calculations. The correlation between the reaction paths and the number of water molecules (n) was examined. For n = 3 and n = 4, concerted reaction paths were obtained. However, for n = 5, a stepwise path including an ion pair intermediate was found with small activation energies. The n = 4 + 3 and n = 4 + 3 + 9 models were calculated to give further small activation energies, where n = 4 constitutes the reaction center and +3 and +3 + 9 denote the number of catalytic water molecules. The combination of the in-plane deprotonation at the N9 site and the out-of-plane protonation at the N7 site makes the n = 4 model probable. Three protonated n = 4 + 3 + 9 routes, a, b, and c, composed of purineH(+)(H(2)O)(4+3+9) were investigated. The n = 4 + 3 moiety is also included in the three routes, and the route c (with the N1 protonation) was found to be most favorable. The purine tautomerization was found to involve the Zundel cation in the ion pair intermediate. PMID- 22201219 TI - Predictors of moderated drinking in a primarily alcohol-dependent sample of men who have sex with men. AB - Understanding for whom moderated drinking is a viable, achievable, and sustainable goal among those with a range of alcohol use disorders (AUD) remains an important public health question. Despite common acceptance as severe risk factors, there is little empirical evidence to conclude whether co-occurring mental health disorders or drug dependence contribute to an individual's inability to successfully moderate his drinking. Utilizing secondary data analysis, the purpose of this study was to identify predictors of moderation among both treatment-seeking and non-treatment-seeking, primarily alcohol dependent, problem-drinking men who have sex with men (MSM), with an emphasis on the high risk factors psychiatric comorbidity and drug dependence. Problem drinkers (N=187) were assessed, provided feedback about their drinking, given the option to receive brief AUD treatment or change their drinking on their own, and then followed for 15 months. Findings revealed that neither psychiatric comorbidity or drug dependence predicted ability to achieve moderation when controlling for alcohol dependence severity. Those who were younger, more highly educated, and had more mild alcohol dependence were more likely to achieve moderated drinking. Impact of treatment on predictors is explored. Limitations of this study and arenas for future research are discussed. PMID- 22201221 TI - Monitoring biodegradation of ethene and bioremediation of chlorinated ethenes at a contaminated site using compound-specific isotope analysis (CSIA). AB - Chlorinated ethenes are commonly found in contaminated groundwater. Remediation strategies focus on transformation processes that will ultimately lead to nontoxic products. A major concern with these strategies is the possibility of incomplete dechlorination and accumulation of toxic daughter products (cis-1,2 dichloroethene (cDCE), vinyl chloride (VC)). Ethene mass balance can be used as a direct indicator to assess the effectiveness of dechlorination. However, the microbial processes that affect ethene are not well characterized and poor mass balance may reflect biotransformation of ethene rather than incomplete dechlorination. Microbial degradation of ethene is commonly observed in aerobic systems but fewer cases have been reported in anaerobic systems. Limited information is available on the isotope enrichment factors associated with these processes. Using compound-specific isotope analysis (CSIA) we determined the enrichment factors associated with microbial degradation of ethene in anaerobic microcosms (epsilon = -6.70/00 +/- 0.40/00, and -4.00/00 +/- 0.80/00) from cultures collected from the Twin Lakes wetland area at the Savannah River site in Georgia (United States), and in aerobic microcosms (epsilon = -3.00/00 +/- 0.30/00) from Mycobacterium sp. strain JS60. Under anaerobic and aerobic conditions, CSIA can be used to determine whether biotransformation of ethene is occurring in addition to biodegradation of the chlorinated ethenes. Using delta(13)C values determined for ethene and for chlorinated ethenes at a contaminated field site undergoing bioremediation, this study demonstrates how CSIA of ethene can be used to reduce uncertainty and risk at a site by distinguishing between actual mass balance deficits during reductive dechlorination and apparent lack of mass balance that is related to biotransformation of ethene. PMID- 22201220 TI - Thermodynamic dissection of estrogen receptor-promoter interactions reveals that steroid receptors differentially partition their self-association and promoter binding energetics. AB - Steroid receptors define a family of ligand-activated transcription factors. Recent work has demonstrated that the receptors regulate distinct but overlapping gene networks, yet the mechanisms by which they do so remain unclear. We previously determined the microscopic binding energetics for progesterone receptor (PR) isoform assembly at promoters containing multiple response elements. We found that the two isoforms (PR-A and PR-B) share nearly identical dimerization and intrinsic DNA binding free energies but maintain large differences in cooperative free energy. Moreover, cooperativity can be modulated by monovalent ion binding and promoter layout, suggesting that differences in cooperativity might control isoform-specific promoter occupancy and thus receptor function. To determine whether cooperative binding energetics are common to other members of the steroid receptor family, we dissected the thermodynamics of estrogen receptor-alpha (ER-alpha):promoter interactions. We find that the ER alpha intrinsic DNA binding free energy is identical to that of the PR isoforms. This was expected, noting that receptor DNA binding domains are highly conserved. Unexpectedly, ER-alpha generates negligible cooperativity-orders of magnitude less than predicted based on our studies of the PR isoforms. However, analysis of the cooperativity term suggests that it reflects a balance between highly favorable cooperative stabilization and unfavorable promoter bending. Moreover, ER-alpha cooperative free energy is compensated for by a large increase in dimerization free energy. Collectively, the results demonstrate that steroid receptors differentially partition not only cooperative energetics but also dimerization energetics. We speculate that this ability serves as a framework for regulating receptor-specific promoter occupancy and thus receptor-specific gene regulation. PMID- 22201222 TI - Resistive switching induced by metallic filaments formation through poly(3,4 ethylene-dioxythiophene):poly(styrenesulfonate). AB - We report the design and fabrication of Al/poly(3,4-ethylene dioxythiophene):poly(styrenesulfonate) (PEDOT:PSS)/Cu resistive memory devices that utilize the Cu redox reaction and conformational features of PEDOT:PSS to achieve resistive switching. The top Cu electrode acts as the source of the redox ions that are injected through the PEDOT:PSS layer during the forming process. The Cu filament is confirmed directly using the cross-sectional images of transmission electron microscopy and energy-dispersive X-ray spectroscopy. The resultant resistive memory devices can operate over a small voltage range, i.e., the switching-on threshold voltage is less than 1.5 V and the absolute value of the switching-off threshold voltage is less than 1.0 V. The on/off current ratio is as large as 1 * 10(4) and the two different resistance states can be maintained over 10(6) s. Moreover, the devices present good thermal stability that the resistive switching can be observed even at temperature up to 160 degrees C, at which the oxidation of the Cu top electrode is the failure factor. Furthermore, the cause of failure for Al/PEDOT:PSS/Cu memory devices at higher temperature is confirmed to be the oxidation of Cu top electrode. PMID- 22201223 TI - Direct methoxypyridine functionalization approach to magellanine-type Lycopodium alkaloids. AB - A concise enantioselective approach to the tetracyclic core of the magellanine type Lycopodium alkaloids is reported. Key to this approach is the use of the Hajos-Parrish reaction to set a challenging quaternary stereocenter, thereby guiding the stereoselectivity for the remainder of the synthesis, as well as the use of a palladium-mediated direct pyridine functionalization reaction to forge the tetracyclic core. PMID- 22201224 TI - Hydroxyl radical formation upon oxidation of reduced humic acids by oxygen in the dark. AB - Humic acids (HAs) accept and donate electrons in many biogeochemical redox reactions at oxic/anoxic interfaces. The products of oxidation of reduced HAs by O(2) are unknown but are expected to yield reactive oxygen species, potentially including hydroxyl radical (.OH). To quantify the formation of .OH upon oxidation of reduced HAs by O(2), three HAs were reduced electrochemically to well-defined redox states and were subsequently oxidized by O(2) in the presence of the .OH probe terephthalate. The formation of .OH upon oxidation increased with increasing extent of HA reduction. The yield of .OH ranged from 42 to 160 mmol per mole of electrons donated by the reduced HA. The intermediacy of hydrogen peroxide (H(2)O(2)) in the formation of .OH was supported by enhancement of .OH formation upon addition of exogenous H(2)O(2) sources and by the suppression of .OH formation upon addition of catalase as a quencher of endogenous H(2)O(2). The formation of .OH in the dark during oxidation of reduced HA represents a previously unknown source of .OH formation at oxic/anoxic interfaces and may affect the biogeochemical and pollutant redox dynamics at these interfaces. PMID- 22201225 TI - Electrically conducting nanopatterns formed by chemical e-beam lithography via gold nanoparticle seeds. AB - We report the formation of thiol nanopatterns on SAM covered silicon wafers by converting sulfonic acid head groups via e-beam lithography. These thiol groups act as binding sites for gold nanoparticles, which can be enhanced to form electrically conducting nanostructures. This approach serves as a proof-of concept for the combination of top-down and bottom-up processes for the generation of electrical devices on silicon. PMID- 22201226 TI - Robot-assisted upper pole nephrectomy in adult patients with duplicated renal collecting systems. AB - Duplicated renal collecting systems are a common congenital anomaly, with patients usually presenting in childhood, rarely in adult life. To our knowledge, only one case of robot-assisted heminephrectomy in adults has been described. We reviewed the medical records of four adult patients with symptomatic unilateral duplicated collecting systems and nonfunctioning upper pole renal units (NFUPRU) who underwent robot-assisted laparoscopic heminephrectomy at our institutions. Heminephrectomy for NFUPRU should be approached differently than partial nephrectomy, because of complex vascular anatomy. Patients who are undergoing this procedure have brief hospital stays, minimal morbidity, preservation of renal function, and resolution of symptoms. Robot-assisted laparoscopy is well suited for this procedure because it allows improved visualization during dissection of the unique vascular anatomy as well as scaling of surgeon movements and improved ergonomics. PMID- 22201227 TI - Aqueous solvation of polyalanine alpha-helices with specific water molecules and with the CPCM and SM5.2 aqueous continuum models using density functional theory. AB - We present density functional theory (DFT) calculations at the X3LYP/D95(d,p) level on the solvation of polyalanine alpha-helices in water. The study includes the effects of discrete water molecules and the CPCM and AMSOL SM5.2 solvent continuum model both separately and in combination. We find that individual water molecules cooperatively hydrogen-bond to both the C- and N-termini of the helix, which results in increases in the dipole moment of the helix/water complex to more than the vector sum of their individual dipole moments. These waters are found to be more stable than in bulk solvent. On the other hand, individual water molecules that interact with the backbone lower the dipole moment of the helix/water complex to below that of the helix itself. Small clusters of waters at the termini increase the dipole moments of the helix/water aggregates, but the effect diminishes as more waters are added. We discuss the somewhat complex behavior of the helix with the discrete waters in the continuum models. PMID- 22201228 TI - Prognostic evaluation of electrocochleography in idiopathic sudden sensorineural hearing loss. AB - CONCLUSION: Abnormal action potential (AP) recovery from adaptation was manifested as increased recovery (iR) or decreased recovery (dR) relative to the normal recovery range. dR was not analyzed statistically due to the very small number of cases. iR is considered an unfavorable prognostic indicator, whereas a normal AP recovery (nR), enhanced SP/AP ratio (>=0.35), and lower AP threshold are favorable prognostic indicators for idiopathic sudden sensorineural hearing loss (iSSNHL). OBJECTIVES: This study aimed to determine the prognostic efficacy of AP recovery examinations associated with other electrocochleography (ECochG) findings in iSSNHL. METHODS: ECochG was performed transtympanically in 58 iSSNHL ears. AP recovery was measured by a paired-click stimulation paradigm, and hearing outcome was classified into three groups. Additionally, the relationships of other confounding prognostic factors to hearing outcomes were assessed. RESULTS: iR was significantly more common in the no-recovery group, while nR and an enhanced SP/AP ratio were significantly more common in the cure and improvement groups. The AP threshold was significantly lower in the cure group than in the other two groups. The other confounding prognostic factors generally showed similar trends to those reported previously. PMID- 22201229 TI - Three-dimensional tracking and visualization of hundreds of Pt-Co fuel cell nanocatalysts during electrochemical aging. AB - We present an electron tomography method that allows for the identification of hundreds of electrocatalyst nanoparticles with one-to-one correspondence before and after electrochemical aging. This method allows us to track, in three dimensions, the trajectories and morphologies of each Pt-Co nanocatalyst on a fuel cell carbon support. In conjunction with the use of atomic-scale electron energy loss spectroscopic imaging, our experiment enables the correlation of performance degradation of the catalyst with changes in particle/interparticle morphologies, particle-support interactions, and the near-surface chemical composition. We found that aging of the catalysts under normal fuel cell operating conditions (potential scans from +0.6 to +1.0 V for 30,000 cycles) gives rise to coarsening of the nanoparticles, mainly through coalescence, which in turn leads to the loss of performance. The observed coalescence events were found to be the result of nanoparticle migration on the carbon support during potential cycling. This method provides detailed insights into how nanocatalyst degradation occurs in proton exchange membrane fuel cells (PEMFCs) and suggests that minimization of particle movement can potentially slow down the coarsening of the particles and the corresponding performance degradation. PMID- 22201230 TI - Contrast enhancement of the inner ear in magnetic resonance images taken at 10 minutes or 4 hours after intravenous gadolinium injection. AB - CONCLUSION: Contrast enhancement of the inner ear by three-dimensional fluid attenuated inversion recovery magnetic resonance imaging (3D-FLAIR MRI) taken 4 h after intravenous gadolinium (Gd) injection was better than when taken at 10 min. Using heavily T2-weighted 3D-FLAIR MRI, visualization of endolymphatic hydrops (EH) was possible in the vestibule and the cochlea after a standard intravenous dose of Gd. OBJECTIVES: To define a suitable time point for imaging Gd uptake in the inner ear acquired with heavily T2-weighted 3D-FLAIR MRI after standard intravenous Gd administration. METHODS: Using a 3 Tesla MRI unit, heavily T2 weighted 3D-FLAIR MRI images were taken twice at approximately 10 min (conventional timing) and 4 h after intravenous gadodiamide (0.1 mmol/kg) injection in 10 patients with inner ear diseases including Meniere's disease. RESULTS: The 4 h delay increased Gd enhancement of the 3D-FLAIR MRI images of the perilymphatic space in both symptomatic and asymptomatic ears. The increase in Gd enhancement was greater in symptomatic than in asymptomatic ears. Using this heavily T2-weighted 3D-FLAIR technique, EH was observed in both the cochlea and vestibule in images taken 4 h after the intravenous Gd injection. PMID- 22201231 TI - Modulation of nerve fibers in the rat thyroarytenoid muscle following recurrent laryngeal nerve injury. AB - CONCLUSION: Regeneration of nerve fibers in the thyroarytenoid (TA) muscle occurred actively after damage on the recurrent laryngeal nerve (RLN) compared with the vagus nerve (VN). However, remyelination did not occur after damage on the RLN. OBJECTIVES: To determine the regeneration process of nerve fibers in the TA muscle following transection and immediate anastomosis of the RLN or VN. METHODS: Three types of animal model were prepared: an RLN anastomosis model (RLNa), a VN anastomosis model (VNa), and a peroneal nerve anastomosis model (PNa). Animals were sacrificed at five time points following the procedure. The modulation of axons, myelin sheaths, Schwann cells (SCs), nerve terminals (NTs), and acetylcholine receptors (AchRs) in the TA or tibialis anterior muscles was examined by immunohistochemical analysis. The ratios of the expression areas in axons, myelin sheaths, and SCs, and the number of NTs and AchRs in the treated (T) and untreated (U) sides (T/U) were evaluated. RESULTS: At 18 weeks, the T/U ratios of expression in RLNa, VNa, and PNa were 68.5, 0, and 100.4%, respectively, in axons; 0, 0, and 97.6% in myelin sheaths; 53.7, 0, and 93.6% in SCs; 61.0, 0, and 96.4% in NTs; and 99.4, 67.0, and 101.2% in AchRs. PMID- 22201233 TI - Commentary: thirty years of AIDS in America: a story of infinite hope. AB - The year 2011 marks the thirtieth anniversary of the first case reports in the United States of what we now know to be end-stage HIV disease. This chronological milestone provides an opportunity to reflect upon the changing context of the American HIV/AIDS epidemic. Using two seminal documents as a framework, the 1986 Institute of Medicine Report, "Confronting AIDS," and the 2010 National HIV/AIDS Strategy, this descriptive analysis details our accomplishments in addressing the domestic U.S. epidemic and outlines what remains to be done on the long road to eradication of HIV disease. The past three decades have witnessed tremendous biomedical and behavioral advances in preventing, diagnosing, and treating HIV disease. However, to fully realize the promise of these scientific advances, such that we achieve the vision of the National HIV/AIDS Strategy, we must develop effective strategies to surmount a number of salient challenges, including: unbalanced combinations of prevention interventions; programs that are not of adequate scale to achieve population-level results; systems of service delivery that do not function in an integrated fashion; and social and economic structures that increase the vulnerability of populations who are at risk for or living with HIV disease. PMID- 22201234 TI - Education and HIV/AIDS-30 years on. AB - Education has long been identified as having a key role to play in reducing HIV related risk and vulnerability, and in mitigating the impact of the epidemic on affected individuals and communities. This article reflects on progress over a 30 year period with respect to older and more emergent forms of education concerning HIV and AIDS: treatment education, education for HIV prevention, and education to encourage a positive and supportive community response. It points to a number of priorities for the future. These include analyzing more carefully different forms of HIV-related education, their consequences and effects, and identifying the specific effectivity of education in general and HIV-related education in particular in achieving positive outcomes. The potential of education to enable new ways of seeing, understanding, and hoping is stressed, as is the need to support education processes and systems that "think" faster than the epidemic. PMID- 22201235 TI - Transmen: the HIV risk of gay identity. AB - Many female-to-male transgender individuals, or transmen, are situated within the gay community, one of the highest risk communities for HIV, yet there has been little research regarding the experience of risk for these transmen. Seventeen transmen were interviewed regarding their sexuality and HIV risk behavior. Fourteen of the 17 reported having non-trans gay men as sexual partners. Risk behaviors included not using condoms with multiple partners who were HIV positive, or of unknown HIV status. Aspects of risk included the unfamiliarity of the gay community and the lack of safe sex negotiating skills. The dynamics of acceptance and rejection between transmen and non-trans gay men impacted risk by compromising safety. Incorrect assumptions regarding transmen, non-trans gay men, and risk included beliefs that neither person could be at risk. Other aspects included the impact of testosterone on sexual behavior, the changed bodies of transmen, and sex work. PMID- 22201236 TI - "We're going to have to cut loose some of our personal beliefs": barriers and opportunities in providing HIV prevention to African American men who have sex with men and women. AB - In the United States, there is an urgent need to provide HIV prevention services to African American men who have sex with men and women (MSMW) but who do not identify as gay or homosexual. Engaging these men in HIV prevention has historically been challenging. This study used qualitative methodology to explore the beliefs and experiences from community-based service providers (n = 21) and from African American MSMW (n = 21) regarding the provision of HIV prevention education and counseling to these men. Data analysis revealed that (a) African American MSMW who do not identify as gay can challenge service providers' assumptions about sexual behavior and sexual identity; (b) service providers' attitudes toward these men can be affected by ambivalent or negative beliefs that pervade the general community; (c) African American MSMW need safe and nonjudgmental spaces that offer HIV risk reduction, but they also might experience anxiety about disclosing same-sex behaviors to counselors. Findings highlighted the complexities related to culture, masculinity, and sexuality as determinants of HIV risk in African American MSMW, and findings also revealed tensions between these factors that may affect the quality of HIV prevention services. Service providers may need additional training to provide appropriate and non-judgmental HIV prevention counseling and education. PMID- 22201237 TI - The effectiveness of MI4MSM: how useful is motivational interviewing as an HIV risk prevention program for men who have sex with men? A systematic review. AB - Among men who have sex with men (MSM), the principal risk practice for HIV infection is unprotected anal intercourse, often engaged in under the influence of alcohol and other substances. Both behaviors are targeted through the much used counseling approach motivational interviewing (MI). We conducted a systematic review of the effectiveness of behavioral interventions adapting the principles and techniques of MI on HIV risk behaviors for MSM. Ten randomized controlled trials, which included 6,051 participants at baseline, were eligible for inclusion. Nine outcomes, of which seven were for sexual behavior outcomes, were sufficiently similar to compute meta-analyses. With the exception of one outcome, drinks per day at short-term follow-up, there were no significant differences between the groups receiving MI and the control groups. The effectiveness of MI as a prevention strategy for HIV risk behaviors among MSM is uncertain and continued work to craft more effective HIV prevention programming for this group should be done. PMID- 22201238 TI - Enhancing HIV communication between parents and children: efficacy of the Parents Matter! Program. AB - We examine efficacy of the Parents Matter! Program (PMP), a program to teach African-American parents of preadolescents sexual communication and HIV prevention skills, through a multicenter, randomized control trial. A total of 1115 parent-child participants were randomized to one of three intervention arms (enhanced, brief, control). Percentages and 95% confidence intervals compare parents' perception of child readiness to learn about sexual issues, communication effectiveness, and dyad concordance from baseline to 12 months postintervention. Wilcoxon rank sum tests compare the changes in scores measuring communication content in HIV/AIDS, abstinence, and condom use. Compared to control, parents in the enhanced arm increased perception of child readiness to learn about sex (16% vs. 29%; p < .001), and a greater proportion of parent-child dyads reported concordant responses on communication topics: HIV/AIDS (15%, 95% CI = 8-21%; p < .001), abstinence (13%, 95% CI = 7-20%; p < .001), condoms (15%, 95% CI = 9-22%; p < .001). Increases in communication scores in HIV/AIDS, abstinence, and condom use were greater in the enhanced arm than control (p < 0.01). We conclude that the enhanced PMP can help parents educate children about HIV and prepare children to avoid sexual risk. PMID- 22201239 TI - Preliminary efficacy of a computer-delivered HIV prevention intervention for African American teenage females. AB - This study translated SiHLE (Sisters Informing, Healing, Living, and Empowering), a 12-hour Centers for Disease Control and Prevention evidence-based group-level intervention for African American females 14-18 years of age, into a 2-hour computer-delivered individual-level intervention. A randomized controlled trial (n = 178) was conducted to examine the efficacy of the new Multimedia SiHLE intervention. Average condom-protected sex acts (proportion of vaginal sex acts with condoms, last 90 days) for sexually active participants receiving Multimedia SiHLE rose from M = 51% at baseline to M = 71% at 3-month follow-up (t = 2.06, p = .05); no statistically significant difference was found in the control group. Non-sexually active intervention group participants reported a significant increase in condom self-efficacy (t = 2.36, p = .02); no statistically significant difference was found in the control group. The study provides preliminary support for the efficacy of a computer-delivered adaptation of a proven HIV prevention program for African American teenage women. This is consistent with meta-analyses that have shown that computer-delivered interventions, which can often be disseminated at lower per-capita cost than human-delivered interventions, can influence HIV risk behaviors in positive fashion. PMID- 22201240 TI - "The anticipation alone could kill you": past and potential clients' perspectives on HIV testing in non-health care settings. AB - HIV testing in non-health care settings is an effective strategy for increasing the proportion of persons aware of their infection. We conducted 21 focus groups with 186 past and potential clients in five U.S. cities to explore attitudes and experiences related to HIV counseling and testing in non-health care settings. Qualitative analysis yielded several key themes. HIV-related stigma and fear emerged as a main theme throughout the discussions. Knowing one's HIV status quickly and accurately was of primary importance; HIV prevention counseling was secondary. Participants prioritized a supportive, nonjudgmental environment with adequate privacy and confidentiality. Provision of immediate emotional support, medical information, and linkage services to HIV-infected clients were considered essential. Staff with HIV-specific skills to address clients' emotional and informational needs was considered a strength of non-health care testing programs. Frequently, however, participants compared non-health care settings unfavorably to health care settings regarding privacy, competency, confidentiality, and test accuracy. Recommendations for enhancing counseling and testing services in non-health care settings are discussed. PMID- 22201242 TI - The effect of soy isoflavone on bone mineral density. PMID- 22201243 TI - Emotions in context: pictorial influences on affective attributions. AB - The visual illusion Terror Subterra, by Roger Shepard (1990), depicts a seemingly large creature chasing another in a tunnel, yet both creatures are physically identical. In addition to this visual illusion, the two creatures also appear to exhibit different emotions, as the background creature (the pursuer) appears angry whereas the foreground creature (the pursued) appears fearful. We explored this context effect by first establishing the magnitude of the emotional bias effect. We then modified the original drawing in various ways, such as equating for perceived size, removing one creature from the scene, and removing the pictorial context altogether. Findings suggest that the emotional bias is due to the pictorial setting and to the perceived social-emotional relationship between the two creatures. These results highlight the importance of both perceptual and social-emotional influences in driving affective attributions. PMID- 22201244 TI - Revisiting the psychology of intelligence analysis: from rational actors to adaptive thinkers. AB - Intelligence analysis is a decision-making process rife with ambiguous, conflicting, irrelevant, important, and excessive information. The U.S. Intelligence Community is primed for psychology to lend its voice to the "analytic transformation" movement aimed at improving the quality of intelligence analysis. Traditional judgment and decision making research serves as a starting point, though recent developments in decision science advance additional relevant perspectives that are critical to improving intelligence analysis. Naturalistic decision making offers insights into the challenging information world of intelligence analysis and expert judgment. Research on group decision making shows that group processes are often dependent on the distribution of information within the group, while information foraging theory suggests that intelligence analysts may be viewed as "informavores" who use adaptive strategies to form key judgments efficiently. Psychologists should capitalize on these advances in research and theory to engage the intelligence community on its own grounds and take the lead on intelligence analytic reform. A potential research agenda and recommendations to optimize intelligence community effectiveness are offered. PMID- 22201245 TI - Do other-reports of counterproductive work behavior provide an incremental contribution over self-reports? A meta-analytic comparison. AB - Much of the recent research on counterproductive work behaviors (CWBs) has used multi-item self-report measures of CWB. Because of concerns over self-report measurement, there have been recent calls to collect ratings of employees' CWB from their supervisors or coworkers (i.e., other-raters) as alternatives or supplements to self-ratings. However, little is still known about the degree to which other-ratings of CWB capture unique and valid incremental variance beyond self-report CWB. The present meta-analysis investigates a number of key issues regarding the incremental contribution of other-reports of CWB. First, self- and other-ratings of CWB were moderately to strongly correlated with each other. Second, with some notable exceptions, self- and other-report CWB exhibited very similar patterns and magnitudes of relationships with a set of common correlates. Third, self-raters reported engaging in more CWB than other-raters reported them engaging in, suggesting other-ratings capture a narrower subset of CWBs. Fourth, other-report CWB generally accounted for little incremental variance in the common correlates beyond self-report CWB. Although many have viewed self-reports of CWB with skepticism, the results of this meta-analysis support their use in most CWB research as a viable alternative to other-reports. PMID- 22201246 TI - Coordinated action in multiteam systems. AB - This study investigated coordinated action in multiteam systems employing 233 correspondent systems, comprising 3 highly specialized 6-person teams, that were engaged in an exercise that was simultaneously "laboratory-like" and "field like." It enriches multiteam system theory through the combination of theoretical perspectives from the team and the large organization literatures, underscores the differential impact of large size and modular organization by specialization, and demonstrates that conventional wisdom regarding effective coordination in traditional teams and large organizations does not always transfer to multiteam systems. We empirically show that coordination enacted across team boundaries at the component team level can be detrimental to performance and that coordinated actions enacted by component team boundary spanners and system leadership positively impact system performance only when these actions are centered around the component team most critical to addressing the demands of the task environment. PMID- 22201247 TI - The common fate model for dyadic data: variations of a theoretically important but underutilized model. AB - Studying dyads, very often there is a theoretical construct that has an effect on both members, such as relationship harmony or shared environment. To model such influences, the common fate model (CFM) is often the most appropriate approach. In this article, we address conceptual and statistical issues in the use of the standard CFM and present a series of variations, all of which are estimated by structural equation modeling (SEM). For indistinguishable dyad members (e.g., gay couples), we describe the use of a multilevel SEM method. Throughout the paper, we draw connections to the actor-partner interdependence model (APIM). We also discuss the analysis of hybrid models that combines both the CFM and the APIM. The models are illustrated using data from heterosexual couples. PMID- 22201249 TI - Dispositional optimism: a psychological resource for Mexican-origin mothers experiencing economic stress. AB - Dispositional optimism is believed to be an important psychological resource that buffers families against the deleterious consequences of economic adversity. Using data from a longitudinal study of Mexican-origin families (N = 674), we tested a family stress model specifying that maternal dispositional optimism and economic pressure affect maternal internalizing symptoms, which, in turn, affects parenting behaviors and children's social adjustment. As predicted, maternal optimism and economic pressure had both independent and interactive effects on maternal internalizing symptoms, and the effects of these variables on changes over time in child social adjustment were mediated by nurturant and involved parenting. The findings replicate and extend previous research on single-parent African American families (Taylor, Larsen-Rife, Conger, Widaman, & Cutrona, 2010), and demonstrate the generalizability of the positive benefits of dispositional optimism in another ethnic group and type of family structure. PMID- 22201248 TI - Partner aggression in high-risk families from birth to age 3 years: associations with harsh parenting and child maladjustment. AB - Aggression between partners represents a potential guiding force in family dynamics. However, research examining the influence of partner aggression (physically and psychologically aggressive acts by both partners) on harsh parenting and young child adjustment has been limited by a frequent focus on low risk samples and by the examination of partner aggression at a single time point. Especially in the context of multiple risk factors and around transitions such as childbirth, partner aggression might be better understood as a dynamic process. In the present study, longitudinal trajectories of partner aggression from birth to age 3 years in a large, high-risk, and ethnically diverse sample (N = 461) were examined. Specific risk factors were tested as predictors of aggression over time, and the longitudinal effects of partner aggression on maternal harsh parenting and child maladjustment were examined. Partner aggression decreased over time, with higher maternal depression and lower maternal age predicting greater decreases in partner aggression. While taking into account contextual and psychosocial risk factors, higher partner aggression measured at birth and a smaller decrease over time independently predicted higher levels of maternal harsh parenting at age 3 years. Initial level of partner aggression and change over time predicted child maladjustment indirectly (via maternal harsh parenting). The implications of understanding change in partner aggression over time as a path to harsh parenting and young children's maladjustment in the context of multiple risk factors are discussed. PMID- 22201250 TI - Children's questions about interparent conflict and violence: what's a mother to say? AB - This research examined the relation between mothers' responses to children's questions about interparent conflict and children's adjustment. Participants were 134 mothers and their children (70 boys, 64 girls), aged 7 to 10. In each family, an act of intimate-partner violence (IPV) had recently occurred. Mothers' responses to children's questions about interparent conflict were assessed via a semistructured interview coded to reflect the extent to which the mothers' responses addressed the content of the children's questions. Mothers and children reported on physical IPV. Mothers also reported on interparent conflict, parent child aggression, and maternal warmth. Children's adjustment was assessed via mothers' and children's reports at two time points 6 months apart. The extent to which mothers' responses addressed the content of the children's questions about interparent conflict was negatively associated with children's adjustment problems, after accounting for the frequency of physical IPV, frequency of interparent conflict, parent-child aggression, and maternal warmth. These associations emerged cross-sectionally and prospectively. However, in those prospective analyses that accounted for children's baseline levels of adjustment, maternal responsiveness was not associated with later children's adjustment problems. PMID- 22201251 TI - Demand and withdraw behaviors in couples with a history of infidelity. AB - Although relationship distress and dissolution are common consequences of sexual involvement outside a committed relationship, there is little empirical information regarding communication behaviors of couples who have experienced extradyadic involvement (EDI). This study examined male and female demand and withdraw behaviors in videotaped conflict discussions among 170 married or seriously dating couples categorized into 3 groups: those without a history of sexual EDI, those with a history of sexual EDI that was known to the other partner, and those with a history of "unknown" (undisclosed or undiscovered) sexual EDI. Both men and women in a relationship where there was at least one unknown EDI demonstrated the highest levels of demand behaviors. Furthermore, demand behaviors were higher for participating partners (those engaging in an outside sexual relationship) in relationships with an unknown EDI compared with participating partners in relationships with a known EDI. Conversely, demand behaviors were higher among nonparticipating partners in relationships with known EDI, compared to with nonparticipating partners in relationships with unknown EDI. Withdraw behaviors demonstrated a less pronounced and less consistent pattern of elevation by EDI group, and role within EDI, compared with demand behaviors. Clinical and relational implications for these findings are discussed. PMID- 22201252 TI - In situ generation of well-dispersed ZnO quantum dots on electrospun silica nanotubes with high photocatalytic activity. AB - The ZnO quantum dots-SiO(2) nanotubes (ZQDs-SNTs) nanocomposite was successfully fabricated by direct heat treatment of the electrospun zinc acetate/tetraethyl orthosilicate (TEOS)/polymer nanotubes (NTs). The results indicated that the ZnO quantum dots (ZQDs) with diameter about 3-5 nm were highly dispersed on the SiO(2) nanotubes (SNTs). And, there might be Zn-O-Si bonds between ZQDs and SiO(2) matrix, which formed interface states in the ZQDs-SNTs nanocomposite. The photocatalytic studies revealed that the ZQDs-SNTs nanocomposite exhibited high photocatalytic activity to degrade Rhodamine B (RB) under ultraviolet (UV) light irradiation, which might be ascribed to two reasons. The first one was the high dispersity of ZQDs; another one was the high separation efficiency of photogenerated electron-hole pairs due to the trap effect for photogenerated electrons of the interface states between ZQDs and SiO(2). During the photocatalytic reaction, the ZQDs-SNTs nanocomposite also exhibited high chemical stability in a wide range of pH values, which might be ascribed to the protective action of SiO(2) and the presence of Zn-O-Si bonds between ZQDs and SiO(2). Furthermore, the ZQDs-SNTs nanocomposites could be easily recycled because of their one-dimensional nanostructure property. PMID- 22201253 TI - Theoretical investigation on the chiral diamine-catalyzed epoxidation of cyclic enones: mechanism and effects of cocatalyst. AB - The asymmetric epoxidation of 2-cyclohexen-1-one with aqueous H(2)O(2) as oxidant, 1,2-diaminocyclohexane as catalyst, and a Bronsted acid trifluoroacetic acid (TFA) as cocatalyst has been studied by performing density functional theory calculations. It is confirmed that the catalyzed epoxidation proceeds via sequential nucleophilic addition and ring-closure processes involving a ketiminium intermediate. Four possible pathways associated with two Z isomers and two E isomers of ketiminium have been explored in detail. Our calculation indicates that these four pathways have high barriers and a small energy gap between two more favorable R and S pathways. We have analyzed the effects of the TFA anion and H(2)O on the activity and enantioselectivity of catalytic epoxidation. It is found that the TFA anion acts as a counterion to stabilize the transition states of the catalytic epoxidation by hydrogen-bond acceptance, leading to decreases in the barriers of the nucleophilic addition and ring closure processes. The most significant decrease occurred in the ring-closure step of the Z-R-pathway, resulting in H-bond-induced enantioselectivity. Our calculations also show that water cooperates with TFA to further increase the reaction rate significantly. PMID- 22201254 TI - Toxic groundwater contaminants: an overlooked contributor to urban stream syndrome? AB - Screening for common groundwater contaminants was performed along eight urban stream reaches (100s-1000s of m) at approximately 25-75 cm below the streambeds. Four sites had known or suspected chlorinated-solvent plumes; otherwise no groundwater contamination was known previously. At each site, between 5 and 22 contaminants were detected at levels above guideline concentrations for the preservation of aquatic life, while several others were detected at lower levels, but which may still indicate some risk. Contaminants of greatest concern include numerous metals (Cd, Zn, Al, Cu, Cr, U), arsenic, various organics (chlorinated and petroleum), nitrate and ammonium, and chloride (road salt likely), with multiple types occurring at each site and often at the same sampling location. Substantial portions of the stream reaches (from 40 to 88% of locations sampled) possessed one or more contaminants above guidelines. These findings suggest that this diffuse and variable-composition urban groundwater contamination is a toxicity concern for all sites and over a large portion of each study reach. Synergistic toxicity, both for similar and disparate compounds, may also be important. We conclude that groundwater contaminants should be considered a genuine risk to urban stream aquatic ecosystems, specifically benthic organisms, and may contribute to urban stream syndrome. PMID- 22201255 TI - Synthesis and polymerization of substituted ammonium sulfonate monomers for advanced materials applications. AB - Sulfonated polymers have found use as ion-exchange membranes for use in fuel cells, water purification, electroactive devices, and inorganic materials templating and synthesis. Improving the materials for these applications and opening up new applications requires the ability to synthesis targeted or more complex sulfonated polymers, which includes tailoring the chemistry (copolymerization across a wider range of solubility) and/or polymer architecture (block, graft, nanoparticle). This article will summarize the recent work using sulfonated monomers with substituted ammonium counterions as a versatile route for enabling this goal. Two main benefits of these monomers are as follows. First, they are useful for preparing amphiphilic copolymers, which is a challenge using traditional acidic or alkali salt forms of sulfonated monomers. Second, sulfonated polymers with substituted ammonium counterions are useful polymers for obtaining unique material properties, such as organo-gelation of low polarity solvents or obtaining ionic liquid polymers for the fabrication of solid polymer electrolytes. PMID- 22201256 TI - Synthesis of cationic carbosilane dendrimers via click chemistry and their use as effective carriers for DNA transfection into cancerous cells. AB - New amine-terminated carbosilane dendrimers have been prepared by a Huisgen cycloaddition ("click chemistry" reaction) of azide-terminated carbosilane dendrimers with two different propargyl amines. The corresponding cationic derivatives with peripheral ammonium groups were obtained by subsequent addition of MeI. Quaternized dendrimers are soluble and stable in water or other protic solvents for long time periods, and have been studied as nonviral vectors for the transfection of DNA to cancer cells. In this study DNA-dendrimeric nanoparticles (dendriplexes) formulated with two different families of cationic carbosilane dendrimers (family 1 (G1, G2 and G3) and family 2 (G1, G2)) were characterized and evaluated for their ability to transfect cells in vitro and in vivo. Dendriplex derived from second generation dendrimer of family 1 (F1G2 5/1 (+/-)) increased the efficiency of plasmid-mediated gene transfer in HepG2 cells as compared to naked DNA and the commercial control dendrimer. Also, intravenously administered dendriplex F1G3 20/1 (+/-) is superior in terms of gene transfer efficiency in vivo. PMID- 22201257 TI - Green rust formation during Fe(II) oxidation by the nitrate-reducing Acidovorax sp. strain BoFeN1. AB - Green rust (GR) as highly reactive iron mineral potentially plays a key role for the fate of (in)organic contaminants, such as chromium or arsenic, and nitroaromatic compounds functioning both as sorbent and reductant. GR forms as corrosion product of steel but is also naturally present in hydromorphic soils and sediments forming as metastable intermediate during microbial Fe(III) reduction. Although already suggested to form during microbial Fe(II) oxidation, clear evidence for GR formation during microbial Fe(II) oxidation was lacking. In the present study, powder XRD, synchrotron-based XAS, Mossbauer spectroscopy, and TEM demonstrated unambiguously the formation of GR as an intermediate product during Fe(II) oxidation by the nitrate-reducing Fe(II)-oxidizer Acidovorax sp. strain BoFeN1. The spatial distribution and Fe redox-state of the precipitates associated with the cells were visualized by STXM. It showed the presence of extracellular Fe(III), which can be explained by Fe(III) export from the cells or extracellular Fe(II) oxidation by an oxidant diffusing from the cells. Moreover, GR can be oxidized by nitrate/nitrite and is known as a catalyst for oxidation of dissolved Fe(II) by nitrite/nitrate and may thus contribute to the production of extracellular Fe(III). As a result, strain BoFeN1 may contribute to Fe(II) oxidation and nitrate reduction both by an direct enzymatic pathway and an indirect GR-mediated process. PMID- 22201259 TI - Understanding structures and hydrogen bonds of ionic liquids at the electronic level. AB - Due to their unique properties, ionic liquids (ILs) have attracted the academic and industrial attentions. However, recent controversies have focused on what are the main forces to determine the behaviors of ILs. In this work, a detailed DFT calculation was carried out to investigate the intermolecular interactions in two typical ILs, [Emim][BF(4)] and [Bmim][PF(6)]. The results indicate that hydrogen bonds (H-bonds) are the major intermolecular structural feature between cations and anions. Although the electrostatic force remains the major noncovalent force (70% of the total energy by energy decomposition calculation), the interaction energies calculated at different theoretical levels indicate that H-bond and van der Waals interactions cannot be ignored. However, the H-bonded capacities from natural bond orbital (NBO) delocalization energies do not show the consistent changes in the total interaction energies and number of H-bonds. Based on the canonical orbitals analysis, it is found that the sigma-type orbital overlap and the partial charges transfer between anion and cation, finally, result in the significant energy reduction and rationalize the preferable location of anion, which is an essential understanding for the interaction and structure in the ion pair. Additionally, the strong agreement between the experimental IR spectra and the calculated vibrations implies that the structures of the larger ion clusters provide a reasonable depiction for bulk ILs at room temperature condition. PMID- 22201258 TI - Impact of treatment processes on the removal of perfluoroalkyl acids from the drinking water production chain. AB - The behavior of polyfluoralkyl acids (PFAAs) from intake (raw source water) to finished drinking water was assessed by taking samples from influent and effluent of the several treatment steps used in a drinking water production chain. These consisted of intake, coagulation, rapid sand filtration, dune passage, aeration, rapid sand filtration, ozonation, pellet softening, granular activated carbon (GAC) filtration, slow sand filtration, and finished drinking water. In the intake water taken from the Lek canal (a tributary of the river Rhine), the most abundant PFAA were PFBA (perfluorobutanoic acid), PFBS (perfluorobutane sulfonate), PFOS (perfluorooctane sulfonate), and PFOA (perfluorooctanoic acid). During treatment, longer chain PFAA such as PFNA (perfluorononanoic acid) and PFOS were readily removed by the GAC treatment step and their GAC effluent concentrations were reduced to levels below the limits of quantitation (LOQ) (0.23 and 0.24 ng/L for PFOS and PFNA, respectively). However, more hydrophilic shorter chain PFAA (especially PFBA and PFBS) were not removed by GAC and their concentrations remained constant through treatment. A decreasing removal capacity of the GAC was observed with increasing carbon loading and with decreasing carbon chain length of the PFAAs. This study shows that none of the treatment steps, including softening processes, are effective for PFAA removal, except for GAC filtration. GAC can effectively remove certain PFAA from the drinking water cycle.The enrichment of branched PFOS and PFOA isomers relative to non branched isomers during GAC filtration was observed during treatment. The finished water contained 26 and 19 ng/L of PFBA and PFBS. Other PFAAs were present in concentrations below 4.2 ng/L The concentrations of PFAA observed in finished waters are no reason for concern for human health as margins to existing guidelines are sufficiently large. PMID- 22201260 TI - Formation mechanism of carbogenic nanoparticles with dual photoluminescence emission. AB - We present a systematic investigation of the formation mechanism of carbogenic nanoparticles (CNPs), otherwise referred to as C-dots, by following the pyrolysis of citric acid (CA)-ethanolamine (EA) precursor at different temperatures. Pyrolysis at 180 degrees C leads to a CNP molecular precursor with a strongly intense photoluminescence (PL) spectrum and high quantum yield formed by dehydration of CA-EA. At higher temperatures (230 degrees C) a carbogenic core starts forming and the PL is due to the presence of both molecular fluorophores and the carbogenic core. CNPs that exhibit mostly or exclusively PL arising from carbogenic cores are obtained at even higher temperatures (300 and 400 degrees C, respectively). Since the molecular fluorophores predominate at low pyrolysis temperatures while the carbogenic core starts forming at higher temperatures, the PL behavior of CNPs strongly depends on the conditions used for their synthesis. PMID- 22201261 TI - ERCC1 polymorphisms and risk of adult glioma in a Chinese population: a hospital based case-control study. AB - To examine the associations of two polymorphisms in excision repair cross complementing rodent repair deficiency complementation group 1 (ERCC1) gene, C8092A (rs3212986) and T19007C (rs11615), with the risk of adult glioma, we performed a hospital-based case-control study with 257 new cases of glioma and 278 controls in Wenzhou, China. Results showed that polymorphisms C8092A and T19007C in ERCC1 gene were not associated with the risk of glioma in a Chinese population. Further studies in Chinese populations with larger sample sizes are still warranted. PMID- 22201262 TI - Restoring hearing using total ossicular replacement prostheses--analysis of 3D finite element model. AB - CONCLUSIONS: During total ossicular replacement surgery, a better auditory functional recovery is obtained when the stapes footplate is retained. Also, the best hearing restoration is obtained when the total ossicular replacement prosthesis (TORP) is placed onto the center of the stapes footplate during operation. OBJECTIVES: The effects of TORPs connecting to different positions of the stapes footplate or oval window membrane on hearing restoration were investigated. METHODS: A healthy volunteer's right ear was scanned to obtain the CT data, which were digitalized using a self-compiling program and imported into PATRAN software to establish a 3D finite element model, and a harmonic response analysis was carried out using NASTRAN software. Then the effect of TORPs connecting to different positions on the stapes footplate or oval window membrane was studied. RESULTS: The displacement curve of the stapes footplate was in good agreement with that of the normal ear when the TORP was connected onto the center of the stapes footplate. The best hearing restoration was obtained when the TORP was placed onto the center of the stapes footplate. The displacement curve of the stapes footplate was basically equivalent to that of the normal ear when the TORP was connected onto the anterior site, while the displacement curve of the stapes footplate differed from that of the normal ear when the TORP was connected onto the posterior site. In addition, when the TORP was connected onto the oval window membrane, the displacement curve of the stapes footplate was different from that of the normal ear. PMID- 22201263 TI - Evaluating the epidemiology and morbidity burden associated with human papillomavirus in Israel: accounting for CIN1 and genital warts in addition to CIN2/3 and cervical cancer. AB - BACKGROUND: Human papillomavirus (HPV) infection is mostly associated with cervical cancer (CC). However, it can cause other illnesses as well, all of which impact on people's wellbeing and consume healthcare resources. Measures for prevention or early detection of these conditions differ in their effectiveness and cost. An informative evaluation of the projected benefit of these measures depends on understanding the current unmet need, not only limited to CC. OBJECTIVE: To evaluate the burden of HPV-related conditions in Israel, including CC, cervical precancerous lesions and genital warts. METHODS: A retrospective database analysis was conducted for the second largest health management organization (HMO) in Israel, covering approximately 1.8 million people. Records were drawn following a search for key words indicative of related diagnoses, lab results, medications, or procedures for the time period of 2006-2008. Prevalence, incidence and resource utilization were analysed. Findings were extrapolated to the whole Israeli population using age and gender incidence rates. RESULTS: Incidence of CC was found to be 5 per 100,000 females. Incidences of cervical intraepithelial neoplasia (CIN) grades 1, 2 and 3 were 74, 27 and 36 per 100,000 females, respectively. Incidence of genital warts was 239 and 185 per 100,000 for men and women, respectively. The overall annual economic burden was calculated to be $US48,838,058 (year 2010 values). CONCLUSIONS: HPV poses a significant burden in terms of health (clinical and quality of life) and in monetary terms, even for conditions that are sometimes regarded as benign, such as CIN1 or genital warts. Current findings should be used for proper evaluation of measures to reduce HPV related morbidity and mortality, such as regular screening and vaccination. PMID- 22201264 TI - Understanding consumer preferences in the context of managed competition: evidence from a choice experiment in Colombia. AB - BACKGROUND: In many countries, health insurance coverage is the primary way for individuals to access care. Governments can support access through social insurance programmes; however, after a certain period, governments struggle to achieve universal coverage. Evidence suggests that complex individual behaviour may play a role. OBJECTIVES: Using a choice experiment, this research explored consumer preferences for health insurance in Colombia. We also evaluated whether preferences differed across consumers with differing demographic and health status factors. METHODS: A household field experiment was conducted in Bogota in 2010. The sample consisted of 109 uninsured and 133 low-income insured individuals. Each individual evaluated 12 pair-wise comparisons of hypothetical health plans. We focused on six characteristics of health insurance: premium, out of-pocket expenditure, chronic condition coverage, quality of care, family coverage and sick leave. A main effects orthogonal design was used to derive the 72 scenarios used in the choice experiment. Parameters were estimated using conditional logit models. Since price data were included, we estimated respondents' willingness to pay for characteristics. RESULTS: Consumers valued health benefits and family coverage more than other attributes. Additionally, differences in preferences can be exploited to increase coverage. The willingness to pay for benefits may partially cover the average cost of providing them. CONCLUSION: Policy makers might be able to encourage those insured via the subsidized system to enrol in the next level of the social health insurance scheme through expanding benefits to family members and expanding the level of chronic condition coverage. PMID- 22201265 TI - National health insurance reform in South Africa: estimating the implications for demand for private health insurance. AB - BACKGROUND: A recent health reform proposal in South Africa proposes universal access to a comprehensive package of healthcare services in the public sector, through the implementation of a national health insurance (NHI) scheme. Implementation of the scheme is likely to involve the introduction of a payroll tax. It is implied that the introduction of the payroll tax will significantly reduce the size of the private health insurance market. OBJECTIVE: The objective of this study was to estimate the impact of an NHI payroll tax on the demand for private health insurance in South Africa, and to explore the broader implications for health policy. METHODS: The study applies probit regression analysis on household survey data to estimate the change in demand for private health insurance as a result of income shocks arising from the proposed NHI. RESULTS: The introduction of payroll taxes for the proposed NHI was estimated to result in a reduction to private health insurance membership of 0.73%. This suggests inelasticity in the demand for private health insurance. In the literature on the subject, this inelasticity is usually due to quality differences between alternatives. In the South African context, there may be other factors at play. CONCLUSION: An NHI tax may have a very small impact on the demand for private health insurance. Although additional financial resources will be raised through a payroll tax under the proposed NHI reform, systemic problems within the South African health system can adversely affect the ability of the NHI to translate additional finances into better quality healthcare. If these systemic challenges are not adequately addressed, the introduction of a payroll tax could introduce inefficiencies within the South African health system. PMID- 22201266 TI - Insights from triangulation of two purchase choice elicitation methods to predict social decision making in healthcare. AB - BACKGROUND: Discrete choice experiments (DCEs) and the Juster scale are accepted methods for the prediction of individual purchase probabilities. Nevertheless, these methods have seldom been applied to a social decision-making context. OBJECTIVE: To gain an overview of social decisions for a decision-making population through data triangulation, these two methods were used to understand purchase probability in a social decision-making context. METHODS: We report an exploratory social decision-making study of pharmaceutical subsidy in Australia. A DCE and selected Juster scale profiles were presented to current and past members of the Australian Pharmaceutical Benefits Advisory Committee and its Economic Subcommittee. RESULTS: Across 66 observations derived from 11 respondents for 6 different pharmaceutical profiles, there was a small overall median difference of 0.024 in the predicted probability of public subsidy (p = 0.003), with the Juster scale predicting the higher likelihood. While consistency was observed at the extremes of the probability scale, the funding probability differed over the mid-range of profiles. There was larger variability in the DCE than Juster predictions within each individual respondent, suggesting the DCE is better able to discriminate between profiles. However, large variation was observed between individuals in the Juster scale but not DCE predictions. CONCLUSIONS: It is important to use multiple methods to obtain a complete picture of the probability of purchase or public subsidy in a social decision-making context until further research can elaborate on our findings. This exploratory analysis supports the suggestion that the mixed logit model, which was used for the DCE analysis, may fail to adequately account for preference heterogeneity in some contexts. PMID- 22201267 TI - Nanoscale organization of mitochondrial microcompartments revealed by combining tracking and localization microscopy. AB - While detailed information on the nanoscale-organization of proteins within intracellular membranes has emerged from electron microcopy, information on their spatiotemporal dynamics is scarce. By use of a photostable rhodamine attached specifically to Halo-tagged proteins in mitochondrial membranes, we were able to track and localize single protein complexes such as Tom20 and ATP synthase in suborganellar structures in live cells. Individual membrane proteins in the inner and outer membrane of mitochondria were imaged over long time periods with localization precisions below 15 nm. Projection of single molecule trajectories revealed diffusion-restricting microcompartments such as individual cristae in mitochondria. At the same time, protein-specific diffusion characteristics within different mitochondrial membranes could be extracted. PMID- 22201268 TI - Preoperative aspirin is safe in patients undergoing urologic robot-assisted surgery. AB - PURPOSE: To determine the impact of preoperative aspirin on bleeding and other complications in patients undergoing robot-assisted radical prostatectomy and nephrectomy. PATIENTS AND METHODS: We identified all patients who underwent robot assisted radical prostatectomy or robot-assisted nephrectomy by a single surgeon between August 2008 and August 2010. We compared patients in whom aspirin had not been administered for 7 days with those who received aspirin the morning of surgery. Patients on other antiplatelet agents or anticoagulants were excluded. RESULTS: Forty-four patients underwent prostatectomy without recent aspirin, and 51 received preoperative aspirin. There were no significant differences between the two groups in terms of age, body mass index, American Society of Anesthesiologists score, prostate-specific antigen level, or highest Gleason score. Operative time (182 vs 174 min, P=0.19), median blood loss (175 vs 100 mL, P=0.12), and duration of hospital stay (1 vs 1 day, P=0.08) were similar between the two groups, respectively. No patient received a transfusion. Three patients who had not received aspirin and one who had were readmitted within 30 days. In the nephrectomy cohort, 12 patients had not received aspirin and 14 had. There were no differences in median blood loss (65 vs 50 mL, P=0.96), median operative time (176 vs 140 min, P=0.14), or median hospital stay (2 vs 2 days, P=0.74). No patient received a transfusion. CONCLUSIONS: The administration of aspirin to patients undergoing robot-assisted radical prostatectomy and nephrectomy appears to be safe. The risk of cardiovascular complications resulting from stopping aspirin may exceed the risk of perioperative bleeding and associated complications. PMID- 22201269 TI - Modulation of transcription factor Nrf2 in an in vitro model of traumatic brain injury. AB - Traumatic brain injury (TBI) afflicts approximately 1.4 million people in the United States and TBIs have been labeled a major cause of death and disability on a global scale. Regulatory responses in a variety of neuronal loss conditions have supported the protective involvement of the nuclear factor (erythroid derived 2)-like 2 (Nrf2) transcription factor. Nrf2 regulates antioxidant enzyme genes, and an increase in Nrf2 expression may counteract oxidative damage that results from TBI. Elevated Nrf2 may ultimately act through the upregulation of downstream target genes such as thioredoxin (Trx) and heat-shock protein-70 (HSP70) and this may reduce neuronal loss. We performed multiple mild biaxial stretch injuries to neuroblastoma cells in culture, and examined the effects of the Nrf2 activator, tert-butylhydroquinone (tBHQ). We also compared the stretch injury to oxidative insult. We confirmed that Trx and HSP70 were upregulated by treatment with tBHQ. We observed that tBHQ protected neurons from either insult, and that this was evident by different measures of cell viability and a decrease in annexin V binding. Neuronal health after insult was improved approximately 50% by tBHQ, indicating that neurons exposed to TBI in vitro can be protected. PMID- 22201271 TI - Comparative study of computerized dynamic posturography and the SwayStar system in healthy subjects. AB - CONCLUSIONS: For healthy subjects, posturography and SwayStarTM results are basically comparable, when they are obtained under the same sensory stimulation conditions. However, the management of the information and the mathematical analyses in the two systems are not comparable. OBJECTIVES: Postural control represents man's ability to maintain the center of pressures inside the limits of stability. Posturography is a set of techniques that objectively studies and quantifies the postural control. The present study analyzed the different parameters of the dynamic computerized posturography and SwayStar systems related to balance, to determine whether the results of the two systems in the same healthy subject are equivalent. METHODS: Seventy healthy individuals, with a mean age of 44.9 years, were homogeneously divided into seven age groups. Postural studies with a Neurocom((r)) Smart Balance Master posturography platform (sensorial organization test), with the SwayStar((r)) system (14 tests), and another sensorial organization test were recorded simultaneously with the two posturographs. The Pearson correlation test was used for the statistical study (p < 0.05). RESULTS: Comparison of the independent records showed correlation only in the Romberg position with eyes closed on a normal surface and in the Romberg position with open eyes on moving/foam surface. We found correlation for all conditions when simultaneously recorded. PMID- 22201272 TI - Development and description of the culture/climate assessment scale. AB - This article describes the development, implementation, and preliminary psychometric testing of the Culture/Climate Assessment Scale (CCAS), designed and used by a school of nursing. The CCAS comprises 37 items arranged into five scales of communication, decision support, level of conflict, teamwork, and general work satisfaction, as well as three additional items that measure personal level of stress, perceived level of change, and overall level of morale. Faculty and staff completed the CCAS in three progressive administrations over a 5-year period to provide empirical data to chart the progress to improve the organizational culture and climate of one school of nursing. Preliminary testing of the CCAS supports its continued use in nursing education and other academic environments. PMID- 22201273 TI - Using transformational change to improve organizational culture and climate in a school of nursing. AB - A positive organizational culture and climate is closely associated with an affirming workplace and job satisfaction. Especially during a time of faculty shortages, academic leaders need to be cognizant of the culture and climate in schools of nursing. The culture of an organization affects employees, systems, and processes, and if the culture becomes problematic, transformational leadership is essential to create change. The purpose of this article is to describe an 8-year journey to change the culture and climate of a school of nursing from one of dissatisfaction and distrust to one of high employee satisfaction and trust. Kotter's model for transformational change was used to frame a longitudinal study using the Cultural and Climate Assessment Scale to transform the organizational culture and climate of a school of nursing. PMID- 22201274 TI - Simulation stimulates learning in a childbearing clinical course. AB - Preparing nursing students to become integral members of today's health care team presents educators with unique challenges in both classroom and clinical settings. This study examined the effectiveness of adding high-fidelity simulation to a childbearing clinical course. Our systematic research addressed the importance of evaluating the outcomes of using simulation on both knowledge acquisition and clinical competency. We found simulation to have a positive effect on not only student clinical performance, but also knowledge development in the undergraduate child-bearing clinical course. These outcome data will inform the curriculum changes needed as we strive to facilitate student proficiency in clinical concepts and skills and prepare the next generation of nurses entering our increasingly complex health care system. PMID- 22201275 TI - Development and pilot testing of the faculty advisor evaluation questionnaire. AB - The importance of academic advising has been established in part by its designation as an element in the American Association of Colleges of Nursing's Standards for Accreditation. In addition, academic advising plays an essential role in students' development, academic success, satisfaction, recruitment, and retention; therefore, access to valid and reliable evaluation tools is of considerable importance. The purpose of this study was to develop and pilot test the Faculty Advisor Evaluation Questionnaire (FAEQ), which is an instrument developed from qualitative nursing research. The psychometric properties were explored using face and content validity, internal consistency reliability, and principle components factor analysis. The four-factor solution of the resulting 30-item questionnaire accounted for 81% of the variability. Cronbach's alpha values of the four factors ranged from 0.885 to 0.974. The FAEQ should elicit valid and reliable results, although further testing is needed to validate the findings in a larger and more diverse sample. PMID- 22201276 TI - Overcoming all obstacles: a framework for embedding interprofessional education into a large, multisite Bachelor of Science Nursing program. AB - As the delivery of health care becomes more complex and challenging, the need for all health care professionals to collaborate as a team has been identified. Nurses are an integral part of the health care team, so it is critical that their education prepare them for interprofessional collaborative practice. Although many academic settings are currently offering interprofessional education (IPE) in the form of compulsory and elective activities and courses, it may not be enough nor an option for programs with large volumes of students who are distributed across a variety of sites and locations. This article outlines a framework that has been successfully adopted by one large school of nursing that chose to integrate interprofessional competencies throughout its curriculum. This IPE agenda is cost-effective, sustainable, and accessible, and it can be adapted to meet the needs of other prelicensure programs that face similar obstacles or challenges with offering IPE. PMID- 22201277 TI - Biological and clinical significance of p75NTR expression in laryngeal squamous epithelia and laryngocarcinoma. AB - CONCLUSION: The apparent features of p75 neurotrophin receptor (p75(NTR)) expression indicated that p75(NTR) would serve as a potential stem cell marker for normal human laryngeal squamous epithelia. In human laryngeal squamous cell carcinoma (LSCC) p75(NTR) is differentially expressed. The abnormal expression and distribution of p75(NTR) may indicate malignant transformation. OBJECTIVE: To investigate the expression of p75(NTR) and its possible roles in normal laryngeal squamous epithelia and LSCC. METHODS: We used immunohistochemistry methods to examine normal laryngeal epithelia, para-cancer mucosa with dysplasia, laryngeal papilloma, and LSCC specimens for the expression of p75(NTR), nerve growth factor (NGF), -tyrosine kinase receptor (TrkA), p63, and Ki67. Immunocytochemistry and flow cytometry were used to examine the expression of p75(NTR) in Hep-2 cells. RESULTS: The expression of p75(NTR) was only located in basal cells of normal laryngeal epithelia, consistent with the staining features of epithelial stem cells as evidenced by parallel staining of p63, a putative keratinocyte stem cell marker. p75(NTR) is differentially expressed in LSCC, although no significant relationship was found with many clinicopathologic factors, this expression and distribution may correlate to malignant transformation and tumor proliferation. Co-expression of p75(NTR) and CD133 was confirmed, showing the association of p75(NTR)-positive cells with cancer stem cells in Hep-2 cells. PMID- 22201278 TI - Does the perception that stress affects health matter? The association with health and mortality. AB - OBJECTIVE: This study sought to examine the relationship among the amount of stress, the perception that stress affects health, and health and mortality outcomes in a nationally representative sample of U.S. adults. METHODS: Data from the 1998 National Health Interview Survey were linked to prospective National Death Index mortality data through 2006. Separate logistic regression models were used to examine the factors associated with current health status and psychological distress. Cox proportional hazard models were used to determine the impact of perceiving that stress affects health on all-cause mortality. Each model specifically examined the interaction between the amount of stress and the perception that stress affects health, controlling for sociodemographic, health behavior, and access to health care factors. RESULTS: 33.7% of nearly 186 million (unweighted n = 28,753) U.S. adults perceived that stress affected their health a lot or to some extent. Both higher levels of reported stress and the perception that stress affects health were independently associated with an increased likelihood of worse health and mental health outcomes. The amount of stress and the perception that stress affects health interacted such that those who reported a lot of stress and that stress impacted their health a lot had a 43% increased risk of premature death (HR = 1.43, 95% CI [1.2, 1.7]). CONCLUSIONS: High amounts of stress and the perception that stress impacts health are each associated with poor health and mental health. Individuals who perceived that stress affects their health and reported a large amount of stress had an increased risk of premature death. PMID- 22201280 TI - Effects of prior light exposure on early evening performance, subjective sleepiness, and hormonal secretion. AB - In sighted humans, light intensity, timing, exposure duration, and spectral composition of light are important to entrain the endogenous circadian pacemaker to the 24-h day-night cycle. We tested the impact of two realistic office lighting conditions during the afternoon on subjective sleepiness, hormonal secretion, and cognitive performance in the early evening hours. Twenty-nine young subjects came twice and spent 8 h (12:00-20:00) in our laboratory, where they were exposed for 6 h to either artificial light (AL) or to mainly daylight (DL). In the early evening, we assessed their salivary cortisol and melatonin secretion, subjective sleepiness, and cognitive performance (n-back test) under dim light conditions. Subjects felt significantly more alert at the beginning of the evening after the DL condition, and they became sleepier at the end of the evening after the AL condition. For cognitive performance we found a significant interaction between light conditions, mental load (2- or 3-back task) and the order of light administration. On their first evening, subjects performed with similar accuracy after both light conditions, but on their second evening, subjects performed significantly more accurately after the DL in both n-back versions and committed fewer false alarms in the 2-back task compared to the AL group. Lower sleepiness in the evening was significantly correlated with better cognitive performance (p < .05). In summary, even short-term lighting conditions during the afternoon had an impact on cognitive task performance in the evening. This rapid effect was only distinguishable on the second day of training, when a difficult task had been sufficiently practiced. PMID- 22201282 TI - Nanocrystalline brookite with enhanced stability and photocatalytic activity: influence of lanthanum(III) doping. AB - Metastable TiO(2) polymorphs are more promising materials than rutile for specific applications such as photocatalysis or catalysis support. This was clearly demonstrated for the anatase phase but still under consideration for brookite, which is difficult to obtain as pure phase. Moreover, the surface doping of anatase with lanthanum ions is known to both increase the thermal stability of the metastable phase and improve its photocatalytic activity. In this study, TiO(2) nanoparticles of almost only the brookite structure were prepared by a simple sol-gel procedure in aqueous solution. The nanoparticles were then doped with lanthanum(III) ions. The thermal stability of the nanoparticles was analyzed by X-ray diffraction and kinetic models were successfully applied to quantify phases evolutions. The presence of surface sorbed lanthanum(III) ions increased the phase stability of at least 200 degrees C and this temperature shift was attributed to the selective phase stabilization of metastable TiO(2) polymorphs. Moreover, the combination of the surface doping ions and the thermal treatment induces the vanishing of the secondary anatase phase, and the photocatalytic tests on the doped brookite nanoparticles demonstrated that the doping increased photocatalytic activity and that the extent depended on the duration of the sintering treatment. PMID- 22201283 TI - Assignment of aluminum corroles absorption bands to electronic transitions by femtosecond polarization resolved VIS-pump IR-probe spectroscopy. AB - We combine femtosecond polarization resolved VIS-pump IR-probe spectroscopy with DFT and TD-DFT calculations to identify and assign absorption bands to electronic transitions for corroles. These macrocycles and their corresponding metal complexes are receiving great attention because of their utility in many fields, while many of their spectroscopic features have not yet been fully described. Analysis of the perturbed free induction decay provides information about the bleaching signal at time zero and allows for determination of overlapping excited state and bleaching signal amplitudes. The S(0) -> S(1) and S(0) -> S(2) transitions in the Q-band of the hexacoordinated Al(tpfc)(py)(2) and Br(8)Al(tpfc)(py)(2) absorption spectra are explicitly assigned. Angles between these electronic transition dipole moments (tdms) with a single vibrational transition dipole moment of (53 +/- 2) degrees and (34 +/- 2) degrees when excited at 580 and 620 nm for hexacoordinated Al(tpfc)(py)(2) and (51 +/- 2) degrees and (43 +/- 2) degrees when excited at 590 and 640 nm for hexacoordinated Br(8)Al(tpfc)(py)(2) were determined. The relative angles between the two lowest electronic tdms are (90 +/- 8) degrees and (94 +/- 3) degrees for Al(tpfc)(py)(2) and Br(8)Al(tpfc)(py)(2), respectively. Angles are determined before time zero by polarization resolved perturbed free induction decay and after time zero by polarization resolved transients. Comparison of corrole's wave functions with those of porphine show that the reduced symmetry in the corrole molecules results in lifting of Q-band degeneracy and major reorientation of the electronic transition dipole moments within the molecular scaffold. This information is necessary in designing optimal corrole-based electron and energy transfer complexes. PMID- 22201281 TI - To modulate and be modulated: estrogenic influences on auditory processing of communication signals within a socio-neuro-endocrine framework. AB - Gonadal hormones modulate behavioral responses to sexual stimuli, and communication signals can also modulate circulating hormone levels. In several species, these combined effects appear to underlie a two-way interaction between circulating gonadal hormones and behavioral responses to socially salient stimuli. Recent work in songbirds has shown that manipulating local estradiol levels in the auditory forebrain produces physiological changes that affect discrimination of conspecific vocalizations and can affect behavior. These studies provide new evidence that estrogens can directly alter auditory processing and indirectly alter the behavioral response to a stimulus. These studies show that: 1) Local estradiol action within an auditory area is necessary for socially relevant sounds to induce normal physiological responses in the brains of both sexes; 2) These physiological effects occur much more quickly than predicted by the classical time-frame for genomic effects; 3) Estradiol action within the auditory forebrain enables behavioral discrimination among socially relevant sounds in males; and 4) Estradiol is produced locally in the male brain during exposure to particular social interactions. The accumulating evidence suggests a socio-neuro-endocrinology framework in which estradiol is essential to auditory processing, is increased by a socially relevant stimulus, acts rapidly to shape perception of subsequent stimuli experienced during social interactions, and modulates behavioral responses to these stimuli. Brain estrogens are likely to function similarly in both songbird sexes because aromatase and estrogen receptors are present in both male and female forebrain. Estrogenic modulation of perception in songbirds and perhaps other animals could fine-tune male advertising signals and female ability to discriminate them, facilitating mate selection by modulating behaviors. PMID- 22201285 TI - Influence of real-world engine load conditions on nanoparticle emissions from a DPF and SCR equipped heavy-duty diesel engine. AB - The experiments aimed at investigating the effect of real-world engine load conditions on nanoparticle emissions from a Diesel Particulate Filter and Selective Catalytic Reduction after-treatment system (DPF-SCR) equipped heavy duty diesel engine. The results showed the emission of nucleation mode particles in the size range of 6-15 nm at conditions with high exhaust temperatures. A direct result of higher exhaust temperatures (over 380 degrees C) contributing to higher concentration of nucleation mode nanoparticles is presented in this study. The action of an SCR catalyst with urea injection was found to increase the particle number count by over an order of magnitude in comparison to DPF out particle concentrations. Engine operations resulting in exhaust temperatures below 380 degrees C did not contribute to significant nucleation mode nanoparticle concentrations. The study further suggests the fact that SCR equipped engines operating within the Not-To-Exceed (NTE) zone over a critical exhaust temperature and under favorable ambient dilution conditions could contribute to high nanoparticle concentrations to the environment. Also, some of the high temperature modes resulted in DPF out accumulation mode (between 50 and 200 nm) particle concentrations an order of magnitude greater than typical background PM concentrations. This leads to the conclusion that sustained NTE operation could trigger high temperature passive regeneration which in turn would result in lower filtration efficiencies of the DPF that further contributes to the increased solid fraction of the PM number count. PMID- 22201284 TI - Field, experimental, and modeling study of arsenic partitioning across a redox transition in a Bangladesh aquifer. AB - To understand redox-dependent arsenic partitioning, we performed batch sorption and desorption experiments using aquifer sands subjected to chemical and mineralogical characterization. Sands collected from the redox transition zone between reducing groundwater and oxic river water at the Meghna riverbank with HCl extractable Fe(III)/Fe ratio ranging from 0.32 to 0.74 are representative of the redox conditions of aquifers common in nature. One brown suboxic sediment displayed a partitioning coefficient (K(d)) of 7-8 L kg(-1) at equilibrium with 100 MUg L(-1) As(III), while two gray reducing sediments showed K(d) of 1-2 L kg( 1). Lactate amendment to aquifer sands containing 91 mg kg(-1) P-extractable As resulted in the reduction of As and Fe with sediment Fe(III)/Fe decreasing from 0.54 to 0.44, and mobilized an equivalent of 64 mg kg(-1) As over a month. Desorption of As from nonlactate-amended sediment was negligible with little change in sediment Fe(III)/Fe. This release of As is consistent with microbial reduction of Fe(III) oxyhydroxides and the resulting decrease in the number of surface sites on Fe(III) oxyhydroxides. Arsenic partitioning (K(d)) in iron-rich, sulfur-poor aquifers with circumneutral pH is redox-dependent and can be estimated by HCl leachable sediment Fe(III)/Fe ratio with typical Fe concentrations. PMID- 22201286 TI - Diazo transfer and click chemistry in the solid phase syntheses of lysine-based glycodendrimers as antagonists against Escherichia coli FimH. AB - Uropathogenic Escherichia coli infections, ultimately leading to cystitis and pyelonephritis, are initially mediated by the adhesion of the bacterial FimH to the transmembrane glycoprotein uroplakin-1a present at the surface of urothelial cells. The adhesion is based on the recognition and high avidity binding between the high-mannose glycans of the uroplakin and the FimH, a mannose-specific lectin located at the tip of type 1 fimbriae. We found that synthetic multiantennary mannopyranosides glycodendrons, harboring triazole functionality at the anomeric position, were potent hemagglutination inhibitors of guinea pig erythrocytes and E. coli. A mannosylated dendrimer exposing up to sixteen sugar residues showed an HAI titer of 1 MUM and was thus 500-fold more potent than the corresponding monovalent methyl alpha-d-mannopyranoside. The synthesis of the glycodendrons involved highly efficient solid-phase synthesis of branched l-lysine scaffolds, diazo transfer reaction on the terminal amine residues, and 1,3-dipolar copper catalyzed azide-alkyne cycloaddition using propargyl alpha-d-mannopyranoside. PMID- 22201287 TI - Positioning of antioxidant quercetin and its metabolites in lipid bilayer membranes: implication for their lipid-peroxidation inhibition. AB - Among numerous biological activities, natural polyphenols are antioxidants widely distributed in plants capable of inhibiting lipid peroxidation, which belongs to the most serious degenerative cell processes. Positioning of antioxidants in lipid bilayers can provide an insight to the lipid-peroxidation inhibition at the molecular level. This work aims at determining the location and orientation of quercetin and its most representative (glucuronidated, methylated, and sulfated) metabolites in lipid bilayer via molecular dynamic simulations. We show that quercetin derivatives penetrate the lipid bilayer and that the depths of penetration depend on molecular charge and substitutional variations. In the presence of charged substituents (sulfates and glucuronidates), the molecule is pulled toward the lipid bilayer surface. The orientation also depends on substitution as H-bonds are formed between the polar head groups of the bilayer and the (i) OH groups, (ii) sugar, and (iii) sulfate moieties of the antioxidants. As flavonoids and their derivatives are preferentially localized in the lipid bilayer membrane or on the bilayer/water interface, they readily concentrate in a relatively narrow membrane region. Despite the low concentrations of flavonoids in food, their spatial confinement in the membrane greatly enhances their local concentration in this vital region, thus increasing their importance for in vivo biological activities including oxidative stress defense. PMID- 22201288 TI - Discrete assembly of synthetic peptide-DNA triplex structures from polyvalent melamine-thymine bifacial recognition. AB - We have designed a 21-residue alpha-peptide that simultaneously recognizes two decadeoxyoligothymidine (dT(10)) tracts to form triplexes with a peptide-DNA strand ratio of 1:2. The synthetic peptide side chain displays 10 melamine rings, which provide a bifacial thymine-recognition interface along the length of the 21 residue peptide. Recognition is selective for thymine over other nucleobases and drives the formation of ternary peptide.[dT(10)](2) complexes as well as heterodimeric peptide.[dT(10)C(10)T(10)] hairpin structures with triplex stems. PMID- 22201289 TI - Comparison of the diagnostic value of 3 T MRI after intratympanic injection of GBCA, electrocochleography, and the glycerol test in patients with Meniere's disease. AB - CONCLUSION: 3 T MRI after intratympanic injection of gadolinium-based contrast agent (GBCA) is more useful for the diagnosis of endolymphatic hydrops compared with the glycerol test and electrocochleography (ECoG). OBJECTIVE: To investigate the relationship between 3 T MRI after intratympanic injection of GBCA, the glycerol test, and ECoG in patients with Meniere's disease (MD). METHODS: A total of 20 patients with MD were evaluated. Diluted gadodiamide (a gadolinium-based contrast agent) was administered to the bilateral tympanic cavity by injection through the tympanic membrane. After 24 h, the endolymphatic hydrops was evaluated by a 3.0 T MR scanner. To investigate cochlear hydrops, the glycerol test and ECoG were carried out in all patients. RESULTS: A positive result was observed in 11 patients (55%) in the glycerol test and in 12 patients (60%) by ECoG. The incidence of positive findings when evaluating the same patients with both the glycerol test and ECoG increased to 75%. Nineteen of 20 (95%) patients showed positive results for 3 T MRI. PMID- 22201291 TI - Attendance at a psychological support group for people with multiple sclerosis and low mood. AB - PURPOSE: A cognitive behavioural group promoting psychological adjustment for people with multiple sclerosis (MS) was found to reduce psychological distress. Not all those offered treatment attended the group sessions. The aims were to examine the rates of attendance and to evaluate feedback from participants. METHOD: Participants with MS and low mood were recruited to a randomized trial comparing attendance at a psychological support group with a usual care control group. The attendance at each session was determined and those who attended were compared with those who failed to attend using a Mann-Whitney U-test or chi squared. A sample of participants completed a telephone feedback questionnaire to determine their views of the group. RESULTS: The 44 participants who attended four or more sessions were not significantly different from the 28 who attended fewer than four sessions on demographic variables, disability, self-efficacy or quality of life, but significantly fewer men attended than women (p = 0.03). Participants' feedback from the group was mainly positive, and no factors were identified associated with non-attendance. CONCLUSIONS: Men were less likely to attend group treatment sessions than women, but no other variables were associated with non-attendance. Attendance rates influence the effectiveness of interventions and reasons for non-attendance need to be determined. PMID- 22201292 TI - Development of FRET-based ratiometric fluorescent Cu2+ chemodosimeters and the applications for living cell imaging. AB - Coumarin-rhodamine-based compounds 1a,b were rationally designed and synthesized as novel FRET ratiometric fluorescent chemodosimeters. Ratiometric chemodosimeters 1a,b exhibit several favorable features, including a large variation in the emission ratio, well-resolved emission peaks, high sensitivity, high selectivity, low cytotoxicity, and good cell membrane permeability. Importantly, these excellent attributes enable us to demonstrate ratiometric imaging of Cu(2+) in living cells by using these novel ratiometric fluorescent chemodosimeters. PMID- 22201290 TI - Small-molecule-modified surfaces engage cells through the alphavbeta3 integrin. AB - Integrins play myriad and vital roles in development and disease. They connect a cell with its surroundings and transmit chemical and mechanical signals across the plasma membrane to the cell's interior. Dissecting their roles in cell behavior is complicated by their overlapping ligand specificity and shared downstream signaling components. In principle, immobilized synthetic peptides can mimic extracellular matrix proteins by supporting integrin-mediated adhesion, but most short peptide sequences lack selectivity for one integrin over others. In contrast, synthetic integrin antagonists can be highly selective. We hypothesized that this selectivity could be exploited if antagonists, when immobilized, could support cellular adhesion and activate signaling by engaging specific cell surface integrins. To investigate this possibility, we designed a bifunctional (RGD)-based peptidomimetic for surface presentation. Our conjugate combines a high affinity integrin ligand with a biotin moiety; the former engages the alpha(v)beta(3) integrin, and the latter allows for presentation on streptavidin coated surfaces. Surfaces decorated with this ligand promote both cellular adhesion and integrin activation. Moreover, the selectivity of these surfaces for the alpha(v)beta(3) integrin can be exploited to capture a subset of cells from a mixed population. We anticipate that surfaces displaying highly selective small molecule ligands can reveal the contributions of specific integrin heterodimers to cell adhesion and signaling. PMID- 22201293 TI - Poly(ethylene glycol)-based multidentate oligomers for biocompatible semiconductor and gold nanocrystals. AB - We have developed a new set of multifunctional multidentate OligoPEG ligands, each containing a central oligomer on which were laterally grafted several short poly(ethylene glycol) (PEG) moieties appended with either thioctic acid (TA) or terminally reactive groups. Reduction of the TAs (e.g., in the presence of NaBH(4)) provides dihydrolipoic acid (DHLA)-appended oligomers. Here the insertion of PEG segments in the ligand structure promotes water solubility and reduces nonspecific interactions, while TA and DHLA groups provide multidentate anchoring onto Au nanoparticles (AuNPs) and ZnS-overcoated semiconductor quantum dots (QDs), respectively. The synthetic route involves simple coupling chemistry using N,N-dicylohexylcarbodiimide (DCC). Water-soluble QDs and AuNPs capped with these ligands were prepared via cap exchange. As prepared, the nanocrystals dispersions were aggregation-free, homogeneous, and stable for extended periods of time over pH ranging from 2 to 14 and in the presence of excess electrolyte (2 M NaCl). The new OligoPEG ligands also allow easy integration of tunable functional and reactive groups within their structures (e.g., azide or amine), which imparts surface functionalities to the nanocrystals and opens up the possibility of bioconjugation with specific biological molecules. The improved colloidal stability combined with reactivity offer the possibility of using the nanocrystals as biological probes in an array of complex and biologically relevant media. PMID- 22201294 TI - Implementing an influenza vaccination programme for adults aged >=65 years in Poland: a cost-effectiveness analysis. AB - BACKGROUND AND OBJECTIVES: Influenza is a common respiratory disease occurring in seasonal patterns, and may lead to severe complications in frail populations such as the elderly. In Poland, influenza vaccination is recommended for people aged >=65 years; however the vaccine coverage rate in the elderly is very low. The fact that influenza vaccine is neither reimbursed by the National Health Insurance (Narodowy Fundusz Zdrowia [NFZ]) nor financed via a National Immunization Program (NIP) could be a reason for the low coverage rate. This study assessed the cost effectiveness of the full reimbursement of an influenza vaccination programme in Poland for people aged >=65 years. METHODS: A decision analytic model was developed to compare costs and outcomes associated with the current situation in which influenza vaccination is not reimbursed and a new situation in which it would be fully covered by the NFZ. The model was parameterized to Poland using data from the literature and from the Central Statistic Office of Poland. Within the elderly population, 50% were considered to be at high risk of influenza complications. An influenza attack rate of 3.5% was used for calculation purposes. Influenza-associated hospitalizations and death rates were estimated at 439.9 per 100 000 person-years and 79.1 per 100 000 person-years, respectively. Cost estimates were derived from a cost study conducted in Poland. Costs are presented in Polish Zloty (PLN) [2009 mean exchange rate: 1 PLN = ?0.232]. Only direct medical costs were included to fit to the NFZ perspective. To reflect the seasonality of influenza, a time horizon of 1 year was chosen. Life-years and quality-adjusted life-years (QALYs) accumulated over future years were discounted at a rate of 5% as recommended by Polish guidelines. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: In Poland, the introduction of the public funding of influenza vaccination for people aged >=65 years would cost PLN 79 million when an increase in coverage rate from 13.5% to 40% is assumed. 23 900 cases of influenza, 1777 hospitalizations and 548 premature deaths would be averted each year due to the influenza vaccination programme. Fifty-seven persons would need to be vaccinated to prevent one case of influenza. To prevent one hospitalization and one death due to influenza, 842 and 2809 individuals would need to be vaccinated, respectively. The new strategy would be very cost effective compared with the current situation with an incremental cost-effectiveness ratio (ICER) of PLN26 118/QALY, which is below the 2009 yearly gross domestic product (GDP) per capita. Deterministic sensitivity analyses demonstrated that the most influential variables for the ICER were vaccine efficacy against death, excess hospitalization rate, utility norms, influenza attack rate, vaccine efficacy against hospitalization, and discount rates. All ICERs computed were below the threshold of 3 GDP per capita. From the probabilistic analysis, the proposed new influenza vaccination programme, if implemented, was predicted to be cost effective from the NFZ perspective with a probability of 100%, given the same threshold. CONCLUSION: Implementing a vaccination programme in Poland in which influenza vaccination would be fully reimbursed by the NFZ for people aged >=65 years would be a very cost-effective strategy. PMID- 22201296 TI - Outcomes of uvulopalatopharyngoplasty with harmonic scalpel after failure of continuous positive airway pressure in sleep apnea syndrome. AB - CONCLUSIONS: Our data highlight that uvulopalatopharyngoplasty (UPPP) with harmonic scalpel (HS) is a reliable treatment in selected patients affected by obstructive sleep apnea (OSA) and users of continuous positive airway pressure (CPAP). OBJECTIVES: The aim of this paper was to verify the efficacy and applicability of UPPP with HS in the treatment of patients affected by OSA and users of CPAP. METHODS: A total of 21 patients with a retropalatal obstruction and users of CPAP underwent UPPP with HS and were evaluated (before and 6 months after surgery) using the apnea/hypopnea index (AHI); oxygen desaturation index >=4% (ODI(4)); Epworth Sleepiness Scale (ESS); snoring level (SL); subjective assessment of the postoperative pain on postoperative days 1, 3, and 10; and number of days until return to solid food. RESULTS: Six months after surgery: AHI decreased significantly (p < 0.05) from 31.8 +/- 2.83 to 9.0 +/- 0.68; ODI(4) was 2.1 +/- 0.4 vs a preoperative value of 24.0 +/- 1.9; ESS scores were also significantly decreased (p < 0.05) from 14.0 +/- 3.7 to 4.7 +/- 2.2; SL was significantly lower (p < 0.05) 1.6 +/- 0.3 vs 7.9 +/- 0.8. Postoperatively, patients experienced lower levels of pain and the median of time to return to normal diet was 3 days. PMID- 22201295 TI - Flucloxacillin and diclofenac do not cause recurrence of neuromuscular blockade after reversal with sugammadex. AB - BACKGROUND: Sugammadex, a modified gamma-cyclodextrin, facilitates rapid reversal of rocuronium- and vecuronium-induced neuromuscular blockade (NMB). Cyclodextrins are known for their ability to form inclusion complexes with various drugs. Theoretically, molecules with a high affinity for sugammadex could interact and displace sugammadex from the sugammadex-rocuronium or sugammadex-vecuronium complex, potentially resulting in the recurrence of NMB due to recirculation of free rocuronium or vecuronium. OBJECTIVE: This study aimed to evaluate whether the administration of high doses of flucloxacillin or diclofenac can result in recurrence of NMB through displacement of sugammadex from its complex with rocuronium or vecuronium, following successful reversal of NMB by a suboptimal dose of sugammadex 2 mg/kg. Flucloxacillin has previously been identified using a modelling approach as a drug with displacement potential, while diclofenac was assessed due to its common intravenous use in the peri-operative and post-surgery setting. METHODS: This was a randomized, open-label, parallel, single-centre study conducted at SGS Life Services-CPU, Antwerp, Belgium. Twenty-four healthy, propofol-anaesthetized, adult volunteers were randomized to either rocuronium 0.6 mg/kg or vecuronium 0.1 mg/kg, followed by a suboptimal dose of sugammadex 2 mg/kg 15 minutes after induction of NMB. Five minutes after successful sugammadex reversal, subjects received either diclofenac 75 mg (15-minute infusion) or flucloxacillin 2 g (5-minute infusion) according to randomization. The suboptimal dose of sugammadex and relatively high doses of diclofenac and flucloxacillin were applied to create favourable conditions for the potential displacement of sugammadex from the sugammadex-rocuronium or sugammadex-vecuronium complex, and thus possible recurrence of NMB due to recirculation of free rocuronium or vecuronium. Possible recurrence of NMB was assessed by neuromuscular monitoring, performed with acceleromyography, and was continued until ~90 minutes after the start of diclofenac or flucloxacillin administration. Recurrence of NMB was concluded if three consecutive train-of-four (TOF) ratios were <0.8. RESULTS: Following successful reversal with a suboptimal dose of sugammadex 2 mg/kg administered 15 minutes after NMB induction, subsequent administration of diclofenac or flucloxacillin did not result in recurrence of NMB in any subject based on measurement of TOF ratios during anaesthesia and neuromuscular function tests upon awakening. There were no adverse events considered to be related to sugammadex. CONCLUSION: Administration of flucloxacillin or diclofenac does not result in recurrence of NMB through displacement of sugammadex from the sugammadex-rocuronium or sugammadex-vecuronium complex. PMID- 22201297 TI - Cranioplasty after decompressive craniectomy: the effect of timing on postoperative complications. AB - Decompressive craniectomy (DC) due to intractably elevated intracranial pressure mandates later cranioplasty (CP). However, the optimal timing of CP remains controversial. We therefore analyzed our prospectively conducted database concerning the timing of CP and associated post-operative complications. From October 1999 to August 2011, 280 cranioplasty procedures were performed at the authors' institution. Patients were stratified into two groups according to the time from DC to cranioplasty (early, <=2 months, and late, >2 months). Patient characteristics, timing of CP, and CP-related complications were analyzed. Overall CP was performed early in 19% and late in 81%. The overall complication rate was 16.4%. Complications after CP included epidural or subdural hematoma (6%), wound healing disturbance (5.7%), abscess (1.4%), hygroma (1.1%), cerebrospinal fluid fistula (1.1%), and other (1.1%). Patients who underwent early CP suffered significantly more often from complications compared to patients who underwent late CP (25.9% versus 14.2%; p=0.04). Patients with ventriculoperitoneal (VP) shunt had a significantly higher rate of complications after CP compared to patients without VP shunt (p=0.007). On multivariate analysis, early CP, the presence of a VP shunt, and intracerebral hemorrhage as underlying pathology for DC, were significant predictors of post-operative complications after CP. We provide detailed data on surgical timing and complications for cranioplasty after DC. The present data suggest that patients who undergo late CP might benefit from a lower complication rate. This might influence future surgical decision making regarding optimal timing of cranioplasty. PMID- 22201298 TI - Does the Hounsfield unit value determined by computed tomography predict the outcome of percutaneous nephrolithotomy? AB - PURPOSE: We aimed to evaluate whether the Hounsfield unit (HU) value predicts outcome in percutaneous nephrolithotomy (PCNL). PATIENTS AND METHODS: One hundred and seventy-nine patients who had undergone PCNL in our clinics in the last 4 years were included. Demographic and clinical data of the patients and complications, if any, were recorded. The mean age of the patients was 45.3 +/- 14.3 years (range 5-82 y), and 111 of them were males (62%). The mean stone size and HU values were found to be 693.1 +/- 628.0 (95-4200) mm(2) and 706.3 +/- 245.0 (214-1325), respectively. RESULTS: In logistic regression analysis, the size of the stone, the opacity of the stone, and the HU values were found to be independent predictors of the failure of the procedure (P<0.05). A cutoff value of 677.5 was used for the HU in the receiver operating characteristics analysis. Having a HU value under the cutoff value increased the likelihood of procedure failure by 2.65 times, whereas stones residing in the staghorn localization increased failure by 5.68. It was also observed that if the stone's size was 485 mm(2) or more, the chance of failure increased by 1.9, whereas when the stone was nonopaque, failure increased by 6.04 times (P<0.05). There was a positive correlation between hematocrit decrease and a decrease in HU values (P<0.05), but no correlation was observed between the HU values and duration of surgery or fluoroscopy (P>0.05). CONCLUSION: In addition to the size and location of the stones, the HU value determined in the unenhanced CT scan may be one of the parameters affecting PCNL outcomes. PCNL is a more efficient method in stones with higher HU values. Therefore, the HU values may be a useful tool for the selection of the treatment modality in patients with renal stones. PMID- 22201299 TI - Genetic architecture of the Delis-Kaplan Executive Function System Trail Making Test: evidence for distinct genetic influences on executive function. AB - OBJECTIVE: To examine how genes and environments contribute to relationships among Trail Making Test (TMT) conditions and the extent to which these conditions have unique genetic and environmental influences. METHOD: Participants included 1,237 middle-aged male twins from the Vietnam Era Twin Study of Aging. The Delis Kaplan Executive Function System TMT included visual searching, number and letter sequencing, and set-shifting components. RESULTS: Phenotypic correlations among TMT conditions ranged from 0.29 to 0.60, and genes accounted for the majority (58 84%) of each correlation. Overall heritability ranged from 0.34 to 0.62 across conditions. Phenotypic factor analysis suggested a single factor. In contrast, genetic models revealed a single common genetic factor but also unique genetic influences separate from the common factor. Genetic variance (i.e., heritability) of number and letter sequencing was completely explained by the common genetic factor while unique genetic influences separate from the common factor accounted for 57% and 21% of the heritabilities of visual search and set shifting, respectively. After accounting for general cognitive ability, unique genetic influences accounted for 64% and 31% of those heritabilities. CONCLUSION: A common genetic factor, most likely representing a combination of speed and sequencing, accounted for most of the correlation among TMT 1-4. Distinct genetic factors, however, accounted for a portion of variance in visual scanning and set shifting. Thus, although traditional phenotypic shared variance analysis techniques suggest only one general factor underlying different neuropsychological functions in nonpatient populations, examining the genetic underpinnings of cognitive processes with twin analysis can uncover more complex etiological processes. PMID- 22201301 TI - Superior intellectual ability in schizophrenia: neuropsychological characteristics. AB - OBJECTIVE: It has been suggested that neurocognitive impairment is a core deficit in schizophrenia. However, it appears that some patients with schizophrenia have intelligence quotients (IQs) in the superior range. In this study, we sought out schizophrenia patients with an estimated premorbid Intelligence Quotient (IQ) of at least 115 and studied their neuropsychological profile. METHOD: Thirty-four patients meeting diagnostic criteria for schizophrenia or schizoaffective disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV), with mean estimated premorbid IQ of 120, were recruited and divided into two subgroups, according to whether or not their IQ had declined by at least 10 points from their premorbid estimate. Their performance on an extensive neuropsychological battery was compared with that of 19 IQ-matched healthy controls and a group of 16 "typical" schizophrenia patients with estimated premorbid IQ <110, using one way ANOVAs and profile analysis using MANOVAs. RESULTS: Schizophrenia patients whose estimated premorbid and current IQ both lay in the superior range were statistically indistinguishable from IQ matched healthy controls on all neurocognitive tests. However, their profile of relative performance in subtests was similar to that of typical schizophrenia patients. Patients with superior premorbid IQ and evidence of intellectual deterioration had intermediate scores. CONCLUSIONS: Our results confirm the existence of patients meeting DSM-IV diagnostic criteria for schizophrenia who have markedly superior premorbid intellectual level and appear to be free of gross neuropsychological deficits. We discuss the implications of these findings for the primacy of cognitive deficits in schizophrenia. PMID- 22201300 TI - Altered implicit category learning in anorexia nervosa. AB - OBJECTIVE: Recent research has identified specific cognitive deficits in patients with anorexia nervosa (AN), including impairment in executive functioning and attention. Another such cognitive process, implicit category learning has been less studied in AN. This study examined whether implicit category learning is impaired in AN. METHOD: Twenty-one women diagnosed with AN and 19 control women (CW) were administered an implicit category learning task in which they were asked to categorize simple perceptual stimuli (Gabor patches) into one of two categories. Category membership was based on a linear integration (i.e., an implicit task) of two stimulus dimensions (orientation and spatial frequency of the stimulus). RESULTS: AN individuals were less accurate on implicit category learning relative to age-matched CW. Model-based analyses indicated that, even when AN individuals used the appropriate (i.e., implicit) strategy they were still impaired relative to CW who also used the same strategy. In addition, task performance in AN patients was worse the higher they were in self-reported novelty seeking and the lower they were in sensitivity to punishment. CONCLUSIONS: These results indicate that AN patients have implicit category learning deficits, and given this type of learning is thought to be mediated by striatal dopamine pathways, AN patients may have deficits in these neural systems. The finding of significant correlations with novelty seeking and sensitivity to punishment suggests that feedback sensitivity is related to implicit learning in AN. PMID- 22201302 TI - Effects of familiarity and cognitive function on naturalistic action performance. AB - OBJECTIVE: This study investigated the effects of familiarity on the performance of routine (familiar) naturalistic actions (NAs) that had been performed several times prior to the experiment (e.g., making coffee) and novel (unfamiliar) naturalistic actions (NNAs) that had not been performed prior to instruction (e.g., making a mock volcano). We hypothesized that similar psychological processes were associated with both types of action, but that memory and executive functions would be more important for NNAs. METHOD: In Experiment 1, 18 undergraduates verbally described NAs and NNAs as they observed the tasks being performed. In Experiment 2, stroke patients, impaired (n = 4) or unimpaired (n = 4) on a test of general cognitive function, and 12 controls, physically enacted and arranged in correct order photos of NAs and NNAs. RESULTS: In Experiment 1, the central (crux), but not the noncentral (noncrux) actions, associated with NAs and NNAs were verbally described. In Experiment 2, NA and NNA enactment and photo arrangement performance was lower in the impaired group compared with controls. The impaired group had higher omission (omitting an action) than commission (performing an action incorrectly) crux action error rates for NAs, but the reverse pattern for NNAs. NA performance was more strongly associated with general cognitive function, whereas NNA performance correlated more strongly with executive functioning and memory measures. CONCLUSION: Both types of task involve overlapping cognitive processes. Memory and executive function may be more important for NNAs because these tasks are encoded into memory at study. PMID- 22201303 TI - A novel method for making dorsal horn lesions. AB - OBJECTIVE: Dorsal root entry zone (DREZ) lesioning for intractable pain currently requires a multi-level laminectomy for direct access to all spinal cord segments intended to be lesioned. The hypothesis is that a silastic rubber catheter can be inserted into the dorsal horn (through a single laminectomy site) and advanced down several spinal cord segments, while staying exclusively in the dorsal horn. METHODS: A cervical laminectomy was performed in four sheep. Standard cerebrospinal fluid drainage catheters were introduced into the dorsal horn through a small incision in the DREZ. The catheters were advanced caudally along the longitudinal cord axis for a distance of 8-11 cm. Neurophysiological monitoring was done. The cord was excised from the spinal canal, fixed in formalin and cut in serial axial slices at 1 cm intervals to assess the position of the catheter within the spinal cord. RESULTS: The catheter stayed within the grey column of the spinal cord dorsal horn, along the entire length of its insertion. Electrophysiological data confirmed that dorsal horn activity was totally ablated after catheter passage in three sheep, and partially ablated in the fourth. CONCLUSION: The intrinsic architecture of the spinal cord tissue allows the predictable passage of the catheter through the column of dorsal horn grey matter. Dorsal horn lesioning can be accomplished without direct access to the cord segments selected for surgery. PMID- 22201304 TI - Synthesis of multifunctional nanostructured zinc-iron mixed oxide photocatalyst by a simple solution-combustion technique. AB - A series of nanostructure zinc-iron mixed oxide photocatalysts have been fabricated by solution-combustion method using urea as the fuel, and nitrate salts of both iron and zinc as the metal source. Different characterization tools, such as X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), diffuse reflectance UV-visible spectra (DRUV-vis), electron microscopy, and photoelectrochemical measurement were employed to establish the structural, electronic, and optical properties of the material. Electron microscopy confirmed the nanostructure of the photocatalyst. The synthesized photocatalysts were examined towards photodegradation of 4-chloro-2-nitro phenol (CNP), rhodamine 6G (R6G), and photocatalytic hydrogen production under visible light (lambda >= 400 nm). The photocatalyst having zinc to iron ratio of 50:50 showed best photocatalytic activity among all the synthesized photocatalysts. PMID- 22201305 TI - Surgical treatment of endolymphatic sac tumor. AB - The objective of this study was to understand the clinical characteristics of endolymphatic sac tumor and to optimize its diagnosis and treatment. We carried out a retrospective review of 11 patients diagnosed as having endolymphatic sac tumor based on operative findings and pathological features, and their clinical manifestations, differential diagnosis, and surgical approaches are discussed in detail. The lesions of 10 cases were completely surgically resected, two cases via the mastoid approach, 8 cases via the oto-cervical or cranio-oto-cervical combined approach. In one case the tumor was partially removed and the patient received adjuvant radiotherapy. In operation, four cases had facial-hypoglossal neural anastomosis, two cases had great auricular nerve graft, and in four cases the facial nerve integrity remained. Survival follow-up data range from 14 months to 10 years. We conclude that endolymphatic sac tumor is very rare and easily misdiagnosed. Reasonable surgical treatment can provide a good prognosis. PMID- 22201323 TI - Optoelectronic properties of hyperbranched polythiophenes. AB - Branched conjugated architectures should possess the advantage of isotropic charge transport compared to conventional linear conjugated polymers, as for example poly(3-hexylthiophene) (P3HT) which is commonly used in organic solar cells. This contribution investigates the optoelectronic properties of branched poly(thiophene)s p3T and p4T synthesized in a straightforward one-pot procedure by oxidative coupling of branched trithiophene and tetrathiophene monomers with FeCl(3). These polymers can be regarded as model systems for ideal amorphous conjugated materials. Optical characterization in solution and in thin films together with cyclic voltammetry data suggests the applicability of these materials for the use in organic solar cell devices. In particular, the HOMO and LUMO levels of the branched polythiophenes are shifted to lower energy values as compared to linear P3HT. Field effect mobilities are in the order of 10(-4) cm(2)/(V s). A first optimization of solar cell devices based on the branched polythiophene materials in combination with PCBM as acceptor resulted in efficiencies of 0.6% with open-circuit voltages being about 30% higher (up to 714 mV) than normally found with P3HT. PMID- 22201324 TI - Prospective, randomized, double-blind, contralateral eye comparison of myopic LASIK with optimized aspheric or prolate ablations. AB - PURPOSE: To compare the postoperative outcomes of aspheric or prolate LASIK for myopia and myopic astigmatism. METHODS: In this double-blind, bilateral, randomized trial, 40 patients (80 eyes) with -0.75 to -7.00 diopters (D) of manifest refraction spherical equivalent (MRSE) underwent optimized aspheric treatment zone ablation (OATz group) in 1 eye and optimized prolate ablation (OPA group) in the fellow eye. Six-month postoperative outcomes were compared for MRSE and visual acuity, contrast sensitivity, patient satisfaction, ocular higher order aberrations (HOAs), and spherical aberration. The Wilcoxon signed rank test, Mann-Whitney U test, and paired t test were used for testing differences between groups. P<.05 was statistically significant. Main outcome measures included HOAs, spherical aberration, visual and refractive outcomes, and contrast sensitivity. RESULTS: Postoperatively, 36 patients (72 eyes) were evaluated. The MRSE was -0.07+/-0.23 D for the OPA group and +0.02+/-0.24 D for the OATz group (P>.05). Two (5%) eyes in the OPA group and 1 (3%) eye in the OATz group (P=.114) lost 1 line of corrected distance visual acuity. Postoperative visual acuity was not statistically different between groups (P>.05). Statistically lower change was noted in spherical aberration (0.011 MUm) in the OPA group versus the OATz group (0.099 MUm) (P<.001). Statistically higher induction of coma was noted in the OPA group (P=.035). No statistically significant differences were noted in photopic, mesopic, or glare contrast sensitivity and patient satisfaction between groups (P>.05, for all comparisons). CONCLUSIONS: The refractive and visual outcomes of OPA and OATz were equivalent. However, the postoperative optical quality of OPA-treated eyes was better. PMID- 22201325 TI - Electric vehicles in China: emissions and health impacts. AB - E-bikes in China are the single largest adoption of alternative fuel vehicles in history, with more than 100 million e-bikes purchased in the past decade and vehicle ownership about 2* larger for e-bikes as for conventional cars; e-car sales, too, are rapidly growing. We compare emissions (CO(2), PM(2.5), NO(X), HC) and environmental health impacts (primary PM(2.5)) from the use of conventional vehicles (CVs) and electric vehicles (EVs) in 34 major cities in China. CO(2) emissions (g km(-1)) vary and are an order of magnitude greater for e-cars (135 274) and CVs (150-180) than for e-bikes (14-27). PM(2.5) emission factors generally are lower for CVs (gasoline or diesel) than comparable EVs. However, intake fraction is often greater for CVs than for EVs because combustion emissions are generally closer to population centers for CVs (tailpipe emissions) than for EVs (power plant emissions). For most cities, the net result is that primary PM(2.5) environmental health impacts per passenger-km are greater for e cars than for gasoline cars (3.6* on average), lower than for diesel cars (2.5* on average), and equal to diesel buses. In contrast, e-bikes yield lower environmental health impacts per passenger-km than the three CVs investigated: gasoline cars (2*), diesel cars (10*), and diesel buses (5*). Our findings highlight the importance of considering exposures, and especially the proximity of emissions to people, when evaluating environmental health impacts for EVs. PMID- 22201328 TI - Is ADHD diagnosed in accord with diagnostic criteria? Overdiagnosis and influence of client gender on diagnosis. AB - OBJECTIVE: Unresolved questions exist concerning diagnosis of ADHD. First, some studies suggest a potential overdiagnosis. Second, compared with the male-female ratio in the general population (3:1), many more boys receive ADHD treatment compared with girls (6-9:1). We hypothesized that this occurs because therapists do not adhere to Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) and International Classification of Diseases (10th rev.; ICD-10) criteria. Instead, we hypothesized that, in accordance with the representativeness heuristic, therapists might diagnose attention deficit/hyperactivity disorder (ADHD) if a patient resembles their concept of a prototypical ADHD child, leading therapists to overlook certain exclusion criteria. This may result in overdiagnosis. Furthermore, as ADHD is more frequent in males, a boy might be seen as a more prototypical ADHD child and might therefore receive an ADHD diagnosis more readily than a girl would. METHOD: We sent a case vignette to 1,000 child psychologists, psychiatrists, and social workers and asked them to give a diagnosis. Four versions of the vignette existed: Vignette 1 (ADHD) fulfilled all DSM-IV/ICD-10 criteria of ADHD. Vignettes 2-4 (non-ADHD) included several ADHD symptoms but stated other ADHD criteria were nonfulfilled. Therefore, an ADHD diagnosis could not be given. Furthermore, boy and girl versions of each vignette were created. RESULTS: In Vignettes 2-4 (non-ADHD), 16.7% of therapists diagnosed ADHD. In the boy version of these vignettes, therapists diagnosed ADHD around 2 times more than they did with the girl vignettes. CONCLUSIONS: Therapists do not adhere strictly to diagnostic manuals. Our study suggests that overdiagnosis of ADHD occurs in clinical routine and that the patient's gender influences diagnosis considerably. Thorough diagnostic training might help therapists to avoid these biases. PMID- 22201327 TI - Racial/ethnic differences in adults in randomized clinical trials of binge eating disorder. AB - OBJECTIVE: Recent studies suggest that binge eating disorder (BED) is as prevalent among African American and Hispanic Americans as among Caucasian Americans; however, data regarding the characteristics of treatment-seeking individuals from racial and ethnic minority groups are scarce. The purpose of this study was to investigate racial/ethnic differences in demographic characteristics and eating disorder symptoms in participants enrolled in treatment trials for BED. METHOD: Data from 11 completed randomized, controlled trials were aggregated in a single database, the Clinical Trials of Binge Eating Disorder (CT-BED) database, which included 1,204 Caucasian, 120 African American, and 64 Hispanic participants assessed at baseline. Age, gender, race/ethnicity, education, body mass index (BMI), binge eating frequency, and Eating Disorder Examination (EDE) Restraint, Shape, Weight, and Eating Concern subscale scores were examined. RESULTS: Mixed model analyses indicated that African American participants in BED treatment trials had higher mean BMI than Caucasian participants, and Hispanic participants had significantly greater EDE shape, weight, and eating concerns than Caucasian participants. No racial or ethnic group differences were found on the frequency of binge eating episodes. Observed racial/ethnic differences in BED symptoms were not substantially reduced after adjusting for BMI and education. Comparisons between the CT-BED database and epidemiological data suggest limitations to the generalizability of data from treatment-seeking samples to the BED community population, particularly regarding the population with lower levels of education. CONCLUSIONS: Further research is needed to assess alternative demographic, psychological, and culturally specific variables to better understand the diversity of treatment-seeking individuals with BED. PMID- 22201329 TI - Changes in the cupula after disruption of the membranous labyrinth. AB - CONCLUSION: Various changes were observed in the cupula, including shrinkage and enlarged volume, following the disruption of the membranous labyrinth. Cupular change after membranous labyrinth disruption may be a pathology of vestibular disorders. OBJECTIVES: To observe the morphological changes of the cupula after disruption of the membranous labyrinth and to compare the cupular changes with changes in the compound action potential (CAP) of the ampullary nerve. METHODS: A labyrinthine injury model was created by puncturing the membranous labyrinth of bullfrogs. The cupula was observed from 3 to 17 days after the membrane puncture. The CAP in response to mechanical endolymphatic flow was recorded from the ampullary nerve. The correlation between cupular change and CAP positivity was evaluated using the authors' scale. RESULTS: Various kinds of cupular changes including shrinkage were observed. Cupular change was more severe after a longer survival period. Large or elongated volume of the cupula was also observed, which was not observed in our previous study using gentamicin. The CAP could be recorded even when the cupular change was severe. PMID- 22201330 TI - Vision-fair neuropsychological assessment in normal aging, Parkinson's disease and Alzheimer's disease. AB - We examined performance of healthy older and younger adults and individuals with Alzheimer's disease (AD) and Parkinson's disease (PD) on digit cancellation, a task putatively sensitive to cognitive impairment, but possibly affected by visual impairment, particularly in contrast sensitivity. Critical contrast thresholds were established to create custom stimulus arrays that were proximally matched across individuals. Age- and PD-related differences in search were fully accounted for by the sensory deficit. Increased contrast benefited AD patients, but could not override cognitive impairment. We conclude that visually fair neuropsychological testing can effectively compensate for normal age- and PD related visual changes that affect cognitive performance. PMID- 22201331 TI - Differential trajectories of age-related changes in components of executive and memory processes. AB - Several studies have demonstrated age-related declines in general executive function and memory. In this study, we examined cross-sectional and longitudinal age effects in more specific cognitive processes that constitute executive function and memory. We postulated that, whereas some components of executive and memory functions would show age differences and longitudinal declines, other specific abilities would be maintained or even improve with repeated testing. In a sample of individuals >=55 years old from the Baltimore Longitudinal Study of Aging, we found longitudinal declines in inhibition, manipulation, semantic retrieval, phonological retrieval, switching, and long-term memory over a maximum of 14 years follow-up. In contrast, abstraction, capacity, chunking, discrimination, and short-term memory were maintained or even improved longitudinally, probably due in part to repeated testing. Moreover, whereas several different abilities were correlated across participants' cross-sectional performance, longitudinal changes in performance showed more heterogeneous trajectories. Finally, compared with cross-sectional performance, longitudinal trajectories showed better distinction between participants with and those without later cognitive impairment. These results show that longitudinal cognitive aging of executive and memory functions is not a uniform process but a heterogeneous one and suggest that certain executive and memory functions remain stable despite age-related declines in other component processes. PMID- 22201332 TI - Emotions and physical health in the second half of life: interindividual differences in age-related trajectories and dynamic associations according to socioeconomic status. AB - The importance of socioeconomic status (SES) for psychological functioning over the life span is increasingly acknowledged in psychological research. The Reserve Capacity Model by Gallo and Matthews (2003) suggests that SES is not only linked to physical health but also to the experience of positive and negative emotions. Moreover, due to differential amounts of psychosocial resources, cross-domain associations between emotions and health might differ according to SES. The present study examined age-related developments in positive affect (PA), negative affect (NA), and physical health, as well as dynamic associations between health and emotions in the second half of life. We looked at differences in these trajectories and their interrelationships according to education as one aspect of SES. We used data of up to three waves spanning 12 years from the nationally representative German Ageing Survey (N = 3,847, AgeT1 = 40-85 years). Applying multiple-group dual change score models, we found differential age-related change in PA and physical health, but not in NA, in two groups differing in level of education. NA did only predict change in physical health in low-educated individuals, whereas physical health was equally strongly related to change in PA in both education groups. These results indicate that SES not only affects changes in physical health and emotional functioning but also their interrelationships. PMID- 22201333 TI - The relationship between identity, intimacy, and midlife well-being: findings from the Rochester Adult Longitudinal Study. AB - The present study used longitudinal data on 182 adults between the ages of 20 and 54 (104 men, 78 women) from the Rochester Adult Longitudinal Study (RALS), assessed on four occasions, to test the hypothesis that identity and intimacy during the course of early and middle adulthood predict well-being at midlife. A cross-lagged panel model was estimated yielding the following findings: (a) Scores on both scales during the college years predicted midlife satisfaction intimacy directly, and identity through the course of development from ages 20 to 54; moreover, identity in midlife, but not intimacy, was significantly linked with well-being at this same point in time; and (b) identity and intimacy unexpectedly did not predict one another over time, having been controlled for factor stability in identity and intimacy over time. The findings are discussed in terms of Erikson's psychosocial theory of development and the developmental moments and historical cohorts that characterize the present sample. PMID- 22201334 TI - Retest learning in the absence of item-specific effects: does it show in the oldest-old? AB - This study examined whether the nonitem-specific retest learning effects, previously shown with young-old adults primarily in their 60s and 70s, could be extended to oldest-old adults aged 80 and onward. Twenty-one oldest-olds participated in an 8-session retest training program with three ability domains: perceptual speed, inductive reasoning, and visual attention. Their data were compared with the data of 30 young-olds collected in a previous work (Yang, Reed, Russo, & Wilkinson, 2009). The two age groups showed largely equivalent retest learning effects. In addition, only young-olds were able to benefit from item specific retest learning, specifically in reasoning and perceptual speed tests. PMID- 22201335 TI - Single-step direct fabrication of pillar-on-pore hybrid nanostructures in anodizing aluminum for superior superhydrophobic efficiency. AB - Conventional electrochemical anodizing processes of metals such as aluminum typically produce planar and homogeneous nanopore structures. If hydrophobically treated, such 2D planar and interconnected pore structures typically result in lower contact angle and larger contact angle hysteresis than 3D disconnected pillar structures and, hence, exhibit inferior superhydrophobic efficiency. In this study, we demonstrate for the first time that the anodizing parameters can be engineered to design novel pillar-on-pore (POP) hybrid nanostructures directly in a simple one-step fabrication process so that superior surface superhydrophobicity can also be realized effectively from the electrochemical anodization process. On the basis of the characteristic of forming a self-ordered porous morphology in a hexagonal array, the modulation of anodizing voltage and duration enabled the formulation of the hybrid-type nanostructures having controlled pillar morphology on top of a porous layer in both mild and hard anodization modes. The hybrid nanostructures of the anodized metal oxide layer initially enhanced the surface hydrophilicity significantly (i.e., superhydrophilic). However, after a hydrophobic monolayer coating, such hybrid nanostructures then showed superior superhydrophobic nonwetting properties not attainable by the plain nanoporous surfaces produced by conventional anodization conditions. The well-regulated anodization process suggests that electrochemical anodizing can expand its usefulness and efficacy to render various metallic substrates with great superhydrophilicity or -hydrophobicity by directly realizing pillar-like structures on top of a self-ordered nanoporous array through a simple one-step fabrication procedure. PMID- 22201336 TI - Anxiolytics reduce residual dizziness after successful canalith repositioning maneuvers in benign paroxysmal positional vertigo. AB - CONCLUSIONS: This study suggests that adjuvant anti-anxiety medication may be helpful for patients with benign paroxysmal positional vertigo (BPPV) even after a successful canalith repositioning procedure (CRP). OBJECTIVE: Although the CRP is an effective treatment for BPPV, many patients suffer from persistent dizziness despite successful CRPs. The aim of this study was to evaluate the effect of adjuvant anxiolytic medication on residual dizziness after successful CRP. METHODS: Between January 2011 and March 2011, 73 patients were diagnosed with BPPV and they underwent successful treatment with CRPs. The patients were randomly assigned to either the medication group or the control group. The patients in the medication group were prescribed low dose etizolam for 2 weeks whereas the patients in the control group were not prescribed any medication. All patients were scheduled to return 2 weeks after evaluation of subjective visual vertical. Subjective symptoms before and after CRP were measured using the Dizziness Handicap Inventory (DHI) and the Activities-specific Balance Confidence (ABC) scale. RESULTS: Both groups demonstrated a significant improvement in DHI scores. However, the medication group showed significantly greater decrease in the functional (p = 0.018) and emotional (p = 0.030) subscale scores, as well as in the total DHI (p = 0.038) score. PMID- 22201337 TI - Reversible hybridization of DNA anchored to a lipid membrane via porphyrin. AB - The binding of zinc-porphyrin-anchored linear DNA to supported lipid membranes was studied using quartz crystal microbalance with dissipation monitoring (QCM D). The hydrophobic anchor is positioned at the ninth base of 39-base-pair-long DNA sequences, ensuring that the DNA is positioned parallel to the membrane surface when bound, an important prerequisite for using this type of construct for the creation of two-dimensional (2D) DNA patterns on the surface. The anchor consists of a porphyrin group linked to the DNA via two or three phenylethynylene moieties. Double-stranded DNA where one of the strands was modified with either of these anchors displayed irreversible binding, although binding to the membrane was faster for the derivatives with the short anchor. The binding and subsequent hybridization of single-stranded constructs on the surface was demonstrated at 60 degrees C, for both anchors, revealing a coverage-dependent behavior. At low coverage, hybridization results in an increase in mass (as measured by QCM-D) by a factor of ~1.5, accompanied by a slight increase in the rigidity of the DNA layer. At high coverage, hybridization expels molecules from the membrane, associated with an initial increase, followed by a decrease in DNA mass (as detected both by QCM-D and by an optical technique). Melting of the DNA on the surface was performed, followed by rehybridization of the single-stranded species left on the surface with their complementary strand, demonstrating the reversibility inherent in using DNA for the formation of membrane-confined nanopatterns. PMID- 22201338 TI - Sulfur-doped graphene as an efficient metal-free cathode catalyst for oxygen reduction. AB - Tailoring the electronic arrangement of graphene by doping is a practical strategy for producing significantly improved materials for the oxygen-reduction reaction (ORR) in fuel cells (FCs). Recent studies have proven that the carbon materials doped with the elements, which have the larger (N) or smaller (P, B) electronegative atoms than carbon such as N-doped carbon nanotubes (CNTs), P doped graphite layers and B-doped CNTs, have also shown pronounced catalytic activity. Herein, we find that the graphenes doped with the elements, which have the similar electronegativity with carbon such as sulfur and selenium, can also exhibit better catalytic activity than the commercial Pt/C in alkaline media, indicating that these doped graphenes hold great potential for a substitute for Pt-based catalysts in FCs. The experimental results are believed to be significant because they not only give further insight into the ORR mechanism of these metal-free doped carbon materials, but also open a way to fabricate other new low-cost NPMCs with high electrocatalytic activity by a simple, economical, and scalable approach for real FC applications. PMID- 22201339 TI - Panurethral stricture after photovaporization of the prostate for benign prostatic hyperplasia. AB - PURPOSE: To report the development of panurethral stricture disease and other lower urinary tract abnormalities as a complication of photovaporization of the prostate (PVP). PATIENTS AND METHODS: We evaluated three patients who were referred for the treatment of urethral stricture disease after PVP. Evaluation included antegrade cystoscopy, urethroscopy, retrograde urethrography, and cystourethrography. RESULTS: All three patients had panurethral stricture disease, and a low capacity bladder with bilateral vesicoureteral reflux had developed in one patient as a complication of PVP. CONCLUSIONS: Although not previously reported, a potential complication of PVP is devastating panurethral stricture disease. PMID- 22201340 TI - Hierarchy of higher-level physical functions: a longitudinal investigation on a nationally representative population of community-dwelling middle-aged and elderly persons. AB - PURPOSE: Understanding the hierarchy of higher-level physical functions to infer disability level (mild, moderate or severe) is essential for the precise targeting of preventive interventions and has been examined previously in a cross sectional study. Based on longitudinal data, this study evaluated the hierarchy of higher-level physical functions. METHODS: Data from a cohort of 2729 community dwelling persons aged over 50 with no initial disability were drawn from the "Survey of Health and Living Status of the Elderly in Taiwan" from 1996 through 2007. The three-level hierarchy of eight chosen activities was examined by the median ages to disability onset with survival analyses and by Cox regressions, which examined the effects of sex and age on the development of this hierarchy. RESULTS: The progression of incident disability was as follows: mild level running, carrying weight, and squatting; moderate level-climbing stairs, walking, and standing; and severe level-grasping and raising arms up. Women and older persons were at greater risk of developing more severe levels of disability. Another Cox regression with one index activity from each hierarchical level revealed similar results. CONCLUSIONS: The three-level hierarchy of higher-level physical functions has been validated longitudinally, suggesting rich research and clinical implications. PMID- 22201341 TI - PEGylation of interferon-beta-1a: a promising strategy in multiple sclerosis. AB - Achieving optimal patient benefit from biological therapies can be hindered by drug instability, rapid clearance requiring frequent dosing or potential immune reactions. One strategy for addressing these challenges is drug modification through PEGylation, a well established process by which one or more molecules of polyethylene glycol (PEG) are covalently attached to a biological or small molecule drug, effectively transforming it into a therapy with improved pharmacokinetic and pharmacodynamic properties. Numerous PEGylated therapeutics are currently available, all of which have at least comparable efficacy, safety and tolerability to their unmodified forms. A PEGylated form of interferon-beta 1a (PEG-IFNbeta-1a) is being developed to address an unmet medical need for safer, more effective and more convenient therapies for multiple sclerosis (MS). Phase I study data suggest that PEG-IFNbeta-1a should provide patients with a first-line therapy with a more convenient dosing regimen while maintaining the established efficacy, safety and tolerability of presently available IFNbeta-1a. The ongoing global ADVANCE phase III study will determine the clinical efficacy of PEG-IFNbeta-1a in patients with relapsing MS. PMID- 22201343 TI - Traumatic craniocervical dissociation. PMID- 22201370 TI - Principles of cranial base ossification in humans and rats. AB - CONCLUSIONS: 1. The principle of bilateral symmetry depends on the chordal cartilage that is the keystone in cranial base ossification in rats and humans, due to its anatomical situation and for the production of the chordin protein that regulates the bone morphogenetic protein BMP-7. 2. In humans and in rats, foramen lacerum closure follows a line of intramembranous ossification that depends on BMP-7, regulated by the first branchial pouch. 3. The cranial base ossification patterns and centres are similar in humans and in rats, except in the otic capsule, palate and the lateral pterygoid plate. 4. The neural crest may induce cranial ossification through the cranial nerves. OBJECTIVES: To study the patterns of cranial base ossification in humans and in rats, considering the chordal cartilage, and the otic, nasal and orbit capsules, as well as the participation of the branchial arches and pouches. METHODS: This was a light microscopy study of human fetal specimens obtained from spontaneous abortions with the following crown-rump-lengths (crl) 45, 74, 90, 134, 145 and 270 mm, and a 1-day-old neonate (360 mm crl), who had died of sudden death syndrome. We also examined Webster albino rat embryos of 16, 18 and 20 days of gestation and a postnatal series of rats 8 h and 1, 3, 4, 6, 7, 10 and 13 days old, as well as adult animals. RESULTS: In the 45 mm human fetus, the chordal cartilage with the nasal, otic and orbit capsules initiates cranial base ossification. Foramen lacerum closure begins in the 16-day-old rat embryo, following a line of membranous ossification between the external pterygoid process and the lateral alisphenoidal wing at ovalis foramen level. This is not a timing symmetrical process, which may persist until the 10th postnatal day in the rat. In the human fetus of 74 mm, the foramen lacerum space is closed by a membranous fusion ossification between the chordal cartilage and otic capsule, finishing at the 270 mm specimen. Endochondral ossification of the human otic capsule first appeared in the 145 mm (18 weeks) fetal specimen with four ossifying centres. The rat otic cartilaginous capsule showed rapid endochondral ossification, in the third and fourth postnatal day specimens. PMID- 22201371 TI - Formation of Pb(III) intermediates in the electrochemically controlled Pb(II)/PbO2 system. AB - The formation of lead dioxide PbO(2), an important corrosion product in drinking water distribution systems with lead-bearing plumbing materials, has been hypothesized to involve Pb(III) intermediates, but their nature and formation mechanisms remain unexplored. This study employed the electrochemical (EC) method of rotating ring disk electrode (RRDE) and quantum chemical (QC) simulations to examine the generation of intermediates produced during the oxidation of Pb(II) to PbO(2). RRDE data demonstrate that PbO(2) deposition and reduction involves at least two intermediates. One of them is a soluble Pb(III) species that undergoes further transformations to yield immobilized PbO(2) nanoparticles. The formation of this intermediate in EC system is mediated by hydroxyl radicals (OH(*)), as was evidenced by the suppression of intermediates formation in the presence of the OH(*) scavenger para-chlorobenzoic acid. QC simulations confirmed that the oxidation of Pb(II) by OH(*) proceeds via Pb(III) species. These results show that Pb(III) intermediates play an important role in the reactions determining transitions between Pb(II) and Pb(IV) species and could impact lead release in drinking water. PMID- 22201342 TI - HIV-associated neurological disorders: a guide to pharmacotherapy. AB - In the era of highly active antiretroviral therapy (HAART), HIV-1-associated neurocognitive disorder (HAND) continues to be a common and significant morbidity among individuals infected with HIV. The term HAND encompasses a spectrum of progressively severe CNS involvement, ranging from asymptomatic neurocognitive impairment and minor neurocognitive disorder through to the most severe form of HIV-associated dementia (HAD). While the incidence of HAD has declined significantly with HAART, the milder forms of HAND persist. In addition, HAND now develops in individuals with less advanced immunosuppression. The reasons for the persistence of milder forms of HAND in individuals treated with HAART are not entirely known. There are several hypotheses to explain this phenomenon that include the legacy effect, a failure of antiretroviral agents to reverse neurological damage, poor access of antiretroviral agents to the CNS, chronic systemic immune activation associated with microbial translocation products, sustained CNS inflammation, the improved survival of HIV-seropositive individuals and the possible contribution from aging, amyloid deposition and other co morbidities. In contrast, the incidence of HIV-associated CNS opportunistic processes including progressive multifocal leukoencephalopathy, tuberculosis, CNS toxoplasmosis, cytomegalovirus encephalitis, cryptococcosis and primary CNS lymphoma has declined dramatically with the introduction of HAART. This review briefly summarizes our current understanding of HAND and the pathological mechanisms involved, namely direct injury from HIV-1 and viral proteins, indirect neurotoxicity from proinflammatory cytokines and chronic, sustained immune activation in the CNS. To date, only HAART has been shown to benefit HAND despite numerous controlled trials of adjunctive 'anti-inflammatory' agents. Although HAART has a profound impact on the incidence and severity of HAND, there exists a 'therapeutic gap' as even HAART that is effective at inducing durable virological suppression may only partially reverse HAND. In addition, there may be potential CNS adverse effects of antiretroviral agents. There is an ongoing multicentre clinical trial to investigate the role of the CNS Penetration-Effectiveness index, an indicator of drug permeability and availability in the CNS, to help guide the choice of antiretroviral agents in the treatment of HAND. With recent recommendations for earlier treatment intervention with HAART for HIV-1 infection, it remains to be seen the effects of this on HAND. There is an urgent need to better define the therapeutic guidelines for the prevention and treatment of HAND. PMID- 22201372 TI - Formal intermolecular [2 + 2] cycloaddition reaction of allenamide [corrected] with alkenes via gold catalysis. AB - An efficient method was developed to construct the densely functionalized cyclobutane[corrected] adducts through formal intermolecular cycloaddition of allenamides [corrected] with electron-rich olefins via gold catalysis, in which vinyl ethers/amides and electron-rich styrenes worked very well. In addition, a series of allenamide [corrected] dimerization products were prepared from the same allenamide [corrected] substrates. PMID- 22201373 TI - The ontogenesis of lateralized behavior in the domestic cat, Felis silvestris catus. AB - For the first time, the development of paw preferences in the domestic cat, Felis silvestris catus, is explored. Twelve cats were tested at ages 12 weeks, 6 months, and 1 year on a challenge requiring them to use one of their paws to retrieve food. To control for repeated testing of the same cats at different ages, the subjects' paw preferences were compared with those of cats tested just once, at 6 months (n = 11) or 1 year (n = 14) of age. Analysis revealed a significant effect of age on the distribution of cats' paw preferences. Cats were significantly more likely to be ambilateral than paw preferent at 12 weeks and at 6 months but more likely to display a lateral bias in paw use at 1 year. There was a significant positive correlation between cats' paw preferences at 6 months and at 1 year. Lateralized behavior was strongly sex related. Females had a greater preference for using their right paw; males were significantly more inclined to adopt their left. Analysis revealed no significant difference in the direction or strength of paw preferences of cats tested longitudinally or cross sectionally at 6 months or 1 year of age. Findings indicate that cats develop paw preferences by 1 year and hint at a relative stability in preferred paw use over time. The strong sex effect observed strengthens the case for the influence of a biological mechanism in the emergence of motor asymmetry in cats. PMID- 22201375 TI - Coordination of Adsorbed Boron: A FTIR Spectroscopic Study. PMID- 22201374 TI - Binding of Cu(II) to the Surface and Exudates of the Alga Dunaliella tertiolecta in Seawater. PMID- 22201376 TI - Cationic Surfactant Sorption to a Vermiculitic Subsoil via Hydrophobic Bonding. PMID- 22201377 TI - Individual particle types in the aerosol of phoenix, Arizona. PMID- 22201378 TI - Industrial emission control using lidar techniques. PMID- 22201380 TI - Time Trends in Levels, Patterns, and Profiles for Polychlorinated Dibenzo-p dioxins, Dibenzofurans, and Biphenyls in a Sediment Core from the Baltic Proper. PMID- 22201379 TI - Characterization of indoor air quality in the cities of sao paulo and rio de janeiro, Brazil. PMID- 22201381 TI - Chlorobenzenes in field soil with a history of multiple sewage sludge applications. PMID- 22201382 TI - Sorption of Benzo[a]pyrene and Phenanthrene on Suspended Harbor Sediment as a Function of Suspended Sediment Concentration and Salinity: A Laboratory Study Using the Cosolvent Partition Coefficient. PMID- 22201383 TI - Sulfidation-Regeneration Cycles of ZnO- and CaO-Containing Sorbents. PMID- 22201385 TI - Strong-Acid, carboxyl-group structures in fulvic Acid from the suwannee river, georgia. 1. Minor structures. PMID- 22201384 TI - Laboratory and Field Investigation of the DNPH Cartridge Technique for the Measurement of Atmospheric Carbonyl Compounds. PMID- 22201386 TI - Strong-Acid, carboxyl-group structures in fulvic Acid from the suwannee river, georgia. 2. Major structures. PMID- 22201388 TI - Regularized least-squares methods for the calculation of discrete and continuous affinity distributions for heterogeneous sorbents. PMID- 22201387 TI - Atrazine Exposures through Drinking Water: Exposure Assessments for Ohio, Illinois, And Iowa. PMID- 22201390 TI - Degradation of organophosphorus pesticides and their transformation products in estuarine waters. PMID- 22201389 TI - Rapid distillationless "free cyanide" determination by a flow injection ligand exchange method. PMID- 22201391 TI - Reductive dechlorination of carbon tetrachloride in water catalyzed by mineral supported biomimetic cobalt macrocycles. PMID- 22201392 TI - Metal ion binding to humic substances: application of the non-ideal competitive adsorption model. PMID- 22201393 TI - Fate of microbial metabolites of hydrocarbons in a coastal plain aquifer: the role of electron acceptors. PMID- 22201394 TI - Normalization and elemental sediment contamination in the coastal United States. PMID- 22201396 TI - Biomass burning in the Amazon: characterization of the ionic component of aerosols generated from flaming and smoldering rainforest and savannah. PMID- 22201395 TI - Microbial transformations and biological effects of fungicide-derived benzothiazoles determined in industrial wastewater. PMID- 22201397 TI - Monitoring Methods for Polycyclic Aromatic Hydrocarbons and Their Distribution in House Dust and Track-in Soil. PMID- 22201398 TI - TiO2-Mediated Photochemical Disinfection of Escherichia coli Using Optical Fibers. PMID- 22201399 TI - Fractionation and oxidation of chromium in tannery waste- and sewage sludge amended soils. PMID- 22201401 TI - Factors Associated with PCB Concentrations in Lake Michigan Fish. PMID- 22201400 TI - Reduced mineralization of low concentrations of phenanthrene because of sequestering in nonaqueous-phase liquids. PMID- 22201402 TI - Alkoxy Radical Isomerization Products from the Gas-Phase OH Radical-Initiated Reactions of 2,4-Dimethyl-2-pentanol and 3,5-Dimethyl-3-hexanol. PMID- 22201403 TI - Effect of aging of chemicals in soil on their biodegradability and extractability. PMID- 22201405 TI - Comment on "bioremediation in the rhizosphere". PMID- 22201404 TI - Investigation of a sequential filtration technique for particle fractionation. PMID- 22201406 TI - Bioremediation in the biosphere. Reply to comments. PMID- 22201407 TI - The spawning of the "gray" literature. PMID- 22201408 TI - Complete remission after bevacizumab plus temozolomide in a patient with recurrent glioblastoma multiforme. PMID- 22201409 TI - Role of neck ultrasound during follow-up care of head and neck squamous cell carcinomas. AB - CONCLUSION: No impact of neck ultrasound on the detection rate of neck recurrences of head and neck squamous cell carcinomas (HNSCCs) was seen. The outcome of salvage therapy was not influenced by close neck ultrasound monitoring during follow-up. Tendencies of earlier detection of neck recurrences were noticed. OBJECTIVES: Neck ultrasound is more feasible for frequent application than computed tomography, while having comparable sensitivity and specificity in detecting neck metastasis. Before this study the effect of neck ultrasound on salvage therapy of neck recurrences when used in short defined intervals during follow-up was unknown. METHODS: A total of 140 patients with primarily surgically treated HNSCC were enrolled in a follow-up program with defined close time intervals. Neck ultrasound was applied during every follow-up visit. Recurrence rate, survival rate, and outcome of salvage therapy were determined. RESULTS: Overall recurrences occurred in 35.0% of patients. Local, regional, and distant recurrences were found in 11.4%, 7.9%, and 15.7%. Hypopharyngeal carcinoma and advanced staged tumor showed highest recurrence rates. In all, 24.5% of all recurrences were treated successfully by salvage therapy. Resection of local, regional, and distant recurrences resulted in 3-year survival rates of 43.8%, 36.4%, and 4.5%. The outcome of secondary therapy worsened with advancing initial primary tumor stage. PMID- 22201410 TI - Preparation and fuel cell performance of catalyst layers using sulfonated polyimide ionomers. AB - Sulfonated polyimide (SPI-8) ionomers were used as binders in the catalyst layers, and their fuel cell performance was evaluated. SPI-8 ionomers functioned well in the anode with only minor overpotential even at low humidity (50% relative humidity (RH)). In contrast, the cathode performance was significantly dependent on the content and molecular weight of the ionomers and humidity of the supplied gases. Higher molecular weight of the ionomer caused larger potential drop at high current density at 80 and 100% RH since oxygen supply and/or water discharge became insufficient due to higher water uptake (swelling) of the ionomer. Similar results were obtained at higher ionomer content, because of the increase of thickness in the catalyst layer. The mass transport was improved with decreasing humidity, however, proton conductivity became lower. While the maximum values of j(@0.70 V) for all membrane electrode assemblies (MEAs) were ca. 0.35 A/cm(2), each electrode could have the different appropriate operating conditions. The results suggest that the parameters such as oxygen supply, proton conductivity, and water uptake and discharge need to be carefully optimized in the catalyst layers for achieving reasonable cathode performance with hydrocarbon ionomers. PMID- 22201411 TI - But for the bad, there would not be good: Grounding valence in brightness through shared relational structures. AB - Light and dark are used pervasively to represent positive and negative concepts. Recent studies suggest that black and white stimuli are automatically associated with negativity and positivity. However, structural factors in experimental designs, such as the shared opposition in the valence (good vs. bad) and brightness (light vs. dark) dimensions might play an important role in the valence-brightness association. In 6 experiments, we show that while black ideographs are consistently judged to represent negative words, white ideographs represent positivity only when the negativity of black is coactivated. The positivity of white emerged only when brightness and valence were manipulated within participants (but not between participants) or when the negativity of black was perceptually activated by presenting positive and white stimuli against a black (vs. gray) background. These findings add to an emerging literature on how structural overlap between dimensions creates associations and highlight the inherently contextualized construction of meaning structures. PMID- 22201412 TI - Dissociating contingency awareness and conditioned attitudes: evidence of contingency-unaware evaluative conditioning. AB - Whether human evaluative conditioning can occur without contingency awareness has been the subject of an intense and ongoing debate for decades, troubled by a wide array of methodological difficulties. Following recent methodological innovations, the available evidence currently points to the conclusion that evaluative conditioning effects do not occur without contingency awareness. In a simulation, we demonstrate, however, that these innovations are strongly biased toward the conclusion that evaluative conditioning requires contingency awareness, confounding the measurement of contingency memory with conditioned attitudes. We adopt a process-dissociation procedure to separate the memory and attitude components. In 4 studies, the attitude parameter is validated using existing attitudes and applied to probe for contingency-unaware evaluative conditioning. A fifth experiment incorporates a time-delay manipulation confirming the dissociability of the attitude and memory components. The results indicate that evaluative conditioning can produce attitudes without conscious awareness of the contingencies. Implications for theories of evaluative conditioning and associative learning are discussed. PMID- 22201413 TI - Individual differences in the strength of taxonomic versus thematic relations. AB - Knowledge about word and object meanings can be organized taxonomically (fruits, mammals, etc.) on the basis of shared features or thematically (eating breakfast, taking a dog for a walk, etc.) on the basis of participation in events or scenarios. An eye-tracking study showed that both kinds of knowledge are activated during comprehension of a single spoken word, even when the listener is not required to perform any active task. The results further revealed that an individual's relative activation of taxonomic relations compared to thematic relations predicts that individual's tendency to favor taxonomic over thematic relations when asked to choose between them in a similarity judgment task. These results indicate that individuals differ in the relative strengths of their taxonomic and thematic semantic knowledge and suggest that meaning information is organized in 2 parallel, complementary semantic systems. PMID- 22201414 TI - On the dynamics of action representations evoked by names of manipulable objects. AB - Two classes of hand action representations are shown to be activated by listening to the name of a manipulable object (e.g., cellphone). The functional action associated with the proper use of an object is evoked soon after the onset of its name, as indicated by primed execution of that action. Priming is sustained throughout the duration of the word's enunciation. Volumetric actions (those used to simply lift an object) show a negative priming effect at the onset of a word, followed by a short-lived positive priming effect. This time-course pattern is explained by a dual-process mechanism involving frontal and parietal lobes for resolving conflict between candidate motor responses. Both types of action representations are proposed to be part of the conceptual knowledge recruited when the name of a manipulable object is encountered, although functional actions play a more central role in the representation of lexical concepts. PMID- 22201415 TI - Attention and working memory capacity: insights from blocking, highlighting, and knowledge restructuring. AB - The concept of attention is central to theorizing in learning as well as in working memory. However, research to date has yet to establish how attention as construed in one domain maps onto the other. We investigate two manifestations of attention in category- and cue-learning to examine whether they might provide common ground between learning and working memory. Experiment 1 examined blocking and highlighting effects in an associative learning paradigm, which are widely thought to be attentionally mediated. No relationship between attentional performance indicators and working memory capacity (WMC) was observed, despite the fact that WMC was strongly associated with overall learning performance. Experiment 2 used a knowledge restructuring paradigm, which is known to require recoordination of partial category knowledge using representational attention. We found that the extent to which people successfully recoordinated their knowledge was related to WMC. The results illustrate a link between WMC and representational-but not dimensional-attention in category learning. PMID- 22201416 TI - Comparative studies on some metrics for external validation of QSPR models. AB - Quantitative structure-property relationship (QSPR) models used for prediction of property of untested chemicals can be utilized for prioritization plan of synthesis and experimental testing of new compounds. Validation of QSPR models plays a crucial role for judgment of the reliability of predictions of such models. In the QSPR literature, serious attention is now given to external validation for checking reliability of QSPR models, and predictive quality is in the most cases judged based on the quality of predictions of property of a single test set as reflected in one or more external validation metrics. Here, we have shown that a single QSPR model may show a variable degree of prediction quality as reflected in some variants of external validation metrics like Q2(F1), Q2(F2), Q2(F3), CCC, and r2(m) (all of which are differently modified forms of predicted variance, which theoretically may attain a maximum value of 1), depending on the test set composition and test set size. Thus, this report questions the appropriateness of the common practice of the "classic" approach of external validation based on a single test set and thereby derives a conclusion about predictive quality of a model on the basis of a particular validation metric. The present work further demonstrates that among the considered external validation metrics, r2(m) shows statistically significantly different numerical values from others among which CCC is the most optimistic or less stringent. Furthermore, at a given level of threshold value of acceptance for external validation metrics, r2(m) provides the most stringent criterion (especially with Deltar2(m) at highest tolerated value of 0.2) of external validation, which may be adopted in the case of regulatory decision support processes. PMID- 22201417 TI - Covalently functionalized single-walled carbon nanotubes at reverse micellar interface: a strategy to improve lipase activity. AB - The present work reports covalent functionalization of single-walled carbon nanotubes (f-SWNTs) to introduce hydrophilicity to the otherwise amphiphobic nanotubes. The charge and spacer length of the functional moiety were varied by using quaternized ethylene diamine, 6-aminocaproate, quaternized (ethylenedioxy)bis(ethylamine), and a poly(ethylene glycol) (PEG) unit (f-SWNT-1 to f-SWNT-4, respectively). These f-SWNTs with varying degrees of hydrophilicity were incorporated within cetyltrimethyl ammonium bromide (CTAB) reverse micelles to develop stable self-assembled nanohybrids. An optimum hydrophilicity on the SWNT surface led to interfacial localization of f-SWNTs resulting in the augmentation of space at the interface. A surface-active enzyme, lipase, localized at this enhanced interface of f-SWNT-containing CTAB reverse micelles exhibited significant activation (2.5-fold) compared to that in the absence of the nanoconstructs. This improvement in lipase activity was mainly due to the smooth occupancy of lipase and also presumably because of the increase in the concentrations of both substrate and the enzyme at the augmented interface. Interestingly, the f-SWNTs that activate lipase in reverse micelles deactivate the same enzyme in water. The dispersion of f-SWNTs in water and its matching integration at the interface of reverse micelles were confirmed through transmission electron microscopic (TEM) investigations. The interfacial localization of these nanoconstructs was also established from the distinct fluorescence behavior of a hydrophobic fluorescent probe, fluorescein isothiocyanate (FITC), adsorbed onto the f-SWNT surface. In concurrence with the observed lipase activity, the corresponding changes in the enzyme conformation within f-SWNTs integrated reverse micelle as well as in aqueous medium were studied by circular dichroism (CD) and Fourier transform infrared (FTIR) spectroscopy. PMID- 22201418 TI - Ureteroscopy for transplant lithiasis. AB - BACKGROUND AND PURPOSE: The optimal management of renal and ureteral calculi in transplanted kidneys is not well defined. Although larger (>1.5 cm) stone burdens are generally treated with percutaneous nephrolithotomy (PCNL), smaller stones may be reasonably approached with retrograde or antegrade ureteroscopy (URS). We report our multicenter experience with URS for transplant lithiasis. PATIENTS AND METHODS: URS performed for stone disease within a transplanted kidney were retrospectively identified at three stone-referral centers between 2006 and 2011. Demographic and disease parameters were recorded, as were perioperative and postoperative details. RESULTS: Twelve patients underwent URS for a calculus in a transplant renal unit and/or ureter. For retrograde procedures (7), access to the ureteral orifice was facilitated by the use of a Kumpe catheter; a two-wire (safety and working guidewire) technique was used. For antegrade procedures (5), the ureteroscope was passed into the kidney using a two-wire technique without tract dilation. All stones but one necessitated holmium:yttrium-aluminum-garnet laser lithotripsy with extraction of stone fragments. All patients were stone free on postoperative imaging except for one patient with a 2-mm fragment that was observed. Stone analysis included calcium oxalate (6), calcium phosphate (4), and struvite (1). CONCLUSION: Antegrade and retrograde URS are safe and effective treatments for patients with simple stone burdens in a transplanted kidney. Although retrograde access to the ureter can be challenging, specialized techniques and modern endoscope technology facilitate this process. Antegrade URS for small stone burdens can be performed safely and effectively without tract dilation. PMID- 22201419 TI - Spotlight on ustekinumab in moderate to severe plaque psoriasis. AB - Ustekinumab (StelaraTM) is a human monoclonal antibody that binds to the p40 subunit common to both interleukin (IL)-12 and IL-23. It is indicated in the US for use in adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. In the EU, it is indicated for those who failed to respond to, have a contraindication to, or are intolerant of other systemic therapies or phototherapy. In well designed, randomized clinical trials, regimens of subcutaneous ustekinumab 45 or 90 mg provided a rapid and durable improvement in Psoriasis Area and Severity Index scores for patients with moderate to severe plaque psoriasis. Treatment with ustekinumab 45 or 90 mg also improved health-related quality-of-life scores from baseline. More limited data indicate that ustekinumab also improves the symptoms of arthritis in patients with plaque psoriasis and psoriatic arthritis. Subcutaneous ustekinumab was generally well tolerated in clinical trials; most adverse events were mild in intensity and did not require dosage adjustment. A pooled analysis of clinical trial data indicated no specific patterns of infection for recipients of ustekinumab and that infection rates remained stable following cumulative exposure to the agent. Thus, subcutaneous ustekinumab provides an effective and well tolerated alternative for the symptomatic treatment of patients with moderate to severe plaque psoriasis. PMID- 22201420 TI - Reusable antifouling viscoelastic adhesive with an elastic skin. AB - Although the viscoelasticity or tackiness of a pressure-sensitive adhesive gives it strength owing to energy dissipation during peeling, it also renders it nonreusable because of structural changes such as the formation of fibrils, cohesive failure, and fouling. However, an elastic layer has good structural integrity and cohesive strength but low adhesive energy. We demonstrate an effective composite adhesive in which a soft viscoelastic bulk layer is imbedded in a largely elastic thin skin layer. The composite layer is able to meet the conflicting demands of the high peel strength comparable to the viscoelastic core and the structural integrity, reusability, and antifouling properties of the elastic skin. Our model adhesive is made of poly(dimethylsiloxane), where its core and skin are created by varying the cross-linking percentage from 2 to 10%. PMID- 22201421 TI - Bicunningines A and B, two new dimeric diterpenes from Cunninghamia lanceolata. AB - Two unprecedented dimeric diterpenoids, with a 2,3-dihydrofuran ring fusing an abietane and a 4,5-seco-abietane diterpene, were isolated from Cunninghamia lanceolata. Their structures were elucidated by spectroscopic measurements, and their absolute configurations were determined by quantum chemical TDDFT ECD calculations, chemical transformations, and Mosher's method. The Mosher method carried out with MPA and MTPA esters of the sterically hindered sec-hydroxyl group gave contradictory results, while MPA afforded the correct absolute configuration. PMID- 22201445 TI - Comparison of noninvasive evaluation of endolymphatic hydrops in Meniere's disease and endolymphatic space in healthy volunteers using magnetic resonance imaging. AB - CONCLUSIONS: The comparison of noninvasive standard evaluation of endolymphatic hydrops in Meniere's disease and the endolymphatic space in healthy volunteers using magnetic resonance imaging (MRI) evaluation should be carried out first. OBJECTIVE: To compare the standard evaluation of endolymphatic hydrops in Meniere's disease and the endolymphatic space in healthy volunteers in the cochlea and the vestibule in the same age group by applying noninvasive intratympanic gadolinium (Gd) perfusion through the eustachian tube and three dimensional fluid-attenuated inversion recovery magnetic resonance imaging (3D FLAIR MRI). METHODS: This was a prospective study. 3D-FLAIR MRI was performed with a 3 Tesla (3 T) unit 24 h after intratympanic administration of Gd through the eustachian tube in 6 patients with medically active and intractable Meniere's disease and 20 healthy volunteers. Pure tone test and tympanometry were performed 24 h before Gd was administered, and 24 h and 1 month after Gd administration. RESULTS: Gd was present in the perilymph of the inner ear, which clearly displayed the endolymphatic space on 3D-FLAIR MRI with a visible borderline between the perilymph and the endolymph. In 45-55-year-old healthy volunteers, the normal value for the endolymphatic space in the cochlea ranged between 8% and 26%, and that in the vestibule was between 20% and 41%. According to the normal value for the endolymphatic space, four of six patients had a ratio of more than 26% in the cochlea; moreover, four of six patients had a ratio of more than 41% in the vestibule. All the patients had a ratio of more than the normal value in the cochlea and/or the vestibule. No significant changes in pure tone test and tympanometry were noted. PMID- 22201446 TI - Copper oxide nanoparticle mediated DNA damage in terrestrial plant models. AB - Engineered nanoparticles, due to their unique electrical, mechanical, and catalytic properties, are presently found in many commercial products and will be intentionally or inadvertently released at increasing concentrations into the natural environment. Metal- and metal oxide-based nanomaterials have been shown to act as mediators of DNA damage in mammalian cells, organisms, and even in bacteria, but the molecular mechanisms through which this occurs are poorly understood. For the first time, we report that copper oxide nanoparticles induce DNA damage in agricultural and grassland plants. Significant accumulation of oxidatively modified, mutagenic DNA lesions (7,8-dihydro-8-oxoguanine; 2,6 diamino-4-hydroxy-5-formamidopyrimidine; 4,6-diamino-5-formamidopyrimidine) and strong plant growth inhibition were observed for radish (Raphanus sativus), perennial ryegrass (Lolium perenne), and annual ryegrass (Lolium rigidum) under controlled laboratory conditions. Lesion accumulation levels mediated by copper ions and macroscale copper particles were measured in tandem to clarify the mechanisms of DNA damage. To our knowledge, this is the first evidence of multiple DNA lesion formation and accumulation in plants. These findings provide impetus for future investigations on nanoparticle-mediated DNA damage and repair mechanisms in plants. PMID- 22201447 TI - Labile zinc-assisted biological phosphate chemosensing and related molecular logic gating interpretations. AB - Herein, molecular fluorescence 'OFF-ON' behavior with aqueous addition of biological phosphate and Zn(2+) is studied with Zn(2)(slys)(2)Cl(2) [H(2)slys = 6 amino-2-{(2-hydroxybenzylidene)amino}hexanoic acid], a fluorescent water-soluble complex, using various spectroscopic tools (e.g., (31)P NMR, UV-vis, emission, and CD spectroscopy) at the micromolar level. Adduct-dependent fluorescence intensity changes can be interpreted as a two-input (cation/anion) implication molecular logic gating system. A displacement study of PPi from the dizinc complex is also reported. Diphosphate and triphosphate addition/displacements were also studied. (31)P NMR spectroscopy shows gradual NMR peak shifts from bound ADP/GDP to free ADP/GDP with increasing [PPi]. In the emission spectrum, fluorescence quenching is shown: CD signal maxima decrease with addition of PPi. These displacement events are also tested with triphosphates (ATP, GTP), and their binding strength/displacement ability over ADP/GDP is quantified: PPi > ATP ~ GTP (3.35 +/- 0.77 * 10(4) M(-1) for PPi, 7.73 +/- 1.79 * 10(3) M(-1) for ATP, 9.21 +/- 2.88 * 10(3) M(-1) for GTP over 1.ADP). Many anions and cations were also screened for selectivity. Tubulin polymerization was assayed in the presence of 1 and its copper analogue which reflected a slight inhibition in polymerization. PMID- 22201448 TI - Multiple imitation mechanisms in children. AB - Four studies using a computerized paradigm investigated whether children's imitation performance is content-specific and to what extent dependent on other cognitive processes such as trial-and-error learning, recall, and observational learning. Experiment 1 showed that 3-year-olds could successfully imitate what we call novel cognitive rules (e.g., first -> second -> third), which involved responding to 3 different pictures whose spatial configuration varied randomly from trial to trial. However, these same children failed to imitate what we call novel motor-spatial rules (e.g., up -> down -> right), which involved responding to 3 identical pictures that remained in a fixed spatial configuration from trial to trial. Experiment 2 showed that this dissociation was not due to a general difficulty in encoding motor-spatial content, as children successfully recalled, following a 30-s delay, a new motor-spatial sequence that had been learned by trial and error. Experiment 3 replicated these results and further demonstrated that 3-year-olds can infer a novel motor-spatial sequence following observation of a partially correct and partially incorrect response-a dissociation between imitation and observational learning (or emulation learning). Finally, Experiment 4 presented 3-year-olds with "familiar" motor-spatial sequences that involved making a linear response (e.g., left -> middle -> right) as well as "novel" motor spatial sequences (e.g., right -> up -> down) used in Experiments 1-3 that were nonlinear and always involved a change in direction. Children had no difficulty imitating familiar motor-spatial sequences but again failed to imitate novel motor-spatial sequences. These results suggest that there may be multiple, dissociable imitation learning mechanisms that are content-specific. More importantly, the development of these imitation systems appears to be independent of the operations of other cognitive systems, including trial and error learning, recall, and observational learning. PMID- 22201449 TI - Mother-child communication about location: giving and following directions for finding hidden objects. AB - We conducted 2 experiments to examine how mothers structure directions to young children for finding hidden objects and how young children use these directions to guide their searches. In Experiment 1, we examined the reference frames mothers use to communicate with their 2.5-, 3-, and 3.5-year-old children about location by asking mothers to verbally disambiguate a target hiding container from an identical nontarget hiding container. We found that mothers' reference frame use was primarily governed by the relative proximity of the target container to the landmark and themselves. Older children were more successful in following directions than were younger children, and children were more likely to search successfully in response to a person than to a landmark frame of reference. In Experiment 2, we further investigated how 3-year-old children follow directions involving person and landmark frames of reference by asking mothers to use either only themselves or only the landmark to describe the target location. Children in the person reference frame condition successfully followed their mother's directions when the target was relatively close to the mother, but not when the target was relatively far from the mother. Children in the landmark reference frame condition were at chance regardless of the relative proximity of the target to the landmark. The discussion focuses on the roles of spatial proximity and reference frames in mother-child spatial communication. PMID- 22201450 TI - Occam's rattle: children's use of simplicity and probability to constrain inference. AB - A growing literature suggests that generating and evaluating explanations is a key mechanism for learning and inference, but little is known about how children generate and select competing explanations. This study investigates whether young children prefer explanations that are simple, where simplicity is quantified as the number of causes invoked in an explanation, and how this preference is reconciled with probability information. Both preschool-aged children and adults were asked to explain an event that could be generated by 1 or 2 causes, where the probabilities of the causes varied across conditions. In 2 experiments, it was found that children preferred explanations involving 1 cause over 2 but were also sensitive to the probability of competing explanations. Adults, in contrast, responded on the basis of probability alone. These data suggest that children employ a principle of parsimony like Occam's razor as an inductive constraint and that this constraint is employed when more reliable bases for inference are unavailable. PMID- 22201451 TI - Coulomb blockade in a coupled nanomechanical electron shuttle. AB - We demonstrate single electron shuttling through two coupled nanomechanical pendula. The pendula are realized as nanopillars etched out of the semiconductor substrate. Coulomb blockade is found at room temperature, allowing metrological applications. By controlling the mechanical shuttling frequency we are able to validate the different regimes of electron shuttling. PMID- 22201452 TI - Long-term middle ear pressure measurements in inner ear disorders. AB - CONCLUSION: Repetitive portable tympanometry is a feasible method to examine long term middle ear pressure profile. This method might be suitable for detecting patients with Meniere's disease whose middle ear pressure shows intermittently pathological values. OBJECTIVES: Contradictory study results regarding middle ear pressure in patients with Meniere's disease might be due to solitary tympanometric measurements. Pathological pressure conditions in patients with pressure regulation disorders might be missed by a single examination. The aim of the study was to examine the pressure profile of patients with Meniere's disease by long-term measurements. METHODS: Patients with Meniere's disease (n = 33), patients with sudden hearing loss (n = 20), and healthy subjects (n = 30) were examined. Patients carried out long-term middle ear pressure measurements with the portable tympanometer Otoflex 100. Examinations were carried out during daily activities at defined time intervals. RESULTS: Significant negative middle ear pressure were seen in patients with Meniere's disease compared with patients with sudden hearing loss and healthy subjects (p < 0.01). Average middle ear pressure in patients with Meniere's disease was -43 daPa, in patients with sudden hearing loss it was 2 daPa, and in healthy subjects it was 4 daPa. Patients with Meniere's disease showed a large variability of pressure values ranging from strongly pathological to normal values during long-term measurements. PMID- 22201453 TI - Tenotomy of the middle ear muscles causes a dramatic reduction in vertigo attacks and improves audiological function in definite Meniere's disease. AB - CONCLUSIONS: Because the presented data reveal an immediate and persistent reduction of vertigo and a clear improvement in hearing function and functional scales, we conclude tenotomy to be effective in unilateral, definite Meniere's disease - laying the foundation for future prospective, randomized controlled trials. OBJECTIVES: This study compares the unique long-term results of tenotomy of the stapedius and tensor tympani muscles in definite Meniere's disease refractory to medical treatment and presents a hypothesis on why tenotomy seems effective. METHODS: This was an interventional cohort study. The study sample comprised 30 patients (15 males, 15 females; average age 57 +/- 13.1 years) with definite Meniere's disease (AAO-HNS criteria, 1995). Patients were evaluated pre- and postoperatively using pure tone audiometry, AAO-HNS questionnaires regarding vertigo attacks, functional level scores, and tinnitus, and were followed up for 2-9 years. Postoperative values were calculated for the patient collective as a whole and consequently divided into three equal postoperative terms of 3 years each. RESULTS: A statistically significant improvement of inner ear hearing levels postoperatively (p = 0.041) and a major reduction in vertigo attacks in all groups (p < 0.001) with complete absence of attacks in 26/30 patients was noted. Results remained constant up to 9 years postoperatively. Although tinnitus persisted, the intensity was lower overall (p = 0.013). PMID- 22201454 TI - Nanospheric [M20(OH)12(maleate)12(Me2NH)12]4+ clusters (M = Co, Ni) with O(h) symmetry. AB - Nanospheric hydroxo-bridged clusters of [M(20)(OH)(12)(maleate)(12)(Me(2)NH)(12)](BF(4))(3)(OH).nH(2)O (M = Co (1), Ni (2)) with O(h) symmetry were afforded under hydrothermal condition with Co(BF(4))(2).6H(2)O/Ni(BF(4))(2).6H(2)O and fumaric acid in a DMF/EtOH mixed solvent. They are characterized by elemental analysis, IR, and X-ray diffraction. X-ray single crystal diffraction analyses show that these two complexes are isostructural containing an ideally cubic M(8) core in that each two M atoms are doubly bridged at the edges by one OH(-) and one maleate, while these OH(-) and maleate groups are coordinated further by exterior identical 12 M atoms which construct a perfect M(12) icosahedron to encapsulate the cubic core. To our knowledge, such large clusters with O(h) symmetry are seldom. The variable temperature magnetic susceptibility studies reveal that these two isostructures exhibit antiferromagnetic interactions. PMID- 22201455 TI - Evaluation of creatinine, cystatin C and eGFR by different equations in professional cyclists during the Giro d'Italia 3-weeks stage race. AB - Abstract In this study, creatinine-based equations to evaluate glomerular filtration rate (eGFR) were proposed to more accurately assess kidney function, and cystatin C, a parameter not dependent on muscular mass, was introduced to improve GFR calculation in professional cyclists during a long-lasting race. Nine cyclists participating in the 2011 Giro d'Italia were recruited. Blood and anthropometrical data were collected the day before (T-1) the race, on the 12th day (T 12) and on the 22nd day (T 22) of the race. Haemoglobin and haematocrit were registered. Haemodilution was observed at T 12, whilst stabilization was evident at T 22. Creatinine, cystatin C concentrations and eGFR values were not modified during the observed period; only GFR evaluated with the Cockcroft-Gault (CG) formula and expressed as ml/min/1.73 m(2) significantly decreased (p < 0.05) at T 22 in comparison with T-1, probably as a consequence of weight decrease. Cystatin C levels were in the reference range, while creatinine concentrations were lower. The lowest eGFR values were observed with CG normalized and the Modification of Diet in Renal Disease (MDRD) formulas. A good correlation was observed between the MDRD and the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations and between CG normalized and both CKD-EPI and MDRD formulas. The worst correlation was registered between CKD-EPI creatinine and cystatin C and all the other equations. In conclusion, adaptive mechanisms of renal function allow athletes to maintain stable creatinine, cystatin C and eGFR values during a long-lasting race. The use of GFR equations to evaluate general health status of sportsmen should be recommended with caution, considering also weight modification during competition. PMID- 22201456 TI - Phyto-inspired silica nanowires: characterization and application in lipase immobilization. AB - Silica nanostructures were phyto-fabricated on different surfaces by using pomegranate (Punica granatum) leaf extracts. On zinc films, nanowires were obtained. On other surfaces such as silica, alumina, zinc oxide, and glass, spherical aggregates, cubic assemblies, microflakes, and acicular structures, respectively, were observed. The nanowires developed on Zn surfaces were characterized by scanning electron microscope-energy dispersive spectrometer (SEM EDS), X-ray diffraction (XRD), photoluminescence, and Fourier transform infrared (FTIR) spectroscopic analysis. XRD profiles displayed peaks at 2.4, 4.9, and 12.1 degrees indicating the presence of silica nanostructures. When excited at 340 nm, the reaction mixtures displayed a characteristic blue luminescence at 404 nm. FTIR spectra showed the existence of Si-OH and Si-O-Si bonds. The nanowires were functionalized with amine groups and used for the covalent immobilization of Candida rugosa lipase. The immobilized enzyme displayed better pH and temperature stability and retained 80% activity after 20 cycles. This paper highlights a novel route for the phyto-mediated growth of silica nanowires on Zn surfaces, their characterization and effective use as a matrix for enzyme immobilization. PMID- 22201457 TI - Gap surface plasmon waveguides with enhanced integration and functionality. AB - We propose and investigate theoretically and experimentally L-shaped gap surface plasmon waveguides (L-GSPWs) formed by a dielectric film (strip) partially enclosed between two metal films. The proposed L-GSPWs combine the benefits of strong plasmon localization in a nanogap, significant propagation distance, low cross-talk between two neighboring waveguides, high transmission through a sharp 90 degrees bend, and simplicity of fabrication by means of the standard lithography combined with the thin film deposition. PMID- 22201458 TI - Metastable Ge1-xCx alloy nanowires. AB - Carbon-containing alloy materials such as Ge(1-x)C(x) are attractive candidates for replacing silicon (Si) in the semiconductor industry. The addition of carbon to diamond lattice not only allows control over the lattice dimensions, but also enhances the electrical properties by enabling variations in strain and compositions. However, extremely low carbon solubility in bulk germanium (Ge) and thermodynamically unfavorable Ge-C bond have hampered the production of crystalline Ge(1-x)C(x) alloy materials in an equilibrium growth system. Here we successfully synthesized high-quality Ge(1-x)C(x) alloy nanowires (NWs) by a nonequilibrium vapor-liquid-solid (VLS) method. The carbon incorporation was controlled by NW growth conditions and the position of carbon atoms in the Ge matrix (at substitutional or interstitial sites) was determined by the carbon concentration. Furthermore, the shrinking of lattice spacing caused by substitutional carbon offered the promising possibility of band gap engineering for photovoltaic and optoelectronic applications. PMID- 22201459 TI - Potential use of glucuronylglucosyl-beta-cyclodextrin/dendrimer conjugate (G2) as a DNA carrier in vitro and in vivo. AB - In this study, we evaluated the polyamidoamine starburst dendrimer (dendrimer, generation 2: G2) conjugate with 6-O-alpha-(4-O-alpha-D-glucuronyl)-D-glucosyl beta-cyclodextrin (GUG-beta-CDE (G2)) as a gene transfer carrier. The in vitro gene transfer activity of GUG-beta-CDE (G2, degree of substitution (DS) of cyclodextrin (CyD) 1.8) was remarkably higher than that of dendrimer (G2) conjugate with alpha-CyD (alpha-CDE (G2, DS 1.2)) and that with beta-CyD(beta-CDE (G2, DS 1.3)) in A549 and RAW264.7 cells. The particle size, zeta-potential, DNase I-catalyzed degradation, and cellular association of plasmid DNA (pDNA) complex with GUG-beta-CDE (G2, DS 1.8) were almost the same as those of the other CDEs. Fluorescent-labeled GUG-beta-CDE (G2, DS 1.8) localized in the nucleus 6 h after transfection of its pDNA complex in A549 cells, suggesting that nuclear localization of pDNA complex with GUG-beta-CDE (G2, DS 1.8), at least in part, contributes to its high gene transfer activity. GUG-beta-CDE (G2, DS 1.8) provided higher gene transfer activity than alpha-CDE (G2, DS 1.2) and beta-CDE (G2, DS 1.3) in kidney with negligible changes in blood chemistry values 12 h after intravenous injection of pDNA complexes with GUG-beta-CDE (G2, DS 1.8) in mice. In conclusion, the present findings suggest that GUG-beta-CDE (G2, DS 1.8) has the potential for a novel polymeric pDNA carrier in vitro and in vivo. PMID- 22201460 TI - Illusory continuity without sufficient sound energy to fill a temporal gap: examples of crossing glide tones. AB - The gap transfer illusion is an auditory illusion where a temporal gap inserted in a longer glide tone is perceived as if it were in a crossing shorter glide tone. Psychophysical and phenomenological experiments were conducted to examine the effects of sound-pressure-level (SPL) differences between crossing glides on the occurrence of the gap transfer illusion. We found that the subjective continuity-discontinuity of the crossing glides changed as a function of the relative level of the shorter glide to the level of the longer glide. When the relative level was approximately between -9 and +2 dB, listeners perceived the longer glide as continuous and the shorter glide as discontinuous, that is, the gap transfer illusion took place. The glides were perceived veridically below this range, that is, gap transfer did not take place, whereas above this range the longer glide and the shorter glide were both perceived as continuous. The fact that the longer glide could be perceived as continuous even when the crossing shorter glide was 9 dB weaker indicates that the longer glide's subjective continuity cannot be explained within the conventional framework of auditory organization, which assumes reallocation of sound energy from the shorter to the longer glide. The implicated mechanisms are discussed in terms of the temporal configuration of onsets and terminations and the time-frequency distribution of sound energy. PMID- 22201461 TI - Tie my hands, tie my eyes. AB - Previous studies have demonstrated that motor abilities allow us not only to execute our own actions and to predict their consequences, but also to predict others' actions and their consequences. But just how deeply are motor abilities implicated in action observation? If an observer is prevented from acting while witnessing others' actions, will this impact on their making sense of others' behavior? We recorded proactive eye movements while participants observed an actor grasping objects. The participants' hands were either freely resting on the table or tied behind their back. Proactivity of gaze behavior was dramatically impaired when participants observed others' actions with their hands tied. Since we don't literally perceive actions with our hands, the effect may be explained by the hypothesis that effective observation of action depends not only on motor abilities but on being in a position to exercise them. This suggests, for the first time, that actions are observed best when we are actually in the position to perform them. PMID- 22201462 TI - Do endogenous and exogenous action control compete for perception? AB - Human actions are guided either by endogenous action plans or by external stimuli in the environment. These two types of action control seem to be mediated by neurophysiologically and functionally distinct systems that interfere if an endogenously planned action suddenly has to be performed in response to an exogenous stimulus. In this case, the endogenous representation has to be deactivated first to give way to the exogenous system. Here we show that interference of endogenous and exogenous action control is not limited to motor related aspects but also affects the perception of action-related stimuli. Participants associated two actions with contingent sensory effects in learning blocks. In subsequent test blocks, preparing one of these actions specifically impaired responding to the associated effect in an exogenous speeded detection task, yielding a blindness-like effect for arbitrary, learned action effects. In accordance with the theory of event coding, this finding suggests that action planning influences perception even in the absence of any physical similarities between action and to-be-perceived stimuli. PMID- 22201463 TI - Does ease to block a ball affect perceived ball speed? Examination of alternative hypotheses. AB - According to an action-specific account of perception, the perceived speed of a ball can be a function of the ease to block the ball. Balls that are easier to stop look like they are moving slower than balls that are more difficult to stop. This was recently demonstrated with a modified version of the classic computer game Pong (Witt & Sugovic, 2010). However, alternative explanations can also explain these results without resorting to nonoptical effects on perception. To examine whether blocking ease influences perception, we conducted several experiments. We examined whether the apparent effects were due to the type of perceptual judgment, the timing of the judgment, and the effectiveness of the paddle. The results are consistent with a perceptual explanation, and help build a case that blocking ease can influence perceived speed. PMID- 22201464 TI - Attentional control in visual signal detection: effects of abrupt-onset and no onset stimuli. AB - The attention literature distinguishes two general mechanisms by which attention can benefit performance: gain (or resource) models and orienting (or switching) models. In gain models, processing efficiency is a function of a spatial distribution of capacity or resources; in orienting models, an attentional spotlight must be aligned with the stimulus location, and processing efficiency is a function of when this occurs. Although they involve different processing mechanisms, these models are difficult to distinguish empirically. We compared performance with abrupt-onset and no-onset Gabor patch stimuli in a cued detection task in which we obtained distributions of reaction time (RT) and accuracy as a function of stimulus contrast. In comparison to abrupt-onset stimuli, RTs to miscued no-onset stimuli were increased and accuracy was reduced. Modeling the data with the integrated system model of Philip L. Smith and Roger Ratcliff (2009) provided evidence for reallocation of processing resources during the course of a trial, consistent with an orienting account. Our results support a view of attention in which processing efficiency depends on a dynamic spatiotemporal distribution of resources that has both gain and orienting properties. PMID- 22201465 TI - Operating characteristics of the implicit learning system supporting serial interception sequence learning. AB - The memory system that supports implicit perceptual-motor sequence learning relies on brain regions that operate separately from the explicit, medial temporal lobe memory system. The implicit learning system therefore likely has distinct operating characteristics and information processing constraints. To attempt to identify the limits of the implicit sequence learning mechanism, participants performed the serial interception sequence learning (SISL) task with covertly embedded repeating sequences that were much longer than most previous studies: ranging from 30 to 60 (Experiment 1) and 60 to 90 (Experiment 2) items in length. Robust sequence-specific learning was observed for sequences up to 80 items in length, extending the known capacity of implicit sequence learning. In Experiment 3, 12-item repeating sequences were embedded among increasing amounts of irrelevant nonrepeating sequences (from 20 to 80% of training trials). Despite high levels of irrelevant trials, learning occurred across conditions. A comparison of learning rates across all three experiments found a surprising degree of constancy in the rate of learning regardless of sequence length or embedded noise. Sequence learning appears to be constant with the logarithm of the number of sequence repetitions practiced during training. The consistency in learning rate across experiments and conditions implies that the mechanisms supporting implicit sequence learning are not capacity-constrained by very long sequences nor adversely affected by high rates of irrelevant sequences during training. PMID- 22201466 TI - Distinguishing different strategies of across-dimension attentional selection. AB - Selective attention in multidimensional displays has usually been examined using search tasks requiring the detection of a single target. We examined the ability to perceive a spatial structure in multi-item subsets of a display that were defined either conjunctively or disjunctively. Observers saw two adjacent displays and indicated whether the to-be-selected items within the two displays matched in terms of their spatial structure (the identity of the corresponding items within these subsets was not relevant to the task). The observers in our study could readily perceive conjunctively defined subsets, but had great difficulty with disjunctively defined subsets. The results pose a challenge to the popular idea that attention is guided by a "priority map" that sums bottom-up and top-down factors, whereas they are directly predicted by Boolean map theory of visual attention. PMID- 22201467 TI - Eye movements during scene recollection have a functional role, but they are not reinstatements of those produced during encoding. AB - Current debate in mental imagery research revolves around the perceptual and cognitive role of eye movements to "nothing" (Ferreira, Apel, & Henderson, 2008; Richardson, Altmann, Spivey, & Hoover, 2009). While it is established that eye movements are comparable when inspecting a scene (or hearing a scene description) as when visualizing it from memory (Johansson, Holsanova, & Holmqvist, 2006), the exact purpose of these eye movements remains elusive. Are eye movements during recall purely epiphenomenal or do they have a functional purpose? Here we address this question in four experiments where eye movements were prohibited either during the encoding or recall phases. Experiments 1 and 2 showed that maintaining central fixation during visual or auditory encoding, respectively, had no effect on how eye movements were executed during recall (but it did hinder memory retrieval). Thus, oculomotor events during recall are not reinstatements of those produced during encoding. When fixation was restricted during recall, Experiments 3 and 4 revealed that scene recollection was altered and impaired, irrespective of the modality of encoding. The functional role of eye movements during mental visualization is therefore apparent in this perturbation of visuospatial capabilities. PMID- 22201468 TI - Tagging multiple emotional stimuli: negative valence has little benefit. AB - Six experiments examined the influence of emotional valence on the tagging and enumeration of multiple targets. Experiments 1, 5 and 6 found that there was no difference in the efficiency of tagging/enumerating multiple negative or positive stimuli. Experiment 2 showed that, when neutral-expression face distractors were present, enumerating negative targets was faster overall, but was only more efficient for small numbers of targets. Experiments 3 and 4 determined that this negative target advantage was most likely caused by increased attentional guidance to negatively-valenced stimuli and was not based on simple visual feature differences. The findings suggest that a multiple-target negative stimulus advantage will only occur under conditions of attentional competition, and for relatively small numbers of targets. The results are discussed in relation to theories of multiple- and single-item processing, threat-priority mechanisms, and the types of representations that support different attentional tasks. PMID- 22201469 TI - The effect of fMRI (noise) on cognitive control. AB - Stressful situations, the aversiveness of events, or increases in task difficulty (e.g., conflict) have repeatedly been shown to be capable of triggering attentional control adjustments. In the present study we tested whether the particularity of an fMRI testing environment (i.e., EPI noise) might result in such increases of the cognitive control exerted. We found that participants were more effective in controlling episodic retrieval of previous stimulus-response bindings (Experiment 1), in switching to a new task (Experiment 2), and shielding a current goal from distracting response tendencies (Experiment 3) if they were exposed to challenging task situations, such as 70 dB echo planar imaging noise sampled from an fMRI scanner. These findings have considerable theoretical implications in questioning the widespread assumption that people are equally devoted to easy and more challenging tasks, and methodological implications in raising the possibility that experiments carried out in fMRI scanners or under otherwise challenging conditions systematically overestimate contributions from cognitive control processes. PMID- 22201470 TI - All set! Evidence of simultaneous attentional control settings for multiple target colors. AB - Although models of visual search have often assumed that attention can only be set for a single feature or property at a time, recent studies have suggested that it may be possible to maintain more than one attentional control setting. The aim of the present study was to investigate whether spatial attention could be guided by multiple attentional control settings for color. In a standard spatial cueing task, participants searched for either of two colored targets accompanied by an irrelevantly colored distractor. Across five experiments, results consistently showed that nonpredictive cues matching either target color produced a significant spatial cueing effect, while irrelevantly colored cues did not. This was the case even when the target colors could not be linearly separated from irrelevantly cue colors in color space, suggesting that participants were not simply adopting one general color set that included both target colors. The results could not be explained by intertrial priming by previous targets, nor could they be explained by a single inhibitory set for the distractor color. Overall, the results are most consistent with the maintenance of multiple attentional control settings. PMID- 22201471 TI - Moving along the mental number line: Interactions between whole-body motion and numerical cognition. AB - Active head turns to the left and right have recently been shown to influence numerical cognition by shifting attention along the mental number line. In the present study, we found that passive whole-body motion influences numerical cognition. In a random-number generation task (Experiment 1), leftward and downward displacement of participants facilitated small number generation, whereas rightward and upward displacement facilitated the generation of large numbers. Influences of leftward and rightward motion were also found for the processing of auditorily presented numbers in a magnitude-judgment task (Experiment 2). Additionally, we investigated the reverse effect of the number space association (Experiment 3). Participants were displaced leftward or rightward and asked to detect motion direction as fast as possible while small or large numbers were auditorily presented. When motion detection was difficult, leftward motion was detected faster when hearing small number and rightward motion when hearing large number. We provide new evidence that bottom-up vestibular activation is sufficient to interact with the higher-order spatial representation underlying numerical cognition. The results show that action planning or motor activity is not necessary to influence spatial attention. Moreover, our results suggest that self-motion perception and numerical cognition can mutually influence each other. PMID- 22201472 TI - Does equilibrium passive sampling reflect actual in situ bioaccumulation of PAHs and petroleum hydrocarbon mixtures in aquatic worms? AB - Over the past couple of years, several analytical methods have been developed for assessing the bioavailability of environmental contaminants in sediments and soils. Comparison studies suggest that equilibrium passive sampling methods generally provide the better estimates of internal concentrations in organisms and thus of subsequent risks. However, field studies to validate the potential of passive sampling to predict actual in situ bioaccumulation are scarce and limited information only exists on selected, individual compounds. The present study investigated whether bioaccumulation of PAH and complex petroleum hydrocarbon mixtures in field-exposed aquatic worms could be predicted properly with passive samplers. To this end, in situ bioaccumulation in aquatic worms at 6 PAH contaminated locations and 8 petroleum hydrocarbon (oil)-contaminated locations was compared with the results of in situ solid phase micro extraction (SPME) applications. For the oil-contaminated sediments, bioaccumulation was also assessed in the lab with polyoxymethylene solid phase extraction (POM-SPE). Actual PAH bioaccumulation was generally predicted within a factor of 4 with in situ SPME, using temperature-adjusted SPME fiber-water partition coefficients and lab-derived bioaccumulation factors (BAFs) for the worm species used, demonstrating the method's potential under field conditions. In situ SPME appeared to be less suitable for predicting bioaccumulation of oil however, in contrast to POM-SPE in the lab, which assessed in situ oil bioaccumulation within a factor of 3, while also closely reflecting the actual distribution of oil boiling point fractions (the hydrocarbon block profile) as accumulated by the worms. All in all, the results indicated that (specific) equilibrium passive samplers, either applied in the field or the lab, have great potential for assessing bioaccumulation of environmental contaminant mixtures from field contaminated sediments. PMID- 22201473 TI - Adeno-associated virus serotype 9 transduction in the central nervous system of nonhuman primates. AB - Widespread distribution of gene products at clinically relevant levels throughout the CNS has been challenging. Adeno-associated virus type 9 (AAV9) vector has been reported as a good candidate for intravascular gene delivery, but low levels of preexisting antibody titers against AAV in the blood abrogate cellular transduction within the CNS. In the present study we compared the effectiveness of vascular delivery and cerebrospinal fluid (CSF) delivery of AAV9 in transducing CNS tissue in nonhuman primates. Both delivery routes generated similar distribution patterns, although we observed a more robust level of transduction after CSF delivery. Consistent with previous reports administering AAV9, we found greater astrocytic than neuronal tropism via both routes, although we did find a greater magnitude of CNS transduction after CSF delivery compared with intravascular delivery. Last, we have demonstrated that delivery of AAV9 into the CSF does not shield against AAV antibodies. This has obvious implications when developing and/or implementing any clinical trial studies. PMID- 22201474 TI - Expectations for feedback in adverse drug reporting by healthcare professionals in the Netherlands. AB - BACKGROUND: In 2010, the Netherlands Pharmacovigilance Centre Lareb received more than 4000 reports from healthcare professionals (HCPs). All HCPs received individual personal feedback containing information about the reported drug adverse drug reaction (ADR) association. It is unclear what type of information HCPs expect in this feedback letter. OBJECTIVE: The aim of the study was to examine the expectations of the personal feedback of HCPs who reported an ADR to the Netherlands Pharmacovigilance Centre Lareb. METHODS: A questionnaire survey was conducted among a random sample of 1200 pharmacists, general practitioners (GPs) and medical specialists who reported an ADR to the Netherlands Pharmacovigilance Centre Lareb between 1 January 2009 and 27 January 2010. Responders and non-responders were compared on the basis of profession, number of reports submitted to the pharmacovigilance since 2007 and their last report being serious or not. Questions were asked about the importance of personal feedback and the type of information reporters would like to see in their personal feedback. Both linear and logistic regression analysis were performed, with correction for possible confounding factors. RESULTS: The response rate to the questionnaire was 34.6% (n = 399). The type of information the respondents generally would like to see in their personal feedback is information about the time course of the ADR and information about the pharmacological mechanism. However, GPs were, in general, less interested in receiving feedback than pharmacists and medical specialists. Most of the respondents were (very) unsatisfied if they received only a confirmation letter instead of personal feedback. Personalized feedback was considered to be (very) important for reporting an ADR in the future. Most of the respondents (80.3%) stated that the personal feedback increased their knowledge. Only 0.6% of respondents had not read the personalized feedback. No differences were found between responders and non-responders, with the exception that responders had reported statistically more often to the Netherlands Pharmacovigilance Centre Lareb in the past 3 years. CONCLUSIONS: Most of the respondents would like personal feedback instead of a standard confirmation letter. In general, pharmacists and medical specialists would like more information than GPs. The information in this study is useful in generating more customized personal feedback in the future, and could be useful for other pharmacovigilance centres that are interested in writing personalized feedback to make available to reporters. PMID- 22201476 TI - Quantitative NMR-derived interproton distances combined with quantum mechanical calculations of 13C chemical shifts in the stereochemical determination of conicasterol F, a nuclear receptor ligand from Theonella swinhoei. AB - Here we report the first application of combined accurate ROE-distance analysis with DFT calculations of NMR chemical shifts to achieve the relative configuration assignment of a marine natural product, conicasterol F, a new polyhydroxylated steroid isolated from the marine sponge Theonella swinhoei. We demonstrate the substantial advantages of this combined approach as a tool for structural studies of natural products, providing a powerful alternative to, or information to underpin, total synthesis when more classical NMR data analysis fails to provide unequivocal results. In this paper, we also describe the isolation and structure elucidation of conicasterol F and its 24-ethyl derivative, theonellasterol I, and their pharmacological evaluation as human nuclear receptor modulators. PMID- 22201478 TI - Theoretical study on oligoacenes and polycyclic aromatic hydrocarbons using the restricted active space self-consistent field method. AB - This is the first study, to my knowledge, to report the optimized geometries and vibrational frequency analysis for oligoacenes (naphthalene, anthracene, naphtacene, and pentacene) and polycyclic aromatic hydrocarbons (PAHs; perylene, phenanthrene, and picene) by using the restricted active space self-consistent field (RASSCF) method. For naphthalene, both the complete active space self consistent field (CASSCF) and RASSCF calculations were performed. As a result, it was confirmed that the RASSCF, with its small computational costs, is appropriate for oligoacenes and PAHs. It should be noted that, for anthracene and perylene, the optimized geometries under D(2h) symmetry were not the minimum energy points, whereas the optimized geometries under C(s) symmetry were the minimum energy points. For naphthalene, anthracene, naphtacene, pentacene, and phenanthrene, the calculated bond lengths and infrared absorption spectra by the RASSCF were in good agreement with the experimental values. PMID- 22201477 TI - Tenuipyrone, a novel skeletal polyketide from the entomopathogenic fungus, Isaria tenuipes, cultivated in the presence of epigenetic modifiers. AB - The concomitant addition of the histone deacetylase inhibitor and the DNA methyltransferase inhibitor to the culture medium of an entomopathogenic fungus, Isaria tenuipes, greatly enhanced its secondary metabolite production and led to the isolation of tenuipyrone (1), a novel polyketide with an unprecedented tetracyclic ring system bearing a spiroketal structural component, along with two known C(10)-polyketides, cephalosporolide B (2), which is a plausible biosynthetic precursor of 1, and cephalosporolide F (3). PMID- 22201475 TI - Methods for assessing the preventability of adverse drug events: a systematic review. AB - BACKGROUND: Preventable adverse drug events (ADEs) are common in both outpatient and inpatient settings. However, the proportion of preventable ADEs varies considerably in different studies, even when conducted in the same setting, and methods for assessing the preventability of ADEs are diverse. OBJECTIVE: The aim of this article is to identify and systematically evaluate methods for assessing the preventability of ADEs. DATA SOURCES: Seven databases (Cochrane, CINAHL, EMBASE, IPA, MEDLINE, PsycINFO and Web of Science) were searched in September 2010 utilizing the databases' index terms and other common terminology on preventable ADEs. No limits for the years of publication were set. Reference lists of included original articles and relevant review articles were also screened. STUDY SELECTION: After applying predetermined inclusion and exclusion criteria on 4161 unique citations, 142 (3.4%) original research articles were included in the review. One additional article was included from reference lists. Outcome measures of included studies had to include the frequency of ADEs and the assessment of their preventability. Studies were excluded if they focused on individuals with one specific type of treatment, medical condition, medical procedure or ADE. DATA EXTRACTION: Measurement instruments for determining the preventability of ADEs in each article were extracted and unique instruments were compared. The process of assessing the preventability of ADEs was described based on reported actions taken to standardize and conduct the assessment, and on information about the reliability and validity of the assessment. DATA SYNTHESIS: Eighteen unique instruments for determining the preventability of ADEs were identified. They fell under the following four groups: (i) instruments using a definition of preventability only (n = 3); (ii) instruments with a definition of preventability and an assessment scale for determining preventability (n = 5); (iii) instruments with specific criteria for each preventability category (n = 3); and (iv) instruments with an algorithm for determining preventability (n = 7). Of actions to standardize the assessment process, performing a pilot study was reported in 21 (15%), and use of a standardized protocol was reported in 18 (13%), of the included 143 articles. Preventability was assessed by physicians in 86 (60%) articles and by pharmacists in 41 (29%) articles. In 29 (20%) articles, persons conducting the assessment were described as trained for or experienced in preventability assessment. In 94 (66%) articles, more than one person assessed the preventability of each case. Among these 94 articles, assessment was done independently in 73 (51%) articles. Procedures for managing conflicting assessments were diverse. The reliability of the preventability assessment was tested in 39 (27%) articles, and 16 (11%) articles referred to a previous reliability assessment. Reliability ranged from poor to excellent (kappa 0.19 0.98; overall agreement 26-97%). Four (3%) articles mentioned assessing validity, but no sensitivity or specificity analyses or negative or positive predictive values were presented. CONCLUSIONS: Instruments for assessing the preventability of ADEs vary from implicit instruments to explicit algorithms. There is limited evidence for the validity of the identified instruments, and instrument reliability varied significantly. The process of assessing the preventability of ADEs is also commonly imprecisely described, which hinders the interpretation and comparison of studies. For measuring the preventability of ADEs more accurately and precisely in future, we believe that existing instruments should be further studied and developed, or that one or more new instruments should be developed, and the validity and reliability of the existing and new instruments be established. PMID- 22201479 TI - Effects of septal deviation on the airflow characteristics: using computational fluid dynamics models. AB - CONCLUSIONS: Computational fluid dynamics (CFD) methods can provide detailed information on airflow characteristics in models of septal deviation. Different locations of septal deviation lead to variation of nasal airflow. Both the location of the septal deviation and the inferior turbinate hypertrophy in the concave side may play an important role in airflow patterns and airflow velocity. OBJECTIVE: To investigate the airflow patterns and air velocity in different septal deviation models during inspiration, using CFD methods. METHODS: Commercial software was used to construct three-dimensional (3D) models of nasal cavities with paranasal sinuses from the computed tomography (CT) scans of 15 patients with septal deviation and 4 controls. Considering the location of the most prominent point of the nasal septum, patients were classified into caudal, anterior, and media deviation groups. RESULTS: Unlike airflow in the controls, airflow in the septal deviation models showed asymmetry in bilateral nasal cavities. The airflow patterns varied in the convex and concave sides in different septal deviation models. Caudal septal deviation models had the maximal peak velocity, while the the minimal peak velocity was found in the media deviation models. The peak velocity was not always located in the convex side, but was sometimes in the concave side. PMID- 22201480 TI - Modern and fossil contributions to polycyclic aromatic hydrocarbons in PM2.5 from North Birmingham, Alabama in the southeastern U.S. AB - Analyzing the radiocarbon ((14)C) content of polycyclic aromatic hydrocarbons (PAHs) in atmospheric particulate matter can provide estimates on the source contributions from biomass burning versus fossil fuel. The relative importance of these two sources to ambient PAHs varies considerably across regions and even countries, and hence there is a pressing need to apportion these sources. In this study, we advanced the radiocarbon analysis from bulk carbon to compound class specific radiocarbon analysis (CCSRA) to determine Delta(14)C and delta(13)C values of PAHs in PM(2.5) samples for investigating biomass burning and fossil fuel source contributions to PAHs from one of the Southeastern Aerosol Research and Characterization (SEARCH) sites in North Birmingham (BHM), Alabama during winter (December 2004-February 2005) and summer (June-August 2005) by accelerator mass spectrometry. To compare our ambient samples to known sources, we collected and analyzed fenceline samples from the vicinity of a coke plant in BHM. As expected, PAHs from the coke plant fenceline samples had very low radiocarbon levels. Its Delta(14)C varied from -990 to -9700/00, indicating that 97 to 99% were of fossil source. PAHs in the ambient PM(2.5) had Delta(14)C from -968 to 911 0/00, indicating that 92-97% of PAHs were from fossil fuel combustion. These levels indicated the dominance of fossil sources of ambient PAHs. The radiocarbon level of ambient PAHs was higher in winter than in summer. Winter samples exhibited depleted delta(13)C value and enriched Delta(14)C value because of the increased contribution of PAHs from biomass burning source. However, biomass burning contributed more to heavier PAHs (modern source accounting for 6-8%) than lighter ones with a modern contribution of 3%. PMID- 22201509 TI - Selective deposition and self-assembly of triblock copolymers into matrix arrays for membrane protein production. AB - To improve the stability of cell membrane mimics, there has been growing interest in the use of block copolymers. Here, we present an easy approach to create an array of planar polymeric matrices capable of hosting membrane proteins. The array of polymeric matrices was formed by the selective deposition of triblock copolymers onto an array of hydrophilic islands situated within a hydrophobic background. The thickness of these matrices corresponds to the length of a single polymer chain. These polymeric matrices were used to host cell-free expressed membrane proteins, and offers a prototype from which a membrane protein array can be created for diagnostics or drug discovery purposes. PMID- 22201510 TI - Study of the excited-state proton-transfer reaction of 5-cyano-2-naphthol in sub- and supercritical water. AB - The excited-state proton-transfer (ESPT) reaction of 5-cyano-2-naphthol (5CN2) has been investigated in sub- and supercritical water using time-resolved fluorescence measurements. Under ambient conditions, a very fast decay of the fluorescence from the excited state of normal 5CN2 (ROH*) and a simultaneous increase of the fluorescence from the excited state of the anion species (RO(-)*) were observed, as reported previously. The very high ESPT rate was evaluated as 0.12 ps(-1). With increasing temperature at a constant pressure of 39.0 MPa, the proton transfer became slow. At 615 K and 39.0 MPa, another fluorescence from a new unknown chemical species appeared, which was assigned to the contact ion pair (CIP) of RO(-)* and the hydronium ion. With decreasing pressure at 664 K, the fluorescence from RO(-)* disappeared, and the fluorescence from ROH* and CIP was observed. At the very low density of supercritical water, only the fluorescence decay of ROH* was detected. The reaction dynamics was analyzed with the help of singular value decomposition and spectral decomposition using model functions. The ESPT rate was correlated with the solvent dielectric constant and/or the hydrogen-bonding ability. PMID- 22201511 TI - Preparation of dually, pH- and thermo-responsive nanocapsules in inverse miniemulsion. AB - pH- and thermo-sensitive nanocapsules were successfully synthesized via inverse miniemulsion copolymerization of N-isopropyl acrylamide (NIPAM), N,N'-methylene bisacrylamide (MBA), and a functional monomer, 4-vinyl pyridine (4-VP). The size and size distribution of nanocapsules were measured by dynamic light scattering (DLS). The particle morphology was observed by transmission electron microscopy (TEM). The final morphology of particles was strongly influenced by the hydrophobicity of functional monomers. The use of a hydrophilic functional monomer, acrylic acid, led to the formation of solid particles, while the use of the more hydrophobic functional monomer, 4-VP, resulted in the formation of nanocapsules. The particle morphology, size, and size distribution were investigated in terms of the content of 4-VP, MBA, and the type and content of surfactant. The pH- and thermo-sensitivities were characterized by measuring the size variation with the change of temperature and pH. The organic-inorganic nanocapsules were prepared by coating a layer of silica particles on the surface of the sensitive nanocapsules. PMID- 22201512 TI - Inadequate opening capacity of the eustachian tube in Meniere's disease. AB - CONCLUSION: In this physiological study subjects with Meniere's disease (MD) had high resistance to opening of the eustachian tube (ET) in three of four provocation tests. These subjects can be exposed to pressure deviations in the middle ear (ME) above their equalizing capacity. Transmission of the pressure deviations to the inner ear fluids and influence of the symptoms of MD are feasible. OBJECTIVE: The aim of the study was to reveal potential inadequacy in the ET equilibration capacity and deviations in ME pressure in patients with MD. METHODS: Direct ME pressure measurements were made during provocation tests of the ET, and continuously during the daytime and night-time in 21 patients with unilateral, definite and active MD. Twenty subjects with healthy ears (HEs) were used for comparison. RESULTS: In all, 15/21 subjects could not equilibrate an induced positive and/or negative pressure in the ME by deglutition; 9/21 subjects were not able to perform Valsalva's manoeuvre. All the controls could effectively perform these manoeuvres. However, the continuous measurements showed a similar pressure pattern in patients with MD and the controls, i.e. a slightly negative mean ME pressure during the daytime and positive pressure during sleep. PMID- 22201513 TI - Tunable growth factor delivery from injectable hydrogels for tissue engineering. AB - Current sustained delivery strategies of protein therapeutics are limited by the fragility of the protein, resulting in minimal quantities of bioactive protein delivered. In order to achieve prolonged release of bioactive protein, an affinity-based approach was designed which exploits the specific binding of the Src homology 3 (SH3) domain with short proline-rich peptides. Specifically, methyl cellulose was modified with SH3-binding peptides (MC-peptide) with either a weak affinity or strong affinity for SH3. The release profile of SH3-rhFGF2 fusion protein from hyaluronan MC-SH3 peptide (HAMC-peptide) hydrogels was investigated and compared to unmodified controls. SH3-rhFGF2 release from HAMC peptide was extended to 10 days using peptides with different binding affinities compared to the 48 h release from unmodified HAMC. This system is capable of delivering additional proteins with tunable rates of release, while maintaining bioactivity, and thus is broadly applicable. PMID- 22201515 TI - Evaluation of the pharmacokinetics, biotransformation and hepatic transporter effects of troglitazone in mice with humanized livers. AB - The pharmacokinetics, biotransformation and hepatic transporter effects of troglitazone were investigated following daily oral dosing, at 300 and 600 mg/kg, for 7 days to control (SCID) and chimeric (PXB) mice with humanized livers. Clinical chemistry revealed no consistent pattern of changes associated with troglitazone treatment in the PXB mouse. Human MRP2 but not mouse mrp2 was down regulated following troglitazone treatment. Pharmacokinetic analysis revealed similar T(max) values for troglitazone in both mouse groups, a mono- and bi phasic elimination phase in PXB and SCID mice, respectively, but a 3- to 5- and 2 to 5-fold higher C(max) and AUC, respectively, in PXB mice. Oxidative and conjugative metabolic pathways were identified, with the sulfate being the predominant metabolite in PXB compared to SCID mice (4- to 13-fold increase in liver and blood, respectively). The glucuronide conjugate was predominant in SCID mice. There was no evidence of glutathione conjugation. The primary oxidative pathways were mono- and di-oxidations which may also be attributed to quinone or hydroquinone derivatives. Several metabolites were observed in PXB mice only. As the troglitazone metabolic profiles in the PXB mouse were similar to reported human data the PXB mouse model can provide a useful first insight into circulating human metabolites of xenobiotics metabolized in the liver. PMID- 22201516 TI - DSM-5: proposed changes to depressive disorders. AB - The Diagnostic and Statistical Manual of Mental Disorders (DSM) is currently undergoing a revision that will lead to a fifth edition in 2013. Proposed changes for DSM-5 include the creation of several new categories of depressive disorder. Some nosologists have expressed concern that the proposed changes could yield many 'false-positive diagnoses' in which normal distress is mislabeled as a mental disorder. Such confusion of normal distress and mental disorder undermines the interpretability of clinical trials and etiological research, causes inefficient allocation of resources, and incurs risks of unnecessary treatment. To evaluate these concerns, I critically examine five proposed DSM-5 expansions in the scope of depressive and grief disorders: (1) a new mixed anxiety/depression category; (2) a new premenstrual dysphoric disorder category; (3) elimination of the major depression bereavement exclusion; (4) elimination of the adjustment disorder bereavement exclusion, thus allowing the diagnosis of subsyndromal depressive symptoms during bereavement as adjustment disorders; and (5) a new category of adjustment disorder related to bereavement for diagnosing pathological non-depressive grief. I examine each proposal's face validity and conceptual coherence as well as empirical support where relevant, with special attention to potential implications for false-positive diagnoses. I conclude that mixed anxiety/depression and premenstrual dysphoric disorder are needed categories, but are too broadly drawn and will yield substantial false positives; that the elimination of the bereavement exclusion is not supported by the evidence; and that the proposed elimination of the adjustment-disorder bereavement exclusion, as well as the new category of grief-related adjustment disorder, are inconsistent with recent grief research, which suggests that these proposals would massively pathologize normal grief responses. PMID- 22201518 TI - Drop detachment and motion on fuel cell electrode materials. AB - Liquid water is pushed through flow channels of fuel cells, where one surface is a porous carbon electrode made up of carbon fibers. Water drops grow on the fibrous carbon surface in the gas flow channel. The drops adhere to the superficial fiber surfaces but exhibit little penetration into the voids between the fibers. The fibrous surfaces are hydrophobic, but there is a substantial threshold force necessary to initiate water drop motion. Once the water drops begin to move, however, the adhesive force decreases and drops move with minimal friction, similar to motion on superhydrophobic materials. We report here studies of water wetting and water drop motion on typical porous carbon materials (carbon paper and carbon cloth) employed in fuel cells. The static coefficient of friction on these textured surfaces is comparable to that for smooth Teflon. But the dynamic coefficient of friction is several orders of magnitude smaller on the textured surfaces than on smooth Teflon. Carbon cloth displays a much smaller static contact angle hysteresis than carbon paper due to its two-scale roughness. The dynamic contact angle hysteresis for carbon paper is greatly reduced compared to the static contact angle hysteresis. Enhanced dynamic hydrophobicity is suggested to result from the extent to which a dynamic contact line can track topological heterogeneities of the liquid/solid interface. PMID- 22201517 TI - Age-related changes in the ratio of Mcl-1/Bax expression in the rat cochlea. AB - CONCLUSION: Down-regulation of the ratio of Mcl-1/Bax expression may contribute to age-related sensory cell degeneration in the cochlea. OBJECTIVE: To better understand the involvement of Bcl-2 family members in the regulation of age related sensory cell death, we examined the expression patterns of Bcl-2 associated protein X (Bax) and its suppressor, myeloid cell leukemia 1 (Mcl-1) in young and aging rat cochleae. METHODS: Young (2-3 months) and aging (27-28 months) Fischer rats were used. The auditory brainstem response (ABR) thresholds elicited by tone bursts at 4, 8, 16, 32, and 40 kHz were measured. The expression patterns of Mcl-1 and Bax genes at both the mRNA and protein levels were examined using a real-time RT-PCR assay and Western blot. Distribution of Mcl-1 and Bax expression in the cochlear sensory epithelia was evaluated using immunohistology and nuclear staining. RESULTS: Aging cochleae exhibited a significant elevation of ABR thresholds. This change was accompanied by significant reduction in Mcl-1 expression at both the mRNA and the protein levels and in the ratio of expression levels of Mcl-1/Bax genes in the aging subjects. Importantly, the changes in Mcl 1 and Bax expression are spatially related to the sensory cells showing the sign of degeneration. PMID- 22201519 TI - Exciton superposition states in CdSe nanocrystals measured using broadband two dimensional electronic spectroscopy. AB - Coherent superpositions among eigenstates are of interest in fields as diverse as photosynthesis and quantum computation. In this report, we used two-dimensional electronic spectroscopy (2D ES) to measure the decoherence time of a superposition of the two lowest-energy excitons in colloidal CdSe nanocrystals (cubic phase) in solution at room temperature. In the electron-hole representation, the quantum coherence is, remarkably, a twelve-particle correlation. By comparing the measured 2D ES to simulations, we also explored the effects of inhomogeneous broadening and examined the spectroscopic signatures of biexcitons. PMID- 22201520 TI - Economic and humanistic burden of external genital warts. AB - External genital warts (EGW) are a sexually transmitted infection caused by various strains of human papillomavirus (HPV). Several studies have described the direct and indirect costs of EGW, while others have reported on the burden of EGW in terms of the impact on the quality of life (QOL) of patients. The arrival of a quadrivalent HPV vaccine that protects against both cervical cancer and EGW requires a proper understanding of the impact of vaccines on costs and QOL. Using pre-defined search terms and inclusion/exclusion criteria, we performed a systematic review of the economic and humanistic burden of EGW. The focus of our review was on literature describing the direct and indirect costs of EGW per episode of care (EoC) or per year, as well as the impact of EGW on disease specific, generic, or preference-based QOL measures. We also reviewed the literature on the national economic burden of EGW from the perspectives of different countries. Other aspects of EGW management that can inform economic modelling studies, such as length of EoC, number of physician visits and indirect costs, were also explored. Our review sheds light on the high economic and humanistic burden of EGW and important differences in the costs between men and women, as well as the differences in health resource utilization and costs across countries. Our study also highlights the dearth of information on the impact of EGW on the QOL and productivity of patients. PMID- 22201521 TI - Cost effectiveness of treatment with new agents in advanced non-small-cell lung cancer: a systematic review. AB - In past decades, studies focusing on new chemotherapeutic agents for patients with inoperable non-small-cell lung cancer have reported only modest gains in survival. These health gains are achieved at considerable cost, but economic evidence is lacking on superiority of one agent in terms of cost effectiveness. The objective of this systematic review was to assess fully published cost effectiveness studies comparing the new agents docetaxel, paclitaxel, vinorelbine, gemcitabine and pemetrexed, and the targeted therapies erlotinib and gefitinib with one another. We performed systematic searches in the bibliographic databases PubMed, EMBASE and Health Economic Evaluations (HEED) [via the Cochrane Library] for fully published studies from the past 10 years. Studies were screened by two independent reviewers according to a priori inclusion criteria. The methodological quality of the included studies was evaluated by two independent reviewers using standardized assessment tools. A total of 222 potential studies were identified; 11 studies and six reviews were included. The methodological quality of the full economic evaluations was fairly good. Transparency in costs and resource use, details on statistical tests and sensitivity analysis were points for improvement. In first-line treatment, gemcitabine+cisplatin was cost effective compared with other platinum-based regimens (paclitaxel, docetaxel and vinorelbine). In one study, pemetrexed+cisplatin was cost effective compared with gemcitabine+cisplatin in patients with non-squamous-cell carcinoma. In second-line treatment, docetaxel was cost effective compared with best supportive care; erlotinib was cost effective compared with placebo; and docetaxel and pemetrexed were dominated by erlotinib. We found indications of superiority in terms of cost effectiveness for gemcitabine+cisplatin in a first-line setting, and for erlotinib in a second-line setting. PMID- 22201523 TI - Anatomical feature of the middle cranial fossa in fetal periods: possible etiology of superior canal dehiscence syndrome. AB - CONCLUSION: Different from adults, the superior semicircular canal (SSC) protrudes into the cranium during the fetal period. This might cause adhesion of the membranous labyrinth to dura as the bony labyrinth develops much later than the membranous labyrinth. This adhesion interferes with ossification and leads to a bony defect in the SSC. OBJECTIVES: The purpose of this study was to investigate a possible etiology of superior canal dehiscence syndrome (SCDS) from a view point of ontogeny. METHODS: Forty-two adult cadavers and 4 fetal cadavers were used for macroscopic observation of the middle cranial fossa (MCF). In addition, six fetuses underwent computed tomography (CT) examinations. The volume data of the CT obtained from four adults were also used for comparison. Using these CT data, we investigated the anatomic relationship between the MCF and SSC. RESULTS: The SSC and the cochlea in fetuses protruded into the cranium in macroscopic anatomy and CT examination. On the other hand, the SSC of all adults was completely or mostly buried in the temporal bone. PMID- 22201524 TI - Drill and chop: modified vertical chop technique for hard cataract. AB - The authors describe a technique to improve the control and safety of vertical chopping during hard cataract surgery. Whereas the conventional vertical chop technique uses a sharp vertical chopper, the proposed technique uses a short blunt chopper. This requires complete engagement of the central nucleus by a phaco tip. The authors first drilled a hole into the endonucleus. By rotating the Kelman phaco tip clockwise, the nucleus was deeply impaled horizontally and firmly engaged with the phaco tip. This was followed by vertical chopping. This technique results in safer and more effective vertical chopping in patients with hard cataracts. PMID- 22201525 TI - Reproducibility of macular thickness measurement among five OCT instruments: effects of image resolution, image registration, and eye tracking. AB - BACKGROUND AND OBJECTIVE: To study the effect of image resolution, eye tracking, and image registration on central macular thickness reproducibility (rCMT) among spectral-domain and time-domain optical coherence tomography (SD-OCT and TD-OCT) instruments. PATIENTS AND METHODS: Seventy-six eyes were imaged (44 normal, 32 maculopathy) either twice using four SD-OCT and one TD-OCT devices or three times using Spectralis SD-OCT (with and without eye tracking) (Heidelberg Engineering, Inc., Heidelberg, Germany). Cirrus images (Carl Zeiss Meditec, Dublin, CA) were further analyzed with three-point image registration. RESULTS: All instruments had superior rCMT in normal versus pathologic eyes (P < .001). No difference in rCMT was noted among instruments in normal eyes (P = .92), but TD-OCT was superior to SD-OCT (P = .017) in pathologic eyes. Cirrus image registration improved rCMT for normal eyes (P = .04), with borderline improvement in pathologic eyes (P = .06). Spectralis eye tracking improved rCMT in normal (P = .01) and pathologic (P = .004) eyes. CONCLUSION: Higher image resolution with SD OCT may not improve rCMT, but image registration and eye tracking options may improve rCMT. PMID- 22201526 TI - Binaural dichotic presentation to reduce the effects of spectral masking in moderate bilateral sensorineural hearing loss. AB - OBJECTIVE: The objective of the study was to evaluate the effectiveness of binaural dichotic presentation using comb filters with complementary magnitude responses, based on fixed bandwidth and auditory critical bandwidth, in improving speech perception by persons with moderate bilateral sensorineural hearing loss, and to assess its effect on localization of the sound source. DESIGN AND STUDY SAMPLE: Listening tests involving consonant recognition and source direction identification were conducted on six normal-hearing subjects under simulated hearing loss and on eleven subjects with moderate bilateral sensorineural loss in quiet. RESULTS: The tests on normal-hearing subjects showed higher recognition scores and smaller response times for the comb filters based on the auditory critical bandwidth. The tests using these comb filters on the hearing-impaired subjects resulted in an increase of 14%-31% (mean: 22%) in recognition scores and a significant decrease in response times, with no significant effect on the identification of the direction of broadband sound sources. CONCLUSIONS: The results show that dichotic presentation may be useful for speech processing in binaural hearing aids. PMID- 22201527 TI - Development of a corpus of Mandarin sentences in babble with homogeneity optimized via psychometric evaluation. AB - OBJECTIVE: To develop a corpus of sentences in babble noise that is suitable for Mandarin-speaking children. Two experiments were conducted with specific aims of (1) developing sentence material that is grammatically and semantically within the linguistic abilities of children; and (2) improving the efficiency of the test by equalizing the relative intelligibility of individual items in sentences. DESIGN AND STUDY SAMPLE: Sentences were extracted from spoken material of Chinese children aged between 4 and 5 years of age. The sentences were tested for intelligibility in a four-talker babble by 96 adult native speakers of Mandarin. Psychometric functions were generated, and used for adjusting signal-to-noise ratios of individual items by varying the level of the time-locked babble to equate intelligibility of the target speech. These adjusted stimuli were tested for intelligibility using a different group of 64 adult listeners. RESULTS: The signal-to-noise ratio for 50% correct was not different before and after adjustments (- 6.1 dB and - 6.0 dB, respectively). However, there was a significant reduction in standard deviation from 2.3 dB before adjustment to 1.1 dB after adjustment (p < 0.05). CONCLUSIONS: The experiments established a corpus of Mandarin BKB-like sentences with four-talker babble as competing noise, in which the test items' homogeneity was optimized via psychometric evaluation (HOPE). PMID- 22201528 TI - Frequency selectivity of contralateral residual acoustic hearing in bimodal cochlear implant users, and limitations on the ability to match the pitch of electric and acoustic stimuli. AB - OBJECTIVE: To assess the reliability of across-ear, acoustic-electric pitch/timbre comparisons for determining effective characteristic frequencies of cochlear implant electrodes. STUDY SAMPLE: Nine CI users with contralateral residual acoustic hearing. DESIGN: Absolute acoustic thresholds in the unimplanted ear were measured and frequency selectivity was assessed via psychophysical tuning curves. An adjustment method was used to match the percepts elicited by pulse trains on individual electrodes with various acoustic signals (pure tones, narrow-band noises, and bandpass filtered pulse trains). The starting frequency of the acoustic signal was roved and matches were obtained at different loudness levels. RESULTS: Acoustic frequency selectivity varied widely. Two subjects showed clear evidence of frequency selectivity extending above 500 Hz. Only these subjects produced consistent pitch matches over repeated measurements. For other subjects, the acoustic frequency eventually selected tended to correlate with the initially presented frequency. There was limited evidence of level effects and these were inconsistent across subjects and electrodes. CONCLUSIONS: Across-modality pitch/timbre matching appears unlikely to provide a generally applicable method for determining the effective characteristic frequencies of cochlear implant electrodes. Frequency selectivity above 500 Hz may be necessary for consistent pitch/timbre matches. PMID- 22201529 TI - Multiple origins of endosymbiosis within the Enterobacteriaceae (gamma Proteobacteria): convergence of complex phylogenetic approaches. AB - BACKGROUND: The bacterial family Enterobacteriaceae gave rise to a variety of symbiotic forms, from the loosely associated commensals, often designated as secondary (S) symbionts, to obligate mutualists, called primary (P) symbionts. Determination of the evolutionary processes behind this phenomenon has long been hampered by the unreliability of phylogenetic reconstructions within this group of bacteria. The main reasons have been the absence of sufficient data, the highly derived nature of the symbiont genomes and lack of appropriate phylogenetic methods. Due to the extremely aberrant nature of their DNA, the symbiotic lineages within Enterobacteriaceae form long branches and tend to cluster as a monophyletic group. This state of phylogenetic uncertainty is now improving with an increasing number of complete bacterial genomes and development of new methods. In this study, we address the monophyly versus polyphyly of enterobacterial symbionts by exploring a multigene matrix within a complex phylogenetic framework. RESULTS: We assembled the richest taxon sampling of Enterobacteriaceae to date (50 taxa, 69 orthologous genes with no missing data) and analyzed both nucleic and amino acid data sets using several probabilistic methods. We particularly focused on the long-branch attraction-reducing methods, such as a nucleotide and amino acid data recoding and exclusion (including our new approach and slow-fast analysis), taxa exclusion and usage of complex evolutionary models, such as nonhomogeneous model and models accounting for site specific features of protein evolution (CAT and CAT+GTR). Our data strongly suggest independent origins of four symbiotic clusters; the first is formed by Hamiltonella and Regiella (S-symbionts) placed as a sister clade to Yersinia, the second comprises Arsenophonus and Riesia (S- and P-symbionts) as a sister clade to Proteus, the third Sodalis, Baumannia, Blochmannia and Wigglesworthia (S- and P-symbionts) as a sister or paraphyletic clade to the Pectobacterium and Dickeya clade and, finally, Buchnera species and Ishikawaella (P-symbionts) clustering with the Erwinia and Pantoea clade. CONCLUSIONS: The results of this study confirm the efficiency of several artifact-reducing methods and strongly point towards the polyphyly of P-symbionts within Enterobacteriaceae. Interestingly, the model species of symbiotic bacteria research, Buchnera and Wigglesworthia, originated from closely related, but different, ancestors. The possible origins of intracellular symbiotic bacteria from gut-associated or pathogenic bacteria are suggested, as well as the role of facultative secondary symbionts as a source of bacteria that can gradually become obligate maternally transferred symbionts. PMID- 22201533 TI - Characterization and evaluation of two novel fluorescent sigma-2 receptor ligands as proliferation probes. AB - We synthesized and characterized two novel fluorescent sigma-2 receptor selective ligands, SW120 and SW116, and evaluated these ligands as potential probes for imaging cell proliferation. Both ligands are highly selective for sigma-2 receptors versus sigma-1 receptors. SW120 and SW116 were internalized into MDA-MB 435 cells, and 50% of the maximum fluorescent intensity was reached in 11 and 24 minutes, respectively. In vitro studies showed that 50% of SW120 or SW116 washed out of cells in 1 hour. The internalization of SW120 was reduced ~30% by phenylarsine oxide, an inhibitor of endocytosis, suggesting that sigma-2 ligands are internalized, in part, by an endocytotic pathway. Subcellular localization studies using confocal and two-photon microscopy showed that SW120 and SW116 partially colocalized with fluorescent markers of mitochondria, endoplasmic reticulum, lysosomes, and the plasma membrane, suggesting that sigma-2 receptors localized to the cytoplasmic organelles and plasma membrane. SW120 did not colocalize with the nuclear dye 4',6-diamidino-2-phenylindole. In vivo studies showed that the uptake of SW120 in solid tumors and peripheral blood mononuclear cells of mice positively correlated with the expression level of the cell proliferation marker Ki-67, suggesting that sigma-2 fluorescent probes may be used to image cell proliferation in mice. PMID- 22201532 TI - Techniques for molecular imaging probe design. AB - Molecular imaging allows clinicians to visualize disease-specific molecules, thereby providing relevant information in the diagnosis and treatment of patients. With advances in genomics and proteomics and underlying mechanisms of disease pathology, the number of targets identified has significantly outpaced the number of developed molecular imaging probes. There has been a concerted effort to bridge this gap with multidisciplinary efforts in chemistry, proteomics, physics, material science, and biology--all essential to progress in molecular imaging probe development. In this review, we discuss target selection, screening techniques, and probe optimization with the aim of developing clinically relevant molecularly targeted imaging agents. PMID- 22201534 TI - Model system for live imaging of neuronal responses to injury and repair. AB - Although it has been well established that induction of growth-associated protein 43 (GAP-43) during development coincides with axonal outgrowth and early synapse formation, the existence of neuronal plasticity and neurite outgrowth in the adult central nervous system after injuries is more controversial. To visualize the processes of neuronal injury and repair in living animals, we generated reporter mice for bioluminescence and fluorescence imaging bearing the luc (luciferase) and gfp (green fluorescent protein) reporter genes under the control of the murine GAP-43 promoter. Reporter functionality was first observed during the development of transgenic embryos. Using in vivo bioluminescence and fluorescence imaging, we visualized induction of the GAP-43 signals from live embryos starting at E10.5, as well as neuronal responses to brain and peripheral nerve injuries (the signals peaked at 14 days postinjury). Moreover, three dimensional analysis of the GAP-43 bioluminescent signal confirmed that it originated from brain structures affected by ischemic injury. The analysis of fluorescence signal at cellular level revealed colocalization between endogenous protein and the GAP-43-driven gfp transgene. Taken together, our results suggest that the GAP-43-luc/gfp reporter mouse represents a valid model system for real time analysis of neurite outgrowth and the capacity of the adult nervous system to regenerate after injuries. PMID- 22201535 TI - Use of an image restoration process to improve spatial resolution in bioluminescence imaging. AB - To improve spatial resolution in in vivo bioluminescence imaging, a photon scattering correction, image restoration method was tested. The chosen algorithm was tested on in vivo bioluminescent images acquired on three representative tumor models: subcutaneous, pulmonary, and disseminated peritoneal. Tumor size was chosen as a quantitative criterion, such that the tumor reference measurements (determined photographically or by computed tomography) were compared to those derived from bioluminescent images, before and after restoration. This technique allowed a significant reduction to be achieved in the relative error between reference measurements and dimensions derived from bioluminescent images. In addition, improved delineation of the tumor foci was achieved. The restoration method allows spatial resolution in bioluminescence imaging to be improved, with interesting perspectives in terms of staging and quantitation in experimental oncology. PMID- 22201536 TI - Imaging of non- or very subtle contrast-enhancing malignant gliomas with [11C] methionine positron emission tomography. AB - In patients with World Health Organization (WHO) grade III glioma with a lack of or minimal (< 1 cm3) magnetic resonance imaging (MRI) contrast enhancement, the volume of the metabolically active part of the tumor was assessed by [11C] methionine positron emission tomography (MET-PET). Eleven patients with WHO grade III gliomas underwent MET-PET and MRI (contrast-enhanced T1- and T2-weighted images). To calculate the volumes in cubic centimeters, threshold-based volume of interest analyses of the metabolically active tumor (MET uptake index >= 1.3), contrast enhancement, and the T2 lesion were performed after coregistration of all images. In all patients, the metabolically active tumor volume was larger than the volume of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) enhancement (20.8 +/- 18.8 vs 0.29 +/- 0.25 cm3; p < .001). With the exception of one patient, the volumes of contrast enhancement were located within the metabolically active tumor volume. In contrast, in the majority of patients, MET uptake overlapped with the T2 lesion and reached beyond it (in 10 of 12 MRIs/MET PET scans). The present data suggest that in patients with WHO grade III glioma with minimal or a lack of contrast enhancement, MET-PET delineates metabolically active tumor tissue. These findings support the use of combined PET-MRI with radiolabeled amino acids (eg, MET) for the delineating of the true extent of active tumor in the diagnosis and treatment planning of patients with gliomas. PMID- 22201537 TI - Assessment of molecular imaging of angiogenesis with three-dimensional ultrasonography. AB - Molecular imaging (MI) with ultrasonography relies on microbubble contrast agents (MCAs) adhering to a ligand-specific target for applications such as characterizing tumor angiogenesis. It is projected that ultrasonic (US) MI can provide information about tumor therapeutic response before the detection of phenotypic changes. One of the limitations of preclinical US MI is that it lacks a comprehensive field of view. We attempted to improve targeted MCA visualization and quantification by performing three-dimensional (3D) MI of tumors expressing alphavbeta3 integrin. Volumetric acquisitions were obtained with a Siemens Sequoia system in cadence pulse sequencing mode by mechanically stepping the transducer elevationally across the tumor in 800-micron increments. MI was performed on rat fibrosarcoma tumors (n = 8) of similar sizes using MCAs conjugated with a cyclic RGD peptide targeted to alphavbeta3 integrin. US MI and immunohistochemical analyses show high microbubble targeting variability, suggesting that individual two-dimensional (2D) acquisitions risk misrepresenting more complex heterogeneous tissues. In 2D serial studies, where it may be challenging to image the same plane repeatedly, misalignments as small as 800 microns can introduce substantial error. 3D MI, including volumetric analysis of inter- and intra-animal targeting, provides a thorough way of characterizing angiogenesis and will be a more robust assessment technique for the future of MI. PMID- 22201538 TI - Spectroscopically well-characterized RGD optical probe as a prerequisite for lifetime-gated tumor imaging. AB - Labeling of RGD peptides with near-infrared fluorophores yields optical probes for noninvasive imaging of tumors overexpressing alphanubeta3 integrins. An important prerequisite for optimum detection sensitivity in vivo is strongly absorbing and highly emissive probes with a known fluorescence lifetime. The RGD Cy5.5 optical probe was derived by coupling Cy5.5 to a cyclic arginine-glycine aspartic acid-d-phenylalanine-lysine (RGDfK) peptide via an aminohexanoic acid spacer. Spectroscopic properties of the probe were studied in different matrices in comparison to Cy5.5. For in vivo imaging, human glioblastoma cells were subcutaneously implanted into nude mice, and in vivo fluorescence intensity and lifetime were measured. The fluorescence quantum yield and lifetime of Cy5.5 were found to be barely affected on RGD conjugation but dramatically changed in the presence of proteins. By time domain fluorescence imaging, we demonstrated specific binding of RGD-Cy5.5 to glioblastoma xenografts in nude mice. Discrimination of unspecific fluorescence by lifetime-gated analysis further enhanced the detection sensitivity of RGD-Cy5.5-derived signals. We characterized RGD-Cy5.5 as a strongly emissive and stable probe adequate for selective targeting of alphanubeta3 integrins. The specificity and thus the overall detection sensitivity in vivo were optimized with lifetime gating, based on the previous determination of the probes fluorescence lifetime under application relevant conditions. PMID- 22201539 TI - Positron emission tomographic imaging of the cannabinoid type 1 receptor system with [11C]OMAR ([11C]JHU75528): improvements in image quantification using wild type and knockout mice. AB - In this study, we assessed the feasibility of using positron emission tomography (PET) and the tracer [11C]OMAR ([11C]JHU75528), an analogue of rimonabant, to study the brain cannabinoid type 1 (CB1) receptor system. Wild-type (WT) and CB1 knockout (KO) animals were imaged at baseline and after pretreatment with blocking doses of rimonabant. Brain uptake in WT animals was higher (50%) than in KO animals in baseline conditions. After pretreatment with rimonabant, WT uptake lowered to the level of KO animals. The results of this study support the feasibility of using PET with the radiotracer [11C]JHU75528 to image the brain CB1 receptor system in mice. In addition, this methodology can be used to assess the effect of new drugs in preclinical studies using genetically manipulated animals. PMID- 22201544 TI - Biogenesis of inner membrane proteins in Escherichia coli. AB - The inner membrane proteome of the model organism Escherichia coli is composed of inner membrane proteins, lipoproteins and peripherally attached soluble proteins. Our knowledge of the biogenesis of inner membrane proteins is rapidly increasing. This is in particular true for the early steps of biogenesis - protein targeting to and insertion into the membrane. However, our knowledge of inner membrane protein folding and quality control is still fragmentary. Furthering our knowledge in these areas will bring us closer to understand the biogenesis of individual inner membrane proteins in the context of the biogenesis of the inner membrane proteome of Escherichia coli as a whole. This article is part of a Special Issue entitled: Biogenesis/Assembly of Respiratory Enzyme Complexes. PMID- 22201543 TI - Kinetic studies of the reactions of O(2) and NO with reduced Thermus thermophilus ba(3) and bovine aa(3) using photolabile carriers. AB - The reactions of molecular oxygen (O(2)) and nitric oxide (NO) with reduced Thermus thermophilus (Tt) ba(3) and bovine heart aa(3) were investigated by time resolved optical absorption spectroscopy to establish possible relationships between the structural diversity of these enzymes and their reaction dynamics. To determine whether the photodissociated carbon monoxide (CO) in the CO flow-flash experiment affects the ligand binding dynamics, we monitored the reactions in the absence and presence of CO using photolabile O(2) and NO complexes. The binding of O(2)/NO to reduced ba(3) in the absence of CO occurs with a second-order rate constant of 1*10(9)M(-1)s(-1). This rate is 10-times faster than for the mammalian enzyme, and which is attributed to structural differences in the ligand channels of the two enzymes. Moreover, the O(2)/NO binding in ba(3) is 10-times slower in the presence of the photodissociated CO while the rates are the same for the bovine enzyme. This indicates that the photodissociated CO directly or indirectly impedes O(2) and NO access to the active site in Tt ba(3), and that traditional CO flow-flash experiments do not accurately reflect the O(2) and NO binding kinetics in ba(3). We suggest that in ba(3) the binding of O(2) (NO) to heme a(3)(2+) causes rapid dissociation of CO from Cu(B)(+) through steric or electronic effects or, alternatively, that the photodissociated CO does not bind to Cu(B)(+). These findings indicate that structural differences between Tt ba(3) and the bovine aa(3) enzyme are tightly linked to mechanistic differences in the functions of these enzymes. This article is part of a Special Issue entitled: Respiratory Oxidases. PMID- 22201545 TI - Efficient dehydration of fructose to 5-hydroxymethylfurfural catalyzed by a recyclable sulfonated organic heteropolyacid salt. AB - The dehydration of fructose to 5-hydroxymethylfurfural (5-HMF) with room temperature ionic liquids (ILs) is a way of producing liquid fuels from renewable resources, but separation of products and IL is energy intensive. In this work, a heteropolyacid salt of an IL-forming cation functionalized with a propanesulfonate group, 1-(3-sulfonicacid)propyl-3-methyl imidazolium phosphotungstate ([MIMPS](3)PW(12)O(40)), was used as a catalyst-rather than as a solvent-in the conversion of fructose to 5-HMF. The maximum yield of 5-HMF was 99.1% at 120 degrees C after 2h using sec-butanol as solvent, and the catalyst was separated from the reaction mixture by a simple process at the end of the reaction and reused six times without loss of activity. PMID- 22201546 TI - Styryl conjugated coumarin caged alcohol: efficient photorelease by either one photon long wavelength or two-photon NIR excitation. AB - The synthesis and photorelease properties of a new phototrigger for alcohols are described. Compared to ester 4 caged by the reported [7-(diethylamino)coumarin-4 yl]methoxycarbonyl (DEACM) phototrigger, the caged ester 3 shows an efficient single-photon photolysis efficiency upon irradiation of long wavelength light (lambda = 475 nm) and a stronger two-photon photolysis sensitivity with 800 nm laser light. Its promising properties and the efficient photorelease of adenosine make it very useful as a caging group for biological applications. PMID- 22201547 TI - Volumetric properties of the molten globule state of cytochrome c in the thermal three-state transition evaluated by pressure perturbation calorimetry. AB - Thermodynamic properties, including volumetric properties, provide important information on protein stability and folding. Pressure perturbation calorimetry (PPC) is an effective technique for evaluating the temperature dependence of the thermal expansion coefficient, alpha(p), of biomaterials. Recently, the thermal N to-D transition of cytochrome c at nearly pH 4 was found to be a three-state transition including a molten globulelike intermediate state. In this study, the thermal N-to-D transition of cytochrome c was examined by PPC measurements with a three-state model. As far as we know, this is the first report of a three-state analysis of PPC, since two-state analyses are traditionally applied. The V(p) of the MG1-like intermediate state in the N-to-D transition at pH 4 was found to be the value between the partial volumes of the N and D states, suggesting an increase of the hydrophobic hydration in this intermediate state. PMID- 22201548 TI - Conformational changes of alpha-lactalbumin adsorbed at oil-water interfaces: interplay between protein structure and emulsion stability. AB - The conformation and structural dimensions of alpha-lactalbumin (alpha-La) both in solution and adsorbed at oil-water interfaces of emulsions were investigated using synchrotron radiation circular dichroism (SRCD) spectroscopy, front-face tryptophan fluorescence (FFTF) spectroscopy, and dual polarization interferometry (DPI). The near-UV SRCD and the FFTF results demonstrated that the hydrophobic environment of the aromatic residues located in the hydrophobic core of native alpha-La was significantly altered upon adsorption, indicating the unfolding of the hydrophobic core of alpha-La upon adsorption. The far-UV SRCD results showed that adsorption of alpha-La at oil-water interfaces created a new non-native secondary structure that was more stable to thermally induced conformational changes. Specifically, the alpha-helical conformation increased from 29.9% in solution to 45.8% at the tricaprylin-water interface and to 58.5% at the hexadecane-water interface. However, the beta-sheet structure decreased from 18.0% in solution to less than 10% at both oil-water interfaces. The DPI study showed that adsorption of alpha-La to a hydrophobic C18-water surface caused a change in the dimensions of alpha-La from the native globule-like shape (2.5-3.7 nm) to a compact/dense layer approximately 1.1 nm thick. Analysis of the colloidal stability of alpha-La stabilized emulsions showed that these emulsions were physically stable against droplet flocculation at elevated temperatures both in the absence and in the presence of 120 mM NaCl. In the absence of salt, the thermal stability of emulsions was due to the strong electrostatic repulsion provided by the adsorbed alpha-La layer, which was formed after the adsorption and structural rearrangement. In the presence of salt, although the electrostatic repulsion was reduced via electrostatic screening, heating did not induce strong and permanent droplet flocculation. The thermal stability of alpha-La stabilized emulsions in the presence of salt is a combined effect of the electrostatic repulsion and the lack of covalent disulfide interchange reactions. This study reports new information on the secondary and tertiary structural changes of alpha La upon adsorption to oil-water interfaces. It also presents new results on the physical stability of alpha-La stabilized emulsions during heating and at moderate ionic strength (120 mM NaCl). The results broaden our understanding of the factors controlling protein structural change at emulsion interfaces and how this affects emulsion stability. PMID- 22201549 TI - Effects of aging on blood brain barrier and matrix metalloproteases following controlled cortical impact in mice. AB - Aging alters the ability of the brain to respond to injury. One of the major differences between the adult and aged brain is that comparable injuries lead to greater blood brain barrier disruption in the aged brain. The goals of these studies were to quantify the effects of age on BBB permeability using high field strength MRI T1 mapping and to determine whether activation of matrix metalloproteases, their inhibitors, or expression of blood brain barrier structural proteins, occludin, zonnula occludins-1 (ZO-1) and claudin-5 were altered following injury to the aged C57/BL6 mouse brain. T1 mapping studies revealed greater blood brain barrier permeability in the aged (21-24 months old) brain than in the adult (4-6 months old) following controlled cortical impact. The increased blood brain barrier permeability in the pericontusional region was confirmed with IgG immunohistochemistry. MMP-9 activity was increased following controlled cortical impact in the aged brain, and this was accompanied by increased MMP-9 gene expression. MMP-2 activity was higher in the uninjured aged brain than in the adult brain. Occludin and ZO-1 mRNA levels were unchanged following injury in either age group, but claudin-5 mRNA levels were lower in the aged than the adult brain following injury. These results demonstrate quantitative increases in blood brain barrier permeability in the aged brain following injury that are accompanied by increased MMP-9 activation and decreased blood brain barrier repair responses. PMID- 22201550 TI - Traumatic brain injury and trichloroethylene exposure interact and produce functional, histological, and mitochondrial deficits. AB - Mitochondria play a pivotal role in the development of pathology associated with Parkinson's disease (PD), traumatic brain injury (TBI), and following exposure to the environmental toxin trichloroethylene (TCE). Evidence from humans indicates that both TBI and TCE can play a role in the development of PD and that each of these insults result in significant mitochondrial dysfunction. In the current studies we hypothesized that exposure to both TCE and TBI would result in increased pathology associated with PD. To test this hypothesis, 16 week old male Fischer 344 rats were administered TCE for either one or two weeks by oral gavage. Following exposure to TCE, rats were subjected to either a sham, mild (1.0mm), or moderate (2.0mm) controlled cortical impact TBI. Given the strong connection between mitochondrial function and PD, TBI, and TCE, tissue from the striatum and substantia nigra were analyzed 6h after the TBI. Neither TCE exposure, TBI, nor the combination of the two insults resulted in mitochondrial deficits at 6h post-TBI in the substantia nigra. Unlike the substantia nigra, the striatum exhibited significant mitochondrial dysfunction. Exposure to TCE alone for two weeks resulted in approximately a 75% reduction in mitochondrial function (p<0.05) in the striatum whereas TBI alone resulted in approximately a 30% reduction in striatal mitochondrial function. Following 1 week exposure to TCE followed by TBI, there was a significant reduction (50%) in mitochondrial function (p<0.05) which required the presence of both insults. Beginning 12 days after the injury significant motor impairment was observed with Rotarod testing. Animals exposed to TCE and a moderate TBI exhibited performance which was approximately 50% of controls (p<0.01). Cylinder testing revealed that at 30 days post-injury animals exposed to TCE and a moderate TBI also had about a 34% reduction in the usage of the contralateral fore paw and this impairment was significantly worse than both control animals and animals exposed to TCE and a mild TBI (p<0.05). At 30 days post-injury there was a 13-17% reduction in the number of tyrosine hydroxylase (TH) positive neurons in the substantia nigra (p<0.05), which was the result of protein loss and not cell death. Loss of TH positive neurons did not result in changes in striatal TH fiber density or levels of the dopamine transporter or type-2 dopamine receptor. Additionally, exposure to TCE prior to the TBI did not increase the loss of cortical tissue, indicating regional specificity for TCE induced deficits. These studies provide further evidence for the connection between TCE, TBI, and PD and lend support to the concept that PD develops from a multifactorial injury scenario. PMID- 22201551 TI - Protection from diabetes-induced peripheral sensory neuropathy--a role for elevated glyoxalase I? AB - Diabetic neuropathy is a common complication of diabetes mellitus with over half of all patients developing neuropathy symptoms due to sensory nerve damage. Diabetes-induced hyperglycemia leads to the accelerated production of advanced glycation end products (AGEs) that alter proteins, thereby leading to neuronal dysfunction. The glyoxalase enzyme system, specifically glyoxalase I (GLO1), is responsible for detoxifying precursors of AGEs, such as methylglyoxal and other reactive dicarbonyls. The purpose of our studies was to determine if expression differences of GLO1 may play a role in the development of diabetic sensory neuropathy. BALB/cJ mice naturally express low levels of GLO1, while BALB/cByJ express approximately 10-fold higher levels on a similar genetic background due to increased copy numbers of GLO1. Five weeks following STZ injection, diabetic BALB/cJ mice developed a 68% increase in mechanical thresholds, characteristic of insensate neuropathy or loss of mechanical sensitivity. This behavior change correlated with a 38% reduction in intraepidermal nerve fiber density (IENFD). Diabetic BALB/cJ mice also had reduced expression of mitochondrial oxidative phosphorylation proteins in Complexes I and V by 83% and 47%, respectively. Conversely, diabetic BALB/cByJ mice did not develop signs of neuropathy, changes in IENFD, or alterations in mitochondrial protein expression. Reduced expression of GLO1 paired with diabetes-induced hyperglycemia may lead to neuronal mitochondrial damage and symptoms of diabetic neuropathy. Therefore, AGEs, the glyoxalase system, and mitochondrial dysfunction may play a role in the development and modulation of diabetic peripheral neuropathy. PMID- 22201552 TI - Inter-individual variation in the anticonvulsant effect of phenobarbital in the pilocarpine rat model of temporal lobe epilepsy. AB - Despite a large therapeutic arsenal of old and new antiepileptic drugs (AEDs), there remains a substantial unmet need for the patients with refractory (AED resistant) epilepsy. Animal models of refractory epilepsy are needed for at least two goals; (1) better understanding of the mechanisms underlying resistance to AEDs, and (2) development of more efficacious AEDs for patients with refractory seizures. It is only incompletely understood why two patients with seemingly identical types of epilepsy and seizures may respond differently to the same AED. Prompted by this well-known clinical phenomenon, we tested whether epileptic rats from the same epilepsy model respond differently to AEDs and previously discovered phenobarbital (PB) responsive and resistant animals in groups of rats in which epilepsy had been induced by sustained electrical stimulation of the basolateral amygdala (BLA). In the present study, we used the same approach for the widely used pilocarpine model of temporal lobe epilepsy. Epileptic rats from this model were continuously video/EEG monitored over seven consecutive weeks, starting with a predrug control period of two weeks, then two weeks of daily treatment with PB at maximum tolerated doses, and finally a postdrug control period of three weeks. In those rats that were included in response selection, 50% did not adequately respond to PB, whereas PB significantly decreased seizure frequency and severity in another 50% of the animals. Responders and nonresponders did not differ in predrug seizure frequency, PB plasma levels or hippocampal neurodegeneration, but behavioral differences were observed in anxiety models. These findings demonstrate that in the pilocarpine model, similar to epilepsy patients, epileptic rats differ in their response to an AED, which is most likely due to as yet unknown genetic factors. PMID- 22201553 TI - Visible photolysis and amperometric detection of S-nitrosothiols. AB - The concentration of S-nitrosothiols (RSNOs), endogenous transporters of the signaling molecule nitric oxide (NO), fluctuate greatly in physiology often as a function of disease state. RSNOs may be measured indirectly by cleaving the S-N bond and monitoring the liberated NO. While ultraviolet photolysis and reductive based cleavage both decompose RSNOs to NO, poor selectivity and the need for additional reagents preclude their utility clinically. Herein, we report the coupling of visible photolysis (i.e., 500-550 nm) and amperometric NO detection to quantify RSNOs with greater selectivity and sensitivity. Enhanced sensitivity (up to 1.56 nA MUM(-1)) and lowered theoretical detection limits (down to 30 nM) were achieved for low molecular weight RSNOs (i.e., S-nitrosoglutathione, S nitrosocysteine) by tuning the irradiation exposure. Detection of nitrosated proteins (i.e., S-nitrosoalbumin) was also possible, albeit at a decreased sensitivity (0.11 nA MUM(-1)). This detection scheme was used to measure RSNOs in plasma and illustrate the potential of this method for future physiological studies. PMID- 22201554 TI - Ovarian stem cells and aging. AB - OBJECTIVE: To review successes to date in the field of ovarian stem cell research and discuss the evidence supporting their potential to rejuvenate the follicular pool during adult life; to present factors that may contribute to their competence; and to address the question of why menopause is an inevitable outcome of advanced age if ovarian stem cells exist. METHOD: In a review of the literature, relevant articles were identified through a PubMed literature search from inception to July 2010. RESULTS: The current concept that mammalian ovaries possess a static ovarian reserve is at odds with the experimental results discussed in this review. Ovarian stem cells are likely to be the source of germline stem cells during fetal and adult life, due to their potential to differentiate into competent oocytes given a suitable environment. CONCLUSIONS: Stem cells in different compartments share properties such as pluripotency, self renewal, and diminished regenerative potential in old age. Our model of ovarian stem cell aging suggests that menopause is driven by an age-related decline in ovarian stem cell function rather than depletion of a non-renewable follicular reserve. Understanding how ovarian stem cells interact with their surrounding environment moves us a step closer to controlling the female biological clock when it might be clinically desirable. PMID- 22201555 TI - EEG synchronization characteristics of functional connectivity and complex network properties of memory maintenance in the delta and theta frequency bands. AB - Task-dependent changes of nonlinear-linear synchronization features and graph theoretical properties of the delta and theta frequencies were analyzed in the present EEG study that were related to episodic memory maintenance processes. Synchronization was found to increase with respect to both the delta and theta bands within the frontal and parietal areas and also between these regions. Results of graph theoretical analysis indicated a task-related shift towards small-world network topology in the theta band. PMID- 22201556 TI - Perception of musical timbre in congenital amusia: categorization, discrimination and short-term memory. AB - Congenital amusia is a neurodevelopmental disorder that is characterized primarily by difficulties in the pitch domain. The aim of the present study was to investigate the perception of musical timbre in a group of individuals with congenital amusia by probing discrimination and short-term memory for real-world timbral stimuli as well as examining the ability of these individuals to sort instrumental tones according to their timbral similarity. Thirteen amusic individuals were matched with thirteen non-amusic controls on a range of background variables. The discrimination task included stimuli of two different durations and pairings of instrumental tones that reflected varying distances in a perceptual timbre space. Performance in the discrimination task was at ceiling for both groups. In contrast, amusic individuals scored lower than controls on the short-term timbral memory task. Amusic individuals also performed worse than controls on the sorting task, suggesting differences in the higher-order representation of musical timbre. These findings add to the emerging picture of amusia as a disorder that has consequences for the perception and memory of musical timbre, as well as pitch. PMID- 22201558 TI - No increased risk of sudden sensorineural hearing loss following recent herpes zoster: a nationwide population-based study. AB - CONCLUSION: There is no increased risk for sudden sensorineural hearing loss (SSNHL) among people who have experienced a recent herpes zoster attack, compared with a matching population. OBJECTIVE: The pathogenesis of SSNHL remains unknown, but viral infection is considered to be one of the main causes. The objective of this case-cohort study was to investigate the frequency and risk for SSNHL following a recent herpes zoster attack in the general population. METHODS: We extracted 313 612 patients with herpes zoster from a nationwide health registry in Taiwan, and also randomly selected 313 612 matched control subjects. Each participant was individually tracked for 2 months from their index ambulatory care visit to identify those who developed SSNHL. Stratified Cox proportional hazard regressions were conducted to analyze the risk of SSNHL for the sampled patients. RESULTS: Of the sample of 627 224 patients, 121 (0.02%) had SSNHL during the 2-month follow-up period, 59 from the study group (0.02% of the herpes zoster patients) and 62 from the comparison group (0.02% of patients without herpes zoster). Regression analysis revealed no increased adjusted hazard of SSNHL during the 2-month follow-up period for patients with herpes zoster as compared to those without (hazard ratio = 0.89, 95% confidence interval (CI) = 0.63-1.28, p = 0.540). PMID- 22201557 TI - Rapid evolution of the compact and unusual mitochondrial genome in the ctenophore, Pleurobrachia bachei. AB - Ctenophores are one of the most basally branching lineages of metazoans with the largest mitochondrial organelles in the animal kingdom. We sequenced the mitochondrial (mtDNA) genome from the Pacific cidipid ctenophore, Pleurobrachia bachei. The circular mitochondrial genome is 11,016 nts, with only 12 genes, and one of the smallest metazoan mtDNA genomes recorded. The protein coding genes are intronless cox1-3, cob, nad1, 3, 4, 4L and 5. The nad2 and 6 genes are represented as short fragments whereas the atp6 gene was found in the nuclear genome. Only the large ribosomal RNA subunit and two tRNAs were present with possibly the small subunit unidentifiable due to extensive fragmentation. The observed unique features of this mitochondrial genome suggest that nuclear and mitochondrial genomes have evolved at very different rates. This reduced mtDNA genome sharply contrasts with the very large sizes of mtDNA found in other basal metazoans including Porifera (sponges), and Placozoa (Trichoplax). PMID- 22201560 TI - 15th biennial Canadian neuro-oncology meeting. PMID- 22201559 TI - Thrombocytopenia-absent-radius syndrome in a child showing a larger 1q21.1 deletion than the one in his healthy mother, and a significant downregulation of the commonly deleted genes. AB - Thrombocytopenia-absent-radius (TAR) syndrome is a rare condition characterized by thrombocytopenia and bilateral absence of the radii with presence of both thumbs. The phenotype has a variable expression. A 200 kb minimal deletion at 1q21.1 is present in all patients. However, the microdeletion, ranging up to 1100 kb in length, is not sufficient to cause the disease. Indeed it is present in 75 80% of unaffected parents. It is assumed that the phenotype develops only in the presence of one or more additional, as-yet-unknown, deletion modifiers (mTARs). We report here on a child affected by TAR syndrome associated with Langerhans cell histiocytosis. Unexpectedly, he showed a 2.029 kb deletion at 1q21.1, almost twice that of the unaffected mother (957 kb). Interestingly, the mother-to-son increased size of the deleted region was already observed in two cases of constitutional diseases, although both resulting as chromosomal terminal deletions. Noteworthy, qPCR experiments, never before performed for patients with TAR syndrome, disclosed that the proband had a statistically significant downregulation of the majority of the genes mapping inside the part of the deletion shared with the mother. The mother, on the contrary, did not show the same downregulation. In summary, the present report adds new insights on the pathogenesis of TAR syndrome, that may represent fruitful directions for future research. PMID- 22201561 TI - Opposite regulatory effects of TRPC1 and TRPC5 on neurite outgrowth in PC12 cells. AB - The transient receptor potential (TRPC) family of Ca2+ permeable, non-selective cation channels is abundantly expressed in the brain, and can function as store operated (SOC) and store-independent channels depending on their interaction with the ER Ca2+ sensor STIM1. TRPC1 and TRPC5 have critical roles in neurite outgrowth, however which of their functions regulate neurite outgrowth is unknown. In this study, we investigated the effects of TRPC channels and their STIM1-induced SOC activity on neurite outgrowth of PC12 cells. We report that PC12 cell differentiation down-regulates TRPC5 expression, whereas TRPC1 expression is retained. TRPC1 and TRPC5 interact with STIM1 through the STIM1 ERM domain. Transfection of TRPC1 and TRPC5 increased the receptor-activated Ca2+ influx that was markedly augmented by the co-expression of STIM1. Topical expression of TRPC1 in PC12 cells markedly increased neurite outgrowth while that of TRPC5 suppressed neurite outgrowth. Suppression of neurite outgrowth by TRPC5 requires the channel function of TRPC5. However, strikingly, multiple lines of evidence show that the TRPC1-induced neurite outgrowth was independent of TRPC1 mediated Ca2+ influx. Thus, a) TRPC1 and TRPC5 similarly increased Ca2+ influx but only TRPC1 induced neurite outgrowth, b) the constitutively STIM1(D76A) mutant that activates Ca2+ influx by TRPC and Orai channels did not increase neurite outgrowth, c) co-expression of TRPC5 with TRPC1 suppressed the effect of TRPC1 on neurite outgrowth, d) and most notable, channel-dead pore mutant of TRPC1 increased neurite outgrowth to the same extent as TRPC1(WT). Suppression of TRPC1-induced neurite outgrowth by TRPC5 was due to a marked reduction in the surface expression of TRPC1. We conclude that the regulation of neurite outgrowth by TRPC1 is independent of Ca2+ influx and TRPC1-promoted neurite outgrowth depends on the surface expression of TRPC1. It is likely that TRPC1 acts as a scaffold at the cell surface to assemble a signaling complex to stimulate neurite outgrowth. PMID- 22201562 TI - Influencing safe perioperative practice through accountability. PMID- 22201563 TI - Connecting the dots. PMID- 22201565 TI - Congress speaker interviews. Interviewed by AORN. PMID- 22201572 TI - Developing good working relationships among personnel in the OR and SPD. PMID- 22201573 TI - A practical guide to applying lean tools and management principles to health care improvement projects. AB - Manufacturing organizations have used Lean management principles for years to help eliminate waste, streamline processes, and cut costs. This pragmatic approach to structured problem solving can be applied to health care process improvement projects. Health care leaders can use a step-by-step approach to document processes and then identify problems and opportunities for improvement using a value stream process map. Leaders can help a team identify problems and root causes and consider additional problems associated with methods, materials, manpower, machinery, and the environment by using a cause-and-effect diagram. The team then can organize the problems identified into logical groups and prioritize the groups by impact and difficulty. Leaders must manage action items carefully to instill a sense of accountability in those tasked to complete the work. Finally, the team leaders must ensure that a plan is in place to hold the gains. PMID- 22201574 TI - Kaizen: a process improvement model for the business of health care and perioperative nursing professionals. AB - Kaizen is a proven management technique that has a practical application for health care in the context of health care reform and the 2010 Institute of Medicine landmark report on the future of nursing. Compounded productivity is the unique benefit of kaizen, and its principles are change, efficiency, performance of key essential steps, and the elimination of waste through small and continuous process improvements. The kaizen model offers specific instruction for perioperative nurses to achieve process improvement in a five-step framework that includes teamwork, personal discipline, improved morale, quality circles, and suggestions for improvement. PMID- 22201575 TI - Patients count on it: an initiative to reduce incorrect counts and prevent retained surgical items. AB - Retained surgical items were the most frequently reported sentinel event in 2010, according to The Joint Commission. Perioperative nurse leaders at Children's Hospital Boston, a pediatric teaching hospital, conducted a quality improvement initiative to reduce or eliminate incorrect counts and count discrepancies, which increase the risk of an item being unintentionally retained after surgery. Work included educating the perioperative staff members, standardizing count practices, formally reviewing every reported count discrepancy with the nursing team, and reviewing and revising the count policy for prevention of retained surgical items. The initiative reduced the number of incorrect counts and count discrepancies by 50% between 2009 to 2010. These initiatives continue to be expanded, and the results have been sustained on an ongoing basis. PMID- 22201576 TI - Implementing AORN recommended practices for surgical attire. AB - Surgical attire is intended to protect both patients and perioperative personnel. AORN published the "Recommended practices for surgical attire" to guide perioperative RNs in establishing protocols for selecting, wearing, and laundering surgical attire. Perioperative RNs should work with vendors and managers to ensure appropriate surgical attire is available, model the correct practices for donning and wearing surgical attire, and teach team members about evidence-based practices. The recommendation that surgical attire not be home laundered is supported by evidence that perioperative nurses can share with their colleagues and managers to help support appropriate practices. Hospital and ambulatory surgery center scenarios have been included as examples of appropriate execution of these recommended practices. PMID- 22201578 TI - Culture of safety: safe work hours in the OR. PMID- 22201580 TI - Routine goes awry. PMID- 22201581 TI - Hsp60 protein pattern in coral is altered by environmental changes in light and temperature. AB - The heat shock protein Hsp60 exhibited marked oscillation during a 12-hour day period when the coral Turbinaria reniformis was maintained in the laboratory under constant conditions of light (200MUE) and temperature (27 degrees C). A biphasic pattern of Hsp60 was apparent, punctuated by a low protein level at the midpoint of the 12-hour day period. Oscillation of Hsp60 was also apparent when coral was kept in darkness in lieu of a scheduled light period. The pattern of Hsp60 was altered when coral was exposed to increased light intensity (400MUE) or temperature elevation (32 degrees C). These observations suggest that Hsp60 in coral exhibits oscillation that is altered by increased light and temperature elevation. PMID- 22201582 TI - The clinical significance and management of lesion motion due to respiration during PET/CT scanning. AB - Lesion movement during positron emission tomography (PET) scan acquisition due to normal respiration is a common source of artefact. A PET scan is acquired in multiple couch positions of between 2 and 5 min duration with the patient breathing freely. A PET-avid lesion will become blurred if affected by respiratory motion, an effect similar to that created when a person moves in a photograph. This motion also frequently causes misregistration between the PET and computed tomography (CT) scan acquired for attenuation correction and anatomical correlation on hybrid scanners. The compounding effects of blurring and misregistration in whole-body PET/CT imaging make accurate characterization of PET-avid disease in areas of high respiratory motion challenging. There is also increasing interest in using PET quantitatively to assess disease response in both clinical reporting and trials. However, at this stage, no response criteria take the effect of respiratory motion into account when calculating the standardized uptake value on a PET scan. A number of different approaches have been described in the literature to address the issue of respiratory motion in PET/CT scanning. This review details the clinical significance of lesion movement due to respiration and discusses various imaging techniques that have been investigated to manage the effects of respiratory motion in PET/CT scanning. PMID- 22201583 TI - Critical issues in delivery of RNAi therapeutics in vivo. AB - RNA interference (RNAi) is a fundamental mechanism of gene regulation and has been harnessed to produce a new class of drugs for treatment of various diseases. A key issue in these applications is how to effectively deliver RNAi therapeutics into target cells. This review is focused on advances in RNA delivery in vivo. To achieve it, novel strategies have been developed to enhance stability of RNA in cells and tissues, overcome barriers to transport of RNA or its carriers in the body, and reduce immunogenicity and cytotoxicity of treatment. Approaches to RNA delivery are divided into three categories in this review: biological, chemical, and physical. Advantages and disadvantages of each method are discussed. At present, effective delivery of RNAi therapeutics in vivo is still a challenge although significant advances have been made in this field. PMID- 22201584 TI - Non-invasive delivery of iRNAs, proteins, peptides, cytokines and nanoparticles. PMID- 22201585 TI - Pharmacokinetics/pharmacodynamics model-supported early drug development. AB - Pharmacokinetic/pharmacodynamic (PK/PD) modeling & simulation (M&S) provides quantitative assessment of dose/exposure-response relationships with extensive applications at the late stage drug development as well as during regulatory decision making. However, at preclinical and early phase clinical drug development, the importance of PK/PD M&S has not been as widely recognized. We reviewed selected PK/PD M&S literatures in order to convey importance of M&S in these early development phases. We focused on the application of M&S to select and optimize lead candidates, the use of preclinical PK/PD data to project the range of clinical doses, and the development of comprehensive dose/exposure response models that can be used to forecast the probability of achieving a target response based on Phase 1 safety, PK and biomarker information. We also reviewed several other M&S approaches that are often used in early drug development such as physiologically-based pharmacokinetic (PBPK) modeling, meta analysis, PK-pharmacogenomics modeling, and etc. Our aims were to provide expert opinions on the practical utility of PK/PD model-based approaches that have positive impact on early decision-making with the goal of improving the success rate of early to late stage drug development. PMID- 22201586 TI - Ultrasound-induced blood-brain barrier opening. AB - Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this paper is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD), and the safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It is hereby shown that the BBB can be disrupted safely and transiently under specific acoustic pressures (under 0.45 MPa) and microbubble (diameter under 8 MUm) conditions. PMID- 22201588 TI - Nanocarriers for the simultaneous co-delivery of therapeutic genes and anticancer drugs. AB - Due to the molecular complexity of cancer, combination therapy is becoming increasingly important for better long-term prognosis with fewer side effects. To further increase the therapeutic effects, advanced drug delivery systems (DDSs), capable of simultaneously delivering multiple drugs to the site of action with specific time-programmed release profiles, are important requirements. Nanocarriers for the simultaneous co-delivery of multiple chemical drugs in combination therapy have been extensively reviewed. Here we focus on the nanotechnology enabled DDSs for the simultaneous co-delivery of therapeutic genes and chemical drugs for cancer treatment. The opportunities for this combination strategy and their challenges will be discussed. PMID- 22201589 TI - Challenges and strategies in developing microneedle patches for transdermal delivery of protein and peptide therapeutics. AB - The birth of microneedles, an array of needles sufficiently long to penetrate epidermis but small enough to do not cause skin injury and pain feeling, has offered a highly promising solution for non-invasive delivery of protein and peptide drugs, a long-cherished desire over eighty years. However, the attempts to develop clinically feasible microneedle transdermal delivery methods encountered series of difficulties, for which a decade research efforts have yet to result in a single product. Microneedles may be incorporated into devices as skin pre-treatment tools, skin microinjectors as well as transdermal patches by their functions in drug delivery. They may also be categorized to insoluble solid microneedles, hollow microneedles, soluble/degradable solid microneedles and phase-transition microneedles by their structure and forming materials. This review article is aimed to update the progress and discuss the technical challenges raised in developing protein/peptide loaded microneedle patches. PMID- 22201587 TI - Experimental methods and transport models for drug delivery across the blood brain barrier. AB - The blood-brain barrier (BBB) is a dynamic barrier essential for maintaining the micro-environment of the brain. Although the special anatomical features of the BBB determine its protective role for the central nervous system (CNS) from blood born neurotoxins, however, the BBB extremely limits the therapeutic efficacy of drugs into the CNS, which greatly hinders the treatment of major brain diseases. This review summarized the unique structures of the BBB, described a variety of in vivo and in vitro experimental methods for determining the transport properties of the BBB, e.g., the permeability of the BBB to water, ions, and solutes including nutrients, therapeutic agents and drug carriers, and presented newly developed mathematical models which quantitatively correlate the anatomical structures of the BBB with its barrier functions. Finally, on the basis of the experimental observations and the quantitative models, several strategies for drug delivery through the BBB were proposed. PMID- 22201590 TI - Release of growth factors, cytokines and therapeutic molecules by hyaluronan based hydrogels. AB - Hyaluronan (HA) is a highly biocompatible biopolymer that is widely used for a variety of therapeutic purposes including surgical preparations, adhesion prevention, viscosupplementation and drug and cytokine delivery. Delivery can be accomplished effectively when HA-based carriers are synthesized in the form of hydrogels, though doing so normally requires chemical modification of the native HA structure. Solute delivery from HA-based gels can be either "simple", that is from a gel not including separate components intended to control release, or "regulated" when specific components are included for that purpose. A variety of modified forms of HA have been developed and used for delivery of desired molecules in therapeutic, clinical, veterinary and laboratory research environments, and the number of such applications is likely to grow in future years. PMID- 22201591 TI - Nanocarriers to solid tumors: considerations on tumor penetration and exposure of tumor cells to therapeutic agents. AB - Solid tumors constitute the majority of diagnosed cancers. For effective killing, therapeutic agents should ideally be delivered uniformly and at lethal doses to all cancer cells comprising the tumors, while keeping normal organ toxicities to a minimum. This requirement sets two of the major challenges in drug delivery to solid cancers: uniformity in delivery, and delivery of at least a minimum amount of therapeutics per cancer cell. Herein we review various approaches that aim to improve the penetration and content release of delivered therapeutic agents from nanocarriers of self-assembling nature. Biophysical characteristics of solid tumors are briefly discussed to motivate and rationalize the design of reported nanoparticle structures. This review does not aim to be exhaustive of the various designs and strategies, but to mostly give a flavor of the general current directions aiming to address these challenges. PMID- 22201592 TI - Editorial: The Bioenergetics of Cancer, the Warburg Hypothesis and the Mitochondrial Function PMID- 22201593 TI - Cell hierarchy, metabolic flexibility and systems approaches to cancer treatment. AB - The proliferative cancer cell paradigm that has driven cancer drug development for the past 50 years has failed to generate treatments that cure most metastatic adult cancers. This view is supported not only by cumulative experience with conventional cytotoxic anticancer drugs, but also by the application of highly targeted anticancer compounds against, for example, BCR-ABL in CML and mutant BRAF in metastatic melanoma. Such drugs often send their respective cancers into complete molecular remission but fail to effect cures because a small population of quiescent or slowly selfrenewing cancer cells that are drug and radiation resistant survive treatment indefinitely. This review explores the grounds for an emerging cancer paradigm that views cancer as a disorganized tissue with hierarchical cellular compartments in which the boudaries are less well-defined than in normal tissues with plasticity controlled by epigenetic changes mediated by the local microenvironment. Increased metabolic flexibility and adaptability give cancer cells an additional survival advantage that may be able to be targeted with drugs like metformin. Combining approaches that target the increased metabolic flexibility of cancer cells as well as ablating rapidly proliferating cells and self-renewing cancer stem cells in individual cancers are needed to address the holy grail of cancer cure. PMID- 22201594 TI - p53 regulation of energy metabolism and mitochondria regulation of p53 in cancer cells: an insight into the role of manganese superoxide dismutase. AB - Accumulated evidence suggests that p53 plays an important role in the regulation of metabolism and intracellular redox homeostasis through transcription-dependent and -independent mechanisms. Mitochondria, the power plant of cells, provide cells with ATP for their functions by regulating energy metabolism. In addition, as the byproducts of metabolism, reactive oxygen species (ROS) generated in the mitochondria can serve as signaling molecules to regulate p53 function. The regulation of p53 by mitochondria, especially redox-mediated regulation, may be involved in controlling the cellular switch between survival and death. The interplay between p53 and manganese superoxide dismutase (MnSOD), an important mitochondrial antioxidant enzyme, is an example of how nuclear and mitochondrial p53 coordinate their response to different levels of stress and contribute to the fate of cells. PMID- 22201595 TI - Combined chemotherapy or biotherapy with jasmonates: targeting energy metabolism for cancer treatment. AB - Mitochondria are known to play a key role in various cellular processes essential to both the life and death of cells, including calcium homeostasis, programmed cell death, and energy metabolism. Over 80 years ago, Otto Warburg discovered that in contrast to normal cells which produce most of their ATP via mitochondrial oxidative phosphorylation, cancer cells preferentially utilize glycolysis for production of ATP, a phenomenon known today as the "Warburg effect", and one which has been of great importance in the emergence of novel drugs and chemotherapeutic agents specifically targeting cancer cells. Several groups have reported in recent years that members of the plant stress hormones family of jasmonates, and some of their synthetic derivatives, exhibit anti cancer activity in vitro and in vivo. Jasmonates have been shown to act directly on mitochondria of cancer cells, leading to mitochondrial swelling, membrane depolarization and cytochrome c release. Throughout the last few years, different groups have demonstrated that combination of jasmonates and various cytotoxic and chemotherapeutic agents yielded a synergistic cytotoxic effect. These results have been demonstrated in a variety of different cancer cell lines and may provide a strong basis for future clinical treatments which involve combination of MJ and different anti-cancerous agents. The potential synergistic effect may allow reduction of the administered dose, decrease of unwanted side effects, and reduction of the likelihood that the tumor will display resistance to the combined therapy. PMID- 22201596 TI - Regulation of the metabolism of polyunsaturated Fatty acids and butyrate in colon cancer cells. AB - Experimental and epidemiological evidence supports the idea that dietary fat and fiber influence colon carcinogenesis. Particularly, their components, n-3 polyunsaturated fatty acids (PUFAs) and butyrate, have been proven to exhibit beneficial effects on colon epithelial cell metabolism, signaling, and kinetics, thus preventing colon inflammation and cancer. Moreover, these effects may be strengthened by PUFA and butyrate combination. It appears that administration of these compounds might be a relatively nontoxic form of supportive therapy improving cancer treatment outcomes and slowing down or preventing recurrence of certain types of cancer. However, their efficient application has to be based on solid scientific evidence of their mechanisms of action from the molecular and cellular to the organismal level. In this review, we emphasize the role of lipids and their metabolism during tumor development, describe some important mechanisms considering cellular and molecular levels of PUFA and butyrate action in colon epithelial cells, and particularly focus on the interaction of their metabolism and the signaling pathways with respect to the differences in response of normal and cancer colon cells. PMID- 22201598 TI - Targeting the mitochondrial electron transport chain complexes for the induction of apoptosis and cancer treatment. AB - Treatment of cancer is by no means universally successful and often manifests harmful side effects. The best way to improve the success rate and reduce the side effects would be to develop compounds that are able to kill cancer cells while leaving normal cells unaffected. In this respect, mitocans (an acronym from 'mitochondria' and 'cancer'), a summary term we proposed for compounds that induce cell death by targeting mitochondria, show an encouraging trend. Here we provide an overview of mitocans specific for the mitochondrial electron transport chain. These mitocans are particularly interesting, because a frequent consequence of electron transport chain inhibition is the induction of superoxide formation resulting in the preferential killing of cancer cells, as these tend to be more sensitive than normal cells to sudden increases in oxidative stress. Furthermore, macromolecular complexes of the electron transport chain only rarely mutate in cancer, and represent useful targets for anti-cancer drug development when widely-applicable agents are sought. PMID- 22201600 TI - Potentiation of anti-cancer treatment by modulators of energy metabolism. AB - Oncogene-driven proliferative signaling in tumor cells requires comprehensive upregulation of cellular energy metabolism and macromolecule syntheses. These alterations are now known to include not only upregulated glycolysis, but also increased fatty acid metabolism, glutaminolysis, deregulated mitochondrial function and more. Many prospective targets for tumor-specific pharmacological modulation of metabolism have therefore been identified. While the prospective drugs do not necessarily show very high antitumor activity by themselves, they may by depriving tumor cells of energy and building blocks for repair and proliferation come to be of major clinical use as potentiators of standard chemotherapeutic drugs and/or radiation. To this end, not only inhibitors of specific enzyme functions are being investigated, but also drugs affecting the complex signaling networks that regulate organismal and cellular energy status. This review provides examples of how modulators of energy metabolism (MEMs) targetting different aspects of tumor cell metabolism have been found to potentiate cancer treatment in vitro and in vivo. PMID- 22201597 TI - Use of anti-cancer drugs, mitocans, to enhance the immune responses against tumors. AB - Cytotoxic drugs in cancer therapy are used with the expectation of selectively killing and thereby eliminating the offending cancer cells. If they should die in an appropriate manner, the cells can also release danger signals that promote an immune reaction that reinforces the response against the cancer. The identity of these immune-enhancing danger signals, how they work extra- and intracellularly, and the molecular mechanisms by which some anti-cancer drugs induce cell death to bring about the release of danger signals are the major focus of this review. A specific group of mitocans, the vitamin E analogs that act by targeting mitochondria to drive ROS production and also promote a more immunogenic means of cancer cell death exemplify such anti-cancer drugs. The role of reactive oxygen species (ROS) production and the events leading to the activation of the inflammasome and pro-inflammatory mediators induced by dying cancer cell mitochondria are discussed along with the evidence for their contribution to promoting immune responses against cancer. Current knowledge of how the danger signals interact with immune cells to boost the anti-tumor response is also evaluated. PMID- 22201601 TI - Regulation of glycolytic and mitochondrial metabolism by ras. AB - High glucose uptake is a characteristic of most metastatic tumors and activation of Ras signaling in immortalized cells increases glycolytic flux into lactate, de novo nucleic acid synthesis and the tricarboxylic acid cycle, and increases NADH shuttling, oxygen consumption and uncoupling of ATP synthase from the proton gradient. Fructose-2,6- bisphosphate, C-Myc, HIF1alpha and AKT each have been found to be key regulators of glycolysis and to be controlled by Ras signaling, and there is abundant evidence for cross-talk between these regulators. The reprogramming of glycolytic and mitochondrial metabolism by Ras enables an integrated activation of energetic and anabolic pathways via the redox state of NADH that is required for the survival and growth of neoplastic cells in poorly vascularized tumors. Several small molecule antagonists specific for essential metabolic enzymes have been found to be selectively toxic to Ras-transformed cells as opposed to wild-type cells, indicating that this metabolic reprogramming and addiction may have utility for the development of anti-neoplastic agents. PMID- 22201602 TI - Carbon monoxide--a toxic gas on the edge to clinical application. PMID- 22201603 TI - Carbon monoxide, a two-face for the protection of the liver. AB - Carbon monoxide is generally believed to be a 'toxic' gas molecule due to its binding capability with hemoglobin. Overexposure to carbon monoxide leads to a hypoxic state that may cause the death of a mammalian. In contrast, directly exposure of carbon monoxide may protect cells or organs from various disease insults. The paradox effects of carbon monoxide might vary on the ways of exposure and the amounts being exposed. Here we highlighted the characteristics of this gas molecule and summarized its protective effects and therapeutic potentials in liver diseases and liver transplantation. PMID- 22201604 TI - Role of carbon monoxide in vascular diseases. AB - During the degradation of heme by the enzyme heme oxygenase (HO), Carbon monoxide (CO) is generated. Although it is considered as a non-significant and potentially toxic waste gas of heme catabolism, CO is a key signaling molecule used to regulate different cardiovascular functions. In this review, we focus the protective roles of CO in vascular injury/disease, which may be important to explore the overall protective roles of HO-1/CO system in the pathogenesis of human vascular disease. PMID- 22201606 TI - Heme Oxygenase-1/CO as protective mediators in cigarette smoke- induced lung cell injury and chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a disease involving airways restriction, alveolar destruction, and loss of lung function, primarily due to cigarette smoke (CS) exposure. The inducible stress protein heme oxygenase-1 (HO 1) has been implicated in cytoprotection against the toxic action of many xenobiotics, including CS. HO-1 also protects against elastase-induced emphysema. Differential expression of HO-1 in epithelial cells and macrophages may contribute to COPD susceptibility. Genetic polymorphisms in the HO-1 gene, which may account for variations in HO-1 expression among subpopulations, may be associated with COPD pathogenesis. Carbon monoxide (CO), a primary reaction product of HO-1 has been implicated in cytoprotection in many acute lung injury models, though it's precise role in chronic CS-induced lung injury remains unclear. CO is a potential biomarker of CS exposure and of inflammatory lung conditions. To date, a single clinical trial has addressed the possible therapeutic potential of CO in COPD patients. The implications of the cytoprotective potential of HO-1/CO system in CS-induced lung injury and COPD are discussed. PMID- 22201605 TI - Role of carbon monoxide in kidney function: is a little carbon monoxide good for the kidney? AB - Carbon monoxide (CO) is an endogenously produced gas resulting from the degradation of heme by heme oxygense or from fatty acid oxidation. Heme oxygenase (HO) enzymes are constitutively expressed in the kidney (HO-2) and HO-1 is induced in the kidney in response to several physiological and pathological stimuli. While the beneficial actions of HO in the kidney have been recognized for some time, the important role of CO in mediating these effects has not been fully examined. Recent studies using CO inhalation therapy and carbon monoxide releasing molecules (CORMs) have demonstrated that increases in CO alone can be beneficial to the kidney in several forms of acute renal injury by limiting oxidative injury, decreasing cell apoptosis, and promoting cell survival pathways. Renal CO is also emerging as a major regulator of renal vascular and tubular function acting to protect the renal vasculature against excessive vasoconstriction and to promote natriuresis by limiting sodium reabsorption in tubule cells. Within this review, recent studies on the physiological actions of CO in the kidney will be explored as well as the potential therapeutic avenues that are being developed targeting CO in the kidney which may be beneficial in diseases such as acute renal failure and hypertension. PMID- 22201607 TI - Carbon monoxide in acute lung injury. AB - Despite modern clinical practice in critical care medicine, acute lung injury still causes unacceptably high rates of morbidity and mortality. Therefore, the challenge today is to identify new and effective strategies in order to improve the outcome of these patients. Carbon monoxide, endogenously produced by the heme oxygenase enzyme system, has emerged as promising gaseous therapeutic that exerts protective effects against inflammation, oxidative and mechanical stress, and apoptosis, thus potentially limiting acute lung injury. In this review we discuss the effects of inhaled carbon monoxide on acute lung injury that results from ischemia-reperfusion, transplantation, sepsis, hyperoxia, or mechanical ventilation, the latter referred to as ventilator-induced lung injury. Multiple investigations using in vivo and in vitro models have demonstrated anti inflammatory, anti-apoptotic, and anti-proliferative properties of carbon monoxide in the lung when applied at low dose prior to or during stressful stimuli. The molecular mechanisms that are modulated by carbon monoxide exposure are still not fully understood. Carbon monoxide mediated lung protection involves several signaling pathways including mitogen activated protein kinases, nuclear factor-kappaB, activator protein-1, Akt, peroxisome proliferating- activated receptor-gamma, early growth response-1, caveolin-1, hypoxia-inducible factor 1alpha, caspases, Bcl-2-family members, heat shock proteins, or molecules of the fibrinolytic axis. At present, clinical trials on the efficacy and safety of CO investigate whether the promising laboratory findings might be translatable to humans. PMID- 22201608 TI - Cytoprotection by inhaled carbon monoxide before cardiopulmonary bypass in preclinical models. AB - Although a potentially toxic gaseous molecule, carbon monoxide recently gains rising scientifically and clinical interest as its beneficial effects and mechanisms of action are defined substantially in various in vitro and in vivo experiments. Its anti-inflammatory, anti-apoptotic and anti-proliferative properties but its increasing impact concerning numerous disease models in means of protection, well describe this gas as a new and challenging therapeutic alternative. In this review, we focus on the extensively analyzed advantageous value of pre- and postconditioning with inhaled carbon monoxide in the context of lung and kidney injury, induced by the low perfusion during and after cardiopulmonary bypass. Mechanisms like the heat shock response as well as an expanded view regarding toxicity and side effects are described broadly. PMID- 22201609 TI - Application of carbon monoxide for transplantation. AB - Carbon monoxide (CO) is an invisible, chemically inert, colorless and odorless gas and is toxic at high concentrations due to its interference with oxygen delivery. However, CO is endogenously and physiologically generated in mammalian cells via the catabolism of heme in a rate-limiting step of heme oxygenase systems, and CO potently protects against cellular injury. CO relaxes blood vessels and exerts anti-thrombotic effects by inhibiting platelet aggregation and derepressing fibrinolysis. In addition, CO reduces ischemia/reperfusion injury and inflammatory responses. CO inhibits apoptosis of endothelial and epithelial cells and reduces proliferation of smooth muscle cells, fibroblasts and T lymphocytes. Thus, there is accumulating evidence to support the notion that CO treatment of transplant donors, organs, or recipients can prevent graft dysfunction due to rejection or ischemia/reperfusion injury. This invited review discusses recent advances and current knowledge pertaining to CO research in the field of transplantation. In addition, we will discuss the clinical applicability of CO as a promising therapeutic strategy for the treatment of transplant patients. PMID- 22201610 TI - Carbon monoxide--toxicity of low-dose application. AB - Carbon monoxide (CO) has long been considered a purely toxic by-product of incomplete combustion processes. Acute exposure to high concentrations of CO is one of the leading causes of fatal poisoning in industrial countries. However, after two decades of intensive research, there is ample evidence that CO endogenously produced by heme oxygenase enzymes has essential physiological functions and is of vital importance for cellular hemostasis. Furthermore, exogenously applied CO in low concentrations mediates potent cytoprotective effects. An overwhelming number of different in vitro and in vivo models demonstrated the protective action of CO application, e.g., in ischemia/reperfusion, transplantation, oxidative stress, inflammation, and others. Protection by this gaseous molecule could be illustrated for most organs, most species, and for different routes of administration. Now being on the verge of entering clinical trials, the question emerges whether the administration of low-dose CO would be safe for patients when used as a potential therapeutic. Therefore, this review summarizes in particular toxicological data obtained from low-dose CO exposure and discusses its impact on a possible clinical application. PMID- 22201611 TI - Carbon monoxide and the pancreas. AB - Carbon monoxide (CO), often referred to as the silent killer, is a colorless, odorless and tasteless gas. It combines with hemoglobin to produce carboxyhemoglobin, which is ineffective for delivering oxygen to animal and human tissues. On the other hand, CO is endogenously produced in the body as a byproduct of heme degradation catalyzed by the heme oxygenase (HO) enzymes. In the past decade, evidence has accumulated to suggest important physiological roles for CO in mammalian tissues. In the pancreas, modulation of endogenous CO production or administration of exogenous CO may represent a therapeutic option for the treatment of endocrine and exocrine pancreatic disorders. In cell culture, CO exerts anti-diabetic effects and brief exposure of purified mouse islets to CO ameliorates functional performance after transplantation. Recent advances include the observation that CO carriers possess potent anti proliferative effects in an in vitro model of pancreatic fibrosis. In vivo, CO confers tissue protection in animal models of pancreatic disease, including those with hyperglycemia and inflammatory injury of the gland. However, there are still a number of unanswered questions surrounding its physiological and pathophysiological relevance and the preferred route of CO administration in the pancreas still remains to be settled. This brief review focuses on the roles, effects and mechanisms of action of CO in the pancreas. PMID- 22201612 TI - Antibacterial effects of carbon monoxide. AB - Carbon monoxide (CO) is a colourless and odourless gas that has long been considered as a potent respiratory poison. Recent advances have demonstrated its production by haem oxygenases in both mammals and microbes, and it has roles as a gasotransmitter in higher organisms. This review concentrates on the application of CO, via carbon monoxide-releasing molecules (CO-RMs), as an anti-bacterial agent. Currently, the scope of literature on the effects of CO on bacteria is small, and we have included discussions on the production of CO by bacteria via haem oxygenase enzymes, the use of CO as an energy source, and existing knowledge on CO sensors in bacteria. CO is known to target haem proteins and is an effective inhibitor of respiration, even when provided at concentrations much higher than prevailing oxygen. We review here data suggesting that CO-RMs are more effective inhibitors of respiration than is CO gas, perhaps due to the ability of CO-RMs to deliver CO selectively to intracellular targets. We also consider the recently reported transcriptomic consequences of CO-RM treatment of Escherichia coli, revealing a myriad of unexpected targets for CO and potential CO sensors. Finally, we consider the use of CO and CO-RMs as anti-bacterial agents in vivo, and the future prospects for this gaseous molecule. PMID- 22201614 TI - The penetration of renal mass biopsy in daily practice: a survey among urologists. AB - BACKGROUND AND PURPOSE: The vast increase in recent publications on renal mass biopsy (RMB) suggests an increased interest in the subject. The objective of the survey was to assess the use of RMB in current urologic practice, including related factors such as indications and patterns in practice. METHODS: The link to a web-based questionnaire ( www.surveymonkey.com ) was sent to all registered e-mail addresses (1854) of members of the Endourological Society in December 2010. The questionnaire contained six epidemiologic questions, 10 regarding patterns of practice, one regarding the influence of the literature, and one on future techniques. Chi-square test (for trends) was used to assess statistical significant differences among categorical answers. RESULTS: In total, 190 responders completed the survey of whom 73% indicated performing RMB "never" or "rarely" compared with 9% performing RMB in 25% to 100% of cases. Thirteen percent of responders reported never to take a RMB. Of the latter, significantly fewer practice in university hospitals (6% vs 20%-30%, P=0.003). Main indications to perform RMB are still tumors in solitary/transplant kidneys and in metastatic disease. Lack of influence on clinical management and risk of false negatives were the main reasons not to perform biopsies. Sixty-one percent prefer histological biopsies compared with 8% who prefer cytological aspiration; 31% indicated that they combine both techniques. Other tissue differentiation techniques (Optical Coherence Tomography, Raman-spectroscopy) are unknown to 65% of urologists. CONCLUSION: RMB is not yet applied widely in urologic practice, with academic urologists performing RMB less infrequently. Core biopsies are still preferred, although combined with cytologic punctures by a considerable number of responders. PMID- 22201613 TI - Overexpression of TWIST2 correlates with poor prognosis in head and neck squamous cell carcinomas. AB - Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of tumors with variable presentation and clinical behavior. Despite improvements in surgical and radiation therapy techniques, the 5-year survival rate has not improved significantly over the past decades. Thus, there is an urgent need to identify novel markers that may allow for the development of personalized therapeutic approaches. In the present study we evaluated the prognostic role of the expression of genes related to the induction of epithelial mesenchymal transition (EMT). To this aim, a consecutive series of 69 HNSCC were analyzed for the expression of TWIST1, TWIST2, SNAI1, SNAI2, E-Cadherin, N-Cadherin and Vimentin.TWIST1, TWIST2, SNAI1 and SNAI2 were significantly overexpressed in HNSCC, with TWIST2, SNAI1 and SNAI2 being more markedly increased in tumors compared to normal mucosae. The expression of TWIST1 and SNAI2 was associated with upregulation of mesenchymal markers, but failed to correlate with pathological parameters or clinical behaviour. In contrast, we found that upregulation of TWIST2, which was independent of the activation of a mesenchymal differentiation program, correlated with poor differentiation grade (p=0.016) and shorter survival (p=0.025), and identifies a subset of node-positive oral cavity/pharynx cancer patients with very poor prognosis (p less than 0.001). Overall our study suggests that the assessment of TWIST2 expression might help to stratify HNSCC patients for risk of disease progression, pointing to TWIST2 as a potential prognostic marker. PMID- 22201615 TI - Local and global responses of insect motion detectors to the spatial structure of natural scenes. AB - As a consequence of the non-linear correlation mechanism underlying motion detection, the variability in local pattern structure and contrast inherent within natural scenes profoundly influences local motion responses. To accurately interpret optic flow induced by self-motion, neurons in many dipteran flies smooth this "pattern noise" by wide-field spatial integration. We investigated the role that size and shape of the receptive field plays in smoothing out pattern noise in two unusual hoverfly optic flow neurons: one (HSN) with an exceptionally small receptive field and one (HSNE) with a larger receptive field. We compared the local and global responses to a sequence of panoramic natural images in these two neurons with a parsimonious model for elementary motion detection weighted for their spatial receptive fields. Combined with manipulation of size and contrast of the stimulus images, this allowed us to separate spatial integration properties arising from the receptive field, from other local and global non-linearities, such as motion adaptation and dendritic gain control. We show that receptive field properties alone are poor predictors of the response to natural scenes. If anything, additional non-linearity enhances the pattern dependence of HSN's response, particularly to vertically elongated features, suggesting that it may serve a role in forward fixation during hovering. PMID- 22201616 TI - Th1 and Th2 cytokine profiles in malignant pleural effusion. AB - BACKGROUND: The alteration of Th1 and Th2 cytokine levels is the subject of controversy in pleural effusions caused by malignancy, a situation that favors a Th2 immune response. OBJECTIVE: To examine the different levels of IL-4 and IL-10 (Th2 cytokines), and IL-2 and interferon-gamma (IFN-gamma) (Th1 cytokines) in malignant and non-malignant pleural effusions. METHOD: The cytokine levels in pleural fluid of 62 patients with malignant pleural effusion (44 with lung cancer and 18 with extrathoracic tumors), 8 with tuberculous and 8 with congestive heart failure pleural effusion were analyzed using enzyme-linked immunosorbent assays. RESULTS: IL-2 was below the detectable concentration of the assay. A significant decrease in IFN-gamma level was observed in malignant but not in congestive heart failure cases compared to tuberculous cases. IL-10 levels were higher in malignant and tuberculous pleural effusions than in congestive heart failure pleural effusions, however, this difference did not reach the significant level. IL-4 levels were also increased non-significantly in lung cancer pleural effusions compared to the other groups. CONCLUSION: Our results show a wide variation in IL-4, IL-10, and IFN-gamma levels in malignant pleural effusions, a pattern which was not convincing enough to differentiate the cause of effusion. PMID- 22201617 TI - Cytokine profile in the endometrium of normal fertile and women with repeated implantation failure. AB - BACKGROUND: Repeated Implantation Failure (RIF) is one of the most intricate obstacles in assisted reproduction. The cytokine and chemokine composition of uterine cavity seem to play important roles in the implantation process. OBJECTIVE: To compare the cytokine profile in the endometrium of normal fertile women and those with repeated implantation failure. METHODS: After enzymatic digestion of endometrial tissues, whole endometrial cells and endometrial stromal cells from RIF and normal fertile women were cultivated and stimulated for cytokine secretion. The levels of IL-10, TGF-beta, IFN-gamma, IL-6, IL-8 and IL 17 in culture supernatants of the two groups were assayed by ELISA and compared together. RESULTS: Endometrial stromal cells and whole endometrial cells of normal fertile women produced higher levels of IL-6, IL-8 and TGF-beta compared to RIF group, although this difference was statistically significant only in endometrial stromal cells (p=0.005, 0.002 and 0.001, respectively). In addition, endometrial stromal cells of normal fertile women produced lower levels of IL-10 in comparison with RIF group (p=0.005). CONCLUSION: Disturbances in cytokine production at the feto-maternal interface could be a cause of implantation failure. A pro-inflammatory cytokine milieu seems to be pivotal for successful implantation. PMID- 22201618 TI - IL-4 can inhibit IL-17 production in collagen induced arthritis. AB - BACKGROUND: IL-4 is a cytokine that induces differentiation of naive helper T cells into Th2 cells. Once activated by IL-4, Th2 cells subsequently produce additional IL-4. OBJECTIVE: To examine the effect of IL-4 on IL-17 production and its effect in Collagen-Induced Arthritis (CIA) mice. METHOD: In this study, a chicken collagen-II-induced experimental arthritis (CIA) model was used in DBA/1 mice to investigate the relationship between IL-4 and IL-17 as well as other inflammatory factors. On the 38th day after the mice were induced with CIA, the expression of IL-17 and IL-4 as well as IFN-gamma and IL-13 in sera of the mice was measured by QRT-PCR and ELISA. RESULT: The result of QRT-PCR analysis of IL 17 and IL-4 mRNA levels in the spleen showed that IL-17 is increased significantly at the onset of CIA in the spleen (p<0.01). Meanwhile, IL-17 is generally reduced at the peak of CIA but IL-4 is increased significantly at this peak in the spleen when the weight of the animal was taken into consideration (p<0.05). CONCLUSION: IL-4 can be involved in the production of IL-17 at especially the peak of CIA. These results imply that the inhibition of IL-17 may decrease the expression of IL-1beta and IL-6 production which will result in the aggravation of arthritis. PMID- 22201619 TI - FOXP3 and TGF-beta gene polymorphisms in allergic rhinitis. AB - BACKGROUND: Regulatory CD4+ T (Treg) cells are effective in maintaining immune tolerance. OBJECTIVE: To investigate single nucleotide polymorphisms (SNPs) of Transforming Growth Factor beta-1 (TGF-beta1) and Forkhead Box Protein 3 (FOXP3) genes in Iranian patients with allergic rhinitis (AR). METHODS: Variations at codons 10 and 25 of TGF-beta1 and FOXP3 at positions -3279 A>C and -924 A>G were evaluated in AR patients and compared with controls. In a case-control study, 155 AR patients and 163 allergy-free controls were genotyped using polymerase chain reaction sequence-specific primer (PCR-SSP) technique. RESULTS: The analysis of the frequency of these SNPs showed that the haplotype formed by FOXP3 -3279 A allele occurred significantly more frequently in patients than controls (odds ratio=1.44, 95% CI=1.312-2.66; p=0.001). CONCLUSION: Our results suggest that polymorphism in FOXP3 gene is associated with susceptibility to AR. PMID- 22201620 TI - Immunoinhibitory effect of teuclatriol a guaiane sesquiterpene from Salvia mirzayanii. AB - BACKGROUND: Salvia mirzayanii, a native plant to Iran, is shown to have immunomodulatory effects on lymphocyte proliferation. OBJECTIVE: To identify the bioactive immunomodulatory compound(s) present in S. mirzayanii. METHODS: The crude extract was fractionated to five fractions in two steps using different solvents. The fractions were subjected to bioassay-guided fractionation. All the fractions were tested for bioactivity on human activated-peripheral blood lymphocytes (PBLs) using cell proliferation assay. RESULTS: The methanol fraction (Fr. M) showed the highest inhibitory effect on PBLs compared to other fractions. Fr. M was applied on a gravity column chromatography for further fractionation. Resultant fractions, demonstrated inhibitory effects at higher concentrations. Fr. 4 with an 18.9 +/- 0.2% inhibitory activity at 200 ug/ml and with the highest quantity was applied on preparative TLC plates for further purification. The final purified compound was identified as teuclatriol, a guaiane sesquiterpene, by NMR analysis. This compound showed a significant anti-proliferative effect on human activated-peripheral blood lymphocytes (IC50, 72.8 +/- 5.4 ug/ml). CONCLUSION: Teuclatriol was found to be one of the compounds responsible for the immunoinhibitory effect of Salvia mirzayanii. We suggest further studies on teuclatriol, exploring its mechanism of action as an immunomodulatory compound. PMID- 22201621 TI - Immune responses to antigens of in vitro reared Echinococcus granulosus adult worms in Balb/c mice. AB - BACKGROUND: Cystic echinococcosis (CE), also known as echinococcosis/hydatidosis, is one of the most important parasitic diseases in the world. It enhances both humoral and cellular (Th1 and Th2) responses in infected host. Different antigens of the worm may favor the Th1 or Th2 immune responses in CE patients. OBJECTIVE: To evaluate the humoral and cellular immune responses of Balb/c mice against the crude and excretory/secretory (E/S) antigens of in vitro reared Echinococcus granulosus adult worms. METHODS: A total of 20 Balb/c mice divided into 5 groups of 4 mice each. Three groups of mice (n=4) were immunized with crude, E/S and an immunodominant antigen of in vitro reared Echinococcus granulosus adult worms on day 1 and 28. The fourth and the fifth groups were negative control groups and received PBS plus adjuvant, or nothing, respectively. Two weeks after the second injection, the mice were killed and their blood was collected for determining antibody responses, and their spleens were employed for proliferation assay. Total IgG was measured by indirect ELISA. Spleen cells of immunized mice were cultivated and exposed to different antigens of adult worms including E/S and crude antigens. Levels of IFN-gamma, IL-12, IL-4 and IL-10 were measured in the recovered cell culture supernatants by capture ELISA. RESULTS: Total IgG assay showed the highest level of antibody produced in mice immunized with crude antigens. Proliferation assay showed a statistically significant production of cytokines in the mice immunized with crude antigens (p<0.05). The highest levels of IFN-gamma, IL-12 and IL-4 were produced in mice immunized with crude antigen of the in vitro reared Echinococcus granulosus adult worms followed by E/S antigens. Immunodomonant antigen induced the lowest levels of cytokines (IL-12, IFN-gamma, IL-4 and IL-10) in immunized mice. CONCLUSION: Significant levels of Th1 related cytokines (IFN-gamma and IL-12) were produced in Balb/c mice immunized with crude antigen of the in vitro reared Echinococcus granulosus adult worms. PMID- 22201622 TI - A Leishmania infantum FML-ELISA for the detection of symptomatic and asymptomatic canine visceral leishmaniasis in an endemic area of Iran. AB - BACKGROUND: Visceral leishmaniasis (VL) is caused by Leishmania infantum in Mediterranean basin and is an endemic disease in some parts of Iran. Canines are the main reservoirs of VL in most of the endemic areas. Different serological methods have been introduced for diagnosis of canine visceral leishmaniasis (CVL). OBJECTIVE: In this survey a Fucose-Mannose Ligand (FML) ELISA, using native L. infantum antigen, was developed and its validity for detection of infected dogs in comparison with direct agglutination test (DAT) and PCR was evaluated. METHODS: Blood samples of sixty ownership dogs (<= 3 years old) were collected from Meshkin-shahr district in Ardabil province, North-west of Iran. Sera were separated for serological assays (DAT and FML-ELISA) and the buffy coats were collected for molecular evaluation. RESULTS: Two out of the 60 (3.33%) samples were found to be positive (antibody titer of >= 1/320) in DAT while seven of the 60 (11.66%) samples were positive by FML-ELISA. Nine out of 60 (15%) buffy coat samples showed a band about 680 bp indicative of L. infantum in PCR. Three out of 60 dogs had Kala-azar symptoms and were positive by PCR and FML-ELISA, while two of these three dogs had antibody titers >1/320 in their serum samples. The sensitivity and specificity of FML-ELISA for the detection of CVL in both symptomatic and asymptomatic dogs were found to be 77.8% and 100%, respectively. CONCLUSION: Considering the acceptable sensitivity and high specificity of FML ELISA, use of this serological method can be recommended for epidemiological surveys of CVL. PMID- 22201623 TI - IgG avidity test for the diagnosis of acute Toxoplasma gondii infection in early pregnancy. AB - BACKGROUND: Toxoplasmosis is well known as an important infection in pregnant women. Although many serologic methods are available, diagnosis of early Toxoplasmosis may be extremely difficult. OBJECTIVE: To detect the Toxoplasma IgG antibodies developed at the early stage of infection in pregnant women. METHODS: 225 pregnant women, who were in the 2nd to 4th month of their pregnancy, enrolled in this study. Anti-toxoplasma IgG, IgM and IgG avidity were evaluated by ELISA method. RESULTS: The patients were categorized into three groups as follows: Group A, 124 cases; IgG+, IgM+, 55.1%; group B, 99 cases; IgG+, IgM-, 44%; and group C, 2 cases; IgG -, IgM +, 0.9%. Fifty five percent of the pregnant women had positive IgG and IgM among which 7.1% had low avidity which revealed an active infection in the pregnant women. In the current study, 44% of pregnant women had positive IgG and negative IgM, all of which had high avidity, which is an indication that in our population the level of toxoplasmosis infection is high and most women have had contacts with this parasite before pregnancy. CONCLUSION: In this study, the low avidity test was 7.1% showing that the occurrence of toxoplasmosis infection is still a serious issue. Observation of 45.8% high avidity among group A suggests that either IgM has a high half-life or there is a false positive IgM as a result of rheumatologic disorders. Therefore, avidity test is important in predicting maternal toxoplasmosis which is of value in disease treatment. PMID- 22201625 TI - Black balls and diagnostic reasoning. PMID- 22201627 TI - Developing military cultural competency in health care providers. PMID- 22201628 TI - Toward an integrated research community. PMID- 22201629 TI - Time to move on from the term faculty development. PMID- 22201630 TI - Management lessons for improving medical students' clerkship experience. PMID- 22201631 TI - Commentary: a sense of story, or why teach reflective writing? AB - Reflective writing is being introduced in many medical schools in the United States and abroad for a variety of reasons and with a variety of goals in mind. As Wald and colleagues write, multiple methods, including the rubric introduced in their study, have been proposed for rating or grading this writing to quantify the gains obtained. The authors of this commentary detail the assumptions both about reflection and about writing implied in Wald and colleagues' work. They then describe a reciprocal model of writing as discovery, suggesting that the writing itself is what teaches the skills of reflection. Equipping medical students with a sense of story may well be the active ingredient in whatever gains are observed in teaching reflective writing. PMID- 22201632 TI - Commentary: "I hope i'll continue to grow": rubrics and reflective writing in medical education. AB - One respected tradition in medical education holds that physicians should struggle to maintain sensibility, openness, and compassion in the face of strong contravening tendencies. However, today's medical education is structured around a more recent tradition, which maintains that physicians should struggle to develop emotional detachment as a prerequisite for objectivity. In this model, sensibility and reflective capacity are potentially subversive. Reflective writing is one component of a revisionist approach to medical education that explicitly addresses reflective "habits of the mind" as core competencies and builds on existential concerns voiced by medical students. In response to Wald and colleagues' study, the authors reflect on the role of repeated formative feedback in developing reflective capacity. Formative feedback is as critical in this process as it is in traditional clinical learning. The authors emphasize that well-designed rubrics can assist learners in delineating desired outcomes and teachers in providing appropriate guidance. PMID- 22201633 TI - Commentary: the relative research unit: providing incentives for clinician participation in research activities. AB - Recent nationwide initiatives to accelerate clinical and translational research, including comparative effectiveness research, will increasingly require clinician participation in research-related activities at the point-of-care, activities such as participant recruitment for clinical research studies and systematic data collection. A key element to the success of such initiatives that has not yet been adequately addressed is how to provide incentives to clinicians for the time and effort that such participation will require. Models to calculate the value of clinical care services are commonly used to compensate clinicians, and similar models have been proposed to calculate and compensate researchers' efforts. However, to the authors' knowledge, no such model has been proposed for calculating the value of research-related activities performed by noninvestigator clinicians, be they in academic or community settings. In this commentary, the authors propose a new model for doing just that. They describe how such a relative research unit model could be used to provide both direct and indirect incentives for clinician participation in research activities. Direct incentives could include financial compensation, and indirect incentives could include credit toward promotion and tenure and toward the maintenance of specialty board certification. The authors discuss the principles behind this relative research unit approach as well as ethical, funding, and other considerations to fully developing and deploying such a model, across academic environments first and then more broadly across the health care community. PMID- 22201634 TI - A surgeon at night. PMID- 22201635 TI - Artist's statement: memories of mentorship. PMID- 22201638 TI - AM last page. Applying Knowles' andragogy to resident teaching. PMID- 22201639 TI - Linearity and nonlinearity in HIV/STI transmission: implications for the evaluation of sexual risk reduction interventions. AB - A mathematical model of HIV/sexually transmitted infections (STI) transmission was used to examine how linearity or nonlinearity in the relationship between the number of unprotected sex acts (or the number of sex partners) and the risk of acquiring HIV or a highly infectious STI (such as gonorrhea or chlamydia) affects the utility of sexual behavior change measures as indicators of the effectiveness of HIV/STI risk-reduction interventions. Findings indicate that the risk of acquiring HIV through vaginal intercourse is essentially a linear function of the number of unprotected sex acts and is nearly independent of the number of sex partners. Consequently, the number of unprotected sex acts is an excellent marker for the risk of acquiring HIV through vaginal intercourse, whereas the number of sex partners is largely uninformative. In general, the number of unprotected sex acts is not an adequate marker for the risk of acquiring a highly infectious STI due to the highly nonlinear per act transmission dynamics of these STIs. The number of sex partners is a reasonable indicator of STI risk only under highly circumscribed conditions. A theoretical explanation for this pattern of results is provided. The contrasting extent to which HIV and highly infectious STIs deviate from the linearity assumption that underlies sexual behavior outcome measures has important implications for the use of these measures to assess the effectiveness of HIV/STI risk-reduction interventions. PMID- 22201640 TI - Inspiration. PMID- 22201641 TI - Enterococcal infectious crystalline keratopathy in a wearer bandage contact lens. PMID- 22201642 TI - Negative correlation between body mass index category and physical activity perceptions in children. AB - Children's physical activity (PA) choices are influenced by their perceived ability (adequacy) and inclination toward (predilection) PA. The study's purpose was to determine the association of body mass index (BMI) category with PA perceptions in sixth-grade children. A total of 267 children (119 boys, 148 girls; age 11+ y; ht 1.53 SD 0.08 m; wt 49.0 SD 13.5 kg; BMI 20.7 SD 4.8) provided informed consent and completed the study. All were measured for body weight and height and completed the Children's Self-perceptions of Adequacy in and Predilection for Physical Activity (CSAPPA) scale. Spearman rank-order correlation analysis was conducted between total CSAPPA score (and three factor scores of adequacy, predilection, and enjoyment) and BMI category relative to gender, body weight classification and for all children. A significant negative correlation was identified between BMI category (p<0.01) and CSAPPA total, adequacy, and predilection score for all children. Girls (but not boys) showed significant negative correlation between BMI category and all CSAPPA scores. A significant negative correlation in BMI category and PA perceptions exists in children, with the relationship being stronger in girls. Children with increased BMI may have adverse perceptions of PA and risks for sedentary behavior. PMID- 22201643 TI - Upper extremity neurodynamic tests: range of motion asymmetry may not indicate impairment. AB - Upper extremity (UE) neurodynamic tests are used to examine neural tissue in patients with neuro-musculoskeletal disorders. Although comparisons between involved and uninvolved limbs are made clinically, minimal data exist reflecting the normal variation between sides. The purpose of this study was to determine if within-subject differences exist between limbs in the UE component of neurodynamic tests of the median, radial, and ulnar nerves. Sixty-one healthy subjects were examined. Difference between limbs for the median nerve-biased test was significant (right=16.4 degrees +/- 11.4 degrees , left=20.1 degrees +/- 13.7 degrees ; p=0.045). There was no significant difference between limbs for the radial or ulnar nerve-biased tests. Correlation between limbs was poor for all tests (median r(2) =0.14; radial r(2) =0.20; ulnar r(2) =0.13). Lower-bound scores were calculated to determine the amount of difference needed to consider asymmetry beyond measurement error; the scores for each neurodynamic test were as follows: median 27 degrees , radial 20 degrees , and ulnar 21 degrees . The results of this study show that between-limb values have low correlation and that it may be normal for an individual to have range of motion differences between limbs with neurodynamic tests. PMID- 22201645 TI - The impact of social roles on trait judgments: a critical reexamination. AB - Consistent with social role theory's assumption that the role behavior of men and women shapes gender stereotypes, earlier experiments have found that men's and women's occupancy of the same role eliminated gender-stereotypical judgments of greater agency and lower communion in men than women. The shifting standards model raises the question of whether a shift to within-sex standards in judgments of men and women in roles could have masked underlying gender stereotypes. To examine this possibility, two experiments obtained judgments of men and women using measures that do or do not restrain shifts to within-sex standards. This measure variation did not affect the social role pattern of smaller perceived sex differences in the presence of role information. These findings thus support the social role theory claim that designations of identical roles for subgroups of men and women eliminate or reduce perceived sex differences. PMID- 22201644 TI - Naive and primed murine pluripotent stem cells have distinct miRNA expression profiles. AB - Over the last years, the microRNA (miRNA) pathway has emerged as a key component of the regulatory network of pluripotency. Although clearly distinct states of pluripotency have been described in vivo and ex vivo, differences in miRNA expression profiles associated with the developmental modulation of pluripotency have not been extensively studied so far. Here, we performed deep sequencing to profile miRNA expression in naive (embryonic stem cell [ESC]) and primed (epiblast stem cell [EpiSC]) pluripotent stem cells derived from mouse embryos of identical genetic background. We developed a graphical representation method allowing the rapid identification of miRNAs with an atypical profile including mirtrons, a small nucleolar RNA (snoRNA)-derived miRNA, and miRNAs whose biogenesis may differ between ESC and EpiSC. Comparison of mature miRNA profiles revealed that ESCs and EpiSCs exhibit very different miRNA signatures with one third of miRNAs being differentially expressed between the two cell types. Notably, differential expression of several clusters, including miR290-295, miR17 92, miR302/367, and a large repetitive cluster on chromosome 2, was observed. Our analysis also showed that differentiation priming of EpiSC compared to ESC is evidenced by changes in miRNA expression. These dynamic changes in miRNAs signature are likely to reflect both redundant and specific roles of miRNAs in the fine-tuning of pluripotency during development. PMID- 22201646 TI - Encephalopathy in children: an approach to assessment and management. AB - Childhood encephalopathy is an uncommon but significant paediatric presentation and is associated with significant mortality and long-term morbidity in survivors. By definition it is a somewhat non-specific presentation with a wide differential diagnosis and long list of possible investigations. Choice of investigation, including neuroimaging modality, can be a daunting prospect for the clinician faced with the encephalopathic child and it is important to select appropriately for a high diagnostic yield. Initial management centres on good emergency care irrespective of cause. More specific therapies however vary enormously, and appropriate treatment is important and influences outcome. Evidence exists for management of many of the individual conditions causing encephalopathy. This review aims to outline a clinical approach to selecting investigations to identify a specific cause and provides an overview of the treatment for the commoner causes of encephalopathy that a general paediatrician may reasonably expect to be faced with. PMID- 22201647 TI - ABIDEC drops and peanut allergy. PMID- 22201649 TI - The top 10 redux. PMID- 22201648 TI - Antiviral activity of four types of bioflavonoid against dengue virus type-2. AB - BACKGROUND: Dengue is a major mosquito-borne disease currently with no effective antiviral or vaccine available. Effort to find antivirals for it has focused on bioflavonoids, a plant-derived polyphenolic compounds with many potential health benefits. In the present study, antiviral activity of four types of bioflavonoid against dengue virus type -2 (DENV-2) in Vero cell was evaluated. Anti-dengue activity of these compounds was determined at different stages of DENV-2 infection and replication cycle. DENV replication was measured by Foci Forming Unit Reduction Assay (FFURA) and quantitative RT-PCR. Selectivity Index value (SI) was determined as the ratio of cytotoxic concentration 50 (CC50) to inhibitory concentration 50 (IC50) for each compound. RESULTS: The half maximal inhibitory concentration (IC50) of quercetin against dengue virus was 35.7 MUg mL 1 when it was used after virus adsorption to the cells. The IC50 decreased to 28.9 MUg mL-1 when the cells were treated continuously for 5 h before virus infection and up to 4 days post-infection. The SI values for quercetin were 7.07 and 8.74 MUg mL-1, respectively, the highest compared to all bioflavonoids studied. Naringin only exhibited anti-adsorption effects against DENV-2 with IC50 = 168.2 MUg mL-1 and its related SI was 1.3. Daidzein showed a weak anti-dengue activity with IC50 = 142.6 MUg mL-1 when the DENV-2 infected cells were treated after virus adsorption. The SI value for this compound was 1.03. Hesperetin did not exhibit any antiviral activity against DENV-2. The findings obtained from Foci Forming Unit Reduction Assay (FFURA) were corroborated by findings of the qRT-PCR assays. Quercetin and daidzein (50 MUg mL-1) reduced DENV-2 RNA levels by 67% and 25%, respectively. There was no significant inhibition of DENV-2 RNA levels with naringin and hesperetin. CONCLUSION: Results from the study suggest that only quercetin demonstrated significant anti-DENV-2 inhibitory activities. Other bioflavonoids, including daidzein, naringin and hesperetin showed minimal to no significant inhibition of DENV-2 virus replication. These findings, together with those previously reported suggest that select group of bioflavonoids including quercetin and fisetin, exhibited significant inhibitory activities against dengue virus. This group of flavonoids, flavonol, could be investigated further to discover the common mechanisms of inhibition of dengue virus replication. PMID- 22201650 TI - People and events. PMID- 22201651 TI - Chemotherapy administration: using simulation case-based scenarios to assess chemotherapy competency. PMID- 22201652 TI - Chemotherapy-induced infertility in patients with testicular cancer. PMID- 22201653 TI - Revisions to the 2009 American Society of Clinical Oncology/Oncology Nursing Society chemotherapy administration safety standards: expanding the scope to include inpatient settings. AB - In November 2009, the American Society of Clinical Oncology (ASCO) and the Oncology Nursing Society (ONS) jointly published a set of 31 voluntary chemotherapy safety standards for adult patients with cancer, as the end result of a highly structured, multistakeholder process. The standards were explicitly created to address patient safety in the administration of parenteral and oral chemotherapeutic agents in outpatient oncology settings. In January 2011, a workgroup consisting of ASCO and ONS members was convened to review feedback received since publication of the standards, to address interim changes in practice, and to modify the standards as needed. The most significant change to the standards is to extend their scope to the inpatient setting. This change reflects the conviction that the same standards for chemotherapy administration safety should apply in all settings. The proposed set of standards has been approved by the Board of Directors for both ASCO and ONS and has been posted for public comment. Comments were used as the basis for final editing of the revised standards. The workgroup recognizes that the safety of oral chemotherapy usage, nononcology medication reconciliation, and home chemotherapy administration are not adequately addressed in the original or revised standards. A separate process, cosponsored by ASCO and ONS, will address the development of safety standards for these areas. PMID- 22201654 TI - A randomized, clinical trial of education or motivational-interviewing-based coaching compared to usual care to improve cancer pain management. AB - PURPOSE/OBJECTIVES: To test the effectiveness of two interventions compared to usual care in decreasing attitudinal barriers to cancer pain management, decreasing pain intensity, and improving functional status and quality of life (QOL). DESIGN: Randomized clinical trial. SETTING: Six outpatient oncology clinics (three Veterans Affairs [VA] facilities, one county hospital, and one community-based practice in California, and one VA clinic in New Jersey)Sample: 318 adults with various types of cancer-related pain. METHODS: Patients were randomly assigned to one of three groups: control, standardized education, or coaching. Patients in the education and coaching groups viewed a video and received a pamphlet on managing cancer pain. In addition, patients in the coaching group participated in four telephone sessions with an advanced practice nurse interventionist using motivational interviewing techniques to decrease attitudinal barriers to cancer pain management. Questionnaires were completed at baseline and six weeks after the final telephone calls. Analysis of covariance was used to evaluate for differences in study outcomes among the three groups. MAIN RESEARCH VARIABLES: Pain intensity, pain relief, pain interference, attitudinal barriers, functional status, and QOL. FINDINGS: Attitudinal barrier scores did not change over time among groups. Patients randomized to the coaching group reported significant improvement in their ratings of pain-related interference with function, as well as general health, vitality, and mental health. CONCLUSIONS: Although additional evaluation is needed, coaching may be a useful strategy to help patients decrease attitudinal barriers toward cancer pain management and to better manage their cancer pain. IMPLICATIONS FOR NURSING: By using motivational interviewing techniques, advanced practice oncology nurses can help patients develop an appropriate plan of care to decrease pain and other symptoms. PMID- 22201656 TI - Increasing mammography and cervical cancer knowledge and screening behaviors with an educational program. AB - PURPOSE/OBJECTIVES: To evaluate the effectiveness of using an educational program based on self-efficacy to increase knowledge and create behavior change regarding recommended mammography and Papanicolaou (Pap) test screening guidelines. DESIGN: Pretest and post-test, prospective. SETTING: An urban county in northern Indiana. SAMPLE: 56 women who attended one of four educational programs and 47 women who responded 15 months later. METHODS: The one-hour educational programs based on self-efficacy included vicarious experiences and verbal persuasion regarding breast and cervical screening practices. Two programs were offered to local church groups as part of a health fair, and two were offered through health promotion initiatives sponsored by private businesses. MAIN RESEARCH VARIABLES: Demographics, knowledge of breast and cervical cancer, and screening behaviors. FINDINGS: Knowledge of risk and screening guidelines increased significantly immediately following the educational program (p < 0.001) and did not decrease significantly 15 months later (p = 0.57). Family history and history of human papillomavirus and sexually transmitted diseases were the top known risk factors for breast and cervical cancers, respectively. Participant-reported rates of screening behaviors increased 15 months later for mammography (100%) and Pap test (84%). CONCLUSIONS: Educational interventions based on self-efficacy increased knowledge of breast and cervical health and helped increase the rate of mammography and Pap tests. IMPLICATIONS FOR NURSING: Preparing women with strategies to complete a mammogram and Pap test is an important approach to enhancing self-efficacy and increasing screening behaviors. PMID- 22201655 TI - The interaction of perceived risk and benefits and the relationship to predicting mammography adherence in African American women. AB - PURPOSE/OBJECTIVES: To test the interaction of perceived risk and benefits and how they impact stage of mammography readiness and adherence. DESIGN: Cross sectional study. SETTING: Community gathering centers and healthcare clinics across Indiana. SAMPLE: 299 African American women who had not had a mammogram in more than 18 months. METHODS: In-person interviews were used to collect data on sociodemographics, health belief variables, and stage of readiness to undertake mammography screening. Four categories were created to measure the combined magnitude of high or low levels of perceived risk and benefit, with health belief variables linked to modified mammography screening behavior. MAIN RESEARCH VARIABLES: Perceived risks and benefits, stage of readiness, and mammography adherence. FINDINGS: The lowest rate of mammography adherence was in women with a high perceived risk and low perceived benefit toward mammography adherence (26%). The highest rate of adherence was in women with a high perceived benefit and low perceived risk (46%). Differences in mammography adherence were statistically significant between the groups (p = 0.009). CONCLUSIONS: The interaction of high perceived risk and low perceived benefits impacted readiness to undergo screening mammography. IMPLICATIONS FOR NURSING: Reducing disparities in breast cancer diagnosis and survival requires timely and efficient mammography adherence. African American medically underserved women with high perceived risk and low perceived benefits exhibited a reluctance to move forward with mammography adherence. Interventions are needed to increase the perception of mammography benefit and to subsequently reduce breast cancer mortality rates in that population. PMID- 22201657 TI - Women's experiences with antiestrogen therapy to treat breast cancer. AB - PURPOSE/OBJECTIVES: To understand the experiences of women undergoing antiestrogen therapy (AET) to treat breast cancer. RESEARCH APPROACH: Content analysis of tape-recorded focus group interviews. SETTING: Breast oncology center of a large medical center in the northeastern United States. PARTICIPANTS: Purposive sample of 21 women undergoing AET to treat breast cancer. METHODOLOGIC APPROACH: A nonexperimental qualitative, descriptive design using open-ended interviews and content analysis to isolate themes. MAIN RESEARCH VARIABLES: Women's experiences with AET. FINDINGS: Five themes were isolated and were focused on the overall experience of having breast cancer: symptoms related to AET, shared decision making, being strong for others, discovering new priorities, and recognizing vulnerability. CONCLUSIONS: Oral therapies are an increasingly popular treatment option for various types of cancer, particularly in women with estrogen-sensitive breast cancer. Although this type of treatment has been efficacious in terms of disease-free and overall survival, women undergoing AET face many challenges related to treatment. Healthcare providers need to understand women's perceptions of AET and its effects as a first step in the process of developing interventions to improve care. INTERPRETATION: More research is needed to distinguish whether the presence of preexisting chronic illness, differences in type of AET, age, and ethnicity impact the overall experience of women on AET. Individual interviews may be necessary to fully explore the experience. Oncology nurses should implement surveillance care to explore the effects of AET on women with breast cancer. PMID- 22201658 TI - Senior peer counseling by telephone for psychosocial support after breast cancer surgery: effects at six months. AB - PURPOSE/OBJECTIVES: To evaluate the efficacy of senior peer counseling by telephone for supplemental psychosocial support of older women after breast cancer surgery. DESIGN: Experimental, randomized block, longitudinal. SETTING: A community-based senior service agency and a community hospital-based breast surgical oncology practice in an urban area of California. SAMPLE: 142 women newly diagnosed and scheduled for surgery for stage 0-III breast cancer (X age = 61.8, range = 50-94). METHODS: Participants were stratified by age and randomized to receive telephone calls from a peer counselor (a) once per week for five weeks beginning within 72 hours postsurgery, (b) once weekly for five weeks beginning six weeks postsurgery, and (c) by request. Assessments were conducted before surgery, postintervention, and six months after surgery. Questionnaires included the Hospital Anxiety and Depression Scale, the Interpersonal Relationship Inventory, and the Brief COPE. MAIN RESEARCH VARIABLES: Anxious mood, social support, and coping by seeking instrumental support. FINDINGS: At six months, significant main effects of age were noted for social support, fear of recurrence, and resource use. Significant independent effects of age and intervention were noted for coping by seeking instrumental support. After controlling for age, a significant interaction effect of intervention and time was observed for coping by seeking instrumental support. CONCLUSIONS: Peer counseling may affect instrumental support seeking and appears to be differentially received by age group. Additional study is needed to better understand who benefits most and how from peer counseling. IMPLICATIONS FOR NURSING: Trained senior peer counselor volunteers, supervised by a skilled clinical team, may be a useful adjunct in addressing psychosocial needs of women after breast cancer surgery. PMID- 22201659 TI - Timing and sustainability of an exercise intervention in women with breast cancer during and after cancer treatment. AB - PURPOSE/OBJECTIVES: To compare changes in frequency, duration, and intensity of exercise behaviors over time in women with breast cancer between those who started their exercise intervention at the beginning of chemotherapy (EE) and those who started at the completion of chemotherapy (CE). DESIGN: A secondary data analysis of a randomized, controlled trial for exercise intervention. SETTING: Five cancer centers in the San Francisco Bay Area in California. SAMPLE: 66 outpatient women with breast cancer who were receiving chemotherapy. METHODS: Piecewise linear mixed models analysis was used to study changes in exercise behaviors over time in the EE group during and after treatment. In addition, linear mixed models analysis was used to examine changes between the EE and CE groups after treatment. Participants were in the trial for various length of time (EE group: 19-86 weeks; CE group: 6-43 weeks). MAIN RESEARCH VARIABLES: Exercise frequency, intensity, and duration. FINDINGS: In the EE group, weekly exercise duration increased significantly during treatment (p = 0.02). In addition, weekly exercise intensity increased significantly during treatment (p = 0.02) and decreased significantly after treatment (p = 0.003). After treatment, initial weekly exercise duration was significantly lower in the CE group than in the EE group (p = 0.01). No significant differences existed in frequency and intensity over time between the EE and CE groups. CONCLUSIONS: Women with breast cancer can sustain exercise behaviors when they start an exercise intervention in the beginning of chemotherapy treatment. IMPLICATIONS FOR NURSING: Strategies to support patients in maintaining their exercise habit may be needed during the post-treatment period. PMID- 22201660 TI - Sociocultural differences and colorectal cancer screening among African American men and women. AB - PURPOSE/OBJECTIVES: To examine sociocultural factors that influence an informed decision about colorectal cancer (CRC) screening among African American men and women. DESIGN: Descriptive, cross-sectional. SETTING: A medical center, a National Cancer Institute-designated comprehensive cancer center, and various social organizations and barbershops in a midwestern city of the United States. SAMPLE: A purposive sample of African American women (n = 65) and African American men (n = 64) aged 50 years and older. METHODS: Participants completed a self-administered survey. MAIN RESEARCH VARIABLES: Cultural identity, CRC beliefs, family support, and informed decision. FINDINGS: Family support was positively related to CRC beliefs among participants, and CRC beliefs were positively related to an informed decision. However, among men, family support positively related to an informed decision about CRC screening. In addition, t test results indicated that the men and women were significantly different. Family support predicted CRC beliefs among men (p < 0.01) and women (p < 0.01). CRC beliefs predicted CRC screening informed decisions among men (p < 0.01) and women (p < 0.05). However, the accounted variance was dissimilar, suggesting a difference in the impact of the predictors among the men and women. CONCLUSIONS: Family support has a significant impact on CRC beliefs about CRC screening among African Americans. However, how men and women relate to the variables differs. IMPLICATIONS FOR NURSING: To improve CRC screening rates, informed decision making interventions for African Americans should differ for men and women and address family support, CRC beliefs, and elements of cultural identity. PMID- 22201663 TI - The effects of P6 acupressure and nurse-provided counseling on chemotherapy induced nausea and vomiting in patients with breast cancer. AB - PURPOSE/OBJECTIVES: To evaluate the effects of pericardium 6 (P6) acupressure and nurse-provided counseling on chemotherapy-induced nausea and vomiting (CINV) in patients with breast cancer. DESIGN: Randomized, controlled trial. SETTING: A university cancer center in Seoul, South Korea. SAMPLE: 120 women who were beginning their second cycle of adjuvant chemotherapy after definitive surgery for breast cancer and who had more than mild levels of nausea and vomiting with the first cycle of chemotherapy. METHODS: Participants were assigned randomly into four groups: control (placebo on SI3), counseling only, P6 acupressure only, and P6 acupressure plus nurse-provided counseling. The experiences of upper gastrointestinal distress were measured by the Rhodes Index of Nausea, Vomiting, and Retching for acute (day 1) and delayed (day 2 to day 5) CINV. MAIN RESEARCH VARIABLES: Nausea, retching, vomiting, P6 acupressure, and counseling. FINDINGS: No significant differences were found in the demographic and disease-related variables among the four groups. The levels of CINV were significantly different among the groups from day 2 to day 5. The CINV differences were attributed mainly to the difference between the control group and the group with P6 acupressure plus nurse-provided counseling. The effects of acupressure were proven from day 2 to day 5, and the effects of nurse-provided counseling were proven on day 4 and were close to significance level on day 5. CONCLUSIONS: Synergic effects of P6 acupressure with nurse-provided counseling appeared to be effective in reducing CINV in patients with breast cancer. IMPLICATIONS FOR NURSING: P6 acupressure combined with counseling by nurses is a safe and easy-to-apply tool in CINV management in practice. PMID- 22201664 TI - Instrumental relating and treatment decision making among older women with early stage breast cancer. AB - PURPOSE/OBJECTIVES: To understand how women aged 70 years and older who had recently undergone treatment for early-stage breast cancer experienced treatment decision making. RESEARCH APPROACH: Qualitative, descriptive study guided by grounded theory. SETTING: PARTICIPANTS' houses and apartments in southern California. PARTICIPANTS: 18 women, aged 70-94 years, who completed treatment for primary, early-stage breast cancer 3-15 months prior (X = 8.5 months). METHODOLOGIC APPROACH: Twenty-eight semistructured personal interviews that lasted, on average, 104 minutes. Data were collected and analyzed using constructivist grounded theory. MAIN RESEARCH VARIABLES: Gero-oncology perspective of treatment decision making. FINDINGS: A major finding was that the power of relating spontaneously was used as a vehicle to connect with others. That process, which the authors called "instrumental relating," was grounded in a foundation of mutual caring for themselves and others. Within that mutual caring, the women participated in three ways of relating to share in treatment decision making: obtaining information, interpreting healthcare providers, and determining the trustworthiness of their providers. Those ways of relating were effortlessly and simultaneously employed. CONCLUSIONS: The women used their expert abilities of relating to get the factual and emotional information that they needed. That information supported what the women perceived to be decisions that were shared and effective. INTERPRETATION: The findings are the first evidence of the importance of relating as a key factor in decision making from the personal perspective of older women with early-stage breast cancer. This work serves as a springboard for future clinical interventions and research opportunities to individualize communication and enhance effective decision making for older patients who wish to participate in their cancer care. PMID- 22201665 TI - Clinical subgroups of a psychoneurologic symptom cluster in women receiving treatment for breast cancer: a secondary analysis. AB - PURPOSE/OBJECTIVES: To investigate clinical subgroups using an empirically identified psychoneurologic symptom cluster (depressed mood, cognitive disturbance, fatigue, insomnia, and pain) and to examine the differences among subgroups in the selected demographic and clinical variables, as well as in patient outcome (i.e., functional performance). DESIGN: Secondary analysis. SETTING: A university health science center in Salt Lake City, UT, and a National Cancer Institute-designated comprehensive cancer center in Philadelphia, PA. SAMPLE: 282 patients with breast cancer undergoing chemotherapy or radiotherapy. METHODS: Cluster analyses were conducted to identify subgroups. Multinomial logistic regression and one-way analyses of variance were used to examine the differences among subgroups. MAIN RESEARCH VARIABLES: Depressed mood, cognitive disturbance, fatigue, insomnia, pain, and functional performance. FINDINGS: Patients were classified into four distinct subgroups based on their symptom cluster experience: all low symptom, high fatigue and low pain, high pain, and all high symptom. Such patient classification patterns were consistent across the treatment trajectory, although group memberships were inconsistent. After initiating treatment, two additional subgroups emerged: high depressed mood and cognitive disturbance, and high fatigue and insomnia. Subgroups differed in physical performance status at baseline, symptom burden, and treatment modality in a relatively consistent pattern across time points. Patients in the all-high symptom subgroup experienced the most serious limitations in activities across all time points. CONCLUSIONS: Patient subgroups exist that share the unique experience of psychoneurologic symptoms. IMPLICATIONS FOR NURSING: Findings are useful to determine who needs more intensive symptom management during cancer treatment. Future studies should examine whether specific symptom management strategies are more efficient for certain subgroups. PMID- 22201666 TI - Chemotherapy-related cognitive impairment: the breast cancer experience. AB - PURPOSE/OBJECTIVES: To provide an in-depth description of the experience of chemotherapy-related cognitive impairment (CRCI) for women with breast cancer and identify related information that women would find useful prior to chemotherapy and at the onset of cognitive changes. RESEARCH APPROACH: Qualitative, descriptive design. SETTING: Academic breast cancer survivorship center in Kansas City, KS. PARTICIPANTS: 18 breast cancer survivors within 6-12 months of having completed chemotherapy who self-reported changes in cognitive function. METHODOLOGIC APPROACH: Data were collected with a demographic questionnaire, semistructured interviews, and a focus group. Qualitative content analysis was performed. FINDINGS: Study themes were Life With Chemobrain, How I Changed, How I Cope, and How to Teach Me. Participants described difficulty with short-term memory, focusing, word finding, reading, and driving. Issues with fatigue, trouble sleeping, neuropathy, balance, and coordination also were of concern. Coping strategies included writing things down, depending on others, focusing on one task at a time, and giving oneself permission to make mistakes. Participants described exercise and getting enough rest to be helpful and recommended activities to stimulate the mind. Participants wanted information about the potential for CRCI prior to initiating chemotherapy and desired an individualized approach to education. Specific recommendations for education were provided. CONCLUSIONS: The study results provide a framework for understanding the experience of CRCI that can be used to guide development of patient and family education and generate questions for additional research. INTERPRETATION: Application of the study results will enhance informed consent, validate the experience of CRCI, and contribute to patient satisfaction. PMID- 22201667 TI - Self-transcendence in stem cell transplantation recipients: a phenomenologic inquiry. AB - PURPOSE/OBJECTIVES: To understand the meaning of self-transcendence, or the ability to go beyond the self, for patients who have had a stem cell transplantation. RESEARCH APPROACH: A phenomenologic investigation guided by the interpretive philosophy of Heidegger. SETTING: A cancer center in a major urban academic medical center. PARTICIPANTS: 4 men and 4 women ages 45-63 who had received a stem cell transplantation in the previous year. METHODOLOGIC APPROACH: Two or three unstructured, open-ended interviews were conducted with each participant. Data were extracted, analyzed, and interpreted according to the Colaizzi method. MAIN RESEARCH VARIABLES: Self-transcendence. FINDINGS: Self transcendence emerged as a process that was triggered by the suffering the participants experienced as they lived through the physical effects of the treatment, faced death, drew strength from within themselves, and perceived a spiritually influenced turning point. The experience of a human connection lessened their feelings of vulnerability in the process. As the participants recovered, they described being transformed both physically and personally. CONCLUSIONS: The findings from this study highlight the power inherent in patients to not only meet the challenges they face, but to grow from their experiences. The findings also highlight patients' deep need for a human connection and the power that nurses and other healthcare professionals have to provide that connection. INTERPRETATION: The caring connections established by health-care professionals can ease the ability of patients to access the inner resource of self-transcendence and reduce their feelings of vulnerability. PMID- 22201668 TI - A path analysis: a model of depression in Korean women with breast cancer mediating effects of self-esteem and hope. AB - PURPOSE/OBJECTIVES: To test a hypothetical model of depression in Korean women with breast cancer and to test the mediating effects of self-esteem and hope. DESIGN: Cross-sectional design. SETTING: Participants were recruited from three general hospitals and one cancer hospital in Busan, South Korea. SAMPLE: 214 Korean women diagnosed with breast cancer (stages I-III). METHODS: All participants completed questionnaires (e.g., Zung Self-Rating Depression scale, Herth Hope Scale, Rosenberg Self-Esteem Scale, Health Self-Rating Scale in Health and Activity survey, Kang's Family Support Scale). Based on the literature, Mplus, version 3.0, was used to determine the best depression model with path analysis. MAIN RESEARCH VARIABLES: Depression, self-esteem, hope, perceived health status, religious beliefs, family support, economic status, and fatigue. FINDINGS: Self-esteem was directly affected by perceived health status, religious beliefs, family support, economic status, and fatigue. Hope was directly affected by family support, self-esteem, and how patients perceived their health status. Depression was directly affected by self-esteem and hope. The path analysis model explained 31% of the variance in depression in Korean women with breast cancer. CONCLUSIONS: A model of depression in Korean women with breast cancer was developed, and self-esteem and hope were mediating factors of depression. IMPLICATIONS FOR NURSING: Self-esteem and hope must be considered when developing services to reduce depression in Korean women with breast cancer. PMID- 22201669 TI - Professional navigation framework: elaboration and validation in a Canadian context. AB - PURPOSE/OBJECTIVES: To elaborate, refine, and validate the professional navigation framework in a Canadian context. RESEARCH APPROACH: A two-step approach consisting of a qualitative evaluative design and formal consultations. SETTING: Two applications of professional navigators in Quebec and Nova Scotia, Canada. PARTICIPANTS: Patient navigators, medical oncology specialists, nurses and oncology staff, administrators, family physicians, patients with cancer, and patients' families and significant others. METHODS: Individual interviews (n = 49) and focus groups (n = 10) were conducted with professional navigators, patients and family members, front-line staff, family physicians, and health administrators. Formal consultations (n = 13) occurred with clinical experts, managers, and researchers from across Canada. MAIN RESEARCH VARIABLES: The interview guide was based on an evaluative conceptual framework integrating questions related to the implementation process of the role of professional navigators and their organizational and clinical functions. FINDINGS: Results support a bi-dimensional framework and define key role functions. The first dimension, health system-oriented, refers to continuity of care. The second dimension, patient-centered, corresponds to empowerment. For each dimension, related concepts were illustrated from data. Examples of outcomes also were suggested. CONCLUSIONS: The framework brings clarity to the role and functions of professional navigators and suggests relevant outcomes for program evaluations. INTERPRETATION: With a clear definition of their role, professional navigators may be more efficient and less challenged in terms of setting priorities and making decisions while having to face demands from the health system and patients. The integrative framework could improve the effectiveness of cancer navigation programs. PMID- 22201670 TI - Physician, patient, and contextual factors affecting treatment decisions in older adults with cancer and models of decision making: a literature review. AB - PURPOSE/OBJECTIVES: To review physician, patient, and contextual factors that affect treatment decision making in older adults diagnosed with cancer, and to relate those factors to theoretical models of decision making. DATA SOURCES: PubMed (1966 to April 2010), PsycINFO (1967 to April 2010) and CINAHL(r) (1982 to April 2010) databases were searched to access relevant medical, psychological, and nursing literature. DATA SYNTHESIS: Physician factors in treatment decisions included physician's personal beliefs and values, medical expertise, practice type, perception of lowered life expectancy, medical factors, power, and communication style. Patient factors included personal beliefs and values, ethnicity, decisional control preferences, previous health-related experience, perception of the decision-making process, and personal factors. Contextual factors included availability of caregiver, insurance, financial status, and geographical barrier. CONCLUSIONS: A diverse group of factors were identified, which are likely to form a unique framework to understand clinical decision making and plan future investigations in older adult patient populations. Using longitudinal and prospective designs to examine the real-time interplay of patient, physician, and contextual factors will enable a better understanding of how those divergent factors influence actual treatment decisions. IMPLICATIONS FOR NURSING: Oncology nurses can advocate autonomous (patient-driven), shared, or family-controlled treatment decisions, depending on an older patient's decisional role preference. Nurses can support patient autonomy during treatment decision making by coaching patients to engage in discussion of various evidence-based treatment options and a comprehensive discussion of the probability of success for each option with specialist providers. Oncology nurses may be able to promote treatment decisions that are consistent with a patient's personal preferences and values, with strong consideration of the patient's personal contexts. PMID- 22201672 TI - TAp73alpha protects small cell lung carcinoma cells from caspase-2 induced mitochondrial mediated apoptotic cell death. AB - Caspase-2 is ubiquitously expressed and the most evolutionarily conserved mammalian caspase. It can be activated by a range of death stimuli prior to Bax activation and the occurrence of apoptotic mitochondrial dysfunctions. Caspase-2 has also been reported to exert tumour suppressor function in vivo. The full length TAp73alpha isoform is found up-regulated in various tumour types, and is reported in a cell-type specific manner to repress drug-induced apoptosis. Here, we report that TAp73alpha represses caspase-2 enzymatic activity and by this means reduce caspase-2 induced Bax activation, loss of mitochondrial transmembrane potential and resulting apoptosis. The inhibitory effect on caspase 2 requires the presence of the DNA binding domain and SAM domain region of TAp73alpha. In conclusion, the ability of TAp73alpha to act as an inhibitor of caspase-2-induced cell death together with its up-regulation in certain tumour types strengthen the potential oncogenic activities for this protein. PMID- 22201671 TI - Small peripheral lung adenocarcinoma: CT and histopathologic characteristics and prognostic implications. AB - Since the introduction of computed tomography (CT), detection of small lung cancer, especially small peripheral adenocarcinoma, is common. Recently, the morphological characteristics, including thin-section CT and pathologic findings, and prognosis of small peripheral lung adenocarcinomas have been studied extensively. The radiologic and microscopic findings correlate well with each other and are closely associated with tumour prognosis. Most importantly, some subtypes of small lung adenocarcinomas with specific CT or pathologic features are curable. Therefore, all defining characteristics (CT, pathologic and prognostic) of this kind of tumour should be integrated to improve our understanding, provide guidelines for management and accurately assess its prognosis. PMID- 22201673 TI - Redox redux: protecting the ischemic myocardium. AB - Cardiac ischemia-reperfusion (I-R) injury occurs upon prompt restoration of blood flow to the ischemic myocardium after an acute myocardial infarction. Interestingly, many of the features of I-R injury are related to impaired mitochondrial signaling and mitochondrial dysfunction. Restoring cardiac energy bioavailability and reduction-oxidation (redox) signaling are therefore important in recovery after I-R injury. In this issue of the JCI, Yoshioka and colleagues describe an important and unexpected role for thioredoxin-interacting protein (TXNIP) in the control of mitochondrial respiration and cell energy metabolism. Their findings could open the door for development of TXNIP-targeted therapeutic approaches for the treatment of cardiac I-R injury. PMID- 22201674 TI - IL-1 and atherosclerosis: a murine twist to an evolving human story. AB - Inflammation is a critical component of atherosclerosis. IL-1 is a classic proinflammatory cytokine that has been linked to atherosclerosis. A clinical trial has been launched in which an antibody specific for IL-1beta is being studied for its effects on cardiovascular events in patients with atherosclerosis. In this issue of the JCI, Alexander et al. report that mice lacking the receptor for IL-1 unexpectedly have features of advanced atherosclerosis that suggest the atherosclerotic plaques may be less stable. These findings illustrate the complexity of inflammatory pathways in atherosclerosis and suggest the need for careful calibration of antiinflammatory approaches to atherosclerosis. PMID- 22201675 TI - Rare serotype adenoviral vectors for HIV vaccine development. AB - Human adenoviral vectors are being developed for use in candidate vaccines for HIV-1 and other pathogens. However, this approach suffered a setback when an HIV 1 vaccine using an adenovirus type 5 (Ad5) vector failed to reduce, and might even have increased, the rate of HIV infection in men who were uncircumcised and who had preexisting antibodies specific for Ad5. This increased interest in the evaluation of serologically distinct adenoviral vectors. In this issue of the JCI, Frahm and coworkers report evidence that preexisting cellular immune responses directed toward Ad5 reduce the immunogenicity of antigens expressed in Ad5-vectored vaccines and have cross-reacting potential with non-Ad5 adenoviral vectors. The implications of this observation need to be carefully evaluated in future clinical trials of all serotypes of adenovirus-vectored vaccines. PMID- 22201676 TI - Hold tight or you'll fall off: CD151 helps podocytes stick in high-pressure situations. AB - Glomerulosclerosis is a general term for scarring of the kidney glomerulus. It cannot be reversed. As glomerulosclerosis accumulates, the diseased kidney progresses to end-stage renal disease. Treatment with inhibitors of the renin angiotensin system often decreases the rate of progression of glomerulosclerosis in chronic kidney diseases. Although the mechanisms by which these inhibitors mediate their beneficial effects are incompletely understood, it has been suggested that they act, at least in part, by reducing intraglomerular blood pressure and thereby shear stress-induced loss of podocytes, a key component of the glomerular filtration barrier. In this issue of the JCI, Sachs and colleagues provide experimental confirmation of the critical role of tight adhesion of podocytes to the glomerular basement membrane for maintaining glomerular integrity and provide evidence that inhibition of the renin-angiotensin system reduces glomerulosclerosis in animals with less tightly adherent podocytes, presumably by reducing intraglomerular blood pressure. PMID- 22201677 TI - The flip-flop HuR: part of the problem or the solution in fighting cancer? AB - Chronic inflammation has long been appreciated to play a critical role in tumor development and maintenance. Among the mechanisms involved in coordinating the initiation and resolution of inflammation are those responsible for modifying mRNA stability and/or translation. Several studies have linked the RNA-binding protein HuR, which increases mRNA stability, with malignant transformation. However, in this issue of the JCI, Yiakouvaki et al. compellingly demonstrate in mice that increased HuR activity in myeloid cells has a protective role in the onset of pathologic intestinal inflammation (i.e., colitis) and colitis associated cancer (CAC). These observations highlight the need to understand the roles of HuR in distinct cell populations in vivo and suggest that enhancing HuR activity may be of clinical benefit in protecting against pathologic inflammation and cancer. PMID- 22201678 TI - Alteration of hypothalamic cellular dynamics in obesity. AB - The number of people who suffer from obesity and one or more of its adverse complications is rapidly increasing. It is becoming clear that diet, exercise, and other lifestyle modifications are insufficient strategies to combat this growing problem. Greater understanding of the mechanisms controlling our desire to feed and our ability to balance energy intake with energy expenditure are key to the development of pharmacological approaches for treating obesity. Although great strides have been made in our understanding of how the hypothalamus regulates feeding and energy balance, much less is known about how obesity affects the structure of the hypothalamus. The authors of two papers in this issue of the JCI have addressed this issue by examining the effects of obesity on neurons and glia in the hypothalamus. These studies reveal that obesity may be in part due to hypothalamic injury, which leads to inflammation and reduced neurogenesis. These findings support the notion that obesity is a disease that affects multiple organs, including the brain, and that disruption of normal brain function leads to abnormal regulation of peripheral metabolism. PMID- 22201679 TI - Blood pressure influences end-stage renal disease of Cd151 knockout mice. AB - Podocytes of the kidney adhere tightly to the underlying glomerular basement membrane (GBM) in order to maintain a functional filtration barrier. The clinical importance of podocyte binding to the GBM via an integrin-laminin-actin axis has been illustrated in models with altered function of alpha3beta1 integrin, integrin-linked kinase, laminin-521, and alpha-actinin 4. Here we expanded on the podocyte-GBM binding model by showing that the main podocyte adhesion receptor, integrin alpha3beta1, interacts with the tetraspanin CD151 in situ in humans. Deletion of Cd151 in mouse glomerular epithelial cells led to reduced adhesive strength to laminin by redistributing alpha3beta1 at the cell-matrix interface. Moreover, in vivo podocyte-specific deletion of Cd151 led to glomerular nephropathy. Although global Cd151-null B6 mice were not susceptible to renal disease, as has been shown previously, increasing blood and transcapillary filtration pressure induced nephropathy in these mice. Importantly, blocking the angiotensin-converting enzyme in renal disease-susceptible global Cd151-null FVB mice prolonged their median life span. Together, these results establish CD151 as a crucial modifier of integrin-mediated adhesion of podocytes to the GBM and show that blood pressure is an important factor in the initiation and progression of Cd151 knockout-induced nephropathy. PMID- 22201680 TI - Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice. AB - In the CNS, the hypothalamic arcuate nucleus (ARN) energy-balance circuit plays a key role in regulating body weight. Recent studies have shown that neurogenesis occurs in the adult hypothalamus, revealing that the ARN energy-balance circuit is more plastic than originally believed. Changes in diet result in altered gene expression and neuronal activity in the ARN, some of which may reflect hypothalamic plasticity. To explore this possibility, we examined the turnover of hypothalamic neurons in mice with obesity secondary to either high-fat diet (HFD) consumption or leptin deficiency. We found substantial turnover of neurons in the ARN that resulted in ongoing cellular remodeling. Feeding mice HFD suppressed neurogenesis, as demonstrated by the observation that these mice both generated fewer new neurons and retained more old neurons. This suppression of neuronal turnover was associated with increased apoptosis of newborn neurons. Leptin deficient mice also generated fewer new neurons, an observation that was explained in part by a loss of hypothalamic neural stem cells. These data demonstrate that there is substantial postnatal turnover of the arcuate neuronal circuitry in the mouse and reveal the unexpected capacity of diet and leptin deficiency to inhibit this neuronal remodeling. This insight has important implications for our understanding of nutritional regulation of energy balance and brain function. PMID- 22201681 TI - Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice. AB - Clinical complications of atherosclerosis arise primarily as a result of luminal obstruction due to atherosclerotic plaque growth, with inadequate outward vessel remodeling and plaque destabilization leading to rupture. IL-1 is a proinflammatory cytokine that promotes atherogenesis in animal models, but its role in plaque destabilization and outward vessel remodeling is unclear. The studies presented herein show that advanced atherosclerotic plaques in mice lacking both IL-1 receptor type I and apolipoprotein E (Il1r1-/-Apoe-/- mice) unexpectedly exhibited multiple features of plaque instability as compared with those of Il1r1+/+Apoe-/- mice. These features included reduced plaque SMC content and coverage, reduced plaque collagen content, and increased intraplaque hemorrhage. In addition, the brachiocephalic arteries of Il1r1-/-Apoe-/- mice exhibited no difference in plaque size, but reduced vessel area and lumen size relative to controls, demonstrating a reduction in outward vessel remodeling. Interestingly, expression of MMP3 was dramatically reduced within the plaque and vessel wall of Il1r1-/-Apoe-/- mice, and Mmp3-/-Apoe-/- mice showed defective outward vessel remodeling compared with controls. In addition, MMP3 was required for IL-1-induced SMC invasion of Matrigel in vitro. Taken together, these results show that IL-1 signaling plays a surprising dual protective role in advanced atherosclerosis by promoting outward vessel remodeling and enhancing features of plaque stability, at least in part through MMP3-dependent mechanisms. PMID- 22201682 TI - Deletion of thioredoxin-interacting protein in mice impairs mitochondrial function but protects the myocardium from ischemia-reperfusion injury. AB - Classic therapeutics for ischemic heart disease are less effective in individuals with the metabolic syndrome. As the prevalence of the metabolic syndrome is increasing, better understanding of cardiac metabolism is needed to identify potential new targets for therapeutic intervention. Thioredoxin-interacting protein (Txnip) is a regulator of metabolism and an inhibitor of the antioxidant thioredoxins, but little is known about its roles in the myocardium. We examined hearts from Txnip-KO mice by polony multiplex analysis of gene expression and an independent proteomic approach; both methods indicated suppression of genes and proteins participating in mitochondrial metabolism. Consistently, Txnip-KO mitochondria were functionally and structurally altered, showing reduced oxygen consumption and ultrastructural derangements. Given the central role that mitochondria play during hypoxia, we hypothesized that Txnip deletion would enhance ischemia-reperfusion damage. Surprisingly, Txnip-KO hearts had greater recovery of cardiac function after an ischemia-reperfusion insult. Similarly, cardiomyocyte-specific Txnip deletion reduced infarct size after reversible coronary ligation. Coordinated with reduced mitochondrial function, deletion of Txnip enhanced anaerobic glycolysis. Whereas mitochondrial ATP synthesis was minimally decreased by Txnip deletion, cellular ATP content and lactate formation were higher in Txnip-KO hearts after ischemia-reperfusion injury. Pharmacologic inhibition of glycolytic metabolism completely abolished the protection afforded the heart by Txnip deficiency under hypoxic conditions. Thus, although Txnip deletion suppresses mitochondrial function, protection from myocardial ischemia is enhanced as a result of a coordinated shift to enhanced anaerobic metabolism, which provides an energy source outside of mitochondria. PMID- 22201683 TI - Obesity is associated with hypothalamic injury in rodents and humans. AB - Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control. PMID- 22201684 TI - Human adenovirus-specific T cells modulate HIV-specific T cell responses to an Ad5-vectored HIV-1 vaccine. AB - Recombinant viruses hold promise as vectors for vaccines to prevent infectious diseases with significant global health impacts. One of their major limitations is that preexisting anti-vector neutralizing antibodies can reduce T cell responses to the insert antigens; however, the impact of vector-specific cellular immunity on subsequent insert-specific T cell responses has not been assessed in humans. Here, we have identified and compared adenovirus-specific and HIV specific T cell responses in subjects participating in two HIV-1 vaccine trials using a vaccine vectored by adenovirus serotype 5 (Ad5). Higher frequencies of pre-immunization adenovirus-specific CD4+ T cells were associated with substantially decreased magnitude of HIV-specific CD4+ T cell responses and decreased breadth of HIV-specific CD8+ T cell responses in vaccine recipients, independent of type-specific preexisting Ad5-specific neutralizing antibody titers. Further, epitopes recognized by adenovirus-specific T cells were commonly conserved across many adenovirus serotypes, suggesting that cross-reactivity of preexisting adenovirus-specific T cells can extend to adenovirus vectors derived from rare serotypes. These findings provide what we believe to be a new understanding of how preexisting viral immunity may impact the efficacy of vaccines under current evaluation for prevention of HIV, tuberculosis, and malaria. PMID- 22201685 TI - Myeloid cell expression of the RNA-binding protein HuR protects mice from pathologic inflammation and colorectal carcinogenesis. AB - The innate immune response involves a variety of inflammatory reactions that can result in inflammatory disease and cancer if they are not resolved and instead are allowed to persist. The effective activation and resolution of innate immune responses relies on the production and posttranscriptional regulation of mRNAs encoding inflammatory effector proteins. The RNA-binding protein HuR binds to and regulates such mRNAs, but its exact role in inflammation remains unclear. Here we show that HuR maintains inflammatory homeostasis by controlling macrophage plasticity and migration. Mice lacking HuR in myeloid-lineage cells, which include many of the cells of the innate immune system, displayed enhanced sensitivity to endotoxemia, rapid progression of chemical-induced colitis, and severe susceptibility to colitis-associated cancer. The myeloid cell-specific HuR deficient mice had an exacerbated inflammatory cytokine profile and showed enhanced CCR2-mediated macrophage chemotaxis. At the molecular level, activated macrophages from these mice showed enhancements in the use of inflammatory mRNAs (including Tnf, Tgfb, Il10, Ccr2, and Ccl2) due to a lack of inhibitory effects on their inducible translation and/or stability. Conversely, myeloid overexpression of HuR induced posttranscriptional silencing, reduced inflammatory profiles, and protected mice from colitis and cancer. Our results highlight the role of HuR as a homeostatic coordinator of mRNAs that encode molecules that guide innate inflammatory effects and demonstrate the potential of harnessing the effects of HuR for clinical benefit against pathologic inflammation and cancer. PMID- 22201687 TI - Kinematic changes using weightlifting shoes on barbell back squat. AB - The purpose of this study was to validate a higher degree of foot segment angle by wearing the weightlifting (WL) shoes and to determine the kinematic differences between WL shoes and running shoes during the barbell back squat. College-aged individuals volunteered to participate in this study (N = 25). After warm-up, subjects performed 60% of 1RM barbell back squat. Reflective markers were placed on lower extremity joints and end of the bar to create segments to analyze kinematics of the barbell back squat from a 2-dimensional view. Three separate repeated measure analyses of variance were used at p = 0.05. Results showed that there was a difference between the footwear conditions; foot segment angle of 3.5 degrees (p < 0.05) and trunk lean of 22 mm (p < 0.05) were captured when wearing WL shoes. However, thigh segment peak flexion angle was not statistically different (p = 0.37). Wearing WL shoes seems to be beneficial in reducing the overall trunk lean, because this position is believed to reduce the amount of shear stress in the lower back area. Back squat with WL shoes also increased foot segment angle and possibly contributes to greater muscle excitation in knee extensors. Weightlifting shoes did not help reach thigh segment closer to horizontal as compared with the running shoe condition. It is recommended that WL shoes be used by those who are prone to displaying a forward trunk lean and who aim to increase knee extensor activation. PMID- 22201686 TI - Creatine kinase-mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved. AB - ATP is required for normal cardiac contractile function, and it has long been hypothesized that reduced energy delivery contributes to the contractile dysfunction of heart failure (HF). Despite experimental and clinical HF data showing reduced metabolism through cardiac creatine kinase (CK), the major myocardial energy reserve and temporal ATP buffer, a causal relationship between reduced ATP-CK metabolism and contractile dysfunction in HF has never been demonstrated. Here, we generated mice conditionally overexpressing the myofibrillar isoform of CK (CK-M) to test the hypothesis that augmenting impaired CK-related energy metabolism improves contractile function in HF. CK-M overexpression significantly increased ATP flux through CK ex vivo and in vivo but did not alter contractile function in normal mice. It also led to significantly increased contractile function at baseline and during adrenergic stimulation and increased survival after thoracic aortic constriction (TAC) surgery-induced HF. Withdrawal of CK-M overexpression after TAC resulted in a significant decline in contractile function as compared with animals in which CK M overexpression was maintained. These observations provide direct evidence that the failing heart is "energy starved" as it relates to CK. In addition, these data identify CK as a promising therapeutic target for preventing and treating HF and possibly diseases involving energy-dependent dysfunction in other organs with temporally varying energy demands. PMID- 22201688 TI - Heart rate responses and technical-tactical aspects of official 5-a-side youth soccer matches played on clay and artificial turf. AB - Using a randomized crossover design, this study aimed to compare the heart rate (HR) responses and match analysis parameters (i.e., type of action; the number of players involved in an action; the number of passes performed in a collective action; precision of the shots; lost balls; ball interceptions; dribblings; and tackles) of official 5-a-side youth male soccer matches played over 2 pitch surface (i.e., clay vs. artificial turf) conditions. Twenty-two young male soccer players (age 8.3 +/- 0.4 years) engaged in 2 consecutive 15-minute periods in each experimental condition. During the match, 53% of HR responses exceeded 85% of the individual HR(peak). No difference emerged between both pitch surfaces and match periods for HR and match analysis indicators. The two 15-minute periods resulted in being appropriate for 8-year-old players, in resembling the intensity of play and the intermittent nature of adult soccer. The similar HR responses and technical-tactical patterns observed on the 2 surfaces indicate that youth match play is not affected by differences in pitch surface. To support the development of individual and team skills of young soccer players, coaches are advised to prioritize game knowledge based on divergent thinking and experience, rather than traditional teaching based on instructions. PMID- 22201689 TI - Influence of wrestling on the physiological and skill demands of small-sided games. AB - This study investigated the influence of wrestling on the physiological and skill demands of small-sided games. Twenty-eight elite rugby league players ([mean +/- SE] age, 21.6 +/- 0.5 years) participated in this within-subject crossover study. On day 1, 14 players played 2, 8-minute small-sided games, whereas the remaining 14 players played identical games with intermittent wrestling throughout. Each game was separated by 90 seconds. On day 2, the groups were crossed over. Movement was recorded by a global positioning system unit (miniMaxX, Catapult Innovations, Melbourne, Australia), sampling at 5 Hz. Each small-sided game was filmed to track the number of possessions and the number and quality of disposals. The games without wrestling resulted in a greater (p < 0.05) total distance covered (2,475 +/- 31 vs. 1,964 +/- 27 m) and greater distance covered in low (930 +/- 19 vs. 842 +/- 19 m), moderate (1,120 +/- 28 vs. 752 +/- 26 m), high (332 +/- 16 vs. 240 +/- 12 m), and very-high (24 +/- 4 vs. 15 +/- 3 m) velocity movement intensities. Conversely, the games with wrestling resulted in a significantly greater (p < 0.05) distance covered in mild, moderate, and maximal accelerations and a greater number of repeated high-intensity effort bouts (2.1 +/- 0.2 bouts vs. 0.2 +/- 0.1 bouts). No significant differences (p > 0.05) were detected between games with and without wrestling for the total number of involvements, receives, passes, effective passes, ineffective passes, and disposal efficiency. The results of this study demonstrate that intermittent wrestling reduces the running demands but increases the repeated high-intensity effort demands of small-side games. Furthermore, these physiological changes occur without compromising the volume of skill executions, the number of errors, or disposal efficiency. From a practical perspective, these results suggest that intermittent wrestling may be a useful supplement to small-sided games to concurrently train repeated-effort ability and skills under game-specific fatigue. PMID- 22201690 TI - Lactate threshold and performance adaptations to 4 weeks of training in untrained swimmers: volume vs. intensity. AB - The purpose of this study was to investigate the impact of 4 weeks of high intensity vs. high-volume swim training on lactate threshold (LT) characteristics and performance. Thirteen untrained swimmers with a mean age of 19.0 +/- 0.5 undertook an incremental swimming test before and after 4 weeks of training for the determination of LT. Performance was evaluated by a 50-m maximum freestyle test. The swimmers were assigned to 1 of each of 2 training groups. The high intensity group (n = 6) focused on sprint training (SP) and swam a total of 1,808 +/- 210 m. The high-volume group (n = 7) followed the same program as the SP group but swam an additional 1,100 m (38% more) of endurance swimming (SP + End). A training effect was evident in both groups as seen by the similar improvements in sprint performance of the 50-m maximum time (p < 0.01), peak velocity increases and the lower value of lactate at the individual LTs (p < 0.01). Lactate threshold velocity improved only in the SP + End group from 1.20 +/- 0.12 m.s(-1) pretraining to 1.32 +/- 0.12 m.s(-1) posttraining (p = 0.77, effect size = 1, p < 0.01), expressed by the rightward shifts of the individual lactate velocity curves, indicating an improvement in the aerobic capacity. Peak lactate and lactate concentrations at LT did not significantly change. In conclusion, this study was able to demonstrate that 4 weeks of either high-intensity or high volume training was able to demonstrate similar improvements in swimming performance. In the case of lack of significant changes in lactate profiling in response to high-intensity training, we could suggest a dissociation between the 2. PMID- 22201691 TI - Effect of high-intensity interval training on cardiovascular function, VO2max, and muscular force. AB - The purpose of this study was to examine the effects of short-term high-intensity interval training (HIIT) on cardiovascular function, cardiorespiratory fitness, and muscular force. Active, young (age and body fat = 25.3 +/- 4.5 years and 14.3 +/- 6.4%) men and women (N = 20) of a similar age, physical activity, and maximal oxygen uptake (VO2max) completed 6 sessions of HIIT consisting of repeated Wingate tests over a 2- to 3-week period. Subjects completed 4 Wingate tests on days 1 and 2, 5 on days 3 and 4, and 6 on days 5 and 6. A control group of 9 men and women (age and body fat = 22.8 +/- 2.8 years and 15.2 +/- 6.9%) completed all testing but did not perform HIIT. Changes in resting blood pressure (BP) and heart rate (HR), VO2max, body composition, oxygen (O2) pulse, peak, mean, and minimum power output, fatigue index, and voluntary force production of the knee flexors and extensors were examined pretraining and posttraining. Results showed significant (p < 0.05) improvements in VO2max, O2 pulse, and Wingate-derived power output with HIIT. The magnitude of improvement in VO2max was related to baseline VO2max (r = -0.44, p = 0.05) and fatigue index (r = 0.50, p < 0.05). No change (p > 0.05) in resting BP, HR, or force production was revealed. Data show that HIIT significantly enhanced VO2max and O2 pulse and power output in active men and women. PMID- 22201692 TI - Strength training affects tendon cross-sectional area and freely chosen cadence differently in noncyclists and well-trained cyclists. AB - The effects of strength training on freely chosen cadence and physiological responses in cyclists and recreationally active individuals were investigated. Well-trained cyclists were assigned to either usual endurance training combined with strength training (C-ES; n = 11) or usual endurance training only (C-E; n = 9). Recreationally active individuals (R-S; n = 7) performed the same strength training as C-ES did (4 lower body exercises, 3 * 4-10 repetition maximum [RM], twice a week for 12 weeks). The R-S and C-ES increased 1RM to a similar extent after 4 and 12 weeks (p < 0.01), whereas 1RM remained unchanged in C-E. Only R-S increased patellar tendon cross-sectional area (CSA; 7 +/- 1%, p < 0.001). After 4 weeks, R-S reduced freely chosen cadence, oxygen consumption, heart rate, rating of perceived exertion, and blood lactate concentration during cycling at 125 W. These responses remained reduced throughout the intervention period (p < 0.05). No significant changes were observed in these physiological variables in C ES and C-E. In conclusion, freely chosen cadence during submaximal cycling was reduced in recreationally active individuals after a period of strength training but was not reduced in well-trained cyclists. The reduced freely chosen cadence may be associated with the observed increase in patellar tendon CSA through a morphological-sensory-motor interaction. A practical application is that heavy strength training can reduce freely chosen cadence during submaximal cycling and thereby improve cycling economy in recreationally active individuals, whereas other mechanisms should account for improved performance after strength training in well-trained cyclists. PMID- 22201693 TI - An examination of current practices and gender differences in strength and conditioning in a sample of varsity high school athletic programs. AB - Currently, little is known about strength and conditioning programs at the high school level. Therefore, the purpose of this research was to explore current practices in strength and conditioning for varsity high school athletes in selected sports. The following were specifically examined: who administers programs for these athletes, what kinds of training activities are done, and whether the responsible party or emphasis changes depending on the gender of the athletes. Coaches of varsity soccer, basketball, softball, and baseball in 3 large Idaho school districts were asked to complete an online survey. Sixty-seven percent (32/48) of the questionnaires were completed and used for the study. The majority of coaches (84%) provided strength and conditioning opportunities for their athletes, although only 37% required participation. Strength training programs were designed and implemented primarily by either physical education teachers or head coaches. Compared with coaches of male athletes, coaches of female athletes were less likely to know the credentials of their strength coaches, and they were less likely to use certified coaches to plan and implement their strength and conditioning programs. Most programs included dynamic warm-ups and cool-downs, plyometrics, agility training, speed training, and conditioning, and most programs were conducted 3 d.wk(-1) (76%) for sessions lasting between 30 and 59 minutes (63%). Compared with their female counterparts, male athletes were more likely to have required training, participate in strength training year round, and train using more sessions per week. This study provides additional information related to the practice of strength and conditioning in a sample of high school athletic teams. PMID- 22201694 TI - Effect of various warm-up devices on bat velocity of intercollegiate softball players. AB - Numerous warm-up devices are available for use by softball players while they are in the on-deck circle. It is difficult to know which warm-up device produces the greatest bat velocity (BV) in the batter's box for softball players because on deck studies with these individuals are sparse. Because the majority of warm-up device research has been conducted with baseball players, the primary purpose of this study was to examine the effect of various warm-up devices on the BV of female intercollegiate softball players and compare the results with those of male baseball players. A secondary purpose was to evaluate 2 new commercially available resistance devices as warm-up aids. Nineteen Division I intercollegiate softball players (age = 19.8 +/- 1.2 years, height = 167.0 +/- 4.7 cm, body mass = 69.2 +/- 8.6 kg, lean body mass = 49.6 +/- 3.6 kg, % body fat = 27.9 +/- 5.9) participated in a warm-up with 1 of 8 resistance devices on separate days. Each of the 8 testing sessions had players perform a standardized dynamic warm-up, 3 maximal dry swings mimicking their normal game swing with the assigned warm-up device, 2 comfortable dry swings with a standard 83.8-cm, 652-g (33-in., 23-oz) softball bat followed by 3 maximal game swings (20-second rest between swings) while hitting a softball off a batting tee with the same standard softball bat. Results indicated that there were no statistically significant differences in BV after using any of the 8 warm-up devices (510.3-2,721.5 g or 18-96 oz) similar to in previous baseball research. This indicates that the results for both male and female intercollegiate players are similar and that intercollegiate softball players can use any of the 8 warm-up devices in the on-deck circle and have similar BVs. However, similar to in other previous baseball research, it is not recommended that female intercollegiate softball players warm up with the popular commercial donut ring in the on-deck circle because it produced the slowest BV. PMID- 22201695 TI - Is there an association between variables of postural control and strength in prepubertal children? AB - The risk of sustaining falls and sports-related injuries is particularly high in children. Deficits in balance and muscle strength represent 2 important intrinsic fall and injury-risk factors. Therefore, the purpose of this study was to investigate the relationship between variables of static and dynamic postural control and isometric and dynamic muscle strength and to find out whether there is an association between measures of postural control and muscle strength in prepubertal children. Thirty children participated in this study (age 6.7 +/- 0.5 years; body mass index 16.0 +/- 1.8 kg.m(-2)). Biomechanic tests included the measurements of maximal isometric torque and rate of force development (RFD) of the plantar flexors on an isokinetic device, jumping power and height (countermovement jump [CMJ]) on a force plate, and the assessment of static and dynamic posture during bipedal stance on a balance platform. The significance level was set at p < 0.05. No significant associations were observed between variables of static and dynamic postural control. Significant positive correlations were detected between the RFD of the plantar flexors and CMJ height (r = 0.425, p < 0.01). No statistically significant associations were found between measures of postural control and muscle strength. The nonsignificant correlations between static and dynamic postural control and muscle strength imply that primarily dynamic measures of postural control should be incorporated in fall and injury-risk assessment and that postural control and muscle strength appear to be independent of each other and may have to be trained in a complementary manner for fall and injury-preventive purposes. PMID- 22201696 TI - Relationships between National Football League combine performance measures. AB - The purpose of this study was to investigate the relationships between the athletic skills measured at the National Football League (NFL) combine. The combine comprises the following tests: 36.6-m sprint with split times at 9.1 and 18.3 m, vertical and horizontal jumps, 18.3-m shuttle run, 3-cone drill, and 102.1-kg bench press. Draftees to the NFL who participated in the annual combine from 2005 to 2009 were included in the study (n = 1,136). Pearson's (r) correlations were calculated to determine the relationships between the tests, and coefficients of determination (r) were used to determine common variance. The 9.1-, 18.3-, and 36.6-m sprint times are nearly perfectly correlated (r ranges from 0.900 to 0.967) as are the change-of-direction ability tests, 18.3-m shuttle run, and 3-cone drill (r = 0.948), suggesting similar skills are being measured. Performance in both jumping tasks is more strongly associated with longer sprint distances, suggesting mechanisms such as the stretch-shortening cycle may be more important at maximal, or near-maximal, speeds. The correlations between change-of direction ability and sprinting and jumping are generally much weaker (r ranges from 0.250 to -0.653), suggesting less association and independent motor skills. Although not particularly large correlation coefficients, bench press performance is positively correlated with outcomes in all running drills and inversely correlated with jump abilities, suggesting that in the observed cohort, upper body strength may be of little benefit to these tasks. Incorporation of a nonacceleration influenced (i.e., moving start) measure of maximal speed may be preferred if the intention of a test battery is to measure independent motor skills. Further, when constructing test batteries, either the 18.3-m shuttle or 3 cone drill is likely sufficient as a measure of change-of-direction ability. Test batteries should be constructed to measure independent motor skills. PMID- 22201697 TI - Higher muscle mass but lower gynoid fat mass in athletes using anabolic androgenic steroids. AB - This study evaluated the relationship between anabolic androgenic steroid (AAS) use and body constitution. Dual-energy x-ray absorptiometry was used to measure bone mineral density (BMD, g.cm(-2)) of the total body, arms, and legs. Total gynoid and android fat mass (grams) and total lean mass (grams) were measured in 10 strength trained athletes (41.4 +/- 7.9 years) who had used AASs for 5-15 years (Doped) and 7 strength trained athletes (29.4 +/- 6.2 years) who had never used AASs (Clean). Seventeen sedentary men (30.3 +/- 2.1 years) served as Controls. Doped athletes had significantly more lean body mass (85.5 +/- 3.8 vs. 75.3 +/- 2.5 vs. 60.7 +/- 1.9, p < 0.001) and a greater index of fat-free/fat mass (5.8 vs. 2.6 vs. 2.5, p < 0.001) compared with Clean athletes and Controls. Doped athletes also had significantly less gynoid fat mass compared with that of Clean athletes (2.8 +/- 0.4 vs. 4.8 +/- 0.2 kg, p = 0.02). There were no differences in BMD between the athletes (p = 0.39-0.98), but both groups had significantly higher BMDs at all sites compared with that of Controls (p = 0.01 to <0.001). Thus, long-term AAS use seems to alter body constitution, favoring higher muscle mass and reduced gynoid fat mass without affecting BMD. PMID- 22201698 TI - Baseline strength can influence the ability of salivary free testosterone to predict squat and sprinting performance. AB - The objective of this study was to determine if salivary free testosterone can predict an athlete's performance during back squats and sprints over time and the influence baseline strength on this relationship. Ten weight-trained male athletes were divided into 2 groups based on their 1 repetition maximum (1RM) squats, good squatters (1RM > 2.0 * body weight, n = 5) and average squatters (1RM < 1.9 * body weight, n = 5). The good squatters were stronger than the average squatters (p < 0.05). Each subject was assessed for squat 1RM and 10-m sprint times on 10 separate occasions over a 40-day period. A saliva sample was collected before testing and assayed for free testosterone and cortisol. The pooled testosterone correlations were strong and significant in the good squatters (r = 0.92 for squats, r = -0.87 for sprints, p < 0.01), but not significant for the average squatters (r = 0.35 for squats, r = -0.18 for sprints). Cortisol showed no significant correlations with 1RM squat and 10-m sprint performance, and no differences were identified between the 2 squatting groups. In summary, these results suggest that free testosterone is a strong individual predictor of squat and sprinting performance in individuals with relatively high strength levels but a poor predictor in less strong individuals. This information can assist coaches, trainers, and performance scientists working with stronger weight-trained athletes, for example, the preworkout measurement of free testosterone could indicate likely training outcomes or a readiness to train at a certain intensity level, especially if real-time measurements are made. Our results also highlight the need to separate group and individual hormonal data during the repeated testing of athletes with variable strength levels. PMID- 22201699 TI - Isometric force development of some muscle groups in athletes. AB - In a large sample of both male and female athletes, subdivided by age and sex, a development curve of isometric muscule force (F) was analyzed for hand flexors, upper-body flexors and extensors, and knee extensors (PDS). A sample of 1,857 male and 1,009 female athletes, aged 8-30 years, subdivided by their age and sex, was used to measure the mean values of isometric muscle force of certain muscle groups by way of 5 topologically defined tests. Based on the results, isometric muscle force (F) development curves are shown and analyzed for the right-hand and left-hand (PLS) flexors, upper-body flexors (PTR), upper-body extensors (OTR), and knee extensors (ONO). The application of certain statistical programs gave rise to equations of the relationship between isometric force and age. The maximum mean value of PLS was chosen as the reference value or "the gold standard," with which PTR, OTR, and ONO were subsequently compared. The relationships were 1:1:1:2.8:5.9 (for male athletes), and 1:1:1.3:3.2:5.2 (for female athletes). The newly derived relationship was recognized as "the canon." The results may have practical application in athletes' fitness and conditioning. Every topologically defined muscle force has its own patterns and rules that should be closely followed in the training process, because any generalization may lead to false conclusions. PMID- 22201700 TI - Correlates of chronic disease and patient-provider discussions among middle-aged and older adult males: Implications for successful aging and sexuality. AB - OBJECTIVE: Effective erectile dysfunction (ED) treatments and cardiovascular disease (CVD) and diabetes risk assessments are available, but require patient provider communication. The present study explored this issue using 2010 National Social Life, Health and Aging Project data for males age 57 years and older (n = 1011). METHODS: Multinomial logistic regression was performed to compare factors associated with being without CVD/diabetes (39.9%), being diagnosed with CVD only (43.1%), and having comorbid CVD/diabetes (CVD 17.0%). Logistic regression compared factors associated with having ever discussed sexual issues with physicians. RESULTS: CVD-only participants were more likely to be >= 75 years (p = 0.004) and smoke (p = 0.019); CVD&D participants were more likely to report activity limitations (p < 0.001) and less likely to have sex within the previous year (p = 0.014). Compared to CVD-only, men with CVD&D were more likely to be minorities, obese, have daily activity limitations, and report erectile difficulties (all p < 0.05). Males discussing sexual issues with physicians were more likely to report higher education [OR = 1.68, p = 0.001], have sex in previous year [OR = 1.73, p = 0.006], and have erectile difficulties [OR = 2.26, p < 0.001]. DISCUSSION: Increased patient and provider awareness and communication are needed to lifestyle behaviors, promote self-care practices, and improve health care utilization among male patients affected by chronic disease and ED. PMID- 22201702 TI - Radiofrequency-assisted intact specimen biopsy of breast tumors: critical evaluation according to the IDEAL recommendations. AB - Radiofrequency-assisted intact specimen biopsy (RFIB) has been introduced for percutaneous biopsy or removal of breast tumors. Using radiofrequency cutting, the system enables the radiologist to obtain an intact sample of the target lesion. According to the IDEAL recommendations, we performed a critical evaluation of our initial experience with RFIB. Between June and November 2010, radiography-guided RFIB was performed in 19 female patients. All patients presented with suspicious microcalcifications (BI-RADS III-V) on mammography. Biopsy specimen integrity, thermal damage and histologic diagnosis were assessed by an expert breast pathologist. Data on technical success, diagnostic and therapeutic accuracy and periprocedural complications were collected and analyzed. The median age of the patients was 59 years. Median lesion diameter on mammography was 8 mm (range 2-76 mm). The procedure was successful in 16/19 (84%) patients and unsuccessful in 3/19 (16%) patients (2 non-representative samples, 1 sample with extensive thermal damage). Histologic analysis of the RFIB specimen revealed 12/19 (63%) benign lesions and 7/19 (37%) malignancies (4 ductal carcinoma in situ (DCIS) lesions and 3 invasive ductal carcinomas). In 1 patient, a DCIS lesion was completely removed with RFIB. Overall, 3 periprocedural complications occurred (1 wound leakage, 1 arterial hemorrhage and 1 infection requiring oral antibiotics). Tissue sampling of suspicious breast lesions can be performed successfully with RFIB. In 1 patient DCIS was radically excised with RFIB, which illustrates its potential as a minimally invasive therapeutic procedure for removal of small breast tumors. This is an interesting focus for further research when larger probe sizes become available. PMID- 22201701 TI - Resistance to diet-induced adiposity in cannabinoid receptor-1 deficient mice is not due to impaired adipocyte function. AB - BACKGROUND: Overactivity and/or dysregulation of the endocannabinoid system (ECS) contribute to development of obesity. In vitro studies indicate a regulatory role for the cannabinoid receptor 1 (CB1) in adipocyte function and CB1-receptor deficient (CB1-/-) mice are resistant to high fat diet-induced obesity. Whether this phenotype of CB1-/- mice is related to altered fat metabolism in adipose tissue is unknown. METHODS: We evaluated adipose tissue differentiation/proliferation markers and quantified lipogenic and lipolytic activities in fat tissues of CB1-/- and CB1+/+ mice fed a high-fat (HF) or a high fat/fish oil (HF/FO) diet as compared to animals receiving a low-fat chow diet. Comparison between HF diet and HF/FO diet allowed to investigate the influence of dietary fat quality on adipose tissue biology in relation to CB1 functioning. RESULTS: The adiposity-resistant phenotype of the CB1-/- mice was characterized by reduced fat mass and adipocyte size in HF and HF/FO-fed CB1-/- mice in parallel to a significant increase in energy expenditure as compared to CB1+/+ mice. The expression levels of adipocyte differentiation and proliferation markers were however maintained in these animals. Consistent with unaltered lipogenic gene expression, the fatty acid synthesis rates in adipose tissues from CB1-/- and CB1+/+ mice were unchanged. Whole-body and adipose-specific lipoprotein lipase (LPL) activities were also not altered in CB1-/- mice. CONCLUSIONS: These findings indicate that protection against diet-induced adiposity in CB1-deficient mice is not related to changes in adipocyte function per se, but rather results from increased energy dissipation by oxidative and non oxidative pathways. PMID- 22201703 TI - Attrition in web-based treatment for problem drinkers. AB - BACKGROUND: Web-based interventions for problem drinking are effective but characterized by high rates of attrition. There is a need to better understand attrition rates in order to improve the completion rates and the success of Web based treatment programs. OBJECTIVE: The objectives of our study were to (1) examine attrition prevalence and pretreatment predictors of attrition in a sample of open-access users of a Web-based program for problem drinkers, and (2) to further explore attrition data from our randomized controlled trial (RCT) of the Web-based program. METHODS: Attrition data from two groups of Dutch-speaking problem drinkers were collected: (1) open-access participants enrolled in the program in 2009 (n = 885), and (2) RCT participants (n = 156). Participants were classified as noncompleters if they did not complete all 12 treatment sessions (9 assignments and 3 assessments). In both samples we assessed prevalence of attrition and pretreatment predictors of treatment completion. Logistic regression analysis was used to explore predictors of treatment completion. In the RCT sample, we additionally measured reasons for noncompletion and participants' suggestions to enhance treatment adherence. The qualitative data were analyzed using thematic analysis. RESULTS: The open-access and RCT group differed significantly in the percentage of treatment completers (273/780, 35.0% vs 65/144, 45%, chi(2) (1) = 5.4, P = .02). Logistic regression analysis revealed a significant contribution of treatment readiness, gender, education level, age, baseline alcohol consumption, and readiness to change to predict treatment completion. The key reasons for noncompletion were personal reasons, dissatisfaction with the intervention, and satisfaction with their own improvement. The main suggestions for boosting strategies involved email notification and more flexibility in the intervention. CONCLUSIONS: The challenge of Web-based alcohol treatment programs no longer seems to be their effectiveness but keeping participants involved until the end of the treatment program. Further research should investigate whether the suggested strategies to improve adherence decrease attrition rates in Web-based interventions. If we can succeed in improving attrition rates, the success of Web-based alcohol interventions will also improve and, as a consequence, their public health impact will increase. TRIAL: International Standard Randomized Controlled Trial Number (ISRCTN): 39104853; http://www.controlled-trials.com/ISRCTN39104853 (Archived by WebCite at http://www.webcitation.org/63IKDul1T). PMID- 22201705 TI - Electrical impedance tomography: potentials and pitfalls. AB - PURPOSE OF REVIEW: Electrical impedance tomography (EIT) is a useful noninvasive tool for monitoring ventilation finding its way into the clinical setting. The focus of this review is to discuss the balance between the potential for EIT as a clinical monitor accepting a level of uncertainty and the scientific demand for absolute perfection. RECENT FINDINGS: The controversy concerning whether EIT impedance changes can be safely used to monitor lung volume changes now appears to be solved after recent elegant studies. It is now high time to display lung volume changes measured by EIT in clinical units, that is in millilitres following calibration versus tidal volume. A growing number of indices for regional ventilation distribution are emerging some of which should be further evaluated and developed for clinical decision support. SUMMARY: Already now EIT is a useful clinical monitor. Still more work is needed to develop and interpret indices which are simple enough to be used in the clinical setting to guide the clinician towards effective and safe ventilator management. PMID- 22201704 TI - Phosphatase inhibitor, sodium stibogluconate, in combination with interferon (IFN) alpha 2b: phase I trials to identify pharmacodynamic and clinical effects. AB - Since sodium stibogluconate (SSG) inhibited phosphatases including SHP-1 and augmented anti-tumor actions of IFN-alpha2b in vitro and in mice, two Phase I trials of SSG/IFN-alpha2b combination were undertaken to evaluate safety and target inhibition. Escalating doses of SSG (200-1200 mg/m2) and fixed doses of IFN-alpha2b (3x106 units/m2) with or without chemotherapy (dacarbazine, vinblastine, cisplatin) were evaluated for side effects and impact on SHP-1 phospho-substrates and IFNalpha-stimulated-genes (ISGs) in peripheral blood in 40 patients with metastatic melanoma, soft tissue sarcomas, gastrointestinal stromal tumors, and breast or colorectal carcinomas who did not have other established treatment options. Common adverse events were bone marrow suppression, fatigue, gastrointestinal upset, and asymptomatic lipase elevation (n=13); the latter was dose related and mostly after 10d of SSG/IFN-alpha2b in combination. Levels of SHP-1 substrates (pSTAT1, pSTAT3, pLck and pSlp76) were increased (up to 3x) in peripheral blood cells following SSG with no potentiation by combination with IFN alpha2b. Representative ISGs in peripheral blood were induced after IFN-alpha2b at 4 and 24 hrs with selective modulations by combination. The median time on trials was 2.3 months (10-281d) with no objective regression of disease. Alive at 1y were 17/40 (43%) patients and after 2y were 8/40 (20%) following treatment initiation. These data demonstrate that SSG impacted signal molecules consistent with PTP inhibition and was tolerated in combination with IFN-alpha2b. Phase II investigations of SSG could safely utilize doses of up to 1200 mg/m2 of SSG for up to 10d alone or in combination with IFN-alpha2b with or without chemotherapy. PMID- 22201706 TI - Targeted alpha therapy: part I. AB - The possibility of pinpointing biological targets, and thereby potentially targeting and eradicating small tumors or even single cancer cells, is a tantalizing concept that has been discussed since the magic-bullet concept was first presented by Paul Erlich in the beginning of the 20th century in connection with his work on tissue staining for histological examinations and the work by Kohler and Milstein on antibody production published in 1975. This concept now seems feasible through the use of highly specific targeting constructs, chemical labeling of radioactive substances to these targeting constructs that results in high specific activities, radioimmunocomplexes with good stability even after injection, and the use of radionuclides emitting alpha( alpha)-particles having exceedingly high ionizing density and, therefore, a high probability of killing cells along its track in tissue. The short range of the emitted alpha-particles makes them even more interesting by minimizing unwanted irradiation of normal tissue surrounding the targeted cancer cells of interest, assuming high specificity of the targeting construct and good stability of the chemical bonds between the targeting construct and the alpha-particle emitter. Targeted Alpha Therapy (TAT), in which an alpha-particle emitting radionuclide is specifically directed to the biological target, is gaining more attention as new targets, targeting constructs, chemical labeling techniques, and alpha-particle emitters are, respectively, identified, constructed, developed, and made available. Results and improvements are now being published at an increasing rate and the number of conceivable applications is expanding, especially in the field of cancer treatment. Therefore, it is of utmost importance to provide an overview of the overall progress in the research field of TAT on a regular basis. However, problems such as limited or delayed diffusion of the alpha-radioimmunocomplex and inhomogeneous activity distributions in the targeted tumors, resulting in inhomogeneous absorbed dose distributions, are challenges that need to be addressed. These challenges need to be overcome before TAT becomes a standard treatment for diseases such as micrometastatic cancer. Hopefully, when enough funding will be provided and, hence, more treatment strategies of TAT will reach the clinical level the importance to conduct controlled, randomized trials with sufficient patient numbers, enabling statistical significance to occur must be emphasized in order to be able to properly compare and evaluate different approaches. In this issue, of the two hot-topic issues for targeted alpha therapy, articles discuss the recent developments in radionuclide availability, biomolecular targeting, labeling chemistry, and dosimetry for the most promising alpha-particle emitters. In the first article, Zalutsky et al. discuss the possibilities and limitations of using the promising alpha-particle emitter, 211At, and emphasize the need for funding new cyclotrons and prioritizing beam times of already existing cyclotrons to improve the availability of 211At. Haddad et al. describe the status of the ARRONAX project through which a number of important nuclear medicine radionuclides will be produced, including some of those suitable for TAT. Relevant targeting constructs and their associated antigens used today and candidates for use in the future are discussed by Olafsen et al. in the third article. The next article, by Scott Wilbur, discusses chemical and radiochemical issues of radiolabeling using alpha-particle emitting radionuclides, e.g. factors that are important in selecting chelation or bonding reagents during the development of alpha-particle emitting radiopharmaceuticals. Lindegren at al. continue the discussion of chemical considerations in the following article, but focuses on pre-targeting techniques, which will hopefully enhance both the activity distribution in the targeted tumor and the tumor-to normal tissue absorbed dose ratio. The two final articles discuss different aspects of the dosimetry related to alpha-particles. The article by Sgouros et al. discusses how knowledge of the microscopic distribution of alpha-particle emitters is necessary to perform correct dosimetry, as well as the importance of the translation of activity distributions obtained in pre-clinical studies to the human situation, which requires micro-scale models of the source-target geometry at human dimensions according to the authors. Chouin et al. focus in the following article on the microdosimetry of alpha-particles. The authors present basic concepts and some applications of the microdosimetry for TAT, and conclude microdosimetry should only be considered when alternative approaches fail to provide an account of a given biological endpoint. The intention of this particular hot-topic issue is to present an up-to-date overview of key areas in the research field of TAT, i.e. radionuclides available, targeting constructs, labeling chemistry, and dosimetry. This issue will hopefully be followed by similar ones jointly produced by contributions from the research community active in the field, of which most researchers are participating in these two particular issues, i.e. Targeted Alpha Therapy - Part I and II. PMID- 22201707 TI - Astatine-211: production and availability. AB - The 7.2-h half life radiohalogen (211)At offers many potential advantages for targeted alpha-particle therapy; however, its use for this purpose is constrained by its limited availability. Astatine-211 can be produced in reasonable yield from natural bismuth targets via the (209)Bi(alpha,2n)(211)At nuclear reaction utilizing straightforward methods. There is some debate as to the best incident alpha-particle energy for maximizing 211At production while minimizing production of (210)At, which is problematic because of its 138.4-day half life alpha particle emitting daughter, (210)Po. The intrinsic cost for producing (211)At is reasonably modest and comparable to that of commercially available (123)I. The major impediment to (211)At availability is attributed to the need for a medium energy alpha-particle beam for its production. On the other hand, there are about 30 cyclotrons in the world that have the beam characteristics required for (211)At production. PMID- 22201708 TI - The ARRONAX project. AB - A new high-energy and high-intensity cyclotron, ARRONAX, has been set into operation in 2010. ARRONAX can accelerate both negative ions (H- and D-) and positive ions (He++ and HH+). Protons can be accelerated from 30 MeV up to 70 MeV with a maximum beam intensity of 2 * 375 MUAe whereas He++ can be accelerated at 68 MeV with a maximum beam current of 70 MUAe. The main fields of application of ARRONAX are radionuclide production for nuclear medicine and irradiation of inert or living materials for radiolysis and radiobiology studies. A large part of the beam time will be used to produce radionuclides for targeted radionuclide therapy (copper-67, scandium-47 and astatine-211) as well as for PET imaging (scandium 44, copper-64, strontium-82 for rubidium-82 generators and germanium-68 for gallium-68 generators). Since the beginning of the project a particular interest has been devoted to alpha-radionuclide therapy using complex ligands like antibodies and astatine-211 has been selected as a radionuclide of choice for such type of applications. Associated with appropriate carriers, all these radionuclides will respond to a maximum of unmet clinical needs. PMID- 22201709 TI - Protein targeting constructs in alpha therapy. AB - The progress in the field of targeted alpha-particle therapy (TAT) has to a great extent been enhanced by developments in both recombinant DNA technology and radionuclide labeling chemistry. Advances in genomics and proteomics have promoted an increase in the identification of novel targets and molecules that can define different diseases, such as cancer. In radioimmunotherapy (RIT), the primary goal is to improve delivery to and therapeutic efficacy of the cancer cells, whilst minimizing toxicity. Different approaches have been investigated to achieve this, such as reducing the size of the carrier, pretargeting, multidosing, locoregional administration and using a cocktail of radiolabeled monoclonal antibodies for targeting multiple antigens simultaneously. Some of these approaches have been encouraging, but translation of TAT into the clinic has been slow, in part because of the limited availability and the short physical half-lives of some of the available alpha-particle emitters. The clinical studies carried out to date have been promising, although many challenges remain in order to make TAT safe and economically feasible. In this paper a number of different targeting constructs used hitherto that may be promising carriers for TAT in the future are presented and discussed. The constructs include enzymatic cleaved antibody fragments (Fab and F(ab)2 fragments); genetically engineered antibody fragments (scFv monomer, dimer (i.e. diabody) and tetramer, CH2 domain deleted antibody fragments); other protein targeting constructs such as affibodies and peptides as well as liposomal delivery. PMID- 22201710 TI - Chemical and radiochemical considerations in radiolabeling with alpha-emitting radionuclides. AB - A review of chemical and radiochemical factors that must be considered when radiolabeling targeting agents with radionuclides is presented. The review discusses factors that are important in choice of radionuclide and choice of chelation or bonding reagents to use in the development of an alpha-emitting radiopharmaceutical. Chemical parameters, such as physical properties and pendant groups for radiolabeling, are reviewed. A major portion of the review outlines the development of chelates and labeling conditions for radiometals, and application of these reagents/conditions to radiometals. Acyclic and macrocyclic chelates containing amine and carboxylic acid coordination groups are highlighted, with examples of bifunctional chelates for biomolecule conjugation. Information is presented on over 60 radiometal-binding chelates. 211At radiolabeling is separated from that of radiometals, and the various reagents used for radiolabeling have been reviewed. Although not all 211At-labeling reagents are reviewed (due to another recent review), nearly 50 reagents studied in the development of pendant groups for labeling with 211At are described. The review also discusses how therapeutic doses of alpha-emitting radiopharmaceuticals can be affected by the radionuclide used and how radiation damage to the radiopharmaceutical can be minimized. PMID- 22201711 TI - Pretargeted radioimmunotherapy with alpha-particle emitting radionuclides. AB - Alpha-particle emitting radionuclides are attractive for targeted cancer therapies due to their physicochemical properties. Their high linear energy transfer (LET) and short particle range makes them particularly toxic at a microscopic level, which is ideal for treating disseminated micrometastases. However, their cytotoxic properties also place special demands on the pharmacokinetics of the tumor specific carrier vector, where high tumor-to-normal tissue ratios are a prerequisite. Tumor specific antibodies are perhaps the most common vector for targeted therapy, but due to pharmacokinetics considerations antibodies will generally not meet the standard for alpha-particle radioimmunotherapy. However, the tumor specificity of monoclonal antibodies may be used in pretargeting techniques, strategies used to increase the selectivity of the radioactivity. The basic concept of pretargeting relies on a separate administration of a modified antibody and a radioactive ligand. The modified antibody is first injected and allowed to localize on the tumor. Then, the radiolabeled ligand is injected, which is a small molecule that rapidly localizes the modified antibody on tumor cells while non-localized ligand rapidly clears from the circulation, preferably through renal filtration. Several pretargeting strategies have been developed, in particular the avidin-biotin system and bispecific antibodies. Approaches under evaluation are the use of complementary DNA, morpholinos, and the use of infinite antigen binding. Preclinical and clinical studies of pretargeting have shown that favorable distribution of the radioactivity can be achieved, which may increase dose to the tumor as compared with the dose from directly labeled antibodies, and most important decrease the dose to normal tissues. This survey describes different pretargeting strategies, and includes a review of pretargeting with alpha emitting radionuclides. PMID- 22201712 TI - Modelling and dosimetry for alpha-particle therapy. AB - As a consequence of the high potency and short range of alpha-particles, radiopharmaceutical therapy with alpha- particle emitting radionuclides is a promising treatment approach that is under active pre-clinical and clinical investigation. To understand and predict the biological effects of alpha-particle radiopharmaceuticals, dosimetry is required at the micro or multi-cellular scale level. At such a scale, highly non-uniform irradiation of the target volume may be expected and the utility of a single absorbed dose value to predict biological effects comes into question. It is not currently possible to measure the pharmacokinetic input required for micro scale dosimetry in humans. Accordingly, pre-clinical studies are required to provide the pharmacokinetic data for dosimetry calculations. The translation of animal data to the human requires a pharmacokinetic model that links macro- and micro-scale pharmacokinetics thereby enabling the extrapolation of micro-scale kinetics from macroscopic measurements. These considerations along with a discussion of the appropriate physical quantity and related units for alpha-particle radiopharmaceutical therapy are examined in this review. PMID- 22201713 TI - Alpha-particle microdosimetry. AB - With the increasing availability of alpha emitters, targeted alpha-particle therapy has emerged as a solution of choice to treat haematological cancers and micrometastatic and minimal residual diseases. Alpha-particles are highly cytotoxic because of their high linear energy transfer (LET) and have a short range of a few cell diameters in tissue, assuring good treatment specificity. These radiologic features make conventional dosimetry less relevant for that context. Stochastic variations in the energy deposited in cell nuclei are important because of the microscopic target size, low number of alpha- particle traversals, and variation in LET along the alpha-particle track. Microdosimetry provides a conceptual framework that aims at a systematic analysis of the stochastic distribution of energy deposits in irradiated matter. The different quantities of microdosimetry and the different methods of microdosimetric calculations were described in the early eighties. Since then, numerous models have been published through the years and applied to analyse experimental data or to model realistic therapeutic situations. Major results have been an accurate description of the high toxicity of alpha-particles, and the description of the predominant effect of activity distribution at the cellular scale on toxicity or efficacy of potential targeted alpha-particle therapies. This last factor represents a major limitation to the use of microdosimetry in vivo because determination of the source - target distribution is complicated. The future contributions of microdosimetry in targeted alpha-particle therapy research will certainly depend on the ability to develop high-resolution detectors and on the implementation of pharmaco-kinetic models at the tumour microenvironment scale. PMID- 22201727 TI - Prophylactic treatment uptake and compliance with recommended follow up among HIV exposed infants: a retrospective study in Addis Ababa, Ethiopia. AB - BACKGROUND: Children are being infected by HIV/AIDS mainly through mother-to child transmission. In Ethiopia currently more than 135,000 children are living with HIV/AIDS. The aim of this study was to describe the pattern of ARV uptake after birth, co-trimoxazole prophylaxis and follow up compliance, and to examine which factors are associated with the intervention outcome. METHODS: A retrospective quantitative study design was used for data collection through two hospitals. All infants who were delivered by HIV infected mothers between October 2008 and August 2009 were included and information regarding treatment adherence during their first 6 months of age was collected. FINDINGS: 118 HIV exposed infant-mother pairs were included in the study. 107 (90.7%) infants received ARV prophylaxis at birth. Sixty six (56%) of the infants were found to be adherent to co-trimoxazole prophylactic treatment. The majority (n = 110(93.2%)) of infants were tested HIV negative with DNA/PCR HIV test at the age of sixth weeks. Infants who took ARV prophylaxis at birth were found to be more likely to adhere with co trimoxazole treatment: [OR = 9.43(95% CI: 1.22, 72.9)]. Similarly, infants whose mothers had been enrolled for HIV/ART care in the same facility [OR = 14(95% CI: 2.6, 75.4)], and children whose fathers were tested and known to be HIV positive [OR = 3.0(95% CI: 1.0, 9.0)] were more likely to adhere than their counterparts. Infants feeding practice was also significantly associated with adherence chi2 test, p < 0.01. CONCLUSION: The proportion of ARV uptake at birth among HIV exposed infants were found to be high compared to other similar settings. Mother infant pair enrolment in the same facility and the infant's father being tested and knew their HIV result were major predictors of infants adhering to treatment and follow up. However, large numbers of infants were lost to follow up. PMID- 22201728 TI - MDA-9/syntenin: a positive gatekeeper of melanoma metastasis. AB - Melanoma differentiation associated gene-9 (MDA-9), synonymous with syntenin, is an adapter protein that provides a central role in regulating cell-cell and cell matrix adhesion. MDA-9/syntenin transduces signals from the cell-surface to the interior through its interaction with a plethora of additional proteins and actively participates in intracellular trafficking and cell-surface targeting, synaptic transmission, and axonal outgrowth. Recent studies demarcate a seminal role of MDA-9/syntenin in cancer metastasis. In the context of melanoma, MDA 9/syntenin functions as a positive regulator of melanoma progression and metastasis through interactions with c-Src and promotes the formation of an active FAK/c-Src signaling complex leading to NF-k B and matrix metalloproteinase (MMP) activation. The present review provides a current perspective of our understanding of the important features of MDA-9/syntenin and its significant role in tumor cell metastasis with special focus on molecular mechanism of action. PMID- 22201729 TI - Purinergic signalling in osteoblasts. AB - The skeleton is maintained throughout life via the finely tuned actions of osteoblasts and osteoclasts, with disruption in this balance eventually leading to bone disease. The exact mechanisms balancing these actions are not fully known, although several regulatory systems are known to be involved. The involvement of purinergic signalling in bone has come to light over the past 20 years or so. This review will highlight the current knowledge of purinergic signalling in osteoblasts - covering expression of P2 receptors, mechanisms of ATP release and degradation, P2 receptor mediated signalling and finally the functional consequences of P2 receptor signalling in bone. PMID- 22201731 TI - Histamine regulation of innate and adaptive immunity. AB - Histamine influences many cell types involved in the regulation of innate and adaptive immune responses including antigen-presenting cells (APCs), Natural Killer (NK) cells, epithelial cells, T lymphocytes and B lymphocytes. These cells express histamine receptors (HRs) and also secrete histamine, which can selectively recruit the major effector cells into tissue sites and affect their maturation, activation, polarization and effector functions leading to tolerogenic or pro-inflammatory responses. Histamine and its four receptors represent a complex system of immunoregulation with distinct effects of receptor subtypes and their differential expression, which changes according to the stage of cell differentiation as well as micro-environmental influences. In this review, we discuss histamine receptor expression and differential activation of cells within both the innate and adaptive immune response and the signal transduction mechanisms which influence their activity. PMID- 22201730 TI - The hematopoietic stem cell niche. AB - Hematopoietic stem cells (HSCs) possess the ability to self-renew and to differentiate to mature progeny along multiple different hematopoietic lineages. The function of HSCs depends upon the signals from surrounding cells found within the highly specialized microenvironment termed the hematopoietic stem cell niche. Understanding and exploiting the HSC niche is a goal of basic scientists and clinicians alike. Recent studies have focused on defining the cellular components and molecular factors critical to this microenvironment. Here we review recent findings, discuss unresolved questions, and examine the clinical implications of our current knowledge of the HSC niche. PMID- 22201732 TI - Musashi1: an RBP with versatile functions in normal and cancer stem cells. AB - Musashi1 (Msi1) is a highly conserved RNA binding protein that was initially identified in Drosophila by its ability to regulate sensory organ development and asymmetric cell division. Studies in mammalian cells reveal multiple functions for Musashi1 in normal and abnormal processes by mediating different post transcriptional processes. According to our recent studies, Musashi1 very likely controls hundreds of targets, forming networks that regulate apoptosis, differentiation, proliferation and cell cycle. Musashi1 is a characteristic stem cell marker that regulates the balance between self-renewal and differentiation. Over-expression of Musashi1 has been associated with numerous tumor types and its function is required for tumor growth in breast, colon, medulloblastoma and glioblastoma. Musashi1 has also been implicated in neurogenesis and neurodegenerative diseases, and is emerging as a potential therapeutic target in both regenerative medicine and cancer. PMID- 22201733 TI - Differentiating human stem cells into neurons and glial cells for neural repair. AB - Research on the biology of adult stem cells, embryonic stem cells and induced pluripotent stem cells, as well as cell-based strategies for treating nervous system disorders has begun to create the hope that these cells may be used for therapy in humans after injury or disease. In animal models of neurological diseases, transplantation of stem cells or their derivatives can improve function not only due to direct replacement of lost neurons or glia, but also by providing trophic support. Despite intense research efforts to translate these studies from the bench to bedside, critical problems remain at several steps in this process. Recent technological advancements in both the derivation of stem cells and their directed differentiation to lineage-committed progenitors have brought us closer to therapeutic applications. Several preclinical studies have already explored the behavior of transplanted cells with respect to proliferation, migration, differentiation and survival, especially in complex pathological disease environments. In this review, we examine the current status, progress, pitfalls, and potential of these stem cell technologies, focusing on directed differentiation of human stem cells into various neural lineages, including dopaminergic neurons, motor neurons, oligodendroglia, microglia, and astroglia, and on advancements in cell-based regenerative strategies for neural repair and criteria for successful therapeutic applications. PMID- 22201735 TI - Bone mineralization. AB - This review attempts to summarize the findings made available by the literature on the mineralization of bone. The types of bone, their structures and compositions, the nature and organization of organic and inorganic matter, the organic-inorganic relationships, and the mineralization mechanism itself, are the main topics of the present review. As in other hard tissues, bone mineralization occurs in, and is conditioned by, the components of the organic matrix. Collagen fibrils have long been considered the factor that is able to induce the deposition of apatite crystallites through a process of heterogeneous nucleation. Interfibrillar non-collagenous proteins are now considered to be co-factors that permit crystallite deposition. The main components of these proteins are reviewed. It is hypothesized that two independent types of mineral are present in bone, one contained in the collagen fibrils and corresponding to the granular, electron-dense bands, and the other contained in the interfibrillar spaces and corresponding to needle- and filament-like crystals. The deposition mechanism of these mineral structures remains elusive. The formation of the crystallites through an epitaxial mechanism is discussed. PMID- 22201734 TI - Cooperative Hedgehog-EGFR signaling. AB - It has been known for many years that cooperative interactions between oncogenes (e.g. RAS, MYC, BCL2) can fuel cancer growth (1-5), but the restricted druggability of many of those interacting cancer genes has hampered translation of combined targeting to medical cancer therapy. The identification and characterization of cooperative cancer signaling pathways amenable to medical therapy is therefore a crucial step towards the establishment of efficient targeted combination treatments urgently needed to improve cancer therapy. Here we review recent findings of our group and colleagues on the molecular mechanisms of cooperative Hedgehog/GLI and Epidermal Growth Factor Receptor (EGFR) signaling, two clinically relevant oncogenic pathways involved in the development of many human malignancies. We also discuss the possible implications of these findings for the design of a therapeutic regimen relying on combined targeting of key effectors of both pathways. PMID- 22201736 TI - Epigenetic mechanisms of plant-derived anticancer drugs. AB - Epigenetic mechanisms are essential for normal development and maintenance of adult life. Disruption of epigenetic processes results in deregulated gene expression and leads to life-threatening diseases, in particular, cancer. Global epigenetic alterations are a hallmark of cancer. Cancer epigenetics revealed the deregulation of all components of the epigenetic machinery including DNA methylation, histone modifications, chromatin structure, and non-coding RNAs. Drugs targeting epigenetic processes, or "epi-drugs", are at the forefront of drug discovery, and plant-derived compounds have shown promise. Most of the plant derived anticancer drugs that work through epigenetic mechanisms are polyphenols; the others are alkaloids, organosulfur compounds, and terpenoids. This review focuses on the epigenetic machinery and its basis for cancer therapy, highlights plant-derived anticancer drugs with epigenetic mechanisms of action, and discusses their potential use in epigenetic therapy. PMID- 22201739 TI - Genetic determinants of acquired cholestasis: a systems biology approach. AB - Cholestatic liver diseases encompass a complex spectrum of intrahepatic and cholangiocellular cholestasis, whose etiologies include genetic and environmental components. This review focuses on the role of the genetic component of three adult cholestatic diseases, namely, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and intrahepatic cholestasis of pregnancy (ICP). In particular, we integrate genomic, molecular, and physiological data to understand the putative interplay between the underlying genetic mechanisms involved in the susceptibility of these diseases. This approach is based on the hypothesis that a more integrative knowledge of the genetic determinants of cholestatic diseases may have a strong impact on the development of improved therapies. We also propose the strategy of gene prioritization to identity potential candidate genes for disease susceptibility, and show some examples of "leading genes of human cholestatic pathways". Finally, based on the hypothesis that common physiologic processes and molecular networks may influence the risk of adult cholestatic diseases, we used a candidate gene prioritization application based on the use of a protein-protein interaction network as part of the 'interactome'. PMID- 22201740 TI - Angiotensin II induces inflammation leading to cardiac remodeling. AB - Hypertension, especially for elevated renin-angiotensin II (Ang II), induces cardiac fibrosis and remodeling. Ang II, acting via its receptors, causes both hemodynamic and nonhemodynamic effects. These effects trigger a series of inflammatory responses. Recent studies have demonstrated that hypertension stimulates infiltration of leukocytes into heart, and interaction among macrophages, T cells, and monocytic fibroblast precursor cells regulates the imbalance of pro-inflammatory and anti-inflammatory factors. Several studies have demonstrated that the inflammatory microenvironment in hypertensive heart promotes a forward feedback infiltration of leukocytes, differentiation of monocytes, and formation of myofibroblasts. An increased number of myofibroblasts, the dominant source of extracellular matrix production, results in deposition of collagen and cardiac remodeling. A thorough understanding of the pathological process underlying hypertension-induced cardiac remodeling may help in prevention and treatment. PMID- 22201737 TI - The role of tristetraprolin in cancer and inflammation. AB - Messenger RNA decay is a critical mechanism to control the expression of many inflammation- and cancer-associated genes. These transcripts are targeted for rapid degradation through AU-rich element (ARE) motifs present in the mRNA 3' untranslated region (3'UTR). Tristetraprolin (TTP) is an RNA-binding protein that plays a significant role in regulating the expression of ARE-containing mRNAs. Through its ability to bind AREs and target the bound mRNA for rapid degradation, TTP can limit the expression of a number of critical genes frequently overexpressed in inflammation and cancer. Regulation of TTP occurs on multiple levels through cellular signaling events to control transcription, mRNA turnover, phosphorylation status, cellular localization, association with other proteins, and proteosomal degradation, all of which impact TTP's ability to promote ARE mediated mRNA decay along with decay-independent functions of TTP. This review summarizes the current understanding of post-transcriptional regulation of ARE containing gene expression by TTP and discusses its role in maintaining homeostasis and the pathological consequences of losing TTP expression. PMID- 22201738 TI - HuR function in disease. AB - The cytoplasmic events that control mammalian gene expression, primarily mRNA stability and translation, potently influence the cellular response to internal and external signals. The ubiquitous RNA-binding protein (RBP) HuR is one of the best-studied regulators of cytoplasmic mRNA fate. Through its post transcriptional influence on specific target mRNAs, HuR can alter the cellular response to proliferative, stress, apoptotic, differentiation, senescence, inflammatory and immune stimuli. In light of its central role in important cellular functions, HuR's role in diseases in which these responses are aberrant is increasingly appreciated. Here, we review the mechanisms that control HuR function, its influence on target mRNAs, and how impairment in HuR-governed gene expression programs impact upon different disease processes. We focus on HuR's well-recognized implication in cancer and chronic inflammation, and discuss emerging studies linking HuR to cardiovascular, neurological, and muscular pathologies. We also discuss the progress, potential, and challenges of targeting HuR therapeutically. PMID- 22201741 TI - Computerized modeling techniques predict the 3D structure of H4R: facts and fiction. AB - The functional characterization of proteins presents a daily challenge r biochemical, medical and computational sciences, especially when the structures are undetermined empirically, as in the case of the Histamine H4 Receptor (H4R). H4R is a member of the GPCR superfamily that plays a vital role in immune and inflammatory responses. To date, the concept of GPCRs modeling is highlighted in textbooks and pharmaceutical pamphlets, and this group of proteins has been the subject of almost 3500 publications in the scientific literature. The dynamic nature of determining the GPCRs structure was elucidated through elegant and creative modeling methodologies, implemented by many groups around the world. H4R which belongs to the GPCR family was cloned in 2000; understandably, its biological activity was reported only 65 times in pubmed. Here we attempt to cover the fundamental concepts of H4R structure modeling and its implementation in drug discovery, especially those that have been experimentally tested and to highlight some ideas that are currently being discussed on the dynamic nature of H4R and GPCRs computerized techniques for 3D structure modeling. PMID- 22201742 TI - Cell death and survival signalling in the cardiovascular system. AB - The loss of cells is an important factor in many diseases, including those of the cardiovascular system. Whereas apoptosis is an essential process in development and tissue homeostasis, its occurrence is often associated with various pathologies. Apoptosis of neurons that fail to make appropriate connections is essential for the selection of correct neural signalling in the developing embryo, but its appearance in adults is often associated with neurodegenerative disease. Similarly, in the cardiovascular system, remodeling of the mammalian outflow tract during the transition from a single to dual series circulation with four chambers is accompanied by a precise pattern of cell death, but apoptosis of cardiomyocytes contributes to ischemia-reperfusion injury in the heart. In many cases, it is unclear whether apoptosis represents a causative association or merely a consequence of the disease itself. There are many excellent reviews on cell death in the cardiovascular system (1-5); in this review we outline the critical signalling pathways that promote the survival of cardiovascular cells, and their relevance to both physiological cell death and disease. PMID- 22201744 TI - Hepatitis C virus' initial encounters: mechanisms of innate immunity. AB - HCV is a single-stranded RNA virus that affects approximately 210 million people worldwide causing chronic disease in 80% of those infected. With the development of new models of study, and a better understanding of the innate immune response, the way this virus induces and evades an immune response at the beginning of the infection has started to be recognized as a critical stage for the development of the chronic state. Still, even with so much information, the question remains as to how the virus establishes itself successfully in the host; a critical question that can lead to life-saving answers. In this review we aim to understand the initial interaction of the virus with its host based on the current literature that links innate immunity and HCV's effects over it. PMID- 22201745 TI - Genome-wide impact of endogenous antisense transcripts in eukaryotes. AB - Recent transcriptomic studies revealed that extensive proportions of genomes are transcribed, despite the limited fraction of protein-coding gene loci in the whole genome. Most transcripts are considered to be 'cryptic' output of the genome because of the lack of functional evidence; however, recent progress in molecular analyses has revealed that some of these transcripts at least have functional significance. This review article examines evidence of the functional significance of endogenous cis-antisense transcripts, which are the transcriptional output from the opposite strand of annotated genes. These transcripts are one of the most common types of transcripts that do not correspond to any protein-coding loci. Historical molecular studies revealed the existence of antisense transcripts associated with dozens of gene loci, whereas more recent genome-wide studies have shown that many genes have an antisense counterpart thus stimulating investigations into the functional significance of endogenous antisense transcripts. Here, we summarize the recent progress in the genome-wide characterization of the antisense transcriptome, and discuss the biological mechanisms that underlie the regulatory machinery of eukaryotic gene expression with respect to the potential roles of endogenous cis-antisense transcripts. PMID- 22201746 TI - Regulation of transcription in cancer. AB - The purpose of this article is to provide an overview on the regulation of transcription in cancer cells. We describe here standard mechanisms of transcription in eukaryotic cells, an influence of common promoter polymorphisms contributing to malignant progression and DNA methylation as significant aspect of gene regulation. We also described transcription factors mechanism of action, and how their alteration can result in cancer. PMID- 22201743 TI - Tissue factor pathway inhibitor: structure-function. AB - TFPI is a multivalent, Kunitz-type proteinase inhibitor, which, due to alternative mRNA splicing, is transcribed in three isoforms: TFPIalpha, TFPIdelta, and glycosyl phosphatidyl inositol (GPI)-anchored TFPIbeta. The microvascular endothelium is thought to be the principal source of TFPI and TFPIalpha is the predominant isoform expressed in humans. TFPIalpha, apparently attached to the surface of the endothelium in an indirect GPI-anchor-dependent fashion, represents the greatest in vivo reservoir of TFPI. The Kunitz-2 domain of TFPI is responsible for factor Xa inhibition and the Kunitz-1 domain is responsible for factor Xa-dependent inhibition of the factor VIIa/tissue factor catalytic complex. The anticoagulant activity of TFPI in one-stage coagulation assays is due mainly to its inhibition of factor Xa through a process that is enhanced by protein S and dependent upon the Kunitz-3 and carboxyterminal domains of full-length TFPIalpha. Carboxyterminal truncated forms of TFPI as well as TFPIalpha in plasma, however, inhibit factor VIIa/tissue factor in two-stage assay systems. Studies in gene-disrupted mice demonstrate the physiological importance of TFPI. PMID- 22201747 TI - WW domain-containing proteins: retrospectives and the future. AB - WW domains are protein modules that mediate protein-protein interactions through recognition of proline-rich peptide motifs (PRM) and phosphorylated serine/threonine-proline sites. WW domains are found in many different structural and signaling proteins that are involved in a variety of cellular processes, including RNA transcription and processing, protein trafficking and stability, receptor signaling, and control of the cytoskeleton. WW domain-containing proteins and complexes have been implicated in major human diseases including cancer as well as in major signaling cascades such as the Hippo tumor suppressor pathway, making them targets for new diagnostics and therapeutics. In this review, we discuss how WW domains provide versatile platforms that link individual proteins into physiologically important networks and the indispensible role of WW domain-containing proteins in biology and pathology, especially tumorogenesis. PMID- 22201748 TI - Multiple roles of proline transport and metabolism in trypanosomatids. AB - Trypanosomatids are a large family of unicellular eukaryotes, many of which are parasites in higher eukaryotes including man. Much of our understanding of metabolism in these organisms has been gained form the study of the human infective representatives (Trypanosoma brucei subpecies, Trypanosoma cruzi and Leishmania spp.) which are transmitted by blood-feeding arthropods. The insect vectors of these parasites use proline as a principal carbon and energy source circulating in their haemolymph. Accordingly the insect-forms of the human infectious parasites have evolved to exploit abundant proline when in this environment, but being able to activate different biochemical pathways when in other environments. Interestingly, if glucose is available, metabolic capability can shift to make this carbohydrate the preferred substrate. Proline has also been shown to play key roles in osmoregulation, differentiation in representatives of the group and may even play a role in immunosuppression elicited by the American trypanosome T. cruzi. This review focuses on recent progress in understanding the different aspects of proline metabolism in trypanosomatids, with a particular interest on the insect forms. PMID- 22201750 TI - (Pro)renin receptor and prorenin: their plausible sites of interaction. AB - Before discovery of (pro)renin receptor, prorenin was regarded as a source of renin and probable diagnostic marker for diabetic nephropathy/Wilms' tumor. It is now considered that prorenin can perform renin activity by binding to (P)RR and binding mechanism of (pro)renin to (P)RR was indicated in many in vitro studies. Considering the physiological importance and pathological involvement of (P)RR, it is indeed a demand of time to determine the three dimensional structure of (P)RR to design (P)RR blocker(s) effective for (pro)renin. It may also facilitate to explain the incompatible data about the effective application of decoy peptide as (P)RR blocker. So far, studies have discussed the bindings of (pro)renin to (P)RR using peptides mimicking the structures of ligands (e.g., the decoy including "handle" region peptide, the "hinge" peptide etc). In this review, the binding mechanism of ligands has been highlighted from the structural aspect of (P)RR using several anti-(P)RR antibodies designed from the primary structure of (pro)renin receptor. Therefore, this review would give us a clue regarding the plausible binding region(s) for prorenin in the (P)RR. PMID- 22201749 TI - Substrate channeling in proline metabolism. AB - Proline metabolism is an important pathway that has relevance in several cellular functions such as redox balance, apoptosis, and cell survival. Results from different groups have indicated that substrate channeling of proline metabolic intermediates may be a critical mechanism. One intermediate is pyrroline-5 carboxylate (P5C), which upon hydrolysis opens to glutamic semialdehyde (GSA). Recent structural and kinetic evidence indicate substrate channeling of P5C/GSA occurs in the proline catabolic pathway between the proline dehydrogenase and P5C dehydrogenase active sites of bifunctional proline utilization A (PutA). Substrate channeling in PutA is proposed to facilitate the hydrolysis of P5C to GSA which is unfavorable at physiological pH. The second intermediate, gamma glutamyl phosphate, is part of the proline biosynthetic pathway and is extremely labile. Substrate channeling of gamma-glutamyl phosphate is thought to be necessary to protect it from bulk solvent. Because of the unfavorable equilibrium of P5C/GSA and the reactivity of gamma-glutamyl phosphate, substrate channeling likely improves the efficiency of proline metabolism. Here, we outline general strategies for testing substrate channeling and review the evidence for channeling in proline metabolism. PMID- 22201751 TI - Profiling of linker histone variants in ovarian cancer. AB - H1 linker histones play a key role in facilitating higher order chromatin folding. Emerging evidence suggests that H1 and its multiple variants are important epigenetic factors in modulating chromatin function and gene expression. Ovarian cancer is a devastating disease, ranking the fifth leading cause of all women cancer death due to its poor prognosis and difficulty in early diagnosis. Although epigenetic alterations in ovarian cancers are being appreciated in general, the role of H1 has not been explored. Here, using quantitative RT-PCR assays, we systematically examined the expression of 7 H1 genes in 33 human epithelial ovarian tumors. Whereas the expression of H1.3 was markedly increased, the expression of H10, H1.1, H1.4 and H1x were significantly reduced in malignant adenocarcinomas compared with benign adenomas. Strikingly, ovarian adenocarcinomas and adenomas exhibited characteristic expression patterns, and expression profiling of 7 H1 genes in tumor samples discriminated adenocarcinomas vs. adenomas with high accuracy. These findings indicate that the expression of H1 variants is exquisitely regulated and may serve as potential epigenetic biomarkers for ovarian cancer. PMID- 22201753 TI - H4 receptors in mast cells and basophils: a new therapeutic target for allergy? AB - It has long been recognised that mast cells and basophils are prominent sources of preformed histamine in humans and that this biogenic amine serves as one of the most important inflammatory mediators. In allergic diseases, histamine has previously been shown to partially modulate symptoms such as airway obstruction, mucus secretion, reddening of the skin and itch, all of which were attributed to engagement of H1-receptors with the amine. However, more recently it has been shown that certain key biological functions of histamine, such as itch, are also crucially controlled by H4-receptor stimulation, resulting in a growing interest in combinational anti-H1 and -H4 therapeutic approaches. Moreover, research is beginning to shed light on a role of H4-receptors in mast cell precursor trafficking to various tissues commonly affected by allergic inflammation. Furthermore, H4-receptors are also expressed on mature basophils and other effector cells of allergic reactions, such as eosinophils. This presents exciting possibilities in terms of potentially modulating the pro-allergic function of these cells as well as. PMID- 22201754 TI - A distinctive role for galectin-7 in cancer ? AB - The galectins are a family of evolutionay-conserved carbohydrate-binding proteins. They are distributed widely in all living organisms and have been implicated in many essential functions including development, differentiation, cell-cell adhesion, cell-matrix interaction, growth regulation, apoptosis. Several members of the galectin family have also been shown to be involved in cancer progression and metastasis. In the case of galectin-7, several studies have reported alterations in its expression pattern during cancer progression. In a variety of tumors, its expression can range from being completely down regulated to highly up-regulated. Accordingly, its precise role in this field is still debated. The evidence shows that galectin-7 may promote or inhibit cancer development. In this article, we review the data concerning expression and roles of galectin-7 in cancer and propose a comprehensive view of its contribution during cancer progression. PMID- 22201755 TI - Metals in Alzheimer's disease: a systemic perspective. AB - Many results from in vitro and animal studies have highlighted the important role played by specific metals, such as copper, iron and zinc, in the diverse toxic pathways on which Alzheimer's disease (AD) develops. Metals seem to mediate the aggregation and neurotoxicity of amyloid-beta (ABeta), the main constituent of the amyloid plaques, commonly seen in AD (1). The link between metals and AD has been mostly investigated with a focus on their local accumulation in defined areas of the brain critical for AD. In the present review, I have instead approached the issue from the different perspective of a systemic, rather than local, alteration of copper and iron status. This view is supported by the results of a series of in vivo studies demonstrating that abnormalities of metals homeostasis correlate with the main deficits and specific markers of AD, such as ABeta and Tau proteins in the cerebrospinal fluid. These findings clearly suggest that local metals accumulation in brain areas critical for AD should be viewed within a wider framework of metals systemic alteration. PMID- 22201756 TI - Eph/ephrin signaling in cell-cell and cell-substrate adhesion. AB - Cell-cell and cell-matrix adhesion are critical processes for the formation and maintenance of tissue patterns during development, as well as control of invasion and metastasis of cancer cells. Although great strides have been made regarding our understanding of the processes that play a role in cell adhesion and cell movement, the precise mechanisms by which diverse signaling events regulate cell and tissue architecture are poorly understood. One group of cell surface molecules, Eph receptor tyrosine kinases, and their membrane-bound ligands, ephrins, are key regulators in these processes. It is the ability of Eph/ephrin signaling pathways to regulate cell-cell adhesion and motility that establishes this family as a formidable system for regulating tissue separation and morphogenesis. Moreover, the de-regulation of this signaling system is linked to the promotion of more aggressive and metastatic tumors in humans. PMID- 22201757 TI - Resveratrol and diallyl disulfide enhance curcumin-induced sarcoma cell apoptosis. AB - Malignant tumors of mesenchimal origin such as rhabdomyosarcoma and osteosarcoma are highly aggressive pedriatic malignancies with a poor prognosis. Indeed, the initial response to chemotherapy is followed by chemoresistance. Diallyl disulfide (DADS), resveratrol (RES) and curcumin (CUR) are dietary chemopreventive phytochemicals which have been reported to have antineoplastic activity on rhabdomyosarcoma and osteosarcoma cells as single drugs. In this study we evaluated whether, as compared to the single compounds, the combination of DADS+RES, DADS+CUR and RES+CUR resulted in an enhancement of their antitumor potential on malignant rhabdoid (SJ-RH4, RD/18) or osteosarcoma (Saos-2) cell lines. Through FACS analysis and activated caspase-3 labeling we demonstrate that CUR induces apoptosis of rabdomyosarcoma and osteosarcoma cells and that this effect is potentiated when CUR is combined with RES or DADS. Further, we explored the effects of the compounds, alone or in combination, on signal transduction pathways involved in apoptosis and growth of cancer cells and show that in rhabdomyosarcoma cells the apoptotic effect of CUR, either alone or in combination, is independent of p53 activity. Our findings suggest that CUR and CUR-based combinations may have relevance for the treatment of p53-deficient cancers, which are often unaffected by conventional chemotherapies or radiotherapy. PMID- 22201752 TI - Genetic variant associations of human SP-A and SP-D with acute and chronic lung injury. AB - Pulmonary surfactant, a lipoprotein complex, maintains alveolar integrity and plays an important role in lung host defense, and control of inflammation. Altered inflammatory processes and surfactant dysfunction are well described events that occur in patients with acute or chronic lung disease that can develop secondary to a variety of insults. Genetic variants of surfactant proteins, including single nucleotide polymorphisms, haplotypes, and other genetic variations have been associated with acute and chronic lung disease throughout life in several populations and study groups. The hydrophilic surfactant proteins SP-A and SP-D, also known as collectins, in addition to their surfactant-related functions, are important innate immunity molecules as these, among others, exhibit the ability to bind and enhance clearance of a wide range of pathogens and allergens. This review focuses on published association studies of human surfactant proteins A and D genetic polymorphisms with respiratory, and non respiratory diseases in adults, children, and newborns. The potential role of genetic variations in pulmonary disease or pathogenesis is discussed following an evaluation, and comparison of the available literature. PMID- 22201758 TI - DNA polymerases: mechanistic insight from biochemical and biophysical studies. AB - In vivo the DNA polymerases are responsible for replicative and repair DNA synthesis. These enzymes use the pre-existing 3'-OH group of a primer annealed to a single-stranded DNA template to incorporate monophosphate deoxynucleosides (dNMPs) in a sequential and directional manner. Although all DNA polymerases share a similar catalytic core constituted by a palm, a thumb and a fingers domain and a similar chemical mechanism of dNMP incorporation that requires two metal cations, they intrinsically differ by the nature of the step that controls the incorporation of dNMP and by their capacity to cope with lesions. Several factors, such as the size of the active site, the flexibility of the DNA in the active site or the presence of protein subdomains devoid of known catalytic activity but able to accommodate small DNA loops, control the fidelity of DNA polymerases. Auxiliary replication factors, such as the processivity factor or the single-stranded DNA binding protein, can also modulate the intrinsic properties of DNA polymerases and therefore fine-tune the. PMID- 22201759 TI - In vivo studies on nonmuscle myosin II expression and function in heart development. AB - Nonmuscle myosin II-B (NM II-B) plays an important role in cardiac development and function. Genetic ablation of NM II-B in mice results in both cellular and structural defects involving cardiac myocytes. These abnormalities include a ventricular septal defect, double outlet of the right ventricle, myocyte hypertrophy and premature onset of myocyte binucleation due to abnormalities in cytokinesis. The mice die by embryonic day (E) 14.5 due to defects in heart development. Conditional ablation of NM II-B in cardiac myocytes after E11.5 allows study of NM II-B function in adult myocytes. BaMHC/BaMHC mice are born with enlarged cardiac myocytes, some of which are multinucleated. Between 6-10 months of age they develop a cardiomyopathy. Many of these mice develop a marked widening of the intercalated discs. The loss of NM II-B from the intercalated discs primarily affects the adhesion junctions rather than the gap junctions and desmosomes. Interestingly, the loss of NM II-B results in a decrease in the actin binding protein mXin which also has been shown to cause disruption of the intercalated disc in addition to cardiac arrhythmias (Gustafson-Wagner et al. Am J Physiol Heart Circ Physiol. 2007, 293:H2680-92). Finally we review the evidence showing that ablation of NM II-C (which also localizes to the intercalated disc) in mouse hearts deficient in NM II-B expression results in destabilization of N cadherin and beta-catenin in the intercalated disc. PMID- 22201761 TI - Long term cultured HL-60 cells are intrinsically resistant to Ara-C through high CDA activity. AB - Cytarabine (araC) is a highly active antimetabolite against hematological malignancy while the agent shows limited activity for some patients despite maintenance or continued therapy with ara-C-containing regiments. In this study, we focused to elucidate the mechanism of intrinsic resistance to araC. The concentration of intracellular ara-CTP and incorporated ara-CTP were monitored in human leukemia cell line-HL-60 for different passages in parental with its variant HL-60R. The expression of mRNA for deoxycytidine kinase (dCK), cytidine deaminas (CDA), human equilibrative nucleoside transporter 1 (hENT1), and cytosolic 50-nucleotidase II (cN-II) were examined by Real-time PCR in HL-60 and HL-60R for different passages. And activities of two metabolizing enzymes for araC, dCK and CDA were further examined. The results showed that the concentration of intracellular ara-CTP was significantly reduced and the ara-U increased in HL-60 cells for 50 passages compared with the 5 passages, and associated with higher CDA activity. All the factors in HL-60R cells did not change by the incubation of ara-C. In conclusion, the long term cultured cells are intrinsically resistant to ara-C through high CDA activity, but not low DCK activity. PMID- 22201760 TI - Unique structural features and sequence motifs of proline utilization A (PutA). AB - Proline utilization A proteins (PutAs) are bifunctional enzymes that catalyze the oxidation of proline to glutamate using spatially separated proline dehydrogenase and pyrroline-5-carboxylate dehydrogenase active sites. Here we use the crystal structure of the minimalist PutA from Bradyrhizobium japonicum (BjPutA) along with sequence analysis to identify unique structural features of PutAs. This analysis shows that PutAs have secondary structural elements and domains not found in the related monofunctional enzymes. Some of these extra features are predicted to be important for substrate channeling in BjPutA. Multiple sequence alignment analysis shows that some PutAs have a 17-residue conserved motif in the C-terminal 20-30 residues of the polypeptide chain. The BjPutA structure shows that this motif helps seal the internal substrate-channeling cavity from the bulk medium. Finally, it is shown that some PutAs have a 100-200 residue domain of unknown function in the C-terminus that is not found in minimalist PutAs. Remote homology detection suggests that this domain is homologous to the oligomerization beta-hairpin and Rossmann fold domain of BjPutA. PMID- 22201762 TI - Effect of pre-freezing rate on porosity ratio and mechanical property of pig aorta. AB - Vacuum freeze-dried blood is a good material for vascular grafts. However, studies on this technology are few, particularly on physical performance change of freeze-dried blood vessel at different pre-freezing rate. In our study, pig aortas were non-invasively scanned by micro-CT in each stage of freeze-drying at different pre-freezing rates, then comparing the porosity ratio and grey level under different conditions with each other to analysis the influence of different methods on the aorta. The mechanical properties of rehydrated pig aorta and fresh one were compared by texture profile analyzer to investigate the influence of different pre-freezing rates on mechanical properties in pig aorta. Our results showed that the proper pre-freezing rate for freeze-drying were 1 C/min. The changing rates of porosity rate and the average gray scale value were 16.6% and 3.64% respectively after freeze-dried. The puncture tolerance (PT) and circumferential tensile stress were increased about 20% and 30% respectively, and the axial tensile stress (ATS) were decreased about 20% in rehydrated aorta compared with fresh aorta. We otherwise conclude that under optimized process conditions, freeze-dried aorta with proper porosity rate and mechanical properties approximate fresh aorta could be preparation. PMID- 22201763 TI - Brain at work: time, sparseness and superposition principles. AB - Many studies explored mechanisms through which the brain encodes sensory inputs allowing a coherent behavior. The brain could identify stimuli via a hierarchical stream of activity leading to a cardinal neuron responsive to one particular object. The opportunity to record from numerous neurons offered investigators the capability of examining simultaneously the functioning of many cells. These approaches suggested encoding processes that are parallel rather than serial. Binding the many features of a stimulus may be accomplished through an induced synchronization of cell's action potentials. These interpretations are supported by experimental data and offer many advantages but also several shortcomings. We argue for a coding mechanism based on a sparse synchronization paradigm. We show that synchronization of spikes is a fast and efficient mode to encode the representation of objects based on feature bindings. We introduce the view that sparse synchronization coding presents an interesting venue in probing brain encoding mechanisms as it allows the functional establishment of multi-layered and time-conditioned neuronal networks or multislice networks. We propose a model based on integrate-and-fire spiking neurons. PMID- 22201764 TI - Proline dehydrogenase: a key enzyme in controlling cellular homeostasis. AB - Proline dehydrogenase (ProDH), also called proline oxidase (POX), is a universal enzyme in living organisms. It catalyzes the oxidation of L-proline to delta1 pyrroline-5-carboxylate leading to the release of electrons, which can be transferred to either electron transfer systems or to molecular oxygen. ProDH is not only essential for proline catabolism but also plays key roles in providing energy, shuttling redox potential between cellular compartments and reactive oxygen species production. Structural analysis of prokaryotic ProDHs already gives some insights into the biochemical activity and biological functions of this enzyme, which can be extended to eukaryotic ProDHs based on sequence similarities. Here we report the most recent investigations on the biochemical and regulation of ProDH at transcriptional, post-transcriptional and translational levels. The biological roles of ProDH in cell homeostasis and adaptation through energetic, developmental, adaptive, physiological and pathological processes in eukaryotes are presented and discussed to create a framework for future research direction. PMID- 22201765 TI - Molecular insights into primary hyperoxaluria type 1 pathogenesis. AB - Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder of glyoxylate metabolism caused by the deficiency of liver peroxisomal alanine:glyoxylate aminotransferase (AGT), a pyridoxal 5'-phosphate (PLP) dependent enzyme. The PH1 pathogenesis is mostly due to single point mutations (more than 150 so far identified) on the AGXT gene, and is characterized by a marked heterogeneity in terms of genotype, enzymatic and clinical phenotypes. This article presents an up to date review of selected aspects of the biochemical properties of the two allelic forms of AGT and of some PH1-causing variants. These recent discoveries highlight the effects at the protein level of the pathogenic mutations, and, together with previous cell biology and clinical data, (i) improve the understanding of the molecular basis of PH1 pathogenesis, and (ii) help to delineate perspectives for predicting the response to pyridoxine treatment or for suggesting new strategies for PH1 patients bearing the analyzed mutations. PMID- 22201766 TI - Enhancing graft-versus-leukemia after transplant: the rise of anti-cancer vaccines. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only truly effective curative treatment for refractory hematological malignancies. Unfortunately, relapse and transplant rejection continue to be of major concern. In order to enhance the effectiveness of the HSCT, various strategies have been explored to amplify the graft versus leukemia (GvL) effect. Cancer vaccines have emerged in recent years as a promising strategy for the immunotherapeutic treatment of cancer. Evidence shows that they are most likely to have the greatest effect in the setting of minimal residual disease and as adjuvant agents. With this in mind, researchers have begun to explore the use of cancer vaccines in conjunction with HSCT, with exciting results. There has also been recent work examining the effect of novel adjuvants or blockers of negative immune regulation to augment the effect of cancer vaccines in both the transplant and non-transplant settings. The addition of these agents may prove. PMID- 22201767 TI - Uric acid, hyperuricemia and vascular diseases. AB - Uric acid is the product of purine metabolism. It is known that hyperuricemia, defined as high levels of blood uric acid, is the major etiological factor of gout. A number of epidemiological reports have increasingly linked hyperuricemia with cardiovascular and neurological diseases. Studies highlighting the pathogenic mechanisms of uric acid point to an inflammatory response as the primary mechanism for inducing gout and possibly contributing to uric acid's vascular effects. Monosodium urate (MSU) crystals induce an inflammatory reaction, which are recognized by toll-like receptors (TLRs). These TLRs then activate NALP3 inflammasome. MSU also triggers neutrophil activation and further produces immune mediators, which lead to a proinflammatory response. In addition, soluble uric acid can also mediate the generation of free radicals and function as a pro-oxidant. This review summarizes the epidemiological studies of hyperuricemia and cardiovascular disease, takes a brief look at hyperuricemia and its role in neurological diseases, and highlights the studies of the advanced pathological mechanisms of uric acid and inflammation. PMID- 22201768 TI - Mechanisms of cancer-associated glycosylation changes. AB - Cell membrane glycoconjugates undergo characteristic changes as a consequence of neoplastic transformation. The cancer-associated carbohydrate structures play key roles in cancer progression by altering the cell-cell and cell-environment interactions. In this review, we will discuss some of the most relevant cancer associated carbohydrate structures, including the beta1,6-branching of N-linked chains, the sialyl Lewis antigens, the alpha2,6-sialylated lactosamine, the Thomsen-Friedenreich-related antigens and gangliosides. We will describe the mechanisms leading to the expression of these structures and their interactions with sugar binding molecules, such as selectins and galectins. Finally, we will discuss how the glycosylation machinery of the cell is controlled by signal transduction pathways, epigenetic mechanisms and responds to hypoxia. PMID- 22201769 TI - The role of microRNAs in glioma initiation and progression. AB - micoRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by targeting the mRNAs of a large number of human genes. Gliomas are the most common and deadly primary human brain tumors and are thought to originate from transformed stem-like cells (GSCs). microRNAs are frequently deregulated in cancer and gliomas and their deregulation has been associated with various aspects of glioma pathobiology. The present review summarizes the published literature on the role of miRNAs in gliomas with a focus on their role in GSCs. PMID- 22201770 TI - Tissue specific epigenetic differences in CRH gene expression. AB - Corticotropin Releasing Hormone (CRH), a 41-amino acid peptide, is a major regulator of hypothalamic-pituitary-adrenal axis function. CRH also has important roles in several processes pertaining to pregnancy and parturition, including being a possible regulator of gestational length and predictor of pre-term birth. Regulation of the CRH promoter exhibits some tissue-specificities, the most well characterized example being glucocorticoids, which can stimulate placental CRH production but suppress hypothalamic CRH. In the last decade there has been growing interest in the role of epigenetic regulation of gene expression. Modification of the structure of chromatin is an example of epigenetic change affecting gene expression. We have found that inhibition of histone deacetylases results in an increase in CRH expression in the AtT20 pituitary cell line, but a decrease in CRH expression in the placenta. In this paper we review tissue specific differences in CRH gene expression, and discuss how epigenetic chromatin modification mechanisms can relate to tissue specific differences in expression of CRH. PMID- 22201771 TI - Plasmodium sporozoite motility: an update. AB - Plasmodium, the causative agent of malaria, employs its own actin/myosin-based motor for forward locomotion, penetration of molecular and cellular barriers, and invasion of target cells. The sporozoite is unique amongst the extracellular Plasmodium developmental forms in that it has to cross considerable distances and different tissues inside the mosquito and vertebrate hosts to ultimately reach a parenchymal liver cell, the proper target cell where to transform and replicate. Throughout this dangerous journey, the parasite alternates between being passively transported by the body fluids and using its own active cellular motility to seamlessly glide through extracellular matrix and cell barriers. But irrespective of the chosen path, the sporozoite is compelled to keep on moving at a fairly fast pace to escape destruction by host defense mechanisms. Here, we highlight and discuss recent findings collected in Plasmodium sporozoites and related parasites that shed new light on the biological significance of apicomplexan motility and on the structure and regulation of the underlying motor machinery. PMID- 22201772 TI - The Na+/L-proline transporter PutP. AB - The Na+/L-proline transporter PutP is a member of the Na+/solute symporter family (TC 2A.21, SLC5), which contains several hundred proteins of pro- and eukaryotic origin. Within the family, the capability of L-proline uptake is restricted to proteins of prokaryotes. PutP contributes to the use of L-proline as a nutrient. In addition, the transporter may supply cells with compatible solute during adaptation to osmotic stress. Based on these and other functions, PutP is of significance for various bacteria-host interactions including the virulence of human pathogens. A homology model of Escherichia coli PutP was generated based on the crystal structure of the Vibrio parahaemolyticus Na+/galactose symporter. According to the model, PutP has a core structure of five plus five transmembrane domains forming an inverted repeat similar as originally revealed by the crystal structure of the Na+/leucine transporter LeuT. The homology model is experimentally verified by Cys cross-linking and site-directed spin labeling in combination with electron paramagnetic resonance spectroscopy. The putative sites of Na+ and L-proline binding are described, and a putative transport mechanism is discussed. PMID- 22201773 TI - Functions of p120ctn in development and disease. AB - p120 catenin (p120ctn), a component of the cadherin-catenin complex, was the first member to be identified in a most interesting subfamily of the Armadillo family. Several p120ctn isoforms are generated by alternative splicing. These isoforms fulfill pleiotropic functions according to their subcellular localization: modulating the turnover rate of membrane-bound cadherins, regulating the activation of small Rho GTPases in the cytoplasm, and modulating nuclear transcription. Over the last two decades, knowledge of p120ctn has grown remarkably, and this has been achieved in part by using different animal models. At least in frog and mammals, p120ctn is essential for normal development and homeostasis. Here we will discuss the effects of different p120ctn isoforms on cadherin turnover and on signaling in the cytoplasm and the nucleus. We will also elaborate on the structure and function of other members of the p120ctn subfamily: ARVCF, p0071 and delta-catenin. Finally, we will overview the respective roles of p120ctn family members in pathological processes, and particularly in cancer as p120ctn is frequently. PMID- 22201774 TI - The Wnt signaling pathways and cell adhesion. AB - In multicellular organisms, the processes of tissue and organ formation are governed by morphogenetic signaling pathways. The Wnt pathways regulate morphogenesis by controlling cell adhesion and migration; processes that when corrupted, lead to tumorgenesis. It is well known that the Wnt signaling pathways affect adhesion and migration via downstream effectors. Canonical Wnt signaling regulates cell adhesion by regulating the stability of beta-Catenin, a component of the adherens junction. Whereas, non-canonical signaling modulates cytoskeletal dynamics by regulating the activity of downstream effectors that function to organize the cytoskeleton. Recent studies have uncovered a multitude of points of crosstalk between the Wnt pathways and the mechanisms that control cellular architecture, from the level of receptors to the level of transcription. At the same time, cellular mechanisms that are responsible for the regulation of adhesion and migration also function to modulate the activity of several Wnt pathway components. Uncovering these points of crosstalk may lead to better understanding and treatment of the processes that can lead to tumorgenesis. PMID- 22201776 TI - Gonadal transactivation of STARD1, CYP11A1 and HSD3B. AB - The steroidogenic acute regulatory protein, cytochrome P450 cholesterol side chain cleavage enzyme and specific 3beta-hydroxysteroid dehydrogenase/delta5 delta4 isomerases initiate the essential process of steroidogenesis in the gonads. Testicular and ovarian expression of their respective genes, STARD1, CYP11A1 and gonadal HSD3B, is primarily controlled by gonadotropins with contributions by various growth factors. Gonadotropins through their receptors switch on cyclic AMP signaling pathways that recruit NR5A, GATA and often CREB, NR4A, or Sp1 transcription factors to regulatory regions of each gene's promoter to elicit transcription. The specific combination of transcription factors involved depends on the cellular context. In this review, we summarize current understanding of the factors that control transactivation of the STARD1, CYP11A1 and gonadal HSD3B genes in Leydig cells in the testis and the theca, differentiating granulosa and luteal cells in the ovary. PMID- 22201775 TI - The TR (i)P to Ca2+ signaling just got STIMy: an update on STIM1 activated TRPC channels. AB - Calcium is a ubiquitous signaling molecule, indispensable for cellular metabolism of organisms from unicellular life forms to higher eukaryotes. The biological function of most eukaryotic cells is uniquely regulated by changes in cytosolic calcium, which is largely achieved by the universal phenomenon of store-operated calcium entry (SOCE). The canonical TRPs and Orai channels have been described as the molecular components of the store-operated calcium channels (SOCC). Importantly, the ER calcium-sensor STIM1 has been shown to initiate SOCE via gating of SOCC. Since the discovery of STIM1, as the critical regulator of SOCE, there has been a flurry of observations suggesting its obligatory role in regulating TRPC and Orai channel function. Considerable effort has been made to identify the molecular details as how STIM1 activates SOCC. In this context, findings as of yet has substantially enriched our understanding on, the modus operandi of SOCE, the distinct cellular locales that organize STIM1-SOCC complexes, and the physiological outcomes entailing STIM1-activated SOCE. In this review we discuss TRPC channels and provide an update on their functional regulation by STIM1. PMID- 22201778 TI - FES/FER kinase signaling in hematopoietic cells and leukemias. AB - FES and FES-related (FER) comprise a unique subfamily of protein-tyrosine kinases (PTKs) that signal downstream of several classes of receptors involved in regulating hematopoietic cell development, survival, migration, and inflammatory mediator release. Activated alleles of FES are potent inducers of myeloid differentiation, however FES-deficient mice have only subtle differences in hematopoiesis. This may reflect overlapping function of other kinases such as FER. Studies of FES- and FER-deficient mice have revealed more prominent roles in regulating the activation of mature innate immune cells, including macrophages and mast cells. Recently, new insights into regulation of FES/FER kinases has emerged with the characterization of their N-terminal phospholipid-binding and membrane targeting FER/CIP4 homology-Bin/Amphyphysin/Rvs (F-BAR) and F-BAR extension (FX) domains. The F-BAR/FX domains regulate subcellular localization and FES/FER kinase activation. FES kinase activity is also enhanced upon ligand binding to its SH2 domain, which may lead to further phosphorylation of the same ligand, or other ligand-associated proteins. In mast cells, SH2 ligands of FES/FER include KIT receptor PTK, and the high affinity IgE receptor (FceRI) that trigger rapid activation of FES/FER and signaling to regulators of the actin cytoskeleton and membrane trafficking. Recently, FES/FER have also been implicated in growth and survival signaling in leukemias driven by oncogenic KIT and FLT3 receptors. With further definition of their roles in immune cells and their progenitors, FES/FER may emerge as relevant therapeutic targets in inflammatory diseases and leukemias. PMID- 22201777 TI - STIM and Orai proteins and the non-capacitative ARC channels. AB - The ARC channel is a small conductance, highly Ca2+-selective ion channel whose activation is specifically dependent on low concentrations of arachidonic acid acting at an intracellular site. They are widely distributed in diverse cell types where they provide an alternative, store-independent pathway for agonist activated Ca2+ entry. Although biophysically similar to the store-operated CRAC channels, these two conductances function under distinct conditions of agonist stimulation, with the ARC channels providing the predominant route of Ca2+ entry during the oscillatory signals generated at low agonist concentrations. Despite these differences in function, like the CRAC channel, activation of the ARC channels is dependent on STIM1, but it is the pool of STIM1 that constitutively resides in the plasma membrane that is responsible. Similarly, both channels are formed by Orai proteins but, whilst the CRAC channel pore is a tetrameric assembly of Orai1 subunits, the ARC channel pore is formed by a heteropentameric assembly of three Orai1 subunits and two Orai3 subunits. There is increasing evidence that the activity of these channels plays a critical role in a variety of different cellular activities. PMID- 22201779 TI - Role of secreted factors in the regulation of hematopoietic stem cells by the bone marrow microenvironment. AB - The stem cell microenvironment (in vivo known as niche) is a specific space in the bone marrow (BM), which nurses hematopoietic stem cells and regulates their self-renewal and differentiation using extrinsic cues, such as secreted factors. The niche plays a major role in regulating the number of blood cells and also protects stem cells against excessive proliferation. Till date, several possible secreted regulators of HSC function have been reported. Many of these were originally isolated from stromal cells and the cell lines isolated from hematopoietic tissues. These secreted factors act in concert and not only regulate HSC, but also the niche cells. It has also become clear that deregulation of the niche function is a potential cooperating factor during the development of hematological malignancies. An understanding of how the niche participates in HSC maintenance and repair through soluble factors can offer new opportunities for the development of novel therapeutic tools against hematological malignancies. PMID- 22201780 TI - The biology of equine mesenchymal stem cells: phenotypic characterization, cell surface markers and multilineage differentiation. AB - Mesenchymal stem cells (MSCs) are multipotent stem cells that can give rise to a range of connective tissue cells including osteoblasts, chondrocytes and adipocytes. MSCs have been isolated from humans and a variety of animal species including rodents, dogs, horses and rabbits. There is currently no consensus on how these cells are identified and characterized. This is partly due to the lack of standardized specific cell surface markers for MSCs. The aim of this review is to examine the literature on equine MSCs and establish whether there is a well defined phenotype for these cells. Equine MSCs have been obtained from four main sources, bone marrow, adipose tissue, umbilical cord (blood and matrix) and peripheral blood. MSCs from these tissue sources have been shown to undergo chondrogenic, adipogenic and osteogenic differentiation. However the markers used to identify these cells vary significantly in the literature. Despite this, CD90 and CD34 seem to be reliable positive and negative markers respectively. Our understanding of the biology of equine MSCs will benefit from better reagents for their phenotypic characterization. The antibodies and molecular probes needed for the reliable identification of equine MSCs are not standardized and this is a high priority for future research. PMID- 22201781 TI - Epigenetic regulation of transcription in Drosophila. AB - Post-translational modification of histones is a major mechanism of epigenetic regulation of eukaryotic transcription. Drosophila has proven to be an important model system for the study of histone modifying enzymes and the cross talk that occurs between the various modifications. Polytene chromosome analysis and genome wide chromatin immunoprecipitation (ChIP) studies have provided much insight into the location of marks and many of the enzymes that perform the catalytic reactions. Gene specific effects have been determined through study of flies carrying mutations in histone modifying enzymes. This review will highlight classic studies and present recent progress on both the localization data and mutant analyses. This information has been used to assign function to the marks and to the enzymes that place or remove them, critical for the process of transcriptional regulation. PMID- 22201782 TI - Regulation of inducible gene expression by natural antisense transcripts. AB - Natural antisense transcripts are frequently transcribed from many genes in eukaryotes. Although natural antisense transcripts have been recognized for a long time, their importance has been overlooked due to their heterogeneity, low expression level, and unknown function. Genes induced in responses to various external stimuli are transcriptionally regulated by the activation of a gene promoter and post-transcriptionally regulated by controlling mRNA stability and translatability. Recent studies have shed light on the functions of natural antisense transcripts at the post-transcriptional level. An antisense transcript may regulate gene expression with cis-controlling elements on the mRNA, and the antisense transcript itself may act in concert with trans-acting factors, including various proteins that bind to cis-controlling elements, drugs, and microRNAs. A novel mechanism recently reported to regulate mRNA stability includes the interaction of the antisense transcript with mRNA by hybridization to single-stranded loops in secondary structures. This antisense transcript mediated post-transcriptional regulation may be one of the general mechanisms for the regulation of inducible gene expression and presents the possibility of the involvement of natural antisense transcripts in disease. PMID- 22201783 TI - Liver transplantation in chronic cholestatic conditions. AB - Primary biliary cirrhosis and primary sclerosing cholangitis are two most frequently encountered cholestatic condition in adults. Liver transplantation is an excellent option in patients who progress to end-stage liver disease. In these patients typical indications for liver transplantation are no different than in other conditions requiring transplantation. Liver transplantation however might be also suggested for specific indications even in patients with otherwise well preserved liver function. 5-year survival after liver transplantation in primary biliary cirrhosis was reported to be between 78 and 87%. Survival rates after liver transplantation in primary sclerosing cholangitis are considered favorable when compared to many other indications for this procedure. Nevertheless, in both primary biliary cirrhosis and primary sclerosing cholangitis recurrence of the disease after liver transplantation can be observed. Cystic fibrosis, biliary atresia, Alagille syndrome and progressive familiar intrahepatic cholestasis are cholestatic conditions in children. Liver transplantation represents an effective treatment in majority of cases fulfilling the criteria for this procedure. PMID- 22201784 TI - Function of the INO80 chromatin remodeling complex in DNA replication. AB - ATP-dependent chromatin remodeling complexes are involved in several nuclear processes. In particular the INO80 remodeling complex is an essential factor during transcription and DNA repair. Recently, several labs have described a novel role for INO80 during DNA replication. Moreover, Falbo et al. have presented evidence linking INO80's activities to the DNA damage tolerance pathways during replication (1). In this review we will discuss and integrate the results obtain by these various research groups to describe a novel role for INO80 in DNA replication. PMID- 22201785 TI - Mitotic checkpoint control and chromatin remodeling. AB - In order to maintain chromosomal stability during cell division, eukaryotic cells have evolved a number of surveillance mechanisms termed checkpoints. These checkpoints monitor the completion of essential molecular and cellular processes of one stage before entering another. The spindle checkpoint watches the bi orientation attachment of spindle microtubules to all condensed chromosomes before initiation of nuclear division during mitosis. Histones are subject to a number of post-translational modifications during the cell cycle, which may in turn modify or facilitate cell cycle progression. Recent studies suggest that mitotic proteins including Bub1 and Sgo1 that are involved in the spindle checkpoint also play a major role in the regulation of histone modifications and chromatin remodeling. This mini-review summarizes emerging information about the new role of spindle checkpoint proteins in chromatin remodeling. PMID- 22201786 TI - Histones and genome integrity. AB - Chromosomes undergo extensive structural rearrangements during the cell cycle, from the most open chromatin state required for DNA replication to the highest level of compaction and condensation essential for mitotic segregation of sister chromatids. It is now widely accepted that chromatin is a highly dynamic structure that participates in all DNA-related functions, including transcription, DNA replication, repair, and mitosis; hence, histones have emerged as key players in these cellular processes. We review here the studies that implicate histones in functions that affect the chromosome cycle, defined as the cellular processes involved in the maintenance, replication, and segregation of chromosomal DNA. Disruption of the chromosome cycle affects the integrity of the cellular genome, leading to aneuploidy, polyploidy or cell death. Histone stoichiometry, mutations that affect the structure of the nucleosome core particle, and mutations that affect the structure and/or modifications of the histone tails, all have a direct impact on the fidelity of chromosome transmission and the integrity of the genome. PMID- 22201787 TI - Rapid signaling of steroid hormones in the vertebrate nervous system. AB - Steroid hormones easily cross the blood-brain barrier because of their physicochemical lipid solubility. The hormones act through nuclear receptor mediated mechanisms and modulate gene transcription. In contrast to their genomic actions, the non-genomic rapid action of steroid hormones, acting via various types of membrane-associated receptors, reveals pharmacological properties that are distinct from the actions of the intracellular nuclear receptors. As a result, non-genomic rapid actions have gained increased scientific interest. However, insight into the phylogenic and/or comparative actions of steroids in the brain is still poorly understood. In this review, we summarize recent findings concerning the rapid, non-genomic signaling of steroid hormones in the vertebrate central nervous system, and we discuss (using a comparative view from fish to mammals) recently published data regarding the mechanism underlying physiology and behavior. PMID- 22201788 TI - Bacterial chromosome segregation. AB - Dividing cells have mechanisms to ensure that their genomes are faithfully segregated into daughter cells. In bacteria, the description of these mechanisms has been considerably improved in the recent years. This review focuses on the different aspects of bacterial chromosome segregation that can be understood thanks to the studies performed with model organisms: Escherichia coli, Bacillus subtilis, Caulobacter crescentus and Vibrio cholerae. We describe the global positionning of the nucleoid in the cell and the specific localization and dynamics of different chromosomal loci, kinetic and biophysic aspects of chromosome segregation are presented. Finally, a presentation of the key proteins involved in the chromosome segregation is made. PMID- 22201789 TI - From myofibril to membrane; the transitional junction at the intercalated disc. AB - Cardiomyocytes are coordinated by linking together at their ends through the intercalated disc. The intercalated disc with its complex folded membrane, encompasses many structural and signalling functions and is thought to play a role in cell growth and sarcomere addition. Its relationship to the contractile myofibrils is central to myocyte function. The myofibrils continue their ordered sarcomeric structure up to the edge of the intercalated disc where there is no terminal Z-disc but, instead a transitional junction. Thin actin-containing filaments from the final half sarcomere extend beyond their normal length through the transitional junction to the folded intercalated disc membrane where tension is transmitted. The peaks of the membrane folds also occur at the transitional level. They are spectrin rich and associated with sarcoplasmic reticulum vesicles. A subset of Z-disc proteins including titin, alpha-actinin and ZASP/cypher/oracle are found in the transitional region while others such as telethonin and FATZ/calsarcin/myozenin are absent. The presence of titin enables ordered sarcomeres to be maintained independently of changes in the amplitude of the membrane folds. The transitional junction is therefore poised to act as a site for a new Z-disc/SR/T-tubule complex and sarcomere addition. The evidence for this is reviewed. PMID- 22201790 TI - Histone ubiquitylation and chromatin dynamics. AB - Histones are subject to several post-translational modifications, which act to regulate gene expression and other processes on the DNA template. One such modification is the addition of a single ubiquitin moiety, which has been reported to influence chromatin dynamics and exhibit cross-talk with other histone modifications. Mono-ubiquitylation of H2B has been reported in eukaryotes as divergent as budding yeast, flies and humans, and is linked to transcriptional activation and gene silencing. Furthermore, ubiquitylation of H2A is also important for transcriptional repression in higher eukaryotes, and both histones play key roles in DNA repair. In this review, we will give an overview of the enzymes important for ubiquitylation and deubiquitylation of the various histone species, before examining the role of ubiquitylated histones in shaping the chromatin landscape and thus controlling the accessibility of DNA to effector proteins, through putative roles in promoting histone-histone interactions and stabilizing the structure of nucleosomes. We will finally discuss other processes reported to involve ubiquitylation of histones, including DNA repair, recombination and mRNA processing, underlining the diverse actions of these modifications. PMID- 22201791 TI - Mitochondrial and nuclear genomic integrity after oxidative damage in Saccharomyces cerevisiae. AB - All cells have the ability to adjust their metabolism to their changing environment to be able to survive. This adaptation is coordinated by various systems in the cell and mitochondria seem to play a unique and important role. Most endogenous oxidative damage to cells is actually generated as a byproduct of the mitochondrial function, which in turn damages mitochondrial structures more extensively due to their proximity to the source. Excessive damage to mitochondria leads to loss of parts or all of mtDNA, but unlike other organisms, S. cerevisiae cells are able to survive without mtDNA or respiration when grown on fermentative carbon sources. This allows studies of the role of mitochondria in the maintenance of cellular integrity, since lack of mitochondrial DNA frequently leads to genomic instability. Mitochondria are known for their role in respiration, ATP production and apoptosis, but it is now becoming clear that their function is intimately connected to diverse processes such as calcium and iron homeostasis and amino acid metabolism, and thus their dysfunction is not well tolerated. In this review, we discuss the mechanisms by which mitochondrial dysfunction can lead to genomic instability and the effect of the carbon source on this process. PMID- 22201792 TI - Mechanistic insights into type III restriction enzymes. AB - Type III restriction-modification (R-M) enzymes need to interact with two separate unmethylated DNA sequences in indirectly repeated, head-to-head orientations for efficient cleavage to occur at a defined location next to only one of the two sites. However, cleavage of sites that are not in head-to-head orientation have been observed to occur under certain reaction conditions in vitro. ATP hydrolysis is required for the long-distance communication between the sites prior to cleavage. Type III R-M enzymes comprise two subunits, Res and Mod that form a homodimeric Mod2 and a heterotetrameric Res2Mod2 complex. The Mod subunit in M2 or R2M2 complex recognizes and methylates DNA while the Res subunit in R2M2 complex is responsible for ATP hydrolysis, DNA translocation and cleavage. A vast majority of biochemical studies on Type III R-M enzymes have been undertaken using two closely related enzymes, EcoP1I and EcoP15I. Divergent opinions about how the long-distance interaction between the recognition sites exist and at least three mechanistic models based on 1D- diffusion and/or 3D- DNA looping have been proposed. PMID- 22201793 TI - Histamine in two component system-mediated bacterial signaling. AB - Histamine is a key mediator governing vital cellular processes in mammals beyond its decisive role in inflammation. Recent evidence implies additional actions in both eukaryotes and prokaryotes. Besides its function in host defense against bacterial infections, histamine elicits largely undefined actions in microorganisms that may contribute to bacteria-host interactions. Bacterial proliferation and adaptation are governed by sophisticated signal transduction networks, including the versatile two-component systems (TCSs) that comprise sensor histidine kinases and response regulators and rely on phosphotransfer mechanisms to exert their modulatory function. The AtoSC TCS regulates fundamental cellular processes such as short-chain fatty acid metabolism, poly (R)-3-hydroxybutyrate (cPHB) biosynthesis and chemotaxis in Escherichia coli. The implication of exogenous histamine in the AtoSC-mediated cPHB biosynthesis and in E. coli chemotactic behavior is indicative of a putative function of histamine in bacterial physiology. The data raise questions on the significance of histamine actions in bacteria-host symbiosis, dysbiosis and pathogenicity as well as on the possible consequences upon therapeutic administration of histamine receptor targeting agents and in particular ligands of the recently identified immunomodulatory H4 receptor. PMID- 22201795 TI - Vascular inflammation is a missing link for diabetes-enhanced atherosclerotic cardiovascular diseases. AB - Diabetes is associated with major life-threatening complications such as a markedly increased risk of cardiovascular disease, even in the presence of rigid glycemic control. Indeed, nearly 75% of diabetic patients eventually die of cardiovascular disease or cardiovascular complications. A striking feature of the diabetic cardiovascular phenotype is the appearance of accelerated atherosclerosis, which resembles atherosclerosis that may be encountered in the non-diabetic individual, except that it is more extensive, aggressive, and occurs at an earlier age. Atherosclerosis (or atherosclerotic vascular disease; ASVD), is a pathological syndrome affecting arterial vessels characterized by narrowing of the vascular lumen secondary to intravascular buildup of fatty material such as cholesterol, aggregated cellular debris, and inflammatory change in the vascular endothelium. Seemingly distinct, these two well-defined disorders are nevertheless, intimately and intricately linked. In fact, these two pathologies appear to be linked by common signaling pathways and shared regulatory systems that appear to go awry in an as yet poorly understood manner. In recent years, a body of evidence has been growing that suggests that inflammation peculiar to the vascular system, occurs in the diabetic patient. This review aims to present the empirical underpinning of the hypothesis that inflammatory change in the vasculature might be the integrated mechanism that connects a diabetic phenotype with its attendant vascular complications. PMID- 22201794 TI - RUNX1 and RUNX1-ETO: roles in hematopoiesis and leukemogenesis. AB - RUNX1 is a transcription factor that regulates critical processes in many aspects of hematopoiesis. RUNX1 is also integral in defining the definitive hematopoietic stem cell. In addition, many hematological diseases like myelodysplastic syndrome and myeloproliferative neoplasms have been associated with mutations in RUNX1. Located on chromosomal 21, the RUNX1 gene is involved in many forms of chromosomal translocations in leukemia. t(8;21) is one of the most common chromosomal translocations found in acute myeloid leukemia (AML), where it results in a fusion protein between RUNX1 and ETO. The RUNX1-ETO fusion protein is found in approximately 12% of all AML patients. In this review, we detail the structural features, functions, and models used to study both RUNX1 and RUNX1-ETO in hematopoiesis over the past two decades. PMID- 22201797 TI - Regulation of cellular responses by deubiquitinating enzymes: an update. AB - The conjugation of ubiquitin as either a monomer or as a chain has long been known to regulate the stability, localisation, trafficking and/or function of many intracellular proteins. However, the recent explosion in our knowledge of the enzymes responsible for the removal of ubiquitin suggests they also play an important role in the regulation of many processes. Here we examine what is known about the role of deubiquitinating enzymes (DUBs), with particular emphasis upon their impact on cellular responses to external stimuli. In addition, we look at the evidence that although these enzymes are heavily outnumbered by those responsible for ubiquitin conjugation, that these enzymes may still be important cellular regulators, due to their ability to play multiple roles which can be cell type and cell context specific. PMID- 22201798 TI - Localization status of hepatocellular transporters in cholestasis. AB - Vectorial transport of osmotically active solutes from blood into bile is essential for bile flow generation. Therefore, the localization status of hepatocellular transporters involved in this function is critical. These transporters are localized either in the plasma membrane or in an endosomal, submembranous compartment, from where they undergo recycling to the plasma membrane. The balance between exocytic targeting/endocytic internalization from/to this recycling compartment is therefore a chief determinant of the liver capability to secrete bile. Furthermore, its impairment may lead to sustained endocytic internalization, eventually resulting in transporter degradation. Exacerbated internalization of hepatocellular transporters occurs in several experimental models of cholestasis, and also in most human cholestatic liver diseases. This review outlines the possible mechanisms explaining this alteration (e.g., alteration of the organization of actin or actin-transporter linking proteins), and the mediators involved (e.g., activation of "cholestatic" signaling pathways). Finally, several experimental therapeutic approaches based upon the administration of compounds that stimulate exocytic targeting of canalicular transporters (e.g., cAMP, tauroursodeoxycholate) are described with regard to their capability to prevent cholestatic alterations resulting from transporter internalization. PMID- 22201799 TI - Understanding TLR9 action in Epstein-Barr virus infection. AB - The Epstein-Barr virus (EBV) establishes persistent latent infection in peripheral blood memory B cells, may cause infectious mononucleosis, and is associated with cancers including endemic Burkitt's lymphoma (BL). Although latent EBV transforms B cells in vitro, additional factors including immunocompromised status or, as in endemic BL, a co-infection with the malaria parasite Plasmodium falciparum seem to be required for the development of EBV associated cancers. Toll-like receptors (TLRs) like TLR9 are capable to recognize EBV and launch innate immune responses, which may limit the spread of the virus and may contribute to control outgrowth of latently EBV-infected B cells. On the other hand, EBV may interfere with the expression and functionality of TLR9, thereby manipulating host immune responses towards favoring long-term survival of the virus. Triggering of TLR9 by bacterial, viral or P. falciparum DNA may impact on the proliferation of EBV-infected B cells and on the balance between latent and lytic EBV. Thus, TLR9 signaling in EBV-infected B cells may be beneficial for the host but also for the highly adapted human gammaherpesvirus EBV. PMID- 22201796 TI - Current understanding of usher syndrome type II. AB - Usher syndrome is the most common deafness-blindness caused by genetic mutations. To date, three genes have been identified underlying the most prevalent form of Usher syndrome, the type II form (USH2). The proteins encoded by these genes are demonstrated to form a complex in vivo. This complex is localized mainly at the periciliary membrane complex in photoreceptors and the ankle-link of the stereocilia in hair cells. Many proteins have been found to interact with USH2 proteins in vitro, suggesting that they are potential additional components of this USH2 complex and that the genes encoding these proteins may be the candidate USH2 genes. However, further investigations are critical to establish their existence in the USH2 complex in vivo. Based on the predicted functional domains in USH2 proteins, their cellular localizations in photoreceptors and hair cells, the observed phenotypes in USH2 mutant mice, and the known knowledge about diseases similar to USH2, putative biological functions of the USH2 complex have been proposed. Finally, therapeutic approaches for this group of diseases are now being actively explored. PMID- 22201800 TI - Stat5 assumes distinct functions in mammary gland development and mammary tumor formation. AB - The mammary epithelium comprises luminal and basal cells which originate from multipotent mammary stem cells (MaSCs). They form ductal structures embedded in the mammary fat pad in virgin mice and differentiate during pregnancy into alveoli under the control of hormones and growth factors and the activation of specific transcription factors. Genetic manipulations of embryonic stem cells and the derivation of transgenic mice allowed the study of regulatory genes in mammary epithelial cells of particular differentiation states. We describe an alternative approach to investigate stage dependent gene functions in transgenic mammary glands based on ex vivo, genetically manipulated MaSCs and the reconstitution of functional epithelium upon their transplantation into cleared fat pads. Modification of MaSCs with Stat5 suppressing shRNA or a constitutively active variant of Stat5 showed that Stat5 assumes essential roles in alveolar lineage commitment, proliferation, differentiation and survival. Its persistent activation during post-lactational involution causes the formation of non metastatic adenocarcinomas, resembling the human luminal breast cancer subtype. The tumor cells express estrogen and progesterone receptor (ER+PR+) and activated Stat3 and Stat5. They could become valuable to assess the therapeutic potential of anti-estrogens, aromatase inhibitors and Stat3 and Stat5 inhibition on tumor growth. PMID- 22201801 TI - Genetics of isolated auditory neuropathies. AB - Auditory neuropathies are disorders combining absent or abnormal auditory brainstem responses with preserved otoacoustic emissions and/or cochlear microphonics. These features indicate a normal function of cochlear outer hair cells. Thus, the primary lesion might be located in the inner hair cells, in the auditory nerve or in the intervening synapse. Auditory neuropathy is observed in up to 10 percent of deaf infants and children, either as part of some systemic neurodegenerative diseases or as an isolated entity. Research on the genetic causes of isolated auditory neuropathies has been remarkably successful in the last few years. Here we review the current knowledge on the structure, expression and function of the genes and proteins so far known to be involved in these disorders, as well as the clinical features that are associated with mutations in the different genes. This knowledge is permitting to classify isolated auditory neuropathies into etiologically homogeneous types, so providing clues for the better diagnosis, management and therapy of the affected subjects. PMID- 22201802 TI - The eggshell: structure, composition and mineralization. AB - The calcareous egg is produced by all birds and most reptiles. Current understanding of eggshell formation and mineralization is mainly based on intensive studies of one species - the domesticated chicken Gallus gallus. The majority of constituents of the chicken eggshell have been identified. In this article we review eggshell microstructure and ultrastructure, and the results of recent genomic, transcriptomic and proteomic analyses of the chicken eggshell matrix to draw attention to areas of current uncertainty such as the potential role of amorphous calcium carbonate and the specific nature of the molecules that initiate (nucleate) mammillary cone formation and terminate palisade layer calcification. Comparative avian genomics and proteomics have only recently become possible with the publication of the Taeniopygia guttata (zebra finch) genome. Further rapid progress is highly anticipated with the soon-to-be-released genomes of turkey (Meleagris gallopavo) and duck (Anas platyrhynchos). These resources will allow rapid advances in comparative studies of the organic constituents of avian eggshell and their functional implications. PMID- 22201804 TI - LPS-pretreated bone marrow stem cells as potential treatment for myocardial infraction. AB - The purpose of this study is too investigate the distribution, the number, and the survival time of rat bone marrow mesenchymal stem cells (BMSCs), implanted in rats with myocardial infarction (MI), that were initially pretreated with low dose of LPS. Adult rats were randomly divided into control group, the MI group, 0.1, 1 and 5 mg/kg LPS-pretreated groups. Following the injection of CM-Dil labeled into the mid left anterior descending coronary artery ligation in the left ventricle wall, the number and survival time of red fluorescent labeled BMSCs were determined in the myocardial infarction 48h, 1, 3, and 4 weeks post injection.. In addition, BMSC cell survival and apoptosis as well as the expression of associated proteins were also studied. After 1 week, the number of red fluorescent cells decreased significantly in MI group and 0.1mg/kg LPS groups, and the decrease was more obvious in 5mg/kg LPS group. However, a large number of BMSCs was apparent in 1mg/kg LPS group, the survival of positive cells was higher than MI group (P less than 0.05), part of the transplanted stem cells migrated into the injured area of the myocardial tissue, and in the injury centers more cardiac stem cells were grouped together. Following 3-4 weeks post implantation of BMSCs, fluorescence almost disappeared in MI group , while it was still present and scattered in 1mg/kgLPS. Furthermore, while BMSCs showed low survival rate in the MI group, reduced apoptosis was observed in low-dose LPS groups. PMID- 22201805 TI - Gating and permeation of Orai channels. AB - Ca2+ release-activated Ca2+ channels mediate a sustained Ca2+ influx following depletion of endoplasmic reticulum stores. This signalling cascade that triggers T-cell activation or mast cell degranulation involves STIM1, the Ca2+ sensor in the endoplasmic reticulum, and the Ca2+ selective Orai channel in the plasma membrane. This review describes the molecular mechanism (s) governing the STIM1/Orai signalling machinery. Moreover, we provide an overview on additional proteins modulating or interacting with the STIM1/Orai1 system. A structure function relationship highlights regions within STIM1/Orai proteins contributing to activation, permeation and inactivation of CRAC currents. PMID- 22201803 TI - Alterations in the Smad pathway in human cancers. AB - Members of the TGF-beta superfamily exhibit various biological activities, and perturbations of their signaling are linked to certain clinical disorders including cancer. The role of TGF-beta signaling as a tumor suppressor pathway is best illustrated by the presence of inactivating mutations in genes encoding TGF beta receptors and Smads in human carcinomas. This perspective is further supported by studies of tumor development in mouse models after modulation of receptors and Smads. TGF-beta also controls processes such as cell invasion, immune regulation, and microenvironment alterations that cancer cells may exploit to their advantage for their progression. Consequently, the output of a TGF-beta response is highly situation dependent, across different tissues, and also in cancer in general. Understanding the mechanisms of TGF-beta superfamily signaling is thus important for the development of new ways to treat various types of cancer. This review focuses on recent advances in understanding the Smad dependent TGF-beta pathway as it relates to human carcinogenesis. PMID- 22201806 TI - Mesenchymal stem cells enhance the differentiation of c-kit+ cardiac stem cells. AB - C-kit+ cardiac stem cells (CSCs) were isolated from neonatal rat and tested for the expression of Nkx2.5 and GATA-4 genes which are important in cardiac development. C-kit+ CSCs were plated into the well below the insert of transwell inserts and bone marrow mesenchymal stem cells (BMMSCs) were plated into the inserts. The expression of cardiac Troponin T (cTnT), p27, CDK2, transforming growth factor-beta receptor II (TGF-beta R II), and Smad2 protein in CSCs were tested by western blot. Expression of p27, TGF-beta R II and Smad2 was found to be upregulated in the co-culture group. In contrast, the expression of CDK2 was downregulated. Our results suggest that BMMSCs could promote the differentiation of c-kit+ CSCs, probably through paracrine activity via the TGF-beta signaling pathway. PMID- 22201809 TI - DNA repair mechanisms protect our genome from carcinogenesis. AB - Human cells are constantly exposed to DNA damage. Without repair, damage can result in genetic instability and eventually cancer. The strong association between the lack of DNA damage repair, mutations and cancer is dramatically demonstrated by a number of cancer-prone human syndromes, such as xeroderma pigmentosum (XP), ataxia-telangiectasia (AT) and Fanconi anemia (FA). This review focuses on the historical discoveries related with these three diseases and describes their impact on the understanding of DNA repair mechanisms and the causes of human cancer. As deficiencies in DNA repair are also often related with progeria symptoms, unrepaired damage and aging are somehow related. Several other pathologies associated with DNA repair defects, genetic instability and increased cancer risk are also discussed. In fact, studies with cells from these many syndromes have helped in understanding important levels of protection against cancer and aging, although little help has actually been conferred to the patients in terms of therapy. Finally, the recent advances in combined basic and translational research on DNA repair and chemotherapy are presented. PMID- 22201807 TI - Expressing genes do not forget their LINEs: transposable elements and gene expression. AB - Historically the accumulated mass of mammalian transposable elements (TEs), particularly those located within gene boundaries, was viewed as a genetic burden potentially detrimental to the genomic landscape. This notion has been strengthened by the discovery that transposable sequences can alter the architecture of the transcriptome, not only through insertion, but also long after the integration process is completed. Insertions previously considered harmless are now known to impact the expression of host genes via modification of the transcript quality or quantity, transcriptional interference, or by the control of pathways that affect the mRNA life-cycle. Conversely, several examples of the evolutionary advantageous impact of TEs on the host gene structure that diversified the cellular transcriptome are reported. TE-induced changes in gene expression can be tissue- or disease-specific, raising the possibility that the impact of TE sequences may vary during development, among normal cell types, and between normal and disease-affected tissues. The understanding of the rules and abundance of TE-interference with gene expression is in its infancy, and its contribution to human disease and/or evolution remains largely unexplored. PMID- 22201808 TI - LINEs, SINEs and other retroelements: do birds of a feather flock together? AB - Mobile elements account for almost half of the mass of the human genome. Only the retroelements from the non-LTR (long terminal repeat) retrotransposon family, which include the LINE-1 (L1) and its non-autonomous partners, are currently active and contributing to new insertions. Although these elements seem to share the same basic amplification mechanism, the activity and success of the different types of retroelements varies. For example, Alu-induced mutagenesis is responsible for the majority of the documented instances of human disease induced by insertion of retroelements. Using copy number in mammals as an indicator, some SINEs have been vastly more successful than other retroelements, such as the retropseudogenes and even L1, likely due to differences in post-insertion selection and ability to overcome cellular controls. SINE and LINE integration can be differentially influenced by cellular factors, indicating some differences between in their amplification mechanisms. We focus on the known aspects of this group of retroelements and highlight their similarities and differences that may significantly influence their biological impact. PMID- 22201810 TI - Deer antler innervation and regeneration. AB - Nervous system injuries are a major cause of impairment in the human society. Up to now, clinical approaches have failed to adequately restore function following nervous system damage. The regenerative cycle of deer antlers may provide basic information on mechanisms underlying nervous system regeneration. The present contribution reviews the actual knowledge on the antler innervation and the factors responsible for its regeneration and fast growth. Growing antlers are profusely innervated by sensory fibers from the trigeminal nerve, which regenerate every year reaching elongation rates up to 2 cm a day. Antler nerves grow through the velvet in close association to blood vessels. This environment is rich in growth promoting molecules capable of inducing and guiding neurite outgrowth of rat sensory neurons in vitro. Conversely, endocrine regulation failed to show effects on neurite outgrowth in vitro, in spite of including hormones of known promoting effects on axon growth. Additional studies are needed to analyze unexplored factors promoting on growth in antlers such as electric potentials or mechanical stretch, as well as on the survival of antler innervating neurons. PMID- 22201811 TI - Diverse functions of nuclear non-coding RNAs in eukaryotic gene expression. AB - Recent genome-wide analyses revealed that eukaryotic genomes are almost entirely transcribed, generating a large number of short or long non-protein coding RNAs (non-coding RNAs; ncRNAs). Rapidly accumulating experimental evidence suggests that ncRNAs are not just transcriptional noise, but have biological roles in gene expression. In this review, we focus on the functions of nuclear-localized ncRNAs including the spliceosomal small nuclear RNAs. These nuclear ncRNAs play diverse regulatory roles in a wide-range of nuclear reactions, such as transcription, precursor-mRNA (pre-mRNA) splicing, nuclear structure formation, nuclear trafficking, and chromatin remodeling. The regulatory functions of ncRNAs in these reactions are reinforced by target-site recognition through base-pairing or formation of an RNA/DNA triple helix. Recent studies revealed an unexpected linkage between the machineries for RNA interference (RNAi)-mediated gene silencing and pre-mRNA splicing. In addition, the biogenesis of some ncRNAs was found to overlap with the pathway of pre-mRNA splicing. Our understanding of the mechanisms of coordinated gene regulation in the nucleus has increased dramatically through studies on nuclear ncRNAs. A new paradigm of "ncRNA regulation" is now emerging. PMID- 22201812 TI - Molecular mechanisms of natural killer cell regulation. AB - Natural Killer (NK) cells are important for early immune reactions against viral infections and cancer. They are regulated by a highly redundant system of different activating and inhibitory receptors. Here we summarize our current understanding about the regulation of these cells and describe how mathematical modeling and systems biology approaches can help to shed some light on the complex regulatory network that governs NK cell reactivity. PMID- 22201814 TI - Anti-apoptotic effects of melatonin in retinal pigment epithelial cells. AB - Recent studies have revealed that melatonin exerts strong anti-apoptotic effects. Retina secretes melatonin, and melatonin receptors are distributed in almost all the layers of retina, including the layer of retinal pigment epithelial (RPE) cells. However, it is not known whether melatonin inhibits apoptosis through its anti-oxidant effects and how it works in RPE cells. Here, we show that melatonin decreases H2O2-induced apoptosis in RPE cells partially through protection of mitochondria. Melatonin decreased reactive oxygen species in mitochondria and mitochondrial DNA damage, alleviated structural damage and inhibited cytochrome C release. PMID- 22201813 TI - The natural history of ubiquitin and ubiquitin-related domains. AB - The ubiquitin (Ub) system is centered on conjugation and deconjugation of Ub and Ub-like (Ubls) proteins by a system of ligases and peptidases, respectively. Ub/Ubls contain the beta-grasp fold, also found in numerous proteins with biochemically distinct roles unrelated to the conventional Ub-system. The beta-GF underwent an early radiation spawning at least seven clades prior to the divergence of extant organisms from their last universal common ancestor, first emerging in the context of translation-related RNA-interactions and subsequently exploding to occupy various functional niches. Most beta-GF diversification occurred in prokaryotes, with the Ubl clade showing dramatic expansion in the eukaryotes. Diversification of Ubl families in eukaryotes played a major role in emergence of characteristic eukaryotic cellular sub-structures and systems. Recent comparative genomics studies indicate precursors of the eukaryotic Ub system emerged in prokaryotes. The simplest of these combine an Ubl and an E1 like enzyme in metabolic pathways. Sampylation in archaea and Urmylation in eukaryotes appear to represent recruitment of such systems as simple protein tagging apparatuses. However, other prokaryotic systems incorporated further components and mirror the eukaryotic condition in possessing an E2, a RING-type E3 or both of these components. Additionally, prokaryotes have evolved conjugation systems independent of Ub ligases, such as the Pup system. PMID- 22201815 TI - Genomic instability of surgical sample and cancer-initiating cell lines from human glioblastoma. AB - Glioblastoma multiforme (GBM) is the most aggressive brain tumor in the adult human, with an average survival of 16 months. A small population of cells within the GBM termed cancer-initiating cells is responsible for the initiation and maintenance of the tumor mass. The traditional glioblastoma cancer cells, grown with serum containing media, display increased rate of genomic instability events, which in turn renders the cell cultures with little resembling to the original tumor, making doubtful their use as preclinical models for screening therapeutic agents. On the contrary, the cancer-initiating cells grown in serum free media seems to show lower rate of genomic instability processes. However, considering the diversity of genetic and/or epigenetic background, we will need to evaluate the possibility of using different culture conditions to allow for the isolation and culture of such cancer-initiating cells diversity, keeping, at the same time, the genomic instability rate as the original tumor. We summarized the main genetic and epigenetic mechanisms that are driving genomic instability in cancer-initiating cells from human glioblastoma. PMID- 22201818 TI - Update on the epidermal differentiation complex. AB - On human chromosome 1q21, a 2-Mb region called the epidermal differentiation complex comprises many genes encoding structural and regulatory proteins that are of crucial importance for keratinocyte differentiation and stratum corneum properties. Apart from those for involucrin and loricrin, most of the genes are organized in four families: the genes encoding EF-hand calcium-binding proteins of the S100A family, the genes encoding the small proline rich proteins (SPRRs) and the late cornified envelope (LCE) proteins, two families of cornified cell envelope components, and the genes encoding the S100-fused type proteins (SFTPs). This review focuses on the SPRRs, LCE proteins and SFTPs. It describes their structures, their specific functions and, when known, the mechanisms involved in the regulation of their expression. It also highlights their possible involvement in skin diseases. PMID- 22201819 TI - Cardiac tissue engineering: current state and perspectives. AB - The goal of cardiac tissue engineering is to treat cardiovascular diseases through the implantation of engineered functional tissue replacements or the injection of cells and biomaterials, as well as to provide engineered cardiac constructs that can be used as an in vitro model of healthy or diseased heart tissues. This field is rapidly advancing with the new discoveries and improvements in stem cell technologies, materials science, and bioreactor design. In this review, some of the progress made in cardiac tissue engineering in the recent years, as well as the challenges that need to be overcome in future studies, will be discussed. The topics include the advances in engineering stem cell-derived cardiac tissues, the use of natural or synthetic polymers and decellularized organs as engineering scaffolds, the scaffold-free cell sheet engineering approach, the application of perfusion and mechanical or electrical stimulation in bioreactors, the organization of cardiac cells through microfabrication techniques, and the vascularization of engineered cardiac tissues in vitro and in vivo. PMID- 22201816 TI - Regulation of the Wip1 phosphatase and its effects on the stress response. AB - Wip1 (PPM1D) is a stress responsive PP2C phosphatase that plays a key role in stress signaling. Although originally identified as a gene induced by p53 after genotoxic stress, we now know that Wip1 expression is additionally regulated by other mechanisms. Wip1 is not only a target of p53, but is also a target of other transcription factors, including Estrogen Receptor-alpha and NF-kappaB. Additionally, Wip1 expression is regulated by post-transcriptional mechanisms such as mRNA stabilization and alternative splicing. Upon induction, Wip1 dampens the stress response by dephosphorylating and inactivating proteins such as p53, p38 MAPK, and ATM, usually as part of a negative feedback loop. As a result, Wip1 functions to abrogate cell cycle checkpoints and inhibit senescence, apoptosis, DNA repair, and the production of inflammatory cytokines. Furthermore, Wip1 is overexpressed in several types of human cancers and has oncogenic functions. The regulation of Wip1, the role of Wip1 in stress signaling, and the cooperation of Wip1 with oncogenes in promoting tumorigenesis will be discussed in this review. PMID- 22201820 TI - The osteon: the micromechanical unit of compact bone. AB - The research techniques available for investigation of secondary osteons in human bone enable establishment of their biological composition and quantification of their mechanical properties. Further, the data generated through current research techniques facilitate studies on the significance of osteons in normal and pathological conditions, including via multi-scale modeling conducted with a view of building realistic models of virtual bone, suitable for applications from orthopaedic challenges to endocrine disorders. The understanding of the biomechanical function of the osteon requires clarification of the molecular cellular processes that form, maintain and remodel the osteon and affect the mechanical function. In turn, the mechanical function affects the biology of the osteon. In retrospective, the investigation of osteons has focused on the unraveling of the complex combination of elementary components to discern the major factors that define the mechanical behavior. The micro-structural environment that leads to macroscopic fracture remains unclear. Arrangement, distribution and quality of the elementary components may participate in fracture risk. The latest results underline the fundamental role of the orientation of collagen type I and of carbonated hydroxyapatite crystallites. PMID- 22201817 TI - Differential impact of Toll-like receptor signaling on distinct B cell subpopulations. AB - B cells exhibit a range of functional responses following TLR engagement including immunoglobulin and cytokine production, proliferation, antigen presentation and migration. However, B cell intrinsic TLR responses appear to be precisely programmed based upon the developmental stage of the cell. B cell subpopulations classified as innate immune cells including marginal zone and B-1 B cells exhibit robust responses to TLR stimulation. In contrast, activation of other B cell subsets is constrained via a variety of developmentally regulated events. In this review we provide an overview of TLR responses in murine and human B cells and specifically highlight patterns of TLR expression and developmentally regulated functional responses. PMID- 22201821 TI - Immunogenic epitopes of Hantaviruses' N protein are restricted to conserved regions. AB - The Bunyaviridae virus family is composed by five genera, of which the Hantavirus genus is one of the most important representatives. Occasionally, these viruses can be transmitted to humans, giving rise to severe diseases that present high mortality rates. We analyzed the amino acid sequences of the nucleocapsid (N) proteins of 34 different hantaviruses to investigate the potential mechanisms involved in immunogenicity against hantaviruses. Immunogenic epitopes described in the literature through experimental analyses for Sin Nombre (SNV), Puumala (PUUV), and Hantaan (HTNV) viruses' species were retrieved. We identified and characterized the regions believed to be responsible for the induction of immune response in hosts. We found that N protein epitopes described in the literature for PUUV, SNV and HTNV viruses are all located in highly conserved regions of the protein. The high conservation of these regions suggests that a cross-reactive immune response among different hantaviruses can be induced. PMID- 22201822 TI - SNCG gene silencing in gallbladder cancer cells inhibits key tumorigenic activities. AB - We recently determined that synuclein-gamma (SNCG) is highly expressed in human gallbladder cancer (GBC), and its abnormal expression is associated with tumor aggressiveness. To investigate the effects of SNCG gene silencing on the tumorigenic profiles of the GBC cell line, NOZ, short-hairpin RNA (shRNA) interference was employed. Specifically, the SNCG transcript was targeted by SNCG shRNA lentiviral particles designed to silence SNCG gene expression. Following selection of NOZ cells stably expressing SNCG-shRNA, SNCG expression was examined by western blot and semi-quantitative RT-PCR analyses. Phenotypic hallmarks of gallbladder carcinogenesis were assayed by CCK-8, soft agar (colony formation), modified Boyden-Chamber (invasion), and flow cytometry (cell-cycle and apoptosis) assays. Our results showed that SNCG gene silencing in NOZ cells inhibited cell growth, colony formation, and invasion. In addition, it directly increased the effectiveness of paclitaxel in inducing G2/M cell-cycle arrest and cell apoptosis. Data from our in vivo study showed a decrease in tumor growth and weight in mice injected with SNCG-silenced NOZ cells. Together, these findings suggest that SNCG plays an important role in the progression of GBC. PMID- 22201823 TI - CD proteome and beyond - technologies for targeting the immune cell surfaceome. AB - Communication between cells of the immune system and the organism is dependent on information processing mediated by proteins of the cell surface. The cell surface proteome consists of a group of functionally diverse proteins, which not only enables but also limits the interaction capacities of cells within their particular microenvironment. Although these proteins represent a highly important proteome for immunological research, most routinely used technologies for their detection only allow for a fragmented view of the ensemble of cell surface located proteins. A major bottleneck is the limited availability of high quality antibodies against cell surface protein targets that altogether impedes a Systems Biology view on the cell surface proteome (surfaceome) and its concerted functions during signal processing. Recent developments in mass spectrometry based technologies enable now complementary approaches for the qualitative and quantitative analysis of the surfaceome. Here, we highlight recent progress in the field towards the identification and quantification of the surfaceome as an important subproteome forming the information gateway of the cell. PMID- 22201824 TI - Permeation and gating mechanisms in store-operated CRAC channels. AB - Ca2+ is a ubiquitous signaling messenger mediating many essential cellular functions such as excitability, exocytosis and transcription. Among the different pathways by which cellular Ca2+ signals are generated, the entry of Ca2+ through store-operated Ca2+ release-activated Ca2+ (CRAC) channels has emerged as a widespread mechanism for regulating Ca2+ signaling in many eukaryotic cells. CRAC channels are implicated in the physiology and pathophysiology of numerous cell types, underlie several disease processes including a severe combined immunodeficiency syndrome, and have emerged as major targets for drug development. Although little was known of the molecular mechanisms of CRAC channels for several decades, the discovery of Orai1 as a prototypic CRAC channel pore-subunit, and the identification of STIM1 as the ER Ca2+ sensor, have led to rapid progress in our understanding of many aspects of CRAC channel behavior. This review examines the molecular features of the STIM and Orai proteins that regulate the activation and conduction mechanisms of CRAC channels. PMID- 22201825 TI - Suppressor of cytokine signaling proteins as regulators of innate immune signaling. AB - The innate immune system builds up the body's first line of defense against invading pathogenic microorganisms. For effective defense of pathogenic invaders, a structured inflammatory reaction has to be initiated that is strongly dependent on cell-to-cell communication. Inflammation in turn is a potentially autodestructive reaction that is tightly controlled to balance antimicrobial activity and host damage. Suppressor of cytokine signaling (SOCS) proteins have been identified as crucial negative regulators of various hematopoietic cytokines employing Janus kinas (JAK) and signal transducer and activator of transcription (STAT) signaling. Further results now imply that also signaling by pattern recognition receptors (PRR) of the innate immune system that use a distinct signaling cascade induce and get regulated by SOCS proteins. Thus, SOCS proteins not only modulate cell communication through JAK/STAT dependent cytokines but also regulate signaling by pattern recognition receptors including the Toll-like receptors (TLRs). A model is presented that integrates the current, partly conflicting, data on the role of SOCS proteins in innate immunity's NFkappaB signaling. PMID- 22201826 TI - The role of diet in gastric cancer: still an open question. AB - The risk of gastric cancer is often related to lifestyle and diet. There have been several studies on correlation between Nutrition and the risk of gastric cancer with different and sometimes contradictory results. Here we reviewed the role of nutrition as risk/protective factor in the development of gastric cancer. PMID- 22201827 TI - Cross-reactivity of autoreactive T cells with MBP and viral antigens in patients with MS. AB - In this study, we detected the viral DNA of Human Herpes Virus 6 (HHV-6) in the sera and cell-free cerebrospinal fluid (CSF) of Chinese multiple sclerosis (MS) patients. The results revealed that the copy numbers of serum HHV-6 viral DNA were higher in MS than in normal subjects (NS) or in other neurologic diseases (OND). We also found that in the MS subjects, most T cells recognizing myelin basic protein (MBP) were cross-reactive and could be activated by a synthetic peptide corresponding to residues of HHV-6 or EBV. The estimated precursor frequency of these cross-reactive T cells recognizing both peptides, MBP and HHV 6 or EBV, was significantly elevated in MS compared with that in controls. More significant was the presence of CD8+ cytotoxic cross-reactive T cells, as they could directly induce injury to oligodendrocytes that are known to express both MBP and MHC class I molecules. The study provides important evidence for understanding the potential role of HHV-6 or EBV infection in the pathogenesis of MS. PMID- 22201828 TI - iPSCs are transcriptionally and post-transcriptionally indistinguishable from fESCs. AB - Induced pluripotent stem cells (iPSCs) are generated by reprogramming mouse or human somatic cells to a pluripotent state by introducing key transcription factors and have great therapeutic potential. It has been illustrated that the transcriptional and post-transcriptional profiles of nuclear-transferred embryonic stem cells (ntESCs) is identical to those of embryonic stem cells derived from fertilized blastocysts (fESCs). Although iPSCs seem to be indistinguishable from fESCs, the degree of transcriptomic and proteomic similarity among iPSCs, ntESCs, and fESCs has not yet been elucidated completely. To investigate whether iPSCs and fESCs have similar therapeutic potential, we compared mRNA and protein pro?les of mouse iPSC, ntESCs, and matching fESCs lines using microarray technology, iTRAQ method, and bioinformatic analyses. Real-time PCR, two-dimensional LC, and MS/MS analyses were further conducted to study the expression of speci?c transcripts and identify and quantitate 929 proteins. Our results demonstrate that, like ntESCs, the iPSC and matching fESCs lines have very similar transcriptional and protein expression profiles. This is consistent with their similar developmental potential. PMID- 22201829 TI - Functions of p120ctn isoforms in cell-cell adhesion and intracellular signaling. AB - The functions of many organs depend on the generation of an epithelium. The transition from a set of loosely connected nonpolarized cells to organized sheets of closely associated polarized epithelial cells requires the assembly of specialized cell junctions. In vertebrates, three major types of junctions are responsible for epithelial integrity: adherens junctions, tight junctions, and desmosomes. p120 catenin (p120ctn) is an Armadillo family member and a component of the cadherin-catenin complex in the adherens junction. It fulfils pleiotropic functions according to its subcellular localization: modulating the turnover rate of membrane-bound cadherins, regulating the activation of small RhoGTPases in the cytoplasm, and modulating nuclear transcription. Over the last two decades, knowledge of p120ctn obtained from in vitro experiments has been confirmed and extended by using different animal models. It has become clear that p120ctn is essential for normal development and homeostasis, at least in frog and mammals. p120ctn is a Src substrate that can be phosphorylated at different tyrosine, serine and threonine residues and can dock various kinases and phosphatases. Thereby, p120ctn regulates the phosphorylation status and the junctional stability of the cadherin-catenin complex. Multiple p120ctn isoforms are generated by alternative splicing, which allows the translation to be initiated from four start codons and enables the inclusion of four alternatively used exons. We will discuss the effects of different p120ctn isoforms on cadherin turnover and intracellular signaling, in particular RhoGTPase activity and phosphorylation events. PMID- 22201830 TI - Developmental and environmental regulatory pathways in alpha-proteobacteria. AB - Spatial and temporal control of cell differentiation and morphogenesis plays a key role in prokaryotes as well as eukaryotes. This is particularly important for bacteria that divide asymmetrically, as they generate two morphologically and functionally distinct daughter cells. Several alpha-proteobacteria, including the aquatic, free-living Caulobacter crescentus, the symbiotic rhizobia and the plant and animal pathogens Agrobacterium and Brucella, have been shown to undergo asymmetrical division. C. crescentus has become a model system for the study of the regulatory networks, in particular the control of the cell cycle, the cytokinetic machinery, the cytoskeleton and the functions required for duplication and differentiation in general. As the bulk of these regulatory networks and functions is conserved in most alpha-proteobacteria, we recapitulate the recent advances in understanding these spatially and temporally controlled processes, focusing on cell cycle progression, DNA replication and partitioning, cell division and regulation of specific phenotypes that vary during the cell cycle or in the case of different lifestyles (like extracellular polysaccharide production) in C. crescentus and other alpha-proteobacteria. PMID- 22201831 TI - The role of shelterin in maintaining telomere integrity. AB - The ends of eukaryotic chromosomes need to be protected from detection as DNA double strand breaks by the DNA damage response pathways. Failure to do so would have devastating consequences for genome integrity. Packaging of chromosome ends into protective structures called telomeres prevents checkpoint activation and DNA repair/recombination activities. Several studies on a variety of organisms have revealed that protein complexes with specificity for telomeric DNA protect chromosome ends from being recognized as DNA double-strand breaks and regulate telomere maintenance by the telomerase. In this review, we will discuss the consequences of telomere dysfunction and our understanding of how telomere integrity is maintained. PMID- 22201832 TI - Architectural roles of long noncoding RNAs in the intranuclear formation of functional paraspeckles. AB - The eukaryotic nucleus is highly compartmentalized, and this structural complexity allows the regulation of complex gene expression pathways. Some of the subnuclear structures called nuclear bodies are known to contain RNAs. Recently multiple noncoding RNAs (ncRNAs) have been identified as products from regions covering large portions of mammalian genomes. Several abundant ncRNAs were found to localize in nuclear bodies, suggesting new roles for ncRNAs in these nuclear bodies. Paraspeckle, one of these nuclear bodies, contains specific ncRNAs, termed MEN (Multiple Endocrine Neoplasia) epsilon/beta ncRNAs, and characteristic RNA-binding proteins. Paraspeckle is ubiquitously observed in cultured cell lines but is cell type-specific in mouse tissues. Paraspeckle reportedly plays an important role in the nuclear retention of inosine-containing mRNAs and is regulated under stress conditions. Intriguingly, MEN epsilon/beta ncRNAs are prerequisite for the formation of paraspeckles, indicating architectural roles for these ncRNAs and, presumably, significant roles in the nuclear retention of mRNAs as well. This review focuses on known aspects of the paraspeckle structure and its components, and we attempt here to construct a model of the ncRNA dependent formation of nuclear body structures. PMID- 22201833 TI - Nanotechnology in stem cells research: advances and applications. AB - Human beings suffer from a myriad of disorders caused by biochemical or biophysical alteration of physiological systems leading to organ failure. For a number of these conditions, stem cells and their enormous reparative potential may be the last hope for restoring function to these failing organ or tissue systems. To harness the potential of stem cells for biotherapeutic applications, we need to work at the size scale of molecules and processes that govern stem cells fate. Nanotechnology provides us with such capacity. Therefore, effective amalgamation of nanotechnology and stem cells - medical nanoscience or nanomedicine - offers immense benefits to the human race. The aim of this paper is to discuss the role and importance of nanotechnology in stem cell research by focusing on several important areas such as stem cell visualization and imaging, genetic modifications and reprogramming by gene delivery systems, creating stem cell niche, and similar therapeutic applications. PMID- 22201834 TI - Hyperglycemia as a mechanism of pancreatic cancer metastasis. AB - As a vital step in the progression of cancer, metastasis poses the largest problem in cancer treatment and is the main cause of death of cancer patients. In pancreatic cancer, almost 80% of patients have locally deteriorated or metastatic disease and thus are not appropriate for resection at the time of diagnosis. Due to the high rate of incidence and mortality, it is crucial to study the molecular mechanisms of metastasis to clarify therapeutic targets to hinder the spread of cancer. Diabetes mellitus has long been considered a potential risk factor for pancreatic cancer. In this review, we comprehensively describe the role of hyperglycemia in governing critical steps of the metastatic process. In particular, we focus on the hyperglycemia-dependent aspects of the Epithelial Mesenchymal Transition (EMT) and vascular dysfunction. Furthermore, we discuss how hyperglycemia-related production of reactive oxygen species (ROS) may play an important role in these two processes. A deep understanding of metastasis mechanisms will identify novel targets for therapeutic intervention. PMID- 22201835 TI - RHAMM and CD44 peptides-analytic tools and potential drugs. AB - CD44 and RHAMM are two extracellar matrix receptors whose principle ligand is the polysaccharide hyaluronan (HA). Both proteins are involved in wound repair and their aberrant regulation contributes to a variety of diseases including arthritis and cancer. Over the past decade, a number of peptide-based therapeutics that block the binding of CD44 or RHAMM-specific ligands have been developed and tested in experimental models of disease. Here, we review the structure of each of these proteins, the functions they control and the mechanisms, including their interactions with each other, responsible for these functions. We also review the development of peptide mimics that block the key functions of CD44 and RHAMM and their use in experimental models of disease. PMID- 22201836 TI - DC-SIGN modulates DC maturation and function in rat renal tubulointerstitial lesions. AB - The role of DC-SIGN in tubulointerstitial lesions (TILs) and the effect of anti-P selectin lectin-EGF domain monoclonal antibody (PsL-EGFmAb) were investigated in rat nephrotoxic nephritis (NTN). On Day 4, immature DC-SIGN+DCs infiltrated into renal tubulointerstitium and matured by Day 14, showing increased migratory capacity and ability to induce T cell proliferation. The distribution of DC-SIGN+ DC significantly correlated with crescent formation, TIL severity, and changes in renal function. RANTES and TNF-alpha mRNA were continuously up-regulated from Day 4, while IL-10 mRNA was down-regulated after a marked increase on Day 4. Expression of IFN-gamma and IL-4 mRNA increased on Day 14 due to DC maturation. PsL-EGFmAb suppressed DC maturation, migration and ability to activate T cells. It also down-regulated TNF-alpha and up-regulated IL-10, resulting in a Th1/Th2 bias. The number of crescents decreased and TILs and renal function improved. These results suggest that DC-SIGN mediates DC tubulointerstitial infiltration and is an important regulator of local immune reactions and TILs. PsL-EGFmAb inhibited DC migration, maturation and function by targeting DC-SIGN, and may therefore be a potential treatment for NTN. PMID- 22201837 TI - Processing-independent analysis of peptide hormones and prohormones in plasma. AB - Peptide hormones are post-translationally matured before they reach a structure in which they can fulfill their biological functions. The prohormone processing may encompass a variety of endoproteolytic cleavages, N- and C-terminal trimmings, and amino acid derivatizations. The same prohormone can be variably processed in different cell types and, in addition, diseased cells often change the processing of a given precursor. The translational process is often either increased or decreased in diseased cells, which renders the ensuing modifications of the prohormone incomplete. Consequently, a variable mixture of precursors and processing-intermediates accumulates in plasma. In order to exploit disturbed posttranslational processing for diagnostic use and at the same time provide an accurate measure of the translational product, a simple analytical principle named "processing-independent analysis" (PIA) was designed. PIA-methods quantitate the total mRNA product irrespective of the degree of processing. PIA methods have now been developed for a number of prohormones and proteins, and their diagnostic potential appears promising in diagnosis of cardiovascular disease and in several malignancies. PMID- 22201839 TI - Proline metabolism and cancer. AB - Proline plays a special role in cancer metabolism. Proline oxidase (POX), a.k.a. proline dehydrogenase (PRODH), is among a few genes induced rapidly and robustly by P53, the tumor suppressor. Ectopic expression of POX under control of tet-off promoter initiated mitochondrial apoptosis. The mechanism activated by POX is mediated by its production of ROS. In immunodeficient mice, POX overexpression markedly retarded growth of xenograft tumors. In human tumors of the digestive tract and kidney, POX was markedly decreased, suggesting that the suppressive effect of POX was downregulated. This was not due to POX gene mutations or hypermethylation. Instead, a microRNA, miR-23b*, expressed at high levels in tumors, was a potent inhibitor of POX expression. Furthermore, antagomirs of miR 23b* reversed the downregulated expression of POX and its tumor-suppressive effect, thereby providing a therapeutic strategy. POX not only responds to genotoxic stress, but also to inflammatory and metabolic stress. Depending on microenvironmental and temporal factors, POX can mediate oppositely-directed responses-programmed cell death, on the one hand, and survival, on the other. PMID- 22201840 TI - Sequence variations affecting AU-rich element function and disease. AB - Adenylate-uridylate rich elements (AREs) in the 3'UTRs of many transiently expressed genes regulate mRNA instability and translation. Such ARE-genes are involved in vital biological processes like cellular growth, differentiation, and immunity. Defects in their expression contribute to a variety of disease conditions like cancer, autoimmune diseases, diabetes, and cardiovascular and chronic inflammatory diseases. Over the past two decades, considerable progress has been made in understanding the mode of regulation of AREs containing mRNAs by RNA-binding proteins, miRNAs, and signaling pathways. This review focuses on the less documented sequence variation affecting ARE functions and its relation to disease. We discuss reports describing genetic polymorphisms, alternative polyadenylation, and alternative splicing that can lead to the loss or gain of function of AREs, often with significant implications to disease. PMID- 22201838 TI - PPAR gamma, bioactive lipids, and cancer progression. AB - In this article we review the evolution of cancer research involving PPARgamma, including mechanisms, target genes, and clinical applications. For the last thirteen years, the effects of PPARgamma activity on tumor biology have been studied intensely. Most of this research has focused upon the potential for employing agonists of this nuclear receptor in cancer treatment. As a monotherapy such agonists have shown little success in clinical trials, while they have shown promise as components of combination treatments both in culture and in animal models. Other investigations have explored a possible role for PPARgamma as a tumor suppressor, and as an inducer of differentiation of cancer stem cells. Whereas early studies have yielded variable conclusions regarding the prevalence of PPARgamma mutations in cancer, the protein level of this receptor has been more recently identified as a significant prognostic marker. We predict that indicators of PPARgamma activity may also serve as predictive markers for tailoring treatments. PMID- 22201841 TI - Antimycobacterials from natural sources: ancient times, antibiotic era and novel scaffolds. AB - Mycobacteria are a group of aerobic, non-motile, acid fast bacteria that have a characteristic cell wall composed of a mycolyl-arabinogalactan-peptidoglycan complex. They display different phenotypic attributes in their growth, color and biochemistry. Tuberculosis (TB) is defined as the infection with Mycobacterium tuberculosis complex and was declared a global health emergency principally because of the appearance of multidrug-resistant strains and the associated risk of infection in immune-compromised population. There is an urgent clinical need for novel, potent and safe anti-TB drugs. Natural products have been used since antiquity for treating diverse complaints and novel pharmacophores are discovered every year. Two of the most potent used antimycobacterials, the rifamycins and streptomycin, were first detected in Streptomyces bacteria. Plants are also the source of an exquisite variety of antimicrobials that can lead to useful therapeutics in the future. In this review, natural preparations used since antiquity for treating tuberculosis are described, together with a rapid view of the 20th century antibiotic development against TB. Finally a summary of the most potent recent natural antimycobacterials is displayed. PMID- 22201842 TI - Effects of hypothermia on brain injury induced by status epilepticus. AB - We investigated the neuroprotective efficacy of hypothermia after status epilepticus (SE) in immature rats. In addition, the expression levels of NMDAR1 and c-Jun were measured to establish a possible signaling mechanism for hypothermia-induced neuroprotection. Pilocarpine-treated rats were randomly divided into 2 groups: group D (diazepam) and group DH (diazepam plus hypothermia). Compared to the control (group NS) rats, Pilocarpine-induced SE significantly enhanced the expression of NMDAR1 and c-Jun in the hippocampus, and also significantly increased the numbers of necrotic and apoptotic pyramidal neurons. The DH group exhibited significantly fewer necrotic and apoptotic hippocampal pyramidal neurons and reduced NMDAR1 expression than group D. In contrast, early expression of c-Jun was significantly higher in the hippocampi of hypothermia-treated rats than in the hippocampi of group D, while late c-Jun expression was significantly lesser than group D. Our results show mild post ictal hypothermia partially rescues neuronal cell death in the hippocampus following SE. We further suggest that elevated NMDAR1 expression exacerbates SE induced neuronal death in pilocarpine-treated rats, while early c-Jun overexpression, concomitant with hypothermia, suppresses subsequent neuronal death. PMID- 22201843 TI - Acidic bone matrix proteins and their roles in calcification. AB - Mammalian bones are composed of calcium phosphate crystals in a protein matrix. The major form of the calcium phosphate is hydroxyapatite. The most abundant matrix protein in bone is type I collagen. Collagen contributes to the mechanical properties of bone and is necessary for calcification of the tissue. In addition to collagen, several acidic proteins are present as minor components. Osteocalcin is a gamma-carboxyglutamic acid-containing protein of bone, which has an affinity to hydroxyapatite and can prevent crystal growth. Bone sialoprotein (BSP) and osteopontin are acidic glycophosphoproteins of bone. These proteins have RGD cell attachment sequences and consecutive sequences of acidic amino acids. The poly glutamic acid sequences of BSP act as possible nucleation sites for hydroxyapatite crystals. Dentin phosphoprotein is the major non-collagenous protein of dentin. This protein has (Asp-Ser-Ser) repeat sequences, in which most of the Ser residues are phosphorylated. Some of these acidic matrix proteins are immobilized on the collagen fibrils and induce nucleation of hydroxyapatite crystals. They can also modulate crystal shape by adsorption on a specific face of the crystals. PMID- 22201844 TI - Immune and non-immune functions of the immunoproteasome. AB - The biological importance of the ubiquitin-proteasome system in the control of myriad cellular processes has been well-recognized; however, the pathophysiological significance of the immunoproteasome, the inducible form of the proteasome, has not been well-comprehended until lately. The primary function of the immunoproteasome was originally believed to improve MHC-I antigen presentation. It now becomes evident that the immunoproteasome possesses broader biological functions. It regulates proinflammatory cytokine production, and T cell differentiation and proliferation. Alongside immune functions, the immunoproteasome has been demonstrated to relieve oxidative stress by the efficient turnover of oxidatively-damaged proteins and by allaying the formation of harmful protein aggregates. Furthermore, it has been implicated to regulate tumor cell growth and control muscle mass. Finally, the immunoproteasome has recently drawn considerable attention as a potential novel therapeutic target for cancer and autoimmune disease. This review will give an overview of the structure and function of the immunoproteasome, highlight its functional diversity in both immune and non-immune responses, and discuss the relationship between the dysregulation of the immunoproteasome and the development of several human diseases. PMID- 22201845 TI - Nuclear receptor control of opposing macrophage phenotypes in cardiovascular disease. AB - Macrophages have important physiological roles and display a high degree of heterogeneous phenotypes in response to a variety of stimuli. In particular, the spectrum of alternatively activated macrophages has been a focus because many lines of evidence indicate a cardioprotective role for this macrophage phenotype. This phenotype is controlled in part by opposing nuclear transcription factors including the PPARs that stimulate alternative activation and the recently recognized role of the mineralocorticoid receptor in stimulating classically activated macrophages. This review highlights some of the recent findings involving alternatively activated macrophages and these nuclear receptors in cardiovascular disease. PMID- 22201846 TI - Application of cell-free expression of GFP for evaluation of microsystems. AB - Coupled cell-free transcription-translation (CFTT) of green fluorescent protein (GFP) has been applied as a reporter system to microfluidic chip-related technologies. In polymerase chain reaction (PCR)-based biomolecular logic gate system, in which addition of primer set and amplification of PCR product represent input and output signal respectively, GFP gene was inserted in the template DNA, which was then amplified, transcribed and translated to GFP. The green fluorescence reported as if the amplification has occurred or not, that is, the fluorescence reports positive output signal. CFTT of GFP was also adopted to evaluate on-chip capillary electrophoresis (CE)-based DNA fractionation, which was developed to isolate single DNA species from reaction mixture of DNA ligase catalyzed DNA-assembly. As a model system, GFP gene was inserted in the target DNA fragment. The collected fraction was amplified with PCR and subjected to a CFTT system, and green fluorescence was observed showing that the fractionation was successful. These results showed that CFTT of GFP is a useful tool to verify, estimate, and monitor microfluidic chip-related technologies in which cell-free protein synthesis is involved. PMID- 22201847 TI - Preclinical studies with synthetic peptides in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that causes multi-organ damage and significant morbidity and mortality. Various efforts have been made to modulate the imbalanced immune responses in this disease. The manipulation of the immune system through the use of soluble synthetic peptides serving as antigenic epitopes, in repeated doses, has been shown to induce immune tolerance and to reduce the clinical manifestations of the disease in murine models. Although clinical trials in humans with the anti-DNA Ig peptide hCDR1 have failed, recent results from a clinical trial with another peptide, p140, have shown promise. This review provides an overview on the preclinical and translational work with synthetic peptides in SLE. PMID- 22201849 TI - Innovative approaches in the embryonic stem cell test (EST). AB - The embryonic stem cell test (EST) is a high-throughput in vitro screening assay for developmental toxicity free of animal use. The EST uses the ability of murine embryonic stem cells to differentiate into the mesodermal cardiac lineage in combination with two cytotoxicity test systems. Validation of the EST showed that the test system is very promising as an alternative method to animal testing, however to optimize predictability and increase knowledge on the applicability domain of the EST, improvements to the method were proposed and studied. In this review we discuss the first definition of the EST followed by the innovative approaches which have been proposed to increase the predictivity of the EST, including implementation of molecular endpoints in the EST, such as omics technologies and the addition of alternative differentiation models to the testing paradigm, such as neural and osteoblast differentiation and the use of human stem cells. These efforts to improve the EST increase the value of embryonic stem cells used as in vitro systems to predict developmental toxicity. PMID- 22201848 TI - Soluble E-cadherin: more than a symptom of disease. AB - Epithelial (E)-cadherin is a homophilic adhesion molecule which is responsible for maintenance of baso-lateral cell adhesion and polarity. E-cadherin can be lost from the cell surface by proteolytic cleavage, resulting in the generation of an 80kDa fragment referred to a soluble E-cadherin (sE-cad). Although originally discovered in the conditioned media of breast cancer cells and later verified in the fluids of cancer patients, today sE-cad has been reported in patients with viral and bacterial infections, organ failure, and benign disease. The proteases implicated in this cleavage event include members of the disintegrin family (ADAM10 and 15), bacterial proteases (gingipains and BFT), cathepsins (B, L, S), matrix metalloproteases (MMP-2, 3, 7, 9, and 14), Kallikrein-7 (KLK7), and plasmin. Stimulus that induces sE-cad generation by ADAMs, MMPs, KLK7, and plasmin in vitro ranges from serum withdrawal to pro inflammatory cytokines to growth factors. The cellular or physiologic consequences of sE-cad accumulation include the disruption of adherens junctions, cellular migration and invasion, induction of MMPs, as well as cell signaling, suggesting that sE-cad may contribute to disease progression. PMID- 22201850 TI - Oxidative stress: the achilles' heel of neurodegenerative diseases of the retina. AB - Age-related macular degeneration (AMD) is the leading cause of blindness among adults in the developed countries. It is characterized by the progressive loss of central vision. AMD is classified into two forms: dry and wet. Dry AMD involves the accumulation of deposits in the RPE and Bruch's membrane; Wet AMD is characterized by neovascularization in the choroid. Whether the two forms of AMD share the same mechanism for the disease development is presently not clear. Oxidative stress, inflammation, and ER-stress are the common modes for the pathogenesis of AMD. In addition, other risk factors and several signaling pathways have been implicated as causative factors of AMD. In this paper, the mechanisms underlying AMD, risk factors involved in the pathology, representative animal models, and therapeutic treatment strategies are reviewed. PMID- 22201851 TI - Role of estrogens in spermatogenesis. AB - Aromatase converts irreversibly androgens into estrogens and is present in the endoplasmic reticulum of various cells of mammalian testes ; at least in rodents, all testicular cells except peritubular cells express aromatase. In testis, high affinity estrogen receptors, ERalpha and/or ERbeta, together with a membrane rapid effect recently described, mediate the effects of estrogens. From the experimental models, in vitro studies and data collected in patients, it is now demonstrated that estrogens play an important role in the testis of vertebrates. At least it is supported by the widespread distribution of estrogen receptors in the testicular cells and the simultaneous presence of a biologically active aromatase in all germ cells (especially in meiotic and post-meiotic stages). Thus the role of estrogens (intracrine, autocrine and / or paracrine) in spermatogenesis (proliferation, apoptosis, survival and maturation) and more generally, in male reproduction is now evidenced, and much more complex than previously predicted. PMID- 22201852 TI - Role of anti-EGFR target therapy in colorectal carcinoma. AB - The epidermal growth factor receptor (EGFR) has become an important target in cancer treatment. In consequence, drugs directed at this and other molecular targets are an increasingly important part of the treatment of numerous tumours. Cetuximab and panitumumab, two monoclonal antibodies that target EGFR, have proved to be effective in metastatic colorectal cancer treatment. However, some patients do not respond to treatment with EGFR inhibitors and, for this reason, interest in the identification of patients most likely to benefit from treatment with these agents has grown considerably. K-Ras, a member of the RAS family of signalling proteins plays an important role in EGFR- mediated regulation of cellular proliferation and survival. Patients with wild-type K-Ras were found to have significantly greater overall survival, progression-free survival and/or response rate compared with patients harbouring K-Ras mutations. PMID- 22201853 TI - Peritoneal endometriosis is an inflammatory disease. AB - Peritoneal endometriosis is a chronic inflammatory disease characterized by increased numbers of peritoneal macrophages and their secreted products. Inflammation plays a major role in pain and infertility associated with endometriosis, but is also extensively involved in the molecular processes that lead to peritoneal lesion development. Peritoneal oxidative stress is currently thought to be a major constituent of the endometriosis-associated inflammatory response. Excessive production of reactive oxygen species, secondary to peritoneal influx of pro-oxidants such as heme and iron during retrograde menstruation, may induce cellular damage and increased proinflammatory gene expression through nuclear factor-kappa B activation. In particular, prostaglandin biosynthetic enzyme expression is regulated by this transcriptional factor, and increased peritoneal prostaglandin concentrations have been demonstrated in endometriosis. In the light of available data collected from patient biopsies, as well as in vitro and in vivo studies, the respective involvement and potential molecular interactions of iron, nuclear factor-kappa B and prostaglandins in the pathogenesis of endometriosis are explored and discussed. The key role of peritoneal macrophages is emphasized and potential therapeutic targets are examined. PMID- 22201854 TI - Purinergic signaling in giant cell formation. AB - Cell fusion into multinucleated giant cells (MGC) is an essential process that contributes to many important biological mechanisms in mammalians. In the bone and immune system, macrophages are endowed with a remarkable potential for cell fusion events as evidenced by their propensity to fuse with other cells and between themselves during both normal processes and disease. Macrophage fusion is critical for the normal development of multinucleated osteoclasts, the cells responsible for bone resorption. Macrophages from various tissue compartments also undergo fusion into MGC, a hallmark of granulomatous inflammation. To date, the mechanisms underlying macrophage fusion remain poorly understood. Receptor ligand interactions are thought to mediate this process and several lines of evidence implicate purinergic receptors in both osteoclast and MGC formation. Notably, the P2X7 receptor for extracellular ATP is expressed in osteoclasts and in many types of granulomas associated with infection, foreign body response and sterile inflammation. Through their ability to sense extracellular cues and ATP, a messenger of intercellular communication, purinergic receptors likely contribute to cell-cell interactions that result in macrophage fusion. PMID- 22201855 TI - Domestic endotoxin exposure and asthma in children: epidemiological studies. AB - Homes contain low but measurable concentrations of endotoxin that have been linked to household conditions such as the presence of animals, smoking, crowding, and farm living. While endotoxin exposure in early life appears to have a protective effect for childhood asthma; the evidence from prospective cohort studies of young children suggests that endotoxin exposure contributes to early development of wheeze. Higher domestic endotoxin levels are linked to greater asthma severity in school age children unless children are farm residents where, higher doses of farm-related endotoxin seem to offer some protection against asthma. Currently there are inconsistencies between epidemiological studies examining the role of endotoxin and children's respiratory health that may be due, in part, to selection bias of study populations, timing between measurement of endotoxin levels and the assessment of asthma symptoms. Although there is good evidence to demonstrate that endotoxin exposure in homes is associated with wheeze in children, and less likely to be associated with asthma, understanding the mediating roles of atopy, genetic and other environmental factors requires further and extensive exploration. PMID- 22201856 TI - Osteoarthritis: genetic factors, animal models, mechanisms, and therapies. AB - Osteoarthritis (OA) is the most common form of joint disease. OA frequently affects knees, hips, hands, and the spine. It is characterized by the progressive destruction of articular cartilage and subchondral bone accompanied by low-grade inflammation that together result in pain and deformity. Recent studies have shed light on the nature of OA genetic susceptibility and confirmed a number of candidate genes involved in the destruction of the synovium, articular cartilage, and subchondral bone in OA pathogenesis. During the progression of OA, there are several cellular changes in joints, including an increase in the number of activated osteoclasts and macrophages and an infiltration of the synovium by activated T-cells and B-cells. Pro-inflammatory mediators (e.g. interleukin IL-1, IL-1beta, IL-6, IL-17, and IL-18, and Tumor necrosis actor-alpha), proteinases (e.g. matrix metalloproteinase 9 and cathepsin K), and regulators of cartilage and bone formation (e.g. BMPs) have been shown to have important roles in OA progression at the molecular level. Studies have suggested that OA shares several common characteristics with rheumatoid arthritis (RA). To systematically understand OA, this review summarizes OA disease genes, mouse models of human disease experimental mouse models, mechanisms of OA pathogenesis, and current OA therapies. PMID- 22201857 TI - Bioconjugated nanomaterials on devices for infectious disease diagnostics. AB - The successful use of the nanoscale-dependent properties of nanomaterials on infectious diseases diagnostics devices lies on a well-engineered surface of both the probes and the transducer. Engineering probe and transducer surfaces involve functionalization of nanomaterials, conjugation to biorecognition elements and nanopatterning. This review presents the most common and most promising functional groups, bioconjugation schemes and patterning strategies of nanomaterials on sensing devices and their specific application to infectious pathogen detection. PMID- 22201859 TI - Hyponatremia and hypernatremia in the newborn: in medio stat virtus. AB - Hyponatremia and hypernatremia are complex clinical problems that occur frequently in full term newborns and in preterm infants admitted to the Neonatal Intensive Care Unit (NICU) although their real frequency and etiology are incompletely known. Pathogenetic mechanisms and clinical timing of hypo hypernatremia are well known in adult people whereas in the newborn is less clear how and when hypo-hypernatremia could alter cerebral osmotic equilibrium and after how long time brain cells adapt themselves to the new hypo-hypertonic environment. Aim of this review is to present a practical approach and management of hypo-hypernatremia in newborns, especially in preterms. PMID- 22201860 TI - Oxidative stress defense and repair systems of the ocular lens. AB - It is well accepted that reactive oxygen species (ROS) play a critical role in many biological processes including disease and longevity. Oxidation of proteins has been linked to many disease states and even the aging process itself. This was first proposed as "The free radical theory of aging" in 1956 by Denham Harman which suggests that free radicals causes cumulative and irreversible damage to macromolecules, loss of cellular function and cell death over time directly impacting health and lifespan. Cellular damage from ROS exposure has been termed oxidative stress, which is an imbalance between cellular ROS production and the ability of the cell to regulate ROS levels and repair damage caused by ROS. This review focuses on the role of oxidative stress in the eye lens as a model for understanding the role of oxidative stress systems in age-related human disease. PMID- 22201858 TI - Recent advances on tea polyphenols. AB - Over the past decade many scientific and medical studies have focused on green tea for its long-purported health benefits. There is convincing evidence that tea is a cup of life. It has multiple preventive and therapeutic effects. This review thus focuses on the recent advances of tea polyphenols and their applications in the prevention and treatment of human cancers. Of the various polyphenols in tea, (-)-Epigallocatechin-3-gallate (EGCG) is the most abundant, and active compound studied in tea research. EGCG inhibits several molecular targets to inhibit cancer initiation and modulates several essential survival pathways to block cancer progression. Herein, we describe the various mechanisms of action of EGCG and also discuss previous and current ongoing clinical trials of EGCG and green tea polyphenols in different cancer types. PMID- 22201861 TI - Effect of chemopreventive agents on differentiation of mouse embryonic stem cells. AB - Chemopreventive agents are derived from edible plants and from ancient time is a part of daily intake for many humans and animals. There are several lines of compelling evidence from epidemiological, clinical and laboratory studies that these dietary constituents are associated in reducing cancer risks. However, developmental toxicity of these natural compounds cannot be excluded. In the present study, we examined the effect of chemopreventive agents on the differentiation of mouse embryonic stem cells (ESCs) as an in vitro embryotoxicity model. We assumed that inhibition of developmentally regulated genes in vitro might predict developmental toxicity also under in vivo conditions. We found that epigallocatechin gallate (EGCG) (20 microM) induced the expression of mesodermal and cardiomyocyte genes and a significant increase in the number and the percentage of cardiomyocytes. The increase of the subpopulation correlated with higher numbers of beating foci and beating frequencies. Curcumin on the other hand at 0.4 mM was seen to enhance expression of ectodermal transcripts. Quercetin (2.5 microM) was found to inhibit several developmentally regulated genes. PMID- 22201863 TI - Peripheral cholesterol, metabolic disorders and Alzheimer's disease. AB - Strong correlations have been made between high levels of blood cholesterol and the risk to suffer Alzheimer's disease (AD). The question arises on how a peripheral event contributes to a disease that so severely affects the integrity and function of the Central Nervous System. Hypercholesterolemia has been also associated to peripheral metabolic disorders like diabetes, obesity or atherosclerosis that, in turn, predispose to AD. Here we review data, which point to alterations in blood cholesterol levels as a link between these metabolic disorders and AD. We describe and discuss common, cholesterol-related, molecular mechanisms and strategies to fight these conditions that, altogether, constitute a major cause of death in our societies. PMID- 22201862 TI - The nicotinic acetylcholine receptor: smoking and Alzheimer's disease revisited. AB - Epidemiological studies regarding Alzheimer's disease (AD) in smokers currently suggest inconsistent results. The clinicopathological findings also vary as to how AD pathology is affected by smoking behavior. Even though clinicopathological, functional, and epidemiological studies in humans do not present a consistent picture, much of the in vitro data implies that nicotine has neuroprotective effects when used in neurodegenerative disorder models. Current studies of the effects of nicotine and nicotinic agonists on cognitive function in both the non-demented and those with AD are not convincing. More data is needed to determine whether repetitive activation of nAChR with intermittent or acute exposure to nicotine, acute activation of nAChR, or long-lasting inactivation of nAChR secondary to chronic nicotine exposure will have a therapeutic effect and/or explain the beneficial effects of those types of drugs. Other studies show multifaceted connections between nicotine, nicotinic agonists, smoking, and nAChRs implicated in AD etiology. Although many controversies still exist, ongoing studies are revealing how nicotinic receptor changes and functions may be significant to the neurochemical, pathological, and clinical changes that appear in AD. PMID- 22201864 TI - Dietary patterns and prostatic diseases. AB - Dietary patterns play a role on prostatic diseases in association with genetic, behavioral, occupational and environmental ones. Data from reviewed literature provide evidences of a possible relationship between dietary habits and the incidence of prostate disorders, even if it is not enough to justify a widespread adoption of new dietary habits. In this review the role of dietary patterns, including the use of supplements, in the prevention and treatment of the most frequent and known prostatic diseases, benign prostatic hyperplasia (BPH) and prostate cancer (PC) was analyzed. A limited number of well designed trials were identified in which diet and dietary supplement intervention appeared to slow disease progression. Although conclusive evidences are limited, the current data suggest that a diet low in total calories and fat, high in vegetables and fruits and that body weight control could be possibly effective in preventing prostatic diseases. On the other hand care must be taken to ensure that over-consumption of dietary supplements does not occur because it may be harmful. PMID- 22201865 TI - Gliomagenesis: a game played by few players or a team effort? AB - Glioblastoma multiforme (GBM) represents the most aggressive and deadliest brain tumor of adults. To date, cell heterogeneity within GBM has been explained by the "hierarchical" model of tumorigenesis, aka the "cancer stem cell" hypothesis. In agreement with this model, only rare tumor cells, namely the cancer stem cells (CSCs), are responsible for GBM initiation and, as such, are considered the favored target of therapy. However, multiple evidence has recently indicated that tumor-initiating cells (TICs) may not represent a restricted and infrequent GBM component; rather, they might constitute most of the cells within the tumor bulk. Here we review several studies that recently shed new light on the process of gliomagenesis. We critically analyze the methodological inconsistencies and drawbacks that are causing protracted controversy in the field. Finally, we discuss the clinical implications and the novel therapeutic scenarios that have been put forward by the presence of functionally and molecularly distinct subpopulations of GBM-initiating cells within the same tumor. PMID- 22201866 TI - Chronic psychosocial stress exposes Alzheimer's disease phenotype in a novel at risk model. AB - Because of the extensive individual variations in the time of onset and severity of the prevalent sporadic form of Alzheimer's disease (AD), a patient-related external factor must be assumed to play a significant role in the development of the disease. Since stress is increasingly recognized as an external factor in the development of AD, a number of labs, including this lab, have shown that chronic stress or corticosterone administration worsens the AD phenotype in both transgenic and non-transgenic models of the disease. Recently we develop a novel at-risk model that correlates with seemingly normal individuals who are predisposed to develop AD. This review is a summarized recount of the findings we have reported on the effect of chronic psychosocial stress in this at-risk model of AD. Behavioral (learning and memory tests), electrophysiological and molecular findings indicated that even mild chronic psychosocial stress clearly transforms this seemingly normal rat model to a full-fledge AD phenotype. PMID- 22201867 TI - The effect of exercise on IGF-I on muscle fibers and satellite cells. AB - Skeletal muscles are able to adapt to over - or under-use. In response to enhanced use, such as exercise, skeletal muscles undergo morphological and physiological changes possibly including injury and regeneration of muscle fibers (myofibers). The regeneration process includes addition or replacement of myofiber nuclei (myonuclei) (1). Myonuclei are terminally differentiated, thus maintenance and repair of myofibers are attributed to satellite cells, the myogenic stem cells. Up to date little is known about the differential effects of different growth factors on satellite cell and their subsequent contribution in exercise. The adaptation of skeletal muscles to altered use is governed by three major processes: satellite (stem) cell activity, gene transcription, and protein translation. A defect in any of these processes could interfere with muscle maintenance and regeneration. This review focuses on current understanding of the effects of resistance and endurance exercise on skeletal muscle fibers (myofibers) and on the skeletal muscle stem cells, satellite cells. We first summarize in brief the basic biology of skeletal satellite cells; the types of exercise and the basic biology of IGF-I. We then discuss the interplay between IGF skeletal muscle and satellite cells. PMID- 22201868 TI - Antibacterial agents from actinomycetes - a review. AB - The discovery of Penicillin in 1928 and that of Streptomycin in 1943, has been pivotal to the exploration of nature as a source of new lead molecules. Globally, the microbiologist today is acknowledged as a crucial player in the drug discovery program. The microbial products, especially those from actinomycetes have been a phenomenal success for the past seven decades. Bioprospecting for new leads are often compounded by the recurrence of known antibiotics in newer microbial isolates. Despite all these deterrents, actinomycetes have proved to be a sustained mine of novel antibiotics, which selectively destroys the pathogens without affecting the host tissues. Each of these antibiotics is unique in their mode of action. Their versatility and immense economic value is something, which is extremely noteworthy. The anti-infective turn-over of over 79 billion US dollars in 2009, includes about 166 antibiotics and derivatives such as the Beta lactam peptide antibiotics, the macrolide polyketide erythromycin, tetracyclines, aminoglycosides, daptomycin, tigecycline, most of which are produced by actinomycetes (1). Actinomycetes continue to play a highly significant role in drug discovery and development. Among the bioactive compounds that have been obtained so far from microbes, 45 % are produced by actinomycetes, 38 % by fungi and 17 % by unicellular eubacteria (2). Further many chemically synthesized drugs owe their origin to natural sources. In this review article, we highlight the recent antibiotics from actinomycetes with emphasis on their source, structures, activity, mechanism of action and current status. PMID- 22201869 TI - ZnO materials and surface tailoring for biosensing. AB - ZnO nanostructured materials, such as films and nanoparticles, could provide a suitable platform for development of high performance biosensors due to their unique fundamental material properties. This paper reviews different preparation techniques of ZnO nanocrystals and material issues like wettability, biocompatibility and toxicity, which have an important relevance to biosensor functionality. Efforts are made to summarize and analyze existing results regarding surface modification and molecular attachments for successful biofunctionalization and understanding of the mechanisms involved. A section is devoted to implementations of tailored surfaces in biosensors. We end with conclusions on the feasibility of using ZnO nanocrystals for biosensing. PMID- 22201870 TI - Bladder tumors and aromatic amines - historical milestones from Ludwig Rehn to Wilhelm Hueper. AB - We know today that environmental factors must be regarded as a significant cause of the urinary bladder carcinoma. In Germany, the urinary bladder carcinoma is the second most common urological tumor among men and the most common among women and more than 100 occupational bladder cases are recognized and compensated per year. Scientific studies of this problem reach back to the 18th century. However it was only in 1895 that the surgeon Ludwig Rehn firstly described 3 cases of occupational bladder tumors in at most 45 fuchsine workers in Frankfurt / M. This extremely significant discovery was followed by a description of a large number of cases of urinary bladder tumors among workers in the paint industry. Nevertheless, it was impossible to induce bladder cancer in animals by aromatic amines for many years. In the 1930s, the pathologist Wilhelm C. Hueper was the first to induce bladder cancer in animal experiments, applying beta-naphthylamine to dogs. Based on these experiments and corroborated by epidemiologic studies, beta-naphthylamine was banned in Germany and many countries from the 1950s on. This review will highlight work and life of these two pioneering medical researchers. PMID- 22201871 TI - Tissue factor in blood cells and endothelial cells. AB - There are contradictory reports about the synthesis and expression of TF antigen/activity in blood cells and plasma and in the surrounding environment of endothelial cells. In this review article we focus on the many divergent findings on the expression and presence of TF in various blood cells, plasma and endothelial cells in normal and pathological states. The widespread use of antibodies with inferior and misleading specificity and TF activity assays with low sensitivity/specificity, may be the major explanation for all the controversy. Based on our own experience and many other recent reports, pertaining to the concept of so called blood borne TF, we conclude that TF is exclusively expressed in and associated with circulating monocytes in blood of healthy individuals. However, several pathological conditions are associated with activated monocytes, shedding TF-rich microparticles that are transferred to activated platelets, neutrophils, and endothelial cells. PMID- 22201872 TI - Coronary artery ectasia: current concepts and interventions. AB - Coronary artery ectasia (CAE) is a well-recognized angiographic finding, characterized by abnormal dilatation of the coronary arteries. We reviewed the current concepts of the condition including etiology, pathogenesis, flow alterations, clinical implications, prognosis and treatment. CAE is often viewed as a variant of obstructive coronary atherosclerosis. Exaggerated positive vascular remodeling due to inflammation, and chronic overstimulation of the endothelium by nitric oxide are potential causative mechanisms. The condition is associated with cardiovascular risk factors such as smoking and hypertension, while it appears to be inversely associated with age and diabetes mellitus. Patients with CAE typically present with angina, and are at risk for myocardial infarctions and sudden cardiac death due to slow flow, coronary vasospasm, dissection, and/or intracoronary thrombosis. CAE may be a diffuse disease associated with dilatation in other parts of the vasculature. As the incidence of this not so benign condition is expected to rise, the optimal treatment options remain undefined. Medical therapy with anticoagulants, nitrates and calcium channel blockers has been proposed and seems rational; however prospective studies with proof of efficacy are needed. PMID- 22201873 TI - Immunoinformatics: how in silico methods are re-shaping the investigation of peptide immune specificity. AB - In the past decade, information technology has enabled synergistic advances in key domains of immunological research including the development of diagnostics and vaccines. Computational methods of epitope mapping now play instrumental roles in bench experiments, by facilitating the selection of immunogenic targets and the modeling of downstream cellular responses. In this article, we summarize the latest development and application of immune epitope prediction methods and discuss future directions in this field which could enhance our understanding of immune specificity. PMID- 22201875 TI - STIM and Orai in cellular proliferation and division. AB - Cellular proliferation and division are central processes in the development, survival and evolution of living systems. Transitioning into the cell division phase of the cell cycle encompasses dramatic remodeling of cellular organelles and signaling modules including Ca2+ signaling. As well, Ca2+ signals play important roles during progression through various stages of the cell cycle. A ubiquitous Ca2+ influx pathway that is activated based on intracellular Ca2+ store content is store-operated Ca2+ entry (soce). SOCE is activated through a complex interplay between a Ca2+ channel at the cell membrane, Orai1, and a Ca2+ sensor that localizes to the endoplasmic reticulum, STIM1. Herein, we discuss potential roles and regulation of STIM and Orai proteins during cellular proliferation. PMID- 22201874 TI - Development and deployment of antigen arrays for investigation of B-cell fine specificity in autoimmune disease. AB - Recent developments in proteomic technologies have enabled the high-throughput, multiplex measurement of large panels of antibodies in biological fluids of patients with immune-driven diseases. Antigen microarrays are increasingly being used to delineate the natural history of autoantibody formation and epitope spread, and thus gain insight into the pathogenesis of autoimmune diseases, as well as into host immunity and its shortcomings. Characterization of autoimmunity that precedes the onset of clinically apparent disease has the potential to guide disease prevention using either conventional immunosupression or novel, antigen specific tolerizing therapies. In addition, autoantibody profiling has the potential to identify molecular subtypes of a disease, which could allow for prediction of disease outcomes such as severity, tissue damage, and response to therapy. PMID- 22201876 TI - Trophinin in cell adhesion and signal transduction. AB - The process of human embryo implantation is mediated not only by evolutionarily conserved mechanisms but by activities unique to humans. Among the latter, evidence suggests that the cell adhesion molecule trophinin plays a unique role in human embryo implantation. Here, we describe characteristics of trophinin protein and of the trophinin-associated proteins bystin and tastin. We then describe trophinin-mediated signal transduction in trophectoderm cells during human embryo implantation and events related to human sperm tail motility. We also report dual roles for trophinin in human cancers in terms of promoting malignancy in some tumor types and suppressing it in others. PMID- 22201877 TI - The role of nutrition in the development of esophageal cancer: what do we know? AB - Cancer of the esophagus is the eighth most common cancer by incidence worldwide and ranks sixth as the most common cause of cancer death. It is unique among the gastrointestinal tract malignancies because it embodies two distinct histopatologic types, squamous cell carcinoma and adenocarcinoma. Which type of cancer occurs in a given patient or predominates in a given geographic area depends on many variables, including individual lifestyle, socioeconomic pressures, environmental factors and diet and nutrition. Generally for both squamous cell carcinoma and adenocarcinoma of the esophagus case-control studies provide evidence of a protective effect of fruits and vegetables. Here we review the role of nutrition in the etiology of esophageal cancer. PMID- 22201878 TI - Tissue factor in health and disease. AB - Tissue Factor (TF) is a crucial initiator of the extrinsic coagulation cascade. TF is expressed on cells which are normally sequestered from blood. However, upon injury TF is exposed to the blood resulting in activation of the coagulation cascade. TF dependent generation of coagulation proteases also initiates intracellular signaling through protease activated receptors. Pathologic TF expression is found in patients with a number of different diseases. This review will describe the roles of TF in health and disease as well as discuss approaches to reduce pathologic TF expression. PMID- 22201879 TI - Vitamin C and E consumption and coronary heart disease in men. AB - Atherosclerotic cardiovascular diseases (CVD) are a major source of mortality and morbidity in general population. Oxidative modification of low density lipoprotein (LDL) represent the most important determinant factor in the development and progression of atherosclerotic lesions. Oxidative damage and the production of free radicals (FRs) in the endothelium are some of the main factors involved in the pathogenesis of the atherosclerotic process which causes CVD. Appropriate nutritional practices are of central importance in managing risk and treatment of CVD; indeed, many current guidelines contain nutritional recommendations to reduce the risk of these diseases. In observational studies vitamin C and E, the most prevalent natural antioxidant vitamins, have suggested that supplemental users have lower rate of coronary events. Despite these data, several large randomized controlled trials (RCTs) have failed to confirm the benefits for vitamin C and E in cardiovascular (CV) prevention. The aim of this review is to examine the studies published in literature which report the effect of supplementation with antioxidant vitamins (C,E) in the primary and secondary prevention of CVD in men due to atherosclerotic process. PMID- 22201881 TI - Tissue factor pathway inhibitor as a multifunctional mediator of vascular structure. AB - Tissue factor pathway inhibitor (TFPI) is a potent regulator of tissue factor - factor VII-dependent activation of the tissue factor pathway. TFPI is a serine protease inhibitor that contains three Kunitz domains and a basic carboxyl terminus. TFPI is primarily expressed on endothelial cells, and murine models have demonstrated that its expression regulates vascular thrombosis. The localization of TFPI expression and the requirement for TFPI in development suggest a potential role in regulating vascular structure. Data from animal studies suggest that vascular expression of TFPI inhibits pathologic vascular remodeling and inhibits angiogenesis. The mechanism for these effects is diverse and includes tissue factor and factor Xa-dependent and -independent mechanisms. PMID- 22201880 TI - Posttranslational modifications of tissue factor. AB - Tissue factor (TF), a membrane protein, is an initiator of blood coagulation in vivo. In this review we discuss how posttranslational modifications affect activity and other properties of TF. Glycosylation of the extracellular domain and the composition of carbohydrates at three glycosylation sites have an influence on TF activity in the extrinsic FXase by increasing the rate of FX proteolysis. No influence of TF glycosylation on the activity of the FVIIa/TF complex towards small synthetic substrates was observed, suggesting that glycosylation has no effect on TF interaction with FVIIa. There are no published data suggesting a direct influence of phosphorylation or palmitoylation in the cytoplasmic domain on TF procoagulant activity. There has been a debate in the recent literature related to the role and formation of the Cys186-Cys209 disulfide bond. Published opinions from various laboratories range from this bond being essential for the expression of cell TF activity to having no role in it. Overall, it is clear that some modifications of TF have an effect on TF procoagulant activity, signaling functions and trafficking. The influences of other modifications are debatable. PMID- 22201882 TI - Microdialysis: improving local chemotherapy in cancer using a mathematical model. AB - Although intratumoral chemotherapy administration has been evaluated in the past, its results have not been frequently comparable to those from systemic administration. We recently described microdialysis as a method for local chemotherapy administration with increasing effectiveness while reducing systemic toxicity. We present a mathematical model which supports the successful application of this procedure in optimizing the administered drug in different cases, using informatics tools and considering several parameters. We also review and discuss important aspects of cancer biology that should be taken into consideration in cancer chemotherapy, such as tumor heterogeneity, drug resistance and metastasis, and how this technique may be used to overcome any set backs presented by these. PMID- 22201883 TI - Novel targets for detection of cancer and their modulation by chemopreventive natural compounds. AB - Cancer affects the lives of millions of people. Several signaling pathways have been proposed as therapeutic targets for cancer therapy, and many more continue to be validated. With the identification and validation of therapeutic targets comes the question of designing novel strategies to effectively counter such targets. Natural compounds from dietary sources form the basis of many ancient medicinal systems. They are pleiotropic i.e. they act on multiple targets, and, therefore, are often the first agents to be tested against a novel therapeutic target. This review article summarizes the knowledge so far on some actively pursued targets - Notch, CXCR4, Wnt and sonic hedgehog (shh) pathways, the process of epithelial-mesenchymal transition (EMT) as well as molecular markers such as uPA-uPAR, survivin, FoxM1, and the microRNAs. We have performed an extensive survey of literature to list modulation of these targets by natural agents such as curcumin, indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), resveratrol, epigallocatechin-3-gallate (EGCG), genistein etc. We believe that this review will stimulate further research for elucidating and appreciating the value of these wonderful gifts from nature. PMID- 22201884 TI - New strategies in cancer chemoprevention by phytochemicals. AB - Fruits, vegetables, spices, herbs and/or beverages are typical foods containing various phytochemicals that have been used for prevention and treatment of a variety of human ailments since time immemorial. Nowadays, a large number of individuals are motivating towards the use of phytochemicals inorder to prevent or treat chronic diseases. Recent research efforts have been greatly emphasized on the recognition of naturally occurring plant derived substances that are capable of inhibiting, retarding or reversing the development of cancer. Several epidemiological annotations and a number of laboratory studies have indicated cancer chemopreventive and anti-carcinogenic potential of plant derived agents that have been traditionally used for treatment of varied human disorders in different parts of the globe. Molecular mechanisms which are involved for eliciting the effects of phytochemicals in cancerous cells are noticed in a range of experimental systems. This has opened up new avenue for researchers working in the field of chemoprevention and merits further scrutiny to establish the role of phytochemicals in prevention of fatal human diseases like cancer. PMID- 22201885 TI - Targeting rapid action of sex-steroid receptors in breast and prostate cancers. AB - Human breast and prostate cancers are complex diseases caused by the progressive accumulation of gene mutations combined with epigenetic deregulation of critical genes and derangement of signaling pathways. Compelling evidence indicates that steroid hormones elicit non-genomic responses in cytoplasm of target cells. In this cellular location, steroid-coupled receptors recruit signaling effectors or scaffold proteins, thereafter activating multiple pathways leading to proliferation, survival, migration and invasiveness. Thus, the immediate challenge is the dissection of key upstream events regulating steroid response in target tissues to prevent progression and improve treatment of breast and prostate cancers. Progress in our understanding of the molecular mechanisms that play a master role in these cancers has strongly stimulated the search for specific inhibitors of key signaling molecules. This review aims to give an up-to date report of the complex network regulating non-genomic action of steroid hormones in target cells. The final section highlights recent advances from our laboratory and future directions in alternative approaches for the treatment of breast and prostate cancers. PMID- 22201886 TI - Extended hepatic resection in advanced hepatoblastoma. AB - Complete surgical resection of the primary tumor is one of the most important prognostic factors for hepatoblastoma (HB). This goal can mean a relevant challenge in some cases of advanced HB, especially since an anatomical resection should be realised. Over recent years several surgical techniques for advanced liver resections in children have been developed and refined. In this article the authors summarize their own experience with advanced liver resections for HB and give an overview over indications and specifications for the different approaches. PMID- 22201887 TI - Hepatoblastoma throughout SIOPEL trials - clinical lessons learnt. AB - International Childhood Liver Tumors Strategy Group (SIOPEL) introduced the concept of preoperative chemotherapy in hepatoblastoma, most common malignant liver tumor in children. This required introduction of the preoperative tumor staging system called PRETEXT. SIOPEL 1 study proved the value of preoperative chemotherapy consisting of cisplatin and doxorubicin (PLADO) in hepatoblastoma leading to 5-year overall survival of 75 % and event-free-survival of 66 %. Both presence of metastases and PRETEXT were significant prognostic factors which led to development of two risk categories: standard (SR) and high risk (HR) hepatoblastomas. In SIOPEL 2 study two different strategies were developed for SR and HR tumors with corresponding 3-year overall and progression-free survival of 91 % and 89 %, and 53 % and 48 % respectively. In the next SIOPEL 3 SR arm study monotherapy regimen based on CDDP alone was non-inferior to PLADO for SR hepatoblastoma and less toxic. Cisplatin-based chemotherapy in combination with delayed definitive surgery / liver transplantation improved the survival of children with hepatoblastoma. However certain patients, especially those with metastatic disease and low alphafetoprotein still have inferior prognosis. PMID- 22201888 TI - Activation of Wnt and Myc signaling in hepatoblastoma. AB - Hepatoblastoma (HB) is the most common type of pediatric liver cancer. This tumor is thought to derive from hepatic progenitor cells that are arrested at various stages of liver development, as illustrated by a variety of histologic subtypes. Recent genomic studies have led to better understand the molecular pathogenesis of HB, to point out the crucial roles of the Wnt Myc signaling pathways in malignant transformation of liver progenitor cells. Molecular classification of HB based on genome-wide studies, as well as identification of reliable diagnostic prognostic markers, open the way to the development of new personalized targeted therapies for the management of aggressive lethal childhood tumors. PMID- 22201889 TI - Molecular imaging and photodynamic therapy in hepatoblastoma. AB - Molecular imaging is a novel field in cancer research combining various in vivo imaging modalities with molecular biology. Different techniques such as magnetic resonance tomography (MRI), positron emission tomography (PET), optical imaging methods (bioluminescence, fluorescence), or combination of these are used in basic research as well as in patients in different tumor entities. In hepatoblastoma (HB), there are only few reports on molecular imaging methods in a preclinical (optical imaging) and clinical setting (PET, PET-CT). Unimprovable treatment outcomes of patients in advanced tumor stages require novel treatment approaches. Photodynamic diagnosis (PDD) and photodynamic therapy (PDT) are novel diagnostic and therapeutic tools. Photodynamic diagnosis allows in vitro and in vivo detection of tumor cells using their fluorescending behaviour. PDT is a novel anticancer treatment approach leading to tumor cell destruction via apoptosis. In hepatoblastoma, there are only few reports on in vitro and in vivo studies using this treatment modality. First results seem to be promising and further studies will be required to further evaluate these techniques and to transfer them into clinical settings. This paper reviews different modalities of molecular imaging, photodynamic diagnosis and photodynamic therapy in childhood hepatoblastoma. PMID- 22201890 TI - Treatment of hepatoblastoma in the German cooperative pediatric liver tumor studies. AB - Treatment with neoadjuvant and adjuvant chemotherapy together with tumor resection changed treatment strategies in hepatoblastoma and led to prospective cooperative studies. The treatment strategies and results of three German liver tumor studies HB89, HB94 and HB99 are reviewed. Here we provide an overview of the treatment of this tumor in the years 1989 to 2008 in Germany. The treatment protocols, aim of studies and results are outlined. The overall-survival (OS), response to chemotherapy and toxicity are followed over this period of different treatment. The overall-survival improved over the last years with 75 % in HB89, 77 % in HB94 and 89 % HB99. Patients with potentially resectable tumors have a good prognosis although the treatment was reduced over the last years. Patients with non resectable tumors or lung metastases have also a better but still bad prognosis. The intensified treatment for these patients in Germany in the last years showed comparable results to international studies but no advantage. PMID- 22201891 TI - Sialyltransferases functions in cancers. AB - Abnormally elevated levels of sialylated tumor associated carbohydrate antigens are frequently described at the surface of cancer cells and/or secreted in biological fluids. It is now well established that this over-expression may result from deregulation in sialyltransferases enzymatic activity involved in their biosynthesis, but the precise molecular mechanisms remain unknown. Twenty different human sialyltransferases preside to the sialylation of glycoconjugates, either glycolipids or glycoproteins. This review summarizes the current knowledge on human sialyltransferases implicated in the altered expression of sialylated tumor associated antigens, the molecular basis of their regulated expression in cancer cells and the various tools developed by researchers and clinicians for their study in pathological samples. PMID- 22201892 TI - Hair dye use and risk of human cancer. AB - Over 50% of the adult population will use hair dyes at some point in their lifetimes. Hair dyes consist of various chemicals and the composition of these chemicals vary by hair dye types. Chemicals p-phenylenediamine and aminophenyl have been suggested as possible carcinogens or mutagens in experimental studies. The scientific community has been interested in this potential public health impact and the results of published epidemiological studies are summarized here. The current evidence provides limited evidences on the association between personal hair dye use and human cancer risk, except for the possibility of hematopoietic cancers and to a lesser extent, bladder cancer. Risk appears to be affected by time period of use and by specific genetic polymorphisms. Future studies should investigate potential gene and environment interaction to assess possible genetic susceptibility. Several methodological issues should also be considered in future studies including completed hair dye use information such as on timing, duration, frequency and type of hair dye product use. PMID- 22201893 TI - Recent developments in multifunctional hybrid nanoparticles: opportunities and challenges in cancer therapy. AB - Multifunctional hybrid nanoparticles combine some of the unique physical and chemical characteristics of two or more classes of materials, such as polymers, liposomes, metals, quantum dots and mesoporous silica among others, to create a versatile and robust new class of nanoparticles. Here we discuss the most recent synthetic strategies to create these hybrid systems and analyze four key design aspects: stability, encapsulation of therapeutic and imaging agents, controlled release of encapsulated agents, and biocompatibility. Through the combination of multiple nanomaterials, hybrid nanoparticles aim to expand the functionality of single-component systems, using the strengths of one material to improve on weaknesses of another. We then examine how hybrid nanoparticle platforms provide unique opportunities in cancer therapy, specifically in the treatment of multidrug resistant cancer. Finally, we discuss some of the challenges hybrid nanoparticles systems might face in their large scale synthesis and commercialization in the biopharmaceutical industry. PMID- 22201894 TI - Dietary supplements and natural products in breast cancer trials. AB - The association between breast cancer and modifiable health behaviors is well supported. At least one-half of all cancers are suggested to have a dietary component. It is not surprising therefore that many of the dietary agents and natural health products that have attracted the attentions of scientists and practitioners are now moving into clinical trials. In this report, we review 65 clinical intervention trials evaluating over 30 dietary supplements and natural health products for use in breast cancer. The products being tested in these trials fall broadly into the following categories: (i) vitamins, minerals, cofactors; (ii) herbal extracts; (iii) amino acids; (iv) fatty acids; (v) animal products; (vi) probiotics; (vii) phytochemicals; and (viii) combination formulations. Trial outcome measures include risk modification, efficacy testing (with dietary supplements alone or dietary supplement-anticancer drug combinations), toxicity reduction, biomarker identification, symptom management, and quality of life parameters. The wide range of interests in natural product testing at the clinical trial level supports the potential utility of these agents in the breast cancer prevention, treatment, and management regimens of the future. PMID- 22201896 TI - Transcriptional regulation of CFTR gene expression. AB - Cystic Fibrosis results from mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The gene was identified in 1989, but more than 20 years later, the regulatory mechanisms controlling its complex expression are still not fully understood. Though the promoter binds transcription factors and drives some aspects of CFTR gene expression, it cannot alone account for tissue specific control. This implicates other distal cis-acting elements in cell-type specific regulation of CFTR expression. Several of these elements, including intronic enhancers and flanking insulators, were identified within or near the CFTR locus. Here we summarize the known regulatory mechanisms controlling CFTR transcription, including those acting through elements in the promoter and others elsewhere in the locus. A special focus will be elements that contribute to tissue specific regulation of expression. PMID- 22201897 TI - Neuroimaging biomarkers in bipolar disorder. AB - There is an urgent need to identify objective biomarkers for the assessment of bipolar disorder, to improve diagnosis and prognostic evaluation. Neuroimaging is a particularly promising approach. We review here the structural and functional neuroimaging studies carried out on bipolar disorder. These studies have led to the development of neurobiological models of bipolar disorder assuming cortical limbic dysregulation. Dorsal brain structures are thought to decrease in volume and activity in bipolar disorder, reducing inhibition of the ventral-limbic network and enhancing emotional responses. These models also assume abnormal prefrontal-subcortical limbic connectivity. This abnormal connectivity has been identified by both diffusion tensor imaging studies (anatomical connectivity) and functional MRI (functional connectivity). However, studies are currently limited by the heterogeneity of the patients included. Future research should include studies to validate biomarkers for the assessment of bipolar disorder and studies of large and well characterized samples of patients with bipolar disorder. PMID- 22201895 TI - Toxicological significance of azo dye metabolism by human intestinal microbiota. AB - Approximately 0.7 million tons of azo dyes are synthesized each year. Azo dyes are composed of one or more R1-N=N-R2 linkages. Studies have shown that both mammalian and microbial azoreductases cleave the azo bonds of the dyes to form compounds that are potentially genotoxic. The human gastrointestinal tract harbors a diverse microbiota comprised of at least several thousand species. Both water-soluble and water-insoluble azo dyes can be reduced by intestinal bacteria. Some of the metabolites produced by intestinal microbiota have been shown to be carcinogenic to humans although the parent azo dyes may not be classified as being carcinogenic. Azoreductase activity is commonly found in intestinal bacteria. Three types of azoreductases have been characterized in bacteria. They are flavin dependent NADH preferred azoreductase, flavin dependent NADPH preferred azoreductase, and flavin free NADPH preferred azoreductase. This review highlights how azo dyes are metabolized by intestinal bacteria, mechanisms of azo reduction, and the potential contribution in the carcinogenesis/mutagenesis of the reduction of the azo dyes by intestinal microbiota. PMID- 22201898 TI - Neuroprotective role of estrogens: relationship with insulin/IGF-1 signaling. AB - Postmenopausal women have an elevated risk of developing a neurodegenerative disease. These clinical observation supported by basic research, suggest that estrogens are neuroprotective. Insulin resistance represents an independent factor in the etiology of age-associated disease and metabolic syndrome should be considered as a contributing factor to the higher post-menopausal vulnerability to neurological disorders. Elucidating the relationship between insulin resistance associated with aging in females, and the cross-talk between estradiol, insulin, and insulin-like growth factor (IGF-1) signaling pathways, will lead to a more complete understanding of the mechanism underlying estradiol mediated neuroprotection. In past decades, estrogen replacement therapy (ERT) was commonly used as a palliative therapy during menopause, but the mid-term and long term effects of estrogen as possible promoters of breast cancer and the increased risk of coronary illness or stroke, has limited current usage. A deeper understanding of the molecular mechanisms common to all forms of neurodegenerative diseases may hasten the development of protective strategies against chronic age-related deterioration and acute illness, ultimately providing a better quality of life for the elderly. PMID- 22201899 TI - Peripheral blood mRNA expression patterns to differentiate hepatocellular carcinoma from other hepatic diseases. AB - Peripheral blood genes expressions profiling (GeXP) have been convinced to be more specific for the diagnosis of cancer and other diseases, and the GeXP system provides an ideal method to analyze multiple genes expression in one normalized and equable system. We aim to differentiate hepatocellular carcinoma from other hepatic diseases based on peripheral blood and the GeXP system. Fifteen selected hepatic diseases related genes with two house-keeping genes for normalization were detected by the GeXP system. The diagnosis model was based on K nearest neighbor classifier and cross validation, and software based on MATLAB software was built for differential diagnosis of hepatic diseases. Eight hepatic related genes were demonstrated to show an obvious statistic difference in expressions while the K nearest neighbors classifier showed that the accuracy for normal controls, hepatitis B, liver cirrhosis, hepatocellular carcinoma and the Other group was separately 80.57 %, 78.17 %, 84.48 %, 73.24 % and 85.85 %. The set of validation has been carried out to assess the accuracy of Model Two and the accuracy was even higher than the set of building for the model, except for the hepatitis B (HBV) group. A sensitive and specific GeXP system of eight genes has been developed for the accurate differential diagnosis of hepatic disease. PMID- 22201901 TI - SP-A and SP-D in host defense against fungal infections and allergies. AB - Innate immunity mediated by pattern recognition proteins is relevant in the host defense against fungi. SP-A and SP-D are two such proteins belonging to the class of collagen domain containing C-type lectins, or collectins. They bind to the sugar moieties present on the cell walls of various fungi in a dose dependent manner via their carbohydrate recognition domain (CRD). SP-A and SP-D directly interact with alveolar macrophages, neutrophils, lymphocytes. We review these roles of SP-A and SP-D against various clinically relevant fungal pathogens and fungal allergens. SP-A and SP-D gene deficient mice showed increased susceptibility/ resistance to various fungal infections. Patients of fungal infections and allergies are reported with alterations in the serum or lung lavage levels of SP-A and SP-D. There are studies associating the gene polymorphisms in SP-A and SP-D with alterations in their levels or functions or susceptibility of the host to fungal diseases. In view of the protective role of SP-D in murine models of Aspergillus fumigatus infections and allergies, therapeutic use of SP-D could be explored further. PMID- 22201902 TI - Nutritional issues in heart transplant candidates and recipients. AB - Heart transplant is the golden standard in the management of end-stage heart failure. Recent studies have pointed out the role of nutritional issues in patients evaluated for heart transplant listing. In particular, extremes in body habitus, cachexia and obesity, have been characterized and identified as independent prognostic factors and clinically relevant target for therapeutic interventions. Effects of such conditions exert a prognostic implication well beyond waiting time up to early post transplant setting. Changes in posttransplant clinical conditions and nutritional status have been recently described in their pattern of presentation and implications on weight gain, reversal of preoperative cachexia and early and late morbidity and mortality. New onset diabetes mellitus and metabolic syndrome have been disclosed as relevant clinical conditions in this setting. Implications for tailoring of immunosuppressive therapy and dietary prescription emerged as main stem of long term recipient management. All this issues have been reviewed focusing on the clinical relevance of this growing body of knowledge and emphasizing the role of a multidisciplinary approach for selection and management of heart transplant recipients. PMID- 22201904 TI - Vitamin-D regulation of bone mineralization and remodelling during growth. AB - Vitamin D status relates to two bone diseases, osteomalacia and osteoporosis which arise from distinct pathophysiogical pathways. They can occur in children as well as adults. Osteomalacia or rickets arises from a delay in mineralization and can be caused by severe vitamin D deficiency where the key to curing osteomalacia is the endocrine action of circulating 1,25-dihydroxyvitamin D to normalize the active intestinal transport of calcium and phosphate. Osteoporosis or sub-optimal bone mineral accretion during growth is a risk factor for fracture in children. Current evidence suggests serum 25-hydroxyvitamin D levels between 20 and 80 nmol/L are associated with decreased bone mineral content as a result, at least partly, of reduced vitamin D metabolism and activity within bone cells. The local synthesis of 1,25-dihydroxyvitamin D within bone is necessary to modulate bone resorption and promote bone formation. Thus an adequate vitamin D status is necessary for vitamin D activity within bone to establish a healthy skeleton. PMID- 22201903 TI - Modes of exocytosis and electrogenesis underlying canine biphasic insulin secretion. AB - Biphasic insulin secretion in response to glucose consists of a transient first phase followed by a progressive second phase. It is a well described feature of whole perfused pancreases as well as isolated pancreatic islets of Langerhans. Applying to single cell assays of exocytosis (capacitance monitoring and amperometry) to single canine Beta-cells we have examined the time courses of granule exocytosis in response to voltage-clamp depolarizations that mimic two modes of glucose-induced electrical activity, and then compared these to biphasic insulin secretion. Action potentials evoked in short trains at frequencies similar those recorded during first phase insulin secretion trigger phasic exocytosis from a small pool of insulin granules that are likely docked near voltage-activated Ca2+ channels. In contrast, prolonged voltage-clamp pulses mimicking plateau depolarizations occur during second phase insulin secretion and trigger tonic or continuous exocytosis. Comparing the latter results with ones obtained using photorelease of caged Ca2+ in other insulin-secreting cells, we suggest that tonic exocytosis likely results from granule release from a highly Ca2+-sensitive pool of insulin granules, likely located further from Ca2+ channels. Both phasic and tonic modes of exocytosis are enhanced by glucose, via its metabolism. Hence, in canine Beta-cells we propose that two distinct modes of exocytosis, tuned to two types of electrical activity, may underlay biphasic insulin secretion. PMID- 22201900 TI - The immunomodulating roles of glycoproteins in epithelial ovarian cancer. AB - The complexity of the immune system demands an intricate defense mechanism by tumors. Ovarian and other tumors employ specific glycoproteins and the associated glycan sequences to modulate immune responses. Glycoproteins enable tumor cells that express or secrete these molecules to evade immune cell attack and induce the immune system to promote tumor growth. This review focuses first on the immune environment in ovarian cancer, and the mechanisms of activation and inhibition that immune cells undergo in order to either attack or ignore a target cell. Next we illustrate the immunomodulatory roles of ovarian cancer-associated glycans and glycoproteins in 1. preventing immune synapse formation, 2. serving as ligands of immune cell receptors, 3. scavenging cytokines and chemokines, and 4. participating in the formation of autoantibodies against the tumor. The importance of these immunomodulating strategies from the view points of understanding the tumor immunology of ovarian tumors, potential origin of such mechanisms, and specific strategies to circumvent the glycoconjugate-mediated suppression of immune responses is discussed in this review. PMID- 22201906 TI - Linking atherosclerosis to Alzheimer's disease: focus on biomarkers. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an important vascular component, ultimately resulting in dementia. Recent years have witnessed an enormous interest in the field of biomarkers in medicine both in the field of atherosclerosis and neurodegeneration. Numerous studies have recently reported altered levels of biomarkers of atherosclerotic vascular disease in patients with AD. This review provides an overview of clinical studies assessing biomarkers of atherosclerosis/vascular disease in the serum/plasma of patients with AD and highlights future directions in the field. The study of specific biomarkers of atherosclerosis in AD can contribute to identify different components of the pathophysiology and the complex mechanisms underlying the progression of the disease. PMID- 22201905 TI - The emerging roles of prohibitins in folliculogenesis. AB - Prohibitins are members of a highly conserved eukaryotic protein family containing the stomatin/prohibitin/flotillin/HflK/C (SPFH) domain (also known as the prohibitin (PHB) domain) found in divergent species from prokaryotes to eukaryotes. Prohibitins are found in unicellular eukaryotes, fungi, plants, animals and humans. Prohibitins are ubiquitously expressed and present in multiple cellular compartments including the mitochondria, nucleus, and the plasma membrane, and shuttles between the mitochondria, cytosol and nucleus. Multiple functions have been attributed to the mitochondrial and nuclear prohibitins, including cellular differentiation, anti-proliferation, and morphogenesis. In the present review, we focus on the recent developments in prohibitins research related to folliculogenesis. Based on current research findings, the data suggest that these molecules play important roles in modulating specific responses of granulose cells to follicle stimulating hormone (FSH) by acting at multiple levels of the FSH signal transduction pathway. Understanding the molecular mechanisms by which the intracellular signaling pathways utilize prohibitins in governing folliculogenesis is likely to result in development of strategies to overcome fertility disorders and suppress ovarian cancer growth. PMID- 22201907 TI - The crustacean cuticle: structure, composition and mineralization. AB - Crustaceans have a rigid exoskeleton, which is made of a layered cuticle, covering the soft body parts for protection from conspecific competitors and/or interspecific predators. Calcium carbonate adds rigidity to the crustacean cuticle, which consequently means that growth only occur at each molt. The current study presents a review of existing literature on crustacean exoskeleton cuticle physiology and biochemistry in relation to the molting process with special reference to calcification. As a result, research matter where knowledge remains limited has been identified during the molting process, including 1) whether the same or different epithelial cells are responsible for the decomposition and/or reconstruction of chitin and proteins, 2) how calcium carbonate levels are regulated at the cellular level during transfer between the cuticle and body organs, and 3) what factors maintain the amorphous state of calcium carbonate following deposition in the exoskeleton and temporary storage organs. The identification of these areas of focus provides a basis on which targeted future research may be developed, and potentially applied to other invertebrate or even vertebrate processes. PMID- 22201908 TI - T-cell phosphokinome as a fingerprint of effective graft versus leukemia. AB - Bone marrow and hematopoietic stem cell transplants are given to leukemia patients after chemotherapy and ablative preconditioning, but a significant number will suffer from graft versus host disease (GvHD), where donor immune cells attack recipient tissues. Some graft versus leukemia (GvL) activity protects from leukemia relapse, but determining this balance requires multi factorial consideration. Genetic and cytokine studies have attempted to improve patient outcome predictions, but there is still far to go. Here, we describe important considerations of the phosphokinome as a fingerprint for predicting GvHD and GvL with partial least squares regression (PLSR) multivariate analysis. Distinguishing factors of GvHD and GvL will first be highlighted to appropriately measure T cell responses to cues that stimulate opposite, orthogonal, and overlapping responses. We will also discuss important kinase signaling cascades predicting cellular responses of cytokine expression, proliferation, and death linked with GvHD or GvL. Higher throughput methods to characterize these signals and different model systems will be discussed, along with benefits and challenges of using the T cell phosphokinome as a fingerprint to predict GvHD and GvL. PMID- 22201909 TI - Blocking IDO activity to enhance anti-tumor immunity. AB - Tumors express potentially immunogenic antigens, yet the immune response to these antigens is typically profoundly suppressed. Patients with established tumors behave as if they were functionally tolerant to any antigens associated with the tumor. This tolerance reflects a process of active immune suppression elicited by the tumor, and represents a critical barrier to successful anti-tumor immunotherapy. Indoleamine 2,3-dioxygenase (IDO) is a natural immunoregulatory mechanism contributes to immune suppression and tolerance in a variety of settings. In tumor-bearing hosts, animal models suggest that tumor-induced IDO helps create a tolerogenic milieu within the tumor and the associated tumor draining lymph nodes. IDO directly suppresses the proliferation and differentiation of effector T cells, and markedly enhances the suppressor activity of regulatory T cells (Tregs). Together, these effects contribute to the inability of the immune system to respond effectively to tumor antigens. Treatment of tumor-bearing animals with IDO-inhibitor drugs enhances anti-tumor immune responses, and IDO-inhibitors are synergistic with a variety of chemotherapeutic drugs, anti-tumor vaccines and other immunotherapy. Strategies to pharmacologically inhibit IDO may thus enhance immune-mediated responses following conventional chemotherapy, and may be synergistic with other forms of immunotherapy. PMID- 22201910 TI - Apoptosis, spermatogenesis and male infertility. AB - Apoptosis is an essential physiological process demonstrated to play important roles in diverse physiological processes. As true for several other organs, apoptosis occurs at a high rate in the primary male reproductive organ, testis. Apoptosis is also exhibited by spermatozoa in the human ejaculate. Caspase activation, externalization of phosphatidylserine, alteration of mitochondrial membrane potential and DNA fragmentation are markers of apoptosis found in ejaculated human spermatozoa. These markers appear in excess in sub-fertile men and functionally incompetent spermatozoa. The importance of apoptotic pathway in spermatogenesis and sperm maturation is also indicated by the expression of several markers of this pathway in the testis and epididymis, respectively. This process of regulated cell death serves several important functions in the testis, a few of which include maintaining appropriate germ cell to Sertoli cells ratio, removing defective germ cells and maintenance of overall quality control in sperm production. This review presents an update on the role of apoptosis in male reproduction and fertility, and implications of altered apoptosis in male infertility. PMID- 22201911 TI - Proteinase-activated receptors in the endometrium and endometriosis. AB - Proteinase-activated receptors (PARs) are G protein-coupled receptors activated by various proteinases. PARs play important roles in haemostasis, thrombosis, and inflammation. PAR1 and PAR2 are expressed in endometrial cells from the eutopic endometrium and endometriotic cells derived from endometriotic lesions. A typical activator of PAR1, thrombin, and a typical activator of PAR2, tryptase, are produced in the endometrium as well as endometriotic lesions. PAR1 activation in endometrial stromal cells induces production of vascular endothelial growth factor and matrix metalloproteinases, and increases activities of tissue-type and urokinase-type plasminogen activator. PAR2 activation in endometrial stromal cells stimulates interleukin (IL)-8 and stem cell factor production and proliferation of the cells. PAR1 activation in endometriotic stromal cells induces production of IL-8, monocyte chemotactic protein-1, and cyclooxygenase-2, and proliferation of the cells. PAR2 activation in endometriotic stromal cells increases secretion of IL-6 and IL-8, and the number of the cells. These findings indicate a wide range of function of PAR1 and PAR2 in the endometrium and endometriosis, and suggest PAR1 and PAR2 as possible therapeutic targets for endometriosis. PMID- 22201912 TI - Role of sirtuins, calorie restriction and physical activity in aging. AB - Recently it has been discovered that Sirtuins represent pivotal regulators of lifespan. Caloric restriction (CR) enhances longevity from yeast to mammals. Whereas the relationship between Sirt-1 and CR is clear, the molecular mechanisms by which Sir2 increases longevity are still unknown. In mammals, CR induces physiological and behavioral changes, and many studies have shown that CR decreases production of reactive oxygen species production thus minimizing oxidative damage, leading to the hypothesis that CR by reducing oxidative stress extends the lifespan by counteraction of aging. In fact, the pathophysiology of aging and age-related diseases involves oxidative stress as an early stage in its development. Recently we found that in aged rats the SIRT1 activity was decreased in heart and adipose tissue, showing as aging is characterized in vivo by a reduced efficiency of this key-regulator of longevity. Whereas several studies have reported that increased physical activity can improve mean life span presumably by reducing mortality risk from many age-related diseases, exercise and longevity studies have failed to document an exercise effect on maximum life span. However, in aged rats a moderate prolonged exercise training is able to induce increase in SIRT1 activity, suggesting that this tool could counteract age related dysfunctions. PMID- 22201913 TI - Beneficial effects of propolis on human health and neurological diseases. AB - Propolis is a natural product, collected by honeybees Apis mellifera, from various plant sources. Propolis is extensively used in foods and beverages because it improves human health. It contains more than 300 natural compounds such as polyphenols, phenolic aldehydes, sequiterpene-quinones, coumarins, amino acids, steroids and inorganic compounds. Propolis exhibits a broad spectrum of biological and pharmacological properties such as antimicrobial, antioxidant, anti-inflammatory, immunomodulatory, antitumor, anticancer, antiulcer, hepatoprotective, cardioprotective, and neuroprotective actions. The chemical composition and beneficial properties of propolis vary greatly depending on the phytogeographical areas, seasonal collection time, and botanical source. Polyphenols found in fruits and vegetables are beginning to receive increased attention due to their vital role in protecting neural cells from oxidative stress and neuroinflammation associated with normal aging and chronic age-related diseases. Propolis is one of the most abundant sources of polyphenols (mainly flavonoids and phenolic acids). This overview is an attempt to discuss the molecular mechanism underlying the potential beneficial effects of propolis on human health and neurological diseases. PMID- 22201914 TI - Natural antioxidants in prevention and management of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease that causes dementia in the elderly. As the aging population increases, the prevalence of AD has increased remarkably worldwide and AD has become one of the leading causes of disability and death among the elderly. A number of drugs have been approved for the treatment of AD; however, they produce only modest benefits and have a wide range of side effects. Therefore, extensive studies are underway to identify effective drugs that are free of undesirable side effects. As accumulating evidences have implicated oxidative stress in the initiation and progression of AD, the potential of using nature antioxidants for prevention and treatment of AD has attracted considerable attention. The present review discusses the involvement of oxidative stress in the pathogenesis of AD and the neuroprotective effects of natural antioxidants, such as Ginkgo biloba flavonoids, soybean isoflavones, theanine and nicotine in cell culture and AD transgenic animal models, specifically, their inhibition on Abeta-induced neurotoxicity and the underlined molecular mechanisms. PMID- 22201915 TI - Traditional Chinese herbal medicine and cerebral ischemia. AB - Stroke is an important cause of mortality and morbidity worldwide but effective therapeutic strategy for the prevention of brain injury in patients with cerebral ischemia is lacking. Although tissue plasminogen activator (t-PA) has been used to treat stroke patients, this therapeutic strategy is confronted with ill side effects and is limited to patients within 3 hours of a stroke. Stroke-mediated cell death is a complex interplay of aberrant events involving excitotoxicity, acidosis, inflammation, oxidative stress, peri-infarct depolarization, and apoptosis. Due to the complexity of the events and the disappointing results from single agent trials, the combination of thrombolytic therapy and effective neural protection therapy may be an alternative strategy for patients with cerebral ischemia. Traditional Chinese herbal medicine has been described in ancient medicine systems as a treatment for various ailments associated with stroke. Recently, there have been reports of its benefits in treating stroke. This review will focus on various traditional Chinese herbal medicines and their neuroprotective effects on cerebral ischemia. PMID- 22201916 TI - Therapeutic effect of near infrared (NIR) light on Parkinson's disease models. AB - Parkinson's disease (PD) is a neurodegenerative disorder that affects large numbers of people, particularly those of a more advanced age. Mitochondrial dysfunction plays a central role in PD, especially in the electron transport chain. This mitochondrial role allows the use of inhibitors of complex I and IV in PD models, and enhancers of complex IV activity, such as NIR light, to be used as possible therapy. PD models fall into two main categories; cell cultures and animal models. In cell cultures, primary neurons, mutant neuroblastoma cells, and cell cybrids have been studied in conjunction with NIR light. Primary neurons show protection or recovery of function and morphology by NIR light after toxic insult. Neuroblastoma cells, with a gene for mutant alpha-synuclein, show similar results. Cell cybrids, containing mtDNA from PD patients, show restoration of mitochondrial transport and complex I and IV assembly. Animal models include toxin-insulted mice, and alpha-synuclein transgenic mice. Functional recovery of the animals, chemical and histological evidence, and delayed disease progression show the potential of NIR light in treating Parkinson's disease. PMID- 22201917 TI - The immune plasticity of mesenchymal stromal cells from mice and men: concordances and discrepancies. AB - During the last decade, mesenchymal stromal cells (MSCs) have generated numbers of clinical trials to address inflammatory diseases such as GVHD, Crohn's disease and lupus. Animal models and therapeutic protocols in patients have demonstrated their anti-inflammatory and immunosuppressive properties towards adaptive immune cells. However, the basis of their immune suppression remains hotly debated. In the present review, we discuss the comparative isolation of human and rodent MSCs, their respective immune properties, whether constitutive or licensed by inflammatory or immune reactions, as well as differential efficacy as observed in GVHD clinical trials and related mouse models. Rodent MSCs display a number of immune differences with human MSCs regarding to ease of isolation, licensing pathways resulting in immunosuppression, and expression of immune mediators. These observations urge for caution when translating results generated in murine models into clinical settings. PMID- 22201918 TI - Myeloid-derived suppressor cells: therapeutic modulation in cancer. AB - Improved understanding of the cellular and molecular basis of adaptive immunity has been realized over the past few decades, leading to the development of novel immunotherapeutic strategies capable of promoting host anti-tumor immunity. In order to achieve clinically meaningful results, further understanding of the mechanisms by which tumors suppress host immunity, and the development of therapeutic strategies which overcome tumor-associated immune suppression, will be necessary. Myeloid-derived cells with potent immunosuppressive properties are ubiquitous in human cancers. Improved mechanistic understanding of factors promoting their development, activation and mechanisms of immune suppression are being translated into novel therapeutic approaches, and will be summarized herein. PMID- 22201919 TI - The heart in atherosclerotic renovascular disease. AB - Atherosclerotic renovascular disease (ARVD) is associated with a high rate of cardiovascular disease and mortality. ARVD is an independent risk factor for adverse outcome in coronary artery disease and there is a correlation between the presence of ARVD and severity of cardiovascular disease. ARVD is the most common cause of secondary hypertension and can be found in up to half of elderly patients with chronic heart failure. Abnormal cardiac structure and / or function will be present in 95 % of ARVD patients, with left ventricular hypertrophy (LVH) and diastolic dysfunction the predominant abnormalities. These are likely to be due in part to over-activity of the renin-angiotensin pathway. Up to now, randomised trials have shown no benefit of renal artery revascularisation over medical therapy in terms of cardiovascular events but small case series clearly demonstrate situations where cardiac structure and function respond to revascularisation. Future strategies must focus on accurately identifying sub groups of ARVD patients for whom revascularisation should be first line therapy. PMID- 22201920 TI - Molecular biomarkers of lung carcinoma. AB - Lung carcinoma is still the leading cause of cancer deaths in men and women. There is a constantly increasing need to find molecular biomarkers for lung cancer which can be used for risk stratification, early detection, treatment selection, prognosis and monitoring for recurrence. Recent advances in imaging and improved bronchoscopic techniques have intensified interest in lung carcinoma screening techniques, especially in new molecular markers which can help cytopathologists to make a definitive diagnosis on very small specimens in non invasive, non-expensive, simple and efficient manner. Several decades of intensive research have originated numerous potential lung carcinoma molecular biomarkers but only few turned out to be useful in clinic. The review describes types of biomarkers, sources and techniques for their identification in cancer diagnosis and therapy. A deep understanding of each biomarker will be a key to efficiently diagnose lung carcinomas and direct patients toward beneficial drugs based on individual patient profile. PMID- 22201921 TI - Endothelial microparticles in transplant patients - great potential but a long way to go. AB - This overview provides information on the current state of endothelial microparticle research. Microparticles are small membrane vesicles shed by different cell types, which contain cell surface proteins and cytoplasmic components of the original cell. The microparticle production is a part of normal cell function, but it increases by apoptotic cells and cells under stress. Numerous evidences suggest that circulating endothelial microparticles may be a marker of endothelial cell function. Endothelial cells play an important role in the pathogenesis of allograft dysfunction and rejection. The endothelium is one of the main targets in allograft rejection. Recent studies have indicated that levels of circulating endothelial microparticles change in patients with solid organ transplants, including kidneys. We believe that circulating endothelial microparticles may be a useful tool of allograft function monitoring and/or a diagnostic marker of allograft rejection. PMID- 22201922 TI - Epithelial-to-mesenchymal transition: possible role in meningiomas. AB - Epithelial-to-mesenchimal transition (EMT) is a process involved in invasion and metastasis of tumors. The occurrence of EMT during tumor progression resembles the developmental scenario and sheds light on important mechanisms for the initial step of metastasis - invasion where noninvasive tumor cells acquire motility and ultimately disseminate to distant organs. The hallmark of EMT is the loss of expression of the cell-cell adhesion molecule E-cadherin. The numerous reports by many authors as well as our own results indicate that E-cadherin plays a role in CNS tumors - meningiomas. Our studies showed that 73 % of meningiomas had downregulation of E-cadherin. Moreover, loss of heterozygosity of E-cadherin was observed in 32 % of meningiomas. Bound to E-cadherin in adherens junctions is beta-catenin, whose translocation to the nucleus is yet another molecular event involved in EMT. In our study beta-catenin was progressively upregulated from meningothelial to atypical, while 60 % of anaplastic meningiomas showed upregulation and nuclear localization of the protein. The elucidation of molecular mechanisms that govern EMT will offer new approaches and targets to restrain metastasis. PMID- 22201923 TI - Biomedical aspects of pyridoxal 5'-phosphate availability. AB - The biologically active form of vitamin B6, pyridoxal 5'-phosphate (PLP), is a cofactor in over 160 enzyme activities involved in a number of metabolic pathways, including neurotransmitter synthesis and degradation. In humans, PLP is recycled from food and from degraded PLP-dependent enzymes in a salvage pathway requiring the action of pyridoxal kinase, pyridoxine 5'-phosphate oxidase and phosphatases. Once pyridoxal 5'-phosphate is made, it is targeted to the dozens different apoenzymes that need it as a cofactor. The regulation of the salvage pathway and the mechanism of addition of PLP to the apoenzymes are poorly understood and represent a very challenging research field. Severe neurological disorders, such as convulsions and epileptic encephalopathy, result from a reduced availability of pyridoxal 5'-phosphate in the cell, due to inborn errors in the enzymes of the salvage pathway or other metabolisms and to interactions of drugs with PLP or pyridoxal kinase. Multifactorial neurological pathologies, such as autism, schizophrenia, Alzheimer's disease, Parkinson's disease and epilepsy have also been correlated to inadequate intracellular levels of PLP. PMID- 22201924 TI - The impact of aromatic amines on the environment: risks and damages. AB - Aromatic amines are a group of chemicals whose ubiquitous presence in the environment is a result of the multitude of sources from which they originate. These compounds are widely used as raw materials or at intermediate stages in the manufacturing of industrial chemicals such as pesticides, medicines, dyestuffs, polymers, surfactants, cosmetics and corrosion inhibitors, especially in dyestuff factories. As with most chemical carcinogens, aromatic amines need to be metabolized into reactive electrophiles in order to exert their carcinogenic effects. This activation typically involves N-oxidation of arylamines to yield N hydroxyarylamines. Since these amines are potential carcinogenic agents and are discharged into the atmosphere, water and soil, they constitute an important class of environmental pollutants of enormous concern due to the potential for human exposure. PMID- 22201925 TI - Nonsyndromic X-linked hearing loss. AB - To date, 135 loci and 50 genes have been identified as causes of nonsyndromic hearing loss. Until recently, four loci (DFN2, DFN3, DFN4, and DFN6) had been implicated in nonsyndromic X-linked hearing loss; however, a new classification (DFNX1-5) has been proposed to reduce confusion in the terminology. The different types of nonsyndromic X-linked hearing loss demonstrate various clinical features in terms of the onset and progressiveness of hearing loss, pattern of audiogram, and the presence or absence of inner ear malformations. In addition to the POU3F4 gene, which was the first gene identified as causing nonsyndromic X-linked hearing loss, a second gene, PRPS1, has recently been identified to be the causative gene of DFNX1 (DFN2). This study reviews the new classification system, as well as the clinical features, molecular genetics, and developmental pathogenesis of different forms of nonsyndromic X-linked hearing loss. PMID- 22201926 TI - Genetic and epigenetic signatures of breast cancer subtypes. AB - Breast cancer is a heterogeneous disease at both the histological and molecular levels. The current model of breast tumorigenesis suggests that the normal mammary stem cell and the various progenitors that arise thereof can be transformed and generate lineage-restricted tumor phenotypes. This model is supported by observations that the different subtypes of breast cancer share transcriptional signatures intrinsic to normal components of the mammary epithelium. Studies have since elaborated these molecular signatures to include recurrent genetic abnormalities, patterns of DNA methylation and dysregulation of microRNAs. Here we aim to review the current state of knowledge concerning the cellular etiology of breast cancer subtypes and the genetic, transcriptional and epigenetic aberrations associated with each subtype. PMID- 22201927 TI - Increased levels of hemoglobin and alpha1-microglobulin in Huntington's disease. AB - Hemoglobin released from damaged erythrocytes is a major pro-oxidant, generator of free radicals and inflammatory mediator. Huntington's disease is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities, in which oxidative stress has been suggested as a possible pathogenic mechanism. In the present work we have investigated levels of hemoglobin and markers of oxidative damage, including the heme- and radical scavenger alpha1-microglobulin, in plasma and urine samples from two separate sample cohorts, including controls, premanifest gene carriers and subjects at different stages of Huntington's disease. The results show statistically significant increased levels of hemoglobin and alpha1-microglobulin in Huntington's disease urine samples. Interestingly, urine hemoglobin levels correlate with clinical severity. The results suggest that hemolysis may be linked to the pathogenesis of Huntington's disease and that assay of hemoglobin and alpha1-microglobulin may provide biomarkers that are linked to biologically relevant processes. PMID- 22201928 TI - Fluctuation of systemic immunity in melanoma and implications for timing of therapy. AB - Evidence suggests that immunological response in chronic inflammation is dynamic, oscillating between active immunity and tolerance. We hypothesized that a similar dynamic exists in melanoma and administration of therapy during a unique phase of such oscillation could impact clinical outcome. Patients with metastatic melanoma eligible to undergo temozolomide underwent serial measurements of C-reactive protein (CRP) and immune biomarkers every 2-3 days for 2 weeks before starting therapy. Treatment was initiated prior to the estimated next CRP peak, or on day 14 post-registration if a peak was not identified. Time profiles of measured biomarkers were analyzed by fitting serially measured data points to 9 mathematical functions and were correlated to time of therapy and outcome. Data suggested that metastatic melanoma patients exhibit a dynamic immune response. The fluctuation of several biomarkers fitted cosine functions with periods which were multiples of 3-4 days. Chemotherapy delivery during a unique phase of this cycle seemed to correlate with improved response. Individualized conventional chemotherapy delivery by synchronizing treatment with pre-existing patient specific biorhythms may improve clinical outcomes in metastatic melanoma. PMID- 22201930 TI - The tau-like protein in silkworm (Bombyx mori) induces microtubule bundle formation. AB - Tau proteins are major microtubule-associated proteins (MAPs), which promote polymerization of tubulin and determine spacings between microtubules in axons of both the central and peripheral nervous systems (CNS and PNS). Here, we cloned and identified a tau-like protein BmTau from silkworm, Bombyx mori (GenBank accession number FJ904935). The coding sequence of BmTau is 723 bases long and encodes an approximate 30 kDa protein. In the C-terminus of BmTau are contained four predicted microtubule-binding domains, which share strong sequence homology to its ortholog in Drosophila melanoganster. Relative real-time PCR analysis showed ubiquitous expression of BmTau in both neurons and non-neural cells, with its mRNA abundantly expressing in brain but significantly less detected in trachea, fat body, and silkgland. Furthermore, immunocytochemical studies in BmN cells transfected with EGFP-BmTau indicated that BmTau functioned as microtubule bundling protein as its orthologues. PMID- 22201931 TI - Stromal phenotype of dental follicle stem cells. AB - It has been suggested that stem/progenitor cells exist in dental tissue. This study identified adult mesenchymal stem/stromal cell-like populations in the dental follicle of human impacted third molars.The immunohistochemical analysis, of dental follicle using known stem-cell markers: Cytokeratins (AE1-AE3), Smooth Muscle Actin, Ki-67, CD34, CD44, CD45, CD56, and CD133. A positive reaction for at least one of the markers typical of stromal phenotype (CD56, CD44 and CD271) was observed in seven cases . Interestingly, all positive cases showed coexpression of CD44 and CD56, except for one case which was CD56 positive and CD44 negative. Immunohistochemical reaction was negative in all 27 cases for Ki 67, Cytokeratins, Smooth Muscle Actin, CD34, CD133 and CD45. The association: negative for CD34, CD45, CD133, and positive for CD44, CD56 (markers of a subpopulation of stem cells from bone marrow) suggests these may be quiescent mesenchymal stem cells, a hypothesis supported by the negativity of Ki-67 (proliferative index). Our results are compatible with the identification of immature fibroblast cells with phenotypic features of stromal stem cells in the dental follicle. PMID- 22201932 TI - Influence of lifestyle habits, nutritional status and insulin resistance in NAFLD. AB - Non alcoholic fatty liver disease (NAFLD) is associated with obesity, diabetes and insulin resistance (IR). The aim of our study was to assess the relationship between IR, anthropometry, lifestyle habits, resting energy expenditure (REE) and degree of fatty liver at ultrasound in 48 overweight patients with NAFLD as compared to 24 controls without fatty liver, matched for age. Nutritional status, alcohol intake and physical activity were assessed by skinfold thickness measurements, a 7-day diary, and SenseWear armband (SWA). REE was assessed by both SWA (REE-SWA) and a Vmax metabolic cart (REE-Vmax). Fatty liver was measured by US and the Doppler Power Index was calculated. IR was assessed using the HOMA index. There was significant correlation between waist circumference, HOMA, Doppler power index and fatty liver grade at US. Multivariate analysis showed that alteration of waist circumference, Doppler power index, and HOMA were the major significant predictors of fatty liver. Our data demonstrated a significant association between NAFLD and central adiposity and IR. PMID- 22201933 TI - Determination of nanoparticles in biological matrices. AB - Human exposure to nanoparticles has increased considerably due to anthropogenic activities dominated by coal and diesel oil fuel combustion. Not only the inhalation of nanoparticles, which nowadays is considered to be the most significant via of exposure to nanomaterials, but also the gradually more employment of nanoparticles in products such as cosmetics, deodorants, textiles, or even food is broadening the exposure to those materials. Developing the previous applications will obviously require the use of analytical methodologies to analyse biological matrices in order to assess potential risks in their use and take appropriate corrective actions. This chapter describes a general overview of the most important analytical techniques for the analysis of nanoparticles in biological matrices. PMID- 22201934 TI - ECM analog technology: a simple tool for exploring cell-ECM dynamics. AB - Cells in a functional tissue display a highly interactive relation with their neighboring cells and associated biochemical milieu. Serious disruption in the existing homeostatic balance in the extra-cellular matrix (ECM) may lead to abnormal response by the cells. With insufficient understanding of Cell-ECM interaction and in absence of simple tools for in vitro cell-culture in 3D, we still have to rely on the data generated by growing cells in 2D. In order to comprehend Cell-ECM dynamics it is important to recreate in vivo like microenvironment in 3D. Senescence and loss of function commonly observed in cells cultured in 2D are expected to be surmounted using such tools. Unlike prevailing belief that 3D culture is required only for tissue engineering (TE) and regenerative medicine, simple and easy to handle tools for ex vivo 3D culture may lead to greater impact. With the potential to improve our understanding about cellular behavior, both in normal and abnormal surroundings, they may eventually influence the diagnosis. Here we discuss some of the tools for cell culture in 3D, made available through novel cell-interactive ECM analog technology. PMID- 22201929 TI - Sex hormones, aging, and Alzheimer's disease. AB - A promising strategy to delay and perhaps prevent Alzheimer's disease (AD) is to identify the age-related changes that put the brain at risk for the disease. A significant normal age change known to result in tissue-specific dysfunction is the depletion of sex hormones. In women, menopause results in a relatively rapid loss of estradiol and progesterone. In men, aging is associated with a comparatively gradual yet significant decrease in testosterone. We review a broad literature that indicates age-related losses of estrogens in women and testosterone in men are risk factors for AD. Both estrogens and androgens exert a wide range of protective actions that improve multiple aspects of neural health, suggesting that hormone therapies have the potential to combat AD pathogenesis. However, translation of experimental findings into effective therapies has proven challenging. One emerging treatment option is the development of novel hormone mimetics termed selective estrogen and androgen receptor modulators. Continued research of sex hormones and their roles in the aging brain is expected to yield valuable approaches to reducing the risk of AD. PMID- 22201935 TI - LOH of PTCH1 region in BCC and ovarian carcinoma: microsatellite vs. HRM analysis. AB - Loss of heterozygosity (LOH) of tumor suppressor genes is a frequent event in tumorigenesis. LOH is most often analyzed by microsatellite typing, but here we offer a fast and efficient method for simultaneous SNP genotyping and mutation scanning, which can also be used for LOH detection. High resolution melting (HRM) provides simple variant detection, and can be adopted for a wide range of applications. When a melting profile for a specific SNP is determined, the screening can be done without the need for sequencing, and only the melting profiles differing from the established melting profiles should be sequenced. LOH of PTCH1 gene is often found in a series of different tumors, for example basal cell carcinoma (BCC) and ovarian carcinoma (OC). In this study LOH was detected in 50 % of BCC and 27.27 % of OC, and the detection rates of microsatellite typing and HRM were comparable. Both methods depended only on the heterozygosity of the loci analyzed, but HRM offers an additional advantage of detection of all sequence variants in the gene of interest. PMID- 22201937 TI - Prostaglandin E synthase is regulated in postnatal mouse testis. AB - Prostaglandins have important roles in the male reproductive system. In this study, we report on the distribution and regulation of cPGES during postnatal development of mouse testis. The expression of cPGES was weak in testis 5 days after birth and increased through the 10th and 15th day. From the 20th day onward, the cPGES expression in testis reached the level of adult mice. cPGES was expressed at a constantly low level in Sertoli cells in the testis from infant to adult stages. With the occurrence of meiosis during puberty, a high level of cPGES was detected in the spermatocytes and round spermatids, which was then maintained throughout the adulthood. In addition, cPGES was found highly expressed in the epididymis, seminal vesicles and vas deferens This suggests that cPGES in Sertoli cells in infant to juvenile mouse testis contributes to a basic PGE2 synthesis in seminiferous tubules. However, the high level of cPGES in spermatocytes and spermatids may maintain a high amount of PGE2 in seminiferous tubules, which may be tightly coupled with the spermatogenic cycle. PMID- 22201938 TI - Functional oncoimaging techniques with potential clinical applications. AB - Structural imaging is currently used in standard clinical practice on a daily basis to qualitatively or semiquantitatively detect, characterize stage, assess post-therapeutic change in, and determine recurrence of malignant tumors based on structural features or gross degree of contrast enhancement. Unfortunately, structural imaging does not provide information about tumor physiology, biological processes, and molecular features, and as such tumors cannot be fully characterized and monitored. In order to improve the evaluation of tumors and to reduce cancer-related morbidity and mortality, there is a need for functional imaging modalities which allow visualization and quantification of physiological and biochemical processes in vivo. This article will review a selection of the wide variety of functional imaging methods available for non-invasive evaluation of tumor physiology and molecular processes. PMID- 22201939 TI - Oncology biomarkers for gynecologic malignancies. AB - Current therapies efficiently treat most patients with gynecologic malignancies detected at an early stage. Thus, the identification of oncology biomarkers for screening and monitoring of occult tumors has been highly prioritized. Hyperglycosylated human chorionic gonadotropin (hCG) epitomizes oncologic biomarker, as the serum level of this hormone is elevated in virtually all cases of gestational trophoblastic diseases. On the other hand, despite the availability of various markers such as CA125, CA19.9, CA15.3, CA72-4, Inhibin, beta-hCG, AFP, CEA and many more biomarkers under investigation, fewer than 25 % of all ovarian cancers are currently detected in stage I. Large efforts have been undertaken to further identify composite markers for gynecologic malignancies that may exhibit greater specificity when studied over time, as well as to develop risk models and screening algorithms aimed at improving the specificity and sensitivity of diagnostic tests. In this review, we provide a comprehensive analysis of the biomarkers currently used in clinics for gynecologic malignancies, as well as an outlook of the most promising oncologic biomarkers currently under study. PMID- 22201936 TI - Obesity-related glomerulopathy and podocyte injury: a mini review. AB - Obesity-related glomerulopathy (ORG) is morphologically defined as focal segmental glomerulosclerosis and glomerulomegaly. Podocyte hypertrophy and reduced density are related to proteinuria which in a portion of patients is in the nephrotic range and evolvs towards renal failure. This article reviews the pathogenetic mechanisms of podocyte injury or dysfunction and lists new possible antiproteinuric strategies based on pharmaceutical targeting of the reported pathogenetic mechanisms. The pathogenetic mechnisms discussed include: renin angiotensin system, plasminogen activation inhibitor-1 (PAI-1), lipid metabolism, adiponectin, macrophages and proinflammatory cytokines, oxidative stress. The proposed antiproteinuric strategies include: AT2 receptor blockers; adipokine complement C19 TNF-related protein-1 blocker; selective PAI-1 inhibitor; farnesoid x receptor activation; increase of circulating adiponectin; selective antiinflammatory drugs; more potent antioxidants (Heme oxigenase, NOX4 inhibitors). However, because ORG is a rare disease, the need for a long term pharmaceutical approach in obese proteinuric patients should be carefully evaluated and limited to the cases with progressive loss of renal function. PMID- 22201940 TI - Endocrine relationships between rank - related behavior and antler growth in deer. AB - In this review, we analyze endocrine aspects of the relationships between antlerogenesis and rank-related behavior. The explanation of these relationships has been based on the presumption that the antler growth is regulated by hormones modulated by agonistic behavior. Originally, we assumed that these relationships are primarily testosterone dependent. In the eighties, it was reported that the insulin-like growth factor 1 (IGF-1) is the antler-stimulating hormone. This hypothesis was supposed to replace an earlier theory that the antler-stimulating hormones are either androgens or their derivatives. Here, we present historical and recent views on these issues. In particular, we analyze the arguments in favor and against the role of testosterone and IGF-1 in antler growth and present a comparison of the results obtained across some deer species. In this context, we review and discuss experiments with castration of various deer species and analyze data from papers dealing with in vivo studies. We conclude that testosterone and not IGF-1 is the main antler stimulating and regulating hormone, and that concentrations of testosterone may be modified by social behavior. PMID- 22201941 TI - Versatility of oxidoreductases in the remediation of environmental pollutants. AB - Enzymatic transformation of recalcitrant and other pollutants is a promising eco friendly alternative to physico-chemical methods in environmental remediation. This review summarizes some of the significant advances in applications of oxidative enzymes for treatment of xenobiotics. The review also discusses some of the underlying principles and enzyme reaction mechanisms in the detoxification or removal of xenobiotic compounds such as dyes, phenolic compounds, nitroaromatic compounds and polyaromatic hydrocarbons, as a way of remediating contaminated soils or wastewaters. PMID- 22201942 TI - Towards three-dimensional structural analysis of (pro)renin receptor. AB - The (pro)renin receptor is a single-spanning membrane protein that binds both renin and its inactive precursor prorenin. The receptor binding enhances the catalytic activity of renin and induces non-proteolytic activation of prorenin as well as triggers intracellular signaling with either renin or prorenin as a ligand. Three-dimensional structural information of (pro)renin receptor is important to understand the receptor binding. This information is not available due to the lack of its three-dimensional structure. In this review, we summarize the binding properties of (pro)renin receptor, provide the results of structure prediction and point out the issues to be tackled towards three-dimensional structural analysis of this receptor. PMID- 22201943 TI - Hepatocellular carcinoma stem cells: origins and roles in hepatocarcinogenesis and disease progression. AB - Hepatocellular carcinoma (HCC) is a treatment-resistant malignancy with an increasing incidence worldwide. More than 500,000 individuals suffer from this disease annually. Risk factors for human HCC include hepatitis B and C infections, dietary aflatoxin, alcohol abuse, smoking, and oral contraceptive use. Accumulating evidence suggests that liver stem cells play a critical role in HCC development and progression. Dedifferentiated hepatocytes, hepatic oval cells and bone marrow cells are the three major types of liver stem cells, and CD133, CD90, and EpCAM are identified as specific antigenic markers for HCC stem cells. Wnt, Hedgehog, and the angiogenic signalings are main pathways that regulate the HCC stem cell self-renewal and pluripotential, and may be potential targets for novel therapeutic strategies of this malignancy. This review article provides an update in the studies of live and HCC stem cells. PMID- 22201944 TI - Genetically modified stem cells for the treatment of neurological diseases. AB - The central nervous system has a very poor regenerative potential and is difficult to access. This partly explains why neurological diseases often lack appropriate therapeutic options and represent the most significant burden for healthcare systems. Progress in understanding the molecular background of neurological diseases requires innovative approaches offering new hope for the patients. One of the most intriguing and promising options is the combination of stem cells with gene therapy. Unlike fibroblasts, stem cells exhibit a high tropism for disease-affected tissue and integrate into the nervous tissue. This makes them ideal candidates for the production and delivery of molecules of interest for treating the nervous system. This article reviews the methodology for obtaining pluripotent stem cells (iPSCs) as precursors for neuronal cells, glial cells and the current state of the art in applications of genetically modified stem cells in animal models of neurodegenerative diseases, stroke, axonal damage, tumors and epilepsy. PMID- 22201945 TI - Temporal and spatial expression of AIF in the mouse uterus during early pregnancy. AB - Apoptosis-inducing factor (AIF) is a phylogenetically old, bifunctional protein with a pro-apoptotic function and redox activity. AIF regulates apoptosis and also plays a role in the defense against stress depending on its subcellular localization. Embryo implantation is a complicated process, in which an activated blastocyst interacts with a receptive uterus. The expression and regulation of AIF were investigated in this study in the mouse uterus during early pregnancy, pseudopregnancy, delayed implantation, artificial decidualization and under hormonal treatment using in situ hybridization, immunohistochemistry and real time PCR. During early pregnancy, temporally and spatially regulated patterns of AIF expression were found in the mouse uterus; AIF expression in the luminal epithelium and glandular epithelium is regulated by steroid hormones; AIF mRNA expression in the stroma is influenced by the active blastocyst; and AIF protein was found to be located in the cytoplasm rather than the nucleus through confocal microscope. Our data suggest that AIF might play an important role during mouse embryo implantation and that the role of AIF might be implemented through its physiological activity rather than through its pro-apoptotic function in the mouse uterus during this period. PMID- 22201947 TI - FVIIa as therapeutic agent in hemophilia and beyond. AB - Around 20 % of the patients with severe hemophilia develop inhibitory antibodies against the factor they lack. In these patients the administration of FVIII/FIX concentrates are not hemostatically effective. Since FVIIa is not enzymatically active unless complexed with tissue factor (TF) exposed following an injury to the vessel wall, it was considered an attractive candidate for improved treatment of patients with inhibitors. Plasma-derived FVIIa was purified and shown to induce hemostasis in two hemophilia A patients with inhibitors. Later recombinant FVIIa (rFVIIa) was developed and pharmacological doses have an efficacy rate of around 90 % in serious bleedings and permit major orthopaedic surgery. These findings were a breakthrough in understanding the FVII-TF pathway in hemostasis. The initially formed FVIIa-TF complexes provide a limited amount of thrombin, activating FVIII, FV, FXI as well as platelets. On the activated platelet surface the full burst of thrombin necessary for generating a firm fibrin hemostatic plug occurs. In case of impaired thrombin generation, loose fibrin plugs easily dissolved are formed. Extra rFVIIa enhances thrombin generation and generates tight fibrin plugs. PMID- 22201946 TI - Lipidome analysis reveals antifungal polyphenol curcumin affects membrane lipid homeostasis. AB - This study shows that antifungal curcumin (CUR), significantly depletes ergosterol levels in Candida albicans. CUR while displaying synergy with fluconazole (FLC) lowers ergosterol. However, CUR alone at its synergistic concentration (lower than MIC50), could not affect ergosterol contents. For deeper insight of CUR effects on lipids, we performed high throughput mass spectroscopy (MS) based lipid profiling of C. albicans cells. The lipidome analysis revealed that there were no major changes in phosphoglycerides (PGLs) composition following CUR treatment of Candida, however, significant differences in molecular species of PGLs were detected. Among major SPLs, CUR treatment resulted in the reduction of ceramide and accumulation of IPCs levels. The lipidome of CUR treated cells confirmed a dramatic drop in the ergosterol levels with a simultaneous accumulation of its biosynthetic precursors. This was further supported by the fact that the mutants defective in ergosterol biosynthesis (ERG2 and ERG11) and those lacking the transcription factor regulating ergosterol biosynthesis, UPC2, were highly susceptible to CUR. Our study first time shows that CUR, for its antifungal activity, targets and down regulates delta 5, 6 desaturase (ERG3) resulting in depletion of ergosterol. This results in parallel accumulation of ergosterol biosynthetic precursors, generation of reactive oxygen species (ROS) and cell death. PMID- 22201949 TI - Natural suppressor cells; past, present and future. AB - Myeloid Derived Suppressor Cells (MDSCs) are a mixed group of bone marrow-derived myeloid cells containing macrophages, granulocytes, immature DCs and early myeloid precursors that have immune suppressive activity. MDSCs infiltrate the BM, spleen and peripheral blood of tumors-bearing experimental animals and are found in the blood of cancer patients as a result of tumor-induced alterations in myelopoiesis. Evidence from murine model systems indicated that myeloid-derived cells with suppressor activity also accumulate in non-tumor bearing hosts in response to infection, chemotherapy, stress, and immune senescence. MDSCs are considered key negative regulators of immune responses. Their association with tumor-associated immune defects make MDSCs an attractive target for therapeutic intervention in cancer. PMID- 22201948 TI - Different molecular targets of Icariin on bMSCs in CORT and OVX -rats. AB - Icariin (ICA) is an active component of Herba Epimedium effective in preventing osteoporosis. Bone mesenchymal stem cells (bMSCs) are an important target by which ICA promotes osteogenesis. However, its molecular mechanisms are poorly defined. In the present study, we induced osteoporosis in rats by corticosterone (CORT) and ovariectomy (OVX), treated both with ICA for 2 weeks or 3 months. As results, both models displayed bone loss tendency within 2 weeks and a significant bone loss after 3 months. ICA promoted bMSCs diffenentiation from CORT rat, and increased the secretion of osteocalcin, collagen I, runt-related transcription factor 2 in OVX model. Gene profile revealed a marked shift of gene expression by ICA, with much more significance in CORT rats. These potential molecular targets were involved in cell communication, adhesion, cycle and cytokines secretion. But very few genes overlapped in these two models, suggesting the effects and molecular mechanisms of ICA on osteoporosis might be pathogenesis-dependent. However, the Notch signaling pathway was common in both models, and should be paid close attention to for further study. PMID- 22201950 TI - Mfd and transcriptional derepression cause genetic diversity in Bacillus subtilis. AB - Scientists have been aware for many years of genetic programs that get activated under stress and produce genetic variants in cells that escape non-proliferating conditions. These programs are well conserved in all organisms and expand our view of evolution. They mediate genome instability, create diversity in antibody formation, expand metabolism and increase fitness of pathogens within host environments. Error-prone DNA replication and repair are genetic variability causing agents that get stimulated by the onset of cellular stresses. Embedded in these programs is the ability to limit mutagenesis to defined genomic regions and times, ensuring integrity of most of the genome. Recent evidence suggests that factors involved in RNA polymerase (RNAP) processivity or transcriptional derepression contribute to the generation of stress-induced mutations. In Bacillus subtilis, transcription-associated mutagenesis has been shown to be independent of recombination-dependent repair and, in some cases, of the Y DNA polymerases. Central to stationary-phase mutagenesis in B. subtilis is the requirement for Mfd, transcription coupling repair factor, which suggests a novel mechanism from those described in other model systems. PMID- 22201951 TI - BNP and iNOS in decompensated chronic heart failure: a linear correlation. AB - Heart Failure (HF) is characterized by activation inflammatory mediators that contributes to the disease progression. Brain natriuretic peptide (BNP) plasma levels increase in HF with a prognostic significance. The aim of this study was to evaluate the expression and activity of inducible nitric oxide synthase (iNOS) in peripheral blood mononuclear cell (PBMC) extracted from patients and a possible linear correlation between iNOS and plasma levels of BNP in decompensated chronic HF (DCHF) patients. To establish the DCHF, thirty-five male patients were evaluated. All patients were venesected within 24 h of admission to exclude an inflammatory state through evaluation of c-reactive protein. Only twenty subjects showed symptoms of DCHF were included in the study. Other patients were included in the control group. In DCHF, left ventricular ejection fraction (LVEF) percent was reduced and systolic pulmonary artery pressure (PAPs) was increased. Furthermore, iNOS expression and BNP plasma levels were significantly higher in patients with DCHF as compared to controls group. These findings indicate that in DCHF patients, iNOS activity exhibits a significant linear correlation with plasmatic BNP level. PMID- 22201952 TI - Role of the RNA-binding protein Hfq in Serratia plymuthica. AB - The RNA-binding protein Hfq has been well studied as a global post transcriptional regulator which controls diverse cellular processes in bacteria. However, the function in the genus of Serratia has remained unexplored. Here we show that beyond mutation in Hfq resulting in their growth defects, Hfq has global effects on a variety of biocontrol-related phenotypes in the endophytic strain G3 of Serratia plymuthica, including antifungal activity, production of exoenzymes, as well as motility and biofilm formation. Especially for the first time, Hfq is observed to control biosynthesis of auxin indole-3-acetic acid (IAA) and antibiotic pyrrolnitrin (PRN), which are key determinants responsible for plant growth promotion and suppression of phytopathogens, respectively by G3. Additionally, Hfq is also required for the production of RpoS, a major stress sigma factor in G3. In contrast to E. coli, translation of hfq in G3 is positively autoregulated. Further investigation of the molecular mechanisms involved in regulation of IAA and pyrrolnitrin production by Hfq and its role in the regulatory networks of G3 will help to optimize the beneficial plant-microbe interactions. PMID- 22201953 TI - Diagnostic and therapeutical role of vitamin D in chronic hepatitis C virus infection. AB - Although initially identified as a calcium homeostatic hormone, vitamin D is now known to have pleiotropic functions, dealing with both innate and adaptative immunity. Calcitriol mediates its biological effects by binding to the vitamin D receptor (VDR), which is expressed not only by intestine, bone and kidney but also on cell membranes of T lymphocytes, B lymphocytes, dendritic cells and macrophages. Vitamin D plays a role on the degree of liver damage in patients with chronic hepatitis C (CHC): low vitamin D levels have been associated with high hepatic necroinflammatory activity and progression of liver fibrosis. Vitamin D, in CHC patients, could also affect the response to antiviral therapy: in fact, recent studies have shown a relationship between low responsiveness to IFN-based therapy and low vitamin D serum levels. Further studies are required to better assess if vitamin D could work as a reliable noninvasive marker of liver fibrosis and whether vitamin D supplementation could be given to all CHC patients together with standard antiviral treatment, in order to improve the rate of sustained virological response (SVR). PMID- 22201954 TI - Cytogenetics of hepatoblastoma. AB - The cytogenetics of hepatoblastoma demonstrate recurring events which include whole chromosome trisomies, most commonly trisomy of chromosome 2, 8, or 10. In addition, unbalanced translocations involving a breakpoint on the proximal short arm of chromosome 1 are observed which result in a duplication of the long arm of chromosome 1q. The most commonly involved reciprocal chromosomal arm is 4q, although the reciprocal chromosome is highly variable and always results in a loss of chromosomal material. The full significance of these chromosomal changes has yet to be confirmed in large studies, however a suggestion of an association of duplication of regions of 2q with a poor prognosis. A rare sub-type of hepatoblastoma, known as the small cell undifferentiated variant, is associated with deletion or translocation of 22q, the locus of the rhabdoid tumor gene, SMARCB1. PMID- 22201955 TI - Liver transplantation in the management of unresectable hepatoblastoma in children. AB - Complete surgical resection is essential to long-term survival in children with hepatoblastoma. We present the guidelines from the Children's Oncology Group (COG), liver tumor study group of the Societe Internationale Oncologie Pediatrique (SIOPEL), and German Pediatric Oncology Group (GPOH) for early referral of children with potentially unresectable hepatoblastoma to a specialty center with expertise in extreme resection and liver transplantation. Patients who will become candidates for liver transplantation should receive chemotherapy following the same protocols as for children undergoing a partial hepatectomy. The Pediatric Liver Unresectable Tumor Observatory (PLUTO) is an international prospective database established to collect data and make future recommendations on controversial issues regarding the use of transplant in hepatoblastoma including: 1) What is the optimal treatment of multifocal tumors. 2) What is the role of extreme resection vs. liver transplant in patients with major venous involvement. 3) What is the role of transplant in patients who present with lung metastasis. 3) Should patients with tumor relapse be offered a rescue transplant. 4) What is the role of pre- and post- transplant chemotherapy. PMID- 22201956 TI - Tanshinone IIA pretreatment attenuates hepatic ischemia-reperfusion. AB - Tanshinone IIA (Tan IIA), an active component derived from Salvia miltiorrhiza root, has been used to treat various ischemic cardiovascular and cerebrovascular diseases. However, its impact on hepatic ischemia/reperfusion (I/R) injury remains unclear. Here, we addressed this issue by using a 90-minute partial liver ischemia model. Mice were administered Tan IIA intragastrically for 3 days before ischemia and were assessed for liver damage 6-h after reperfusion. Tan IIA pretreatment significantly inhibited serum aminotransferases and proinflammatory cytokine levels along with reduced inflammatory infiltration and liver damage. Mechanistic studies revealed that Tan IIA suppressed TLR4 expression in nonparenchymal cells (NPCs) and induced heme oxygenase-1 (HO-1) production in both parenchymal and NPCs. Moreover, the phosphorylation of AKT and ERK1/2 in the liver was enhanced, while the phosphorylation of JNK, p38 and p65 was suppressed. These results suggest Tan IIA can suppress TLR4 signaling which then enhances HO 1 expression along with reduced proinflammatory cytokine expressions in the liver, and Tan IIA could be a useful candidate drug in clinic for prevention and treatment of hepatic I/R injury. PMID- 22201957 TI - Size matters: smart copolymeric nanohydrogels: synthesis and applications. AB - In this work the synthesis of smart nanoparticles capable of respond to external stimulus (pH and temperature variations) is reported. To avoid post polymerization modification, functionalized monomers able to respond to pH and temperature changes were and then polymerized. The synthesized monomers have the capability for coupling with folic acid which is the target molecule. For this reason their polymers can be used as targeted drug delivery systems. Smart polymeric nanoparticles were prepared by direct and inverse microemulsion polymerization of the synthesized monomers. The nanoparticles were charged with drugs and their release kinetic was studied. PMID- 22201958 TI - Oxidative stress and inflammatory bowel disease. AB - Inflammatory Bowel Disease (IBD) is a chronic relapsing and remitting inflammatory condition of the gastrointestinal tract. The exact cause of IBD remains undetermined, the condition appears to be related to a combination of genetic and environmental factors. While many gaps in our knowledge still exist, the last two decades have witnessed an unprecedented progress not only in the etiology ; but mainly in the mechanisms underlying the chronic inflammatory response, immunologic and genetic aspects. We review some recent points of research in pathogenesis with special stress on oxidative stress and its correlations with disease activity. PMID- 22201959 TI - Appraisal of the porcine kidney autotransplantation model. AB - Animal models are extensively used for transplantation related research, especially kidney transplantation. Porcine autotransplantation models are considered to be favorable regarding translatability to the human setting. The key determinants for translatability of the model are discussed, comprising animal age, development, anatomy, anesthesia and surgical protocols, and perioperative care. With the detailed discussion of these determinants and the pitfalls in diagnosing animal discomfort, an attempt is made to provide a uniform porcine kidney autotransplantation model with tools to improve currently used models. PMID- 22201960 TI - Ethanol and adult CNS neurodamage: oxidative stress, but possibly not excitotoxicity. AB - Evidence from experiments with adult rodents chronically treated with ethanol via either repetitive binges or continuous intake/exposure supports the occurrence of brain oxidative stress and, at least in binge intoxication/rat models, its essential causative role in neurodamage. However, pharmacological antagonism experiments reveal that N-methyl-D-aspartate (NMDA) receptor-dependent excitotoxicity is not responsible for adult mammalian brain neurodegeneration caused by repetitive binge ethanol intoxication and withdrawals. Since NMDA receptor antagonists apparently are untested with respect to neuronal death/loss in continuous intake/ingestion rodent models, e.g., ethanol/water or ethanol/liquid diets, it is therefore erroneous to assert, as is often done, that excitotoxicity is an important mechanism for ethanol-induced adult mammalian brain damage. Alternatively, results from several laboratories indicate that neurodegeneration due to chronic binge ethanol exposure/withdrawal may be dependent on redox transcription factor signaling and neuroinflammatory/oxidative stress pathways (increased arachidonic acid mobilization and pro-inflammatory cytokines; decreased anti-inflammatory cytokines) downstream of microglial/astroglial activation and moderate yet significant brain edema. PMID- 22201961 TI - Interferon-beta-1b protects against multiple sclerosis-induced endothelial cells apoptosis. AB - Disruption of the blood-brain-barrier (BBB) due to endothelial cell (EC) injury is an essential step in formation of multiple sclerosis (MS) lesions. We investigated the role of endothelial cell (EC) apoptosis in the pathophysiology of MS, studying the therapeutic effect of IFN-beta-1b against MS sera-induced endothelial apoptosis. Human umbilical vein endothelial cells were treated with sera from patients with active MS (in relapse), MS in remission, or sera from healthy volunteers (each n = 5). Apoptosis was assessed by annexin V-propidium iodide staining. Effects of IFN-beta-1b on EC apoptosis were tested at increasing doses (10, 100, and 1000 U/ml). Nitrite (NO2--) levels were determined in culture supernatants. EC apoptosis was increased by sera from exacerbating MS patients, but not remission, compared to healthy individuals (p less than 0.001). Effects were blocked by IFN-beta-1b at 10 U/ml (p less than 0.05), but not higher doses, and was associated with increased NO/NO2- production (less than 0.05). EC apoptosis leading to disruption of the BBB may play a role in MS etiology and represents a novel therapeutic mechanism of action for IFN-beta-1b in MS therapy. PMID- 22201962 TI - Calcium signaling as a regulator of hematopoiesis. AB - Different extracellular signaling molecules that bind to receptors on the cell membrane use calcium ions for signal transduction. Due to the opening of receptor operated calcium channels, some cytokine receptors and G-protein coupled receptors induce an increase of intracellular calcium concentration upon activation. Calcium ion is a versatile intracellular secondary messenger that control many different cellular functions by changing its cytoplasmic concentration. A specific and complex network of signaling proteins recognizes intracellular calcium alterations to modulate cellular processes. Some reports have previously demonstrated that calcium also regulates hematopoiesis. This review examines the participation of intracellular calcium in hematopoiesis after the stimulus of various myeloid cytokines such as interleukin-3 and granulocyte macrophage colony-stimulating factor. In addition, the role of adenosine triphosphate and its receptors in inducing calcium increases during hematopoiesis is discussed. Lastly, the participation of this ion in myeloid proliferation and differentiation by cytokines and P2 receptors is also discussed. PMID- 22201963 TI - Alternative hypothesis for the origin of osteoporosis: the role of Mn. AB - Antlers represent an ideal experimental model for bone biology studies, because of their easy accessibility, and their rapid growth. Findings from our previous studies revealed that Mn plays an essential role in incorporating the circulating bone Ca to the growing antlers. Based on these findings, we hypothesize that Mn, an essential mineral for Ca fixation (or incorporation) into bones, might be released from bone, during its remodeling, to be available for prioritized function, most likely, brain function; Consequently, Ca incorporation will be dramatically affected, leading to osteoporosis, particularly in elderly people. Therefore, osteoporosis would precede brain malfunctioning diseases such as Alzheimer's or Parkinson's, and clinical data are available to support some of the predictions derived from this hypothesis. PMID- 22201964 TI - Oxidative stress inflammation and endothelial dysfunction in obstructive sleep apnea. AB - Obstructive sleep apnea syndrome (OSA) is a breathing disorder in sleep. In recent years, this entity has emerged as a major public health problem due to its high prevalence and the profound impact on patients' health and quality of life. A large body of evidence identified OSA as an independent risk factor for cardiovascular morbidity and mortality. Also an association was demonstrated with additional cardiovascular risk factors. This has led to intensive research on the mechanisms involved. The main characteristics of OSA are the recurrent pauses in respiration which result in intermittent hypoxia (IH) and hypercapnia, accompanied by decreased blood oxygen saturation and arousals during sleep. The associations of OSA with cardiovascular morbidities rely on the cyclic nature of the IH, and implicate the apnea related multiple cycles of hypoxia/reoxygenation with increased production of reactive oxygen species (ROS), thereby initiating inflammation. This review summarizes the main findings in oxidative stress/inflammation in the context of OSA and its consequences to possible cardiovascular outcomes through the development of endothelial dysfunction and early clinical signs of atherosclerosis. PMID- 22201965 TI - Inflammatory bowel disease in veterinary medicine. AB - Canine and feline inflammatory bowel disease (IBD) denotes a heterogeneous group of idiopathic, chronic, relapsing inflammatory disorders of the gastrointestinal tract that are immunologically-mediated. While their exact etiologies remain unknown, results from basic science and clinical studies suggest that interplay between genetic factors and enteric bacteria are crucial for disease development, owing to abnormal host responses directed against the commensal microbiota. Key clinical signs include vomiting, diarrhea and weight loss, and histopathologic lesions of inflammation may involve the stomach, small intestine, or colon. Recent advances in molecular tools, disease activity indices, and biomarker development now permit objective assessment of IBD severity at diagnosis and in response to various therapies. Treatment of IBD involves both dietary and pharamacologic interventions as well as therapeutic manipulation of the enteric microbiota through the use of antibiotics and soluble fiber (prebiotic) supplements. Here we provide a comprehensive overview on the etiopathogenesis, clinical features, diagnosis strategies, current treatment recommendations, and outcomes from veterinary studies in dogs and cats with IBD. We also offer scientific comparison between human and canine IBD. PMID- 22201966 TI - Estrogen receptors in lipid raft signalling complexes for neuroprotection. AB - Estrogens exert a plethora of actions conducted to brain preservation and functioning. Some of these actions are initiated in lipid rafts, which are particular microstructures of the plasma membrane. Preservation of lipid raft structure in neurons is essential for signal transduction against different injuries, such as Alzheimer's disease (AD). These membrane structures appear to be disrupted as this neuropathology evolves, and that may largely contribute to dysfunction of raft resident proteins involved in intracellular signalling. This review includes a survey of some protein interactions that are involved in the structural maintenance and signal transduction mechanisms for neuronal survival against AD. Particularly relevant are the rapid mechanisms developed by estrogen to prevent neuronal death, through membrane estrogen receptors (mER) interactions with a voltage-dependent anion channel (VDAC) and other protein markers within neuronal lipid rafts. These interactions may have important consequences in estrogen mechanisms to achieve neuroprotection against amyloid beta (Abeta induced toxicity). PMID- 22201968 TI - Current concepts on the immunopathogenesis of inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is comprised of both ulcerative colitis (UC) and Crohn's disease (CD) and is a chronic inflammatory disorder that results from a dysregulated immune response in genetically susceptible individuals. Data from genome-wide association studies (GWAS) have identified approximately 70 genetic loci that confer susceptibility to CD and over 30 loci that are associated with UC. These genetic loci guide the understanding of the molecular mechanisms of these gene products and reveal that alterations in the immune response underlie the pathophysiology of IBD. This review highlights critical areas in the microbiome, innate immune response, and the adaptive immune response that lead to the chronic mucosal inflammation typically seen in IBD. PMID- 22201967 TI - Maternal protein restriction regulates IGF2 system in placental labyrinth. AB - This study was to test the hypothesis that altered IGF2 system in the placental labyrinth zone (LZ) impairs feto-placental growth in response to maternal protein restriction. Rats were fed a 20% protein diet and an isocaloric 6 % protein diet (LP) from day 1 to days 14, 18, or 21 of pregnancy. The effects of diet, gender of placenta and fetus, and day of pregnancy on placental weight, fetal weight, and expression of the IGF2 axis in the placental LZ and amino acids in maternal plasma were analyzed. Growth restriction occurred in both female and male fetuses by LP, coincident with impaired LZ growth and efficiency. The expression of Igf2, Igf2P0, Igf1r, Igf2r, Insr, Igfbp1, and Igfbp2 in placental LZ were affected by diet, gender and/or day of pregnancy. Concentrations of total essential amino acids and total nonessential amino acids were reduced and increased, respectively, in maternal plasma of LP-fed rats. These results indicate that adaptation of the IGF2 system in rat LZ occurs in a sex- and time-dependent manner in response to maternal protein restriction; however, these adaptations cannot prevent the growth restriction of both male and female fetuses during late pregnancy. PMID- 22201970 TI - Magnetization transfer imaging of acute black holes in patients on glatiramer acetate. AB - The aim of this study was to determine evolution of T1 unenhanced hypointense lesions (acute or chronic black holes (ABHs, CBHs)) by measuring their magnetization transfer ratio (MTR) changes over 12 months. 40 glatiramer acetate (GA)-naive patients with relapsing-remitting MS who presented with 1 or more contrast-enhancing lesions (CELs) at baseline underwent 1.5-T MRI at baseline and after 12 months. Lesions were classified into 4 patterns based on differences in lesion isointensity or hypointensity over 12 months. Of 115 CELs detected at baseline, 64, after 12 months, followed pattern A (isointense-isointense), 6 pattern B (isointense-hypointense), 33 pattern C (hypointense-isointense), and 12 pattern D (hypointense-hypointense). MTR significantly increased for all unenhanced T1 hypointense lesions (p = 0.02). Highest MTR increases were observed for patterns C (ABHs +18.2 %, p less than 0.001) and D (CBHs +34.2 %, p = 0.023), but significant improvement was also detected for pattern A (+1.4 %, p = 0.046); no significant MTR changes were found for pattern B. GA treatment significantly recovered MTR in ABHs and CBHs, possibly indicating a greater potential for remyelination. PMID- 22201969 TI - MicroRNAs and other mechanisms regulate interleukin-17 cytokines and receptors. AB - Interleukin-17 cytokines are a family of pro-inflammatory cytokines. Our current studies found: i) IL-17 cytokines are not ubiquitously expressed, but several receptors and TRAF3IP2 are ubiquitously expressed in tissues with a few exceptions; ii) heart and vascular tissue are in the second tier of readiness to respond to IL-17 cytokine stimulation; iii) alternative transcription starting sites and alternative spliced isoforms are found in IL-17 cytokine and receptor transcripts; iv) higher hypomethylation status is associated with higher expressions of IL-17 receptors; v) the binding sites of several RNA binding proteins are found in the 3'UTRs of the mRNAs of IL-17 cytokines and receptors; and vi) numerous microRNA binding sites are statistically equivalent to that of experimentally verified microRNAs-mRNA interactions in the 3'UTRs of IL-17 cytokine and receptor mRNAs. These results suggest that mechanisms including alternative promoters, alternative splicing, RNA binding proteins, and microRNAs regulate the structures and expressions of IL-17 cytokines and receptors. These results provide an insight into the roles of IL-17 in mediating inflammation and immunity. PMID- 22201971 TI - Health benefits of wine and alcohol from neuroprotection to heart health. AB - Controversy is common during efforts to define the role of nutrition in health, but few modern reflections of such controversy are as vivid as the debate over wine. There exists no query that chronic alcohol abuse, a leading worldwide problem, causes neuronal dysfunction and brain damage. However, various epidemiologic studies in recent years have indicated that in comparisons with abstainers or never drinkers, light/moderate alcohol/wine consumers have lower risks of age-dependent cognitive decline and/or dementia, including Alzheimer's disease (AD) Neurodegenerative diseases such as AD and Parkinson's (PD) diseases are defined by a progressive neuronal dysfunction and an ensuing behavioral dysfunction. Epidemiologic studies from numerous disparate populations reveal that individuals with the habit of daily moderate wine consumption enjoy significant reductions in all-cause and particularly cardiovascular and neurodegenerative mortality when compared with individuals who abstain or who drink alcohol in excess. Apart from the alcohol present in the wine, other trace compounds and polyphenolic compounds such as resveratrol naturally present in wine and grapes also exert neuroprotective and cardioprotective activities. PMID- 22201973 TI - The role of cancer stem cells in relapse of solid tumors. AB - Recurrence at secondary locations, often years after removal of the primary tumor, accounts for most of the mortality associated with solid tumors. Metastasis, resistance to chemo- and radiotherapy, and eventual relapse have been attributed to a distinct tumor subpopulation known as cancer stem cells (CSCs). In this review, we consider the properties of CSCs that lead to these outcomes, in particular the relation between epithelial-to-mesenchymal transition, stemness, and tumor initiation. We compare recent clinical and laboratory studies of breast cancer, glioblastoma, and melanoma that illustrate how most current anticancer regimens select for cells with mesenchymal and CSC properties and therefore sow the seeds of relapse. Finally, we discuss the emerging paradigm of combined therapy that targets both CSC and non-CSC tumor components. PMID- 22201974 TI - Database documentation of retrotransposon insertion polymorphisms. AB - Retrotransposons constitute more than 40 percent of the human genome with L1, Alu, SVA, and HERVs known to remain active in transposition. Retrotransposition contribute to genetic diversity in the form of retrotransposon insertion polymorphism (RIP) that is defined as the presence or absence of a retrotransposon insertion among human populations at a specific genomic location. So far close to 5000 cases of RIPs have been identified with more than 50 cases associated with disease. A large number of new RIPs are being and to be identified from newly available personal genomes data, making RIPs an important source of genetic variations/mutations that deserve proper documentation. In this review, we discuss the special characteristics of RIPs and the challenges in their compiling and annotating, and we examine the current status of database documentation of RIPs and describe in details the design, data schema, and utilities of dbRIP, which is currently the only database dedicated to the documentation of retrotransposon insertion polymorphism. Some future perspectives and outstanding issues associated with documentation of RIPs are also presented. PMID- 22201972 TI - Tissue factor: mechanisms of decryption. AB - It is generally believed that only a small fraction of the tissue factor (TF) found on cell surfaces is active whereas the vast majority is cryptic in coagulation. It is unclear how cryptic TF differs from the coagulant active TF or potential mechanisms involved in transformation of cryptic TF to the coagulant active form. Exposure of phosphatidylserine (PS) in response to various chemical or pathophysiological stimuli has been considered as the most potent inducer of TF decryption. In addition to PS, TF self-association and association with specialized membrane domains may also play a role in TF decryption. It has been suggested recently that protein disulfide isomerase regulates TF decryption through its oxidoreductase activity by targeting Cys186-Cys209 disulfide bond in TF extracellular domain or regulating the PS equilibrium at the plasma membrane. However, this hypothesis requires further validation to become an accepted mechanism. In this article, we critically review literature on TF encryption/decryption with specific emphasis on recently published data and provide our perspective on this subject. PMID- 22201975 TI - Fibrosis: is it a coactivator disease? AB - Fibrosis is an abnormal fibroblast-activation-associated pathological manifestation in injured organs where excessive non-physiological synthesis and accumulation of extracellular matrix (ECM) proteins by activated/differentiated fibroblasts disrupts tissue homeostasis. Like other eukaryotic genes, expression of ECM protein genes not only depends on its gene sequences in the regulatory region but also influenced by non-genetic factors called epigenetic regulators including acetyltransferases, deacetylases, methyltransferases and microRNAs. The acetyltransferase p300 (ATp300), a transcriptional coactivator, is a major player in the epigenetic regulation of genes whose products are involved in cellular growth, proliferation, apoptosis and essential for embryonic development. ATp300 acetylates specific lysine residues in histones and transcription factors (KAT) and as a transcriptional coactivator it forms a bridge between upstream regulatory element binding protein complex and basal transcriptional machinery. Abnormal coactivator activity-associated diseases are known as coactivator diseases. Abnormalities in ATp300 activities in adults are associated with numerous diseases. Here, we review the significant roles of ATp300 in epigenetic regulation of collagen synthesis and deposition in extracellular spaces, matrix remodeling and tissue fibrogenesis. The present day understanding on the distinct role of acetyltransferases, deacetylases, and deacetylase inhibitors on epigenetic regulation of matrix remodeling and fibrosis has also been discussed. PMID- 22201976 TI - A modified histoimmunochemistry-assisted method for in situ RPE evaluation. AB - We have developed a method for morphological evaluation of retinal pigment epithelium (RPE) with minimal perturbation of RPE-Bruch's membrane choriocapillaris complex (RBCC). To prepare RBCC, the anterior segments of the eye were removed. The remaining eye cup was radially cut into 4 to 6 pieces from periphery to the optic nerve head. Each piece was carefully dissected into 3 parts: sclera, RBCC and neurosensory retina. RBCC flatmount with RPE monolayer facing up was formed by several relaxing radial cuts. After immuno-staining with tissue specific markers, the RBCC could be distinguished as the superficial RPE monolayer and the underneath choriocapillaris layers by fluorescence microscopy. The density, distribution, and morphology of RPE cells varied among species. This method may have brought several advantages for RPE screening over other means, because of its straight forward approach, minimal manipulation of samples, plus there is no requirement for bleaching, which result in high efficiency for result readout. For a complete morphological study of RPE in situ, this method may be combined with other methods, such as cryosections, scanning electron microscopy, etc. PMID- 22201978 TI - Antler regrowth as a form of epimorphic regeneration in vertebrates - a comparative view. AB - The annual regrowth of deer antlers is a unique case of extensive appendage regeneration in mammals. This review compares basic aspects of antler regeneration with epimorphic regeneration in other vertebrate taxa. The mesenchymal cells that build up the regenerating antler are not derived from dedifferentiated cells in the pedicle stump, but from the proliferation of cells of the pedicle periosteum; and based on different lines of evidence it has more recently been suggested that the pedicle periosteum contains stem cells that are periodically activated to produce a new antler. This constitutes a difference to urodele limb regeneration, where the blastema is (largely) formed from dedifferentiated cells. Antler regeneration involves healing of the large casting wound with no or only minor scarring, making the antler an interesting model for the control of scarring in mammals. Contrary to urodele limb regeneration, antler regrowth does not depend on a functional nerve supply. In our view, a comparative analysis of different regeneration phenomena, including antler regeneration, probably offers the best chance for achieving significant progress in regenerative medicine. PMID- 22201979 TI - Beta-adrenoceptor signaling pathways mediate cardiac pathological remodeling. AB - Beta-adrenoceptors (ARs), members of the G protein-coupled receptor (GPCR) superfamily, play a key role in the rapid regulation of myocardial function. Meanwhile, chronic catecholamine stimulation of adrenoceptors has been proved to be involved in the adverse myocardial remodeling, including cardiac hypertrophy, fibrosis, and apoptosis, which finally develop into heart failure. In the clinical situation, sympathetic hyperactivity is a key factor in the development of heart failure, and beta-blockers greatly improve the outcome of the disease. However, heart failure is still one of the leading causes of death. Therefore, a full understanding of the mechanism of beta-AR-mediated cardiac remodeling could indicate more targets for treating heart failure. This review summarizes a number of important signaling pathways involved in the process of cardiac pathological remodeling under chronic adrenergic stimulation. PMID- 22201980 TI - Inflammatory bowel disease: review and future view. AB - Inflammatory bowel disease (IBD) is chronic problem that cause an inflammation of the intestines. Significant progress has been made in recent years to the field of IBD epidemiology, pathogenesis and treatment and a number of new insights have been created. Also, there is an increasing interest in the discovery of different new aspects related diagnosis and treatment. In this review we will highlight few points related to current situation of inflammatory bowel disease and some areas of progress in different fields. PMID- 22201981 TI - Mathematical modeling of hematological malignancies. AB - Mathematical models addressing important aspects of hematological malignancies have recently facilitated an improved understanding of the involved complex biological processes and the prediction of potential targets for therapeutic approaches. These models investigate a wide spectrum of topics ranging from metabolic processes, gene regulatory networks and signal transduction up to the behavior of cell populations. However, despite this range of biological processes, the modeling strategies share many common features. Biological knowledge is translated into abstract descriptions representing complex networks and the parameters of these mathematical models are derived from literature data or estimated from experimental measurements. The established mathematical models are used to interrogate key properties of the investigated system by model simulations. These predictions are validated based on previously published or novel experiments. Additionally, new drug targets are predicted or novel insights into biological processes are provided. Here, we summarize the strategies employed to establish four mathematical models that address different processes in leukemia and lymphoma cells. Furthermore, we show how these systems biology approaches could contribute to elucidate the pathobiology of hematological malignancies. PMID- 22201982 TI - Fertility preservation in women with ovarian endometriosis. AB - Endometriosis is one of the most frequently encountered benign diseases in gynecology. Complete resolution of endometriosis is not yet possible, but therapy has essentially three main objectives: (1) to preserve and improve fertility, (2) to reduce pain, and (3) to delay recurrence for as long as possible. The aim of this paper is to focus on fertility preservation in women with severe endometriosis. In moderate and severe endometriosis, a medico-surgical approach remains the gold standard, but more and more papers are reporting a low ovarian reserve after laparoscopic cystectomy for endometriomas. Indeed, very frequently, normal ovarian tissue is excised together with the endometrioma wall. Ovarian surgery in endometriosis patients should therefore be performed by experienced surgeons in order to both preserve and improve fertility. Preservation of ovarian tissue should be considered in all patients at serious risk of future fertility impairment, particularly before any treatment likely to result in ovarian endometriosis recurrence and/or premature ovarian failure. PMID- 22201977 TI - Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease. AB - Growing evidence supports roles for brain insulin and insulin-like growth factor (IGF) resistance and metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). Whether the underlying problem stems from a primary disorder of central nervous system (CNS) neurons and glia, or secondary effects of systemic diseases such as obesity, Type 2 diabetes, or metabolic syndrome, the end-results include impaired glucose utilization, mitochondrial dysfunction, increased oxidative stress, neuroinflammation, and the propagation of cascades that result in the accumulation of neurotoxic misfolded, aggregated, and ubiquitinated fibrillar proteins. This article reviews the roles of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism, and discusses therapeutic strategies and lifestyle approaches that could be used to prevent, delay the onset, or reduce the severity of AD. Finally, it is critical to recognize that AD is heterogeneous and has a clinical course that fully develops over a period of several decades. Therefore, early and multi-modal preventive and treatment approaches should be regarded as essential. PMID- 22201983 TI - LINE-1: creators of neuronal diversity. AB - Long interspersed nucleotide element 1 (L1) is a family of non-LTR retrotransposons that can replicate and reintegrate into the host genome. L1s have considerably influenced mammalian genome evolution by retrotransposing during germ cell development or early embryogenesis, leading to massive genome expansion. In humans, over 30 % of the genome can be attributed to L1-mediated retrotransposition. Historically, L1s were thought to only retrotranspose during gametogenesis and in neoplastic processes, but recent studies have shown that L1s are extremely active in the mouse, rat, and human neuronal progenitor cells (NPCs). In fact, it is estimated that the hippocampus and other regions of the brain may have multiple insertions per cell. These insertions can dramatically impact neuronal transcriptional expression, creating unique transcriptomes of individual neurons. Furthermore, transcriptional activation of L1 elements mimics the transcription activation of the NeuroD1 gene, suggesting a prominent role of L1 expression during neurogenesis. PMID- 22201984 TI - What is homeopathy? An introduction. AB - Homeopathy is based on the idea of 'let like be cured by like'. It was founded by Samuel Hahnemann in the late 18th century, although similar concepts existed earlier. Homeopathy became popular in the 19th century in part because of its success in epidemics but declined during most of the 20th century. Its popularity increased in the late 20th and early 21st centuries in many parts of the world. Homeopathy is controversial because of its use of highly dilute medicines. There is a significant body of clinical research including randomised clinical trials and meta-analyses of such trials which suggest that homeopathy has actions which are not placebo effects. Cohort, observational and economic studies have yielded favourable results. There are several schools of homeopathy. Systems which use homeopathic medicines based on symbolism and metaphor are not homeopathy. Despite the long history of scientific controversy, homeopathy has proved resilient and is now geographically widespread. There is a significant body of scientific evidence with positive results. Homeopathy is an anomaly around which deserves further investigation. PMID- 22201985 TI - Primary sclerosing cholangitis: etiopathogenesis and clinical management. AB - Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease characterized by the destruction of medium to large-sized bile ducts and intense, concentric fibrosis. Complications from PSC include bacterial cholangitis, cirrhosis, and cholangiocarcinoma and a therapy that might alter the natural history of the disease remains lacking. Our understanding of the pathogenesis of PSC also remains rudimentary but several theories exist, suggesting roles for genetic susceptibility, abnormal innate immune responses lymphocyte trafficking, and toxic bile formation. Medical and surgical therapies, short of liver transplantation, have been disappointing. Currently, the management of PSC is aimed largely at the endoscopic treatment of dominant biliary strictures and complications of cholestasis until the disease has progressed to cirrhosis, at which time liver transplantation is indicated. Progress in our basic understanding of PSC is desperately needed in order to rationally design new therapeutic approaches to this disease. PMID- 22201986 TI - Mitochondrial DNA related cardiomyopathies. AB - Cardiomyopathies are a heterogeneous group of diseases characterized by impaired heart muscle function. Over the last few years, interest in mitochondrial cardiomyopathies has been galvanized by a number of significant molecular biology discoveries. There is overwhelming evidence that genetic factors play a pivotal role in the pathogenesis of primary cardiomyopathies. Mitochondrial cardiomyopathy is a cardiomyopathy in which the clinical and pathological phenotype result from mitochondrial diseases due to pathogenic mutation in both mitochondrial and/or nuclear genes causing defects in the oxidative phosphorylation system (OXPHOS) in cardiac muscle. We review and provide an update of the current concepts, molecular genetics, clinical features, pathology, diagnostic modalities, and latest therapeutic options in mitochondrial cardiomyopathies specifically caused by mutations in the mitochondrial DNA (mtDNA). PMID- 22201987 TI - Treatment of hepatoblastoma: the North American cooperative group experience. AB - In North America, children with malignant liver tumors have been treated in a cooperative group study since early 1970s. This manuscript describes the results of these studies. PMID- 22201988 TI - Endocrine disruptors in utero cause ovarian damages linked to endometriosis. AB - Timed pregnant Balb-C mice were treated from day 1 of gestation to 7 days after delivery with the endocrine disruptor bisphenol a (BPA) (100, or 1,000 microg/kg/day). After delivery, pups were hold for three months; then, ovaries were analyzed in their entirety. We found that in the ovaries of BPA-treated animals the number of primordial follicles and of developing follicles was significantly lower than in the untreated animals. Moreover, the number of atretic follicles was significantly higher in the treated animals. Finally, we found that the animals displaying endometriosis-like phenotype had a more severe impairment of the ovaries in term of number of primordial and developing follicles in comparison with the other mice exposed to BPA. In conclusion, we describe for the first time a complex phenotype in mice, elicited by pre-natal exposition to BPA, that includes ovarian lesions and endometriosis. Considering the high incidence of endometriosis and of the premature ovarian failure associated to infertility in these patients, the data showed prompt a thoroughly reconsideration of the pathological framing of these lesions. PMID- 22201989 TI - Evaluation of unintended electrical stimulation from MR gradient fields. AB - Exposure of patients with active implants (e.g. cardiac pacemakers and neurostimulators) to magnetic gradient fields (kHz range) during magnetic resonance imaging presents safety issues, such as unintended stimulation. Magnetically induced electric fields generate currents along the implant's lead, especially high at the distal tip. Experimental evaluation of the induced electric field was previously conducted. This study aimed to perform the same evaluation by means of computational methods, using two commercially available software packages (SemcadX and COMSOL Multiphysics). Electric field values were analyzed 1-3 mm from the distal tip. The effect of the two-electrode experimental probe was evaluated. The results were compared with previously published experimental data with reasonable agreement at locations more than 2-3 mm from the distal tip of the lead. The results were affected by the computational mesh size, with up to one order of magnitude difference for SEMCAD (resolution of 0.1 mm) compared to COMSOL (resolution of 0.5 mm). The results were also affected by the dimensions of the two-electrode probe, suggesting careful selection of the probe dimensions during experimental studies. PMID- 22201991 TI - Stress and its impact on farm animals. AB - This article presents a brief overview of stress and its impact on growth, production, reproduction and disease susceptibility in farm animals. A single measure of stress might not be a reliable indicator and it is usually more informative to combine multiple indicators of stress to assess animal welfare. Popular measures of stress such as alterations in hormonal profiles can be complemented with behavioral and immunological changes. Traditional approaches are insufficient to unravel the role of large number of genes and interconnected genetic pathways leading to multiple responses to stresses. Modern genomic and proteomics methodologies used in identifying the biomarkers and molecular mechanisms of stress response have also been described briefly. With a better understanding of the basic biology, altered physiological processes and the genes/proteins involved in stress adaptability, it would be possible to develop methodologies for selection of animals with better performance and devise strategies for animal welfare. PMID- 22201992 TI - Micro segmented-flow in biochemical and cell-based assays. AB - Micro-segmented flow (e.g. in microfluidic channels, capillaries or a length of tubing) has become a promising technique in modern biology. Compared to conventional formats such as microtiter plates, sample volumes can be reduced about 1000-fold, thus allowing a massive reduction of assay costs and the use of samples available in low quantities, only (e.g. primary cells). Furthermore, assays can be highly parallelized and performed at superb spatio-temporal resolution. Here, we review the state-of-the-art in micro-segmented flow as applied in biochemical, cell- and multicellular organisms-based assays. We discuss likely future applications such as single cell / single organism proteomics and transcriptomics and point out the specific advantages and limitations compared to emulsion-based (droplet-based) approaches. PMID- 22201993 TI - Proteomic analysis of peach fruit moth larvae treated with phosphine. AB - Phosphine has been used worldwide for the control of stored-product insects for many years. However, the molecular mechanism of its toxicity is not clearly understood. In the current study, larvae of the peach fruit moth were fumigated with phosphine. Proteomic analysis was then performed to identify the regulated proteins. Our results confirmed the phosphine toxicity on the peach fruit moth. The median lethal time LT50 was 38.5 h at 330 ppm at 25 degrees C. During fumigation, the respiration of the peach fruit moth was extremely inhibited. Of the 26 regulated proteins, 16 were identified by MALDI-TOF mass spectrometry after a 24 h treatment. The proteins were classified as related to metabolism (25 %), anti-oxidation (6 %), signal transduction (38 %), or defense (19 %). The rest (13 %) were unclassified. Phosphine regulation of ATP and glutathione contents, as well as of ATP synthase and glutathione S-transferase 2 activities were confirmed by enzyme activity analysis. These results demonstrate that complex transcriptional regulations underlie phosphine fumigation. New theories on the mechanism of phosphine toxicity may also be established based on these results. PMID- 22201990 TI - Pathogenesis of Chagas disease: time to move on. AB - Trypanosoma cruzi is the etiologic agent of Chagas disease. The contributions of parasite and immune system for disease pathogenesis remain unresolved and controversial. The possibility that Chagas disease was an autoimmune progression triggered by T. cruzi infection led some to question the benefit of treating chronically T. cruzi-infected persons with drugs. Furthermore, it provided the rationale for not investing in research aimed at a vaccine which might carry a risk of inducing autoimmunity or exacerbating inflammation. This viewpoint was adopted by cash-strapped health systems in the developing economies where the disease is endemic and has been repeatedly challenged by researchers and clinicians in recent years and there is now a considerable body of evidence and broad consensus that parasite persistence is requisite for pathogenesis and that antiparasitic immunity can be protective against T. cruzi pathogenesis without eliciting autoimmune pathology. Thus, treatment of chronically infected patients is likely to yield positive outcomes and efforts to understand immunity and vaccine development should be recognized as a priority area of research for Chagas disease. PMID- 22201994 TI - Mechanism of the relaxant effect of rosuvastatin lactone on rat aortic rings. AB - The relaxant effect of the lactone of rosuvastatin was evaluated on aortic rings from male Wistar rats (250-300 g) with and without endothelium, precontracted with 1.0 microM phenylephrine. The lactone presented a greater potency than rosuvastatin in relaxing aortic rings. Unlike rosuvastatin, the effect of its lactone was endothelium-independent. Pretreatment with either indomethacin (10 microM) or mevalonate (1 mM) did not inhibit the relaxant effect of the lactone. L-NAME (10 microM), 1400 W (10 microM), or tetraethylammonium (TEA, 10 mM) partially inhibited the relaxant effect of the lactone on endothelium-denuded aortic rings. However, cycloheximide (10 microM) or the combination of TEA plus L NAME completely inhibited the relaxant effect. The NOS-2 was only present in endothelium-denuded aortic rings, as demonstrated by immunoblot with lactone treated rings. In conclusion, rosuvastatin was associated with a relaxant effect dependent on both endothelium and HMG-CoA reductase in rat aorta, whereas the lactone exhibited an endothelium and HMG-CoA reductase-independent relaxant effect. Both nitric oxide produced by NOS-2 and K+ channels are involved in the relaxant effect of the lactone. PMID- 22201995 TI - Polyamines analysis by HPLC and their application as tumor markers. AB - Cancers are one of the main causes of human deaths globally. Great effort has been dedicated to the search for sensitive and specific markers of cancer. Polyamines including mainly putrescine (PUT), spermidine (SPD), and spermine (SP), are promising tumor markers since their excretion is frequently elevated in patients with various types of cancers. In the present study, we developed an efficient high performance liquid chromatographic (HPLC) method for the determination of polyamines in human serum using dansyl chloride for pre-column derivatization. All polyamines were separated within 10 min. The analytical method is simple, rapid, and highly reproducible. We applied of 11 cancers as objects of study, and made comparisons between polyamines and other 24 common tumor markers with six indexes: specificity, sensitivity, negative predictive value, positive predictive value, total effective, and the mean value. We drew the conclusion that polyamines are promising tumor markers, and they might be of great value in diagnosing cancers, predicting therapeutic success, or indicating the relapse of tumors. PMID- 22201996 TI - Prognostic relevance of the expressions of CAV1 and TES genes on 7q31 in melanoma. AB - The 7q31 locus contains several genes affected in cancer progression. Although evidences exist regarding its impact on tumorigenesis, the role of genetic alterations and the expressions of locus-related genes are still controversial. Our study aimed to define the 7q31 copy number alterations in primary melanomas, primary-metastatic tumor pairs and cell lines. Data were correlated with clinical pathological parameters. Genetic data show that 7q31 copy number distribution was heterogeneous in both primary and metastatic tumors. Extra copies were highly accompanied by chromosome 7 polisomy, and significantly increased in primary lesions with poor prognosis. Additionally, we determined the mRNA and protein levels of the locus-related CAV1 and TES genes. TES mRNA level was associated with metastatic location. CAV1 mRNA and protein levels were significantly higher in thicker tumors, however, lack of protein was also observed in a subpopulation of thin lesions. Expressions of CAV1 and TES were not associated with 7q31 alterations. In conclusion, 7q31 amplification can predict unfavorable outcome. Alterations of TES mRNA level may predict the location of metastasis. CAV1 possibly affect the cancer cell invasion. PMID- 22201997 TI - Conversion of mouse fibroblasts to sphere cells induced by AlbuMAXI-containing medium. AB - The reprogramming of fibroblasts to pluripotent stem cells and the direct conversion of fibroblasts to functional neurons has been successfully manipulated by ectopic expression of defined factors. We demonstrate that mouse fibroblasts can be converted into sphere cells by detaching the fibroblast cells by protease and then using the AlbuMAX I-containing culture medium without genetic alteration. AlbuMAX I is a lipid-rich albumin. Albumin-associated lipids arachidonic acid (AA) and pluronic F-68 were responsible for this effect. The converted colonies were positive for both alkaline phosphatase and surface specific embryonic antigen-1 (SSEA-1) staining. Global gene expression analysis indicated that the sphere cells were in an intermediate state compared with mES cells and MEF cells. The sphere cells were able to differentiate into tissues representing all three embryonic germ layers following retinoic acid treatment, and differentiated into smooth muscle cells following treatment with vascular endothelial growth factor (VEGF). The study presented a potential novel approach to transdifferentiate mouse fibroblast cells into other cell lineages mediated by AlbuMAX I-containing culture medium. PMID- 22201998 TI - Cell biology perspectives in phage biology. AB - Cellular biology has long been restricted to large cellular organisms. However, as the resolution of microscopic methods increased, it became possible to study smaller cells, in particular bacterial cells. Bacteriophage biology is one aspect of bacterial cell biology that has recently gained insight from cell biology. Despite their small size, bacteriophages could be successfully labeled and their cycle studied in the host cells. This review aims to put together, although non extensively, several cell biology studies that recently pushed the elucidation of key mechanisms in phage biology, such as the lysis-lysogeny decision in temperate phages or genome replication and transcription, one step further. PMID- 22201999 TI - Sex, death and the (nerve) cell. AB - Men and women not only look different, but they have different risks of multiple diseases like migraine, neurodegenerative disorders or numerous cancers. Even the nerve cells may die in different ways and exhibit different sensitivity to pro apoptotic factors. Some of the differences can be explained by the action of sex hormones, but the experiments on four core genotype mouse model, in which XX and XY mice can be of either sex showed that not all differences are due to hormones. An example of a disease with no simple explanation of sex bias is Leber hereditary optic neuropathy, a mitochondrial disease with about 4:1 male to female ratio. The apoptotic death of retinal ganglion cells forming an optic disc is a proposed mechanism of the disease pathophysiology. The mechanisms causing different sensitivity of the nerve cells of male and female subjects may be responsible for the gender bias in LHON and merit further studies. PMID- 22202000 TI - Morphogenetic aspects of deer antler development. AB - Deer antlers are unique mammalian appendages that have potential for application as a valuable model for biomedical research, such as organ regeneration, bone development and growth control. In this review we described the morphogenetic aspects of antler development, by summarizing relevant information accumulated over the course of our antler research in combine with other published papers. Antler development consists of two distinct phenomena: generation and regeneration. Generation starts with the initiation of a pair of pedicles, permanent bony protuberances on the skull of a male deer, when the animal approaches puberty; proceeds to transformation to antlers when the pedicles reach a species-specific height (around 5 cm in red deer); and terminates with total antler calcification and velvet (antler skin) shedding. Regeneration commences in the spring of the subsequent year with the initiation of new soft antlers growing from the pedicle stumps that remain following the casting of the previous hard antlers; proceeds to the elaboration of multi-branched antlers in summer; and ends up with total antler calcification and velvet shedding in autumn, resulting in the formation of hard bony antlers in winter. Therefore, this paper not only lays the foundation for further development of this valuable biomedical model, but also provides comprehensive background knowledge that will be of use to readers when reading the papers featured in this special issue. PMID- 22202001 TI - How a single amino acid change may alter the immunological information of a peptide. AB - What types of amino acid substitutions are functionally tolerated in an epitope? This question is of importance because the immunogenicity, pathogenicity, and therapeutic potential of a peptide can be determined by a single amino acid change. As an example, a single amino acid change in the encephalitogenic myelin oligodendrocyte glycoprotein WYRSPFSRVV peptide confers the capacity to ameliorate and reverse experimental autoimmune encephalomyelitis. Currently, no rule is available to predict/explain the functional outcomes of amino acid changes. To address this issue, we examined the role of single amino acid changes in immune responses by applying proteomic similarity analyses to available data. We found that the loss or gain of immunological information in a peptide epitope following an amino acid substitution often is related to a gain or loss in the proteomic similarity. Rare, but significant epitopic sequences become immunologically insignificant when an amino acid change makes them common, repeated sequences. This study confirms that low similarity to the host proteome is a major factor in modulating the immune epitope repertoire. PMID- 22202002 TI - Toll-like receptor function in primary B cell defects. AB - Primary immunodeficiency diseases include more than 150 different genetic defects, classified on the basis of the mutations or physiological defects involved. The first immune defects to be well recognized were those of adaptive immunity affecting B cell function and resulting in hypogammaglobulinemia and defects of specific antibody production; more recently, novel defects of innate immunity have been described, some involving Toll-like receptors (TLRs) and their signaling pathways. Furthermore, it is increasingly evident that the innate and adaptive pathways intersect and reinforce each other. B cells express a number of TLRs, which when activated lead to cell activation, up-regulation of co stimulatory molecules, secretion of cytokines, up-regulation of recombination enzymes, isotype switch and immune globulin production. TLR activation of antigen presenting cells leads to heightened cytokine production, providing additional stimuli for B cell development and maturation. Recent studies have demonstrated that patients with common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) have altered TLR responsiveness. We review TLR defects in these disorders of B cell development, and discuss how B cell gene defects may modulate TLR signaling. PMID- 22202004 TI - Tumor-stroma interactions in tumorigenesis: lessons from stem cell biology. AB - Research in recent years has accumulated a wealth of novel insight into mechanisms by which tumor cells interact with activated fibroblasts, endothelial cells, inflammatory and immune cells and the extracellular matrix. Cancer and stromal cells co-evolve throughout tumorigenesis. As a result, the tumor stroma is now regarded as an essential contributor to tumor establishment, progression and dissemination. Moreover, the formation of suitable stroma niches has emerged as a prime determinant of metastasis. Notably, malignant tumors adopt numerous mechanisms that are also operative in embryonic and adult stem cell biology. Tumor sites show functional characteristics with striking similarities to stem cell niches. This review summarizes the current view of disease-relevant communication between tumor cells and the tumor stroma and relates it to interactions of stem cells and their respective niches. Progress in understanding the pivotal role of the microenvironment in both tumor and stem cell biology renders the tumor stroma an interesting potential future target for specific cancer therapies. PMID- 22202003 TI - Molecular recognition theory and sense-antisense interaction: therapeutic applications in autoimmunity. AB - Perhaps behind only the understanding of the genetic code in importance is the comprehension of protein sequence and structure in its effect on modern scientific investigation. How proteins are structured and interact dictates a considerable amount of the body's processes in maintaining homeostasis. Unfortunately, in diseases of autoimmunity, these processes are directed against the body itself and most of the current clinical responses are severely lacking. This review addresses current therapeutics involved in the treatment of various autoimmune diseases and details potential future therapeutics designed with a more targeted approach. Detailed in this manuscript is the concept of utilizing peptides possessing an inverse hydropathy to the immunogenic region of proteins to generate anti-idiotypic (anti-Id) and anti-clonotypic T cell receptor (TCR) antibodies (Abs). Theoretically, the anti-Id Abs cross react with Id Abs and negate the powerful machinery of the adaptive immune response with little to no side effects. A series of studies by a number of groups have shown this to be an exciting and intriguing concept that will likely play a role in the future treatment of autoimmune diseases. PMID- 22202005 TI - Endogenous anticancer mechanisms: metastasis. AB - Metastases, rather than the primary tumors from which these malignant growths are spawned, are culpable for greater than 90 % of human cancer-associated mortality. Metastases arise through the completion of a series of cell-biological events - collectively termed "the invasion-metastasis cascade" - which involve the dissemination of tumor cells to distant organ sites and their subsequent adaptation to these foreign microenvironments. Importantly, a number of endogenous mechanisms exist that serve to prevent metastatic progression. These safeguards must be overcome by incipient metastatic tumor cells in order for them to generate detectable metastases. Here, I highlight four endogenous mechanisms that protect against the development of metastatic disease in breast carcinomas. I discuss how the expression of these genes are dampened during malignant progression, the downstream responses they orchestrate, and clinical opportunities to therapeutically target these mechanisms. Indeed, one potentially effective strategy for the remediation of metastatic disease involves the reactivation of endogenous anti-metastasis mechanisms. Therefore, knowledge regarding endogenous anti-metastasis mechanisms may both further our comprehension of the basic etiology of metastasis and also guide the treatment of human tumors. PMID- 22202007 TI - MRI biomarkers in Huntington's disease. AB - Huntington's disease (HD) is a devastating neurodegenerative disease affecting the brain resulting in neuronal dysfunction and neuronal loss. Since the identification of the gene responsible for HD, genetic testing has become widely available, allowing for genetic status of persons at risk for HD to be determined. For the effective evaluation of future therapeutic trials a great need exists for sensitive biomarkers. In (premanifest) HD, MRI of the brain is one of the most logical candidates as a biomarker, as opposed to clinical measures, since brain neurons are the main target of the disease. These biomarkers can facilitate early detection of disease related changes, but are also needed to monitor disease progression from the premanifest phase of HD onwards. MRI derived parameters have this biomarker potential as they have been shown to identify brain abnormalities before symptom onset. In this review the available MRI techniques of conventional MRI, Diffusion Tensor Imaging, Magnetization Transfer Imaging, Magnetic Resonance Spectroscopy and Functional MRI will be discussed and the findings will be placed into context of different HD stages. PMID- 22202006 TI - Lysosomal protein trafficking in Giardia lamblia: common and distinct features. AB - Giardia is a flagellated protozoan parasite that has to face different microenvironments during its life cycle in order to survive. All cells exchange materials with the extracellular medium through the reciprocal processes of endocytosis and secretion. Unlike more evolved cells, Giardia lacks a defined endosomal/lysosomal system, but instead possesses peripheral vacuoles that play roles in endocytosis, degradation, recycling, and secretion of proteins during growth and differentiation of the parasite. This review focuses on recent reports defining the role of different molecules involved in protein trafficking to the peripheral vacuoles, and discusses possible mechanisms of receptor recycling. Since Giardia is an early-branching protist, the study of this parasite may lead to a clearer understanding of the minimal machinery required for protein transport in eukaryotic cells. PMID- 22202008 TI - Focal cerebral ischemia activates neurovascular restorative dynamics in mouse brain. AB - Cerebral ischemia triggers regeneration of neural stem/progenitor cells (NSCs/NPCs), which are associated with neovascularization and white matter repair in the brain. This study analyzed the dynamics of neurogenesis, neovascularization, and white matter injury/repair after middle cerebral artery occlusion (MCAO) and elucidated their temporal association. Mice were subjected to MCAO for 60 minutes and sacrificed up to 28 days after reperfusion. Neurogenesis and angiogenesis, as measured by double staining of 5-bromo-2 deoxyuridine (BrdU) with DCX or tomato lectin, respectively, were substantially activated soon after ischemia and persisted for 4 weeks. Despite the moderate recovery of functional vessels in infarct margin from 7 days post-ischemia, a significant decrease in vascular density remained over time. Clusters of immature neurons localized proximal to angiogenic blood vessels beginning 14 days after ischemia, suggesting interplay between neurogenesis and revascularization. Progenitors of oligodendrocytes (NG2+) constitutively presented in the normal brain and proliferated soon after ischemia. However, axon damage and the loss of white matter integrity after ischemic stroke were almost irreversible, as revealed by sustained decreases of myelin basic protein (MBP) and neurofilament 200 expression. PMID- 22202009 TI - miRNAs are stable in colorectal cancer archival tissue blocks. AB - MicroRNAs (miRNAs) have prognostic and therapeutic value for colorectal cancers RCs). Although formalin-fixed paraffin-embedded (FFPE) tissues are available for biomarker studies, the stability of miRNAs in these tissues stored for long periods (more than 20 years) is unknown. The present effort involved analysis of 345 FFPE CRC tissues, stored for 6 to 28 years (1982-2004), for the expression of six miRNAs (miR-20a, miR-21, miR-106a, miR-181b, miR-203, and miR-324-5p) using TaqMan(r) microRNA assays and quantitative real-time PCR (qRT-PCR). Evaluation, by linear regression analysis, of miRNA expression among archived CRC tissues found similar levels of all six miRNAs in tissues stored over this period (correlation coefficients, R2, ranged from less than 0.0001-0.009; and t-test p values were greater than or equal to 0.05). Thus, miRNAs are stable in FFPE tissues stored for long periods of time, and such samples can be used for discovery of biomarkers. PMID- 22202010 TI - Tracking the molecular signature of developing skeletal tissues. AB - We isolated cells from their native in vivo microenvironment using the Laser Capture Micro dissection (LCM). Bone and cartilage tissues were studied from mouse embryonic (18dpc) processed by cry sections enabled the cell isolation from anatomical complexity of skeletal tissues using the LCM technique. RNA was purified from the isolated cells and followed with amplification stage to hybridize on gene array for high through (HT) put analysis to profile the tissues gene expression. Bioinformatics profiling of the differential expression performed according to the tissue origin highlighted the common and divergent genes in the regulation of these tissues. Specifically, we identified that genes related to cell replication and cell metabolism were more prominent in bone, while organic acid metabolism was more prominent in cartilage. This study has demonstrated the utility of applying HT microarray analysis using RNA from small number of cells isolated by LCM from skeletal tissues. The bioinformatics provides insight which has not yet been explored for the developing skeletal tissues. The power of LCM application provides a platform to make a broad molecular analysis using transcriptom analysis to reveal the molecular signature of tissues in their nature environment. PMID- 22202011 TI - Role of WWOX/WOX1 in Alzheimer's disease pathology and in cell death signaling. AB - Alzheimer's disease (AD) is the most common form of dementia with a progressive course. AD pathology is a manifestation of the underlying severity and neuroanatomic involvement of specific vulnerable brain regions and circuits that are responsible for neuronal dysfunction and death. The etiology of AD is largely unknown. It has been hypothesized that multiple factors, including genetic components, oxidative stress, intracellular or extracellular accumulation of amyloid, dysfunction of cystoskeletal and synapse components, neuronal loss by apoptosis, neuronal excitotoxicity, inflammation, mitochondria dysfunction, etc., may play important roles in the onset of the disease. WWOX/WOX1 is a candidate tumor suppressor. Human WWOX gene, encoding the WW domain-containing oxidoreductase (designated WWOX, FOR, or WOX1) protein, has been mapped to a fragile site on the chromosome ch16q23.3-24.1. Functionally, the WW domain is not only a tumor suppressor, but also a participant in molecular interactions, signaling, and apoptosis in many diseases. In this article, we review the potential mechanism by which WWOX/WOX1 may participate in the pathogenesis of AD with a focus on cell death signaling pathways in neurons. PMID- 22202012 TI - N-Acetyltransferase 2 genotype, exfoliated urothelial cells and benzidine exposure. AB - Most studies report an association of the slow N-acetyltransferase 2 (NAT2) status with elevated bladder cancer risk. In this study, NAT2 genotypes and the decades-long records of Papanicolaou's grading of exfoliated urothelial cells in a former benzidine-exposed cohort of the Shanghai dyestuff industry (29 bladder cancer patients; 307 non-cancer cohort members, some of them presenting different grades of pre-malignant alterations of exfoliated urothelial cells) were investigated. The cohort members had been enrolled in regular medical surveillance since mid-1980s. No overall increase of slow NAT2 genotypes in the former benzidine-exposed bladder cancer patients was found, compared with non diseased members of the same cohort. A lower presentation of the homozygous wild genotype NAT2 4/4 was observed in bladder cancer patients, compared with non diseased members with averaged Papanicolaou's grading (APG)3 II (OR=0.31, 95 percent CI 0.10-0.96, p=0.034) or with APG less than II (OR=0.36,95 percent CI 0.12-1.10, p=0.063). Nevertheless, neither a protective influence of rapid NAT2 genotypes on bladder cancer risk nor on pre-malignant cytological alterations could be confirmed by the present data. PMID- 22202013 TI - The thermoneutral zone: implications for metabolic studies. AB - A thermoneutral environment is important for many human physiological studies. The thermoneutral zone (TNZ) is defined as the range of ambient temperatures without regulatory changes in metabolic heat production or evaporative heat loss. Many factors influence the thermoneutral zone, such as body composition, clothing, energy expenditure, age and gender. These factors have the potential to introduce bias in study results and therefore need to be taken into consideration in many metabolic studies or studies on obesity, medical conditions, thermal comfort or vigilance. Given new developments on the TNZ combined with historical views the aim of this review is to 1) provide insight in how the human TNZ is affected by internal and external factors, 2) indicate how skin blood flow characteristics could be used as an objective criterion for determining whether someone is in the thermoneutral zone, 3) explain implications of the TNZ on metabolic studies and 4) indicate future directions to enhance understanding of the TNZ, especially for the elderly and obese. PMID- 22202014 TI - Localization and distribution of wolframin in human tissues. AB - Wolframin is a transmembrane glycoprotein of 890 aminoacids, encoded by WFS1 gene. WFS1 mutations are responsible for Wolfram syndrome, an autosomal recessive disorder. In the present paper, we first characterized the polyclonal wolframin antibody by dot blot. Secondly, we verified antibody specificity by western blotting using different human cell lines. Thirdly, we studied wolframin localization in human foetal (14-35 weeks) and adult tissues by immunohistochemistry. Wolframin expression was distributed in many organs, with different tissue and cell localization and expression levels. In foetal systems, wolframin expression was faint at 14-16 weeks and increased when development proceeded. In adult human tissues a variable positive staining was observed in both simple and stratified epithelia. A moderate wolframin expression was observed in liver and in the endocrine portion of the pancreas. In conclusion, our data suggest that this protein may have important roles in a number of different tissues, including many that are not known to be affected by WFS1 linked diseases. The immunopositivity in adult human tissues suggests that it may function maintaining physiological cellular homeostasis. PMID- 22202015 TI - Nutritional support in patients with acute pancreatitis. AB - Pancreatitis is a diffuse systemic immuno-inflammatory response to a localized process of auto-digestion within the pancreatic gland, caused by premature activation of proteolytic digestive enzymes. According to the ATLANTA criteria (1992) we recognized a mild and a severe acute pancreatitis (SAP ) . Mortality rate in SAP account up to the 20 percent and most complications and deaths are due to an inflammatory immune response to pancreatic necrosis and/or infection. Patients affected by SAP rapidly incur accelerated catabolism and thus nutritional support is essential, especially in the earliest period of the disease. Recent observations show that the route of nutritional support may also affect disease severity and its course. In this view several important questions about nutritional support need to be addressed : indication , timing, enteral vs parenteral and composition . With this review we analyze the state-of-the-art and we present a decisional flow chart to better manage the nutritional support in SAP. PMID- 22202016 TI - Sleep deprivation, sleep apnea and cardiovascular diseases. AB - Sleep dramatically influences cardiovascular regulation. Changes in sleep duration or quality as seen in sleep disorders may prevent blood pressure to fall during sleep as expected in human physiology. This supports the increased prevalence of hypertension and drug-resistant hypertension in those with sleep loss. Other cardiovascular outcomes i.e. coronary lesions seem to be associated with sleep duration. Systemic inflammation, oxidative stress and endothelial dysfunction seem to be associated with both sleep loss and sleep disorders. The most critical example is Obstructive Sleep Apnea (OSA). Sympathetic activation, oxidative stress and systemic inflammation are the main intermediary mechanisms associated with sleep apnea and intermittent hypoxia. There are now convincing data regarding the associations between hypertension, arrhythmias, stroke, coronary heart disease, increased cardiovascular mortality and OSA. There are also data in OSA and in animal models supporting the link between sleep apnea and atherosclerosis and dysmetabolism. Whether treating sleep apnea enables the reversal of chronic cardiovascular and metabolic consequences of OSA, remains to be studied in adequately designed studies, particularly in comparison with usual treatment strategies. PMID- 22202017 TI - TGF-beta 1/Smad3 expression and its effects on carotid intimal hyperplasia. AB - We investigated expression of TGF-beta 1/Smad3 after balloon injury in rat carotid arteries as well as the effects of blocking the TGF-beta 1/smad3 signaling pathway on carotid intimal hyperplasia. Rats were randomly divided into control group (C group) and injury group (S group). The latter were randomly divided into intervention group (antisense Smad3 adenovirus vector transfection after balloon injury) and blank control group (blank adenovirus vector transfection after balloon injury). Expression of Smad3 mRNA 1 d, 3 d, 1 week, 2 weeks and 1 month after injury and intima/media thickness ratios 1 d, 2 weeks and 3 months after injury in the intervention group were significantly lower than those in the injury group. Ki-67 expression in the intervention group was inhibited as shown in immunohistochemistry studies. These results demonstrated that antisense Smad3 adenovirus vector transfection can block TGF-beta 1/Smad3 signal transduction and thus inhibit intimal hyperplasia. PMID- 22202018 TI - Medicinal chemistry and nanomedicine for reproductive cancer therapeutics. AB - Nanomedicine is an interdisciplinary research field where chemistry, physics, biology, engineering, nanotechnology, and medicine meet one other. Many novel nanoparticles have been designed, synthesized, and evaluated for selective targeting of cancer cells, delivering, and releasing the anticancer drugs in a controlled manner. In this review article we discuss the current status and future prospects of medicinal chemistry of nanomedicine with particular attention to nanoparticle systems that are in various stages of development for cancer therapy in reproductive medicine. PMID- 22202019 TI - Fungal endophytes: a potential source of antifungal compounds. AB - The prevalence of invasive fungal infections has increased significantly during organ transplantation, cancer chemotherapy and allogeneic bone marrow transplantation. However, only a limited number of antifungal agents are currently available for the treatment of life-threatening fungal infections. Although new antifungal agents have been introduced in the market, the development of resistance to antifungal drugs has become increasingly apparent, especially in patients with long term treatment. Microbial natural products have always been an alternative natural source for the isolation of novel molecules for various therapeutic applications. Endophytes are the microorganisms that colonize internal tissues of all plant species and represent an abundant and dependable source of bioactive and chemically novel compounds with potential for exploitation in a wide variety of medical, agricultural and industrial arenas. In the present review several metabolites obtained from endophytic fungi with a potential as antifungal agents are mentioned with bioactivity including volatile organic compounds. The compounds reported here with a diverse scaffold can be a potential starting point for new antifungal agents either as such or after chemical modification. PMID- 22202020 TI - Arylamine drugs: genotoxic-carcinogenic activity of NO-derivatives. AB - This review provides information on arylamine drugs which have been tested for the formation of N-nitroso compounds (NOC) by reacting with nitrite, and on the genotoxic-carcinogenic effects of their nitrosation products. In an extensive search we have found that 109 arylamine drugs were examined for their ability to react with nitrite, and 105 of them (96.3 %) were found to form NOC or in some cases other reactive species. Moreover, 78 arylamine drugs were examined in short term genotoxicity tests and/or in long-term carcinogenicity assays, either in combination with nitrite or using their nitrosation product; 67 of them (85.9 %) have been found to give at least one positive response. Only a small fraction, the 19.1 % of theoretically nitrosatable arylamine drugs, has been examined for the possible formation of genotoxic-carcinogenic NOC, guidelines for genotoxicity testing of pharmaceuticals do not indicate the need of appropriate tests, and patients are not informed that the drug-nitrite interaction and the consequent risk can be reduced to a large extent by consuming the nitrosatable drug with ascorbic acid. PMID- 22202021 TI - Histology of epiphyseal cartilage calcification and endochondral ossification. AB - Cartilage calcification is carried out by chondrocytes as they hypertrophy and begin to secrete matrix vesicles. Calcification initiates when calcium phosphates appear inside these matrix vesicles, forming hydroxyapatite crystals that eventually break through the membrane to form calcifying globules, as in bone calcification. However, the extracellular environment in cartilage is different from that in bone: cartilage is abundant in proteoglycans but contains a small amount of osteopontin. Hypertrophic chondrocytes secrete vesicles in the cartilaginous matrix of intercolumnar septae only, forming well-calcified longitudinal septae and poorly-calcified transverse partitions. Such pattern of vesicle deposition permits the invasion of endothelial cells, which infiltrate into cartilage and induce migration of osteogenic and osteoclastic cells. Osteoclasts resorb the excess of calcified globules in the partitions, shaping calcified cartilage cores paralleling the longitudinal axis of long bones. After the formation of these calcified cartilage cores, endochondral ossification involves a series of well-defined events in which osteogenic cells deposit new bone onto the cartilage core and form primary trabecules. This review presents the histology of epiphyseal cartilage calcification and endochondral ossification. PMID- 22202022 TI - The contributions of unscheduled neuronal cell cycle events to the death of neurons in Alzheimer's disease. AB - Alzheimer's disease is a neurodegenerative disorder that accounts for the majority of the dementia in individuals over the age of 65. While much has been learned about the biology and biochemistry of the tau tangles and beta-amyloid plaques, less is known about the cell biology of the neuronal cell death process. This review examines one feature of this process, the unexpected occurrence of unscheduled cell cycle events in mature and normally non-mitotic neurons in the at-risk neuronal populations. The correlation of neuronal cell cycling and cell death is not unique to Alzheimer's, but the evidence in both human Alzheimer's disease and its mouse models suggests that these events are early disease related processes, that they are driving forces of the disease rather than indirect symptoms. Defining the biochemistry behind cell cycle initiation holds promise as a fresh therapeutic approach in the battle against this devastating disease. PMID- 22202023 TI - The JNK signalling transduction pathway in the brain. AB - Among the numerous intracellular signalling pathways that control brain development and pathogenesis c-Jun N-terminal kinases have a leading role in the Central Nervous System. JNKs regulate a wide range of processes in brain development, plasticity, repair/regeneration, neuronal death and neuroinflammation. Indeed, accumulating evidence underline the potential of JNK targeted molecules towards the treatment of neurodegenerative disorders. The focus of the presenting review is to provide an overview of the reported data linking JNKs to brain function and dysfunction. PMID- 22202024 TI - Humoral immunity-mediated chronic rejection in liver transplantation is associated with predominant IL-10 expression. AB - Chronic rejection is a major cause of graft dysfunction and retransplantation after liver allotransplantation. Recent studies have implicated humoral response in this chronic rejection reaction. However, the manner in which humoral response is activated has not been fully investigated. In the present study, we address this question using our previously established chronic allograft liver rejection model induced by low-dose immunosuppressive cyclosporine (CsA) following Dark Agouti (DA) to Brown Norway (BN) liver transplantation. High-level donor-specific antibodies (IgG1 isotype), C4d deposition and histological graft damage indicated the involvement of humoral rejection in this chronic rejection reaction. In vitro assay showed that alloantibodies from pre-sensitized BN recipients induced apoptosis of bile ductal cells isolated from donor livers and the production of pro-fibrosis factors (TGF-beta, PDGF and FGF). Statistical analysis showed that the serum level of IL-10 was positively correlated with that of donor-specific antibodies (IgG1 isotype). Blockade of IL-10 in vivo down-regulated the level of donor-specific antibodies and ameliorated the outcome of chronic rejection. This suggests that humoral response in chronic allograft liver rejection is associated with Th2 type cytokine IL-10 and that Th2 response might promote chronic rejection by inducing a humoral response. PMID- 22202025 TI - Autophagy in the stress-induced myocardium. AB - Cardiovascular disease is a leading cause of death worldwide, particularly in Western societies. During an ischaemic insult, ventricular pressure from the heart is diminished as a result of cardiac myocyte death by necrosis and apoptosis. Autophagy is a process whereby cells catabolise intracellular proteins in order to generate ATP in times of stress such as nutrient starvation and hypoxia. Emerging evidence suggests that autophagy plays a positive role in cardiac myocyte survival during periods of cellular stress performing an important damage limitation function. By promoting cell survival, cardiac myocyte loss is reduced thereby minimising the potential of heart failure. In contrast, it has been reported that autophagy can also be a form of cell death. By considering the various animal models of autophagy, we examine the role of the Signal Transducers and Activator of Transcription (STAT) proteins in the autophagic response. Additionally we review the role of the tumour suppressor, p53 and its family member p73 and their potential role in the autophagic response. PMID- 22202026 TI - Cancer stem cells and resistance to chemo and radio therapy. AB - Cancer stem cells (CSCs, or tumor initiating cells) are responsible for tumor initiation. If cancer treatment kills most of cancer cells in the stage of transit amplifying and differentiation without killing the stem cells, the surviving CSCs will eventually lead to recurrence of tumors. Studies have suggested that CSCs may be the primary mediators of resistance to chemo- and radio-therapy, leading to failure in cancer therapy. Numerous targets are being investigated for their potential involvement in the self-renewal and chemo- and radio-resistance of cancer cells. However, despite the intensive efforts invested into characterizing the role of cancer stem cells, there is a sense of uncertainty regarding the identity and number of these cells as well as the implications in cancer treatment. In this review, we will discuss the identification of CSCs by cell surface markers, the biology of CSCs, and the role of CSCs in resistance to radio- and chemo-therapy. This review will discuss the advances in targeting CSCs to improve the efficacy of chemo- and radio-therapy. PMID- 22202027 TI - Comparison and evaluation of network clustering algorithms applied to genetic interaction networks. AB - The goal of network clustering algorithms detect dense clusters in a network, and provide a first step towards the understanding of large scale biological networks. With numerous recent advances in biotechnologies, large-scale genetic interactions are widely available, but there is a limited understanding of which clustering algorithms may be most effective. In order to address this problem, we conducted a systematic study to compare and evaluate six clustering algorithms in analyzing genetic interaction networks, and investigated influencing factors in choosing algorithms. The algorithms considered in this comparison include hierarchical clustering, topological overlap matrix, bi-clustering, Markov clustering, Bayesian discriminant analysis based community detection, and variational Bayes approach to modularity. Both experimentally identified and synthetically constructed networks were used in this comparison. The accuracy of the algorithms is measured by the Jaccard index in comparing predicted gene modules with benchmark gene sets. The results suggest that the choice differs according to the network topology and evaluation criteria. Hierarchical clustering showed to be best at predicting protein complexes; Bayesian discriminant analysis based community detection proved best under epistatic miniarray profile (EMAP) datasets; the variational Bayes approach to modularity was noticeably better than the other algorithms in the genome-scale networks. PMID- 22202028 TI - Matrix metalloproteinases in T cell mediated pulmonary diseases. AB - Lung transplantation is the only conclusive treatment for many patients suffering from end-stage pulmonary disease. Unfortunately, the leading cause of death in lung transplant recipients is the development of chronic rejection known as obliterative bronchiolitis, characterized by extensive remodeling. Matrix metalloproteinases (MMPs) are endopeptidases known for their role in matrix remodeling and their involvement in many biological processes including end-stage pulmonary disease and transplant rejection. Our understanding of MMPs involvement in pulmonary immunity is rapidly expanding. As a result there has been some focus on MMPs role in T cell-associated pulmonary diseases, such as pulmonary fibrosis, emphysema, asthma and bronchiolitis obliterans syndrome. However, not much is known about the role of MMPs in regulating immune cell function. It is now commonly known that MMP inhibition via, broad spectrum or specific synthetic or naturally occurring inhibitors (TIMPs) can down regulated many pulmonary disease states. In this review, we explore the idea that T cell targeted MMP inhibition may provide a novel approach of immune regulation in the treatment of T cell mediated diseases. PMID- 22202029 TI - Immuno- inflammatory markers of bipolar disorder: a review of evidence. AB - Bipolar is a severe psychiatric disorder which ethiopathogenesis remains unclear. Despite a clearly established heritability, genetic studies have failed to elucidate the underlying mechanism of bipolar disorder, most likely due to the contributing role of environmental factors in the genesis of the disease.. Environmental factors have been consistently described to induce immuno inflammation dysfunction, which are also known to play a role in the pathogenesis of bipolar disorders as due to the combined actions of small effects in many different genes interacting with environmental factors). Several mechanisms might explain the pro-inflammatory processes observed in bipolar disorder. Emerging evidence support the pathophysiological role of Human Endogenous Retroviruses, which reactivation (normally silenced), can be induced by infectious agents during pregnancy, early childhood and/or adolescence. ,Neurotoxic effects and inflammatory state are induced, which might in turn and after a prodromal phase, trigger acute mood episodes,. The present paper reviews the role of the immuno inflammatory processes as key contributors to the bipolar disorders pathophysiology , the evidence supporting immuno-genetic predisposition,background, and the the possible implications of retroviruses reactivation in the pathogenesis of bipolar disorder. PMID- 22202031 TI - Proteasome inhibition overcomes TRAIL resistance in human hepatoblastoma cells. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is responsible for cell death in many cancer cells while being non-toxic for most normal cells. In this study, we investigated the role of TRAIL in human hepatoblastoma (HB) cells and analyzed different approaches to reverse TRAIL resistance in these tumors. Death receptors DR4 and DR5 expression was found on all analyzed primary HB samples and on the cell lines HuH6 and HepT1 by immunofluorescence staining. Recombinant TRAIL alone did not induce in vitro cytotoxicity. Decoy receptor blocking by antibodies led to moderate effects in HepT1 but not in HUH6 cells, whereas FLIP knock-down using siRNA rendered HUH6 cells but not HepT1 cells sensible to TRAIL. Bcl-2 inhibition with ABT-737 enhanced TRAIL-mediated apoptosis in all HB cells. Strongest cytotoxic TRAIL effects were seen in HB cell lines with synchronous proteasome inhibition using bortezomib. FLIP and Bcl-2 contributed to the TRAIL resistance in HB. Overcoming TRAIL resistance in HB by proteasome inhibitors has been identified a possible additive to improve treatment results in HB patients with drug resistant tumors. PMID- 22202030 TI - The neuroprotective effects of apocynin. AB - The recognition of health benefits of phytomedicines and herbal supplements lead to an increased interest to understand the cellular and molecular basis of their biological activities. Apocynin (4-hydroxy-3-methoxy-acetophenone) is a constituent of the Himalayan medicinal herb Picrorhiza kurroa which is regarded as an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, a superoxide-producing enzyme. NADPH oxidase appears to be especially important in the modulation of redox-sensitive signaling pathways and also has been implicated in neuronal dysfunction and degeneration, and neuroinflammmation in diseases ranging from stroke, Alzheimer's and Parkinson's diseases to psychiatric disorders. In this review, we aim to give an overview of current literature on the neuroprotective effects of apocynin in the prevention and treatment of neurodegenerative disorders. Particular attention is given to in vivo studies. PMID- 22202033 TI - Isolated lung perfusion. AB - Isolated lung perfusion (ILP) has been historically used as a method to study basic lung physiologic concepts using animal models. More recently, ILP has been applied in lung transplantation and thoracic oncology. In lung transplantation, ILP has been used to assess physiological integrity of donor lungs after the organ is removed from the donor. This procedure is called Ex vivo Lung Perfusion (EVLP), and it has also been proposed as a method for active treatment and repair of injured unsuitable donor organs ex vivo. In oncology, ILP is an attractive method to deliver high dose chemotherapy to treat pulmonary metastatic disease. Since the lung vasculature is isolated in vivo, this technique is called in vivo lung perfusion (IVLP). This review will focus on the rationale, technical aspects, experimental and clinical experience of EVLP and IVLP. A perspective on the future use of these techniques is described. PMID- 22202034 TI - Mitochondrial dysfunction in cholestatic liver diseases. AB - Cholestatic liver diseases are characterized by blockade of bile flow from the liver to the intestine, and accumulation of hydrophobic bile acids in the liver and plasma. As a consequence an inflammatory response evolves associated with increased apoptosis, oxidative stress, and eventually fibrosis. Cholestasis is associated with profound metabolic changes, alterations in the mitochondrial function, decreased fatty acid oxidation, and increased glycolisis. Mitochondria play a central role in the development of this liver disease because they mediate death receptor signaling - triggered by inflammatory cytokines or bile acids - and contribute to oxidative damage, metabolic disorder, and onset of fibrosis. During the pathogenesis of biliary cirrhosis mitochondria's need for renewal is hampered by a blunted mitochondrial biogenesis. Lack of stimulation of mitochondrial renewal helps to explain mitochondrial impairment in long-term cholestasis. The marked depletion of mitochondrial DNA and occurrence of mitochondrial DNA deletions are probably relevant contributors to the progression of this severe disease. All these findings certainly support the consideration of long-term cholestasis as a secondary mitochondrial hepatopathy. PMID- 22202032 TI - L1 expression and regulation in humans and rodents. AB - Long interspersed elements type 1 (LINE-1s, or L1s) have impacted mammalian genomes at multiple levels. L1 transcription is mainly controlled by its 5' untranslated region (5'UTR), which differs significantly among active human and rodent L1 families. In this review, L1 expression and its regulation are examined in the context of human and rodent development. First, endogenous L1 expression patterns in three different species-human, rat, and mouse-are compared and contrasted. A detailed account of relevant experimental evidence is presented according to the source material, such as cell lines, tumors, and normal somatic and germline tissues from different developmental stages. Second, factors involved in the regulation of L1 expression at both transcriptional and posttranscriptional levels are discussed. These include transcription factors, DNA methylation, PIWI-interacting RNAs (piRNAs), RNA interference (RNAi), and posttranscriptional host factors. Similarities and differences between human and rodent L1s are highlighted. Third, recent findings from transgenic mouse models of L1 are summarized and contrasted with those from endogenous L1 studies. Finally, the challenges and opportunities for L1 mouse models are discussed. PMID- 22202037 TI - Modulation of normal and malignant plasma cells function by toll-like receptors. AB - Toll-like receptors (TLRs) are well known activators of immune responses, but their involvement in the plasma cell (PC) differentiation process remains mostly unknown. This review is focused on the expression and function of TLRs on normal PCs and their malignant counterpart, Multiple Myeloma cells. We report studies that suggest a role for TLR ligands as adjuvants of the humoral immune response through the survival of newly generated immature PCs. On the contrary, TLRs do not seem to be involved in the long-term maintenance of PCs in the bone marrow. Multiple Myeloma cells express a broad range of TLRs, and show heterogeneous responses to different ligands. These double-edged-sword effects are presented and discussed in the context of tumor progression, and as putative therapeutic targets. PMID- 22202035 TI - Physiological and pathophysiological functions of SOCE in the immune system. AB - Calcium signals play a critical role in many cell-type specific effector functions during innate and adaptive immune responses. The predominant mechanism to raise intracellular (Ca2+) used by most immune cells is store-operated Ca2+ entry (SOCE), whereby the depletion of endoplasmic reticulum (ER) Ca2+ stores triggers the influx of extracellular Ca2+. SOCE in immune cells is mediated by the highly Ca2+ selective Ca2+-release-activated Ca2+ (CRAC) channel, encoded by ORAI1, ORAI2 and ORAI3 genes. ORAI proteins are activated by stromal interaction molecules (STIM) 1 and 2, which act as sensors of ER Ca2+ store depletion. The importance of SOCE mediated by STIM and ORAI proteins for immune function is evident from the immunodeficiency and autoimmunity in patients with mutations in STIM1 and ORAI1 genes. These patients and studies in gene-targeted mice have revealed an essential role for ORAI/STIM proteins in the function of several immune cells. This review focuses on recent advances made towards understanding the role of SOCE in immune cells with an emphasis on the immune dysregulation that results from defects in SOCE in human patients and transgenic mice. PMID- 22202038 TI - Bone cells and the mechanisms of bone remodelling. AB - Bone is a peculiar connective tissue which functionally interacts with many other organs and tissues, including bone marrow, lymphoid tissue, kidney, adipose tissue, endocrine pancreas, brain and gonads. Bone functions are accomplished by three principal cell types: the osteoblasts, cells of mesenchymal origin having osteogenic functions, the osteoclasts, giant multinucleated cells arising from the monocyte-macrophage line and devoted to resorb bone, and the osteocytes, the latter arising from mature osteoblasts that, once deposited the bone matrix, remain trapped in it, becoming quiescent cells. Osteocytes are known for their role as mechanosensors, however, old and new evidence showed their active contribution to mineral homeostasis. Moreover, the cross-talk between bone cells is crucial, since a correct bone homeostasis relies on a right coupling between osteoblast and osteoclast functions. Any deregulation of this coupling is responsible for bone disease condition, which reflects on other organs with which bone interacts. PMID- 22202036 TI - Life is a pattern: vascular assembly within the embryo. AB - The formation of the vascular system is one of the earliest and most important events during organogenesis in the developing embryo because the growing organism needs a transportation system to supply oxygen and nutrients and to remove waste products. Two distinct processes termed vasculogenesis and angiogenesis lead to a complex vasculature covering the entire body. Several cellular mechanisms including migration, proliferation, differentiation and maturation are involved in generating this hierarchical vascular tree. To achieve this aim, a multitude of signaling pathways need to be activated and coordinated in spatio-temporal patterns. Understanding embryonic molecular mechanism in angiogenesis further provides insight for therapeutic approaches in pathological conditions like cancer or ischemic diseases in the adult. In this review, we describe the current understanding of major signaling pathways that are necessary and active during vascular development. PMID- 22202040 TI - Telomere and telomerase in stem cells: relevance in ageing and disease. AB - Telomeres, at the end of chromosomes provide genomic stability. During embryonic development, telomerase, a reverse transcriptase elongates the ends of the DNA. In somatic cells, the activity of telomerase decreases after birth leading to shortening of telomere with cell division, which thereby triggers senescence. In embryonic stem cells and germ cells, telomere length is maintained. In adults, the tissue specific stem cells have telomerase activity, but it is not enough to maintain the length of telomere. The stem cells also undergo the process of ageing but it is delayed as compared to the somatic cells. Studies on the genetic disorder, dyskeratosis congenital, caused by mutations in the human telomerase, reiterate the importance of telomere maintenance in human stem cells. This review covers the role of telomere and telomerase in stem cells and their relevance in disease and ageing. PMID- 22202041 TI - Which role for EGFR therapy in breast cancer? AB - EGFR and HER2 are highly expressed in 15-30% of breast cancer tissues. Therefore, EGFR and its downstream signaling pathways are promising anti-tumour targets. HER2 overexpression is often associated with estrogen receptor (ER) and progesterone receptor (PR) negativity, high histological grade, high rates of cell proliferation and lymph node involvement. Moreover, it is correlated with disease aggressiveness, increased rates of recurrence and poorer survival in node positive breast cancer patients, whereas the prognostic significance in patients with node-negative tumors remains somewhat controversial. This paper focuses on the therapeutic strategy for treatment of HER2 overexpressing breast cancer in advanced stages of disease, as well as in the adjuvant and neo-adjuvant settings. PMID- 22202042 TI - Psychological stressors as interventions: good out of the evil. AB - Stress in general can be defined as a state of threatened balance, equilibrium or harmony that tends to disturb the homeostasis of the body. Stress can be of many kinds viz. psychological, physiological, social, emotional, and nutritional. Albeit the distinct kinds of stress stated in the aforementioned stress list, it is hard to bring out a clear distinction between them since each stress may precede or succeed the manifestation of any other. The studies discussed in the review elucidate effects of psychological stressors (PS) on diseases such as cancer, AIDS, epidermal abnormalities, obesity, and various inflammatory diseases like colonic inflammations, Coronary Artery Disease (CAD), Coronary Heart Disease (CHD), asthma. From these studies, further attempt was made to establish the basic mechanisms which come into play during a stressor stimulus and consequently modulate the physiology of the body. In this review we have highlighted effects of PS on diseases while simultaneously building on the modes of operation of PS to alter physiology and its further implications in developing potential psychotherapeutic methods for disease treatment. PMID- 22202039 TI - Structure and function of the solid tumor niche. AB - Although the hematopoietic stem cell (HSC) niche has been an active area of study, the concept of the bone marrow microenvironment (BMM) harboring a niche for solid metastatic tumor cells has only recently been considered. The HSC niche and microenvironment that is thought to constitute the solid tumor niche share many of the same structural and functional components, suggesting the possibility that the HSC and tumor niche are one in the same. The osteoblast is a critical component for each of these niches, and is important for regulating cellular processes such homing and migration, growth and survival, and quiescence and dormancy. Current understanding of the HSC niche may provide more insight to better defining the solid tumor niche. As role of the niche in regulating these processes is better understood, new insights to the role of the BMM in metastatic disease may be gained, and provide more potential targets for therapy. PMID- 22202044 TI - Intranasal treatment of neurodegenerative diseases and stroke. AB - Although the blood-brain barrier (BBB) restricts access to the central nervous system (CNS) for the use of systemically administered therapies, an alternative approach, the non-invasive method of intranasal delivery, can rapidly target delivery of molecules to the CNS. Intranasal delivery has the distinct advantages of circumventing the BBB while minimizing systemic exposure. This novel approach to treating neurological illnesses will be examined in detail in this review. We will review current understanding of the mechanisms underlying intranasal delivery to the CNS, along with discussion of pathways permitting entry from the nasal cavity into the CNS, particularly those involving the olfactory and trigeminal nerves. Significant preclinical research has been performed to develop and improve our current approaches to intranasal treatments. We will examine the evidence behind the use of intranasal delivery in chronic neurodegenerative conditions such as Alzheimer's Disease and diabetes-mediated cerebral degeneration, as well as in acute conditions such as stroke. PMID- 22202043 TI - Structure and function of the hematopoietic cancer niche: focus on chronic lymphocytic leukemia. AB - Chronic Lymphocytic Leukemia (CLL) is a B cell malignancy characterized by the accumulation of mature monoclonal CD5-positive B cells in the blood, secondary lymphoid tissues, and marrow. The infiltration of CLL cells in lymphoid tissues is a key element of disease pathogenesis. It is in such tissues that are found the microenvironments that provide CLL cells protection from spontaneous and/or drug-induced apoptosis. CLL cells actively shape their microenvironment by producing cytokines and chemokines, and by subverting normal accessory cells to promote leukemia-cell survival, proliferation, and escape from immune detection. In this review, we discuss how CLL cells disrupt the niches required for normal hematopoiesis or immune function and subvert normal cells in the microenvironment to support neoplastic cell growth and survival. PMID- 22202045 TI - Diet, obesity and breast cancer: an update. AB - Numerous studies indagated the relationship between dietary pattern or specific nutrients and breast cancer (BC) risk and survival. Different ethnic o social groups show differences in breast cancer incidence that could be explained by different dietary patterns. Furthermore, many nutrients could reasonably increase the risk of cancer because of their content of carcinogens or their precursors as well as of promoting substances. However, the only convincing evidences linking life style to increased BC risk are related to obesity and moderate intake of alcohol and limited to postmenopause. Saturated fat, red meat, high temperature cooking have been indicated as possible risk factors, but adjusted analyses have not confirmed this association or have limited the relationship to specific subgroups. Even the protective effect of fiber, fruit, vegetables and phytoestrogens has been suggested but not definitively demonstrated. Thus, healthy dietary patterns, with abstention from alcohol and weight control, reduce the risk of cancer or at least improve the survival of affected women by reducing the incidence of comorbidities. PMID- 22202046 TI - Cancer chemoprevention by nuts: evidence and promises. AB - Chemoprevention is the use of chemical compounds to interfere with the early precancerous stages of carcinogenesis and thereby reverse tumor formation. Many chemopreventive agents, either natural or synthetic, have been identified. Some of the most promising compounds are found in vegetables and fruits. There are numerous mechanisms of action by which these components can intervene in the prevention of cancer, although they have not been fully elucidated. It is worth to note that some foods contain different bioactive compounds. Therefore the possibility exists that combinations of compounds, naturally occurring in those foods, may have a cumulative or even synergistic effect. Nuts are very rich in different bioactive compounds whose anti-cancer properties have already been described. Epidemiologic studies have already suggested that nuts consumption may be potentially beneficial in the incidence of other diseases, such as coronary heart disease and diabetes. Although the results are not conclusive, recent studies show possible cancer protective effects of nuts. This review will focus on the laboratory and clinical evidence of nuts chemopreventive and therapeutic properties. PMID- 22202047 TI - Neural crest stem cells and their potential application in a therapy for deafness. AB - Neurosensory hearing loss is a common condition that has major social and economic implications. Recent advances in stem cell research and in cochlear implantation are offering renewed hopes to people suffering from damage to the auditory hair cells and their associated neurons. Several putative donor cell types are currently being explored, including embryonic stem cells, different types of adult stem cell and the recently described induced-pluripotent stem cells. In this review, we draw attention to the potential application of neural crest stem cells for the treatment of deafness. This population shares a similar developmental origin with the cells of the otic placode, the molecular machinery controlling their maturation and differentiation is comparable and they can produce related sensory neurons. More importantly, pockets of neural crest stem cells remain in the adult body in regions of relatively easy access, facilitating their use for autologous transplantation and therefore avoiding the need for immunosuppression and the problems of tissue rejection. Their exploration and application to hearing conditions could facilitate the development of a clinically-viable, cell-based. PMID- 22202048 TI - Development of safe and effective nonviral gene therapy by eliminating CpG motifs from plasmid DNA vector. AB - Nonviral gene therapy is expected to become a regular treatment for a variety of difficult-to-treat diseases, such as cancer and virus infection. Plasmid DNA, which is used in most nonviral gene delivery systems, usually contains, unmethylated cytosine-guanine dinucleotides, so called CpG motifs. CpG motifs are recognized by immune cells as a danger signal, leading to an inflammatory response. Such inflammatory responses could affect the safety and effectiveness of nonviral gene therapy. Therefore, reducing the number of CpG motifs in plasmid DNA has been used to increase the potency of plasmid DNA-based gene therapy. Previous studies have demonstrated that CpG reduction can extend the time period of transgene expression from plasmid DNA after in vivo gene transfer. In this review, the biological functions of the CpG motif are briefly summarized. Then, safety issues of nonviral gene therapy are discussed from the viewpoint of the inflammatory response to the CpG motif in plasmid DNA, and the effects of the CpG motif in plasmid DNA on the transgene expression profile of nonviral gene transfer are reviewed. PMID- 22202050 TI - TRPC channels as prospective targets in atherosclerosis: terra incognita. AB - Transient Receptor Potential Canonical (TRPC) proteins are non-selective cation channels ubiquitously expressed throughout the cardiovascular system, where they participate as Ca2+/Na+-permeable channels and/or signaling platforms in various physiological and pathophysiological mechanisms. TRPCs have been implicated in essential hypertension, cardiac hypertrophy and endothelial dysfunction. Despite these pathologies being related, directly or indirectly to development of atherosclerotic lesions, the potential role of TRPCs in the pathogenesis of atherosclerosis remains unexplored. Recent studies from our laboratory showing an obligatory requirement of TRPC3 in the inflammatory signaling linked to monocycle recruitment to coronary endothelium, suggest for the first time potential pathophysiological relevance of a member of the TRPC group in atherogenesis. This brings about the question whether we can envision TRPCs as potential targets for diagnosis, prognosis and/or treatment of atherosclerosis. Here we revisit some of the existing knowledge on TRPCs and cardiovascular pathology and discuss it within the context of cellular/molecular processes related to atherogenesis. Potential limitations and advantages of TRPCs as prospectives targets in atherosclerosis are discussed and confronted against. PMID- 22202049 TI - Discovery of new anticancer agents from higher plants. AB - Small organic molecules derived from higher plants have been one of the mainstays of cancer chemotherapy for approximately the past half a century. In the present review, selected single chemical entity natural products of plant origin and their semi-synthetic derivatives currently in clinical trials are featured as examples of new cancer chemotherapeutic drug candidates. Several more recently isolated compounds obtained from plants showing promising in vivo biological activity are also discussed in terms of their potential as anticancer agents, with many of these obtained from species that grow in tropical regions. Since extracts of only a relatively small proportion of the ca. 300,000 higher plants on earth have been screened biologically to date, bioactive compounds from plants should play an important role in future anticancer drug discovery efforts. PMID- 22202051 TI - Potent natural aphrodisiacs for the management of erectile dysfunction and male sexual debilities. AB - The area of natural product research is rapidly progressing from traditional medicine to modern medicine having proper scientific basis of its usage. However, identifying the active constituent or the basis of its mechanism holds the key to synthesis of these drugs in the laboratory. Traditional Indian literature such as Ayurveda has listed several plant and animal based resources for treatment of almost every ailment. Erectile dysfunction and male sexual debilities are among the most explored areas in traditional medicine. A number of natural products, mostly plant based, have been claimed to cure erectile dysfunction and related male sexual debilities. These products often are aphrodisiac and have multi-fold effects on male reproductive system. This review aims at compiling the animal and plant based resources which bear promise of treating loss of libido and erectile dysfunction. A special emphasis is paid to find out scientific basis of their usage. The identification of potential resources could help undertake further studies to establish their possible mechanism of action; opening the doors to proper clinical trials for human use. PMID- 22202052 TI - Multiple roles of RBM4 in muscle cell differentiation. AB - Muscle cell differentiation involves gene regulation at both transcriptional and post-transcriptional steps. Post-transcriptional control requires various RNA binding proteins. The multi-functional RNA binding motif 4 (RBM4) protein participates in both precursor mRNA splicing regulation and translational control in muscle cells. In myoblasts, RBM4 promotes the expression of many muscle specific mRNAs from individual genes via its activity in modulating alternative splicing. In addition, RBM4 transiently translocates to the cytoplasm during myogenesis, where it participates in translation control. RBM4 may act in conjunction with a subset of muscle-specific microRNAs to modulate their activity in translation suppression. Overexpression of RBM4 promotes muscle cell differentiation, suggesting that RBM4 acts as a positive myogenic regulator. In this review, we discuss recent data regarding how RBM4. PMID- 22202054 TI - Tissue specificities of tumor induction by aromatic amines. AB - Certain aryl compounds that have nitrogen substitutions on their ring structures are, following metabolic conversion to reactive derivatives, able to elicit toxic responses by virtue of their modifications of protein and nucleic acid. This group of compounds is often referred to as aromatic amines (AA), although from a structural perspective, compounds that can be converted metabolically to crucial AA derivatives are also capable of producing the same adverse biological effects. These effects include cellular death, mutagenic events and tumor induction. Importantly, in humans, AA can induce tumors in the urinary tract, and possibly other tissues. This contribution addresses the mechanisms by which AA are likely to produce these carcinogenic consequences. PMID- 22202055 TI - Reviewing the role of peptide rarity in bacterial toxin immunomics. AB - In the past decade, renewed efforts have been made toward the development of vaccines against cancers, infectious agents, autoimmune diseases, and allergies. These efforts have led to the accumulation of numerous peptide sequences experimentally validated as epitopes. However, the factors that render a peptide immunogenic and, more generally, the nature of the antigen-antibody recognition process remain unclear. Based on the hypothesis that potential epitopes correspond to rare sequences and/or structures, we analytically review the data on the molecular structure and properties of immunoreactive sequences derived from (or evoked by) Clostridium tetani, Bacillus anthracis, and C. botulinum toxins. A cohesive picture emerges when peptide motifs are absent or scarcely represented in endogenous self proteins as they define a common immune signature of bacterial toxin B-cell immune determinants. Likewise, the scientific literature also shows that the heavy chain third complementarity-determining regions (CDR3s) from antitoxin antibodies are characterized as being formed by rare peptide sequences. The present meta-analysis aims to provide a key to understanding the molecular nature of the immune recognition process and, in turn, to contribute to the development of effective and safe peptide-based diagnostic tools and vaccine applications. PMID- 22202053 TI - The potential origin of glioblastoma initiating cells. AB - Despite intensive clinical and laboratory research and effort, Glioblastoma remains the most common and invariably lethal primary cancer of the central nervous system. The identification of stem cell and lineage-restricted progenitor cell populations within the adult human brain in conjunction with the discovery of stem-like cells derived from gliomas which are themselves tumorigenic and have been shown to have properties of self-renewal and multipotency, has led to the hypothesis that this population of cells may represent glioma initiating cells. Extensive research characterizing the anatomic distribution and phenotype of neural stem cells in the adult brain, and the genetic underpinnings needed for malignant transformation may ultimately lead to the identification of the cellular origin for glioblastoma. Defining the cellular origin of this lethal disease may ultimately provide new therapeutic targets and modalities finally altering an otherwise bleak outcome for patients with glioblastoma. PMID- 22202056 TI - Role of histamine H4 receptors in the gastrointestinal tract. AB - The location and functional role of histamine H4 receptors (H4Rs) in the gastrointestinal tract (GI) is reviewed, with particular reference to their involvement in the regulation of gastric acid secretion, gastric mucosal defense, intestinal motility and secretion, visceral sensitivity, inflammation, immunity and carcinogenesis. H4Rs have been detected in different cell types of the gut, including immune cells, paracrine cells, endocrine cells and neurons; moreover, H4R expression was reported in human colorectal cancer specimens. Functional studies with selective H4R ligands demonstrated protective effects in several experimental models of gastric mucosal damage and intestinal inflammation, suggesting a potential therapeutic role of drugs targeting this new receptor subtype in GI disorders, such as allergic enteropathy, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and cancer. PMID- 22202058 TI - TGF-b signaling in cartilage homeostasis and osteoarthritis. AB - Healthy cartilage is maintained by a delicate balance between the anabolic and catabolic activities of articular chondrocytes. This involves actions of numerous cytokines and growth factors that regulate the synthesis and degradation of extracellular matrix components which maintain the functional integrity of the joint. An imbalance between the activities of these anabolic and catabolic factors leads to cartilage degradation resulting in osteoarthritis (OA), a chronic degenerative joint disorder characterized by destruction of articular cartilage, alterations of subchondral bone and synovial fibrosis. Among the cytokines and growth factors that have been studied in the context of cartilage homeostasis and OA, transforming growth factor-beta TGF-beta has emerged as an important molecule that plays a critical role in the development, growth, maintenance and repair of articular cartilage. Deregulation of its signaling and responses has been shown to be involved in OA. Several components of the TGF-beta pathway, including extracellular, cell surface and intracellular molecules, display altered expression or action in OA. In this review, we discuss the regulatory mechanisms of TGF-beta signaling and link these mechanisms to cartilage function, highlighting the important role of TGF-beta in maintaining cartilage function and integrity. We also summarize the alterations in the molecular events of TGF-beta signaling and responses that may contribute to OA progression and discuss the potential of targeting the TGF-beta signaling pathway for the development of novel therapies for OA. PMID- 22202057 TI - RAGE is a key cellular target for Abeta-induced perturbation in Alzheimer's disease. AB - RAGE, a receptor for advanced glycation endproducts, is an immunoglobulin-like cell surface receptor that is often described as a pattern recognition receptor due to the structural heterogeneity of its ligand. RAGE is an important cellular cofactor for amyloid beta-peptide (Abeta)-mediated cellular perturbation relevant to the pathogenesis of Alzheimer's disease (AD). The interaction of RAGE with Abeta in neurons, microglia, and vascular cells accelerates and amplifies deleterious effects on neuronal and synaptic function. RAGE-dependent signaling contributes to Abeta-mediated amyloid pathology and cognitive dysfunction observed in the AD mouse model. Blockade of RAGE significantly attenuates neuronal and synaptic injury. In this review, we summarize the role of RAGE in the pathogenesis of AD, specifically in Abeta-induced cellular perturbation. PMID- 22202059 TI - Therapeutics target of CXCR4 and its downstream in peritoneal carcinomatosis of gastric cancer. AB - Patients with advanced gastric carcinoma, especially peritoneal dissemination, have a poor prognosis. Various treatments have been used for peritoneal dissemination of gastric cancer, but there is no effective therapy for this condition. At present, similar proprieties of chemokines between trafficking of leukocytes during immune and inflammatory reactions and organ selective migration of cancer cells during metastasis are widely recognized. In particular, chemokine CXCL12 and its receptors CXCR4 are now known to play an important role in cancer progression. Recently, we reported for the first time that CXCR4 and its ligand, CXCL12, were involved in the development of peritoneal carcinomatosis of gastric cancer, and additionally, clarified the molecular mechanisms of the cell signaling pathways by which gastric cancer develops metastatic ability via CXCR4 and mTOR. In this review, we focus on the biological functions of chemokine receptors, particularly CXCR4 expressed on gastric cancer cells, and the therapeutic strategies targeting CXCR4-mediating signaling pathways in peritoneal carcinomatosis. PMID- 22202060 TI - A better way forward: targeting hedgehog signaling in liver cancer. AB - Accumulated experimental evidence indicates that Hedgehog (Hh) signaling regulates cell proliferation and specification in a variety of organs during embryonic development. However, abnormal activation of this pathway in postnatal tissues has been linked to a large number of human cancers. With respect to the liver, it is known that Hh signaling not only influences bipotential precursor cells capable of pancreas and liver development, but is also implicated in the pathogenesis of liver tumors such as hepatoblastoma, hepatocellular and cholangiocellular carcinoma, if aberrantly activated. Blockade of Hh signaling by several specific inhibitors has been proven to successfully inhibit tumor growth of various Hh-associated cancers in vitro and in preclinical mouse models, and recent clinical data suggest that the implementation of novel anticancer therapeutics based on Hh interference into commonly accepted regimens are within reach. Thus, it is highly probable that Hh targeted therapies could be used for the treatment of Hh-dependent liver cancers in the future. PMID- 22202061 TI - Gene-based continuous expression of FVIIa for the treatment of hemophilia. AB - Qualitative or quantitative defects in the genes for coagulation factors VIII (FVIII) or IX (FIX) result in a life-threatening, bleeding phenotype (hemophilia A (HA) or B (HB), respectively). Although hemophilia treatment by clotting factor replacement is effective, a proportion of patients develop neutralizing antibodies (inhibitors) to the infused factor that complicate the disease management. For inhibitor patients, recombinant human activated coagulation Factor VII (rhFVIIa), when administered at therapeutic doses, has been shown to bypass the deficiency in FVIII or FIX and result in hemostasis. As an alternative to this protein infusion therapy, a gene-based approach for the treatment of hemophilia with inhibitors has been developed, using continuous expression of a transgene coding for FVIIa following viral-mediated delivery. This approach was validated in hemophilic mice and, notably, in dogs as a model that closely resembles the human disease. In particular, liver-directed FVIIa gene delivery in hemophilic dogs resulted in multi-year transgene expression that ameliorated the bleeding phenotype, without thrombotic complications. These data support the gene based FVIIa expression as a novel bypass therapy for hemophilia with inhibitors. PMID- 22202062 TI - Operation 'p53 Hunt' to combat cancer: theaflavins in action. AB - With phytochemicals executing a plethora of anti-tumor mechanisms, targeting the 'guardian angel' p53 appears to be a critical strategy to energize the process of cancer therapeutics. Regulation of anti-tumor p53 functions by dietary plant polyphenols particularly black tea and its active component theaflavins has gained immense recognition from the point of view of both efficacy and safety. This review highlights the complexities of p53 functions, molecular mechanisms of its inactivation in cancer, and therapeutic strategies for rescuing p53 dysfunction in tumors using theaflavins. It describes how theaflavins, by steering a single molecular target - p53, regulate multiple hallmarks of carcinogenesis i.e., tumor glycolysis, angiogenesis, metastasis, apoptosis and drug resistance. Additionally, considering the rising of the current concept of cancer stem cells (CSCs), the sole participant in tumor evolution, the review discusses about the possible role of theaflavin-p53 cross talk in targeting CSCs. Such attempts to target the complexities of p53 functions during neogenesis will be of immense help in developing a "new" strategy for successful cancer prevention and therapy by theaflavins. PMID- 22202063 TI - The TRE17/USP6 oncogene: a riddle wrapped in a mystery inside an enigma. AB - De-ubiquitinating enzymes (DUBs) play critical roles in diverse cellular processes, including intracellular trafficking, protein turnover, inflammatory signaling, and cell transformation. The first DUB to be identified as an oncogene was TRE17/Ubiquitin-specific protease 6 (USP6)/Tre-2. In addition to encoding a USP, TRE17 also contains a TBC (Tre-2/Bub2/Cdc16) domain implicated in GTPase regulation and trafficking. Though first described almost two decades ago, remarkably little has been elucidated regarding TRE17's molecular and cellular functions. However, recent work has implicated TRE17 as a key etiological factor in aneurysmal bone cyst (ABC), a locally recurrent pediatric bone tumor, and identified potential pathways through which it acts. In this review, we discuss the most up-to-date findings on the molecular functions of TRE17, the role of its USP and TBC domains, and potential models for how it contributes to transformation and ABC pathogenesis. PMID- 22202064 TI - Curcumin: the multi-targeted therapy for cancer regression. AB - Tumors are multifaceted; in fact, numerous things happen in synchrony to enable tumor promotion and progression. Any type of cancer is associated with the modification of 300-500 normal genes and characterized by the deregulation of cell signaling pathways at multiple steps leading to cancer phenotype. Thus a proper management of tumorigenesis requires the development of multi-targeted therapies. Several adverse effects associated with present day cancer therapies and the thirsts for multi-targeted safe anticancer drug instigate the use of natural polyphenol, curcumin. It appears to involve a blend of anti-carcinogenic, pro-apoptotic, anti-angiogenic, anti-metastatic, immunomodulatory and antioxidant activities. Also the molecular mechanisms implicated for the pleotropic activities of curcumin are diverse and seem to involve a combination of cell signaling pathways at multiple levels of tumorigenesis. Being a potent scavenger of reactive oxygen species, curcumin also ameliorates systemic toxicity in tumor bearer. Taken together, by placing particular emphasis on molecular basis of tumor promotion and progression this review summarizes the anti-cancer properties of curcumin that may be exploited for successful clinical cancer prevention. PMID- 22202065 TI - Promise and failure of targeted therapy in breast cancer. AB - The current molecular targets in breast cancer (BC) clinical trials were identified before the advent of the genomic era and their relevance was confirmed and validated by the introduction of gene profiling. Pioneering molecular analyses and repeated data validations on different gene platforms have thus far served to define 5 subtypes of BC based on their gene signature: luminal A, luminal B, normal-like, HER2-positive, and basal. Luminal A and B tumors are estrogen receptor (ER)-positive, while basal-like are mostly negative for ER, progesterone receptor, and HER2, i.e., triple-negative. Normal-like tumors resemble normal breast tissue and the HER2 subtype is characterized by HER2 overexpression. Here, we summarize current targeted therapeutic options for the luminal, HER2-positive, and basal-like BC subtypes with respect to results observed in clinical trials as a step toward optimizing their appropriate application in the different clinical settings. We give particular consideration to the ER- and HER2-targeted therapies approved for clinical practice with respect to their merits and shortcomings in early and advanced disease, and mention the therapeutic options currently available and potentially promising for the basal-like subtype. PMID- 22202067 TI - Oxidative stress induced cellular signaling in RPE cells. AB - Oxidative stress is an important factor in the etiology of age-related macular degeneration. In the retinal pigment epithelium, oxidative stress induces protective pathways, notably the phosphatidylinositide 3-kinase (PI3K)/Akt and the nuclear factor erythroid-2 related factor 2 (Nrf2) pathways, but also vascular endothelial growth factor (VEGF) and neuroprotectin D1 (NPD-1) signaling conduct cell protection. Strong oxidative insults result in cell death, mainly mediated via a mitochondrial apoptotic pathway, including cytochrome c release and caspase activation. The role of mitogen activated protein kinases (MAPK) in oxidative stress signaling is diverse and conflicting, conducting protective as well as apoptotic pathways, in addition to involvement in a variety of other cell responses, such as VEGF or matrix metalloproteinases (MMP) upregulation. In addition to signaling deciding cell fate, first insights in inflammatory and extracellular matrix-altering signaling are emerging. PMID- 22202068 TI - Targeting endoplasmic reticulum stress for cancer therapy. AB - The endoplasmic reticulum (ER) stress response, in combination with autophagy, represents an adaptive mechanism to support cellular survival in response to a great variety of detrimental conditions, such as low nutrient levels, hypoxia, calcium imbalance, or accumulation of misfolded proteins. However, when stress conditions become too severe and excessive, this cellular stress response system turns on its pro-apoptotic module, which then gains dominance and triggers cell death. In tumor cells, the cell-protective features of the ER stress response appear to be chronically activated and thus provide support for continuous proliferation and survival even under adverse microenvironmental conditions, which may include chemotherapy. However, persistent activity of these pro survival pathways primarily in tumor cells may provide a window of opportunity for therapeutic intervention that is principally aimed at these tumor-specific conditions. Appropriate therapeutic regimens would seek to further aggravate this already engaged system in tumor cells in order to exhaust its protective features and instead trigger its pro-apoptotic module. There is accumulating evidence that this can indeed be accomplished, and that tumor-specific ER stress can be exploited by treatment with select pharmacological agents. The principles of this promising new approach to cancer therapy, as well as representative ER stress aggravating compounds, will be presented in this review. PMID- 22202069 TI - Staufen: from embryo polarity to cellular stress and neurodegeneration. AB - Staufen is a double-stranded RNA-binding protein that forms RNA granules by RNA dependent and -independent interactions. Staufen was initially described in Drosophila as a key molecule for targeting maternal mRNAs. In vertebrates, two highly similar paralogs with several splicing variants mediate mRNA transport, thus affecting neuron plasticity, learning and memory. Staufen also regulates translation and mRNA decay. In recent years, Staufen was shown to be an important regulatory component of stress granules (SGs), which are large aggregates of silenced mRNPs specifically induced upon acute cellular stress. SGs contribute to cell survival by reprogramming translation and inhibiting pro-apoptotic pathways, and Staufen appears to negatively modulate SG formation by several mechanisms. More recently, mammalian Staufen was found in RNA granules and pathological cytoplasmic aggregates related to SGs containing huntingtin, TDP43, FUS/TLS or FMRP. In addition, Staufen binds CUG repeats present in mutant RNAs causative of degenerative conditions, thus ameliorating disease. Finally, Staufen affects HIV and influenza infection at several levels. Collectively, these observations unveil important roles for Staufen-mediated post-transcriptional regulation in a growing number of human diseases. PMID- 22202066 TI - New applications of old metal-binding drugs in the treatment of human cancer. AB - Significant advances in the use of metal complexes, precipitated by platinum, have fostered a renewed interest in harnessing their rich potential in the treatment of cancer. In addition to platinum-based complexes, the anticancer properties of other metals such as ruthenium have been realized, and ruthenium based compounds are currently being investigated in clinical trials. Since the process of drug development can be expensive and cumbersome, finding new applications of existing drugs may provide effective means to expedite the regulatory process in bringing new drugs to the clinical setting. Encouraging findings from laboratory studies reveal significant anticancer activity from different classes of metal-chelating compounds, such as disulfiram, clioquinol, and dithiocarbamate derivatives that are currently approved for the treatment of various pathological disorders. Their use as coordination complexes with metals such as copper, zinc, and gold that target the ubiquitin-proteasome pathway have shown significant promise as potential anticancer agents. This review discusses the unique role of several selected metals in relation to their anti-cancer properties as well as the new therapeutic potential of several previously approved metal-chelating drugs. In vitro and in vivo experimental evidence along with mechanisms of action (e.g., via targeting the tumor proteasome) will also be discussed with anticipation of strengthening this exciting new concept. PMID- 22202070 TI - Suppression of autophagy by BCR/ABL. AB - Imatinib and second generation BCR/ABL tyrosine kinase inhibitors (TKIs) serve now as standard therapies for patients with chronic myelogenous leukemia (CML); however, CML stem cells are intrinsically insensitive to the cell death-inducing effects of TKIs, allowing the persistence of a "reservoir" of BCR/ABL-expressing CML-initiating cells potentially responsible for disease relapse and progression. Although it is still controversial whether the "insensitivity" of CML stem cells to treatment with TKI is due to BCR/ABL-dependent or independent mechanisms, treatment with IM appears to suppress BCR/ABL-dependent signaling in CML stem cells with no adverse effects on their survival. Recent evidence indicates that BCR/ABL suppresses and treatment of CML cells with IM/TKIs induces autophagy, a genetically-regulated process of adaptation to metabolic stress which could allow tumor cells to become metabolically inert enabling their survival under conditions that may mimic growth factor/nutrients deprivation. Based on this hypothesis, TKI-induced autophagy may "antagonize" TKI-induced cell death and inhibition of autophagy may eliminate this survival mechanism by restoring "sensitivity" of CML stem cells to treatment with IM/TKI. Consistent with this, phenotypically and functionally defined CML-enriched stem cells insensitive to treatment with TKI are efficiently eliminated by the combination of TKI and chloroquine, an inhibitor of late stage autophagy. Thus, inhibition of autophagy may improve the potent and specific effects of TKIs by rendering CML stem cells sensitive to these targeted therapies. PMID- 22202071 TI - Histamine receptor subtypes: a century of rational drug design. AB - Histamine plays an important role as neurotransmitter and chemical mediator in multiple physiological and pathophysiological processes in central and peripheral tissues. In the last century the extensive study of its actions in the human body, resulted in the identification of four G protein-coupled receptor (GPCR) subtypes (H1R-H4R), mediating numerous effects. The successful application of H1R and H2R antagonists/inverse agonists in the treatment of allergic conditions and gastric ulcer proved that these two receptors are excellent drug targets. Ligands for H3R are currently in advanced stages of clinical development for a broad spectrum of mainly central diseases (e.g. narcolepsy, Alzheimer's disease, epilepsy and schizophrenia). Meanwhile, preclinical research in the H4R field, focused on inflammatory and immunological processes, led to the evaluation of the first H4R-targeting clinical candidates. Drug development for each histamine receptor subtype will be discussed with a special focus on H3R and H4R ligands. PMID- 22202072 TI - The contrasting oncogenic and tumor suppressor roles of FES. AB - The FES gene was first discovered as a protein-tyrosine kinase-encoding retroviral oncogene. The ability of v-FES to transform cells in vitro and initiate cancer in vivo has been established by cell culture, engraftment and transgenic mouse studies. The corresponding cellular c-FES proto-oncogene encodes a cytoplasmic FES protein-tyrosine kinase with restrained catalytic activity relative to its retrovirally encoded homologs. These observations have stimulated a search for mutations or inappropriate expression of c-FES in human cancers and research aimed at understanding the functions of the FES kinase and its potential involvement in cancer and other diseases. Paradoxically, although first identified as an oncogene, genetic evidence has also implicated c-fes as a potential tumor suppressor. This review will describe observations from basic and translational research which shapes our current understanding of the physiological, cellular and molecular functions of the FES protein-tyrosine kinase and its potential roles in tumorigenesis. We also propose a model to reconcile the conflicting oncogenic and tumor suppressor roles of c-FES in tumorigenesis. PMID- 22202073 TI - Tumor gangliosides and T cells: a deadly encounter. AB - Despite major advances in understanding the mechanisms of tumor immunity, its successful translation into effective tumor immunotherapy is hindered by the ability of tumors to foster a tolerant microenvironment and to activate a plethora of immunosuppressive mechanisms. Among different strategies employed by tumors to thwart immune responses, shedding of immunosuppressive molecules, such as sialic acid-containing glycosphingolipids, gangliosides, by the tumor is one important strategy. Aberrant and elevated expression of gangliosides has been demonstrated on the surface of cancer cells. Here we discuss about the molecular mechanisms underneath the contribution of tumor gangliosides in targeting multiple steps of T cell response. We shall also underscore the contribution of T regulatory, NK and dendritic cells in this immunosuppressive network. Inhibitory effects of gangliosides ultimately converge to T cell apoptosis in receptor dependent and -independent manners via IL-2 deprivation, ROS production, cytochrome c release, NFkappaB inhibition and caspase activation. Current wealth of information promises a future scenario in which synchronized blockade of immunosuppressive mechanisms and removal of inhibitory signals might be effective in overcoming immunological tolerance and promoting tumor regression. PMID- 22202076 TI - Endosomal trafficking in animal cytokinesis. AB - Cytokinesis is the terminal stage of eukaryotic cell division in which the cytoplasm of a dividing cell is partitioned between two daughter cells. In animal cells, this multifaceted cellular process is spatially and temporally regulated and requires dramatic remodeling of the cytoskeleton and plasma membrane. Animal cytokinesis proceeds when the acto-myosin contractile-ring, formed at the equatorial cortex of a dividing cell, advances inward like a 'purse string' and is a major driving-force for the separation of the two daughter cells. In this review, we highlight many of the recent advances in our understanding of the function and mechanisms of action of the endocytic protein machinery that control animal cytokinesis. This includes regulation of endosome delivery and targeting by Rab and ARF GTPases, their effectors FIP3, FIP4 and JIP4, the exocyst and centralsplindlin complexes and phosphoinositides. Roles for endosomal SNAREs, BRUCE and the ESCRT pathway in the membrane remodeling processes that lead to abscission are also discussed. PMID- 22202074 TI - Chimeric antibody receptors (CARs): driving T-cell specificity to enhance anti tumor immunity. AB - Adoptive transfer of antigen-specific T cells is a compelling tool to treat cancer. To overcome issues of immune tolerance which limits the endogenous adaptive immune response to tumor-associated antigens, robust systems for the genetic modification and characterization of T cells expressing chimeric antigen receptors (CARs) to redirect specificity have been produced. Refinements with regards to persistence and trafficking of the genetically modified T cells are underway to help improve the potency of genetically modified T cells. Clinical trials utilizing this technology demonstrate feasibility, and increasingly, antitumor activity, paving the way for multi-center trials to establish the efficacy of this novel T-cell therapy. PMID- 22202075 TI - Regulation of cardiac excitability by protein kinase C isozymes. AB - Cardiac excitability and electrical activity are determined by the sum of individual ion channels, gap junctions and exchanger activities. Electrophysiological remodeling during heart disease involves changes in membrane properties of cardiomyocytes and is related to higher prevalence of arrhythmia associated morbidity and mortality. Pharmacological and genetic manipulation of cardiac cells as well as animal models of cardiovascular diseases are used to identity changes in electrophysiological properties and the molecular mechanisms associated with the disease. Protein kinase C (PKC) and several other kinases play a pivotal role in cardiac electrophysiological remodeling. Therefore, identifying specific therapies that regulate these kinases is the main focus of current research. PKC, a family of serine/threonine kinases, has been implicated as potential signaling nodes associated with biochemical and biophysical stress in cardiovascular diseases. In this review, we describe the role of PKC isozymes that are involved in cardiac excitability and discuss both genetic and pharmacological tools that were used, their attributes and limitations. Selective and effective pharmacological interventions to normalize cardiac electrical activities and correct cardiac arrhythmias will be of great clinical benefit. PMID- 22202077 TI - Myocardial substrate metabolism in heart disease. AB - Cardiac disease is commonly associated with changes in energy substrate metabolism. Fatty acid and glucose represent the main fuels used by the heart, and characteristic alterations in substrate preference and utilisation occur early in many cardiac disease processes. Different substrate classes (lipids, carbohydrates) have different metabolic efficiencies, both in terms of energy (ATP) yield and in terms of oxygen requirement; changes in metabolic efficiency may affect, positively and negatively, cardiac function. Furthermore, metabolic diseases alter substrate supply to the heart, which may have an impact on cardiac function. One challenge is to establish whether a primary metabolic abnormality in myocardial fuel utilisation leads to cardiac dysfunction, or whether changes in substrate selection are a consequence of the disease state. The distinction is important as the ability to manipulate cardiac substrate utilisation may offer a therapeutic opportunity for cardiac disease. PMID- 22202078 TI - Molecular mechanisms of the neuroprotective/neurorescue action of multi-target green tea polyphenols. AB - Mounting evidence suggests that lifestyle factors, especially nutrition are essential factor for healthy ageing. However, as a result of the increase in life expectance, neurodegenerative diseases like Alzheimer's and Parkinson's (AD and PD, respectively) are becoming an increasing burden, as aging is their main risk factor. Brain aging and neurodegenerative diseases of the elderly are characterized by oxidative damage, dysregulation of redox metals homeostasis and inflammation. Thus, it is not surprising that a large amount of drugs/agents in therapeutic use for these conditions are antioxidants/metal complexing, bioenergetic and anti-inflammatory agents. Natural plant polyphenols (flavonoids and non-flavonoids) are the most abundant antioxidants in the diet and as such, are ideal nutraceuticals for neutralizing stress-induced free radicals and inflammation. Human epidemiological and new animal data suggest that green and black flavonoids named catechins, may help protecting the aging brain and reduce the incidence of dementia, AD and PD. This review will present salient features of the beneficial multi-pharmacological actions of black and green tea polyphenols in aging and neurodegeneration, and speculate on their potential in drug combination to target distinct pathologies as a therapeutic disease modification approach. PMID- 22202079 TI - Stroke, angiogenesis and phytochemicals. AB - Stroke, or brain attack, is the third leading cause of death and the leading cause of adult disability worldwide. There is a great demand for intervention therapy. Unfortunately, although more than 700 drugs that target neuroprotection showed beneficial effects in preclinical animal studies, none of them proved efficacious in treating stroke patients. There is recent interest in understanding mechanism for post-ischemic angiogenesis in the penumbra area, and correlation of the extent of angiogenesis with survival in stroke patients. It is postulated that besides replenishing oxygen and nutrients to ischemic tissue, angiogenesis may play a crucial role in neural protection and tissue recovery. Consequently, therapeutic agents to promote angiogenesis and formation of new vessels after stroke can offer promising approach. Several large population epidemiological and clinical studies have revealed a reciprocal relationship between intake of phytochemicals and incidence of stroke. However, the detailed cellular and molecular mechanisms leading to these beneficial effects remain to be elucidated. In this article, we review the current knowledge on phytochemicals and post-ischemic angiogenesis, and discuss the possibility of a combinatorial treatment, including neuroprotection, angiogenesis, neurogenesis, and phytochemicals regimen for stroke. PMID- 22202080 TI - Optimizing stem cell collection through CXCR4 antagonists. AB - Currently, nearly all the autologous stem cell transplantation and majority of allogeneic stem cell transplantation are performed using circulating peripheral blood stem cells. At steady conditions, less than 0.05 percent of the peripheral white cells are believed to be CD34+, a surrogate marker for stem cells. The content of hematopoietic CD34+ cells in the blood can be increased dramatically following recovery from myelosuppressive chemotherapy and/or the administration of hematopoietic growth factors (GM-CS or G-CSF), and an engrafting dose of stem cells can be collected by large volume apheresis following hematopoietic cytokine treatment. However these strategies fail to result in an adequate number of hematopoietic cells in 5-30 percent of the cases, limiting the ability of patients to receive high dose chemotherapy and stem cell transplantation in the treatment of their cancer. Plerixafor, a CXCR4 antagonist has been found to be a potent stem cell mobilizer and it's superiority used in combination with G-CSF over G-CSF alone has been seen in non-Hodgkin's lymphoma and multiple myeloma in double blind randomized phase III clinical trials, leading to FDA (Food and Drug Administration) approval. This review article describes the development of plerixafor to mobilize stem cells and optimal strategies for stem cell collection from peripheral blood. PMID- 22202081 TI - Inflammation and thrombosis: new insights. AB - Vessel wall endothelial damage initiates a local inflammatory response, which promotes a prothrombotic state driven by tissue factor, adhesion molecules, and pro-inflammatory cytokines. Understanding how natural inflammatory mechanisms promote a procoagulant state, may lead to the development of new pharmacological interventions targeted at thrombosis. PMID- 22202082 TI - 14-3-3zeta cooperates with phosphorylated Plk1 and is required for correct cytokinesis. AB - Proteins of the 14-3-3 family are functionally conserved in eukaryotic kingdom which participates in diversified and critical cellular processes. However, the exact roles of these proteins in mitotic regulation has remained elusive. Polo like kinase 1 (Plk1) is a serine/threonine protein kinase that plays multiple critical functions such as centrosome maturation, mitotic chromosome segregation, cytokinesis, and the DNA damage response. Here we show that 14-3-3zeta interacts and cooperates with Plk1 in mitotic progress. 14-3-3zeta is associated with the spindle at metaphase and concentrated in the midbody during cytokinesis. Using yeast two hybrid assay, we found a functional connection between 14-3-3zeta and Plk1. We demonstrate that phosphorylation of Plk1 at S330 and S597 promotes its interaction with 14-3-3zeta. Importantly, 14-3-3zeta cooperates with Plk1 in ensuring successful cytokinesis. We conclude that mitotic phosphorylation of Plk1 promotes interaction with 14-3-3zeta and this interaction is required for faithful cytokinesis. Taken together with the results of previous studies, our results suggest 14-3-3 family emerges as a novel player in mitotic regulation: cooperation with Plk1 to ensure a faithful cytokinesis. PMID- 22202083 TI - Nox enzymes and oxidative stress in atherosclerosis. AB - Oxidative stress is a major contributor to the etiology of all severe vascular pathologies, such as atherosclerosis. NADPH oxidases (Nox) are a class of multicomponent enzymes whose unique function is the generation of reactive oxygen species (ROS) in the vascular cells and in circulating immune cells interacting with blood vessels. Physiological production of Nox-derived ROS contributes to the maintenance of vascular homeostasis. In pathological states, hyperactivity of Nox induces oxidative stress. Nox-derived ROS interact and stimulate other enzymatic sources of oxygen/nitrogen reactive intermediates, and amplify the initial response to insults. In atherosclerosis, Nox-induced lipid peroxidation is highly deleterious and expands the free radical reactions initially produced by activated Nox. Therefore, understanding the molecular mechanisms of Nox regulation, vascular and subcellular compartmentalization of ROS production and its subsequent biological significance, may lead to a focused and effective anti oxidative stress therapy. We present here, recent advances in Nox regulation in the vasculature and discuss novel potential intrinsic feedback mechanisms and current and pharmacological perspectives to target Nox, which may have an impact in vascular health and disease. PMID- 22202084 TI - EGF-receptor signaling and epithelial-mesenchymal transition in human carcinomas. AB - The epidermal growth factor receptor (EGF-R) signaling pathway maintains a balance between cell proliferation, differentiation and apoptosis, and thus it is believed that EGF-R signaling pathways play an important role in the development and progression of several human carcinomas. Epithelial-mesenchymal transition (EMT) describes the dedifferentiation switch between polarized epithelial cancer cells and contractile and motile mesenchymal (invasive) cells during cancer progression and metastasis. Activation of EGF-R signaling regulates EMT associated invasion and migration in normal and malignant epithelial cells. In contrast, blocking EGF-R and consequently its pathways, by a monoclonal antibody (mAb) or a tyrosine kinase inhibitor (TKI), inhibit cellular migration and invasion, suggesting an essential role for EGF-R inhibitors in the control of cancer metastasis. The purpose of this review is to summarize current information regarding the role of EGF-R signaling on EMT during human cancer progression and metastasis. PMID- 22202085 TI - Innate and adaptive immunity in host-microbiota mutualism. AB - Healthy individuals live in peaceful co-existence with an immense load of intestinal bacteria. This symbiosis is advantageous for both the host and the bacteria. For the host it provides access to otherwise undigestible nutrients and colonization resistance against pathogens. In return the bacteria receive an excellent nutrient habitat. The mucosal immune adaptations to the presence of this commensal intestinal microflora are manifold. Although bacterial colonization has clear systemic consequences, such as maturation of the immune system, it is striking that the mutualistic adaptive (T and B cells) and innate immune responses are precisely compartmentalized to the mucosal immune system. Here we summarize the mechanisms of mucosal immune compartmentalization and its importance for a healthy host-microbiota mutualism. PMID- 22202086 TI - Deciphering the role of Toll-like receptors in humoral responses to Borreliae. AB - The bacteria of the genus Borrelia are arthropod-borne spirochetes that cause relapsing fever and Lyme disease in humans. Like most arthropod-borne pathogens, Borreliae must survive in the periphery of their vertebrate hosts to allow for transmission to another arthropod vector. These spatial and temporal restrictions require that Borreliae evade the adaptive immune response. Borreliae have evolved genetic mechanisms that alter their surface protein expression, thereby altering the antigenic target presented to the host. To control Borreliae infection, the host relies on a rapid humoral response. While it is clear that B cell antigen receptor signaling is a critical requirement for the specific antibody responses, growing evidence suggests that additional signaling by innate immune receptors such as Toll-like receptors is necessary for optimal T cell-dependent and T cell independent antibody responses. This review is focused on the role of Toll-like receptors in B cell responses to relapsing fever and Lyme disease Borreliae. PMID- 22202087 TI - Sulphur-containing non enzymatic antioxidants: therapeutic tools against cancer. AB - The prevention of oxidation is an essential process in all cells, as decreased antioxidant protection may lead to cytotoxicity, mutagenicity and carcinogenicity. The mechanisms by which oxidative stress contributes to carcinogenesis include modulation of gene expression and induction of genetic modifications. Cellular methylation and antioxidant metabolism are linked by the transsulfuration pathway, which converts the methionine cycle intermediate, homocysteine, to cysteine, the limiting reagent in glutathione synthesis. Taurine can protect cells from oxidant-induced injury scavenging strong oxidant and cytotoxic agents, and lipoic acid can regenerate glutathione. N-acetylcysteine has anticancer properties such as counteractions against mutagens and prevention of tumor progression. The oxidizing agents react with the thiol group of these non enzymatic antioxidants determining cellular redox potential, and modulating several biological events, since different redox-sensitive molecules are involved in many cell responses such as proliferation, growth arrest, and death. The high metabolic activity characteristic of cancer cells often upregulates oxidative stress protection mechanisms. In fact, glutathione depletion is an early hallmark observed in apoptosis and it has been demonstrated as a common feature of cancer. PMID- 22202088 TI - TGF-beta antiproliferative effects in tumor suppression. AB - The TGF-beta signaling pathway controls multiple functions of cancer cells and the surrounding stromal tissue. Some TGF-beta actions suppress cancer formation, while others contribute to tumor progression. Evidence supporting a tumor suppressive role for the TGF-beta/Smad signaling axis is presented here. These data are compiled from cell culture studies, animal models, analyses of human tumors, and investigations of polymorphisms of TGF-beta pathway components and their associated cancer risk. Therapeutic strategies for cancer treatment involving either restoring or potentiating TGF-beta tumor suppressive activities, or blocking TGF-beta tumor promoting functions are considered. PMID- 22202090 TI - The role of tumor-associated macrophage in tumor progression. AB - The tumor progression is not only regulated by metastasis promoting and suppressing genes in cancer cells but it is also strongly influenced by the interaction between cancer cells and the stromal cells. An abundance of inflammatory mediators and leukocytes has been known to promote cancer metastasis, and tumor associated macrophages (TAM) are the key players in the link between inflammation and cancer. TAM are derived from peripheral blood monocytes that are recruited into the tumor by inflammatory chemokines. Upon activation by cancer cells, TAM gain the ability of pro-tumoral functions including expression of various growth factors, promotion of angiogenesis and suppression of adaptive immunity, and many of these factors also play critical roles in cancer metastasis. In this review, we will summarize the recent information about the function of TAM in the inflammatory micro-environment of solid tumors and discuss the potential targets for future therapeutic approaches. PMID- 22202091 TI - Role of microRNAs in leukemia stem cells. AB - Leukemia cells can carry a small subset of poorly differentiated cells, which are considered to be precursors of lymphoblasts, myeloblasts, or monoblasts. Thus these cells are also called leukemia stem cells (LSCs) because they are capable of instigating, maintaining and serially propagating leukemia in vivo, while retaining the ability to differentiate into committed progeny that lack these properties. Like hematopoietic stem cells (HSCs), LSCs possess the ability of self-renewal under a complex regulatory system. The recent discovery of microRNAs may shed new light on regulation of LSCs and leukemogenesis. As master gene regulators, microRNAs participate in these processes through coordinated work with key transcription factors required for hematopoiesis. Therefore, microRNAs could play a critical role in normal HSCs as well as LSCs. The purpose of this review is to provide updates on the role of microRNAs in HSCs and LSCs and to highlight their potential in differentiation therapy of leukemias. PMID- 22202092 TI - Roles of microRNAs in cancer stem cells. AB - MicroRNAs are a class of endogenous non-coding RNAs that function as important regulatory molecules via the RNA interference mechanism. Since microRNAs play a fundamental role in regulation of a variety of cellular, physiological, and developmental processes, their aberrant expression can lead to a variety of human diseases including cancer. In particular, microRNAs have been implicated in regulation of stem cells as well as cancer stem cells. Given that cancer stem cells are believed to be responsible for the cancer initiation, metastasis and chemotherapy resistance, a better understanding of how microRNAs mediate gene expression in cancer stem cells will help identify novel cancer biomarkers and therapeutic targets, and as a result, it will aid in the development of better strategy for cancer treatment. In this review, we will update recent advances in microRNAs involved in cancer stem cells and their gene regulations in these cells. PMID- 22202089 TI - Pathologic effects of RNase-L dysregulation in immunity and proliferative control. AB - The endoribonuclease RNase-L is the terminal component of an RNA cleavage pathway that mediates antiviral, antiproliferative and immunomodulatory activities. Inactivation or dysregulation of RNase-L is associated with a compromised immune response and increased risk of cancer, accordingly its activity is tightly controlled and requires an allosteric activator, 2',5'-linked oligoadenylates, for enzymatic activity. The biological activities of RNase-L are a result of direct and indirect effects of RNA cleavage and microarray analyses have revealed that RNase-L impacts the gene expression program at multiple levels. The identification of RNase-L-regulated RNAs has provided insights into potential mechanisms by which it exerts antiproliferative, proapoptotic, senescence inducing and innate immune activities. RNase-L protein interactors have been identified that serve regulatory functions and are implicated as alternate mechanisms of its biologic functions. Thus, while the molecular details are understood for only a subset of RNase-L activities, its regulation by small molecules and critical roles in host defense and as a candidate tumor suppressor make it a promising therapeutic target. PMID- 22202093 TI - The origin of cancer stem cells. AB - Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are cancer cells that possess capability of proliferation, differentiation, and self renewal. It is widely believed that CSCs play critical role in the initiation, metastasis, and relapse of cancers, but the origin of CSCs remains unclear. Up to date, several hypotheses have been described, and cell fusion and horizontal gene transfer, which may occur during development and tissue repair process, are considered as important origins of CSCs. In addition, critical gene mutations in stem cells, progenitor cells or even differentiated cells may also contribute to the formation of CSCs, and cell microenvironment is critical to CSC self-renewal and differentiation. The ongoing efforts to identify the CSCs origins may shed more light on understanding of cancer initiation and progression, as well as the development of novel cancer therapies. PMID- 22202095 TI - Anti-Thomsen-Friedenreich-Ag (anti-TF-Ag) potential for cancer therapy. AB - Thomsen-Friedenreich antigen (TF-Ag) is the disaccharide (Gal beta1-3 GalNAc alpha), which is also known as the core 1 structure. The presence of this disaccharide on the surface of approximately 90 percent of carcinomas is due to altered glycosylation in these tumors. TF-Ag plays a role in the adhesive properties of tumor cells involved in metastasis. Treatment of mice with JAA-F11, a monoclonal antibody to TF-Ag alpha inhibited lung metastasis and improved prognosis in a mouse breast cancer model. The presence of naturally occurring antibodies to TF-Ag in cancer patients is related to improved prognosis. The pancarcinoma expression of TF-Ag, combined with the evidence of a mechanistic role for TF-Ag in cancer spread, show that this target would have clinical utility. The presence of naturally occurring antibody to TF-Ag indicates that increasing the anti-TF-Ag antibody would be safe for the cancer patient and indicates that tolerance would not have to be broken to create this immune response. Finally, the prognostic improvements seen clinically and in animal models indicate that this is an important vaccine target. PMID- 22202094 TI - Modulation of cell cycle regulators by HDACs. AB - Histone deacetylases (HDACs) catalyze the deacetylation of lysine residues on histones and non-histone proteins. HDACs have been shown to control the functions of key cell cycle proteins. Consistent with this, the overexpression of HDACs has been observed in multiple cancers, resulting in deregulation of the cell cycle and uncontrolled proliferation. This review focuses on the impact that HDACs have on cell cycle control through the deacetylation of proteins. PMID- 22202096 TI - Integrating structure and function of 'tandem-repeat' galectins. AB - Galectins (GALs) are evolutionarily-conserved lectins defined by at least one carbohydrate recognition domain (CRD) with affinity for beta-galactosides and conserved sequence motifs. Although the biological roles of some members of this family, including the 'proto-type' GAL-1 and the 'chimera-type' GAL-3 have been widely studied, the functions of 'tandem-repeat' galectins are just emerging. The subgroup of 'tandem-repeat' galectins (GAL-4, -6, -8, -9, and -12) contain two distinct CRDs, connected by a linker peptide. Here we integrated and distilled the available information on 'tandem-repeat' galectins, their specific structures, potential ligands and biological activities in inflammatory and neoplastic diseases. While GAL-4 has been implicated in inflammatory bowel diseases, either as a pro-inflammatory or pro-apoptotic mediator, GAL-8 plays roles in autoimmune diseases such as rheumatoid arthritis and lupus erythematosus and modulates tumor progression. GAL-9 controls allergic inflammation and Th1/Th17-mediated autoimmunity and has prognostic value in certain tumor types. Finally, GAL-12 plays important roles in adipocyte physiology. Although this information is just emerging, further studies are needed to dissect the biological roles of 'tandem-repeat' galectins in health and disease. PMID- 22202097 TI - The regulation and activity of interleukin-12. AB - Interleukin-12 (IL-12) is a key cytokine in the development of T helper type 1 (Th1) cell polarization, and its production of IL-12 is redundantly regulated. An important pro-inflammatory cytokine, IL-12 has been shown to have potent immunomodulatory, antitumor, and anti-infection activity in vitro and in vivo. Therefore, following a series of promising results from preclinical animal models experiments, researchers have begun to explore the clinical use of recombinant human IL-12 (rhIL-12) for treating a variety of diseases. In a series of phase I and phase II clinical trials related to cancer, viral infections, and hematopoietic stem cell transplants (HSCT), various strategies of rhIL-12 administration have been used with promising preliminary clinical results associated with tolerable toxicities. PMID- 22202098 TI - Chromosomal mutations involved in antibiotic resistance in Staphylococcus aureus. AB - Staphylococcus aureus is an important pathogen involved in infections in both the community and hospital setting. Strains that are resistant to multiple classes of antibiotics, particularly methicillin-resistant strains (MRSA), are prevalent in nosocomial infections and are associated with high morbidity and mortality rates. Such antibiotic-resistant strains limit the therapeutic options and place a burden on the health care system. In the hospital setting, horizontal gene transfer plays an important role in disseminating antibiotic resistant determinants among S. aureus. However, resistance to all known classes of antibiotics have been attributed to genes found within the S. aureus chromosome or to due to mutation as a result of selection pressure. Spontaneous mutations, in particular, are pivotal in the emergence of novel resistances. Consequently, newer drugs with better activity and/or antibacterial agents with novel targets need to be developed to combat and control the further spread of antibiotic resistance. PMID- 22202100 TI - Prophylactic vaccines for prevention of prostate cancer. AB - Prostate cancer is the most prevalent cancer and the second leading cause of cancer death in men. There are various modalities for treatment of prostate cancer. Immunotherapy with several vaccines and antibodies has also been successfully used with positive clinical outcome in prostate cancer patients. The majority of these vaccines are palliative and have been employed when a person is already diagnosed with prostate cancer. The aim of this article is to review various vaccines that have been examined for immunoprophylactic prevention of initiation/development/metastasis of prostate cancer. The Pubmed database and Google Scholar search identified 26 articles on various vaccines that have been investigated for prophylactic prevention of cancer development. These vaccines targeted prostate-specific/restricted antigens (PSA/PSMA/PSCA), oncoproteins (GRP/MUC family, erbB2/HER-2/neu), whole tumor cell antigens, prostate regulating hormones (GnRH/testosterone), and various cytokines and immune modulators. The data indicates that the development of immunoprophylactic vaccines for prostate cancer is an exciting proposition, which can translate into a viable reality for clinical application in humans. PMID- 22202099 TI - Insulin resistance, metabolic stress, and atherosclerosis. AB - Atherosclerosis, a pathological process that underlies the development of cardiovascular disease, is the primary cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). T2DM is characterized by hyperglycemia and insulin resistance (IR), in which target tissues fail to respond to insulin. Systemic IR is associated with impaired insulin signaling in the metabolic tissues and vasculature. Insulin receptor is highly expressed in the liver, muscle, pancreas, and adipose tissue. It is also expressed in vascular cells. It has been suggested that insulin signaling in vascular cells regulates cell proliferation and vascular function. In this review, we discuss the association between IR, metabolic stress, and atherosclerosis with focus on 1) tissue and cell distribution of insulin receptor and its differential signaling transduction and 2) potential mechanism of insulin signaling impairment and its role in the development of atherosclerosis and vascular function in metabolic disorders including hyperglycemia, hypertension, dyslipidemia, and hyperhomocysteinemia. We propose that insulin signaling impairment is the foremost biochemical mechanism underlying increased cardiovascular morbidity and mortality in atherosclerosis, T2DM, and metabolic syndrome. PMID- 22202102 TI - Hypothalamic Akt/PKB signaling in regulation of food intake. AB - Recent tremendous advances in our understanding of the regulation of food intake are expected to contribute to the treatment of obesity in the near future. The hypothalamus is a center for regulation of food intake and NPY/AgRP and POMC neurons are key regulators of food intake in the arcuate nucleus. The level of energy in the body is monitored by energy sensors in the hypothalamus. A variety of signals originating from peripheral organs to sense the status of energy converge on the hypothalamus and diverse neurons in the hypothalamus are involved in determining the output of signal to regulate food intake. Therefore, it is important to understand the signals and energy sensors in the hypothalamus. In this review, we describe the potential role of Akt/PKB signaling as an energy sensor that regulates food intake. PMID- 22202103 TI - Azines as histamine H4 receptor antagonists. AB - Since 2000, when the histamine H4 receptor (H4R) was cloned, it has constituted an interesting target for drug development. Pharmacological studies suggest the potential utility of histamine H4R antagonists/inverse agonists in the treatment of inflammatory diseases, e.g. allergic rhinitis, asthma, atopic dermatitis, colitis, or pruritus. The first H4R ligands were non-selective compounds, but intensive chemical and pharmacological work has led to the discovery of highly potent and selective H4R antagonists (e.g. JNJ7777120, CZC-13788, PF-2988403, A 940894, A-987306). The first compound (UR-63325) has finally entered into clinical studies for the treatment of allergic respiratory diseases (completing the phase I ascending dose trial) and has been found to be safe and well tolerated. The number of scientific publications and patent applications in the H4 field is increasing annually. Among the diverse chemical structures of the H4R antagonists described a 2-aminopyrimidine scaffold is repeatedly found. This review looked at recent advances in the search for H4R antagonists as reflected in patent applications/patents and peer-reviewed publications over the last two years. The work concerns azines (mono-, di-, triazines) and their fused analogues. The chemistry and pharmacology has been described. PMID- 22202101 TI - The role of mTOR signaling in Alzheimer disease. AB - The buildup of Abeta and tau is believed to directly cause or contribute to the progressive cognitive deficits characteristic of Alzheimer disease. However, the molecular pathways linking Abeta and tau accumulation to learning and memory deficits remain elusive. There is growing evidence that soluble forms of Abeta and tau can obstruct learning and memory by interfering with several signaling cascades. In this review, I will present data showing that the mammalian target of rapamycin (mTOR) may play a role in Abeta and tau induced neurodegeneration. PMID- 22202104 TI - Advances in sonoporation strategies for cancer. AB - We will focus on the therapeutic applications of ultrasound (US) for gene transfection or 'sonoporation'. Sonoporation therapy or 'sonotherapy' is an emerging physical method for delivering drugs and/or nucleic acids for treating cancer. Because of its non-invasive nature, sonotherapy has the potential to be competitive with other treatment delivery methods such as viruses or lipofection. For nucleic acid delivery, sonoporation in the presence of microbubbles (MB) significantly enhances transfection efficiency. Sonoporation is an ideal means of delivering pDNA, and it has a similar efficiency as electroporation or other physical gene therapy techniques, with potentially fewer side effects. Typically, nonphysical means of gene delivery have suffered from lower efficiencies compared to viral vectors, however, several studies suggest that sonoporation pDNA delivery could be a simple and inexpensive method that only requires a plasmid, MB, and a sonoporation device. Sonoporation could also be used to target MB to certain cells/tissues, delivering localized therapies. Using high-performance probes, more precise and safer sonoporation treatments will be developed, and newer therapeutic prospects will be realized. PMID- 22202105 TI - Strategies to adapt cellular processes to nutrient availability in bacteria. AB - Bacteria are able to adapt to nutrient availability in the environment. For example, when nutritional conditions are not favorable, bacterial size can be reduced and duplication time can be significantly extended in comparison to rich growth conditions. These observations suggest that essential cellular processes like cell division, morphogenesis and chromosome dynamics are highly coordinated with central metabolism to ensure the production of fit progeny. The aim of this review is to provide an overview extending from physiological observations done more than fifty years ago to recent discoveries showing strategies to control essential functions in relation with metabolism in the model bacterium Bacillus subtilis. PMID- 22202106 TI - Endogenous anticancer mechanisms (EACMs). AB - Cells capable of starting the track towards cancer are probably abundant in an organism, but the likelihood of any of these cells to evolve to a deadly disease is very low. This occurs in part due to several safekeeping mechanisms shaped by evolution to detect and eliminate potential cancer-forming cells, which will be defined here as endogenous anticancer mechanisms (EACMs). Virtually any cellular process has safekeeping mechanisms that detect and correct mishaps that could evolve into potentially harmful cellular behavior, but some aspects of these mechanisms seem to have been selected by evolution to protect organisms against cancer. The mechanisms that will be discussed here and in the reviews of this series are: cell senescence, DNA repair, cell cycle control, apoptosis, autophagy, block of the invasion and metastasis cascade, block of cell reprogramming and immune surveillance. Here I will present the basic features and the importance of each EACM and review the involvement of these processes in preventing cancer growth together with their importance in cancer prevention and therapeutics. PMID- 22202107 TI - A role for TLRs in Moraxella-superantigen induced polyclonal B cell activation. AB - A number of microorganisms are capable of binding immunoglobulins (Igs) in a manner, which excludes binding to conventional antigen binding sites. Interaction of such bacterial proteins with surface immunoglobulins leads to polyclonal activation of B-lymphocytes. A recent example is Moraxella catarrhalis that binds to B lymphocytes in an IgD-dependent manner and induces proliferation and differentiation of B lymphocytes leading to the production of unspecific Igs. The activation is mediated by Moraxella IgD binding protein (MID), which specifically binds to both soluble IgD and the IgD B cell receptor (BCR). Besides cross linking the BCR, whole Moraxella and outer membrane vesicles (OMVs) engage Toll like receptors (TLRs) to further increase the response. TLR activation leads to initiation of signaling pathways, which evoke a proinflammatory response against the invading microbes. Polyclonal B cell activation has in general been implicated in various phenomenons that are detrimental for the host but beneficial for pathogens, for example, autoimmune manifestations and redirection of the immune system. PMID- 22202109 TI - Antiviral escape strategies developed by bunyaviruses pathogenic for humans. AB - New or re-emerging pathogens for humans have emerged outside of their usual endemic range during the last decade originating severe public health concern and economical losses. Climate changes have played a significant role in the emergence or re-emergence of arboviruses. Among these pathogens, several viruses belong to the Bunyaviridae family. This family is composed of RNA viruses grouped into five genera Orthobunyavirus, Hantavirus, Nairovirus, Phlebovirus and Tospovirus characterized by their antigenic, genetic and ecological properties. These viruses use cellular proteins to promote their own replication/transcription and reciprocally the host induces, in response, an important transcriptional reprogramming to activate antiviral defences including the interferon type I pathways. The virulence of the pathogenic bunyaviruses is directly linked to the roles of viral virulence factors and their capacity to counteract the host pathways. This review summarizes the various strategies developed by the different genera of the Bunyaviridae family to overcome and escape the innate immune response and eventually other cellular functions. PMID- 22202110 TI - Pediatric proteomics: an introduction. AB - The overall goal of this series is to detail the paradigm shift that proteomics will bring to the practice of pediatric medicine and research. Proteomics is the global study of proteins in a biological system, tissue or bodily fluid. This first review will provide a brief overview of proteomics and describe its niche in the other "omics" of system biology. The underlying technology and methodology will be outlined as well as the obstacles that must be surmounted before pediatric proteomics is optimally useful for clinicians. The potential of proteomics in the area of personalized pediatric medicine will also be discussed since this is of particular clinical relevance. The second article in this series will focus on the application of proteomics to neonatology with particular emphasis on diseases where oxidative stress plays a key pathophysiological role. PMID- 22202112 TI - The formation and mineralization of mollusk shell. AB - In the last years, the field of mollusk biomineralization has known a tremendous mutation. The most recent advances deal with the nanostructure of shell biominerals, and with the identification of several shell matrix proteins: on one hand, the complex hierarchical organization of shell biominerals has been deciphered in few models, like nacre. On the other hand, although proteins represent a minor shell component, they are the major macromolecules that control biocrystal synthesis. Until recently, the paradigm was to consider that this control occurs by two antagonist mechanisms: crystal nucleation and growth inhibition. Emerging models try to translate a more complex reality, illustrated by the huge variety of shell proteins, characterized so far. The primary structure of many of them is composed of different functional domains, some of which exhibit enzymatic activity, while others may be involved in cell signalling. Many of them have unknown functions. Today, the shell matrix appears as a whole system, which regulates protein-mineral, protein-protein, and epithelium-mineral interactions. These aspects should be taken in account for the future models of shell formation. PMID- 22202111 TI - Sensory functions of motile cilia and implication for bronchiectasis. AB - Cilia are specialized organelles that extend from the cell surface into the local environment. Cilia of the airway epithelia are motile to provide mucociliary clearance. On other cells, solitary cilia are specialized to detect chemical or mechanosensory signals. Sensory proteins in motile cilia have recently been identified that detect fluid flow, bitter taste and sex hormones. The relationship of these sensory functions in motile cilia to disease is now being revealed. An example are the polycystin-1 and polycystin-2 proteins that function as a flow sensor in kidney cilia and are mutated in autosomal dominant polycystic kidney disease (ADPKD). These polycystins are also expressed in motile cilia, potentially operating as sensors in the lung. Computed tomography studies from patients with ADPKD reveal evidence of bronchiectasis, suggesting polycystins are important in lung function. The motile cilia expression of this protein complex, as well as sensory channel TRPV4, bitter taste and sex hormones receptors, indicate that the cilia is wired to interpret environmental cues. Defective signaling of sensory proteins may result in a ciliopathy that includes lung disease. PMID- 22202113 TI - Alpha, beta-and gamma-secretases in Alzheimer's disease. AB - Generation of Amyloid peptide (Abeta) is at the beginning of a cascade that leads to Alzheimer's disease. Currenty, the mechanisms of Abeta generation and Abeta prevention are subject of intensive research. Amyloid precursor protein (APP), as well as beta- and gamma-secretases are the principal players involved in Abeta production, while alpha-secretase cleavage on APP prevents Abeta deposition. Inhibitors or modulators that target beta- and gamma-secretases as well as alpha secretase activators are promising candidates for treatment of Alzheimer's disease. A deep knowledge of the secretases is required to develop disease modifying drugs that target them. The most challenging quest is to translate the growing knowledge about the cell biology of secretases and their mechanisms of action into effective therapeutics. Here, we review the main features of the secretases. PMID- 22202108 TI - Differential roles of NADPH oxidases in vascular physiology and pathophysiology. AB - Reactive oxygen species (ROS) are produced by all vascular cells and regulate the major physiological functions of the vasculature. Production and removal of ROS are tightly controlled and occur in discrete subcellular locations, allowing for specific, compartmentalized signaling. Among the many sources of ROS in the vessel wall, NADPH oxidases are implicated in physiological functions such as control of vasomotor tone, regulation of extracellular matrix and phenotypic modulation of vascular smooth muscle cells. They are involved in the response to injury, whether as an oxygen sensor during hypoxia, as a regulator of protein processing, as an angiogenic stimulus, or as a mechanism of wound healing. These enzymes have also been linked to processes leading to disease development, including migration, proliferation, hypertrophy, apoptosis and autophagy. As a result, NADPH oxidases participate in atherogenesis, systemic and pulmonary hypertension and diabetic vascular disease. The role of ROS in each of these processes and diseases is complex, and a more full understanding of the sources, targets, cell-specific responses and counterbalancing mechanisms is critical for the rational development of future therapeutics. PMID- 22202114 TI - Endometrial biology during trophoblast invasion. AB - Attainment of successful implantation depends upon the synchronized changes in the endometrium before and after the arrival of blastocyst into the uterine cavity. The cues obtained from the receptive endometrium helps in proliferation and differentiation of the trophoblast cells. During the course of invasive differentiation, the trophoblast cells undergo several morphological, biochemical and molecular changes to gain the invasive capabilities. In turn, close apposition of the developing embryo brings out functional and morphological changes into the hormone primed receptive endometrium. Global gene expression profiling of the endometrium in response to the developing embryo or in response to the pregnancy hormone, human chorionic gonadotropin, in primate and human models, suggest that the endometrial-embryo cross-talk mainly influences three biological processes. Biological processes getting influenced by the blastocyst "signals" are associated with immunomodulation, biosensing and invasion. Pro- and anti-invasive paracrine factors expressed by different endometrial cell populations regulate the trophoblast invasion through activation of diverse signaling pathways. Identification of the gene signatures involved in embryo endometrial dialogue would enhance our understanding about the pathologies like miscarriages and endometriosis. PMID- 22202115 TI - Inflammatory bowel diseases: emerging therapies and promising molecular targets. AB - An enormous amount of pathoetiologic information continues to accrue from animal models of inflammatory bowel disease and study of the gut microbiome that is providing expanded insight into the causes and mechanisms of inflammatory bowel diseases. This knowledge is being translated into new therapeutics that are being tested in Crohn's and ulcerative colitis patients with an aim to enhance treatment responses by moving away from immunosuppression and toward immunomodulation. In the last decade, the frontier of emerging IBD therapy has been dominated by biological agents that specifically target pro-inflammatory cytokines most notably tumor necrosis factor-alpha. However, it is clear that the gaps in therapy (primary and secondary non-response and the potential for drug side effects and intolerances) continue. To fill these gaps, various approaches are being employed to develop novel strategies, from inhibiting additional pro inflammatory cytokines to focusing on blocking inflammatory cell trafficking, decreasing inflammatory cell mass, enhancing regulatory cell function and reinforcing epithelial barrier function. To these ends, aggressive and innovative research is being pursued to develop more robust treatment strategies and identify key molecular targets. PMID- 22202116 TI - The multiple roles of tissue factor in wound healing. AB - The procoagulant role of tissue factor (TF) is well recognized. The ability to form a hemostatic clot is essential to normal healing of an injury. However, TF also has additional activities as a regulator of cellular processes. Both by production of coagulant molecules that also have cytokine and growth factor-like activities, and by directly mediating cell signaling events, TF has the potential to influence the course and tempo of healing. The literature in this are remains somewhat sparse, but suggests that modulation of TF expression plays a role in modulating the host response to injury. PMID- 22202117 TI - Genome-wide analysis discloses reversal of the hypoxia-induced changes of gene expression in colon cancer cells by zinc supplementation. AB - Hypoxia-inducible factor 1 (HIF-1), the major transcription factor specifically activated during hypoxia, regulates genes involved in critical aspects of cancer biology, including angiogenesis, cell proliferation, glycolysis and invasion. The HIF-1a subunit is stabilized by low oxygen, genetic alteration and cobaltous ions, and its over-expression correlates with drug resistance and increased cancer mortality in various cancer types, therefore representing an important anticancer target. Zinc supplementation has been shown to counteract the hypoxic phenotype in cancer cells, in vitro and in vivo, hence, understanding the molecular pathways modulated by zinc under hypoxia may provide the basis for reprogramming signalling pathways for anticancer therapy. Here we performed genome-wide analyses of colon cancer cells treated with combinations of cobalt, zinc and anticancer drug and evaluated the effect of zinc on gene expression patterns. Using Principal Component Analysis we found that zinc markedly reverted the cobalt-induced changes of gene expression, with reactivation of the drug induced transcription of pro-apoptotic genes. We conclude that the hypoxia pathway is a potential therapeutic target addressed by zinc that also influences tumor cell response to anticancer drug. PMID- 22202118 TI - Human organic cation transporter 1 is expressed in lymphoma cells and increases susceptibility to irinotecan and paclitaxel. AB - Antineoplastic agents directed at nuclear and cytoplasmic targets in tumor cells represent the current mainstay of treatment for patients with disseminated malignant diseases. Cellular uptake of antineoplastics is a prerequisite for their efficacy. Five of six lymphoma cell lines as well as primary samples from chronic lymphocytic leukemia patients demonstrated significant expression of SLC22A1 mRNA coding for organic cation transporter 1 (OCT1). Functionally, the antineoplastic agents irinotecan, mitoxantrone, and paclitaxel inhibited the uptake of the organic cation [(3)H]1-methyl-4-pyridinium iodide into OCT1 transfected Chinese hamster ovary model cells, with K(i) values of 1.7, 85, and 50 MUM, respectively. Correspondingly, OCT1-positive cell lines and transfectants exhibited significantly higher susceptibilities to the cytotoxic effects of irinotecan and paclitaxel compared with those of OCT1-negative controls. We hypothesize that OCT1 can contribute to the susceptibility of cancer cells to selected antineoplastic drugs. In the future, an expression analysis of the transporters and the application of transporter-specific antineoplastic agents could help to tailor cancer therapy. PMID- 22202119 TI - A Theileria parva isolate of low virulence infects a subpopulation of lymphocytes. AB - Theileria parva is a tick-transmitted protozoan parasite that infects and transforms bovine lymphocytes. We have previously shown that Theileria parva Chitongo is an isolate with a lower virulence than that of T. parva Muguga. Lower virulence appeared to be correlated with a delayed onset of the logarithmic growth phase of T. parva Chitongo-transformed peripheral blood mononuclear cells after in vitro infection. In the current study, infection experiments with WC1(+) gammadelta T cells revealed that only T. parva Muguga could infect these cells and that no transformed cells could be obtained with T. parva Chitongo sporozoites. Subsequent analysis of the susceptibility of different cell lines and purified populations of lymphocytes to infection and transformation by both isolates showed that T. parva Muguga sporozoites could attach to and infect CD4(+), CD8(+), and WC1(+) T lymphocytes, but T. parva Chitongo sporozoites were observed to bind only to the CD8(+) T cell population. Flow cytometry analysis of established, transformed clones confirmed this bias in target cells. T. parva Muguga-transformed clones consisted of different cell surface phenotypes, suggesting that they were derived from either host CD4(+), CD8(+), or WC1(+) T cells. In contrast, all in vitro and in vivo T. parva Chitongo-transformed clones expressed CD8 but not CD4 or WC1, suggesting that the T. parva Chitongo transformed target cells were exclusively infected CD8(+) lymphocytes. Thus, a role of cell tropism in virulence is likely. Since the adhesion molecule p67 is 100% identical between the two strains, a second, high-affinity adhesin that determines target cell specificity appears to exist. PMID- 22202120 TI - Targeted disruption of Toxoplasma gondii serine protease inhibitor 1 increases bradyzoite cyst formation in vitro and parasite tissue burden in mice. AB - As an intracellular protozoan parasite, Toxoplasma gondii is likely to exploit proteases for host cell invasion, acquisition of nutrients, avoidance of host protective responses, escape from the parasitophorous vacuole, differentiation, and other activities. T. gondii serine protease inhibitor 1 (TgPI1) is the most abundantly expressed protease inhibitor in parasite tachyzoites. We show here that alternative splicing produces two TgPI1 isoforms, both of which are secreted via dense granules into the parasitophorous vacuole shortly after invasion, become progressively more abundant over the course of the infectious cycle, and can be detected in the infected host cell cytoplasm. To investigate TgPI1 function, the endogenous genomic locus was disrupted in the RH strain background. DeltaTgPI1 parasites replicate normally as tachyzoites but exhibit increased bradyzoite gene transcription and labeling of vacuoles with Dolichos biflorus lectin under conditions promoting in vitro differentiation. The differentiation phenotype can be partially complemented by either TgPI1 isoform. Mice infected with the DeltaTgPI1 mutant display ~3-fold-increased parasite burden in the spleen and liver, and this in vivo phenotype is also complemented by either TgPI1 isoform. These results demonstrate that TgPI1 influences both parasite virulence and bradyzoite differentiation, presumably by inhibiting parasite and/or host serine proteases. PMID- 22202121 TI - Plasmodium falciparum 19-kilodalton merozoite surface protein 1 (MSP1)-specific antibodies that interfere with parasite growth in vitro can inhibit MSP1 processing, merozoite invasion, and intracellular parasite development. AB - Merozoite surface protein 1 (MSP1) is a target for malaria vaccine development. Antibodies to the 19-kDa carboxy-terminal region referred to as MSP1(19) inhibit erythrocyte invasion and parasite growth, with some MSP1-specific antibodies shown to inhibit the proteolytic processing of MSP1 that occurs at invasion. We investigated a series of antibodies purified from rabbits immunized with MSP1(19) and AMA1 recombinant proteins for their ability to inhibit parasite growth, initially looking at MSP1 processing. Although significant inhibition of processing was mediated by several of the antibody samples, there was no clear relationship with overall growth inhibition by the same antibodies. However, no antibody samples inhibited processing but not invasion, suggesting that inhibition of MSP1 processing contributes to but is not the only mechanism of antibody-mediated inhibition of invasion and growth. Examining other mechanisms by which MSP1-specific antibodies inhibit parasite growth, we show that MSP1(19) specific antibodies are taken up into invaded erythrocytes, where they persist for significant periods and result in delayed intracellular parasite development. This delay may result from antibody interference with coalescence of MSP1(19) containing vesicles with the food vacuole. Antibodies raised against a modified recombinant MSP1(19) sequence were more efficient at delaying intracellular growth than those to the wild-type protein. We propose that antibodies specific for MSP1(19) can mediate inhibition of parasite growth by at least three mechanisms: inhibition of MSP1 processing, direct inhibition of invasion, and inhibition of parasite development following invasion. The balance between mechanisms may be modulated by modifying the immunogen used to induce the antibodies. PMID- 22202122 TI - Broadly protective Shigella vaccine based on type III secretion apparatus proteins. AB - Shigella spp. are food- and waterborne pathogens that cause severe diarrheal and dysenteric disease associated with high morbidity and mortality. Individuals most often affected are children under 5 years of age in the developing world. The existence of multiple Shigella serotypes and the heterogenic distribution of pathogenic strains, as well as emerging antibiotic resistance, require the development of a broadly protective vaccine. All Shigella spp. utilize a type III secretion system (TTSS) to initiate infection. The type III secretion apparatus (TTSA) is the molecular needle and syringe that form the energized conduit between the bacterial cytoplasm and the host cell to transport effector proteins that manipulate cellular processes to benefit the pathogen. IpaB and IpaD form a tip complex atop the TTSA needle and are required for pathogenesis. Because they are common to all virulent Shigella spp., they are ideal candidate antigens for a subunit-based, broad-spectrum vaccine. We examined the immunogenicity and protective efficacy of IpaB and IpaD, alone or combined, coadministered with a double mutant heat-labile toxin (dmLT) from Escherichia coli, used as a mucosal adjuvant, in a mouse model of intranasal immunization and pulmonary challenge. Robust systemic and mucosal antibody- and T cell-mediated immunities were induced against both proteins, particularly IpaB. Mice immunized in the presence of dmLT with IpaB alone or IpaB combined with IpaD were fully protected against lethal pulmonary infection with Shigella flexneri and Shigella sonnei. We provide the first demonstration that the Shigella TTSAs IpaB and IpaD are promising antigens for the development of a cross-protective Shigella vaccine. PMID- 22202123 TI - O-antigen-deficient Francisella tularensis Live Vaccine Strain mutants are ingested via an aberrant form of looping phagocytosis and show altered kinetics of intracellular trafficking in human macrophages. AB - We examined the uptake and intracellular trafficking of F. tularensis Live Vaccine Strain (LVS) and LVS with disruptions of wbtDEF and wbtI genes essential for synthesis of the O antigen of lipopolysaccharide. Unlike parental bacteria, O antigen-deficient LVS is efficiently killed by serum with intact complement but not by serum lacking terminal complement components. Opsonization of O-antigen deficient LVS in serum lacking terminal complement components allows efficient uptake of these live bacteria by macrophages. In the presence of complement, whereas parental F. tularensis LVS is internalized within spacious pseudopod loops, mutant LVS is internalized within tightly juxtaposed multiple onion-like layers of pseudopodia. Without complement, both parental and mutant LVSs are internalized within spacious pseudopod loops. Thus, molecules other than O antigen are important in triggering dramatic pseudopod extensions and uptake by spacious pseudopod loops. Following uptake, both parental and mutant LVSs enter compartments that show limited staining for the lysosomal membrane glycoprotein CD63 and little fusion with secondary lysosomes. Subsequently, both parental and mutant LVSs lose their CD63 staining. Whereas the majority of parental LVS escapes into the cytosol by 6 h after uptake, mutant LVS shows a marked lag but does escape by 1 day after uptake. Despite the altered kinetics of phagosome escape, both mutant and parental strains grow to high levels within human macrophages. Thus, the O antigen plays a role in the morphology of uptake in the presence of complement and the kinetics of intracellular growth but is not essential for escape, survival, altered membrane trafficking, or intramacrophage growth. PMID- 22202124 TI - Effectiveness of a school-based fluoride mouthrinse program. AB - The aims of this study were to estimate the caries-preventive effects of a school based weekly fluoride mouthrinse (FMR) program and to determine whether its effectiveness varied by school-level caries risk. We used clinical and parent reported data for 1,363 children in grades 1 through 5 from a probability sample of North Carolina (NC) schoolchildren. Children's caries experience was measured using decayed and filled primary (d(2,3)fs) and total (d(2,3)fs+D(2,3)MFS) tooth surfaces. Program participation was quantified using 'FMR years'. To estimate caries risk at program entry, children were matched with NC kindergarten surveillance data representing school-level mean untreated decay (low-risk school: < 1 and high-risk school: >= 1 untreated carious teeth). Mean d(2,3)fs was 4.1 [95% confidence limits (CL) = 3.7, 4.5]. Overall, each 'FMR year' was associated with weak reduction of caries prevalence in the primary [prevalence ratio (PR) = 0.98; 95% CL = 0.90, 1.06] and the mixed dentition (PR = 0.98; 95% CL = 0.91, 1.05). We found a trend toward a larger caries-preventive benefit among children in high-risk schools compared with those in low-risk schools (i.e., 55% vs. 10% caries reduction for 5 to 6 yrs of FMR participation compared to none). Although this difference was not confirmed statistically, our results indicate that children in high-risk schools, as identified by school-level surveillance data, may experience substantial caries-preventive benefits from long-term FMR participation. PMID- 22202125 TI - N-Myc regulates expression of the detoxifying enzyme glutathione transferase GSTP1, a marker of poor outcome in neuroblastoma. AB - Amplification of the transcription factor MYCN is associated with poor outcome and a multidrug-resistant phenotype in neuroblastoma. N-Myc regulates the expression of several ATP-binding cassette (ABC) transporter genes, thus affecting global drug efflux. Because these transporters do not confer resistance to several important cytotoxic agents used to treat neuroblastoma, we explored the prognostic significance and transcriptional regulation of the phase II detoxifying enzyme, glutathione S-transferase P1 (GSTP1). Using quantitative real time PCR, GSTP1 gene expression was assessed in a retrospective cohort of 51 patients and subsequently in a cohort of 207 prospectively accrued primary neuroblastomas. These data along with GSTP1 expression data from an independent microarray study of 251 neuroblastoma samples were correlated with established prognostic indicators and disease outcome. High levels of GSTP1 were associated with decreased event-free and overall survival in all three cohorts. Multivariable analyses, including age at diagnosis, tumor stage, and MYCN amplification status, were conducted on the two larger cohorts, independently showing the prognostic significance of GSTP1 expression levels in this setting. Mechanistic investigations revealed that GSTP1 is a direct transcriptional target of N-Myc in neuroblastoma cells. Together, our findings reveal that N-Myc regulates GSTP1 along with ABC transporters that act to control drug metabolism and efflux. Furthermore, they imply that strategies to jointly alter these key multidrug resistance mechanisms may have therapeutic implications to manage neuroblastomas and other malignancies driven by amplified Myc family genes. PMID- 22202127 TI - The beneficial role of vitamin D in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia in the elderly individuals and is associated with progressive neurodegeneration of the human neocortex. Patients with AD have a high prevalence of vitamin D deficiency, which is also associated with low mood and impaired cognitive performance in older people. Genetic studies have provided the opportunity to determine which proteins link vitamin D to AD pathology (ie, the major histocompatibility complex class II molecules, vitamin D receptor, renin-angiotensin system, apolipoprotein E, liver X receptor, Sp1 promoter gene, and the poly(ADP-ribose) polymerase-1 gene). Vitamin D also exerts its effect on AD through nongenomic factors, that is, L type voltage-sensitive calcium channels, nerve growth factor, the prostaglandins, cyclooxygenase 2, reactive oxygen species, and nitric oxide synthase. In conclusion, vitamin D clearly has a beneficial role in AD and improves cognitive function in some patients with AD. Calcitriol, 1 alpha,25-dihydroxyvitamin D3, is best used for AD because of its active form of vitamin D(3) metabolite and its receptor in the central nervous system. PMID- 22202149 TI - The superorganism account of human sociality: how and when human groups are like beehives. AB - Biologists call highly cooperative and socially integrated animal groups like beehives and ant colonies "superorganisms." In such species, the colony acts like an organism despite each animal's physical individuality. This article frames human sociality through the superorganisms metaphor by systematically reviewing the superorganismic features of human psychology. These features include (1) mechanisms to integrate individual units, (2) mechanisms to achieve unity of action, (3) low levels of heritable within-group variation, (4) a common fate, and (5) mechanisms to resolve conflicts of interest in the collective's favor. It is concluded that human beings have a capacity to partly and flexibly display each of these superorganismic properties. Group identification is a key mechanism that activates human superorganismic properties, and threats to the group a key activating condition. This metaphor organizes diverse aspects of human psychology (e.g., normative conformity, social identity processes, religion, and the "rally around the flag" reflex) into a coherent framework. PMID- 22202128 TI - Blood lactate as a predictor for in-hospital mortality in patients admitted acutely to hospital: a systematic review. AB - BACKGROUND: Using blood lactate monitoring for risk assessment in the critically ill patient remains controversial. Some of the discrepancy is due to uncertainty regarding the appropriate reference interval, and whether to perform a single lactate measurement as a screening method at admission to the hospital, or serial lactate measurements. Furthermore there is no consensus whether the sample should be drawn from arterial, peripheral venous, or capillary blood. The aim of this review was: 1) To examine whether blood lactate levels are predictive for in hospital mortality in patients in the acute setting, i.e. patients assessed pre hospitally, in the trauma centre, emergency department, or intensive care unit. 2) To examine the agreement between arterial, peripheral venous, and capillary blood lactate levels in patients in the acute setting. METHODS: We performed a systematic search using PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL up to April 2011. 66 articles were considered potentially relevant and evaluated in full text, of these ultimately 33 articles were selected. RESULTS AND CONCLUSION: The literature reviewed supported blood lactate monitoring as being useful for risk assessment in patients admitted acutely to hospital, and especially the trend, achieved by serial lactate sampling, is valuable in predicting in-hospital mortality. All patients with a lactate at admission above 2.5 mM should be closely monitored for signs of deterioration, but patients with even lower lactate levels should be considered for serial lactate monitoring. The correlation between lactate levels in arterial and venous blood was found to be acceptable, and venous sampling should therefore be encouraged, as the risk and inconvenience for this procedure is minimal for the patient. The relevance of lactate guided therapy has to be supported by more studies. PMID- 22202150 TI - The magic-bullet: moving the concept towards reality - part II. PMID- 22202152 TI - Targeted alpha therapy with 213Bi. AB - The potential of targeted therapy with the alpha emitter 213Bi has been successfully demonstrated in a large number of preclinical studies and several clinical trials have provided evidence for its feasibility, safety and therapeutic efficacy. This review describes methods for the production of 225Ac and 225Ac/213Bi radionuclide generators, gives an overview of selected preclinical studies and summarizes the current clinical experience with 213Bi. PMID- 22202151 TI - Applications of 211At and 223Ra in targeted alpha-particle radiotherapy. AB - Targeted radiotherapy using agents tagged with alpha-emitting radionuclides is gaining traction with several clinical trials already undertaken or ongoing, and others in the advanced planning stage. The most commonly used alpha-emitting radionuclides are 213Bi, 211At, 223Ra and 225Ac. While each one of these has pros and cons, it can be argued that 211At probably is the most versatile based on its half life, decay scheme and chemistry. On the other hand, for targeting bone metastases, 223Ra is the ideal radionuclide because simple cationic radium can be used for this purpose. In this review, we will discuss the recent developments taken place in the application of 211At-labeled radiopharmaceuticals and give an overview of the current status of 223Ra for targeted alpha-particle radiotherapy. PMID- 22202154 TI - Toxicity and relative biological effectiveness of alpha emitting radioimmunoconjugates. AB - Radioimmunotherapy based on alpha-particle emitters has excellent properties as a treatment against micrometastatic and disseminated cancers because of the short path length (50 - 80 MUm) and high linear energy transfer (~ 100 keV/ MUm). Alpha particles produce clustered DNA double-strand breaks and highly reactive hydroxyl radicals when hitting biological tissue. Hence, targeted alpha-particle therapy offers the potential of selective tumor cell killing with low damage to surrounding normal tissue. The ideal applications for targeted alpha-therapy are in treating neoplastic cells in circulation or when cancer cells are present as free-floating cells or spread along compartment walls. This review will provide a brief overview of the most promising radionuclides for targeted alpha-therapy and compare their relative biological effectiveness (RBE) and normal tissue toxicity. PMID- 22202153 TI - Actinium-225 in targeted alpha-particle therapeutic applications. AB - Alpha particle-emitting isotopes are being investigated in radioimmunotherapeutic applications because of their unparalleled cytotoxicity when targeted to cancer and their relative lack of toxicity towards untargeted normal tissue. Actinium- 225 has been developed into potent targeting drug constructs and is in clinical use against acute myelogenous leukemia. The key properties of the alpha particles generated by 225Ac are the following: i) limited range in tissue of a few cell diameters; ii) high linear energy transfer leading to dense radiation damage along each alpha track; iii) a 10 day halflife; and iv) four net alpha particles emitted per decay. Targeting 225Ac-drug constructs have potential in the treatment of cancer. PMID- 22202155 TI - Patient-specific alpha-particle dosimetry. AB - Alpha-particle therapy has received increased attention during the last few years because of the development of new targeting constructs and new labeling techniques and the availability of suitable alpha-particle - emitting radionuclides. This work provides an overview of methods that have been used in clinical trials in estimating the absorbed dose to tumors and healthy tissue in patients following such alpha-particle therapy. Similarities and differences compared to conventional therapies using beta--particle emitters are presented. The specific challenges of establishing accurate dosimetry for alpha- particles in the individual patient are also discussed, as is the effect that improved patient-specific dosimetry might have on the overall efficacy of this type of therapy. PMID- 22202156 TI - Future prospects for targeted alpha therapy. AB - The objectives in the application of targeted alpha therapy (TAT) for cancer therapy are reviewed. These relate to elimination of isolated cancer cells, cell clusters and tumors. Requirements for isolated cancer cells are good cellular targeting, high specific activity, and very short range. The regression of cell clusters in the peri-vascular space requires high capillary permeability and short range cross fire whereas for developed tumors, good bioavailabilty and anti capillary activity are essential. Current sources of alpha radiation are reviewed and the prospects for commercial sources for clinical application are discussed. The Ac:Bi generator is the most practical alpha source, bringing therapy to Nuclear Medicine with the same practicality as the Mo:Tc generator has for imaging. The status quo of TAT is briefly reviewed with respect to dose normalization, real time microdosimetry and biological dosimetry for deterministic and stochastic effects and toxicity. The role of Monte Carlo calculations is emphasized. The strengths and weaknesses of TAT are examined and the way forward for clinical acceptance is discussed. PMID- 22202157 TI - Microwave accelerated labeling methods in the synthesis of radioligands for positron emission tomography imaging. AB - Nuclear imaging using positron emission tomography [PET] is a powerful technique with clinical applications which include oncology, cardiovascular disease and CNS disorders. Conventional chemical syntheses of the short half-life radionuclides used in the process however imposes numerous limitations on scope of available ligands. By utilizing microwave assisted synthesis methods many of these limitations can be overcome, paving the way for the design of diverse families of agents with defined cellular targets. This review will survey recent developments in the field with emphasis on the period 2006-2011. Positron emission tomography [PET] has become one of the most powerful in vivo imaging modalities, capable of delivering mm3 resolution of radiotracer distribution and metabolism [1]. When combined with anatomic imaging methods (MRI, CT) co-registered multimode images offer the potential to track metabolic and physiologic events in diseased states and guide and accelerate clinical trials of investigational new drugs. Also, this same methodology can be used to evaluate first pass pharmacokinetics/pharmacodynamics in early stage drug discovery. Though powerful as a technique only a limited number of drugs have seen clinical use and to date only one drug 2-fluoro-deoxy-D-glucose (FDG) has received FDA approval [2]. One of the drawbacks of PET imaging is the need for tracers labeled with an appropriate nuclide and the half-lives of these agents places special constraints on the chemical synthesis. Among the most popular are 11C (t1/2 =20.4 min) and 18F (t 1/2 =109.8 min) labeled compounds and this has resulted in a resurgence of interest in practical application of their chemistries [3,4]. This review will focus on microwave mediated methods of acceleration of organic reactions used for the production of labeled PET image contrast agents, with emphasis on the five year period 2006 to 2011. PMID- 22202158 TI - Preparation and primary bioevaluation of 99mTc-labeled-1-thio-beta-D-glucose as melanoma targeting agent. AB - The development of specific radiolabeled probes towards molecular markers in vivo has gained interest as targeted imaging agents for a more accurate detection of diseases. The aim of this study was to evaluate early detection of melanoma tumor based on 1-thio-beta-D-glucose (1-TG) radiolabeled with technetium-99m. 99mTc-1 TG has been synthesized and evaluated in vitro and in vivo for melanoma uptake. Tumor-cell uptake of the 99mTc complex was performed with cultured B16F1 murine melanoma cells which were also used for the in vivo studies. The methodology consisted in radiopharmaceutical synthesis followed by intravenous administration of 99mTc-1-TG in melanoma bearing mice and scintigraphic imaging. 1-thio-beta-D glucose was labeled with 99mTc under reductive conditions using SnCl2. Radiolabeling efficiency was > 96%. 99mTc-1-TG showed high melanoma uptake in vitro. This was confirmed in vivo since a significant difference of 99mTc-1- TG uptake between melanoma model and the control joint was observed. General biodistribution showed renal uptake. The scintigraphic images showed tumor selective uptake of the 1-TG labeled, in tumor-bearing mice This study indicates effective labeling of 1-thio-beta-D-glucose with 99mTc that shows potential as a new type of specific probe for melanoma detection. PMID- 22202159 TI - Nitroimidazole radiopharmaceuticals in bioimaging: part I: synthesis and imaging applications. AB - The paper is review on synthesis of nitroimidazole radiosensitizers useful in imaging of tumor cells. Nitroimidazole compounds are radiolabeled probes for specific use in imaging such as 18F for positron emission tomography; 99mTc for single photon emission computed tomography; 123I, or 131I for computer assisted tomography and 19F for magnetic resonance imaging. In synthesis of radiopharmaceutical compounds, parent nitroimidazole is modified to thiopyranosyl nucleosides, neuraminic acid derivatives followed by nitro group deprotection substitution and radiolabeling by specific isotopes. Commercial attempts have been made to radiolabel the nitroimidazole by [18F]fluorine, [131I or 123I]iodine, [99mTc]technicium and [64Cu]copper on modified side chain of nitroimidazole compounds to design multimodal and multifunctional imaging techniques to detect and monitor the tumor hypoxia by measuring distribution of radiatiolabel or radiation. Nitroimidazole initially showed poor diffusion and poor stability in tissues with neurotoxicity concern limited its use as radiosensitizer. In last decade, several nitroimidazole derivatives were developed as potent less toxic and highly stable radiopharmaceuticals with optimized radiolabel concentration with high detectability of tumor oxygen or hypoxia. Currently, nitroimidazole based radiopharmaceuticals have emerged as multimodal and multifunctional hypoxia reporters with antitumor, anti-ischemic, anti-inflammatory and tumor targeting properties. In conclusion, nitroimidazole based radiopharmaceuticals are a new generation hypoxia biosensors for localized theradiagnostic utility in clinical medicine. PMID- 22202160 TI - Nitroimidazole radiopharmaceuticals in hypoxia: part II cytotoxicity and radiosensitization applications. AB - Feasibility paper explores the cytotoxicity of nitroimidazole on tumor cells and liver cells to establish the 2'-nitroimidazole as radiosensitizer in cancer therapy and hypoxia monitoring. Hypothesis is that the presence of substituted nitro group on 2' position of imidazole ring is more enzyme sensitive and determinant of biochemical cytotoxicity as hypoxia reporter in isolated tumor cells or tumor tissues. Radiolabeling of nitroimidazole imparts tracer properties to locate the distribution (radiosensitizer) of nitroimidazole in the body. A 'theradiagnostic criteria of hypoxia' using nitroimidazole radiosensitizer is proposed based on tumor killing by enhanced tumor oxygen tension (therapeutics) and altered metabolizing enzymes (diagnostics) due to cytotoxicity of radiosensitizer. Both properties of nitroimidazole cytotoxicity and oxygen sensitivity place the nitroimidazole compounds in the class of tumor therapy and hypoxia detection. Initially nitroimidazole cytotoxicity was reported as antiparasitic drug. Now radiolabeled 2'-nitroimidazole is potential radiosensitizer in hypoxia treatment and monitoring in last two decades. Hydrophilic double radiolabel groups on imidazole ring offer multimodal imaging and active nitro- or imidazole ring in nitroimidazoles interact with intracellular metabolism in liver by biotransformation and biooxidation to cause cytotoxicity as biomarker of hypoxia. Nitroimidazole metabolizing and xenobiotic enzymes showed regulatory role to excrete out nitroimidazole from the body and reduced stay time in tissue. Nitroimidazoles showed physicochemical properties with poor tissue diffusion, less antioxidant redox potential and long retention time in tissue making them poor choice of hypoxia markers. Key of success is achieving 2'-Nitroimidazole based multimodal radiopharmaceuticals as less cytotoxic, more tumor oxygen specific multifunctional reporters of apoptosis, proliferation, and hypoxia in theradiagnostics and radiation oncology. PMID- 22202161 TI - Carotid artery disease and interventional therapy. AB - PURPOSE OF REVIEW: Major results of recent clinical trials for carotid artery disease are changing the understanding of management. RECENT FINDINGS: A major trial comparing carotid endarterectomy with carotid angioplasty and stenting for symptomatic or asymptomatic patients suggests comparable results by overall outcomes analyses, and different results by subset analyses. These results modify the findings of prior trials. SUMMARY: Based on age there appear to be differences in outcomes that may influence decision for management for such patients. PMID- 22202162 TI - Late intervention with anti-BRAF(V600E) therapy induces tumor regression in an orthotopic mouse model of human anaplastic thyroid cancer. AB - Human anaplastic thyroid cancer (ATC) is a lethal disease with an advanced clinical presentation and median survival of 3 months. The BRAF(V600E) oncoprotein is a potent transforming factor that causes human thyroid cancer cell progression in vitro and in vivo; therefore, we sought to target this oncoprotein in a late intervention model of ATC in vivo. We used the human ATC cell line 8505c, which harbors the BRAF(V600E) and TP53(R248G) mutations. Immunocompromised mice were randomized to receive the selective anti-BRAF(V600E) inhibitor, PLX4720, or vehicle by oral gavage 28 d after tumor implantation, 1 wk before all animals typically die due to widespread metastatic lung disease and neck compressive symptoms in this model. Mice were euthanized weekly to evaluate tumor volume and metastases. Control mice showed progressive tumor growth and lung metastases by 35 d after tumor implantation. At that time, all control mice had large tumors, were cachectic, and were euthanized due to their tumor-related weight loss. PLX4720-treated mice, however, showed a significant decrease in tumor volume and lung metastases in addition to a reversal of tumor-related weight loss. Mouse survival was extended to 49 d in PLX4720-treated animals. PLX4720 treatment inhibited cell cycle progression from 28 d to 49 d in vivo. PLX4720 induces striking tumor regression and reversal of cachexia in an in vivo model of advanced thyroid cancer that harbors the BRAF(V600E) mutation. PMID- 22202163 TI - Conophylline suppresses pancreatic stellate cells and improves islet fibrosis in Goto-Kakizaki rats. AB - Activin A is a differentiation factor for beta-cells and is effective to promote beta-cell neogenesis. Activin A is also an autocrine activator of pancreatic stellate cells, which play a critical role in fibrogenesis of the pancreas. Conophylline (CnP) is a natural compound, which reproduces the effect of activin on beta-cell differentiation and promotes beta-cell neogenesis when administered in vivo. However, its effect on stellate cells is not known. We therefore investigated the effect of CnP on stellate cells both in vitro and in vivo. Unlike activin A, CnP inhibited activation of cultured stellate cells and reduced the production of collagen. We then analyzed the involvement of stellate cells in islet fibrosis in Goto-Kakizaki (GK) rats, a model of type 2 diabetes mellitus. In pancreatic sections obtained from 6-wk-old GK rats, CD68-positive macrophages and glial fibrillary acidic protein- and alpha-smooth muscle actin-positive stellate cells infiltrated into islets. Later, the number of macrophages was increased, and the alpha-smooth muscle actin staining of stellate cells became stronger, indicating the involvement of stellate cells in islet fibrosis in GK rats. When CnP was administered orally for 4 wk, starting from 6 wk of age, invasion of stellate cells and macrophages was markedly reduced and islet fibrosis was significantly improved. The insulin content was twice as high in CnP treated rats. These results indicate that CnP exerts antifibrotic actions both in vitro and in vivo and improves islet fibrosis in Goto-Kakizaki rats. PMID- 22202165 TI - Prolyl carboxypeptidase regulates energy expenditure and the thyroid axis. AB - Hypothalamic alpha-melanocyte-stimulating hormone (alpha-MSH) plays a central role in regulating energy uptake and expenditure. Prolyl carboxypeptidase (PRCP), a protease expressed in the hypothalamus, is responsible for the degradation of alpha-MSH. PRCP null animals (PRCP(gt/gt) mice) display elevated alpha-MSH in the hypothalamus, lower body weight, and are protected from diet induced obesity. Here, we report that PRCP(gt/gt) mice have a significant decrease in fat mass, although an increase in lean mass was also observed. In agreement with low fat accumulation, reduced leptin levels were found. Consistent with the effect of alpha-MSH on energy metabolism, PRCP(gt/gt) mice had increased energy expenditure with elevated circulating thyroid hormone levels and brown adipose tissue uncoupling protein 1 mRNA levels compared with control mice when exposed to regular diet. TRH mRNA levels in the PVN were significantly higher in fed PRCP(gt/gt) animals compared with fed wild-type controls. Fasting significantly decreased TRH mRNA levels in both PRCP(gt/gt) and wild-type (WT) mice. However, TRH mRNA levels in fasted PRCP(gt/gt) animals were significantly higher than those of fasted WT mice. Refeeding analysis after fasting showed a reduced food intake in PRCP(gt/gt) compared with WT mice. Finally, TRH mRNA levels in T(3) treated hypothyroid PRCP(gt/gt) mice showed a non significant reduction compared with those of hypothyroid PRCP(gt/gt) mice, supporting the impairment of the hypothalamo-pituitary-thyroid axis in PRCP(gt/gt) mice. All together, these data confirm that PRCP plays a role in the regulation of energy metabolism. PMID- 22202164 TI - Sexually dimorphic testosterone secretion in prenatal and neonatal mice is independent of kisspeptin-Kiss1r and GnRH signaling. AB - Kisspeptin, encoded by the Kiss1 gene, stimulates GnRH secretion and is therefore critical for sex steroid secretion at puberty and in adulthood. However, kisspeptin's role in regulating sex steroid secretion earlier in development is unexplored. In rodents, testosterone (T) levels are higher in prenatal and newborn males than females. We determined whether kisspeptin-Kiss1r and GnRH signaling plays a role in sexually dimorphic perinatal T secretion in mice. Our results demonstrate that 1) T levels in newborn males are elevated at 4 h but not 20 h after birth, but hypothalamic Kiss1 and neurokinin B (NKB) levels in males are not different between these time points (and both are lower than in females); 2) serum T levels in newborn Kiss1r knockout (KO) males are higher than in newborn females and similar to wild-type (WT) males; 3) perinatal hypothalamic progesterone receptor (Pgr) expression, which is dependent on circulating levels of gonadally produced T, is significantly higher in prenatal and newborn Kiss1r KO and WT males than similarly aged females; 4) multiple measures of testicular growth and function are not different between developing Kiss1r KO and WT mice until after postnatal d 5; and 5) GnRH neurons of newborn males do not exhibit high c-fos coexpression, and newborn hypogonadal (hpg) male mice (lacking GnRH) secrete elevated T, similar to newborn WT males. We conclude that, unlike in puberty and adulthood, elevated T secretion in prenatal and neonatal mice is independent of both kisspeptin and GnRH signaling, and the necessity of kisspeptin-Kiss1r signaling for testicular function is first apparent after d 5. PMID- 22202166 TI - Pro-GRP-derived peptides are expressed in colorectal cancer cells and tumors and are biologically active in vivo. AB - Amidated gastrin-releasing peptide (GRP) is the prototypical autocrine growth factor. Nonamidated peptides derived from the C terminus of pro-GRP are also biologically active in colorectal cancer (CRC) cell lines in vitro, via a receptor distinct from the GRP receptor. The aims of this study were to measure the amounts of pro-GRP-derived peptides in human CRC cell lines and tumors, characterize the immunoreactive peptide, and investigate its effect on proliferation in vitro and in vivo. Pro-GRP-derived peptides were quantitated by region-specific ELISA in extracts of five human CRC cell lines and 20 tumors. The immunoreactive material was purified by HPLC and its mass and sequence established by mass spectrometry. The concentration of GRPamide was determined by RIA. Proliferation of DLD-1 cells and murine gastrointestinal mucosa was measured by [(3)H]-thymidine incorporation and mitotic index, respectively. In CRC cell extracts, ELISA for pro-GRP-derived peptides detected 3-152 fmol/10(6) cells. The immunoreactive peptide was purified and identified as pro-GRP42-98. Resected stage III tumors contained significantly less pro-GRP immunoreactivity than stage II tumors, and no amidated GRP was detected in cell lines or tumors. Stable transfection of DLD-1 cells with pro-GRP short hairpin RNA, or treatment with a monoclonal anti-pro-GRP antibody, significantly reduced proliferation. Pro-GRP42 98, pro-GRP47-68, and pro-GRP80-97 significantly stimulated mitosis in colonic, but not small intestinal, mucosa of 10-wk-old mice. We conclude that nonamidated peptides derived from the C terminus of pro-GRP are expressed in significant quantities in CRC cell lines and tumors and stimulate the proliferation of CRC cells and of normal colonic mucosa. Such peptides are attractive targets for novel CRC therapies. PMID- 22202167 TI - Reactive oxygen species are required for the hypothalamic osmoregulatory response. AB - Free radicals, or reactive oxygen species (ROS), are highly reactive byproducts of oxygen degradation. They are well known for their cellular toxicity, but few studies have analyzed their potential role in homeostatic processes. We investigated ROS production and function during the arginine vasopressin (AVP) hypothalamic response to hyperosmolarity. Six-week-old male C3H/HeJ mice were subjected to salt loading for 2 or 8 d. The osmotic axis was progressively activated and reached a new steady-state status at 8 d as demonstrated by monitoring of plasmatic osmolality and c-Fos and AVP expression in the supraoptic nucleus (SON). Free radicals, visualized by dihydroethidine staining and measured by 2'-7'dichlorofluorescein diacetate assays, were detected after 2 d of salt loading. The activity and expression of superoxide dismutase 2 and catalase were concomitantly up-regulated in the SON, suggesting that free radicals are detoxified by endogenous antioxidant systems, thereby avoiding their deleterious effects. The early phase of the osmoregulatory response has been investigated using an acute hyperosmotic model; free radicals were produced 45 min after an ip injection of 1.5 m NaCl. This was followed by an increase in c-Fos and AVP expression and an increase in superoxide dismutase 2 and catalase activities. alpha-Lipoic acid, a ROS scavenger, administrated during the 3 d before the hypertonic ip injection, abolished the increase of AVP. These findings establish that hyperosmolarity causes ROS production in the SON, which is essential for AVP increase. This demonstrates the importance of free radicals as physiological signaling molecules in the regulation of body-fluid balance. PMID- 22202168 TI - Changes in serum thioredoxin among individuals chronically exposed to arsenic in drinking water. AB - It is well known that oxidative damage plays a key role in the development of chronic arsenicosis. There is a complex set of mechanisms of redox cycling in vivo to protect cells from the damage. In this study, we examined the differences in the levels of serum thioredoxin1 (TRX1) among individuals exposed to different levels of arsenic in drinking water and detected early biomarkers of arsenic poisoning before the appearance of skin lesions. A total of 157 subjects from endemic regions of China were selected and divided into arsenicosis group with skin lesions (total intake of arsenic: 8.68-45.71mg-year) and non-arsenicosis group without skin lesions, which further divided into low (0.00-1.06mg-year), medium (1.37-3.55mg-year), and high (4.26-48.13mg-year) arsenic exposure groups. Concentrations of serum TRX1 were analyzed by an ELISA method. Levels of water arsenic and urinary speciated arsenics, including inorganic arsenic (iAs), monomethylated arsenic (MMA), and dimethylated arsenic (DMA), were determined by hydride generation atomic absorption spectrometry. Our results showed that the levels of serum TRX1 in arsenicosis patients were significantly higher than that of the subjects who were chronically exposed to arsenic, but without skin lesions. A positive correlation was seen between the levels of serum TRX1 and the total water arsenic intake or the levels of urinary arsenic species. The results of this study indicate that arsenic exposure could significantly change the levels of human serum TRX1, which can be detected before arsenic-specific dermatological symptoms occur. This study provides further evidence on revealing the mechanism of arsenic toxicity. PMID- 22202170 TI - Biodiversity characterization of cellulolytic bacteria present on native Chaco soil by comparison of ribosomal RNA genes. AB - Sequence analysis of the 16S ribosomal RNA gene was used to study bacterial diversity of a pristine forest soil and of two cultures of the same soil enriched with cellulolytic bacteria. Our analysis revealed high bacterial diversity in the native soil sample, evidencing at least 10 phyla, in which Actinobacteria, Proteobacteria and Acidobacteria accounted for more than 76% of all sequences. In both enriched samples, members of Proteobacteria were the most frequently represented. The majority of bacterial genera in both enriched samples were identified as Brevundimonas and Caulobacter, but members of Devosia, Sphingomonas, Variovorax, Acidovorax, Pseudomonas, Xanthomonas, Stenotrophomonas, Achromobacter and Delftia were also found. In addition, it was possible to identify cellulolytic taxa such as Acidothermus, Micromonospora, Streptomyces, Paenibacillus and Pseudomonas, which indicates that this ecosystem could be an attractive source for study of novel enzymes for cellulose degradation. PMID- 22202169 TI - Female CGG knock-in mice modeling the fragile X premutation are impaired on a skilled forelimb reaching task. AB - The fragile X premutation is a tandem CGG trinucleotide repeat expansion in the fragile X mental retardation 1 (FMR1) gene between 55 and 200 repeats in length. A CGG knock-in (CGG KI) mouse has been developed that models the neuropathology and cognitive deficits reported in fragile X premutation carriers. Previous studies have demonstrated that CGG KI mice have spatiotemporal information processing deficits and impaired visuomotor function that worsen with increasing CGG repeat length. Since skilled forelimb reaching requires integration of information from the visual and motor systems, skilled reaching performance could identify potential visuomotor dysfunction in CGG KI mice. To characterize motor deficits associated with the fragile X premutation, 6 month old female CGG KI mice heterozygous for trinucleotide repeats ranging from 70-200 CGG in length were tested for their ability to learn a skilled forelimb reaching task. The results demonstrate that female CGG KI mice show deficits for learning a skilled forelimb reaching task compared to wildtype littermates, and that these deficits worsen with increasing CGG repeat lengths. PMID- 22202171 TI - Complexity of cell-cell interactions between Pseudomonas sp. AS1 and Acinetobacter oleivorans DR1: metabolic commensalism, biofilm formation and quorum quenching. AB - Acinetobacter oleivorans DR1 lacks an upper pathway for naphthalene degradation and cannot grow using naphthalene as sole carbon source; however, it is capable of growing under naphthalene-amended conditions in the presence of naphthalene degrading Pseudomonas sp. AS1. 1H-NMR spectroscopy, high-performance liquid chromatography and gene expression analyses showed that salicylate is a major secreted metabolic intermediate during naphthalene degradation by strain AS1 and that, in turn, it supports the growth of strain DR1. Interspecies biofilm formation, monitored using confocal laser scanning microscopy and microtiter assays, demonstrated that biofilm formation by strain AS1 increased dramatically in the presence of strain DR1 because of the exopolysaccharides generated by the latter. Furthermore, the metabolic commensal interaction of the two strains altered the initial attachment behavior of strain DR1 during biofilm formation. When this strain was cultivated alone under naphthalene-amended conditions, the cells immediately attached to the surface, probably due to the absence of usable substrates, whereas similar behavior was not observed in the mixed culture. This interspecies cell-cell interaction became more complex due to quenching of the quorum-sensing signal of strain DR1 by strain AS1. These complex metabolic and physiological interactions observed in mixed cultures suggest that interspecies interaction is more complicated than previously surmised. PMID- 22202172 TI - 6-Position optimization of tricyclic 4-quinolone-based inhibitors of glycogen synthase kinase-3beta: discovery of nitrile derivatives with picomolar potency. AB - We previously disclosed tricylic, 6-carboxylic acid-bearing 4-quinolones as GSK 3beta inhibitors. Herein we discuss the optimization of this series to yield a series of more potent 6-nitrile analogs with insignificant anti-microbial activity. Finally, kinase profiling indicated that members of this class were highly specific GSK-3 inhibitors. PMID- 22202173 TI - Copy number of adenoviral vector genome transduced into target cells can be measured using quantitative PCR: application to vector titration. AB - Both transfection and adenovirus vectors are commonly used in studies measuring gene expression. However, the real DNA copy number that is actually transduced into target cells cannot be measured using quantitative PCR because attached DNA present on the cell surface is difficult to distinguish from successfully transduced DNA. Here, we used Cre/loxP system to show that most of the transfected DNA was in fact attached to the cell surface; in contrast, most of the viral vector DNA used to infect the target cells was present inside the cells after the cells were washed according to the conventional infection protocol. We applied this characteristic to adenoviral vector titration. Current methods of vector titration using the growth of 293 cells are influenced by the effect of the expressed gene product as well as the cell conditions and culture techniques. The titration method proposed here indicates the copy numbers introduced to the target cells using a control vector that is infected in parallel (relative vector titer: rVT). Moreover, the new titration method is simple and reliable and may replace the current titration methods of viral vectors. PMID- 22202174 TI - MT1-MMP modulates the mechanosensitivity of osteocytes. AB - Membrane-type matrix metalloproteinase-1 (MT1-MMP) is expressed by mechanosensitive osteocytes and affects bone mass. The extracellular domain of MT1-MMP is connected to extracellular matrix, while its intracellular domain is a strong modulator of cell signaling. In theory MT1-MMP could thus transduce mechanical stimuli into a chemical response. We hypothesized that MT1-MMP plays a role in the osteocyte response to mechanical stimuli. MT1-MMP-positive and knockdown (siRNA) MLO-Y4 osteocytes were mechanically stimulated with a pulsating fluid flow (PFF). Focal adhesions were visualized by paxillin immunostaining. Osteocyte number, number of empty lacunae, and osteocyte morphology were measured in long bones of MT1-MMP(+/+) and MT1-MMP(-/-) mice. PFF decreased MT1-MMP mRNA and protein expression in MLO-Y4 osteocytes, suggesting that mechanical loading may affect pericellular matrix remodeling by osteocytes. MT1-MMP knockdown enhanced NO production and c-jun and c-fos mRNA expression in response to PFF, concomitantly with an increased number and size of focal adhesions, indicating that MT1-MMP knockdown osteocytes have an increased sensitivity to mechanical loading. Osteocytes in MT1-MMP(-/-) bone were more elongated and followed the principle loading direction, suggesting that they might sense mechanical loading. This was supported by a lower number of empty lacunae in MT1-MMP(-/-) bone, as osteocytes lacking mechanical stimuli tend to undergo apoptosis. In conclusion, mechanical stimulation decreased MT1-MMP expression by MLO-Y4 osteocytes, and MT1 MMP knockdown increased the osteocyte response to mechanical stimulation, demonstrating a novel and unexpected role for MT1-MMP in mechanosensing. PMID- 22202175 TI - Identification of host cell proteins which interact with herpes simplex virus type 1 tegument protein pUL37. AB - The herpes simplex virus type 1 (HSV-1) structural tegument protein pUL37, which is conserved across the Herpesviridae family, is known to be essential for secondary envelopment during the egress of viral particles. To shed light on additional roles of pUL37 during viral replication a yeast two-hybrid screen of a human brain cDNA library was undertaken. This screen identified ten host cell proteins as potential pUL37 interactors. One of the interactors, serine threonine kinase TAOK3, was subsequently confirmed to interact with pUL37 using an in vitro pulldown assay. Such host cell/pUL37 interactions provide further insights into the multifunctional role of this herpesviral tegument protein. PMID- 22202176 TI - Evidencing the role of lactose permease in IPTG uptake by Escherichia coli in fed batch high cell density cultures. AB - The lac-operon and its components have been studied for decades and it is widely used as one of the common systems for recombinant protein production in Escherichia coli. However, the role of the lactose permease, encoded by the lacY gene, when using the gratuitous inducer IPTG for the overexpression of heterologous proteins, is still a matter of discussion. A lactose permease deficient strain was successfully constructed. Growing profiles and acetate production were compared with its parent strain at shake flask scale. Our results show that the lac-permease deficient strain grows slower than the parent in defined medium at shake flask scale, probably due to a downregulation of the phosphotransferase system (PTS). The distributions of IPTG in the medium and inside the cells, as well as recombinant protein production were measured by HPLC MS and compared in substrate limiting fed-batch fermentations at different inducer concentrations. For the mutant strain, IPTG concentration in the medium depletes slower, reaching at the end of the culture higher concentration values compared with the parent strain. Final intracellular and medium concentrations of IPTG were similar for the mutant strain, while higher intracellular concentrations than in medium were found for the parent strain. Comparison of the distribution profiles of IPTG of both strains in fed-batch fermentations showed that lac-permease is crucially involved in IPTG uptake. In the absence of the transporter, apparently IPTG only diffuses, while in the presence of lac permease, the inducer accumulates in the cytoplasm at higher rates emphasizing the significant contribution of the permease-mediated transport. PMID- 22202177 TI - CYP105A1 mediated 3-hydroxylation of glimepiride and glibenclamide using a recombinant Bacillus megaterium whole-cell catalyst. AB - CYP105A1 from Streptomyces griseolus belongs to a widespread family of soluble prokaryotic cytochromes P450. For in vitro studies we established an electron transfer system, consisting of the ferredoxin Etp1(fd) and the ferredoxin reductase Arh1 from the fission yeast Schizosaccharomyces pombe. We investigated the metabolism of glibenclamide and glimepiride, hypoglycemic drugs of sulfonylurea type, and determined corresponding in vitro kinetic parameters. The resulting 3-cyclohexyl-hydroxylation activity towards glibenclamide and glimepiride was demonstrated by NMR analysis. Furthermore, the main product of glibenclamide, cis-3-hydroxy-glibenclamide is identical with the phase-1 metabolite of this drug in human. The orientation of glimepiride and glibenclamide in the active site of the enzyme is shown by a computational docking model. For high scale production of sulfonylurea derivatives, we designed whole-cell biocatalysts based on Bacillus megaterium MS941. Surprisingly, the system expressing only CYP105A1 showed a similar activity towards hydroxylation of glimepiride and glibenclamide compared to the system expressing additionally the redox partners, Arh1 and Etp1(fd)(516-618), indicating that the host strain provides a functional endogenous electron transfer system. PMID- 22202178 TI - Helicobacter pylori stimulates epithelial cell migration via CagA-mediated perturbation of host cell signaling. AB - Helicobacter pylori CagA is delivered into gastric epithelial cells, where undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif to interact with Src homology 2-containing protein tyrosine phosphatase-2 (SHP2) oncoprotein. CagA also binds to partitioning-defective 1 (PAR1) polarity regulating kinase via the CagA multimerization (CM) sequence. To investigate pathophysiological role of CagA-SHP2 and/or CagA-PAR1 interaction in H. pylori infection, we generated H. pylori isogenic strains producing a phosphorylation resistant CagA and a CagA without CM sequence. Infection studies revealed that deregulation of epithelial cell motility was more prominent in the wild-type strain than in the mutant strains. Thus, both CagA-SHP2 and CagA-PAR1 interactions are involved in the pathogenicity of cagA-positive H. pylori. PMID- 22202179 TI - Chemokines and cytokines in patients with an occult Onchocerca volvulus infection. AB - Repeated ivermectin treatment will clear microfilaria (Mf) of Onchocerca volvulus from skin and eyes of onchocerciasis patients while adult filaria remains alive and reproductive, and such occult O. volvulus infection may persist for years. To investigate the effect of residual adult filaria on the immune response profile, chemokines and cytokines were quantified 1) in onchocerciasis patients who developed an occult O. volvulus infection (Mf-negative) due to repeated ivermectin treatments, 2) patients who became Mf-negative without ivermectin treatments due to missing re-infection, and 3) endemic and non-endemic O. volvulus Mf-negative controls. With occult O. volvulus infection, serum levels of pro-inflammatory chemokines MCP-1/CCL2, MIP-1alpha/CCL3, MIP-1beta/CCL4, MPIF 1/CCL23 and CXCL8/IL-8 enhanced and approached higher concentrations as determined in infection-free controls, whilst regulatory and Th2-type cytokines and chemokines MCP-4/CCL13, MIP-1delta/CCL15, TARC/CCL17 and IL-13 lessened. Levels of Eotaxin-2/CCL24, MCP-3/CCL7 and BCA-1/CXCL13 remained unchanged. At 3 days post-initial ivermectin treatment, MCP-1/CCL2, MCP-4/CCL13, MPIF-1/CCL23 and Eotaxin-2/CCL24 were strongly enhanced, suggesting that monocytes and eosinophil granulocytes have mediated Mf clearance. In summary, with occult and expiring O. volvulus infections the serum levels of inflammatory chemokines enhanced over time while regulatory and Th2-type-promoting cytokines and chemokines lessened; these changes may reflect a decreasing effector cell activation against Mf of O. volvulus, and in parallel, an enhancing inflammatory immune responsiveness. PMID- 22202180 TI - Characterization of the in vitro binding and inhibition kinetics of primary amine oxidase/vascular adhesion protein-1 by glucosamine. AB - BACKGROUND: Primary-amine oxidase (PrAO) catalyzes the oxidative deamination of endogenous and exogenous primary amines and also functions, in some tissues, as an inflammation-inducible endothelial factor, known as vascular adhesion protein 1. VAP-1 mediates the slow rolling and adhesion of lymphocytes to endothelial cells in a number of inflammatory conditions, including inflammation of the synovium. METHODS: Glucosamine binding to the enzyme was assessed spectrofluorometrically and the kinetics of inhibition of PrAO were determined spectrophotometrically through the use of direct or coupled assays, in the presence of different substrates. RESULTS: Glucosamine is not a substrate for PrAO, but acts as a time-dependent inhibitor of PrAO activity, displaying mixed inhibition kinetics. The observed inhibition and binding were augmented in the presence of H(2)O(2). CONCLUSIONS: Significant in vitro effects on PrAO require glucosamine in the millimolar concentration range and it is not clear at this stage whether a low but persistent level of PrAO inhibition might contribute to the anti-arthritic response. GENERAL SIGNIFICANCE: This work was aimed at characterizing the interactions of PrAO/VAP-1 with glucosamine, a widely used "over-the-counter" supplement for the treatment of osteoarthritis. PMID- 22202181 TI - Evaluation of the efficacy of a recombinant Entamoeba histolytica cysteine proteinase gene (EhCP5) antigen in Minipig. AB - Entamoeba histolytica cysteine proteinase gene 5(EhCP5) is one of the major proteinase genes of all EhCP-transcripts. The amebiasis cysteine proteinase gene encoding an antigen from E. histolytica, as well as the recombinant EhCP5, obtained by cloning and expression of the EhCP5 gene in heterologous host Escherichia coli BL-21 (DE3), were used to evaluate their ability to induce immune protective responses in Minipig against challenge infection in a minipig E. histolytica model. There was a 52.27% reduction (P<0.001) in the group of recovery of challenged E. histolytica compared with that in the control group. Specific anti-EhCP5 antibodies from immune protected minipig had significantly higher levels of immunoglobulin G (IgG) (P<0.0001). Our data will help to know the mechanism of vaccinal protection of E. histolytica. PMID- 22202182 TI - Echinococcus granulosus: different cytokine profiles are induced by single versus multiple experimental infections in dogs. AB - Modulation of host responses is an important strategy by which parasites ensure successful establishment and persistence. Host counteraction against this modulation may be required for the host to develop resistance to infection. In this pilot study, experimental infection of dogs with Echinococcus granulosus induced a strong polarization of the cytokine response towards a Th2 phenotype. Consecutive rounds of infection and cure induced resistance to infection resulting in a dramatically lower parasite burden. Repeatedly-infected resistant dogs also lost immune polarization and developed a balanced Th1/Th2 response. No major differences were observed in the production of regulatory cytokines (IL-10, TGF-beta) between dogs with high parasite load and dogs with only few intestinal parasites. These results suggest that E. granulosus-driven immunomodulation contributes to successful infection in the definitive host. This information might be relevant for the development of more effective vaccines against this stage of the parasite. PMID- 22202183 TI - Functionalized quantum dots with dopamine dithiocarbamate as the matrix for the quantification of efavirenz in human plasma and as affinity probes for rapid identification of microwave tryptic digested proteins in MALDI-TOF-MS. AB - Functionalized quantum dots with dopamine dithiocarbamate (QDs-DDTC) were utilized for the first time as an efficient material for the quantification of efavirenz in human plasma of HIV infected patients and rapid identification of microwave tryptic digest proteins (cytochrome c, lysozyme and BSA) by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The synthesized QDs-DDTC was characterized by using spectroscopic (UV visible, FT-IR and (1)H NMR) and microscopic (SEM and TEM) techniques. Functionalized QDs-DDTC exhibited a high desorption/ionization efficiency for the rapid quantification of small molecules (efavirenz, tobramycin and aspartame) at low-mass region. QDs-DDTC has well ability to trap target species, and capable to transfer laser energy for efficient desorption/ionization of analytes with background-free detection. The use of QDs-DDTC as a matrix provided good linearity for the quantification of small molecules (R(2)=~0.9983), with good reproducibility (RSD<10%), in the analysis of efavirenz in the plasma of HIV infected patients by the standard addition method. We also demonstrated that the use of functionalized QDs-DDTC as affinity probes for the rapid identification of microwave tryptic digested proteins (cytochrome c, lysozyme and BSA) by MALDI-TOF MS. QDs-DDTC-based MALDI-TOF-MS approach provides simplicity, rapidity, accuracy, and precision for the determination of efavirenz in human plasma of HIV infected patients and rapid identification of microwave tryptic digested proteins. This new material presents a marked advance in the development of matrix-free mass spectrometric methods for the rapid and precise quantitative determination of a variety of molecules. This article is part of a Special Issue entitled: Proteomics: The clinical link. PMID- 22202184 TI - Development of a combined chemical and enzymatic approach for the mass spectrometric identification and quantification of aberrant N-glycosylation. AB - Direct mass spectrometric analysis of aberrant protein glycosylation is a challenge to the current analytical techniques. Except lectin affinity chromatography, no other glycosylation enrichment techniques are available for analysis of aberrant glycosylation. In this study, we developed a combined chemical and enzymatic strategy as an alternative for the mass spectrometric analysis of aberrant glycosylation. Sialylated glycopeptides were enriched with reverse glycoblotting, cleaved by endoglycosidase F3 and analyzed by mass spectrometry with both neutral loss triggered MS(3) in collision induced dissociation (CID) and electron transfer dissociation (ETD). Interestingly, a great part of resulted glycopeptides were found with fucose attached to the N acetylglucosamine (N-GlcNAc), which indicated that the aberrant glycosylation that is carrying both terminal sialylation and core fucosylation was identified. Totally, 69 aberrant N-glycosylation sites were identified in sera samples from hepatocellular carcinoma (HCC) patients. Following the identification, quantification of the level of this aberrant glycosylation was also carried out using stable isotope dimethyl labeling and pooled sera sample from liver cirrhosis and HCC was compared. Six glycosylation sites demonstrated elevated level of aberrancy, which demonstrated that our developed strategy was effective in both qualitative and quantitative studies of aberrant glycosylation. PMID- 22202185 TI - Analysis of cellular proteome alterations in porcine alveolar macrophage cells infected with 2009 (H1N1) and classical swine H1N1 influenza viruses. AB - The H1N1/2009 influenza virus has the potential to cause a human pandemic, and sporadic cases of human-to-pig transmission have been reported. In this study, two influenza viruses were isolated from pigs. A phylogenetic analysis showed that the A/swine/NanChang/F9/2010(H1N1) (F9/10) strain shared a high degree of homology with the pandemic H1N1/2009 virus, and A/swine/GuangDong/34/2006 (H1N1) (34/06) strains was a classical swine influenza virus. A proteomic analysis was performed to investigate possible alterations of protein expression in porcine alveolar macrophage (PAM) cells infected by the F9/10 and 34/06 viruses over different time courses. Using 2-DE in association with MALDI-TOF MS/MS, we identified 13 up-regulated and 21 down-regulated protein spots, including cytoskeleton proteins, cellular signal transduction proteins, molecular biosynthesis proteins and heat shock proteins. The most significant changes in the infected cells were associated with molecular biosynthesis proteins and heat shock proteins. We analysed the biological characteristics of the F9/10 and 34/06 viruses in vivo and in vitro. The F9/10 virus showed greater pathogenicity than the 34/06 virus in PAM cells and mice. This study provides insights into the biologic characteristics, potential virulence alteration and cross-species transmission mechanisms of the pandemic H1N1/2009. PMID- 22202186 TI - Study of nurse workarounds in a hospital using bar code medication administration system. AB - This study analyzed registered nurse workarounds in an academic medical center using bar code medication administration technology. Nurse focus groups and a survey were used to determine the frequency and potential causes of workarounds. More than half of the nurses surveyed indicated that they administered medications without scanning the patient or medications during the last shift worked. Benefits of this study include considerations when implementing bar code medication administration technology that may minimize the development of these workarounds in practice. PMID- 22202187 TI - Neurobiology of language recovery after stroke: lessons from neuroimaging studies. AB - Language is organized in large-scale, predominantly left-lateralized, temporo parieto-frontal networks in the human brain. After focal brain damage (eg, ischemic stroke), this network organization enables the brain to adaptively reorganize language functions in order to compensate lesion effects. Here, we summarize how structural and functional neuroimaging methods contribute to the current understanding of loss and recovery of language functions after stroke. This includes voxelwise lesion-behavior mapping, functional imaging for mapping reorganizational mechanisms from acute to chronic stroke, as well as imaging based outcome prediction. The review is complemented by an introductory section on language organization in the healthy brain. PMID- 22202188 TI - Transcranial magnetic stimulation and aphasia rehabilitation. AB - Repetitive transcranial magnetic stimulation (rTMS) has been reported to improve naming in chronic stroke patients with nonfluent aphasia since 2005. In part 1, we review the rationale for applying slow, 1-Hz, rTMS to the undamaged right hemisphere in chronic nonfluent aphasia patients after a left hemisphere stroke; and we present a transcranial magnetic stimulation (TMS) protocol used with these patients that is associated with long-term, improved naming post-TMS. In part 2, we present results from a case study with chronic nonfluent aphasia where TMS treatments were followed immediately by speech therapy (constraint-induced language therapy). In part 3, some possible mechanisms associated with improvement after a series of TMS treatments in stroke patients with aphasia are discussed. PMID- 22202189 TI - First decade of research on constrained-induced treatment approaches for aphasia rehabilitation. AB - Approaches for treating poststroke language impairments (aphasia) based on constraint-induced (CI) principles were first introduced in 2001. CI principles as previously applied to upper extremity and locomotor retraining in stroke survivors were derived from basic neuroscience. They comprise forced-use of the affected modality, a gradual rebuilding of targeted functions using a highly intensive treatment protocol, administered in a behaviorally relevant context. CI based approaches have stimulated considerable neurorehabilitation research interest in the past decade. The original CI aphasia treatment protocol was tailored to improve functional communication in chronic aphasia (ie, 6-12mo after stroke) and more recently, it has been adapted to treat language impairments in acute stroke survivors as well. Moreover, CI therapy applied to aphasia has been used as a model to assess language network plasticity in response to treatment using functional imaging techniques. In the following article, we review the first 10 years of behavioral and functional brain imaging research on CI-based approaches for aphasia rehabilitation. PMID- 22202190 TI - Advanced magnetic resonance neuroimaging of language function recovery after aphasic stroke: a technical review. AB - Two advanced magnetic resonance neuroimaging techniques, functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), have recently made their way into clinically oriented research and hold great promise to study the brain's adaptive changes of function and structure after aphasic stroke, respectively. Such functional and structural neuroplasticity is thought to underlie the recovery of language function, occurring spontaneously and/or in the context of therapeutic intervention. With fMRI, brain activity can be visualized. Spontaneous brain activity, present in multiple brain networks, is measured with resting-state fMRI and language-related brain activity by having the subject perform a language task during scanning (task-based fMRI). With DTI the major white matter tracts, such as the dorsal and ventral language pathways and the commissural fibers, can be visualized and quantified. Both techniques are entirely noninvasive and thus offer the unique opportunity to perform multiple assessments within the same subject. To gain more insight in functional and structural neuroplasticity after aphasic stroke, advanced magnetic resonance neuroimaging studies in specific patient populations, at several stages after stroke and in the course of language recovery, are needed. Such studies will help to clarify the influence of the many factors that play a role in the recovery of language function and are thus vital to further the development of aphasia therapy. Application of these techniques in aphasic stroke patients, however, is not without challenge. The purpose of this article is to discuss the methodologic challenges of fMRI and DTI in the assessment of language recovery after aphasic stroke. PMID- 22202191 TI - Melodic Intonation Therapy: present controversies and future opportunities. AB - This article describes the state of the art of Melodic Intonation Therapy (MIT), a structured aphasia therapy program using the melodic aspects of language (intonation, rhythm, and stress) to improve language production. MIT was developed in the 1970s and is still used worldwide. Nevertheless, we argue that many questions crucial for the clinical application of MIT are still unanswered. First, a review of MIT effect studies is presented showing that evidence from well-designed group studies is still lacking. It is also unclear which aspects of MIT contribute most to its therapeutic effect and which underlying neural mechanisms are involved. Two cases are presented illustrating unsolved questions concerning MIT in clinical practice, such as candidacy and the best timing of this therapy. PMID- 22202192 TI - Using phonemic cueing of spontaneous naming to predict item responsiveness to therapy for anomia in aphasia. AB - BACKGROUND: Anomia refers to difficulties retrieving words and is 1 of the most common symptoms of aphasia and hence often the target of therapy. The principal aim of the present study was to explore, for the first time, whether it is possible to predict the responsiveness of individual words to naming therapy from the psycholinguistic properties of those words and from the length of the phonemic cue required to name them. The relationship between this form of cueing and the outcome of naming therapy is of particular interest given that cueing is an established research and clinical tool within aphasiology, and is commonly used to probe naming performance. METHOD: By amalgamating data from 3 previous studies, we were able to analyze data from 22 participants with chronic aphasia, yielding cueing and therapy data for 1080 target words. Cross-session changes in cueing and naming accuracy were collated for 298 target words. RESULTS: The results demonstrated that items which were accurately named after therapy (both at 1 wk and 5 wk later) required a significantly shorter phonemic cue to prompt correct naming in assessments prior to therapy. Imageability was a significant predictor of the required cue level, whereas word age of acquisition and word frequency were not. Highly imageable words required less cueing and were more likely to be accurately named posttherapy. A novel analysis of cross-session accuracy revealed that, even though the required cue length reduced across the first 6 of 10 therapy sessions, the relationship between the required cue length and final posttherapy accuracy was present throughout therapy. DISCUSSION: The findings are discussed in the context of their clinical implications for intervention, specifically for therapies that focus on accurate production of specific word targets. Themes for future related research are also considered. PMID- 22202193 TI - Rehabilitation for cognitive-communication disorders in right hemisphere brain damage. AB - Although the left hemisphere of the brain has long been linked with language, the right cerebral hemisphere also contributes importantly to cognitive operations that underlie language processing and communicative performance. Adults with right hemisphere damage (RHD) typically do not have aphasia, but they often have communication disorders that may have a substantial impact on their social functioning. After a brief summary of communicative and cognitive characteristics of RHD in adults and of extant theoretical accounts of common communicative difficulties, this article discusses rehabilitation issues, approaches, evidence, and needs. PMID- 22202194 TI - Rehabilitation targeted at everyday communication: can we change the talk of people with aphasia and their significant others within conversation? AB - OBJECTIVE: To investigate whether aphasia therapy can change the talk of speakers with aphasia and/or their significant others within conversation. DESIGN: Small number of intervention studies targeting conversations involving speakers with aphasia are reviewed. All are single case studies. SETTING: Key assessment in the studies was an audio or video recording of 1 or more conversations between the dyad, usually made in the home setting. Intervention in these studies took place in the participants' home or another setting, such as a therapy room. PARTICIPANTS: In all of the studies reviewed, the participants consisted of a person with aphasia (PWA) and a significant other, usually the PWA's spouse. INTERVENTIONS: In all studies, therapy took the form of a behavioral intervention involving the provision of feedback to the significant other and/or PWA on their conversational behaviors uncovered by a conversation analysis assessment. Handouts, transcripts, discussion, and video feedback were used. Suggestions to permit participants to cope better with the effects of aphasia within conversation were given, and opportunities for practicing these strategies within conversation were provided. MAIN OUTCOME MEASURES: Postintervention, 1 or more conversations involving the PWA and significant other were recorded in the same manner as the preintervention. Conversations were analyzed in relation to changes in the behaviors targeted in intervention, such as those involved in topic initiation or repair of linguistic errors. RESULTS: Each of the studies reviewed presented evidence that the talk of people with aphasia and/or their significant others can be changed in conversation. In some studies the evidence is primarily qualitative, in the form of observed changes to conversational behaviors postintervention. Some studies produce stronger evidence by combining qualitative and quantitative analyses of change. CONCLUSIONS: There is evidence that intervention targeting conversations involving an aphasic speaker can achieve change. Future studies should move beyond single case designs, include more robust, quantifiable evidence of change, and provide evidence of maintenance of change. PMID- 22202196 TI - Sustained release microspheres of ropinirole hydrochloride: effect of process parameters. AB - An emulsion solvent evaporation method was employed to prepare microspheres of ropinirole hydrochloride, a highly water soluble drug, by using ethylcellulose and PEG with the help of 32 full factorial design. The microspheres were made by incorporating the drug in a polar organic solvent, which was emulsified using liquid paraffin as an external oil phase. Effects of various process parameters such as viscosity of the external phase, selection of the internal phase, surfactant selection and selection of stirring speed were studied. Microspheres were evaluated for product yield, encapsulation efficiency and particle size. Various drug/ethylcellulose ratios and PEG concentrations were assayed. In vitro dissolution profiles showed that ethylcellulose microspheres were able to control release of the drug for a period of 12 h. PMID- 22202195 TI - Finding cancer's weakest link. AB - The biological programs of vertebrates exhibit a remarkable degree of functional degeneracy, adaptive compensation and robustness, to preserve homeostasis and generate reproducible phenotypic outputs irrespective of variations in signal strength, noise and quality. Cancers are difficult to treat not only because they are so mechanistically diverse but also because they adapt or evolve in response to any pharmacological elective pressure we impose upon them. Hence, an ideal cancer drug target would exert a function both necessary for cancer cell survival and functionally non-redundant, rendering it impossible for tumor cells to compensate for, or evolve independence from, the inhibitory effect of any drug aimed at that target. In this review, we discuss the unique, non-degenerate and highly pleiotropic role played by Myc in coordinating, engaging and maintaining the diverse intracellular and extracellular programs required for cell proliferation in vivo. These properties make Myc a compelling candidate cancer drug target, at least in principle: an assertion recently reinforced by new in vivo genetic data. PMID- 22202197 TI - Optimized and validated flow-injection spectrophotometric analysis of topiramate, piracetam and levetiracetam in pharmaceutical formulations. AB - Application of a sensitive and rapid flow injection analysis (FIA) method for determination of topiramate, piracetam, and levetiracetam in pharmaceutical formulations has been investigated. The method is based on the reaction with ortho-phtalaldehyde and 2-mercaptoethanol in a basic buffer and measurement of absorbance at 295 nm under flow conditions. Variables affecting the determination such as sample injection volume, pH, ionic strength, reagent concentrations, flow rate of reagent and other FIA parameters were optimized to produce the most sensitive and reproducible results using a quarter-fraction factorial design, for five factors at two levels. Also, the method has been optimized and fully validated in terms of linearity and range, limit of detection and quantitation, precision, selectivity and accuracy. The method was successfully applied to the analysis of pharmaceutical preparations. PMID- 22202198 TI - Crystal modifications and dissolution rate of piroxicam. AB - Piroxicam is a nonsteroidal anti-inflammatory drug with low aqueous solubility which exhibits polymorphism. The present study was carried out to develop polymorphs of piroxicam with enhanced solubility and dissolution rate by the crystal modification technique using different solvent mixtures prepared with PEG 4000 and PVP K30. Physicochemical characteristics of the modified crystal forms of piroxicam were investigated by X-ray powder diffractometry, FT-IR spectrophotometry and differential scanning calorimetry. Dissolution and solubility profiles of each modified crystal form were studied and compared with pure piroxicam. Solvent evaporation method (method I) produced both needle and cubic shaped crystals. Slow crystallization from ethanol with addition of PEG 4000 or PVP K30 at room temperature (method II) produced cubic crystal forms. Needle forms produced by method I improved dissolution but not solubility. Cubic crystals produced by method I had a dissolution profile similar to that of untreated piroxicam but showed better solubility than untreated piroxicam. Cubic shaped crystals produced by method II showed improved dissolution, without a significant change in solubility. Based on the XRPD results, modified piroxicam crystals obtained by method I from acetone/benzene were cube shaped, which correlates well with the FTIR spectrum; modified needle forms obtained from ethanol/methanol and ethanol/acetone showed a slight shift of FTIR peak that may be attributed to differences in the internal structure or conformation. PMID- 22202199 TI - Determination of donepezil hydrochloride in human plasma and pharmaceutical formulations by HPLC with fluorescence detection. AB - A sensitive, isocratic reversed-phase high performance liquid chromatographic method involving fluorescence detection was developed for the determination of donepezil hydrochloride in tablets and in human plasma. Pindolol was used as an internal standard. Good chromatographic separation was achieved by using an analytical column C18. The system operated at room temperature using a mobile phase consisting of methanol, phosphate buffer (0.02 mol L-1) and triethyl amine (pH 3.5) (55 : 45 : 0.5, V/V/V) at a flow rate 0.9 mL-1 min. The analyte and internal standard were extracted from human plasma via liquid-liquid extraction. The proposed method was validated for sensitivity, selectivity, linearity, accuracy and precision. The calibration curve was linear over the range of 5-2000 ng mL-1 of donepezil with detection limit of 1.5 ng mL-1. Intra- and inter-day relative standard deviations were less than 2.5%. The method was found to be suitable for quality control of donepezil hydrochloride in bulk drug as well as in human plasma. PMID- 22202200 TI - Synthesis, in vitro anticancer screening and radiosensitizing evaluation of some new 4-[3-(substituted)thioureido]-N-(quinoxalin-2-yl)-benzenesulfonamide derivatives. AB - Sulfonamides and quinoxaline derivatives possess many types of biological activities and have been recently reported to show substantial antitumor activity. This paper reports the synthesis of novel thioureido sulfaquinoxaline derivatives. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against a human liver cell line (HEPG2) and showed higher activity than the reference drug doxorubicin. 4-(3-(4-Ethylbenzoate) thioureido)-N-(quinoxalin-2-yl)benzenesulfonamide (9) (IC50 = 15.6 MUmol L-1), N (pyridin-2-yl)-4-(3-(4-(N-quinoxalin-2-yl sulfamoyl)phenyl)thioureido)benzenesulfonamide (10) (IC50 = 26.8 MUmol L-1) and N (quinoxalin-2-yl)-4-(3-(4-(N-thiazol-2 ylsulfamoyl)phenyl)thioureido)benzenesulfonamide (11) (IC50 = 24.4 MUmol L-1) were the most potent compared to doxorubicin (IC50 = 71.8 MUmol L-1). The most potent compounds 9, 10 and 11 were evaluated as radiosensitizing agents by subjecting the compounds to gamma-irradiation (8 kGy). PMID- 22202201 TI - Preliminary studies on the effect of rebamipide against the trypsin and egg albumin induced experimental model of asthma. AB - The present investigation was carried out to study the effect of rebamipide in experimentally induced bronchial asthma in mice. Trypsin and egg-albumin induced chronic model of asthma was used and various parameters were measured on the 35th day. The asthmatic control group showed lower level of haemoglobin saturation with oxygen, tidal volume, airflow rate and higher respiratory rate, serum bicarbonate level, eosinophil count in bronchoalveolar lavage fluid and histamine level compared to the normal control group. Dexamethasone and rebamipide treated groups showed the return of all the above parameters towards normal values. Histopathological examination of lungs showed more prominent alveolar and muscular layer destruction in the asthmatic control group than in dexamethasone and rebamipide treated groups. Rebamipide showed a beneficial effect and might be used for the treatment of bronchial asthma. PMID- 22202202 TI - Liquid antisolvent precipitation process for solubility modulation of bicalutamide. AB - Liquid antisolvent process was explored as a solubility modulating tool. Bicalutamide, a poorly water soluble drug, was used as a candidate. Low aqueous solubility and poor dissolution of bicalutamide results into poor and variable bioavailability. Therefore, the objective of the present work was to modify the solubility of bicalutamide using the liquid antisolvent precipitation process. HPMC E5 and Poloxamer 407 were shortlisted as a hydrophilic polymer and surfactant, respectively, for the process. Process optimization was done with respect to the hydrophilic polymer, surfactant and drug loading concentration. The resultant microcrystals were characterized with various instrumental techniques for material characterization such as IR, DSC, SEM, XRD, particle size, specific surface area and dissolution kinetics. PMID- 22202203 TI - Antimicrobial potential of 3-hydroxy-2-methylene-3-phenylpropionic acid derivatives. AB - Twenty Baylis-Hillman adducts were synthesized from different aromatic aldehydes and activated vinyl derivatives. The adducts, which are differently substituted 3 hydroxy-2-methylene-3-phenylpropionic acid derivatives, were screened for their antimicrobial activity in vitro by the serial dilution method. Many of these molecules displayed potent antibacterial and antifungal activities. The ease of synthesis from low-cost starting materials along with potent antimicrobial activity of these molecules provide the lead for further improvement of activity and reflect the possibility of therapeutic use. PMID- 22202204 TI - Assay of lercanidipine hydrochloride in dosage forms using nucleophilic substitution reaction. AB - A simple and sensitive spectrophotometric method has been developed for the assay of lercanidipine hydrochloride (LER) in bulk and in formulations. The method is based on the formation of coloured species between the drug and 1,2 naphthaquinone-4-sulphonic acid sodium salt (NQS) by means of nucleophilic substitution reaction. Absorbance was measured at lambda(max) = 460 nm. The method was analyzed statistically. The system obeyed the Beer's law in the range 20-100 MUg mL-1. Molar absorptivity value was found to be 4.79 * 103 L mol-1 cm 1. Limits of detection and quantification were found to be as low as 0.04 and 0.13 MUg mL-1. Precision (RSD, 0.4%) and accuracy (recovery 99.2 +/- 0.6 to 101.1 +/- 0.8%) of the developed method were evaluated. PMID- 22202205 TI - Macromolecular prodrugs. XIII. Hydrosoluble conjugates of 17beta-estradiol and estradiol-17beta-valerate with polyaspartamide polymer. AB - Two hydrosoluble conjugates of 17beta-estradiol (ED) and estradiol-17beta valerate (EV) with polyaspartamide polymer were prepared and characterized. ED and EV were first chemically modified and bound to poly[alpha,beta-(N-2 hydroxyethyl-DL-aspartamide)]-poly[alpha,beta-(N-2-aminoethyl-DL-aspartamide)] (PAHA), a hydrosoluble polyaspartamide-type copolymer bearing both hydroxyl and amino groups. ED was first converted to 17-hemisuccinate (EDS) and then bound to PAHA. In the resulting conjugate PAHA-EDS, the estradiol moiety was linked to the polymer through a 2-aminoethylhemisuccinamide spacer. On the other hand, EV was first converted to estradiol-17beta-valerate-3-(benzotriazole-1-carboxylate), which readily reacted with amino groups in PAHA affording the polymer-drug conjugate PAHA-EV. In the prepared conjugate PAHA-EV, the estradiol moiety was covalently bound to the polyaspartamide backbone by carbamate linkage, through an ethylenediamine spacer. The polymer-drug conjugates were designed and prepared with the aim to increase water-solubility, bioavailability and to improve drug delivery of the lipophilic estrogen hormone. PMID- 22202221 TI - Paradoxical signaling pathways in developing thymocytes. AB - Thymocytes are subjected to processes of selection during their life in the thymus; negative selection for autoreactive thymocytes and positive selection for self-MHC restricted self-tolerant cells. Interestingly, signals for positive or negative selection originate from the same receptor. More importantly, evidence showed that both death and survival signals are mediated by the MAPK pathway. The degree and order of ERK activation, but not other MAPK proteins, has been found to be different in either cases of cell fate. Therefore, it is suspected that the kinetics of ERK after activation may dictate cell death or survival. There are two important GEF proteins that are involved in Ras/ERK activation, RasGRP and SOS. It is thought that the level, order and kinetics of ERK are influenced upstream by the type of GEF. This review discusses the role of both GEF proteins in positive and negative selection and how this reflects on ERK activation. PMID- 22202222 TI - Unconventional treatment options in severe asthma: an overivew. AB - In Canada, asthma is the leading cause of admission in hospital. About of 80% of the death from asthma is preventable. Severe asthma is defined as a patient with persistent symptoms despite the use of adequate controller therapy, including multiple courses of oral glucocorticosteroids. However, about 10% of patients with severe asthma remain poorly controlled despite optimal treatment and these patients have the greatest morbidity and mortality. The management of refractory severe asthma remains extremely challenging. For patients with refractory severe asthma, the adjunct therapies recommended by national guidelines only included oral glucocorticosteroid and anti-IgE antibody (omalizumab) therapy. Currently, there is limited published literature on the unconventional treatments of refractory severe asthma. The objective of this review article is to provide an updated therapeutic overview of unconventional treatment options for refractory severe asthma. PMID- 22202223 TI - Overview of plant-derived vaccine antigens: Dengue virus. AB - This review highlights the advantages and current status of plant-derived vaccine development with special reference to the dengue virus. There are numerous problems involved in dengue vaccine development, and there is no vaccine against all four dengue serotypes. Dengue vaccine development using traditional approaches has not been satisfactory in terms of inducing neutralizing antibodies. Recently, these issues were addressed by showing a very good response to inducing neutralizing antibodies by plant-derived dengue vaccine antigens. This indicates the feasibility of using plant-derived vaccine antigens as a low cost method to combat dengue and other infectious diseases. The application of new methods and strategies such as dendritic cell targeting in cancer therapy, severe acute respiratory syndrome, tuberculosis, human immune deficiency virus, and malaria might play an important role. These new methods are more efficient than traditional protocols. It is expected that in the near future, plant-derived vaccine antigens or antibodies will play an important role in the control of human infectious diseases. PMID- 22202224 TI - Decrease in brain distribution of fluvoxamine in experimental hyperlipidemic rats. AB - PURPOSE: Many clinical reports and trials have suggested that fluvoxamine (FLV) reduces plasma lipoprotein levels. However, few studies have reported the effect of plasma lipoproteins on FLV pharmacokinetics. The aim of the present study was to investigate the affinities of FLV to plasma lipoproteins and the effect of plasma lipoproteins on the biodistribution of FLV using an experimental hyperlipidemic (HL) rat model. METHODS: HL rats were prepared by intraperitoneal administration of Poloxamer-407 solution (1.0 g/kg). In vitro protein binding and distribution of FLV in plasma lipoproteins were determined in control and HL rats. In vivo pharmacokinetic study (intravenous administration of FLV, 5.0 mg/kg) and biodistribution analysis for brain and liver at a steady state (infusion, 1.5 mg/kg/hr, 6 hrs) were also performed. RESULTS: The plasma protein binding of FLV was around 83% and 95% in control and HL rats, respectively, whereas the FLV recoveries in triglyceride-rich lipoprotein fractions were increased in HL. Therefore, the elevation of lipoproteins was likely responsible for the increase in protein binding in HL. After intravenous administration, the area under the plasma concentration vs. time curve (AUC) in HL was 3.9-fold greater than that in control rats, whereas the distribution ratio of FLV plasma concentration to the brain at a steady state was decreased to approximately 20% of that of the control. CONCLUSIONS: FLV has an affinity to plasma lipoproteins, and their elevation might decrease the FLV biodistribution to brain; the plasma lipoprotein levels could not be found to correlate positively with the FLV pharmacokinetic effect in brain, but rather may attenuate it. PMID- 22202225 TI - In vitro anti-inflammatory effects of hyaluronic acid in ethanol-induced damage in skin cells. AB - Ethyl alcohol (ethanol) is commonly applied in cosmetic and pharmaceutical preparations, as well as disinfectant for chronic wounds. OBJECTIVE: The present study aimed to appraise physiological levels of ethanol-induced damage in skin cells in vitro and the possible repair by hyaluronic acid (HA). In addition, we aimed to establish cytokine-chemokine networks in the cellular media and the modulation of cytokines such as tumor necrosis factor-alpha (TNF-B), interferon alpha (IFN-alpha), transforming growth factor-beta (TGF-B), interleukins (IL) such as IL1-B and IL-6, as well as matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP). DESIGN AND METHODS: We treated human A431 epidermoid skin cells and mouse fibroblasts with ethanol at a concentration of 100 mM over 24 hours (h). A separate experiment looked at the effects of 2 consecutive treatments with 100 mM ethanol for 24 h each. HA obtained from umbilical cord excision was used at two concentration levels (2% and 4%) to determine its efficacy in the treatment. We measured cytotoxicity and cytokine networks in the media. RESULTS: Treatment of cells with 100 mM ethanol increased cytotoxicity, as well as the release of pro-inflammatory cytokines into the culture medium. CONCLUSIONS: Ethanol may induce cytotoxicity in skin cells by enhancing the effects of pro-inflammatory cytokines. HA reduced the amount of pro inflammatory cytokines released into the media both in human A431 epidermoid skin cells and in mouse fibroblasts. PMID- 22202226 TI - Low-concentration methylene blue maintains energy production and strongly improves survival of Leigh syndrome French Canadian skin fibroblasts. AB - Leigh syndrome French Canadian (LSFC) is a recessive disease caused by mutations in the LRPPRC gene (leucine-rich pentatricopeptide repeat containing protein). These mutations induce a cytochrome c oxidase (COX) deficiency resulting in episodes of acute acidotic crisis that will often lead to death. There is no effective treatment. Methylene blue (MB) is a redox dye that increases COX content and activity in vitro and in vivo suggesting that MB could prevent and treat LSFC. In this study, the protective effect of low-concentration MB was tested on two LSFC cell lines, including LSFC-F1, homozygous for the mutation A354V, and LSFC-F2 a compound heterozygous for the mutations A354V and C12775STOP. MB effect on metabolic activity was assessed on both LSFC cells in stable and acidotic conditions. For LSFC-F1, results showed that metabolic activity drastically decline after 96 hours in both conditions but not LSFC-F2 and normal cells. MB completely prevents the decrease of metabolic activity in LSFC-F1. Intracellular ATP content was also measured in both culture media. After 96 hours in acidotic medium, ATP content was almost completely depleted for both LSFC cells. Interestingly, MB completely restores ATP content in LSFC-F1 and LSFC F2 cells. Finally, MB strongly improves the survival of both LSFC cells. PMID- 22202227 TI - Composition of air pollution particles and oxidative stress in cells, tissues, and living systems. AB - Epidemiological studies demonstrated an association between increased levels of ambient air pollution particles and human morbidity and mortality. Production of oxidants, either directly by the air pollution particles or by the host response to the particles, appears to be fundamental in the biological effects seen after exposure to particulate matter (PM). However, the precise components and mechanisms responsible for oxidative stress following PM exposure are yet to be defined. Direct oxidant generation by air pollution particles is attributed to organic and metal components. Organic compounds generate an oxidative stress through redox cycling of quinone-based radicals, by complexing of metal resulting in electron transport, and by depletion of antioxidants by reactions between quinones and thiol-containing compounds. Metals directly support electron transport to generate oxidants and also diminish levels of antioxidants. In addition to direct generation of oxidants by organic and metal components, cellular responses contribute to oxidative stress after PM exposure. Reactive oxygen species (ROS) production occurs in the mitochondria, cell membranes, phagosomes, and the endoplasmic reticulum. Oxidative stress following PM exposure initiates a series of cellular reactions that includes activation of kinase cascades and transcription factors and release of inflammatory mediators, which ultimately lead to cell injury or apoptosis. Consequently, oxidative stress in cells and tissues is a central mechanism by which PM exposure leads to injury, disease, and mortality. PMID- 22202228 TI - Reconstructing human exposures using biomarkers and other "clues". AB - Biomonitoring is the process by which biomarkers are measured in human tissues and specimens to evaluate exposures. Given the growing number of population-based biomonitoring surveys, there is now an escalated interest in using biomarker data to reconstruct exposures for supporting risk assessment and risk management. While detection of biomarkers is de facto evidence of exposure and absorption, biomarker data cannot be used to reconstruct exposure unless other information is available to establish the external exposure-biomarker concentration relationship. In this review, the process of using biomarker data and other information to reconstruct human exposures is examined. Information that is essential to the exposure reconstruction process includes (1) the type of biomarker based on its origin (e.g., endogenous vs. exogenous), (2) the purpose/design of the biomonitoring study (e.g., occupational monitoring), (3) exposure information (including product/chemical use scenarios and reasons for expected contact, the physicochemical properties of the chemical and nature of the residues, and likely exposure scenarios), and (4) an understanding of the biological system and mechanisms of clearance. This review also presents the use of exposure modeling, pharmacokinetic modeling, and molecular modeling to assist in integrating these various types of information. PMID- 22202229 TI - Developmental and reproductive outcomes in humans and animals after glyphosate exposure: a critical analysis. AB - Glyphosate is the active ingredient of several widely used herbicide formulations. Glyphosate targets the shikimate metabolic pathway, which is found in plants but not in animals. Despite the relative safety of glyphosate, various adverse developmental and reproductive problems have been alleged as a result of exposure in humans and animals. To assess the developmental and reproductive safety of glyphosate, an analysis of the available literature was conducted. Epidemiological and animal reports, as well as studies on mechanisms of action related to possible developmental and reproductive effects of glyphosate, were reviewed. An evaluation of this database found no consistent effects of glyphosate exposure on reproductive health or the developing offspring. Furthermore, no plausible mechanisms of action for such effects were elucidated. Although toxicity was observed in studies that used glyphosate-based formulations, the data strongly suggest that such effects were due to surfactants present in the formulations and not the direct result of glyphosate exposure. To estimate potential human exposure concentrations to glyphosate as a result of working directly with the herbicide, available biomonitoring data were examined. These data demonstrated extremely low human exposures as a result of normal application practices. Furthermore, the estimated exposure concentrations in humans are >500-fold less than the oral reference dose for glyphosate of 2 mg/kg/d set by the U.S. Environmental Protection Agency (U.S. EPA 1993). In conclusion, the available literature shows no solid evidence linking glyphosate exposure to adverse developmental or reproductive effects at environmentally realistic exposure concentrations. PMID- 22202232 TI - Sentinel node biopsy for early oral carcinoma. AB - PURPOSE OF REVIEW: Sentinel node biopsy (SNB) in oral squamous cell carcinomas (OSCCs) has been under investigation since more than a decade. Numerous published studies and recent important scientific data support its role as an alternative standard of care apart from elective neck dissection. RECENT FINDINGS: During the past 2 years, a large-scale multicentric validation trial and long-term follow ups of major observational trials have demonstrated the accuracy and oncological safety and efficacy of SNB to stage a cN0 early stage OSCC. Histologic and molecular parameters of the primary tumors possibly predicting occult disease in the neck have been evaluated, but SNB with the use of step-serial sectioning and immunohistochemistry remains the most accurate staging method. SNB has been shown to be clearly superior to elective neck dissection with regard to complications and morbidity. The modern technique of quantitative real-time reverse transcriptase-polymerase chain reaction has been successfully used for the rapid intraoperative assessment of the sentinel nodes, allowing a one-stage procedure in all patients. The procedure of SNB is currently expanding to other areas like the supraglottic larynx and the previously treated neck. SUMMARY: SNB in OSCC is a minimally invasive and highly reliable staging method of the cN0 neck and has become the standard of care in many centers throughout the world. Recent developments have led to a wider clinical application and improved acceptance. PMID- 22202231 TI - The self-transcendence scale: an investigation of the factor structure among nursing home patients. AB - PURPOSE: Self-transcendence, the ability to expand personal boundaries in multiple ways, has been found to provide well-being. The purpose of this study was to examine the dimensionality of the Norwegian version of the Self Transcendence Scale, which comprises 15 items. BACKGROUND: Reed's empirical nursing theory of self-transcendence provided the theoretical framework; self transcendence includes an interpersonal, intrapersonal, transpersonal, and temporal dimension. DESIGN: Cross-sectional data were obtained from a sample of 202 cognitively intact elderly patients in 44 Norwegian nursing homes. RESULTS: Exploratory factor analysis revealed two and four internally consistent dimensions of self-transcendence, explaining 35.3% (two factors) and 50.7% (four factors) of the variance, respectively. Confirmatory factor analysis indicated that the hypothesized two- and four-factor models fitted better than the one factor model (cx (2), root mean square error of approximation, standardized root mean square residual, normed fit index, nonnormed fit index, comparative fit index, goodness-of-fit index, and adjusted goodness-of-fit index). CONCLUSIONS: The findings indicate self-transcendence as a multifactorial construct; at present, we conclude that the two-factor model might be the most accurate and reasonable measure of self-transcendence. IMPLICATIONS: This research generates insights in the application of the widely used Self-Transcendence Scale by investigating its psychometric properties by applying a confirmatory factor analysis. It also generates new research-questions on the associations between self-transcendence and well-being. PMID- 22202230 TI - Sur7 promotes plasma membrane organization and is needed for resistance to stressful conditions and to the invasive growth and virulence of Candida albicans. AB - The human fungal pathogen Candida albicans causes lethal systemic infections because of its ability to grow and disseminate in a host. The C. albicans plasma membrane is essential for virulence by acting as a protective barrier and through its key roles in interfacing with the environment, secretion of virulence factors, morphogenesis, and cell wall synthesis. Difficulties in studying hydrophobic membranes have limited the understanding of how plasma membrane organization contributes to its function and to the actions of antifungal drugs. Therefore, the role of the recently discovered plasma membrane subdomains termed the membrane compartment containing Can1 (MCC) was analyzed by assessing the virulence of a sur7Delta mutant. Sur7 is an integral membrane protein component of the MCC that is needed for proper localization of actin, morphogenesis, cell wall synthesis, and responding to cell wall stress. MCC domains are stable 300-nm sized punctate patches that associate with a complex of cytoplasmic proteins known as an eisosome. Analysis of virulence-related properties of a sur7Delta mutant revealed defects in intraphagosomal growth in macrophages that correlate with increased sensitivity to oxidation and copper. The sur7Delta mutant was also strongly defective in pathogenesis in a mouse model of systemic candidiasis. The mutant cells showed a decreased ability to initiate an infection and greatly diminished invasive growth into kidney tissues. These studies on Sur7 demonstrate that the plasma membrane MCC domains are critical for virulence and represent an important new target for the development of novel therapeutic strategies. IMPORTANCECandida albicans, the most common human fungal pathogen, causes lethal systemic infections by growing and disseminating in a host. The plasma membrane plays key roles in enabling C. albicans to grow in vivo, and it is also the target of the most commonly used antifungal drugs. However, plasma membrane organization is poorly understood because of the experimental difficulties in studying hydrophobic components. Interestingly, recent studies have identified a novel type of plasma membrane subdomain in fungi known as the membrane compartment containing Can1 (MCC). Cells lacking the MCC-localized protein Sur7 display broad defects in cellular organization and response to stress in vitro. Consistent with this, C. albicans cells lacking the SUR7 gene were more susceptible to attack by macrophages than cells with the gene and showed greatly reduced virulence in a mouse model of systemic infection. Thus, Sur7 and other MCC components represent novel targets for antifungal therapy. PMID- 22202233 TI - [The development of a novel cancer vaccine using Peptide vaccine for patients with advanced pancreatic cancer]. AB - Vascular endothelial growth factor receptor 2 (VEGFR2) is an essential factor in tumor angiogenesis and the growth of pancreatic cancer. In addition, it is overexpressed in tumor blood vessels, however, VEGFR2 is not expressed in normal vessels, which makes an attractive candidate as a molecular target for antiangiogenic cancer immunotherapy. Furthermore, the tumor cell-indirect immunotherapy targeting VEGFR2 is expected to overcome tumor immune escape. The phase I clinical trial using VEGFR2-169 peptide that successfully induced specific CTLs in cancer patients, combined with gemcitabine (GEM), was conducted for patients with advanced pancreatic cancer. VEGFR2-169 was subcutaneously injected weekly in a dose-escalation manner( doses of 0.5, 1.0, 2.0 mg/body, 6 patients/1 cohort). GEM was administered at a dose of 1,000 mg/m2 on days 1, 8 and 15 in a 28-day cycle. No dose limiting toxicity was observed. Specific CTLs reacting to VEGFR2-169 were induced in 11 (61%) of the 18 patients. Our protocol was safe and well-tolerated. VEGFR2-169 was immunogenic under the condition with GEM treatment. From an immunological point of view, the optimal dose might be 2.0 mg/body. A randomized phase II/III clinical trial started in January 2009 to demonstrate the clinical benefits of VEGFR2-169 for advanced pancreatic cancer patients. PMID- 22202234 TI - [Preliminary study of Peptide vaccine with UFT/LV as adjuvant setting for stage III colorectal cancer]. AB - cDNA microarray technology has been used to identify HLA-A24-restricted epitope peptides as potential targets for cancer vaccination in metastatic colorectal cancer patients. We conducted a clinical trial of two novel cancer-specific peptides( RNF43, TOMM34) with UFT/LV for the treatment of recurrent colorectal cancer. Among 23 patients, 21 patients had completed the protocol. All patients were well tolerated with no severe toxicities. The median survival time was 24.4 months. Furthermore, we investigated the relationship between CTL response to both antigens and overall survival. The best long-term survival was observed in the group with CTL responses against both antigens, followed by the group showing CTL responses against only RNF43 or TOMM34. The patients with no response had the lowest survival. Based on the results, we started a randomized trial of the current protocol, as adjuvant immunochemotherapy in following curative resection of Stage III colorectal cancer patients. PMID- 22202235 TI - [Randomized phase II trial to compare S-1 and S-1/PSK for advanced or recurrent gastric cancer-lessons from the results]. AB - BACKGROUND: This is a randomized phase II trial to evaluate non-inferiority of progression-free surviva(l PFS) by comparing S-1 and S-1/PSK for advanced or recurrent gastric cancer. Sample size was calculated to be 120. However, the trial was terminated because of slow accrual. This exploratory analysis was done by collecting the minimum data. RESULTS: Only 8 patients were enrolled. Four patients were randomly assigned to S-1 and the others to S-1/PSK. Performance status was 0 in all 8 patients. Median age was 64. Median overall survival was 13.7 months in all 8 patients, 8 . 9 months in S-1 group, and 13 . 7 months in S 1/PSK group. CONCLUSION: When considering PS 0 in 8 patients enrolled, an overall survival was comparable to that observed in S-1 group of other phase III trials. Standard chemotherapy for advanced gastric cancer was changed to S-1/CDDP by SPIRITS phase III trial which was presented just after this trial was initiated, which would be a major cause of slow accrual. When conducting phase III trial, we should carefully determine design and standard arm by considering on-going phase III trial. PMID- 22202236 TI - [In vitro culture of human dendritic cells by using a HydroCellTM]. AB - Cancer Immunotherapy using dendritic cells would be a feasible and useful tool for cancer treatment. However, no immunotherapy has been approved in Japan because of a lack of any randomized clinical studies. We are now trying to develop an automatic dendritic cell culture system in order to perform a large scale randomized clinical trial. In this study, we investigated the utility of a HydroCellTM for in vitro culture of human dendritic cells induced from peripheral blood monocytes. The dendritic cells grew one and a half times when they were cultured in a HydroCellTM. All the cells were floating and harvested easily without any enzymes. The cells expressed the CD80 and CD83 molecules on their surface and still had strong phagocytosis. This results demonstrated that a HydroCellTM was a useful tool for in vitro culture of dendritic cells. PMID- 22202237 TI - [Analysis of the mechanism of apoptosis induction by PSK]. AB - Previously, we reported that PSK induces apoptosis and growth inhibition in HL60 cells. In this study, we tried to clarify the mechanism of how PSK induces apoptosis. Because several reports suggested that apoptosis of HL60 cells is mediated by activation of p38MAPK, we examined whether p38MAPK is involved in PSK induced apoptosis. First, we found that PSK induced p38MAPK phosphorylation, which is considered as its activation. Next, we demonstrated that SB203580, inhibitor of p38MAPK, inhibited PSK-induced apoptosis. These results suggest that p38MAPK plays an important role in PSK-induced apoptosis. PMID- 22202238 TI - [The effect of immune-based therapy with cytotoxic T lymphocyte and molecular targeting therapy for HER2 in esophageal squamous cell carcinoma]. AB - Although esophageal squamous cell carcinoma (ESCC) patients have recently been treated with the combined modality therapy, the prognosis remains poor. For the development of new strategies in ESCC, we examined possibilities of the immune based therapy with cytotoxic T lymphocyte (CTL) and the molecular targeting therapy for HER2 against ESCC in this study. At first, we assessed HER2 and MHC class I expression by immunohistochemistry in ESCC patients and analyzed the correlation between them. Subsequently, the effect of molecular targeting therapy for HER2 was evaluated in a panel of ESCC cell lines. According to these results, we suggested that HER2 over-expressing ESCC patients (11.8%) are good candidates for the molecular targeting therapy for HER2 and HER2 negative/low-expressing ESCC patients (88.2%) for the immune-based therapy with CTL. Furthermore, the combination therapy of Herceptin and lapatinib is a new promising strategy for HER2 positive ESCC patients (29.4%). PMID- 22202239 TI - [S-1/krestin immunochemotherapy for patients with advanced gastric cancer]. AB - BACKGROUND: S-1 mono-therapy for advanced gastric cancer is hard to continue in some patients due to adverse events. We retrospectively examined the patients who received S-1/Krestin( PSK) immunochemotherapy for advanced gastric cancer. METHODS: During September 2006 to August 2008, 3 patients had received S-1/PSK. S 1 was given for 6-week schedule or 3-week schedule, and PSK was for everyday during the S-1 treatment. RESULTS: Cases 1 and 2 had lymph node metastases after surgery. Case 3 had peritoneal metastasis. The median treatment duration was 112 days. The median overall survival was 552 days. All patients stopped the treatment due to progression of disease. There were no patients who stopped the treatment due to adverse events. CONCLUSIONS: PSK may increase the compliance of S-1. PMID- 22202240 TI - [Hyperthemia enhances activated lymphocytes and molecular target therapy]. AB - We already informed that a combination therapy of hyperthermia and activated lymphocytes therapy reduced the tumor growth and lung metastasis synergistically in mice model. In this study we treated mice inoculated LLC tumors with hyperthermia or molecular target drugs (erlotinib 25 mg/kg/day and sorafenib 10 mg/kg/day). Both of hyperthermia and molecular target therapy reduced not only tumor growth but also lung metastasis. And a combination therapy of hyperthermia and molecular target therapy reduced more of the tumor growth and lung metastasis synergistically. The expression of HER2 and VEGFR was reduced by hyperthermia and molecular target drugs. Apoptosis was enhanced by hyperthermia and molecular target drugs synergistically. PMID- 22202241 TI - [Study of indoleamine 2,3-dioxygenase expression in patients of thyroid cancer]. AB - We evaluated a clinical significance of indoleamine 2,3-dioxygenase (IDO) in thyroid cancers. Operative specimens obtained from 20 patients with thyroid cancers were investigated by semi-quantitative RT-PCR with specific primers against IDO. The correlations among IDO expression, clinicopathologic factors and prognosis were studied. An expression of IDO was observed in 100% for both of the cancer specimens and the non-cancer specimens. The IDO expression of cancer specimens was significantly higher than the non-cancer specimens. The expression of IDO did not correlate to histologic classification, tumor size, lymphatic invasion, venous invasion and lymph nodes metastasis, but it was correlated to clinical stage. There was no correlation for survival rate after surgery between the high IDO level group and low IDO level group. The serum IDO levels of cancer patients were higher than that of a healthy volunteer measured by semi quantitative RT- PCR and HPLC. It is suggested that the expression of IDO in thyroid cancer patients may play critical role for immunosuppression of those patients. PMID- 22202242 TI - [Long-term follow-up study: indolemamine 2,3-dioxygenase activity during chemotherapy or hormone therapy in patients with breast cancer]. AB - We evaluated a significance of indoleamine 2,3-dioxygenase( IDO) in breast cancer patients during chemotherapy or hormone therapy every three months after the therapy. IDO activity can be measured by kynurenine( Kyn)/tryptophan (Trp) ratio. Trp and Kyn were measured by high performance liquid chromatography (HPLC). The correlations about Kyn/ Trp ratio between chemotherapy group and hormone therapy group in pre-chemotherapies or post-chemotherapies were studied. The Kyn/Trp ratio of chemotherapy group in post-FEC chemotherapy phase and in post-wPTX chemotherapy phase was higher than in pre-chemotherapy phase. And the Kyn/Trp ratio of chemotherapy group is significantly higher than hormone therapy in post FEC chemotherapy phase and in post-wPTX chemotherapy phase. There were no significant changes for the Trp/Kyn ratio of hormone therapy group in each phase. After the chemotherapy, there was no correlation between both groups. These results suggest that the hormone therapy may be less invasive for breast cancer patients than the chemotherapy. PMID- 22202243 TI - [Analysis of postoperative pulmonary complications after esophagectomy for esophageal cancer]. AB - We examined factors contributing to an onset of postoperative pulmonary complications following esophagectomy for esophagus cancer. One hundred thirty two cases of the resected esophageal cancer were studied. We considered the relationship between preoperative patient factors, operative factors, clinical stage factors and postoperative pulmonary complications. Postoperative pulmonary complication was observed in 27 cases (20%). The incidence of postoperative pulmonary complications was significantly higher in patients aged 70 and above and those with a preoperative serum albumin value of less than 4 .0 g/dL. Additionally, these two factors were correlated with an onset of postoperative pulmonary complications in multivariate analyses. A decrease of preoperative serum albumin value was reflecting the chronic poor nutritional condition. Moreover, it was possible that poor nutritional condition served as a prognostic factor of postoperative complications in relation to reduction of cellular immunity. The results indicated that there was a possibility of decreasing an onset of postoperative pulmonary complications using various nutrition managements before operations. PMID- 22202244 TI - [Our experience of the treatment with XELOX+/-Bevacizumab for unresectable advanced colorectal cancer]. AB - XELOX for unresectable advanced colorectal cancer has been approved in Japan. We report here an experience of the treatment with XELOX+/-bevacizumab in our department. We thought that the regimen has some merits in the patient's quality of life. Forty-five patients were treated with XELOX+/-bevacizumab. In evaluable 23 cases, partial response (PR) was obtained in 13 cases and stable disease (SD) and progressive disease (PD) were in 5 and 5 cases, so that the response rate and disease control rate were 56.5% and 78.2%, respectively. In the first-line administration of 19 cases, the response rate and disease control rate were respectively 80.0% and 90.0%. Hand-foot syndrome was observed in 13.2% (grade 2) and 6 .6% (grade 3). We think that it is important to control hand-foot syndrome for a continuation of XELOX+/-bevacizumab. PMID- 22202245 TI - [Hyperthermic immunotherapy was effective in 3 CR cases as the standard treatments had no effects or could not be enforced]. AB - We treated 1, 225 advanced or recurrent cancer patients with hyperthermia or immunotherapy (2005/7-2010/12). We had 174 (14.7%)clinical benefit cases (CR, PR and long SD) including 32 complete response (CR) cases. CASE 1: A 63-year-old male, rectal cancer, post operative recurrence with MRSA abscess located in abdomen. He was treated with dendritic cell therapy and hyperthermia. He showed a CR. CASE 2: A 62-year-old female, ovarian cancer, post operative recurrence. She was treated with standard chemotherapy, but she showed a PD. Then she was treated with dendritic cell therapy and hyperthermia. She showed a CR. CASE 3: A 46-year old female, lung cancer, postoperative recurrence. She was treated with standard chemotherapy and molecular target therapy, but she showed a PD. Then she was treated with dendritic cell therapy and hyperthermia. She showed a CR. PMID- 22202246 TI - [Peptide vaccine therapy with TLR-9 agonist for patients with esophageal squamous cell carcinoma]. AB - Patients with advanced carcinoma are thought to have an impaired immune surveillance system. Therefore, the potent helper action is required for the induction of an antitumor immune response in such patients. We evaluated the efficacy of CpG-ODN, which is TLR-9 agonist, as cancer vaccine adjuvant through in vitro experiments. We also conducted a phase I clinical trial for patients with advanced esophageal squamous cell carcinoma (ESCC) using peptide vaccine in combination with CpG-B. In vitro experiments showed that CpG-ODN caused various immune-modifications, suggesting an efficacy of CpG-ODN as peptide vaccine adjuvant. Moreover, the immune monitoring data in phase I clinical trial suggested that CpG-B augmented the generation of antigen-specific T cell responses and innate immunity. These data indicated that the vaccination with cancer-testis antigen derived peptide in combination with CpG-B may be useful as a new immunotherapy for patients with advanced ESCC. PMID- 22202247 TI - [Usefulness of endoscopic salvage treatment in a patient with local failure esophageal cancer after CRT]. AB - Chemoradiotherapy (CRT) is widely used as non-surgical treatment for esophageal cancer in recent years. CRT is very useful, but it allows about 40% relapse. Salvage surgery after CRT, long-term survival can be expected, but perioperative mortality is high. In contrast, EMR for local failure after definitive CRT has been reported showing a 5-year survival rate of 49. 1%. If it can safely control of local failure, then we thought it's useful for long-term survival. If the depth of invasion was to the submucosal layer of the local failure lesion, we performed an endoscopic resection. If vertical margins are positive pathologically, we have added a photodynamic therapy. In cases of difficult endoscopic resection, PDT alone was performed. We experienced a case of recurrent esophageal cancer after CRT was useful for local treatment with PDT and EMR. PMID- 22202248 TI - [Salvage esophagectomy after definitive chemoradiation therapy]. AB - Recently, the number of patients undergoing definitive chemoradiotherapy (CRT) for not only incurable esophageal carcinoma, but also resectable tumor has increased. Accordingly, salvage surgery has been conducted for residual or relapsed tumor after definitive CRT. We compared the surgical outcome of 7 cases undergoing salvage esophagectomy (SE) in our hospital, with those of planned CRT( in which 40 Gy external beam was radiated) followed by surgery (PS) and surgery alone (SA). Anastomotic leakage rate of SE (43%) was significantly higher than that of PS (3%) and SA (7%). Respiratory complication rate of SE was higher than that of PS and SA, but not significantly. Hospital mortality rate of SE was 28% and that rate increased in proportion to radiated dose. Salvage surgery should be performed for patients in which complete resection of esophageal cancer could be achieved because of its high rate of mortality and morbidity. PMID- 22202249 TI - [A case of S-1/CDDP chemotherapy for inoperable advanced gastric cancer which led to gastrectomy with histological complete response]. AB - As the treatment for inoperable advanced gastric cancer, S-1/CDDP combination therapy (SP chemotherapy) has become a standard treatment. In our hospital, a second course of chemotherapy was performed on an outpatient basis in order to improve a traditional QOL. In this case, it showed remarkable effects in 15 months after starting chemotherapy. Then gastrectomy was performed. Histological findings of the resected specimens confirmed pCR in all tumors. We report on progress of this case and explain about the ingenuity of SP chemotherapy. PMID- 22202250 TI - [A case of advanced gastric cancer with splenic vein thrombus successfully treated with S-1 plus CPT-11 neoadjuvant chemotherapy]. AB - A 63-year-old male admitted for hematemesis was diagnosed with type 3 advanced gastric cancer located in the upper and middle body of the stomach in an endoscopic examination. Abdominal computed tomography demonstrated lymph nodes metastasis and a splenic vein thrombus. Since curative resection was not deemed possible, we performed neoadjuvant chemotherapy using S-1 (120 mg, day 1-21) plus CPT-11 (135 mg, day 1 and 15) except for down-staging. After 4 courses of chemotherapy, gastric tumor and metastatic lymph nodes were reduced in size and the splenic vein thrombus was disappeared, and then total gastrectomy was performed (tub2, T2 (MP) N0 H0 M0 P0 CY0, Stage IB). S-1 medication was applied as adjuvant chemotherapy. Forty months passed from the operation, the patient remains alive with no signs of relapse. PMID- 22202251 TI - [A long-term survival case of liver metastases from gastric cancer treated with radiofrequency ablation and radiotherapy]. AB - A 64-year-old man was diagnosed as gastric cancer (cT4N1M0, Stage IIIB). Left upper abdominal evisceration was performed in July 2008. CT scan revealed liver metastases in the segments 6 and 8 about 4-month after the surgery. Liver metastases increased during postoperative adjuvant chemotherapy. We treated the metastases with local therapy. He received radiotherapy (total of 60 Gy) for a liver metastasis in the segment 8 in November 2009. He received radiotherapy (total of 50 Gy) for a liver metastasis in the segment 6 in November 2010 after a total of 3-radiofrequency ablation (RFA) was performed. Partial response was obtained. We have experienced a successful case of liver metastases from gastric cancer treated with RFA and radiotherapy. PMID- 22202252 TI - [Laparoscopic partial gastrectomy for gastric submucosal tumor-indications and limitations of single-incision laparoscopic surgery]. AB - Because gastric submucosal tumors can be treated by local resection without lymph node dissection, laparoscopic local resection is widely used to manage relatively small tumors less than 5 cm in diameter. On the other hand, single-incision laparoscopic surgery (SILS) to perform laparoscopic cholecystectomy was feasible. SILS requires only a single incision in the umbilical region; it has better cosmetic outcomes than conventional laparoscopic surgery. The relative difficulty and ease of local gastric resection depends to a large part on tumor location and morphologic characteristics. Extraluminal submucosal tumor of the stomach can be locally resected by SILS using an automated suturing device regardless of tumor location. Intraluminal tumor located in the greater curvature of the gastric body can be treated by SILS, whereas intraluminal lesions located in the lesser curvature and near the gastric cardia or pylorus are difficult to manage by SILS. Laparoscopic and endoscopic cooperative surgery (LECS) is useful for resecting an appropriate amount of tissue at any site. In patients with lesions located near the gastric cardia or pylorus, closure with an automatic suture device may be difficult. Such patients should be switched to reduced-port surgery with a coaxial port, and hand-sewn closure is useful. PMID- 22202253 TI - [A case of failed laparoscopic and endoscopic cooperative surgery (LECS) for gastrointestinal stromal tumor of the stomach]. AB - Recently, laparoscopic and endoscopic cooperative surgery (LECS) for submucosal gastric tumor has been developed to avoid an excessive surgical resection of gastric wall, which causes a deformity of the stomach and reduced oral intake. We report here a case of failed LECS for gastric submucosal tumor, and discuss the cause of failure. An 89-year-old woman underwent LECS for an intraluminal type submucosal tumor involving the upper and posterior gastric wall. Specifically, two sites of the gastric wall were fixed with subumbilical and left latero abdominal wall approaches and two trocars with balloons were introduced into the stomach. Endoscopic submucosal resection was performed circumferentially around the tumor. Then, we tried to lift the tumor using an Endo-loop(r). However, the amount of lifting was not sufficient for a safe surgical resection because the surgical field was extremely narrow. Therefore, we converted LECS to open surgery. In conclusion, it is important to consider clinical factors such as body size, tumor size and tumor location when planning LECS. Particularly, the intraabdominal suturing technique instead of using a linear stapler is desirable for a tumor involving the posterior wall. PMID- 22202254 TI - [Novel treatment strategy using Trafermin(r) consisting of bFGF for intractable pancreatic fistula following gastrectomy for gastric cancer-a case report with literature reviews]. AB - Despite recent perioperative technological advances in gastric cancer, intractable pancreatic fistula is still a major critical complication following gastrectomy and should be specifically targeted in the effort to improve postoperative outcomes. We preliminary report here a successfully treated case with intractable pancreatic fistula using Trafermin(r) consisting of basic fibroblast growth factor (bFGF). A 67-year-old man underwent laparoscopic proximal gastrectomy with radical lymphadenectomy for early proximal gastric cancer (pT1bN0M0). After surgery, pancreatic fistula was occurred. Pancreatic fistula persisted for three months despite of surgical and several conservative treatments. After obtaining informed consent, we started to inject 50 MUg/day of Trafermin(r) through a drainage tube into the dehiscence of pancreas. Consequently, pancreatic fistula was successfully closed within three weeks. Our novel treatment technique is simple, rapid and not costly. If informed consent was obtained from patients with low risk of recurrences, this technique should be recommended as one of the treatment choices for intractable pancreatic fistula following curative gastrectomy for gastric cancer. PMID- 22202255 TI - [Assessment of five-metallic stent placement cases for malignant duodenal stenosis]. AB - We report five-metallic stent placement cases for malignant duodenal stenosis. Two of them received a placement of Ultraflex by over-the-wire (OTW) procedure, and the other three received a placement of WallFlex by through-the-scope (TTS) procedure. We assessed the baseline characteristic of the patient, procedural time and food intake after the stent placement for both OTW and TIS groups. OTW GROUP CASE 1: A 93-year-old woman with cancer of the ampulla of Vater, 60 min. in procedure time and low-residue diet after stent replacement. OTW GROUP CASE 2: A 76-year-old man with pancreatic cancer, 90 min. in procedure time and low-residue diet after stent replacement. TTS GROUP CASE 1: A 56-year-old man with recurrent postoperative bile duct cancer and gallbladder cancer, 16 min. in procedure time and full diet after stent replacement. TTS group case 2: A 79-year-old woman with pancreatic cancer, 40 min. in procedure time and liquids only after stent placement. TTS GROUP CASE 3: A 64-year-old woman with pancreatic cancer, 17 min. in procedure time and liquids only after stent placement. In comparison with OTW, TTS placement was much easier and it took a shorter procedural time. However, we consider that a selection of suitable stents and an assessment of the location for good food intake after stent placement are more important. PMID- 22202256 TI - [Treatment of early rectal carcinoma by transanal resection-a case report]. AB - A 55-year-old female was admitted to Ogikubo Hospital for severe anemia and prolapse of a tumor from the anus, which had developed over 2 years. Rectal examination revealed a giant soft tumor. Endoscopic study revealed a lobulated giant tumor with a granular surface. Gastrografin-enema study showed a giant tumor, which was full of the rectum. Pathological examination showed a well differentiated carcinoma. No other prominent metastatic lesions were demonstrated. The transanal diagnostic resection of rectal cancer was performed in October 2010. This correct diagnosis showed both well differentiated adenocarcinoma and intramucosal carcinoma. We therefore recommend that a tumor of the lower rectum should undergo a diagnostic excision by means of either a local excision, ESD or TEM. PMID- 22202257 TI - [A case of low anterior resection combined with resection of the prostate seminal vesicle urethra for douglas' pouch metastasis of the colon cancer]. AB - A-71-year-old man with sigmoid colon cancer underwent sigmoidectomy in 2004. Ascites cytology was positive. He had a postoperative chemotherapy, but cancer recurred on the Douglas' pouch in the first year after the surgery. After chemoradiation, he underwent a low anterior resection with combined resection of the prostate seminal vesicle urethra in 2005. Four years after the recurrence, metastasis of the right lung S9 occurred, and he underwent right lower lobectomy. One year later, metastasis of the left lung S6 occurred, he underwent a partial resection of S6. Later a local recurrence has not been observed. Among the colon cancer recurrence, we think the surgery was effective for local recurrence disease with adequate observation. PMID- 22202258 TI - [A case of mucinous cystadenocarcinoma of the appendix with abdominal wall abscess successfully treated by percutaneous drainage and systemic chemotherapy-a case report]. AB - A 76-year-old woman was diagnosed of mucinous cystadenocarcinoma of the appendix. Since there was wide direct invasion into the right psoas muscle, she was judged as inoperable although she had no bowel obstruction. She was received FOLFIRI and bevacizumab treatment. After the first cycle, the tumor progressed rapidly and formed the abdominal wall abscess at the right groin. Since she had a fever and pain at the right groin and the abscess reached the hypodermic, we put a drainage tube into the abscess. The tube was placed, which made her symptoms improved markedly. We have been continuing with FOLFIRI treatment and drainage for 10 months without progressive disease. We report a rare case of the conservative therapy of mucinous cystadenocarcinoma of appendix with abdominal wall abscess. PMID- 22202259 TI - [Pulmonary arterial infusion therapy for lung metastasis of colorectal cancer]. AB - We have developed a pulmonary arterial infusion therapy for lung metastasis of colorectal cancer. Catheterization into pulmonary artery followed by occlusion with ballooning enabled the stasis of blood flow in the unilateral lung for 30 minutes. CDDP was infused via catheter to occluded pulmonary artery. Although no serious adverse events occurred in 5 cases, a tumor reduction in size was not observed. Loco-regional therapy for lung metastasis of colorectal cancer is limited because of recent progress of systemic therapy. However, a development of the procedure of pulmonary arterial infusion may enable a future success of local therapy for lung metastasis of colorectal cancer with a new drug, which is effective in such a short time disposure to tumor as 30 minutes. PMID- 22202260 TI - [Three cases of giant rectal gastrointestinal stromal tumor]. AB - The frequency of rectal gastrointestinal stromal tumor (GIST) is relatively low. We have experienced three cases of giant rectal GIST. Case 1 was treated with sunitinib after imatinib failed by Stevens-Johnson syndrome as neoadjuvant therapy. Case 2 was treated with imatinib as neoadjuvant therapy. These neoadjuvant therapies had no effect on tumor size. All patients underwent an abdominoperineal resection. The mean major axis was 11 .7 cm. Immnohistochemical staining showed that CD34 and KIT were positive. The term of follow-up is short, but no recurrences have been found in all cases. It has been reported that imatinib as neoadjuvant therapy is useful for radical resection in cases of giant rectal GIST. Furthermore, neoadjuvant therapy seems to be one of the treatment options for locally advanced rectal GIST. However, in cases of GIST patients not responding to imatinib, we should perform a surgical resection immediately. PMID- 22202261 TI - Treatment results of peritonectomy combined with perioperative chemotherapy for colorectal cancer-patients with peritoneal carcinomatosis. AB - Operation results of 81 colorecatal cancer-patients with peritoneal carcinomatosis (PC) treated with peritonectomy plus perioperative chemotherapy are reported. The patients who had the following evidences are considered to be eligible for peritonectomy: 1) No evidence of N3 lymph node involvement, 2) No evidence of hematogenous metastasis, 3) No progressive disease after preoperative chemotherapy, 4) No severe co-morbidities or no poor general condition. Complete cytoreduction resection is aimed for removing all macroscopic tumors by peritonectomy using electrosurgical techniques. The completeness of cytoreduction (CC scores) after peritonectomy is classified into the following 4 criteria: CC-0 no peritoneal seeding was exposed during the complete exploration, CC-1-residual tumor nodules are less than 2.5 mm in diameter, CC-2-nodules are between 2 .5 mm and 25 mm in diameter, CC-3-nodules are greater than 25 mm in diameter, CC-2 and CC-3 are regarded as incomplete cytoreduction. Operation time and blood loss were 237 +/- 124 min. (799-90 min) and 1,598 +/- 1,411 mL (6,500-20 mL), respectively. Postoperative complications developed in 37( 46%) patients. The patients received CC-0/ -1 resection survived significantly longer than those of CC-2/ -3 group. The patients with PCI <= 10 survived significantly longer than those with PCI>= 11. CC and PCI scores are the independent prognostic factors. The relative risk for death of CC-2/-3 group was 4.6-fold higher than that of CC-0/ -1 group. Accordingly, peritonectomy is indicated for patients with PCI score<= 10. PMID- 22202262 TI - [Two cases of curative resection for locally recurrent rectal cancer with high level sacrectomy after preoperative chemoradiation therapy (CRT)]. AB - We herein report two cases of locally recurrent rectal cancer that were successfully treated by surgical resection of shrunken tumor by pre-operative CRT. Although one case had a relapse in 7 months after the operation, the prognostic difference between two cases was discussed. CASE 1: A 54-year-old male had a pre-sacral mass (54 mm) six months after an anterior resection for advanced rectal cancer. We planned a surgical resection after CRT (radiation 50 Gy, CPT 11, UFT and LV). The tumor had a good response (33 mm) allowing a dissection area between sacral bone and posterior margin. Low anterior resections with sacral bone resection (below S3) were done to prevent S1 nerve roots injury and spinal fluid leakage. Macroscopically, a surgical margin was well secured. The patient is alive for 84 months after the surgery without an evidence of recurrence. CASE 2: A 66-year-old man had an anal bleeding. He underwent Hartmann's maneuver for advanced rectal cancer. MRI revealed a recurrent tumor (66 mm) occupying up to the 1st sacral bone. CRT was carried out. After a tumor response was (35 mm) obtained, and total pelvic exenteration with sacral bone resection below S3 was carried out, achieving R0 operation. However, He had relapsed at 7 months after the operation. PMID- 22202263 TI - [Radiofrequency ablation therapy for a pelvic recurrence from rectal cancer after radiotherapy in patient on maintenance hemodialysis-a case report]. AB - A 75-year-old man, who was on maintenance hemodialysis, underwent a radiotherapy for locally recurrence of rectal cancer. A pain palliation was achieved and serum tumor markers were reduced. However, after six months, a tumor re- growth was detected and sacral pain was increased. Then, a radiofrequency ablation (RFA) was performed repeatedly as a palliative therapy and pain palliation was achieved. RFA is a safe and effective palliative therapy for patients of poor-risk, such as a terminal stage or hemodialysis patient. Furthermore, it is able to perform repeatedly when the response was not satisfactory. However, a Cool-tip electrode could not to be placed because tumors were hardened by radiotherapy and a repeat of RFA. Then a development of novel Cool-tip electrode may be needed. PMID- 22202264 TI - Extraperitoneal presentation of pseudomyxoma peritonei as retroperitoneal invasion with skin fistula-a case report. AB - Pseudomyxoma peritonei (PMP) is characterized by mucinous ascites and implants throughout the peritoneal cavity. The tumor rarely involves retroperitoneum. We present a patient of PMP with retroperitoneal presentation and spontaneous development of a skin fistula. There had been only 7 such cases reported. PMID- 22202265 TI - [Treatment strategy of papillary thyroid carcinoma for the unmarried woman]. AB - We report an unmarried woman with papillary thyroid cancer. The patient was a 20 year-old woman who had neck tumor. The ultrasonography (US), CT, and aspiration biopsy cytology (ABC) were performed. The diagnosis of the tumor was papillary carcinoma of thyroid. The total thyroidectomy plus lymph nodes dissection (D2a) were performed. Two years after the first operation, we recognized lymph nodes swelling at her right neck. The US guided ABC was performed. The diagnosis was the metastasis of lymph node from thyroid cancer. We performed lymph nodes dissection again. Three years after the first operation, we detected the swelleing of lymph nodes again at her right neck. We performed lymph nodes dissection again. We recommended a therapeutic use of iodine radioisotopes. However, she rejected the therapy because she strongly wanted to be pregnant. Generally speaking, it is difficult to determine the therapeutic use of iodine radioisotopes for unmarried women. After seven years from the first operation, she delivered a baby girl. We plan to use of iodine radioisotopes for adjuvant therapy when she delivers her 2nd baby. This case suggested that a treatment strategy for unmarried thyroid cancer patients should be made thoughtfully with care. PMID- 22202266 TI - [The prognosis of skin recurrence in breast carcinoma patients]. AB - In this study, we evaluated the clinical presentation of patients with skin recurrence in breast cancer patients. We treated 1, 228 cases of breast cancer patients during 2004 to 2010. The skin recurrences were recognized in 11 patients. The duration of showing skin recurrence was 1 .8 years. The muscle preserving radical mastectomy was performed in all cases. And surgical margins of all cases were negative. All cases were not performed radiation therapy. Nine cases were received chemotherapy as adjuvant therapy. Seven cases received endocrine therapy. After recurrence, they were treated by multi- disciplinary therapy. The surgical resection was useful to judge the effect of other therapies. The observation period was 2. 2 years. Two patients died, but 8 other patients are still alive. PMID- 22202267 TI - [Local control of advanced breast cancer with mohs'paste]. AB - We report two cases of primary advanced breast cancer that was locally controlled by using Mohs'paste. CASE 1: A 70- year-old woman was suffering massive exudates and offensive smell from her right giant breast tumor. Histopathological examination showed an invasive ductal carcinoma. However, she didn't have distant metastases. The patient received chemotherapy and the breast tumor has been fixed using Mohs'paste, and dissected. The giant tumor became flat and dry, so we could perform a radical operation. Then, she had contra-lateral axillary lymph node metastases. We performed a resection of left axillary lymph node and radiation therapy. After two years, we have not found a new lesion. CASE 2: A 54-year- old woman with right local advanced breast cancer discharged massive exudates and oozed blood. Histopathologically, she had an invasive ductal carcinoma. Moreover, she had lung and contra-lateral axillary lymph node metastases. She received chemotherapy and the breast tumor has been fixed using Mohs'paste, and dissected. The bleeding and exudates stopped almost completely, and the breast tumor became flat and dry. Both patients had experienced a mild pain, but their QOL improved remarkably. It is suggested that the patient with local advanced breast cancer may be controlled by using Mohs' paste. PMID- 22202268 TI - [Surgical resection for elderly patient with skin invasion of breast cancer]. AB - We report a locally advanced elderly breast carcinoma with skin invasion. The patient was a 96-year-old woman who had a breast lump. The palpable tumor was 3 .5 cm in diameter. Ultrasonography revealed a low echoic mass. A core needle biopsy for the breast tumor led to a diagnosis of an invasive ductal carcinoma positive for estrogen receptor and progesteron receptor, and negative for HER2/neu protein expression. She underwent a tumorectomy including the cancer invasive skin by local anesthesia. Because her respiratory function was unbearable to perform a muscle-preserving mastectomy with general anesthesia. The surgical margins of the resected specimen were negative. The clinicopathological stage, according to the UICC-pTNM classification, was Stage III C (T4b, N0, M0). After the operation, she was administered aromatase inhibitor. The patient has been well and remained disease-free during a follow-up period of 3 years. The surgical excision with local anesthesia was useful for locally advanced super senior breast cancer patients who were impossible to perform general anesthesia by various kinds of factors. PMID- 22202269 TI - [A case of non-palpating breast cancer with huge lymph node metastasis]. AB - We report a case of non-palpating breast cancer with huge lymph node metastasis. The patient was a 58-year-old woman who had a huge tumor at her right armpit. The tumor was 4 cm in diameter. Aspiration biopsy cytology for the tumor was performed. The diagnosis is Class V. Mammography showed an ill-defined mass at her right breast. Ultrasonography revealed a low echoic mass at the C area of her right breast. A core needle biopsy for the breast tumor led to a diagnosis of an invasive ductal carcinoma positive for estrogen receptor and progesterone receptor, and negative for HER2/neu protein expression. She received 4 cycles of CEF (E: 60 mg/tri-weekly) plus 12 cycles of paclitaxe (l80 mg/weekly). After chemotherapy, she received muscle preserving mastectomy plus axillary lymph nodes dissection. In histopathology, there were no carcinoma cells in resected breast tissue and resected lymph nodes. Therefore, the effect of chemotherapy was diagnosed as a pathological complete response. After operation, she was administered aromatase inhibitor. The patient has been well and remained disease free during a follow-up period of 6 years. PMID- 22202270 TI - [Lumpectomy and sentinel lymph node navigation surgery for breast cancer under local anesthesia]. AB - We studied and analyzed therapeutic outcomes of a radical surgery under local anesthesia for breast cancer in our department. Subjects were 42 patients with breast cancer whose diagnoses were definitely made before surgery. Indications were: localized DCIS diagnosed preoperatively; invasive carcinoma less than 3 cm in tumor diameter on ultrasound; and clinically tumors with negative axillary lymph nodes. Operative procedures included lumpectomy associated with sentinel lymph node navigation biopsy. We could perform the operation under local anesthesia in all of the 42 patients, and were not demanded to shift from local to general anesthesia. Two patients had sentinel lymph nodes metastasis. Surgical stumps were positive in 14 patients( 33.3%). None of serious complications were encountered. Today's radical operation under local anesthesia for breast cancer is a useful procedure as minimally invasive surgery as for the indications employed in this study. PMID- 22202271 TI - [A case of primary malignant lymphoma of the spleen which was difficult to be diagnosed]. AB - A 55-year-old woman who had a chief complaint of left abdominal and back pain. She was diagnosed with pancreatic cancer associated with splenic metastasis (Stage IVb) by CT and MRI study and was treated with chemotherapy of gemcitabine (GEM). Chemotherapy was discontinued due to adverse event (grade 3). CT study at this point reveals the effectiveness of GEM. The tumor was localized, and an operation was performed. The tumor was diagnosed as primary malignant lymphoma (diffuse large B-cell lymphoma) of the spleen. The splentic tumor is extremely rare, so a surgical treatment was indicated for making a correct diagnosis. This was an interesting case of malignant lymphoma that GEM revealed a cytoreductive result. PMID- 22202272 TI - [Intraoperative localization of recurrent pancreatic insulinoma-a resected case of the metastatic lesions in the residual pancreas and the lymph node]. AB - We describe herein a 39-year-old woman with tumor recurrence in the residual pancreas and metastasis to the lymph node about 5 years after an eneclation for insulinoma in the body of the pancreas. A certain day in the morning in June 2002, she was immediately admitted to our hospital due to impairment of consciousness based hypoglycemia. On diagnostic imaging including an arterial stimulation venous sampling, localization of the recurrent lesions was not identified. In October 2002, we underwent laparotomy for the purpose of localization of the recurrent lesions and treatment. During the operation, peripheral blood glucose level, portal blood glucose level and portal insulin level were measured periodically. The mobilization started from the tail of the pancreas. Blood glucose levels were gradually elevated during the mobilization. The pancreas was mobilized to the right edge of the portal vein and was resected. Histopathological diagnosis was recurrent insulinoma in a peripancreatic lymph node and intra-pancreatic subcapsular tumor embolization. Postoperative course was uneventful. More than 8 years after surgery, she is doing well without signs of recurrence. PMID- 22202273 TI - [A case of refractory pancreatic fistula following pancreaticoduodenectomy treated successfully by intestinal decompression catheter insertion to jejunum under local anesthesia]. AB - The case was an 80-year-old woman with inferior bile duct cancer. The patient had undergone subtotal stomach-preserving pancreaticoduodenectomy with end-to-side pancreaticojejunostomy. Postoperative pancreatic fistula was observed in a short period and was treated by somatostatin analog administration and abscess drainage. Despite these conservative therapies, pancreatic fistula resulted in abdominal bleeding from the branch of dorsal pancreatic artery, which stopped by emergent transcatheter arterial embolization. Because pancreatic fistula had become refractory, the intestinal decompression catheter insertion was performed under local anesthesia to the jejunum located directly below abdominal wall. After this surgery, pancreatic fistula was resolved over a few weeks. This technique could be safely performed and avoided the injury of drainage fistula, and was considered to be an option for treating refractory pancreatic fistula. PMID- 22202274 TI - [A case report of intrahepatic cholangiocarcinoma diagnosed as lung cancer with liver metastasis treated with radiofrequency ablation]. AB - In December 2008, a 43-year-old male who had been pointed out a nodular shadow in the right upper field on a chest radiography was admitted to hospital. A 35 mm mass infiltrating to superior vena cava in the right upper lobe of the lung, and 32 mm mass in the liver at S7 were detected by CT. Pathological diagnosis of the liver tumor was adenocarcinoma. Under the diagnosis of lung carcinoma and liver metastasis, systemic chemotherapy was started from January 2009. Radiofrequency ablation (RFA) therapy was added for liver S7 mass in February, and radiation therapy was performed for lung mass in December. The lung lesion has markedly reduced, but the liver lesion recurred in October 2009, which continued to grow up to 80 mm until August 2010. He presented to our hospital with the diagnosis of liver metastasis of controlled primary lung cancer. In October, we performed right hepatectomy with diaphragma and right lung resection. The pathological diagnosis was intrahepatic cholangiocarcinoma. Multiple recurrences in remnant liver, lung and peritoneal metastasis were detected in January 2011. For intrahepatic cholangiocarcinoma, hepatectomy is the only established treatment, and RFA treatment remains controversial. Clinical diagnosis of multiple cancers should be decided with caution. PMID- 22202275 TI - [A case of huge liver metastases from the colon cancer suffered from abdominal pain (an amount of LDH was beyond 4,000 IU/L)]. AB - We report a case suffered from an abdominal pain with huge hepatic metastases from the colon cancer. After laparoscopic partial colectomy with a three-time treatment of high dose hepatic arterial infusion by 5-FU (HDHAI), the tumor was decreased in size. Unfortunately she had an infectious pseudoaneurysm at the site of puncture. She was given with a drainage and F-F bypass. She has at last successfully done hepatectomy, radiofrequency ablation (RFA), and insertion of catheter at the site of common hepatic artery from gastroepiploic artery. Then she received a half HDHAI and systemic chemotherapy of CPT-11. However, residual liver metastases happened twice, but we could have them operated all (9.3 months after and 20.5 months after from first operation). If the liver metastases were the most threatening factor of life, HDHAI and repeated hepatectomy maybe effective for prolongation of life. PMID- 22202276 TI - [A case of successful surgical resection after repeated transcatheter arterial chemoembolization for far advanced multiple hepatocellular carcinomas in both lobes associated with Vp2 portal vein tumor thrombus]. AB - Treatments for hepatocellular carcinoma (HCC) include surgical resection, transcatheter arteral chemoembolization (TACE), percutaneous local therapy and systemic chemotherapy. However, it is difficult to perform a curative treatment for patients with far advanced multiple hepatocellular carcinomas. Here we report a case of successful surgical resection after repeated TACE for far advanced multiple hepatocellular carcinomas in both lobes associated with Vp2 portal vein tumor thrombus. A 54-year-old male who had multiple HCC lesions in lateral, median and right lobes with portal vein tumor thrombus was admitted to our hospital. Three attempts of TACE resulted in a successful control of the tumors in the right lobe. Left hepatic lobectomy was therefore performed, and a relapse free survival was obtained for over 5 years after surgery. PMID- 22202277 TI - [A case of ruptured gastrointestinal stromal tumor of the duodenum with intraabdominal bleeding]. AB - We report a case of ruptured gastrointestinal stromal tumor (GIST) of the duodenum with intraabdominal bleeding. A 50-year-old man was admitted to our hospital because of sudden epigastralgia. Enhanced computed tomography (CT) showed a tumor measuring about 14 cm in diameter on the ventral side of the right kidney and intrapelvic fluid collection. We performed an emergency operation. At laparotomy, the tumor was originated from the 2nd portion of the duodenum without attaching to the retroperitoneum. We resected the tumor radically. Histopathologically, the tumor arose from the proper muscle layer of the duodenum, and was positive for c-kit and negative for CD34 and alpha-SMA on immunostaining. Then the tumor was diagnosed as GIST of the duodenum. Adjuvant therapy by imatinib 400 mg/day is now being done because this case is thought to be clinically malignant GIST. PMID- 22202279 TI - [A case report of long-term survival in the patient with anorectal malignant melanoma]. AB - Malignant melanoma of the anorectal region is rare, and the prognosis is considered to be poor. We present a case of long-term survival in a 56-year-old patient with primary malignant melanoma in the anorectal area, who complained of anal bleeding. Barium enema showed an elevated lesion in the anorectal region. Colonoscopy revealed a 3 cm sessile tumor with focal pigmentation, and a satellite nodule, 1 cm in diameter. Based on diagnosis of malignant melanoma by biopsy, abdominoperineal resection with lateral node dissection was performed. Pathologically the tumor remained in the mucosa, and no lymph node metastasis was found. This patient refused any adjuvant chemotherapy after the operation, and remains well without any sign of recurrence for seven years. PMID- 22202278 TI - [A case report of multiple adenocarcinoma in small intestine after total gastrectomy by Roux-en-Y re-construction]. AB - This is a very rare case report of multiple small intestine cancer in jejunal loop of Roux-en-Y re-construction, duodenum and jejunum. A 51-year-old man had undergone total gastrectomy by Roux-en-Y re-construction for Stage III B gastric cancer in 1997. In 2008, he underwent partial jejunectomy and partial ilectomy for ileus due to small intestine adenocarcinoma, located at the jejunum 50 cm distal from Roux-en-Y anastomotic region and at the ileum 20 cm proximal from the ileocecal region. PET/CT suspected a recurrence and peritoneal dissemination, so he had undergone S-1/docetaxel treatment since 2009. In 2010, he was diagnosed as obstructive jaundice due to duodenal tumor revealed by CT. Furthermore, enteroscopy revealed duodenal advanced cancer, type 2 advanced cancer and five polyps in jejunal loop, type 2 advanced cancer and type II a early cancer in jejunum. He could not undergo both pancreatoduodenectomy and choledochojejunostomy because of the invasion to hepatoduodenal ligament. He underwent partial jejunectomy for the advanced cancer in jejunal loop 10 cm proximal form Roux-en-Y anastomotic region and in jejunum 50 cm distal from Roux en-Y anastomotic region for prevention of ileus. PMID- 22202280 TI - [Preoperative chemoradiation (XELOX/RT) therapy for anal canal adenocarcinoma with the metastasis to inguinal lymph node]. AB - For a woman with poorly-differentiated anal canal adenocarcinoma in acknowledgment of metastasis to right inguinal lymph node, we gave radiotherapy combined with capecitabine as chemotherapy. Then the next two months, we performed XELOX therapy. Subsequently, we performed laparoscopic rectal amputation+D1 dissection+right groin lymph node dissection. The effect of preoperative chemoradiotherapy and pathological examination of the main tumor was Grade 2. And the right inguinal lymph node showed only a mucous persistence. Capecitabine was given as an adjuvant postoperative treatment and did not show a recurrence for five months after the operation. For a treatment for anal canal adenocarcinoma in acknowledgment of metastasis to inguinal lymph node, preoperative chemoradiotherapy may be effective. PMID- 22202281 TI - [A case of mucinous adenocarcinoma of descending colon with abscess formation and solitary metastasis at right side of the abdomen]. AB - A 59-year-old man realized a left lower abdominal pain and palpable mass about a month ago. He was admitted to our hospital because of the pain and high fever. Blood examinations revealed high levels of white blood cell count and CRP. Ultrasonography showed a wall thickness of the descending colon and 7 cm cystic mass with air around. Moreover, a 6 cm cystic mass was found an outside of the ascending colon. We first treated with antibiotics under the diagnosis of abscesses because of perforation of diverticulum. Colonoscopy revealed an obstructing tumor in descending colon and biopsy specimens of the tumor showed adenocarcinoma. The preoperative diagnosis of the right side tumor was unclear. We performed a partial resection of the descending colon, and the tumor outside of the ascending colon was resected. The pathological diagnosis of the tumors was both mucinous carcinoma of the colon. Mucinous carcinoma tends to be more found in the right side of the colon than in the left side. The rate of lymph node metastasis and dissemination is higher than that in differentiated adenocarcinoma. We report a rare case of mucinous carcinoma originated from the left side of the colon with a solitary dissemination in opposite side of the abdomen. PMID- 22202282 TI - [A case whose lung metastasis was detected and resected eleven years after resection of primary colon cancer]. AB - In July 1999, a 79-year-old man underwent sigmoidectomy and D3 lymphadectomy for sigmoid colon cancer (ss, n(-), stage II, cur A). In September 2000, hepatectomy of right lobe and cholecystectomy were performed for his liver metastasis. Every three to six months follow-up had been kept since adjuvant chemotherapy (200 mg/day of 5-FU per os for two years) completed. Eleven years and two months after sigmoidectomy (in September 2010), a chest X-ray examination detected a small nodule in upper area of his right lung, which was diagnosed as either primary lung cancer or metastatic lung tumor followed by chest CT scan and PET-CT examination. In November 2010, laparoscopy-assisted partial resection of his right lung was performed. Histochemical examination of the resected lung tumor resulted cytokeratin 7(-), cytokeratin 20(+) and TTF-1(-), confirming its final diagnosis as lung metastasis from sigmoid colon cancer. He has been alive for six months without any recurrence since resection of his lung metastasis. It was a very rare case to have more than ten-year interval between colon cancer resection and detection of its lung metastasis. However, when we diagnosed the patient with lung tumor, who had undergone a colorectal resection, we should consider if he had a lung metastasis from colorectal cancer. PMID- 22202283 TI - [A case of recurrent rectal cancer with paraaortic lymph node metastasis treated by FOLFIRI therapy leading to complete response]. AB - A 56-year-old woman was referred to our hospital because of melena. After examinations she was diagnosed with rectal cancer. Anterior resection was performed and the final diagnosis was Stage IIIa. She was treated with adjuvant chemotherapy consisting of UFT/Uzel for one year, followed by UFT alone for one year. Two years after the surgery, abdominal CT suggested solitary paraaortic lymph node metastasis. As the patient denied a surgical treatment, mFOLFOX6 chemotherapy was induced. However, the patient developed a grade 3 allergic side effect, FOLFIRI was administered. Six months after the chemotherapy was started, the paraaortic lymph node metastasis had disappeared. After 50 courses, the case was considered to have achieved a clinical CR which has been maintained now. FOLFIRI was effective for recurrent rectal cancer with paraaortic LN metastasis. PMID- 22202284 TI - Evaluation of preoperative computed tomography in estimating peritoneal cancer index in peritoneal carcinomatosis. AB - PURPOSE: To evaluate the utility of CT of peritoneal carcinomatosis (PC) by comparing preoperative radiological and intraoperative peritoneal cancer index (PCI) scores. MATERIAL AND METHOD: This study collected 76 patients of PC from different disease origins. The sensitivity, specificity and accuracy were calculated in each of the abdominopelvic region, and by tumor histologic type. RESULT: An overall sensitivity of CT was 69%. The detection rate was highest in appendix and lowest in stomach group( 84% and 47%, respectively) by the origin of primary disease. There was a lower detection rate (59% vs 79%, p=0.001), and a higher underestimation rate (29% vs 21%, p<0.05) of small bowel lesion compared with overall abdomino-pelvic region. CT predicted an individual regional PCI score accurately in 65%, underestimated in 24%, and overestimated in 11%. CT detection rate in small tumor (<0.5 cm) was 29%, and increased to 97% with nodules size exceeding 5 cm. CT significantly underestimated the clinical PCI value in overall. CONCLUSION: The sensitivity of CT in detecting PC was influenced by histologic type, tumor location and size. CT underestimated the clinical PCI score in PC patient. PMID- 22202285 TI - [A case report of multiple advanced hepatocellular carcinomas treated by combination therapy with hepatectomy and particle therapy]. AB - We report a case of multiple advanced hepatocellular carcinomas (HCC) with bilobar distribution treated by combination therapy of hepatectomy and particle therapy (carbon ion therapy). A 73-year-old man who had been pointed out hepatic tumors on abdominal CT was referred to our hospital in February 2010. Advanced HCCs; 8 cm Vp3 and 6 cm in the left lobe, 4 cm in the posterior segment, and 1 .5 cm in the S8 area, were detected by abdominal dynamic CT and EOB-MRI etc. Curative resection was not applied due to insufficiency of liver function and unfavorable anatomical tumor locations. Accordingly we have developed a novel combination therapy of hepatectomy and particle therapy. First we performed left lobectomy in March 2010, followed by administration of particle therapy to the posterior segment for local control in May. Then, transcatheter arterial chemoembolization was administered 4 times for residual tumors. The patient survives for 15 months after the initial therapy with good local control. PMID- 22202286 TI - [Pancreatic resection for metastatic tumors to the pancreas]. AB - We report 3 cases of resectable pancreatic metastasis. CASE 1: A 76-year-old woman was followed after nephrectomy for renal cell carcinoma for 13 years. CT examination demonstrated a high vascular lesion in the pancreatic body and tail. We conducted distal pancreatectomy and diagnosed with metastatic tumor from renal cell carcinoma. She died of liver metastasis 8 years after pancreatic resection. CASE 2: A 64-year-old man, who had undergone right lower lobectomy for lung cancer a year ago, was found to have a mass in the pancreatic tail. We performed distal pancreatectomy and diagnosed with metastatic tumor from lung cancer. He died of lung metastasis 12 months after pancreatic resection. CASE 3: A 62- year old woman, who had undergone left nephrectomy for renal cell carcinoma 3 years ago, was found to have a mass in the pancreatic body. With a diagnosis of metastatic pancreatic tumor from renal cell carcinoma, distal pancreatectomy was done. She died of liver and lung metastases 15 months after pancreatic resection. Long-term survival can be achieved in patients undergoing a pancreatic standard resection including lymphadenectomy for isolated metastasis from nonpancreatic sites. PMID- 22202287 TI - [A rare case of huge triple-negative of accessory breast cancer enlarged during the course of chemotherapy]. AB - A 38-year-old premenopausal woman with a right axillary mass was told that she had an atheroma. The mass enlarged. An infectious atheroma was suspected, and incision and drainage were performed. A mass 4 cm in diameter was palpated in the right axillary region. Ultrasonography showed a mass 6 cm in diameter, and magnetic resonance imaging revealed a hypervascular mass at the same site. Stage IIIB triple-negative of accessory breast cancer (T4bN1M0) was diagnosed. The patient received four courses of FEC 100 (5-fluorouracil, epirubicin, and cyclophosphamide) as preoperative chemotherapy, but progressive disease was diagnosed, and the regimen was switched to weekly paclitaxel. The tumor became ulcerated and friable, and the hemoglobin level fell to 6 g/dL. Emergency surgery was thus performed. Postoperatively, the patient received six courses of chemotherapy with paclitaxel plus gemcitabine. Accessory breast cancer is extremely rare, but should be borne in mind when an axillary mass is encountered. In our patient, progressive disease had developed during the preoperative chemotherapy for accessory breast cancer. Although treatment was switched to a different regimen, bleeding was detected, and the patient underwent a semi emergency surgery. PMID- 22202288 TI - [A case of breast cancer postoperative metastases to the liver obtained cCR]. AB - A case is a 55-year-old woman. We noticed the right breast lump in May 2006. It was papillotubular carcinoma, ER(-), PgR -), HER2 (3+) by needle biopsy. The patient was introduced to our department in November 2006 for a close inspection and treatment. The palpation showed a mass without a firm flexibility, which was a border indistinctness of about 2 cm in size in the right AB area. We did not find a distant metastasis either. We operated for Bt+Ax (level II) in December. It was T2N0M0, stage IIA papillotubular carcinoma, ER(-), PgR(-), HER2 (3+) with histopathology. We recommended an adjuvant therapy but the patient refused. Since then we followed her up. After two years from the operation, multiple metastases were observed to the liver, FEC therapy was started. CT revealed that metastasized tumors were disappeared after six courses of treatment. Echography obtained cCR. Generally speaking, chemotherapy was effective for breast cancer as we compared it to endemic cancer of other organs. Meanwhile, it has been reported that many kinds of newly developed medicines for the treatment are available and effective. On the other hand, a selection of therapeutic drugs could be a problem for metastasized organs. PMID- 22202289 TI - [Study of breast carcinoma with non-inflammatory skin involvement (t4b)]. AB - In this study, we evaluated the clinical presentation of patients with T4b breast cancer, and analyzed the impact of non- inflammatory skin involvement on long term survival. We treated 1 228 cases of breast cancer patients during 2004 to 2010. The T4b breast cancers were 52 cases out of these 1,228 patients. The primary treatment methods of these T4b patients were chemotherapy (67.3%), surgical therapy (26.9%), endocrine therapy (5.8%), and radiation therapy (0%). The probability that surgical resection was performed over the duration of treatment was 88. 5%. The mean time to progression (TTP) was 3.9 years. The disease specific mean survival time (MST) of T4b breast cancer patients was 5.9 years. There was no difference among the surgical and non-surgical therapy groups in the long-term survival period, but the surgical therapy group was much better than non-surgical therapy group in terms of non-recurrent survival ratio. In viewing from the control of bleeding of the patients, the surgical therapy was effective and improved the quality of life during a time of the therapy. PMID- 22202290 TI - [A novel Cisplatin delivery system for malignant ascites-bearing mice-a basic experimentation]. AB - The authors used 70% deacetylated chitin and cisplatin (CDDP) to devise a novel anticancer drug delivery system (DDS). We examined in vitro release of the CDDP from the system. The novel system was intraperitoneally( ip) given to malignant ascites-bearing mice, and the survival time of each animal was recorded. The related oncolytic mechanism was immunologically investigated. More than 70-90% of the CDDP was gradually delivered from the system in 24 hours. Nineteen animals among 30 treated with our system survived for longer than 4 weeks, and a recurrence of ascites was nil. A 4- week survival rate of the animals with ip injected conventional CDDP was 5/14. All non-treated animals had massive ascites and died within 4 weeks. Immunologic studies suggested that cytotoxic immunoresponse was induced in the mice treated with the novel system. Our newly devised system warrants for clinical applications in the treatment of malignant ascites. PMID- 22202291 TI - [A case report of the combination therapy with S-1 plus CDDP intraperitoneal chemotherapy for CY positive cancer patient]. AB - A male patient in his 50s underwent distal gastrectomy for gastric cancer. In operation, there was no peritoneal dissemination. But peritoneal lavage cytology revealed positive peritoneal dissemination. Thus, we set an intraperitoneal infuser port to this patient. On specimen, a type-3 tumor was located in the gastric lesser of antrum to angle. Microscopic examination of specimens revealed a signet ring cell carcinoma and poorly differentiated adenocarcinoma under serosa, and positive of lymph node metastasis. The diagnosis was pT4N2M1P0CY1H0, Stage IV( Japanese classification of gastric carcinoma The 14 Edition). CDDP was administered through the infuser port (on day 7, a first dose of 60 mg/m2 and 30 mg/m2 for second) combined with oral administration of S-1 (100 mg/body) for two weeks, with one week of drug withdrawal. This chemotherapy was repeated for 11 courses. After that, peritoneal lavage cytology became negative. S-1 oral administration was continued for four years, and this patient has been well for five years and six months after the surgery. Therefore, it is suggested that intraperitoneal chemotherapy with cisplatin is an effective treatment for microscopical peritoneal dissemination. PMID- 22202292 TI - [A pilot study of intraperitoneal gemcitabine for reduction of peritoneal dissemination in advanced pancreatic cancer]. AB - We schemed intraperitoneal gemcitabine (ipGEM) for reduction of peritoneal dissemination to three patients with unresectable and one patient with recurrent pancreatic cancer, followed by intraperitoneal catheter and subcutaneous port placement. Two locally advanced cases were performed for intra-operative radiotherapy, and one of 2 locally advanced cases was performed for gastrojejunostomy. And another locally advanced case had ileostomy. The recurrent case was resected for metastatic tumor of abdominal wall. In one of locally advanced cases, we couldn't perform ipGEM for progression of disease. In two remaining locally advanced cases, we could keep on doing ipGEM, and the patients did not experience with abdominal discomfort or hematological toxicity. PMID- 22202293 TI - [The significance of chemoradiation therapy for TNM cStage II - III esophageal squamous cell carcinoma]. AB - The value of chemoradiation therapy (CRT) followed by surgery is unknown in Japan. PATIENT AND METHOD: Thirty Patients with TNM cStage II - III squamous cell carcinoma (SCC) of the esophagus were divided into CRT (40 Gy) followed by surgery( arm A) and definitive CRT( 60 Gy()arm B). The correlations between several clinicopathological factors and survival time were examined. RESULTS: The effective rate (CR+PR) of CRT was 75% in arm A versus 88.9% in arm B (p= 0.32). There was no significant difference about the median survival time (arm A: 17. 4 months, arm B: 12. 6 months, p= 0.18). The two-year survival rate was 40 . 4% in arm A versus 41 . 6% in arm B (p=0.35). CONCLUSION: Our retrospective study showed no significant difference in prognosis between CRT followed by surgery and definitive CRT. Definitive CRT might be a choice of therapy for curative esophageal carcinoma. PMID- 22202294 TI - [Clinical outcomes in patients with brain metastasis from gastric cancer]. AB - Brain metastasis from gastric cancer is uncommon and difficult to treat. Patients with brain metastasis had a poor prognosis with simultaneous and multiple metastases to other organs. Four patients with brain metastasis were reported. All patients were male with the median age of 76 years and the diagnosis was stage IA in one, stage IIIA in 2 and stage IV in one. Three patients underwent gastrectmy and one patient in stage IV received chemotherapy as the initial treatment. An interval between the initial treatment and the diagnosis of brain metastasis was 11, 24, 30 and 83 months, respectively. The symptoms of brain metastasis were stagger in two, unconsciousness in one and headache in one. The treatment for brain metastases were a surgical resection for two lesions larger than 3 cm and gamma-knife radiotherapy was performed for the other lesions. The duration of survival from the treatment for brain metastasis was 45, 48, 58 and 94 days, respectively. Multidisciplinary treatment, including a surgical resection and stereotactic radiosurgery such as gamma-knife for brain metastasis is thought to improve the quality of life, but not prolong survival due to metastases to other organs. The development of effective systemic treatment will be necessary in order to prolong survival. PMID- 22202295 TI - [A case of liver metastases from gastric cancer treated with stereotactic body radiation therapy]. AB - A 69-year-old man underwent distal gastrectomy in September 2007 for type 2 gastric cancer with liver metastasis (S5) in LM area (p-T2N3aM1, Stage IV). After the operation, we performed chemotherapy. But the liver metastasis was enlarged, so we performed a partial hepatectomy in July 2008. After hepatectomy, liver metastases appeared on S6 and S7 in February 2009. So we performed the fifth-line chemotherapy with paclitaxel. The effect of paclitaxel was not so good. Therefore, SBRT was performed for the liver metastases (S6/7 and S7) in December 2009 and February 2010. After SBRT, he had no recurrent tumor. SBRT was one of the effective treatments for liver metastases from gastric cancer. PMID- 22202296 TI - [Prolonged complete response obtained by radiation and chemotherapy with paclitaxel in a case of recurrent gastric cancer in the rectovesical pouch]. AB - The case is a 75-year-old man, who underwent curative resection for the upper part of stomach cancer (Stage II), and was without a recurrence for two years. The patient had been well until September 2006, when CT examination revealed a 5 cm tumor in the rectovesical pouch. The tumor was histologically diagnosed as a peritoneal metastasis of gastric cancer through CT-guided percutaneous needle biopsy. Chemotherapy with S-1 was initiated, but it resulted in progressive disease. To locally control the growing tumor and avoid rectal stenosis, irradiation was applied for a total of 56 Gy in December 2007 and then followed by chemotherapy with paclitaxel. He obtained a complete response 7-month later, and remains CR for 3 years by receiving paclitaxel chemotherapy. Although chemotherapy is of choice for gastric cancer recurrence, in some cases radiotherapy can play an important role in local control even in peritoneal metastasis. PMID- 22202297 TI - [Complete remission of liver metastasis from gall bladder carcinoma after stereotactic radiotherapy-a case report]. AB - A 75-year-old man was diagnosed as gall bladder carcinoma by postoperative histological examination following laparoscopic cholecystectomy. He underwent the second surgery of resection of liver bed and port sites with lymph node dissection. Isolated hepatic metastasis of 20 mm in diameter was found in S4/8 by MRI 18 months postoperatively, and stereotactic radiotherapy (52.8 Gy/4 Fr) was done for the metastatic lesion. The lesion could not be detected by CT 7 months after the radiotherapy, and thereafter no local recurrence has been observed for 24 months. However, lymph node metastasis of #9 was diagnosed 31 months postoperatively. Liniac radiotherapy (60 Gy/20 Fr)was performed and stable disease has been obtained for 9 months. The patient is alive at present of 43 months after surgery without any other site of the disease, and his quality of life is well maintained. Stereotactic radiotherapy showed an excellent local therapeutic effect without any serious complications, suggesting that this is a potent modality for isolated liver metastasis of gall bladder carcinoma. PMID- 22202298 TI - [Long-term clinical effects of preoperative radiotherapy on anal function after intersphincteric resection]. AB - BACKGROUND: The aim of this study was to determine whether preoperative radiotherapy had an influence on the anal function of patients having an intersphincteric resection (ISR). METHODS: We evaluated a long-term outcome and postoperative anal function in 22 patients having undergone ISR for low rectal cancer. RESULTS: There was no significant difference between the irradiated and nonirradiated group in the postoperative complications and oncological outcome. After a median follow-up of 6 .8 years, the number of bowel movements per 24 hours in patients with and without radiation was 4 .5 and 2 .7, respectively. Poor anal function assessed by Wexner incontinence score and Kirwan classification were significantly associated with preoperative radiotherapy. CONCLUSION: Preoperative radiotherapy was identified as a risk factor with the greatest negative impact on anal function after ISR. PMID- 22202299 TI - [Squamous cell carcinoma of the anal canal showing pathological complete response after S-1 plus radiotherapy -a case report]. AB - The patient was a 53-year-old woman who underwent colonoscopy for anal pain and melena. We diagnosed her with Stage I (T2N0M0) anal canal squamous cell carcinoma by biopsy specimen and CT scan. We recommended chemo-radiotherapy because she hoped to keep her anus. For this patient, we planned an S-1 administration at a dose of 120 mg/ body/day for consecutive 14 days followed by 7 days of rest period with whole pelvis and bilateral inguinal radiation (total 45 Gy/25 Fr). Then we added a booster radiation (14 Gy/7 Fr) to a local area for 5 days followed by 2 days of rest period. After 2 weeks of chemo-radiotherapy, we could not detect any tumors by colonoscopy. We diagnosed it as a pathological complete response for biopsy specimen. PMID- 22202300 TI - [A case of mediastinal lymph node metastasis from rectal cancer successfully treated by carbon ion radiotherapy]. AB - We report a case of mediastinal lymph node metastasis from rectal cancer successfully treated by carbon ion radiotherapy. A 65-year-old woman underwent sigmoid colostomy against unresectable rectal cancer. After chemoradiotherapy, primary rectal cancer became resectable and low anterior resection was performed. Curative local resection was done and chemoradiotherapeutic effect was grade 2. Chemotherapy after the operation wasn't effective enough and the size of the mediastinal lymph node increased. So she underwent carbon ion radiotherapy (52.8 Gy) which markedly decreased the lymph node size (-48%). Multi-modality therapy, such as radiation, chemotherapy, operation and carbon ion radiotherapy was applied. Successfully, locally advanced rectal cancer was resected and distant lymph node metastasis was controllable. PMID- 22202301 TI - [Anal squamous cell carcinoma-a report of 6 cases]. AB - In Japan, surgical therapy is utilized as the main treatment modality for anal squamous cell carcinoma (SCC). Subjects were 6 patients with anal SCC treated at our hospital from 2000-2010, and a study was made on the treatment. In the early 3 cases (Stage IIIA, IIIB, IIIB), chemoradiotherapy (CRT) was used as adjuvant therapy on the premise of surgery. All of them were considered as stable disease, and they all experienced postoperative complications. The average length of the hospital stay was 45 days. Two cases are still surviving without recurrence, but the other one developed a distant metastasis. In contrast, we selected CRT with curative intent in the late 3 cases(Stage II, IIIA, IIIB). Two cases were considered as complete response (CR), and the other one considered as partial response (PR) was performed a salvage operation. Two cases are still surviving without recurrence, but the other case metastasized to the internal iliac lymph nodes. CRT with curative intent for anal SCC demonstrated a good antitumor effect. Salvage operation was safely performed, and showed a good prognosis. PMID- 22202302 TI - [A case of perianal squamous cell carcinoma attaining a complete response over five years with chemoradiotherapy]. AB - We report a case with perianal squamous cell carcinoma, which showed a complete response more than five years after chemoradiotherapy. A 69-year-old-man was introduced to our hospital for the diagnosis of squamous cell carcinoma [T3 (8.0 * 8.0 cm) N0M0, Stage II]. The patient was treated by chemoradiotherapy, which consisted of 5-FU 750 mg/m2/ day (continuous intravenously) on days 1-5 and 29 33, and mitomycin C 10 mg/m2 on days 1 and 29 and radiation at 2 Gy/day for 5 days per week (total dose 60 Gy). The patient tolerated this treatment with no severe adverse effects. Tumor disappeared completely 1 month after this treatment with no adjuvant therapy. The patient has been alive with no sign of recurrence for 6 years. PMID- 22202303 TI - [Preoperative chemoradiotherapy with S-1 for advanced low rectal cancer]. AB - We reviewed the patients with neoadjuvant chemoradiotherapy (CRT) with S-1 to evaluate the feasibility and effectiveness for locally advanced lower rectal cancer. The CRT regimen consisted of pelvic irradiation (45 Gy in fractions of 1.8 Gy), five days a week. A treatment of oral S-1 (80 mg/m2 per day) on days 1 14 and 22-35 was given during radiotherapy. Patients underwent a curative resection with lateral lymph node resection at 6-8 weeks intervals after neoadjuvant CRT. The response rate on pathological study was 60% (all were grade 2), and no patients had lateral lymph node metastases. Grade 1 or 2 adverse effects occurred in all patients during CRT, but the CRT was achieved in all patients. We found two patients had surgical complications with wound infection and one patient with anastomotic leakage. All complications were improved by conservative treatment. The neoadjuvant CRT was feasible and effective treatment for all patients with locally advanced rectal cancer. We have started a phase II study of the neoadjuvant CRT. PMID- 22202304 TI - [Two resected cases of extragastric gastric cancer growth with gastrocolic fistula]. AB - We report two resected cases of extragastric gastric cancer growth with gastrocolic fistula whose prognoses were fairly good with surgery and chemotherapy. CASE 1: A 45-year-old man was admitted to a nearby clinic complaining of fever and abdominal pain. Endoscopy revealed gastric mucosa associated white moss under tumor-like lesions to the mucous cancer biopsy results. The patient underwent surgery; the transverse colon had adhered to the posterior wall of the stomach, so a distal gastrectomy and a partial resection of the transverse colon were performed. He enjoyed a good QOL for 56 months after the surgery. CASE 2: A 69-year-old man. An upper GI examination revealed a protrusion at the posterior wall of the stomach, and the barium leaked from the lesion to the colon. Diagnosis of stomach cancer surgery took place. He died 20 months after the surgery. PMID- 22202305 TI - [Assessment of the cost of laparoscopy-assisted gastrectomy]. AB - BACKGROUND: The cost of laparoscopic gastrectomy (LG) has not been fully clarified yet. PATIENTS AND METHODS: The actual cost for the instruments used for surgery was examined between LG and conventional open gastrectomy( OG) by separating distant (l D-) and total (l T-) gastrectomy in a total of 20 patients(5 for each)during Oct 2010 and Feb 2011. The profit was defined as the difference of the actual cost and the operation fee including the instruments determined by the insurance and compared. RESULTS: The fee for D-OG, T-OG, D-LG, and T-LG were 708, 700 yen, 856 , 400 yen, 783 , 600 yen and 922 , 300 yen, respectively. The mean profits of D-OG, T-OG, D-LG, and T-LG were 408 , 297 yen, 475 , 812 yen, 308, 681 yen and 269 , 478 yen, respectively. CONCLUSION: Appropriate surgical and instrumental fees should be determined considering the actual cost. PMID- 22202306 TI - [A case of gastric neuroendocrine cell carcinoma successfully treated by neoadjuvant chemotherapy]. AB - A 74-year-old man, whose chief complaint was epigastralgia, was referred to our hospital and diagnosed gastric cancer with liver metastasis. Gastrointestinal endoscopy showed a tumor on the lesser curvature of cardia of stomach. He was diagnosed as neuroendocrine cell carcinoma by biopsy specimens. He was treated by combined chemotherapy of CPT-11 and CDDP. After 11 courses, endoscopic examination revealed a complete disappearance of the primary tumor. CT-scan and MRI showed that the liver metastasis had been disappeared. We diagnosed as clinical CR and performed total gastrectomy with lymph node dissection and partial hepatectomy. Histological findings revealed a few cells in stomach and no cancer cells in the liver. He was treated with adjuvant chemotherapy of S-1. After 3-course, he suffered from anemia of grade 3, thus we interrupted chemotherapy. The patient remains alive for 28 months without recurrence. We conclude that chemotherapy was effective for neuroendocrine cell carcinoma of the stomach, which was to be considered of poor prognosis, and that liver resectomy was often effective. PMID- 22202307 TI - [Wallflex duodenal stenting for gastric outlet obstruction caused by inoperable advanced gastric cancer]. AB - INTRODUCTION: Wallflex duodenal stent (WDS) placement for gastric outlet obstruction caused by malignant disease has been covered by health insurance in Japan since April 2010. We have placed five-WDS for three gastric outlet obstructions caused by inoperable advanced gastric cancer. CASE 1: A 67-year-old male diagnosed as having Stage IV gastric cancer with liver, lung, and lymph node metastases underwent a WDS placement during first-line chemotherapy. He was able to consume a soft diet orally for about five months thereafter. He underwent a WDS replacement for stent obstruction by tumor ingrowth and finally died due to the primary tumor 11 months after the first visit. CASE 2: A 63-year-old male diagnosed as having Stage IV gastric cancer with liver and lymph node metastases underwent a WDS placement during the first-line chemotherapy. He was able to consume a soft diet orally for about three months thereafter. He died due to the primary tumor six months after the first visit. CASE 3: A 72-year-old male diagnosed as having Stage IV gastric cancer with liver and lymph node metastases underwent a WDS placement during the first-line chemotherapy. He was able to consume a soft diet orally for about four months and subsequently received the fourth-line chemotherapy. He underwent a WDS replacement for stent obstruction by tumor ingrowth and finally died due to the primary tumor nine months after the first visit. CONCLUSIONS: WDS stent placements for gastric outlet obstruction caused by inoperable advanced gastric cancer were performed safely and enabled the consumption of a soft diet orally for at least three months. This approach is expected to be a safe and effective treatment option. PMID- 22202308 TI - [A case report of scirrhous gastric carcinoma diagnosed by staging laparoscopy]. AB - The case is a sixty-something man with a complication of epigastric abdominal pain. X-ray and endoscopic examination of upper gastrointestinal tract showed a rigidity of the gastric wall and the presence of giant folds on gastric body and fornix. Scirrhous type of gastric cancer was suspected and gastric forceps biopsy was performed at many points under the retreated endoscopic examinations. However, the histologic findings revealed no malignant features. We performed staging laparoscopy, and by peritoneal washing cytology and biopsy of a nodule of abdominal wall, he was diagnosed with advanced gastric carcinoma with peritoneal dissemination. In conclusion, staging laparoscopy is one of the useful methods for diagnosis and determination of the management of scirrhous type gastric carcinoma. PMID- 22202309 TI - [A case of recurrent mantle cell lymphoma with gastrointestinal bleeding]. AB - A 64-year-old man had a sudden onset of gastrointestinal bleeding. He had been diagnosed as systemic mantle cell lymphoma (MCL) 27 months ago, and the first line chemotherapy was undergone. After maintaining CR state during 12 months, he showed PD. Upper gastrointestinal endoscopy revealed multiple lymphomatous polyps, and active bleeding was noticed from the ulceration of the top of these polyps. After hemostasis was gained, biopsies were done twice and a local recurrence of MCL was diagnosed finally by immunohistological examination. In consequence of the second-line chemotherapy including bendamustine, he was introduced into CR again. We present this rare case of long-term follow up of MCL with a series of upper gastrointestinal endoscopy. PMID- 22202310 TI - [A case of adenocarcinoma of the esophagogastric junction successfully treated with chemoradiation therapy]. AB - The patient was an 80-year-old female with chief complaint of anemia. She was diagnosed as a type 3 gastric cancer (por/tub2) of the esophagogastric junction by gastrointestinal endoscopy in November 2010. CT scan revealed no distant metastasis and we diagnosed as c-stage II B (T4aN0M0). However, severe COPD was detected by the respiratory function test. Considering her age and respiratory function, we decided that total gastrectomy under general anesthesia was difficult. She was treated with radiation( 50.4 Gy/28 Fr) and the combination chemotherapy of S-1( 80 mg/m2, day 1-21) plus low-dose CDDP (6 mg/m2, day 1-5, 8 12, 15-19) during her hospitalization, and treated with S-1 mono-therapy as an outpatient. The tumor was reduced and the hemorrhage was not seen though the response was SD. Moreover, she did not experience any adverse event of grade 3 or more. The chemoradiation therapy appears to be effective for patients of adenocarcinoma of the esophagogastric junction. PMID- 22202311 TI - [A case of recurrent gastric cancer successfully treated with radiation therapy]. AB - We report a case of recurrent gastric cancer that was effectively controlled with radiation therapy. A 63-year-old man underwent total gastrectomy, cholecystectomy and D2 dissection in February 2006 for early gastric cancer in the upper third area that was diagnosed with papillary adenocarcinoma and Stage IA (T1 (SM), N0, H0, P0, CY0, M0). He underwent lateral segmentectomy of the liver for liver metastasis of S2/3. He suffered from No. 12 lymph node(LN)metastasis in February 2009, so CPT-11, next to S-1, was administered. Portal tumor thrombosis (PTT) and liver S8 metastasis were observed in September 2009. First, chemoradiotherapy (CRT) ( S-1 80 mg/body+total of 65 Gy per 26 Fr) for #12 LN and PTT was performed and, in turn, stereotactic radiation therapy (SRT: total of 52.8 Gy per 4 Fr) was performed. A complete response in all of tumors was noted and he was presently alive with no sign of recurrence after 19 months after CRT and SRT. Grade 3 or 4 adverse events were not recognized. It is thought that radiation therapy is one of effective treatments for localized metastasis from gastric cancer. PMID- 22202312 TI - [A case of multiple bone metastases from gastric cancer successfully treated with chemo-radiotherapy]. AB - A 75-year-old man underwent distal gastrectomy for gastric cancer (CY+, Stage IV) in June 2009. About 4 months after surgery, he had a strong pain in a right shoulder, and became writing difficulty. Some imaging examinations revealed multiple bone metastases, and it was diagnosed that the pain was caused by the tumor of cervical spine. Systemic chemotherapy was started using a regimen of S 1/CDDP, and radiotherapy (30 Gy) was performed for the cervical tumor at the same time. After two-course of the chemotherapy, the shoulder pain disappeared. About 12 months after surgery, he had a strong pain in a left leg, and became walking difficulty. Some imaging examinations revealed a progression of the tumor of lumbar spine. Radiotherapy (30 Gy) was demonstrated for the tumor. After the treatment, the leg pain disappeared. We experienced a case of multiple bone metastases successfully treated with chemo-radiotherapy. PMID- 22202313 TI - [A case of locally advanced pancreas cancer effectively treated by multidisciplinary strategy]. AB - A 64-year-old female with a primary complaint of abdominal and back pain was diagnosed as locoregionally advanced pancreas cancer. She underwent distal pancreatectomy and received postoperative adjuvant chemotherapy of gemcitabine (GEM). Abdominal CT after 14 months showed a local recurrence without far organ metastasis. She was treated with radiation and the chemotherapy of S-1, which resulted in a stable control by a follow up CT. Then she is undergoing the combination chemotherapy of GEM and S-1. The patient is alive for 26 months after the operation. PMID- 22202314 TI - [An example case that chemoradiotherapy was succeeded for unresectable pancreas cancer]. AB - BACKGROUND: Prognosis of pancreas cancer is extremely poor. For unresectable pancreas cancer, there has not been an effective method of treating. In our institution, the mean survival time was 13 . 6 months for a chemoradiotherapy case that used gemcitabine (GEM), but was 7.3 months for a non-treatment case in locally advanced and metastatic pancreas cancer. This time, we experienced a good case for unresectable pancreas cancer treated with chemoradiotherapy using GEM/S 1 that clearly exhibited a decrease in tumor size by tumor marker. PMID- 22202315 TI - [A long-term survival case of recurrent pancreatic vipoma with liver metastases treated by a combination of surgical resection and loco-regional therapies]. AB - We report a case of recurrent pancreatic VIPoma with liver and peritoneal metastases who has been surviving over 7 years by a successful treatment with a combination of surgical resection and loco-regional therapies. A 59-year-old female underwent distal pancreatectomy for pancreatic endocrine tumor. Five years after pancreatectomy, she had a recurrence of liver and peritoneal metastases with the symptoms by hypersecretion of VIP, and she underwent hepatectomy and peritoneal tumor resection. Seven months later, multiple liver metastases appeared and were treated with transcatheter arterial chemoembolization (TACE). Additionally radiofrequency ablation( RFA) for remnant viable lesion was performed. Seven years and eight months after primary panceatectomy and two years and six months after resection of the liver and peritoneal recurrences, she is now disease-free with good quality of life. The progression of well differentiated pancreatic neuroendocrine carcinoma is usually slow. It is potentially useful in controlling of liver metastases to combine the loco regional therapy like TACE and RFA with surgical resection. PMID- 22202316 TI - [A case of peritoneal recurrence of invasive carcinoma derived from IPMN after distal pancreatectomy]. AB - The patient was a 62-year-old man who underwent distal pancreatectomy and partial resection of transverse colon with diagnosis of cystic tumor of pancreas tail in July 2006. In histology, the tumor was an invasive carcinoma derived from intraductal tumor. So, Chemotherapy using gemcitabine (GEM) was administered. Eleven months after the operation, abdominal contrast-enhanced CT showed a cystic tumor in the subdiaphragm and CEA increased to 15 .2 ng/mL. Combination chemotherapy using GEM and S-1 was administered under the diagnosis of peritoneal recurrence. CEA decreased to a normal level, but 19 months after the operation, CA19-9 increased to 187 .7 U/mL. Then, radiotherapy (a total of 40 Gy) was performed. Twenty two months after the radiotherapy, though chemotherapy using S 1 was continued, CA19-9 re- increased to 134 .2 U/mL. Abdominal contrast-enhanced CT and PET detected no other recurrent lesion. A tumor resection was performed in January 2010. In immunostaining MUC1(+), MUC2(-), MUC5AC(+), MUC6(+) and mucus expression forms as well as with previous specimen, and was diagnosed as recurrence of the invasive carcinoma derived from intraductal tumor. PMID- 22202317 TI - [Usefulness of immediate reconstruction after mastectomy for inflammatory breast cancer with muscle cutaneous flap]. AB - CASE 1: A 59-year-old female patient with left inflammatory breast cancer (HER2 type) T4N1M0, stage III B. Although a partial response (PR) was observed after chemotherapy, an increase of the tumor was confirmed, and thus she underwent pectoralis-conserving mastectomy and immediate reconstruction with a rectus abdominis flap. After the surgery, the patient continued to undergo radiotherapy and administration of trastuzumab. At present, after 1 year and 3 months, she is alive with no recurrence. CASE 2: A 67-year-old female patient with left inflammatory breast cancer (triple negative) T4N2M0, stage III B. Since a variety of chemotherapeutics were ineffective, she underwent mastectomy with pectoralis resection and immediate reconstruction with a rectus abdominis flap to control pain/bleeding caused by the increased tumor. Although radiotherapy and chemotherapy were performed after the surgery, lung and hepatic metastases were developed 6 months after the surgery, and she died in the 10th month after the surgery. CONCLUSION: In mastectomy for inflammatory breast cancer, an immediate reconstruction with a muscle cutaneous flap enabled unhesitating mastectomy in a wide area, and thus we consider this will be a useful technique. PMID- 22202318 TI - [A case of breast adenomyoepithelioma that was diagnosed by local excision]. AB - A case is a 72-year-old woman with right breast lump detected by palpation. In the end of November 2009, we palpated a mass with clear boundaries in the right D area. Breast echography showed a nearly 3 cm tumor in the cyst. MRI showed an augmented effect of marginal irregular 3 cm in size. A diagnosis was adenomyoepithelioma by needle biopsy. We performed lumpectomy because a breast cancer was suspected. Histopathology findings were adenomyoepithelioma ER(+), PgR(-), HER2(0), alpha SMA(+). A diagnosis of adenomyoepithelioma is rather hard by means of imaging or biopsy. When this disorder was in doubt, a tissue analysis is indispensable for a determination of diagnosis because we were able to make a diagnosis by local excision without an excessive invasion. So we herein report our experience of adenomyoepithelioma with reference. PMID- 22202319 TI - [Two cases of stromal sarcoma, so-called malignant fibrous histiocytoma of breast treated with reduction surgery]. AB - CASE 1: A 64-year-old woman with right breast cancer had a partial mastectomy and radiotherapy four years ago was admitted to our hospital because of right breast mass. The vacuum associated biopsy of tumor resulted in breast sarcoma, thus a nipple-spearing mastectomy was performed. The final histological diagnosis was stromal sarcoma, and was identical to histological findings of malignant fibrous histiocytoma. Three months after the operation, a chest wall recurrence appeared. Although tumor resection with latissimus dorsi flap was performed, there were pleural dissemination and malignant pleural effusion. She died six months after the first surgery. CASE 2: A 60-year-old woman was admitted to our hospital because of left breast mass, but she refused a further clinical examination. She readmitted fourteen months later due to a huge sized left breast mass with necrosis and smelling discharge. CT scan showed a huge tumor of left breast and multiple lung metastases. Biopsy of the tumor resulted in breast sarcoma. Total mastectomy with split thickness skin grafting was performed. The final histological diagnosis was identical to the first case. A local recurrence appeared thirty days after the operation, and she died fifty-one days after the operation. PMID- 22202320 TI - [A case of squamous cell cancer of the breast in which effective hemostasis was obtained by preoperative emergency radiation]. AB - A case was a 40-year-old woman. Her right breast was presented with massive bleeding ulcer and fixed with a pectoral muscle. Diagnosis of Stage IIIb breast cancer( T4b, N1, M0) showed a high inflammatory response and severe anemia. Palliative surgery was difficult because of hemostasis, and her general health also was in poor condition. The pathological diagnosis was squamous cell cancer. We underwent a total of 30 Gy radiation emergency hemostasisose. After radiation and chemotherapy, the lesion was undergone a radical surgery, and was reduced in size significantly. It was diagnosed as squamous cell cancer, which was more sensitive to general radiation so neoadjuvant chemoradiation therapy was effective. PMID- 22202321 TI - [Postoperative axillary-lymph-node recurrence in breast cancer patients]. AB - We investigated 13 cases of axillary-lymph-node recurrence, who received an operation for an early stage breast cancer. They are the first recurrence of only regional without metastatic disease; the 4 patients, who had sentinel-lymph-node by biopsy at first operation, received an axillary lymph adenectomy, and 5 patients received re-lymph-adectomy after axillary lymph node dissection. The other 4 patients received only systemic therapy. Receptor conversion between primary and lymph-node recurrent site was identified for ER in 2 patients; one showed a lower expression of ER and the other showed for HER2. These led to a change in the subsequent treatment plan; 6 patients had systemic chemotherapy after recurrence, 1 patient had endocrine, 2 patients had trastuzumab and 4 patients continued the same treatment prior to surgery. Ten out of 13 patients were alive without recurrence, and 3 patients were with distant metastasis. However, one of the 3 patients who had a distant metastasis died due to brain and lung metastasis. Axillary node recurrence should be treated with axillary dissection, if possible, and receptor measurement in primary and recurrent site is useful for subsequent treatment. PMID- 22202322 TI - [A case of breast cancer liver metastases responding to lapatinib and capecitabine therapy]. AB - We report a 55-year-old female with liver metastases from breast cancer who responded to lapatinib and capecitabine combination therapy as third-line. She was diagnosed as invasive ductal carcinoma (T1cN1M0, stage IIA). Biomarker of breast cancer was negative hormone receptor (ER-, PgR-) and overexpression of HER2(HercepTest 3+). We started preoperative chemotherapy with weekly paclitaxel followed by FEC100. Then mastectomy with axillary dissection was performed. Histopathology of the breast and lymph nodes showed complete disappear of invasive cancer cells( pCR, grade 3). We performed her adjuvant therapy with trastuzumab after surgery. The liver metastases developed 5 months after surgery. We treated her in trasutumab combined with vinorelbine, and followed by docetaxel during one year and four months. Because liver metastases re-grew during the combination therapy with trastuzumab, we switched to lapatinib and capecitabine combination therapy. After four months of administration, abdominal CT revealed liver metastases were remarkably reduced in size. The efficacy of chemotherapy lasted for eight months. PMID- 22202323 TI - [A case of scalp metastases from breast cancer successfully treated with letrozole]. AB - A 62-years-old woman visited a dermatology clinic for hard mass at her scalp. Clinicallly, the mass was hard and alopecic. The diameter was 3 cm. A skin biopsy was done and histpathological examination showed adenocarcinoma. Immunehistchemically, estrogen receptor was positive. It was suspected that breast cancer could be metastasized to the scalp, but mammography, ultrasound, and positron emission tomography showed no particular metastases in her breast and other organs. Magnetic resonance imaging showed enhanced lesions in her birateral breast. Needle biopsy was done and pathological findings showed bilateral breast carcinoma and metastases to the scalp. So we started endocrine therapy using letrozole, the mass was shrunk to 1 cm after 6-month. It is rare that breast cancer was metastasized to the scalp. But Conner et al. reported that 84% of metastatic scalp carcinoma was from the breast, so we should examine the breast more carefully. PMID- 22202324 TI - [A case of giant thyroid tumor locally excised]. AB - A case was a 59-year-old woman. We noted a cervical swelling more than 30 years ago but we neglected it. We also confirmed hypothyroidism and the patient's progress was satisfactory with an internal treatment. However, the cervical swelling gradually became enlarged, we operated on her. Cervical echography findings revealed whole thyroid gland swells. Cervical CT also showed a thyroid swelling which pressed into the trachea. Total thyroidectomy was performed. Histopathological laboratory findings were of nodular hyperplasia with chronic thyroiditis. The thyroid tumor weighted 240 g, and the size was about 10 * 10 * 3.8 cm. We observed a postoperative temporary hypothyroidism. In case that the thyroid function was stable and a low possibility of malignancy in the laboratory findings, we should follow the disease progress carefully. Furthermore, it is important that a local excision has to be carefully performed because of a gradual enlargement of the disease accompanied with accessory symptom as well as a cosmetic attractiveness. PMID- 22202325 TI - [A case of rapidly growing recurrent thyroid carcinoma performed tracheobronchial expandable metallic stent (EMS) therapy]. AB - The case is a 60-year-old female who underwent an operation as a right lobectomy of the thyroid and the resection of neck enlarged cystic lymph nodes in 2006. Pathological results were adenomatous goiter and the metastatic lymph nodes of papillary thyroid carcinoma. The primary lesion of thyroid carcinoma was not found. In four years after the operation, the local recurrence with anaplastic formation of the tumor occurred and tracheobronchial expandable metallic stent( EMS) therapy was performed to the tracheal stenosis. But she died of rapidly enlargement of the anaplastic thyroid carcinoma in two months after stent therapy. It was necessary to observe this case severely after the first operation because the primary lesion of the thyroid carcinoma was not resected. The tracheobronchial EMS therapy was effective to the respiratory failure for a short term caused by the tracheal stenosis of the thyroid anaplastic carcinoma. PMID- 22202326 TI - [Stereotactic radiotherapy following chemo-radiotherapy for lymph node metastasis of stage III non-small-cell lung cancer]. AB - It has been expected that stereotactic radiotherapy (SRT) is one of the useful treatments for non-resectable early lung cancer. In the case radiotherapy was thought to be difficult due to the wideness of irradiation area, it is probable to undergo chemo-radiotherapy safely using SRT for a primary lesion. We report two cases of Stage III non-small-cell lung cancer, which underwent SRT for primary tumors following chemo-radiotherapy for the lymph node metastasis. In both two cases, a reduction of V20 (the normal pulmonary volume to receive radiation exposure: more than 20 Gy) was a possibility, and symptomatic radiation pneumonitis was not observed. PMID- 22202327 TI - [A case of unresectable mediastinal carcinoma obtaining clinical complete response after sequential chemoradiotherapy]. AB - A man in his sixties was pointed out a solitary anterior mediastinal tumor 3 cm in diameter by CT scan with a complaint of chest compression, which grew 7 cm in diameter involving right subclavian and common carotic arteries and left innominate vein and superior vena cava 2 months later. FDG-PET/CT showed a high abnormal uptake only in the mediastinal tumor. A histological diagnosis of mediastinal poorly differentiated carcinoma or mediastinal lymph node metastasis of unknown origin was made by medistinoscopic biopsy. After 4 courses of chemotherapy with carboplatin and paclitaxel, the tumor was markedly decreased but was judged as unresectable because of residual involvement of great vessels. Addition of 60 Gy of radiotherapy targeted for the tumor resulted in further decrease in diameter of the tumor in CT scan and disappearance of abnormal uptake of the tumor in FDG-PET/CT thus regarded as clinical complete response. Since then, a disease free status has been maintained for 16 months. PMID- 22202328 TI - [A case of bilateral 3-lung lesion (metastatic and primary tumour, tumourlet) resected simultaneously]. AB - A 70-year-old male patient underwent right nephrectomy for renal clear cell carcinoma. After 8 years an X-ray showed a nodule on the left lung, and CT scan detected it to be a 15 * 12 mm mass in S1+2 segment of the left lung. CT also detected another 15 * 7 mm mass in the right S3 segment. These lesions had a high FDG accumulation. Pre-operative diagnosis is bilateral pulmonary metastases from renal cell carcinoma, and bilateral lung segmentectomy was performed. Left S1+2 resected tumor was histologically clear cell carcinoma by intra-operative examination, then right S3 segmentectomy was done. And that time, small tumor was found in the middle lung lobe, and a wedge resection was performed. These specimens revealed a primary lung carcinoma of right S3, and tumourlet of middle lobe. It is very rare that three different histlogical types of lung tumor were found. PMID- 22202329 TI - [A response to erlotinib hydrochloride in the case of post-operative recurrent thymoma]. AB - A 43-year-old female was diagnosed with a recurrence of thymoma 6 years after the operation. Eight kinds of systemic chemotherapy were undergone for over 6 years. As the 9th chemotherapy, erlotinib hydrochloride was prescribed and the tumor decreased in size about 8 weeks later. PMID- 22202330 TI - [Curative resection for bulky gastrointestinal stromal tumor with conversion therapy by imatinib]. AB - Imatinib is a standard treatment for unresectable gastrointestinal stromal tumor (GIST). We described the case of a 66- year-old woman with bulky GIST of which a diameter was 25 cm. Therefore, we decided the tumor was unresectable. After 2 year administration of imatinib, the diameter of tumor was reduced to 6 cm. After 3-year administration of imatinib, the diameter of tumor was increased to 8 cm. The patient did not have any distant metastasis. He underwent a resection of the tumor. The historical examination showed that c-kit and CD34 were positive. The number of mitosis was 12/50 HPF. Conversion chemotherapy for bulky GIST may contribute to a curative resection. PMID- 22202331 TI - [Twenty-one-year survival case of rectal GIST treated with combined therapies]. AB - A 55-year-old man underwent Miles' operation with a diagnosis of rectal leiomyosarcoma in 1990. From 1998 to 2004, he had liver and lung metastases and local site recurrent tumors which were removed surgically. Immunohistochemically the recurrent tumor was positive for c-kit and CD34, and the diagnosis of GIST was confirmed. He took an adjuvant imatinib mesylate for half a year in 2004. In July 2005, he had a recurrent tumor in upper mediastinum. We restarted an imatinib after radiation therapy, and got a clinical CR. After he had interstitial pneumonitis in 2009, he stopped taking inmatinb. Then he took sunitinb for two months after an operation for the sixth local recurrence in February 2010. But the upper mediastium recurrent tumor occurred again in November 2010. We restarted sunitinb and got a clinical PR. The patient is now alive and well for 21 years after the initial operation by combined therapies. PMID- 22202332 TI - [A case report of huge abdominal recurrent tumor of small intestinal GIST after 15 years from the operation with primary lesion]. AB - A man in his 60s was given an emergency operation 15 years ago for abdominal bleeding. His tumor of small intestine was resected and diagnosed as small intestinal leiomyosarcoma. He came to our hospital because of his abdominal masses 15 years after the initial operation. CT scan showed a 15 cm-sized solid and cystic tumor in the pelvic cavity. The tumor was diagnosed as GIST by PET-CT and MRI. The tumor was resected, and pathological findings led to the diagnosis of GIST with this tumor. Previous tumor cells were slightly-positive for kit immunohistological examination, but did not resemble this tumor cells morphologically. So genetic tests were performed and revealed two tumors had same mutations of c- kit. Finally, we could diagnose the tumor was recurrent metastases of small intestinal GIST 15 years after the initial surgery. kit mutation analysis was useful for a diagnosis of recurrences and predictions of the clinical response to imatinib in GISTs. PMID- 22202333 TI - [Therapeutic effect of mFOLFOX6 for synchronous unresectable liver metastases from colorectal cancer]. AB - The current chemotherapy for metastatic colon cancer has improved an overall survival. In this study, we retrospectively analyzed the efficacy of mFOLFOX6 in colorectal cancer patients with synchronous unresectable liver metastases and compared the prognosis between before and after the administration of mFOLFOX6. The subject was 28 patients of colorectal cancer with synchronous unresectable liver metastasis who received mFOLFOX6 as a first-line treatment from 2005 to 2010. The median frequency of mFOLFOX6 was 10 times( range, 2-24 times), relative dose intensity of oxaliplatin was 75.0% (range, 42 .9-100), response rate was 32%, and median progression-free survival was 9 . 9 months. Surgical resection of colorectal liver metastases was performed to 4 patients (14.3%) as a conversion therapy. The overall survival of the patients with mFOLFOX6 was significantly better than that of 31 patients who received the chemotherapy via hepatic artery or the chemotherapy before the administration of oxaliplatin (31.8 months vs. 15 .1 months, p<0.01). Our results suggested that mFOLFOX6 treatment for unresectable liver metastases of colorectal cancer was made not only the conversion therapy possible, but it has improved the prognosis when compared with previous treatment without oxaliplatin. PMID- 22202334 TI - [Recurrance of disappearing colorectal liver metastases after mFOLFOX6 regimen]. AB - Some colorectal liver metastases disappear during chemotherapy. Some of those disappearing lesions recur, but there are few reports aiming this topic. We examined 6 patients with 55 disappearing liver metastases (DLMs) during mFOLFOX6 regimen. Six DLMs were resected, of which 3 (50%) had remnant cancer cells. Among the 49 DLMs not resected, 9 recurred after 23.5 (4.2-41.4) months. Cumulative risks of recurrence were 10.5% at 1 year, 10.5% at 2 years and 27. 5% at 3 years. Among these, some went through additional mFOLFOX6 or FOLFIRI regimen after they disappeared, but there was no significant difference among the number of the chemotherapy regimen and whether recurrences occur or not. The recurrence rate of the DLMs may be small, but further review with larger-scale group of DLMs is warranted. PMID- 22202335 TI - [The clinical outcome of mFOLFOX6 treatment for colorectal cancer patients who underwent resection of liver metastasis -comparison between synchronous and metachronous liver metastasis]. AB - Only a few reports have suggested the efficacy of adjuvant chemotherapy including oxaliplatin based regimens following surgical resection of liver metastases from colorectal cancer. Since an administration of mFOLFOX6 was approved to medical insurance for advanced colorectal cancer as adjuvant chemotherapy, we applied mFOLFOX6 treatment (6 to 12 courses) to the patients who underwent curative resection of colorectal liver metastasis. The subjects were 14 patients who underwent curative resection for synchronous or metachronous colorectal liver metastasis and received mFOLFOX6 treatment postoperatively from January 2006 to January 2011. We retrospectively analyzed the patient's characteristics, relapse free survival, overall survival, and adverse events in these patients. Synchronous liver metastasis was found in 5 patients, while metachronous liver metastasis was observed in 9 patients. There were no significant differences between these patients in terms of clinical characteristics, the relapse free survival and overall survival. All patients had some adverse events including bone-marrow suppression and diarrhea. Especially, grade 3 or higher bone-marrow suppression were recognized in 6 patients (42.8%). Neurologic toxicity (<= grade 2) was observed in 10 patients (71.4%). Adjuvant chemotherapy with mFOLFOX6 treatment following surgical resection of synchronous or metachronous liver metastasis was safely administered. We will further examine the benefit of mFOLFOX6 treatment for the patients who undergo a surgical resection of liver metastasis in the future. PMID- 22202336 TI - [Prediction of the efficacy of modified FOLFOX6 therapy according to the mRNA levels of thymidylate synthase (TS), excision repair cross-complementing-1 and 2( ERCC-1 and ERCC-2) and methylenetetrahydrofolate dehydrogenase( MTHFD) in the primary lesion of colorectal cancer]. AB - The aim of this study was to determine whether mRNA levels of thymidylate synthase (TS), excision repair cross-complementing -1 (ERCC-1), excision repair cross-complementing-2 (ERCC-2) and methylenetetrahydrofolate dehydrogenase( MTHFD) mRNA in the primary tumor could predict a tumor response in patients with unresectable liver metastasis from colorectal cancer treated with mFOLFOX6 therapy as a first-line treatment. Eighteen patients with unresectable liver metastasis from colorectal cancer treated with mFOLFOX6 therapy as a first-line treatment were enrolled in this study. There were no significant differences between the response rate and these enzymes mRNA levels. In ERCC-1 and MTHFD mRNA expression, the progression-free survival time tended to be longer in patients with low levels than in patients with high levels( ERCC-1: p=0.08, MTHFD: p=0.07). The progression-free survival time was significantly longer in patients with both ERCC-1 and MTHFD mRNA were low levels than in patients with other( p=0.03). The levels of ERCC-1 and MTHFD were low in patients who could perform a conversion therapy. There were no significant differences between an overall survival time and these enzymes mRNA levels. In this study, the ERCC-1 and MTHFD mRNA expression may be useful for the prediction of progression-free survival time in patients with unresectable liver metastasis from colorectal cancer treated with mFOLFOX6 therapy. PMID- 22202337 TI - [The Relationship between the efficacy of mFOLFOX6 treatment and the expression of TS, DPD, TP, and ERCC-1 in unresectable colorectal cancer]. AB - It has been reported that thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), and excision repair cross complementing-1 (ERCC-1) were useful markers to predict the efficacy of anti cancer agents including 5-fluorouracil (5-FU) and oxaliplatin for unresectable advanced colorectal cancer. In this study, we analyzed the relationship between the expression of these enzymes and the clinical significance in 49 Stage IV colorectal cancer patients who received mFOLFOX6 as a first-line treatment and evaluated the usefulness of these enzymes for predicting the efficacy of mFOLFOX6. There was no relationship between the expression of each enzyme and response rate. The progression-free survival of the patients with low TP expression was significantly longer than that of the patients with high TP expression( p<0.01). In the analysis of overall survival, the patients with low TP or low DPD expression were better than that with high TP expression or high DPD expression (p=0. 04, p=0. 04, respectively). Our results indicated that TP and DPD expression would be a useful marker to predict the efficacy of mFOLFOX6 in the patients with unresectable colorectal cancer. PMID- 22202338 TI - [Analysis of hepatic lymph node metastasis in liver metastases from colorectal cancer]. AB - We analyzed the clinical significance of hepatic lymph node metastasis in 48 patients who underwent a resection of colorectal liver metastases with hepatic lymph node (HN) dissection from 2001 to 2010. The frequency and the site of HN metastasis were investigated to clarify the relationship between clinical background and the significance of HN metastasis. In the frequency of HN metastases, positive lymph node metastases were detected in three (9.1%) out of 33 cases with synchronous liver metastasis and in one (6.7%) out of 15 cases with metachronous liver metastasis. In the site of HN metastasis, No. 8a and No. 12a lymph node metastasis was observed in one case each. No. 12b lymph node metastasis was seen in two cases. These cases with the presence of HN metastasis recurred within 13 months. On multivariate analysis using Cox proportional hazards models, hepatic lymph node metastases was an independent risk factor for overall survival (hazard ratio (95% CI): 4.165 (1.018-17.044), p=0.04). Our results indicated that HN metastases in colorectal liver metastases were a poor prognostic factor. Based on the results, we will examine the efficacy of adjuvant chemotherapy for the patients with HN metastases in the future. PMID- 22202339 TI - [Results of preoperative chemoradiotherapy for T4 rectal cancer]. AB - We reviewed clinical records of 11 cases with preoperative chemoradiotherapy to evaluate the clinical effectiveness of chemoradiotherapy for T4 rectal cancer. The preoperative radiotherapy consisted of 40-50 Gy delivered in fractions of 1 .8- 2.0 Gy per day, five days per week. A treatment of 5-fluorouracil, 500 mg/body per day intravenously, or oral UFT-E (300 mg/m2) with l-leucovorin (75 mg) per day, or oral S-1 (80 mg/m2) per day five days per week, was given during radiotherapy. One patient died due to pelvic abscess in 63 days after chemoradiotherapy. Invasive findings to the adjacent organs identified by CT and MRI disappeared in 6 cases with complete or partial response 1 month after chemoradiotherapy. Curative surgery was performed in 7 patients. Although the adjacent organs were also removed during surgery in 7 patients, there was no histological invasion to the adjacent organs in 4 patients, and one patient had histological complete disappearance of tumor. Although complications after surgery were found in all of the patients, they were improved by conservative treatment. Two of 7 patients with curative surgery had recurrence, but the rest of them survived without recurrence. Preoperative chemoradiotherapy was expected to be an effective treatment to improve the resection rate and prognosis for T4 rectal cancer. However, it was thought that it was necessary to be careful about severe toxicity, such as pelvic abscess. PMID- 22202340 TI - [Multimodal treatment for MFH originating from the psoas muscle-a case report]. AB - A 51-year-old male presented with lower abdominal mass and thigh and lumbar pain. CT scan showed a large retroperitoneal tumor compressing the lumbar vertebrae and IVC. Arterial infusion of mitomycin C, epirubicin and DSM was performed for unresectable tumor. The tumor was shrunken and the infusion repeated in 6 and 10 weeks later until right femoral palsy occurred. Radical resection with lumbar fascicles and psoas muscle and IORT (25 Gy) was performed. Local recurrence appeared before the sacrum in the next year. Arterial infusion and resection was done. Local recurrence invading the right common iliac artery was found five years later. The tumor and the artery were resected, followed by extra-anatomical ilio-iliac bypass. Local recurrences occurred in the 6th, 7th and 9th year. Radiation therapy was effective. But for the last recurrence, no radiation was applicable because of over dosage. As the most important thing in the treatment of MFH is to resect the tumor with curative margin at the initial operation, and the retroperitoneum and pelvic cavity are not good places to obtain good margins, multimodal treatment including irradiation should have been considered even preoperatively. Also consultation with orthopedic oncologists, radiologists, vascular surgeons and team practice are essential to get curative margins. PMID- 22202341 TI - [A case of the long-term survivor of rectal cancer who suffered from successive metastases to ovarium, peritoneum, liver, bone and para-aortic lymphonode]. AB - A 37-year-old female, who had undergone a low anterior resection for lower rectal cancer, had been received chemotherapy (FOLFOX4, FOLFIRI) for 2 years because of right ovarian metastasis occurred and removed 9 months after the first operation. One month after 2 years of continued chemotherapy, progressive metastases happened to occur successively (rt lunge, left ovarium, liver, para-aortic lymphonode, Virchow lymphonode and bone). Right upper lobe pnemonectomy was performed first, then, peritonectomy, total hysterectomy with left oophorectomy and a partial resection of the small bowel were done. IRIS, as postoperative chemotherapy, performed with hepatic arterial infusion (HAI) of CPT-11 and 5- FU resulted in getting a minimal response for about 10 months. Because of the hepatic arterial thrombosis at 10 months after the previous operation, we could not continue HAI with systemic chemotherapy, that was resulted in the progresion of mutiple metastases, and that the patient died 62 months after the first surgery. Immunohistochemical analyses with MIB-1 stainning of four surgical specimens revealed 80% positive cells in the cancerous tissues. PMID- 22202342 TI - [A case of metastatic rectal cancer in an extremely aged patient successfully treated with mFOLFOX6 plus bevacizumab]. AB - The safety and usefulness of FOLFOX therapy for elderly patients with metastatic colorectal cancer have not been clarified yet. We report an extremely aged patient case of metastatic colorectal cancer that was treated successfully with modified FOLFOX6 (mFOLFOX6) plus bevacizumab therapy. An 85-year-old man was diagnosed as having a low rectal cancer with paraaortic and left inguinal lymph node involvement. He was given mFOLFOX6 therapy after sigmoid colostomy. Bevacizumab was added to mFOLFOX6 after the second course. Although he experienced grade 2 neurtropenia and grade 1 neurotoxicity, the maximal diameter of the metastatic lymph nodes was decreased to a normal diameter after 9 courses. The primary tumor also disappeared and the biopsy revealed no cancer cells. He remains free of recurrence for 12 months after the end of chemotherapy. PMID- 22202343 TI - [Three cases of patients in their eighties who received anti-EGFR antibody mono therapy as first-line treatment for metastatic colorectal cancer]. AB - We report three cases of patients in their eighties who received anti-EGFR antibody mono-therapy as first-line treatment for metastatic colorectal cancer. CASE 1: An 86-year-old woman who received cetuximab after a colostomy for unresectable rectal cancer with synchronous liver and lung metastases. Serum levels of CEA and CA19-9 showed a significant decrease at 2 months, after which they showed a gradual increase. Computed tomography (CT) revealed a reduction in the rectal tumor. CASE 2: An 82-year-old woman who received cetuximab for peritoneal metastases after a transverse colectomy. Serum levels of CEA and CA19 9 decreased to normal levels at 2 months, and CT imaging revealed disappearance of the tumor in the peritoneal cavity. CASE 3: A 79-year-old man who received panitumumab for lung, liver and para-aortic lymph node metastases after a descending colectomy. Serum levels of CEA and CA19-9 showed a decrease at 1 month, after which they showed a gradual increase. No marked change in the tumor was observed by CT. No change was observed in performance status or Vulnerable Elders Survey( VES-13) score, and the effect on overall condition was minimal. Grade 1-2 acneiform skin rash, paronychia, and desquamation, and grade 2-3 dry skin and pruritis were observed. More precise instructions on measures for dealing with skin rash are necessary to obtain higher drug compliance. PMID- 22202344 TI - [A case of unresectable multiple hepatic metastases from colorectal cancer successfully treated with panitumumab therapy on third-line]. AB - In a patient with multiple liver metastases of colorectal cancer in whom tumor response had been achieved by 5-FU hepatic arterial infusion, the catheter for arterial infusion chemotherapy was occluded resulting in re-elevation of tumor marker levels. Second-line IRIS therapy using S-1 and CPT-11 was started. IRIS therapy reduced tumor marker levels to a degree greater than that previously achieved with 5-FU hepatic arterial infusion, and diagnostic imaging allowed a judgment of partial response. But tumor marker levels increased gradually. After all, diagnostic imaging allowed a judgment of progressive disease and an eminent elevation of tumor marker levels in one year. Third-line panitumumab therapy was started. Panitumumab therapy reduced tumor marker levels to a degree greater than that previously achieved with 5-FU hepatic arterial infusion and IRIS therapy, and diagnostic imaging allowed a judgment of partial response. We report herein a successful case. Hepatic arterial infusion therapy is one of the treatment methods characterized by a lower incidence of adverse reactions, relatively low cost, and expectation of high anti-tumor efficacy as compared to chemotherapy such as FOLFIRI. IRIS therapy does not require a port insertion and pump carrying, and its cost is about half of FOLFIRI therapy. When used as second-line therapy for unresectable colorectal cancer, non-inferiority of IRIS therapy to FOLFIRI therapy has been demonstrated in a phase II/III clinica (l FIRIS) study. We may say that IRIS therapy is promising as an equivalent to hepatic arterial infusion therapy in the treatment of liver metastases of colorectal cancer. In addition, we may say that panitumumab therapy is promising as an equivalent to hepatic arterial infusion therapy and IRIS therapy. PMID- 22202345 TI - [mFOLFOX6 and FOLFIRI/bevacizumab treatment in a patient on hemodialysis with metastatic colon cancer]. AB - A 58-year-old woman, who was undergoing peritoneal dialysis( PD) for chronic kidney disease (CKD) and had been operated by sigmoidectomy for early colonic cancer, was diagnosed as peritoneal recurrence of the colonic cancer. Her treatment for CKD was switched from PD to hemodialysis. She was administered mFOLFOX6 therapy(reducing the dose to 70%). Hemodialysis was performed 1 hour after administration of oxaliplatin on day 1 and repeated two days later after the completion of drug administration. No serious adverse events were observed. After 10 courses of mFOLFOX6, an ovarian metastasis was appeared. We then changed the regimen to FOLFIRI (70% dose)/bevacizumab (BV). Neutropenia (grade 4) was observed after the second treatment. After some rest, 21 courses of FOLFIRI/BV therapy were performed safely by reducing the dose to 60%. We thought that a reduced dose of FOLFIRI/BV therapy appeared to be safe for a patient with chronic kidney disease who is on hemodialysis. PMID- 22202346 TI - [A case report of pathologically complete response of rectal cancer after preoperative treatment of CPT-11, S-1, and radiation therapy]. AB - A 52-year-old woman diagnosed with lower rectal cancer was referred to our hospital for the operation of anal sphincter preservation. Rectal examination and colonoscopy showed a type 2 semicircular tumor on the posterior wall at 4 .5-7 cm from anal verge with incomplete mobility (cT3). She was diagnosed as the moderately differentiated tubular adenocarcinoma by biopsy. Computed tomography and magnetic resonance imaging showed no sign of invasion to the surrounding organs and metastasis to lymph nodes or the other organs (cN0, cM0). We performed a preoperative chemoradiotherapy (CRT) combined with S-1 and CPT-11. Radiation (1.8 Gy) was administered a total of 45 Gy( day 1-5, 8-12, 15-19, 22-26, 29-33). S-1 was taken orally( 100 mg/day: day 1-5, 8-12, 22-26, 29-33), and CPT-11 was administered intravenously (60 mg/m2: day 1, 8, 22, 29). Endoscopy after CRT showed a reduction of the tumor size (from semicircular to quarter-circular) and lowering of marginal wall. Rectal examination revealed an improvement of tumor mobility. Eight weeks after CRT, the patient underwent ISR with partial ESR and covering ileostomy pathological examination demonstrated no residual cancer cell in the primary lesion and lymph node (Grade 3, pCR). Preoperative CRT can be a promising tool for locally advanced rectal cancer. PMID- 22202347 TI - [A case of long-term survival after curative resection of advanced rectal cancer treated by pre-operative chemoradiotherapy]. AB - We report a long-term survival case of rectal cancer that was initially thought unresectable treated with chemoradiotherapy (CRT). The patient was a 50s female with advanced rectal cancer and liver metastasis. The primary tumor was expanded locally and made abscess around the rectum. We evaluated the primary lesion as unresectable, and we performed CRT after colostomy. After radiation therapy (total 60 Gy) and chemotherapy with S-1 (3 courses), the primary tumor was remarkably reduced. The liver metastasis showed a progressive growth in size but not in number. She underwent complete resection of rectal tumor and partial resection of metastatic liver tumor. Postoperative course was uneventful, and she is alive without a recurrence for 5 years after the surgery. PMID- 22202348 TI - [A case of rectal cancer with interstitial pneumonia successfully treated with preoperative radiation therapy]. AB - We report here a case of rectal cancer with interstitial pneumonia was successfully treated with preoperative radiation therapy. An 81-year-old man with complaints of constipation and melena was admitted to our hospital for the purpose of close inspection and medical treatment. In colonoscopic examination, we found a type-3 9 cm tumor in mainly occupied lower rectum (Rb), which developed all circumference-related stenosis. We diagnosed the tumor as Group V (adenocarcinoma) in biopsy. In abdominal computed tomography (CT) scan, the rectal tumor was directly invaded to the prostate and left internal obturator muscle. We diagnosed it to be cStage II rectal cancer (Rb) from various image findings. In addition, chest CT showed interstitial pneumonia. At first therapy, we did not perform pelvic evisceration nor chemotherapy because the patient was aged having interstitial pneumonia. We performed loop colostomy and preoperative radiation therapy (total 50 Gy). After the radiation therapy, there was a notable reduction in tumor, and a direct invasion to the prostate and left internal obturator muscle was not identified upon imaging. After the one year course of radiotherapy, we performed Mile's operation. After the operation, we did not perform adjuvant chemotherapy, but there has been no recurrence observed. PMID- 22202349 TI - [Curative laparoscopic surgery performed after neoadjuvant chemotherapy for locally advanced rectal cancer invading into the vagina]. AB - A 60-year-old woman with locally advanced rectal cancer, which had infiltrated into the vagina, was referred to our department in September 2010. She received 4 courses of neoadjuvant chemotherapy; the tumor size reduced, but the fistula was not closed. Because the tumor size had reduced, we performed a laparoscopic surgery. The laparoscopic surgery involved perineal proctectomy and resection of the posterior wall of the vagina, along with dissection of the bilateral lymph nodes. The efficacy of the neoadjuvant chemotherapy was judged as Grade 2. Neoadjuvant chemotherapy should be considered in patients with locally advanced lower rectal cancer with infiltration into other organs. PMID- 22202350 TI - [Two cases of neuroendocrine carcinoma of the rectum]. AB - We report two cases of neuroendocrine carcinoma of the rectum. CASE 1: A 50s woman was diagnosed as rectal cancer and underwent anterior resection of the rectum and lymphnode dissection. The histological diagnosis was neuroendocrine carcinoma with peritoneal dissemination. She was treated with chemotherapy as an outpatient. One year later from the operation, multiple liver metastases were revealed and she died eight months later. CASE 2: A 50s man underwent endoscopic mucosal resection (EMR) of the rectum as rectal tumor and histological diagnosis was an early well-moderate deferenciated carcinoma and its cut-tend was unclear. He received a careful follow-up. One year later, a follow-up colonoscopy revealed a submucosal tumor in the lower rectum. He was diagnosised with local reccurence of rectal cancer, and then underwent an abdominoperineal resection of the rectum and lymphnode dissection. The histological diagnosis was poorly differenciated neuroendocrine carcinoma with lymphnode metastasis. Two months later from the operation, a local reccurence was revealed and he was treated with octreotide and irradiation. PMID- 22202351 TI - [A case of colonic neuroendocrine carcinoma with severe liver dysfunction by multiple liver metastases successfully treated with hepatic arterial infusion]. AB - A 63-year-old male was diagnosed as ascending colon cancer with severe liver dysfunction caused by multiple liver metastases. Initially, hepatic arterial infusion (HAI) chemotherapy was started to reduce the size of metastatic tumors and to prevent a liver failure. After 7 courses of HAI chemotherapy, he recovered from liver dysfunction, and underwent right hemicolectomy. Pathological examination of the resected specimen revealed the tumor was neuroendocrine carcinoma. After surgery, a systemic infusion of mFOLFOX6/bevacizumab regimen was started. A partial response (PR) of metastatic lesions was observed. Irinotecan/cetuximab was administered as the second-line. He survived for 10 months after HAI. HAI for colonic neuroendocrine carcinoma with severe liver dysfunction by multiple liver metastases might be benefitial to prevent a liver failure. PMID- 22202352 TI - [A long-term survival case of neuroendocrine tumor of the sigmoid colon with multiple liver metastases]. AB - It has been reported that neuroendocrine tumor (NET) of the large intestine with distant metastasis is rare and carries poor prognosis. We report a case of colonic NET with hepatic metastases, who was successfully treated by combined therapy. A 71-year-old man with sigmoid colon tumor underwent sigmoidectomy and histopathological examination disclosed the tumor was NET grade 1. Multiple liver metastases and lymph node metastasis on the posterior surface of the pancreatic head were detected at the time of surgery. Trans-catheter arterial chemoembolization (TACE; doxorubicin and ethiodized oil and gelatine sponge particle) was performed. Partial response (PR) was observed after 2 times of administration. Radiation therapy was performed for the lymph node metastasis eight months after surgery and PR was observed. The patient was alive after 48 months and TACE was continued. Combined therapy including surgery, irradiation, and chemotherapy, although not yet standardized, is required against NET with hepatic metastases. PMID- 22202353 TI - [A case of anal canal cancer with pagetoid spread and inguinal lymph node involvement]. AB - We report a rare case of pSM anal canal cancer with pagetoid spread and inguinal lymph node involvement. A 74-year- old woman was admitted to our hospital complaining of a perianal erythematous lesion. Preoperative skin biopsy revealed an infiltration of pagetoid cells and signet-ring cell carcinoma cells, which were positive for CK20 and negative for GCDFP 15 by immunohistochemical stainings. Colonoscopy demonstrated an elevated lesion located just above the dentate line. Total pelvic exenteration with lateral and inguinal lymph node dissection followed by skin reconstruction with gluteal thigh flap was performed. Histological examination of the anal tumor revealed moderately differentiated adenocarcinoma infiltrating the submucosa( pSM) with left lymph node involvement. We should note that pSM anal canal cancer with pagetoid spread might cause inguinal lymph node metastasis, even though such cases have rarely been reported in the literature. PMID- 22202354 TI - [Multidisciplinary treatment including pneumonectomy for squamous cell carcinoma of the anal canal-a case report]. AB - In August 2008, a 52-year-old woman presented to our hospital with a complaint of bleeding upon defecation. The patient underwent lower gastrointestinal endoscopy with biopsy. PRb indicated a type 2 lesion in one-third of the circumference. The patient was diagnosed with squamous cell carcinoma by biopsy. Imaging did not reveal any metastasis to other organs. In September, she underwent an abdominoperineal resection of the rectum. Postoperative histopathological findings were PRb, type 2, A, N3, H0, P0, M0, and Stage III b. Adjuvant chemotherapy of oral S-1 was started. In January 2009, contrast-enhanced abdominal CT revealed a pelvic recurrence, and the patient underwent chemoradiotherapy. In October, chest CT showed a 5-mm solitary pulmonary metastasis in the right apex of the lung. In March 2010, chest CT showed a slight enlargement of the tumor in the right apex, but no other metastatic lesion was observed. In April, the patient underwent a thoracoscopic partial pneumonectomy. It has been 16 months postoperatively, and no recurrence has been observed. In the present report, we describe a case of squamous cell carcinoma of the anal canal that underwent multidisciplinary treatment including pneumonectomy. We also include a brief literature review. PMID- 22202355 TI - [A case report of chemoradiotherapy combined with S-1 responding to squamous cell carcinoma of the anal canal]. AB - A 79-year-old woman was reffered to our hospital with the chief complaint of hematochezia. Type-2 tumor was found on anal canal by colonoscopy, and pathologic examination revealed a poorly differentiated squamous cell carcinoma. Computed tomography of the abdomen demonstrated obturatory node metastasis. The patient was diagnosed as having squamous cell carcinoma of the anal cana (l cStage III). After four months from chemoradiation (66 Gy/33 Fr plus S-1), the ulcer side was improved completely to epithelization, and abdominal CT scan showed a remarkable reduction of obturatory node metastasis. She was obtained a complete response. Now the patient is disease-free for ten months after chemoradiation. PMID- 22202356 TI - [A case successfully treated with abdominoperineal resection after preoperative chemoradiation therapy for anal cancer]. AB - A 46-year-old female was diagnosed with anal squamous cell carcinoma. Chemoradiation therapy was administered for a first-line therapy. Two courses of enforced 5-FU/MMC combination therapy were administered along with radiotherapy (60 Gy). This chemoradiation therapy had complete response. However, three months after, anal cancer had a local recurrence. Since there was no distant metastasis, abdoninoperineal resection was performed. No complications were observed after the operation. We conclude that abdominoperineal resection may be effective in the treatment of anal cancer in cases which the local recurrence was observed after chemoradiation therapy. PMID- 22202357 TI - [Two cases of ovarian metastasis of colon cancer]. AB - CASE 1: A 45-year-old female underwent sigmoidectomy, simple total hysterectomy and bilateral adnexotomy for sigmoid colon cancer and a right ovarian metastasis in December 2007. As adjuvant chemotherapy, S-1 was conducted for six months. She remains disease-free for 38 months after the surgery. CASE 2: A 61-year-old female underwent simple total hysterectomy and bilateral adnexotomy for bilateral ovarian tumors following the surgery for colon cancer, metastatic liver cancer and gastric cancer in January 2010. As adjuvant chemotherapy, capecitabine was administered seven times. Five months after the last surgery, para-aortic lymph node recurrence was diagnosed. FOLFIRI/panitumumab therapy was maintained. For both of the two cases in immune-staining, CK20 staining was positive, and CK7 staining was negative. Ovarian tumors were diagnosed as metastasis from colon cancer. Ovarian metastasis of colon cancer is a relatively rare event, but a long term survival case has been reported by multimodality therapy including surgery. PMID- 22202358 TI - [A case of laparoscopic radiofrequency ablation for liver metastatic tumor from colorectal carcinoma]. AB - Hepatic resection is a first choice for resectable liver metastatic tumor from colorectal carcinoma. In the case of unresectable tumor or a refusal to operation, laparoscopic radiofrequency ablation (RFA) becomes an option to treat. We report a case of laparoscopic RFA for liver metastatic tumor from colorectal carcinoma. A 74-year-old woman had a laparoscopic transverse colectomy for transverse colon cancer with multiple liver metastases in February 2009. She received UFT/LV and liver metastases were reduced. After the second course, the patient desired to stop chemotherapy. But the liver metastases had grown again. We recommended a hepatic resection. Since she didn't want to have the operation, we performed RFA. After the RFA, a liver metastasis was detected twice. After tumors were located near other organs, we performed a laparoscopic RFA. At 9 months after undergoing last RFA, she had no recurrence in the liver. We thought laparoscopic RFA was safe and effective for the lesion, which was difficult to treat with percutaneous approach RFA. PMID- 22202359 TI - [A case of advanced transvers colon cancer with inguinal lymph node metastasis]. AB - An 80-year-old woman complaining of a right inguinal induration and pain was performed an inguinal lymph node resection. Histological examination with immnohistochemistry revealed that the lymph node was metastasis of colon carcinoma. With total colonoscopy, she was diagnosed as advanced transvers colon cancer with right inguinal lymph node metastasis. She was performed a right hemi colectomy. She was dead with peritoneal metastasis of colon cancer 2 years and 1 month later. We report this case that was diagnosed having transverse colon cancer with inguinal lymph node metastasis. PMID- 22202360 TI - [An example of metastasis to the iliopsoas muscle from sigmoid colon cancer]. AB - Even though skeletal muscle, making up about 40% of body weight, is the largest organ in the human body, metastasis from malignant lesions is rare. Among reports of metastasis, those involving the iliopsoas muscle are numerous but few reports involve resection. Reported here is one example we experienced where metastasis developed in the iliopsoas muscle following colectomy, resection was then made possible by radiotherapy and chemotherapy. The case involved a 71-year- old male in which a Hartmann procedure was performed for sigmoid colon cancer. The pathology was Type 3 (8 * 7 cm, adenocarcinoma( mod), ss or more, ly1, v1, n0, ow(-), aw or ew(+), stage II). Upon additional sampling, thermal degredation of neoplastic cells was shown and outpatient oral UFT was performed. Five years following surgery, lymphoadenopathy was noted in the area of the left iliac artery upon US and CT. PET showed a probable metastasis to the left iliopsoas muscle. Early esophageal and stomach cancer were diagnosed by GFT. The esophageal cancer was located 30-32 cm from the incisors, unstained, Borrmann type 1, penetrating deeper than the muscularis propria. Biopsy revealed a diagnosis of tubular adenocarcinoma. ESD was performed for the esophageal cancer and one month later, a total gastrectomy D1+beta was performed. During surgery, the iliopsoas muscle tumor was determined to be large and impossible to resect. Radiotherapy of 10MV X-ray, 8 fields, 65-70 Gy/26 times for 6 . 5 weeks was performed for residual tumor but had no effect on tumor size. Fifteen courses of FOLFOX+bevacizumab were then performed. The tumor was markedly reduced in size, unidentifiable upon CT but showed slight uptake on PET and resection of the suspected residual tumor was performed. Histologically, atypical cells were shown in scarred muscle and connective tissue, however, degradation by chemotherapy was high. Residual tumor at resection margins was found, findings consistent with metastasis form sigmoid colon cancer. Taking into account the age and condition of the patient following surgery, chemotherapy was changed to S-1. Currently, 5 months after resection, there has been no recurrence. PMID- 22202361 TI - [A case of transverse colon cancer without a recurrence lesion after five years from resection of hepatic metastasis]. AB - The treatment of hepatic metastasis of colon cancer was in progress by new biochemical agents. Generally, a resection was the first alternative treatment against hepatic metastasis of colon cancer, but new antitumor agents were more effective than conventional antitumor agents. Disappearance of metastasis for colon cancer treated with only antitumor agents was commenced to report. We were experienced a case of transverse colon cancer without a recurrence lesion after five years from the resection of hepatic metastasis. A case was a 77-year-old man. He was operated against transverse colon cancer in February 2003. Pathological stage was ss, n0, Stage II. In April 2004, serum CEA was increased. CT examination was not detected a hepatic metastasis but ultrasound examination and MRI detected the metastasis at S7 lesion in the liver. In July 2004, he was admitted to S-1 and PSK until October 2004. In December 2004, the lesion of hepatic metastasis was reduced and serum CEA was decreased. But in September 2005, the metastatic lesion was re-grown. A resection for hepatic metastasis was executed in November 2005. After the resection for hepatic metastasis, he was admitted to UFT/ UZEL from January 2006 to October 2006. Present time( June 2011), the lesion of recurrence was not detected by several examinations (CT, MRI, Ultrasound etc). PMID- 22202362 TI - [Repeated resections for originally unresectable liver metastasis from colorectal cancer after multiagent chemotherapy]. AB - We describe the case of a 74-year-old man with liver resection for originally unresectable liver metastasis from colorectal cancer after multiagent chemotherapy. Eleven bilobar liver metastases appeared four months after curative resection for double cancer of sigmoid colon and upper rectum. After 6 courses of multiagent chemotherapy (mFOLFOX 6 with bevacizumab), the number of liver metastasis decreased from 11 to 5. The patient underwent curative resection for liver metastasis. A new lesion of 7 mm in the segment 6 appeared 8 months after an initial liver resection. After 3 months' observation, two more liver metastases appeared. All liver metastases were resected. Solitary lung metastasis appeared 10 months after the second liver resection. The lung metastasis was also resected. The patient was alive with no evidence of disease in 33 months after the initial liver resection. We experienced the case with repeated liver resections after multiagent chemotherapy for originally unresectable bilobar liver metastasis. The therapeutic strategy which combines surgical resection with cytotoxic chemotherapy will be important more than ever. PMID- 22202363 TI - [A case of no recurrence over 10 years in advanced rectal cancer with bleeding treated by urgent arterial embolization followed by synchronous liver resection and extended lymph node dissection]. AB - A 68-year-old woman was brought by ambulance due to abrupt anal bleeding. Elastic hard and solid mass was found in rectal examination. The pathological diagnosis of the tumor revealed adenocarcinoma. The metastatic 40 * 40 mm liver tumor was also found at CT scan. Acute bleeding with hemoglobin level of 6 .0 g/dL necessitated an urgent arterial embolization of bilateral internal iliac artery and superior rectal artery. After recovery from the systemic condition, radical operation was performed, comprising abdomino-perineal resection of the rectum with extended lymph node dissection involving paraaortic area followed by synchronous liver resection. Arterial infusion of 5-FU (11.0 g in total) via proper hepatic artery was added postoperatively. She was followed for over 12 years, and no recurrence was observed. PMID- 22202364 TI - [A case of colon cancer with long-term survival treated by resection of recurrence on the rectum and chemotherapy for lung metastasis]. AB - A 69-year-old male was operated on sigmoidectomy for sigmoid colon cancer (SS, N2, H0, P0, M0, stage IIIb) 7 years ago. Two years later, he was diagnosed for rectal cancer and bilateral lung metastases by TBLB. We performed Mile's operation, and the rectal focus was pathologically diagnosed with a recurrence of sigmoid colon cancer. After surgery, chemotherapy with FOLFOX was started for bilateral lung metastases, resulting in CR during the 22 months. But bilateral lung metastases were exacerbated, and then we administered several other chemotherapies. Five years have passed since chemotherapy started, although the focuses tended to progress. Right now, he has been a chemotherapy outpatient for last 5 years. PMID- 22202365 TI - [A case of long-term survival by combined modality therapy for liver and pulmonary metastasis of rectal cancer]. AB - We report a case of rectal cancer diagnosed in 2001, which enforced a rectal low anterior resection. Then, metastatic liver cancer and metastatic lung cancer recurred and we enforced an operation for both. Furthermore, metastatic lung cancer recurred again and enforced chemotherapy with radiation and systemic chemotherapy for approximately seven years. The metastatic lung cancer was reduced now in 2011, so that the chemotherapy has not been used since then. In our case, we mainly performed a surgical and radiation therapy for a local recurrent site therapy in the first half because we did not have much choice for a systemic chemotherapy like we have now. In the later half, we mainly performed a systemic chemotherapy to control the local recurrent site. A treatment policy for colon cancer recommends a surgical treatment by the guidelines, or even though chemotherapy has been developed at present, if a local therapy is practical. There were many cases where metastases had occurred right after surgery so a local site therapy by excision was good at all unconditionally. However, as a result of our case in a local site therapy combined with whole body chemotherapy, we report here that a long- term survival was obtainable. We also include a brief literature review. PMID- 22202366 TI - [A surgical case of descending colon cancer with abdominal wall abscess after drainage of abscess]. AB - We report a surgical case of descending colon cancer with abdominal wall abscess. A 72-year-old man was admitted to a hospital because of left lower abdominal mass with slight pain. An abdominal CT showed a left lower abdominal wall abscess adjacent to the descending colonic wall thickening. We diagnosed an abdominal wall abscess due to descending colon cancer or colon diverticulitis. The abscess was drained under local anesthesia releasing foul-smelling pus and air. After abscess drainage and general improvement in his condition, we conducted subtotal colectomy with lymph node dissection and excision of abdominal wall abscess cavity. Pathological findings indicated moderately differentiated adenocarcinoma of the descending colon (pT4, pN0, sH0, sP0, sM0, fStage II). The carcinoma had invaded the abdominal wall and transverse colon, but the cancer cells were not shown in the abdominal wall abscess cavity. In abdominal wall abscess treatment, colon cancer should be considered as a potential underlying cause. CT proved useful for assessing the status of the tumor and the abscess. We conducted a radical operation for descending colon cancer after the drainage for abdominal wall abscess. PMID- 22202367 TI - [Two cases of recurrence at anastomosis site with leakage after operation for rectal cancer]. AB - We report two cases of recurrence at an anastomosis site with leakage after operation for rectal cancer. In these cases, we thought that an implantation on leakage sites should be occurring by remaining stool with cancer cell. Colorectal cancer with ileus owing to obstacle by tumor, such as our cases, has a high risk of leakage at the anastomosis site and developed a complication that increased the risk of local recurrence. In our case of colorectal cancer with ileus owing to stenosis by tumor, a treatment method including the selection of operation should be contemplated how to prevent a local recurrence. PMID- 22202368 TI - [A case of delayed colonic perforation after metallic stent placement for advanced descending colon cancer during bevacizumab-based chemotherapy]. AB - A 73-year-old man with advanced descending colon cancer and peritoneal metastases underwent a self-expandable metallic stent placement under fluoroscopic guidance on October 2007. The stent placement was successful without early complication. After 6 courses of FOLFOX4 followed by 7 courses of FOLFIRI, he received Bevacizumab-based chemotherapy from August 2008. In April 2009, he was admitted to our hospital with severe abdominal pain due to perforation of descending colon. Although emergent surgery was performed, he developed DIC and died on the 21 postoperative days. This case suggests that metallic stent placement for colorectal cancer cases might increase the risk of bowel perforation during Bevacizumab-based chemotherapy. PMID- 22202370 TI - [A case of liver tumor diagnosed 5 years after gastrectomy against gastric cancer]. AB - A-62-year-old man with gastric cancer underwent gastrectomy 5 years ago, and an abdominal computed tomography scan detected a 15 mm early enhanced lesion located liver (S8) in 2008. Although primary or metastatic were unclear, we underwent partial hepatectomy( S8) as it was an isolated liver tumor. Pathological finding showed adenocarcinoma, and immunostaining was negative for cytokeratin (CK) 7 and positive for CK20 which was the same in primary gastric cancer, so it was diagnosed liver metastasis of gastric cancer. The patient was living at the time, but he passed away 24 months after hepatectomy. We report herein the case of resectable case of liver tumor 5 years after gastrectomy against gastric cancer. PMID- 22202369 TI - [A case of encephalopathy that was suspected to be caused by chemotherapy for colon cancer]. AB - We report a case of encephalopathy that was suspected to be caused by chemotherapy for liver metastasis from sigmoid colon cancer. A 72-year-old male was suspected that he had drug-induced eukoencephalopathy because he was presented with physical disorders during the FOLFOX/bevacizumab therapy. Although a brain MRI revealed Alzheimer disease, leukoencephalopathy was not excluded from the diagnoses due to a fact that his findings could not be compared before and after the chemotherapy. If leukoencephalopathy was suspected, chemotherapy should have been discontinued as soon as possible. Although a partial response was achieved, chemotherapy had to be discontinued in this case. The cases whose physical and neurological disorders were at risk due to a past history need an examination for nervous system in order to make a comparison with the findings before and after chemotherapy. PMID- 22202371 TI - [A case of AFP-producing gastric cancer patient with liver relapse occurred three months after endoscopic mucosal resection (EMR) and gastrectomy]. AB - A 60s male was admitted to our hospital for a diagnosis of gastric tumor sized 20 mm in diameter at the fornix of the stomach. Endoscopic mucosal resection (EMR) was performed, and the resected tumor was pap, m, ly0, v0, HMX, VM0, pathologically. One month after the EMR, the local recurrence was confirmed and a partial gastrectomy was performed. Pathological findings were tub1, sm2, ly1, v1, HM0, VM0. Total gastrectomy was added because of the possibility of the lymph node metastasis. Pathological findings revealed no residual cancers. The final pathological diagnosis was T1b(sm2) N0H0P0M0, Stage IA, based on the Japanese classification of gastric cancer. Three months thereafter, CT showed multiple liver metastases. Immunohistochemical study of the operated tumor revealed AFP producing gastric cancer. Chemotherapy was performed, but he died of the gastric cancer. Endoscopic treatment is a minimally invasive therapeutic strategy, but it requires a considerable care in application. PMID- 22202372 TI - [Prognosis and clinical course of gastric cancer with para-aortic lymph node metastasis after curative D2 gastrectomy and adjuvant chemotherapy with S-1]. AB - BACKGROUND: Survival and clinical course were unknown in patients with recurrence of para-aortic lymph node after curative D2 gastrectomy and adjuvant S-1 chemotherapy. METHODS: The study examined clinical characteristics and prognosis of 3 patients who had para-aortic nodal recurrence after curative D2 gastrectomy and S-1 adjuvant chemotherapy. RESULTS: Initial stage was III C in all of the patients. Median treatment interval of S-1 was 8 . 8 months. Para-aortic nodal metastasis was single in 2 and multiple in 1 patient. Median survival time was 14 .3 months. Other recurrent sites than para- aortic node were not seen in all of the patients. CONCLUSIONS: In the times of S-1 adjuvant chemotherapy, it is valuable to know whether para-aortic node should be resected prophylactically, or be treated after recurrence, or be treated by locally or systemically. PMID- 22202373 TI - [A case of locally advanced gastric cancer responding to preoperative S-1/CDDP combination chemotherapy]. AB - A 59-year-old man visited our department with the complaint of an abdominal mass. After detailed examination, he was diagnosed with cT3 (SE) N2M0, cStage III C gastric cancer and underwent a 3 course preoperative S-1/CDDP combination chemotherapy. After tumor down-staging was achieved after the 3 course combination chemotherapy, a surgery was scheduled. The patient underwent distal gastrectomy with D2 lymph node dissection. Histopathological diagnosis was M, type 1, 75 * 35 mm, papillary>moderately-differentiated tubular adenocarcinoma [pT2 (MP), ly3, v0, pN2, Stage IIB]. The patient is now treated with oral S-1 as postoperative adjuvant chemotherapy on an outpatient basis, and there are no signs of recurrence as of 1 year after the surgery. Preoperative chemotherapy appears to be a promising treatment option for gastric cancer with extensive lymph node metastasis. PMID- 22202374 TI - [A case of unresectable gastric cancer with pyloric stenosis which was resectable by chemotherapy after gastrojejunostomy]. AB - A man in his fifties was referred to our hospital for anorexia and vomiting. Upper gastrointestinal endoscopy showed a gastric cancer (Borrmann Type 3) with pyloric stenosis. We performed gastrojejunostomy to allow oral intake for a tumor invading the pancreas head (cT4bN1H0P0CY1, Stage IV). After the operation, systemic chemotherapy with S-1 (120 mg/m2) was administered from July 2007, which caused grade 3 mucositis oral and drug rash after one week. Then, bi- weekly administration of CPT-11 (60 mg/m2) and CDDP (30 mg/m2) was started from August 2007 as second-line chemotherapy. The treatment was repeated for 14 courses till an allergic reaction happened. A weekly paclitaxel (PTX) therapy (80 mg/m2) was started from January 2009 as third-line. After 6 courses, CT showed that direct invasion to the pancreas was not clear any more, so a distal gastrectomy with D1 lymphadenectomy was performed on August 2009 (ypT3N- 1P0CY0, Stage IIB). The patient received 9 courses of weekly PTX therapy and after that the treatment has been discontinued. Recurrence was not observed for 48 months after an initial treatment. PMID- 22202375 TI - [Two cases of advanced gastric cancer completely responding to S-1 neoadjuvant chemotherapy]. AB - CASE 1: A 67-year-old man had advanced gastric cancer with lymph node metastasis (cT3N1M0, cStage IIIA). S-1 120 mg was administered for 21 days as neoadjuvant chemotherapy (NAC). A month later, total gastrectomy (with splenectomy) was performed. Histopathological examination revealed no cancer cells in the gastric wall and dissected lymph nodes. CASE 2: A 62-year-old man had advanced gastric cancer with lymph node metastasis (cT4aN2M0, cStage IIIB). He was treated with daily oral administration of S-1 120 mg (28-day administration followed by 7-day rest, and then 14- day administration) as NAC. A month later, total gastrectomy was performed. Histopathological examination revealed no cancer cells in the gastric wall and dissected lymph nodes. In both cases, the pathological effect was judged as grade 3. This suggests that NAC with S-1 mono-therapy can have a distinct therapeutic value for advanced gastric cancer. PMID- 22202376 TI - [Combination chemotherapy using docetaxel, cisplatin, and S-1 for far advanced gastric cancer]. AB - Combination of docetaxel, cisplatin, and S-1 (DCS) is expected as a new treatment regimen for far advanced gastric cancer. We performed DCS chemotherapy for six patients, including four cases with invasion to pancreas, three cases with para aortic lymph node metastasis, and two cases with liver metastasis. Clinical stages were either IIIC or IV for all of the patients. The patients received 2-4 courses of docetaxel (40 mg/m2) and cisplatin (60 mg/m2) on day 1, and S-1 (80 mg/m2) on days 1-14 every 4 weeks. The response rate was 83% (5 PR and 1 SD), and the disease control rate was 100%. Grade 3/4 neutropenia, grade 3 febrile neutropenia, and grade 3 diarrhea were observed in three cases (50%), one case (17%), and one case (17%), respectively. Four of six patients underwent R0 surgery after DCS chemotherapy, and no severe complication was occurred. Histological responses were Grade 2 for two cases, Grade 1b for one case, and Grade 1a for one case, respectively. DCS regimen showed a high objective tumor response, and also is one of the promising regimens as neoadjuvant setting for far advanced gastric cancer. PMID- 22202377 TI - [A case report of stage IV inoperable gastric cancer demonstrating a cCR treated with S-1/Paclitaxe (l PTX) therapy]. AB - We report a case of Stage IV inoperable gastric cancer demonstrating a cCR treated with S-1/PTX. The patient was a 65-year-old female with advanced gastric cancer. CT scan suggested an invasion of tumor into a pancreatic body, jejunum and transverse colon. Staging laparoscopy showed it to be positive with peritoneal washing cytology and peritoneal dissemination. The surgical findings were T4a (SE) N2M1H0P1CY1, Stage IV. Chemotherapy was conducted with a combination of S-1/CDDP. After 2 courses of this regimen, the endoscopy findings did not show an improvement, so we decided to change the chemotherapy to S-1/PTX as second-line treatment. After 2 courses of this regimen, the endoscopy findings revealed a reduction of the primary tumor. After 19 courses, histopathological examination of biopsy specimen showed Group 1. Second-line chemotherapy was continued for 28 courses. The patient has had no recurrence without chemotherapy and been alive for 91 months after diagnosis. PMID- 22202378 TI - [A case of long-term survival after undergoing S-1 based multidisciplinary therapy for liver metastasis of gastric cancer]. AB - We encountered a case of gastric cancer accompanied with liver metastasis, which had a good response to chemotherapy of S-1. A 68-year-old female was admitted to our hospital due to further examination of gastric tumor detected by an outpatient physician. She was found to have a type-3 gastric cancer in upper gastrointestinal endoscopy and a metastatic tumor of the liver in abdominal CT. Although chemotherapy of S-1 was inducted for the lesions, both the primary and liver tumors were dramatically reduced. We subsequently performed total gastrectomy and partial hepatectomy. Abdominal CT scan at 11 months after the initial operation revealed metachronous liver metastasis. She received combination chemotherapy of S-1 and CDDP. After 5 courses of the combination chemotherapy, the liver tumor disappeared. She has survived for 8 years without a recurrence after the initial operation. There was negative findings of immunostaining with thymidylate synthetase (TS), which was target enzyme for 5-FU at a biopsy sample of the primary gastric tumor before chemotherapy of S-1. TS immunostaining may be a useful marker for S-1 combined therapy for gastric cancer associated with liver metastases. PMID- 22202379 TI - [Treatment of S-1 plus weekly CDDP for advanced gastric cancer]. AB - We analyzed the clinical efficacy and safety of chemotherapy using S-1 plus weekly CDDP( w-CS therapy) for unresectable gastric cancer. Twenty one patients were treated with this treatment. S-1 80 mg/m2/day was administered for 2 weeks followed by a 1-week rest. CDDP 20 mg/m2 was injected intravenously on day 1 and 8. The overall response rate was 52. 3%. The disease control rate was 85.7%. Grade 3 or 4 major toxicity comprised neutropenia (14.2%), thrombocytopenia (4.7%) and plasma creatinine elevation (4.7%). w-CS therapy is satisfied resulting with efficacy and safety. Thus, future clinical trials and accumulation of futher cases are warranted. PMID- 22202380 TI - [Two case reports-a control of the bleeding from advanced gastric cancer, unable to undergo resection, but was possible by transcatheter arterial embolization (TAE)]. AB - CASE 1: A 61-year-old man having advanced gastric cancer was presented with massive hematemesis. We could not control bleeding by gastrointestinal endoscopic hemostatic therapy, so we performed a transcatheter arterial embolization (TAE). We performed embolization on the left gastric artery. CASE 2: A 58-year-old man having advanced gastric cancer was presented with hematemesis. We could not control bleeding by gastrointestinal endoscopic procedure, so we conducted TAE. We performed embolization on the left gastric artery and right gastric artery. In both cases, hemostasis was achieved by TAE, and effectively controlled the bleeding from advanced gastric cancer. PMID- 22202381 TI - [A case report-highly advanced gastric cancer leading to perforation during neoadjuvant chemotherapy with docetaxel, cisplatin and S-1]. AB - A 70-year-old man was found to have advanced gastric cancer with a deep ulcer and multiple lymph-node metastases. Although the tumor was resectable, we predicted that the patient would have a poor outcome. We therefore administered neoadjuvant chemotherapy with docetaxel, cisplatin, and S-1 to improve the prognosis before curative resection. On day 15 of chemotherapy, sudden abdominal pain occurred, and we performed an emergency surgery for a diagnosis of panperitonitis due to gastric cancer perforation. The defect in the gastric wall was about 2 cm in diameter and was located in the anterior wall of the antrum, consistent with the center of the tumor. The operative findings suggested that the perforation was caused by chemotherapy-induced necrosis of gastric cancer cells. We saved the patient's life, but intensive care with high-dose catecholamine therapy was needed for several days after the surgery. Gastric cancer perforation induced by neoadjuvant chemotherapy appeared to be more severe than perforation caused by other factors. The adverse effects of chemotherapy apparently increased the severity. Our findings suggest that the risk of gastric cancer perforation should be borne in mind when we administer neoadjuvant chemotherapy to patients who have advanced gastric cancer with a deep ulcer. PMID- 22202382 TI - [The use of bevacizumab in refractory peritoneal dissemination of gastric cancer with malignant ascites-two case reports]. AB - Vascular endothelial growth factor (VEGF) plays an important role in proliferation of cancer cells, angiogenesis and vascular permeability in peritoneal dissemination. In addition, the release of VEGF by tumor cells has been identified as a main factor promoting the intraperitoneal secretion of fluid. Accordingly, recent evidence suggests that targeting VEGF may have the potential to suspend the ascites production resulting from peritoneal metastasis. We previously reported the effects of bevacizumab (BEV) on the growth inhabitation of peritoneal nodules and the reduction of ascites in peritoneal metastatic models. Here we present two cases of women (62 and 42 years old) with refractory peritoneal dissemination of scirrhous gastric cancer and server symptomatic ascites. They required frequent paracenteses for ascites which was resistant to systemic and intraperitoneal chemotherapy of S-1 and taxane. We treated them with intravenous BEV (5-10 mg/kg) with dramatic improvement in their ascites. BEV may have a role in the management of malignant ascites in the patient with refractory gastric cancer which should be confirmed in a larger series of well selected patients. PMID- 22202383 TI - [Peritoneal lavage cytology under local anesthesia for detection of peritoneal recurrence after surgery]. AB - Gastric cancer with positive peritoneal lavage cytology shows a very poor prognosis due to frequent peritoneal recurrence after surgery. Therefore, we have introduced neoadjuvant intra-peritoneal and systemic chemotherapy( NIPS) for gastric cancer with peritoneal microscopic and/or microscopic dissemination before surgery. In patients subjected to the strategy, we have experienced two cases of advanced gastric cancer with CY1, which had been treated with NIPS and curative surgery, had been performed with second peritoneal lavage cytology two years after surgery. In those two cases, S-1 was discontinued due to the negative results of peritoneal lavage cytology. We will present the cases. PMID- 22202384 TI - [Loco-regional chemotherapy at the outpatient clinic for gastric cancer patients with home enteral nutrition]. AB - In over the 10 years from 2000-2010, 21 gastric cancer patients received loco regional chemotherapy with home enteral nutrition (HEN) at an outpatient clinic because of insufficient oral intake. These loco-regional chemotherapy regimens consisted of 5 intra-aortic chemotherapies, 4 hepato-arterial infusions and 12 intra-peritoneal chemotherapies. Five out of 8 cases that had measurable lesions showed PR, and 3 cases revealed PD. The patients received HEN with peptide central formula, 400-1,200 kcal/day in night time. The average duration of HEN was 12.9 months. The post-operative nutritional management was needed for continuation and securing of outpatient chemotherapy. The author reported an experience of the outpatient loco-regional chemotherapy with HEN for the gastric cancer patients who could not eat a sufficient volume of food. PMID- 22202385 TI - [A case of small intestinal cancer in the efferent loop of roux-en Y reconstruction after total gastrectomy and liver metastases]. AB - A 61-year-old woman, who had undergone total gastrectomy and distal splenopancreatectomy with Roux-en Y reconstruction for a gastric cancer 16 years earlier, was found primary small intestinal cancer located in intestinal loop of Roux- en Y in gastrointestinal endoscopy for abdominal pain. Computed tomography showed liver metastases which were 8 cm in diameter at lateral segment and 1 cm in diameter at segment 8 of the liver. In the operation, the small intestinal cancer was located in the rho-anastomosis in the loop of Roux-en Y with the other jejunum fistula. We performed lateral segment hepatectomy, partial hepatectomy of segment 8, partial resection of small intestine including loop of rho-Roux-en Y, partial resection of transverse colon, and restoration Roux-en Y again. We succeeded in preserving double tract anastomosis at duodenum. Histological examination revealed a moderately differentiated adenocarcinoma of the small intestine and segment 8 of the liver, and angiomyolipoma of lateral segment of the liver. It is extremely rare for small intestinal cancer to arise in a loop of Roux-en Y reconstruction caused by total gastrectomy. PMID- 22202386 TI - [An operated case of metastasis to the small intestine from lung cancer]. AB - We report a rare case of a 68-year-old man with long-term survival after a surgical treatment of solitary metachronous small intestinal metastasis from lung cancer. He underwent a right upper lobectomy for primary lung adenocarcinoma. Thirty -four months after the operation, a tumor of small bowel was detected by computed tomography. The tumor was resected and diagnosed as a metastasis from lung cancer. Eighteen months after resection of metastasis, a tumor located at mesentery of the jejunum was pointed out. The tumor was resected and also diagnosed as a metastasis from lung cancer. The postoperative course was uneventful, and the patient is still alive without recurrence for 3 years after the last operation. We reviewed of 222 Japanese cases that underwent a resection of small intestinal metastasis from lung cancer. Although the prognosis was extremely poor for those who underwent a resection of the primary lung cancer and who had no remnant metastatic lesion at the time of metastasectomy, they seem to have a longer survival time. PMID- 22202387 TI - [A case report of GIST of the small intestine with multiple liver abscesses]. AB - We report a case of a woman in her fifties presenting with abdominal pain, headache and high fever. Blood examination showed a high CRP level and liver dysfunction, and then abdominal CT scan showed multiple liver masses and a 5 cm submucosal tumor of the small intestine. We diagnosed the multiple liver masses as liver abscesses, so we administered antibiotics. We suspected that the tumor was a cause of liver abscesses, and then performed a resection of the tumor and partial small intestine on the third day of hospitalization. We diagnosed the tumor as GIST because it was positive for c-kit and CD34 by immunohistochemistry. One of the resected liver nodules showed negative for c-kit and CD34, and we diagnosed it as a liver abscess. We performed percutaneous transhepatic abscess drainage (PTAD) because she ran into high fever after the operation, and then she recovered. We consider she has the possibility of liver metastasis, so we administered imatinib mesylate to her. No recurrence was found for 11 months after the operation. This case provides valuable information because there are few reports of GIST with liver abscesses. PMID- 22202388 TI - [A case of gastrointestinal stromal tumor (GIST) successfully treated with resection after a long-term control medication by molecular targeted drugs]. AB - We report a case of GIST successfully treated with resection after a long-term control medication by molecular targeted drugs. A 59-year-old man underwent an un complete resection for multiple abdominal tumors. The patient was treated with imatinib at a dose of 400 mg/day for high risk GIST. Since he had PD 22 months after the treatment, sunitinib was administered at a dose of 50 mg/day. However, abdominal tumor grew, and melena and intra-abdominal hemorrhage were appeared. After 27 months from the first treatment, a resection of tumors was performed to control abdominal hemorrhage. After the operation, abdominal tumor was successfully controlled with the treatment of imatinib. PMID- 22202389 TI - [Treatment strategy for stage II/III (non-T4) advanced esophageal cancer in high risk patients]. AB - We evaluated treatment strategies for Stage II/III (non-T4) advanced esophageal cancer in high-risk (HR) patients and analyzed the relationship between E-PASS scoring system (E-PASS) and HR patients retrospectively. The subjects were 85 patients who received the treatment for Stage II/III (non-T4) advanced esophageal cancer between 2006 and 2010 in our institute. The patients were divided into the HR and non high-risk (NHR) group. In this study, HR patients were defined as satisfying at least one of the following criteria; over 75 years old, performance status >= 2, presence of sever heart, respiratory, liver, renal dysfunction and diabetes mellitus. Using these criteria, there were 35 patients (41%) in the HR group. In the HR group, the ratio of surgical treatment was significantly lower than that in the NHR group (p<0.01), and minimal invasive surgery was performed. In the patients who underwent surgery, there was no difference in morbidity rate and overall survival between the HR and the NHR group. A preoperative risk score (PRS) in E-PASS system was positively correlated with HR patients satisfying our classification( rs=0.63, p<0.01). Our results indicated that overall survival of the HR patients was not inferior to that of the NHR patients, even if minimal invasive surgical methods were performed for the HR patients with Stage II/III (non-T4) advanced esophageal cancer. Moreover, we found that our HR classification would be a useful index to decide the treatment for Stage II/III (non-T4) advanced esophageal cancer, as well as the PRS in E-PASS. PMID- 22202390 TI - [A case of advanced esophageal cancer patient surviving more than 7 years treated with chemoradiotherapy]. AB - We report here a long-term survival case of advanced esophageal cancer with distant lymph node metastases, treated with definitive chemoradiotherapy (CRT). A man in his 60s with disturbance of swallowing was diagnosed as middle esophageal cancer involving multiple metastases of distant lymph nodes. CRT (combination of 5-FU and nedaplatin every four weeks for four courses with 66 Gy of radiation) was administered. After a completion of CRT, CT scan revealed shrinking metastatic lymph nodes. No tumor but a scar at the site of cancer was observed by endoscopy, and histopathology of biopsy specimen detected no tumor cells. From these results, we diagnosed the curative effect of CRT as complete response. Five years after CRT, a swelling of left inguinal lymph node with uptake of fluorine 18-fluorodeoxyglucose appeared and was extirpated, and the swelling was diagnosed histopathologically as metastasis of esophageal cancer. The patient is surviving with no recurrence for 7 years and 8 months from the first diagnosis. In cases of highly advanced esophageal cancer, a long-term follow-up should be performed. PMID- 22202391 TI - [A case of advanced esophageal cancer invaded to the trachea with PCR after preoperative chemoradiotherapy, which relapsed at the time of three years and seven months after resection]. AB - A male in his 40s was diagnosed with type-3 advanced esophageal cancer in the upper thoracic and cervical esophagus, which invaded to the trachea. We administered a low-dose FP combination therapy (5-FU and CDDP) along with 40 Gy radiotherapy. This chemoradiotherapy reduced the esophageal tumor significantly, and then we performed subtotal esophagectomy. Histological examination of the resected specimens revealed no residual cancer cells in the primary lesion or regional lymph nodes. No recurrence had occurred for about three years and seven months after the operation. However, CT revealed that the patient had the signs of recurrence (bone and lung), and finally he died four years and eight months after the operation. Preoperative chemoradiotherapy is potentially effective for advanced esophageal cancer invaded to adjacent organs. Although chemoradiotherapy yielded a complete response in our case( an advanced esophageal cancer patient), a patient follow-up is necessary because a recurrence may occur along the way. PMID- 22202392 TI - [A case report of long-term survival of endocrine cell carcinoma of the esophagus with chemo-radiation therapy]. AB - The patient was an 84-year-old man, who was diagnosed with cT3N2 (101L, 109L) M0, stage III esophageal cancer. The tumor, immunohistochemically, was stained positive for CD56 and NSE yielding a definitive diagnosis of endocrine cell carcinoma of the esophagus. We selected chemo-radiation therapy (5-FU/CDDP and 2 Gy/day total 60 Gy) for this patient. As adjuvant chemotherapy, 7 courses of chemotherapy with 5-FU/CDDP, was performed. At 8 months from the chemo-radiation therapy, the disease was diagnosed as cCR. But two years later, lung metastasis appeared, so we started chemotherapy with docetaxel/CDDP/5-FU. After 2 courses, lung metastasis was almost disappeared. He has been survived for four years and five months after chemo-radiation. This case suggests that chemo( FP) -radiation therapy and adjuvant chemotherapy could be an effective treatment for endocrine cell carcinoma of the esophagus. PMID- 22202393 TI - [Two cases of complete response of primary esophageal carcinoma treated with 5 FU/CDDP as neoadjuvant chemotherapy]. AB - CASE 1: A 67-year-old man with lower thoracic esophageal carcinoma, T2N0M0, cStage II, underwent neoadjuvant chemotherapy (NAC) with 5-FU/CDDP. After 2 courses of NAC, radical resection of the esophageal carcinoma was performed. Primary tumor was not palpable, and lymph node swelling was not found in the resected specimens. Pathologic examination of the resected specimens revealed no malignant cells in the esophagus. Histologic effect of the NAC was grade 3. We obtained down-staging of carcinoma in T0N0M0, fStage 0. CASE 2: A 58-year-old man with thoracic esophageal cancer, T3N2M0, cStage III, underwent NAC with 5 FU/CDDP. After 2 courses of NAC, radical resection of the esophageal carcinoma was performed. Primary tumor was not found in the resected specimens. Pathologic examination of the resected specimens revealed only an irregular fibrosis of esophageal wall, and no malignant cells in the esophagus. Two lymph node metastasis and surrounding fibrosis was found. We obtained down-staging of carcinoma in T0N2M0, fStage II. We report two cases of complete response of primary esophageal carcinoma treated with 5-FU/CDDP as neoadjuvant chemotherapy. PMID- 22202394 TI - [A case of residual metastatic lymph node lesion following definitive chemoradiotherapy for T4 esophageal cancer, successfully treated by outpatient clinic-based sequential chemotherapy with docetaxel followed by S-1]. AB - Patients with T4 esophageal cancer generally have poor prognosis. Of these patients, prognosis of non-responder to chemoradiothrapy (CRT) is extremely poor. We report a case of residual lymph node metastasis following definitive CRT, which showed a good response to outpatient clinic-based chemotherapy consisting of docetaxel (DOC) followed by S-1 in a patient with T4 esophageal cancer. The patient was a 65-year-old man with the diagnosis of squamous cell carcinoma of the middle thoracic esophagus with the 5 cm size lymph node metastasis with tracheal invasion along right recurrent laryngeal nerve [T4 (106recR-rt subclavian A) N2M0, Stage IVa]. He underwent induction chemotherapy with two courses of FP followed by one course of DCF. As a result, primary tumor was judged as complete response on endoscopy, and the lymph node lesion was judged as partial response, but unresectable on CT. Then, he underwent definitive CRT (FP+60 Gy). Following CRT, although the lymph node lesion was judged as non-CR on CT, a significant decrease of FDG uptake (PET-CR) was observed on PET-CT. Five months later, a recurrence of the lymph node lesion was observed on PET-CT. Then, he underwent outpatient clinic-based chemotherapy with DOC( 60 mg/m2, triweekly) followed by S-1( 80 mg/ body/day, 6 weeks/course, administration for 4 weeks with 2 weeks cessation). DOC was administered for 8 months, and was converted to S-1 because of the regrowth of the lesion on PET-CT. After 3 months following initiation of S-1, a remarkable decrease of the lesion was observed on PET-CT. During outpatient clinic observation, the residual lymph node lesion after definitive CRT was well controlled over 1 year, and no new metastatic lesions were observed at other sites. Sequential chemotherapy with DOC followed by S-1 may be effective in controlling progression of resistant tumor against prior CRT. PMID- 22202395 TI - [Efficacy and safety of biweekly nedaplatin in combination with docetaxel as second-line chemotherapy in patients with unresectable or recurrent esophageal cancer]. AB - There is no standard approach for second-line chemotherapy after a failure of the first-line regimen, fluorouracil and cisplatin -based chemotherapy in patients with unresectable or recurrent esophageal cancer. We have treated with biweekly nedaplatin (CDGP 40 mg/m2) in combination with docetaxe (l DOC 30 mg/m2) as second-line chemotherapy and investigated its efficacy and safety. Fifteen patients were retrospectively assessed in this study. Response rate (RR) and disease control rate (DCR) were 0 and 6.7%, respectively. Median time to progression( TTP) and median survival time( MST) were 2.1 and 7.0 months. Neutropenia and thrombocytopenia of grade 3 were seen in 4 (26.7%) and 1 (6.7%) patients, but no other serious adverse effects were detected. Based on the results, a biweekly nedaplatin/docetaxel regimen was safely received on an outpatient basis but not enough to provide a significant survival benefit. Quality of life and minimization of adverse effects are key considerations in second-line chemotherapy. Thereby, future trials should assess a quality of life in conjunction with different combination of active drugs and doses. PMID- 22202396 TI - [A case report of esophageal carcinoma developing esophago-brochial fistula successfully treated by esophageal bypass surgery]. AB - We have experienced a case of esophageal carcinoma developing esophago-bronchial fistula that was successfully treated by esophageal bypass surgery followed by chemo-radiation. A man aged 64 years old with developed esophago- bronchial fistula after initial chemo-radiation was undergone a gastric bypass surgery to separate esophagus and bronchus. Though closure of fistula was just 4 months after definitive chemo-radiation, an oral feeding was possible until the death of the patient. Stent placement for esophageal carcinoma was less invasive treatment though chemo-radiation after a stent placement was accompanied by high incidence of stent associated morbidity. Since esophageal bypass surgery can definitely separate airway from esophagus, chemo-radiation with oral feeding can be easily carried out. Esophageal bypass surgery was a treatment recommendation for the patient with esophageal carcinoma invading trachea or bronchus. PMID- 22202397 TI - [The cover stent custody case that acknowledged QOL improvement on traffic between trachea and esophagus of esophagus cancer]. AB - The case was a 60-year-old man. The patient with a main complaint of husky voice was introduced by a nearby doctor to our otolaryngology department at the end of August 2009. Because of the wall thickening image of the upper part (Ut domain) esophagus, left infraclavicular lymph node and mediastium lymphadenopathy syndrome observed by head and neck CT, the patient was transferred to surgery department. Squamous cell carcinoma was diagnosed based on the upper part gastrointestinal tract endoscopy showing a type-3 advanced cancer of the upper thoracic esophagus sized 25-30 cm from nostril. The patient was in PD, fever and coughing, though we performed 2 FAP therapies. A chest CT revealed that there was a passage between the trachea and esophagus. Then, radiation therapy( a total of 60 Gy, 2 Gy at a time) was enforced. After the radio therapy, a covered type Ultraflex esophagus stent was inserted due to a fistula, though the tumor was reduced to 6 mm in size. The patient was passed away five months after the stent custody; a solid food intake was possible until just before he died. PMID- 22202398 TI - [A clinical case of the esophagogastric malignancy palliated with covered metallic stent with anti-reflux mechanism]. AB - Esohophageal stents are often used in treating malignant stricture. But, when stents are placed across the esophagogastric junction, they may lead to esophagogastric reflux. We report a case of successfully treated esophagogastric strictures using the new stent with anti-reflux mechanism (long cover type Niti STM esophageal stent). A 78-year-old man presenting with severe strictures from the lower esophagus to cardiac part of stomach was histopathologically diagnosed as adenocarcinoma. CT scan images showed multiple liver metastatic tumors. However, he refused chemotherapy. Palliation using long cover type Niti-STM esophageal stent was performed. No adverse effect was occurred. He started solid meals on the 7th postoperative day. He was thereafter able to ingest solid meals without the symptom of esophgogastric reflux and stenosis until he died of the primary disease two month later. PMID- 22202399 TI - [Three cases of the malignant esophageal stenosis successfully treated with the Niti-STM esophageal stent]. AB - We herein report three cases of the malignant esophageal stenosis successfully treated with the Niti-STM esophageal stent. CASE 1: The hilar lung cancer and its mediastinal lymph node metastasis pressed the esophagus extramurally and caused the marked stenosis. CASE 2: A metastatic lymph node along the left laryngeal nerve caused the stenosis of the trachea. A primary esophageal lesion located at the middle thoracic esophagus also caused the marked stenosis. At first, tracheal stent was placed because of dyspnea, and two weeks later, we placed an esophageal stent. Case 3: Esophageal cancer at lower thoracic esophagus after definitive radiation therapy caused the marked stenosis. Because of the stenosis of esophago gastric junction( EGJ), we used an esophageal stent with a long cover in order to prevent a reflux into the esophagus. This new Niti-STM esophageal stent was easy to place at the stenosis without difficulty using a conventional device. The symptom was improved immediately for each case. We hope this new device will be used widely. PMID- 22202400 TI - [A case of lung resection after chemotherapy due to lung metastases derived from esophageal cancer resection]. AB - We report a rare case of esophageal cancer resection in which lung metastases was resected after chemotherapy with paclitaxel. A 59-year-old man with epigastralgia as a chief concern was referred to our hospital and was diagnosed with esophageal cancer by gastrointestinal fiber. In June 2007, the cancer was resected and followed by 3 courses of weekly chemotherapy with paclitaxel. In January 2009, chest computed tomography showed lung nodules (Rt-S1 and Rt-S5), and positron emission tomography (PET) showed uptake (Rt-S1); a final diagnosis of multiple lung metastases was made. Thereafter, the patient underwent 8 courses of weekly chemotherapy with paclitaxel. In December 2009, the growing Rt-S1 nodule was detected but no other lesion. The patient underwent a resection of lung metastases followed by 5 courses of weekly chemotherapy with paclitaxel. As of June 2011, the patient was alive and disease free. In conclusion, the resection of solitary lung metastases derived from esophageal cancer should be considered because it may improve survival. PMID- 22202401 TI - [A case of malignant melanoma of the esophagus]. AB - A 56-year-old female with chest pain after a meal was found to have the black mucous membrane of the middle intrathoracic esophagus by esophagogastroduodenoscopy. The lesion was diagnosed as primary malignant esophageal melanoma without lymph nodes and other organ metastasis. We underwent a subtotal esophageal by right thoracotomy and laparotomy. She survives with relapse-free for 3 years after the surgery. There is no standard therapy because primary malignant esophageal melanoma is not common. However, we thought a surgical treatment should be performed for a curatively resectable case. PMID- 22202402 TI - [A case of distal cholangiocarcinoma with high sensitivity to neoadjuvant chemoradiation therapy]. AB - We hypothesized that neoadjuvant chemoradiation therapy for cholangiocarcinoma (NACRAC) using gemcitabine would improve the prognosis of resected cases. Phase II trial of NACRAC is ongoing. We report a very effective case to NACRAC for distal cholangiocarcinoma, which markedly reduced the size and levels of the tumor markers. The patient was a 50- year-old man who presented jaundice. Serum tumor markers were clearly elevated, and abdominal CT scan revealed an enhanced mass in the lower bile duct, a dilatation of the intrahepatic to the middle bile duct and a swollen regional lymph node. After NACRAC, the tumor markers were decreased within a normal range. Also on CT scan, the main tumor was slightly detectable and the swollen node was reduced more than 30% in short diameter. Therefore, the effect of NACRAC was considered PR in RECIST guidelines (ver.1 .1). Pancreaticoduodenectomy was performed 2 weeks after NACRAC. No perioperative complications occurred. Pathological examination showed a good response, Grade 2b on Oboshi-Shimosato's classification. In this case, NACRAC had a good effect in imaging and pathological findings as well as in the tumor markers. Therefore, the neoadjuvant chemoradiation therapy has a potential to improve the prognosis for cholangiocarcinoma. PMID- 22202403 TI - [A case report of cholangiectasis with cholangiocarcinoma]. AB - This is a case report of cholangiectasis with cholangiocarcinoma in a 37-year-old female. Both computed tomography (CT) and endoscopic retrograde cholangio pancreatography (ERCP) demonstrated gallstone, and intrahepatic bile duct dilatation with the stone. The diagnosis was intrahepatic cholangiectasis without common bile duct-dilatation. Hepatectomy of segment 3 with resection of the extrahepatic bile duct and reconstruction of the biliary tract was performed. Upon pathological examination, an early stage of cholangiocarcinoma was pointed out within the small range of common bile duct without dilatation or stone. Cholangiocarcinoma with cholangiectasis has been reported to be induced by counter flow of pancreas and intestinal juice because of the pancreaticobiliary maljunction. So we usually choose a diversion operation as our tactics to get rid of the counter flow of those digestive juices. Despite the above-mentioned tendency, this is a very rare case of carcinogenesis in common bile duct without dilatation. PMID- 22202404 TI - [Curative resection of gallbladder cancer with simultaneous liver metastasis]. AB - A 67-year-old man visited our hospital for further check-up of biliary tract disease since his two brothers suffered from biliary tract cancer. Abdominal CT scan revealed a wall thickning at the fundus of gallbladder and its vascularity was rich. Chronic cholecystitis was diagnosed, however, cancer was highly suspected. Cholecystectomy was performed and the frozen section of the gallbladder was compatible for cancer. Therefore, segment-4a and -5 liver resections with regeonal lymph node dissection were added. Although preoperative radiological findings were free of liver metastasis, the resected liver specimen included a nodule of 1 cm in segment-5. Extrahepatic bile duct was not resected because the stump of the cystic duct was free from cancer. The final pathological diagnosis according to the TNM classification was pT3N1M1, Stage IV. We considered the patient to be in the high-risk group of recurrence, adjuvant chemotherapy using both gemcitabine and S-1 was performed. S-1 (80 mg/body/day) was scheduled on day 1-14, and gemcitabine (1,000 mg/body) was scheduled on day 8, day 15. The treatment was continued for two years (a total of 28 courses) without experiencing advese events. The patient is cancer free by means of radiological and hematological studies. Gallbladder cancer with liver metastasis in segment-4a and/or -5 can be considered as "local" metastasis, which a liver resection and adjuvant therapy may lead to a good prognosis. PMID- 22202405 TI - [Gallbladder carcinomas with a single lymph node involvement behind biliary tract -two resected cases]. AB - Case 1 was an 85-year-old man, who was pointed out a gallbladder tumor by screening CT scan after bladder cancer. The tumor was arisen in the gallbladder body, 1 .5 cm in diameter. He underwent a radical surgery; the gallbladder-bed was resected with more than 1 cm margin, and lymphadenectomy was done preserving biliary tract. Pathologically his tumor was papillary adenocarcinoma suspected to invade to the liver-bed minimally. A lymph node involvement was solitary located at right side of hepatoduodenal ligament (behind biliary tract). Case 2 was a 73 year-old man who was pathologically diagnosed to be advanced gallbladder carcinoma after laparoscopic cholecystectomy. CT scan and MRI revealed a mass sized 2 cm in diameter, at the gallbladder-bed, and PET exam showed a hot spot at this site only. Therefore, he underwent a radical surgery like case 1. Pathologically the tumor was moderately differentiated adenocarcinoma, and a lymph node involvement was solitary and located behind a biliary tract. Both patients have been recurrent free for more than 22 months and 15 months, respectively. Two lymphatic drainage routes have been suggested, one is the route which runs right side of hepatoduodenal ligament, another runs via left side of the ligament, along hepatic artery. Our two cases are considered to be solitary metastatic cases along the right side route. A clinical case of solitary node positive seems to be known for its relatively good prognosis. In order to justify our cases, we need a longer follow-up period, or we should have more cases to be experienced. PMID- 22202406 TI - [A case of long-term survival of a patient with intrahepatic bile duct cancer and early nodal recurrence who responded to S-1 therapy]. AB - A 71-year-old man was referred to our hospital for further evaluation of hepatic dysfunction. A diagnostic workup revealed an intrahepatic bile duct cancer, and a right hepatic lobectomy was performed. Postoperative adjuvant chemotherapy with gemcitabine (1,000 mg/m2, given for 3 weeks, followed by a 1 week rest) was begun. Because grade 3 anorexia developed, the dose of gemcitabine was decreased to 800 mg/m2 from the third cycle of chemotherapy. Computed tomography showed nodal recurrence 6 months after surgery. One year after surgery, computed tomography revealed an extensive periaortic nodal recurrence, as well as recurrence in the remnant liver. Treatment was switched to S-1 (100 mg/ day, given for 3 weeks, followed by a 1 week rest). Grade 3 thrombocytopenia was developed during the tenth cycle of therapy. The treatment schedule was therefore changed to 3 weeks of therapy, followed by a 2 week rest. From the 36th cycle, the dose of S-1 was lowered to 80 mg/day (given for 2 weeks, followed by a 2 week rest). Nodal recurrence was resolved in 2 years after the start of treatment with S-1, and recurrence in the remnant liver nearly resolved in 4 years after starting the treatment, indicating a partial response. The carcinoembryonic antigen level fell to the normal range and the CA19-9 level remains at about 100 U/mL. Although the patient had grade 2 thrombocytopenia, he is now receiving the 43rd cycle of S-1 and remains alive for 5 years and 1 month after surgery. We believe that the continuation of chemotherapy while monitoring the patient's general condition led to an improved outcome. PMID- 22202407 TI - [A case of malignant lymphoma of the gallbladder after chemotherapy for malignant lymphoma of the skin and right intraocular]. AB - A case is a 65-year-old female. She was diagnosed as T-cell malignant lymphoma (skin and right intraocular). Chemotherapy( THP-COP) was performed for 6 months and she was in remission. A gallbladder tumor was pointed out in August 2010, and she was admitted to our department for the purpose of excision biopsy of the gallbladder tumor. In abdominal US, we confirmed an iso-hypoechoic tumor. The tumor size was 24 * 14 mm. We considered the invasion depth was subserosa. We observed the tumor which had the imaging effectiveness in the body of gallbladder by abdominal CT. The invasion was suspected in the liver bed side. In PET-CT, We observed an accumulation of SUVmax 8 . 5 in the body of gallbladder. The protruded lesion of 33 .5 mm in diameter was detected by MRI to the body of gallbladder, and an invasion was also suspected. Cholecystectomy was performed to this case. By operative US, the gallbladder tumor was SMT and existed in the symmetric side of liver bed. Pathological diagnosises were malignant lymphoma and peripheral T-cell lymphoma. PMID- 22202408 TI - [A novel gemcitabine delivery system]. AB - Indocyanine green (ICG) is specifically excreted through the biliary tracts. The authors applied ICG as a carrier of gemcitabine (GEM) to devising a novel drug delivery system. Our newly devised chitin flakes, ICG and GEM were mixed together. Then physiological saline solution was added to the mixture to form the system. The release profiles of GEM and ICG from the system were examined at various times in vitro. Anticancer activities of the GEM and ICG delivered from the system were detected by MTT assay method using human pancreatic cancer cell lines. The novel system was visco-elastic green sol at room temperature and changed to gel at body temperature. Seventy to 80% of GEM was gradually delivered from the system in 24 hours, and 30 to 50% of ICG was slowly released over 24 hours. The released GEM favorably demonstrated anticancer activities against the cancer cells, while the ICG released from the system showed no oncolytic activities. These suggested that our devised system would be clinically useful as a novel tool in cancer chemotherapy. PMID- 22202409 TI - [Re-resection for local recurrence in the remnant pancreas after pancreaticoduodenectomy for pancreatic cancer- a case report]. AB - A 70-year-old female suffered from jaundice was admitted to our hospital for a tumor in the pancreas head. CA19-9 and DUPAN-2 levels were increased in laboratory test. Enhanced abdominal computed tomography (CT) scan revealed a low density area of pancreas head. Cytology of pancreatic juice was performed by ERCP, and malignant cells were detected. Pancreaticoduodenectomy was performed under a diagnosis of pancreatic cancer (T3N1M0, stage III). Despite of adjuvant chemotherapy (gemcitabine) after surgery, CT scan revealed a low density area in the cut end of remnant pancreas at 3 months, which was accompanied with elevation of and CA19-9 and DUPAN-2 levels. We diagnosed as a recurrent pancreatic cancer of remnant pancreas without any other side of recurrence and re-resection was performed. Because of chylous ascites and depression following a second surgery, postoperative adjuvant chemotherapy could not be started. Re-recurrence was detected at 3 months after the second surgery, and she died 6 months after the surgery. Remnant or repeated pancreatectomy for local recurrent pancreatic carcinomas is extremely rare with limited number of cases reported in the literature. We report our experience, and discuss the significance of re resection for recurrence of remnant pancreas. PMID- 22202410 TI - [A safely resected case of hypervascular pancreatic giant tumor after preoperative arterial embolization]. AB - A 73-year-old woman visited our hospital for a treatment of pancreatic tumor that increased steadily in size of 6 cm in diameter in 1999 to 13 cm in 2008, while remaining in asymptomatic condition throughout this follow-up time. The tumor was big and flowed from many vessels such as portal and superior mesenteric veins and the celiac and superior mesenteric arteries. These were critical for determining tumor respectability and the risk of massive intra-operative hemorrhage was felt to be considerable. Therefore, preoperative embolization of the tumor-feeding arteries arising from the celiac axis (gastroduodenal, splenic and dorsal pancreatic arteries) was performed on the previous day of operation. Tumor resection with pancreaticoduodenectomy and partial resection of portal vein and reconstruction were performed. We got to SMA with the use of "paraduodenal mesenteric approach", we called, and we finished the operation without a blood transfusion. The final pathology confirmed the diagnosis of serous microcystic adenoma. PMID- 22202411 TI - [A case report of port-site metastasis of pancreatic cancer after laparoscope assistted distal pancreatectomy]. AB - Laparosopic port-site metastasis is rare, but a well recognized outcome following surgery in gastroenterological surgery for gastric cancer, colon cancer and gallbladder cancer with its etiology was not clearly understood. We report a port site metastasis of pancreatic cancer diagnosed by position emission tomography( PET). A 49-year-old man was diagnosed as splenic tumor with pancreatic tail invasion due to malignant lymphoma, and received a laparoscope assisted distal pancreatectomy. Unsuspected pancreatic cancer was discovered with histological result of moderate differentiated invasive ductal adenocarcinoma of the pancreas infiltrating spleen. Systemic chemotherapy with 1,000 mg/m2 of gemcitabine (GEM) was performed for six months. Unfortunately, our patients relapsed one year after the surgery with multiple lesions in the peritoneum, abdominal wall, as well as a laparoscopic port-site metastasis. He was started on 100 mg/body of S-1 daily, subsequently, combined chemotherapy with GEM( 80 mg/m2) and S-1( 80 mg/body) was also performed. Furthermore, he underwent palliative radiation therapy( 40 Gy) to care the pain. Fortunately, a long-term survival of 3 years was elicited by these systemic treatments and radiography. Laparoscopic port-site metastases are associated with presence of advanced cancer. Therefore, we should carefully precede a laparoscopic resection against pancreatic cancer. PMID- 22202412 TI - [A case of intraductal mucinous neoplasms with the whole main pancreatic duct dilation treated via segment pancreatectomy]. AB - The patient was a 77-year-old woman. She was diagnosed as intraducal papillary mucinous neoplasms (IPMN). She refused an operation for 3 years. After all, a nodule in the main pancreatic duct was pointed out, she agreed and was referred to us. Her past history showed pacemaker implantation for third-degree atrioventricular block, and no impaired glucose tolerance. Abdominal CT showed a dilated whole pancreatic duct and a multilocular cystic tumor. Endoscopic retrograde pancreatography showed a marked dilation of the main pancreatic duct. We diagnosed as main duct IPMN. Intraoperative US showed no nodule in pancreatic duct, and there was no suspicious lesion of invasive cancer. We performed segmental pancreatectomy between the left side of common bile duct and the pancreas tail. The tumor was resected with clear margins. Both cut-ends of the main pancreatic duct were anastomosed to a jejunal loop. The postoperative course was excellent. She was discharged on day 16. The glycemic control was good, she needed no treatment for diabetes. Total pancreatectomy has many problems such as insulin and pancreatic polypeptide deficiency, hypoglycemia, malabsorption, diarrhea and liver dysfunction. We avoided total pancreatectomy so that her quality of life was maintained. Still a careful follow -up is required. PMID- 22202413 TI - [A case of pancreatic mucinous carcinoma which includes calcification]. AB - A 60-year-old woman was pointed out a tumor, 2.6 cm in diameter, at the pancreas body, by screening ultrasonography examination. Jaundice and anemia were absent and no abdominal mass was palpable on physical examination. Enhanced CT revealed the tumor directly invaded to splenic vein, but lymph node metastases were not detected. ERCP showed a pancreatic duct was obstructed by the tumor, accompanied with dilatation of the peripheral pancreas duct. Because we cannot rule out the malignancy tumor, pancreatoduodenectomy and lymphadenectomy was done. The tumor was very hard and serosal invasion was suspicious in the operative findings. Histopathological study showed that the tumor was occupied with colloid differentiation, in which free mucinous epithelial malignant cells were floating. Then we diagnosed the tumor to be pancreatic mucinous carcinoma. Extra pancreatic extension such as vascular involvement was not proved microscopically. However, ten months after the resection, CT scan showed a recurrent tumor sized 4 cm diameter, at the middle abdominal cavity, which suspected to be disseminated diseases. Mucinous carcinoma occurs relatively rare in pancreas, of which the incidence is 1 .4% in pancreatic adenocarcinomas. We report herein the pancreatic mucinous carcinoma case with a calcificated region, which resulted in early recurrence with abdominal seeding. PMID- 22202414 TI - [A case of intrahepatic cholangiocarcinoma with invasion to right adrenal gland]. AB - A 64-year-old woman was admitted for epigastralgia. Abdominal computed tomography demonstrated a large tumor in the right lobe of the liver to adrenal grand. An aspiration tumor biopsy was performed because of difficulty in diagnosing the tumor, and the pathological findings suggested intrahepatic cholangiocarcinoma. At surgery right hepatic lobectomy with caudate lobe combined with right adrenal glandectomy and diaphragmectomy was performed. Pathological findings showed moderately differentiated tubular adenocarcinoma with invasion to right adrenal gland, but no lymph node metastasis was involved nor invasion of lymph vessel and vein. The postoperative course was uneventful and the woman remains recurrence free for 12 months after the surgery. PMID- 22202415 TI - [A long-term survival case after two resections of the peritoneal metastasis from hepatocellular carcinoma]. AB - A 70-year-old man with type B hepatitis had ruptured HCC in segment 5, and he underwent with TAE at other hospital in June 2007. Then, he was introduced to our hospital in July 2007. Partial hepatectomy( S5) was performed in August 2007 (pT2N0M0, Stage II). Afterward, he underwent TACE therapy twice because of multiple intrahepatic recurrences. Abdominal CT revealed a viable recurrence lesion (S5), and peritoneal dissemination (surface of S3) in June 2009. We carried out partial hepatectomy (S5), and removal of peritoneal dissemination because of good liver function and without any other extra hepatic recurrence in July 2009. Histologically, the intrahepatic lesion( S5) and the S3 surface lesion were diagnosed as moderately differentiated HCC. In July 2010, abdominal CT revealed three lesions of peritoneal dissemination (right subphrenic lesion, hepatic flexure of the colon, neighborhood of left ureter, then the second removal of peritoneal dissemination was performed. In January 2011, he had multiple lung metastatic lesions, and multiple bone metastatic lesions were occurred in March 2011, then his general condition was getting worse. In April 2011, he was dead 46 months after the first TAE therapy for ruptured HCC, or 21 months after the first resection of peritoneal dissemination. Surgical resection of peritoneal dissemination of HCC may improve a survival for patients whose intrahepatic lesion is contorollable. PMID- 22202416 TI - [A case of intrahepatic recurrence of intrahepatic cholangiocarcinoma treated with repeated hepatectomy]. AB - A 60-year-old man with intrahepatic cholangiocarcinoma (ICC) underwent a left hepatectomy. Following the procedure, S-1 was administered during the period of five months. About two years after the hepatectomy, the patient underwent a hepatic resection again for remunant hepatic recurrences of ICC. Aggressive surgical resection may be the only method to assure a good outcome. An indication of resection for the hepatic recurrence of ICC will be examined in the future. PMID- 22202417 TI - [A case of successful second look operation for hepatocellular carcinoma with right atrial tumor thrombus]. AB - We report a case of advanced hepatocellular carcinoma (HCC) with right atrial tumor thrombus treated by interferon (IFN)-combinated chemotherapies and second look operation. A case was a 56-year-old man who had right upper abdominal and back pain. The abdominal CT revealed an early enhanced lesion in the posterior segment of the liver with right atrial tumor thrombus. The patient underwent 2 courses of IFN-beta/adriamycin combination therapy and followed by surgical resection. Due to severe congestive live, we only surgically resected tumor thrombi at right atrium, inferior vena cava, and right hepatic vein. Additionally, we closed posterior branch and right hepatic vein to prevent from a tumor progression. Following 16 months of IFN/5-FU and IFN/S-1 therapy, we performed a right posterior sectionectomy of the liver. Twelve months after the second operation, liver tumor relapsed and we performed transcatheter arterial chemoembolizatin, followed by IFN-combinateted chemotherapies. Thereafter, we continued chemotherapy for 14 months. The tumor progressed into the bile duct, and he died after 3 years and 8 months from the initial treatment. The case suggests that some patients with HCC with major vascular invasion and tumor thrombus can gain a long-term survival by multifocal treatment including surgery and chemotherapy. PMID- 22202418 TI - [A case with juvenile hepatocellular carcinoma without hepatitis underwent right hepatic Trisegmentectomy]. AB - A CASE REPORT: A 20-year-old man with juvenile hepatocellular carcinoma (HCC) without HBV, nor HCV infections. A complaint of pain in the right abdomen, wherein a bulky hepatic tumor occupying a large area of the right lobe as well as tumors that were 20 mm and 10 mm in size in liver regions S2 and S3, respectively, were observed via an abdominal CT scan. A biopsy resulted in a diagnosis of well-differentiated hepatocarcinoma. The main voluminous tumor mass in the right lobe was resected, but the tumor still remained in the lateral segment after the surgery. On day 21 after the surgery, we initiated a therapy for the remaining tumor. He is still alive 36 months after surgery. PMID- 22202419 TI - [Pure laparoscopic surgery for repeat hepatectomy]. AB - In this study, we evaluate the capability of pure laparoscopic surgery for repeat hepatectomy. From June 2010 through March 2011, 15 cases of primary hepatectomy (hepatocellular carcinoma 11, liver metastasis 4) and 6 cases of re-hepatectomy patients (all cases were hepatocellular carcinoma) were underwent pure laparoscopic hepatectomy. As for the liver function in primary hepatectomy and re hepatectomy, liver damage A/B was 8/7 and 2/4, median ICG R15 was 18 (4- 42) % and 30 (10-35) %, respectively. As for operative variables in primary hepatectomy and re-hepatectomy, the median operative duration was 265 (105-673) minutes, 296 (157-475) minutes, the median amount of bleeding was 10 (small amount-2,000) cc, 25 (small amount-140) cc, and the median post-operative hospital stay was 10 (6 17) days and 11 (6-24) days, respectively. Primary hepatectomy and re-hepatectomy represented equal clinical outcomes, although re-hepatectomy patients had lower hepatic function compared with primary hepatectomy patients. PMID- 22202420 TI - [Usefulness of intraoperative fluorescent imaging using indocyanine green for repeated resection of hepatocellular carcinoma]. AB - For recurrent hepatic tumors with treatment history or cirrhosis, small region including extrahepatic tumors that cannot be identified on routine ultrasonography, we used a fluorescent imaging with indocyanine green (ICG) for repeated resection of hepatocellular carcinoma. The patients were consisted of 4 men and 2 women with a mean age of 61.5 (37-66) years. Five cases of intra or extra hepatic tumors could be identified with fluorescent imaging system. Two cases were a local recurrence after TACE, 1 case was a small tumor exited in liver surface, 1 case could be identified the area of vascular invasion of subcutaneous recurrence, and 1 case was a mediastinal small lymph node metastasis of hepatocellular carcinoma. Fluorescent imaging using ICG was considered to be useful for identification of recurrent hepatocellular carcinoma that cannot be identified by a routine ultrasonography. PMID- 22202421 TI - [A case of successful treatment by interferon-alpha and 5-fluorouracil combination therapy (FAIT) and transcatheter arterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus]. AB - We report a case of successful treatment by interferon-alpha (IFN) and 5 fluorouracil (5-FU) combination therapy and transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). A 70-year-old woman, who was diagnosed as unresectable HCC with PVTT in the main trunk of portal vein and multiple intrahepatic metastases, was admitted to our hospital for further treatment for HCC. First, she was treated by 3 courses of IFN and 5-FU combination therapy. Three courses after the combination therapy, PVTT was shrunken and portal flow to the liver was reperfused. Therefore, she was treated by TACE for intrahepatic tumors. She received a repeat treatment of the combination therapy and TACE. Four years after the initial treatment, she is still alive with good condition with intrahepatic tumors. This case suggested that some patient of HCC with PVTT could get a long term survival if an initial treatment was succeeded and could apply further treatment such as TACE. PMID- 22202422 TI - [A case of complete response to interferon-alpha and S-1 combination therapy for multiple pulmonary recurrences of hepatocellular carcinoma after hepatic resection]. AB - A 77-year-old man was diagnosed as hepatocellular carcinoma, and was referred to our hospital. After he was treated by transcatheter chemoembolization, he underwent a left hepatic lobectomy of the liver and cholecystectomy. Serum AFP and PIVKA-II remarkably elevated 7 months after surgery, and CT scan revealed multiple metastatic nodules in bilateral lungs. The nodules were diagnosed as lung metastasis of HCC. Because the lesions grew larger, S-1/IFN was administered. Diagnostic imaging and tumor markers showed a marked improvement after 4 courses of S-1/IFN therapy, and he is still alive with good condition without recurrence and progression of tumors. PMID- 22202423 TI - [A case of successful surgical resection followed by S-1 administration for hepatocellular carcinoma with lung metastases and a tumor thrombus into right atrium]. AB - A case of a 68-year-old man with hepatocellular carcinoma (HCC) is presented. He underwent partial liver resection for three times and transcatheter arterial chemoembolization (TACE) for three times. Follow-up CT revealed a recurrent hepatic surface mass with malignant extended into the inferior vena cava (IVC) and right atrium (RA). CT scan also revealed multiple metastatic nodules in bilateral lungs. The tumor thrombus into the RA and the hepatic surface mass were successfully treated with surgical resection. Pathological specimen allowed the diagnosis of poorly-differentiated HCC. Adjuvant chemotherapy with S-1 resulted in complete remission of lung metastases. Tumor markers showed a significant improvement after S-1 administration. This case report suggests that a surgical resection followed by S-1 administration would be effective for a patient with lung metastases and a tumor thrombus into IVC or RA. PMID- 22202424 TI - [Our experience of the treatment with sorafenib for unresectable hepatocellular carcinoma]. AB - We report here the experience of the treatment with sorafenib for advanced hepatocellular carcinoma (HCC) in our department. Forty patients received the therapy of sorafenib until April 2011. Twenty seven unresectable advanced HCC, 7 lung metastasis, 6 bone metastasis, 3 abdominal lymph node metastasis, and 2 peritoneal dissemination were included. The median duration of sorafenib treatment was 197 days. Grade 3 adverse event occurred in 9 patients (22.5%), and grade 4 adverse event occurred in 1 patient (3%). The response rate and disease control rate were 5% and 55%, respectively (CR 2, PR 0, SD 20, PD 9). The median overall survival was 15.2 months, and median recurrence-free survival was 3.7 months. These results suggested that a prevention of adverse events would lead to a continued treatment with sorafenib, and could expect to have a prolonged survival in patients with advanced HCC. PMID- 22202425 TI - [Three cases of hepatocellular carcinoma without distant metastasis effectively treated by sorafenib]. AB - Sorafenib is a novel, orally administered multi-kinase inhibitor that has recently been approved for the treatment of advanced hepatocellular carcinoma. We report three cases of hepatocellular carcinoma without distant metastasis effectively treated by sorafenib. Case 1 was a 71-year-old male with multiple hepatocellular carcinomas, Child-Pugh status A, and asthma. He received sorafenib 400 mg twice daily. The efficacy evaluated by the RECIST was partial response. Case 2 was a 75-year-old male with multiple hepatocellular carcinomas and Child Pugh status A. He previously received surgical resection and transarterial chemoembolization. He received sorafenib 400 mg twice daily. The efficacy evaluated by the RECIST and modified RECIST was partial response and complete response, respectively. Case 3 was a 62-year-old male with multiple hepatocellular carcinomas and Child-Pugh status A. He previously received surgical resection, percutaneous radiofrequency ablation therapy and transarterial chemoembolization. He received sorafenib 400 mg twice daily. The efficacy evaluated by the RECIST was stable disease. The majority of adverse events were grade 1-2 stomatitis and hand-foot skin reaction. No patients discontinued the treatment because of adverse events. Sorafenib might be promising as an effective therapy for advanced hepatocellular carcinoma without distant metastasis. PMID- 22202426 TI - [The possible role of sorafenib as a part of the multimodal treatment for hepatocellular carcinoma]. AB - The role of sorafenib is unclear in multimodal treatment for hepatocellular carcinoma (HCC). We analyzed patients who underwent multimodal treatment including surgical operation for advanced HCC after administration of sorafenib. A 79- year-old man underwent extended right hepatectomy for Stage III huge HCC. Three years later, multiple recurrences observed in the liver, and an extrahepatic tumor was diagnosed. Peritoneal seeding was suspected, thus we decided to start a sorafenib administration. After 11 months, new intrahepatic lesions were detected, but extrahepatic tumor was unchanged. We considered the extrahepatic tumor was solitary and resectable, and new lesions in the liver were still treatable, then we attempted a surgical treatment with partial hepatectomy and ablation therapy. The tumor was successfully resected, and residual viable tumors were treated by radiofrequency ablation. The patient remains alive without recurrence at 7 months. We could perform a surgical treatment for another 2 patients with sorafenib treatment. These results suggested that there are cases of advance HCC in which multimodality treatment including surgical treatment can be achieved after sorafenib administration. PMID- 22202427 TI - [A long-term survival case in Jehovah 's witness with simultaneous liver metastases of colon cancer by synchronous liver resection followed by a successful size reduction with chemotherapy]. AB - A bloodless surgery was required in the case of simultaneous liver metastases of colon cancer, one of which invaded at the confluence of left hepatic vein and inferior vena cava. In order to assure the safety and curability, hepatic arterial infusion chemotherapy aiming to size reduction was preceded to synchronous liver resection for a 53-year-old Jehovah's witness male. After gaining the reduction of tumor, synchronous liver resection was safely performed under a hemodilutional autotransfusion. The patient has been alive for 6 years under the withdrawal from chemotherapy. PMID- 22202428 TI - [A case of metastatic liver tumor from gastric carcinoma curatively undergoing left hemihepatectomy and caudate lobectomy with ivc reconstruction]. AB - A 72-year-old male underwent distal gastrectomy with D2 dissection for type 2 advanced gastric carcinoma. Nine months after the surgery, CT scan revealed a solitary liver metastatic legion with IVC invasion. We selected a surgical intervention because of allegic reaction of S-1 and rapid progression of tumor. Left hemihepatectomy and caudate lobectomy with IVC reconstruction was performed. IVC was resected partially and repaired with polytetrafluoroethylene (PTFE) patch graft. The postoperative course was uneventful. The patient was discharged on the 11th postoperative day. He is alive without a recurrence 9 months after surgery and is undergoing weekly paclitaxel. Although the indication of extended hepatectomy is controversial, aggressive surgery with chemotherapy would contribute to improve a prognosis of the patients with metastatic liver tumor from gastric carcinoma. PMID- 22202429 TI - [Hepatic metastasis from gastric GIST radically resected after imatinib mesylate therapy-a case report]. AB - We report a case of hepatic metastasis from gastric gastrointestinal stromal tumor (GIST), which was safely resected with preoperative imatinib therapy. A 60 year-old woman was hospitalized and underwent a treatment for hepatic SOL at another hospital prior to gastric GIST resection. Computed tomography revealed a tumor compressing the right and middle hepatic vein. The tumor volume decreased after an initiation of imatinib therapy aimed at preserving the middle hepatic vein. Although tumor volume was further decreased over the course of twelve months, a new lesion appeared, suggesting a progressive disease. Our findings suggest that a radical resection of gastric GIST to preserve the middle hepatic vein is possible. PMID- 22202430 TI - [Hepatic intra-arterial infusion of BAK immune cells to treat metastatic liver cancer]. AB - Based on the "living with cancer" concept while maintaining a favorable QOL and avoiding side effects and drug resistance, we have developed a new immune cell treatment called BAK (BRM activated killer) therapy, primarily using CD56+ cells for a case of advanced progressive solid cancer. In the present case, we administered BAK cells by hepatic intra-arterial infusion to a patient who happened to be a surgeon and wished to undergo this therapy. The patient was a 52 year- old male surgeon who underwent surgery for rectal cancer in April 2007. Heavy particle radiotherapy was administered when liver metastases were identified in July 2008. Starting in December 2008, 10 billion BAK cells were administered each month by hepatic intra-arterial infusion via a catheter on a total of six different occasions. The 10 billion autologous lymphocytes were suspended in 200 mL of Ringer's solution and returned to the patient by hepatic intra-arterial infusion over a period of one hour. Interactions between the activated lymphocytes and liver cancer cells increased levels of serum alpha1AG, an inflammation marker, but these levels normalized following the sixth and final administration. Conventional drip-infusion BAK therapy was administered thereafter. Diagnostic imaging, including PET-CT and PET, confirmed a complete disappearance of liver metastases. This case suggests the effectiveness of hepatic intra-arterial infusion BAK cell therapy in treating liver cancer. PMID- 22202431 TI - [A long-term survival case in advanced mucinous cystadenocarcinoma of the appendix using cytoreductive surgery and S-1/CDDP chemotherapy]. AB - Prognosis of patients with advanced mucinous cystadenocarcinoma of the appendix (AMCA) is extremely poor. However, there has been no established treatment strategy. We preliminary report here a successfully treated case with AMCA using intensive cytoreductive surgery and chemotherapy. A 61-year-old woman had a right lower abdominal pain and was diagnosed as acute appendicitis. At surgery, about 5 cm tumor with mucosal fluid was detected at the distal part of the appendix. The tumor was invading the ileum and bladder. We performed appendectomy with tumor, partial resection of the small intestine and debridement of mucosal fluid. Histopathology revealed AMCA invading the ileum and bladder. After non curative surgery, we started S-1 plus cisplatin chemotherapy, which S-1 was given orally, twice daily for 3 consecutive weeks, and cisplatin was given intravenously on day 1, 8 and 15 followed by a 3-week rest period. After 6 courses starting with chemotherapy, a complete response was obtained. We followed by S-1 until two years after the initial surgery. At 36 months after the initial surgery, CT scan demonstrated a peritoneal recurrence. Then, she underwent intensive peritonectomy with intraperitoneal hyperthermic chemotherapy. Currently, she had no apparent recurrence for 59 months after initial surgery. PMID- 22202432 TI - [A case of pleural extension of mucinous tumor with pseudomyxoma peritonei]. AB - We report a case of pleural extension of mucinous tumor with pseudomyxoma peritonei. A 64-year-old man was diagnosed as pseudomyxoma peritonei according to the findings of abdominal CT scan and cytologic examination of the ascitic fluid. At laparotomy in November 2007, jelly-like ascites and a child-head size mutinous tumor involving the greater omentum, transverse colon, and ascending colon were found. Mucious nodules scattered on the undersurface of the right and left hemidiaphragms. In addition, transhiatal extension of mucinous tumors was also extended through the esophageal hiatus, suggesting that thoracic extension of pseudomyxoma peritonei. To avoid an excessive surgical stress, thracotomy was not performed. Cytoreduction surgery was conducted. Postoperative course was uneventful. Although systemic chemotherapy was performed after surgery, intra abdominal tumor enlarged gradually. Cytoreduction surgery was performed again in September 2008. Thereafter, intra-abdomial tumor enlarged gradually and his physical condition deteriorated. He died 26 months after the first surgery. PMID- 22202433 TI - [A case of lung metastases after surgery for colon cancer demonstrating complete response for more than six years after treatment with UFT/LV]. AB - A 54-year-old female with cecal cancer underwent Rt. hemicolectomy in December 2000. The lesion was mod, ss, p1(+), n1, stage IV. The level of CEA increased around August 2002. Abdominal CT revealed a recurrent tumor in the RLQ in July 2003, peritoneal dissemination was suspected. In December 2003, we performed a partial resection of the ileum and transverse colon including initial anastomosis. Lung metastases were found by chest CT in right S4, S5, S9 and S3, S8 in February 2004. Because of experience of severe side effect of intravenous chemotherapy, UFT/LV was administered from February 2004. Chest CT revealed the disappearance of tumor in September 2004, and no signs of recurrence were observed for 65 months. PMID- 22202434 TI - [A case of recurrent intra-abdominal pediatric desmoid tumor undergoing surgical intervention for 6 times]. AB - A 15-year-old male patient with palpable abdominal tumor presented to our hospital. CT scan revealed a giant tumor, 15 cm in diameter, with infiltration to the pancreas body. In addition, the tumor invaded to the greater curvature of the stomach and the transverse colon. We performed distal gastrectomy, distal pancreatectomy, splenectomy and transverse colectomy. The final diagnosis of histopathology was desmoid tumor. The tumor recurred locally 9 months after the surgery. Recurrent legion was unresectable because of the invasion to the orifice of SMV and weekly combination chemotherapy of VLB and MTX was started. Although a partial response was achieved for a local recurrent legion after 20 courses, CT scan showed other new recurrent multiple lesions in the abdominal cavity. Due to the severe abdominal discomfort and intestinal obstruction, a reduction surgery was performed 5 times in total. Endocrine therapy and administration of NSAID were not effective. Tumor progression was uncontrollable, and the patient died 5 years and 8 months after the initial surgery. PMID- 22202435 TI - [Ultrasound guided vacuum-assisted biopsy for diagnosis of malignant lymphoma]. AB - Tailor-made treatment for lymphoma has been proposed, based on the information on prognostic on predictors or on molecular targets. This recent evolutions necessitated the collection of sufficient tissue samples for their preoperative evaluation. Since needle biopsy or needle aspiration cytology may not provide enough tissue for histo-pathologic diagnosis, incisional and excisional biopsies are commonly performed. In this study, we applied a handheld vacuum-assisted biopsy (VAB) system, as an alternative to the conventional incisional and excisional biopsies, to evaluate its feasibility in the biopsy -based diagnosis of malignant lymphoma. The subjects were nine patients with clinically suspected malignant lymphoma. All of them were correctly diagnosed with a diagnostic accuracy of 100%, and lymphoma sub-types could be defined according to the New WHO classification. There was no complication associated with the procedure. Lymph node biopsy for diagnosis of malignant lymphoma using this minimally invasive VAB technique allows a simple and safe collection of sufficient samples with good-quality, and promises to contribute to a precise molecular-based diagnosis. PMID- 22202436 TI - Is the core-periphery labour market structure related to perceived health? findings of the Northern Swedish Cohort. AB - BACKGROUND: There is controversy as to whether peripheral employment is related to poor health status or not. This study aims at examining whether 1) the accumulation of time in peripheral labour market positions is associated with psychological distress and poor or average self-rated health; 2) the proposed association is different among women than among men. METHOD: Participants in the 1995 and 2007 follow-up surveys of the Northern Swedish Cohort (n = 985) completed self-administered questionnaires about psychological and general health and about employment positions during the follow-up years. Associations between 12 year peripheral labour market positions (no, low, medium and high exposure) and health were examined using logistic regression. RESULTS: Exposure to peripheral employment was positively related to psychological distress in both women and men (p-values for trend < 0.001). Adjustment for sociodemographics and psychological distress at baseline, as well as for unemployment and being out of the labour market at the follow-up, resulted in attenuation of the odds ratios, particularly in the group with high exposure to peripheral employment, although results remained significant in men in the fully adjusted model. Women and men with high exposure to peripheral employment had high odds of poor or average self rated health, but the association was rendered non-significant after adjustment for the covariates. CONCLUSIONS: Our findings suggest that exposure to peripheral employment positions has an impact particularly on mental health, partly due to the over-representation of other unfavourable social and employment conditions among those with substantial exposure to peripheral employment. PMID- 22202437 TI - Ultrasound mediated catalyst free synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6 ones leading to novel quinoline derivatives: their evaluation as potential anti cancer agents. AB - A facile and catalyst free synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-ones has been accomplished via the reaction of 4-chloro-2-oxo-2H-chromene-3 carbaldehyde with various aromatic amines in the presence of ultrasound. Some of these compounds were converted to the corresponding 2-(3-(hydroxymethyl)quinolin 2-yl)phenols and further structure elaboration of a representative quinoline derivative is presented. Molecular structure of two representative compounds was confirmed by single crystal X-ray diffraction study. Many of these compounds were evaluated for their anti-proliferative properties in vitro against four cancer cell lines and several compounds were found to be active. Further in vitro studies indicated that inhibition of sirtuins could be the possible mechanism of action of these molecules. PMID- 22202438 TI - Long non-coding RNAs in Huntington's disease neurodegeneration. AB - Neurodegeneration in the brains of Huntington's disease patients is accompanied by widespread changes in gene regulatory networks. Recent studies have found that these changes are not restricted to protein-coding genes, but also include non coding RNAs (ncRNAs). One particularly abundant but poorly understood class of ncRNAs is the long non-coding RNAs (lncRNAs), of which at least ten thousand have been identified in the human genome. Although we presently know little about their function, lncRNAs are widely expressed in the mammalian nervous system, and many are likely to play critical roles in neuronal development and activity. LncRNAs are now being implicated in neurodegenerative processes, including Alzheimer's (AD) and Huntington's disease (HD). In the present study, I discuss the potential significance of lncRNAs in HD. To support this, I have mined existing microarray data to discover seven new lncRNAs that are dysregulated in HD brains. Interestingly, several of these contain genomic binding sites for the transcriptional repressor REST, a key mediator of transcriptional changes in HD, including the known REST target lncRNA, DGCR5. Previously described lncRNAs TUG1 (necessary for retinal development) and NEAT1 (a structural component of nuclear paraspeckles) are upregulated in HD caudate, while the brain-specific tumour suppressor MEG3 is downregulated. Three other lncRNAs of unknown function are also significantly changed in HD brains. Many lncRNAs regulate gene expression through formation of epigenetic ribonucleoprotein complexes, including TUG1 and MEG3. These findings lead me to propose that lncRNA expression changes in HD are widespread, that many of these result in altered epigenetic gene regulation in diseased neurons, and that contributes to neurodegeneration. Therefore, elucidating lncRNA network changes in HD may be important in understanding and treating this and other neurodegenerative processes. PMID- 22202439 TI - Molecular effects of gallium on osteoclastic differentiation of mouse and human monocytes. AB - We had previously reported that gallium (Ga) inhibited both the differentiation and resorbing activity of osteoclasts in a dose-dependent manner. To provide new insights into Ga impact on osteoclastogenesis, we investigated here the molecular mechanisms of Ga action on osteoclastic differentiation of monocytes upon Rankl treatment. We first observed that Ga treatment inhibited the expression of Rankl induced early differentiation marker genes, while the same treatment performed subsequently did not modify the expression of late differentiation marker genes. Focusing on the early stages of osteoclast differentiation, we observed that Ga considerably disturbed both the initial induction as well as the autoamplification step of Nfatc1 gene. We next demonstrated that Ga strongly up regulated the expression of Traf6, p62 and Cyld genes, and we observed concomitantly an inhibition of IkappaB degradation and a blockade of NFkappaB nuclear translocation, which regulates the initial induction of Nfatc1 gene expression. In addition, Ga inhibited c-Fos gene expression, and subsequently the auto-amplification stage of Nfatc1 gene expression. Lastly, considering calcium signaling, we observed upon Ga treatment an inhibition of calcium-induced Creb phosphorylation, as well as a blockade of gadolinium-induced calcium entry through TRPV-5 calcium channels. We identify for the first time Traf6, p62, Cyld, IkappaB, NFkappaB, c-Fos, and the calcium-induced Creb phosphorylation as molecular targets of Ga, this tremendously impacting the expression of the master transcription factor Nfatc1. In addition, our results strongly suggest that the TRPV-5 calcium channel, which is located within the plasma membrane, is a target of Ga action on human osteoclast progenitor cells. PMID- 22202440 TI - Microbiology of regressive autism. AB - This manuscript summarizes some of our earlier work on the microbiology of autism subjects' stool specimens, as compared with stools from control subjects. Our most recent data indicating that Desulfovibrio may play an important role in regressive autism is also presented. In addition, we present information on antimicrobial susceptibility patterns of Desulfovibrio using the CLSI agar dilution susceptibility technique. In addition, we summarize data from our earlier studies showing the impact of various antimicrobial agents on the indigenous bowel flora. This shows that penicillins and cephalosporins, as well as clindamycin, have a major impact on the normal bowel flora and therefore might well predispose subjects to overgrowth of such organisms as Clostridium difficile, and of particular importance for autism, to Desulfovibrio. PMID- 22202441 TI - On being an (Anaerobe) ID fellow with Sid. PMID- 22202442 TI - Influence of lactose and lactate on growth and beta-galactosidase activity of potential probiotic Propionibacterium acidipropionici. AB - Dairy propionibacteria are microorganisms of interest for their role as starters in cheese technology and as well as their functions as probiotics. Previous studies have demonstrated that Propionibacterium acidipropionici metabolize lactose by a beta-galactosidase that resists the gastrointestinal transit and the manufacture of a Swiss-type cheese, so that could be considered for their inclusion in a probiotic product assigned to intolerant individuals. In the present work we studied the effect of the sequential addition of lactose and lactate as first or second energy sources on the growth and beta-galactosidase activity of P. acidipropionici Q4. The highest beta-galactosidase activity was observed in a medium containing only lactate whereas higher final biomass was obtained in a medium with lactose. When lactate was used by this strain as a second energy source, a marked increase of the intracellular pyruvate level was observed, followed by lactate consumption and increase of specific beta galactosidase activity whereas lactose consumption became negligible. On the contrary, when lactose was provided as second energy source, lactic acid stopped to be metabolized, a decrease of the intracellular pyruvate concentration was observed and beta-galactosidase activity sharply returned to a value that resembled the observed during the growth on lactose alone. Results suggest that the relative concentration of each substrate in the culture medium and the intracellular pyruvate level were decisive for both the choice of the energetic substrate and the beta-galactosidase activity in propionibacteria. This information should be useful to decide the most appropriate vehicle to deliver propionibacteria to the host in order to obtain the highest beta-galactosidase activity. PMID- 22202456 TI - Cdx2 controls expression of the protocadherin Mucdhl, an inhibitor of growth and beta-catenin activity in colon cancer cells. AB - BACKGROUND & AIMS: The intestine-specific homeobox transcription factor Cdx2 is an important determinant of intestinal identity in the embryonic endoderm and regulates the balance between proliferation and differentiation in the adult intestinal epithelium. Human colon tumors often lose Cdx2 expression, and heterozygous inactivation of Cdx2 in mice increases colon tumorigenesis. We sought to identify Cdx2 target genes to determine how it contributes to intestinal homeostasis. METHODS: We used expression profiling analysis to identify genes that are regulated by Cdx2 in colon cancer cells lines. Regulation and function of a potential target gene were further investigated using various cell assays. RESULTS: In colon cancer cell lines, Cdx2 directly regulated the transcription of the gene that encodes the protocadherin Mucdhl. Mucdhl localized to the apex of differentiated cells in the intestinal epithelium, and its expression was reduced in most human colon tumors. Overexpression of Mucdhl inhibited low-density proliferation of colon cancer cells and reduced tumor formation in nude mice. One isoform of Mucdhl interacted with beta-catenin and inhibited its transcriptional activity. CONCLUSIONS: The transcription factor Cdx2 activates expression of the protocadherin Mucdhl, which interacts with beta catenin and regulates activities of intestinal cells. Loss of Cdx2 expression in colon cancer cells might reduce expression of Mucdhl and thereby lead to tumor formation. PMID- 22202457 TI - Fibronectin extra domain-A promotes hepatic stellate cell motility but not differentiation into myofibroblasts. AB - BACKGROUND & AIMS: Myofibroblasts are the primary cell type involved in physiologic wound healing and its pathologic counterpart, fibrosis. Cellular fibronectin that contains the alternatively spliced extra domain A (EIIIA) is up regulated during these processes and is believed to promote myofibroblast differentiation. We sought to determine the requirement for EIIIA in fibrosis and differentiation of myofibroblasts in rodent livers. METHODS: We used a mechanically tunable hydrogel cell culture system to study differentiation of primary hepatic stellate cells and portal fibroblasts from rats into myofibroblasts. Liver fibrosis was induced in mice by bile duct ligation or administration of thioacetamide. RESULTS: EIIIA was not required for differentiation of rat hepatic stellate cells or portal fibroblasts into fibrogenic myofibroblasts. Instead, hepatic stellate cells cultured on EIIIA containing cellular fibronectin formed increased numbers of lamellipodia; their random motility and chemotaxis also increased. These increases required the receptor for EIIIA, the integrin alpha(9)beta(1). In contrast, the motility of portal fibroblasts did not increase on EIIIA, and these cells expressed little alpha(9)beta(1). Male EIIIA(-/-) mice were modestly protected from thioacetamide induced fibrosis, which requires motile hepatic stellate cells, but not from bile duct ligation-induced fibrosis, in which portal fibroblasts are more important. Notably, myofibroblasts developed during induction of fibrosis with either thioacetamide or bile duct ligation in EIIIA(-/-) mice. CONCLUSIONS: EIIIA is dispensable for differentiation of hepatic stellate cells and portal fibroblasts to myofibroblasts, both in culture and in mouse models of fibrosis. Our findings, however, indicate a role for EIIIA in promoting stellate cell motility and parenchymal liver fibrosis. PMID- 22202459 TI - Integrative genomic identification of genes on 8p associated with hepatocellular carcinoma progression and patient survival. AB - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is an aggressive malignancy; its mechanisms of development and progression are poorly understood. We used an integrative approach to identify HCC driver genes, defined as genes whose copy numbers associate with gene expression and cancer progression. METHODS: We combined data from high-resolution, array-based comparative genomic hybridization and transcriptome analysis of HCC samples from 76 patients with hepatitis B virus infection with data on patient survival times. Candidate genes were functionally validated using in vitro and in vivo models. RESULTS: Unsupervised analyses of array comparative genomic hybridization data associated loss of chromosome 8p with poor outcome (reduced survival time); somatic copy number alterations correlated with expression of 27.3% of genes analyzed. We associated expression levels of 10 of these genes with patient survival times in 2 independent cohorts (comprising 319 cases of HCC with mixed etiology) and 3 breast cancer cohorts (637 cases). Among the 10-gene signature, a cluster of 6 genes on 8p, (DLC1, CCDC25, ELP3, PROSC, SH2D4A, and SORBS3) were deleted in HCCs from patients with poor outcomes. In vitro and in vivo analyses indicated that the products of PROSC, SH2D4A, and SORBS3 have tumor-suppressive activities, along with the known tumor suppressor gene DLC1. CONCLUSIONS: We used an unbiased approach to identify 10 genes associated with HCC progression. These might be used in assisting diagnosis and to stage tumors based on gene expression patterns. PMID- 22202458 TI - The membrane-bound mucin Muc1 regulates T helper 17-cell responses and colitis in mice. AB - BACKGROUND & AIMS: T helper (Th) 17 cells produce the effector cytokine interleukin (IL)-17, along with IL-22, which stimulates colonic epithelial cells to produce a membrane-bound mucin, Muc1. Muc1 is a component of the colonic mucus, which functions as a lubricant and a physiologic barrier between luminal contents and mucosal surface. The gene MUC1 has been associated with susceptibility to inflammatory bowel disease; we investigated the role of Muc1 in development of colitis in mice. METHODS: Muc1 and RAG1 were disrupted in mice (Muc/RAG double knockout mice); Th1-mediated colitis was induced by intravenous injection of CD4(+)CD45RB(high) T cells. We also studied Th2-mediated colitis using mice with disruptions in Muc1 and T-cell receptor alpha chain (Muc/TCR double knockout mice). RESULTS: Muc1 deficiency led to the development of more severe forms of Th1- and Th2-induced colitis than controls. Loss of Muc1 increased colonic permeability and the Th17-cell, but not Th2 or Th1 cell, response in the inflamed colon. Loss of Muc1 also promoted expansion of an innate lymphoid cell population (Lin(-) ckit(-) Thy1(+) Sca1(+)) that produces IL-17. The expansion of Th17 adaptive immune cells and innate lymphoid cells required the commensal microbiota. CONCLUSIONS: Muc1, which is up-regulated by Th17 signaling, functions in a negative feedback pathway that prevents an excessive Th17 cell response in inflamed colons of mice. Disruption of this negative feedback pathway, perhaps by variants in Muc1, might contribute to inflammatory bowel disease in patients. PMID- 22202460 TI - BMP2, BMP4, noggin, BMPRIA, BMPRIB, and BMPRII are differentially expressed in the adult rat spinal cord. AB - Bone morphogenetic proteins (BMPs) are members of the transforming growth factor beta (TGF-beta) superfamily. BMPs, such as BMP2 and BMP4, exert its biological functions by interacting with membrane bound receptors belonging to the serine/threonine kinase family including bone morphogenetic protein receptor I (BMPRIA, BMPRIB) and type II (BMPRII). Functions of BMPs are also regulated in the extracellular space by secreted antagonistic regulators such as noggin. Although BMP2, BMP4, noggin, BMPRIA, BMPRIB, and BMPRII expressions have been well described in the central nervous system, little information is available for their expressions in the spinal cord. We, thus, investigated these protein expressions in the adult rat spinal cord using immunohistochemistry. Here, we show that BMP2, BMP4, noggin, BMPRIA, BMPRIB, and BMPRII are widely and differentially expressed in the spinal cord. Besides abundant BMP2, BMP4, noggin, BMPRIA, BMPRIB, and BMPRII protein expressions in neurons, we detected them also in astrocytes, oligodendrocytes, and ependymal cells. In addition, we found BMPRIA, BMPRIB, and BMPRII protein expressions in microglia. Interestingly, we also observed that these proteins are strongly expressed in many kinds of axons in both ascending and descending tracts. These data indicate that BMP2, BMP4, noggin, BMPRIA, BMPRIB, and BMPRII proteins are more widely expressed in the adult spinal cord than previously reported, and their continued abundant expressions in the adult spinal cord strongly support the idea that BMP signaling plays pivotal roles in the adult spinal cord. PMID- 22202463 TI - Work stress among university teachers: gender and position differences. AB - The aim of this study was to investigate exposure to stress at work in university teachers and see if there were differences between men and women as well as between positions. The study was carried out online and included a representative sample of 1,168 teachers employed at universities in Croatia. This included all teaching positions: assistants (50%), assistant professors (18%), associate professors (17%), and full professors (15%). Fifty-seven percent of the sample were women. The participants answered a questionnaire of our own design that measured six groups of stressors: workload, material and technical conditions at work, relationships with colleagues at work, work with students, work organisation, and social recognition and status. Women reported greater stress than men. Assistant professors, associate professors, and full professors reported greater stress related to material and technical conditions of work and work organisation than assistants, who, in turn, found relationships with colleagues a greater stressor. Full professors, reported lower exposure to stress at work than associate professors, assistant professors, and assistants. PMID- 22202461 TI - Rapid enrichment of presynaptic protein in boutons undergoing classical conditioning is mediated by brain-derived neurotrophic factor. AB - Presynaptic structural modifications are thought to accompany activity-dependent synaptic plasticity and learning. This may involve the conversion of nonfunctional synapses into active ones or the generation of entirely new synapses. Here, using an in vitro neural analog of classical conditioning, we investigated presynaptic structural changes restricted to auditory nerve synapses that convey the conditioned stimulus (CS) by tract tracing using fluorescent tracers combined with immunostaining for the synaptic vesicle-associated protein synaptophysin. The results show that the size of presynaptic auditory boutons increased and the area and fluorescence intensity of punctate staining for synaptophysin were enhanced after conditioning. This occurred only for auditory nerve boutons apposed to the dendrites but not the somata of abducens motor neurons. Conditioning increased the percentage of boutons that were immunopositive for synaptophysin and enhanced the number of synaptophysin puncta they contained. Pretreatment with antibodies against brain-derived neurotrophic factor (BDNF) inhibited these conditioning-induced structural changes. There was also a net increase in the number of boutons apposed to abducens motor neurons after conditioning or BDNF treatment. These data indicate that the rapid enrichment of presynaptic boutons with proteins required for neurotransmitter recycling and release occurs during classical conditioning and that these processes are mediated by BDNF. PMID- 22202462 TI - Does GSTP1 polymorphism contribute to genetic damage caused by ageing and occupational exposure? AB - The aim of our study was to see the effects of GSTP1 polymorphism on biomarkers of ageing, including micronuclei (MN), comet tail length, and relative telomere length in automobile repair workers, who are exposed to a broad spectrum of potential mutagens. The analysis was performed on buccal cells collected from occupationally exposed and non-exposed (control) subjects. Samples were analysed using cytogenetic and molecular methods, including restriction fragment length polymorphism (RFLP), MN test, comet assay, and real-time PCR. The results confirmed the DNA damaging effects of substances used in the mechanical workshops, but did not confirm the influence of GSTP1 gene polymorphism on DNA damage. However, further studies on both occupationally exposed and control populations are needed to understand the relationship between GSTP1 polymorphism and genome damage. PMID- 22202464 TI - The effect of laurel leaf extract against toxicity induced by 2,3,7,8 tetrachlorodibenzo-p-dioxin in cultured rat hepatocytes. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a very toxic environmental pollutant that raises great public concern about its impact on human health. Recent studies indicate that laurel leaf extract exhibits antioxidant properties that can counter the toxic effects of certain compounds in the liver. The aim of this study was to assess how effective LE is against the toxicity of TCDD in a primary culture of rat hepatocytes. The extract (50 mg L(-1), 100 mg L(-1), and 200 mg L(-1)) was added to cultures alone or with TCDD (1.61 mg L(-1) and 3.22 mg L(-1)) for 48 hours. Cell viability was measured using the [3-(4,5-dimethyl thiazol-2-yl) 2,5-diphenyltetrazolium bromide] (MTT) assay and the lactate dehydrogenase (LDH) cytotoxicity assay, while oxidative damage was assessed by measuring total antioxidant capacity (TAC) and total oxidative stress (TOS). DNA damage was also analysed using the micronucleus (MN) assay of the cultured hepatocytes. TCDD alone lowered, and laurel extract had no effect on cell viability. TCDD also increased TOS and significantly decreased TAC. It significantly increased the frequency of micronucleated hepatocytes in a dose dependent manner. In cultures exposed to LE alone, TOS did not change and TAC significantly increased in a dose-dependent manner. Added to TCDD, laurel countered its toxic effects and showed protective effects against TCDD-mediated DNA damage. This points to the therapeutic potential of laurel against TCDD toxicity in the liver. PMID- 22202465 TI - Acute toxicity of veterinary and agricultural formulations of organophosphates dichlorvos and diazinon in chicks. AB - Formulation components of organophosphate insecticidal preparations might affect their toxic action in animals. The objective of this study was to examine and compare the acute toxicity and cholinesterase inhibition in seven to 14-day-old chicks dosed orally with dichlorvos and diazinon in standard veterinary and agricultural formulations. The acute (24 h) oral median lethal doses (LD50) of the formulations were determined using the up-and-down method. Respective LD50 of dichlorvos of the veterinary and agricultural formulations in chicks were 11.1 mg kg(-1) and 6.51 mg kg(-1) and those of diazinon 6.4 mg kg(-1) and 6.7 mg kg(-1). Plasma and brain cholinesterase activities were measured by electrometry after in vivo and in vitro exposure to organophosphates. The chicks showed signs of cholinergic toxicosis within one hour of dosing. Dichlorvos (8 mg kg(-1)) and diazinon (4 mg kg(-1)) in the veterinary and agricultural formulation significantly reduced both plasma and brain cholinesterase activities in the chicks. The veterinary formulation of dichlorvos reduced plasma ChE by 60% and agricultural by 40% and brain ChE by 93% and 87%, respectively. In contrast, ChE inhibition by diazinon in the agricultural formulation of diazinon was stronger than by the veterinary formulation; 72% vs. 64% in plasma and 97% vs. 80% in the brain, respectively. The highest in vitro inhibitions were observed with dichlorvos in the agricultural formulation (50%) in the brain samples and with diazinon in the agricultural formulation (52%) in the plasma samples. While they exist, differences between formulations cannot be taken as a rule and further investigations should inventory the toxicity of standard veterinary and agricultural organophosphate formulations in addition to the known data for pure forms. PMID- 22202466 TI - Changes in the lower Drava River water quality parameters over 24 years. AB - The goal of this study was to analyse 13 physico-chemical and microbiological parameters of the Drava River water at three sampling sites in the lower Drava region (eastern Croatia) over two distinct periods: the pre-war period between 1985 and 1992 and the post-war period between 1993 and 2008. Over both periods, most parameters kept within the tolerable water quality limits, while NO3-N, NH4 N and BOD5 were higher. The lower Drava showed slight organic pollution with high concentrations of dissolved oxygen. High levels of total coliforms and heterotrophic bacteria in the post-war period were only found downstream of the town of Osijek. Upstream of Osijek, the river showed a tendency for improvement. PMID- 22202467 TI - Legionella species in year-round vs. seasonal accommodation water supply systems. AB - The purpose of this study was to compare the quality of hot water between eleven hotels in the Split-Dalmatia County, Croatia that are open year round and 10 summer season hotels and retirement homes with irregular use of water. We took 122 samples between May and December 2009. Water temperature and free residual chlorine were measured in situ. Physical and chemical analysis included pH, electrical conductivity, and concentrations of iron, manganese, copper, zinc, calcium, and magnesium that were measured using atomic absorption spectrophotometry, while the Legionella species were determined using a cultivation method on buffered charcoal yeast extract agar. Differences in metal concentrations between the seasonal and year-round accommodation facilities were negligible, save for zinc that was higher in year-round (0.341 mg L(-1)) than in seasonal facilities (0.130 mg L(-1)). Samples from all year-round and six summer season hotels were negative to the Legionella species, but four seasonal facilities turned up with positive samples to Legionella pneumophila. Our study has demonstrated that water quality differs between year-round and seasonal accommodation facilities. These findings suggest that metal plumbing components and associated corrosion products are important factors in the survival and growth of Legionella species in water distribution systems. PMID- 22202468 TI - Eosinophilic inflammation in allergic rhinitis and nasal polyposis. AB - On histopathological examination, nasal polyps and nasal mucosa in allergic rhinitis show different forms of pseudostratified respiratory epithelium, whereas the dominant characteristic of lamina propria is an eosinophilic infiltration. The aim of this study was to compare interleukin (IL)-5 and eosinophilic cationic protein (ECP) levels in the nasal fluid of 42 patients: 12 with allergic rhinitis and nasal septal deviation, 17 non-atopic patients with nasal polyposis, and 13 atopic nasal polyp patients were enrolled in this cross-sectional study. Nasal secretion samples were collected a few days before surgery. The levels of IL-5 were measured using flow cytometry and the ECP using a commercial ELISA kit. In addition, we counted eosinophils in hematoxylin-and-eosin-stained sections of all nasal polyp and all nasal mucosa samples taken from the inferior nasal turbinates during septoplasty. A significantly higher concentration of IL-5 was found in the nasal fluid of atopic patients with nasal polyposis than in non-atopic nasal polyp patients (p=0.025) and patients with allergic rhinitis (p=0.05). ECP was higher in atopic nasal polyp patients than in patients with allergic rhinitis (p<0.0001) and than in non-atopic nasal polyp patients (p<0.0001). Polyp eosinophils were higher in atopic' than in non-atopic patients (p<0.0001) and higher than in the mucosa of patients with allergic rhinitis (p<0.0001). These however had significantly more mucosal eosinophils than was found in the polyps of non-atopic patients' (p=0.025). ECP levels in nasal fluid and eosinophil counts in tissue specimens correlated well in all three groups of patients. Our study has shown that atopic nasal polyp patients have a higher level of eosinophilic inflammation than non-atopic patients with nasal polyps and patients with allergic rhinitis. PMID- 22202469 TI - [Mineral oil drinking water pollution accident in Slavonski Brod, Croatia]. AB - On 21 September 2008, heavy oil penetrated the drinking water supply in Slavonski Brod, Croatia. The accident was caused by the damage of heat exchange units in hot water supply. The system was polluted until the beginning of November, when the pipeline was treated with BIS O 2700 detergent and rinsed with water. Meanwhile, water samples were taken for chemical analysis using spectrometric and titrimetric methods and for microbiological analysis using membrane filtration and total plate count. Mineral oils were determined with infrared spectroscopy. Of the 192 samples taken for mineral oil analysis, 55 were above the maximally allowed concentration (MAC). Five samples were taken for polycyclic aromatic hydrocarbon (PAH), benzene, toluene, ethylbenzene, and xylene analysis (BTEX), but none was above MAC. Epidemiologists conducted a survey about health symptoms among the residents affected by the accident. Thirty-six complained of symptoms such as diarrhoea, stomach cramps, vomiting, rash, eye burning, chills, and gastric disorders.This is the first reported case of drinking water pollution with mineral oil in Slavonski Brod and the accident has raised a number of issues, starting from poor water supply maintenance to glitches in the management of emergencies such as this. PMID- 22202470 TI - [Polycyclic aromatic hydrocarbons in air]. AB - Polycyclic aromatic hydrocarbons (PAHs) are a large group of organic compounds consisting of two or more condense aromatic rings. They are products of incomplete combustion or pyrolysis of organic matter. Because some PAHs such as Benzo[a]pyrene (BaP) are proven carcinogens and mutagens, it is necessary to continuously monitor their concentrations in the air, water, and soil. PAHs with two or three aromatic rings are stable in the gas phase, while most PAHs with five or more aromatic rings bond to particles. Higher concentrations of PAHs are present in the atmosphere of urban areas, mostly in the winter, due to heating. In the summer, these concentrations drop because most PAHs are unstable at high temperatures and break down by oxidation and photooxidation. Measurements of PAHs in the air include sampling on the filter paper or solid adsorbent, extraction, and chromatographic analysis. This review presents the measurements of BaP in some locations in the world and compares them with the findings in Croatia. PMID- 22202471 TI - Indoor exposure to mould allergens. AB - Humid indoor environments may be colonised by allergenic filamentous microfungi (moulds), Aspergillus spp., Penicillium spp., Cladosporium spp., and Alternaria spp. in particular. Mould-induced respiratory diseases are a worldwide problem. In the last two decades, mould allergens and glucans have been used as markers of indoor exposure to moulds. Recently, mould allergens Alt a 1 (Alternaria alternata) and Asp f 1 (Aspergillus fumigatus) have been analysed in various environments (residential and occupational) with enzyme-linked immunosorbent assays, which use monoclonal or polyclonal antibodies. Household Alt a 1 and Asp f 1 levels were usually under the limit of the method detection. By contrast, higher levels of mould allergens were found in environments with high levels of bioaerosols such as poultry farms and sawmills. Data on allergen Alt a 1 and Asp f 1 levels in agricultural settings may provide information on possible colonisation of respective moulds and point out to mould-related diseases in occupants. PMID- 22202472 TI - Bisphenol-A in canned food products: is it really required? PMID- 22202473 TI - Copper and the herbicide atrazine impair the stress response of the freshwater fish Prochilodus lineatus. AB - In order to evaluate the effects of copper and atrazine on the stress response of the freshwater fish Prochilodus lineatus, juvenile fish were pre-exposed to copper (20 MUg L(-1)) or atrazine (10 MUg L(-1)) for 24 h and then submitted to air exposure for 3 min. Simultaneously fish kept in dechlorinated water for 24 h were subjected to air exposure and a non-stress group was not subjected to air stress or any contaminants. Animals were sampled immediately (t0) and after 1, 3 and 6 h of air exposure (t1, t3 and t6 respectively) for the analysis of plasma cortisol, glucose and Na(+), hepatic glycogen, branchial Na(+)/K(+)-ATPase (NKA), number of red blood cells per cubic millimeter of blood (RBC), hematocrit (Hct) and hemoglobin content (Hb). In fish pre-exposed to copper the stress response was inhibited, and at t1 and t3 both cortisol and glucose remained significantly lower compared to fish subjected to air stress only. In fish pre-exposed to atrazine there was no rise in cortisol, but there was an increase in plasma glucose, RBC, Hct and Hb at t0 and a return of these parameters to basal levels at t1, as they did not differ significantly in relation to non-stressed fish. Animals pre-exposed to either Cu or atrazine showed a significant reduction in NKA activity at t1 and t3, in relation to air stressed fish. These results clearly indicate that copper and atrazine impair cortisol stress response of P. lineatus and that fish subjected to a contaminant-induced stress, either by copper or atrazine, may not be able to respond to any additional stressors. PMID- 22202474 TI - Along the road not taken: how many myosin heads act on a single actin filament at any instant in working muscle? AB - We reconsider the use of stiffness measurements to estimate N, the number of myosin heads acting (working at any instant to produce tension) on a single actin filament in vertebrate striated muscle, and give reasons for our rejection of numbers produced from such measurements. We go on to present a different approach to the problem, citing and extending a model bearing on the value of N which is derived from other physiological and biochemical data and which offers insight into the fundamental actin-myosin contractile event as an impulsive force. New experimental data accumulating over the past decade support this model, in which the myosin heads act sequentially along the actin filament (this is an example of Conformational Spread). In this model only a single myosin head acts on a single actin filament to produce an impulse at any given instant in normally-contracting muscle, either in the isometric or the isotonic mode, so N = 1. However, extra impulses occur within the same time frame after quick release of length or tension. The predictions of this sequential model are in striking agreement with a large body of recent detailed biophysical and biochemical evidence. We suggest that this warrants further in-depth experimental work, specifically to explore and test the sequential model and its implications. PMID- 22202493 TI - Exogenous glucagon-like peptide-1 for hyperglycemia in critically ill patients. AB - OBJECTIVE: To review literature evaluating the safety and efficacy of exogenous glucagon-like peptide-1 (GLP-1) for hyperglycemia in critically ill patients. DATA SOURCES: PubMed was queried (inception to September 3, 2011), using the search term glucagon-like peptide-1. The search was limited to studies published in English and conducted in humans. Regular and late-breaking abstracts from the American Diabetes Association Scientific Sessions in 2009 and 2010 were also searched using the same search term. STUDY SELECTION AND DATA EXTRACTION: All abstracts were screened for eligibility, which consisted of studies reporting the effects of intravenous GLP-1 administration on glycemic control in critically ill patients. Data extracted from eligible trials included study and population characteristics, measures of glycemic efficacy, and safety. DATA SYNTHESIS: Our search resulted in the identification of 2105 potentially relevant articles; of those, 7 were reviewed. All included publications evaluated the use of intravenous GLP-1 (1.2-3.6 pmol/kg/min) compared with insulin or placebo infused for 4.5-72 hours in critically ill patients. The majority (n = 4) of studies included only patients from a surgical intensive care setting, and 71% (n = 5) of trials included those with a history of diabetes. Relative to insulin or placebo, GLP-1 therapy effectively lowered blood glucose concentrations in all trials. Out of 81 total study participants receiving GLP-1, only 4 had documented hypoglycemia (<60 mg/dL), 4 reported nausea, and 2 experienced vomiting. No other serious adverse events were reported. CONCLUSIONS: All trials reviewed suggest that GLP-1 may be a promising agent for the management of hyperglycemia in critically ill patients, regardless of diabetes status. Additional studies in more heterogeneous intensive care settings comparing GLP-1 with insulin, the current standard of care, are necessary. These studies should evaluate long-term safety and effectiveness of GLP-1 therapy on morbidity and mortality outcomes in critically ill populations. PMID- 22202494 TI - Use of topical tranexamic acid or aminocaproic acid to prevent bleeding after major surgical procedures. AB - OBJECTIVE: To evaluate the literature describing topical use of tranexamic acid or aminocaproic acid for prevention of postoperative bleeding after major surgical procedures. DATA SOURCES: Literature was retrieved through MEDLINE (1946 September 2011) and International Pharmaceutical Abstracts (1970-September 2011) using the terms tranexamic acid, aminocaproic acid, antifibrinolytic, topical, and surgical. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All identified articles in English were evaluated. Clinical trials, case reports, and meta-analyses describing topical use of tranexamic acid or aminocaproic acid to prevent postoperative bleeding were included. DATA SYNTHESIS: A total of 16 publications in the setting of major surgical procedures were included; the majority of data were for tranexamic acid. For cardiac surgery, 4 trials used solutions containing tranexamic acid (1-2.5 g in 100-250 mL of 0.9% NaCl), and 1 trial assessed a solution containing aminocaproic acid (24 g in 250 mL of 0.9% NaCl). These solutions were poured into the chest cavity before sternotomy closure. For orthopedic procedures, all of the data were for topical irrigation solutions containing tranexamic acid (500 mg-3 g in 50-100 mL of 0.9% NaCl) or for intraarticular injections of tranexamic acid (250 mg to 2 g in 20-50 mL of 0.9% sodium chloride, with or without carbazochrome sodium sulfate). Overall, use of topical tranexamic acid or aminocaproic acid reduced postoperative blood loss; however, few studies reported a significant reduction in the number of packed red blood cell transfusions or units given, intensive care unit stay, or length of hospitalization. CONCLUSIONS: Topical application of tranexamic acid and aminocaproic acid to decrease postsurgical bleeding after major surgical procedures is a promising strategy. Further data are needed regarding the safety of this hemostatic approach. PMID- 22202492 TI - Phospholipase PLA2G7, associated with aggressive prostate cancer, promotes prostate cancer cell migration and invasion and is inhibited by statins. AB - Prostate cancer is the second leading cause of cancer mortality in men in developed countries. Due to the heterogeneous nature of the disease, design of novel personalized treatments is required to achieve efficient therapeutic responses. We have recently identified phospholipase 2 group VII (PLA2G7) as a potential drug target especially in ERG oncogene positive prostate cancers. Here, the expression profile of PLA2G7 was studied in 1137 prostate cancer and 409 adjacent non-malignant prostate tissues using immunohistochemistry to validate its biomarker potential and putative association with disease progression. In order to reveal the molecular alterations induced by PLA2G7 impairment, lipidomic and gene expression profiling was performed in response to PLA2G7 silencing in cultured prostate cancer cells. Moreover, the antineoplastic effect of statins combined with PLA2G7 impairment was studied in prostate cancer cells to evaluate the potential of repositioning of in vivo compatible drugs developed for other indications towards anti-cancer purposes. The results indicated that PLA2G7 is a cancer-selective biomarker in 50 % of prostate cancers and associates with aggressive disease. The alterations induced by PLA2G7 silencing highlighted the potential of PLA2G7 inhibition as an anti-proliferative, pro-apoptotic and anti migratorial therapeutic approach in prostate cancer. Moreover, the anti proliferative effect of PLA2G7 silencing was potentiated by lipid-lowering statins in prostate cancer cells. Taken together, our results support the potential of PLA2G7 as a biomarker and a drug target in prostate cancer and present a rationale for combining PLA2G7 inhibition with the use of statins in prostate cancer management. PMID- 22202495 TI - Warfarin for venous thromboembolism prophylaxis after elective hip or knee arthroplasty: exploring the evidence, guidelines, and challenges remaining. AB - BACKGROUND: Guidelines for the prevention of venous thromboembolism (VTE) after elective total hip or knee arthroplasty (THA/TKA) have been developed separately by the American Academy of Orthopaedic Surgeons (AAOS) and the American College of Chest Physicians (ACCP). Differences exist in approaches to preventing postoperative VTE through prophylaxis. OBJECTIVE: To compare trials using vitamin K antagonists (VKAs) and differences in guidelines to determine the benefits and drawbacks of warfarin for VTE prophylaxis following THA/TKA. DATA SOURCES: Guidelines from the AAOS published in 2009 and revised in 2011 and from the ACCP published in 2008 were compared for recommendations on the use of VKAs. A MEDLINE search from 1960 to November 2009 was conducted to identify pertinent articles on the use of warfarin or VKAs for VTE prophylaxis following THA/TKA. Search terms included warfarin, vitamin K antagonist, total hip or total knee replacement, and total hip or total knee arthroplasty. STUDY SELECTION AND DATA EXTRACTION: Only clinical trials in which warfarin was the primary agent for prophylaxis compared to other anticoagulants were included. DATA SYNTHESIS: Data on differences between guideline recommendations for the use of VKAs and the importance of a deep vein thrombosis or asymptomatic events were extracted. Thirteen comparative trials using VKAs for VTE prophylaxis and international normalized ratio (INR) targets were assessed. Overall, the incidence of bleeding tended to be lower with the use of VKAs, but thrombosis when including asymptomatic events was numerically higher when comparing INR targets. However, INR targets varied, with no comparative trials assessing the AAOS 2009 recommended INR target of 1.5-2.0. The AAOS guidelines initially recommended a longer duration of therapy and expressed stronger support for the use of aspirin for prophylaxis; however, in 2011, its guidelines were revised, with no specific recommendations as to agent, dose, or INR target goal. CONCLUSIONS: Warfarin is an effective agent to prevent VTE after elective THA/TKA. The most effective approach, including extended warfarin use up to 4 weeks or longer, has not been determined. PMID- 22202496 TI - I-SAVE study: impact of sedation, analgesia, and delirium protocols evaluated in the intensive care unit: an economic evaluation. AB - BACKGROUND: Intensive care units (ICUs) account for considerable health care costs. Adequate pain and sedation management is important to clinical care. OBJECTIVE: To determine whether implementing a protocol for management of analgesia, sedation, and delirium in the ICU would save costs. METHODS: With data from the I-SAVE (Impact of Sedation, Analgesia and Delirium Protocols Evaluated in the Intensive Care Unit: an Economic Evaluation) study, a prospective pre- and postprotocol design was used. Between the 2 periods, protocols for systematic management of sedation, analgesia, and delirium were implemented. Cost effectiveness was calculated by associating the variation of cost and effectiveness measures (proportion of patients within targeted pain, sedation, and delirium goals). Total costs (in 2004 Canadian dollars), by patient, consisted of the sum of sedation, analgesia, and delirium drug acquisition costs during the ICU stay and the cost of the ICU stay. RESULTS: A total of 1214 patients, 604 in the preprotocol group and 610 in the postprotocol group, were included. The mean (SD) ICU length of stay and the duration of mechanical ventilation were shorter among patients of the postprotocol group compared with those of the preprotocol group (5.43 [6.43] and 6.39 [8.05] days, respectively; p = 0.004 and 5.95 [6.80] and 7.27 [9.09] days, respectively; p < 0.009). The incidence of delirium remained the same. The proportion of patients with Richmond Agitation and Sedation (RASS) scores between -1 and +1 increased from 57.0% to 66.2% (p = 0.001), whereas the proportion of patients with a numeric rating scale (NRS) score of 1 or less increased from 56.3% to 66.6% (p < 0.001). The mean total cost of ICU hospitalization decreased from $6212.64 (7846.86) in the preprotocol group to $5279.90 (6263.91) in the postprotocol group (p = 0.022). The cost analyses for pain and agitation management improved; the proportion of patients with RASS scores between -1 and +1 or NRS scores of 1 or less increased significantly in the postprotocol group while costing, on average, $932.74 less per hospitalization. CONCLUSIONS: Establishing protocols for patient-driven management of sedation, analgesia, and delirium is a cost-effective practice and allows savings of nearly $1000 per hospitalization. PMID- 22202497 TI - Glycemic control and preventive care measures of indigent diabetes patients within a pharmacist-managed insulin titration program vs standard care. AB - BACKGROUND: Studies assessing pharmacist-led services have noted positive clinical diabetes outcomes; however, studies assessing pharmacist impact on glycemic control through insulin titration and adherence to American Diabetes Association (ADA) preventive care measures in an indigent population are limited. OBJECTIVE: To assess the impact of a pharmacist-managed insulin titration program compared to standard medical care on glycemic control and preventive care measures in an indigent population with diabetes. METHODS: This retrospective cohort study compared pharmacist-managed insulin titration to standard care; all patients received primary care services through a county-funded health center serving a low-income minority population. The pharmacist-managed patients, referred by the primary care provider, received telephone calls to assess blood glucose levels, encourage preventive care examinations, and titrate insulin doses through collaborative drug therapy management. Standard care patients received diabetes care solely from the primary care provider. Student t test was used to evaluate the primary outcome, glycemic control, assessed by change in hemoglobin A(1c) (A1C) between groups from baseline to various time points and study end. Secondary outcomes included attainment of preventive care measures and A1C goal of less than 7% and change in weight and total daily insulin dose from baseline to study end. RESULTS: Sixty-nine patients in the pharmacist-managed group (intervention) and 57 standard care patients (control) were evaluated. The pharmacist-managed group showed a significant difference in A1C at all time points, including, study end, compared to standard care (-1.3% vs -0.18%, respectively; p = 0.001). In addition, the intervention group more often completed the ADA's recommended preventive care measures; all differences were statistically significant. CONCLUSIONS: Pharmacist-provider collaboration can result in significant clinical improvements, including A1C reduction and adherence to preventive care measures, when compared to standard care in a medically underserved population with diabetes. PMID- 22202498 TI - Dabigatran use in a postoperative coronary artery bypass surgery patient with nonvalvular atrial fibrillation and heparin-PF4 antibodies. AB - OBJECTIVE: To present a case of dabigatran use for nonvalvular atrial fibrillation in a patient from a population for whom it has not been studied. Postoperative coronary artery bypass patients have significant bleeding risk and potential to develop heparin-induced thrombocytopenia (HIT). CASE SUMMARY: A 70 year-old male with a history of paroxysmal atrial fibrillation in sinus rhythm prior to surgery developed atrial fibrillation on postoperative day 2 after coronary artery bypass surgery. Because of thrombocytopenia, anticoagulation to decrease stroke risk with atrial fibrillation was initiated with dabigatran 150 mg orally twice daily beginning on postoperative day 4. Later on postoperative day 4, after dabigatran was administered, the patient's HIT screening test was positive for heparin/PF4 antibodies; however, he was not clinically diagnosed with HIT. Heparin was not used postoperatively and transition dosing from dabigatran to warfarin was started on postoperative day 8, the day of discharge. At the time of the outpatient follow-up appointment, the patient had no signs of thrombosis or bleeding complications. DISCUSSION: Dabigatran is a direct thrombin inhibitor approved for nonvalvular atrial fibrillation. In this case, the physician ordered dabigatran for an approved use, according to manufacturer labeling. However, patients with this diagnosis would have been excluded from the RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) trial, on which Food and Drug Administration approval was based. Our patient had thrombocytopenia with a low pretest probability for HIT but was positive for heparin/PF4 antibodies, based on enzyme immunoassay testing. Dabigatran was continued for atrial fibrillation and not switched to any other direct thrombin inhibitor, such as argatroban, lepirudin, or bivalirudin, which are listed in the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th edition, for the Treatment and Prevention of Heparin Induced Thrombocytopenia. CONCLUSIONS: Further research on the use of dabigatran in patients with recent coronary bypass surgery and heparin/PF4 antibodies is needed before any recommendations can be made. PMID- 22202499 TI - Lung transplantation across donor-specific anti-human leukocyte antigen antibodies: utility of bortezomib therapy in early graft dysfunction. AB - OBJECTIVE: To report the usefulness of bortezomib therapy in a sensitized lung transplant recipient experiencing antibody-mediated rejection. CASE SUMMARY: During a pretransplant evaluation, a 62-year-old woman with usual interstitial pneumonitis developed a diverticular bleed requiring transfusions, which elevated her panel reactive antibody to 98% for human leukocyte antigen (HLA) class I and 71% for class II. She underwent desensitization to decrease her panel reactive antibody levels. She received a double lung transplant across a weak HLA class II incompatibility but developed respiratory failure due to early graft dysfunction. On postoperative day (POD) 14 she was found to have donor-specific antibodies (DSA) to HLA class I and class II antigens. She received intravenous immunoglobulin (IVIG), plasmapheresis, and bortezomib to reduce the DSA. Repeat DSA testing on POD 80 demonstrated a 50% reduction in DSA, which became undetectable at POD 255. DISCUSSION: Antibody-mediated rejection (AMR) is difficult to diagnose and treat in lung transplantation. Since primary treatment options such as plasmapheresis and IVIG alone may not adequately eradicate DSA, the proteasome inhibitor bortezomib can be of additional value for the treatment of AMR. Bortezomib causes apoptosis of plasma cells, thus eliminating the production of allograft-specific DSA. CONCLUSIONS: This is the first report describing the utility of bortezomib for early graft dysfunction in a highly sensitized lung transplant recipient. Although this patient had preformed donor specific anti-HLA antibodies, AMR was successfully treated with a combination of plasmapheresis, IVIG, and bortezomib. At time of writing, the patient continued to have excellent graft function 2 years posttransplant. Bortezomib is a potent inhibitor of plasma cell production and it appears to be useful for the treatment of antibody-mediated graft dysfunction. PMID- 22202502 TI - JCMS: your partner in continuing professional development. PMID- 22202504 TI - The Royal College's new Maintenance of Certification Program streamlines learning into three sections. PMID- 22202506 TI - Topical psoriasis therapy in the age of biologics: evidence-based treatment recommendations. AB - BACKGROUND: Although the range of therapeutic options has expanded dramatically in recent years, topical agents remain ubiquitous and indispensable tools for treating psoriasis at all levels of severity. The 2009 Canadian psoriasis guidelines considered evidence supporting various monotherapies and combination regimens. OBJECTIVE: Here we review all approved topical agents, including corticosteroids, calcineurin inhibitors, vitamin D analogues, and retinoids, used in psoriasis and develop additional treatment recommendations, using the Scottish Intercollegiate Guidelines Network (SIGN) system to evaluate strength of evidence, as in the original guidelines. CONCLUSION: We propose that topical treatments have a place in the long-term management of patients with moderate to severe plaque psoriasis, including those receiving concomitant photo- or systemic therapy. Topical agents are effective and appropriate treatments for psoriasis as long as the physician is attentive to signs of local adverse events and seeks opportunities to reduce the dose or treatment frequency during chronic use. PMID- 22202507 TI - Pyoderma gangrenosum: the great pretender and a challenging diagnosis. AB - BACKGROUND: The initial presentation of pyoderma gangrenosum (PG) is virtually indistinguishable from a pyogenic infection, making debridement appear necessary. However, operative approaches often lead to exacerbation and rapid extension through pathergy. OBJECTIVE AND METHODS: In attempts to increase awareness of this condition and minimize misdiagnoses, a review of published reports involving PG of the hand and digits was performed and included 35 patients in addition to our case of a 14-year-old female with a history of ulcerative colitis. RESULTS: Of the total cases, 29 patients were misdiagnosed as having an infection and subsequently treated with antibiotics; 13 of these patients also had debridement of their lesions. Twenty-eight patients had associated medical conditions, including ulcerative colitis, Crohn disease, diabetes mellitus, and cancer. CONCLUSION: When approached with a rapidly growing ulcerated lesion that does not respond to operative therapy, the possibility of PG should be entertained and a high-dose corticosteroid regimen and/or immunomodulator therapy implemented. PMID- 22202501 TI - Drug delivery to the brain in Alzheimer's disease: consideration of the blood brain barrier. AB - The successful treatment of Alzheimer's disease (AD) will require drugs that can negotiate the blood-brain barrier (BBB). However, the BBB is not simply a physical barrier, but a complex interface that is in intimate communication with the rest of the central nervous system (CNS) and influenced by peripheral tissues. This review examines three aspects of the BBB in AD. First, it considers how the BBB may be contributing to the onset and progression of AD. In this regard, the BBB itself is a therapeutic target in the treatment of AD. Second, it examines how the BBB restricts drugs that might otherwise be useful in the treatment of AD and examines strategies being developed to deliver drugs to the CNS for the treatment of AD. Third, it considers how drug penetration across the AD BBB may differ from the BBB of normal aging. In this case, those differences can complicate the treatment of CNS diseases such as depression, delirium, psychoses, and pain control in the AD population. PMID- 22202508 TI - Hairless descendants of Mexican hairless dogs: an experimental model for studying hypertrophic scars. AB - BACKGROUND/OBJECTIVE: In previous studies, the author noticed hypertrophic scar formation in hairless dogs. The purpose of this study was to evaluate both grossly and histopathologically hypertrophic scars in hairless dogs to explore any similarities with hypertrophic scars in humans and to introduce these dogs as an appropriate model for further investigation on hypertrophic scarring. METHODS: Full-thickness wounds were made on the dorsolumbar skin of hairless dogs. Hypertrophic scarring was examined with three methods: clinical observations, dihydroxyphenylalanine (DOPA)-positive melanocytes, and skin histopathology. RESULTS: Hairless dogs clinically developed the formation of hyperpigmented and hypertrophic scars that did not extend beyond the original wound margins. In hypertrophic scars of hairless dogs, the split epidermal sheet showed an increased number of DOPA-positive melanocytes with well-developed dendrites exhibiting activated melanocytes. There were very few DOPA-positive melanocytes in the repaired skin of haired dogs. Histopathologic examinations demonstrated that hypertrophic scars were fully reepithelialized and granulation tissue formation was accompanied by inflammatory cell infiltration. There was remodeling of thick collagens and fine elastic fibers in the course of hypertrophic scar formation. CONCLUSION: Experimental hypertrophic scars produced in hairless dogs have morphologic properties similar to those of human hypertrophic scars. PMID- 22202509 TI - Lupus miliaris disseminatus faciei with extrafacial involvement in a 17-year-old white girl. AB - BACKGROUND: Lupus miliaris disseminatus faciei (LMDF) is a benign condition characterized by a papular eruption located in the central face. Histologic studies of the papules show granulomatous infiltrates with central necrosis. The condition is self-limited and usually resolves within 1 to 2 years yet can be cosmetically debilitating, given the location and potential for scarring. Granulomatous periorificial dermatitis similarly affects the face with granulomatous lesions and may overlap clinically with LMDF. CONCLUSION: This report highlights the challenge in differentiating and treating uncommon granulomatous facial dermatoses. PMID- 22202510 TI - Multiple cutaneous granular cell tumors: case report of a 19-year-old African American female. AB - BACKGROUND AND OBJECTIVE: This is a somewhat rare case of a 19-year-old African American female with multiple cutaneous granular cell tumors. Granular cell tumors are of neural origin, except in rare cases, and are considered benign, with a low incidence of malignancy. The clinical presentation varies greatly, but these tumors are most commonly painful and slow growing, with two-thirds occurring on the head and neck. Patients are most commonly in their second to fourth decades of life, two-thirds are black, and two-thirds are women. Granular cell tumors are diagnosed by the characteristic pathologic findings of polygonal cells with eosinophilic granular cytoplasm. CONCLUSION: These tumors are most commonly singular but can be multiple in 10 to 15% of patients. Older patient age, rapid growth or enlargement, and a history of local recurrence should raise concern for malignant behavior. The distribution and family history in this case are suggestive of possible mosaicism. PMID- 22202511 TI - Cutaneous manifestations of modern technology use. AB - BACKGROUND: Modern-age technology is increasingly implicated in traditional dermatologic conditions. OBJECTIVE: This review provides a concise overview of the cutaneous manifestations from modern technology use. METHODS: We describe a case of laptop computer-induced erythema ab igne and provide a review of the literature pertaining to the etiology, clinical features, diagnosis, and management of reported cases of dermatoses resulting from the use of modern technology. RESULTS: Sources of modern technology implicated in the reported cases include video games, laptop computers, personal computers and accessories, and smart and cellular phones. These presentations have primarily been localized to the extremities, particularly the hands and face. Diagnoses were associated with trauma or repetitive strain, irritant contact dermatitis, or allergic contact sensitivities. Removal of the offending agent was most often described as effective in symptom resolution. CONCLUSION: It is important to consider modern age sources as part of the index of suspicion for diagnosing traditional dermatologic conditions. These manifestations will likely increase over time with the pervasive popularity and use of modern technology. Early recognition of the offending agent will be beneficial in differentiating the etiology for effective management. PMID- 22202512 TI - Malignant fibrous histiocytoma masquerading as gluteal abscess. PMID- 22202513 TI - Concurrent allergic contact dermatitis of the index fingers and lips from toothpaste: report of three cases. PMID- 22202514 TI - Mercury levels in vitiligo patients. PMID- 22202539 TI - Prostatic urethral lift: two-year results after treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia. AB - OBJECTIVE: To evaluate the effectiveness of the prostatic urethral lift in relieving lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia. METHODS: A total of 64 men, aged>=55 years, with moderate to severe symptomatic benign prostatic hyperplasia were treated and followed up at 6 Australian institutions. The treatment consisted of transurethral delivery of small implants to secure the prostatic lobes in an open condition, thereby reducing obstruction of the urethral lumen. The effectiveness, including International Prostate Symptom Score, quality of life, benign prostatic hyperplasia Impact Index, and peak urethral flow rate were assessed at 2 weeks and 3, 6, 12, and 24 months. The effect of this treatment on erectile and ejaculatory function was assessed using the Sexual Health Inventory for Men and Male Sexual Health Questionnaire for Ejaculatory Dysfunction. RESULTS: The prostatic urethral lift improved LUTS symptoms rapidly and durably. The International Prostate Symptom Score was reduced 42% at 2 weeks, 49% at 6 months, and 42% at 2 years in evaluable patients. The peak flow rate improved by >=30% (2.4 mL/s) at all intervals compared with baseline. No compromise in sexual function was observed after this treatment. CONCLUSION: The present study demonstrated that LUTS and flow improvements without compromising sexual function. Although this was an early study with a small cohort, this therapy shows promise as a new option for patients with LUTS. PMID- 22202540 TI - Editorial comment. PMID- 22202542 TI - Is ultrasound imaging inferior to computed tomography or magnetic resonance imaging in evaluating renal mass size? AB - OBJECTIVE: To evaluate whether ultrasonography was inferior in detecting the size of a renal mass preoperatively because of the increased attention on the harmful effects of ionizing radiation in medical imaging. METHODS: A prospectively maintained database was reviewed of all patients who underwent renal ultrasonography before definitive therapy for the renal mass. Every patient who underwent ultrasound imaging also underwent computed tomography (CT) or magnetic resonance imaging (MRI), or both, before treatment. The size of the largest tumor identified per imaging modality was compared among the modalities using correlation and analysis of variance. RESULTS: A total of 116 patients underwent ultrasound imaging before therapy. Of these patients, 80 also underwent MRI, 66 underwent CT, and 38 underwent all 3 modalities before treatment. The average pathologic tumor size for the entire cohort was 4.45 cm (range 1-13). The size differences between CT and MRI compared with ultrasound were small (<3.5%). Compared with MRI and CT, ultrasound was also well correlated (P<.001 and P<.001). In patients who underwent all 3 imaging modalities, no difference was found in the average tumor size (P=.896). CONCLUSION: Ultrasound imaging does not appear to be inferior to CT and MRI in the imaging of renal masses. This is useful in reducing the costs and levels of radiation exposure for the long-term follow-up of patients receiving active surveillance. PMID- 22202543 TI - Editorial comment. PMID- 22202544 TI - The effect of noise-cancelling headphones or music on pain perception and anxiety in men undergoing transrectal prostate biopsy. AB - OBJECTIVE: To assess the effect of noise-cancelling headphones with or without music on patient pain and anxiety associated with routine, office-based transrectal ultrasound (TRUS)-guided prostate biopsy in a prospective randomized study. METHODS: Patients scheduled for prostate biopsy as a result of elevated prostate-specific antigen and/or abnormal digital rectal examination were prospectively enrolled and randomized into a control, noise-cancelling headphones, or music-headphones group. Patients completed pain and anxiety questionnaires and had their physiological parameters assessed before and after the procedure and compared across groups. RESULTS: Eighty-eight patients were enrolled. Pain scores increased from baseline across all study groups, with the lowest mean score in the music group. No appreciable change was noted in anxiety scores after the procedure between groups (P>.05). Although postbiopsy systolic blood pressure values remained comparable with baseline levels in all groups, postbiopsy diastolic blood pressure increased in the control and headphones groups (P=.062 and .088, respectively) but remained stable in the music group (P=.552) after biopsy, indicating lesser physiological response to anxiety and pain in this group. CONCLUSION: Music-induced attention shift during prostate biopsy may have a beneficial impact on procedural anxiety and pain perception, but no apparent effect was noted for use of headphones alone. Further studies are necessary to explore strategies to reduce perceived anxiety and pain in men undergoing prostate biopsy. PMID- 22202545 TI - Editorial comment. PMID- 22202547 TI - Patency rates of microsurgical vasoepididymostomy for patients with idiopathic obstructive azoospermia: a prospective analysis of factors associated with patency--single-center experience. AB - OBJECTIVE: To evaluate the factors that might be associated with the patency rates of microsurgical vasoepididymostomy for idiopathic obstructive azoospermia. METHODS: From January 2009 to July 2010, we evaluated the data from 73 men with obstructive azoospermia who had undergone longitudinal intussusception vasoepididymostomy. The mean age was 30.9+/-4.9 years (range 22-48). The outcomes were analyzed by the pre- or intraoperative clinical findings: epididymal fullness, unilateral or bilateral procedure, site of anastomosis, and epididymal fluid findings. RESULTS: The mean follow-up was 13.5+/-5.3 months (range 4-22) for 53 patients (72.6%). The overall patency rate was 71.7% (n=38). The patency rate was 87.2%, 80.7%, 78.8%, 100%, and 83.7% for epididymal fullness, bilateral surgery, corpus anastomosis, caudal anastomosis, and flowing fluid with motile sperm, respectively. The natural pregnancy rate was 33.3% at a mean of 9.9+/-4.2 months of follow-up. CONCLUSION: Longitudinal intussusception vasopididymostomy can provide a good patency rate, with success associated with epididymal fullness, bilateral surgery, distal epididymal anastomosis, and flowing fluid with motile sperm. PMID- 22202549 TI - Editorial comment. PMID- 22202548 TI - Clinical impact of residual extraretroperitoneal masses in patients with advanced nonseminomatous germ cell testicular cancer. AB - OBJECTIVE: Integration of platinum-based chemotherapy and surgical resection of residual masses is essential in the management of advanced nonseminomatous germ cell tumors (NSGCT). We reviewed our institutional experience in patients undergoing resection of extraretroperitoneal (ERP) residual masses after chemotherapy to assess its impact on cancer progression and survival. METHODS: Between 1989 and 2003, 532 patients with advanced NSGCT underwent postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) with a median follow-up of 41 months. Survival probabilities were estimated by the Kaplan-Meier method. Cox proportional hazards regression analysis was used to determine the prognostic significance of risk factors for progression and survival. RESULTS: Of 532 patients, 402 (76%) underwent PC-RPLND alone, and 130 (24%) underwent resection of ERP residual disease concurrently or in a staged fashion within 6 weeks. Concordance between retroperitoneal (RP) and ERP sites of disease was 83% in the presence of fibrosis, 42% for teratoma, and 47% for viable NSGCT. Overall, 34% of patients undergoing resection of ERP residual disease had either teratoma or viable disease on final pathology. Five-year probability of freedom from progression was 74% (95% CI 65%, 82%) and disease-specific survival was 84% (95% CI 75%, 89%). On multivariable analysis the histologic findings at the ERP site were significant predictors of disease progression, independent of the RP findings. CONCLUSION: Our data suggest that teratoma or viable NSGCT is present in approximately one-third of patients undergoing resection of residual ERP disease. The presence of residual ERP teratoma and viable NSGCT predicts for cancer progression independent of RP histology. PMID- 22202550 TI - Editorial comment. PMID- 22202551 TI - Editorial comment. PMID- 22202553 TI - Use of patient-specific MRI-based prostate mold for validation of multiparametric MRI in localization of prostate cancer. AB - OBJECTIVE: To demonstrate the use of a patient-specific magnetic resonance imaging (MRI)-based prostate mold to generate histologic sections that directly correlate to axial MRI slices in a patient with anteriorly located prostate cancer. Anteriorly located prostate cancer has traditionally been difficult to detect on digital rectal examination and transrectal ultrasound-guided biopsy. Multiparametric MRI has potential as a valuable tool for the diagnosis and focal treatment of prostate cancer. A significant difficulty to date has been accurate correlation between the magnetic resonance images and histopathologic specimens. METHODS: A patient-specific mold from a preoperative T2-weighted MRI scan was created to hold and shape the prostate specimen. Slots for slicing were positioned at 6-mm increments coplanar to the axial MRI slices. After surgical excision, the specimen was inked to maintain the orientation and fixed in formalin. The seminal vesicles were excised, and the prostate was oriented in the mold such that the color-coding matched the anatomic labels on the mold. The specimen was sliced with a single blade and the resultant 6-mm tissue blocks were used for histologic analysis. RESULTS: Preoperative multiparametric MRI revealed a lesion in the right anterior transition zone that was positive on T2-weighed MRI, apparent diffusion coefficient maps of diffusion-weighted MRI, magnetic resonance spectroscopy, and dynamic contrast-enhanced MRI. The histologic sections obtained using the mold demonstrated a similar Gleason score 6 (3+3) lesion in the right anterior transition zone, correlating with the MRI findings. CONCLUSION: The use of patient-specific prostate molds to register the MRI findings with the histopathologic specimen in prostate cancer could offer several benefits compared with current specimen processing techniques. This technique might further validate MRI as an accurate tool for prostate cancer localization and staging. PMID- 22202554 TI - Re: Kim et al.: Influence of prostatic calculi on lower urinary tract symptoms in middle-aged men (Urology 2011;78:447-449). PMID- 22202556 TI - Immunomodulating tellurium compounds as anti-cancer agents. AB - Tellurium is a rare element, which has been regarded as a toxic, non-essential trace element; its biological role, if any, has not been clearly established to date. The investigation of therapeutic activities of tellurium compounds is rather limited in the literature, despite the relative abundance of tellurium in the human body. Nevertheless, the varied activities of tellurium agents in both malignant and normal cells are extremely exciting, though very complex. Not surprisingly, an increased interest in tellurium among biological chemists and pharmacists has fuelled the search for more and more diverse tellurium compounds. The present review will focus on two small inorganic tellurium complexes, ammonium trichloro(dioxoethylene-O,O')tellurate (AS101) and Octa-O-bis-(R,R) tartarate ditellurane (SAS), thoroughly investigated by us, converging at their anti-cancer properties, and elucidating their mechanism of action. AS101 is probably the most extensively studied synthetic tellurium compound from the standpoint of its biological activity. It is a potent immunomodulator (both in vitro and in vivo) with a variety of potential therapeutic applications. It is probably the only tellurium compound to be tested in phase I/II clinical studies in cancer patients. The effects of AS101 and SAS are primarily caused by their specific Te(IV) redox-modulating activities enabling the inactivation of cysteine proteases such as cathepsin B, inhibition of specific tumor survival proteins like survivin, or obstruction of tumor IL-10 production. All of these have profound consequences regarding anti-tumor activity or sensitization of tumors to chemotherapy. These properties, coupled with the excellent safety profile of the compounds, suggest promising anti-cancer therapeutic potential for tellurium compounds such as AS101 or SAS. PMID- 22202557 TI - Toward improving patient safety through voluntary peer-to-peer assessment. AB - Health care has primarily used retrospective review approaches to identify and mitigate hazards, with little evidence of measurable and sustained improvements in patient safety. Conversely, the nuclear power industry has used a prospective peer-to-peer (P2P) assessment process grounded in open information exchange and cooperative organizational learning to realize substantial and sustainable improvements in safety. In comparing approaches, it is evident that health care's sluggish progress stems from weaknesses in hazard identification and mitigation and in organizational learning. This article proposes creating and implementing a structured prospective P2P assessment model in health care, similar to that used in the nuclear power industry, to accelerate improvements in patient safety. PMID- 22202559 TI - Emulsion droplet sizing using low-field NMR with chemical shift resolution and the block gradient pulse method. AB - Pulsed Field Gradient (PFG) measurements are commonly used to determine emulsion droplet size distributions based on restricted self-diffusion within the emulsion droplets. Such measurement capability is readily available on commercial NMR bench-top apparatus. A significant limitation is the requirement to selectively detect signal from the liquid phase within the emulsion droplets; this is currently achieved using either relaxation or self-diffusion contrast. Here we demonstrate the use of a 1.1 T bench-top NMR magnet, which when coupled with an rf micro-coil, is able to provide sufficient chemical shift resolution such that unambiguous signal selection is achieved from the dispersed droplet phase. We also improve the accuracy of the numerical inversion process required to produce the emulsion droplet size distribution, by employing the Block Gradient Pulse (bgp) method, which partially relaxes the assumptions of a Gaussian phase distribution or infinitely short gradient pulse application inherent in current application. The techniques are successfully applied to size 3 different emulsions. PMID- 22202558 TI - Medical necessity in emergency medical services transports. AB - The purpose of this study was to generate national estimates of the prevalence of medically unnecessary emergency medical services (EMS) transports to emergency departments (EDs) over time and to identify characteristics that may be associated with medically unnecessary transports. A previously published algorithm was applied to operationalize medical necessity based on ED diagnosis to 10 years of data from the National Hospital Ambulatory Medical Care Survey. The trend over time was reported using descriptive statistics weighted to produce national estimates. Nationally, the proportion of EMS transports that were medically unnecessary increased from 13% to 17% over the 10-year study period. Individual demographic characteristics, including insurance status, were not predictive of inappropriate utilization. EMS transports for medically unnecessary complaints increased from 1997 to 2007. Our findings from a nationally representative sample highlight the opportunity for alternative patient delivery strategies for select patients seeking EMS services. PMID- 22202560 TI - Osteoprotegerin (OPG) and TNF-related apoptosis-inducing ligand (TRAIL) levels in malignant and benign pericardial effusions. AB - OBJECTIVES: Osteoprotegerin (OPG) is a regulator of bone and vascular homeostasis and acts as a decoy receptor for proapoptotic TNF-related apoptosis-inducing ligand (TRAIL). DESIGN AND METHODS: We assessed pericardial and serum levels of OPG and TRAIL in pericardial effusions (PE) of malignant (mPE, n=24) or non malignant (nPE, n=34) origin, and in pericardial fluid (PF, n=25) of coronary artery disease (CAD) patients by ELISA. RESULTS: OPG was at least 5 fold higher in PE or PF compared to serum, with a significantly higher ratio of pericardial to serum OPG in patients with mPE or nPE compared to PF (mPE vs. PF, p=0.011; nPE vs. PF, p<0.001). TRAIL was only detectable in mPE and PF. Logistic regression analysis revealed that a high ratio of pericardial to serum OPG and high TRAIL in PE were the best variable combination to predict malignancy of PE. CONCLUSIONS: Pericardial and systemic OPG or TRAIL are potential diagnostic tools to discriminate between malignant or benign PE. PMID- 22202562 TI - "Half plate of rice to a male casual sexual partner, full plate belongs to the husband": findings from a qualitative study on sexual behaviour in relation to HIV and AIDS in northern Tanzania. AB - BACKGROUND: A thorough understanding of the contexts of sexual behaviour of the people who are vulnerable to HIV infection is an important component in the battle against AIDS epidemic. We conducted a qualitative study to investigate perceptions, attitudes and practices of sexually active people in three districts of northern Tanzania with the view of collecting data to inform the formulation of appropriate complementary interventions against HIV and AIDS in the study communities. METHODS: We conducted 96 semi-structured interviews and 48 focus group discussions with sexually active participants (18-60 years of age) who were selected purposively in two fishing and one non-fishing communities. RESULTS: The study revealed a number of socio-economic and cultural factors which act as structural drivers of HIV epidemic. Mobility and migration were mentioned to be associated with the risk of HIV acquisition and transmission. Sexual promiscuous behaviour was common in all study communities. Chomolea, (a quick transactional sex) was reported to exist in fishing communities, whereas extramarital sex in the bush was reported in non-fishing community which was predominantly Christian and polygamous. Traditional practices such as Kusomboka (death cleansing through unprotected sex) was reported to exist. Other risky sexual behaviour and traditional practices together with their socio-economic and cultural contexts are presented in details and discussed. Knowledge of condom was low as some people mistook them for balloons to play with and as decorations for their living rooms. Acute scarcity of condoms in some remote areas such as vizingani (fishing islands) push some people to make their own condoms locally known as kondomu za pepsi using polythene bags. CONCLUSIONS: HIV prevention efforts can succeed by addressing sexual behaviour and its socio-economic and cultural contexts. More innovative, interdisciplinary and productive structural approaches to HIV prevention need to be developed in close collaboration with affected communities and be closely related to policy-making and implementation; to go beyond the limited success of traditional behavioural and biomedical interventions to particularly address the underlying social and structural drivers of HIV risk and vulnerability in the study communities. PMID- 22202581 TI - Assessment of prognostic circulating tumor cells in a phase III trial of adjuvant immunotherapy after complete resection of stage IV melanoma. AB - OBJECTIVE: To verify circulating tumor cell (CTC) prognostic utility in stage IV resected melanoma patients in a prospective international phase III clinical trial. BACKGROUND: Our studies of melanoma patients in phase II clinical trials demonstrated prognostic significance for CTCs in patients with AJCC stage IV melanoma. CTCs were assessed to determine prognostic utility in follow-up of disease-free stage IV patients pre- and during treatment. METHODS: After complete metastasectomy, patients were prospectively enrolled in a randomized trial of adjuvant therapy with a whole-cell melanoma vaccine, Canvaxin, plus Bacille Calmette-Guerin (BCG) versus placebo plus BCG. Blood specimens obtained pretreatment (n = 244) and during treatment (n = 214) were evaluated by quantitative real-time reverse-transcriptase polymerase chain reaction (qPCR) for expression of MART-1, MAGE-A3, and PAX3 mRNA biomarkers. Univariate and multivariate Cox analyses examined CTC biomarker expression with respect to clinicopathological variables. RESULTS: CTC biomarker(s) (>= 1) was detected in 54% of patients pretreatment and in 86% of patients over the first 3 months. With a median follow-up of 21.9 months, 71% of patients recurred and 48% expired. CTC levels were not associated with known prognostic factors or treatment arm. In multivariate analysis, pretreatment CTC (> 0 vs. 0 biomarker) status was significantly associated with disease-free survival (DFS; HR 1.64, P = 0.002) and overall survival (OS; HR 1.53, P = 0.028). Serial CTC (>0 vs. 0 biomarker) status was also significantly associated with DFS (HR 1.91, P = 0.02) and OS (HR 2.57, P = 0.012). CONCLUSION: CTC assessment can provide prognostic discrimination before and during adjuvant treatment for resected stage IV melanoma patients. PMID- 22202583 TI - Tumor deposits in colorectal cancer: a moving target. PMID- 22202582 TI - Vagal innervation of the hepatic portal vein and liver is not necessary for Roux en-Y gastric bypass surgery-induced hypophagia, weight loss, and hypermetabolism. AB - OBJECTIVE: To determine the role of the common hepatic branch of the abdominal vagus on the beneficial effects of Roux-en-Y gastric bypass (RYGB) on weight loss, food intake, food choice, and energy expenditure in a rat model. BACKGROUND: Although changes in gut hormone patterns are the leading candidates in RYGB's effects on appetite, weight loss, and reversal of diabetes, a potential role for afferent signaling through the vagal hepatic branch potentially sensing glucose levels in the hepatic portal vein has recently been suggested in a mouse model of RYGB. METHODS: Male Sprague-Dawley rats underwent either RYGB alone (RYGB; n = 7), RYGB + common hepatic branch vagotomy (RYGB + HV; n = 6), or sham procedure (sham; n = 9). Body weight, body composition, meal patterns, food choice, energy expenditure, and fecal energy loss were monitored up to 3 months after intervention. RESULTS: Both RYGB and RYGB + HV significantly reduced body weight, adiposity, meal size, and fat preference, and increased satiety, energy expenditure, and respiratory exchange rate compared with sham procedure, and there were no significant differences in these effects between RYGB and RYGB + HV rats. CONCLUSIONS: Integrity of vagal nerve supply to the liver, hepatic portal vein, and the proximal duodenum provided by the common hepatic branch is not necessary for RYGB to reduce food intake and body weight or increase energy expenditure. Specifically, it is unlikely that a hepatic portal vein glucose sensor signaling RYGB-induced increased intestinal gluconeogenesis to the brain depends on vagal afferent fibers. PMID- 22202584 TI - Multidimensional analysis of the learning curve for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal surface malignancies. AB - OBJECTIVE: To evaluate the learning curve of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in treating peritoneal surface malignancies (PSM). SUMMARY AND BACKGROUND: CRS and HIPEC to treat PSM is a complex procedure with a significant morbidity. A long-lasting training program is required to acquire expertise in this type of operation. METHODS: We performed CRS using peritonectomy procedures. HIPEC through the closed abdomen technique employed cisplatin and mitomycin-C or cisplatin and doxorubicin. Risk-adjusted sequential probability ratio test was used to assess the learning curve on a series of 420 cases of PSM on the basis of rates of incomplete cytoreduction and G3-5 morbidity (NCI-CTCAE v3). We determined control limits setting the type I/II error rates and unacceptable odds ratios (ORs) for the outcomes being studied. We performed the risk adjustment using logistic regression model. RESULTS: Rates of incomplete cytoreduction, G3-5 morbidity, and postoperative mortality rates were 10.2%, 28.5%, and 2.1%, respectively. The risk-adjusted sequential probability ratio test curve crossed the lower control limit at the 137 th and 149 th case, respectively, for incomplete cytoreduction and G3-5 morbidity. At those points, the actual ORs are lower than the prespecified ORs for outcomes being studied. Therefore, we estimated that approximately 140 cases are necessary to ensure surgical proficiency in CRS and HIPEC. CONCLUSIONS: CRS and HIPEC to treat PSM has a steep learning curve requiring 140 procedures to acquire expertise. PMID- 22202585 TI - Petrochemicals and the labor force: does the "public" include working people? PMID- 22202586 TI - Regarding trade secrets and the right-to-know. PMID- 22202587 TI - A response to Draper et al., "Occupational health nursing and the quest for professional authority". PMID- 22202589 TI - Deconstructing a state-of-the-art review of the asbestos brake industry. AB - State of the art is a legal concept that describes what was known as knowable by experts including manufacturer's state of knowledge about the potential hazards of their product(s) at a point in time. In 2004, Paustenbach et al. published a state-of-the-art review that describes the development of knowledge about asbestos hazards to brake mechanics performing asbestos brake installation and maintenance. Paustenbach et al.'s review, however, omits important pieces of corporate knowledge, dismisses several historical scientific conclusions and ignores the way experts have applied the results of scientific research to protect workers and consumers handling asbestos brakes. By taking their state-of the-art review out of the legal liability context, Paustenbach et al. create a misleading version of events that fails to properly address the question of what asbestos brake manufacturers knew or should have known about the potential hazards of their brakes to mechanics over time. Without proper presentation of this information, judges and juries cannot adequately assess whether these companies had a duty to warn or take other action to prevent injury to those exposed to their asbestos brakes. PMID- 22202590 TI - Protecting disaster responder health: lessons (not yet?) learned. AB - Recent developments at the National Institute for Occupational Safety and Health (NIOSH), the Occupational Safety and Health Administration (OSHA), and the National Institute for Environmental Health Sciences (NIEHS) indicate that each of these agencies is wrestling with how to better protect the health of disaster workers. This article urges increased reliance on comprehensive exposure assessments, more protective exposure benchmarks, the precautionary principle, and the hierarchy of controls of hazards. Additional issues, such as methods and content of worker training, as well as enforcement of applicable standards, are also considered. Finally, an effort is made to clarify the goals of disaster response. PMID- 22202591 TI - Promoting job safety for workers with intellectual disabilities: the staying safe at work training curriculum. AB - In the United States, approximately 125,000 people with disabilities are employed through Community Rehabilitation Programs in manufacturing, assembly, and service jobs. These jobs have significant hazards and, consequently, the workers are at risk of injury. Training that empowers workers to participate in prevention efforts can help reduce work-related injuries. In general this kind of health and safety training in the United States is limited. It is even more so for workers with intellectual disabilities, in part because there have not been programs for teaching individuals with cognitive challenges health and safety skills, adapted to their learning needs. This paper describes the development and promotion of the Staying Safe at Work curriculum of UC Berkeley's Labor Occupational Health Program, which is designed for use by support agencies and employers of workers with intellectual disabilities. The goal of this program is to teach these workers essential occupational safety and health skills in a manner they can understand. PMID- 22202592 TI - Patterns of mortality among Wisconsin Uniroyal tire manufacturing workers. AB - The goal of this analysis was to determine the patterns of mortality among deceased workers of the former Uniroyal, Inc. Plant in Eau Claire, Wisconsin, who were exposed to solvents. After collecting information on cause of death, we conducted a standardized proportional mortality ratio (PMR) and proportional cancer mortality ratio (PCMR) analysis. The results of the PCMR analysis indicate that former Uniroyal workers experienced elevated mortality due to cancers, especially lymphohematopoietic cancers, compared to other Wisconsin decedents. The former workers and family members were pursuing litigation at the time of publication. We received the list of deceased workers from plaintiffs' attorney and were compensated for conducting the analysis; the funder did not directly participate in any part of the study or influence the results. We conclude there is evidence of excess lymphohematopoietic cancer in this worker cohort. PMID- 22202593 TI - Now is the time for us to become the leaders we have been waiting for. AB - The budget crisis in California threatens to cut even more resources from the state workplace health and safety agency, Cal/OSHA. This crisis is completely artificial as there are tremendous resources in the state-if the corporations, and the rich who own them, paid taxes. But even with adequate funding, the goal of reducing worker injuries, illnesses, and fatalities can be achieved only by a grassroots occupational safety and health movement that empowers informed workers to be active in protecting their own health at work, and ensures that employers and government mobilize the resources required for safe and healthy workplaces. This is the text of a speech given at the Worksafe Mini-Summit for a Revitalized State Occupational Safety and Health Program, Emeryville, CA, March 25, 2011. PMID- 22202594 TI - Ban asbestos phenomenon: the winds of change. AB - The shift in the public perception of asbestos from "magic mineral" to "deadly dust" owes much to the mobilization by asbestos victims, ban-asbestos activists, health and safety campaigners, and individuals concerned about the global asbestos death toll. Cognizant of the proven links between asbestos and disease, governments of industrialized countries banned further use, as a result of which consumption shifted to developing countries; between 2000 and 2010, asbestos use in Asia grew dramatically. In the face of a powerful industry lobby, members of the ban-asbestos network have lobbied national governments to outlaw asbestos use, challenged industry propaganda, and cooperated with social partners on coordinated multinational initiatives. Major developments in the campaign to end the mining, sale, and use of asbestos which have taken place over the last 50 years are delineated in this paper. PMID- 22202598 TI - CRIP1 expression is correlated with a favorable outcome and less metastases in osteosarcoma patients. AB - Predicting the clinical course of osteosarcoma patients is a crucial prerequisite for a better treatment stratification in these highly aggressive neoplasms of bone. In search of new and reliable biomarkers we recently identified cysteine rich intestinal protein 1 (CRIP1) to have significant prognostic impact in gastric cancer and therefore decided to investigate its role also in osteosarcoma. For this purpose we analyzed 223 pretherapeutic and well characterized osteosarcoma samples for their immunohistochemical expression of CRIP1 and correlated our findings with clinico-pathological parameters including follow-up, systemic spread and response to chemotherapy. Interestingly and contrarily to gastric cancer, we found CRIP1 expression more frequently in patients with long-term survival (10-year survival 73% in positive vs. 54% in negative cases, p = 0.0433) and without metastases (p = 0.0108) indicating a favorable prognostic effect. CRIP1 therefore seems to represent a promising new biomarker in osteosarcoma patients which should be considered for a prospective validation. PMID- 22202599 TI - In vitro effects of 2-hydroxyestradiol-17beta on ovarian follicular steroid secretion in the catfish Heteropneustes fossilis and identification of the receptor and signaling mechanisms. AB - Ovarian pieces containing postvitellogenic follicles were incubated in vitro with different concentrations of the catecholestrogen 2-hydroxyestradiol-17beta (2 OHE(2)) to evaluate its effects on steroid production and germinal vesicle breakdown (GVBD) in the catfish Heteropneustes fossilis. The incubation with 2 OHE(2) induced a shift in steroidogenic pattern: the C(19) and C(18) steroids testosterone (T) and estradiol-17beta (E(2)), respectively were significantly decreased with a concomitant significant increase in the C(21) steroids progesterone (P(4)), 17-hydroxyprogesterone (17-OHP), 17,20beta-dihydroxy-4 pregnen-3-one (17,20beta-DP), 17,20alpha-dihydroxy-4-pregnen-3-one (17,20alpha DP) and cortisol (F). Concomitantly, the catecholestrogen induced dose dependently GVBD response, the first sign of meiosis resumption. The co- and pre incubations of the ovarian pieces with 2-OHE(2), and adrenergic (phentolamine, alpha-blocker and propranolol, beta-blocker) or estrogen (tamoxifen) receptor blockers resulted in inhibition of the stimulatory effect of the catecholestrogen on C(21) steroids and reversed the inhibition of testosterone and E(2). The alpha blocker was more effective than the beta-blocker. Our results suggest that 2 OHE(2) appears to employ both adrenergic (alpha-type) and estrogen receptor mechanisms in mediating the effects. The co- or pre-incubation of ovarian pieces with IBMX (a cAMP elevating drug), H89 (a protein kinase A inhibitor), and PD098059 (a MAP kinase kinase inhibitor) significantly inhibited the stimulatory effect of 2-OHE(2) on the C(21) steroids. The effect of chelerythrine (a protein kinase C inhibitor), on the other hand, varied with the incubation condition. In the co-incubation, the steroids showed varied effects: 17,20beta-DP, testosterone and E(2) were elevated, and P(4) and 17-OHP were decreased. In the pre-incubation set up, all the steroids were inhibited except E(2). The inhibition by the blockers was higher in the pre-incubation groups. Taken together, the data suggest the involvement cAMP-protein kinase A, protein kinase C and MAP kinase pathways in the modulation of the steroidogenic activity. PMID- 22202600 TI - Identification of Ras, Pten and p70S6K homologs in the Pacific oyster Crassostrea gigas and diet control of insulin pathway. AB - Insulin pathways were demonstrated from invertebrates to vertebrates to be involved in the regulation of numerous processes including storage metabolism and reproduction. In addition, insulin system may integrate variations of environmental conditions like dietary restrictions. In the Pacific oyster Crassostrea gigas, reproductive and storage compartments are closely intricated in the gonadal area and their respective development was found to be dependant of trophic conditions. For these reasons, C. gigas is an original and interesting model for investigating the role of insulin control in the balance between storage and reproduction and the integration of environmental parameters. On the basis of sequence conservation, we identified three potential elements of the oyster insulin pathway, Ras, Pten and p70S6K and we investigated their expression levels in various tissues. In the gonadal area, we used laser microdissection in order to precise the targeted contribution of insulin signaling to the restoration of storage tissue and to the control of vitellogenesis. Food deprivation during gametogenesis reinitiation stage led to reduced proliferations of gonia and also to modulate insulin signal by transcriptional activation of insulin pathway elements. PMID- 22202601 TI - Effects of prenatal stress on hypothalamic-pituitary-adrenal (HPA) axis function over two generations of guinea pigs (Cavia aperea f. porcellus). AB - Prenatal stress can alter hypothalamic-pituitary-adrenal axis function with potential consequences for later life. The aim of our study was to examine in guinea pigs (Cavia aperea f. porcellus) the effects of stress experienced during F0 pregnancy on glucocorticoid levels in plasma and feces, as well as challenge performance, in F1 offspring (n=44) and fecal glucocorticoid levels in F2 offspring (n=67). F1 animals were either born to F0 dams that had been stressed with strobe light during early to mid pregnancy, resulting in a short term increase but long-term down-regulation of maternal glucocorticoid levels, or to undisturbed F0 dams. The same stressor was used as a challenge for F1 offspring at age 26 days and around 100 days. Basal plasma cortisol concentrations during early F1 development, as well as overall glucocorticoid levels at challenge tests, were lower in F1 animals that were prenatally stressed than in control animals. Fecal cortisol metabolites were initially at lower levels in prenatally stressed F1 animals, relative to control animals, but shifted to higher levels around day 68, with an additional sex difference. Effects were also seen in the F2 generation, as male but not female offspring of prenatally stressed F1 animals had significantly higher levels of cortisol metabolites in feces after weaning. We conclude that stress exposure of F0 dams resulted in lower basal glucocorticoid levels in F1 offspring during the pre-pubertal phase and during stress exposure, but higher glucocorticoid levels in post-adolescent F1 animals. Also in males of F2 generation effects of stress exposure of F0 dams were detected. PMID- 22202602 TI - Sculpting reproductive circuits: relationships among hormones, morphology and behavior in anole lizards. AB - Morphology parallels function on a variety of levels in reproductive circuits in anole lizards, as in many vertebrate groups. For example, across species within the anole genus the muscle fibers regulating extension of a throat fan used in courtship are larger in males than females. Endocrine factors controlling behavior and morphology have been studied in detail in one species, the green anole (Anolis carolinensis). This review briefly describes the results that have been obtained and highlights key areas for future investigation that will provide insights on mechanisms from a comparative perspective. PMID- 22202603 TI - Corticosterone responses differ between lines of great tits (Parus major) selected for divergent personalities. AB - Animal 'personality' describes consistent individual differences in suites of behaviors, a phenomenon exhibited in diverse animal taxa and shown to be under natural and sexual selection. It has been suggested that variation in personality reflects underlying physiological variation; however there is limited empirical evidence to test this hypothesis in wild animals. The hypothalamic-pituitary adrenal axis is hypothesized to play a central role in personality variation. Here we tested whether in great tits Parus major variation in personality traits is related to plasma concentrations of corticosterone (CORT). Using a capture restraint protocol we examined baseline and stress-induced CORT levels in two captive experimental groups: (1) birds selected for divergent personalities ('fast-bold' and 'slow-shy' explorers); and (2) non-selected offspring of wild parents. We first tested for differences in CORT between selection lines, and second examined the relationship between responses in a canonical personality test and CORT concentrations in non-selected birds. We found support for our prediction that the slow-shy line would exhibit a higher acute stress response than the fast-bold line, indicating a genetic correlation between exploratory behavior and stress physiology. We did not, however, find that continuous variation in exploratory behavior co-varies with CORT concentrations in non selected birds. While our results provide support for the idea that personality emerges as a result of correlated selection on behavior and underlying physiological mechanisms, they also indicate that this link may be particularly evident when composite personality traits are the target of selection. PMID- 22202604 TI - Nutrition-regulated lipolysis in rainbow trout (Oncorhynchus mykiss) is associated with alterations in the ERK, PI3K-Akt, JAK-STAT, and PKC signaling pathways. AB - Previous studies have shown that food deprivation, which occurs naturally in the life cycle of many species of fish, results in cessation of growth and catabolism of stored energy reserves, including lipids. In this study, we used rainbow trout (Oncorhynchus mykiss) to identify the cellular mechanisms involved with this metabolic shift. Fish were placed on one of five dietary regimes--fed continuously for 2 or 4 weeks, fasted continuously for 2 or 4 weeks, or fasted 2 weeks then refed 2 weeks--and the effects on organismal growth and lipid catabolism and on the activation state of signaling elements (e.g., Akt, ERK, JAK STAT, PKC) in selected tissues were measured. Fasting for either 2 or 4 weeks significantly retarded growth in terms of body weight, body length, and body condition; refeeding restored growth such that body length and body condition were similar to measures seen in continuously fed fish. Fasting activated lipid catabolism by stimulating the mRNA expression and catalytic activity of hormone sensitive lipase (HSL). Two HSL-encoding mRNAs have been characterized, and the expression of both forms of mRNA in 2- and 4-week fasted fish were significantly elevated over levels in fed fish in all tissues. In adipose tissue, liver, and white muscle, HSL activity was significantly elevated in 2- and 4-week fasted fish compared to fed animals; whereas in red muscle, HSL activity was significantly elevated compared to fed fish after 4 weeks of fasting. Refeeding reversed both fasting-associated HSL mRNA expression and HSL activity. Fasting resulted in the deactivation of Akt, JAK2, and STAT5 in adipose tissue, liver, and red and white muscle. By contrast, fasting activated ERK and PKC in all tissues measured. Refeeding reversed fasting-associated alterations in the activation state of all signal elements. These findings suggest that deactivation of Akt and JAK-STAT in conjunction with activation of ERK and PKC underlie fasting-associated growth retardation and lipolysis. PMID- 22202606 TI - Elaborate color patterns of individual chicken feathers may be formed by the agouti signaling protein. AB - Hair and feather pigmentation is mainly determined by the distribution of two kinds of melanin, eumelanin and pheomelanin, which produce brown to black and yellow to red colorations, respectively. The agouti signaling protein (ASIP) acts as an antagonist or an inverse agonist of the melanocortin 1 receptor (MC1R), a G protein-coupled receptor for alpha-melanocyte-stimulating hormone (alpha-MSH). This antagonism of the MC1R by ASIP on melanocytes initiates a switch of melanin synthesis from eumelanogenesis to pheomelanogenesis in mammals. In the present study, we isolated multiple ASIP mRNA variants generated by alternative splicing and promoters in chicken feather follicles. The mRNA variants showed a discrete tissue distribution. However, mRNAs were expressed predominantly in the feather pulp of follicles. Paralleling mRNA distribution, ASIP immunoreactivity was observed in feather pulp. Interestingly, ASIP was stained with pheomelanin but not eumelanin in pulp areas that face developing barbs. We suggest that the elaborate color pattern of individual feathers is formed in part by the antagonistic action of ASIP that is produced by multiple mRNA variants in chicken feather follicles. PMID- 22202605 TI - Quantitative proteomics in teleost fish: insights and challenges for neuroendocrine and neurotoxicology research. AB - Neuroendocrine systems integrate both extrinsic and intrinsic signals to regulate virtually all aspects of an animal's physiology. In aquatic toxicology, studies have shown that pollutants are capable of disrupting the neuroendocrine system of teleost fish, and many chemicals found in the environment can also have a neurotoxic mode of action. Omics approaches are now used to better understand cell signaling cascades underlying fish neurophysiology and the control of pituitary hormone release, in addition to identifying adverse effects of pollutants in the teleostean central nervous system. For example, both high throughput genomics and proteomic investigations of molecular signaling cascades for both neurotransmitter and nuclear receptor agonists/antagonists have been reported. This review highlights recent studies that have utilized quantitative proteomics methods such as 2D differential in-gel electrophoresis (DIGE) and isobaric tagging for relative and absolute quantitation (iTRAQ) in neuroendocrine regions and uses these examples to demonstrate the challenges of using proteomics in neuroendocrinology and neurotoxicology research. To begin to characterize the teleost neuroproteome, we functionally annotated 623 unique proteins found in the fish hypothalamus and telencephalon. These proteins have roles in biological processes that include synaptic transmission, ATP production, receptor activity, cell structure and integrity, and stress responses. The biological processes most represented by proteins detected in the teleost neuroendocrine brain included transport (8.4%), metabolic process (5.5%), and glycolysis (4.8%). We provide an example of using sub-network enrichment analysis (SNEA) to identify protein networks in the fish hypothalamus in response to dopamine receptor signaling. Dopamine signaling altered the abundance of proteins that are binding partners of microfilaments, integrins, and intermediate filaments, consistent with data suggesting dopaminergic regulation of neuronal stability and structure. Lastly, for fish neuroendocrine studies using both high-throughput genomics and proteomics, we compare gene and protein relationships in the hypothalamus and demonstrate that correlation is often poor for single time point experiments. These studies highlight the need for additional time course analyses to better understand gene-protein relationships and adverse outcome pathways. This is important if both transcriptomics and proteomics are to be used together to investigate neuroendocrine signaling pathways or as bio-monitoring tools in ecotoxicology. PMID- 22202620 TI - Development of the nursing problem list subset of SNOMED CT(r). AB - OBJECTIVE: To create an interoperable set of nursing diagnoses for use in the patient problem list in the EHR to support interoperability. DESIGN: Queries for nursing diagnostic concepts were executed against the UMLS Metathesaurus to retrieve all nursing diagnoses across four nursing terminologies where the concept was also represented in SNOMED CT. A candidate data set was retrieved and included the nursing diagnoses and corresponding SNOMED CT concepts from the UMLS Metathesaurus. The team members identified the concepts that met the semantic selection criteria for inclusion in the nursing problem list. RESULTS: 1320 concepts were returned in the initial UMLS Metathesaurus query of nursing diagnostic concepts. Further analysis was conducted to identify those nursing diagnostic concepts mapped to SNOMED CT and duplicate concepts were removed resulting in 591 unique UMLS Metathesaurus concepts. The query extracted all concepts from two of the nursing terminologies that contained interventions and outcomes. After cleaning the dataset, the final count of SNOMED CT concepts in the nursing problem list subset is 369. CONCLUSIONS: The problem list is a key component of the patient care and has been acknowledged as critical by the EHR Meaningful Use criteria. Nursing diagnoses on the problem list are foundational for constructing a nursing care plan. A multidisciplinary patient problem list will facilitate communication and evaluation of the contribution of nursing care to the patient's clinical care experiences and outcomes. PMID- 22202640 TI - Erufosine simultaneously induces apoptosis and autophagy by modulating the Akt mTOR signaling pathway in oral squamous cell carcinoma. AB - We investigated the anticancer activity of erufosine in oral squamous carcinoma cell lines in terms of cell proliferation, colony formation, induction of autophagy/apoptosis, cell cycle and mTOR signaling pathway. Erufosine showed dose dependent cytotoxicity in all cell lines, it induced autophagy as well as apoptosis, G2 cell cycle arrest and modulation of cyclin D1 expression. Further erufosine downregulated the phosphorylation of major components of mTOR pathway, like p-Akt at Ser473 and Thr308 residues, p-Raptor, p-mTOR, p-PRAS40 and its downstream substrates p-p70S6K and p-4EBP1 in a dose-dependent manner. The pre treatment of tumor cells with p-mTOR siRNA increased cytotoxic effects of erufosine comparable to cisplatin but higher than rapamycin. PMID- 22202639 TI - Gender-specific methylation differences in relation to prenatal exposure to cigarette smoke. AB - Epigenetic alterations may mechanistically explain the developmental origins of adult disease, namely the hypothesis that many complex adult chronic diseases originate as a result of conditions encountered in utero. If true, epigenetically regulated imprinted genes, critical to normal growth and development, may partially mediate these outcomes. We determined the influence of in utero exposure to cigarette smoking on methylation at two differentially methylated regions (DMRs) regulating Insulin-like Growth Factor 2 (IGF2) and H19, and how this might relate to birth weight of infants born to 418 pregnant women. Smoking status was ascertained through self-report and medical records. Bisulfite pyrosequencing was used to measure methylation in umbilical cord blood DNAs. Least squares DNA methylation means at each DMR and birth weight were compared between infants of smokers and non-smokers, using generalized linear models. While there were no significant differences at the H19 DMR, infants born to smokers had higher methylation at the IGF2 DMR than those born to never smokers or those who quit during pregnancy (49.5%, SD=8.0 versus 46.6%, SD=5.6 and 45.8%, SD=6.3, respectively; p=0.0002). The smoking-related increase in methylation was most pronounced in male offspring (p for sex interaction=0.03), for whom approximately 20% of smoking-related low birth weight was mediated by DNA methylation at the IGF2 DMR. Our findings suggest that IGF2 DMR plasticity is an important mechanism by which in utero adjustments to environmental toxicants are conferred. Larger studies to replicate these findings are required. PMID- 22202641 TI - Epigenetic biomarkers of colorectal cancer: Focus on DNA methylation. AB - The original theory of the multi-step process of colorectal cancer (CRC), suggesting that the disease resulted from the accumulation of mutations in oncogenes and tumor suppressor genes in colonic mucosa cells, has been largely revised following the observation that epigenetic modifications of several genes occur in the average CRC genome. Therefore, the current opinion is that CRCs are the consequence of the accumulation of both mutations and epigenetic modifications of several genes. This mini-review article focuses on DNA methylation biomarkers in CRC. Recent large-scale DNA methylation studies suggest that CRCs can be divided into at least three-four subtypes according to the frequency of DNA methylation and those of mutations in key CRC genes. Despite hundreds of genes might be epigenetically modified in CRC cells, there is interest in the identification of DNA methylation biomarkers to be used for CRC diagnosis, progression, tendency to tissue invasion and metastasis, prognosis, and response to chemotherapeutic agents. Moreover, DNA methylation largely depends on one-carbon metabolism, the metabolic pathway required for the production of S-adenosylmethionine, the major intracellular methylating agent. Complex interactions are emerging among dietary one-carbon nutrients (folates, vitamin B6, vitamin B12, methionine, and others), their metabolic genes, CRC risk, and DNA methylation profiles in CRC. Moreover, active research is also focused on the possible contribution of folic acid dietary fortification during pregnancy and the possible methylation of CRC-related genes in the offspring. PMID- 22202642 TI - CD49f-based selection of circulating tumor cells (CTCs) improves detection across breast cancer subtypes. AB - Circulating tumor cells (CTCs) can be enumerated using CellSearch, but not all breast cancer subtypes, specifically those with epithelial-mesenchymal transition (EMT) characteristics, sufficiently express the enrichment (EpCAM) and selection (CK8/18/19) markers used in this method. While CD146 can detect EpCAM-negative CTCs, we here evaluated the value of various cytokeratins and CD49f to detect CK8/18/19-negative CTCs. The tested cytokeratins provided no substantial benefit, but adding CD49f to CK8/18/19 as a selection marker resulted in improved recovery of normal-like cell lines. Combined staining of CK8/18/19 and CD49f after CD146/EpCAM enrichment is likely to further improve CTC detection in breast cancer. PMID- 22202643 TI - [What's new in clinical dermatology?]. AB - This year more than 3000 medical articles referenced in PubMed concerned dermatology. Our critical analysis covers different fields of dermatology: including epidemiology, clinical, diagnostic and prognostic factors. AIDS is 30 years old and the national HIV/AIDS plan for 2010-2014 recommends generalized screening facilitated by the introduction of rapid tests for diagnostic orientation. In infectious diseases, novelties concern polyomavirus, HTLV-1, leprosy, staphylococcus infections, resistance to antibiotics and scabies. Diseases of the scalp consecutive to practices of black women hairstyles were the subject of important articles. There were two important developments in acne: first, a simplified and more operational classification, secondly a suicidal risk associated with severe forms. Lymphocyte Th-17 immunity is involved in clinical phenomena either by excess (genetic or drug) or default (genetic causes). Allergology: in several studies, false negative patch tests have been published. The natural history of nevi is specified by three important articles. Serological tests to practice in cases of dermatomyositis and bullous pemphigoid are specified. PMID- 22202644 TI - [What's new in dermatological research?]. AB - Dermatological research has been very active this year. Most of the numerous fields investigated involve the mechanisms of cutaneous regeneration and barrier function. A novel target of early ultraviolet-induced skin photodamage, the Syk kinase, has been recently identified. Synergistic relationship between telomere damage and cutaneous progerin production during cell senescence may also participate in the natural skin aging process. Interestingly, ultraviolet radiation induces an inhibitory effect on subcutaneous lipogenesis. Androgenetic alopecia or common baldness is not characterized by loss of hair follicle stem cells but by a defect in the conversion of hair follicle stem cells into active progenitor cells. It has been shown that the cornified envelope functions not only as a physicomechanical barrier, but also as both a biochemical line of antoxidant defense and an immunological line of defense. Like human papillomaviruses, Merckel cell polyomavirus belongs to the skin microbiome and different studies have demonstrated the protective role of epidermal resident microflora through the activation of innate immunity. Production of antimicrobial peptides and the activation of inflammasome and plasmacytoid dendritic cells are involved in the modulation of the cutaneous barrier function. Results from different studies suggest that IL-22 and IL-36 may be common mediators of both innate and adaptive immune responses. All these pathways interact not only to maintain cutaneous homeostasis and integrity (wound healing) but also to regulate autoinflammatory and autoimmune dermatoses (psoriasis, lupus, rosacea, atopic dermatitis, etc...). In addition, molecular mechanisms that regulate T helper type 2 differentiation and the retention at the site of inflammation of Th2 cells have been identified. New promising therapeutic targets for different chronic dermatosis are thus suggested. Mechanobiology and mechanotransduction are also emerging fields that investigate mechanical interactions between living cells and their environment and the conversion of mechanical cues into biochemical signals. Electronic second skin is now a current concept through bio-integrated epidermal electronics platforms used for different monitoring and stimulations of body functions. PMID- 22202645 TI - [What's new in internal medicine: emerging treatments for systemic lupus erythematosus]. AB - Today corticosteroids plus hydroxychloroquine are the cornerstone in the treatment of Systemic Lupus Erythematosus (SLE). In severe cases, particularly in proliferative glomerulonephritis, cyclophosphamide or mycofenolate mofetil are used in induction and mycofenolate mofetil or azathioprine are used to maintain the remission. Corticosteroid sparing is an important goal. New and future treatments of SLE focus on B and T cells down regulation and co-stimulation, cytokine inhibition, and open the concept of immune vaccination. However, positive phase III randomized studies in SLE remain rare. Rituximab (a chimeric monoclonal anti-CD 20 antibody) was the first promising biologic agent showing interesting results in large case series but 2 phases III randomised studies didn't reach their primary objective. This probably emphasizes the limit of the current tools used for the evaluation of the disease and point out the design of the studies using high dose of corticosteroids, immunosuppressive drugs and the use of rituximab as add on treatment and are not face to face with conventional treatment. Abatacept (CTLA4-Ig) also failed to meet its primary end point in a randomised controlled trial in non-nephritis SLE. A post-hoc analysis suggests however that abatacept may be beneficial in lupus patients with arthritis however, it will probably never be approved for that indication. Belimumab (a human monoclonal antibody to BLyS) is the first biologic agent which reached its primary end point in 2 different randomised controlled trials using a new index for the evaluation of the activity of the diseases taking into account the physicians judgement (SLE responder index). Lots of phase I/II studies are currently ongoing particular targeting on interferon alpha, interleukin 6, B cell CD22 and C5 complement component. PMID- 22202646 TI - [What's new in pediatric dermatology in 2011?]. AB - Based on the review of the medical publications, this article summarizes the main advances in the field of pediatric dermatology which occurred during the last year. The main results concern psoriasis, atopic dermatitis, acne and hemangiomas. A particular attention was given to genodermatoses. PMID- 22202647 TI - [What's new in dermato-oncology?]. AB - One of the major advance concerning skin carcinoma is the development of targeted therapy: anti-patch/sonic/hedgehog for basal cell carcinoma (BCC) and anti-EGFR for squamous cell carcinoma (SCC). These therapies are indicated for advanced non surgically removable tumors. Their anti-tumoral efficacy has been shown, their effect seems to be suspensive which raises the question of their tolerability for long term use. Laboratory work have shown that BCC and SCC stem cells locate in different cell compartments and follow distinct molecular events which explains their distinct behaviour. The role of HPV in EBDR skin cancers has been ruled out. Photodynamic therapy induced-immunosuppression can be prevented by lowering the light fluence. The gene responsible for the Ferguson Smith syndrome has been identified: it is the gene encoding TGFBR1. Its implication in SCC needs to be determined. A new compound, PEP005, (ingenol mebutate) should soon enlarge therapeutical options for actinic keratosis. Concerning melanoma, results of the two phase III studies using two innovative therapies (anti-Braf and ipilimumab) have been published. Comparative study between anti-Braf and DTIC has shown a response rate of 48.4 % with vemurafenib and 5.5 % with DTIC. The risk of death was diminished by 67 %. These results have allowed to switch to vemurafenib patients with progression under DTIC. However, the initial response is followed by relapse in a majority of cases. Mechanisms of this resistance have been studied and the inhibition of several molecules involved in different or identical pathway should help to resolve that problem. The combination ipilimumab+ DTIC gives better results than DTIC alone. The adverse events of this association are slightly different than those seen with ipilimumab alone. They must be known by prescribers. Some discussions are on their way between the two companies developping anti-Braf and ipilimumab to develop therapeutic strategies combining both treatments. 20 to 30 % of patients taking anti-Braf drugs will develop SCC (due to paradoxal activation of MAPK in non Braf mutated cells). PEG interferon seems to be indicated in ulcerated melanoma with lymph node micrometastasis. Some other targeted molecules such as C-KIT and anti-MEK are under evaluation. The effect of sunscreens on melanoma risk prevention has been reported in an Australian study. A low vitamine D status is reported to have a bad prognosis in melanoma and is observed in fair skin patients at risk. Recommendations for the care and follow up of patients with Merkel carcinoma have been published. The elevated risk of positive sentinel lymph nodes in these patients does not allow to define a subgroup of Merkel patients that could be spared from the technique. Sarcoma also benefit from targeted therapy especially DFSP with imatinib. Other molecules among which mTOR inhibitors are being evaluated in sarcomas. A collaborative work has allowed to classify and evaluate in a more standardized way cutaneous T lymphomas and should help future trials. Some microRNA can be used as diagnostic tools or therapies in T cell cutaneous lymphomas. Finally a review of modern therapeutical strategies in cutaneous lymphomas has been published. PMID- 22202648 TI - [What's new in dermatological therapy?]. AB - Several good-quality randomised trials brought useful information on how to manage severe skin infections and develop anti-staphylococcus strategies. Trials on common warts did not bring any valuable solution. Rituximab and omalizumab have seen their indications becoming more precise or broadened. Meta-analyses have been particularly numerous, but most of the time with no decisive conclusion, since this methodology presents strong limitations for studying safety data. Most important work has been rather directed toward analysing safety data rather than efficacy. Among the most important results, are those from a retrospective cohort of patients taking isotretinoin: suicidal risk has to be linked to severe acne itself, rather than to the drug. PMID- 22202650 TI - Cloning, expression, purification, and characterization of a glutamate-specific endopeptidase from Bacillus licheniformis. AB - A gene encoding a glutamate-specific endopeptidase (GSE) from Bacillus licheniformis (BL) has been cloned in Escherichia coli cells. The recombinant protein was expressed as cytoplasmic insoluble inclusion bodies. Immobilized metal affinity chromatography was employed to purify the protein, and then a 27 kDa GSE intermediate was obtained by gradient urea dialysis. The remaining pro peptide was completely removed by treatment with trypsin to obtain mature GSE-BL with a molecular weight of 26 kD at a final yield of up to 140.9 mg/L. With Z (benzyloxycarbomyl)-Phe-Leu-Glu-pNA (p-nitroanilide) as the substrate, the optimal temperature and pH conditions for the enzyme were 37 degrees C and 8.5, respectively, K(m) was 1.495 +/- 0.034 mM, and V(max) was 50.237 MUmol/mg min. The presence of calcium and ferrous ions enhanced the catalytic activity of GSE BL. These results suggest that the recombinant protein is a relatively stable specific proteinase that could be effectively utilized in protein structure analysis, peptide synthesis, and the food industry. PMID- 22202649 TI - Lack of efficacy of curcumin on neurodegeneration in the mouse model of Niemann Pick C1. AB - In order to determine the efficacy of curcumin in ameliorating symptoms of neurodegeneration in the mouse model of Niemann-Pick C1, a variety of formulations and dosages of curcumin, one comparable to one previously reported as efficacious, were provided orally to Npc1(-/-)mice. Plasma levels of curcumin, survival, tests of motor performance, and memory (in some cases) were performed. We found variable, but mild, increases in survival (1.5% to 18%). The greatest increased survival occurred with the highest dose (which was unformulated) while the control for the lipidated formulation (containing phosphatidylcholine and stearic acid) had an equivalent impact and other formulations, while not significantly increased, are also not statistically different in effect from the highest dose. We conclude that curcumin is not a highly efficacious treatment for neurodegeneration in Npc1(-/-) mice. Phosphatidylcholine and stearic acid should be studied further. PMID- 22202651 TI - Caenorhabditis elegans Hsp70-1 expresses highly in bacteria, is sufficiently soluble, and has a catalytic constant similar to Hsc70 and BiP. AB - Caenorhabditis elegans has been used as a model organism to study the roles of molecular chaperones in cellular processes. C. elegans heat shock protein 70-1 (CeHsp70-1) is the first of the 13-member Hsp70 family genes identified so far in the organism. The protein product of this gene, CeHsp70-1, has been shown to play an important role in conferring thermo-tolerance and longevity on C. elegans. Here, we present the results of the first work to over-express, purify and characterize the ATP hydrolyzing activity of a member of the C. elegans Hsp70s. Recombinant CeHsp70-1 was found to be highly expressed and sufficiently soluble in Escherichia coli. The protein was purified to homogeneity using a combination of nickel affinity, ion exchange and size-exclusion chromatography. Kinetic properties of the basal ATPase activity of the enzyme in a low-salt buffer were determined using a colorimetric assay. The specific activity (V(max) per mg protein), K(m) and k(cat) values obtained for CeHsp70-1 were 25 nmol/min/mg, 50 MUM and 0.28 min-1, respectively. The catalytic constant (k(cat)) of the protein was found to be similar to that of heat shock cognate 70 (Hsc70) and binding immunoglobulin protein (BiP). At low concentrations, CeHsp70-1 existed mostly in its monomeric form. This work provides a platform for kinetic studies of other members of the C. elegans Hsp70 molecular chaperones. PMID- 22202666 TI - RAGE mediates vascular injury and inflammation after global cerebral ischemia. AB - The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor involved in a diverse range of pathological conditions. To analyze the roles of RAGE and its decoy receptor, endogenous secretory RAGE (esRAGE), in the global cerebral ischemia, three different mouse cohorts, wild-type, RAGE-/-, and esRAGE transgenic (Tg) mice were subjected to bilateral common carotid artery occlusion (BCCAO). RT-PCR and immunohistochemical analysis revealed that expression of RAGE was induced in the vascular cells at 12 h, and then in the neurons and glia from 3 to 7 days in the hippocampus after BCCAO. The numbers of surviving neurons in the hippocampal CA1 region were significantly higher in RAGE /- and esRAGE Tg mice than those in wild-type mice in the periods between 24 h and 7 days after BCCAO. Lower levels of 3-nitrotyrosine (3-NT) and higher levels of endothelial nitric oxide synthase (eNOS), together with enlarged vascular areas were observed in RAGE-/- and esRAGE Tg mice at 12 h after BCCAO. In the later periods, expressions of glia-derived inflammatory mediators TNFalpha and inducible nitric oxide synthase (iNOS) were reduced in RAGE-/- and esRAGE Tg mice. These results suggest that RAGE may contribute to delayed neuronal death after global cerebral ischemia by enhancing vascular injury and deleterious glia mediated inflammation. PMID- 22202668 TI - Neurochemical characterization of the striatum and the nucleus accumbens in L type Ca(v)1.3 channels knockout mice. AB - L-type Ca(v)1.3 channels control the autonomous pacemaking of the substantia nigra (SN) dopamine (DA) neurons, which maintains the sustained release of DA in the striatum, its target structure. The persistent engagement of L-type channels during pacemaking might lead to increased vulnerability to environmental stressors or degenerative processes, providing a mechanism for the development of Parkinson's disease (PD). Interestingly, L-type channels are not necessary for pacemaking, opening the possible use of calcium channel antagonists as neuroprotective agents for PD without disturbing normal DA function. In this study we aimed to evaluate the consequences of Ca(v)1.3 channels deletion at the neurochemical level. For this purpose, tissue concentrations of DA and their respective metabolites were measured using high performance liquid chromatography (HPLC) in the striatum and the nucleus accumbens (NAcc) of mice lacking the gene for the Ca(v)1.3 channel subunit (CACNA1D) and compared to those in wild-type mice. Striatal DA level did not differ between the two groups. In contrast, the level of serotonin, glutamate, GABA, and taurine were increased by more than 50% in the striatum of Ca(v)1.3 null mice. Neurotransmitters levels in the NAcc did not differ between the different groups. In conclusion, our results neurochemically corroborate the robustness of the nigrostriatal DA neurons in the absence of Ca(v)1.3 channels, but suggest that complete deletion of this channel affected a variety of other transmitter systems. PMID- 22202667 TI - Promotion of beta-amyloid production by C-reactive protein and its implications in the early pathogenesis of Alzheimer's disease. AB - C-reactive protein (CRP) and beta-amyloid protein (Abeta) are involved in the development of Alzheimer's disease (AD). However, the relationship between CRP and Abeta production is unclear. In vitro and in vivo experiments were performed to investigate the association of CRP with Abeta production. Using the rat adrenal pheochromocytoma cell line (PC12 cells) to mimic neurons, cytotoxicity was evaluated by cell viability and supernatant lactate dehydrogenase (LDH) activity. The levels of amyloid precursor protein (APP), beta-site APP cleaving enzyme (BACE-1), and presenilins (PS-1 and PS-2) were investigated using real time polymerase chain reaction and Western blotting analysis. Abeta1-42 was measured by enzyme-linked immunosorbent assay. The relevance of CRP and Abeta as well as potential mechanisms were studied using APP/PS1 transgenic (Tg) mice. Treatment with 0.5-4.0 MUM CRP for 48 h decreased cell viability and increased LDH leakage in PC12 cells. Incubation with CRP at a sub-toxic concentration of 0.2 MUM increased the mRNA levels of APP, BACE-1, PS-1, and PS-2, as well as Abeta1-42 production. CRP inhibitor reversed the CRP-induced upregulations of the mRNA levels of APP, BACE-1, PS-1, and PS-2, and the protein levels of APP, BACE 1, PS-1, and Abeta1-42, but did not reversed Abeta1-42 cytotoxicity. The cerebral levels of CRP and Abeta1-42 in APP/PS1 Tg mice were positively correlated, accompanied with the elevated mRNA expressions of serum amyloid P component (SAP), complement component 1q (C1q), and tumor necrosis factor-alpha (TNF alpha). These results suggest that CRP cytotoxicity is associated with Abeta formation and Abeta-related markers expressions; CRP and Abeta were relevant in early-stage AD; CRP may be an important trigger in AD pathogenesis. PMID- 22202669 TI - Cardiovascular magnetic resonance for the assessment of patients undergoing transcatheter aortic valve implantation: a pilot study. AB - BACKGROUND: Before trans-catheter aortic valve implantation (TAVI), assessment of cardiac function and accurate measurement of the aortic root are key to determine the correct size and type of the prosthesis. The aim of this study was to compare cardiovascular magnetic resonance (CMR) and trans-thoracic echocardiography (TTE) for the assessment of aortic valve measurements and left ventricular function in high-risk elderly patients submitted to TAVI. METHODS: Consecutive patients with severe aortic stenosis and contraindications for surgical aortic valve replacement were screened from April 2009 to January 2011 and imaged with TTE and CMR. RESULTS: Patients who underwent both TTE and CMR (n = 49) had a mean age of 80.8 +/- 4.8 years and a mean logistic EuroSCORE of 14.9 +/- 9.3%. There was a good correlation between TTE and CMR in terms of annulus size (R2 = 0.48, p < 0.001), left ventricular outflow tract (LVOT) diameter (R2 = 0.62, p < 0.001) and left ventricular ejection fraction (LVEF) (R2 = 0.47, p < 0.001) and a moderate correlation in terms of aortic valve area (AVA) (R2 = 0.24, p < 0.001). CMR generally tended to report larger values than TTE for all measurements. The Bland Altman test indicated that the 95% limits of agreement between TTE and CMR ranged from -5.6 mm to + 1.0 mm for annulus size, from -0.45 mm to + 0.25 mm for LVOT, from -0.45 mm2 to + 0.25 mm2 for AVA and from -29.2% to 13.2% for LVEF. CONCLUSIONS: In elderly patients candidates to TAVI, CMR represents a viable complement to transthoracic echocardiography. PMID- 22202670 TI - Some comments on recent discussion of the Boyle van't Hoff relationship. AB - The estimation of several cellular biophysical parameters must be made in order to mathematically predict optimal cryopreservation protocols. These parameters include total cell volume, osmotically inactive volume, cell surface area, and relative water and solute permeabilities. Recent attention has been paid to the determination of the osmotically inactive volume and, specifically, an argument was made suggesting that this volume was incorrectly determined in the literature [4]. Here we show that this assertion is false. PMID- 22202671 TI - The type and extent of injuries in vitrified mouse oocytes. AB - To improve the vitrification of mouse oocytes using straws, we attempted to estimate the type and extent of injuries during vitrification with a vitrification solution EAFS10/10. Injuries in oocytes were assessed based on cellular viability, the integrity of the plasma membrane, the status of the meiotic spindle/chromosomes, and morphological appearance. For morphologically normal oocytes, the ability to be fertilized and to develop into blastocysts was examined. Morphological assessment revealed 15% of oocytes to be injured by intracellular ice formed during vitrification, and 10% by osmotic swelling during removal of the cryoprotectant. When assessed by the status of spindles/chromosomes, the most sensitive criterion, damage was found in 16% of oocytes without any treatment. This value was similar to the proportion of fresh oocytes that did not cleave after insemination (13%). On exposure to EAFS10/10, the spindles/chromosomes were affected in 33% of oocytes. The exposure reduced the rate of cleavage by 18% points and the rate of development into blastocysts by 19 points. Vitrification reduced these rates by 15% and 36% points, respectively. Although the mechanism responsible for this moderate toxic effect on developmental ability is not known, information obtained in the present study will be useful to develop a practical method for the vitrification of mouse oocytes using straws. PMID- 22202673 TI - Cell-type specific regulation of myostatin signaling. AB - The transforming growth factor (TGF)-beta family member myostatin is an important regulator of myoblast, adipocyte, and fibroblast growth and differentiation, but the signaling mechanisms remain to be established. We therefore determined the contribution of myostatin type I receptors activin receptor-like kinase-4 (ALK4) and -5 (ALK5) and different coreceptors in C2C12 myoblasts, C3H10T1/2 mesenchymal stem cells, and 3T3-L1 fibroblasts, as well as in primary myoblast and fibroblasts. We performed siRNA-mediated knockdown of each receptor and measured signaling activity using Smad3-dependent luciferase and Smad2 phosphorylation assays with nontargeting siRNA as control. We find that myostatin utilizes ALK4 in myoblasts, whereas it has a preference for ALK5 in nonmyogenic cells. Notably, our results show that coreceptor Cripto is expressed in myoblasts but not in the nonmyogenic cells and that it regulates myostatin activity. More specifically, myostatin requires Cripto in myoblasts, whereas Cripto represses activin activity and TGF-beta signaling is Cripto independent. Cripto-mediated myostatin signaling is dependent on both epidermal growth factor (EGF)-like and Cripto-FRL1-cryptic (CFC) domains, whereas activin signaling is solely conferred by the CFC domain. Furthermore, Cripto down-regulation enhances myoblast differentiation, showing its importance in myostatin signaling. Together, our results identify a molecular mechanism that explains the cell-type specific aspects of signaling by myostatin and other TGF-beta family members. PMID- 22202674 TI - Glutathione-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity. AB - To investigate the effects of the predominant nonprotein thiol, glutathione (GSH), on redox homeostasis, we employed complementary pharmacological and genetic strategies to determine the consequences of both loss- and gain-of function GSH content in vitro. We monitored the redox events in the cytosol and mitochondria using reduction-oxidation sensitive green fluorescent protein (roGFP) probes and the level of reduced/oxidized thioredoxins (Trxs). Either H(2)O(2) or the Trx reductase inhibitor 1-chloro-2,4-dinitrobenzene (DNCB), in embryonic rat heart (H9c2) cells, evoked 8 or 50 mV more oxidizing glutathione redox potential, E(hc) (GSSG/2GSH), respectively. In contrast, N-acetyl-L cysteine (NAC) treatment in H9c2 cells, or overexpression of either the glutamate cysteine ligase (GCL) catalytic subunit (GCLC) or GCL modifier subunit (GCLM) in human embryonic kidney 293 T (HEK293T) cells, led to 3- to 4-fold increase of GSH and caused 7 or 12 mV more reducing E(hc), respectively. This condition paradoxically increased the level of mitochondrial oxidation, as demonstrated by redox shifts in mitochondrial roGFP and Trx2. Lastly, either NAC treatment (EC(50) 4 mM) or either GCLC or GCLM overexpression exhibited increased cytotoxicity and the susceptibility to the more reducing milieu was achieved at decreased levels of ROS. Taken together, our findings reveal a novel mechanism by which GSH-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity. PMID- 22202676 TI - Influenza A virus inhibits cytoplasmic stress granule formation. AB - An important component of the mammalian stress response is the reprogramming of translation. A variety of stresses trigger abrupt polysome disassembly and the accumulation of stalled translation preinitiation complexes. These complexes nucleate cytoplasmic stress granules (SGs), sites of mRNA triage in which mRNAs from disassembling polysomes are sorted and the fates of individual transcripts are determined. Here, we demonstrate that influenza A virus (IAV) actively suppresses SG formation during infection, thereby allowing translation of viral mRNAs. Complete inhibition of SG formation is dependent on the function of the viral nonstructural protein 1 (NS1); at late times postinfection, cells infected with NS1-mutant viruses formed SGs in a double-stranded RNA-activated protein kinase (PKR)-dependent fashion. In these cells, SG formation correlated with inhibited viral protein synthesis. Together, these experiments demonstrate the antiviral potential of SGs and reveal a viral countermeasure that limits SG formation. PMID- 22202675 TI - Evidence for anti-inflammatory effects of C5a on the innate IL-17A/IL-23 axis. AB - There is growing evidence that the complement activation product C5a positively or negatively regulates inflammatory functions. The studies presented here report that C5a exerts anti-inflammatory effects by altering production of the cytokines IL-17A and IL-23 during endotoxic shock in young adult male C57BL/6J mice and has similar effects on macrophages from the same mice. IL-17A and IL-23 both appeared in plasma during endotoxemia, and their neutralization improved survival. The relevant sources of IL-17A during endotoxemia were not CD4(+) cells, gammadelta T cells, or NK cells but CD11b(+)F4/80(+) macrophages. The addition in vitro of C5a to lipopolysaccharide-activated peritoneal macrophages dose dependently antagonized the production of IL-17A (IC(50), 50-100 nM C5a) and IL-23 (IC(50), 10 nM C5a). This suppression required the receptor C5aR, but was independent of the second C5a receptor, C5L2. Genetic absence of C5aR was associated with much higher levels of IL-17A and IL-23 during endotoxic shock. Mechanistically, C5a mediated its effects on the IL-17A/IL-23 axis in a 2-step process. C5a caused activation of the PI3K-Akt and MEK1/2-ERK1/2 pathways, resulting in induction of IL-10, which powerfully inhibited production of IL-17A and IL-23. These data identify previously unknown mechanisms by which the anaphylatoxin C5a limits acute inflammation and antagonizes the IL-17A/IL-23 axis. PMID- 22202692 TI - MiR-382 targeting of kallikrein 5 contributes to renal inner medullary interstitial fibrosis. AB - Previously we have shown that microRNA miR-382 can facilitate loss of renal epithelial characteristics in cultured cells. This study examined the in vivo role of miR-382 in the development of renal interstitial fibrosis in a mouse model. Unilateral ureteral obstruction was used to induce renal interstitial fibrosis in mice. With 3 days of unilateral ureteral obstruction, expression of miR-382 in the obstructed kidney was increased severalfold compared with sham operated controls. Intravenous delivery of locked nucleic acid-modified anti-miR 382 blocked the increase in miR-382 expression and significantly reduced inner medullary fibrosis. Expression of predicted miR-382 target kallikrein 5, a proteolytic enzyme capable of degrading several extracellular matrix proteins, was reduced with unilateral ureteral obstruction. Anti-miR-382 treatment prevented the reduction of kallikrein 5 in the inner medulla. Furthermore, the protective effect of the anti-miR-382 treatment against fibrosis was abolished by renal knockdown of kallikrein 5. Targeting of kallikrein 5 by miR-382 was confirmed by 3'-untranslated region luciferase assay. These data support a completely novel mechanism in which miR-382 targets kallikrein 5 and contributes to the development of renal inner medullary interstitial fibrosis. The study provided the first demonstration of an in vivo functional role of miR-382 in any species and any organ system. PMID- 22202704 TI - Intravenous immunoglobulins prevent the breakdown of the blood-brain barrier in experimentally induced sepsis. AB - INTERVENTIONS: The effects of immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M on blood-brain barrier integrity and survival rates in septic rats were comparatively investigated. MEASUREMENTS: Sepsis was induced by cecal ligation and perforation in Sprague-Dawley rats. The animals were divided into the following groups: Sham, cecal ligation and perforation, cecal ligation and perforation plus immunoglobulin G (250 mg/kg, intravenous), and cecal ligation and perforation plus immunoglobulins enriched with immunoglobulin A and immunoglobulin M (250 mg/kg, intravenous). Immunoglobulins were administered 5 mins before cecal ligation and perforation and the animals were observed for behavioral changes for 24 hrs following cecal ligation and perforation. Blood-brain barrier permeability was functionally and structurally evaluated by determining the extravasation of Evans Blue and horseradish peroxidase tracers, respectively. Immunohistochemistry and Western blotting for occludin were performed. MAIN RESULTS: The high mortality rate (34%) noted in the septic rats was decreased to 15% and 3% by immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M, respectively (p < .01). Both immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M alleviated the symptoms of sickness behavior in the septic rats, with the animals becoming healthy and active. Increased extravasation of Evans Blue into the brain tissue of the septic rats was markedly decreased with the administration of both immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M (p < .01). Occludin expression remained essentially unchanged in all groups, including the cecal ligation and perforation group. In the cecal ligation and perforation group, increased luminal and abluminal vesicles containing electron-dense horseradish peroxidase-reaction product were noted in the cytoplasm of endothelial cells located in the hippocampus and the cerebral cortex. Tight junction was ultrastructurally intact, suggesting that the transcellular pathway is responsible for the blood-brain barrier breakdown in sepsis. Following immunoglobulin G or immunoglobulins enriched with immunoglobulin A and immunoglobulin M treatment, no ultrastructural evidence of leaky capillaries in the brain was observed in the septic rats, indicating the blockade of the transcellular pathway by immunoglobulins administration. CONCLUSIONS: Our study suggests that immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M improve the integrity of the blood-brain barrier and inhibits cecal ligation and perforation induced symptoms of sickness behavior in rats. PMID- 22202705 TI - Tidal recruitment assessed by electrical impedance tomography and computed tomography in a porcine model of lung injury*. AB - OBJECTIVES: To determine the validity of electrical impedance tomography to detect and quantify the amount of tidal recruitment caused by different positive end-expiratory pressure levels in a porcine acute lung injury model. DESIGN: Randomized, controlled, prospective experimental study. SETTING: Academic research laboratory. SUBJECTS: Twelve anesthetized and mechanically ventilated pigs. INTERVENTIONS: Acute lung injury was induced by central venous oleic acid injection and abdominal hypertension in seven animals. Five healthy pigs served as control group. Animals were ventilated with positive end-expiratory pressure of 0, 5, 10, 15, 20, and 25 cm H2O, respectively, in a randomized order. MEASUREMENTS AND MAIN RESULTS: At any positive end-expiratory pressure level, electrical impedance tomography was obtained during a slow inflation of 12 mL/kg of body weight. Regional-ventilation-delay indices quantifying the time until a lung region reaches a certain amount of impedance change were calculated for lung quadrants and for every single electrical impedance tomography pixel, respectively. Pixel-wise calculated regional-ventilation-delay indices were plotted in a color-coded regional-ventilation-delay map. Regional-ventilation delay inhomogeneity that quantifies heterogeneity of ventilation time courses was evaluated by calculating the scatter of all pixel-wise calculated regional ventilation-delay indices. End-expiratory and end-inspiratory computed tomography scans were performed at each positive end-expiratory pressure level to quantify tidal recruitment of the lung. Tidal recruitment showed a moderate inter individual (r = .54; p < .05) and intra-individual linear correlation (r = .46 up to r = .73 and p < .05, respectively) with regional-ventilation-delay obtained from lung quadrants. Regional-ventilation-delay inhomogeneity was excellently correlated with tidal recruitment intra- (r = .90 up to r = .99 and p < .05, respectively) and inter-individually (r = .90; p < .001). CONCLUSIONS: Regional ventilation-delay can be noninvasively measured by electrical impedance tomography during a slow inflation of 12 mL/kg of body weight and visualized using ventilation delay maps. Our experimental data suggest that the impedance tomography-based analysis of regional-ventilation-delay inhomogeneity provides a good estimate of the amount of tidal recruitment and may be useful to individualize ventilatory settings. PMID- 22202706 TI - Meeting standards of high-quality intensive care unit palliative care: clinical performance and predictors. AB - OBJECTIVES: High-quality care for intensive care unit patients and families includes palliative care. To promote performance improvement, the Agency for Healthcare Research and Quality's National Quality Measures Clearinghouse identified nine evidence-based processes of intensive care unit palliative care (Care and Communication Bundle) that are measured through review of medical record documentation. We conducted this study to examine how frequently the Care and Communication Bundle processes were performed in diverse intensive care units and to understand patient factors that are associated with such performance. DESIGN: Prospective, multisite, observational study of performance of key intensive care unit palliative care processes. SETTINGS: A surgical intensive care unit and a medical intensive care unit in two different large academic health centers and a medical-surgical intensive care unit in a medium-sized community hospital. PATIENTS: Consecutive adult patients with length of intensive care unit stay >=5 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between November 2007 and December 2009, we measured performance by specified day after intensive care unit admission on nine care process measures: Identify medical decision-maker, advance directive and resuscitation preference, distribute family information leaflet, assess and manage pain, offer social work and spiritual support, and conduct interdisciplinary family meeting. Multivariable regression analysis was used to determine predictors of performance of five care processes. We enrolled 518 (94.9%) patients and 336 (83.6%) family members. Performances on pain assessment and management measures were high. In contrast, interdisciplinary family meetings were documented for <20% of patients by intensive care unit day 5. Performance on other measures ranged from 8% to 43%, with substantial variation across and within sites. Chronic comorbidity burden and site were the most consistent predictors of care process performance. CONCLUSIONS: Across three intensive care units in this study, performance of key palliative care processes (other than pain assessment and management) was inconsistent and infrequent. Available resources and strategies should be utilized for performance improvement in this area of high importance to patients, families, and providers. PMID- 22202707 TI - Transfer of multidrug-resistant bacteria to healthcare workers' gloves and gowns after patient contact increases with environmental contamination. AB - OBJECTIVE: To assess the role of environmental contamination in the transmission of multidrug-resistant bacteria to healthcare workers' clothing. DESIGN: Prospective cohort. SETTING: Six intensive care units at a tertiary care hospital. SUBJECTS: Healthcare workers including registered nurses, patient care technicians, respiratory therapists, occupational/physical therapists, and physicians. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred twenty of 585 (20.5%) healthcare worker/patient interactions resulted in contamination of healthcare workers' gloves or gowns. Multidrug-resistant Acinetobacter baumannii contamination occurred most frequently, 55 of 167 observations (32.9%; 95% confidence interval [CI] 25.8% to 40.0%), followed by multidrug-resistant Pseudomonas aeruginosa, 15 of 86 (17.4%; 95% CI 9.4% to 25.4%), vancomycin-resistant Enterococcus, 25 of 180 (13.9%, 95% CI 8.9, 18.9%) and methicillin-resistant Staphylococcus aureus, 21 of 152 (13.8%; 95% CI 8.3% to 19.2%). Independent risk factors associated with healthcare worker contamination with multidrug-resistant bacteria were positive environmental cultures (odds ratio [OR] 4.2; 95% CI 2.7-6.5), duration in room for >5 mins (OR 2.0; 95% CI 1.2 3.4), performing physical examinations (OR 1.7; 95% CI 1.1-2.8), and contact with the ventilator (OR 1.8; 95% CI, 1.1-2.8). Pulsed field gel electrophoresis determined that 91% of healthcare worker isolates were related to an environmental or patient isolate. CONCLUSIONS: The contamination of healthcare workers' protective clothing during routine care of patients with multidrug resistant organisms is most frequent with A. baumannii. Environmental contamination was the major determinant of transmission to healthcare workers' gloves or gowns. Compliance with contact precautions and more aggressive environmental cleaning may decrease transmission. PMID- 22202708 TI - What is the role of chest compression depth during out-of-hospital cardiac arrest resuscitation?. AB - BACKGROUND: The 2010 international guidelines for cardiopulmonary resuscitation recently recommended an increase in the minimum compression depth from 38 to 50 mm, although there are limited human data to support this. We sought to study patterns of cardiopulmonary resuscitation compression depth and their associations with patient outcomes in out-of-hospital cardiac arrest cases treated by the 2005 guideline standards. DESIGN: Prospective cohort. SETTING: Seven U.S. and Canadian urban regions. PATIENTS: We studied emergency medical services treated out-of-hospital cardiac arrest patients from the Resuscitation Outcomes Consortium Epistry-Cardiac Arrest for whom electronic cardiopulmonary resuscitation compression depth data were available, from May 2006 to June 2009. MEASUREMENTS: We calculated anterior chest wall depression in millimeters and the period of active cardiopulmonary resuscitation (chest compression fraction) for each minute of cardiopulmonary resuscitation. We controlled for covariates including compression rate and calculated adjusted odds ratios for any return of spontaneous circulation, 1-day survival, and hospital discharge. MAIN RESULTS: We included 1029 adult patients from seven U.S. and Canadian cities with the following characteristics: Mean age 68 yrs; male 62%; bystander witnessed 40%; bystander cardiopulmonary resuscitation 37%; initial rhythms: Ventricular fibrillation/ventricular tachycardia 24%, pulseless electrical activity 16%, asystole 48%, other nonshockable 12%; outcomes: Return of spontaneous circulation 26%, 1-day survival 18%, discharge 5%. For all patients, median compression rate was 106 per minute, median compression fraction 0.65, and median compression depth 37.3 mm with 52.8% of cases having depth <38 mm and 91.6% having depth <50 mm. We found an inverse association between depth and compression rate ( p < .001). Adjusted odds ratios for all depth measures (mean values, categories, and range) showed strong trends toward better outcomes with increased depth for all three survival measures. CONCLUSIONS: We found suboptimal compression depth in half of patients by 2005 guideline standards and almost all by 2010 standards as well as an inverse association between compression depth and rate. We found a strong association between survival outcomes and increased compression depth but no clear evidence to support or refute the 2010 recommendations of >50 mm. Although compression depth is an important component of cardiopulmonary resuscitation and should be measured routinely, the most effective depth is currently unknown. PMID- 22202709 TI - Comparison of SpO2 to PaO2 based markers of lung disease severity for children with acute lung injury. AB - OBJECTIVE: Given pulse oximetry is increasingly substituting for arterial blood gas monitoring, noninvasive surrogate markers for lung disease severity are needed to stratify pediatric risk. We sought to validate prospectively the comparability of SpO2/Fio2 to PaO2/Fio2 and oxygen saturation index to oxygenation index in children. We also sought to derive a noninvasive lung injury score. DESIGN: Prospective, multicentered observational study in six pediatric intensive care units. PATIENTS: One hundred thirty-seven mechanically ventilated children with SpO2 80% to 97% and an indwelling arterial catheter. INTERVENTIONS: Simultaneous blood gas, pulse oximetry, and ventilator settings were collected. Derivation and validation data sets were generated, and linear mixed modeling was used to derive predictive equations. Model performance and fit were evaluated using the validation data set. MEASUREMENTS AND MAIN RESULTS: One thousand one hundred ninety blood gas, SpO2, and ventilator settings from 137 patients were included. Oxygen saturation index had a strong linear association with oxygenation index in both derivation and validation data sets, given by the equation oxygen saturation index = 2.76 1 0.547*oxygenation index (derivation). 1/SpO2/Fio2 had a strong linear association with 1/PaO2/Fio2 in both derivation and validation data sets given by the equation 1/SpO2/Fio2 = 0.00232 1 0.443/PaO2/Fio2 (derivation). SpO2/Fio2 criteria for acute respiratory distress syndrome and acute lung injury were 221 (95% confidence interval 215-226) and 264 (95% confidence interval 259-269). Multivariate models demonstrated that oxygenation index, serum pH, and Paco(2) were associated with oxygen saturation index (p < .05); and 1/PaO2/Fio2, mean airway pressure, serum pH, and Paco2 were associated with 1/SpO2/Fio2 (p < .05). There was strong concordance between the derived noninvasive lung injury score and the original pediatric modification of lung injury score with a mean difference of 20.0361 alpha0.264 sd. CONCLUSIONS: Lung injury severity markers, which use SpO2, are adequate surrogate markers for those that use PaO2 in children with respiratory failure for SpO2 between 80% and 97%. They should be used in clinical practice to characterize risk, to increase enrollment in clinical trials, and to determine disease prevalence. PMID- 22202710 TI - Systemic human orbital fat-derived stem/stromal cell transplantation ameliorates acute inflammation in lipopolysaccharide-induced acute lung injury. AB - OBJECTIVE: Acute lung injury results in acute respiratory distress syndrome. There is no standard therapy for acute respiratory distress syndrome but supportive care. Stem cells offer a new therapeutic potential for tissue regeneration as a result of their self-renewal, multipotency, and paracrine capabilities. The objective of this study is to investigate the effects and the mechanisms of systemic human orbital fat-derived stem/stromal cell transplantation on lipopolysaccharide-induced acute lung injury. DESIGN: Prospective, randomized, controlled study. SETTING: University-affiliated research institute. SUBJECTS: Male BALB/c mice. INTERVENTIONS: Twenty-five micrograms lipopolysaccharide in 50 MUL sterile saline or 50 MUL of sterile saline was delivered through intratracheal injection. Twenty mins later, the animals were further randomized into subgroups that received either a tail vein injection of 3 * 10 orbital fat-derived stem/stromal cells in 50 MUL phosphate buffered saline or 50 MUL phosphate-buffered saline. MEASUREMENTS AND MAIN RESULTS: Low immunogenicity and immune-tolerated of orbital fat-derived stem/stromal cells were observed in this xenotransplanted model. Orbital fat derived stem/stromal cells significantly reduced lipopolysaccharide-induced pulmonary inflammation, which was evidenced by a decrease in total protein concentration and neutrophil counts in alveolar fluid through bronchoalveolar lavage, reduced endothelial and alveolar epithelial permeability as well as neutrophil (Ly6G-expressing cells) and macrophage (CD68-expressing cells) infiltration. Lipopolysaccharide-induced expression of CD14, inducible nitric oxide synthase, and transforming growth factor-beta in lung tissue was significantly inhibited by orbital fat-derived stem/stromal cells. Orbital fat derived stem/stromal cells not only reduced the circulation numbers of macrophages and neutrophils (CD11b-expressing cells), but also decreased systemic proinflammatory chemokine levels such as macrophage inflammatory protein-1-gamma, B-lymphocyte chemoattractant, interleukin-12, and subsequent circulation helper T cell (CD4-expressing cells) numbers. Furthermore, few human orbital fat-derived stem/stromal cells were detectable in the recipient lung after acute inflammation subsided. CONCLUSIONS: Systemic orbital fat-derived stem/stromal cell transplantation was effective in modulating inflammation during acute lung injury. The therapeutic effect was attributed to the inhibition of acute inflammatory responses. PMID- 22202711 TI - Statins and outcomes in patients with bloodstream infection: a propensity-matched analysis. AB - OBJECTIVE: The pleiotropic effects of statins, 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitor, have been shown to modify inflammatory cell signaling on the immune response to infection. It was postulated that statins may be a good candidate as novel therapeutic agents for the treatment of sepsis. We investigated whether ongoing statin therapy is associated with mortality in patients with bloodstream infection. DESIGN: A retrospective cohort study. SETTING: Two tertiary hospitals in Bronx, NY. PATIENTS: Adult patients in the hospital with bloodstream infection and categorized according to statin therapy as an outpatient or inpatient before bacteremia. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Of 2,139 bacteremic hospitalized patients, 592 (28%) received statins before blood cultures and 677 (32%) died within 90 days. On multivariate adjustment, the association between statin therapy and 90-day all-cause mortality was statistically significant (hazard ratio, 0.78; 95% confidence interval [CI] 0.65-0.94), but statin users and nonusers differed significantly on many baseline clinical factors. Using the propensity score matched analysis to balance the differences between groups, the association was no longer significant (hazard ratio 0.99; 95% CI 0.77-1.25). Multivariate analysis after stratifying by decile in propensity score for statin use demonstrated similar results (hazard ratio 0.86; 95% CI 0.70-1.06). Statin use was not associated with reduced intensive care unit admission (odds ratio [OR], 0.86; 95% CI 0.59-1.26), hospital length of stay (beta = -0.8 days; 95% CI -2.2 to 1.7 days), intensive care unit length of stay (beta = -0.1 days; 95% CI -3.7 to 3.8 days), or need for mechanical or noninvasive ventilation (OR 1.03; 95% CI 0.70-1.51). CONCLUSION: After adjusting for the propensity to receive statin therapy, no statistically significant association between statin therapy before bloodstream infection and survival was identified. PMID- 22202712 TI - A comparison of critical care research funding and the financial burden of critical illness in the United States. AB - OBJECTIVES: To estimate federal dollars spent on critical care research, the cost of providing critical care, and to determine whether the percentage of federal research dollars spent on critical care research is commensurate with the financial burden of critical care. DESIGN AND DATA SOURCES: The National Institutes of Health Computer Retrieval of Information on Scientific Projects database was queried to identify funded grants whose title or abstract contained a key word potentially related to critical care. Each grant identified was analyzed by two reviewers (three if the analysis was discordant) to subjectively determine whether it was definitely, possibly, or definitely not related to critical care. Hospital and total costs of critical care were estimated from the Premier Database, state discharge data, and Medicare data. To estimate healthcare expenditures associated with caring for critically ill patients, total costs were calculated as the combination of hospitalization costs that included critical illness as well as additional costs in the year after hospital discharge. MEASUREMENTS AND MAIN RESULTS: Of 19,257 grants funded by the National Institutes of Health, 332 (1.7%) were definitely related to critical care and a maximum of 1212 (6.3%) grants were possibly related to critical care. Between 17.4% and 39.0% of total hospital costs were spent on critical care, and a total of between $121 and $263 billion was estimated to be spent on patients who required intensive care. This represents 5.2% to 11.2%, respectively, of total U.S. healthcare spending. CONCLUSIONS: The proportion of research dollars spent on critical care is lower than the percentage of healthcare expenditures related to critical illness. PMID- 22202713 TI - Volume-limited versus pressure-limited hemodynamic management in septic and nonseptic shock. AB - OBJECTIVES: To evaluate the effect of hemodynamic management guided by upper limits of cardiac filling volumes or pressures on durations of mechanical ventilation and lengths of stay in critically ill patients with shock. DESIGN: Prospective, randomized, clinical trial. SETTING: Mixed intensive care unit of a large teaching hospital and mixed intensive care unit of a tertiary care, academic medical center. PATIENTS: A total 120 septic (n = 72) and nonseptic (n = 48) shock patients, randomized (after stratification) to transpulmonary thermodilution (n = 60) or pulmonary artery catheter (n = 60) between February 2007 and July 2009. INTERVENTIONS: Hemodynamic management was guided by algorithms including upper limits for fluid resuscitation of extravascular lung water (<10 mL/kg) and global end-diastolic volume index (<850 mL/m) in the transpulmonary thermodilution group and pulmonary artery occlusion pressure (<18 20 mm Hg) in the pulmonary artery catheter group for 72 hrs after enrollment. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were ventilator-free days and lengths of stay in the intensive care unit and the hospital. Secondary outcomes included organ failures and mortality. Cardiac comorbidity was more frequent in nonseptic than in septic shock. Ventilator-free days, lengths of stay, organ failures, and 28-day mortality (overall 33.3%) were similar between monitoring groups. Transpulmonary thermodilution (vs. pulmonary artery catheter) monitoring was associated with more days on mechanical ventilation and longer intensive care unit and hospital lengths of stay in nonseptic (p = .001) but not in septic shock. In both conditions, fewer patients met the upper limit of volume than of pressure criteria at baseline and transpulmonary thermodilution (vs. pulmonary artery catheter) monitoring was associated with a more positive fluid balance at 24 hrs. CONCLUSIONS: Hemodynamic management guided by transpulmonary thermodilution vs. pulmonary artery catheter in shock did not affect ventilator free days, lengths of stay, organ failures, and mortality of critically ill patients. Use of the a transpulmonary thermodilution algorithm resulted in more days on mechanical ventilation and intensive care unit length of stay compared with the pulmonary artery catheter algorithm in nonseptic shock but not in septic shock. This may relate to cardiac comorbidity and a more positive fluid balance with use of transpulmonary thermodilution in nonseptic shock. PMID- 22202730 TI - The versatile stellate cell - more than just a space-filler. AB - Most epithelia contain multiple cell types that interact to perform the roles required of the tissue. In insect epithelia, the apical plasma membrane V-ATPase dominates ion-transport models, and (as in vertebrates) is usually found in specialized intercalated cell types or regions. The Malpighian tubules of several insect Orders contain not just a mitochondrion-rich principal cell expressing high levels of V-ATPase, but a smaller, intercalated "type II", "secondary" or "stellate" cell. Recent data show that this cell type plays a key role in control of chloride and water flux across the tissue, but also may play other, still unsuspected dynamic roles. PMID- 22202731 TI - Exploring long non-coding RNAs through sequencing. AB - Long non-coding RNAs (lncRNAs) are emerging as an important class of regulatory transcripts that are implicated in a variety of biological functions. RNA sequencing, along with other next-generation sequencing-based approaches, enables their study on a genome-wide scale, at maximal resolution, and across multiple conditions. This review discusses how sequencing-based studies are providing global insights into lncRNA transcription, post-transcriptional processing, expression regulation and sites of function. The next few years will deepen our insight into the overall contribution of lncRNAs to genome function and to the information flow from genotype to phenotype. PMID- 22202746 TI - Colony-stimulating factor-1 receptor protein expression is a specific marker for goldfish (Carassius auratus L.) macrophage progenitors and their differentiated cell types. AB - Signaling through the colony-stimulating factor-1 receptor (CSF-1R) mediates the proliferation, differentiation, and activation of macrophages and their progenitors. In this study we report on the use of an anti-goldfish CSF-1R antibody to specifically recognize a population of CSF-1R positive cells from goldfish tissues. Furthermore, using our previously characterized primary kidney macrophage culture system, we show that CSF-1R positive cells include monocytes, macrophages, and their progenitor cells. Freshly isolated progenitor cells had a higher median florescent intensity ratio than those progenitor cells cultured for up to four days. The decrease in CSF-1R expression on the progenitor cells coincides with the appearance and development of monocytes and macrophages. Monocytes were consistently CSF-1R+ and maintained the high level of CSF-1R expression as they developed into macrophages. Like that of mammalian systems, CSF-1R is expressed on all macrophage sub-populations (progenitors, monocytes, macrophages), and CSF-1R expression increases with macrophage development in teleosts. PMID- 22202747 TI - Occupational exposure to neurotoxic substances in Asian countries - challenges and approaches. AB - The fact that a conference on neurotoxicity was held in China triggered the idea to provide an insight into occupational diseases, their development and the approaches to investigate them in Asian countries. A historical review, a meta analysis, and studies on humans and animals provide impressions on past and current problems. The Korean example showed that each newly introduced industry is accompanied by its own problems as regards occupational diseases. Mercury and carbon disulfide were of importance in the beginning, whereas solvents and manganese became important later. Outbreaks of diseases were important reasons to guide both the public and the governmental attention to prevention and allowed within a relatively short time considerable progress. As the example on the replacement of 2-bromopropane by 1-bromopropane showed, also the introduction of chemicals that are more beneficial for the environment may result in additional occupational risks. A lower mutagenicity of 1-bromopopane was shown to be associated with a greater neurotoxicity in Japanese studies. Although occupational health and diseases are commonly related to adults, child workers exposed to solvents were examined in a Lebanese study. The study started outlining the health hazards in young workers because they might be at a much greater risk due to the not yet completed maturation of their nervous system. That some occupational diseases are not yet a focus of prevention was shown by the study on pesticides. If at all, the serious health consequences resulting from excessive exposure were investigated. Research enabling precautionary actions was not available from the international literature. Despite globalization the knowledge on occupational diseases is not yet "globalized" and each country obviously undergoes its own development triggered by local experiences. Economic development that requires a healthy workforce, but also public interest that challenges governmental regulations further efforts on the prevention of occupational diseases. The paper reflects a summary of the talks presented at the symposium "Occupational Neurotoxicities in Asian Countries" as part of the 11th International Symposium on Neurobehavioral Methods and Effects in Occupational and Environmental Health. PMID- 22202776 TI - BMP inhibition by DAN in Hensen's node is a critical step for the establishment of left-right asymmetry in the chick embryo. AB - During left-right (L-R) axis formation, Nodal is expressed in the node and has a central role in the transfer of L-R information in the vertebrate embryo. Bone morphogenetic protein (BMP) signaling also has an important role for maintenance of gene expression around the node. Several members of the Cerberus/Dan family act on L-R patterning by regulating activity of the transforming growth factor beta (TGF-beta) family. We demonstrate here that chicken Dan plays a critical role in L-R axis formation. Chicken Dan is expressed in the left side of the node shortly after left-handed Shh expression and before the appearance of asymmetrically expressed genes in the lateral plate mesoderm (LPM). In vitro experiments revealed that DAN inhibited BMP signaling but not NODAL signaling. SHH had a positive regulatory effect on Dan expression while BMP4 had a negative effect. Using overexpression and RNA interference-mediated knockdown strategies, we demonstrate that Dan is indispensable for Nodal expression in the LPM and for Lefty-1 expression in the notochord. In the perinodal region, expression of Dan and Nodal was independent of each other. Nodal up-regulation by DAN required NODAL signaling, suggesting that DAN might act synergistically with NODAL. Our data indicate that Dan plays an essential role in the establishment of the L-R axis by inhibiting BMP signaling around the node. PMID- 22202748 TI - Pathophysiology of manganese-associated neurotoxicity. AB - Manganese (Mn) is a well established neurotoxin associated with specific damage to the basal ganglia in humans. The phenotype associated with Mn neurotoxicity was first described in two workers with occupational exposure to Mn oxide (Couper, 1837). Although the description did not use modern clinical terminology, a parkinsonian illness characterized by slowness of movement (bradykinesia), masked facies, and gait impairment (postural instability) appears to have predominated. Nearly 100 years later an outbreak of an atypical parkinsonian illness in a Chilean Mn mine provided a phenotypic description of a fulminant neurologic disorder with parkinsonism, dystonia, and neuropsychiatric symptoms (Rodier, 1955). Exposures associated with this syndrome were massive and an order of magnitude greater than modern exposures (Rodier, 1955; Hobson et al., 2011). The clinical syndrome associated with Mn neurotoxicity has been called manganism. Modern exposures to Mn occur primarily through occupations in the steel industry and welding. These exposures are often chronic and varied, occurring over decades in the healthy workforce. Although the severe neurologic disorder described by Rodier and Couper are no longer seen, several reports have suggested a possible increased risk of neurotoxicity in these workers (Racette et al., 2005b; Bowler et al., 2007; Harris et al., 2011). Based upon limited prior imaging and pathologic investigations into the pathophysiology of neurotoxicity in Mn exposed workers (Huang et al., 2003), many investigators have concluded that the syndrome spares the dopamine system distinguishing manganism from Parkinson disease (PD), the most common cause of parkinsonism in the general population, and a disease with characteristic degenerative changes in the dopaminergic system (Jankovic, 2005). The purpose of this symposium was to highlight recent advances in the understanding of the pathophysiology of Mn associated neurotoxicity from Caenorhabditis elegans to humans. Dr. Aschner's presentation discussed mechanisms of dopaminergic neuronal toxicity in C. elegans and demonstrates a compelling potential role of Mn in dopaminergic degeneration. Dr. Guilarte's experimental, non-human primate model of Mn neurotoxicity suggests that Mn decreases dopamine release in the brain without loss of neuronal integrity markers, including dopamine. Dr. Racette's presentation demonstrates a unique pattern of dopaminergic dysfunction in active welders with chronic exposure to Mn containing welding fumes. Finally, Dr. Dydak presented novel magnetic resonance (MR) spectroscopy data in Mn exposed smelter workers and demonstrated abnormalities in the thalamus and frontal cortex for those workers. This symposium provided some converging evidence of the potential neurotoxic impact of Mn on the dopaminergic system and challenged existing paradigms on the pathophysiology of Mn in the central nervous system. PMID- 22202804 TI - Synthesis of cis- and trans-3-aminocyclohexanols by reduction of beta enaminoketones. AB - We describe a protocol developed for the preparation of beta-enaminoketones derived from 1,3-cyclohexanediones, and their subsequent reduction by sodium in THF-isopropyl alcohol to afford cis- and trans-3-aminocyclohexanols. PMID- 22202803 TI - Hepatic leptin signalling and subdiaphragmatic vagal efferents are not required for leptin-induced increases of plasma IGF binding protein-2 (IGFBP-2) in ob/ob mice. AB - AIMS/HYPOTHESIS: The fat-derived hormone leptin plays a crucial role in the maintenance of normal body weight and energy expenditure as well as in glucose homeostasis. Recently, it was reported that the liver-derived protein, insulin like growth factor binding protein-2 (IGFBP-2), is responsible for at least some of the glucose-normalising effects of leptin. However, the exact mechanism by which leptin upregulates IGFBP-2 production is unknown. Since it is believed that circulating IGFBP-2 is predominantly derived from the liver and leptin has been shown to have both direct and indirect actions on the liver, we hypothesised that leptin signalling in hepatocytes or via brain-liver vagal efferents may mediate leptin control of IGFBP-2 production. METHODS: To address our hypothesis, we assessed leptin action on glucose homeostasis and plasma IGFBP-2 levels in both leptin-deficient ob/ob mice with a liver-specific loss of leptin signalling and ob/ob mice with a subdiaphragmatic vagotomy. We also examined whether restoring hepatic leptin signalling in leptin receptor-deficient db/db mice could increase plasma IGFBP-2 levels. RESULTS: Continuous leptin administration increased plasma IGFBP-2 levels in a dose-dependent manner, in association with reduced plasma glucose and insulin levels. Interestingly, leptin was still able to increase plasma IGFBP-2 levels and improve glucose homeostasis in both ob/ob mouse models to the same extent as their littermate controls. Further, restoration of hepatic leptin signalling in db/db mice did not increase either hepatic or plasma IGFBP-2 levels. CONCLUSIONS/INTERPRETATION: Taken together, these data indicate that hepatic leptin signalling and subdiaphragmatic vagal inputs are not required for leptin upregulation of plasma IGFBP-2 nor blood glucose lowering in ob/ob mice. PMID- 22202805 TI - Template directed reversible photochemical ligation of oligodeoxynucleotides. AB - We demonstrated that 5-vinyldeoxyuridine ((V)U) and 5-carboxyvinyldeoxyuridine ((CV)U) can be used to photoligate a longer oligonucleotide (ODN) from smaller ODNs on a template. By performing irradiation at 366 nm, these artificial nucleotides make photoligated ODNs with high efficiency without any side reactions. Moreover, by performing irradiation at 312 nm, these photoligated ODNs were reversed to the original ODN. (V)U needs to be irradiated 366 nm for 6 h, but (CV)U needs to be irradiated at 366 nm for 15 min. Finally, we made a self assembled structure with an ODN containing (CV)U and observed the photoligated ODN by photoirradiation. PMID- 22202806 TI - Synthesis of 1,4-disubstituted mono and bis-triazolocarbo-acyclonucleoside analogues of 9-(4-hydroxybutyl)guanine by Cu(I)-catalyzed click azide-alkyne cycloaddition. AB - A series of novel mono-1,2,3-triazole and bis-1,2,3-triazole acyclonucleoside analogues of 9-(4-hydroxybutyl)guanine was prepared via copper(I)-catalyzed 1,3 dipolar cycloaddition of N-9 propargylpurine, N-1-propargylpyrimidines/as triazine with the azido-pseudo-sugar 4-azidobutylacetate under solvent-free microwave conditions, followed by treatment with K(2)CO(3)/MeOH, or NH(3)/MeOH. All compounds studied in this work were screened for their antiviral activities [against human rhinovirus (HRV) and hepatitis C virus (HCV)] and antibacterial activities against a series of Gram positive and negative bacteria. PMID- 22202807 TI - Chromone and flavonoid alkaloids: occurrence and bioactivity. AB - The chromone and flavonoid alkaloids represent an unusual group of structurally diverse secondary metabolites, derived from the convergence of multiple biosynthetic pathways that are widely distributed through the plant and animal kingdoms. Many of them have been discovered through bioassay-guided chemical investigations of traditional medicines, suggesting potential therapeutic significance. Their unique structures and varied pharmacological activities may provide important new leads for the discovery of drugs with novel mechanisms of action. Potential therapeutic indications are as diverse as cancer and viral infections, inflammation and immunomodulation, neurological and psychiatric conditions, and diabetes. PMID- 22202808 TI - Molecular properties of water-unextractable proteoglycans from Hypsizygus marmoreus and their in vitro immunomodulatory activities. AB - Four proteoglycans were sequentially extracted from Hypsizygus marmoreus using 0.1 M NaOH (alkali-soluble proteoglycans [F1] and alkali-insoluble proteoglycans [F3]) and 0.1 M HCl (acid-soluble proteoglycans [F2] and acid-insoluble proteoglycans [F4]), and their structures and immunomodulatory activities were investigated. The proteoglycans were found to contain carbohydrates (19.8-82.4%) with various amounts of proteins (7.7-67.3%), and glucose was the major monosaccharide unit present, along with trace amounts of galactose. The molecular weights (Mw) and the radius of gyration (Rg) of these proteoglycans showed ranges of 16 * 10(4)-19,545 * 10(4) g/mol and 35-148 nm, respectively, showing significant variations in their molecular conformations. The backbones of F1 and F2 were mainly connected through a-(1->3), (1->4) and b-(1->6)-glycosidic linkages with some branches. The F1 and F2 proteoglycans significantly stimulated Raw264.7 cells to release nitric oxide (NO), prostaglandin E2 (PGE(2)) and various cytokines, such as IL-1beta, TNF-alpha and IL-6 by inducing their mRNA expressions. PMID- 22202809 TI - Disruption of a glutathione reductase encoding gene in Acremonium chrysogenum leads to reduction of its growth, cephalosporin production and antioxidative ability which is recovered by exogenous methionine. AB - Glutathione is a ubiquitous thiol in eukaryotic cells, and its high intracellular ratio of reduced form (GSH) to oxidized form (GSSG) is largely maintained by glutathione reductase (GR) using NADPH as electron donor. glrA, a glutathione reductase encoding gene, was found and cloned from Acremonium chrysogenum by searching its genomic sequence based on similarity. Its deduced protein exhibits high similarity to GRs of other eukaryotic organisms. Disruption of glrA resulted in lack of GR activity and accumulation of a high level of GSSG in A. chrysogenum. Overexpression of glrA dramatically enhanced GR activity and the ratio of GSH/GSSG in this fungus. The spore germination and hyphal growth of glrA disruption mutant was strongly reduced in chemical defined medium. Meanwhile, the mutant was more sensitive to hydrogen peroxide than the wild-type strain. We found that the glrA mutant recovered normal germination and growth by adding exogenous methionine (Met). Exogenous Met also enhanced the antioxidative ability of both the mutant and wild-type strain. GSH determination indicated that the total GSH and ratio of GSH/GSSG in the mutant or wild-type strain were significantly increased when addition of Met into the medium. The glrA mutant grew poorly and could not produce detectable cephalosporin in the fermentation medium without Met. However, its growth and cephalosporin production was restored with addition of exogenous Met. These results indicate that glrA is required for the normal growth and protection against oxidative damage in A. chrysogenum, and its absence can be complemented by exogenous Met. PMID- 22202810 TI - Nitric oxide alleviates heat stress-induced oxidative damage in Pleurotus eryngii var. tuoliensis. AB - High temperature is one of the major impediments limiting the growth and development of most edible fungi. While many efforts have been made in agricultural practice, the mechanism for resistance to high temperature remains elusive. Nitric oxide (NO) is considered as a signaling molecule involved in regulation of diverse physiological processes and stress responses in animals and plants. However, the role of NO in regulating fungal, particularly edible fungi, response to abiotic stresses, is unknown. The present study demonstrated that NO could effectively alleviate oxidative damage induced by heat stress in mycelia of Pleurotus eryngii var. tuoliensis. Heat stress induced increased thiobarbituric acid reactive substance (TBARS) content in mycelia, and the NO donor sodium nitroprusside (SNP) dramatically decreased TBARS content under high temperature. Moreover, the specific NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline-1-1-oxyl-3-oxide (cPTIO), could arrest the SNP action under the stress. Heat stress induced an increase in endogenous NO production in mycelial cells. However, the effect was significantly blocked by the NO synthase (NOS) inhibitor l-N(G)-nitroarginine methyl ester (l-NAME). In contrast, nitrate reductase (NR) activities were not obviously altered during heat stress. The NR suppressor tungstate had no effect on intracellular NO abundance under heat stress. These results suggest that NO can effectively protect mycelia of edible fungi from heat stress-induced oxidative damage and the NOS-dependent NO production may participate in the response to heat stress. PMID- 22202811 TI - Ribosomal biosynthesis of alpha-amanitin in Galerina marginata. AB - Amatoxins, including alpha-amanitin, are bicyclic octapeptides found in mushrooms (Agaricomycetes, Agaricales) of certain species in the genera Amanita, Galerina, Lepiota, and Conocybe. Amatoxins and the chemically similar phallotoxins are synthesized on ribosomes in Amanita bisporigera, Amanita phalloides, and Amanita ocreata. In order to determine if amatoxins are synthesized by a similar mechanism in another, distantly related mushroom, we obtained genome survey sequence data from a monokaryotic isolate of Galerinamarginata, which produces alpha-amanitin. The genome of G. marginata contains two copies of the alpha amanitin gene (GmAMA1-1 and GmAMA1-2). The alpha-amanitin proprotein sequences of G. marginata (35 amino acids) are highly divergent from AMA1 of A. bisporigera except for the toxin region itself (IWGIGCNP in single-letter amino acid code) and the amino acids immediately upstream (N[A/S]TRLP). G. marginata does not contain any related toxin-encoding sequences besides GmAMA1-1 and GmAMA1-2. DNA from two other alpha-amanitin-producing isolates of Galerina (G. badipes and G. venenata) hybridized to GmAMA1, whereas DNA from the toxin non-producing species Galerinahybrida did not. Expression of the GmAMA1 genes was induced by growth on low carbon. RNASeq evidence indicates that both copies of GmAMA1 are expressed approximately equally. A prolyl oligopeptidase (POP) is strongly implicated in processing of the cyclic peptide toxins of A. bisporigera and Conocybe apala. G. marginata has two predicted POP genes; one, like AbPOPB of A. bisporigera, is present only in the toxin-producing isolates of Galerina and the other, like AbPOPA of A. bisporigera, is present in all species. Our results indicate that G.marginata biosynthesizes amatoxins on ribosomes by a pathway similar to Amanita species, involving a genetically encoded proprotein of 35 amino acids that is post-translationally processed by a POP. However, due to the high degree of divergence, the evolutionary relationship between AMA1 in the genera Amanita and Galerina is unclear. PMID- 22202812 TI - A systematic survey of the response of a model NF-kappaB signalling pathway to TNFalpha stimulation. AB - White's lab established that strong, continuous stimulation with tumour necrosis factor-alpha (TNFalpha) can induce sustained oscillations in the subcellular localisation of the transcription factor nuclear factor kappaB (NF-kappaB). But the intensity of the TNFalpha signal varies substantially, from picomolar in the blood plasma of healthy organisms to nanomolar in diseased states. We report on a systematic survey using computational bifurcation theory to explore the relationship between the intensity of TNFalpha stimulation and the existence of sustained NF-kappaB oscillations. Using a deterministic model developed by Ashall et al. in 2009, we find that the system's responses to TNFalpha are characterised by a supercritical Hopf bifurcation point: above a critical intensity of TNFalpha the system exhibits sustained oscillations in NF-kB localisation. For TNFalpha below this critical value, damped oscillations are observed. This picture depends, however, on the values of the model's other parameters. When the values of certain reaction rates are altered the response of the signalling pathway to TNFalpha stimulation changes: in addition to the sustained oscillations induced by high-dose stimulation, a second oscillatory regime appears at much lower doses. Finally, we define scores to quantify the sensitivity of the dynamics of the system to variation in its parameters and use these scores to establish that the qualitative dynamics are most sensitive to the details of NF-kappaB mediated gene transcription. PMID- 22202844 TI - Molecular pharmacology of the mouse melatonin receptors MT1 and MT2. AB - The main melatonin receptors are two G-protein coupled receptors named MT(1) and MT(2). Having described the molecular pharmacology of the human versions of these receptors, we turned to two of the three species most useful in studying melatonin physiology: rat and sheep (a diurnal species used to understand the relationship between circadian rhythm and depression). We also employed previously used compounds to describe the mouse melatonin receptors; despite the early cloning of mouse receptors, few molecular pharmacology studies on these receptors exist. To our surprise, we detected no major differences between the data obtained from mice and those from other species. PMID- 22202867 TI - The 1st International Symposium on Fermented Meats, was held in Freising/Germany from April 13-16, 2011. Preface. PMID- 22202868 TI - Metabolism of nitrate in fermented meats: the characteristic feature of a specific group of fermented foods. AB - Within the universe of food fermentation processes the multi-purpose use of nitrate and/or nitrite is a unique characteristic of meat fermentations. These curing agents play a decisive role in obtaining the specific sensory properties, stability and hygienic safety of products such as fermented sausages, ham and, more recently, emulsion type of sausages. The use of nitrate is the traditional method in curing processes and requires its reduction to reactive nitrite. Thus, nitrate reduction is the key event that is exclusively performed by microorganisms. Under controlled fermentation conditions starter cultures are used that contain staphylococci and/or Kocuria varians, which in addition to strongly affecting sensory properties exhibit efficient nitrate reductase activity. To obtain clean label products some plant sources of nitrate have been in use. When producing thermally treated sausages (e.g. of emulsion type), starter cultures are used that form nitrite before cooking takes place. Staphylococci reduce nitrite to ammonia after nitrate has been consumed. K. varians is devoid of nitrite reductase activity. Nitrate and nitrite reductases are also present in certain strains of lactobacilli. It was shown that their application as starter cultures warrants efficient activity in sausages made with either nitrate or nitrite. NO is formed from nitrite in numerous chemical reactions among which disproportionation and reaction with reductants either added or endogenous in meat are of practical importance. Numerous nitrosation and nitrosylation reactions take place in the meat matrix among which the formation of nitrosomyoglobin is of major sensory importance. Safety considerations in meat fermentation relate to the safe nature of the starter organisms and to the use of nitrate/nitrite. Staphylococci ("micrococci") in fermented meat have a long tradition in food use but have not received the QPS status from the EFSA. They require, therefore, thorough assessment with regard to toxigenicity and pathogenicity determinants as well as presence of transferable antibiotic resistance. Nitrate and nitrite are still considered basically undesired in food. The main objections are based on their potential to form nitrosamines with carcinogenic potential. In view of new results from intensive research of NO, potential risks are opposed by positive effects on human health. PMID- 22202869 TI - Identification of staphylococci and dominant lactic acid bacteria in spontaneously fermented Swiss meat products using PCR-RFLP. AB - Pathogenic, spoilage, and technologically important microorganisms were monitored in 21 spontaneously fermented Swiss meat products manufactured with meat from wildlife or animals grown in natural habitat. Thereby, PCR-restriction fragment length polymorphism (RFLP) on rpoB and 16S rRNA gene sequences provided a powerful tool for fast and accurate identification of the main microbial population. Lactobacillus sakei and Lactobacillus curvatus dominated in fermented meat products followed by Staphylococcus species, which constituted 88.2% of all Gram-positive, catalase-positive cocci (GCC(+)) with cell counts varying from 2.6 to 7.0 log cfu/g during maturation. Staphylococcus equorum was prevalent in frequency and cell counts during maturation (18.0%; 5.0-7.3 log cfu/g) and in the end products (28.4%; 1.8-6.2 log cfu/g) implicating a new presumptive starter species for meat fermentation. Nine out of 14 end products indicated safety risks to consumers due to the high incidence of Staphylococcus saprophyticus or Staphylococcus epidermidis combined with cell counts of 7.4 and 4.9 log cfu/g, respectively. This fact was supported by the detection of Staphylococcus aureus and Enterobacteriaceae in ready-to-eat products strongly exceeding the tolerable limit of 2 log cfu/g. Spontaneously fermented meat products produced from wildlife or animals grown in natural habitats not only gave rise to hygienic and safety concerns but also provided new presumptive starter strains. PMID- 22202870 TI - Species diversity and metabolic impact of the microbiota are low in spontaneously acidified Belgian sausages with an added starter culture of Staphylococcus carnosus. AB - Quality of fermented sausages is affected by acidifying lactic acid bacteria (LAB) and colour- and flavour-promoting coagulase-negative staphylococci (CNS), whether or not used as starter culture. Artisan fermented sausages are often perceived as superior to industrial variants, partially because of the specific microbiota due to spontaneous acidification, which may be considered as an artisan characteristic. Therefore, two kinds of spontaneously acidified Belgian sausages were prepared (Belgian-type salami and Boulogne sausage), but with addition of a Staphylococcus carnosus culture. The Belgian-type salami was made from pork and beef, whereas the Boulogne sausage contained pork and horse meat. In all cases, Lactobacillus sakei was the dominant LAB species present on the raw materials and during fermentation, whereas enterococci remained present in the background. Enterobacteriaceae vanished after fermentation. The CNS species diversity on the raw materials was large and differed between the pork, beef, and horse meat. Nevertheless, this species diversity was annihilated during fermentation by the added S. carnosus culture. The volatiles fraction was mainly composed of aldehydes that originated from lipid oxidation and spices-derived compounds. Aromatic compounds that are typically associated to CNS activity, such as end-products from the metabolism of branched-chain amino acids, were not present in the Belgian-type salami and only marginally present in the Boulogne sausage. In conclusion, spontaneous acidification of Belgian-type fermented sausages leads to dominance of L. sakei and is no guarantee for bacterial contribution to the aroma profile when S. carnosus is added as a starter culture. PMID- 22202871 TI - Catalase-positive cocci in fermented sausage: Variability due to different pork breeds, breeding systems and sausage production technology. AB - The aim of this study was to compare the ecology of catalase-positive cocci (CPC) present in traditional fermented sausages produced using different breeds of pork, each of which was raised in two different environments and processed using two different technologies. Semi-quantitative molecular methods were used to determine bacterial identities. Almost all fermentations were characterised by a significant increase in CPC during the first few days of fermentation, reaching values of 10(5)-10(6) cfu g(-1) within 3 days. Staphylococcus xylosus and Staphylococcus equorum species, which were detected over the course of fermentation, were found to be the predominant population in all the monitored fermentation. Staphylococcus haemolyticus, Staphylococcus lentus, Micrococcus luteus, Macrococcus caseolyticus and Staphylococcus succinus were also present, but their concentrations were found to vary under the different experimental conditions. Using cluster analysis, we concluded that a plant-specific CPC ecology existed. In addition, the breed of pork used for production was found to influence the presence of some CPC species. However, from this study, it was not possible to reach the same conclusion regarding the breeding system used. PMID- 22202872 TI - Fingerprint of lactic acid bacteria population in beef carpaccio is influenced by storage process and seasonal changes. AB - We have investigated the population structure of lactic acid bacteria (LAB) for several beef carpaccio available on the market with the purpose of comparing the effect of storage process (modified-atmosphere packaging and vacuum-packaging) and of seasonal changes on this microbial population. Out of 60 samples we have characterised 214 isolates accounting for 10 LAB species and 35 isolates accounting for 11 non-LAB species. Lactobacillus sakei, Leuconostoc carnosum and Leuconostoc mesenteroides were the most prevailing LAB species with a frequency of identification within 66%, 62% and 52% of the samples respectively. These 3 species were also characterised by a phenotypic intra-species diversity of isolates based on colony morphology. We showed that the prevalence was increased 1.5 fold for L. sakei and L. mesenteroides during the summer sampling in comparison to the spring or the fall sampling suggesting an environmental origin of these two species. Seasonal variations were also observed for the prevalence of Lactobacillus fuchuensis and L. carnosum in spring (2- and 1.5-fold increase, respectively) and of Brochothrix thermosphacta in fall (6-fold increase). Finally, we demonstrated that the growth potential after the sell-by-date was favourable of 1.25 log(10) cfu g(-1) to Leuconostoc spp. in modified-atmosphere packaging and of 1.38 log(10) cfu g(-1) to Lactobacillus spp. in vacuum packaging. In conclusion, we show that important and unsuspected traits in bacterial population dynamics can be unravelled by large sampling strategies. We discuss about the need to take this assessment into account for further studies on bacterial ecosystems of meat. PMID- 22202873 TI - Intraspecies diversity of Lactobacillus sakei response to oxidative stress and variability of strain performance in mixed strains challenges. AB - Lactobacillus sakei is a meat-borne lactic acid bacterium species exhibiting a wide genomic diversity. We have investigated the diversity of response to various oxidative compounds, between L. sakei strains, among a collection representing the genomic diversity. We observed various responses to the different compounds as well as a diversity of response depending on the aeration conditions used for cell growth. A principal component analysis revealed two main phenotypic groups, partially correlating with previously described genomic clusters. We designed strains mixes composed of three different strains, in order to examine the behavior of each strain, when cultured alone or in the presence of other strains. The strains composing the mixtures were chosen as diverse as possible, i.e. exhibiting diverse responses to oxidative stress and belonging to different genomic clusters. Growth and survival rates of each strain were monitored under various aeration conditions, with or without heme supplementation. The results obtained suggest that some strains may act as "helper" or "burden" strains depending on the oxidative conditions encountered during incubation. This study confirms that resistance to oxidative stress is extremely variable within the L. sakei species and that this property should be considered when investigating starter performance in the complex meat bacterial ecosystems. PMID- 22202874 TI - Comparison of different IlvE aminotransferases in Lactobacillus sakei and investigation of their contribution to aroma formation from branched chain amino acids. AB - Branched chain aminotransferases (IlvE/BcaT), specific for leucine, isoleucine, and valine initialize the formation of methyl-branched volatiles, which are strongly linked to the typical aroma of cured meat products. Lactobacillus sakei, one of the dominating lactic acid bacteria species for meat fermentations and commonly used as starter lacks this enzyme, whereas the presence of IlvE has been reported for Lactobacillus paracasei, a non-starter lactic acid bacterium occurring in meat products and with probiotic properties, in Staphylococcus carnosus, a catalase positive cocci also used as starter for meat products, and in Enterococcus faecalis belonging to the natural microbiota of meat and that may impact on the aroma of fermented meat products. The genes for branched-chain aminotransferases of these three bacterial species were used to complement the IlvE negative strain L. sakei TMW1.1322. For that purpose, ilvE genes were heterologously expressed in L. sakei TMW1.1322 under the control of the constitutive L. sakei promotor pldhL via replicative plasmids and chromosomal integration. To examine effective expression the constructs were transcriptionally coupled to mCherry, a red fluorescent protein. Aminotransferase activities and formation of volatile compounds were compared. Activities of L. sakei ArcT and AspD purified enzymes were also measured. Conversion of branched chain amino acids to the corresponding alpha-keto-acids was significantly increased in all transformants expressing the ilvE genes. The activity of IlvE obtained from L. paracasei was highest. Substrate specificities of IlvEs towards leucine, isoleucine and valine were similar. However, enhanced transaminase activities did not increase formation of the respective methyl-branched volatiles by recombinant L. sakei strains. This indicates that presence of ilvE cannot be the only bottleneck in aroma formation from amino acids. Amino acid or peptide uptake into the cell via specific transport systems and the conversion of alpha keto acids to the corresponding aldehydes, alcohols and carboxylic acids must be considered as further limiting steps. PMID- 22202875 TI - Metabolism of amino acids, dipeptides and tetrapeptides by Lactobacillus sakei. AB - The microbial degradation of proteins, peptides and amino acids generates volatiles involved in the typical flavor of dry fermented sausage. The ability of three Lactobacillus sakei strains to form aroma compounds was investigated. Whole resting cells were fermented in phosphate buffer with equimolar amounts of substrates consisting of dipeptides, tetrapeptides and free amino acids, respectively. Dipeptides disappeared quickly from the solutions whereas tetrapeptides were only partially degraded. In both approaches the concentration of free amino acids increased in the reaction mixture but did not reach the equimolar amount of the initial substrates. When free amino acids were fed to the bacteria their levels decreased only slightly. Although peptides were more rapidly degraded and/or transported into the cells, free amino acids produced higher amounts of volatiles. It is suggested, that after transport into the cell peptides are only partially hydrolyzed to their amino acids, while the rest is metabolized via alternative metabolic pathways. The three L. sakei strains differed to some extend in their ability to metabolize the substrates to volatile compounds. In a few cases this was due to the position of the amino acids within the peptides. Compared to other starter cultures used for the production of dry fermented sausages, the metabolic impact of the L. sakei strains on the formation of volatiles was very low. PMID- 22202876 TI - Production of volatile compounds by Lactobacillus sakei from branched chain alpha keto acids. AB - Lactobacillus sakei belongs to the main flora of raw fermented sausages and is used as starter culture. Bacterial starter cultures can convert amino acids to alpha-keto acids by aminotransferases. These alpha-keto acids are the precursors of aroma active aldehydes, alcohols and carboxylic acids. In this study the formation of aldehydes, alcohols and carboxylic acids from leucine, isoleucine, valine and the corresponding alpha-keto acids are analysed in model fermentations with two different strains of L sakei. In the absence and upon addition of leucine, isoleucine and valine they produced 1 MUg/ml 3-methylbutanoic, 0.2 MUg/ml 2-methylbutanoic acid and 3 MUg/ml 2-methylpropanoic acid, respectively. Upon addition of alpha-ketoisocaproic acid, alpha-keto-3-methyl-pentanoic acid or alpha-ketoisovaleric acid the amount of the corresponding carboxylic acid was increased to 40 MUg/ml 3-methylbutanoic acid, 20 MUg/ml 2-methylbutanoic acid and 35 MUg/ml 2-methylpropanoic acid. The response patterns of the strains and amounts of carboxylic acids produced were similar. This behaviour was typical when compared with other strains of L. sakei and suggests general lack of transaminase activity and a limit in the transport of branched chain amino acids and their conversion to volatiles, some of which can contribute to the aroma of fermented sausages. PMID- 22202877 TI - Prevention of Aspergillus ochraceus growth on and Ochratoxin a contamination of sausages using ozonated air. AB - Mycotoxigenic moulds can grow on the surface of sausages and reduce the safety of these sausages for consumption. The aim of this study was to prevent the growth of Aspergillus ochraceus and the presence of Ochratoxin A (OTA) on the surface of Milano-type sausages using ozonated air. Spores of A. ochraceus were used to inoculate the casings of the sausages after casing. A portion of the lot (35 samples) was ripened in typical rooms, and another portion (35 samples) was dried and ripened in a separate room that was treated with gaseous ozone. The gas was delivered at night (8 h/day) at a concentration of ~1 ppm. The temperature and relative humidity during the drying and ripening were the same for both rooms. Our results demonstrate that the gaseous ozone treatment prevented the growth of A. ochraceus and, consequently, the presence of OTA. In contrast, A. ochraceus grew and produced OTA on the untreated sausages. Moreover, the use of ozone did not influence the ripening, physico-chemical parameters, peroxide value or sensorial characteristics of the sausages. PMID- 22202878 TI - The biosynthesis of ochratoxin A by Penicillium as one mechanism for adaptation to NaCl rich foods. AB - Penicillium.nordicum is an ochratoxin A producing filamentous fungus, which is adapted to sodium chloride and protein rich food environments like certain cheeses or dry cured meats. Penicillium.verrucosum usually occurs on cereals but can also be isolated from brined olives. It could be shown that sodium chloride has a profound influence on the regulation of ochratoxin A biosynthesis in both Penicillium species. High amounts of ochratoxin A are produced by P. nordicum over a wide concentration range of NaCl (5-100 g/l) with a weak optimum at about 20 g/l after growth on YES medium. P. verrucosum shifts secondary metabolite biosynthesis after growth on YES medium from citrinin at low to ochratoxin at elevated NaCl concentrations. The ochratoxin A biosynthesis of P. nordicum is accompanied by an induction of the otapksPN gene, the gene of the ochratoxin A polyketide synthase. A mutant strain unable to produce ochratoxin showed a drastic growth reduction under high NaCl conditions. Determination of the dry weight and the chloride content in the mycelium of the P. nordicum wild type strain and a non-ochratoxin A producing mutant strain showed a much higher increase of both parameters in the mutant compared to the wild type. These results suggest, that the constant biosynthesis and excretion of ochratoxin A, which itself contains a chloride atom, ensures a partial chloride homeostasis in the fungal cell. This mechanism may support the adaptation of ochratoxin A producing Penicillia to NaCl rich foods. PMID- 22202879 TI - Traditional 'air-dried' fermented sausages from Central Germany. AB - Traditional varieties of fermented pork sausages from Central Germany are different from related meat products in various aspects. First, they are prepared from "warm" pork immediately after slaughter. The meat is then minced, mixed with spices and minimal amounts of sugars, salt and nitrate, and the stuffed sausages ripen for a minimum of 6-8 weeks at temperatures below 15 degrees C. Second, surface mould growth during ripening is regularly removed or suppressed. The manufacturing methods require a minimum of investments and labour and reflect the socio-economic situation in the manufacturing area. The sausages have a good record of safety, and a preliminary risk assessment indicates that pathogens are kept under sufficient control by the extended ripening at low temperatures. Small scale (artisanal) manufacture of these products is only possible with a flexible interpretation of the hygienic principles set up in current legislation. PMID- 22202880 TI - Effect of brine thawing/salting on endogenous enzyme activity and sensory quality of Iberian dry-cured ham. AB - Simultaneous brine thawing/salting process was applied as an alternative to traditional pile salting process using 51 frozen Iberian hams. The effect of this type of salting process on endogenous enzyme activity and sensory quality of Iberian dry-cured hams was analysed. The frozen hams were simultaneously thawed and salted with saturated brine, with and without vacuum pulses, and were compared to hams thawed under refrigeration and traditionally salted. The peptidase and lipase activities were measured at the end of salting and post salting stages. The activity of cathepsin B+L was reduced in the two brine salted batches while few differences among batches were observed for the other peptidases. Several lipase activities were significantly reduced in the two brine salted batches. The brine thawed processing affected the free fatty acid content at the different stages although the differences were more appreciated at the beginning of the process and no differences were observed at the end. The long ripening time makes these differences negligible and the consumer did not appreciate any differences between the sensory quality of Iberian brine/thawed hams and traditional Iberian thawed pile salted hams. PMID- 22202881 TI - The effects of different levels of orange fiber and fat on microbiological, physical, chemical and sensorial properties of sucuk. AB - The effects of orange fiber and fat levels on the physical, chemical and microbiological properties of sucuk (Turkish dry-fermented sausage) were investigated. Different levels of orange fiber (0, 2 and 4%) were added to sucuk batters with different levels of fat (10, 15 and 20%). Sucuk samples were analyzed during ripening. Lactic acid bacteria, Micrococcus/Staphylococcus and pH value were effected very significantly by orange fiber. Orange fiber caused a decrease in residual nitrite levels and an increase in the TBARS values. L(*) and b(*) values of sucuk samples increased with the use of fiber. Fiber use also decreased the cooking loss. No statistically significant difference was found between control and 2% fiber groups in terms of texture, color, odor taste and general acceptability scores. While fat levels had significant effects on cooking loss, taste and L(*) values, ripening time effected all analyzed parameters. PMID- 22202882 TI - Neural correlates of numbers and mathematical terms. AB - Numerical processing has been demonstrated to be subserved typically by the brain regions around the bilateral intraparietal sulcus (IPS). The goal of the current study was to investigate whether the processing of mathematical terms shared the same brain regions with numerical processing. Healthy adult participants performed semantic distance judgment tasks on five types of materials, including geometric terms, algebraic terms, linguistic terms, words for tools and other common objects, and Arabic numbers. Brain activation was measured with functional magnetic resonance imaging (fMRI). The results showed that geometric terms had greater activation than algebraic terms, linguistic terms and tool words in the horizontal IPS, but algebraic terms did not have greater activation than linguistic terms and tool words in this region. Arabic numbers showed greater activation than non-number materials (including geometric terms, algebraic terms, linguistic terms and tool words) in the bilateral IPS, right inferior frontal gyrus and bilateral middle frontal gyrus, but the non-number materials showed stronger activation in the left inferior frontal gyrus and left middle temporal gyrus. These results suggest that the brain area for the processing of numbers (the left IPS) seems to be involved in semantic processing of geometric terms, but not that of other mathematical terms such as algebraic terms. Both algebraic and geometric terms share similar brain organization with basic semantic processing in the left temporal and frontal regions. PMID- 22202886 TI - Adherence to streptococci facilitates Fusobacterium nucleatum integration into an oral microbial community. AB - The development of multispecies oral microbial communities involves complex intra and interspecies interactions at various levels. The ability to adhere to the resident bacteria or the biofilm matrix and overcome community resistance are among the key factors that determine whether a bacterium can integrate into a community. Fusobacterium nucleatum is a prevalent Gram-negative oral bacterial species that is able to adhere to a variety of oral microbes and has been implicated in playing an important role in the establishment of multispecies oral microbial community. However, the majority of experiments thus far has focused on the physical adherence between two species as measured by in vitro co-aggregation assays, while the community-based effects on the integration of F. nucleatum into multispecies microbial community remains to be investigated. In this study, we focus on community integration of F. nucleatum. We demonstrated using an established in vitro mice oral microbiota (O-mix) that the viability of F. nucleatum was significantly reduced upon addition to the O-mix due to cell contact-dependent induction of hydrogen peroxide (H(2)O(2)) production by oral community. Interestingly, this inhibitory effect was significantly alleviated when F. nucleatum was allowed to adhere to its known interacting partner species (such as Streptococcus sanguinis) prior to addition. Furthermore, this aggregate formation-dependent protection was absent in the F. nucleatum mutant strain DeltaFn1526 that is unable to bind to a number of Gram-positive species. More importantly, this protective effect was also observed during integration of F. nucleatum into a human salivary microbial community (S-mix). These results suggest that by adhering to other oral microbes, F. nucleatum is able to mask the surface components that are recognized by H(2)O(2) producing oral community members. This evasion strategy prevents detection by antagonistic oral bacteria and allows integration into the developing oral microbial community. PMID- 22202887 TI - Seasonal dynamics and modeling of a Vibrio community in coastal waters of the North Sea. AB - Vibrio species are ubiquitously distributed in marine waters all over the world. High genome plasticity due to frequent mutation, recombination, and lateral gene transfer enables Vibrio to adapt rapidly to environmental changes. The genus Vibrio comprises several human pathogens, which commonly cause outbreaks of severe diarrhea in tropical regions. In recent years, pathogenic Vibrio emerged also in coastal European waters. Little is known about factors driving the proliferation of Vibrio spp. in temperate waters such as the North Sea. In this study a quantification of Vibrio in the North Sea and their response to biotic and abiotic parameters were assessed. Between January and December 2009, Vibrio at Helgoland Roads (North Sea, Germany) were quantified using fluorescence in situ hybridization. Vibrio numbers up to 3.4 * 10(4) cells * mL(-1) (2.2% of total microbial counts) were determined in summer, but their abundance was significantly lower in winter (5 * 10(2) cells * mL(-1)). Correlations between Vibrio and nutrients (SiO(2), PO(4) (3-), DIN), Secchi depth, temperature, salinity, and chlorophyll a were calculated using Spearman rank analysis. Multiple stepwise regression analysis was carried out to analyze the additive influence of multiple factors on Vibrio. Based on these calculations, we found that high water temperature and low salinity best explained the increase of Vibrio cell numbers. Other environmental parameters, especially nutrients and chlorophyll a, also had an influence. All variables were shown to be subject to the overall seasonal dynamics at Helgoland Roads. Multiple regression models could represent an efficient and reliable tool to predict Vibrio abundances in response to the climate change in European waters. PMID- 22202888 TI - Macromolecular response of individual algal cells to nutrient and atrazine mixtures within biofilms. AB - Pollutant effects on biofilm physiology are difficult to assess due to differential susceptibility of species and difficulty separating individual species for analysis. Also, measuring whole assemblage responses such as metabolism can mask species-specific responses, as some species may decrease and others increase metabolic activity. Physiological responses can add information to compositional data, and may be a more sensitive indicator of effect. It is difficult, however, to separate individual species for biochemical analyses. Agricultural runoff often contains multiple pollutants that may alter algal assemblages in receiving waters. It is unclear how mixtures containing potential algal growth stimulators and inhibitors (e.g., nutrients and herbicides) alter algal assemblage structure and function. In research presented here, algal biofilms were exposed to nutrients, atrazine, and their mixtures, and assemblage level structural and functional changes were measured. Synchrotron infrared microspectroscopy (IMS) was used to isolate the biochemical changes within individual cells from a dominant species of a green alga (Mougeotia sp.), a diatom (Navicula sp.), and a cyanobacterium (Hapalosiphon sp.). At the assemblage level, mixtures generally increased algal biovolume, decreased chlorophyll a, and had no effect on metabolism or ammonium uptake. Navicula had a strong negative response to atrazine initially, but later was more affected by nutrients. Hapalosiphon responded positively to both atrazine and nutrients, and Mougeotia did not exhibit any biochemical trends. Generally, biochemical changes in each species were similar to cells experiencing low stress conditions, with increased relative protein and decreased relative lipid. IMS provided direct evidence that individual species in a natural biofilm can have unique responses to atrazine, nutrients, and mixtures. Results suggest that the initial benthic community composition should have a strong influence on the overall impact of agricultural pollutants. PMID- 22202889 TI - Burning fire-prone Mediterranean shrublands: immediate changes in soil microbial community structure and ecosystem functions. AB - Wildfires subject soil microbes to extreme temperatures and modify their physical and chemical habitat. This might immediately alter their community structure and ecosystem functions. We burned a fire-prone shrubland under controlled conditions to investigate (1) the fire-induced changes in the community structure of soil archaea, bacteria and fungi by analysing 16S or 18S rRNA gene amplicons separated through denaturing gradient gel electrophoresis; (2) the physical and chemical variables determining the immediate shifts in the microbial community structure; and (3) the microbial drivers of the change in ecosystem functions related to biogeochemical cycling. Prokaryotes and eukaryotes were structured by the local environment in pre-fire soils. Fire caused a significant shift in the microbial community structure, biomass C, respiration and soil hydrolases. One-day changes in bacterial and fungal community structure correlated to the rise in total organic C and NO(3)(-)-N caused by the combustion of plant residues. In the following week, bacterial communities shifted further forced by desiccation and increasing concentrations of macronutrients. Shifts in archaeal community structure were unrelated to any of the 18 environmental variables measured. Fire induced changes in the community structure of bacteria, rather than archaea or fungi, were correlated to the enhanced microbial biomass, CO(2) production and hydrolysis of C and P organics. This is the first report on the combined effects of fire on the three biological domains in soils. We concluded that immediately after fire the biogeochemical cycling in Mediterranean shrublands becomes less conservative through the increased microbial biomass, activity and changes in the bacterial community structure. PMID- 22202890 TI - Application of triphasic pulses with adjustable phase amplitude ratio (PAR) for cochlear ECAP recording: II. recovery functions. AB - Triphasic electrical stimulation pulses with an adjustable phase amplitude ratio (PAR) can reduce stimulus artifacts in electrically evoked compound actions potentials (ECAPs) recording in the cochlea (see companion paper Bahmer and Baumann, submitted for publication). The present study describes the application of triphasic pulses in forward masking paradigms for recording recovery functions. Masking was found to be most effective using equal masker-probe PAR settings. Results were compared with data applying artifact cancellation strategy for biphasic pulses according to Miller et al. (2000). Measurements were accomplished in five subjects (S1-S5) with an equal masker-probe PAR setting, whereby more detailed test series were carried out in one subject (S1). All subjects were users of MED-EL SONATAti100 or PULSARci100 cochlear implants (Innsbruck, Austria). Parameters like asymptote level, absolute refractory period and time constant were determined by fitting exponential functions to the recovery functions. Detailed measurements collected on 11 electrode locations in subject S1 showed similar parameter profiles on basal electrode contacts for both triphasic and Miller artifact cancellation methods, whereas apical/middle electrode contacts differed in part largely. Compared to Miller's artifact cancellation method estimated asymptote levels were lower with triphasic stimulation; the estimated absolute refractory period and time constants were estimated higher on apical electrodes. Results obtained in subjects S2-S5 showed considerable variances and a proper parametrization of the recovery function was possible only very selectively for triphasic pulse stimulation. In these cases, congruencies in estimated asymptote levels and time constants were found when triphasic stimulation and biphasic stimulation according to Miller were compared. PMID- 22202891 TI - Identification of plant RAD52 homologs and characterization of the Arabidopsis thaliana RAD52-like genes. AB - RADiation sensitive52 (RAD52) mediates RAD51 loading onto single-stranded DNA ends, thereby initiating homologous recombination and catalyzing DNA annealing. RAD52 is highly conserved among eukaryotes, including animals and fungi. This article reports that RAD52 homologs are present in all plants whose genomes have undergone extensive sequencing. Computational analyses suggest a very early RAD52 gene duplication, followed by later lineage-specific duplications, during the evolution of higher plants. Plant RAD52 proteins have high sequence similarity to the oligomerization and DNA binding N-terminal domain of RAD52 proteins. Remarkably, the two identified Arabidopsis thaliana RAD52 genes encode four open reading frames (ORFs) through differential splicing, each of which specifically localized to the nucleus, mitochondria, or chloroplast. The A. thaliana RAD52-1A ORF provided partial complementation to the yeast rad52 mutant. A. thaliana mutants and RNA interference lines defective in the expression of RAD52-1 or RAD52-2 showed reduced fertility, sensitivity to mitomycin C, and decreased levels of intrachromosomal recombination compared with the wild type. In summary, computational and experimental analyses provide clear evidence for the presence of functional RAD52 DNA-repair homologs in plants. PMID- 22202903 TI - The three isoforms of nitric oxide synthase distinctively affect mouse nocifensive behavior. AB - Nitric oxide synthases (NOSs) have been shown to modulate thermal hyperalgesia and mechanical hypersensitivity in inflammatory and neuropathic pain. However, little is known about the effect of NOSs on baseline function of sensory nerve fibers. Using genetic deficiency and pharmacologic inhibition of NOSs, we examined the impact of the three isoforms NOS1, NOS2, and NOS3 on baseline nocifensive behavior by measuring current vocalization threshold in response to electrical stimulation at 5, 250, 2000 Hz that preferentially stimulate C, Adelta, and Abeta fibers. In response to 5, 250 and 2000 Hz, NOS1-deficient animals had significantly higher current vocalization thresholds compared with wild-type. Genetic deficiency of NOS2 was associated with higher current vocalization thresholds in response to 5 Hz (C-fiber) stimulation. In contrast, NOS3-deficient animals had an overall weak trend toward lower current vocalization thresholds at 5 Hz and significantly lower current vocalization threshold compared with wild-type animals at 250 and 2000 Hz. Therefore, NOSs distinctively affect baseline mouse current vocalization threshold and appear to play a role on nocifensive response to electrical stimulation of sensory nerve fibers. PMID- 22202904 TI - Ozone and biofiltration as an alternative to reverse osmosis for removing PPCPs and micropollutants from treated wastewater. AB - This pilot-scale research project investigated and compared the removal of pharmaceuticals and personal care products (PPCPs) and other micropollutants from treated wastewater by ozone/biofiltration and reverse osmosis (RO). The reduction in UV254 absorbance as a function of ozone dose correlated well with the reduction in nonbiodegradable dissolved organic carbon and simultaneous production of biodegradable dissolved organic carbon (BDOC). BDOC analyses demonstrated that ozone does not mineralize organics in treated wastewater and that biofiltration can remove the organic oxidation products of ozonation. Biofiltration is recommended for treatment of ozone contactor effluent to minimize the presence of unknown micropollutant oxidation products in the treated water. Ozone/biofiltration and RO were compared on the basis of micropollutant removal efficiency, energy consumption, and waste production. Ozone doses of 4-8 mg/L were nearly as effective as RO for removing micropollutants. When wider environmental impacts such as energy consumption, water recovery, and waste production are considered, ozone/biofiltration may be a more desirable process than RO for removing PPCPs and other trace organics from treated wastewater. PMID- 22202905 TI - Upregulation of presynaptic mGluR2, but not mGluR3 in the epileptic medial perforant path. AB - Presynaptic metabotropic glutamate receptors (mGluRs) at glutamatergic synapses play a major role in governing release probability. Previous reports indicated a downregulation of group III mGluRs at the lateral perforant path-granule cell synapse in the chronically epileptic hippocampus. Here, we investigated the mGluR dependent presynaptic inhibition at the medial perforant path-granule cell synapse in the pilocarpine-treated chronically epileptic rat. The specific group II mGluR agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV, 10MUM) significantly depressed medial perforant path-evoked responses in control slices, but significantly more so in epileptic tissue. This depression was accompanied by a significant increase of the paired-pulse ratio in both animal groups indicating a presynaptic mechanism. Moreover, we also found that this significantly enhanced DCG-IV effect in the medial perforant path recorded in slices from pilocarpine-treated rats was due to a significant increase of mGluR2, but not mGluR3 transcripts in the entorhinal cortex using quantitative real-time reverse transcriptase-PCR. Immunohistochemistry confirmed the increased expression of group II mGluRs in the epileptic medial molecular layer. These results demonstrate that chronic epilepsy not only causes downregulation of mGluRs in the hippocampus, but may also lead to enhanced expression of these receptors - at least in the medial perforant path. PMID- 22202906 TI - Adoptive T-cell therapy for malignant melanoma patients with TILs obtained by ultrasound-guided needle biopsy. AB - Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) can mediate objective responses in up to 50% of malignant melanoma patients with a good performance status refractory to standard treatments. Current protocols for generation of TILs rely on open surgery for access to tumor tissue. We obtained tumor material by ultrasound-guided core needle biopsy or surgery from melanoma patients with progressive disease and were able to isolate >5 * 10(6) TILs from 23 of 24 patients who were subsequently treated with these cells. One-third of the individual TIL-positive cultures displayed interferon gamma activity after stimulation with relevant melanoma cell lines. When expanded TILs were used for treatment in combination with daily low dose s.c. IL-2 after prior lymphodepleting chemotherapy, we observed objective clinical responses in one patient treated with TILs obtained from surgery and 4 patients treated with TILs from core biopsies. The results of this study demonstrate for the first time the potential of core biopsies for generation of relevant numbers of TILs that can mediate objective responses in patients with metastatic malignant melanoma. Ultrasound-guided core needle biopsy is a robust, safe and inexpensive approach to obtain tumor tissue for TIL generation, and is especially valuable in instances where surgery is contraindicated. PMID- 22202907 TI - Cellular and transcriptomic analysis of human mesenchymal stem cell response to plasma-activated hydroxyapatite coating. AB - Atmospheric pressure plasma has recently emerged as a technique with a promising future in the medical field. In this work we used the technique as a post deposition modification process as a means to activate hydroxyapatite (HA) coatings. Contact angle goniometry, optical profilometry, scanning electron microscopy morphology imaging and X-ray photoelectron spectroscopy analysis demonstrate that surface wettability is improved after treatment, without inducing any concomitant damage to the coating. The protein adsorption pattern has been found to be preferable for MSC, and this may result in greater cell attachment and adhesion to plasma-activated HA than to untreated samples. Cell cycle distribution analysis using flow cytometry reveals a faster transition from G(1) to S phase, thus leading to a faster cell proliferation rate on plasma activated HA. This indicates that the improvement in surface wettability independently enhances cell attachment and cell proliferation, which is possibly mediated by FAK phosphorylation. Pathway-specific polymerase chain reaction arrays revealed that wettability has a substantial influence on gene expression during osteogenic differentiation of human MSC. Plasma-activated HA tends to enhance this process by systemically deregulating multiple genes. In addition, the majority of these deregulated genes had been appropriately translated, as confirmed by ELISA protein quantification. Lastly, alizarin red staining showed that plasma-activated HA is capable of improving mineralization for up to 3 weeks of in vitro culture. It was concluded from this study that atmospheric pressure plasma is a potent tool for modifying the biological function of a material without causing thermal damage, such that adhesion molecules and drugs might be deposited on the original coating to improve performance. PMID- 22202908 TI - Kinetics and the role of off-stoichiometry in the environmentally driven phase transformation of commercially available zirconia femoral heads. AB - The low-temperature polymorphic transformation behavior of two types of commercially available femoral head, both made of 3 mol.% Y(2)O(3)-stabilized tetragonal ZrO(2) polycrystals (3Y-TZP), was examined by in vitro experiments. Both materials contained a small amount (0.25 wt.%) of Al(2)O(3), but they differed slightly in their SiO(2) impurity content, in the morphology and crystallinity of the dispersed Al(2)O(3) phase, and in grain size. In vitro experiments were conducted in a water-vapor environment at temperatures in the range 90-134 degrees C and for periods of time up to 500 h. Despite the materials having the same nominal composition, quite different behaviors were found in the hydrothermal environment for the two types of femoral head investigated. A phenomenological description of the kinetics of monoclinic nuclei formation/growth led to the experimental determination of activation energy values for the environmentally driven polymorphic transformation. From the material physics viewpoint, cathodoluminescence spectroscopy enabled us to rationalize the role of surface stoichiometry on the mechanisms leading to polymorphic transformation. Spectroscopic experiments unveiled some new relevant aspects of surface off-stoichiometry, which lie behind the different phase transformation kinetics experienced by the investigated femoral heads. PMID- 22202910 TI - Cold atmospheric pressure gas plasma enhances the wear performance of ultra-high molecular weight polyethylene. AB - Ultra-high molecular weight polyethylene (UHMWPE) is frequently employed in joint replacements because of its high biocompatibility; however, this material does not exhibit particularly strong wear performance, thus potentially reducing the longevity of such devices. Numerous techniques have been investigated to increase the resistance to wear of UHMWPE, but they are all based on expensive machinery and require a high level of safety precautions. Cold atmospheric pressure gas plasma treatment is an inexpensive process that has been used as a surface modification method and as a sterilization technique. We demonstrate for the first time that a helium/oxygen cold atmospheric pressure gas plasma can be used to enhance the wear performance of UHMWPE without affecting the cytocompatibility of the material. The exposure to a cold atmospheric pressure gas plasma results in a greater level of crosslinking of the polyethylene chains. As a consequence of the higher crosslinking, the material stiffness of the treated surface is increased. PMID- 22202909 TI - Aligned silk-based 3-D architectures for contact guidance in tissue engineering. AB - An important challenge in the biomaterials field is to mimic the structure of functional tissues via cell and extracellular matrix (ECM) alignment and anisotropy. Toward this goal, silk-based scaffolds resembling bone lamellar structure were developed using a freeze-drying technique. The structure could be controlled directly by solute concentration and freezing parameters, resulting in lamellar scaffolds with regular morphology. Different post-treatments, such as methanol, water annealing and steam sterilization, were investigated to induce water stability. The resulting structures exhibited significant differences in terms of morphological integrity, structure and mechanical properties. The lamellar thicknesses were ~2.6 MUm for the methanol-treated scaffolds and ~5.8 MUm for water-annealed. These values are in the range of those reported for human lamellar bone. Human bone marrow-derived mesenchymal stem cells (hMSC) were seeded on these silk fibroin lamellar scaffolds and grown under osteogenic conditions to assess the effect of the microstructure on cell behavior. Collagen in the newly deposited ECM was found aligned along the lamellar architectures. In the case of methanol-treated lamellar structures, the hMSC were able to migrate into the interior of the scaffolds, producing a multilamellar hybrid construct. The present morphology constitutes a useful pattern onto which hMSC cells attach and proliferate for guided formation of a highly oriented extracellular matrix. PMID- 22202921 TI - Ocular manifestation of systemic lupus erythematosus. AB - The purpose of this study is to determine the ocular manifestations of systemic lupus erythematosus and its correlation with the disease activity. Fifty-two lupus patients and 20 healthy controls were included in this study. All patients have undergone complete rheumatological, neurological, and ophthalmic examination including visual acuity, slit-lamp examination of the anterior segment, and dry eye evaluation using Rose Bengal stain and Schirmer test. Fundus examination and fundus photography were done to the suspected cases. Eighteen patients (34.6%) had ocular lesion, from which only 13 (25%) patients were symptomatic. Keratoconjunctivitis was the most common ocular lesion. There was a highly statistically significant difference between patients and controls as regarding all ocular lesions (P > 0.0001). There was good correlation between disease activity index and presence of ocular lesion. Ocular manifestations are common in SLE patients. Lupus retinopathy may reflect systemic, particularly CNS, vascular damage. PMID- 22202922 TI - Retracted article: The clinical and laboratory features in Turkish systemic sclerosis patients: a single-center experience. PMID- 22202940 TI - Phytochemical composition of "mountain tea" from Sideritis clandestina subsp. clandestina and evaluation of its behavioral and oxidant/antioxidant effects on adult mice. AB - PURPOSE: The goals of this study were to monitor the effect of drinking of herbal tea from Sideritis clandestina subsp. clandestina for 6 weeks on behavioral and oxidant/antioxidant parameters of adult male mice and also to evaluate its phytochemical composition. METHODS: The phytochemical profile of the Sideritis tea was determined by liquid chromatography-UV diode array coupled to ion-trap mass spectrometry with electrospray ionization interface. The effects of two doses of the herbal infusion (2 and 4% w/v, daily) intake on anxiety-like state in mice were studied by the assessment of their thigmotactic behavior. The oxidant/antioxidant status of brain (-Ce), liver and heart of adult male Balb-c mice following the consumption of Sideritis tea was also evaluated via the measurement of malondialdehyde (MDA) and reduced glutathione (GSH) levels using fluorometric assays. Our study was further extended to determine the antioxidant effects of the herbal tea on specific brain regions (cerebral cortex, cerebellum and midbrain). RESULTS: The identified compounds were classified into several natural product classes: quinic acid derivatives, iridoids, phenylethanol glycosides and flavonoids. Our results showed that only the 4% Sideritis tea exhibited anxiolytic-like properties as evidenced by statistically significant (p < 0.05) decrease in the thigmotaxis time and increase in the number of entries to the central zone in comparison with the control group. Consumption of both tea doses (2 and 4% w/v) elevated GSH (12 and 28%, respectively, p < 0.05) and decreased MDA (16 and 29%, p < 0.05) levels in brain (-Ce), while liver and heart remained unaffected. In regard to the effect of herbal tea drinking (2 and 4% w/v) on specific brain regions, it caused a significant increase in GSH of cerebellum (13 and 36%, respectively, p < 0.05) and midbrain (17 and 36%, p < 0.05). Similarly, MDA levels were decreased in cerebellum (45 and 79%, respectively, p < 0.05) and midbrain (50 and 63%, respectively, p < 0.05), whereas cerebral cortex remained unaffected. CONCLUSIONS: Mountain tea drinking prevents anxiety-related behaviors and confers antioxidant protection to rodent's tissues in a region-specific, dose-dependent manner, and its phytochemical constituents are shown for the first time. PMID- 22202952 TI - Comparison of experimental porous silicone implants and porous silicone implants. AB - BACKGROUND: To investigate the extent and pattern of fibrovascular ingrowth of porous silicone sphere implants compared to porous polyethylene implants. METHODS: Experimental porous silicone sphere implants and porous polyethylene implants were implanted in the left socket of 20 New Zealand white rabbits after enucleation. Fibrovascular ingrowth and maturation was evaluated at 4 weeks and 8 weeks after implantation by histopathologic examination and scanning electron microscope. RESULTS: At 4 weeks after surgery, porous polyethylene implants showed deeper fibrovascular ingrowth than porous silicone sphere implants; 42.4% versus 34.2% of radius of the implants respectively (p = 0.047). However there was no significant difference in the depth of fibrovascular ingrowth between the two groups at 8 weeks after implantation, although porous polyethylene implants showed deeper fibrovascular ingrowth than porous silicone sphere implants; 71.6% versus 63.6% (p = 0.102). CONCLUSIONS: Porous silicone orbital implants demonstrated a comparable extent of fibrovascular ingrowth to that for porous polyethylene implants. Therefore, this new porous silicone sphere implant may be a good candidate to substitute for current porous implants at a lower cost. PMID- 22202953 TI - Sildenafil therapy for bronchopulmonary dysplasia: not quite yet. PMID- 22202954 TI - A novel technique for difficult removal of a neonatal peripherally inserted central catheter (PICC). AB - Peripherally inserted central catheters have become commonplace in the neonatal intensive care unit for long-term hyperalimentation and medication administration. Removal of the catheter at the conclusion of therapy is routinely relatively easy. We describe a case of a retained catheter that was unresponsive to typical noninvasive interventions and was subsequently removed using a unique non-surgical approach. PMID- 22202955 TI - Severe postnatal cytomegalovirus infection with multisystem involvement in an extremely low birth weight infant. AB - Cytomegalovirus (CMV) infection is the most common intrauterine and perinatal viral infection. Postnatal CMV infection is acquired mainly from breast milk and may cause severe illness in preterm infants. We report an extremely low birth weight infant who presented with a sepsis-like syndrome and multiple organ involvement, notably hepatitis and pneumonitis, and treated with ganciclovir without adverse effect or relapse. PMID- 22202956 TI - Acampomelic campomelic dysplasia in genetic male without sex reversal. PMID- 22202958 TI - A case for an in utero etiology of chronic SDH/effusion of infancy. PMID- 22202959 TI - Response to 'a case for an in utero etiology of chronic SDH/effusions of infancy'. PMID- 22202960 TI - A clinical study of internal fixation, debridement and interbody thoracic fusion to treat thoracic tuberculosis via posterior approach only. AB - PURPOSE: We evaluated the clinical efficacy and feasibility of one-stage posterior internal fixation, debridement and interbody thoracic fusion in the treatment of thoracic tuberculosis. METHODS: Sixty adult patients with monosegmental thoracic tuberculosis were studied retrospectively: 34 men and 26 women with an average age of 37.5 years. Operating time, blood loss, time in bed, complications, neurological function, rate of deformity correction and rate of interbody fusion were investigated. RESULTS: All cases were followed up for 27.5 months on average. Average mean operating time was 251 min, evaluated blood loss during operation 780 ml, rate of kyphosis correction 79%, corrected kyphosis angle 25 degrees and loss of corrected angle 1.2 degrees . Patients whose neurological function improved accounted for 90.1%. Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) decreased to normal levels three months after operation. The rate of bone fusion was 100%, with a 100% cure rate. No severe complications or spinal cord injury occurred. CONCLUSIONS: This approach can successfully remove the focus of tuberculosis with complete interbody thoracic fusion after operation, which restores spinal stability. PMID- 22202962 TI - Failure rate of a rotating hinge knee design due to yoke fracture of the hinged tibial insert: a retrospective data analysis and review of the literature. AB - PURPOSE: Rotating hinge knee prostheses are known to provide inherent stability. Yoke fractures of the hinged tibial insert of modern generation rotating hinge devices are a matter of continued concern. The aim of this study was to describe incidence and management of yoke fracture of the LPSTM hinged tibial insert. METHODS: Retrospective data analysis of two institutions identified 40 patients with a LPSTM total knee arthroplasty. Implant survival and prosthetic complications was calculated according to Kaplan-Meier. RESULTS: Out of the group of 40 patients, four fractures of the metal yoke occurred in four cases (failure rate: 10%). Furthermore, a second fracture occurred in two patients. The overall revision-free prosthetic survival was 57% at 38 months, while prosthetic survival until yoke fracture was 86% at 38 months. CONCLUSION: Handling yoke fractures as mechanical complication includes replacing the hinged insert, stabilization of the joint and joint line height preservation in order to decrease the cantilever effect at the insert-base plate interface. PMID- 22202961 TI - Contemporary femoral designs in total knee arthroplasty: effects on the patello femoral congruence. AB - PURPOSE: The objective of this study was to evaluate the radiological and clinical correlations between implant design and patellar positioning in patients who underwent TKA utilizing femoral implants with modern designs. METHODS: Thirty consecutive PFC PS Sigma TKAs, characterized by a new prolonged anterior flange and a "smoother" trochlea, were prospectively reviewed. All patellae were replaced. All patients were evaluated pre-operatively and prospectively at two years follow-up both clinically according to the Knee Society score as well as radiographically. This included computed tomography (CT); patellar tilt, patellar conformity angle, patellar lateralization, and femoral component external rotation in relation to the clinical trans-epicondylar axis. RESULTS: Average patellar tilt at follow-up was 3 degrees (+/-7.5 degrees ) with respect to a pre operative 18.5 degrees (+/-8.5 degrees ). Average patellar congruence angle at follow-up was -3 degrees (range, -11 degrees to +9 degrees ) with respect to a pre-operative 10.3 degrees (range, + 1.5 degrees to 25.5 degrees ). Average lateralization index at follow-up was 2.7 mm (range, -3.4 mm to +7.1 mm) with respect to a pre-operative 12.2 mm (+/- 4.8 mm). Femoral component positioning related to the trans-epicondylar axis showed an external rotation of 2.80 degrees (+/- 2.10 degrees ) at follow-up with respect to 5.7 degrees (+/- 1.80 degrees ). Clinically, two (6.6%) patients reported patello-femoral complications related to imperfections in the surgical technique more than the implant's design. CONCLUSIONS: This study highlighted that modern femoral designs in TKA allow for a correct reproducibility of a normal patello-femoral conformity. Strict surgical principles are paramount to avoid patello-femoral complications even when modern implants are used. PMID- 22202963 TI - Impact of impurities in biodiesel-derived crude glycerol on the fermentation by Clostridium pasteurianum ATCC 6013. AB - During the production of biodiesel, crude glycerol is produced as a byproduct at 10% (w/w). Clostridium pasteurianum has the inherent potential to grow on glycerol and produce 1,3-propanediol and butanol as the major products. Growth and product yields on crude glycerol were reported to be slower and lower, respectively, in comparison to the results obtained from pure glycerol. In this study, we analyzed the effect of each impurity present in the biodiesel-derived crude glycerol on the growth and metabolism of glycerol by C. pasteurianum. The crude glycerol contains methanol, salts (in the form of potassium chloride or sulfate), and fatty acids that were not transesterified. Salt and methanol were found to have no negative effects on the growth and metabolism of the bacteria on glycerol. The fatty acid with a higher degree of unsaturation, linoleic acid, was found to have strong inhibitory effect on the utilization of glycerol by the bacteria. The fatty acid with lower or no degrees of unsaturation such as stearic and oleic acid were found to be less detrimental to substrate utilization. The removal of fatty acids from crude glycerol by acid precipitation resulted in a fermentation behavior that is comparable to the one on pure glycerol. These results show that the fatty acids in the crude glycerol have a negative effect by directly affecting the utilization of glycerol as the carbon source, and hence their removal from crude glycerol is an essential step towards the utilization of crude glycerol. PMID- 22202964 TI - Enzymatic synthesis of S-adenosylhomocysteine: immobilization of recombinant S adenosylhomocysteine hydrolase from Corynebacterium glutamicum (ATCC 13032). AB - Recombinant S-adenosylhomocysteine hydrolase from Corynebacterium glutamicum (CgSAHase) was covalently bound to Eupergit(r) C. The maximum yield of bound protein was 91% and the catalytic efficiency was 96.9%. When the kinetic results for the immobilized enzyme were compared with those for the soluble enzyme, no decrease in the catalytic efficiency of the former was detected. Both soluble and immobilized enzymes showed similar optimum pH and temperature ranges. The reuse of immobilized CgSAHase caused a loss of synthetic activity due to NAD(+) release, although the binding to the support was sufficiently strong for up to 5 cycles with 95% conversion efficiency. The immobilized enzyme was incubated every 3 cycles with 100 MUM NAD(+) to recover the loss of activity after 5 cycles. This maintained the activity for another 50 cycles. The purification of S adenosylhomocysteine (SAH) provided an overall yield of 76% and 98% purity as determined by HPLC and NMR analyses. The results indicate the suitability of immobilized CgSAHase for synthesizing SAH and other important S nucleosidylhomocysteine. PMID- 22202965 TI - Cultivation-independent analysis of archaeal and bacterial communities of the formation water in an Indian coal bed to enhance biotransformation of coal into methane. AB - Biogenic origin of the significant proportion of coal bed methane has indicated the role of microbial communities in methanogenesis. By using cultivation independent approach, we have analysed the archaeal and bacterial community present in the formation water of an Indian coal bed at 600-700 m depth to understand their role in methanogenesis. Presence of methanogens in the formation water was inferred by epifluorescence microscopy and PCR amplification of mcrA gene. Archaeal 16S rRNA gene clone library from the formation water metagenome was dominated by methanogens showing similarity to Methanobacterium, Methanothermobacter and Methanolinea whereas the clones of bacterial 16S rRNA gene library were closely related to Azonexus, Azospira, Dechloromonas and Thauera. Thus, microbial community of the formation water consisted of predominantly hydrogenotrophic methanogens and the proteobacteria capable of nitrogen fixation, nitrate reduction and polyaromatic compound degradation. Methanogenic potential of the microbial community present in the formation water was elucidated by the production of methane in the enrichment culture, which contained 16S rRNA gene sequences showing close relatedness to the genus Methanobacterium. Microcosm using formation water as medium as well as a source of inoculum and coal as carbon source produced significant amount of methane which increased considerably by the addition of nitrite. The dominance of Diaphorobacter sp. in nitrite amended microcosm indicated their important role in supporting methanogenesis in the coal bed. This is the first study indicating existence of methanogenic and bacterial community in an Indian coal bed that is capable of in situ biotransformation of coal into methane. PMID- 22202966 TI - Bactericidal activity of Musca domestica cecropin (Mdc) on multidrug-resistant clinical isolate of Escherichia coli. AB - The housefly (Musca domestica) larvae have been used clinically to cure osteomyelitis, decubital necrosis, lip boil, ecthyma and malnutritional stagnation ever since the Ming/Qing Dynasty (1368 Anno Domini) till now, in China. In prior research, we have cloned and characterized a new gene of antimicrobial peptide cecropin from M. domestica larvae. This peptide was potently active against Gram-positive and Gram-negative bacteria standard strain. In the present study, we evaluated the possibility of Mdc to be a potential bactericidal agent against clinical isolates of multidrug-resistant (MDR) Escherichia coli and to elucidate the related antimicrobial mechanisms. Antimicrobial activity assays indicated a minimal inhibitory concentration (MIC) of 1.56 MUM. Bactericidal kinetics at MIC showed that Mdc rapid killing of MDR E. coli. Lipopolysaccharide (LPS) dose-dependently suppressed Mdc antibacterial potency indicates that LPS is the initial binding site of Mdc in E. coli. Propidium iodide-based flow cytometry revealed that Mdc causes E. coli membrane permeabilization. Transmission electron micrographs further indicated that a remarkable damage in the bacteria's outer and inner membrane, even the leakage of cytoplasmic contents induced by Mdc. DNA binding experimental result implies that DNA is one of the possible intracellular targets of Mdc. Of note, Mdc did not show a perceptible cytotoxic effect on human red blood cells. Altogether, these results suggest that Mdc could be an excellent candidate for the development of more efficacious bactericidal agents. PMID- 22202967 TI - Stability, oviposition attraction, and larvicidal activity of binary toxin from Bacillus sphaericus expressed in Escherichia coli. AB - Bacillus sphaericus produces a two-chain binary toxin composed of BinA (42 kDa) and BinB (51 kDa), which are deposited as parasporal crystals during sporulation. The toxin is highly active against Culex larvae and Aedes and Anopheles mosquitoes, which are the principal vectors for the transmission of malaria, yellow fever, encephalitis, and dengue. The use of B. sphaericus and Bacillus thuringiensis in mosquito control programs is limited by their sedimentation in still water. In this study, the binA and binB genes were cloned and the recombinant BinAB protein was expressed in three strains of Escherichia coli. These recombinant strains were used in a toxicity assay against Culex quinquefasciatus larvae. The highest expression level was achieved when both proteins were expressed in a single operon construct. The BinAB protein expressed in the E. coli Arctic strain showed higher larvicidal activity than either of the recombinant proteins from the E. coli Ril or pLysS strains. Furthermore, it had the highest oviposition attraction (49.1%, P < 0.05). These data suggest that biologically active recombinant BinA and BinB toxins might be useful in mosquito control programs, delivered by inactivated bacterial cells or in traps. PMID- 22202968 TI - Quantification and characterization of beta-lactam resistance genes in 15 sewage treatment plants from East Asia and North America. AB - The emerging antibiotic resistance genes in the aquatic environment have aroused public concern. As beta-lactam is the most widely used group of antibiotics, beta lactam resistance genes were selected to investigate their distribution and diversity in the activated sludge from 15 geographically different sewage treatment plants (STPs) of China, Singapore, USA, and Canada. Specific PCR and quantitative real-time PCR (q-PCR) were used to investigate the occurrence and abundance of nine beta-lactam resistance genes. Five genes (OXA-1, OXA-2, OXA-10, ampC, and TEM-1) were detected in most of the sludge collected, while three genes (mecA, CTX-M-1, and SME) were not found in any sludge sample. The total abundances of the six detected beta-lactam resistance genes in the 15 STPs varied from 5.34 * 10(1) copies/ng DNA (ampC) to 5.49 * 10(4) copies/ng DNA (OXA-1). Overall, OXA-1 had the highest total concentration, followed by IMP and OXA-10. Noticeably, the abundances of TEM-1 in Chinese STPs were generally higher than those in the STPs of other countries, while the abundances of OXA-2 and IMP in the STPs of North America were much greater than those of East Asia. A total of 78 clones carrying beta-lactam resistance genes were randomly selected from six clone libraries for phylogenetic diversity analysis; the similarity of these cloned genes to known beta-lactam resistance genes with sequence identities ranged from 96% to 100%. Furthermore, OXA-1, ampC, and IMP were found to be more diverse than the other beta-lactam resistance genes. PMID- 22202969 TI - Quercetin treatment changes fluxes in the primary metabolism and increases culture longevity and recombinant alpha1-antitrypsin production in human AGE1.HN cells. AB - Addition of the flavonoid quercetin to cultivations of the alpha(1)-antitrypsin (A1AT) producing human AGE1.HN.AAT cell line resulted in alterations of the cellular physiology and a remarkable improvement of the overall performance of these cells. In a first screening in 96-well plate format, toxicity and the effect of quercetin on the lactate/glucose ratio was analyzed. It was found that quercetin treatment reduced the lactate/glucose ratio dose dependently. An increase in culture longevity, viable cell density (160% of control), and A1AT concentration (from 0.39 g/L in the control to 0.76 g/L with quercetin, i.e., 195% of the control) was observed in batch cultivation with 10 MUM quercetin compared to the control. A detailed analysis of quercetin effects on primary metabolism revealed dose-dependent alterations in metabolic fluxes. Quercetin addition resulted in an improved channeling of pyruvate into the mitochondria accompanied by reduced waste product formation and stimulation of TCA cycle activity. The observed changes in cellular physiology can be explained by different properties of quercetin and its metabolites, e.g., inhibition of specific enzymes, stimulation of oxidation of cytoplasmic, and mitochondrial NADH resulting in reduced NADH/NAD(+) ratio, and cytoprotective activity. The present study shows that the addition of specific effectors to the culture medium represents a promising strategy to improve the cellular metabolic phenotype and the production of biopharmaceuticals. The provided results contribute, additionally, to an improved understanding of quercetin action on the metabolism of human cells in a general physiological context. PMID- 22202970 TI - Plant exudates promote PCB degradation by a rhodococcal rhizobacteria. AB - Rhodococcus erythropolis U23A is a polychlorinated biphenyl (PCB)-degrading bacterium isolated from the rhizosphere of plants grown on a PCB-contaminated soil. Strain U23A bphA exhibited 99% identity with bphA1 of Rhodococcus globerulus P6. We grew Arabidopsis thaliana in a hydroponic axenic system, collected, and concentrated the plant secondary metabolite-containing root exudates. Strain U23A exhibited a chemotactic response toward these root exudates. In a root colonizing assay, the number of cells of strain U23A associated to the plant roots (5.7 * 105 CFU g-1) was greater than the number remaining in the surrounding sand (4.5 * 104 CFU g-1). Furthermore, the exudates could support the growth of strain U23A. In a resting cell suspension assay, cells grown in a minimal medium containing Arabidopsis root exudates as sole growth substrate were able to metabolize 2,3,4'- and 2,3',4-trichlorobiphenyl. However, no significant degradation of any of congeners was observed for control cells grown on Luria-Bertani medium. Although strain U23A was unable to grow on any of the flavonoids identified in root exudates, biphenyl-induced cells metabolized flavanone, one of the major root exudate components. In addition, when used as co-substrate with sodium acetate, flavanone was as efficient as biphenyl to induce the biphenyl catabolic pathway of strain U23A. Together, these data provide supporting evidence that some rhodococci can live in soil in close association with plant roots and that root exudates can support their growth and trigger their PCB-degrading ability. This suggests that, like the flagellated Gram-negative bacteria, non-flagellated rhodococci may also play a key role in the degradation of persistent pollutants. PMID- 22202971 TI - The protective effects of metyrosine, lacidipine, clonidine, and moxonidine on kidney damage induced by unilateral ureteral obstruction in rats. AB - PURPOSE: To investigate the effects of metyrosine, lacidipine, clonidine, and moxonidine on the renal damage in rats with unilateral ureteral ligation by examining the histological evidence of parenchymal damage and tubular dilatation, as well as biochemical changes indicating cell membrane damage and DNA oxidation. METHODS: Thirty-six albino Wistar rats were randomly divided into six equal groups: a healthy (intact) group, a unilateral ureteral ligation (control) group, and four drug treatment groups given metyrosine (50 mg/kg), lacidipine (2 mg/kg), clonidine (0.075 mg/kg), or moxonidine (0.2 mg/kg), respectively, for 10 days. The latter five groups underwent ligation of the left ureter. Ten days after the operation, we removed both kidneys from each rat in the control and drug treatment groups for renal pathological and biochemical [malondialdehyde (MDA), total glutathione, 8-hydroxy-2-deoxyguanine (8-OH-Gua)] examinations. Spectrophotometric assays were used to detect the malondialdehyde and total glutathione levels of the renal tissue. High-performance liquid chromatography was used to measure the 8-hydroxy-2-deoxyguanine levels. RESULTS: When the drug treatment groups were compared with the control group, the drug treatment groups' total glutathione level was higher and their malondialdehyde level was lower than that of the control group (P < 0.05), especially in the clonidine group (P < 0.0001). The 8-hydroxy-2-deoxyguanine levels of the drug treatment groups, except the lacidipine group, were significantly lower than that of the control group (P < 0.0001). There was no significant difference between the contralateral kidneys of the treatment groups and control group, according to the biochemical results. As revealed via light microscopy, clonidine and moxonidine treatment significantly reduced the tubular and glomerular damage, as well as the tubular dilation. The interstitial inflammation of the kidneys in the lacidipine group was higher than that of the other treatment groups. However, the apoptotic cell count was at a high level in both the lacidipine and metyrosine groups. The increase in the collagen content was most pronounced in the lacidipine and metyrosine groups. An examination of the contralateral kidneys showed no marked pathological findings. CONCLUSIONS: The use of a direct or indirect alpha2 adrenergic receptor agonist for the temporary treatment of unilateral ureteral obstruction-induced renal damage may be important for preventing renal structural injury. A more advanced study is necessary to determine the mechanisms underlying the protective effects of these drugs with regard to renal damage in ureteral obstruction. PMID- 22202972 TI - The effects of the Kampo medicine (Japanese herbal medicine) "Daikenchuto" on the surgical inflammatory response following laparoscopic colorectal resection. AB - PURPOSES: The inflammatory response after surgery is associated with various postoperative complications. The aim of the present prospective study was to evaluate the effects of Daikenchuto (DKT) (a Japanese herbal medicine) on the inflammatory response in patients following laparoscopic colorectal resection. METHODS: Thirty patients who underwent laparoscopic colectomy for colorectal carcinoma were divided into two groups: a DKT intake group (D group, n = 15) and a control group (C group, n = 15). The D group took 7.5 g/day of DKT from the day after surgery until the 7th postoperative day. The body temperature, heart rate, WBC count, lymphocyte count, C-reactive protein (CRP) level, beta-D: -glucan level and Candida index were compared between the two groups. RESULTS: The patients' mean age in the D group was significantly younger than that in the C group. D3 lymph node dissection was performed more often in the D group. The time until first flatus was significantly shorter in the D group (1.8 +/- 0.5 days) than in the C group (2.7 +/- 0.5 days). The CRP level was significantly lower in the D group (4.6 +/- 0.6 mg/dl) than in the C group (8.3 +/- 1.1 mg/dl) on the 3rd postoperative day. CONCLUSIONS: Postoperative DKT administration significantly suppressed the CRP level and shortened the time until first flatus. DKT administration also significantly suppressed postoperative inflammation following surgery for colorectal cancer. PMID- 22202973 TI - A UK population-based study of the relationship between mental disorder and victimisation. AB - PURPOSE: To establish the prevalence of victimisation in a UK population-based sample and to investigate the association between mental disorder and victimisation in both cross-sectional and prospective manner, whilst adjusting for potential confounds. METHODS: Data from the National Child Development Study (NCDS) were used to examine criminal victimisation, violent victimisation, and mental disorder at age 46 yerars, and also to measure history of mental disorder, when cohort members were aged 23, 33 and 42 years. Variables considered to be potential confounders or mediators of the association, including socio-economic status, family income, financial strain, education, housing ownership status, heavy drinking and gender, all measured at age 46 years, were considered in multivariate analyses. RESULTS: The prevalence of criminal victimisation amongst cohort members in the 12 months preceding interview was 15%; 2.2% of the participants reported experiencing violent victimisation in the past year. Mental disorder at age 46 was significantly associated with criminal and violent victimisation, even after adjusting for potential confounds. A prior history of mental disorder was found to be a robust predictor of criminal and violent victimisation. CONCLUSIONS: This study provides evidence that those with a mental disorder are at elevated risk of victimisation, including violent victimisation. That such an association might reflect an underlying causal relationship is further supported by the confirmation that the association holds true when mental disorder is measured well before the assessment of victimisation risk, and that it persists despite adjustment for a number of potential confounding factors. PMID- 22202974 TI - Cellular FLICE-inhibitory protein protects against cardiac remodelling after myocardial infarction. AB - Cellular FLICE-inhibitory protein (cFLIP) is a member of the tumour necrosis factor signalling pathway and a regulator of apoptosis, and it has a role in cardiac remodelling following myocardial infarction (MI) that remains largely uncharacterised. This study aimed to determine the function of cFLIP as a potential mediator of post-infarction cardiac remodelling. Our results show diminished cFLIP expression in failing human and murine post-infarction hearts. Genetically engineered cFLIP heterozygous (cFLIP+/-, HET) mice, cardiac-specific cFLIP-overexpressing transgenic (TG) mice and their respective wild-type (WT) and non-transgenic controls were subjected to MI by permanent ligation of their left anterior descending artery. Cardiac structure and function were assessed by echocardiography and pressure-volume loop analysis. Apoptosis, inflammation, angiogenesis, and fibrosis were evaluated in the myocardium. The HET mice showed exacerbated left ventricular (LV) contractile dysfunction, dilatation, and remodelling compared with WT mice 28 days after MI. Impaired LV function in the HET mice was associated with increases in infarct size, hypertrophy, apoptosis, inflammation, and interstitial fibrosis, and reduced capillary density. The TG mice displayed the opposite phenotype after MI. Moreover, adenovirus-mediated overexpression of cFLIP decreased LV dilatation and improved LV function and remodelling in both HET and WT mice. Further analysis of signalling events suggests that cFLIP promotes cardioprotection by interrupting JNK1/2 signalling and augmenting Akt signalling. In conclusion, our results indicate that cFLIP protects against the development of post-infarction cardiac remodelling. Thus, cFLIP gene delivery shows promise as a clinically powerful and novel therapeutic strategy for the treatment of heart failure after MI. PMID- 22202993 TI - Initial parathyroid surgery in 606 patients with renal hyperparathyroidism. AB - BACKGROUND: The aim of the present study was to evaluate the outcome of different surgical procedures for patients on permanent dialysis who underwent initial parathyroidectomy for renal hyperparathyroidism (rHPT). METHODS: Out of a prospective database of patients who underwent parathyroid surgery for rHPT between 1976 and 2009, patients on permanent dialysis who underwent initial parathyroidectomy were further analyzed regarding perioperative biochemical changes and postoperative outcome. RESULTS: A total of 606 patients were analyzed. Total parathyroidectomy with autotransplantation (group A) was performed in 504 patients, total parathyroidectomy without autotransplantation in 32 (group B), subtotal parathyroidectomy in 21 (group C), and incomplete parathyroidectomy in 49 (group D). After surgery, mean calcium levels dropped from 2.76 to 1.91 mmol/l in group A, from 2.67 to 2.11 mmol/l in group B, from 2.70 to 2.09 mmol/l in group C, and from 2.65 to 1.94 mmol/l in group D. The parathyroid hormone level dropped from 1,371.4 pg/ml to 28.8 pg/ml in group A, from 1,078.4 pg/ml to 27.0 pg/ml in group B, from 2,377.9 pg/ml to 61.4 pg/ml in group C, and from 1,010.2 pg/ml to 99.5 pg/ml in group D. Persistent rHPT occurred in 2/504 patients from group A (0.4%), 0/32 patients from group B (0%), 1/21 patients from group C (4.8%), and 2/49 patients from group D (4.1%). After a mean follow-up of 57.6 months, recurrent rHPT occurred in 27/504 patients from group A (5.4%), in 0/32 patients from group B (0%), in 2/21 patients from group C (9.5%), and in 3/49 patients from group D (6.1%). CONCLUSIONS: Total parathyroidectomy with or without autotransplantation is a feasible and safe surgical procedure for patients on permanent dialysis with otherwise uncontrollable rHPT. PMID- 22202994 TI - Axillary and supraclavicular recurrences are rare after axillary lymph node dissection in breast cancer. AB - BACKGROUND: This study was designed to evaluate the incidence of and risk factors for axillary recurrence (AR) and supraclavicular recurrence (SR) in breast cancer patients with axillary lymph node dissection. METHODS: The study was based on 1,180 patients with unilateral invasive breast cancer operated between January 2000 and December 2003. The median duration of follow-up was 78 months. RESULTS: The 7-year AR incidence was 0.7% and SR incidence was 1.3%. Twelve of the 14 SR patients and 4 of the 8 AR patients had concomitant distant recurrences. No risk factors for AR were identified. Histological tumor grade III as well as estrogen and progesterone negativity were risk factors for SR. SR, but not AR, was an independent risk factor for poor breast cancer-specific survival [hazard ratio, 10.116; P < 0.0001]. Among N1 patients, the extent of radiotherapy (RT) had no influence on regional recurrences. Among N2-N3 patients, the 7-year regional recurrence rates were 34.3% in patients without RT, 0% in patients with local RT, and 1.2% in patients with locoregional RT (P < 0.0001). CONCLUSIONS: AR and SR are rare events that often are detected concomitantly with distant metastases. SRs are associated with aggressive disease and poor survival. Our results also suggest that regional RT reduces regional recurrences in N2-N3 patients but not in N1 patients, but the retrospective, nonrandomized study setting renders this conclusion as uncertain. PMID- 22202995 TI - Tuberculous peritonitis: the closer you go, the more confused you get. PMID- 22203016 TI - Positional statement of the European Society of Endocrine Surgeons (ESES) on malignant adrenal tumors. PMID- 22203015 TI - Clinical impact of TP53 alterations in adrenocortical carcinomas. AB - BACKGROUND: To evaluate the role of somatic TP53 mutations and to correlate somatic and germline mutations with results of immunostaining, a large cohort of ACC patients was analyzed. PATIENTS AND METHODS: Patients with ACC who underwent potential curative surgery at the authors' department were screened for TP53 somatic and germline mutations in exons 5, 6, 7, 8, and 10 by DHPLC analysis. Aberrant samples were further analyzed by direct sequencing. Immunostaining was performed on corresponding paraffin sections in all patients. Complete clinical and follow-up data were correlated with the status of TP53. RESULTS: Thirty ACC patients were included. Four of 30 patients showed aberrant DHPLC configuration and direct sequencing confirmed 2 (7%) germline mutations (R337H, R248W), 1 (3%) somatic mutation (R213X), and 1 (3%) noncoding polymorphism (g.17708 A>T). The only patient with a positive family history harbored a TP53 mutation. Tumors of the three patients with mutations showed aberrant p53 expression in more than 10% of cells by immunostaining, compared to only 3 of 27 patients without mutations (p = 0.009). Aberrant p53 expression (>5%) was detected in 12/30 (40%) ACCs. The latter was associated with an increased Ki67 and van Slooten index (p <= 0.001; p = 0.020). Disease-free survival decreased significantly in patients with aberrant p53 IHC of more than 5% of cells (65.7 +/- 12.4 vs. 26.6 +/- 8.7 months; p = 0.043 log rank test). CONCLUSIONS: Patients with ACC revealed aberrant expression of p53 in 40%, and mutations were identified in 25% of these patients. Therefore aberrant p53 expression should be considered an indicator for genetic testing. A subgroup of apparently sporadic ACC is caused by TP53 germline mutations, and family history is a strong indicator for p53 germline mutations. PMID- 22203030 TI - Pilocytic astrocytoma with abundant oligodendroglioma-like component. AB - An 18-year-old girl presented with a history of visual disturbance without headache, nausea, or vomiting in May 2010. In July 2010, the patient visited our hospital because of visual disturbance. Head magnetic resonance images revealed hydrocephalus caused by a ring-enhancing mass lesion located in the vermis. Total tumor removal was performed. Histological findings revealed that honeycomb cells resembling oligodendrocytes accounted for most parts of the tumor. Rosenthal fibers and hyaline droplets were seen in a small portion. The tumor cells were immunoreactive for GFAP and Olig2, but none of the tumor cells were immunoreactive for Symaptophysin, EMA, or IDH 1. according to these findings, the tumor was diagnosed as pilocytic astrocytoma with an abundant oligodendroglioma like component. Pilocytic astrocytoma is known to be associated with an oligodendroglioma-like component; however, the differential diagnosis for oligodendroglioma may be difficult when an oligodendroglioma-like component occupies most of the tumor. PMID- 22203031 TI - Pleomorphic xanthoastrocytoma: a new differential diagnosis for a pediatric pineal neoplasm. AB - The pleomorphic xanthoastrocytoma (PXA) is an infrequently occurring benign astrocytic tumor with a predilection for the temporal and parietal cortices of children and young adults. We describe its occurrence in an unusual location in a 15-year-old boy who presented with raised intracranial pressure of short duration. Imaging showed a 3 * 3.2 * 3.5 cm mass in the pineal region extending into the quadrigeminal cistern. It had a contrast-enhancing solid component and a larger, ventrally located, peripherally enhancing cystic component. Total excision of the lesion was achieved via a modified left Poppen's approach. Histopathology and immunochemistry were suggestive of a PXA. This is the first report in the pediatric literature describing a PXA in the pineal region. PMID- 22203032 TI - Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC. AB - Fibrin-related markers (FRMs) such as fibrin and fibrinogen degradation products (FDPs), d-dimer, and soluble fibrin monomer complex (SFMC) were prospectively evaluated in 522 patients using the overt disseminated intravascular coagulation (DIC) diagnostic criteria. The differences in all FRMs between the DIC group and the non-DIC group, and those between the survivors and nonsurvivors were significant in the patients with infections. In an analysis of all patients, DIC score cutoff values of 2 and 3 points for FDP, d-dimer, and SFMC were recommended to be 8.3 and 42.0 MUg/mL, 2.4 and 22.0 MUg/mL, and 3.4 and 138.0 MUg/mL, respectively. In conclusion, the adequate cutoff value is thus considered to be useful for both making a diagnosis of DIC and for predicting the outcome. Fibrin related markers are therefore thought to be more useful for making a diagnosis of DIC based on infections than based on any other underlying disorders. PMID- 22203033 TI - JAK2 (V617F) mutation is not associated with thrombosis in Behcet syndrome. AB - The Janus kinase 2(V617F) (JAK2 (V617F)) mutation is an acquired genetic defect that is considered to enhance thrombosis in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Thrombosis is also a well-defined component of Behcet syndrome (BS). The aim of this study was to determine the frequency of JAK2 ( V617F ) mutation in BS-associated thrombosis. A total of 152 patients with BS (62 with thrombosis and 90 without thrombosis) were enrolled. An additional 186 patients with MPNs and 107 healthy blood donors were included to serve as diseased and healthy controls, respectively. None of the patients with BS and healthy controls carried the JAK2 (V617F) mutation, whereas 67% of patients with MPNs were positive for JAK2 ( V617F ). The frequency of thrombosis in patients with MPNs was not statistically different between carriers and non-carriers of JAK2 ( V617F ) mutation. Our data suggest that JAK2 (V617F) is not directly related to thrombosis in MPNs and in other thrombotic entities, such as BS. PMID- 22203034 TI - Effects of tissue factor pathway inhibitor-2 expression on biological behavior of BeWo and JEG-3 cell lines. AB - OBJECTIVES: To investigate the effect of tissue factor pathway inhibitor-2 (TFPI 2) expression on biological behavior of BeWo and JEG-3 cell lines. MATERIAL AND METHODS: The expression of TFPI-2 in BeWo and JEG-3 cells was upregulated by pEGFP-N3-TFPI-2 and downregulated by small interference RNA transfection, confirmed by Western blotting assay and real-time polymerase chain reaction (RT PCR). Boyden chamber, Cell Counting Kit-8 (CCK-8), and Hoechst 33258/terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL) assays were used for migration, invasion, and proliferation/apoptosis analysis, respectively. RESULTS: In Western blotting and RT-PCR assay, protein and messenger RNA (mRNA) expression of TFPI-2 in transfected BeWo and JEG-3 cells were confirmed. Expression of TFPI-2 inhibited BeWo and downregulated JEG-3 cell migration, invasion, proliferation, and induced apoptosis (P < .05) in Boyden chamber, CCK 8, Hoechst 33258, and TUNEL detection, respectively. CONCLUSIONS: TFPI-2 expression caused invasion and proliferation impair and induced apoptosis in TFPI 2 regulated BeWo and JEG-3 cells. It provides a clue for potential role of TFPI-2 in trophoblast. PMID- 22203035 TI - Treatment regimen with bevacizumab decreases mean platelet volume in patients with metastatic colon cancer. AB - The risk of thromboemboli is increased in patients with cancer, and this is precipitated by the chemotherapeutic agents. Bevacizumab is an anti-vascular endothelial growth factor monoclonal antibody and has an importance in the treatment of metastatic colon cancer. The association between bevacizumab, which is demonstrated to increase the risk of thromboemboli, and mean platelet volume (MPV), which is a marker of thrombocyte function, has been investigated within study. A total of 74 patients with metastatic colon cancer were included in the study and the levels of platelets (PLTs), MPV, and platecrit (PCT) values were recorded in SPSS 16.0 program both at baseline and at the >third month. There were significant decreases in 3 parameters (PLT, MPV, and PCT) during the treatment period with bevacizumab (P = .009, P = .001, and P = .000, respectively). Unlike cases with thrombosis, there is a significant decrease in MPV in combination treatments with bevacizumab. PMID- 22203036 TI - Hepatic artery stenosis in antiphospholipid syndrome. PMID- 22203037 TI - Proteins associated with the exon junction complex also control the alternative splicing of apoptotic regulators. AB - Several apoptotic regulators, including Bcl-x, are alternatively spliced to produce isoforms with opposite functions. We have used an RNA interference strategy to map the regulatory landscape controlling the expression of the Bcl-x splice variants in human cells. Depleting proteins known as core (Y14 and eIF4A3) or auxiliary (RNPS1, Acinus, and SAP18) components of the exon junction complex (EJC) improved the production of the proapoptotic Bcl-x(S) splice variant. This effect was not seen when we depleted EJC proteins that typically participate in mRNA export (UAP56, Aly/Ref, and TAP) or that associate with the EJC to enforce nonsense-mediated RNA decay (MNL51, Upf1, Upf2, and Upf3b). Core and auxiliary EJC components modulated Bcl-x splicing through different cis-acting elements, further suggesting that this activity is distinct from the established EJC function. In support of a direct role in splicing control, recombinant eIF4A3, Y14, and Magoh proteins associated preferentially with the endogenous Bcl-x pre mRNA, interacted with a model Bcl-x pre-mRNA in early splicing complexes, and specifically shifted Bcl-x alternative splicing in nuclear extracts. Finally, the depletion of Y14, eIF4A3, RNPS1, SAP18, and Acinus also encouraged the production of other proapoptotic splice variants, suggesting that EJC-associated components are important regulators of apoptosis acting at the alternative splicing level. PMID- 22203039 TI - Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor beta-initiated prostate cancer epithelial-mesenchymal transition. AB - Epithelial-mesenchymal transition (EMT) is implicated in various pathological processes within the prostate, including benign prostate hyperplasia (BPH) and prostate cancer progression. However, an ordered sequence of signaling events initiating carcinoma-associated EMT has not been established. In a model of transforming growth factor beta (TGFbeta)-induced prostatic EMT, SLUG is the dominant regulator of EMT initiation in vitro and in vivo, as demonstrated by the inhibition of EMT following Slug depletion. In contrast, SNAIL depletion was significantly less rate limiting. TGFbeta-stimulated KLF4 degradation is required for SLUG induction. Expression of a degradation-resistant KLF4 mutant inhibited EMT, and furthermore, depletion of Klf4 was sufficient to initiate SLUG-dependent EMT. We show that KLF4 and another epithelial determinant, FOXA1, are direct transcriptional inhibitors of SLUG expression in mouse and human prostate cancer cells. Furthermore, self-reinforcing regulatory loops for SLUG-KLF4 and SLUG FOXA1 lead to SLUG-dependent binding of polycomb repressive complexes to the Klf4 and Foxa1 promoters, silencing transcription and consolidating mesenchymal commitment. Analysis of tissue arrays demonstrated decreased KLF4 and increased SLUG expression in advanced-stage primary prostate cancer, substantiating the involvement of the EMT signaling events described in model systems. PMID- 22203038 TI - A switch of G protein-coupled receptor binding preference from phosphoinositide 3 kinase (PI3K)-p85 to filamin A negatively controls the PI3K pathway. AB - Frequent oncogenic alterations occur in the phosphoinositide 3-kinase (PI3K) pathway, urging identification of novel negative controls. We previously reported an original mechanism for restraining PI3K activity, controlled by the somatostatin G protein-coupled receptor (GPCR) sst2 and involving a ligand regulated interaction between sst2 with the PI3K regulatory p85 subunit. We here identify the scaffolding protein filamin A (FLNA) as a critical player regulating the dynamic of this complex. A preexisting sst2-p85 complex, which was shown to account for a significant basal PI3K activity in the absence of ligand, is disrupted upon sst2 activation. FLNA was here identified as a competitor of p85 for direct binding to two juxtaposed sites on sst2. Switching of GPCR binding preference from p85 toward FLNA is determined by changes in the tyrosine phosphorylation of p85- and FLNA-binding sites on sst2 upon activation. It results in the disruption of the sst2-p85 complex and the subsequent inhibition of PI3K. Knocking down FLNA expression, or abrogating FLNA recruitment to sst2, reversed the inhibition of PI3K and of tumor growth induced by sst2. Importantly, we report that this FLNA inhibitory control on PI3K can be generalized to another GPCR, the mu opioid receptor, thereby providing an unprecedented mechanism underlying GPCR-negative control on PI3K. PMID- 22203040 TI - CD2AP regulates SUMOylation of CIN85 in podocytes. AB - Podocytes are highly differentiated and polarized epithelial cells located on the visceral side of the glomerulus. They form an indispensable component of the glomerular filter, the slit diaphragm, formed by several transmembrane proteins and adaptor molecules. Disruption of the slit diaphragm can lead to massive proteinuria and nephrotic syndrome in mice and humans. CD2AP is an adaptor protein that is important for the maintenance of the slit diaphragm. Together with its paralogue, CIN85, CD2AP belongs to a family of adaptor proteins that are primarily described as being involved in endocytosis and downregulation of receptor tyrosine kinase activity. We have shown that full-length CIN85 is upregulated in podocytes in the absence of CD2AP, whereas in wild-type cells, full-length CIN85 is not detectable. In this study, we show that full-length CIN85 is postranslationally modified by SUMOylation in wild-type podocytes. We can demonstrate that CIN85 is SUMOylated by SUMO-1, -2, and -3 and that SUMOylation is enhanced in the presence of CD2AP. Conversion of lysine 598 to arginine completely abolishes SUMOylation and leads to increased binding of CIN85 to nephrin. Our results indicate a novel role for CD2AP in regulating posttranslational modification of CIN85. PMID- 22203042 TI - Development of safety profile evaluating pharmacokinetics, pharmacodynamics and toxicity of a combination of pioglitazone and olmesartan medoxomil in Wistar albino rats. AB - Pioglitazone (PIO), an antidiabetic drug and olmesartan medoxomil (OLM), an antihypertensive drug were administered orally alone and in combination to Wistar albino rats for evaluation of pharmacokinetics, pharmacodynamics and repeated dose 28-day oral toxicity of individual drugs and their combination. Pharmacokinetic study was performed by orally administering PIO and OLM at single dose of 3 and 2mg/kg, respectively alone and in combination analyzing the plasma samples using LC-MS/MS. Antidiabetic activity evaluation was done in type-2 diabetes mellitus induced animals at same dose level as in pharmacokinetic study daily for 30 days. PIO and/or OLM were administered orally to animals at daily doses of 50, 100 and 150 mg/kg for 28 days for toxicity study. There was no significant alteration in the pharmacokinetic parameters of either drug indicating absence of any pharmacokinetic interaction when co-administered. Positive pharmacodynamic interaction between PIO and OLM was established in this study. Two drugs in combination showed no evidence of potentiation of 28-day repeated dose toxicity in animals. Again, drugs, alone and in combination, caused only minor changes in clinical-laboratory tests and histopathological change was not found in the experiment performed. In conclusion, PIO and OLM combination can primarily be stated as safe in terms of present toxicity and pharmacokinetics findings. PMID- 22203043 TI - A refined approach to estimate exposure for use in calculating the Maximum Residue Limit of veterinary drugs. AB - Maximum Residue Limits (MRLs) are standards that represent the maximum residue concentration expected to be found if a veterinary drug is administered according to good practice in the use of veterinary drugs (GVP). MRLs are established only where the exposure to residues in food resulting from particular use patterns of the veterinary drug pass a public health risk assessment. The current model diet as used by major regulators overstates mean consumption of food for populations when compared to results from food surveys of actual consumption. Exposure to residues is overestimated when calculating long-term (chronic) exposure using the model diet leading to the risk to consumers being overstated. Additionally the model diet underestimates the size of large portions eaten by the group of consumers that eat large quantities of a particular food in a single meal potentially leading to understating of risks associated with exposure to residues of drugs that produce an adverse effect after a single exposure. A revision of dietary consumption figures is proposed that will better match the consumption figures used in point-estimates of dietary exposure to the timeframe for consumption that is relevant to the reference dose. PMID- 22203041 TI - AU-rich-element-dependent translation repression requires the cooperation of tristetraprolin and RCK/P54. AB - AU-rich elements (AREs), residing in the 3' untranslated region (UTR) of many labile mRNAs, are important cis-acting elements that modulate the stability of these mRNAs by collaborating with trans-acting factors such as tristetraprolin (TTP). AREs also regulate translation, but the underlying mechanism is not fully understood. Here we examined the function and mechanism of TTP in ARE-mRNA translation. Through a luciferase-based reporter system, we used knockdown, overexpression, and tethering assays in 293T cells to demonstrate that TTP represses ARE reporter mRNA translation. Polyribosome fractionation experiments showed that TTP shifts target mRNAs to lighter fractions. In murine RAW264.7 macrophages, knocking down TTP produces significantly more tumor necrosis factor alpha (TNF-alpha) than the control, while the corresponding mRNA level has a marginal change. Furthermore, knockdown of TTP increases the rate of biosynthesis of TNF-alpha, suggesting that TTP can exert effects at translational levels. Finally, we demonstrate that the general translational repressor RCK may cooperate with TTP to regulate ARE-mRNA translation. Collectively, our studies reveal a novel function of TTP in repressing ARE-mRNA translation and that RCK is a functional partner of TTP in promoting TTP-mediated translational repression. PMID- 22203044 TI - Incidence and radiologic predictor of postoperative patellar instability after Fulkerson procedure of the tibial tuberosity for recurrent patellar dislocation. AB - PURPOSE: Excellent results of anteromedialization of the tibial tuberosity for recurrent patellar dislocation have been reported; however, the contribution of the preoperative anatomic factors to postoperative patellar instability has not been well established. The purpose of this study was to investigate the mid-term results and the incidence of postoperative patellar instability after Fulkerson procedure for recurrent patella dislocation, and to determine the radiologic predictor of the postoperative patellar instability. METHODS: Sixty-two knees of 41 patients underwent Fulkerson procedure with or without lateral retinacular release for recurrent patellar dislocation and were followed-up for 85-155 months. Predisposing anatomic factors for recurrent patellar dislocation were evaluated preoperatively, including valgus knee alignment (femorotibial angle), patella alta (Insall-Salvati ratio), trochlear dysplasia (trochlear depth), lateral patellar displacement (congruence angle) and lateral malposition of the tibial tuberosity (tibial tuberosity-trochlear groove distance). The relationship between the measurements of anatomic factors and postoperative patellar instability, which was defined by the patellar re-dislocation or residual apprehension after surgery, was analyzed. RESULTS: The Fulkerson score and the Kujala score were significantly improved from the median of 65 (35-80) points and 68 (36-82) points preoperatively to 95 (60-100) points and 92 (57-100) points at the final follow-up, respectively. Three knees (4.8%) experienced postoperative patellar re-dislocation and 4 knees (6.5%) showed the positive apprehension sign at the final follow-up. The statistical analysis showed that the postoperative patellar instability correlated with only patella alta. CONCLUSION: Patella alta was the only predictor of postoperative patellar instability after Fulkerson procedure. These results indicated that isolated Fulkerson procedure should not be indicated for recurrent patellar dislocation with severe patella alta. LEVEL OF EVIDENCE: Case-control study, Level III. PMID- 22203045 TI - Difference in knee joint position sense in athletes with and without patellofemoral pain syndrome. AB - PURPOSE: The purpose of this study was to evaluate knee joint position sense (JPS) in athletes with patellofemoral pain syndrome (PFPS) and compare it with healthy participants under non-weight bearing (sitting) and weight bearing (standing) conditions. METHODS: Twenty patients and 20 healthy athletes participated in this study. JPS was evaluated by active replication of knee angles with visual cues eliminated. Two target angles in sitting and one in standing were tested. Each test and replication was repeated three times. By subtracting the test angle from the replicated angle, the absolute error was calculated as a dependent variable. RESULTS: No significant difference in knee JPS was found between groups either in the sitting or in the standing tests. CONCLUSION: It seems that PFPS does not affect the knee JPS in athletes. The lack of deficiency in patients could possibly be attributed to their severity of knee pathology, pain intensity and their physical activity level. LEVEL OF EVIDENCE: Case-control study, Level III. PMID- 22203046 TI - Platelet-rich plasma intra-articular injections for cartilage degeneration and osteoarthritis: single- versus double-spinning approach. AB - PURPOSE: To compare the safety and efficacy of two different approaches of platelet-rich plasma (PRP) production methods as intra-articular injection treatment for knee cartilage degenerative lesions and osteoarthritis (OA). METHODS: The study involved 144 symptomatic patients affected by cartilage degenerative lesions and OA. Seventy-two patients were treated with 3 injections of platelet concentrate prepared with a single-spinning procedure (PRGF), the other 72 with 3 injections of PRP obtained with a double-spinning approach. The patients were evaluated prospectively at the enrollment and at 2, 6, and 12 months' follow-up with IKDC, EQ-VAS and Tegner scores; adverse events and patient satisfaction were also recorded. RESULTS: Both treatment groups presented a statistically significant improvement in all the scores evaluated at all the follow-up times. Better results were achieved in both groups in younger patients with a lower degree of cartilage degeneration. The comparative analysis showed similar improvements with the two procedures: in particular, IKDC subjective evaluation increased from 45.0 +/- 10.1 to 59.0 +/- 16.2, 61.3 +/- 16.3, and 61.6 +/- 16.2 at 2, 6, and 12 months in the PRGF group, and from 42.1 +/- 13.5 to 60.8 +/- 16.6, 62.5 +/- 19.9, and 59.9 +/- 20.0 at 2, 6, and 12 months in the PRP group, respectively. Concerning adverse events, more swelling (P = 0.03) and pain reaction (P = 0.0005), were found after PRP injections. CONCLUSIONS: Although PRP injections produced more pain and swelling reaction with respect to that produced by PRGF, similar results were found at the follow-up times, with a significant clinical improvement with respect to the basal level. Better results were achieved in younger patients with a low degree of cartilage degeneration. LEVEL OF EVIDENCE: II. PMID- 22203047 TI - Biomechanical stability of different suture fixation techniques for tibial eminence fractures. AB - PURPOSE: Displaced tibial eminence fractures require surgical fixation in order to obtain a stable knee joint. Suture fixation with FiberWire((r)) seems to be the most favorable therapeutic option. Biomechanical studies show failure of this technique most commonly due to a suture cutout with subsequent fracture of the tibial eminence fragment. The goal of this study is to compare the biomechanical properties of three different techniques of suture fixation using FiberWire((r)). METHODS: Bone mineral density was evaluated in 18 human knee specimens by pqCT, and three similar groups were formed. A standardized anterior tibial eminence fracture was created, and suture fixation was performed using one of three different techniques in 6 specimens each. Cyclic and destructive testing was conducted. RESULTS: Significant differences between the three techniques could be shown neither in the cycles needed to achieve a steady state nor in a failure load or initial stiffness. Almost all specimens failed by suture cutout. CONCLUSION: The presented modification of the existing technique for suture fixation of tibial eminence fractures did not lead to an increased initial stability nor did it lower the rate of suture cutout. All tested suture techniques showed comparable initial stiffness and failure load. PMID- 22203048 TI - An image analysis method to quantify the lateral pivot shift test. AB - PURPOSE: Although various kinematic measurements with advanced technology have been used for quantitative evaluation of the pivot shift test, there is no clinically available quantification method of the pivot shift test. The purpose was to describe a novel image analysis technique for quantitative assessment of the pivot shift test using universally available and affordable devices. METHODS: Five ACL deficient knees were tested during examination under anesthesia. Three skin markers were attached to bony landmarks on the lateral side of the knee joint, (1) Gerdy's tubercle, (2) fibular head, and (3) lateral epicondyle. A standard digital video camera captured motion of the lateral aspect of the knee during the pivot shift test. The image was processed into a 2-dimensional (2-D) coordinate system with Image J software (National Institute of Health, USA) to trace the three landmarks. The anteroposterior (AP) position of the femur was calculated on consecutive still images extracted from the video recording. AP translation over time was reported. RESULTS: The reduction phase of the pivot shift could be tracked consistently by a sudden anterior translation of the distal femur. The sudden anterior translation of the lateral epicondyle was on average 3.7 +/- 2.1 mm and occurred within 0.2 +/- 0.1 s from the start of this anterior translation till the end. CONCLUSION: The sudden shift of the lateral compartment of the knee joint was successfully detected by this newly developed image analysis measurement method. This image analysis technique facilitates a simple and affordable method to evaluate the lateral pivot shift test. LEVEL OF EVIDENCE: Diagnostic studies, Level IV. PMID- 22203049 TI - No effect on performance tests from a neuromuscular warm-up programme in youth female football: a randomised controlled trial. AB - PURPOSE: The objective of the present randomised controlled trial was to study the effect of a neuromuscular warm-up programme on performance tests in youth female football. METHODS: Four youth female football teams with players aged 12 16 years were randomised into an intervention group and control group. The intervention was a 15-min neuromuscular warm-up programme carried out twice a week during the 11-week study period. Baseline and follow-up measurements of performance were made indoors and included the star excursion balance test, a countermovement jump test, a triple-hop for distance test, a modified Illinois agility test, and 10- and 20-m sprint tests. RESULTS: Fifty-two players (intervention 28; control 24) took part in baseline measurements, and after dropout, 41 players (intervention 23; control 18) were included for analysis. Minor positive changes were seen in the control group compared to the intervention group for a sub-score of the star excursion balance test (P < 0.05) and in the modified Illinois agility test (P < 0.05). No improvement was seen in the intervention group from baseline to follow-up. CONCLUSIONS: The study showed that a neuromuscular warm-up programme carried out during 11 weeks did not improve performance in youth female football. This could indicate that the programme does not contain sufficient stimulus to improve performance. A low player attendance at training sessions, and low specificity between exercises in the warm-up programme and the evaluated performance tests may also contribute to the lack of effect. LEVEL OF EVIDENCE: I. PMID- 22203050 TI - Cell-free repair of small cartilage defects in the Goettinger minipig: which defect size is possible? AB - PURPOSE: Cartilage repair of full-thickness chondral defects in the knees of Goettinger minipigs was assessed by treatment with cell-free collagen type-I gel plugs of three different sizes. METHODS: In 6 adult Goettinger minipigs, three full-thickness chondral defects were created in the trochlear groove of one knee of the hind leg. These defects were treated with a cell-free collagen type-I gel plug of 8, 10, or 12 mm diameter. All animals were allowed unlimited weight bearing. After 1 year, the animals were killed. Immediately after recovery, a non destructive biomechanical testing was performed. The repair tissue quality was evaluated immunohistologically, collagen type-II protein was quantified, and a semiquantitative score (O'Driscoll score) was calculated. RESULTS: After 1 year, a high number of cells migrated into the initially cell-free collagen gel plugs and a hyaline-like repair tissue had been created. The O'Driscoll scores were: 8 mm, 21.2 (SD, 2.8); 10 mm, 21.5 (SD, 1.6); and 12 mm, 22.3 (SD, 1.0). The determination of the e-modulus, creep and relaxation revealed that mechanical properties of the two smaller defects were closer to unaffected hyaline cartilage. CONCLUSIONS: As cell-free collagen type-I gel plugs of all three different sizes created hyaline-like repair tissue, this system seems suitable for the treatment of even larger defects. PMID- 22203052 TI - High anaplastic lymphoma kinase immunohistochemical staining in neuroblastoma and ganglioneuroblastoma is an independent predictor of poor outcome. AB - Anaplastic lymphoma kinase (ALK) mutations occur in 3% to 11% of neuroblastoma (NBL) cases and are associated with high ALK levels. However, high ALK levels appear to be a mutation-independent hallmark of NBL. Evidence about the prognostic relevance of ALK mutations and ALK tumor positivity in patients with NBL has been inconclusive. In this study, we investigated the prognostic relevance of ALK positivity by IHC and ALK mutation status by PCR sequencing in 71 NBL, 12 ganglioneuroblastoma (GNBL), and 20 ganglioneuroma samples in a multivariate model. ALK mutations were present in 2 of 72 NBL and 2 of 12 GNBL samples, which all contained many ALK-positive cells (>50%). In addition, half of all NBL samples showed ALK positivity in most (>50%) of tumor cells, whereas half of the GNBL showed staining in <20% of the tumor cells. In most ganglioneuroma samples, a low percentage of tumor cells stained positive for ALK, which mainly involved ganglion cells. Higher percentages of ALK-positive cells in NBL and GNBL patient samples correlated with inferior survival in univariate and multivariate analyses with established prognostic factors, such as stage, age, and MYCN status. In conclusion, ALK positivity by IHC is an independent, poor prognostic factor in patients with GNBL and NBL. ALK IHC is an easy test suitable for future risk stratification in patients with NBL and GNBL. PMID- 22203053 TI - Adenovirus-mediated gene transfer of TGF-beta1 to the renal glomeruli leads to proteinuria. AB - The mechanism of proteinuria in many common kidney diseases involves glomerular hemodynamic effects and local expression of angiogenic, fibrogenic, and vasoactive factors. Transforming growth factor (TGF)-beta has been associated with many diseases involving proteinuria and renal fibrosis. TGF-beta has been shown to induce podocyte dedifferentiation in vitro, but its in vivo effects on the glomerular filtration barrier are not well described. In this study, we used an adenovirus vector to transfer active TGF-beta1 to the glomeruli of rat kidneys. Transient TGF-beta1 overexpression induced significant proteinuria, podocyte foot process effacement, nephrin down-regulation, and nephrinuria. The expression of synaptopodin was also significantly down-regulated by TGF-beta1. Increased glomerular expression of Snail, suggestive of an in vivo dedifferentiation process, was associated with a loss of podocyte epithelial markers. The expression of angiopoietin-1 and angiopoietin-2 was significantly increased in TGF-beta1-transfected glomeruli, and TGF-beta1 increased the expression of the angiopoietin receptor, Tie2, in podocyte cell culture. TGF beta1 down-regulated nephrin and synaptopodin expression in podocytes in cell culture; this effect was reversed by the blockade of both angiopoietin and Tie2 activities. These findings suggest that locally produced TGF-beta1 can cause podocyte dedifferentiation marked by a loss of synaptopodin, nephrin, and foot process effacement, partly regulated by angiopoietins. This process represents a novel pathway that may explain proteinuria in a variety of common renal diseases. PMID- 22203054 TI - Co-regulation of transcellular and paracellular leak across microvascular endothelium by dynamin and Rac. AB - Increased permeability of the microvascular endothelium to fluids and proteins is the hallmark of inflammatory conditions such as sepsis. Leakage can occur between (paracellular) or through (transcytosis) endothelial cells, yet little is known about whether these pathways are linked. Understanding the regulation of microvascular permeability is essential for the identification of novel therapies to combat inflammation. We investigated whether transcytosis and paracellular leakage are co-regulated. Using molecular and pharmacologic approaches, we inhibited transcytosis of albumin in primary human microvascular endothelium and measured paracellular permeability. Blockade of transcytosis induced a rapid increase in paracellular leakage that was not explained by decreases in caveolin 1 or increases in activity of nitric oxide synthase. The effect required caveolin 1 but was observed in cells depleted of clathrin, indicating that it was not due to the general inhibition of endocytosis. Inhibiting transcytosis by dynamin blockade increased paracellular leakage concomitantly with the loss of cortical actin from the plasma membrane and the displacement of active Rac from the plasmalemma. Importantly, inhibition of paracellular leakage by sphingosine-1 phosphate, which activates Rac and induces cortical actin, caused a significant increase in transcytosis of albumin in vitro and in an ex vivo whole-lung model. In addition, dominant-negative Rac significantly diminished albumin uptake by endothelia. Our findings indicate that transcytosis and paracellular permeability are co-regulated through a signaling pathway linking dynamin, Rac, and actin. PMID- 22203055 TI - Chemokine receptor CCR1 disruption limits renal damage in a murine model of hemolytic uremic syndrome. AB - Shiga toxin (Stx)-producing Escherichia coli is the main etiological agent that causes hemolytic uremic syndrome (HUS), a microangiopathic disease characterized by hemolytic anemia, thrombocytopenia, and acute renal failure. Although direct cytotoxic effects on endothelial cells by Stx are the primary pathogenic event, there is evidence that indicates the inflammatory response mediated by polymorphonuclear neutrophils and monocytes as the key event during HUS development. Because the chemokine receptor CCR1 participates in the pathogenesis of several renal diseases by orchestrating myeloid cell kidney infiltration, we specifically addressed the contribution of CCR1 in a murine model of HUS. We showed that Stx type 2-treated CCR1(-/-) mice have an increased survival rate associated with less functional and histological renal damage compared with control mice. Stx type 2-triggered neutrophilia and monocytosis and polymorphonuclear neutrophil and monocyte renal infiltration were significantly reduced and delayed in CCR1(-/-) mice compared with control mice. In addition, the increase of the inflammatory cytokines (tumor necrosis factor-alpha and IL-6) in plasma was delayed in CCR1(-/-) mice compared with control mice. These data demonstrate that CCR1 participates in cell recruitment to the kidney and amplification of the inflammatory response that contributes to HUS development. Blockade of CCR1 could be important to the design of future therapies to restrain the inflammatory response involved in the development of HUS. PMID- 22203056 TI - Surgical outcomes and prognostic factors of cervical spondylotic myelopathy in diabetic patients. AB - BACKGROUND: There have been a few reports on the surgical outcomes of cervical myelopathy in diabetic patients; however, those studies included ossification of the posterior longitudinal ligament. This study investigated whether surgical outcome of expansive laminoplasty (ELAP) for diabetic patients with cervical spondylotic myelopathy (CSM) differs from that for non-diabetic patients and determined prognostic factors in diabetic patients. METHODS: We retrospectively reviewed 78 patients with CSM after excluding the cases with other medical conditions, which could affect surgical outcome from 222 consecutive patients who had undergone ELAP between 2000 and 2008 in our hospital. The patients were divided into two groups: diabetic patients (Group 1) and non-diabetic patients (Group 2). We evaluated differences in age, gender, pre- and postoperative Japanese Orthopaedic Association (JOA) score, recovery rate (RR), symptom duration, and postoperative complications between the two groups. In Group 1, the correlation between RR and factors indicating the severity of diabetes mellitus was assessed. RESULTS: There were 13 patients in Group 1 and 65 in Group 2. There was no significant difference in age, gender, JOA score before or after surgery, or symptom duration between the two groups. Group 1 showed poorer recovery of sensory and motor function in the lower extremities. A negative correlation was observed between RR and the preoperative hemoglobin A(1c) (HbA(1c)) level in Group 1. CONCLUSIONS: Diabetic patients experienced benefits from ELAP similar to non-diabetic patients. A negative correlation between RR and preoperative HbA(1c) level suggests that strict blood sugar control is recommended before surgery. PMID- 22203057 TI - Comparison of three suture techniques and three suture materials on gap formation and failure load in ruptured tendons: a human cadaveric study. AB - INTRODUCTION: There is a large variety of ruptures of tendons and ligaments in trauma surgery. Reliable data about the most appropriate suture technique and suture material for ruptured tendons are sparse. This human cadaveric study compares the biomechanical properties of three suture materials and three suture techniques for semitendinosus tendon repair. METHOD: Sixty-three human cadaver hamstring tendons underwent tenotomy and repair with either Baseball suture, Kessler suture, or a novel "Hannover" suture, using either PDS 2-0, Ethibond 2-0, or Fiberwire 2-0. Biomechanical analysis included pretensioning the constructs with 2 N for 50 s, then cyclic loading of 500 cycles between 2 and 15 N at 1 Hz in a servohydraulic testing machine with measurement of elongation. After this, ultimate failure load and failure mode analysis was performed. RESULTS: Ruptures repaired by FiberwireTM as suture material and the Baseball suture technique were able to withstand significantly higher maximum failure loads (72.8 +/- 22.0 N, p < 0.001) than the Kessler suture and the Hannover suture, while ruptures repaired by Fiberwire and the Kessler suture technique showed the lowest elongation after cyclic loading (14.6 +/- 3.8 mm, p = 0.15). CONCLUSION: These findings may be of relevance for the future clinical treatment of tendon ruptures. Further in vivo clinical application studies are desirable for the future. PMID- 22203059 TI - Comment on the article "Germline SMARCB1 mutation predisposes to multiple meningiomas and schwannomas with preferential location of cranial meningiomas at the falx cerebri" by van den Munckhof et al. PMID- 22203060 TI - Percutaneous stabilization of impending pathological fracture of the proximal femur. AB - OBJECTIVE: Percutaneous osteosynthesis plus cementoplasty (POPC) is a minimally invasive technique that has never been reported before and that we have prospectively evaluated for patients with impending pathological fracture of the proximal femur. METHODS: We performed POPC in 12 patients (3 males, 9 females) with metastasis of the proximal femur with a high risk of fracture (Mirels' score >=8) between February 2010 and July 2011. Patients were not candidates for standard surgical stabilization. We analyzed the feasibility, duration, and complication of the procedure, the risk of fracture, the decrease in pain (Visual Analog Scale, VAS), and length of stay in hospital. Data were prospectively collected in all patients. RESULTS: The mean Mirels' score was 9.8 +/- 1.2 (range, 8-11). The technical success was 100%. POPC was performed under general anesthesia (n = 6) or conscious sedation (n = 6). The mean duration was 110 +/- 43 (range, 60-180) minutes. All patients stood up and walked the second day after the procedure. The average length of stay in the hospital was 4 +/- 1.6 (range, 2 7) days. We experienced two hematomas in two patients and no thromboembolic complication. For symptomatic patients (n = 8), VAS decreased from 6.5/10 (range, 2-9) before treatment to 1/10 (range, 0-3) 1 month after. No fracture occurred after a median follow-up of 145 (range, 12-608) days. CONCLUSIONS: POPC for impending pathological fracture of the proximal femur seems to be a promising alternative for cancer patients who are not candidates for surgical stabilization. Further studies are required to confirm this preliminary experience. PMID- 22203061 TI - Balloon-assisted retrieval of tilted OptEase IVC filter. PMID- 22203063 TI - Use of a multilayered stent for the treatment of hepatic artery pseudoaneurysm after liver transplantation. PMID- 22203087 TI - Dopamine D4 and D5 receptor gene variant effects on clozapine response in schizophrenia: replication and exploration. AB - OBJECTIVES: This study aimed to: 1) replicate previously reported associations between dopamine D4 receptor gene (DRD4) polymorphisms and antipsychotic (AP) response in a clozapine (CLZ) response sample; and 2) explore possible associations of polymorphisms across dopamine D5 receptor gene (DRD5) as well as other DRD4 regions. METHODS: DRD4 exon III 48-bp, intron I (G)(n), and 120-bp repeat polymorphisms, and three DRD4 single nucleotide polymorphisms (SNPs); and DRD5 (CA/CT/GT)(n) microsatellite and four DRD5 SNPs were assessed using standard genotyping and statistical procedures. RESULTS: We report evidence, which does not survive correction for multiple testing, supporting previous DRD4 findings. Findings of interest include the 120-bp 1-copy allele, intron I (G)(n) 142-bp/140 bp genotype, and exon III 4R allele with CLZ response. All DRD5 tests were negative. CONCLUSIONS: Overall, these results suggest a possible minor contribution of DRD4 variants, but not DRD5 variants, towards the AP/CLZ response phenotype. PMID- 22203088 TI - Family satisfaction with care provided by nurse practitioners to nursing home residents with dementia at the end of life. AB - The purpose of this study was to examine family satisfaction with care provided by nurse practitioners (NP) to nursing home (NH) residents with dementia. A survey was mailed to 239 family members of nursing home residents who died with dementia. One open-ended question was added to provide comment about the care provided by the NP. A total of 131 surveys were returned (response rate 55%). The study revealed that 98% of family members agreed that they were satisfied with the end-of-life care provided by the NP. Survey responses were used to analyze the associations of communication, comfort, and satisfaction with NPs to total satisfaction with end-of-life care. Pearson's correlations demonstrated that overall satisfaction was significantly associated with NP-family communication, resident comfort, and satisfaction with NP care. Findings suggested that NPs using a model of care that emphasizes advance care planning, communication, and comfort results in high satisfaction of family members. PMID- 22203089 TI - Involvement of actin cytoskeleton in macrophage apoptosis induced by cationic liposomes. AB - We clarified whether actin cytoskeleton is involved in the macrophage apoptosis induced by cationic liposomes composed of stearylamine (SA-liposomes). Externalization of phosphatidylserine induced by SA-liposomes was suppressed by cytochalasin D, a specific inhibitor of polymerization of F-actin. Furthermore, activation of PKCdelta and reactive oxygen species (ROS) generation, which could be involved in the macrophage apoptosis, were inhibited by cytochalasin D. Microscopical observation revealed the co-localization of 1,1'-dioctadecyl 3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled SA-liposomes and fluorescein-labeled phalloidin, which specifically binds to F-actin, and this co localization was also inhibited by cytochalasin D. Co-localization of SA liposomes and F-actin was also inhibited by the pre-treatment of cells with chondroitinase ABC. These findings could be the first observation concerning the contribution of the proteoglycan-actin cytoskeleton-ROS generation pathway to apoptosis induced by SA-liposomes in macrophages. PMID- 22203090 TI - The role of Ile87 of CYP158A2 in oxidative coupling reaction. AB - Both CYP158A1 and CYP158A2 are able to catalyze an oxidative C-C coupling reaction producing biflaviolin or triflaviolin in Streptomyces coelicolor A3(2). The substrate-bound crystal structures of CYP158A2 and CYP158A1 reveal that the side chain of Ile87 in CYP158A2 points to the active site contacting the distal flaviolin molecule, however, the bulkier side chain of Lys90 in CYP158A1 (corresponding to Ile87 in CYP158A2) is toward the distal surface of the protein. These results suggest that these residues could be important in determining product regiospecificity. In order to explore the role of the two residues in catalysis, the reciprocal mutants, Ile87Lys and Lys90Ile, of CYP158A2 and CYP158A1, respectively, were generated and characterized. The mutant Ile87Lys enzyme forms two isomers of biflaviolin instead of three isomers of biflaviolin in wild-type CYP158A2. CYP158A1 containing the substitution of lysine with isoleucine has the same catalytic activity compared with the wild-type CYP158A1. The crystal structure of Ile87Lys showed that the BC loop in the mutant is in a very different orientation compared with the BC loop in both CYP158A1/A2 structures. These results shed light on the mechanism of the oxidative coupling reaction catalyzed by cytochrome P450. PMID- 22203091 TI - Ovarian hyperstimulation syndrome in a patient with frozen-thawed embryo transfer and dichorionic diamniotic pregnancy. PMID- 22203092 TI - Previable preterm rupture of membranes: gestational and neonatal outcomes. AB - INTRODUCTION: Previable (less than 24 weeks) premature rupture of membranes complicates about 1 in every thousand births and is responsible for substantial perinatal mortality. SUBJECTS AND METHODS: In this paper, we retrospectively analyzed one twin and 35 singleton pregnancies. RESULTS: Twenty cases occurred before and 16 after 20 weeks. Latency period ranged from 0 to 137 days, with an average of 35 days. Amniotic fluid index was reduced in 27 cases and normal in 6 cases. Expectant management was adopted in 31 cases (86%), five patients declined and opted for termination (14%) at admission or during the course of pregnancy. Steroids were prescribed for 12 patients at or after 24 weeks (39%), leukocyte count at admission varied from 6,000 to 16,200/mm(3), with an average of 11,310, in only 9% it was greater than 15,000, immature forms were present in 10 cases (28%). Clinical chorioamnionitis occurred in 71%, being three times more frequent in parous women. Bacteriuria was present in 2 of 30 cases (6.6%). Two women developed laboratorial and clinical signs of sepsis, none of them needed hysterectomy. There were no maternal deaths. Mean gestational age at delivery was 24 weeks, ranging from 16 to 39 weeks. In the expectant group, preterm delivery rate was 68%. There was one case of abruption. Cesarean rate was 31%. Neonatal mortality was 42% (8 cases). Overall neonatal survival was 35% (11 in 32 newborns). CONCLUSION: Perinatal mortality is high in pregnancies complicated by previable rupture of membranes, however gestational age at occurrence is a strong predictor of outcome. An individualized approach is the best management option regarding maternal risks and fetal outcomes. PMID- 22203093 TI - Alteration in placental expression of bile acids transporters OATP1A2, OATP1B1, OATP1B3 in intrahepatic cholestasis of pregnancy. AB - PURPOSE: To investigate whether bile acids transporters organic anion transporting polypeptides 1A2 (OATP1A2), organic anion transporting polypeptides 1B1 (OATP1B1), organic anion transporting polypeptides 1B3 (OATP1B3) were differently expressed in placenta of intrahepatic cholestasis of pregnancy (ICP). METHODS: Thirty pregnant women with ICP were recruited and 30 normal pregnant women served as control. The expression of mRNA and protein were analyzed by real time PCR and Western blotting. The localization of OATP1A2, OATP1B1, OATP1B3 were investigated by immunohistochemistry. RESULTS: The expression of mRNA and protein of both OATP1A2 and OATP1B3 were significantly lower in ICP placenta than normal placenta (P < 0.05). OATP1B1 mRNA was detected by RT-PCR in 8 ICP placentas and 7 control placentas, but protein expression of OATP1B1 was not found in any of the 60 placentas. By immunohistochemistry we found that OATP1A2 was obviously localized to vasculo-syncytial membrane (VSM) and apical surface of syncytiotrophoblasts, while OATP1B3 was localized to VSM of the syncytiotrophoblasts. CONCLUSIONS: The expression of OATP1A2 and OATP1B3 in placenta decreased in ICP. The down-regulation of these transporters may be involved in the pathophysiology of ICP. PMID- 22203094 TI - Gender characterization in a large series of Brazilian patients with spondyloarthritis. AB - An increasing number of women have been diagnosed with spondyloarthritis (SpA) in recent decades. While a few studies have analyzed gender as a prognostic factor of the disease, no studies have addressed this matter with a large number of patients in South America, which is a peculiar region due to its genetic heterogeneity. The aim of the present study was to analyze the influence of gender on disease patterns in a large cohort of Brazilian patients with SpA. A prospective study was carried out involving 1,505 patients [1,090 males (72.4%) and 415 females (27.6%)] classified as SpA according to the European Spondyloarthropaties Study Group criteria who attended at 29 reference centers for rheumatology in Brazil. Clinical and demographic variables were recorded and the following disease indices were administered: Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Radiologic Index (BASRI), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), and Ankylosing Spondylitis Quality of Life (ASQoL). Ankylosing spondylitis (AS) was the most frequent disease in the group (65.4%), followed by psoriatic arthritis (18.4%), undifferentiated SpA (6.7%), reactive arthritis (3.3%), arthritis associated to inflammatory bowel disease (3.2%), and juvenile SpA (2.9%). The male-to-female ratio was 2.6:1 for the whole group and 3.6:1 for AS. The females were older (p < 0.001) and reported shorter disease duration (p = 0.002) than the male patients. The female gender was positively associated to peripheral SpA (p < 0.001), upper limb arthritis (p < 0.001), dactylitis (p = 0.011), psoriasis (p < 0.001), nail involvement (p < 0.001), and family history of SpA (p = 0.045) and negatively associated to pure axial involvement (p < 0.001), lumbar inflammatory pain (p = 0.042), radiographic sacroiliitis (p < 0.001), and positive HLA-B27 (p = 0.001). The number of painful (p < 0.001) and swollen (p = 0.006) joints was significantly higher in the female gender, who also achieved higher BASDAI (p < 0.001), BASFI (p = 0.073, trend), MASES (p = 0.019), ASQoL (p = 0.014), and patient's global assessment (p = 0.003) scores, whereas the use of nonsteroidal anti-inflammatory drugs (p < 0.001) and biological agents (p = 0.003) was less frequent in the female gender. Moreover, BASRI values were significantly lower in females (p < 0.001). The female gender comprised one third of SpA patients in this large cohort and exhibited more significant peripheral involvement and less functional disability, despite higher values in disease indices. PMID- 22203095 TI - Ultrasonographic findings of Achilles tendon and plantar fascia in patients with calcium pyrophosphate deposition disease. AB - The aims of the study were to detect the frequency of involvement of the Achilles tendon and plantar fascia in patients with calcium pyrophosphate deposition disease (CPPD) by high-frequency gray-scale ultrasonography (US) and power Doppler sonography (PDS) and to correlate these findings with demographic and clinical data. Two groups of patients were enrolled: group I (38 patients with CPPD) and group II (22 patients with knee OA). US/PDS examination of the heels was performed to both groups. In the CPPD group, US/PDS examination of the Achilles tendon revealed: calcification in 57.9%, enthesophytosis in 57.9%, enthesopathy in 23.7%, vascular sign in 21%, bursitis in 13.2%, and cortical bone irregularity in 10.5%. US/PDS examination of plantar fascia in the CPPD group revealed: calcification in 15.8%, cortical bone irregularity in 78.9%, enthesophytosis in 60.5%, and planter fasciitis in 42.1%. In patients with CPPD, age was significantly correlated with enthesophytosis and deep retrocalcaneal bursitis (p = 0.01 and p = 0.04, respectively). Heel tenderness and posterior talalgia were significantly correlated with Achilles tendon enthesopathy, vascular sign, and deep retrocalcaneal bursitis (p = 0.0001 for each). Inferior talalgia was significantly correlated with plantar fasciitis (p = 0.0001). The sensitivity of ultrasonography for detection of calcifications in Achilles tendon and plantar fascia was 57.9% and 15.8%, respectively, and the specificity was 100% for both. To conclude, ultrasonographic Achilles tendon and plantar fascia calcifications are frequent findings in patients with CPPD. These calcifications have a high specificity and can be used as a useful indirect sign of CPPD. PMID- 22203096 TI - New evidence for roles of antinucleosome antibodies in systemic lupus erythematosus. PMID- 22203098 TI - Biochemical characterization and FAD-binding analysis of oleate hydratase from Macrococcus caseolyticus. AB - A putative fatty acid hydratase gene from Macrococcus caseolyticus was cloned and expressed in Escherichia coli. The recombinant enzyme was a 68 kDa dimer with a molecular mass of 136 kDa. The enzymatic products formed from fatty acid substrates by the putative enzyme were isolated with high purity (>99%) by solvent fractional crystallization at low temperature. After the identification by GC-MS, the purified hydroxy fatty acids were used as standards to quantitatively determine specific activities and kinetic parameters for fatty acids as substrates. Among the fatty acids evaluated, specific activity and catalytic efficiency (k(cat)/K(m)) were highest for oleic acid, indicating that the putative fatty acid hydratase was an oleate hydratase. Hydration occurred only for cis-9-double and cis-12-double bonds of unsaturated fatty acids without any trans-configurations. The maximum activity for oleate hydration was observed at pH 6.5 and 25 degrees C with 2% (v/v) ethanol and 0.2 mM FAD. Without FAD, all catalytic activity was abolished. Thus, the oleate hydratase is an FAD dependent enzyme. The residues G29, G31, S34, E50, and E56, which are conserved in the FAD-binding motif of fatty acid hydratases (GXGXXG((A/S))X((15 21))E((D))), were selected by alignment, and the spectral properties and kinetic parameters of their alanine-substituted variants were analyzed. Among the five variants, G29A, G31A, and E56A showed no interaction with FAD and exhibited no activity. These results indicate that G29, G31, and E56 are essential for FAD binding. PMID- 22203099 TI - Polyol osmolytes stabilize native-like cooperative intermediate state of yeast hexokinase A at low pH. AB - Osmolytes produced under stress in animal and plant systems have been shown to increase thermal stability of the native state of a number of proteins as well as induce the formation of molten globule (MG) in acid denatured states and compact conformations in natively unfolded proteins. However, it is not clear whether these solutes stabilize native state relative to the MG state under partially denaturing conditions. Yeast hexokinase A exists as a MG state at pH 2.5 that does not show any cooperative transition upon heating. Does the presence of some of these osmolytes at pH 2.5 help in the retention of structure that is typical of native state? To answer this question, the effect of ethylene glycol (EG), glycerol, xylitol, sorbitol, trehalose and glucose at pH 2.5 on the structure and stability of yeast hexokinase A was investigated using spectroscopy and calorimetry. In presence of the above osmolytes, except EG, yeast hexokinase at pH 2.5 retains native secondary structure and hydrophobic core and unfolds with excessive heat absorption upon thermal denaturation. However, the cooperative structure binds to ANS suggesting that it is an intermediate between MG and the native state. Further, we show that at high concentration of polyols at pH 2.5, except EG, which populates a non-native ensemble, DeltaH(cal)/DeltaH(van) approaches unity indicative of two-state unfolding. The results suggest that osmolytes stabilize cooperative protein structure relative to non-cooperative ensemble. These findings have implications toward the structure formation, folding and stability of proteins produced under stress in cellular systems. PMID- 22203119 TI - Anti-cholinergic effect of singulair on isolated rat's tracheal smooth muscle. AB - Singulair (Montelukast) is a potent and selective leukotriene D(4) receptor antagonist, often used in treating inflammatory conditions of the respiratory system such as allergic rhinitis and asthma. However, the effects of singulair given intratracheally have rarely been well explored. To verify the effect of singulair, which acts on the tracheal smooth muscle directly in vitro. We used our preparation to test the effects of singulair on isolated rat's tracheal smooth muscle. The following assessments of singulair were performed: (1) effect on the tracheal smooth muscle resting tension, (2) effect on contraction caused by 10(-6) M methacholine as a parasympathetic mimetic, and (3) effect of the drugs on electrically induced tracheal smooth muscle contractions. The results indicated that the addition of methacholine to the incubation medium caused the trachea to contract in a dose-dependent manner. Addition of singulair at doses of 10(-5) M or above elicited a significant relaxation response to 10(-6) M methacholine-induced contraction. Singulair could not inhibit electrical field stimulation-induced spike contraction. It also had a minimal effect on the basal tension of trachea as the concentration increased. This study showed that the high concentrations of singulair also had an anti-cholinergic effect for relieving symptoms of asthma. PMID- 22203120 TI - Pain assessment of the intratympanic injections: a prospective comparative study. AB - The objective of the study is to compare the pain level of three methods of intratympanic (IT) injections using prospective, randomized clinical study in a tertiary care center. 39 patients with Meniere's disease and 30 patients with sudden sensorineural hearing loss are included. Excluded were patients treated for a chronic pain or those who took any pain killer for the last 24 h. Each patient received one IT injection a week, for three consecutive weeks. Three methods of IT injections were compared, with the application of EMLA cream on the tympanic membrane filling the external auditory canal 60 min before the procedure, with subcutaneous injection of lidocaine 1% with 1:100,000 epinephrine in the external auditory canal, and finally with an IT injection without any previous anesthesia. The pain intensity was immediately measured at 5 min, and then 45 min after the procedure, each time using four pain rating scales (visual analogue scale, numerical rating scale, verbal rating scale and categorical rating scale). No difference in pain intensity between the three methods of IT injections was detected by the visual analogue scale and numerical rating scale (p > 0.05). 45.8% of patients preferred the IT injection without previous anesthesia. However, methylprednisolone has been associated with pain intensity greater than that of gentamicin 45 min after the injection (p < 0.05). The IT injection performed without any previous anesthesia is an interesting option since it has not been shown to be more painful than the other methods of injections, and spares the patient from disadvantages associated with the anesthesia. PMID- 22203121 TI - Improvement in urinary retention due to recurrent anastomotic prostate cancer treated with various therapies by intra-arterial infusion of cisplatin and ifosfamide. AB - Although many treatments have been applied to treat hormone-refractory prostate cancer (HRPC), therapeutic outcome is not altogether satisfactory. In the case of locally recurring HRPC, uncontrolled gross hematuria, dysuria, and scalding are often experienced. We report a patient who improved following intra-arterial infusion of cisplatin (CDDP) and ifosfamide (IFM) to treat urinary retention caused by locally recurring HRPC. After chemotherapy, cancer volume was remarkably reduced and symptoms improved. PMID- 22203122 TI - An evaluation of SNP-based PCR methods for the detection of beta-lactamase negative ampicillin-resistant Haemophilus influenzae. AB - Forty-four previously characterized strains of Haemophilus influenzae were used to evaluate the specificity of previously published SNP PCR primers for the detection of the N526K substitution in PBP3 of BLNAR isolates using real-time PCR. Hasegawa et al. primers that amplify strains without a substitution at 526 and fail to amplify strains with N526K were 100% sensitive and specific for detecting N526K. However, primer sets of Hasegawa et al. and Nakamura et al. designed to amplify strains with N526K, but not strains without a substitution, were unable to do this reliably because the primers were specific for N526K encoded by AAG and failed to amplify strains with N526K encoded by AAA. A review of N526K strains deposited on GenBank revealed an even distribution of AAG and AAA codons for N526K in European and Australian BLNAR strains, whereas only the AAG codon was seen in Japanese strains. The exclusive presence of the AAG codon in Japanese strains appears to be independent of the use of the SNP PCR primers evaluated here and remains unexplained. PMID- 22203124 TI - Initial experience on the application of 320-row CT angiography with low-dose prospective ECG-triggered in children with congenital heart disease. AB - To investigate the clinical significance of the application of 320-row CT angiography with low-dose prospective ECG-triggered target scanning in children with complex congenital heart disease (CHD), and to compare with the results from transthoracic echocardiography (TTE). 22 patients (male 12 cases, female 10 cases, average age: 18 months, range: 14 days-9 years, average weight: 13 kg) received an examination through 320-row CT angiography with low-dose prospective ECG-triggered volume target scan mode and transthoracic echocardiography. The center of phase window for data collection in this study was set to 40% of the R R interval. Of these, 18 patients received surgery and 4 patients received conventional cardiac angiography (CCA). The diagnostic accuracy of 320-row CTA was calculated according to the examination results from surgical and/or cardiac angiography. The overall quality score for CTA images was divided into five levels. The results were compared with the research data of radiation doses obtained from patients with congenital heart disease who had received CT angiography. Complex congenital heart disease was confirmed by surgical or CCA in each of 22 patients, with 42 cases of large vascular malformations outside the heart cavity, and 26 of intracardiac malformations. The diagnostic accuracy of 320-row CT angiography and transthoracic echocardiography for large vascular malformation outside the heart cavity was 95.2 and 80.9%, respectively; for intracardiac malformation the accuracy was 88.5 and 100.0%, respectively. There was significant difference between 320-row CT and transthoracic echocardiography in the diagnosis of large vascular malformation outside the heart cavity (P < 0.05) with better results in 320-row CT, and no significant difference was found in the diagnosis of intracardiac malformation (P > 0.05). The average subjective image quality score was 4.4 +/- 0.7 points. The average effective dose was 0.42 +/- 0.08 mSv. 320-row CT enables direct visualization of the vascular configuration and shape of the aorta, pulmonary artery, and other large vessels to diagnose extracardiac vascular malformations. Combined with transthoracic echocardiography, 320-row CT is a promising technology that may be able to replace catheter based angiography to evaluate congenital cardiovascular malformations. PMID- 22203134 TI - Effect of prostaglandin E1 on pulmonary arterial hypertension following corrective surgery for congenital heart disease. AB - OBJECTIVE: To evaluate the therapeutic effects of prostaglandin E(1) (PGE(1)) on residual pulmonary arterial hypertension (PAH) after corrective surgery for congenital heart disease. METHODS: Thirty-one patients with postoperational PAH were randomly divided into control group (n = 15) and PGE(1) group (n = 16, 6 courses of intravenous PGE(1) plus conventional therapy). Mean pulmonary arterial pressure (MPAP), right ventricular ejection fraction (RVEF), and left ventricular ejection fraction (LVEF) were measured by echocardiography before and 3, 6, and 12 months after the treatment. Arterial oxygen pressure (Pao (2)) was monitored. RESULTS: In both groups, MPAP decreased and RVEF, LVEF, and Pao (2) increased at 6 and 12 months following surgery. In the PGE(1) group, the MPAP (32.2 +/- 5.2 vs 40.2 +/- 5.1 mm Hg; P = .008) was lower and RVEF (66.6% +/- 6.5% vs 54.9% +/- 2.1%; P = .019), LVEF (65.9% +/- 3.9% vs 53.5% +/- 5.1%; P = .031), and Pao (2) (94.3% +/- 11.2% vs 93.1% +/- 11.3%; P = .009) was higher than in the control group 12 months after the surgery. Four patients (26.7%) in the control group died of pulmonary hypertension crisis, but there was no death in the PGE(1) group (P = .029). Cumulative survival rate in the control group were 86.7%, 80%, 73.3%, and 73.3% at 1, 2, 3, and 5 years, respectively. CONCLUSIONS: Intravenous PGE(1) therapy after corrective surgery for congenital heart disease was associated with a reduction in mean pulmonary arterial pressure and a lower risk of death. PMID- 22203148 TI - Emotional status: diagnosis and treatment for severe psychiatric disorders. PMID- 22203158 TI - Age-related changes in detection of spatial novelty. AB - Age-related changes in novelty detection for object-place associations was assessed in 6-mo and 25-mo-old Fisher 344/Brown Norway (F344/BN) rats. Old rats showed significant deficits compared to young rats in detecting spatial displacement of objects. The data suggest that object-place novelty detection is impaired in aged F344/BN rats using a rapidly acquired, exploratory-based task. The results may have important implications for the selection of efficient memory paradigms for future aging studies. PMID- 22203159 TI - Genetic ablation of the GluK4 kainate receptor subunit causes anxiolytic and antidepressant-like behavior in mice. AB - There is a clear link between dysregulation of glutamatergic signaling and mood disorders. Genetic variants in the glutamate receptor gene GRIK4, which encodes the kainate receptor subunit GluK4, alter the susceptibility for depression, bipolar disorder and schizophrenia. Here we demonstrate that Grik4(-/-) mice have reduced anxiety and an antidepressant-like phenotype. In the elevated zero-maze, a test for anxiety and risk taking behavior, Grik4(-/-) mice spent significantly more time exploring the open areas of the maze. In anxiogenic tests of marble burying and novelty-induced suppression of feeding, anxiety-like behavior was consistently reduced in knockout animals. In the forced swim test, a test of learned helplessness that is used to determine depression-like behavior, knockout mice demonstrated significantly less immobility suggesting that Grik4 ablation has an antidepressant-like effect. Finally, in the sucrose preference test, a test for anhedonia in rodents, Grik4(-/-) mice demonstrated increased sucrose preference. Expression of the GluK4 receptor subunit in the forebrain is restricted to the CA3 region of the hippocampus and dentate gyrus regions where KARs are known to modulate synaptic plasticity. We tested whether Grik4 ablation had effects on mossy fiber (MF) plasticity and found there to be a significant impairment in LTP likely through a loss of KAR modulation of excitability of the presynaptic MF axons. These studies demonstrate a clear anxiolytic and antidepressant phenotype associated with ablation of Grik4 and a parallel disruption in hippocampal plasticity, providing support for the importance of this receptor subunit in mood disorders. PMID- 22203160 TI - Validation of reference genes for gene expression studies in peanut by quantitative real-time RT-PCR. AB - Quantitative real-time reverse transcription PCR (qRT-PCR), a sensitive technique for quantifying gene expression, depends on the stability of the reference gene(s) used for data normalization. Only a few studies on the reference genes have been done with peanut to date. In the present study, 14 potential reference genes in peanut were evaluated for their expression stability using the geNorm and NormFinder statistical algorithms. Expression stability was assessed by qRT PCR across 32 biological samples, including various tissue types, seed developmental stages, salt and cold treatments. The results showed that the best ranked references genes differed across the samples. UKN1, UKN2, TUA5 and ACT11 were the most stable across all the tested samples. A combination of ACT11, TUA5, UKN2, PEPKR1 and TIP41 would be appropriate as a reference panel for normalizing gene expression data across the various tissues tested, whereas the combination of TUA5 and UKN1 was the most suitable for seed developmental stages. TUA5 and EF1b exhibited the most stable expression under cold treatment. For salt-treated leaves, TUA5 and UKN2 were the most stably expressed and HDC and UKN1 for salt treated roots. The relative gene expression level of peanut Cys(2)/His(2)-type zinc finger protein gene AhZFP1 was analyzed in order to validate the reference genes selected for this study. These results provide guidelines for the selection of reference genes under different experimental conditions and also a foundation for more accurate and widespread use of qRT-PCR in peanut gene analysis. PMID- 22203161 TI - A crossover hotspot near his-3 in Neurospora crassa is a preferential recombination termination site. AB - During analysis of 148 unselected Neurospora crassa octads, an above average rate of crossing over was detected within a 360-base region near the 3' end of his-3, suggesting a hotspot for crossing over about 1.8 kb away from the recombination initiation site within cog. Homozygous deletion of the 360-base region increases exchanges in his-3 and on the far side of his-3 from cog, with the heterozygote showing an intermediate increase. We conclude that recombination events initiated at cog terminate within the 360-base sequence more often than in other sections of the cog-his-3 interval and, since some of these terminations will be resolved as crossovers, a cluster of crossovers at this location is the outcome. Removal of this termination site increases the chance that an event will reach his-3, resulting in recombination within the gene, or extend past it to yield a crossover on the other side of his-3. The deleted sequence has substantial predicted secondary structure, including a complex predicted stem-loop, suggesting that DNA secondary structure may be responsible for the termination. PMID- 22203175 TI - Serum albumin level accurately reflects antioxidant potentials in idiopathic nephrotic syndrome. AB - BACKGROUND: Recent observation revealed that serum albumin plays an important role in the host defense mechanism as it is one of the important antioxidants. This study was conducted to investigate whether hypoalbuminemia contributes to a decreased biological antioxidant potentials (BAP) in idiopathic nephrotic syndrome (INS). METHODS: Fifty three heparinised blood samples were obtained from 8 patients with INS (median 13.5 years). Eighteen samples from 6 patients with Henoch-Schonlein purpura (HSP median 7 years) were served as control. Intravenous human albumin preparation was also applied for comparison. Measurement of BAP in blood and human albumin preparation was determined by a newly developed devise called FRAS4((r)). Comparison among groups and relationships between BAP and albumin concentrations or c-reactive protein (CRP) were studied by Kruskal-Wallis test and Spearman rank correlation test, respectively. RESULTS: Serum levels of BAP was significantly lower in patients with nephrotic relapse than those in patients with nephrotic remission or HSP. BAP correlated well with serum albumin levels. Positive relationship was also found between concentration of albumin in human preparation and BAP. Weakly positive CRP sera disclosed both hypoalbuminemia and low BAP. CONCLUSION: Our results suggest that decreased antioxidant potentials caused by hypoalbuminemia in INS may contribute to an aberrant immunity. PMID- 22203176 TI - Fungal culture of musculoskeletal tissue: what's the point? AB - There have not been any studies that review the prevalence of fungal isolates using selective media from samples of banked musculoskeletal tissue retrieved from living and cadaveric donors. A total of 2,036 swab and 2,621 biopsy samples of musculoskeletal tissue from tissue banks were received from the 1st August 2008 till 31st December 2010. Routine culture for fungi using selective media with a prolonged incubation period failed to demonstrate a greater prevalence of fungal isolates than by using non-selective culture media alone. Using selective culture fungi were recovered from only two Sabouraud agar plates (0.1%) but not from non-selective media. During the same period fungi were isolated from three graft samples cultured in non-selective broth media only (0.1%). There was no correlation of fungal isolates from selective or non-selective media inoculated at the same time nor from multiple graft samples collected from the same donor supporting the possibility of an exogenous source for fungal isolates rather than an endogenous source. PMID- 22203177 TI - Development and characterization of a cell line TTCF from endangered mahseer Tor tor (Ham.). AB - Tor tor is an important game and food fish of India with a distribution throughout Asia from the trans-Himalayan region to the Mekong River basin to Malaysia, Pakistan, Bangladesh and Indonesia. A new cell line named TTCF was developed from the caudal fin of T. tor for the first time. The cell line was optimally maintained at 28 degrees C in Leibovitz-15 (L-15) medium supplemented with 20% fetal bovine serum (FBS). The propagation of TTCF cells showed a high plating efficiency of 63.00%. The cytogenetic analysis revealed a diploid count of 100 chromosomes at passage 15, 30, 45 and 60 passages. The viability of the TTCF cell line was found to be 72% after 6 months of cryopreservation in liquid nitrogen (-196 degrees C). The origin of the cell lines was confirmed by the amplification of 578- and 655-bp sequences of 16S rRNA and cytochrome oxidase subunit I (COI) genes of mitochondrial DNA (mtDNA) respectively. TTCF cells were successfully transfected with green fluorescent protein (GFP) reporter plasmids. Further, immunocytochemistry studies confirm its fibroblastic morphology of cells. Genotoxicity assessment of H2O2 in TTCF cell line revealed the utility of TTCF cell line as in vitro model for aquatic toxicological studies. PMID- 22203178 TI - Putatively functional PLCE1 variants and susceptibility to esophageal squamous cell carcinoma (ESCC): a case-control study in eastern Chinese populations. AB - BACKGROUND: A novel variant rs2274223 located in the phospholipase C epsilon 1 (PLCE1) gene was found to be associated with risk of esophageal squamous cell carcinoma (ESCC) by 2 large-scale genome-wide association studies (GWASs) in Chinese populations. In this study, we aimed to assess such an association in an eastern Chinese population and to address its possibly functional role in the etiology of ESCC. METHODS: A total of 1061 ESCC cases and 1211 controls were recruited and successfully genotyped for 2 single nucleotide polymorphisms (SNPs) (rs2274223 and rs11187870) of the PLCE1 gene by the TaqMan assay. Real-time PCR and immunohistochemical (IHC) analysis were applied to assess mRNA and protein expression levels, respectively, in a subset of tumor samples. RESULTS: SNP rs2274223 was independently associated with risk of ESCC (adjusted odds ratio [OR], 1.49; 95% confidence interval [95% CI], 1.03-2.17 for GG vs AA), and SNP rs11187870 was also found to be associated with risk of ESCC assuming a dominant model (adjusted OR, 1.20; 95% CI, 1.00-1.44 for CG/CC vs GG). The Grs2274223Crs11187870 haplotype increased the risk for ESCC by 1.22-fold (95% CI, 1.04-1.42). Further experiments showed that overall PLCE1 mRNA expression was lower in tumor than in paired normal tissues (0.067+/-0.016 vs 0.264+/-0.067, P<.05), and the IHC analysis showed the normal tissues of rs2274223 GG genotype had a lower PLCE1 staining score than that of the AG genotype (0.40+/-0.22 vs 1.33+/-0.32, P<.05). CONCLUSIONS: PLCE1 SNP rs2274223 A>G change may reduce gene expression, and the variant G genotypes might contribute to risk of ESCC. PMID- 22203179 TI - Cytokeratin 7 is a predictive marker for survival in patients with esophageal squamous cell carcinoma. AB - BACKGROUND: Patients diagnosed with stage II and III esophageal squamous cell carcinoma (ESCC) have variable prognosis. This group would benefit greatly from the discovery of prognostic markers that are capable of identifying individuals for whom adjuvant treatment would be advantageous. The aim of this study was to investigate the impact of immunohistochemically detected cytokeratin 7 (CK7) expression on disease-free survival, overall survival (OS), or therapeutic outcome in patients with ESCC. METHODS: Immunohistochemical analysis of CK7 was performed on 225 surgically resected specimens of stage 0-III ESCC. RESULTS: In total, 20 (9%) of 225 ESCC cases were positive for CK7. In stage 0-III ESCC patients, CK7 expression was statistically significantly associated with OS, independent of clinical covariates, including tumor, node, metastasis system stage. In stage II and III ESCC patients (n = 124), CK7 expression was significantly associated with poorer OS (P = 0.0377). Furthermore, in stage II and III ESCC patients who did not receive adjuvant chemotherapy (n = 73), CK7 expression was significantly associated with poorer OS (P = 0.0003). CK7 expression was not associated with therapeutic outcome in patients with stage II and III ESCC who received adjuvant chemotherapy. In patients with CK7-positive ESCC (n = 16), receipt of adjuvant chemotherapy tended to be beneficial for patients with stage II and III ESCC (P = 0.0654). CONCLUSIONS: Immunohistochemical analysis of CK7 will help to identify high-risk patients. PMID- 22203180 TI - Treatment for T1-2 oral squamous cell carcinoma with or without perineural invasion: neck dissection and postoperative adjuvant therapy. AB - BACKGROUND: Although perineural invasion (PNI) has been a poor prognostic factor for head and neck cancers, few studies have focused on oral squamous cell carcinoma (OSCC). The independent significance of PNI in early T1-2 OSCC and the benefit of treatment modification based on PNI status have not been assessed. This study investigated the role of PNI in T1-2 OSCC patients, with focus on the controversial issues of neck management and postoperative adjuvant therapy. METHODS: PNI status was re-reviewed under hematoxylin and eosin staining in tumors of 307 consecutive T1-2 OSCC patients. Oncologic and survival outcomes were analyzed by univariate and multivariate analyses. RESULTS: PNI was identified in 84 (27.4%) patients, correlating with several established poor prognostic factors. In multivariate analysis, PNI remained an independent predictor for neck metastasis, neck recurrence, and a worse 5-year disease specific survival. Elective neck dissection contributed to a significantly better 5-year disease-specific survival only in cN0 patients with PNI-positive tumors (P = 0.0071) but not in those with PNI-negative tumors (P = 0.3566). In low-risk patients who were treated by surgery alone, including neck dissection, the 5-year disease-specific survival rates were almost the same in those with PNI-positive tumors and those with PNI-negative tumors (92.0 vs. 92.9%; P = 0.9104). CONCLUSIONS: Elective neck dissection is indicated for cN0 patients with PNI positive tumors for the efficacy of improving disease-specific survival as well as neck control. However, low-risk PNI-positive patients who undergo neck dissection do not need postoperative adjuvant therapy, because the residual risk from PNI is minimal. PMID- 22203181 TI - Prognostication of soft tissue sarcomas based on chromosome 17q gene and protein status: evaluation of TOP2A, HER-2/neu, and survivin. AB - BACKGROUND: Topoisomerase 2 alpha (TOP2A), HER-2/neu, and survivin are genes that lie on chromosome 17 and correlate with the prognosis and prediction of target driven therapy against tumors. In a previous study, we showed that TOP2A transcripts levels were significantly higher in soft tissue sarcomas (STS) than in benign tumors and desmoid-type fibromatoses (FM). Because these genes have been insufficiently examined in STS, we aimed to identify alterations in TOP2A and HER-2 expression by fluorescent in situ hybridization and immunohistochemistry, as well as that of survivin, and correlate them with clinicopathologic findings to assess their prognostic value. METHODS: Eighteen FM and 244 STS were included. Fluorescent in situ hybridization and immunohistochemistry were performed on a tissue microarray. RESULTS: TOP2A and survivin were more highly expressed in sarcomas than in FM. TOP2A was an independent predictor of an unfavorable prognosis; it was combined with formerly established prognostic factors (primarily histologic grade and tumor size at diagnosis) to create a prognostic index that evaluated overall survival. Gene amplification/polysomy (13%) did not correlate with protein overexpression. Survivin and HER-2 expression were not associated with patient outcomes. CONCLUSIONS: These findings might become valuable in the management of patients with STS and possibly in the prospective evaluation of responses to new target driven therapies. PMID- 22203182 TI - Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow up results of Radiation Therapy Oncology Group 0132. AB - BACKGROUND: Imatinib inhibits the KIT and PDGFR tyrosine kinases, resulting in its notable antitumor activity in gastrointestinal stromal tumor (GIST). We previously reported the early results of a multi-institutional prospective trial (RTOG 0132) using neoadjuvant/adjuvant imatinib either in primary resectable GIST or as a planned preoperative cytoreduction agent for metastatic/recurrent GIST. METHODS.: Patients with primary GIST (>=5 cm, group A) or resectable metastatic/recurrent GIST (>=2 cm, group B) received neoadjuvant imatinib (600 mg/day) for approximately 2 months and maintenance postoperative imatinib for 2 years. We have now updated the clinical outcomes including progression-free survival, disease-specific survival, and overall survival at a median follow-up of 5.1 years, and we correlate these end points with duration of imatinib therapy. RESULTS: Sixty-three patients were originally entered (53 analyzable: 31 in group A and 22 in group B). Estimated 5-year progression-free survival and overall survival were 57% in group A, 30% in group B; and 77% in group A, 68% in group B, respectively. Median time to progression has not been reached for group A and was 4.4 years for group B. In group A, in 7 of 11 patients, disease progressed >2 years from registration; 6 of 7 patients with progression had stopped imatinib before progression. In group B, disease progressed in 10 of 13 patients>2 years from registration; 6 of 10 patients with progressing disease had stopped imatinib before progression. There was no significant increase in toxicity compared with our previous short-term analysis. CONCLUSIONS: This long term analysis suggests a high percentage of patients experienced disease progression after discontinuation of 2-year maintenance imatinib therapy after surgery. Consideration should be given to studying longer treatment durations in intermediate- to high-risk GIST patients. PMID- 22203183 TI - Does the final intraoperative PTH level really have to fall into the normal range to signify cure? AB - BACKGROUND: Intraoperative parathyroid hormone (IOPTH) helps shorten the duration of surgery and increase the likelihood of surgical cure. Although general consensus agrees that the IOPTH should fall by 50%, there is much debate as to whether the IOPTH needs to fall into the normal range. METHODS: We retrospectively reviewed a prospective database of patients undergoing surgery for treatment of primary hyperparathyroidism. We included all patients with an IOPTH that fell by >50% by 10 or 15 min, but that did not fall into the normal range (parathyroid hormone remained >= 60 pg/ml). We excluded patients who had undergone prior neck surgery or had known multiple endocrine neoplasia 1 or 2. RESULTS: A total of 1,231 patients underwent a parathyroidectomy, 155 of whom met the study's inclusion/exclusion criteria (12.6%). A total of 117 patients had an IOPTH fall by 50% by 10 min, and 38 patients' IOPTH fell by 50% by 15 min. Overall surgical cure rate was 98.7%. One patient from the 10-minute group and one patient from the 15-minute group had persistent disease on follow-up. One patient in the 15-minute group had recurrent disease. With a mean +/- SEM 18.1 +/ 2.1 months' follow-up, the recurrence rate in this cohort was 0.6%. The average calcium at last follow-up was 9.4 +/- 0.0 mg/dl. CONCLUSIONS: Allowing the IOPTH to fall by 50% by 15 min, regardless of whether the IOPTH falls into the normal range, results in a high success rate when performed by experienced surgeons. This helps reduce intraoperative time used waiting for additional parathyroid hormone levels and the risks associated with unnecessary bilateral neck exploration. PMID- 22203184 TI - Predictors for microinvasion of small hepatocellular carcinoma <= 2 cm. AB - BACKGROUND: Hepatocellular carcinoma (HCC) <= 2 cm in diameter is considered to have a low potential for malignancy. METHODS: A retrospective review was undertaken of 149 patients with primary solitary HCC <= 2 cm who underwent initial hepatic resection between 1994 and 2010. The independent predictors of the microinvasion (MI) such as portal venous, hepatic vein, or bile duct infiltration and/or intrahepatic metastasis were identified by multivariate analysis. Prognosis of patients with HCC <= 2 cm accompanied by MI was compared to that of patients with HCC <= 2 cm without MI. RESULTS: Forty-three patients with HCC <= 2 cm had MI in patients (28.9%). Three independent predictors of the MI were revealed: invasive gross type (simple nodular type with extranodular growth or confluent multinodular type), des-gamma-carboxy prothrombin (DCP) >100 mAU/ml, and poorly differentiated. Disease-free survival rates of patients with HCC <= 2 cm with MI (3 year 44%) were significantly worse than those for HCC <= 2 cm without MI (3 year 72%). This disadvantage of disease-free survival rate of patients with HCC <= 2 cm with MI could be dissolved by hepatic resection with a wide tumor margin of >= 5 mm (P = 0.04). CONCLUSIONS: Even in cases of HCC <= 2 cm, patients who are suspected of having invasive gross type tumors in preoperative imaging diagnosis or who have a high DCP level (>100 mAU/ml) are at risk for MI. Therefore, in such patients, hepatic resection with a wide tumor margin should be recommended. PMID- 22203185 TI - Factors affecting lymph node yield in patients undergoing axillary node dissection for primary breast cancer: a single-institution review. AB - BACKGROUND: A minimum of 10 level I/II axillary nodes is recommended for accurate breast cancer staging. The goal of this study was to assess the effect of neoadjuvant chemotherapy on lymph node yield at axillary lymph node dissection. METHODS: A single-institution National Comprehensive Cancer Network (NCCN) breast cancer database was queried for cases with axillary node dissection from 2000 to 2008. All dissections were performed at the same institution. Demographic, chemotherapy, and clinicopathologic data were collected. Age and body mass index at diagnosis were calculated for subset analyses. Statistical analyses used Student's t-test or analysis of variance with Tukey multiple comparison and Fisher's exact test. RESULTS: Two hundred forty patients had axillary node dissection after neoadjuvant chemotherapy; an additional 903 women with primary lymph node dissection were identified as contemporaneous control subjects. There was a far lower nodal yield in patients undergoing axillary dissection after neoadjuvant chemotherapy than those undergoing primary surgery. Patients with pathologic stage II or III disease undergoing primary surgery had more lymph nodes at axillary dissection than stage I disease. CONCLUSIONS: Age, type of breast surgery, body mass index, and clinical stage have no effect on yield of lymph nodes at axillary lymph node dissection. Neoadjuvant chemotherapy, however, is associated with a far fewer nodes at axillary dissection, and alteration of the guidelines should be considered for this population of patients. PMID- 22203187 TI - Simultaneous acquisition of 13Calpha-15N and 1H-15N-15N sequential correlations in proteins: application of dual receivers in 3D HNN. AB - We describe here, adaptation of the HNN pulse sequence for multiple nuclei detection using two independent receivers by utilizing the detectable (13)C(alpha) transverse magnetization which was otherwise dephased out in the conventional HNN experiment. It enables acquisition of 2D (13)C(alpha)-(15)N sequential correlations along with the standard 3D (15)N-(15)N-(1)H correlations, which provides directionality to sequential walk in HNN, on one hand, and enhances the speed of backbone assignment, on the other. We foresee that the implementation of dual direct detection opens up new avenues for a wide variety of modifications that would further enhance the value and applications of the experiment, and enable derivation of hitherto impossible information. PMID- 22203188 TI - Smoking prevalence among monks in Thailand. AB - Previous studies among Buddhist monks in Thailand have reported smoking rates to be as high as 55%. Because 95% of Thais are Buddhist, monks are highly influential in establishing normative behavioral patterns. As the first population-based study on smoking among Buddhist monks in Thailand, this study aims to determine the smoking prevalence in six regions of the country, and to examine smoking knowledge, risk perceptions, behaviors, and associated demographics among full-fledged and novice monks (n = 6,213). Results demonstrated that the overall prevalence for current smoking monks is 24.4% (95% confidence interval [24.453, 24.464]), with regional differences ranging from 14.6% (North) to 40.5% (East). Findings suggest that integrating prevention and cessation programming into religious courses may be one avenue for reaching many incoming monks. Further, involving monks in tobacco control education and setting a nonsmoking standard among them is vital to the success of reducing smoking rates among the general population in Thailand. PMID- 22203189 TI - The chromodomain-containing NH(2)-terminus of Chromator interacts with histone H1 and is required for correct targeting to chromatin. AB - The chromodomain protein, Chromator, can be divided into two main domains, a NH(2)-terminal domain (NTD) containing the chromodomain (ChD) and a COOH-terminal domain (CTD) containing a nuclear localization signal. During interphase Chromator is localized to chromosomes; however, during cell division Chromator redistributes to form a macro molecular spindle matrix complex together with other nuclear proteins that contribute to microtubule spindle dynamics and proper chromosome segregation during mitosis. It has previously been demonstrated that the CTD is sufficient for targeting Chromator to the spindle matrix. In this study, we show that the NTD domain of Chromator is required for proper localization to chromatin during interphase and that chromosome morphology defects observed in Chromator hypomorphic mutant backgrounds can be largely rescued by expression of this domain. Furthermore, we show that the ChD domain can interact with histone H1 and that this interaction is necessary for correct chromatin targeting. Nonetheless, that localization to chromatin still occurs in the absence of the ChD indicates that Chromator possesses a second mechanism for chromatin association and we provide evidence that this association is mediated by other sequences residing in the NTD. Taken together these findings suggest that Chromator's chromatin functions are largely governed by the NH(2)-terminal domain whereas functions related to mitosis are mediated mainly by COOH-terminal sequences. PMID- 22203190 TI - Similarities and differences between "uncapped" telomeres and DNA double-strand breaks. AB - Telomeric DNA is present at the ends of eukaryotic chromosomes and is bound by telomere "capping" proteins, which are the (Cdc13-Stn1-Ten1) CST complex, Ku (Yku70-Yku80), and Rap1-Rif1-Rif2 in budding yeast. Inactivation of any of these complexes causes telomere "uncapping," stimulating a DNA damage response (DDR) that frequently involves resection of telomeric DNA and stimulates cell cycle arrest. This is presumed to occur because telomeres resemble one half of a DNA double-strand break (DSB). In this review, we outline the DDR that occurs at DSBs and compare it to the DDR occurring at uncapped telomeres, in both budding yeast and metazoans. We give particular attention to the resection of DSBs in budding yeast by Mre11-Xrs2-Rad50 (MRX), Sgs1/Dna2, and Exo1 and compare their roles at DSBs and uncapped telomeres. We also discuss how resection uncapped telomeres in budding yeast is promoted by the by 9-1-1 complex (Rad17-Mec3-Ddc1), to illustrate how analysis of uncapped telomeres can serve as a model for the DDR elsewhere in the genome. Finally, we discuss the role of the helicase Pif1 and its requirement for resection of uncapped telomeres, but not DSBs. Pif1 has roles in DNA replication and mammalian and plant CST complexes have been identified and have roles in global genome replication. Based on these observations, we suggest that while the DDR at uncapped telomeres is partially due to their resemblance to a DSB, it may also be partially due to defective DNA replication. Specifically, we propose that the budding yeast CST complex has dual roles to inhibit a DSB like DDR initiated by Exo1 and a replication-associated DDR initiated by Pif1. If true, this would suggest that the mammalian CST complex inhibits a Pif1-dependent DDR. PMID- 22203191 TI - Protection from glutamate-induced excitotoxicity by memantine. AB - This study investigates whether the uncompetitive N-methyl-D-aspartic acid receptor antagonist, memantine, is able to protect dissociated cortical neurons from glutamate-induced excitotoxicity (GIE). Treatment with glutamate resulted in a significant loss of synchronization of neuronal activity as well as a significant increase in the duration of synchronized bursting events (SBEs). By administering memantine at the same time as glutamate, we were able to completely prevent these changes to the neuronal activity. Pretreatment with memantine was somewhat effective in preventing changes to the culture synchronization but was unable to fully protect the synchronization of electrical activity between neurons that showed high levels of synchronization prior to injury. Additionally, memantine pretreatment was unable to prevent the increase in the duration of SBEs caused by GIE. Thus, the timing of memantine treatment is important for conferring neuroprotection against glutamate-induced neurotoxicity. Finally, we found that GIE leads to a significant increase in the burst duration. Our data suggest that this may be due to an alteration in the inhibitory function of the neurons. PMID- 22203192 TI - Large, but not small sustained tensile strains stimulate adipogenesis in culture. AB - Understanding the mechanoresponsiveness of adipocytes and the characteristics of the mechanical stimuli that regulate adipogenesis is critically important in establishing knowledge in regard to the long-term effects of a sedentary lifestyle (or immobility in extreme medical conditions) as well as concerning obesity and related diseases. In this study we subjected 3T3-L1 preadipocytes cultured on elastic substrata to different levels of static equiaxial tensile strains within the physiological range, up to substrate tensile strain (STS) of 12%, while inducing differentiation in the cultures. Based on prior work which revealed that adipogenesis is accelerated in cultures subjected to STS of 12% by activating the mitogen-activated protein kinase kinase signaling pathway, we were specifically interested in identifying the STS levels which trigger this process. We hence monitored the production and accumulation of lipid droplets (LDs) using a non-destructive, image-processing-based method that we have previously developed, for a period of 4 weeks. The experimental data demonstrated accelerated adipogenesis in the cultures subjected to STS levels of 6%, 9%, and 12% with respect to cultures subjected to STS of 3% and (non-stretched) control cultures. This accelerated adipogenic response to the large sustained STS manifested in significantly larger numbers and greater sizes of LDs in the cultures that were stretched to large STS levels (p < 0.05), starting at approximately day 14 following induction of differentiation. Hence, indeed, there appears to be a certain tensile strain threshold, or domain-which is found within the physiological range-above which the responsiveness of adipocytes to sustained static stretching increases and is manifested in accelerated adipogenesis. PMID- 22203212 TI - Microarray analysis of differentially expressed genes between Brassica napus strains with high- and low-oleic acid contents. AB - An increase in oleic acid (C18:1) content is a desirable trait. Despite the critical roles of the two desaturases, FAD2 and FAD3, in the control of fatty acid desaturation, a dispute remains over whether inactivation of their genes alone is sufficient enough to generate the high-oleic trait. To address this question, we employed microarray technology to investigate the difference in gene expression profile between two different Brassica napus strains with high-C18:1 (71.71%) and low-C18:1 (55.6%) contents, respectively. Our study revealed 562 differentially expressed genes, of which 194 genes were up-regulated and 368 down regulated. Based on the Gene Ontology classification, these genes were classified into 23 functional categories. Three of the up-regulated genes represent B. napus homologs of Arabidopsis genes encoding a cytosolic isoform of pyruvate kinase (AT3G55810), Delta9 acyl-lipid desaturase (AT1G06080, ADS1) and fatty acyl-ACP thioesterase B (AT1G08510), respectively. Conversely, the homologs of two Arabidopsis sequences encoding Delta9 acyl-lipid desaturase (AT2G31360, ADS2) and FAD3 desaturase (AT2G29980) were down-regulated in the high-oleic acid strain. Furthermore, 60 differentially expressed genes were classified as associated with relevant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Collectively, our results suggest that expressing the high-oleic acid trait may require a coordinated regulation of diverse regulatory and metabolic gene networks in addition to inactivation of the FAD2 and FAD3 genes in the oilseed. A set of the differentially expressed genes identified in this study will facilitate our efforts to tap the germplasms with the potential to express the high-oleic acid trait. PMID- 22203213 TI - Molecular evolution of a family of resistance gene analogs of nucleotide-binding site sequences in Solanum lycopersicum. AB - Nucleotide-binding site-leucine-rich repeats (NBS-LRR) gene families are one of the major plant resistance genes. Genomic NBS evolution was studied in many plant species for diverse arrays of NBS gene families. In this study, we focused on one family of NBS sequences in an attempt to understand how closely related NBS sequences evolved in the light of selection in domesticated plant species. A phylogenetic analysis revealed five major clades (A-E) and five subclades (A1-A5) within clade A of cloned NBS sequences. Positive selection was only detected in newly evolved NBS lineages in subclades of clade A. Positively selected codon sites were found among NBS sequences of clade A. A sliding-window analysis revealed that regions with Ka/Ks ratios of >1 were in the inter-motifs when paired clades were compared, but regions with Ka/Ks ratios of >1 were found across NBS sequences when subclades of clade A were compared. Our results based on a family of closely related NBS sequences showed that positive selection was first exerted on specific lineages across all NBS sequences after selective constraints. Subsequently, sequences with mutations in commonly conserved motifs were scrutinized by purifying selection. In the long term, conserved high frequency alleles in commonly conserved motifs and changes in inter-motifs were maintained in the investigated family of NBS sequences. Moreover, codons identified to be under positive selection in the inter-motifs were mainly located in regions involved in functions of ATP binding or hydrolysis. PMID- 22203215 TI - Regenerating gene (REG) 1 alpha promotes pannus progression in patients with rheumatoid arthritis. AB - INTRODUCTION: A protein analysis using mass spectrometry revealed the existence of serum proteins with significant quantitative changes after the administration of infliximab. Among these proteins, regenerating gene (REG) 1alpha appears to be related to the pathogenesis of rheumatoid arthritis (RA). Therefore, the present study was conducted to examine the mechanism of REG1alpha in RA disease progression. METHODS: Serum samples were collected from RA patients and normal healthy controls. REG1alpha expression was evaluated by ELISA, RT-PCR, and indirect immunofluorescence microscopy. The functions of REG1alpha on synovial fibroblasts with regard to apoptosis, receptor activator of NF-kappaB ligand (RANKL) expression, and cellar proliferation were evaluated using siRNA to inhibit the intrinsic REG1alpha mRNA expression. RESULTS: The serum concentrations of REG1alpha in RA patients were higher than in normal healthy controls. The high expression of REG1alpha was also observed in the synovial tissue of RA patients compared to those of osteoarthropathy patients. In addition, tumor necrosis factor-alpha (TNF-alpha) upregulated REG1alpha expression in the synovial fibroblasts cell line (MH7A). Inhibition of REG1alpha expression suppressed the induction of RANKL expression by TNF-alpha. Furthermore, exogenous recombinant REG1alpha protein inhibited apoptosis and promoted cell proliferation in MH7A cells. These effects were abolished in the REG1alpha-siRNA MH7A cells. CONCLUSION: The present data suggest that TNF-alpha induces aberrant REG1alpha expression and that REG1alpha plays an important role in aberrant cell proliferation and RANKL expression of synovial fibroblasts, ultimately resulting in pannus formation. Restoration of normal physiological REG1alpha expression may contribute to disease amelioration. PMID- 22203214 TI - Bay846, a new irreversible small molecule inhibitor of EGFR and Her2, is highly effective against malignant brain tumor models. AB - The epidermal growth factor receptor (EGFR) pathway is aberrantly activated in tumors and plays a key role in promoting tumor growth. Small molecule inhibitors which bind reversibly to EGFR have demonstrated limited clinical activity. Thus, there is a continued need to develop novel EGFR inhibitors with improved anti tumor activity. Bay846 is a newly developed small molecule inhibitor that binds irreversibly to the tyrosine kinase domains of EGFR and Her2. The in vitro and in vivo efficacy of Bay846 was tested using a panel of nine human malignant brain tumor (glioma) models. Lapatinib, a reversible inhibitor of EGFR and Her2, was included for comparison. Six glioma cell lines were sensitive to Bay846 treatment. Bay846 strongly suppressed tumor cell growth in vitro by inducing cell lysis/death rather than cell cycle arrest. Consistent with this, Bay846 had potent anti-tumor activity which led to regressions in tumor size. The active, phosphorylated form of EGFR was reduced by Bay846 treatment in vitro and in tumors. Importantly, the efficacy of Bay846 was significantly greater than lapatinib in all assays. Bay846-sensitivity was associated with expression of a wild-type PTEN in conjunction with high levels of an oncogenic EGFR variant (A289V or EGFRvIII). These studies demonstrate that targeting the EGFR pathway with the irreversible inhibitor Bay846 has great potential to increase the efficacy of this cancer therapy. PMID- 22203216 TI - Magnetic resonance imaging (MRI) detection of synovitis and bone lesions of the wrists and finger joints in early-stage rheumatoid arthritis: comparison of the accuracy of plain MRI-based findings and gadolinium-diethylenetriamine pentaacetic acid-enhanced MRI-based findings. AB - OBJECTIVE: To explore whether synovitis and bone lesions in the wrists and finger joints visualized by plain magnetic resonance imaging (MRI)-based findings correspond exactly or not to those judged by gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced MRI-based findings. METHODS: Magnetic resonance imaging of the wrists and finger joints of both hands were examined in 51 early-stage rheumatoid arthritis (RA) patients whose median disease duration from the onset of articular manifestations to entry was 5 months, by both plain (T1 and short-time inversion recovery images) and Gd-DTPA-enhanced MRI (post contrast fat-suppressed T1-weighted images) simultaneously. We focused on 15 sites per hand, to examine the presence of synovitis and bone lesions (bone edema and bone erosion). Gd-DTPA-enhanced MRI-based findings were considered "true" lesions, and we evaluated the accuracy of plain MRI-based findings in comparison to Gd-DTPA-enhanced MRI-based findings. RESULTS: Synovitis, judged by plain MRI based findings, appeared as false-positive at pretty frequency; thus, the specificity, positive predictive value and accuracy of the findings were low. The rate of enhancement (E-rate) in false-positive synovitis sites was significantly low compared with true-positive synovitis sites where Gd-DTPA enhancement appears. In contrast to synovitis, the false-positivity of bone lesions, judged by plain MRI-based findings, was very low compared with Gd-DTPA-enhanced MRI based findings. CONCLUSION: Synovitis judged by plain MRI-based findings is sometimes considered false-positive especially in sites where synovitis is mild. However, plain MRI is effective in identifying bone lesions in the wrist and finger joints in early-stage RA. PMID- 22203217 TI - Estimates of phenotypic and genetic parameters for birth weight of Brown Swiss calves in Turkey using an animal model. AB - A study was conducted to assess the influence of genetic and environmental factors on Brown Swiss calf birth weight, and to estimate variance components, genetic parameters, and breeding values. Data were collected on 1,761 Brown Swiss calves born from 1990 to 2005 in the Konuklar State Farm in Turkey. Mean birth weight for all calves was 39.3 +/- 0.09 kg. Least squares mean birth weights for male and female Brown Swiss calves were 40.3 +/- 0.02 and 39.0 +/- 0.02 kg, respectively. Variance components, genetic parameters, and breeding values for birth weight in Brown Swiss calves were estimated by restricted error maximum likelihood (REML)-best linear unbiased prediction(BLUP) procedures using an MTDFREML (multiple trait derivative free restricted maximum likelihood) program employing an animal model. Direct heritability (h(d)(2)), maternal heritability (h(m)(2)), total heritability (h(T)(2)), r(am) and c(am) estimates were 0.12, 0.09, 0.23, -0.58, and -0.06, respectively. The estimated maternal permanent environmental variance expressed as a proportion of the phenotypic variance (c(2)) was 0.05. Breeding values were estimated for the trait and used to evaluate genetic trends across the time period investigated. The genetic trend linear regression was not different from zero. No genetic trend for birth weight was expected, since there had been no direct selection pressure on the trait. Absence of a trend confirms that there was no change due to selection pressure on correlated traits. Genetic and environmental parameter estimates were similar to literature values indicating that effective selection methods used in more developed improvement programs would be effective in Turkey as well. PMID- 22203218 TI - Determinants of farmers' choice for veterinary service providers in Nepal Mountains. AB - This study was aimed to analyze factors that affect farmers' choice for major actors of veterinary service providers in village areas of Kaski district of Nepal, with the objective of identifying choice-specific attributes which could be addressed for improving the penetration of professional veterinary services in village areas. The information was obtained from 125 farmers using a structured questionnaire. A proportional hazard model was used for data analysis because of its ability to accommodate the attributes of both the chooser and the choice simultaneously. The results showed that village animal health workers (VAHWs) were the most preferred service providers followed by veterinarians and mid-level technicians. The farmers' age and education level had a significant but inverse relationship with the probability of choosing any of the three service providers. From our study, we found that the main choice-specific attributes with a significant impact on the choice probability was the distance to the preferred service provider. Since there was a high preference for VAHW, this suggests the possibility of poorly trained service providers dominating veterinary service market in village areas of Kaski district. Hence, the efforts put forward in the legalization of VAHW system in Nepal should first address the constraints that obstruct the accessibility of professional veterinary service providers in village areas. PMID- 22203219 TI - Mutation risk associated with paternal and maternal age in a cohort of retinoblastoma survivors. AB - Autosomal dominant conditions are known to be associated with advanced paternal age, and it has been suggested that retinoblastoma (Rb) also exhibits a paternal age effect due to the paternal origin of most new germline RB1 mutations. To further our understanding of the association of parental age and risk of de novo germline RB1 mutations, we evaluated the effect of parental age in a cohort of Rb survivors in the United States. A cohort of 262 Rb patients was retrospectively identified at one institution, and telephone interviews were conducted with parents of 160 survivors (65.3%). We classified Rb survivors into three groups: those with unilateral Rb were classified as sporadic if they had no or unknown family history of Rb, those with bilateral Rb were classified as having a de novo germline mutation if they had no or unknown family history of Rb, and those with unilateral or bilateral Rb, who had a family history of Rb, were classified as familial. We built two sets of nested logistic regression models to detect an increased odds of the de novo germline mutation classification related to older parental age compared to sporadic and familial Rb classifications. The modeling strategy evaluated effects of continuous increasing maternal and paternal age and 5-year age increases adjusted for the age of the other parent. Mean maternal ages for survivors classified as having de novo germline mutations and sporadic Rb were similar (28.3 and 28.5, respectively) as were mean paternal ages (31.9 and 31.2, respectively), and all were significantly higher than the weighted general US population means. In contrast, maternal and paternal ages for familial Rb did not differ significantly from the weighted US general population means. Although we noted no significant differences between mean maternal and paternal ages between each of the three Rb classification groups, we found increased odds of a survivor being in the de novo germline mutation group for each 5-year increase in paternal age, but these findings were not statistically significant (de novo vs. sporadic ORs 30-34 = 1.7 [0.7-4], >= 35 = 1.3 [0.5-3.3]; de novo vs. familial ORs 30-34 = 2.8 [1.0-8.4], >= 35 = 1.6 [0.6-4.6]). Our study suggests a weak paternal age effect for Rb resulting from de novo germline mutations consistent with the paternal origin of most of these mutations. PMID- 22203230 TI - Early adult-onset orbital apex Langerhans cell histiocytosis histologically confirmed during "truly spontaneous" regression. PMID- 22203231 TI - Orbital solitary fibrous tumor: a clinicopathologic study of ten cases with long term follow-up. AB - BACKGROUND: Solitary fibrous tumor (SFT) is a rare spindle-cell benign neoplasm and located in orbit. The present research represents case reports of ten patients with orbital SFT. METHOD: Prognosis was assessed by clinic service and telephone interview. Clinical data were retrieved from the medical records. Immunohistochemistry for CD34, CD99, EMA, HMB-45, Bcl-2, GFAP, S-100, MBP, CK, and MIB-1 was performed. Distributions of time to progression and recurrence between different operative methods were estimated using the Kaplan-Meier method and compared using the log-rank test. FINDINGS: The ten patients included six men and four women (range: 19-75 years). The most common initial symptom was painless proptosis (n = 6). After the ten initial surgeries, with four requiring gross total resection (GRT) and six requiring subtotal resection (STR), an additional nine were required to remove recurrent tumors. Eighteen samples were obtained for pathological examination (the third sample for case 4 was not achieved). Cellular areas with partial hemangiopericytoma pattern were noted in four samples (4/18); scarce mitosis was noted in six samples (6/18). All SFTs (18/18) were positive for CD34, CD99 and vimentin, while all SFTs (18/18) were negative for EMA, CK, MBP, HBM-45 and GFAP. Bcl-2 was positive in 13/18 cases, while S-100 was negative in 14/18 cases. The MIB-1 labeling index varied from 1% to 3%. Follow-up was available for nine patients with a median of 88 months. All four patients who underwent GTR on initial operation did not recur; while the five patients who underwent STR recurred. The log-rank test showed that the incomplete surgical resection was significantly associated with recurrence (p = 0.015). CONCLUSIONS: Orbital SFT is a rare mesenchymal tumor and painless proptosis is the most common initial symptom. Immunohistochemistry should be used to differentiate SFT from other tumors. Orbital SFT usually has a non-aggressive histological characteristic, and has a good prognosis if GTR is performed. Postoperative regular and long-term follow-up remains mandatory to monitor recurrence. PMID- 22203233 TI - A chemoenzymatic approach toward the identification of fucosylated glycoproteins and mapping of N-glycan sites. AB - Fucose (Fuc)-containing glycoconjugates play important roles in numerous physiological and pathological processes. Given the biological importance of post translational glycosylation, a specific and robust strategy for the identification of fucosylated glycoproteins is highly desirable. In this study, we demonstrate an alternative way of labeling of fucosylated structures by metabolic engineering, using a chemoenzymatic approach. In this approach, the activities of Bacteroides fragilis 9343 L-fucokinase/guanosine-5'-diphosphate-Fuc pyrophosphorylase and human alpha1,3-fucosyltransferase 9 are combined in a Namalwa cellular model. Interestingly, this system could be applied to labeling of alkyne-modified fucosylated glycoproteins. N-Glycan site mapping and identification were done using an in vitro selective chemical ligation reaction and isotope-coded glycosylation site-specific tagging, subsequent to liquid chromatography-tandem mass spectrometry analysis. This work illustrates the use of a click chemistry-based strategy combined with a glycoproteomic technique to get further insight into the pattern of Fuc-mediated biological processes and functions. PMID- 22203232 TI - Characterization of interleukin-33 and soluble ST2 in serum and their association with disease severity in patients with chronic kidney disease. AB - INTRODUCTION: This study aims to test the serum levels of interleukin-33 (IL-33) and soluble ST2 (sST2) in patients with chronic kidney disease (CKD) and to evaluate their association with disease severity. METHODS: Sixty-nine patients with CKD were enrolled, disease severity was assessed, and clinical data were collected. Twelve healthy volunteers served as healthy individuals. Serum IL-33 and sST2 were tested by enzyme-linked immunosorbent assay. RESULTS: The patients were classified into five categories based on their estimated glomerular filtration rate (eGFR). No difference was found as to the serum concentration of IL-33 between CKD patients and healthy individuals (p = 0.656), while a higher serum level of sST2 was found in CKD patients (p = 0.003). The correlation analysis revealed a significant correlation between the serum level of sST2 and disease severity (r = 0.586; p < 0.001). A higher level of sST2 was found in CKD patients with elevated parathyroid hormone (p = 0.001). Serum sST2 correlated with parathyroid hormone (r = 0.412; p < 0.001), serum phosphorus (r = 0.545; p < 0.001), and serum calcium (r = -0.494; p < 0.001). CONCLUSION: An elevated concentration of serum sST2 is found in CKD patients and correlates with disease severity. Serum sST2 may be also associated with parathyroid hormone disorder of CKD. The sST2 may have an important role in the development of CKD or as a marker of disease severity. PMID- 22203234 TI - Is thyroid-stimulating hormone within the normal reference range a risk factor for atherosclerosis in women? AB - The relationship between overt hypothyroidism and cardiovascular risk has been well documented and some data also suggest an association between cardiovascular risk and subclinical hypothyroidism. The aim of our study was to investigate, in a large cohort of euthyroid women, the association of thyroid stimulating hormone (TSH) within the normal reference range with cardiovascular risk factors. The study was carried out on 744 women with normal thyroid function (TSH 0.3-4.9 MUU/mL). Women with TSH above the median (>=2.1 MUU/mL) were more obese, had greater waist girth, were more hypertensive and had higher levels of total cholesterol (TC), serum triglycerides (TG), blood sugar (BG) and lower levels of HDL-cholesterol (HDL-C) than women with TSH below the median. TSH was significantly correlated with body mass index (BMI), waist circumference, BG, TG, TC, HDL-C and hypertension. Multiple backward stepwise regression analysis with age, waist circumference and TSH as independent variables confirmed the strong association of TSH with BG, TG, HDL-C and hypertension. A total of 205 patients (28%) fulfilled the definition criteria of the metabolic syndrome and the prevalence of metabolic syndrome was significantly greater in patients with TSH above than in patients with TSH below the median. Results of logistic analysis, including age and TSH as predictor variables, confirmed the association of TSH with metabolic syndrome.The results of this study suggest that TSH in the upper limits of the reference range (above 2.1 MUU/ml) is associated with a less favourable cardiometabolic profile and consequently with a higher risk of developing cardiovascular diseases. PMID- 22203235 TI - Chlamydia pneumoniae entry into epithelial cells by clathrin-independent endocytosis. AB - A gram-negative obligate intracellular bacterium, Chlamydia pneumoniae, is a common respiratory pathogen. Here, we examined the invasion and attachment of C. pneumoniae K6 into nonphagocytic HL epithelial cell line by manipulating host plasma membranes by using cholesterol-depleting methyl-beta-cyclodextrin (MbetaCD) and cholesterol-loading MbetaCD complexed cholesterol (chol-MbetaCD). The invasion was attenuated by MbetaCD-treatment while chol-MbetaCD augmented the attachment and invasion. In addition, the invasion was inhibited by cholesterol sequestering reagents, nystatin and filipin. Furthermore, exposure of host cells to sphingomyelinase inhibited the invasion. RNA interference was used to assay the role of clathrin and human scavenger receptor B, type I (SR-BI) in the entry of C. pneumoniae into A549 lung epithelial adenocarcinoma cells. In contrast to Chlamydia trachomatis L2, the entry of C. pneumoniae was found to be independent of clathrin. In addition, the entry was found to be SR-BI-independent, but interestingly, the chlamydial growth was attenuated in the SR-BI-silenced cells. These findings suggest that the attachment and invasion of C. pneumoniae into nonphagocytic epithelial cells is dependent on the formation of cholesterol- and sphingomyelin-rich plasma membrane microdomains, and the entry is a clathrin independent process. In addition, our data indicate that SR-BI supports the growth of C. pneumoniae in epithelial cells. PMID- 22203236 TI - Treatment of homonymous visual field defects. AB - OPINION STATEMENT: A clinical presentation of a retrochiasmal or homonymous visual field defect (HVFD) usually represents a permanent visual impairment. The visual and functional ramifications of HVFD will vary by patient. Comprehensive care-the clinical evaluation and consideration for treatment of HVFD-includes vision rehabilitation provided by optometrists, occupational therapists, or ophthalmologists. On the basis of individual patient needs, the eye care practitioner typically uses one or both of the following approaches to treat the HVFD: (1) field enhancement (also referred to in the literature as "field expansion"), in which optical systems incorporating prism are prescribed to optimize the use of the remaining vision, and (2) rehabilitative techniques including saccadic training ("compensation training") or vision restorative therapy ("restitution training"). Although lacking in strength, the evidence does support benefits from field enhancement and saccadic training for patients with HVFD, but vision restorative therapy has not been shown to be an effective option. PMID- 22203237 TI - Bevacizumab for glioblastoma refractory to vascular endothelial growth factor receptor inhibitors. AB - Glioblastoma (GBM) is a highly vascular tumor dependent on angiogenesis through the vascular endothelial growth factor (VEGF) signaling cascade. Inhibition of VEGF signaling is an important therapeutic strategy. We report our experience with bevacizumab (BEV), a VEGF targeting antibody, following failure of a VEGF receptor targeting tyrosine kinase inhibitor (TKI). We retrospectively identified patients treated on clinical trials with VEGFR-TKIs for recurrent GBM followed by BEV at next recurrence. Survival was estimated by the Kaplan-Meier method. Fourteen patients were identified (six women; median age 57). All received VEGFR TKIs (sunitinib 11, cediranib 2, sorafenib 1) then BEV at next recurrence. There were no radiographic responses to VEGFR-TKIs; best response was stable disease in 50% (7/14). Patients received BEV alone (21%, 3/14) or in combination with chemotherapy (79%, 11/14). On BEV, 29% (4/14) had a partial response, and 36% (5/14) stabilized. Of evaluable patients, 42% (5/12) had neurological improvement and 56% (5/9) reduced corticosteroid requirement. Median survival on BEV was 7.8 months (95% CI 4.0-15.8), median progression-free survival (PFS) was 4.0 months (95% CI 1.6-10.5), and the 6-month PFS rate was 29% (95% CI 9-52). Our radiographic and survival outcomes with BEV following progression after VEGFR TKIs are similar to data from studies of BEV as initial salvage therapy, although our sample size was small. Prior exposure to VEGFR-TKIs may not preclude response to BEV, but sensitivity to BEV may be lower following more robust VEGFR inhibition. PMID- 22203238 TI - Importance of prostate volume in the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculators: results from the prostate biopsy collaborative group. AB - OBJECTIVES: To compare the predictive performance and potential clinical usefulness of risk calculators of the European Randomized Study of Screening for Prostate Cancer (ERSPC RC) with and without information on prostate volume. METHODS: We studied 6 cohorts (5 European and 1 US) with a total of 15,300 men, all biopsied and with pre-biopsy TRUS measurements of prostate volume. Volume was categorized into 3 categories (25, 40, and 60 cc), to reflect use of digital rectal examination (DRE) for volume assessment. Risks of prostate cancer were calculated according to a ERSPC DRE-based RC (including PSA, DRE, prior biopsy, and prostate volume) and a PSA + DRE model (including PSA, DRE, and prior biopsy). Missing data on prostate volume were completed by single imputation. Risk predictions were evaluated with respect to calibration (graphically), discrimination (AUC curve), and clinical usefulness (net benefit, graphically assessed in decision curves). RESULTS: The AUCs of the ERSPC DRE-based RC ranged from 0.61 to 0.77 and were substantially larger than the AUCs of a model based on only PSA + DRE (ranging from 0.56 to 0.72) in each of the 6 cohorts. The ERSPC DRE-based RC provided net benefit over performing a prostate biopsy on the basis of PSA and DRE outcome in five of the six cohorts. CONCLUSIONS: Identifying men at increased risk for having a biopsy detectable prostate cancer should consider multiple factors, including an estimate of prostate volume. PMID- 22203239 TI - Exosomes released by K562 chronic myeloid leukemia cells promote angiogenesis in a Src-dependent fashion. AB - Exosomes, microvesicles of endocytic origin released by normal and tumor cells, play an important role in cell-to-cell communication. Angiogenesis has been shown to regulate progression of chronic myeloid leukemia (CML). The mechanism through which this happens has not been elucidated. We isolated and characterized exosomes from K562 CML cells and evaluated their effects on human umbilical endothelial cells (HUVECs). Fluorescent-labeled exosomes were internalized by HUVECs during tubular differentiation on Matrigel. Exosome localization was perinuclear early in differentiation, moving peripherally in cells undergoing elongation and connection. Exosomes move within and between nanotubular structures connecting the remodeling endothelial cells. They stimulated angiotube formation over a serum/growth factor-limited medium control, doubling total cumulative tube length (P = 0.003). Treatment of K562 cells with two clinically active tyrosine kinase inhibitors, imatinib and dasatinib, reduced their total exosome release (P < 0.009); equivalent concentrations of drug-treated exosomes induced a similar extent of tubular differentiation. However, dasatinib treatment of HUVECs markedly inhibited HUVEC response to drug control CML exosomes (P < 0.002). In an in vivo mouse Matrigel plug model angiogenesis was induced by K562 exosomes and abrogated by oral dasatinib treatment (P < 0.01). K562 exosomes induced dasatinib-sensitive Src phosphorylation and activation of downstream Src pathway proteins in HUVECs. Imatinib was minimally active against exosome stimulation of HUVEC cell differentiation and signaling. Thus, CML cell-derived exosomes induce angiogenic activity in HUVEC cells. The inhibitory effect of dasatinib on exosome production and vascular differentiation and signaling reveals a key role for Src in both the leukemia and its microenvironment. PMID- 22203241 TI - In vivo quantification of tumor receptor binding potential with dual-reporter molecular imaging. AB - PURPOSE: Receptor availability represents a key component of current cancer management. However, no approaches have been adopted to do this clinically, and the current standard of care is invasive tissue biopsy. A dual-reporter methodology capable of quantifying available receptor binding potential of tumors in vivo within a clinically relevant time scale is presented. PROCEDURES: To test the methodology, a fluorescence imaging-based adaptation was validated against ex vivo and in vitro measures of epidermal growth factor receptor (EGFR) binding potential in four tumor lines in mice, each line expected to express a different level of EGFR. RESULTS: A strong correlation was observed between in vivo and ex vivo measures of binding potential for all tumor lines (r = 0.99, p < 0.01, slope = 1.80 +/- 0.48, and intercept = -0.58 +/- 0.84) and between in vivo and in vitro for the three lines expressing the least amount of EGFR (r = 0.99, p < 0.01, slope = 0.64 +/- 0.32, and intercept = 0.47 +/- 0.51). CONCLUSIONS: By providing a fast and robust measure of receptor density in tumors, the presented methodology has powerful implications for improving choices in cancer intervention, evaluation, and monitoring, and can be scaled to the clinic with an imaging modality like SPECT. PMID- 22203240 TI - CLT1 targets angiogenic endothelium through CLIC1 and fibronectin. AB - Angiogenesis is important for tumor growth and metastasis. CLT1 (CGLIIQKNEC), a peptide that binds to tumor interstitial spaces in the presence of fibrin fibronectin, has structural similarity to the anti-angiogenic beta-sheet peptides anastellin and anginex. This similarity is reflected in the ability of CLT1 to form co-aggregates with fibronectin that induce an unfolded protein response and cause autophagic cell death in proliferating endothelial cells. CLT1 cytotoxicity is mediated at least in parts by a novel CLT1 binding protein, Chloride Intracellular Channel 1 (CLIC1), which promotes internalization of CLT1 fibronectin co-aggregates in a mechanism that depends on the LIIQK amino acid sequence of CLT1. LIIQK encompasses amino acid residues relevant for CLT1 binding to CLIC1 and in addition, facilitates the formation of CLT1-fibronectin co aggregates, which in turn promote translocation of CLIC1 to the endothelial cell surface through ligation of integrin alphavbeta3. Paralleling the in vitro results, we found that CLT1 co-localizes with CLIC1 and fibronectin in angiogenic blood vessels in vivo, and that CLT1 treatment inhibited angiogenesis and tumor growth. Our findings show that CLT1 is a new anti-angiogenic compound, and its mechanism of action is to form co-aggregates with fibronectin, which bind to angiogenic endothelial cells through integrins, become internalized through CLIC1 and elicit a cytotoxic unfolded protein response. The simple structure and high potency of CLT1 make it a potentially useful compound for anti-angiogenic treatments. PMID- 22203243 TI - PAHs in surface sediments from coastal and estuarine areas of the northern Bohai and Yellow Seas, China. AB - Polycyclic aromatic hydrocarbon (PAH) concentrations and their risks in surface sediments (n = 35) collected from coastal and estuarine areas of the northern Bohai and Yellow Seas, China, were investigated in 2008. Total concentrations of PAHs ranged from 52.3 to 1,870.6 ng/g dry weight. The greatest concentrations were observed in the Dou River of Tangshan where waste water from small factories is discharged into the river without treatment. At other locations, municipal sewage was the primary contributor of PAHs. Regional differences in concentrations of PAHs in sediments are related to human activities. Concentrations of PAHs were significantly correlated with concentrations of organic carbon in sediments. The patterns of relative concentrations and types of PAHs observed and knowledge of the potential sources, as well as the results of a principal component analysis, are consistent with the primary sources of PAHs in sediments of the northern Bohai Sea and Yellow Sea, being derived from the high temperature pyrolytic processes such as combustion of fossil fuel. While concentrations of PAHs at most locations did not exceed the effects range median stated by the numerical effect-based sediment quality guidelines of the United States, concentrations of PAHs at some locations were similar to or greater than the effects range low. PMID- 22203244 TI - Effects of sugammadex on immunoreactivity of calcineurin in rat testes cells after neuromuscular block: a pilot study. AB - Reversal of neuromuscular blockage induced by steroidal neuromuscular blocking agents such as rocuronium can be achieved using normal dose of sugammadex, which has been shown to be very effective for such reversal. In this study, we determined the effects of sugammadex on calcineurin immunoreactivity by examining the histopathological and histochemical structure of rat testis cells after neuromuscular blockage. Moreover, the regional distribution levels of calcineurin immunopositive testes cells were investigated. Eighteen adult male, Sprague Dawley rats were divided into one control and two study groups. Study groups 1 and 2 rats received sugammadex at doses of 16 and 96 mg kg(-1) i.v., respectively, after rocuronium treatment (mg kg(-1) i.v.). The control group received intravenous 0.9% NaCl 1 ml. i.v without any drug. Our study demonstrates that sugammadex is safe and effective for reversal of rocuronium effects in rats, as well as in other animals and humans. Furthermore, histopathological examination indicates that high levels of sugammadex-rocuronium complexes accumulate a little in testis tissue. We found that rocuronium-sugammadex complexes were remained in circulation for a long time resulting in a decrease in interstitial space, testis size, germ cell numbers and Leydig cell numbers. Calcineurin immunoreactivity was higher in the experimental groups than the control group due to increase of calcium level. The results suggest that sugammadex-rocuronium complexes are cause histopathological and immunohistochemical changes in testis interstitial tissues, as well as changes in sperm density and germ cell number. PMID- 22203245 TI - Basic fibroblast growth factor supports expansion of mouse compact bone-derived mesenchymal stem cells (MSCs) and regeneration of bone from MSC in vivo. AB - Some progress has been made in development of methods to regenerate bone from cultured cells, however no method is put to practical use. Here, we developed methods to isolate, purify, and expand mesenchymal stem cells (MSCs) from mouse compact bone that may be used to regenerate bone in vivo. These cells were maintained in long-term culture and were capable of differentiating along multiple lineages, including chondrocyte, osteocyte, and adipocyte trajectories. We used standard cell isolation and culture methods to establish cell cultures from mouse compact bone and bone marrow. Cultures were grown in four distinct media to determine the optimal composition of culture medium for bone-derived MSCs. Putative MSCs were subjected to flow cytometry, alkaline phosphatase assays, immunohistochemical staining, and several differentiation assays to assess cell identity, protein expression, and developmental potential. Finally, we used an in vivo bone formation assay to determine whether putative MSCs were capable of regenerating bone. We found that compact bone of mice was a better source of MCSs than the bone marrow, that growth in plastic flasks served to purify MSCs from hematopoietic cells, and that MSCs grown in basic fibroblast growth factor (bFGF)-conditioned medium were, based on multiple criteria, superior to those grown in leukemia inhibitory factor-conditioned medium. Moreover, we found that the MSCs isolated from compact bone and grown in bFGF conditioned medium were capable of supporting bone formation in vivo. The methods and results described here have implications for understanding MSC biology and for clinical purpose. PMID- 22203267 TI - Modeling nitrate-nitrogen removal process in first-flush reactor for stormwater treatment. AB - Stormwater runoff is one of the most common non-point sources of water pollution to rivers, lakes, estuaries, and coastal beaches. While most pollutants and nutrients, including nitrate-nitrogen, in stormwater are discharged into receiving waters during the first-flush period, no existing best management practices (BMPs) are specifically designed to capture and treat the first-flush portion of urban stormwater runoff. This paper presents a novel BMP device for highway and urban stormwater treatment with emphasis on numerical modeling of the new BMP, called first-flush reactor (FFR). A new model, called VART-DN model, for simulation of denitrification process in the designed first-flush reactor was developed using the variable residence time (VART) model. The VART-DN model is capable of simulating various processes and mechanisms responsible for denitrification in the FFR. Based on sensitivity analysis results of model parameters, the denitrification process is sensitive to the temperature correction factor (b), maximum nitrate-nitrogen decay rate (K (max)), actual varying residence time (T (v)), the constant decay rate of denitrifiying bacteria (v (dec)), temperature (T), biomass inhibition constant (K (b)), maximum growth rate of denitrifiying bacteria (v (max)), denitrifying bacteria concentration (X), longitudinal dispersion coefficient (K (s)), and half-saturation constant of dissolved carbon for biomass (K (Car-X)); a 10% increase in the model parameter values causes a change in model root mean square error (RMSE) of -28.02, -16.16, 12.35, 11.44, -9.68, 10.61, -16.30, -9.27, 6.58 and 3.89%, respectively. The VART DN model was tested using the data from laboratory experiments conducted using highway stormwater and secondary wastewater. Model results for the denitrification process of highway stormwater showed a good agreement with observed data and the simulation error was less than 9.0%. The RMSE and the coefficient of determination for simulating denitrification process of wastewater were 0.5167 and 0.6912, respectively, demonstrating the efficacy of the VART-DN model. PMID- 22203268 TI - Medical guidelines, physician density, and quality of care: evidence from German SHARE data. AB - We use German SHARE data to study the relationship between district general practitioner density and the quality of preventive care provided to older adults. We measure physician quality of care as the degree of adherence to medical guidelines (for the management of risk factors for cardiovascular disease and the prevention of falls) as reported by patients. Contrary to theoretical expectations, we find only weak and insignificant effects of physician density on quality of care. Our results shed doubt on the notion that increasing physician supply will increase the quality of care provided in Germany's present health care system. PMID- 22203269 TI - The role of human leukocyte antigens as predisposing and/or protective factors in patients with idiopathic thrombotic thrombocytopenic purpura. AB - Fifty-four adult German patients suffering from idiopathic thrombotic thrombocytopenic purpura (TTP) have been examined for HLA class II. All patients presented autoantibodies against ADAMTS13 and ADAMTS13 activity levels <5%. Blood samples have been analyzed for HLA-DRB1 and DQB1 alleles using sequence-specific primer PCR and sequence-specific oligonucleotide PCR. Reference data of German bone marrow and blood donors were obtained from www.allelefrequencies.net. The results were evaluated employing two-sided binomial tests, and p values were corrected using the Benjamini-Hochberg procedure. A significant accumulation for DQB1*02:02 (p < 0.001) and DRB1*11 (p = 0.003) was found within the patient group. Twenty percent (DQB1*02:02) or 48.1% (DRB1*11) of TTP patients were tested positive for the particular HLA antigen compared to 1.2% (DQB1*02:02) or 23.5% (DRB1*11) in the control group. A tendency for a reduced occurrence of HLA DRB1*04 was revealed (7.4% in patients compared to 24.6% in controls). An association between the HLA antigens DQB1*02:02 and DRB1*11 and disease susceptibility for idiopathic TTP has been found. A higher risk for disease outbreak within persons carrying the mentioned alleles can be assumed. The reduced occurrence of HLA-DRB1*04 in TTP patients indicates a possible protective effect of this HLA allele in disease development. PMID- 22203270 TI - The validation of screening tests: meet the new screen same as the old screen? AB - The focus of this report is to examine the process of validation of new screening tests designed to detect the problem gambler in research and practice settings. A hierarchical or phases of evaluation model is presented as a conceptual framework to describe the basic features of the validation process and its implications for application and interpretation of test results. The report describes a number of threats to validity in the form of sources of unintended bias that when unrecognized may lead to incorrect interpretations of study results and the drawing of incorrect conclusions about the usefulness of the new screening tests. Examples drawn from the gambling literature on problem gambling are used to illustrate some of the more important concepts including spectrum bias and clinical variation in test accuracy. The concept of zones of severity and the bias inherent in selecting criterion thresholds are reviewed. A definition of reference or study gold standard is provided. The use of 2-stage designs to establish validity by efficiently using reference standards to determine indices of accuracy and prevalence is recommended. PMID- 22203309 TI - Molecular golems. PMID- 22203311 TI - Molecular electronics: Flipping a single proton switch. PMID- 22203312 TI - Nanofluidics: Neither shaken nor stirred. PMID- 22203313 TI - Nanoimaging: Image contrast using time. PMID- 22203315 TI - Two types of defective RNAs arising from the tomato black ring virus genome. AB - Short defective RNAs (D-RNAs) associated with tomato black ring virus (TBRV) were isolated, cloned and sequenced. As a result, two types of D-RNAs associated with different TBRV isolates were identified. Both types were derived from RNA1. The first one contained sequences from the 5' and 3' untranslated regions (UTR) and from the 5' region of a single large open reading frame. The second one included a portion of the coding region for the RNA-dependent RNA polymerase flanked by a short fragment of the 5' UTR and the entire 3' UTR. The possible nature and origin of these RNA species is discussed. PMID- 22203317 TI - Results of a proof-of-concept, dose-finding, double-blind, placebo-controlled study of RX-10100 (Serdaxin(r)) in subjects with major depressive disorder. AB - BACKGROUND: RX-10100 (Serdaxin(r)), a nonantibiotic small molecule beta-lactam compound, has shown potent antidepressant and anxiolytic activities in preclinical models. RX-10100 does not bind to the serotonin transporter or other receptors associated with monoamine activity. In microdialysis studies with rats, RX-10100 increased the release of dopamine and serotonin metabolites. A clinical proof-of-concept study was conducted to determine the clinical effectiveness of RX-10100 in treating depression. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel group study of people with depression (n = 77; HAM-D-17 baseline score >= 20). Eligible subjects were randomly assigned to receive RX-10100 (5, 10, or 15 mg twice daily) or placebo for 8 weeks. Change from baseline in the MADRS total score was the primary endpoint. RESULTS: Mean changes in MADRS scores were -46.0%, -37.9%, and -41.4%, for 5, 10, and 15 mg RX 10100, respectively, as compared with 43.1% for placebo. In subjects with severe depression (baseline MADRS >= 29; n = 28) scores improved 55.6% with 5 mg RX 10100 but only 34% with placebo (p = 0.041). In an analysis of responders (i.e., subjects with 50% change from baseline score), 64.3% of subjects treated with 5 mg RX-10100 responded. All doses of RX-10100 were well-tolerated. CONCLUSION: In this proof-of-concept study, RX-10100 treatment (5 mg twice daily) improved MADRS scores in subjects with severe depression. RX-10100 does not appear to have many of the typical side effects of other antidepressants. These results indicate a need for larger studies further evaluating RX-10100 at 5 mg and lower doses. PMID- 22203318 TI - Cue-elicited heart rate variability and attentional bias predict alcohol relapse following treatment. AB - RATIONALE: Identification of malleable neurocognitive predictors of relapse among alcohol-dependent individuals is important for the optimization of health care delivery and clinical services. OBJECTIVES: Given that alcohol cue-reactivity can predict relapse, we evaluated cue-elicited high-frequency heart rate variability (HFHRV) and alcohol attentional bias (AB) as potential relapse risk indices. METHOD: Alcohol-dependent patients in long-term residential treatment who had participated in mindfulness-oriented therapy or an addiction support group completed a spatial cueing task as a measure of alcohol AB and an affect modulated alcohol cue-reactivity protocol while HFHRV was assessed. RESULTS: Post treatment HFHRV cue-reactivity and alcohol AB significantly predicted the occurrence and timing of relapse by 6-month follow-up, independent of treatment condition and after controlling for alcohol dependence severity. Alcohol dependent patients who relapsed exhibited a significantly greater HFHRV reactivity to stress-primed alcohol cues than patients who did not relapse. CONCLUSIONS: Cue-elicited HFHRV and alcohol AB can presage relapse and may therefore hold promise as prognostic indicators in clinical settings. PMID- 22203319 TI - Methylphenidate modulates sustained attention and cortical activation in survivors of traumatic brain injury: a perfusion fMRI study. AB - RATIONALE: Methylphenidate (MPH), the most widely prescribed psychostimulant to treat many neuropsychiatric conditions, is reported to improve attention and speed of processing in survivors of traumatic brain injury (TBI). The neural correlate of this efficacy, however, remains unclear. OBJECTIVE: Using perfusion functional magnetic resonance imaging (fMRI) as a biomarker of regional neural activity, the current study aimed to examine the neural correlates of single-dose (0.3 mg/kg) MPH administration in a randomized double-blind placebo-controlled crossover study design. METHODS: Twenty-three individuals with moderate to severe TBI were tested on two occasions approximately 1 week apart. Perfusion fMRI scanning was carried out at rest and while participants performed cognitive tasks requiring sustained attention and working memory. RESULTS: Behaviorally, MPH significantly improved both accuracy and reaction time (RT) in the sustained attention task but only RT in the working memory task. A trend of global reduction of cerebral blood flow by MPH was observed in all task conditions including resting. Voxel-wise whole-brain analysis revealed an interaction effect of drug by condition (MPH-placebo X task-rest) for the sustained attention task in the left posterior superior parietal cortex and parieto-occipital junction (BA 7/19). The magnitude of drug-related deactivation of this area during task performance was correlated with improvement in RT. CONCLUSION: Suppression of activity in this area during task performance may reflect a compensatory mechanism by which MPH ameliorates attention impairments in TBI. PMID- 22203320 TI - Adult coeliac disease in Ireland: a case series. AB - BACKGROUND: The clinical spectrum of adult coeliac disease (ACD) is varied with limited Irish data. AIMS AND OBJECTIVES: The aim of this study was to analyse the presenting symptoms, associated conditions and complications in a consecutive series of patients with ACD. METHODS: Data were obtained from database on patients with ACD between 1988 and 2004. RESULTS: One hundred and six patients (69F:37M, mean age: 46, range: 23-95 years) were included. The modes of presentation were diarrhoea in 44 patients (45%), weight loss in 41 (42%), anaemia in 37 (38%), abdominal pain in 15 (15%), fatigue in 8 (8%), hypocalcaemia in 4 (4%) and steatorrhoea in 4 (4%). Associated conditions included thyroid disorders in 7 patients (7%), bipolar affective disorder in 4 (4%), major depression in 3 (3%), rheumatoid disease in 3 (3%), inflammatory bowel disease in 4 (4%) and type I diabetes mellitus in 2 (2%). Malignancy emerged as a major complication in 15 patients (15%) CONCLUSION: The presenting features of ACD are diverse and associated with high risk of malignancy. PMID- 22203321 TI - Development of a transgenic early flowering pear (Pyrus communis L.) genotype by RNAi silencing of PcTFL1-1 and PcTFL1-2. AB - Trees require a long maturation period, known as juvenile phase, before they can reproduce, complicating their genetic improvement as compared to annual plants. 'Spadona', one of the most important European pear (Pyrus communis L.) cultivars grown in Israel, has a very long juvenile period, up to 14 years, making breeding programs extremely slow. Progress in understanding the molecular basis of the transition to flowering has revealed genes that accelerate reproductive development when ectopically expressed in transgenic plants. A transgenic line of 'Spadona', named Early Flowering-Spadona (EF-Spa), was produced using a MdTFL1 RNAi cassette targeting the native pear genes PcTFL1-1 and PcTFL1-2. The transgenic line had three T-DNA insertions, one assigned to chromosome 2 and two to chromosome 14 PcTFL1-1 and PcTFL1-2 were completely silenced, and EF-Spa displayed an early flowering phenotype: flowers developed already in tissue culture and on most rooted plants 1-8 months after transfer to the greenhouse. EF Spa developed solitary flowers from apical or lateral buds, reducing vegetative growth vigor. Pollination of EF-Spa trees generated normal-shaped fruits with viable F1 seeds. The greenhouse-grown transgenic F1 seedlings formed shoots and produced flowers 1-33 months after germination. Sequence analyses, of the non transgenic F1 seedlings, demonstrated that this approach can be used to recover seedlings that have no trace of the T-DNA. Thus, the early flowering transgenic line EF-Spa obtained by PcTFL1 silencing provides an interesting tool to accelerate pear breeding. PMID- 22203323 TI - Molecular characterization of a new waxy allele with partial expression in spelt wheat. AB - Starch composition which is dependent on the waxy protein, the enzyme responsible for amylose synthesis in the grain, is an important aspect of the wheat quality. In this report, we describe the characterization of a novel Wx-A1 allele (Wx-A1g formerly known as -Wx-A1a) in Spanish spelt wheat lines which is responsible for a remarkable decline in the concentration of Wx-A1 protein found in the endosperm. Comparison of the DNA sequences in the Wx-A1a and Wx-A1g alleles showed the presence of a 160-bp insertion within the fourth intron in the latter. This insertion had some characteristics of a transposable-like element. RT-PCR analysis showed the presence of normal and aberrant mRNA transcripts in the Wx A1g lines, indicating that the aberrant transcripts are un-spliced and contained the longer fourth intron. This may be related to the low level of Wx-A1 protein in these lines. In addition, a simple and fast PCR assay was designed for differentiating among different Wx-A1 alleles (a, b, f and g). The mutation described here is not related to either of the Wx-A1 mutations identified previously in common and durum wheats and could help to extend the range of amylose content of wheats. PMID- 22203322 TI - Catalytic and structural diversity of the fluazifop-inducible glutathione transferases from Phaseolus vulgaris. AB - Plant glutathione transferases (GSTs) comprise a large family of inducible enzymes that play important roles in stress tolerance and herbicide detoxification. Treatment of Phaseolus vulgaris leaves with the aryloxyphenoxypropionic herbicide fluazifop-p-butyl resulted in induction of GST activities. Three inducible GST isoenzymes were identified and separated by affinity chromatography. Their full-length cDNAs with complete open reading frame were isolated using RACE-RT and information from N-terminal amino acid sequences. Analysis of the cDNA clones showed that the deduced amino acid sequences share high homology with GSTs that belong to phi and tau classes. The three isoenzymes were expressed in E. coli and their substrate specificity was determined towards 20 different substrates. The results showed that the fluazifop-inducible glutathione transferases from P. vulgaris (PvGSTs) catalyze a broad range of reactions and exhibit quite varied substrate specificity. Molecular modeling and structural analysis was used to identify key structural characteristics and to provide insights into the substrate specificity and the catalytic mechanism of these enzymes. These results provide new insights into catalytic and structural diversity of GSTs and the detoxifying mechanism used by P. vulgaris. PMID- 22203324 TI - Novel anti-cancer compounds for developing combinatorial therapies to target anoikis-resistant tumors. AB - Anoikis, a cell death pathway induced by loss of normal cell-matrix attachment or upon adhesion to a non-native matrix, ensures the balance between proliferative potential of normal cells and maintenance of tissue integrity. Thereby, anoikis serves as a potential molecular barrier against oncogenic transformation of normal cells. Cancer cells acquire anoikis resistance for survival and distant metastatic progression. During the acquisition of anoikis resistance, tumors modulate multiple cell signaling parameters through changes in the expression of up-stream receptors and by dynamically calibrating the dependency on down-stream signaling cascades. Many compounds that target the tumor-acquired switches in integrins, tumor antigens, growth factors, metabolic pathways, oxidative and osmotic-stress signaling are in various phases of pre-clinical and clinical development. Combinatorial approaches maximize the therapeutic efficacy and minimize the activation of alternate signaling pathways, which will otherwise contribute to drug resistance. In this regard, an integrated analysis of the mechanisms of action of potential drugs and lead compounds that can target significant nodes of anoikis signaling networks will provide a rational frame work for further development and clinical use of respective agents, by formulating more effective combinatorial therapies, in patients with distinct drug-sensitivity profiles. PMID- 22203325 TI - Protected graft copolymer (PGC) basal formulation of insulin as potentially safer alternative to Lantus(r) (insulin-glargine): a streptozotocin-induced, diabetic Sprague Dawley rats study. AB - PURPOSE: To develop a long-acting formulation of native human insulin with a similar pharmacodynamics (PD) profile as the insulin analogue insulin glargine (Lantus(r), Sanofi-Aventis) with the expectation of retaining native human insulin's superior safety profile as insulin glargine is able to activate the insulin-like growth factor 1 (IGF-1) receptor and is linked to a number of malignancies at a higher rate than regular human insulin. METHODS: Development of protected graft copolymer (PGC) excipients that bind native human insulin non covalently and testing blood glucose control obtained with these formulations in streptozotocin-induced diabetic Sprague Dawley rats compared to equally dosed insulin glargine. RESULTS: PGC-formulations of native human insulin are able to control blood glucose to the same extent and for the same amount of time after s.c. injection as the insulin analogue insulin glargine. No biochemical changes were made to the insulin that would change receptor binding and activation with their possible negative effects on the safety of the insulin. CONCLUSION: Formulation with the PGC excipient offers a viable alternative to biochemically changing insulin or other receptor binding peptides to improve PD properties. PMID- 22203327 TI - The effect of water plasticization on the molecular mobility and crystallization tendency of amorphous disaccharides. AB - PURPOSE: To study how water plasticization affects the molecular mobility and crystallization tendency of freeze-dried trehalose, sucrose, melibiose and cellobiose. METHODS: Freeze-dried disaccharides were subjected to different relative humidity atmospheres and their physical stabilities were evaluated. Lyophilizate water sorption tendencies and glass transition temperatures were modeled using Brunauer-Emmett-Teller (BET) and Gordon-Taylor (GT) equations, respectively. Sucrose and cellobiose crystallization tendencies were compared by using the concept of reduced crystallization temperature (RCT), and the molecular mobilities of trehalose and melibiose were compared by measuring their T(1)H relaxation time constants. RESULTS: Based on the BET and GT models, water sorption tendency and the resulting plasticizing effect were different in sucrose when compared to the other disaccharides. Trehalose and melibiose exhibited generally slower crystallization rates when compared to sucrose and cellobiose. Amorphous melibiose was shown to be particularly stable within the studied water content range, which may have partly been caused by its relatively slow molecular mobility. CONCLUSIONS: Slow amorphous-to-crystalline transition rate is known to be important for lyoprotecting excipients when formulating a robust drug product. The physical stabilities of amorphous trehalose and melibiose even with relatively high water contents might make their use advantageous in this respect compared to sucrose and cellobiose. PMID- 22203326 TI - Bioequivalence of highly variable drugs: a comparison of the newly proposed regulatory approaches by FDA and EMA. AB - PURPOSE: To explore the comparative performance of the recently proposed bioequivalence (BE) approaches, FDA(s) and EMA(s), by the FDA working group on highly variable drugs and the EMA, respectively; to compare the impact of the GMR constraint on the two approaches; and to provide representative plots of % BE acceptance as a function of geometric mean ratio, sample size and variability. METHODS: Simulated BE studies and extreme GMR versus CV plots were used. Three sequence, three period crossover studies with two treatments were simulated using four levels of within-subject variability. RESULTS: The FDA(s) and EMA(s) approaches were identical when variability was <30%. In all other cases, the FDA(s) method was more permissive than EMA(s). The major discrepancy was observed for variability values >50%. The GMR-constraint was necessary for FDA(s), especially for drugs with high variabilities. For EMA(s), the GMR-constraint only became effective when sample size was large and variability was close to 50%. CONCLUSIONS: A significant discrepancy in the performances of FDA(s) and EMA(s) was observed for high variability values. The GMR-constraint was essential for FDA(s), but it was of minor importance in case of the EMA(s). PMID- 22203328 TI - Partnerships in drug abuse prevention services research: perspectives from the National Institute on Drug Abuse. PMID- 22203330 TI - Physeal distraction for joint preservation in malignant metaphyseal bone tumors in children. AB - BACKGROUND: Physeal distraction facilitates metaphyseal bone tumor resection in children and preserves the adjacent joint. The technique was first described by Canadell. Tumor resection procedures allowing limb-sparing reconstruction have been used increasingly in recent years without compromising oncologic principles. QUESTIONS/PURPOSES: We report our results with Canadell's technique by assessing tumor control, functional outcome, and complications. METHODS: Six consecutive children with primary malignant metaphyseal bone tumors underwent physeal distraction as a part of tumor resection. Tumor location was the distal femur in four patients, the proximal humerus in one patient, and the proximal tibia in one patient. The functional outcome was evaluated after a minimum of 18 months (median, 62 months; range, 18-136 months) using the Musculoskeletal Tumor Society (MSTS) score and the Toronto Extremity Salvage Score (TESS). RESULTS: At latest followup, five patients were alive and disease-free and one had died from metastatic disease. All tumor resections resulted in local control; there were no local recurrencies. The mean MSTS score was 79% (range, 53%-97%) and corresponding mean TESS was 83% (range, 71%-92%). In one case, postoperative infection required amputation of the proximal lower leg. All physeal distractions were successful except for one patient in whom distraction resulted in rupturing into the tumor. This situation was salvaged by transepiphyseal resection. CONCLUSIONS: We consider Canadell's technique a useful tool in the armamentarium to treat children with malignant tumors that are in close proximity to an open physis. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22203329 TI - Pathomechanics of Gowers' sign: a video analysis of a spectrum of Gowers' maneuvers. AB - BACKGROUND: Gowers' sign is a screening test for muscle weakness, typically seen in Duchenne muscular dystrophy but also seen in numerous other conditions. The mildest presentations and the variations of Gowers' sign are poorly described in the literature but are important to recognize to help with early diagnosis of a neuromuscular problem. QUESTIONS/PURPOSES: We therefore (1) defined the characteristics of the mildest forms and the compensatory mechanism used, (2) categorized the spectrum of this sign as seen in various neuromuscular diseases, and (3) provide educational videos for clinicians. METHODS: We videotaped 33 patients with Gowers' sign and three healthy children. Weakness was categorized as: mild = prolonged or rise using single-hand action; moderate = forming prone crawl position and using one or two hands on thigh; severe = more than two thigh maneuvers, rising with additional aid, or unable to rise. RESULTS: The earliest changes were exaggerated torso flexion, wide base, and equinus posturing, which reduce hip extension moment, keep forces anterior to the knee, and improve balance. Patients with moderate weakness have wide hip abduction, shifts in pelvic tilt, and lordosis, which reduce knee extension moment, improve hamstrings moment arm, and aide truncal extension. The classic Gowers' sign (severe) exaggerates all mechanisms. CONCLUSIONS: The classically described Gowers' sign is usually a late finding. However more subtle forms of Gowers' sign including mild hand pressure against the thigh and prone crawl position should be recognized by clinicians to initiate additional diagnostic tests. PMID- 22203331 TI - Reelin: a possible link between hippocampal sclerosis and cortical dyslamination in the setting of FCD type IIIa. AB - Reelin is a glycoprotein that acts as a stop signal for neuronal migration during brain ontogenesis. It plays an important role in the remodeling of the hippocampal formation and in stabilizing cortical architecture. We studied immunohistochemically 30 cases of focal cortical dysplasia (FCD) type IIIa to verify whether Reelin could represent the pathogenetic link between HS and cortical dyslamination in the setting of FCD type IIIa. Our results suggest that a subset of FCD type IIIa (namely abnormal cortical layering associated with MTS and GCD type 2) exists in which loss of Reelin appears to be the common pathogenetic basis. On the contrary in the other cases the presence of a common pathogenetic link remains to be demonstrated. PMID- 22203332 TI - Screening for the hereditary spastic paraplaegias SPG4 and SPG3A with the multiplex ligation-dependent probe amplification technique in a large population of affected individuals. AB - Hereditary spastic paraplaegias are a group of clinically and genetically heterogeneous neurodegenerative disorders characterised by progressive spasticity and weakness in the lower limbs. The most common forms of hereditary spastic paraplaegia are SPG4 and SPG3A caused by sequence variants in the SPAST and ATL1 genes, as well as by deletions and duplications not detected by standard techniques. In this study, we used the multiplex ligation-dependent probe amplification (MLPA) analysis for screening 93 patients (52 familial and 41 isolated cases). As a result, we identified 11 different deletions and 1 duplication in the SPAST gene and a single exon deletion in the ATL1 gene. These results indicate that micro-rearrangements in the SPAST gene are a fairly frequent cause of hereditary spastic paraplaegia and that MLPA is a useful and efficient technique to detect a considerable proportion of the mutations in the most common forms of hereditary spastic paraplaegias. PMID- 22203334 TI - Sural nerve pathology in ALS patients: a single-centre experience. AB - Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of upper and lower motor neurons. Sensory involvement is thought not to be a feature of ALS. We reviewed 17 cases of sural nerve biopsies performed in a large cohort of ALS patients referred to our centre over a 23-year period. More than two-third of biopsies revealed a variable degree of axonal loss. In one case, pathological findings suggested the concomitant presence of an inherited neuropathy, subsequently confirmed by genetic evaluation. In another case, pathological and neurographic data were similar to those of an inflammatory demyelinating neuropathy, but the clinical course corroborated the diagnosis of ALS. Our data confirm that sensory nerve involvement may be found in ALS patients. This finding should prompt physicians to carefully investigate a possible alternative diagnosis, but does not exclude the possibility that the patient may have ALS. PMID- 22203335 TI - Ataxic hemiparesis in a patient with posterior cortical borderzone infarction. PMID- 22203336 TI - Diagnostic and therapeutic challenges. PMID- 22203333 TI - Sleep-related movement disorders. AB - Several movement disorders may occur during nocturnal rest disrupting sleep. A part of these complaints is characterized by relatively simple, non-purposeful and usually stereotyped movements. The last version of the International Classification of Sleep Disorders includes these clinical conditions (i.e. restless legs syndrome, periodic limb movement disorder, sleep-related leg cramps, sleep-related bruxism and sleep-related rhythmic movement disorder) under the category entitled sleep-related movement disorders. Moreover, apparently physiological movements (e.g. alternating leg muscle activation and excessive hypnic fragmentary myoclonus) can show a high frequency and severity impairing sleep quality. Clinical and, in specific cases, neurophysiological assessments are required to detect the presence of nocturnal movement complaints. Patients reporting poor sleep due to these abnormal movements should undergo non pharmacological or pharmacological treatments. PMID- 22203337 TI - Re: Factors affecting wound leakage in 23-gauge sutureless pars plana vitrectomy. PMID- 22203338 TI - Glucose and lipid metabolism in the pancreas of rainbow trout is regulated at the molecular level by nutritional status and carbohydrate intake. AB - Glucose and lipid metabolism in pancreatic islet organs is poorly characterized. In the present study, using as a model the carnivorous rainbow trout, a glucose intolerant fish, we assessed mRNA expression levels of several genes involved in glucose and lipid metabolism (including ATP-citrate lyase; carnitine palmitoyltransferase-1 isoforms, CPT; the mitochondrial isoform of the phosphoenolpyrutave carboxykinase, mPEPCK and pyruvate kinase, PK) and glucosensing (glucose transporter type 2, Glut2; glucokinase, GK and the potassium channel, K(ATP)) in Brockmann bodies. We evaluated the response of these parameters to changes in feeding status (food deprived vs. fed fish) as well as to changes in the amount of carbohydrate (dextrin) in the diet. A general inhibition of the glycolytic (including the glucosensing marker GK) and beta oxidation pathways was found when comparing fed versus food-deprived fish. When comparing fish feeding on either low- or high-carbohydrate diets, we found that some genes related to lipid metabolism were more controlled by the feeding status than by the carbohydrate content (fatty acid synthase, CPTs). Findings are discussed in the context of pancreatic regulation of glucose and lipid metabolism in fish, and show that while trout pancreatic metabolism can partially adapt to a high-carbohydrate diet, some of the molecular actors studied seem to be poorly regulated (K(ATP)) and may contribute to the glucose intolerance observed in this species when fed high-carbohydrate diets. PMID- 22203339 TI - Functional gastrointestinal disorders among adolescents with poor sleep: a school based study in Shanghai, China. AB - PURPOSE: This study aimed to determine whether functional gastrointestinal disorders are more common among adolescents with self-reported poor sleep. METHODS: Junior middle school and senior high school students (n = 1,362) were recruited from schools in Shanghai. Students completed two questionnaires: the questionnaire for irritable bowel syndrome (IBS) in adolescents and the Pittsburgh Sleep Quality Index. RESULTS: The prevalence of poor sleep was 34.29% [95% confidence interval (CI) = 31.77-36.81] and there was no significant difference between genders (P = 0.991). The tendency towards poor sleep increased with age, with age group yielding a significant effect (P = 0.001). In junior middle school and senior high school students, the propensity towards poor sleep was 30.10% (95% CI = 27.08-33.12%) and 42.11% (95% CI = 37.67-46.55%), respectively. Among students with poor sleep, the prevalence of IBS was 19.70% (95% CI = 16.09-23.31). After adjusting for age, sex, night pain, and psychological factors, IBS was significantly more common in students with poor sleep (odds ratio = 1.92; 95% CI = 1.07-2.58). CONCLUSION: We conclude that IBS is prevalent in students with poor sleep. Poor sleep was independently associated with IBS among adolescents in Shanghai China. PMID- 22203363 TI - History effect and timing of force production introduced in a skeletal muscle model. AB - Skeletal muscle modelling requires a detailed description of muscular force production. We have performed a series of experiments on mouse skeletal muscles to give a basis for an improved description of the muscular force production. Our previous work introduced a force modification in isometric phases, which was based on the work performed by or on the muscle during transient-length-varying contractions. Here, state-space diagrams were used to investigate the timing aspects of the force production. These show a dominant exponential nature of the force development in isometric phases of the contractions, reached after a non exponential phase, assumed as an activation or deactivation stage and not further analysed here. The time constants of the exponential functions describing isometric force redevelopment after length variations appear to be related to the one for an initial isometric contraction, but depending on the previous history. The timing of force production calculated from the state-space diagrams was in agreement with the generally accepted muscle properties, thereby demonstrating the reliability of the method. A macroscopic muscular model consisting of a contractile element, parallel and series elastic elements was developed. The parameters from the experiment analysis, particularly the force modification after non-isometric contractions and the time constants, were reproduced by the simulations. The relationship between time constants introduced in a mechanistic model and the measured macroscale timings is discussed. PMID- 22203340 TI - Life expectancy gap between the Francophone majority and Anglophone minority of a Canadian population. AB - Language is an important determinant of health, but analyses of linguistic inequalities in mortality are scant, especially for Canadian linguistic groups with European roots. We evaluated the life expectancy gap between the Francophone majority and Anglophone minority of Quebec, Canada, both over time and across major provincial areas. Arriaga's method was used to estimate the age and cause of death groups contributing to changes in the life expectancy gap at birth between 1989-1993 and 2002-2006, and to evaluate patterns across major provincial areas (metropolitan Montreal, other metropolitan centres, and small cities/rural areas). Life expectancy at birth was greater for Anglophones, but the gap decreased over time by 1.3 years (52% decline) in men and 0.9 years (47% decline) in women, due to relatively sharper reductions in Francophone mortality from several causes, except lung cancer which countered reductions in women. The life expectancy gap in 2002-2006 was widest in other metropolitan centres (men 5.1 years, women 3.2 years), narrowest in small cities/rural areas (men 0.8 years, women 0.7 years), and tobacco-related causes were the main contributors. Only young Anglophones <40 years in small cities/rural areas had mortality higher than Francophones, resulting in a narrower gap in these areas. Differentials in life expectancy favouring Anglophones decreased over time, but varied across areas of Quebec. Tobacco-related causes accounted for the majority of the current life expectancy gap. PMID- 22203364 TI - Association of nephrotic syndrome with immune reconstitution inflammatory syndrome. AB - BACKGROUND: Up to 50% of patients with severe immune deficiency experience an excessive inflammatory response called immune reconstitution inflammatory syndrome (IRIS) after the initiation of antiretroviral therapy (ART). IRIS has been observed after various opportunistic infections with pathogens such as mycobacteria, including Bacille Calmette-Guerin, cryptococci, human herpesvirus 8, non-Hodgkin's lymphoma, and progressive multifocal leukoencephalopathy. Non acquired immune deficiency-defining illnesses can also deteriorate after commencement of ART. Renal IRIS has been reported in a few patients with mycobacterial infections, but to the best of our knowledge no cases of nephrotic syndrome and IRIS have been described. CASE-DIAGNOSIS/TREATMENT: We report the case of an infant with human immunodeficiency virus-1 (HIV-1) infection, Pneumocystis pneumonia, and encephalopathy. During immune reconstitution the patient developed nephrotic syndrome. Treatment of nephrotic syndrome was initiated with prednisone, an angiotensin-converting enzyme inhibitor (lisinopril), and low-molecular-weight heparin. ART was continued, but only a low level of lopinavir/ritonavir could be achieved. There was no relapse of nephrotic syndrome during 10 months of follow-up. CONCLUSIONS: Nephrotic syndrome may occur in infants during immune reconstitution and should not be overlooked. PMID- 22203365 TI - What do the latest guidelines tell us about UTIs in children under 2 years of age. AB - The American Academy of Pediatrics (AAP) recently published new guidelines on diagnosing and managing infants and children younger than 2 years who have had a febrile urinary tract infection (UTI). They recommend, as previously did the National Institute for Health and Clinical Excellence (NICE) in the UK, a marked reduction in the imaging that these children should undergo. Both NICE and AAP agree that prophylactic antibiotic treatment should not be routinely used in these children, even in those with major vesicoureteric reflux. PMID- 22203366 TI - Oral intake of gamma-aminobutyric acid affects mood and activities of central nervous system during stressed condition induced by mental tasks. AB - gamma-Aminobutyric acid (GABA) is a kind of amino acid contained in green tea leaves and other foods. Several reports have shown that GABA might affect brain protein synthesis, improve many brain functions such as memory and study capability, lower the blood pressure of spontaneously hypertensive rats, and may also have a relaxation effect in humans. However, the evidence for its mood improving function is still not sufficient. In this study, we investigated how the oral intake of GABA influences human adults psychologically and physiologically under a condition of mental stress. Sixty-three adults (28 males, 35 females) participated in a randomized, single blind, placebo-controlled, crossover-designed study over two experiment days. Capsules containing 100 mg of GABA or dextrin as a placebo were used as test samples. The results showed that EEG activities including alpha band and beta band brain waves decreased depending on the mental stress task loads, and the condition of 30 min after GABA intake diminished this decrease compared with the placebo condition. That is to say, GABA might have alleviated the stress induced by the mental tasks. This effect also corresponded with the results of the POMS scores. PMID- 22203367 TI - Preclinical pharmacokinetics of MEHD7945A, a novel EGFR/HER3 dual-action antibody, and prediction of its human pharmacokinetics and efficacious clinical dose. AB - PURPOSE: MEHD7945A is a novel dual-action monoclonal antibody in which each of the two antigen-binding fragments is capable of binding to EGFR and HER3 with high affinity. It is being evaluated as a potential therapy for human cancer. The purpose of these studies was to characterize the pharmacokinetics (PK) of MEHD7945A in mouse and monkey and predict its human PK and efficacious dose. METHODS: PK of MEHD7945A was determined in SCID beige mice and cynomolgus monkeys after administration of single intravenous doses. Human PK profiles were projected from monkey PK profiles using a species-invariant time method, and human population PK parameters were estimated using a nonlinear, two-compartment model comprising specific (target-mediated) and nonspecific clearance pathways. The antitumor efficacy in mice bearing human tumor xenografts was used in conjunction with human PK projections to estimate human efficacious doses. RESULTS: The total clearance of MEHD7945A decreased with increase in dose in both mouse and monkey. The nonspecific clearance in monkey was estimated to be 14 mL/day/kg. The predicted nonspecific clearance range in humans was 6-10 mL/day/kg. Doses of 8-12 mg/kg administered every 2 weeks in humans were predicted to achieve exposure of 300 day MUg/mL per week to match the efficacious exposure observed in xenograft models. CONCLUSIONS: The PK of MEHD7945A was nonlinear in mouse and monkey in the dose range tested. The nonspecific clearance in monkey was approximately twofold higher than typical humanized IgG1 antibodies. The projected human efficacious dose and dose regimen appear to be achievable in patients. PMID- 22203368 TI - Preclinical pharmacokinetics of MFGR1877A, a human monoclonal antibody to FGFR3, and prediction of its efficacious clinical dose for the treatment of t(4;14) positive multiple myeloma. AB - PURPOSE: MFGR1877A is a human IgG1 monoclonal antibody that binds to fibroblast growth factor receptor 3 (FGFR3) and is being investigated as a potential therapy for relapsed/refractory FGFR3+ multiple myeloma. The purpose of these studies was to characterize the pharmacokinetics (PK) of MFGR1877A in mouse, rat, and monkey and predict its human PK and efficacious dose. METHODS: PK of MFGR1877A was determined in athymic nude mice, Sprague-Dawley rats and cynomolgus monkeys after administration of single intravenous doses. Human PK profiles were projected from monkey PK profiles using a species-invariant time method, and human population PK parameters were estimated using a non-linear, two-compartment model comprising specific (target-mediated) and non-specific clearance pathways. The anti-tumor efficacy in mice bearing human tumor xenografts was used in conjunction with inhibitory activity in cell proliferation assays and human PK projections to estimate clinical efficacious dose. RESULTS: The PK of MFGR1877A in mice was non linear in the dose range of 1-50 mg/kg, while in rats and monkeys, PK was non linear in the dose range of 1-10 mg/kg and linear at doses >= 10 mg/kg. The predicted non-specific clearance range in humans was 2.6-4.4 mL/day/kg. Doses ranging from 2 to 3 mg/kg weekly to 6-10 mg/kg every 4 weeks were predicted to achieve the target exposure in >= 90% of multiple myeloma patients. CONCLUSIONS: The predicted non-specific clearance of MFGR1877A in humans is similar to typical human IgG1 antibodies and will be verified in a Phase 1 study. The projected human efficacious dose and regimen appear to be achievable in patients. PMID- 22203369 TI - Succinobucol induces apoptosis in vascular smooth muscle cells. AB - Probucol inhibits the proliferation of vascular smooth muscle cells in vitro and in vivo, and the drug reduces intimal hyperplasia and atherosclerosis in animals via induction of heme oxygenase-1 (HO-1). Because the succinyl ester of probucol, succinobucol, recently failed as an antiatherogenic drug in humans, we investigated its effects on smooth muscle cell proliferation. Succinobucol and probucol induced HO-1 and decreased cell proliferation in rat aortic smooth muscle cells. However, whereas inhibition of HO-1 reversed the antiproliferative effects of probucol, this was not observed with succinobucol. Instead, succinobucol but not probucol induced caspase activity and apoptosis, and it increased mitochondrial oxidation of hydroethidine to ethidium, suggestive of the participation of H(2)O(2) and cytochrome c. Also, succinobucol but not probucol converted cytochrome c into a peroxidase in the presence of H(2)O(2), and succinobucol-induced apoptosis was decreased in cells that lacked cytochrome c or a functional mitochondrial complex II. In addition, succinobucol increased apoptosis of vascular smooth muscle cells in vivo after balloon angioplasty mediated vascular injury. Our results suggest that succinobucol induces apoptosis via a pathway involving mitochondrial complex II, H(2)O(2), and cytochrome c. These unexpected results are discussed in light of the failure of succinobucol as an antiatherogenic drug in humans. PMID- 22203370 TI - Electrochemical release of hepatocyte-on-hydrogel microstructures from ITO substrates. AB - This paper describes a novel platform that utilizes micropatterning and electrochemistry to release cells-on-hydrogel microstructures from conductive indium tin oxide (ITO) substrates. In this approach, UV photopolymerization was employed to micropattern heparin-based hydrogels onto glass substrates containing ITO electrodes. ITO/glass substrates were first functionalized with acrylated silane to promote attachment of hydrogel structures. The surfaces containing hydrogel micropatterns were further functionalized with poly(ethylene glycol) thiol, rendering the regions around the hydrogel structures non-fouling to proteins and cells. After incubating surfaces with collagen (I), primary rat hepatocytes were shown to selectively attach on top of the hydrogel and not on surrounding glass/ITO regions. Electrical activation of specific ITO electrodes ( 1.8 V vs. Ag/AgCl reference) was then used to release cells-on-hydrogel microstructures from the substrate. Immunostaining and reverse transcription polymerase chain reaction analysis of albumin, an important indicator of hepatic function, showed that the hepatocyte-on-hydrogel microstructures released from the surface maintained their function at levels similar to hepatocytes remaining on the culture substrate. In the future, switchable conductive substrates described here may be to collect cell samples at different time points and may also be used for harvesting cell-carrying vehicles for transplantation studies. PMID- 22203371 TI - High-resolution mass spectrometry for integrated qualitative and quantitative analysis of pharmaceuticals in biological matrices. AB - Quantitative and qualitative high-resolution (HR) dependent and independent acquisition schemes on a QqTOF MS (with resolving power 20,000-40,000) were investigated for the analysis of pharmaceutical compounds in biological fluids. High-resolution selected reaction monitoring (HR-SRM) was found to be linear over three orders of magnitude for quantitative analysis of paracetamol in human plasma, offering a real alternative to triple quadrupole LC-SRM/MS. Metabolic stability of talinolol in microsomes was characterized by use of three different acquisition schemes: (i) information-dependent acquisition (IDA) with a TOF MS experiment as survey scan and product-ion scan as dependent scan; (ii) MS(ALL) by collecting TOF mass spectra with and without fragmentation by alternating the collision energy of the collision cell between a low (i.e., 10 eV) and high setting (i.e., 40 eV); and (iii) a novel independent acquisition mode referred to as "sequential window acquisition of all theoretical fragment-ion spectra" (SWATH) or "global precursor ions scan mode" (GPS) in which sequential precursor ions windows (typically 20 u) are used to collect the same spectrum precursor and fragment ions using a collision energy range. SWATH or GPS was found to be superior to IDA or MS(ALL) in combination with UHPLC for qualitative analysis but requires a rapidly acquiring mass spectrometer. Finally, the GPS concept was used for QUAL/QUAN analysis (i.e. integration of qualitative and quantitative analysis) of bosentan and its metabolites in urine over a concentration range from 5 to 2,500 ng mL(-1). PMID- 22203372 TI - Characterization of lapis lazuli and corresponding purified pigments for a provenance study of ultramarine pigments used in works of art. AB - In this paper, we propose an analytical methodology for attributing provenance to natural lapis lazuli pigments employed in works of art, and for distinguishing whether they are of natural or synthetic origin. A multitechnique characterization of lazurite and accessory phases in lapis lazuli stones from Afghan, Siberian and Chilean quarries, on the pigments obtained by their purification, and on synthetic ultramarine pigments was performed. According to the results obtained, infrared spectroscopy is not a suitable technique for distinguishing the provenance of lapis lazuli, but a particular absorbance band makes it relatively easy to determine whether it is of natural or synthetic origin. On the other hand, EDS elemental composition and XRD patterns show the presence of specific mineral phases associated with specific lapis lazuli sources, and can be used to distinguish the provenance of the stones as well as albeit to a lesser extent-the corresponding purified blue pigments. In contrast, FEG-SEM observations clearly show different stone textures depending on their provenance, although these distinctive features do not persist in the corresponding pigments. PCA analyses of EDS data allow Afghan lapis lazuli stone to be distinguished from Chilean and Siberian ones, and can distinguish between the pigments resulting from their purification as well as synthetic blue ones. Although this methodology was developed using a limited number of samples, it was tested on lapis lazuli pigments collected from three paintings (from the fourteenth to sixteenth centuries) in order to perform a preliminary validation of the technique, and based on the results, the provenance of the blue pigments employed in those artworks is proposed. Finally, upon analytically monitoring the process of purifying lapis lazuli to obtain the corresponding pigments, it was found that ion-exchange reactions occur between the alkali modifiers of silicate/aluminosilicate phases and free carboxylic acids present in the doughy mixture of natural terpenes and ground stone, namely pastello. These reactions favor (i) the retention of silicate phases in the organic mixture and (ii) the selective extraction of lazurite due to the formation of Bronsted acidic sites [Al(OH)Si], which are responsible for its high hydrophilicity in comparison to the one of the other species present in the lapis lazuli stone. PMID- 22203373 TI - Application of gas-diffusion microextraction to the analysis of free and bound acetaldehyde in wines by HPLC-UV and characterization of the extracted compounds by MS/MS detection. AB - In wines, the presence of high levels of acetaldehyde (AA) not only is responsible for undesirable characteristic odours but can also cause health adverse effects. Such sensorial activity of AA can be overcome by adding sulphites during winemaking, due to the formation of adducts between AA and sulphites, which lower the sensorial impact of AA. Nevertheless, bound AA can be released during wine storage; therefore, the knowledge of its total amount can be important to estimate the long-term wine quality. The proposed methodology is based on the extraction of AA from wines using gas-diffusion microextraction and determination by liquid chromatography. Free and bound forms of AA could be differentiated and determined using an alkaline hydrolysis step to dissociate the sulphites-AA adducts. This methodology was successfully applied to different wine types, with free AA values ranging between 5 and 26 mg L(-1) and total form between 154 and 906 mg L(-1). Bound AA was above 90% of the total content determined for all samples analysed, and higher amounts were obtained for white wines (around 98%). Other carbonyl compounds were also identified in the extracts using mass spectrometry. PMID- 22203374 TI - Prediction of response to anticancer treatment as simple as the resolution of ordinary differential equations? PMID- 22203375 TI - Lamellar macular hole following intravitreal pegaptanib sodium (Macugen) injection for diabetic macular edema. AB - To report on a patient who developed a lamellar macular hole 1 month after an intravitreal pegaptanib sodium injection. Interventional case report. A 66 year old patient developed a lamellar macular hole 1 month after an intravitreal pegaptanib sodium injection for diabetic macular edema (DME). The pathogenesis of the lamellar macular hole in our case can be attributed to the intravitreal injection that may have induced vitreous incarceration, causing vitreoretinal traction at the macula and development of a lamellar macular hole. Alternatively or in association, pegaptanib itself may have caused the lamellar macular hole by inducing sudden reduction of the DME and exacerbation of tangential traction of the posterior vitreous on the overlying macular retina. Lamellar macular hole seems to be a potential complication of pegaptanib injection even in patients without pretreatment clinically detectable vitreomacular traction. PMID- 22203376 TI - Antimicrobials: Reversing resistance with phage. PMID- 22203378 TI - The influence of Christian conversion in Mapuche traditional medicine in Temuco, Chile: toward a cultural syncretism or a form of ideological assimilation? AB - The Mapuche communities living in the urban areas of Chile have undergone radical cultural changes due to Christian conversion. This article analyzes the influence of these changes on the Mapuche ideas and practices of the traditional healers (machi) and patients in Temuco (IX Region), Chile, and the changes and adaptations in the perceptions of healing practices and rituals by the patients. The paper shows how, despite some evident challenges, the encounter with the religion of Christianity can create a process of cultural and spiritual syncretism and push traditional medicine toward an increased specialization in the therapeutic practices. PMID- 22203379 TI - Religiosity for promotion of behaviors likely to reduce new HIV infections in Uganda: a study among Muslim youth in Wakiso District. AB - The study was done to determine the association between religiosity and behaviors likely to reduce new HIV infections among 1,224 Muslim youth. Respondents with Sujda, the hyperpigmented spot on the forehead due to prostration during prayers, were more likely to abstain from sex, be faithful in marriage, and avoid alcohol and narcotics. Males wearing a Muslim cap were more likely to abstain from sex and avoid alcohol and narcotics. Females wearing the long dress (Hijab) were also more likely to avoid alcohol. This data should be used by stakeholders in promoting behaviors likely to reduce new HIV infections among Muslims. PMID- 22203380 TI - Transforming the self and healing the body through the use of testimonies in a divine retreat center, Kerala. AB - In this article, we analyze the collective healing process that takes place on a weekly basis in the Divine Retreat Center (DRC) in Muringoor, Kerala. We argue that disease in the DRC is understood either as a psycho-somatic or as a spirito somatic phenomenon. In contrast to other Charismatic communities, however, the body is the locus on which the medical effects of the healing become visible. The whole process is divided into several phases: First, there is a cleansing and disengagement procedure that aims to purify and liberate the participants through confession and counseling. Thereafter comes a climatic phase of personal emptying, transition and re-orientation during which the healing itself takes place. The procedure is finally completed with the person being spiritually "refilled" by the Holy Spirit. The dominant recurring element in the whole process is the continuous statement of healing "testimonies." As an integral part of the healing procedure, these statements are used to share personal experiences among the participants in the center. They are produced in a strict format in order to be spread far beyond through various media (TV, newspaper, Internet, etc.). They thereby constitute a speech genre that follows specific rules and patterns. Through shaping one's own biography in the frame of the testimonies, so we argue, the actual transformation of the self and therefore the miracle healing takes place. PMID- 22203377 TI - From the regulation of peptidoglycan synthesis to bacterial growth and morphology. AB - How bacteria grow and divide while retaining a defined shape is a fundamental question in microbiology, but technological advances are now driving a new understanding of how the shape-maintaining bacterial peptidoglycan sacculus grows. In this Review, we highlight the relationship between peptidoglycan synthesis complexes and cytoskeletal elements, as well as recent evidence that peptidoglycan growth is regulated from outside the sacculus in Gram-negative bacteria. We also discuss how growth of the sacculus is sensitive to mechanical force and nutritional status, and describe the roles of peptidoglycan hydrolases in generating cell shape and of D-amino acids in sacculus remodelling. PMID- 22203381 TI - Vitiligo-like hypopigmentation and metastatic melanoma of unknown primary site: friends or foes? PMID- 22203382 TI - Chemotherapy-induced bowel obstruction in small cell lung cancer: a case report. AB - This case report focuses on an elderly gentleman with extensive stage small cell lung cancer (SCLC) who experienced episodes of bowel obstruction shortly after commencing first-line chemotherapy with cisplatin and etoposide. The patient had no radiological or pathological evidence of intra-abdominal carcinomatosis or paraneoplastic bowel disease secondary to SCLC. Although neurotoxicity is commonly associated with platinum agents, the effect is predominantly peripheral as opposed to autonomic. The authors conclude that the observations documented in this case were secondary to etoposide; a podophyllotoxin that can bind microtubules and inhibit fast axonal transport. Although paralytic ileus is well recognised with podophyllotoxin poisoning, to our knowledge, this is the first report to associate bowel obstruction with standard doses of etoposide and highlights the need for physicians to be aware of such deleterious effects in patients treated with this cytotoxic agent. PMID- 22203384 TI - Tobacco branding, plain packaging, pictorial warnings, and symbolic consumption. AB - We use brand association and symbolic consumption theory to explore how plain cigarette packaging would influence the identities young adults cocreate with tobacco products. Group discussions and in-depth interviews with 86 young adult smokers and nonsmokers investigated how participants perceive tobacco branding and plain cigarette packaging with larger health warnings. We examined the transcript data using thematic analysis and explored how removing tobacco branding and replacing this with larger warnings would affect the symbolic status of tobacco brands and their social connotations. Smokers used tobacco brand imagery to define their social attributes and standing, and their connection with specific groups. Plain cigarette packaging usurped this process by undermining aspirational connotations and exposing tobacco products as toxic. Replacing tobacco branding with larger health warnings diminishes the cachet brand insignia creates, weakens the social benefits brands confer on users, and represents a potentially powerful policy measure. PMID- 22203385 TI - Developing sensory awareness in qualitative interviewing: a portal into the otherwise unexplored. AB - Within the social sciences there has been an increased interest in the senses. Much of this work has focused on ethnographic methods and has concentrated on research about the senses. In this article we focus on interviews and examine the value of expanded interviewing strategies that use the senses as access points. We argue that a sensory awareness can enrich interviews by offering a portal to otherwise unexplored illness or health care experiences which are either too difficult to articulate or too intangible to describe. Sensory awareness incorporates not only attentiveness to the research environment but also the utilization of sensory questions or prompts to gain insight into the research experience. We draw from a variety of empirical studies, and offer methodological guidance to the researcher while exploring ethical and challenging aspects of incorporating sensory awareness into the research interview. PMID- 22203386 TI - Using a theory-driven conceptual framework in qualitative health research. AB - The role and merits of highly inductive research designs in qualitative health research are well established, and there has been a powerful proliferation of grounded theory method in the field. However, tight qualitative research designs informed by social theory can be useful to sensitize researchers to concepts and processes that they might not necessarily identify through inductive processes. In this article, we provide a reflexive account of our experience of using a theory-driven conceptual framework, the Normalization Process Model, in a qualitative evaluation of general practitioners' uptake of a free, pilot, language interpreting service in the Republic of Ireland. We reflect on our decisions about whether or not to use the Model, and describe our actual use of it to inform research questions, sampling, coding, and data analysis. We conclude with reflections on the added value that the Model and tight design brought to our research. PMID- 22203387 TI - Acculturation phenomena experienced by the spouses of Korean international students in the United States. AB - I explored the ways in which Korean international students' spouses perceived and coped with the challenges associated with the adaptation process. I used in-depth interviews to examine how they dealt with life challenges, barriers, and coping strategies associated with acculturative stress. Three themes were identified: challenging life experiences and barriers as immigrants, the experience of emotional and psychological distress and stress, and new identified family structures. Two coping strategies used with acculturative stress were addressed: the recognition of personal strength and involvement in meaningful activities. I found that purposeful and meaningful activities associated with volunteerism, as well as cultural values and beliefs, played important roles in coping with stress. Further investigation into the role of meaningful activities for immigrants is necessary to have a better understanding of the phenomenon. PMID- 22203388 TI - The narrative approach as a learning strategy in the formation of novice researchers. AB - Novice researchers must be trained to be ethical practitioners. This means more than just knowing how to gain ethics approval and being familiar with the codes of ethics. Rather, researchers need to develop their ethical awareness, perception, and judgment, and their capabilities to reflect and act when actually in the field, which we refer to as "situated research ethics." We employ the concept of "formation" as a useful pedagogical frame accentuating the importance of integrating knowledge, research skills, and ethical capabilities in research practice. We suggest that a narrative approach is consistent with formation, and is useful in research ethics training. This approach uses storytelling and engaging with stories to enable the development of ethical know-how in research. We conclude the article by focusing on the benefits and limitations of this approach. PMID- 22203389 TI - Family caregivers' health in connection with providing care. AB - Our aim was to investigate connections between Swedish family caregivers' health and providing care for an ill relative by conducting a systematic search and synthesis of previous research. We analyzed 31 articles using first qualitative content analysis then hermeneutic analysis. Analysis resulted in three derived themes-sliding sideways into caregiving, caregiving in reciprocity, and caregiving in disintegration-and a main interpretation and conceptual model of Swedish family caregivers' health-caregiving in a sphere of beliefs. Results indicated that Swedish family caregivers' beliefs, experiences of reciprocity, or nonsupport, together with quality of interpersonal relationships and feelings of responsibility and guilt, have a profound impact on their health. These results point to the value and importance of nurses gaining an understanding of family caregivers' beliefs and experiences of reciprocity or nonsupport to effectively promote family caregivers' health. PMID- 22203390 TI - Morbimortality of pandemic influenza A H1N1 infection in kidney transplant recipients requiring hospitalization: a comparative analysis with nonimmunocompromised patients. AB - BACKGROUND: Clinical and epidemiological data of pandemic influenza A H1N1 infection in solid-organ transplant recipients have been described, but scarce data compare these outcomes with nonimmunocompromised patients. METHODS: We retrospectively reviewed and compared the clinical presentation, morbidity, and mortality of all kidney transplant (KT) and nonimmunocompromised (non-KT) patients admitted for at least 12 hr with a diagnosis of pandemic influenza A H1N1 infection in a single hospital complex during the 2009 pandemic. RESULTS: There were 22 patients in the KT group (29.3%) and 53 in the non-KT group (70.7%). The prevalence of diabetes was higher in KT group (27.3% vs. 5.7%) while chronic pulmonary disease was more frequent in non-KT group (34% vs. 9.1%). Clinical and radiological presentations and duration of disease were similar between the two groups. The incidence of acute renal failure was higher among KT patients (40.9% vs. 17%). No differences in the rate of intensive care unit admission (22.7% vs. 22.6%) or hospital mortality (9.1% vs. 7.5%) were observed. For the overall population, poor outcome, defined as intensive care unit admission or death, was associated with in-hospital acquisition (relative risk [RR]=42.6 [95% confidence interval {95% CI } 2.2-831.9], P=0.003), symptom onset more than 48 hr (RR=12.17 [95% CI 1.3-117.2], P=0.007), and acute renal failure (RR=11.8 [95% CI 2.9-48.8], P<0.001). Among KT recipients, in-hospital acquisition was the only covariate associate with poor outcome (RR=30.0 [95% CI 2.1-421.1], P=0.004). CONCLUSIONS: No significant differences in morbidity and mortality were observed comparing KT and non-KT patients infected with pandemic H1N1 influenza A virus. PMID- 22203391 TI - Risk factors that increase mortality after living donor liver transplantation. AB - BACKGROUND: Female liver to male recipient is a well-accepted risk factor for graft loss in cadaveric liver transplantation. However, gender matching is infeasible because of an insufficient number of available donors. No studies have been performed on the role of gender in the field of living donor liver transplantation. This report investigates the effect of gender mismatch on the outcome of living donor liver transplantation. METHODS: A total of 335 patients and donors were classified into four groups according to the following gender combinations: male donor to male recipient group (n=104), male donor to female recipient group (n=120), female donor to male recipient (FM) group (n=59), and female donor to female recipient group (n=52). Patient and graft survival were compared among the groups. We performed a multivariable analysis to identify the factors associated with patient mortality. RESULTS: The 1-, 3-, 5-, and 10-year patient survival rates in the FM group were 80.6%, 66.8%, 61.8%, and 47.7%, respectively. The FM group showed significantly shorter patient survival compared with the other three groups. Independent risk factors for patient mortality were: FM group (P=0.006), pretransplant diabetes mellitus (P=0.001), and a model for end-stage liver disease score more than or equal to 20 (P=0.004). CONCLUSIONS: Male recipients of transplants from female donors, pretransplant diabetes mellitus, and a model for end-stage liver disease score more than or equal to 20 have poor survival rates. PMID- 22203392 TI - Febrile response induced by cecal ligation and puncture (CLP) in rats: involvement of prostaglandin E2 and cytokines. AB - The purpose of the present study was to better understand the events involved in the febrile response induced by cecal ligation and puncture (CLP), a complex infectious process. To this end, we conducted in vivo experiments in rats examining (1) fever development, (2) bacterial number in the infection focus and in blood, (3) peripheral and hypothalamic synthesis of cytokines, (4) hypothalamic and cerebrospinal fluid (CSF) synthesis of prostaglandin E(2) (PGE(2)), (5) the effect of anti-IL-6 antibody on fever, and (6) the effect of celecoxib on fever and hypothalamic synthesis of PGE(2) after CLP induction. We found that CLP promotes fever and animal death depending on the number of punctures. The peak of CLP-induced fever overlapped with the maximal increase in the number of bacteria in the infectious focus and blood, which occurred at 6 and 12 h. The peak of the febrile response also coincided with increased amounts of interleukin (IL)-1beta, IL-6 and IL-10 in the peritoneal exudate and serum; IL-6 in the hypothalamus and PGE(2) in the CSF and predominantly in the hypothalamus. Moreover, intracerebroventricularly injected anti-IL-6 antibody reduced the febrile response while celecoxib reduced the fever and PGE(2) amount in the hypothalamus induced by CLP. Tumor necrosis factor (TNF)-alpha peaked at 3 h at all sites studied. Conversely, IL-10 concentration decreased in the hypothalamus. These findings show that the peak of CLP-induced fever is accompanied by an increase of bacteria in peritoneal fluid (local infection) and blood; local synthesis of pyrogenic (IL-1beta, IL-6) and antipyretic (IL-10) cytokines and central production of IL-6 and PGE(2), suggesting that these last are the central mediators of this response. PMID- 22203393 TI - Effects of different substrate composition on biosynthesis of polyhydroxybutyrate co-hydroxyvalerate by recombinant Escherichia coli. AB - Cupriavidus necator is well known for its ability to accumulate polyhydroxybutyrate (PHB). When supplemented with propionic acid (or sodium propionate) in the growth medium, the bacterium is also able to synthesize polyhydroxybutyrate-co-hydroxyvalerate (PHBV). In order to increase the fraction of 3-hydroxyvalerate (3HV) in PHBV, we cloned the propionate permease gene prpP from C. necator and the propionyl-CoA synthase gene prpE from Cupriavidus taiwanensis and transformed into an Escherichia coli containing phaCAB operon of C. necator. The effects on PHBV accumulation in cells co-expressed with phaCAB and prpE or prpP in the media contained mixed carbon sources (glucose and sodium propionate) were evaluated. The HV fraction in PHBV increased when prpE or prpP was overexpressed in the cells. Concentrations of yeast extracts could also affect the fraction of HV. In addition, when glucose was replaced by sodium pyruvate, sodium succinate, or sodium gluconate, only PHB were detected in the recombinant strains. PMID- 22203394 TI - Production of D-tagatose, a functional sweetener, utilizing alginate immobilized Lactobacillus fermentum CGMCC2921 cells. AB - D-tagatose is a ketohexose that can be used as a novel functional sweetener in foods, beverages, and dietary supplements. This study was aimed at developing a high-yielding D-tagatose production process using alginate immobilized Lactobacillus fermentum CGMCC2921 cells. For the isomerization from D-galactose into D-tagatose, the immobilized cells showed optimum temperature and pH at 65 degrees C and 6.5, respectively. The alginate beads exhibited a good stability after glutaraldehyde treatment and retained 90% of the enzyme activity after eight cycles (192 h at 65 degrees C) of batch conversion. The addition of borate with a molar ratio of 1.0 to D-galactose led to a significant enhancement in the D-tagatose yield. Using commercial beta-galactosidase and immobilized L. fermentum cells, D-tagatose was successfully obtained from lactose after a two step biotransformation. The relatively high conversion rate and productivity from D-galactose to D-tagatose of 60% and 11.1 g l-1 h-1 were achieved in a packed-bed bioreactor. Moreover, lactobacilli have been approved as generally recognized as safe organisms, which makes this L. fermentum strain an attracting substitute for recombinant Escherichia coli cells among D-tagatose production progresses. PMID- 22203395 TI - Extraction of soluble fiber from distillers' grains. AB - The feasibility of using coproducts from dry grind corn ethanol production as a substrate for the production of soluble fiber was examined. Acid- and base catalyzed hydrolysis experiments were performed using sulfuric acid and sodium hydroxide to partially hydrolyze hemicellulose content of whole stillage, a precursor to distillers' grains, to soluble fiber. The influences of temperature, reaction time, and hydrolyzing agent concentration on the formation of soluble fiber were studied. Soluble fiber was recovered by precipitation in a 95% ethanol solution. Results indicate that appreciable quantities of soluble fiber may be extracted using either acid- or base-catalyzed reactions. The highest yield of soluble fibers was 13.2 g per 100 g-db of treated whole stillage using one weight percent sodium hydroxide at 80oC for 1 h. HPLC analysis was used to quantify the amount of monomeric sugars which were formed during the hydrolysis procedures. PMID- 22203396 TI - Laccase production and enzymatic modification of lignin by a novel Peniophora sp. AB - A novel laccase producing Basidiomycete Peniophora sp. (NFCCI-2131) was isolated from pulp and paper mill effluent. The optimal temperature and initial pH for laccase production by the isolate in submerged culture were found to be 30 and 4.6 degrees C, respectively. Maltose (20 g l-1) and tryptone (1.0 g l-1) were the most suitable carbon and nitrogen sources for laccase production. Cu2+ (1.0 mM) and veratryl alcohol induced maximum laccase production giving 6.6 and 6.07 U/ml laccase activity, respectively. Under optimised culture conditions, 7.6 U/ml activity was obtained, which was 2.4 times higher than that was achieved in basal medium. An evaluation of the delignification efficiency of the crude enzyme in the presence of redox mediators [2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) and (1-hydroxybenzotriazole)] revealed structural changes in lignin and existence of many active centres for both chemical and biological degradation of lignin following enzymatic treatment. PMID- 22203397 TI - Hydrolysis of native and heat-treated starches at sub-gelatinization temperature using granular starch hydrolyzing enzyme. AB - The effect of heat treatment below the gelatinization temperature on the susceptibility of corn, mung bean, sago, and potato starches towards granular starch hydrolysis (35 degrees C) was investigated. Starches were hydrolyzed in granular state and after heat treatment (50 degrees C for 30 min) by using granular starch hydrolyzing enzyme for 24 h. Hydrolyzed heat-treated starches showed a significant increase in the percentage of dextrose equivalent compared to native starches, respectively, with corn 53% to 56%, mung bean 36% to 47%, sago 15% to 26%, and potato 12% to 15%. Scanning electron microscopy micrographs showed the presence of more porous granules and surface erosion in heat-treated starch compared to native starch. X-ray analysis showed no changes but with sharper peaks for all the starches, suggested that hydrolysis occurred on the amorphous region. The amylose content and swelling power of heat-treated starches was markedly altered after hydrolysis. Evidently, this enzyme was able to hydrolyze granular starches and heat treatment before hydrolysis significantly increased the degree of hydrolysis. PMID- 22203398 TI - Production of oils from acetic acid by the oleaginous yeast Cryptococcus curvatus. AB - The feasibility of the conversion of acetic acid, a metabolite commonly obtained during anaerobic fermentation processes, into oils using the yeast Cryptococcus curvatus was reported. This microorganism exhibited very slow growth rates on acetate as carbon source, which led to design a two-stage cultivation process. The first consisted of cell growth on glucose as carbon source until its complete exhaustion. The second step involved the use of acetate as carbon source under nitrogen limitation in order to induce lipid accumulation. A typical experiment performed in a bioreactor involved a preliminary yeast growth with a glucose initial concentration of 15 g/L glucose. Further additions of acetate and nitrogen source allowed a final lipid accumulation up to 50% (w/w). These promising results demonstrated the suitability of the technique proposed. PMID- 22203399 TI - Identification of cadmium-excluding Welsh onion (Allium fistulosum L.) cultivars and their mechanisms of low cadmium accumulation. AB - PURPOSE: Screening out cadmium (Cd) excluding cultivars of a crop in agricultural production is an effective way to prohibit Cd entering into food chain. METHODS: A judging criterion for Cd-excluding cultivars based on food safety was suggested and used in the identification of Cd-excluding welsh onion (Allium fistulosum L.) cultivars. A pot culture experiment was carried out to screen out Cd-excluding cultivars, of which the results were confirmed by plot experiments. The relevant factors of Cd accumulation in the pseudostem were analyzed and used in the correlation analysis aiming to study the low Cd accumulation mechanisms. RESULTS: The concentration of Cd in the pseudostem of welsh onions was 0.08-0.20, 0.18 0.41, and 0.26-0.61 mg/kg fresh weight (FW) under three treatments (1.0, 2.5, and 5.0 mg/kg), respectively. The significant (p < 0.05) difference in the concentration of Cd in the pseudostem was observed among 25 welsh onion cultivars, but Cd contamination in soil had little influence on biomass and the contents of soluble sugar, NO(3)(-)-N, and eight other elements in the tested welsh onion cultivars. Two cultivars were identified as Cd-excluding cultivars, mainly because the accumulation of Cd in their pseudostem was only 0.041 +/- 0.003 and 0.046 +/- 0.002 mg/kg FW, and 0.054 +/- 0.001 and 0.066 +/- 0.011 mg/kg FW, when growing in plots with Cd concentration of 0.49 and 0.99 mg/kg, respectively. CONCLUSIONS: Ribentiegancongwang and Wuyeqi could be identified as Cd-excluding cultivars. Low bioaccumulation factor of the roots was the main mechanism of Cd-excluding welsh onion cultivars. PMID- 22203400 TI - Removal of hexavalent chromium of contaminated soil by coupling electrokinetic remediation and permeable reactive biobarriers. AB - PURPOSE: In this study, a novel and ecological alternative have been developed to treat soils contaminated with hexavalent chromium coupling two well-known systems: electrokinetic remediation and permeable reactive biobarriers. The electric field promotes the electromigration of the hexavalent chromium oxyanions towards the anode. The biobarriers were placed before the anode electrode, in order to promote the reduction and retention of the chromium migrating in its direction. Thus, this technology provided a global treatment to soil removal without subsequent treatments of the contaminated effluents. METHODS: The electrokinetic system was coupled with two different permeable reactive biobarriers composed by Arthrobacter viscosus bacteria, supported either in activated carbon or zeolite. An electric field of 10 V was applied and two different treatment times of 9 and 18 days were tested. RESULTS: Removal values of 60% and 79% were obtained when electrokinetic treatment was coupled with zeolite and activated carbon biobarriers, respectively, for a test period of 18 day. The reduction of hexavalent chromium to trivalent chromium was around 45% for both systems. CONCLUSIONS: In this work, two types of biobarriers were efficiently coupled to electrokinetic treatment to decontaminate soil with Cr(VI). Furthermore, the viability of the new coupling technology developed (electrokinetic + biobarriers) to treat low-permeability polluted soils was demonstrated. PMID- 22203401 TI - Characterization of particulate polycyclic aromatic hydrocarbons in the East of France urban areas. AB - BACKGROUND: Air samples collected on three different urban sites in East of France (Strasbourg, Besancon, and Spicheren), from April 2006 to January 2007, were characterized to measure the concentrations of polycyclic aromatic hydrocarbons (PAHs) in the particulate phase (PM(10)) and to examine their seasonal variation, diurnal variations, and emission sources. RESULTS: The average concentrations of SigmaPAHs were 12.6, 9.5, and 8.9 ng m(-3) for the Strasbourg, Besancon, and Spicheren sites, respectively. Strong seasonal variations of individual PAH concentrations were found at the three sampling sites, with higher levels in the winter that gradually decreased to the lowest levels in the summer. The diurnal variations of PAH concentrations in summer presented highest concentrations during the morning (04:00-10:00) and the evening (16:00-22:00) times, indicating the important contribution from vehicle emissions, in the three sampling sites. Furthermore, the ratio of BaP/BeP suggests that the photochemical degradation of PAHs can suppress their concentrations in the midday/afternoon (10:00-16:00), time interval of highest global irradiance. In winter, concentrations of PAH were highest during the evening (16:00-22:00) time, suggesting that domestic heating can potentially be an important source for particulate PAH, for the three sampling sites. CONCLUSION: Diagnostic ratios were used to identify potential sources of PAHs. Results showed that vehicle emissions may be the major source of PAHs, especially in summer, with a prevalent contribution of diesel engines rather than gasoline engines at the three sites studied, independently of the seasons. PMID- 22203402 TI - Bioremediation of chromium by novel strains Enterobacter aerogenes T2 and Acinetobacter sp. PD 12 S2. AB - PURPOSE: This study had an objective to identify the most potent chromium resistant bacteria isolated from tannery effluent and apply them for bioremediation of chromium in tannery effluents. METHODS: Two such strains (previously characterized and identified by us)--Enterobacter aerogenes (NCBI GenBank USA Accession no. GU265554) and Acinetobacter sp. PD 12 (NCBI GenBank USA Accession no. GU084179)--showed powerful chromium resistivity and bioremediation capabilities among many stains isolated from tannery waste. Parameters such as pH, concentration of hexavalent chromium or Cr (VI), and inoculum volume were varied to observe optimum bioconversion and bioaccumulation of Cr (VI) when the said strains were grown in M9 minimal salt media. E. aerogenes was used to remediate chromium from tannery effluents in a laboratory level experiment. RESULTS: Observation by Scanning Electron Microscope and chromium peak in Energy Dispersive X-ray Spectroscopic microanalysis revealed that E. aerogenes helped remediate a moderate amount of Cr (VI) (8-16 mg L(-1)) over a wide range of pH values at 35-37 degrees C (within 26.05 h). High inoculum percentage of Acinetobacter sp. PD 12 also enabled bioremediation of 8-16 mg L(-1) of Cr (VI) over a wide range of temperature (25-37 degrees C), mainly at pH 7 (within 63.28 h). The experiment with real tannery effluent gave very encouraging results. CONCLUSION: The strain E. aerogenes can be used in bioremediation of Cr (VI) since it could work in actual environmental conditions with extraordinarily high capacity. PMID- 22203403 TI - Acute and chronic toxicity of benzotriazoles to aquatic organisms. AB - PURPOSE: Resulting from their intensive use as corrosion inhibitors in aircraft deicing and anti-icing fluids (ADAF) and for silver protection in dishwasher detergents benzotriazoles (BTs) are widespread in European surface waters. The current study aimed on an ecotoxicological characterization of 1H-benzotriazole (1H-BT) and 5-methyl-1H-benzotriazole (5MBT). METHODS: Acute and chronic OECD guideline tests were conducted with primary producers (Desmodesmus subspicatus, Lemna minor) and two daphnia species (Daphnia magna, Daphnia galeata) to characterize the hazard of these chemicals. Additionally, the estrogenic activity of both BTs was analyzed in vitro using a recombinant yeast estrogen screen (YES). RESULTS: Both BTs revealed significant effects in acute and chronic experiments, but exhibited no estrogenic activity in the YES. The algal growth test displayed an inhibited cell number increase with effect concentration (EC) values of EC(10) 1.18 and 2.86 mg l(-1) for 1H-BT and 5MBT, respectively. In the Lemna test, EC(10) values were 3.94 mg l(-1) (1H-BT) and 2.11 mg l(-1) (5MBT). D. magna was also affected with EC(50) (48 h) values of 107 mg l(-1) for 1H-BT and 51.6 mg l(-1) for 5MBT. D. galeata was more sensitive with an EC(50) (48 h) of 14.7 mg 1H-BT l(-1) and 8.13 mg 5MBT l(-1). In the 21-day reproduction tests with D. magna, the EC(10) for 5MBT was 5.93 mg l(-1) while 1H-BT showed no adverse effects. D. galeata turned out to be more sensitive in the chronic study with EC(10) values of 0.97 mg l(-1) for 1H-BT and 0.40 mg l(-1) for 5 MBT. CONCLUSION: Because BTs are regularly found in the aquatic environment at lower MUg l(-1) concentrations reflecting their persistence and poor elimination during wastewater treatment processes, a preliminary risk assessment was conducted. There is little indication that BTs pose a risk for aquatic ecosystems at current exposure levels during most of the year. However, it cannot be excluded that in winter with a higher usage of ADAFs environmental concentrations may well exceed the level that is considered safe for aquatic organisms. PMID- 22203404 TI - Role of the Dickeya dadantii Dps protein. AB - During infection, the phytopathogenic enterobacterium Dickeya dadantii has to cope with iron-limiting conditions and the production of reactive oxygen species by plant cells. A tight control of the bacterial intracellular iron content is necessary for full virulence of D. dadantii: previous studies have shown that the ferritin FtnA and the bacterioferrtin Bfr, devoted to iron storage, contribute differentially to the virulence of this species. In this work, we investigated the role of the Dps miniferritin in iron homeostasis in D. dadantii. We constructed a Dps-deficient mutant by reverse genetics. This mutant grew like the wild-type stain under iron starvation and showed no decreased iron content. However, the dps mutant displayed an increased sensitivity to hydrogen peroxide in comparison to the wild-type strain. This hydrogen peroxide susceptibility only occurs when bacteria are in the stationary phase. Unlike the bfr and the ftnA mutants, the dps mutant is not affected in its pathogenicity on host plants. The dps gene expression is induced at the stationary phase of growth. The Sigma S transcriptional factor is necessary for this control. Furthermore, dps expression is positively regulated by the oxidative stress response regulator OxyR during the exponential growth phase, after hydrogen peroxide treatment. These results indicate that the Dps miniferritin from D. dadantii has a minor role in iron homeostasis, but is important in conferring tolerance to hydrogen peroxide and for survival of cells that enter the stationary phase of growth. PMID- 22203406 TI - Serial endoscopic analysis of the glottis following laser cordectomy: from an oncological perspective. AB - From the oncological point of view, discrimination between the normal healing process and a pathological condition following laser surgery of the larynx is important in the management of possible residual/recurrent disease. However, the wound-healing process following laser surgery of the larynx is not well understood, especially regarding the gross morphological changes over time. The aims of this study were to analyze the serial temporal changes in the laryngeal endoscopic findings following laser cordectomy and to define the process involved in stabilization of the laryngeal mucosa. The study group comprised 46 consecutive patients with early glottic cancer undergoing laser cordectomy using the CO(2) laser. All outpatient clinic endoscopic examinations were documented and archived, and were examined serially in a semiquantitative manner to assess the dynamic change and the process involved in stabilization of the laryngeal mucosa. Clinical parameters affecting the healing process were analyzed. Mucosal stabilization was achieved at a median of 57 days. The laryngeal mucosa was stabilized within 100 days following the surgery in 80.4% of the patients. Tumor base width was significantly correlated with healing time. Early healers (<=40 days) had smaller tumors and had undergone a less-extensive procedure. Recurrences were observed in 33% of the patients with delayed healing for over 100 days. Healing of the laryngeal mucosa took no more than 100 days following laser cordectomy in the majority of the patients. Therefore, cautious waiting for up to 3 months (100 days) may be warranted to discriminate between the normal healing process and a pathological condition in order to establish a proper management plan and avoid unnecessary biopsy. PMID- 22203405 TI - The role of non-HDL cholesterol in risk stratification for coronary artery disease. AB - Despite aggressive lipid-lowering therapy, patients continue to be at significant risk of coronary heart disease (CHD). Assessment of non-high-density lipoprotein cholesterol (non-HDL-C) provides a measure of cholesterol contained in all atherogenic particles. In the third Adult Treatment Panel (ATP III) guidelines of the US National Cholesterol Education Program, non-HDL-C was introduced as a secondary target of therapy in persons with triglycerides >=200 mg/dL. A recent meta-analysis of the relationship between non-HDL-C reduction and CHD risk showed non-HDL-C as an important target of therapy for CHD prevention. Most lipid modifying drugs used as monotherapy have a 1:1 relationship between percent non HDL-C lowering and percent CHD reduction. In the EPIC-Norfolk prospective population study, 21,448 participants without diabetes or CHD between 45 and 79 years of age were followed for 11.0 years. Participants with high non-HDL-C levels were at increased CHD risk independently of their LDL-C levels. Also, compared to apolipoprotein B, non-HDL-C appears to be a better choice given the fact that no additional tests or costs are needed and established cut points are already available. Future guidelines should emphasize the importance of non-HDL-C for guiding cardiovascular prevention strategies with an increased need to have non-HDL-C reported on routine lipid panels. PMID- 22203407 TI - Long-term follow-up on cardiac function following fulminant myocarditis requiring percutaneous extracorporeal cardiopulmonary support. AB - Fulminant myocarditis is a rapidly progressive, life-threatening disease with severe impairment of systolic left ventricle function in the acute phase. However, the long-term prognosis of patients who survive the acute phase with percutaneous extracorporeal cardiopulmonary support (PCPS) is not established. The purpose of this study was to elucidate the long-term follow-up on chronic cardiac function and long-term outcome. Twenty consecutive patients with fulminant myocarditis in the acute phase supported by PCPS were enrolled between January 1995 and March 2010. Echocardiography was performed at least three times; acute phase (within 3 days from onset), predischarge (days 3-30), and chronic phase (>6 months, 2.67 +/- 2.19 years, mean +/- SD). The clinical events were queried by their medical record and questionnaires. Eight patients (40%) died in the acute phase. The time course of ejection fraction (%) by echocardiography was 22.7 +/- 9.8, 53.1 +/- 7.2, and 57.2 +/- 9.6 in acute, predischarge, and chronic phase, respectively. Diastolic dimension (mm) was 46.8 +/- 7.4, 51.3 +/- 2.9, and 50.4 +/- 1.8, and systolic dimension (mm) was 41.4 +/- 7.7, 36.8 +/- 4.0, and 35.2 +/- 3.3 in acute, predischarge, and chronic phase, respectively. There was no recurrence or admission related to heart failure during the follow-up period. The cardiac function of patients with fulminant myocarditis recovers rapidly during their stay in hospital. The cardiac function of predischarge patients remains unchanged in the chronic phase. The long-term survival of fulminant myocarditis appears favorable in the chronic phase. PMID- 22203408 TI - Comparison of stroke work between repaired tetralogy of Fallot and normal right ventricular physiologies. AB - Adult patients who underwent tetralogy of Fallot repair surgery (rTOF) confront life-threatening ailments due to right ventricular (RV) myocardial dysfunction. Pulmonary valve replacement (PVR) needs to be performed to restore the deteriorating RV function. Determination of correct timing to perform PVR in an rTOF patient remains subjective, due to the unavailability of quantifiable clinical diagnostic parameters. The objective of this study is to evaluate the possibility of using RV body surface area (BSA)-indexed stroke work (SW(I)) to quantify RV inefficiency in TOF patients. We hypothesized that RV SW(I) required to push blood to the lungs in rTOF patients is significantly higher than that of normal subjects. Seven patients with rTOF pathophysiology and eight controls with normal RV physiology were registered for this study. Right ventricular volume and pressure were measured using cardiac magnetic resonance imaging and catheterization, respectively. Statistical analysis was performed to quantify the difference in SW(I) between the RV of the rTOF and control groups. Right ventricular SW(I) in rTOF patients (0.176 +/- 0.055 J/m(2)) was significantly higher by 93.4% (P = 0.0026) than that of controls (0.091 +/- 0.030 J/m(2)). Further, rTOF patients were found to have significantly higher (P < 0.05) BSA normalized RV end-systolic volume, end-systolic pressure, and regurgitation fraction than control subjects. Ejection fraction and peak ejection rate of rTOF patients were significantly lower (P < 0.05) than those of controls. Patients with rTOF pathophysiology had significantly higher RV SW(I) compared with subjects with normal RV physiology. Therefore, RV SW(I) may be useful to quantify RV inefficiency in rTOF patients along with currently used clinical end points such as RV volume, pressure, regurgitation fraction, and ejection fraction. PMID- 22203409 TI - Assessment of platelet function by whole blood impedance aggregometry in coronary artery bypass grafting patients on acetylsalicylic acid treatment may prompt a switch to dual antiplatelet therapy. AB - Residual platelet reactivity (RPR) following coronary artery bypass grafting (CABG) might be related to thrombotic complications and major ischemic cardiac events. The aim of this study was to evaluate the changes in platelet reactivity monitored pre- and postoperatively using multiple-electrode aggregometry (MEA) and to propose an alternative therapeutic approach in a subgroup of patients with postoperative RPR. Ninety-nine patients undergoing elective CABG were enrolled in the study, of whom 41 (41.4%) were diabetic. Preoperatively, all patients received 100 mg acetylsalicylic acid (ASA), with 47 of 99 (47.4%) patients receiving an additional 75 mg clopidogrel (CLO). The blood samples were drawn the day before surgery, and on the first and 4th postoperative day. Platelet count and fibrinogen level were documented, as well as type and daily dose of antiplatelet therapy (APT) received pre- and postoperatively. Multiple-electrode aggregometry using tests based on arachidonic acid (ASPI test) and adenosine diphosphate (ADP test) was performed on the day before and 4 days after surgery. Preoperatively, we detected 31 of 99 (31.3%) patients with RPR (ASPI > 30 AUC). Platelet count correlated with both the ASPI (P = 0.03) and ADP (0.002) tests. Fibrinogen correlated with ADP test values (P < 0.001) and was found to have a higher level in the diabetic subgroup (P = 0.01). In comparison with preoperative results, we detected higher values of ASPI test postoperatively (P = 0.04), with 46 of 99 (46.5%) patients having RPR despite a higher dose of 300 mg ASA being administered. Postoperatively, diabetic patients had higher ASPI test values (P = 0.01), and a higher proportion of patients with RPR compared with the nondiabetic subgroup (58.5 vs 38%, P = 0.04). The subgroup of patients with detected ASPI >30 AUC at the 4th postoperative day consequently received as a part of our clinical routine an additional 75 mg CLO per day, in terms of platelet inhibition optimization. Multiple-electrode aggregometry can recognize patients with RPR during both the pre- and post-CABG period. Postoperatively administered ASA (300 mg) did not sufficiently inhibit platelet aggregation in 46.5% of post-CABG patients. In this group of patients a switch to dual APT should be considered. PMID- 22203410 TI - Impact of sewage contaminated water on soil, vegetables, and underground water of peri-urban Peshawar, Pakistan. AB - The use of sewage-contaminated municipal water for irrigation of crops is an old practice in many big cities of Pakistan. Since the wastewater is rich in nutrients, it increases crops yield substantially but at the cost of food quality. The objective of this study was to investigate sewage water irrigation as a source of accumulation of heavy metals in soil and its subsequent transfer to crops and underground water. Sewage water, soil, groundwater, and crop samples were collected from selected areas around Peshawar city and analyzed for heavy metals concentration by atomic absorption spectroscopic method. Analysis of data revealed a considerable impact of the irrigation practices in the peri-urban Peshawar. Statistical analysis of the data showed a positive correlation between heavy metals concentration and soil carbon contents on the one hand and cation exchange capacity on the other. A strongly negative correlation was observed between metal contents and soil pH. The vertical movement of heavy metals from contaminated soil has polluted crops and underground water. The results indicated higher concentration of toxic metals in soil accumulated due to long-term sewage contaminated water irrigation and their subsequent transfer to our food chain. The practice, if continued un-noticed may pose a threat of phytotoxicity to the local population. PMID- 22203411 TI - Flocculation of metals during mixing of Siyahrud River water with Caspian Sea water. AB - Flocculation of dissolved Cu, Mn, Ni, Zn, and Pb during mixing of Siyahrud River water with water sample of Caspian Sea at nine different salinity regimes was investigated. The maximum flocculation of elements occurs in the salinities 1.670/00 to 3.670/00 (except for Zn). The flocculation trend of Zn (80.9) >Mn (58.3) > Cu (30.5) > Ni (25.9) > Pb (19.5) indicates that flocculation of metals have nonlinear behavior towards salinity changes during estuarine mixing. Electrical conductivity shows a linear behavior in different proportions of salinity which is in contrast with the behavior of other studied parameters. Cluster analysis indicates that pH and NO(3) are governing factors in the flocculation of Cu, Mn, and Pb. The results of this research show that 80.9%, 19.5%, 25.9%, 30.5%, and 58.3% of dissolved Zn, Pb, Ni, Cu, and Mn flocculate during estuarine mixing. Total amount of studied dissolved element flowing in to the Caspian Sea would decrease from 5.62 to 2.76 t/year. PMID- 22203412 TI - Spatial distribution and sources of trace elements in sediments affected by old mining activities. AB - The distribution of trace elements throughout mining areas is an important issue because abandoned tailings could be a major source of environmental pollution. In order to analyze the spatial variation of trace elements in a zone where mining activities took place and to identify pollution sources in the study area, a three-step study was carried out at a regional, at a local, and a detailed scale. In addition, a conceptual model of trace elements dispersion was established and confirmed by a geographic information system. The results obtained allowed to establish points affected by primary, secondary, and tertiary contamination, according to their proximity to contamination sources and as a function of attenuation processes which could take place in the studied area. PMID- 22203413 TI - Limnochemistry and nutrient dynamics in Upper Lake, Bhopal, India. AB - In limnetic ecosystem, water quality depends upon physical, chemical, and biological factors. Effects of temperature, light scattering, and absorption by suspended and dissolved matter, transport, and mixing of nutrients within the lake are the significant factors as far as water quality is concerned. Nutrient loading into the lake and internal cycling of nutrients is always a matter of concern and critical to number of processes. During the winter season, heat and momentum transfer at the lake surface and the temperature-density relation of water destabilize the water column and drive vertical mixing and transport processes. The deepening of the surface layer produces nutrient transfer from the hypolimnion into the euphotic zone of epilimnion. It may also resuspend sediments that would have settled under stratified conditions, or redistribute particles that may still be in suspension. Thus, there exists a complex connection between the hydrodynamics and water quality issues. Present study is an effort to understand how seasonal changes in the limnetic ecosystem regulate the limnochemistry and movement of nutrient. The study revealed that significant variations of nutrients and organic load were observed between epilimnion and hypolimnion during summer season, and the lake was found in hyper-eutrophic condition throughout the study period. PMID- 22203414 TI - Cerebellar function and dysfunction--what did we learn from 4th International Symposium, Society for Research on the Cerebellum in Japan? PMID- 22203416 TI - Effective removal of endocrine-disrupting compounds by lignin peroxidase from the white-rot fungus Phanerochaete sordida YK-624. AB - The removal of endocrine-disrupting compounds (EDCs) by lignin peroxidase from white-rot fungus Phanerochaete sordida YK-624 (YK-LiP1) was investigated. Five endocrine disruptors, p-t-octylphenol (OP), bisphenol A (BPA), estrone (E(1)), 17beta-estradiol (E(2)), and ethinylestradiol (EE(2)) were eliminated by YK-LiP1 more effectively than lignin peroxidase from P. chrysosporium (Pc-LiP), and OP and BPA were disappeared almost completely in the reaction mixture containing YK LiP1 after a 24-h treatment. Particularly, the removal of estrogenic activities of E(2) and EE(2), which show much higher estrogenic activities than other EDCs such as BPA and OP, were removed following 24-h treatment with YK-LiP1. Moreover, 5,5'-bis(1,1,3,3-tetramethylbutyl)-[1,1'-biphenyl]-2,2'-diol and 5,5'-bis-[1-(4 hydroxy-phenyl)-1-methyl-ethyl]-biphenyl-2,2'-diol were identified as the main metabolite from OP or BPA, respectively. These results suggest that YK-LiP1 is highly effective in removing of EDCs by the oxidative polymerization of these compounds. PMID- 22203417 TI - Some concerns about the article: "High doses of oxycodone-naloxone combination may provide poor analgesia.". PMID- 22203418 TI - Adherence of stem cell transplant recipients receiving glucocorticoid therapy to an exercise-based rehabilitation program. AB - The high acuity of hematopoietic stem cell transplant (HSCT) recipients receiving glucocorticoid (GC) therapy for acute graft vs. host disease (aGVHD) may limit their adherence to an exercise-based rehabilitation program and hence, slow their recovery. To make this determination, the medical records of 59 subacute outpatient stem cell transplant recipients receiving methylprednisolone (MP) were reviewed for demographic, anthropometric and medical information. Performance on the repeated sit-to-stand, 50-ft walk and 6-min walk tests were determined before and after completing a 4-week progressive exercise rehabilitation program and outcomes were compared by a paired t-test (P < 0.05). Thirty-two patients (54%) finished a treatment plan (adherent group), completing 80% of the prescribed sessions and were reevaluated. Twenty-seven patients (46%) did not complete the rehabilitation program (nonadherent group), primarily because of readmission to the hospital (18 patients, 62%). The adherent group did not significantly improve their physical performance (p > 0.05). However, a subgroup of 40% of these patients did experience clinically significant improvements in their physical performance.These findings 1) support the feasibility of having HSCT recipients receiving GC therapy to participate in an exercise-based rehabilitation program and 2) suggest that to do so can result in clinically significant improvements in functional capacity. PMID- 22203420 TI - Function of the syndecan-4 cytoplasmic domain in oligomerization and association with alpha-actinin in turkey muscle satellite cells. AB - Syndecan-4 (S4) is a cell membrane heparan sulfate proteoglycan that plays a role in satellite cell mediated myogenesis. S4 modulates the proliferation of myogenic satellite cells, but the mechanism of how S4 functions during myogenesis is not well understood. In other cell systems, S4 has been shown to form oligomers in the cell membrane and interact through its cytoplasmic domain with the cytoskeletal protein alpha-actinin. This study addressed if S4 forms oligomers and interacts with alpha-actinin in muscle. The S4 cytoplasmic domain was found to interact with alpha-actinin in a phosphatidylinositol-4,5-bisphosphate dependent manner, but did not associate with vinculin. Through confocal microscopy, both S4 and syndecan-4 without the cytoplasmic domain were localized to the cell membrane. Although the cytoplasmic domain was necessary for the interaction with alpha-actinin, S4 oligomer formation occurred in the absence of the cytoplasmic domain. These data indicated that S4 function in skeletal muscle is mediated through the formation of oligomers and interaction with the cytoskeletal protein alpha-actinin. PMID- 22203419 TI - Hydrogen sulfide protects H9c2 cells against doxorubicin-induced cardiotoxicity through inhibition of endoplasmic reticulum stress. AB - The roles of hydrogen sulfide (H(2)S) and endoplasmic reticulum (ER) stress in doxorubicin (DOX)-induced cardiotoxicity are still unclear. This study aimed to dissect the hypothesis that H(2)S could protect H9c2 cells against DOX-induced cardiotoxicity by inhibiting ER stress. Our results showed that exposure of H9c2 cells to DOX significantly inhibited the expression and activity of cystathionine gamma-lyase (CSE), a synthetase of H(2)S, accompanied by the decreased cell viability and the increased reactive oxygen species (ROS) accumulation. In addition, exposure of cells to H(2)O(2) (an exogenous ROS) mimicked the inhibitory effect of DOX on the expression and activity of CSE. Pretreatment with N-acetyl-L: -cysteine (NAC) (a ROS scavenger) attenuated intracellular ROS accumulation, cytotoxicity, and the inhibition of expression and activity of CSE induced by DOX. Notably, the ER stress-related proteins, including glucose regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) were obviously upregulated in DOX-treated H9c2 cells. Pretreatment with sodium hydrosulfide (NaHS, a H(2)S donor) before DOX exposure markedly suppressed DOX-induced overexpressions of GRP78 and CHOP, cytotoxicity and oxidative stress. In conclusion, we have demonstrated that ROS-mediated inhibition of CSE is involved in DOX-induced cytotoxicity in H9c2 cells, and that exogenous H(2)S can confer protection against DOX-induced cardiotoxicity partly through inhibition of ER stress. PMID- 22203421 TI - Protective effects of arachidonic acid against palmitic acid-mediated lipotoxicity in HIT-T15 cells. AB - Saturated fatty acids have been considered major contributing factors in type 2 diabetes, whereas unsaturated fatty acids have beneficial effects for preventing the development of diabetes. However, the effects of polyunsaturated fatty acids in pancreatic beta cells have not been reported. Here, we examined the effects of arachidonic acid (AA) on palmitic acid (PA)-mediated lipotoxicity in clonal HIT T15 pancreatic beta cells. AA prevented the PA-induced lipotoxicity as indicated by cell viability, DNA fragmentation and mitochondrial membrane potential, whereas eicosatetraynoic acid (ETYA), a non-metabolizable AA, had little effect on PA-induced lipotoxicity. In parallel with its protective effects against PA induced lipotoxicity, AA restored impaired insulin expression and secretion induced by PA. AA but not ETYA increased intracellular triglyceride (TG) in the presence of PA compared with PA alone, and xanthohumol, a diacylglycerol acyltransferase (DGAT) inhibitor, reversed AA-induced protection from PA. Taken together, our results suggest that AA protects against PA-induced lipotoxicity in clonal HIT-T15 pancreatic beta cells, and the protective effects may be associated with TG accumulation, possibly through sequestration of lipotoxic PA into TG. PMID- 22203422 TI - TOP2 gene is involved in the pathogenicity of Candida albicans. AB - Candida albicans is a common cause of morbidity in hospitalized and immunosuppressed patients. There are still many unknown genes involved in the virulence of C. albicans. The present study aims to examine the effect of TOP2 gene in candidal virulence, including hyphal growth, phospholipase and proteinase activity. Targeted gene disruption of both TOP2 alleles in a wild-type strain of C. albicans produced hyphae more efficiently. TOP2 disruption also increased phospholipase and proteinase activities, and enhanced virulence as assessed by host tissue colonization in systemic infection model. The result of reverse transcription PCR displayed that PLB1 and SAP4 expressions of top2 mutants was significantly upregulated when compared with the isogenic parental strain. Together, these results indicated that TOP2 gene was involved in candidal pathogenicity, and the major reasons for the comparatively high virulence of null mutants were the higher capacity to produce hyphae and the increased phospholipase and proteinase activities, at least in part. PMID- 22203423 TI - Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function. AB - The HYDE scoring function consistently describes hydrogen bonding, the hydrophobic effect and desolvation. It relies on HYdration and DEsolvation terms which are calibrated using octanol/water partition coefficients of small molecules. We do not use affinity data for calibration, therefore HYDE is generally applicable to all protein targets. HYDE reflects the Gibbs free energy of binding while only considering the essential interactions of protein-ligand complexes. The greatest benefit of HYDE is that it yields a very intuitive atom based score, which can be mapped onto the ligand and protein atoms. This allows the direct visualization of the score and consequently facilitates analysis of protein-ligand complexes during the lead optimization process. In this study, we validated our new scoring function by applying it in large-scale docking experiments. We could successfully predict the correct binding mode in 93% of complexes in redocking calculations on the Astex diverse set, while our performance in virtual screening experiments using the DUD dataset showed significant enrichment values with a mean AUC of 0.77 across all protein targets with little or no structural defects. As part of these studies, we also carried out a very detailed analysis of the data that revealed interesting pitfalls, which we highlight here and which should be addressed in future benchmark datasets. PMID- 22203424 TI - Interaction of flucloxacillin and quinidine. PMID- 22203425 TI - Osteonecrosis and leg ulceration in Indian sickle cell patients. PMID- 22203426 TI - Etiology of severe anemia amongst adolescent children. PMID- 22203427 TI - Prevalence and correlates of sustained hypertension in adolescents of rural Wardha, central India. AB - OBJECTIVE: To study the prevalence of hypertension and its determinants among adolescents in rural areas of Wardha. METHODS: The cross-sectional study was carried out in villages under PHC Talegaon (Talatule) of Wardha district of central India. Out of total population of 37,946 in the PHC, 7435 were adolescents. For the study purpose 1055 adolescents' were selected by simple random sampling method. Among sampled adolescents, 990 were interviewed and examined. The study was conducted during January 2008-December 2008. Hypertension was defined as raised BP (average SBP and/or DBP >95th percentile) for age, sex and height on two additional occasions. Data thus generated was entered and analyzed using epi_info 6. RESULTS: The prevalence of hypertension and pre hypertension was found to be 3.4% and 10.6% respectively. Bivariate analysis showed significant association (p < 0.05) of hypertension and prehypertension with age, education, occupation, type of family, use of smokeless tobacco, amount of salt consumption, nutritional status, education level of mother and blood pressure level of mother, and father. On multivariate analysis of the present study, the final model by ordinal logistic regression showed significant association of hypertension/pre-hypertension of adolescents with age, type of family, BMI of adolescent and blood pressure of mother and father. CONCLUSIONS: The prevalence of hypertension and pre-hypertension was 3.4% and 10.6% respectively. The significant correlates of hypertension and pre-hypertension were age, type of family, BMI of subject and blood pressure of mother and father. PMID- 22203428 TI - Magnetisation transfer effects of Q2TIPS pulses in ASL. AB - OBJECT: In pulsed arterial spin labelling (ASL), Q2TIPS saturation pulses are used to actively control the temporal width of the labelled bolus. However, these Q2TIPS pulses also induce magnetisation transfer (MT) effects in the adjacent tissue. In this work, we investigated how Q2TIPS-related MT alters tissue signal in pulsed ASL and, consequently, CBF quantification. MATERIALS AND METHODS: Seven volunteers were studied at 3 tesla using a multi-TI FAIR sequence and 3D-GRASE readout with background suppression. Q2TIPS pulses were used and the spacing between RF pulses was varied to modulate MT effects. Computer simulations were designed to mimic in-vivo signals at multiple TI values. RESULTS: Q2TIPS associated MT was found to reduce tissue T1 and M0 values by up to 42 and 50% respectively; leading to a reduction of up to 40% in the effectiveness of background suppression and, therefore, increased sensitivity to motion for the longest TI values. In addition, greater MT effects were associated with reduced grey matter CBF estimates of up to 15%. CONCLUSIONS: The MT effect associated with the Q2TIPS pulse train has a significant effect on tissue signal. It is recommended that MT effects are characterised and both background suppression and Q2TIPS schemes are accordingly optimised to reduce the effects of MT on accuracy and precision of CBF estimation. PMID- 22203429 TI - Iatrogenic Cushing syndrome due to nasal steroid drops. AB - Iatrogenic Cushing syndrome may occur as an undesirable outcome of high-dose glucocorticoids treatments. This may also cause hypothalamus-hypophysis-adrenal axis suppression. While this situation may be caused more frequently with oral and topical glucocorticoid therapy, iatrogenic Cushing syndrome in childhood, caused by steroid-containing nasal drops, is a rare event. Hereby, we present a baby who developed iatrogenic Cushing syndrome induced by long-term use of steroid-containing nasal drops for choanal atresia. In conclusion, the serious side effects of the nasal drops should have been explained to the family, and their long-term use should have been refrained. PMID- 22203430 TI - Respiratory hospitalizations and respiratory syncytial virus prophylaxis in special populations. AB - Palivizumab utilization, compliance, and outcomes were examined in infants with preexisting medical diseases within the Canadian Registry Database (CARESS) to aid in developing guidelines for potential "at-risk" infants in the future. Infants who received >=1 dose of palivizumab during the 2006-2010 respiratory syncytial virus (RSV) seasons at 29 sites were recruited and utilization, compliance, and outcomes related to respiratory infection/illness (RI) events were collected monthly. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for premature infants <=35 completed weeks gestational age (GA) who met standard approval criteria (group 1) compared to those with medical disorders (group 2) using Cox proportional hazards regression models with adjustment for potential confounding factors. Of 7,339 registry infants, 4,880 were in group 1 and 952 in group 2, which included those with Down syndrome (20.3%), upper airway anomalies (18.7%), pulmonary diseases (13.3%), and cystic fibrosis (12.3%). Group 2 were older at enrollment (10.2 +/- 9.2 vs. 3.5 +/- 3.1 months, p < 0.0005), had higher GA (35.9 +/- 6.0 vs. 31.0 +/- 5.4 weeks, p < 0.0005), and were less compliant with treatment intervals (69.4% vs. 72.6%, p = 0.048). A greater proportion of group 2 infants were hospitalized for RI (9.0% vs. 4.2%, p < 0.0005) and RSV (2.4% vs. 1.3%, p = 0.003) (unadjusted). Being in group 2 was associated with an increased risk of RI (HR = 2.0, 95%CI 1.5-2.5, p < 0.0005), but not RSV hospitalization (HR = 1.6, 95% CI 0.9-2.8, p = 0.106). In infants receiving palivizumab, those with underlying medical disorders, though not currently approved for prophylaxis, are at higher risk for RI events compared with preterm infants. However, risk of RSV hospitalizations is similar. PMID- 22203431 TI - Urinary matrix metalloproteinases-2/9 in healthy infants and haemangioma patients prior to and during propranolol therapy. AB - The mechanism of therapeutic success of propranolol for severe infantile haemangioma remains unclear. Propranolol was shown to modify matrix metalloproteinase (MMP) levels, which are associated with tumour pathogenesis. We hypothesized that urinary MMP2/9 is higher in patients with infantile haemangioma compared to healthy infants and that propranolol reduces MMP2/9 levels and thus leads to an involution of the haemangioma. In this case, MMP2/9 could be used as a marker of indicated therapy or therapeutic success. Urinary samples were taken before, 2 weeks after, and 2 months after the beginning of propranolol treatment in haemangioma patients and once in healthy controls. Activity of MMP2/9 was determined by commercially available activity kits. Urine of 22 haemangioma patients and 21 control subjects was obtained. Propranolol therapy had significant success in all patients. MMP2/9 was present in most samples, the younger the children the higher the MMP2 levels. Haemangioma patients showed lower levels of MMP2. The MMP2 levels were significantly higher after 2 weeks of propranolol than prior to therapy. There were no differences in MMP9 levels. CONCLUSIONS: Presence of MMP2/9 in the urine of infants <1 year can be explained by high rate of physiological tissue remodelling. Unexpectedly, MMP2 was lower in the urine of haemangioma patients and higher 2 weeks after propranolol treatment. Taking this and the diverse results in literature into account, the correlation between MMPs, proliferation, and regression of haemangiomas and propranolol remains unclear. PMID- 22203432 TI - Inflation times during resuscitation of preterm infants. AB - Data on the effects of a prolonged inflation time during the resuscitation of very prematurely born infants are limited; one study showed no effect, and in another, although lower bronchopulmonary dysplasia (BPD) rates were seen, that effect could have been due to the prolonged inflation time, the positive end expiratory pressure applied or the combination of the two. The aims of our study were to assess the length of inflation times used during face mask and t-piece resuscitation of prematurely born infants in the labour suite and determine whether prolonged inflations led to longer inflation flow times. A respiration monitor (NM3 respiratory profile monitor) was used to record flow, airway pressure and tidal volume changes. The first five inflations for each baby were analysed. Forty prematurely born infants (median gestational age 30, range 26-32 weeks) were examined. Their median inflation pressure was 17.6 (range 12.2-27.4) cm H2O, inflation time 0.89 (range 0.33-2.92) s, expiratory tidal volume 1.01 (range 0.02-11.41) ml/kg and inflation flow time 0.11 (range 0.04-0.54) s. There was no significant relationship between the inflation time and the inflation flow time, but there was a significant relationship between the inflation pressure and the inflation flow time (p = 0.024). CONCLUSION: These results suggest that prolonging inflation times during face mask resuscitation of prematurely born infants would not improve ventilation as prolonged inflation did not lead to longer inflation flow times. PMID- 22203434 TI - Parity and mortality from causes other than breast cancer in breast cancer patients. PMID- 22203433 TI - The future of autoimmunity. AB - There have been enormous strides in our understanding of autoimmunity. These strides have come under the umbrellas of epidemiology, immunological phenotype and function, disease definitions and classification and especially new therapeutic reagents. However, while these advances have been herculean, there remains enormous voids. Some of these voids include genetic susceptibility and the interaction of genes and environment. The voids include induction of tolerance in preclinical disease and definitions of host susceptibility and responses to the expensive biologic agents. The voids include the so-called clustering of human autoimmune diseases and the issues of whether the incidence is rising in our western society. Other voids include the relationships between microbiology, vaccination, gut flora, overzealous use of antibiotics, and the role of nanoparticles and environmental pollution in either the induction or the natural history of disease. One cannot even begin to address even a fraction of these issues. However, in this special issue, we are attempting to discuss clinical issues in autoimmunity that are not usually found in generic reviews. The goal is to bring to the readership provocative articles that ultimately will lead to improvement in patient care. PMID- 22203435 TI - Antitumor effects of cytoplasmic delivery of an innate adjuvant receptor ligand, poly(I:C), on human breast cancer. AB - Innate adjuvant receptors are expressed in immune cells and some types of cancers. If antitumor therapies targeting these receptors are established, it is likely that they will be therapeutically beneficial because antitumor effects and immune-cell activation can be induced simultaneously. In this study, we tested this possibility of using an innate adjuvant receptor ligand, polyinosinic polycytidylic acid [poly(I:C)], to treat human breast cancer cell lines. Three breast cancer cell lines (MCF-7, MDA-MB-231, and BT-549) were used in this study. Poly(I:C) was transfected into these cancer cells to stimulate melanoma differentiation-associated gene (MDA) 5, which is a cytoplasmic adjuvant receptor. Poly(I:C) transfection significantly reduced the viability of all cell lines in a manner partially dependent on MDA5. Flow cytometeric analyses and immunoblot assays revealed that the antitumor effect depended on both caspase dependent apoptosis and c-Myc- and cyclinD1-dependent growth arrest. Interestingly, poly(I:C) transfection was accompanied by autophagy, which is thought to protect cancer cells from apoptosis after poly(I:C) transfection. In a xenograft mouse model, local transfection of poly(I:C) significantly inhibited the growth of xenografted MDA-MB-231 cells. Our findings indicate that cytoplasmic delivery of poly(I:C) can induce apoptosis and growth arrest of human breast cancer cells, and that therapy-associated autophagy prevents apoptosis. The results of this study suggest that the innate adjuvant receptors are promising targets and that their ligands could serve as antitumor reagents, which have the potential to simultaneously induce antitumor effects and activate immune cells. PMID- 22203436 TI - Biologically effective dose and breast cancer conservative treatment: is duration of radiation therapy really important? AB - To evaluate if biologically effective dose (BED), and in particular the duration of radiation treatment, has an effect on local relapse risk. Between January 2000 and December 2008 a total of 762 patients with T1-2 N0/+ breast cancer was treated with breast-conserving surgery and radiotherapy, with and without hormone therapy and chemotherapy. Adjuvant radiation therapy was administered to a total dose of 60-66 Gy in 30-33 fractions. The computed BEDs were divided in four groups: <43.1, 43.1-44.9, 45.0-46.1, and >46.1 Gy (A-D, respectively). Kaplan Meier method was used to calculate local relapse rates. Cox regression method was used to identify prognostic factors of local relapse. Evaluated variables were age, tumor histology, tumor size, surgical margin status, axillary nodal status, tumor grading, adjuvant therapies, adjuvant chemotherapy alone, adjuvant hormone therapy alone, adjuvant anthracyclines, and BEDs values. 8-year local relapse rates were 18.0% for group A, 8.5% for group B, 4.6% for group C, and 2.7% for group D (P=0.008). Multivariate Cox regression analysis showed that BEDs values were associated with higher local relapse risk (P=0.001). In our study, a prolongation of radiotherapy treatment, intended as a lower BED value, after breast-conserving surgery is associated with an increased risk of local relapse. Considering the wide range of results published in other studies, hypofractionation for breast cancer should be considered, at the moment, feasible in selected patients. PMID- 22203437 TI - Imatinib in chronic myeloid leukemia elderly patients. PMID- 22203438 TI - Ischemic mitral regurgitation: not only a bystander. AB - Ischemic mitral regurgitation (MR) is a common complication of left ventricular (LV) dysfunction related to chronic coronary artery disease. This complex multifactorial disease involves global and regional LV remodeling, as well as dysfunction and distortion of the components of the mitral valve including the chordae, the annulus, and the leaflets. Its occurrence is associated with a poor prognosis. The suboptimal results obtained with the most commonly used surgical strategy, involving mitral valve annuloplasty with coronary bypass grafting, emphasize the need to develop alternative surgical techniques targeting the causal mechanisms of the disease. A comprehensive preoperative assessment of mitral valve configuration and LV geometry and function and an accurate quantification of MR severity at rest and during exercise may contribute to improve risk stratification and to tailor the surgical strategy according to the individual characteristics of the patient. PMID- 22203439 TI - Active surveillance of renal masses in von Hippel-Lindau disease: growth rates and clinical outcome over a median follow-up period of 56 months. AB - To evaluate the natural outcome of a surveillance strategy for enhancing renal masses associated with von Hippel-Lindau disease (VHL). From January 1988 to June 2011, a watchful waiting strategy was carried out in 16 cases with 42 enhancing renal masses. Clinical data were reviewed to determine tumor growth rate, subsequent interventions, and outcome of follow-up. During a median follow-up of 83 months (range, 55-279), 18 surgical interventions were performed in 13 cases; local recurrence of tumor occurred in 4 cases; 4 patients died (two of metastasis disease, one of CNS Hemangioblastomas with hemorrhage, and one of an unrelated disease) and 12 survived. The median follow-up duration for 42 renal masses was 56 months (range, 19-116 months). The mean tumor growth rate observed was 0.529 cm/year (range, 0.036-1.870 cm/year). The mean growth rate of the tumors larger than 3 cm was 0.573 cm/year, which was not significantly different from that of those smaller tumors (growth rate 0.507 cm/year, P = 0.5905). There was no significant correlation between initial tumor size and growth rate in our cohort with a correlation coefficient of 0.149(P = 0.3480). At the last follow-up, 38 (90.5%) tumors were larger than 3 cm and no metastasis disease developed among tumors <=4 cm. Progression to metastatic disease was detected in 2 patients. The majority of the enhancing renal masses with VHL disease may still be indolent and do not metastasize during a long period of follow-up even in tumors larger than 3 cm. Metastatic potential during active surveillance appears to be low in VHL patients with Renal tumors <=4 cm. PMID- 22203440 TI - Angiotensinase and vasopressinase activities in hypothalamus, plasma, and kidney after inhibition of angiotensin-converting enzyme: basis for a new working hypothesis. AB - Reducing angiotensin II (Ang II) production via angiotensin-converting enzyme (ACE) inhibitors is a key approach for the treatment of hypertension. However, these inhibitors may also affect other enzymes, such as angiotensinases and vasopressinase, responsible for the metabolism of other peptides also involved in blood pressure control, such as Ang 2-10, Ang III, Ang IV, and vasopressin. We analyzed the activity of these enzymes in the hypothalamus, plasma, and kidney of normotensive adult male rats after inhibition of ACE with captopril. Aspartyl- (AspAP), glutamyl- (GluAP), alanyl- (AlaAP) and cystinyl-aminopeptidase (CysAP) activities were measured fluorimetrically using arylamides as substrates. Systolic blood pressure (SBP), water intake, and urine flow were also measured. Captopril reduced SBP and increased urine flow. In the hypothalamus, GluAP and AspAP increased, without significant changes in either AlaAP or CysAP. In contrast with effects in plasma, GluAP was unaffected, AspAP decreased, while AlaAP and CysAP increased. In the kidney, enzymatic activities did not change in the cortex, but decreased in the medulla. These data suggest that after ACE inhibition, the metabolism of Ang I in hypothalamus may lead mainly to Ang 2-10 formation. In plasma, the results suggest an increased formation of Ang IV together with increased vasopressinase activity. In the kidney, there is a reduction of vasopressinase activity in the medulla, suggesting a functional reduction of vasopressin in this location. The present data suggest the existence of alternative pathways in addition to ACE inhibition that might be involved in reducing BP after captopril treatment. PMID- 22203441 TI - Experimental models of developmental hypothyroidism. AB - Hypothyroidism is a systemic disease resulting from either thyroid gland's anatomical and functional absence or lack of hypophyseal stimulation, both of which can lead to deficiency in thyroid hormone (TH) production. TH is essential for human and animal development, growth, and function of multiple organs. Children with deficient TH can develop alterations in central nervous system (CNS), striated muscle, bone tissue, liver, bone marrow, and cardiorespiratory system. Among the clinical outlook are signs like breathing difficulty, cardiac insufficiency, dysphagia, and repeated bronchial aspiration, constipation, muscle weakness, cognitive alterations, cochlear dysfunction, reduced height, defects in temperature regulation, anaemia, jaundice, susceptibility to infection, and others. Experimental and clinical studies have shown that TH is very essential for normal brain development. Other research work based on mice pointed out that a reduced level of TH in pregnant mother leads to congenital hypothyroidism in animal models and it is associated with mental retardation, deep neurologic deficiency that impacts on cognitive, learning, and memory functions. The principal experimental model studies that have focused on hypothyroidism are reviewed in this study. This is important on considering the fact that almost all animal species require thyroid hormones for their metabolism. PMID- 22203442 TI - Anticoagulation control of pharmacist-managed collaborative care versus usual care in Thailand. AB - OBJECTIVE: There has been a lack of evidence of the effects of pharmacist-managed warfarin therapy (PMWT) in developing countries (e.g. Southeast Asian countries) where the patients' characteristics, genetic make-up, clinical practice and healthcare system are different from the Western world. This study aimed to compare the anticoagulation control and clinical outcomes associated with warfarin therapy provided by PMWT to usual care (UC) in the Thai population. SETTING: A 1,000-bed tertiary-care hospital in Nakornratchasima province of Thailand. METHOD: A quasi-experimental study comparing PMWT and UC in patients receiving long-term warfarin therapy. For PMWT group, clinical pharmacists optimised the warfarin therapy and suggested recommendations (e.g. dose adjustment, safer alternative drugs, and follow-up time) to physicians. The UC group received the standard care. MAIN OUTCOME MEASURE: Time in therapeutic range (TTR), both actual- and expanded-TTR, bleeding and thromboembolic complications, and physician' acceptance of pharmacist suggestions. RESULTS: Of 433 patients enrolled, 220 and 213 were in the PMWT and UC groups respectively. At baseline, patient's characteristics of both groups were comparable. At the end of follow-up period, patients in the PMWT group had significantly higher actual-TTR (48.3% vs. 40.1%; P < 0.001) and expanded-TTR (62.7% vs. 53.9%; P < 0.001) compared to those in the UC group. Rates of major bleeding were 4.4 vs 4.5 events per 100 person years for the PMWT and UC groups, respectively. Pharmacists performed 284 interventions with an acceptance rate of 80.3% from physicians. CONCLUSION: Pharmacist-managed warfarin therapy resulted in a significantly better anticoagulation control. This study showed that a collaborative approach in anticoagulation management can be successfully implemented in a developing country. Implementation of such care model in other developing countries should be considered. PMID- 22203443 TI - The performance of phase analysis of gated SPECT myocardial perfusion imaging in the presence of perfusion defects: a simulation study. AB - BACKGROUND: Phase analysis has been developed and validated to measure left ventricular dyssynchrony from gated SPECT myocardial perfusion imaging. The purpose of this study is to evaluate its performance in regions with perfusion defects. METHODS: A special version of the eXtended CArdiac Torso digital phantom was developed to track B-spline points in each temporal frame. A region of 35 B spline points in the inferior wall with normal and abnormal perfusion uptakes were simulated. Phase shifts were simulated in the same region, representing dyssynchronous contraction. Gated SPECT data were analyzed using a modified phase analysis algorithm, which tracked the same 35 B-spline points to calculate their phases. RESULTS: Phases and phase shifts measured in the B-spline points with perfusion uptake in the range of 50%-10% did not significantly differ from those measured in the same B-spline points with normal perfusion uptake. CONCLUSION: Phase analysis can accurately measure phases in regions with abnormal perfusion uptake as low as 10% of the perfusion uptake in the normal regions, which corresponded to a regional signal-to-noise ratio (SNR) of 12.0 or greater. In 42 consecutive patients with myocardial infarction >20% of the left ventricle, only two patients had a SNR within the perfusion defects below that threshold. PMID- 22203444 TI - A step forward in the use of SPECT imaging with I-123 MIBG. PMID- 22203445 TI - Automated quantitative Rb-82 3D PET/CT myocardial perfusion imaging: normal limits and correlation with invasive coronary angiography. AB - BACKGROUND: We aimed to characterize normal limits and to determine the diagnostic accuracy for an automated quantification of 3D 82-Rubidium (Rb-82) PET/CT myocardial perfusion imaging (MPI). METHODS: We studied 125 consecutive patients undergoing Rb-82 PET/CT MPI, including patients with suspected coronary artery disease (CAD) and invasive coronary angiography, and 42 patients with a low likelihood (LLk) of CAD. Normal limits for perfusion and function were derived from LLk patients. QPET software was used to quantify perfusion abnormality at rest and stress expressed as total perfusion deficit (TPD). RESULTS: Relative perfusion databases did not differ in any of the 17 segments between males and females. The areas under the receiver operating characteristic curve for detection of CAD were 0.86 for identification of >=50% and >=70% stenosis. The sensitivity/specificity was 86%/86% for detecting >=50% stenosis and 93%/77% for >=70% stenosis, respectively. In regard to normal limits, mean rest and stress left ventricular ejection fraction (LVEF) were 67% +/- 10% and 75% +/- 9%, respectively. Mean transient ischemic dilation ratio was 1.06 +/- 0.14 and mean increase in LVEF with stress was 7.4% +/- 6.1% (95th percentile of 0%). CONCLUSION: Normal limits have been established for 3D Rb-82 PET/CT analysis with QPET software. Fully automated quantification of myocardial perfusion PET data shows high diagnostic accuracy for detecting obstructive CAD. PMID- 22203446 TI - Cardiac risk assessment by gated single-photon emission computed tomography in asymptomatic end-stage renal disease patients at the start of dialysis. AB - OBJECTIVES: This study assessed the impact of cardiac risk assessment using gated single-photon emission computed tomography (SPECT) on cardiac events in end-stage renal disease (ESRD) patients. METHODS: We evaluated 215 asymptomatic patients who began dialysis between January 2005 and April 2009. Baseline electrocardiography and echocardiography were performed in all the patients. The subjects were stratified into low- and high-risk groups according to the baseline cardiac status, and gated SPECT was additionally recommended for the high-risk patients. RESULTS: The study population consisted of 50 low- and 165 high-risk patients undergoing SPECT. Among the high-risk patients, 75 (45.5%) showed perfusion defects on SPECT and their overall cardiac-event rate per person-year of follow-up was 15.0%, significantly higher than 4.5% in high-risk group without perfusion defect and 1.2% in low-risk group. The presence of perfusion defect was a significant independent predictor of adverse cardiac events [hazard ratio (HR) 2.11; 95% confidence interval (CI) 1.05-4.24; P = .035]. When gated SPECT was added to the clinical and the echocardiographic variables, the prognostic stratification significantly improved (P < .001). However, coronary revascularization was not associated with improved cardiac event-free survival (HR 0.62; 95% CI 0.26-1.52; P = .296). CONCLUSIONS: Gated SPECT may provide additional prognostic information for cardiac risk stratification, particularly among high-risk patients starting dialysis. PMID- 22203447 TI - Yield of a novel ultra-low-dose computed tomography device mounted on a dedicated cardiac SPECT system in improving the accuracy of myocardial perfusion imaging and the detection of chest abnormalities. AB - BACKGROUND: To examine the yield of an ultra-low-dose computed tomography (CT) transmission module for attenuation-correction (AC) on a dedicated cardiac camera in evaluation of SPECT-myocardial perfusion imaging (MPI) in the diagnosis of CAD and for additional chest abnormalities. METHODS: The study group included 150 patients with known or suspected CAD referred for technetium sestamibi SPECT MPI. CT transmission scanning (effective radiation 0.17 mSv) was performed after each gated SPECT scan. AC and non-corrected (NC) SPECT scans were evaluated on a 5 point scale using a 17-segment model, and the sum stress score (SSS) and sum rest score (SRS) were calculated for each condition. Overall image quality, sensitivity and normalcy rate (51 patients) and processing of 28 CT slices were screened for chest findings. RESULTS: CT-based AC significantly improved image quality (P = .01). Mean SSS was 3.8 +/- 5.8 with AC and 6.1 +/- 7.1 with NC (P < .001); the respective SRS values were 2.6 +/- 6.3 and 3.9 +/- 7.7 (P < .001). The sensitivity of detecting >=70% stenosis was 71% and 86% (P = NS) and the normalcy rate was 30% and 89% (P < .0001) in NC and AC SPECT MPI, respectively. Chest CT: lung abnormalities in 31%, aortic calcifications in 27%, and hiatus hernia in 5%. CONCLUSIONS: Ultra-low-dose CT for AC of SPECT-MPI improves image quality, diagnostic accuracy and suggests detection of chest findings. PMID- 22203448 TI - Myocardial perfusion imaging in very elderly patients with suspected coronary artery disease: never too late! PMID- 22203449 TI - Phylogenetic analysis reveals the surprising diversity of an oxygenase class. AB - As metalloenzymes capable of transforming a broad range of substrates with high stereo- and regio-specificity, the multicomponent Rieske oxygenases (ROs) have been studied in bacterial systems for applications in bioremediation and industrial biocatalysis. These studies include genetic and biochemical investigations, determination of enzyme structure, phylogenetic analysis, and enzyme classification. Although RO terminal oxygenase components (RO-Os) share a conserved domain structure, their sequences are highly divergent and present significant challenges for identification and classification. Herein, we present the first global phylogenetic analysis of a broad range of RO-Os from diverse taxonomic groups. We employed objective, structure-based criteria to significantly reduce the inclusion of erroneously aligned sequences in the analysis. Our findings reveal that RO biochemical studies to date have been largely concentrated in an unexpectedly narrow portion of the RO-O sequence landscape. Additionally, our analysis demonstrates the existence two distinct groups of RO-O sequences. Finally, the sequence diversity recognized in this study necessitates a new RO-O classification scheme. We therefore propose a P450 like naming system. Our results reveal a diversity of sequence and potential catalytic functionality that has been wholly unappreciated in the RO literature. This study also demonstrates that many commonly used bioinformatic tools may not be sufficient to analyze the vast amount of data available in current databases. These findings facilitate the expanded exploration of RO catalytic capabilities in both biological and technological contexts and increase the potential for practical exploitation of their activities. PMID- 22203450 TI - Structural characterization of a carbon monoxide adduct of a heme-DNA complex. AB - The structure of a carbon monoxide (CO) adduct of a complex between heme and a parallel G-quadruplex DNA formed from a single repeat sequence of the human telomere, d(TTAGGG), has been characterized using 1H and 13C NMR spectroscopy and density function theory calculations. The study revealed that the heme binds to the 3'-terminal G-quartet of the DNA though a pi-pi stacking interaction between the porphyrin moiety of the heme and the G-quartet. The pi-pi stacking interaction between the pseudo-C2-symmetric heme and the C4-symmetric G-quartet in the complex resulted in the formation of two isomers possessing heme orientations differing by 180 degrees rotation about the pseudo-C2 axis with respect to the DNA. These two slowly interconverting heme orientational isomers were formed in a ratio of approximately 1:1, reflecting that their thermodynamic stabilities are identical. Exogenous CO is coordinated to heme Fe on the side of the heme opposite the G-quartet in the complex, and the nature of the Fe-CO bond in the complex is similar to that of the Fe-CO bonds in hemoproteins. These findings provide novel insights for the design of novel DNA enzymes possessing metalloporphyrins as prosthetic groups. PMID- 22203451 TI - The quality of male fertility data in major U.S. surveys. AB - Researchers continue to question fathers' willingness to report their biological children in surveys and the ability of surveys to adequately represent fathers. To address these concerns, this study evaluates the quality of men's fertility data in the 1979 and 1997 cohorts of the National Longitudinal Survey of Youth (NLSY79 and NLSY97) and in the 2002 National Survey of Family Growth (NSFG). Comparing fertility rates in each survey with population rates based on data from Vital Statistics and the U.S. Census Bureau, we document how the incomplete reporting of births in different surveys varies according to men's characteristics, including their age, race, marital status, and birth cohort. In addition, we use Monte Carlo simulations based on the NSFG data to demonstrate how birth underreporting biases associations between early parenthood and its antecedents. We find that in the NSFG, roughly four out of five early births were reported; but in the NLSY79 and NLSY97, almost nine-tenths of early births were reported. In all three surveys, incomplete reporting was especially pronounced for nonmarital births. Our results suggest that the quality of male fertility data is strongly linked to survey design and that it has implications for models of early male fertility. PMID- 22203452 TI - Beyond absenteeism: father incarceration and child development. AB - High rates of incarceration among American men, coupled with high rates of fatherhood among men in prison, have motivated recent research on the effects of parental imprisonment on children's development. We use data from the Fragile Families and Child Wellbeing Study to examine the relationship between paternal incarceration and developmental outcomes for approximately 3,000 urban children. We estimate cross-sectional and longitudinal regression models that control not only for fathers' basic demographic characteristics and a rich set of potential confounders, but also for several measures of pre-incarceration child development and family fixed effects. We find significant increases in aggressive behaviors and some evidence of increased attention problems among children whose fathers are incarcerated. The estimated effects of paternal incarceration are stronger than those of other forms of father absence, suggesting that children with incarcerated fathers may require specialized support from caretakers, teachers, and social service providers. The estimated effects are stronger for children who lived with their fathers prior to incarceration but are also significant for children of nonresident fathers, suggesting that incarceration places children at risk through family hardships including and beyond parent-child separation. PMID- 22203453 TI - Preserving the continuity of round ligament along with hernia sac in indirect inguinal hernia repair in female children does not increase the recurrence rate of hernia. Experience with 217 cases. AB - PURPOSE: In the standard classical method of indirect inguinal hernia (IIH) repair in female children, after transligation of hernia sac along with round ligament at the level of internal ring, the distal portion is divided or cut off, thereby removing a possible future support for the internal genital organs. In this article, we propose a modification to the standard technique for IIH repair which preserves the continuity of round ligament along with hernia sac without increasing the recurrence rate. METHODS: In a 3-year prospective clinical trial, from March 2007 to March 2010, IIH repairs were performed on 217 female children. In all of these cases, the hernia sac along with round ligament is only transligated at the level of internal ring and a window is created in the distal portion of the sac to prevent a hydrocele formation and the continuity of round ligament along with hernia sac was preserved. The charts of these patients were then analyzed to determine if recurrence had occurred. In addition, we noted any other early postoperative complications such as wound infection, bleeding, and tolerance. RESULTS: Within the 25-month mean follow-up period (6-36 months), none of the patients developed any of the above-mentioned complications. The most important result of this study was that preserving the continuity of round ligament along with hernia sac did not increase the rate of recurrence. CONCLUSION: On the basis of results obtained from this study, we conclude that preserving the continuity of round ligament along with hernia sac in female children during IIH repair does not increase the rate of recurrence, and is less intrusive to the normal anatomy of the inguinal region and needs less time to do. PMID- 22203454 TI - Proposed new simple scoring system to identify indications for urgent ERCP in acute cholangitis based on the Tokyo Guidelines. AB - BACKGROUND/PURPOSE: The Tokyo Guidelines (TG) have enabled more accurate diagnosis of acute cholangitis (AC). This study was undertaken to develop a new prognostic scoring system to predict the need for urgent endoscopic retrograde cholangiopancreatography (ERCP) based on the clinical findings on admission. METHODS: We prospectively reviewed 40 consecutive cases of AC and divided them into an urgent-ERCP group and an elective-ERCP group. RESULTS: Univariate analysis identified four factors that predicted the need for urgent ERCP: serum albumin level below 3.0 g/dl, blood urea nitrogen level above 20 mg/dl, platelet count below 120,000/MUl, and the presence of systemic inflammatory response syndrome. These four predictors plus four predictors of organ dysfunction in the TG: shock, consciousness disturbance, respiratory failure, and prothrombin time/international normalized ratio >1.5, were used to devise a scoring system in which 1 point was assigned for the first four predictors and 2 points were assigned for the latter four predictors (maximum score possible: 12 points). The receiver-operator characteristic curve of the scores showed good test performance for predicting the need for urgent ERCP and for predicting a positive blood culture, and the areas under the concentration curves (AUCs) were 0.96 and 0.97, respectively. The optimal cut-off value for urgent ERCP was 2 points. CONCLUSIONS: This new simple scoring system allows identification of high-risk AC patients soon after admission to hospital. PMID- 22203455 TI - Effects of antiviral therapy on long-term outcome after liver resection for hepatitis B virus-related hepatocellular carcinoma. AB - BACKGROUND/PURPOSE: We investigated the effects of nucleos(t)ide analogues (NAs) on long-term outcome in patients following curative treatment for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: This study involved 70 of the 76 patients who had undergone liver resection for HBV-related HCC in our department; 6 patients were excluded due to non-curative resection or advanced cancer. The 70 patients were divided into three groups, as follows: 13 patients with high serum concentration of HBV DNA (>=4 log(10) copies/mL) and no antiviral therapy (high viral group); 46 patients who received antiviral therapy during the serial follow up (antiviral therapy group) because of high viral concentration (>=4 log(10) copies/mL); and 11 patients with low serum concentration of HBV DNA (<4 log(10) copies/mL) and no antiviral therapy (low viral group). RESULTS: Tumor-free survival rate was significantly higher in the low viral group than in the high viral group (P = 0.0058). Multivariate analysis revealed that a high serum concentration of HBV DNA (>=4 log(10) copies/mL) (risk ratio 6.717, 95% confidence interval 1.435-31.434, P = 0.0156) was an independent risk factor for a short tumor-free survival time. Tumor-free survival rate was significantly higher in the antiviral therapy group than in the high viral group (P = 0.0478). Multivariate analysis revealed that presence of multiple tumors (risk ratio 2.857, 95% confidence interval 1.403-5.816, P = 0.0038) was an independent risk factor for a short tumor-free survival time. The cumulative survival rate was significantly higher in the antiviral therapy group than in the high viral group (P = 0.0025). Multivariate analysis revealed that not undergoing antiviral therapy (risk ratio 0.121, 95% confidence interval 0.024-0.608, P = 0.0104) was an independent risk factor for a short survival time. CONCLUSIONS: A high serum concentration of HBV DNA (>=4 log(10) copies/mL) was a strong risk factor for HCC recurrence after resection of HBV-related HCC. Antiviral therapy with NAs improved the long-term outcome after resection of HBV-related HCC in patients with high serum concentrations of HBV DNA. PMID- 22203456 TI - Proposed indications for limited resection of early ampulla of Vater carcinoma: clinico-histopathological criteria to confirm cure. AB - BACKGROUND: Limited resection is reserved for patients with high operative risk or benign adenomas. We aimed to define indications for limited resection of early ampulla of Vater carcinoma with curative intent through detailed preoperative examinations and histopathological evaluations. METHODS: We performed a retrospective cohort study of all consecutive Japanese patients who underwent resection for ampulla of Vater neoplasms at our hospital from 1986 to 2010. RESULTS: A total of 75 patients were identified. Moderately/poorly differentiated histology, lympho-vascular/perineural invasion, and duodenal/pancreatic invasion were significant risk factors for lymph node metastases. Macroscopically, non exposed protruded- or ulcerative-type disease did not correlate directly with lymph node metastases; however, these tumor types were associated with other invasive features. In a subset of early carcinomas fulfilling the conditions of exposed protruded adenoma or papillary/well-differentiated adenocarcinoma determined by endoscopic biopsy, negative duodenal invasion determined by endoscopic ultrasonography, no tumor infiltration into the pancreatic duct determined by intraductal ultrasound, and diameter of the pancreatic duct <=3 mm determined by endoscopic retrograde cholangiopancreatography (N = 11), the incidence of lymph node metastasis and tumor infiltration into the pancreatic duct was 0%. CONCLUSION: Strictly selected patients with early ampulla of Vater carcinomas may benefit from limited resection if the resected specimen is evaluated to confirm all histopathological criteria. PMID- 22203457 TI - Aging and physical mobility in group-housed Old World monkeys. AB - While indices of physical mobility such as gait speed are significant predictors of future morbidity/mortality in the elderly, mechanisms of these relationships are not understood. Relevant animal models of aging and physical mobility are needed to study these relationships. The goal of this study was to develop measures of physical mobility including activity levels and gait speed in Old World monkeys which vary with age in adults. Locomotor behaviors of 21 old ([Formula: see text] = 20 yoa) and 24 young ([Formula: see text] = 9 yoa) socially housed adult females of three species were recorded using focal sample and ad libitum behavior observation methods. Self-motivated walking speed was 17% slower in older than younger adults. Likewise, young adults climbed more frequently than older adults. Leaping and jumping were more common, on average, in young adults, but this difference did not reach significance. Overall activity levels did not vary significantly by age, and there were no significant age by species interactions in any of these behaviors. Of all the behaviors evaluated, walking speed measured in a simple and inexpensive manner appeared most sensitive to age and has the added feature of being least affected by differences in housing characteristics. Thus, walking speed may be a useful indicator of decline in physical mobility in nonhuman primate models of aging. PMID- 22203459 TI - Angiotensin-converting enzyme inhibitors and incidence of mild cognitive impairment. The Italian Longitudinal Study on Aging. AB - Midlife elevated blood pressure and hypertension contribute to the development of Alzheimer's disease (AD) and overall dementia. We sought to estimate whether angiotensin-converting enzyme inhibitors (ACE-Is) reduced the risk of developing mild cognitive impairment (MCI) in cognitively normal individuals. In the Italian Longitudinal Study on Aging, we evaluated 1,445 cognitively normal individuals treated for hypertension but without congestive heart failure from a population based sample from eight Italian municipalities with a 3.5-year follow-up. MCI was diagnosed with current clinical criteria. Dementia, AD, and vascular dementia were diagnosed based on DSM-IIIR criteria, NINCDS-ADRDA criteria, and ICD-10 codes. Among 873 hypertension-treated cognitively normal subjects, there was no significant association between continuous exposure to all ACE-Is and risk of incident MCI compared with other antihypertensive drugs [hazard ratio (HR), 0.45, 95% confidence interval (CI), 0.16-1.28]. Captopril exposure alone did not significantly modify the risk of incident MCI (HR, 1.80, 95% CI, 0.39-8.37). However, the enalapril sub-group alone (HR, 0.17, 95% CI, 0.04 -0.84) or combined with the lisinopril sub-group (HR, 0.27, 95% CI, 0.08-0.96), another ACE-I structurally related to enalapril and with similar potency, were associated with a reduced risk of incident MCI. Study duration exposure to ACE-Is as a "class" was not associated with incident MCI in older hypertensive adults. However, within-class differences linked to different chemical structures and/or drug potencies may exist, with a possible effect of the enalapril and lisinopril sub groups in reducing the risk of incident MCI. PMID- 22203461 TI - 1H, 13C, 15N assignment and secondary structure determination of glutamine amido transferase subunit of gaunosine monophosphate synthetase from Methanocaldococcus jannaschii. AB - Sequence specific resonance assignments have been obtained for (1)H, (13)C and (15)N nuclei of the 21 kDa (188 residues long) glutamine amido transferase subunit of guanosine monophosphate synthetase from Methanocaldococcus jannaschii. From an analysis of (1)H and (13)C(alpha), (13)C(beta) secondary chemical shifts, (3) JH(N)H(alpha) scalar coupling constants and sequential, short and medium range (1)H-(1)H NOEs, it was deduced that the glutamine amido transferase subunit has eleven strands and five helices as the major secondary structural elements in its tertiary structure. PMID- 22203460 TI - Cytoskeleton remodeling and alterations in smooth muscle contractility in the bovine jejunum during nematode infection. AB - Gastrointestinal nematodes of the genus Cooperia are arguably the most important parasites of cattle. The bovine jejunal transcriptome was characterized in response to Cooperia oncophora infection using RNA-seq technology. Approximately 71% of the 25,670 bovine genes were detected in the jejunal transcriptome. However, 16,552 genes were expressed in all samples tested, probably representing the core component of the transcriptome. Twenty of the most abundant genes accounted for 12.7% of the sequences from the transcriptome. A 164-h infection seemingly induced a minor change in the transcriptome (162 genes). Additionally, a total of 162,412 splice junctions were identified. Among them, 1,164 appeared unique to 1 of the 2 groups: 868 splice junctions were observed only in infected animals, while 278 were only present in all 4 control animals. Biological functions associated with muscle contraction were predominant Gene Ontology terms enriched in the genes differentially expressed by infection. The primary function of two of the four regulatory networks impacted was related to skeletal and muscular systems. A total of 34 pathways were significantly impacted by infection. Several pathways were directly related to host immune responses, such as acute phase response, leukocyte extravasation, and antigen presentation, consistent with previous findings. Calcium signaling and actin cytoskeleton signaling were among the pathways most significantly impacted by infection in the bovine jejunum. Together, these data suggest that smooth muscle hypercontractility may be initiated as a result of a primary C. oncophora infection, which may represent a mechanism for host responses in the jejunum during nematode infection. PMID- 22203458 TI - Age-related changes in human and non-human primate white matter: from myelination disturbances to cognitive decline. AB - The cognitive decline associated with normal aging was long believed to be due primarily to decreased synaptic density and neuron loss. Recent studies in both humans and non-human primates have challenged this idea, pointing instead to disturbances in white matter (WM) including myelin damage. Here, we review both cross-sectional and longitudinal studies in humans and non-human primates that collectively support the hypothesis that WM disturbances increase with age starting at middle age in humans, that these disturbances contribute to age related cognitive decline, and that age-related WM changes may occur as a result of free radical damage, degenerative changes in cells in the oligodendrocyte lineage, and changes in microenvironments within WM. PMID- 22203462 TI - Occurrence of nonylphenol and nonylphenol monoethoxylate in soil and vegetables from vegetable farms in the Pearl River Delta, South China. AB - Low molecular-mass nonylphenol ethoxylates (NPEOs) and 4-nonylphenol (NP) are biodegradation products of higher molecular mass NPEOs used as surface active agents, and they are endocrine-disrupting contaminants. In this study, surface soil (0-20 cm) samples and different vegetable samples were collected from 27 representative vegetable farms located in Shenzhen, Dongguan, and Huizhou within the Pearl River Delta region, South China, and NP and nonylphenol monoethoxylate (NP(1)EO) were analyzed using high-performance liquid chromatography with ultraviolet detection. The results show that NP and NP(1)EO were detected in soil and vegetable samples. The concentrations of NP and NP(1)EO in soil samples ranged from nondetectable (ND) to 7.22 MUg kg(-1) dry weight (dw) and from ND to 8.24 MUg kg(-1) dw, respectively. The average concentrations of both NP and NP(1)EO in soil samples decreased in the following order: Dongguan > Huizhou > Shenzhen. The levels of NP and NP(1)EO in vegetable samples varied from 1.11 to 4.73 MUg kg(-1) dw and from 1.32 to 5.33 MUg kg(-1) dw, respectively. The greatest levels of both NP and NP(1)EO were observed in water spinach, and the lowest levels of NP and NP(1)EO were recorded in cowpea. The bioconcentration factors (the ratio of contaminant concentration in plant tissue to soil concentration) of NP and NP(1)EO were <1.0 (mean 0.535 and 0.550, respectively). The occurrences of NP and NP(1)EO in this study are compared with other studies, and their potential sources are discussed. PMID- 22203463 TI - Preservation of corneal endothelium after pars plana tube insertion of the Ahmed glaucoma valve. AB - PURPOSE: To investigate surgical outcomes after pars plana implantation of the Ahmed glaucoma valve (ppAGV). METHODS: The intraocular pressure, corneal endothelial damage and post-surgical complications of 31 consecutive refractory glaucoma eyes of 26 subjects who underwent ppAGV were prospectively studied at two centers. RESULTS: Cell density (CD) at the central cornea decreased by 3.5 +/ 15.0 and 10.2 +/- 18.9% at 6 and 12 months, respectively. The CD loss at 1 year was comparable with the loss after cataract surgery alone (6.5 +/- 8.5%, P = 0.441). Hexagonality (Hex) changed little, from 41.5 +/- 15.6% at baseline to 41.8 +/- 14.9% (P = 0.976) at 6 months and 41.6 +/- 10.2% (P = 0.58) at 12 months. The coefficient of variation of the central corneal endothelium area (CV) changed from 40.7 +/- 9.0% at baseline to 45.7 +/- 12.6% (P = 0.078) at 6 months and 45.5 +/- 11.2% (P = 0.013) at 12 months. Concomitant cataract surgery was a significant risk factor for CD loss. The probabilities of success or qualified success at 1 year were 66.1 and 83.6%, respectively. Most of the posterior segment complications, which were noted in 6 of 31 eyes (19%), were self limiting, except for 2 eyes (6%) that developed retinal detachment as a consequence of kissing choroidal detachment. CONCLUSIONS: Corneal endothelial damage was minimal, and the success probability was relatively high after ppAGV in refractive glaucoma cases. PMID- 22203464 TI - Progression detection in different stages of glaucoma: mean deviation versus visual field index. AB - PURPOSE: We evaluated and compared visual field index (VFI) and mean deviation (MD) capacity in detecting glaucoma progression at different stages. METHODS: Participants were classified as having early-, moderate-, or advanced-stage glaucoma. Trend-based approaches (TA) using linear regression analysis of the VFI and MD (VFI TA, MD TA) over patient age were performed. The rate was determined by both approaches at different stages of glaucoma. RESULTS: We analyzed 173 eyes of 173 participants (mean follow-up 6.2 years). Glaucoma progressed in 24 eyes (13.9%) as determined by VFI TA and in 21 eyes (12.1%) as determined by MD TA. Agreement between VFI TA and MD TA was moderate to good (kappa = 0.617). The rate was -0.29 +/- 2.31 dB per year as determined by MD TA and 1.25 +/- 4.79% per year as determined by VFI TA. Progression rate according to glaucoma severity was not significantly different among subgroups when assessed by both trend-based approaches. CONCLUSION: VFI TA and MD TA performed similarly in measuring different stages of glaucoma progression. However, VFI TA and MD TA did not have agree perfectly in glaucoma progression detection. As glaucomatous changes can be general or localized, we suggest that changes in the MD and VFI should be considered when monitoring glaucoma progression through all stages. PMID- 22203465 TI - Modeling the impact of common noise inputs on the network activity of retinal ganglion cells. AB - Synchronized spontaneous firing among retinal ganglion cells (RGCs), on timescales faster than visual responses, has been reported in many studies. Two candidate mechanisms of synchronized firing include direct coupling and shared noisy inputs. In neighboring parasol cells of primate retina, which exhibit rapid synchronized firing that has been studied extensively, recent experimental work indicates that direct electrical or synaptic coupling is weak, but shared synaptic input in the absence of modulated stimuli is strong. However, previous modeling efforts have not accounted for this aspect of firing in the parasol cell population. Here we develop a new model that incorporates the effects of common noise, and apply it to analyze the light responses and synchronized firing of a large, densely-sampled network of over 250 simultaneously recorded parasol cells. We use a generalized linear model in which the spike rate in each cell is determined by the linear combination of the spatio-temporally filtered visual input, the temporally filtered prior spikes of that cell, and unobserved sources representing common noise. The model accurately captures the statistical structure of the spike trains and the encoding of the visual stimulus, without the direct coupling assumption present in previous modeling work. Finally, we examined the problem of decoding the visual stimulus from the spike train given the estimated parameters. The common-noise model produces Bayesian decoding performance as accurate as that of a model with direct coupling, but with significantly more robustness to spike timing perturbations. PMID- 22203466 TI - The role of health literacy on African American and Hispanic/Latino perspectives on cancer clinical trials. AB - Although cancer clinical trials are important for discovering lifesaving therapies, participation remains low among racial/ethnic minorities, and little research explores the role of health literacy in racial/ethnic minority perceptions of cancer clinical trials (CCTs). Five focus groups (n = 50) with African American and Hispanic participants explored CCT perceptions using a multidimensional health literacy framework. We found poor scientific literacy including misconceptions of scientific information, perceptions of clinical trials as uncertain and fear; limited civic literacy around topics of trust, perceptions of participants as guinea pigs, and concerns about of IRB protections; and cultural literacy challenges regarding the importance of home remedies for health, use of native language, and the importance of race/ethnicity matching to health care professionals. Results highlight the importance of attending to scientific literacy, cultural literacy, and civic literacy. Future educational interventions regarding cancer clinical trials should address the importance of health literacy in understanding cancer clinical trial decision making. PMID- 22203467 TI - The suppression of FOXM1 and its targets in breast cancer xenograft tumors by siRNA. AB - As an oncogenic transcription factor, the Forkhead box protein M1 (FOXM1) is overexpressed in human tumors. FOXM1 promotes tumorigenesis by regulating genes associated with cell cycle progression and cell proliferation, and its inhibition in cell lines has been shown to sensitize cells to apoptosis. In this report, we examined the possibility of suppressing FOXM1 in tumors in vivo, through the administration of FoxM1-specific siRNA. Firstly, we determined the functionality of siRNA treatment in subcutaneous MDA-MB-231-luc breast cancer tumors. We found that upon encapsulation into a PEI-based delivery agent, fluorescently-labeled siRNA was retained within tumors when administered intratumorally. Injection of anti-luciferase siRNA was also able to suppress tumor-associated luciferase for at least 48 hours. More importantly, repeat administrations of PEI-encapsulated anti-FoxM1 siRNA resulted in the reduced expression of FOXM1 protein levels in tumors. In addition, both the protein levels and mRNA levels of cdc25B and Aurora B Kinase, transcriptional targets of FOXM1 were also reduced in tumors treated with anti-FoxM1 siRNA. p27, an indirect target of FOXM1 associated with growth inhibition was further found be increased in tumors treated with FoxM1-siRNA. Our data suggests that anti-FoxM1 siRNA can be functional when administered into tumors in an in vivo system, and that anti-FoxM1 siRNA holds potential as part of a therapy for cancer treatment. PMID- 22203468 TI - Cord blood nesfatin-1 and apelin-36 levels in gestational diabetes mellitus. AB - To assess maternal serum and cord blood apelin-36 and nesfatin-1 concentrations in pregnant women with and without gestational diabetes mellitus (GDM). Thirty pregnant women with GDM and 30 gestational age matched healthy pregnant subjects participated to the study. Maternal serum and cord blood nesfatin-1 and apelin-36 levels were measured with ELISA, at the time of birth. The relationships between maternal serum and cord blood nesfatin-1 and apelin-36 levels, anthropometric and metabolic parameters were also assessed. Maternal serum apelin-36 levels were found higher (13.5 +/- 8.3 vs. 9.6 +/- 5.9 ng/ml, P = 0.001) and nesfatin-1 levels were found lower (5.5 +/- 8.1 vs. 8.1 +/- 23.9 ng/ml, P = 0.001) in patients with GDM compared with control pregnant women. However, the cord blood apelin-36 levels (8.8 +/- 4.3 and 8.2 +/- 1.9 ng/ml, P = 0.618) and nesfatin-1 levels (5.4 +/- 4.0 and 6.2 +/- 10.3 ng/ml, P = 0.688) were similar in the GDM and control groups, respectively. Maternal serum apelin-36 and nesfatin-1 levels correlated positively with their respective cord blood levels. Maternal serum and cord blood apelin-36 levels correlated negatively with the gestational age and birth weight. Similarly maternal serum and cord blood nesfatin-1 levels correlated negatively with the gestational age, but there was no correlation with the birth weight. We did not find a correlation between maternal serum apelin-36 and nesfatin-1 levels, maternal age, BMI, fasting glucose, fasting insulin, and HOMA-IR. Also cord blood apelin-36 and nesfatin-1 levels did not correlate with the maternal age, BMI, HOMA-IR, cord blood glucose, and cord blood insulin levels. Our results indicate that apelin-36 concentrations increase and nesfatin 1 concentrations decrease in maternal serum of women with GDM. PMID- 22203470 TI - [The German Version of the Childhood Trauma Questionnaire (CTQ): psychometric characteristics in a representative sample of the general population]. AB - The Childhood Trauma Questionnaire (CTQ) has become internationally accepted as an assessment of traumatic childhood experiences. The short version assesses aspects of childhood abuse and neglect. In order to check the psychometric properties of the German short form, the CTQ was used within a representative sample of the German population (N=2 500). The five factor structure of the original version showed only a sufficient model fit, because of high intercorrelations and weak internal consistency of the scale "physical neglect". The internal consistency of the other subscales was high with alpha>=0.80. Construct validity was supported by positive correlations with measures of anxiety/depression and negative correlations with life satisfaction. The German short form of the CTQ is a reliable and valid self rating instrument to assess childhood maltreatment retrospectively. The subscale "physical neglect" should be applied with caution. PMID- 22203469 TI - Neutralizing antibodies and control of HIV: moves and countermoves. AB - It is now evident that powerful antibodies directed to conserved regions of HIV-1 envelope protein develop during chronic infection in some individuals and that these antibodies can neutralize a broad array of diverse isolates in vitro, so termed broadly neutralizing antibodies (bNAbs). A great deal of effort is directed internationally at understanding the ontogeny of NAbs during infection as well as in designing and testing immunogens that can elicit bNAbs in animal models and in humans. Given the parrying tactics of Env, multiple approaches, along with high-resolution structural studies, will be needed to reach a degree of understanding sufficient to design an effective vaccine. We discuss and note here some of the most important recent advances in our knowledge of how neutralizing antibodies develop in vivo, the recent discovery of extremely powerful neutralizing monoclonal antibodies isolated from natural infection, enhanced methodologies that have accelerated discoveries on both fronts, and the progress made in eliciting potent NAbs with limited breadth by vaccination. PMID- 22203471 TI - Down-regulation of PDCD4 expression is an independent predictor of poor prognosis in human renal cell carcinoma patients. AB - OBJECTIVES: The tumor suppressor gene entitled programmed cell death 4 (PDCD4) encodes a protein that inhibits neoplastic transformation and invasion. The aim of this study was to investigate the expression of PDCD4 and its prognostic roles in human renal cell carcinoma (RCC). MATERIALS AND METHODS: A total of 32 paired fresh tumor specimens and adjacent non-cancerous renal tissue from RCC patients by western blot to detect the difference of PDCD4 expression in tumor tissues and non-cancerous tissues. 66 RCC paraffin-embedded specimens and 18 normal renal tissues were analyzed by immunohistochemistry to investigate the association of PDCD4 expression with RCC clinicopathological features. RESULTS: PDCD4 expression was significantly decreased in RCC compared with normal renal tissues (P = 0.03), and it was found to be significantly associated with RCC metastasis (P = 0.007), tumor T-stage (P = 0.022) and tumor grade (P = 0.015). The mean overall survival was significantly decreased in the low PDCD4 group compared to the high PDCD4 group (low PDCD4: mean overall survival 41.9 months, high PDCD4: mean overall survival 52.9 months, P = 0.008). CONCLUSION: PDCD4 expression strongly correlated to RCC stage, tumor grade, tumor metastasis and tumor-related death. PDCD4 expression was also appears to be a marker in RCC prognosis. PMID- 22203472 TI - Pharmacologic inhibition of mTOR antagonizes the cytotoxic activity of pemetrexed in non-small cell lung cancer. AB - PURPOSE: Pemetrexed, an inhibitor of thymidylate synthase (TS) and additional folate-dependent enzymes, is clinically active in patients suffering from "non squamous" non-small cell lung cancer (NSCLC). High expression of TS has been implied as biomarker predictive of resistance to pemetrexed. Against this background, we studied whether inhibition of mTOR could lower expression of TS and thus sensitize NSCLC cells to pemetrexed. METHODS AND RESULTS: Using squamous cell carcinoma and adenocarcinoma NSCLC cell lines, we observed that constitutive TS expression levels failed to correlate with sensitivity to growth inhibition or apoptosis imposed by pemetrexed in vitro. Interestingly, pemetrexed strongly induced TS RNA and protein expression in all cell lines. The allosteric "rapalogue" mTOR inhibitor everolimus suppressed constitutive, but not pemetrexed induced TS expression. Surprisingly, cotreatment with everolimus protected NSCLC cells against pemetrexed-induced apoptosis. This resulted in increased long-term clonogenic survival of NSCLC cells treated with pemetrexed plus everolimus as compared to pemetrexed alone. No such negative interaction was observed when everolimus was combined with recombinant TRAIL, a proliferation-independent proapoptotic agent. CONCLUSIONS: Rapalogues may suppress the antitumor activity of pemetrexed by slowing cell cycle progression. This should be considered when combining pemetrexed and mTOR inhibitors in NSCLC treatment. PMID- 22203473 TI - Mutational activation of FGFR3: no involvement in the development of renal cell carcinoma. AB - BACKGROUND: Somatic point mutations in the fibroblast growth factor receptor 3 (FGFR3) gene have been identified in certain types of urological cancers, especially urothelial carcinoma of the bladder and the renal pelvis, and could be correlated with a favourable outcome. However, comprehensive data on the FGFR3 mutation status in renal cell carcinoma (RCC) are still missing. METHODS: In order to investigate a possible role for FGFR3 mutations in renal cell carcinogenesis, we performed a sequence-based mutational analysis of FGFR3 in 238 primary RCC. The cohort obtained the common RCC subtypes including 101 clear cell, 50 papillary and 68 chromophobe RCC specimens. The analysed regions encompassed all FGFR3 point mutations previously described in epithelial tumours and other noncutaneous epithelial malignancies. RESULTS: No mutations were detected in any renal tumour type examined, and all cases showed wild-type sequence. CONCLUSION: Our results argue against an involvement of mutational activation of FGFR3 in the development of RCC. A recently described cystic renal dysplasia in a patient with thanatophoric dysplasia type 1 due to a germ line FGFR3 mutation might portend to an involvement of mutational FGFR3 activation in renal cyst formation, but this speculation needs further evaluation. PMID- 22203474 TI - TH1, a DUF640 domain-like gene controls lemma and palea development in rice. AB - The developmental regulation of grasses lemma and palea and their relationship to the floral organs in dicots had been variously explicated and extensively debated. Here, we characterized a triangular hull mutant th1-1 from EMS mutagenized Oryza sativa ssp. indica cv. 93-11. The th1-1 mutant exhibited obviously triangular hull with tortuous and slender lemma/palea. Using a map based cloning strategy, the TH1 gene was narrowed down to a 60-kb region on the long arm of chromosome 2. Sequence verification revealed that the th1-1 mutant harbored 1-bp deletion in exon 2 of LOC_Os02g56610 which resulted in a frame shift mutation. The RNA-interference transgenic plants of LOC_Os02g56610 displayed a similar phenotype to the th1 mutant. Consequently, LOC_Os02g56610 was identified as the TH1 gene which encoded 248 amino acids and contained a DUF640 domain. RT-PCR analysis and GUS staining showed that the transcripts of TH1 mainly accumulated in young inflorescence, lemma and palea of spikelet. These results suggested that TH1 was an important gene controlling the lemma and palea development in rice. PMID- 22203475 TI - Pharmacophore modeling and virtual screening studies to identify new c-Met inhibitors. AB - Mesenchymal epithelial transition factor (c-Met) is an attractive target for cancer therapy. Three-dimensional pharmacophore hypotheses were built based on a set of known structurally diverse c-Met inhibitors. The best pharmacophore model, which identified inhibitors with an associated correlation coefficient of 0.983 between their experimental and estimated IC(50) values, consisted of two hydrogen bond acceptors, one hydrophobic, and one ring aromatic feature. The highly predictive power of the model was rigorously validated by test set prediction and Fischer's randomization method. The high values of enrichment factor and receiver operating characteristic (ROC) score indicated the model performed fairly well at distinguishing active from inactive compounds. The model was then applied to screen compound database for potential c-Met inhibitors. A filtering protocol, including druggability and molecular docking, were also applied in hits selection. The final 38 molecules, which exhibited good estimated activities, desired binding mode and favorable drug likeness were identified as potential c Met inhibitors. Their novel backbone structures could be served as scaffolds for further study, which may facilitate the discovery and rational design of potent c Met kinase inhibitors. PMID- 22203476 TI - Efficacy of interspinous process lumbar fusion with recombinant human bone morphogenetic protein-2 delivered with a synthetic polymer and beta-tricalcium phosphate in a rabbit model. AB - INTRODUCTION: As a powerful bone-inducing cytokine, rhBMP-2 has been used as a bone graft substitute in combination with animal-derived collagen to achieve interbody or posterolateral spinal fusion. Successful interspinous process fusion using rhBMP-2 in combination with synthetic carrier materials would offer a safe, minimally invasive spinal fusion option for the treatment of spinal disorders. The aims of the present study were to achieve interspinous process fusion by implanting rhBMP-2-retaining degradable material instead of bone grafting and to evaluate efficacy for vertebral stabilization. MATERIALS AND METHODS: A polymer gel (200 mg), beta-tricalcium phosphate powder (400 mg), and rhBMP-2 (0, 30, 60 or 120 MUg) were mixed to generate a plastic implant, which was then placed during surgery to bridge the L5-6 interspinous processes of 58 rabbits. Control animals received implants either without rhBMP-2 or with autogenous bone chips from the iliac crest. L5-6 vertebrae were recovered 8 weeks postoperatively. Interspinous process fusion was evaluated by radiography, biomechanical bending test, intradiscal pressure (IDP) measurement, and histology. RESULTS: In bending tests, strength of fusion was significantly greater in BMP60 and BMP120 groups than in sham, BMP0, BMP30 or autogenous bone groups. IDP at L5-6 was significantly reduced in BMP60 and BMP120 groups compared to sham, BMP0, BMP30, and autograft groups. Histologically, coronal sections of the fusion mass showed a bone mass bridging both spinous processes. CONCLUSION: Solid interspinous process fusion was achieved in rabbit models by 8 weeks after implanting the biodegradable bone-inducing material. These results suggest a potential new less invasive option without bone grafting for the treatment of lumbar disorders. PMID- 22203477 TI - Small biopsy specimens reliably indicate p16 expression status of oropharyngeal squamous cell carcinoma. AB - Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC) is associated with favorable patient survival. Tumor HPV status at primary diagnosis is critical for proper management, and p16 immunohistochemistry (IHC) has emerged as a reliable, single, surrogate marker. It is not known, however, if small biopsy specimens are completely adequate for p16 evaluation. From a database of oropharyngeal SCC for which p16 IHC and histologic typing were already performed, all patients (32) who had available in-house primary tumor biopsy specimens and also subsequent surgical resections were analyzed. p16 IHC was performed along with histologic typing into: Type 1 keratinizing SCC, Type 2 nonkeratinizing SCC with maturation, and Type 3 nonkeratinizing SCC. Staining was graded on both biopsies and resections as follows: 0=negative; 1+ =1-25% of tumor cells positive; 2+ =26-50%; 3+ =51-75%; 4+ =76-100%. Strictly considering p16 score, perfect biopsy-resection correlation was present in 28 of 32 cases (85%), including 6/9 (67%) Type 1, 6/7 (86%) Type 2, and 16/16 (100%) Type 3 cases. Considering p16 expression binarily as 51% tumor cell staining or more (3+ or 4+) being positive and lesser amounts (0, 1+, or 2+) as being negative, there was perfect biopsy-resection correlation for all 32 cases. With p16 expression in resection specimens considered the gold standard, p16 IHC in biopsies was both 100% sensitive and specific. Our results demonstrate that p16 staining in diagnostic biopsies reliably reflects whole tumor staining results, and suggest that biopsies do not suffer from false negatives or positives. PMID- 22203479 TI - Gene overexpression and gene silencing in Birch using an Agrobacterium-mediated transient expression system. AB - As transient expression systems are effective methods for the functional characterization of genes, a transient gene expression and silencing system was developed for Betula platyphylla Suk (Chinese Birch). Firstly, the cinnamoyl-CoA reductase (CCR) gene and its promoter were isolated from Chinese Birch. The vectors for overexpression of CCR and RNAi-based silence of CCR were constructed and transformed into Agrobacterium, respectively. Overexpression and silence of the CCR gene were respectively, performed on Birch seedlings using an Agrobacterium-mediated transient expression system. The expression levels of CCR were determined using real-time PCR. The results showed that the transcripts of CCR notably increased in the Birch plants transformed with the CCR overexpression construct, and notably decreased in plants transformed with the silencing construct when compared with nontransgenic plants. These studies confirmed that this transient genetic transformation system works well on Birch plants, and can be used for the functional characterization of genes and protein production in Birch. PMID- 22203480 TI - Monocyte to macrophage differentiation-associated (MMD) positively regulates ERK and Akt activation and TNF-alpha and NO production in macrophages. AB - Macrophage activation is modulated by both environmental cues and endogenous programs. In the present study, we investigated the role of a PAQR family protein, monocyte to macrophage differentiation-associated (MMD), in macrophage activation and unveiled its underlying molecular mechanism. Our results showed that while MMD expression could be detected in all tissues examined, its expression level is significantly up-regulated upon monocyte differentiation. Within cells, EGFP-MMD fusion protein could be co-localized to endoplasmic reticulum, mitochondria, Golgi apparatus, but not lysosomes and cytoplasm. MMD expression is up-regulated in macrophages after LPS stimulation, and this might be modulated by RBP-J, the critical transcription factor of Notch signaling. Overexpression of MMD in macrophages increased the production of TNF-alpha and NO upon LPS stimulation. We found that MMD overexpression enhanced ERK1/2 and Akt phosphorylation in macrophages after LPS stimulation. Blocking Erk or Akt by pharmacological agent reduced TNF-alpha or NO production in MMD-overexpressing macrophages, respectively. These results suggested that MMD modulates TNF-alpha and NO production in macrophages, and this process might involves Erk or Akt. PMID- 22203481 TI - Association between ATM polymorphisms and cancer risk: a meta-analysis. AB - To date, epidemiological studies have assessed the association between Ataxia telangiectasia mutated (ATM) gene polymorphisms and cancer risk, including lung cancer, breast cancer, glioma and pancreatic cancer. However, the results of these studies remain controversial. We aimed to examine the associations between two SNPs (rs664143 and rs664677) and cancer risk by conducting a meta-analysis of case-control studies. A total of 12 publications were included in this meta analysis, 8 for rs664143 and 7 for rs664677. Overall, rs664143 heterozygote carriers turned out to be associated with cancer risk (OR = 1.18, 95% CI 1.02 1.36). In the subgroup analysis by cancer type, we observed that the ATM rs664143 polymorphism was significantly associated with lung cancer risk (GA vs. GG: OR = 1.48, 95% CI 1.18-1.85, AA vs. GG: OR = 1.51, 95% CI 1.18-1.93) and rs664677 polymorphism was associated with decreased lung cancr risk and increased breast cancer risk (for lung cancer: TC vs. TT: OR = 0.76, 95% CI 0.62-0.92, CC vs. TT: OR = 0.80, 95% CI 0.64-0.99 and for breast cancer: TC vs. TT: OR = 1.42, 95% CI 1.17-1.73, CC vs. TT: OR = 1.51, 95% CI 1.21-1.87). In the subgroup analysis by region, we also observed that individuals with ATM rs664143 GA or AA genotype had an obvious increased cancer risk among Asian people (GA vs. GG: OR = 1.40, 95% CI 1.20-1.63, AA vs. GG: OR = 1.37, 95% CI 1.16-1.62). In conclusion, ATM rs664143 polymorphism was associated with cancer susceptibility. ATM rs664143 polymorphism was significantly associated with lung cancer risk. ATM rs664677 polymorphism was associated with decreased lung cancer risk as well as increased breast cancer risk. PMID- 22203482 TI - Molecular cloning and characterization of the promoter of SmGGPPs and its expression pattern in Salvia miltiorrhiza. AB - Geranylgeranyl diphosphate (GGPP) synthase is an important branch point enzyme in terpenoid biosynthesis. It regulates the formation of diterpenoid, such as tanshinones. We cloned a gene for GGPP synthase SmGGPPs involved in diterpenoid biosynthesis from Salvia miltiorrhiza. At 2,767 bp long, this gene comprises an intron and two exons that encode a polypeptide of 364 amino acid residues. Then the 5' flanking sequence of SmGGPPs was characterized by bioinformatics method. Deletion analysis of the promoter of SmGGPPs using tobacco plant displayed that the promoter was induced by heat and cold. To further search these cis-elements involved in induction regulation in the 5' flanking sequence of SmGGPPs, many putative cis-elements were predicted with the PlantCARE and PLACE databases. A group of putative cis-acting elements are involved in induction regulation, including G-Box, WRKY, MYC and ATCT motifs. Real-time PCR analysis revealed that SmGGPPs is mainly expressed in the leaves and can also be induced by various factors, such as NaCl, wounding, high temperature, darkness, pathogen, methyl jasmonate, abscisic acid, salicylic acid, and gibberellins. This study provides useful information for further study of SmGGPPs and its regulator effect on the biosynthetic process of tanshinones so that researchers can improve the tanshinone contents in S. miltiorrhiza. PMID- 22203483 TI - Evaluation of suitable reference genes for quantitative RT-PCR during development and abiotic stress in Panonychus citri (McGregor) (Acari: Tetranychidae). AB - Quantitative real time reverse transcriptase polymerase chain reaction (RT-qPCR) is preferred for gene expression analysis in living organisms. Currently, it is a valuable tool for biological and ecological studies as it provides a relatively straightforward way to assess the relevance of transcriptional regulation under developmental and stress tolerance conditions. However, studies have shown that some commonly used reference genes varied among different experimental treatments, thus, systematic evaluation of reference genes is critical for gene expression profiling, which is often neglected in gene expression studies of arthropods. The aim of this study is to identify the suitable reference genes for RT-qPCR experiments involving various developmental stages and/or under abiotic stresses in citrus red mite Panonychus citri, a key pest in citrus orchards worldwide. GeNorm, NormFinder, and Bestkeeper software analysis indicates that elongation factor-1 alpha (ELF1A), RNA polymerase II largest subunit, alpha tublin, and glyceraldhyde-3-phosphate dehydrogenase (GAPDH) are the most stable reference genes in various developmental stages, meanwhile, ELF1A and GAPDH were the most stable reference genes under various abiotic stresses. Furthermore, this study will serve as a resource to screen reference genes for gene expression studies in any other spider mite species. PMID- 22203484 TI - No association of monocyte chemoattractant protein-1 -2518 A/G polymorphism with the risk of primary glomerulonephritis in the Polish population. AB - Various studies have indicated that chemokines such as monocyte chemotactic protein-1 (MCP-1) play an important role in the pathogenesis of primary glomerulonephritis (GN) and other glomerular diseases. Moreover, patients with primary GN display aberrant galactosylation of the O-linked carbohydrate moieties of IgA. Therefore, we analysed the distribution of the functional MCP-1 -2518 A > G (rs 1024611) and 1 beta 1,3-galactosyltransferase (C1GalT1) 1365 A > G (rs1047763) polymorphic variants in patients with primary GN (n = 144) and controls (n = 437) in a sample of the Polish population. We did not find a significant difference in the prevalence of the MCP-1 -2518 A > G and C1GalT1 1365 A > G polymorphisms in patients with primary GN and healthy individuals. Odds Ratio (OR) for GN patients with the MCP-1 -2518 GG genotype was 0.869 (95% CI = 0.410-1.840, P = 0.7130), and OR of the -2518 GG and -2518AG genotypes was 1.004 (95% CI = 0.689-1.464, P = 0.9836). OR for C1GalT1 1365AA genotype was 0.484 (95% CI = 0.181-1.293, P = 0.1402) and OR of the 1365AA and 1365AG genotypes was 0.839 (95% CI = 0.573-1.228, P = 0.3651). We also did not observe a difference in the distribution of alleles between patients and controls. The MCP 1 -2518 G allelic OR was 0.976 (95% CI = 0.725-1.314, P = 0.8744). The OR for the C1GalT1 1365A allele was 0.816 (95% CI = 0.596-1.118, P = 0.205). Moreover, there was no significant association between the MCP-1 -2518 A > G and C1GalT1 1365 A > G genotypes with different morphological types of primary GN or clinical manifestations. Our observations indicate that the MCP-1 -2518 A > G and C1GalT1 1365 A > G polymorphisms might not be a risk factor in the incidence of primary GN in the Polish population. PMID- 22203485 TI - Cloning and the expression pattern of Spatzle gene during embryonic development and bacterial challenge in Artemia sinica. AB - Spatzle gene codes for a NGF-like protein, it involves in the embryonic development and innate immune response of insects and other invertebrate. In dorsal ventral axis differentiation, proSpatzle is activated by serine endoproteases Easter and then binds to the Toll receptor in ventral axis of oocyte which initiates the ventral axis development. Besides, it could also be activated by another protease named Spatzle-processing enzyme (SPZ) to mediate Toll pathway which involves in innate immune response in fungal and Gram-positive bacterial infection of invertebrate. In this paper, a full-length cDNA of Spatzle was firstly isolated from Artemia sinica which belonged to Spatzle-4 family. The expression of Spatzle was investigated at various stages during the embryonic development of A. sinica using real-time PCR and immunohistochemistry assays. The result showed that the high expression level of Spatzle appeared at 7 and 10 days of the embryo. A gradual increased level of Spatzle transcript occurred after being challenged with Gram-positive bacteria. Immunohistochemistry assay showed that Spatzle was mainly expressed in the cephalothorax and on the alimentary canal surface during embryonic development. This new Spatzle member showed a constitutive and regional expression during the embryonic development of A. sinica. It may play an important role in dorsal-ventral differentiation at the early development stages and in immune response pathway at the pseudoadult and adult stage, as well as during infection. PMID- 22203486 TI - Intercellular adhesion molecule 1 gene K469E polymorphism is associated with coronary heart disease risk: a meta-analysis involving 12 studies. AB - Coronary atherosclerosis is a leading cause of coronary heart disease (CHD). Atherosclerotic lesion is a complex polygenic disease in which gene-environment interactions play a critical role in disease onset and progression. The ICAM1 gene-E469K polymorphism has been reported to be associated with CHD, but results were conflicting. A systematic review and meta-analysis of the published studies were performed to gain a clearer understanding of this association. The PubMed, Embase, and CNKI databases were searched for case-control studies published up to August 2011. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. Twelve eligible studies, comprising 2,157 cases and 1,952 controls, were included in the meta-analysis. The pooled result showed that the ICAM1 gene-E469K polymorphism was significantly associated with an increased risk of CHD (OR = 1.496, 95% CI = 1.363-1.642, for the allele K vs. allele E; OR = 1.919, 95% CI = 11.635-2.253, for the K allele carriers vs. EE). Subgroup analysis supported the results in the Asian populations and in the Caucasian populations. This meta-analysis suggests that the ICAM1 gene K469E polymorphism is associated with CHD risk and the K allele is a more significant risk factor for developing CHD among Asian and Caucasians populations. PMID- 22203487 TI - Absence of JAK2V617F mutation in patients with beta-thalassemia major and thrombocytosis due to splenectomy. AB - The report of Janus Kinase 2 (JAK2) mutations in myeloid malignancies with high frequency in myeloproliferative neoplasms has been well known since 2005. By monitoring allele burden, it is found that the expression of JAK2V617F mutation is increasing significantly from essential thrombocytosis to polycythemia vera. Furthermore, JAK2 abnormalities are reported in the majority of unexplained thrombotic episodes. Thalassemic syndromes are characterized by ineffective erythropoiesis and thrombocytosis, mainly due to splenectomy. The high incidence of thromboembolic events has led to the identification of a prothrombotic state in these patients. The contribution of JAK2 mutations to the hypercoagulable state of thalassemic patients is still unknown. Furthermore, the potential role of Janus Kinase mutations in hepcidin expression and consequently in ineffective erythropoiesis is still under investigation. This study was scheduled to determine whether the presence of JAK2V617F mutation in thalassemic patients is associated with thrombocytosis. We studied 20 patients DNA with beta-thalassemia for JAK2V617F mutation by using RG-PCR method. None of the patients were positive for this particular mutation. More studies are needed to prove the role of JAK2 in ineffective erythropoiesis, iron metabolism and thrombocytosis and to determine if using JAK2 inhibitors in thalassemic patients can be a potential therapeutic option. PMID- 22203488 TI - pSDTV vector: a modification of the pBluescript SK+ plasmid in order to perform PCR-fragments TA-cloning using Eam1105I restriction endonuclease. AB - Some of the approaches for cloning PCR products obtained with conventional Taq polymerases which do not involve modifications of the ends of the vector or the insert are based on the use of restriction enzymes which can generate 3' thymine single nucleotide overhangs, such as Eam1105I (AhdI). Due to the presence of Eam1105I restriction site within the beta-lactamase gene, this is not achievable with a number of the most widely used cloning vectors descending from the pUC family, for which the selection is based on the ampicillin resistance. In this report we describe the construction of a vector for TA-cloning, based on the abolishment of the Eam1105I recognition site within the beta-lactamase gene by site-directed mutagenesis, and the introduction of a stuffer flanked by Eam1105I target sites within the polylinker of the pBluescript SK+ plasmid. PMID- 22203489 TI - Familial genetic risk factors in premature cardiovascular disease: a family study. AB - Cardiovascular disease (CVD) is closely associated with familial predisposition. The aim of the present study was to investigate predisposing risk factors in the family of a young patient who underwent coronary artery bypass graft surgery due to CVD. The father and uncle of the patient died at an early age due to myocardial infarction. Various stages of CVD were identified in both of the patient's brothers (28 and 32 years of age). Biochemical tests (fasting blood glucose, lipid profile, urea, creatinine and liver enzymes) and a complete blood count (haemoglobin, haematocrit, white blood cell count, and platelet count) were performed. Physiological coagulation inhibitory factors (protein C, protein S, and antithrombin III), prothrombotic genetic risk factors (factor V Leiden, plasminogen activator inhibitor-1, methylenetetrahydrofolate reductase A1C and C6T, angiotensin-converting enzyme, beta-fibrinogen, glycoprotein IIIa and factor XIII) and homocysteine levels were evaluated in all cases. Defects were observed in many genetic factors and in the systems regulated by these factors. The results were compatible with those reported in the literature. In conclusion, it is possible to determine a specific family history in young adults with CVD. From this perspective, the emergence of more serious CVD may be prevented by providing disease-related information to the other family members and implementing preventive measures. PMID- 22203490 TI - Molecular cloning, characterization, and function analysis of a mevalonate pyrophosphate decarboxylase gene from Ganoderma lucidum. AB - This study investigated the role of the mevalonate pyrophosphate decarboxylase gene in the triterpene biosynthetic pathway of Ganoderma lucidum. The mevalonate pyrophosphate decarboxylase gene (mvd) was isolated using a degenerate primer-PCR technique. An analysis of the Gl-mvd transcription profile revealed a positive correlation between the expression of the Gl-mvd gene and triterpene content changes in G. lucidum during development. Furthermore, a promoter deletion analysis was conducted in G. lucidum to investigate the promoter activity and the role of methyl jasmonate (MeJA) responsive elements in the mvd promoter under the MeJA elicitor. The overexpression of Gl-mvd increased triterpene accumulation compared with the wild-type strain and increased the expression of several genes involved in the triterpene biosynthetic pathway. The findings of this study suggest that mvd may play an important role in triterpene biosynthesis regulation. Moreover, there may be the interactions among the genes involved in the triterpene biosynthetic pathway in the G. lucidum. Additionally, this study provides an approach for improving triterpene content through the overexpression of a key gene. PMID- 22203491 TI - The dynamic interplay in chromatin remodeling factors polycomb and trithorax proteins in response to DNA damage. AB - The dynamic interplay in polycomb group (PcG) and trithorax group (TrxG) proteins in response to DNA damage directly involves in the DNA double strand breaks (DSBs) sites and potentially function in both homologous recombination (HR) and nonhomologous end joining (NHEJ) pathways. The process includes chromatin remodeling that is a major mechanism used by cells to relax chromatin in DNA damage response (DDR) and repair. PcGs show resistance ability to the process while, some tumor suppressor genes involves in the DDR and repair by interacting with TrxGs. Understanding how the dynamic interplay in PcGs and TrxGs impacts on DDR will shed light on the mechanisms of carcinogenesis and develop a new target from anti-DDR related drugs. PMID- 22203492 TI - Key Concepts in the Early Immunology of HIV-1 Infection. AB - Though HIV-1 is a sexually transmitted infection, the gut associated lymphoid tissue (GALT) that houses about 60% of the body's total immune cells is unequivocally the earliest and most important target of HIV-1. In this review we summarize recent data regarding the early events in HIV-1 pathogenesis, with special emphasis on pathogenic effects on the GALT. PMID- 22203493 TI - Association of suboptimal health status and cardiovascular risk factors in urban Chinese workers. AB - Suboptimal health status (SHS) has become a new public health challenge in urban China. Despite indications that SHS may be associated with progression or development of chronic diseases such as cardiovascular and metabolic diseases, there are few reports on SHS investigations. To explore the relationship between SHS and traditional cardiovascular risk factors, a cross-sectional study was conducted in a sample of 4,881 workers employed in 21 companies in urban Beijing. Blood pressure, glucose, lipid levels (total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol and triglycerides), cortisol, and body mass index were measured. SHS score was derived from data collection in the SHS questionnaire (SHSQ-25). Univariate analysis and linear two-level model were used to analyze the association of SHS with the cardiovascular risk factors. Serum cortisol level was much higher among the SHS high-score group than that among the low SHS score group (204.31 versus 161.33 ng/ml, P < 0.001). In a linear two-level model, we found correlation between SHS and systolic blood pressure, diastolic blood pressure, plasma glucose, total cholesterol, and HDL cholesterol among men, and correlation between SHS and systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, and HDL cholesterol among women after controlling for age, education background, occupation, smoking, and physical activity. SHS is associated with cardiovascular risk factors and contributes to the development of cardiovascular disease. SHS should be recognized in the health care system, especially in primary care. PMID- 22203494 TI - Molecules involved in epithelial-mesenchymal transition and epithelial-stromal interaction in phyllodes tumors: implications for histologic grade and prognosis. AB - The aim of this study was to investigate the expression of molecules associated with epithelial-mesenchymal transition (EMT) and epithelial-stromal interactions (ESI) and to evaluate their roles in phyllodes tumors (PTs). Tissue microarrays (TMAs) were constructed from 207 PT specimens (157 benign, 34 borderline and 16 malignant). The presence of EMT-related markers including N-cadherin, Twist, TGF beta, HMGA2, S100A4 and Ezrin as well as ESI-related molecules such as SDF1 and CXCR4 among the TMAs was assessed immunohistochemically. Immunohistochemical results were analyzed in terms of clinicopathologic parameters. For higher grade PTs, expressions of Twist (p < 0.001), HMGA2 (p = 0.005), S100A4 (p < 0.001), CXCR4 (p < 0.001) and TGF-beta (p < 0.001) were higher. As PTs showed higher stromal cellularity, higher stromal mitosis, stromal overgrowth and infiltrative tumor margin, the expressions of Twist, HMGA2 and CXCR4 in the stromal component thereof were increased (p < 0.05). High Twist expression in the stromal component was associated with shorter disease-free survival (DFS) and overall survival (OS) (p < 0.001) as well as shorter OS in multivariate COX analysis (p = 0.031, odds ratio: 24.6). In conclusion, the expressions of Twist, HMGA2, TGF-beta and S100A4, which are EMT-associated molecules, and CXCR4, an ESI-associated molecule, were increased in the stromal component of advanced grade PTs. Further, high expression of Twist in the stromal component was correlated with poorer prognoses. PMID- 22203495 TI - CA 19-9 in pancreatic cancer: retrospective evaluation of patients with suspicion of pancreatic cancer. AB - CA 19.9 serum levels were prospectively determined in 573 patients admitted to hospital for suspicion of pancreatic cancer. The final diagnosis was 77 patients with no malignancy, 389 patients with pancreatic cancer, 37 neuroendocrine pancreatic cancer, 28 cholangiocarcinomas, 4 gallbladder cancer, 27 ampullary carcinomas, and 11 periampullary carcinomas. CA 19.9 was determined using a commercial assay from Roche Diagnostics, and 37 U/ml was considered as the upper limit of normality. Abnormal CA 19.9 serum levels were found in 27%, 81.5%, 85.7%, 59.3%, 63.6%, and 18.9% of patients with benign diseases, pancreatic cancer, cholangiocarcinomas, and ampullary, periampullary, or neuroendocrine tumors. Significantly higher concentrations of CA 19.9 were found in patients with than in those without malignancy or with neuroendocrine tumors. CA 19.9 serum levels were higher in pancreatic cancer or cholangiocarcinoma than in other malignancies (p < 0.0001). CA 19.9 serum levels were also correlated with tumor stage, treatment (significantly lower concentrations in resectable tumors), and tumor location (the highest in those located in the body, the lowest in those in the tail or uncinate) and site of metastases (highest in liver metastases). A trend to higher CA 19.9 serum concentrations was found in patients with jaundice, but only with statistical significance in the early stages. Using 50 or 100 U/ml in patients with jaundice, CA 19.9 was useful as an aid in the diagnosis of pancreatic cancer (sensitivity 77.9%, specificity 95.9%) as well as tumor resectability in pancreatic cancer with different cutoffs according to tumor location and bilirubin serum levels with specificities ranging from 90% to 100%. CA 19.9 is the tumor marker of choice in pancreatic adenocarcinomas, with a clear relationship with tumor location, stage, and resectability. PMID- 22203496 TI - Targeting the endothelin axis in prostate carcinoma. AB - Prostate cancer is the most common malignancy in men in Western countries. Until the last decade, the main available therapeutic options were based on hormonal therapy. For castration-refractory prostate carcinoma, from 2004, the combination of chemotherapy with docetaxel and prednisone has shown to improve survival in this subset of patients. Many agents have been tested either alone or in combination with this standard therapy, trying to find synergistic effects between drugs, and to target specific pathways that influence tumor growth, invasiveness, angiogenesis, and the development of distant metastasis. Endothelin antagonists have been recently studied, as they can get involved in many of these oncogenic pathways, and results are encouraging; nevertheless, the right setting to use them, whether to use them in monotherapy or in combination with other agents, and if they really improve the survival of our patients, are questions that remain to be addressed. In this review, we summarize the role of endothelins in tumoral biology and specifically in prostate carcinoma natural history, and the results obtained in the clinical trials involving this new therapeutic group. PMID- 22203498 TI - Serological monitoring of paediatric visceral leishmaniasis By IFA and ELISA methods. AB - OBJECTIVE: Visceral leishmaniasis (VL) is endemic in all Mediterranean countries including Turkey, and children are at greater risk than adults in endemic areas. In VL patients, serological assays are considered to be sensitive for the diagnosis and/or follow up. The aim of this study was to assess the usefulness of serology for following up of childhood VL in Turkey. METHODS: Sera obtained from twenty parasitologically confirmed children with VL were tested using IFAT and ELISA. The patients were monitored clinically and serologically (range: 20-500 days) during and after treatment. All VL patients were treated with meglumine antimonate. RESULTS: Anti-Leishmania antibodies in successfully treated VL patients showed a steep decline but, in three patients who had relapsed, an increase was detected. Significantly lower values were observed after treatment with both serological techniques. Mean ELISA optical density values before and after treatment were: 0.78 +/- 0.36 (0.26-1.76) and 0.38 +/- 0.24 (0.09-0.83) respectively, (p < 0.001) and mean IFAT values (log10 transformed titers) before and after treatment were: 3.02 +/- 0.90 (1.81-4.51) and 2.16 +/- 0.75 (1.20-3.90) respectively, (p < 0.001). CONCLUSION: ELISA and IFAT are valuable not only for diagnosis but also for monitoring of drug therapy in childhood visceral leishmaniasis as rapid and non-invasive techniques. PMID- 22203497 TI - Mutant p53 uses p63 as a molecular chaperone to alter gene expression and induce a pro-invasive secretome. AB - Mutations in the TP53 gene commonly result in the expression of a full-length protein that drives cancer cell invasion and metastasis. Herein, we have deciphered the global landscape of transcriptional regulation by mutant p53 through the application of a panel of isogenic H1299 derivatives with inducible expression of several common cancer-associated p53 mutants. We found that the ability of mutant p53 to alter the transcriptional profile of cancer cells is remarkably conserved across different p53 mutants. The mutant p53 transcriptional landscape was nested within a small subset of wild-type p53 responsive genes, suggesting that the oncogenic properties of mutant p53 are conferred by retaining its ability to regulate a defined set of p53 target genes. These mutant p53 target genes were shown to converge upon a p63 signalling axis. Both mutant p53 and wild-type p63 were co-recruited to the promoters of these target genes, thus providing a molecular basis for their selective regulation by mutant p53. We demonstrate that mutant p53 manipulates the gene expression pattern of cancer cells to facilitate invasion through the release of a pro-invasive secretome into the tumor microenvironment. Collectively, this study provides mechanistic insight into the complex nature of transcriptional regulation by mutant p53 and implicates a role for tumor-derived p53 mutations in the manipulation of the cancer cell secretome. PMID- 22203499 TI - [Investigation of anti-Toxoplasma gondii antibodies among foreign students in a high school]. AB - OBJECTIVE: Toxoplasmosis is a major health problem in both developed and developing countries. Infection is transmitted to humans by consumption of raw or undercooked meat containing tissue cysts and by ingesting foods contaminated with oocysts from the feces of infected cats and felidae. In this study, it was aimed to investigate the incidence of T. gondii antibodies in 347 high school students from 28 different countries studying in Kayseri city. METHODS: These students had ages ranging between 15 and 21 (average: 17.52 +/- 1.36). Serum samples were researched by IFAT for T. gondii IgG and IgM antibodies. RESULTS: 81 (23.3%) students were found to be seropositive for IgG, and 6 (1.72%) of students were positive for both IgG and IgM. There was no IgM seropositivity in IgG negative serum specimens. IgG avidity test was also done for 87 subjects who were found to be seropositive for anti-T. gondii IgG. The results indicated that 8 (9.2%) patients have equivocal range avidity and 79 (90.8%) patients have high avidity. CONCLUSION: As a result, this disease, which is important in children and adolescents, can lead to severe disease staes. Therefore, in various regions, especially in the pediatric age group, sero-prevalence tests and necessary measures are needed in high sero-prevalent areas. PMID- 22203500 TI - [Characterization of Toxoplasma gondii proteins from various strains]. AB - OBJECTIVE: Toxoplasma gondii the causative agent of toxoplasmosis, is a worldwide intracellular protozoan parasite that infects all warm blooded animals including humans. It can be devastating to immunocompromised humans and congenital transmission may result in severe clinical spectrum. It causes economic losses due to abortus in animals. Toxoplasmosis diagnosis depends on direct and indirect methods. Besides the Sabin-Feldman test, which is accepted to be the reference test, serologic tests such as ELISA and immunofluorescence antibody tests are means of indirect diagnosis. As detected antibodies in serologic tests are correlated with antigens that cause their synthesis, it is important to know different proteins of different strains. In this study RH, Ankara and TS-4 strains were used and differences between their proteins were examined. METHODS: RH and Ankara strains were inoculated into the peritoneal cavity of mice. TS- 4 strain was produced in Vero cell culture. Tachyzoites collected by peritoneal wash were lysed and lyophilised. This was run on SDS-PAGE gel and protein bands were compared with a standard protein ladder after staining with polychromatic silver stain. RESULTS: It was observed that, while Ankara and RH strains had dense bands between 60-70 kDa and at 15 kDa, the most prominent bands of TS-4 strain were 60 ve 115 kDa bands. CONCLUSION: RH and Ankara strains have the same protein bands while TS-4 strain has different and fewer protein bands than the others. PMID- 22203501 TI - [Seroprevalence of Toxoplasma gondii in Pirlak sheep in the Afyonkarahisar Province of Turkey]. AB - OBJECTIVE: This study was carried out between June-December 2008 to determine the prevalence of toxoplasmosis in Pirlak sheep in the Suhut district of Afyonkarahisar. METHODS: Blood samples technically collected from 123 sheep older than one year old and 63 sheep younger than one year old were tested for Toxoplasma gondii antibodies using the Sabin- Feldman dye test. RESULTS: Out of the 186 sera examined, 184 (98.92%) were seropositive at different dilutions (84 samples at 1/16, 79 at 1/64 and 21 at 1/256). The seroprevalence was 99.19% for sheep above 1 year old and 98.41% for sheep under 1 year old. CONCLUSION: We believe that this study carried out on Pirlak sheep would be useful for other studies on the effect of parasitism on the economy. PMID- 22203502 TI - [Molecular characterization of Babesia bovis msa-2c gene]. AB - OBJECTIVE: This study was carried out to determine the molecular characterization of msa-2c gene of one Babesia bovis isolate from cattle in the Aegean Region and to compare identities with similar isolates from the World and Turkey. METHODS: Between 2008-2010 blood samples were collected from a total of 235 cattle localized in 9 provinces of the Marmara and Aegean Regions. Smears were prepared, genomic DNA's were extracted from the blood samples and investigated for Babesia species by RLB. PCR was performed on one sample determined as B. bovis, the obtained amplicon was purified, sequenced and deposited to GenBank. Identities with similar isolates from Turkey and the World were investigated. RESULTS: Bovine babesiosis was not determined in the microscopic examination. According to the RLB results there was no B. bovis positivity in cattle from the Marmara Region, while only one B. bovis positivity was detected in cattle from the Aegean Region. The molecular prevalence of B. bovis was determined as 0.42% in the total of the examined 235 cattle. The sequenced B. bovis isolate shared 91-92% and 89 96% identities with the isolates from Turkey and the World, respectively. CONCLUSION: Molecular characterization of msa-2c gene region of B. bovis detected from cattle in the Aegean Region was carried out in this study. PMID- 22203503 TI - [Incidence in Sivas of Trichomonas vaginalis in patients with vaginitis]. AB - OBJECTIVE: Trichomonas vaginalis infection is a common disease among women and an important public health problem. The present study is performed to determine the prevalence of T. vaginalis among the 258 women admitted to Sivas State Hospital, Gynecology Department with a variety of symptoms and vaginitis. The ages of patients ranges from 17 to 80 years. METHODS: During the gynecologic examination two samples were taken from the vagina fornix and the first one was placed t in SF (Serum Physiological), the second in Cysteine-Peptone-Liver-Maltose (CPLM). The samples in SF were examined under light microscope immediately. Culture samples were incubated at 37 degrees C and examined after 24-48 hours. RESULTS: Of all the samples, 5 (1.9%) were positive with DM and 4 were positive with CPLM for the presence of trophozoites. Additionally, the parasite was most common among women whose ages ranged between 41 and 50 (4.8%). CONCLUSION: When compared to other studies from other parts of the country, the prevalence rate was found to be low. Moreover, T. vaginalis infection has to be considered during a gynecological examination. PMID- 22203504 TI - Effect of different concentrations of hypertonic saline at different times on protoscoleces of hydatid cyst isolated from liver and lung. AB - OBJECTIVE: Most surgeons inject scoloidal materials into the cyst before or after its removal, since any contamination to normal sites will cause re-growth of the same cyst. The aim of this study was to determine the lethal effect of hypertonic saline at different doses and different times on protoscolexes of lung and liver. METHODS: The livers and lungs of killed animals with hydatid cyst disease were gathered from Urmia Industrial Abattoirs. They were transferred to the university parasitological lab immediately. The hydatid cyst fluid was aspirated with a 10 mm syringe and poured into a 15 cc tubes. The movement of protoscoleces and staining with 0.1% eosin was the test to determine viability of protoscoleces. Those with color absorption were those which were not viable. Different concentrations of hypertonic saline were given at different time. RESULTS: The results showed that in 20% of hypertonic saline in the 4th minute, 80% of protoscoleces were alive while in the 5th minute 50% were alive, in the 7th minute 20% and 8th minute 5%, 9th minute all of them were dead. In the 10% concentration, at up to 9 minutes 50% were alive, in the 18th minute 20% and in 30 minutes 10% of protoscoleces were alive. In the 5% concentration at up to 10 minutes 90% were alive while in the 22nd minute 80% and in 30 minutes 70% of protoscoleces were alive. CONCLUSION: When we inject 20% hypertonic saline into the cyst cavity there is aprobability that the cyst contaminates the bile duct and liver through the small hole we made. This material may cause widespread necrosis of the liver. We should use 10% hypertonic saline minimally for 45 minute before surgery and after cyst removal, since the hypertonic saline itself may cause injury to the biliary system. PMID- 22203505 TI - The prevalence of Pediculus humanus capitis in two primary schools of Hacilar, Kayseri. AB - OBJECTIVE: Pediculosis capitis is a worldwide public health concern, and today, head lice are seen in all socio-economic levels. The infestation usually occurs by head-to-head contact and children, primarily girls, aged 3-12 years are mostly affected. In the present study a total of 405 pupils (214 boys and 191 girls) from two pre- and primary schools in the Kayseri-Hacilar region were examined for pediculosis capitis during March 2010. METHODS: Lice and/or eggs were detected by visual examination of the children's hair. RESULTS: Out of 405 children, 44 (10.9%) were infested with head lice. There were significant differences between the schools and the gender while no significant differences could be found between infestation and child's age, education of the parents, income of the family, housing type, source of water, and the presence or absence of a bathroom. CONCLUSION: Head lice remain a public health problem and more emphasis should be given to the education of parents regarding their biology and control. PMID- 22203506 TI - [The effects of chitin synthesis inhibitor, diflubenzuron on the larvae of Culex pipiens (L.) and Culiseta longiareolata (Macquart) (Diptera: Culicidae)]. AB - OBJECTIVE: The aim of the present study was to detect effects of diflubenzuron on Culex pipiens and Culiseta longiareolata larvae, and determine the weekly mortality rate and most effective dose of diflubenzuron during the study. METHODS: The lower and higher doses (0.016, 0.032, and 0.064 mg(ai)/cm(2)) than 0.05 mg(ai)/cm(2) which are brecommended for granular formulation of diflubenzuron by WHO (World Health Organization) was applied against 1st, 2nd, 3rd and 4th instars under laboratory conditions and mortality was recorded. RESULTS: According to our data, diflubenzuron was more effective against early instars, and it was found most effective in the 4th and 3(th) week post-treatment in the application for Culex pipiens and Culiseta longiareolata larvae respectively. In addition, the most effective dose of diflubenzuron was obtained as 0.064 mg(ai)/cm(2) (LC50 > 4640 ppm, LC90 = 0.0034 ppm). Furthermore Culiseta longiareolata was more sensitive than Culex pipiens larvae. CONCLUSION: Knowing the specific mortality rate of diflubenzuron in different mosquitoe species and larvae stages, plays an important role in determining the resistance against diflubenzuron. PMID- 22203507 TI - [The seasonal distribution and effect of tench fish (Tinca tinca L., 1758) helminthes parasites living in Terkos lake]. AB - OBJECTIVE: The aim of this study, carried out from August, 2009 to July, 2010, was to determine the seasonal distribution of tench fish (Tinca tinca L. 1758) helminthes inhabiting the Terkos lake. METHODS: Living fish gathered from the study area were brought into the laboratory. The species analysis done by ecto and endo parasites of the fish were investigated. RESULTS: During the study, a total of 165 tenches (T. tinca) were investigated. Endoparasites in tenches were found to be plerocercoids of Ligula intestinalis plerocercoid (Linnaeus, 1758), Caryophyllaeus laticeps (Pallas, 1781), Bothriocephalus acheilognathi (Yamaguti, 1934) and Proteocephalus torulosus (Bats ch, 1786) from Cestoda, Asymphylodora tincae (Modeer, 1790) from Digenea and ectoparasite in tenches were found to be Piscicola geometra (Linnaeus, 1761) from Hirudinea. CONCLUSION: The study shows that among these parasites those which were widespread were: Asymphylodora tincae spreads more in spring, Ligula intestinalis in autumn, Caryophyllaeus laticeps, Bothriocephalus acheilognathi and Protocephalus torulosus in summer and Piscicola geometra in winter. PMID- 22203508 TI - [Diagnostic dilemma: analysis of 11 cases of hydatid disease]. AB - OBJECTIVE: Hydatid cyst disease is a parasitic disease caused by the tapeworm Echinococcus granulosus. This disease may cause atypical clinical and radiological features and complications that cause difficulties in diagnosis. Misdiagnoses may result in delay in treatment. We aimed to examine the characteristics and surgical results of hydatid cyst disease with atypical clinical features. METHODS: Hydatid cyst patients with atypical clinical and radiological features diagnosed in the department of chest surgery, between 2006 and 2009 were retrospectively evaluated according to sex, age, symptoms, radiological diagnosis, surgical procedures applied and postoperative complications. Eleven patients with atypical clinical features were analyzed for misdiagnoses and challenges in the diagnosis and results of treatment. RESULTS: Nine patients (81.82%) were male and 2 patients (18.18%) were female and their mean age was 35.33 +/- 17.52 years. Parapneumonic effusion and thoracic empyema (5 patients), lung cancer (3 patients), congenital cystic adenomatoid malformation (1 patient), lung abscess (2 patients) disease were the misdiagnosed diseases in hydatid cyst disease. All patients were treated surgically. Hydatid disease was confirmed pathologically. CONCLUSION: Hydatid cyst may imitate other chest diseases when it causes atypical clinical features. Misdiagnosis may cause delay in surgical treatment. PMID- 22203509 TI - [A case of leech infestation mimicking upper respiratory tract infection]. AB - Urban life and industrialization leads to a decrease in the incidence of many parasitic diseases. Especially, using the supervised water supplies in urban areas decreases the chance of such infestations and limits it in rural areas. However, the people who live in urban areas and have diseases such as kidney stones think that mountain waters may be beneficial for their illness. These types of water supplies are generally unsafe, uncontrolled and septic. That is why usage of them can cause some elusive parasitic infestations in people who live in urban areas. It is meaningful to submit the case described below to illustrate the possibility of parasitic infestations in patients who have upper respiratory tract infection symptoms who are admitted to the physician. PMID- 22203510 TI - [Urogenital myiasis caused by Psychoda albipennis]. AB - Myiasis is a cause of urogenital parasitosis. In this study, a 29 year-old male patient who was admitted to our hospital with urinary discharge of worms has been presented. Larvae were examined parasitologically and urogenital myiasis caused by Psychoda albipennis larvae was diagnosed. No other pathological findings were detected in the patient and the symptoms resolved spontaneously within a few days. Despite the fact that urinary myiasis is very rare in humans, it should be considered in patients with urinary complaints. Apparently, a quick recovery without treatment is possible in most cases. PMID- 22203511 TI - [Travel related urinary schistosomiasis: case report]. AB - Schistosomiasis is the second most frequent parasitic infection worldwide after malaria and is a major public health problem in various countries of the world. In our country due to the increasingf travel to endemic regions, the number of cases is also rising. We report herein a case of schistosomiasis who resided in Africa five years earlier and was referred to hospital with hematuria. Direct microscopic examination of the urine specimen revealed Schistosoma haematobium eggs. Epidemiology and clinical significance of schistosomiasis are also discussed. PMID- 22203512 TI - [Hydatid cyst presenting with multiple recurrence and pelvic involvement: case report]. AB - Hydatid cyst disease is a parasitic infection which is caused by the metacestode form of Echinococcus granulosus and affects primarily the liver and lung. Bone involvement is found in 1% of patients afflicted with this disease. The spine is involved in about 50% of these cases. Herein, we report a 70 year old male case with pelvic and spinal hydatid cyst who was operated on eleven times. PMID- 22203513 TI - Novel alginate based nanocomposite hydrogels with incorporated silver nanoparticles. AB - Alginate colloid solution containing electrochemically synthesized silver nanoparticles (AgNPs) was investigated regarding the nanoparticle stabilization and possibilities for production of alginate based nanocomposite hydrogels in different forms. AgNPs were shown to continue to grow in alginate solutions for additional 3 days after the synthesis by aggregative mechanism and Ostwald ripening. Thereafter, the colloid solution remains stable for 30 days and could be used alone or in mixtures with aqueous solutions of poly(vinyl alcohol) (PVA) and poly(N-vinyl-2-pyrrolidone) (PVP) while preserving AgNPs as verified by UV Vis spectroscopy studies. We have optimized techniques for production of Ag/alginate microbeads and Ag/alginate/PVA beads, which were shown to efficiently release AgNPs decreasing the Escherichia coli concentration in suspensions for 99.9% over 24 h. Furthermore, Ag/hydrogel discs based on alginate, PVA and PVP were produced by freezing-thawing technique allowing adjustments of hydrogel composition and mechanical properties as demonstrated in compression studies performed in a biomimetic bioreactor. PMID- 22203514 TI - Double protein functionalized poly-epsilon-caprolactone surfaces: in depth ToF SIMS and XPS characterization. AB - In biomaterial research, great attention has focussed on the immobilization of biomolecules with the aim to increase cell-adhesive properties of materials. Many different strategies can be applied. In previously published work, our group focussed on the treatment of poly-epsilon-caprolactone (PCL) films by an Ar plasma, followed by the grafting of 2-aminoethyl methacrylate (AEMA) under UV irradiation. The functional groups introduced, enabled the subsequent covalent immobilisation of gelatin. The obtained coating was finally applied for the physisorption of fibronectin. The successful PCL surface functionalization was preliminary confirmed using XPS, wettability studies, AFM and SEM. In the present article, we report on an in-depth characterization of the materials developed using ToF-SIMS and XPS analysis. The homogeneous AEMA grafting and the subsequent protein coating steps could be confirmed by both XPS and ToF-SIMS. Using ToF SIMS, it was possible to demonstrate the presence of polymethacrylates on the surface. From peak deconvoluted XPS results (C- and N-peak), the presence of proteins could be confirmed. Using ToF-SIMS, different positive ions, correlating to specific amino-acids could be identified. Importantly, the gelatin and the fibronectin coatings could be qualitatively distinguished. Interestingly for biomedical applications, ethylene oxide sterilization did not affect the surface chemical composition. This research clearly demonstrates the complementarities of XPS and ToF-SIMS in biomedical surface modification research. PMID- 22203515 TI - Cress seed mucilage based buccal mucoadhesive gel of venlafaxine: in vivo, in vitro evaluation. AB - Venlafaxine is a newer antipsychotic drug which shows first pass effect. Cress seed is also called as garden cress or green salad. This study examined the mechanical (gel strength, adhesiveness) and rheological properties of cress seed mucilage based gels that contain different ratios of carbopol 934 P (0.5-1.5%). In addition, diffusion of venlafaxine from gel formulations was evaluated. The selected formulation was further analyzed for pharmacokinetic parameters in rabbits. All formulations exhibited pseudoplastic flow with thixotropy. Formulation F5 showed the C(max) of 24.19 +/- 0.72 ng/ml by buccal route of administration and 17.98 +/- 1.15 ng/ml by oral route of administration. The bioavailability of F5 by buccal route was 54.44% and that of by oral route was 39.60%. A combination of the cress seed mucilage and carbopol 934 P resulted in a prolonged and higher venlafaxine delivery by buccal route of administration. PMID- 22203516 TI - Programmed water-induced shape-memory of bioabsorbable poly(D,L-lactide): activation and properties in physiological temperature. AB - This study reports of the novel water-induced shape-memory of bioabsorbable poly(D,L-lactide). We have developed an orientation-based programming process that generates an ability for poly(D,L-lactide) to transform its shape at 37 degrees C in an aqueous environment without external energy and to adapt to a predefined stress level by stress generation or relaxation. In this orientation programming process, polymer material is deformed and oriented at an elevated temperature and subsequently cooled down while retaining its deformed shape, tension, and polymer chain entanglements. At body temperature and in an aqueous environment, the shape-memory is activated by the plasticizing effect of water molecules diffused into the polymer matrix causing an entropy-driven directed relaxation of oriented and preloaded polymer chains. This plasticizing effect is clearly seen as a decrease of the onset glass transition temperature by 10-13 degrees C. We found that gamma-irradiation used for sterilizing the orientation programmed materials strongly affected the shape-recovery rate, but not the recovery ratio. Both non-gamma-irradiated and gamma-irradiated sample materials showed excellent shape-recovery ratios during a ten-week test period: 94 and 97%, respectively. The orientation-programmed materials generated a predefined load in a 37 degrees C aqueous environment when their shape-recovery was restricted, but when external tension was applied to them, they adapted to the predefined level by stress relaxation. Our results show that functionality in terms of shape memory can be generated in bioabsorbable polymers without tailoring the polymer chain structure thus shortening the time from development of technology to its utilization in medical devices. PMID- 22203517 TI - Local bisphosphonate release versus hydroxyapatite coating for stainless steel screw fixation in rat tibiae. AB - Implant fixation in bone can be improved by a coating that delivers bisphosphonates locally, or by a hydroxyapatite (HA) coating. In this study, we compared these different types of coatings. For mechanical testing, 30 rats were assigned into three groups, and similar screws were implanted bilaterally in the proximal tibiae. The rats received screws that were either uncoated, coated with nano-crystalline hydroxyapatite or coated with a bisphosphonate releasing protein matrix. After 4 weeks, one screw was subjected to pull-out testing, and the contra-lateral one to torsion testing. For morphology, 30 rats were assigned to similar treatment groups, but received only one screw each. Bisphosphonates enhanced the pull-out force by 41% (P = 0.02) compared to controls, HA increased the pull-out force although not significantly. Conversely, HA increased the maximal torque by 64% (P = 0.02). Morphometry showed higher bone volume around bisphosphonate screws in comparison to HA-coated screws (P < 0.001) and controls (P < 0.001). The results suggest that bisphosphonates improve fixation by increasing the amount of surrounding bone, whereas HA mainly improves bone to implant attachment. PMID- 22203518 TI - Ecological momentary assessment of the relationship between intention and physical activity behavior in bariatric surgery patients. AB - BACKGROUND: Performing habitual physical activity (PA) is challenging for many bariatric surgery patients. PURPOSE: We used electronic ecological momentary assessment to naturalistically examine whether insufficient PA among bariatric surgery patients was due to infrequent PA intentions or inadequate follow through on PA intentions. METHOD: Twenty-one patients 6-months post-bariatric surgery were recruited from multiple clinics in Providence, Rhode Island, USA. Participants used a palmtop computer upon waking for 6 days to indicate whether they intended to be active, and if so, the amount of PA they intended to perform in bouts >=10 min. Each evening, participants reported PA minutes and barriers encountered that day. RESULTS: All 21 participants reported intending to be active on at least 1 day but only 9 (42%) intended to be active on >=70% of days. Twelve (57%) participants performed PA on each of the days they intended, but none achieved the amount of PA they intended on all of these days. Overall, participants had PA intentions on 81 of 123 days (66%); these were partially implemented (>=10 PA minutes) on 49 days, but fully implemented on only 15 days. Participants spent 34 min in PA, or 20 fewer minutes than intended. "Lack of time" was the only frequently cited barrier, particularly on days that PA was neither intended nor performed. CONCLUSION: Few patients intended to be active on a near daily basis and all patients had difficulty in implementing their intentions. Interventions that target planning strategies may help facilitate PA intentions and limit discrepancy between intended and actual PA. PMID- 22203519 TI - Sacral nerve modulation in the treatment of chronic pelvic pain. AB - BACKGROUND: Chronic pelvic pain is a common condition that significantly compromises the quality of life of affected patients. Unfortunately, despite treatment procedures, the results are often ineffective and symptoms persist for years. For these reasons, the search for less aggressive treatment options with fewer negative consequences leading to minimally invasive techniques was conducted. OBJECTIVE: The aim of the present study was to evaluate the efficacy of sacral nerve modulation in the treatment of chronic pelvic pain. Moreover, we aimed to identify potential predictors of positive results of sacral neuromodulation through the comparison between failed and successful patients. PATIENTS: From January 2004 to December 2009, all consecutive patients suffering from chronic pelvic pain and tested for sacral nerve modulation in three pelvic floor dedicated centers were evaluated. Severity of symptoms were analyzed by a visual analog scale (VAS) RESULTS: Twenty-seven patients (2 males; mean age, 53 years) were tested for sacral nerve modulation in the screening period and were included in the present study. The mean duration of pain was 51 months (range, 10 132 months). The mean preoperative VAS was 7.8 (range, 5-10). Previous pelvic surgery was reported in 18 patients (66.5%). Sixteen patients (59%) fulfil the successful criteria and were definitively implanted. The mean follow-up was 37 months (range, 12-71 months). The mean preoperative VAS was 8.1 (range, 6-8) and decreased to 2.1 +/- 1.2 at 6-month follow-up (p < 0.0001), to 2.1 +/- 1.1 at 12 months (16 patients), to 2.0 +/- 1.2 at 24 months (13 patients), to 2.3 +/- 1.4 at 36 months (9 patients), to 2.1 +/- 1.5 at 48 months (5 patients), and to 1.9 +/- 1.3 at 60 months (3 patients). CONCLUSIONS: Sacral neuromodulation proved to be effective in the treatment of some patients affected by chronic pelvic pain, and the effect persists over time. A positive screening phase and a positive response to gabapentin or pregabalin showed to be predictors of a successful response. Multiple localizations of pelvic pain and pain occurred after stapler surgery seem to be negative factors for the success of the treatment. PMID- 22203520 TI - Development of transgenic watermelon resistant to Cucumber mosaic virus and Watermelon mosaic virus by using a single chimeric transgene construct. AB - Watermelon, an important fruit crop worldwide, is prone to attack by several viruses that often results in destructive yield loss. To develop a transgenic watermelon resistant to multiple virus infection, a single chimeric transgene comprising a silencer DNA from the partial N gene of Watermelon silver mottle virus (WSMoV) fused to the partial coat protein (CP) gene sequences of Cucumber mosaic virus (CMV), Cucumber green mottle mosaic virus (CGMMV) and Watermelon mosaic virus (WMV) was constructed and transformed into watermelon (cv. Feeling) via Agrobacterium-mediated transformation. Single or multiple transgene copies randomly inserted into various locations in the genome were confirmed by Southern blot analysis. Transgenic watermelon R(0) plants were individually challenged with CMV, CGMMV or WMV, or with a mixture of these three viruses for resistance evaluation. Two lines were identified to exhibit resistance to CMV, CGMMV, WMV individually, and a mixed inoculation of the three viruses. The R(1) progeny of the two resistant R(0) lines showed resistance to CMV and WMV, but not to CGMMV. Low level accumulation of transgene transcripts in resistant plants and small interfering (si) RNAs specific to CMV and WMV were readily detected in the resistant R(1) plants by northern blot analysis, indicating that the resistance was established via RNA-mediated post-transcriptional gene silencing (PTGS). Loss of the CGMMV CP-transgene fragment in R1 progeny might be the reason for the failure to resistant CGMMV infection, as shown by the absence of a hybridization signal and no detectable siRNA specific to CGMMV in Southern and northern blot analyses. In summary, this study demonstrated that fusion of different viral CP gene fragments in transgenic watermelon contributed to multiple virus resistance via PTGS. The construct and resistant watermelon lines developed in this study could be used in a watermelon breeding program for resistance to multiple viruses. PMID- 22203521 TI - Novel long-lasting impregnation technique transferred from clothing to bednets: extended efficacy and residual activity of different pyrethroids against Aedes aegypti as shown by EN ISO 6330-standardized machine laundering. AB - A novel long-lasting insecticide-treated net (LLIN) has been designed by embedding the pyrethroids deltamethrin, cyfluthrin, permethrin, or etofenprox, onto the fibres of bed net cotton fabric by transferring a new polymer-coating technique from clothing to netting material. EN ISO 6330, the more stringent European Norm for domestic washing and drying procedures for textile testing, has been newly employed to monitor and validate more precise wash durability and residual bioactivity of LLINs. Wash durability, residual insecticidal activity and mosquito landing/biting protection has been investigated and compared with four commercially available LLINs. The pyrethroid-embedding impregnation technique allows binding of high concentrations exceeding 8,000 mg permethrin/m(2) within one single-polymer layer. Recovery rates of 95.7 +/- 5.8%, 92.4 +/- 14.0%, 70.2 +/- 9.1%, and 64.2 +/- 6.3% for cyfluthrin; 32.4 +/- 11.4%, 32.4 +/- 12%, 35.1 +/- 16.2%, and 35.8 +/- 15.7% for deltamethrin; 75.3 +/- 12.9%, 57.1 +/- 15.8%, 48.5 +/- 4.0%, and 35.6 +/- 4.7% for etofenprox; and 95.7 +/- 5.8%, 80.2 +/- 8.6%, 39.1 +/- 7.9%, and 34.1 +/- 8.8% were measured after 1, 5, 10, and 20 launderings. Laundering resistance was highest with cyfluthrin > deltamethrin ~ etofenprox ~ permethrin. After one and five launderings, commercial LLINs revealed percentage pyrethroid recovery rates of 26.3 +/- 11.8% and 0.9 +/- 1.2% for the Care Plus((r)) net; 31.8% and 28.9% for the Permanet((r)) 2.0; 61.4% and 45.6% for the Net Protect((r)); and 80.4% and 68.3% for the Conmanet((r)). Recovery rates reveal that the polymer-coating method resulted in extended wash durability. Dose-dependent 100% knockdown rates were most effective with deltamethrin > cyfluthrin > permethrin ~ etofenprox. LLINs tested at concentrations up to 8,000 mg permethrin/m(2) did not protect from mosquito bites. Results on long-lasting efficacy and bioactivity of the polymer coating technique show that this new LLIN technique is a highly promising potential candidate for future malaria control strategies. Standardized machine laundering and drying according to EN ISO 6330 is highly recommended to monitor and validate wash durability and residual activity of LLINs. PMID- 22203522 TI - Characterization of microRNAs in Taenia saginata of zoonotic significance by Solexa deep sequencing and bioinformatics analysis. AB - The beef tapeworm Taenia saginata infects human beings with symptoms ranging from nausea, abdominal discomfort to digestive disturbances and intestinal blockage. In the present study, microRNA (miRNA) expressing profile in adult T. saginata was analyzed using Solexa deep sequencing and bioinformatics analysis. A total of 15.8 million reads was obtained by Solexa sequencing, and 13.3 million clean reads (1.73 million unique sequences) was obtained after removing reads smaller than 18 nt. Ten conserved miRNAs corresponding to 607,382 reads were found when matching the reads against known miRNAs of Schistosoma japonicum in miRBase database. The miR-71 had the most abundant expression in T. saginata, followed by miR-219-5p, but some other common miRNAs such as let-7, miR-40, and miR-103 were not identified in T. saginata. Nucleotide bias analysis found that the known miRNAs showed high bias and the uracil was the dominant nucleotide, particularly at the first and 11th positions which were almost at the beginning and middle of conserved miRNAs. One novel miRNA (Tsa-miR-001) corresponding to ten precursors was identified and confirmed by stem-loop RT-PCR. To our knowledge, this is the first report of miRNA profiles in T. saginata, which will contribute to better understanding of the complex biology of this zoonotic trematode. The reported data of T. saginata miRNAs should provide valuable references for miRNA studies of closed related zoonotic Taenia cestodes such as Taenia solium and Taenia asiatica. PMID- 22203523 TI - Modification of disodium cromoglycate passage across lung epithelium in vitro via incorporation into polymeric microparticles. AB - Two microparticle systems containing disodium cromoglycate (DSCG) alone or with polyvinyl alcohol (DSCG/PVA) were produced via spray drying and compared in terms of their physicochemical characteristics, aerosol performance and drug uptake across a pulmonary epithelial cell line (Calu-3), cultured under air interface conditions. The particle size distribution of DSCG and DSCG/PVA were similar, of spherical geometry, amorphous and suitable for inhalation purposes. Aerosolisation studies using a modified twin-stage impinger showed the DSCG/PVA to have greater aerosol performance than that of DSCG alone. Aerosol particles of DSCG and DSCG/PVA were deposited onto the surface of the Calu-3 air interface epithelium monolayer and the drug uptake from apical to basal directions measured over time. Drug uptake was measured across a range of doses to allow comparison of equivalent drug and powder mass deposition. Analysis of the data indicated that the percentage cumulative drug uptake was independent of the mass of powder deposited, but dependent on the formulation. Specifically, with the formulation containing DSCG, the diffusion rate was observed to change with respect to time (indicative of a concentration-dependent diffusion process), whilst DSCG/PVA showed a time-independent drug uptake (suggesting a zero-order depot release). PMID- 22203524 TI - Mean diffusivity as a potential diffusion tensor biomarker of motor rehabilitation after electrical stimulation incorporating task specific exercise in stroke: a pilot study. AB - Changes in diffusion tensor imaging (DTI) values co-occur with neurological and functional changes after stroke. However, quantitative DTI metrics have not been examined in response to participation in targeted rehabilitative interventions in chronic stroke. The primary purpose of this pilot study was to examine whether changes in DTI metrics co-occur with paretic arm movement changes among chronic stroke patients participating in a regimen of electrical stimulation targeting the paretic arm. Three subjects exhibiting stable arm hemiparesis were administered 30-minute (n = 1) or 120-minute (n = 2) therapy sessions emphasizing paretic arm use during valued, functional tasks and incorporating an electrical stimulation device. These sessions occurred every weekday for 8 weeks. A fourth subject served as a treatment control, participating in a 30-minute home exercise regimen without electrical stimulation every weekday for 8 weeks. DTI and behavioral outcome measures were acquired at baseline and after intervention. DTI data were analyzed using a region of interest (ROI) approach, with ROIs chosen based on tract involvement in sensorimotor function or as control regions. Behavioral outcome measures were the Fugl-Meyer Scale (FM) and the Action Research Arm Test (ARAT). The treatment control subject exhibited gains in pinch and grasp, as shown by a 5-point increase on the ARAT. The subject who participated in 30-minute therapy sessions exhibited no behavioral gains. Subjects participating in 120-minute therapy sessions displayed consistent impairment reductions and distal movement changes. DTI changes were largest in subjects two and three, with mean diffusivity (MD) decreases in the middle cerebellar peduncle and posterior limb of the internal capsule following treatment. No changes in fractional anisotropy (FA) were observed for sensorimotor tracts. Our preliminary results suggest that active rehabilitative therapies augmented by electrical stimulation may induce positive behavioral changes which are underscored by DTI changes indicative of increased white matter tract integrity in regions specific to sensory-motor function. PMID- 22203525 TI - Red blood cell transfusion in the neurological ICU. AB - Red blood cell transfusion (RBCT) is a common therapy used in the intensive care unit to treat anemia. However, due to deleterious side effects and questionable efficacy, the clinical benefit of RBCT in patients who are not actively bleeding is unclear. The results of randomized controlled trials suggest there is no benefit to a liberal transfusion practice in general critical care populations. Whether the results of these trials are applicable to brain injured patients is unknown, as patients with primary neurological injury were excluded. This article reviews the efficacy and complications of RBCT, as well as the relationship between RBCT and its outcome in both the general intensive care unit and neurologically critically ill populations. PMID- 22203526 TI - Nummular headache update. AB - Nummular headache is characterized by head pain exclusively felt in a rounded or elliptical area, typically 1 to 6 cm in diameter. The pain remains confined to the same symptomatic area, which does not change in shape or size with time. The symptomatic area may be localized in any part of the head but mostly in the parietal region. Rarely, the disorder may be multifocal, each symptomatic area keeping all the characteristics of nummular headache. The pain is generally mild or moderate, commonly described as oppressive or stabbing, and lasting minutes, hours, or days, with a remitting or unremitting pattern. Superimposed on the baseline pain, there may be spontaneous or triggered exacerbations. During and between symptomatic periods, the affected area may show variable combinations of hypoesthesia, dysesthesia, paresthesia, tenderness, and trophic changes. Nummular headache emerges as a primary disorder with a clear-cut clinical picture developed in a unique topography. PMID- 22203528 TI - Evidence for graft colonization with periodontal pathogens in lung transplant recipients. A pilot study. AB - Bronchiolitis obliterans syndrome (BOS) is a major cause of late graft dysfunction in lung transplant recipients. There is increasing evidence that beside alloimmunologic injury also non-alloimmunologic inflammatory conditions may raise the risk of acute and chronic rejection. The oral cavity represents a possible reservoir for pathogenic bacteria due to its close anatomical proximity. In this pilot study, the presence of pathogenic periodontal bacteria in the oral cavity as well as in the lungs of lung transplant recipients was investigated for the first time. Eight lung transplant recipients underwent broncho-alveolar lavage, transbronchial biopsies, and endobronchial biopsies. In addition to routinely performed examinations, pulmonary as well as plaque samples were assessed for Aggregatibacter actinomycetemcomitans (Aa), Tannerella forsythia (Tf), Porphyromonas gingivalis (Pg), and Treponema denticola (Td) with the aid of a hybridization technique. No or only one periodontal pathogen (solitarily Pg) was found in the gingival plaques of five of the eight patients (group A). In three patients, two or more periodontal pathogens were detetectable in the gingival samples (group B). Whereas group A also had not more than one periodontal pathogen in the lungs, group B had more than one species in the lungs. In group B, all patients suffered from BOS, whereas in group A only one patient was affected. This is the first evidence for the presence of periodontal pathogens in the lungs of lung transplant recipients. Further studies with larger cohorts are required to elucidate potential links between periodontal infection, pulmonary colonization, and rejection. PMID- 22203529 TI - The cover. Portrait of a lady, probably a member of the Cromwell family. PMID- 22203530 TI - A piece of my mind. Making the call. PMID- 22203531 TI - NIH's Undiagnosed Diseases Program reports on successes, challenges. PMID- 22203532 TI - IOM: Health IT needs better oversight. PMID- 22203533 TI - Remote interventions may facilitate weight loss. PMID- 22203527 TI - Metformin: multi-faceted protection against cancer. AB - The biguanide metformin, a widely used drug for the treatment of type 2 diabetes, may exert cancer chemopreventive effects by suppressing the transformative and hyperproliferative processes that initiate carcinogenesis. Metformin's molecular targets in cancer cells (e.g., mTOR, HER2) are similar to those currently being used for directed cancer therapy. However, metformin is nontoxic and might be extremely useful for enhancing treatment efficacy of mechanism-based and biologically targeted drugs. Here, we first revisit the epidemiological, preclinical, and clinical evidence from the last 5 years showing that metformin is a promising candidate for oncology therapeutics. Second, the anticancer effects of metformin by both direct (insulin-independent) and indirect (insulin dependent) mechanisms are discussed in terms of metformin-targeted processes and the ontogenesis of cancer stem cells (CSC), including Epithelial-to-Mesenchymal Transition (EMT) and microRNAs-regulated dedifferentiation of CSCs. Finally, we present preliminary evidence that metformin may regulate cellular senescence, an innate safeguard against cellular immortalization. There are two main lines of evidence that suggest that metformin's primary target is the immortalizing step during tumorigenesis. First, metformin activates intracellular DNA damage response checkpoints. Second, metformin attenuates the anti-senescence effects of the ATP-generating glycolytic metabotype-the Warburg effect-, which is required for self-renewal and proliferation of CSCs. If metformin therapy presents an intrinsic barrier against tumorigenesis by lowering the threshold for stress induced senescence, metformin therapeutic strategies may be pivotal for therapeutic intervention for cancer. Current and future clinical trials will elucidate whether metformin has the potential to be used in preventive and treatment settings as an adjuvant to current cancer therapeutics. PMID- 22203534 TI - Lymph node evaluation for colon cancer. PMID- 22203535 TI - Sugar-sweetened beverages in the Supplemental Nutrition Assistance Program. PMID- 22203536 TI - Consideration of multiple chronic diseases in randomized controlled trials. PMID- 22203537 TI - Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction. AB - CONTEXT: Introduction of highly sensitive troponin assays into clinical practice has substantially improved the evaluation of patients with chest pain. OBJECTIVE: To evaluate the diagnostic performance of a highly sensitive troponin I (hsTnI) assay compared with a contemporary troponin I (cTnI) assay and their serial changes in the diagnosis of acute myocardial infarction (AMI). DESIGN, SETTING, AND PATIENTS: A total of 1818 patients with suspected acute coronary syndrome were consecutively enrolled at the chest pain units of the University Heart Center Hamburg, the University Medical Center Mainz, and the Federal Armed Forces Hospital Koblenz, all in Germany, from 2007 to 2008. Twelve biomarkers including hsTnI (level of detection, 3.4 pg/mL) and cTnI (level of detection, 10 pg/mL) were measured on admission and after 3 and 6 hours. MAIN OUTCOME MEASURES: Diagnostic performance for AMI of baseline and serial changes in hsTnI and cTnI results at 3 hours after admission to the emergency department. RESULTS: Of the 1818 patients, 413 (22.7%) were diagnosed as having AMI. For discrimination of AMI, the area under the receiver operating characteristic (ROC) curve was 0.96 (95% CI, 0.95-0.97) for hsTnI on admission and 0.92 (95% CI, 0.90-0.94) for cTnI on admission. Both were superior to the other evaluated diagnostic biomarkers. The use of hsTnI at admission (with the diagnostic cutoff value at the 99th percentile of 30 pg/mL) had a sensitivity of 82.3% and a negative predictive value (for ruling out AMI) of 94.7%. The use of cTnI (with the diagnostic cutoff value at the 99th percentile of 32 pg/mL) at admission had a sensitivity of 79.4% and a negative predictive value of 94.0%. Using levels obtained at 3 hours after admission, the sensitivity was 98.2% and the negative predictive value was 99.4% for both hsTnI and cTnI assays. Combining the 99th percentile cutoff at admission with the serial change in troponin concentration within 3 hours, the positive predictive value (for ruling in AMI) for hsTnI increased from 75.1% at admission to 95.8% after 3 hours, and for cTnI increased from 80.9% at admission to 96.1% after 3 hours. CONCLUSIONS: Among patients with suspected acute coronary syndrome, hsTnI or cTnI determination 3 hours after admission may facilitate early rule-out of AMI. A serial change in hsTnI or cTnI levels from admission (using the 99th percentile diagnostic cutoff value) to 3 hours after admission may facilitate an early diagnosis of AMI. PMID- 22203539 TI - CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. AB - CONTEXT: The US Food and Drug Administration recently recommended that CYP2C19 genotyping be considered prior to prescribing clopidogrel, but the American Heart Association and American College of Cardiologists have argued evidence is insufficient to support CYP2C19 genotype testing. OBJECTIVE: To appraise evidence on the association of CYP2C19 genotype and clopidogrel response through systematic review and meta-analysis. DATA SOURCES: PubMed and EMBASE from their inception to October 2011. STUDY SELECTION: Studies that reported clopidogrel metabolism, platelet reactivity or clinically relevant outcomes (cardiovascular disease [CVD] events and bleeding), and information on CYP2C19 genotype were included. DATA EXTRACTION: We extracted information on study design, genotyping, and disease outcomes and investigated sources of bias. RESULTS: We retrieved 32 studies of 42,016 patients reporting 3545 CVD events, 579 stent thromboses, and 1413 bleeding events. Six studies were randomized trials ("effect-modification" design) and the remaining 26 reported individuals exposed to clopidogrel ("treatment-only" design). In treatment-only analysis, individuals with 1 or more CYP2C19 alleles associated with lower enzyme activity had lower levels of active clopidogrel metabolites, less platelet inhibition, lower risk of bleeding (relative risk [RR], 0.84; 95% CI, 0.75-0.94; absolute risk reduction of 5-8 events per 1000 individuals), and higher risk of CVD events (RR, 1.18; 95% CI, 1.09-1.28; absolute risk increase of 8-12 events per 1000 individuals). However, there was evidence of small-study bias (Harbord test P = .001). When analyses were restricted to studies with 200 or more events, the point estimate was attenuated (RR, 0.97; 95% CI, 0.86-1.09). In effect-modification studies, CYP2C19 genotype was not associated with modification of the effect of clopidogrel on CVD end points or bleeding (P > .05 for interaction for both). Other limitations included selective outcome reporting and potential for genotype misclassification due to problems with the * allele nomenclature for cytochrome enzymes. CONCLUSION: Although there was an association between the CYP2C19 genotype and clopidogrel responsiveness, overall there was no significant association of genotype with cardiovascular events. PMID- 22203540 TI - Grading the new US Preventive Services Task Force prostate cancer screening recommendation. PMID- 22203538 TI - Perceptions of appropriateness of care among European and Israeli intensive care unit nurses and physicians. AB - CONTEXT: Clinicians in intensive care units (ICUs) who perceive the care they provide as inappropriate experience moral distress and are at risk for burnout. This situation may jeopardize patient quality of care and increase staff turnover. OBJECTIVE: To determine the prevalence of perceived inappropriateness of care among ICU clinicians and to identify patient-related situations, personal characteristics, and work-related characteristics associated with perceived inappropriateness of care. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional evaluation on May 11, 2010, of 82 adult ICUs in 9 European countries and Israel. Participants were 1953 ICU nurses and physicians providing bedside care. MAIN OUTCOME MEASURE: Perceived inappropriateness of care, defined as a specific patient-care situation in which the clinician acts in a manner contrary to his or her personal and professional beliefs, as assessed using a questionnaire designed for the study. RESULTS: Of 1651 respondents (median response rate, 93% overall; interquartile range, 82%-100% [medians 93% among nurses and 100% among physicians]), perceived inappropriateness of care in at least 1 patient was reported by 439 clinicians overall (27%; 95% CI, 24%-29%), 300 of 1218 were nurses (25%), 132 of 407 were physicians (32%), and 26 had missing answers describing job title. Of these 439 individuals, 397 reported 445 situations associated with perceived inappropriateness of care. The most common reports were perceived disproportionate care (290 situations [65%; 95% CI, 58%-73%], of which "too much care" was reported in 89% of situations, followed by "other patients would benefit more" (168 situations [38%; 95% CI, 32%-43%]). Independently associated with perceived inappropriateness of care rates both among nurses and physicians were symptom control decisions directed by physicians only (odds ratio [OR], 1.73; 95% CI, 1.17-2.56; P = .006); involvement of nurses in end-of-life decision making (OR, 0.76; 95% CI, 0.60-0.96; P = .02); good collaboration between nurses and physicians (OR, 0.72; 95% CI, 0.56-0.92; P = .009); and freedom to decide how to perform work-related tasks (OR, 0.72; 95% CI, 0.59-0.89; P = .002); while a high perceived workload was significantly associated among nurses only (OR, 1.49; 95% CI, 1.07-2.06; P = .02). Perceived inappropriateness of care was independently associated with higher intent to leave a job (OR, 1.65; 95% CI, 1.04-2.63; P = .03). In the subset of 69 ICUs for which patient data could be linked, clinicians reported received inappropriateness of care in 207 patients, representing 23% (95% CI, 20%-27%) of 883 ICU beds. CONCLUSION: Among a group of European and Israeli ICU clinicians, perceptions of inappropriate care were frequently reported and were inversely associated with factors indicating good teamwork. PMID- 22203541 TI - Prostate cancer screening--time to abandon one-size-fits-all approach? PMID- 22203542 TI - Missing the mark on prostate-specific antigen screening. PMID- 22203543 TI - Prostate cancer screening--the evidence, the recommendations, and the clinical implications. PMID- 22203544 TI - Perceived inappropriateness of care in the ICU: what to make of the clinician's perspective? PMID- 22203545 TI - Pharmacogenomics and clopidogrel: irrational exuberance? PMID- 22203546 TI - JAMA patient page. Cushing syndrome and Cushing disease. PMID- 22203547 TI - Safety and efficacy of lacosamide in the intensive care unit. AB - BACKGROUND: Seizures are common in critically ill patients and can impact morbidity and mortality. Traditional anti-epileptic drugs (AEDs) in this setting are not always effective and are associated with adverse events and drug interactions. Lacosamide (LCM) is a new AED which is available in parental form although few studies have evaluated the safety and efficacy of LCM in critically ill patients. METHODS: Critically ill patients at Emory University Hospital who received LCM from April 1, 2009 to February 1, 2010 were retrospectively reviewed. Primary outcome measure was incidence and time to seizure cessation. Adverse effects were also recorded. RESULTS: LCM was administered in 24 patients including 13 episodes of refractory status epilepticus (RSE) occurring in 10 patients and for treatment of isolated seizures or following resolution of RSE in an additional 14 patients. Seizure cessation was achieved in 5/13 (38%) episodes of RSE (mean 11.2 h) while there was at least a 50% decrease in seizure frequency in 7/13 (54%). 11/14 patients (76%) who received LCM for treatment of isolated seizures or prevention of seizure recurrence remained seizure free. Three patients experienced a decline in systolic blood pressure (> 20 mmHg) while one patient experienced unexplained fever and one patient had elevation of liver function tests. CONCLUSIONS: This preliminary data suggests that LCM may be a safe and effective alternative for treatment of seizures in critically ill patients. Further prospective, randomized controlled trials are needed to confirm these findings and further explore the incidence of adverse effects. PMID- 22203548 TI - Cupriavidus and Burkholderia species associated with agricultural plants that grow in alkaline soils. AB - The presence of Burkholderia, Cupriavidus, and Ralstonia species in northeastern Mexico was investigated. An analysis of the root surrounding soil from different agricultural plants led to the isolation of Burkholderia and Cupriavidus species but no Ralstonia strains. Most Cupriavidus species were unknown and grouped into two clusters according to ARDRA profiles. The 16S rRNA sequence analysis showed that the Cupriavidus isolates were highly related among them and with different Cupriavidus species with validated names. However, SDS-PAGE profiles were distinct among the different ARDRA profiles and to other Cupriavidus species examined, suggesting new species in the genus. This shows that Cupriavidus is more widely associated with plants than previously appreciated. The BCC isolate was 99% similar to B. cenocepacia by recA sequence analysis. Additionally, most Cupriavidus strains from the two largest groups grew on media containing up to 0.1 mg/ml of copper, 10.0 mg/ml arsenic and 1.0 mg/ml zinc. Burkholderia strains grew on media containing up to 10.0 mg/ml zinc, 5.0 mg/ml arsenic and 0.1 mg/ml copper. PMID- 22203550 TI - The use of Pseudomonas fluorescens P13 to control sclerotinia stem rot (Sclerotinia sclerotiorum) of oilseed rape. AB - Sclerotinia stem rot (SSR) caused by the fungus Sclerotinia sclerotiorum has been an increasing threat to oilseed rape (Brassica napus L.) cultivation. Efficient and environment-friendly treatments are much needed. Here we focus on microbial control. The Pseudomonas fluorescens P13 that was isolated from oilseed rape cultivation soil, proved to be a useful biocontrol strain for application. Morphology, physiological and biochemical tests and 16S rDNA analysis demonstrated that it was P. fluorescens P13 and that it had a broad antagonistic spectrum, significantly lessening the mycelial growth of S. sclerotiorum by 84.4% and suppressing sclerotial formation by 95-100%. Scanning electron microscopy studies attested that P13 deformed S. sclerotiorum mycelia when they were cultured together. P13 did not produce chitinase but did produce hydrogen cyanide (HCN) which was likely one of the antagonistic mechanisms. The density of P13 remained at a high level (>=10(6) CFU/ml) during 5 weeks in the rhizosphere soil and roots. P13 reduced SSR severity at least by 59% in field studies and also promoted seedling growth (p<0.05) at the seedling stage. From these data, our work provided evidence that P13 could be a good alternative biological resource for biocontrol of S. sclerotiorum. PMID- 22203549 TI - Lactobacillus salivarius REN counteracted unfavorable 4-nitroquinoline-1-oxide induced changes in colonic microflora of rats. AB - Probiotics and carcinogens both have a significant effect on the microfloral composition of the human intestine. The objective of this study was to investigate the impact of an important carcinogen, 4-Nitroquinoline-1-Oxide on colonic microflora and the efficacy of the probiotic Lactobacillus salivarius REN as an agent of counteracting these effects. Using denaturing gradient gel electrophoresis (DGGE) combined with redundancy analysis, we demonstrated that both 4-Nitroquinoline-1-Oxide and L. salivarius REN significantly altered the bacterial communities of rat colons. A total of 27 bacterial strains were identified as being affected by treatment with 4-Nitroquinoline-1-Oxide or L. salivarius REN using a t-value biplot combined with band sequencing. 4 Nitroquinoline-1-Oxide treatment increased the abundance of two potential pathogens (one Helicobacter strain and one Desulfovibrio strain), as well as reducing the abundance of two potentially beneficial strains (one Ruminococcaceae strain and one Rumen bacteria). The Helicobacter strain was initally detected in carcinogen-treated rat intestinal microflora, but L. salivarius REN treatment effectively suppressed the growth of the Helicobacter strain. These results suggested that L. salivarius REN may be a potential probiotic, efficiently acting against the initial infection with, and the growth of pathogenic bacteria. PMID- 22203551 TI - Complete genome of Leptospirillum ferriphilum ML-04 provides insight into its physiology and environmental adaptation. AB - Leptospirillum ferriphilum has been identified as the dominant, moderately thermophilic, bioleaching microorganism in bioleaching processes. It is an acidic and chemolithoautrophic bacterium that gains electrons from ferrous iron oxidation for energy production and cell growth. Genetic information about this microorganism has been limited until now, which has hindered its further exploration. In this study, the complete genome of L. ferripilum ML-04 is sequenced and annotated. The bacterium has a single circular chromosome of 2,406,157 bp containing 2,471 coding sequences (CDS), 2 rRNA operons, 48 tRNA genes, a large number of mobile genetic elements and 2 genomic islands. In silico analysis shows L. ferriphilum ML-04 fixes carbon through a reductive citric acid (rTCA) cycle, and obtains nitrogen through ammonium assimilation. The genes related to "cell envelope biogenesis, outer membrane" (6.9%) and "DNA replication, recombination and repair" (5.6%) are abundant, and a large number of genes related to heavy metal detoxification, oxidative and acidic stress defense, and signal transduction pathways were detected. The genomic plasticity, plentiful cell envelope components, inorganic element metabolic abilities and stress response mechanisms found the base for this organism's survival in the bioleaching niche. PMID- 22203552 TI - Characterization and screening of plant probiotic traits of bacteria isolated from rice seeds cultivated in Argentina. AB - Many seeds carry endophytes, which ensure good chances of seedling colonization. In this work, we have studied the seed-borne bacterial flora of rice varieties cultivated in the northeast of Argentina. Surface-sterilized husked seeds of the rice cultivars CT6919, El Paso 144, CAMBA, and IRGA 417 contained an average of 5*10(6) CFU/g of mesophilic and copiotrophic bacteria. Microbiological, physiological, and molecular characterization of a set of 39 fast-growing isolates from the CT6919 seeds revealed an important diversity of seed-borne mesophiles and potential plant probiotic activities, including diazotrophy and antagonism of fungal pathogens. In fact, the seed-borne bacterial flora protected the rice seedlings against Curvularia sp. infection. The root colonization pattern of 2 Pantoea isolates from the seeds was studied by fluorescence microscopy of the inoculated axenic rice seedlings. Both isolates strongly colonized the site of emergence of the lateral roots and lenticels, which may represent the entry sites for endophytic spreading. These findings suggest that rice plants allow grain colonization by bacterial species that may act as natural biofertilizers and bioprotectives early from seed germination. PMID- 22203553 TI - A survey of the geographic distribution of Ophiocordyceps sinensis. AB - Ophiocordyceps sinensis is one of the best known fungi in Traditional Chinese Medicine. Many efforts have been devoted to locating the production areas of this species resulting in various reports; however, its geographic distribution remains incompletely understood. Distribution of O. sinensis at the county level is clarified in this work based on both a literature search and fieldwork. More than 3600 publications related to O. sinensis were investigated, including scientific papers, books, and online information. Herbarium specimens of O. sinensis and field collections made by this research group during the years 2000 2010 were examined to verify the distribution sites. A total of 203 localities for O. sinensis have been found, of which 106 are considered as confirmed distribution sites, 65 as possible distribution sites, 29 as excluded distribution sites and three as suspicious distribution sites. The results show that O. sinensis is confined to the Tibetan Plateau and its surrounding regions, including Tibet, Gansu, Qinghai, Sichuan, and Yunnan provinces in China and in certain areas of the southern flank of the Himalayas, in the countries of Bhutan, India and Nepal, with 3,000 m as the lowest altitude for the distribution. The fungus is distributed from the southernmost site in Yulong Naxi Autonomous County in northwestern Yunnan Province to the northernmost site in the Qilian Mountains in Qilian County, Qinghai Province, and from the east edge of the Tibetan Plateau in Wudu County, Gansu Province to the westernmost site in Uttarakhand, India. The clarification of the geographic distribution of O. sinensis will lay the foundation for conservation and sustainable use of the species. PMID- 22203554 TI - Assessment of resistomycin, as an anticancer compound isolated and characterized from Streptomyces aurantiacus AAA5. AB - A new actinomycete strain, isolated from humus soils in the Western Ghats, was found to be an efficient pigment producer. The strain, designated AAA5, was identified as a putative Streptomyces aurantiacus strain based on cultural properties, morphology, carbon source utilization, and analysis of the 16S rRNA gene. The strain produced a reddish-brown pigmented compound during the secondary metabolites phase. A yellow compound was derived from the extracted pigment and was identified as the quinone-related antibiotic resistomycin based on ultraviolet-visible spectrophotometry, fourier transform infrared spectroscopy, liquid chromatography and mass spectroscopy, and nuclear magnetic resonance analyses. The AAA5 strain was found to produce large quantities of resistomycin (52.5 mg/L). It showed potent cytotoxic activity against cell lines viz. HepG2 (hepatic carcinoma) and HeLa (cervical carcinoma) in vitro, with growth inhibition (GI(50)) of 0.006 and 0.005 MUg/ml, respectively. The strain also exhibited broad antimicrobial activities against both Gram-positive and Gram negative bacteria. Therefore, AAA5 may have great potential as an industrial resistomycin-producing strain. PMID- 22203555 TI - Comparative genomic analysis of bacteriophage EP23 infecting Shigella sonnei and Escherichia coli. AB - Bacteriophage EP23 that infects Escherichia coli and Shigella sonnei was isolated and characterized. The bacteriophage morphology was similar to members of the family Siphoviridae. The 44,077 bp genome was fully sequenced using 454 pyrosequencing. Comparative genomic and phylogenetic analyses showed that EP23 was most closely related to phage SO-1, which infects Sodalis glossinidius and phage SSL-2009a, which infects engineered E. coli. Genomic comparison indicated that EP23 and SO-1 were very similar with each other in terms of gene order and amino acid similarity, even though their hosts were separated in the level of genus. EP23 and SSL-2009a displayed high amino acid similarity between their genes, but there was evidence of several recombination events in SSL-2009a. The results of the comparative genomic analyses further the understanding of the evolution and relationship between EP23 and its bacteriophage relatives. PMID- 22203556 TI - Identification, origin, and evolution of leaf nodulating symbionts of Sericanthe (Rubiaceae). AB - Bacterial leaf symbiosis is an intimate association between bacteria and plants in which endosymbionts are housed within leaf nodules. This phenomenon has been reported in three genera of Rubiaceae (Pavetta, Psychotria, and Sericanthe), but the bacterial partner has only been identified in Psychotria and Pavetta. Here we report the identification of symbiotic bacteria in two leaf nodulating Sericanthe species. Using 16S rRNA data and common housekeeping genetic markers (recA and gyrB) we studied the phylogenetic relationships of bacterial endosymbionts in Rubiaceae. Endosymbionts of leaf nodulating Rubiaceae were found to be closely related and were placed as a monophyletic group within the genus Burkholderia (beta-Proteobacteria). The phylogenetic analyses revealed a pattern of strict host specificity and placed the two investigated endosymbionts at two distinct positions in the topology of the tree, suggesting at least two different evolutionary origins. The degree of sequence divergence between the Sericanthe endosymbionts and their relatives was large enough to propose the Sericanthe endosymbionts as new species ('Candidatus Burkholderia andongensis' and 'Candidatus Burkholderia petitii'). In a second part of this study, the pylogenetic relationships among nodulating and non-nodulating Sericanthe species were investigated using sequence data from six chloroplast regions (rps16, trnG, trnL-trnF, petD, petA-psbJ, and atpI-atpH). Overall, genetic variation among the plastid markers was insufficient to enable phylogenetic estimation. However, our results could not rule out the possibility that bacterial leaf symbiosis originated once in a common ancestor of the Sericanthe species. PMID- 22203557 TI - Isolation and identification of lipopeptide antibiotics from Paenibacillus elgii B69 with inhibitory activity against methicillin-resistant Staphylococcus aureus. AB - Two lipopeptide antibiotics, pelgipeptins C and D, were isolated from Paenibacillus elgii B69 strain. The molecular masses of the two compounds were both determined to be 1,086 Da. Mass-spectrometry, amino acid analysis and NMR spectroscopy indicated that pelgipeptin C was the same compound as BMY-28160, while pelgipeptin D was identified as a new antibiotic of the polypeptin family. These two peptides were active against all the tested microorganisms, including antibiotic-resistant pathogenic bacterial strains such as methicillin-resistant Staphylococcus aureus (MRSA). Time-kill assays demonstrated that pelgipeptin D exhibited rapid and effective bactericidal action against MRSA at 4*MIC. Based on acute toxicity test, the intraperitoneal LD50 value of pelgipeptin D was slightly higher than that of the structurally related antimicrobial agent polymyxin B. Pelgipeptins are highly potent antibacterial and antifungal agents, particularly against MRSA, and warrant further investigation as possible therapeutic agents for bacteria infections resistant to currently available antibiotics. PMID- 22203558 TI - Expression of the Lactobacillus plantarum malE gene is regulated by CcpA and a MalR-like protein. AB - Lactobacillus plantarum is commonly used in the food industry as a starter in various fermentations, especially in vegetable fermentations, in which starch is a common substrate. This polysaccharide, which is obtained from potatoes or corn and is hydrolysed mainly to maltose and glucose by acids or enzymes, is commercially used for the production of lactate by lactic acid fermentation. In this study, we describe the regulation of malE gene expression in L. plantarum. This gene, located in a 7-gene cluster, probably organized in an operon, encodes a putative maltose/maltodextrin-binding protein. We studied the expression of malE in L. plantarum LM3 (wild type) and in LM3-2 (ccpA1), which carries a null mutation in the ccpA gene, encoding the catabolite control protein A (CcpA). In the presence of glucose, expression of the MalE protein was higher in the mutant strain as compared to that in the wild-type strain. Transcription of the malE gene was induced by maltose and regulated by a CcpA-mediated carbon catabolite repression. Further, we isolated strains carrying mutations in 2 genes, lp_0172 and lp_0173, whose deduced amino acid sequences share significant identity with MalR, a regulator of the maltose operon in several gram-positive bacteria. A double mutant exhibited glucose-insensitive malE transcription, while absence of the functional Lp_0172 open reading frame had no effect on malE expression. PMID- 22203559 TI - Responses in the expression of extracellular proteins in methicillin-resistant Staphylococcus aureus treated with rhodomyrtone. AB - Rhodomyrtone from a medicinal plant species, Rhodomyrtus tomentosa, is a challenged effective agent against Gram-positive bacteria, especially methicillin resistant Staphylococcus aureus (MRSA). The present study was undertaken to provide insight into MRSA extracellular protein expression following rhodomyrtone treatment. Secreteomic approach was performed on a representative clinical MRSA isolate exposing to subinhibitory concentration rhodomyrtone (0.174 MUg/ml). The identified extracellular proteins of a response of MRSA to rhodomyrtone treated condition were both suppressed and overexpressed. Staphylococcal antigenic proteins, immunodominant antigen A (IsaA) and staphylococcal secretory antigen (SsaA) involved in cell wall hydrolysis were downregulated after the treatment. The results suggested that rhodomyrtone may interfere with WalK/WalR (YycG/YycF) system. Other enzymes such as lipase precursor and another lipase, glycerophosphoryl diester phosphodiesterase, were absent. In contrast, cytoplasmic proteins such as SpoVG and glycerol phosphate lipoteichoic acid synthase, and ribosomal proteins were found in the treated sample. Appearance of several cytoplasmic proteins in the treated culture supernatant revealed that the bacterial cell wall biosynthesis was disturbed. This finding provides a proteomic mapping of extracellular proteins after rhodomytone treatment. Extensive investigation is required for this natural compound as it has a great potency as an alternative anti-MRSA drug. PMID- 22203560 TI - Dynamical analysis of yeast protein interaction network during the sake brewing process. AB - Proteins interact with each other for performing essential functions of an organism. They change partners to get involved in various processes at different times or locations. Studying variations of protein interactions within a specific process would help better understand the dynamic features of the protein interactions and their functions. We studied the protein interaction network of Saccharomyces cerevisiae (yeast) during the brewing of Japanese sake. In this process, yeast cells are exposed to several stresses. Analysis of protein interaction networks of yeast during this process helps to understand how protein interactions of yeast change during the sake brewing process. We used gene expression profiles of yeast cells for this purpose. Results of our experiments revealed some characteristics and behaviors of yeast hubs and non-hubs and their dynamical changes during the brewing process. We found that just a small portion of the proteins (12.8 to 21.6%) is responsible for the functional changes of the proteins in the sake brewing process. The changes in the number of edges and hubs of the yeast protein interaction networks increase in the first stages of the process and it then decreases at the final stages. PMID- 22203561 TI - Molecular characterization of chloranilic acid degradation in Pseudomonas putida TQ07. AB - Pentachlorophenol is the most toxic and recalcitrant chlorophenol because both aspects are directly proportional to the halogenation degree. Biological and abiotic pentachlorophenol degradation generates p-chloranil, which in neutral to lightly alkaline environmental conditions is hydrolyzed to chloranilic acid that present a violet-reddish coloration in aqueous solution. Several genes of the degradation pathway, cadR-cadCDX, as well as other uncharacterized genes (ORF5 and 6), were isolated from a chloranilic acid degrading bacterium, Pseudomonas putida strain TQ07. The disruption by random mutagenesis of the cadR and cadC genes in TQ07 resulted in a growth deficiency in the presence of chloranilic acid, indicating that these genes are essential for TQ07 growth with chloranilic acid as the sole carbon source. Complementation assays demonstrated that a transposon insertion in mutant CAD82 (cadC) had a polar effect on other genes contained in cosmid pLG3562. These results suggest that at least one of these genes, cadD and cadX, also takes part in chloranilic acid degradation. Based on molecular modeling and function prediction, we strongly suggest that CadC is a pyrone dicarboxylic acid hydrolase and CadD is an aldolase enzyme like dihydrodipicolinate synthase. The results of this study allowed us to propose a novel pathway that offers hypotheses on chloranilic acid degradation (an abiotic by-product of pentachlorophenol) by means of a very clear phenotype that is narrowly related to the capability of Pseudomonas putida strain TQ07 to degrade this benzoquinone. PMID- 22203562 TI - Shift of phylogenic position in megalocytiviruses based on three different genes. AB - Major capsid protein (MCP), the adenosine triphosphatase (ATPase), and the PstI fragment genes from five Japanese and three Korean megalocytivirus isolates were sequenced and phylogenetically analyzed with known megalocytiviruses. Phylogenetic trees formed three major clusters (M1, M2, and M3 or P1, P2, and P3), and genogroup I was divided into two minor clusters (M1a/M1b and P1a/P1b) using three target genes. Sequence identity was >97% within each cluster, except cluster II of the PstI fragment (>94% of sequence identity). Interestingly, different genotyping patterns were observed for the same isolates depending on the gene analyzed. The JPN-YelTail and JPN-BfTuna isolates located in the minor M1a cluster, based on MCP and ATPase nucleotide sequences, appeared in the minor P1b cluster based on the PstI fragment, suggesting a shift of phylogenic position in megalocytiviruses. Further study will be conducted to compare the viral antigenicity and pathogenicity between the two isolates showing the shift of phylogenic position and the other isolates clustered within genogroup I. PMID- 22203563 TI - Frequency of antibiotic resistance in Helicobacter pylori strains isolated from the northern population of Iran. AB - The purpose of this study was to evaluate the primary resistance rates of recent clinical Helicobacter pylori isolates to the most commonly used antibiotics in Iran. Two hundreds and ten patients presenting with gastric maladies between January and July of 2009 were enrolled in this study. Endoscopy was performed, and biopsy specimens were collected from each patient for subsequent bacterial culture of H. pylori. Single colony isolates from each patient were then used for antimicrobial susceptibility testing. The disk diffusion method was used to determine susceptibility patterns. One hundred and ninety-seven of the patients were H. pylori positive (93.8%). The rates of resistance to tetracycline, amoxicillin, ciprofloxacin, metronidazole, clarithromycin, and furizoladone were 37.1%, 23.9%, 34.5%, 65.5%, 45.2%, and 61.4%, respectively. A significant association between amoxicillin resistance and disease state (P<0.05) was identified. Furthermore, some double, triple, quadruple, and quintuple combinations of antibiotic resistance were found to be associated with disease state. This study evaluated the prevalence of H. pylori resistance to the most commonly prescribed antibiotics used in Iran and showed that resistance rates were generally higher than previously reported. This data adds to the growing body of evidence that suggests there is increasing antibiotic resistance among H. pylori isolates, which likely is responsible for the decreasing efficacy of anti H. pylori therapy at the local and global level. Hence, there is a need for continued monitoring of resistance patterns, especially at the local level, and for incorporation of that information into treatment regimens for H. pylori infections. PMID- 22203564 TI - Antibacterial efficacy of lytic Pseudomonas bacteriophage in normal and neutropenic mice models. AB - Recently, lytic bacteriophages (phages) have been focused on treating bacterial infectious diseases. We investigated the protective efficacy of a novel Pseudomonas aeruginosa phage, PA1O, in normal and neutropenic mice. A lethal dose of P. aeruginosa PAO1 was administered via the intraperitoneal route and a single dose of PA1O with different multiplicities of infection (MOI) was treated into infected mice. Immunocompetent mice infected with P. aeruginosa PAO1 were successfully protected by PA1O of 1 MOI, 10 MOI or 100 MOI with 80% to 100% survival rate. No viable bacteria were found in organ samples after 48 h of the phage treatment. Phage clearing patterns were different in the presence or absence of host bacteria but PA1O disappeared from all organs after 72 h except spleen in the presence of host bacteria. On the contrary, PA1O treatment could not protect neutropenic mice infected with P. aeruginosa PAO1 even though could extend their lives for a short time. In in vitro phage-neutrophil bactericidal test, a stronger bactericidal effect was observed in phage-neutrophil co treatment than in phage single treatment without neutrophils, suggesting phage neutrophil co-work is essential for the efficient killing of bacteria in the mouse model. In conclusion, PA1O can be possibly utilized in future phage therapy endeavors since it exhibited strong protective effects against virulent P. aeruginosa infection. PMID- 22203565 TI - Functional definition of LuxS, an autoinducer-2 (AI-2) synthase and its role in full virulence of Streptococcus suis serotype 2. AB - Quorum sensing is a widespread chemical communication in response to fluctuation of bacterial population density, and has been implicated into bacterial biofilm formation and regulation of expression of virulence factors. The luxS gene product, S-ribosylhomocysteinase, catalizes the last committed step in biosynthetic pathway of autoinducer 2 (AI-2), a signaling molecule for inter species quorum sensing. We found a luxS homologue in 05ZYH33, an epidemic strain of Streptococcus suis serotype 2 (SS2) in China. A luxS null mutant (DeltaluxS) of 05ZYH33 strain was obtained using an approach of homologous recombination. LuxS was determined to be required for AI-2 production in 05ZYH33 strain of S. suis 2. Inactivation of luxS gene led to a wide range of phenotypic changes including thinner capsular walls, increased tolerance to H(2)O(2), reduced adherence capacity to epithelial cells, etc. In particular, loss of LuxS impaired dramatically its full virulence of SS2 in experimental model of piglets, and functional complementation restored it nearly to the level of parent strain. Genome-wide transcriptome analyses suggested that some known virulence factors such as CPS are down-regulated in the DeltaluxS mutant, which might in part explain virulence attenuation by luxS deletion. Similarly, 29 of 71 genes with different expression level were proposed to be targets candidate regulated by LuxS/AI-2-dependent quorum sensing. PMID- 22203566 TI - Functional analysis of a Hansenula polymorpha MNN2-2 homologue encoding a putative UDP-N-acetylglucosamine transporter localized in the endoplasmic reticulum. AB - The Kluyveromyces lactis UDP-GlcNAc transporter (KlMnn2-2p) is responsible for the biosynthesis of N-glycans containing N-acetylglucosamine. A putative gene of Hansenula polymorpha encoding a KlMnn2-2p homologue, HpMNN2-2, was identified and investigated for its function. The deletion mutant strain of HpMNN2-2 (Hpmnn2 2Delta) showed increased sensitivity to geneticin, hygromycin B, and tunicamycin. However, the Hpmnn2-2Delta strain exhibited increased resistance to Calcofluor white, an inhibitor of chitin biosynthesis, along with a reduced chitin content. The localization of HpMnn2-2p at the endoplasmic reticulum-enriched membrane, different from the Golgi localization of a K. lactis homologue, further supports the involvement of HpMnn2-2p in cell wall chitin biosynthesis. PMID- 22203567 TI - Detection of a unique fibrinolytic enzyme in Aeromonas sp. JH1. AB - A fibrinolytic enzyme was found in a Gram-negative bacterium, Aeromonas sp. JH1. SDS-PAGE and fibrinzymography showed that it was a 36 kDa, monomeric protein. Of note, the enzyme was highly specific for fibrinogen molecules and the hydrolysis rate of fibrinogen subunits was highest for alpha, beta, and gamma chains in that order. The first 15 amino acids of N-terminal sequence were X-D-A-T-G-P-G-G-N-V-X T-G-K-Y, which was distinguishable from other fibrinolytic enzymes. The optimum pH and temperature of the enzyme were approximately 8.0 and 40 degrees C, respectively. Therefore, these results provide a fibrinolytic enzyme with potent thrombolytic activity from the Aeromonas genus. PMID- 22203568 TI - Gramella jeungdoensis sp. nov., isolated from a solar saltern in Korea. AB - A non-motile, Gram-stain-negative, yellow pigmented, rod-shaped bacterium, strain HMD3159(T), was isolated from a solar saltern in Korea. The major fatty acids were iso-C(15:0) (26.3%), iso-C(17:0) 3OH (12.1%), iso-C(16:0) (12.0%), summed feature 3 (comprising C(16:1) omega7c and/or C(16:1) omega6c; 11.0%) and summed feature 9 (iso-C17:1 omega9c and/or 10-methyl C(16:0); 10.0%). The major respiratory quinone was MK-6. The DNA G+C content was 40.9 mol%. The phylogenetic tree based on 16S rRNA gene sequences showed that strain HMD3159(T) formed a lineage within the genus Gramella and closely related to Gramella gaetbulicola (95.5% sequence similarity), Gramella portivictoriae (94.9%), Gramella echinicola (94.6%), and Gramella marina (93.6%). On the basis of the evidence presented in this study, strain HMD3159(T) represents a novel species of the genus Gramella, for which the name Gramella jeungdoensis sp. nov., is proposed. The type strain is HMD3159(T) (=KCTC 32123(T) =CECT 7683(T)). PMID- 22203569 TI - Bacillus manliponensis sp. nov., a new member of the Bacillus cereus group isolated from foreshore tidal flat sediment. AB - A Gram-positive, endospore-forming, new Bacillus species, strain BL4-6(T), was isolated from tidal flat sediment of the Yellow Sea. Strain BL4-6(T) is a straight rod, with motility by peritrichate flagella. The cell wall contains meso diaminopimelic acid, and the major respiratory quinone is menaquinone-7. The major fatty acids are iso-C(15:0) and summed feature 3 (containing C(16:1) omega7c/iso-C(15:0) 2OH, and/or iso-C(15:0) 2OH/C(16:1) omega7c). Cells are catalase-positive and oxidase-negative. The G+C content of the genomic DNA is 38.0 mol%. Based on a comparative 16S rRNA gene sequence analysis, the isolate belongs to the genus Bacillus, forms a clade with the Bacillus cereus group, and is closely related to Bacillus mycoides (98.5%), Bacillus cereus (98.5%), Bacillus anthracis (98.4%), Bacillus thuringiensis (98.4%), Bacillus weihenstephanensis (98.1%), and Bacillus pseudomycoides (97.5%). The isolate showed less than 85% similarity of the gyrA gene sequence and below 95% similarity of the rpoB gene sequence to the members of this group. DNA-DNA relatedness between strain BL4-6(T) and B. cereus group was found to be in a range of 22.8-42.3%, and thus BL4-6(T) represents a unique species. On the basis of these studies, strain BL4-6(T) (=KCTC 13319(T) =JCM 15802(T)) is proposed to represent the type strain of a novel species, Bacillus manliponensis sp. nov. PMID- 22203570 TI - Cohnella soli sp. nov. and Cohnella suwonensis sp. nov. Isolated from soil samples in Korea. AB - Two bacterial isolates from soil samples taken in Korea, strains YM2-7(T) and WD2 19(T), were characterized using a polyphasic approach. The cells were strictly aerobic, Gram-positive, motile with peritrichous flagella, and rod-shaped. Both strains formed ellipsoidal bulging positioned subterminal spores. Phylogenetic analysis of their 16S rRNA gene sequences revealed a clear affiliation with the Firmicutes. The 16S rRNA gene sequence similarity between YM2-7(T) and WD2-19(T) was 96.5%. Strains YM2-7(T) and WD2-19(T) showed 16S rRNA gene sequence similarities of 93.0-96.5% to type strains of recognized Cohnella species. The G+C contents of the DNA of strains YM2-7(T) and WD2-19(T) were 52.2 and 55.6 mol%, respectively. The major fatty acids of strains YM2-7(T) and WD2-19(T) were anteiso-C15:0 (44.4%), C16:0 (19.2%), and iso-C16:0 (16.8%) and anteiso-C15:0 (46.5%), iso-C16:0 (21.8%), and C16:0 (11.2%), respectively. Both strains contained menaquinone with seven isoprene units (MK-7) as the predominant quinone. Both strains had diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and lysophosphatidylglycerol as the major polar lipids. Comparative analysis of phenotypic and phylogenetic traits indicated that strains YM2-7(T) and WD2-19(T) represented two novel species of the genus Cohnella. The names Cohnella soli sp. nov. (type strain YM2-7(T) =KACC 13346(T) =NBRC 106486(T)), and Cohnella suwonensis sp. nov. (type strain WD2-19T =KACC 13347(T) =NBRC 106485(T)) are proposed for these organisms. PMID- 22203571 TI - Mitochondrial phylogeny reveals intraspecific variation in Peronospora effusa, the spinach downy mildew pathogen. AB - Since about two hundred years, downy mildew caused by Peronospora effusa is probably the most economically important disease of spinach (Spinacia oleracea). However, there is no information on the global phylogeographic structure of the pathogen and thus it is unclear whether a single genotype occurs worldwide or whether some local genetic variation exists. To investigate the genetic variability of this pathogen, a sequence analysis of two partial mitochondrial DNA genes, cox2 and nad1, was carried out. Thirty-three specimens of Peronospora effusa from four continents were analyzed, including samples from Australia, China, Japan, Korea, Mexico, Russia, Sweden, and the USA. Despite the potential anthropogenic admixture of genotypes, a phylogeographic pattern was observed, which corresponds to two major groups, an Asian/Oceanian clade and another group, which includes American/European specimens. Notably, two of six Japanese specimens investigated did not belong to the Asian/Oceanian clade, but were identical to three of the specimens from the USA, suggestive of a recent introduction from the USA to Japan. As similar introduction events may be occurring as a result of the globalised trade with plant and seed material, a better knowledge of the phylogeographic distribution of pathogens is highly warranted for food security purposes. PMID- 22203572 TI - Leucobacter kyeonggiensis sp. nov., a new species isolated from dye waste water. AB - A Gram-positive, aerobic, non-motile bacterium designated F3-P9(T), was isolated from dye waste water in Korea and was characterized using a polyphasic taxonomic approach. Comparative 16S rRNA gene sequence analysis showed that strain F3-P9(T) belongs to genus Leucobacter. The 16S rRNA gene sequence similarities among strain F3-P9(T) and validated representatives of the genus Leucobacter ranged from 95.9-97.4%. Strain F3-P9(T) exhibited DNA-DNA relatedness values below 48% with respect to Leucobacter species. The G+C content of the genomic DNA was 67.5 mol%. F3-P9(T) contained MK-11 as the major respiratory quinone. The major fatty acids were anteiso-C(15:0) (48.5%), anteiso-C(17:0) (22.7%), and iso-C(16:0) (14.5%). The peptidoglycan was composed of L-2,4-diaminbutyric acid, alanine, glycine, and glutamic acid. The polar lipid profile showed a major amount of diphosphatidylglycerol (DPG), a moderate amount of phosphatidylglycerol (PG), and two unknown glycolipids. On the basis of its phenotypic and genotypic properties and its phylogenetic distinctiveness, strain F3-P9(T) (KEMC 211-128(T) =KACC 16572(T) =JCM 17539(T)) should be classified in the genus Leucobacter as the type strain of a novel species, for which the name Leucobacter kyeonggiensis sp. nov. is proposed. PMID- 22203573 TI - IL-10 suppresses bactericidal response of macrophages against Salmonella Typhimurium. AB - We report, herein, an attempt to determine whether an IL-10-induced immunological state affects the response of macrophages against Salmonella Typhimurium (ST). Pretreatment with mrIL-10 induced the intracellular invasion of ST into macrophages in a dose-dependent manner. It also activated AKT phosphorylation, cyclin D1, Bcl-X(L), and COX-2 upon ST infection, which may correlate with Salmonella's survival within the macrophages. However, I-kappaB phosphorylation was shown to be inhibited, along with the expression of TNF-alpha and MIP-2alpha mRNA. Therefore, IL-10 not only suppresses the bactericidal response of macrophages against ST, but also ultimately causes infected macrophages to function as hosts for ST replication. PMID- 22203574 TI - Isolation and characterization of self-fertile suppressors from the sterile nsdD deletion mutant of Aspergillus nidulans. AB - To identify downstream and/or interactive factors of the nsdD gene, which encodes a positive regulator of sexual development of Aspergillus nidulans, suppressor mutants displaying a self-fertile phenotype were isolated from a sterile nsdD deletion mutant. At least five different loci (sndA-E) were identified and genetically analyzed. In the nsdD (+) background, most of the suppressors showed a marked increment of sexual development, even under the stress conditions that normally inhibited sexual development. The common phenotype of the suppressor mutants suggested the involvement of the snd genes in the negative regulation of sexual development in response to the environmental factors. PMID- 22203575 TI - Molecular characterization of two strains of porcine group C rotavirus. AB - Group C rotaviruses are an important cause of acute gastroenteritis in humans and animals. Fecal samples were collected from a porcine herd in July, 2009. Group C rotavirus RNA was detected using RT-PCR for the VP6 gene. The identified strain was further characterized by sequencing and phylogenetic analysis of the partial VP4, and complete VP6 and VP7 gene sequences. The partial VP4 and complete VP6 gene sequences of the CUK-5 strain were most closely related to those of the CUK 6 strain of group C rotaviruses. Phylogenetic analysis of the VP7 gene of the 2 strains (CUK-5 and CUK-6) and reference strains of group G rotavirus by the neighbor-joining method also confirmed that CUK-5 and CUK-6 belonged to type G5 and G1 strains, respectively. This study provides useful data for the prediction of newly appearing variants of porcine group C rotaviruses in neighboring countries through comparisons with GCRVs and fundamental research for vaccine development. PMID- 22203576 TI - How hot are your ions in TWAVE ion mobility spectrometry? AB - Effective temperatures of ions during traveling wave ion mobility spectrometry (TWIMS) analysis were measured using singly protonated leucine enkephalin dimer as a chemical thermometer by monitoring dissociation of the dimer into monomer, as well as the subsequent dissociation of monomer into a-, b-, and y-ions, as a function of instrumental parameters. At fixed helium cell and TWIMS cell gas flow rates, the extent of dissociation does not vary significantly with either the wave velocity or wave height, except at low (<500 m/s) wave velocities that are not commonly used. Increasing the flow rate of nitrogen gas into the TWIMS cell and decreasing the flow rate of helium gas into the helium cell resulted in greater dissociation. However, the mobility distributions of the fragment ions formed by dissociation of the dimer upon injection into the TWIMS cell are nearly indistinguishable from those of fragment ions formed in the collision cell prior to TWIMS analysis for all TWIMS experiments. These results indicate that heating and dissociation occur when ions are injected into the TWIMS cell, and that the effective temperature subsequently decreases to a point at which no further dissociation is observed during the TWIMS analysis. An upper limit to the effective ion temperature of 449 K during TWIMS analysis is obtained at a helium flow rate of 180 mL/min, TWIMS flow rate of 80 mL/min, and traveling wave height of 40 V, which is well below previously reported values. Effects of ion heating in TWIMS on gas-phase protein conformation are presented. PMID- 22203578 TI - Mentorship in anesthesia: how little we know. PMID- 22203577 TI - [Dentin bonding of cements. The bonding of cements with dentin in combination with various indirect restorative materials]. AB - The number of both luting agents and restorative materials available on the market has rapidly increased. This study compared various types of luting agents when used to bond different indirect, laboratory restorative materials to dentin. Cylinders were produced of six restorative materials (gold alloy, titanium, feldspathic porcelain, leucite-glass ceramic, zirconia, and an indirect resin composite). Following relevant pretreatment, the end surface of the cylinders were luted to ground, human dentin with eight different luting agents (DeTrey Zinc [zinc phosphate cement], Fuji I [conventional glass ionomer cement], Fuji Plus [resin-modified glass ionomer cement], Variolink II [conventional etch-and rinse resin cement], Panavia F2.0 and Multilink [self-etch resin cements], RelyX Unicem Aplicap and Maxcem [self-adhesive resin cements]). After water storage at 37 degrees C for one week, the shear bond strength of the specimens was measured and the fracture mode was examined stereo-microscopically. Restorative material and luting agent both had a significant effect on bond strength and there was a significant interaction between the two variables. The zinc phosphate cement and the glass ionomer cements resulted in the lowest bond strengths, whereas the highest bond strengths were found with the two self-etch and one of the self adhesive resin cements. PMID- 22203579 TI - The detection of pCR after PST by contrast-enhanced ultrasonography for breast cancer. AB - BACKGROUND: Primary systemic therapy (PST; such as chemotherapy) has been approved as the standard therapy. Breast-conserving surgery is involved in 60-70% of breast cancer operations, and cancer can spread in the period between the initial treatment and preoperative chemotherapy. To reduce the residual tumor in persistent disease of breast tissue, determining the margin including normal tissue when removing the tumor is very difficult. With the development of the color Doppler method, contrast-enhanced ultrasonography (CEUS) allows visualization of the tumor bloodstream. The availability and efficacy of CEUS for setting the resection margin in breast-conserving surgery were examined and compared with MRI imaging as tools for making decisions for breast-conserving surgery. METHODS: One hundred seventy patients underwent breast cancer operations: 59 were PST(+) and 111 PST(-). Imaging studies, ultrasonography and MRI, to measure the size of the tumor were performed twice, before and after chemotherapy, for PST patients. This was carried out not only to measure the residual tumor size after PST, but also to detect whether pathologically complete response (pCR) had been achieved or not. Fifty-nine patients received CEUS after PST, and we determined the precision of CEUS and conventional US. RESULTS: The sensitivity of CEUS for pCR was 80.0% (95% CI 0.571-0.88), specificity 98.0% (95% CI 0.933-0.996), positive predictive value 88.9% (95% CI 0.635-0.978) and negative predictive value 96.0% (95% CI 0.914-0.976). The difference between the pathological examination and ultrasonography, conventional ultrasonography and CEUS was -4.455 +/- 2.02 and 2.582 +/- 2.298 cm (95% CI -13.11 to -0.96, p = 0.0235); CEUS was near the diameter of the actual pathological examination. CONCLUSION: Contrast-enhanced ultrasonography is suitable for the preoperative examination, especially after PST, to determine the resection margin before breast-conserving surgery and detects pCR, which can help to avoid surgical procedures in the future. PMID- 22203580 TI - Should we treat minimal breast cancer lesions? PMID- 22203581 TI - Serum leptin level and waist-to-hip ratio (WHR) predict the overall survival of metastatic breast cancer (MBC) patients treated with aromatase inhibitors (AIs). AB - INTRODUCTION: Our objective was to determine whether serum leptin levels and obesity-related factors could affect outcome for metastatic breast cancer (MBC) patients treated with aromatase inhibitors (AIs). METHODS: Sixty MBC patients treated with first line hormonal therapy were enrolled in this study. RESULTS: Median age was 51 years (range 28-75). Median leptin level was 19400 pg/ml (1970 91900) and estradiol level 29.6 pg/ml (4.0-181.9). Factors associated with overall survival in univariate analysis were age and waist-to-hip ratio (WHR), whereas only WHR retained significance in the multivariate analysis. However, no factor was associated with progression-free survival. However, WHR was found to be a significant prognostic marker only if the leptin level was >=19400 pg/ml (HR = 0.38; 95% CI: 0.16-0.91). CONCLUSIONS: This study suggests that serum leptin levels and WHR together may serve as potential prognostic markers in MBC patients treated with AIs. PMID- 22203583 TI - Pathological aspects of the intraductal spread of breast cancer. AB - The intraductal spread of breast cancer is a major cause of local recurrence following breast-conserving therapy. To properly understand this pathology, three dimensional (3D) cancer localization within the mammary ductal-lobular system (MDLS) is necessary. To this end we generated computer-assisted 3D reconstructions of all MDLSs using 2-mm-thick serial sections of surgically resected specimens. We then analyzed the characteristics of intraductal spread of breast cancer. In our study of quadrantectomy specimens from patients with primary invasive breast carcinoma, the intraductal spread of breast cancer was found to be continuous from the invasive tumor and spreading along the mammary glandular tree. The pattern is categorized into three types: the central type, the peripheral type, and the extensive type. The central type was found to be most common. A 3D analysis of total mastectomy specimen from a patient with primary non-invasive breast carcinoma revealed regional intraductal spread extending within and filling a single MDLS. The analysis also revealed the presence of ductal anastomoses connecting adjacent MDLSs. These ductal anastomoses were found to be an anatomical risk factor for extensive intraductal spread of breast cancer across multiple MDLSs. To minimize residual non-invasive components of breast carcinoma in the conserved breast, which is strongly associated with the outcome of local control of breast-conserving therapy, it is necessary to determine the optimum surgical margins in a flexible, patient specific manner. This determination should be based on anatomical characteristics of the MDLS, such as those identified in the present study. PMID- 22203582 TI - Clinical application of the one-step nucleic acid amplification method to detect sentinel lymph node metastasis in breast cancer. AB - BACKGROUND: The one-step nucleic acid amplification (OSNA) method can assess the expression level of cytokeratin 19 mRNA in sentinel lymph nodes in breast cancer. We compared the time required for diagnosis and concordance of results between the OSNA method and conventional intraoperative pathological examination. We then examined the relationship between the frequency of non-sentinel lymph node metastasis and (1) the expression level of CK19 mRNA in the sentinel lymph nodes and (2) clinico-pathological features of the primary tumor. METHODS: In the comparison study, pairs of sentinel lymph node sections from 53 consecutive patients were examined: one section by hematoxylin-eosin staining and the other by OSNA assay. The latter involved reverse-transcription loop-mediated isothermal amplification of cytokeratin 19 mRNA, assessed quantitatively. In the second phase, 306 sentinel lymph nodes were removed from 248 consecutive patients, and whole sentinel lymph nodes were examined by OSNA assay alone. RESULTS: OSNA assay was a little more time-consuming than conventional pathological diagnosis (34-45 vs. 22-25 min, p < 0.0001). Concordance between the two methods was 93%. The frequency of non-sentinel lymph node metastasis (p < 0.0001) and the total number of lymph node metastases (p < 0.0001) increased with the amount of cytokeratin 19 mRNA on OSNA assay. We found no significant relationship between the amount of cytokeratin 19 mRNA in sentinel lymph nodes and breast cancer immunohistochemical subtype. CONCLUSIONS: The OSNA method is suitable to detect sentinel lymph node metastasis and to predict the possibility of non-sentinel metastasis. This semi automated quantitative analysis system reduces the burden on pathologists. PMID- 22203584 TI - [Infections with pneumococci, menigococci, H. influenzae and diphtheria in Germany: the RKI Reference Network for Invasive Bacterial Infections (IBI) at the 5th Wurzburg Workshop on Epidemiology, Prevention and Therapy for Invasive Meningococcal Diseases 2010 (meeting report)]. AB - The surveillance and prevention of invasive bacterial infections requires flexible strategic coordination of all involved health-care professionals. For this purpose, the German National Reference Centres for Meningococci, Streptococci and the Consultant Laboratories for Haemophilus influenzae and diphtheria have formed the Reference Network for Invasive bacterial infections (IBI). The 5th Wurzburg Workshop on Meningococcal Diseases 2010 provided the network with a forum for the interdisciplinary exchange between scientists, public health professionals, medical microbiologists and clinicians. The topics covered the analysis of surveillance data for meningococcal disease in the last decade, as well as methods to control for antibody response following vaccination, including a serum bactericidal antibody (SBA) assay, and the development of new vaccines that also include the most common serogroup B. The presentation on diphtheria showed that this rare disease in Germany has become a diagnostic challenge, and that apart from the classical pathogen also toxigenic C. ulcerans strains must be considered. Due to the successful vaccination against Hib, H. influenzae disease has changed from a classical childhood disease to an infection of elderly people mainly caused by unencapsulated strains. Following the introduction of vaccines, changes in the serotype distribution and antibiotic resistance profiles have become apparent for S. pneumoniae infections. The epidemiological data were complemented by clinical aspects concerning the vaccination of immunocompromised children. PMID- 22203585 TI - Antistaphylococcal activity of TD-1792, a multivalent glycopeptide-cephalosporin antibiotic. AB - TD-1792 is a new multivalent glycopeptide-cephalosporin antibiotic with potent activity against Gram-positive bacteria. The in vitro activity of TD-1792 was tested against 527 Staphylococcus aureus isolates, including multidrug-resistant isolates. TD-1792 was highly active against methicillin-susceptible S. aureus (MIC(90), 0.015 MUg/ml), methicillin-resistant S. aureus, and heterogeneous vancomycin-intermediate S. aureus (MIC(90), 0.03 MUg/ml). Time-kill studies demonstrated the potent bactericidal activity of TD-1792 at concentrations of <= 0.12 MUg/ml. A postantibiotic effect of >2 h was observed after exposure to TD 1792. PMID- 22203587 TI - Reevaluation of the critical concentration for drug susceptibility testing of Mycobacterium tuberculosis against pyrazinamide using wild-type MIC distributions and pncA gene sequencing. AB - Pyrazinamide (PZA) is a potent first-line agent for the treatment of tuberculosis (TB) with activity also against a significant part of drug-resistant Mycobacterium tuberculosis strains. Since PZA is active only at acid pH, testing for susceptibility to PZA is difficult and insufficiently reproducible. The recommended critical concentration for PZA susceptibility (MIC, 100 mg/liter) used in the Bactec systems (460 and MGIT 960) has not been critically evaluated against wild-type MIC distributions in clinical isolates of Mycobacterium tuberculosis. Using the Bactec MGIT 960 system, we determined the PZA MICs for 46 clinical M. tuberculosis isolates and compared the results to pncA sequencing and previously obtained Bactec 460 data. For consecutive clinical isolates (n = 15), the epidemiological wild-type cutoff (ECOFF) for PZA was 64 mg/liter (MIC distribution range, <= 8 to 64 mg/liter), and no pncA gene mutations were detected. In strains resistant in both Bactec systems (n = 18), the PZA MICs ranged from 256 to >= 1,024 mg/liter. The discordances between pncA sequencing, susceptibility results in Bactec 460, and MIC determinations in Bactec MGIT 960 were mainly observed in strains with MICs close to or at the ECOFF. We conclude that in general, wild-type and resistant strains were clearly separated and correlated to pncA mutations, although some isolates with MICs close to the ECOFF cause reproducibility problems within and between methods. To solve this issue, we suggest that isolates with MICs of <= 64 mg/liter be classified susceptible, that an intermediary category be introduced at 128 mg/liter, and that strains with MICs of >128 mg/liter be classified resistant. PMID- 22203586 TI - Presence of lamivudine or emtricitabine is associated with reduced emergence of nonnucleoside reverse transcriptase inhibitor mutations in an efavirenz-based intermittent antiretroviral treatment regimen. AB - Efavirenz concentrations were measured in 21 patients during an interruption cycle of the ANRS 106 Window trial. The median efavirenz concentrations in the patients 12 h, 3 days, and 7 days after discontinuation of the drug were 1,962 ng/ml, 416 ng/ml, and 112 ng/ml, respectively. The half-life ranged from 27 to 136 h. No relationship between efavirenz exposure and detection of nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations was demonstrated. Patients who were treated by a lamivudine- or emtricitabine-based regimen had a lower risk of NNRTI mutation selection. PMID- 22203588 TI - Environmental KPC-producing Escherichia coli isolates in Portugal. PMID- 22203589 TI - Impact of mutations at residue I223 of the neuraminidase protein on the resistance profile, replication level, and virulence of the 2009 pandemic influenza virus. AB - Amino acid substitutions at residue I223 of the neuraminidase (NA) protein have been identified in 2009 pandemic influenza (pH1N1) variants with altered susceptibilities to NA inhibitors (NAIs). We used reverse genetics and site directed mutagenesis to generate the recombinant A/Quebec/144147/09 pH1N1 wild type virus (WT) and five (I223R, I223V, H275Y, I223V-H275Y, and I223R-H275Y) NA mutants. A fluorimetry-based assay was used to determine 50% inhibitory concentrations (IC(50)s) of oseltamivir, zanamivir, and peramivir. Replicative capacity was analyzed by viral yield assays in ST6GalI-MDCK cells. Infectivity and transmission of the WT, H275Y, and I223V-H275Y recombinant viruses were evaluated in ferrets. As expected, the H275Y mutation conferred resistance to oseltamivir (982-fold) and peramivir (661-fold) compared to the drug-susceptible recombinant WT. The single I223R mutant was associated with reduced susceptibility to oseltamivir (53-fold), zanamivir (7-fold) and peramivir (10 fold), whereas the I223V virus had reduced susceptibility to oseltamivir (6-fold) only. Interestingly, enhanced levels of resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir (1,647-, 17,347-, and 16-fold increases in IC(50)s, respectively) were observed for the I223R-H275Y recombinant, while the I223V-H275Y mutant exhibited 1,733-, 2,707-, and 2-fold increases in respective IC(50)s. The I223R and I223V changes were associated with equivalent or higher viral titers in vitro compared to the recombinant WT. Infectivity and transmissibility in ferrets were comparable between the recombinant WT and the H275Y or I223V-H275Y recombinants. In conclusion, amino acid changes at residue I223 may alter the NAI susceptibilities of pH1N1 variants without compromising fitness. Consequently, I223R and I223V mutations, alone or with H275Y, need to be thoroughly monitored. PMID- 22203590 TI - Ocular distribution, spectrum of activity, and in vivo viral neutralization of a fully humanized anti-herpes simplex virus IgG Fab fragment following topical application. AB - Herpes simplex ocular infection is a major cause of corneal blindness. Local antiviral treatments exist but are associated with corneal toxicity, and resistance has become an issue. We evaluated the biodistribution and efficacy of a humanized anti-herpes simplex virus (anti-HSV) IgG FAb fragment (AC-8; 53 kDa) following repeated topical administration. AC-8 was found in the corneal epithelium, anterior stroma, subepithelial stromal cells, and retinal glial cells, with preferential entry through the ocular limbus. AC-8 was active against 13 different strains of HSV-1, with 50% and 90% mean effective concentrations (MEC(50) and MEC(90), respectively) ranging from 0.03 to 0.13 MUg/ml, indicating broad-spectrum activity. The in vivo efficacy of AC-8 was evaluated in a mouse model of herpes-induced ocular disease. Treatment with low-dose AC-8 (1 mg/ml) slightly reduced the ocular disease scores. A greater reduction of the disease scores was observed in the 10-mg/ml AC-8-treated group, but not as much as with trifluridine (TFT). AC-8 treatment reduced viral titers but less than trifluridine. AC-8 did not display any toxicity to the cornea or other structures in the eye. In summary, topical instillation of an anti-HSV FAb can be used on both intact and ulcerated corneas. It is well tolerated and does not alter reepithelialization. Further studies to improve the antiviral effect are needed for AC-8 to be considered for therapeutic use. PMID- 22203591 TI - Comparative pharmacodynamics and antimutant potentials of doripenem and imipenem with ciprofloxacin-resistant Pseudomonas aeruginosa in an in vitro model. AB - To compare the antipseudomonal efficacy of doripenem and imipenem as well as their abilities to restrict the enrichment of resistant Pseudomonas aeruginosa, multiple-dosing regimens of each drug were simulated at comparable values of the cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (T(>MIC)) and ratios of the 24 hour area under the curve (AUC(24)) to the MIC. Three clinical isolates of ciprofloxacin-resistant P. aeruginosa (MIC of doripenem, 1 MUg/ml; MICs of imipenem, 1, 2, and 2 MUg/ml) were exposed to thrice-daily doripenem or imipenem for 3 days at AUC(24)/MIC ratios of from 50 to 170 h (doripenem) and from 30 to 140 h (imipenem). The antimicrobial effects for susceptible and resistant subpopulations of bacteria were expressed by the areas between control growth and time-kill curves (I(E)s) and areas under the bacterial mutant concentration curves (AUBC(M)s), respectively. With each antibiotic, the I(E) and AUBC(M) versus log AUC(24)/MIC relationships were bacterial strain independent. At similar AUC(24)/MIC ratios, doripenem was slightly less efficient than imipenem against susceptible and resistant subpopulations of bacteria. However, doripenem appeared to be somewhat more efficient than imipenem at clinically achievable AUC(24)s related to the means of the MICs for the three studied strains and had higher antimutant potentials for two of the three strains. PMID- 22203592 TI - In vitro evaluation of novel compounds against selected resistant Pseudomonas aeruginosa isolates. AB - We describe the activities of RX-P763, RX-P766, RX-P770, RX-P792, RX-P793, and RX P808 against strains of resistant Pseudomonas aeruginosa. These compounds target the large subunit of the bacterial ribosome and have broad-spectrum activities against multidrug-resistant pathogens. All compounds demonstrated in vitro activity against P. aeruginosa, with MIC(90) values of 4 to 8 MUg/ml (range, 0.5 to 64). These novel compounds had narrow MIC distributions and maintained activity despite resistance phenotypes to other commonly utilized agents. PMID- 22203593 TI - Partial excision of blaKPC from Tn4401 in carbapenem-resistant Klebsiella pneumoniae. AB - We describe a novel Tn4401 variant (Tn4401d) in epidemic Klebsiella pneumoniae clone ST258, from which a partial bla(KPC) fragment has been excised along with ISKpn7 and a partial tnpA fragment. Nested-PCR experiments confirmed that this region can be removed from distinct Tn4401 isoforms in both K. pneumoniae and Escherichia coli. This study highlights that the region surrounding bla(KPC) is undergoing recombination and that Tn4401 itself is heterogeneous and highly plastic. PMID- 22203594 TI - Prevalence of antimicrobial resistance among clinical isolates of Bacteroides fragilis group in Canada in 2010-2011: CANWARD surveillance study. AB - Clinical isolates of the Bacteroides fragilis group (n = 387) were collected from patients attending nine Canadian hospitals in 2010-2011 and tested for susceptibility to 10 antimicrobial agents using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method. B. fragilis (59.9%), Bacteroides ovatus (16.3%), and Bacteroides thetaiotaomicron (12.7%) accounted for ~90% of isolates collected. Overall rates of percent susceptibility were as follows: 99.7%, metronidazole; 99.5%, piperacillin-tazobactam; 99.2%, imipenem; 97.7%, ertapenem; 92.0%, doripenem; 87.3%, amoxicillin-clavulanate; 80.9%, tigecycline; 65.9%, cefoxitin; 55.6%, moxifloxacin; and 52.2%, clindamycin. Percent susceptibility to cefoxitin, clindamycin, and moxifloxacin was lowest for B. thetaiotaomicron (n = 49, 24.5%), Parabacteroides distasonis/P. merdae (n = 11, 9.1%), and B. ovatus (n = 63, 31.8%), respectively. One isolate (B. thetaiotaomicron) was resistant to metronidazole, and two isolates (both B. fragilis) were resistant to both piperacillin-tazobactam and imipenem. Since the last published surveillance study describing Canadian isolates of B. fragilis group almost 20 years ago (A.-M. Bourgault et al., Antimicrob. Agents Chemother. 36:343-347, 1992), rates of resistance have increased for amoxicillin clavulanate, from 0.8% (1992) to 6.2% (2010-2011), and for clindamycin, from 9% (1992) to 34.1% (2010-2011). PMID- 22203595 TI - In vitro activity of BMS-790052 on hepatitis C virus genotype 4 NS5A. AB - The antiviral profile of BMS-790052, a potent hepatitis C virus (HCV) replication complex inhibitor targeting nonstructural protein NS5A, is well characterized for HCV genotype-1. Here, we report that BMS-790052 inhibits hybrid replicons containing HCV genotype-4 NS5A genes with 50% effective concentrations (EC(50)s) ranging from 7 to 13 pM. NS5A residue 30 was an important site for BMS-790052 selected resistance in the hybrid replicons. Our results support the potential of BMS-790052 as a valuable component of combination therapy for HCV genotype-4 chronic infection. PMID- 22203597 TI - First report of the multidrug resistance gene cfr in Enterococcus faecalis of animal origin. AB - The multiresistance gene cfr was identified for the first time in an Enterococcus faecalis isolate of animal origin. The 32,388-bp plasmid pEF-01, which carried the cfr gene, was sequenced completely. Three copies of the insertion sequence IS1216 were identified in pEF-01, and the detection of a cfr- and IS1216 containing amplicon by inverse PCR suggests that IS1216 may play a role in the dissemination of cfr by a recombination process. PMID- 22203596 TI - Influence of soil use on prevalence of tetracycline, streptomycin, and erythromycin resistance and associated resistance genes. AB - This study examined differences in antibiotic-resistant soil bacteria and the presence and quantity of resistance genes in soils with a range of management histories. We analyzed four soils from agricultural systems that were amended with manure from animals treated with erythromycin and exposed to streptomycin and/or oxytetracycline, as well as non-manure-amended compost and forest soil. Low concentrations of certain antibiotic resistance genes were detected using multiplex quantitative real-time PCR (qPCR), with tet(B), aad(A), and str(A) each present in only one soil and tet(M) and tet(W) detected in all soils. The most frequently detected resistance genes were tet(B), tet(D), tet(O), tet(T), and tet(W) for tetracycline resistance, str(A), str(B), and aac for streptomycin resistance, and erm(C), erm(V), erm(X), msr(A), ole(B), and vga for erythromycin resistance. Transposon genes specific for Tn916, Tn1549, TnB1230, Tn4451, and Tn5397 were detected in soil bacterial isolates. The MIC ranges of isolated bacteria for tetracycline, streptomycin, and erythromycin were 8 to >256 MUg/ml, 6 to >1,024 MUg/ml, and 0.094 to >256 MUg/ml, respectively. Based on 16S rRNA gene similarity, isolated bacteria showed high sequence identity to genera typical of soil communities. Bacteria with the highest MICs were detected in manure-amended soils or soils from agricultural systems with a history of antibiotic use. Non-manure-amended soils yielded larger proportions of antibiotic resistant bacteria, but these had lower MICs, carried fewer antibiotic resistance genes, and did not display multidrug resistance (MDR). PMID- 22203598 TI - Trends in the susceptibility of clinically important resistant bacteria to tigecycline: results from the Tigecycline In Vitro Surveillance in Taiwan study, 2006 to 2010. AB - The Tigecycline In Vitro Surveillance in Taiwan (TIST) study, a nationwide, prospective surveillance during 2006 to 2010, collected a total of 7,793 clinical isolates, including methicillin-resistant Staphylococcus aureus (MRSA) (n = 1,834), penicillin-resistant Streptococcus pneumoniae (PRSP) (n = 423), vancomycin-resistant enterococci (VRE) (n = 219), extended-spectrum beta lactamase (ESBL)-producing Escherichia coli (n = 1,141), ESBL-producing Klebsiella pneumoniae (n = 1,330), Acinetobacter baumannii (n = 1,645), and Stenotrophomonas maltophilia (n = 903), from different specimens from 20 different hospitals in Taiwan. MICs of tigecycline were determined following the criteria of the U.S. Food and Drug Administration (FDA) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST-2011). Among drug resistant Gram-positive pathogens, all of the PRSP isolates were susceptible to tigecycline (MIC(90), 0.03 MUg/ml), and only one MRSA isolate (MIC(90), 0.5 MUg/ml) and three VRE isolates (MIC(90), 0.125 MUg/ml) were nonsusceptible to tigecycline. Among the Gram-negative bacteria, the tigecycline susceptibility rates were 99.65% for ESBL-producing E. coli (MIC(90), 0.5 MUg/ml) and 96.32% for ESBL-producing K. pneumoniae (MIC(90), 2 MUg/ml) when interpreted by FDA criteria but were 98.7% and 85.8%, respectively, when interpreted by EUCAST-2011 criteria. The susceptibility rate for A. baumannii (MIC(90), 4 MUg/ml) decreased from 80.9% in 2006 to 55.3% in 2009 but increased to 73.4% in 2010. A bimodal MIC distribution was found among carbapenem-susceptible A. baumannii isolates, and a unimodal MIC distribution was found among carbapenem-nonsusceptible A. baumannii isolates. In Taiwan, tigecycline continues to have excellent in vitro activity against several major clinically important drug-resistant bacteria, with the exception of A. baumannii. PMID- 22203599 TI - First identification of blaIMI-1 in an Enterobacter cloacae clinical isolate from France. PMID- 22203600 TI - A novel agent effective against Clostridium difficile infection. AB - N(2)-(3,4-Dichlorobenzyl)-7-(2-[1-morpholinyl]ethyl)guanine (MorE-DCBG, 362E) is a synthetic purine that selectively inhibits the replication-specific DNA polymerase of Clostridium difficile. MorE-DCBG and its analogs strongly inhibited the growth of a wide variety of C. difficile strains. When administered orally in a hamster model of C. difficile-specific colitis, 362E was as effective as oral vancomycin, the current agent of choice for treating severe forms of the human disease. PMID- 22203601 TI - Efficacy of sitafloxacin-based rescue therapy for Helicobacter pylori after failures of first- and second-line therapies. AB - Sitafloxacin-based triple therapy achieved 83.6% (per-protocol) and 78.2% (intention-to-treat) success in eradicating Helicobacter pylori among 78 Japanese patients after clarithromycin-based first-line and metronidazole-based second line triple therapies failed. Eradication succeeded in 32 out of 43 patients, even with gyrA mutation-positive Helicobacter pylori (per protocol). The position of the gyrA mutation (N87 or D91) was determined to be a better marker than MIC levels for predicting outcomes of sitafloxacin-based treatment. PMID- 22203602 TI - Identification of novel N-(morpholine-4-carbonyloxy) amidine compounds as potent inhibitors against hepatitis C virus replication. AB - To identify novel compounds that possess antiviral activity against hepatitis C virus (HCV), we screened a library of small molecules with various amounts of structural diversity using an HCV replicon-expressing cell line and performed additional validations using the HCV-JFH1 infectious-virus cell culture. Of 4,004 chemical compounds, we identified 4 novel compounds that suppressed HCV replication with 50% effective concentrations of ranging from 0.36 to 4.81 MUM. N'-(Morpholine-4-carbonyloxy)-2-(naphthalen-1-yl) acetimidamide (MCNA) was the most potent and also produced a small synergistic effect when used in combination with alpha interferon. Structure-activity relationship (SAR) analyses revealed 4 derivative compounds with antiviral activity. Further SAR analyses revealed that the N-(morpholine-4-carbonyloxy) amidine moiety was a key structural element for antiviral activity. Treatment of cells with MCNA activated nuclear factor kappaB and downstream gene expression. In conclusion, N-(morpholine-4-carbonyloxy) amidine and other related morpholine compounds specifically suppressed HCV replication and may have potential as novel chemotherapeutic agents. PMID- 22203603 TI - Reshuffling of Aspergillus fumigatus cell wall components chitin and beta-glucan under the influence of caspofungin or nikkomycin Z alone or in combination. AB - Chitin and beta-glucan are major cell wall components of Aspergillus spp. We investigated the antifungal activity of chitin synthesis inhibitors nikkomycin Z, polyoxin D, flufenoxuron, lufenuron, and teflubenzuron, alone and combined with the beta-glucan synthesis inhibitor caspofungin. Only nikkomycin Z and caspofungin were found to act synergistically. The nikkomycin Z-induced chitin decrease corresponded with a beta-glucan increase, while with the caspofungin induced beta-glucan decrease, an increase in chitin was found. This could explain the synergistic activity of this combination of drugs. PMID- 22203604 TI - Comparative effects of micafungin, caspofungin, and anidulafungin against a difficult-to-treat fungal opportunistic pathogen, Candida glabrata. AB - The aim of this study was to compare the in vitro and in vivo activities of micafungin, caspofungin, and anidulafungin against Candida glabrata. The MICs against 28 clinical isolates showed that the overall susceptibilities to caspofungin and to micafungin were not statistically different in the absence of human serum, whereas the isolates were less susceptible to micafungin than to caspofungin in its presence. Minimum fungicidal concentrations, as well as time kill experiments, showed that caspofungin was more active than anidulafungin, while micafungin was superior to either caspofungin or anidulafungin without serum; its addition rendered caspofungin and micafungin equally effective. A murine model of systemic candidiasis against a C. glabrata-susceptible isolate was performed to study the effects of all three echinocandins, and kidney burden counts showed that caspofungin, micafungin, and anidulafungin were active starting from 0.25, 1, and 5 mg/kg of body weight/day, respectively. Two echinocandin-resistant strains of C. glabrata were selected: C. glabrata 30, a laboratory strain harboring the mutation Fks2p-P667T, and C. glabrata 51, a clinical isolate harboring the mutation Fks2p-D666G. Micafungin activity was shown to be as effective as or more effective than that of caspofungin or anidulafungin in terms of MICs. In vivo studies against these resistant strains showed that micafungin was active starting from 1 mg/kg/day, while caspofungin was effective only when administrated at higher doses of 5 or 10 mg/kg/day. Although a trend toward colony reduction was observed with the highest doses of anidulafungin, a significant statistical difference was never reached. PMID- 22203605 TI - Characterization of resistance to the nonnucleoside NS5B inhibitor filibuvir in hepatitis C virus-infected patients. AB - Filibuvir (PF-00868554) is an investigational nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural 5B (NS5B) RNA-dependent RNA polymerase currently in development for treating chronic HCV infection. The aim of this study was to characterize the selection of filibuvir-resistant variants in HCV infected individuals receiving filibuvir as short (3- to 10-day) monotherapy. We identified amino acid M423 as the primary site of mutation arising upon filibuvir dosing. Through bulk cloning of clinical NS5B sequences into a transient-replicon system, and supported by site-directed mutagenesis of the Con1 replicon, we confirmed that mutations M423I/T/V mediate phenotypic resistance. Selection in patients of an NS5B mutation at M423 was associated with a reduced replicative capacity in vitro relative to the pretherapy sequence; consistent with this, reversion to wild-type M423 was observed in the majority of patients following therapy cessation. Mutations at NS5B residues R422 and M426 were detected in a small number of patients at baseline or the end of therapy and also mediate reductions in filibuvir susceptibility, suggesting these are rare but clinically relevant alternative resistance pathways. Amino acid variants at position M423 in HCV NS5B polymerase are the preferred pathway for selection of viral resistance to filibuvir in vivo. PMID- 22203606 TI - In vitro characterization of the activity of PF-05095808, a novel biological agent for hepatitis C virus therapy. AB - PF-05095808 is a novel biological agent for chronic hepatitis C virus (HCV) therapy. It comprises a recombinant adeno-associated virus (AAV) DNA vector packaged into an AAV serotype 8 capsid. The vector directs expression of three short hairpin RNAs (shRNAs) targeted to conserved regions of the HCV genome. These shRNAs are processed by the host cell into the small interfering RNAs which mediate sequence-specific cleavage of target regions. For small-molecule inhibitors the key screens needed to assess in vitro activity are well defined; we developed new assays to assess this RNA interference agent and so to understand its therapeutic potential. Following administration of PF-05095808 or corresponding synthetic shRNAs, sequence-specific antiviral activity was observed in HCV replicon and infectious virus systems. To quantify the numbers of shRNA molecules required for antiviral activity in vitro and potentially also in vivo, a universal quantitative PCR (qPCR) assay was developed. The number of shRNA molecules needed to drive antiviral activity proved to be independent of the vector delivery system used for PF-05095808 administration. The emergence of resistant variants at the target site of one shRNA was characterized. A novel RNA cleavage assay was developed to confirm the spectrum of activity of PF-05095808 against common HCV clinical isolates. In summary, our data both support antiviral activity consistent with an RNA interference mechanism and demonstrate the potential of PF-05095808 as a therapeutic agent for chronic HCV infection. PMID- 22203607 TI - The monoamine oxidase A inhibitor clorgyline is a broad-spectrum inhibitor of fungal ABC and MFS transporter efflux pump activities which reverses the azole resistance of Candida albicans and Candida glabrata clinical isolates. AB - Resistance to the commonly used azole antifungal fluconazole (FLC) can develop due to overexpression of ATP-binding cassette (ABC) and major facilitator superfamily (MFS) plasma membrane transporters. An approach to overcoming this resistance is to identify inhibitors of these efflux pumps. We have developed a pump assay suitable for high-throughput screening (HTS) that uses recombinant Saccharomyces cerevisiae strains hyperexpressing individual transporters from the opportunistic fungal pathogen Candida albicans. The recombinant strains possess greater resistance to azoles and other pump substrates than the parental host strain. A flow cytometry-based HTS, which measured increased intracellular retention of the fluorescent pump substrate rhodamine 6G (R6G) within yeast cells, was used to screen the Prestwick Chemical Library (PCL) of 1,200 marketed drugs. Nine compounds were identified as hits, and the monoamine oxidase A inhibitor (MAOI) clorgyline was identified as an inhibitor of two C. albicans ABC efflux pumps, CaCdr1p and CaCdr2p. Secondary in vitro assays confirmed inhibition of pump-mediated efflux by clorgyline. Clorgyline also reversed the FLC resistance of S. cerevisiae strains expressing other individual fungal ABC transporters (Candida glabrata Cdr1p or Candida krusei Abc1p) or the C. albicans MFS transporter Mdr1p. Recombinant strains were also chemosensitized by clorgyline to other azoles (itraconazole and miconazole). Importantly, clorgyline showed synergy with FLC against FLC-resistant C. albicans clinical isolates and a C. glabrata strain and inhibited R6G efflux from a FLC-resistant C. albicans clinical isolate. Clorgyline is a novel broad-spectrum inhibitor of two classes of fungal efflux pumps that acts synergistically with azoles against azole resistant C. albicans and C. glabrata strains. PMID- 22203608 TI - Centre-surround inhibition is a general aspect of famous-person recognition: evidence from negative semantic priming from clearly visible primes. AB - A centre-surround attentional mechanism was proposed by Carr and Dagenbach (Journal of Experimental Psychology: Learning, Memory, and Cognition 16: 341-350, 1990) to account for their observations of negative semantic priming from hard-to perceive primes. Their mechanism cannot account for the observation of negative semantic priming when primes are clearly visible. Three experiments (Ns = 30, 46, and 30) used a familiarity decision with names of famous people, preceded by a prime name with the same occupation as the target or with a different occupation. Negative semantic priming was observed at a 150- or 200-ms SOA, with positive priming at shorter (50-ms) and longer (1,000-ms) SOAs. In Experiment 3, we verified that the primes were easily recognisable in the priming task at an SOA that yielded negative semantic priming, which cannot be predicted by the original centre-surround mechanism. A modified version is proposed that explains transiently negative semantic priming by proposing that centre-surround inhibition is a normal, automatically invoked aspect of the semantic processing of visually presented famous names. PMID- 22203609 TI - Comparative examination of inner ear in wild type and pituitary adenylate cyclase activating polypeptide (PACAP)-deficient mice. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) is a multifunctional neuropeptide with well-known neuroprotective and neurotrophic effects. The involvement of PACAP in sensory processing has also been documented, but little is known about its effects in the auditory system. PACAP and its specific receptor (PAC1) are present in the cochlea and in brain structures involved in auditory pathways. Recently, we have shown that PACAP protects cochlear cells against oxidative stress-induced apoptosis. The endolymphatic Ca(2+) concentration controlled by Ca(2+) buffers of the hair cells is essential for the normal hearing processes. In this study we examined the localization of PAC1 receptor and Ca(2+) buffering proteins (parvalbumin, calretinin, calbindin) in the inner ear of 5-day-old PACAP-deficient mice compared with wild-type mice in order to get a closer insight into the effect of endogenous PACAP in the cochlear function. We did not find differences in the distribution pattern of PAC1 receptors between the two groups, but wild-type animals showed significantly higher PAC1 receptor expression. In contrast, inner and outer hair cells of PACAP deficient mice showed more pronounced parvalbumin, calbindin, and calretinin immunopositivity compared with wild-type mice. Elevated endolymphatic Ca(2+) is deleterious for cochlear function, while the high concentration of Ca(2+) buffers in hair cells may offer protection. The increased immunoreactivity of Ca(2+) binding proteins in the absence of PACAP provide further evidence the important role of PACAP in the hearing processes. PMID- 22203610 TI - Effects of chemotherapeutics on organotypic corticostriatal slice cultures identified by a panel of fluorescent and immunohistochemical markers. AB - Effects of chemotherapeutics on glioma cell lines and spheroids are usually investigated without evaluating the effects of chemotherapeutics on normal brain tissue. To perform such investigations, the aim of this study was to establish a panel of markers for detection of general cell death and more specific neuronal and glial degeneration induced by chemotherapeutics in organotypic rat corticostriatal slice cultures. The slice cultures were exposed to the alkylating agents temozolomide (TMZ) and nimustine (ACNU), the tyrosine kinase inhibitor imatinib mesylate (IM) and the microtubule-destabilizing agent vincristine (VCR). Densitometric measurements of uptake of the fluorescent dye propidium iodide (PI) were used for quantifying cellular degeneration. Moreover, paraffin sections were hematoxylin eosine stained and immunostained for the neuronal marker microtubule associated protein 2 (MAP2), the astroglial marker glial fibrillary acidic protein (GFAP), and the oligodendroglial marker p25alpha. The results showed that the supposed clinically relevant drug concentrations were non-toxic. However, a time dependent increase in PI uptake was observed for high drug concentrations, except for TMZ, where no toxicity was observed. Corresponding immunostaining showed loss of MAP2 and increased expression of GFAP and p25alpha for cultures exposed to 1,000 nM VCR. Cultures exposed to high concentrations of ACNU and IM disintegrated, leaving no tissue for histology. In conclusion, corticostriatal slice cultures and the established panel of markers represent an excellent tool for detecting toxicity induced by chemotherapeutics. Toxicity was not detected at clinical concentrations, but high concentrations with toxic effects were identified suggesting that some of the earlier identified anti-cancer effects are general cytotoxic effects and not specific anti-cancer effects. PMID- 22203611 TI - Neuromodulatory propensity of Bacopa monnieri leaf extract against 3 nitropropionic acid-induced oxidative stress: in vitro and in vivo evidences. AB - We previously reported the propensity of Bacopa monnieri (BM) leaf powder to modulate endogenous levels of oxidative stress markers in the brain of prepubertal mice. In this study, we tested the hypothesis that pretreatment with an alcoholic extract of BM (BME) could provide neuroprotection against 3 nitropropionic acid (3-NPA)-induced oxidative stress under in vitro and in vivo conditions. In chemical systems, BME exhibited multiple free radical scavenging ability. Further, BME pretreatment completely abolished 3-NPA-induced oxidative stress response in brain (striatum, St) mitochondria in vitro. Likewise, pretreatment of dopaminergic (N27 cell lines) cells with BME not only abrogated the generation of reactive oxygen species (ROS) levels, but also offered marked protection against 3-NPA-mediated cytotoxicity. These findings were further validated employing a 3-NPA mice model in vivo. We determined the degree of oxidative stress induction, redox status, enzymic antioxidants, protein oxidation, and cholinergic function in various brain regions of male mice provided with BME for 10 days (prophylaxis) followed by 3-NPA challenge (75 mg/kg bw/day, i.p.). BME prophylaxis completely prevented 3-NPA-induced oxidative dysfunctions in St and other brain regions. 3-NPA-induced robust elevation of oxidative markers (malondialdehyde levels, ROS generation, hydroperoxide levels and protein carbonyls) in cytosol of brain regions was predominantly abolished among mice given BME prophylaxis. Interestingly, BME prophylaxis also prevented the depletion of reduced glutathione, thiol levels, and perturbations in antioxidant enzymes caused by 3-NPA. Collectively these findings provide evidence on the significant prophylactic neuroprotective efficacy of BME in prepubertal mice brain. Based on these data, it is hypothesized that BME can serve as a useful adjuvant in protecting brain against oxidative-mediated neurodegenerative disorders involving oxidative stress conditions. PMID- 22203613 TI - A qualitative study using a systemic perspective exploring the remediation of abusive interactions in intimate heterosexual couples. AB - Very little attention has been paid to both partners beliefs about why violence in their previously abusive relationship has stopped or significantly reduced despite well-documented details in the research literature outlining the characteristics of both victims and perpetrators. This study aimed to provide some understanding of how each partner believed that the violence has ended. However their answers often were not definitive; instead, they uncovered the complexities in their relationship and their struggle to overcome the uncertainty they have to achieve and maintain successful remediation. The article is based on a qualitative Interpretative Phenomenological Analysis (IPA) study that explored the nature of the relationship between six heterosexual couples before and after a therapeutic intervention for the men perpetrators, which followed the Duluth Model. The study included how they both understood the violence and how they maintained nonviolence in their relationship. The men were notably still in the process of reprocessing their understanding of why they were violent and they needed to further understand their reactions to maintain their nonviolence. The IPA themes provided some understanding of how the participants thought they had a better understanding of the factors that had maintained their relationship since the termination of the intervention. The themes, generated from the interviews provided by the perpetrators and their victims, are explored and some explanations for the successful continuation of their relationship following treatment are suggested. Implications for widening the treatment options for men perpetrators are suggested in addition to providing treatment options for couples who wish to remain within their relationships and need help to identify unhelpful and dangerous patterns of interaction. PMID- 22203612 TI - Altered voltage dependent calcium currents in a neuronal cell line derived from the cerebral cortex of a trisomy 16 fetal mouse, an animal model of Down syndrome. AB - Human Down syndrome (DS) is determined by the trisomy of autosome 21 and is expressed by multiple abnormalities, being mental retardation the most striking feature. The condition results in altered electrical membrane properties (EMPs) of fetal neurons, which are qualitatively identical to those of trisomy 16 fetal mice (Ts16), an animal model of the human condition. Ts16 hippocampal cultured neurons reportedly exhibit increased voltage-dependent calcium currents (I (Ca)) amplitude. Since Ts16 animals are unviable, we have established immortalized cell lines from the cerebral cortex of Ts16 (named CTb) and normal littermates (named CNh). Using the whole-cell patch-clamp technique, we have now studied I (Ca) in CTb and CNh cells. Current activation occurs at -40 mV in both cell lines (V (holding) = -80 mV). Trisomic cells exhibited a 2.4 fold increase in the maximal Ca(2+) current density compared to normal cells (CNh = -6.3 +/- 0.77 pA/pF, n = 18; CTb = -16.4 +/- 2.423 pA/pF; P < 0.01, n = 13). Time dependent kinetics for activation and inactivation did not differ between the two cell types. However, steady state inactivation studies revealed a 15 mV shift toward more depolarized potentials in the trisomic condition, suggesting that altered voltage dependence of inactivation may underlie the increased current density. Further, the total charge movement across the membrane is increased in CTb cells, in agreement with that expected by the potential sensitivity shift. These results indicate that CTb cells present altered Ca(2+) currents, similar to those of Ts16 primary cultured central neurons. The CTb cell line represents a model for studying DS-related impairments of EMPs. PMID- 22203614 TI - An evaluation of intimate partner violence intervention with incarcerated offenders. AB - The following study is an evaluation of the Moderate Intensity Family Violence Prevention Program (MIFVPP). The sample consisted of 298 male federal offenders who participated in the MIFVPP while incarcerated or on release within the community. Participants were assessed pre-, mid-, and postprogram using an assessment battery consisting of self-report questionnaires and facilitator-rated evaluation scales. Results of the study found uniform and significant (p < .001) improvement for pre and post program change in the self-report questionnaires and in the facilitator ratings. A positive improvement in motivation, whether assessed by the participant or facilitator, was associated with improvement in program outcomes and significant within, between, and interaction effects were found when participant program performance over time was compared among grouped postprogram ratings of motivation. The implication for the efficacy of addressing offender motivation to change in intimate partner violence (IPV) interventions is discussed. PMID- 22203615 TI - Leadership in multiple perpetrator stranger rape. AB - Sexual offences by multiple perpetrators are more violent and involve more severe forms of sexual violation than those perpetrated by a lone offender. Often a clear leader exists within these groups. Questions have been raised as to the relative risk of reoffending and the potentially differing criminogenic needs of leaders and followers. However, a recent study comparing leaders and followers in juvenile multiple perpetrator rapes (t'Hart-Kerkhoffs et al., 2011) failed to find some of the expected differences. It was proposed that this might be due, in part, to the way leaders and followers were classified in the study. Before work can progress in this area, it is important to devise reliable and valid means of identifying leaders and followers in multiple perpetrator rape. This article reports on a study which investigated the utility of two different methods of identifying leadership. The Scale of Influence (Porter & Alison, 2001) was applied to a sample of 256 offenders responsible for 95 multiple perpetrator rapes from the United Kingdom. Following this, the relative number of directives uttered by offenders was used to designate leadership. In 66% of the offences sampled, a leader was designated using the number of directives uttered compared with 80% when using the Scale of Influence. When combining both measures to form a composite measure of leadership, this percentage increased to 89%. Classifications of offenders as leaders, followers, and neither, according to the Scale of Influence, the count of directives, and the composite measure, were compared with classifications made by a practitioner to assess their concordance. The composite measure showed the greatest agreement with practitioner opinion. These findings suggest that the Scale of Influence could be developed to take account of other ways that leadership is displayed during multiple perpetrator rapes. PMID- 22203616 TI - Service utilization, perceived changes of self, and life satisfaction among women who experienced intimate partner abuse: the mediation effect of empowerment. AB - This study explored the growth experiences of women abused by their intimate partner, specifically focusing on the associations between social services and empowerment, perceived changes of self, and life satisfaction. The potential effects of demographic variables, social support, coping, and experience of partner abuse were also explored. A survey study was conducted through the collaboration of social workers in the Centers of Prevention and Intervention for Domestic Violence and private sectors in Taiwan. Through contact by their social workers, 191 participants completed the questionnaires. The results revealed that the participants had growth mainly in their psychological and interpersonal domains. The independent variables in the regression model explained 45.3% (adjusted) variance in perceived changes of self. In addition to empowerment and negative impact of violence, intensity of contact and professional relationship were two important service variables that directly and significantly correlated with perceived changes of self. A significant amount of variance (adjusted R2 = .556) in life satisfaction could be explained by the independent variables. Social support and empowerment directly correlated with life satisfaction. The findings also supported the mediation effect of empowerment. Seven variables (e.g., social support, coping method, and professional relationship) indirectly associated with perceived changes of self and life satisfaction through empowerment. PMID- 22203618 TI - The role of gender in officially reported intimate partner abuse. AB - The role of gender in intimate partner abuse (IPA) perpetration and victimization has been debated for the last several decades. Two perspectives have emerged regarding this debate. Researchers from the family violence perspective argue that men and women are violent at near equal rates and call for a reframing of the issue from one of woman battering to one of family violence. In contrast, feminist researchers maintain that men make up the majority of perpetrators and women the majority of victims in cases of intimate partner abuse. While some have put forth arguments explaining these differences, this debate is far from over. Using official reported cases of IPA, this study examines 815 IPA cases of which 13% were female perpetrated in an attempt to clarify gender differences and similarities among male and female offenders beyond prevalence rates. Special attention is paid to contextual differences and similarities and implications this research has for future research and policy. PMID- 22203617 TI - Psychiatric correlates of medical care costs among veterans receiving mental health care. AB - Research on increased medical care costs associated with posttraumatic sequelae has focused on posttraumatic stress disorder (PTSD). However, the provisional diagnosis of Disorders of Extreme Stress Not Otherwise Specified (DESNOS) encompasses broader trauma-related difficulties and may be uniquely related to medical costs. We investigated whether DESNOS severity was associated with greater nonmental health medical care costs in veterans receiving mental health care. Participants were 106 men and 105 women receiving VA outpatient mental health treatment. A standardized interview assessed DESNOS severity. The dependent variables consisted of primary and specialty medical treatment costs. Sequential zero-inflated negative binomial regression was used to evaluate the variance in medical costs accounted for by DESNOS severity, controlling for PTSD severity and established predisposing, enabling, and need-based health care factors. Contrary to our hypothesis, in fully adjusted models, DESNOS severity independently added a significant amount of variance to lower specialty medical care costs, whereas PTSD did not consistently account for significant variance in medical care costs. Greater DESNOS severity appears to be associated with lower specialty medical care costs but not primary care costs. These findings may indicate that patients with DESNOS symptoms are at risk for being underreferred for specialty care. PMID- 22203619 TI - Containing the secret of child sexual abuse. AB - This study reports a grounded theory study of the process of how children tell of their experiences of child sexual abuse from the perspectives of young people and their parents. Individual interviews were conducted with 22 young people aged 8 to 18, and 14 parents. A theoretical model was developed that conceptualises the process of disclosure as one of containing the secret of child sexual abuse. Three key dynamics were identified: the active withholding of the secret on the part of the child, the experience of a 'pressure cooker effect' reflecting a conflict between the wish to tell and the wish to keep the secret, and the confiding itself which often occurs in the context of an intimacy being shared. Children's experiences of disclosure were multidetermined and suggest the need for multifaceted and multisystemic approaches to prevention and intervention. The need for the secret to be contained, individually and interpersonally in appropriate safeguarding and therapeutic contexts needs to be respected in helping children tell. PMID- 22203620 TI - Sexual assault nurse examiners' perceptions of their relationship with doctors, rape victim advocates, police, and prosecutors. AB - In response to the negative and inefficient treatment of rape victims by emergency room personnel, the first Sexual Assault Nurse Examiner (SANE) programs began in the late 1970s. While SANEs, doctors, rape victim advocates, police officers and prosecutors work together to ensure the most comprehensive and sensitive care of rape victims, they all have very different roles and objectives. This research explores SANEs' perceptions of their relationships with other professionals who treat or interact with rape victims. Data from interviews with 39 Sexual Assault Nurse Examiners from four East Coast states indicate positive relationships are marked by open communication, respect shown towards SANEs as well as rape victims, and a sense of appreciation among SANEs. On the contrary, negative relationships result when SANEs believe police treat victims poorly, when advocates overstep boundaries and question SANEs about evidence collection or the exam, and when prosecutors fail to properly prepare them to testify during a trial. PMID- 22203621 TI - Dating norms and dating violence among ninth graders in Northeast Georgia: reports from student surveys and focus groups. AB - This mixed-methods study describes the norms supporting male-to-female and female to-male dating violence in a diverse sample of ninth graders. The quantitative study, based on student surveys (n = 624), compared norms supporting dating violence by sex, race/ethnicity, and dating status, and it examined the relation between dating violence norms and physical aggression and victimization. The qualitative study, based on 12 focus groups, explored participants' views of dating aggression. Findings revealed more support for female-to-male aggression, greater acceptance of norms supporting dating violence by non-White students, a strong association between norms and physical aggression but only in males, and a high correlation between victimization and perpetration. Participants rejected male-to-female dating aggression because of peer pressure not to hit girls, parents' beliefs that denounce dating violence, the superior physical advantage of boys over girls, and legal consequences. Results highlight the importance of culturally sensitive and gender-specific interventions. PMID- 22203622 TI - Bullying among adolescents in North Cyprus and Turkey: testing a multifactor model. AB - Peer bullying has been studied since the 1970s. Therefore, a vast literature has accumulated about the various predictors of bullying. However, to date there has been no study which has combined individual-, peer-, parental-, teacher-, and school-related predictors of bullying within a model. In this sense, the main aim of this study was to test a multifactor model of bullying among adolescents in North Cyprus and Turkey. A total of 1,052 adolescents (554 girls, 498 boys) aged between 13 and 18 (M = 14.7, SD = 1.17) were recruited from North Cyprus and Turkey. Before testing the multifactor models, the measurement models were tested according to structural equation modeling propositions. Both models indicated that the psychological climate of the school, teacher attitudes within classroom, peer relationships, parental acceptance-rejection, and individual social competence factors had significant direct effects on bullying behaviors. Goodness of-fit indexes indicated that the proposed multifactor model fitted both data well. The strongest predictors of bullying were the psychological climate of the school following individual social competence factors and teacher attitudes within classroom in both samples. All of the latent variables explained 44% and 51% of the variance in bullying in North Cyprus and Turkey, respectively. PMID- 22203623 TI - A mixed methods study of participant reaction to domestic violence research in Jordan. AB - Research on domestic violence against women has increased considerably over the past few decades. Most participants in such studies find the exercise worthwhile and of greater benefit than emotional cost; however, systematic examination of participant reaction to research on violence is considerably lacking, especially in the Middle East region. This study begins to fill this gap by examining women's reactions to domestic violence research in Jordan and whether a personal history of violence is associated with unfavorable experiences. This sequential exploratory mixed methods study included 17 focus group discussions (FGD) with women in Amman followed by a survey conducted in reproductive health clinics throughout the country (pilot n = 30; survey n = 517). Open coding was used to identify the theme related to participant reaction in the FGD data. This construct was further examined by the subsequent survey that included dichotomous questions inquiring whether the respondent thought the study questions were important and whether they were angry or felt resentment as a result of the survey. One open-ended question on the survey provided additional qualitative data on the theme that was combined with the FGD data. Themes identified in the qualitative data pertained to expressions of gratitude and comments on the survey's value. Findings of this study indicate that Jordanian women's responses to the research process are similar to women currently represented by the extant literature in that a vast majority of its participants felt that the study was important (95%) and it did not evoke anger or resentment (96%). Many even found the study to be useful to them personally or to society. Among those who had a negative emotional reaction, most still found the research to be important. This study's findings highlight the safety and potential benefits of ethically conducted violence research. PMID- 22203624 TI - Examining self-protection measures guarding Adult Protective Services social workers against compassion fatigue. AB - Little research has focused on the risk factors, effects, and experiences of compassion fatigue among gerontological social workers. This qualitative study explores the experiences and perspectives of nine Adult Protective Services (APS) social workers in relation to compassion fatigue. Results show that the APS social workers combined personal characteristics and professional factors to develop boundary-setting mechanisms that protected them from experiencing the deleterious symptoms and effects of compassion fatigue. Implications center around the elements needed to implement boundaries in order to maintain a separation between the work and home environment. Suggestions for future research are provided. PMID- 22203625 TI - Intimate partner violence and alcohol problems in interethnic and intraethnic couples. AB - Despite the growing number of interethnic marriages in the United States, few studies have examined intimate partner violence (IPV) in interethnic couples. This article examined past-year occurrences of IPV across interethnic and intraethnic couples and tested correlates of IPV specifically in interethnic couples. Data were from a national survey of couples 18 years of age and older from the 48 contiguous states. Interethnic couples (n = 116) included partners from different ethnic backgrounds, including Black-White, Hispanic-White, and Black-Hispanic couples. White (n = 555), Black (n = 358), and Hispanic (n = 527) intraethnic couples included partners with the same ethnicity. Data analyses were prevalence rates and logistic regressions. The analysis showed that interethnic couples were comparatively younger and had shorter relationships than intraethnic White, Black, and Hispanic couples. Male partners in interethnic couples had higher rates of binge drinking and alcohol problems compared with male partners in intraethnic couples. Past-year prevalence rates for any occurrence of IPV and acts of severe IPV were higher for interethnic couples relative to intraethnic couples. Most occurrences of IPV for interethnic couples were mutual. Factors predicting IPV among interethnic couples included marital status, couples' age, male alcohol problems, and female impulsivity. Mounting evidence points to interethnic couples as a high-risk group for IPV. Interethnic couples may be at greater risk for IPV because of their younger age, binge drinking, and alcohol problems. Future research could build on this study by examining cohort effects and regional differences in IPV for interethnic couples and the risk for IPV across interethnic couples of different ethnic compositions. PMID- 22203626 TI - Victims' influence on intimate partner violence revictimization: an empirical test of dynamic victim-related risk factors. AB - Research has reported that not only characteristics of the perpetrator but also characteristics of the victim influence risk for intimate partner violence (IPV). This would suggest that prevention of repeat abuse could benefit from a focus on both perpetrator and victim characteristics. Knowledge on factors that are within victims' sphere of influence is important because a focus on victim characteristics can help victims to take control of their situations and can thereby empower them. Dynamic victim-related factors are most relevant here as these are factors that can be changed or improved, in contrast to unchangeable static factors. Surprisingly, however, little is known about how victim-related factors affect risk for revictimization of IPV. The current study was conducted among a Dutch sample of 156 female, help-seeking IPV victims. The aim was to examine to what extent prior IPV and, in particular, dynamic victim-related factors influence risk for future IPV. In accordance with the models articulated by Foa, Cascardi, Zoellner and Feeny, we studied how the three key factors from their models-partner violence, victims' psychological difficulties, and victims' resilience-related to risk for IPV revictimization. Results provide support for several key factors (partner violence and victims' psychological difficulties) and, moreover, show which victim-related factors contribute to revictimization risk above and beyond the influence of prior violence committed by a partner against the victim (i.e., victims' prior IPV victimizations). Findings are discussed in terms of recommendations for practice and future research. PMID- 22203627 TI - Characteristics of victims of sexual abuse by gender and race in a community corrections population. AB - The purpose of this study was to examine how victims of sexual abuse in a community corrections population differ as a result of their sex and race. Of the 19,422 participants, a total of 1,298 (6.7%) reported a history of sexual abuse and were compared with nonabused participants. The sample was analyzed by race gender groups (White men, White women, African American men, and African American women) using univariate and logistic regression analyses, which were conducted separately for each group. White women were the most likely to report a history of sexual abuse (26.5%), followed by African American women (16.0%), White men (4.0%), and African American men (1.1%). For all groups, histories of suicidal ideation and suicide attempts were associated with a history of sexual abuse. Sexual abuse was associated with substance abuse problems for women but not the men. Cannabis dependence was associated with sexual abuse for the White women while cocaine dependence was associated with sexual abuse for the African American women. Several other variables were associated with sexual abuse for women but not men, including lower education (White women only), a history of violent offenses (White women only), and living in a shelter (African American women only). African American men tended to have higher levels of education; this was the only variable uniquely associated with either male group. Receiving psychiatric medications was associated with sexual abuse for all groups except African American men and a history of sex for drugs was associated with sexual abuse for all groups except White men. Consistent with national sample, women, particularly White women, were more likely to be victims of sexual abuse. The gender-race differences for the sociodemographic factors associated with sexual abuse, particularly the risk of substance abuse for women, suggest the need for tailored interventions for sexual abuse prevention and treatment. PMID- 22203628 TI - Social anxiety as a predictor of dating aggression. AB - By far, most research on the behavior of socially anxious individuals has focused on the "flight" rather than the "fight" response described in the traditional conceptualization of anxiety. More recently, however, there has been some speculation and emerging evidence suggesting that social anxiety and aggression may be related. The present study examined social anxiety as a predictor of dating aggression within a late adolescent sample. Two forms of dating aggression were assessed: physical aggression, such as slapping, use of a weapon, or forced sexual activity, and psychological aggression, such as slamming doors, insulting, or refusing to talk to one's partner. One aspect of social anxiety, Fear of Negative Evaluation (FNE), emerged as a significant predictor of male dating aggression, even after controlling for relationship quality. Notably, FNE was most predictive of increased aggression of both types when men also perceived their romantic relationship to be more antagonistic. Despite its demonstrated importance as a contextual variable, however, relationship quality did not mediate the association between FNE and psychological or physical aggression. Implications for prevailing conceptualizations of social anxiety and dating aggression are discussed. PMID- 22203630 TI - Predicting overt and cyber stalking perpetration by male and female college students. AB - In this study, self-report student surveys on early childhood maltreatment, attachment styles, alcohol expectancies, and narcissistic personality traits are examined to determine their influence on stalking behavior. Two subtypes of stalking were measured using Spitzberg and Cupach's (2008) Obsessive Relational Intrusion: cyber stalking (one scale) and overt stalking (comprised of all remaining scales). As t tests indicated that men and women differed significantly on several variables, OLS regression models were run separately for men (N = 807) and women (N = 934). Results indicated that childhood sexual maltreatment predicted both forms of stalking for men and women. For men, narcissistic vulnerability and its interaction with sexual abuse predicted stalking behavior (overt stalking R2 = 16% and cyber stalking R2 = 11%). For women, insecure attachment (for both types of stalking) and alcohol expectancies (for cyber stalking) predicted stalking behavior (overt stalking R2 = 4% and cyber stalking R2 = 9%). We discuss the methodological and policy implications of these findings. PMID- 22203629 TI - The economic costs of partner violence and the cost-benefit of civil protective orders. AB - Partner violence affects a significant number of women and their children each year. Estimates of the economic costs of partner violence are substantial. However, most estimates of the costs of partner violence are made at the aggregate level rather than the individual level. Estimating costs at the individual level allows for a wider range of costs of partner violence to be considered. This study is one of the first to examine a wide range of economic costs of partner violence and to examine the economic costs and cost-benefits of civil protective orders. Overall, including changes in quality of life, protective orders were estimated to have saved taxpayers in one small state US$85 million in a 1-year period. More generally, this study provides a framework to address more specific complexities associated with cost-benefit analyses of partner violence and the impact of justice system interventions. PMID- 22203631 TI - The role of alcohol and victim sexual interest in Spanish students' perceptions of sexual assault. AB - Two studies investigated the effects of information related to rape myths on Spanish college students' perceptions of sexual assault. In Study 1, 92 participants read a vignette about a nonconsensual sexual encounter and rated whether it was a sexual assault and how much the woman was to blame. In the scenario, the man either used physical force or offered alcohol to the woman to overcome her resistance. Rape myth acceptance (RMA) was measured as an individual difference variable. Participants were more convinced that the incident was a sexual assault and blamed the woman less when the man had used force rather than offering her alcohol. In Study 2, 164 college students read a scenario in which the woman rejected a man's sexual advances after having either accepted or turned down his offer of alcohol. In addition, the woman was either portrayed as being sexually attracted to him or there was no mention of her sexual interest. Participants' RMA was again included. High RMA participants blamed the victim more than low RMA participants and were less certain that the incident was a sexual assault, especially when the victim had accepted alcohol and was described as being sexually attracted to the man. The findings are discussed in terms of their implications for the prevention and legal prosecution of sexual assault. PMID- 22203632 TI - Adult violence with the mother and sibling as predictors of partner violence. AB - The present study provides the first available evaluation of how violence with the mother and siblings during adulthood is associated with the occurrence of partner violence in young adults. Because a pattern of reciprocal partner violence is well documented, the authors hypothesized that reciprocal violence would also be found for adults and their mothers and for adults and their siblings. The authors also hypothesized that reciprocal violence with the mother and sisters would explain variance in partner violence even when controlling for other known predictors (poverty, poor family support, stress, anger, low self esteem). Study participants included 377 college adults (114 men, 263 women; mean age = 24.4 years) who completed questionnaires to report their present violence to and from their mothers, sisters, brothers, and romantic partners. Violence is measured with a modified Conflict Tactics Scale. No sibling gender differences are found in violence reported as adults. Factor analysis confirms good fit for three clusters of reciprocal violence for adults: violence with the mother, violence with siblings, violence with the romantic partner. Violence with the mother and siblings significantly explains variance in partner violence even after controlling for other contextual variables, but only for women. One interpretation of present results is that because women receive less socialization than men to use violence, these two within-family models of violence have more significance for increasing their risk of partner violence. Partner violence prevention programs could include participation of mothers and siblings to enhance development of more peaceful conflict resolution patterns within and outside the family. PMID- 22203633 TI - Reducing risk for sexual victimization: an analysis of the perceived socioemotional consequences of self-protective behaviors. AB - The current study examined college women's perceptions of the positive and negative socioemotional consequences associated with engaging in self-protective behaviors to reduce risk for sexual victimization. At baseline, women completed assessments of the extent to which they would experience positive or negative socioemotional consequences as a result of engaging in various self-protective behaviors. At a 2-month follow-up, women reported on their engagement in self protective behaviors and experience of sexual victimization over the interim (N = 143). At baseline, some self-protective strategies were perceived as having more positive or negative socioemotional consequences than others. Perceiving a high level of negative socioemotional consequences associated with taking precautions prior to a date was associated with sexual victimization over the 2-month follow up. PMID- 22203634 TI - Repetition, power imbalance, and intentionality: do these criteria conform to teenagers' perception of bullying? A role-based analysis. AB - The criteria that researchers use to classify aggressive behaviour as bullying are 'repetition', 'power imbalance', and 'intent to hurt'. However, studies that have analyzed adolescents' perceptions of bullying find that most adolescents do not simultaneously consider these three criteria. This paper examines adolescents' perceptions of bullying and of the different forms it takes, and whether these perceptions vary according to the teen's role of victim, aggressor, or witness in a bullying situation. The data acquisition instrument was a questionnaire applied to a sample of 2295 teenagers. The results show that none of these three groups considered the criterion of repetition to be important to define bullying. A further conclusion was that both aggressors and witnesses used the criteria of 'power imbalance' and 'intent to hurt' to identify a situation of bullying, although the aggressors placed especial emphasis on the superiority of power over the victim, while the witnesses emphasized the intent to hurt the victim. One noteworthy finding was that victims do not consider the factor 'power imbalance'. The factor that determined their perceptions was the 'intent to hurt'. Finally, some modes of bullying were seen as forms of typical teen social interactions, and the perception depended significantly on the adolescent's role as aggressor, victim, or witness. PMID- 22203635 TI - Associations between intimate partner violence and emotional distress among pregnant women in Durban, South Africa. AB - Intimate partner violence (IPV) during pregnancy has been associated with multiple negative health outcomes including emotional distress during pregnancy. However, little is known about IPV during pregnancy and its association with emotional distress among South African women. The objectives of this study were to determine the prevalence of both emotional distress and IPV during pregnancy, to identify whether different exposures of violence were associated with emotional distress and to assess whether social support attenuated the relationship between IPV and emotional distress. Pregnant women enrolled in the South Africa HIV Antenatal and Posttest Support Study (SAHAPS) who completed the baseline survey were included in this cross sectional analysis. We used logistic regression models to explore bivariate and multivariate relationships between the proposed covariates and emotional distress. Nearly a quarter of women experienced some type of IPV during the current pregnancy, with psychological violence being the most prevalent. The odds of emotional distress was 1.41 times (95% CI: [1.26, 1.57]) higher for each additional episode of psychological violence and 2.01 times (95% CI: [1.16, 3.77]) higher for each additional episode of sexual violence during pregnancy, adjusting for other covariates. Physical violence was only marginally associated with increased odds of emotional distress. Finally, social support was marginally significant as a main effect but did not attenuate the relationship between IPV and emotional distress. The high prevalence of IPV among South African women and its association with emotional distress during pregnancy suggest that interventions that reduce violence during or prior to pregnancy are needed. PMID- 22203636 TI - State employment protection statutes for victims of domestic violence: public policy's response to domestic violence as an employment matter. AB - Evidence indicates that domestic violence has negative consequences on victims' employment; yet employers lag in recognizing this as a workplace issue. To address the problem, some states have established several policy solutions. To understand the scope of the public sector's response to domestic violence as a workplace issue, a content analysis of state-level employment protection policies for domestic violence victims (N = 369) was conducted. Results indicate three broad policy categories: (a) policies that offer work leave for victims; (b) policies that aim to reduce employment discrimination of domestic violence victims; and (c) policies that aim to increase awareness and safety in the workplace. Subcategories emerged within each of these three categories. Implementation of employment protection policies varies significantly across states. Implications for workplaces, practitioners, and policy leaders are discussed. PMID- 22203637 TI - The effect of acculturation and immigration on the victimization and psychological distress link in a national sample of Latino women. AB - Distinct bodies of research have examined the link between victimization and psychological distress and cultural variables and psychological health, but little is known about how cultural variables affect psychological distress among Latino victims. Substantial research has concluded that Latino women are more likely than non-Latino women to experience trauma-related symptoms following victimization. In addition, examination of different types of cultural adaptation has found results supporting the idea that maintaining ties with one's culture of origin may be protective against negative mental health outcomes. The present study evaluates the effect of victimization, immigrant status, and both Anglo and Latino orientation on psychological distress in a national sample of Latino women. Results indicate that along with the total count of victimization experiences, Anglo and/or Latino orientation were strong predictors of all forms of psychological distress. Anglo orientation also functioned as a moderator between victimization and psychological distress measures for anger, dissociation, and anxiety. The results suggest a more nuanced and complex interaction between cultural factors, victimization, and psychological distress. PMID- 22203639 TI - Assessing desistance in child molesters: a qualitative analysis. AB - The aim of the study was to investigate the process of desistance from sexual crime by comparing two groups of child molesters: One group was deemed to be desisting, while men in the other group were deemed as being still potentially active offenders. Men in the desisting group reported being optimistic for the future, reported an enhanced sense of personal agency and a more internalized locus of control, and identified treatment as being a turning point in their lives. In comparison, men in the active group were found to be more pessimistic and were more likely to blame external events, or situations, for their problems. One of the most striking findings of the research was that the desisting group had found a place within a social group or network, unlike the still potentially active offenders who all described a life of social isolation and alienation. PMID- 22203638 TI - Peer influences on the dating aggression process among Brazilian street youth: a brief report. AB - This study explored risk factors for adolescent dating aggression (ADA) among Brazilian street youth. Forty-three adolescents, between the ages of 13 and 17 years, were recruited at services centers in Porto Alegre, Brazil. Simultaneous multiple regression revealed that ADA was significantly predicted by adolescent dating victimization (ADV), and that this relationship was moderated by peer involvement in dating aggression. Results also revealed that peer involvement in dating aggression did not significantly predict ADA. These findings suggested that having peers who are involved in dating aggression exacerbates the effects of dating victimization on ADA among Brazilian street youth. However, ADV might be a stronger risk factor for dating aggression in this population, because when controlling for the effects of victimization in dating conflicts peer abuse toward romantic partners did not uniquely contribute to ADA. PMID- 22203640 TI - Intimate partner violence perpetration by court-ordered men: distinctions among subtypes of physical violence, sexual violence, psychological abuse, and stalking. AB - This study continues previous work documenting the structure of violence perpetrated by males against their female intimate partners. It assesses the construct validity of a measurement model depicting associations among eight subtypes of perpetration: moderate physical violence, severe physical violence, forced or coerced sexual violence, sexual violence where consent was not possible, emotional/verbal psychological abuse, dominance/isolation psychological abuse, interactional contacts/surveillance related stalking, and stalking involving mediated contacts. Data were obtained from a sample of 340 men arrested for physical assault of a female spouse or partner, and court ordered into batterer intervention programs. Men were surveyed before starting the intervention. Confirmatory factor analyses (CFA) supported the validity of model as evidenced by good model to data fit and satisfaction of requirements for fit statistics. In addition, the eight factor solution was characterized by a slightly better model to data fit than a four factor higher order solution described in the author's previous work. Latent variable correlations across the broader categories of intimate partner violence (IPV) revealed that the violence subtypes were mostly moderately positively correlated and ranged from .381 (emotional/verbal psychological abuse with interactional contacts/surveillance related stalking) to .795 (dominance/isolation psychological with abuse with forced sex). Future studies should determine whether there are distinct risk factors and health outcomes associated with each of the eight IPV perpetration subtypes and identify possible patterns of co-occurrence. PMID- 22203641 TI - A cadaveric study of needle insertion at PC6 in eight wrists of four subjects and an understanding of the anatomy. AB - The anatomical structures vulnerable to acupuncture around the PC6 acupuncture point were investigated. Needles were inserted in PC6 of eight wrists from four cadavers to a depth of 2 cm, the forearms were dissected and the adjacent structures around the path of the needles were observed. The needles passed between the tendons of the palmaris longus and flexor carpi radialis muscles and then penetrated the flexor digitorum superficialis, flexor digitorum profundus and pronator quadratus muscles. The inserted needles were located adjacent to the median nerve. To minimise the risk of unintended injury by acupuncture, it is recommended that needles should not be inserted deeply at the PC6 acupuncture point. An understanding of the anatomical variations of the median nerve and the persistent median artery in the forearm is of clinical importance when performing acupuncture procedures. PMID- 22203642 TI - Is there a difference between the effects of one-point and three-point indirect moxibustion stimulation on skin temperature changes of the posterior trunk surface? AB - OBJECTIVE: To determine whether any difference exists in responses to indirect moxibustion relative to thermal stimulation sites. METHODS: Twenty one healthy men of mean+/-SD age 22.5+/-6.1 years were randomly divided into two groups, one receiving a single moxibustion stimulation in three locations (the three-point stimulation group, n=10 participants) and the other receiving three stimulations in one location (the one-point stimulation group, n=11 participants). The thermal stimulation sites were GV14, GV9 and GV4 acupuncture points. A thermograph was used to obtain the skin temperature on the posterior trunks of the participants. To analyse skin temperature, four arbitrary frames (the scapular, interscapular, lumbar and vertebral regions) were made on the posterior trunk. RESULT: An increase in skin temperature on the posterior trunk was observed following both one- and three-point moxibustion administrations. The skin temperature of the lumbar region showed a significant increase after three-point stimulation compared with single-point stimulation (p=0.011). There was also a significant increase in skin temperature of the spinal region after three-point stimulation compared with one-point stimulation (p=0.046). CONCLUSION: Administration of single moxibustion doses on the GV14, GV9 and GV4 points produces greater changes in skin temperature than three applications of moxibustion to the GV14 point only. PMID- 22203643 TI - Discrimination against Muslim American adolescents. AB - Although there is ample evidence of discrimination toward Muslim Americans in general, there is limited information specific to Muslim American adolescents. The few existing studies specific to this age group suggest that Muslim American adolescents encounter much discrimination from teachers, school administrators, and classmates. This descriptive qualitative study complements the few existing studies on Muslim American adolescents by obtaining in-depth description of the discrimination they encounter. The sample was 14 Muslim American adolescents who participated in one of two gender-specific focus groups about their discrimination experiences. Findings identified school settings as rife with discrimination toward Muslims, portrayed Muslim girls as at risk for harassment by strangers in public places, and illustrated how Muslim youth cope with discrimination. The study findings sensitize school nurses to the nature of the problem and provide direction for intervention. PMID- 22203644 TI - Patient preference for emergency care: can and should it be changed? AB - The authors use a statewide survey to examine care seeking behavior in the emergency department (ED). Most patients who go to the ED (69.3%) do so mainly for conditions they believe are urgent. Time before seeking ED care is highly variable from immediately (28.7%) to more than 1 week (7.0%) and is only weakly related to the perceived urgency of medical condition. Healthier individuals initiate ED care more rapidly than sicker patients. In retrospect, 80.4% of patients would go to the same ED if they had the same medical episode but this percentage falls substantially with increased ED waiting time. Subject to some limitations uncovered in model specification tests, the study highlights several correlates of ED care seeking behavior that may be useful for designing strategies to divert some patients away from the ED. It also raises larger questions, however, about whether diversion is optimal from patient and health system perspectives. PMID- 22203645 TI - Factors associated with parental activation in pediatric hematopoietic stem cell transplant. AB - Patient activation, the extension of self-efficacy into self-management, is an essential component of effective chronic care. In pediatric populations, caregiver activation is also needed for proper disease management. This study investigates the relationships between parental activation and other characteristics of parent-child dyads (N = 198) presenting for pediatric hematopoietic stem cell transplant. Parental activation concerning their child's health was assessed using the Parent Patient Activation Measure (Parent-PAM), a modified version of the well-validated Patient Activation Measure (PAM). Using hierarchical linear regression and following the Belsky process model for determining parenting behaviors, a multivariate model was created for parental activation on behalf of their child that showed that the parent's age, rating of their own general health, self-activation, and duration of the child's illness were significantly related to Parent-PAM score. Our findings characterize a potentially distinct form of activation in a parent-child cohort preparing for a demanding clinical course. PMID- 22203647 TI - Hospital religious affiliation and outcomes for high-risk infants. AB - The effect of hospital organizational affiliation on perinatal outcomes is unknown. Using the 2004 American Hospital Association Annual Survey and Healthcare Cost and Utilization Project State Inpatient Databases, the authors examined relationships among organizational affiliation, equipment and service availability and provision, and in-hospital mortality for 5,133 infants across five states born with very low and extremely low birth weight and congenital anomalies. In adjusted bivariate probit selection models, the authors found that government hospitals had significantly higher mortality rates than not-for-profit nonreligious hospitals. Mortality differences among other types of affiliation (Catholic, not-for-profit religious, not-for-profit nonreligious, and for-profit) were not statistically significant. This is encouraging as health care reform efforts call for providers at facilities with different institutional values to coordinate care across facilities. Although there are anecdotes of facility religious affiliation being related to health care decisions, the authors did not find evidence of these relationships in their data. PMID- 22203646 TI - A compilation of strategies for implementing clinical innovations in health and mental health. AB - Efforts to identify, develop, refine, and test strategies to disseminate and implement evidence-based treatments have been prioritized in order to improve the quality of health and mental health care delivery. However, this task is complicated by an implementation science literature characterized by inconsistent language use and inadequate descriptions of implementation strategies. This article brings more depth and clarity to implementation research and practice by presenting a consolidated compilation of discrete implementation strategies, based on a review of 205 sources published between 1995 and 2011. The resulting compilation includes 68 implementation strategies and definitions, which are grouped according to six key implementation processes: planning, educating, financing, restructuring, managing quality, and attending to the policy context. This consolidated compilation can serve as a reference to stakeholders who wish to implement clinical innovations in health and mental health care and can facilitate the development of multifaceted, multilevel implementation plans that are tailored to local contexts. PMID- 22203648 TI - Characterization of 24 transferable microsatellite loci in four skullcaps (Scutellaria, Labiatae). AB - PREMISE OF THE STUDY: Transferable polymorphic microsatellite loci for four skullcaps, Scutellaria indica, S. taiwanensis, S. austrotaiwanensis, and S. playfairii, were developed for future studies of the mating system and population structure of these species. Interspecific amplification was also tested in various Scutellaria species. METHODS AND RESULTS: Twelve novel polymorphic microsatellite loci were isolated from four S. taiwanensis specimens, and seven are interspecifically transferable. Microsatellite loci developed from S. austrotaiwanensis in a previous study were also analyzed in the other three species, and 12 loci were found to be transferable. Allele numbers of the total 24 loci for S. indica, S. taiwanensis, S. playfairii, and S. austrotaiwanensis are two to four, two, two to five, and two to three, respectively, with an expected heterozygosity ranging from 0.114-0.661, 0.062-0.499, 0.280-0.730, and 0.268-0.662, respectively. The interspecies transferability of these 24 loci was further tested in another 10 Scutellaria species, including three species native to Taiwan. Seventeen loci were found to be interspecifically amplifiable, especially among the Taiwan native species. CONCLUSIONS: These highly polymorphic and transferable loci will be useful for future studies of the mating system of closely related Scutellaria species. PMID- 22203650 TI - Microsatellite markers derived from Calophyllum inophyllum (Clusiaceae) expressed sequence tags. AB - PREMISE OF THE STUDY: Robust markers are required (inter alia) for assessing origins of Calophyllum inophyllum populations on the Bonin Islands, Japan. Therefore, informative expressed sequence tag (EST)-based microsatellite or simple sequence repeat (SSRs) markers in the species were sought. METHODS AND RESULTS: Using 135378 ESTs derived from de novo pyrosequencing, primers for 475 EST-SSRs were developed, 48 of which were tested for PCR amplification. Thirty six of the 48 primers showed clear amplification, with 23 displaying polymorphism in sampled populations. Expected heterozygosity in the samples from the Bonin Islands and Ryukyu Islands populations ranged from 0.041 to 0.697 and from 0.041 to 0.773, respectively. CONCLUSIONS: As EST-SSRs are potentially tightly linked with functional genes, and reportedly more transferable to related species than anonymous genomic SSRs, the developed primers have utility for future studies of the origins, genetic structure, and conservation of C. inophyllum and related species. PMID- 22203649 TI - Isolation of compound microsatellite markers in Begonia fenicis (Begoniaceae) endemic to East and Southeast Asian islands. AB - PREMISE OF THE STUDY: We developed compound microsatellite markers for Begonia fenicis, a species endemic to eastern and southeastern Asian islands, to investigate geographical genetic structure. METHODS AND RESULTS: Using the compound microsatellite marker technique, 21 markers were developed and six polymorphic markers were characterized for samples from four islands in Taiwan and southern Japan. The number of alleles per locus ranged from two to six (mean = 4.33). Observed and expected heterozygosities were 0.125-0.725 (0.383) and 0.498-0.719 (0.641), and polymorphic information content was 0.371-0.664 (0.567). The interspecific transferability of the 21 markers was evaluated for eight species of the section Diploclinium from the Philippines; 15 markers were successfully amplified in one to eight species. CONCLUSIONS: These results indicate the utility of the six microsatellite markers in B. fenicis to investigate geographical genetic structure. The transferable markers are potentially useful for other species of the section. PMID- 22203651 TI - Microsatellite markers for the Chinese endangered and endemic orchid Cymbidium tortisepalum (Orchidaceae). AB - PREMISE OF THE STUDY: Microsatellite primers were developed in the Chinese endangered and endemic orchid, Cymbidium tortisepalum, to investigate its genetic diversity and population genetic structure, and to identify its varieties. METHODS AND RESULTS: Using the Fast Isolation by AFLP of Sequences Containing repeats (FIASCO) protocol, 15 primer sets were identified in two wild populations. The number of alleles per locus ranged from two to six, with a mean of 3.5. The observed and expected heterozygosities varied from 0.250 to 0.917 and from 0.228 to 0.841, respectively. All of these primers successfully amplified in the congener C. goeringii, and 12 were found useful in C. faberi and C. sinense. CONCLUSIONS: These markers will facilitate further studies on the population genetics and molecular identification of C. tortisepalum, its varieties, and other congener species. PMID- 22203652 TI - DNA-based assays to distinguish date palm (Arecaceae) gender. AB - PREMISE OF THE STUDY: Date palm (Phoenix dactylifera) is one of the oldest cultivated trees and is critical to the development of arid land. The date palm is a dioecious monocot with separate male and female trees. This presents a challenge in development as it is impossible to distinguish trees until they flower approximately five to eight years after planting. METHODS AND RESULTS: We have developed PCR-based assays capable of sex differentiation in multiple date palm cultivars. The primers are designed across gender-specific polymorphisms and demonstrated greater than 90% accuracy in distinguishing date palm gender across multiple varieties. CONCLUSIONS: These results indicate that the primers should be helpful in rapidly distinguishing date palm gender from the earliest stages that DNA can safely be collected. This is a vast savings in time over present approaches. PMID- 22203653 TI - Intraspecific variation in Podostemum ceratophyllum (Podostemaceae): evidence of refugia and colonization since the last glacial maximum. AB - PREMISE OF THE STUDY: Intraspecific variation among 20 populations of Podostemum ceratophyllum Michx. was investigated to test the hypothesis of range expansion from southern refugia since the last glacial maximum. METHODS: Six noncoding regions of chloroplast DNA were sequenced in 60 individuals. Populations were divided into two groups, north and south of the glacial boundary, in addition to isolated populations in Arkansas and Honduras. Variation in populations north of the boundary was compared with variation in populations to the south and in the isolated populations. KEY RESULTS: Nucleotide diversity was an order of magnitude lower in populations north of the glacial boundary than in those to the south. The Arkansas and Honduras populations showed no variation. The predominant haplotype in northern populations was also found in a Virginia population. CONCLUSIONS: Reduced variation north of the glacial boundary suggests a founder event associated with range expansion since the last glacial maximum. Colonization probably occurred from populations in refugia located several hundred kilometers south of the glacial boundary. The results provide insight into the effects of past and current climate change on patterns of geographic distribution and genetic variation in aquatic plants. PMID- 22203654 TI - New microsatellite markers for garlic, Allium sativum (Alliaceae). AB - PREMISE OF THE STUDY: A new set of microsatellite or simple sequence repeat (SSR) markers for garlic, an important medicinal spice, was developed to aid studies of genetic diversity and to define efficient strategies for germplasm conservation. METHODS AND RESULTS: Using a (CT)(8)- and (GT)(8)-enriched library, a total of 16 SSR loci were developed and optimized in garlic. Ten loci were found to be polymorphic after screening 75 accessions. The parameters used to characterize the loci were observed and expected heterozygosity, number of alleles, Shannon Index, and polymorphism information content (PIC). A total of 44 alleles were identified, with an average of 4.4 alleles per loci. The vast majority of loci were moderate to highly informative according to PIC and the Shannon Index. CONCLUSION: The new SSR markers have the potential to be informative tools for genetic diversity, allele mining, mapping and associative studies, and in the management and conservation of garlic collections. PMID- 22203655 TI - Evolutionary origin of the Asteraceae capitulum: Insights from Calyceraceae. AB - PREMISE OF THE STUDY: Phylogenies based on molecular data are revealing that generalizations about complex morphological structures often obscure variation and developmental patterns important for understanding the evolution of forms, as is the case for inflorescence morphology within the well-supported MGCA clade (Menyanthaceae + Goodeniaceae + Calyceraceae + Asteraceae). While the basal families share a basic thyrsic/thyrsoid structure of their inflorescences, Asteraceae possesses a capitulum that is widely interpreted as a racemose, condensed inflorescence. Elucidating the poorly known inflorescence structure of Calyceraceae, sister to Asteraceae, should help clarify how the Asteraceae capitulum evolved from thyrsic/thyrsoid inflorescences. METHODS: The early development and structure of the inflorescence of eight species (five genera) of Calyceraceae were studied by SEM, and patterns of evolutionary change were interpreted via phylogenetic character mapping. KEY RESULTS: The basic inflorescence structure of Calyceraceae is a cephalioid (a very condensed botryoid/thyrsoid). Optimization of inflorescence characters on a DNA sequence derived tree suggests that the Asteraceae capitulum derives from a simple cephalioid through two morphological changes: loss of the terminal flower and suppression of the cymose branching pattern in the peripheral branches. CONCLUSIONS: Widely understood as a condensed raceme, the Asteraceae capitulum is the evolutionary result of a very reduced, condensed thyrsoid. Starting from that point, evolution worked separately only on the racemose developmental control/pattern within Asteraceae and mainly on the cymose developmental control/pattern within Calyceraceae, producing head-like inflorescences in both groups but with very different diversification potential. We also discuss possible remnants of the ancestral cephalioid structure in some Asteraceae. PMID- 22203656 TI - Characterization and cross application of novel microsatellite markers for a rare sedge, Lepidosperma gibsonii (Cyperaceae). AB - PREMISE OF THE STUDY: Ten polymorphic microsatellite loci for the rare sword sedge Lepidosperma gibsonii (Cyperaceae) were characterized for the future study of population structure, hybridization, and clonality. METHODS AND RESULTS: Twenty samples from each of three populations were screened with the markers to assess genetic variation. Observed population heterozygosities ranged from 0.35 to 1.00, and number of alleles observed per locus ranged from eight to 23. No departures from Hardy-Weinberg equilibrium were detected for any locus in any population. Single samples from 14 species were screened to examine the transferability of the microsatellites to other species of Lepidosperma. At least eight out of 10 loci amplified in all species tested. CONCLUSIONS: These loci will be useful for studying genetic variation, hybridization, dispersal, and breeding systems in Lepidosperma, a ubiquitous element of the flora of southern Australia. PMID- 22203657 TI - Role of continuous monitoring for optimizing management strategies in patients with early arrhythmia recurrences after atrial fibrillation ablation. PMID- 22203658 TI - The Yin and Yang of convective cooling in radiofrequency catheter ablation. PMID- 22203659 TI - "Cardiac KATP": a family of ion channels. PMID- 22203660 TI - How to perform and interpret provocative testing for the diagnosis of Brugada syndrome, long-QT syndrome, and catecholaminergic polymorphic ventricular tachycardia. PMID- 22203661 TI - Signals and signal processing for the electrophysiologist: part I: electrogram acquisition. PMID- 22203662 TI - Signals and signal processing for the electrophysiologist: part II: signal processing and artifact. PMID- 22203663 TI - Teaching points with 3-dimensional mapping of cardiac arrhythmia: how to overcome potential pitfalls during substrate mapping? PMID- 22203665 TI - Successful ablation of an epicardial ventricular tachycardia using a surgical ablation tool. PMID- 22203666 TI - Letter by Opthof et al regarding article, "Prolonged Tpeak to tend interval on the resting electrocardiogram is associated with increased risk of sudden cardiac death". PMID- 22203668 TI - The internal region leucine-rich repeat 6 of decorin interacts with low density lipoprotein receptor-related protein-1, modulates transforming growth factor (TGF)-beta-dependent signaling, and inhibits TGF-beta-dependent fibrotic response in skeletal muscles. AB - Decorin is a small proteoglycan, composed of 12 leucine-rich repeats (LRRs) that modulates the activity of transforming growth factor type beta (TGF-beta) and other growth factors, and thereby influences proliferation and differentiation in a wide array of physiological and pathological processes, such as fibrosis, in several tissues and organs. Previously we described two novel modulators of the TGF-beta-dependent signaling pathway: LDL receptor-related protein (LRP-1) and decorin. Here we have determined the regions in decorin that are responsible for interaction with LRP-1 and are involved in TGF-beta-dependent binding and signaling. Specifically, we used decorin deletion mutants, as well as peptides derived from internal LRR regions, to determine the LRRs responsible for these decorin functions. Our results indicate that LRR6 and LRR5 participate in the interaction with LRP-1 and TGF-beta as well as in its dependent signaling. Furthermore, the internal region (LRR6i), composed of 11 amino acids, is responsible for decorin binding to LRP-1 and subsequent TGF-beta-dependent signaling. Furthermore, using an in vivo approach, we also demonstrate that the LRR6 region of decorin can inhibit TGF-beta mediated action in response to skeletal muscle injury. PMID- 22203669 TI - Interleukin 32 (IL-32) contains a typical alpha-helix bundle structure that resembles focal adhesion targeting region of focal adhesion kinase-1. AB - IL-32 can be expressed in several isoforms. The amino acid sequences of the major IL-32 isoforms were used to predict the secondary and tertiary protein structure by I-TASSER software. The secondary protein structure revealed coils and alpha helixes, but no beta sheets. Furthermore, IL-32 contains an RGD motif, which potentially activates procaspase-3 intracellular and or binds to integrins. Mutation of the RGD motif did not result in inhibition of the IL-32beta- or IL 32gamma-induced cytotoxicity mediated through caspase-3. Although IL-32alpha interacted with the extracellular part of alphaVbeta3 and alphaVbeta6 integrins, only the alphaVbeta3 binding was inhibited by small RGD peptides. Additionally, IL-32beta was able to bind to alphaVbeta3 integrins, whereas this binding was not inhibited by small RGD peptides. In addition to the IL-32/integrin interactions, we observed that IL-32 is also able to interact with intracellular proteins that are involved in integrin and focal adhesion signaling. Modeling of IL-32 revealed a distinct alpha-helix protein resembling the focal adhesion targeting region of focal adhesion kinase (FAK). Inhibition of FAK resulted in modulation of the IL 32beta- or IL-32gamma-induced cytotoxicity. Interestingly, IL-32alpha binds to paxillin without the RGD motif being involved. Finally, FAK inhibited IL 32alpha/paxillin binding, whereas FAK also could interact with IL-32alpha, demonstrating that IL-32 is a member of the focal adhesion protein complex. This study demonstrates for the first time that IL-32 binds to the extracellular domain of integrins and to intracellular proteins like paxillin and FAK, suggesting a dual role for IL-32 in integrin signaling. PMID- 22203670 TI - A chemokine receptor CXCR2 macromolecular complex regulates neutrophil functions in inflammatory diseases. AB - Inflammation plays an important role in a wide range of human diseases such as ischemia-reperfusion injury, arteriosclerosis, cystic fibrosis, inflammatory bowel disease, etc. Neutrophilic accumulation in the inflamed tissues is an essential component of normal host defense against infection, but uncontrolled neutrophilic infiltration can cause progressive damage to the tissue epithelium. The CXC chemokine receptor CXCR2 and its specific ligands have been reported to play critical roles in the pathophysiology of various inflammatory diseases. However, it is unclear how CXCR2 is coupled specifically to its downstream signaling molecules and modulates cellular functions of neutrophils. Here we show that the PDZ scaffold protein NHERF1 couples CXCR2 to its downstream effector phospholipase C (PLC)-beta2, forming a macromolecular complex, through a PDZ based interaction. We assembled a macromolecular complex of CXCR2.NHERF1.PLC beta2 in vitro, and we also detected such a complex in neutrophils by co immunoprecipitation. We further observed that the CXCR2-containing macromolecular complex is critical for the CXCR2-mediated intracellular calcium mobilization and the resultant migration and infiltration of neutrophils, as disrupting the complex with a cell permeant CXCR2-specific peptide (containing the PDZ motif) inhibited intracellular calcium mobilization, chemotaxis, and transepithelial migration of neutrophils. Taken together, our data demonstrate a critical role of the PDZ-dependent CXCR2 macromolecular signaling complex in regulating neutrophil functions and suggest that targeting the CXCR2 multiprotein complex may represent a novel therapeutic strategy for certain inflammatory diseases. PMID- 22203671 TI - Glypican-1 stimulates Skp2 autoinduction loop and G1/S transition in endothelial cells. AB - The heparan sulfate proteoglycan glypican-1 (GPC1) is involved in tumorigenesis and angiogenesis and is overexpressed frequently in tumor and endothelial cells (ECs) in human gliomas. We demonstrated previously that in brain EC, GPC1 regulates mitotic cyclins and securin as well as mitosis and that GPC1 is required for progression through the cell cycle. To characterize the molecular mechanism underlying cell cycle regulation by GPC1, we systematically investigated its effects on key G(1)/S checkpoint regulators and on major signaling pathways reportedly activated by Dally (Division abnormally delayed) the Drosophila GPC1 homologue. We found that elevated GPC1 affected a wide range of G(1)/S checkpoint regulators, leading to inactivation of the G(1)/S checkpoint and increased S phase entry, apparently by activating the mitogen-independent Skp2 autoinduction loop. Specifically, GPC1 suppressed CDK inhibitors (CKIs), including p21, p27, p16, and p19, and the D cyclins, and induced CDK2 and Skp2. GPC1 may trigger the Skp2 autoinduction loop at least partially by suppressing p21 transcription as knockdown of p21 by RNAi can mimic the effect of GPC1 on the cell cycle regulators related to the loop. Moreover, multiple mitogenic signaling pathways, including ERK MAPK, Wnt and BMP signaling, were significantly stimulated by GPC1 as has been reported for Dally in Drosophila. Notably, the c Myc oncoprotein, which is frequently up-regulated by both ERK and Wnt signaling and functions as a potent transcription repressor for CKIs as well as D cyclins, was also significantly induced by GPC1. These findings provide mechanistic insights into how GPC1 regulates the cell cycle and proliferation. PMID- 22203672 TI - c-Cbl ubiquitin ligase regulates focal adhesion protein turnover and myofibril degeneration induced by neutrophil protease cathepsin G. AB - The neutrophil-derived serine protease, cathepsin G (Cat.G), has been shown to induce myocyte detachment and apoptosis by anoikis through down-regulation of focal adhesion (FA) signaling. However, the mechanisms that control FA protein stability and turnover in myocytes are not well understood. Here, we have shown that the Casitas b-lineage lymphoma (c-Cbl), adaptor protein with an intrinsic E3 ubiquitin ligase activity, is involved in FA and myofibrillar protein stability and turnover in myocytes. Cat.G treatment induced c-Cbl activation and its interaction with FA proteins. Deletion of c-Cbl using c-Cbl knock-out derived myocytes or inhibition of c-Cbl ligase activity significantly reduced FA protein degradation, myofibrillar degeneration, and myocyte apoptosis induced by Cat.G. We also found that inhibition of the proteasome activity, but not the lysosome or the calpain activity, markedly attenuated FA and myofibrillar protein degradation induced by Cat.G. Interestingly, c-Cbl activation induced by Cat.G was mediated through epidermal growth factor receptor (EGFR) transactivation as inhibition of EGFR kinase activity markedly attenuated c-Cbl phosphorylation and FA protein degradation induced by Cat.G. These findings support a model in which neutrophil protease Cat.G promotes c-Cbl interaction with FA proteins, resulting in enhanced c-Cbl-mediated FA protein ubiquitination and degradation, myofibril degradation, and subsequent down-regulation of myocyte survival signaling. PMID- 22203673 TI - Engineering upper hinge improves stability and effector function of a human IgG1. AB - Upper hinge is vulnerable to radical attacks that result in breakage of the heavy light chain linkage and cleavage of the hinge of an IgG1. To further explore mechanisms responsible for the radical induced hinge degradation, nine mutants were designed to determine the roles that the upper hinge Asp and His play in the radical reactions. The observation that none of these substitutions could inhibit the breakage of the heavy-light chain linkage suggests that the breakage may result from electron transfer from Cys(231) directly to the heavy-light chain linkage upon radical attacks, and implies a pathway separate from His(229) mediated hinge cleavage. On the other hand, the substitution of His(229) with Tyr showed promising advantages over the native antibody and other substitutions in improving the stability and function of the IgG1. This substitution inhibited the hinge cleavage by 98% and suggests that the redox active nature of Tyr did not enable it to replicate the ability of His to facilitate radical induced degradation. We propose that the lower redox potential of Tyr, a residue that may be the ultimate sink for oxidizing equivalents in proteins, is responsible for the inhibition. More importantly, the substitution increased the antibody's binding to FcgammaRIII receptors by 2-3-fold, and improved ADCC activity by 2 fold, while maintaining a similar pharmacokinetic profile with respect to the wild type. Implications of these observations for antibody engineering and development are discussed. PMID- 22203674 TI - Mechanism of MTA1 protein overexpression-linked invasion: MTA1 regulation of hyaluronan-mediated motility receptor (HMMR) expression and function. AB - Even though the hyaluronan-mediated motility receptor (HMMR), a cell surface oncogenic protein, is widely up-regulated in human cancers and correlates well with cell motility and invasion, the underlying molecular and nature of its putative upstream regulation remain unknown. Here, we found for the first time that MTA1 (metastatic tumor antigen 1), a master chromatin modifier, regulates the expression of HMMR and, consequently, its function in breast cancer cell motility and invasiveness. We recognized a positive correlation between the levels of MTA1 and HMMR in human cancer. Furthermore, MTA1 is required for optimal expression of HMMR. The underlying mechanism includes interaction of the MTA1.RNA polymerase II.c-Jun coactivator complex with the HMMR promoter to stimulates its transcription. Accordingly, selective siRNA-mediated knockdown of HMMR in breast cancer cells substantially reduces the invasion and migration of cells. These findings reveal a regulatory role for MTA1 as an upstream coactivator of HMMR expression and resulting biological phenotypes. PMID- 22203675 TI - Axin pathway activity regulates in vivo pY654-beta-catenin accumulation and pulmonary fibrosis. AB - Epithelial to mesenchymal transition (EMT) and pulmonary fibrogenesis require epithelial integrin alpha3beta1-mediated cross-talk between TGFbeta1 and Wnt signaling pathways. One hallmark of this cross-talk is pY654-beta-catenin accumulation, but whether pY654-beta-catenin is a biomarker of fibrogenesis or functionally important is unknown. To clarify further the role of beta-catenin in fibrosis, we explored pY654-beta-catenin generation and function. alpha3beta1 was required for TGFbeta1-mediated activation of Src family kinases, and Src inhibition blocked both pY654 and EMT in primary alveolar epithelial cells (AECs). TGFbeta1 stimulated beta-catenin/Lef1-dependent promoter activity comparably in immortalized AECs stably expressing WT beta-catenin as well as Y654E or Y654F beta-catenin point mutants. But EMT was abrogated in the Tyr to Phe mutant. pY654-beta-catenin was sensitive to the axin beta-catenin turnover pathway as inhibition of tankyrase 1 led to high AEC axin levels, loss of pY654 beta-catenin, and inhibition of EMT ex vivo. Mice given a tankyrase inhibitor (50 mg/kg orally) daily for 7 days beginning 10 days after intratracheal bleomycin had improved survival over controls. Treated mice developed raised axin levels in the lung that abrogated pY654-beta-catenin and attenuated lung Snail1, Twist1, alpha-smooth muscle actin, and type I collagen accumulation. Total beta-catenin levels were unaltered. These findings identify Src kinase(s) as a mediator of TGFbeta1-induced pY654-beta-catenin, provide evidence that pY654-beta-catenin levels are a critical determinant of EMT and fibrogenesis, and suggest regulation of axin levels as a novel therapeutic approach to fibrotic disorders. PMID- 22203676 TI - Amidoxime reductase system containing cytochrome b5 type B (CYB5B) and MOSC2 is of importance for lipid synthesis in adipocyte mitochondria. AB - Reduction of hydroxylamines and amidoximes is important for drug activation and detoxification of aromatic and heterocyclic amines. Such a reductase system was previously found to be of high activity in adipose tissue and liver, and furthermore, in vitro studies using recombinant truncated and purified enzymes suggested the participation of cytochrome b(5) reductase (CYB5R), cytochrome b(5) (CYB5), and molybdenum cofactor sulfurase C-terminal containing 1 and 2 (MOSC1 and -2). Here, we show that purified rat liver outer mitochondrial membrane contains high amidoxime reductase activity and that MOSC2 is exclusively localized to these membranes. Moreover, using the same membrane fraction, we could show direct binding of a radiolabeled benzamidoxime substrate to MOSC2. Following differentiation of murine 3T3-L1 cells into mature adipocytes, the MOSC2 levels as well as the amidoxime reductase activity were increased, indicating that the enzyme is highly regulated under lipogenic conditions. siRNA mediated down-regulation of MOSC2 and the mitochondrial form of cytochrome b(5) type B (CYB5B) significantly inhibited the reductase activity in the differentiated adipocytes, whereas down-regulation of MOSC1, cytochrome b(5) type A (CYB5A), CYB5R1, CYB5R2, or CYB5R3 had no effect. Down-regulation of MOSC2 caused impaired lipid synthesis. These results demonstrate for the first time the direct involvement of MOSC2 and CYB5B in the amidoxime reductase activity in an intact cell system. We postulate the presence of a novel reductive enzyme system of importance for lipid synthesis that is exclusively localized to the outer mitochondrial membrane and is composed of CYB5B, MOSC2, and a third unknown component (a CYB5B reductase). PMID- 22203677 TI - Detailed structural-functional analysis of the Kruppel-like factor 16 (KLF16) transcription factor reveals novel mechanisms for silencing Sp/KLF sites involved in metabolism and endocrinology. AB - Kruppel-like factor (KLF) proteins have elicited significant attention due to their emerging key role in metabolic and endocrine diseases. Here, we extend this knowledge through the biochemical characterization of KLF16, unveiling novel mechanisms regulating expression of genes involved in reproductive endocrinology. We found that KLF16 selectively binds three distinct KLF-binding sites (GC, CA, and BTE boxes). KLF16 also regulated the expression of several genes essential for metabolic and endocrine processes in sex steroid-sensitive uterine cells. Mechanistically, we determined that KLF16 possesses an activation domain that couples to histone acetyltransferase-mediated pathways, as well as a repression domain that interacts with the histone deacetylase chromatin-remodeling system via all three Sin3 isoforms, suggesting a higher level of plasticity in chromatin cofactor selection. Molecular modeling combined with molecular dynamic simulations of the Sin3a-KLF16 complex revealed important insights into how this interaction occurs at an atomic resolution level, predicting that phosphorylation of Tyr-10 may modulate KLF16 function. Phosphorylation of KLF16 was confirmed by in vivo (32)P incorporation and controlled by a Y10F site-directed mutant. Inhibition of Src-type tyrosine kinase signaling as well as the nonphosphorylatable Y10F mutation disrupted KLF16-mediated gene silencing, demonstrating that its function is regulatable rather than constitutive. Subcellular localization studies revealed that signal-induced nuclear translocation and euchromatic compartmentalization constitute an additional mechanism for regulating KLF16 function. Thus, this study lends insights on key biochemical mechanisms for regulating KLF sites involved in reproductive biology. These data also contribute to the new functional information that is applicable to understanding KLF16 and other highly related KLF proteins. PMID- 22203678 TI - RNA chaperone activity of human La protein is mediated by variant RNA recognition motif. AB - La proteins are conserved factors in eukaryotes that bind and protect the 3' trailers of pre-tRNAs from exonuclease digestion via sequence-specific recognition of UUU-3'OH. La has also been hypothesized to assist pre-tRNAs in attaining their native fold through RNA chaperone activity. In addition to binding polymerase III transcripts, human La has also been shown to enhance the translation of several internal ribosome entry sites and upstream ORF-containing mRNA targets, also potentially through RNA chaperone activity. Using in vitro FRET-based assays, we show that human and Schizosaccharomyces pombe La proteins harbor RNA chaperone activity by enhancing RNA strand annealing and strand dissociation. We use various RNA substrates and La mutants to show that UUU-3'OH dependent La-RNA binding is not required for this function, and we map RNA chaperone activity to its RRM1 motif including a noncanonical alpha3-helix. We validate the importance of this alpha3-helix by appending it to the RRM of the unrelated U1A protein and show that this fusion protein acquires significant strand annealing activity. Finally, we show that residues required for La mediated RNA chaperone activity in vitro are required for La-dependent rescue of tRNA-mediated suppression via a mutated suppressor tRNA in vivo. This work delineates the structural elements required for La-mediated RNA chaperone activity and provides a basis for understanding how La can enhance the folding of its various RNA targets. PMID- 22203679 TI - Direct binding of specific AUF1 isoforms to tandem zinc finger domains of tristetraprolin (TTP) family proteins. AB - Tristetraprolin (TTP) is the prototype of a family of CCCH tandem zinc finger proteins that can bind to AU-rich elements in mRNAs and promote their decay. TTP binds to mRNA through its central tandem zinc finger domain; it then promotes mRNA deadenylation, considered to be the rate-limiting step in eukaryotic mRNA decay. We found that TTP and its related family members could bind to certain isoforms of another AU-rich element-binding protein, HNRNPD/AUF1, as well as a related protein, laAUF1. The interaction domain within AUF1p45 appeared to be a C terminal "GY" region, and the interaction domain within TTP was the tandem zinc finger domain. Surprisingly, binding of AUF1p45 to TTP occurred even with TTP mutants that lacked RNA binding activity. In cell extracts, binding of AUF1p45 to TTP potentiated TTP binding to ARE-containing RNA probes, as determined by RNA gel shift assays; AUF1p45 did not bind to the RNA probes under these conditions. Using purified, recombinant proteins and a synthetic RNA target in FRET assays, we demonstrated that AUF1p45, but not AUF1p37, increased TTP binding affinity for RNA ~5-fold. These data suggest that certain isoforms of AUF1 can serve as "co activators" of TTP family protein binding to RNA. The results raise interesting questions about the ability of AUF1 isoforms to regulate the mRNA binding and decay-promoting activities of TTP and its family members as well as the ability of AUF1 proteins to serve as possible physical links between TTP and other mRNA decay proteins and structures. PMID- 22203680 TI - Assembly and architecture of biogenesis of lysosome-related organelles complex-1 (BLOC-1). AB - BLOC-1 (biogenesis of lysosome-related organelles complex-1) is critical for melanosome biogenesis and has also been implicated in neurological function and disease. We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ~300 A long and ~30 A in diameter. The individual domains are flexibly connected such that the linear chain undergoes bending by as much as 45 degrees . Two stable subcomplexes were defined, pallidin-Cappuccino-BLOS1 and dysbindin Snapin-BLOS2. Both subcomplexes are 1:1:1 heterotrimers that form extended structures as indicated by their hydrodynamic properties. The two subcomplexes appear to constitute flexible units within the larger BLOC-1 chain, an arrangement conducive to simultaneous interactions with multiple BLOC-1 partners in the course of tubular endosome biogenesis and sorting. PMID- 22203681 TI - Regulation of the Ste20-like kinase, SLK: involvement of activation segment phosphorylation. AB - Expression and activation of the Ste20-like kinase, SLK, is increased during kidney development and recovery from ischemic acute kidney injury. SLK promotes apoptosis, and it may regulate cell survival during injury or repair. This study addresses the role of phosphorylation in the regulation of kinase activity. We mutated serine and threonine residues in the putative activation segment of the SLK catalytic domain and expressed wild type (WT) and mutant proteins in COS-1 or glomerular epithelial cells. Compared with SLK WT, the T183A, S189A, and T183A/S189A mutants showed reduced in vitro kinase activity. SLK WT, but not mutants, increased activation-specific phosphorylation of c-Jun N-terminal kinase (JNK) and p38 kinase. Similarly, SLK WT stimulated activator protein-1 reporter activity, but activation of activator protein-1 by the three SLK mutants was ineffective. To test if homodimerization of SLK affects phosphorylation, the cDNA encoding SLK amino acids 1-373 (which include the catalytic domain) was fused with a cDNA for a modified FK506-binding protein, Fv (Fv-SLK 1-373). After transfection, the addition of AP20187 (an FK506 analog) induced regulated dimerization of Fv-SLK 1-373. AP20187-stimulated dimerization enhanced the kinase activity of Fv-SLK 1-373 WT. In contrast, kinase activity of Fv-SLK 1-373 T183A/S189A was weak and was not enhanced after dimerization. Finally, apoptosis was increased after expression of Fv-SLK 1-373 WT but not T183A/S189A. Thus, phosphorylation of Thr-183 and Ser-189 plays a key role in the activation and signaling of SLK and could represent a target for novel therapeutic approaches to renal injury. PMID- 22203683 TI - "Double-Doyle" intranasal airway splint technique. PMID- 22203682 TI - Transient receptor potential canonical channels are required for in vitro endothelial tube formation. AB - In endothelial cells Ca(2+) entry is an essential component of the Ca(2+) signal that takes place during processes such as cell proliferation or angiogenesis. Ca(2+) influx occurs via the store-operated Ca(2+) entry pathway, involving stromal interaction molecule-1 (STIM1) and Orai1, but also through channels gated by second messengers like the transient receptor potential canonical (TRPC) channels. The human umbilical vein-derived endothelial cell line EA.hy926 expressed STIM1 and Orai1 as well as several TRPC channels. By invalidating each of these molecules, we showed that TRPC3, TRPC4, and TRPC5 are essential for the formation of tubular structures observed after EA.hy926 cells were plated on Matrigel. On the contrary, the silencing of STIM1 or Orai1 did not prevent tubulogenesis. Soon after being plated on Matrigel, the cells displayed spontaneous Ca(2+) oscillations that were strongly reduced by treatment with siRNA against TRPC3, TRPC4, or TRPC5, but not siRNA against STIM1 or Orai1. Furthermore, we showed that cell proliferation was reduced upon siRNA treatment against TRPC3, TRPC5, and Orai1 channels, whereas the knockdown of STIM1 had no effect. On primary human umbilical vein endothelial cells, TRPC1, TRPC4, and STIM1 are involved in tube formation, whereas Orai1 has no effect. These data showed that TRPC channels are essential for in vitro tubulogenesis, both on endothelial cell line and on primary endothelial cells. PMID- 22203684 TI - Retraction. Antiemetic efficacy of low-dose midazolam in patients undergoing thyroidectomy. PMID- 22203685 TI - Predictors of tonsillectomy after previous adenoidectomy for upper airway obstruction. AB - OBJECTIVE: (1) Characterize risk factors for subsequent tonsillectomy in pediatric patients undergoing primary adenoidectomy for upper airway obstruction. (2) Compare rates of subsequent tonsillectomy between adenoidectomy patients with and without upper airway obstruction. STUDY DESIGN: Historical cohort study with a nested case-control study. Cohort data were analyzed using Kaplan-Meier plots and a multiple regression model. Case-control data were analyzed using logistic regression. SUBJECTS AND METHODS: Patients undergoing adenoidectomy without tonsillectomy at the University of Missouri between 1995 and 2010 were identified using billing records and selected chart review. A nested case-control study with detailed chart review was conducted to determine predictors of subsequent tonsillectomy in patients with upper airway obstruction. RESULTS: Of 1291 patients identified in the historical cohort, 7.8% later underwent tonsillectomy. Age younger than 3 years (P = .027), female sex (P < .0001), and upper airway obstruction (P = .001) were found to be significant predictors of subsequent tonsillectomy. In the nested case-control study, potential predictors investigated included adenoidectomy indications, symptoms, smoke exposure, weight, comorbidities, and tonsil size at the time of adenoidectomy. Of these, only tonsil size was significant, with an increased odds of future tonsillectomy of 2.5 (P = .01) for each unit increase in tonsil size. CONCLUSION: Patients undergoing adenoidectomy for upper airway obstruction are likely to be at an increased risk of subsequent tonsillectomy when compared with those with other indications. Within this subgroup of patients with upper airway obstruction, young age, female sex, and large tonsil size may further increase the risk of subsequent tonsillectomy. PMID- 22203686 TI - Inner ear effects of canal wall down mastoidectomy. AB - OBJECTIVE: To evaluate the inner ear effects of canal wall down (CWD) mastoidectomy without ossiculoplasty in the treatment of chronic otitis media (COM) with regard to sensorineural hearing loss (SNHL) and reported tinnitus and dizziness-related disability. SETTING: Tertiary care academic medical center. SUBJECTS AND METHODS: Prospective study of 86 patients treated by CWD mastoidectomy without ossiculoplasty for COM with or without cholesteatoma. Standard patient workup included preoperative audiogram and completion of 2 surveys: Dizziness Handicap Inventory (DHI) and Tinnitus Handicap Inventory (THI). Patients underwent repeat audiogram, DHI, and THI surveys at 4 to 6 months postoperatively. Preoperative and postoperative data were analyzed. RESULTS: No significant SNHL occurred after CWD mastoidectomy. Thirteen patients (13/34 [38%]) had DHI improvement greater than 18 points, indicating a significant improvement in dizziness-related disability. Three patients developed new-onset postoperative dizziness complaints. Twenty patients (20/43 [46.5%]) had THI improvement greater than 7 points, indicating a significant improvement in tinnitus-related disability. Five patients developed new-onset postoperative tinnitus complaints. The odds ratio for improving DHI and THI scores after surgery was 6.6 (1.8 to 25.0) and 4.2 (95% confidence interval, 1.45% to 12.2%), respectively. CONCLUSION: In this study, CWD mastoidectomy without ossiculoplasty in the treatment of COM did not cause significant SNHL. In addition, using the DHI and THI measures, patient-perceived disability from dizziness and tinnitus, respectively, was shown to decrease after mastoid surgery. PMID- 22203687 TI - Endothelial cells present an innate resistance to glucocorticoid treatment: implications for therapy of primary vasculitis. AB - BACKGROUND: In contrast to other chronic inflammatory diseases glucocorticoids alone do not maintain sufficient remission in primary vasculitis. The reasons for this therapeutic failure remain unclear. OBJECTIVES: To investigate the molecular effects glucocorticoids exert on endothelial cells (EC) and to elucidate the molecular pathways responsible. METHODS: A comparative approach was used to treat human micro and macrovascular EC as well as monocytes long and short term with glucocorticoids or glucocorticoids and tumour necrosis factor alpha (TNFalpha). Gene expression changes were analysed applying microarray technology, sophisticated bioinformatic work-up and quantitative reverse transcription PCR. Glucocorticoid receptor translocation processes were traced by cell fractionation assays and immunofluorescence microscopy. RESULTS: In EC glucocorticoids completely failed to inhibit the expression of immune response genes both after sole glucocorticoid exposure and glucocorticoid treatment of a TNFalpha-induced proinflammatory response. In contrast, an impressive downregulation of proinflammatory genes was seen in monocytes. The study demonstrated that the glucocorticoid receptor is comparably expressed in EC and monocytes, and demonstrated good translocation of ligand-bound glucocorticoid receptor allowing genomic glucocorticoid actions. Refined gene expression analysis showed that in EC transactivation takes place and causes glucocorticoid side effects on growth and metabolism whereas transrepression-mediated anti-inflammatory effects as in monocytes are missing. Insufficient induction of SAP30, an important constituent of the Sin3A-histone deacetylase complex, in EC suggests impairment of transrepression due to co-repressor absence. CONCLUSIONS: The impressive unresponsiveness of EC to anti-inflammatory glucocorticoid effects is associated with deficiencies downstream of glucocorticoid receptor translocation not affecting transactivation but transrepression. The findings provide the first molecular clues to the poor benefit of glucocorticoid treatment in patients with primary vasculitis. PMID- 22203689 TI - CD90 is identified as a candidate marker for cancer stem cells in primary high grade gliomas using tissue microarrays. AB - Although CD90 has been identified as a marker for various kinds of stem cells including liver cancer stem cells (CSCs) that are responsible for tumorigenesis, the potential role of CD90 as a marker for CSCs in gliomas has not been characterized. To address the issue, we investigated the expression of CD90 in tissue microarrays containing 15 glioblastoma multiformes (GBMs), 19 WHO grade III astrocytomas, 13 WHO grade II astrocytomas, 3 WHO grade I astrocytomas and 8 normal brain tissues. Immunohistochemical analysis showed that CD90 was expressed at a medium to high level in all tested high-grade gliomas (grade III and GBM) whereas it was barely detectable in low-grade gliomas (grade I and grade II) and normal brains. Double immunofluorescence staining for CD90 and CD133 in GBM tissues revealed that CD133(+) CSCs are a subpopulation of CD90(+) cells in GBMs in vivo. Flow cytometry analysis of the expression of CD90 and CD133 in GBM derived stem-like neurospheres further confirmed the conclusion in vitro. The expression levels of both CD90 and CD133 were reduced along with the loss of stem cells after differentiation. Furthermore, the limiting dilution assay demonstrated that the sphere formation ability was comparable between the CD90(+)/CD133(+) and the CD90(+)/CD133(-) populations of GBM neurospheres, which is much higher than that of the CD90(-)/CD133(-) population. We also performed double staining for CD90 and a vascular endothelial cell marker CD31 in tissue microarrays which revealed that the CD90(+) cells were clustered around the tumor vasculatures in high-grade glioma tissues. These findings suggest that CD90 is not only a potential prognostic marker for high-grade gliomas but also a marker for CSCs within gliomas, and it resides within endothelial niche and may also play a critical role in the generation of tumor vasculatures via differentiation into endothelial cells. PMID- 22203690 TI - Pharmacoproteomic study of three different chondroitin sulfate compounds on intracellular and extracellular human chondrocyte proteomes. AB - Chondroitin sulfate (CS) is a symptomatic slow acting drug for osteoarthritis (OA) widely used for the treatment of this highly prevalent disease, characterized by articular cartilage degradation. However, little is known about its mechanism of action, and recent large scale clinical trials have reported variable results on OA symptoms. Herein, we aimed to study the modulations in the intracellular proteome and the secretome of human articular cartilage cells (chondrocytes) treated with three different CS compounds, with different origin or purity, by two complementary proteomic approaches. Osteoarthritic cells were treated with 200 MUg/ml of each brand of CS. Quantitative proteomics experiments were carried out by the DIGE and stable isotope labeling with amino acids in cell culture (SILAC) techniques, followed by LC-MALDI-MS/MS analysis. The DIGE study, carried out on chondrocyte whole cell extracts, led to the detection of 46 spots that were differential between conditions in our study: 27 were modulated by CS1, 4 were modulated by CS2, and 15 were modulated by CS3. The SILAC experiment, carried out on the subset of chondrocyte-secreted proteins, allowed us to identify 104 different proteins. Most of them were extracellular matrix components, and 21 were modulated by CS1, 13 were modulated by CS2, and 9 were modulated by CS3. Each of the studied compounds induces a characteristic protein profile in OA chondrocytes. CS1 displayed the widest effect but increased the mitochondrial superoxide dismutase, the cartilage oligomeric matrix protein, and some catabolic or inflammatory factors like interstitial collagenase, stromelysin 1, and pentraxin-related protein. CS2 and CS3, on the other hand, increased a number of structural proteins, growth factors, and extracellular matrix proteins. Our study shows how, from the three CS compounds tested, CS1 induces the activation of inflammatory and catabolic pathways, whereas CS2 and CS3 induce an anti-inflammatory and anabolic response. The data presented emphasize the importance of employing high quality CS compounds, supported by controlled clinical trials, in the therapy of OA. Finally, the present work exemplifies the usefulness of proteomic approaches in pharmacological studies. PMID- 22203691 TI - Sequential multiplexed analyte quantification using peptide immunoaffinity enrichment coupled to mass spectrometry. AB - Peptide immunoaffinity enrichment coupled to selected reaction monitoring (SRM) mass spectrometry (immuno-SRM) has emerged as a technology with great potential for quantitative proteomic assays. One advantage over traditional immunoassays is the tremendous potential for concurrent quantification of multiple analytes from a given sample (i.e. multiplex analysis). We sought to explore the capacity of the immuno-SRM technique for analyzing large numbers of analytes by evaluating the multiplex capabilities and demonstrating the sequential analysis of groups of peptides from a single sample. To evaluate multiplex analysis, immuno-SRM assays were arranged in groups of 10, 20, 30, 40, and 50 peptides using a common set of reagents. The multiplex immuno-SRM assays were used to measure synthetic peptides added to plasma covering several orders of magnitude concentration. Measurements made in large multiplex groups were highly correlated (r(2) >= 0.98) and featured good agreement (bias <= 1%) compared with single-plex assays or a 10-plex configuration. The ability to sequentially enrich sets of analyte peptides was demonstrated by enriching groups of 10 peptides from a plasma sample in a sequential fashion. The data show good agreement (bias <= 1.5%) and similar reproducibility regardless of enrichment order. These significant advancements demonstrate the utility of immuno-SRM for analyzing large numbers of analytes, such as in large biomarker verification experiments or in pathway-based targeted analysis. PMID- 22203692 TI - Identification of a monocyte-predisposed hierarchy of hematopoietic progenitor cells in the adventitia of postnatal murine aorta. AB - BACKGROUND: Hematopoiesis originates from the dorsal aorta during embryogenesis. Although adult blood vessels harbor progenitor populations for endothelial and smooth muscle cells, it is not known if they contain hematopoietic progenitor or stem cells. Here, we hypothesized that the arterial wall is a source of hematopoietic progenitor and stem cells in postnatal life. METHODS AND RESULTS: Single-cell aortic disaggregates were prepared from adult chow-fed C57BL/6 and apolipoprotein E-null (ApoE(-/-)) mice. In short- and long-term methylcellulose based culture, aortic cells generated a broad spectrum of multipotent and lineage specific hematopoietic colony-forming units, with a preponderance of macrophage colony-forming units. This clonogenicity was higher in lesion-free ApoE(-/-) mice and localized primarily to stem cell antigen-1-positive cells in the adventitia. Expression of stem cell antigen-1 in the aorta colocalized with canonical hematopoietic stem cell markers, as well as CD45 and mature leukocyte antigens. Adoptive transfer of labeled aortic cells from green fluorescent protein transgenic donors to irradiated C57BL/6 recipients confirmed the content of rare hematopoietic stem cells (1 per 4 000 000 cells) capable of self-renewal and durable, low-level reconstitution of leukocytes. Moreover, the predominance of long-term macrophage precursors was evident by late recovery of green fluorescent protein-positive colonies from recipient bone marrow and spleen that were exclusively macrophage colony-forming units. Although trafficking from bone marrow was shown to replenish some of the hematopoietic potential of the aorta after irradiation, the majority of macrophage precursors appeared to arise locally, suggesting long-term residence in the vessel wall. CONCLUSIONS: The postnatal murine aorta contains rare multipotent hematopoietic progenitor/stem cells and is selectively enriched with stem cell antigen-1-positive monocyte/macrophage precursors. These populations may represent novel, local vascular sources of inflammatory cells. PMID- 22203693 TI - Aortic tissue as a niche for hematopoiesis. PMID- 22203695 TI - Very late stent thrombosis and late target lesion revascularization: no end in sight. PMID- 22203696 TI - Type 2 diabetes mellitus is associated with faster degeneration of bioprosthetic valve: results from a propensity score-matched Italian multicenter study. AB - BACKGROUND: The present study was aimed at determining the impact of type 2 diabetes mellitus (DM) on postoperative bioprosthetic structural valve degeneration. METHODS AND RESULTS: Twelve Italian centers participated in the study. Patient data refer to bioprosthetic implantations performed from November 1988 to December 2009, which resulted in 6184 patients (mean age 71.3+/-5.4 years, 60.1% male) being enrolled. Of these patients, 1731 (27.9%) had type 2 DM. The propensity score-matching algorithm successfully matched 1113 patients with type 2 DM with the same number of no-DM patients. The postmatching standard differences were less than 0.1 for each of the covariates, and 64.2% of DM patients were matched. The early (30 days) mortality rate was 7.8% (n=87) versus 2.9% (n=33) in patients with or without type 2 DM (P<0.001), respectively. Seven year freedom from valve deterioration was significantly lower in patients with DM (73.2% [95% confidence interval, 61.6-85.5] versus 95.4% [95% confidence interval, 83.9-100], P<0.001). In Cox regression models with robust SEs that accounted for the clustering of matched pairs, DM was the strongest predictor of structural valve degeneration (hazard ratio 2.39 [95% confidence interval 2.28 3.52]). When we allowed for interaction between type 2 DM and other key risk factors, DM remained a significant predictor beyond any potentially associated variable. CONCLUSIONS: Patients with type 2 DM undergoing bioprosthetic valve implantation are at high risk of early and long-term mortality, as well as of structural valve degeneration. PMID- 22203697 TI - Differences in the pharmacokinetics of 4-amino-3-chlorophenyl hydrogen sulfate, a metabolite of resatorvid, in rats and dogs. AB - The pharmacokinetics of 4-amino-3-chlorophenyl hydrogen sulfate, M-III of resatorvid, in rats and dogs were investigated using radiolabeled M-III ([(14)C]M III). The elimination half-life of (14)C in the plasma of rats was approximately 1/30 of that of dogs after intravenous dosing of [(14)C]M-III at 0.5 mg/kg to rats and dogs. The in vitro and in vivo plasma protein binding ratios of M-III were relatively high and were the same in both species. The intrinsic clearance (CL(int)) of M-III in rats was much higher than the glomerular filtration rate in rats. Furthermore, the concentration of [(14)C]M-III in the kidney of rats was much higher than that in the plasma. On the contrary, in dogs, the concentration of [(14)C]M-III in the kidney was very much lower than that in the plasma. These results indicated that M-III was effectively taken up into the kidney and was excreted into the urine in rats; however, in dogs, ineffective renal uptake of M III was presumed. When [(14)C]M-III and probenecid were simultaneously and continually infused intravenously to rats, the CL(int) of M-III decreased with increasing plasma concentrations of probenecid, indicating that kidney uptake of M-III in rats was inhibited by probenecid. It was also thought that uptake by the organic anion transport system(s) in the basolateral membrane is involved in the renal uptake of M-III in rats. The pharmacokinetic differences of M-III between rats and dogs are considered to be mainly caused by the difference in the urinary excretion via the renal distribution processes. PMID- 22203694 TI - Very late stent thrombosis and late target lesion revascularization after sirolimus-eluting stent implantation: five-year outcome of the j-Cypher Registry. AB - BACKGROUND: There is a scarcity of long-term data from large-scale drug-eluting stent registries with a large enough sample to evaluate low-frequency events such as stent thrombosis (ST). METHODS AND RESULTS: Five-year outcomes were evaluated in 12 812 consecutive patients undergoing sirolimus-eluting stent (SES) implantation in the j-Cypher registry. Cumulative incidence of definite ST was low (30 day, 0.3%; 1 year, 0.6%; and 5 years, 1.6%). However, late and very late ST continued to occur without attenuation up to 5 years after sirolimus-eluting stent implantation (0.26%/y). Cumulative incidence of target lesion revascularization within the first year was low (7.3%). However, late target lesion revascularization beyond 1 year also continued to occur without attenuation up to 5 years (2.2%/y). Independent risk factors of ST were completely different according to the timing of ST onset, suggesting the presence of different pathophysiological mechanisms of ST according to the timing of ST onset: acute coronary syndrome and target of proximal left anterior descending coronary artery for early ST; side-branch stenting, diabetes mellitus, and end stage renal disease with or without hemodialysis for late ST; and current smoking and total stent length >28 mm for very late ST. Independent risk factors of late target lesion revascularization beyond 1 year were generally similar to those risk factors identified for early target lesion revascularization. CONCLUSION: Late adverse events such as very late ST and late target lesion revascularization are continuous hazards, lasting at least up to 5 years after implantation of the first-generation drug-eluting stents (sirolimus-eluting stents), which should be the targets for developing improved coronary stents. PMID- 22203698 TI - Three-dimensional motor neuron morphology estimation in the Drosophila ventral nerve cord. AB - Type-specific dendritic arborization patterns dictate synaptic connectivity and are fundamental determinants of neuronal function. We exploit the morphological stereotypy and relative simplicity of the Drosophila nervous system to model the diverse neuronal morphologies of individual motor neurons (MNs) and understand underlying principles of synaptic connectivity in a motor circuit. Our computational approach aims at the reconstruction of the neuron morphology, namely the robust segmentation of the neuron volumes from their surroundings with the simultaneous partitioning into their compartments, namely the soma, axon, and dendrites. We use the idea of cosegmentation, where every image along the z -axis (depth) is segmented using information from "neighboring" depths. We use 3-D Haar like features to model appearance. Because soma and axon are determined by their distinctive shapes, we define an implicit shape representation of the 2-D segmentation sets to drive cosegmentation and achieve the desired partitioning. We validate our method using image stacks depicting single neurons labeled with green fluorescent protein (GFP) and serially imaged with laser scanning confocal microscopy. PMID- 22203699 TI - Robust white matter lesion segmentation in FLAIR MRI. AB - This paper discusses a white matter lesion (WML) segmentation scheme for fluid attenuation inversion recovery (FLAIR) MRI. The method computes the volume of lesions with subvoxel precision by accounting for the partial volume averaging (PVA) artifact. As WMLs are related to stroke and carotid disease, accurate volume measurements are most important. Manual volume computation is laborious, subjective, time consuming, and error prone. Automated methods are a nice alternative since they quantify WML volumes in an objective, efficient, and reliable manner. PVA is initially modeled with a localized edge strength measure since PVA resides in the boundaries between tissues. This map is computed in 3-D and is transformed to a global representation to increase robustness to noise. Significant edges correspond to PVA voxels, which are used to find the PVA fraction alpha (amount of each tissue present in mixture voxels). Results on simulated and real FLAIR images show high WML segmentation performance compared to ground truth (98.9% and 83% overlap, respectively), which outperforms other methods. Lesion load studies are included that automatically analyze WML volumes for each brain hemisphere separately. This technique does not require any distributional assumptions/parameters or training samples and is applied on a single MR modality, which is a major advantage compared to the traditional methods. PMID- 22203700 TI - A framework for the recognition of high-level surgical tasks from video images for cataract surgeries. AB - The need for a better integration of the new generation of computer-assisted surgical systems has been recently emphasized. One necessity to achieve this objective is to retrieve data from the operating room (OR) with different sensors, then to derive models from these data. Recently, the use of videos from cameras in the OR has demonstrated its efficiency. In this paper, we propose a framework to assist in the development of systems for the automatic recognition of high-level surgical tasks using microscope videos analysis. We validated its use on cataract procedures. The idea is to combine state-of-the-art computer vision techniques with time series analysis. The first step of the framework consisted in the definition of several visual cues for extracting semantic information, therefore, characterizing each frame of the video. Five different pieces of image-based classifiers were, therefore, implemented. A step of pupil segmentation was also applied for dedicated visual cue detection. Time series classification algorithms were then applied to model time-varying data. Dynamic time warping and hidden Markov models were tested. This association combined the advantages of all methods for better understanding of the problem. The framework was finally validated through various studies. Six binary visual cues were chosen along with 12 phases to detect, obtaining accuracies of 94%. PMID- 22203701 TI - Toothbrushing region detection using three-axis accelerometer and magnetic sensor. AB - Due to the possible occurrence of periodontal disease at an early age, it is important to have proper toothbrushing habits as early as possible. With this aim, the feasibility and concept of a smart toothbrush (ST) capable of tracing toothbrushing motion and orientation information was suggested. In this study, we proposed the advanced ST system and brushing region classification algorithm. In order to trace the brushing region and the orientation of a toothbrush in the mouth, we required the absolute coordinate information of ST. By using tilt compensated azimuth (heading) algorithm, we found the inclination and orientation information of the toothbrush, and the orientation information while brushing inner tooth surfaces showed specific heading features that could be reliably discriminated from other brushing patterns. In order to evaluate the feasibility of clinical usage of the proposed ST, 16 brushing regions were investigated by 15 individual healthy subjects. The proposed ST system demonstrated 97.1%(+/-0.91) of the region detection accuracy and 15 brushing regions could be classified. This study also showed that the proposed ST system may be helpful for dental care personnel in patient education and instruction for oral hygiene regarding brushing habits. PMID- 22203702 TI - Estimation and modeling of QT-interval adaptation to heart rate changes. AB - This paper introduces a new method for QT-interval estimation. It consists in a batch processing mode of the improved Woody's method. Performance of this methodology is evaluated using synthetic data. In parallel, a new model of QT interval dynamics behavior related to heart rate changes is presented. Since two kinds of QT response have been pointed out, the main idea is to split the modeling process into two steps: 1) the modeling of the fast adaptation, which is inspired by the electrical behavior at the cellular level relative to the electrical restitution curve, and 2) the modeling of the slow adaptation, inspired by experimental works at the cellular level. Both approaches are based on a low-complexity autoregressive process whose parameters are estimated using an unbiased estimator. This new modeling of QT adaptation, combined with the presented QT-estimation process, is applied to several ECG recordings with various heart rate variability dynamics. Its potential is then illustrated on ECG recorded during rest, atrial fibrillation episodes, and exercise. Meaningful results in agreement with physiological knowledge at the cellular level are obtained. PMID- 22203703 TI - Endovascular magnetically guided robots: navigation modeling and optimization. AB - This paper deals with the benefits of using a nonlinear model-based approach for controlling magnetically guided therapeutic microrobots in the cardiovascular system. Such robots used for minimally invasive interventions consist of a polymer binded aggregate of nanosized ferromagnetic particles functionalized by drug-conjugated micelles. The proposed modeling addresses wall effects (blood velocity in minor and major vessels' bifurcations, pulsatile blood flow and vessel walls, and effect of robot-to-vessel diameter ratio), wall interactions (contact, van der Waals, electrostatic, and steric forces), non-Newtonian behavior of blood, and different driving designs as well. Despite nonlinear and thorough, the resulting model can both be exploited to improve the targeting ability and be controlled in closed-loop using nonlinear control theory tools. In particular, we infer from the model an optimization of both the designs and the reference trajectory to minimize the control efforts. Efficiency and robustness to noise and model parameter's uncertainties are then illustrated through simulations results for a bead pulled robot of radius 250 MUm in a small artery. PMID- 22203704 TI - Hierarchical scale-based multiobject recognition of 3-D anatomical structures. AB - Segmentation of anatomical structures from medical images is a challenging problem, which depends on the accurate recognition (localization) of anatomical structures prior to delineation. This study generalizes anatomy segmentation problem via attacking two major challenges: 1) automatically locating anatomical structures without doing search or optimization, and 2) automatically delineating the anatomical structures based on the located model assembly. For 1), we propose intensity weighted ball-scale object extraction concept to build a hierarchical transfer function from image space to object (shape) space such that anatomical structures in 3-D medical images can be recognized without the need to perform search or optimization. For 2), we integrate the graph-cut (GC) segmentation algorithm with prior shape model. This integrated segmentation framework is evaluated on clinical 3-D images consisting of a set of 20 abdominal CT scans. In addition, we use a set of 11 foot MR images to test the generalizability of our method to the different imaging modalities as well as robustness and accuracy of the proposed methodology. Since MR image intensities do not possess a tissue specific numeric meaning, we also explore the effects of intensity nonstandardness on anatomical object recognition. Experimental results indicate that: 1) effective recognition can make the delineation more accurate; 2) incorporating a large number of anatomical structures via a model assembly in the shape model improves the recognition and delineation accuracy dramatically; 3) ball-scale yields useful information about the relationship between the objects and the image; 4) intensity variation among scenes in an ensemble degrades object recognition performance. PMID- 22203705 TI - Constrained registration for motion compensation in atrial fibrillation ablation procedures. AB - Fluoroscopic overlay images rendered from preoperative volumetric data can provide additional anatomical details to guide physicians during catheter ablation procedures for treatment of atrial fibrillation (AFib). As these overlay images are often compromised by cardiac and respiratory motion, motion compensation methods are needed to keep the overlay images in sync with the fluoroscopic images. So far, these approaches have either required simultaneous biplane imaging for 3-D motion compensation, or in case of monoplane X-ray imaging, provided only a limited 2-D functionality. To overcome the downsides of the previously suggested methods, we propose an approach that facilitates a full 3-D motion compensation even if only monoplane X-ray images are available. To this end, we use a training phase that employs a biplane sequence to establish a patient specific motion model. Afterwards, a constrained model-based 2-D/3-D registration method is used to track a circumferential mapping catheter. This device is commonly used for AFib catheter ablation procedures. Based on the experiments on real patient data, we found that our constrained monoplane 2-D/3-D registration outperformed the unconstrained counterpart and yielded an average 2 D tracking error of 0.6 mm and an average 3-D tracking error of 1.6 mm. The unconstrained 2-D/3-D registration technique yielded a similar 2-D performance, but the 3-D tracking error increased to 3.2 mm mostly due to wrongly estimated 3 D motion components in X-ray view direction. Compared to the conventional 2-D monoplane method, the proposed method provides a more seamless workflow by removing the need for catheter model re-initialization otherwise required when the C-arm view orientation changes. In addition, the proposed method can be straightforwardly combined with the previously introduced biplane motion compensation technique to obtain a good trade-off between accuracy and radiation dose reduction. PMID- 22203706 TI - Kalman filtered MR temperature imaging for laser induced thermal therapies. AB - The feasibility of using a stochastic form of Pennes bioheat model within a 3-D finite element based Kalman filter (KF) algorithm is critically evaluated for the ability to provide temperature field estimates in the event of magnetic resonance temperature imaging (MRTI) data loss during laser induced thermal therapy (LITT). The ability to recover missing MRTI data was analyzed by systematically removing spatiotemporal information from a clinical MR-guided LITT procedure in human brain and comparing predictions in these regions to the original measurements. Performance was quantitatively evaluated in terms of a dimensionless L(2) (RMS) norm of the temperature error weighted by acquisition uncertainty. During periods of no data corruption, observed error histories demonstrate that the Kalman algorithm does not alter the high quality temperature measurement provided by MR thermal imaging. The KF-MRTI implementation considered is seen to predict the bioheat transfer with RMS error < 4 for a short period of time, ?t < 10 s, until the data corruption subsides. In its present form, the KF-MRTI method currently fails to compensate for consecutive for consecutive time periods of data loss ?t > 10 sec. PMID- 22203707 TI - Interventional 4-D C-arm CT perfusion imaging using interleaved scanning and partial reconstruction interpolation. AB - Tissue perfusion measurement during catheter-guided stroke treatment in the interventional suite is currently not possible. In this work, we present a novel approach that uses a C-arm angiography system capable of computed tomography (CT) like imaging (C-arm CT) for this purpose. With C-arm CT one reconstructed volume can be obtained every 4-6 s which makes it challenging to measure the flow of an injected contrast bolus. We have developed an interleaved scanning (IS) protocol that uses several scan sequences to increase temporal sampling. Using a dedicated 4-D reconstruction approach based on partial reconstruction interpolation (PRI) we can optimally process our data. We evaluated our combined approach (IS-PRI) with simulations and a study in five healthy pigs. In our simulations, the cerebral blood flow values (unit: ml/100 g/min) were 60 (healthy tissue) and 20 (pathological tissue). For one scan sequence the values were estimated with standard deviations of 14.3 and 2.9, respectively. For two interleaved sequences the standard deviations decreased to 3.6 and 1.5, respectively. We used perfusion CT to validate the in vivo results. With two interleaved sequences we achieved promising correlations ranging from r=0.63 to r=0.94. The results suggest that C arm CT tissue perfusion imaging is feasible with two interleaved scan sequences. PMID- 22203708 TI - Interactive image segmentation using Dirichlet process multiple-view learning. AB - Segmenting semantically meaningful whole objects from images is a challenging problem, and it becomes especially so without higher level common sense reasoning. In this paper, we present an interactive segmentation framework that integrates image appearance and boundary constraints in a principled way to address this problem. In particular, we assume that small sets of pixels, which are referred to as seed pixels, are labeled as the object and background. The seed pixels are used to estimate the labels of the unlabeled pixels using Dirichlet process multiple-view learning, which leverages 1) multiple-view learning that integrates appearance and boundary constraints and 2) Dirichlet process mixture-based nonlinear classification that simultaneously models image features and discriminates between the object and background classes. With the proposed learning and inference algorithms, our segmentation framework is experimentally shown to produce both quantitatively and qualitatively promising results on a standard dataset of images. In particular, our proposed framework is able to segment whole objects from images given insufficient seeds. PMID- 22203709 TI - Edge-preserving image regularization based on morphological wavelets and dyadic trees. AB - Despite the tremendous success of wavelet-based image regularization, we still lack a comprehensive understanding of the exact factor that controls edge preservation and a principled method to determine the wavelet decomposition structure for dimensions greater than 1. We address these issues from a machine learning perspective by using tree classifiers to underpin a new image regularizer that measures the complexity of an image based on the complexity of the dyadic-tree representations of its sublevel sets. By penalizing unbalanced dyadic trees less, the regularizer preserves sharp edges. The main contribution of this paper is the connection of concepts from structured dyadic-tree complexity measures, wavelet shrinkage, morphological wavelets, and smoothness regularization in Besov space into a single coherent image regularization framework. Using the new regularizer, we also provide a theoretical basis for the data-driven selection of an optimal dyadic wavelet decomposition structure. As a specific application example, we give a practical regularized image denoising algorithm that uses this regularizer and the optimal dyadic wavelet decomposition structure. PMID- 22203710 TI - Side-information-dependent correlation channel estimation in hash-based distributed video coding. AB - In the context of low-cost video encoding, distributed video coding (DVC) has recently emerged as a potential candidate for uplink-oriented applications. This paper builds on a concept of correlation channel (CC) modeling, which expresses the correlation noise as being statistically dependent on the side information (SI). Compared with classical side-information-independent (SII) noise modeling adopted in current DVC solutions, it is theoretically proven that side information-dependent (SID) modeling improves the Wyner-Ziv coding performance. Anchored in this finding, this paper proposes a novel algorithm for online estimation of the SID CC parameters based on already decoded information. The proposed algorithm enables bit-plane-by-bit-plane successive refinement of the channel estimation leading to progressively improved accuracy. Additionally, the proposed algorithm is included in a novel DVC architecture that employs a competitive hash-based motion estimation technique to generate high-quality SI at the decoder. Experimental results corroborate our theoretical gains and validate the accuracy of the channel estimation algorithm. The performance assessment of the proposed architecture shows remarkable and consistent coding gains over a germane group of state-of-the-art distributed and standard video codecs, even under strenuous conditions, i.e., large groups of pictures and highly irregular motion content. PMID- 22203711 TI - Parameter selection for total-variation-based image restoration using discrepancy principle. AB - There are two key issues in successfully solving the image restoration problem: 1) estimation of the regularization parameter that balances data fidelity with the regularity of the solution and 2) development of efficient numerical techniques for computing the solution. In this paper, we derive a fast algorithm that simultaneously estimates the regularization parameter and restores the image. The new approach is based on the total-variation (TV) regularized strategy and Morozov's discrepancy principle. The TV norm is represented by the dual formulation that changes the minimization problem into a minimax problem. A proximal point method is developed to compute the saddle point of the minimax problem. By adjusting the regularization parameter adaptively in each iteration, the solution is guaranteed to satisfy the discrepancy principle. We will give the convergence proof of our algorithm and numerically show that it is better than some state-of-the-art methods in terms of both speed and accuracy. PMID- 22203712 TI - Masked object registration in the Fourier domain. AB - Registration is one of the most common tasks of image analysis and computer vision applications. The requirements of most registration algorithms include large capture range and fast computation so that the algorithms are robust to different scenarios and can be computed in a reasonable amount of time. For these purposes, registration in the Fourier domain using normalized cross-correlation is well suited and has been extensively studied in the literature. Another common requirement is masking, which is necessary for applications where certain regions of the image that would adversely affect the registration result should be ignored. To address these requirements, we have derived a mathematical model that describes an exact form for embedding the masking step fully into the Fourier domain so that all steps of translation registration can be computed efficiently using Fast Fourier Transforms. We provide algorithms and implementation details that demonstrate the correctness of our derivations. We also demonstrate how this masked FFT registration approach can be applied to improve the Fourier-Mellin algorithm that calculates translation, rotation, and scale in the Fourier domain. We demonstrate the computational efficiency, advantages, and correctness of our algorithm on a number of images from real-world applications. Our framework enables fast, global, parameter-free registration of images with masked regions. PMID- 22203713 TI - Quaternion structural similarity: a new quality index for color images. AB - One of the most important issues for researchers developing image processing algorithms is image quality. Methodical quality evaluation, by showing images to several human observers, is slow, expensive, and highly subjective. On the other hand, a visual quality matrix (VQM) is a fast, cheap, and objective tool for evaluating image quality. Although most VQMs are good in predicting the quality of an image degraded by a single degradation, they poorly perform for a combination of two degradations. An example for such degradation is the color crosstalk (CTK) effect, which introduces blur with desaturation. CTK is expected to become a bigger issue in image quality as the industry moves toward smaller sensors. In this paper, we will develop a VQM that will be able to better evaluate the quality of an image degraded by a combined blur/desaturation degradation and perform as well as other VQMs on single degradations such as blur, compression, and noise. We show why standard scalar techniques are insufficient to measure a combined blur/desaturation degradation and explain why a vectorial approach is better suited. We introduce quaternion image processing (QIP), which is a true vectorial approach and has many uses in the fields of physics and engineering. Our new VQM is a vectorial expansion of structure similarity using QIP, which gave it its name-Quaternion Structural SIMilarity (QSSIM). We built a new database of a combined blur/desaturation degradation and conducted a quality survey with human subjects. An extensive comparison between QSSIM and other VQMs on several image quality databases-including our new database-shows the superiority of this new approach in predicting visual quality of color images. PMID- 22203714 TI - Blind adaptive sampling of images. AB - Adaptive sampling schemes choose different sampling masks for different images. Blind adaptive sampling schemes use the measurements that they obtain (without any additional or direct knowledge about the image) to wisely choose the next sample mask. In this paper, we present and discuss two blind adaptive sampling schemes. The first is a general scheme not restricted to a specific class of sampling functions. It is based on an underlying statistical model for the image, which is updated according to the available measurements. A second less general but more practical method uses the wavelet decomposition of an image. It estimates the magnitude of the unsampled wavelet coefficients and samples those with larger estimated magnitude first. Experimental results show the benefits of the proposed blind sampling schemes. PMID- 22203715 TI - Variational adaptive correlation method for flow estimation. AB - A variational approach is presented to the estimation of turbulent fluid flow from particle image sequences in experimental fluid mechanics. The approach comprises two coupled optimizations for adapting size and shape of a Gaussian correlation window at each location and for estimating the flow, respectively. The method copes with a wide range of particle densities and image noise levels without any data-specific parameter tuning. Based on a careful implementation of a multiscale nonlinear optimization technique, we demonstrate robustness of the solution over typical experimental scenarios and highest estimation accuracy for an international benchmark data set (PIV Challenge). PMID- 22203716 TI - Sparse approximation using M-term pursuit and application in image and video coding. AB - This paper introduces a novel algorithm for sparse approximation in redundant dictionaries called the M-term pursuit (MTP). This algorithm decomposes a signal into a linear combination of atoms that are selected in order to represent the main signal components. The MTP algorithm provides an adaptive representation for signals in any complete dictionary. The basic idea behind the MTP is to partition the dictionary into L quasi-disjoint subdictionaries. A k-term signal approximation is then iteratively computed, where each iteration leads to the selection of M <= L atoms based on thresholding. The MTP algorithm is shown to achieve competitive performance with the matching pursuit (MP) algorithm that greedily selects atoms one by one. This is due to efficient partitioning of the dictionary. At the same time, the computational complexity is dramatically reduced compared to MP due to the batch selection of atoms. We finally illustrate the performance of MTP in image and video compression applications, where we show that the suboptimal atom selection of MTP is largely compensated by the reduction in complexity compared with MP. PMID- 22203717 TI - Local color vector binary patterns from multichannel face images for face recognition. AB - This paper proposes a novel face descriptor based on color information, i.e., so called local color vector binary patterns (LCVBPs), for face recognition (FR). The proposed LCVBP consists of two discriminative patterns: color norm patterns and color angular patterns. In particular, we have designed a method for extracting color angular patterns, which enables to encode the discriminating texture patterns derived from spatial interactions among different spectral-band images. In order to perform FR tasks, the proposed LCVBP feature is generated by combining multiple features extracted from both color norm patterns and color angular patterns. Extensive and comparative experiments have been conducted to evaluate the proposed LCVBP feature on five public databases. Experimental results show that the proposed LCVBP feature is able to yield excellent FR performance for challenging face images. In addition, the effectiveness of the proposed LCVBP feature has successfully been tested by comparing other state-of the-art face descriptors. PMID- 22203718 TI - Boundary operation of 2-D nonseparable linear-phase paraunitary filter banks. AB - This paper proposes a boundary operation technique of 2-D nonseparable linear phase paraunitary filter banks (NS-LPPUFBs) for size limitation. The proposed technique is based on a lattice structure consisting of the 2-D separable block discrete cosine transform and nonseparable support-extension processes. The bases are allowed to be anisotropic with the fixed critically subsampling, overlapping, orthogonal, symmetric, real-valued, and compact-support properties. First, the blockwise implementation is developed so that the basis images can be locally controlled. The local control of basis images is shown to maintain orthogonality. This property leads a basis termination (BT) technique as a boundary operation. The technique overcomes the drawback of NS-LPPUFBs that the popular symmetric extension method is invalid. Through some experimental results of diagonal texture coding, the significance of the BT is verified. PMID- 22203719 TI - Multiview deblurring for 3-D images from light-sheet-based fluorescence microscopy. AB - We propose an algorithm for 3-D multiview deblurring using spatially variant point spread functions (PSFs). The algorithm is applied to multiview reconstruction of volumetric microscopy images. It includes registration and estimation of the PSFs using irregularly placed point markers (beads). We formulate multiview deblurring as an energy minimization problem subject to L1 regularization. Optimization is based on the regularized Lucy-Richardson algorithm, which we extend to deal with our more general model. The model parameters are chosen in a profound way by optimizing them on a realistic training set. We quantitatively and qualitatively compare with existing methods and show that our method provides better signal-to-noise ratio and increases the resolution of the reconstructed images. PMID- 22203720 TI - Classification of seizure and non-seizure EEG signals using empirical mode decomposition. AB - In this paper, we present a new method for classification of electroencephalogram (EEG) signals using empirical mode decomposition (EMD) method. The intrinsic mode functions (IMFs) generated by EMD method can be considered as a set of amplitude and frequency modulated (AM-FM) signals. The Hilbert transformation of IMFs provides an analytic signal representation of the IMFs. The two bandwidths, namely amplitude modulation bandwidth (B(AM)) and frequency modulation bandwidth (B(FM)), computed from the analytic IMFs, have been used as an input to least squares support vector machine (LS-SVM) for classifying seizure and non-seizure EEG signals. The proposed method for classification of EEG signals based on the bandwidth features (B(A M) and B (FM)) and the LS-SVM has provided better classification accuracy than the method of Liang et. al [20]. The experimental results with the recorded EEG signals from a published dataset are included to show the effectiveness of the proposed method for EEG signal classification. PMID- 22203721 TI - A novel semiautomated atherosclerotic plaque characterization method using grayscale intravascular ultrasound images: comparison with virtual histology. AB - Intravascular ultrasound (IVUS) virtual histology (VH-IVUS) is a new technique, which provides automated plaque characterization in IVUS frames, using the ultrasound backscattered RF-signals. However, its computation can only be performed once per cardiac cycle (ECG-gated technique), which significantly decreases the number of characterized IVUS frames. Also atherosclerotic plaques in images that have been acquired by machines, which are not equipped with the VH software, cannot be characterized. To address these limitations, we have developed a plaque characterization technique that can be applied in grayscale IVUS images. Our semiautomated method is based on a three-step approach. In the first step, the plaque area [region of interest (ROI)] is detected semiautomatically. In the second step, a set of features is extracted for each pixel of the ROI and in the third step, a random forest classifier is used to classify these pixels into four classes: dense calcium, necrotic core, fibrotic tissue, and fibro-fatty tissue. In order to train and validate our method, we used 300 IVUS frames acquired from virtual histology examinations from ten patients. The overall accuracy of the proposed method was 85.65% suggesting that our approach is reliable and may be further investigated in the clinical and research arena. PMID- 22203722 TI - A stochastic control approach to optimally designing hierarchical flash sets in P300 communication prostheses. AB - The P300-based speller is a well-established brain-computer interface for communication. It displays a matrix of objects on the computer screen, flashes each object in sequence, and looks for a P300 response induced by flashing the desired object. Most existing P300 spellers uses a fixed set of flash objects. We demonstrate that performance can be significantly improved by sequential selections from a hierarchy of flash sets containing variable number of objects. Theoretically, the optimal hierarchy of flash sets--with respect to a given statistical language model--can be found by solving a stochastic control problem of low computational complexity. Experimentally, statistical analysis demonstrates that the average time per output character at 85% accuracy is reduced by over 50% using our variable-flash-set approach as compared to traditional fixed-flash-set spellers. PMID- 22203723 TI - Normal molecular repair mechanisms in regenerative peripheral nerve interfaces allow recording of early spike activity despite immature myelination. AB - Clinical use of neurally controlled prosthetics has advanced in recent years, but limitations still remain, including lacking fine motor control and sensory feedback. Indwelling multi-electrode arrays, cuff electrodes, and regenerative sieve electrodes have been reported to serve as peripheral neural interfaces, though long-term stability of the nerve-electrode interface has remained a formidable challenge. We recently developed a regenerative multi-electrode interface (REMI) that is able to record neural activity as early as seven days post-implantation. While this activity might represent normal neural depolarization during axonal regrowth, it can also be the result of altered nerve regeneration around the REMI. This study evaluated high-throughput expression levels of 84 genes involved in nerve injury and repair, and the histological changes that occur in parallel to this early neural activity. Animals exhibiting spike activity increased from 29% to 57% from 7 to 14 days following REMI implantation with a corresponding increase in firing rate of 113%. Two weeks after implantation, numbers of neurofilament-positive axons in the control and REMI implanted nerves were comparable, and in both cases the number of myelinated axons was low. During this time, expression levels of genes related to nerve injury and repair were similar in regenerated nerves, both in the presence or absence of the electrode array. Together, these results indicate that the early neural activity is intrinsic to the regenerating axons, and not induced by the REMI neurointerface. PMID- 22203724 TI - Independence of amplitude-frequency and phase calibrations in an SSVEP-based BCI using stepping delay flickering sequences. AB - This study proposes a steady-state visual evoked potential (SSVEP)-based brain computer interface (BCI) independent of amplitude-frequency and phase calibrations. Six stepping delay flickering sequences (SDFSs) at 32-Hz flickering frequency were used to implement a six-command BCI system. EEG signals recorded from Oz position were first filtered within 29-35 Hz, segmented based on trigger events of SDFSs to obtain SDFS epochs, and then stored separately in epoch registers. An epoch-average process suppressed the inter-SDFS interference. For each detection point, the latest six SDFS epochs in each epoch register were averaged and the normalized power of averaged responses was calculated. The visual target that induced the maximum normalized power was identified as the visual target. Eight subjects were recruited in this study. All subjects were requested to produce the "563241" command sequence four times. The averaged accuracy, command transfer interval, and information transfer rate (mean +/- std.) values for all eight subjects were 97.38 +/- 5.97%, 3.56 +/- 0.68 s, and 42.46 +/- 11.17 bits/min, respectively. The proposed system requires no calibration in either the amplitude-frequency characteristic or the reference phase of SSVEP which may provide an efficient and reliable channel for the neuromuscular disabled to communicate with external environments. PMID- 22203725 TI - An electric field model for prediction of somatosensory (S1) cortical field potentials induced by ventral posterior lateral (VPL) thalamic microstimulation. AB - Microstimulation (MiSt) is used experimentally and clinically to activate localized populations of neural elements. However, it is difficult to predict-and subsequently control-neural responses to simultaneous current injection through multiple electrodes in an array. This is due to the unknown locations of neuronal elements in the extracellular medium that are excited by the superposition of multiple parallel current sources. We, therefore, propose a model that maps the computed electric field in the 3-D space surrounding the stimulating electrodes in one brain region to the local field potential (LFP) fluctuations evoked in a downstream region. Our model is trained with the recorded LFP waveforms in the primary somatosensory cortex (S1) resulting from MiSt applied in multiple electrode configurations in the ventral posterolateral nucleus (VPL) of the quiet awake rat. We then predict the cortical responses to MiSt in "novel" electrode configurations, a result that suggests that this technique could aid in the design of spatially optimized MiSt patterns through a multielectrode array. PMID- 22203726 TI - Relationship between clinical assessments of function and measurements from an upper-limb robotic rehabilitation device in cervical spinal cord injury. AB - Upper limb robotic rehabilitation devices can collect quantitative data about the user's movements. Identifying relationships between robotic sensor data and manual clinical assessment scores would enable more precise tracking of the time course of recovery after injury and reduce the need for time-consuming manual assessments by skilled personnel. This study used measurements from robotic rehabilitation sessions to predict clinical scores in a traumatic cervical spinal cord injury (SCI) population. A retrospective analysis was conducted on data collected from subjects using the Armeo Spring (Hocoma, AG) in three rehabilitation centers. Fourteen predictive variables were explored, relating to range-of-motion, movement smoothness, and grip ability. Regression models using up to four predictors were developed to describe the following clinical scores: the GRASSP (consisting of four sub-scores), the ARAT, and the SCIM. The resulting adjusted R(2) value was highest for the GRASSP "Quantitative Prehension" component (0.78), and lowest for the GRASSP "Sensibility" component (0.54). In contrast to comparable studies in stroke survivors, movement smoothness was least beneficial for predicting clinical scores in SCI. Prediction of upper-limb clinical scores in SCI is feasible using measurements from a robotic rehabilitation device, without the need for dedicated assessment procedures. PMID- 22203727 TI - Thyroid nodules: risk stratification for malignancy with ultrasound and guided biopsy. AB - Replacing palpating fingers with an ultrasound (US) probe has resulted in an epidemic of thyroid nodules. Despite the high prevalence of thyroid nodules in the general population, thyroid malignancy is rare. Although no imaging modality can accurately predict the nature of every nodule, high-resolution US is the most sensitive, easily available and cost-effective diagnostic test available to detect thyroid nodules, measure their dimensions and identify their structure. The presence of calcifications, irregular spiculated outline, hypoechogenicity in a solid nodule, chaotic intranodular vascularity and an elongated shape are well known US features of malignancy in thyroid nodules. Cervical lymph node metastasis and extrathyroidal extension of a thyroid nodule are highly specific for malignancy but seen infrequently. Spongiform nodules, purely or predominantly cystic nodules, nodules with well-defined hypoechoic halo and echogenic as well as isoechoic nodules are usually benign. None of the US characteristics have 100% accuracy in detecting or excluding malignancy. Fine-needle biopsy is currently the best triage test for pre-operative evaluation of a thyroid nodule. There is no significant difference in the risk for malignancy between palpable and non palpable nodules and size is not a reliable indicator for their malignant potential. The best tool for risk stratification for malignancy in thyroid nodules is US and guided biopsy of nodules with suspicious imaging features. This is especially relevant in patients with multinodular goitre. PMID- 22203728 TI - CEP-28122, a highly potent and selective orally active inhibitor of anaplastic lymphoma kinase with antitumor activity in experimental models of human cancers. AB - Anaplastic lymphoma kinase (ALK) is constitutively activated in a number of human cancer types due to chromosomal translocations, point mutations, and gene amplification and has emerged as an excellent molecular target for cancer therapy. Here we report the identification and preclinical characterization of CEP-28122, a highly potent and selective orally active ALK inhibitor. CEP-28122 is a potent inhibitor of recombinant ALK activity and cellular ALK tyrosine phosphorylation. It induced concentration-dependent growth inhibition/cytotoxicity of ALK-positive anaplastic large-cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), and neuroblastoma cells, and displayed dose dependent inhibition of ALK tyrosine phosphorylation in tumor xenografts in mice, with substantial target inhibition (>90%) for more than 12 hours following single oral dosing at 30 mg/kg. Dose-dependent antitumor activity was observed in ALK positive ALCL, NSCLC, and neuroblastoma tumor xenografts in mice administered CEP 28122 orally, with complete/near complete tumor regressions observed following treatment at doses of 30 mg/kg twice daily or higher. Treatment of mice bearing Sup-M2 tumor xenografts for 4 weeks and primary human ALCL tumor grafts for 2 weeks at 55 or 100 mg/kg twice daily led to sustained tumor regression in all mice, with no tumor reemergence for more than 60 days postcessation of treatment. Conversely, CEP-28122 displayed marginal antitumor activity against ALK-negative human tumor xenografts under the same dosing regimens. Administration of CEP 28122 was well tolerated in mice and rats. In summary, CEP-28122 is a highly potent and selective orally active ALK inhibitor with a favorable pharmaceutical and pharmacokinetic profile and robust and selective pharmacologic efficacy against ALK-positive human cancer cells and tumor xenograft models in mice. PMID- 22203729 TI - Treatment-related protein biomarker expression differs between primary and recurrent ovarian carcinomas. AB - The molecular characteristics of recurrent ovarian cancers following chemotherapy treatment have been poorly characterized. Such knowledge could impact salvage therapy selection. Since 2008, we have profiled 168 patients' ovarian cancers to determine the expression of proteins that may predict chemotherapy response or are targets for drugs that are in clinical trials for ovarian cancer treatment. Expression of epidermal growth factor receptor (EGFR), HER2, VEGF, ER, c-Met, IGF1R, Ki67, COX2, PGP/MDR1, BCRP, MRP1, excision repair complementation group 1 (ERCC1), MGMT, TS, RRM1, TOPO1, TOP2A, and SPARC was measured by immunohistochemical analyses at Clinical Laboratory Improvement Amendments certified laboratories. Our univariate analysis of 56 primary and 50 recurrent tumors from patients with advanced stage ovarian serous carcinoma revealed that PGP and ERCC1 were significantly upregulated in recurrent lesions (P < 0.05). To determine whether these or any of the other markers were differentially expressed in specimens obtained from the same individual at diagnosis and at recurrence, we analyzed 43 matched tumor specimens from 19 advanced stage ovarian carcinoma patients. We confirmed the expression differences in PGP and ERCC1 that were observed in the cohort analysis but discovered that the expression levels of BCRP, RRM1, and COX2 were also discordant in more than 40% of the matched tumor specimens. These results may have implications both for the use of biomarkers in therapy selection as well as for their discovery and validation. Expression of these and other candidate response biomarkers must be evaluated in much larger studies and, if confirmed, support the need for profiling of recurrent tumor specimens in future clinical trials. PMID- 22203730 TI - Inhibition of STAT3 signaling pathway by nitidine chloride suppressed the angiogenesis and growth of human gastric cancer. AB - STAT3 has been strongly implicated in human malignancies, and constitutive activation of STAT3 serves a crucial role in cell survival, angiogenesis, immune evasion, and inflammation. In this study, we showed that nitidine chloride, a natural phytochemical alkaloid derived from Zanthoxylum nitidum (Roxb) DC, exerts potent anticancer activity through STAT3 signaling cascade. Nitidine chloride dose dependently suppressed VEGF-induced endothelial cell proliferation, migration, and tubular structure formation in vitro and dramatically reduced VEGF triggered neovascularization in mouse cornea and Matrigel plugs in vivo. This angiogenesis inhibition mediated by nitidine chloride was well interpreted by the suppression of Janus kinase 2/STAT3 signaling and STAT3 DNA-binding activity in endothelial cells. Furthermore, nitidine chloride suppressed the constitutively activated STAT3 protein, its DNA-binding activity, and the expression of STAT3 dependent target genes, including cyclin D1, Bcl-xL, and VEGF in human gastric cancer cells. Consistent with the earlier findings, nitidine chloride inhibited gastric tumor cell growth and induced tumor cell apoptosis in vitro and effectively suppressed the volume, weight, and microvessel density of human SGC 7901 gastric solid tumors (n = 8) at a dosage of 7 mg/kg/d (intraperitoneal injection). Immunohistochemistry and Western blot analysis further revealed that the expression of STAT3, CD31, and VEGF protein in xenografts was remarkably decreased by the alkaloid. Taken together, we propose that nitidine chloride is a promising anticancer drug candidate as a potent STAT3 signaling inhibitor. PMID- 22203731 TI - Dual combination therapy targeting DR5 and EMMPRIN in pancreatic adenocarcinoma. AB - The goal of the study was to assess the efficacy of combined extracellular matrix metalloprotease inducer (EMMPRIN)- and death receptor 5 (DR5)-targeted therapy for pancreatic adenocarcinoma in orthotopic mouse models with multimodal imaging. Cytotoxicity of anti-EMMPRIN antibody and anti-DR5 antibody (TRA-8) in MIA PaCa-2 and PANC-1 cell lines was measured by ATPlite assay in vitro. The distributions of Cy5.5-labeled TRA-8 and Cy3-labeled anti-EMMPRIN antibody in the 2 cell lines were analyzed by fluorescence imaging in vitro. Groups 1 to 12 of severe combined immunodeficient mice bearing orthotopic MIA PaCa-2 (groups 1-8) or PANC-1 (groups 9-12) tumors were used for in vivo studies. Dynamic contrast-enhanced-MRI was applied in group 1 (untreated) or group 2 (anti-EMMPRIN antibody). The tumor uptake of Tc-99m-labeled TRA-8 was measured in group 3 (untreated) and group 4 (anti-EMMPRIN antibody). Positron emission tomography/computed tomography imaging with (18)F-FDG was applied in groups 5 to 12. Groups 5 to 8 (or groups 9 to 12) were untreated or treated with anti-EMMPRIN antibody, TRA-8, and combination, respectively. TRA-8 showed high killing efficacy for both MIA PaCa-2 and PANC-1 cells in vitro, but additional anti-EMMPRIN treatment did not improve the cytotoxicity. Cy5.5-TRA-8 formed cellular caps in both the cell lines, whereas the maximum signal intensity was correlated with TRA-8 cytotoxicity. Anti-EMMPRIN therapy significantly enhanced the tumor delivery of the MR contrast agent, but not Tc-99m-TRA-8. Tumor growth was significantly suppressed by the combination therapy, and the additive effect of the combination was shown in both MIA PaCa-2 and PANC-1 tumor models. PMID- 22203732 TI - Safety, pharmacokinetics, and activity of GRN1005, a novel conjugate of angiopep 2, a peptide facilitating brain penetration, and paclitaxel, in patients with advanced solid tumors. AB - GRN1005 is a novel peptide-drug conjugate composed of paclitaxel covalently linked to a peptide, angiopep-2, that targets the low-density lipoprotein receptor-related protein 1. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and efficacy of GRN1005 in patients with advanced solid tumors. Patients in sequential cohorts (one patient per cohort until grade 2 toxicity, then 3 + 3 design) received intravenous GRN1005 at escalating doses between 30 and 700 mg/m(2) once in every 21 days. In the maximum tolerated dose (MTD) expansion group, patients were required to have brain metastases. Fifty-six patients received GRN1005, including 41 with brain metastases (median number of prior therapies = 4). MTD was 650 mg/m(2); the main dose-limiting toxicity was myelosuppression. Sixteen of 20 patients dosed at the MTD had brain metastases. Pharmacokinetics was dose linear and the mean terminal-phase elimination half life was 3.6 hours. No evidence of accumulation was observed after repeat dosing. No anti-GRN1005 antibodies were detected. Five of the 20 patients (25%) dosed at 650 mg/m(2) (MTD), three of whom had previous taxane therapy, achieved an overall partial response (breast, n = 2; non-small cell lung cancer, n = 2; and ovarian cancer, n = 1); responses in all five patients were also accompanied by shrinkage of brain lesions (-17% to -50%). In addition, six patients (11%; doses 30-700 mg/m(2)) experienced stable disease that lasted 4 months or more. GRN1005 was well tolerated and showed activity in heavily pretreated patients with advanced solid tumors, including those who had brain metastases and/or failed prior taxane therapy. PMID- 22203733 TI - Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA-damaging agents and antimetabolites. AB - Many anticancer agents damage DNA and arrest cell-cycle progression primarily in S or G(2) phase of the cell cycle. Previous studies with the topoisomerase I inhibitor SN38 have shown the efficacy of the Chk1 inhibitor UCN-01 to overcome this arrest and induce mitotic catastrophe. UCN-01 was limited in clinical trials by unfavorable pharmacokinetics. SCH900776 is a novel and more selective Chk1 inhibitor that potently inhibits Chk1 and abrogates cell-cycle arrest induced by SN38. Like UCN-01, abrogation of SN38-induced arrest enhances the rate of cell death but does not increase overall cell death. In contrast, SCH900776 reduced the growth-inhibitory concentration of hydroxyurea by 20- to 70-fold. A similar magnitude of sensitization was observed with cytarabine. A 5- to 10-fold sensitization occurred with gemcitabine, but no sensitization occurred with cisplatin, 5-fluorouracil, or 6-thioguanine. Sensitization occurred at hydroxyurea concentrations that marginally slowed DNA replication without apparent activation of Chk1, but this led to dependence on Chk1 that increased with time. For example, when added 18 hours after hydroxyurea, SCH900776 induced DNA double-strand breaks consistent with rapid collapse of replication forks. In addition, some cell lines were highly sensitive to SCH900776 alone, and these cells required lower concentrations of SCH900776 to sensitize them to hydroxyurea. We conclude that some tumors may be very sensitive to the combination of SCH900776 and hydroxyurea. Delayed administration of SCH900776 may be more effective than concurrent treatment. SCH900776 is currently in phase I clinical trials, and these results provide the rationale and schedule for future clinical trials. PMID- 22203734 TI - DNA methyltransferase inhibitor, zebularine, delays tumor growth and induces apoptosis in a genetically engineered mouse model of breast cancer. AB - Zebularine is a novel potent inhibitor of both cytidine deaminase and DNA methylation. We examined the effect of zebularine on mammary tumor growth in genetically engineered MMTV-PyMT transgenic mice that develop mammary tumors at 60 days of age with 100% penetrance. The MMTV-PyMT transgenic mice were randomized at 46 days of age into control (n = 25) and zebularine (n = 25) treatment groups and monitored for parameters of tumor growth. Zebularine was administered at 5 mg/mL in drinking water. We observed a significant delay in the growth of mammary tumors in zebularine-treated mice with a statistically significant reduction (P = 0.0135) in total tumor burden at 94 days of age when the mice were sacrificed. After 48 days of zebularine treatment, the tumors were predominantly necrotic compared with untreated animals. In addition, a high apoptotic index by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was observed as early as 13 days following treatment. Immunoblot analysis showed depletion of DNMT1 and partial depletion of DNMT3b after zebularine treatment. Microarray analyses of global gene expression identified upregulation of twelve methylation-regulated genes as well as a set of candidate cancer genes that participate in cell growth and apoptosis. In summary, zebularine inhibits the growth of spontaneous mammary tumors and causes early onset of tumor cell necrosis and apoptosis in a genetically engineered mouse model of breast cancer. Defining the parameters of zebularine-mediated tumor inhibition may advance the future development of DNA methyltransferase inhibitors as an effective cancer treatment. PMID- 22203735 TI - Increased angiotensin II-induced hypertension and inflammatory cytokines in mice lacking angiotensin-converting enzyme N domain activity. AB - -Angiotensin-converting enzyme (ACE) is composed of the N- and C-terminal catalytic domains. To study the role of the ACE domains in the inflammatory response, N-knockout (KO) and C-KO mice, models lacking 1 of the 2 ACE domains, were analyzed during angiotensin II-induced hypertension. At 2 weeks, N-KO mice have systolic blood pressures that averaged 173+/-4.6 mm Hg, which is more than 25 mm Hg higher than the blood pressures observed in wild-type or C-KO mice (146+/-3.2 and 147+/-4.2 mm Hg). After 3 weeks, blood pressure differences between N-KO, C-KO, and wild-type were even more pronounced. Macrophages from N KO mice have increased expression of tumor necrosis factor alpha after stimulation with either lipopolysaccharide (about 4-fold) or angiotensin II (about 2-fold), as compared with C-KO or wild-type mice. Inhibition of the enzyme prolyl oligopeptidase, responsible for the formation of acetyl-SerAspLysPro and other peptides, eliminated the blood pressure difference and the difference in tumor necrosis factor alpha expression between angiotensin II-treated N-KO and wild-type mice. However, this appears independent of acetyl-SerAspLysPro. These data establish significant differences in the inflammatory response as a function of ACE N- or C-domain catalytic activity. They also indicate a novel role of prolyl oligopeptidase in the cytokine regulation and in the blood pressure response to experimental hypertension. PMID- 22203736 TI - Mechanisms of dopamine D(1) and angiotensin type 2 receptor interaction in natriuresis. AB - Renal dopamine D(1)-like receptors (D(1)Rs) and angiotensin type 2 receptors (AT(2)Rs) are important natriuretic receptors counterbalancing angiotensin type 1 receptor-mediated tubular sodium reabsorption. Here we explore the mechanisms of D(1)R and AT(2)R interactions in natriuresis. In uninephrectomized, sodium-loaded Sprague-Dawley rats, direct renal interstitial infusion of the highly selective D(1)R agonist fenoldopam induced a natriuretic response that was abolished by the AT(2)R-specific antagonist PD-123319 or by microtubule polymerization inhibitor nocodazole but not by actin polymerization inhibitor cytochalasin D. By confocal microscopy and immunoelectron microscopy, fenoldopam translocated AT(2)Rs from intracellular sites to the apical plasma membranes of renal proximal tubule cells, and this translocation was abolished by nocodazole. Because D(1)R activation induces natriuresis via an adenylyl cyclase/cAMP signaling pathway, we explored whether this pathway is responsible for AT(2)R recruitment and AT(2)R mediated natriuresis. Renal interstitial coinfusion of the adenylyl cyclase activator forskolin and 3-isobutly-1-methylxanthine induced natriuresis that was abolished either by PD-123319 or nocodazole but was unaffected by specific the D(1)R antagonist SCH-23390. Coadministration of forskolin and 3-isobutly-1 methylxanthine also translocated AT(2)Rs to the apical plasma membranes of renal proximal tubule cells; this translocation was abolished by nocodazole but was unaffected by SCH-23390. The results demonstrate that D(1)R-induced natriuresis requires AT(2)R recruitment to the apical plasma membranes of renal proximal tubule cells in a microtubule-dependent manner involving an adenylyl cyclase/cAMP signaling pathway. These studies provide novel insights regarding the mechanisms whereby renal D(1)Rs and AT(2)Rs act in concert to promote sodium excretion in vivo. PMID- 22203738 TI - Rate of decline of forced vital capacity predicts future arterial hypertension: the Coronary Artery Risk Development in Young Adults Study. AB - Lung function studies in middle-aged subjects predict cardiovascular disease mortality. We studied whether greater loss of forced vital capacity (FVC) early in life predicted incident hypertension. The sample was 3205 black and white men and women in the Coronary Artery Risk Development in Young Adults Study examined between 1985 and 1986 (Coronary Artery Risk Development in Young Adults year 0, ages 18-30 years) and 2005-2006 and who were not hypertensive by year 10. FVC was assessed at years 0, 2, 5, 10, and 20. Proportional hazard ratios and linear regression models predicted incident hypertension at years 15 or 20 (n=508) from the change in FVC (FVC at year 10 - peak FVC, where peak FVC was estimated as the maximum across years 0, 2, 5, and 10). Covariates included demographics, center, systolic blood pressure, FVC maximum, smoking, physical activity, asthma, and body mass index. Unadjusted cumulative incident hypertension was 25% in the lowest FVC loss quartile (Q1; median loss: 370 mL) compared with 12% cumulative incident hypertension in those who achieved peak FVC at year 10 (Q4). Minimally adjusted hazard ratio for Q1 versus Q4 was 2.21 (95% CI: 1.73-2.83), and this association remained significant in the fully adjusted model (1.37; 95% CI: 1.05 1.80). Decline in FVC from average age at peak (29.4 years) to 35 years old predicted incident hypertension between average ages 35 and 45 years. The findings may represent a common pathway that may link low normal FVC to cardiovascular disease morbidity and mortality. PMID- 22203737 TI - NADPH oxidase and PKC contribute to increased Na transport by the thick ascending limb during type 1 diabetes. AB - Type 1 diabetes triggers protein kinase C (PKC)-dependent NADPH oxidase activation in the renal medullary thick ascending limb (mTAL), resulting in accelerated superoxide production. As acute exposure to superoxide stimulates NaCl transport by the mTAL, we hypothesized that diabetes increases mTAL Na(+) transport through PKC-dependent and NADPH oxidase-dependent mechanisms. An O(2) sensitive fluoroprobe was used to measure O(2) consumption by mTALs from rats with streptozotocin-induced diabetes and sham rats. In sham mTALs, total O(2) consumption was evident as a 0.34+/-0.03 U change in normalized relative fluorescence (DeltaNRF)/min per mg protein. Ouabain (2 mmol/L) reduced O(2) consumption by 69+/-4% and 500 MUmol/L furosemide reduced O(2) consumption by 58+/-8%. Total O(2) consumption was accelerated in mTAL from diabetic rats (0.74+/-0.07 DeltaNRF/min/mg protein; P<0.05 versus sham), reflecting increases in ouabain- and furosemide-sensitive O(2) consumption. NADPH oxidase inhibition (100 MUmol/L apocynin) reduced furosemide-sensitive O(2) consumption by mTAL from diabetic rats to values not different from sham. The PKC inhibitor calphostin C (1 MUmol/L) or the PKCalpha/beta inhibitor Go6976 (1 MUmol/L) decreased furosemide-sensitive O(2) consumption in both groups, achieving values that did not differ between sham and diabetic. PKCbeta inhibition had no effect in either group. Similar inhibitory patterns were evident with regard to ouabain-sensitive O(2) consumption. We conclude that NADPH oxidase and PKC (primarily PKCalpha) contribute to an increase in O(2) consumption by the mTAL during type 1 diabetes through effects on the ouabain-sensitive Na(+)-K(+)-ATPase and furosemide sensitive Na(+)-K(+)-2Cl(-) cotransporter that are primarily responsible for active transport Na(+) reabsorption by this nephron segment. PMID- 22203739 TI - Sodium depletion enhances renal expression of (pro)renin receptor via cyclic GMP protein kinase G signaling pathway. AB - (Pro)renin receptor (PRR) is expressed in renal vasculature, glomeruli, and tubules. The physiological regulation of this receptor is not well established. We hypothesized that sodium depletion increases PRR expression through cGMP- protein kinase G (PKG) signaling pathway. Renal PRR expressions were evaluated in Sprague-Dawley rats on normal sodium or low-sodium diet (LS) and in cultured rat proximal tubular cells and mouse renal inner medullary collecting duct cells exposed to LS concentration. LS augmented PRR expression in renal glomeruli, proximal tubules, distal tubules, and collecting ducts. LS also increased cGMP production and PKG activity. In cells exposed to normal sodium, cGMP analog increased PKG activity and upregulated PRR expression. In cells exposed to LS, blockade of guanylyl cyclase with 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one decreased PKG activity and downregulated PRR expression. PKG inhibition decreased phosphatase protein phosphatase 2A activity; suppressed LS-mediated phosphorylation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, c-Jun, and nuclear factor-kappaB p65; and attenuated LS-mediated PRR upregulation. LS also enhanced DNA binding of cAMP response element binding protein 1 to cAMP response elements, nuclear factor-kappaB p65 to nuclear factor kappaB elements, and c-Jun to activator protein 1 elements in PRR promoter in proximal tubular cells. We conclude that sodium depletion upregulates renal PRR expression via the cGMP-PKG signaling pathway by enhancing binding of cAMP response element binding protein 1, nuclear factor-kappaB p65, and c-Jun to PRR promotor. PMID- 22203740 TI - KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism. AB - Primary aldosteronism is the most frequent cause of endocrine hypertension. Three forms of familial hyperaldosteronism (FH) have been described, named FH-I to III. Recently, a mutation of KCNJ5 has been shown to be associated with FH-III, whereas the cause of FH-II is still unknown. In this study we searched for mutations in KCNJ5 in 46 patients from 21 families with FH, in which FH-I was excluded. We identified a new germline G151E mutation in 2 primary aldosteronism affected subjects from an Italian family and 3 somatic mutations in aldosterone producing adenomas, T158A described previously as a germline mutation associated with FH-III, and G151R and L168R both described as somatic mutations in aldosterone-producing adenoma. The phenotype of the family with the G151E mutation was remarkably milder compared with the previously described American family, in terms of both clinical and biochemical parameters. Furthermore, patients with somatic KCNJ5 mutations displayed a phenotype indistinguishable from that of sporadic primary aldosteronism. The functional characterization of the effects of the G151E mutation in vitro showed a profound alteration of the channel function, with loss of K(+) selectivity, Na(+) influx, and membrane depolarization. These alterations have been postulated to be responsible for voltage gate Ca(2+) channel activation, increase in cytosolic calcium, and stimulation of aldosterone production and adrenal cell proliferation. In conclusion, we describe herein a new mutation in the KCNJ5 potassium channel associated with FH-III, responsible for marked alterations of channel function but associated with a mild clinical and hormonal phenotype. PMID- 22203741 TI - Deletion of G protein-coupled estrogen receptor increases endothelial vasoconstriction. AB - Endogenous estrogens mediate protective effects in the cardiovascular system, affecting both endothelium-dependent and endothelium-independent mechanisms. Previous studies have suggested that nonselective estrogen receptor agonists such as endogenous estrogens inhibit endothelium-dependent vasoconstriction; however, the role of estrogen receptors in this response has not yet been clarified. This study investigated whether the intracellular transmembrane G protein-coupled estrogen receptor (GPER) regulates vascular reactivity in mice. Effects of chronic deficiency (using mice lacking the GPER gene) and acute inhibition (using the GPER-selective antagonist G15) on endothelium-dependent and endothelium independent vascular reactivity, and the effects of GPER deficiency on vascular gene expression and structure were investigated. We found that chronic GPER deficiency is associated with increased endothelial prostanoid-mediated vasoconstriction but has no effect on endothelial nitric oxide bioactivity, gene expression of endothelial nitric oxide synthase and thromboxane prostanoid (TP) receptor, or vascular structure. GPER deletion also increases TP receptor mediated contraction. Acute GPER blockade enhances endothelium-dependent contractions and reduces endothelial nitric oxide bioactivity. Contractions in response to TP receptor activation are unaffected by G15. In conclusion, this study identifies GPER as the first estrogen receptor with inhibitory activity on endothelium-dependent contractility. These findings may be important for understanding and treating diseases associated with increased endothelial vasoconstrictor prostanoid activity such as hypertension and obesity. PMID- 22203742 TI - Genome-wide profiling of blood pressure in adults and children. AB - Hypertension is an important determinant of cardiovascular morbidity and mortality and has a substantial heritability, which is likely of polygenic origin. The aim of this study was to assess to what extent multiple common genetic variants contribute to blood pressure regulation in both adults and children and to assess overlap in variants between different age groups, using genome-wide profiling. Single nucleotide polymorphism sets were defined based on a meta-analysis of genome-wide association studies on systolic blood pressure and diastolic blood pressure performed by the Cohort for Heart and Aging Research in Genome Epidemiology (n=29 136), using different P value thresholds for selecting single nucleotide polymorphisms. Subsequently, genetic risk scores for systolic blood pressure and diastolic blood pressure were calculated in an independent adult population (n=2072) and a child population (n=1034). The explained variance of the genetic risk scores was evaluated using linear regression models, including sex, age, and body mass index. Genetic risk scores, including also many nongenome-wide significant single nucleotide polymorphisms, explained more of the variance than scores based only on very significant single nucleotide polymorphisms in adults and children. Genetic risk scores significantly explained <=1.2% (P=9.6*10(-8)) of the variance in adult systolic blood pressure and 0.8% (P=0.004) in children. For diastolic blood pressure, the variance explained was similar in adults and children (1.7% [P=8.9*10(-10)] and 1.4% [P=3.3*10(-5)], respectively). These findings suggest the presence of many genetic loci with small effects on blood pressure regulation both in adults and children, indicating also a (partly) common polygenic regulation of blood pressure throughout different periods of life. PMID- 22203743 TI - Adrenergic cardiovascular control before and after removal of stimulatory alpha-1 adrenoreceptor antibodies. PMID- 22203744 TI - Sildenafil prevents and reverses transverse-tubule remodeling and Ca(2+) handling dysfunction in right ventricle failure induced by pulmonary artery hypertension. AB - Right ventricular (RV) failure (RVF) is the main cause of death in patients with pulmonary artery hypertension (PAH). Sildenafil, a phosphodiesterase type 5 inhibitor, was approved recently for treatment of PAH patients. However, the mechanisms underlying RV contractile malfunction and the benefits of sildenafil on RV function are not well understood. We aimed to investigate the following: (1) the ultrastructural and excitation-contraction coupling alterations underlying PAH-induced RVF; (2) whether the ultrastructural changes are reversible; and (3) the mechanisms underlying the therapeutic benefits of sildenafil in PAH-RVF. We used a single injection of monocrotaline in Wistar rats to induce pulmonary vascular proliferation, which led to PAH and RVF. RV myocytes displayed severe transverse (T)-tubule loss and disorganization, as well as blunted and dys-synchronous sarcoplasmic reticulum Ca(2+) release. Sildenafil prevented and reversed the monocrotaline-induced PAH and LV filling impairment. Early intervention with sildenafil prevented RV hypertrophy and the development of RVF, T-tubule remodeling, and Ca(2+) handling dysfunction. Although late treatment with sildenafil did not reverse RV hypertrophy in animals with established RVF, RV systolic function was improved. Furthermore, late intervention partially reversed both the impairment of myocyte T-tubule integrity and Ca(2+) handling protein and sarcoplasmic reticulum Ca(2+) release function in monocrotaline-treated rats. In conclusion, PAH-induced increase in RV afterload causes severe T-tubule remodeling and Ca(2+) handling dysfunction in RV myocytes, leading to RV contractile failure. Sildenafil prevents and partially reverses ultrastructural, molecular, and functional remodeling of failing RV myocytes. Reversal of pathological T-tubule remodeling, although incomplete, is achievable without the regression of RV hypertrophy. PMID- 22203745 TI - Blood pressure threshold for abnormal ocular fundus findings is lower than expected. PMID- 22203746 TI - Mutations of the potassium channel KCNJ5 causing aldosterone-producing adenomas: one or two hits? PMID- 22203747 TI - Hydroxysteroid (17-beta) dehydrogenase 1 is dysregulated by miR-210 and miR-518c that are aberrantly expressed in preeclamptic placentas: a novel marker for predicting preeclampsia. AB - In this study, to search for novel preeclampsia (PE) biomarkers, we focused on microRNA expression and function in the human placenta complicated with PE. By comprehensive analyses of microRNA expression, we identified 22 microRNAs significantly upregulated in preeclamptic placentas, 5 of which were predicted in silico to commonly target the mRNA encoding hydroxysteroid (17-beta) dehydrogenase 1 (HSD17B1), a steroidogenetic enzyme expressed predominantly in the placenta. In vivo HSD17B1 expression, at both the mRNA and protein levels, was significantly decreased in preeclamptic placentas. Of these microRNAs, miR 210 and miR-518c were experimentally validated to target HSD17B1 by luciferase assay, real-time PCR, and ELISA. Furthermore, we found that plasma HSD17B1 protein levels in preeclamptic pregnant women reflected the decrease of its placental expression. Moreover, a prospective cohort study of plasma HSD17B1 revealed a significant reduction of plasma HSD17B1 levels in pregnant women at 20 to 23 and 27 to 30 weeks of gestation before PE onset compared with those with normal pregnancies. The sensitivities/specificities for predicting PE at 20 to 23 and 27 to 30 weeks of gestation were 0.75/0.67 (cutoff value=21.9 ng/mL) and 0.88/0.51 (cutoff value=30.5 ng/mL), and the odds ratios were 6.09 (95% CI: 2.35 15.77) and 7.83 (95% CI: 1.70-36.14), respectively. We conclude that HSD17B1 is dysregulated by miR-210 and miR-518c that are aberrantly expressed in preeclamptic placenta and that reducing plasma level of HSD17B1 precedes the onset of PE and is a potential prognostic factor for PE. PMID- 22203748 TI - Severe hypertension with large-vessel arteritis. PMID- 22203749 TI - Vascular remodeling in hypertension: mechanisms and treatment. PMID- 22203750 TI - Photo quiz: skin rash and extremity swelling in an adolescent. PMID- 22203751 TI - Routine confirmation of positive nucleic acid amplification test results for Neisseria gonorrhoeae is not necessary. PMID- 22203753 TI - Cerebrospinal fluid (CSF) lactic acid levels: a rapid and reliable way to differentiate viral from bacterial meningitis or concurrent viral/bacterial meningitis. PMID- 22203755 TI - Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. AB - PURPOSE: Olaparib (AZD2281), an orally active poly (ADP-ribose) polymerase inhibitor that induces synthetic lethality in BRCA1- or BRCA2-deficient cells, has shown promising clinical efficacy in nonrandomized phase II trials in patients with ovarian cancer with BRCA1 or BRCA2 deficiency. We assessed the comparative efficacy and safety of olaparib and pegylated liposomal doxorubicin (PLD) in this patient population. PATIENTS AND METHODS: In this multicenter, open label, randomized, phase II study, patients with ovarian cancer that recurred within 12 months of prior platinum therapy and with confirmed germline BRCA1 or BRCA2 mutations were enrolled. Patients were assigned in a 1:1:1 ratio to olaparib 200 mg twice per day or 400 mg twice per day continuously or PLD 50 mg/m(2) intravenously every 28 days. The primary efficacy end point was Response Evaluation Criteria in Solid Tumors (RECIST) -assessed progression-free survival (PFS). Secondary end points included objective response rate (ORR) and safety. RESULTS: Ninety-seven patients were randomly assigned. Median PFS was 6.5 months (95% CI, 5.5 to 10.1 months), 8.8 months (95% CI, 5.4 to 9.2 months), and 7.1 months (95% CI, 3.7 to 10.7 months) for the olaparib 200 mg, olaparib 400 mg, and PLD groups, respectively. There was no statistically significant difference in PFS (hazard ratio, 0.88; 95% CI, 0.51 to 1.56; P = .66) for combined olaparib doses versus PLD. RECIST-assessed ORRs were 25%, 31%, and 18% for olaparib 200 mg, olaparib 400 mg, and PLD, respectively; differences were not statistically significant. Tolerability of both treatments was as expected based on previous trials. CONCLUSION: The efficacy of olaparib was consistent with previous studies. However, the efficacy of PLD was greater than expected. Olaparib 400 mg twice per day is a suitable dose to explore in further studies in this patient population. PMID- 22203756 TI - Association of obesity with DNA mismatch repair status and clinical outcome in patients with stage II or III colon carcinoma participating in NCCTG and NSABP adjuvant chemotherapy trials. AB - PURPOSE: Although the importance of obesity in colon cancer risk and outcome is recognized, the association of body mass index (BMI) with DNA mismatch repair (MMR) status is unknown. PATIENTS AND METHODS: BMI (kg/m(2)) was determined in patients with TNM stage II or III colon carcinomas (n = 2,693) who participated in randomized trials of adjuvant chemotherapy. The association of BMI with MMR status and survival was analyzed by logistic regression and Cox models, respectively. RESULTS: Overall, 427 (16%) tumors showed deficient MMR (dMMR), and 630 patients (23%) were obese (BMI >= 30 kg/m(2)). Obesity was significantly associated with younger age (P = .021), distal tumor site (P = .012), and a lower rate of dMMR tumors (10% v 17%; P < .001) compared with normal weight. Obesity remained associated with lower rates of dMMR (odds ratio, 0.57; 95% CI, 0.41 to 0.79; P < .001) after adjusting for tumor site, stage, sex, and age. Among obese patients, rates of dMMR were lower in men compared with women (8% v 13%; P = .041). Obesity was associated with higher recurrence rates (P = .0034) and independently predicted worse disease-free survival (DFS; hazard ratio [HR], 1.37; 95% CI, 1.14 to 1.64; P = .0010) and overall survival (OS), whereas dMMR predicted better DFS (HR, 0.59; 95% CI, 0.47 to 0.74; P < .001) and OS. The favorable prognosis of dMMR was maintained in obese patients. CONCLUSION: Colon cancers from obese patients are less likely to show dMMR, suggesting obesity related differences in the pathogenesis of colon cancer. Although obesity was independently associated with adverse outcome, the favorable prognostic impact of dMMR was maintained among obese patients. PMID- 22203757 TI - Artificial prostate-specific antigen persistence after radical prostatectomy. PMID- 22203758 TI - Effect of early palliative care on chemotherapy use and end-of-life care in patients with metastatic non-small-cell lung cancer. AB - PURPOSE: Prior research shows that introducing palliative care soon after diagnosis for patients with metastatic non-small-cell lung cancer (NSCLC) is associated with improvements in quality of life, mood, and survival. We sought to investigate whether early palliative care also affects the frequency and timing of chemotherapy use and hospice care for these patients. PATIENTS AND METHODS: This secondary analysis is based on a randomized controlled trial of 151 patients with newly diagnosed metastatic NSCLC presenting to an outpatient clinic at a tertiary cancer center from June 2006 to July 2009. Participants received either early palliative care integrated with standard oncology care or standard oncology care alone. By 18-month follow-up, 133 participants (88.1%) had died. Outcome measures included: first, number and types of chemotherapy regimens, and second, frequency and timing of chemotherapy administration and hospice referral. RESULTS: The overall number of chemotherapy regimens did not differ significantly by study group. However, compared with those in the standard care group, participants receiving early palliative care had half the odds of receiving chemotherapy within 60 days of death (odds ratio, 0.47; 95% CI, 0.23 to 0.99; P = .05), a longer interval between the last dose of intravenous chemotherapy and death (median, 64.00 days [range, 3 to 406 days] v 40.50 days [range, 6 to 287 days]; P = .02), and higher enrollment in hospice care for longer than 1 week (60.0% [36 of 60 patients] v 33.3% [21 of 63 patients]; P = .004). CONCLUSION: Although patients with metastatic NSCLC received similar numbers of chemotherapy regimens in the sample, early palliative care optimized the timing of final chemotherapy administration and transition to hospice services, key measures of quality end-of-life care. PMID- 22203759 TI - Comparing poly (ADP-ribose) polymerase inhibitors with standard chemotherapy in BRCA-mutated, recurrent ovarian cancer: lessons learned from a negative trial. PMID- 22203760 TI - Treatment of patients with advanced neurofibromatosis type 2 with novel molecularly targeted therapies: from bench to bedside. PMID- 22203762 TI - Breast cancer radiotherapy and coronary artery stenosis: location, location, location. PMID- 22203761 TI - Activation of peripheral-blood granulocytes is strongly correlated with patient outcome after immunotherapy with anti-GD2 monoclonal antibody and granulocyte macrophage colony-stimulating factor. AB - PURPOSE: Adjuvant therapy using anti-GD2 monoclonal antibody and granulocyte macrophage colony-stimulating factor (GM-CSF) has shown treatment success for patients with high-risk neuroblastoma (NB). Although there is ample evidence on how the antibody targets NB, in vivo contribution by GM-CSF remains unclear. This report investigates granulocyte activation and its correlation with treatment outcome. PATIENTS AND METHODS: Patients enrolled onto NCT00072358 received multiple treatment cycles, each consisting of anti-GD2 antibody 3F8 plus subcutaneous (SC) GM-CSF. Peripheral-blood (PB) samples from 151 patients were collected on day 0 and day 4 of cycle 1. PB from a subgroup of 35 patients had intravenous (IV) instead of SC GM-CSF during cycle 4. Samples were analyzed by flow cytometry for CD11a, CD63, CD87, and CD11b and its activation epitope CBRM1/5. RESULTS: Comparing cycle 1 day 4 PB samples with day 0 PB samples, five of five activation marker-positive granulocytes were significantly higher. The change in frequency and mean fluorescence intensity of CBRM1/5-positive granulocytes correlated with progression-free survival (PFS; P = .024 and P = .008, respectively). A multivariable analysis identified increasing CBRM1/5 positive granulocytes and missing killer immunoglobulin-like receptor ligand as positive independent prognostic factors for PFS, whereas second-line cyclophosphamide-based therapy before protocol entry negatively influenced outcome. Thirty-five patients who received SC GM-CSF at cycle 1 and IV GM-CSF at cycle 4 had significantly less CBRM1/5 activation after IV GM-CSF. In contrast, 63 patients who received SC GM-CSF at both cycles had comparable CBRM1/5 activation. CONCLUSION: GM-CSF-induced granulocyte activation in vivo is associated with improved patient outcome. This activation was more apparent when GM-CSF was given by the SC route instead of IV route. PMID- 22203763 TI - "HER majesty's a pretty nice girl but she changes from day to day". PMID- 22203764 TI - Unilateral exophthalmos and multiple subcutaneous nodules as a result of extranodal marginal zone lymphoma. PMID- 22203765 TI - It takes a village. PMID- 22203766 TI - Potential utility of an expression array signature for predicting anthracycline responsiveness or resistance. PMID- 22203768 TI - Zirconium-89-trastuzumab positron emission tomography as a tool to solve a clinical dilemma in a patient with breast cancer. PMID- 22203767 TI - Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. AB - PURPOSE: Our group has previously published the Graded Prognostic Assessment (GPA), a prognostic index for patients with brain metastases. Updates have been published with refinements to create diagnosis-specific Graded Prognostic Assessment indices. The purpose of this report is to present the updated diagnosis-specific GPA indices in a single, unified, user-friendly report to allow ease of access and use by treating physicians. METHODS: A multi institutional retrospective (1985 to 2007) database of 3,940 patients with newly diagnosed brain metastases underwent univariate and multivariate analyses of prognostic factors associated with outcomes by primary site and treatment. Significant prognostic factors were used to define the diagnosis-specific GPA prognostic indices. A GPA of 4.0 correlates with the best prognosis, whereas a GPA of 0.0 corresponds with the worst prognosis. RESULTS: Significant prognostic factors varied by diagnosis. For lung cancer, prognostic factors were Karnofsky performance score, age, presence of extracranial metastases, and number of brain metastases, confirming the original Lung-GPA. For melanoma and renal cell cancer, prognostic factors were Karnofsky performance score and the number of brain metastases. For breast cancer, prognostic factors were tumor subtype, Karnofsky performance score, and age. For GI cancer, the only prognostic factor was the Karnofsky performance score. The median survival times by GPA score and diagnosis were determined. CONCLUSION: Prognostic factors for patients with brain metastases vary by diagnosis, and for each diagnosis, a robust separation into different GPA scores was discerned, implying considerable heterogeneity in outcome, even within a single tumor type. In summary, these indices and related worksheet provide an accurate and facile diagnosis-specific tool to estimate survival, potentially select appropriate treatment, and stratify clinical trials for patients with brain metastases. PMID- 22203769 TI - Posterior reversible encephalopathy syndrome during ipilimumab therapy for malignant melanoma. PMID- 22203770 TI - High-dose chemotherapy as adjuvant therapy in breast cancer: could there be a survival benefit? PMID- 22203771 TI - Effect of the accountable care act of 2010 on clinical trial insurance coverage. AB - PURPOSE: The Affordable Care Act (ACA) of 2010 implemented dramatic changes in our health care system. The new law requires that insurers and health plans provide coverage for individuals participating in clinical trials. Currently, there are states that already have laws or agreements requiring clinical trial coverage, but there remain deficiencies that will need to be addressed to achieve compliance with the new law. METHODS: State mandates were reviewed to determine current laws and agreements. The ACA was reviewed to outline its provisions, and these were compared with current mandates to identify deficiencies. RESULTS: Eighteen states meet the requirements set forth by the ACA either through a state law or agreement; 33 states do not meet the requirements. Of these 33 states, 15 do not have any existing laws or agreements in place regarding clinical trials. In states that have deficient policies in place, the most common deficiency is the lack of phase I coverage. The second most common deficiency in policy is coverage of only therapeutic studies. CONCLUSION: Most states currently do not meet the requirements of the ACA and will be required to make changes by 2014. The implications of the ACA with regard to insurance coverage of clinical trials remain unclear as implementation of the legislation unfolds. State governments can take steps to ensure insurance coverage by creating and expanding agreements with insurance companies. PMID- 22203772 TI - Distribution of coronary artery stenosis after radiation for breast cancer. AB - PURPOSE: To study distribution of coronary artery stenosis among patients with breast cancer (BC) and to assess correlation between radiotherapy (RT) and location of stenosis. PATIENTS AND METHODS: A Swedish BC cohort diagnosed from 1970 to 2003 was linked to registers of coronary angiography from 1990 to 2004, which yielded 199 patients. Stenoses of the coronary arteries were graded from 0 to 5, where 0 indicated a normal vessel and 5 indicated occlusion. Two hotspot areas for radiation were defined: proximal right coronary artery (prox RCA), mid and distal left anterior descending artery and distal diagonal (mdLAD + dD). RT regimens were categorized as high or low risk of irradiating the hotspot areas. Left breast/chest wall was considered high risk for mdLAD + dD; left internal mammary chain (IMC), high risk for prox RCA and mdLAD + dD from 1970 to 1995 and thereafter solely for mdLAD + dD; and right IMC, high risk for prox RCA. Other RT targets and no RT were considered low risk. Results were expressed in odds ratios (ORs) and 95% CIs. RESULTS: For irradiated left- versus right-sided BC, the OR for grade 3 to 5 stenosis in mdLAD + dD was 4.38 (95% CI, 1.64 to 11.7), and for grade 4 to 5 stenosis, the OR was 7.22 (95% CI, 1.64 to 31.8). For high-risk RT versus low-risk or no RT, the OR for grade 3 to 5 stenosis in hotspot areas was 1.90 (95% CI, 1.11 to 3.24). CONCLUSION: An increase of stenosis in mdLAD + dD in irradiated left-sided BC and an association between high-risk RT and stenosis in hotspot areas for radiation indicate a direct link between radiation and location of coronary stenoses. PMID- 22203773 TI - Paclitaxel, not bevacizumab, was primarily responsible for the favorable effects seen in the RIBBON-2 trial. PMID- 22203774 TI - Dose intensification in hormone receptor-negative and/or human epidermal growth factor receptor 2-negative high-risk primary breast cancer. PMID- 22203775 TI - Identification of a new plasma biomarker of Alzheimer's disease using metabolomics technology. AB - We performed unbiased analysis of steroid-related compounds to identify novel Alzheimer's disease (AD) plasma biomarkers using liquid chromatography atmospheric pressure chemical ionization-mass spectroscopy. The analysis revealed that desmosterol was found to be decreased in AD plasma versus controls. To precisely quantify variations in desmosterol, we established an analytical method to measure desmosterol and cholesterol. Using this LC-based method, we discovered that desmosterol and the desmosterol/cholesterol ratio are significantly decreased in AD. Finally, the validation of this assay using 109 clinical samples confirmed the decrease of desmosterol in AD as well as a change in the desmosterol/cholesterol ratio in AD. Interestingly, we could also observe a difference between mild cognitive impairment and control. In addition, the decrease of desmosterol was somewhat more significant in females. Receiver operating characteristic (ROC) analysis between controls and AD, using plasma desmosterol shows a score of 0.80, indicating a good discrimination power for this marker in the two reference populations and confirms the potential usefulness of measuring plasma desmosterol levels for diagnosing AD. Further analysis showed a significant correlation of plasma desmosterol with Mini-Mental State Examination scores. Although larger sample populations will be needed to confirm this diagnostic marker sensitivity, our studies demonstrate a sensitive and accurate method of detecting plasma desmosterol concentration and suggest that plasma desmosterol could become a powerful new specific biomarker for early and easy AD diagnosis. PMID- 22203777 TI - NCCN molecular testing white paper: effectiveness, efficiency, and reimbursement. AB - Personalized medicine in oncology is maturing and evolving rapidly, and the use of molecular biomarkers in clinical decision-making is growing. This raises important issues regarding the safe, effective, and efficient deployment of molecular tests to guide appropriate care, specifically regarding laboratory developed tests and companion diagnostics. In May 2011, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations to identify challenges and provide guidance regarding molecular testing in oncology and its corresponding utility from clinical, scientific, and coverage policy standpoints. The NCCN Molecular Testing Work Group identified challenges surrounding molecular testing, including health care provider knowledge, determining clinical utility, coding and billing for molecular tests, maintaining clinical and analytic validity of molecular tests, efficient use of specimens, and building clinical evidence. PMID- 22203778 TI - Dynamics of social, political, and economic institutions. PMID- 22203779 TI - Dilation of malignant strictures in endoscopic ultrasound staging of esophageal cancer and metastatic spread of disease. AB - Background. Dilation of malignant strictures in endoscopic ultrasound (EUS) staging of esophageal cancer is safe, but no data exists regarding the subsequent development of metastases. Aim. Compare the rates of metastases in esophageal cancer patients undergoing EUS staging who require esophageal dilation in order to pass the echoendoscope versus those who do not. Methods. We reviewed consecutive patients referred for EUS staging of esophageal cancer. We evaluated whether dilation was necessary in order to pass the echoendoscope, and for the subsequent development of metastases after EUS at various time intervals. Results. Among all patients with similar stage (locally advanced disease, defined as T3, N0, M0 or T1-3, N1, M0), there was no difference between the dilated and nondilated groups in the rates of metastases at 3 months (14% versus 10%), P = 1.0, 6 months (28% versus 20%), P = 0.69, 12 months (43% versus 40%), P = 1.0, or ever during a mean followup of 15 months (71% versus 55%), P = 0.48. Conclusions. Dilation of malignant strictures for EUS staging of esophageal cancer does not appear to lead to higher rates of distant metastases. PMID- 22203780 TI - Training in EUS-Guided Fine Needle Aspiration: Safety and Diagnostic Yield of Attending Supervised, Trainee-Directed FNA from the Onset of Training. AB - Background. The optimal time to initiate hands-on training in endoscopic ultrasound fine needle aspiration (EUS-FNA) is unclear. We studied the feasibility of initiating EUS-FNA training concurrent with EUS training. Methods. Three supervised trainees were instructed on EUS-FNA technique and allowed hands on exposure from the onset of training. The trainee and attending each performed passes in no particular order. During trainee FNA, the attending provided verbal instruction as needed but no hands-on assistance. A blinded cytopathologist assessed the adequacy (cellularity) and diagnostic yield of individual passes. Primary outcomes compared cellularity and diagnostic yield of attending versus fellow FNA passes. Results. We analyzed 305 FNA sites, including pancreas (51.2%), mediastinal/upper abdominal lymph node (LN) (28.5%) and others (20.3%). The average proportion of fellow passes with AC was similar to attending FNA pancreas: 70.3 versus 68.8%; LN: 79.0 versus 81.7%; others 65.5 versus 68.7%; P > 0.05); these did not change significantly during the training period. Among cases with confirmed malignancy (n = 179), the sensitivity of EUS-FNA was 78.8% (68.4% fellow-only versus 69.6% attending only). There were no EUS-FNA complications. Conclusions. When initiated at the onset of EUS training, attending-supervised, trainee-directed FNA is safe and has comparable performance characteristics to attending FNA. PMID- 22203781 TI - Force characteristics of the rat sternomastoid muscle reinnervated with end-to end nerve repair. AB - The goal of this study was to establish force data for the rat sternomastoid (SM) muscle after reinnervation with nerve end-to-end anastomosis (EEA), which could be used as a baseline for evaluating the efficacy of new reinnervation techniques. The SM muscle on one side was paralyzed by transecting its nerve and then EEA was performed at different time points: immediate EEA, 1-month and 3 month delay EEA. At the end of 3-month recovery period, the magnitude of functional recovery of the reinnervated SM muscle was evaluated by measuring muscle force and comparing with the force of the contralateral control muscle. Our results demonstrated that the immediately reinnervated SM produced approximately 60% of the maximal tetanic force of the control. The SM with delayed nerve repair yielded approximately 40% of the maximal force. Suboptimal recovery of muscle force after EEA demonstrates the importance of developing alternative surgical techniques to treat muscle paralysis. PMID- 22203782 TI - Pathophysiology of the peritoneal membrane during peritoneal dialysis: the role of hyaluronan. AB - During peritoneal dialysis (PD), constant exposure of mesothelial cells to bioincompatible PD solutions results in the denudation of the mesothelial monolayer and impairment of mesothelial cell function. Hyaluronan, a major component of extracellular matrices, is synthesized by mesothelial cells and contributes to remesothelialization, maintenance of cell phenotype, and tissue remodeling and provides structural support to the peritoneal membrane. Chronic peritoneal inflammation is observed in long-term PD patients and is associated with increased hyaluronan synthesis. During inflammation, depolymerization of hyaluronan may occur with the generation of hyaluronan fragments. In contrast to native hyaluronan which offers a protective role to the peritoneum, hyaluronan fragments exacerbate inflammatory and fibrotic processes and therefore assist in the destruction of the tissue. This paper will discuss the contribution of mesothelial cells to peritoneal membrane alterations that are induced by PD and the putative role of hyaluronan in these processes. PMID- 22203783 TI - Sample preparation techniques for the untargeted LC-MS-based discovery of peptides in complex biological matrices. AB - Although big progress has been made in sample pretreatment over the last years, there are still considerable limitations when it comes to overcoming complexity and dynamic range problems associated with peptide analyses from biological matrices. Being the little brother of proteomics, peptidomics is a relatively new field of research aiming at the direct analysis of the small proteins, called peptides, many of which are not amenable for typical trypsin-based analytics. In this paper, we present an overview of different techniques and methods currently used for reducing a sample's complexity and for concentrating low abundant compounds to enable successful peptidome analysis. We focus on techniques which can be employed prior to liquid chromatography coupled to mass spectrometry for peptide detection and identification and indicate their advantages as well as their shortcomings when it comes to the untargeted analysis of native peptides from complex biological matrices. PMID- 22203784 TI - The use of pluripotent stem cell for personalized cell therapies against neurological disorders. AB - Although there are a number of weaknesses for clinical use, pluripotent stem cells are valuable sources for patient-specific cell therapies against various diseases. Backed-up by a huge number of basic researches, neuronal differentiation mechanism is well established and pluripotent stem cell therapies against neurological disorders are getting closer to clinical application. However, there are increasing needs for standardization of the sourcing pluripotent stem cells by establishing stem cell registries and banking. Global harmonization will accelerate practical use of personalized therapies using pluripotent stem cells. PMID- 22203785 TI - Gene expression analysis of in vitro cocultures to study interactions between breast epithelium and stroma. AB - The interactions between breast epithelium and stroma are fundamental to normal tissue homeostasis and for tumor initiation and progression. Gene expression studies of in vitro coculture models demonstrate that in vitro models have relevance for tumor progression in vivo. For example, stromal gene expression has been shown to vary in association with tumor subtype in vivo, and analogous in vitro cocultures recapitulate subtype-specific biological interactions. Cocultures can be used to study cancer cell interactions with specific stromal components (e.g., immune cells, fibroblasts, endothelium) and different representative cell lines (e.g., cancer-associated versus normal-associated fibroblasts versus established, immortalized fibroblasts) can help elucidate the role of stromal variation in tumor phenotypes. Gene expression data can also be combined with cell-based assays to identify cellular phenotypes associated with gene expression changes. Coculture systems are manipulable systems that can yield important insights about cell-cell interactions and the cellular phenotypes that occur as tumor and stroma co-evolve. PMID- 22203786 TI - The application of three-dimensional collagen-scaffolds seeded with myoblasts to repair skeletal muscle defects. AB - Three-dimensional (3D) engineered tissue constructs are a novel and promising approach to tissue repair and regeneration. 3D tissue constructs have the ability to restore form and function to damaged soft tissue unlike previous methods, such as plastic surgery, which are able to restore only form, leaving the function of the soft tissue often compromised. In this study, we seeded murine myoblasts (C2C12) into a collagen composite scaffold and cultured the scaffold in a roller bottle cell culture system in order to create a 3D tissue graft in vitro. The 3D graft created in vitro was then utilized to investigate muscle tissue repair in vivo. The 3D muscle grafts were implanted into defect sites created in the skeletal muscles in mice. We detected that the scaffolds degraded slowly over time, and muscle healing was improved which was shown by an increased quantity of innervated and vascularized regenerated muscle fibers. Our results suggest that the collagen composite scaffold seeded with myoblasts can create a 3D muscle graft in vitro that can be employed for defect muscle tissue repair in vivo. PMID- 22203787 TI - Simultaneous identification and quantification of canrenone and 11-alpha-hydroxy canrenone by LC-MS and HPLC-UVD. AB - A procedure for simultaneous identification and quantification of canrenone and its biotransformed product 11-alpha-hydroxy-canrenone by high-performance liquid chromatography with ultraviolet detector (HPLC-UVD) and mass spectrometry (LC-MS) methods was proposed. The optimal determination variables on the HPLC-UVD or LC MS coupled with a ZORBAX Eclipse XDB-C18 column (150 mm * 4.6 mm, 5 MUm) were set as follows: detection wavelength of 280 nm, mobile phase of water and methanol gradient elution, temperature for the chromatographic column of 30 degrees C, flow rate of mobile phase of 0.8 mL/min, sample injection volume of 5 MUL, and elution time of 40 min. The MS conditions were set as follows: the flow rate of sheath gas, aux gas, and sweep gas were kept at 35 arb, 5 arb, and 0 arb, respectively. The temperature of capillary was held at 300 degrees C, and capillary voltage was set at 30.00 V. Tube lens were performed at 100.00 V. The proposed method was validated by linearity (r2 >= 0.9910), average recovery (94.93%, RSD1.21%), precision (RSD <= 1.31%), limit of detection, and limit of quantification (LOD 0.1~0.12 mg/L, LOQ 0.5~0.67 mg/L), which proved to be affordable for simultaneously determining canrenone and its bio-transformed product 11-alpha-hydroxy-canrenone. PMID- 22203788 TI - The fur transcription regulator and fur-regulated genes in Clostridium botulinum A ATCC 3502. AB - Clostridium botulinum is a spore-forming bacterium that can produce a very powerful neurotoxin that causes botulism. In this study, we have investigated the Fur transcription regulators in Clostridium botulinum and Fur-regulated genes in Clostridium botulinum A ATCC 3502. We found that gene loss may be the main cause leading to the different numbers of Fur transcription regulators in different Clostridium botulinum strains. Meanwhile, 46 operons were found to be regulated by the Fur transcription regulator in Clostridium botulinum A ATCC 3502, involved in several functional classifications, including iron acquisition, iron utilization, iron transport, and transcription regulator. Under an iron restricted medium, we experimentally found that a Fur transcription regulator (CBO1372) and two operons (DedA, CBO2610-CBO2614 and ABC transporter, CBO0845 CBO0847) are shown to be differentially expressed in Clostridium botulinum A ATCC 3502. This study has provided-us novel insights into the diversity of Fur transcription regulators in different Clostridium botulinum strains and diversity of Fur-targeted genes, as well as a better understanding of the dynamic changes in iron restriction occurring in response to this stress. PMID- 22203789 TI - Seasonal abundance and suppression of fruit-piercing moth Eudocima phalonia (L.) in a citrus orchard in Sarawak. AB - Seasonal population of the fruit-piercing moths Eudocima spp. was monitored throughout the citrus growing seasons in a citrus orchard and in site adjacent to secondary forest from July 2007 to June 2009. The moth was detected practically throughout the year with activity lowest during the wet months (September February) when fruits are still available and while highest during the dry months (May-June) which also coincided with the main fruiting season. The effects of an nC24 horticultural mineral oil (HMO) on the citrus fruit damage caused by fruit piecing moths was also determined. The percent fruit damage was significantly lowest (P<=0.05) in HMO-treated plots (8.4), followed by Dimethoate-treated plots (11.6) and untreated plots (22.5). However, there was no significant difference between HMO and Dimethoate treated plots indicating HMO is effective in reducing percent fruit damage. PMID- 22203790 TI - Quercetin protects primary human osteoblasts exposed to cigarette smoke through activation of the antioxidative enzymes HO-1 and SOD-1. AB - Smokers frequently suffer from impaired fracture healing often due to poor bone quality and stability. Cigarette smoking harms bone cells and their homeostasis by increased formation of reactive oxygen species (ROS). The aim of this study was to investigate whether Quercetin, a naturally occurring antioxidant, can protect osteoblasts from the toxic effects of smoking. Human osteoblasts exposed to cigarette smoke medium (CSM) rapidly produced ROS and their viability decreased concentration- and time-dependently. Co-, pre- and postincubation with Quercetin dose-dependently improved their viability. Quercetin increased the expression of the anti-oxidative enzymes heme-oxygenase- (HO-) 1 and superoxide dismutase- (SOD-) 1. Inhibiting HO-1 activity abolished the protective effect of Quercetin. Our results demonstrate that CSM damages human osteoblasts by accumulation of ROS. Quercetin can diminish this damage by scavenging the radicals and by upregulating the expression of HO-1 and SOD-1. Thus, a dietary supplementation with Quercetin could improve bone matter, stability and even fracture healing in smokers. PMID- 22203791 TI - Project P.A.T.H.S. in Hong Kong: new curriculum in response to adolescent developmental issues. PMID- 22203792 TI - Phylogeny and ontogeny of the habenular structure. AB - Habenula is an epithalamic nucleus connecting the forebrain with the ventral midbrain and hindbrain that plays a pivotal role in decision making by regulating dopaminergic and serotonergic activities. Intriguingly, habenula has also attracted interest as a model for brain asymmetry, since many vertebrates show left-right differences in habenula size and neural circuitry. Despite the functional significance of this nucleus, few studies have addressed the molecular mechanisms underlying habenular development. Mammalian habenula consists of the medial and lateral habenulae, which have distinct neural connectivity. The habenula shows phylogenetic conservation from fish to human, and studies using genetically accessible model animals have provided molecular insights into the developmental mechanisms of the habenula. The results suggest that development of the habenular asymmetry is mediated by differential regulation of the neurogenetic period for generating specific neuronal subtypes. Since the orientation and size ratio of the medial and lateral habenulae differ across species, the evolution of those subregions within the habenula may also reflect changes in neurogenesis duration for each habenular subdivision according to the evolutionary process. PMID- 22203793 TI - Prey capture behavior evoked by simple visual stimuli in larval zebrafish. AB - Understanding how the nervous system recognizes salient stimuli in the environment and selects and executes the appropriate behavioral responses is a fundamental question in systems neuroscience. To facilitate the neuroethological study of visually guided behavior in larval zebrafish, we developed "virtual reality" assays in which precisely controlled visual cues can be presented to larvae whilst their behavior is automatically monitored using machine vision algorithms. Freely swimming larvae responded to moving stimuli in a size dependent manner: they directed multiple low amplitude orienting turns (~20 degrees ) toward small moving spots (1 degrees ) but reacted to larger spots (10 degrees ) with high-amplitude aversive turns (~60 degrees ). The tracking of small spots led us to examine how larvae respond to prey during hunting routines. By analyzing movie sequences of larvae hunting paramecia, we discovered that all prey capture routines commence with eye convergence and larvae maintain their eyes in a highly converged position for the duration of the prey-tracking and capture swim phases. We adapted our virtual reality assay to deliver artificial visual cues to partially restrained larvae and found that small moving spots evoked convergent eye movements and J-turns of the tail, which are defining features of natural hunting. We propose that eye convergence represents the engagement of a predatory mode of behavior in larval fish and serves to increase the region of binocular visual space to enable stereoscopic targeting of prey. PMID- 22203794 TI - Cell-Based Neurorestorotherapy in Amyotrophic Lateral Sclerosis - Scientific Truth should Rely on Facts, but Not Conjecture. PMID- 22203795 TI - EEG and autonomic responses during performance of matching and non-matching to sample working memory tasks with emotional content. AB - Working memory (WM) is a memory system responsible for the temporary storage of information and its utilization in problem solving. The central executive is theorized as the controller of storage functions that support WM. Neurophysiological data suggest that electroencephalographic (EEG) theta and alpha oscillations in frontal and midline regions are involved in neural communication between the central executive and storage functions during WM performance. Emotion is known to modulate several memory systems, including WM, through central and peripheral pathways. However, the physiological effect (EEG; autonomic nervous activity) of emotion over WM are not well described. In this study we aimed to identify physiological responses related to emotional WM performance. EEG (21 channels), heart rate (HR), and galvanic skin response (GSR) recordings were obtained from 54 volunteers while performing delayed matching and non-matching to sample tasks (DMTS/DNMTS). Emotional and neutral pictures from the International Affective Picture System and geometric figures were used as stimuli. As expected, WM performance was accompanied by presence of theta (frontal and midline electrodes) and alpha power (parietal electrodes). Beta and gamma oscillations were concentrated in frontopolar and left temporal regions. The DNMTS task was accompanied by higher increases in beta power, HR, and GSR compared to the DMTS task. Correlation analyses showed a positive tendency for gamma in the Fp2 site, ratio of LF/HF and skin conductance in both tasks. The HR results indicate an inverse reaction related to parasympathetic and sympathetic nervous system during the performance of the tasks. Taken together, our results contribute to elucidate the complex interactions between central and autonomic nervous systems in the modulation of emotional WM tasks. PMID- 22203796 TI - Enhanced training protects memory against amnesia produced by concurrent inactivation of amygdala and striatum, amygdala and substantia nigra, or striatum and substantia nigra. AB - Memory is markedly impaired when normal activity of any of a number of cerebral structures is disturbed after a learning experience. A growing body of evidence indicates, however, that such interference with neuronal function becomes negligible when the learning experience is significantly enhanced. We now report on the effects of enhanced training on retention after temporary inactivation of cerebral nuclei known to be involved in memory, namely the substantia nigra (SN), striatum (STR), and amygdala (AMY). When training was conducted with a relatively low intensity of footshock (1.0 mA), post-training infusion of lidocaine into the SN, STR, or AMY produced a marked memory deficit. Increasing the aversive stimulation to 2.0 mA protected memory from the amnesic effect of intranigral lidocaine, but there was still a deficit after its infusion into the STR and AMY. Administration of lidocaine into each of these nuclei, in the groups that had been trained with 3.0 mA, was completely ineffective in producing alterations in memory consolidation. Simultaneous infusion of lidocaine into STR + SN, AMY + SN, or AMY + STR was also ineffective in altering memory formation when the highest footshock intensity was used for training. To our knowledge, this is the first demonstration that an enhanced learning experience guards against memory deficits after simultaneous temporary interruption of neural activity of brain nuclei heretofore thought to be necessary for memory formation. These findings support the proposition that brain structures involved in memory processing are functionally connected in series during memory consolidation and that, after an enhanced learning experience, these structures become functionally connected in parallel. PMID- 22203797 TI - Developmental Changes in the Profiles of Dyscalculia: An Explanation Based on a Double Exact-and-Approximate Number Representation Model. AB - Studies on developmental dyscalculia (DD) have tried to identify a basic numerical deficit that could account for this specific learning disability. The first proposition was that the number magnitude representation of these children was impaired. However, Rousselle and Noel (2007) brought data showing that this was not the case but rather that these children were impaired when processing the magnitude of symbolic numbers only. Since then, incongruent results have been published. In this paper, we will propose a developmental perspective on this issue. We will argue that the first deficit shown in DD regards the building of an exact representation of numerical value, thanks to the learning of symbolic numbers, and that the reduced acuity of the approximate number magnitude system appears only later and is secondary to the first deficit. PMID- 22203798 TI - Elemental spiking neuron model for reproducing diverse firing patterns and predicting precise firing times. AB - In simulating realistic neuronal circuitry composed of diverse types of neurons, we need an elemental spiking neuron model that is capable of not only quantitatively reproducing spike times of biological neurons given in vivo-like fluctuating inputs, but also qualitatively representing a variety of firing responses to transient current inputs. Simplistic models based on leaky integrate and-fire mechanisms have demonstrated the ability to adapt to biological neurons. In particular, the multi-timescale adaptive threshold (MAT) model reproduces and predicts precise spike times of regular-spiking, intrinsic-bursting, and fast spiking neurons, under any fluctuating current; however, this model is incapable of reproducing such specific firing responses as inhibitory rebound spiking and resonate spiking. In this paper, we augment the MAT model by adding a voltage dependency term to the adaptive threshold so that the model can exhibit the full variety of firing responses to various transient current pulses while maintaining the high adaptability inherent in the original MAT model. Furthermore, with this addition, our model is actually able to better predict spike times. Despite the augmentation, the model has only four free parameters and is implementable in an efficient algorithm for large-scale simulation due to its linearity, serving as an element neuron model in the simulation of realistic neuronal circuitry. PMID- 22203799 TI - Synaptic scaling in combination with many generic plasticity mechanisms stabilizes circuit connectivity. AB - Synaptic scaling is a slow process that modifies synapses, keeping the firing rate of neural circuits in specific regimes. Together with other processes, such as conventional synaptic plasticity in the form of long term depression and potentiation, synaptic scaling changes the synaptic patterns in a network, ensuring diverse, functionally relevant, stable, and input-dependent connectivity. How synaptic patterns are generated and stabilized, however, is largely unknown. Here we formally describe and analyze synaptic scaling based on results from experimental studies and demonstrate that the combination of different conventional plasticity mechanisms and synaptic scaling provides a powerful general framework for regulating network connectivity. In addition, we design several simple models that reproduce experimentally observed synaptic distributions as well as the observed synaptic modifications during sustained activity changes. These models predict that the combination of plasticity with scaling generates globally stable, input-controlled synaptic patterns, also in recurrent networks. Thus, in combination with other forms of plasticity, synaptic scaling can robustly yield neuronal circuits with high synaptic diversity, which potentially enables robust dynamic storage of complex activation patterns. This mechanism is even more pronounced when considering networks with a realistic degree of inhibition. Synaptic scaling combined with plasticity could thus be the basis for learning structured behavior even in initially random networks. PMID- 22203800 TI - Spike train auto-structure impacts post-synaptic firing and timing-based plasticity. AB - Cortical neurons are typically driven by several thousand synapses. The precise spatiotemporal pattern formed by these inputs can modulate the response of a post synaptic cell. In this work, we explore how the temporal structure of pre synaptic inhibitory and excitatory inputs impact the post-synaptic firing of a conductance-based integrate and fire neuron. Both the excitatory and inhibitory input was modeled by renewal gamma processes with varying shape factors for modeling regular and temporally random Poisson activity. We demonstrate that the temporal structure of mutually independent inputs affects the post-synaptic firing, while the strength of the effect depends on the firing rates of both the excitatory and inhibitory inputs. In a second step, we explore the effect of temporal structure of mutually independent inputs on a simple version of Hebbian learning, i.e., hard bound spike-timing-dependent plasticity. We explore both the equilibrium weight distribution and the speed of the transient weight dynamics for different mutually independent gamma processes. We find that both the equilibrium distribution of the synaptic weights and the speed of synaptic changes are modulated by the temporal structure of the input. Finally, we highlight that the sensitivity of both the post-synaptic firing as well as the spike-timing-dependent plasticity on the auto-structure of the input of a neuron could be used to modulate the learning rate of synaptic modification. PMID- 22203801 TI - On the estimation of population-specific synaptic currents from laminar multielectrode recordings. AB - Multielectrode array recordings of extracellular electrical field potentials along the depth axis of the cerebral cortex are gaining popularity as an approach for investigating the activity of cortical neuronal circuits. The low-frequency band of extracellular potential, i.e., the local field potential (LFP), is assumed to reflect synaptic activity and can be used to extract the laminar current source density (CSD) profile. However, physiological interpretation of the CSD profile is uncertain because it does not disambiguate synaptic inputs from passive return currents and does not identify population-specific contributions to the signal. These limitations prevent interpretation of the CSD in terms of synaptic functional connectivity in the columnar microcircuit. Here we present a novel anatomically informed model for decomposing the LFP signal into population-specific contributions and for estimating the corresponding activated synaptic projections. This involves a linear forward model, which predicts the population-specific laminar LFP in response to synaptic inputs applied at different positions along each population and a linear inverse model, which reconstructs laminar profiles of synaptic inputs from laminar LFP data based on the forward model. Assuming spatially smooth synaptic inputs within individual populations, the model decomposes the columnar LFP into population specific contributions and estimates the corresponding laminar profiles of synaptic input as a function of time. It should be noted that constant synaptic currents at all positions along a neuronal population cannot be reconstructed, as this does not result in a change in extracellular potential. However, constraining the solution using a priori knowledge of the spatial distribution of synaptic connectivity provides the further advantage of estimating the strength of active synaptic projections from the columnar LFP profile thus fully specifying synaptic inputs. PMID- 22203802 TI - Maternal programming of reproductive function and behavior in the female rat. AB - Parental investment can be used as a forecast for the environmental conditions in which offspring will develop to adulthood. In the rat, maternal behavior is transmitted to the next generation through epigenetic modifications such as methylation and histone acetylation, resulting in variations in estrogen receptor alpha expression. Natural variations in maternal care also influence the sexual strategy adult females will adopt later in life. Lower levels of maternal care are associated with early onset of puberty as well as increased motivation to mate and greater receptivity toward males during mating. Lower levels of maternal care are also correlated with greater activity of the hypothalamus-pituitary gonadal axis, responsible for the expression of these behaviors. Contrary to the transition of maternal care, sexual behavior cannot simply be explained by maternal attention, since adoption studies changed the sexual phenotypes of offspring born to low caring mothers but not those from high caring dams. Indeed, mothers showing higher levels of licking/grooming have embryos that are exposed to high testosterone levels during development, and adoption studies suggest that this androgen exposure may protect their offspring from lower levels of maternal care. We propose that in the rat, maternal care and the in utero environment interact to influence the reproductive strategy female offspring display in adulthood and that this favors the species by allowing it to thrive under different environmental conditions. PMID- 22203803 TI - Chemical exposure as etiology in developmental origin of adult onset human cancer. AB - Chemical exposures are in principle preventable causes of cancer. People are exposed to chemicals already during fetal period and the possibility of disturbances in human development by chemical compounds leading to cancer later in life has been proven by diethylstilbestrol. The mechanisms most probably include epigenetic modifications of promoter regions of key genes. The world-wide increases in cancer incidence and concurrent increase in the number and quantity of chemicals in the environment raises concerns about a link between these two. Developmental origin and related mechanisms in chemically induced human cancer are worth pursuing. PMID- 22203804 TI - Identification of behavioral and metabolic factors predicting adiposity sensitivity to both high fat and high carbohydrate diets in rats. AB - Individuals exhibit a great variation in their body weight (BW) gain response to a high fat diet. Identification of predictive factors would enable better directed intervention toward susceptible individuals to treat obesity, and uncover potential mechanisms for treatment targeting. We set out to identify predictive behavioral and metabolic factors in an outbred rat model. 12 rats were analyzed in metabolic cages for a period of 5 days during both high carbohydrate diet (HCD), and transition to a high fat diet (HFD). After a recovery period, rats were given a HFD for 6 days to identify those resistant or sensitive to it according to BW gain. Rats were dissected at the end of the study to analyze body composition. This showed that small differences in final BW hid large variations in adiposity, allowing separation of rats into a second classification (final adiposity). Since these rats had been fed a HCD during most of their life, under which most of the adiposity presumably evolved, we considered this carbohydrate sensitivity or -resistance. Meal size and meal number were found to be good predictors of sensitivity to a HFD, intensity of motor activity and ingestion speed good predictors of sensitivity to a HCD. Rats that were sensitive to the HCD could be resistant to the HFD and vice versa. This points to four types of individuals (carbohydrate/fat resistant/sensitive) though our sample size inhibited deeper investigation of this. This contributes to the idea that to be "obesity prone" does not necessarily need a HFD, it can also happen under a HCD, and be a hidden adiposity change with stable BW. PMID- 22203805 TI - Localization of the sensory neurons and mechanoreceptors required for stretch evoked colonic migrating motor complexes in mouse colon. AB - The pacemaker and pattern generator that underlies the cyclical generation of spontaneous colonic migrating motor complexes (CMMCs) has recently been identified to lie within the myenteric plexus and/or muscularis externa. Neither the mucosa, nor the release of substances from the mucosa were found to be required for the spontaneous generation of CMMCs. However, it is known that stretch applied to the colonic wall can also evoke CMMCs and since stretch of the gut wall is known to stimulate the mucosa, it is not clear whether release of substances from the mucosa and/or submucosal plexus are required for stretch evoked CMMCs. Therefore, the aim of this study was to determine whether circumferential stretch-evoked CMMCs require the presence of the mucosa and/or submucosal plexus in isolated mouse colon. Spontaneous CMMCs were recorded from full length sheet preparations of colon in vitro. Graded circumferential stretch (at a rate of 100 MUm/s) applied to a 15-mm segment of mid-distal colon reliably evoked a CMMC, which propagated to the oral recording site. Sharp dissection to remove the mucosa and submucosal plexus from the entire colon did not prevent spontaneous CMMCs and circumferential stretch-evoked CMMCs were still reliably evoked by circumferential stretch, even at significantly lower thresholds. In contrast, in intact preparations, direct stimulation of the mucosa (without accompanying stretch) proved highly inconsistent and rarely evoked a CMMC. These observations lead to the inescapable conclusion that the sensory neurons activated by colonic stretch to initiate CMMCs lie in the myenteric plexus, while the mechanoreceptors activated by stretch, lie in the myenteric ganglia and/or muscularis externa. Stretch activation of these mechanoreceptors does not require release of any substance(s) from the mucosa, or neural inputs arising from submucosal ganglia. PMID- 22203807 TI - Impaired cerebellar functional connectivity in schizophrenia patients and their healthy siblings. AB - The long-standing notion of schizophrenia as a disorder of connectivity is supported by emerging evidence from recent neuroimaging studies, suggesting impairments of both structural and functional connectivity in schizophrenia. However, investigations are generally restricted to supratentorial brain regions, thereby excluding the cerebellum. As increasing evidence suggests that the cerebellum contributes to cognitive and affective processing, aberrant connectivity in schizophrenia may include cerebellar dysconnectivity. Moreover, as schizophrenia is highly heritable, unaffected family members of schizophrenia patients may exhibit similar connectivity profiles. The present study applies resting-state functional magnetic resonance imaging to determine cerebellar functional connectivity profiles, and the familial component of cerebellar connectivity profiles, in 62 schizophrenia patients and 67 siblings of schizophrenia patients. Compared to healthy control subjects, schizophrenia patients showed impaired functional connectivity between the cerebellum and several left-sided cerebral regions, including the hippocampus, thalamus, middle cingulate gyrus, triangular part of the inferior frontal gyrus, supplementary motor area, and lingual gyrus (all p < 0.0025, whole-brain significant). Importantly, siblings of schizophrenia patients showed several similarities to patients in cerebellar functional connectivity, suggesting that cerebellar dysconnectivity in schizophrenia might be related to familial factors. In conclusion, our findings suggest that dysconnectivity in schizophrenia involves the cerebellum and that this defect may be related to the risk to develop the illness. PMID- 22203806 TI - Obsessive-compulsive disorder comorbidity: clinical assessment and therapeutic implications. AB - Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder affecting approximately 1-3% of the population. OCD is probably an etiologically heterogeneous condition. Individuals with OCD frequently have additional psychiatric disorders concomitantly or at some time during their lifetime. Recently, some authors proposed an OCD sub-classification based on comorbidity. An important issue in assessing comorbidity is the fact that the non-response to treatment often involves the presence of comorbid conditions. Non-responsive patients are more likely to meet criteria for comorbid axis I or axis II disorders and the presence of a specific comorbid condition could be a distinguishing feature in OCD, with influence on the treatment adequacy and outcome. PMID- 22203808 TI - Yoga lessons for consciousness research: a paralimbic network balancing brain resource allocation. AB - Consciousness has been proposed to play a key role in shaping flexible learning and as such is thought to confer an evolutionary advantage. Attention and awareness are the perhaps most important underlying processes, yet their precise relationship is presently unclear. Both of these processes must, however, serve the evolutionary imperatives of survival and procreation. They are thus intimately bound by reward and emotion to help to prioritize efficient brain resource allocation in order to predict and optimize behavior. Here we show how this process is served by a paralimbic network consisting primarily of regions located on the midline of the human brain. Using many different techniques, experiments have demonstrated that this network is effective and specific for self-awareness and contributes to the sense of unity of consciousness by acting as a common neural path for a wide variety of conscious experiences. Interestingly, hemodynamic activity in the network decreases with focusing on external stimuli, which has led to the idea of a default mode network. This network is one of many networks that wax and vane as resources are allocated to accommodate the different cyclical needs of the organism primarily related to the fundamental pleasures afforded by evolution: food, sex, and conspecifics. Here we hypothesize, however, that the paralimbic network serves a crucial role in balancing and regulating brain resource allocation, and discuss how it can be thought of as a link between current theories of so-called "default mode," "resting state networks," and "global workspace." We show how major developmental disorders of self-awareness and self-control can arise from problems in the paralimbic network as demonstrated here by the example of Asperger syndrome. We conclude that attention, awareness, and emotion are integrated by a paralimbic network that helps to efficiently allocate brain resources to optimize behavior and help survival. PMID- 22203809 TI - State-dependent visual processing. AB - The temporal dynamics and anatomical correlates underlying human visual cognition are traditionally assessed as a function of stimulus properties and task demands. Any non-stimulus related activity is commonly dismissed as noise and eliminated to extract an evoked signal that is only a small fraction of the magnitude of the measured signal. We review studies that challenge this view by showing that non stimulus related activity is not mere noise but that it has a well-structured organization which can largely determine the processing of upcoming stimuli. We review recent evidence from human electrophysiology that shows how different aspects of pre-stimulus activity such as pre-stimulus EEG frequency power and phase and pre-stimulus EEG microstates can determine qualitative and quantitative properties of both lower and higher-level visual processing. These studies show that low-level sensory processes depend on the momentary excitability of sensory cortices whereas perceptual processes leading to stimulus awareness depend on momentary pre-stimulus activity in higher-level non-visual brain areas. Also speed and accuracy of stimulus identification have likewise been shown to be modulated by pre-stimulus brain states. PMID- 22203810 TI - The role of finger representations and saccades for number processing: an FMRI study in children. AB - A possible functional role of finger representations for the development of early numerical cognition has been the subject of recent debate; however, until now, only behavioral studies have directly supported this view. Working from recent models of number processing, we focused on the neural networks involved in numerical tasks and their relationship to the areas underlying finger representations and saccades in children aged 6-12 years. We were able to differentiate three parietal circuits that were related to distinct aspects of number processing. Abstract magnitude processing was subserved by an association area also activated by saccades and visually guided finger movements. Addition processes led to activation in an area only engaged during saccade encoding, whereas counting processes resulted in the activation of an area only activated during visually guided finger movements, namely in the anterior intraparietal sulcus. Apart from this area, a large network of specifically finger-related brain areas including the ventral precentral sulcus, supplementary motor area, dorso-lateral prefrontal cortex, insula, thalamus, midbrain, and cerebellum was activated during (particularly non-symbolic) exact addition but not during magnitude comparison. Moreover, a finger-related activation cluster in the right ventral precentral sulcus was only present during non-symbolic addition and magnitude comparison, but not during symbolic number processing tasks. We conclude that finger counting may critically mediate the step from non-symbolic to symbolic and exact number processing via somatosensory integration processes and therefore represents an important example of embodied cognition. PMID- 22203811 TI - A possible physiological basis for the discontinuity of consciousness. AB - A comparison is made between the frequency of local minima in the analytic power (AP) of intracranial EEG (ECoG) from waking and unconscious human subjects and the frequency of putative frames of consciousness reported in earlier psychological literature. In ECoG from unconscious subjects, the frequency of deep minima in AP is found to be a linear function of bandwidth. In contrast, in ECoG from conscious subjects, the bandwidth/minima-frequency curve saturates or plateaus at minima frequencies similar to the frequencies of previously reported frames of consciousness. This result is consistent with the hypothesis that local minima in AP may act as the shutter in a cinematographic model of consciousness. The fact that artificially generated samples of black noise with power spectra similar to ECoG data give similar results in the analyses above suggests that the discontinuous nature of consciousness is not due to some specifically biological factor, but is simply a consequence of the physical properties of the 1/f (aka power law) oscillations that are widely found in nature. PMID- 22203812 TI - On the temporal and functional origin of l2 disadvantages in speech production: a critical review. AB - Despite a large amount of psycholinguistic research devoted to the issue of processing differences between a first and a second language, there is no consensus regarding the locus where these emerge or the mechanism behind them. The aim of this article is to briefly examine both the behavioral and neuroscientific evidence in order to critically assess three hypotheses that have been put forward in the literature to explain such differences: the weaker links, executive control, and post-lexical accounts. We conclude that (a) while all stages of processing are likely to be slowed down when speaking in an L2 compared to an L1, the differences seem to originate at a lexical stage; and (b) frequency of use seems to be the variable mainly responsible for these bilingual processing disadvantages. PMID- 22203814 TI - Late vision: processes and epistemic status. AB - In this paper, I examine the processes that occur in late vision and address the problem of whether late vision should be construed as a properly speaking perceptual stage, or as a thought-like discursive stage. Specifically, I argue that late vision, its (partly) conceptual nature notwithstanding, neither is constituted by nor does it implicate what I call pure thoughts, that is, propositional structures that are formed in the cognitive areas of the brain through, and participate in, discursive reasoning and inferences. At the same time, the output of late vision, namely an explicit belief concerning the identity and category membership of an object (that is, a recognitional belief) or its features, eventually enters into discursive reasoning. Using Jackendoff's distinction between visual awareness, which characterizes perception, and visual understanding, which characterizes pure thought, I claim that the contents of late vision belong to visual awareness and not to visual understanding and that although late vision implicates beliefs, either implicit or explicit, these beliefs are hybrid visual/conceptual constructs and not pure thoughts. Distinguishing between these hybrid representations and pure thoughts and delineating the nature of the representations of late vision lays the ground for examining, among other things, the process of conceptualization that occurs in visual processing and the way concepts modulate perceptual content affecting either its representational or phenomenal character. I also do not discuss the epistemological relations between the representations of late vision and the perceptual judgments they "support" or "guide" or "render possible" or "evidence" or "entitle." However, the specification of the epistemology of late vision lays the ground for attacking that problem as well. PMID- 22203813 TI - Attention and olfactory consciousness. AB - Understanding the relation between attention and consciousness is an important part of our understanding of consciousness. Attention, unlike consciousness, can be systematically manipulated in psychophysical experiments and a law-like relation between attention and consciousness is waiting to be discovered. Most attempts to discover the nature of this relation are focused on a special type of attention: spatial visual attention. In this review I want to introduce another type of attention to the discussion: attention to the olfactory modality. I will first clarify the position of attention to smells in a general taxonomy of attention. I will then review the mechanisms and neuroanatomy of attention and consciousness in the olfactory system before using the newly introduced system to provide evidence that attention is necessary for consciousness. PMID- 22203815 TI - Electrostatically Stabilized Magnetic Nanoparticles - An Optimized Protocol to Label Murine T Cells for in vivo MRI. AB - We present a novel highly efficient protocol to magnetically label T cells applying electrostatically stabilized very small superparamagnetic iron oxide particles (VSOP). Our long-term aim is to use magnetic resonance imaging (MRI) to investigate T cell dynamics in vivo during the course of neuroinflammatory disorders such as experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Encephalitogenic T cells were co-incubated with VSOP, or with protamine-complexed VSOP (VProt), respectively, at different conditions, optimizing concentrations and incubation times. Labeling efficacy was determined by atomic absorption spectrometry as well as histologically, and evaluated on a 7 T MR system. Furthermore, we investigated possible alterations of T cell physiology caused by the labeling procedure. T cell co-incubation with VSOP resulted in an efficient cellular iron uptake. T2 times of labeled cells dropped significantly, resulting in prominent hypointensity on T2*-weighted scans. Optimal labeling efficacy was achieved by VProt (1 mM Fe/ml, 8 h incubation; T2 time shortening of ~80% compared to untreated cells). Although VSOP promoted T cell proliferation and altered the ratio of T cell subpopulations toward a CD4(+) phenotype, no effects on CD4 T cell proliferation or phenotypic stability were observed by labeling in vitro differentiated Th17 cells with VProt. Yet, high concentrations of intracellular iron oxide might induce alterations in T cell function, which should be considered in cell tagging studies. Moreover, we demonstrated that labeling of encephalitogenic T cells did not affect pathogenicity; labeled T cells were still capable of inducing EAE in susceptible recipient mice. PMID- 22203816 TI - Cognitive rehabilitation in Parkinson's disease: evidence from neuroimaging. AB - Cognitive impairment in Parkinson's disease (PD) has received little attention to date and as such, there are currently very few treatment options available. The aim of the present study was to determine whether cognitive training might alleviate these cognitive symptoms and if so, whether such changes might be correlated with altered brain patterns. The performance of 10 PD patients and 10 paired healthy controls was assessed in a modified version of the Stroop task performed in association with functional magnetic resonance imaging, and half of the PD patients were given 6 months of cognitive daily training based on Sudoku exercises. Results showed that the training program improved the cognitive performance in the Stroop test of the trained Parkinson's patients during MRI, specifically in terms of reaction time, and of correct and missing answers. Moreover, training provoked reduced cortical activation patterns with respect to untrained patients that were comparable to the patterns of activation observed in controls. Based on these findings, we propose that cognitive training can contribute significantly to save brain resources in PD patients, maybe by readdressing the imbalance caused by the alterations to inhibitory circuitry. Furthermore, these data strongly support the development and use of standardized cognitive training programs in PD patients. PMID- 22203817 TI - Sporothrix schenckii Cell Wall Peptidorhamnomannans. AB - This mini-review article is dedicated to clarifying certain important biochemical aspects of Sporothrixschenckii cell wall peptidorhamnomannans. Cell wall components involved in the host interaction such as antigens as well as a gp70 adhesin are important molecules present on the surface of the yeast parasitic phase. Other structural glycoconjugates present on the fungus cell surface are also described here. Knowledge of the fine structure of carbohydrate epitopes expressed on the surface in both morphological phases of S. schenckii permitted the development of non-invasive immunochemical methods to diagnose human and feline sporotrichosis. PMID- 22203819 TI - The Structure of the Hantavirus Zinc Finger Domain is Conserved and Represents the Only Natively Folded Region of the Gn Cytoplasmic Tail. AB - Hantaviruses, of the family Bunyaviridae, are present throughout the world and cause a variety of infections ranging from the asymptomatic to mild and severe hemorrhagic fevers. Hantaviruses are enveloped anti-sense RNA viruses that contain three genomic segments that encode for a nucleocapsid protein, two membrane glycoproteins (Gn and Gc), and an RNA polymerase. Recently, the pathogenicity of hantaviruses has been mapped to the carboxyl end of the 150 residue Gn cytoplasmic tail. The Gn tail has also been shown to play a role in binding the ribonucleoprotein (RNP), a step critical for virus assembly. In this study, we use NMR spectroscopy to compare the structure of a Gn tail zinc finger domain of both a pathogenic (Andes) and a non-pathogenic (Prospect Hill) hantavirus. We demonstrate that despite a stark difference in the virulence of both of these viruses, the structure of the Gn core zinc finger domain is largely conserved in both strains. We also use NMR backbone relaxation studies to demonstrate that the regions of the Andes virus Gn tail immediately outside the zinc finger domain, sites known to bind the RNP, are disordered and flexible, thus intimating that the zinc finger domain is the only structured region of the Gn tail. These structural observations provide further insight into the role of the Gn tail during viral assembly as well as its role in pathogenesis. PMID- 22203818 TI - Extended-Spectrum Beta-Lactamases Producing E. coli in Wildlife, yet Another Form of Environmental Pollution? AB - Wildlife is normally not exposed to clinically used antimicrobial agents but can acquire antimicrobial resistant bacteria through contact with humans, domesticated animals and the environment, where water polluted with feces seems to be the most important vector. Escherichia coli, an ubiquitous commensal bacterial species colonizing the intestinal tract of mammals and birds, is also found in the environment. Extended-spectrum beta-lactamases producing E. coli (ESBL-E. coli) represent a major problem in human and veterinary medicine, particular in nosocomial infections. Additionally an onset of community-acquired ESBL-E. coli infections and an emergence in livestock farming has been observed in recent years, suggesting a successful transmission as well as persistence of ESBL-E. coli strains outside clinical settings. Another parallel worldwide phenomenon is the spread of ESBL-E. coli into the environment beyond human and domesticated animal populations, and this seems to be directly influenced by antibiotic practice. This might be a collateral consequence of the community onset of ESBL-E. coli infections but can result (a) in a subsequent colonization of wild animal populations which can turn into an infectious source or even a reservoir of ESBL-E. coli, (b) in a contribution of wildlife to the spread and transmission of ESBL-E. coli into fragile environmental niches, (c) in new putative infection cycles between wildlife, domesticated animals and humans, and (d) in problems in the medical treatment of wildlife. This review aims to summarize the current knowledge on ESBL-E. coli in wildlife, in turn underlining the need for more large scale investigations, in particular sentinel studies to monitor the impact of multiresistant bacteria on wildlife. PMID- 22203820 TI - Real-Time PCR Quantification and Diversity Analysis of the Functional Genes aprA and dsrA of Sulfate-Reducing Prokaryotes in Marine Sediments of the Peru Continental Margin and the Black Sea. AB - Sulfate-reducing prokaryotes (SRP) are ubiquitous and quantitatively important members in many ecosystems, especially in marine sediments. However their abundance and diversity in subsurface marine sediments is poorly understood. In this study, the abundance and diversity of the functional genes for the enzymes adenosine 5'-phosphosulfate reductase (aprA) and dissimilatory sulfite reductase (dsrA) of SRP in marine sediments of the Peru continental margin and the Black Sea were analyzed, including samples from the deep biosphere (ODP site 1227). For aprA quantification a Q-PCR assay was designed and evaluated. Depth profiles of the aprA and dsrA copy numbers were almost equal for all sites. Gene copy numbers decreased concomitantly with depth from around 10(8)/g sediment close to the sediment surface to less than 10(5)/g sediment at 5 mbsf. The 16S rRNA gene copy numbers of total bacteria were much higher than those of the functional genes at all sediment depths and used to calculate the proportion of SRP to the total Bacteria. The aprA and dsrA copy numbers comprised in average 0.5-1% of the 16S rRNA gene copy numbers of total bacteria in the sediments up to a depth of ca. 40 mbsf. In the zone without detectable sulfate in the pore water from about 40-121 mbsf (Peru margin ODP site 1227), only dsrA (but not aprA) was detected with copy numbers of less than 10(4)/g sediment, comprising ca. 14% of the 16S rRNA gene copy numbers of total bacteria. In this zone, sulfate might be provided for SRP by anaerobic sulfide oxidation. Clone libraries of aprA showed that all isolated sequences originate from SRP showing a close relationship to aprA of characterized species or form a new cluster with only distant relation to aprA of isolated SRP. For dsrA a high diversity was detected, even up to 121 m sediment depth in the deep biosphere. PMID- 22203821 TI - Structural Features of Antiviral APOBEC3 Proteins are Linked to Their Functional Activities. AB - Human APOBEC3 (A3) proteins are cellular cytidine deaminases that potently restrict the replication of retroviruses by hypermutating viral cDNA and/or inhibiting reverse transcription. There are seven members of this family including A3A, B, C, DE, F, G, and H, all encoded in a tandem array on human chromosome 22. A3F and A3G are the most potent inhibitors of HIV-1, but only in the absence of the virus-encoded protein, Vif. HIV-1 utilizes Vif to abrogate A3 functions in the producer cells. More specifically, Vif, serving as a substrate receptor, facilitates ubiquitination of A3 proteins by forming a Cullin5 (Cul5) based E3 ubiquitin ligase complex, which targets A3 proteins for rapid proteasomal degradation. The specificity of A3 degradation is determined by the ability of Vif to bind to the target. Several lines of evidence have suggested that three distinct regions of A3 proteins are involved in the interaction with Vif. Here, we review the biological functions of A3 family members with special focus on A3G and base our analysis on the available structural information. PMID- 22203822 TI - Unusual features of pomoviral RNA movement. AB - Potato mop-top pomovirus (PMTV) is one of a few viruses that can move systemically in plants in the absence of the capsid protein (CP). Pomoviruses encode the triple gene block genetic module of movement proteins (TGB 1, 2, and 3) and recent research suggests that PMTV RNA is transported either as ribonucleoprotein (RNP) complexes containing TGB1 or encapsidated in virions containing TGB1. Furthermore, there are different requirements for local or systemic (long-distance) movement. Research suggests that nucleolar passage of TGB1 may be important for the long-distance movement of both RNP and virions. Moreover, and uniquely, the long-distance movement of the CP-encoding RNA requires expression of both major and minor CP subunits and is inhibited when only the major CP sub unit is expressed. This paper reviews pomovirus research and presents a current model for RNA movement. PMID- 22203823 TI - Can the 'head-turning sign' be a clinical marker of Alzheimer's disease? AB - AIMS: To investigate the incidence and severity of the 'head-turning sign' (HTS), i.e. turning the head back to the caregiver(s) for help, in patients with various dementias and discuss its clinical specificity in Alzheimer's disease (AD). METHODS: WE INVESTIGATED THE INCIDENCE AND SEVERITY OF HTS WHILE ADMINISTERING A SHORT COGNITIVE TEST (THE REVISED HASEGAWA DEMENTIA RATING SCALE: HDSR) in outpatients with AD [125 patients, including 4 with AD + vascular dementia (VaD)], 8 with amnestic mild cognitive impairment (aMCI), 34 with dementia with Lewy bodies (DLB), 8 with progressive supranuclear palsy (PSP) and 6 with VaD. RESULTS: Significant differences were found among the 5 disease groups in the incidence and severity of HTS, and HDSR scores. Given the significant differences between AD and DLB in post hoc analyses, patients were dichotomized into AD related (AD and aMCI) and AD-nonrelated (PSP, DLB and VaD) groups. Both incidence (41 vs. 17%, p = 0.002) and severity of HTS (0.80 +/- 1.13 vs. 0.21 +/- 0.60, p = 0.001) were significantly higher in the AD-related group, while average age and HDSR scores were comparable between both groups. AD-related disease, female gender and low HDSR score contributed significantly to the occurrence and severity of HTS. CONCLUSIONS: HTS can be a clinical marker of AD and aMCI, and may represent a type of excuse behavior as well as a sign of dependency on and trust in the caregivers. PMID- 22203824 TI - Long latency and high variability in accuracy-speed of prosaccades in Alzheimer's disease at mild to moderate stage. AB - BACKGROUND: Studying saccades is a useful tool to investigate brain function. There is still controversy regarding deficits in prosaccades in Alzheimer's disease (AD), and a study of saccades in subjects with mild cognitive impairment (MCI) has not been published to date. METHODS: We examined horizontal saccades in 10 healthy elderly, and 9 MCI and 9 AD patients. Two tasks were used: gap (fixation target extinguishes prior to target onset) and overlap (fixation stays on after target onset). Eye movements were recorded with the Skalar IRIS system. RESULTS: (1) Latencies were shorter in the gap than in the overlap task (a gap effect) in all three groups of subjects: healthy elderly, MCI and AD; (2) for both tasks, latency of saccades was longer for AD patients than for healthy and MCI subjects, and (3) accuracy and mean velocity were normal in MCI and AD subjects, however, variability in accuracy-speed was higher for AD patients than for healthy and MCI subjects in the overlap task. CONCLUSIONS: Abnormalities in reaction time and accuracy-speed variability reflect deficits in cerebral areas involved in the triggering and execution of saccades; a saccade test can be useful to follow up the evolution of MCI subjects as some of them may develop AD disease. PMID- 22203825 TI - An overview of longitudinal data analysis methods for neurological research. AB - The purpose of this article is to provide a concise, broad and readily accessible overview of longitudinal data analysis methods, aimed to be a practical guide for clinical investigators in neurology. In general, we advise that older, traditional methods, including (1) simple regression of the dependent variable on a time measure, (2) analyzing a single summary subject level number that indexes changes for each subject and (3) a general linear model approach with a fixed subject effect, should be reserved for quick, simple or preliminary analyses. We advocate the general use of mixed-random and fixed-effect regression models for analyses of most longitudinal clinical studies. Under restrictive situations or to provide validation, we recommend: (1) repeated-measure analysis of covariance (ANCOVA), (2) ANCOVA for two time points, (3) generalized estimating equations and (4) latent growth curve/structural equation models. PMID- 22203826 TI - Impaired knowledge of driving laws is associated with recommended driving cessation in cognitively impaired older adults. AB - BACKGROUND/AIMS: The present study examined if knowledge of driving laws independently predicts on-the-road driving performance among cognitively impaired older adults. METHODS: The current study consisted of retrospective observational analyses on 55 cognitively impaired older adults (77.9 +/- 6.4 years) that completed an on-the-road driving evaluation, a 20-item knowledge test of driving laws, and a brief cognitive test battery. RESULTS: Logistic regression found poorer performance on the knowledge test was significantly associated with greater likelihood of recommended driving cessation beyond important demographic and cognitive variables (p < 0.05). CONCLUSION: Cognitively impaired patients' ability to drive may be related to their knowledge regarding common driving laws, in addition to their current level of cognitive functioning. PMID- 22203827 TI - A Novel FEM-Based Numerical Solver for Interactive Catheter Simulation in Virtual Catheterization. AB - Virtual reality-based simulators are very helpful for trainees to acquire the skills of manipulating catheters and guidewires during the vascular interventional surgeries. In the development of such a simulator, however, it is a great challenge to realistically model and simulate deformable catheters and guidewires in an interactive manner. We propose a novel method to simulate the motion of catheters or guidewires and their interactions with patients' vascular system. Our method is based on the principle of minimal total potential energy. We formulate the total potential energy in the vascular interventional circumstance by summing up the elastic energy deriving from the bending of the catheters or guidewires, the potential energy due to the deformation of vessel walls, and the work by the external forces. We propose a novel FEM-based approach to simulate the deformation of catheters and guidewires. The motion of catheters or the guidewires and their responses to every input from the interventionalist can be calculated globally. Experiments have been conducted to validate the feasibility of the proposed method, and the results demonstrate that our method can realistically simulate the complex behaviors of catheters and guidewires in an interactive manner. PMID- 22203828 TI - Diabetic nephropathy amelioration by a low-dose sitagliptin in an animal model of type 2 diabetes (Zucker diabetic fatty rat). AB - This study was performed to assess the effect of chronic low-dose sitagliptin, a dipeptidyl peptidase 4 inhibitor, on metabolic profile and on renal lesions aggravation in a rat model of type-2 diabetic nephropathy, the Zucker diabetic fatty (ZDF) rat. Diabetic and obese ZDF (fa/fa) rats and their controls ZDF (+/+) were treated for 6 weeks with vehicle (control) or sitagliptin (10 mg/kg/bw). Blood/serum glucose, HbA1c, insulin, Total-c, TGs, urea, and creatinine were assessed, as well as kidney glomerular and tubulointerstitial lesions (interstitial fibrosis/tubular atrophy), using a semiquantitative rating from 0 (absent/normal) to 3 (severe and extensive damage). Vascular lesions were scored from 0-2. Sitagliptin in the diabetic rats promoted an amelioration of glycemia, HbA1c, Total-c, and TGs, accompanied by a partial prevention of insulinopenia. Furthermore, together with urea increment prevention, renal lesions were ameliorated in the diabetic rats, including glomerular, tubulointerstitial, and vascular lesions, accompanied by reduced lipid peroxidation. In conclusion, chronic low-dose sitagliptin treatment was able to ameliorate diabetic nephropathy, which might represent a key step forward in the management of T2DM and this serious complication. PMID- 22203830 TI - Autonomic neuropathy in diabetes mellitus and obesity: an update. PMID- 22203829 TI - Maternal obesity and the early origins of childhood obesity: weighing up the benefits and costs of maternal weight loss in the periconceptional period for the offspring. AB - There is a need to understand the separate or interdependent contributions of maternal prepregnancy BMI, gestational weight gain, glycaemic control, and macronutrient intake on the metabolic outcomes for the offspring. Experimental studies highlight that there may be separate influences of maternal obesity during the periconceptional period and late gestation on the adiposity of the offspring. While a period of dietary restriction in obese mothers may ablate the programming of obesity, it is associated with an activation of the stress axis in the offspring. Thus, maternal obesity may result in epigenetic changes which predict the need for efficient fat storage in postnatal life, while maternal weight loss may lead to epigenetic changes which predict later adversity. Thus, development of dietary interventions for obese mothers during the periconceptional period requires a greater evidence base which allows the effective weighing up of the metabolic benefits and costs for the offspring. PMID- 22203831 TI - Glucagon-like peptide-1 and diabetes. PMID- 22203833 TI - Dynamic aerobic exercise induces baroreflex improvement in diabetic rats. AB - The objective of the present study was to investigate the effects of an acute aerobic exercise on arterial pressure (AP), heart rate (HR), and baroreflex sensitivity (BRS) in STZ-induced diabetic rats. Male Wistar rats were divided into control (n = 8) and diabetic (n = 8) groups. AP, HR, and BRS, which were measured by tachycardic and bradycardic (BR) responses to AP changes, were evaluated at rest (R) and postexercise session (PE) on a treadmill. At rest, STZ diabetes induced AP and HR reductions, associated with BR impairment. Attenuation in resting diabetes-induced AP (R: 103 +/- 2 versus PE: 111 +/- 3 mmHg) and HR (R: 290 +/- 7 versus PE: 328 +/- 10 bpm) reductions and BR dysfunction (R: -0.70 +/- 0.06 versus PE: -1.21 +/- 0.09 bpm/mmHg) was observed in the postexercise period. In conclusion, the hemodynamic and arterial baro-mediated control of circulation improvement in the postexercise period reinforces the role of exercise in the management of cardiovascular risk in diabetes. PMID- 22203832 TI - The pathophysiology of HIV-/HAART-related metabolic syndrome leading to cardiovascular disorders: the emerging role of adipokines. AB - Individuals infected with human immunodeficiency virus (HIV) frequently demonstrate metabolic syndrome (MS) associated with increased incidence of cardiovascular disorders. Characteristics of HIV infection, such as immunodeficiency, viral load, and duration of the disease, in addition to the highly active antiretroviral therapy (HAART) have been suggested to induce MS in these patients. It is well documented that MS involves a number of traditional cardiovascular risk factors, like glucose, lipids, and arterial blood pressure abnormalities, leading to extensive atherogenic arterial wall changes. Nevertheless, the above traditional cardiovascular risk factors merely explain the exacerbated cardiovascular risk in MS. Nowadays, the adipose-tissue derivatives, known as adipokines, have been suggested to contribute to chronic inflammation and the MS-related cardiovascular disease. In view of a novel understanding on how adipokines affect the pathogenesis of HIV/HAART-related MS and cardiovascular complications, this paper focuses on the interaction of the metabolic pathways and the potential cardiovascular consequences. Based on the current literature, we suggest adipokines to have a role in the pathogenesis of the HIV/HAART-related MS. It is crucial to understand the pathophysiology of the HIV/HAART-related MS and apply therapeutic strategies in order to reduce cardiovascular risk in HIV patients. PMID- 22203834 TI - Prevalence of metabolic syndrome components in an urban Mexican sample: comparison between two classifications. AB - Background. The aim of this study was to examine the prevalence of metabolic syndrome (MS) components in an urban Mexican sample. Methods. A total of 854 subjects were included. Anthropometric, blood pressure measurements, clinical data, and overnight fasting blood samples were obtained from all subjects. Results. In accordance with definitions by the American Heart Association/ National Heart, Lung, and Blood Institute (AHA/NHLBI) and the International Diabetes Federation (IDF), the prevalence of MS among participants was 59.7 and 68.7%, respectively. The prevalence of MS was higher in women and in individuals older than 45 years of age. More than 40% of the subjects fulfilled four criterions of MS according to both definitions. Conclusions. There was a high prevalence of MS components in an urban Mexican sample. Therefore, strong strategies had to be developed for early detection of MS and its components to prevent DMT2 and atherothrombotic complications in these patients. PMID- 22203835 TI - Cholesterol synthesis is associated with hepatic lipid content and dependent on fructose/glucose intake in healthy humans. AB - Visceral obesity and fatty liver have been related to high synthesis and low absorption of cholesterol. This study aimed to investigate the associations of cholesterol metabolism with liver and visceral fat content in healthy humans. Another objective was to explore the effects of very-high-fructose and very-high glucose diets on cholesterol homeostasis. We report on a cohort of 20 people (12 males, 8 females; age 30.5 +/- 2.0 years; body mass index 25.9 +/- 0.5 kg/m(2)) who completed a four-week dietary intervention study. Between the baseline and the followup examination the study participants in addition to a balanced weight maintaining diet received 150 g of either fructose or glucose per day. Visceral and liver fat were measured with magnetic resonance (MR) imaging and (1)H-MR spectroscopy, respectively. Cholesterol absorption and synthesis were estimated from the serum noncholesterol sterol concentrations. Performing cross-sectional analyses the lanosterol and desmosterol to cholesterol ratios were positively correlated with visceral and liver fat content (all P < .03). The lathosterol to cholesterol ratio decreased in response to high-fructose diet (P = .006) but not in response to high-glucose diet. To conclude, visceral and liver fat content are associated with cholesterol synthesis in healthy humans. Furthermore, cholesterol synthesis appears to be dependent on fructose/glucose intake. PMID- 22203836 TI - Endoplasmic reticulum stress-related factors protect against diabetic retinopathy. AB - The endoplasmic reticulum (ER) is a principal mediator of signal transduction in the cell, and disruption of its normal function (a mechanism known as ER stress) has been associated with the pathogenesis of several diseases. ER stress has been demonstrated to contribute to onset and progression of diabetic retinopathy (DR) by induction of multiple inflammatory signaling pathways. Recent studies have begun to describe the gene expression profile of ER stress-related genes in DR; moreover, genes that play a protective role against DR have been identified. P58(IPK) was determined to be able to reduce retinal vascular leakage under high glucose conditions, thus protecting retinal cells. It has also been found by our lab that ER-associated protein degradation factors exhibit significantly different expression patterns in rat retinas under sustained high glucose conditions. Future research based upon these collective genomic findings will contribute to our overall understanding of DR pathogenesis as well as identify potential therapeutic targets. PMID- 22203838 TI - Nosocomial infections in burned patients in motahari hospital, tehran, iran. AB - Burn patients are at high risk of developing nosocomial infection because of their destroyed skin barrier and suppressed immune system, compounded by prolonged hospitalization and invasive therapeutic and diagnostic procedures. Studies on nosocomial infection in burn patients are not well described. The objective of the present study was to identify the causative bacterial of nosocomial infection and to determine the incidence of nosocomial infection and their changing during hospitalization in burned patients admitted to in the Motahari Hospital, Tehran, Iran. During the second part of 2010, 164 patients were included in this study. Samples were taken the first 48 hours and the fourth week after admission to Motahari Burn hospital. Isolation and identification of microorganisms was performed using the standard procedure. Of the 164 patients, 717 samples were taken and 812 bacteria were identified, 610 patients were culture positive on day 7 while 24 (17.2%) on 14 days after admission. The bacteria causing infections were 325 Pseudomonas, 140 Acinetobacter, 132 Staphylococcus aureus, and 215 others. The percentage of mortality was 12%. All of patients had at least 1 positive culture with Pseudomonas and/or with Acinetobacter. Hospitals suggest continuous observationof burn infections and increase strategies for antimicrobial resistance control and treatment of infectious complications. PMID- 22203839 TI - Thigmotropism of malignant melanoma cells. AB - During malignant melanoma (MM) progression including incipient metastasis, neoplastic cells follow some specific migration paths inside the skin. In particular, they progress along the dermoepidermal basement membrane, the hair follicles, the sweat gland apparatus, nerves, and the near perivascular space. These features evoke the thigmotropism phenomenon defined as a contact-sensing growth of cells. This process is likely connected to modulation in cell tensegrity (control of the cell shape). These specifically located paucicellular aggregates of MM cells do not appear to be involved in the tumorigenic growth phase, but rather they participate in the so-called "accretive" growth model. These MM cell collections are often part of the primary neoplasm, but they may, however, correspond to MM micrometastases and predict further local overt metastasis spread. PMID- 22203840 TI - Ultrasound and 3D Skin Imaging: Methods to Evaluate Efficacy of Striae Distensae Treatment. AB - Background. Over time, the striae rubra develop into striae alba that appear white, flat, and depressed. It is very important to determine the optimum striae management. In order to evaluate the effectiveness of these therapies, objective measurement tools are necessary. Objective. The aim of this study is to evaluate if ultrasonography and PRIMOS can be used to obtain an objective assessment of stretch marks type and stage; furthermore, we aim to apply these techniques to evaluate the efficacy of a topical treatment. Methods. 20 volunteers were enrolled with a two-month study. A marketed cosmetic product was used as the active over one body area. The controlateral area with stretch marks was treated with a "placebo" formulation without active, as a control. The instrumental evaluation was carried out at the beginning of the trial (baseline values or t(0)), after 1 month (t(1)), and at the end of the study (t(2)). Results. PRIMOS was able to measure and document striae distensae maturation; furthermore, ultrasound imaging permitted to visualize and diagnose the striae. Statistical analysis of skin roughness demonstrated a statistically significant reduction of Rp value only in a treated group. In fact, the Rp value represented a maximum peak height in the area selected. These results demonstrated that after two months of treatment only the striae rubra can be treated successfully. Conclusions. This work demonstrated that the 22MHz ultrasound can diagnose stretch marks; PRIMOS device can detect and measure striae distensae type and maturation. Furthermore, the high-frequency ultrasound and the 3D image device, described in this work, can be successfully employed in order to evaluate the efficacy of a topical treatment. PMID- 22203837 TI - Mitochondrial dysregulation in the pathogenesis of diabetes: potential for mitochondrial biogenesis-mediated interventions. AB - Muscle mitochondrial metabolism is a tightly controlled process that involves the coordination of signaling pathways and factors from both the nuclear and mitochondrial genomes. Perhaps the most important pathway regulating metabolism in muscle is mitochondrial biogenesis. In response to physiological stimuli such as exercise, retrograde signaling pathways are activated that allow crosstalk between the nucleus and mitochondria, upregulating hundreds of genes and leading to higher mitochondrial content and increased oxidation of substrates. With type 2 diabetes, these processes can become dysregulated and the ability of the cell to respond to nutrient and energy fluctuations is diminished. This, coupled with reduced mitochondrial content and altered mitochondrial morphology, has been directly linked to the pathogenesis of this disease. In this paper, we will discuss our current understanding of mitochondrial dysregulation in skeletal muscle as it relates to type 2 diabetes, placing particular emphasis on the pathways of mitochondrial biogenesis and mitochondrial dynamics, and the therapeutic value of exercise and other interventions. PMID- 22203841 TI - Multiphoton laser microscopy and fluorescence lifetime imaging for the evaluation of the skin. AB - Multiphoton laser microscopy is a new, non-invasive technique providing access to the skin at a cellular and subcellular level, which is based both on autofluorescence and fluorescence lifetime imaging. Whereas the former considers fluorescence intensity emitted by epidermal and dermal fluorophores and by the extra-cellular matrix, fluorescence lifetime imaging (FLIM), is generated by the fluorescence decay rate. This innovative technique can be applied to the study of living skin, cell cultures and ex vivo samples. Although still limited to the clinical research field, the development of multiphoton laser microscopy is thought to become suitable for a practical application in the next few years: in this paper, we performed an accurate review of the studies published so far, considering the possible fields of application of this imaging method and providing high quality images acquired in the Department of Dermatology of the University of Modena. PMID- 22203842 TI - White Matter Lesions Are Not Related to beta-Amyloid Deposition in an Autopsy Based Study. AB - Population-based studies have investigated the relation between beta-amyloid levels in cerebrospinal fluid or plasma and white matter lesions (WMLs). However, these circulating levels of beta-amyloid in cerebrospinal fluid or plasma may not reliably reflect the actual degree of amyloid present in the brain. Therefore, we investigated the relation between WMLs and beta-amyloid plaques and amyloid angiopathy in brain tissue. WML on MRI or CT were rated in 28 nondemented patients whose neuroimaging was available prior to death. beta-amyloid in plaques and arterioles were immunohistochemically stained and quantified in postmortem brain necropsies. WMLs were present in 43% of the total population. Both cortex and periventricular region showed no differences for beta-amyloid deposition in either plaques or blood vessel walls in patients with WMLs compared to those without WMLs. Thus, our results indicate that there is no relation between the degree of WMLs and beta-amyloid deposition in the brain. PMID- 22203843 TI - Oxidative Stress and Down Syndrome: A Route toward Alzheimer-Like Dementia. AB - Down syndrome (DS) is one of the most frequent genetic abnormalities characterized by multiple pathological phenotypes. Indeed, currently life expectancy and quality of life for DS patients have improved, although with increasing age pathological dysfunctions are exacerbated and intellectual disability may lead to the development of Alzheimer's type dementia (AD). The neuropathology of DS is complex and includes the development of AD by middle age, altered free radical metabolism, and impaired mitochondrial function, both of which contribute to neuronal degeneration. Understanding the molecular basis that drives the development of AD is an intense field of research. Our laboratories are interested in understanding the role of oxidative stress as link between DS and AD. This review examines the current literature that showed oxidative damage in DS by identifying putative molecular pathways that play a central role in the neurodegenerative processes. In addition, considering the role of mitochondrial dysfunction in neurodegenerative phenomena, results demonstrating the involvement of impaired mitochondria in DS pathology could contribute a direct link between normal aging and development of AD-like dementia in DS patients. PMID- 22203844 TI - Oxaliplatin-induced neuropathy in colorectal cancer. AB - Oxaliplatin use in palliative and adjuvant treatment of colon cancer is frequently limited by cumulative neurotoxicity, leading to reduced quality of life and decreased dose. The mechanism of this neurotoxicity is unclear, but may relate to neuronal voltage-gated sodium channels involving calcium chelation by a metabolite of the drug. Various preventative measures have been tested to reduce the incidence of neurotoxicity, including calcium and magnesium infusions, dose interruption of the drug, and prophylactic neuromodulatory agents. Despite the promising efficacy of these measures, they are not universally accepted. Less is known about the best way to treat established neurotoxicity, which is permanent in some patients, although venlafaxine has shown promise in small clinical trials. This paper analyzes the extent, cause and risk factors for neuropathy, and the potential preventative and therapeutic treatments for oxaliplatin-induced neuropathy. PMID- 22203845 TI - alpha2 Integrin-Dependent Suppression of Pancreatic Adenocarcinoma Cell Invasion Involves Ectodomain Regulation of Kallikrein-Related Peptidase-5. AB - Previous reports demonstrate that the alpha2-integrin (alpha2) mediates pancreatic ductal adenocarcinoma (PDAC) cell interactions with collagens. We found that while well-differentiated cells use alpha2 exclusively to adhere and migrate on collagenI, poorly differentiated PDAC cells demonstrate reduced reliance on, or complete loss of, alpha2. Since well-differentiated PDAC lines exhibit reduced in vitro invasion and alpha2-blockade suppressed invasion of well differentiated lines exclusively, we hypothesized that alpha2 may suppress the malignant phenotype in PDAC. Accordingly, ectopic expression of alpha2 retarded in vitro invasion and maintenance on collagenI exacerbated this effect. Affymetrix profiling revealed that kallikrein-related peptidase-5 (KLK5) was specifically upregulated by alpha2, and reduced alpha2 and KLK5 expression was observed in poorly differentiated PDAC cells in situ. Accordingly, well differentiated PDAC lines express KLK5, and KLK5 blockade increased the invasion of KLK5-positive lines. The alpha2-cytoplasmic domain was dispensable for these effects, demonstrating that the alpha2-ectodomain and KLK5 coordinately regulate a less invasive phenotype in PDAC. PMID- 22203846 TI - Endometriosis gene expression heterogeneity and biosignature: a phylogenetic analysis. AB - Endometriosis is a multifactorial disease with poorly understood etiology, and reflecting an evolutionary nature where genetic alterations accumulate throughout pathogenesis. Our objective was to characterize the heterogeneous pathological process using parsimony phylogenetics. Gene expression microarray data of ovarian endometriosis obtained from NCBI database were polarized and coded into derived (abnormal) and ancestral (normal) states. Such alterations are referred to as synapomorphies in a phylogenetic sense (or biomarkers). Subsequent gene linkage was modeled by Genomatix BiblioSphere Pathway software. A list of clonally shared derived (abnormal) expressions revealed the pattern of heterogeneity among specimens. In addition, it has identified disruptions within the major regulatory pathways including those involved in cell proliferation, steroidogenesis, angiogenesis, cytoskeletal organization and integrity, and tumorigenesis, as well as cell adhesion and migration. Furthermore, the analysis supported the potential central involvement of ESR2 in the initiation of endometriosis. The pathogenesis mapping showed that eutopic and ectopic lesions have different molecular biosignatures. PMID- 22203847 TI - The Fetal Safety of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers. AB - Angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are known to cause fetal renal damage in pregnancy. Due to conflicting reports in the literature, their safety after first trimester exposure has been debated. Our aim was to determine whether the use of ACE inhibitors or ARBs in the first trimester of pregnancy is associated with an increased risk for major malformations or other adverse outcomes. All subjects were prospectively enrolled from among women contacting a teratogen information service. At initial contact, details of maternal medical history and exposures were collected and follow-up interviews were conducted to ascertain pregnancy outcomes. Two comparator groups, women with hypertension treated with other antihypertensives, and healthy controls were also recruited. Baseline maternal characteristics were not different among the three groups. There were no differences in rates of major malformations. Both the ACE-ARBs and disease matched groups exhibited significantly lower birth weight and gestational ages than the healthy controls (P < 0.001 for both variables). There was a significantly higher rate of miscarriage noted in the ACE/ARB group (P < 0.001). These results suggest that ACE inhibitors/ARBs are not major human teratogens; however, they may be associated with an increased risk for miscarriage. PMID- 22203848 TI - Systemic Embolization and Myocardial Infarction due to Clinically Unrecognized Left Atrial Myxoma. AB - Myxomas are the most common primary tumors of the heart. We report an extraordinary severe case of left atrial myxoma, presenting with stroke, myocardial infarction, and multiple arterial embolism including aorta, splenic and renal arteries, and several peripheral arteries. The patient had previously been diagnosed with systemic vasculitis, a typical but less common finding caused by multiple emboli mimicking vasculitis. The myxoma was removed and atrial septum reconstruction was performed. In summary, early diagnostic differentiation of myxoma from vasculitis is critical, and immediate surgical removal of myxoma is required as the probability of thromboembolic complications increases over time. PMID- 22203849 TI - Resistance exercise reduces skeletal muscle cachexia and improves muscle function in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune, inflammatory disease associated with cachexia (reduced muscle and increased fat). Although strength-training exercise has been used in persons with RA, it is not clear if it is effective for reducing cachexia. A 46-year-old woman was studied to determine: (i) if resistance exercise could reverse cachexia by improving muscle mass, fiber cross-sectional area, and muscle function; and (2) if elevated apoptotic signaling was involved in cachexia with RA and could be reduced by resistance training. A needle biopsy was obtained from the vastus lateralis muscle of the RA subject before and after 16 weeks of resistance training. Knee extensor strength increased by 13.6% and fatigue decreased by 2.8% Muscle mass increased by 2.1%. Average muscle fiber cross-sectional area increased by 49.7%, and muscle nuclei increased slightly after strength training from 0.08 to 0.12 nuclei/MUm(2). In addition, there was a slight decrease (1.6%) in the number of apoptotic muscle nuclei after resistance training. This case study suggests that resistance training may be a good tool for increasing the number of nuclei per fiber area, decreasing apoptotic nuclei, and inducing fiber hypertrophy in persons with RA, thereby slowing or reversing rheumatoid cachexia. PMID- 22203850 TI - Post irradiation spindle cell carcinoma of tonsillar pillar. AB - Spindle cell carcinoma of the tonsillar pillar is a rare malignancy. A case of spindle cell carcinoma of the anterior tonsillar pillar in a 59-year-old man is presented. A growth on the anterior tonsillar pillar, measuring 9 * 7 * 6 mm, was resected. The neoplasm occurred as a complication of radiotherapy (excessive cumulative radiation dose of 60 Gray) for carcinoma larynx with a latency period of three years. Postradiation spindle cell carcinoma is an uncommon disease manifesting as sarcoma in a previously irradiated field, usually with a latent period of 5 years or more. Literature is limited to small series. Histologically, this tonsillar growth was composed of a squamous cell carcinoma (epithelial component) and a spindle cell sarcomatous component. The two components of the tumour were confirmed using the immunohistochemical staining (cytokeratin and vimentin). Further p53 positivity of the sarcomatous elements aided in ruling out radiation-induced nonmalignant changes of mesenchymal tissue. This paper discusses this rare tumour in a common setting. PMID- 22203851 TI - Huntington's Disease: Two-Year Observational Follow-Up of Executive Function Evaluation with CNS Vital Signs Test in an Adult Patient. AB - Huntington's disease (HD) is a genetic, degenerative, and progressive central nervous system disease. It is characterized by motor abnormalities and cognitive and psychiatric symptoms. Objective. To describe the precise degree of clinical severity of patients with HD through a new neurocognitive assessment. Methods. Unprecedented battery of computerized tests, CNSVS (Central Nervous System Vital Signs), was applied at three different moments in 2008, 2009, and 2010. The accurate and reliable CNSVS objectively provided the cognitive state of patients and allowed for the evaluation of disease progression. Case Report. P., 26, female, without any medication, with normal psychomotor development is a parent carrier of HD. In 2008, she was diagnosed with HD in accordance with the Medical Genetics Laboratories. Conclusion. The tests may be useful to reveal the exact measure of the current evolutionary stage of HD patients, allowing for more efficient planning of treatment and future procedures, such as the medication, therapy, and physical activity to be administered. PMID- 22203852 TI - Evidence of acute Mycoplasma infection in a patient with incomplete and atypical kawasaki disease: a case report. AB - The etiology of Kawasaki disease remains unknown despite extensive studies. Some researchers suggest that it is caused by an infectious agent. This is a case report where a patient with incomplete Kawasaki disease was found to have evidence compatible with acute Mycoplasma pneumoniae infection. This is one of the several case reports linking Mycoplasma pneumoniae to Kawasaki disease as a possible trigger. This is perhaps due to a superantigen or is mediated by some other mechanism. Accurate and timely testing for Mycoplasma infections is difficult and has its limitations. Despite this, Mycoplasma pneumoniae should be considered in the differential and workup for Kawasaki disease. PMID- 22203853 TI - Surgical Management of a Rare Case of Congenital DoubleUpper Lip. AB - Congenital double lip is a rare developmental anomaly which usually involves the upper lip. It may occur in isolation or as a part of Ascher's syndrome. The occurrence of double lip may result in facial deformity especially when patient attempts to talk, smile, or even try to show the teeth. It affects esthetics and also interferes with speech and mastication. Although surgery may be undertaken to facilitate speech and mastication, majority of cases are operated for cosmetic reasons. A case of congenital double upper lip which was surgically treated for cosmetic reason is reported. PMID- 22203856 TI - Immunological aspects of human reproduction. PMID- 22203855 TI - Early oral ovalbumin exposure during maternal milk feeding prevents spontaneous allergic sensitization in allergy-prone rat pups. AB - There are conflicting data to support the practice of delaying the introduction of allergenic foods into the infant diet to prevent allergy development. This study investigated immune response development after early oral egg antigen (Ovalbumin; OVA) exposure in a rat pup model. Brown Norway (BN) rat pups were randomly allocated into groups: dam reared (DR), DR pups challenged daily (days 4 13) with oral OVA (DR + OVAc), DR pups challenged intermittently (on day 4, 10, 12, and 13) with oral OVA (DR + OVAi), formula-fed pups (FF), and FF pups challenged daily with oral OVA (FF + OVA). Immune parameters assessed included OVA-specific serum IgE, IgG1, and IgA. Ileal and splenic messenger ribonucleic acid (mRNA) expression of transforming growth factor-beta (TGF-beta1), mothers against decapentaplegic (Smad) 2/4/7, and forkhead box P3 (Foxp3) were determined. Ileum was stained for TGF-beta1 and Smad4. Results. Feeding OVA daily to DR pups maintained systemic and local gut antibody and immunoregulatory marker mRNA responses. Systemic TGF-beta1 was lower in DR + OVAi pups compared to DR and DR + OVAc pups. Feeding OVA to FF pups resulted in significantly greater OVA specific IgE and IgG1, and lower IgA and TGF-beta1 and Smad expression compared to DR pups. Conclusions. Early daily OVA exposure in the presence of maternal milk maintains immune markers associated with a regulated immune response, preventing early allergic sensitization. PMID- 22203854 TI - Apoptosis and the airway epithelium. AB - The airway epithelium functions as a barrier and front line of host defense in the lung. Apoptosis or programmed cell death can be elicited in the epithelium as a response to viral infection, exposure to allergen or to environmental toxins, or to drugs. While apoptosis can be induced via activation of death receptors on the cell surface or by disruption of mitochondrial polarity, epithelial cells compared to inflammatory cells are more resistant to apoptotic stimuli. This paper focuses on the response of airway epithelium to apoptosis in the normal state, apoptosis as a potential regulator of the number and types of epithelial cells in the airway, and the contribution of epithelial cell apoptosis in important airways diseases. PMID- 22203857 TI - MBL interferes with endovascular trophoblast invasion in pre-eclampsia. AB - The spiral arteries undergo physiologic changes during pregnancy, and the failure of this process may lead to a spectrum of pregnancy disorders, including pre eclampsia. Our recent data indicate that decidual endothelial cells (DECs), covering the inner side of the spiral arteries, acquire the ability to synthesize C1q, which acts as a link between endovascular trophoblast and DECs favouring the process of vascular remodelling. In this study, we have shown that sera obtained from pre-eclamptic patients strongly inhibit the interaction between extravillous trophoblast (EVT) and DECs, preventing endovascular invasion of trophoblast cells. We further demonstrated that mannose-binding lectin (MBL), one of the factor increased in pre-eclamptic patient sera, strongly inhibits the interaction of EVT with C1q interfering with the process of EVT adhesion to and migration through DECs. These data suggest that the increased level of MBL in pre-eclampsia may contribute to the failure of the endovascular invasion of trophoblast cells. PMID- 22203858 TI - Blocking type I interferon production: a new therapeutic option to reduce the HIV 1-induced immune activation. AB - Highly active antiretroviral therapy has dramatically improved the morbidity and mortality of HIV-1-infected individuals. A total of 25 licensed drugs provide the basis for an optimized virus-suppressive treatment of nearly each subject. The promises of immune reconstitution and normal life expectancy, however, fall short for a number of patients, either through inadequate recovery of CD4+ T-cell counts or the occurrence of non-AIDS defining malignancies. In this respect, the prevalence of Epstein-Barr virus-associated Hodgkin lymphoma and human papillomavirus-related anal neoplasia is rising in aging HIV-1-infected individuals despite antiretroviral therapy. An important cause appears to be the HIV-1-induced chronic immune activation, propagated by inappropriate release of proinflammatory cytokines and type I interferons. This immune dysregulation can be reduced in vitro by inhibitors blocking the endosomal acidification. Recent data suggest that this concept is also of relevance in vivo, which opens the door for adjuvant immunomodulatory therapies in HIV-1 infection. PMID- 22203859 TI - Development of murine hepatic NK cells during ontogeny: comparison with spleen NK cells. AB - The phenotype of developing liver NK cells (CD3(-)NK1.1(+)) was investigated during mouse ontogeny comparing with spleen NK cells. The highest percentage of hepatic CD27(-)CD11b(-) NK cells occurred at the fetal stage. After birth, the percentage of CD27(-)CD11b(-)NK cells in both the liver and spleen gradually decreased to their lowest level at 6 weeks. More CD27(+)CD11b(-)NK cells were detected in the liver than that in spleen from week 1 to 6. Expression of NKG2A on liver NK cells was decreased but still much higher than that of spleen NK cells after 1 week. The NKG2D expression on liver NK cells increased to its highest level and was significantly higher than on spleen NK cells till 4 weeks. During mouse ontogeny, weaker expression of NKp46 and CD2 and stronger expression of CD69, CD11c, 2B4, and CD73 were observed on liver NK cells. Furthermore, neonatal liver NK cells express higher IFN-gamma and perforin than adult .These results suggest that the maturation process of NK cells is unique in the livers, and liver microenvironments might play critical roles to keep NK cells in an immature status. PMID- 22203860 TI - Nucleotide-binding oligomerization domain-1 and -2 play no role in controlling Brucella abortus infection in mice. AB - Nucleotide-binding oligomerization domain proteins (NODs) are modular cytoplasmic proteins implicated in the recognition of peptidoglycan-derived molecules. Further, several in vivo studies have demonstrated a role for Nod1 and Nod2 in host defense against bacterial pathogens. Here, we demonstrated that macrophages from NOD1-, NOD2-, and Rip2-deficient mice produced lower levels of TNF-alpha following infection with live Brucella abortus compared to wild-type mice. Similar reduction on cytokine synthesis was not observed for IL-12 and IL-6. However, NOD1, NOD2, and Rip2 knockout mice were no more susceptible to infection with virulent B. abortus than wild-type mice. Additionally, spleen cells from NOD1-, NOD2-, and Rip2-deficient mice showed unaltered production of IFN-gamma compared to C57BL/6 mice. Taken together, this study demonstrates that NOD1, NOD2 and Rip2 are dispensable for the control of B. abortus during in vivo infection. PMID- 22203861 TI - Characterization of chronic cutaneous lesions from TNF-receptor-1-deficient mice infected by Leishmania major. AB - Leishmania major-infected TNF receptor 1 deficient (TNFR1 KO) mice resolve parasitism but fail to resolve lesions, while wild-type mice completely heal. We investigated the cell composition, cytokine production, and apoptosis in lesions from L. major-infected TNFR1 KO and wild-type (WT) mice. Chronic lesions from L. major-infected TNFR1 KO mice presented larger number of CD8+ T and Ly6G+ cells. In addition, higher concentrations of mRNA for IFN-gamma CCL2 and CCL5, as well as protein, but lower numbers of apoptotic cells, were found in lesions from TNFR1 KO mice than in WT, at late time points of infection. Our studies showed that persistent lesions in L. major-infected TNFR1 KO mice may be mediated by continuous migration of cells to the site of inflammation due to the presence of chemokines and also by lower levels of apoptosis. We suggest that this model has some striking similarities to the mucocutaneous clinical form of leishmaniasis. PMID- 22203862 TI - Gestational medication use, birth conditions, and early postnatal exposures for childhood asthma. AB - Our aim is to explore (1) whether gestational medication use, mode of delivery, and early postnatal exposure correlate with childhood asthma, (2) the dose responsiveness of such exposure, and (3) their links to early- and late-onset asthma. We conducted a matched case-control study based on the Taiwan Children Health Study, which was a nationwide survey that recruited 12-to-14-year-old school children in 14 communities. 579 mothers of the participants were interviewed by telephone. Exclusive breastfeeding protected children from asthma. Notably, childhood asthma was significantly associated with maternal medication use during pregnancy, vacuum use during vaginal delivery, recurrent respiratory tract infections, hospitalization, main caregiver cared for other children, and early daycare attendance. Exposure to these factors led to dose responsiveness in relationships to asthma. Most of the exposures revealed a greater impact on early onset asthma, except for vacuum use and daycare attendance. PMID- 22203864 TI - Protective Role of Ficus carica Stem Extract against Hepatic Oxidative Damage Induced by Methanol in Male Wistar Rats. AB - The present study was aimed to investigate the antioxidant activity of Ficus carica stem extract (FE) in methanol-induced hepatotoxicity in male Wistar rats. The rats were divided into two batches: 16 control rats (C) drinking tap water and 16 treated rats drinking Ficus carica stem extract for six weeks. Then, each group was divided into two subgroups, and one of them was intraperitoneally injected (i.p.) daily methanol at a dose of 2.37 g/kg body weight i.p. for 30 days, for four weeks. The results showed that FE was found to contain large amounts of polyphenols and carotenoids. The treatment with methanol exhibited a significant increase of serum hepatic biochemical parameters (ALT, AST, ALP, and LDH) and hepatic lipid peroxidation. Hepatic antioxidant enzymes, namely, SOD, CAT, and GSH-Px, were significantly decreased in methanol-treated animals. FE treatment prior to methanol intoxication has significant role in protecting animals from methanol-induced hepatic oxidative damage. PMID- 22203865 TI - Bioassay-Guided Isolation of Cytotoxic Cycloartane Triterpenoid Glycosides from the Traditionally Used Medicinal Plant Leea indica. AB - Leea indica is a medicinal plant used traditionally to cure cancer. In this study, the cytotoxic compounds of L. indica were isolated using bioassay-guided approach. Two cycloartane triterpenoid glycosides, mollic acid arabinoside (MAA) and mollic acid xyloside (MAX), were firstly isolated from L. indica. They inhibited the growth of Ca Ski cervical cancer cells with IC(50) of 19.21 MUM (MAA) and 33.33 MUM (MAX). MRC5 normal cell line was used to calculate selectivity index. MAA and MAX were about 8 and 4 times more cytotoxic to Ca Ski cells compared to MRC5. The cytotoxicity of MAA was characterized by both cytostatic and cytocidal effects. MAA decreased the expression of proliferative cell nuclear antigen, increased sub-G1 cells, and arrested cells in S and G2/M phases. This study provides the evidence for the ethnomedicinal use of L. indica and paves the way for future mechanism studies on the anticancer effects of MAA. PMID- 22203866 TI - Functional foods and nutraceuticals in a market of bolivian immigrants in Buenos Aires (Argentina). AB - This paper presents the results of a research in urban ethnobotany, conducted in a market of Bolivian immigrants in the neighborhood of Liniers, Ciudad Autonoma de Buenos Aires (Argentina). Functional foods and nutraceuticals belonging to 50 species of 18 families, its products, and uses were recorded. Some products are exclusive from the Bolivian community; others are frequent within the community, but they are also available in the general commercial circuit; they are introduced into it, generally, through shops called dieteticas ("health-food stores"), where products associated with the maintenance of health are sold. On this basis, the traditional and nontraditional components of the urban botanical knowledge were evaluated as well as its dynamics in relation to the diffusion of the products. Both the framework and methodological design are innovative for the studies of the urban botanical knowledge and the traditional markets in metropolitan areas. PMID- 22203863 TI - Current status of the immunomodulation and immunomediated therapeutic strategies for multiple sclerosis. AB - Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and CD4(+) T cells form the core immunopathogenic cascade leading to chronic inflammation. Traditionally, Th1 cells (interferon-gamma-producing CD4(+) T cells) driven by interleukin 12 (IL12) were considered to be the encephalitogenic T cells in MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Currently, Th17 cells (Il17-producing CD4(+) T cells) are considered to play a fundamental role in the immunopathogenesis of EAE. This paper highlights the growing evidence that Th17 cells play the core role in the complex adaptive immunity of EAE/MS and discusses the roles of the associated immune cells and cytokines. These constitute the modern immunological basis for the development of novel clinical and preclinical immunomodulatory therapies for MS discussed in this paper. PMID- 22203867 TI - Lignosus rhinocerus (Cooke) Ryvarden: A Medicinal Mushroom That Stimulates Neurite Outgrowth in PC-12 Cells. AB - A national treasure mushroom, Lignosus rhinocerus, has been used to treat variety of ailments by local and indigenous communities in Malaysia. The aim of this study was to investigate the potential of the most valuable part of L. rhinocerus, the sclerotium, on neurite outgrowth activity by using PC-12Adh cell line. Differentiated cells with one thin extension at least double the length of the cell diameter were scored positive. Our results showed that aqueous sclerotium L. rhinocerus extract induced neurite outgrowths of 24.4% and 42.1% at 20 MUg/mL (w/v) of aqueous extract alone and a combination of 20 MUg/mL (w/v) aqueous extract and 30 ng/mL (w/v) of NGF, respectively. Combination of NGF and sclerotium extract had additive effects and enhanced neurite outgrowth. Neuronal differentiation was demonstrated by indirect immunofluorescence of neurofilament protein. Aqueous sclerotium extract contained neuroactive compounds that stimulated neurite outgrowth in vitro. To our knowledge this is the first report on neurite-stimulating activities of L. rhinocerus. PMID- 22203869 TI - Isolation and Identification of Endophytic Fungi from Actinidia macrosperma and Investigation of Their Bioactivities. AB - Endophytic fungi from the Chinese medicinal plant Actinidia macrosperma were isolated and identified for the first time. This was the first study to evaluate their cytotoxic and antitumour activities against brine shrimp and five types of tumour cells, respectively. In total, 17 fungal isolates were obtained. Five different taxa were represented by 11 isolates, and six isolates were grouped into the species of Ascomycete Incertae sedis with limited morphological and molecular data. Cytotoxic activity has been found in most isolates except AM05, AM06, and AM10. The isolates AM07 (4.86 MUg/mL), AM11 (7.71 MUg/mL), and AM17 (14.88 MUg/mL) exhibited significant toxicity against brine shrimp. The results of the MTT assay to assess antitumour activity revealed that 82.4% of isolate fermentation broths displayed growth inhibition (50% inhibitory concentration IC(50)< 100 MUg/mL). Moreover, AM07, AM11, and AM17 showed strong antitumour activity in all the cell lines examined. These results suggest that endophytic fungi in A. macrosperma are valuable for the isolation and identification of novel cytotoxic and antitumour bioactive agents. PMID- 22203868 TI - Greco-arab and islamic herbal-derived anticancer modalities: from tradition to molecular mechanisms. AB - The incidence of cancer is increasing in the developed countries and even more so in developing countries parallel to the increase in life expectancy. In recent years, clinicians and researchers advocate the need to include supportive and palliative care since the establishment of the diagnosis and throughout the duration of treatment, with the goal of improving patients' quality of life. This patient-centered approach in supportive care is also shared by various traditional and complementary medicine approaches. Traditional Arab-Islamic medicine offers a variety of therapeutic modalities that include herbal, nutritional, and spiritual approaches. Physicians and scholars, such as Avicenna (980-1037), Rhazes (965-915), Al Zahrawi (936-1013), and Ibn al Nafis (1218-1288) referred to cancer etiology in various medicinal texts and suggested both preventive and therapeutic remedies to alleviate suffering. This review presents research data related to the anticancer activities of herbs used in Arab-Islamic medicine and allude to their potential role in improving the quality of life of cancer patients. PMID- 22203870 TI - Luteolin Suppresses Inflammatory Mediator Expression by Blocking the Akt/NFkappaB Pathway in Acute Lung Injury Induced by Lipopolysaccharide in Mice. AB - Acute lung injury (ALI), instilled by lipopolysaccharide (LPS), is a severe illness with excessive mortality and has no specific treatment strategy. Luteolin is an anti-inflammatory flavonoid and widely distributed in the plants. Pretreatment with luteolin inhibited LPS-induced histological changes of ALI and lung tissue edema. In addition, LPS-induced inflammatory responses, including increased vascular permeability, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 production, and expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), were also reduced by luteolin in a concentration-dependent manner. Furthermore, luteolin suppressed activation of NFkappaB and its upstream molecular factor, Akt. These results suggest that the protection mechanism of luteolin is by inhibition of NFkappaB activation possibly via Akt. PMID- 22203871 TI - Barriers to integration of traditional and complementary medicine in supportive cancer care of arab patients in northern Israel. AB - In 2008, an Integrative Oncology Program (IOP), aiming to improve patients' quality of life during chemotherapy and advanced cancer, was launched within the Clalit Health Organization's oncology service at the Lin Medical Center, Haifa, Israel. The IOP clinical activity is documented using a research-based registry protocol. In this study, we present an analysis of the registry protocol of 15 Arab patients with cancer who were referred to the IOP. Analysis of patients' reported outcomes using the Edmonton Symptom Assessment Scale suggests that integrative medicine care improves fatigue (P = 0.024), nausea (P = 0.043), depression (P = 0.012), anxiety (P = 0.044), appetite (P = 0.012), and general well-being (P = 0.031). Barriers to integration of traditional and complementary medicine in supportive care of Arab patients are discussed followed by six practical recommendations aimed at improving accessibility of patients to integrative supportive care, as well as compliance with treatments. PMID- 22203872 TI - Ixora parviflora Protects against UVB-Induced Photoaging by Inhibiting the Expression of MMPs, MAP Kinases, and COX-2 and by Promoting Type I Procollagen Synthesis. AB - Ixora parviflora with high polyphenol content exhibited antioxidant activity and reducing UVB-induced intracellular reactive oxygen species production. In this study, results of the photoaging screening experiments revealed that IPE at 1000 MUg/mL reduced the activity of bacterial collagenase by 92.7 +/- 4.2% and reduced the activity of elastase by 32.6 +/- 1.4%. Therefore, we investigated the mechanisms by which IPE exerts its anti-photoaging activity. IPE at 1 MUg/mL led to an increase in type I procollagen expression and increased total collagen synthesis in fibroblasts at 5 MUg/mL. We found that IPE inhibited MMP-1, MMP-3, and MMP-9 expression at doses of 1, 5, and 10 MUg/mL, respectively, in fibroblasts exposed to UV irradiation (40 mJ/cm(2)). Gelatin zymography assay showed that IPE at 50 MUg/mL inhibited MMP-9 secretion/activity in cultured fibroblasts after UVB exposure. In addition, IPE inhibited the phosphorylation of p38, ERK, and JNK induced by UVB. Furthermore, IPE inhibited the UVB-induced expression of Smad7. In addition, IPE at 1 MUg/mL inhibited NO production and COX 2 expression in UV-exposed fibroblasts. These findings show that IPE exhibits anti-inflammatory and anti-photoaging activities, indicating that IPE could be a potential anti-aging agent. PMID- 22203874 TI - Exploring the Links between Ethnobotany, Local Therapeutic Practices, and Protected Areas in Santa Catarina Coastline, Brazil. AB - We investigated the knowledge of medicinal plants in two areas proposed for the creation of protected areas for sustainable use in the city of Imbituba (SC). In this study, we analyzed the influence of gender, form of learning, and modern medicine on medicinal plant knowledge while also reflecting on the relationship of this knowledge to in situ conservation. Data collection was conducted through structured interviews, free listings, guided tours, and collection of botanical material. 197 species of medicinal plants belonging to 70 botanical families were recorded. Gender and the form of learning were factors that significantly influenced the similarity of the knowledge of medicinal plants among the informants. We also observed the existence of a therapeutic pluralism among key informants. Local medicinal plant knowledge emphasizes the importance of strategies to create protected areas of sustainable use as a way to ensure the maintenance of traditional lifestyles and associated local knowledge. PMID- 22203873 TI - The effect of traditional cupping on pain and mechanical thresholds in patients with chronic nonspecific neck pain: a randomised controlled pilot study. AB - Introduction. Cupping has been used since antiquity in the treatment of pain conditions. In this pilot study, we investigated the effect of traditional cupping therapy on chronic nonspecific neck pain (CNP) and mechanical sensory thresholds. Methods. Fifty CNP patients were randomly assigned to treatment (TG, n = 25) or waiting list control group (WL, n = 25). TG received a single cupping treatment. Pain at rest (PR), pain related to movement (PM), quality of life (SF 36), Neck Disability Index (NDI), mechanical detection (MDT), vibration detection (MDT), and pressure pain thresholds (PPT) were measured before and three days after a single cupping treatment. Patients also kept a pain and medication diary (PaDi, MeDi) during the study. Results. Baseline characteristics were similar in the two groups. After cupping TG reported significantly less pain (PR: -17.9 mm VAS, 95%CI -29.2 to -6.6; PM: -19.7, 95%CI -32.2 to -7.2; PaDi: -1.5 points on NRS, 95%CI -2.5 to -0.4; all P < 0.05) and higher quality of life than WL (SF-36, Physical Functioning: 7.5, 95%CI 1.4 to 13.5; Bodily Pain: 14.9, 95%CI 4.4 to 25.4; Physical Component Score: 5.0, 95%CI 1.4 to 8.5; all P < 0.05). No significant effect was found for NDI, MDT, or VDT, but TG showed significantly higher PPT at pain-areas than WL (in lg(kPa); pain-maximum: 0.088, 95%CI 0.029 to 0.148, pain-adjacent: 0.118, 95%CI 0.038 to 0.199; both P < 0.01). Conclusion. A single application of traditional cupping might be an effective treatment for improving pain, quality of life, and hyperalgesia in CNP. PMID- 22203875 TI - In Vitro Antibacterial Activity of Galls of Quercus infectoria Olivier against Oral Pathogens. AB - The galls of Quercus infectoria are commonly used in Malay traditional medicine to treat wound infections after childbirth. In India, they are employed traditionally as dental applications such as that in treatment of toothache and gingivitis. The aim of the present study was to evaluate the antibacterial activity of galls of Quercus infectoria Olivier against oral bacteria which are known to cause dental caries and periodontitis. Methanol and acetone extracts were screened against two Gram-positive bacteria (Streptococcus mutans ATCC 25175 and Streptococcus salivarius ATCC 13419) and two Gram-negative bacteria (Porphyromonas gingivalis ATCC 33277 and Fusobacterium nucleatum ATCC 25586). The screening test of antibacterial activity was performed using agar-well diffusion method. Subsequently, minimum inhibitory concentration (MIC) was determined by using twofold serial microdilution method at a concentration ranging between 0.01 mg/mL and 5 mg/mL. Minimum bactericidal concentration (MBC) was obtained by subculturing microtiter wells which showed no changes in colour of the indicator after incubation. Both extracts showed inhibition zones which did not differ significantly (P < 0.05) against each tested bacteria. Among all tested bacteria, S. salivarius was the most susceptible. The MIC ranges for methanol and acetone extracts were the same, between 0.16 and 0.63 mg/mL. The MBC value, for methanol and acetone extracts, was in the ranges 0.31-1.25 mg/mL and 0.31-2.50 mg/mL, respectively. Both extracts of Q. infectoria galls exhibited similar antibacterial activity against oral pathogens. Thus, the galls may be considered as effective phytotherapeutic agents for the prevention of oral pathogens. PMID- 22203876 TI - Acupuncture for treatment of autism spectrum disorders. AB - Background. There has been lack of reviews of evidence on efficacy, methodology, and/or safety of acupuncture in autism spectrum disorders. This paper examines the emerging evidence of the effects of acupuncture in the treatment of autistic children. Method. A literature review was completed via Medline and three Chinese search engines. A total of 31 studies were evaluated for acupuncture methodology, study design, treatment effects, and tolerability. Results. The acupoints used, the duration of needling, the frequency of treatment, the choice of stimulation, and the course of the treatment were highly variable amongst the studies. Behavioral and/or developmental improvements were reported in all acupuncture treatment studies. All studies reported general tolerability. Weakness of experimental designs was discussed. Conclusions. Vigorously controlled double blinded clinical trials are needed to evaluate the efficacy and safety of acupuncture in children with autism spectrum disorders. PMID- 22203877 TI - Induction of Mitochondria-Mediated Apoptosis in Ca Ski Human Cervical Cancer Cells Triggered by Mollic Acid Arabinoside Isolated from Leea indica. AB - Leea indica is a medicinal plant traditionally used to treat cancer. Through bioassay-guided approach, we isolated mollic acid arabinoside (MAA), for the first time from Leea indica. Here, we present the apoptosis-inducing effect of MAA on Ca Ski cervical cancer cells. Based on DAPI staining, MAA-treated cells manifested nuclear shrinkage, condensation, and fragmentation. We further confirmed the fragmentation of DNA using TUNEL assay. During early apoptosis, MAA caused the perturbation of plasma membrane through externalization of PS, followed by the formation of apoptotic blebs. Prior to these events, MAA triggered rapid dissipation of the mitochondrial membrane potential. In the upstream, MAA increased the expression of Bax, decreased the expression of Bcl-2, and augmented the Bax/Bcl-2 ratio. These findings suggested that MAA induced mitochondrial-mediated apoptosis in Ca Ski cells and thus provide the scientific explanation for the traditional application of this herbal medicine in cancer treatment. PMID- 22203878 TI - Reflections on palliative care from the jewish and islamic tradition. AB - Spiritual care is a vital part of holistic patient care. Awareness of common patient beliefs will facilitate discussions about spirituality. Such conversations are inherently good for the patient, deepen the caring staff patient-family relationship, and enhance understanding of how beliefs influence care decisions. All healthcare providers are likely to encounter Muslim patients, yet many lack basic knowledge of the Muslim faith and of the applications of Islamic teachings to palliative care. Similarly, some of the concepts underlying positive Jewish approaches to palliative care are not well known. We outline Jewish and Islamic attitudes toward suffering, treatment, and the end of life. We discuss our religions' approaches to treatments deemed unnecessary by medical staff, and consider some of the cultural reasons that patients and family members might object to palliative care, concluding with specific suggestions for the medical team. PMID- 22203879 TI - Antiasthmatic Effects of Herbal Complex MA and Its Fermented Product MA128. AB - This study was conducted to determine if oral administration of the novel herbal medicine, MA, and its Lactobacillus acidophilus fermented product, MA128, have therapeutic properties for the treatment of asthma. Asthma was induced in BALB/c mice by systemic sensitization to ovalbumin (OVA) followed by intratracheal, intraperitoneal, and aerosol allergen challenges. MA and MA128 were orally administered 6 times a week for 4 weeks. At 1 day after the last ovalbumin exposure, airway hyperresponsiveness was assessed and samples of bronchoalveolar lavage fluid, lung cells, and serum were collected for further analysis. We investigated the effect of MA and MA128 on airway hyperresponsiveness, pulmonary eosinophilic infiltration, various immune cell phenotypes, Th2 cytokine production, OVA-specific IgE production, and Th1/Th2 cytokine production in this mouse model of asthma. In BALB/c mice, we found that MA and MA128 treatment suppressed eosinophil infiltration into airways and blood, allergic airway inflammation and AHR by suppressing the production of IL-5, IL-13, IL-17, Eotaxin, and OVA-specific IgE, by upregulating the production of OVA-specific Th1 cytokine (IFN-gamma), and by downregulating OVA-specific Th2 cytokine (IL-4) in the culture supernatant of spleen cells. The effectiveness of MA was increased by fermentation with Lactobacillus acidophilus. PMID- 22203880 TI - Spore Powder of Ganoderma lucidum Improves Cancer-Related Fatigue in Breast Cancer Patients Undergoing Endocrine Therapy: A Pilot Clinical Trial. AB - The fatigue prevalence in breast cancer survivors is high during the endocrine treatment. However, there are few evidence-based interventions to manage this symptom. The aim of this study was to investigate the effectiveness of spore powder of Ganoderma lucidum for cancer-related fatigue in breast cancer patients undergoing endocrine therapy. Spore powder of Ganoderma lucidum is a kind of Basidiomycete which is a widely used traditional medicine in China. 48 breast cancer patients with cancer-related fatigue undergoing endocrine therapy were randomized into the experimental or control group. FACT-F, HADS, and EORTC QLQ C30 questionnaires data were collected at baseline and 4 weeks after treatment. The concentrations of TNF-alpha, IL-6, and liver-kidney functions were measured before and after intervention. The experimental group showed statistically significant improvements in the domains of physical well-being and fatigue subscale after intervention. These patients also reported less anxiety and depression and better quality of life. Immune markers of CRF were significantly lower and no serious adverse effects occurred during the study. This pilot study suggests that spore powder of Ganoderma lucidum may have beneficial effects on cancer-related fatigue and quality of life in breast cancer patients undergoing endocrine therapy without any significant adverse effect. PMID- 22203881 TI - Hypocholesterolemic and hepatoprotective effects of "triguero" asparagus from andalusia in rats fed a high cholesterol diet. AB - The cultivated species of the wild autochthonous Asparagus officinalis in Andalusia in Spain is commonly called "triguero" asparagus. This vegetable has traditionally been very much appreciated for its organoleptic and nutritional characteristics. This study has been designed to evaluate the potential effect of different concentrations of freeze-dried asparagus (500, 250, and 125 mg/Kg of body weight/day) on oxidative status and lipid profile in rats fed a cholesterol rich diet. After five weeks of treatment, doses of 250 and 500 mg/Kg of asparagus were able to significantly reduce total cholesterol and LDL cholesterol levels. Atherogenic index was also significantly reduced in a dose-dependent manner by administrating freeze-dried asparagus. A beneficial effect was observed in the HDL cholesterol levels in asparagus-fed groups although the increase was not significant. Consumption of asparagus also improved antioxidant status, assayed superoxide dismutase (SOD) and catalase (CAT) enzymes, and protected against lipid peroxidation. These results show that the intake of green asparagus from Andalusia (Spain) helps to regulate plasma lipid levels and prevents oxidative damage in hypercholesterolemic conditions. PMID- 22203882 TI - A systematic review of the effect of expectancy on treatment responses to acupuncture. AB - Randomised controlled trials (RCTs) of acupuncture often find equivalent responses to real and placebo acupuncture despite both appearing superior to no treatment. This raises questions regarding the mechanisms of acupuncture, especially the contribution of patient expectancies. We systematically reviewed previous research assessing the relationship between expectancy and treatment responses following acupuncture, whether real or placebo. To be included, studies needed to assess and/or manipulate expectancies about acupuncture and relate these to at least one health-relevant outcome. Nine such independent studies were identified through systematic searches of Medline, PsycInfo, PubMed, and Cochrane Clinical Trials Register. The methodology and reporting of these studies were quite heterogeneous, meaning that meta-analysis was not possible. A descriptive review revealed that five studies found statistically significant effects of expectancy on a least one outcome, with three also finding evidence suggestive of an interaction between expectancy and type of acupuncture (real or placebo). While there were some trends in significant effects in terms of study characteristics, their generality is limited by the heterogeneity of study designs. The differences in design across studies highlight some important methodological considerations for future research in this area, particularly regarding whether to assess or manipulate expectancies and how best to assess expectancies. PMID- 22203883 TI - Tanshinone IIA Inhibits Growth of Keratinocytes through Cell Cycle Arrest and Apoptosis: Underlying Treatment Mechanism of Psoriasis. AB - The aim of the present investigation was to elucidate the cellular mechanisms whereby Tanshinone IIA (Tan IIA) leads to cell cycle arrest and apoptosis in vitro in keratinocytes, the target cells in psoriasis. Tan IIA inhibited proliferation of mouse keratinocytes in a dose- and time-dependent manner and induced apoptosis, resulting in S phase arrest accompanied by down-regulation of pCdk2 and cyclin A protein expression. Furthermore, Tan IIA-induced apoptosis and mitochondrial membrane potential changes were also further demonstrated by DNA fragmentation, single-cell gel electrophoresis assay (SCGE), and flow cytometry methods. Apoptosis was partially blocked by the caspase-3 inhibitor Ac-DEVD-CHO. Mitochondrial regulation of apoptosis further downstream was investigated, showing changes in the mitochondrial membrane potential, cytochrome c release into the cytoplasm, and enhanced activation of cleaved caspase-3 and Poly ADP ribose polymerase (PARP). There was also no translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus in apoptotic keratinocytes, indicating Tan IIA-induced apoptosis occurs mainly through the caspase pathway. Our findings provide the molecular mechanisms by which Tan IIA can be used to treat psoriasis and support the traditional use of Salvia miltiorrhiza Bungee (Labiatae) for psoriasis and related skin diseases. PMID- 22203885 TI - Distribution and transmission of medicinal plant knowledge in the andean highlands: a case study from peru and bolivia. AB - This paper presents a study of patterns in the distribution and transmission of medicinal plant knowledge in rural Andean communities in Peru and Bolivia. Interviews and freelisting exercises were conducted with 18 households at each study site. The amount of medicinal plant knowledge of households was compared in relation to their socioeconomic characteristics. Cluster analysis was applied to identify households that possessed similar knowledge. The different modes of knowledge transmission were also assessed. Our study shows that while the amount of plant knowledge is determined by individual motivation and experience, the type of knowledge is influenced by the community of residence, age, migratory activity, and market integration. Plant knowledge was equally transmitted vertically and horizontally, which indicates that it is first acquired within the family but then undergoes transformations as a result of subsequent contacts with other knowledge sources, including age peers. PMID- 22203886 TI - Long-term prediction of emergency department revenue and visitor volume using autoregressive integrated moving average model. AB - This study analyzed meteorological, clinical and economic factors in terms of their effects on monthly ED revenue and visitor volume. Monthly data from January 1, 2005 to September 30, 2009 were analyzed. Spearman correlation and cross correlation analyses were performed to identify the correlation between each independent variable, ED revenue, and visitor volume. Autoregressive integrated moving average (ARIMA) model was used to quantify the relationship between each independent variable, ED revenue, and visitor volume. The accuracies were evaluated by comparing model forecasts to actual values with mean absolute percentage of error. Sensitivity of prediction errors to model training time was also evaluated. The ARIMA models indicated that mean maximum temperature, relative humidity, rainfall, non-trauma, and trauma visits may correlate positively with ED revenue, but mean minimum temperature may correlate negatively with ED revenue. Moreover, mean minimum temperature and stock market index fluctuation may correlate positively with trauma visitor volume. Mean maximum temperature, relative humidity and stock market index fluctuation may correlate positively with non-trauma visitor volume. Mean maximum temperature and relative humidity may correlate positively with pediatric visitor volume, but mean minimum temperature may correlate negatively with pediatric visitor volume. The model also performed well in forecasting revenue and visitor volume. PMID- 22203884 TI - A systematic review and meta-analysis of efficacy, cost-effectiveness, and safety of selected complementary and alternative medicine for neck and low-back pain. AB - Background. Back pain is a common problem and a major cause of disability and health care utilization. Purpose. To evaluate the efficacy, harms, and costs of the most common CAM treatments (acupuncture, massage, spinal manipulation, and mobilization) for neck/low-back pain. Data Sources. Records without language restriction from various databases up to February 2010. Data Extraction. The efficacy outcomes of interest were pain intensity and disability. Data Synthesis. Reports of 147 randomized trials and 5 nonrandomized studies were included. CAM treatments were more effective in reducing pain and disability compared to no treatment, physical therapy (exercise and/or electrotherapy) or usual care immediately or at short-term follow-up. Trials that applied sham-acupuncture tended towards statistically nonsignificant results. In several studies, acupuncture caused bleeding on the site of application, and manipulation and massage caused pain episodes of mild and transient nature. Conclusions. CAM treatments were significantly more efficacious than no treatment, placebo, physical therapy, or usual care in reducing pain immediately or at short-term after treatment. CAM therapies did not significantly reduce disability compared to sham. None of the CAM treatments was shown systematically as superior to one another. More efforts are needed to improve the conduct and reporting of studies of CAM treatments. PMID- 22203887 TI - Mineral-Based Amendments for Remediation. AB - Amending soils with mineral-based materials to immobilize contaminants is both old and new. Although mineral amendments have been used for decades in agriculture, new applications with a variety of natural and reprocessed materials are emerging. By sequestering contaminants in or on solid phases and reducing their ability to partition into water or air, amendments can reduce the risk of exposure to humans or biota. A variety of mineral types are commonly used to amend contaminated soils, with different modes of molecular-scale sequestration. Regulatory, social, and economic factors also influence decisions to employ mineral amendments as a treatment technology. PMID- 22203888 TI - Clinical Aspects of Dermatitis Associated with Dirofilaria repens in Pets: A Review of 100 Canine and 31 Feline Cases (1990-2010) and a Report of a New Clinic Case Imported from Italy to Dubai. AB - Cutaneous dirofilariasis is a parasitic disease caused by the mosquito-borne filarial nematodes Dirofilaria (Nochtiella) repens, living in the subcutaneous tissue of dogs, cats, wild carnivores, and humans. Cases have been recently reported also from Germany, Czech Republic, Hungary, Ukraine, Russia, Austria, Switzerland, France, The Netherlands, and the Middle East. D. repens is not widely known to cause chronic pruritic dermatitis in animals. Dermatological signs observed in 100 canine clinic cases were pruritus (100%), erythema (79%), papulae (62%), focal or multifocal alopecia (55%), hyperkeratosis (18%), crusting (14%), nodules (12%), acantosis (5%), and eczema (3%). Signs other than dermatological were conjunctivitis (46%), anorexia (35%), vomiting (26%), fever (25%), lethargy (20%), and lymph-adenomegaly (10%). A case imported from Italy to Dubai is described. The opportunistic role of D. repens might explain the presence of asymptomatic carriers, the concurrent observation of nondermatological signs, and the development of dermatitis in a subgroup of parasitized dogs. PMID- 22203890 TI - Early life stress and child temperament style as predictors of childhood anxiety and depressive symptoms: findings from the longitudinal study of Australian children. AB - Objective. The purpose of this study was to determine whether the relationship between stressful infant environments and later childhood anxiety and depressive symptoms varies as a function of individual differences in temperament style. Methods. Data was drawn from the Longitudinal Study of Australian Children (LSAC). This study examined 3425 infants assessed at three time points, at 1 year, at 2/3 years and at 4/5 years. Temperament was measured using a 12-item version of Toddler Temperament Scale (TTS) and was scored for reactive, avoidant, and impulsive dimensions. Logistic regression was used to model direct relationships and additive interactions between early life stress, temperament, and emotional symptoms at 4 years of age. Analyses were adjusted for socioeconomic status, parental education, and marital status. Results. Stressful family environments experienced in the infant's first year of life (high versus low) and high reactive, avoidant, and impulsive temperament styles directly and independently predicted anxiety and depressive problems in children at 4 years of age. There was no evidence of interaction between temperament and family stress exposure. Conclusions. Both infant temperament and stress exposures are independent and notable predictors of later anxiety and depressive problems in childhood. The risk relationship between stress exposure in infancy and childhood emotion problems did not vary as a function of infant temperament. Implications for preventive intervention and future research directions are discussed. PMID- 22203889 TI - Alternative Splicing of Fibroblast Growth Factor Receptor IgIII Loops in Cancer. AB - Alternative splicing of the IgIII loop of fibroblast growth factor receptors (FGFRs) 1-3 produces b- and c-variants of the receptors with distinctly different biological impact based on their distinct ligand-binding spectrum. Tissue specific expression of these splice variants regulates interactions in embryonic development, tissue maintenance and repair, and cancer. Alterations in FGFR2 splicing are involved in epithelial mesenchymal transition that produces invasive, metastatic features during tumor progression. Recent research has elucidated regulatory factors that determine the splice choice both on the level of exogenous signaling events and on the RNA-protein interaction level. Moreover, methodology has been developed that will enable the in depth analysis of splicing events during tumorigenesis and provide further insight on the role of FGFR 1-3 IIIb and IIIc in the pathophysiology of various malignancies. This paper aims to summarize expression patterns in various tumor types and outlines possibilities for further analysis and application. PMID- 22203891 TI - Temperament and character in psychotic depression compared with other subcategories of depression and normal controls. AB - Background. Support has been found for high harm avoidance as general vulnerability trait for depression and decreased self-directedness (SD) as central state-related personality change. Additional personality characteristics could be present in psychotic depression (PD). Increased noradrenergic activation in PD predicts the involvement of reward dependence (RD). Methods. The data during the acute episode and after full remission from the same subjects, that we used before, were reanalyzed. The dependence of the 7 dimensions of the Temperament and Character Inventory version 9 on PD, three other subcategories of depression, and a group of normal controls was tested by MANCOVA. Results. Low RD at both time points, and low Cooperativeness during the acute episode, were found as additional characteristics of PD. Conclusion. The combination of two premorbid temperaments, high HA and low RD, and the development of a state-related reduction of two character functions, SD and CO, may be the precondition for the development of combined depressive and psychotic psychopathology. PMID- 22203892 TI - An Increase of the Character Function of Self-Directedness Is Centrally Involved in Symptom Reduction during Remission from Major Depression. AB - Background. Studies with the Temperament and Character Inventory (TCI) in depressive disorders have shown changes (Delta) of the character of Self Directedness (SD) and the temperament of Harm Avoidance (HA). The central question of this study is which of these two changes is most proximally related to the production of depressive symptoms. Methods. The start and endpoint data from a two-year followup of 58 depressed patients were reanalyzed. We used the DeltaHA and DeltaSD scores as well as the Delta scores on three dimensions of psychopathology, called Emotional Dysregulation (ED), Retardation (RET), and Anxiety (ANX). The presence of the main relation between personality and psychopathology was tested in all patients and in four subcategories. The data were analyzed by MANCOVA and Structural Equation Modelling (SEM). Results. DeltaHA and DeltaSD correlated negatively, and only DeltaSD was related (negatively) to DeltaED. This pattern was found in all subcategories. SEM showed DeltaHA and DeltaSD had an ambiguous causal interrelationship, while DeltaSD, DeltaRET, and DeltaANX had unidirectional effects on DeltaED. Conclusion. The results correspond with a central pathogenetic role for a state-related deficit at the character level in depression. This may have important consequences for investigations of endophenotypes and clinical treatment. PMID- 22203893 TI - Cognitive reactivity to success and failure relate uniquely to manic and depression tendencies and combine in bipolar tendencies. AB - The present study examined simultaneously the relations between cognitive reactivity to success and failure, on the one hand, and depression, manic, and bipolar tendencies, on the other hand. Participants (161 students) completed measures of success and failure reactivity, current manic and depressive symptoms, and tendencies towards depression, mania, and bipolarity. Results showed that respondents with a greater tendency towards depression evidenced greater (negative) reactivity to failure, whereas those with a greater tendency toward mania evidenced greater (positive) reactivity to success. Depression vulnerability was unrelated to success reactivity, and manic vulnerability was unrelated to failure reactivity. Tendencies toward bipolarity correlated significantly with both failure and success reactivity in a negative and positive manner, respectively. These findings add to the growing body of literature, suggesting that different features or cognitive tendencies are related to depression vulnerability versus manic vulnerability and imply that these "mirrored" cognitive features both form part of vulnerability to bipolar disorder. PMID- 22203894 TI - Do we really know how to treat a child with bipolar disorder or one with severe mood dysregulation? Is there a magic bullet? AB - Background. Despite controversy, bipolar disorder (BD) is being increasingly diagnosed in under 18s. There is scant information regarding its treatment and uncertainty regarding the status of "severe mood dysregulation (SMD)" and how it overlaps with BD. This article collates available research on treatment of BD in under 18s and explores the status of SMD. Methods. Literature on treatment of BD in under 18s and on SMD were identified using major search engines; these were then collated and reviewed. Results. Some markers have been proposed to differentiate BD from disruptive behaviour disorders (DBD) in children. Pharmacotherapy restricted to short-term trials of mood-stabilizers and atypical antipsychotics show mixed results. Data on maintenance treatment and non pharmacological interventions are scant. It is unclear whether SMD is an independent disorder or an early manifestation of another disorder. Conclusions. Valproate, lithium, risperidone, olanzapine, aripiprazole and quetiapine remain first line treatments for acute episodes in the under 18s with BD. Their efficacy in maintenance treatment remains unclear. There is no validated treatment for SMD. It is likely that some children who are currently diagnosed with BD and DBD and possibly most children currently diagnosed with SMD will be subsumed under the proposed category in the DSM V of disruptive mood dysregulation disorder with dysphoria. PMID- 22203895 TI - Seasonality and sleep: a clinical study on euthymic mood disorder patients. AB - Background. Research on mood disorders has progressively focused on the study of seasons and on the mood in association with them during depressive or manic episodes yet few studies have focused on the seasonal fluctuation that characterizes the patient's clinical course both during an illness episode and during euthymic periods. Methods. 113 euthymic outpatients 46 affected by major recurrent depression and 67 affected by bipolar disorder were recruited. We evaluated the impact of clinical "rhythmical" factors: seasonality, sleep disturbance, and chronotype. Patients completed the SPAQ+ questionnaire, the MEQ questionnaire, and the medical outcomes study (MOS) sleep scale. We used t-test analyses to compare differences of clinical "rhythmical" and sociodemographic variables and of differences in the assessment scales among the diagnostic groups. Results. Patients reporting a family history for mood disorders have higher fluctuations throughout seasons. Sleep disturbance is more problematic in unipolars when compared to bipolars. Conclusions. Sleep, light, and seasonality seem to be three interconnected features that lie at the basis of chronobiology that, when altered, have an important effect both on the psychopathology and on the treatment of mood disorders. PMID- 22203896 TI - Drosophila SOCS Proteins. AB - The importance of signal transduction cascades such as the EGFR and JAK/STAT pathways for development and homeostasis is highlighted by the high levels of molecular conservation maintained between organisms as evolutionary diverged as fruit flies and humans. This conservation is also mirrored in many of the regulatory mechanisms that control the extent and duration of signalling in vivo. One group of proteins that represent important physiological regulators of both EGFR and JAK/STAT signalling is the members of the SOCS family. Only 3 SOCS-like proteins are encoded by the Drosophila genome, and despite this low complexity, Drosophila SOCS proteins share many similarities to their human homologues. SOCS36E is both a target gene and negative regulator of JAK/STAT signalling while SOCS44A and SOCS36E represent positive and negative regulators of EGFR signalling. Here we review our current understanding of Drosophila SOCS proteins, their roles in vivo, and future approaches to elucidating their functions. PMID- 22203897 TI - Fish Suppressors of Cytokine Signaling (SOCS): Gene Discovery, Modulation of Expression and Function. AB - The intracellular suppressors of cytokine signaling (SOCS) family members, including CISH and SOCS1 to 7 in mammals, are important regulators of cytokine signaling pathways. So far, the orthologues of all the eight mammalian SOCS members have been identified in fish, with several of them having multiple copies. Whilst fish CISH, SOCS3, and SOCS5 paralogues are possibly the result of the fish-specific whole genome duplication event, gene duplication or lineage specific genome duplication may also contribute to some paralogues, as with the three trout SOCS2s and three zebrafish SOCS5s. Fish SOCS genes are broadly expressed and also show species-specific expression patterns. They can be upregulated by cytokines, such as IFN-gamma, TNF-alpha, IL-1beta, IL-6, and IL 21, by immune stimulants such as LPS, poly I:C, and PMA, as well as by viral, bacterial, and parasitic infections in member- and species-dependent manners. Initial functional studies demonstrate conserved mechanisms of fish SOCS action via JAK/STAT pathways. PMID- 22203898 TI - Molecular Crosstalk between Integrins and Cadherins: Do Reactive Oxygen Species Set the Talk? AB - The coordinate modulation of the cellular functions of cadherins and integrins plays an essential role in fundamental physiological and pathological processes, including morphogenesis, tissue differentiation and renewal, wound healing, immune surveillance, inflammatory response, tumor progression, and metastasis. However, the molecular mechanisms underlying the fine-tuned functional communication between cadherins and integrins are still elusive. This paper focuses on recent findings towards the involvement of reactive oxygen species (ROS) in the regulation of cell adhesion and signal transduction functions of integrins and cadherins, pointing to ROS as emerging strong candidates for modulating the molecular crosstalk between cell-matrix and cell-cell adhesion receptors. PMID- 22203899 TI - Cervical myelopathy in rheumatoid arthritis. AB - Involvement of the cervical spine is common in rheumatoid arthritis. Clinical presentation can be variable, and symptoms may be due to neck pain or compressive myeloradiculopathy. We discuss the pathology, grading systems, clinical presentation, indications for surgery and surgical management of cervical myelopathy related to rheumatoid arthritis in this paper. We describe our surgical technique and results. We recommend early consultation for surgical management when involvement of the cervical spine is suspected in rheumatoid arthritis. Even patients with advanced cervical myelopathy should be discussed for surgical treatment, since in our experience improvement in function after surgery is common. PMID- 22203901 TI - Can dynamic contrast-enhanced magnetic resonance imaging combined with texture analysis differentiate malignant glioneuronal tumors from other glioblastoma? AB - An interesting approach has been proposed to differentiate malignant glioneuronal tumors (MGNTs) as a subclass of the WHO grade III and IV malignant gliomas. MGNT histologically resemble any WHO grade III or IV glioma but have a different biological behavior, presenting a survival twice longer as WHO glioblastomas and a lower occurrence of metastases. However, neurofilament protein immunostaining was required for identification of MGNT. Using two complementary methods, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and texture analysis (MRI TA) from the same acquisition process, the challenge is to in vivo identify MGNT and demonstrate that MRI postprocessing could contribute to a better typing and grading of glioblastoma. Results are obtained on a preliminary group of 19 patients a posteriori selected for a blind investigation of DCE T1-weighted and TA at 1.5 T. The optimal classification (0/11 misclassified MGNT) is obtained by combining the two methods, DCE-MRI and MRI-TA. PMID- 22203900 TI - Animal Models of MS Reveal Multiple Roles of Microglia in Disease Pathogenesis. AB - Multiple sclerosis (MS) is a progressive inflammatory and demyelinating disease that affects more than 2.5 million people worldwide every year. Current therapies use mostly disease-modifying drugs, focusing on blocking and regulating systemic functions and the central nervous system (CNS) infiltration of immune cells; however, these therapies only attenuate or delay MS symptoms, but are not effective in halting the disease progression. More recent evidence indicated that regulation of inflammation within the CNS might be a better way to approach the treatment of the disease and microglia, the resident immune cells, may be a promising target of therapeutic studies. Microglia activation classically accompanies MS development, and regulation of microglia function changes the outcome of the disease. In this paper, we review the contributions of microglia to MS pathogenesis and discuss microglial functions in antigen presentation, cytokine release, and phagocytosis. We describe data both from animal and human studies. The significant impact of the timing, intensity, and differentiation fate of activated microglia is discussed, as they can modulate MS outcomes and potentially be critically modified for future therapeutic studies. PMID- 22203902 TI - Establishment of Methylation-Specific PCR for the Mouse p53 Gene. AB - Methylation-specific PCR (MSP) of the mouse p53 gene has not yet been reported. We searched the CpG islands, sequenced the bisulfited DNA, and designed PCR primers for methylation and unmethylation sites. DNA from a young mouse produced a strong PCR product with the unmethylated primer and a weaker band with the methylated primer. DNA from an old mouse produced bands of similar intensities with both primers. In radiation-induced tumors, DNA from an old mouse yielded similar bands with both types of primers. We suggest that MSP is a valuable technique for the epigenetic study of the mouse p53 gene. PMID- 22203903 TI - Neurodegeneration in MS and NMO: The Eye and the Blood. PMID- 22203904 TI - Effect of a Targeted Women's Health Intervention in an Inner-City Emergency Department. AB - Objective. To evaluate the effect of an Emergency Department (ED) based, educational intervention for at-risk health behaviors. Methods. A randomized trial over a one-year period. African American women, aged 21-55, presenting to the ED waiting room were eligible. Each participant took a computer-based survey on health risk behaviors. Participants who screened positive on any of four validated scales (for IPV, nicotine, alcohol, or drug dependence) were randomized to standard information about community resources (control) or to targeted educational handouts based upon their screening results (intervention). Participants were surveyed at 3 months regarding contacts with community resources and harm-reduction actions. Results. 610 women were initially surveyed; 326 screened positive (13.7% for IPV, 40.1% for nicotine addiction, 26.6% for alcohol abuse, and 14.4% for drug abuse). 157 women were randomized to intervention and 169 to control. Among women who completed follow-up (n = 71), women in the Intervention Group were significantly more likely to have contacted local resources (37% versus 9%, P = 0.04) and were more likely to have taken risk reducing action (97% versus 79%, P = 0.04). Conclusion. Targeted, brief educational interventions may be an effective method for targeting risk behaviors among vulnerable ED populations. PMID- 22203906 TI - Liposomes for Targeted Delivery of Active Agents against Neurodegenerative Diseases (Alzheimer's Disease and Parkinson's Disease). AB - Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease represent a huge unmet medical need. The prevalence of both diseases is increasing, but the efficacy of treatment is still very limited due to various factors including the blood brain barrier (BBB). Drug delivery to the brain remains the major challenge for the treatment of all neurodegenerative diseases because of the numerous protective barriers surrounding the central nervous system. New therapeutic drugs that cross the BBB are critically needed for treatment of many brain diseases. One of the significant factors on neurotherapeutics is the constraint of the blood brain barrier and the drug release kinetics that cause peripheral serious side effects. Contrary to common belief, neurodegenerative and neurological diseases may be multisystemic in nature, and this presents numerous difficulties for their potential treatment. Overall, the aim of this paper is to summarize the last findings and news related to liposome technology in the treatment of neurodegenerative diseases and demonstrate the potential of this technology for the development of novel therapeutics and the possible applications of liposomes in the two most widespread neurodegenerative diseases, Alzheimer's disease and Parkinson's disease. PMID- 22203905 TI - Helicopter EMS: Research Endpoints and Potential Benefits. AB - Patients, EMS systems, and healthcare regions benefit from Helicopter EMS (HEMS) utilization. This article discusses these benefits in terms of specific endpoints utilized in research projects. The endpoint of interest, be it primary, secondary, or surrogate, is important to understand in the deployment of HEMS resources or in planning further HEMS outcomes research. The most important outcomes are those which show potential benefits to the patients, such as functional survival, pain relief, and earlier ALS care. Case reports are also important "outcomes" publications. The benefits of HEMS in the rural setting is the ability to provide timely access to Level I or Level II trauma centers and in nontrauma, interfacility transport of cardiac, stroke, and even sepsis patients. Many HEMS crews have pharmacologic and procedural capabilities that bring a different level of care to a trauma scene or small referring hospital, especially in the rural setting. Regional healthcare and EMS system's benefit from HEMS by their capability to extend the advanced level of care throughout a region, provide a "backup" for areas with limited ALS coverage, minimize transport times, make available direct transport to specialized centers, and offer flexibility of transport in overloaded hospital systems. PMID- 22203907 TI - Racial disparities in prostate cancer incidence, biochemical recurrence, and mortality. PMID- 22203908 TI - Cholesterol, C-Reactive Protein, and Periodontitis: HMG-CoA-Reductase Inhibitors (Statins) as Effect Modifiers. AB - Common risk factors of periodontitis and cardiovascular diseases fuel the debate on interrelationships between them. The aim is to prove whether statins may influence periodontal parameters by affecting either of these factors. Out of the 4,290 subjects of SHIP (Study of Health in Pomerania), we included subjects aged >30 years (219 with statins, 2937 without) and excluded edentulous. We determined periodontal measures, cholesterol fractions, and inflammation markers. Statin use and periodontal risk factors were assessed. Gingival plaque and periodontal attachment loss were associated with systemic LDL cholesterol (P < 0.001) and C reactive protein CRP (P = 0.019) revealing interaction with statin use. When adjusted for age, sex, smoking, diabetes, education, and dental service, statins were identified as effect modifiers abolishing the relationship between attachment loss and LDL and between gingival plaque and LDL (interactions P < 0.001). No statin-related interaction was detected with increase in CRP. The interaction supports the view of inter-relationships between periodontal and systemic inflammatory mediators. PMID- 22203909 TI - Study of emotional effects of tooth loss in an aging north Indian community. AB - A study was conducted to study the emotional effects of complete and partial loss of teeth in an aging North Indian community. A questionnaire was prepared for 400 elderly people above the age of 60 years, who were interviewed in dental checkup camps. The data was collected and analyzed using chi-square or chi-square exact tests. 25% of the people were found to have difficulty accepting tooth loss, whereas more than 50% of the people reported to have restricted their food choices. Other problems like reduced attendance in social gatherings for lunch/dinner or eating out in public were also noted. 56% felt that dental consultation prior to tooth loss would have helped them in a significant way. It was concluded that tooth loss did not have a marked impact on emotions of the people but affected their daily social activities, however there was negligible difference between complete and partial tooth loss subjects. PMID- 22203910 TI - Preoperative computed tomography-derived bone densities in hounsfield units at implant sites acquired primary stability. AB - The purpose of this study was to evaluate preoperative CT-derived bone densities in Hounsfield units (HU) at implant sites that acquired primary stability, and to compare these values to the optimal bone densities proposed in the literature. Fifty-one patients, 18 males (37 implant sites) and 33 females (67 implant sites) between 2003 and 2010 were assessed. CT data for different jaw sections, regions, and operating procedures were compared using the Kruskal-Wallis test and Scheffe's test for multiple comparisons (P < 0.05). The mean bone density in the maxilla was significantly lower than that in the mandible (P < 0.05); the mean bone densities in the 4 jaw regions decreased in the following order: anterior mandible > anterior maxilla > posterior mandible > posterior maxilla. The bone densities assessed by HU fell into the range of optimal bone densities associated with acquired primary implant stability proposed in the literature. PMID- 22203911 TI - Analysis of IL-1alpha(-889) and IL-1B(+3953) Gene Polymorphism in Syrian Patients with Aggressive Periodontitis: A Pilot Study. AB - Polymorphisms in IL-1 gene have been suggested to influence transcription of IL 1alpha and IL-1B and thereby the pathophysiology of periodontitis. Using genotyping IL-1 test, a pilot study was conducted on 32 Syrian patients with aggressive periodontitis (AgP) and 35 healthy controls to investigate the association between the IL-1alpha(-889), IL-1B(+3953) gene polymorphisms and AgP among schoolchildren. The results revealed a similar distribution of genotypes between patients and controls, and did not support an association between IL-1 gene polymorphisms and AgP, however, the association was significant in male patients only. To determine and confirm any susceptible or resistant genes for AgP, future studies should use many target genes and well-defined related periodontal outcomes. PMID- 22203912 TI - Volume-Based Care among Young Women Diagnosed with Uterine Cancer. AB - Purpose. To characterize volume-based care of uterine cancer among women aged <=50 years. Methods. The Maryland Health Service Cost Review Commission database was accessed for uterine cancer surgical cases from 1994 to 2005. Cross tabulations and logistic regression models were used to evaluate for significant associations among volume-based care and other variables comparing women <=50 years with those aged >50 years. Results. Women <=50 years comprised 13.6% of the cases. Women <=50 years were less likely to be managed by high-volume surgeons (31.6% versus 35.1%, P = 0.02). For women <=50 years, there was a trend toward management at low-volume hospitals (52.0% versus 54.0%, P = 0.22). No deaths were reported among the group of women <=50 years treated by high-volume providers or at high-volume centers. Women <=50 years managed by high-volume surgeons had longer length of stay (P < 0.001) and higher adjusted cost of hospital-related care (P < 0.00). Women <=50 years managed at high-volume centers had higher adjusted cost of hospital-related care (P = 0.01). Conclusion. Primary surgical care of young women with uterine cancer is often performed by low-volume providers. PMID- 22203913 TI - Iron inhibits respiratory burst of peritoneal phagocytes in vitro. AB - Objective. This study examines the effects of iron ions Fe(3+) on the respiratory burst of phagocytes isolated from peritoneal effluents of continuous ambulatory peritoneal dialysis (CAPD) patients, as an in vitro model of iron overload in end stage renal disease (ESRD). Material and Methods. Respiratory burst of peritoneal phagocytes was measured by chemiluminescence method. Results. At the highest used concentration of iron ions Fe(3+) (100 MUM), free radicals production by peritoneal phagocytes was reduced by 90% compared to control. Conclusions. Iron overload may increase the risk of infectious complications in ESRD patients. PMID- 22203914 TI - Circuit mechanisms of memory formation. PMID- 22203916 TI - C-reactive protein levels in the brugada syndrome. AB - Background. Inflammation in the Brugada syndrome (BrS) and its clinical implication have been little studied. Aims. To assess the level of inflammation in BrS patients. Methods. All studied BrS patients underwent blood samples drawn for C-reactive protein (CRP) levels at admission, prior to any invasive intervention. Patients with a previous ICD placement were controlled to exclude those with a recent (<14 days) shock. We divided subjects into symptomatic (syncope or aborted sudden death) and asymptomatic groups. In a multivariable analysis, we adjusted for significant variables (age, CRP >= 2 mg/L). Results. Fifty-four subjects were studied (mean age 45 +/- 13 years, 49 (91%) male). Twenty (37%) were symptomatic. Baseline characteristics were similar in both groups. Mean CRP level was 1,4 +/- 0,9 mg/L in asymptomatic and 2,4 +/- 1,4 mg/L in symptomatic groups (P = .003). In the multivariate model, CRP concentrations >= 2 mg/L remained an independent marker for being symptomatic (P = .018; 95% CI: 1.3 to 19.3). Conclusion. Inflammation seems to be more active in symptomatic BrS. C-reactive protein concentrations >= 2 mg/L might be associated with the previous symptoms in BrS. The value of inflammation as a risk factor of arrhythmic events in BrS needs to be studied. PMID- 22203915 TI - Spines, plasticity, and cognition in Alzheimer's model mice. AB - The pathological hallmarks of Alzheimer's disease (AD)--widespread synaptic and neuronal loss and the pathological accumulation of amyloid-beta peptide (Abeta) in senile plaques, as well as hyperphosphorylated tau in neurofibrillary tangles- have been known for many decades, but the links between AD pathology and dementia and effective therapeutic strategies remain elusive. Transgenic mice have been developed based on rare familial forms of AD and frontotemporal dementia, allowing investigators to test in detail the structural, functional, and behavioral consequences of AD-associated pathology. Here, we review work on transgenic AD models that investigate the degeneration of dendritic spine structure, synaptic function, and cognition. Together, these data support a model of AD pathogenesis in which soluble Abeta initiates synaptic dysfunction and loss, as well as pathological changes in tau, which contribute to both synaptic and neuronal loss. These changes in synapse structure and function as well as frank synapse and neuronal loss contribute to the neural system dysfunction which causes cognitive deficits. Understanding the underpinnings of dementia in AD will be essential to develop and evaluate therapeutic approaches for this widespread and devastating disease. PMID- 22203917 TI - Lifestyle risk factors and cardiovascular disease in cubans and cuban americans. AB - Cardiovascular disease is the leading cause of mortality in Cuba. Lifestyle risk factors for coronary heart disease (CHD) in Cubans have not been compared to risk factors in Cuban Americans. Articles spanning the last 20 years were reviewed. The data on Cuban Americans are largely based on the Hispanic Health and Nutrition Examination Survey (HHANES), 1982-1984, while more recent data on epidemiological trends in Cuba are available. The prevalence of obesity and type 2 diabetes mellitus remains greater in Cuban Americans than in Cubans. However, dietary preferences, low physical activity, and tobacco use are contributing to the rising rates of obesity, type 2 diabetes mellitus, and CHD in Cuba, putting Cubans at increased cardiovascular risk. Comprehensive national strategies for cardiovascular prevention that address these modifiable lifestyle risk factors are necessary to address the increasing threat to public health in Cuba. PMID- 22203918 TI - Free thyroxine level in the high normal reference range prescribed for nonpregnant women may reduce the preterm delivery rate in multiparous. AB - Preterm birth is the most common reason for perinatal morbidity and mortality in the western world. It has been shown that in euthyreotic pregnant women with thyroid autoimmune antibodies, L-Thyroxine replacement reduces preterm delivery rate in singleton pregnancies. We investigated in a nonrandomized retrospective observational study whether L-Thyroxine replacement, maintaining maternal free thyroxine serum level in the high normal reference range prescribed for nonpregnant women also influences the rate of preterm delivery in women without thyroid autoimmune antibodies. As control group for preterm delivery rate, data from perinatal statistics of the State of Baden-Wurttemberg from 2006 were used. The preterm delivery rate in the study group was significantly reduced. The subgroup analysis shows no difference in primiparous but a decline in multiparous by approximately 61% with L-Thyroxine replacement. Maintaining free thyroxine serum level in the high normal reference range prescribed for nonpregnant women may reduce the preterm delivery rate. PMID- 22203919 TI - Neurocognitive correlates of apathy and anxiety in Parkinson's disease. AB - Parkinson's disease (PD) is associated with various nonmotor symptoms including neuropsychiatric and cognitive dysfunction. We examined the relation between apathy, anxiety, side of onset of motor symptoms, and cognition in PD. We hypothesized that PD patients would show different neuropsychiatric and neurocognitive profiles depending on the side of onset. 22 nondemented PD patients (11 right-side onset (RPD) with predominant left-hemisphere pathology, and 11 LPD) and 22 matched healthy controls (NC) were administered rating scales assessing apathy and anxiety, and a series of neuropsychological tests. PD patients showed a higher anxiety level than NC. There was a significant association between apathy, anxiety, and disease duration. In LPD, apathy but not anxiety was associated with performance on nonverbally mediated executive function and visuospatial measures, whereas, in RPD, anxiety but not apathy correlated with performance on verbally mediated tasks. Our findings demonstrated a differential association of apathy and anxiety to cognition in PD. PMID- 22203921 TI - Immunohistochemical assessment of p16, COX-2 and EGFR in HPV-positive cervical squamous intraepithelial lesions. AB - The protein capsid L1 of the human papilloma virus (HPV) - a key factor in the cervical carcinogenesis - is considered, together with p16, EGFR and COX-2, a characteristic marker for the evaluation of the malignancy progression and prognostic, in terms of tumoral aggressiveness. The purpose of the present study was to make a comparative assessment between the immunohistochemical pattern of p16, EGFR and COX-2 and immunochemical expression of L1 HPV capsid protein, in low grade and high-grade cervical squamous intraepithelial lesions, in order to determine the relationship of these tumoral markers with the infection status of HPV, and their practical applicability in patients diagnosis and follow-up. The study group included 50 women with cytological and histopathological confirmed LSIL (low grade SIL) and HSIL (high-grade SIL). The immunoexpression of L1 HPV protein was assessed on conventional cervico-vaginal smears and EGFR, COX-2 and p16 were immunohistochemically evaluated on the corresponding cervical biopsies. From all cervical smears, the HPV L1 capsid protein was expressed in 52% of LSIL and 23% of HSIL. From all cervical biopsies, p16 was positive in 64% of LSIL, 82% of CIN2 and 100% of CIN3, EGFR was overexpressed in 67% of HSIL (56% CIN2 and 43% CIN3) and 32% LSIL. For COX-2, the Allred score was higher in HSIL when compared to LSIL. Our data revealed 33 cases belonging to both LSIL and HSIL categories with the same Allred score. Immunochemical detection of L1 capsid protein, on cervico-vaginal smears, indicates an immune status induced by the HPV infection and may offer prognosis information, mainly in LSIL lesions. The assessment of p16, EGFR, and COX-2 allows to an integrative approach for the progression of squamous intraepithelial lesion, associated or not with the HPV infection. PMID- 22203922 TI - Identifying molecular features for prostate cancer with Gleason 7 based on microarray gene expression profiles. AB - Prostate cancer represents the first leading cause of cancer among western male population, with different clinical behavior ranging from indolent to metastatic disease. Although many molecules and deregulated pathways are known, the molecular mechanisms involved in the development of prostate cancer are not fully understood. The aim of this study was to explore the molecular variation underlying the prostate cancer, based on microarray analysis and bioinformatics approaches. Normal and prostate cancer tissues were collected by macrodissection from prostatectomy pieces. All prostate cancer specimens used in our study were Gleason score 7. Gene expression microarray (Agilent Technologies) was used for Whole Human Genome evaluation. The bioinformatics and functional analysis were based on Limma and Ingenuity software. The microarray analysis identified 1119 differentially expressed genes between prostate cancer and normal prostate, which were up- or down-regulated at least 2-fold. P-values were adjusted for multiple testing using Benjamini-Hochberg method with a false discovery rate of 0.01. These genes were analyzed with Ingenuity Pathway Analysis software and were established 23 genetic networks. Our microarray results provide new information regarding the molecular networks in prostate cancer stratified as Gleason 7. These data highlighted gene expression profiles for better understanding of prostate cancer progression. PMID- 22203924 TI - Sonoelastography of breast lesions: a prospective study of 215 cases with histopathological correlation. AB - BACKGROUND: Elastography is an imaging technique, which displays the hardness of soft tissue, by showing the behavior of tissue when subjected to mechanical stress. The purpose of this study was to assess the role of ultrasound elastography in differential diagnosis of breast lesions. MATERIALS AND METHODS: A prospective study was conducted in our Research Centre, University of Medicine and Pharmacy of Craiova. We introduced in this prospective study 215 patients diagnosed with breast lesions between January 2009 and January 2011. The patients were examined in the supine position and a ductal exploration was made over the breast. The final diagnose was cytology (FNA - fine needle aspiration), histology after excision or follow-up for six months. For obtaining the elastography images, we used a EUS Hitachi EUB 8500 and Siemens ultrasound systems with elastography modules incorporated. For assessment of ultrasound elastography role in differential diagnosis of breast lesions, we performed ROC analysis. RESULTS: The elasticity score for benign lesions was on average 1.95+/-1.1, and for malignant lesions was 4.21+/-0.9. The mean diameter of malignant lesions was 27.3 mm, which was higher than the average diameter of benign lesions (19.9 mm). The most common histology of the benign nodules was fibroadenomas, cysts, and fibrocystic change. Of the malignant nodules, the most common lesion was infiltrative ductal carcinoma. We obtained a sensitivity of 85.3%, and a specificity of 90% (area under the ROC curve=0.908, 95%CI=0.856-0.945 and p=0.0001) when a cut-off point of 3 was used. CONCLUSIONS: Elastography is a method which can complement conventional ultrasound by improving the diagnostic performance. The introduction of ductal ultrasound combined with elastography increased the sensitivity and specificity, the radial technique allowing the precise localization of lesions regarding the breast gland. PMID- 22203923 TI - C677T and A1298C methylenetetrahydropholate reductase (MTHFR) polymorphisms as factors involved in ischemic stroke. AB - BACKGROUND: Ischemic stroke is a major health problem. Data regarding the possible association between ischemic stroke and the polymorphism of methylenetetrahydropholate reductase (MTHFR) C677T and A1298C are still conflictual. AIM: The study tried to assess the association of the two MTHFR polymorphisms with ischemic stroke in a series of patients from a unique hospital center. MATERIALS AND METHODS: The study comprised a total of 127 patients (67 with non-cardioembolic ischemic stroke diagnosed by computed tomography or magnetic resonance imaging) and 60 control cases. The method we used was reverse hybridization performed on peripheral blood for C677T and A1298C polymorphisms. In all patients a careful clinical examination, laboratory analyses of cholesterol, glucose amount and triglycerides, as well as their medical history were available. RESULTS: The mean age of stroke patients was 68.73 years, and 55.2% were males. Gene analysis for C677T disclosed the presence of TT genotype in more control subjects than in stroke series (15% and 7.46% respectively). Also, the overall T allele (CT+TT cases) was present in 71.6% of control cases, as compared with 44.7% stroke patients. 1298C allele was almost equally distributed among the two series. No statistically significant correlations of the two genotypes with infarct localization and dimensions ant with other potential risk factors (hypertension, lipids, diabetes mellitus) were observed. CONCLUSIONS: The two MTHFR polymorphisms, C677T and A1298C, seemed not related to the onset of ischemic stroke in our study. However, they could be rather involved in hemorrhagic stroke, as seen in our control patients. Further evaluation on larger series is mandatory since homocysteine activity (related to MTHFR activity) could be easily influenced by folate or cobalamin derivatives. PMID- 22203925 TI - Correlation between histopathological form and the degree of neuroendocrine differentiations in prostate cancer. AB - Prostate cancer (PCa) is the most frequent neoplasic condition in males, but only 64-65% of the cases are sensitive to hormone therapy. The aim of this study was to investigate the neuroendocrine component of the prostatic carcinoma, in relation to the histopathological form and the degree of differentiation. Biopsies were obtained through transurethral resection, from 82 patients with prostate cancer. In order to assess the histopathological form and the Gleason score, one section from each case was stained with Hematoxylin-Eosin. Additional sections were stained with chromogranin A. We considered neuroendocrine cell hyperplasia to have a higher value than that observed in benign prostatic hyperplasia (BPH) and normal prostate (over three neuroendocrine cells/gland). The quantification of neuroendocrine differentiation (NED) has been significant; the reaction was considered to be weak (2-10% neuroendocrine cells), moderate (10 20%) and intense (over 50%). Cells positive for chromogranin A have been identified in all the cases, but a larger number than that registered in normal tissue has been noted in 59 patients (71.95%). In most of the cases, the neuroendocrine cells have been distributed in small groups among the neoplasic cells, and rarely isolated. In two cases of small cell carcinoma most of the tumoral cells have been positive for chromogranin A. In conclusion, the study of neuroendocrine differentiation in patients with prostatic carcinoma revealed hyperplasia of positive chromogranin A cells, in 71.95% of cases. Neuroendocrine prostatic differentiation is correlated with the advanced stage of evolution and possibly with the resistance to hormonal treatment. PMID- 22203920 TI - Translating cell survival and cell longevity into treatment strategies with SIRT1. AB - The sirtuin SIRT1, a class III NAD(+)-dependent protein histone deacetylase, is present throughout the body that involves cells of the central nervous system, immune system, cardiovascular system, and the musculoskeletal system. SIRT1 has broad biological effects that affect cellular metabolism as well as cellular survival and longevity that can impact both acute and chronic disease processes that involve neurodegenerative disease, diabetes mellitus, cardiovascular disease, and cancer. Given the intricate relationship SIRT1 holds with a host of signal transduction pathways ranging from transcription factors, such as forkhead, to cytokines and growth factors, such as erythropoietin, it becomes critical to elucidate the cellular pathways of SIRT1 to safely and effectively develop and translate novel avenues of treatment for multiple disease entities. PMID- 22203926 TI - Renal subcapsular tertiary lymphoid aggregates in chronic kidney diseases. AB - In the last decade, it has been accepted the formation of tertiary lymphoid organs in the renal parenchyma during inflammatory conditions. These organized cellular aggregates contain B- and T-lymphocytes, dendritic cells, surrounded by neo-lymphatic vessels. They have been described in renal allografts, acute and chronic interstitial nephritis, IgA and membranous nephropathies. The functional characteristics of these lymphoid nodules remained still under consideration. After investigating the renal biopsies of 268 patients with primary and secondary nephropathies, we have selected 20 cases showing lymphoid-like cellular aggregates located just beneath the renal capsule and having close contacts with this kidney envelope. All of these cases also showed an associated medium sized lymphatic vessel. The ultrastructure of these nodules proved to contain more or less the same cellular composition: lymphocytes, dendritic cells, seldom plasma cells and macrophages. We consider these particular subcapsular lymphoid-like nodules to be tertiary lymphatic structures in close association with the perirenal lymphatics, and the first to develop in any type of inflammatory and autoimmune renal condition. PMID- 22203927 TI - VEGF and his R1 and R2 receptors expression in mast cells of oral squamous cells carcinomas and their involvement in tumoral angiogenesis. AB - More than 90% of malignant neoplasms of the oral cavity are squamous carcinomas of oral mucosa and most are conventional type. This study included 60 cases of oral squamous carcinoma processed by usual histological technique and stained with Hematoxylin-Eosin and Alcian Blue-Safranin (Alcian Blue powder from Sigma Aldrich, code A5268-25G) and diagnosed in the Department of Pathology, University of Medicine and Pharmacy of Craiova. Double immunohistochemical (CD105-tryptase, VEGF-, VEGFR1-, VEGFR2-tryptase) or combined histochemical and immunohistochemical reactions (VEGF/ VEGFR1/ VEGFR2/Alcian Blue-Safranin) followed the particular morphological aspects of the mast cells, their relation with the blood vessels and the overlap signal of tryptase and Alcian Blue Safranin/VEGF and its R1 and R2 receptors in mast cells. Immunostaining for VEGF and its R1 and R2 receptors was present both in tumor cells and mast cells. Double immunohistochemical-histochemical reactions allowed us angiogenic profiling the mast cells. The signal overlap was present for VEGF-, VEGFR1-, VEGFR2-tryptase intratumoral and tumor invasion front mast cells. Student's t test for comparison of intratumoral and the invasion front MDM showed highly significant value (p=3.23 E-08). VEGF/ VEGFR1/ VEGFR2/Alcian Blue-Safranin revealed particular morphological aspects of mast cells, in with different morphology, shapes, sizes and degrees of degranulation. Statistical analysis showed a linear correlation between MDM and MVD inside the tumor (Pearson coefficient =0.47) and a weak linear correlation at the front of invasion (Pearson coefficient =0.19). This study has highlighted the importance of mast cells in the tumor growth of the oral squamous carcinomas, especially in terms of their proangiogenic profile (expression of VEGF and its R1 and R2 receptors). In addition, their quantification as MDM makes this parameter a useful prognostic marker. PMID- 22203928 TI - Osteonecrosis of the jaws associated with the use of bisphosphonates. Discussion over 52 cases. AB - BACKGROUND: Osteonecrosis of the jaws is increasing worldwide in patients treated with bisphosphonates. STUDY DESIGN: A retrospective review of 52 patients who were treated during 2007-2010 for bisphosphonate related maxillofacial symptoms of the jaws was conducted. Patient characteristics and other factors that influenced the disease process were studied. RESULTS: Thirteen patients received bisphosphonates for the prevention or treatment of osteoporosis; 39 for preventing bone metastases from malignant tumors. Thirty-six patients were females (age range 32-87 years, median 64 years); 16 were males (age range 30-81 years, median 73.5 years). Bisphosphonate used was ibandronic acid in four cases, alendronate sodium in 14 cases, and zoledronic acid in 34 cases. Mean bisphosphonate treatment period was 22.44 months (95%CI 19.33-25.55). Thirty patients received intravenous, 22 received oral bisphosphonate. The average period until occurrence of maxillofacial symptoms was 6 months (range 0.5-24 months) in subjects with intravenous bisphosphonate and 12.26 months (range 0.25 36 months) in subjects with oral bisphosphonates (p=0.011). CONCLUSIONS: The risk of bisphosphonate related osteonecrosis of the jaws is very high twelve months after oral administration and six months after intravenous administration in patients who have a trigger point in the jaws area. A proper monitoring of patients receiving bisphosphonates can reduce the risk of osteonecrosis and can prevent complications. PMID- 22203929 TI - Evaluation of serum and gingival crevicular fluid C-reactive protein and IL-6 levels in patients with periodontitis and transient ischemic attacks. AB - BACKGROUND: Recent advances have suggested that periodontitis (PD), the paradigm of chronic infection in dental pathology, shares several pathogenic pathways with cardio- and cerebro-vascular disorders (CVD), based on inflammatory mediators including IL-1, IL-6, TNF-alpha. AIM: To assess pro-inflammatory biomarkers (C reactive protein - CRP, IL-6) in serum and gingival crevicular fluid (GCF) in patients with PD and with transient ischemic attacks (TIAs). MATERIALS AND METHODS: Prospective observational study on 143 patients classified as follows: 40 healthy subjects (group A), 50 PD patients (group B) and 53 PD-TIAs patients (group C). The predefined assessment protocol has included: current medical data, risk factors for CRP changes, periodontal status (clinical, orthopantomography, Schei Ruler technique), inflammatory biomarkers (CRP, IL-6). RESULTS: High serum CRP and IL-6 have been reported in both TIAs and PD, while statistically significant increase in GCF CRP only in PD-TIAs (p<0.05). Moreover, both generalized and localized chronic PD may be at higher risk for CVD, since CRP level was higher in these subgroups. However, no significant differences were reported in serum IL-6 between generalized and localized PD. A score function was demonstrated, including bone loss degree, bleeding index, collection site depth, serum and GCF IL-6 and CRP, tooth loss, allowing the classification of PD based on risk for developing TIAs. CONCLUSIONS: CRP and IL-6 are commonly involved in the pathways of PD and TIAs. Interdisciplinary assessment should be promoted in order to implement the stratification of PD patients according to the risk for TIAs as suggested by the proposed algorithm. PMID- 22203930 TI - Microscopic aspects of macrophage system cells in hemorrhagic stroke in humans. AB - Stroke is an important public health issue because it has high morbidity and mortality rates. In addition, it has one of the highest rates of disability in adults. Recent data show that macrophage system cells, especially microglial cells, are involved both in neuroprotective processes and in the neurotoxicity, depending on the type and extent of the brain damage. In our study, using histology and immunohistochemistry techniques, we evaluated the macrophage-type cell reaction in cerebral hemorrhage. We found that the number of CD68-positive cells increased 7-8 folds per square millimeter of cortical surface in the cerebral parenchyma adjacent to the hemorrhage. We identified a large number of perivascular-activated macrophages, in areas distant to the hemorrhage, showing that individuals with hemorrhagic stroke have profound and extensive alterations of the blood-brain barrier. PMID- 22203931 TI - Scanning electron microscopic observation of morphological modifications produced by Fluorostom on enamel surface. AB - In this in vitro study, examination of the morphological changes of enamel surface after topical application of a sodium fluoride solution was performed. Validation of the Fluorostom effectiveness became possible, after 10 years of using for the caries prevention national program. MATERIALS AND METHODS: Sound human enamel sections, ware treated with a 0.05% sodium fluoride solution. Demineralization areas were created with 37% phosphoric acid etching gel for 60 seconds. The demineralization areas were immersed in 100 mL of sodium fluoride solution, twice daily for 30 days. Surface examination was performed at scanning electron microscope and energy dispersion spectrometry. RESULTS: Morphological appearance of fluoride deposits on the enamel surface revealed the presence of globular precipitates. EDX qualitative analysis revealed the presence of fluoride signals. CONCLUSIONS: Globular structures of amorphous CaF2 precipitates, which act as a fluoride reservoir, were observed on the enamel surface after action of Fluorostom, and it can be recommended to prevent and control tooth decay. PMID- 22203932 TI - Expression of CCL18 and interleukin-6 in the plasma of breast cancer patients as compared with benign tumor patients and healthy controls. AB - A growing body of laboratory research has shown that pro-inflammatory cytokines can facilitate tumor growth and metastasis. Our goal was to quantify the expression of CCL18 and IL-6 in patients with breast cancer compared with benign breast tumors patients and healthy women, in order to evaluate if these cytokines could serve for breast cancer diagnosis and evaluation. We also correlated the cytokines level of expression with some clinical and pathological characteristics known as prognostic markers for breast cancer. Plasma samples were obtained before treatment from 58 breast cancers, 41 benign breast tumors and 30 healthy women. The quantitative dosage was performed using ELISA. Wilcoxon test was used to compare groups. IL-6 and CCL18 were dramatically upregulated in breast cancers in comparison with healthy controls, but in comparison with benign tumors only CCL18/PARC was overexpressed at borderline significance in cancers (p=0.05). The plasma from benign breast tumor patients exhibited also significant higher levels of the two cytokines than normal controls. The cytokines profile was not linked to patient age, tumor size, histopathological type, lymph node status or histological grade. IL-6 was significantly upregulated in ER-positive and metastasized cancers. CCL18/PARC presented a significantly higher expression in advanced stage and highly proliferative carcinomas. In summary, IL-6 and CCL18 could clearly distinguish between women with breast cancers and healthy controls. High expression of IL-6 seems to confer a poor prognosis for ER-positive cancers. CCL18 was associated with worse prognosis parameters like high Ki67. PMID- 22203933 TI - VEGFR1 and VEGFR2 immunohistochemical expression in oral squamous cell carcinoma: a morphometric study. AB - Vascular endothelial growth factor (VEGF) is considered one of the main molecules involved in tumor angiogenesis and is largely expressed in oral squamous cell carcinoma (OSCC). His signal is transmitted intracellulary by binding with class III tyrosine kinase receptors, known as VEGF receptor family (VEGFRs). Therefore, we designed this study for quantification of VEGFR1 and VEGFR2 immunohistochemical expression in the tumor cells of OSCC, and compare this expression with clinicopathologic parameters. For this purpose, 46 formalin fixed, paraffin-embedded tissue blocks of OSCC were processed by immunohistochemistry. The immunohistochemical signal was assessed by estimating the area of the objects and the medium pixel intensity per object, as the integrated optical density (IOD). In our study, VEGFR1 staining intensity was significantly higher for tongue localization, while VEGFR2 was higher for the lip. Both markers were higher expressed in the center of the tumor compared to the tumor front. Moderate differentiated tumors exert higher expression levels for VEGFR1 but lower for VEGFR2. pT1 tumors had higher VEGFR1 levels, and when lymph node involvement was present, this was accompanied by elevated expression levels for VEGFR2 and lower levels for VEGFR1. These results point to an inverse profile of these receptors in OSCC, suggesting their involvement in a sequential manner in VEGF signaling regulation. In conclusion, our study revealed that VEGFR1 and VEGFR2 correlate with tumor localization, tumoral area (front vs. center of the tumor), histological differentiation degree, and lymph node involvement, while only VEGFR1 correlated with pT stage. PMID- 22203934 TI - Serum total gangliosides level: clinical prognostic implication. AB - PURPOSE: The gangliosides overexpression contributes to the development of skin melanoma. The purpose of this study was to determine if the total gangliosides serum levels might predict the tumor growth in patients with melanoma or if the transfer of shed cell gangliosides reflects the implication in the clinical prognostic of these patients. PATIENTS AND METHODS: Total gangliosides serum levels were measured in the cryopreserved serum by estimating lipid-associated sialic acid in 761 patients before surgical resection of melanoma, in 406 patients with precancerous pigmentary lesions, and in 410 healthy individuals. This study was performed at the Dermatovenereological Research Center, Bucharest, Romania, during 1991-2010. All sera obtained after surgical resection of melanocytic tumors were analyzed to see if adjuvant therapy (chemo-, immuno-, immunochemo-therapy) induced gangliosides changes in melanoma patients and if the responses were correlated with survival. RESULTS: Total gangliosides serum levels were higher in melanoma patients than in precancerous melanocytic lesions patients or in healthy individuals. Larger tumors in Breslow index and more advanced stage of disease were correlated with higher total gangliosides serum values. Augmented total gangliosides serum levels after melanoma adjuvant treatment were predictive for decreased overall survival, whereas decreased total gangliosides serum levels were predictable for improved overall survival. CONCLUSIONS: A marker for early melanoma complications and survival may be the total gangliosides serum level. PMID- 22203935 TI - VEGF expression in human brain tissue after acute ischemic stroke. AB - Ischemic stroke is the third most common cause of death in humans, requiring further studies to elucidate its pathophysiological background. One potential mechanism to increase oxygen delivery to the affected tissue is induction of angiogenesis. The most potent proangiogenic factor is VEGF. For this reason, our study investigated immunohistochemically VEGF reactivity in different cellular brain compartments from 15 ischemic stroke patients, as well as from 2 age control cases. By enzymatic immunohistochemistry, we investigate VEGF expression in different brain cell compartments and then we quantified its signal intensity by assessing integrated optical densities (IOD). To establish the exact cellular brain topography of VEGF immunoreactivity we performed double fluorescent immunohistochemistry series (VEGF/NeuN, GFAP, CD68, CD105). In control samples, VEGF reactivity was observed especially in neurons from the Brodmann cortical layers IV to VI and in protoplasmic astrocytes from the deeper layers of gray matter and in endothelial cells from normal blood vessels because of systemic hypoxia generated after death. In acute ischemic stroke samples, this reactivity was noticed in all brain cellular compartments but with different intensities. The most reactive compartment was the neurons, the intensity of VEGF reaction decreasing with the lesional age from the core infarct toward intact adjacent brain cortex. With a lower intensity, VEGF reaction was noticed in astrocytes compartments, especially in gemistocytic astrocytes adjacent to the liquefaction zone. We also noticed a weak reaction in activated non-phagocytic microglia from the periphery of liquefaction zones, and high VEGF-CD105 colocalization values at the level of microvessels that surround the infarcted brain area. In conclusion, this reactivity could suggest that VEGF might exhibit neuronal and glial protective effects and also a neoangiogenic property in acute ischemic stroke, facts that may have significant therapeutically impact on these patients. PMID- 22203936 TI - Experimental study on histological changes in the sinus membrane following sinus lift. AB - The aim of this study is to assess the histological changes in the sinus mucosa adjacent to the alloplastic material used for subantral augmentation. MATERIALS AND METHODS: The study included ten sheep and a dog. The first group of five sheep underwent a sinus lift procedure, using PerioGlas as an augmentation material; the second similar group of sheep was the control group. The dog underwent a sinus lift procedure, with PerioGlas augmentation, after the sinus membrane was intentionally perforated and two implants were placed in the same operative step. RESULTS: Scanning electron microscopy (SEM) of the sinus mucosa in the control group revealed cells without cilia between goblet cells. The cilia were uniformly arranged in sections in the same direction. Changes occurred in the sinus mucosa after grafting, such as drastic reduction of ciliated cells, which seemed to be replaced by goblet cells. In all sheep undergoing grafting, generalized fibrosis was found in the mucosal area that came into contact with PerioGlas. In two of the sheep in which grafting was performed, mucoid cysts with pseudo stratified ciliated epithelium were present. Even when the sinus mucosa was perforated (in the dog), the inflammatory process developed in the mucosa did not prevent the integration of the graft and implants. In conclusion, following the sinus lift procedure, changes occur in the sinus membrane to adapt to the new situation, without the appearance of chronic or acute suppurative processes. PMID- 22203937 TI - Neuromuscular assessment in the study of structural changes of striated muscle in multiple sclerosis. AB - The aim of this research is to present the results of neuromuscular assessment using tensiomyography (TMG) in multiple sclerosis for prediction the muscle changes. This study consists of 20 patients, selected conform to certain criteria. Thus, according to diagnosis and MS level, the studied group was divided into two subgroups: subgroup A, consisting of 13 MS patients with clinically detectable gait disorders, and subgroup B, made up of seven MS patients without clinically detectable gait disorders. TMG determines the diagnosis of a certain muscular type and muscular status/condition (fatigue, stress influence on the body, etc.), the diagnosis of a functional muscular symmetry. The investigation has been performed on the shank muscles. The parameters evaluated through TMG were: contraction time (Tc) and the amplitude of muscular displacement in transverse direction - Dm (mm) a parameter which is also correlated with Tc values and depends on the flexibility of muscular tissue. RESULTS: Dm in the case of gastrocnemius muscles (mG) data analysis shows an evolution of functional bilateral right-left asymmetry, which is more pronounced in subgroup A. At the level of posterior shank, Dm values in subgroup A are lower, which means that patients in subgroup A have a higher muscular tone and a maximum response to stimulation. Concerning Tc values, this parameter indicates muscular fatigue at the level of anterior tibialis. CONCLUSIONS: TMG, besides classical methods of paraclinical investigation, improves data generation, standardization, identifies correlations, which may facilitate a precocious diagnosis in morphofunctional changes evolution at muscular level at MS patients. PMID- 22203938 TI - Histopathological aspects and local implications of oxidative stress in patients with oral lichen planus. AB - Aerobic life is connected with continuous production of free radicals, particularly reactive oxygen species (ROS). Cells posses an enzymatic and non enzymatic antioxidant system to maintain redox homeostasis. Oxidant-antioxidant imbalance resulting in excessive accumulation of ROS is defined as oxidative stress. Oral lichen planus (OLP) is a chronic inflammation of unknown etiology. Several researchers suggest that oxidative stress is implicated in the pathogenesis of this disorder. The aim of this study was to evaluate the histopathological alterations and the status of local oxidative stress and antioxidant defense system in patients with OLP. We evaluated and compared the local levels of oxidative stress biomarkers malondialdehyde (MDA) and glutathione (GSH) in patients with OLP with that of normal controls. Increased levels of MDA and decreased levels of GSH suggest the idea of oxidative stress implication in the pathogenesis of oral lichen planus. PMID- 22203939 TI - Gingival inflammatory infiltrate analysis in patients with chronic periodontitis and diabetes mellitus. AB - Diabetes mellitus and periodontal disease are two pathological entities that destructively emphasize each other. The aim of our study was the histological and immunohistochemical analyze of the inflammatory infiltrate in the gingival tissue at patients with diabetes mellitus (DM) and periodontal disease. MATERIALS AND METHODS: The study was achieved on gingival tissue from 40 patients with DM and specific symptoms of periodontal disease. We used Hematoxylin-Eosin and trichromic Goldner-Szekely staining and CD20cy and CD45RO antibodies. RESULTS: In patients with DM under 10 years, we found an intense periodontal lymphocyte inflammatory infiltrate and in patients with a DM evolution more than 10 years, the lymphocyte inflammatory infiltrate had a less intensity. The pattern was mostly diffuse in lamina propria. Many patients had a very abundant plasmocyte infiltrate. During immunohistochemical exam, 25 cases presented CD20 positive immunostaining. The intensity of the inflammatory infiltrate with B-lymphocytes was very low (score 1). All immunohistochemical analyzed cases presented CD45RO positive immunostaining, with a mixed pattern of the T-cell lymphocyte infiltrate. CONCLUSIONS: The nflammatory infiltrate in diabetic periodontal disease was polymorph, mostly with a diffuse pattern in gingival chorion. The intensity of the lymphocyte infiltrate was higher in patients with chronic periodontitis and DM less than 10 years. Positive CD45RO T-lymphocytes were more numerous compared to positive CD20 B-lymphocytes and they were present intra and under epithelial in the gingival of all the patients, no matter of the DM time evolution. PMID- 22203940 TI - Warthin tumor--morphological study of the stromal compartment. AB - Warthin tumor is the second most common benign tumors of the parotid gland, after pleomorphic adenoma. Our study was performed on 21 cases with Warthin tumor diagnosed between 2005-2010, which were analyzed clinically, histologically and immunohistochemically, using anti-CD20 and anti-CD45RO antibodies. The analysis of age distribution within the investigated cases indicated that Warthin tumor incidence is increasing in the seventh decade of life, most patients being male (M/F 5/2). Histopathological, the analysis report of stroma/parenchyma in 14 cases revealed a balanced distribution of the two components, in four cases, the epithelial component was predominant and in three cases, the stromal component was predominant. Immunohistochemical study for the two specific lymphocyte proliferation markers indicated positivity for both epithelial component and stroma. Cell layout of CD45RO and CD20cy at the level of lymphoid stroma had a similar pattern with normal or reactive lymph nodes. PMID- 22203941 TI - Morphological aspects of the kidney: can normality be predicted? AB - PURPOSE: Our study aimed to assess the normal parameters of renal parenchyma and upper urinary tract from a contrast enhanced computed tomography assessment in order to create a mathematical model of normal kidney. PATIENTS AND METHODS: We conducted a retrospective observation study on 520 patients with a normal abdominal contrast enhanced CT scan in our Institute during November 2008 November 2010. All CT examinations were performed using 16 slices Siemens Emotion 2007 (Siemens Medical Solutions, Malvern, PA, USA). Two experienced radiologists evaluated all the evaluations and reformatted axial sections and after excluding patients with urinary tract pathology, the images were transferred to a separate workstation (eFilm Workstation(TM) 2.2.1, Merge Healthcare, Milwaukee, USA). Parameters measured were: the number of kidneys, craniocaudal diameter (CCD) in a coronar reconstruction, transverse diameter (TD) and anteroposterior diameter (APD) as the maximum diameter of the kidneys in the axial sections, parenchymal (PW) and cortical width (CW) in axial sections, kidney pyelon width (KPW), parenchymal index (PI), kidney rotation, measured in relation to the sagittal axial plane of reference (AR) and rotation of the kidney measured in the sagittal plane in relation to the coronary reference (SR). To identify factors that can influence the variables CCD, CW and PW, multivariate regression models were performed using SPSS software (SPSS 15, SPSS Inc., Chicago, Illinois, USA). We considered p<0.05 statistically significant. RESULTS: CCD remains high until the fifth decade of life (p=0.0053 on the right side, p=0.0012 on the left, ANOVA), PW values were found to be somewhat increased (p=0.0293 on the right side, p=0.2924 on the left, ANOVA). There are linear correlations between height and CCD, CW and PW, with statistical significance (p<0.05 each, Spearman rho between 0.13 and 0.4). In multivariate analysis, only BMI, male gender and height had statistical significance. CONCLUSIONS: There is a wide range in size kidney. Among factors that strongly influence the values of CCD, CW, and PW in adults, BMI, male gender and height are most important. Also, cranial and caudal position of the kidney influences renal size. As for the size of the renal cortex, the factor most influencing these values is the absence of a contralateral kidney. PMID- 22203942 TI - Immunohistochemical evaluation of hormone receptors with predictive value in mammary carcinomas. AB - AIM: Immunohistochemical evaluation of hormone receptors (ER, PR) and correlation of immunohistochemical and morpho-clinical data. MATERIALS AND METHODS: The study was performed on paraffin-embedded and HE-stained tissues originating from 100 cases of invasive mammary carcinoma. Monoclonal antibodies, anti-estrogen and anti-progesterone receptors, were used for the immunohistochemical study. The detection system was EnVision HRP and the visualization system was 3,3' diaminobenzidine tetrahydrochloride (DAB). The evaluation of the result was performed using the Allred score. RESULTS: The majority of the studied cases (57%) expressed both types of hormone receptors and in 32% of the cases the hormone receptors were completely absent. The rest of the cases presented a heterogeneous phenotype: 7% presented the ER-/PR+ phenotype and 4% the ER+/PR- phenotype. Compared with the classical phenotype (ER+/PR-), ER+/PR- tumors were more frequent at patients over 50-year-old. The tumors with ER+/PR- were larger than the ER+/PR+ and they were of the invasive ductal carcinoma type with an Allred score for ER under 6. CONCLUSIONS: The predictive value is amplified when the ER status is correlated with the PR status because the heterogeneous phenotypes are identified, especially the ER+/PR- phenotype, which have an aggressive behavior and the lowest response to tamoxifen therapy. PMID- 22203943 TI - Histopathological and immunohistochemical aspects in chronic suppurative maxillary rhinosinusitis. AB - Chronic rhinosinusitis is a multifactorial disease with pathophysiological mechanisms, which remain unclear, and with a high prevalence worldwide. They generate social problems due to the high number of days of leave and relatively elevated medical expenses. The histopathological and immunohistochemical study that we conducted revealed many lesional aspects of the epithelium of the sinus mucosa, which ranged from hypertrophy, hyperplasia and metaplasia, to erosion and discontinuities. In the chorion of the sinus mucosa there was an inflammatory infiltrate composed mainly of lymphocytes, plasma cells and macrophages, and also a highly developed vascular network. Among immune cells, T-cells appeared to be more numerous than B-lymphocytes and macrophages. We believe that microscopic changes are due mainly to microscopic organisms that make up the biofilm of the sinus cavity, whose virulence has been more or less influenced by exogenous or endogenous factors. PMID- 22203944 TI - Cephalometric investigation of Class III dentoalveolar malocclusion. AB - The aim of our study was to identify the most important anatomical landmarks in the cephalometric evaluation of Class III patients and to clarify the morphological characteristics of these cases. A group of 10 Class III orthodontic patients was evaluated in this study. The control group consisted of 10 patients with average occlusion and skeletal characteristics. Digital lateral cephalometric X-rays were performed and different measurements were analyzed. Cephalometric data were evaluated with the CephX specialized software for orthodontic diagnosis and the results were statistically analyzed. The Class III group presented specific characteristics such as prognathic mandible, large gonial angle, short maxillary length, higher lower facial height. These findings can be useful for the diagnosis and treatment planning of orthodontic cases with dental/keletal anomalies, especially in cases when surgical approach is considered. The surgical decision must be taken after an accurate investigation of the lateral cephalometric parameters. PMID- 22203945 TI - Study of cellular changes induced by moderate cerebral ischemia achieved through internal carotid artery ligation. AB - Reduced cerebral blood flow beyond the compensatory mechanisms leads to cerebral hypoxia. Hypoxia causes various lesions of neurons, glial cells and cerebral blood vessels, depending on its duration and intensity. In our study, we reduced cerebral blood flow in the experience animal on average by 30%, by right internal carotid artery ligation. Fifteen days after the onset of hypoxia, by histology and immunohistochemical studies, we identified neuronal, glial and vascular damage. Lesions of nerve and glial cells ranged from changes of cytoplasmic tinting with the development of "red neurons", to neuronal and glial cytolysis with areas of focal necrosis. Vascular lesions were represented by the collapse, fragmentation and discontinuity of capillaries, always associated with a marked perivascular edema. PMID- 22203946 TI - Atypical variant of lichen planus mimicking normal skin histology. AB - We present the case of a 69-year-old Caucasian and non-smoker patient with erythematous, itchy, violaceous lesions on the ankles, wrists, lower legs, forearms and trunk developed within 15 months. Her condition was diagnosed as prurigo and she was treated for a long period of time with antihistaminic drugs, with no resolution of lesions. In October 2008, she presented to a Private Practice of Dermatology in Timisoara. The dermatologist noticed the development of violaceous lesions on her trunk. The patient had similar lesions on the ankles, wrists, lower legs, and forearms for the last eight months. At physical examination many hyperpigmented, 1 to 6 cm, thin plaques were present on the flanks, shoulders, and infra-mammary area. There was no vaginal involvement. This eruption had a good response to topical glucocorticoids, but recurred multiple times after discontinuation of treatment. A biopsy specimen showed some histopathological features of lichen planus. PMID- 22203947 TI - Differential diagnosis of a gastric stromal tumor: case report and literature review. AB - Gastrointestinal stromal tumors account for 0.1-3% of all gastrointestinal neoplasms and are characterized by features that overlap with those of other mesenchymal tumors. We expose the case of a 58-year-old male patient who complained of abdominal pain, weakness and melena. Microscopic examination of surgically resected gastric tumor revealed a neoplastic proliferation composed of spindle cells with eosinophilic cytoplasm, elongated nuclei with rounded ends, palisadic disposition and intracytoplasmic perinuclear vacuoles, low cyto-nuclear polymorphism, mild atypia and mitotic activity of 3-5/50 HPF. Some histopathological features requested differential diagnosis with schwannoma and tumors of myocytary origin, based on immunohistochemical techniques, which have established a final diagnosis of spindle cell gastric stromal tumor. We also reviewed the GIST-related literature and evaluated the possible methods of preoperative diagnosis of GISTs based on endoscopic biopsy. Proper classification of GISTs based on histopathological criteria and immunohistochemical techniques has a great prognostic and therapeutic utility. Future development of endoscopic biopsy methods will refine the management of gastrointestinal stromal tumors. PMID- 22203948 TI - Synchronous carcinoma of the ascending colon and caecum. AB - The caecum and the ascending colon are the colon segments most frequently affected by tumoral synchronism. Synchronous colorectal carcinoma etiopathogenesis is complex and most likely by malignancy of preexisting adenomas (adenoma-adenocarcinoma sequence). The following tumoral synchronism clinical case's particularity is represented by the simultaneous diagnosis of a flat-type adenocarcinoma of the caecum (less common histopathological type) and of a mucinous adenocarcinoma on the ascending colon. Tumor profiles of both carcinomas were examined histologically and immunohistochemically, emphasizing: (1) tumor proliferation different histological type; (2) residual adenomas in the periphery of the flat-type adenocarcinoma; (3) hardly microscopic detectable invasive character of the flat-type carcinoma; (4) mucinous carcinoma's infiltrating character and its immunohistochemical phenotype; (5) both tumor aggressiveness. PMID- 22203949 TI - Periarticular diffuse neurofibroma of the upper limb. AB - The diffuse neurofibroma is an uncommon subtype of neurofibroma that has received little attention in the imaging literature. Most common in ages 10-30, in males and females, with a slight predilection for the trunk, then head and neck, then limbs. May become very large, but very rarely undergo malignant transformation. Treatment of diffuse neurofibromas (not associated with NF1) is often surgical resection. Complete resection is often difficult because of the extensive and infiltrative nature of many of these lesions. To our knowledge, the diffuse neurofibroma has been reported extremely rarely within the shoulder girdle. In this report, we presented an adult patient, without NF1 diagnosed, who developed invalidate status of left upper limb due to a giant diffuse neurofibroma involving the left brachial plexus, with a high growth diffuse pattern and plexiform architecture imagistic, grossly and without results at both surgical interventions. The diagnosed was by MRI and sonographic imaging and histopathologic examination. His immediately survival perspective was not affected but the functionality of the left upper limb was severe reduced. PMID- 22203950 TI - Gastroduodenal-splenic trunk: an anatomical vascular variant. AB - The main classical branches of celiac trunk (CT) are the common hepatic artery (CHA), the left gastric artery (LGA) and the splenic artery (SA). During the educational dissections in a 62-year-old male cadaver a rare variation, the gastroduodenal-splenic trunk (GDST), was observed. GDST divided into SA and gastroduodenal artery (GDA). LGA and accessory left hepatic artery (ALHA) arose directly from the abdominal aorta (AA). Therefore, variations of CT are important for the clinical diagnosis and therapy. PMID- 22203951 TI - Anatomical variations of mandibular first molar and their implications in endodontic treatment. AB - The possible variations of anatomical and morphological characteristics of the teeth are very important especially for the endodontic practitioner. Before beginning any kind of endodontic treatment, the clinician must be always take into account the morphological variations in pulp anatomy. Among all human teeth, the mandibular first permanent molar is one of the most important. It is often affected by caries and usually needs root canal treatment, even at an early age. For the success of its endocanalicular treatment, dentists need to locate all root canals, debride them entirely, and after that fill the whole endocanalicular system with an inert root filling material. Unfilled canals, left like this because they were not detected, can compromise the longevity of the tooth, thus being a source of infection and a main cause of failure of the prosthetic treatment. This article presents two clinical cases of right mandibular first molars with two roots and four canals instead of three. PMID- 22203952 TI - Schooling in adolescence raises IQ scores. AB - Although some scholars maintain that education has little effect on intelligence quotient (IQ) scores, others claim that IQ scores are indeed malleable, primarily through intervention in early childhood. The causal effect of education on IQ at later ages is often difficult to uncover because analyses based on observational data are plagued by problems of reverse causation and self-selection into further education. We exploit a reform that increased compulsory schooling from 7 to 9 y in Norway in the 1960s to estimate the effect of education on IQ. We find that this schooling reform, which primarily affected education in the middle teenage years, had a substantial effect on IQ scores measured at the age of 19 y. PMID- 22203953 TI - Sperm-borne microRNA-34c is required for the first cleavage division in mouse. AB - In mammals, the sperm deliver mRNA of unknown function into the oocytes during fertilization. The role of sperm microRNAs (miRNAs) in preimplantation development is unknown. miRNA profiling identified six miRNAs expressed in the sperm and the zygotes but not in the oocytes or preimplantation embryos. Sperm contained both the precursor and the mature form of one of these miRNAs, miR-34c. The absence of an increased level of miR-34c in zygotes derived from alpha amanitin-treated oocytes and in parthenogenetic oocytes supported a sperm origin of zygotic miR-34c. Injection of miR-34c inhibitor into zygotes inhibited DNA synthesis and significantly suppressed first cleavage division. A 3' UTR luciferase assay and Western blotting demonstrated that miR-34c regulates B-cell leukemia/lymphoma 2 (Bcl-2) expression in the zygotes. Coinjection of anti-Bcl-2 antibody in zygotes partially reversed but injection of Bcl-2 protein mimicked the effect of miR-34c inhibition. Oocyte activation is essential for the miR-34c action in zygotes, as demonstrated by a decrease in 3'UTR luciferase reporter activity and Bcl-2 expression after injection of precursor miR-34c into parthenogenetic oocytes. Our findings provide evidence that sperm-borne miR-34c is important for the first cell division via modulation of Bcl-2 expression. PMID- 22203954 TI - Targeting protein-trafficking pathways alters melanoma treatment sensitivity. AB - Protein-trafficking pathways are targeted here in human melanoma cells using methods independent of oncogene mutational status, and the ability to up-regulate and down-regulate tumor treatment sensitivity is demonstrated. Sensitivity of melanoma cells to cis-diaminedichloroplatinum II (cDDP, cis-platin), carboplatin, dacarbazine, or temozolomide together with velaparib, an inhibitor of poly (ADP ribose) polymerase 1, is increased by up to 10-fold by targeting genes that regulate both protein trafficking and the formation of melanosomes, intracellular organelles unique to melanocytes and melanoma cells. Melanoma cells depleted of either of the protein-trafficking regulators vacuolar protein sorting 33A protein (VPS33A) or cappuccino protein (CNO) have increased nuclear localization of cDDP, increased nuclear DNA damage by platination, and increased apoptosis, resulting in increased treatment sensitivity. Depleted cells also exhibit a decreased proportion of intracellular, mature melanosomes compared with undepleted cells. Modulation of protein trafficking via cell-surface signaling by binding the melanocortin 1 receptor with the antagonist agouti-signaling protein decreased the proportion of mature melanosomes formed and increased cDDP sensitivity, whereas receptor binding with the agonist melanocyte-stimulating hormone resulted in an increased proportion of mature melanosomes formed and in decreased sensitivity (i.e., increased resistance) to cDDP. Mutation of the protein trafficking gene Hps6, known to impair the formation of mature melanosomes, also increased cDDP sensitivity. Together, these results indicate that targeting protein-trafficking molecules markedly increases melanoma treatment sensitivity and influences the degree of melanosomes available for sequestration of therapeutic agents. PMID- 22203956 TI - Secreted Wingless-interacting molecule (Swim) promotes long-range signaling by maintaining Wingless solubility. AB - Lipid-modified Wnt/Wingless (Wg) proteins can signal to their target cells in a short- or long-range manner. How these hydrophobic proteins travel through the extracellular environment remains an outstanding question. Here, we report on a Wg binding protein, Secreted Wg-interacting molecule (Swim), that facilitates Wg diffusion through the extracellular matrix. Swim, a putative member of the Lipocalin family of extracellular transport proteins, binds to Wg with nanomolar affinity in a lipid-dependent manner. In quantitative signaling assays, Swim is sufficient to maintain the solubility and activity of purified Wg. In Drosophila, swim RNAi phenotypes resemble wg loss-of-function phenotypes in long-range signaling. We propose that Swim is a cofactor that promotes long-range Wg signaling in vivo by maintaining the solubility of Wg. PMID- 22203955 TI - Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils. AB - Neutrophil migration to inflamed sites is crucial for both the initiation of inflammation and resolution of infection, yet these cells are involved in perpetuation of different chronic inflammatory diseases. Gastrin-releasing peptide (GRP) is a neuropeptide that acts through G protein coupled receptors (GPCRs) involved in signal transmission in both central and peripheral nervous systems. Its receptor, gastrin-releasing peptide receptor (GRPR), is expressed by various cell types, and it is overexpressed in cancer cells. RC-3095 is a selective GRPR antagonist, recently found to have antiinflammatory properties in arthritis and sepsis models. Here we demonstrate that i.p. injection of GRP attracts neutrophils in 4 h, and attraction is blocked by RC-3095. Macrophage depletion or neutralization of TNF abrogates GRP-induced neutrophil recruitment to the peritoneum. In vitro, GRP-induced neutrophil migration was dependent on PLC-beta2, PI3K, ERK, p38 and independent of Galphai protein, and neutrophil migration toward synovial fluid of arthritis patients was inhibited by treatment with RC-3095. We propose that GRPR is an alternative chemotactic receptor that may play a role in the pathogenesis of inflammatory disorders. PMID- 22203957 TI - Vertebrate-like regeneration in the invertebrate chordate amphioxus. AB - An important question in biology is why some animals are able to regenerate, whereas others are not. The basal chordate amphioxus is uniquely positioned to address the evolution of regeneration. We report here the high regeneration potential of the European amphioxus Branchiostoma lanceolatum. Adults regenerate both anterior and posterior structures, including neural tube, notochord, fin, and muscle. Development of a classifier based on tail regeneration profiles predicts the assignment of young and old adults to their own class with >94% accuracy. The process involves loss of differentiated characteristics, formation of an msx-expressing blastema, and neurogenesis. Moreover, regeneration is linked to the activation of satellite-like Pax3/7 progenitor cells, the extent of which declines with size and age. Our results provide a framework for understanding the evolution and diversity of regeneration mechanisms in vertebrates. PMID- 22203958 TI - Mechanical compression drives cancer cells toward invasive phenotype. AB - Uncontrolled growth in a confined space generates mechanical compressive stress within tumors, but little is known about how such stress affects tumor cell behavior. Here we show that compressive stress stimulates migration of mammary carcinoma cells. The enhanced migration is accomplished by a subset of "leader cells" that extend filopodia at the leading edge of the cell sheet. Formation of these leader cells is dependent on cell microorganization and is enhanced by compressive stress. Accompanied by fibronectin deposition and stronger cell matrix adhesion, the transition to leader-cell phenotype results in stabilization of persistent actomyosin-independent cell extensions and coordinated migration. Our results suggest that compressive stress accumulated during tumor growth can enable coordinated migration of cancer cells by stimulating formation of leader cells and enhancing cell-substrate adhesion. This novel mechanism represents a potential target for the prevention of cancer cell migration and invasion. PMID- 22203959 TI - Legume pectate lyase required for root infection by rhizobia. AB - To allow rhizobial infection of legume roots, plant cell walls must be locally degraded for plant-made infection threads (ITs) to be formed. Here we identify a Lotus japonicus nodulation pectate lyase gene (LjNPL), which is induced in roots and root hairs by rhizobial nodulation (Nod) factors via activation of the nodulation signaling pathway and the NIN transcription factor. Two Ljnpl mutants produced uninfected nodules and most infections arrested as infection foci in root hairs or roots. The few partially infected nodules that did form contained large abnormal infections. The purified LjNPL protein had pectate lyase activity, demonstrating that this activity is required for rhizobia to penetrate the cell wall and initiate formation of plant-made infection threads. Therefore, we conclude that legume-determined degradation of plant cell walls is required for root infection during initiation of the symbiotic interaction between rhizobia and legumes. PMID- 22203960 TI - Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. AB - Aire is a transcriptional regulator that induces expression of peripheral tissue antigens (PTA) in thymic medullary epithelial cells (MECs), driving immunological self-tolerance in differentiating T cells. To elucidate its mechanistic pathways, we examined its transcriptional impact in MECs in vivo by microarray analysis with mRNA-spanning probes. This analysis revealed initiation of Aire-activated genes to be comparable in Aire-deficient and wild-type MECs, but with a block to elongation after 50-100 bp in the absence of Aire, suggesting activation by release of stalled polymerases by Aire. In contrast, patterns of activation by transcription factors such as Klf4 were consistent with regulation of initiation. Mapping of Aire and RNA polymerase-II (Pol-II) by ChIP and high-throughput sequencing (ChIP-seq) revealed that Aire bound all Pol-II-rich transcriptional start sites (TSS), irrespective of its eventual effect. However, the genes it preferentially activated were characterized by a relative surfeit of stalled polymerases at the TSS, which resolved once Aire was introduced into cells. Thus, transcript mapping and ChIP-seq data indicate that Aire activates ectopic transcription not through specific recognition of PTA gene promoters but by releasing stalled polymerases. PMID- 22203961 TI - Single-cell proteomic chip for profiling intracellular signaling pathways in single tumor cells. AB - We describe a microchip designed to quantify the levels of a dozen cytoplasmic and membrane proteins from single cells. We use the platform to assess protein protein interactions associated with the EGF-receptor-mediated PI3K signaling pathway. Single-cell sensitivity is achieved by isolating a defined number of cells (n = 0-5) in 2 nL volume chambers, each of which is patterned with two copies of a miniature antibody array. The cells are lysed on-chip, and the levels of released proteins are assayed using the antibody arrays. We investigate three isogenic cell lines representing the cancer glioblastoma multiforme, at the basal level, under EGF stimulation, and under erlotinib inhibition plus EGF stimulation. The measured protein abundances are consistent with previous work, and single-cell analysis uniquely reveals single-cell heterogeneity, and different types and strengths of protein-protein interactions. This platform helps provide a comprehensive picture of altered signal transduction networks in tumor cells and provides insight into the effect of targeted therapies on protein signaling networks. PMID- 22203962 TI - Understanding fast macroscale fracture from microcrack post mortem patterns. AB - Dynamic crack propagation drives catastrophic solid failures. In many amorphous brittle materials, sufficiently fast crack growth involves small-scale, high frequency microcracking damage localized near the crack tip. The ultrafast dynamics of microcrack nucleation, growth, and coalescence is inaccessible experimentally and fast crack propagation was therefore studied only as a macroscale average. Here, we overcome this limitation in polymethylmethacrylate, the archetype of brittle amorphous materials: We reconstruct the complete spatiotemporal microcracking dynamics, with micrometer/nanosecond resolution, through post mortem analysis of the fracture surfaces. We find that all individual microcracks propagate at the same low, load-independent velocity. Collectively, the main effect of microcracks is not to slow down fracture by increasing the energy required for crack propagation, as commonly believed, but on the contrary to boost the macroscale velocity through an acceleration factor selected on geometric grounds. Our results emphasize the key role of damage related internal variables in the selection of macroscale fracture dynamics. PMID- 22203963 TI - Disordered form of the scaffold protein IscU is the substrate for iron-sulfur cluster assembly on cysteine desulfurase. AB - The scaffold protein for iron-sulfur cluster assembly, apo-IscU, populates two interconverting conformational states, one disordered (D) and one structured (S) as revealed by extensive NMR assignments. At pH 8 and 25 degrees C, approximately 70% of the protein is S, and the lifetimes of the states are 1.3 s (S) and 0.50 s (D). Zn(II) and Fe(II) each bind and stabilize structured (S-like) states. Single amino acid substitutions at conserved residues were found that shift the equilibrium toward either the S or the D state. Cluster assembly takes place in the complex between IscU and the cysteine desulfurase, IscS, and our NMR studies demonstrate that IscS binds preferentially the D form of apo-IscU. The addition of 10% IscS to IscU was found to greatly increase H/D exchange at protected amides of IscU, to increase the rate of the S -> D reaction, and to decrease the rate of the D -> S reaction. In the saturated IscU:IscS complex, IscU is largely disordered. In vitro cluster assembly reactions provided evidence for the functional importance of the S&lrarr2;D equilibrium. IscU variants that favor the S state were found to undergo a lag phase, not observed with the wild type, that delayed cluster assembly; variants that favor the D state were found to assemble less stable clusters at an intermediate rate without the lag. It appears that IscU has evolved to exist in a disordered conformational state that is the initial substrate for the desulfurase and to convert to a structured state that stabilizes the cluster once it is assembled. PMID- 22203964 TI - Regulation of oxidative DNA damage repair by DNA polymerase lambda and MutYH by cross-talk of phosphorylation and ubiquitination. AB - It is of pivotal importance for genome stability that repair DNA polymerases (Pols), such as Pols lambda and beta, which all exhibit considerably reduced fidelity when replicating undamaged DNA, are tightly regulated, because their misregulation could lead to mutagenesis. Recently, we found that the correct repair of the abundant and highly miscoding oxidative DNA lesion 7,8-dihydro-8 oxo-2'-deoxyguanine (8-oxo-G) is performed by an accurate repair pathway that is coordinated by the MutY glycosylase homologue (MutYH) and Pol lambda in vitro and in vivo. Pol lambda is phosphorylated by Cdk2/cyclinA in late S and G2 phases of the cell cycle, promoting Pol lambda stability by preventing it from being targeted for proteasomal degradation by ubiquitination. However, it has remained a mystery how the levels of Pol lambda are controlled, how phosphorylation promotes its stability, and how the engagement of Pol lambda in active repair complexes is coordinated. Here, we show that the E3 ligase Mule mediates the degradation of Pol lambda and that the control of Pol lambda levels by Mule has functional consequences for the ability of mammalian cells to deal with 8-oxo-G lesions. Furthermore, we demonstrate that phosphorylation of Pol lambda by Cdk2/cyclinA counteracts its Mule-mediated degradation by promoting recruitment of Pol lambda to chromatin into active 8-oxo-G repair complexes through an increase in Pol lambda's affinity to chromatin-bound MutYH. Finally, MutYH appears to promote the stability of Pol lambda by binding it to chromatin. In contrast, Pol lambda not engaged in active repair on chromatin is subject for proteasomal degradation. PMID- 22203965 TI - Revealing conformational substates of lipidated N-Ras protein by pressure modulation. AB - Regulation of protein function is often linked to a conformational switch triggered by chemical or physical signals. To evaluate such conformational changes and to elucidate the underlying molecular mechanisms of subsequent protein function, experimental identification of conformational substates and characterization of conformational equilibria are mandatory. We apply pressure modulation in combination with FTIR spectroscopy to reveal equilibria between spectroscopically resolved substates of the lipidated signaling protein N-Ras. Pressure has the advantage that its thermodynamic conjugate is volume, a parameter that is directly related to structure. The conformational dynamics of N Ras in its different nucleotide binding states in the absence and presence of a model biomembrane was probed by pressure perturbation. We show that not only nucleotide binding but also the presence of the membrane has a drastic effect on the conformational dynamics and selection of conformational substates of the protein, and a new substate appearing upon membrane binding could be uncovered. Population of this new substate is accompanied by structural reorientations of the G domain, as also indicated by complementary ATR-FTIR and IRRAS measurements. These findings thus illustrate that the membrane controls signaling conformations by acting as an effective interaction partner, which has consequences for the G domain orientation of membrane-associated N-Ras, which in turn is known to be critical for its effector and modulator interactions. Finally, these results provide insights into the influence of pressure on Ras-controlled signaling events in organisms living under extreme environmental conditions as they are encountered in the deep sea where pressures reach the kbar range. PMID- 22203966 TI - High-resolution dose-response screening using droplet-based microfluidics. AB - A critical early step in drug discovery is the screening of a chemical library. Typically, promising compounds are identified in a primary screen and then more fully characterized in a dose-response analysis with 7-10 data points per compound. Here, we describe a robust microfluidic approach that increases the number of data points to approximately 10,000 per compound. The system exploits Taylor-Aris dispersion to create concentration gradients, which are then segmented into picoliter microreactors by droplet-based microfluidics. The large number of data points results in IC(50) values that are highly precise (+/- 2.40% at 95% confidence) and highly reproducible (CV = 2.45%, n = 16). In addition, the high resolution of the data reveals complex dose-response relationships unambiguously. We used this system to screen a chemical library of 704 compounds against protein tyrosine phosphatase 1B, a diabetes, obesity, and cancer target. We identified a number of novel inhibitors, the most potent being sodium cefsulodine, which has an IC(50) of 27 +/- 0.83 MUM. PMID- 22203967 TI - Modulation of NF-kappaB-dependent gene transcription using programmable DNA minor groove binders. AB - Nuclear factor kappaB (NF-kappaB) is a transcription factor that regulates various aspects of immune response, cell death, and differentiation as well as cancer. In this study we introduce the Py-Im polyamide 1 that binds preferentially to the sequences 5'-WGGWWW-3' and 5'GGGWWW-3'. The compound is capable of binding to kappaB sites and reducing the expression of various NF kappaB-driven genes including IL6 and IL8 by qRT-PCR. Chromatin immunoprecipitation experiments demonstrate a reduction of p65 occupancy within the proximal promoters of those genes. Genome-wide expression analysis by RNA-seq compares the DNA-binding polyamide with the well-characterized NF-kappaB inhibitor PS1145, identifies overlaps and differences in affected gene groups, and shows that both affect comparable numbers of TNF-alpha-inducible genes. Inhibition of NF-kappaB DNA binding via direct displacement of the transcription factor is a potential alternative to the existing antagonists. PMID- 22203968 TI - Non-coalescence of oppositely charged droplets in pH-sensitive emulsions. AB - Like charges stabilize emulsions, whereas opposite charges break emulsions. This is the fundamental principle for many industrial and practical processes. Using micrometer-sized pH-sensitive polymeric hydrogel particles as emulsion stabilizers, we prepare emulsions that consist of oppositely charged droplets, which do not coalesce. We observe noncoalescence of oppositely charged droplets in bulk emulsification as well as in microfluidic devices, where oppositely charged droplets are forced to collide within channel junctions. The results demonstrate that electrostatic interactions between droplets do not determine their stability and reveal the unique pH-dependent properties of emulsions stabilized by soft microgel particles. The noncoalescence can be switched to coalescence by neutralizing the microgels, and the emulsion can be broken on demand. This unusual feature of the microgel-stabilized emulsions offers fascinating opportunities for future applications of these systems. PMID- 22203969 TI - Evolutionary constraints on visual cortex architecture from the dynamics of hallucinations. AB - In the cat or primate primary visual cortex (V1), normal vision corresponds to a state where neural excitation patterns are driven by external visual stimuli. A spectacular failure mode of V1 occurs when such patterns are overwhelmed by spontaneously generated spatially self-organized patterns of neural excitation. These are experienced as geometric visual hallucinations. The problem of identifying the mechanisms by which V1 avoids this failure is made acute by recent advances in the statistical mechanics of pattern formation, which suggest that the hallucinatory state should be very robust. Here, we report how incorporating physiologically realistic long-range connections between inhibitory neurons changes the behavior of a model of V1. We find that the sparsity of long range inhibition in V1 plays a previously unrecognized but key functional role in preserving the normal vision state. Surprisingly, it also contributes to the observed regularity of geometric visual hallucinations. Our results provide an explanation for the observed sparsity of long-range inhibition in V1--this generic architectural feature is an evolutionary adaptation that tunes V1 to the normal vision state. In addition, it has been shown that exactly the same long range connections play a key role in the development of orientation preference maps. Thus V1's most striking long-range features--patchy excitatory connections and sparse inhibitory connections--are strongly constrained by two requirements: the need for the visual state to be robust and the developmental requirements of the orientational preference map. PMID- 22203970 TI - Nanoscale buckling deformation in layered copolymer materials. AB - In layered materials, a common mode of deformation involves buckling of the layers under tensile deformation in the direction perpendicular to the layers. The instability mechanism, which operates in elastic materials from geological to nanometer scales, involves the elastic contrast between different layers. In a regular stacking of "hard" and "soft" layers, the tensile stress is first accommodated by a large deformation of the soft layers. The inhibited Poisson contraction results in a compressive stress in the direction transverse to the tensile deformation axis. The hard layers sustain this transverse compression until buckling takes place and results in an undulated structure. Using molecular simulations, we demonstrate this scenario for a material made of triblock copolymers. The buckling deformation is observed to take place at the nanoscale, at a wavelength that depends on strain rate. In contrast to what is commonly assumed, the wavelength of the undulation is not determined by defects in the microstructure. Rather, it results from kinetic effects, with a competition between the rate of strain and the growth rate of the instability. PMID- 22203971 TI - Stochastic coordination of multiple actuators reduces latency and improves chemotactic response in bacteria. AB - Individual neuronal, signal transduction, and regulatory pathways often control multiple stochastic downstream actuators, which raises the question of how coordinated response to a single input can be achieved when individual actuators fluctuate independently. In Escherichia coli, the bacterial chemotaxis pathway controls the activity of multiple flagellar motors to generate the run-and-tumble motion of the cell. High-resolution microscopy experiments have identified the key conformational changes adopted by individual flagella during this process. By incorporating these observations into a stochastic model of the flagellar bundle, we demonstrate that the presence of multiple motors imposes a trade-off on chemotactic performance. Multiple motors reduce the latency of the response below the time scale of the stochastic switching of a single motor, which improves performance on steep gradients of attractants. However, the uncoordinated switching of multiple motors interrupts and shortens cell runs, which thereby reduces signal detection and performance on shallow gradients. Remarkably, when slow fluctuations generated by the adaptation mechanism of the chemotaxis system are incorporated in the model at levels measured in experiments, the chemotactic sensitivity and performance in shallow gradients is partially restored with marginal effects for steep gradients. The noise is beneficial because it simultaneously generates long events in the statistics of individual motors and coordinates the motors to generate a long tail in the run length distribution of the cell. Occasional long runs are known to enhance exploration of random walkers. Here we show that they have the additional benefit of enhancing the sensitivity of the bacterium to very shallow gradients. PMID- 22203972 TI - Topological quantum phase transitions driven by external electric fields in Sb2Te3 thin films. AB - Using first-principles calculations, we show that topological quantum phase transitions are driven by external electric fields in thin films of Sb(2)Te(3). The film, as the applied electric field normal to its surface increases, is transformed from a normal insulator to a topological insulator or vice versa depending on the film thickness. We identify the band topology by directly calculating the Z(2) invariant from electronic wave functions. The dispersion of edge states is also found to be consistent with the bulk band topology in view of the bulk-boundary correspondence. We present possible applications of the topological phase transition as an on/off switch of the topologically protected edge states in nano-scale devices. PMID- 22203973 TI - Ionic strength-dependent persistence lengths of single-stranded RNA and DNA. AB - Dynamic RNA molecules carry out essential processes in the cell including translation and splicing. Base-pair interactions stabilize RNA into relatively rigid structures, while flexible non-base-paired regions allow RNA to undergo conformational changes required for function. To advance our understanding of RNA folding and dynamics it is critical to know the flexibility of these un-base paired regions and how it depends on counterions. Yet, information about nucleic acid polymer properties is mainly derived from studies of ssDNA. Here we measure the persistence lengths (l(p)) of ssRNA. We observe valence and ionic strength dependent differences in l(p) in a direct comparison between 40-mers of deoxythymidylate (dT(40)) and uridylate (rU(40)) measured using the powerful combination of SAXS and smFRET. We also show that nucleic acid flexibility is influenced by local environment (an adjoining double helix). Our results illustrate the complex interplay between conformation and ion environment that modulates nucleic acid function in vivo. PMID- 22203974 TI - Cenozoic climate change influences mammalian evolutionary dynamics. AB - Global climate change is having profound impacts on the natural world. However, climate influence on faunal dynamics at macroevolutionary scales remains poorly understood. In this paper we investigate the influence of climate over deep time on the diversity patterns of Cenozoic North American mammals. We use factor analysis to identify temporally correlated assemblages of taxa, or major evolutionary faunas that we can then study in relation to climatic change over the past 65 million years. These taxa can be grouped into six consecutive faunal associations that show some correspondence with the qualitative mammalian chronofaunas of previous workers. We also show that the diversity pattern of most of these chronofaunas can be correlated with the stacked deep-sea benthic foraminiferal oxygen isotope (delta(18)O) curve, which strongly suggests climatic forcing of faunal dynamics over a large macroevolutionary timescale. This study demonstrates the profound influence of climate on the diversity patterns of North American terrestrial mammals over the Cenozoic. PMID- 22203975 TI - Multiple independent introductions of Plasmodium falciparum in South America. AB - The origin of Plasmodium falciparum in South America is controversial. Some studies suggest a recent introduction during the European colonizations and the transatlantic slave trade. Other evidence--archeological and genetic--suggests a much older origin. We collected and analyzed P. falciparum isolates from different regions of the world, encompassing the distribution range of the parasite, including populations from sub-Saharan Africa, the Middle East, Southeast Asia, and South America. Analyses of microsatellite and SNP polymorphisms show that the populations of P. falciparum in South America are subdivided in two main genetic clusters (northern and southern). Phylogenetic analyses, as well as Approximate Bayesian Computation methods suggest independent introductions of the two clusters from African sources. Our estimates of divergence time between the South American populations and their likely sources favor a likely introduction from Africa during the transatlantic slave trade. PMID- 22203976 TI - Type 1 ryanodine receptor knock-in mutation causing central core disease of skeletal muscle also displays a neuronal phenotype. AB - The type 1 ryanodine receptor (RyR1) is expressed widely in the brain, with high levels in the cerebellum, hippocampus, and hypothalamus. We have shown that L type Ca(2+) channels in terminals of hypothalamic magnocellular neurons are coupled to RyRs, as they are in skeletal muscle, allowing voltage-induced Ca(2+) release (VICaR) from internal Ca(2+) stores without Ca(2+) influx. Here we demonstrate that RyR1 plays a role in VICaR in nerve terminals. Furthermore, in heterozygotes from the Ryr1(I4895T/WT) (IT/+) mouse line, carrying a knock-in mutation corresponding to one that causes a severe form of human central core disease, VICaR is absent, demonstrating that type 1 RyR mediates VICaR and that these mice have a neuronal phenotype. The absence of VICaR was shown in two ways: first, depolarization in the absence of Ca(2+) influx elicited Ca(2+)syntillas (scintilla, spark, in a nerve terminal, a SYNaptic structure) in WT, but not in mutant terminals; second, in the presence of extracellular Ca(2+), IT/+ terminals showed a twofold decrease in global Ca(2+) transients, with no change in plasmalemmal Ca(2+) current. From these studies we draw two conclusions: (i) RyR1 plays a role in VICaR in hypothalamic nerve terminals; and (ii) a neuronal alteration accompanies the myopathy in IT/+ mice, and, possibly in humans carrying the corresponding RyR1 mutation. PMID- 22203977 TI - Thrombocytopenia and erythrocytosis in mice with a mutation in the gene encoding the hemoglobin beta minor chain. AB - Diverse mutations in the genes encoding hemoglobin (Hb) have been characterized in human disease. We describe here a mutation in the mouse Hbb-b2 gene, denoted Plt12, that precisely mimics the human hemoglobin Hotel Dieu variant. The mutation results in increased affinity of Hb for oxygen and Plt12 mutant mice exhibited reduced partial pressure of O(2) in the blood, accompanied by erythrocytosis characterized by elevated erythropoietin levels and splenomegaly with excess erythropoiesis. Most homozygous Hbb-b2(Plt12/Plt12) mice succumbed to early lethality associated with emphysema, cardiac abnormalities, and liver degeneration. Survivors displayed a marked thrombocytopenia without significant deficiencies in the numbers of megakaryocytes or megakaryocyte progenitor cells. The lifespan of platelets in the circulation of Hbb-b2(Plt12/Plt12) mice was normal, and splenectomy did not correct the thrombocytopenia, suggesting that increased sequestration was unlikely to be a major contributor. These data, together with the observation that megakaryocytes in Hbb-b2(Plt12/Plt12) mice appeared smaller and deficient in cytoplasm, support a model in which hypoxia causes thrombocytopenia as a consequence of an inability of megakaryocytes, once formed, to properly mature and produce sufficient platelets. The Plt12 mouse is a model of high O(2)-affinity hemoglobinopathy and provides insights into hematopoiesis under conditions of chronic hypoxia. PMID- 22203978 TI - Cheating monkeys undermine group strength in enemy territory. AB - In many social animals, group-mates cooperate to defend their range against intrusion by neighboring groups. Because group size tends to be highly variable, such conflicts are often asymmetric. Although numerical superiority is assumed to provide a competitive advantage, small groups can generally defend their ranges, even when greatly outnumbered. The prevailing explanation for this puzzling phenomenon is that individuals in relatively large groups experience a greater temptation to flee from conflicts, in effect leveling the balance of power. Using playback experiments simulating territorial intrusions by wild capuchin monkey (Cebus capucinus) groups, we show that such a collective action problem does indeed undermine the competitive ability of large groups. Focal capuchins were more likely to run away from territorial intrusions when their group had a numeric advantage; each one-individual increase in relative group size raised the odds of flight by 25%. However, interaction location had a more important impact on individuals' reactions, creating a strong home-field advantage. After controlling for relative group size, the odds that a focal animal fled were 91% lower in experiments that occurred in the center compared with on the edge of its group's range, whereas the odds that it rushed toward the speaker were more than sixfold higher. These location-dependent patterns of defection and cooperation create a competitive advantage for residents over intruders across a wide range of relative group sizes, which may stabilize range boundaries and provide a general explanation for how groups of widely divergent sizes can coexist, even in the face of intense intergroup competition. PMID- 22203980 TI - Retraction for Lo et al., Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. PMID- 22203979 TI - Lethal arrhythmias in Tbx3-deficient mice reveal extreme dosage sensitivity of cardiac conduction system function and homeostasis. AB - TBX3 is critical for human development: mutations in TBX3 cause congenital anomalies in patients with ulnar-mammary syndrome. Data from mice and humans suggest multiple roles for Tbx3 in development and function of the cardiac conduction system. The mechanisms underlying the functional development, maturation, and maintenance of the conduction system are not well understood. We tested the requirements for Tbx3 in these processes. We generated a unique series of Tbx3 hypomorphic and conditional mouse mutants with varying levels and locations of Tbx3 activity within the heart, and developed techniques for evaluating in vivo embryonic conduction system function. Disruption of Tbx3 function in different regions of the developing heart causes discrete phenotypes and lethal arrhythmias: sinus pauses and bradycardia indicate sinoatrial node dysfunction, whereas preexcitation and atrioventricular block reveal abnormalities in the atrioventricular junction. Surviving Tbx3 mutants are at increased risk for sudden death. Arrhythmias induced by knockdown of Tbx3 in adults reveal its requirement for conduction system homeostasis. Arrhythmias in Tbx3-deficient embryos are accompanied by disrupted expression of multiple ion channels despite preserved expression of previously described conduction system markers. These findings indicate that Tbx3 is required for the conduction system to establish and maintain its correct molecular identity and functional properties. In conclusion, Tbx3 is required for the functional development, maturation, and homeostasis of the conduction system in a highly dosage-sensitive manner. TBX3 and its regulatory targets merit investigation as candidates for human arrhythmias. PMID- 22203981 TI - Role for the molecular chaperones Zuo1 and Ssz1 in quorum sensing via activation of the transcription factor Pdr1. AB - Zuo1 functions as a J-protein cochaperone of its partner Hsp70. In addition, the C terminus of Zuo1 and the N terminus of Ssz1, with which Zuo1 forms a heterodimer, can independently activate the Saccharomyces cerevisiae transcription factor pleiotropic drug resistance 1 (Pdr1). Here we report that activation of Pdr1 by Zuo1 or Ssz1 causes premature growth arrest of cells during the diauxic shift, as they adapt to the changing environmental conditions. Conversely, cells lacking Zuo1 or Ssz1 overgrow, arresting at a higher cell density, an effect overcome by activation of Pdr1. Cells lacking the genes encoding plasma membrane transporters Pdr5 and Snq2, two targets of Pdr1, also overgrow at the diauxic shift. Adding conditioned medium harvested from cultures of wild-type cells attenuated the overgrowth of both zuo1Deltassz1Delta and pdr5Deltasnq2Delta cells, suggesting the extracellular presence of molecules that signal growth arrest. In addition, our yeast two-hybrid analysis revealed an interaction between Pdr1 and both Zuo1 and Ssz1. Together, our results support a model in which (i) membrane transporters, encoded by Pdr1 target genes act to promote cell-cell communication by exporting quorum sensing molecules, in addition to playing a role in pleiotropic drug resistance; and (ii) molecular chaperones function at promoters to regulate this intercellular communication through their activation of the transcription factor Pdr1. PMID- 22203982 TI - Genome and physiology of a model Epsilonproteobacterium responsible for sulfide detoxification in marine oxygen depletion zones. AB - Eutrophication and global climate change lead to expansion of hypoxia in the ocean, often accompanied by the production of hydrogen sulfide, which is toxic to higher organisms. Chemoautotrophic bacteria are thought to buffer against increased sulfide concentrations by oxidizing hydrogen sulfide before its diffusion to oxygenated surface waters. Model organisms from such environments have not been readily available, which has contributed to a poor understanding of these microbes. We present here a detailed study of "Sulfurimonas gotlandica" str. GD1, an Epsilonproteobacterium isolated from the Baltic Sea oxic-anoxic interface, where it plays a key role in nitrogen and sulfur cycling. Whole-genome analysis and laboratory experiments revealed a high metabolic flexibility, suggesting a considerable capacity for adaptation to variable redox conditions. S. gotlandica str. GD1 was shown to grow chemolithoautotrophically by coupling denitrification with oxidation of reduced sulfur compounds and dark CO(2) fixation. Metabolic versatility was further suggested by the use of a range of different electron donors and acceptors and organic carbon sources. The number of genes involved in signal transduction and metabolic pathways exceeds those of other Epsilonproteobacteria. Oxygen tolerance and environmental-sensing systems combined with chemotactic responses enable this organism to thrive successfully in marine oxygen-depletion zones. We propose that S. gotlandica str. GD1 will serve as a model organism in investigations that will lead to a better understanding how members of the Epsilonproteobacteria are able to cope with water column anoxia and the role these microorganisms play in the detoxification of sulfidic waters. PMID- 22203983 TI - Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation. AB - Acute graft-versus-host disease (GvHD) is a major complication that prevents successful outcomes after allogeneic bone marrow transplantation (BMT), an effective therapy for hematological malignancies. Several studies demonstrate that donor T cells and host antigen-presenting cells along with several proinflammatory cytokines are required for the induction of GvHD and contribute to its severity. Increasing evidence demonstrates that human serum-derived alphaalpha-1- anti-trypsin (AAT) reduces production of proinflammatory cytokines, induces anti-inflammatory cytokines, and interferes with maturation of dendritic cells. Using well-characterized mouse models of BMT, we have studied the effects of AAT on GvHD severity. Administration of AAT early after BMT decreased mortality in three models of GvHD and reduced serum levels of proinflammatory cytokines in the allogeneic recipients compared with vehicle (albumin) treated animals. AAT treatment reduced the expansion of alloreactive T effector cells but enhanced the recovery of T regulatory T cells, (Tregs) thus altering the ratio of donor T effector to T regulatory cells in favor of reducing the pathological process. However, despite altering the ratio in vivo, AAT had no direct effects on either the donor T effector cells or T regulatory cells Tregs in vitro. In contrast, AAT suppressed LPS-induced in vitro secretion of proinflammatory cytokines such as TNF-alpha and IL-1beta, enhanced the production of the anti inflammatory cytokine IL-10, and impaired NF-kappaB translocation in the host dendritic cells. In light of its long history of safety in humans, these findings suggest that administration of AAT represents a novel unique and viable strategy to mitigate clinical GvHD. PMID- 22203984 TI - Interpolity exchange of basalt tools facilitated via elite control in Hawaiian archaic states. AB - Ethnohistoric accounts of late precontact Hawaiian archaic states emphasize the independence of chiefly controlled territories (ahupua'a) based on an agricultural, staple economy. However, elite control of unevenly distributed resources, such as high-quality volcanic rock for adze production, may have provided an alternative source of economic power. To test this hypothesis we used nondestructive energy-dispersive X-ray fluorescence (ED-XRF) analysis of 328 lithic artifacts from 36 archaeological features in the Kahikinui district, Maui Island, to geochemically characterize the source groups. This process was followed by a limited sampling using destructive wavelength-dispersive X-ray fluorescence (WD-XRF) analysis to more precisely characterize certain nonlocal source groups. Seventeen geochemical groups were defined, eight of which represent extra-Maui Island sources. Although the majority of stone tools were derived from Maui Island sources (71%), a significant quantity (27%) of tools derived from extraisland sources, including the large Mauna Kea quarry on Hawai'i Island as well as quarries on O'ahu, Moloka'i, and Lana'i islands. Importantly, tools quarried from extralocal sources are found in the highest frequency in elite residential features and in ritual contexts. These results suggest a significant role for a wealth economy based on the control and distribution of nonagricultural goods and resources during the rise of the Hawaiian archaic states. PMID- 22203985 TI - Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma. AB - Because oncogene MET and EGF receptor (EGFR) inhibitors are in clinical development against several types of cancer, including glioblastoma, it is important to identify predictive markers that indicate patient subgroups suitable for such therapies. We investigated in vivo glioblastoma models characterized by hepatocyte growth factor (HGF) autocrine or paracrine activation, or by MET or EGFR amplification, for their susceptibility to MET inhibitors. HGF autocrine expression correlated with high phospho-MET levels in HGF autocrine cell lines, and these lines showed high sensitivity to MET inhibition in vivo. An HGF paracrine environment may enhance glioblastoma growth in vivo but did not indicate sensitivity to MET inhibition. EGFRvIII amplification predicted sensitivity to EGFR inhibition, but in the same tumor, increased copies of MET from gains of chromosome 7 did not result in increased MET activity and did not predict sensitivity to MET inhibitors. Thus, HGF autocrine glioblastoma bears an activated MET signaling pathway that may predict sensitivity to MET inhibitors. Moreover, serum HGF levels may serve as a biomarker for the presence of autocrine tumors and their responsiveness to MET therapeutics. PMID- 22203986 TI - D-amino acid oxidase controls motoneuron degeneration through D-serine. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving an extensive loss of motoneurons. Aberrant excitability of motoneurons has been implicated in the pathogenesis of selective motoneuronal death in ALS. D serine, an endogenous coagonist of N-methyl-D-aspartate receptors, exacerbates motoneuronal death and is increased both in patients with sporadic/familial ALS and in a G93A-SOD1 mouse model of ALS (mSOD1 mouse). More recently, a unique mutation in the D-amino acid oxidase (DAO) gene, encoding a D-serine degrading enzyme, was reported to be associated with classical familial ALS. However, whether DAO affects the motoneuronal phenotype and D-serine increase in ALS remains uncertain. Here, we show that genetic inactivation of DAO in mice reduces the number and size of lower motoneurons with axonal degeneration, and that suppressed DAO activity in reactive astrocytes in the reticulospinal tract, one of the major inputs to the lower motoneurons, predominantly contributes to the D serine increase in the mSOD1 mouse. The DAO inactivity resulted from expressional down-regulation, which was reversed by inhibitors of a glutamate receptor and MEK, but not by those of inflammatory stimuli. Our findings provide evidence that DAO has a pivotal role in motoneuron degeneration through D-serine regulation and that inactivity of DAO is a common feature between the mSOD1 ALS mouse model and the mutant DAO-associated familial ALS. The therapeutic benefit of reducing D serine or controlling DAO activity in ALS should be tested in future studies. PMID- 22203987 TI - Human cytomegalovirus activation of ERK and myeloid cell leukemia-1 protein correlates with survival of latently infected cells. AB - The ability of human CMV (HCMV) to enter and establish a latent infection in myeloid cells is crucial for survival and transmission in the human population. Initial pathogen binding and entry triggers a number of antiviral responses, including the activation of proapoptotic cell death pathways, which must be countered during latency establishment. However, mechanisms responsible for a prosurvival state in myeloid cells upon latent HCMV infection remain completely undefined. We hypothesized that the cellular antiapoptotic machinery must be initially activated by HCMV to promote early survival events upon entry. Here we show that HCMV transiently protects nonpermissive myeloid cells from chemical and virus entry induced cell death by up-regulating a key myeloid cell survival gene, myeloid cell leukemia (MCL)-1 protein. The induction of MCL-1 expression was independent of viral gene expression but dependent on activation of the ERK-MAPK pathway by viral glycoprotein B. Inhibition of ERK-MAPK signaling, inhibition of HCMV fusion, antibody-mediated neutralization of glycoprotein B signaling or expression of a shRNA against MCL-1 all correlated with increased cell death in response to virus infection or chemical stimulation. Finally we show that activation of ERK-MAPK signaling impacts on long-term latency and reactivation in hematopoietic cells. Thus, HCMV primes myeloid cells for from the initial virus cell encounter. Given the importance of ERK and MCL-1 for myeloid cell survival, the successful establishment of HCMV latency in myeloid progenitors begins at the point of virus entry. PMID- 22203989 TI - Unexpectedly high mortality in Pacific herring embryos exposed to the 2007 Cosco Busan oil spill in San Francisco Bay. AB - In November 2007, the container ship Cosco Busan released 54,000 gallons of bunker fuel oil into San Francisco Bay. The accident oiled shoreline near spawning habitats for the largest population of Pacific herring on the west coast of the continental United States. We assessed the health and viability of herring embryos from oiled and unoiled locations that were either deposited by natural spawning or incubated in subtidal cages. Three months after the spill, caged embryos at oiled sites showed sublethal cardiac toxicity, as expected from exposure to oil-derived polycyclic aromatic compounds (PACs). By contrast, embryos from the adjacent and shallower intertidal zone showed unexpectedly high rates of tissue necrosis and lethality unrelated to cardiotoxicity. No toxicity was observed in embryos from unoiled sites. Patterns of PACs at oiled sites were consistent with oil exposure against a background of urban sources, although tissue concentrations were lower than expected to cause lethality. Embryos sampled 2 y later from oiled sites showed modest sublethal cardiotoxicity but no elevated necrosis or mortality. Bunker oil contains the chemically uncharacterized remains of crude oil refinement, and one or more of these unidentified chemicals likely interacted with natural sunlight in the intertidal zone to kill herring embryos. This reveals an important discrepancy between the resolving power of current forensic analytical chemistry and biological responses of keystone ecological species in oiled habitats. Nevertheless, we successfully delineated the biological impacts of an oil spill in an urbanized coastal estuary with an overlapping backdrop of atmospheric, vessel, and land-based sources of PAC pollution. PMID- 22203988 TI - Activation of growth hormone releasing hormone (GHRH) receptor stimulates cardiac reverse remodeling after myocardial infarction (MI). AB - Both cardiac myocytes and cardiac stem cells (CSCs) express the receptor of growth hormone releasing hormone (GHRH), activation of which improves injury responses after myocardial infarction (MI). Here we show that a GHRH-agonist (GHRH-A; JI-38) reverses ventricular remodeling and enhances functional recovery in the setting of chronic MI. This response is mediated entirely by activation of GHRH receptor (GHRHR), as demonstrated by the use of a highly selective GHRH antagonist (MIA-602). One month after MI, animals were randomly assigned to receive: placebo, GHRH-A (JI-38), rat recombinant GH, MIA-602, or a combination of GHRH-A and MIA-602, for a 4-wk period. We assessed cardiac performance and hemodynamics by using echocardiography and micromanometry derived pressure-volume loops. Morphometric measurements were carried out to determine MI size and capillary density, and the expression of GHRHR was assessed by immunofluorescence and quantitative RT-PCR. GHRH-A markedly improved cardiac function as shown by echocardiographic and hemodynamic parameters. MI size was substantially reduced, whereas myocyte and nonmyocyte mitosis was markedly increased by GHRH-A. These effects occurred without increases in circulating levels of growth hormone and insulin-like growth factor I and were, at least partially, nullified by GHRH antagonism, confirming a receptor-mediated mechanism. GHRH-A stimulated CSCs proliferation ex vivo, in a manner offset by MIA-602. Collectively, our findings reveal the importance of the GHRH signaling pathway within the heart. Therapy with GHRH-A although initiated 1 mo after MI substantially improved cardiac performance and reduced infarct size, suggesting a regenerative process. Therefore, activation of GHRHR provides a unique therapeutic approach to reverse remodeling after MI. PMID- 22203990 TI - Growth, metabolic partitioning, and the size of microorganisms. AB - Population growth rate is a fundamental ecological and evolutionary characteristic of living organisms, but individuals must balance the metabolism devoted to biosynthesis and reproduction against the maintenance of existing structure and other functionality. Here we present a mathematical model that relates metabolic partitioning to the form of growth. The model captures the observed growth trajectory of single cells and individuals for a variety of species and taxa spanning prokaryotes, unicellular eukaryotes, and small multicellular eukaryotes. Our analysis suggests that the per-unit costs of biosynthesis and maintenance are conserved across prokaryotes and eukaryotes. However, the relative metabolic expenditure on growth and maintenance of whole organisms clearly differentiates taxa: prokaryotes spend an increasing fraction of their entire metabolism on growth with increasing cell size, whereas eukaryotes devote a diminishing fraction. These differences allow us to predict the minimum and maximum size for each taxonomic group, anticipating observed evolutionary life-history transitions. The framework provides energetic insights into taxonomic tradeoffs related to growth and metabolism and constrains traits that are important for size-structured modeling of microbial communities and their ecological and biogeochemical effects. PMID- 22203991 TI - Targeting oncogenic serine/threonine-protein kinase BRAF in cancer cells inhibits angiogenesis and abrogates hypoxia. AB - Carcinomas are comprised of transformed epithelial cells that are supported in their growth by a dedicated neovasculature. How the genetic milieu of the epithelial compartment influences tumor angiogenesis is largely unexplored. Drugs targeted to mutant cancer genes may act not only on tumor cells but also, directly or indirectly, on the surrounding stroma. We investigated the role of the BRAF(V600E) oncogene in tumor/vessel crosstalk and analyzed the effect of the BRAF inhibitor PLX4720 on tumor angiogenesis. Knock-in of the BRAF(V600E) allele into the genome of human epithelial cells triggered their angiogenic response. In cancer cells harboring oncogenic BRAF, the inhibitor PLX4720 switches off the ERK pathway and inhibits the expression of proangiogenic molecules. In tumor xenografts harboring the BRAF(V600E), PLX4720 extensively modifies the vascular network causing abrogation of hypoxia. Overall, our results provide a functional link between oncogenic BRAF and angiogenesis. Furthermore, they indicate how the tumor vasculature can be "indirectly" besieged through targeting of a genetic lesion to which the cancer cells are addicted. PMID- 22203992 TI - Extensive genetic diversity and substructuring among zebrafish strains revealed through copy number variant analysis. AB - Copy number variants (CNVs) represent a substantial source of genomic variation in vertebrates and have been associated with numerous human diseases. Despite this, the extent of CNVs in the zebrafish, an important model for human disease, remains unknown. Using 80 zebrafish genomes, representing three commonly used laboratory strains and one native population, we constructed a genome-wide, high resolution CNV map for the zebrafish comprising 6,080 CNV elements and encompassing 14.6% of the zebrafish reference genome. This amount of copy number variation is four times that previously observed in other vertebrates, including humans. Moreover, 69% of the CNV elements exhibited strain specificity, with the highest number observed for Tubingen. This variation likely arose, in part, from Tubingen's large founding size and composite population origin. Additional population genetic studies also provided important insight into the origins and substructure of these commonly used laboratory strains. This extensive variation among and within zebrafish strains may have functional effects that impact phenotype and, if not properly addressed, such extensive levels of germ-line variation and population substructure in this commonly used model organism can potentially confound studies intended for translation to human diseases. PMID- 22203993 TI - AMP-activated protein kinase is physiologically regulated by inositol polyphosphate multikinase. AB - The AMP-activated kinase (AMPK) senses the energy status of cells and regulates fuel availability, whereas hypothalamic AMPK regulates food intake. We report that inositol polyphosphate multikinase (IPMK) regulates glucose signaling to AMPK in a pathway whereby glucose activates phosphorylation of IPMK at tyrosine 174 enabling the enzyme to bind to AMPK and regulate its activation. Thus, refeeding fasted mice rapidly and markedly stimulates transcriptional enhancement of IPMK expression while down-regulating AMPK. Also, AMPK is up-regulated in mice with genetic depletion of hypothalamic IPMK. IPMK physiologically binds AMPK, with binding enhanced by glucose treatment. Regulation by glucose of phospho-AMPK in hypothalamic cell lines is prevented by blocking AMPK-IPMK binding. These findings imply that IPMK inhibitors will be beneficial in treating obesity and diabetes. PMID- 22203995 TI - TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2. AB - The decision between survival and death in cells exposed to TNF relies on a highly regulated equilibrium between proapoptotic and antiapoptotic factors. The TNF-activated antiapoptotic response depends on several transcription factors, including NF-kappaB and its RelA/p65 subunit, that are activated through phosphorylation-mediated degradation of IkappaB inhibitors, a process controlled by the IkappaB kinase complex. Genetic studies in mice have identified the IkappaB kinase-related kinase TANK-binding kinase 1 (TBK1; also called NAK or T2K) as an additional regulatory molecule that promotes survival downstream of TNF, but the mechanism through which TBK1 exerts its survival function has remained elusive. Here we show that TBK1 triggers an antiapoptotic response by controlling a specific RelA/p65 phosphorylation event. TBK1-induced RelA phosphorylation results in inducible expression of plasminogen activator inhibitor-2 (PAI-2), a member of the serpin family with known antiapoptotic activity. PAI-2 limits caspase-3 activation through stabilization of transglutaminase 2 (TG2), which cross-links and inactivates procaspase-3. Importantly, Tg2(-/-) mice were found to be more susceptible to apoptotic cell death in two models of TNF-dependent acute liver injury. Our results establish PAI-2 and TG2 as downstream mediators in the antiapoptotic response triggered upon TBK1 activation. PMID- 22203994 TI - Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase. AB - Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 with the guanine nucleotide exchange factor Vav1. The model predicts that NCF2/H389 residue interacts with Vav1 residues E509, N510, E556, and G559 in the ZF domain of Vav1. Furthermore, replacing H389 with Q results in 1.5 kcal/mol weaker binding. To examine the effect of the NCF2 H389Q mutation on NADPH oxidase function, site-specific mutations at the 389 position in NCF2 were tested. Results show that an H389Q mutation causes a twofold decrease in reactive oxygen species production induced by the activation of the Vav-dependent Fcgamma receptor-elicited NADPH oxidase activity. Our study completes the chain of evidence from genetic association to specific molecular function. PMID- 22203996 TI - Evolutionary conservation of the habenular nuclei and their circuitry controlling the dopamine and 5-hydroxytryptophan (5-HT) systems. AB - The medial (MHb) and lateral (LHb) habenulae are a small group of nuclei that regulate the activity of monoaminergic neurons. Disruptions to these nuclei lead to deficits in a range of cognitive and motor functions from sleep to decision making. Interestingly, the habenular nuclei are present in all vertebrates, suggesting that they provide a common neural mechanism to influence these diverse functions. To unravel conserved habenula circuitry and approach an understanding of their basic function, we investigated the organization of these nuclei in the lamprey, one of the phylogenetically oldest vertebrates. Based on connectivity and molecular expression, we show that the MHb and LHb circuitry is conserved in the lamprey. As in mammals, separate populations of neurons in the LHb homolog project directly or indirectly to dopamine and serotonin neurons through a nucleus homologous to the GABAergic rostromedial mesopontine tegmental nucleus and directly to histamine neurons. The pallidal and hypothalamic inputs to the LHb homolog are also conserved. In contrast to other species, the habenula projecting pallidal nucleus is topographically distinct from the dorsal pallidum, the homolog of the globus pallidus interna. The efferents of the MHb homolog selectively target the interpeduncular nucleus. The MHb afferents arise from sensory (medial olfactory bulb, parapineal, and pretectum) and not limbic areas, as they do in mammals; consequently, the "context" in which this circuitry is recruited may have changed during evolution. Our results indicate that the habenular nuclei provide a common vertebrate circuitry to adapt behavior in response to rewards, stress, and other motivating factors. PMID- 22203997 TI - The channel kinase, TRPM7, is required for early embryonic development. AB - Global disruption of transient receptor potential-melastatin-like 7 (Trpm7) in mice results in embryonic lethality before embryonic day 7. Using tamoxifen inducible disruption of Trpm7 and multiple Cre recombinase lines, we show that Trpm7 deletion before and during organogenesis results in severe tissue-specific developmental defects. We find that Trpm7 is essential for kidney development from metanephric mesenchyme but not ureteric bud. Disruption of neural crest Trpm7 at early stages results in loss of pigment cells and dorsal root ganglion neurons. In contrast, late disruption of brain-specific Trpm7 after embryonic day 10.5 does not alter normal brain development. We developed induced pluripotent stem cells and neural stem (NS) cells in which Trpm7 disruption could be induced. Trpm7(-/-) NS cells retained the capacities of self-renewal and differentiation into neurons and astrocytes. During in vitro differentiation of induced pluripotent stem cells to NS cells, Trpm7 disruption prevents the formation of the NS cell monolayer. The in vivo and in vitro results demonstrate a temporal requirement for the Trpm7 channel kinase during embryogenesis. PMID- 22203999 TI - Bacterial bioluminescence as a lure for marine zooplankton and fish. AB - The benefits of bioluminescence for nonsymbiotic marine bacteria have not been elucidated fully. One of the most commonly cited explanations, proposed more than 30 y ago, is that bioluminescence augments the propagation and dispersal of bacteria by attracting fish to consume the luminous material. This hypothesis, based mostly on the prevalence of luminous bacteria in fish guts, has not been tested experimentally. Here we show that zooplankton that contacts and feeds on the luminescent bacterium Photobacterium leiognathi starts to glow, and demonstrate by video recordings that glowing individuals are highly vulnerable to predation by nocturnal fish. Glowing bacteria thereby are transferred to the nutritious guts of fish and zooplankton, where they survive digestion and gain effective means for growth and dispersal. Using bioluminescence as bait appears to be highly beneficial for marine bacteria, especially in food-deprived environments of the deep sea. PMID- 22203998 TI - Rate of meristem maturation determines inflorescence architecture in tomato. AB - Flower production and crop yields are highly influenced by the architectures of inflorescences. In the compound inflorescences of tomato and related nightshades (Solanaceae), new lateral inflorescence branches develop on the flanks of older branches that have terminated in flowers through a program of plant growth known as "sympodial." Variability in the number and organization of sympodial branches produces a remarkable array of inflorescence architectures, but little is known about the mechanisms underlying sympodial growth and branching diversity. One hypothesis is that the rate of termination modulates branching. By performing deep sequencing of transcriptomes, we have captured gene expression dynamics from individual shoot meristems in tomato as they gradually transition from a vegetative state to a terminal flower. Surprisingly, we find thousands of age dependent expression changes, even when there is little change in meristem morphology. From these data, we reveal that meristem maturation is an extremely gradual process defined molecularly by a "meristem maturation clock." Using hundreds of stage-enriched marker genes that compose this clock, we show that extreme branching, conditioned by loss of expression of the COMPOUND INFLORESCENCE gene, is driven by delaying the maturation of both apical and lateral meristems. In contrast, we find that wild tomato species display a delayed maturation only in apical meristems, which leads to modest branching. Our systems genetics approach reveals that the program for inflorescence branching is initiated surprisingly early during meristem maturation and that evolutionary diversity in inflorescence architecture is modulated by heterochronic shifts in the acquisition of floral fate. PMID- 22204000 TI - Milk fat globule-epidermal growth factor 8 is decreased in intestinal epithelium of ulcerative colitis patients and thereby causes increased apoptosis and impaired wound healing. AB - Milk fat globule-epidermal growth factor 8 (MFG-E8) plays an important role in maintaining intestinal barrier homeostasis and accelerating intestinal restitution. However, studies of MFG-E8 expression in humans with ulcerative colitis are lacking. We examined MFG-E8 expression in colonic mucosal biopsies from ulcerative colitis patients and healthy controls (n = 26 each) by real-time quantitative polymerase chain reaction (PCR), Western blot analysis and immunohistochemistry. MFG-E8 mRNA and protein expression was lower in ulcerative colitis patients than in controls. MFG-E8 expression was inversely correlated with mucosal inflammatory activity and clinical disease activity in patients. MFG E8 was present in human intestinal epithelial cells both in vivo and in vitro. Apoptosis induction was also detected in the intestinal epithelium of ulcerative colitis patients by terminal-deoxynucleoitidyl transferase mediated nick-end labeling assay. We used lentiviral vectors encoding human MFG-E8 targeting short hairpin RNA to obtain MFG-E8 knockdown intestinal epithelia cell clones. MFG-E8 knockdown could promote apoptosis in intestinal epithelial cell lines, accompanied by a decrease in level of the antiapoptotic protein B-cell lymphoma 2 (BCL-2) and induction of the proapoptotic protein BCL2-associated protein X (BAX). The addition of recombinant human MFG-E8 led to decreased BAX and cleaved caspase-3 levels and induction of BCL-2 level in intestinal epithelia cells. MFG E8 knockdown also attenuated wound healing on scratch assay of intestinal epithelial cells. The mRNA level of intestinal trefoid factor 3, a pivotal factor in intestinal epithelial cell migration and restitution, was downregulated with MFG-E8 knockdown. In conclusion, we demonstrated that decreased colonic MFG-E8 expression in patients with ulcerative colitis may be associated with mucosal inflammatory activity and clinical disease activity through basal cell apoptosis and preventing tissue healing in the pathogenesis of ulcerative colitis. PMID- 22204002 TI - Patellar resurfacing in total knee replacement: five-year clinical and economic results of a large randomized controlled trial. AB - BACKGROUND: There is conflicting evidence regarding the merits of patellar resurfacing during total knee arthroplasty, as many of the previous randomized controlled trials have not been adequately powered. METHODS: A pragmatic, multicenter, randomized controlled trial was initiated in 1999 in the United Kingdom. Within a partial factorial design, 1715 patients were randomly allocated to receive or not receive patellar resurfacing during total knee arthroplasty. The primary outcome measure was the Oxford Knee Score; secondary measures included the Short Form-12, the EuroQoL 5D, cost, cost-effectiveness, and the need for subsequent knee surgery. RESULTS: The mean Oxford Knee Score was 35 points at five years postoperatively in both groups. There was no significant difference between the groups with respect to the mean Oxford Knee Score (difference, 0.59 point; 95% confidence interval, -0.58 to 1.76 points) or any other outcome measure at five years postoperatively. The outcome was not affected by whether the patella was domed or anatomic. There was no significant difference between the two groups with respect to the prevalence of knee-related readmission, of minor or intermediate reoperation, or of subsequent patella related surgery. The total health care cost for the primary arthroplasty, subsequent monitoring, and any revision surgery did not differ significantly between the two groups. CONCLUSIONS: In the largest randomized controlled trial of patellar resurfacing reported to date, the functional outcome, reoperation rate, and total health care cost five years after primary total knee arthroplasty were not significantly affected by the addition of patellar resurfacing to the surgical procedure. PMID- 22204001 TI - Poly(ADP-ribosyl)ation of high mobility group box 1 (HMGB1) protein enhances inhibition of efferocytosis. AB - Phagocytosis of apoptotic cells by macrophages, known as efferocytosis, is a critical process in the resolution of inflammation. High mobility group box 1 (HMGB1) protein was first described as a nuclear nonhistone DNA-binding protein, but is now known to be secreted by activated cells during inflammatory processes, where it participates in diminishing efferocytosis. Although HMGB1 is known to undergo modification when secreted, the effect of such modifications on the inhibitory actions of HMGB1 during efferocytosis have not been reported. In the present studies, we found that HMGB1 secreted by Toll-like receptor 4 (TLR4) stimulated cells is highly poly(ADP-ribosyl)ated (PARylated). Gene deletion of poly(ADP)-ribose polymerase (PARP)-1 or pharmacological inhibition of PARP-1 decreased the release of HMGB1 from the nucleus to the extracellular milieu after TLR4 engagement. Preincubation of macrophages or apoptotic cells with HMGB1 diminished efferocytosis through mechanisms involving binding of HMGB1 to phosphatidylserine on apoptotic cells and to the receptor for advanced glycation end products (RAGE) on macrophages. Preincubation of either macrophages or apoptotic cells with PARylated HMGB1 inhibited efferocytosis to a greater degree than exposure to unmodified HMGB1, and PARylated HMGB1 demonstrated higher affinity for phosphatidylserine and RAGE than unmodified HMGB1. PARylated HMGB1 had a greater inhibitory effect on Ras-related C3 botulinum toxin substrate 1 (Rac-1) activation in macrophages during the uptake of apoptotic cells than unmodified HMGB1. The present results, showing that PARylation of HMGB1 enhances its ability to inhibit efferocytosis, provide a novel mechanism by which PARP-1 may promote inflammation. PMID- 22204003 TI - Lumbar plexus anatomy within the psoas muscle: implications for the transpsoas lateral approach to the L4-L5 disc. AB - BACKGROUND: The transpsoas lateral surgical approach has been advocated as an alternative to direct anterior approaches for less invasive or minimally invasive access to the spine. Postoperative thigh pain, paresthesia, and/or weakness have been described after the use of this surgical approach. The purpose of this cadaveric anatomic study is to provide a description of the lumbar plexus as it relates to the transpsoas lateral surgical approach. METHODS: Dissection of the lumbar plexus was performed in eighteen cadaveric specimens. Needle markers were placed in the L2-L3, L3-L4, and L4-L5 discs in the midcoronal plane. The anatomic structures were surveyed, and the proximity of the needle to the neural structures was observed. RESULTS: In thirteen of the eighteen specimens, the femoral nerve received its contributions from the L2 to L4 nerve roots and was formed at the L4-L5 disc space. In all specimens, the femoral nerve passed dorsal to or directly at the midpoint of the disc. In three specimens, the needle displaced or was immediately adjacent to the femoral nerve. The femoral nerve was found between the needle and the posterior aspect of the L4-L5 disc space in thirteen of the eighteen specimens. CONCLUSIONS: Because of the proximity of the neural elements, in particular the femoral nerve, to the center of the disc space, the transpsoas lateral surgical approach to the L4-L5 disc space will likely cause intraoperative displacement of neural structures from their anatomic course during retractor dilation. Careful attention should be paid to retractor placement and dilation time during transpsoas lateral access surgery, particularly at the L4-L5 disc. PMID- 22204004 TI - Alterations in recovery from spinal cord injury in rats treated with recombinant human bone morphogenetic protein-2 for posterolateral arthrodesis. AB - BACKGROUND: Treatment of trauma-related spinal instability with use of recombinant human bone morphogenetic protein-2 (rhBMP-2) may appear as a viable option, but little is known of the direct effects of rhBMP-2 on the injured spinal cord. In the current study, we investigated the acute and long-term effects of using rhBMP-2 in the posterolateral spine at the level of a spinal cord injury in rats. METHODS: Fifty-two rats underwent a T10 dorsal hemisection and were assigned to one of two groups: the vehicle control group (twenty-four rats) or the rhBMP-2 group (twenty-four rats). Within each group, animals were further subdivided according to the follow-up period: one week and six weeks after the lesion. For the acute phase, an additional group of four rats received recombinant human albumin, to account for the cross-species inflammatory response. Postoperatively, locomotor function was assessed on a weekly basis with use of an open field scale and digital footprint analysis. After the animals were killed, they were perfused and the spinal cords analyzed for inflammatory markers, gliosis, and extracellular matrix proteins with use of immunohistochemistry. RESULTS: At one week, there was a significant increase in reactive astrocyte, macrophage-microglia, and fibroblast immunoreactivity around the lesion in the rhBMP-2-treated rats relative to controls. Additionally, there was increased staining for chondroitin sulfate proteoglycans. Similar intergroup morphologic differences persisted at six weeks. Functionally, in the acute phase, rhBMP-2-treated animals demonstrated more open field and fine motor control deficits relative to the controls. By six weeks, both groups had equivalent functional scores, but those treated with rhBMP-2 retained significantly greater paw angle changes than the control animals. CONCLUSIONS: Our findings indicate that in a rat model, rhBMP-2 use in the vicinity of a penetrating spinal cord injury triggers detrimental changes in the morphology of the spinal cord lesion and alters functional recovery. PMID- 22204005 TI - Histopathology of femoral head donations: a retrospective review of 6161 cases. AB - BACKGROUND: Although total hip arthroplasty is one of the most common orthopaedic surgical procedures, it remains unclear whether histopathological examination of the excised femoral head adds to the quality of patient care. We propose that assessment of femoral heads resected during total hip arthroplasty and donated for allograft use may provide a profile of femoral head pathology that benefits total hip arthroplasty patients and bone donors. METHODS: We retrospectively analyzed the histological findings reported for 6161 femoral heads donated for allograft use between 1993 and 2006. Specimens obtained during total hip arthroplasty and specimens donated at death were reviewed. Follow-up investigations that resulted from abnormal histopathological findings were also reviewed. The Western Australian Cancer Registry was used to determine whether patients with a suspected neoplasm were subsequently diagnosed with such a disease. A retrospective review of the histopathological findings was conducted to evaluate and reclassify all previous observations of abnormalities. RESULTS: One hundred and five femoral heads demonstrated abnormal or reactive histopathological features not reported prior to surgery and were rejected for allograft use. A reactive lymphocytic infiltrate, most likely due to osteoarthritis, was the most commonly identified feature (forty-five cases). Other features observed in twenty-seven cases were also most likely due to the presence of severe osteoarthritis. Ten femoral heads demonstrated plasmacytosis, which may have been related to osteoarthritis. Two patients were diagnosed with Paget's disease, and two, with rheumatoid arthritis. Nineteen patients had a suspected neoplasm. Of these nineteen, eight cases of non-Hodgkin's lymphoma or chronic lymphocytic leukemia and one case of myelodysplastic syndrome were confirmed on further investigation. One subsequently confirmed malignancy was detected per 770 femoral heads examined. CONCLUSIONS: Our findings indicate that, even with a detailed medical history and careful physical examination, clinically important diseases including neoplasms and Paget's disease are observed in patients diagnosed with osteoarthritis prior to total hip arthroplasty. Histological examination plays an integral role in quality assurance in femoral head banking, and it also represents a possible early diagnostic test for bone and bone-marrow-related diseases in patients undergoing total hip arthroplasty. PMID- 22204006 TI - Bone contusion and associated meniscal and medial collateral ligament injury in patients with anterior cruciate ligament rupture. AB - BACKGROUND: The present study examined the prevalence of bone contusions in patients with anterior cruciate ligament (ACL) injury as well as its association with tears of the lateral meniscus, medial meniscus, and medial collateral ligament (MCL). METHODS: Eighty-one patients with an arthroscopy-proven ACL rupture for whom magnetic resonance images (MRI) were acquired within six weeks after the initial trauma were examined. The bone contusions on the lateral femoral condyle, lateral aspect of the tibial plateau, medial femoral condyle, and medial aspect of the tibial plateau were documented. The injury to MCL was also observed with MRI. The tears of the lateral meniscus and medial meniscus were detected during arthroscopy. The prevalence of lateral meniscus, medial meniscus, and MCL injuries was compared with the existence of the bone contusions. RESULTS: Sixty-eight (84%) of the eighty-one knees had bone contusions on magnetic resonance imaging. The prevalence of bone contusions was 68%, 73%, 24%, and 26% in the lateral femoral condyle, lateral aspect of the tibial plateau, medial femoral condyle, and medial aspect of the tibial plateau, respectively. There were two fractures of the posterolateral aspect of the tibial plateau and two fractures of the posteromedial aspect of the tibial plateau. The overall prevalences of injury to the lateral meniscus and medial meniscus were 54% (forty-four of eighty-one) and 51% (forty-one of eighty-one), respectively. The prevalence of MCL injuries was 22% (eighteen of eighty-one). The prevalences of lateral meniscus (p = 0.010), medial meniscus (p = 0.011), and MCL (p = 0.066) injuries increased as the bone contusion progressed from being absent, to involving only the lateral compartment, and finally to involving both lateral and medial compartments. CONCLUSIONS: Bone contusions were prevalent in patients with ACL ruptures, and injuries of the menisci and the MCL tended to increase with the progression of bone contusion. The contrecoup mechanism of bone contusion on the medial compartment resulting from an ACL injury was supported. These results suggest that a higher-energy injury led to a more extensive bone contusion and a greater prevalence of associated injury of other anatomic structures in the knee. PMID- 22204007 TI - Prevalence and clinical relevance of radiographic signs of impingement in metal on-metal hybrid hip resurfacing. AB - BACKGROUND: Implant-related impingement has been reported following metal-on metal hip resurfacing, and reactive osseous patterns associated with implant-bone impingement have been identified. The purpose of this study was to determine the prevalence and clinical implications of radiographic signs of femoral neck acetabular cup impingement following metal-on-metal hip resurfacing. METHODS: Serial anteroposterior and lateral radiographs made five to 12.9 years postoperatively were available for ninety-one of the first 100 metal-on-metal hip resurfacing procedures (in eighty-nine patients) performed by the senior author. These radiographs were reviewed by a single independent observer, who was blinded to the clinical results. Radiographic signs of impingement were assessed and were correlated with clinical outcomes. RESULTS: Twenty hips (in eighteen patients) had at least one of two reactive osseous signs: a solitary exostosis (six hips, 7%) and an erosive "divot-type" deformity (twenty hips, 22%). Each radiographic sign occurred predominantly at the superior aspect of the femoral neck just distal to the femoral component. None of the patients with such an impingement sign reported any symptoms or discomfort during examination of the range of hip motion. These patients had a greater mean postoperative University of California Los Angeles activity score and a greater mean range of hip motion than the patients without an impingement sign. Based on the numbers available, there was no association between component size, abduction angle and anteversion angle of the socket, femoral stem-femoral shaft angle, or femoral component-femoral neck ratio and the occurrence of repetitive impingement signs on radiographs. CONCLUSIONS: The reactive osseous features identified in this study should facilitate the radiographic assessment of impingement in other patients following hip resurfacing arthroplasty. Longer-term follow-up is needed to determine whether radiographic signs of impingement are of prognostic consequence. PMID- 22204008 TI - Patients' preferred and retrospectively perceived levels of involvement during decision-making regarding carpal tunnel release. AB - BACKGROUND: Patient-centered care requires physicians to respond to patients' preferences, including their preferences regarding treatment decision-making. The authors surveyed patients to determine their preoperative preferences and their retrospectively perceived levels of involvement in decision-making for carpal tunnel release, and they attempted to identify factors that affect patient preferences and experiences. METHODS: Seventy-eight patients who underwent carpal tunnel release for carpal tunnel syndrome were requested to indicate their preferred level of involvement preoperatively and to assess their actual levels of involvement postoperatively, using a Control Preferences Scale containing five levels that range from fully active to fully passive. Clinical and demographic factors that potentially affected patients' preoperative preferences and postoperative assessments of levels of involvement were analyzed. RESULTS: Fifty nine patients (76%) indicated preoperatively that they preferred shared decision making, and sixty-six (85%) thought postoperatively that they had experienced this type of decision-making. The correlation between preoperative and postoperative Control Preferences Scale assessments was significant (r = 0.525, p < 0.001). A history of a surgical procedure was independently associated with a preoperative preference for a more active role (odds ratio = 4.2), and patients with a caregiver (odds ratio = 4.0) or private insurance (odds ratio = 2.6) were more likely to experience an active role. Patients who preferred a collaborative role had lower scores on the Disabilities of the Arm, Shoulder and Hand questionnaire than those who preferred a fully active role (p = 0.002) or a fully passive role (p = 0.009). CONCLUSIONS: The majority of patients with carpal tunnel syndrome preferred to share surgical decision-making with the surgeon, and those who preferred a collaborative role had less severe symptoms than those who preferred a fully active or a fully passive role. A history of a surgical procedure, having a caregiver, and having private insurance were associated with a more active role. This information may assist the establishment of patient centered consultation in patients with carpal tunnel syndrome. PMID- 22204009 TI - Aneurysmal bone cyst of the cervical spine in children. AB - BACKGROUND: Approximately 50% of patients with aneurysmal bone cyst of the spine are in the pediatric age group. Aneurysmal bone cyst is considered a locally aggressive benign tumor that may involve the posterior and anterior elements of the spine. Intralesional extended curettage and bone-grafting is the mainstay of treatment of aneurysmal bone cysts involving the long bones. However, the proximity to neurovascular structures and the potential remaining growth of the spine make its management in the spine more challenging. We evaluated the clinical presentation and the results of surgical treatment, following complete intralesional curettage along with spinal arthrodesis in pediatric patients with aneurysmal bone cysts of the cervical spine. METHODS: We retrospectively reviewed the cases of seven children who were surgically treated for a primary aneurysmal bone cyst of the cervical spine between 1988 and 2008. There were four boys and three girls who had a mean age of 11.9 years (range, eight to 16.2 years) at the time of diagnosis. The mean duration of follow-up was 46.5 months (range, twenty six to ninety-eight months). The mean age at the time of follow-up was sixteen years (range, 10.6 to 24.6 years). RESULTS: Neck pain was the most common presenting symptom, and radiculopathy was the most common finding on physical examination. Radiographs, computed tomography, and magnetic resonance imaging were highly suggestive for the diagnosis that was confirmed histologically in all patients. The majority (four) of the patients required combined anterior and posterior approaches for complete removal of the tumor and arthrodesis of the spine. Two patients required additional procedures: one for a local recurrence and one for nonunion of the atlantooccipital junction. All patients were free of evidence of recurrent disease at the time of the last follow-up. With the exception of one patient who had permanent Horner syndrome, all patients were asymptomatic. CONCLUSIONS: Preoperative arterial embolization, complete tumor excision by intralesional curettage and burring, followed by local spinal fusion, yield satisfactory results with a low rate of complications and low recurrence in children with an aneurysmal bone cyst of the cervical spine. PMID- 22204010 TI - Continuous infusion nerve block provided better pain control than a single bolus after major ankle or hindfoot surgery. PMID- 22204011 TI - Limited evidence supports the effectiveness of autologous blood injections for chronic tendinopathies. PMID- 22204012 TI - Bisphosphonate use for >=5 years increased risk for subtrochanteric or femoral shaft fractures. PMID- 22204013 TI - Surgical techniques for complex proximal tibial fractures. PMID- 22204014 TI - What's new in spine surgery. PMID- 22204015 TI - Lengthening osteotomy for reconstruction following wide resection of the distal part of the ulna: a report of two cases. PMID- 22204016 TI - Intramuscular anabolic steroid injection leading to life-threatening clostridial myonecrosis: a case report. PMID- 22204017 TI - Conservative treatment for cervical radiculopathy due to extensive foraminal disc calcification in children: a case report. PMID- 22204018 TI - Patellar resurfacing for total knee replacement: ultimate answer may lie in subgroups: commentary on an article by Suzanne Breeman, PhD, et al.: "Patellar resurfacing in total knee replacement: five-year clinical and economic results of a large randomized controlled trial". PMID- 22204019 TI - Cadaveric study suggests femoral nerve at risk during transpsoas approach to L4 L5 disc: commentary on an article by Timothy T. Davis, MD, et al.: "Lumbar plexus anatomy within the psoas muscle: implications for the transpsoas lateral approach to the L4-L5 disc". PMID- 22204020 TI - Rat study leaves unanswered questions about using rhBMP-2 for spinal cord injury in humans: commentary on an article by Anton E. Dmitriev, PhD, et al.: "Alterations in recovery from spinal cord injury in rats treated with recombinant human bone morphogenetic protein-2 for posterolateral arthrodesis". PMID- 22204023 TI - Genetic diversity and relationship of global faba bean (Vicia faba L.) germplasm revealed by ISSR markers. AB - Genetic diversity and relationships of 802 faba bean (Vicia faba L.) landraces and varieties from different geographical locations of China and abroad were examined using ISSR markers. A total of 212 repeatable amplified bands were generated with 11 ISSR primers, of which 209 were polymorphic. Accessions from North China showed highest genetic diversity, while accessions from central China showed low level of diversity. Chinese spring faba bean germplasm was clearly separated from Chinese winter faba bean, based on principal component analysis and UPGMA clustering analysis. Winter accessions from Zhejiang (East China), Jiangxi (East China), Sichuan (Southwest China) and Guizhou (Southwest China) were quite distinct to that from other provinces in China. Great differentiation between Chinese accessions and those from rest of the world was shown with a UPGMA dendrogram. AMOVA analyses demonstrated large variation and differentiation within and among groups of accessions from China. As a continental geographic group, accessions from Europe were genetically closer to those from North Africa. Based on ISSR data, grouping results of accessions from Asia, Europe and Africa were obviously associated with their geographical origin. The overall results indicated that the genetic relationship of faba bean germplasm was closely associated with their geographical origin and their ecological habit. PMID- 22204022 TI - Geometry sensing by dendritic cells dictates spatial organization and PGE(2) induced dissolution of podosomes. AB - Assembly and disassembly of adhesion structures such as focal adhesions (FAs) and podosomes regulate cell adhesion and differentiation. On antigen-presenting dendritic cells (DCs), acquisition of a migratory and immunostimulatory phenotype depends on podosome dissolution by prostaglandin E(2) (PGE(2)). Whereas the effects of physico-chemical and topographical cues have been extensively studied on FAs, little is known about how podosomes respond to these signals. Here, we show that, unlike for FAs, podosome formation is not controlled by substrate physico-chemical properties. We demonstrate that cell adhesion is the only prerequisite for podosome formation and that substrate availability dictates podosome density. Interestingly, we show that DCs sense 3-dimensional (3-D) geometry by aligning podosomes along the edges of 3-D micropatterned surfaces. Finally, whereas on a 2-dimensional (2-D) surface PGE(2) causes a rapid increase in activated RhoA levels leading to fast podosome dissolution, 3-D geometric cues prevent PGE(2)-mediated RhoA activation resulting in impaired podosome dissolution even after prolonged stimulation. Our findings indicate that 2-D and 3-D geometric cues control the spatial organization of podosomes. More importantly, our studies demonstrate the importance of substrate dimensionality in regulating podosome dissolution and suggest that substrate dimensionality plays an important role in controlling DC activation, a key process in initiating immune responses. PMID- 22204025 TI - Retraction. Lymphocyte infiltration in breast cancer: a key prognostic factor that should not be ignored. PMID- 22204026 TI - Basophilic stippling: a lead to the diagnosis. PMID- 22204027 TI - Re: stereopsis in drug Naive parkinson's disease patients. PMID- 22204028 TI - Isolated recurrent monocular vision loss as a presentation of temporal arteritis. PMID- 22204021 TI - Eph-dependent cell-cell adhesion and segregation in development and cancer. AB - Numerous studies attest to essential roles for Eph receptors and their ephrin ligands in controlling cell positioning and tissue patterning during normal and oncogenic development. These studies suggest multiple, sometimes contradictory, functions of Eph-ephrin signalling, which under different conditions can promote either spreading and cell-cell adhesion or cytoskeletal collapse, cell rounding, de-adhesion and cell-cell segregation. A principle determinant of the balance between these two opposing responses is the degree of receptor/ligand clustering and activation. This equilibrium is likely altered in cancers and modulated by somatic mutations of key Eph family members that have emerged as candidate cancer markers in recent profiling studies. In addition, cross-talk amongst Ephs and with other signalling pathways significantly modulates cell-cell adhesion, both between and within Eph- and ephrin-expressing cell populations. This review summarises our current understanding of how Eph receptors control cell adhesion and morphology, and presents examples demonstrating the importance of these events in normal development and cancer. PMID- 22204029 TI - Wilson's disease only presenting with isolated unilateral resting tremor. PMID- 22204030 TI - [Support of psychiatric care at Great Earthquake of Eastern Japan and a workshop for reconstructive measures (1)]. PMID- 22204031 TI - [Apolipoprotein E and neuro-psychiatric diseases]. PMID- 22204032 TI - [After 70 years of silence--An expression of regret at the 2010 Congress of German Society of Psychiatry, Psychotherapy and Neurology. (Addendum) "Psychiatry under the Nazi Regime--recollection and responsibility", a speech given by Frank Schneider, President of DGPPN at a memorial ceremony]. PMID- 22204033 TI - Knowledge, attitudes, and practices related to treatment and prevention of cholera, Haiti, 2010. AB - In response to the recent cholera outbreak, a public health response targeted high-risk communities, including resource-poor communities in Port-au-Prince, Haiti. A survey covering knowledge and practices indicated that hygiene messages were received and induced behavior change, specifically related to water treatment practices. Self-reported household water treatment increased from 30.3% to 73.9%. PMID- 22204034 TI - Cholera prevention training materials for community health workers, Haiti, 2010 2011. AB - Stopping the spread of the cholera epidemic in Haiti required engaging community health workers (CHWs) in prevention and treatment activities. The Centers for Disease Control and Prevention collaborated with the Haitian Ministry of Public Health and Population to develop CHW educational materials, train >1,100 CHWs, and evaluate training efforts. PMID- 22204035 TI - Cholera in United States associated with epidemic in Hispaniola. AB - Cholera is rare in the United States (annual average 6 cases). Since epidemic cholera began in Hispaniola in 2010, a total of 23 cholera cases caused by toxigenic Vibrio cholerae O1 have been confirmed in the United States. Twenty-two case-patients reported travel to Hispaniola and 1 reported consumption of seafood from Haiti. PMID- 22204036 TI - [Electron microscopic visualization of the myosin head dynamics to ATP in myosin filaments using the gas environmental chamber. II novel approach for movement of myosin head with ATP hydrolysis]. PMID- 22204037 TI - [Electron microscopic visualization of the myosin head dynamics to ATP in myosin filaments using the gas environmental chamber. I. Setting up optimum condition and visualization of myosin head movement]. PMID- 22204038 TI - [Method for resection of the residual upper left lobe following subsegment removal]. PMID- 22204039 TI - Multinational cholera outbreak after wedding in the Dominican Republic. AB - We conducted a case-control study of a cholera outbreak after a wedding in the Dominican Republic, January 22, 2011. Ill persons were more likely to report having consumed shrimp on ice (odds ratio 8.50) and ice cubes in beverages (odds ratio 3.62). Travelers to cholera affected areas should avoid consuming uncooked seafood and untreated water. PMID- 22204041 TI - Haiti in the context of the current global cholera pandemic. PMID- 22204040 TI - Travel Health Alert Notices and Haiti cholera outbreak, Florida, USA, 2011. AB - To enhance the timeliness of medical evaluation for cholera-like illness during the 2011 cholera outbreak in Hispaniola, printed Travel Health Alert Notices (T HANs) were distributed to travelers from Haiti to the United States. Evaluation of the T-HANs' influence on travelers' health care-seeking behavior suggested T HANs might positively influence health care-seeking behavior. PMID- 22204042 TI - Preparing health care workers for a cholera epidemic, Dominican Republic, 2010. PMID- 22204043 TI - Understanding the cholera epidemic, Haiti. PMID- 22204045 TI - [Organization of academic papers (3)]. PMID- 22204044 TI - [Imaging diagnosis Q & A: Leiomyoma of the esophagus]. PMID- 22204046 TI - Fecal steroid evaluation to monitor reproductive status in wild ungulate females using enzyme immunoassay commercial kits. AB - Analysis of reproductive hormones in fecal samples is necessary for the noninvasive monitoring of reproductive status in free-ranging species. The aim of the present study was to establish an easy noninvasive method to monitor reproductive status in wild ungulate females. Feces were collected daily, weekly, or three or four times a week directly from the soil for a period ranging from 1 to 9.8 mo. Fecal estradiol and progestagens were monitored in nine wild ungulate females (Barbary sheep, Ammotragus lervia [n = 3]; European bison, Bison bonasus [n = 1]; auroch, Bos taurus primigenius [n = 2]; sitatunga, Tragelaphus spekii gratus [n = 2]; and Indian rhinoceros, Rhinoceros unicornis [n = 1]) by using commercially available enzyme immunoassay kits prepared for human serum or plasma. In the species evaluated in this study, luteal phase, abortion, and gestation patterns corresponded closely with changes in fecal progestagens. Luteal phase and gestation values differed significantly (P < 0.001) from basal values, whereas progestagens values after abortion were not significantly different (P > 0.05) from basal values. For estradiol excretory patterns, follicular phase and pregnancy values differed significantly (P < 0.001) from basal values, but differences between values after abortion and basal values were not significant (P > 0.05); length of estrous cycles were clearly defined through estradiol data. This study demonstrates that ovarian function in the wild ungulate females studied can be monitored by enzyme-linked immunosorbent assay (ELISA). Therefore, ELISA methodologies used here could be a practical alternative to other ELISAs that require more complex procedures or whose commercial availability is difficult. PMID- 22204047 TI - Holding power of three different pin designs in the femur and ulna of the common buzzard (Buteo buteo). AB - External skeletal fixation is generally considered the best stabilization technique for immobilizing avian long bone fractures, but one of its major complications is the failure of bone-fixation pin interface or the loss of holding power. Consequently, this study is aimed at elucidating which pin design offers more pull-out strength in certain bones of the common buzzard (Buteo buteo). To achieve this objective, three pin designs (a smooth design and two negative profile threaded designs, with different thread pitch) were placed in five positions along the femur and ulna of the common buzzard. The pin pull-out strength was measured with the purpose of comparing medullary and pneumatic bones, insertion sites, and pin designs. Threaded pins with negative profile showed greater holding power than smooth pins (P < 0.05). When comparing holding power between the ulna and femur, no differences were found for smooth pins, whereas threaded pins showed more pull-out strength in the ulna than in the femur (P < 0.05). There were no differences observed related to pin location along the same bone when considering the same pin type. These results suggest that negative profile threaded pins have more holding power than smooth pins and that pneumatic bones provide less pull-out strength to negative profile threaded pins than medullary bones. PMID- 22204048 TI - Fecal steroid analysis for evaluating ovarian function in the greater kudu (Tragelaphus strepsiceros) and lesser kudu (Tragelaphus imberbis). AB - Seasonal reproductive-endocrine norms have not been described for the genus Tragelaphus, which consists of seven species of African antelope. Longitudinal patterns of progesterone metabolite excretion were assessed by radioimmunoassays in fecal samples collected noninvasively (three to seven samples per week) from greater kudu (Tragelaphus strepsiceros, n = 4) and lesser kudu (Tragelaphus imberbis, n = 4). Progesterone metabolite excretion patterns revealed seasonal estrous cycles in both species, and discrimination of pregnant versus nonpregnant females was achieved in lesser kudu. These data reveal the value of fecal progesterone metabolites for establishing reproductive-endocrine norms in both zoo-maintained and free-living antelopes of the genus Tragelaphus. PMID- 22204049 TI - Cold stress induces an adrenocortical response in bottlenose dolphins (Tursiops truncatus). AB - Two adult bottlenose dolphins (Tursiops truncatus) were individually housed in aboveground pools over a 10-day period and exposed to decreasing water temperatures to determine whether cold stress activated the hypothalamic pituitary-adrenal axis. To serve as controls, two additional adult dolphins were similarly housed for the same duration but at ambient water temperatures (16.8 19.6 degrees C). Across all subjects, water temperatures ranged from 4.2 to 19.6 degrees C. Voluntary blood draws were made from each dolphin every 2-3 days, and serum was analyzed via radioimmunoassay for cortisol and aldosterone. Dolphins exposed to cold water showed an increase in serum cortisol and aldosterone as temperature declined; at the coldest water exposure, cortisol was more than three times and aldosterone more than two times the levels measured at ambient temperature. Elevations occurred before the water temperature declined below the individual animal's lower critical temperature, the point at which the metabolic rate increases to compensate for the loss of body heat. Variations in corticosteroids were unrelated to the 10-day isolation period, suggesting that the response was related to the cold stress and not impacted by the isolation. Elevations in cortisol and aldosterone were lower than those observed in force captured and stranded dolphins. Although potentially related to the general adaptive stress response, elevations in cortisol and aldosterone may have other adaptive functions related to mitigating impacts resulting from cold environmental temperatures. PMID- 22204050 TI - Echocardiographic parameters of captive western lowland gorillas (Gorilla gorilla gorilla). AB - A total of 163 echocardiographic studies on western lowland gorillas (Gorilla gorilla gorilla) were submitted for evaluation; 140 from 99 animals were suitable for analysis. Of these, 81 studies (42 studies from 35 males ranging in age from 11-41+ yr and 39 studies from 31 females ranging in age from 11-41+ yr) are reported here. Three studies from 3 females and 56 studies from 30 males were excluded from this report due to cardiac abnormalities. Cardiac parameters measured were aortic root (Ao Rt) diameter and left atrial (L atrium) size. Left ventricular (LV) measurements included left ventricular internal diameter in systole (LVID(s)) and diastole (LVID(d)) as well as diastolic septal (IVS) and posterior wall thickness (LVPW). Values considered to be normal in females > 11 yr of age were: Ao Rt < 3.5 cm, L atrium < 4.0 cm, LVID(d) < 5.0 cm, IVS < 1.4 cm, LVPW < 1.4 cm, and ejection fraction (EF) > 60%. The data from male gorillas show a separation in animals based on three cardiac parameters: systolic function, LV cavity size, and LV wall thickness. Male gorillas > 11 yr of age fall into two groups; unaffected and affected. Unaffected animals are defined as those with no echocardiographic abnormalities and a consistent Ao Rt of < 4.0 cm, LVID(d) of < 6.0 cm, IVS and LVPW of <1.5 cm, and an EF of > 58%. The affected group consisted of male gorillas that exhibited changes in echocardiographic parameters representing the presence of cardiovascular disease. The results determined in this database, gathered from data collected from 1999-2009, suggest a sex-based difference between males and females with predominantly males demonstrating evidence of cardiac disease. The most striking finding seen in this study is that of progressive LV hypertrophy and depressed LV EF in affected adult male gorillas. PMID- 22204051 TI - A comparison of two field chemical immobilization techniques for bobcats (Lynx rufus). AB - Anesthetic protocols that allow quick induction, short processing time, and rapid reversal are necessary for researchers performing minimally invasive procedures (including morphometric measurements or attachment of radiocollars). The objective of this study was to evaluate the effectiveness of medetomidine and butorphanol as a substitute for xylazine in ketamine-based field immobilization protocols for bobcats (Lynx rufus) to reduce recovery and total field times. During 2008 and 2009, 11 bobcats were immobilized with an intramuscular combination of ketamine (10 mg/kg)-xylazine (0.75 mg/kg) (KX) or ketamine (4 mg/kg)-medetomidine (40 mcg/kg)-butorphanol (0.4 mg/kg) (KMB). Time to initial sedation, recumbency, and full anesthesia were recorded postinjection. Time to head up, sternal, standing, full recovery, and total processing times were recorded post-reversal. Throughout anesthesia, heart rate (HR), respiratory rate (RR), rectal temperature (RT), and noninvasive hemoglobin-oxygen saturation (SpO2) were recorded at 5-min intervals. The KX combination had a median time to full anesthesia of 10 min, a median recovery time of 46 min, and a median total processing time of 83 min. Alternatively, the KMB combination had a median time to full anesthesia of 21 min, a median recovery time of 18 min, and a median total processing time of 64 min. The KX protocol produced a median HR of 129 beats/min, RR of 25 breaths/min, RT of 38.3 degrees C, and SpO2 of 93%. The KMB protocol produced a median HR of 97 beats/min, RR of 33 breaths/min, RT of 38.4 degrees C, and SpO2 of 92%. Though both protocols provided safe and reliable sedation, the benefits of using medetomidine and butorphanol to lower ketamine doses and decrease processing time for brief nonsurgical sedation of bobcats in the field are presented. PMID- 22204052 TI - Clinical and physiologic effects of sodium chloride baths in goldfish (Carassius auratus). AB - Sodium chloride (salt; NaCl) has been used for freshwater fish to decrease stress and manage a variety of disease conditions. Recommendations for dose and duration vary greatly. The purpose of this study was to determine the potential adverse clinical and physiologic side effects of different concentrations of saltwater baths on goldfish. Eleven goldfish (Carassius auratus) were used in a cross-over study to assess the effects of three different salt concentrations (5, 10, and 20 g/L) on plasma biochemistries and clinical response. Baseline plasma chemistries were obtained and analyzed immediately prior to placing the goldfish into the saltwater bath and after the fish was removed. A 2-wk washout period was used in between each treatment. Significant differences were found in fish in the sodium (10 g/L, P = 0.007; 20 g/L, P = 0.01), chloride (10 g/L, P = 0.006; 20 g/L, P = 0.001), and alanine aminotransferase (10 g/L, P = 0.002; 20 g/L, P = 0.004) after their exposure to 10 and 20 g/L saltwater. Glucose levels were found to differ significantly after exposure to all three NaCl concentrations (5 g/L, P = 0.0009; 10 g/L, P = 0.0001; 20 g/L, P = 0.0005). Clinically, 5 g/L and 10 g/L saltwater baths were well tolerated by the fish for the duration of the intended 12-hr treatments, with only one goldfish being removed during the 10 g/L bath at 7 hr for listlessness. The average time goldfish spent in the 20 g/L salt bath was 43 min, with six (54%) of the fish remaining in the 20 g/L salt bath for the intended 60-min treatment period. The remaining 5 (46%) goldfish were removed because they became listless or dyspneic. All of the fish recovered from the treatments without complication. The results of this study suggest that goldfish tolerate saltwater baths but that physiologic disturbances can occur at the higher doses. PMID- 22204053 TI - Occurrence of Cryptosporidium spp. in Antillean manatees (Trichechus manatus) and Amazonian manatees (Trichechus inunguis) from Brazil. AB - Infections by Cryptosporidium spp. in aquatic mammals is a major concern due to the possibility of the waterborne transmission of oocysts. The aim of the present study was to report the occurrence of Cryptosporidium spp. in Antillean manatees (Trichechus manatus) and Amazonian manatees (Trichechus inunguis) from Brazil. Fecal samples were collected and processed using Kinyoun's method. Positive samples were also submitted to the direct immunofluorescence test. The results revealed the presence of Cryptosporidium spp. oocysts in 12.5% (17/136) of the material obtained from the Antillean manatees and in 4.3% (05/115) of the samples from the Amazonian manatees. Cryptosporidium spp. infection was more prevalent in captive animals than in free-ranging specimens. PMID- 22204055 TI - Visceral leishmaniasis in a captive crab-eating fox Cerdocyon thous. AB - Visceral leishmaniasis (VL) is a zoonotic disease with worldwide distribution. The crab-eating fox (Cerdocyon thous) is considered a wild reservoir of many zoonotical diseases, particularly VL. This study reported the presence of Leishmania infantum amastigotes in different organs of one captive C. thous found dead in a zoo. This animal was positive by the indirect fluorescence antibody test and had many clinical signs of VL. Intracellular amastigote forms of L. infantum were seen in neutrophils and macrophages in sample tissues from skin, lymph nodes (popliteal, submandibular, prescapular, and mesenteric), spleen, and liver. The numbers of positive cells and intracellular parasites were higher in macrophages than in neutrophils. In addition, polymerase chain reaction demonstrated extensive distribution of Leishmania DNA in C. thous tissues from multiple organs. The presence of intracellular amastigotes in neutrophils and macrophages as well as DNA of the parasite in tissues, specifically skin demonstrate that this crab-eating fox is an adequate host for L. infantum and reinforce the importance of VL for symptomatic wild canids kept in captivity in endemic areas. PMID- 22204054 TI - Pathologic lesions in chimpanzees (Pan trogylodytes schweinfurthii) from Gombe National Park, Tanzania, 2004-2010. AB - During a population decline or disease outbreak, the true risk of specific diseases to a wild population is often difficult to determine because of a lack of baseline disease information. To better understand the risk of disease in an endangered and scientifically important population of chimpanzees (Pan trogylodytes schweinfurthii), a health monitoring program was initiated in Gombe National Park, Tanzania. As part of this health monitoring program, comprehensive necropsies with histopathology were conducted on chimpanzees (n = 11; 5 male, 6 female), ranging in age from fetal to 44 yr, that were found dead between August 2004 and January 2010. In contrast to previous reports, respiratory disease was not noted as a cause of morbidity or mortality. Trauma was the most common cause of death in these 11 chimpanzees. All of the chimpanzees greater than 1 yr of age had intestinal and mesenteric parasitic granulomas associated with true strongyles consistent with Oesophagostomum spp. The relative numbers of granulomas increased with age and, in some cases, may have been a cause of weight loss and diarrhea. Simian immunodeficiency virus (SIV)cpz infection was documented in four deceased apes, all of whom exhibited varying amounts of lymphoid depletion including two females with marked CD4+ T cell loss consistent with endstage SIVmac or human immunodeficiency virus infections. Myocardial megalokaryosis was common in chimpanzees greater than 1 mo of age; yet myocardial interstitial fibrosis, a common lesion in captive chimpanzees, was uncommon and only noted in two aged chimpanzees. These findings provide important information on causes of morbidity and mortality in wild chimpanzees, information that can be used to interpret findings during population declines and lead to better management of this population in the context of disease risk. PMID- 22204056 TI - Evaluation of medetomidine-alfaxalone and medetomidine-ketamine in semi-free ranging Bennett's wallabies (Macropus rufogriseus). AB - Twenty-six adult semi-free-ranging Bennett's wallabies were anesthetized. Animals in group MA received medetomidine 0.1 mg/kg and alfaxalone 4 mg/kg i.m. in a 5-ml dart, whereas those in group MK received medetomidine 0.1 mg/kg and ketamine 5 mg/kg i.m. in a 3-ml dart. Dosages were based on estimated body weights. The wallabies were allowed to recover spontaneously or, if still nonresponsive at the end of the procedure, were given atipamezole 0.5 mg/kg (half the dose via i.m. and the other half via i.v.). Heart rate and respiratory rate were monitored at 5 min intervals, temperature at 10-min intervals, and two arterial blood samples were taken for blood gas analysis. Statistical analysis was performed by using analysis of variance (P < 0.05). The use of 5-ml darts in group MA compared with 3-ml darts in group MK could potentially increase the risk of iatrogenic trauma and should be considered. Induction and maintenance of anesthesia were satisfactory in both groups. There were no significant differences between the groups in mean time to first effect, recumbency, and approach, or to time to sternal recumbency and standing after reversal with atipamezole. Although bradycardia was present in both groups, no statistical differences were calculated for respiratory rate and heart rate, whereas the mean cloacal temperature was significantly lower in group MA (P = 0.01). Mixed acid-base disturbances occurred in both groups. All but one animal in group MK needed atipamezole at the end of the procedure. No adverse effects were observed after recovery. PMID- 22204057 TI - Evaluation of modified techniques for immobilization of wild ring-tailed lemurs (Lemur catta). AB - Wild ring-tailed lemurs (Lemur catta) can be anesthetized with Telazol via blow dart, but improved techniques are needed so that each lemur is reliably induced with a single dart. Medetomidine-butorphanol (MB) is a good supplemental protocol to be administered once the lemurs are captured, but other protocols may provide longer periods of sedation and immobility. One possible way of increasing the efficacy of each dart is to increase the time it is retained in the leg. In this investigation, a "double-sleeve" technique was used to try to increase the time of dart retention. This technique used a standard silicone sleeve on the needle, along with a second sleeve at the needle hub. Induction values were compared between lemurs darted with double-sleeve needles and those induced with needles that each had a single silicone sleeve. Once the lemurs were induced, supplementation with MB (0.04 mg/kg and 0.2 mg/kg) was compared with supplementation with ketamine-medetomidine (KM) (10 mg/ kg and 0.04 mg/kg). Twenty-three lemurs were darted with Telazol by using single-sleeve needles, and 24 were darted with double-sleeve needles. The number of darts per lemur and number of escapes were not different between animals darted with a single sleeve compared with a double-sleeve; thus, there were no significant improvements in induction success with the double-sleeve technique. Adequate sedation and muscle relaxation were achieved with both MB and KM; however, lemurs that received MB were more relaxed and needed fewer additional supplements that those that received KM. Single-sleeve dart needles are recommended for Telazol induction of ring-tailed lemurs via blow dart and MB is preferable to KM for supplemental sedation and muscle relaxation. PMID- 22204058 TI - Survey of ixodid ticks and two tick-borne pathogens in African buffaloes, Syncerus caffer, from the Caprivi Strip, Namibia. AB - A capture operation to ascertain health status in free-ranging buffaloes from six different areas in the Caprivi Strip in the northeast corner of Namibia was conducted in October 2009. Basic information on the ticks and tick-borne pathogens normally found in wildlife from this area are scarce. The objective of this study was to assess the host status of African buffaloes, Syncerus caffer, for ixodid ticks and two selected tick-borne pathogens in the Caprivi Strip, a key area bordering Angola, Zambia, Botswana, and Zimbabwe. Four different tick species have been identified among the 233 collected specimens, and, of 95 tested buffaloes, 54 (57%) were positive for Theileria parva, whereas only 3 (3%) showed evidence of being infected with Ehrlichia ruminantium. PMID- 22204059 TI - Fish quarantine: current practices in public zoos and aquaria. AB - The primary goal of quarantine is to reduce the risk of introducing infectious diseases into established collections. Fish quarantine is inherently complex because of the variety of species, environmental requirements, and facilities. To examine current practices, questionnaires were submitted to 60 public zoos and aquaria, predominantly in North America. Questions reviewed system type (closed, flow-through), quarantine length, diagnostics, treatments, and cleaning and disinfection. Forty-two of the 60 institutions responded. Most institutions had separate quarantine protocols for freshwater teleosts, marine teleosts, and elasmobranchs. Ninety-five percent of institutions had a minimum quarantine period of 30 days or more. Sixty-four percent of institutions used isolated areas for some or all of their fish quarantine. Twenty-five percent had designated fish quarantine staff. All institutions used regular visual examinations to assess animal health. Fifty-four percent of the institutions carried out routine hands on diagnostics on some fish; this was more common for elasmobranchs than teleosts. All institutions carried out necropsies on mortalities. Fifteen percent of institutions performed histopathology on almost all fresh mortalities; 54% percent performed histopathology on less than 10% of mortalities. Prophylactic treatments were common in closed systems, in particular, formalin immersion for teleosts, freshwater dips and copper sulfate immersion for marine teleosts, and praziquantel immersion for marine teleosts and elasmobranchs. Institutions using dips generally did so at the start or end of quarantine. Fenbendazole- and praziquantel-medicated foods were used commonly in teleosts, but dosages varied greatly. Cleaning and disinfection of systems and equipment increased in response to known pathogens. These results can be used to compare and discuss fish quarantine practices at display facilities in order to improve quarantine success. PMID- 22204060 TI - Evaluation of passive transfer in captive greater kudu (Tragelaphus strepsiceros). AB - Failure of passive transfer (FPT) in captive greater kudu (Tragelaphus strepsiceros) calves can lead to increased morbidity and mortality. In this retrospective study, serum samples from neonatal kudu calves were tested for immunoglobulin using different tests validated for domestic ruminants, including measurement of gamma globulin (GG) measured by protein electrophoresis, total solids (TS) measured by calibrated refractometry, total protein (TP) and globulins measured by colorimetry, gamma glutamyltransferase (GGT), and the zinc sulfate turbidity test (ZSTT). In a logistic regression model, TP, TS, globulins, and the natural log transform of GGT were the only significant parameters associated with FPT. Various historic parameters related to the dam, as well as calf weight, sex, glucose, and packed cell volume, were not significant. Based on the results, FPT in greater kudu is defined as GG of < 0.5 g/dl, a value lower than that in domestic cattle. TS measured by refractometry has an 80% sensitivity and a 100% specificity for FPT in greater kudu. With FPT defined as GG < 0.5 g/dl, kudu calves with a TS < 4.8 g/dl and a negative ZSTT have an increased probability of requiring medical intervention and additional diagnostics may be warranted. PMID- 22204061 TI - Dietary isoflavone absorption, excretion, and metabolism in captive cheetahs (Acinonyx jubatus). AB - Dietary isoflavones, capable of influencing reproductive parameters in domestic cats (Felis catus), have been detected in commercial diets fed to captive cheetahs (Acinonyx jubatus). However, the absorptive and metabolic capacity of cheetahs towards isoflavones has not yet been studied. Experiments were designed to describe the plasma concentration-time curve, metabolite profile, and urinary and fecal excretion of genistein and daidzein in cheetahs following consumption of isoflavones. Four adult cheetahs were administered a single oral bolus of genistein and daidzein, and five juvenile cheetahs consuming a milk replacer formula found to contain isoflavones were also included. Urine was collected from all animals, and blood and feces were also collected from adult cheetahs following isoflavone exposure. Samples were analyzed for isoflavone metabolite concentration by liquid chromatography-electrospray ionization-multiple reaction ion monitoring mass spectrometry and high-performance liquid chromatography. Sulfate conjugates were the primary metabolites detected of both genistein and daidzein (60-80% of total isoflavones present) in the plasma and urine of cheetahs. A smaller proportion of daidzein was detected as conjugates in the urine of juvenile cheetahs, compared to adult cheetahs. Other metabolites included unconjugated genistein and daidzein, O-desmethylangolensin, and dihydrodaidzein, but not equol. Only 33% of the ingested genistein dose, and 9% of daidzein, was detected in plasma from adult cheetahs. However, of the ingested dose, 67% of genistein and 45% of daidzein were detected in the feces of adults. This study revealed that cheetahs appear efficient in their conjugation of absorbed dietary isoflavones and only a small fraction of ingested dose is absorbed. However, the capacity of the cheetah to conjugate genistein and daidzein with sulfate moieties appears lower than reported in the domestic cat. This may confer greater opportunity for biologic activity of isoflavones in the cheetah than would be predicted from findings in the domestic cat. However, further investigation is required. PMID- 22204062 TI - Plasma biochemistry values of recently wild-caught purple mouth moray eels (Gymnothorax vicinus). AB - The primary purpose of this study was to establish plasma biochemistry parameters for healthy recently wild-caught purple mouth moray eels (Gymnothorax vicinus) to provide a baseline of data for improved medical care in an aquarium or zoologic setting and for wild health assessments. Thirty-one clinically healthy purple mouth moray eels of unknown age and sex were caught from the wild, and were anesthetized 50 days following capture for blood collection from the ventral coccygeal vein. The median plasma biochemistry values were as follows: hematocrit = 21%, creatinine kinase = 2,100 U/L, lactate dehydrogenase = 97 U/L, aspartate aminotransferase = 88 U/L, alanine aminotransferase = 51 U/L, alkaline phosphatase 3,939 U/L, gamma-glutamyl transpeptidase = 1 U/L, amylase = 40 U/L, blood urea nitrogen = < 11 mg/dl, glucose = 21 mg/dl, calcium = 12.5 mg/dl, triglyceride = 206 mg/dl, creatinine = 0.1 mg/dl, cholesterol = 334 mg/dl, total bilirubin = < 0.1 mg/dl, phosphorus = 6.5 mg/dl, total protein = 4.2 g/dl, albumin = 1.5 g/dl, globulin = 2.7 g/dl, albumin/ globulin ratio = 0.6, sodium = 185 mmol/L, potassium = 3.7 mmol/L, and chloride = 175 mmol/L. Alkaline phosphatase isoenzyme results indicate that the majority of the plasma alkaline phosphatase is the liver isoenzyme. The data acquired in this study also provide baseline values for cholesterol and triglycerides in recently wild-caught moray eels to aid in monitoring elevations to these values in an aquarium setting over time so adjustments to the dietary regime may be utilized to prevent or improve conditions such as lipid keratopathy. PMID- 22204063 TI - Effects of intramuscular meloxicam administration on prostaglandin E2 synthesis in the North American bullfrog (Rana catesbeiana). AB - Meloxicam is a commonly used nonsteroidal anti-inflammatory drug (NSAID) in veterinary medicine, but its use in amphibians has not been reported in the literature. NSAIDs are known to act by providing anti-inflammatory and analgesic actions by inhibiting the synthesis of prostaglandin E2 (PGE2). The objective of this study was to evaluate whether the intramuscular administration of meloxicam would decrease the circulating serum PGE2 levels in the North American bullfrog (Rana catesbeiana) following tissue trauma induced by a punch biopsy. Eighteen adult North American bullfrogs were randomly assigned to two treatment groups: meloxicam (0.1 mg/kg i.m.) and control (0.9% saline i.m.). Blood was obtained via cardiocentesis immediately prior to administration of the two treatment regimes and serum was frozen. A 4-mm punch biopsy was taken from the right triceps femoris muscle to induce an inflammatory response. Twenty-four hours later, a second blood sample was collected and serum was harvested and frozen. Serum PGE2 concentrations were measured using a commercial PGE2 enzyme assay (EIA) kit. Twenty-four hours following the biopsy, the mean circulating PGE2 levels of animals treated with meloxicam was 57.79 +/- 12.35 pg/ml, which did not differ significantly from animals that were treated with saline (85.63 +/- 17.55 pg/ml, P > or = 0.05). The calculated means of the absolute change between the circulating baseline PGE2 levels and the postinjury circulating PGE2 levels were significantly lower in animals treated with meloxicam (13.11 +/- 17.31 pg/ml) than in control animals treated with saline (46.14 +/- 38.02 pg/ml) (P < or = 0.05). These results suggest that the systemic administration of meloxicam at a dosage of 0.1 mg/kg once daily suppresses circulating serum PGE2 levels postinjury in the North American bullfrog. PMID- 22204064 TI - Disseminated fungal infection in two species of captive sharks. AB - In this report, two cases of systemic mycosis in captive sharks are characterized. These cases were progressive and ultimately culminated in terminal disease. Paecilomyces lilacinus, an uncommon pathogen in human and veterinary medicine, was associated with areas of necrosis in the liver, heart, and gill in a great hammerhead shark (Sphyrna mokarran). Fungal growth was observed from samples of kidney, spleen, spinal fluid, and coelomic cavity swabs. Dual fungal infection by Exophiala pisciphila and Mucor circinelloides was diagnosed in a juvenile zebra shark (Stegostoma fasciatum). Both fungi were present in the liver, with more severe tissue destruction associated with E. pisciphila. E. pisciphila also produced significant necrosis in the spleen and gill, while M. circinelloides was associated with only minimal tissue changes in the heart. Fungal cultures from liver, kidney, and spleen were positive for both E. pisciphila and M. circinelloides. Identification of P. lilacinus and M. circinelloides was based on colonial and hyphal morphology. E. pisciphila was identified by sequence analysis of the 28S rRNA D1/D2 region and the internal transcribed spacer (ITS) region between the 18S and 28S rRNA subunit. These cases, and a lack of information in the literature, highlight the need for further research and diagnostic sampling to further characterize the host pathogen interaction between elasmobranchs and fungi. PMID- 22204065 TI - An outbreak of Salmonella enterica serotype Choleraesuis in goitered gazelle (Gazella subgutrosa subgutrosa) and a Malayan tapir (Tapirus indicus). AB - An outbreak of Salmonella enterica serotype Choleraesuis enteritis occurred in two juvenile goitered gazelles and an adult Malayan tapir over a period of 5 wk at the Minnesota Zoo. Diagnosis was made postmortem on one gazelle and one tapir, and a second gazelle was diagnosed via fecal culture. The death of the tapir was attributed to S. enterica serovar Choleraesuis septicemia, while salmonellosis was considered to be a contributing factor besides ostertagiasis for the death of one goitered gazelle and for the diarrhea of another goitered gazelle. A third gazelle became ill in the same time period, but Salmonella infection was not confirmed by culture. All exhibited the clinical signs of profuse, watery diarrhea. The gazelles developed a protein-losing enteropathy, and the tapir showed signs of sepsis and endotoxemia. Serotyping and pulsed-field gel electrophoresis revealed the Salmonella isolates to be indistinguishable from each other. One year prior to this outbreak, Salmonella sp. was cultured from a Visayan warty pig (Sus cebifrons) housed in the same building as the tapir. After further investigation into the outbreak, spread of this pathogen was speculated to be associated with human movement across animal areas. PMID- 22204066 TI - Computed tomography of granulomatous pneumonia with oxalosis in an American alligator (Alligator mississippiensis) associated with Metarhizium anisopliae var anisopliae. AB - An 18-yr-old, male, albino, American alligator (Alligator mississippiensis) was evaluated for decreased appetite and abnormal buoyancy. Computed tomography (CT) of the coelomic cavity showed multifocal mineral and soft tissue attenuating pulmonary masses consistent with pulmonary fungal granulomas. Additionally, multifocal areas of generalized, severe emphysema and pulmonary and pleural thickening were identified. The alligator was euthanized and necropsy revealed severe fungal pneumonia associated with oxalosis. Metarhizium anisopliae var. anisopliae was cultured from lung tissue and exhibited oxalate crystal formation in vitro. Crystals were identified as calcium oxalate monohydrate by X-ray powder defractometry. Fungal identification was based on morphology, including tissue sporulation, and DNA sequence analysis. This organism is typically thought of as an entomopathogen. Clinical signs of fungal pneumonia in nonavian reptiles are often inapparent until the disease is at an advanced stage, making antemortem diagnosis challenging. This case demonstrates the value of CT for pulmonary assessment and diagnosis of fungal pneumonia in the American alligator. Fungal infection with associated oxalosis should not be presumed to be aspergillosis. PMID- 22204067 TI - Genitourinary and pulmonary multidrug resistant Mycobacterium tuberculosis infection in an Asian elephant (Elephas maximus). AB - A female Asian elephant (Elephas maximus) developed vaginal and trunk discharge. Cultures were positive for pan-susceptible Mycobacterium tuberculosis. Isoniazid and pyrazinamide were given rectally and monitored by serum levels. After being trained at 10 mo to accept oral dosing, treatment was changed and rifampin was added. Oral medications were administered for another 10 mo. A year after completion of therapy, the vaginal discharge increased and cultures yielded M. tuberculosis, resistant to isoniazid and rifampin. Treatment with oral ethambutol, pyrazinamide, and enrofloxacin and intramuscular amikacin was initiated. Although followup cultures became negative, adverse reactions to medications precluded treatment completion. Due to public health concerns related to multidrug resistant M. tuberculosis (MDR-TB), the elephant was euthanized. Postmortem smears from the lung, peribronchial, and abdominal lymph nodes yielded acid-fast bacteria, although cultures were negative. This case highlights important considerations in the treatment of M. tuberculosis in animals and the need for a consistent approach to diagnosis, treatment, and follow-up. PMID- 22204068 TI - Anesthesia of Tibetan yak (Bos grunniens) using thiafentanil - xylazine and carfentanil - xylazine. AB - The use of 0.025 +/- 0.012 mg/kg (median +/- interquartile range) thiafentanil with 0.15 +/- 0.03 mg/kg xylazine (TX) and 0.011 +/- 0.0015 mg/kg carfentanil with 0.25 +/- 0.093 mg/kg xylazine (CX), with dosages based on estimated bodyweight, was used in the anesthesia of 37 Tibetan yak (Bos grunniens) housed within a drive-through animal park setting. The median time to lateral recumbency was 5 and 7 min for each group, respectively. With the addition of propofol in 8 CX animals and 17 TX animals, the anesthetic plane was suitable for a wide range of procedures. The median time to standing recovery following administration of naltrexone was 4 +/- 3.5 min with TX and 7 +/- 1.5 min with CX. There was one fatality and one case of renarcotization in the TX group. Overall, the dosages used in the study provided a reliable and useful anesthetic induction protocol, with TX animals demonstrating a more rapid induction and recovery with less cardiac depression than CX animals. PMID- 22204069 TI - Immunocontraception in Eastern gray squirrels (Sciurus carolinensis): morphologic changes in reproductive organs. AB - Eastern gray squirrels (EGS) (Sciurus carolinensis) damage trees through bark stripping or gnawing due to territorial marking or agonistic gnawing behavior in concert with higher densities. This study was conducted to determine the effects of a contraceptive vaccine on EGS and its reproductive organ histology. Free ranging urban EGS were vaccinated with the immunocontraceptive GonaCon. All EGS were > or = 6 mo of age as determined by a combination of pelage characteristics and body weights. The vaccine was administered by injection at a dosage rate of 0.4 ml containing 400 microg of GnRH-mollusk protein conjugate i.m. in the thigh to 33 EGS (17 male [m], 16 female [f]) in trapping session 1 (TS1), 23 (14 m, 9 f) in trapping session 2 (TS2), and 11 (8 m, 3 f) in trapping session 3 (TS3). A sham injection containing 0.4 ml saline-AdjuVac was given as control to 22 EGS (16 m, 6 f) in TS1, 20 (12 m, 8 f) in TS2, and 8 (4 m, 4 f) in TS3. In the last trapping session (TS4), 35 EGS (16 treated, 19 control) were killed for necropsy to evaluate histologic changes in testes and ovaries. Treated EGS males had testicular, prostatic, and epididymal atrophy compared with control EGS males. The tubuli seminiferi and prostatic glandular lumen of treated EGS males were atrophic, and the epididymal lumen contained no sperm cells. No histologic changes were observed in treated EGS females; however, females likely were not collected when changes due to GonaCon would have been observed. There were no observable histologic differences in the pituitary gland of treated and control EGS. There were no statistically significant differences in either testosterone or progesterone concentrations between control and treated EGS. Although there were no serious side effects to the vaccine, six EGS developed injection site abscesses. GonaCon may be a potential tool for EGS population control. PMID- 22204070 TI - Attempted in vitro maturation and fertilization of postmortem Sumatran rhinoceros (Dicerorhinus sumatrensis) oocytes. AB - A study was conducted opportunistically to evaluate the potential of rescuing immature oocytes from the ovaries of the Sumatran rhinoceros postmortem. Recovered oocytes (n = 30) were placed in maturation culture for 36 hr and inseminated with frozen-thawed homologous spermatozoa. After culture, evaluation of nuclear maturation status revealed that a large number of oocytes were degenerated (n = 21), but nine oocytes were assessed at the germinal vesicle (n = 3), metaphase I (n = 3), and metaphase II (n = 3) stages. Frozen-thawed Sumatran rhinoceros spermatozoa were capable of binding to the zona pellucida of in vitro matured oocytes, but no fertilization or cleavage resulted. In conclusion, relatively large numbers of oocytes can be obtained by ovarian follicular aspiration postmortem in the Sumatran rhinoceros, and some of these oocytes are capable of achieving nuclear maturation in vitro. However, additional studies are required to improve maturation success and achieve fertilization in culture. PMID- 22204071 TI - Disseminated histoplasmosis in a Bengal tiger (Panthera tigris). AB - Disseminated infection with Histoplasma capsulatum was diagnosed in a 7-yr-old female Bengal tiger (Panthera tigris). Clinical signs were nonspecific with the exception of brief periods of tachypnea for 5 days prior to death. H. capsulatum organisms were found in the lungs, tracheobronchial lymph nodes, and liver. Diagnosis was confirmed by tracheal wash, urine H. capsulatum enzyme immunoassay, and necropsy results. This report represents the first published account of disseminated histoplasmosis in a tiger. PMID- 22204072 TI - Necrotic enteritis in collared (Pecari tajacu) and white-lipped (Tayassu pecari) peccaries. AB - An outbreak of necrotic enteritis caused by Clostridium perfringens type C was diagnosed in captive collared (Pecari tajacu) and white-lipped (Tayassu pecari) peccaries housed in the Laboratory of Applied Ethology of Universidade Estadual de Santa Cruz located in Ilheus, State of Bahia, Brazil. Four collared peccaries and three white-lipped peccaries, all juveniles (25-105 days old), were affected. For all affected animals, lethargy and inappetance were followed by sudden death within 24 hours. Histopathology of intestinal wall, culture of C. perfringens type C, and the identification of beta-toxin from intestinal content confirmed the diagnosis. PMID- 22204073 TI - Fatal coccidiosis by Isospora icterus (Upton & Whitaker, 2000) in captive Campo Troupial (Icterus jamacaii) in Brazil. AB - An outbreak of coccidiosis by Isospora icterus (I. icterus, Upton & Whitaker, 2000) in captive Campo Troupial (Icterus jamacaii) (Gmelin, 1788) at the Wild Animals Triage Center (IBAMA, Belo Horizonte, Brazil) is described. Clinical history and the necropsy findings documented diarrhea with diffuse necrotic enteritis. Sporulated oocysts (n = 100) had a bilayered wall, were subspherical, and measured 30.1 (27.5-32.5) microm in length and 28.5 (26.2-30.0) microm in width. A polar body but no micropyle was present and the length/width ratio was 1.1 (1.00-1.2). Each oocyst contained two ellipsoidal sporocysts measuring 17.6 (15.0-20.0) microm in length and 12.9 (12.5-15.0) microm in width, with a length/width ratio of 1.4 (1.2-1.5), and with Stieda and sub-Stieda bodies. Each sporocyst contained four sporozoites with granular sporocyst residuum. Oocysts were compatible with those from I. icterus, previously described in Campo Troupial. PMID- 22204074 TI - Aeromonas hydrophila-associated septicemia in captive crocodiles (Crocodylus johnstoni and Crocodylus porosus). AB - Five 25-yr-old crocodiles (Crocodylus johnstoni and Crocodylus porosus) were diagnosed with Aeromonas hydrophila-associated septicemia accelerated by improper thermoregulation. At necropsy, pulmonary congestion and pleural effusion were the main lesions in the thorax. Necrotizing enteritis, intestinal hemorrhage, fibrinous serositis, hepatitis, and pancreatitis were observed in the abdominal cavities of all five crocodiles. Aeromonas hydrophila was identified in the pleural effusions and abdominal ascites of all necropsied crocodiles by using an API system 20NE. Aeromonas hydrophila infection and evaluation of virulence were confirmed by polymerase chain reaction targeting the 16S rRNA and extracellular hemolysin gene. The crocodiles in the present case were housed in an indoor facility at a private zoo that failed to optimize land and water portions of the enclosure, exposing the animals to impeded thermoregulation, and it is suggested that the pathogenesis was accelerated by the improper thermoregulation-induced stress. This is the first description of A. hydrophila pathogenicity associated with impeded thermoregulation in reptiles. PMID- 22204075 TI - Disseminated infection due to Mycobacterium avium subsp. avium in an Asian elephant (Elephas maximus). AB - A disseminated infection caused by Mycobacterium avium subspecies avium (MAA) was diagnosed in a 57-yr-old male Asian elephant (Elephas maximus) housed at the Seoul Zoo, Gyeonggi, Republic of Korea. An apparent granulomatous inflammation with central caseous necrosis was evident in the lung sections. To confirm mycobacterial infection, polymerase chain reaction-restriction enzyme polymorphism analysis (PCR-RFLP) of the rpoB and hsp65 genes was performed from multiple organs and cultured bacteria. The PCR-RFLP revealed a M. avium subspecies. MAA was identified by multiplex PCR for detection of IS901 and IS1311. Thus, it is believed that MAA caused the disseminated infection in this case. Although the source of infection was not determined, the elephant may have become infected through contamination of soil and feed by free-living birds infected with MAA. This is the first reported case of disseminated infection due to MAA in a captive elephant in the Republic of Korea. PMID- 22204076 TI - Bilateral hydronephrosis secondary to endometriosis managed by endoscopic ureteral stent placement in a captive Guinea baboon (Papio papio). AB - Spontaneous endometriosis is an estrogen-dependent, progressive and painful disease that affects a variety of nonhuman primates, including several species of baboons (Papio sp.). This case documents multimodal management of severe endometriosis in a captive female baboon within a zoological institution. An 18 yr-old, intact female Guinea baboon (Papio papio) was found to have an enlarged uterus. Fifteen months post ovariohysterctomy, scarring associated with endometrial tissue resulted in ureteral strictures, bilateral hydronephrosis, and azotemia. Cystoscopic placement of bilateral ureteral stents with fluoroscopy was performed and resulted in short-term clinical improvement. The animal's condition declined and euthanasia was elected 4 mo after ureteral stent placement. Severe endometriosis with secondary inflammation resulting in bilateral hydroureter and hydronephrosis, as well as concurrent cystitis, ureteritis, and pyelonephritis were confirmed at necropsy. Despite possible complications, ureteral stents can be considered a useful therapeutic option in patients with ureteral disease. PMID- 22204077 TI - Pleural actinomycosis in a free-ranging river otter (Lontra canadensis). AB - Actinomycosis, presenting as chronic proliferative pyogranulomatous pleuritis associated with sulfur granules, was diagnosed in a mature male river otter (Lontra canadensis) captured near Victoria, British Columbia, Canada, in April 2010. The river otter died during sedation for clinical examination and was necropsied immediately. Bacteria of the genus Actinomyces are commensals of the mucous membranes in a wide range of animals and people that act as opportunistic pathogens. This is the first report of actinomycosis in a river otter. PMID- 22204078 TI - Ovariohysterectomy of three vampire bats (Desmodus rotundus). AB - Three sexually mature female common vampire bats (Desmodus rotundus) housed at the North Carolina Zoological Park, Asheboro, North Carolina, were selected for surgical ovariohysterectomy. All animals were induced and maintained with isoflurane anesthetic gas. Magnification loop glasses were worn by the surgeon for the procedure. A ventral midline incision was made into the abdominal cavity. Simple micro-ophthalmic surgical packs along with hemoclips were used to perform the ovariohysterectomies. The linea alba and muscular layers were closed using a simple continuous suture pattern with 4-0 polydioxanone suture. The skin was apposed using a horizontal mattress suture pattern with 4-0 polydioxanone suture. Animals recovered with minimal deleterious side effects. Animals were housed together in a recovery chamber and administered meloxicam at 0.2 mg/kg placed in their blood meal once daily for 7 days postoperatively, after which they were returned to their normal enclosures. PMID- 22204079 TI - Dermatophytosis (Trichophyton mentagrophytes) in a Coquerel's sifaka (Propithecus coquereli). AB - A 19-yr-old intact male Coquerel's sifaka (Propithecus coquereli) was evaluated for a crusting facial dermatopathy. Fungal culture and histopathology of skin biopsies were consistent with dermatophytosis caused by Trichophyton mentagrophytes, and treatment with the antifungal medication terbinafine was initiated. After 1 mo of treatment, all clinical signs had resolved and a fungal culture of the skin was negative. The sifaka was treated with terbinafine for a total of 81 days. Two additional fungal cultures were taken and found to be negative for the presence of dermatophytes, the last culture being taken 1 mo after discontinuation of terbinafine. To the authors' knowledge, this is the first reported case of dermatophytosis in a prosimian species and the first reported treatment of a prosimian with the antifungal drug terbinafine. PMID- 22204080 TI - Occurrence of Toxoplasma gondii antibodies in Dasyprocta aguti from Brazil: comparison of diagnostic techniques. AB - In this study, the occurrence of antibodies to Toxoplasma gondii in Brazilian agouti (Dasyprocta aguti) was compared by modified agglutination test (MAT) and indirect fluorescent antibody test (IFAT) using anti-capybara conjugate. Sera from 109 animals were tested using MAT (1:25 cut-off) and IFAT (1:16 cut-off); 19% were positive by MAT, and 18% were positive by IFAT. Overall, the 17 IFAT positive samples were also positive for MAT. The four positive MAT samples with a titer < or = 200 were IFAT negative. All negative samples obtained by MAT matched with the results of the IFAT. Comparing both tests, and considering MAT as the gold standard, the sensitivity of IFAT was 81%, the specificity was 100%, the accuracy was 97%, the positive predictive value (PPV) was 100%, and the negative predictive value 96%. The kappa value agreement was 87.3% (75.1-99.6%). The anti capybara conjugate can be successfully used to perform IFAT in Brazilian agouti with maximum specificity and PPV. PMID- 22204081 TI - Clinical challenge. Subcutaneous mass, fibroma. PMID- 22204082 TI - Clinical challenge. Squamous cell carcinoma. PMID- 22204083 TI - Clinical challenge. Diskospondylitis of L6-L7 in a snow leopard cub (Uncia uncia). PMID- 22204084 TI - Improving healthcare. PMID- 22204085 TI - Hospital waiting time: the forgotten premise of healthcare service delivery? AB - PURPOSE: This is a national study which aims to determine the average waiting time in Malaysian public hospitals and to gauge the level of patient satisfaction with the waiting time. It also aims to identify factors perceived by healthcare providers which contribute to the waiting time problem. DESIGN/METHODOLOGY/APPROACH: Self-administered questionnaires were the main method of data collection. Two sets of questionnaires were used. The first set solicited information from patients on their waiting time expereince. The second set elucidated information from hospital employees on the possible causes of lengthy waiting time. The questionnaires were administered in 21 public hospitals throughout all 13 states in Malaysia. A total of 13,000 responses were analysed for the patient survey and almost 3,000 were analysed for the employee survey. FINDINGS: The findings indicate that on average, patients wait for more than two hours from registration to getting the prescription slip, while the contact time with medical personnel is only on average 15 minutes. Employee surveys on factors contributing to the lengthy waiting time indicate employee attitude and work process, heavy workload, management and supervision problems, and inadequate facilities to be among the contributory factors to the waiting time problem. SOCIAL IMPLICATIONS: Public healthcare in Malaysia is in a state of "excess demand", where demand for subsidised healthcare far outstrips supply, due to the large fee differential between public and private healthcare services. There is a need for hospital managers to reduce the boredom faced by patients while waiting, and to address the waiting time problem in a more scientific manner, as has been carried out in other countries through simulation and modelling techniques. ORIGINALITY/VALUE: Healthcare organisations are keen to address their waiting time problem. However, not much research has been carried out in this area. The study thus fills the lacuna in waiting time studies in healthcare organisations. PMID- 22204086 TI - Influence of organizational culture on quality healthcare delivery. AB - PURPOSE: The purpose of this paper is to identify if aspects of organizational culture may indicate a new terrain in the cultural influences-quality healthcare relationship. This research stems from the author's belief that viewing the role of head of department or directorate as pivotal to health care management is critical to health care planning and quality healthcare delivery. DESIGN/METHODOLOGY/APPROACH: Interviews were undertaken among 50 professional clinician and non-clinician managers working in the role of head of department, in acute care hospitals in Ireland. The sample was drawn from the total population of 850 managers, utilized in a previous survey study. FINDINGS: Organizational culture is more complex than was previously thought. Several cultural influences such as excellence in care delivery, ethical values, involvement, professionalism, value-for-money, cost of care, commitment to quality and strategic thinking were found to be key cultural determinants in quality care delivery. RESEARCH LIMITATIONS/IMPLICATIONS: Health care managers perceive that in order to deliver quality focused care they need to act in a professional, committed manner and to place excellence at the forefront of care delivery, whilst at the same time being capable of managing the tensions that exist between cost effectiveness and quality of care. These tensions require further research in order to determine if quality of care is affected in a negative manner by those tensions. ORIGINALITY/VALUE: Originality relates to the new cultural terrain presented in this paper that recognizes the potential of health service managers to influence the organizations' culture and through this influence to take a greater part in ensuring that quality health care is delivered to their patients. It also seems to be important that value-for-money is viewed as an ethical means of delivering healthcare, and not as a conflict between quality and cost. PMID- 22204087 TI - Cost-analysis of nutrition support in patients with severe acute pancreatitis. AB - PURPOSE: The purpose of this research was to assess the preferred route of nutrition support (enteral versus parenteral) for treatment of severe acute pancreatitis in the acute care setting. Further, in cases when enteral nutrition is the preferred route, is nasal-bridling a lower-morbidity and cost-effective method? DESIGN/METHODOLOGY/APPROACH: A retrospective review of pre-existing data from an 870-bed hospital system. Medical records were reviewed via an online database system (n = 25 patients) with severe acute pancreatitis. Length of stay and cost were analyzed. FINDINGS: More patients received TPN versus the nasal jejunal (post-pyloric) tube feeds group. No significant relationship was found between total cost and number of co-morbidities or between either of the two treatment groups. However, a medium to large effect size was shown which could indicate a significant relationship in a larger sample size. ORIGINALITY/VALUE: The findings of this research add to the literature already available and will be of interest to those who specialize in this area. PMID- 22204088 TI - Managing healthcare quality in Ghana: a necessity of patient satisfaction. AB - PURPOSE: The study aims to examine how communication, provider courtesy, support/care, environment of the facility and waiting time significantly predict patients' satisfaction with quality of healthcare in two hospitals located in northern Ghana. DESIGN/METHODOLOGY/APPROACH: An exploratory study of which 324 respondents were selected using stratified and convenient sampling techniques. Results are presented using a multiple regression model. FINDINGS: The results revealed that of the five-factor model, support/care, environment of the facility and waiting time determine patients' satisfaction with quality of healthcare delivery. The explanatory power of the dependent variable was explained by 51 percent. ORIGINALITY/VALUE: The findings suggest that internal and external health sector stakeholders may possibly use this study as a precursor to improve service quality in the two hospitals in particular and others in general. PMID- 22204090 TI - Research proposal to my readers. PMID- 22204089 TI - Primary care patient satisfaction segmentation. AB - PURPOSE: The aim of this study is to examine patient satisfaction with non physician staff as related to patient demographics, satisfaction with physician, and intentions to recommend their physicians to others. DESIGN/METHODOLOGY/APPROACH: A survey was conducted at two internal medicine primary care clinics affiliated with a major university health system. A latent class analysis was used to detect patient subpopulations based on profiles of response for five satisfaction-with-staff indicators. FINDINGS: The response rate was 86.46 percent (479 of 554). Analyses revealed four patient subpopulation segments. Segment I (n = 241) patients uniformly indicated a high level of satisfaction across the five satisfaction-with-staff indicators. These patients tended to be older and less educated, and have lower incomes relative to patients in other segments. Patients in Segment II (n = 83) expressed satisfaction with staff caring and need accommodation, but dissatisfaction with access to their physicians. Patients in Segment III (n = 51) indicated high levels of satisfaction with access and low levels of satisfaction with staff caring and need accommodation. Segment IV (n = 104) patients uniformly expressed low levels of satisfaction across all indicators and generally were younger and more educated, as well as hadhigher incomes than other patients. ORIGINALITY/VALUE: Patients have different expectations from their non-physician staff, e.g. younger, more affluent, and educated patients expressed dissatisfaction with staff. This suggests that non-physician staff should provide extra/further responsiveness to have these patients' needs met. Generally, approaches that are differentially targeted to specific patient subgroups are likely to be more efficient and patient-oriented than undifferentiated approaches. PMID- 22204091 TI - The solemn lady with the lantern. PMID- 22204092 TI - Monoclonal antibodies: an introduction. PMID- 22204093 TI - Complications of monoclonal antibody therapy. PMID- 22204095 TI - Use of monoclonal antibodies in oncology. PMID- 22204094 TI - Monoclonal antibodies in rheumatic diseases. PMID- 22204096 TI - The role of monoclonal antibodies in neurological disorders. PMID- 22204097 TI - Monoclonal antibody use in inflammatory bowel disease. PMID- 22204098 TI - Preventable death: accidental drug overdose in Rhode Island. PMID- 22204099 TI - Improving physician hand-offs. PMID- 22204100 TI - The pt-vehicles, ancient and modern. PMID- 22204101 TI - Healthy scepticism about social enterprises. PMID- 22204102 TI - NHS employers limit staff leave ahead of mass pensions walkout. PMID- 22204103 TI - Campaign to raise standards of care attracts high-level support. PMID- 22204104 TI - Activists vow to continue fight for mandatory regulation of HCAs. PMID- 22204105 TI - Union reps allege bullying from trusts trying to cut labour costs. PMID- 22204106 TI - A profession in the spotlight: what makes good quality care? PMID- 22204107 TI - Nations unite in war against global killers. AB - Non-communicable diseases such as cancer, cardiovascular disease and diabetes are responsible for two thirds of deaths worldwide. Nurses are ideally placed to influence change--both in the lifestyles of patients, and in public health policy. PMID- 22204108 TI - Strategy for change. AB - Nursing Standard and the Patients Association organised an emergency meeting of senior figures in health care. They came up with a list of the causes, solutions and priorities for action needed to guarantee delivery of the fundamentals of care. PMID- 22204109 TI - Offer of a quick fix. AB - Supplying newly released prisoners with the heroin antidote naloxone may reduce fatal overdoses. Naloxone programmes are established in Scotland and Wales and a major trial is to begin in England. PMID- 22204110 TI - Use of patient diaries in critical care. AB - The use of patient diaries in critical care in the UK is increasing, but there is little evidence-based research available to support this. The National Institute for Health and Clinical Excellence (NICE) has recommended that services should be developed to meet the psychological care needs of patients following critical illness. One response to this has been the introduction of patient diaries. To gain insight into the use of patient diaries in critical care, a literature review was conducted. This article provides an overview of the literature and suggests how it can inform clinical practice in relation to diary use in critical care and beyond. PMID- 22204112 TI - Vulnerable adults. PMID- 22204111 TI - Management of patients with cellulitis of the lower limb. AB - This article aims to help practitioners develop an understanding of cellulitis of the lower limb. It focuses on the identification of cellulitis, differentiating it from other common conditions, and discusses treatment and management strategies. The article includes information for prevention and early recognition of the condition in an attempt to reduce frequent recurrences. PMID- 22204113 TI - Imported labour. PMID- 22204114 TI - With a little foresight. PMID- 22204115 TI - Thoughts and feelings. PMID- 22204116 TI - Compressive mechanical properties of bovine cortical bone under varied loading rates. AB - Bone tissue functions in varied mechanical systems of the body under static and dynamic conditions. Therefore, it is essential to understand the mechanical responses of bone at varied loading rates, especially those at fast loading rates. This study has investigated the effect of loading rate on the compressive mechanical properties of bovine cortical bone. Bone specimens of 3.85 mm in diameter and 7.7 mm in length were compressed longitudinally with the loading rates of 2 to 2000 mm/s (corresponding strain rates of 0.26 to 260 s(-1)). As a result, bovine cortical bone showed high linear elasticity when the loading rate was slow, and exhibited three definite regions of linear elasticity, plastic deformation, and densification at faster loading rates. The elastic modulus showed no dependency on the loading rate. Compressive strength, strain at fracture, and toughness increased as the loading rate increased under the condition that the loading rates were slower than each critical loading rate of 1000, 100, and 1500 mm/s, respectively. However, all showed no significant changes when the loading rates were faster than the corresponding critical loading rates. In conclusion, as the loading rate increased, changes in the compressive mechanical parameters were different depending on the parameter and the loading rate range. Compressive mechanical behaviour of bovine cortical bone showed a brittle nature under high strain rates (strain rates > 13 s(-1)). These findings should be reflected in the biomimetic simulation of biomaterials for bone tissue repair and engineering. PMID- 22204117 TI - Challenges associated with using bovine serum in wear testing orthopaedic biopolymers. AB - For appropriate in vitro wear testing of prostheses and their biomaterials, the choice of lubricant is critical. Bovine serum is the lubricant recommended by several international standards for wear testing artificial joints and their biomaterials because the wear rate and wear mechanisms closely match clinical results of polyethylene bearings. The main problem with the use of bovine serum as a lubricant is protein degradation and precipitation formation, effects that are recognized as having a direct impact on wear processes. Hence, some researchers have questioned the validity of using bovine serum in simulator testing. This paper reviews the various lubricants used in laboratory wear studies and also the properties of the synovial fluid that the lubricant is trying to replicate. It is clear from the literature survey that the composition of bovine-serum-based lubricants does not match that of synovial fluid. In view of this conclusion, it is suggested that there is a need to develop an alternative lubricant that can replace bovine serum. PMID- 22204118 TI - Functional and structural effects of percutaneous edge-to-edge double-orifice repair under cardiac cycle in comparison with suture repair. AB - Percutaneous procedures for double-orifice mitral valve repair using the MitraClip device (clip) have been recently introduced as new treatment options as alternatives to medical management and open-heart surgery, especially for patients with high estimated operative risk. Similarly to the open-heart surgical technique, where suturing is used, the clip creates a double-orifice configuration that not only improves the closing function of the valve, but also significantly modifies its behaviour, particularly in the diastolic phase. While several clinical trials have been conducted, and are ongoing, in order to assess the safety and effectiveness of this technique, a deeper knowledge of the structural and functional effects on the valve, and of the cyclic loads transmitted to the clip itself, would allow a comparison with other repair techniques, and could serve as a foundation for possible further optimization of the clip design. The effects of the MitraClip device developed by Evalve Inc. were studied by means of a finite element model of the mitral valve, specifically developed to study the structural effects of the original, suture-based, edge-to edge technique. A second model was developed in order to simulate the effects of a suture with similar extension from the leaflet edge in a direction to the annulus, in order to compare the two repair techniques. The mitral valve area and transvalvular pressure gradient predicted by the models for the clip and the suture are quite similar. Similar leaflet cyclic stresses, both in value and in location, were noted for the two mechanisms of linking the leaflets, while minor differences were found in the load transmitted to the suture and the clip, with slightly higher values for the clip. The model satisfactorily allowed functional parameters (valve area and transvalvular pressure gradient) and structural parameters (load, leaflet stress) to be determined. Overall, the structural effects of the clip and the suture are quite similar under the cyclic loading conditions imposed by the cardiac cycle. PMID- 22204119 TI - Replicating interbody device subsidence with lumbar vertebraesurrogates. AB - Bone surrogates are proposed alternatives to human cadaveric vertebrae for assessing interbody device subsidence. A synthetic vertebra with representations of cortices, endplates and cancellous bone was recently developed as an alternative surrogate to polyurethane foam blocks. The ability of the two surrogates to replicate subsidence has not been fully assessed, and was evaluated by indenting them with ring-shaped indenters and comparing their performance with human cadaveric vertebrae using qualitative characteristics and indentation metrics. The sensitivity of each surrogate to a centrally or peripherally placed indenter was of particular interest. Many indentation characteristics of the foam blocks were similar to those of human cadaveric vertebrae, except their insensitivity to centrally and peripherally placed indenters, owing to their homogeneous mechanical properties. This is distinctly different from the cadaveric vertebrae, where a peripherally placed indenter indented significantly less than a centrally placed indenter, because of endplates. By contrast, the synthetic vertebra was sensitive to peripherally placed indenters owing to its bi material composition, including a thickened peripheral endplate. However, an overly strong synthetic endplate resulted in unrepresentative indentation shape and depth. Both surrogates produced similar results to human cadaveric vertebrae in certain respects, but neither is accurate enough in terms of material property distribution to model subsidence completely in human cadaveric vertebrae. PMID- 22204120 TI - Effect of side holes in cervical fusion cages: a finite element analysis study. AB - The objective of this study was to investigate the effect of side holes on the predicted von Mises stress levels in cervical spinal fusion cages subjected to compressive loading. Models with between zero and ten side holes were developed. Finite element analysis (FEA) was used to simulate compression of the cage, made from the polymer PEEK (polyetheretherketone), between two adjacent vertebrae. The analyses were validated by experimental tests. In all of the models, the von Mises stress was highest at the cage-vertebrae interface with peak stresses of between 14 and 18 MPa. Increasing the Young's modulus of the vertebrae from 12 to 30 GPa increased the peak stress on average by 29 per cent. The stresses in the models were lower than the compressive strength of PEEK (118 MPa), and are well within the PEEK fatigue strength reported (60 MPa at 10 million cycles). This study suggests that the number of side holes had a negligible effect on the stress distribution within the cage; the stress magnitudes were fairly constant across all of the models and did not change substantially with the number of holes. Hence, a cervical cage with side holes is unlikely to fail in compression. PMID- 22204121 TI - Repeated measurement of mechanical properties in viable osteochondral explants following a single blunt impact injury. AB - The objective of this work was to develop a method for repeated same-site measurement of mechanical properties suitable for the detection of degenerative changes in a biologically active explant model after a single blunt impact injury. Focal blunt impact injuries to articular surfaces lead to local cartilage degeneration and loss of mechanical properties. We employed a repeated measurement methodology to determine variations in mechanical same-site properties before and after injury in living cartilage, with the hypothesis that normalization with initial mechanical properties may provide a clearer evaluation of impact effects and improve our understanding of the biologic responses to impact injury. Bovine osteochondral explants were cultured for up to 14 days after impact injury. Indentation tests were performed before and after impact injury to assess relative changes in mechanical properties. Creep strain increased significantly in impacted explants after 7 days and in both impacted and control explants after 14 days. Further analysis at 14 days revealed decreases in stretch factor beta, creep time constant and local compressive modulus. A repeated measures methodology reliably detected changes in the mechanical behaviour of viable osteochondral explants after a single impact injury. PMID- 22204122 TI - A p-type finite element solution for the simulation of O2 transport in articular cartilage tissue: heterogeneous and porous media. AB - The partial pressure of oxygen (pO2) is suggested to have a regulatory effect on chondrocyte biosynthetic activities, and its effect during expansion is unknown. The authors hypothesize that oxygen tension due to mechanical deformation or swelling could be as important as direct mechanical effects on cell biosynthetic activities. While there are plenty of studies on measuring and/or modelling pO2 in articular cartilage (AC) for static (rest) conditions, to the best of the authors' knowledge there are very few such studies on pO2 in AC for dynamic conditions such as swelling or tissue deformation. In this study, it is attempted to develop a model to study the dynamics of oxygen transport in AC. A high precision hybrid element is designed using the p-type finite element method, by which diffusion and convection are incorporated as a single element. A domain decomposition method is used that allows the use of a different type of discretization with independent discretization variables in non-overlapping sub domains, for a generic three-dimensional approach to elliptic boundary value problems of order 2 or higher. The formulation developed in this study might be used in determining the necessary flow conditions to cultivate tissue constructs in tissue repair and tissue engineering. PMID- 22204123 TI - Elastic properties of polycaprolactone at small strains are significantly affected by strain rate and temperature. AB - Tensile tests were conducted on polycaprolactone at various strain rates and temperatures. Focusing on the mechanical properties within only the small-strain elastic region, i.e. up to the inflection point in the stress-strain diagram, it was found that strain rate and temperature had significant effects on the polymer. This finding implies that the effects of strain rate and temperature on the elastic properties of polycaprolactone should be considered in the design and manufacture of rigidity-sensitive, load-bearing applications, including use as biomaterial for scaffolds in tissue engineering applications. PMID- 22204124 TI - Phytochemicals and bioactivities of Anemone raddeana Regel: a review. AB - Anemone raddeana, usually called as'"Toujian Liang" in China, is an Anemone herb belonging to the Ranunculaceae family. Until now there are in total 67 of chemical components identified including triterpenoids, steroids, lactones, fats and oils, saccharide and alkaloids. A broad spectrum of pharmacological activity of A. raddeana compounds have been reported, such as antitumor, antimicrobial, anti-inflammatory, sedative and analgesic activites, as well as anti-convulsant and anti-histamine effects. In view of this, we initiated this short review to present the phytochemical and pharmacological profile of A. raddeana to support future studies in this discipline. PMID- 22204125 TI - Preparation and determination of desethylamiodarone in dog lung by HPLC-MS. AB - A novel method was developed for the preparation and determination of desethylamiodarone in dog lung by high-performance liquid chromatography (HPLC) with amiodarone as a standard. The selected dog was orally given amiodarone, then executed and the active metabolite desethylamiodirone in lung tissue was isolated, concentrated and purified by Waters C18 column (25 mm x 250 mm, 10 microm) with mobile phase of acetonitrile-100 mmol/L acetic acid containing 15 mmol/L diethylamine (55:45 v/v) at a flow rate of 10.0 mL/min. Hypersil ODS2 column (4.6 mm x 250 mm 5 microm) was used to analyze amiodarone and desethylamiodarone, with the same mobile phase at a flow rate of 1.0 mL/min, the detection wavelength was 237.5 nm. Atmosperic pressure electronic spray ionization (AP-ESI) and ion mass spectral (m/z) of 618.1(M + H) were selected to validate desethylamiodarone. The f(i) of desethylamiodarone and amiodarone were 1.04 +/- 0.02 and 1.020 +/- 0.01, respectively. It indicated that desethylamiodarone can be separated and purified by preparational HPLC after Mass Spectrometry (MS) validation and quantified according to f(i) of amiodarone indirectly. The proposed method enables the preparation and determination of desethylamiodarone in dog lung successfully. PMID- 22204126 TI - Validation of a LC/MS/MS method for the quantitation of a new gastroprokinetic agent SHR116958 and its metabolite in rat plasma. AB - A liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was succesfully developed for the simultaneous determination of SHR116958 (a new gastroprokinetic agent) and its metabolite in rat plasma under the condition that tamsulosin was used as the internal standard. The analytes and internal standard were extracted by liquid-liquid extraction (LLE). After electrospray ionization, positive ion fragments were detected in the multiple reaction monitoring (MRM) mode with a triple quadrupole tandem mass spectrometer. The method was linear in the concentration range of 2.71-5560 ng x mL(-1) with an average correlation > 0.99 for both SHR116958 and its metabolite. Moreover, the method was validated according to FDA guidance in terms of accuracy and precision, in the meanwhile stability of compounds was well established in a battery of studies, i.e., bench top, autosampler and long-term storage stability as well as freeze/thaw cycles. Therefore, the method proved to be suitable for pharmacokinetics study of SHR116958 and its metabolite in rat. PMID- 22204127 TI - Spectrophotometric and spectrofluorimetric determination of atomoxetine in pharmaceutical preparations. AB - Visible spectrophotometric and spectrofluorimetric methods were developed for the determination of atomoxetine in pharmaceutical preparations. The spectrophotometric method was based on a nucleophilic substitution reaction of atomoxetine with 1,2-naphthoquinone-4-sulphonate (NQS) in an alkaline medium to form an orange-colored product. The absorbance-concentration plot is rectilinear over the range 5-40 microg mL(-1). The limits of detection and quantification were calculated to be 0.02 microg mL(-1) and 0.06 microg mL(-1), respectively. The spectrofluorimetric method was based on the derivatization reaction of 4 chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) with atomoxetine to produce a fluorescent derivative. The formed highly fluorescent derivative that was measured at 462 nm after excitation at 533 nm. The fluorescence-concentration plot is rectilinear over the range 10-500 ng mL(-1). The limits of detection and quantification were calculated to be 0.19 ng mL(-1) and 0.57 ng mL(-1). The analytical performance of both methods was fully validated, and the results were satisfactory. The methods have been successfully applied for the determination of the studied drug in capsules and the results obtained ware in good agreement with those obtained by the reference method. PMID- 22204128 TI - Multi criteria decision making to select the suitable method for the preparation of nanoparticles using an analytical hierarchy process. AB - Selecting the right method for the preparation of nanoparticles is a crucial decision. A wrong decision can result in the product having to be formulated and developed again. One tool that can be useful in determining the most appropriate method is the Analytical Hierarchy Process (AHP). AHP has been employed in almost all areas related to decision-making problems. In this paper, the results of a case study illustrate that the AHP concept can assist designers in the effective evaluation of various methods available for the preparation of nanoparticles. This paper presents the methodology of selecting the most suitable method for preparing nanoparticles using the analytical hierarchy process. PMID- 22204129 TI - Design and gamma scintigraphic evaluation of colon specific pectin-EC pellets of secnidazole prepared by powder layering technology. AB - The aim of the present study was to prepare a colon targeted pellet formulation of secnidazole and to evaluate the formulation in vitro and in vivo by a gamma scintigraphy method. Pectin/ethyl cellulose in different ratios and in different coating labels with plasticizer was used to prepare secnidazole pellets by a powder layering technique. The formulations were tagged with 99mTC-DTPA, a tracer in gamma scintigraphy to evaluate its transit behavior in rabbits. Morphology and compatibility were studied using Scanning Electron Microscopy, IR spectroscopy and Differential Scanning Calorimetry were used for the characterization of prepared pellets. The in-vitro study suggested that pectin (59%) esterification and ethyl cellulose 45cps at 20% coating label led to an optimum bacterial enzyme dependent released behavior. The optimized formulation was subjected to an in vivo transit study. Scintigraphy images clearly indicated that the formulation can delay the drug release prior to the colon. The average time of gastric emptying and colon arrival was 57 min and 6.08 h, respectively. The coated pellets prepared by powder layering technology successfully released drug in the colon indicating that site specificity has been achieved with pectin 59% esterification and ethyl cellulose 45 cps at 1:2 ratio with 20% coating label. PMID- 22204130 TI - Formulation, and physical, in vitro and ex vivo evaluation of transdermal ibuprofen hydrogels containing turpentine oil as penetration enhancer. AB - The aim of the present study was to investigate the transdermal permeation enhancing capability of turpentine oil for ibuprofen from hydrogels. Ibuprofen 1% w/v hydrogels were developed with carboxypolymethylene with and without turpentine oil. Turpentine oil was incorporated in increasing concentrations, i.e. 0.5, 1, 1.5, 2, 2.5 and 3% of the total gel formulation, and its permeation enhancing effect was examined. Gels were examined physically for pH, viscosity, spreadability, extrudability, smoothness and appearance. To study the in vitro and ex vivo permeation potential of formulated gels, permeation studies were performed with a Franz diffusion cell using cellulose membrane and excised rabbit abdominal skin. Ibuprofen hydrogel with 3% turpentine oil showed a maximum flux of 10.87 mg/cm2/h across artificial skin and 17.26 mg/cm2/h across rabbit abdominal skin. PMID- 22204131 TI - Design and optimization of some collagen-minocycline based hydrogels potentially applicable for the treatment of cutaneous wound infections. AB - Topical delivery systems for the treatment of different infected cutaneous wounds based on natural biopolymers are widely studied. The development of some topical hydrogels with type I collagen and minocycline by the experimental design technique, based on response surface methodology and Taguchi's approach, and the evaluation of their kinetic properties is presented. The concentrations of polymer, drug and cross-linking agent were selected as independent variables for the face centered composite design and low, medium and high concentration as variation levels for each factor. Minocycline kinetic release was investigated using a modified Franz diffusion cell. The drug release followed the Higuchi model. Three formulations having optimal minocycline release profiles were selected. They can be used as potential drug topical release systems for the treatment of infected cutaneous tissue. PMID- 22204132 TI - Does lactobionic acid affect the colloidal structure and skin moisturizing potential of the alkyl polyglucoside-based emulsion systems? AB - Moisturizing creams are the most prescribed products in dermatology, essential in maintaining healthy skin as well as in the topical treatment of some diseases. The irritation potential of commonly used emulsifiers and moisturizing ingredients, but also their mutual interactions, could affect the functionality and safety of those dermopharmaceutics. The aim of this study was to promote moisturizing alkyl polyglucoside (APG)-based emulsion as vehicle for lactobionic acid (LA), advantageous representative of the alphahydroxyacids (AHAs) multifunctional moisturizers, assessing the safety for use (in vitro acute skin irritation test using cytotoxicity assay compared with in vivo data obtained using skin bioengineering methods) and in vivo moisturizing capacity (bioengineering of the skin). In order to investigate possible interactions between APG mild natural emulsifier-based emulsion and LA, a deeper insight into the colloidal structure of the placebo and the emulsion with LA was given using polarization and transmission electron microscopy, rheology, thermal and texture analysis. This study showed that APG-based emulsions could be promoted as safe cosmetic/dermopharmaceutical vehicles and carriers for extremely acidic and hygroscopic AHA class of actives (specifically LA); prospective safety for human use of both APG and LA with the correlation between in vivo and in vitro findings was shown. However, it was revealed that LA strongly influenced the colloidal structure of the emulsion based on APGs and promoted the formation of lamellar structures which reflects onto the mode of water distribution within the cream. The advantageous skin hydrating potential of LA-containing emulsion vs. placebo was unlikely to be achieved, pointing that emulsions stabilized by lamellar liquid crystalline structures probably are not satisfying carriers for highly hygroscopic actives in order to reach the full moisturizing potential. Safe and effective use on dry skin is presumed. PMID- 22204133 TI - Increase of therapeutic activity of doxorubicin by long circulating liposomes in combination with curcumin. AB - In this study, doxorubicin (DOX)-loaded long circulating liposomes combined with curcumin (CUR) (DOX-CUR-LCLs) were successfully prepared as a novel formulation for cancer treatment. The particle size and distribution, zeta potential, drug loading capacity, and entrapment efficiency (EE) of the preparation were characterized. The in vitro anti-tumor activities of DOX-CUR-LCLs and DOX-LCLs against A549 cells were then evaluated and compared with that of free DOX. Cytotoxicity evaluation showed that DOX-CUR-LCLs had a significantly higher antitumor activity than other DOX preparations. These results suggest that novel DOX-CUR-LCLs, combination of DOX and CUR administered in long-circulating liposomes, could improve antitumor activity. PMID- 22204134 TI - Alpha-Asarone incorporated in mixed micelles suitable for intravenous administration: formulation, in-vivo distribution and anaphylaxis study. AB - Alpha-Asarone is clinically used as a commercial intravenous formulation (CA AREs). However, Polysorbate 80, a solubilizing agent contained in the formulation has been reported to be toxic. To enhance the aqueous solubility of ARE and to reduce the toxicity of CA-AREs caused by solubilizing agents, ARE loaded soybean phosphatidylcholine-deoxysodium cholate-mixed micelles (ARE-SPC-DC-MMs) were prepared and characterized in this study. Furthermore, pharmacokinetics and tissue distributions of ARE-SPC-DC-MMs and CA-AREs were also investigated. Additionally, the anaphylaxis of both of the two formulations was evaluated. The mean size of mixed micelles (ARE-SPC-DC-MMs) was 24.74 +/- 1.14 nm and the ARE solubility within the mixed micelles was approximately 30-fold greater than that of free drug in water. ARE-SPC-DC-MMs showed pharmacokinetic parameters similar to CA-AREs. AUC(0-->t) (mg/L x min) of ARE-SPC-DC-MMs was lower in spleen than that of CA-AREs (p < 0.05) while it was greater in the lung (p < 0.05). There was no significant difference in other organs. These findings demonstrated that in comparison with CA-AREs, ARE-SPC-DC-MMs had similar properties in vivo, but led to higher accumulation of ARE in lungs. Meanwhile there was nearly no anaphylactic reaction caused by ARE-SPC-DC-MMs, but reactions could be observed in the CA-AREs group with significantly higher histamine release. In conclusion, ARE-SPC-DC-MMs could be an excellent substitute for commercially available CA AREs for intravenous administration. PMID- 22204135 TI - A PKC-beta inhibitor prompts the HUVECs apoptosis-induced by advanced glycation end products. AB - The accumulation of advanced glycation end products (AGEs) on micro-vasculature has been demonstrated to be a key factor in diabetes mellitus development. Evidence suggests that AGEs triggered apoptotic changes in human umbilical vein endothelial cells (HUVECs) and protein kinase C (PKC)-beta plays a pivotal role in AGEs-induced micro-vascular dysfunction. Thus the effect of the selective PKC beta inhibitor (LY333531) on AGEs-induced HUVEC apoptosis and proliferation was investigated. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was used to determine the cells viability after being incubated with AGEs and LY333531. Acridine orange/ethidium bromide (AO/EB) fluorescence detection was applied to observe the pro-apoptosis effects of AGEs and LY333531. Bcl-2, Bax and Bad proteins' expression were determined by StreptAvidin-Biotin-enzyme Complex (SABC) immunocytochenistry. The results showed that pretreatment with LY333531 strikingly decreased the chance of HUVEC survival and the effect of LY333531 on apoptotic cell death in HUVEC significantly increased compared with the AGEs group. Blockade of PKC-beta up-regulated the expression of Bax and Bad proteins and down- regulated the expression of Bcl-2 protein. Moreover, LY333531 reduced the ratio of Bcl-2/Bax. The results indicate that the selective PKC-beta inhibitor, LY333531, can further prompt AGEs-induced endothelial cells apoptosis. The increased expression of Bax, Bad and decreased expression of Bcl-2 and Bcl 2/Bax ratio are associated with the apoptotic process. PMID- 22204136 TI - Identification of carboxylesterases expressed in rat intestine and effects of their hydrolyzing activity in predicting first-pass metabolism of ester prodrugs. AB - Carboxylesterases (CESs) located in the intestine play an unique role in the absorption of many drugs especially ester prodrugs. In order to determine the expression and hydrolyzing activity of CESs isozymes (CES1 and CES2) located in rat intestine, the activities of CES1 and CES2 were evaluated by the intestinal S9 incubation with imidapril and irinotecan (CPT-11), the substrates of CES1 and CES2, respectively. The distribution characteristics of CES1, CES2, Pregnane X Receptor (PXR) and Constitutive Androstane Receptor were analyzed by real-time polymerase chain reaction (RT-PCR) or Western blot. Imidaprilat metabolized from imidapril by CES1 was too low to be detected in rat intestinal S9 fractions, while there was little and even no expression of CES1 mRNA in intestinal segments. In contrast, Vmax values for CPT-11 diminished gradually from proximal to distal segments within the rat intestine which was consistent with the mRNA expression level of CES2. These results indicated that CES2 represents the major CESs isoform in the rat complete intestine and decreased from duodenum to colon, whereas the expression of CES1 was too low to influence the metabolism of ester prodrugs. The expression of PXR and CAR decreased slightly along the entire intestine on both mRNA and protein levels which indicated that PXR and CAR may be one of the major factors which contribute to the expression of CES1 and CES2. Thus, the knowledge about the characteristic and site-specific expression of CES1 and CES2 in rat intestine will help to predict the oral bioavailability of ester prodrugs. PMID- 22204137 TI - Glutathione peroxidase isoenzymes in human tumor cell lines. AB - A set of human tumor cell lines was characterized in terms of the GPx isoenzymes GPx1, -2, -3 and -4. Semiquantitative PCR was used to investigate the GPx mRNA transcripts and the GPx activity was determined photometrically. As a result of culturing under standard conditions, diverse distribution of GPx mRNA and basic GPx activity was found in the investigated cell lines. PCR results showed nearly ubiquitous existence of the isoenzymes GPx1 and GPx4. GPx2 mRNA transcript was only detected in the colonic cell line CaCo-2. After detection of the GPx3 mRNA transcripts in most of the tested cell lines, an ELISA was performed to investigate if the GPx3 protein is present as well. However, the GPx3 protein could not be detected. Glutathione peroxidases contain the amino acid selenocysteine in their active centre. Selenocysteine contains selenium instead of sulfur in cysteine. Therefore, the influence of selenium on GPx activity and GPx isoenzyme distribution was investigated. Cell culturing with additional selenium showed a clear elevation of GPx activity in Mono Mac 6 cells but no gain of mRNA transcripts or any change in the isoenzyme's distribution. PMID- 22204138 TI - Research on an in vitro cell system for testing the neurotoxicity of kynurenine pathway metabolites. AB - Quinolinic acid (QUIN), kynurenine acid (KYNA) and 3-hydroxykynurenine (3-HK) - metabolites of the kynurenine pathway are considered to be associated with many central nervous system diseases. However, in neuroscience research in order to test neurotoxicity or neuroprotection against these compounds only primary cell models are available. In this investigation we aimed to develop a simple, rapid and accurate cellular in vitro model using immortalized human neuroblastoma cell lines, namely SK-N-SH and SH-SY5Y differentiated by treatment with various agents. In order to alter the cell response to the neurotoxins, tumor necrosis factor-alpha and retinoic acid (RA) as differentiating agents and modulation of the cellular metabolism through changing the sugar composition from galactose to glucose in media were used. Our results indicated that although RA differentiation of both cell lines induced the expression of neuronal features, cell vulnerability after exposure to control neurotoxicants (salsolinol, 6 hydroxydopamine) and 3-HK was decreased in comparison to untreated cells and was not influenced after exposure to QUIN and KYNA. Interestingly, the same observations were done in cells grown in galactose containing media. PMID- 22204140 TI - [Support of lifestyle modifications in health care: effectiveness and means]. AB - The effectiveness of non-drug interventions within the health care as well as the most effective means of inducing lifestyle modification are reviewed on the basis of systematic reviews and meta-analyses. Health care is not the right place for intervening in the lifestyles of healthy people, but among those at risk or already affected with a disease significant effects can be achieved with relatively minor measures. Motivational interviewing is effective in view of the minor effort required. It suits for most patients and all lifestyles. Follow-up and provision of feedback as part of routine consultations will increase the effectiveness. PMID- 22204139 TI - Genetic transformation of Salvia austriaca by Agrobacterium rhizogenes and diterpenoid isolation. AB - Hairy roots of Salvia austriaca Jacq. transformed with Agrobacterium rhizogenes strain A4 were obtained and transgenic status of the roots was confirmed by polymerase chain reaction (PCR) using rolB and rolC specific primers. The root cultures growing in half-strength Gamborg (1/2 B5) liquid medium supplemented with sucrose (30 g L(-1)) under light conditions (photoperiod: 16 h light/8 h dark) were examined for their ability to produce diterpenoids. From n-hexane extract the abietane-type diterpenoids royleanone, 15-deoxyfuerstione and taxodione were isolated and identified. This is the first report on the genetic transformation of S. austriaca. PMID- 22204141 TI - [Acute intracompartmental pressure syndrome in the foot of children and the young]. AB - Acute intracompartmental pressure syndrome is a surgical emergency situation. The syndrome is rare and is most commonly associated with a high-energy trauma. It may occur also without trauma, for instance in muscular overloading. The syndrome should be suspected, when a child suffers from acute foot pain. The treatment is immediate compartment release surgery. A delay can be critical, because complications may remain persistent. PMID- 22204142 TI - [Vascular malformations associated with Marfan syndrome, Ehlers-Danlos syndrome and neurofibromatosis 1 and their surgical treatment]. AB - The Marfan syndrome, vascular type Ehlers-Danlos syndrome and neurofibromatosis 1 are associated with vascural complications that may be fatal. Therefore, referral to treatment should be properly timed, followed by therapy taking special features of the disease into consideration. When treating a vascular malformation related to an inherited disorder, it is important to collaborate with clinical geneticists in order to obtain genetic counseling and DNA diagnostics as well as to elucidate the status of close relatives. PMID- 22204143 TI - [Out-of-hospital cardiac arrest]. AB - Cardiac arrest as the first symptom of coronary artery disease is not uncommon. Some of previously healthy people with sudden cardiac arrest may be saved by effective resuscitation and post-resuscitative therapy. The majority of cardiac arrest patients experience the cardiac arrest outside of the hospital, in which case early recognition of lifelessness, commencement of basic life support and entry to professional care without delay are the prerequisites for recovery. After the heart has started beating again, the clinical picture of post resuscitation syndrome must be recognized and appropriate treatment utilized. PMID- 22204144 TI - [Congenital ciliary dysfunction in children]. AB - Congenital ciliary dysfunctions are recessively inherited disorders. The disorder is poorly recognized, if the patient has no situs inversus. The diagnosis is delayed, being made on the average at the age of over five years. The review deals with a recent European multinational survey of the occurrence, genetics, diagnostics and treatment of congenital ciliary dysfunctions. Data of Finnish pediatric patients under treatment have also been collected for the survey. The number of congenital ciliary dysfunctions found in Finland is approximately one fifth of that found in other Nordic countries. PMID- 22204145 TI - [Brain concussion]. AB - Brain concussion is a common disturbance caused by external forces or acceleration affecting the head. It may be accompanied by transient loss of consciousness and amnesia. Typical symptoms include headache, nausea and dizziness; these may remain for a week or two. Some patients may experience transient loss of inability to create new memories or other brief impairment of mental functioning. Treatment is symptomatic. Some patients may suffer from prolonged symptoms, the connection of which with brain concession is difficult to show. Almost invariably the prognosis of brain concussion is good. PMID- 22204146 TI - [Prolonged abdominal discomfort, ascites and pleural fluid]. AB - A 67-year-old man had been examined for 1.5 years for hypersedimentation, abdominal discomfort and pleural effusion, but the cause had remained unclear. With progressive weight loss the patient was admitted to the ward for examinations, whereupon the diagnosis of a rare disease began to unravel. PMID- 22204147 TI - [Pulmonary nocardiosis in a farmer]. AB - We describe a farmer who was diagnosed to have pulmonary nocardiosis as an occupational disease. This case is the first occupational pulmonary nocardiosis in Finland, where the infection is rare altogether. The way of exposure is typical and there is a similar case published earlier in Germany. Because farmers are significantly exposed to organic dusts, bacteria and molds, it is always important to consider the possibility of an occupational disease even in the case of an acute infection. PMID- 22204148 TI - [Update on current care guidelines: urinary tract infections]. AB - This guideline is focused on the diagnostics and treatment of acute, recurrent and relapsing urinary tract infections in adults and children. Sexually transmitted diseases are not addressed, but must be considered in differential diagnostics. The resistance prevalence of the causative microbes and the ecological adverse effects of antimicrobial agents were considered important factors in selecting optimal therapeutic choices for the guideline. Diagnosis and management of cystitis in otherwise healthy women aged 18-65 years can be based on structured telephone interviews. Primary antimicrobiotic drugs are nitrofurantoin, pivmesillinam and trimetoprim for three days. PMID- 22204149 TI - Let's do what our most successful opponents have done. PMID- 22204150 TI - Improving physician grassroots in Iowa. PMID- 22204151 TI - Medicare payment in 2012 for Iowa physicians--GPCIs and the SGR. PMID- 22204152 TI - Payment system changes: what can we expect? PMID- 22204153 TI - New resident work rules raise questions. PMID- 22204154 TI - Transparency and medical records: proceed with caution. PMID- 22204155 TI - Meeting the demand for more nephrologists. PMID- 22204156 TI - Dialysis access: issues and considerations. PMID- 22204157 TI - Using online surveillance to monitor EPO dosing. PMID- 22204158 TI - Why patient participation in modality choice is important. PMID- 22204159 TI - Informed consent: what nephrologists should tell their patients about renal replacement options. PMID- 22204160 TI - Improving quality and outcomes with alternative dialysis modalities. PMID- 22204161 TI - Challenges and opportunities in modality options education. PMID- 22204162 TI - What we learn from studies on more frequent dialysis. PMID- 22204163 TI - New Medicare payment rules encourage home dialysis, but how to get patients started? PMID- 22204164 TI - Why self-care can make a difference. PMID- 22204165 TI - The international quotidian dialysis registry. PMID- 22204166 TI - Improving workflow in the dialysis clinic: part 2. PMID- 22204167 TI - Medicare Part D: challenges for dialysis patients. Part 1. AB - Dialysis patients require numerous medications and have high prescription drug costs compared with general Medicare patients, possibly making them more vulnerable to Medicare Part D policy-related issues. The purpose of this study was to identify problems that dialysis patients experience with Medicare Part D through a survey of dialysis social workers. The online survey was posted on www.kidneyhealthcarecoverage.org and results were collected from January 2010 through October 2010. It was completed by 184 social workers in 38 states, representing 14,200 patients. The greatest Part D plan restrictions were seen with the highest cost prescription medications--Lanthanum carbonate, sevelamer carbonate, and cinacalcet. Seventeen percent of social workers reported that dialysis patients were "very frequently" or "frequently" unaware of available Medicare Part D coverage and 54% reported that up to 20% of their patients continued to have no insurance coverage for prescription drugs. Social workers reported that patients affected by the coverage gap exhibited various changes in medication-taking behavior, such as skipping doses and decreasing dosing frequency. Higher out-of-pocket costs for some dialysis patients during the coverage gap led to reduced use of medications; such gaps in treatment could lead to increased use of medical services, but further data are needed. Currently, the government is slowly phasing out the coverage gap; this process should be completed by 2020. The anticipated shift of self-administered bone and mineral disorder medications from Part D into the dialysis bundle in 2014 has the potential to affect dialysis patients' access to these medications. PMID- 22204168 TI - PQRI: looking back, looking forward. PMID- 22204169 TI - Disaster management never part of the medical curriculum in Pakistan. PMID- 22204170 TI - Practicing urologist learning laparoscopy: no short cut to short cuts! AB - OBJECTIVE: To emphasize the importance of regular exercising in dry lab in initial phase of learning of laparoscopic surgery by a practicing urologist. METHODS: The study was performed at Dry Lab -Jayaramdas Patel Academic Centre (JPAC) attached to Muljibhai Patel Urological Hospital, Nadiad, India. The study is based on 30 sets of exercises of four standard tasks utilized to learn Hand Eye coordination for Laparoscopic Surgery. All sets were performed by a single participant over a period of 19 days and the exercise record was retrospectively analyzed. The participant had limited exposure of one year in a low volume laparoscopy center. Correlation between Exercise number and Task Completion Time (TCT) was calculated by Pearson's Correlation Coefficient and its significance is assessed by Student paired t test. RESULTS: The current study describes 30 exercises of 4 standard tasks for hand-eye-coordination. Although the study was completed in 19 days but there were two intervals which point to the objective of this study. First interval was of 3 days and it occurred after 4th exercise. At 5th exercise the Task Completion Time started rising more than the 2nd exercise. This regression further worsened on 6th exercise which had an interval of 2 days. Here the (TCT) went up almost equal to 1st exercise (1050 vs 1054 seconds). Mean time for IT1, IT2, IT3, IT4 and TCT of over all exercises were calculated as 24.2 +/- 3.7, 121.9 +/- 54.9, 233 +/- 73.5, 199 +/- 55.1 and 582.5 +/- 174.8 seconds respectively. Significant correlation was noticed between number of exercises performed and improvement in time taken for individual tasks (IT 2 to IT4) and TCT. However there was no significant impact on Task 1. CONCLUSION: Regular Dry Lab exercises improves hand eye coordination and psychomotor skill dedicated continuous exercising has significant impact in reducing TCT. PMID- 22204171 TI - Relationship of length of transverse process of seventh cervical vertebra with positive nerve conduction studies in cases of brachialgia. AB - OBJECTIVES: To determine the association between length of transverse process of seventh cervical vertebrae on plain x-ray cervical spine AP-view and nerve conduction studies of respective patients having brachialgia. METHODS: The study was carried out at Department of Radiology, Military Hospital Rawalpindi in collaboration with Armed Forces Institute of Rehabilitation Medicine (AFIRM) Rawalpindi from January 2004 to December 2004. A total of 160 adult subjects were enrolled in this study including 80 volunteers with no history of brachialgia. Eighty subjects suffered from brachialgia and were documented to have abnormal nerve conduction studies/Electromyography referred from AFIRM Rawalpindi. X-ray cervical spine AP-view of all patients was taken. Relative risk (RR) was calculated to determine the association. RESULTS: Eighty percent (64 out of 80) patients with brachialgia and documented abnormal nerve conduction studies had prominent transverse process of seventh cervical vertebrae on x-ray cervical spine AP-view. RR for developing brachialgia was 2.64 and association was statistically significant. CONCLUSION: X-ray cervical spine AP-view is a simple, quick and tolerable method of measuring transverse process of seventh cervical vertebra. This can predict which individuals are more likely to develop brachialgia. PMID- 22204172 TI - Antihyperlipidaemic effects of Eugenia jambolana fruit in diet induced hyperlipidaemic rats. AB - OBJECTIVE: To evaluate the antihyperlipidaemic effects of Eugenia jambolana fruit pulp in diet induced hyperlipidaemic rats and to compare them with Simvastatin. METHODS: An experimental randomised control study was conducted on seventy five male albino rats, divided into five groups labelled A, B, C, D and E with fifteen rats in each group. Group A was kept as normal control, groups B, C, D and E were given hyperlipidaemic diet for six weeks. In group B no further intervention was done, group C and group D were given ethanolic extract of Eugenia Jambolana and Simvastatin respectively for eight weeks. Group E was given combination of both for same duration. Serum total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides were measured at zero, six and fourteen weeks. RESULTS: At fourteenth week significant reductions in total cholesterol, low density lipoprotein cholesterol and triglycerides and a rise in high density lipoprotein cholesterol was observed in interventional groups C, D and E as compared to experimental hyperlipidaemic control group B (p < 0.05). There was no significant difference at baseline (zero weeks) serum total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides of groups A, B, C, D & E; p > 0.24, p > 0.37, p > 0.89, p > 0.2, respectively. On sixth week, there was no significant difference between groups B, C, D and E (p > 0.05). However, 15 rats of group A had significant lower levels of cholesterol, high density lipoproteins, low density lipoproteins and triglycerides when compared to 60 rats of groups B, C, D and E (p < 0.05). CONCLUSION: In male albino rats ethanolic extract of Eugenia Jambolana fruit pulp was as effective as simvastatin in lowering serum total cholesterol, low density lipoprotein cholesterol and triglycerides and increasing high density lipoprotein cholesterol. PMID- 22204173 TI - Efficacy of transcutaneous electrical nerve stimulation and its different modes in patients with trigeminal neuralgia. AB - OBJECTIVE: To see the efficacy of Transcutaneous Electrical Nerve Stimulation therapy and its different modes in trigeminal neuralgia, refractory or partially responsive to drug therapy and to find out the comparative effectiveness of different modes of TENS therapy in these cases. METHODS: This was a prospective analytical study, conducted at Rabia Moon Institute of Neurological Sciences over a period of one year. Thirty one patients diagnosed as suffering from trigeminal neuralgia according to International Headache Society Criteria, either Classic Trigeminal Neuralgia (CTN) or Symptomatic Trigeminal Neuralgia (STN) were randomly subjected to two different modes of Transcutaneous Electrical Nerve Stimulation (TENS) therapy. Severity of pain was assessed on visual analogue scale prior to treatment and fifteen days after therapy and results were than compared. RESULTS: Out of 31 patients, 20 females and 11 males, with a mean age of 50.1 +/- 11 years, 26 (83.7%) improved significantly with application of TENS, only 5 (16.3%) patients remained unresponsive to this form of therapy. Study also showed a better efficacy of constant mode of therapy over burst mode. CONCLUSION: Transcutaneous electrical nerve stimulation is an effective, easy to use therapy with minimal side effects in patients suffering from trigeminal neuralgia not responding to conventional treatment. Constant mode of this therapy was a slightly better option than burst mode therapy. PMID- 22204174 TI - Bulbar uretheral stricture repair with buccal mucosa graft urethroplasty. AB - OBJECTIVE: To evaluate the use of buccal mucosa graft in single stage urethral reconstruction of bulbar urethral stricture. METHODS: In Armed Forces Institute of Urology Rawalpindi, from Jan 2008 to Oct 2009, 56 patients underwent single stage dorsal onlay urethroplasty using buccal mucosa graft for long bulbar urethral strictures (> 2cm). Urethra was incised along the strictured segment in the 12 o'clock (dorsal) position starting from the distal end. A buccal mucosa graft of required length was harvested. The graft was anchored in a spread fixed fashion to the corporal bodies opposing the dorsally incised strictured urethra. The urethra was rotated back to the normal anatomic position. The margins of urethral incision were sutured to the fixed graft edge and corporal body using interrupted 4-0 vicryl. After completion of right margin's stitches, a 16 Fr silicon catheter was placed and then left margin stitches were completed. RESULTS: Only 54 out of 56 patients could be evaluated because 2 patients were lost to follow up. Mean age of the patients was 48 +/- 11.32 years (range 19-67 yrs). Mean length of the buccal mucosa graft was 3.4 +/- 0.6 cm (range 2.6 - 5.5 cm). Duration of follow up was 4-20 months, mean 16.3 +/- 3.65 months. In 47 (87%) patients, the procedure was successful, 7 (13%) patients developed recurrence, out of these 7 patients, 2 (3.7%) required optical urethrotomy and 5 (9.25%) patients responded to urethral dilatation. Mean operative time was 92 +/- 13.22 minutes. CONCLUSION: Buccal mucosa graft urethroplasty produces encouraging results in long bulbar urethral strictures. Longer follow up is required. PMID- 22204175 TI - Evaluation of bone mineral density in premenopausal women with type-2 diabetes mellitus in Zahedan, southeast Iran. AB - OBJECTIVE: To determine the BMD in premenopausal women with type-2 diabetes mellitus. METHODS: This case-control study was performed on 60 premenopausal women with type-2 diabetes mellitus and 60 normal premenopausal subjects. The groups were not completely matched regarding BMI; but they were in the range of obesity. Bone mineral density was determined using dual energy X-ray absorptiometry (DXA) to define bone mineral density (BMD) in second to fourth lumbar vertebrae and the neck of the femur (g/cm2). RESULTS: The results showed that BMD, T- and Z-score of femoral neck, total femur, L2, and Ward's were not significantly different between type 2 diabetic and normal premenopausal women (p > 0.5). A significant increase of L3 BMD and L2-L4 Z-score was observed in diabetic group (p < 0.05). In addition BMD, T- and Z-score of L4 were significantly higher in type 2 diabetic women than normal premenopausal women (P < 0.05). CONCLUSION: Higher BMD was noted over the spine in diabetic group which may be due to higher BMI in this group. PMID- 22204176 TI - Evaluation of predominant Neisseria gonorrhoeae strain types and its correlation with fluoroquinolone resistance in Pakistan. AB - OBJECTIVE: To study the predominant Neisseria gonorrhoeae strain types in Pakistan and to evaluate their correlation with fluoroquinolone resistance. METHOD: A total of 314 strains were collected from 2007-2009. Of these 112 strains were randomly selected for serotyping via the coagglutination technique. Fluoroquinolone susceptibility was checked through the E-test method. Chi square was performed to assess the correlation between the strain type and fluoroquinolone resistance pattern. RESULTS: N. gonorrhoeae isolates were typed in two serogroups and 28 serovars. Serogroup WI comprised 40% (n = 45) whereas WII/WIII was 60% (n = 67). Most commonly isolated serovar belonged to serogroup WI namely Aorst (10%). The other predominant circulating serovars of the serogroup WI were Aost (9%) and Ast (8%) and Bsy (8%), Bopyt (5%) and Bprt (4.5%) in the serogroup WII/III. Fluoroquinolone resistance was 98%, with an MIC of 2 microg/mL in 47%, 4 microg/mL in 36% and > 32 microg/mL in 12% of the isolates. On inferential analysis no significant correlation was observed between fluoroquinolone resistance and any particular serovars. CONCLUSION: A diverse population of N. gonorrhoeae serovars suggesting influx of a variety of gonococcal strains with high fluoroquinolone resistance was identified. This resistance was not associated with any particular serovars, so we speculated inappropriate use of fluoroquinolones in the community to be a major cause. Injudicious fluoroquinolone use in the community should be strongly discouraged to curtail increase in antimicrobial resistance. Furthermore, continuous surveillance of prevalent serovars will be critical to assess genetic alterations of endemic and imported strains to design effective disease control measures. PMID- 22204177 TI - Training of general practitioners about smoking cessation counseling. AB - OBJECTIVES: To study general practitioners' knowledge regarding smoking and their formal educational training on quitting smoking and associated readiness for providing associated services. METHODS: This cross sectional study was carried out using an anonymous WHO based questionnaire. According to sample size estimated based on general practitioners' population ratio, review literatures and response rate probability; it was given to the 5140 general practitioners selected by random quota sampling method from a total of 25,600 practitioners all over the country at the time of the study. RESULTS: There were 3804 (74%) males with 16% being smokers and 4.6% having a history of smoking. Thirty percent of the subjects felt that they were ready for smoking cessation counseling, but only 9% had received formal training for it during medical school or post graduate training, while more than 80% perceived such training as necessary. Smoking cessation intervention during physician visits was associated with increased patient satisfaction especially among those who smoked. CONCLUSION: Formal training for smoking cessation among the study subject was inadequate. They were of the opinion that more courses should be included in medical school as better trained doctors could make good counselors. PMID- 22204178 TI - Use of syndromic management algorithm for sexually transmitted infections and reproductive tract infections management in community settings in Karachi. AB - OBJECTIVE: Syndromic management is promoted as a measure to manage and control STIs in resource poor settings. This research was conducted to assess the diagnosis and prescription patterns using syndromic management algorithms as part of a community-based reproductive health programme. METHODS: The research was conducted in four squatter settlements of Karachi. Health care providers working for a reproductive health programme in these settlements received similar training on the use of algorithms. The people in these settlements had comparable socioeconomic and cultural backgrounds and access to health services. The medical records of 400 women who attended the centres for RTI/STIs were randomly selected. These records were reviewed for diagnosis and prescription patterns. RESULTS: The diagnoses by and prescription practices of the health care providers differed greatly across the four clinics. As often there are more than one etiologic agents for most of the STI/RTI syndromes, algorithms allow multiple antibiotics use. However, this research pointed that despite diagnosing many patients as suffering from one particular infection, a large number of patients were prescribed more than one antibiotic. CONCLUSION: It appeared that the health care providers had difficulties in using the algorithms, pointing to the need for ongoing support and training. The difficulty in correctly diagnosing STIs/RTIs could be the reason for over prescription. There is likelihood that the use of algorithms without sufficient support might contribute to the problems of drug resistance and prescription of drugs when they are contraindicated. Effective use of syndromic management algorithms requires training for effective communication, understanding about the locally prevalent STIs & RTIs, and periodic assessments of the quality of services. PMID- 22204179 TI - The metabolic syndrome in type 2 diabetic subjects in Gorgan, Iran. AB - OBJECTIVE: To assess the prevalence of the metabolic syndrome in subjects diagnosed with Type 2 diabetes in Gorgan, Iran. METHODS: Data were collected from 200 subjects with Type 2 diabetes mellitus and they were categorized as with or without the metabolic syndrome. Metabolic syndrome was diagnosed using Adult Treatment Panel-III (ATP-III) guidelines. RESULTS: The overall metabolic syndrome prevalence was 51.50%. The mean age of all the subjects was 53.65 +/- 9.50 years. There were 122 females and 78 males of whom 65 females and 38 males had the metabolic syndrome. The mean duration of diabetes was 7.70 +/- 1.29 years. Mean triglycerides were 185.15 +/- 56.63 mg/dl, and fasting blood glucose 153 +/- 19.6 mg/dl. These levels were significantly higher in the subjects with type-2 diabetes with metabolic syndrome, but the mean HDL-cholesterol was 37.96 +/- 5.09 mg/dl and this was lower (p < 0.001). Female and male subjects with metabolic syndrome had significantly longer (except HDL-cholesterol) duration of diabetes, higher Triglyceride, and fasting blood glucose levels (p < 0.001, p < 0.05). CONCLUSION: This study showed a high prevalence of the metabolic syndrome in subjects with type 2 diabetes. Females were more affected than males. PMID- 22204180 TI - In vitro susceptibility of typhoidal Salmonellae against newer antimicrobial agents: a search for alternate treatment options. AB - OBJECTIVES: To determine the minimum inhibitory concentrations (MICs) of ceftriaxone, azithromycin, pefloxacin, cefipime and imipenem for Salmonella Typhi (S. Typhi) and Paratyphi. METHODS: One hundred and fifty four isolates of Salmonella Typhi and S. Paratyphi A, B and C growing in blood culture were selected. MICs of ceftriaxone, azithromycin, pefloxacin, cefipime and imipenem were performed by agar dilution method as recommended by clinical laboratory standard institutes. RESULTS: MIC90 of azithromycin and pefloxacin was 8 microg/ml, cefipime was 0.06 microg/ml and imipenem was 0.5 microg/ml. None of the strains were found to be resistant to ceftriaxone but 3 isolates showed higher MIC value of 2 microg/ml. CONCLUSION: Azithromycin appears a suitable alternate for the treatment of typhoid in the community. Imipenem and cefipime are good options in complicated cases to be treated in hospital settings. Pefloxacin cannot be used as MICs are higher. Presence of isolates with higher MIC of ceftriaxone is serious and stresses upon continuous laboratory surveillance to guide clinicians appropriately. PMID- 22204181 TI - Clinical, sonographic and cytological evaluation of small versus large thyroid nodules. AB - OBJECTIVE: To study the clinical presentation, thyroid function tests, ultrasound (US) features, cytology and surgical pathology results of patients undergoing fine needle aspiration (FNA) biopsy of thyroid nodules and to determine if a significant difference exists in the above variables between small (less than 1 cm) and large (1 cm or more) thyroid nodules. METHODS: The study is a retrospective chart review study involving patients undergoing FNA of thyroid nodules at Marshall University Endocrine Clinic. Study data on patient demographics, clinical presentation, physical examination findings, thyroid function tests, US features, cytology and surgical pathology were collected and analyzed. RESULTS: A total of 122 patients were included in the study including 18 patients with small and 104 patients with large thyroid nodules. Females were 88%. The overall mean age of patients was 56 +/- 15 years. Most of the patients (63%) were asymptomatic on presentation. Only 20% patients had their nodules reported to be palpable on physical examination. Solitary nodules as well as the dominant nodule in multi-nodular goiters in both groups were more frequently localized to the right lobe of thyroid gland. The mean US size was 0.7 +/- 0.15 cm for small and 2.4 +/- 1.2 cm for large nodules. Patients with small nodules presented at an earlier age (45 +/- 14 years Vs 58 +/- 15, years p = 0.008) and were more likely to have family history of thyroid cancer (p = 0.023), as compared to patients with large nodules. However, there was no other significant difference identified in clinical presentation, cytology results and prevalence rate of thyroid cancer between patients with small and large thyroid nodules. CONCLUSION: In this study patients with small thyroid nodules presented at an earlier age and were more likely to have family history of thyroid cancer as compared to those with large nodules. There were no other significant differences in other study variables between small and large thyroid nodules. Further studies with large sample size in each group are needed to verify our results. PMID- 22204182 TI - Parents' opinion of quality of life (QOL) in Pakistani thalassaemic children. AB - OBJECTIVE: To find out the physical, social, psychological life aspects and overall quality of life among thalassaemic children in Pakistan. METHODS: This cross-sectional study was done in ten Thalassaemia treatment centres in three major cities of Pakistan during the year 2007-08. The study population comprised of 221 thalassaemic children ranging from 4 to 12 years age brought for blood transfusion by their parents. All ethical considerations were taken into account during the study. Questions related to physical, social and psychological aspects that assess quality of life (QOL) of children with thalassaemia were asked and were further analyzed using SPSS version 12.0. RESULTS: Out of total 221 thalassaemic patients surveyed, the majority (61%) were boys with a mean age of 8.5 +/- 2.26 years for both sexes. An overwhelming majority of parents (86%) felt that the disease did not affect the child's family or social relationships. However, poorer quality of life (QOL) was found against psychological aspects (p < 0.05) and overall parent satisfaction for child's health (p < 0.001). Adverse impact of thalassaemia was also found for pain (73%), sleep (50%), eating habits (49%), leisure activities (54%) and task concentration (51%) among the participants. CONCLUSION: There was a substantial amount of concern raised by the parents for various aspects of QoL in their affected children. Hence, it is crucial to provide proper health education to parents for better understanding of the disease and rehabilitation of their thalassaemic children. PMID- 22204183 TI - Focused abdominal CT scan for acute appendicitis in children: can it help in need? AB - OBJECTIVE: To evaluate the focused abdominal CT scan [FACT] in clinically equivocal cases of acute appendicitis in paediatric population. METHODS: A cross sectional study was conducted at the Radiology Department of Aga Khan Hospital, from August 2007 to November 2008. A total of 84 patients (42 males & 42 females) with clinically equivocal signs and symptoms of acute appendicitis referred to radiology department for CT evaluation were studied. CT findings were compared with histopathology and clinical follow-up. RESULTS: The sensitivity of focused CT for acute appendicitis was 91%; specificity was 69% and accuracy of 76% while PPV and NPV were 58%, 94% respectively. CONCLUSION: Focused unenhanced CT is a quick, accurate and non invasive modality for the assessment of clinically equivocal cases of acute appendicitis for ruling out patients and reducing negative appendectomies. PMID- 22204184 TI - Rhinocerebral zygomycosis in Pakistan: clinical spectrum, management, and outcome. AB - OBJECTIVE: To study the disease spectrum and salient management features of 36 patients with histopathologically-confirmed rhinocerebral zygomycosis seen at our academic center over a 16-year period. METHODS: Retrospective review of patients admitted to the Aga Khan University Hospital in Karachi, Pakistan from January 1991 to December 2006 with histopathologically-confirmed zygomycosis of the head and neck. RESULTS: Mean patient age was 40 +/- 5.0 years (range, 34-63 years), and 23 (64%) patients were male. Thirty-two (89%) patients were referred from clinical services other than otolaryngology. Underlying predisposing conditions included diabetes mellitus (21 patients), haematologic diseases (9), and renal failure (6). Twenty (55%) patients had limited sinonasal disease, ten (28%) had orbital involvement, and six (17%) had intracranial extension. All patients underwent rigid nasal endoscopy and biopsy, and black necrotic tissue was seen in 22 (61%) instances warranting endoscopic or open surgical debridement. Four of 6 patients undergoing open surgery required orbital exenteration. Overall patient survival was 56% (20/36 patients). Diabetic patients had improved survival (17/21, or 81%) compared to patients with haematologic disorders (3/9, or 33%) (p = 0.001). All six patients with intracerebral disease died. Eighteen of the 22 (82%) patients treated with surgery plus amphotericin B survived vs. two of 14 (14%) receiving amphotericin B alone (p < 0.001). CONCLUSIONS: In rhinocerebral zygomycosis, an aggressive, multidisciplinary, diagnostic and therapeutic approach that utilizes CT or MRI staging, and combines endoscopic or open surgical debridement with amphotericin B-based antifungal therapy offers the best chance of recovery. PMID- 22204185 TI - Use of a pneumonia management tool to manage children with pneumonia at the first level health care facilities. AB - OBJECTIVE: To describe the application and evaluation of Pneumonia Management Tool (PMT) to manage children with non-severe pneumonia (NSP) at the first level health care (FLHC) facilities according to the standard case management (SCM) guidelines for acute respiratory infections (ARI). METHOD: The ARI SCM guidelines were simplified to a PMT and used by health workers at 14 FLHC facilities to assess, manage and monitor children with NSP and to educate caretakers on home care and follow-up visits. The district supervisors provided on the job support to various cadres of health workers of both public and private facilities. RESULTS: Of 949 children with NSP, 940 (99%) were successfully treated at FLHC facilities. Caretakers found PMT useful and of 1888 follow-up visits: 1872 (99.2%) brought PMT copy; 1627 (86.2%) brought their children to the facility; 1799 (95.3%) were on time and; 1857 (98.4%) had maintained antibiotic compliance. Using PMT, health workers adherence to SCM guidelines improved from 14% at baseline to 29% after training and 65% with on the job support. The practices remained similar among various cadres of health workers. CONCLUSIONS: Health workers used PMT in managing children with NSP, counselling caretakers on home care, follow-up visits and monitoring the treatment outcome. District level supervision helped to maintain a uniform skill enhancement. PMID- 22204186 TI - Role of pyrethroids in control of malaria amongst refugee population. AB - Malaria is a human disease caused by sporozoan parasite belonging to genus plasmodium. According to World Health Organization (WHO) estimates for year 2006, there were 247 million clinical infections and 0.88 million deaths due to malaria. Malaria control programmes aim to contain the disease and reduce its' burden on the refugees by adopting various methods to reduce the incidence of malaria by targeting the mosquitos. Most of the displaced people live in Asia and Africa, where host countries lack the resources to support them. Under these conditions, the methods adopted for control of malaria should be both effective and safe. Pyrethroids form the mainstay of preventive measures due to their efficacy and safety in mammals. They can be used as (a) indoor residual sprays, (b) impregnation of bednets, blankets/top sheets, curtains and personal clothing, (c) pyrethroid containing coils, mats and vaporizers and (d) livestock sponging. PMID- 22204187 TI - Regional health accounts for Pakistan--expenditure disparities on provincial and district level. AB - Since May 2009 the first National Health Accounts (NHA) for Pakistan have been finalised and published by Federal Bureau of Statistics (FBS) in cooperation with German Technical Cooperation (GTZ). This paper goes one step ahead of the report and analyses in more detail the regional differences in health expenditure structures in Pakistan. The further analyses can be divided into four parts: health expenditures in provinces (Provincial Health Accounts, PHA), Punjab provincial and district governments health expenditures and its comparison with ADB figures, all districts of Pakistan and comparison between total district government and provincial government expenditure for each province; the latter calculation is applied as indication for the degree of fiscal autonomy of the districts in each province. Consequently, first the provincial health expenditures by Financial Agents is analysed and compared between the provinces which leads to very heterogeneous results (section 2); the per capita health expenditures differ from 16 to 23 USD. Secondly, NHA results on Punjab district government are compared with available ADB results and differences in methods as possible reasons for different results are presented (section 3). Third, district data of all district governments in all four Pakistani provinces are analysed on the level of detailed function codes in section 4; the aim is to discover regional differences between districts of the same as well as of different provinces. Fourth, in section 5 the degree of fiscal autonomy on health of the districts in each province is analysed; therefore the ordinance description is reviewed and total district government with total provincial government expenditures are compared per province. Finally recommendations for future rounds of NHA in Pakistan are given regarding formats and necessities of detailed health expenditure data collection to ensure evidence based decision making not only on federal, but also on provincial and district level. PMID- 22204188 TI - Effect of smoke on PAPP-A and lipid profile in normal rats. AB - Cigarette smoking is a major risk factor for atherosclerosis and cardiovascular disease. Active and passive cigarette smoke exposure predisposes to cardiovascular events. Pregnancy associated plasma protein-A is a metalloproteinase of the metzincin super family. It cleaves specific insulin like growth factor binding proteins thereby regulating local insulin like growth factor bioavailability which is a mediator of atherosclerosis. In this study we wanted to establish if Pregnancy associated plasma protein-A levels are increased in normal rats and if the Lipid profile was affected, if exposed to passive smoking. Sixty albino rats of Sprague-Dawley strain were used, weighing 200-250 gm. Both the groups were kept in identical chambers. One group of 30 rats was further exposed to cigarette smoke. Blood triglycerides were determined by enzymatic colorimetric method. In this animal study it was seen that smoking had no effect on (triglycesides), cholesterol, LDL and HDL levels. Smoke exposure has no effect on pregnancy associated plasma protein-A (PAPP-A) levels. PMID- 22204189 TI - Successful surgical embolectomy in acute massive bilateral pulmonary embolism. AB - Acute massive pulmonary embolism is a life-threatening emergency that must be promptly diagnosed and managed. A 52-year-old man presented with progressively increasing dyspnoea for three days. He had a previous history of chronic obstructive pulmonary disease and was currently a heavy smoker. Examination revealed bilateral wheezing. Chest x-ray and electrocardiography showed non specific changes. The patient was initially treated as a case of chronic obstructive pulmonary disease exacerbation secondary to pneumonia. However, despite optimum medical management, his oxygen saturation deteriorated. Emergent computed tomography scan of chest showed bilateral massive pulmonary emboli. As the patient's haemodynamic status rapidly deteriorated, cardiothoracic surgery team was immediately consulted and the patient was taken to the operating room. Under cardiopulmonary bypass, bilateral open embolectomy was performed. Following surgical intervention, the patient made a remarkable recovery. PMID- 22204190 TI - Schwannoma of the tongue in a ten-year old child. AB - The case of a 10-year-old girl is presented who had a slow-growing, painless swelling on the left side of the tongue since six months. This was associated with disturbances in mastication and phonation. Examination revealed a 5 cm x 4 cm. globular smooth, mobile mass on left side of the tongue. There was no neurological deficit and no neck nodes palpable. She underwent excision of the mass under general anaesthesia. Complete enucleation with primary closure was carried out. The patient had an uneventful postoperative recovery and histological evaluation was consistent with schwannoma. The patient was recurrence free after one year. PMID- 22204191 TI - Aortic dissection or myocardial infarction? AB - Aortic dissection is a rare and a life threatening event. Classically, aortic dissection presents as sudden, severe chest, back or abdominal pain that is characterized as ripping or tearing in nature. However, a timely diagnosis can be elusive in the event of an atypical presentation. So, a high index of clinical suspicion is mandatory for the accurate and rapid diagnosis of aortic dissection. We report a case of a 56 years old male who presented with signs and symptoms of myocardial infarction and was later found to have aortic dissection. This patient was successfully managed with surgery. PMID- 22204192 TI - Leaking pseudoaneurysm of hepatic artery: a potentially life-threatening complication of a common procedure. AB - We report a case of leaking pseudoaneurysm of right hepatic artery in a 54-year old female after laparoscopic cholecystectomy who presented with massive gastrointestinal haemorrhage and was successfully managed with angiography and coil embolization. PMID- 22204193 TI - Paranormal phenomena: is there a role for mental health professionals? PMID- 22204194 TI - Evidence based treatment of schizophrenia: do we know enough? PMID- 22204195 TI - Cigarette smoking and medical students at King Edward Medical University, Lahore (Pakistan). AB - OBJECTIVES: To observe the frequency of cigarette smoking in medical students of King Edward Medical University and to determine associated variables. METHOD: A cross-sectional survey was conducted and data was collected through a self administered questionnaire from students at King Edward Medical University. Information about demographic characteristics, smoking status in family, number of cigarettes smoked/day, influence for starting it and use of nicotine replacement therapy was obtained. Duration of study was from April 1 to May 30, 2009. Smoker was defined as a person who, at the time of survey smoked cigarettes either daily or occasionally. RESULTS: Response rate was 65.4%, of these 396 (60.55%) were male and 88 (13.45%) were smokers. Smoking was more among the male students than females (p-value < 0.001). The greatest percentage of smokers was in 3rd Year (n = 29, 26.85%), majority were of 21-30 years age (n = 59, 19.53%), started smoking between 11-20 years (n = 48, 54.54%), smoked < 10 cigarettes/day (n = 37, 42.04%) and started smoking due to influence of friends (n = 53, 60.23%). Majority (n = 69, 78.4%) had no intention to quit in the next 6 months. Lack of Incentive (n = 32, 36.36%) and Addiction (n = 24, 27.27%) were the main reasons for not quitting. CONCLUSION: Our results showed a substantial trend of cigarette smoking in medical students in Pakistan. Prevalence is more in higher classes. Majority have a smoker in their family and had started smoking under influence of peers and media. They find it relaxing and addictive, hence difficult to quit. Nicotine use was found to be uncommon. PMID- 22204196 TI - Warm autoimmune haemolytic anaemia and autoimmune hepatitis in an asymptomatic carrier of hepatitis B virus. AB - Warm antibody autoimmune haemolytic anaemia, a rare disease (0.2-1 per 100,000 populations), is due to the presence of warm agglutinins that react with protein antigens on the surface of red blood cells causing their premature destruction. Here, we present a case report of a 10 year old girl who came with features of haemolytic anaemia and history of blood transfusion since 3 years. On admission. laboratory test revealed that she had autoimmune hepatitis type 1 and was also an asymptomatic carrier of hepatitis B virus with positive HBs Ag. Steroid therapy resulted in clinical and laboratory remission. Direct antiglobulin test was negative after anaemia resolution, hepatitis B virus antigenemia persisted. To our knowledge, warm antibody autoimmune hemolytic anaemia has not previously been described in association with autoimmune hepatitis and asymptomatic carrier state of hepatitis B virus. PMID- 22204197 TI - Glance at the management of contaminated wounds. PMID- 22204198 TI - Nutrition for the underprivileged: a challenge. PMID- 22204199 TI - State of children in Pakistan--confronting reality. PMID- 22204200 TI - Evaluation of prevalence of low and high level mupirocin resistance in methicillin resistant Staphylococcus aureus isolates at a tertiary care hospital. AB - OBJECTIVE: To evaluate the trend of mupirocin resistance in MRSA, isolated at the Clinical Microbiology Laboratory of a tertiary care hospital. METHODS: A total of 200 MRSA strains recovered over a 2 year period from various body sites were tested using the 5 and 200 microg discs of mupirocin to detect its resistance. RESULTS: High level and low level mupirocin resistance were detected in zero and 1% of MRSA strains, respectively. Resistance to other non beta lactam antibiotics was also high. No MRSA strains were found to be resistant to vancomycin and tegicycline. CONCLUSION: Mupirocin resistance was found to be very low among local clinical isolates of MRSA. Its judicious use to decolonize nasal carriers should be promoted among hospitalized patients to avoid further transmission and infections due to prevalent endemic MRSA strains in any health care setting. Concomitantly, regular surveillance and effective infection control initiatives are desirable to reduce the incidence of health care associated infections due to MRSA and also of mupirocin resistance. PMID- 22204201 TI - Comparison of frequency of obesity in high risk non diabetic young individuals with low risk non diabetic young individuals. AB - OBJECTIVE: To assess the body mass index and waist circumferences of high risk non diabetic young individuals and compare them with low risk non diabetic young individuals. METHOD: A cross sectional, case control comparative study was conducted in the department of medicine, LUMHS from January 2008 to March 2009. Five hundred individuals 20-40 years of age were selected and divided into two groups i.e. Group A: high risk (250 individuals) and Group B: low risk (250 individuals) on the basis of same age and gender. Group A included those who had positive family history of type 2 DM in 1st degree relatives while group B had no family history of type 2 DM in 1st degree relatives. The blood pressure, BMI and Waist Circumference was measured and Fasting Blood Sugar was estimated in each individual. In each group 125 (50%) were males and 125 (50%) were females. RESULTS: In group A 58% and in group B 28.8% individuals represented raised BMI whereas 42% in group A and 36% in group B individuals showed an increased waist circumference. Mean fasting blood glucose was significantly higher in Group A than in Group B (P = 0.001). CONCLUSION: Impaired Fasting Glucose is strongly associated with family history of type 2 diabetes mellitus. Presence of obesity specially in high risk non-diabetic young individuals emphasize the need for routine health screening for early institution of preventive measures. PMID- 22204202 TI - Regular post dinner walk; can be a useful lifestyle modification for gastroesophageal reflux. AB - OBJECTIVES: To evaluate the correlation of gastroesophageal reflux disease (GERD) symptoms with routine post dinner physical activity and time interval before going to bed, in multiethnic South Asian population. METHODS: Prospective, cross sectional analytical, multicenter study was conducted from February 2009 to March 2010. Patient's relative sitting in outpatient clinics with no comorbids, nonsmoker and non alcoholic were included. They were asked to fill a validated GERD questionnaire and were also inquired about routine post dinner physical activity (lying, sitting, walking) and dinner-bed time interval. Odds Ratios (OR) and their 95% Confidence Intervals (CI) were estimated using Logistic Regression, with gastroesophageal reflux (GER) symptoms as an outcome. RESULTS: Subjects analyzed were 1875. Mean age was 35.37 +/- 12.69 years of which 689 (36.74%) had GERD symptoms. GERD symptoms were 42.08% in routine post dinner recumbency position. While 35.17% and 30.52% had the symptoms in post dinner sitting and walking before going to bed [OR for walking 0.66 (95% CI 0.5-0.88) when compared with lying posture]. GERD symptoms were 45.86% among those with dinner-bed time of one hour, progressively decreasing to 41.68%, 31.45% and 29.88% in the second, third and forth hour respectively. Odds ratio was significant only at 3rd [0.55 (0.41-0.74)] and > or = 4th hr [0.51 (0.37-0.71)] when compared with first hour. CONCLUSION: Regular post dinner walk and > 3 hour dinner-bed time interval were less associated with GERD symptoms. PMID- 22204203 TI - Comparison of trans patellar approach and medial parapatellar tendon approach in tibial intramedullary nailing for treatment of tibial fractures. AB - OBJECTIVES: To evaluate the post-operative complications of intramedullary nailing technique by transpatellar approach compared to medial parapatellar approach. METHODS: Fifty patients with tibial fractures treated by intramedullary nailing through two transpatellar (t-group) and medial parapatellar (p-group) approaches were studied. Knee pain was assessed with visual analogue scale (VAS) for 2 weeks, 1, 3 and 6 months and range of motion (ROM) in 2 weeks and 3 months after surgery. RESULTS: There were 23 males and 2 females with a mean age of 28.68 +/- 5.78 years in t-group and 21 males and 4 females with a mean age of 28.80 +/- 5.82 in p-group. There was significant difference in knee pain score after 3 months (p = 0.013) and 6 months (p = 0.009) between the two study groups (p-group had less pain than t-group). But there was not significant difference between the two study groups in range of motion after 2 weeks and 3 months of surgery. CONCLUSION: Our study recommends medial parapatellar tendon approach, although both approaches are safe. PMID- 22204204 TI - Effect of low and high glycaemic index drink on sleep pattern in children. AB - OBJECTIVES: To evaluate the effect of high and low glycaemic index drinks on children's sleep pattern. METHODS: Eight children underwent 3 nights of full polysomnography study, one familiarization and two test nights consecutively. On the test nights, 1 hour before bedtime, the children had a milk drink of either low or high GI in a random order. The glycaemic loads (GL) were 7.4 and 52.8 for low and high GI drink respectively. RESULTS: The mean of total arousal index in the first half of night after the high GI was greater than that of low GI drink. (12.9 +/- 4.6 vs. 9.9 +/- 2.2, P = 0.03). NREM arousal index in the first half of night after the high GI was also higher than that of low GI drink. (12.7 +/- 4.8 vs. 9.6 +/- 2.3, P = 0.05). Other sleep parameters did not show any significant difference in low GI and high GI diets. CONCLUSION: NREM and total arousal indices were higher in those who consumed high GI drinks compared with low GI, one hour before sleep. It seems that the high quantity consumption of carbohydrates close to the bedtime is accompanied by frequent arousals and may affect the sleep quality. PMID- 22204205 TI - Ocular complications of functional endoscopic sinus surgery. AB - OBJECTIVES: To evaluate the ocular complication of functional endoscopic sinus surgery in patients with chronic sinus disease. METHODS: In a prospective descriptive, cross-sectional study without control group, 53 patients who underwent functional endoscopic sinus surgery for refractory chronic sinus diseases were evaluated. Patients underwent a complete Otolaryngology and Ocular examination and functional endoscopic sinus surgery. RESULTS: A total of 53 functional endoscopic sinus surgery procedures were included in this study. Mean age of patients was 37.56 +/- 1.74 years (range from 20 to 60); 26 (49.1 per cent) were females and 27 (50.1 per cent) were males. Of these patients, 24 (45.3 per cent) had rhinosinusitis without nasal polyposis, and the rest 29 (54.7 per cent) had rhinosinusitis with nasal polyposis. Among the 53 cases, there were 7 (13.1%) with ocular complications following functional endoscopic sinus surgery; one case (1.9%) of cellulitis, 6 cases (11.3%) of lids swelling and conjunctival injection. It was noted that 83.77% improved postoperatively, concerning pain in the head and face. The difference between postoperative complications and causes (two groups sinusitis with nasal polyp and sinusitis without nasal polyp) was statistically meaningful (p = 0.001). There was not significant difference in post-operative complications between the two age groups; below and above 40 years (p = 0.45). CONCLUSION: Functional endoscopic sinus surgery is an effective treatment modality against medical therapy for chronic sinus diseases. PMID- 22204206 TI - Magnetic resonance spectroscopy in focal brain lesions. AB - OBJECTIVE: To describe the spectrum of Magnetic Resonance spectroscopy in focal brain lesions and determine its diagnostic accuracy using histopathology as gold standard in differentiating neoplastic and non-neoplastic focal brain lesions. METHODS: The study was conducted in Department of Radiology, Aga Khan University Hospital, Karachi from Dec 2006 till Jan 2009. Fifty three patients found to have focal brain lesions on magnetic resonance imaging (MRI) were included in the study. Magnetic Resonance spectroscopy (MRS) was performed in these focal lesions. These lesions were deemed neoplastic and non-neoplastic on MR Spectrum findings. Correlation of all these findings was done with histopathology obtained in all these patients. Sensitivity, specificity, positive, negative predictive values and diagnostic accuracy of MR Spectroscopy was calculated. Percentage agreement between spectroscopy and histopathology was also calculated using kappa statistics. RESULTS: Increase Choline/creatine and Choline/NAA ratio noted in neoplastic lesions compared to nonneoplastic lesion with significant p-value. MR Spectroscopy has a sensitivity of 93.02%, specificity of 70%, positive predictive value of 93.02%, negative predictive value of 70% and diagnostic accuracy of 88.67% in differentiating neoplastic and non-neoplastic brain lesions. Kappa statistics shows a good agreement between MR Spectroscopy and histopathology (k = 0.630). CONCLUSION: Magnetic Resonance spectroscopy (MRS) is non-invasive sensitive, however, relatively nonspecific modality in differentiating neoplastic and non-neoplastic brain lesions. This modality should be considered as an adjunct to conventional imaging rather than replacement for histopathological evaluation. PMID- 22204207 TI - Prevalence and causes of low vision and blindness in Tehran Province, Iran. AB - OBJECTIVE: To determine the prevalence and causes of blindness and low vision selected population at Tehran province, Iran in 2006. METHODS: A population-based cross-sectional study was conducted in the rural and urban population of Tehran province, Iran. The study design was based on the World Health Organization (WHO) criteria and a pilot study. Multi-stage cluster random sampling method was used and sample size was calculated based on the distribution of population in Tehran province derived from the national census and estimated rate of blindness from the pilot study. Information was collected using a questionnaire filled after screening by optometrists and referral examinations by ophthalmologists. Categorization of blindness and low vision was based on the International Classification of Diseases version 10 (ICD-10). RESULTS: Overall, 11,975 subjects with mean age of 27.77 +/- 18.9 years participated (primary response rate of 90.4%). The prevalence of bilateral blindness was 1.09% (95% CI: 0.90-1.61%). There was a significant positive correlation with age (P < 0.001) but no significant difference by gender. The prevalence of low vision in both eyes was 4.04% (95% CI: 3.69-4.39%). The prevalence of bilateral low vision increased with age (P < 0.001) and was higher among females (OR = 1.42, 95% CI: 1.16-1.74). The leading causes of visual impairment were cataract (33.9%), amblyopia due to uncorrected refractive errors (22.7%), vitreo-retinal diseases (12.3%), corneal blindness (10%) and diabetic retinopathy (4.92%). CONCLUSION: The prevalence of blindness and low vision in Tehran province, Iran is similar to other developing countries. The majority of cases have treatable and/or preventable causes; reduction of blindness can be achieved by appropriate screening strategies. PMID- 22204208 TI - A peer-based study on adolescence nutritional health: a lesson learned from Iran. AB - OBJECTIVE: To study the adolescence opinions' among nutritional habits and beliefs. METHODS: To conduct a multi disciplinary approach through involving adolescence/youth for finding their mental needs and their suggestion for solving them, we designed a qualitative approach based on grounded theory. For data collection a semi-structured guide questioner designed and 16 focus group discussions were conducted by trained peers with youth aged 10-19 years. RESULTS: According to FGDs results, although majority of participants agreed on the important role of nutrition in health and the effect of nutritional habits on different aspect of health, they used modern and publicized fast foods. On the other hand, most of female and male participants said that different factors influenced the girls and boys diet selection i. e. girls' paid more attention to diet selection and taste and health of foods, whereas boys were careless and gluttony caused more food to be consumed. CONCLUSION: Adolescents' information (both genders) regarding nutritional problems resulting from improper food habits were not satisfactory. Peer-based health programmes through target groups for capacity building and participation of stakeholders will fulfill the objectives. PMID- 22204209 TI - Acute vertebral compression fracture: differentiation of malignant and benign causes by diffusion weighted magnetic resonance imaging. AB - OBJECTIVE: To evaluate the sensitivity, specificity and accuracy of diffusion weighted (DWI) magnetic resonance imaging (MRI) in the diagnosis and differentiation between benign (osteoporotic/infectious) and malignant vertebral compression fractures in comparison with histology findings and clinical follow up. METHODS: The study was conducted at the Radiology Department, Aga Khan University Hospital (AKUH) Karachi. It was a one year cross-sectional study from 01/01/2009 to 01/01/2010. Forty patients with sixty three vertebral compression fractures were included. Diffusion-weighted sequences and apparent diffusion coefficient (ADC) images on a 1.5 T MR scanner were obtained in all patients to identify the vertebral compression fracture along with benign and malignant causes. Imaging findings were compared with histopathologic results and clinical follow-up. RESULTS: Diffusion-weighted MR imaging found to have, 92% sensitivity, 90% specificity and accuracy of 85% in differentiation of benign and malignant vertebral compression fracture while PPV and NPV were 78 % and 90% respectively. CONCLUSION: Diffusion weighted magnetic resonance imaging offers a safe, accurate and non invasive modality to differentiate between the benign and malignant vertebral compression fracture. PMID- 22204210 TI - Leprosy in Iran: an analysis of 195 cases from 1994-2009. AB - OBJECTIVES: To estimate the prevalence of Leprosy in Azerbaijan, Iran. METHODS: A total of 195 new leprosy cases referred to and registered in Bababaghi Center, Azerbaijan, Northwest of Iran from 1994-2009 were studied. RESULTS: Of the 195 new cases, 131 (67/2%) were males and 64 (32/8%) females. They were born in Azerbaijan with the peak age of the disease at their fourth decade. The most common form of the disease, especially in male patients, was lepromatous leprosy. Skin problems, especially eyebrow hair loss, constituted the most frequent sign of the disease. The most involved nerve was ulnar nerve. CONCLUSION: Although, leprosy is a rare disease in Iran it is still encountered. It is important for the physicians to be aware of its diagnosis when they see a patient with chronic dermatitis and peripheral nerve involvement. PMID- 22204211 TI - Terrorist bombings: medical response in a developing country. AB - OBJECTIVE: To evaluate the process of transport and immediate Emergency Department (ER) management of mass casualties following the recent bomb blasts in Karachi and review in detail the medical response and management of victims undertaken in these two incidents. METHODS: Eyewitness accounts of the victims, medical personnel and newspaper clippings were used to understand and identify difficulties faced during the rescue process. Data regarding presenting injuries and their outcomes was also collected from all victims presenting to the emergency department at Aga Khan University Hospital. RESULTS: Seventy nine individuals died and over 250 victims were injured in the two incidents. All victims and dead bodies were shifted to the nearest public sector hospital overwhelming the health care facility. Subsequently all victims were evacuated to private sector hospitals creating similar difficulties. Over half of the victims presenting at the emergency department had minor injuries and did not require admission. Most patients requiring admission needed orthopaedic intervention. CONCLUSION: A comprehensive disaster plan with a centralized command and control system is required for the city of Karachi, involving all stake holders including charity ambulance services, security agencies, and trauma management facilities. Training courses and exercises for health care personnel should also be made mandatory to achieve professional excellence. PMID- 22204212 TI - Prevalence of Ecstasy use and predisposing factors among Iranian female high school students. AB - OBJECTIVES: To determine prevalence of ecstasy use and its predisposing factors among Iranian high school female students in Tehran, capital of Iran. METHODS: In this cross-sectional study, 2350 female students of 36 high schools from Tehran, were selected by multi-stage cluster sampling to determine prevalence of ecstasy use and its predisposing factors. SPSS- version 13 was employed to conduct analysis through chi-square, fisher's exact test and logistic regression methods. RESULTS: The prevalence of ecstasy use was 2.3% (95% CI: 1.7-2.9%). Party was the most prevalent place of first use (65%) and access was easy for most users (63%). In multivariate analysis, smoking (P-V = 0.005), alcohol use (P-V = 003), use of other substances (P-V < 0.001), being in relationship with boys (P-V = 0.015), families without one or two parents (P-V = 0.020), night spending at friends home without parents' permission (P-V = 0.001) were associated with ecstasy use. CONCLUSION: Due to relation of ecstasy use with other substances, designed programmes should be comprehensive, with different strategies and collaboration of several sectors. The main strategies are to improve students' health literacy, family support, to limit supply and access, and to legislate appropriate regulatory laws. PMID- 22204213 TI - Triphasic computed tomography (CT) scan in focal tumoral liver lesions. AB - OBJECTIVE: To assess the diagnostic accuracy of triphasic spiral CT in differentiating benign from malignant focal tumoral liver lesions. METHODS: The study was conducted in Department of Radiology of Aga Khan University Hospital and Sind Institute of Urology and Transplantation, Karachi from Feb 2006 to Feb 2007. By convenient sampling, 45 patients found to have focal tumoral liver lesions were recruited for one year period and their triphasic CT scans findings were evaluated and later correlated with histopathology. Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of triphasic CT scan were calculated. RESULTS: Among 45 patients, 136 liver lesions (11 benign and 125 malignant) were detected with the help of different enhancement patterns. Out of these, 37(82.2%) patients had malignant while 8 (17.8%) had benign lesions. On later histopathological examination, 35 (77.8%) of the total 45 cases had malignant lesions while 10 (22.2%) were diagnosed as benign lesions. Based on these results, it could be assessed that triphasic CT Scan has a sensitivity of 100%, specificity of 80%, positive predictive value of 94.5%, negative predictive value of 100% and diagnostic accuracy of 95.5% in differentiating benign from malignant liver lesions. CONCLUSION: Triphasic CT Scan is a good non-invasive tool in characterizing and differentiating benign from malignant liver lesions. PMID- 22204214 TI - Outcome of primary percutaneous coronary intervention at public sector tertiary care hospital in Pakistan. AB - OBJECTIVES: To determine the outcome of Primary Precutaneous Coronary Intervention (PCI) in our setup and compare the results with the west. METHODS: This study was conducted at a tertiary care teaching Hospital (National Institute of Cardiovascular Diseases Karachi, Pakistan) during January 1st, 2008 to December 31st, 2008. A total of 113 patients were enrolled who came with STEMI and agreed to go for Primary PCI. We excluded the patients who had history of Thrombolytic therapy within 24 hours, presented with Non ST-elevation Myocardial Infarction (NSTEMI) and coronary angiogram revealed significant left Main or equivalent disease. All Patients received Aspirin, Clopidogrel and Platelet Glycoprotein IIB IIIA Inhibitor. After Primary PCI patients were planned to follow at one month, 3 months and 6 months. Primary end point was to document death, MI, CABG and rehospitalization. RESULTS: Out of 113 cases, 102 (90.3%) were male and 11 (9.7%) were female, Mean age was 51.2 +/- 11.7 years, 54 (47.8%) patients had Hypertension, 28 (24.8%) were Diabetics and 44 (38.9%) were Smokers. Immediate success was achieved in 111 (98.2%) cases. In hospital mortality was 5.3% (3.5% in cardiogenic shock, 1.7% in non-shock patients). Mean Door to Balloon time remained 98.4 minutes. Twelve patients were lost to follow up. Therefore at 6 months, out of 101 patients, 8 (7.9%) died, 5 (4.9%) underwent Coronary Artery Bypass Graft (CABG) surgery and 5 (4.9 %) had been re hospitalized either for recurrent myocardial infarction or heart failure. CONCLUSION: Optimal results of primary percutaneous coronary intervention can be achieved for acute STEMI in a developing country at a tertiary care public sector hospital. The results are comparable and nearly similar to the west. PMID- 22204215 TI - Maternal mortality and morbidity of unsafe abortion in a university teaching hospital of Karachi, Pakistan. AB - OBJECTIVE: To study the mortality and morbidity of unsafe abortion in a University Teaching Hospital. METHODS: A cross-sectional, descriptive study was conducted in Department of Obstetrics and Gynaecology, Unit III, Dow Medical College and Civil Hospital Karachi from January 2005 to December 2009. Data regarding the sociodemographic characteristics, reasons and methods of abortion, nature of provider, complications and treatment were collected for 43 women, who were admitted with complications of unsafe abortion, and an analysis was done. RESULTS: The frequency of unsafe abortion was 1.35% and the case fatality rate was 34.9%. Most of the women belonged to a very poor socioeconomic group (22/43; 51.2%) and were illiterate (27/43; 62.8%). Unsafe abortion followed an induced abortion in 29 women and other miscarriages in 14 women. The majority of women who had an induced abortion were married (19/29, 65.5%). A completed family was the main reason for induced abortion (14/29; 48.2%) followed by being unmarried (8/29, 27.5%) and domestic violence in 5/29 cases (17.2%). Instruments were the commonest method used for unsafe abortion (26/43; 68.4%).The most frequent complication was septicaemia (34; 79%) followed by uterine perforation with or without bowel perforation (13, 30.2%) and haemorrhage (9; 20.9%). Majority of induced abortions were performed by untrained providers (22/26; 84.6%) compared to only 3/14 cases (21.4%) of other miscarriages (p = 0.0001). CONCLUSION: The high maternal mortality and morbidity of unsafe abortion in our study highlights the need for improving contraceptive and safe abortion services in Pakistan. PMID- 22204216 TI - Genotyping of hepatitis C virus isolated from hepatitis patients in Southeast of Iran by Taqman Realtime PCR. AB - OBJECTIVES: To check TaqMan Realtime PCR in detecting genotypes of hepatitis C virus in Iran. METHODS: From July 2007 to April 2009, HCV genotyping was done on 52 patients who were referred to Research Centre for infectious Disease and Tropical Medicine, in Bou-Ali Hospital, Zahedan University of Medical Sciences. All these patients had proven hepatitis C infection. RESULTS: Out of 52 anti HCV positive samples, 28 (53.84%) had genotype 1, 2 cases (3.88%) had genotype 2, 12 (23.08%) had genotype 3 and 7 (13.4%) had genotype 4. Mixed infection with genotypes 1 and 3 was seen in 3 cases (5.77%). CONCLUSION: TaqMan probes for detecting genotyping of HCV were successful in picking genotyping of HCV infection especially those with mixed genotypes. PMID- 22204217 TI - Role of APACHE score in predicting mortality in chest ICU. AB - OBJECTIVE: To determine the first 24 hours mean values of APACHE II score for two outcomes (alive or dead) in patients admitted in chest ICUs. METHODS: A prospective study was conducted in the Department of Chest, Jinnah Postgraduate Medical Centre Hospital, Karachi from January 2009 to December 2009. Patients of all ages and either gender admitted in chest ICU for any cause, were consecutively enrolled. All patients with incomplete records and missing variables including laboratory investigations or who had not been followed up due to any reason were excluded. Patients who were readmitted in the ICU were also excluded. The main outcomes were the first 24 hours mean APACHE II score of the sample and first 24 hours mean APACHE II score of patients who were later discharged or had died. RESULTS: The mean age of the patients was 53.16 +/- 19.29 years. Out of 143 participants 84 (58.7%) were males and 59 (41.3%) females. The main diagnosis included COPD with acute exacerbation 63 (44.05%), post TB fibrosis 17 (11.88%), acute severe asthma 14 (9.79%) and pneumonia 12 (8.39%) patients. The results found that 63 out of 143 patients were alive whereas 80 patients died. The mean APACHE II score on first 24 hours was 20.09 +/- 7.49. The mean 24 hours APACHE II score of patients who were discharged and who died was 18.93 +/- 7.19 and 22.33 +/- 7.80 respectively. CONCLUSION: Our preliminary results showed that it is recommended to determine the cut off levels of APACHE II scores in patients admitted with chest ICU. PMID- 22204218 TI - Noninvasive positive pressure ventilation in hospital setting. AB - Noninvasive positive pressure ventilation (NPPV) refers to the delivery of mechanical ventilation to the lungs using techniques that do not require an endotracheal intubation. In the past decade NPPV has gained wide acceptance and is now used more frequently after development of portable ventilators, new modes of ventilation and other equipments. This article will provide a comprehensive overview of the current stage of NPPV in acute and chronic settings. It will appraise the evidence based efficacy of NPPV in patients who presented with acute exacerbation of chronic hypercapneic respiratory failure. The main focus of discussion in this article is to provide detailed knowledge regarding choosing appropriate ventilators and interfaces, selecting appropriate patients and initiating NPPV and their weaning. PMID- 22204219 TI - Battling with breast cancer ... addressing the issues. AB - In the background of the current situation of breast cancer in Pakistan, with its rising incidence and mortality, non affordability and inaccessibility to screening, diagnosis and treatment, Patel Hospital took up the task of addressing these issues at a local level, by initiating an annual free breast camp in the year 2006. In 2008 an inclusion criteria was defined to focus on high risk women for breast cancer. A comparative analysis over a period of three years was done. In the focused camps, in which 28% patients were found to have a positive family history. Most women were symptomatic. Total 11 patients were diagnosed to have cancer after evaluation. Six patients underwent definitive treatment. A problem with lack of awareness, regarding screening and treatment protocols was identified. Family history seems to be an important risk factor in our set up signifying the need to introduce extensive screening programmes. PMID- 22204220 TI - Congenital diaphragmatic hernia presenting in the sixth decade mimicking pneumonia. AB - Congenital diaphragmatic hernia presentation in adults is extremely rare. Patients who present with late diaphragmatic hernias complain of a wide variety of symptoms and diagnosis can be difficult. We report a case of a 64 year old male who presented with a six month history of cough, shortness of breath and weight loss. The most common strategy to treat a Bochdalek hernia is via a thoracotomy or laparotomy or both. In our patient the repair was performed with a thoracotomy. PMID- 22204221 TI - Dengue fever associated with acute scrotal oedema: two case reports. AB - Scrotal oedema associated with dengue fever is a rare and self limiting condition resolving in a few days without any complication or sequelae. This is a report of two cases of dengue fever associated with acute scrotal and penile oedema. PMID- 22204222 TI - Isloated tubal torsion in a fourteen year old girl. AB - Isolated torsion of fallopian tube is a rare event and often difficult to diagnose. This report describes such a condition in a patient who presented with pain lower abdomen and underwent laproscopy primarily by surgeons with the suspicion of appendicitis but eventually ended up in right salpingectomy because of isolated right tubal torsion. The issue of future fertility was obviously considered but unfortunately the tube could not be preserved because of necrosis and haemorrhage inside it. Tubal torsion should however be kept in mind in the differential diagnosis of lower abdominal pain in women of all ages. PMID- 22204223 TI - Supracristal ventricular septal defect with severe right coronary cusp prolapse. AB - The case of a 20 years old male, diagnosed as supracristal ventricular septal defect (VSD) for last 6 years is being presented. He came in emergency department with decompensated congestive cardiac failure. After initial stabilization, he underwent transthoracic echocardiogram which showed large supracristal VSD, severely prolapsing right coronary cusp, severe aortic regurgitation and severe pulmonary hypertension. Right heart catheterization was performed which documented reversible pulmonary vascular resistance after high flow oxygen inhalation. He underwent VSD repair, right coronary cusp was excised and aortic valve was replaced by mechanical prosthesis. Post operative recovery was uneventful. He was discharged home in one week. PMID- 22204224 TI - Preliminary report--near total laryngectomy for SCC larynx. AB - A retrospective analysis was performed on patients subjected to near-total laryngectomy at Aga Khan University Hospital Karachi from September 2006 and May 2010, to evaluate the functional outcome of Near Total Laryngectomy and its effect on disease control. In all of these advanced stage laryngeal hypopharyngeal squamous cancer patients, the disease was limited to one side of the larynx-hypopharynx. Four patients were staged as T3 and rest were T4; near total laryngectomy was done in all 07 patients. Post operative adjuvant radiotherapy was given to 06 patients. All of these patients are on regular oral diet and maintaining their body weight. Six patients are using their preserved hemi larynx effectively. Mean follow up of these patients was 15 months. Three patients developed regional recurrence whereas the remaining four patients were well till their last follow-up. Near total laryngectomy is a safe surgical option even for advanced laryngeal-hypopharyngeal cancer without compromising oncological clearance. It gives patients their own physiological voice that does not require maintenance but at the expense of permanent tracheostomy. PMID- 22204225 TI - Medical negligence: a growing problem in Pakistan. PMID- 22204226 TI - What are the emerging therapeutic alternatives to warfarin in stroke patients? How would the results of RE-LY benefit Pakistanis? PMID- 22204227 TI - Knowledge of first aid and basic life support amongst medical students: a comparison between trained and un-trained students. AB - OBJECTIVE: To compare the level of knowledge of medical students trained in first aid with those with no training. METHODOLOGY: This study was conducted on a convenience sample of 250 (125 trained and 125 untrained) medical students. A pre tested self administered questionnaire was used for data collection. The questionnaire covered all the major topics of FA-BLS. RESULTS: Amongst the trained students 99 (79.2%) had been trained at their respective medical colleges. The correct responses by the trained students were significantly better than untrained students regarding CPR, Recovery position, Asthma and Bleeding. The mean number of correct answers for trained students was 6.13 +/- 2.1 while 4.94 +/- 2.06 out of the total 13 questions for untrained students. CONCLUSION: Although the knowledge of trained students was found to be better than those of untrained students yet the mean of trained students was less than 50% which is not satisfactory. In order to improve the knowledge of medical students on first aid, their knowledge should be reinforced every year. PMID- 22204228 TI - Factors affecting the utilization of antenatal care among women of reproductive age in Nurpur Shahan. AB - Antenatal care is important for the prevention of maternal and foetal mortality and morbidity. The purpose of this study was to determine the frequency of utilization of antenatal care and to identify the factors that affect it. A cross sectional survey was conducted in the community of Nurpur Shahan, Islamabad, Pakistan in January 2010 using a structured questionnaire. Included were 390 women of reproductive age who were questioned about their knowledge of antenatal care and its utilization. The frequency of utilization of antenatal care was (84.4%). Among those who never used the antenatal care, permission to use the facility and ignorahce were the main reasons. Education of both the wife and husband with this regard must be worked upon. PMID- 22204229 TI - Stem cells and tissue engineering in dentistry--a myth or reality. PMID- 22204230 TI - IL-28B polymorphism and response to anti-hepatitis C therapy. PMID- 22204231 TI - Complications related to cochlear implants: experience in Tehran. AB - OBJECTIVE: Cochlear implantation (CI) is an effective treatment for profound deaf patients. To study the cochlear implant complications in patients at Amir Aalam Hospital. METHODS: The study population involved 177 profoundly deaf patients, implanted within the same cochlear implant center. RESULTS: Twenty-four (13.6%) patients experienced complications. Early complications accrued in 9 (37.7%) patients within the first 24 hours. Eight (4.5%) patients had major complications including facial nerve paralysis, suture rupture and prosthesis rejection. Prosthesis rejection 6 (30%) was the most frequent major complication. Minor complications were found in 16 (9%) cases which were managed medically. Older age with CI was correlated with higher major complications. CONCLUSION: In contrast to minor complications, the frequency of major complications in this cohort was higher than that published by other groups. PMID- 22204232 TI - Neonates--a neglected paediatric age group. AB - OBJECTIVE: To determine a change in the mortality of admitted children (neonates and children above 28 days of age to less than 17 years) and to document a change in the causes of neonatal admissions along with their mortality during a four year period. METHODS: Conducted in Pediatric Unit-I, Bahawal Victoria Hospital, Bahawalpur. The data of all the children admitted from 1st January 2005 to 31st December 2008 was analyzed. RESULTS: The mortality among admitted neonates was significantly higher than that of children of postneonatal age group. There was decrease in mortality among not only total admitted children but also among admitted children with postneonatal age group, i.e., 1 month to less than 17 years of age over a four year period (2005-2008) while no such decrease was seen in children of neonatal age group. The three common causes of neonatal admission and deaths were sepsis, birth asphyxia and prematurity. CONCLUSION: There was no improvement in neonatal mortality over a 4 year period. However, a decrease in postneonatal mortality was seen. PMID- 22204233 TI - Monopolar transurethral resection of the big prostate, experience at Prince Hussein Bin Abdullah Urology Center. AB - OBJECTIVE: To evaluate and review our experience in management of patients with big size prostate using monopolar transurethral resection of the prostate (TURP). METHODS: Between January 2005 and March 2010, TURP was performed on 198 patients with prostate size between 80 and 120 grams. The patients were subjected to standard urologic pre-operative evaluation and they were given 5 alpha reductase inhibitor for two weeks before surgery. TURP was performed using 27F continuous flow resectoscope, Otis urethrotomy and suction cystostomy were done, and 500 ml normal saline with 20mg furosomide was given intraoperatively. Catheterization time, hospital stay, peri-operative and late complications were recorded. All patients were seen at 6 weeks and 6 months post surgery in the outpatient clinic. Symptoms and complications were evaluated and histopathological diagnoses were recorded. RESULTS: The mean age was 67 +/- 3.7 years (range 57-80 years). Of these, 102 patients presented with retention and obstructive uropathy, 36 with recurrent haematuria, 12 with urinary bladder stones, 11 with recurrent urinary tract infection and 37 patients with moderate to severe international prostate symptom score (IPSS) and not responding to medical treatment. The mean prostate volume was 88 +/- 8.22 grams (range 80-120 grams) with an average residual urine of 160 ml (range 20-1500 ml). The mean Qmax was 6.8 +/- 1.7 ml/sec (range 2.1 11.7 ml/sec) and the mean IPSS score was 20.2 +/- 6.2 (range 15-30). The average operative time was 72 +/- 6.2 minutes (range 58-92 minutes). The mean drop in haemoglobin was 3.2 +/- 0.6 mg/dl (range 2.1-6.1 mg/dl) and immediate post operative mean sodium drop was 3 +/- 1.36 mmol/l (range 0.9-13 mmol/l). Blood transfusion was needed in 17 patients (8.6%), two patients developed TURP syndrome (1%), and clot retention occurred in two patients (1%). The average time of hospital stay was 2.3 +/- 0.25 days, catheterization time was 48-72 hours, and re-catheterization was needed in three patients (1.5%). The mean IPSS score six weeks after surgery was 9.9 +/- 1.7 (range 6-21) and the mean Qmax was 18.1 +/- 2.1 ml/sec (range 6-22). Urethral stricture and bladder neck contracture occurred in 12 and 3 patients respectively (6 and 1.5%). Completion TURP was needed in four patients (2%). CONCLUSIONS: Standard monopolar TURP with some modification in resection technique in addition to perioperative care will allow the urologist to treat benign prostate hyperplasia with prostate size between 80-120 grams successfully in centers where new laser technology is not available. PMID- 22204234 TI - Comparison of chromogenic urinary tract infection medium with cysteine lactose electrolyte deficient media in a resource limited setting. AB - OBJECTIVES: To compare the chromogenic UTI medium (CUM) with cysteine lactose electrolyte deficient medium (CLED) in terms of isolation of uropathogens, turnaround time and cost. METHODS: A total of 251 urine samples were selected and inoculated on both CLED and CUM, growth was observed after 24 and 48 hours of incubation. Isolates were identified by colony's colour and biochemical tests. Turnaround time for identification and cost was calculated till final identification of microorganisms. RESULTS: A discrepancy in isolation was observed in seven samples with growth on CUM in 24 hours while in 48 hours on CLED. There was 100% agreement in identification by both media. Almost 50% samples were identified within 24 hours by using CUM in contrast to CLED where most samples were identified in 48 hours. Total number of reagents used and total cost for processing of a specimen including technologist and consultant time by using CUM is significantly low in comparison to CLED. CONCLUSION: CUM can replace CLED as a primary isolation media for urine culture in clinical laboratories in Pakistan as it is user friendly, facilitates early reporting and saves cost. PMID- 22204235 TI - Outcomes of primary angle closure glaucoma management. AB - OBJECTIVE: To investigate the results of primary angle closure glaucoma (PACG) management on intraocular pressure (IOP). METHODS: This was a cross-sectional study conducted in the ophthalmology Department, Tabriz Medical Sciences University, Nikookary Eye Hospital, Tabriz, Iran. Subjects with angle closure were treated with YAG laser iridotomy at the time of diagnosis. These patients were re-examined in follow-up period for Patency of iridotomy, intraocular pressure (IOP), visual acuity, gonioscopic findings and automated threshold perimetry and peripapillary RNFL thickness for detecting progression. Iridotomy was classified unsuccessful in eyes where further surgical intervention was required or in which there was a loss of visual acuity to < 3/60 from glaucomatous optic neuropathy. All primary angle-closure glaucoma subjects (244 eyes) who had undergone Nd:YAG laser iridotomy between 2005 and 2008 were studied. RESULTS: A total of 244 patients were studied. The mean age of the study population was 64.60+9. 49 years with a median of 66 years (range: 45-80). The mean follow-up period was 21.59 +/- 12.37 months. Nd:YAG laser iridotomy for primary angle-closure glaucoma controlled the condition without any need for further medical or surgical therapy in 37 (15.2% ) cases, but the remainder who required added treatment included: 152 eyes (62.3%) medical treatment., 23 eyes (9.4%) trabeculectomy, 18 eyes (7.4%) phacoemulsification surgery, 8 eyes (3.3%) phacoemulsification with trabeculectomy and 6 eyes (2.5%) cyclophotocoagulation. In this study Nd:YAG laser iridotomy as a prophylactic procedure in the fellow eye of all patients was effective in preventing an acute angle-closure attack in the all the follow-up period. CONCLUSIONS: For most eyes with primary angle closure glaucoma after Nd: YAG laser iridotomy, additional medicine and surgery was required in the follow-up period. Medication therapy was needed more than other therapy. Early phacoemulsification appeared to be more effective in preventing IOP rise in uncontrolled cases. PMID- 22204236 TI - Application of geographical information system (GIS) for mapping road traffic injuries using existing source of data in Karachi, Pakistan--a pilot study. AB - OBJECTIVE: To assess the feasibility of using Geographical Information System for mapping of road traffic injuries with an existing data source in a developing country. METHODS: The study was a retrospectives case series of road traffic injury cases registered with the medico-legal office located in the three major trauma centers in Karachi for the period of January 1, 2004 till December 31st, 2004. Spatial data analysis was performed using ARCVIEW 3.1. RESULTS: Out of 3650 of all road traffic injury, only 3% had locations detailed and accurate enough allowing mapping on a GIS map in the first attempt. Even after using detailed town maps and field exercises more than a quarter cases (n=1088; 30%) of road traffic injuries (RTIs) could not be properly located. We identified 25 areas of one kilometer or less in Karachi accounting for 27% of all RTIs. Five corridors of road measuring 27.7 km accounted for 590 (23%) of all RTIs with known locations. CONCLUSIONS: Existing sources of data from the medico-legal system in Karachi failed to provide exact information on crash site. Such datasets can however be used to define high risk areas/neighbourhoods. PMID- 22204237 TI - Prevalence of peripheral arterial disease in type 2 diabetics in Pakistan. AB - OBJECTIVES: To observe the prevalence of peripheral arterial disease (PAD) and associated factors among people with type 2 diabetes in Pakistan. METHODS: A multicenter cross-sectional study was carried out at eight centers in all the provinces of Pakistan on people with type 2 diabetes. History of symptoms related to Peripheral arterial disease were noted and anthropometric measurements were recorded. Ankle brachial index (ABI) was measured using Doppler ultrasound; patients with ABI < 0.9 were classified as having low ABI. RESULTS: There were 830 patients in the study, (49% males and 51% females). Females were younger and had a higher body mass index (BMI) (p < 0.001). The prevalence of peripheral arterial disease was 31.6% with a 95% CI of 28.4% to 34.8%. There was no significant difference in the proportion of low ABI between males (30%) and females (33%) (p = 0.29). Patients with low ABI were found to have significantly higher BMI (p = 0.02) and waist circumference (p = 0.001). The most common symptom in the patients with low ABI was pain on walking (84%), followed by numbness of the feet (64%). There was a significant difference in the reporting of all the symptoms (p < 0.05) except for numbness of the feet (p = 0.57) as compared to patients with normal ABI. No association was found between low ABI and duration of diabetes mellitus or cigarette smoking. There was no significant association between cardiovascular conditions and low ABI. CONCLUSION: Peripheral arterial disease is common among people with type 2 diabetes in Pakistan and needs to be properly evaluated by the medical professionals as early diagnosis can help prevent future complications. PMID- 22204238 TI - Reproductive and sexual health issues: knowledge, opinion and attitude of medical graduates from Karachi. AB - OBJECTIVES: To asses the knowledge, opinion and attitude of medical graduates regarding selected reproductive tract infections, diagnosis of sexual dysfunction, identification of sexual abuse and other sexual health issues in Fatima Baqai Hospital Gadap Town. METHODS: A cross sectional study conducted from January 2009 to July 2009 in Fatima Baqai Hospital Karachi. An anonymous, self administrated structured questionnaire was completed by medical graduates. Formal/informal interviews were also arranged. The questionnaire and interviews addressed socio-demographic features, reproductive problems knowledge, attitudes and experience of those medical graduates. Descriptive statistics were analyzed by SPSS version 11. RESULT: A total of 50 medical graduates participate in the study. Of the total nearly half scored less than 50% in the knowledge section. Attitude and practices assessment suggested a tendency to be judgmental, gender/rights discriminatory and with little provision for enabling clients to make their own decision, so essential for quality sexual health provision. CONCLUSION: The level of reproductive and sexual health knowledge among the participant medical graduates were lower than expected. Attitudes and opinions indicate judgmental approach and indicating lack of experience of training in dealing with sexuality issues. PMID- 22204239 TI - Histological pattern of paediatric renal diseases in northern Pakistan. AB - OBJECTIVE: To determine histological spectrum of renal diseases among the paediatric population in the province Khyber Pukhtunkhwa, and to note any change in histological pattern with age and serum creatinine. METHODS: This is a retrospective analysis of 415 paediatric renal biopsies performed at the department of nephrology, Lady Reading Hospital Peshawar from 1998-2005. Children from 3 to 15 years of age, having renal disease and indications for biopsy, underwent ultrasound guided percutaneous renal biopsy. Indications included nephrotic syndrome, nephritic/nephrotic syndrome with renal insufficiency and nephrotic syndrome with steroid resistance. Patients with acute or chronic renal failure were not included. The specimens were examined without immunoflorescence, under light microscopy using different staining techniques, Results were analyzed for different age groups, serum creatinine levels and for both male and females with renal disease. RESULTS: The overall male to female ratio in the study was 1.6: 1. Nephrotic syndrome was most common indication for renal biopsy in 50% of the cases, followed by renal insufficiency (26%) and steroid resistance (24%). In children with primary glomerulonephritis, minimal change disease (MCD) was found to be the most common histological pattern (24.09%), followed by focal segmental glomerulosclerosis (FSGS), 18.30%; mesangioproliferative glomerulonephritis (GN) (MsePGN), 17.83%; mesangiocapillary GN (MPGN), 11.08%; post streptococcal proliferative GN (Post. strep GN), 10.60%; membranous GN (MGN), 4.82%; crescentic GN (Cres.GN), 4.34%. Among children with secondary GN, chronic sclerosing GN was found to be most common (1.93%), followed by chronic tubulo interstitial nephritis (Chr.TIN), 1.69% and hypertensive nephropathy (H.Neph), 1.69%; Renal Amyloidosis, 0.96% and Lupus Nephritis III, 0.96%; acute tubular necrosis (ATN), 0.72%; Alport's Syndrome (0.48%). Overall, MCD was the most common histological pattern in all age groups and among children with serum creatinine < 1.2 mg/dll. However, that with serum creatinine between 1.3 to 3 mg/dl, MsePGN was found to be more common. Age turned out to be significant factor, in contrast to serum creatinine, in determining various histological patterns. CONCLUSION: This study highlighted the histological patterns of renal disease among pediatric population from northern part of Pakistan. MCD was on the top followed by FSGS, but frequency of MCD was less than cited in earlier studies. PMID- 22204240 TI - Relationship between Helicobacter pylori infection and serum ferritin level in primary school children of Tehran-Iran. AB - OBJECTIVE: To determine the relationship between serum Ferritin levels and Helicobacter pylori antibody titer (IgG) in primary school children with H.pylori infection. METHODS: This cross-sectional study was performed among 6-12 year old healthy primary schoolchildren in Tehran during the academic year 2005-2006. Specimen collection was done by cluster and randomization methods (multistage sampling) Personal information and laboratory results were compiled in questionnaires and data was analyzed by descriptive and analytical statistics via SPSSv.15 software. RESULTS: One thousand six hundred sixty five primary school children (43% boys, 57% girls) with mean age 9.2 +/- 1.5 years were enrolled into the study. H.pylori IgG antibody titer was positive in 26% (432 cases) with mean values of 0.79 +/- 0.42 ISR units in boys and 0.75 +/- 0.39 ISR units in girls, which showed a significant statistical difference (P = 0.004). H.pylori infection was more common among children of large families or those with low economic status (P = 0.002). Twenty nine percent of children (477 cases)had low serum Ferritin levels, which was significantly higher among boys (P > 0.05); 32 82 +/- 33.12 mg/dL in boys and 43.23 +/- 2.5 mg/dL in girls. Out of the children with low serum Ferritin levels, 71% (334 cases) had negative and 28% (132 patients) had positive H.pylori antibody titers (IgG levels). Also, 296 children (25%) with normal Ferritin levels had H.pylori infection. CONCLUSIONS: We did not find a significant relationship between H.pylori infection and low serum Ferritin or iron deficiency anaemia. PMID- 22204241 TI - Late presentation of breast cancer: a dilemma. AB - OBJECTIVE: To asses factors responsible for late presentation of breast cancer in Nawabshah. METHODS: This descriptive study was conducted at a private and a public sector hospital of Nawabshah, Pakistan, from Jan 2004 to Dec 2008. RESULTS: Sixty females were admitted and selected as study subjects during the study period with mean age of 43.5 +/- 10.38 years and range (28-80 years). Patients with poor economic status were 49 (81.6%) and remaining 11 (18.3%) were from middle class. Sixteen (26.6%) patients were literate, with 3 of them being educated to secondary level. In our study 58 (96.6%) patients with breast carcinoma noted lumps in respective breasts as incidental findings in breast self examination. Only in 2 (3.3%) patients family physicians noted a lump and referred them to a proper health care facility. Fifty-eight (96.6%) patients belonged to rural areas. In 95% patients, first visit regarding the breast symptoms was made after 6 months of initiation of symptoms. Three (5%) patients in this study presented in stage I, 15 (25%) in stage II, 23 (38.3%) in stage III and 19 (31.6%) in stage IV. CONCLUSION: Most cases of breast cancer presented in advanced stage probably due to poor economic status, illiteracy and negligence by patients or their family members and general practioners. PMID- 22204242 TI - Death analysis of childhood acute lymphoblastic leukaemia; experience at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Pakistan. AB - OBJECTIVES: To analyze the common causes of death in childhood Acute Lymphoblastic Leukaemia (ALL) patients during therapy at Paediatric Oncology Department of Shaukat Khanum Memorial Cancer Hospital. METHODS: Retrospective descriptive study conducted at Paediatric Oncology department at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore Pakistan. All registered cases of ALL from 12 months to 18 years of age who expired between May 2001 to December 2005 were included. Mortality data was collected and analyzed regarding age, sex, WBC count, immunophenotype, treatment protocol, remission, and timing of death with respect to treatment protocol and the cause of death. RESULTS: Out of 304 new cases of ALL registered in the study period, 74 (24%) died during treatment. During induction 39 of 74 (52.7%) died, 33 (44.5%) in first remission and 2 (2.8%) before initiation of therapy. Infection alone or in combination with other factors was responsible for deaths in 63 of 74 (85%) cases. Septicemia, pulmonary and gastrointestinal infections were documented in 37/63 (58.7%), 44/63 (69%) and 8/63 (12.6%) cases respectively. Eight (10.8%) died due to haemorrhage. Three (4%) deaths were secondary to chemotherapy induced toxicity. CONCLUSION: Infection is the major cause of mortality in ALL patients in our study population. To improve survival it is imperative to improve supportive care especially prevention and management of infection. PMID- 22204243 TI - Non-traumatic coma in paediatric patients: etiology and predictors of outcome. AB - OBJECTIVE: To determine the common etiological features of non-traumatic coma in children and evaluate possible predictors of morbidity and mortality in these patients. METHOD: A cross sectional study was carried out at the Paediatric Department of Civil Hospital Karachi from February 2008 to February 2009. In total 100 children, up to 14 years of age having history of non-traumatic coma were included. At the time of enrolment demographic data, clinical features, laboratory parameters and radiological workup were recorded. Data was entered and analyzed with SPSS version 16. Descriptive statistics were generated for all variables. Relationships between categorical variables were evaluated by examining cross-tabulations, chi2 test and Fisher's exact tests. P-values < 0.05 were considered statistically significant. RESULTS: Mean age of the patients in months were 45 months. Male female ratio was 1.45:1. Among 65 survivors 38 (58%) showed no disability and 27 (41%) showed disability. Infections emerged as major cause of mortality (n=23, 79%). Clinical features that showed association with mortality included hypothermia (P = 0.032), hypotension (P = 0.002), altered breathing pattern (P = 0.0001), non reactive pupils (P = 0.001), low Glasgow coma scale (GCS) (P = 0.038), hypotonia (P = 0.002), hyporeflexia (P = 0.0001) and muscle power score of two (P = 0.043). CONCLUSION: Infections were the leading cause of non-traumatic coma as well as the leading cause of mortality in our study. Hypothermia, hypotension, altered breathing pattern, non reactive pupils, low GCS, hypotonia, hyporeflexia and low muscle power score were significantly associated with mortality in children presenting with non-traumatic coma. PMID- 22204244 TI - Effect of passive cigarette smoke on mouse placenta and the role of antioxidants. AB - OBJECTIVE: To study the effects of passive cigarette smoke on the architecture of mouse placenta and to observe the preventive role of antioxidants if any. METHODS: It was a randomized control trial. Female mice of Balb C strain (51) were mated and grouped as follows: Groups, C: control, S: exposed to smoke and SV: exposed to smoke and given antioxidants (vitamin C, E) and sacrificed at 19 dpc (days post coitus). 14 animals from C, 12 from S and 14 from SV had healthy pregnancies. Their placentae were studied microscopically. The relative thickness of the labyrinthine, spongiotrophoblast-I, spongiotrophoblast-II, and decidual layers were measured. The area of spongiotrophoblast-I was calculated using a computerized software programme. RESULTS: The mean relative thickness and area of the spongiotrophoblast-I in S (14.46 +/- 1.88%, 5.89 +/- 0.87%) was significantly more (p = 0.03, p = 0.035 respectively) as compared to the controls (9.47 +/- 1.31%, 3.95 +/- 0.24%). In SV these values (13.96 +/- 1.2% and 5.74 +/- 0.82%) did not show any significant improvement as compared to S (p = 0.035). The mean relative thickness of the labyrinthine, spongiotrophoblast II, and decidual layer in the control group was 44.49 +/- 2.51%, 19.06 +/- 2.48, 19.44 +/- 0.68 respectively. None of these showed any significant difference from each other in the three groups. CONCLUSION: Cigarette smoke causes a significant disturbance in the architecture of mouse placenta which could not be prevented by antioxidants. Therefore, these effects may be due to other toxic substances present in the smoke rather than free radicals. PMID- 22204245 TI - Hepatitis B vaccination coverage in medical students at a medical college of Mirpurkhas. AB - OBJECTIVES: To estimate the coverage of Hepatitis B vaccine in medical students enrolled in a private Medical College. METHODS: This cross sectional study was done at Muhammad Medical College Mirpurkhas. It has a total of 375 medical students from first year to final year. All students were interviewed using a pre structured urdu translated questionnaire to find out the vaccination status of these students and the reasons for not getting vaccinated. RESULTS: A total of 395 medical students were approached to participate in the study but only 375 (95%) students (M=214, F=159) gave response. Out of the total 375 students, 214 (57%) were vaccinated against Hepatitis B. Amongst this group 188 (87.8%) had completed their vaccination schedule of 03 doses and 26 (13%) were partially vaccinated. Vaccination uptake was higher (55.6%) in males as compared to females (44.3%). Reasons of not vaccination were lack of motivation ( 29.2%), no need felt (24.8%), (3) never thought of vaccination (21.7%), fear of injection (10.5%) and lack of belief in vaccination (8.07%). Only 130 (60.7%) students were screened before taking the vaccine. The self reported seropositivity of Hepatitis B Surface Antigen in medical students was 3.7%. CONCLUSIONS: Despite the availability and accessability of a cost effective Hepatitis B vaccine since mid 80's, the vaccination coverage among medical students is low. Health education needs to be improved in all medical students especially in the private sector. PMID- 22204246 TI - Hospital-based study on the use of herbal medicine in patients with coronary artery disease in Jordan. AB - OBJECTIVE: To determine the frequency and pattern of herbal therapy use among patients with chronic coronary artery disease as self remedies. METHODS: This cross-sectional study was conducted by face to face interview of 690 consecutive patients visiting the outpatient department at Queen Alia Heart Institute during the period 1/6/2008 to 1/6/2009. Data was collected using a specially designed questionnaire. RESULTS: Overall frequency of herbal use was 14.1%. The most commonly used herbs in Jordan were hawthorn and ginger. A total of 27 local and one Chinese herbal product were used, while the use of adulterated formulae were absent. Pharmacists were never consulted regarding the quantity or frequency of herb use. Side effects were rare. CONCLUSION: The use of medicinal herbs among cardiac patients in Jordan is not uncommon and consists largely of local herbs. Active role of pharmacists and doctors for counseling patients on the appropriate use of herbal products should prevent toxicity, ensure proper modes of preparation and optimize safety and efficacy. PMID- 22204247 TI - Cataract surgery at Marie Adelaide Leprosy Centre Karachi: an audit. AB - OBJECTIVE: To determine the outcome of cataract surgery in terms of visual results, intra and postoperative complications at Marie Adelaide Leprosy Centre. METHODS: The study was carried out at Marie Adelaide Leprosy Centre Karachi from May 2005 to December 2007. Surgical results of all outpatients operated for cataract from May 2005 to December 2007 were assessed. The data was collected using the CBM guidelines based on WHO monitoring systems for quality monitoring. Patients having uncomplicated cataract were included. Postoperative follow up was done at discharge, 1 week, 4 weeks and after 12 weeks, visual acuity was recorded as good (6/6-6/18), borderline (6/18-6/60) and poor (< 6/60), intraoperative and postoperative complications were also noted. RESULTS: During the study period a total of 1457 patients underwent cataract surgery. There were 826 male patients and 631 female patients, their age ranged from 20 to over 80 years. Preoperatively 1023 (70.2%) patients had poor, 362 (24.8%) patients had borderline while only 73 (5%) patients had good visual acuity while at discharge 962 (66%) patients had good, 392 (26.9%) patients had borderline and 104 (7.1%) patients had poor visual acuity. On an average among all the best corrected visual acuity was good in 97.2%, borderline in 2.2% and poor in 0.6% patients at 1 week, 4 weeks and >12 weeks follow up respectively. A large number of patients, 565 (38.7%) did not turn up after discharge for follow up, presumed reasons were: good vision, unable to return because of socioeconomic reasons, ill health and few of the patients expired. Intraoperative complications seen were posterior capsular rent with vitreous loss 70 (4.8%), zonular dehiscence 3 (0.2%), posterior loss of cortical matter 2 (0.1%) and iris prolapse in 4 (0.2%) cases. Immediate postoperative complication was striate keratopathy 157(10.7%), late were chronic anterior uveitis 3 (0.2%), corneal decompensation 2 (0.1%) choroidal and retinal detachment 1 (0.06%) each, Intraocular Lens (IOL) subluxation 4 (0.2%) and Posterior capsular opacification 40 (2.7%). CONCLUSION: In our study visual outcome achieved was comparable to the standards set by World Health Organization. In complicated cases functional vision can be achieved with timely management. PMID- 22204248 TI - Glycated haemoglobin--a marker and predictor of cardiovascular disease. AB - Glycated haemoglobin is formed by simple chemical reaction between haemoglobin and blood glucose. It represents a reliable and moving average of blood glucose over preceding three months. In 2009 the International Expert Committee recommended the use of HbA1c to diagnose diabetes with a cut-off of 6.5%. Studies have shown that HbA1c even in the range of 5.5% to 6.5% poses considerably high risk of morbidity and mortality due to cardiovascular disease. HbA1c as a test is important because about 220 million people have diabetes and with increasing life expectancy and emergence of type 2 diabetes in children makes it even more important. Each 1% increase in HbA1c poses 15-18% relative risk of cardiovascular disease in T1DM and T2DM respectively. CVD is a major cause of death and disability among diabetes patients and glycated haemoglobin itself is proportionately linked with excess CV morbidity and mortality. UKPDS-35 demonstrated 14% reduction in the incidence of acute myocardial infarction with only 1% reduction in HbA1c in T2DM patients. The DCCT reported significant reduction in retinopathy and nephropathy in T1DM, the follow up trial EDIC demonstrated 42% reduction in CVD with intensive reduction of HbAlc. This review is written to remind ourselves of the importance of this simple test which can predict early CV mortality in patients without prior CVD and poor prognosis in established cardiovascular disease. In a country like ours, Pakistan; where diabetes is prevalent with poor health awareness and limited resources, a test like HbA1c which costs Rs, 500.00 twice a year should be considered a cost effective way to avoid the long term diabetes complications, which once start unfolding put enormous burden on already stretched healthcare resources which could easily be avoided by intensive control of diabetes. PMID- 22204249 TI - Genital examination of Hijras. AB - There is a common belief in Pakistan that hijras are born hermaphrodites or have undergone an emasculation procedure. There are many studies about socio-sexual behaviour of hijras, but one rarely finds any study regarding genital examination of hijras. Four hundred hijras from Karachi and Lahore were examined as part of National Study of Reproductive Tract Infection conducted in 2004. A random sample of the Gurus of Hijras in each city was taken and all hijras under selected Gurus were included in the study. The purpose of study was explained to each Guru/participant and only those, who consented, were included. Out of 400 hijras, penis and testes were absent in only three hijras (0.8%). Among the remaining 397 hijras, 98.3% were circumcised and 1.7% were non-circumcised. Inguinal Lymphadenopathy was the most common finding. The study dispels the myth that Hijras in Pakistan have ambiguous genitalia, are hermaphrodites or have undergone removal of male sexual organs. PMID- 22204250 TI - Cerebral nocardiosis. AB - Localized and multisystem nocardiosis is an opportunistic disease that occurs commonly in immunocompromised patients. Rarely, it is also seen in immunocompetent individuals. The most common disease sites include lung, skin and central nervous system. We report a case of 73 years old man who is a known case of rheumatoid arthritis for more than 15 years and was on Methotrexate and Prednisolone. Now presented with generalized tonic clonic seizures. His Magnetic Resonace Imaging (MRI) scan showed a ring enhancing lesion with mild surrounding oedema in right posterior parietal cortex. Based on the finding, the most probable diagnosis of cerebral abscess was suggested. Patient underwent right sided craniotomy with aspiration of abscess. Serum Gram staining showed branching Gram-positive rods, and serum culture showed colonies of Nocardia Asteroides. He was started on Sulfamethoxazole-Trimethoprim. On follow-up examination, the patient showed marked improvement clinically and was discharged in stable condition on long term antibiotic therapy. This case highlights the importance of including nocardia on the differential diagnosis especially in patients who present with abnormal MRI scan findings that mimic tuberculoma or neoplastic disease. Clinical awareness of this condition could expedite the diagnostic process and help improve morbidity and mortality. PMID- 22204251 TI - Respiratory arrest due to airway obstruction following endoscopic removal of Trichobezoar. AB - A trichobezoar is a ball of swallowed hair that collects in the stomach and fails to pass through the intestines. Upper gastrointestinal endoscopy is usually useful for diagnosis and retrieval of a portion of the gastric Trichobezoars but can have complications. Upper airway obstruction may occur during removal of bezoar. This complication may be life threatening. We report the case of a 17 year-old girl who presented with severe anaemia and hypoproteinaemia. During diagnostic upper GI endoscopy, a large piece of hairball compressed the upper airway, leading to cyanosis, respiratory arrest and cardiovascular collapse. The patient was immediately intubated and transferred to the operation room for emergency esophagoscopy. In the operation room, after haemodynamic stabilization the otolaryngologist removed the large piece by esophagoscope. Then the patient was transferred to ICU ward with spontaneous ventilation. The day after, she became stable and conscious. PMID- 22204252 TI - Pneumomediastinum and subcutaneous emphysema due to blunt neck injury: a case report and review of the literature. AB - Minor blunt neck injury from childhood trauma is a relatively common condition which can be potentially life-threatening in only rare circumstances. Pneumomediastinum may develop in up to 10% patients who have sustained blunt cervical or thoracic trauma and may be a significant cause of morbidity and mortality in affected individuals because of the associated damage to the oesophagus, larynx or trachea. Management of this condition varies from conservative approach with close observation and antibiotherapy to surgical interventions, depending on the extent and severity of aerodigestive injuries. We present a paediatric blunt neck trauma accompanied by subcutaneous emphysema and pneumomediastinum secondary to a bicycle accident (neck striking the handlebar). Its radiologic appearance, clinical presentation, and the options for initial management in the emergency department (ED) are reviewed. PMID- 22204253 TI - Optic chiasma involvement secondary to allergic fungal rhinosinusitis. AB - Optic chiasma compression is a very rare complication of allergic fungal rhino sinusitis. Here we report the rare case of a 35-year-old female suffering from unilateral visual loss presented with allergic fungal sinusitis with sphenoid sinus involvement. Examination showed nasal polyposis and unilateral hemianopia. Computerized tomography and magnetic resonance imaging showed bilateral nasal polyposis with intracranial extension; however, the optic nerve was free. The patient underwent functional endoscopic surgery and medical management in the form of steroids and oral antifungal therapy, resulting in complete recovery of the visual field loss. Patient was started on immunotherapy according to the skin prick test. No clinical nor radiological recurrence of the disease was evident within 2 years. Immediate management both surgically and medically is important. Immunotherapy is an essential part for long term control. PMID- 22204254 TI - Variants of renal cell carcinoma; an experience at a single centre in Pakistan. AB - Renal cell carcinomas (RCC) have been considered as a single entity, until recently. Today, however, these are not considered as a single tumour but instead represent various distinguishable entities, each having unique histology, cytogenetic and molecular features. The variants of renal cell carcinoma can be easily recognized histologically and hence one can identify tumours having similar clinical course, morphology, genetics, prognosis and possibly treatment. This descriptive study carried over a period of one and a half year at Shifa International Hospital, Islamabad, focuses on presenting our data of various variants of renal cell carcinoma and the need for their recognition as the correct diagnosis may help to modify the therapeutic protocol. During the study period a total of 13 cases of RCC were diagnosed with the clear cell variant as the most frequent type (n=9; 69.2%). There was one case each of chromophobe renal carcinoma, medullary carcinoma, mucinous tubular and spindle cell carcinoma and multilocular cystic renal carcinoma. The average size of tumour ranged from 2.8 cm to 9.0 cm. Furhman's nuclear grade 2 was most frequently encountered (n=6; 46%) while the most frequent pathologic tumour stage was pT2 (n=7; 54%). This series is limited due to small sample size. More such studies on a larger scale with incorporation of follow up data are recommended to obtain population based statistics and identify biologically favourable variants in which nephron sparing surgery may be a suitable option. PMID- 22204255 TI - Smoking and mental health: do we have adequate insight? PMID- 22204256 TI - My patient just had a transient ischaemic attack. Can I predict his risk for stroke? Is stroke inevitable or preventable? PMID- 22204257 TI - Smokeless tobacco use prevention and cessation (S-TUPAC): a need of the time. PMID- 22204258 TI - Plagiarism--is there a solution? PMID- 22204259 TI - Pakistani medical students' specialty preference and the influencing factors. AB - OBJECTIVE: To elucidate the specialty preferences of Pakistani medical students and the factors which influence medical students to make the decision regarding which specialty to pursue. METHODS: Both basic sciences and clinical students from four medical colleges of Pakistan, i.e., Dow Medical College, Sindh Medical College, Liaquat National Medical College and Muhammad Medical College, were included in the cross-sectional survey during the period of July 2008 to Jan' 2009. After ethical acceptance, data was collected using convenient sampling technique. The questionnaire covered the following demographic details: 13 common specialties and 15 influencing factors. RESULTS: Questionnaires included in the analysis were 771. Most students gave preference to surgery and its associated sub-specialties (50.3%) followed by internal medicine (26.8%), paediatrics (23.2%), dermatology (16.7%), gynaecology and obstetrics (16.7%), psychiatry (13.1%), radiology (10.8%), ENT (8.8%), anaesthesiology (8.7%), administrative medicine (8.6%), orthopaedics (8.2%), ophthalmology (7.5%), and laboratory medicine (6.1%). The highly considered factors (regarding specialties) chosen by 70% of the medical students were: applicable to respective personalities of the individuals, prestige and respect, international opportunities, and time commitment. Surgical-skills, job availability, financial rating, academic performance, and a role model were moderately influencing factors. Hospital environment, parents, general practice, peer-pressure and personal health were the least influential. CONCLUSION: This trend suggests competition in surgery and its sub-specialties along with internal medicine, paediatrics, dermatology, gynaecology and obstetrics. Specialty suited to personality, time commitment, prestige/respect and international opportunity, influenced more than 70% of the students. PMID- 22204260 TI - The routine epidemics of dengue and our role in management. PMID- 22204261 TI - God father of mucosal cosmos--revealing the mysterious role of vitamin D receptor in inflammatory bowel disease. PMID- 22204262 TI - Bottom-up quality improvement theory and practice. PMID- 22204263 TI - Three-level quality assessment of a dental hospital using EFQM. AB - PURPOSE: This article aims to measure quality by applying the European Foundation for Quality Management (EFQM) excellence model at three different participation levels, in a Karachi teaching university dental hospital. DESIGN/METHODOLOGY/APPROACH: The case study assessed the eight EFQM model excellence concepts as benchmarks for providing quality services: results orientation; customer focus; leadership and constancy of purpose; management by processes and facts; people development and involvement; continuous learning, innovation and improvement; partnership development; and corporate social responsibility. This study was conducted at Hamdard University Dental Hospital (HUDH), located in Karachi - part of the largest privately-owned university in Pakistan. Data were collected through in-depth interviews with internal stakeholders at three levels (management, faculty and student). FINDINGS: Continuous learning, innovation and improvement; partnership development; and corporate social responsibility were satisfactorily represented. RESEARCH LIMITATIONS/IMPLICATIONS: The EFQM assessment was limited to a single university dental hospital, hence findings cannot be generalized. ORIGINALITY/VALUE: The article highlights that it is envisaged that this exercise will bring about a positive change in attitude and will stimulate institute staff to kick start the self assessment process and implement measures leading to better quality practices, thus establishing a continuous quality improvement cycle. PMID- 22204264 TI - Reducing queues: demand and capacity variations. AB - PURPOSE: The aim of this paper is to investigate how waiting lists or queues could be reduced without adding more resources; and to describe what factors sustain reduced waiting-times. DESIGN/METHODOLOGY/APPROACH: Cases were selected according to successful and sustained queue reduction. The approach in this study is action research. FINDINGS: Accessibility improved as out-patient waiting lists for two clinics were reduced. The main success was working towards matching demand and capacity. It has been possible to sustain the improvements. RESEARCH LIMITATIONS/IMPLICATIONS: Results should be viewed cautiously. Transferring and generalizing outcomes from this study is for readers to consider. However, accessible healthcare may be possible by paying more attention to existing solutions. PRACTICAL IMPLICATIONS: The study indicates that queue reduction activities should include acquiring knowledge about theories and methods to improve accessibility, finding ways to monitor varying demand and capacity, and to improve patient processing by reducing variations. ORIGINALITY/VALUE: Accessibility is considered an important dimension when measuring service quality. However, there are few articles on how clinic staff sustain reduces waiting lists. This paper contributes accessible knowledge to the field. PMID- 22204265 TI - Improving maternal healthcare utilisation in sub-Saharan Africa through micro finance. AB - PURPOSE: This paper aims to examine links between women's access to micro-finance and how they use maternal healthcare services in sub-Saharan Africa (SSA). DESIGN/METHODOLOGY/APPROACH: The authors use theoretical and empirical literature to propose a framework to sustain and improve women's access to maternal healthcare services through micro-financing. FINDINGS: It is found that improved access to micro-finance by women, combined with education may enhance maternal health service uptake. RESEARCH LIMITATIONS/IMPLICATIONS: The paper does not consider empirical data in the analysis. The authors advocate empirically testing the framework proposed in other SSA countries. SOCIAL IMPLICATIONS: It is important to empower women by facilitating their access to education and micro finance. This has implications for improving maternal healthcare utilization in SSA. ORIGINALITY/VALUE: The paper moves beyond poor access to maternal health services in SSA and proposes a framework for providing sustainable solutions. PMID- 22204266 TI - Professional involvement in the design of accreditation manuals. AB - PURPOSE: This paper aims to describe the participation of health professionals as key agents for the successful definition of skills manuals supporting professional accreditation in Andalusia (Spain). DESIGN/METHODOLOGY/APPROACH: The increasing extent to which different stakeholders are recognized reflects the importance they hold in all decision-making processes. The Andalusian Agency for Healthcare Quality's commitment to this process has facilitated the healthcare professionals' participation when professional skills manuals are designed for their respective specialities. FINDINGS: The process involved over 400 healthcare professionals from 58 disciplines between March 2005 and January 2008. Results were conditioned by several factors, some acting as drivers while others represented a barrier. RESEARCH LIMITATIONS/IMPLICATIONS: The experience relates to a specific geographical context. Healthcare professionals eligible to participate had to be in active employment and working for the Andalusian Public Health Service. There was an overrepresentation of members from scientific associations. PRACTICAL IMPLICATIONS: Co-operation based on mutual trust is the essential ingredient accounting for the success of participative involvement. ORIGINALITY/VALUE: The paper incorporates all categories of personnel and specialities in a regional healthcare system that covers eight million inhabitants and employs over 90,000 professionals, includes 33 public hospitals, more than 1,500 primary care centres and other healthcare units. PMID- 22204267 TI - Chronic respiratory patient control by multivariate charts. AB - PURPOSE: This article seeks to explain how to monitor the chronic obstructive disease patient and control any complications so that timely treatment can be applied. DESIGN/METHODOLOGY/APPROACH: Control charts and statistical process control (SPC) theory were used on chronic respiratory patient follow-up and control. Controlling several variables simultaneously, using univariate charts, can be misleading, more so when there are correlated variables, so multivariate and univariate control charts were studied. FINDINGS: One-sided control charts are preferable when the aim is to detect changes in the mean solely in one direction. Thus, one-sided, univariate and multivariate charts were built, which identified previously undetected out-of-control events. RESEARCH LIMITATIONS/IMPLICATIONS: The study's main limitation is its retrospective nature. However, following-up individual patients can highlight medical therapy effects. PRACTICAL IMPLICATIONS: The article concludes that control charts, in particular one-sided ones, are a valuable tool for monitoring chronic respiratory patients, thus contributing to medical decision making. ORIGINALITY/VALUE: The article highlights control chart application to chronic respiratory patient follow-up, permitting a global view of patient evolution over time. PMID- 22204268 TI - ISO 9001 in a neonatal intensive care unit (NICU). AB - PURPOSE: The aim of this paper is to present the process for approving and certifying a neonatal intensive care unit to ISO 9001 standards. DESIGN/METHODOLOGY/APPROACH: The process started with the department head's decision to improve services quality before deciding to achieve ISO 9001 certification. Department processes were mapped and quality management mechanisms were developed. Process control and performance measurements were defined and implemented to monitor the daily work. A service satisfaction review was conducted to get feedback from families. FINDINGS: In total, 28 processes and related work instructions were defined. Process yields showed service improvements. Family satisfaction improved. RESEARCH LIMITATIONS/IMPLICATIONS: The paper is based on preparing only one neonatal intensive care unit to the ISO 9001 standard. PRACTICAL IMPLICATIONS: The case study should act as an incentive for hospital managers aiming to improve service quality based on the ISO 9001 standard. ORIGINALITY/VALUE: ISO 9001 is becoming a recommended tool to improve clinical service quality. PMID- 22204269 TI - Measuring, evaluating and improving hospital quality parameters/dimensions--an integrated healthcare quality approach. AB - PURPOSE: This paper aims to examine the major factors affecting cumulative summation, to empirically examine the major factors affecting satisfaction and to address the question whether patients in Kazakhstan evaluate healthcare similarly or differently from patients in Egypt and Jordan. DESIGN/METHODOLOGY/APPROACH: A questionnaire, adapted from previous research, was distributed to Kazakhstan inpatients. The questionnaire contained 39 attributes about five newly-developed quality dimensions (5Qs), which were identified to be the most relevant attributes for hospitals. The questionnaire was translated into Russian to increase the response rate and improve data quality. Almost 200 usable questionnaires were returned. Frequency distribution, factor analysis and reliability checks were used to analyze the data. FINDINGS: The three biggest concerns for Kazakhstan patients are: infrastructure; atmosphere; and interaction. Hospital staffs concern for patients' needs, parking facilities for visitors, waiting time and food temperature were all common specific attributes, which were perceived as concerns. These were shortcomings in all three countries. Improving health service quality by applying total relationship management and the 5Qs model together with a customer-orientation strategy is recommended. PRACTICAL IMPLICATIONS: Results can be used by hospital staff to reengineer and redesign creatively their quality management processes and help move towards more effective healthcare quality strategies. SOCIAL IMPLICATIONS: Patients in three countries have similar concerns and quality perceptions. ORIGINALITY/VALUE: The paper describes a new instrument and method. The study assures relevance, validity and reliability, while being explicitly change-oriented. The authors argue that patient satisfaction is a cumulative construct, summing satisfaction as five different qualities (5Qs): object; processes; infrastructure; interaction and atmosphere. PMID- 22204272 TI - Retroperitoneal laparoendoscopic single-site simple nephrectomy: initial experience. AB - PURPOSE: To present our early experience with retroperitoneal laparoendoscopic single-site (LESS) simple nephrectomy. PATIENTS AND METHODS: A total of 16 patients with benign nonfunctioning kidney underwent retroperitoneal LESS nephrectomy by one experienced laparoscopic surgeon. A single-port access was inserted through an approximately 3-cm lumbar incision made below the 12th rib along the midaxillary line. Standard steps of multisite retroperitoneoscopic nephrectomy technique with a combination of conventional and bent laparoscopic instruments were performed. RESULTS: Retroperitoneal LESS nephrectomy was performed in 15 cases successfully. The procedure of one patient (genitourinary tuberculosis) needed conversion to open surgery because of the severe adhesions surrounding the kidney, which resulted in failure to progress. Overall, the mean operative time was 85 (75-140) minutes, and estimated blood loss was 56 (20-110) mL. The mean time to resume oral diet was 1.5 days. The mean postoperative hospital stay was 4 (3-5) days. Perioperative complications were limited to one case of transient postoperative fever. No major intraoperative and postoperative complication occurred. CONCLUSIONS: Retroperitoneal LESS nephrectomy performed by an experienced laparoscopic surgeon is feasible and safe, offering improved cosmesis, although it remains technically challenging. Retroperitoneal LESS nephrectomy should be selectively used in terms of patients' specific conditions. PMID- 22204273 TI - Ionic structures of nanobased FeCl3/[C4mim]Cl ionic liquids. AB - We synthesized a series of FeCl(3)/[C(4)mim]Cl (iron(III) chloride with 1-butyl-3 methylimidazolium chloride) ionic liquids. The temperature dependence of the Raman spectra of the FeCl(3)/[C(4)mim]Cl ionic liquids was measured for the first time to analyze their ionic species. In addition, the infrared spectra, thermodynamic properties, and freeze-fracture transmission electron microscopy were combined together with the Raman spectra to reveal the microscopic information of the FeCl(3)/[C(4)mim]Cl ionic liquids. When the mole ratio of FeCl(3)/[C(4)mim]Cl is less than 1, the Raman scattering identifies the presence of [FeCl(4)](-) in the ionic liquid. When FeCl(3) is in excess, [Fe(2)Cl(7)](-) begins to appear. Besides, we found that the relative intensity of the two symmetry vibrations of [Fe(2)Cl(7)](-) is changing as the temperature is varied. The strength of the interionic interactions in FeCl(3)/[C(4)mim]Cl ionic liquids follows the order 1/1.5 > 1.5/1 > 1/1 due to the formation of [FeCl(4)](-) and [Fe(2)Cl(7)](-). The nanostructures in FeCl(3)/[C(4)mim]Cl ionic liquids were observed for the first time by using biological imaging. The sizes of the local domains are found to be tens of nanometers. PMID- 22204275 TI - Baicalein mediates inhibition of migration and invasiveness of skin carcinoma through Ezrin in A431 cells. AB - BACKGROUND: Ezrin is highly expressed in skin cancer and promotes tumor metastasis. Ezrin serves as a promising target for anti-metastasis therapy. The aim of this study is to determine if the flavonoid bacailein inhibits the metastasis of skin cancer cells through Ezrin. METHODS: Cells from a cutaneous squamous carcinoma cell line, A431, were treated with baicalein at 0-60 MUM to establish the non-cytotoxic concentration (NCC) range for baicalein. Following treatment with baicalein within this range, total Ezrin protein (both phosphorylated and unphosphorylated forms) and phosphorylated-Ezrin (phos-Ezrin) were detected by western blotting, and Ezrin RNA was detected in A431 cells using reverse transcription-polymerase chain reaction (RT-PCR). Thereafter, the motility and invasiveness of A431 cells following baicalein treatment were determined using wound-healing and Boyden chamber invasion assays. Short interfering RNA (si-RNA) specifically targeting Ezrin was transfected into A431 cells, and a si-RNA Ezrin-A431 cell line was established by G418 selection. This stable cell line was transiently transfected with Ezrin and mutant Ezrin plasmids, and its motility and invasiveness was subsequently determined to clarify whether bacailein inhibits these processes through Ezrin. RESULTS: We determined the range of NCCs for baicalein to be 2.5-40 MUM in A431 cells. Baicalein displayed a dose- and time-dependent inhibition of expressions of total Ezrin and phos-Ezrin within this range NCCs. In addition, it exerted this inhibitory effect through the reduction of Ezrin RNA transcript. Baicalein also inhibited the motility and invasiveness of A431 skin carcinoma cells within the range of NCCs, in a dose- and time-dependent manner. A431 cell motility and invasiveness were inhibited by 73% and 80% respectively when cells were treated with 20 MUM baicalein. However, the motility and invasiveness of A431 cells containing the Ezrin mutant were not effectively inhibited by baicalein. CONCLUSIONS: Baicalein reduces the migration and invasiveness of A431 cells through the inhibition of Ezrin expression, which leads to the suppression of tumor metastasis. PMID- 22204276 TI - Accuracy of the piko-1 pocket spirometer. AB - BACKGROUND: Good asthma control is the main goal of long-term asthma treatment. According to the Global Initiative for Asthma (GINA) guidelines (www.ginasthma.com), medical professionals assess asthma control based on specific questions regarding asthma symptoms and by spirometry measuring forced expiratory volume in 1 second (FEV(1)). Patients trained in early self-detection of asthma exacerbations use a symptom-based questionnaire, such as the Asthma Control Test (ACT) [Nathan RA, Sorkness CA, Kosinski M, et al. Development of the Asthma Control Test. A survey for assessing asthma control. J Allergy Clin Immunol 2004; 113:59-64]. However, some patients may prefer harder indicators, like peak flow values, when considering how to act within their regular asthma self-management plan. OBJECTIVES: Monitoring of FEV(1) at home could be an even more valuable alternative to recording peak flow values. The inexpensive handheld pocket spirometer "Piko-1(r)" offers the opportunity to monitor and store consecutive FEV(1) values. This study assesses the accuracy of the Piko-1 device. METHODS: Twenty volunteers tested 20 Piko-1 devices over five consecutive days. All results were compared to daily FEV(1) values, as measured by a calibrated reference spirometer. RESULTS: Overall, the accuracy was acceptable, although Piko-1 tended to underestimate FEV(1) in the lower range. Moreover, there was no evidence of major heterogeneity between Piko-1 devices. CONCLUSION: The Piko-1 FEV(1) measurements are sufficiently accurate to start a clinical trial to compare the detection of asthma exacerbations with this device and based on asthma symptoms alone. PMID- 22204277 TI - Autostratification in drying colloidal dispersions: effect of particle interactions. AB - When particles differing in size or charge are mixed and cast, vertical segregation is an inevitable phenomenon in the produced films. Apart from the Peclet number, which is the ratio of evaporation to diffusion rates, particle interactions play a crucial role in determining the distribution of particles in the dried films. Trueman et al. (1) developed a model for vertical segregation of particles during drying. Their numerical solution assumed that the chemical potentials were determined entirely by entropy. We report the effect of particle interactions in various systems: (i) charged particles with different Peclet numbers and (ii) charged particles with the same Peclet numbers. An experimental study has also been carried out for particles with Peclet numbers straddling unity; the experimental results conform with the behavior predicted theoretically. PMID- 22204279 TI - Fragmentation of beta-hydroxy hydroperoxides. AB - A beta-hydroxy hydroperoxide was obtained through base-catalyzed disproportionation of a hydroperoxy endoperoxide available by singlet oxygenation of cyclohepta-1,4-diene. Vitamins E and C induce fragmentation of this beta hydroxy hydroperoxide generating aldehydes, especially in the presence of redox active metal ions such as those present in vivo, e.g., under conditions of "iron overload". This chemistry may contribute to the oxidative cleavage of polyunsaturated fatty acyls that produces similar aldehydes, which damage proteins and DNA through covalent adduction resulting in "oxidative injury". PMID- 22204280 TI - Aggregation behaviors of dodecyl sulfate-based anionic surface active ionic liquids in water. AB - Halogen-free, low-cost alkyl sulfate-based surface active ionic liquids (SAILs), 1-butyl-3-methylimidazolium dodecyl sulfate ([C(4)mim][C(12)SO(4)]), and N-butyl N-methylpyrrolidinium dodecyl sulfate ([C(4)MP][C(12)SO(4)]) were easily synthesized through ion exchange reaction. The aggregation behaviors of [C(4)mim][C(12)SO(4)] and [C(4)MP][C(12)SO(4)] in aqueous solution were investigated by surface tension, electric conductivity, and static fluorescence quenching. Both [C(4)mim][C(12)SO(4)] and [C(4)MP][C(12)SO(4)] have rather lower cmc, gamma(cmc) values and higher pC(20), pi(cmc) values than those reported for the traditional ionic surfactant, sodium dodecyl sulfate (SDS), and imidazolium based SAIL, 1-dodecyl-3-methylimidazolium bromide ([C(12)mim]Br), with the same hydrocarbon chain length. The thermodynamic parameters evaluated from electric conductivity measurements show that the micelle formation of [C(4)mim][C(12)SO(4)] and [C(4)MP][C(12)SO(4)] is entropy-driven in the temperature range investigated. Lower average aggregation number indicates that the micelles of two SAILs present much looser structure. It is found that both the nature and the ring type of counterions can affect the aggregation behavior in aqueous solution. (1)H NMR results of [C(4)mim][C(12)SO(4)] were used to further verify the mechanism of micelle formation. Hydration ability and steric hindrance of the imidazolium or pyrrolidinium counterion as well as the cooperative hydrophobic interaction of longer alkyl chain of [C(12)SO(4)] anion and comparatively shorter alkyl chain of [C(4)mim] or [C(4)MP] cation are proposed to play critical roles in the aggregation of [C(4)mim][C(12)SO(4)] and [C(4)MP][C(12)SO(4)]. PMID- 22204282 TI - PennVet researcher awarded National Medal of Science. PMID- 22204278 TI - Apoptotic signaling in mouse odontogenesis. AB - Apoptosis is an important morphogenetic event in embryogenesis as well as during postnatal life. In the last 2 decades, apoptosis in tooth development (odontogenesis) has been investigated with gradually increasing focus on the mechanisms and signaling pathways involved. The molecular machinery responsible for apoptosis exhibits a high degree of conservation but also organ and tissue specific patterns. This review aims to discuss recent knowledge about apoptotic signaling networks during odontogenesis, concentrating on the mouse, which is often used as a model organism for human dentistry. Apoptosis accompanies the entire development of the tooth and corresponding remodeling of the surrounding bony tissue. It is most evident in its role in the elimination of signaling centers within developing teeth, removal of vestigal tooth germs, and in odontoblast and ameloblast organization during tooth mineralization. Dental apoptosis is caspase dependent and proceeds via mitochondrial mediated cell death with possible amplification by Fas-FasL signaling modulated by Bcl-2 family members. PMID- 22204283 TI - Development of a nested polymerase chain reaction assay for the detection of Eimeria macusaniensis in camelid feces. AB - OBJECTIVE: To test the ability of a nested PCR assay to detect Eimeria macusaniensis at various stages of infection in alpacas. ANIMALS: 4 healthy adult alpacas with no detectable E. macusaniensis. PROCEDURES: Alpacas were inoculated with 2 * 10(4) sporulated oocysts. Serial fecal samples collected during the next 38 days were tested via sucrose flotation and PCR assay. RESULTS: Oocyst passage was detected via fecal flotation in all 4 alpacas 31 to 35 days after inoculation. Three had positive results for PCR assays on samples obtained 7 to 14 days after inoculation. One alpaca subsequently was removed from the study because of weight loss and inappetence. Two remaining alpacas had positive PCR reactions 28 and 31 days after inoculation, up to 7 days before oocysts appeared in the feces. All fecal samples with positive results for flotation also had positive results for PCR assay. CONCLUSIONS AND CLINICAL RELEVANCE: The PCR assay was able to detect early (7 to 14 days) and late (28 to 31 days) prepatent infection. These positive results suggested that the assay could have been detecting DNA unassociated with oocysts or detecting shedding earlier than has been previously recognized. The gap between the early and late detection periods may not be evident in alpacas receiving a larger or continuous inoculum, as might occur with natural infection. Use of a PCR assay for analysis of fecal samples may be valuable for detection of E. macusaniensis during the prepatent period, thus aiding in the identification and control of infected animals. PMID- 22204284 TI - Efficacy of ABT-116, an antagonist of transient receptor potential vanilloid type 1, in providing analgesia for dogs with chemically induced synovitis. AB - OBJECTIVE: To investigate the ability of ABT-116 (a proprietary antagonist of transient receptor potential vanilloid type 1) administered at 2 doses to attenuate lameness in dogs with experimentally induced urate synovitis. ANIMALS: 8 purpose-bred mixed-breed dogs. PROCEDURES: In a 4-way crossover study, dogs orally received each of low-dose ABT-116 treatment (LDA; 10 mg/kg), high-dose ABT 116 treatment (HDA; 30 mg/kg), firocoxib (5 mg/kg), and no treatment (nontreatment) once a day for 2 days, in a randomly assigned order. Synovitis was induced on the second day of each treatment period by intra-articular injection of either stifle joint with sodium urate, alternating between joints for each treatment period, beginning with the left stifle joint. Ground reaction forces, clinical lameness scores, and rectal temperature were assessed before the injection (baseline) and at various points afterward. RESULTS: Lameness scores at the 2-, 6-, and 12-hour assessment points were higher than baseline scores for HDA and nontreatment, whereas scores at the 2- and 6-hour points were higher than baseline scores for LDA. For firocoxib, there was no difference from baseline scores in lameness scores at any point. Compared with baseline values, peak vertical force and vertical impulse were lower at 2 and 6 hours for HDA and nontreatment and at 2 hours for LDA. No changes in these values were evident for firocoxib. The HDA or LDA resulted in higher rectal temperatures than did treatment with firocoxib or nothing, but those temperatures did not differ among treatments. CONCLUSIONS AND CLINICAL RELEVANCE: HDA had no apparent effect on sodium urate-induced lameness; LDA did attenuate the lameness but not as completely as firocoxib treatment. High rectal temperature is an adverse effect of oral ABT-116 administration that may be of clinical concern. PMID- 22204285 TI - Development and validation of a canine radius replica for mechanical testing of orthopedic implants. AB - OBJECTIVE: To design and fabricate fiberglass-reinforced composite (FRC) replicas of a canine radius and compare their mechanical properties with those of radii from dog cadavers. SAMPLE: Replicas based on 3 FRC formulations with 33%, 50%, or 60% short-length discontinuous fiberglass by weight (7 replicas/group) and 5 radii from large (> 30-kg) dog cadavers. PROCEDURES: Bones and FRC replicas underwent nondestructive mechanical testing including 4-point bending, axial loading, and torsion and destructive testing to failure during 4-point bending. Axial, internal and external torsional, and bending stiffnesses were calculated. Axial pullout loads for bone screws placed in the replicas and cadaveric radii were also assessed. RESULTS: Axial, internal and external torsional, and 4-point bending stiffnesses of FRC replicas increased significantly with increasing fiberglass content. The 4-point bending stiffness of 33% and 50% FRC replicas and axial and internal torsional stiffnesses of 33% FRC replicas were equivalent to the cadaveric bone stiffnesses. Ultimate 4-point bending loads did not differ significantly between FRC replicas and bones. Ultimate screw pullout loads did not differ significantly between 33% or 50% FRC replicas and bones. Mechanical property variability (coefficient of variation) of cadaveric radii was approximately 2 to 19 times that of FRC replicas, depending on loading protocols. CONCLUSIONS AND CLINICAL RELEVANCE: Within the range of properties tested, FRC replicas had mechanical properties equivalent to and mechanical property variability less than those of radii from dog cadavers. Results indicated that FRC replicas may be a useful alternative to cadaveric bones for biomechanical testing of canine bone constructs. PMID- 22204286 TI - Validation of spectrophotometric assays for serum paraoxonase type-1 measurement in dogs. AB - OBJECTIVE: To evaluate and validate 3 spectrophotometric assays for measuring serum activity of paraoxonase type-1 (PON1), an enzyme associated with high density lipoproteins, in dogs. ANIMALS: 22 healthy adult dogs and 10 dogs with eccentrocytosis. PROCEDURES: 2 methods were adapted for use in 96-well microplates with phenyl acetate and 5-thiobutyl butyrolactonase as substrates, and 1 was adapted for use in an automated analyzer with p-nitrophenyl acetate as substrate. Blood samples were collected from all dogs, serum was harvested, and serum PON1 activity was measured with each method. RESULTS: Imprecision was low for all 3 methods, with the exception of interassay imprecision for 5-thiobutyl butyrolactonase, and results were linear across serial sample dilutions. The 3 methods were able to detect low PON1 activity when EDTA was used for blood sample collection, yielded lower PON1 values in sick dogs with eccentrocytosis than in healthy dogs, and yielded highly correlated results. CONCLUSIONS AND CLINICAL RELEVANCE: The methods described here may allow a wider use of PON1 activity as a biomarker of oxidative stress in dogs in clinical and research settings. Results of each method were robust and precise (with the exception of the interassay values for the lactonase method), and the methods were easy to set up in a laboratory. PMID- 22204287 TI - Computed tomographic features of the osseous structures of the external acoustic meatus, tympanic cavity, and tympanic bulla of llamas (Lama glama). AB - OBJECTIVE: To evaluate the osseous structures of the external acoustic meatus, tympanic cavity, and tympanic bulla of llamas (Lama glama) by use of computed tomography (CT) and establish measurement values for use in detection of abnormalities associated with the external or middle ear in llamas. ANIMALS: 10 adult llama heads without any evidence of ear disease. PROCEDURES: Heads of 10 healthy llamas euthanized by use of a captive bolt striking the dorsal aspect of the skull were collected. Transverse images of the heads were acquired with 1-mm slice thickness, and images were reconstructed in sagittal and dorsal planes. Measurements of the bony structures of the external and middle ear of each head were obtained. RESULTS: The osseous external acoustic meatus curved ventrally as it tracked medially. Its narrowest portion was located at the level of the tympanic annulus. The tympanic bulla conformation differed widely from the bubble shaped tympanic bulla in dogs and cats. The bulla was divided by the stylohyoid fossa into a larger caudolateral and a smaller caudomedial process; its interior had a honeycombed structure with pneumatized cells similar to the honeycombed appearance of the human mastoid process. CONCLUSIONS AND CLINICAL RELEVANCE: Results provided new information regarding the shape and dimensions of the osseous external and middle ear structures in adult llamas without ear disease. Specific landmarks for location of the external acoustic meatus, tympanic cavity, and tympanic bulla in relation to each other were identified. Knowledge of the CT appearance of normal structures will help clinicians to identify changes attributable to middle ear otitis, external ear canal stenosis, or congenital malformations of the ear in this species. PMID- 22204288 TI - Effects of ischemia and reperfusion on production of nitrotyrosine, activation of eosinophils, and apoptosis in the large colonic mucosa of horses. AB - OBJECTIVE: To assess the effects of ischemia and reperfusion on indicators of oxidative stress, activation of eosinophils, and apoptosis in the large colonic mucosa of horses. ANIMALS: 40 horses. PROCEDURES: In 1 or two 20-cm-long segments of the pelvic flexure, ischemia was induced for 1 or 2 hours followed by no reperfusion or 30 minutes and 18 hours of reperfusion in anesthetized horses. Mucosal specimens were collected before (controls; n = 20 horses) and after each period of ischemia, and full-thickness tissue samples were collected after each period of reperfusion. Sections of colonic tissues were stained for histomorphometric analysis or assessment of eosinophil accumulation. Nitrotyrosine was identified immunohistochemically, and severity of apoptosis was determined via the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method. RESULTS: Numbers of mucosal eosinophils were similar before induction of ischemia, after ischemia, and after ischemia reperfusion. Eosinophil nitrotyrosine production increased significantly during ischemia and continued through 30 minutes of reperfusion; production was decreased at 18 hours of reperfusion but remained greater than that of the controls. In other leukocytes, nitrotyrosine generation peaked at 1 hour of ischemia and again at 18 hours of reperfusion. Compared with control findings, epithelial apoptosis increased gradually at 1 through 2 hours of ischemia with no further progression after reperfusion. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that resident eosinophils in the large colon of horses react to mucosal injury from ischemia and reperfusion and may undergo oxidative stress under those conditions. Epithelial apoptosis could contribute to tissue damage. PMID- 22204289 TI - Effects of increases in dietary fat intake on plasma lipid and lipoprotein cholesterol concentrations and associated enzyme activities in cats. AB - OBJECTIVE: To determine the effects of increases in dietary intake of polyunsaturated and saturated fatty acids on plasma lipid and lipoprotein concentrations and activity of associated enzymes in healthy domestic cats. ANIMALS: 16 healthy adult sexually intact female cats. PROCEDURES: A baseline diet (40% energy from fat) and 4 test diets, with increased amounts of fat (51% and 66% energy from fat) from the addition of polyunsaturated and saturated fatty acids, were fed for 6 weeks each. Plasma cholesterol, triglyceride, and lipoprotein cholesterol concentrations, along with activities of lipoprotein lipase, hepatic lipase, and lecithin-cholesterol acyl transferase, were measured at the end of each feeding period. RESULTS: Diet, amount of fat, or ratio of polyunsaturated to saturated fatty acids had no effect on plasma concentrations of cholesterol, triglycerides, and very-low-density or high-density lipoproteins or the activity of lecithin-cholesterol acyl transferase. Low-density lipoprotein concentrations were significantly lower in cats fed a high-fat diet containing polyunsaturated fatty acids. Lipoprotein concentration and hepatic lipase activity were significantly higher in cats fed the fat-supplemented diets, and this was unrelated to whether diets were enriched with polyunsaturated or saturated fatty acids. CONCLUSIONS AND CLINICAL RELEVANCE: Diets containing up to 66% of energy from fat were tolerated well by healthy cats and did not affect plasma lipid concentrations. Therefore, high-fat diets probably will not contribute to hypercholesterolemia or hypertriglyceridemia in cats. PMID- 22204290 TI - Daily endogenous cortisol production and hydrocortisone pharmacokinetics in adult horses and neonatal foals. AB - OBJECTIVE: To compare daily endogenous cortisol production rate and the pharmacokinetics of an i.v. bolus of hydrocortisone between neonatal foals and adult horses. ANIMALS: 10 healthy full-term 2- to 4-day-old foals and 7 healthy adult horses. PROCEDURES: Blood samples were collected from each horse every 15 to 20 minutes for 24 hours for determination of 24-hour mean cortisol concentration. Afterward, dexamethasone (0.08 mg/kg) was administered i.v. to suppress endogenous cortisol production. Twelve hours afterward, hydrocortisone sodium succinate (1.0 mg/kg) was administered as a rapid i.v. bolus and serial blood samples were collected to determine hydrocortisone pharmacokinetics. Cortisol concentrations, daily cortisol production rate, and hydrocortisone pharmacokinetics were determined, and results were compared between adult horses and foals. RESULTS: The mean +/- SD 24-hour cortisol concentration was significantly lower in foals (20 +/- 4 ng/mL) than in horses (26 +/- 6 ng/mL), but the daily cortisol production rate was significantly greater in foals (6,710 +/- 320 ng/kg/d) than in horses (2,140 +/- 400 ng/kg/d). For hydrocortisone, foals had a significantly greater volume of distribution at steady state (1.92 +/ 1.11 L/kg) and total body clearance (1.39 +/- 0.108 L/kg/h) and significantly lower peak plasma concentration (1,051 +/- 343 ng/mL) than did horses (0.58 +/- 0.15 L/kg, 0.349 +/- 0.065 L/kg/h, and 8,934 +/- 3,843 ng/mL, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Important differences were detected in cortisol production and metabolism between neonatal foals and adult horses consistent with lower plasma protein binding of cortisol in foals. This decrease may contribute to cortisol insufficiency during prolonged critical illness in neonatal foals. PMID- 22204291 TI - Evaluation of factors associated with the risk of infection with Cryptosporidium parvum in dairy calves. AB - OBJECTIVE: To identify risk factors associated with Cryptosporidium parvum infection in dairy calves. ANIMALS: 108 case animals and 283 control animals. PROCEDURES: Case animals were calves infected with C. parvum, and controls were infected with Cryptosporidium bovis (n = 67) or calves not infected with Cryptosporidium spp. Fecal samples were tested via the flotation concentration method for Cryptosporidium spp. Samples were genotyped by sequencing of the 18s rRNA gene. Associations between host, management, geographic, and meteorologic factors and Cryptosporidium genotype were assessed. RESULTS: Younger calves and calves housed in a cow barn were more likely to be infected with both genotypes. Herd size and hay bedding were associated with an increased risk of infection with C. parvum, and Jersey breed was a risk factor for C. bovis infection. Compared with a flat surface, a steeper slope was significantly associated with a decreased likelihood of infection with both genotypes, and precipitation influenced the risk of C. parvum infection only. CONCLUSIONS AND CLINICAL RELEVANCE: Risk factors for calf infection with C. parvum differed from those for infection with C. bovis. Results may be useful to help design measures that reduce animal exposure and decrease public health risk and economic losses associated with C. parvum infection in cattle. PMID- 22204292 TI - Evaluation of homologous and heterologous protection induced by a virulent field strain of orf virus and an orf vaccine in goats. AB - OBJECTIVE: To evaluate cross protection provided by administration of contagious ecthyma vaccines against strains of orf virus in goats. ANIMALS: 126 Boer-Spanish crossbred goats (3 to 20 days old). PROCEDURES: 85 goats were vaccinated with a goat-derived contagious ecthyma vaccine. Of these, 41 were challenge exposed with the virus strain for the contagious ecthyma vaccine, 40 were challenge exposed with a more virulent field strain of orf virus, and 4 were lost to predation or died. Another 41 goats were vaccinated with a vaccine produced from a more virulent field strain of orf virus; of these, 18 were challenge exposed with the virus strain of the goat-derived contagious ecthyma vaccine, 18 were challenge exposed with the more virulent field strain of orf virus, and 5 were lost to predation or died. RESULTS: Vaccination with the goat-derived contagious ecthyma vaccine did not significantly reduce the number of goats with lesions or lesion severity caused by challenge exposure with the more virulent field strain of orf virus. Vaccination with the vaccine produced from the more virulent field strain of orf virus significantly reduced the number of goats with lesions attributable to challenge exposure with the virus strain of the goat-derived contagious ecthyma vaccine, but it failed to significantly reduce lesion severity. CONCLUSIONS AND CLINICAL RELEVANCE: Vaccination did not result in cross protection for the 2 strains of orf virus. This may have been attributable to antigenic differences and may be a factor in outbreaks of contagious ecthyma in vaccinated goats. PMID- 22204293 TI - Lesion severity at processing as a predictor of Salmonella contamination of swine carcasses. AB - OBJECTIVE: To measure the relationship between gross lesions in swine carcasses observed at a processing plant and Salmonella contamination and to determine whether nonexpert assessments of lesion status would correspond with swine pathologists' judgments. ANIMALS: Carcasses of 202 conventionally raised and 156 antimicrobial-free pigs in a Midwestern US processing plant examined from December 2005 to January 2006. PROCEDURES: 4 replicates were conducted. For each, freshly eviscerated carcasses were identified as having or lacking visceral adhesions by a nonexpert evaluator and digital carcass photographs were obtained. Swab specimens were obtained from carcasses before the final rinse stage of processing, and bacterial culture for Salmonella spp and Enterococcus spp was performed. Subsequently, carcass photographs were numerically scored for lesion severity by 3 veterinary pathologists. Results were used to test the ability of lesion detection to predict bacterial contamination of carcasses and the agreement between judgments of the inexperienced and experienced assessors. RESULTS: The probability of Salmonella contamination in carcasses with lesions identified at the abattoir was 90% higher than that in carcasses lacking lesions, after controlling for replicate identity and antimicrobial use. The receiver operating characteristic curve and Cohen kappa indicated close agreement between lesion detection at the abattoir and by the 3 pathologists. CONCLUSIONS AND CLINICAL RELEVANCE: Findings indicated the presence of lesions could be used to predict Salmonella contamination of swine carcasses and that a nonexpert processing-line assessment of lesions could be used to discriminate between healthy and chronically ill swine before their entry into the human food supply. PMID- 22204294 TI - Effects of phenylbutazone on gene expression of cyclooxygenase-1 and -2 in the oral, glandular gastric, and bladder mucosae of healthy horses. AB - OBJECTIVE: To assess gene expressions of cyclooxygenase-1 and -2 in oral, glandular gastric, and urinary bladder mucosae and determine the effect of oral administration of phenylbutazone on those gene expressions in horses. ANIMALS: 12 healthy horses. PROCEDURES: Horses were allocated to receive phenylbutazone or placebo (6 horses/group); 1 placebo-treated horse with a cystic calculus was subsequently removed from the study, and those data were not analyzed. In each horse, the stomach and urinary bladder were evaluated for ulceration via endoscopy before and after experimental treatment. Oral, glandular gastric, and urinary bladder mucosa biopsy specimens were collected by use of a skin punch biopsy instrument (oral) or transendoscopically (stomach and bladder) before and after administration of phenylbutazone (4.4 mg/kg, p.o., q 12 h) in corn syrup or placebo (corn syrup alone) for 7 days. Cyclooxygenase-1 and -2 gene expressions were determined (via quantitative PCR techniques) in specimens collected before and after the 7-day treatment period and compared within and between groups. Prior to commencement of treatment, biopsy specimens from 7 horses were used to compare gene expressions among tissues. RESULTS: The cyclooxygenase-1 gene was expressed in all tissues collected. The cyclooxygenase-2 gene was expressed in the glandular gastric and bladder mucosae but not in the oral mucosa. Cyclooxygenase gene expressions were unaffected by phenylbutazone administration. CONCLUSIONS AND CLINICAL RELEVANCE: Cyclooxygenase-2 was constitutively expressed in glandular gastric and bladder mucosae but not in the oral mucosa of healthy horses. Oral administration of phenylbutazone at the maximum recommended dosage daily for 7 days did not affect cyclooxygenase-1 or -2 gene expression. PMID- 22204295 TI - Morphometric features of the craniocervical junction region in dogs with suspected Chiari-like malformation determined by combined use of magnetic resonance imaging and computed tomography. AB - OBJECTIVE: To objectively describe morphometric features of the craniocervical junction region of Cavalier King Charles Spaniels (CKCSs) and non-CKCS dogs with suspected Chiari-like malformation (CLM) and identify associations between these features and the presence of other malformations in this region. ANIMALS: 216 CKCSs and 58 non-CKCS dogs. PROCEDURES: Magnetic resonance and computed tomographic images of the head and craniocervical junction region of patients evaluated because of suspected CLM were assessed for cerebellar compression (CC), ventral spinal cord compression at the C1-C2 articulation (medullary kinking), and dorsal spinal cord compression at the C1-C2 articulation (dorsal compression). A compression index was calculated for each of these 3 locations in each dog. Multiple logistic regression analysis was performed to determine whether breed (CKCS vs non-CKCS) and compression index values were associated with the presence of other craniocervical junction abnormalities. RESULTS: All 274 dogs had CC; medullary kinking was identified in 187 (68.2%) and dorsal compression was identified in 104 (38.0%). Atlantooccipital overlapping (AOO) was identified in 76 (27.7%) dogs. Breed of dog (CKCS vs non-CKCS) and value of CC index were the only significant predictors of AOO. The CKCSs had an almost 5-fold decrease in risk of AOO, compared with the non-CKCS dogs, and the risk of AOO nearly doubled for every 10% increase in CC index. CONCLUSIONS AND CLINICAL RELEVANCE: The anatomic abnormality responsible for CC was AOO in a substantial percentage of dogs suspected to have CLM. The CC index value may be used to help differentiate subtypes of craniocervical junction abnormalities in dogs. PMID- 22204296 TI - Evaluation of Clostridium novyi-NT spores in dogs with naturally occurring tumors. AB - OBJECTIVE: To establish the maximum tolerated dose of Clostridium novyi-NT spores in tumor-bearing dogs and evaluate spore germination within tumors and tumor response. ANIMALS: 6 client-owned dogs. PROCEDURES: A standard dose-escalation study was planned, with maximum tolerated dose defined as the highest dose at which 0 or 1 of 6 dogs had dose-limiting toxicoses (DLT). Dogs received 1 dose of C. novyi-NT spores i.v.. Toxicoses were graded and interventions performed according to specific guidelines. Grade 3 or higher toxicosis or any toxicosis combination that substantially affected patient status was considered DLT. Clinical response was measured by use of response evaluation criteria in solid tumors at 28 days. RESULTS: The first 2 dogs had DLT. The dose was decreased. Two of the next 4 dogs had DLT; therefore, dose administration was stopped because the study endpoint had been reached. The most common toxicosis was fever (n = 6 dogs). Two dogs developed abscesses (1 within a nasal carcinoma and 1 splenic abscess) attributable to C. novyi-NT infection; both required surgical intervention. Clostridium novyi-NT was cultured from 1 of 6 tumors. Five dogs were available for response assessment (4 had stable disease; 1 had progressive disease). CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that C. novyi-NT can germinate within tumors of dogs. Toxicosis, although common and sometimes severe, was manageable with treatment. Further studies in dogs with superficial tumors may allow for continued dose escalation and provide information for use in clinical trials in veterinary and human oncology. PMID- 22204297 TI - Assessment of plasma uracil-to-dihydrouracil concentration ratio as an indicator of dihydropyrimidine dehydrogenase activity in clinically normal dogs and dogs with neoplasia or renal insufficiency. AB - OBJECTIVE: To determine and compare the ratio of uracil (U) to dihydrouracil (UH(2)) concentrations in plasma as an indicator of dihydropyrimidine dehydrogenase activity in clinically normal dogs and dogs with neoplasia or renal insufficiency. ANIMALS: 101 client- and shelter-owned dogs. PROCEDURES: Study dogs included 74 clinically normal dogs, 17 dogs with neoplasia, and 10 dogs with renal insufficiency. For each dog, a blood sample was collected into an EDTA containing tube; plasma U and UH(2) concentrations were determined via UV high performance liquid chromatography, and the U:UH(2) concentration ratio was calculated. Data were compared among dogs grouped on the basis of sex, clinical group assignment, reproductive status (sexually intact, spayed, or castrated), and age. RESULTS: Mean +/- SEM U:UH(2) concentration ratio for all dogs was 1.55 +/- 0.08 (median, 1.38; range, 0.4 to 7.14). In 14 (13.9%) dogs, the U:UH(2) concentration ratio was considered abnormal (ie, > 2). Overall, mean ratio for sexually intact dogs was significantly higher than that for neutered dogs; a similar difference was apparent among males but not females. Dogs with ratios > 2 and dogs with ratios <= 2 did not differ significantly with regard to sex, clinical group, reproductive status, or age. CONCLUSIONS AND CLINICAL RELEVANCE: Determination of the U:UH(2) concentration ratio was easy to perform. Ratios were variable among dogs, possibly suggesting differences in dihydropyrimidine dehydrogenase activity. However, studies correlating U:UH(2) concentration ratio and fluoropyrimidine antimetabolite drug tolerability are required to further evaluate the test's validity and its appropriate use in dogs. PMID- 22204298 TI - Effect of submaximal aerobic exercise on platelet function, platelet activation, and secondary and tertiary hemostasis in dogs. AB - OBJECTIVE: To investigate whether submaximal aerobic exercise in dogs is followed by activation of all phases of coagulation as has been reported for humans. ANIMALS: 9 healthy Beagles. PROCEDURES: 30 minutes before dogs were exercised, a 16-gauge central venous catheter was placed in a jugular vein of each dog by use of the catheter-through-the-needle technique. Samples were collected before exercise, after running on a treadmill (6 km/h for 13 minutes), and at 60 minutes. Platelet activation was evaluated with platelet morphology indices (mean platelet component, mean platelet volume, and number of large platelets) provided by a laser-based hematology system. Platelet function was assessed in hirudin anticoagulated whole blood with an impedance-based aggregometer with collagen as the agonist (final concentrations, 0, 1.6, 3.2, 5, and 10 MUg/mL). Prothrombin time, activated partial thromboplastin time, and concentrations of fibrinogen, factor VIII, antithrombin, protein C, protein S, and fibrin D-dimer were determined automatically. Kaolin-activated thromboelastography variables R (reaction time), K (clot formation time), angle alpha, maximal amplitude, and G (clot stability) were measured in recalcified citrated whole blood. RESULTS: Exercise resulted in a significant decrease in mean platelet volume and the number of large platelets but did not change the mean platelet component, which reflected platelet activation as well as platelet function. Secondary and tertiary coagulation did not change significantly, nor did thromboelastography variables. CONCLUSIONS AND CLINICAL RELEVANCE: Aerobic exercise resulted in a decrease in the number of large and thus most likely activated platelets but otherwise had no major impact on coagulation in dogs. PMID- 22204299 TI - Effects of tidal volume, ventilatory frequency, and oxygen insufflation flow on the fraction of inspired oxygen in cadaveric horse heads attached to a lung model. AB - OBJECTIVE: To measure the effects of tidal volume, ventilatory frequency, and oxygen insufflation flow on the fraction of inspired oxygen in cadaveric horse heads attached to a lung model. SAMPLE: 8 heads of equine cadavers. PROCEDURES: Each cadaveric horse head was intubated with a nasotracheal tube that extended into the proximal portion of the trachea. Oxygen was delivered through an oxygen catheter contained within and extending to the tip of the nasotracheal tube. The trachea was connected to the lung model by use of a spiral-wound hose with a sampling adaptor. Eight treatment combinations involving 2 tidal volumes (5 and 8 L), 2 ventilatory frequencies (6 and 12 mechanical breathes/min), and 2 insufflation rates (10 and 15 L/min) were applied to each head. Hand-drawn inspired gas samples were collected and analyzed for oxygen concentrations. RESULTS: The fraction of inspired oxygen (measured at mid trachea) ranged from 26.8% to 39.4%. Fraction of inspired oxygen was significantly higher with a smaller tidal volume, lower ventilatory frequency, and higher insufflation rate. CONCLUSIONS AND CLINICAL RELEVANCE: In the study model, measured fraction of inspired oxygen varied with ventilatory pattern as well as oxygen insufflation rate. Clinically, this information could be beneficial for interpretation of data regarding arterial blood gases and hemoglobin saturation and in making appropriate oxygen insufflation decisions for anesthetized horses that are breathing room air. PMID- 22204300 TI - Effect of prolonged administration of clenbuterol on airway reactivity and sweating in horses with inflammatory airway disease. AB - OBJECTIVE: To determine whether prolonged administration of clenbuterol results in tachyphylaxis, specifically regarding its bronchoprotective properties and effect on sweating in horses. ANIMALS: 8 Thoroughbreds with inflammatory airway disease. PROCEDURES: In a crossover design, horses received clenbuterol (0.8 MUg/kg, p.o., q 12 h) or placebo for 21 days, with a washout period of >= 30 days between the 2 treatments. Airway reactivity was evaluated by use of flowmetric plethysmography and histamine broncho-provocation before (day 0; baseline) and every 7 days after the start of treatment. Sweat function was evaluated via response to epinephrine administered ID before and every 10 days after the start of treatment. RESULTS: The concentration of histamine required to increase total airway obstruction by 35% (PC35) was significantly reduced during treatment with clenbuterol (mean change, 11.5 mg/mL), compared with during administration of the placebo (mean change, -1.56 mg/mL), with a peak effect at 14 days. Tachyphylaxis was evident by day 21, with 7 of 8 horses having a PC35 below the baseline value (mean change, -0.48 mg/mL), which returned to baseline values during the washout period. No effect of clenbuterol was seen in sweat response to epinephrine administration. CONCLUSIONS AND CLINICAL RELEVANCE: Clenbuterol initially reduced airway sensitivity to inhaled histamine, but tachyphylaxis that resulted in increased airway reactivity was evident by day 21. Although no effects on sweating were detected, the technique may not have been sensitive enough to identify subtle changes. Prolonged administration of clenbuterol likely results in a clinically important reduction in its bronchodilatory effects. PMID- 22204301 TI - Respiratory mechanics and results of cytologic examination of bronchoalveolar lavage fluid in healthy adult alpacas. AB - OBJECTIVE: To evaluate respiratory mechanical function and bronchoalveolar lavage (BAL) cytologic results in healthy alpacas. ANIMALS: 16 client-owned adult alpacas. PROCEDURES: Measurements of pulmonary function were performed, including functional residual capacity (FRC) via helium dilution, respiratory system resistance via forced oscillatory technique (FOT), and assessment of breathing pattern by use of respiratory inductive plethysmography (RIP) in standing and sternally recumbent alpacas. Bronchoalveolar lavage was performed orotracheally during short-term anesthesia. RESULTS: Mean +/- SD measurements of respiratory function were obtained in standing alpacas for FRC (3.19 +/- 0.53 L), tidal volume (0.8 +/- 0.13 L), and respiratory system resistance at 1 Hz (2.70 +/- 0.88 cm H(2)O/L/s), 2 Hz (2.98 +/- 0.70 cm H(2)O/L/s), 3 Hz (3.14 +/- 0.77 cm H(2)O/L/s), 5 Hz (3.45 +/- 0.91 cm H(2)O/L/s), and 7 Hz (3.84 +/- 0.93 cm H(2)O/L/s). Mean phase angle, as a measurement of thoracoabdominal asynchrony, was 19.59 +/- 10.06 degrees , and mean difference between nasal and plethysmographic flow measurements was 0.18 +/- 0.07 L/s. Tidal volume, peak inspiratory flow, and peak expiratory flow were significantly higher in sternally recumbent alpacas than in standing alpacas. Cytologic examination of BAL fluid revealed 58.52 +/- 12.36% alveolar macrophages, 30.53 +/- 13.78% lymphocytes, 10.95 +/- 9.29% neutrophils, 0% mast cells, and several ciliated epithelial cells. CONCLUSIONS AND CLINICAL RELEVANCE: Pulmonary function testing was tolerated well in nonsedated untrained alpacas. Bronchoalveolar lavage in alpacas yielded samples with adequate cellularity that had a greater abundance of neutrophils than has been reported in horses. PMID- 22204302 TI - Comparison of equine tendon- and bone marrow-derived cells cultured on tendon matrix with or without insulin-like growth factor-I supplementation. AB - OBJECTIVE: To compare in vitro expansion, explant colonization, and matrix synthesis of equine tendon- and bone marrow-derived cells in response to insulin like growth factor-I (IGF-I) supplementation. SAMPLE: Cells isolated from 7 young adult horses. PROCEDURES: Tendon- and bone marrow-derived progenitor cells were isolated, evaluated for yield, and cultured on autogenous cell-free tendon matrix for 7 days. Samples were analyzed for cell viability and expression of collagen type I, collagen type III, and cartilage oligomeric matrix protein mRNAs. Collagen and glycosaminoglycan syntheses were quantified over a 24-hour period. RESULTS: Tendon- and bone marrow-derived cells required 17 to 19 days of monolayer culture to reach 2 passages. Mean +/- SE number of monolayer cells isolated was higher for tendon-derived cells (7.9 +/- 0.9 * 10(6)) than for bone marrow-derived cells (1.2 +/- 0.1 * 10(6)). Cell numbers after culture for 7 days on acellular tendon matrix were 1.6- to 2.8-fold higher for tendon-derived cells than for bone marrow-derived cells and 0.8- to 1.7-fold higher for IGF-I supplementation than for untreated cells. New collagen and glycosaminoglycan syntheses were significantly greater in tendon-derived cell groups and in IGF-I supplemented groups. The mRNA concentrations of collagen type I, collagen type III, and cartilage oligomeric matrix protein were not significantly different between tendon- and bone marrow-derived groups. CONCLUSIONS AND CLINICAL RELEVANCE: In vitro results of this study suggested that tendon-derived cells supplemented with IGF-I may offer a useful resource for cell-based strategies in tendon healing. PMID- 22204303 TI - Responses of equine tendon- and bone marrow-derived cells to monolayer expansion with fibroblast growth factor-2 and sequential culture with pulverized tendon and insulin-like growth factor-I. AB - OBJECTIVE: To compare in vitro expansion of equine tendon- and bone marrow derived cells with fibroblast growth factor-2 (FGF-2) supplementation and sequential matrix synthesis with pulverized tendon and insulin-like growth factor I (IGF-I). SAMPLE: Cells from 6 young adult horses. PROCEDURES: Progenitor cells were expanded in monolayers with FGF-2, followed by culture with autogenous acellular pulverized tendon and IGF-I for 7 days. Initial cell isolation and subsequent monolayer proliferation were assessed. In pulverized tendon cultures, cell viability and expression of collagen types I and III and cartilage oligomeric matrix protein (COMP) mRNAs were assessed. Collagen and glycosaminoglycan syntheses were quantified over a 24-hour period. RESULTS: Monolayer expansion with FGF-2 significantly increased the mean +/- SE number of tendon-derived cells (15.3 +/- 2.6 * 10(6)), compared with bone marrow-derived cells (5.8 +/- 1.8 * 10(6)). Overall, increases in collagen type III and COMP mRNAs were seen in tendon-derived cells, compared with results for bone marrow derived cells. After IGF-I supplementation, increases in collagen type I and type III mRNA expression were seen in bone marrow-derived cells, compared with results for unsupplemented control cells. Insulin-like growth factor-I significantly increased collagen synthesis of bone marrow-derived cells. Monolayer expansion with FGF-2 followed by IGF-I supplementation significantly increased glycosaminoglycan synthesis in tendon-derived cells. CONCLUSIONS AND CLINICAL RELEVANCE: Tendon-derived cells had increased cell numbers and matrix synthesis after monolayer expansion with FGF-2, compared with results for bone marrow derived cells. In vivo experiments with FGF-2-expanded tendon-derived cells are warranted to evaluate effects on tendon healing. PMID- 22204305 TI - Genomics in 2011: challenges and opportunities. AB - As we come to the end of 2011, Genome Biology has asked some members of our Editorial Board for their views on the state of play in genomics. What was their favorite paper of 2011? What are the challenges in their particular research area? Who has had the biggest influence on their careers? What advice would they give to young researchers embarking on a career in research? PMID- 22204304 TI - Transgenic neuronal overexpression reveals that stringently regulated p23 expression is critical for coordinated movement in mice. AB - BACKGROUND: p23 belongs to the highly conserved p24 family of type I transmembrane proteins, which participate in the bidirectional protein transport between the endoplasmic reticulum and Golgi apparatus. Mammalian p23 has been shown to interact with gamma-secretase complex, and modulate secretory trafficking as well as intramembranous processing of amyloid precursor protein in cultured cells. Negative modulation of beta-amyloid production by p23 in cultured cell lines suggested that elevation of p23 expression in neurons might mitigate cerebral amyloid burden. RESULTS: We generated several lines of transgenic mice expressing human p23 in neurons under the control of Thy-1.2 promoter. We found that even a 50% increase in p23 levels in the central nervous system of mice causes post-natal growth retardation, severe neurological problems characterized by tremors, seizure, ataxia, and uncoordinated movements, and premature death. The severity of the phenotype closely correlated with the level of p23 overexpression in multiple transgenic lines. While the number and general morphology of neurons in Hup23 mice appeared to be normal throughout the brain, abnormal non-Golgi p23 localization was observed in a subset of neurons with high transgene expression in brainstem. Moreover, detailed immunofluorescence analysis revealed marked proliferation of astrocytes, activation of microglia, and thinning of myelinated bundles in brainstem of Hup23 mice. CONCLUSIONS: These results demonstrate that proper level of p23 expression is critical for neuronal function, and perturbing p23 function by overexpression initiates a cascade of cellular reactions in brainstem that leads to severe motor deficits and other neurological problems, which culminate in premature death. The neurological phenotype observed in Hup23 mice highlights significant adverse effects associated with manipulating neuronal expression of p23, a previously described negative modulator of gamma-secretase activity and beta-amyloid production. Moreover, our report has broader relevance to molecular mechanisms in several neurodegenerative diseases as it highlights the inherent vulnerability of the early secretory pathway mechanisms that ensure proteostasis in neurons. PMID- 22204306 TI - Development and characterization of phyto-vesicles of wedelolactone for hepatoprotective activity. AB - Wedelolactone is isolated from the dried leaves of Eclipta alba (L.) and reported to be effective as a potential hepatoprotective, antibacterial and anti hemorrhagic. Pharmacokinetic studies of wedelolactone reveal its poor absorption through the intestine. The objective of the present study is to enhance bioavailability of wedelolactone by its complexation with phosphatidyl choline and then formulating it as phyto-vesicles for hepatoprotective activity. The complex of wedelolactone rich fraction was prepared with phosphatidyl choline and characterized on the basis of solubility, melting point, thin layer chromatography (TLC), UV, IR and NMR spectroscopy. The complex was further converted into phyto-vesicles and characterized. The hepatoprotective potential of phyto-vesicles was compared with complex, wedelolactone rich fraction and physical mixture of wedelolactone rich fraction and phosphatidyl choline by in vitro method. The results revealed that hepatoprotective activity is better in case of phyto-vesicles as compared to the complex, physical mixture and the wedelolactone itself. Enhanced bioavailability of the wedelolactone complex may be due to the amphiphillic nature of the complex, which greatly enhance the water and lipid solubility of the compound. The present study clearly indicates the superiority of phyto-vesicles over the complex and wedelolactone, in terms of better absorption and improved hepatoprotective activity. PMID- 22204307 TI - The signaling pathway of Campylobacter jejuni-induced Cdc42 activation: Role of fibronectin, integrin beta1, tyrosine kinases and guanine exchange factor Vav2. AB - BACKGROUND: Host cell invasion by the foodborne pathogen Campylobacter jejuni is considered as one of the primary reasons of gut tissue damage, however, mechanisms and key factors involved in this process are widely unclear. It was reported that small Rho GTPases, including Cdc42, are activated and play a role during invasion, but the involved signaling cascades remained unknown. Here we utilised knockout cell lines derived from fibronectin-/-, integrin-beta1-/-, focal adhesion kinase (FAK)-/- and Src/Yes/Fyn-/- deficient mice, and wild-type control cells, to investigate C. jejuni-induced mechanisms leading to Cdc42 activation and bacterial uptake. RESULTS: Using high-resolution scanning electron microscopy, GTPase pulldowns, G-Lisa and gentamicin protection assays we found that each studied host factor is necessary for induction of Cdc42-GTP and efficient invasion. Interestingly, filopodia formation and associated membrane dynamics linked to invasion were only seen during infection of wild-type but not in knockout cells. Infection of cells stably expressing integrin-beta1 variants with well-known defects in fibronectin fibril formation or FAK signaling also exhibited severe deficiencies in Cdc42 activation and bacterial invasion. We further demonstrated that infection of wild-type cells induces increasing amounts of phosphorylated FAK and growth factor receptors (EGFR and PDGFR) during the course of infection, correlating with accumulating Cdc42-GTP levels and C. jejuni invasion over time. In studies using pharmacological inhibitors, silencing RNA (siRNA) and dominant-negative expression constructs, EGFR, PDGFR and PI3-kinase appeared to represent other crucial components upstream of Cdc42 and invasion. siRNA and the use of Vav1/2-/- knockout cells further showed that the guanine exchange factor Vav2 is required for Cdc42 activation and maximal bacterial invasion. Overexpression of certain mutant constructs indicated that Vav2 is a linker molecule between Cdc42 and activated EGFR/PDGFR/PI3-kinase. Using C. jejuni mutant strains we further demonstrated that the fibronectin-binding protein CadF and intact flagella are involved in Cdc42-GTP induction, indicating that the bacteria may directly target the fibronectin/integrin complex for inducing signaling leading to its host cell entry. CONCLUSION: Collectively, our findings led us propose that C. jejuni infection triggers a novel fibronectin >integrin-beta1->FAK/Src->EGFR/PDGFR->PI3-kinase->Vav2 signaling cascade, which plays a crucial role for Cdc42 GTPase activity associated with filopodia formation and enhances bacterial invasion. PMID- 22204308 TI - Lifetime economic burden of prostate cancer. AB - BACKGROUND: Prostate cancer (PCa) is the most common cancer affecting men in the United States. The initial treatment and subsequent monitoring of PCa patients places a large burden on U.S. health care systems. The objectives of this study were to estimate the total and disease-related per-patient lifetime costs using a phase-based model of cancer care for PCa patients enrolled in Medicare. METHODS: A model was developed to estimate life-time costs for patients diagnosed with PCa. Patients >= 65 years old and diagnosed with PCa between calendar years 1991 2002 were selected from the SEER database. Using SEER, we estimated survival times for PCa patients from diagnosis until death. The period of time patients contributed to treatment phases was determined using an algorithm designed to model the natural history of PCa. Costs were obtained from the US SEER-Medicare database and estimated during specific phases of care. Cost estimates were then combined with survival data to yield total and PCa-related life-time costs. RESULTS: Overall, the model estimated life-time costs of $110,520 (95% CI 110,324 110,739) per patient. PCa-related costs made up approximately 31% of total costs ($34,432). CONCLUSIONS: Prostate cancer places a significant burden on U.S. health-care systems with average life-time PCa-related costs in excess of $30,000. PMID- 22204309 TI - Impact of acute stress on antimicrobial polypeptides mRNA copy number in several tissues of marine sea bass (Dicentrarchus labrax). AB - BACKGROUND: In comparison to higher vertebrates, fish are thought to rely heavily on innate immune system for initial protection against pathogen invasion because their acquired immune system displays a considerably poor immunological memory, and short-lived secondary response. The endogenous antimicrobial polypeptides (AMPPs) directly and rapidly killing pathogens such as bacteria, fungi, parasites, and viruses are included within the realm of innate defenses. In addition to piscidins, AMPPs that in recent years have been shown to be commonly linked to innate defense, are histones and their polypeptide fragments, and peptides derived from the respiratory protein hemoglobin. There is evidence that a number of stresses lead to significant regulation of AMPPs and thus their monitoring could be a highly sensitive measure of health status and risk of an infectious disease outbreak, which is a major impediment to the continued success of virtually all aquaculture enterprises and is often the most significant cause of economic losses. RESULTS: We firstly isolated and deposited in Genbank database the cDNA sequences encoding for hemoglobin-beta-like protein (Hb-LP) [GeneBank: JN410659], H2B histone-like protein 1 (HLP1) GenBank: JN410660], and HLP2 [GenBank: JN410661]. The "de novo" prediction of the three-dimensional structures for each protein is presented. Phylogenetic trees were constructed on Hb-LP, HLP1, and HLP2 sequences of sea bass and those of other teleost, avian, reptiles, amphibian and mammalian species. We then used real time RT-PCR technology to monitor for the first time in sea bass, dynamic changes in mRNA copy number of Hb-LP, HLP1, HLP2, and dicentracin in gills, skin, eyes, stomach and proximal intestine in response to acute crowding/confinement stress. We showed that acute crowding stress induces an increase in the expression levels of the aforementioned genes, in gills and skin of sea bass, but not in other tissues, and that this expression patterns are not always rapidly reversed upon re-exposure to normal conditions. CONCLUSION: The higher expression of the four target genes in gills and skin of sea bass suggests that this AMPP represents a first and immediate line of defense in combating pathogens and stressors since these tissues constitute the first physiological barriers of the animal. PMID- 22204310 TI - Orf virus DNA vaccines expressing ORFV 011 and ORFV 059 chimeric protein enhances immunogenicity. AB - BACKGROUND: ORFV attenuated live vaccines have been the main prophylactic measure against contagious ecthyma in sheep and goats in the last decades, which play an important role in preventing the outbreak of the disease. However, the available vaccines do not induce lasting immunity in sheep and goats. On the other hand, variation in the terminal genome of Orf virus vaccine strains during cell culture adaptation may affect the efficacy of a vaccine. Currently, there are no more effective antiviral treatments available for contagious ecthyma. RESULTS: We constructed three eukaryotic expression vectors pcDNA3.1-ORFV011, pcDNA3.1 ORFV059 and pcDNA3.1-ORFV011/ORFV059 and tested their immunogenicity in mouse model. High level expression of the recombinant proteins ORFV011, ORFV059 and ORFV011/ORFV059 was confirmed by western blotting analysis and indirect fluorescence antibody (IFA) tests. The ORFV-specific antibody titers and serum IgG1/IgG2a titers, the proliferation of lymphocytes and ORFV-specific cytokines (IL-2, IL-4, IL-6, IFN-gamma, and TNF-alpha) were examined to evaluate the immune responses of the vaccinated mice. We found that mice inoculated with pcDNA3.1 ORFV 011/ORFV059 had significantly stronger immunological responses than those inoculated with pcDNA3.1-ORFV011, pcDNA3.1-ORFV059, or pcDNA3.1-ORFV011 plus pcDNA3.1-ORFV059. Compared to other vaccine plasmids immunized groups, pcDNA3.1 ORFV011/ORFV059 immunized group enhances immunogenicity. CONCLUSIONS: We concluded that DNA vaccine pcDNA3.1-ORFV011/ORFV059 expressing ORFV011 and ORFV059 chemeric-proteins can significantly improve the potency of DNA vaccination and could be served as more effective and safe approach for new vaccines against ORFV. PMID- 22204311 TI - Comparison of percutaneous radiofrequency thermal ablation and surgical resection for small hepatocellular carcinoma. AB - BACKGROUND: The purpose of this investigation was to compare the outcome of percutaneous radiofrequency thermal ablation therapy (PRFA) with surgical resection (SR) in the treatment of single and small hepatocellular carcinoma (HCC). METHODS: We conducted a retrospective cohort study on 231 treatment naive patients with a single HCC <= 3 cm who had received either curative PRFA (162 patients) or curative SR (69 patients). All patients were regularly followed up after treatment at our department with blood and radiologic tests. RESULTS: The 1 , 3- and 5-year overall survival rates after PRFA and SR were 95.4%, 79.6% and 63.1%, respectively in the PRFA group and 100%, 81.4% and 74.6%, respectively in the SR group. The corresponding recurrence free survival rates at 1, 3 and 5 years after PRFA and SR were 82.0%, 38.3% and 18.0%, respectively in the PRFA group and 86.0%, 47.2% and 26.0%, respectively in the SR group. In terms of overall survival and recurrence free survival, there were no significant differences between these two groups. In comparison of PRFA group patients with liver cirrhosis (LC) (n = 127) and SR group patients with LC (n = 50) and in comparison of PRFA group patients without LC (n = 35) and SR group patients without LC (n = 19), there were also no significant differences between two groups in terms of overall survival and recurrence free survival. In the multivariate analysis of the risk factors contributing to overall survival, serum albumin level was the sole significant factor. In the multivariate analysis of the risk factors contributing to recurrence free survival, presence of LC was the sole significant factor. The rate of serious adverse events in the SR group was significantly higher than that in the PRFA group (P = 0.023). Hospitalization length in the SR group was significantly longer than in the PRFA group (P = 0.013). CONCLUSIONS: PRFA is as effective as SR in the treatment of single and small HCC, and is less invasive than SR. Therefore, PRFA could be a first choice for the treatment of single and small HCC. PMID- 22204312 TI - The effectiveness of screening and brief intervention on reducing driving while intoxicated citations. AB - The purpose of this study was to use retrospective data, including citations for driving while intoxicated (DWI), to assess the long-term effectiveness of a program consisting of Screening and Brief Intervention (SBI) for at-risk alcohol users and its impact on traffic safety. A second objective was to study ethnic differences in response to SBI. During the time period of 1998-1999, LCF Research, together with the Lovelace Health System, participated in the Cutting Back SBI study for at-risk drinkers. A total of 426 subjects exhibiting at-risk drinking behaviors from the New Mexico cohort were examined for the study, including 211 subjects who received a brief counseling intervention and 215 in the no intervention control group. This study examined DWI citations for all 426 subjects during the 5 years following the Cutting Back study. The brief interventions were shown to have had a significant impact on reducing DWI citations for at-risk drinkers, with the added benefit lasting for the 5-year duration of the study. The SBI was found to be most effective at reducing DWI citations for Hispanic at-risk drinkers. Evidence is presented to show that screening to identify at-risk drinkers followed by a brief intervention has a statistically significant lasting impact on improving traffic safety. PMID- 22204313 TI - Uptake of prevention of mother to child transmission interventions in Kenya: health systems are more influential than stigma. AB - BACKGROUND: We set out to determine the relative roles of stigma versus health systems in non-uptake of prevention of mother to child transmission (PMTCT) of HIV-1 interventions: we conducted cross-sectional assessment of all consenting mothers accompanying infants for six-week immunizations. METHODS: Between September 2008 and March 2009, mothers at six maternal and child health clinics in Kenya's Nairobi and Nyanza provinces were interviewed regarding PMTCT intervention uptake during recent pregnancy. Stigma was ascertained using a previously published standardized questionnaire and infant HIV-1 status determined by HIV-1 polymerase chain reaction. RESULTS: Among 2663 mothers, 2453 (92.1%) reported antenatal HIV-1 testing. Untested mothers were more likely to have less than secondary education (85.2% vs. 74.9%, p=0.001), be from Nyanza (47.1% vs. 32.2%, p<0.001) and have lower socio-economic status. Among 318 HIV-1 infected mothers, 90% reported use of maternal or infant antiretrovirals. Facility delivery was less common among HIV-1-infected mothers (69% vs. 76%, p=0.009) and was associated with antiretroviral use (p<0.001). Although internal or external stigma indicators were reported by between 12% and 59% of women, stigma was not associated with lower HIV-1 testing or infant HIV-1 infection rates; internal stigma was associated with modestly decreased antiretroviral uptake. Health system factors contributed to about 60% of non-testing among mothers who attended antenatal clinics and to missed opportunities in offering antiretrovirals and utilization of facility delivery. Eight percent of six-week old HIV-1-exposed infants were HIV-1 infected. CONCLUSIONS: Antenatal HIV-1 testing and antiretroviral uptake was high (both more than 90%) and infant HIV-1 infection risk was low, reflecting high PMTCT coverage. Investment in health systems to deliver HIV-1 testing and antiretrovirals can effectively prevent infant HIV-1 infection despite substantial HIV-1 stigma. PMID- 22204314 TI - New mechanisms of neuronal injury and neuroprotection. PMID- 22204315 TI - Protein degradation pathways after brain ischemia. AB - There are two major routes for clearance of aberrant cellular components: (i) the ubiquitin-proteasomal system (UPS); and (ii) the autophagy pathway. The UPS degrades individual abnormal proteins, whereas the autophagy pathway is the chief route for bulk degradation of large abnormal protein aggregates and aberrant organelles. Impairments of the protein degradation pathways are closely tied with many human diseases. Brain ischemia leads to protein misfolding and aggregation, resulting in overproduction of protein aggregate-associated organelles. Brain ischemia also damages protein degradation pathways. This chapter will discuss molecular mechanisms underlying the impairments of the UPS and autophagy pathways and how such impairments lead to multiple organelle failure and delayed neuronal death after brain ischemia. PMID- 22204316 TI - Roles of chemokine CXCL12 and its receptors in ischemic stroke. AB - Chemokine CXC ligand 12 (CXCL12), originally named stromal cell-derived factor-1 (SDF-1), is a member of the CXC chemokine subfamily. CXCL12 is found to be expressed by all cell types that are presented in the central nervous system (CNS). It works in conjunction with the G-protein coupled receptor CXCR4, which is found at the surface of a variety of cells including neurons, astrocytes, microglia, bone marrow-derived cells, as well as other progenitor cells. Recent studies revealed that CXCL12 could also bind and signal through receptor CXCR7. CXCL12 and CXCR4 are constitutively expressed in the brain but are up-regulated in the ischemic penumbra regions following ischemic stroke. CXCL12/CXCR4 play important roles in multiple processes after ischemic stroke, which include inflammatory response, focal angiogenesis, and the recruitment of bone marrow derived cells (BMCs) and neural progenitor cell (NPC) to injury. In addition to its roles in stroke pathology, CXCL12 is also thought to be a key regulator in stroke repairing. This review will focus on the function of CXCL12/CXCR4 in post stroke inflammation and neurovascular repairing. The potential application of CXCL12 modulation in clinical stroke treatment is also discussed. PMID- 22204318 TI - Estrogen, neuroprotection and neurogenesis after ischemic stroke. AB - Stroke is the third most common cause of death, particularly of the elderly. Despite considerable advances in knowledge about the mechanisms of cell death after stroke, a treatment for stroke remains exclusive. For a long time, estrogen was thought of only as a "sex hormone". Studies have documented that estrogen plays an important role in regulating behavioral and physiological events beyond the reproductive system. Most animal studies have shown that estrogens exert neuroprotective and neurogenesis effects in vivo and in vitro after ischemic stroke. However, clinical and epidemiological evidence shows that estrogen increases the risk of coronary heart disease, stroke, and breast cancer. The discrepancy between animal studies and clinical data emphasizes the importance of performing further investigations using appropriate animal models, and gaining a deeper understanding of the mechanisms of estrogen-mediated neuroprotection and neurogenesis. This review focuses on recent advances in estrogen-mediated neuroprotection and neurogenesis after ischemic stroke, highlighting its potential molecular and cellular mechanisms. PMID- 22204319 TI - NOX inhibitors as a therapeutic strategy for stroke and neurodegenerative disease. AB - NADPH oxidase was originally identified in immune cells as playing an important microbicidal role. In neurodegenerative and cerebrovascular diseases, inflammation is increasingly being recognized as contributing negatively to neurological outcome, with NADPH-oxidase as an important source of superoxide. Recently, several forms of this oxidase have been found in a variety of non immune cells. Neuronal NADPH oxidase is thought to participate in longterm potentiation and intercellular signaling. However, excessive superoxide production is damaging and has been shown to play an important role in the progression of brain injury. NADPH oxidase is a multisubunit complex composed of membrane-associated gp91(phox) and p22(phox) subunits and cytosolic subunits, p47(phox), p67(phox), and p40(phox) and Rac. When NADPH oxidase is activated through phosphorylatoin of p47(phox), cytosolic subunits translocate to the cell membrane and fuse with the catalytic subunit, gp91(phox). The activated enzyme complex transports electrons to oxygen, thus producing the superoxide anion (O2 ), a precursor of reactive oxygen species. The advantage of a targeted NADPH oxidase inhibitor that would inhibit the production of superoxide non-phagocytic cells is clear. To date no such therapeutically viable inhibitor exists but recent research using current inhibitors has enhanced our knowledge of the role of NADPH oxidase in CNS diseases and provides impetus to develop a very specific, potent and safe NADPH oxidase inhibitor. PMID- 22204317 TI - From rapid to delayed and remote postconditioning: the evolving concept of ischemic postconditioning in brain ischemia. AB - Ischemic postconditioning is a concept originally defined to contrast with that of ischemic preconditioning. While both preconditioning and postconditioning confer a neuroprotective effect on brain ischemia, preconditioning is a sublethal insult performed in advance of brain ischemia, and postconditioning, which conventionally refers to a series of brief occlusions and reperfusions of the blood vessels, is conducted after ischemia/reperfusion. In this article, we first briefly review the history of preconditioning, including the experimentation that initially uncovered its neuroprotective effects and later revealed its underlying mechanisms-of-action. We then discuss how preconditioning research evolved into that of postconditioning--a concept that now represents a broad range of stimuli or triggers, including delayed postconditioning, pharmacological postconditioning, remote postconditioning--and its underlying protective mechanisms involving the Akt, MAPK, PKC and K(ATP) channel cell-signaling pathways. Because the concept of postconditioning is so closely associated with that of preconditioning, and both share some common protective mechanisms, we also discuss whether a combination of preconditioning and postconditioning offers greater protection than preconditioning or postconditioning alone. PMID- 22204320 TI - Functional roles of synaptic and extrasynaptic NMDA receptors in physiological and pathological neuronal activities. AB - The N-methyl-D-aspartate (NMDA) receptor is a major type of ionotropic glutamate receptor. Many studies have shown that NMDA receptors play a pivotal role in the central nervous system (CNS) under both physiological and pathological conditions. The functional diversity of NMDA receptors can be mainly attributed to their different subunit compositions that perform multiple functions in various situations. Furthermore, recent reports have indicated that synaptic and extrasynaptic NMDA receptors have distinct compositions and couple with different signaling pathways: while synaptic NMDA receptors tend to promote cell survival, extrasynaptic NMDA receptors promote cell death. Currently, intensive efforts are being made to study the pathological role of extrasynaptic NMDA receptors in order to find a more effective approach for the treatment of neurologic disorders. Here we reviewed some recent progress on the participation of synaptic and extrasynaptic NMDA receptors in neurologic diseases including epilepsy, ischemia, schizophrenia, depression and some neurodegenerative diseases. PMID- 22204321 TI - NAD+ metabolism and NAD(+)-dependent enzymes: promising therapeutic targets for neurological diseases. AB - Numerous studies have indicated that four interacting factors, including oxidative stress, mitochondrial alterations, calcium dyshomeostasis and inflammation, play crucial pathological roles in multiple major neurological diseases, including stroke, Alzheimer's disease (AD) and Parkinson's disease (PD). Increasing evidence has also indicated that NAD(+) plays important roles in not only mitochondrial functions and energy metabolism, but also calcium homeostasis and inflammation. The key NAD(+)-consuming enzyme--poly(ADP-ribose) polymerase-1 (PARP-1) and sirtuins--have also been shown to play important roles in cell death and aging, which are two key factors in the pathology of multiple major age-dependent neurological diseases: PARP-1 plays critical roles in both inflammation and oxidative stress-induced cell death; and sirtuins also mediate the process of aging, cell death and inflammation. Thus, it is conceivable that increasing evidence has suggested that NAD(+) metabolism and NAD(+)-dependent enzymes are promising targets for treating a number of neurological illnesses. For examples, the key NAD(+)-dependent enzymes SIRT1 and SIRT2 have been indicated to strongly affect the pathological changes of PD and AD; PARP-1 inhibition can profoundly reduce the brain injury in the animal models of multiple neurological diseases; and administration of either NAD(+) or nicotinamide can also decrease ischemic brain damage. Future studies are necessary to further investigate the roles of NAD+ metabolism and NAD+-dependent enzymes in neurological diseases, which may expose novel targets for treating the debilitating illnesses. PMID- 22204323 TI - Mechanisms of neuronal damage and neuroprotection underlying ischemia/reperfusion injury after physical exercise. AB - The effects of exercise pre-conditioning on lessening the impact of ischemia/reperfusion injury provide pivotal information and potential targets for future pharmacological intervention. Exercise induces increased expression of neurotrophic factors, the extracellular matrix (ECM) proteins, integrins, angiogenic factors, as well as tumor necrosis factor (TNF-alpha) and heat shock proteins (Hsp-70). These factors all directly enhance the neurovascular unit and alleviate the harmful effects following ischemia/reperfusion injury. Furthermore, pre-conditioning decreases expression of matrix metalloproteinase (MMP-9) and Toll-like receptor-4, which ameliorates the inflammatory response and apoptosis following ischemic insult. Perhaps most importantly, exercise pre-conditioning shows a propensity to simultaneously favor cell survival mechanisms and inhibit apoptotic pathways via interactions between TNF-alpha and Hsp-70, which are regulated by extracellular signal-regulated kinases-1 and -2 (ERK1/2). Finally, chronic exercise preconditioning increases cerebral metabolism, effectively enhancing the neuronal response to increase ATP production following periods of hypoxia. The purpose of this review is to demonstrate the various effects of exercise pre-conditioning on the neural response to ischemia/reperfusion injury as a means of demonstrating potential targets for prevention and treatment of acute ischemic events. PMID- 22204325 TI - Value of carnitine therapy in kidney dialysis patients and effects on cardiac function from human and animal studies. AB - Cardiovascular complications are the leading cause of mortality, accounting for 50% of all deaths among patients with end-stage renal disease (ESRD). The majority of these deaths are from cardiac causes. The mechanisms underlying the enhanced susceptibility to myocardial ischaemia and subsequent morbidity in ESRD remain ill-defined. Numerous metabolic derangements accompany myocardial ischaemia and reperfusion and play a pivotal role in the development of concurrent myocardial dysfunction. Carnitine plays a critical role in myocardial energy metabolism, as the transporter of long chain fatty acyl intermediates across the inner mitochondrial membrane for beta oxidation and as a central regulator of carbohydrate metabolism. Myocardial carnitine is significantly depleted during ischaemia and more particularly in uraemic patients and those on dialysis therapy. Carnitine treatment has cardiovascular benefits including modulation of myocardial metabolism, reduction in necrotic cell death and infarct size, decrease in the incidence of arrhythmias and preservation of mechanical function. This review details the profile of substrate metabolism in the uraemic heart and the impact of carnitine supplementation on metabolism and function of the reperfused heart and finally the experimental and clinical evidence for carnitine replacement therapy, in particular its impact on the uraemic heart via modulation of function and energetics. PMID- 22204324 TI - Physiological and pathological functions of acid-sensing ion channels in the central nervous system. AB - Protons are important signals for neuronal function. In the central nervous system (CNS), proton concentrations change locally when synaptic vesicles release their acidic contents into the synaptic cleft, and globally in ischemia, seizures, traumatic brain injury, and other neurological disorders due to lactic acid accumulation. The finding that protons gate a distinct family of ion channels, the acid-sensing ion channels (ASICs), has shed new light on the mechanism of acid signaling and acidosis-associated neuronal injury. Accumulating evidence has suggested that ASICs play important roles in physiological processes such as synaptic plasticity, learning/memory, fear conditioning, and retinal integrity, and in pathological conditions such as brain ischemia, multiple sclerosis, epileptic seizures, and malignant glioma. Thus, targeting these channels may lead to novel therapeutic interventions for neurological disorders. The goal of this review is to provide an update on recent advances in our understanding of the functions of ASICs in the CNS. PMID- 22204326 TI - Implant placement and immediate loading with fixed restorations in augmented sockets. Five-year results. A case report. AB - In this report, a case is presented in which a patient received eight implants 10 months after tooth extraction and socket preservation. The implants were placed in both arches (maxilla = 4, mandible = 4) and immediately loaded using fixed partial restorations; they remained functional over 5 years. No changes in bleeding on probing or plaque index were observed; however, a 1.5-mm probing attachment level loss was observed during the first 3 years (mean: 0.25 mm/year) with no subsequent changes. PMID- 22204327 TI - A review on biological activities and chemical synthesis of hydrazide derivatives. AB - There has been considerable interest in the development of novel compounds with anticonvulsant, antioxidant, hormone antagonist, analgesic, anti-inflammatory, antiplatelet, antimalarial, antimicrobial, antimycobacterial, antitumoral, vasodilator, antiviral and anti-trypanosomal activities. Hydrazones possessing an azometine -NHN=CH- proton constitute an important class of compounds for new drug development. Therefore, many researchers have synthesized these compounds as target structures and evaluated their biological activities. These observations have been guiding for the development of new hydrazide derivatives that possess varied biological activities. PMID- 22204328 TI - Multi-targeted histone deacetylase inhibitors in cancer therapy. AB - The heterogeneous nature of cancer requires a comprehensive approach for attacking the multiple mechanisms underlying the initiation and progression of cancers. Histone deacetylase inhibitors (HDACi) have emerged as a new class of anticancer agents, targeting the biological processes including cell cycle, apoptosis and differentiation. Studies have revealed that HDACi are synergistic with diverse classes of anticancer therapies including targeted therapeutics and conventional anticancer agents. Extensive medicinal chemistry efforts have yielded a wide range of chemical structures, indicative of the structural flexibility of HDACi. These findings have supported a strategy to generate multi targeted HDACi by combining structural features from HDACi and other anticancer agents. HDACi can also be connected to a motif that allows for a selective delivery. Highlighting current examples, this brief review focuses on the rational design of multi-targeted inhibitors based on the examination and manipulation of chemical structures. PMID- 22204322 TI - Current research on opioid receptor function. AB - The use of opioid analgesics has a long history in clinical settings, although the comprehensive action of opioid receptors is still less understood. Nonetheless, recent studies have generated fresh insights into opioid receptor mediated functions and their underlying mechanisms. Three major opioid receptors (MU-opioid receptor, MOR; delta-opioid receptor, DOR; and kappa-opioid receptor, KOR) have been cloned in many species. Each opioid receptor is functionally sub classified into several pharmacological subtypes, although, specific gene corresponding each of these receptor subtypes is still unidentified as only a single gene has been isolated for each opioid receptor. In addition to pain modulation and addiction, opioid receptors are widely involved in various physiological and pathophysiological activities, including the regulation of membrane ionic homeostasis, cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as some neurodegenerative disorders. In some species, they play an essential role in hibernation. One of the most exciting findings of the past decade is the opioid-receptor, especially DOR, mediated neuroprotection and cardioprotection. The upregulation of DOR expression and DOR activation increase the neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers (depending on stress duration and severity) different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of homeostasis and increased pro-survival signaling (e.g., PKC-ERK-Bcl 2) and antioxidative capacity. In the heart, PKC and KATP channels are involved in the opioid receptor mediated cardioprotection. The DOR-mediated neuroprotection and cardioprotection have the potential to significantly alter the clinical pharmacology in terms of prevention and treatment of life-threatening conditions like stroke and myocardial infarction. The main purpose of this article is to review the recent work done on opioids and their receptor functions. It shall provide an informative reference for better understanding the opioid system and further elucidation of the opioid receptor function from a physiological and pharmacological point of view. PMID- 22204329 TI - n-3 fatty acid-derived lipid mediators in the brain: new weapons against oxidative stress and inflammation. AB - Neuroprotectins, resolvins, and maresins are subfamilies of endogenous oxygenated metabolites derived from n-3 or omega-3 fatty acids (eicosapentaenoic and docosahexaenoic acids). These metabolites are associated with signal transduction processes involved in downregulation of oxidative stress, neuroinflammation and apoptosis. Eicosapentaenoic acid-derived E-series resolvins (RvE1 and RvE2) and docosahexaenoic acid-derived D-series resolvins (RvD1 and RvD2) and neuroprotectins have potent anti-inflammatory and proresolution, and antioxidant properties. They not only retard excessive inflammatory process, but also promote resolution by enhancing clearance of apoptotic cells and debris from inflamed brain tissue and vasculature leading to tissue homeostasis. These actions may underlie the beneficial effects of eicosapentaenoic acid and docosahexaenoic acid in normal human health, neurotraumatic and neurodegenerative diseases. Aspirin initiates resolution not only by exerting antithrombotic actions, but also triggering biosynthesis of specific and stereoselective epimers of resolvins, protectins, and maresins. In addition during the onset of resolution, these lipid mediators also display potent protective roles in neural systems, liver, lungs, and eyes. Potent anti-inflammatory actions of resolvins, and protectins in models of chronic human diseases indicate that down-regulation in resolution pathways may contribute to the decrease in the intensity of many chronic neurodegenerative and visceral diseases. PMID- 22204330 TI - Potential therapeutic targeting of platelet-mediated cellular interactions in atherosclerosis and inflammation. AB - Cellular interactions among platelets, leukocytes and endothelial cells are considered as a major cause of inflammation and atherosclerosis in many diseases. Via exposed surface receptors and released soluble substances, activated platelets play a crucial role in the initiation of inflammatory processes, resulting in endothelial injury and leading to formation of atherosclerotic plaque with possible thrombotic complications. Classic anti-platelet treatments (e.g. cyclooxygenase inhibitor or ADP-receptor antagonist) have favorable effects in patients with vascular diseases, but they also have several limitations such as increased bleeding risk or non-responsiveness. Thus, the need and opportunities for developing novel therapeutic inhibitors for platelet-mediated events are obvious. Animal and (pre)clinical human studies have suggested that some recently produced specific antagonists of P-selectin from alpha-granules, as well as its main ligand/receptor P-selectin Glycoprotein Ligand-1, the two major platelet chemokines CXCL4 and CCL5, as well as CD40L, may be considered potential new candidates in the treatment of atherogenesis and inflammation. In this review, we summarize the pathophysiological roles of these effectors in platelet activation and acute or chronic inflammation, and discuss the latest findings on promising antagonistic agents in basic and clinical studies in the prevention of platelet-mediated cellular interactions. PMID- 22204331 TI - Exploration of chemical space based on 4-anilinoquinazoline. AB - Chemical space is defined as all possible small organic molecules, including those present in biological systems, which is so vast that so far only a tiny fraction of it has been explored. Indeed, a thorough examination of all "chemical space" is practically impossible. The success of three EGFR inhibitors (Gefitnib, Erlotinib, Lapatinib) suggests that 4-anilinoquinazoline scaffold is still worth developing in the future. To date hundreds of this sort of derivatives have been synthesized and show potent anticancer activities. Most of the compounds have been proved to be EGFR/HER2 kinase inhibitors, binding at the hinge region of the ATP site and some lead compounds have been optimized against a number of different kinases, including VEGFR-2, Src, Aurora A/B, Tpl, Clk and PDE10A. Now there is now a rich pipeline of novel anticancer agents based on 4 anilinoquinazoline in early phase clinical trials. This review will highlight the exploration of chemical space of 4-anilinoquinazoline in the past ten years and we hope that increasing knowledge of the SAR and cellular processes underlying the antitumor-activity of anilinoquinazoline derivatives will be beneficial to the rational design of new generation of small molecule anticancer drugs. PMID- 22204332 TI - Structure-based design in the GPCR target space. AB - The G protein-coupled receptors (GPCRs) are membrane proteins that transmit signals via G-protein coupling. They have long been the target of small molecule therapeutics accounting for 30% of the launched drug targets. They are subdivided into several classes, with rhodopsins corresponding to the largest class. Furthermore, a high number of new rhodopsin-like GPCR proteins are included in the druggable genome, thus they are projected to continue being of value to the pharmaceutical and biotechnology sectors. We present a comprehensive review of the structural information pertaining to GPCRs, in light of the most recently deposited crystal structures, along with comparisons of the available to-date structures at different activation states. Finally, computational approaches to GPCR modeling are discussed in conjunction with critical perspectives regarding feasibility and limitations. PMID- 22204333 TI - Structure-function relationships of iodinated contrast media and risk of nephrotoxicity. AB - Characteristics of CM have greatly changed over time. First-generation ionic CM have many-fold (5-7) greater osmolalities than plasma. Subsequently non ionic CM generations were looked for to reduce osmolality, and encompass nonionic monomers and nonionic dimers reaching osmolality as low as that of plasma (iso-osmolar CM) but paying however dear, as viscosity is considerably increased. Intrarenal microcirculation has its "Achilles" heel in the outer medulla, where the smallness of capillary lumen and the slackness of the capillary mesh render regular blood flow at high risk, mainly because it is the same area in which the only renal work needing oxygen is made and? Iodinated CM may exert their nephrotoxic effects in three different ways: by interfering with vascular hemodynamics, by interfering with intratubular fluid volume and composition, and by producing direct cytotoxic effects to glomerular and tubular cells due to iodine by-itself. Furthermore, effects of oxygen free radical can damage glomerular cells by increasing the permeability and tubular cells impairing specific function and leading to apoptosis. Although clinical nephrotoxicity has considerably improved over time, there is no evidence for an a priori superiority of a specific CM. In general, low-osmolar (2-3 times blood) and iso-osmolar (the same as blood) CM are recommended, keeping in mind that within last generation CM dimeric iso-somolar compounds reach viscosity values higher than monomeric low osmolar compounds and hyperviscosity is a neglected mechanisms of nephrotoxicity. We suggest that CM should be classified not only by osmolality, but also by viscosity. PMID- 22204334 TI - 2-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid with inbuilt beta-N hydroxy-gamma-keto-acid pharmacophore as HCV NS5B polymerase inhibitors. AB - The inbuilt 2-N-hydroxy-1-oxo-3-carboxylic acid of isoquinolone was designed as pyrophosphate mimic for hepatitis C NS5B polymerase. Various 2-hydroxy-1-oxo-1,2 dihydroisoquinoline-3-carboxylic acid derivatives 11a-p were synthesized and evaluated as HCV NS5B polymerase inhibitors. Compound 11c exhibited moderate inhibitory potency based on the inorganic pyrophosphate generation (IC50 = 9.5 MUM) and based on NTP incorporation by NS5B enzyme (IC50 = 5.9 MUM). Compound 11c demonstrated antiviral activity (EC50 = 15.7 MUM) and good selectivity in HCV genotype 1b replicon Ava.5 cells. Compound 11c reduced the interaction of NTP to NS5B polymerase. Docking model showed that 11c situated in similar orientation to the bound uridine triphosphate in the active site of NS5B polymerase. As a result, 2-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid was disclosed as a novel inbuilt beta-N-Hydroxy-gamma-keto-acid pharmacophore for HCV NS5B polymerase inhibitors. PMID- 22204335 TI - Targeting DNA topoisomerase I with non-camptothecin poisons. AB - DNA topoisomerase I is required for DNA relaxation during a variety of cellular functions. The identification of camptothecins as specific enzyme poisons and their clinical efficacy have stimulated extensive efforts to exploit topoisomerase I as a therapeutic target for cancer. However, several limitations of camptothecins, such as low solubility and stability, high toxicity, and the occurrence of resistance, have encouraged the development of non-camptothecin topoisomerase I inhibitors. Different natural and synthetic compounds (e.g., indolocarbazoles, dibenzonaphthyridine and indenoisoquinoline) have been extensively studied as alternatives to camptothecins and have been proved to be promising therapeutic agents. In this review, we comparatively evaluate the preclinical results obtained with the different non-camptothecin poisons proposed thus far as topoisomerase I inhibitors, with special reference to cellular pharmacology, and discuss the perspective for their use in the clinical setting. PMID- 22204336 TI - Ion channels and cancers. PMID- 22204337 TI - Cardiotonic steroids-mediated targeting of the Na(+)/K(+)-ATPase to combat chemoresistant cancers. AB - A large proportion of cancer patients fail to respond to conventional chemotherapy because of the intrinsic resistance of their cancer to pro-apoptotic stimuli and/or the acquisition of a multidrug resistant (MDR) phenotype during chronic chemotherapy. A new angle in chemotherapeutics against these cancer types associated with dismal prognoses would be the targeting of specific ion channels and pumps over expressed by cancer cells as compared to normal cells. Several reports suggest that the alpha subunits of the Na(+)/K(+)-ATPase (referred as sodium pump from now on) could be such targets, using cardiotonic steroids (CS) including cardenolides and bufadienolides. A significant proportion of non-small cell-lung cancers (NSCLCs), glioblastomas (GBMs), melanomas and kidney cancers overexpresses the alpha-1 subunit of the sodium pump as compared to corresponding normal tissues, while colon cancers overexpress the alpha-3 subunit. Thus, a deeper knowledge of the structure-activity relationship (SAR), in terms of CS mediated anticancer effects, to the sodium pump alpha subunits might enable the identification of potent anticancer agents with limited cardiotoxicity. The current review provides an in depth SAR analysis with respect to cardenolide- versus bufadienolide-mediated anticancer effects. Moreover, pharmacological data from in vitro and in vivo experiments, as well as pre-clinical and clinical trials regarding cardenolides to combat cancers associated with dismal prognoses are presented. PMID- 22204338 TI - Is the multifunctional Na(+)/H(+) exchanger isoform 1 a potential therapeutic target in cancer? AB - The Na(+)/H(+) exchanger isoform 1 (NHE1) is a ubiquitously expressed transporter fulfilling a variety of cell physiological tasks. By importing Na(+) and exporting H(+), NHE1 contributes to regulatory volume increase and cytoplasmic pH homeostasis. In addition it anchors the cytoskeleton in the plasma membrane. NHE1 plays a critical role in mediating the progression of reperfusion injuries after ischemia. Moreover, it is upregulated and/or overexpressed in a number of tumour cells. In many cases an elevated NHE1 activity can be correlated with an increase in cell motility and malignancy. Consequently, NHE1 including its regulators may represent potential targets in anticancer therapy. Different NHE1 inhibitors are compared and possible clinical exploitations of NHE1 inhibition are discussed. PMID- 22204339 TI - Targeting the voltage-dependent K(+) channels Kv1.3 and Kv1.5 as tumor biomarkers for cancer detection and prevention. AB - Potassium channels (KCh) are a diverse group of membrane proteins that participate in the control of the membrane potential. More than eighty different KCh genes have been identified, which are expressed in virtually all living cells. In addition to nerve and cardiac action potentials, these proteins are involved in a number of physiological processes, including cell volume regulation, apoptosis, immunomodulation and differentiation. Furthermore, many KCh have been reported to play a role in proliferation and cell cycle progression in mammalian cells, and an important number of studies report the involvement of KCh in cancer progression. The voltage dependent potassium (Kv) channels, in turn, form the largest family of human KCh, which comprises about 40 genes. Because Kv1.3 and Kv1.5 channels modulate proliferation of different mammalian cells, these proteins have been analyzed in a number of tumors and cancer cells. In most cancers, the expression patterns of Kv1.3 and Kv1.5 are remodeled, and in some cases, a correlation has been established between protein abundance and grade of tumor malignancy. The list of cancers evaluated is constantly growing, indicating that these proteins may be future targets for treatment. The aim of this review is to provide an updated overview of Kv1.3 and Kv1.5 channels during cancer development. Unlike Kv1.5, Kv1.3 is characterized by a very selective and potent pharmacology, which could lead to specific pharmacological targeting. Because potassium channels may play a pivotal role in tumor cell proliferation, these proteins should be taken into account when designing new cancer treatment strategies. PMID- 22204340 TI - Approaches targeting K(V)10.1 open a novel window for cancer diagnosis and therapy. AB - K(V)10.1 has recently become generally accepted as a promising cancer target, as it is ectopically expressed in the majority of solid tumors. Due to its cell surface accessibility, K(V)10.1 has a strong potential for tumor treatment and diagnosis. Given that its mode of action is likely independent of conventional cancer pathways such as tyrosine kinases, K(V)10.1 opens a novel window for treating cancer. In this review we will give an overview of the current status of data linking K(V)10.1 to cancer, and propose techniques that could exploit K(V)10.1's properties for the management of cancer. PMID- 22204341 TI - Targeting ion channels in leukemias: a new challenge for treatment. AB - Leukemias, as other cancers, bear several genetic alterations of tumor-related genes, such as point mutations, translocations, epigenetic modifications, often accompanied by gene amplification or inactivation. The identification of tumor related genes provides considerable insight into the biology of leukemias and opens the way to more specific pharmacological treatments. These genes comprise several ion channels and pumps, as the transport mechanisms associated with volume control, proliferation and apoptosis are often altered in cancers. In leukemic cells, such changes are observed as early as the stem cell stage. Ion channels can regulate other malignant features, such as lack of differentiation, increased migratory and invasive phenotype and chemoresistance. The role of certain voltage-gated K(+) channels, such as K(v)11.1 (also known as hERG1) can be largely attributed to modulation of cell adhesion to the extracellular matrix (ECM). K(v)11.1 exerts pleiotropic regulatory effects by forming multiprotein membrane complexes with integrin receptors in both acute myeloid leukemias (AML) and acute lymphoblastic leukemias (ALL). By recruiting growth factor and chemokine receptors, these complexes form signaling hubs that control neoplastic progression. Work in mice shows that blocking K(v)11.1 has a protective effect in acute leukemias. Ion channels are most promising targets for anti-leukemic therapy, because of their accessibility from the extracellular side and the thorough understanding of their pharmacology. In ALL cells, K(v)11.1 inhibitors abrogate the protective effect of bone marrow stromal cells and enhance the cytotoxicity of some common antileukemic drugs. Hence, ion channel modulators could overcome chemoresistance in acute leukemias, a major hindrance to therapeutic success. PMID- 22204342 TI - Targeting SKCa channels in cancer: potential new therapeutic approaches. AB - Many studies have reported changes in potassium channel expression in many cancers and the involvement of these channels in various stages of cancer progression. By contrast, data concerning SKCa channels (small conductance calcium-activated potassium channels) have only recently become available. This review aims i) to present the structure and physiology of SKCa channels, ii) to provide an overview of published data concerning the SKCa proteins produced in tumor cells, and, whenever possible, the biological function assigned to them and iii) to review previous and novel modulators of SKCa channels. SKCa channels are activated by low concentrations of intracellular calcium and consist of homo- or heteromeric assemblies of alpha-subunits named SK1, SK2 and SK3. SK2-3 channels are expressed in tumors and have been assigned a biological function in cancer cells: the enhancement of cell proliferation and cell migration by hijacking the functions of SK2 and SK3 channels, respectively. Two major classes of SKCa modulators have been described: toxins (apamin) and small synthetic molecules. Most SKCa blockers are pore blockers, but some modify the calcium sensitivity of SKCa channels without interacting with the apamin binding site. In this review, we present edelfosine and ohmline as atypical anticancer agents and novel SK3 inhibitors. Edelfosine and ohmline are synthetic alkyl-lipids with structures different from all previously described SKCa modulators. They should pave the way for the development of a new class of migration-targeted anticancer agents. We believe that such blockers have potential for use in the prevention or treatment of metastasis. PMID- 22204343 TI - Mitochondrial VDAC1: function in cell life and death and a target for cancer therapy. AB - Found at the outer mitochondrial membrane, the voltage-dependent anion channel, VDAC, assumes a crucial position in the cell, serving as the main interface between mitochondrial and cellular metabolisms by mediating transport of ions and metabolites. VDAC thus functions as a gatekeeper, controlling cross-talk between mitochondria and the rest of the cell. Moreover, its location at the boundary between the mitochondria and the cytosol enables VDAC to interact with proteins that mediate and regulate the integration of mitochondrial functions with other cellular activities. Here, we review current knowledge related to the roles played by VDAC in the regulation of cell life and cell death, with relation to cancer. The current concepts of altered metabolism in cancer cells are presented with specific emphasis on mitochondrial, more specifically VDAC1-bound hexokinase (HK), facilitating and promoting the high glycolytic tumor phenotype. In this respect, the up-regulation of HK expression in tumor cells and its binding to VDAC provide both a metabolic benefit and apoptosis-suppressive capacity that offers the cell a growth advantage and increases its resistance to chemotherapy. VDAC has also been recognized as a key protein in mitochondria-mediated apoptosis since it is the proposed target for the pro- and antiapoptotic Bcl-2-family of proteins, as well as due to its function in the release of apoptotic proteins located in the inter-membranal space. These and other functions point to VDAC1 as being a rational target for the development of a new generation of therapeutics. PMID- 22204344 TI - Advancements in Z-DNA: development of inducers and stabilizers for B to Z transition. AB - Z-DNA, an active element in genome, has drawn intense interest in chemical and biological field. Its dynamic and transient state makes it challenging to target and regulate. Thus, stabilizing and inducing Z-DNA both in vitro and in vivo is essential, so far, much many efforts have been made in these aspects. However, Z DNA's induction and stabilization are always performed in high salt condition and sequence-dependent, limited inducers or stabilizers have been achieved with breakthrough in the aspects of real physiological condition and sequence independence. Herein, we give a review of some typical kinds of Z-DNA inducers and stabilizers, discussing their inducing or stabilizing condition, mechanism, structural relationship and their limitation as well, attempted to get some implication and guidance for Z-DNA inducer or stabilizer design. PMID- 22204346 TI - Polysaccharide-K (PSK) in cancer--old story, new possibilities? AB - Polysaccharide-K (PSK, Krestin) is one of the most commonly used medicinal mushroom extracts with a long history as an additive in cancer therapy in Asia, especially in Japan. PSK has a documented anti-tumor activity both in vitro and in vitro, in various types of cancers, including colorectal, gastric, breast, liver, pancreatic, and lung cancer. Despite PSK having been studied for about 40 years as an immune modulator and biological response modifier, the mechanisms of action by PSK have not yet been clearly and completely elucidated. This review aims to provide an up-to-date account for the effects of PSK in cancer with the hope of thereby providing an increased understanding of the molecular mechanisms of PSK and also its potential as an additive in modern cancer therapy. PMID- 22204345 TI - Developments in chemical approaches to treat tuberculosis in the last decade. AB - Tuberculosis (TB) caused by Mycobacterium tuberculosis claims millions of lives each year globally. Although it can be controlled by currently available drug regimen (DOTS), yet the emergence of multidrug resistance (MDR) and extensively drug resistance (XDR) TB is a growing concern. The increasing rate of MDR-TB, co infection with HIV and XDR-TB necessitates the development of new anti-TB agents that have a practical impact on tuberculosis control. This review article gives a brief introduction of tuberculosis, present day problems, traditional and new anti-TB drug targets, currently used drugs, their mode of action, the pipeline compounds and a short description of new chemical entities (NCE's) as antitubercular agents developed in last 10 years. PMID- 22204347 TI - Nanotechnology based diagnostic and therapeutic strategies for neuroscience with special emphasis on ischemic stroke. AB - Ischemic stroke is the second leading cause of death and long-term disability worldwide, for which no effective therapies are available. The increasing prevalence of ischemic stroke and related health risks, combined with the lack of effective therapies, highlight the desperate need for continued research for exploring the safe and effective drugs, which favourably influence multiple pathways leading to neuroprotection and extend the benefit to a larger number of patients diagnosed with stroke. Numerous preclinical studies have reported very promising results using "neuroprotectants", all of which have failed at clinical trials because of either safety issues or lack of efficacy. The delivery of many potentially therapeutic neuroprotectants and diagnostic compounds to specific areas of the brain is restricted by the blood-brain barrier (BBB). Nanoparticles (NPs) have colossal applications that could revolutionize the treatment of ischemic stroke. NPs can readily transmigrate across the BBB without compromising its integrity. Recent striking developments in nanotechnology have produced a great deal of nano-devices, which could be used for the treatment and neuronal regeneration following ischemic stroke. This article attempts to convey the untapped potentials of nanopharmaceuticals for the treatment of ischemic stroke. Looking towards the future, this review focuses on the potential applications of nanoparticulate systems for the delivery of therapeutic cargo into the brain for imparting neuroprotection against ischemic stroke. This review also provides an overview of targeted NPs, which are being used for imaging, neuroprotection and regeneration of ischemic brain. PMID- 22204348 TI - Recognition of nucleic acid ligands by toll-like receptors 7/8: importance of chemical modification. AB - Toll-like receptors 7 and 8 (TLR7/8), known as pattern recognition receptors (PRR), are currently viewed as important targets for the development of new therapies for multiple diseases. Therefore, manipulating the immune response by using TLR7/8 agonists or antagonists might be of therapeutic value. Nucleic acid like structures are well-known TLR7/8 ligands, such as single-stranded RNA (ssRNA), small interfering RNA (siRNA), CpG-oligodeoxynucleotides (ODNs) and nucleoside analogues. However, these nucleic acid TLR7/8 ligands show a variety of pharmacological properties and change of their structures offers a high degree of diversity. Unnatural modified nucleosides have been explored to expand the properties and the applications of nucleic acid. In this regard, chemical modification of nucleosides is very useful for production of specific pharmacological qualities of nucleic acid TLR7/8 ligands. In this review, we will summarize the characteristics of nucleic acid TLR7/8 ligand system and describe the applications of chemical modifications, with a focus on potency and structure activity relationships (SAR). PMID- 22204351 TI - Publisher's Notes. PMID- 22204349 TI - Cancer regulator microRNA: potential relevance in diagnosis, prognosis and treatment of cancer. AB - MicroRNAs (miRNAs) are small (typically 22 nucleotides) non-coding, endogenous, single-stranded RNAs. MiRNA genes are evolutionarily conserved and are located within the introns or exons of protein-coding genes, as well as in intergenic areas. Before the discovery of miRNAs, it had been known that a large part of the genome is not translated into proteins. This so called "junk" DNA was thought to be evolution debris with no function. Recently, the explosive research in this area has established miRNAs as powerful regulators of gene expression. While only about 1,424 human miRNA sequences have been identified so far, genomic computational analysis indicates that as many as 50,000 miRNAs may exist in the human genome, and each may have multiple targets based on similar sequences in the 3'-UTR of mRNA. MiRNAs have been implicated in different areas such as the immune response, neural development, DNA repair, apoptosis, oxidative stress response and others and it is impressive the list of diseases which have recently been found to be associated with abnormal miRNA expression. Here, we focus our attention on the importance of cancer regulator miRNAs. They are divided into oncomiRs and anti-oncomiRs that negatively regulate tumor suppressor genes and oncogenes, respectively. Importantly, the association of miRNAs with cancer has prompted additional functional classification of these short RNAs and their potential relevance in cancer diagnosis, prognosis and treatment. PMID- 22204352 TI - Economic incentives to reduce employee smoking: a health insurance surcharge for tobacco using state of kansas employees. AB - Abstract Cigarette smoking has been clearly established as the single most important, preventable cause of morbidity and mortality. Employers are actively working to reduce smoking among current employees, and a growing number will not hire smokers. While most efforts have focused on either 1) helping smokers overcome their habit, or 2) banning or severely limiting worksite smoking, very little has been done to provide strong economic incentives for current employees to give up smoking. This paper reports on the planning and implementation of a $10 per month surcharge added to employee contributions for health insurance for persons employed by the State of Kansas. Family coverage is not affected. Also discussed is a similiar effort in the Colorado state employee group health plan. PMID- 22204353 TI - Spouse intention to encourage cardiac patient participation in exercise. AB - Abstract The aim of this study was to identify factors that influenced the intention of spouses to encourage cardiac patients to attend exercise classes. A sample of 134 spouses completed questionnaires investigating variables specified in the theory of reasoned action (Fishbein and Ajzen). Multiple regression was used with intention to encourage exercise participation as the outcome. Independent variables included: attitude toward helping, subjective social norm regarding helping, perceived efficacy of providing help, approval of patient exercising, and perceived outcomes (costs and benefits) of patient participation. Subjective social norm and approval were the only significant predictors of intention to encourage participation (R(2) = 0.41, p<0.0001). This suggests that interventions to improve spouse support for cardiac patient exercise be directed at the spouse social role rather than attitudes toward helping. PMID- 22204355 TI - Phase II Cardiac Wellness at the Adolph Coors Company. PMID- 22204354 TI - Connectedness: some skills for spiritual health. AB - Abstract This article explores the relationship between connectedness and spiritual health. Three forms of connectedness are discussed: connecting with oneself, with others, and with a larger meaning or purpose. Eight connectedness skills are suggested. Combined, these skills may lead to an enhanced sense of spiritual well-being. PMID- 22204357 TI - Tobacco use among adolescents: directions for research. PMID- 22204356 TI - Health promotion data for state health departments: telephone versus in-person survey estimates of smoking and alcohol use. AB - Abstract During 1988, more than 40 state health departments conducted telephone surveys to obtain state-specific population estimates of the prevalence of adult health behaviors and health practices. However, the comparability of estimates obtained from these telephone surveys with more expensive in-person surveys has not been assessed in an applied setting. This study compared the prevalence estimates of smoking and binge drinking obtained from a telephone survey (N = 1,492) with an in-person survey (N = 2,802) which were conducted by the state of Michigan during 1982-1983. Although the standard errors for the differences in the estimates for the two surveys were relatively large, the actual differences were consistently small within most age-, sex-, and education-specific groups. Despite certain limitations, telephone surveys provide a reasonable alternative to in-person surveys for estimating the prevalence of health behaviors. The data obtained from these surveys are being used to set state health objectives, to plan state-wide health promotion programs, and to support public health legislation. PMID- 22204358 TI - DataBase: Research and Evaluation Results. PMID- 22204359 TI - Business aspects of health promotion. PMID- 22204360 TI - Recognition of the reviewers of the american journal of health promotion. PMID- 22204361 TI - Networking. PMID- 22204363 TI - Professional association profiles. PMID- 22204365 TI - Resource reviews. PMID- 22204366 TI - Perspectives beyond health promotion. PMID- 22204367 TI - Recalculate total daily dose and confirm exactly how much insulin your patient is taking prior to changing mode of insulin delivery. PMID- 22204368 TI - Evaluating the clinical utility of the Profile of Oral Narrative Ability for 4 year-old children. AB - This study investigated if the story retelling and comprehension task Ana Gets Lost, that is frequently used with school-aged children, has clinical utility with a preschool population. The study also assessed the task's concurrent and predictive validity with norm-referenced tests of language performance. A total of 92 typically-developing 4-year-old children participated. After 12 months, 57 children were available for a follow-up session. At each session, children listened twice to the story while looking at the pictures and then retold the story without the use of pictures. After the first exposure the children were asked comprehension questions to assess their oral narrative comprehension. Children's performance was analysed on measures of comprehension, narrative quality, semantics, morphosyntax, and verbal productivity to provide a Profile of Oral Narrative Ability (PONA). Results showed normal distribution of some of the measures and acceptable concurrent and predictive correlations with two norm referenced measures of language ability. Although the results indicate the potential usefulness of this tool with preschool children, further research should investigate its potential as a screening measure of oral narrative performance. PMID- 22204370 TI - Inflammation in atherosclerosis: current therapeutic approaches. PMID- 22204371 TI - Pathophysiology of atherosclerosis: the role of inflammation. AB - Atherosclerosis is a disease of arteries and is characterized by endothelial dysfunction, vascular inflammation, and the build-up of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall. A number of factors commonly characterized as "risk factors" for atherosclerosis have been identified to facilitate the development of atherosclerosis by decreasing NO bioavailability in the vascular endothelium. The serious clinical manifestations of atherosclerosis (including coronary heart disease, stroke, and peripheral vascular disease) augment the need of performing the appropriate diagnostic methods to the patients. The most important diagnostic methods include the usage of biochemical markers and the invasive and non-invasive imaging techniques assessing endothelial function. The main drug categories that have been proved to ameliorate the inflammatory state in atherosclerosis are angiotensin converting enzyme inhibitors/angiotensin receptors blockers, statins, and antioxidants. PMID- 22204372 TI - Inflammatory disorders and atherosclerosis: new therapeutic approaches. AB - Recent evidence suggests that patients with chronic inflammatory disorders are at increased cardiovascular risk. A number of different mechanisms have been postulated to contribute to atherosclerotic disease progression in these patients including traditional cardiovascular risk factors, cytokine upregulation, immume mediated pathways and increased oxidative stress. Novel treatments target inflammatory pathways and have beneficial effect on rheumatic disease activity however; their impact on cardiovascular risk reduction remains unclear. Further longitudinal studies are required to assess the value of different therapeutic approaches on cardiovascular outcome of these patients. PMID- 22204373 TI - Inflammation in hypertension: current therapeutic approaches. AB - The role of inflammation as crucial underlying process contributing to the initiation and the progression of atherosclerosis as well as its clinical manifestations is well established. Recent data have demonstrated also a strong association between essential hypertension and inflammatory process. In addition, several studies have shown that tissue expression and plasma concentrations of several inflammatory biomarkers/mediators are related to increased risk of hypertension. The determination of markers such as acute phase proteins (C reactive protein), adhesion molecules such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and chemokines is crucial in determining therapeutic responses and clinical outcomes of hypertensive patients. In addition, several therapeutic approaches targeting blood pressure may have also beneficial effects in terms of inflammation and thus further clinical benefits. Although the available data are encouraging, further large scale studies are required to evaluate the reported anti-inflammatory effects in management and treatment of arterial hypertension. PMID- 22204374 TI - Inflammatory markers in hyperlipidemia: from experimental models to clinical practice. AB - The role of inflammation in the development and progression of cardiovascular diseases is well established. Systemic inflammation and immune system play a central role in atherogenesis. The strong dependence of the atherosclerotic process on both a state of continuous low grade inflammation and the presence of lipid abnormalities gave impetus to research the association between hyperlipidemia and inflammatory status. In experimental and clinical studies, several inflammatory markers such as C-reactive protein, tumor necrosis factor alpha, interleukin 6, nuclear factor kappa-beta, adhesion molecules, serum amyloid-alpha, lipoprotein-associated phospholipase A2, fibrinogen and sCD40 ligand are associated with lipids level. Although, cholesterol lowering treatment has several important beneficial effects, there is still little clinical experience or data from clinical trials, in order to treat patients with hyperlipidemia and impaired inflammatory status. PMID- 22204375 TI - Potential pathogenic inflammatory mechanisms of endothelial dysfunction induced by type 2 diabetes mellitus. AB - Insulin resistance and the vascular complications of diabetes include activation of the inflammation cascade, endothelial dysfunction, and oxidative stress. The comorbidities of diabetes, namely obesity, insulin resistance, hyperglycemia, hypertension and dyslipidemia collectively aggravate these processes while antihyperglycemic interventions tend to correct them. Increased C-reactive protein, interleukin 6, tumor necrosis factor alpha and especially interstitial cellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E selectin are associated with cardiovascular and non-cardiovascular complications of both type 1 and type 2 diabetes. We sought to review the clinical implications of the inflammation theory, including the relevance of inflammation markers as predictors of type 2 diabetes in clinical studies, and the potential treatments of diabetes, inferred from the pathophysiology. PMID- 22204376 TI - The role of T and B cells in atherosclerosis: potential clinical implications. AB - The chronic inflammation process that characterises atherosclerosis involves both the innate and adaptive arms of the immune system. Several lines of evidence have recently highlighted pivotal roles for T and B lymphocytes - cells that belong to the adaptive immune system - in the development and progression of atherosclerosis. In this review, we summarise the current knowledge on the roles of adaptive immune responses in atherosclerosis and present our views on how a better understanding of these immune mechanisms could shape future therapies to slow down or even prevent this disease. PMID- 22204377 TI - Anti-inflammatory treatment of acute coronary syndromes. AB - The past decade has seen a steady growth in the treatment options available for Acute Coronary Syndromes (ACS), as a consequence of our better understanding of ACS pathophysiology. Administration of fibrinolytics in ST-elevation myocardial infarction, and of potent antiplatelet and anticoagulant drugs in all ACS, has allowed us to considerably improve their outcome. Yet, the rate of adverse cardiac events at early follow-up ranges from 15% to 20%. Thus, to further improve the outcome of ACS or to prevent their occurrence, it is important to identify new therapeutic target. A number of experimental and clinical studies have highlighted the key role of inflammation in all phases of atherosclerosis, from fatty streaks to disrupted plaques and raised levels of inflammatory markers have been associated to a poor outcome despite optimal treatment, including myocardial revascularization. In this review, we will focus on inflammation as a possible new therapeutic target of ACS, discussing the anti-inflammatory treatments in four sections: 1) non specific anti-inflammatory drugs; 2) specific antagonists of key cytokines; 3) immunomodulatory therapies; 4) immunization as promising therapeutic modality against atherosclerosis. PMID- 22204378 TI - Vulnerable plaque and inflammation: potential clinical strategies. AB - Although enormous progress has been made in the prevention and treatment of cardiovascular disease, it still remains the leading cause of death worldwide. During the last decades, advances in the understanding of the pathophysiology of vulnerable plaque progression, coupled with novel diagnostic and therapeutic approaches, created a new opportunity for progress against cardiovascular disease. It has been demonstrated that inflammation, implicated in all stages of atherosclerosis, is an integral part of vulnerable plaque development and progression, leading eventually to plaque instability. Thus, new diagnostic modalities have been proposed for the detection of local plaque inflammation. Moreover, treatments such as stenting, photodynamic therapy, and novel pharmaceutical agents are under consideration as methods to stabilize the vulnerable plaques by inhibiting inflammation. This review provides an overview of the inflammatory process leading to atherosclerotic cardiovascular disease and the potential clinical strategies that may substantially decrease the incidence of events. We will mention the major impact of local and systemic inflammation on plaque advancing and destabilization, the imaging techniques for early detection of vulnerable plaques and the potential therapeutic strategies. PMID- 22204379 TI - Gene therapy targeting inflammation in atherosclerosis. AB - The extensive cross-talk between the immune system and vasculature leading to the infiltration of immune cells into the vascular wall is a major step in atherogenesis. In this process, reactive oxygen species play a crucial role, by inducing the oxidation of LDL and the formation of foam cells, and by activating a number of redox-sensitive transcriptional factors such as nuclear factor kappa B (NFkappa B) or activating protein 1 (AP1), that regulate the expression of multiple pro/anti inflammatory genes involved in atherogenesis. Delivery of genes encoding antioxidant defense enzymes (e.g. superoxide dismutase, catalase, glutathione peroxidase or heme oxygenase- 1) or endothelial nitric oxide synthase (eNOS), suppress atherogenesis in animal models. Similarly, delivery of genes encoding regulators of redox sensitive transcriptional factors (e.g. NF-kappa B, AP-1, Nrf2 etc) or reactive oxygen species scavengers have been successfully used in experimental studies. Despite the promising results from basic science, the clinical applicability of these strategies has proven to be particularly challenging. Issues regarding the vectors used to deliver the genes (and the development of immune responses or other side effects) and the inability of sufficient and sustained local expression of these genes at the target-tissue are some of the main reasons preventing optimism regarding the use of these strategies at a clinical level. Therefore, although premature to discuss about effective "gene therapy" in atherosclerosis at a clinical level, gene delivery techniques opened new horizons in cardiovascular research, and the development of new vectors may allow their extensive use in clinical trials in the future. PMID- 22204381 TI - Isomer- and species-selective infrared spectroscopy of jet-cooled 7H- and 9H-2 aminopurine and 2-aminopurine.H2O clusters. AB - The infrared (IR) spectra of the supersonic-jet cooled 9H- and 7H-tautomers of 2 aminopurine (2AP) and of the 9H-2-aminopurine.H(2)O monohydrate clusters have been measured by mass- and species-selective IR-UV double resonance spectroscopy in the 3200-3900 cm(-1) region, covering the N-H and O-H stretching vibrations. The spectra are complemented by density functional (B3LYP and PW91) and by second order Moller-Plesset (MP2) calculations of the electronic energies and vibrational frequenciesof the respective 2AP tautomers and clusters. The 9H- and 7H-2-aminopurine tautomers were definitively identified by the shifts of their NH and NH(2) symmetric and asymmetric stretching frequencies and by comparison to the B3LYP/TZVP calculated IR spectra. The H-bond topologies of the two previously observed 9H-2-aminopurine.H(2)O isomers (Sinha. R. K.; et al. J. Phys. Chem. A2011, 115, 6208) are definitively identified as the "sugar-edge" isomer A and the "trans-amino-bound" isomer B by comparing their IR spectra to the calculated frequencies and IR intensities of the cluster isomers A, B, C, and D, as well as to the IR spectrum of 9H-2AP. The sugar-edge isomer A involves N9-H...OH(2) and HOH...N3 hydrogen bonds and is predicted to be the most stable form. The amino bound isomer B involves NH(2)...OH(2) and HOH...N1 hydrogen bonds and is calculated to lie 2.5 kJ/mol above isomer A. The H-bond topology of the "cis amino-bound" isomer C is symmetrically related to isomer B, with a hydrogen bond to the N3 of the pyrimidine group. However, it is calculated to lie 7 kJ/mol above isomer A and indeed is not observed in the supersonic jet. Isomer D involves a single H-bond to the N7 position, is predicted to be 14 kJ/mol above A and is therefore not observed. PMID- 22204380 TI - The Alzheimer's beta-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb. AB - BACKGROUND: The beta-secretase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), is a prime therapeutic target for lowering cerebral beta amyloid (Abeta) levels in Alzheimer's disease (AD). Clinical development of BACE1 inhibitors is being intensely pursued. However, little is known about the physiological functions of BACE1, and the possibility exists that BACE1 inhibition may cause mechanism-based side effects. Indeed, BACE1-/- mice exhibit a complex neurological phenotype. Interestingly, BACE1 co-localizes with presynaptic neuronal markers, indicating a role in axons and/or terminals. Moreover, recent studies suggest axon guidance molecules are potential BACE1 substrates. Here, we used a genetic approach to investigate the function of BACE1 in axon guidance of olfactory sensory neurons (OSNs), a well-studied model of axon targeting in vivo. RESULTS: We bred BACE1-/- mice with gene-targeted mice in which GFP is expressed from the loci of two odorant-receptors (ORs), MOR23 and M72, and olfactory marker protein (OMP) to produce offspring that were heterozygous for MOR23-GFP, M72-GFP, or OMP-GFP and were either BACE1+/+ or BACE1 /-. BACE1-/- mice had olfactory bulbs (OBs) that were smaller and weighed less than OBs of BACE1+/+ mice. In wild-type mice, BACE1 was present in OSN axon terminals in OB glomeruli. In whole-mount preparations and tissue sections, many OB glomeruli from OMP-GFP; BACE1-/- mice were malformed compared to wild-type glomeruli. MOR23-GFP; BACE1-/- mice had an irregular MOR23 glomerulus that was innervated by randomly oriented, poorly fasciculated OSN axons compared to BACE1+/+ mice. Most importantly, M72-GFP; BACE1-/- mice exhibited M72 OSN axons that were mis-targeted to ectopic glomeruli, indicating impaired axon guidance in BACE1-/- mice. CONCLUSIONS: Our results demonstrate that BACE1 is required for the accurate targeting of OSN axons and the proper formation of glomeruli in the OB, suggesting a role for BACE1 in axon guidance. OSNs continually undergo regeneration and hence require ongoing axon guidance. Neurogenesis and the regeneration of neurons and axons occur in other adult populations of peripheral and central neurons that also require axon guidance throughout life. Therefore, BACE1 inhibitors under development for the treatment of AD may potentially cause axon targeting defects in these neuronal populations as well. PMID- 22204384 TI - Polypyrrole-palladium nanocomposite coating of micrometer-sized polymer particles toward a recyclable catalyst. AB - A range of near-monodisperse, multimicrometer-sized polymer particles has been coated with ultrathin overlayers of polypyrrole-palladium (PPy-Pd) nanocomposite by chemical oxidative polymerization of pyrrole using PdCl(2) as an oxidant in aqueous media. Good control over the targeted PPy-Pd nanocomposite loading is achieved for 5.2 MUm diameter polystyrene (PS) particles, and PS particles of up to 84 MUm diameter can also be efficiently coated with the PPy-Pd nanocomposite. The seed polymer particles and resulting composite particles were extensively characterized with respect to particle size and size distribution, morphology, surface/bulk chemical compositions, and conductivity. Laser diffraction studies of dilute aqueous suspensions indicate that the polymer particles disperse stably before and after nanocoating with the PPy-Pd nanocomposite. The Fourier transform infrared (FT-IR) spectrum of the PS particles coated with the PPy-Pd nanocomposite overlayer is dominated by the underlying particle, since this is the major component (>96% by mass). Thermogravimetric and elemental analysis indicated that PPy-Pd nanocomposite loadings were below 6 wt %. The conductivity of pressed pellets prepared with the nanocomposite-coated particles increased with a decrease of particle diameter because of higher PPy-Pd nanocomposite loading. "Flattened ball" morphologies were observed by scanning/transmission electron microscopy after extraction of the PS component from the composite particles, which confirmed a PS core and a PPy-Pd nanocomposite shell morphology. X-ray diffraction confirmed the production of elemental Pd and X-ray photoelectron spectroscopy studies indicated the existence of elemental Pd on the surface of the composite particles. Transmission electron microscopy confirmed that nanometer-sized Pd particles were distributed in the shell. Near monodisperse poly(methyl methacrylate) particles with diameters ranging between 10 and 19 MUm have been also successfully coated with PPy-Pd nanocomposite, and stable aqueous dispersions were obtained. The nanocomposite particles functioned as an efficient catalyst for the aerobic oxidative homocoupling reaction of 4 carboxyphenylboronic acid in aqueous media for the formation of carbon-carbon bonds. The composite particles sediment in a short time (=500 mV vs Ag/AgCl. The SNIFTIRS measurements indicate that the alkyl chains within the two adsorbed states of SDS film are in the liquid-crystalline state rather than the gel state. However, the sulfate headgroup is in an oriented state in phase I and is disordered in phase II. The newly acquired SNIFTIR spectroscopy measurements were coupled with previous electrochemical, atomic force microscopy, and neutron reflectivity data to improve the current existing models of the SDS film adsorbed on the Au(111) surface. The IR data support the existence of a hemicylindrical film for SDS molecules adsorbed at the Au(111) surface in phase I and suggest that the structure of the condensed film in phase II can be more accurately modeled by a disordered bilayer. PMID- 22204423 TI - Novel peptide-based scaffolds for drug discovery. PMID- 22204421 TI - Alu elements: know the SINEs. AB - Alu elements are primate-specific repeats and comprise 11% of the human genome. They have wide-ranging influences on gene expression. Their contribution to genome evolution, gene regulation and disease is reviewed. PMID- 22204424 TI - Structure-activity studies on alpha-conotoxins. AB - Conotoxins are small bioactive highly structured peptides from the venom of marine cone snails (genus Conus). Over the past 50 million years these molluscs have developed a complex venom cocktail for each species that is comprised of 100 2000 distinct cysteine- rich peptides for prey capture and defence. This review focuses on an important and well-studied class of conotoxins, the alpha- conotoxins. These alpha-conotoxins are potent and selective antagonists of various subtypes of the nicotinic acetylcholine receptors (nAChRs). Key structure activity relationship studies are presented to illustrate the common motifs, structural features and pharmacophores that define this interesting peptide class. Additionally, their synthesis, chemical modifications, the development of more selective and stable analogues and their therapeutic potential are discussed. PMID- 22204425 TI - Engineering of conotoxins for the treatment of pain. AB - The peptides present in the venoms of marine snails are used by the snails to capture prey, but they have also attracted the interest of drug designers because of their potent activity against therapeutically important targets. These peptides are typically disulfiderich and target a wide range of ion channels, transporters and receptors with exquisite selectivity. In this article, we discuss structural and biological studies on several classes of conotoxins that have potential as drug leads for the treatment of pain. The chemical re engineering of conotoxins via cyclization has been particularly valuable in improving their biopharmaceutical properties. An excellent example is the alpha conotoxin Vc1.1, for which several cyclized analogs have been made. One of them was shown to be orally active in a rat pain model and this analog is currently undergoing pre-clinical development for the treatment of neuropathic pain. Several other alpha-conotoxins, including ImI, AuIB and MII, have proved amenable to cyclization and in all cases improvements in stability are obtained upon cyclization, suggesting that cyclization is a generally applicable approach to conotoxin stabilization. A variety of other chemical re-engineering approaches have also been used. Minor re-engineering of chi-conotoxin MrIa to convert its N terminal residue to pyroglutamic acid proved particularly successful and the modified derivative, Xen2174, is currently in clinical trials for neuropathic pain. PMID- 22204426 TI - The multifaceted activities of mammalian defensins. AB - Defensins are an important family of cationic and cysteine-rich host defense peptides that are widely distributed in plants, fungi, and animals. In mammals, defensins exert potent antimicrobial and immunomodulatory activities linking the innate and adaptive immune responses. These peptides play critical roles in health and disease as defects in their production are associated with abnormal host responses to infection, chronic inflammatory diseases, and cancer. There is much interest in elucidating the structure-function relation and modes of action of the defensins to better understand how these peptides kill microbes and regulate the host immune responses. Such knowledge is expected to help in the design of novel defensin-based therapeutics. This review focuses on the multifaceted antimicrobial and immunomodulatory activities of human and murine defensins. PMID- 22204427 TI - Plant defensins and defensin-like peptides - biological activities and biotechnological applications. AB - Plant defensins are cationic peptides that are ubiquitous within the plant kingdom and belong to a large superfamily of antimicrobial peptides found in several organisms collectively called defensins. The primary structure of these peptides includes 45 to 54 amino acid residues with considerable sequence variation. At the level of three-dimensional structure, they are small and globular, composed of three anti-parallel beta-sheets and one alpha-helix, which is highly conserved among these peptides. The three-dimensional structure is stabilized by four disulfide bridges formed by eight strictly conserved Cys residues. Two of these bridges compose the Cys-stabilized alpha-helix beta-strand motif, which is found in other peptides with biological activities. Plant defensins present numerous biological activities, such as inhibiting protein synthesis, ion channel function and alpha-amylase and trypsin activity; impairing microbial, root hair and parasitic plant growth; mediating abiotic stress and Zn tolerance; altering ascorbic acid redox state; stimulating sweet taste sensation; serving as epigenetic factors; affecting self-incompatibility; and promoting male reproductive development. Some of these biological activities, such as microbial growth inhibition and sweet taste induction, coupled with a scaffold that provides these peptides with incredible physicochemical resistance to harsh environments and the potential for simple amino acid substitution, raise the opportunity to improve the function of defensins or introduce new activities, endowing these peptides with great biotechnological and medical significance. This review will cover the biological activities and roles of plant defensins and will focus on their application in the field of biotechnology. PMID- 22204429 TI - Sunflower trypsin inhibitor 1 as a molecular scaffold for drug discovery. AB - This work is focused on SFTI-1, a member of the Bowman-Birk family of inhibitors. This 14 amino acid cyclic peptide exhibits several features i.e. compact rigidity, well-defined structure and small size that could result in a wide range of potential applications. Some examples of engineering of the specificity of this inhibitor along with structure - activity relationships will be discussed herein. Additionally, potential uses of STFI-1 and its analogs as pharmaceutical agents will be described. PMID- 22204430 TI - Circular micro-proteins and mechanisms of cyclization. AB - Transpeptidation reactions result in the formation of new peptide bonds and this can occur between two separate peptides or within the one peptide. These reactions are catalyzed by enzymes and when the N- and C-terminus of the one peptide are joined it results in the formation of cyclic proteins. Cyclization via head-to-tail linkage of the termini of a peptide chain occurs in only a small percentage of proteins but gives the resultant cyclic proteins exceptional stability. The mechanisms are not well understood and this review documents what is known of the events that lead to cyclization. Gene encoded cyclic proteins are found in both prokaryotic and eukaryotic species. The prokaryotic circular proteins include the bacteriocins and pilins. The eukaryotic circular proteins in mammals include the theta-defensins and retrocyclins. Small cyclic proteins are also found in fungi and a large range of cyclic proteins are expressed in cyanobacteria. Three types of cyclic proteins have been found in plants, the small cyclic proteins of 5-12 amino acids, the cyclic proteins from sunflower which are made up of 12-14 amino acids, and the larger group known as cyclotides which contain 28-37 amino acids. Three classes of enzymes are able to catalyse transpeptidation reactions, these include the cysteine, serine and threonine proteases. However only cysteine and serine proteases have been documented to cyclize proteins. The cyclotides from Oldenlandia affinis, the plant in which cyclotides were first discovered, are processed by an asparaginyl endopeptidase which is a cysteine protease. These proteases cleave an amide bond and form an acyl enzyme intermediate before nucleophilic attack of the amine group of the N terminal residue to form a peptide bond, resulting in a cyclic peptide. PMID- 22204428 TI - Cyclotides, a novel ultrastable polypeptide scaffold for drug discovery. AB - Cyclotides are a unique and growing family of backbone cyclized peptides that also contain a cystine knot motif built from six conserved cysteine residues. This unique circular backbone topology and knotted arrangement of three disulfide bonds makes them exceptionally stable to thermal, chemical, and enzymatic degradation compared to other peptides of similar size. Aside from the conserved residues forming the cystine knot, cyclotides have been shown to have high variability in their sequences. Consisting of over 160 known members, cyclotides have many biological activities, ranging from anti-HIV, antimicrobial, hemolytic, and uterotonic capabilities; additionally, some cyclotides have been shown to have cell penetrating properties. Originally discovered and isolated from plants, cyclotides can also be produced synthetically and recombinantly. The high sequence variability, stability, and cell penetrating properties of cyclotides make them potential scaffolds to be used to graft known active peptides or engineer peptide-based drug design. The present review reports recent findings in the biological diversity and therapeutic potential of natural and engineered cyclotides. PMID- 22204431 TI - Natural and engineered cystine knot miniproteins for diagnostic and therapeutic applications. AB - Cystine knot miniproteins define a class of peptides in the size range of approximately 28-35 amino acid residues that often combine high chemical and biological stability with high potency and selectivity. They share a common structural motif that is defined by three intramolecular disulfide bonds that gives rise to a very stable scaffold. Members of this family cover a broad spectrum of natural bioactivities ranging from antimicrobial and antiviral activities to selective blockage or activation of ion channels, cell surface receptors and extracelluar proteases. In recent years, the spectrum of natural bioactivities of this class of miniproteins was further expanded by application of protein design and directed evolution technologies. Miniproteins have been developed that inhibit platelet aggregation, block asthma-related proteases, act as growth factor mimics or address human tumor targets. Recent reports on miniproteins binding to cancer specific targets indicate that these biomolecules due to their particularly high in vivo stability, high target affinity, good tissue distribution, and fast body clearance are very promising agents that can be endowed with important beneficial features for imaging and therapeutic applications. With the first cystine-knot miniprotein already marketed as an analgesic, more candidates can be expected to find their way into the clinic for diagnostic and therapeutic applications over next years. PMID- 22204432 TI - Structure and modeling of knottins, a promising molecular scaffold for drug discovery. AB - The knottins are extremely stable miniproteins present in many species and are able to perform various tasks. Owing to its small size and its amazing stability, the knottin structural domain is considered as an excellent scaffold for drug development. Several recent databases and web servers dedicated to or aware of knottins have appeared and are shortly described. Altogether they provide a valuable ensemble of data and of specific tools that greatly facilitate knottin based studies. The essential structural features of the knottin scaffold, which heavily rest on the three knotted disulfide bridges for its stability, are reviewed. These include small but well-conserved secondary structures and hydrogen bonding networks, but also several further interactions that have been shown to be essential for stability and/or activity. Examples are supplementary disulfide bridges, side chain hydrogen bonds, or circularization. General structure prediction and modeling tools are not well fitted to knottins, and several specific tools have been developed. Specifically, methods to assign a disulfide connectivity pattern to small disulfide-rich sequences or to build accurate 3D models of knottins are available and are discussed in the review. Although more works are still needed to better understand sequence-structure function relationships, recent studies strongly suggest that existing applications of knottins as drugs (i.e. painkillers), molecules for diagnosis, or insecticidal crop treatment should rapidly generalize and extend to other fields as well, e.g. as antimicrobials. PMID- 22204433 TI - Crotamine, a small basic polypeptide myotoxin from rattlesnake venom with cell penetrating properties. AB - Crotamine, a low molecular weight cationic polypeptide from the venom of the South American rattlesnake Crotalus durissus terrificus is a natural cell penetrating peptide with functional versatility. The presence of nine lysine residues and three disulfide bonds renders crotamine highly compact, stable and positively charged. Topologically, crotamine adopts an ancient beta-defensin fold that is found in diverse families of endogenous and venom polypeptides dedicated to host defense. Crotamine is unique among several classes of bioactive peptides because it possesses both cell penetrating and antimicrobial activities and selective biological action toward some cell types at a given cell cycle phase. Because it can rapidly and efficiently translocate into actively proliferating cells, crotamine is being investigated for labeling highly replicating cells and for use as a chemotherapeutic adjuvant. Peptides derived from crotamine, nucleolar targeting peptides (NrTPs), have been designed and are being studied. NrTPs retain some crotamine properties, such as efficient cellular uptake and preferential nuclear localization whereas they improve upon other properties. For example, NrTPs are smaller than crotamine, show higher preferential nucleolar localization, and better facilitate ZIP-code localization of therapeutic proteins. PMID- 22204435 TI - Melatonin, a promising supplement in inflammatory bowel disease: a comprehensive review of evidences. AB - Inflammation and oxidative process are associated with inflammatory bowel disease (IBD). Regarding anti-inflammatory and antioxidant potentials, melatonin has been found beneficial in several experimental and clinical studies including inflammatory bowel disease (IBD). Our objective in this study is to review and evaluate all non-clinical and clinical studies on the efficacy of melatonin in IBD. All indexing databases were searched for inflammatory bowel disease' and 'melatonin' keywords, without time limit up to May 2011. Three clinical trials and fifteen non-clinical studies are reviewed and analyzed. The majority of these studies indicate that melatonin has a positive impact on IBD with no or negligible side effects. Such results have been mostly explained through free radical scavenging and diminishing inflammation. It is yet crucial to determine the efficacy of melatonin in combination with other established drugs in more clinical trials, not only for further confirmation of its efficacy, but also to investigate its possible side effects in longer durations of therapy. PMID- 22204436 TI - Pleiotropic effects of glucagon-like peptide-1 (GLP-1)-based therapies on vascular complications in diabetes. AB - Accelerated atherosclerosis and microvascular complications are the leading causes of coronary heart disease, end-stage renal failure, acquired blindness and a variety of neuropathies, which could account for disabilities and high mortality rates in patients with diabetes. Glucagon-like peptide-1 (GLP-1) belongs to the incretin hormone family. L cells in the small intestine secrete GLP-1 in response to food intake. GLP-1 not only enhances glucose-evoked insulin release from pancreatic beta-cells, but also suppresses glucagon secretion from pancreatic alpha-cells. In addition, GLP-1 slows gastric emptying. Therefore, enhancement of GLP-1 secretion is a potential therapeutic target for the treatment of type 2 diabetes. Dipeptidyl peptidase-4 (DPP-4) is a responsible enzyme that mainly degrades GLP-1, and the half-life of circulating GLP-1 is very short. Recently, DPP-4 inhibitors and DPP-4-resistant GLP-1 receptor (GLP-1R) agonists have been developed and clinically used for the treatment of type 2 diabetes as a GLP-1-based medicine. GLP-1R is shown to exist in extra-pancreatic tissues such as vessels, kidney and heart, and could mediate the diverse biological actions of GLP-1 in a variety of tissues. So, in this paper, we review the pleiotropic effects of GLP-1-based therapies and its clinical utility in vascular complications in diabetes. PMID- 22204434 TI - In vivo bio-imaging using chlorotoxin-based conjugates. AB - Surgical resection remains the primary component of cancer therapy. The precision required to successfully separate cancer tissue from normal tissue relies heavily on the surgeon's ability to delineate the tumor margins. Despite recent advances in surgical guidance and monitoring systems, intra-operative identification of these margins remains imprecise and directly influences patient prognosis. If the surgeon had improved tools to distinguish these margins, tumor progression and unacceptable morbidity could be avoided. In this article, we review the history of chlorotoxin and its tumor specificity and discuss the research currently being generated to target optical imaging agents to cancer tissue. PMID- 22204437 TI - Copolymer micelles and nanospheres with different in vitro stability demonstrate similar paclitaxel pharmacokinetics. AB - Paclitaxel loaded amphiphilic block copolymer nanoparticles have been demonstrated to enhance the aqueous solubility and improve the toxicity profile as compared to the commercially available product Taxol; however, in many cases long circulation of the drug is not achieved due to rapid partitioning of the drug from the carrier and/or carrier instability upon injection. In this work we investigated the effect of increasing the hydrophobic block length of methoxy poly(ethylene glycol)-block-poly(epsilon-caprolactone) (MePEG-b-PCL) copolymers on the physicochemical properties and in vitro stability of the formed nanoparticles as well as the pharmacokinetics and biodistribution of both the copolymer and solubilized drug. We hypothesized that copolymers composed of high molecular weight hydrophobic blocks (MePEG114-b-PCL104) that form nanoparticles with a kinetically "frozen core" (which we term nanospheres) would better retain their PTX payload as compared to micelles composed of shorter hydrophobic blocks (MePEG114-b-PCL19), thus leading to prolonged drug circulation. Nanospheres solubilized PTX more efficiently, released the drug in a more sustained fashion and were characterized by enhanced stability and drug retention in the presence of plasma proteins as compared to micelles. Using radiolabeled copolymers and PTX, it was found that, upon injection, MePEG114-b-PCL104 circulated for longer than MePEG114-b-PCL19; however, the drug was rapidly eliminated from the blood regardless of the formulation. These results suggest that, despite formulation in more stable nanospheres, PTX was still rapidly extracted from these nanoparticles. PMID- 22204439 TI - Palladium-catalyzed cascade cyclization-oxidative olefination of tert-butyl 2 alkynylbenozates. AB - Palladium(II) can catalyze the oxidative coupling of tert-butyl 2 alkynylbenzoates with olefins such as acrylates and styrenes, leading to isocoumarines. The reaction was carried out under simple aerobic conditions, and in most cases, high selectivity has been attained. PMID- 22204440 TI - Understanding implementation processes of clinical pathways and clinical practice guidelines in pediatric contexts: a study protocol. AB - BACKGROUND: Canada is among the most prosperous nations in the world, yet the health and wellness outcomes of Canadian children are surprisingly poor. There is some evidence to suggest that these poor health outcomes are partly due to clinical practice variation, which can stem from failure to apply the best available research evidence in clinical practice, otherwise known as knowledge translation (KT). Surprisingly, clinical practice variation, even for common acute paediatric conditions, is pervasive. Clinical practice variation results in unnecessary medical treatments, increased suffering, and increased healthcare costs. This study focuses on improving health outcomes for common paediatric acute health concerns by evaluating strategies that improve KT and reduce clinical practice variation. DESIGN/METHODS: Using a multiple case study design, qualitative and quantitative data will be collected from four emergency departments in western Canada. Data sources will include: pre- and post implementation focus group data from multidisciplinary healthcare professionals; individual interviews with the local champions, KT intervention providers, and unit/site leaders/managers; Alberta Context Tool (ACT) survey data; and aggregated patient outcome data. Qualitative and quantitative data will be systematically triangulated, and matrices will be built to do cross-case comparison. Explanations will be built about the success or lack of success of the clinical practice guidelines (CPG) and clinical pathways (CPs) uptake based upon the cross-case comparisons. SIGNIFICANCE: This study will generate new knowledge about the potential causal mechanisms and factors which shape implementation. Future studies will track the impact of the CPG/CPs implementation on children's health outcome, and healthcare costs. PMID- 22204441 TI - Glass forming ability and alloying effect of a noble-metal-based glass former. AB - This work addresses the question on how the glass-forming ability (GFA) of a binary Pd-Ni metallic glass can be enhanced by the alloying effect of Pt. The structural features and slow dynamics of liquid and glassy states on both alloys are investigated by molecular dynamics simulations. Both alloys show typical features of glassy dynamics, namely, the non-Arrhenian behavior of diffusion and relaxation and the fractional Stokes-Einstein relation validity at low temperatures. On the basis of the analysis of the dynamical susceptibilities, we demonstrate that there is a strong influence of the alloying effect on the collective motion of the species, revealing that the GFA of the binary liquid increases with Pt alloying. PMID- 22204443 TI - Unidirectional switching between two flavylium reaction networks by the action of alternate stimuli of acid and base. AB - The introduction of an ester group in the flavylium core allowed the reversible conversion between two different flavylium compounds each one exhibiting its own reaction network. An unidirectional switching cycle between 7-diethylamino-2-(4 (methoxycarbonyl)phenyl)-1-benzopyrylium and 2-(4-carboxyphenyl)-7-diethylamino-1 benzopyrylium was achieved by means of alternate acid and base stimuli. Addition of base to a methanolic solution of the ester derivative gives rise to the trans chalcone of the parent carboxylic acid, which upon acidification of the solution forms the respective flavylium cation. This species esterifies under very acidic conditions to restore the original methyl ester derivative. The chemical reaction networks of both compounds were fully characterized from their thermodynamic and kinetic aspects, by a series of pH jumps followed by UV-vis absorption and emission spectroscopy, stopped flow and (1)H NMR. The crystal structure of the trans-chalcone of the ester derivative was unveiled showing a supramolecular structure involving hydrogen bonding. PMID- 22204444 TI - Determinants of physical activity and exercise in healthy older adults: a systematic review. AB - BACKGROUND: The health benefits of regular physical activity and exercise have been widely acknowledged. Unfortunately, a decline in physical activity is observed in older adults. Knowledge of the determinants of physical activity (unstructured activity incorporated in daily life) and exercise (structured, planned and repetitive activities) is needed to effectively promote an active lifestyle. Our aim was to systematically review determinants of physical activity and exercise participation among healthy older adults, considering the methodological quality of the included studies. METHODS: Literature searches were conducted in PubMed/Medline and PsycINFO/OVID for peer reviewed manuscripts published in English from 1990 onwards. We included manuscripts that met the following criteria: 1) population: community dwelling healthy older adults, aged 55 and over; 2) reporting determinants of physical activity or exercise. The outcome measure was qualified as physical activity, exercise, or combination of the two, measured objectively or using self-report. The methodological quality of the selected studies was examined and a best evidence synthesis was applied to assess the association of the determinants with physical activity or exercise. RESULTS: Thirty-four manuscripts reporting on 30 studies met the inclusion criteria, of which two were of high methodological quality. Physical activity was reported in four manuscripts, exercise was reported in sixteen and a combination of the two was reported in fourteen manuscripts. Three manuscripts used objective measures, twenty-two manuscripts used self-report measures and nine manuscripts combined a self-report measure with an objective measure. Due to lack of high quality studies and often only one manuscript reporting on a particular determinant, we concluded "insufficient evidence" for most associations between determinants and physical activity or exercise. CONCLUSIONS: Because physical activity was reported in four manuscripts only, the determinants of physical activity particularly need further study. Recommendations for future research include the use of objective measures of physical activity or exercise as well as valid and reliable measures of determinants. PMID- 22204445 TI - Mechanism and regulation of nucleocytoplasmic trafficking of smad. AB - Smad proteins are the intracellular mediators of transforming growth factor beta (TGF-beta) signaling. Smads function as transcription factors and their activities require carboxyl-terminal phosphorylation by TGF-beta receptor kinases which are embedded in the cell membrane. Therefore, the translocation of activated Smads from the cytoplasm into the nucleus is a rate-limiting step in TGF-beta signal transduction into the nucleus. On the other hand, the export of Smads out of the nucleus turns off TGF-beta effect. Such spatial control of Smad ensures a tight regulation of TGF-beta target genes. Several cross-talk pathways have been shown to affect TGF-beta signaling by impairing nuclear translocation of Smad, exemplifying the biological importance of the nuclear transport process. Many laboratories have investigated the underlying molecular mechanism of Smad nucleocytoplasmic translocation, combining genetics, biochemistry and sophisticated live cell imaging approaches. The last few years have witnessed the elucidation of several key players in Smad nuclear transport, most importantly the karyopherins that carry Smads across the nuclear envelope and nuclear pore proteins that facilitate the trans-nuclear envelope movement. The foundation is now set to further elucidate how the nuclear transport process is regulated and exploit such knowledge to manipulate TGF-beta signaling. In this review we will discuss the current understanding of the molecular machinery responsible for nuclear import and export of Smads. PMID- 22204446 TI - Fruit development of the diploid kiwifruit, Actinidia chinensis 'Hort16A'. AB - BACKGROUND: With the advent of high throughput genomic tools, it is now possible to undertake detailed molecular studies of individual species outside traditional model organisms. Combined with a good understanding of physiological processes, these tools allow researchers to explore natural diversity, giving a better understanding of biological mechanisms. Here a detailed study of fruit development from anthesis through to fruit senescence is presented for a non model organism, kiwifruit, Actinidia chinensis ('Hort16A'). RESULTS: Consistent with previous studies, it was found that many aspects of fruit morphology, growth and development are similar to those of the model fruit tomato, except for a striking difference in fruit ripening progression. The early stages of fruit ripening occur as the fruit is still growing, and many ripening events are not associated with autocatalytic ethylene production (historically associated with respiratory climacteric). Autocatalytic ethylene is produced late in the ripening process as the fruit begins to senesce. CONCLUSION: By aligning A. chinensis fruit development to a phenological scale, this study provides a reference framework for subsequent physiological and genomic studies, and will allow cross comparison across fruit species, leading to a greater understanding of the diversity of fruits found across the plant kingdom. PMID- 22204447 TI - Mapping private pharmacies and their characteristics in Ujjain district, Central India. AB - BACKGROUND: In India, private pharmacies are ubiquitous yet critical establishments that facilitate community access to medicines. These are often the first points of treatment seeking in parts of India and other low income settings around the world. The characteristics of these pharmacies including their location, drug availability, human resources and infrastructure have not been studied before. Given the ubiquity and popularity of private pharmacies in India, such information would be useful to harness the potential of these pharmacies to deliver desirable public health outcomes, to facilitate regulation and to involve in initiatives pertaining to rational drug use. This study was a cross sectional survey that mapped private pharmacies in one district on a geographic information system and described relevant characteristics of these units. METHODS: This study of pharmacies was a part of larger cross sectional survey carried out to map all the health care providers in Ujjain district (population 1.9 million), Central India, on a geographic information system. Their location vis-a-vis formal providers of health services were studied. Other characteristics like human resources, infrastructure, clients and availability of tracer drugs were also surveyed. RESULTS: A total 475 private pharmacies were identified in the district. Three-quarter were in urban areas, where they were concentrated around physician practices. In rural areas, pharmacies were located along the main roads. A majority of pharmacies simultaneously retailed medicines from multiple systems of medicine. Tracer parenteral antibiotics and injectable steroids were available in 83.7% and 88.7% pharmacies respectively. The proportion of clients without prescription was 39.04%. Only 11.58% of staff had formal pharmacist qualifications. Power outages were a significant challenge. CONCLUSION: This is the first mapping of pharmacies & their characteristics in India. It provides evidence of the urban dominance and close relationship between healthcare provider location and pharmacy location. The implications of this relationship are discussed. The study reports a lack of qualified staff in the presence of a high proportion of clients attending without a prescription. The study highlights the need for the better implementation of regulation. Besides facilitating regulation & partnerships, the data also provides a sampling frame for future interventional studies on these pharmacies. PMID- 22204450 TI - Opening sequence: computational genomics in the era of high-throughput sequencing. AB - A report on the 11th Cold Spring Harbor Laboratory/Wellcome Trust conference on Genome Informatics, Cold Spring Harbor Laboratories, New York, USA, November 2-5, 2011. PMID- 22204448 TI - The effect of systematic pediatric care on neonatal mortality and hospitalizations of infants born with oral clefts. AB - BACKGROUND: Cleft lip and/or palate (CL/P) increase mortality and morbidity risks for affected infants especially in less developed countries. This study aimed at assessing the effects of systematic pediatric care on neonatal mortality and hospitalizations of infants with cleft lip and/or palate (CL/P) in South America. METHODS: The intervention group included live-born infants with isolated or associated CL/P in 47 hospitals between 2003 and 2005. The control group included live-born infants with CL/P between 2001 and 2002 in the same hospitals. The intervention group received systematic pediatric care between the 7th and 28th day of life. The primary outcomes were mortality between the 7th and 28th day of life and hospitalization days in this period among survivors adjusted for relevant baseline covariates. RESULTS: There were no significant mortality differences between the intervention and control groups. However, surviving infants with associated CL/P in the intervention group had fewer hospitalization days by about six days compared to the associated control group. CONCLUSIONS: Early systematic pediatric care may significantly reduce neonatal hospitalizations of infants with CL/P and additional birth defects in South America. Given the large healthcare and financial burden of CL/P on affected families and the relatively low cost of systematic pediatric care, improving access to such care may be a cost-effective public policy intervention. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00097149. PMID- 22204449 TI - Interordinal chimera formation between medaka and zebrafish for analyzing stem cell differentiation. AB - Chimera formation is a standard test for pluripotency of stem cells in vivo. Interspecific chimera formation between distantly related organisms offers also an attractive approach for propagating endangered species. Parameters influencing interspecies chimera formation have remained poorly elucidated. Here, we report interordinal chimera formation between medaka and zebrafish, which separated ~320 million years ago and exhibit a more than 2-fold difference in developmental speed. We show that, on transplantation into zebrafish blastulae, both noncultivated blastomeres and long-term cultivated embryonic stem (ES) cells of medaka adopted the zebrafish developmental program and differentiated into physiologically functional cell types including pigment cells, blood cells, and cardiomyocytes. We also show that medaka ES cells express differentiation gene markers during chimeric embryogenesis. Therefore, the evolutionary distance and different embryogenesis speeds do not produce donor-host incompatibility to compromise chimera formation between medaka and zebrafish, and molecular markers are valuable for analyzing lineage commitment and cell differentiation in interspecific chimeric embryos. PMID- 22204453 TI - No evidence for DNA methylation of the ATM promoter CpG island in chronic lymphocytic leukemia. PMID- 22204452 TI - Impact of palifermin on mucosal toxicity in autologous stem cell transplants using busulfan-melphalan conditioning chemotherapy for Hodgkin and non-Hodgkin lymphoma. PMID- 22204454 TI - Helicobacter pylori-induced thrombocytosis clinically indistinguishable from essential thrombocythemia. PMID- 22204455 TI - First-line treatment with imatinib mesylate in patients with chronic phase chronic myeloid leukemia: experience of a public hospital in a developing country of South America. PMID- 22204457 TI - Clinical characteristics and prognosis of acute bacterial meningitis in elderly patients over 65: a hospital-based study. AB - BACKGROUND: To examine the clinical characteristics of bacterial meningitis in elderly patients. METHODS: 261 patients with adult bacterial meningitis (ABM), collected during a study period of 11 years (2000-2010), were included for study. Among them, 87 patients aged >= 65 years and were classified as the elderly group. The clinical and laboratory characteristics and prognostic factors were analyzed, and a clinical comparison with those of non-elderly ABM patients was also made. RESULTS: The 87 elderly ABM patients were composed of 53 males and 34 females, aged 65-87 years old (median = 71 years). Diabetes mellitus (DM) was the most common underlying condition (34%), followed by end stage renal disease (7%), alcoholism (4%) and malignancies (4%). Fever was the most common clinical manifestation (86%), followed by altered consciousness (62%), leukocytosis (53%), hydrocephalus (38%), seizure (30%), bacteremia (21%) and shock (11%). Thirty-nine of these 87 elderly ABM patients had spontaneous infection, while the other 48 had post-neurosurgical infection. Forty-four patients contracted ABM in a community-acquired state, while the other 43, a nosocomial state. The therapeutic results of the 87 elderly ABM patients were that 34 patients expired and 53 patients survived. The comparative results of the clinical and laboratory characteristics between the elderly and non-elderly ABM patients showed that only peripheral blood leukocytosis was significant. Presence of shock and seizure were significant prognostic factors of elderly ABM patients. CONCLUSIONS: Elderly ABM patients accounted for 34.8% of the overall ABM cases, and this relatively high incidence rate may signify the future burden of ABM in the elderly population in Taiwan. The relative frequency of implicated pathogens of elderly ABM is similar to that of non-elderly ABM. Compared with non-elderly patients, the elderly ABM patients have a significantly lower incidence of peripheral blood leukocytosis. The mortality rate of elderly ABM remains high, and the presence of shock and seizures are important prognostic factors. PMID- 22204461 TI - Publisher's Notes. PMID- 22204462 TI - Initial development of an inventory to assess stress and health risk. AB - Abstract In recent years, considerable attention has been given to the role of individual variables in the stress-illness relationship. Of particular value at this point are measurement tools and studies that evaluate the possible effects of two or more individual variables on health status. This study summarizes the initial development, psychometric properties, and validation of a brief, rationally derived, and reliable stress and health risk factor instrument. The 123-item instrument has shown criterion-related validity with both physical and psychological health outcomes in a study with 194 employees working in several large companies in the Los Angeles area. Implications for future development, application, and research are discussed. PMID- 22204458 TI - Tracheo-brachiocephalic artery fistula after tracheostomy associated with thoracic deformity: a case report. AB - INTRODUCTION: Tracheo-brachiocephalic artery fistulae are critical long-term complications after tracheostomy, reported in 0.6% of patients within three to four weeks after the procedure. In 30% to 50% of cases there is some bleeding prior to onset. Since the onset involves sudden massive bleeding, the prognosis is poor; the reported survival rate is 10% to 30%. The direct cause of bleeding is the formation of a fistula with the trachea subsequent to arterial injury by the tracheostomy tube. Endo-tracheal factors are movement of the tracheostomy tube due to body movement and seizures, pressure exerted by the cuff of the tracheostomy tube, tracheostomy at lower levels, and the fragility of blood vessels and the trachea due to steroid or radiation therapy, and malnutrition. Extra-tracheal factors include prior surgery and deformity and shifting of the trachea and major blood vessels due to congenital kyphoscoliosis or thoracic deformity. There has been no report of the usefulness of contrast-enhanced computed tomography studies to identify the anatomical relationship between the trachea and brachiocephalic artery. CASE PRESENTATION: A 27-year-old Mongolian woman with congenital muscular dystrophy who underwent tracheal intubation for airway management due to pneumonia and granulation development developed a tracheo-brachiocephalic artery fistula during the placement of the tracheostomy tube. It was diagnosed by contrast-enhanced chest computed tomography and repaired. About a month later she developed massive airway bleeding during replacement of the tracheostomy tube. Temporary hemostasis was achieved by compression via cuff inflation. A contrast-enhanced chest computed tomography scan demonstrated a narrowed brachiocephalic artery running along and ventral to the tube and a tracheo-brachiocephalic artery fistula was suspected. She underwent brachiocephalic artery resection and aorta, right common carotid artery, and subclavian artery bypass surgery with an innominate vein, tracheoplasty, and partial sternectomy. We noted marked thoracic deformity; the brachiocephalic artery was compressed by the trachea and chest wall resulting in localized wall necrosis and the development of a tracheo-brachiocephalic artery fistula, a fatal complication whose prevention is important. CONCLUSIONS: We suggest that before tracheostomy, the anatomic relationship between the trachea and brachiocephalic artery must be confirmed by contrast-enhanced chest computed tomography scan. PMID- 22204463 TI - Pediatricians and breastfeeding promotion: attitudes, beliefs, and practices. AB - Abstract This study investigated both the degree to which pediatricians promote breastfeeding in their practices, and the attitudes and beliefs about breastfeeding which are associated with their breastfeeding promotion activities. We interviewed a sample of 59 pediatricians from a large urban area who had a variety of practice types and differing patient populations. Almost one half of the pediatricians in this study reported they did not routinely recommend breastfeeding to the mothers of their patients. In addition, few specific interventions to assist in breastfeeding continuation were reported. However, the overwhelming majority of pediatricians sampled reported very favorable attitudes toward breastfeeding promotion by pediatricians. Infrequent prenatal pediatric visits and the lack of formal training in breastfeeding and its management are discussed as potential barriers to more active participation of pediatricians in current efforts to achieve increased rates of breastfeeding. PMID- 22204464 TI - Self-help versus group approaches to smoking cessation in the workplace: eighteen month follow-up and cost analysis. AB - Abstract This study evaluated the relative efficacy and cost-effectiveness of a stop smoking clinic and self-help kit, and characteristics of those who benefited most from each approach. Employees attended an orientation of quit smoking programs that included a brief description of the American Lung Association's "Freedom From Smoking" clinic and "Freedom From Smoking in 20 Days" self-help kit. Seventy registrants provided both baseline and 18-month follow-up information by questionnaire. The two methods attracted smokers with somewhat different socio-demographic characteristics. The combined quit rate for the two groups was 17 percent at 18 months. Cost per participant was twice as high for the clinic method ($32 vs. $16), but cost per successful quitter was similar in both groups (about $150). In light of these results, employees should continue to be offered a choice of self-help and clinic approaches to smoking cessation in order to reach the largest potential number of participants. PMID- 22204465 TI - A health promotion program for medical students: louisiana state university medical center. PMID- 22204467 TI - A revised research agenda model. PMID- 22204466 TI - The accuracy of substitution rules for health risk appraisals. AB - Abstract Health Risk Appraisals (HRAs) have been in increasingly wide use over the past 20 years as health education tools designed to encourage healthy behaviors. A major criticism of HRAs has been the error introduced by missing or incorrectly-specified responses by clients, especially regarding physiological measures such as blood pressure and cholesterol. Four HRAs were randomly assigned to members of a random sample of Massachusetts residents as part of a trial to assess the reliability and validity of HRA instruments. Two rules for substituting unknown physiological measures were evaluated: the existing rule for an HRA and a new rule, which simply substitutes the age- and gender-specific mean physiological values. Ordinary least squares regression was used to compare risk scores generated from known physiological measures, taken in respondents' homes, with risk scores generated by substitution. Regression slopes were mostly close to 1.0, most intercepts were relatively close to 0.0, and correlations were all extremely high, suggesting good performance of substitution rules on a group level. However, outliers from the regressions tended to be individuals at high risk whose risk was underestimated by the substitution rules. These results raise ethical questions about the use of substitution rules and reinforce the need for taking actual physiological measurements. PMID- 22204468 TI - DataBase: Research and Evaluation Results. PMID- 22204469 TI - Business aspects of health promotion. PMID- 22204470 TI - View point: reflections upon personal health in a failing eco-system. PMID- 22204471 TI - Work and family issues: a new frontier for health promotion. PMID- 22204472 TI - Resource reviews. PMID- 22204473 TI - Perspectives beyond health promotion. PMID- 22204474 TI - Professional association profiles. PMID- 22204476 TI - High-resolution micropatterned Teflon AF substrates for biocompatible nanofluidic devices. AB - We describe a general photolithography-based process for the microfabrication of surface-supported Teflon AF structures. Teflon AF patterns primarily benefit from superior optical properties such as very low autofluorescence and a low refractive index. The process ensures that the Teflon AF patterns remain strongly hydrophobic in order to allow rapid lipid monolayer spreading and generates a characteristic edge morphology which assists directed cell growth along the structured surfaces. We provide application examples, demonstrating the well controlled mixing of lipid films on Teflon AF structures and showing how the patterned surfaces can be used as biocompatible growth-directing substrates for cell culture. Chinese hamster ovary (CHO) cells develop in a guided fashion along the sides of the microstructures, selectively avoiding to grow over the patterned areas. PMID- 22204477 TI - Preliminary comparison of helical tomotherapy and mixed beams of unmodulated electrons and intensity modulated radiation therapy for treating superficial cancers of the parotid gland and nasal cavity. AB - BACKGROUND AND PURPOSE: To investigate combining unmodulated electron beams with intensity-modulated radiation therapy to improve dose distributions for superficial head and neck cancers, and to compare mixed beam plans with helical tomotherapy. MATERIALS AND METHODS: Mixed beam and helical tomotherapy dose plans were developed for two patients with parotid gland tumors and two patients with nasal cavity tumors. Mixed beam plans consisted of various weightings of a enface electron beam and IMRT, which was optimized after calculation of the electron dose to compensate for heterogeneity in the electron dose distribution within the target volume. RESULTS: Helical tomotherapy plans showed dose conformity and homogeneity in the target volume that was equal to or better than the mixed beam plans. Electron-only plans tended to show the lowest doses to normal tissues, but with markedly worse dose conformity and homogeneity than in the other plans. However, adding a 20% IMRT dose fraction (i.e., IMRT:electron weighting = 1:4) to the electron plan restored target conformity and homogeneity to values comparable to helical tomotherapy plans, while maintaining lower normal tissue dose. CONCLUSIONS: Mixed beam treatments offer some dosimetric advantages over IMRT or helical tomotherapy for target depths that do not exceed the useful range of the electron beam. Adding a small IMRT component (e.g., IMRT:electron weighting = 1:4) to electron beam plans markedly improved target dose homogeneity and conformity for the cases examined in this study. PMID- 22204478 TI - Association of HLA-DRB1*14 with rheumatic heart disease patients from Chandigarh, North India. AB - CONTEXT: Acute rheumatic fever (ARF)/rheumatic heart disease (RHD) is a major cause of morbidity and mortality in India, yet, few studies are available on susceptibility markers. OBJECTIVE: To associate human leukocyte antigen (HLA) class II alleles with north Indian RHD patients as genetic susceptibility markers. MATERIALS AND METHODS: HLA alleles were analysed using sequence specific primer-polymerase chain reaction and nucleotide sequencing, while HLA-B27 expression by flowcytometry. RESULTS: Few HLA-DQB1/DRB1 alleles were associated with RHD and HLA-DRB1*14 gene polymorphism revealed two single nucleotide polymorphisms (SNPs) in patients. Bioinformatic predictions showed influence of SNPs on protein function. HLA-B27 was positive in 42.85% ARF patients. CONCLUSION: The study showed association of different HLA class II alleles with RHD in North Indian population. PMID- 22204480 TI - The indolylglyoxylamide scaffold as an useful tool to obtain anxiolytic agents. PMID- 22204481 TI - Translocator protein as a promising target for novel anxiolytics. AB - Neurosteroids are able to rapidly control the excitability of the central nervous system, acting as regulators of type A receptors for GABA. Over the last two decades, many authors have confirmed that neurosteroid level alterations occur in psychiatric disorders, including anxiety disorders. More recently, investigators have manipulated neurosteroidogenesis in an effort to correct neuronal excitation and inhibition imbalances, which may lie at the root of neuropsychiatric conditions. In line with this strategy, emerging data have demonstrated that a promising target for therapy of anxiety disorders is the Translocator Protein (TSPO). TSPO is a five transmembrane domain protein (18 kDa) that is expressed predominantly in steroid-synthesizing tissues. At the subcellular level, TSPO is localized at contact sites between the outer and inner mitochondrial membranes and mediates the rate-limiting step of neurosteroidogenesis. Brain concentrations of neurosteroids can be affected by selective TSPO activation. Indeed, TSPO drug ligands are able to stimulate the primary neurosteroid formations that enhance GABAA receptor activity, pregnenolone and allopregnenalone, both in in vitro steroidogenic cells and in vivo animal models. A spectrum of TSPO ligands has been shown to exert anxiolytic actions when administered in rodents. Some TSPO drug ligands could potentially reach clinical development. For example, recent evidence has shown that the selective TSPO ligand, XBD173 (AC-5216, Emapunil), exerts anxiolytic effects not only in animal models, but also in human volunteers. Herein, we review the current literature regarding the central nervous system biology of TSPO, a promising molecular target, in combination with its available ligands. PMID- 22204482 TI - From the pharmacophore to the homology model of the benzodiazepine receptor: the indolyglyoxylamides affair. AB - Interaction between the so-called benzodiazepine receptor (BzR) and the chemically heterogeneous class of its ligands is still one of the most challenging objects of theoretical studies. In the mid-90s our group began to collaborate with Prof. Antonio Da Settimo and coworkers to a project of synthesis and biological evaluation of indolylglyoxylamides designed as BzR ligands. Herein we review our efforts in designing these compounds and in interpreting their structureaffinity relationships. Our investigations were carried out for years by adopting the pharmacophore/topological model for BzR ligands set up by Cook's group. In an attempt to rationalize some puzzling structure-affinity relationships we speculated in 1998 that our ligands interact with the BzR by assuming one of two alternative binding modes (called "A" and "B") depending on whether or not they were substituted at the 5-position of the indole nucleus. Such a model received support from a considerable amount of experimental data accumulated throughout our researches. About a decade later, docking calculations performed on a homology-built model of the 1 BzR subtype were found in agreement with the hypothesis of mode A and mode B of binding accessible to 5-H and, respectively, 5-Cl/NO2 indole derivatives. PMID- 22204483 TI - Treatment strategies of obsessive-compulsive disorder and panic disorder/agoraphobia. AB - Anxiety disorders represent the most prevalent psychiatric disorders. In addition, a considerable burden is associated with them, not only for individual sufferers, but also for the health care system. However, many patients who might benefit from treatment are not diagnosed or treated. This may partly be due to lack of awareness of the anxiety disorders by primary care practitioners and by the sufferers themselves. In addition, the stigma still associated with psychiatric disorders and lack of confidence in psychiatric treatments are factors leading to no/under recognition and treatment, or the use of unnecessary or inappropriate treatments. This paper aims to provide a comprehensive review of recommendations for the pharmacological treatment of two common anxiety disorders, in particular obsessive-compulsive disorder (OCD) and panic disorder (PD). The first-line treatments of OCD include medium-high doses of selective serotonin reuptake inhibitors (SSRIs) and clomipramine, a tricyclic (TCA) antidepressant with prevalent serotonergic activity. The recommended drugs for PD include SSRIs, TCAs and serotonin-norepinephrine reuptake inhibitors (SNRIs); in treatment-resistant cases, benzodiazepines like alprazolam may be used in patients with no history of addiction and tolerance. Other treatment options include irreversible and reversible monoamine-oxidase inhibitors, hydroxyzine, and others. Besides pharmacological treatments, some psychological strategies have been shown to be effective, in particular, cognitive behavior therapy (CBT) and other variants of behavior therapy that have been sufficiently investigated in controlled studies, and, therefore, will be reviewed herein. PMID- 22204484 TI - Medicinal chemistry of indolylglyoxylamide GABAA/BzR high affinity ligands: identification of novel anxiolytic/non sedative agents. AB - The classical benzodiazepines (Bz) constitute a well-known class of therapeutics displaying hypnotic, anxiolytic and anticonvulsant effects acting upon a specific binding site (BzR) belonging to the GABAA receptor complex. Their usefulness, however, is limited by a broad range of side effects; consequently the fact that the action of GABA with the receptor complex could be allosterically modulated by a wide variety of chemical entities, made the Bz binding site, from late eighties to nowdays, the target of extensive research programmes directed to the identification of new ligands displaying varying degrees of affinity- and efficacy-selectivity for the different GABAA/BzR-subtypes. The principal aim has been to discover ideal sedative-hypnotic agents (selective 1 agonists), anxiolytic agents (selective 2/ 3 agonists), or cognitive enhancers (selective 5 inverse agonists). In this connection, an important contribution in the field of GABAA/BzR ligands was made by the research group directed by Professor Antonio Da Settimo at the University of Pisa. The purpose of this review is therefore to describe the studies, performed from early '80s, on the several classes of BzR ligands developed featuring the indol-3-ylglyoxyl scaffold. All the compounds reported have been summarized on the basis of their main chemical structural features, focusing attention on their SARs, which determined the affinity profiles or efficacy-selectivity. Moreover, the biological studies performed within each class of compounds allowed the identification of new derivatives exhibiting an anxiolytic/nonsedative profile, either in vitro (full 2 agonism and 1 partial agonism/ antagonism) and in vivo (anxiolytic/nonsedative activity in mice). PMID- 22204485 TI - Computational studies on translocator protein (TSPO) and its ligands. AB - The Translocator Protein (18 kDa) (TSPO), previously known as the peripheral benzodiazepine receptor, is widely expressed in glial cells and in peripheral tissues and is involved in a variety of biological processes: steroidogenesis, cell growth and differentiation, apoptosis induction, etc. TSPO basal expression is up-regulated in a number of human pathologies, including a variety of tumors and neuropathologies, such as gliomas and neurodegenerative disorders (Huntington's and Alzheimer's diseases), as well as in various forms of brain injury and inflammation. Furthermore, changes in TSPO receptor levels have been found in anxiety and mood disorders. Nowadays, considerable efforts have been focused on the identification of new TSPO ligands characterized by high-affinity and selectivity. In this review, we report and analyze the main experimental data and the computational procedures and validation methods used for the construction of the TSPO receptor and ligand-based models, describing in detail the most successful results and the new trends. PMID- 22204486 TI - Recent developments in potential anxiolytic agents targeting GABAA/BzR complex or the translocator protein (18kDa) (TSPO). AB - Anxiety disorders are frequent and disabling disorders. For short-term treatment, benzodiazepines are useful due to their rapid onset of anxiolytic action. However, these compounds have sedative properties and may induce tolerance, abuse liability and withdrawal symptoms. First-line choices for the long-term treatment are selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. The major disadvantage of these compounds is their delayed onset of action. It is obvious that there is a need for novel pharmacological approaches that combine a rapid anxiolytic efficacy with the lack of tolerance induction, abuse liability and withdrawal symptoms. A very important target for the development of such compounds is the -amino-butyric-acid (GABA)A receptor. Subtype specific benzodiazepines are being developed, but also phytotherapeutic agents experience a renaissance as GABAA receptor modulators. On the other hand, GABA related compounds, e.g. tiagabine, did not show pronounced anxiolytic efficacy. Neuroactive steroids such as allopregnanolone and tetrahydrodeoxycorticosterone (THDOC) are potent modulators of GABAA receptors. To date synthetic neuroactive steroids could not be established in the treatment of anxiety disorders. Regarding endogenous neurosteroidogenesis, recently the translocator protein (18kDa) (TSPO) has been identified as a potential novel target. TSPO is supposed to play an important role for the synthesis of neuroactive steroids. TSPO ligands may promote the synthesis of neuroactive steroids via induction of cholesterol translocation to the inner mitochondrial membrane. First clinical studies revealed promising results. In this review, we discuss putative compounds affecting the GABAergic system which may provide the basis for fast acting anxiolytics with a favorable side effect profile. PMID- 22204487 TI - Medicinal chemistry of indolylglyoxylamide TSPO high affinity ligands with anxiolytic-like effects. AB - The mitochondrial translocator protein (TSPO) mediates the synthesis of neurosteroids in the CNS, which have been demonstrated to enhance the neurotransmitter GABA response, exhibiting related behavioural properties. Selective TSPO ligands are able to stimulate steroidogenesis with great efficacy, thus representing potential anxiolytic agents. This review describes the development of a class of high affinity ligands to TSPO, N,N-dialkylindol-3 ylglyoxylamides (IGA), from the initial stages of design to the pharmacological characterization of selected compounds for their anxiolytic activity. Affinity data and SARs of the new class of ligands are discussed; the potential applications of compounds characterized by the indolylglyoxylyl scaffold in diagnostic imaging are also pointed out. PMID- 22204488 TI - The GABAA-BZR complex as target for the development of anxiolytic drugs. AB - Anxiety disorders have been linked to alterations in gamma-aminobutyric acid (GABA) neurotransmission. GABA interacts with the ligand-gated ion channels, GABAA receptor (GABAA-R) subtypes, and regulates the flow of chloride into the cell, causing neuron hyperpolarization. GABAA-Rs are assembled from a family of 19 homologous subunit gene products and form mostly hetero-oligomeric pentamers. The major isoforms of the GABAA-Rs contain alpha, beta and gamma subunits and show a regional heterogeneity that is associated with distinct physiological effects. A variety of allosteric ligands can modulate the response to GABA by binding at different sites on the GABAA-R complex. The best characterized binding site is the benzodiazepine (BZ) one, which is located at the alpha/gamma subunit interface. BZs are commonly used in therapy for their effects as anxiolytic, anticonvulsants, myorelaxants and hypnotics. The broad range of pharmacological effects of classical BZs are mediated by the selective activation of different GABAA-R subtypes: the alpha1 subunit containing BZ receptor (BZ-R) mediates sedation, the alpha2 and alpha3 subunit containing BZ-R mediates anxiolysis and myorelaxation, and the alpha5 subunit containing BZ-R mediates cognitive impairment. Based on the current understanding of the diversity of the GABAA-R family, different approaches have been employed to develop drugs that target the GABAA/BZ-R complex with selective anxiolytic action and improved profiles. In this review, we present current knowledge about the role of the GABAA/BZ-R complex in anxiety disorders, new insights into the molecular biology of the receptor complex, and the importance of this target in the development of new therapeutic agents in anxiety. PMID- 22204489 TI - Geometrically constrained derivatives of indolylglyoxylamides as ligands binding the GABAA/BzR complex. AB - Indolylglyoxylamides are a class of distinctive benzodiazepine receptor ligands, proposed in the mid-eighties as open analogues of -carbolines. Thorough and long lasting studies of their structure-activity relationships led to the development of a great deal of derivatives, to satisfy increasingly structural and pharmacophoric requirements of the benzodiazepine binding site in the central nervous system. Efforts to pre-organize their flexible structure in the three dimensional shape adopted when bound to the receptor led to the identification of two novel classes of rigid ligands, characterized by planar tricyclic heteroaromatic cores: the [1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one and the [1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-dione. The present review focuses on these selected classes of ligands, whose rational development, in terms of chemical structures and structure-activity relationships, will be fully discussed. PMID- 22204490 TI - Association study between the gibberellic acid insensitive gene and leaf length in a Lolium perenne L. synthetic variety. AB - BACKGROUND: Association studies are of great interest to identify genes explaining trait variation since they deal with more than just a few alleles like classical QTL analyses. They are usually performed using collections representing a wide range of variability but which could present a genetic substructure. The aim of this paper is to demonstrate that association studies can be performed using synthetic varieties obtained after several panmictic generations. This demonstration is based on an example of association between the gibberellic acid insensitive gene (GAI) polymorphism and leaf length polymorphism in 'Herbie', a synthetic variety of perennial ryegrass. METHODS: Leaf growth parameters, consisted of leaf length, maximum leaf elongation rate (LERmax) and leaf elongation duration (LED), were evaluated in spring and autumn on 216 plants of Herbie with three replicates. For each plant, a sequence of 370 bp in GAI was analysed for polymorphism. RESULTS: Genetic effect was highly significant for all traits. Broad sense heritabilities were higher for leaf length and LERmax with about 0.7 in each period and 0.5 considering both periods than for LED with about 0.4 in each period and 0.3 considering both periods. GAI was highly polymorphic with an average of 12 bp between two consecutive SNPs and 39 haplotypes in which 9 were more frequent. Linkage disequilibrium declined rapidly with distance with r 2 values lower than 0.2 beyond 150 bp. Sequence polymorphism of GAI explained 8 14% of leaf growth parameter variation. A single SNP explained 4% of the phenotypic variance of leaf length in both periods which represents a difference of 33 mm on an average of 300 mm. CONCLUSIONS: Synthetic varieties in which linkage disequilibrium declines rapidly with distance are suitable for association studies using the "candidate gene" approach. GAI polymorphism was found to be associated with leaf length polymorphism which was more correlated to LERmax than to LED in Herbie. It is a good candidate to explain leaf length variation in other plant material. PMID- 22204492 TI - Thermochemical data and additivity group values for ten species of o-xylene low temperature oxidation mechanism. AB - o-Xylene could be a good candidate to represent the family of aromatic hydrocarbons in a surrogate fuel. This study uses computational chemistry to calculate standard enthalpies of formation at 298 K, Delta(f)H degrees (298 K), standard entropies at 298 K, S degrees (298 K), and standard heat capacities C(p) degrees (T) over the temperature range 300 K to 1500 K for ten target species present in the low-temperature oxidation mechanism of o-xylene: o-xylene (1), 2 methylbenzyl radical (2), 2-methylbenzylperoxy radical (3), 2-methylbenzyl hydroperoxide (4), 2-(hydroperoxymethyl)benzyl radical (5), 2 (hydroperoxymethyl)benzaldehyde (6), 1-ethyl-2-methylbenzene (7), 2,3 dimethylphenol (8), 2-hydroxybenzaldehyde (9), and 3-hydroxybenzaldehyde (10). Delta(f)H degrees (298 K) values are weighted averages across the values calculated using five isodesmic reactions and five composite calculation methods: CBS-QB3, G3B3, G3MP2, G3, and G4. The uncertainty in Delta(f)H degrees (298 K) is also evaluated. S degrees (298 K) and C(p) degrees (T) values are calculated at B3LYP/6-311G(d,p) level of theory from molecular properties and statistical thermodynamics through evaluation of translational, rotational, vibrational, and electronic partition functions. S degrees (298 K) and C(p) degrees (300 K) values are evaluated using the rigid-rotor-harmonic-oscillator model. C(p) degrees (T) values at T >= 400 K are calculated by treating separately internal rotation contributions and translational, external rotational, vibrational, and electronic contributions. The thermochemical properties of six target species are used to develop six new additivity groups taking into account the interaction between two substituents in ortho (ORT/CH2OOH/ME, ORT/ET/ME, ORT/CHO/OH, ORT/CHO/CH2OOH) or meta (MET/CHO/OH) positions, and the interaction between three substituents (ME/ME/OH123) located one beside the other (positions numbered 1, 2, 3) for two- or three-substituted benzenic species. Two other additivity groups are also developed using the thermochemical properties of benzenic species taken from the literature: the C/CB/H2/OO and the CB/CO groups. These groups extend the capacities of the group additivity method to deal with substituted benzenic species. PMID- 22204491 TI - Roles of TGFbeta signaling Smads in squamous cell carcinoma. AB - Smad proteins are classified in different groups based on their functions in mediating transforming growth factor beta (TGFbeta) superfamily components. Smad1/5/8 mainly mediate bone morphogenetic proteins (BMP) pathway and Smad2/3 mainly mediate TGFbeta pathway. Smad4 functions as common Smad to mediate both pathways. Previous studies showed many members of TGFbeta superfamily play a role in carcinogenesis. The current review focuses on the role of TGFbeta signaling Smads in squamous cell carcinomas (SCCs). TGFbeta signaling inhibits early tumor development, but promotes tumor progression in the late stage. Although Smad2, Smad3 and Smad4 are all TGFbeta signaling Smads, they play different roles in SCCs. Genetically, Smad2 and Smad4 are frequently mutated or deleted in certain human cancers whereas Smad3 mutation or deletion is infrequent. Genetically engineered mouse models with these individual Smad deletions have provided important tools to identify their diversified roles in cancer. Using these models, we have shown that Smad4 functions as a potent tumor suppressor and its loss causes spontaneous SCCs development; Smad2 functions as a tumor suppressor and its loss promotes SCC formation initiated by other genetic insults but is insufficient to initiate tumor formation. In contrast, Smad3 primarily mediates TGFbeta-induced inflammation. The functions of each Smad also depends on the presence/absence of its Smad partner, thus need to be interpreted in a context specific manner. PMID- 22204493 TI - Hyperglycemia in apolipoprotein E-deficient mouse strains with different atherosclerosis susceptibility. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of atherosclerotic vascular disease, but it is unknown whether the other way around is true too. C57BL/6 (B6) and BALB/cJ (BALB) are two mouse strains that differ markedly in their susceptibility to atherosclerosis. In this study we investigated the development of diet-induced T2DM in these two strains. METHODS AND RESULTS: When deficient in apolipoprotein E (apoE(-/-)) and fed a Western diet for 12 weeks, atherosclerosis-susceptible B6 mice developed significant hyperglycemia. In contrast, atherosclerosis-resistant BALB apoE(-/-) mice had much lower plasma glucose levels than B6.apoE(-/-) mice on either chow or Western diet and during an intraperitoneal glucose tolerance test. In response to glucose BALB.apoE(-/-) mice displayed both the first and second phases of insulin secretion but the second phase of insulin secretion was absent in B6.apoE(-/-) mice. In response to insulin B6.apoE(-/-) mice showed a deeper and longer-lasting fall in blood glucose levels while BALB.apoE(-/-) mice showed little reduction in glucose levels. Pancreatic islet area of BALB.apoE(-/-) mice on light microscopy nearly doubled the area of B6.apoE(-/-) mice. Most circulating proinflammatory cytokines were lower in BALB.apoE(-/-) than in B6.apoE(-/-) mice on the Western diet, as determined by protein arrays. Increased macrophage infiltration in islets was observed in B6.apoE(-/-) mice by immunostaining for Mac2 and also by flow cytometry. CONCLUSION: This study demonstrates that defects in insulin secretion rather than defects in insulin resistance explain the marketed difference in susceptibility to T2DM in the B6.apoE(-/-) and BALB.apoE(-/-) mouse model. A smaller islet mass and more prominent islet inflammation may explain the vulnerability of B6.apoE(-/-) mice to diet-induced diabetes. PMID- 22204494 TI - Timeliness of contact tracing among flight passengers for influenza A/H1N1 2009. AB - BACKGROUND: During the initial containment phase of influenza A/H1N1 2009, close contacts of cases were traced to provide antiviral prophylaxis within 48 h after exposure and to alert them on signs of disease for early diagnosis and treatment. Passengers seated on the same row, two rows in front or behind a patient infectious for influenza, during a flight of >= 4 h were considered close contacts. This study evaluates the timeliness of flight-contact tracing (CT) as performed following national and international CT requests addressed to the Center of Infectious Disease Control (CIb/RIVM), and implemented by the Municipal Health Services of Schiphol Airport. METHODS: Elapsed days between date of flight arrival and the date passenger lists became available (contact details identified - CI) was used as proxy for timeliness of CT. In a retrospective study, dates of flight arrival, onset of illness, laboratory diagnosis, CT request and identification of contacts details through passenger lists, following CT requests to the RIVM for flights landed at Schiphol Airport were collected and analyzed. RESULTS: 24 requests for CT were identified. Three of these were declined as over 4 days had elapsed since flight arrival. In 17 out of 21 requests, contact details were obtained within 7 days after arrival (81%). The average delay between arrival and CI was 3,9 days (range 2-7), mainly caused by delay in diagnosis of the index patient after arrival (2,6 days). In four flights (19%), contacts were not identified or only after > 7 days. CI involving Dutch airlines was faster than non-Dutch airlines (P < 0,05). Passenger locator cards did not improve timeliness of CI. In only three flights contact details were identified within 2 days after arrival. CONCLUSION: CT for influenza A/H1N1 2009 among flight passengers was not successful for timely provision of prophylaxis. CT had little additional value for alerting passengers for disease symptoms, as this information already was provided during and after the flight. Public health authorities should take into account patient delays in seeking medical advise and laboratory confirmation in relation to maximum time to provide postexposure prophylaxis when deciding to install contact tracing measures. International standardization of CT guidelines is recommended. PMID- 22204495 TI - Lansoprazole as a rescue agent in chemoresistant tumors: a phase I/II study in companion animals with spontaneously occurring tumors. AB - BACKGROUND: The treatment of human cancer has been seriously hampered for decades by resistance to chemotherapeutic drugs. Mechanisms underlying this resistance are far from being entirely known. A very efficient mechanism of tumor resistance to drugs is related to the modification of tumour microenvironment through changes in the extracellular and intracellular pH. The acidification of tumor microenvironment depends on proton pumps that actively pump protons outside the cells, mostly to avoid intracellular acidification. In fact, we have shown in pre clinical settings as pre-treatment with proton-pumps inhibitors (PPI) increase tumor cell and tumor responsiveness to chemotherapeutics. In this study pet with spontaneously occurring cancer proven refractory to conventional chemotherapy have been recruited in a compassionate study. METHODS: Thirty-four companion animals (27 dogs and 7 cats) were treated adding to their chemotherapy protocols the pump inhibitor lansoprazole at high dose, as suggested by pre-clinical experiments. Their responses have been compared to those of seventeen pets (10 dogs and 7 cats) whose owners did not pursue any other therapy than continuing the currently ongoing chemotherapy protocols. RESULTS: The drug was overall well tolerated, with only four dogs experiencing side effects due to gastric hypochlorhydria consisting with vomiting and or diarrhea. In terms of overall response twenty-three pets out of 34 had partial or complete responses (67.6%) the remaining patients experienced no response or progressive disease however most owners reported improved quality of life in most of the non responders. On the other hand, only three animals in the control group (17%) experienced short lived partial responses (1-3 months duration) while all the others died of progressive disease within two months. CONCLUSIONS: high dose proton pump inhibitors have been shown to induce reversal of tumor chemoresistance as well as improvement of the quality of life in pets with down staged cancer and in the majority of the treated animals PPI were well tolerated. Further studies are warranted to assess the efficacy of this strategy in patients with advanced cancers in companion animals as well as in humans. PMID- 22204497 TI - Derivation of novel genetically diverse human embryonic stem cell lines. AB - Human embryonic stem cells (hESCs) have the potential to revolutionize many biomedical fields ranging from basic research to disease modeling, regenerative medicine, drug discovery, and toxicity testing. A multitude of hESC lines have been derived worldwide since the first 5 lines by Thomson et al. 13 years ago, but many of these are poorly characterized, unavailable, or do not represent desired traits, thus making them unsuitable for application purposes. In order to provide the scientific community with better options, we have derived 12 new hESC lines at New York University from discarded genetically normal and abnormal embryos using the latest techniques. We examined the genetic status of the NYUES lines in detail as well as their molecular and cellular features and DNA fingerprinting profile. Furthermore, we differentiated our hESCs into the tissues most affected by a specific condition or into clinically desired cell types. To our knowledge, a number of characteristics of our hESCs have not been previously reported, for example, mutation for alpha thalassemia X-linked mental retardation syndrome, linkage to conditions with a genetic component such as asthma or poor sperm morphology, and novel combinations of ethnic backgrounds. Importantly, all of our undifferentiated euploid female lines tested to date did not show X chromosome inactivation, believed to result in superior potency. We continue to derive new hESC lines and add them to the NIH registry and other registries. This should facilitate the use of our hESCs and lead to advancements for patient benefitting applications. PMID- 22204498 TI - The association between delusional-like experiences, and tobacco, alcohol or cannabis use: a nationwide population-based survey. AB - BACKGROUND: Previous population-based studies have found that delusional-like experiences (DLE) are prevalent in the community, and are associated with a wide range of mental health disorders including substance use. The aim of the study was to explore the association between DLE and three commonly used substances- tobacco, alcohol and cannabis. METHODS: Subjects were drawn from the Australian National Survey of Mental Health and Wellbeing 2007. The Composite International Diagnostic Interview was used to identify DLE, common psychiatric disorders, and substance use. We examined the relationship between the variables of interest using logistic regression, adjusting for potential confounding factors. RESULTS: Of 8,773 participants, 8.4% (n=776) subjects endorsed one or more DLE. With respect to tobacco use, compared to nonusers, DLE were more common in those who (a) had daily use, (b) commenced usage aged 15 years or less, and (c) those who smoked heavily (23 or more cigarettes per day). Participants with cannabis use disorders were more likely to endorse DLE; this association was most prominent in those with an onset of 16 years or younger. In contrast, the pattern of association between DLE versus alcohol use or dependence was less consistent, however those with early onset alcohol use disorders were more likely to endorse DLE probe items. CONCLUSIONS: While cannabis use disorders have been previously linked with DLE, our findings linking alcohol and tobacco use and DLE suggest that the influence of these substances on psychosis-related outcomes warrants closer scrutiny in longitudinal prospective studies. PMID- 22204500 TI - Design, construction, and characterization of high-performance membrane fusion devices with target-selectivity. AB - Membrane fusion proteins such as the hemagglutinin glycoprotein have target recognition and fusion accelerative domains, where some synergistically working elements are essential for target-selective and highly effective native membrane fusion systems. In this work, novel membrane fusion devices bearing such domains were designed and constructed. We selected a phenylboronic acid derivative as a recognition domain for a sugar-like target and a transmembrane-peptide (Leu-Ala sequence) domain interacting with the target membrane, forming a stable hydrophobic alpha-helix and accelerating the fusion process. Artificial membrane fusion behavior between the synthetic devices in which pilot and target liposomes were incorporated was characterized by lipid-mixing and inner-leaflet lipid mixing assays. Consequently, the devices bearing both the recognition and transmembrane domains brought about a remarkable increase in the initial rate for the membrane fusion compared with the devices containing the recognition domain alone. In addition, a weakly acidic pH-responsive device was also constructed by replacing three Leu residues in the transmembrane-peptide domain by Glu residues. The presence of Glu residues made the acidic pH-dependent hydrophobic alpha-helix formation possible as expected. The target-selective liposome-liposome fusion was accelerated in a weakly acidic pH range when the Glu-substituted device was incorporated in pilot liposomes. The use of this pH-responsive device seems to be a potential strategy for novel applications in a liposome-based delivery system. PMID- 22204501 TI - Cranial pole nephrectomy in the pig model: anatomic analysis of arterial injuries in tridimensional endocasts. AB - PURPOSE: To assess the intrarenal arteries injuries after cranial pole nephrectomy in a pig model to compare these findings with those in humans. MATERIALS AND METHODS: Polyester resin was injected through the ureter and the renal artery to make three-dimensional casts of 61 pig kidneys. The cranial pole of the kidneys was sectioned at four different sites before the solidification of the resin, and the casts were examined for arterial damage. RESULTS: Section performed through the hilus (15 kidneys): The cranial division of the renal artery was sectioned in two (13.33%) cases, the ventral branch of the cranial division of the renal artery was sectioned in 13 (86.7%) cases, and the dorsal branch of the cranial division of the renal artery was sectioned in 11 (73.34%) cases. Section at 0.5 cm cranial to the hilus (16 kidneys): The cranial division of the renal artery was sectioned in 1 (6.25%) case, the ventral branch of the cranial division of the renal artery was sectioned in 14 (87.5%) cases, and the dorsal branch of the cranial division of the renal artery was sectioned in 13 (81.25%) cases. Section at 1.0 cm cranial to the hilus (15 kidneys): The ventral branch of the cranial division of the renal artery was sectioned in five (33.33%) cases, and the dorsal branch of the cranial division of the renal artery was injured in five (33.33%) cases. Section at 1.5 cm cranial to the hilus (15 kidneys): No lesions were found in the main arteries, only in the interlobular branches. CONCLUSIONS: As previously demonstrated in humans, sections at 1.0 cm or more cranially to the hilus in pigs also showed a significant decrease in damage to the major intrarenal arteries. Therefore, as regards arterial damage, the pig kidney is a useful model for partial nephrectomy in the cranial (upper) pole. PMID- 22204506 TI - Publisher's Notes. PMID- 22204504 TI - Dose to level I and II axillary lymph nodes and lung by tangential field radiation in patients undergoing postmastectomy radiation with tissue expander reconstruction. AB - BACKGROUND: To define the dosimetric coverage of level I/II axillary volumes and the lung volume irradiated in postmastectomy radiotherapy (PMRT) following tissue expander placement. METHODS AND MATERIALS: Twenty-three patients were identified who had undergone postmastectomy radiotherapy with tangent only fields. All patients had pre-radiation tissue expander placement and expansion. Thirteen patients had bilateral expander reconstruction. The level I/II axillary volumes were contoured using the RTOG contouring atlas. The patient-specific variables of expander volume, superior-to-inferior location of expander, distance between expanders, expander angle and axillary volume were analyzed to determine their relationship to the axillary volume and lung volume dose. RESULTS: The mean coverage of the level I/II axillary volume by the 95% isodose line (V(D95%)) was 23.9% (range 0.3 - 65.4%). The mean Ipsilateral Lung V(D50%) was 8.8% (2.2-20.9). Ipsilateral and contralateral expander volume correlated to Axillary V(D95%) in patients with bilateral reconstruction (p = 0.01 and 0.006, respectively) but not those with ipsilateral only reconstruction (p = 0.60). Ipsilateral Lung V(D50%) correlated with angle of the expander from midline (p = 0.05). CONCLUSIONS: In patients undergoing PMRT with tissue expanders, incidental doses delivered by tangents to the axilla, as defined by the RTOG contouring atlas, do not provide adequate coverage. The posterior-superior region of level I and II is the region most commonly underdosed. Axillary volume coverage increased with increasing expander volumes in patients with bilateral reconstruction. Lung dose increased with increasing expander angle from midline. This information should be considered both when placing expanders and when designing PMRT tangent only treatment plans by contouring and targeting the axilla volume when axillary treatment is indicated. PMID- 22204507 TI - An evaluation of the potential role of the physician in influencing community exercise behavior. AB - Abstract The potential influence of physicians upon the exercise behavior of individuals has been examined. Key questions explored were a) whether people believed that their personal physician thought that they should exercise, and b) the level of motivation to comply with these perceived expectations. Subjects were drawn from four independent populations: 1) parents of junior high school students (N = 479); 2) university employees (N = 190); 3) lower-limb disabled adults (N = 62); and 4) pregnant women (N = 68). Questionnaire-based physical activity scores were transformed into Z-scores and the data sets for activity and beliefs were pooled. Multiple regression models were developed for each individual data set and for the combined data. The proportion of the variance in reported physical activity explained by the normative belief regarding the physician and the level of motivation to comply with the perceived physician's expectations was very low (adjusted R(2) = 0.026 for the combined data sets). In general, healthy adults thought that their personal physician wanted them to exercise and were motivated to comply with such advice. In contrast, disabled adults saw their personal physician as opposed to exercise which they were motivated to undertake. These findings are discussed in terms of the importance of social norms as determinants of exercise behavior and the position that physicians should adopt when seeking to enhance exercise behavior. PMID- 22204508 TI - HIV Infection: Assessment of Sexual Risk, Knowledge, and Attitudes Towards Prevention in 1,586 High School Students in the Toulouse Education Authority Area. AB - Abstract In view of the spread of the AIDS epidemic in France, knowledge of the disease and sexual behavior, particularly use of condoms, was examined in 1,586 high school pupils in the Toulouse area. Modes of HIV transmission were found to be well known. However, some misconceptions existed, including the possibility of contagion from drinking utensils or from being around someone with AIDS. One third of the pupils had had sexual intercourse with more than one partner, and of these, 42 percent had never used condoms. A total of 65 percent of those questioned were in favor of condom use, but nearly 25 percent of students who had already used condoms found them difficult to use. Use of condoms appeared more likely if students felt personally at risk. PMID- 22204509 TI - The use of smokeless tobacco among basic airmen. AB - Abstract The use of smokeless tobacco, including both snuff and chewing tobacco, is enjoying a resurgence in popularity in the United States, particularly among teenage males. In order to assess the prevalence of these habits among young Air Force recruits, we administered a questionnaire to a random sample of 1,954 basic airmen at Lackland Air Force Base, Texas, to obtain information on frequency, types, intensity, and duration of smokeless tobacco use in this population. We found that 14.9 percent of the males reported using snuff for an average of 104 minutes per day. Chewing tobacco was reported among 11.1 percent of males with an average daily exposure of 72.1 minutes. The average duration of use of both snuff and chewing tobacco prior to entry into the Air Force was four years. Highest usage for both products was seen among Caucasian males. Users of both types of smokeless tobacco products were also more likely to be cigarette smokers than those who did not use either product. PMID- 22204510 TI - Improving participation in worksite wellness programs: comparing health education classes, a menu approach, and follow-up counseling. AB - Abstract Findings are presented from a study to compare four types of worksite wellness programs to reduce cardiovascular risks. Using a quasi-experimental design, the study was implemented in four large manufacturing plants, similar in demographic characteristics. At the end of the three-year study period, the two sites that included individual outreach and counseling had engaged about 46 percent of identified smokers and 54 percent of the overweight into smoking cessation and weight loss activities, respectively. This compares with fewer than 10 percent at the site offering health education classes only, and less than one percent at the control site. In order to achieve these results, the outreach and follow-up counseling was coupled with a menu of interventions for smoking cessation and weight loss, to accommodate the needs of people who cannot or will not participate in classes. The menu includes guided self-help, one-to-one counseling, mini-groups, and full classes. PMID- 22204511 TI - Rapid assessment of dietary intake of fat, fiber, and saturated fat: validity of an instrument suitable for community intervention research and nutritional surveillance. AB - Abstract Traditional methods to assess changes in dietary intake, for example food frequency questionnaires or 24-hour dietary recalls, are often not practical: they are lengthy, expensive, and unsuitable for telephone administration. This article describes the development and evaluation of an approach to the rapid assessment of the dietary intake of nutrients of most interest in health promotion research; total fat, saturated fat, dietary fiber, and percent of calories from fat. In this validation study on 97 women, short dietary questionnaires were compared to two criterion measures of usual dietary intake, a food frequency questionnaire and the mean of two four-day diet records. Correlations between self-administered short questionnaires and four-day diet records were 0.52, 0.53, 0.61, and 0.40 for total fat, percent of calories from fat, saturated fat, and dietary fiber, respectively. These correlations are similar to those observed between food frequency questionnaires and four-day diet records, which suggests that this approach to developing and administering short dietary questionnaires may be useful in situations where more expensive and time consuming methods of dietary assessment are not practical. PMID- 22204512 TI - DataBase: Research and Evaluation Results. PMID- 22204514 TI - AFB Practitioners' Forum. PMID- 22204513 TI - Business aspects of health promotion. PMID- 22204515 TI - Who is This Young Whippersnapper and What Does S/He Know About My Life? Or, What to do When You're Face to Face with "Them". PMID- 22204516 TI - Resource reviews. PMID- 22204517 TI - Perspectives beyond health promotion. PMID- 22204519 TI - Pharmacogenomics and personalized medicine: the plunge into next-generation sequencing. AB - A report on the 9th Annual Cold Spring Harbor/Wellcome Trust meeting 'Pharmacogenomics and Personalized Medicine', Hinxton, Cambridge, UK, 29 September to 2 October 2011. PMID- 22204520 TI - Primary hyperparathyroidism diagnosed after surgical ablation of a costal mass mistaken for giant-cell bone tumor: a case report. AB - INTRODUCTION: Primary hyperparathyroidism is a common endocrine disorder characterized by elevated parathyroid hormone levels, which cause continuous osteoclastic bone resorption. Giant cell tumor of bone is an expansile osteolytic tumor that contains numerous osteoclast-like giant cells. There are many similarities in the radiological and histological features of giant cell tumor of bone and brown tumor. This is a rare benign focal osteolytic process most commonly caused by hyperparathyroidism. CASE PRESENTATION: We report the unusual case of a 40-year-old Caucasian woman in which primary hyperparathyroidism was diagnosed after surgical ablation of a costal mass. The mass was suspected of being neoplastic and histopathology was compatible with a giant cell tumor of bone. On the basis of the biochemical results (including serum calcium, phosphorous and intact parathyroid hormone levels) primary hyperparathyroidism was suspected and a brown tumor secondary to refractory hyperparathyroidism was diagnosed. CONCLUSIONS: Since giant cell tumor is a bone neoplasm that has major implications for the patient, the standard laboratory tests in patients with bone lesions are important for a correct diagnosis. PMID- 22204522 TI - Ruthenium-arene complexes of curcumin: X-ray and density functional theory structure, synthesis, and spectroscopic characterization, in vitro antitumor activity, and DNA docking studies of (p-cymene)Ru(curcuminato)chloro. AB - The in vitro antiproliferative activity of the title compound on five tumor cell lines shows preference for the colon-rectal tumor HCT116, IC(50) = 13.98 MUM, followed by breast MCF7 (19.58 MUM) and ovarian A2780 (23.38 MUM) cell lines; human glioblastoma U-87 and lung carcinoma A549 are less sensitive. A commercial curcumin reagent, also containing demethoxy and bis-demethoxy curcumin, was used to synthesize the title compound, and so (p-cymene)Ru(demethoxy curcuminato)chloro was also isolated and chemically characterized. The crystal structure of the title compound shows (1) the chlorine atom linking two neighboring complexes through H-bonds with two O(hydroxyl), forming an infinite two-step network; (2) significant twist in the curcuminato, 20 degrees between the planes of the two phenyl rings. This was also seen in the docking of the Ru complex onto a rich guanine B-DNA decamer, where a Ru-N7(guanine) interaction is detected. This Ru-N7(guanine) interaction is also seen with ESI-MS on a Ru complex-guanosine derivative. PMID- 22204523 TI - Extended key-factor/key-stage analysis for longitudinal data. AB - Key-factor/key-stage analysis was originally a descriptive approach to analyze life tables. However, this method can be extended to analyze longitudinal data in pharmaceutical experiments. By dividing the variance into components, the extended key-factor/key-stage analysis indicates which factor is influential, and through which stage the factor generates its influence in determining the outcome of treatments. Such knowledge helps us in constructing a class of nonlinear longitudinal models that can be interpretable than linear models. Example SAS programs and R programs are provided for the calculation. Supplemental materials are available for this article. Go to the publisher's online edition of Journal of Biopharmaceutical Statistics to view the supplemental files. PMID- 22204524 TI - Evaluation of the pre-posterior distribution of optimized sampling times for the design of pharmacokinetic studies. AB - Information theoretic methods are often used to design studies that aim to learn about pharmacokinetic and linked pharmacokinetic-pharmacodynamic systems. These design techniques, such as D-optimality, provide the optimum experimental conditions. The performance of the optimum design will depend on the ability of the investigator to comply with the proposed study conditions. However, in clinical settings it is not possible to comply exactly with the optimum design and hence some degree of unplanned suboptimality occurs due to error in the execution of the study. In addition, due to the nonlinear relationship of the parameters of these models to the data, the designs are also locally dependent on an arbitrary choice of a nominal set of parameter values. A design that is robust to both study conditions and uncertainty in the nominal set of parameter values is likely to be of use clinically. We propose an adaptive design strategy to account for both execution error and uncertainty in the parameter values. In this study we investigate designs for a one-compartment first-order pharmacokinetic model. We do this in a Bayesian framework using Markov-chain Monte Carlo (MCMC) methods. We consider log-normal prior distributions on the parameters and investigate several prior distributions on the sampling times. An adaptive design was used to find the sampling window for the current sampling time conditional on the actual times of all previous samples. PMID- 22204525 TI - Power and sample size calculation for microarray studies. AB - Microarray is a technology to screen a large number of genes to discover those differentially expressed between clinical subtypes or different conditions of human diseases. Gene discovery using microarray data requires adjustment for the large-scale multiplicity of candidate genes. The family-wise error rate (FWER) has been widely chosen as a global type I error rate adjusting for the multiplicity. Typically in microarray data, the expression levels of different genes are correlated because of coexpressing genes and the common experimental conditions shared by the genes on each array. To accurately control the FWER, the statistical testing procedure should appropriately reflect the dependency among the genes. Permutation methods have been used for accurate control of the FWER in analyzing microarray data. It is important to calculate the required sample size at the design stage of a new (confirmatory) microarray study. Because of the high dimensionality and complexity of the correlation structure in microarray data, however, there have been no sample size calculation methods accurately reflecting the true correlation structure of real microarray data. We propose sample size and power calculation methods that are useful when pilot data are available to design a confirmatory experiment. If no pilot data are available, we recommend a two-stage sample size recalculation based on our proposed method using the first stage data as pilot data. The calculated sample sizes are shown to accurately maintain the power through simulations. A real data example is taken to illustrate the proposed method. PMID- 22204526 TI - An estimation method of the clearance for a one-compartment model of a single bolus intravenous injection by a single sampling. AB - In clinical trials, sometimes only a single drug concentration can be measured from a patient, because of the burden on the patient. From a single concentration, we cannot generally obtain point estimates of each pharmacokinetic parameter in a patient. In this article, we propose a method to estimate the clearance using a one-compartment model of a single-bolus intravenous injection from a single concentration at a sampling point between 1.5 and 2.5 half-lives. This method requires an assumed value for the volume of distribution but is robust to misspecification. This approach is illustrated by simulated concentration data and cadralazine concentration data. PMID- 22204527 TI - Two-stage model-free tests of synergy in drug combinations. AB - Laska et al. ( 1994 ) proposed a model-free method of detecting synergy in two drug combinations that requires no assumptions about the underlying dose-response curves of the drugs, just an estimate of the potency ratio of the two drugs. It was noted that the power of this method is highly dependent on the accuracy of the potency ratio estimated, with low power when the estimate is inaccurate. Additionally, the test used to detect synergy (the Min test) has been shown to be conservative in many practical applications, and non-monotonic alternative tests that have greater power have been proposed. We suggest a two-stage, non-monotonic alternative to the Laska et al. model-free test that is less dependent on the accuracy of potency ratio estimate and has greater power in many situations. We illustrate the method with an example of two chemotherapeutic agents. PMID- 22204528 TI - Genomic biomarkers for a binary clinical outcome in early drug development microarray experiments. AB - In this article, we discuss methods to select three different types of genes (treatment related, response related, or both) and investigate whether they can serve as biomarkers for a binary outcome variable. We consider an extension of the joint model introduced by Lin et al. (2010) and Tilahun et al. (2010) for a continuous response. As the model has certain drawbacks in a binary setting, we also present a way to use classical selection methods to identify subgroups of genes, which are treatment and/or response related. We evaluate their potential to serve as biomarkers by applying DLDA to predict the response level. PMID- 22204529 TI - Simultaneous confidence bands for comparisons to placebo, with application to detecting the minimum effective dose. AB - In this article we consider a max-min approach to construct two-sided and one sided simultaneous confidence bands in a dose-response study for the contrast in mean responses of each ascending dose versus placebo. The method utilizes the assumption of monotone non-decreasing dose-response curve. Also discussed is a step-down testing procedure that utilizes the lower bands to estimate the minimum effective dose (MED). The performance of our proposed step-down procedure is assessed by simulations and is shown to be superior to competitors when the MED is the lowest dose in a dose-response study. PMID- 22204530 TI - Interval estimation of the proportion ratio in repeated binary measurements under a stratified randomized clinical trial with noncompliance. AB - The proportion ratio (PR) of a positive response between an experimental treatment and a standard treatment (or placebo) is often used to measure the relative treatment efficacy in a randomized clinical trial (RCT). For ethical reasons, it is almost inevitable to encounter some patients not complying with their assigned treatment. Furthermore, when there are confounders in a RCT or meta-analysis, we commonly employ stratified analysis to control the confounding effects on interval estimation of the PR. On the basis of a general risk multiplicative model, we focus our discussion on interval estimation of the PR in repeated binary data under a stratified RCT with noncompliance. We develop seven asymptotic closed-form interval estimators for the PR. We apply Monte Carlo simulation to study the finite-sample performance of these interval estimators in a variety of situations. We note that the two interval estimators with the logarithmic transformation based on the commonly used weighted least squares (WLS) approach can be liberal, while the three interval estimators with the Mantel-Haenszel (MH) weight derived from various methods can consistently perform well. We also note that the two estimators with the estimated optimal weight defined in the context using Fieller's Theorem and a randomization-based approach may not necessarily produce a confidence interval preferable to the MH-type interval estimators for the PR with respect to accuracy and precision. PMID- 22204531 TI - Sample sizes for estimating differences in proportions--can we keep things simple? AB - Sample sizes for studies that aim to estimate differences in proportions are often calculated using a confidence interval approach. In particular, the methods advocated by Day ( 1988 ) and Bristol ( 1989 ), based on asymptotic normal approximations, are commonly used. We compare these to the Wilson score approach discussed by Newcombe ( 1998 ) and show, except for extreme values, that the Day method gives results close to those of Wilson score method, while that of Bristol is consistently higher. We argue that the asymptotic normal approximation approach of Day serves as a better guide for quick calculations of sample sizes. PMID- 22204532 TI - The log-Burr XII regression model for grouped survival data. AB - The log-Burr XII regression model for grouped survival data is evaluated in the presence of many ties. The methodology for grouped survival data is based on life tables, where the times are grouped in k intervals, and we fit discrete lifetime regression models to the data. The model parameters are estimated by maximum likelihood and jackknife methods. To detect influential observations in the proposed model, diagnostic measures based on case deletion, so-called global influence, and influence measures based on small perturbations in the data or in the model, referred to as local influence, are used. In addition to these measures, the total local influence and influential estimates are also used. We conduct Monte Carlo simulation studies to assess the finite sample behavior of the maximum likelihood estimators of the proposed model for grouped survival. A real data set is analyzed using a regression model for grouped data. PMID- 22204533 TI - A consistency-adjusted strategy for accommodating an underpowered primary endpoint. AB - A clinical trial might involve more than one clinically important endpoint, each of which can characterize the treatment effect of the experimental drug under investigation. Underlying the concept of using such endpoints interchangeably to establish an efficacy claim, or pooling different endpoints to constitute a composite endpoint, is the assumption that findings from such endpoints are consistent with each other. While such an assumption about consistency of efficacy findings appears to be intuitive, it is seldom considered in the design and analysis literature of clinical trials with multiple endpoints. Failure to account for consistency of efficacy findings of two candidate endpoints to establish efficacy, at the design stage, has led to difficulties in interpreting study findings. This article presents a flexible testing strategy for accommodating findings of an alternative to the designated primary endpoint (or a subgroup) to support an efficacy claim. The method is built on the following two premises: (i) Efficacy findings of the designated primary endpoint, although nonsignificant, need to be supportive of those of the alternative endpoint, and (ii) the significance level allocated for testing the second endpoint is determined adaptively based on the magnitude of the p-value for the designated primary endpoint. The method takes into account the hierarchical ordering of the hypotheses tested and the correlation between the test statistics for the two endpoints to increase the chance of a positive trial. We discuss control of the type I error rate for the proposed test strategy and compare its power with that of other methods. In addition, we consider its application to two clinical trials. PMID- 22204534 TI - Optimal design of mixed-effects PK/PD models based on differential equations. AB - There is a vast literature on the analysis of optimal design of nonlinear mixed effects models (NLMMs) described by ordinary differential equations (ODEs) with analytic solution. However, much less has been published on the design of trials to fit such models with nonanalytic solution. In this article, we use the "direct" method to find parameter sensitivities, which are required during the optimization of models defined as ODEs, and apply them to find D-optimal designs for various specific situations relevant to population pharmacokinetic studies using a particular model with first-order absorption and elimination. In addition, we perform two simulation studies. The first one aims to show that the criterion computed from the development of the Fisher information matrix expression is a good measure to compare and optimize population designs, thus avoiding a large number of simulations; In the second one, a sensitivity analysis with respect to parameter misspecification allows us to compare the robustness of different population designs constructed in this article. PMID- 22204535 TI - Letters to the editor. PMID- 22204536 TI - Letters to the editor. PMID- 22204542 TI - R. Hugonnier's 'Strabology'. PMID- 22204541 TI - Resecting the lateral rectus in unilateral duane syndrome. PMID- 22204543 TI - Panoramic exotropia diplopia. PMID- 22204544 TI - Strabology: room for improvement. PMID- 22204545 TI - Renewal of (Moral) MIssion Objectives for Orthoptists and Strabologists: What We ARe All About. PMID- 22204546 TI - Eye candy world: don't think, emote! Strabology surgery for nystagmus; slip? Trypan blue; globe fixes. PMID- 22204547 TI - Binocular ocular motility: breaking with the past: how understanding dynamic ocular motor control and central nervous system plasticity promote novel discovery and therapy of nystagmus. AB - INTRODUCTION: The lure of studying the ocular motor system stems from its anatomic and physiological accessibility, ease of measurement and analysis of function, as well as the promise of providing a direct window into the brain. There is an increasing body of knowledge on how the brain responds to peripheral eye muscle manipulation (surgery, medications, denervation, genetic therapy). Investigations in both animals and humans have established that plasticity within the brain occurs after peripheral neuromuscular (medical or surgical) disruption and repair. PURPOSE: This paper will review and summarize neurophysiological concepts resulting from recent investigations of the ocular motor system and treatment of involuntary oscillations such as nystagmus. METHODS: Review of both a multidisciplinary literature and the authors 25 years experience evaluating, treating and investigating the ocular motor system. CONCLUSIONS: The ocular motor system in man is a continuously controlled, malleable brain-eye system, which is genetically programmed, environmentally modified and contains powerful reparative processes. It begins during development, extends throughout life and is subject to external manipulation in both health and disease. These ideas challenge the historically significant axiom, i.e., that there is eventual (and a final maturing to an end state) "hard-wiring" of much of both the ocular motor and afferent visual systems. Rather, they now are shown to maintain some degree of plasticity throughout life. PMID- 22204548 TI - The use of trypan blue dye for strabismus reoperations, surgery complications, and especially for the identification and recovery of a "slipped" or "lost" extraocular muscle. AB - PURPOSE: To evaluate trypan blue dye in strabismus surgery for tissue identification, to find the lowest optimal concentration, and to describe histological findings. in tissue so stained. METHODS: Trypan Blue dye 0.1% was serially diluted and tested by tissue staining at progressively different concentrations. Fifteen patients were studied using the dye. RESULTS: Trypan Blue 0.1 percent was the optimal concentration. Muscle, tendon and fibrotic tissues were easily identified and distinguished with the dye at this concentration. Such tissue identification was most useful and enhanced the performance of strabismus surgical operations, and especially in identifying and retrieving slipped or temporarily lost extraocular muscles.Also a thin basement-like membrane surrounding the superior oblique muscle tendons was disclosed with PAS stain, suggesting the presence of glycosaminoglycans. CONCLUSIONS: Trypan Blue 0.1percent contrasts the different tissues, dying the muscle sheath, tendons and fibrotic tissues, but not staining the sclera and muscle fibers per se. PMID- 22204549 TI - Periosteal Flap fixation of the Globe for Surgical Treatment of Severe Restrictive Strabismus: A Report of Eight Cases with Outcomes. AB - PURPOSE: Severe paretic and restrictive strabismus presents a challenging surgical problem. Despite aggressive, and often multiple, surgical attempts, patients can have recurrence of large angle binocular misalignments. In this paper, we present a series of patients who underwent apically-based orbital bone periosteal flap fixation of the globe in cases of restrictive strabismus due to isolated third-nerve and sixth-nerve palsies, multiple cranial nerve palsies, and severe ocular fibrosis syndrome. METHODS: We performed a retrospective study at our institution of patients who underwent a periosteal flap fixation. In all cases presented, the creation of the periosteal flap was performed by an orbital surgeon, and the strabismus surgery and follow-up data points were performed and collected by a strabologist. RESULTS: A total of 8 patients underwent a periosteal flap fixation of the globe. The mean age was 48 years old. Three patients had a third cranial nerve palsy, one patient had congenital fibrosis, one patient had sixth cranial nerve palsy, and three patients had multiple cranial nerve palsies. Five patients had a medial periosteal flap constructed, and 3 patients had a temporal periosteal flap. Seven of the 8 patients had stable postoperative strabometry (binocular misalignment) measurements. A single patient required an additional procedure secondary to postoperative drift (a mild recurrence of binocular misalignment). CONCLUSIONS: The surgical correction of severe paretic and restrictive strabismus is complex and can present a formidable challenge. The use of an orbital bone-based periosteal fixation flap, at our institution, has shown satisfactory outcomes not only with regard to improved postoperative deviation, but also, in that most patients required only this single procedure, usually after several prior unsuccessful interventions by standard strabismus surgery procedures. PMID- 22204550 TI - Globe fixation with homologous temporalis fascia transplant for treatment of restrictive esotropia strabismus: an interventional case report and review of the literature. AB - PURPOSE: To report a case of fat adherence complication syndrome after pterygium surgery, sufficiently severe enough to create a recurring significant extraocular motility problem and its ultimate novel and successful management. METHOD: A 75 year old man was referred with an acquired large angle esotropia after pterygium surgery. Multiple previous strabismus surgeries to relieve the esotropia had already been performed but failed. Bilateral poor vision obviated complaints of diplopia but his binocular visual field was halved and his vision overall and his motility vision was handicapped by this limited ocular motility in his right eye. We therefore utilized homologous adjacent temporalis fascia transplantation for re-fixation of his frozen esotropic globe in primary position. Result of Surgery: Not only was the esotropia resolved but he also developed and regained some degree of abduction in this eye. CONCLUSION: Homologous Temporalis fascia transplant can be used safely, for globe fixation in surgical treatment of severe restrictive strabismus. PMID- 22204551 TI - Optically Obvious: Strabometry: CLRTs (Corneal Light Reflection Tests)(i.e.: Hirschberg's and Krimsky's) are Tester (Examiner) Monocular tests, Not Binocular. PMID- 22204552 TI - Consciousness: A Function of Stereoscopic Vision via the Egocenter. PMID- 22204554 TI - Patients with micro or other myocardial infarctions have equal long-term survival. AB - OBJECTIVES: To investigate differences in prognosis after myocardial infarction (MI) in patients classified according to the old and new definitions of MI. Patients not fulfilling the old definitions were classified as having a micro MI. DESIGN: Data on 1216 consecutive patients with a diagnosis of first MI (38.3% women) and who were discharged from or died in one hospital in the 5-year period from 2001 were included in the study. Surviving patients were followed for a mean of 8.2 years. Risk factors and death after MI were analysed according to MI classification. RESULTS: Of the patients, 20.1% were classified as having a micro MI. During follow-up, 47.2% of all the patients died. Patients with micro MI were older and fewer were current smokers than patients with other MI. In multivariate Cox regression analysis for the total risk of mortality, age, diabetes mellitus, a positive smoking history, history of stroke and living alone were significantly related to long-term prognosis, and there was no difference in long-term survival between the two types of MI (p 0.50). CONCLUSIONS: After adjustment for confounders, patients with micro MI had no significant difference in long-term survival compared with those with other MI. PMID- 22204555 TI - Arterial smooth muscle injury causes blood tissue factor elevation predicting restenosis after pci. AB - OBJECTIVE: The predictability of the whole-blood tissue factor levels for restenosis after coronary angioplasty is uncertain. We first probed in depth the association between plasma tissue factor concentrations and the development of restenosis after coronary intervention with an animal pathological model. METHODS AND RESULTS: Thirty pigs were used and their coronary arteries were injured for the dilatation of balloons. Morphological measurements include neointimal area, injury score and the extent of area stenosis. Whole-blood tissue factor levels were measured before and after intervention. The circulating tissue factor levels increased significantly after intervention (baseline value, 328.54 +/- 47.46 pg/ml; at 30th minute, 618.96 +/- 119.08 pg/ml; at 24th hour, 639.34 +/- 116.21 pg/ml) (p < 0.01), and the degrees of tissue factor changes correlated positively to the neointimal hyperplasty (r(30th min) = 0.751, r(24th hour) = 0.72, p < 0.01). There was no significant difference with the baseline whole blood tissue factor (TF) levels between restenotic and non-restenotic cases (330.83 +/- 47.32 vs. 325.1 +/- 49.57 pg/ml) (p > 0.05). The injury of media led to the most distinctive changes of blood tissue factor (p < 0.01). CONCLUSION: Higher values of whole-blood tissue factor may be a predictor of restenosis, and the damaged media might be the main reason of the tissue factor increase. PMID- 22204557 TI - The definition of HIV-associated neurocognitive disorders: are we overestimating the real prevalence? AB - BACKGROUND: A substantial prevalence of mild neurocognitive disorders has been reported in HIV, also in patients treated with combination antiretroviral therapy (cART). This includes a new disorder that has been termed asymptomatic neurocognitive impairment (ANI). DISCUSSION: ANI is identified by performance on formal neuropsychological testing that is at least 1 SD below the mean of normative scores in at least two cognitive domains out of at least five examined in patients without associated symptoms or evident functional impairment in daily living. While two tests are recommended to assess each domain, only one is required to fulfill this diagnostic criterion. Unfortunately, this definition necessitates that about 20% of the cognitively normal HIV-infected population is classified as suffering ANI. This liberal definition raises important ethical concerns and has as well diagnostic and therapeutic implications. Since neither its biological substrate, prognostic significance nor therapeutic implications are clearly established, we recommend that this diagnosis be modified or applied cautiously. SUMMARY: The diagnoses of less severe forms of neurocognitive disorders in HIV relies on the outcomes of neuropsychological testing, and a high proportion of HIV-infected patients with effective cART may be classified as neurocognitively abnormal using the current criteria. The definition of ANI is not stringent, and results in approximately 20% of the population being classified as abnormal. To us this seems an unacceptable false-positive rate. PMID- 22204556 TI - Partners in crime: the TGFbeta and MAPK pathways in cancer progression. AB - The TGFbeta and Ras-MAPK pathways play critical roles in cell development and cell cycle regulation, as well as in tumor formation and metastasis. In the absence of cellular transformation, these pathways operate in opposition to one another, where TGFbeta maintains an undifferentiated cell state and suppresses proliferation, while Ras-MAPK pathways promote proliferation, survival and differentiation. However, in colorectal and pancreatic cancers, the opposing pathways' mechanisms are simultaneously activated in order to promote cancer progression and metastasis. Here, we highlight the roles of the TGFbeta and Ras MAPK pathways in normal and malignant states, and provide an explanation for how the concomitant activation of these pathways drives tumor biology. Finally, we survey potential therapeutic targets in these pathways. PMID- 22204558 TI - Concentration-dependent effects of narciclasine on cell cycle progression in Arabidopsis root tips. AB - BACKGROUND: Narciclasine (NCS) is an Amaryllidaceae alkaloid isolated from Narcissus tazetta bulbs. NCS has inhibitory effects on a broad range of biological activities and thus has various potential practical applications. Here we examine how NCS represses plant root growth. RESULTS: Results showed that the inhibition of NCS on cell division in Arabidopsis root tips and its effects on cell differentiation are concentration-dependent; at low concentrations (0.5 and 1.0 MUM) NCS preferentially targets mitotic cell cycle specific/cyclin complexes, whereas at high concentration (5.0 MUM) the NCS-stimulated accumulation of Kip related proteins (KRP1 and RP2) affects the CDK complexes with a role at both G1/S and G2/M phases. CONCLUSIONS: Our findings suggest that NCS modulates the coordination between cell division and differentiation in Arabidopsis root tips and hence affects the postembryonic development of Arabidopsis seedlings. PMID- 22204560 TI - Endothelio-hematopoietic relationship: getting closer to the beginnings. AB - The close association between hematopoietic and endothelial cells during embryonic development led to the proposal that they may originate from a common ancestor--the hemangioblast. Due to a lack of unique specific markers for in vivo cell fate tracking studies, evidence supporting this theory derives mainly from in vitro differentiation studies. Teixeira and colleagues describe a novel enhancer that drives specific eGFP expression in blood islands of the electroporated chick embryo, thereby presenting a tool potentially suitable for analysis of hemangioblast differentiation and development of blood islands. PMID- 22204561 TI - Carbon dioxide capture in metal-organic frameworks. PMID- 22204564 TI - Multiprotein microcontact printing with micrometer resolution. AB - Depositing multiple proteins on the same substrate in positions similar to the natural cellular environment is essential to tissue engineering and regenerative medicine. In this study, the development and verification of a multiprotein microcontact printing (MUCP) technique is described. It is shown that patterns of multiple proteins can be created by the sequential printing of proteins with micrometer precision in registration using an inverted microscope. Soft polymeric stamps were fabricated and mounted on a microscope stage while the substrate to be stamped was placed on a microscope objective and kept at its focal distance. This geometry allowed for visualization of patterns during the multiple stamping events and facilitated the alignment of multiple stamped patterns. Astrocytes were cultured over stamped lane patterns and were seen to interact and align with the underlying protein patterns. PMID- 22204566 TI - Initial investigation using statistical process control for quality control of accelerator beam steering. AB - BACKGROUND: This study seeks to increase clinical operational efficiency and accelerator beam consistency by retrospectively investigating the application of statistical process control (SPC) to linear accelerator beam steering parameters to determine the utility of such a methodology in detecting changes prior to equipment failure (interlocks actuated). METHODS: Steering coil currents (SCC) for the transverse and radial planes are set such that a reproducibly useful photon or electron beam is available. SCC are sampled and stored in the control console computer each day during the morning warm-up. The transverse and radial - positioning and angle SCC for photon beam energies were evaluated using average and range (Xbar-R) process control charts (PCC). The weekly average and range values (subgroup n = 5) for each steering coil were used to develop the PCC. SCC from September 2009 (annual calibration) until two weeks following a beam steering failure in June 2010 were evaluated. PCC limits were calculated using the first twenty subgroups. Appropriate action limits were developed using conventional SPC guidelines. RESULTS: PCC high-alarm action limit was set at 6 standard deviations from the mean. A value exceeding this limit would require beam scanning and evaluation by the physicist and engineer. Two low alarms were used to indicate negative trends. Alarms received following establishment of limits (week 20) are indicative of a non-random cause for deviation (Xbar chart) and/or an uncontrolled process (R chart). Transverse angle SCC for 6 MV and 15 MV indicated a high-alarm 90 and 108 days prior to equipment failure respectively. A downward trend in this parameter continued, with high-alarm, until failure. Transverse position and radial angle SCC for 6 and 15 MV indicated low-alarms starting as early as 124 and 116 days prior to failure, respectively. CONCLUSION: Radiotherapy clinical efficiency and accelerator beam consistency may be improved by instituting SPC methods to monitor the beam steering process and detect abnormal changes prior to equipment failure.PACS numbers: 87.55n, 87.55qr, 87.56bd. PMID- 22204567 TI - Pontine extension of a tentorial schwannoma without cranial nerve involvement: a case report. AB - INTRODUCTION: Intracranial schwannomas unrelated to the cranial nerves are uncommon. We report a new case of tentorial schwannoma unrelated to the cranial nerves, with extension into the pons. A literature review with discussion of the most relevant pathogenetic aspects is also performed. CASE PRESENTATION: A 42 year-old Caucasian man was admitted with right-sided paresthesias and weakness of his upper and lower extremities. The neurological examination revealed right hemiparesis and hemi-hypoesthesia. A brain magnetic resonance imaging scan revealed a cerebellopontine lesion, arising from the left free edge of the tentorium, and extending into his pons. A piecemeal removal was performed through a retrosigmoid approach. The lesion was not found to be associated with any cranial nerves. The histological examination revealed a schwannoma Antoni type A. His postoperative course was uneventful. At one year follow-up, the patient was neurologically intact and the magnetic resonance imaging of his brain performed at that time showed complete removal without signs of recurrence. CONCLUSION: Tentorial schwannomas are rare clinical entities. Knowledge of their clinical, radiological and anatomical characteristics is very important for the correct diagnosis and management. PMID- 22204568 TI - The association between glucometabolic disturbances, traditional cardiovascular risk factors and self-rated health by age and gender: a cross-sectional analysis within the Malmo Preventive Project. AB - BACKGROUND: The increased risk of cardiovascular disease (CVD) in diabetic compared to non-diabetic subjects seems to decrease with age. Whether this age related reduction applies to CVD risk factors, and whether it is limited to established diabetes mellitus (DM) or also applies to pre-diabetic conditions are not well known. METHODS: Using a cross-sectional design we compared the strength of the correlation between glucometabolic disturbances (by grouping), CVD risk factor burden and self-rated health, in two age groups: middle-aged (57-69 years) and older (70-86 years) subjects, (63% men), participating in the Malmo Preventive Project Re-examination Study (n=18,238). Simple (unadjusted) logistic regression analysis was applied to estimate between-group differences and trends. Interaction analysis was applied to estimate differences between age groups. RESULTS: CVD risk factor burden and the proportion of subjects reporting poor self-rated health increased with increasing glucometabolic disturbance for men and women in both age groups (p-trend<0.0001 for all). The slope of the trend curve with increasing CVD risk factor burden was significantly steeper for older women than for older men (p-interaction=0.002). The slope of the trend curve for poor self-rated health was significantly steeper for middle-aged than for older men (p-interaction=0.005), while no difference was observed between the age groups among women (p-interaction=0.97). CONCLUSIONS: We found no reduction in risk factor accumulation with increasing glucometabolic disturbance between middle-aged and older subjects. Our results indicate life-long CVD risk factor clustering with increased glucometabolic disturbance, and suggest that previously observed age-related reduction in excess CVD risk for subjects with DM might be due to a survival bias. However, our observations indicate more pronounced risk factor clustering and worse self-rated health with increased glucometabolic disturbance in older women than in older men. PMID- 22204571 TI - Publisher's Notes. PMID- 22204569 TI - The relationship, structure and profiles of schizophrenia measurements: a post hoc analysis of the baseline measures from a randomized clinical trial. AB - BACKGROUND: To fully assess the various dimensions affected by schizophrenia, clinical trials often include multiple scales measuring various symptom profiles, cognition, quality of life, subjective well-being, and functional impairment. In this exploratory study, we characterized the relationships among six clinical, functional, cognitive, and quality-of-life measures, identifying a parsimonious set of measurements. METHODS: We used baseline data from a randomized, multicenter study of patients diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder who were experiencing an acute symptom exacerbation (n = 628) to examine the relationship among several outcome measures. These measures included the Positive and Negative Syndrome Scale (PANSS), Montgomery-Asberg Depression Rating Scale (MADRS), Brief Assessment of Cognition in Schizophrenia Symbol Coding Test, Subjective Well-being Under Neuroleptics Scale Short Form (SWN-K), Schizophrenia Objective Functioning Instrument (SOFI), and Quality of Life Scale (QLS). Three analytic approaches were used: 1) path analysis; 2) factor analysis; and 3) categorical latent variable analysis. In the optimal path model, the SWN-K was selected as the final outcome, while the SOFI mediated the effect of the exogenous variables (PANSS, MADRS) on the QLS. RESULTS: The overall model explained 47% of variance in QLS and 17% of the variance in SOFI, but only 15% in SWN-K. Factor analysis suggested four factors: "Functioning," "Daily Living," "Depression," and "Psychopathology." A strong positive correlation was observed between the SOFI and QLS (r = 0.669), and both the QLS and SOFI loaded on the "Functioning" factor, suggesting redundancy between these scales. The measurement profiles from the categorical latent variable analysis showed significant variation in functioning and quality of life despite similar levels of psychopathology. CONCLUSIONS: Researchers should consider collecting PANSS, SOFI, and SWN-K in their trials. This would allow a broad spectrum of assessments that would have the ability to capture a wide range of treatment outcomes and allow for a rich characterization of the subgroups involved. Additional research is needed to identify the critical cognitive measures. TRIALS REGISTRATION: CLINICAL TRIALS REGISTRATION: Predicting Response to Risperidone Treatment Through Identification of Early onset of Antipsychotic Drug Action in SchizophreniaClinicalTrials.gov identifier: NCT00337662; http://www.clinicaltrials.gov/ PMID- 22204572 TI - Stress reduction at the worksite: an evaluation of two methods. AB - Abstract Stress is estimated to cost industry between 75 and 100 billion dollars annually as a result of absenteeism, medical claims and diminished productivity. Two types of stress management programs were studied to evaluate their effectiveness at the worksite. The Time-Life Stress Management Program and a Myers-Briggs Personality Type approach were used. The Time-Life program was given to 113 participants, and 35 participated in the Myers-Briggs program. Baseline stress (strain) scores were obtained using a standardized strain survey instrument. Follow-up strain scores were obtained six to eight months after baseline for 62 percent of the individuals. Both groups showed significant reductions in follow-up strain scores when compared to baseline. Reductions in strain were greater in the group with higher baseline strain scores (Time-Life). Worksite stress management programs have the potential to reduce strain among employees for at least six to eight months. PMID- 22204573 TI - Health conception, health locus of control, and power as predictors of smoking behavior change. AB - Abstract The purpose for this study was to examine the value of health conception, health locus of control, and power as predictors of success or failure with smoking behavior change. Discriminant analysis was used to differentiate between subjects who successfully abstained from smoking and those who resumed smoking following participation in a smoking control program. Results indicated that an external locus of control, including expected outcomes attributed to chance and powerful others, a clinical-based conception of health, and a heightened sense of awareness, distinguished recidivists from successful abstainers. Study findings may have implications for identifying smokers who have a high probability of failing in initial attempts to quit smoking. Special instructions and interventions need to be designed to help these smokers develop a broader definition of health as more than the absence of disease, a greater sense of internal control over health practices, and an increased sense of power for participating in behavioral change. PMID- 22204574 TI - Fitness awards: do they accomplish their intended objectives? AB - Abstract Considerable attention has recently been focused on awards as a means of motivating children and youth to take fitness tests and to become physically active. This research was conducted to determine the number of youth who actually achieve standards for earning the various fitness awards, the extent to which award earners are successful in achieving other recognition for physical performance, and the relative contribution of various fitness components to earning fitness awards. A total of 1, 774 youths (1,227 males and 547 females) ranging in age from 14 to 17 served as subjects in the study. Subjects completed items commonly included in national fitness test batteries, as well as a questionnaire indicating the extent of their athletic accomplishments. Results indicate that very few subjects met criteria for earning fitness awards, and those who did meet these criteria also received recognition for success in athletics. Further, those subjects who met award criteria had discriminant function profiles characterized by power, agility, and speed. These profiles were effective in classifying, and thus predicting, which subjects would be successful in earning awards. Questions should be raised about the motivational effectiveness of awards based on exclusive normative standards since these awards go primarily to those with athletic prowess and motor fitness. PMID- 22204575 TI - Heart smart: a multifaceted cardiovascular risk reduction program for grade school students. AB - Abstract Heart Smart Program is a health education intervention for grades kindergarten through six which encourages the acquisition and maintenance of health-enhancing behaviors. These include nutritious eating habits; physical fitness and exercise; saying "no" to cigarette smoking, alcohol, and drugs; and control of stress. Social Cognitive Theory is used to derive the necessary training concepts for children with reinforcement of these concepts occurring in six areas: the curriculum, school lunch, staff development, physical activity, environment, and parental support. The necessary training mechanisms provide mastery experiences, knowledge transfer, role modeling, and emotional and physiological feedback. The program incorporates the influence of the social environment on learning and builds support from parents, teachers and school staff. PMID- 22204576 TI - Volunteers as providers of heart health programs in churches: a report on implementation. AB - Abstract This project studies the use of church volunteers to reduce cardiovascular disease risk factors among their fellow church members. Our findings focus on the first 12 months of the project and address the following questions: 1) Can volunteers implement these programs with no on-site professional staff? 2) Are volunteer efforts facilitated by a local volunteer task force? and 3) Are implementation efforts aided by readily available professional staff involvement? In the intervention churches, 220 certified Risk Factor Leaders conducted 82 group programs with 740 registrants and 104 blood pressure screenings with 1,834 contacts. Our study shows volunteers to be effective implementers of heart health programs in churches. The involvement of a task force seemed to facilitate volunteer recruitment. Churches with a lower level of professional involvement had more blood pressure screenings. The effect of a task force or professional assistance on other volunteer efforts did not reach statistical significance. PMID- 22204577 TI - Self-selection in responding to a health risk appraisal: are we preaching to the choir? AB - Abstract The objectives of the present study were a) to examine behavioral and sociodemographic factors associated with voluntary response to a health risk appraisal (HRA), and b) to assess the effect of HRA feedback on subsequent preventive health behaviors and risk-taking behaviors. After collection of health behavior data from a larger sample participating in a Navy-wide health promotion evaluation, an HRA was mailed to a random subsample of 625 individuals. A total of 270 (43 %) people responded to the HRA and received printed feedback. Follow up health behavior data were collected one year later from 93 of the 270 HRA respondents. These 93 individuals were then matched with a control group who did not receive an HRA but had provided health behavior data both times. Analyses revealed that HRA respondents were older, better educated, had higher health status, smoked less, consumed less alcohol, and used seat belts more often than nonrespondents. Separate analyses of HRA respondents and matched controls indicated that HRA participation had no significant effect on subsequent preventive health behaviors or risk-taking behaviors. Results suggest limitations of the HRA as an effective due to behavior change. PMID- 22204579 TI - DataBase: Research and Evaluation Results. PMID- 22204578 TI - Health risk assessment: suggested directions for research. PMID- 22204581 TI - Robert f. Allen memorial scholarship awards. PMID- 22204580 TI - Business aspects of health promotion. PMID- 22204582 TI - AFB Practitioners' Forum. PMID- 22204583 TI - The power of feedback. PMID- 22204584 TI - Resource reviews. PMID- 22204586 TI - Letters to the editor. PMID- 22204585 TI - Perspectives beyond health promotion. PMID- 22204589 TI - Metabonomics adds a new dimension to fragile X syndrome. AB - Fragile X syndrome is the most common cause of inherited intellectual disability, but the underlying pathophysiology is complex and effective treatments are lacking. In a recent study of fragile X mental retardation 1 (Fmr1) knockout mice, the metabolic profile of the fragile X brain was determined using proton high-resolution magic angle spinning nuclear magnetic resonance spectroscopy. This analysis revealed deficiencies in four metabolic categories: neurotransmission, osmoregulation, energy metabolism and oxidative stress response. Abnormalities in the metabolic phenotype were linked to the fragile X mental retardation protein using an integrated metabolome and interactome mapping approach, allowing a global picture of the disorder to emerge. PMID- 22204590 TI - Targeting the hemangioblast with a novel cell type-specific enhancer. AB - BACKGROUND: Hemangioblasts are known as the common precursors for primitive hematopoietic and endothelial lineages. Their existence has been supported mainly by the observation that both cell types develop in close proximity and by in vitro differentiation and genetic studies. However, more compelling evidence will arise from tracking their cell fates using a lineage-specific marker. RESULTS: We report the identification of a hemangioblast-specific enhancer (Hb) located in the cis-regulatory region of chick Cerberus gene (cCer) that is able to direct the expression of enhanced green fluorescent protein (eGFP) to the precursors of yolk sac blood and endothelial cells in electroporated chick embryos. Moreover, we present the Hb-eGFP reporter as a powerful live imaging tool for visualizing hemangioblast cell fate and blood island morphogenesis. CONCLUSIONS: We hereby introduce the Hb enhancer as a valuable resource for genetically targeting the hemangioblast population as well as for studying the dynamics of vascular and blood cell development. PMID- 22204591 TI - Donor cells at the G1 phase enhance homogeneous gene expression among blastomeres in bovine somatic cell nuclear transfer embryos. AB - The success rate of bovine somatic cell nuclear transfer (SCNT) embryos to full term has been reported to be higher with G1 cells than with G0 cells. To better understand the reason for this, we analyzed the kinetics of luminescence activity in bovine SCNT embryos from G0 and G1 cells carrying a luciferase gene under the control of the beta-actin promoter during early embryonic development. At 60-h postfusion, when bovine embryonic gene activation (EGA) begins, the luminescence activity was higher in G1-SCNT embryos than G0-SCNT embryos. Moreover, half of the G1-SCNT embryos exhibited homogeneous luminescence among the blastomeres, whereas more than half of the G0-SCNT embryos exhibited mosaic luminescence. To characterize the differential luminescence pattern in SCNT embryos, the expressions of several endogenous genes and the level of DNA methylation were determined in all blastomeres of SCNT embryos with or without luminescence. The expressions of several development-related genes (H2AFZ, GJA1, and BAX) and level of DNA methylation of the SCNT embryos with luminescence were the same as those of normal embryos produced by in vitro fertilization. A higher success rate in G1 SCNT embryos is thought to contribute to homogeneous expression among all blastomeres at EGA. PMID- 22204592 TI - Comparative analysis of nuclear transfer embryo-derived mouse embryonic stem cells. Part I: cellular characterization. AB - Embryonic stem cells derived from nuclear transfer embryos (ntESCs) are particularly valuable for regenerative medicine, as they are a patient-specific and histocompatible cell source for the treatment of varying diseases. However, currently, little is known about their cellular and molecular profile. In the present study, in a mouse model different donor cell-derived ntESCs from various genetic backgrounds were compared with reference ESCs and analyzed comprehensively at the cellular level. A number of pluripotency marker genes were compared by flow cytometry and immunocytochemistry analysis. Significant differences at the protein level were observed for POU5F1, SOX2, FGF4, NANOG, and SSEA-1. However, such differences had no effect on in vitro cell differentiation and cell fate: derivatives of the three germ layers were detected in all ntESC lines. The neural and cardiac in vitro differentiation revealed minor differences between the cell lines, both at the mRNA and protein level. Karyotype analyses and cell growth studies did not reveal any significant variations. Despite some differences observed, the present study revealed that ntESC lines had similar differentiation competences compared to other ESCs. The results indicate that the observed differences may be related to the genotype rather than to the nuclear transfer technology. PMID- 22204593 TI - Comparative analysis of nuclear transfer embryo-derived mouse embryonic stem cells. Part II: gene regulation. AB - In a mouse model nuclear transfer embryo-derived embryonic stem cell lines (ntESCs) of various genetic backgrounds and donor cell types were compared with reference ESCs and analyzed comprehensively at molecular level as a second part of a larger study. Expression profiles of ntESCs established by different NT methods (piezoelectric microinjection or zona-free) were indistinguishable. However, expression profiling analyses identified differentially regulated genes between reference ESCs and ntESCs from different genetic backgrounds. A number of pluripotency and stemness marker genes significantly differed at the mRNA level between the cell lines. However, cluster and lineage analyses revealed that such differences had no effect on cell differentiation and cell fate. Regardless of the donor cell type, gene expression profiles of ntESCs were more similar to each other than to their counterpart fertilized embryo-derived ESCs of the same genotype. Overall, the results indicated that expression profile differences may be related to the genotype rather than to technical variations. PMID- 22204594 TI - Follicular growth-stimulated cows provide favorable oocytes for producing cloned embryos. AB - We examined the influence of recipient oocytes on in vitro development, oxygen consumption, and gene expression in the resulting cloned bovine embryos. Oocytes derived from slaughterhouse ovaries and ovum pickup (OPU)-derived oocytes were used as recipient cytoplasts for the production of cloned embryos. A series of OPU sessions was conducted on Holstein cows without follicular growth treatment (FGT). In the same cows, we then performed dominant follicle ablation and subsequently administered follicle-stimulating hormone and prostaglandin F(2alpha) with controlled internal drug release device before a second series of OPU. Cumulus cells collected from single Holstein cows were used as donor cells. After measurement of oxygen consumption at the blastocyst stage with modified scanning electrochemical microscopy, analysis of 10 genes (CDX2, IFN-tau, PLAC8, OCT4, SOX2, NANOG, ATP5A1, GLUT1, AKR1B1, and IGF2R) was performed with real-time RT-PCR. Rates of fusion, cleavage, and blastocyst formation were not different among the treatment groups. Levels of oxygen consumption in cloned blastocysts derived from slaughterhouse ovaries or OPU without FGT were significantly lower than in blastocysts derived from artificial insemination (AI). However, oxygen consumption was increased in cloned blastocysts derived from OPU with FGT, depending on the individual oocyte donor. Furthermore, gene expression of IFN-tau and OCT4 in cloned blastocysts derived from OPU with FGT was similar to that in AI-derived blastocysts, whereas expression of those genes in cloned blastocysts derived from slaughterhouse ovaries or OPU without FGT was significantly different from that in AI-derived blastocysts. Thus, recipient oocytes collected by OPU in combination with manipulation of follicular growth in donor cows are suitable for producing cloned embryos. PMID- 22204595 TI - Baseline epidemiology of Streptococcus pneumoniae serotypes in Canada prior to the introduction of the 13-valent pneumococcal vaccine. AB - Changes in the epidemiology of Streptococcus pneumoniae were reported worldwide after the introduction of the 7-valent pneumococcal vaccine, particularly an increase in multi-drug resistant (MDR) 19A strains. Subsequently, a 13-valent pneumococcal vaccine (PCV-13) has been introduced. This study assessed the incidence of S. pneumoniae serotypes in all age groups prior to the introduction of PCV-13 in Canada (2007-2009). Eight hundred S. pneumoniae isolates from respiratory specimens and blood cultures were collected as part of a Canadian surveillance study (CANWARD) from patients in 15 tertiary-care centers. Serotyping was performed by the Quellung method and antimicrobial susceptibility testing was performed by broth microdilution in accordance with the Clinical and Laboratory Standards Institute guidelines. The most common serotypes were 19A (8.6%), 3 (7.3%), 22F (6.0%), 4 (4.6%), 5 (4.4%), and 11A (4.4%); and the first serotype 6D isolate in Canada was identified. Serotypes 5, 7F, and 19A were significantly (p<0.001) more frequently isolated from bloodstream infections. Considerable serotype variability was noted for different age groups: 15B (p<0.01) and 19A (p<0.001) were more frequently isolated from children <=2 years old. Overall, 46.4% of currently circulating S. pneumoniae serotypes in Canada are included in PCV-13. Notably, 87.5% of MDR-S. pneumoniae were covered by PCV 13. Accordingly, PCV-13 will provide coverage against a significant proportion of circulating S. pneumoniae strains in Canada, including the critical antimicrobial resistant strains. PMID- 22204596 TI - Antimicrobial susceptibilities and resistance genes of Canadian isolates of Actinobacillus pleuropneumoniae. AB - Actinobacillus pleuropneumoniae is the causative agent of porcine pleuropneumonia, a severe and highly contagious respiratory disease responsible for economic losses in the swine industry worldwide. Although antimicrobial resistance in A. pleuropneumoniae has been recently reported in different countries, the current situation in Canada is unknown. The aim of the current study was to determine the antimicrobial susceptibilities of 43 strains of A. pleuropneumoniae isolated in Canada. In addition, antimicrobial resistance genes were detected with an oligonucleotide microarray. The impact of biofilm formation on susceptibility to antimicrobials was also evaluated. All isolates were susceptible to ceftiofur, florfenicol, enrofloxacin, erythromycin, clindamycin, trimethoprim/sulfamethoxazole, and tilmicosin. A low level of resistance was observed toward tiamulin, penicillin, and ampicillin as well as danofloxacin. We observed a high level of resistance to chlortetracycline (88.4%) and oxytetracycline (90.7%). The strains showing resistance to tetracycline antimicrobials contained at least one of the following tet genes: tetB, tetO, tetH, or tetC. Five isolates showed multiresistance to penicillins (bla(ROB-1)), streptomycin [aph3'' (strA)], sulfonamides (sulII), and tetracyclines (tetO) antimicrobials whereas three others showed multiresistance to streptomycin [aph3'' (strA)], sulfonamides (sulII), and tetracyclines (tetB, tetO, or tetB/tetH) antimicrobials. To the best of our knowledge, this is the first description of tetC gene in Pasteurellaceae. Finally, cells of A. pleuropneumoniae in a biofilm were 100 to 30,000 times more resistant to antimicrobials than their planktonic counterparts. PMID- 22204597 TI - Efficacy of pivmecillinam for treatment of lower urinary tract infection caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae. AB - To evaluate the clinical and bacteriological efficacy of pivmecillinam against lower urinary tract infection (UTI) caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae, patients treated for lower UTI with pivmecillinam (n=8) were studied. Patients treated with nitrofurantoin (n=3) and trimethoprim (n=3) or a combination of these agents with pivmecillinam (n=3) were included as a control group. Antimicrobial susceptibility was determined with EUCAST methodology. Bacteriologic cure was defined as <10(3) CFU/ml at follow-up (30 days), and clinical cure as resolved UTI symptoms after completed treatment. All patients receiving pivmecillinam had good clinical response (8/8), but bacteriological cure rates were low (2/8). However, none of the patients with persisting bacteriuria had a relapse of UTI symptoms within 6 months. All isolates were susceptible to the given antimicrobial. Most isolates belonged to the CTX-M-1 group (n=11, 65%) or CTX-M-9 group (n=4, 24%). Four E. coli isolates belonged to the international clone O25b ST131 (25%). In conclusion, pivmecillinam had good clinical activity against lower UTI caused by ESBL-producing Enterobacteriaceae, but bacteriological cure rates were low. The persistent bacteriuria appears to be of little clinical importance, but larger clinical studies are needed to determine the usefulness of pivmecillinam in infections caused by ESBL-producing bacteria. PMID- 22204598 TI - Non-degradative ubiquitination in Smad-dependent TGF-beta signaling. AB - Transforming growth factor-beta (TGF-beta) signaling is tightly regulated at the level of post-translational modification to transmit quantitative difference in ligand concentration into proportional transcriptional output. Ubiquitination is one such modification with several E3 ubiquitin ligases implicated in TGF-beta signaling in marking crucial pathway components for proteasomal degradation. However, ubiquitination, particularly in the mono- or oligo-ubiquitin modifying form, is also known to regulate incorporation of substrate proteins into signaling complexes that involved in DNA repair, kinase activation, and endocytosis. This review focuses on recent advances in understanding the role of such non-degradative ubiquitination in TGF-beta signaling. PMID- 22204599 TI - A comparative cost analysis of robot-assisted versus traditional laparoscopic partial nephrectomy. AB - BACKGROUND AND PURPOSE: Robot-assisted laparoscopic partial nephrectomy (RALPN) is supplanting traditional laparoscopic partial nephrectomy (LPN) as the technique of choice for minimally invasive nephron-sparing surgery. This evolution has resulted from potential clinical benefits, as well as proliferation of robotic systems and patient demand for robot-assisted surgery. We sought to quantify the costs associated with the use of robotics for minimally invasive partial nephrectomy. METHODS: A cost analysis was performed for 20 consecutive robot-assisted partial nephrectomy (RPN) and LPN patients at our institution from 2009 to 2010. Data included actual perioperative and hospitalization costs as well as professional fees. Capital costs were estimated using purchase costs and amortization of two robotic systems from 2001 to 2009, as well as maintenance contract costs. The estimated cost/case was obtained using total robotic surgical volume during this period. Total estimated costs were compared between groups. A separate analysis was performed assuming "ideal" robotic utilization during a comparable period. RESULTS: RALPN had a cost premium of +$1066/case compared with LPN, assuming actual robot utilization from 2001 to 2009. Assuming "ideal" utilization during a comparable period, this premium decreased to +$334; capital costs per case decreased from $1907 to $1175. Tumor size, operative time, and length of stay were comparable between groups. CONCLUSIONS: RALPN is associated with a small to moderate cost premium depending on assumptions regarding robotic surgical volume. Saturated utilization of robotic systems decreases attributable capital costs and makes comparison with laparoscopy more favorable. Purported clinical benefits of RPN (eg, decreased warm ischemia time, increased utilization of nephron-sparing surgery) need further study, because these may have cost implications. PMID- 22204603 TI - Core/shell nanoparticles: classes, properties, synthesis mechanisms, characterization, and applications. PMID- 22204605 TI - Nanochannel with uniform and Janus surfaces: shear thinning and thickening in surfactant solution. AB - On basis of molecular simulation of confined surfactant solutions, we show that by adding chemical patterns on the inner surface of nanochannels dynamical properties of the confined surfactant solutions could be modified from shear thinning to shear thickening. To this end, we select uniformly hydrophobic and hydrophilic surfaces as well as a stripe-patterned Janus surface as three prototype confining surfaces of nanochannels. In all three nanochannels, when the surfactant solution is under relatively low shear rates, it shears thin. Under moderate shear rates, a sharp decrease in the shear viscosity could occur due to surfactant morphology transition. Under relatively high shear rates, a shear thinning-to-thickening transition can emerge due to the tendency of stratification normal to the confining surface. Our simulation study offers a guide to steering dynamic properties of surfactant fluids in nanofluidic devices through engineering surfaces of nanochannels by design. PMID- 22204600 TI - Ebola haemorrhagic fever outbreak in Masindi District, Uganda: outbreak description and lessons learned. AB - BACKGROUND: Ebola haemorrhagic fever (EHF) is infamous for its high case-fatality proportion (CFP) and the ease with which it spreads among contacts of the diseased. We describe the course of the EHF outbreak in Masindi, Uganda, in the year 2000, and report on response activities. METHODS: We analysed surveillance records, hospital statistics, and our own observations during response activities. We used Fisher's exact tests for differences in proportions, t-tests for differences in means, and logistic regression for multivariable analysis. RESULTS: The response to the outbreak consisted of surveillance, case management, logistics and public mobilisation. Twenty-six EHF cases (24 laboratory confirmed, two probable) occurred between October 21st and December 22nd, 2000. CFP was 69% (18/26). Nosocomial transmission to the index case occurred in Lacor hospital in Gulu, outside the Ebola ward. After returning home to Masindi district the index case became the origin of a transmission chain within her own extended family (18 further cases), from index family members to health care workers (HCWs, 6 cases), and from HCWs to their household contacts (1 case). Five out of six occupational cases of EHF in HCWs occurred after the introduction of barrier nursing, probably due to breaches of barrier nursing principles. CFP was initially very high (76%) but decreased (20%) due to better case management after reinforcing the response team. The mobilisation of the community for the response efforts was challenging at the beginning, when fear, panic and mistrust had to be countered by the response team. CONCLUSIONS: Large scale transmission in the community beyond the index family was prevented by early case identification and isolation as well as quarantine imposed by the community. The high number of occupational EHF after implementing barrier nursing points at the need to strengthen training and supervision of local HCWs. The difference in CFP before and after reinforcing the response team together with observations on the ward suggest a critical role for intensive supportive treatment. Collecting high quality clinical data is a priority for future outbreaks in order to identify the best possible FHF treatment regime under field conditions. PMID- 22204606 TI - Asymptomatic neurocognitive disorders in patients infected by HIV: fact or fiction? AB - Neurocognitive disorders are emerging as a possible complication in patients infected with HIV. Even if asymptomatic, neurocognitive abnormalities are frequently detected using a battery of tests. This supported the creation of asymptomatic neurocognitive impairment (ANI) as a new entity. In a recent article published in BMC Infectious Diseases, Magnus Gisslen and colleagues applied a statistical approach, concluding that there is an overestimation of the actual problem. In fact, about 20% of patients are classified as neurocognitively impaired without a clear impact on daily activities. In the present commentary, we discuss the clinical implications of their findings. Although a cautious approach would indicate a stricter follow-up of patients affected by this disorder, it is premature to consider it as a proper disease. Based on a review of the data in the current literature we conclude that it is urgent to conduct more studies to estimate the overall risk of progression of the asymptomatic neurocognitive impairment. Moreover, it is important to understand whether new biomarkers or neuroimaging tools can help to identify better the most at risk population. Please see related article: http://www.biomedcentral.com/1471 2334/11/356. PMID- 22204607 TI - Drug-to-genome-to-drug, step 2: reversing selectivity in a series of antiplasmodial compounds. AB - In a recent paper, we have described the discovery of antimalarial compounds derived from tadalafil, using a drug-to-genome-to-drug approach ( J. Med. Chem. 2011 , 54 ( 9 ), pp 3222 - 3240 ). We have shown that these derivatives inhibit the phosphodiesterase activity of Plasmodium falciparum and the parasite growth in culture. In this paper, we describe the optimization of these compounds. A direct consequence of our approach based on gene orthology is the lack of selectivity of the compounds over the original activity on the human target. We demonstrate here that it is possible to take advantage of subtle differences in SAR between HsPDE5 inhibition and antiplasmodial activity to improve significantly the selectivity. In particular, the replacement of the piperonyl group in compound 2 by a dimethoxyphenyl group was the best way to optimize selectivity. This observation is consistent with the differences between human and plasmodial sequences in the Q2 pocket receiving this group. PMID- 22204608 TI - Diversity, mobility, and structural and functional evolution of group II introns carrying an unusual 3' extension. AB - BACKGROUND: Group II introns are widespread genetic elements endowed with a dual functionality. They are catalytic RNAs (ribozymes) that are able of self-splicing and they are also mobile retroelements that can invade genomic DNA. The group II intron RNA secondary structure is typically made up of six domains. However, a number of unusual group II introns carrying a unique extension of 53-56 nucleotides at the 3' end have been identified previously in bacteria of the Bacillus cereus group. METHODS: In the present study, we conducted combined sequence comparisons and phylogenetic analyses of introns, host gene, plasmid and chromosome of host strains in order to gain insights into mobility, dispersal, and evolution of the unusual introns and their extension. We also performed in vitro mutational and kinetic experiments to investigate possible functional features related to the extension. RESULTS: We report the identification of novel copies of group II introns carrying a 3' extension including the first two copies in bacteria not belonging to the B. cereus group, Bacillus pseudofirmus OF4 and Bacillus sp. 2_A_57_CT2, an uncharacterized species phylogenetically close to B. firmus. Interestingly, the B. pseudofirmus intron has a longer extension of 70 bases. From sequence comparisons and phylogenetic analyses, several possible separate events of mobility involving the atypical introns could be identified, including both retrohoming and retrotransposition events. In addition, identical extensions were found in introns that otherwise exhibit little sequence conservation in the rest of their structures, with the exception of the conserved and catalytically critical domains V and VI, suggesting either separate acquisition of the extra segment by different group II introns or a strong selection pressure acting on the extension. Furthermore, we show by in vitro splicing experiments that the 3' extension affects the splicing properties differently in introns belonging to separate evolutionary branches. CONCLUSIONS: Altogether this study provides additional insights into the structural and functional evolution of unusual introns harboring a 3' extension and lends further evidence that these introns are mobile with their extension. PMID- 22204610 TI - Population-based outcomes after whole brain radiotherapy and re-irradiation in patients with metastatic breast cancer in the trastuzumab era. AB - PURPOSE: This study examined the population-based use and outcomes of brain radiotherapy (BRT) for brain metastases (BM) from breast cancer with a focus on repeat BRT in the trastuzumab era. METHODS AND MATERIALS: All women with breast cancer diagnosed from 2000-2007 and treated with BRT were retrospectively identified from a provincial database. RESULTS: A total of 441 women with BM from breast cancer were identified. The median age was 55 years and 40% (176/441) had human epidermal growth factor receptor 2 (HER2) positive disease. The median survival (MS) from the initial BRT for all 441 women was 4.5 months. The MS by Radiation Therapy Oncology Group Recursive Partitioning Analysis (RPA) class was: 1 (14.5 months), 2 (6.4 months) and 3 (1.8 months). For the 37 cases receiving repeat BRT, 27% (10/37) had stereotactic radiosurgery (SRS) and 70% (26/37) had HER2 positive disease, of which, 81% (21/26) received trastuzumab in the metastatic setting. For repeat BRT, the median survival by RPA class was: 1 (9.8 months), 2 (7.4 months) and 3 (2.0 months). For RPA class 1 and 2, the one-year overall survival (OS) was 45%. CONCLUSION: The proportion of cases with HER2 positive disease was increased at repeat BRT compared to initial BRT. RPA class 1 and 2 patients should be considered for repeat BRT. PMID- 22204611 TI - High tidal volume mechanical ventilation-induced lung injury in rats is greater after acid instillation than after sepsis-induced acute lung injury, but does not increase systemic inflammation: an experimental study. AB - BACKGROUND: To examine whether acute lung injury from direct and indirect origins differ in susceptibility to ventilator-induced lung injury (VILI) and resultant systemic inflammatory responses. METHODS: Rats were challenged by acid instillation or 24 h of sepsis induced by cecal ligation and puncture, followed by mechanical ventilation (MV) with either a low tidal volume (Vt) of 6 mL/kg and 5 cm H2O positive end-expiratory pressure (PEEP; LVt acid, LVt sepsis) or with a high Vt of 15 mL/kg and no PEEP (HVt acid, HVt sepsis). Rats sacrificed immediately after acid instillation and non-ventilated septic animals served as controls. Hemodynamic and respiratory variables were monitored. After 4 h, lung wet to dry (W/D) weight ratios, histological lung injury and plasma mediator concentrations were measured. RESULTS: Oxygenation and lung compliance decreased after acid instillation as compared to sepsis. Additionally, W/D weight ratios and histological lung injury scores increased after acid instillation as compared to sepsis. MV increased W/D weight ratio and lung injury score, however this effect was mainly attributable to HVt ventilation after acid instillation. Similarly, effects of HVt on oxygenation were only observed after acid instillation. HVt during sepsis did not further affect oxygenation, compliance, W/D weight ratio or lung injury score. Plasma interleukin-6 and tumour necrosis factor-alpha concentrations were increased after acid instillation as compared to sepsis, but plasma intercellular adhesion molecule-1 concentration increased during sepsis only. In contrast to lung injury parameters, no additional effects of HVt MV after acid instillation on plasma mediator concentrations were observed. CONCLUSIONS: During MV more severe lung injury develops after acid instillation as compared to sepsis. HVt causes VILI after acid instillation, but not during sepsis. However, this differential effect was not observed in the systemic release of mediators. PMID- 22204613 TI - Metabolic diversity of progressive kidney disease in 325 patients with type 1 diabetes (the FinnDiane Study). AB - Type 1 diabetic patients with varying severity of kidney disease were investigated to create multimetabolite models of the disease process. Urinary albumin excretion rate was measured for 3358 patients with type 1 diabetes. Prospective records were available for 1051 patients, of whom 163 showed progression of albuminuria (8.3-year follow-up), and 162 were selected as stable controls. At baseline, serum lipids, lipoprotein subclasses, and low-molecular weight metabolites were quantified by NMR spectroscopy (325 samples). The data were analyzed by the self-organizing map. In cross-sectional analyses, patients with no complications had low serum lipids, less inflammation, and better glycemic control, whereas patients with advanced kidney disease had high serum cystatin-C and sphingomyelin. These phenotype extremes shared low unsaturated fatty acids (UFAs) and phospholipids. Prospectively, progressive albuminuria was associated with high UFAs, phospholipids, and IDL and LDL lipids. Progression at longer duration was associated with high HDL lipids, whereas earlier progression was associated with poor glycemic control, increased saturated fatty acids (SFAs), and inflammation. Diabetic kidney disease consists of diverse metabolic phenotypes: UFAs, phospholipids, IDL, and LDL may be important in the subclinical phase, high SFAs and low HDL suggest accelerated progression, and the sphingolipid pathway in advanced kidney injury deserves further research. PMID- 22204614 TI - Novel features of ARS selection in budding yeast Lachancea kluyveri. AB - BACKGROUND: The characterization of DNA replication origins in yeast has shed much light on the mechanisms of initiation of DNA replication. However, very little is known about the evolution of origins or the evolution of mechanisms through which origins are recognized by the initiation machinery. This lack of understanding is largely due to the vast evolutionary distances between model organisms in which origins have been examined. RESULTS: In this study we have isolated and characterized autonomously replicating sequences (ARSs) in Lachancea kluyveri - a pre-whole genome duplication (WGD) budding yeast. Through a combination of experimental work and rigorous computational analysis, we show that L. kluyveri ARSs require a sequence that is similar but much longer than the ARS Consensus Sequence well defined in Saccharomyces cerevisiae. Moreover, compared with S. cerevisiae and K. lactis, the replication licensing machinery in L. kluyveri seems more tolerant to variations in the ARS sequence composition. It is able to initiate replication from almost all S. cerevisiae ARSs tested and most Kluyveromyces lactis ARSs. In contrast, only about half of the L. kluyveri ARSs function in S. cerevisiae and less than 10% function in K. lactis. CONCLUSIONS: Our findings demonstrate a replication initiation system with novel features and underscore the functional diversity within the budding yeasts. Furthermore, we have developed new approaches for analyzing biologically functional DNA sequences with ill-defined motifs. PMID- 22204615 TI - Effectiveness of anodal transcranial direct current stimulation in patients with chronic low back pain: design, method and protocol for a randomised controlled trial. AB - BACKGROUND: Electrical stimulation of central nervous system areas with surgically implanted stimulators has been shown to result in pain relief. To avoid the risks and side effects of surgery, transcranial direct current stimulation is an option to electrically stimulate the motor cortex through the skull. Previous research has shown that transcranial direct current stimulation relieves pain in patients with fibromyalgia, chronic neuropathic pain and chronic pelvic pain. Evidence indicates that the method is pain free, safe and inexpensive. METHODS/DESIGN: A randomised controlled trial has been designed to evaluate the effect of transcranial direct current stimulation over the motor cortex for pain reduction in patients with chronic low back pain. It will also investigate whether transcranial direct current stimulation as a prior treatment enhances the symptom reduction achieved by a cognitive-behavioural group intervention. Participants will be randomised to receive a series of 5 days of transcranial direct current stimulation (2 mA, 20 mins) or 20 mins of sham stimulation; followed by a cognitive-behavioural group programme. The primary outcome parameters will measure pain (Visual Analog Scale) and disability (Oswestry Disability Index). Secondary outcome parameters will include the Fear Avoidance Beliefs Questionnaire, the Funktionsfragebogen Hannover (perceived function), Hospital Anxiety Depression Scale, bothersomeness and Health Related Quality of Life (SF 36), as well as Patient-Perceived Satisfactory Improvement. Assessments will take place immediately prior to the first application of transcranial direct current stimulation or sham, after 5 consecutive days of stimulation, immediately after the cognitive-behavioural group programme and at 4 weeks, 12 weeks and 24 weeks follow-up. DISCUSSION: This trial will help to determine, whether transcranial direct current stimulation is an effective treatment for patients with chronic low back pain and whether it can further enhance the effects of a cognitive behavioural pain management programme. PMID- 22204618 TI - Publisher's Notes. PMID- 22204619 TI - Broadening the scope of worksite stress programs: a guiding framework. AB - Abstract Worksite stress programs have proliferated in recent years. A large proportion of these programs focus on helping individual employees learn about stress and develop better coping skills. Few programs attempt to reduce the stressful aspects of the job or the organizational context. In order to facilitate the development of a broader array of stress reduction programs, the authors provide: 1) a conceptual framework upon which worksite stress programs should be based, 2) a guide to the variety of decision points in the program development process, 3) an exploration of the reasons why a broader range of stress programs have not heretofore been developed, and 4) suggestions for creating a context amenable to innovative worksite stress programs. PMID- 22204616 TI - Health care providers and direct-to-consumer access and advertising of genetic testing in the United States. AB - Marketing pressures, regulatory policies, clinical guidelines, and consumer demand all affect health care providers' knowledge and use of health-related genetic tests that are sold and/or advertised to consumers. In addition, clinical guidelines, regulatory policies, and educational efforts are needed to promote the informed use of genetic tests that are sold and advertised to consumers and health care providers. A shift in culture regarding the regulation of genetic tests that are sold directly to consumers is suggested: by recent actions taken by the US Food and Drug Administration (FDA), including letters sent to direct-to consumer (DTC) genetic testing companies stating that their tests meet the definition of medical devices; by public meetings held by the FDA to discuss laboratory developed tests; and by the convening of the Molecular and Clinical Genetics Panel to gather input on scientific issues concerning DTC genetic tests that make medical claims. This review provides a brief overview of DTC advertising and the regulation of pharmaceuticals and genetic tests in the United States. It highlights recent changes in the regulatory culture regarding genetic tests that are sold to consumers, and discusses the impact on health care providers of selling and advertising genetic tests directly to consumers. PMID- 22204620 TI - Correlates of internists' practices in caring for patients with elevated serum cholesterol. AB - Abstract This study examined the relationship between internists personal health practices, health beliefs, and demographic characteristics and their reported practices in caring for patients with elevated serum cholesterol. A questionnaire was mailed to 271 internists (181 respondents) on the medical staff of an urban university hospital. Perceived ability to provide dietary counseling was consistently associated with interventions offered by the internists themselves, including education, counseling, and use of lipid-lowering drugs and with defining elevation of serum cholesterol at a lower value. It was not associated with referral to the dietitian or the Lipid Clinic. There were only weak and inconsistent associations between physician personal health practices, including diet and having a personal cholesterol goal, and any of the physician reported professional practices examined. These findings strengthen the hypothesis that there is a relationship between physicians' perceived competence and their use of diet counseling and lipid-lowering drugs. PMID- 22204621 TI - Impact of a community-wide stop smoking contest. AB - Abstract This paper presents the results of a follow-up evaluation conducted to assess the impact of a community-wide stop smoking contest conducted in Buffalo, New York in January 1988. The contest challenged smokers to make a pledge to quit jar 30 days to have a chance to win $1,000 cash, a vacation trip, or other prizes. Finalists were randomly selected and chemically tested to verify abstinence. Telephone follow-up interviews were conducted on a sample of 411 contestants six weeks and eight months after the quit date. A total of 2,565 smokers enrolled in the contest. Compared to smokers in the general population, contestants were more likely to be female, white, under age 40, and smoke 25 or more cigarettes daily. Over 90 percent of contestants attempted to stop smoking, 51 percent quit jar the 3D-day contest period, and 32 percent were not smoking after eight months. PMID- 22204623 TI - DataBase: Research and Evaluation Results. PMID- 22204622 TI - The use of behavioral contracting to increase exercise activity. AB - Abstract A cardiovascular risk reduction program used a submaximal treadmill stress test to evaluate physical fitness. Of the 179 individuals who participated in the health education counseling activities which followed testing, 96 signed a behavioral contract to engage in a 12-week aerobic exercise program. Forty-one contractors fully met contract goals, and 21 reported increased activity levels. Analyses examined demographic, risk factor, and attitudinal predictors of contract signing and contract adherence. Contract signing was related to education, smoking, and women's mean body weight. Only women's body weight was related to contract adherence. Attitudes toward exercise were related to neither. Level of contract adherence was significantly related to a decrease in exercising heart rate at the six-month follow-up assessment. These data suggest that contract signing may be a useful device for assessing client motivation and predicting program participation and behavioral change outcomes. PMID- 22204625 TI - AFB Practitioners' Forum. PMID- 22204624 TI - Business aspects of health promotion. PMID- 22204626 TI - Cross-cultural training for health promotion. PMID- 22204628 TI - Perspectives beyond health promotion. PMID- 22204627 TI - Resource reviews. PMID- 22204630 TI - Heterologous expression of Pycnoporus cinnabarinus cellobiose dehydrogenase in Pichia pastoris and involvement in saccharification processes. AB - BACKGROUND: Cellobiose dehydrogenase (CDH) is an extracellular hemoflavoenzyme produced by lignocellulose-degrading fungi including Pycnoporus cinnabarinus. We investigated the cellulolytic system of P. cinnabarinus, focusing on the involvement of CDH in the deconstruction of lignocellulosic biomass. RESULTS: First, P. cinnabarinus growth conditions were optimized for CDH production. Following growth under cellulolytic conditions, the main components secreted were cellulases, xylanases and CDH. To investigate the contribution of P. cinnabarinus secretome in saccharification processes, the Trichoderma reesei enzymatic cocktail was supplemented with the P. cinnabarinus secretome. A significant enhancement of the degradation of wheat straw was observed with (i) the production of a large amount of gluconic acid, (ii) increased hemicellulose degradation, and (iii) increased overall degradation of the lignocellulosic material. P. cinnabarinus CDH was heterologously expressed in Pichia pastoris to obtain large amounts of pure enzyme. In a bioreactor, the recombinant CDH (rCDH) expression level reached 7800 U/L. rCDH exhibited values of biochemical parameters similar to those of the natural enzyme, and was able to bind cellulose despite the absence of a carbohydrate-binding module (CBM). Following supplementation of purified rCDH to T. reesei enzymatic cocktail, formation of gluconic acid and increased hemicellulose degradation were observed, thus confirming the previous results observed with P. cinnabarinus secretome. CONCLUSIONS: We demonstrate that CDH offers an attractive tool for saccharification process enhancement due to gluconic acid production from raw lignocellulosic material. PMID- 22204631 TI - Integrin clustering in two and three dimensions. AB - Integrins are transmembrane proteins that allow cells to bind to their external environment. They are the primary regulators of cell-matrix interactions, with direct roles in cell motility and signaling, which in turn regulate numerous physiological processes. Under common experimental conditions, integrins tend to cluster for sturdy and effective binding to extracellular matrix molecules. These clusters often evolve into focal adhesions, which regulate downstream signaling. However, integrin clusters are more pronounced and have longer lifetimes in two dimensional assays than in more realistic three-dimensional environments. While a number of models and theoretical approaches have focused on integrin binding and diffusion, the reasons for the differences between two- and three-dimensional clustering have remained elusive. In this study, we model an individual cluster attached to a two-dimensional collagen film and attached to collagen fibers of various sizes in three-dimensional matrices. We then discuss how our results explain differences in size and lifetime, and how they hint at reasons for other differences between the two environments. Further, we make predictions regarding the stability of clusters based on different overall intracellular conditions. Our results show good agreement with experiments and provide a quantitative basis for understanding how matrix dimensionality and structure regulate integrin behavior in environments that mimic in vivo conditions. PMID- 22204632 TI - Structures in solutions from joint experimental-computational analysis: applications to cyclic molecules and studies of noncovalent interactions. AB - The potential of an approach combining nuclear magnetic resonance (NMR) spectroscopy, molecular dynamics (MD) simulations, and quantum mechanical (QM) calculations for full structural characterizations in solution is assessed using cyclic organic compounds, namely, benzazocinone derivatives 1-3 with fused five- and eight-membered aliphatic rings, camphoric anhydride 4, and bullvalene 5. Various MD simulations were considered, using force field and semiempirical QM treatments, implicit and explicit solvation, and high-temperature MD calculations for selecting plausible molecular geometries for subsequent QM geometry optimizations using mainly B3LYP, M062X, and MP2 methods. The QM-predicted values of NMR parameters were compared to their experimental values for verification of the final structures derived from the MD/QM analysis. From these comparisons, initial estimates of quality thresholds (calculated as rms deviations) were 0.7 0.9 Hz for (3)J(HH) couplings, 0.07-0.11 A for interproton distances, 0.05-0.08 ppm for (1)H chemical shifts, and 1.0-2.1 ppm for (13)C chemical shifts. The obtained results suggest that the accuracy of the MD analysis in predicting geometries and relative conformational energies is not critical and that the final geometry refinements of the structures selected from the MD simulations using QM methods are sufficient for correcting for the expected inaccuracy of the MD analysis. A unique example of C(sp(3))-H...N(sp(3)) intramolecular noncovalent interaction is also identified using the NMR/MD/QM and the natural bond orbital analyses. As the NMR/MD/QM approach relies on the final QM geometry optimization, comparisons of geometric characteristics predicted by different QM methods and those from X-ray and neutron diffraction measurements were undertaken using rigid and flexible cyclic systems. The joint analysis shows that intermolecular noncovalent interactions present in the solid state alter molecular geometries significantly compared to the geometries of isolated molecules from QM calculations. PMID- 22204633 TI - Multiconfiguration self-consistent field and multireference configuration interaction methods and applications. PMID- 22204636 TI - Drug treatment of hyperuricemia to prevent cardiovascular outcomes: are we there yet? AB - Data supporting an association between high levels of serum urate and cardiovascular disease have continued to emerge. Basic science data, small clinical trials, and epidemiologic studies have provided support for the idea of a true causal effect. In this paper, we present evidence about the association between hyperuricemia and selected cardiovascular diseases. Although data generated so far compellingly support pharmacologic urate-lowering therapy in selected cases with high cardiovascular risk, further evidence is necessary before widely advocating this approach to prevent cardiovascular outcomes putatively associated with hyperuricemia. PMID- 22204637 TI - Targeted 'next-generation' sequencing in anophthalmia and microphthalmia patients confirms SOX2, OTX2 and FOXE3 mutations. AB - BACKGROUND: Anophthalmia/microphthalmia (A/M) is caused by mutations in several different transcription factors, but mutations in each causative gene are relatively rare, emphasizing the need for a testing approach that screens multiple genes simultaneously. We used next-generation sequencing to screen 15 A/M patients for mutations in 9 pathogenic genes to evaluate this technology for screening in A/M. METHODS: We used a pooled sequencing design, together with custom single nucleotide polymorphism (SNP) calling software. We verified predicted sequence alterations using Sanger sequencing. RESULTS: We verified three mutations - c.542delC in SOX2, resulting in p.Pro181Argfs*22, p.Glu105X in OTX2 and p.Cys240X in FOXE3. We found several novel sequence alterations and SNPs that were likely to be non-pathogenic - p.Glu42Lys in CRYBA4, p.Val201Met in FOXE3 and p.Asp291Asn in VSX2. Our analysis methodology gave one false positive result comprising a mutation in PAX6 (c.1268A > T, predicting p.X423LeuextX*15) that was not verified by Sanger sequencing. We also failed to detect one 20 base pair (bp) deletion and one 3 bp duplication in SOX2. CONCLUSIONS: Our results demonstrated the power of next-generation sequencing with pooled sample groups for the rapid screening of candidate genes for A/M as we were correctly able to identify disease-causing mutations. However, next-generation sequencing was less useful for small, intragenic deletions and duplications. We did not find mutations in 10/15 patients and conclude that there is a need for further gene discovery in A/M. PMID- 22204638 TI - The Alvarado score for predicting acute appendicitis: a systematic review. AB - BACKGROUND: The Alvarado score can be used to stratify patients with symptoms of suspected appendicitis; the validity of the score in certain patient groups and at different cut points is still unclear. The aim of this study was to assess the discrimination (diagnostic accuracy) and calibration performance of the Alvarado score. METHODS: A systematic search of validation studies in Medline, Embase, DARE and The Cochrane library was performed up to April 2011. We assessed the diagnostic accuracy of the score at the two cut-off points: score of 5 (1 to 4 vs. 5 to 10) and score of 7 (1 to 6 vs. 7 to 10). Calibration was analysed across low (1 to 4), intermediate (5 to 6) and high (7 to 10) risk strata. The analysis focused on three sub-groups: men, women and children. RESULTS: Forty-two studies were included in the review. In terms of diagnostic accuracy, the cut-point of 5 was good at 'ruling out' admission for appendicitis (sensitivity 99% overall, 96% men, 99% woman, 99% children). At the cut-point of 7, recommended for 'ruling in' appendicitis and progression to surgery, the score performed poorly in each subgroup (specificity overall 81%, men 57%, woman 73%, children 76%). The Alvarado score is well calibrated in men across all risk strata (low RR 1.06, 95% CI 0.87 to 1.28; intermediate 1.09, 0.86 to 1.37 and high 1.02, 0.97 to 1.08). The score over-predicts the probability of appendicitis in children in the intermediate and high risk groups and in women across all risk strata. CONCLUSIONS: The Alvarado score is a useful diagnostic 'rule out' score at a cut point of 5 for all patient groups. The score is well calibrated in men, inconsistent in children and over-predicts the probability of appendicitis in women across all strata of risk. PMID- 22204639 TI - Unraveling the biological functions of Smad7 with mouse models. AB - Smad7 is a key negative regulator of the transforming growth factor beta (TGF beta) signaling and plays an important role in modulating a large array of biological processes. The physiological actions of Smad7 have been extensively investigated by using various mouse models. These studies have pinpointed numerous important in vivo functions of Smad7, including its activity in early embryonic development, fibrosis of many organs, skin cell differentiation, regulation of immune response and inflammation, tumorigenesis, and metabolic control. As most biological activities modulated by Smad7 are closely related to human disorders, it is anticipated that Smad7 will continue to be an intriguing molecule that will be vigorously investigated in the future to strengthen our understanding about the pathogenesis of human diseases. PMID- 22204641 TI - Spectroscopic study of the photofixation of SO2 on anatase TiO2 thin films and their oleophobic properties. AB - Photoinduced SO(2) fixation on anatase TiO(2) films was studied by in situ Fourier transform infrared (FTIR) and X-ray photoelectron spectroscopy (XPS). The TiO(2) films were prepared by reactive DC magnetron sputtering and were subsequently exposed to 50 ppm SO(2) gas mixed in synthetic air and irradiated with UV light at substrate temperatures between 298 and 673 K. Simultaneous UV irradiation and SO(2) exposure between 373 and 523 K resulted in significant sulfur (S) deposits on crystalline TiO(2) films as determined by XPS, whereas amorphous films contained negligible amounts of S. At substrate temperatures above 523 K, the S deposits readily desorbed from TiO(2). The oxidation state of sulfur successively changed from S(4+) for SO(2) adsorbed on crystalline TiO(2) films at room temperature without irradiation to S(6+) for films exposed to SO(2) at elevated temperatures with simultaneous irradiation. In situ FTIR was used to monitor the temporal evolution of the photoinduced surface reaction products formed on the TiO(2) surfaces. It is shown that band gap excitation of TiO(2) results in photoinduced oxidation of SO(2), which at elevated temperatures become coordinated to the TiO(2) lattice through interactions with O vacancies and form sulfite and sulfate surface species. These species makes the surface acidic, which is manifested in nondetectable adherence of stearic acid to the modified surface. The modified films show good chemical stability as evidenced by sonication and repeated recycling of the films. The results suggest a new method to functionalize wide band gap oxide surfaces by means of photoinduced reactions in reactive gases at elevated substrate temperatures. In the case of anatase TiO(2) in reactive SO(2) gas, we here show that such functionalization yields surfaces with excellent oleophobic properties, as probed by adhesion of stearic acid. PMID- 22204640 TI - A refined, rapid and reproducible high resolution melt (HRM)-based method suitable for quantification of global LINE-1 repetitive element methylation. AB - BACKGROUND: The methylation of DNA is recognized as a key mechanism in the regulation of genomic stability and evidence for its role in the development of cancer is accumulating. LINE-1 methylation status represents a surrogate measure of genome-wide methylation. FINDINGS: Using high resolution melt (HRM) curve analysis technology, we have established an in-tube assay that is linear (r > 0.9986) with a high amplification efficiency (90-105%), capable of discriminating between partcipant samples with small differences in methylation, and suitable for quantifying a wide range of LINE-1 methylation levels (0-100%)--including the biologically relevant range of 50-90% expected in human DNA. We have optimized this procedure to perform using 2 MUg of starting DNA and 2 ng of bisulfite converted DNA for each PCR reaction. Intra- and inter-assay coefficients of variation were 1.44% and 0.49%, respectively, supporting the high reproducibility and precision of this approach. CONCLUSIONS: In summary, this is a completely linear, quantitative HRM PCR method developed for the measurement of LINE-1 methylation. This cost-efficient, refined and reproducible assay can be performed using minimal amounts of starting DNA. These features make our assay suitable for high throughput analysis of multiple samples from large population-based studies. PMID- 22204642 TI - Active potassium supplementation might be mandatory during laparoscopic adrenalectomy for primary hyperaldosteronism. AB - BACKGROUND AND PURPOSE: It is well recognized that monitoring of the serum potassium level during laparoscopic adrenalectomy for primary hyperaldosteronism is critical. Nevertheless, the guideline for prevention and management of hypokalemia during the operation has not been established to date. In this study, we investigated whether active potassium supplementation could prevent electrolyte imbalance during laparoscopic adrenalectomy for primary hyperaldosteronism. PATIENTS AND METHODS: From January 2007 to May 2011, 35 patients underwent transperitoneal laparoscopic adrenalectomy for primary hyperaldosteronism (Conn's syndrome). The hemodynamic and electrolyte changes during the operation were recorded serially. In first 10 patients (group A), potassium was replaced passively on demand. Based on this result, potassium was actively supplemented during the operation in the subsequent 25 patients (group B). The perioperative parameters, hemodynamic changes, and serum potassium levels were analyzed and compared between the two groups. RESULTS: The patients' demographic data, initial blood pressure, and serum electrolyte levels were similar in both groups. The operative time was shorter in group B (P=0.035). The mean serum potassium level was decreased by 0.7 mmol/L during the first 30 minutes in group A. Based on this result, potassium was actively supplemented from the beginning of the operation in group B. The mean hypokalemic events were 4 +/- 2 in group A. None of the patients in group B, however, experienced hypokalemia. The hemodynamic events (sudden increase of blood pressure) and mean blood pressure changes during the operation were similar in both groups. CONCLUSION: Our results demonstrate that serum potassium levels are constantly decreasing during laparoscopic adrenalectomy for primary aldosteronism. Active supplementation of potassium during the operation might prevent a hypokalemic event. PMID- 22204643 TI - Drug-like properties: guiding principles for the design of natural product libraries. AB - While natural products or their derivatives and mimics have contributed around 50% of current drugs, there has been no approach allowing front-loading of chemical space compliant with lead- and drug-like properties. The importance of physicochemical properties of molecules in the development of orally bioavailable drugs has been recognized. Classical natural product drug discovery has only been able to undertake this analysis retrospectively after compounds are isolated and structures elucidated. The present approach addresses front-loading of both extracts and subsequent fractions with desired physicochemical properties prior to screening for drug discovery. The physicochemical profiles of natural products active against two neglected disease targets, malaria and African trypanosomiasis, are presented based on this strategy. This approach can ensure timely development of natural product leads at a hitherto unachievable rate. PMID- 22204644 TI - XopR, a type III effector secreted by Xanthomonas oryzae pv. oryzae, suppresses microbe-associated molecular pattern-triggered immunity in Arabidopsis thaliana. AB - Xanthomonas oryzae pv. oryzae is the causal agent of bacterial blight of rice. The XopR protein, secreted into plant cells through the type III secretion apparatus, is widely conserved in xanthomonads and is predicted to play important roles in bacterial pathogenicity. Here, we examined the function of XopR by constructing transgenic Arabidopsis thaliana plants expressing it under control of the dexamethasone (DEX)-inducible promoter. In the transgenic plants treated with DEX, slightly delayed growth and variegation on leaves were observed. Induction of four microbe-associated molecular pattern (MAMP)-specific early defense genes by a nonpathogenic X. campestris pv. campestris hrcC deletion mutant were strongly suppressed in the XopR-expressing plants. XopR expression also reduced the deposition of callose, an immune response induced by flg22. When transiently expressed in Nicotiana benthamiana, a XopR::Citrine fusion gene product localized to the plasma membrane. The deletion of XopR in X. oryzae pv. oryzae resulted in reduced pathogenicity on host rice plants. Collectively, these results suggest that XopR inhibits basal defense responses in plants rapidly after MAMP recognition. PMID- 22204645 TI - Activation of the Arabidopsis thaliana mitogen-activated protein kinase MPK11 by the flagellin-derived elicitor peptide, flg22. AB - Mitogen-activated protein kinases (MAPK) mediate cellular signal transduction during stress responses, as well as diverse growth and developmental processes in eukaryotes. Pathogen infection or treatments with conserved pathogen-associated molecular patterns (PAMPs) such as the bacterial flagellin-derived flg22 peptide are known to activate three Arabidopsis thaliana MAPK: MPK3, MPK4, and MPK6. Several stresses, including flg22 treatment, are known to increase MPK11 expression but activation of MPK11 has not been shown. Here, we show that MPK11 activity can, indeed, be increased through flg22 elicitation. A small-scale microarray for profiling defense-related genes revealed that cinnamyl alcohol dehyrogenase 5 requires MPK11 for full flg22-induced expression. An mpk11 mutant showed increased flg22-mediated growth inhibition but no altered susceptibility to Pseudomonas syringae, Botrytis cinerea, or Alternaria brassicicola. In mpk3, mpk6, or mpk4 backgrounds, MPK11 is required for embryo or seed development or general viability. Although this developmental deficiency in double mutants and the lack of or only subtle mpk11 phenotypes suggest functional MAPK redundancies, comparison with the paralogous MPK4 reveals distinct functions. Taken together, future investigations of MAPK roles in stress signaling should include MPK11 as a fourth PAMP-activated MAPK. PMID- 22204646 TI - Contribution of rpfB to cell-to-cell signal synthesis, virulence, and vector transmission of Xylella fastidiosa. AB - In Xylella fastidiosa the fatty acid signal molecule diffusible signaling factor (DSF) is produced and sensed by components of the regulation of pathogenicity factors (rpf) cluster; lack of DSF production in RpfF mutants results in a non vector-transmissible phenotype yet cells are hypervirulent to grape. rpfB has not been characterized in Xylella fastidiosa, although its homolog has been suggested to be required for DSF synthesis in Xanthomonas campestris pv. campestris. We show that RpfB is involved in DSF processing in both Xylella fastidiosa and Xanthomonas campestris, affecting the profile of DSF-like fatty acids observed in thin-layer chromatography. Although three fatty acids whose production is dependent on RpfF were detected in Xylella fastidiosa and Xanthomonas campestris wild-type strains, their respective rpfB mutants accumulated primarily one chemical species. Although no quantifiable effect of rpfB on plant colonization by Xylella fastidiosa was found, insect colonization and transmission was reduced. Thus, RpfB apparently is involved in DSF processing, and like Xanthomonas campestris, Xylella fastidiosa also produces multiple DSF molecules. It is possible that Xylella fastidiosa coordinates host vector and plant colonization by varying the proportions of different forms of DSF signals via RpfB. PMID- 22204647 TI - Genome-wide analysis of the response of Dickeya dadantii 3937 to plant antimicrobial peptides. AB - Antimicrobial peptides constitute an important factor in the defense of plants against pathogens, and bacterial resistance to these peptides have previously been shown to be an important virulence factor in Dickeya dadantii, the causal agent of soft-rot disease of vegetables. In order to understand the bacterial response to antimicrobial peptides, a transcriptional microarray analysis was performed upon treatment with sub-lethal concentration of thionins, a widespread plant peptide. In all, 36 genes were found to be overexpressed, and were classified according to their deduced function as i) transcriptional regulators, ii) transport, and iii) modification of the bacterial membrane. One gene encoding a uricase was found to be repressed. The majority of these genes are known to be under the control of the PhoP/PhoQ system. Five genes representing the different functions induced were selected for further analysis. The results obtained indicate that the presence of antimicrobial peptides induces a complex response which includes peptide-specific elements and general stress-response elements contributing differentially to the virulence in different hosts. PMID- 22204649 TI - Transdermal delivery of alprazolam from a monolithic patch: formulation based on in vitro characterization. AB - Alprazolam, a benzodiazepine widely used for the treatment of psychiatric disorders, has been aimed to be formulated in a transdermal delivery system (TDS) prototype. A series of TDS prototypes dosed in all cases at 0.35 mg.cm(-2) of alprazolam were prepared as a monolithic drug in adhesive matrix using acrylic pressure-sensitive adhesives (PSA) of acrylate vinyl acetate (Duro-tack((r))). The effects of several permeation enhancers as azone, transcutol, propylene glycol, dodecyl alcohol, decyl alcohol, diethanolamine, N-methyl pyrrolidone and lauric acid were studied. Prototypes have been characterized based on adhesion parameters (peel adhesion and shear adhesion), in vitro human skin permeation and in vitro drug release according to European Pharmacopoeia for the selected prototype. Best results show that a combination of permeation enhancers from different chemical groups is able to provide almost a 33 fold increase in the transdermal alprazolam flux of an aqueous saturated dispersion (from 0.054 +/- 0.019 to 1.76 +/- 0.21 MUg h.cm(-2)). Based on these in vitro flux data, a predictive simulation of the achievable plasmatic levels was performed assuming a constant systemic infusion of drug. In summary, it is possible to obtain a prototype of a TDS of alprazolam with adequate adhesive properties (peel adhesion and shear adhesion) and able to predict sustained therapeutic plasmatic levels. PMID- 22204650 TI - Intraoperative device closure of perimembranous ventricular septal defects in the young children under transthoracic echocardiographic guidance; initial experience. AB - OBJECTIVES: This study aimed to assess the safety and feasibility of intraoperative device closure of perimembranous ventricular septal defects (VSD) in young children guided by transthoracic echocardiography (TTE). METHODS: We enrolled 18 patients from our hospital to participate in the study from June 2011 to September 2011. A minimal inferior median incision was performed after full evaluation of the perimembranous VSD by real-time TTE, and a domestically made device was inserted to occlude the perimembranous VSD. The proper size of the device was determined by means of transthoracic echocardiographic analysis. RESULTS: Implantation was ultimately successful in 16 patients using TTE guidance. In these cases, the complete closure rate immediately following the operation and on subsequent follow-up was 100%. Symmetric devices were used in 14 patients, and asymmetric devices were used in two patients. Two patient were transformed to surgical treatment, one for significant residual shunting, and the other for unsuccessful wire penetration of the VSD. The follow-up periods were less than nine months, and only one patient had mild aortic regurgitation. There were no instances of residual shunt, noticeable aortic regurgitation, significant arrhythmia, thrombosis, or device failure. CONCLUSIONS: Minimally invasive transthoracic device closure of perimembranous VSDs is safe and feasible, using a domestically made device under transthoracic echocardiographic guidance, without the need for cardiopulmonary bypass. This technique should be considered an acceptable alternative to surgery or device closure guided by transesophageal echocardiography in selected young children. However, a long-term evaluation of outcomes is necessary. PMID- 22204652 TI - Novel association patterns of cardiac remodeling markers in patients with essential hypertension and atrial fibrillation. AB - BACKGROUND: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are essential for the cardiac extracellular matrix (ECM) remodeling. We investigated differences in serum levels of these markers between patients with atrial fibrillation (AF) and sinus rhythm (SR). METHODS: Serum levels of MMP-2, MMP-3, MMP-9 and TIMP-1 were measured in 86 patients: 27 on SR without any AF history, 33 with paroxysmal and 26 with permanent AF. All subjects had essential hypertension, normal systolic function and no coronary artery disease. RESULTS: Patients with AF had higher MMP-2, MMP-3 and MMP-9 and lower TIMP-1 compared to SR subjects (all p < 0.001). Paroxysmal AF was associated with higher MMP-2 levels compared to permanent AF (p < 0.001). Matrix metalloproteinase-9 but not MMP-3 was higher in permanent compared to paroxysmal AF group (p < 0.001). Patients with AF had lower levels of TIMP-1 compared to those with SR while permanent AF subjects had lower TIMP-1 levels than those with paroxysmal AF (p < 0.001 for both comparisons). Lower TIMP-1 was the only independent factor associated with AF (OR: 0.259, 95%CI: 0.104-0.645, p = 0.004). CONCLUSIONS: In hypertensives, paroxysmal AF and permanent AF differ with respect to serum MMPs. Increased MMP-2 is associated with paroxysmal, whereas increased MMP-9 with permanent AF. Additionally, lower levels of TIMP-1 had a strong association with AF incidence. PMID- 22204653 TI - Mining the gastric cancer secretome: identification of GRN as a potential diagnostic marker for early gastric cancer. AB - Gastric cancer is the second leading cause of cancer deaths worldwide, and currently, there are no clinically relevant biomarkers for gastric cancer diagnosis or prognosis. In this study, we applied a 2D-LC-MS/MS based approach, in combination with iTRAQ labeling, to study the secretomes of the gastric cancer cell lines AGS and MKN7. By performing a comparative analysis between the conditioned media and the whole cell lysates, our workflow allowed us to differentiate the bona fide secreted proteins from the intracellular contaminants within the conditioned media. Ninety proteins were found to have higher abundance in the conditioned media as compared to the whole cell lysates of AGS and MKN7 cells. Using a signal peptide and nonclassical secretion prediction tool and an online exosome database, we demonstrated that up to 92.2% of these 90 proteins can be exported out of the cells by classical or nonclassical secretory pathways. We then performed quantitative comparisons of the secretomes between AGS and MKN7, identifying 43 differentially expressed secreted proteins. Among them, GRN was found to be frequently expressed in gastric tumor tissues, but not in normal gastric epithelia by immunohistochemistry. Sandwich ELISA assay also showed elevation of serum GRN levels in gastric cancer patients, particularly those with early gastric cancer. Receiver operating characteristic (ROC) curves analysis confirmed that serum GRN can provide diagnostic discriminations for gastric cancer patients. PMID- 22204654 TI - Pathogenic and genetic diversity of Xanthomonas translucens pv. undulosa in North Dakota. AB - Bacterial leaf streak (BLS), caused by Xanthomonas translucens pv. undulosa, has become more prevalent recently in North Dakota and neighboring states. From five locations in North Dakota, 226 strains of X. translucens pv. undulosa were collected and evaluated for pathogenicity and then selected strains were inoculated on a set of 12 wheat cultivars and other cereal hosts. The genetic diversity of all strains was determined using repetitive sequence-based polymerase chain reaction (rep-PCR) and insertion sequence-based (IS)-PCR. Bacterial strains were pathogenic on wheat and barley but symptom severity was greatest on wheat. Strains varied greatly in aggressiveness, and wheat cultivars also showed differential responses to several strains. The 16S ribosomal DNA sequences of the strains were identical, and distinct from those of the other Xanthomonas pathovars. Combined rep-PCR and IS-PCR data produced 213 haplotypes. Similar haplotypes were detected in more than one location. Although diversity was greatest (~92%) among individuals within a location, statistically significant (P <= 0.001 or 0.05) genetic differentiation among locations was estimated, indicating geographic differentiation between pathogen populations. The results of this study provide information on the pathogen diversity in North Dakota, which will be useful to better identify and characterize resistant germplasm. PMID- 22204655 TI - Application of image analysis in studies of quantitative disease resistance, exemplified using common bacterial blight-common bean pathosystem. AB - The effectiveness of image analysis (IA) compared with an ordinal visual scale, for quantitative measurement of disease severity, its application in quantitative genetic studies, and its effect on the estimates of genetic parameters were investigated. Studies were performed using eight backcross-derived families of common bean (Phaseolus vulgaris) (n = 172) segregating for the molecular marker SU91, known to be associated with a quantitative trait locus (QTL) for resistance to common bacterial blight (CBB), caused by Xanthomonas campestris pv. phaseoli and X. fuscans subsp. fuscans. Even though both IA and visual assessments were highly repeatable, IA was more sensitive in detecting quantitative differences between bean genotypes. The CBB phenotypic difference between the two SU91 genotypic groups was consistently more than fivefold for IA assessments but generally only two- to threefold for visual assessments. Results suggest that the visual assessment results in overestimation of the effect of QTL in genetic studies. This may have been caused by lack of additivity and uneven intervals of the visual scale. Although visual assessment of disease severity is a useful tool for general selection in breeding programs, assessments using IA may be more suitable for phenotypic evaluations in quantitative genetic studies involving CBB resistance as well as other foliar diseases. PMID- 22204657 TI - The use of standard calendar software by individuals with acquired brain injury and cognitive complaints: a mixed methods study. AB - PURPOSE: To explore the actual use of standard calendar software by people with acquired brain injury (ABI) and healthy individuals. METHOD: Mixed methods design with qualitative and quantitative analyses of the respondents' use of calendar software. Fifteen individuals with ABI and 15 healthy participants were enrolled. Participants were asked to execute five consecutive tasks using standard calendar software, which resembled everyday use of an electronic calendar. RESULTS: The core processes "task execution" and "information processing" were influenced by internal factors (cognitive and emotional processes and fatigue) as well as environmental factors (software features and distractions). Results obtained by qualitative and quantitative methods showed similar reaction patterns in both groups. However, ABI patients had more cognitive problems and showed stronger emotions during task performance than healthy participants. Healthy participants were more successful and needed less time and mental effort to perform a task. CONCLUSIONS: Although ABI patients were able to use standard calendar software, they became upset more easily, needed more effort, became tired sooner and more suddenly. Strategies to support ABI patients in the use of calendar software are suggested from multi-disciplinary perspectives. PMID- 22204658 TI - Clinical outcomes of single-visit oral prophylaxis: a practice-based randomised controlled trial. AB - BACKGROUND: Practice-based general dental practitioners routinely provide "scale and polish" or "oral prophylaxis" to patients attending their practices. Despite its routine provision, there is no evidence to support the clinical effectiveness of single-visit scale and polish, nor the frequency at which it should be provided. A recent systematic review recommended that future trials investigating scale and polish should involve dental practice patients. METHODS: A practice based parallel randomised controlled trial with 24-month follow-up was conducted. Healthy adults (Basic Periodontal Examination [BPE] codes <3) were randomly assigned to 3 groups (6-month, 12-month, or 24-month interval between scale and polish). The primary outcome was gingival bleeding with the hypothesis that 6 monthly scale and polish would result in lower prevalence than 12-month or 24 month frequency. Follow-up measurements were recorded by examiners blinded to the allocation. 125, 122 and 122 participants were randomised to the 6-month, 12 month and 24-month groups respectively. Complete data set analyses were conducted for 307 participants: 107, 100, and 100 in the 6-month, 12-month and 24-month groups respectively. Chi-square test and ANOVA were used to compare treatment groups at follow-up. Logistic regression and ANCOVA were used to estimate the relationship between outcome and treatment group, adjusted for baseline values. Multiple imputation analyses were also carried out for participants with incomplete data sets. RESULTS: Prevalence of gingival bleeding at follow-up was 78.5% (6-month), 78% (12-month) and 82% (24-month) (p = 0.746). There were no statistically significant differences between groups with respect to follow-up prevalence of plaque and calculus. Statistically significant differences detected in the amount (millimetres) of calculus were too small to be clinically significant. Seventeen (4.6%) participants were withdrawn from the trial to receive additional treatment. CONCLUSIONS: This trial could not identify any differences in outcomes for single-visit scale and polish provided at 6, 12 and 24 month frequencies for healthy patients (with no significant periodontal disease). However, this is the first trial of scale and polish which has been conducted in a general practice setting and the results are not conclusive. Larger trials with more comprehensive measurement and long-term follow up need to be undertaken to provide a firm evidence base for this intervention. This trial informs the design of future practice-based trials on this subject. PMID- 22204659 TI - Comparative one-factor-at-a-time, response surface (statistical) and bench-scale bioreactor level optimization of thermoalkaline protease production from a psychrotrophic Pseudomonas putida SKG-1 isolate. AB - BACKGROUND: Production of alkaline protease from various bacterial strains using statistical methods is customary now-a-days. The present work is first attempt for the production optimization of a solvent stable thermoalkaline protease by a psychrotrophic Pseudomonas putida isolate using conventional, response surface methods, and fermentor level optimization. RESULTS: The pre-screening medium amended with optimized (w/v) 1.0% glucose, 2.0% gelatin and 0.5% yeast extract, produced 278 U protease ml(-1) at 72 h incubation. Enzyme production increased to 431 Uml(-1) when Mg2+ (0.01%, w/v) was supplemented. Optimization of physical factors further enhanced protease to 514 Uml(-1) at pH 9.0, 25 degrees C and 200 rpm within 60 h. The combined effect of conventionally optimized variables (glucose, yeast extract, MgSO4 and pH), thereafter predicted by response surface methodology yielded 617 U protease ml(-1) at glucose 1.25% (w/v), yeast extract 0.5% (w/v), MgSO4 0.01% (w/v) and pH 8.8. Bench-scale bioreactor level optimization resulted in enhanced production of 882 U protease ml(-1) at 0.8 vvm aeration and 150 rpm agitation during only 48 h incubation. CONCLUSIONS: The optimization of fermentation variables using conventional, statistical approaches and aeration/agitation at fermentor level resulted in ~13.5 folds increase (882 Uml(-1)) in protease production compared to un-optimized conditions (65 Uml(-1)). This is the highest level of thermoalkaline protease reported so far by any psychrotrophic bacterium. PMID- 22204660 TI - Self-assembly of catecholic macroinitiator on various substrates and surface initiated polymerization. AB - A catechol-containing macroinitiator has been designed for the surface-initiated atom transfer radical polymerization (SI-ATRP) from various substrates at ambient temperature. Temperature-sensitive poly(N-isopropyl acrylamide) (PNIPAM) brushes were successfully grafted from a range of substrates surfaces, including metals and polyimides, via SI-ATRP using the resulting macroinitiator, which were characterized by X-ray photoelectron spectroscopy (XPS), water contact angle measurements, and atomic force microscopy (AFM). Effects of the temperature response behavior of PNIPAM brushes on the water contact angles and the impedance of the modified surfaces were also exhibited. The self-assembled film of macroinitiator and the resulting polymer brushes were both stable to soaking of basic solvents, and the brushes did not show any exfoliation or delamination even after 2 h of ultrasonic test. The advantages of the macroinitiator in strong interactions with surfaces and high stability and convenience make it possible to modify the native materials with polymer brushes in a convenient and nondestructive way. Importantly, the macroinitiator is compatible with microcontact printing, and patterned polymer brushes on Ti plate were demonstrated by microcontact printing of BrDOPAMA and the following SI-ATRP. PMID- 22204661 TI - Long-term prognosis of breast cancer detected by mammography screening or other methods. AB - INTRODUCTION: Previous studies of breast cancer have shown that patients whose tumors are detected by mammography screening have a more favorable survival. Little is known, however, about the long-term prognostic impact of screen detection. The purpose of the current study was to compare breast cancer-specific long-term survival of patients whose tumors were detected in mammography screening compared with those whose tumors were detected by other methods. METHODS: Breast cancer patients diagnosed within five specified geographical areas in Finland in 1991 and 1992 were identified (N = 2,936). Detailed clinical, treatment and outcome data, as well as tissue samples, were collected. Women with in situ carcinoma, distant metastases at the time of primary diagnosis and women who were not treated surgically were excluded. The main analyses were performed after excluding patients with other malignancy or contralateral breast cancer, followed by sensitivity analyses with different exclusion criteria. Median follow up time was 15.4 years. Univariate and multivariate analyses of breast cancer specific survival were performed. RESULTS: Of patients included in the main analyses (n = 1,884), 22% (n = 408) of cancers were screen-detected and 78% (n = 1,476) were detected by other methods. Breast cancer-specific 15-year survival was 86% for patients with screen-detected cancer and 66% for patients diagnosed using other methods (P < 0.0001, HR = 2.91). Similar differences in survival were observed in women at screening age (50 to 69 years), as well as in clinically important subgroups, such as patients with small tumors (<= 1 cm in diameter) and without nodal involvement (N0). Women with breast cancer diagnosed on the basis of screening mammography had a more favorable prognosis than those diagnosed outside screening programs, following adjustments according to patient age, tumor size, axillary lymph node status, histological grade and hormone receptor status. Significant differences in the risk of having future contralateral breast cancer according to method of detection were not observed. CONCLUSIONS: Breast cancer detected by mammography screening is an independent prognostic factor in breast cancer and is associated with a more favorable survival rate as well as in long term follow-up. PMID- 22204664 TI - A comparative study of total quality management of health care system in India and Iran. AB - BACKGROUND: Total quality management (TQM) has a great potential to address quality problems in a wide range of industries and improve the organizational performance. The growing need to take initiatives by hospitals in countries like India and Iran to improve the service quality and reduce wastage of resources has inspired the authors to develop a survey instrument to measure health care quality and performance in the two countries. METHODS: Based on the Baldrige health care criteria for performance excellence 2009-2010 and the guidelines proposed by the American Hospitals Association for hospitals in pursuit of excellence, compared health care services in three countries. The data are collected from the capital cities and their nearby places in India and Iran. Using ANOVAs, three groups in quality planning and performance have been compared. RESULT: Results showed there is significantly difference between groups and in no case the hospitals from India and Iran are found scoring close to the benchmarks. The average scores of Indian and Iranian hospitals on different constructs of the IHCQPM model are compared with the major results achieved by the recipients of the MBNQ award. CONCLUSION: In no case the hospitals from India and Iran are found scoring close to the benchmarks (Baldrige health care criteria for performance excellence 2009-2010 and the guidelines proposed by the American Hospitals Association for hospitals). These results suggested to health care services more attempt to achieve high quality in management and performance. PMID- 22204662 TI - Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders. AB - BACKGROUND: Serum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis rON or longitudinally extensive transverse myelitis-LETM) remains unresolved. RESULTS: We analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels. CONCLUSIONS: We could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response. PMID- 22204670 TI - Photochemistry of (eta6-anisole)Cr(CO)3 and (eta6-thioanisole)Cr(CO)3: evidence for a photoinduced haptotropic shift of the thioanisole ligand, a picosecond time resolved infrared spectroscopy and density functional theory investigation. AB - The photochemistry of (eta(6)-anisole)Cr(CO)(3) and (eta(6)-thioanisole)Cr(CO)(3) was investigated by picosecond time-resolved infrared spectroscopy in n-heptane solution at 298 K. Two independent excited states are populated following 400 nm excitation of each of these complexes. An excited state with some metal-to-CO charge-transfer character is responsible for the CO-loss process, which is slow compared to CO-loss from Cr(CO)(6). Observed first order rate constants of 1.8 * 10(10) s(-1) and 2.5 * 10(10) s(-1) were obtained for the anisole and thioanisole complexes, respectively. The second excited state has metal-to-arene charge transfer character and results in a haptotropic shift of the thioanisole ligand. DFT calculations characterized the excited states involved and the nature of the haptotropic shift intermediate observed for the thioanisole species. PMID- 22204665 TI - Determinants of patient satisfaction in ambulatory oncology: a cross sectional study based on the OUT-PATSAT35 questionnaire. AB - BACKGROUND: The aim of this study was to identify factors associated with satisfaction with care in cancer patients undergoing ambulatory treatment. We investigated associations between patients' baseline clinical and socio demographic characteristics, as well as self-reported quality of life, and satisfaction with care. METHODS: Patients undergoing ambulatory chemotherapy or radiotherapy in 2 centres in France were invited, at the beginning of their treatment, to complete the OUT-PATSAT35, a 35 item and 13 scale questionnaire evaluating perception of doctors, nurses and aspects of care organisation. Additionally, for each patient, socio-demographic variables, clinical characteristics and self-reported quality of life using the EORTC QLQ-C30 questionnaire were recorded. RESULTS: Among 692 patients included between January 2005 and December 2006, only 6 were non-responders. By multivariate analysis, poor perceived global health strongly predicted dissatisfaction with care (p < 0.0001). Patients treated by radiotherapy (vs patients treated by chemotherapy) reported lower levels of satisfaction with doctors' technical and interpersonal skills, information provided by caregivers, and waiting times. Patients with primary head and neck cancer (vs other localisations), and those living alone were less satisfied with information provided by doctors, and younger patients (< 55 years) were less satisfied with doctors' availability. CONCLUSIONS: A number of clinical of socio-demographic factors were significantly associated with different scales of the satisfaction questionnaire. However, the main determinant was the patient's global health status, underlining the importance of measuring and adjusting for self-perceived health status when evaluating satisfaction. Further analyses are currently ongoing to determine the responsiveness of the OUT PATSAT35 questionnaire to changes over time. PMID- 22204669 TI - Potentially inappropriate prescribing in older people with dementia in care homes: a retrospective analysis. AB - BACKGROUND: Older people in general and care home residents in particular are at high risk of suboptimal or inappropriate prescribing. To date, research into potentially inappropriate prescribing (PIP) has not focused on care home residents and/or has not utilized the recently developed and validated Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) criteria. OBJECTIVE: The aim of this study was to estimate the prevalence of PIP in older people with dementia living in six residential care homes in England, using the STOPP criteria. METHODS: A retrospective analysis was conducted using medication data collected for older people with dementia in six residential care homes in England who participated in the prospective, longitudinal EVIDEM - End of Life (EoL) study. Of the 133 residents recruited to the study, medication administration records were available for and reviewed at two timepoints (approximately 16 weeks apart) for 119 residents and 110 residents, respectively. The prevalence of PIP at these timepoints was determined using 31 of the 65 STOPP criteria applicable when there is no access to residents' medical records. RESULTS: At the first timepoint, 68 potentially inappropriate medications (PIMs) were identified. Fifty-five residents (46.2%) were prescribed one or more PIM(s), eleven (9.2%) were prescribed two or more PIMs and two (1.7%) were prescribed three PIMs. Thirteen of the 31 STOPP criteria utilized in this study (41.9%) were used to identify PIP. Long-term (i.e. >1 month) neuroleptics (antipsychotics) were the most frequently prescribed PIMs (n = 25; 21.0%), followed by non steroidal anti-inflammatory drugs (NSAIDs) for >3 months, proton pump inhibitors (PPIs) at maximum therapeutic dosage for >8 weeks, tricyclic antidepressants (TCAs) in patients with dementia and long-term (i.e. >1 month), long-acting benzodiazepines. At the second timepoint, 57 PIMs were identified; 45 residents (40.9%) were prescribed one or more PIM(s) and 10 (9.1%) were prescribed two or more PIMs, but only one resident (0.9%) was prescribed three PIMs. Of the 31 STOPP criteria utilized in this study, ten (32.3%) were used to identify PIP. Long-term (i.e. >1 month) antipsychotics were again the most frequently prescribed PIMs (n = 21; 19.1%), followed by PPIs at maximum therapeutic dosage for >8 weeks, NSAIDS for >3 months and TCAs in patients with dementia. A significant correlation was found at both timepoints between the number of medicines prescribed and occurrence of PIP. CONCLUSIONS: This study found that over two-fifths of older people with dementia residing in six residential care homes in England were prescribed at least one PIM at each timepoint. Long-term (i.e. >1 month) antipsychotics, NSAID use for >3 months and PPI use at maximum therapeutic dosage for >8 weeks were the most prevalent PIMs. Regular medication review that targets, but is not limited to, these medications is required to reduce PIP in the residential care home setting. The STOPP criteria represent a useful tool to facilitate such review in this patient population. PMID- 22204671 TI - Chemical oscillators in structured media. AB - Evolution is a characteristic feature of living systems, and many fundamental processes in life, including the cell cycle, take place in a periodic fashion. From a chemistry perspective, these repeating phenomena suggest the question of whether reactions in which concentrations oscillate could provide a basis and/or useful models for the behavior of organisms, and perhaps even their ability to evolve. In this Account, we examine several aspects of the behavior of the prototype oscillating chemical reaction, the Belousov-Zhabotinsky (BZ) system, carried out in microemulsions, arrays of micrometer-sized aqueous droplets suspended in oil, or hydrogels. Each of these environments contains elements of the compartmentalization that likely played a role in the development of the first living cells, and within them we observe behaviors not found in the BZ reaction in simple aqueous solution. Several of these phenomena resemble traits displayed by living organisms. For example, the nanodroplets in a BZ microemulsion "communicate" with each other through a phenomenon analogous to quorum sensing in bacteria to produce a remarkable variety of patterns and waves on length scales 10(5) times the size of a single droplet. A photosensitive version can "remember" an imposed image. Larger, micrometer-sized droplets exhibit similarly rich behavior and allow for the observation and control of individual droplets. These droplets offer promise for building arrays capable of computation by varying the strength and sign of the coupling between drops. Gels that incorporate a BZ catalyst and are immersed in a solution containing the BZ reactants change their shape and volume in oscillations that follow the variation in the redox state of the catalyst. Using this phenomenon, we can construct phototactic gel "worms" or segments of gel that attract one another. Whether such systems will provide more realistic caricatures of life, and whether they can serve as useful materials will largely depend on the successful integration of various properties, including communication, motion, and memory, which we observed in separate experiments. Theoretical approaches that couple reaction and diffusion processes to mechanical and other material properties are likely to play a key role in this integration, and we describe one such approach. The evolution of systems of coupled chemical oscillators presents another challenge to the development of these systems, but one that we expect to be solved. PMID- 22204673 TI - Confirming the CMS nominee--overcoming poisonous politics. PMID- 22204672 TI - Three patients with full facial transplantation. AB - Unlike conventional reconstruction, facial transplantation seeks to correct severe deformities in a single operation. We report on three patients who received full-face transplants at our institution in 2011 in operations that aimed for functional restoration by coaptation of all main available motor and sensory nerves. We enumerate the technical challenges and postoperative complications and their management, including single episodes of acute rejection in two patients. At 6 months of follow-up, all facial allografts were surviving, facial appearance and function were improved, and glucocorticoids were successfully withdrawn in all patients. PMID- 22204674 TI - Achieving accountable care--"It's not about the bike". PMID- 22204676 TI - Darwin and the Declaration. AB - Does the prima facie contradiction between the Declaration of Independence's description of the separate and unique "creation" of human beings and Darwin's evolutionary account indicate a broader contradiction between theories of human rights and Darwinian evolution? While similar troubling questions have been raised and answered in the affirmative since Darwin's time, this article renews, updates and significantly fortifies such answers with original arguments. If a "distilled" formulation of the Declaration's central claims, shorn of complicating entanglements with both theology and comprehensive philosophical doctrines, may still be in contradiction with Darwinian evolutionary theory, this should be cause for substantial concern on the part of all normative political theorists, from Straussians to Rawlsians. Despite the notable recent efforts of a few political theorists, evolutionary ethicists and sociobiologists to establish the compatibility of Darwinian evolutionary theory with moral norms such as the idea of natural or human rights, I argue that significant obstacles remain. PMID- 22204677 TI - Death with "dignity": the wedge that divides the disability rights movement from the right to die movement. AB - Much of the American debate over physician assisted death (PAD) is framed as an ideological split between conservatives and liberals, pro life and pro choice advocates, and those who emphasize morality versus personal autonomy. Less examined, but no less relevant, is a split within the ranks of progressives--one that divides those supporting a right to die in the name of human rights from disability rights activists who invoke human rights to vehemently oppose euthanasia. This paper reviews how "dignity" serves both as a divisive wedge in this debate but also as a value that can span the divide between groups and open the way to productive discourse. Supporters of legalized euthanasia use "dignity" to express their position that some deaths might indeed be accelerated. At the same time, opponents adopt the concept to argue that physician assisted suicide stigmatizes life with a disability. To bridge this divide, the worldviews of two groups, Compassion & Choices and Not Dead Yet, are studied. The analysis concludes that the two organizations are more parallel than contrary--a finding that offers opportunities for dialogue and perhaps even advances in public policy. PMID- 22204678 TI - Physical attractiveness, issue agreement, and assimilation effects in candidate appraisal. AB - This study examines the cognitive and affective factors of candidate appraisal by manipulating candidate attractiveness and levels of issue agreement with voters. Drawing upon research in evolutionary psychology and cognitive neuroscience, this analysis proposes that automatic processing of physical appearance predisposes affective disposition toward more attractive candidates, thereby influencing cognitive processing of issue information. An experimental design presented attractive and unattractive candidates who were either liberal or conservative in a mock primary election. The data show strong partial effects for appearance on vote intention, an interaction between appearance and issue agreement, and a tendency for voters to assimilate the dissimilar views of attractive candidates. We argue that physical appearance is important in primary elections when the differences in issue positions and ideology between candidates is small. PMID- 22204679 TI - Founders' forum. Essays on biopolitics. Introduction. PMID- 22204680 TI - Biopolicy after three decades. PMID- 22204681 TI - Building strong research associations: interdisciplinarity, theory-building, and policy in politics and the lifesciences and health services research. PMID- 22204682 TI - The synergism hypothesis: thirty years later. PMID- 22204683 TI - Back to the future: reflecting on the legacies of Lynton K. Caldwell, Robert H. Blank, and Andrea Bonnicksen. PMID- 22204684 TI - The role of biopolitics in environmental security analysis. PMID- 22204685 TI - Identity challenges: facing the Association for Politics and the Life Sciences. PMID- 22204686 TI - From outrage to orthodoxy? Sociobiology and political science at 35. PMID- 22204687 TI - Toward a theory of revolution: the legacy of James C. Davies in historical perspective. PMID- 22204688 TI - A founder's reflections. PMID- 22204689 TI - What hath biopolitics wrought? PMID- 22204690 TI - Reflections: An impish perspective reprised. PMID- 22204691 TI - Jim Schubert: Sui generis in life and as a scholar of biopolitics. PMID- 22204692 TI - Towards consilience: thirty years of the Association for Politics and the Life Sciences. PMID- 22204697 TI - Potassium-titanyl-phosphate laser vaporization of the prostate: a case series of an unusual complication. AB - Abstract Despite its increasing use in the management of symptomatic benign prostatic hyperplasia, the long-term complications after potassium-titanyl phosphate photoselective vaporization of the prostate are poorly reported. We describe a rare complication of this technology-calculi formation in the prostatic urethra. All patients presented with visible hematuria and variable lower urinary tract symptoms up to 5 years after the original surgery. In all cases, the calculi were successfully removed endoscopically. Possible causes for this unusual complication are discussed, and the importance of warning patients about this potential long-term complication are highlighted. PMID- 22204698 TI - Dealing with locally-driven degradation: A quick start option under REDD+. AB - The paper reviews a number of challenges associated with reducing degradation and its related emissions through national approaches to REDD+ under UNFCCC policy. It proposes that in many countries, it may in the short run be easier to deal with the kinds of degradation that result from locally driven community over exploitation of forest for livelihoods, than from selective logging or fire control. Such degradation is low-level, but chronic, and is experienced over very large forest areas. Community forest management programmes tend to result not only in reduced degradation, but also in forest enhancement; moreover they are often popular, and do not require major political shifts. In principle these approaches therefore offer a quick start option for REDD+. Developing reference emissions levels for low-level locally driven degradation is difficult however given that stock losses and gains are too small to be identified and measured using remote sensing, and that in most countries there is little or no forest inventory data available. We therefore propose that forest management initiatives at the local level, such as those promoted by community forest management programmes, should monitor, and be credited for, only the net increase in carbon stock over the implementation period, as assessed by ground level surveys at the start and end of the period. This would also resolve the problem of nesting (ensuring that all credits are accounted for against the national reference emission level), since communities and others at the local level would be rewarded only for increased sequestration, while the national reference emission level would deal only with reductions in emissions from deforestation and degradation. PMID- 22204699 TI - Examining the BMI-mortality relationship using fractional polynomials. AB - BACKGROUND: Many previous studies estimating the relationship between body mass index (BMI) and mortality impose assumptions regarding the functional form for BMI and result in conflicting findings. This study investigated a flexible data driven modelling approach to determine the nonlinear and asymmetric functional form for BMI used to examine the relationship between mortality and obesity. This approach was then compared against other commonly used regression models. METHODS: This study used data from the National Health Interview Survey, between 1997 and 2000. Respondents were linked to the National Death Index with mortality follow-up through 2005. We estimated 5-year all-cause mortality for adults over age 18 using the logistic regression model adjusting for BMI, age and smoking status. All analyses were stratified by sex. The multivariable fractional polynomials (MFP) procedure was employed to determine the best fitting functional form for BMI and evaluated against the model that includes linear and quadratic terms for BMI and the model that groups BMI into standard weight status categories using a deviance difference test. Estimated BMI-mortality curves across models were then compared graphically. RESULTS: The best fitting adjustment model contained the powers -1 and -2 for BMI. The relationship between 5-year mortality and BMI when estimated using the MFP approach exhibited a J shaped pattern for women and a U-shaped pattern for men. A deviance difference test showed a statistically significant improvement in model fit compared to other BMI functions. We found important differences between the MFP model and other commonly used models with regard to the shape and nadir of the BMI mortality curve and mortality estimates. CONCLUSIONS: The MFP approach provides a robust alternative to categorization or conventional linear-quadratic models for BMI, which limit the number of curve shapes. The approach is potentially useful in estimating the relationship between the full spectrum of BMI values and other health outcomes, or costs. PMID- 22204700 TI - Games with a scientific purpose. AB - The protein folding game Foldit shows that games are an effective way to recruit, engage and organize ordinary citizens to help solve difficult scientific problems. PMID- 22204701 TI - Novel films for drug delivery via the buccal mucosa using model soluble and insoluble drugs. AB - Bioadhesive buccal films are innovative dosage forms with the ability to adhere to the mucosal surface and subsequently hydrate to release and deliver drugs across the buccal membrane. This study aims to formulate and characterize stable carrageenan (CAR) based buccal films with desirable drug loading capacity. The films were prepared using CAR, poloxamer (POL) 407, various grades of PEG (plasticizer) and loaded with paracetamol (PM) and indomethacin (IND) as model soluble and insoluble drugs, respectively. The films were characterized by texture analysis, thermogravimetric analysis (TGA), DSC, scanning electron microscopy, X-ray powder diffraction (XRPD), and in vitro drug release studies. Optimized films were obtained from aqueous gels comprising 2.5% w/w kappa-CAR 911, 4% w/w POL 407 and 6% w/w (PM) and 6.5% w/w (IND) of PEG 600 with maximum drug loading of 1.6% w/w and 0.8 % w/w for PM and IND, respectively. TGA showed residual water content of approximately 5% of films dry weight. DSC revealed a T(g) at 22.25 and 30.77 degrees C for PM and IND, respectively, implying the presence of amorphous forms of both drugs which was confirmed by XRPD. Drug dissolution profiles in simulated saliva showed cumulative percent release of up to 45 and 57% of PM and IND, respectively, within 40 min of contact with dissolution medium simulating saliva. PMID- 22204702 TI - Temperature-induced transition from odd-even to even-odd effect in polyelectrolyte multilayers due to interpolyelectrolyte interactions. AB - Within a liquid cell the linear growth of polyelectrolyte multilayers from poly(styrenesulfonate) (PSS) and poly(allylamine hydrochloride) (PAH) is observed with multiple angle null ellipsometry. The salt content is varied between 1 and 4 mol/L NaCl and the temperature between 20 and 55 degrees C. In the linear growth regime, the outermost layer is investigated. At low temperature, a top PSS layer is twice as thick as a top PAH layer (odd-even effect), consistent with the respective monomer volumes and the same water content for both kinds of top polyelectrolyte layers as confirmed by refractive index measurements. On heating, the thickness of a polycation/polyanion bilayer increases. For temperatures exceeding a crossover temperature, a top PAH layer is thicker than a top PSS layer (even-odd effect). Simultaneously, the index of refraction of the respective top layers indicates a compact PSS and a swollen PAH layer. It is suggested that, at elevated temperature and high salt conditions, secondary forces gain importance in comparison to electrostatic forces: therefore, a transition from an odd-even to an even-odd effect occurs, as well as the decreased film stability on drying as described before (Cornelsen, M., et al. Macromolecules 2010, 43, 4300). The ellipsometric data indicate that PAH/PSS layer pairs exceeding 8.6 nm thickness in solution are unstable in air. PMID- 22204703 TI - Talking Mats in a discussion group for people with Huntington's disease. AB - PURPOSE: To evaluate the function of Talking Mats (TM) in a discussion group for people with Huntington's disease (HD). METHOD: Four persons with HD and their group leader participated. The group was videotaped during four discussions, two with and two without TM. A mixed method quantitative and qualitative study was implemented by evaluating the conversations using the protocol Effectiveness Framework of Functional Communication by analyzing the number of follow-up questions and by post discussion interviews. RESULTS: The results showed improved effectiveness of communication for all participants and an increased number of follow-up questions, both from the group leader and from some of the participants. All participants and the leader were positive regarding the use of TM but there were also drawbacks. CONCLUSIONS: TM could be useful in discussion groups for people with HD. An increased number of follow-up questions when TM is used may lead to a deeper understanding within the group. This study is the first of its kind and more research in the area is needed. [Box: see text]. PMID- 22204704 TI - Factors confounding the assessment of reflection: a critical review. AB - BACKGROUND: Reflection on experience is an increasingly critical part of professional development and lifelong learning. There is, however, continuing uncertainty about how best to put principle into practice, particularly as regards assessment. This article explores those uncertainties in order to find practical ways of assessing reflection. DISCUSSION: We critically review four problems: 1. Inconsistent definitions of reflection; 2. Lack of standards to determine (in)adequate reflection; 3. Factors that complicate assessment; 4. Internal and external contextual factors affecting the assessment of reflection. SUMMARY: To address the problem of inconsistency, we identified processes that were common to a number of widely quoted theories and synthesised a model, which yielded six indicators that could be used in assessment instruments. We arrived at the conclusion that, until further progress has been made in defining standards, assessment must depend on developing and communicating local consensus between stakeholders (students, practitioners, teachers, supervisors, curriculum developers) about what is expected in exercises and formal tests. Major factors that complicate assessment are the subjective nature of reflection's content and the dependency on descriptions by persons being assessed about their reflection process, without any objective means of verification. To counter these validity threats, we suggest that assessment should focus on generic process skills rather than the subjective content of reflection and where possible to consider objective information about the triggering situation to verify described reflections. Finally, internal and external contextual factors such as motivation, instruction, character of assessment (formative or summative) and the ability of individual learning environments to stimulate reflection should be considered. PMID- 22204705 TI - Layer-by-layer assembly of two temperature-responsive homopolymers at neutral pH and the temperature-dependent solubility of the multilayer film. AB - We fabricated a layer-by-layer (LbL) film of temperature-responsive homopolymers at neutral pH and studied its temperature-dependent solubility. We first measured the cloud point of mixed solutions of temperature-responsive polymers. The significant decrease of cloud point suggested that the intermolecular interaction between two polymer chains of different kinds was stronger than that between two polymer chains of the same kind. Strong intermolecular interaction between two polymer chains of different kinds is a prerequisite for LbL assembly. On the basis of the decrease of cloud point of mixed solutions of temperature-responsive homopolymers, we selected poly(N-vinylcaprolactam) (PVCL) and poly(2 hydroxypropyl acrylate) (PHPA) for LbL assembly. LbL films of the two polymers were fabricated at neutral pH at a constant temperature. When the film was immersed in purified water at a temperature lower than the assembly temperature, it can be partially dissolved with a diffusion-limited dissolution process. The temperature-responsive solubility of the LbL film is closely connected to the phase behavior of mixed solutions of the two polymers. Additionally, as compared to multilayer films of neutral polymers and poly(carboxylic acid)s, the PVCL/PHPA multilayer film is relatively stable when it was immersed in buffer solutions near physiological pH at the assembly temperature. Such LbL films with temperature-responsive solubility might be used as a dissolvable film or a smart capsule. PMID- 22204707 TI - High density of tryptase-positive mast cells in patients with renal cell carcinoma on hemodialysis: correlation with expression of stem cell factor and protease activated receptor-2. AB - Patients on hemodialysis are at higher risk of renal cell carcinoma probably because of inflammatory and immune system disorders. The aim of this study was to clarify the pathologic roles of 2 phenotypes of mast cells, mast cell tryptase and mast cell chymase, and their correlation with stem cell factor and protease activated receptor 2 in patients with renal cell carcinoma on hemodialysis. The densities of mast cell tryptase and mast cell chymase and expressions of stem cell factor and protease-activated receptor 2 were examined in 35 patients with hemodialysis-renal cell carcinoma and 39 with non-hemodialysis-renal cell carcinoma who were diagnosed and treated in our hospital. Protein expression was examined by immunohistochemistry. The proliferation index represented the number of Ki-67-positive cells. There were no significant differences in clinicopathologic features between the 2 groups. Mast cell tryptase densities in intratumoral (8.3 per high-power field) and peritumoral areas (8.7 per high-power field) were higher in hemodialysis-renal cell carcinoma than non-hemodialysis renal cell carcinoma (2.7 and 5.3 per high-power field). No such significant correlations were detected in mast cell chymase. In hemodialysis-renal cell carcinoma, intratumoral mast cell tryptase density correlated with the proliferation index (P = .039 and P = .008, respectively) and also with stem cell factor and protease-activated receptor 2 expression. Our results emphasize the important roles of mast cell tryptase in cancer cell proliferation and recurrence in hemodialysis-renal cell carcinoma. Stem cell factor and protease-activated receptor 2 seem to up-regulate mast cell tryptase functions in these patients. The results suggest collaborative effects of stem cell factor, mast cell tryptase, and protease-activated receptor 2 on the malignant potential of hemodialysis-renal cell carcinoma. PMID- 22204708 TI - Extracutaneous Merkel cell carcinomas harbor polyomavirus DNA. AB - Merkel cell carcinoma is a neuroendocrine tumor, with characteristic morphological and immunohistochemical features. Originally reported as primary carcinoma of skin, it has been described in numerous other sites such as lymph nodes, oral cavity, breast, vaginal walls, and salivary glands. Recent studies have revealed in cutaneous Merkel cell carcinomas a clonally integrated polyomavirus, named Merkel cell polyomavirus. The aim of the present study was to verify the presence of Merkel cell polyomavirus in 5 cases of primary Merkel cell carcinomas of lymph nodes and 1 case of parotid gland to investigate similarities or differences among Merkel cell carcinomas from various sites. Cases studied were 5 primary Merkel cell carcinomas in lymph nodes, 1 in the parotid gland, and 12 in the skin. Twelve cases of primary and metastatic small cell carcinoma of the lung were also investigated. Immunohistochemistry for keratin 20, chromogranin, synaptophysin, and thyroid transcription factor 1 was performed in all cases. Viral DNA was studied using polymerase chain reaction assay and the products evaluated in agarose gel and sequenced. Cytokeratin 20 and Merkel cell polyomavirus were detected in all cases of primary Merkel cell carcinoma irrespective of their site of origin. On the contrary, all cases of pulmonary small cell carcinoma were negative for both Merkel cell polyomavirus and cytokeratin 20. It appears that cutaneous and extracutaneous Merkel cell carcinomas share similar histologic, immunohistochemical, and molecular features. This is further evidence that Merkel cell carcinomas are a multiorgan carcinoma and that Merkel cell polyomavirus might play a role in the pathogenesis of this neoplasm. PMID- 22204706 TI - The mevalonate pathway in C. elegans. AB - The mevalonate pathway in human is responsible for the synthesis of cholesterol and other important biomolecules such as coenzyme Q, dolichols and isoprenoids. These molecules are required in the cell for functions ranging from signaling to membrane integrity, protein prenylation and glycosylation, and energy homeostasis. The pathway consists of a main trunk followed by sub-branches that synthesize the different biomolecules. The majority of our knowledge about the mevalonate pathway is currently focused on the cholesterol synthesis branch, which is the target of the cholesterol-lowering statins; less is known about the function and regulation of the non-cholesterol-related branches. To study them, we need a biological system where it is possible to specifically modulate these metabolic branches individually or in groups. The nematode Caenorhabditis elegans (C. elegans) is a promising model to study these non-cholesterol branches since its mevalonate pathway seems very well conserved with that in human except that it has no cholesterol synthesis branch. The simple genetic makeup and tractability of C. elegans makes it relatively easy to identify and manipulate key genetic components of the mevalonate pathway, and to evaluate the consequences of tampering with their activity. This general experimental approach should lead to new insights into the physiological roles of the non-cholesterol part of the mevalonate pathway. This review will focus on the current knowledge related to the mevalonate pathway in C. elegans and its possible applications as a model organism to study the non-cholesterol functions of this pathway. PMID- 22204709 TI - Assessment of the prognostic significance of endoglin (CD105) in clear cell renal cell carcinoma using automated image analysis. AB - The behavior of clear cell renal cell carcinoma can be difficult to predict. Angiogenesis has proven to be a useful prognostic indicator in different malignancies. Endoglin (CD105) is a new marker of angiogenesis found to have prognostic utility in various tumors. Here, we provide the first automated digital assessment of intratumoral microvascular density in clear cell renal cell carcinoma using endoglin and CD31 and assess their utility as predictors of clinical outcome. Both endoglin and CD31 expression showed association with advanced tumor stage (P = .025 and P = .011, respectively). There was a significant correlation between CD31 and tumor grade (P = .034). Kaplan-Meier survival curves showed that patients with higher endoglin expression had significantly shorter progression-free survival (P = .010). Patients with higher CD31 expression tended to have a worse prognosis, although this was not statistically significant (P = .082). In univariate analysis using endoglin as a continuous variable, increased endoglin was strongly associated with reduced survival (hazard ratio, 1.74; 95% CI, 1.39-2.18; P = <.001). CD31 also correlated with poor outcomes (hazard ratio, 1.52; 95% CI, 1.24-1.86; P = .001). There was no correlation between CD31 and endoglin expression (r = -0.090, P = .541). Receiver operating characteristic analysis showed the area under the curve to be 0.749 for endoglin and 0.550 for CD31. In conclusion, increased endoglin and CD31 expression are associated with a higher tumor stage and decreased progression free survival. Our automated approach overcomes many limitations of manual quantification. Advances in digital assessment of immunohistochemical markers can be helpful in standardizing the evaluation of tumor biomarkers. PMID- 22204710 TI - Morphology and prognostic value of tumor budding in rectal cancer after neoadjuvant radiotherapy. AB - Tumor budding is an acknowledged prognostic marker in colorectal cancer. This study was conducted to investigate the morphology and prognostic significance of budding in rectal cancer after neoadjuvant radiotherapy. Surgical specimens from 96 consecutive patients who underwent neoadjuvant radiotherapy and curative resection were retrieved to assess budding and other clinicopathologic factors. The morphology and prognostic significance of postirradiation tumor budding were closely associated with tumor regression grade. In the tumor regression grade 1 group, tumor budding presented as "false budding" and did not have a significant association with prognosis. In the tumor regression grade 2 and 3 groups, budding was observed surrounded by radiation-induced fibrosis and large populations of infiltrating inflammatory cells, and budding intensity was significantly associated with histologic differentiation, ypN stage, and lymphovascular invasion (P < .05). Moreover, the low-grade budding subgroup showed a significantly higher rate of 5-year disease-free survival than the high-grade budding subgroup (87.5% versus 55.6%, P < .0001). Multivariate analysis showed that pretreatment serum carcinoembyronic antigen, tumor regression grade, and tumor budding were the major independent factors affecting long-term disease-free survival. In conclusion, postirradiation budding has distinct morphology and prognostic significance in rectal cancer after neoadjuvant radiotherapy. PMID- 22204711 TI - WITHDRAWN: Cytogenetic and molecular genetic study on glioblastoma arising in granular cell astrocytoma: a case report. AB - This article has been withdrawn at the request of the authors. The Publisher apologizes for any inconvenience this may cause. The full Elsevier policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22204712 TI - Reduced nuclear and ectopic cytoplasmic expression of lysyl oxidase-like 2 is associated with lymph node metastasis and poor prognosis in esophageal squamous cell carcinoma. AB - Lysyl oxidase family members have various roles in cancer progression. The aim of this study was to investigate their expression and clinical significance in esophageal squamous cell carcinoma. We examined messenger RNA expression of lysyl oxidase family members including lysyl oxidase and lysyl oxidase-like proteins (lysyl oxidase L) in 10 esophageal squamous cell carcinoma cell lines and 83 pairs of tumor samples by quantitative real-time polymerase chain reaction. All except lysyl oxidase L3 were expressed at high levels in esophageal squamous cell carcinoma, but only lysyl oxidase L2 was associated with lymph node metastasis (P = .034). We examined lysyl oxidase L2 protein further by immunohistochemistry staining in 178 surgically resected esophageal squamous cell carcinoma tissue samples. The protein manifested decreased nuclear expression and increased cytoplasmic expression. Moreover, these 2 events both had significant correlation with the presence of lymph node metastasis (P = .001 and P < .001). Overall survival rates of the patients with esophageal squamous cell carcinoma with decreased nuclear expression or increased cytoplasmic expression of lysyl oxidase L2 were significantly lower than those of the patients with esophageal squamous cell carcinoma with the reverse expression pattern (P = .040 or P = .022). Multivariate analyses revealed that nuclear expression of lysyl oxidase L2 was an independent prognostic factor for esophageal squamous cell carcinoma. These results suggest that lysyl oxidase L2 exerts a critical effect on esophageal squamous cell carcinoma progression and can be a predictive marker of lymph node metastasis and outcome. PMID- 22204713 TI - The Wnt/beta-catenin pathway drives increased cyclin D1 levels in lymph node metastasis in papillary thyroid cancer. AB - We examined the expression of cyclin D1 in conjunction with beta-catenin and the phosphorylated inactive form of glycogen synthase kinase 3beta (GSK-3beta) in benign, nonneoplastic thyroid tissue as well as papillary thyroid carcinoma primary tumors and nodal metastases. We aim to unravel the regulation of cyclin D1 and determine if this cell cycle protein is a useful biomarker for metastatic disease. It is clear that expression of cyclin D1 (P < .0001), beta-catenin (P < .0001), and inactive form of GSK-3beta (P < .0001) are significantly higher in papillary thyroid carcinoma primary tumors than in corresponding benign, nonneoplastic tissue thyroid specimens. Interestingly, beta-catenin and cyclin D1 expressions in papillary thyroid carcinoma are correlated (P = .025), implying that beta-catenin is a factor driving higher levels of cyclin D1 consistent with previous cell models linking Wnt/beta-catenin signaling and cyclin D1 expression. Conversely, inactive form of GSK-3beta expression does not correlate with cyclin D1 (P = .52) or beta-catenin expression (P = .54). We also did not observe any relationship between tumor size and marker expression. Comparing papillary thyroid carcinoma primary tumors with or without nodal metastases, we did not see any differences in expression of inactive form of GSK-3beta (P = .95), beta catenin (P = .14), or cyclin D1 (P = .46). However, in papillary thyroid carcinoma lymph node specimens, the up-regulation of cyclin D1 (P = .0083) was highly significant compared with primary tumors. pGSK-3beta and beta-catenin expression did not vary between primary tumors and nodal specimens. In conclusion, we have demonstrated that expression of cyclin D1 is linked to nodal metastases and that cyclin D1 levels are regulated by Wnt/beta-catenin signaling. GSK pathway-mediated regulation of beta-catenin or cyclin D1 expression does not appear operative in papillary thyroid carcinoma. PMID- 22204714 TI - Overexpression of astrocyte-elevated gene-1 is closely correlated with poor prognosis in human non-small cell lung cancer and mediates its metastasis through up-regulation of matrix metalloproteinase-9 expression. AB - Expression of astrocyte-elevated gene-1, a novel oncoprotein, is elevated in multiple cancers and plays a vital role in tumor cell growth, invasion, angiogenesis, and progression to metastasis. However, the functional significance of astrocyte-elevated gene-1 in non-small cell lung cancer still remains unclear. Our present study showed that the markedly up-regulated expression of astrocyte elevated gene-1 was observed in non-small cell lung cancer cell lines and tissues at the level of both transcription and translation. Simultaneously, ectopic expression or small interfering RNA silencing of astrocyte-elevated gene-1 markedly enhanced or inhibited the invasive ability of non-small cell lung cancer cells, respectively. At the molecular level, we also revealed that the function of astrocyte-elevated gene-1 in promoting metastasis was associated with the activation of matrix metalloproteinase-9 expression. Consistent with these observations, immunostaining analysis revealed a significant positive correlation between astrocyte-elevated gene-1 and matrix metalloproteinase-9. Moreover, subcutaneous xenografts of non-small cell lung cancer cells engineered to express astrocyte-elevated gene-1 were highly invasive compared with the parental cells and expressed a high level of matrix metalloproteinase-9. In archival non-small cell lung cancer specimens, high astrocyte-elevated gene-1 expression correlated significantly with clinical staging (P = .048), differentiation (P = .023), and lymph node metastasis (P = .032). The overall survival time in patients with high astrocyte-elevated gene-1 expression was notably shorter than that in patients with low astrocyte-elevated gene-1 expression (P < .001). Taken together, our results indicate that astrocyte-elevated gene-1 plays a crucial role in the carcinogenesis and aggressiveness of non-small cell lung cancer, promoting its metastasis by modulating matrix metalloproteinase-9 expression and leading to a poor clinical prognosis. PMID- 22204715 TI - Utilization of fluorescence in situ hybridization with cytokeratin discriminators in TOP2A assessment of chemotherapy-treated patients with breast cancer. AB - Tumor biomarkers increasingly provide information for predicting outcomes with chemotherapeutic regimens (personalized medicine). Topo2A is a DNA helicase targeted by anthracyclines, cytotoxic therapeutics used in both adjuvant and palliative treatments of breast cancer. TOP2A gene amplification/deletion is implicated in response to anthracycline-based chemotherapy. We describe an approach for analyzing formalin-fixed, paraffin-embedded breast tumors on tissue microarrays with TOP2A fluorescence in situ hybridization coupled with cytokeratin immunofluorescence to target tumor cells. Stained tissue from patient specimens was imaged and analyzed using Metafer/Metacyte (Metasystems, Waltham, MA, USA), including customized image classifiers. TOP2A/CEN17 ratios of 2.0 or greater (amplified) and 0.8 or less (deleted) were observed for 10.0% and 6.1% of the patients, respectively. Patient outcomes for adjuvant chemotherapy (cyclophosphamide-epirubicin-fluorouracil, cyclophosphamide-methotrexate fluorouracil, no chemotherapy) were evaluated. No statistical significance was achieved for clinical end points regarding TOP2A status in anthracycline-treated patients. However, patients with TOP2A aberrations receiving methotrexate-based therapy exhibited a significant decrease in 5-year distant disease-free survival and breast cancer-specific overall survival, especially for patients with TOP2A deletions (disease-free survival: hazard ratio, 5.31 [P = .001], and breast cancer-specific overall survival: hazard ratio, 6.45 [P <= .001]). No significant differences were seen in patients included in the no-chemotherapy group. Topo2A protein levels were assessed by immunohistochemistry with no correlative statistical relevance to immunofluorescence/fluorescence in situ hybridization based prognosis for cyclophosphamide-epirubicin-fluorouracil or cyclophosphamide methotrexate-fluorouracil groups. Interestingly, aberrant (under)expressing patients in the no-chemotherapy group exhibited better 5-year distant disease free survival (hazard ratio, 0.39; P = .004), trending toward more favorable breast cancer-specific overall survival (hazard ratio, 0.61; P = .11). Our results indicate a strategy by which fluorescence in situ hybridization scoring targeted to cytokeratin-positive tumor cells may provide a tool for added precision and efficiency in TOP2A evaluation from tumor tissue. PMID- 22204716 TI - Clinicopathologic significance and function of S-phase kinase-associated protein 2 overexpression in hepatocellular carcinoma. AB - The F-box protein S-phase kinase-associated protein 2 is frequently overexpressed in human cancers. Herein, we aimed to investigate the expression pattern, clinical significance, and biological function of S-phase kinase-associated protein 2 in hepatocellular carcinoma. Analysis by reverse transcriptase polymerase chain reaction, Western blot, and immunohistochemistry revealed that S phase kinase-associated protein 2 was aberrantly overexpressed in hepatocellular carcinomas relative to adjacent nontumor liver tissues. This overexpression was significantly associated with advanced tumor stage, increased histologic grade, vascular invasion, and intrahepatic metastasis, as well as worse overall survival and higher early recurrence rate. Knockdown of the endogenous S-phase kinase associated protein 2 expression in 1 hepatocellular carcinoma cell line, Huh7, by RNA interference reduced cell proliferation, blocked the cell cycle at G1 phase, and increased apoptosis. S-phase kinase-associated protein 2 silencing resulted in a deregulation of multiple cell-cycle regulatory proteins in Huh7 cells, as detected by quantitative real-time polymerase chain reaction arrays. Furthermore, high S-phase kinase-associated protein 2 immunoreactivity was found to be significantly correlated with reduced expression of P27, P21, and cell-cycle checkpoint kinase 2, as well as with increased expression of transcription factors Dp-1, cyclin D2, and cyclin D1 in hepatocellular carcinoma tissues. These data demonstrate that S-phase kinase-associated protein 2 expression is closely linked to tumor progression and represents an independent predictor of poor prognosis in hepatocellular carcinoma. S-phase kinase-associated protein 2 is involved in hepatocellular carcinoma cell proliferation through regulating numerous genes involved in cell-cycle progression, thereby providing a potential therapeutic target for this malignancy. PMID- 22204717 TI - Influence of retinoblastoma-related gene silencing on the initiation of DNA replication by African cassava mosaic virus Rep in cells of mature leaves in Nicotiana benthamiana plants. AB - BACKGROUND: Geminiviruses mainly infect terminally differentiated tissues and cells in plants. They need to reprogramme host cellular machinery for DNA replication. This process is thought to be mediated by inactivation of cell-cycle repressor proteins and by induction of host DNA synthesis protein expression through actions of the geminviral replication initiator protein (Rep). FINDINGS: Exploiting a Nicotiana benthamiana pOri2 line, which is transformed with a transgene consisting of a direct repeat of the African cassava mosaic virus (ACMV)-replication origin (Ori) flanking a non-viral DNA region, and virus induced RNA silencing (VIGS), the impact of host gene expression on replication of the ACMV-derived replicon was investigated. The ACMV Rep trans-replicated the viral episomal replicon in leaves of young but not older pOri2 plants. Upon VIGS mediated down-regulation of N. benthamiana NbRBR1, the retinoblastoma-related protein gene coding for a negative cell-cycle suppressor, recovered the ability of ACMV Rep for trans DNA replication, whereas the silencing of NbPCNA coding for the sliding clamp of DNA polymerase had no effect. CONCLUSIONS: These results suggest that the cellular machinery for DNA replication in differentiated tissues of older leaves cannot be reprogrammed by Rep alone but may need other uncharacterised viral and plant factors. PMID- 22204718 TI - Risk of cardiac valve regurgitation with dopamine agonist use in Parkinson's disease and hyperprolactinaemia: a multi-country, nested case-control study. AB - BACKGROUND: There is growing evidence that ergot dopamine agonists may induce cardiac valve regurgitation (CVR) in persons with Parkinson's disease. It is unclear whether the CVR risk is increased with ergot-dopamine agonist use in persons with hyperprolactinaemia, in whom the dose is much lower. OBJECTIVE: The aim of the study was to explore the association between different dopamine agonists and CVR in patients with Parkinson's disease or hyperprolactinaemia. DESIGN: Nested case-control studies conducted separately in cohorts of Parkinson's disease and hyperprolactinaemia patients. Cases were patients who developed newly diagnosed CVR. Controls were CVR-free patients from the same cohorts and were matched to cases by age, sex, database and calendar year. SETTING AND PATIENTS: Study patients were identified from over 4.5 million persons in The Health Improvement Network (THIN; UK), Health Search (Italy), and Integrated Primary Care Information (IPCI; the Netherlands) general practice databases in the years 1996-2007. The Parkinson's disease cohort included new users of dopamine agonists or levodopa, while the hyperprolactinaemia cohort included new users or non-users of dopamine agonists. MAIN OUTCOME MEASURE: Risk of newly diagnosed CVR with dopamine agonist use compared with levodopa use in the Parkinson's disease cohort, and dopamine agonist-naive patients in the hyperprolactinaemia cohort. RESULTS: In the Parkinson's disease cohort (7893 dopamine agonist users, 11 766 levodopa users), 85 incident CVR cases were identified. Increased CVR risk was observed for ergot dopamine agonists (adjusted OR [OR(adj)] 3.82; 95% CI 2.14, 6.81), but not for non-ergot dopamine agonists (OR(adj) 1.20; 95% CI 0.63, 2.29). In the hyperprolactinaemia cohort (6740 dopamine agonist users and 14 299 dopamine agonist-naive patients), 37 CVR cases were identified during a mean follow-up of 4.5 years and 3.5 years for new users and non-users of dopamine agonists, respectively. However, no association with ever use of ergot dopamine agonists was observed (OR(adj) 0.47; 95% CI 0.20, 1.19). CONCLUSION: Ergot-derived dopamine agonists are associated with an increased risk of CVR in Parkinson's disease but not in hyperprolactinaemia patients. PMID- 22204720 TI - Building the path to accountable care. PMID- 22204719 TI - Effects of proton pump inhibitors on platelet function in patients receiving clopidogrel: a systematic review. AB - BACKGROUND: There is considerable debate regarding the negative impact of concomitant proton pump inhibitor (PPI) therapy on the antiplatelet efficacy of clopidogrel. AIM: The aim of this study was to perform a systematic review of studies that have evaluated the platelet function of patients receiving clopidogrel alone compared with those receiving both clopidogrel and PPIs. METHODS: We searched MEDLINE, EMBASE and the Cochrane Controlled Trials Register in February 2011 for randomized and non-randomized studies that reported platelet function results in patients taking clopidogrel, with or without PPIs. RESULTS: Our review included 19 studies (13 trials and 6 observational studies) involving 4693 patients. There was considerable heterogeneity in the study designs, patient characteristics, laboratory tests of platelet function, and drug exposure (dose and duration of PPI and clopidogrel). There was some evidence against omeprazole, with five of nine studies demonstrating a significant interaction with clopidogrel. The available platelet function data on esomeprazole (six studies) or pantoprazole (six studies) did not demonstrate a significant interaction. Of the six studies that statistically analysed platelet function data with omeprazole compared with pantoprazole, three showed a significantly greater interaction between omeprazole and clopidogrel, whereas three studies with limited sample sizes were unable to find a significant difference in the effects of omeprazole and pantoprazole. CONCLUSION: Platelet function studies do not demonstrate a clear or consistent interaction between clopidogrel and PPIs. These studies are difficult to interpret given the lack of information on drug exposure (dose and duration), variation in laboratory methodology and lack of genetic information. Consequently, platelet function data are of uncertain clinical relevance in determining the risk of an adverse cardiovascular interaction between PPIs and clopidogrel. Clinicians should continue to clinically assess the gastrointestinal risk of the patients and make their prescribing decision for PPIs based on any anticipated benefits in reducing risk of peptic ulcers and gastrointestinal haemorrhage. PMID- 22204721 TI - Copyright and open access at the bedside. PMID- 22204722 TI - The road less traveled. PMID- 22204724 TI - Incorporation of bevacizumab in the primary treatment of ovarian cancer. AB - BACKGROUND: Vascular endothelial growth factor is a key promoter of angiogenesis and disease progression in epithelial ovarian cancer. Bevacizumab, a humanized anti-vascular endothelial growth factor monoclonal antibody, has shown single agent activity in women with recurrent tumors. Thus, we aimed to evaluate the addition of bevacizumab to standard front-line therapy. METHODS: In our double blind, placebo-controlled, phase 3 trial, we randomly assigned eligible patients with newly diagnosed stage III (incompletely resectable) or stage IV epithelial ovarian cancer who had undergone debulking surgery to receive one of three treatments. All three included chemotherapy consisting of intravenous paclitaxel at a dose of 175 mg per square meter of body-surface area, plus carboplatin at an area under the curve of 6, for cycles 1 through 6, plus a study treatment for cycles 2 through 22, each cycle of 3 weeks' duration. The control treatment was chemotherapy with placebo added in cycles 2 through 22; bevacizumab-initiation treatment was chemotherapy with bevacizumab (15 mg per kilogram of body weight) added in cycles 2 through 6 and placebo added in cycles 7 through 22. Bevacizumab throughout treatment was chemotherapy with bevacizumab added in cycles 2 through 22. The primary end point was progression-free survival. RESULTS: Overall, 1873 women were enrolled. The median progression-free survival was 10.3 months in the control group, 11.2 in the bevacizumab-initiation group, and 14.1 in the bevacizumab-throughout group. Relative to control treatment, the hazard ratio for progression or death was 0.908 (95% confidence interval [CI], 0.795 to 1.040; P=0.16) with bevacizumab initiation and 0.717 (95% CI, 0.625 to 0.824; P<0.001) with bevacizumab throughout. At the time of analysis, 76.3% of patients were alive, with no significant differences in overall survival among the three groups. The rate of hypertension requiring medical therapy was higher in the bevacizumab-initiation group (16.5%) and the bevacizumab-throughout group (22.9%) than in the control group (7.2%). Gastrointestinal-wall disruption requiring medical intervention occurred in 1.2%, 2.8%, and 2.6% of patients in the control group, the bevacizumab-initiation group, and the bevacizumab-throughout group, respectively. CONCLUSIONS: The use of bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy prolongs the median progression free survival by about 4 months in patients with advanced epithelial ovarian cancer. (Funded by the National Cancer Institute and Genentech; ClinicalTrials.gov number, NCT00262847.). PMID- 22204727 TI - Images in clinical medicine. A head shot. PMID- 22204726 TI - Proprotein convertases in health and disease. PMID- 22204728 TI - Case records of the Massachusetts General Hospital. Case 40-2011. A 52-year-old man with weakness, infections, and enlarged adrenal glands. PMID- 22204729 TI - Diabetic stem-cell "mobilopathy". PMID- 22204723 TI - Low-molecular-weight heparin and mortality in acutely ill medical patients. AB - BACKGROUND: Although thromboprophylaxis reduces the incidence of venous thromboembolism in acutely ill medical patients, an associated reduction in the rate of death from any cause has not been shown. METHODS: We conducted a double blind, placebo-controlled, randomized trial to assess the effect of subcutaneous enoxaparin (40 mg daily) as compared with placebo--both administered for 10+/-4 days in patients who were wearing elastic stockings with graduated compression- on the rate of death from any cause among hospitalized, acutely ill medical patients at participating sites in China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia. Inclusion criteria were an age of at least 40 years and hospitalization for acute decompensated heart failure, severe systemic infection with at least one risk factor for venous thromboembolism, or active cancer. The primary efficacy outcome was the rate of death from any cause at 30 days after randomization. The primary safety outcome was the rate of major bleeding during and up to 48 hours after the treatment period. RESULTS: A total of 8307 patients were randomly assigned to receive enoxaparin plus elastic stockings with graduated compression (4171 patients) or placebo plus elastic stockings with graduated compression (4136 patients) and were included in the intention-to-treat population. The rate of death from any cause at day 30 was 4.9% in the enoxaparin group as compared with 4.8% in the placebo group (risk ratio, 1.0; 95% confidence interval [CI], 0.8 to 1.2; P=0.83). The rate of major bleeding was 0.4% in the enoxaparin group and 0.3% in the placebo group (risk ratio, 1.4; 95% CI, 0.7 to 3.1; P=0.35). CONCLUSIONS: The use of enoxaparin plus elastic stockings with graduated compression, as compared with elastic stockings with graduated compression alone, was not associated with a reduction in the rate of death from any cause among hospitalized, acutely ill medical patients. (Funded by Sanofi; LIFENOX ClinicalTrials.gov number, NCT00622648.). PMID- 22204731 TI - Adenocarcinoma in Barrett's esophagus. PMID- 22204733 TI - Change in FEV1 over time in COPD. PMID- 22204734 TI - Change in FEV1 over time in COPD. PMID- 22204735 TI - Community transmission of oseltamivir-resistant A(H1N1)pdm09 influenza. PMID- 22204736 TI - Images in clinical medicine. Lichtenberg figures. PMID- 22204725 TI - A phase 3 trial of bevacizumab in ovarian cancer. AB - BACKGROUND: Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease. METHODS: We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. Outcome measures included progression-free survival, first analyzed per protocol and then updated, and interim overall survival. RESULTS: A total of 1528 women from 11 countries were randomly assigned to one of the two treatment regimens. Their median age was 57 years; 90% had epithelial ovarian cancer, 69% had a serous histologic type, 9% had high-risk early-stage disease, 30% were at high risk for progression, and 70% had stage IIIC or IV ovarian cancer. Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004 by the log-rank test). Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P<0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months. Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone). In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P=0.04 by log-rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months. CONCLUSIONS: Bevacizumab improved progression-free survival in women with ovarian cancer. The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression. (Funded by Roche and others; ICON7 Controlled-Trials.com number, ISRCTN91273375.). PMID- 22204738 TI - Evolution of structure and reactivity in a series of iconic carbenes. AB - We present experimental activation parameters for the reactions of six carbenes (CCl(2), CClF, CF(2), ClCOMe, FCOMe, and (MeO)(2)C) with six alkenes (tetramethylethylene, cyclohexene, 1-hexene, methyl acrylate, acrylonitrile, and alpha-chloroacrylonitrile). Activation energies range from -1 kcal/mol for the addition of CCl(2) to tetramethylethylene to 11 kcal/mol for the addition of FCOMe to acrylonitrile. A generally satisfactory analysis of major trends in the evolution of carbenic structure and reactivity is afforded by qualitative applications of frontier molecular orbital theory, although the observed entropies of activation appear to fall in a counterintuitive pattern. An analysis of computed cyclopropanation transition state parameters reveals significant nucleophilic selectivity of (MeO)(2)C toward alpha-chloroacrylonitrile. PMID- 22204737 TI - Hypotonicity-induced TRPV4 function in renal collecting duct cells: modulation by progressive cross-talk with Ca2+-activated K+ channels. AB - The mouse cortical collecting duct (CCD) M-1 cells were grown to confluency on coverslips to assess the interaction between TRPV4 and Ca(2+)-activated K(+) channels. Immunocytochemistry demonstrated strong expression of TRPV4, along with the CCD marker, aquaporin-2, and the Ca(2+)-activated K(+) channels, the small conductance SK3 (K(Ca)2.3) channel and large conductance BKalpha channel (K(Ca)1.1). TRPV4 overexpression studies demonstrated little physical dependency of the K(+) channels on TRPV4. However, activation of TRPV4 by hypotonic swelling (or GSK1016790A, a selective agonist) or inhibition by the selective antagonist, HC-067047, demonstrated a strong dependency of SK3 and BK-alpha activation on TRPV4-mediated Ca(2+) influx. Selective inhibition of BK-alpha channel (Iberiotoxin) or SK3 channel (apamin), thereby depolarizing the cells, further revealed a significant dependency of TRPV4-mediated Ca(2+) influx on activation of both K(+) channels. It is concluded that a synergistic cross-talk exists between the TRPV4 channel and SK3 and BK-alpha channels to provide a tight functional regulation between the channel groups. This cross-talk may be progressive in nature where the initial TRPV4-mediated Ca(2+) influx would first activate the highly Ca(2+)-sensitive SK3 channel which, in turn, would lead to enhanced Ca(2+) influx and activation of the less Ca(2+)-sensitive BK channel. PMID- 22204740 TI - Synthesis and evaluation of novel modified gamma-lactam prostanoids as EP4 subtype-selective agonists. AB - To identify chemically and metabolically stable subtype-selective EP4 agonists, design and synthesis of a series of modified gamma-lactam prostanoids has been continued. Prostanoids bearing 2-oxo-1,3-oxazolidine, 2-oxo-1,3-thiazolidine and 5-thioxopyrrolidine as a surrogate for the gamma-hydroxycyclopentanone without a troublesome 11-hydroxy group were identified as highly subtype-selective EP4 agonists. Among the tested, several representative compounds demonstrated in vivo efficacy after oral dosing in rats. Their pharmacokinetic and structure-activity relationship studies are presented. PMID- 22204739 TI - Pyrrolo- and pyrazolo-[3,4-e][1,2,4]triazolo[1,5-c]pyrimidines as adenosine receptor antagonists. AB - The discovery and development of adenosine receptor antagonists have represented for years an attractive field of research from the perspective of identifying new drugs for the treatment of widespread disorders such as inflammation, asthma and Parkinson's disease. The present work can be considered as an extension of our structure-activity relationship studies on the pyrazolo[4,3-e][1,2,4]triazolo[1,5 c]pyrimidine (PTP) nucleus, extensively investigated by us as a useful template, in particular, for the identification of A(2A) and A(3) adenosine receptor antagonists. In order to explore the role of the nitrogen at the 7-position, we performed a new synthetic strategy for the preparation of pyrrolo[3,4 e][1,2,4]triazolo[1,5-c]pyrimidine derivatives which can be considered as 7-deaza analogues of the parent PTPs. We also synthesised a novel series of pyrazolo[3,4 e][1,2,4]triazolo[1,5-c]pyrimidines as junction isomers of the reference compounds. In both cases we obtained some examples of potent antagonists (K(i) in the low nanomolar range) with variable selectivity profiles in relation to the nature of substituents introduced at the C(5)-, N(8)- and/or N(9)-positions. The pyrrolo-triazolo-pyrimidine derivative 9b appeared to be a potent A(3) adenosine receptor antagonist (K(i)=10 nM) with good selectivity over hA(1) (74-fold) and hA(2A) (20-fold) adenosine receptors combined with low activity at the hA(2B) subtype (IC(50)=906 nM). Moreover, some examples of high-affinity A(1)/A(2A) dual antagonists have been identified in both series. This work constitutes a new and important contribution for the comprehension of the interaction between PTPs and adenosine receptors. PMID- 22204741 TI - N4-Aryl-6-substitutedphenylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines as receptor tyrosine kinase inhibitors. AB - Six novel N(4)-substitutedphenyl-6-substitutedphenylmethyl-7H-pyrrolo[2,3 d]pyrimidine-2,4-diamines were synthesized as multiple receptor tyrosine kinase (RTK) inhibitors and antitumor agents. An improvement in the inhibitory potency against epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 1 (VEGFR-1) and vascular endothelial growth factor receptor 2 (VEGFR-2) assays and in the A431 cellular proliferation assay was observed for compounds 8-13 over the previously reported 5-7. Three compounds (8, 9 and 13) demonstrated potent, multiple RTK inhibition and were more potent or equipotent compared to the lead compounds 5 and 7 and the standard compounds. Compounds 10 and 12 showed potent inhibition of VEGFR-2 over EGFR, platelet-derived growth factor receptor-beta (PDGFR-beta) and VEGFR-1. The results indicate that the RTK inhibitory profile could be modulated with slight variations to the N(4)-aryl-6 substitutedphenylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamino scaffold. PMID- 22204742 TI - Effective and reversible DNA condensation induced by bifunctional molecules containing macrocyclic polyamines and naphthyl moieties. AB - A series of bifunctional molecules containing macrocyclic polyamines [12]aneN(3) and naphthyl moieties 1-3(a, b) have been designed and synthesized through efficient N-alkylation and copper-mediated alkyne-azide click reactions. Experiments on gel electrophoresis, dynamic light scattering and atomic force microscopy confirmed that 2b and 3b with two [12]aneN(3) units efficiently induced the DNA condensation at the concentration of 120 MUM in less than 5 min. The condensation mechanism was studied by EB displacement fluorescence spectra, viscosity titration, and ionic strength effects. The condensation process was found to be reversible, and the presence of both naphthyl and [12]aneN(3) units in the molecules was proved to be necessary for the effective DNA condensation inductions. Cytotoxicity assay showed that the presence of triazole moieties can result in lower toxicity. PMID- 22204743 TI - What factors affect patients' recall of general practitioners' advice? AB - BACKGROUND: In order for patients to adhere to advice, provided by family doctors, they must be able to recall it afterwards. However, several studies have shown that most patients do not fully understand or memorize it. The aim of this study was to determine the influence of demographic characteristics, education, amount of given advice and the time between consultations on recalled advice. METHODS: A prospective survey, lasting 30 months, was conducted in an urban family practice in Slovenia. Logistic regression analysis was used to identify the risk factors for poorer recall. RESULTS: 250 patients (87.7% response rate) received at least one and up to four pieces of advice (2.4 +/- 0.8). A follow-up consultation took place at 47.4 +/- 35.2 days. The determinants of better recall were high school (OR 0.4, 95% CI 0.15-0.99, p = 0.049) and college education (OR 0.3, 95% CI 0.10-1.00, p = 0.050), while worse recall was determined by number of given instructions three or four (OR 26.1, 95% CI 3.15-215.24, p = 0.002; OR 56.8, 95% CI 5.91-546.12, p < 0.001, respectively) and re-test interval: 15-30 days (OR 3.3, 95% CI 1.06-10.13, p = 0.040), 31-60 days (OR 3.2, 95% CI 1.28 8.07, p = 0.013) and more than 60 days (OR 2.5, 95% CI 1.05-6.02, p = 0.038). CONCLUSIONS: Education was an important determinant factor and warrants further study. Patients should be given no more than one or two instructions in a consultation. When more is needed, the follow-up should be within the next 14 days, and would be of a greater benefit to higher educated patients. PMID- 22204744 TI - Outcomes of Pseudomonas eradication therapy in patients with non-cystic fibrosis bronchiectasis. AB - Pseudomonas aeruginosa infection is associated with poorer outcomes in non-cystic fibrosis bronchiectasis. It is unknown whether early eradication improves outcomes. This retrospective study assessed clinical and microbiological outcomes of eradication therapy following initial Pseudomonas infection. All patients undergoing Pseudomonas eradication therapy from 2004 to 2010 were identified retrospectively and assessed for microbiological eradication, exacerbation frequency, hospital admissions, clinical symptoms and lung function. 30 patients were identified with median follow-up time 26.4 months. Eradication therapy involved intravenous antibiotics (n = 12), intravenous antibiotics followed by oral ciprofloxacin (n = 13) or ciprofloxacin alone (n = 5), combined with 3 months of nebulised colistin. Pseudomonas was initially eradicated from sputum in 24 patients (80.0%). 13/24 patients remained Pseudomonas-free and 11/24 were subsequently reinfected (median time 6.2 months). Exacerbation frequency was significantly reduced from 3.93 per year pre-eradication and 2.09 post eradication (p = 0.002). Admission rates were similar, at 0.39 per year pre eradication and 0.29 post-eradication (p = NS). 20/30 patients reported initial clinical improvement, whilst at one-year follow up, 19/21 had further improved or remained stable. Lung function was unchanged. This study demonstrates that Pseudomonas can be eradicated from a high proportion of patients, which may lead to prolonged clearance and reduced exacerbation rates. This important outcome requires confirmation in a prospective study. PMID- 22204745 TI - Repeated botulinum toxin type A injections for refractory overactive bladder: medium-term outcomes, safety profile, and discontinuation rates. AB - BACKGROUND: Efficacy and safety of botulinum toxin type A (BoNTA) injection is supported by level 1 evidence, but data regarding repeated injections are limited in patients with refractory overactive bladder (OAB) and idiopathic detrusor overactivity (IDO). OBJECTIVES: Describe medium-term outcomes and discontinuation rates for patients adopting repeated BoNTA as a management strategy for IDO. DESIGN, SETTING, AND PARTICIPANTS: Prospective data from a single centre were collected from the first 100 patients. INTERVENTION: Bladder injection of BoNTA (predominantly 200 U onabotulinumtoxinA; Allergan Ltd., Marlow, Buckinghamshire, UK) in an outpatient setting. MEASUREMENTS: OAB symptoms, quality of life, discontinuation rates, interinjection interval, and adverse events were recorded. Data comparisons were performed using a generalised linear model or a chi-square test where appropriate. RESULTS AND LIMITATIONS: Two hundred seven injections were performed in 100 patients. All patients had 1 injection, 53 had a total of 2, 20 had 3, 13 had 4, 10 had 5, 5 had 6, 3 had 7, 1 had 8, 1 had 9, and 1 had 10 injections. Statistics were applied up to five repeated injections. A statistically significant reduction in frequency, urgency, and urge urinary incontinence were seen following the first BoNTA injection compared to baseline. This improvement was maintained after repeated injections and was not statistically different when comparing differences between injections. Thirty seven patients stopped treatment after the first two injections; thereafter, dropouts were rare. The most common reasons for discontinuing treatment were poor efficacy (13%) and clean intermittent self-catheterisation (CISC)-related issues (11%). The incidence of CISC after the first injection was 35%. Bacteriuria was detected in 21% of patients. The mean interinjection interval was 322 d. Limitations included the concurrent use of antimuscarinic drugs in some patients. CONCLUSIONS: BoNTA can provide a safe and effective medium-term management option for patients with refractory IDO. The most common reasons cited for stopping treatment were poor efficacy and CISC-related issues. PMID- 22204746 TI - Finding the correct starting dose for onabotulinumtoxinA. PMID- 22204751 TI - Foreword: International Conference on Environmental Radioactivity--new frontiers and developments. PMID- 22204747 TI - Which preparation of botulinum toxin a should be used, where should it be injected, and how should its efficacy be assessed? PMID- 22204752 TI - Membrane purification in radioactive waste management: a short review. AB - Radiation hazards of radionuclides arising from nuclear plant facilities are well known. Separation technologies are used to concentrate the radionuclides and prevent the spread of this hazard to the environment. The present review describes the recent advances made in radioactive waste treatment using membrane separation technology. The first part discusses the membrane methods for collective separation of radionuclides and the second part discusses the membrane methods for selective separation of individual radionuclides. For the collection separation of radionulides, methods include reverse osmosis, precipitation followed by ultrafiltration or microfiltration and membrane distillation. Individual elements have been separated using liquid supported membranes, polymer inclusion membranes, solid polymer based electrolysis, nanofiltration, electrochemical salt-splitting process and other advanced separation methods. PMID- 22204753 TI - Flexible ureteroscopy in children with von Willebrand disease. AB - BACKGROUND AND PURPOSE: Treatment options for urolithiasis include shockwave lithotripsy (SWL), percutaneous nephrostolithotomy (PCNL), and ureteroscopy. While these treatment options are becoming the standard of care in the pediatric population, children with a bleeding dyscrasia must be approached differently. We report our flexible ureteroscopic experience in children with von Willebrand disease (vWd). PATIENTS AND METHODS: A review of a prospectively maintained database of stone patients was performed. Children with a bleeding diathesis were identified. Stone burden, operative access, intraoperative complications, postoperative complications, stone-free status, and perioperative medical management were evaluated. RESULTS: During a 7-year period, a total of five children with a bleeding disorder underwent 7 ureteroscopic and 10 cystoscopic procedures for urinary calculi. The mean patient age was 72.4 months (range 49 123 mos) at the time of the procedure. There were three boys and two girls. Mean follow-up was 29.7 months (range 8-79 mos). Mean stone burden was 6.1 mm (range 3 14 mm) with an average of 1.3 stones per patient. Four patients were known to have vWd before surgical intervention and were pretreated with desmopressin acetate. The remaining patient was found to have vWd based on significant bleeding after ureteral stent placement. No ureters were actively dilated. Flexible ureteroscopy was performed in all cases regardless of stone location. Stone clearance was 100% (7/7). Complications occurred in 6% of procedures (1/17). CONCLUSIONS: Ureteroscopy is a safe and efficacious modality in the management of urolithiasis in children with a bleeding abnormality. Perioperative medical management of the bleeding diathesis may help reduce complications. PMID- 22204755 TI - [Impact of age on mortality in patients with acute traumatic spinal cord injury requiring intensive care]. AB - OBJECTIVE: To evaluate the impact of age (=65 ans) on hospital mortality in traumatic spinal cord injury requiring intensive care. DESIGN: Retrospective, monocenter. PATIENTS AND METHODS: A total of 131 patients greater or equal to 15 years (<65 years, n=109 and >=65 years, n=22) was analyzed (cervical, n=71; thoracolumbar, n=60), over a 10 years period (1998-2008). The hospital and long term mortality were studied. The risks factors of death were searched by a uni- and multivariate analysis. Intensive care unit (ICU) discharge and long-term neurological recovery, and long-term functional independence measure (FIM) were assessed. RESULTS: Hospital mortality was increased in patients greater or equal to 65 years (41% vs 6%, P<0.001) and long term mortality was not different between the two groups (31% vs 12%, P=0.150). The risks factors of death were age (HR=3.44; IC 95%: 1.53-7.72, P=0.028), previous coronary disease (HR=3.64; IC 95%: 1.25-10.65; P=0.018) and fall injury (HR=2.40; IC 95%: 1.15-5.00, P=0.020). Among survivors, incompletes forms (Frankel B, C, D, E) were significantly more frequent in older patients at ICU discharge and long term follow up. At long term, FIM was similar in the two groups except a better sphincter control in patient greater or equal to 65 years. CONCLUSION: Mortality rate of older people (>=65 years) were greater than those in younger people, mainly caused by an increased hospital mortality. Among survivors, the neurological recovery was better in patients' greater or equal to 65 years, and was associated with a functional status at least comparable than in the youngest patients. PMID- 22204754 TI - Consistent segmentation using a Rician classifier. AB - Several popular classification algorithms used to segment magnetic resonance brain images assume that the image intensities, or log-transformed intensities, satisfy a finite Gaussian mixture model. In these methods, the parameters of the mixture model are estimated and the posterior probabilities for each tissue class are used directly as soft segmentations or combined to form a hard segmentation. It is suggested and shown in this paper that a Rician mixture model fits the observed data better than a Gaussian model. Accordingly, a Rician mixture model is formulated and used within an expectation maximization (EM) framework to yield a new tissue classification algorithm called Rician Classifier using EM (RiCE). It is shown using both simulated and real data that RiCE yields comparable or better performance to that of algorithms based on the finite Gaussian mixture model. As well, we show that RiCE yields more consistent segmentation results when used on images of the same individual acquired with different T1-weighted pulse sequences. Therefore, RiCE has the potential to stabilize segmentation results in brain studies involving heterogeneous acquisition sources as is typically found in both multi-center and longitudinal studies. PMID- 22204756 TI - [Neurological consequences after long-term sedation in the ICU]. AB - Experiments performed in mammals, including non-human primates, have demonstrated an increase in neuronal death rates normally seen in normal brain development. Such an increase is encountered in diseases but also after exposure of the brain to various class of anaesthetics. In living animals, it can (but not always) result in persistent cognitive impairment. Most of the experiments have been conducted in animals which were never exposed to any pain, which questions their relevancy. On the clinical side, all data comes from retrospective studies. Given the multiple bias, they cannot definitely state that a protocol, if toxic, is more or less when compared to another. Until now, prospective follow-up of children exposed to anaesthetics in utero or during the first months of life do not suggest a major deleterious effect. Yet, a minor one, if existing, would be hard to detect among polluting variables (e.g. pathology requiring anaesthesia, long hospitalization after birth, preterm birth, environmental stress...). For sure, when surgery is mandatory during pregnancy, it is generally for maternal indication and should not be a motif strong enough for foetal extraction, especially in terms where the baby has few chances to survive. Second, it is known for years than anaesthesia before 1 year of age is much riskier than after 1 year, whatever the theorical neurotoxicity is. Third, this enforces the need to develop tools enhancing the precision of anaesthesia as much as possible. Meanwhile, when an infant has undergone numerous general anaesthesias, we strongly recommend a long-time neurological follow-up. PMID- 22204757 TI - Posterior urethral injuries associated with motorcycle accidents and pelvic trauma in adolescents: analysis of urethral lesions occurring prior to a bony fracture using a computerized finite-element model. AB - Adolescent males involved in motorcycle accidents are particularly at risk for pelvic injury, which may provoke a posterior urethral injury. The aim of this study was to develop a model to analyze the association between injuries and fractures of the pelvic ring and the risk of posterior urethral injury. METHOD: Based on experience with traffic accident modeling, a computerized finite-element model was extrapolated from a computerized tomography scan of a 15-year-old boy. The anatomic structures concerned in urethral and pelvic ring trauma were isolated, rendered in 3D and given biomechanical properties. The model was verified according to available experiments on pelvic ring trauma. RESULTS: To apply the model, we recreated three impact mechanisms on the pelvic ring: lateral impact, antero-posterior impact and a real car-motorcycle accident situation (postero-lateral impact). In all three situations, stretching of the posterior urethra was identified prior to bony fracture visualization. CONCLUSION: Application of this model allowed us to analyze precisely the link between trauma of the pelvic ring and lesions of the posterior urethra. The results should help to establish guidelines for urethral catheterization in male adolescents in cases of pelvic trauma, even when no bony fracture is present, in order to prevent iatrogenic worsening of a misdiagnosed posterior urethral trauma. PMID- 22204759 TI - Counting on commitment; the quality of primary care-led diabetes management in a system with minimal incentives. AB - BACKGROUND: The aim of the present study was to assess the performance of three primary care-led initiatives providing structured care to patients with Type 2 diabetes in Ireland, a country with minimal incentives to promote the quality of care. METHODS: Data, from three primary care initiatives, were available for 3010 adult patients with Type 2 diabetes. Results were benchmarked against the national guidelines for the management of Type 2 diabetes in the community and results from the National Diabetes Audit (NDA) for England (2008/2009) and the Scottish Diabetes Survey (2009). RESULTS: The recording of clinical processes of care was similar to results in the UK however the recording of lifestyle factors was markedly lower. Recording of HbA1c, blood pressure and lipids exceeded 85%. Recording of retinopathy screening (71%) was also comparable to England (77%) and Scotland (90%). Only 63% of patients had smoking status recorded compared to 99% in Scotland while 70% had BMI recorded compared to 89% in England. A similar proportion of patients in this initiative and the UK achieved clinical targets. Thirty-five percent of patients achieved a target HbA1c of < 6.5% (< 48 mmol/mol) compared to 25% in England. Applying the NICE target for blood pressure (<= 140/80 mmHg), 54% of patients reached this target comparable to 60% in England. Slightly less patients were categorised as obese (> 30 kg/m2) in Ireland (50%, n = 1060) compared to Scotland (54%). CONCLUSIONS: This study has demonstrated what can be achieved by proactive and interested health professionals in the absence of national infrastructure to support high quality diabetes care. The quality of primary care-led diabetes management in the three initiatives studied appears broadly consistent with results from the UK with the exception of recording lifestyle factors. The challenge facing health systems is to establish quality assurance a responsibility for all health care professionals rather than the subject of special interest for a few. PMID- 22204760 TI - Measurement of MicroRNA: a regulator of gene expression. AB - MicroRNAs (miRs) are epigenetic regulators of messenger RNAs' (mRNA) expression of polypeptides. As such, miRs represent an intriguing mechanism by which gene environment interactions are hypothesized to occur on the level of epigenetic control over gene expression. In addition to promising findings from in vitro studies indicating that miRs have the potential to function as therapeutic agents in modifying the course of pathophysiologic conditions, recent human studies revealed changes in miR expression patterns in response to behavioral interventions. The authors provide an overview of how miRs are preserved and isolated from other genetic material and describe commonly used methods for measuring miR in the research setting, including Northern blot, polymerase chain reaction, and microarray. The authors also introduce bioinformatic approaches to analysis of high-throughput miR expression and techniques used to create predictive models of miR-mRNA binding to describe possible physiologic pathways affected by specific miRs. PMID- 22204758 TI - Persistent left superior vena cava: review of the literature, clinical implications, and relevance of alterations in thoracic central venous anatomy as pertaining to the general principles of central venous access device placement and venography in cancer patients. AB - Persistent left superior vena cava (PLSVC) represents the most common congenital venous anomaly of the thoracic systemic venous return, occurring in 0.3% to 0.5% of individuals in the general population, and in up to 12% of individuals with other documented congential heart abnormalities. In this regard, there is very little in the literature that specifically addresses the potential importance of the incidental finding of PLSVC to surgeons, interventional radiologists, and other physicians actively involved in central venous access device placement in cancer patients. In the current review, we have attempted to comprehensively evaluate the available literature regarding PLSVC. Additionally, we have discussed the clinical implications and relevance of such congenital aberrancies, as well as of treatment-induced or disease-induced alterations in the anatomy of the thoracic central venous system, as they pertain to the general principles of successful placement of central venous access devices in cancer patients. Specifically regarding PLSVC, it is critical to recognize its presence during attempted central venous access device placement and to fully characterize the pattern of cardiac venous return (i.e., to the right atrium or to the left atrium) in any patient suspected of PLSVC prior to initiation of use of their central venous access device. PMID- 22204761 TI - Development of a miniaturized DNA microarray for identification of 66 virulence genes of Legionella pneumophila. AB - INTRODUCTION: For the last five years, Legionella sp. infections and legionnaire's disease in Poland have been receiving a lot of attention, because of the new regulations concerning microbiological quality of drinking water. This was the inspiration to search for and develop a new assay to identify many virulence genes of Legionella pneumophila to better understand their distribution in environmental and clinical strains. The method might be an invaluable help in infection risk assessment and in epidemiological investigations. MATERIAL/METHODS: The microarray is based on Array Tube technology. It contains 3 positive and 1 negative control. Target genes encode structural elements of T4SS, effector proteins and factors not related to T4SS. Probes were designed using OligoWiz software and data analyzed using IconoClust software. To isolate environmental and clinical strains, BAL samples and samples of hot water from different and independent hot water distribution systems of public utility buildings were collected. RESULTS: We have developed a miniaturized DNA microarray for identification of 66 virulence genes of L. pneumophila. The assay is specific to L. pneumophila sg 1 with sensitivity sufficient to perform the assay using DNA isolated from a single L. pneumophila colony. Seven environmental strains were analyzed. Two exhibited a hybridization pattern distinct from the reference strain. DISCUSSION: The method is time- and cost-effective. Initial studies have shown that genes encoding effector proteins may vary among environmental strains. Further studies might help to identify set of genes increasing the risk of clinical disease and to determine the pathogenic potential of environmental strains. PMID- 22204762 TI - [Gender and kidney diseases: the clinical importance and mechanisms of modifying effects]. AB - This review focuses on the underlying pathways of gender-dependent renal diseases and presents specific examples of diseases influenced by gender. In the literature it has been shown, in many clinical and experimental observations, that the incidence and the rate of progression of renal disease are influenced by many gender-dependent factors, such as kidney and glomerular size, differences in glomerular hemodynamics, and direct effects of sex hormones on renal tissue and signal pathways such as the renin-angiotensin-aldosterone system and signal molecules (e.g. nitric oxide, reactive oxygen species, cytokines and growth factors). It has been shown that the main female hormone, 17 beta estradiol, is capable of inhibiting inflammatory and pro apoptotic processes and protects the renal tissue. In contrast, the male hormones, testosterone and dehydroepiandrosterone, have the opposite effect. Hormonal manipulation by male or female castration changes the course of renal disease progression and confirms the influence of the sex hormones. Female gender is therefore considered a protective factor in many kidney diseases, such as primary glomerulonephritis, autosomal dominant polycystic kidney disease (ADPKD) and hypertensive nephropathy. Similarly, women are more predisposed to autoimmune diseases with secondary glomerulonephritis, e.g. systemic lupus erythematosus, as the female sex hormones have the ability of autoimmune process activation. After menopause the protective effect of female gender is not observed, which confirms the role of the female sex hormones. PMID- 22204763 TI - Small protein-mediated quorum sensing in a gram-negative bacterium: novel targets for control of infectious disease. AB - Control of Gram-negative bacterial infections of plants and animals remains a major challenge because conventional approaches are often not sufficient to eradicate these infections. One major reason for their persistence seems to be the capability of the bacteria to grow within biofilms that protect them from adverse environmental factors. Quorum sensing (QS) plays an important role in the formation of biofilms. In QS, small molecules serve as signals to recognize bacterial cell population size, leading to changes in expression of specific genes when a signal has accumulated to some threshold concentration. The small protein Ax21 (Activator of XA21-mediated immunity), serves as a QS factor that regulates biofilm formation and virulence in the Gram-negative bacterium, Xanthomonas oryzae pv. oryzae. Knowledge of small protein-mediated QS in Gram negative bacteria can be used to develop new methods to control persistent Gram negative infections. PMID- 22204765 TI - Molecular alterations underlying eosinophilic and mast cell malignancies. AB - Eosinophilic and mast cell disorders are uncommon hematologic entities, but they can carry significant morbidity and lead to devastating end-organ sequelae. In the past ten years, extensive work has led to the discovery of certain molecular abnormalities underlying a subset of these diseases. A significant minority of patients with clonal eosinophilia carry abnormal gene fusions involving PDGFRA, PDGFRB, and FGFR1. These findings have been quite significant, as those individuals with a FIP1L1-PDGFRA fusion have an exquisite susceptibility to tyrosine kinase inhibitors (TKIs), such as imatinib mesylate. Imatinib leads to a rapid remission in these patients and aborts the clinical trajectory of the disease. Unfortunately, TKIs have not been shown to be particularly active in the case of mastocytosis, although the majority of patients with mastocytosis carry a c-KIT alteration, a target of agents such as imatinib. The reason for this decreased sensitivity to TKIs is related to the resistance of the D816V variant of c-KIT, found in the majority of patients with mastocytosis. Nevertheless, investigation is ongoing to define new molecular lesions in these diseases, and potentially new targets for therapy. Clinical trials are also investigating other novel small molecules that may have efficacy against targets currently resistant to imatinib and other TKIs. PMID- 22204766 TI - The pathogenesis of progressive multifocal leukoencephalopathy. AB - Interest in pathogenesis of progressive multifocal leukoencephalopathy (PML) followed the observation of the high risk for the disease in HIV infection and the recent observation of an association with a variety of newer therapeutic modalities, e.g., natalizumab, an alpha4beta1 integrin inhibitor, and efalizumab, an anti-CD11a monoclonal antibody. Any hypothesis of PML pathogenesis must account for a number of facts. Firstly, the causative agent JC virus is ubiquitously present, yet only a vanishingly small number of infected persons develop the disease. Secondly, disorders of cell-mediated immunity increase the risk of the disease, particularly HIV infection. Impaired innate immunity is not a risk for PML, and antibodies against JC virus are not protective. Thirdly, a latent period of several months appears necessary following the administration of natalizumab and efalizumab before PML develops. Fourthly, restoration of the immune system can arrest the PML. It is possible that infection with JC virus occurs with a form of the virus shed in the urine of as many as 40% of all adults and present in sewage worldwide. Once acquired, perhaps through an oropharyngeal route, it may replicate and disseminate. A neurotropic form of JC virus that replicates in glial tissues causes PML when immunosurveillance is impaired. There are many unanswered questions with respect to PML pathogenesis. How is virus acquired? What tissues are infected? What is the origin of the neurotropic form? When does virus enter brain? What is the role of central nervous system immunosurveillance? The lack of an animal model has made answering these questions challenging. PMID- 22204764 TI - Advances in the understanding of mechanisms and therapeutic use of bortezomib. AB - The ubiquitin-proteasome pathway regulates many basic cellular processes and has been proven to be a promising target for cancer therapy. Bortezomib is the first U.S. Food and Drug Administration (FDA) approved proteasome inhibitor used in the treatment of newly diagnosed multiple myeloma, relapsed/refractory multiple myeloma, and mantle cell lymphoma. The anti-cancer mechanisms of bortezomib elucidated by preclinical studies include: upregulation of proapoptotic proteins (e.g., Noxa, IkappaB), inhibition of NFkappaB and its anti-apoptotic target genes, suppression of several anti-apoptotic proteins (e.g., Bcl-XL, Bcl-2, and STAT-3), down-regulation of expression of several proteins involved in DNA repair pathways, and induction of endoplasmic reticulum (ER) stress and pro-apoptotic Unfolded Protein Response (UPR). Bortezomib has potent chemo-/radio-sensitizing effects and can overcome traditional drug resistance in tumors when used in combination with potential chemotherapies. Although bortezomib has been successful in improving clinical outcomes when used in hematological malignancies, relapse may occur in those patients who responded initially. Furthermore, some cytotoxicities (such as peripheral neuropathy) were found to be associated with bortezomib treatment. These observations have encouraged researchers to search for the next generation proteasome inhibitors (including carfilzomib and marizomib) that could overcome bortezomib resistance and have improved properties, reduced toxicities, and broader anticancer activities, based on the lessons learned from the mechanisms and use of bortezomib. This review summarizes the current status of bortezomib as well as several other proteasome inhibitors that are currently under clinical and preclinical investigation. PMID- 22204767 TI - Viral infection and innate pattern recognition receptors in induction of Hashimoto's thyroiditis. AB - Hashimoto's thyroiditis, a common organ-specific autoimmune disease, is multifactorial in which both genetic susceptibility and environmental factors including infection play a critical role in its pathogenesis. Viral infection activates both the innate and adaptive immunity and is implicated as a trigger of Hashimoto's thyroiditis. Candidate viruses include hepatitis C virus and human parvovirus B19. Viral components, which are recognized by innate receptors including Toll-like receptors (TLRs), are detected in thyroid tissues and sera of patients with Hashimoto's thyroiditis. While conflicting results have been obtained regarding the role of TLRs in autoimmune diseases, our preliminary study suggested a contribution of TLR2 and dectin-1 in combination, TLR4, or TLR7 to the production of anti-thyroglobulin antibody in nonobese diabetic mice, a mouse model of Hashimoto's thyroiditis. Despite interesting circumstantial evidence, however, whether viral infection and innate receptors are involved in the development of Hashimoto's thyroiditis remains largely unclear. In this review, we summarize our knowledge regarding the role of viral infection and innate receptors in the etiology of Hashimoto's thyroiditis. PMID- 22204768 TI - IL-13 and its genetic variants: effect on current asthma treatments. AB - Airway hyperresponsiveness is an essential part of the definition of asthma associated temporally with exposure to allergens, certain respiratory viruses, pollutants such as ozone, and certain organic chemicals. Interleukin-13 (IL-13) is implicated as a central regulator in immunoglobulin E (IgE) synthesis, mucus hypersecretion, airway hyperresponsiveness, and fibrosis. The importance of IL-13 in allergic disorders in humans is supported by consistent associations between tissue IL-13 levels and genetic variants in the IL-13 gene and asthma and related traits. Single-nucleotide polymorphisms in IL-13 are associated with allergic phenotypes in several ethnically diverse populations. Glucocorticoids are anti inflammatory medications often used as maintenance therapy in acute and chronic asthma; however, some patients with severe asthma are steroid resistant. IL-13 remains elevated in glucocorticoid insensitive asthma but not in glucocorticoid sensitive asthma. Thus targeting IL-13 and its associated receptors may be a therapeutic approach to the treatment of asthma and/or allergy. This review focuses on the role of IL-13 on airway hyperresponsiveness and corticosteroids resistant asthma both preclinically and clinically. PMID- 22204769 TI - Vaccine adjuvant properties of probiotic bacteria. AB - Vaccine-preventable diseases are still responsible for the deaths of more than 1 million children under the age of 5 years annually, mostly in developing countries. A substantial number of these deaths are due to pneumococcal bacteria and infections with rotavirus. Important issues faced by the WHO, governments, vaccine manufacturers, and international organizations such as UNICEF and the Global Alliance for Vaccines and Immunization (GAVI) are the cost-effective introduction of these life-saving vaccines in resource-poor countries where there is a considerable disease burden, and achieving high rates of completion of vaccination schedules remains elusive. Problems with vaccine coverage and vaccine delivery in these regions are significant, as in some cases large proportions of the target population do not receive adequate vaccination. Consequently, there is a need to develop more effective vaccination strategies that can provide adequate protection with reduced schedules. To date, emphasis has been placed on identifying novel vaccine antigens and adjuvants that induce stronger protective immune responses, as well as developing mucosally-administered vaccines. These approaches would have enormous benefits in allowing safe administration of vaccines in remote areas and may overcome the necessity for multiple doses. In this regard, the use of probiotic bacteria as novel mucosal adjuvants to enhance existing vaccine specific-immune responses offers an exciting new approach. In this review, we discuss the evidence for the role of probiotics in enhancing vaccine responses and provide justification for further investigation into their clinical effects and mechanisms of action. PMID- 22204770 TI - Environmental triggers and epigenetic deregulation in autoimmune disease. AB - The study of epigenetic mechanisms in the pathogenesis of autoimmune diseases is receiving unprecedented attention from clinicians and researchers in the field. Autoimmune disorders comprise a wide range of genetically complex diseases, including systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. Together they affect a significant proportion of the population and have a great economic impact on public health systems. Epigenetic mechanisms control gene expression and are influenced by external stimuli, linking environment and gene function. A variety of environmental agents, such as viral infection, hormones, certain drugs, and pollutants, have been found to influence the development of autoimmune diseases. On the other hand, there is considerable evidence of epigenetic changes, particularly DNA methylation alterations, in diseases like systemic lupus erythematosus, rheumatoid arthritis, or multiple sclerosis. However, the gap in our understanding between the specific effects of external agents and the influence on epigenetic profiles has not yet been filled. Here we review a number of studies describing epigenetic alterations in autoimmune diseases and a range of environmental factors that influence the development of autoimmune diseases. We also discuss potential mechanisms linking environment and epigenetics, consider the prospects for future epigenetic studies addressing the relationship between environment and epigenetics, and comment on the use of drugs with an epigenetic-reversing effect in the clinical management of these diseases. PMID- 22204771 TI - Doxycycline sclerodesis as a treatment option for persistent Morel-Lavallee lesions. AB - INTRODUCTION: Morel-Lavallee lesion is a rare cause of subcutaneous swelling, caused by post-traumatic shearing of the hypodermis from the underlying fascia. Treatment of such lesions is still not well established. OBJECTIVE: To evaluate the results of conservative treatment for these lesions using doxycycline induced sclerodesis followed by elastic compression bandaging. PATIENTS AND METHODS: We treated 16 Morel-Lavallee lesions between May 2005 and December 2008. These lesions developed in 13 male and 3 female patients (mean age 41 years; range 10 74 years) due to various modes of trauma. The lesion involved the thigh region in 13 patients with trochanteric region, gluteal, lower back, and lower abdominal wall being other regions involved. An area of palpable fluctuance was the most consistent examination finding. Treatment was effected by fluid aspiration, doxycycline instillation, and compressive elastic bandaging. Healing was defined as the loss of fluctuation with complete absence of fluid on ultrasonography. RESULTS: The average duration of the persistence of the lesion was 13 months (range, 6-23 months). Most of the lesions had been aspirated previously multiple number of times, average being 3.44 times (range, 1-6 times). All lesions were aspirated and found to be negative on culture. The mean follow up period was 50.44 months (range, 31-74 months). 11 patients showed complete resolution of fluid collection at 4 weeks with another 4 patients resolving at 8 weeks follow up. The lesion persisted in one patient at 12 weeks due to non-compliance to compressive elastic bandaging which subsequently resolved on repeating the procedure. All the lesions healed without any infections or necrosis. No recurrences were detected during the follow up period. A persistent non-fluctuant contour deformity, decreased skin mobility over the site of lesion, and feeling of tightness were the most common problems faced on long term follow up. CONCLUSION: Closed degloving injuries can be managed satisfactorily with doxycycline induced obliteration of the cavity with early healing time without recurrences. PMID- 22204772 TI - Temporal changes in ROTEM(r)-measured coagulability of citrated blood samples from coagulopathic trauma patients. AB - BACKGROUND: Rotational thromboelastometry (ROTEM((r))) relies on citrated blood samples, which are regarded as biologically stable for up to 4 h after venepuncture. However, this recommendation is based on data from normal volunteers. The aim of this study was to evaluate possible temporal changes in the coagulability of blood samples from coagulopathic trauma patients. PATIENTS AND METHODS: This is a prospective series of 10 coagulopathic (maximum clot firmness, MCF<40 mm) trauma patients. ROTEM((r)) EXTEM (tissue factor activated) and FIBTEM (tissue factor activated, cytochalasin D inhibited) analyses were performed on samples obtained on admission, and after approximately 60 min of storage in an incubator, at 37 degrees C. RESULTS: There were statistically significant differences between the median EXTEM MCF (22 mm vs 54 mm, p<0.001) and alpha angle (30.5 vs 59.5 degrees , p=0.004) of the analyses performed immediately after sampling, and 51 min (median) subsequently, but not coagulation time (CT, p=0.133), clot formation time (p=0.0625) or maximum lysis (ML, p=0.154). There were also no differences in median FIBTEM MCF (p=1.00) or CT (p=0.877) between the immediate and delayed analyses. CONCLUSIONS: Repeated ROTEM((r)) EXTEM analysis of citrated samples from coagulopathic trauma patients shows a spontaneous improvement in coagulability with time. The absence of parallel changes on FIBTEM analysis suggests that this effect may be due to a change in platelet function. PMID- 22204773 TI - Finite element analysis of Puddu and Tomofix plate fixation for open wedge high tibial osteotomy. AB - The use of open wedge high tibial osteotomy (HTO) to correct varus deformity of the knee is well established. However, the stability of the various implants used in this procedure has not been previously demonstrated. In this study, the two most common types of plates were analysed (1) the Puddu plates that use the dynamic compression plate (DCP) concept, and (2) the Tomofix plate that uses the locking compression plate (LCP) concept. Three dimensional model of the tibia was reconstructed from computed tomography images obtained from the Medical Implant Technology Group datasets. Osteotomy and fixation models were simulated through computational processing. Simulated loading was applied at 60:40 ratios on the medial:lateral aspect during single limb stance. The model was fixed distally in all degrees of freedom. Simulated data generated from the micromotions, displacement and, implant stress were captured. At the prescribed loads, a higher displacement of 3.25 mm was observed for the Puddu plate model (p<0.001). Coincidentally the amount of stresses subjected to this plate, 24.7 MPa, was also significantly lower (p<0.001). There was significant negative correlation (p<0.001) between implant stresses to that of the amount of fracture displacement which signifies a less stable fixation using Puddu plates. In conclusion, this study demonstrates that the Tomofix plate produces superior stability for bony fixation in HTO procedures. PMID- 22204774 TI - The epidemiology of open fractures in adults. A 15-year review. AB - There is little information available about the epidemiology of open fractures. We examined 2386 open fractures over a 15-year period analysing the incidence and severity of the fractures. The majority of open fractures are low energy injuries with only 22.3% of open fractures being caused by road traffic accidents or falls from a height. The distribution curves of many open fractures are different to the overall fracture distribution curves with high-energy open fractures being commoner in younger males and low energy open fractures in older females. The mode of injury and the different demographic characteristics between isolated and multiple open fractures are also discussed. PMID- 22204776 TI - New triterpenoid glycosides from the roots of Ilex asprella. AB - Eight new triterpenoid glycosides, named ilexasosides A-H, were isolated from the roots of Ilex asprella. Their structures were elucidated by spectroscopic and chemical analyses. Ilexasosides B and D are rare sulfated derivatives of ursane type triterpenoid glycosides. PMID- 22204775 TI - Alcohol and drug dependence symptom items as brief screeners for substance use disorders: results from the Clinical Trials Network. AB - AIM: To address an urgent need for screening of substance use problems in medical settings, we examined substance-specific dependence criteria as potential brief screeners for the detection of patients with a substance use disorder (SUD). METHODS: The sample included 920 opioid-dependent adults who were recruited from outpatient treatment settings at 11 programs in 10 U.S. cities and who completed intake assessments of SUDs for a multisite study of the National Drug Abuse Treatment Clinical Trials Network (CTN003). Data were analyzed by factor analysis, item response theory (IRT), sensitivity, and specificity procedures. RESULTS: Across all substances (alcohol, amphetamines, cannabis, cocaine, sedatives), withdrawal was among the least prevalent symptoms, while taking large amounts and inability to cut down were among the most prevalent symptoms. Items closely related to the latent trait of a SUD showed good-to-high values of area under the receiver operating characteristic curve in identifying cases of a SUD; IRT-defined severe and less discriminative items exhibited low sensitivity in identifying cases of a SUD (withdrawal for all substances; time using for alcohol and sedatives; giving up activities for sedatives). CONCLUSIONS: Study results suggest that withdrawal and time using are much less reliable indicators for a SUD than taking larger amounts than intended and inability to cut down and that the latter two items should be studied further for consideration in developing a simplified tool for screening patients for SUDs in medical settings. These findings have implications for the use of common health indicators in electronic health records systems to improve patient care. PMID- 22204777 TI - Intrathecal granuloma formation as result of opioid delivery: systematic literature review of case reports and analysis against a control group. AB - OBJECTIVE: To investigate the existence of an association between formation of catheter tip intrathecal inflammatory masses with opioid dose and/or concentration. METHODS: A systematic review of catheter tip granulomas case reports and comparison with a control group was carried out. A boolean search was conducted in the electronic databases MEDLINE and EMBASE. The patients' data extracted from the case reports was tested for homogeneity with a control group. Subsequent analysis investigating the association of opioid dose, concentration and flow rate with the formation of catheter tip granulomas was performed. RESULTS: Seventeen articles resulting in 24 patients with granulomata were included in the review. One patient in our department with granuloma formation was added to this group. Control group comprised 31 patients with an average follow-up of 68.3+/-9.7 months. The groups were homogeneous considering the variables age, gender and duration of pain previous to implant. Morphine dose (r=0.821, p<0.001) and concentration (r=0.650, p<0.001) were significantly correlated with the development of catheter tip intrathecal masses. CONCLUSION: Opioid dose and concentration were significantly associated with the development of catheter tip granulomas. A correlation with opioid concentration was confirmed for the first time. PMID- 22204778 TI - Highly sensitive electrochemical detection of cocaine on graphene/AuNP modified electrode via catalytic redox-recycling amplification. AB - We demonstrated a new strategy for highly sensitive electrochemical detection of cocaine by using two engineered aptamers in connection to redox-recycling signal amplification. The graphene/AuNP nanocomposites were electrochemically deposited on a screen printed carbon electrode to enhance the electron transfers. The cocaine primary binding aptamers were self-assembled on the electrode surface through sulfur-Au interactions. The presence of the target cocaine and the biotin modified secondary binding aptamers leads to the formation of sandwich complexes on the electrode surface. The streptavidin-conjugated alkaline phosphatases (ALPs) were used as labels to generate quantitative signals. The addition of the ALP substrate and the co-reactant NADH results in the formation of a redox cycle between the enzymatic product and the electrochemically oxidized species and the signal is thus significantly amplified. Because of the effective modification of the sensing surface and signal amplification, low nanomolar (1 nM) detection limit for cocaine is achieved. The proposed aptamer-based sandwich sensing approach for amplified detection of cocaine thus opens new opportunities for highly sensitive determination of other small molecules. PMID- 22204779 TI - Hydrogen peroxide detection at a horseradish peroxidase biosensor with a Au nanoparticle-dotted titanate nanotube|hydrophobic ionic liquid scaffold. AB - In this work, a novel sensing scaffold, consisting Au nanoparticle (GNP)-dotted TiO(2) nanotubes (TNTs) as the rigid material and the hydrophobic ionic liquid (HIL), 1-decyl-3-methylimidazolium tetrafluoroborate, as the entrapping agent, was applied to facilitate the electron transfer of horseradish peroxidase (HRP) on a glassy carbon electrode. GNPs were immobilised on the TNTs in our work using a one-step reduction of HAuCl(4).3H(2)O by sodium borohydride in the presence of sodium citrate as a stabilising reagent. The morphology and composition of the as synthesised composite materials were characterised by transmission electron microscopy, scanning electron microscopy, X-ray diffraction and Fourier-transform infrared spectroscopy. Cyclic voltammetry of HRP at the modified electrode presented a pair of reproducible, quasi-reversible redox peaks with a peak-to peak separation of 69 mV, indicating electron transfer between HRP and composite electrode. The GNP-TNT|HIL|HRP electrode was then applied to the detection of H(2)O(2) in a pH 7.0 phosphate buffer using chronoamperometry. The biosensor exhibited a linear response in the 15-750 MUM range, and a limit of detection of 2.2 MUM. The biosensor also exhibited stability with 90% of the detection signal retained over a two-week duration. PMID- 22204780 TI - Multifunctional protein particles with dual analytical channels for colorimetric enzymatic bioassays and fluorescent immunoassays. AB - Advanced multifunctional protein particles encapsulated enzymes and antibodies were developed for enzymatic bioassays and immunoassays with colorimetric and fluorescent channels. A colorimetric channel based on color-substrate precipitation was assigned for enzymatic bioassays for the measurement of hydrogen peroxide with the lowest detectable concentration of 10 MUM. A fluorescent channel based on fluorescent labeled antibodies was assigned for immunoassays for the measurement of mouse immunoglobulin G (M IgG) with the lowest detectable concentration of 1.25 MUgL(-1). The protein microparticles were fabricated with a template-assisted self-assembly technique termed "Protein Activation Spontaneous Self-assemble" (PASS). The multifunctional protein particles prepared with the PASS method have the advantages of high loading of analytical biomolecules, integrated biological functions, porous structure, and more importantly, they are optically transparent and fluorescence inactive. These unique features make our protein particles a new generation of bead-based platforms to perform enzyme bioassays and immunoassays. PMID- 22204781 TI - A novel hybridization indicator for the low-background detection of short DNA fragments based on an electrically neutral cobalt(II) complex. AB - An electrically neutral cobalt complex, Co(Eim)(4)(NCS)(2) (Eim=1-ethylimidazole, NCS=isothiocyanate) was synthesized and its interaction with double-stranded DNA (dsDNA) was comprehensively studied by electrochemical methods on a glassy carbon electrode (GCE). The experimental results revealed that the cobalt complex could interact with dsDNA via a specific groove-binding mode with an affinity constant of 3.6*10(5)M(-1). The surface-based studies showed that Co(Eim)(4)(NCS)(2) could electrochemically accumulate within the immobilized dsDNA layer rather than single-stranded DNA (ssDNA) layer. Based on this fact, the cobalt complex was utilized as an electrochemical hybridization indicator for the detection of oligonucleotides related to CaMV35S promoter gene. The results showed that the developed biosensor presented very low background interference due to the negligible affinity of the Co(Eim)(4)(NCS)(2) complex with ssDNA. The hybridization specificity experiments further indicated that the biosensor could well discriminate the complementary sequence from the base-mismatched and the non complementary sequences. The complementary target sequence could be quantified over the range from 5.0*10(-9)M to 2.0*10(-6)M with a detection limit of 2.0*10( 10)M. PMID- 22204782 TI - Surface plasmon resonance-biosensor detects the diversity of responses against epidermal growth factor in various carcinoma cell lines. AB - Surface plasmon resonance (SPR) biosensor detects intracellular signaling events as a change of the angle of resonance (AR). We previously reported that the activation of epidermal growth factor receptor (EGFR) on keratinocytes causes a unique triphasic change of AR, whereas the activation of other receptors, such as IgE receptor and adenosine A3 receptor on mast cells, causes a transient monophasic increase of AR. To study the mechanism of AR changes induced by EGFR activation, we introduced wild and mutated EGFR cDNAs into Chinese hamster ovary (CHO) cells and analyzed changes of AR in response to EGF. CHO cells expressing wild-type EGFR showed a triphasic change of AR, whereas cells expressing kinase dead EGFR (K721M) showed minimum change of AR. A phosphatidylinositol 3-kinase inhibitor, wortmannin, attenuated the third phase of AR change in CHO cells expressing wild-type EGFR. The pattern of AR change was independent on the concentration of EGF. We also analyzed changes of AR with a nontumorigenic keratinocyte cell line, HaCaT, and several cell lines of carcinoma to explore the feasibility of SPR biosensor as a tool for clinical diagnosis. The activation of HaCaT cells and one out of six carcinoma cell lines showed a full triphasic change of AR. In contrast, five out of the six cell lines showed mono- or bi phasic change of AR. These results suggest that EGF induces the SPR signals via the phosphorylation of EGFR, and provide a possibility that the SPR biosensor could be applied to the real-time detection and diagnosis of malignant tumors. PMID- 22204783 TI - Azacitidine in a patient with newly diagnosed acute myeloid leukemia and poor risk cytogenetics: outcomes of prolonged therapy. PMID- 22204784 TI - Development of a surface scanning soil analysis instrument. AB - ANSTO is developing a nuclear field instrument for measurement of soil composition; particularly carbon. The instrument utilises the neutron activation approach with clear advantages over existing soil sampling and laboratory analysis. A field portable compact pulsed neutron generator and gamma-ray detector are used for PGNAA and INS techniques simultaneously. Many elements can be quantified from a homogenised soil volume equivalent to the top soil layers. Results from first test experiments and current developments are reported. PMID- 22204785 TI - A study of non-elastic reaction rates for the ADS materials in the environment of spallation neutrons produced by 1.6 GeV d-beam. AB - For the design and modeling of Accelerator Driven sub-critical System (ADS) a detailed study of response of ADS materials to the spallation neutrons is required. For this purpose reaction rates of different reactions like (n, xn) and (n, xnyp) in 209Bi, natMo, 56Fe, natNi, 55Mn, natTi and natCo materials are determined in an experiment conducted at Nuclotron of JINR, Dubna, using 1.6 GeV d-beam in the 'Energy+Transmutation' set-up. Reaction rates of various (n, xn) and (n, xnyp) reactions are studied in these samples. Results of reaction rates deduced from all the gamma peaks observed in case of 209Bi (n, xn) reactions with x=3-9, natMo (n, gamma), (n, 3n), (n, 6n), 56Fe (n, p), (n, p2n), (n, p4n), natNi (n, 2n), (n, 3n), (n, p), (n, d), (n, t), 55Mn (n, gamma), (n, 2n), (n, 4n), natTi (n, p), (n, d), (n, t) and natCo (n, gamma), (n, xn) reactions with x=2-5 along with (n, p), (n, 2p2n), (n, 2p4n) and (n, 2p6n) are presented. The measured reaction rates for all the elements show good consistency for all the reaction channels and all observed Egamma's of the product nucleus. For all the above mentioned reactions, both experimental as well as theoretical spectrum average cross-sections (sigmasp.av.cs) are deduced and compared. A close agreement is found between the experimental sigmasp.av.cs and theoretical sigmasp.av.cs values. PMID- 22204786 TI - Elemental analysis of coal and coal ASH by PIXE technique. AB - Coal and coal ash samples were characterized by particle induced X-ray emission spectroscopic technique. Sixteen elements, namely K, Ca, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, Ga, As, Rb, Sr, Y and Pb were quantified in this study. Elements like K, Ca, Ti and Fe were present as major elements, whereas, other elements like V, Cr, Mn, Co, Ni, Cu, Zn, As, Se, Rb, Sr and Pb were present in trace level. The enrichment ratio of different ash samples with respect to coal were also estimated and discussed. PMID- 22204787 TI - Assessing a five factor model of PTSD: is dysphoric arousal a unique PTSD construct showing differential relationships with anxiety and depression? AB - Posttraumatic stress disorder's (PTSD) latent structure has been widely debated. To date, two four-factor models (Numbing and Dysphoria) have received the majority of factor analytic support. Recently, Elhai et al. (2011) proposed and supported a revised (five-factor) Dysphoric Arousal model. Data were gathered from two separate samples; War veterans and Primary Care medical patients. The three models were compared and the resultant factors of the Dysphoric Arousal model were validated against external constructs of depression and anxiety. The Dysphoric Arousal model provided significantly better fit than the Numbing and Dysphoria models across both samples. When differentiating between factors, the current results support the idea that Dysphoric Arousal can be differentiated from Anxious Arousal but not from Emotional Numbing when correlated with depression. In conclusion, the Dysphoria model may be a more parsimonious representation of PTSD's latent structure in these trauma populations despite superior fit of the Dysphoric Arousal model. PMID- 22204788 TI - Psychometric properties of the Repetitive Thinking Questionnaire in a clinical sample. AB - Repetitive negative thinking (RNT) is thought to contribute to the maintenance of many emotional disorders. Although several measures of RNT are available, the items of most of these instruments index RNT that is specific to particular diagnostic groups (e.g., RNT about depression symptoms). This has limited our ability to examine the relevance of RNT across diagnostic groups and advance our understanding of RNT as a transdiagnostic process. This study evaluated the psychometric properties of the Repetitive Thinking Questionnaire (RTQ), a transdiagnostic measure of RNT. In a clinical sample of individuals with anxiety and depressive disorders (N = 186), the RTQ demonstrated good internal consistency, convergent, and divergent validity. Supporting the transdiagnostic nature of the measure, the Repetitive Negative Thinking subscale of the RTQ was associated with a variety of negative emotions and metacognitive beliefs, and significantly predicted symptoms of multiple disorders when controlling for neuroticism. Our findings support the use of the RTQ as a transdiagnostic, trans emotional measure of maladaptive repetitive thought following distressing events, with scope to increase efficiency and reduce burden on patients by assessing RNT in clinical settings with one short measure. Experimental and longitudinal research identifying mechanisms driving RNT using the RTQ would be informative for theory and treatment developments. PMID- 22204789 TI - Molecular analyses of a potentially novel Anaplasma species closely related to Anaplasma phagocytophilum detected in sika deer (Cervus nippon yesoensis) in Japan. AB - An Anaplasma species closely related to Anaplasma phagocytophilum detected in sika deer in Hokkaido, Japan was molecularly analyzed using 16S rRNA, citrate synthase (gltA), and heat-shock operon (groEL) gene sequences. Genome walking was performed to determine its complete gltA and groEL sequences (1233 bp and 1650 bp, respectively). Percent identities to the closest A. phagocytophilum sequences from the US and European strains were 98.6-98.8%, 76.5%, and 80.3-80.8% for 16S rRNA, gltA, and groEL genes, respectively. For deduced amino acid sequences, percent identities to the closest A. phagocytophilum sequences were 66.7% and 97.6% for gltA and groEL genes, respectively. Phylogenetic analyses revealed divergence from any known A. phagocytophilum strain. The lower identities and the divergent phylogenetic position of the Anaplasma sp. detected from sika deer in Japan with established A. phagocytophilum strains provide evidence of its potential novelty. PMID- 22204790 TI - Dermatophytes in pet Guinea pigs and rabbits. AB - PROBLEM ADDRESSED: The frequency of dermatophytes in pet Guinea pigs and rabbits. OBJECTIVES: To determine the frequency and types of dermatophytes in pet Guinea pigs and rabbits. METHODS AND APPROACH: First, 2153 samples collected from pet Guinea pigs (n=1132) and rabbits (n=1021) with suspected dermatophytosis and submitted to three different laboratories for fungal culture were analysed. Subsequently, healthy Guinea pigs and rabbits, animals with skin lesions and with noncutaneous diseases were examined prospectively for dermatophytes. RESULTS: Trichophyton (T.) mentagrophytes was the most common fungal species isolated (91.6% and 72.3% of positive cultures from Guinea pigs (n=431) and rabbits (n=83), respectively). Animals with positive fungal culture did not show any gender predisposition, but affected animals were younger than those with negative fungal culture (P<0.0001) or than healthy animals of the prospective part of the study. Dermatophytes were isolated from 14/164 healthy Guinea pigs and 0/140 healthy rabbits. In addition, fungal cultures of Guinea pigs with skin lesions (n=26) and other diseases (n=25) were positive in 7.7% and 8.0% respectively. Samples collected from 17 rabbits with skin lesions and 32 rabbits with noncutaneous disease were all negative in culture. CONCLUSIONS: T. mentagrophytes is the most common dermatophyte in pet Guinea pigs and rabbits, asymptomatic carriers are regularly seen in Guinea pigs, but not in rabbits. PMID- 22204791 TI - Bartonellae of the Namaqua rock mouse, Micaelamys namaquensis (Rodentia: Muridae) from South Africa. AB - The aim of this study was to determine Bartonella prevalence and diversity in Namaqua rock mice, Micaelamys namaquensis, a species endemic to South Africa, which can attain pest status. A total of 100 heart samples collected monthly from March to December were screened for Bartonella genome presence using three primer sets targeting the citrate synthase (gltA) gene, the NADH dehydrogenase gamma subunit (nuoG) gene and the RNA polymerase beta-subunit-encoding gene (rpoB). An overall prevalence of 44% was obtained, with no statistically significant differences or correlations between infection rates and rodent sex, month of capture or season of capture. Phylogenetic analysis of 34 unambiguous gltA sequences revealed the presence of three discrete Bartonella lineages in M. namaquensis, one of which corresponds to Bartonella elizabethae, a species with known zoonotic potential. PMID- 22204792 TI - Proteomic analyses of Ehrlichia ruminantium highlight differential expression of MAP1-family proteins. AB - The Rickettsiales Ehrlichia ruminantium (ER) is the causative agent of heartwater, a fatal tick-borne disease of livestock in sub-Saharan Africa and in the Caribbean, posing strong economical constraints to livestock production. In an attempt to identify the most prominent proteins expressed by this bacterium, especially those encoded by the major antigenic protein 1 (map1) multigene family, a proteome map of ER cultivated in endothelial cells was constructed by using two dimensional gel electrophoresis combined with mass spectrometry. Among the sixty-four spots detected, we could identify only four proteins from the MAP1 family; the other proteins detected were mainly related to energy, amino acid and general metabolism (26%), to protein turnover, chaperones and survival (21%) and to information processes (14%) or classified as hypothetical proteins (23%). Additional studies on MAP1-family protein using immunochemical labeling also revealed that these proteins are differentially expressed along the bacterium life cycle, presenting different structural organization. Interestingly, when infectious elementary bodies (EBs) are released from host cells, MAP1 appears to be organized in SDS and heat-resistant dimers and trimers stabilized by disulfide bridges. Overall, the results presented herein not only reveal the first partial proteome map of ER but provide new insights on the expression ER MAP1-family proteins in host endothelial cells. PMID- 22204793 TI - Plating of humeral shaft fractures: comparison of standard conventional plating versus minimally invasive plating. AB - PURPOSE: This study compared clinical outcomes and complications in patients with humeral shaft fractures treated using two methods of fixation by plating. METHODS: Minimally invasive plate osteosynthesis (MIPO, n=29) was prospectively performed from around the middle of the study period, while open reduction and plate osteosynthesis (ORPO, n=30) had been the original standard method. Locking compression plate was used in these two groups. Major characteristics of the two groups were similar in terms of fracture type, fracture location, age, associated injuries and numbers of open fractures. RESULTS: Primary union was achieved in 28 of 29 in the MIPO and in 27 of 30 in the ORPO. Mean time to union was similar in the two groups. Mean operation time in the MIPO (110min) was shorter than in the ORPO (169min) (P<0.05). Bone grafting was performed in five patients of in the ORPO, but in no patient in the MIPO (P<0.0001). There was one case of deep infection in the ORPO. Functional outcome was satisfactory in both groups. CONCLUSIONS: Minimally invasive plate osteosynthesis may achieve comparable results with the open plate osteosynthesis method in simple as well as complex fractures of humeral shaft. Although MIPO potentially has the radiation hazard, it may reduce the perioperative complications with a shortened operation time. LEVEL OF EVIDENCE: Level III. Case-control study. PMID- 22204794 TI - Anterior shoulder instability arthroscopic treatment outcomes measures: the WOSI correlates with the Walch-Duplay score. AB - PURPOSE: New techniques and instrumentation for arthroscopic management of shoulder instability require accurate measurement tools to investigate possible clinical improvements. The aim of the study was to assess the self-administrated Western Ontario Shoulder Instability Index (WOSI), which is a subjective quality of life measurement tool specific to shoulder instability, and also to validate this score by comparison with the Walch-Duplay score, which is the gold standard score used in Europe. These two scores had never been compared. METHODS: Forty eight patients, who underwent arthroscopic surgery for anterior shoulder instability, were evaluated using the WOSI and the Walch-Duplay score at 42.7 months' follow-up. The correlation between these two scores was investigated. RESULTS: The WOSI significantly correlated with the Walch-Duplay score (global score, and specific items of pain, stability, return to activity). The standard correlation coefficient was 0.8 and the Lin correlation coefficient was 0.65. The WOSI did not correlate with the mobility item of the Walch-Duplay score. DISCUSSION: The WOSI was found to correlate with the Walch-Duplay score. However, the WOSI was more sensitive than the Walch-Duplay score for the assessment of patient satisfaction. It is likely that both self-administrated questionnaires and physical examinations are complementary for an accurate investigation of the functional objective and subjective outcome after shoulder stabilization surgery. TYPE OF STUDY: Retrospective. Level IV. PMID- 22204795 TI - Association of hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichloroethylene (DDE) with in vitro fertilization (IVF) outcomes. AB - BACKGROUND: Hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichloroethylene (DDE) are persistent chlorinated pesticides with endocrine activity that may adversely affect the early stages of human reproduction. OBJECTIVE: Our goal was to determine the association of serum levels of HCB, DDT, and DDE with implantation failure, chemical pregnancy, and spontaneous abortion in women undergoing in vitro fertilization (IVF) from 1994 to 2003. METHODS: Levels of HCB and congeners of DDT and DDE were measured in serum collected during the follicular phase. Multivariable-adjusted statistical models accommodating multiple outcomes and multiple cycles per woman were used to estimate the relation between serum pesticide levels and IVF outcomes. RESULTS: A total of 720 women with a mean +/- SD age 35.4 +/- 4.2 years at enrollment contributed 774 IVF cycles. All samples had detectable levels of HCB, DDT, and DDE, with median levels of 0.087 ng/g serum for HCB, 1.12 ng/g serum for total DDT, and 1.04 ng/g serum for p,p'-DDE. Compared with the lowest quartile (Q1) of HCB, the lipid- and multivariable-adjusted odds ratio (OR) for failed implantation was significantly elevated for those with higher HCB quartiles [Q2 Q4; adjusted ORs: for Q2, 1.71; 95% confidence interval (CI): 1.03, 2.82; for Q3, 2.30; 95% CI: 1.39, 3.81; for Q4, 2.32; 95% CI: 1.38, 3.90] and showed a significantly increasing trend (p = 0.001). No statistically significant associations were observed between DDT/DDE and IVF outcomes or between HCB and chemical pregnancy or spontaneous abortion. CONCLUSIONS: Serum HCB concentrations were on average lower than that of the general U.S. population and associated with failed implantation among women undergoing IVF. PMID- 22204797 TI - Recent advances in understanding the relationship between adenosine metabolism and the function of T and B lymphocytes in diabetes. AB - Adenosine plays an important role in physiology of several organs. Its turnover inside and outside of the cell is controlled by several enzymes and transport processes. The action of extracellular adenosine is mediated via at least four receptors named A(1), A(2A), A(2B), and A(3). Recent studies have reported that adenosine is a significant mediator of regulatory lymphocyte function. Numerous data indicates that adenosine affects T lymphocyte activation, proliferation and lymphocyte-mediated cytolysis. Impaired lymphocyte functioning and enhanced susceptibility to infections is a common feature of human diabetes. This review collects data bringing us closer to understanding the disturbances in lymphocytes adenosine homeostasis in diabetes. Adenosine receptors and nucleoside transporters are targets for potential drugs in many pathophysiological situations. Therefore, action of adenosine on lymphocyte function in diabetes may be important target for modulation of immune responses and understanding of mechanisms leading to several pathologies of immune cells observed in diabetes. PMID- 22204796 TI - Regulation and molecular mechanisms of calcium transport genes: do they play a role in calcium transport in the uterine endometrium? AB - Maintenance of calcium (Ca) balance in the uterus is critically important for many physiological functions, including smooth muscle contraction during embryo implantation. Ca transport genes, i.e., transient receptor potential cation channel subfamily V members 5/6 (TRPV5/6), calbindins, plasma membrane Ca(2+) ATPase 1 (PMCA1), and NCX1/NCKX3, may play roles in the uterus for Ca transport and reproductive function. Although these Ca transport genes may have a role in Ca metabolism, their role(s) and molecular mechanisms require further elucidation. In this review, we highlight the expression and regulation of Ca transport genes in the uterus to clarify their potential role(s). Since Ca transport genes are abundantly expressed in reproductive tissues in a distinct manner, they may be involved in specific uterine functions including fetal implantation, Ca homeostasis, and endometrial cell production. PMID- 22204798 TI - Effects of activated neutrophils on isolated rings of rat thoracic aorta. AB - Local inflammation and respiratory burst of polymorphonuclear leukocytes generate reactive oxygen species (ROS). The aim of our study was to analyze the effects of peritoneal neutrophils on changes of the muscle tension of isolated aorta and compare their effects with those of different ROS. While native neutrophils did not influence muscle tension, the N-formyl-methionyl-leucyl-phenylalanine activated ones evoked a biphasic response on the KCl-precontracted aorta. The effects of activated neutrophils were in both respects similar to those evoked by xanthine/xanthine oxidase (X/XO) and differed from the effects evoked by H(2)O(2) and Fe(2)SO(4)/H(2)O(2). Using H(2)O(2) we demonstrated that the effects of ROS were dependent on the KCl induced initial tension. To exclude the effect of extensive depolarization the action of different ROS was studied also on tissues precontracted by phenylephrine. Under such condition activated neutrophils caused a marked contraction similar to that evoked by X/XO. Their effects differed however, from those of H(2)O(2) and Fe(2)SO(4)/ascorbic acid. These findings and elimination of activated neutrophil-induced contractions as well as the chemiluminiscence by superoxide dismutase suggest that the primarily activated neutrophil-released ROS was superoxide, which can be transformed to peroxynitrite, and other ROS including H(2)O(2). Reduction of all followed-up contractions caused by nordihydroguaiaretic acid, indicate that 5-lipoxygenase metabolites unselectively reduce contractions. In contrast, selective inhibition of activated neutrophil-evoked contraction by indomethacin suggests that cyclooxygenase metabolites are involved mainly in their action on vascular smooth muscle. PMID- 22204799 TI - Effects of melatonin and tryptophan on healing of gastric and duodenal ulcers with Helicobacter pylori infection in humans. AB - Melatonin (MT) and its precursor L-tryptophan (TRP) are implicated in the protection of gastric mucosa against aspirin-induced lesions and in the acceleration of healing of idiopathic gastro-duodenal ulcers, but no information is available whether these agents are also effective in healing of gastroduodenal ulcers accompanied by Helicobacter pylori (H. pylori) infection. In this study three groups A, B and C, each including 7 H. pylori-positive patients with gastric ulcers and 7 H. pylori-positive patients with duodenal ulcers, aging 28 50 years, were randomly assigned for the treatment with omeprazole 20 mg twice daily combined with placebo (group A), MT administered in a dose of 5 mg twice daily (group B) or TRP applied in a dose of 250 mg twice daily (group C). All patients underwent routine endoscopy at day 0 during which the gastric mucosa was evaluated and gastric biopsies were taken for the presence of H. pylori and histopathological evaluation. The rate of ulcer healing was determined by gastroduodenoscopy at day 0, 7, 14 and 21 after the initiation of the therapy. Plasma MT, gastrin, ghrelin and leptin were measured by specific RIA. At day 21, all ulcers were healed in patients of groups B and C but only 3 out of 7 in group A of gastric ulcers and 3 out of 7 in duodenal ulcers. Initial plasma MT showed similar low levels in all three groups but it increased several folds above initial values in ulcer patients at day 7, 14 and 21. Plasma gastrin and leptin levels showed a significant rise over initial values in patients treated with omeprazole and placebo, MT or TRP while plasma ghrelin levels were not significantly affected by these treatments. We conclude that MT or TRP added to omeprazole treatment, significantly accelerates healing rate of H. pylori infected chronic gastroduodenal ulcers over that obtained with omeprazole alone and this likely depends upon the significant rise in plasma MT and possibly also in leptin levels, both hormones involved in the mechanism of gastroprotection and ulcer healing. PMID- 22204800 TI - BPC 157 therapy to detriment sphincters failure-esophagitis-pancreatitis in rat and acute pancreatitis patients low sphincters pressure. AB - Possibly, acute esophagitis and pancreatitis cause each other, and we focused on sphincteric failure as the common causative key able to induce either esophagitis and acute pancreatitis or both of them, and thereby investigate the presence of a common therapy nominator. This may be an anti-ulcer pentadecapeptide BPC 157 (tested for inflammatory bowel disease, wound treatment) affecting esophagitis, lower esophageal and pyloric sphincters failure and acute pancreatitis (10 MUg/kg, 10 ng/kg intraperitoneally or in drinking water). The esophagitis sphincter failure procedure (i.e., insertion of the tubes into the sphincters, lower esophageal and pyloric) and acute pancreatitis procedure (i.e., bile duct ligation) were combined in rats. Esophageal manometry was done in acute pancreatitis patients. In rats acute pancreatitis procedure produced also esophagitis and both sphincter failure, decreased pressure 24 h post-surgery. Furthermore, bile duct ligation alone immediately declines the pressure in both sphincters. Vice versa, the esophagitis-sphincter failure procedure alone produced acute pancreatitis. What's more, these lesions (esophagitis, sphincter failure, acute pancreatitis when combined) aggravate each other (tubes into sphincters and ligated bile duct). Counteraction occurred by BPC 157 therapies. In acute pancreatitis patients lower pressure at rest was in both esophageal sphincters in acute pancreatitis patients. We conclude that BPC 157 could cure esophagitis/sphincter/acute pancreatitis healing failure. PMID- 22204801 TI - 5-HT7 receptors modulate GABAergic transmission in rat hippocampal CA1 area. AB - The effects of the activation of serotonin-7 (5-HT(7)) receptors were investigated in the CA1 area pyramidal cells and stratum radiatum fast spiking GABAergic interneurons of rat hippocampal slices. To activate 5-HT(7) receptors, 5-carboxamidotryptamine (5-CT), a nonselective 5-HT(1A)/5-HT(7) agonist, was applied in the presence of N-[2-[4-(2-methoxyphenyl)-1piperazinyl]ethyl]-N-2 pyridinylcyclohexanecarboxamide (WAY 100635), a selective 5-HT(1A) receptor antagonist. The activation of 5-HT(7) receptors resulted in a dose-dependent increase in the mean frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from pyramidal neurons while the mean amplitude of sIPSCs remained unaltered. A nonselective glutamate receptor antagonist, kynurenic acid, and voltage-gated sodium channel blocker, tetrodotoxin (TTX), attenuated but did not prevent the 5-HT(7) receptor-mediated increase of sIPSCs frequency in pyramidal cells. 5-CT application did not influence the excitability of stratum radiatum interneurons but it dose-dependently increased the mean frequency of spontaneous excitatory postsynaptic currents (sEPSCs) recorded from interneurons while the mean amplitude of sEPSCs remained unaltered. These data suggest that the activation of 5-HT(7) receptors results in an enhancement of the GABAergic transmission in the hippocampal CA1 area via two mechanisms. The first one involves an enhancement of excitatory glutamatergic input to GABAergic interneurons and is likely to be mediated by presynaptic 5-HT(7) receptors. The second effect, most likely related to the activation of 5-HT(7) receptors located on interneurons, results in an enhancement of the release of GABA. PMID- 22204802 TI - Central corticotropin-releasing factor (CRF) may attenuate somatic pain sensitivity through involvement of glucocorticoids. AB - Corticotropin-releasing factor (CRF) is an important regulator of physiological functions and behavior in stress. Analgesia is one of the characteristics of stress reaction and CRF is involved in providing stress-induced analgesia, however, the underlying mechanisms remain to be determined. Exogenous CRF mimics stress effects on pain sensitivity and causes analgesic effect. The present study was performed to investigate the participation of endogenous glucocorticoids in analgesic effects induced by central administration of CRF in anesthetized rats. The participation of glucocorticoids was studied by pharmacological suppression of the hypothalamic-pituitary-adrenocortical (HPA) axis as well as an occupation of glucocorticoid receptors by its antagonist RU 38486. Since CRF administration causes the release of beta-endorphin from the pituitary, the opioid antagonist naltrexone was used to determine the contribution of opioid-dependent mechanism to CRF-induced analgesia. An electrical current threshold test was applied for measurement of somatic pain sensitivity in anesthetized rats. Intracerebroventricular administration of CRF (2 MUg/rat) caused analgesic effects (an increase of pain thresholds) and an increase in plasma corticosterone levels. Pretreatment with naltrexone did not change analgesic effects of central CRF as well as corticosterone levels in blood plasma. However, pharmacological suppression of the HPA axis leading to an inability of corticosterone release in response to CRF resulted in an elimination of CRF-induced analgesic effects. Pretreatment with RU 38486 also resulted in an elimination of CRF-induced effects. The data suggest that CRF-induced analgesic effects may be mediated by nonopioid mechanism associated with endogenous glucocorticoids released in response to central CRF administration. PMID- 22204803 TI - The central histamine level in rat model of vascular dementia. AB - The histaminergic system plays an important role in memory and learning. Deficient histaminergic transmission in the human brain in vascular dementia (VD) has been suggested. To get a better insight into the problem, a rat model of VD based on permanent bilateral occlusion of the common carotid arteries (BCCAO) leading to chronic cerebral hypoperfusion was used. Prior to the BCCAO, male Wistar rats underwent 7 days training and only those animals that positively passed the holeboard memory test were chosen for the study. The rats which were operated on were injected i.p. daily for 6 days with either a monoamine oxidase B inhibitor - PF9601N (40 mg/kg), an acetycholinesterase inhibitor - tacrine (3 mg/kg), a histamine H(3) receptor blocker - DL76 (6 mg/kg) or saline. The first retest (R1) was performed one week after the surgery while each subsequent test was 5-7 days apart. The rats were euthanized 2 or 4 weeks following the operation. The concentration of brain histamine (HA) and the activity of histamine metabolising enzymes were measured using current procedures. The BCCAO drastically increased latency and run time (p<0.001) 54 +/- 30 vs. 3.4 +/- 1.2 and 268 +/- 18 vs. 74 +/- 9, respectively, and affected working memory rather than reference memory as measured by the 1(st) retest (R1). Treatment with either PF9601N or tacrine seems to exert a positive effect on working memory. This tendency disappeared after the drug treatment stopped. Latency and run time, although they improved in R2-R4, never attained the preoperative values. The brain tissues from rats treated with PF9601N showed only 15% and 50% of untreated rat MAO B and MAO A activity, respectively, despite the drug administration having been discontinued for 3 weeks. Other drugs examined did not influence MAO enzymes. Neither did histamine N-methyltransferase activity show changes related to BCCAO nor to the treatments. The hypothalamic HA concentration was significantly reduced after BCCAO: 1.13 +/- 0.1 vs. 1.91 +/- 0.16. Noteworthy, the rats treated with PF9601N or DL76 had brain HA levels not significantly different from their intact counterparts. The rat vascular dementia model supports deficiency in histaminergic system in VD. PMID- 22204804 TI - The quantitative expression of peroxisome proliferator activated receptor (PPAR) genes in porcine endometrium through the estrous cycle and early pregnancy. AB - Peroxisome proliferator activated receptors (PPAR) are a family of the nuclear receptors which play an important role as transcriptional factors. The aim of the present study was to determine the expression of PPARs (alpha, beta, gamma) mRNA in the porcine endometrium during the estrous cycle and periimplantation period. Gilts were divided into two groups (cyclic and pregnant), synchronized and superovulated. The animals from the first group were slaughtered throughout the estrous cycle: 2-4, 5-8, 9-10, 11-12, 13-15, 16-17 and 18-21. Gilts from the second group were inseminated and slaughtered at different days of pregnancy to create subgroups: 5-8, 9-10, 11-12, 13-15, 16-17, 18-21, 21-30. PPAR mRNA expression in the endometrium was analyzed by real-time PCRs. During the estrous cycle the expression of PPARgamma1 mRNA was significantly higher on days 13-15 than at the remaining stages. The expression of PPARalpha and beta transcripts showed a similar pattern and the lowest levels were observed on days 2-4, 16-17 and 18-21 in comparison with the remaining stages (days 5-8, 9-10, 11-12). During pregnancy a significant increase in the expression of PPARgamma1 mRNA was noted on days 16-17, 18-21 and 22-30 compared to earlier stages. The transcript level of PPARbeta was significantly lower on days 11-12 and 22-30 than on days 5-8, 9 10, 13-15. mRNA expression of PPARalpha was high on days beginning from 5-8 until 18-21 and significantly dropped on days 22-30. The results indicate that the endometrial expression of PPARs genes fluctuates during the estrous cycle and pregnancy. PPARalpha and PPARbeta transcript levels show similar profiles during the estrous cycle. The decrease of both transcripts concentration on days 10-12 and 22-30 days in pregnant gilts implicates their role in maternal recognition of pregnancy and the end of implantation, respectively. PMID- 22204805 TI - Metabolic syndrome in type 1 diabetes mellitus. Does it have any impact on the course of pregnancy? AB - To determine whether the symptoms of metabolic syndrome (MS), if accompanied by oxidative stress (OS), in type 1 diabetes mellitus (DM) patients could affect the course of pregnancy and the perinatal outcome. Oxidized low density lipoproteins (ox-LDL) and total lipid peroxides (TLP) were studied in 98 pregnant women with type 1 DM in the I(st) and III(rd) trimesters. 24% of the participants met the criteria of MS. Vascular complications were significantly more frequent in the MS group (41.9% vs. 17.4% in the non-MS group, p<0.05). No differences in the markers of OS between the MS and the non-MS groups were noted in either the I(st) or the III(rd) trimester. A significant gestational rise in Per-Ox was found in both groups. Chronic hypertension was associated with significant differences in ox-LDL levels in both the I(st) and III(rd) trimester. No differences in perinatal outcome, as measured by abnormal birth weight or poor neonatal status (Apgar score<6, umbilical venous and/or arterial pH<7.20), were found. CONCLUSIONS: 1) MS in type 1 DM is associated with some changes in markers of oxidative stress, but it poses no additional risk to the course of pregnancy and perinatal outcome in properly controlled and treated pregnant women with type 1 DM. 2) Maternal hypertension is the only component of MS in diabetic pregnancy that is associated with significant changes in markers of oxidative stress. 3) MS is significantly more frequent in diabetic pregnant women with co-existing vascular complications and obesity. PMID- 22204806 TI - Prevention of ischemia-reperfusion injury in rat ovarian tissue with the on-off method. AB - Ischemia is defined as cell death caused by insufficient perfusion of the tissue due to reduction in arterial or venous blood flow, depletion of cellular energy storages, and accumulation of toxic metabolites. The positive effects of controlled reperfusion are known and are used clinically. But the positive effects of controlled reperfusion on ovarian tissue have not been seen in the literature yet. The biochemical and histopathological comparative investigation of rat ovaries that were experimentally exposed to ischemia (IG), ischemia reperfusion (I/R), and ischemia-controlled reperfusion (ICR) was aimed. Forty rats were divided into four groups (10 rats per group). First group: 3 h ischemia by vascular clips on ovarian tissue. Second group: 3 h ischemia + 1 h reperfusion. Third group: 3 h ischemia + 1 h controlled reperfusion (on-off method: controlled reperfusion by opening and closing the clips (on/off) in 10 second intervals, for 5 times for a total of 100 seconds). Fourth group: healthy rats. Biochemical (tGSH, MDA, and DNA damage level and SOD activity) and histopathological analysis were performed. The highest glutathione and superoxide dismutase measurements were found in ischemia/controlled reperfusion group among the ischemia or ischemia/reperfusion groups. Similarly the damage indicators (malondialdehyde, DNA damage level and histopathological damage grade) were the lowest in ischemia/controlled reperfusion group. These results indicate that controlled reperfusion can be helpful in minimizing ischemia-reperfusion injury in ovarian tissue exposed to ischemia for various reasons (ovarian torsion, tumor, etc.). PMID- 22204807 TI - Activation of the metabolic sensor-AMP activated protein kinase reverses impairment of angiogenesis in aging myocardial microvascular endothelial cells. Implications for the aging heart. AB - Impairment of angiogenesis - new capillary blood vessel formation from pre existing vessels, is frequent in aging tissues and cells. Reduced angiogenesis in aging individuals is associated with increased incidence of myocardial infarctions and other cardiovascular diseases. Therefore there is a need to develop novel strategies to enhance angiogenesis in aging individuals. Our previous study demonstrated aging-related impairment of angiogenesis in aging (vs. young) rat myocardial microvascular endothelial cells (MMEC), and identified reduced activation of the vascular endothelial growth factor (VEGF, the most potent stimulator of angiogenesis) gene as the main underlying mechanism. In the present study we examined the possibility of increasing angiogenesis and activating VEGF gene expression in aging MMECs using a chemical activator of the metabolic sensor - AMP activated protein kinase (AMPK). We hypothesized that activation of VEGF gene in aging MMECs by AMPK would stimulate angiogenesis and reverse the impairment in angiogenesis seen in these cells. We used MMECs isolated from aging (24 months old) Fisher F-344 rats and treated them with 5 aminoimidazole-4-carboxamide ribonucleotide (AICAR), a specific pharmacological stimulator of AMPK. We examined: 1) in vitro angiogenesis; and 2) the expression of phosphorylated AMPK, VEGF, and P-MAPK/Erk1/2. Treatment of aging MMECs with AICAR increased in vitro angiogenesis and VEGF mRNA expression by 2.1-fold and 3.7-fold, respectively. Furthermore, AICAR treatment resulted in phosphorylation of MAPK/Erk1/2. This study demonstrated the successful use AICAR to reverse aging related impairment of angiogenesis in aging MMECs by enhancing VEGF gene expression and also identified phosphorylation of MAPK/Erk1/2 as a likely mechanism of these changes. PMID- 22204808 TI - Escherichia coli physiology and metabolism dictates adaptation to diverse host microenvironments. AB - Bacterial growth in the host is required for pathogenesis. To successfully grow in vivo, pathogens have adapted their metabolism to replicate in specific host microenvironments. These adaptations reflect the nutritional composition of their host niches, inter-bacterial competition for carbon and energy sources, and survival in the face of bactericidal defense mechanisms. A subgroup of Escherichia coli, which cause urinary tract infection, bacteremia, sepsis, and meningitis, have adapted to grow as a harmless commensal in the nutrient-replete, carbon-rich human intestine but rapidly transition to pathogenic lifestyle in the nutritionally poorer, nitrogen-rich urinary tract. We discuss bacterial adaptations that allow extraintestinal pathogenic E. coli to establish both commensal associations and virulence as the bacterium transits between disparate microenvironments within the same individual. PMID- 22204809 TI - Exploitation of host signaling pathways by microbial quorum sensing signals. AB - Environmental and commensal microbes that live within, on and around us have an enormous impact on human health. Recent progress in studies of prokaryotic interplay as well as host-bacteria interactions suggests that secreted microbial products, including quorum sensing signals (QSS), are important mediators of these intrakingdom and interkingdom relations. Reports have assigned QSS diverse and sometimes seemingly contradictory effects on mammalian cell physiology ranging from either blunting of the immune response or exerting pro-inflammatory activities to inducing cellular stress pathways and ultimately apoptosis. Thus, it is still unclear whether microbes utilize QSS to establish and maintain infections via modulation of host signaling pathways or if the eukaryotic host uses the conserved microbial QSS structures as molecular danger beacons to detect and fight infections. Along the same lines exactly how and under what circumstances QSS are detected by host cells remains a mystery, especially considering the distinct chemical properties of the QSS classes with some being small enough to passively diffuse across membranes while others most likely require extracellular recognition mechanisms. PMID- 22204810 TI - Re: L.A. Shanks, T.W. Walker, P.J. McCann, M.J. Kerin, Oral cavity examination: beyond the core curriculum? [Br J Oral Maxillofac Surg 2011]. PMID- 22204811 TI - Does the sequence of data collection influence participants' responses to closed and open-ended questions? A methodological study. AB - BACKGROUND: The sequence used for collecting quantitative and qualitative data in concurrent mixed-methods research may influence participants' responses. Empirical evidence is needed to determine if the order of data collection in concurrent mixed methods research biases participants' responses to closed and open-ended questions. OBJECTIVES: To examine the influence of the quantitative qualitative sequence on responses to closed and open-ended questions when assessing the same variables or aspects of a phenomenon simultaneously within the same study phase. DESIGN: A descriptive cross-sectional, concurrent mixed-methods design was used to collect quantitative (survey) and qualitative (interview) data. The setting was a large multi-site health care centre in Canada. METHODS: A convenience sample of 50 registered nurses was selected and participated in the study. Participants were randomly assigned to one of two sequences for data collection, quantitative-qualitative or qualitative-quantitative. ANALYSIS: Independent t-tests were performed to compare the two groups' responses to the survey items. Directed content analysis was used to compare the participants' responses to the interview questions. RESULTS: The sequence of data collection did not greatly affect the participants' responses to the closed-ended questions (survey items) or the open-ended questions (interview questions). CONCLUSIONS: The sequencing of data collection, when using both survey and semi-structured interviews, may not bias participants' responses to closed or open-ended questions. Additional research is required to confirm these findings. PMID- 22204812 TI - Effective strategies for nurse retention in acute hospitals: a mixed method study. AB - BACKGROUND: The realization of an organizational context that succeeds to retain nurses within their job is one of the most effective strategies of dealing with nursing shortages. OBJECTIVES: First, to examine the impact of nursing practice environments, nurse staffing and nurse education on nurse reported intention to leave the hospital. Second, to provide understanding of which best practices in the organization of nursing care are being implemented to provide sound practice environments and to retain nurses. METHODS: 3186 bedside nurses of 272 randomly selected nursing units in 56 Belgian acute hospitals were surveyed. A GEE logistic regression analysis was used to estimate the impact of organization of nursing care on nurse reported intention to leave controlling for differences in region (Walloon, Flanders, and Brussels), hospital characteristics (technology level, teaching status, and size) and nurse characteristics (experience, gender, and age). For the second objective, in-depth semi-structured interviews with the chief nursing officers of the three high and three low performing hospitals on reported intention to leave were held. RESULTS: 29.5% of Belgian nurses have an intention-to-leave the hospital. Patient-to-nurse staffing ratios and nurse work environments are significantly (p<0.05) associated with intention-to-leave. Interviews with Chief Nurse Officers revealed that high performing hospitals showing low nurse retention were--in contrast to the low performing hospitals- characterized by a flat organization structure with a participative management style, structured education programs and career opportunities for nurses. CONCLUSION: This study, together with the international body of evidence, suggests that investing in improved nursing work environments is a key strategy to retain nurses. PMID- 22204813 TI - Mixed antagonist response and sepsis severity-dependent dysbalance of pro- and anti-inflammatory responses at the onset of postoperative sepsis. AB - It has been postulated that an early systemic inflammatory response syndrome (SIRS) and a subsequent compensatory anti-inflammatory response syndrome (CARS) occur sequentially in sepsis. Co-existence of both is referred to as mixed antagonist response syndrome (MARS). Pro- and anti-inflammatory cytokine production was investigated in patients with postoperative sepsis, a murine peritonitis model and in vitro to further delineate the interaction of hyper- and hypo-inflammation in sepsis. IL-6 and IL-10 were measured in serum samples from 80 patients on d1 and d2 of postoperative sepsis and were similarly determined at various time points after induction of septic peritonitis in mice. Cytokine production of RAW264 macrophages was stimulated in vitro using TLR agonists. IL-6 and IL-10 were measured in supernatants. All cytokine measurements were performed by ELISA. In patients, the initial phase of the immune response to sepsis was characterized by a concomitant elevation of serum IL-6 and IL-10 levels. IL-10 levels were correlated with IL-6 levels in an exponential manner (p<0.001), which could be confirmed in a mouse model of septic peritonitis. In vitro experiments revealed that the observed exponential correlation may occur as function of TLR signaling intensity. Early postoperative sepsis seems to be characterized by a primary MARS. Sepsis severity was positively correlated with a disproportionate elevation of the anti-inflammatory response relative to the pro-inflammatory response, a pattern reminiscent of TLR-driven responses. Detailed characterization of immune responses in sepsis may help to direct standard therapies and to develop effective immunomodulatory strategies. PMID- 22204814 TI - CD200 receptor and macrophage function in the intestine. AB - CD200 receptor 1 is an inhibitory receptor expressed by myeloid cells which has inhibitory effects on macrophage function after binding its ubiquitously expressed ligand CD200. Recent evidence suggests that this is important in controlling inflammatory reactions in the lung and here we have explored if the CD200R1-CD200 axis plays a similar role in other mucosal surfaces such as the intestine. We show for the first time that CD200R1 is expressed selectively by resident macrophages in normal mouse colon and that CD200 is present on many haematopoietic and non-haematopoietic cells in the intestine. Although acute colitis induced by feeding dextran sodium sulphate is associated with an influx of CD200R1(neg) macrophages, CD200R1 KO mice have normal macrophage function in the colon and they do not develop spontaneous intestinal inflammation, nor are they more susceptible to DSS colitis. CD200 KO mice also develop experimental colitis normally and we conclude that CD200R1 does not play an essential role in macrophage homeostasis in the colon, indicating that these molecules may have distinct functions in different mucosal tissues. PMID- 22204815 TI - Galectin-9 ameliorates herpes simplex virus-induced inflammation through apoptosis. AB - Galectin-9 (Gal-9) has been identified as a Tim-3 ligand (L). The Tim-3-Tim-3L interaction serves as a specific down-regulator of the Th1 immune response. It has been reported that Tim-3 expression is higher in patients with inflammatory disorders such as rheumatoid arthritis compared to controls. In a herpes simplex virus-induced Behcet's disease (BD) mouse model, Tim-3 was expressed in a similarly high level. The expression of Gal-9 in macrophages from BD-like mice was lower than in asymptomatic BD normal mice; therefore, we injected 100 MUg of Gal-9 into BD-like mice five times at 3 day intervals and subsequently observed changes in symptoms over 15 days. Gal-9 improved the symptoms of inflammation, decreased the severity score, and increased regulatory T cell expression in treated mice. Moreover, pro-inflammatory cytokine levels were lower in the Gal-9 treated group compared to the control group. Therefore, in the present study, Tim 3-Tim-3L interaction was found to influence inflammatory symptoms in BD-like mice. PMID- 22204816 TI - Decreased levels of alternative co-stimulatory receptors OX40 and 4-1BB characterise T cells from head and neck cancer patients. AB - BACKGROUND AND AIM: Head and neck cancers (HNC) are aggressive tumours. Tumour specific T cells are frequently identified in patients with cancer, although they fail to control tumour progression. A family of proteins called co-stimulatory receptors regulate the function of T cells and may account for T cell dysfunction in cancer. Our aim was to characterise co-stimulatory receptors on T cells in HNC patients to identify novel targets for immunotherapy. METHODS: Peripheral blood mononuclear cells were isolated from HNC patients and healthy controls and the expression of co-stimulatory (OX40, 4-1BB, ICOS) and co-inhibitory (CTLA-4, PD1) receptors was analysed on CD4(+) and CD8(+) T cells using flow cytometry. RESULTS: We found that the levels of co-stimulatory receptors OX40 and 4-1BB were significantly lower on CD4(+) T cells from HNC patients. This was more pronounced in locally advanced tumours (T3/T4) compared to early carcinomas (T1/T2). PD-1 levels were higher on CD8(+) T cells in HNC patients compared to controls. Human papilloma virus (HPV)-specific CD8(+) T cells appeared to be more affected than Influenza-specific T cells. CONCLUSIONS: Our results indicate that expression of co-stimulatory receptors on T cells from HNC patients is imbalanced with a preponderance of inhibitory signals, and reduction of stimulatory signals, especially in advanced disease. Restoring this balance could improve T cell therapy outcomes in HNC. PMID- 22204817 TI - Interferon-gamma-induced PD-L1 surface expression on human oral squamous carcinoma via PKD2 signal pathway. AB - Many cells located in the tumor microenvironment function to protect or promote the ability of tumor cells to escape immune destruction. Previous studies have shown that programmed death ligand-1 (PD-L1), a ligand of the B7 superfamily, is expressed on a series of human tumors and can inhibit anti-tumor immune responses. Interferon-gamma (IFN-gamma), a cytokine produced and secreted by inflammatory cells in the tumor microenvironment, is a main stimulator of PD-L1 expression in tumor cells. Making clear the mechanism of IFN-gamma induced the expression of PD-L1 on tumor cells that is benefit to find a way to inhibit the function of PD-L1 and improve cancer cell-reactive immune responses. Herein, we have identified protein kinase D isoform 2 (PKD2) as an important regulator of PD L1 expression on human oral squamous carcinoma cells induced by IFN-gamma. IFN gamma induced the expression of PD-L1 and PKD2 in human oral squamous carcinoma Tca8113 in both time and dose dependent manner. The expression of PD-L1 was decreased significantly after PKD2 knockdown with shRNA/siRNA interference or PKD chemical inhibitor following induction with IFN-gamma. The apoptosis of CD8(+) T cell which is induced by tumor cells via PD-1/PD-L1 pathway was significantly decreased, as a result, the anti-tumor effects of tumor antigen specific T cell were increased in vivo. Together, these data combined with our previous results, indicate PKD2 as an important target candidate for tumor biotherapy. Inhibition of PKD2 activation not only inhibits PD-L1 expression and promotes an anti-tumor effect, but also decreases drug resistance in chemotherapy. PMID- 22204818 TI - Protection against Streptococcus pneumoniae serotype 1 acute infection shows a signature of Th17- and IFN-gamma-mediated immunity. AB - Acute pneumonia caused by Streptococcus pneumoniae is a major cause of child mortality. Antibodies are considered the main effectors of protection in this clinical presentation of pneumococcal invasive disease. To get new insights into the mechanisms involved in the protective immunity, we established a murine experimental model of protection against acute pneumococcal pneumonia and then evaluated the transcriptional, humoral and cellular responses in protected and non-protected animals. We found that intranasal inoculation of a sublethal dose of S. pneumoniae serotype 1 conferred complete protection against a subsequent challenge with a lethal dose of the same strain. Sublethal infection elicited a strong IgM and IgG antibody response against the capsular polysaccharide, as assessed one week later, and an exacerbated influx of neutrophils into the lungs immediately after the lethal challenge. Genome-wide microarray-based transcriptional analysis of whole lungs showed 149 differentially expressed genes among which we found upregulation of Il17a, Ifng and several IL-17A- and IFN gamma-related genes in protected versus non-protected mice. Kinetics analysis showed higher expression levels of Il17a in protected animals at all time points whereas Ifng was upregulated early in the protected mice and later in the non protected animals. Intracelluar cytokine staining demonstrated that CD4(+) T cells account for a great proportion of the IL-17A produced in the lungs of protected animals. Overall, these results showed that an upregulation of IL-17A- and a timely regulation of IFN-gamma-related gene expression, together with development of a Th17 response, are relevant characteristics of the protective immunity against S. pneumoniae acute pneumonia. PMID- 22204819 TI - Flow cytometry analysis of leukocytes in induced sputum from asthmatic patients. AB - Inflammatory cell counts in induced sputum from asthmatic patients partially correlate with respiratory physiology data. To identify and quantify these inflammatory components, microscopy has been useful but it is not without its limitations. Flow cytometry could be an alternative but still has underlying methodological difficulties. While passing airways, leukocytes undergo morphologic cellular changes that alter their conventional phenotype. To demonstrate the usefulness of cytometry in accurately identifying cellular profiles in induced sputum of asthmatic and chronic cough patients, we introduced a new panel of monoclonal antibodies against specific subset markers. To identify neutrophils, sputum cells were stained with CD45 and CD66b. To identify eosinophils, sputum cells were stained with anti-CD45 and anti-CD125. We co stained CD45, CD14 and CD66b to identify macrophages as CD45+CD14+CD66b- cells. Comparable results of trypan blue exclusion and annexin V-FITC suggested that cytometry manipulation did not decrease cellular viability. Range values were similar in microscopy neutrophils (median 19.9%, range 1.7-90.1%) and CD45+CD66b+ neutrophils (median 31% range 0.9-89%). After gating out CD45- non-leukocyte events, CD45+ and SSC dot-plots defined three patterns of leukocyte distribution. The eosinophil range in microscopic examination was 0-71.3% (median 2.85%) whereas CD45+CD125+ cell range in cytometry was 0-29% (median 3.7%). Since no exclusive markers were found on airways macrophages, we co-stained CD45, CD14 and CD66b to identify macrophages as CD45+CD14+CD66b- cells. Microscopy showed that macrophage and CD45+CD14+CD66b- cell counts were comparable (median 52.3 and range 6.7-94.8 vs median 61 and range 10.5-97.7 respectively). Correlations between neutrophils, eosinophils and macrophages in microscopic examination and flow cytometry were strong (R=0.725, 0.747 and 0.532, respectively p<0.001). This study validates effectiveness of combining specific antibodies and cytometry to quantify inflammatory leukocytes in induced sputum. Multiple markers at a single cell level will deepen our knowledge concerning the phenotype of airway leukocytes. PMID- 22204820 TI - All-trans retinoic acid up-regulates Prostaglandin-E Synthase expression in human macrophages. AB - All-trans retinoic acid (ATRA) is a potent retinoid, which has been used successfully in different clinical settings as a potential drug to treat COPD and emphysema. In the present study, we analyzed genes modulated by ATRA by performing mRNA expression array analysis on alveolar macrophages after treatment with ATRA. Here we observed a 375-fold up-regulation of Prostaglandin-E Synthase (microsomal PGES-1, NM_004878 PTGES) which mediates the conversion of prostaglandin H(2) (PGH(2)) to Prostaglandin E(2) (PGE(2)). We furthermore studied the expression of PTGES after treatment with ATRA in human monocyte derived macrophages (MDMs) and bronchoalveolar lavage (BAL) cells. ATRA up regulated PTGES mRNA expression in MDMs generated with M-CSF by 2500-fold whereas in M-CSF+IL-13 macrophages the up-regulation was only 20-fold. Similarly, ATRA up regulated PTGES mRNA expression by factor 1524 in BAL cells. The up-regulation of PTGES mRNA expression by ATRA is both time and dose dependent. IL-13 suppressed the ATRA induced PTGES expression at both mRNA and protein level in MDM and BAL cells. We also observed that LPS acts synergistically with ATRA in MDMs and strongly induces PTGES expression. ATRA had little impact on cyclooxygenase-1 and -2 (COX-1 and -2) expression as compared to PTGES expression under the same experimental conditions. Furthermore, we observed an induction of PGE(2) levels by ATRA in BAL cells. These data indicate that ATRA is a potent inducer of PTGES expression in human macrophages but not in alternatively activated macrophages and suggest that the eicosanoid pathway is important for ATRA action in macrophages. PMID- 22204821 TI - The use of light for engineered control and reprogramming of cellular functions. AB - Could combating incurable diseases lie in something as simple as light? This scenario might not be too farfetched due to groundbreaking research in optogenetics. This novel scientific area, where genetically encoded photosensors transform light energy into specifically engineered biological processes, has shown enormous potential. Cell morphology can be changed, signaling pathways can be reprogrammed, and gene expression can be regulated all by the control of light. In biomedical applications where precise cell targeting is essential, non invasive light has shown great promise. This article provides a summary of the recent advances that utilize light in genetic programming and precise control of engineered biological functions. PMID- 22204822 TI - Sweet sorghum as a model system for bioenergy crops. AB - Bioenergy is the reduction of carbon via photosynthesis. Currently, this energy is harvested as liquid fuel through fermentation. A major concern, however, is input cost, in particular use of excess water and nitrogen, derived from an energy-negative process, the Haber-Bosch method. Furthermore, the shortage of arable land creates competition between uses for food and fuel, resulting in increased living expenses. This review seeks to summarize recent knowledge in genetics, genomics, and gene expression of a rising model species for bioenergy applications, sorghum. Its diploid genome has been sequenced, it has favorable low-input cost traits, and genetic crosses between different cultivars can be used to study allelic variations of genes involved in stem sugar metabolism and incremental biomass. PMID- 22204823 TI - Prenatal development of the bovine epididymis: light microscopical, glycohistochemical and immunohistochemical studies. AB - Prenatal development of the epididymis was studied in bovine fetuses ranging from 10 to 90cm crown-rump length (CRL) (75-285 pcd). The studies aimed to apply both glycohistochemistry and immunohistochemistry for the detection of the differentiation of the developing prenatal epididymis. Both conventional histological and histochemical techniques were applied on paraffin sections of the epididymis from different fetal stages. Establishment of the urogenital junction between the extra-testicular rete testis and the mesonephric duct, via the growing efferent ductules (ductuli efferentes) was first evident in fetuses with 10cm CRL. At the fetal age of 110 pcd (24cm CRL), the mesonephric duct began to lengthen and coil forming three distinct regions (caput, corpus and cauda). In addition to the macroscopical modifications in the extra-testicular excurrent duct system, histological differentiation involved both the tubular epithelial and the peritubular mesenchymal cells. The epithelium lining the efferent ductules was differentiated into ciliated and non-ciliated columnar cells. The simple epithelium of the epididymal duct increased in height and developed stereocilia on the apical surface. Additionally, some basal cells first appeared at 185 pcd (56cm CRL), within the epithelium lining the cauda only. Lectin histochemistry (WGA, PNA, GSA-I) showed early immunostaining in epithelium of the efferent ductules and in peritubular mesenchymal structures. Immunoreactivity for different proteins (S-100, fibroblast growth factor-1 and factor-2, angiotensin converting enzyme, laminin, alpha-smooth muscle actin) was evident, both in the epithelial and in the peritubular mesenchymal cells as early as at 75 pcd. On the basis of our histochemical observations, we conclude that both glycohistochemistry and immunohistochemistry are useful tools to demonstrate that the differentiation in the peritubular structures and efferent ductular epithelium begins earlier than other components. PMID- 22204824 TI - Fast detection of choline-containing metabolites in liver using 2D 1H-14N three bond correlation (HN3BC) spectroscopy. AB - Detection and quantification of total choline-containing metabolites (CCMs) in tissues by magnetic resonance spectroscopy (MRS) has received considerable attention as a biomarker of cancer. Tissue CCMs are mainly choline (Cho), phosphocholine (PCho), and glycerophosphocholine (GPCho). Because the methyl (1)H resonances of tissue CCMs exhibit small chemical shift differences and overlap significantly in 1D (1)H MRS, quantification of individual components is precluded. Development of a MRS method capably of resolving individual components of tissue CCMs would be a significant advance. Herein, a modification of the 2D (1)H-(14)N HSQC technique is targeted on the two methylene (1)H in the CH(2)O group ((3)J(1H14N)=2.7 Hz) and applied to ex vivo mouse and human liver samples at physiological temperature (37 degrees C). Specifically, the (1)H-(14)N HSQC technique is modified into a 2D (1)H-(14)N three-bond correlation (HN3BC) experiment, which selectively detects the (1)H of CH(2)O coupled to (14)N in CCMs. Separate signals from Cho, PCho, and GPCho components are resolved with high detection sensitivity. A 2D HN3BC spectrum can be recorded from mouse liver in only 1.5 min and from human carcinoma liver tissue in less than 3 min with effective sample volume of 0.2 ml at 14.1T. PMID- 22204826 TI - Influence of light intensity on the toxicity of atrazine to the submerged freshwater aquatic macrophyte Elodea canadensis. AB - Light intensity can have a profound influence on the degree of phytotoxicity experienced by plants exposed to photosystem II (PSII) inhibiting herbicides. This relationship was evaluated in the submerged aquatic macrophyte Elodea canadensis exposed to three different concentrations of atrazine (510, 1000 and 2000 MUg a.i./L) plus an untreated control at three different light intensities (0, 500 and 6000 lx) under static-renewal conditions for 14 days. Under 500 lx light intensity, control plants demonstrated a rapid increase in shoot length but minimal increase in dry shoot weight, suggesting limited photosynthesis. Based on shoot-length and biomass, growth was not affected by any atrazine exposure relative to controls under dark conditions (0 lx). Under low-light conditions at 500 lx, exposures to 510, 1000 and 2000 MUg a.i./L atrazine significantly decreased net shoot lengths by 34%, 38% and 35%, respectively, relative to corresponding (500 lx) controls. However, atrazine exposure under this light condition did not significantly decrease biomass (dry shoot weight). Compared to 6000 lx, only approximately 8% of photosynthetically active radiation (PAR) was measured under 500 lx intensity, indicating that minimal PAR was available for photosynthesis. Under optimal light conditions (6000 lx), net shoot lengths significantly decreased in the treated atrazine groups by 48%, 51% and 68%, and net dry shoot weights (biomass) were significantly decreased by 79%, 81% and 91%, respectively, relative to corresponding (6000 lx) controls. These data show that under low light conditions, atrazine-induced effects on dry shoot weight (biomass) are dependent on available PAR and active photosynthesis. PMID- 22204825 TI - Compressed sensing sodium MRI of cartilage at 7T: preliminary study. AB - Sodium MRI has been shown to be highly specific for glycosaminoglycan (GAG) content in articular cartilage, the loss of which is an early sign of osteoarthritis (OA). Quantitative sodium MRI techniques are therefore under development in order to detect and assess early biochemical degradation of cartilage, but due to low sodium NMR sensitivity and its low concentration, sodium images need long acquisition times (15-25 min) even at high magnetic fields and are typically of low resolution. In this preliminary study, we show that compressed sensing can be applied to reduce the acquisition time by a factor of 2 at 7 T without losing sodium quantification accuracy. Alternatively, the nonlinear reconstruction technique can be used to denoise fully-sampled images. We expect to even further reduce this acquisition time by using parallel imaging techniques combined with SNR-improved 3D sequences at 3T and 7 T. PMID- 22204827 TI - Type I interferons directly down-regulate BCL-6 in primary and transformed germinal center B cells: differential regulation in B cell lines derived from endemic or sporadic Burkitt's lymphoma. AB - Type I interferons (IFN) exert multiple effects on both the innate and adaptive immune system in addition to their antiviral and antiproliferative activities. Little is known, however about the direct effects of type I IFNs on germinal center (GC) B cells, the central components of adaptive B cell responses. We used Burkitt's lymphoma (BL) lines, as a model system of normal human GC B cells, to examine the effect of type I IFNs on the expression of BCL-6, the major regulator of the GC reaction. We show that type I IFNs, but not IFNgamma, IL-2 and TNFalpha rapidly down-regulate BCL-6 protein and mRNA expression, in cell lines derived from endemic, but not from sporadic BL. IFNalpha-induced down-regulation is specific for BCL-6, independent of Epstein-Barr virus and is not accompanied by IRF-4 up-regulation. IFNalpha-induced BCL-6 mRNA down-regulation does not require de novo protein synthesis and is specifically inhibited by piceatannol. The proteasome inhibitor MG132 non-specifically prevents, while inhibitors of alternate type I IFN signaling pathways do not inhibit IFNalpha-induced BCL-6 protein downregulation. We validate our results with showing that IFNalpha rapidly down-regulates BCL-6 mRNA in purified mouse normal GC B cells. Our results identify type I IFNs as the first group of cytokines that can down regulate BCL-6 expression directly in GC B cells. PMID- 22204828 TI - [The Guest Editor's commentary]. PMID- 22204829 TI - [Role of imaging in the diagnostic and therapeutic algorithms of breast cancer]. AB - Early diagnosis and prevention have the most significant effect on overall disease specific outcome; 90% of all breast cancer cases could be cured if diagnosed early and treated accurately. As for all diagnostic methods the most important requirement for diagnostic imaging is to detect breast cancer in its early stage, and to determine accurate tumor staging, in order to select the appropriate therapy. Its role is to monitor the effectiveness of therapy, to follow up patients reliably for early detection of recurrent disease. The spectrum of radiological imaging methods in breast cancer became broader in the past two decades; imaging that provides functional or metabolic data and whole body information such as CT, MRI and PET-CT are now available besides common X ray and ultrasound mammography. The MRI is getting more and more important for the detection and characterization of breast cancer. Multimodal imaging techniques provide more accurate analysis, which is confirmed by increasing statistics authentically, but none of the imaging methods was specific enough to provide histological diagnosis. However, imaging-guided biopsies enable precise histological or cytological confirmation. PMID- 22204830 TI - [Modern diagnostics in breast cancer: nuclear medicine techniques]. AB - The authors discuss the role of nuclear medicine techniques in the modern diagnostics of breast cancer, including the methods currently used in Hungary and the future possibilities. PMID- 22204831 TI - [Modern pathologic diagnostics in breast cancer]. AB - The diagnosis of breast cancer is morphologically based. Pathologic parameters, such as tumor size, lymph node status, and histological grade are well accepted to guide treatment decisions in clinical practice. Estrogen receptor, progesterone receptor and HER2 status are also routinely assessed in today's pathology laboratories to provide further information on predictive and prognostic factors affecting patients' care. Newer molecular techniques, including gene-expression profiling have been widely used to study breast cancer and several molecular prognostic tests already available for clinical use stemmed from these scientific efforts. Authors review prognostically important aspects of the diagnostic pathology and the molecular classification of invasive breast cancer. PMID- 22204832 TI - [Modern breast surgery]. AB - Today, as a result of the complex and coordinated medical treatment of breast malignancies the long-term survival rate reaches 80%. Modern breast surgery plays a prominent role in the multidisciplinary treatment of breast tumors. Breast surgery in the 21st century simultaneously performs medical and aesthetic procedures on the same organ. Modern day breast surgery is founded on a complex view of breast malignancies, multidisciplinary cooperation, oncoplastic practice, and selecting the optimal surgery techniques, based on state of the art tools and a detailed treatment plan. Authors present the evolution of modern breast surgery; discuss the procedures such as mastectomy, breast conservation surgery, axillary lymph node removal, prophylactic mastectomy, as well as possible versions of immediate or delayed breast reconstruction. PMID- 22204834 TI - Will vaccinated women attend cervical screening? A population based survey of human papillomavirus vaccination and cervical screening among young women in Victoria, Australia. AB - OBJECTIVES: To assess human papillomavirus (HPV) vaccination coverage and attitudes to vaccination and Pap screening in young women. DESIGN: Population based telephone survey. SETTING: Victoria, Australia. PARTICIPANTS: 234 women resident in Victoria aged 18-28 years in May 2009. MAIN OUTCOME MEASURES: Self reported HPV vaccination uptake, reasons for non-receipt or failure to complete vaccination, knowledge and attitudes about HPV vaccination and Pap screening, and cervical screening intentions. RESULTS: The response rate for eligible households was 62.4%. Half of the women (56%, n=131) had previously had a Pap test and 74% (age standardised estimate) had received HPV vaccine. Of the vaccinated women, 5% had received one dose only, 18% two doses and 76% had completed the course (1.7% unsure of number of doses). Vaccination uptake was highest in the youngest women (declining from 90% for at least one dose in women aged 18-38.5% in women aged 28; p for trend <0.001). Among women who had heard of the vaccine, 96% knew Pap tests were still needed after it, although 20% thought the vaccine could prevent all cervical cancers and 9% thought the vaccine could treat cervical abnormalities and cancer. Among vaccinated women, 8% of women agreed that having been vaccinated made them less likely to have Pap tests in the future. CONCLUSIONS: Self-reported coverage in this sample was higher than that recorded on the national vaccination register. Young women report the message that Pap tests are required after vaccination, but there are gaps in their knowledge about the limitations of the vaccine so it remains to be seen if they actually follow through with having Pap tests. Ongoing monitoring of cervical screening rates will be important as this cohort ages. PMID- 22204835 TI - Joint use of epidemiological and hospital medico-administrative data to estimate prevalence. Application to French data on breast cancer. AB - BACKGROUND: Estimate complete, limited-duration, and hospital prevalence of breast cancer in a French Departement covered by a population-based cancer registry and in whole France using complementary information sources. METHODS: Incidence data from a cancer registry, national incidence estimations for France, mortality data, and hospital medico-administrative data were used to estimate the three prevalence indices. The methods included a modelling of epidemiological data and a specific process of data extraction from medico-administrative databases. RESULTS: Limited-duration prevalence at 33 years was a proxy for complete prevalence only in patients aged less than 70 years. In 2007 and in women older than 15 years, the limited-duration prevalence at 33 years rate per 100,000 women was estimated at 2372 for Departement Isere and 2354 for whole France. The latter rate corresponded to 613,000 women. The highest rate corresponded to women aged 65-74 years (6161 per 100,000 in whole France). About one third of the 33-year limited-duration prevalence cases were diagnosed five years before and about one fourth were hospitalized for breast-cancer-related care (i.e., hospital prevalence). In 2007, the rate of hospitalized women was 557 per 100,000 in whole France. Among the 120,310 women hospitalized for breast cancer-related care in 2007, about 13% were diagnosed before 2004. CONCLUSION: Limited-duration prevalence (long- and short-term), and hospital prevalence are complementary indices of cancer prevalence. Their efficient direct or indirect estimations are essential to reflect the burden of the disease and forecast median- and long-term medical, economic, and social patient needs, especially after the initial treatment. PMID- 22204836 TI - Modification of red mud by acid treatment and its application for CO removal. AB - Activated red mud (ARM) samples were tested for carbon monoxide (CO) oxidation in the temperature range of 100-500 degrees C. Conversion of >90% was obtained for temperatures above 400 degrees C for all samples. In order to study the effect of hydroxylated phases of iron oxide in red mud on the removal of CO, 'as-received' red mud (RM) and acid digested and re-precipitated red mud (TRM) were also tested under similar conditions. It was found that TRM was more effective in removal of CO with the 50% conversion temperature (T50) 80 degrees C lower than the ARM samples. The samples before and after reaction were characterized by inductively coupled plasma-optical emission spectroscopy (ICP-OES), BET N(2) adsorption, X ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), electron microscopy (SEM and TEM) and temperature programmed reduction (TPR). It was observed that TRM had iron in an amorphous form which then converted to iron oxide after heating. The higher activity of TRM was due to its higher surface area and presence of hydroxylated phase of iron oxide. PMID- 22204837 TI - Pyrolysis of a waste from the grinding of scrap tyres. AB - The fibres that are used to reinforce tyres can be recovered as a waste in the process of grinding of scrap tyres. In this paper beneficiation through pyrolysis is studied since the fibres are made up of polymers with a small amount of rubber because the latter is difficult to separate. The experiments were performed at three temperatures (400, 550 and 900 degrees C) in a horizontal oven. The three products - gas, oil and char - obtained from the pyrolysis were investigated. The composition of the gas was analyzed by means of gas chromatography. The oil was studied by gas chromatography and infrared spectroscopy. The char porous structure was determined by N(2) adsorption. In addition, the topography of the chars was studied by means of scanning electron microscopy (SEM). The products resulting from the pyrolysis of the fibres were compared with those obtained from scrap rubber. PMID- 22204838 TI - Removal of benzene and methyl ethyl ketone vapor: comparison of hypercrosslinked polymeric adsorbent with activated carbon. AB - A novel hypercrosslinked polymeric adsorbent (HY-1) with high surface area and specific bimodal pore size distribution in the regions of micropore (0.5-2.0 nm) and meso-macropore (30-70 nm) was prepared. Adsorption properties of benzene and methyl ethyl ketone (MEK) vapors onto HY-1 were investigated and compared with a commercial microporous activated carbon (m-GAC). The equilibrium adsorption data showed that the adsorption capacities of benzene and MEK on HY-1 were larger than those of m-GAC at the higher relative pressure. The Dubinin-Radushkevich (D-R) equation was found to fit the experimental data well. The isosteric enthalpy of adsorption for benzene and MEK were calculated. The m-GAC exhibited much higher values of DeltaH(st) for the VOCs than HY-1 at the whole loading studied, which can lead to significant temperature rises during the adsorption step. The results of dynamic experiments revealed that HY-1 had a good dynamic adsorption capacity with a longer breakthrough time and shorter length of mass transfer zone due to its specific bimodal property. Therefore, HY-1 will be a particularly efficient and competitive adsorbent for VOCs recovery, especially at medium-high concentrations. PMID- 22204839 TI - Structural violence in long-term, residential care for older people: comparing Canada and Scandinavia. AB - Canadian frontline careworkers are six times more likely to experience daily physical violence than their Scandinavian counterparts. This paper draws on a comparative survey of residential careworkers serving older people across three Canadian provinces (Manitoba, Nova Scotia, Ontario) and four countries that follow a Scandinavian model of social care (Denmark, Finland, Norway, Sweden) conducted between 2005 and 2006. Ninety percent of Canadian frontline careworkers experienced physical violence from residents or their relatives and 43 percent reported physical violence on a daily basis. Canadian focus groups conducted in 2007 reveal violence was often normalized as an inevitable part of elder-care. We use the concept of "structural violence" (Galtung, 1969) to raise questions about the role that systemic and organizational factors play in setting the context for violence. Structural violence refers to indirect forms of violence that are built into social structures and that prevent people from meeting their basic needs or fulfilling their potential. We applied the concept to long-term residential care and found that the poor quality of the working conditions and inadequate levels of support experienced by Canadian careworkers constitute a form of structural violence. Working conditions are detrimental to careworker's physical and mental health, and prevent careworkers from providing the quality of care they are capable of providing and understand to be part of their job. These conditions may also contribute to the physical violence workers experience, and further investigation is warranted. PMID- 22204840 TI - The pervasive effects of racism: experiences of racial discrimination in New Zealand over time and associations with multiple health domains. AB - Self-reported experience of racial discrimination has been linked to a range of health outcomes in various countries and for different ethnic groups. This study builds on previous work in New Zealand to further investigate the prevalence of self-reported experience of racial discrimination by ethnicity, changes over time and associations with multiple health measures. The study uses data from the 2002/03 (n=12,500) and 2006/07 (n=12,488) New Zealand Health Surveys, nationally representative population-based surveys of adults (15+ years). Reported experience of racial discrimination was measured in both surveys and covered 5 items: experience of an ethnically motivated physical or verbal attack; and unfair treatment because of ethnicity by a health professional, in work, or when gaining housing. Ethnicity was classified as Maori, Pacific, Asian or European. Health indicators included measures of: mental health (SF36 mental health scale, psychological distress, doctor diagnosed mental health condition); physical health (self-rated health, SF36 physical functioning scale, cardiovascular disease); and health risk (smoking, hazardous drinking, excess body fat). Logistic regression was used to examine changes in prevalence of reported experience of racial discrimination over time and associations with health. Reported experience of racial discrimination increased between 2002/03 (28.1% ever) and 2006/07 (35.0% ever) among Asian peoples but remained largely unchanged for other ethnic groupings (Maori 29.5%, Pacific 23.0%, European 13.5%). Experience of racial discrimination was associated with all negative health measures except excess body fat. Where there were significant associations, a dose-response relationship was also evident. We conclude that racial discrimination experienced across a range of settings has the potential to impact on a wide range of health outcomes and risk factors. While ongoing research is needed to understand the multifarious nature of racism and the pathways by which it leads to poor health, it is feasible to monitor experiences of racial discrimination in national surveys. PMID- 22204841 TI - Resilience from the point of view of older people: 'There's still life beyond a funny knee'. AB - Resilience is a concept of growing interest in relation to older people and within the context of population ageing. In this paper we explore older people's understandings and experiences of resilience, drawing on interviews and participant-led focus groups with 121 older people living in two case-study communities in Aotearoa, New Zealand. Close reading of extended conversations about what characterises resilience, such as positive attitude, counting blessings or keeping busy, reveal how all of these apparently internal or personal characteristics are deeply embedded in social and physical contexts. We argue that resilience should be seen as a contextualised process which can be both individual and environmental. Older people's experiences highlight the need to consider the effectiveness of environmental community resources and social political structures such as state-funded service availability, as well as the personal characteristics that are usually focused on when considering resilience in old age. We also argue that it is important to consider different aspects of resilience, so that a person or group might face constraints in one area, such as physical or economic wellbeing, but be strong in other areas such as social relationships or mobility. Resilience can mean acknowledging and incorporating 'vulnerability' and balancing wellbeing across a range of areas. Thus even those living with significant illness or hardship can be understood to be ageing well and indeed to be resilient. Far from using resilience as a narrow measure against which to succeed or fail, resilience is a useful concept framing how ageing well can incorporate multidimensional pathways including both vulnerability and flourishing. We must pay adequate attention to the broader physical and social contexts and scales that underpin--or undermine--individual resilience. PMID- 22204843 TI - The role of ultrasound in the diagnosis and follow-up of early inflammatory arthritis. PMID- 22204845 TI - Global and local pitch perception in children with developmental dyslexia. AB - This study investigated global versus local pitch pattern perception in children with dyslexia aged between 8 and 11 years. Children listened to two consecutive 4 tone pitch sequences while performing a same/different task. On the different trials, sequences either preserved the contour (local condition) or they violated the contour (global condition). Compared to normally developing children, dyslexics showed robust pitch perception deficits in the local but not the global condition. This finding was replicated in a simple pitch direction task, which minimizes sequencing and short term memory. Results are consistent with a left hemisphere deficit in dyslexia because local pitch changes are supposedly processed by the left hemisphere, whereas global pitch changes are processed by the right hemisphere. The present data suggest a link between impaired pitch processing and abnormal phonological development in children with dyslexia, which makes pitch pattern processing a potent tool for early diagnosis and remediation of dyslexia. PMID- 22204844 TI - Characterization of the human folate receptor alpha via novel antibody-based probes. AB - Folate receptor alpha (FRA) is a cell surface protein whose aberrant expression in malignant cells has resulted in its pursuit as a therapeutic target and marker for diagnosis of cancer. The development of immune-based reagents that can reproducibly detect FRA from patient tissue processed by varying methods has been difficult due to the complex post-translational structure of the protein whereby most reagents developed to date are highly structure-sensitive and have resulted in equivocal expression results across independent studies. The aim of the present study was to generate novel monoclonal antibodies (mAbs) using modified full length FRA protein as immunogen in order to develop a panel of mAbs to various, non-overlapping epitopes that may serve as diagnostic reagents able to robustly detect FRA-positive disease. Here we report the development of a panel of FRA-specific mAbs that are able to specifically detect FRA using an array of diagnostic platforms and methods. In addition, the methods used to develop these mAbs and their diverse binding properties provide additional information on the three dimensional structure of FRA in its native cell surface configuration. PMID- 22204846 TI - Out-of-hospital cardiac arrest and percutaneous coronary intervention for ST elevation myocardial infarction: long-term survival and neurological outcome. AB - BACKGROUND: Predictors of long-term outcome after ST-elevation myocardial infarction (STEMI) complicated by out-of-hospital cardiac arrest (OHCA) are incompletely understood, including the influence of successful coronary reperfusion. METHODS: We analysed clinical and procedural data as well as 1-year outcome of 72 consecutive patients who underwent primary coronary intervention (PCI) after witnessed OHCA and STEMI and compared the results with 695 patients with STEMI and PCI, but without OHCA. Neurological recovery after OHCA was assessed using the Cerebral Performance Category (CPC) scale. RESULTS: PCI was successful in 83.3% after OHCA vs. 84.3% in the non-OHCA group (p=0.87). One-year mortality was 34.7% vs. 9.5% (p<0.001). 58.3% of the OHCA-patients showed complete neurological recovery (CPC 1) or moderate neurological disability (CPC 2). Another 6.9% showed severe cerebral disability (CPC 3) or permanent vegetative status (CPC 4). Delay from collapse until start of Advanced Cardiopulmonary Life Support (ACLS) was shorter for survivors with CPC status <=2 (median 1 min, range 0-11 min) compared to non-survivors or survivors with CPC status >2 (median 8 min, range 0-13 min), p<0.0001. Age-adjusted multivariate analysis identified 'unsuccessful PCI', 'vasopressors on admission' and 'start of ACLS after >6 min' as independent predictors of negative long-term outcome (death or CPC >2). CONCLUSIONS: Mortality is high in patients with STEMI complicated by OHCA - even though PCI was performed with the same success rate as in patients without OHCA. The majority of survivors had favourable neurological outcomes at 1 year, especially if advanced life support had been started within <=6 min and PCI was successful. PMID- 22204847 TI - Feasibility study of the RenalGuardTM balanced hydration system: a novel strategy for the prevention of contrast-induced nephropathy in high risk patients. AB - BACKGROUND: Contrast-induced nephropathy (CIN) is a frequent complication following angiographic procedures with significant impact on healthcare costs, and long-term outcomes. Multiple reno-protective strategies have been studied but few have shown benefit in prospective randomized studies beyond limiting the exposure to iodinated contrast and adequate intravenous. We studied the performance and safety of a novel system designed to achieve precise real-time high volume fluid balance using a closed loop hydration monitoring and infusion system. METHODS: This prospective, multi-center, FDA approved phase II feasibility study was designed to evaluate the safety and the performance of the RenalGuard matched hydration system. Between October 2006 and November 2007, twenty-three subjects at high risk for CIN (with an estimated glomerular filtration rate (eGFR)<50ml/min/1.73m(2)) undergoing diagnostic or therapeutic catheterization were treated with the system. The primary endpoint of the study was defined as the ability of the system to effectively dynamically match fluid administration to urine output. RESULTS: The 23 subjects at high risk for CIN enrolled had a mean+/-SD eGFR of 39+/-9.3. Patients achieved an hourly urine flow rate of 620+/-400ml/h. The system had a mean effectiveness rate of 99.9% over the duration of therapy with an average saline volume infused of 3825ml closely matched, minute to minute, to urine output of 3579ml. There were no major device related complications from the experimental therapy, though one patient developed hypokalemia requiring replacement. Two subjects (9.5%) developed CIN as defined by >0.5mg/dl or >25% rise in serum creatinine at 48-60h post contrast administration when compared with the baseline. CONCLUSION: The study confirmed that the RenalGuard(TM) system is safe and dynamically balances volume hydration with urine production. Further randomized studies are needed to confirm the efficacy of the system in reducing the incidence of CIN. PMID- 22204848 TI - Tricuspid valve surgery improves cardiac output and exercise performance in patients with Ebstein's anomaly. AB - BACKGROUND: Clinical, hemodynamic and functional effects of tricuspid valve surgery in patients with Ebstein's anomaly are not well understood. METHODS: Sixteen patients (median age of 27.7 years) were examined before and eight months after surgery by means of echocardiography, cardiovascular magnetic resonance (CMR) and cardiopulmonary exercise testing. RESULTS: Peak work load (1.87 to 2.0W/kg; p=0.026), maximum oxygen uptake (21 to 22 ml/kg/min; p=0.034) as well as cardiac output (2.7 to 2.9l/min/m(2); p=0.035) increased postoperatively. The reduction of tricuspid regurgitation led to a higher pulmonary stroke volume (29 to 42ml/m(2), p=0.005) and augmented the left ventricular (LV) volume (55 to 63ml/min/m(2); p=0.001) with a trend to better ejection fraction (61 to 64%; p=0.083). Right ventricular (RV) volume index (124 to 108ml/m2; p=0.034) and ejection fraction (50 to 42%; p=0.036) decreased on CMR. Echocardiographic measurements of RV function also decreased (tricuspid annular plane systolic excursion 2.3 to 1.7; p=0.002; isovolumic acceleration 0.98 to 0.65; p=0.004; and 2-d longitudinal global strain -19.3 to -16.25; p=0.006). CONCLUSION: Tricuspid valve surgery improves exercise capacity in patients with Ebstein's anomaly. The reduction of tricuspid regurgitation decreases the volume of the right ventricle and increases pulmonary antegrade flow. As a result LV volume and cardiac output increase. This hemodynamic benefit occurs despite the preload dependent reduction in RV volume and ejection fraction. PMID- 22204849 TI - Super late stent thrombosis occurred at 8 years after drug-eluting stent implantation. PMID- 22204850 TI - Recurrent acute coronary syndromes are associated with increased shear induced platelet aggregation. A case-control study. PMID- 22204851 TI - LAD dissection following parachute belt trauma during BASE jumping. PMID- 22204852 TI - Diagnostic accuracy of coronary artery calcium for obstructive disease: results from the ACCURACY trial. AB - BACKGROUND: Although numerous trials have demonstrated the diagnostic accuracy of coronary artery calcium (CAC) scanning for prediction of obstructive disease, virtually all studies have been performed using Electron Beam CT (EBCT). We evaluated the diagnostic accuracy of CAC by 64-row CT to detect obstructive coronary stenosis compared to quantitative coronary angiography (QCA) in the ACCURACY multicenter trial. METHODS: 16 sites prospectively enrolled 230 patients (pts) [59.5% males, 57yrs] with chest pain referred for invasive coronary angiography (ICA). Pts underwent CAC scan and CT angiography prior to ICA. Total CAC scores were correlated with angiographically documented stenoses using common cutpoints of CAC >0, >100 and >400. Significant obstructive disease was defined as >50% luminal stenosis by QCA. RESULTS: The per-patient accuracy of CAC by 64 row CT compared to QCA demonstrates a high sensitivity and low specificity for the presence of obstructive disease (>50% stenosis on QCA). With CAC >0, >100 and >400, the sensitivities to predict stenosis were 98%, 88%, and 60%, whereas the specificities were 42%, 71%, and 88%, respectively. CONCLUSIONS: Most previous CAC studies have focused on the fact that significant calcium places patients into a higher risk group in terms of future events, and should lead to more aggressive treatment with preventative therapies. This prospective multicenter results comparing 64-row CAC to QCA demonstrate that CAC using 64-row CT scanner, similar to previously published reports using EBCT, is highly sensitive and moderately specific test to predict significant coronary artery stenosis. The presence of abnormal levels of calcium may place patients into a higher risk group in terms of future events, and lead to more aggressive treatment with preventative therapies. However, the detection of calcium does not always help with a clinical diagnosis particularly in the presence of diffuse moderate coronary atheroma. Whether this information is complementary to CTA data remains to be validated. PMID- 22204853 TI - Serum copeptin/NT-proBNP ratio: a more reliable index of absolute endogenous stress and prognosis during the course of Tako-tsubo cardiomyopathy? PMID- 22204854 TI - Multisite paradoxical embolisms in a patient with patent foramen ovale and pulmonary thromboembolism. PMID- 22204855 TI - The obesity paradox in heart failure: is etiology a key factor? AB - BACKGROUND: Obesity is paradoxically associated with survival in patients with heart failure (HF). Our objective was to assess whether the relationship between body mass index (BMI) and long-term survival is associated with HF etiology (ischemic vs. non-ischemic) in a cohort of ambulatory HF patients. METHODS: BMI and survival status after a median follow-up of 6.1 years (IQR 2.2-7.8) were available for 504 patients (73% men; median age 68 years [IQR 58-74]). Fifty-nine percent of patients had ischemic etiology. Median left ventricular ejection fraction (LVEF) was 30% (IQR 23-39.7%). Most patients were in NYHA functional class II (51%) or III (42%). Patients were divided into four groups according to BMI: low weight (BMI < 20.5 kg/m(2)), normal weight (BMI 20.5 to < 25.5 kg/m(2)), overweight (BMI 25.5 to < 30 kg/m(2)), and obese (BMI >= 30 kg/m(2)). RESULTS: Mortality differed significantly across the BMI strata in non-ischemic patients (log-rank p < 0.0001) but not in ischemic patients. Using normal weight patients as a reference, hazard ratios for low weight, overweight, and obese patients were 2.08 (1.16-3.75, p = 0.014), 0.88 (0.54-1.43, p = 0.60), and 0.49 (0.28-0.86, p = 0.01), respectively, for non-ischemic patients and 1.19 (0.48-2.97, p = 0.71), 0.88 (0.61-1.27, p = 0.48), and 0.96 (0.66-1.41, p = 0.85), respectively, for ischemic patients. After adjusting for age, sex, NYHA functional class, LVEF, co morbidities, and treatment, BMI remained an independent predictor of survival in non-ischemic patients. CONCLUSION: Over long-term follow-up of ischemic and non ischemic HF, the obesity paradox was only observed in patients with non-ischemic HF. PMID- 22204856 TI - Marked lipomatous hypertrophy of the right ventricular wall: a distinct clinicopathological entity from arrhythmogenic right ventricular cardiomyopathy? PMID- 22204857 TI - Differential metabolic effects of rosuvastatin and pravastatin in hypercholesterolemic patients. AB - BACKGROUND: Rosuvastatin and pravastatin have differential hydrophilicity and potency to inhibit hydroxymethylglutaryl-CoA reductase that may be relevant to changes in adiponectin levels, insulin resistance, and the rate of new onset diabetes in large clinical studies. Therefore, we hypothesized that rosuvastatin and pravastatin may have differential metabolic effects in hypercholesterolemic patients. METHODS: This was a randomized, single-blind, placebo-controlled, parallel study. Age, gender, and body mass index were matched. Fifty-four patients were given placebo, rosuvastatin 10mg, or pravastatin 40mg, respectively once daily for 2 months. RESULTS: When compared with pravastatin therapy, rosuvastatin therapy significantly reduced total, LDL cholesterol, and apolipoprotein B levels (P<0.05 by post-hoc comparison), but comparably improved flow-mediated dilation after 2 months. Interestingly, rosuvastatin therapy significantly increased fasting insulin (mean % changes; 28%, P=0.005). and HbA1c (1%, P=0.038) while decreasing plasma adiponectin levels (9%, P=0.010) and insulin sensitivity (assessed by QUICKI; 2%, P=0.007) when compared with baseline. By contrast, pravastatin therapy significantly decreased fasting insulin (8%, P=0.042), and HbA1c levels (1%, P=0.019) while increasing plasma adiponectin levels (36%, P=0.006) and insulin sensitivity (3%, P=0.005) when compared with baseline. Moreover, these differential effects were evident when outcomes of rosuvastatin and pravastatin therapy were directly compared (P=0.002 for insulin levels by ANOVA on Ranks, P=0.003 for adiponectin, P=0.003 for QUICKI, and P=0.010 for HbA1c by ANOVA). CONCLUSIONS: While significantly reducing lipoprotein profiles, rosuvastatin therapy had unwanted metabolic effects in hypercholesterolemic patients when compared with pravastatin therapy, that may be clinically relevant in patients prone to metabolic diseases. PMID- 22204858 TI - [Complex aortic atheroma plaques: study of 71 patients with lacunar infarcts]. AB - BACKGROUND AND OBJECTIVES: To characterize the frequency and the clinical factors of complex aortic atheroma plaques (CAA) in patients with a first-ever lacunar infarct (LI). PATIENTS AND METHODS: Sample of 71 consecutive patients with a first LI (9 of uncertain etiology) included in a stroke registry over a period of 4 years, studied by neuroimaging and suprasternal transthoracic echocardiography with harmonic imaging technology. We analyze the risk factors, clinical data and prognosis. RESULTS: Echocardiography was abnormal in 20 patients (28.2%). Seven patients (9.9%) had simple aortic plaques and 13 (18.3%) had CAA. There were 10 women and 3 men of 79 (range 57-91) years of median age. Pure motor hemiparesis was the most common syndrome present in 5 cases (39%). Hypertension (69%), previous transient ischemic attack (39%) and diabetes (31%) were the main risk factors. Only 3 patients with CAA (4.2% of the total and 33% of LI of uncertain etiology) had no risk factors. Silent infarcts were present in 7 cases (53.8%) (6 LI and one non-LI). No patient died during hospitalization. CONCLUSIONS: The presence of complex aortic atheroma plaques was observed in 18.3% of first-LI patients, with a predominance of females. High risk criteria of aortic embolism was present in 4.2% of LI. CAA should be ruled out in essential LI patients. PMID- 22204859 TI - [The quality and safety in internal medicine. More than words]. PMID- 22204860 TI - The rate of primary hypothyroidism in diabetic patients is greater than in the non-diabetic population. An observational study. AB - BACKGROUND AND OBJECTIVE: The aim of our study was to identify the rate of diabetic patients treated for hypothyroidism and compare them with a group without type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: We reviewed the computerized clinical records of 5161 patients. We identified diabetic patients treated with l-thyroxine. We compared the prevalence of PH with those patients under treatment with levothyroxine without T2DM. We excluded patients with a thyroid neoplasia, thyroid surgery, panhypopituitarism, or surgical complications of multinodular goiter or a thyroid nodule. Subclinical hypothyroidism was not considered. RESULTS: We included 1848 adult patients with T2DM in the study group, 58% women and 42% men. For the control group, we included 3313 non diabetic patients, 55% women and 45% men. The mean age in the study group was 52+/-7 years, and 47+/-4 years in the control group (p<.001). The rate of hypothyroidism in the study group was 5.7%, and in the control group 1.8% (odds ratio of 3.45; 95% confidence interval 2.51-4.79) (p<.001). CONCLUSION: A strong association between T2DM and hypothyroidism was found. We recommend a thyroid profile in all patients with T2DM, similar to the recommendation in type 1 diabetes mellitus. PMID- 22204861 TI - [Should we use tools for the assessment of the risk of diabetes mellitus in Spain?]. PMID- 22204863 TI - HMGB1 signals danger in acute coronary syndrome: emergence of a new risk marker for cardiovascular death? PMID- 22204862 TI - Apolipoprotein M binds oxidized phospholipids and increases the antioxidant effect of HDL. AB - OBJECTIVE: Oxidation of LDL plays a key role in the development of atherosclerosis. HDL may, in part, protect against atherosclerosis by inhibiting LDL oxidation. Overexpression of HDL-associated apolipoprotein M (apoM) protects mice against atherosclerosis through a not yet clarified mechanism. Being a lipocalin, apoM contains a binding pocket for small lipophilic molecules. Here, we report that apoM likely serves as an antioxidant in HDL by binding oxidized phospholipids, thus enhancing the antioxidant potential of HDL. METHODS AND RESULTS: HDL was isolated from wild type mice, apoM-deficient mice, and two lines of apoM-Tg mice with ~2-fold and ~10-fold increased plasma apoM, respectively. Increasing amounts of HDL-associated apoM were associated with an increase in the resistance of HDL to oxidation with Cu(2+) or 2,2'-azobis 2-methyl propanimidamide, dihydrochloride (AAPH) and to an increased ability of HDL to protect human LDL against oxidation. Oxidized phospholipids, but not native phospholipids, quenched the intrinsic fluorescence of recombinant human apoM and the quenching could be competed with myristic acid suggesting selective binding of oxidized phospholipid in the lipocalin-binding pocket of apoM. CONCLUSIONS: The results suggest that apoM can bind oxidized phospholipids and that it increases the antioxidant effect of HDL. This new mechanism may explain at least part of the antiatherogenic potential of apoM. PMID- 22204864 TI - S-Adenosylhomocysteine induces apoptosis and phosphatidylserine exposure in endothelial cells independent of homocysteine. AB - OBJECTIVE: We have previously shown that homocysteine (Hcy) induces phosphatidylserine (PS) exposure, apoptosis and necrosis in human endothelial cells. Since it has been suggested that S-adenosylhomocysteine (SAH) is the main causative factor in Hcy-induced pathogenesis of cardiovascular disease, we evaluate here whether the cytotoxic Hcy effect in endothelial cells is also SAH dependent. METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVECs) were exposed to the following conditions: (1) non-treated control (resulting in 2.8 nM intracellular SAH and 3.1 MUM extracellular l-Hcy); and incubation with (2) 50 MUM adenosine-2,3-dialdehyde (ADA; resulting in 17.7 nM intracellular SAH and 3.1 MUM extracellular l-Hcy), (3) 2.5 mM Hcy (resulting in 20.9 nM intracellular SAH and 1.8 mM extracellular l-Hcy), and (4) 1, 10 and 100 MUM SAH. We then determined the effect of treatment on annexin V-positivity, caspase-3 activity, cytochrome c release (sub)cellular expression of NOX2, NOX4, p47(phox) and nitrotyrosine, and H(2)O(2). Both Hcy and ADA significantly increased PS exposure (n=5), caspase-3 activity (n=6) and cytochrome c release (n=3). Incubation with extracellular SAH alone did not affect cell viability. Both Hcy and ADA also induced similar increases in nuclear NOX2 and (peri)nuclear NOX4, coinciding with (peri)nuclear p47(phox) expression and local reactive oxygen species (ROS) (n=3). Inhibition of NOX-mediated ROS by the flavoenzyme inhibitor diphenylene iodonium (DPI) significantly decreased apoptosis induction (n=3) and ROS production (n=3). CONCLUSION: SAH induces PS exposure and apoptosis in endothelial cells independently of Hcy. Our study therefore shows that Hcy mediated endothelial dysfunction, as determined in the cell model used, is mainly due to SAH accumulation. PMID- 22204865 TI - Inverse relationship between body mass index and coronary artery calcification in patients with clinically significant coronary lesions. AB - AIMS: Mounting data support a 'calcification paradox', whereby reduced bone mineral density is associated with increased vascular calcification. Furthermore, reduced bone mineral density is prevalent in older persons with lower body mass index (BMI). Therefore, although BMI and coronary artery calcification (CAC) exhibit a positive relationship in younger persons, it is predicted that in older persons and/or those at risk for osteoporosis, an inverse relationship between BMI and CAC may apply. We sought to explore this hypothesis in a large group of patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: We accessed our single-center registry for 07/01/1999 to 06/30/2009, extracting data on all patients that underwent PCI. To minimize bias we excluded those at the extremes of age or BMI and non Black/Hispanic/Caucasians, leaving 9993 study subjects (age 66.6+/-9.9 years). Index lesion calcification (ILC) was analyzed with respect to BMI. Comparing index lesions with no angiographic calcification to those with the most severe, mean BMI decreased by 1.11 kgm(-2); a reduction of 3.9% (P<0.0001). By multivariable modeling, BMI was an independent inverse predictor of moderate severe ILC (m-sILC; odds ratio [OR] 0.967, 95% CI 0.953-0.980, P<0.0001). Additional fully adjusted models identified that, compared to those with normal BMI, obese patients had an OR of 0.702 for m-sILC (95% CI 0.596-0.827, P<0.0001). CONCLUSIONS: In a large group of PCI patients, we identified an inverse correlation between BMI and index lesion calcification. These associations are consistent with established paradigms and suggest a complex interrelationship between BMI, body size and vascular calcification. PMID- 22204867 TI - ETHOWATCHER: validation of a tool for behavioral and video-tracking analysis in laboratory animals. AB - We present a software (ETHOWATCHER((r))) developed to support ethography, object tracking and extraction of kinematic variables from digital video files of laboratory animals. The tracking module allows controlled segmentation of the target from the background, extracting image attributes used to calculate the distance traveled, orientation, length, area and a path graph of the experimental animal. The ethography module allows recording of catalog-based behaviors from environment or from video files continuously or frame-by-frame. The output reports duration, frequency and latency of each behavior and the sequence of events in a time-segmented format, set by the user. Validation tests were conducted on kinematic measurements and on the detection of known behavioral effects of drugs. This software is freely available at www.ethowatcher.ufsc.br. PMID- 22204866 TI - The down regulation of neutrophil oxidative metabolism by S100A8 and S100A9: implication of the protease-activated receptor-2. AB - S100A8 and S100A9 regulate polymorphonuclear neutrophils (PMNs) recruitment and represent 40% of PMN cytosolic protein weight. We have shown that S100A8/S100A9 inhibit PMN oxidative metabolism. The present study was designed to elucidate the mechanisms of this anti-oxidative effect. We hypothesized that the protease activated receptor-2 (PAR-2) played a role in the down-regulation of PMN oxidative metabolism by S100A8/S100A9. Freshly isolated PMNs were tested for their ability to oxidize dichlorofluorescin-diacetate. Functional inhibition of PAR-2 with ENMD-1068, the pepducin P2pal-21 or an antibody directed at PAR-2 cleavage/activation site, resulted in a significant inhibition of S100A8 and S100A9 anti-oxidative effect. Conversely, the controlled activation of PAR-2 potentiated S100 anti-oxidative effect. Taken together, the data indicate that the anti-oxidative effect of S100A8/A9 is initiated by PAR-2 activation. S100A8/S100A9 may therefore dampen inflammation without interfering with its initial strength. This finding opens translational possibilities to limit deleterious PMN activation with a dual PAR-2/S100 strategy. PMID- 22204868 TI - Complex activity patterns in arterial wall: results from a model of calcium dynamics. AB - Using a dynamical model of smooth muscle cells in an arterial wall, defined as a system of coupled five-dimensional nonlinear oscillators, on a grid with cylindrical symmetry, we compare the admissible activity patterns with those known from the heart tissue. We postulate on numerical basis the possibility to induce a stable spiral wave in the arterial wall. Such a spiral wave can inhibit the propagation of the axial calcium wave and effectively stop the vasomotion. We also discuss the dynamics of the circumferential calcium wave in comparison to rotors in venous ostia that are a common source of supraventricular ectopy. We show that the velocity and in consequence the frequency range of the circumferential calcium wave is by orders of magnitude too small compared to that of the rotors. The mechanism of the rotor is not likely to involve the calcium related dynamics of the smooth muscle cells. The calcium-related dynamics which is voltage-independent and hard to be reset seems to actually protect the blood vessels against the electric activity of the atria. We also discuss the microreentry phenomenon, which was found in numerical experiments in the studied model. PMID- 22204869 TI - Benefits of peer support in online Japanese breast cancer communities: differences between lurkers and posters. AB - BACKGROUND: Web 2.0 has improved interactions among peers on the Internet, especially for the many online patient communities that have emerged over the past decades. Online communities are said to be particularly beneficial peer support resources for patients with breast cancer. However, most studies of online patient communities have focused on those members who post actively (posters), even though there are many members who participate without posting (lurkers). In addition, little attention has been paid to the usage of online communities among non-English-speaking patients. OBJECTIVE: The present study explored the differences in peer support received by lurkers and posters in online breast cancer communities. It also examined the effects of such support on both groups' mental health. METHODS: We conducted an exploratory, descriptive, cross-sectional, Web-based survey among members of four Japanese online breast cancer communities. In an online questionnaire, we asked questions regarding sociodemographics, disease-related characteristics, mental health, participation in online communities, and peer support received from those communities. RESULTS: Of the 465 people who accessed the questionnaire, 253 completed it. Of the respondents, 113/220 (51.4%) were lurkers. There was no significant difference between lurkers and posters with regard to sociodemographic variables. About half of the posters had been given a diagnosis of breast cancer less than a year previously, which was a significantly shorter period than that of the lurkers (P = .02). The 5 support functions extracted by factor analysis were the same for both posters and lurkers. These were emotional support/helper therapy, emotional expression, conflict, advice, and insight/universality. When the support scores were calculated, insight/universality scored highest for both posters and lurkers, with scores that were not significantly different between the two groups. Among the 5 support scores, emotional support/helper therapy and emotional expression were significantly higher among posters. For posters, emotional support/helper therapy and advice were negatively correlated with the anxiety subscale of the Hospital Anxiety and Depression Scale. Emotional expression, advice, and insight/universality were negatively correlated with the anxiety subscale for lurkers. CONCLUSION: We found that posters felt they received more benefits from online communities than lurkers did, including emotional support, helping other patients, and expressing their emotions. Yet even lurkers were found to gain a certain amount of peer support through online communities, especially with regard to advice and insight/universality. The results demonstrate that participation in online communities--even as a lurker- may be beneficial to breast cancer patients' mental health. PMID- 22204870 TI - [Transvestibular urethrolysis]. AB - OBJECTIVE: Bladder outlet obstruction with obstructive and irritative urinary symptoms may be a complication of surgery for female urinary incontinence. In presence of persistent symptoms, the therapy is surgical and usually consists in an accurate urethrolysis. The way of approach is generally transvaginal. In this paper we propose and describe our experience with a transvestibular approach. MATERIAL AND METHODS: 18 women who had undergone anti-incontinence surgery (TVT 12 pts, TOT 3 pts, Burch retropubic colposuspension 3 pts) with obstruction and/or irritative symptoms underwent to a transvestibular urethrolysys. Five patients had urinary retention and the rest of patients had post voiding residual urine>100 ml. Using a scalpel blade a circum-meatal incision was performed and the urethra was progressively freed, dissecting just below the os pubis upwards and on the vaginal wall downwards, untethering it under direct vision in order to abtain a complete circular freeing of the urethra. In the end, the urethral meatus is repositioned with circular stiches. RESULTS: The operation lasts between 20 and 40 minutes. An urethral catheter was left in place for 24-48 hours and no complications were observed. The post-voiding residual urine decreased in all of the cases and the irritative symptoms were reduced. CONCLUSIONS: The transvestibular approach for urethrolysis is safe and effective regardless of the previous anti-incontinence surgery carried out. This procedure has the advantage of working in a relatively unscarred tissue, allows for a complete untethering of the urethra even in the retropubic space and leaves the vaginal wall intact. PMID- 22204871 TI - Implementation of a cost-effective HPLC/UV-approach for medical routine quantification of donepezil in human serum. AB - A novel, simple, specific and sensitive high performance liquid chromatography (HPLC) assay for the detection and quantification of donepezil in serum of demented patients has been developed and validated. The analytical procedure involves an offline serum preextraction using solid phase extraction (SPE) cartridges (Oasis(r) HLB, Waters Co). The chromatographic analyses were performed on a Dionex HPLC system with a Phenomenex Luna Phenyl-Hexyl analytical column, and a mobile phase with the two components 0.02 mol/l phosphate buffer and acetonitrile. The flow rate was 0.4 ml/min. For the detection of donepezil three different UV wavelengths were used as an interference-control check. Interference tests between donepezil and 100 of the most commonly used concomitant medications allow quantification of donepezil under the polypharmaceutical conditions of the daily clinical routine. The retention time for donepezil was 12.1 min. The method was validated according to the guidelines of the Society of Toxicology and Forensic Chemistry (GTFCh): The calibration curve was linear over a concentration range from 5 to 160 ng/ml (n=8/r2>0.999). No endogenous compounds were found to interfere with the analyte, which was shown by retention times for the comedication most often prescribed to demented patients. The method had an accuracy of >85%. Intra- and inter-assay coefficients of variation were <6% and <8%, respectively, at three different concentrations. The limit of quantification (LOQ) and the limit of detection (LOD) were found to be 6.1 and 1.7 ng/ml for donepezil. Application of the method to patient serum samples discovered that concentrations suggested as "therapeutic" in the literature may only be reached either by high, off-label dosages or by utilization of inhibitory metabolic effects of the comedication. PMID- 22204872 TI - Determination of Carbadox and metabolites of Carbadox and Olaquindox in muscle tissue using high performance liquid chromatography-tandem mass spectrometry. AB - A sensitive and robust LC-APCI-MS/MS method has been developed for the unambiguous detection and quantitative determination of the antimicrobial agent Carbadox, its metabolite quinoxaline-2-carboxylic acid and methyl-3-quinoxaline-2 carboxylic acid the major metabolite of Olaquindox. The method was aimed for application in the assaying of muscle tissue so the developed sample preparation scheme subjected samples to enzymatic digestion prior to the application of solid phase extraction clean-up. Subsequently the purified extracts were analyzed by reversed-phase LC-MS/MS in positive APCI and multiple reaction monitoring mode. The method was validated at a level of 1 MUg/kg. The decision limits CCalpha and detection capability CCbeta ranged from 0.09 MUg/kg to 0.24 MUg/kg and from 0.12 MUg/kg to 0.41 MUg/kg, respectively. The accuracy and precision of the method were satisfactory. The recoveries ranged from 92% to 101% for the metabolites and from 60% to 62% for Carbadox, with coefficient of variances (CVs) less than 12%. The developed method proved efficient and straightforward allowing positive identification and quantitation of the target banned analytes and is thus suitable for application in residue control programmes and metabolism studies. PMID- 22204873 TI - Multiclass analysis of 23 veterinary drugs in milk by ultraperformance liquid chromatography-electrospray tandem mass spectrometry. AB - An ultraperformance liquid chromatography-electrospray tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous detection and confirmation of 23 veterinary (multiclass) drugs in milk was developed and validated. The analytes were extracted by acetonitrile, evaporated and injected into the UPLC-MS/MS system on a Waters UPLC HSS T3 column in gradient mode. Data acquisition under MS/MS was achieved by applying multiple reaction monitoring (MRM) of two ion transitions per compound to provide a high degree of specificity. Results showed good repeatability, and recoveries for the 12 macrolide, 7 beta-lactam and 2 lincosamide antibiotics and 2 other veterinary drugs (morantel, orbifloxacin) used in milk averaged 51.8-139.0%, 51.5-100.6%, 82.4-102.5% and 87.5-99.4%, respectively. The coefficients of variation (C.V.) of the recoveries were less than 15% for intraday and interday precisions. The limits of quantification (LOQs) were all lower than 5 ng/ml. This method was applied to 17 fresh milk samples and only lincomycin was found in milk samples under allowable levels. Overall, this method is a suitable and rapid tool to confirm the presence of 23 veterinary drug residues in milk. PMID- 22204874 TI - Determination of methylphenidate and its metabolite ritalinic acid in urine by liquid chromatography/tandem mass spectrometry. AB - Methylphenidate (MPH) is a drug that is licensed for treatment of ADHD and also narcolepsy. Monitoring of the parent drug and its major metabolite ritalinic acid (RA) in urine is considered necessary to ensure compliance with treatment programmes. A rapid, simple and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay was developed for the determination of MPH and its metabolite RA in human urine. After urine was diluted with water, methylphenidate, the major metabolite ritalinic acid, and d6-amphetamine as the internal standard were resolved on a PFP propyl column using gradient elution of 0.02% ammonium formate and acetonitrile. The total analysis time was 13.5 min. The three compounds were detected using electrospray ionisation in the positive mode. Standard curves were linear over the concentration range 5-5000 MUg/L (r>0.997), bias was <= +/-20%, intra- and inter-day coefficients of variation (imprecision) were <8% and the limit of detection was 5 MUg/L. The limit of quantitation was set at 100 MUg/L. Matrix effects were up to 140% but these were accounted for by the internal standard. The assay is being used successfully in clinical practice to enhance the safe and effective use of methylphenidate. PMID- 22204875 TI - Determination of Bis(9)-(-)-Meptazinol, a bis-ligand for Alzheimer's disease, in rat plasma by liquid chromatography-tandem mass spectrometry: application to pharmacokinetics study. AB - A rapid, simple and sensitive LC-MS/MS method was developed and validated for the determination of Bis(9)-(-)-Meptazinol (B9M) in rat plasma. Protein precipitation method was used for sample preparation, using five volumes of methanol as the precipitation agent. The analytes were separated by a Zorbax Extend-C18 column with the mobile phase of methanol-water (containing 5mM ammonium formate, pH 9.8) (95:5, v/v), and monitored by positive electrospray ionization in multiple reaction monitoring (MRM) mode. Retention time of IS (Bis(5)-(-)-Meptazinol) and B9M were 1.9 min and 3.3 min, respectively. The limit of detection was 0.1 ng/ml and the linear range was 1-500 ng/ml. The relative standard deviation (RSD) of intra-day and inter-day variation was 4.4-6.2% and 6.2-8.9%, respectively. The extraction recoveries of B9M in plasma were over 95%. The method proved to be applicable to the pharmacokinetic study of B9M in rat after intravenous and subcutaneous administration. PMID- 22204876 TI - Can clouds dance? Neural correlates of passive conceptual expansion using a metaphor processing task: Implications for creative cognition. AB - Creativity has emerged in the focus of neurocognitive research in the past decade. However, a heterogeneous pattern of brain areas has been implicated as underpinning the neural correlates of creativity. One explanation for these divergent findings lies in the fact that creativity is not usually investigated in terms of its many underlying cognitive processes. The present fMRI study focuses on the neural correlates of conceptual expansion, a central component of all creative processes. The study aims to avoid pitfalls of previous fMRI studies on creativity by employing a novel paradigm. Participants were presented with phrases and made judgments regarding both the unusualness and the appropriateness of the stimuli, corresponding to the two defining criteria of creativity. According to their respective evaluation, three subject-determined experimental conditions were obtained. Phrases judged as both unusual and appropriate were classified as indicating conceptual expansion in participants. The findings reveal the involvement of frontal and temporal regions when engaging in passive conceptual expansion as opposed to the information processing of mere unusualness (novelty) or appropriateness (relevance). Taking this new experimental approach to uncover specific processes involved in creative cognition revealed that frontal and temporal regions known to be involved in semantic cognition and relational reasoning play a role in passive conceptual expansion. Adopting a different vantage point on the investigation of creativity would allow for critical advances in future research on this topic. PMID- 22204877 TI - Sensitivity to lateral information on a perceptual word identification task in French third and fifth graders. AB - This study aimed at examining sensitivity to lateral linguistic and nonlinguistic information in third and fifth grade readers. A word identification task with a threshold was used, and targets were displayed foveally with or without distractors. Sensitivity to lateral information was inferred from the deterioration of the rate of correct word identification when displayed with distractors. Results show that the two reader groups were sensitive to both right and left lateral information. The area of sensitivity to this information was more extended for the identification of easy words than difficult words. Examination of the detrimental effect of distractors suggests that in both third and fifth graders, the impact of lateral information on foveal processing is the result of a general distraction effect, but also of linguistic processing whose nature remains to be clarified. PMID- 22204878 TI - "Mirror, mirror, on the wall, who in this land is fairest of all?"- Distributional sensitivity in the measurement of socioeconomic inequality of health. AB - This paper explores four alternative indices for measuring health inequalities in a way that takes into account attitudes towards inequality. First, we revisit the extended concentration index which has been proposed to make it possible to introduce changes into the distributional value judgements implicit in the standard concentration index. Next, we suggest an alternative index based on a different weighting scheme. In contrast to the extended concentration index, this new index has the 'symmetry' property. We also show how these indices can be generalized so that they satisfy the 'mirror' property, which may be seen as a desirable property when dealing with bounded variables. We compare the different indices empirically for under-five mortality rates and the number of antenatal visits in developing countries. PMID- 22204879 TI - Viscoelastic properties of model segments of collagen molecules. AB - Collagen is the prime construction material in vertebrate biology, determining the mechanical behavior of connective tissues such as tendon, bone and skin. Despite extensive efforts in the investigation of the origin of collagen unique mechanical properties, a deep understanding of the relationship between molecular structure and mechanical properties remains elusive, hindered by the complex hierarchical structure of collagen-based tissues. In particular, although extensive studies of viscoelastic properties have been pursued at the macroscopic (fiber/tissue) level, fewer investigations have been performed at the smaller scales, including in particular collagen molecules and fibrils. These scales are, however, important for a complete understanding of the role of collagen as an important constituent in the extracellular matrix. Here, using an atomistic modeling approach, we perform in silico creep tests of a collagen-like peptide, monitoring the strain-time response for different values of applied external load. The results show that individual collagen molecules exhibit a nonlinear viscoelastic behavior, with a Young's modulus increasing from 6 to 16GPa (for strains up to 20%), a viscosity of 3.84.+/-0.38Pa.s, and a relaxation time in the range of 0.24-0.64ns. The single molecule viscosity, for the first time reported here, is several orders of magnitude lower than the viscosity found for larger scale single collagen fibrils, suggesting that the viscous behavior of collagen fibrils and fibers involves additional mechanisms, such as molecular sliding between collagen molecules within the fibril or the effect of relaxation of larger volumes of solvent. Based on our molecular modeling results we propose a simple structural model that describes collagen tissue as a hierarchical structure, providing a bottom-up description of elastic and viscous properties form the properties of the tissue basic building blocks. PMID- 22204880 TI - Heme oxygenases from Arabidopsis thaliana reveal different mechanisms of carbon monoxide binding. AB - Heme oxygenases (HO) are widely distributed enzymes involved in the degradation of heme to biliverdin, carbon monoxide and Fe(2+). The model plant Arabidopsis thaliana possesses three functional HOs (HY1, HO3 and HO4) which are thus far biochemically indistinguishable. Here, we investigate binding of the reaction product and putative inhibitor CO to these three HOs with various spectroscopic techniques: Nanosecond time-resolved absorption, millisecond time-resolved multi wavelength absorption and Fourier-transform-infrared difference spectroscopy. Kinetics of CO rebinding were found to differ substantially among the HOs. At low CO concentrations a novel intermediate was identified for HO3 and HO4, substantially slowing down rebinding. All HOs show relatively slow geminate rebinding of CO indicating the existence of an additional transient binding niche for CO. The positions found for the IR absorptions of nu(CO) and nu(FeC) suggest a nonpolar distal binding site for all three HOs. The frequency of the nu(FeC) vibration was calculated by a combination band on which we report here for the first time. Another band in the FTIR difference spectrum could be assigned to a histidine residue, probably the proximal ligand of the heme-iron. The observed different rebinding kinetics among the HOs could indicate adaptation of the HOs to different environments. PMID- 22204881 TI - Synthesis, photoluminescent behaviors, and theoretical studies of two novel ketocoumarin derivatives. AB - Two new coumarin derivatives, 3-[3-(4-formylphenyl)prop-2-enoyl]-coumarin (FEC) and 4-hydroxy-3-[3-(4-formylphenyl)prop-2-enoyl]-coumarin (HFEC), were synthesized and characterized by MS, (1)H NMR, FT-IR, and TG. The UV-vis absorption and photoluminescence (PL) of FEC and HFEC were also studied. Results show that the two compounds exhibit high fluorescence quantum yields, large Stokes shifts, and strong blue emissions. The molecular structures, the lowest energy transitions, the resonance frequencies, and the UV-vis spectra of FEC and HFEC were calculated using the density functional theory (DFT) and time-dependent density functional theory (TD-DFT) at the B3LYP/6-31G(d) level. PMID- 22204882 TI - Study of the surface-enhanced Raman spectroscopy of residual impurities in hydroxylamine-reduced silver colloid and the effects of anions on the colloid activity. AB - The paper investigated the residual ions in hydroxylamine-reduced silver colloid (HRSC) and the relationship between the condition of HRSC and the enhanced mechanisms of this colloid. We also detected the SERS of MB and studied the effects of anions on the Raman signal. In the case of HRSC, the bands of residual ions diminish while the bands of Ag-anions increase gradually with increasing the concentrations of Cl(-) and NO(3)(-). It means the affinity of residual ions on the silver surface is weaker than that of Cl(-) and NO(3)(-) and the residual ions are replaced gradually by the added Cl(-) or NO(3)(-). The Raman signal of residual ions can be detected by treatment with anions that do not bind strongly to the silver surface, such as SO(4)(2-). The most intense band of Ag-anions bonds can be also observed when adding weakly binding anions to the colloid. However, the anions which make up the Ag-anions bonds are residual Cl(-) and the effect of weakly binding anions is only to aggregate the silver particles. Residual Cl(-) can be replaced by I(-) which has the highest affinity. From the detection of methylene blue (MB), the effects of anions on the enhancement of Raman signal are discussed in detail, and these findings could make the conditions suitable for detecting analytes in high efficiency. This study will have a profound implication to SERS users about their interpretation of SERS spectra when obtaining these anomalous bands. PMID- 22204883 TI - Absorption spectra of alpha,omega-diphenylhexadecaoctaene and shorter diphenylpolyenes. AB - Absorption spectrum of alpha,omega-diphenylhexadecaoctaene has been measured along with those of alpha,omega-diphenylpolyenes with one to seven double bonds in the polyene chain in carbon tetrachloride at room temperature. Extrapolation of the observed vibrational frequencies in the 1(1)Bu state measured as a function of polyene double bond number provides the CC and CC stretching frequencies of 1520+/-20 and 1080+/-20 cm(-1), respectively, for diphenylpolyenes with infinite polyene chain length. PMID- 22204884 TI - Theoretical study of the alkoxyls groups effect on PPV-ether excited states, a relationship with femtosecond decay. AB - Based on Density Functional Theory (DFT), the effect of alkoxyl substituents groups on the excited states of new PPV derivative (PPV-ether) are studied. Thus differences on the relaxation energy, the atomic charge distribution and the conjugation length at their excited state are interpreted on the pathways of the nature on the emissive species. Photoluminescence and optical spectra of the corresponding modeling structures are carried out. Furthermore, the life time at the excited state are emphasized either theoretically from oscillator strength or experimentally from time resolved photoluminescence. PMID- 22204885 TI - How do emergency department patients store and dispose of opioids after discharge? A pilot study. AB - INTRODUCTION: Opioid abuse and overdose have increased drastically in recent years. Diversion of opioids used to treat pain, either through theft or sharing, is increasing and may contribute to this misuse. Based on these trends, we designed a study to investigate opioid storage and disposal practices of patients who were prescribed these agents in the emergency department. METHODS: A prospective cohort pilot study was conducted. All adults (aged >=18 years) with a chief complaint of either minor musculoskeletal trauma, renal colic, or acute back pain who were discharged home with an opioid prescription were eligible for inclusion; persons with chronic pain were excluded. Patients were asked to participate in two home interviews in which the research assistant viewed the storage location of the opioid prescription. Safe storage was defined as being stored in a locked container or cabinet. Safe disposal was defined as returning the drugs to a designated location or mixing unused pills with an undesirable substance, placing in a sealable container, and then in the trash. Patients self reported disposal methods. Feasibility of study methods evaluated the ability to conduct home interviews after the ED visit. Descriptive statistics were used to analyze the data. RESULTS: Twenty-five subjects consented to participate; 20 patients completed both home interviews. None of the medications were safely stored. Only 1 patient disposed of the medication, yet did so improperly. CONCLUSION: This pilot study revealed widespread improper storage and disposal of opioids. The study has major implications for education for ED physicians, nurses, and residents. PMID- 22204886 TI - Effect of weather on medical patient volume at Kansas Speedway mass gatherings. AB - INTRODUCTION: Provision for the safety and health care of persons attending mass gathering events presents unique challenges to organizers. This study was designed to determine the factors that contribute to patients seeking medical care during these events. METHODS: We performed a retrospective review of patient care records for visits that occurred during race weekends at the Kansas Speedway from April 2007 to October 2010. Data were collected regarding the overall gathering size of each event to calculate the number of patient encounters per 10,000 attendees. Patients' final disposition was determined to calculate the transfer-to-hospital rate per 10,000 attendees. Weather data, including temperature, humidity, and precipitation, were documented for each event. Negative binomial regression was used to test the relationship between weather factors and the rate of patient encounters. RESULTS: Twenty-two event days over 6 race weekends were evaluated, with a total of 1305 patients (58% male; mean age: 37 years), a mean patient encounter rate of 13 per 10,000 attendees, and a mean transfer-to-hospital rate of 0.24 per 10,000 attendees. Our regression model demonstrated that each 0.55 degrees C (1 degrees F) increase in daily mean temperature was associated with a 4% increase in the rate of total complaints (P = .03) and a 6% increase in major trauma presentations (P = .019). Major trauma events were 2.4 times more frequent at ambient temperatures >17.2 degrees C (63 degrees F) (P = .03). Each inch of precipitation was associated with a 61% decrease in total patient volume (P = .05). CONCLUSION: Weather factors significantly and predictably affect the use of medical services at the Kansas Speedway. Such data regarding mass-gathering events can be used for resource planning. PMID- 22204887 TI - Bioleaching of zinc and manganese from spent Zn-Mn batteries and mechanism exploration. AB - In this work, bioleaching was used to extract valuable Zn and Mn from spent Zn-Mn batteries. The results showed that 96% of Zn extraction was achieved within 24h regardless of energy source types and bioleaching bacteria species. However, initial pH had a remarkable influence on Zn release, extraction dose sharply decreased from 2200 to 500mg/l when the initial pH value increased from 1.5 to 3.0 or higher. In contrast to Zn, all the tested factors evidently affected Mn extraction; the maximum released dose of 3020mg/l was obtained under the optimum conditions. The acidic dissolution by biogenic H(2)SO(4) by the non-contact mechanism was responsible for Zn extraction, while Mn extraction was owed to both contact/biological and non-contact mechanisms. The combined action of acidic dissolution of soluble Mn(2+) by biogenic H(2)SO(4) and reductive dissolution of insoluble Mn(4+) by Fe(2+) resulted in 60% of Mn extraction, while contact of microbial cells with the spent battery material and incubation for more than 7days was required to achieve the maximum extraction of Mn. PMID- 22204888 TI - Palm oil fruit shells as biosorbent for copper removal from water and wastewater: experiments and sorption models. AB - Palm oil fruit shells were evaluated as a new bioadsorbent to eliminate toxic copper from water and wastewater. Without any chemical treatment, palm oil fruit shells were washed, dried and grounded into powder (<75 MUm) for use in the experiments. Characterization showed mesopore based bioadsorbent was prepared from palm oil fruit shells. The results indicate that the highest Cu removal efficiency was found in an aqueous solution with pH of 6.5. The equilibrium sorption capacity of copper was significantly high (between 28 and 60 mg/g) at room temperature. Nonlinear regression analyses for isotherm models revealed that three-parameter isotherms had a better fit to the experimental data (R(2)>0.994) than that of two-parameter isotherms. The copper sorption system was heterogeneous as the values of exponents were lying between 0 and 1. The highly correlated pseudo-second-order kinetics model (R(2)>0.998) ascertained the applicability of copper removal by palm oil fruit shells. PMID- 22204889 TI - Microbial treatment of the monosodium glutamate wastewater by Lipomyces starkeyi to produce microbial lipid. AB - The monosodium glutamate (MSG) wastewater as a medium was treated by Lipomyces starkeyi to produce microbial lipid in the study. The effect of related factors (initial glucose concentration, inoculation concentration, initial culture pH, and cultivation time) on biomass, lipid production and lipid content was discussed, respectively. According to the experiments, the optimal fermentation conditions were determined: addition of 80g/L glucose, 10% inoculation concentration, initial pH about 5.0, incubation time 96h. Under this condition, the biomass production reached up to 4.61g/L, lipid production and lipid content was 1.14g/L and 24.73%, respectively. Simultaneously, protein and COD removal rate was 78.60% and 74.96%, respectively. The main composition of fatty acid in the resultant lipid was analyzed by gas chromatography-mass spectrometry, which showed: oleic acid (C18:1) 35.85%, palmitic acid (C16:0) 19.91%, palmitoleic acid (C16:1) 17.65%, and myristic acid (C14:0) 16.03%. PMID- 22204890 TI - [Mid-ventilation position planning: optimal model for dose distribution in lung tumour]. AB - PURPOSE: The dose distribution for lung tumour is estimated using a 3D-CT scan, and since a person breathes while the images are captured, the dose distribution doesn't reflect the reality. A 4D-CT scan integrates the motion of the tumour during breathing and, therefore, provides us with important information regarding tumour's motion in all directions, the motion volume (ITV) and the time-weighted average position (MVP). PATIENT AND METHODS: Based on these two concepts, we have estimated, for a lung carcinoma case a 3D dose distribution from a 3D-CT scan, and a 4D dose distribution from a 4-D CT scan. To this, we have applied a non rigid registration to estimate the cumulative dose. RESULTS: Our study shows that the 4D dose estimation of the GTV is almost the same when made using MVP and ITV concepts, but sparring of the healthy lung is better done using the MPV model (MVP), as compared to the ITV model. This improvement of the therapeutic index allows, from a projection on the theoretical maximal dose to PTV (strictly restricted to doses for the lungs and the spinal cord), for an increase of about 11% on the total dose (maximal dose of 86 Gy for the ITV and 96 Gy for the MVP). CONCLUSION: Further studies with more patients are needed to confirm our data. PMID- 22204891 TI - Sequence differences in the diagnostic region of the cysteine protease 8 gene of Tritrichomonas foetus parasites of cats and cattle. AB - In order to investigate the genetic variation between Tritrichomonas foetus from bovine and feline origins, cysteine protease 8 (CP8) coding sequence was selected as the polymorphic DNA marker. Direct sequencing of CP8 coding sequence of T. foetus from four feline isolates and two bovine isolates with polymerase chain reaction successfully revealed conserved nucleotide polymorphisms between feline and bovine isolates. These results provide useful information for CP8-based molecular differentiation of T. foetus genotypes. PMID- 22204892 TI - Spatial patterning of vulture scavenged human remains. AB - This article presents the results of a pilot study on the effects of vulture modification to human remains. A donated body from the Willed Body Donation Program was placed at the Forensic Anthropology Research Facility (FARF), an outdoor human decomposition laboratory located at Texas State University-San Marcos. The effects of vulture scavenging on the timing and sequence, and the rate of skeletonization, disarticulation, and dispersal were observed via a motion sensing camera and direct observation. Using GIS (Geographic Information Systems) and GPS (Global Positioning System) technologies and spatial analytical methods, the transport of skeletal elements was mapped in order to analyze dispersal and terrain-influenced patterns of active vulture scavenging. Results showed that the initial scavenging took place 37 days after placement at FARF. This delay in scavenging differs from previous research. After the initial appearance of the vultures, the body was reduced from a fully-fleshed individual to a skeleton within only 5h. This underscores the potential for errors in postmortem interval estimations made at vulture scavenged scenes. Additionally, spatial analysis showed that skeletal elements were dispersed by vultures to lower elevations, and that the disarticulation and dispersal of the skeletal elements occurs early in the scavenging sequence. PMID- 22204893 TI - Are spontaneous fractures possible? An example of clinical application for personalised, multiscale neuro-musculo-skeletal modelling. AB - Elderly frequently present variable degrees of osteopenia, sarcopenia, and neuromotor control degradation. Severely osteoporotic patients sometime fracture their femoral neck when falling. Is it possible that such fractures might occur without any fall, but rather spontaneously while the patient is performing normal movements such as level walking? The aim of this study was to verify if such spontaneous fractures are biomechanically possible, and in such case, which conditions of osteoporosis, sarcopenia, and neuromotor degradation could produce them. To the purpose, a probabilistic multiscale body-organ model validated against controlled experiments was used to predict the risk of spontaneous fractures in a population of 80-years old women, with normal weight and musculoskeletal anatomy, and variable degree of osteopenia, sarcopenia, and neuromotor control degradation. A multi-body inverse dynamics sub-model, coupled to a probabilistic neuromuscular sub-model, and to a femur finite element sub model, formed the multiscale model, which was run within a Monte Carlo stochastic scheme, where the various parameters were varied randomly according to well defined distributions. The model predicted that neither extreme osteoporosis, nor extreme neuromotor degradation alone are sufficient to predict spontaneous fractures. However, when the two factors are combined an incidence of 0.4% of spontaneous fractures is predicted for the simulated population, which is consistent with clinical reports. When the model represented only severely osteoporotic patients, the incidence of spontaneous fractures increased to 29%. Thus, is biomechanically possible that spontaneous femoral neck fractures occur during level walking, due to a combination of severe osteoporosis and severe neuromotor degradation. PMID- 22204894 TI - [Botulinum toxin type A contribution in the treatment of Raynaud's phenomenon due to systemic sclerosis]. AB - AIMS: Raynaud's phenomenon is a vasospastic disorder of the extremities that can lead, in the hands, to pain, disability, ischemic ulcers and digital chronic ischemia. Medical and surgical current treatments are not fully effective while causing side effects. Recent studies have emphasized the value of botulinum toxin type A (BTX A) in the management of primary Raynaud's phenomenon. The originality of Raynaud's syndrome secondary to systemic sclerosis is to combine both arterial vasospasm and sclerosis of the arterial wall, what is supposed to reduce BTX A effects. The purpose of this work is to evaluate BTX A efficiency in patients with Raynaud's phenomenon secondary to systemic sclerosis. PATIENTS AND METHOD: We performed a prospective study for 12 months. Patients with severe Raynaud's phenomenon due to systemic sclerosis were injected with BTX A in the two hands. Evolution of ischemic ulcers, QuickDASH Score, O2 partial pressure, pain were measured before and 30 days after injection. RESULTS: We treated 18 patients. Thirty days after injection, we noticed a complete healing of ulcers, QuickDASH Score was improved from 39.4 to 20, as the O2 partial pressure from 16 to 42 mmHg and the pain from VNS from 6/10 to 2/10. CONCLUSION: BTX A appears to improve significantly Raynaud's phenomenon symptomatology in patients with systemic sclerosis despite the component of arterial sclerosis. PMID- 22204895 TI - Cross-modal warnings for orienting attention in older drivers with and without attention impairments. AB - Older adults are overrepresented in fatal crashes on a per-mile basis. Those with useful field of view (UFOV) reductions show a particularly elevated crash risk that might be mitigated with vehicle-based warnings. To evaluate cross-modal cues that could be used in these warnings, we applied a variation of Posner's orienting of attention paradigm. Twenty-nine older drivers with UFOV impairments and 32 older drivers without impairments participated. Cues were presented in either a single modality or a combination of modalities (visual, auditory, haptic). Drivers experienced three cue types (valid spatial information, invalid spatial information, neutral) and an uncued baseline. Following each cue, drivers discriminated the direction of a target (a Landolt square with a gap facing up or down) in the visual panorama. Drivers with and without UFOV impairments showed comparable response times (RTs) across the different cue modalities and cue types. Both groups benefited most from auditory and auditory/haptic cues. Redundant visual cues, when paired with auditory cues, undermined performance rather than enhanced it. Overall, drivers responded faster to targets with valid spatial information followed by neutral, invalid, and uncued targets. Cues provide the greatest benefit in alerting rather than orienting the driver. The cue expected to be most effective at orienting attention - the extra-vehicular cue - performs most poorly when the spatial information is either invalid or neutral. Even when the spatial information is valid the extra-vehicular cue underperforms the auditory cues. The results suggest that temporal information dominates spatial information in the ability of cues to speed responses to targets. This study represents a first step in assessing whether combining a cognitive science paradigm and a driving simulator environment can quickly assess how different warning signals alert and orient drivers. PMID- 22204896 TI - Why business modeling is crucial in the development of eHealth technologies. AB - The impact and uptake of information and communication technologies that support health care are rather low. Current frameworks for eHealth development suffer from a lack of fitting infrastructures, inability to find funding, complications with scalability, and uncertainties regarding effectiveness and sustainability. These issues can be addressed by defining a better implementation strategy early in the development of eHealth technologies. A business model, and thus business modeling, help to determine such an implementation strategy by involving all important stakeholders in a value-driven dialogue on what the technology should accomplish. This idea also seems promising to eHealth, as it can contribute to the whole development of eHealth technology. We therefore suggest that business modeling can be used as an effective approach to supporting holistic development of eHealth technologies. The contribution of business modeling is elaborated in this paper through a literature review that covers the latest business model research, concepts from the latest eHealth and persuasive technology research, evaluation and insights from our prior eHealth research, as well as the review conducted in the first paper of this series. Business modeling focuses on generating a collaborative effort of value cocreation in which all stakeholders reflect on the value needs of the others. The resulting business model acts as the basis for implementation. The development of eHealth technology should focus more on the context by emphasizing what this technology should contribute in practice to the needs of all involved stakeholders. Incorporating the idea of business modeling helps to cocreate and formulate a set of critical success factors that will influence the sustainability and effectiveness of eHealth technology. PMID- 22204898 TI - Changes in intolerance of uncertainty during cognitive behavior group therapy for social phobia. AB - BACKGROUND AND OBJECTIVES: Recent research suggests that intolerance of uncertainty (IU), most commonly associated with generalized anxiety disorder, also contributes to symptoms of social phobia. This study examines the relationship between IU and social anxiety symptoms across treatment. METHOD: Changes in IU, social anxiety symptoms, and depression symptoms were examined following cognitive behavior group therapy (CBGT) for social phobia (N=32). RESULTS: CBGT led to significant improvements in symptoms of social anxiety and depression, as well as reductions in IU. Reductions in IU were associated with reductions in social anxiety but were unrelated to improvements in depression symptoms. Reductions in IU were predictive of post-treatment social phobia symptoms after controlling for pre-treatment social phobia symptoms and changes in depression symptoms following treatment. LIMITATIONS: The relationship between IU and social anxiety requires further examination within experimental and longitudinal designs, and needs to take into account additional constructs that are thought to maintain social phobia. CONCLUSIONS: Current findings suggest that the enhancing tolerance of uncertainty may play a role in the optimal management of social phobia. Theoretical and clinical implications are discussed. PMID- 22204897 TI - Evaluating the use of a computerized clinical decision support system for asthma by pediatric pulmonologists. AB - PURPOSE: To investigate use of a new guideline-based, computerized clinical decision support (CCDS) system for asthma in a pediatric pulmonology clinic of a large academic medical center. METHODS: We conducted a qualitative evaluation including review of electronic data, direct observation, and interviews with all nine pediatric pulmonologists in the clinic. Outcome measures included patterns of computer use in relation to patient care, and themes surrounding the relationship between asthma care and computer use. RESULTS: The pediatric pulmonologists entered enough data to trigger the decision support system in 397/445 (89.2%) of all asthma visits from January 2009 to May 2009. However, interviews and direct observations revealed use of the decision support system was limited to documentation activities after clinic sessions ended. Reasons for delayed use reflected barriers common to general medical care and barriers specific to subspecialty care. Subspecialist-specific barriers included the perceived high complexity of patients, the impact of subject matter expertise on the types of decision support needed, and unique workflow concerns such as the need to create letters to referring physicians. CONCLUSIONS: Pediatric pulmonologists demonstrated low use of a computerized decision support system for asthma care because of a combination of general and subspecialist-specific factors. Subspecialist-specific factors should not be underestimated when designing guideline-based, computerized decision support systems for the subspecialty setting. PMID- 22204899 TI - Pregnancy implications for systemic lupus erythematosus and the antiphospholipid syndrome. AB - Multidisciplinary approach and patient counselling have been the key points in the improvement of the management of pregnancy in women with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Most of these women can have successful pregnancy when thoroughly informed and instructed on several different issues. Disease activity should be in stable remission prior to pregnancy in order to reduce the chance for flare during pregnancy. To this purpose, medications must be modulated: "safe" drugs should be continued throughout pregnancy, embryotoxic/foetotoxic drugs should be withdrawn timely, and beneficial drugs such as low dose aspirin and heparin should be added for prophylaxis of maternal and foetal outcome, especially in the presence of antiphospholipid antibodies. The safety profile of anti-rheumatic drugs during pregnancy and breastfeeding should be kept constantly updated, as new data from inadvertent exposure accumulates and new drugs (especially biological agents) are available. Patients may carry autoantibodies that can negatively affect the baby, being neonatal lupus the prototypical case of passively acquired autoimmunity. Research has been greatly active in this field and more information on risk stratification and management are now available for counselling. The effect of both autoantibodies and drug exposure has been evaluated in the offspring: some concerns about learning disabilities have been raised, but these are treatable conditions that are likely to be overcome. To counsel a woman with SLE/APS during childbearing age means also to deal with contraception. Despite the "preferred choice" - combined oral contraceptive - may not be suitable for most of the patients, other options are available and should be offered and discussed with the patient. Fertility is not generally affected in SLE/APS patients, but those cases who require assisted reproduction techniques should be carefully evaluated and managed. PMID- 22204900 TI - Sex differences and genomics in autoimmune diseases. AB - Autoimmune diseases (AIDs) are believed to be multifactorial diseases that commonly involve multiple organ systems. About three fourth of the patients afflicted with AIDs are women suggesting that sex differences impact the incidence of AID. However, the proportion of females to males suffering from AID varies depending on the disease. The response to some AID therapeutics also differs in females versus males, suggesting that enrollment of adequate numbers of women and men is important in clinical trials for development of AID drugs. It is known for a long time that genetic factors are important contributors to AID susceptibility. Currently available information suggests that multiple genes with modest association to AID contribute to susceptibility to AID. Also, the associations may differ for the various ethnicities. The major histocompatibility (MHC) locus appears to be a major genetic factor that confers susceptibility to multiple AIDs, even though the locus is complex and has the highest density of genes in the human genome. Thus, the association of different AIDs could be with different genes in the MHC locus. Among the non-MHC genes, some of the risk alleles are shared between different AIDs, but may not be common to all AIDs. For example, genetic polymorphisms in the Protein Tyrosine Phosphatase-22 (PTPN22) gene have reproducibly shown to have association with systemic lupus erythematosus (SLE), Graves' disease (GD), rheumatoid arthritis (RA) and multiple sclerosis (MS), but not with psoriasis. Identification of factors responsible for risk for developing AID and the of the pathways underlying these diseases are likely to help understand subsets of disease, identify responders to a specific treatment and develop better therapeutics for AID. PMID- 22204901 TI - Synthesis and antitumor evaluation of some new 1,3,4-oxadiazole-based heterocycles. AB - The synthetic strategies and characterization of some novel 1,3,4-oxadiazole derivatives carrying different pharmacophores and heterocyclic rings that are relevant to potential antitumor and cytotoxic activities are described. The antitumor activities of the newly synthesized compounds were evaluated according to the protocol of the National Cancer Institute (NCI) in-vitro disease-oriented human cells screening panel assay. The results revealed that five compounds, namely 2, 7a, 11a, 12b, and 17; displayed promising in-vitro antitumor activity in the 4-cell lines assay. Incorporating a thiazole ring to 1,3,4-oxadiazole skeleton resulted in better antitumor activities than those displayed by the pyrazole and thiophene ring systems. Transformation of 1,3,4-oxadiazole 2 to N-(6 amino-7H-pyrazolo[5,1-c][1,2,4]triazol-3-yl)benzamide (15) diminished the antitumor activity. PMID- 22204902 TI - Synthesis and biological activity of novel organoselenium derivatives targeting multiple kinases and capable of inhibiting cancer progression to metastases. AB - The present study reports synthesis and biological activity of novel benzoisoselenazolone compounds derived from ebselen and conjugated to a sugar molecule. Cell proliferation assay using cancer cells combined with in vitro biochemical assays revealed that benzoisoselenazolone 2d, 5a, and 6a exerted anti proliferative activity, which correlated with selective in vitro inhibition of focal adhesion kinase, AKT-1, and protein kinase C-alpha. Active molecules were able to significantly inhibit cell migration and invasion in vitro compared to cells treated with the vehicle alone or ebselen. Moreover, in vivo anticancer activity focusing on lead compound 2d and using an invasive human breast cancer orthotopic mouse model revealed a potent anti-metastatic activity at well tolerated doses. In summary, these novel benzoisoselenazolones we report herein target multiple kinases with established roles in cancer progression and possess anti-invasive and anti-metastatic activity in preclinical models supporting a potential for therapeutic application for human disease. PMID- 22204904 TI - Factors associated with dementia among elderly people living in two cities in Central Africa: the EDAC multicenter study. AB - Risk factors for dementia in American and European countries have been well investigated. However, little research has been carried out in sub-Saharan Africa, where life events as well as environmental, socio-economic, and modifiable risk factors (i.e., cardiovascular risk factors) may differ. Two cross sectional surveys were conducted in representative samples of the older general population living in Bangui (Central African Republic) and Brazzaville (Congo). Dementia was defined according to the DSM-IV criteria. Multivariate regression analyses were performed in order to identify independent factors associated with dementia. Among the 977 elderly Africans included in this analysis, 75 (7.6%) were diagnosed as having dementia. Increasing age, female gender, hypertension, a body mass index <18.5 kg/m2, depressive symptoms, and the lack of a primary education were significantly associated with dementia. Among life events, the death of one parent during childhood and recently having moved house were also associated with dementia. Beyond the usual risk factors for dementia, this study highlights the role of stressful events in low-income countries. Factors associated with dementia in African countries seem different from established factors in high-income countries and require further investigation. PMID- 22204903 TI - Analogues of doxanthrine reveal differences between the dopamine D1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines. AB - Efforts to develop selective agonists for dopamine D(1)-like receptors led to the discovery of dihydrexidine and doxanthrine, two bioisosteric beta-phenyldopamine type full agonist ligands that display selectivity and potency at D(1)-like receptors. We report herein an improved methodology for the synthesis of substituted chromanoisoquinolines (doxanthrine derivatives) and the evaluation of several new compounds for their ability to bind to D(1)- and D(2)-like receptors. Identical pendant phenyl ring substitutions on the dihydrexidine and doxanthrine templates surprisingly led to different effects on D(1)-like receptor binding, suggesting important differences between the interactions of these ligands with the D(1) receptor. We propose, based on the biological results and molecular modeling studies, that slight conformational differences between the tetralin and chroman-based compounds lead to a shift in the location of the pendant ring substituents within the receptor. PMID- 22204905 TI - Fibrillar amyloid-beta1-42 modifies actin organization affecting the cofilin phosphorylation state: a role for Rac1/cdc42 effector proteins and the slingshot phosphatase. AB - The neuronal cytoskeleton regulates numerous processes that occur in normal homeostasis. Under pathological conditions such as those of Alzheimer's disease (AD), major alterations in cytoskeleton organization have been observed and changes in both microtubules and actin filaments have been reported. Many neurodegenerative consequences of AD are linked to the production and accumulation of amyloid peptides (Abeta) and their oligomers, produced from the internal cleavage of the amyloid-beta protein precursor. We previously reported that fibrillar Abeta1-42 (fAbeta) treatment of hippocampal neurons induced an increase in Rac1 and Cdc42 activities linking fAbeta effects with changes in actin dynamics. Here we show fAbeta-induces increased activity of PAK1 and cyclin dependent kinase 5, and that p21-activated kinase (PAK1) activation targets the LIMK1-cofilin signaling pathway. Increased cofilin dephosphorylation under conditions of enhanced LIM-Kinase 1 (LIMK1) activity suggests that fAbeta co stimulates bifurcating pathways impacting cofilin phosphorylation. Overexpression of slingshot (SSH) prevents the augment of F-actin induced by fAbeta after 24 h, suggesting that fAbeta-induced changes in actin assembly involve both LIMK1 and SSH. These results suggest that fAb may alter the PAK1/LIMK1/cofilin axis and therefore actin organization in AD. PMID- 22204906 TI - [Pretibial annular plates: a case of childhood leprosy]. PMID- 22204907 TI - Design and synthesis of novel photoaffinity probes for study of the target proteins of oleanolic acid. AB - To explore the molecular mechanisms of oleanolic acid, two novel photoaffinity probes were synthesized based on the structure-activity relationship reported previously. Their potency were evaluated in an enzyme inhibition assay against rabbit muscle glycogen phosphorylase a (RMGPa), a known target protein of oleanolic acid. The inhibitory activity of probe 2 was only about two-fold less potent than the mother compound oleanolic acid. The photoaffinity labeling experiments were also performed and two proteins were specifically tagged by probe 2. The results suggest that the synthesized probes could be used as powerful tools to isolate and identify the target proteins of oleanolic acid. PMID- 22204908 TI - New benzimidazole derivatives as antiplasmodial agents and plasmepsin inhibitors: synthesis and analysis of structure-activity relationships. AB - The newly synthesized benzimidazole compounds were suggested to be inhibitors of Plasmodium falciparum plasmepsin II and human cathepsin D by virtual screening of an internal library of synthetic compounds. This was confirmed by enzyme inhibition studies that gave IC(50) values in the low micromolar range (2-48MUM). Ligand docking studies with plasmepsin II predicted binding of benzimidazole compounds at the center of the extended substrate-binding cleft. According to the plausible mode of binding, the pyridine ring of benzimidazole compounds interacted with S1' subsite residues whereas the acetophenone moiety was in contact with S1-S3 subsites of plasmepsin II active center. The benzimidazole derivatives were evaluated for capacity to inhibit the growth of intraerythrocytic P. falciparum in culture. Four benzimidazole compounds inhibited parasite growth at ?3MUM. The most active compound 10, 1-(4 phenylphenyl)-2[2-(pyridinyl-2-yl)-1,3-benzdiazol-1-yl]ethanone showed an IC(50) of 160nM. The substitution of a phenyl group and a chlorine atom at the para position of the acetophenone moiety were shown to be crucial for antiplasmodial activity. PMID- 22204909 TI - Synthesis and anti-HCV activity evaluation of anilinoquinoline derivatives. AB - Hepatitis C virus (HCV) infection is a main cause of chronic liver disease, leading to liver cirrhosis and hepatocellular carcinoma (HCC). The objective of our research was to develop effective agents against viral replication. Here, we have synthesized a series of anilinoquinoline derivatives. Based on a cell-based HCV replicon system, we observed that 2-(3'-nitroanilino)quinoline (18) exhibited anti-HCV activity with a 50% effective concentration (EC(50)) value of 7MUM and a selective index (SI) value of 10. In addition, compound 18 possessed the inhibitory effect on HCV NS3/4A protease activity. Therefore, we concluded that the compound 18 possessed a potent activity against HCV replication and could provide as a new lead compound as anti-HCV inhibitor. PMID- 22204910 TI - Differential signaling properties at the kappa opioid receptor of 12-epi salvinorin A and its analogues. AB - The kappa opioid receptor (KOPR) has been identified as a potential drug target to prevent or alter the course of mood, anxiety and addictive disorders or reduce response to stress. In a search for highly potent and selective KOPR partial agonists as pharmacological tools, we have modified 12-epi-salvinorin A, a compound which we have previously observed to be a KOPR partial agonist. Five analogues of 12-epi-salvinorin A were synthesized and their effects on G protein activation as well as beta-arrestin2 recruitment were evaluated. Only 12-epi salvinorin A (1) partially activated signaling through G proteins, yet acted as a full agonist in the beta-arrestin 2 DiscoveRx assay. Other salvinorin analogues tested in these functional assays were full agonists in both assays of KOPR activation. By comparison, the non-selective opioid ligand nalbuphine, known to be a partial agonist for G-protein activation, was also a partial agonist for the beta-arrestin mediated signaling pathway activated through KOPR. PMID- 22204912 TI - Synthesis and evaluation of tetrahedral intermediate mimic inhibitors of 3-deoxy d-manno-octulosonate 8-phosphate synthase. AB - 3-Deoxy-d-manno-octulosonate 8-phosphate (KDO8P) synthase catalyses the first committed step in the biosynthesis of 3-deoxy-d-manno-octulosonate (KDO), an important component of the lipopolysaccharide of Gram-negative bacteria. The pathway for KDO biosynthesis has been identified as a potential target of antibacterial drug design. The reaction catalysed by KDO8P synthase is an aldol like condensation between phosphoenolpyruvate (PEP) and d-arabinose 5-phosphate (A5P) and proceeds through a bisphosphorylated tetrahedral intermediate. In this study a bisphosphate analogue of the tetrahedral intermediate was synthesised and was found to inhibit the metal-dependent KDO8P synthase from Neisseriameningitidis and the metal-dependent KDO8P synthase from Acidithiobacillus ferrooxidans with inhibition constants in the low micromolar range. Additionally, monophosphorylated inhibitors were synthesised to determine the relative importance of the two phosphate groups of this bisphosphate analogue for enzyme inhibition. The removal of either of these two phosphate groups gave less potent inhibitors for both enzymes. PMID- 22204911 TI - Design, synthesis and cytotoxic activity of novel spin-labeled rotenone derivatives. AB - Three series of novel spin-labeled rotenone derivatives were synthesized and evaluated for cytotoxicity against four tumor cell lines, A-549, DU-145, KB and KBvin. All of the derivatives showed promising in vitro cytotoxic activity against the tumor cell lines tested, with IC(50) values ranging from 0.075 to 0.738MUg/mL. Remarkably, all of the compounds were more potent than paclitaxel against KBvin in vitro, and compounds 3a and 3d displayed the highest cytotoxicity against this cell line (IC(50) 0.075 and 0.092MUg/mL, respectively). Based on the observed cytotoxicity, structure-activity relationships have been described. PMID- 22204913 TI - Cellular uptake of highly-functionalized ruthenium(II) tris-bipyridine protein surface mimetics. AB - This manuscript describes cell-uptake studies with HEK 293T cells on a series of ruthenium complexes shown previously to act as receptors for protein surface recognition and was motivated by a desire to establish if these receptors represent suitable templates for further elaboration as inhibitors of protein protein interactions. The results illustrate that large (>3000Da) highly functionalized anionic ruthenium complexes are efficiently transfected via endocytosis to lysosomes with negligible toxicity. PMID- 22204914 TI - Nondestructive monitoring of the repair of enamel artificial lesions by an acidic remineralization model using polarization-sensitive optical coherence tomography. AB - OBJECTIVES: It is difficult to completely remineralize carious lesions because diffusion into the interior of the lesion is inhibited as new mineral is deposited in the outermost layers. In previous remineralization studies employing polarization sensitive optical coherence tomography (PS-OCT), two models of remineralization were employed and in both models there was preferential deposition of mineral in the outer most layer. In this study we attempted to remineralize the entire lesion using an acidic remineralization model and demonstrate that this remineralization can be monitored using PS-OCT. METHODS: Artificial lesions approximately 100-150 MUm in-depth were exposed to an acidic remineralization regimen and the integrated reflectivity from the lesions was measured before and after remineralization using PS-OCT. RESULTS: Automated integration routines worked well for assessing the integrated reflectivity for the lesion areas after remineralization. Although there was a high degree of remineralization, there was still incomplete remineralization of the body of the lesion. CONCLUSION: This study demonstrated that PS-OCT can be used to non destructively measure changes in lesion structure and severity upon exposure to an acidic remineralization model. This study also demonstrated that automated algorithms can be used to assess the lesion severity even with the presence of a weakly reflective surface zone. PMID- 22204916 TI - [Vaginal flap for rectovaginal fistulae in Crohn's disease]. AB - OBJECTIVES: To evaluate efficacy and functional results (sexual activity) of vaginal flap for rectovaginal fistula in Crohn's disease. PATIENTS AND METHODS: From May 2004 to March 2008, we proposed a vaginal flap in patients who had a rectovaginal fistula in Crohn's disease and for which rectal flap was technically impossible. Monitoring included a clinical examination at 1 month and every 3 months for 1 year, Perianal Disease Activity Index for sexual activity evaluation. Every year and in April 2009 the nursing team during a telephone interview filled a standardized questionnaire. RESULTS: We treated 5 patients. At 6 months, 4 of 5 patients were healed. At 7 months, 1 patient presented a new flare up of CD with reopening of the fistula. The other 3 patients were still healed at a median follow-up of 30.66 months (15 to 59). One patient presented dyspareunia during 3 months. DISCUSSION AND CONCLUSION: Vaginal flap is an effective technique that entails neither prolonged dyspareunia nor fecal incontinence. Stoma is not systematic. PMID- 22204915 TI - Effectiveness of self-adhesive luting cements in bonding to chlorhexidine-treated dentin. AB - OBJECTIVES: The aim was to investigate the microtensile bond strength (MU-TBS) and failure pattern of self-adhesive luting cements (SLC) to dentin pre-treated with different concentrations of chlorhexidine (CHX) solutions. METHODS: The occlusal enamel was removed from 30 extracted sound human molars in order to expose a flat dentin. Resin-composite (Filtek Z250, 3M ESPE) discs (12 mm in diameter, 6.0mm thickness) were cemented to the smear layer-covered dentin using the SLC [RelyX U100, 3M ESPE (U100); Multilink Sprint, Ivoclar Vivadent (MS)] with 0.2% or 2.0% CHX solutions. Results were compared with the control, untreated dentin. Six groups were then created based on the SLC and dentin pre treatment (n=5). After 24h of water storage, restored teeth were serially sectioned into beams with a cross-sectional area of 0.8mm(2) at the bonded interface. Subsequently, specimens were tested in tension with a crosshead speed of 0.5mm/min in a universal testing machine, and the failure patterns were classified. Two-way ANOVA and Tukey's tests were performed (alpha=0.05). Additionally, 18 teeth were subjected to energy-dispersive X-ray spectroscopy (EDS) analysis and micromorphology characterization of the smear layer-covered dentin and 0.2% or 2.0% CHX-treated dentin surfaces. RESULTS: The MU-TBS obtained for both control groups were significantly higher, regardless of the CHX concentration and/or the cement used. Bond strengths were significantly higher for U100 than for MS, except when 2.0% CHX was applied. Fractographic analysis indicated that most failures in the control groups occurred cohesively in the SLC. Pre-treated dentin with 0.2% and 2.0% CHX solutions presented higher incidences of adhesive failures. EDS/SEM analysis exhibited varied concentrations of chlorine ions and crystal-shaped precipitates, depending upon the CHX concentration. SIGNIFICANCE: Pre-treatment of dentin with 0.2% or 2.0% CHX adversely affects the bonding efficacy when associated with the SLCs tested. PMID- 22204917 TI - Creating a collimated ultrasound beam in highly attenuating fluids. AB - We have devised a method, based on a parametric array concept, to create a low frequency (300-500 kHz) collimated ultrasound beam in fluids highly attenuating to sound. This collimated beam serves as the basis for designing an ultrasound visualization system that can be used in the oil exploration industry for down hole imaging in drilling fluids. We present the results of two different approaches to generating a collimated beam in three types of highly attenuating drilling mud. In the first approach, the drilling mud itself was used as a nonlinear mixing medium to create a parametric array. However, the short absorption length in mud limits the mixing length and, consequently, the resulting beam is weak and broad. In the second improved approach, the beam generation process was confined to a separate "frequency mixing tube" that contained an acoustically non-linear, low attenuation medium (e.g., water) that allowed establishing a usable parametric array in the mixing tube. A low frequency collimated beam was thus created prior to its propagation into the drilling fluid. Using the latter technique, the penetration depth of the low frequency ultrasound beam in the drilling fluid was significantly extended. We also present measurements of acoustic nonlinearity in various types of drilling mud. PMID- 22204918 TI - Ambient levels of air pollution induce clinical worsening of blepharitis. AB - BACKGROUND: Even though air pollutants exposure is associated with changes in the ocular surface and tear film, its relationship to the clinical course of blepharitis, a common eyelid disease, had not yet been investigated. Our objective was to investigate the correlation between air pollution and acute manifestations of blepharitis. METHOD: We recorded all cases of changes in the eyelids and ocular surface, and rated clinical findings on a scale from zero (normal) to two (severe alterations). Daily values of carbon monoxide, particulate matter smaller than 10 MUm in diameter and nitrogen dioxide concentrations and meteorological variables (temperature and relative humidity) in the vicinity of the medical service were obtained. Specific linear regression models for each outcome were constructed including pollutants as independent variables (single pollutant models). Temperature and humidity were included as confounding variables. RESULTS: increases of 28.8 MUg/m(3) in the concentration of particulate matter and 1.1 ppm in the concentration of CO were associated with increases in cases of blepharitis on the day of exposure (5 cases, 95% CI: 1-10 and 6 cases, 95% CI: 1-12, respectively). CONCLUSION: Exposure to usual air pollutants concentrations present in large cities affects, in a consistent manner, the eyes of residents contributing to the increasing incidence of diseases of the eyelid margin. PMID- 22204919 TI - Quantitative measurement of radiofrequency volumetric tissue reduction by multidetector CT in patients with inferior turbinate hypertrophy. AB - OBJECTIVE: To objectively assess the efficacy of radiofrequency thermal ablation of inferior turbinate hypertrophy. METHODS: Thirty-five patients with nasal obstruction secondary to inferior turbinate hypertrophy were prospectively enrolled. Radiofrequency energy was delivered to four sites in each inferior turbinate. Patients were evaluated before and 8 weeks after intervention. Subjective evaluation of nasal obstruction was performed using a visual analogue scale (VAS), and objective evaluation of the turbinate volume reduction was calculated using multidetector CT. Volumetric measurements of the preoperative inferior turbinate were compared with postoperative values on both sides. RESULTS: The great majority of patients (91.4%) exhibited subjective postoperative improvement. Mean obstruction (VAS) improved significantly from 7.45+/-1.48 to 3.54+/-1.96. Significant turbinate volume reduction was achieved by the surgery on both right and left sides [(preoperative vs. postoperative, right: 6.55+/-1.62cm(3) vs. 5.10+/-1.47cm(3), (P<0.01); left: 6.72+/-1.53cm(3) vs. 5.00+/-1.37cm(3), (P<0.01)] respectively. CONCLUSION: Radiofrequency is a safe and effective surgical procedure in reducing turbinate volume in patients with inferior turbinate hypertrophy. Multidetector CT is an objective method of assessment in detecting radiofrequency turbinate volume reduction. PMID- 22204920 TI - Impact of aging on visual reweighting during locomotion. AB - OBJECTIVES: The purpose of this study was to investigate the ability of young and old subjects to reweight visual cues while walking at normal and fast speeds. METHODS: Ten young (23.49 +/- 4.72) and ten older adults (age 76.22 +/- 3.11) were asked to physically walk straight while viewing a virtual scene in a head mounted display (HMD) unit under three conditions: no visual perturbation, blank (no visual input), and visual perturbation. Subjects performed the tasks walking at two speeds: preferred self-pace and fast. Variables calculated included trajectory, heading angle, and body segment orientations. RESULTS: In the perturbation condition, the older adults walked with higher segmentation and more deviations of the body's centre of mass. Only the young subjects were affected by the walking speed, with an improved performance when walking fast. CONCLUSIONS: Old age affects the ability to re-weight visual information and make postural or locomotor adjustments in real time. The lower errors of the young adults in the fast conditions suggest decreased cortical control of locomotion with increasing speeds. SIGNIFICANCE: Visual information presented in real time can impact on balance and mobility in older adults, and thus should be given serious consideration for the purpose of evaluation and intervention. PMID- 22204921 TI - Differences in excitability between median and superficial radial sensory axons. AB - OBJECTIVE: The aim of this study was to investigate differences in excitability properties of human median and superficial radial sensory axons (e.g., axons innervating the glabrous and hairy skin in the hand). Previous studies have shown that excitability properties differ between motor and sensory axons, and even among sensory axons between median and sural sensory axons. METHODS: In 21 healthy subjects, threshold tracking was used to examine excitability indices such as strength-duration time constant, threshold electrotonus, supernormality, and threshold change at the 0.2 ms inter-stimulus interval in latent addition. In addition, threshold changes induced by ischemia for 10 min were compared between median and superficial radial sensory axons. RESULTS: Compared with radial sensory axons, median axons showed shorter strength-duration time constant, greater threshold changes in threshold electrotonus (fanning-out), greater supernormality, and smaller threshold changes in latent addition. Threshold changes in both during and after ischemia were greater for median axons. CONCLUSIONS: These findings suggest that membrane potential in human median sensory axons is more negative than in superficial radial axons, possibly due to greater activity of electrogenic Na(+)/K(+) pump. These results may reflect adaptation to impulses load carried by median axons that would be far greater with a higher frequency. SIGNIFICANCE: Biophysical properties are not identical in different human sensory axons, and therefore their responses to disease may differ. PMID- 22204922 TI - [Antisynthetase syndrome: a retrospective study of 14 patients]. AB - PURPOSE: Antisynthetase syndrome is a rare entity characterized by myositis (dermatomyositis or polymyositis), interstitial lung disease, arthritis, Raynaud's phenomena and mechanic's hands skin manifestation, and the presence of autoantibodies against aminoacyl-transfer RNA synthetase. PATIENTS AND METHODS: Fourteen patients with antisynthetase syndrome followed-up between 1997 and 2009 were included. We studied retrospectively their clinical, radiological, and pathological findings. RESULTS: The sex ratio women/men was 2.5. Mean age at disease onset was 46 years. Arthritis (43%) and interstitial lung disease (38%) were the most frequent features at disease onset. Seven patients had myositis. Ten patients had anti-Jo1 autoantibodies, three had anti-PL7 and one anti-PL12. Corticosteroid therapy was given in all cases, immunosuppressive drugs in 12 cases, due to initial severity (n=8), disease relapse (n=3) or corticosteroid dependence (n=1). After a mean follow-up of 64 months, nine patients improved, four stabilized and one patient died after lung transplantation, required for pulmonary hypertension. CONCLUSION: The diffusion of immunologic assay will help us in the future to identify the specificity of this syndrome in order to improve care. PMID- 22204923 TI - [Inflammatory myopathies, autoimmune necrotizing myopathies and adult-onset genetic myopathies: differential diagnosis]. AB - The inflammatory myopathies are an important and treatable group of disorders. The diagnostic criteria and the classifications are complex and subject to debate. Furthermore, there is clinical and histopathological overlap between the features of inflammatory myopathies and those of adult-onset genetic myopathies. In this review, we will discuss the two more common pitfalls in inflammatory myopathies diagnosis: firstly, the misdiagnosis between different types of inflammatory myopathies and uncommon myopathies; secondly, the confusion between inflammatory myopathies and genetic myopathies. Among the group of limb-girdle dystrophies, dysferlinopathies are the more common confounding myopathies. An accurate diagnosis is essential for an optimal management in patients with myopathies. PMID- 22204925 TI - Diagnostic value of ultrasound-guided core needle biopsy in patients with salivary gland masses. AB - The salivary glands are unique in the diversity and complexity of their pathologies. Because fine needle aspiration cytology and frozen section are associated with major diagnostic difficulties, the authors analyzed the use of core needle biopsy (CNB) for the histologic assessment of salivary gland lesions. A systematic observational clinicopathologic quality assessment study was performed over 81 months including 161 CNB procedures in 76 patients with salivary gland pathologies. Adequate samples containing the target tissue were obtained in 73 patients. These samples revealed malignant disease in 45 (62%) patients, benign disease in 26 (36%) patients, and were inconclusive in 2 (3%) patients. Follow-up uncovered no false-positive or false-negative results. On the basis of secondary histologic and clinical follow-up, the statistical parameters were calculated as follows: sensitivity 94%; specificity 100%; accuracy 96%; positive predictive value 100%; negative predictive value 90%. The advantages and potential limitations of CNB in patients with salivary gland masses are discussed. CNB is a reliable biopsy technique for the assessment of salivary gland pathologies, although limitations remain for the subclassification of some neoplastic lesions. The authors recommend CNB as the biopsy technique of choice for a selection of indications. PMID- 22204924 TI - Soft tissue stability in segmental distraction of the anterior mandibular alveolar process. A 2-year follow-up. AB - This study evaluated soft tissue changes in adult patients treated with distraction osteogenesis (DOG) of the anterior mandibular alveolar process and related it to different parameters. 33 patients (27 females; 6 males) were analysed retrospectively before surgery at T1 (17.0 days), after surgery at T2 (mean 6.5 days), at T3 (mean 24.4 days), and at T4 (mean 2.0 years). Lateral cephalograms were traced by hand, digitized, superimposed, and evaluated. Statistical analysis was carried out using Kolmogorov-Smirnov test, paired t test, Pearson's correlation coefficient, and linear backward regression analysis. 2 years postoperatively (T4), the net effect of the soft tissue at point B' was 100% of the advancement at point B whilst the lower lip (labrale inferior) followed the advancement of incision inferior to 46%. Increased preoperative age was correlated (p<0.05) with more horizontal backward movement (T4-T3) for labrale superior and pogonion'. Higher NL/ML' angles were significantly correlated (p<0.05) with smaller horizontal soft tissue change at point B'. Gender and the amount of skeletal and dental advancement were not correlated with postoperative soft tissue changes (T4-T3). DOG of the anterior mandibular alveolar process is a valuable alternative for mandibular advancement regarding soft tissue change and predictability. PMID- 22204926 TI - The role of haptic information in shaping coordination dynamics: inertial frame of reference hypothesis. AB - Current research suggests that non-visual perception of the spatial orientation of body segments is tied to vectors representative of their mass moment distribution (v(mm)). Our question was whether the relative orientation of v(mm) of right and left hands (Deltav(mm)=v(mm) left-v(mm) right) constitutes haptic information supporting bimanual coordination and, if so, how it contributes to coordination dynamics. Blindfolded participants coordinated the motions of a pair of cross-shaped, hand-held pendulums that were either symmetrically loaded (Deltav(mm)=0) or asymmetrically loaded (Deltav(mm)?0). The sign and magnitude of Deltav(mm), in particular of the first moment vector, systematically affected the pattern of coordination (indexed by mean relative phase phi), but not its stability. These results suggest that (1) Deltav(mm) specifies a frame of reference about which coordination is organized; and (2) that the changes in pattern were a function of the experimentally induced biases in this perceptual frame of reference and not a function of a functional asymmetry akin to detuning. The implications of the findings to the understanding of perceptual regulation of interlimb coordination were discussed. PMID- 22204927 TI - Transforming neurorehabilitation of walking following stroke: the promise of non invasive brain stimulation--a review. AB - PURPOSE: This narrative review discusses the neurophysiology of human motor cortex as it influences gait, and recent advances in the application of non invasive brain stimulation to the lower limb motor cortex of stroke survivors. Although walking is a high priority following stroke, the efficacy of promising new therapies has yet to warrant their widespread clinical use. For the upper limb, numerous brain stimulation protocols have been described. These protocols, adapted for the leg, are now being used to examine the cortical control of gait. This research discounts the long-held notion that "we walk from our spinal cords". METHODS: Our review describes this research as it relates to the lower limb, especially the use of non-invasive brain stimulation to enhance neuroplasticity. The review also discusses the possible development of a prognostic algorithm for walking recovery after stroke. CONCLUSION: This review concludes with the expectation that novel brain stimulation protocols combined with therapy will eventually demonstrate a level of effectiveness sufficient to promote their wide acceptance in neurorehabilitation settings. PMID- 22204928 TI - Endogenous cortisol is associated with functional connectivity between the amygdala and medial prefrontal cortex. AB - Whether glucocorticoids mediate medial prefrontal cortex (mPFC) regulation of the amygdala in humans remains unclear. In the current study we investigated whether cortisol levels under relatively stress-free circumstances are related to amygdala resting-state functional connectivity with the mPFC. Resting-state fMRI data were acquired from 20 healthy male participants. Salivary cortisol was sampled at multiple times throughout the experiment. The cortisol area under the curve increase (AUCi) was calculated as a measure of cortisol dynamics. Next, seed based correlations were employed on the resting-state fMRI data to reveal regions of amygdala functional connectivity related to variations in cortisol AUCi. The resulting statistical maps were corrected for multiple comparisons using cluster based thresholding (Z>2.3, p<.05). Two regions in the mPFC showed decreasing negative functional connectivity with the amygdala when a lesser decrease in cortisol AUCi was observed: the perigenual anterior cingulate cortex and medial frontal pole (BA10). Although we initially showed a relation with cortisol AUCi, it seemed that the baseline cortisol levels were actually driving this effect: higher baseline cortisol levels related to stronger negative functional connectivity with the mPFC. Endogenous cortisol levels may modulate amygdala functional connectivity with specific regions in the mPFC, even under relatively stress-free circumstances. Our results corroborate previous findings from both animal and human studies, suggesting cortisol-mediated regulation of the amygdala by the mPFC. We propose that through this feedback mechanism the stress response might be adjusted, pointing to the putative role of cortisol in modulating stress- and, more generally, emotional responses. PMID- 22204929 TI - Regulation of physiologic actions of LRRK2: focus on autophagy. AB - BACKGROUND: Mutations in LRRK2 are associated with familial and sporadic Parkinson's disease (PD). Subjects with PD caused by LRRK2 mutations show pleiotropic pathology that can involve inclusions containing alpha-synuclein, tau or neither protein. The mechanisms by which mutations in LRRK2 lead to this pleiotropic pathology remain unknown. OBJECTIVES: To investigate mechanisms by which LRRK2 might cause PD. METHODS: We used systems biology to investigate the transcriptomes from human brains, human blood cells and Caenorhabditis elegans expressing wild-type LRRK2. The role of autophagy was tested in lines of C. elegans expressing LRRK2, V337M tau or both proteins. Neuronal function was measured by quantifying thrashing. RESULTS: Genes regulating autophagy were coordinately regulated with LRRK2. C. elegans expressing V337M tau showed reduced thrashing, as has been noted previously. Coexpressing mutant LRRK2 (R1441C or G2019S) with V337M tau increased the motor deficits. Treating the lines of C. elegans with an mTOR inhibitor that enhances autophagic flux, ridaforolimus, increased the thrashing behavior to the same level as nontransgenic nematodes. CONCLUSION: These data support a role for LRRK2 in autophagy, raise the possibility that deficits in autophagy contribute to the pathophysiology of LRRK2, and point to a potential therapeutic approach addressing the pathophysiology of LRRK2 in PD. PMID- 22204930 TI - Effect of hospital volume on processes of care and 5-year survival after breast cancer: a population-based study on 25000 women. AB - PURPOSE: To compare processes of care and survival for breast cancer by hospital volume in Belgium, based on 11 validated process quality indicators. METHODS: Three databases were linked at the patient level: the Cancer Registry, the population and the claims databases. All women with a diagnosis of invasive breast cancer between 2004 and 2006 were selected. Hospitals were classified according to their annual volume of treated patients: <50 (very low), 50-99 (low), 100-149 (medium) and >= 150 patients (high). Cox and logistic regression models were used to test differences in 5-year survival and in achievement of process indicators across volume categories, adjusting for age, tumor grade and stage. RESULTS: A total of 25178 women with invasive breast cancer were treated in 111 hospitals. Half of the hospitals (N=57) treated <50 patients per year. Six of eleven process indicators showed higher rates in high-volume hospitals: multidisciplinary team meeting, cytological and/or histological assessment before surgery, use of neoadjuvant chemotherapy, breast-conserving surgery rate, adjuvant radiotherapy after breast-conserving surgery, and follow-up mammography. Higher volume was also associated with improved survival. The 5-year observed survival rates were 74.9%, 78.8%, 79.8% and 83.9% for patients treated in very low-, low-, medium- and high-volume hospitals respectively. After case-mix adjustment, patients treated in very-low- or low-volume hospitals had a hazard ratio for death of 1.26 (95% CI 1.12, 1.42) and 1.15 (95% CI 1.01, 1.30) respectively compared with high-volume hospitals. CONCLUSION: Survival benefits reported in high-volume hospitals suggest a better application of recommended processes of care, justifying the centralization of breast cancer care in such hospitals. PMID- 22204931 TI - Morphologic investigation of injury caused by locally applied negative pressure in a rat model. AB - Although some previous studies have reported patients who developed compartment syndrome or died because of locally applied negative pressure, no detailed investigation of pathologic changes caused by negative pressure-induced injury has been reported in the literature. The main purpose of this study was to examine the morphologic characteristics of injury caused by local negative pressure and correlate these with systemic changes. A total of 30 male Wister rats were used. Animals were randomly assigned to 6 groups. Negative pressure was applied to the right hindlimb of each animal in each group for periods of 0 (sham operated), 30, 60, 90, 120, or 180 min using a vacuum pump. Macroscopic and microscopic changes induced by local negative pressure were already observed after 30 min and were exacerbated with time. The proportion of muscle degeneration was highest in the deep tissues, irrespective of exposure time. The observed increase in the weight of the injured hindlimb at 180 min was caused by an approximately 30% fluid shift to the hindlimb, demonstrating that the application of negative pressure to the hindlimb of rats can induce hypovolemic shock. We here reveal the morphologic changes induced by local negative pressure and discuss possible mechanisms of negative pressure-induced injury. PMID- 22204932 TI - Analysis of Camellia sinensis green and black teas via ultra high performance liquid chromatography assisted by liquid-liquid partition and two-dimensional liquid chromatography (size exclusion * reversed phase). AB - Green and black teas (Camellia sinensis) contain compounds ranging from simple phenolics to complex glycosides, many of which have well-recognized health benefits. Here, we describe two methodologies aiming to achieve a comprehensive analysis of hydro-alcoholic extracts of C. sinensis. In the first step, the extracts were partitioned in water, n-butanol, ethyl acetate and chloroform to separate the compounds according to their polarity, yielding less complex samples to be analyzed by ultra high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). Additionally, a comprehensive two dimensional liquid chromatography (2D-LC) technique, employing size exclusion chromatography (SEC) * reversed phase (BEH-C18) was developed. The following compounds were identified on the basis of retention time, UV-spectra and MS fragmentation patterns: catechins, theaflavins and their gallate derivatives; kaempferol, quercetin and myricetin mono-, di-, tri- and tetraglycosides; esters of quinic acid and gallic or hydroxycinnamic acids; purine alkaloids, such as caffeine and theobromine and many lipids. Additionally, there were many novel compounds that were previously undescribed, such as saponin isomers and gallic acid esters of four glycosides of myricetin, quercetin and kaempferol. PMID- 22204933 TI - Gas chromatographic-tandem mass spectrometric analysis of pesticides residues in produce using concurrent solvent recondensation-large volume injection. AB - In the present work, the feasibility of the combined use of concurrent solvent recondensation-large volume injection (CSR-LVI) and interspersed calibration for pesticide residue analysis was investigated. Splitless injections of 5-20 MUL extracts containing 0.25-1g sample per mL(-1) were made into a Carbofrit packed liner and a 0.53 mm I.D., uncoated and deactivated retention gap. The determination was achieved by gas chromatography-tandem quadrupole mass spectrometry (GC-QqQ-MS/MS). The evaluation of the proposed approach was based on analysis of real samples representing a diverse range of commodities such as apples, barley malt, blackcurrants, carrots, clemetines, grapes, leek, plums, rapeseed (green plants) rucola, strawberries and tomatoes. The samples contained a total of 36 different incurred pesticides at different concentration levels. Also, analyses were carried out of artificial samples representing six differing matrices (apples, blackcurrants, carrots, huckleberry, strawberry and tomatoes) which were spiked with pesticides at known concentrations before proceeding with the extraction. When using 15 and 20 MUL CSR-LVI injection, a decrease of about 30% in peak heights compared with injection of 5 MUL was observed. In the case of 5 and 10 MUL injections, no significant difference was observed when employing to the quantification of the incurred and spiked pesticide residues. In the evaluated experimental variants, overall recoveries of the pesticides were 92 +/- 5% with relative standard deviations of 12 +/- 4% on average. All individual recoveries were in the range between 72 and 103 with RSD between 4 and 21%. About 15% of the instrument run time was saved by the application of interspersed calibration with standards injected between sample extracts. PMID- 22204934 TI - Comprehensive hydrophilic interaction and ion-pair reversed-phase liquid chromatography for analysis of di- to deca-oligonucleotides. AB - A comprehensive two-dimensional HPLC approach with a high degree of orthogonality was developed for analysis of di- to deca-oligonucleotides (ONs). Hydrophilic interaction liquid chromatography (HILIC) was used in the first dimension, and ion-pair reversed-phase liquid chromatography (IP-RPLC) was employed in the second dimension. The two dimensions were connected via a ten-port valve interface equipped with octadecyl silica (ODS) traps to immobilize and focus the ONs eluting from the first dimension prior to IP-RPLC separation. An aqueous make up flow was used for effective trapping. The comprehensive two-dimensional HPLC system was optimized with a mixture consisting of 27 oligonucleotide standards. An overall chromatographic peak capacity of 500 was obtained. The use of the volatile buffer triethylamine acetate in the second dimension allowed straightforward coupling to electrospray ionization mass spectrometry (ESI-MS) and detection of each ON in the negative ionization mode. PMID- 22204935 TI - Reinforced polydiphenylamine nanocomposite for microextraction in packed syringe of various pesticides. AB - Reinforced polydiphenylamine (PDPA) nanocomposite was synthesized by oxidation of diphenylamine in 4 molL(-1) sulfuric acid solution containing a fixed amount of carbon nanotubes (CNTs) in the presence of cetyltrimethylammonium bromide (CTAB). The surface characteristic of PDPA and PDPA/CNT nanocomposites was investigated using scanning electron microscopy (SEM). The prepared PDPA/CNT nanocomposite was used as an extraction medium for microextraction in packed syringe (MEPS) of selected pesticides from aquatic environment. The effect of CNT doping level and the presence of surfactant on the extraction capability of nanocomposite was investigated and it was revealed that when 4% (w/w) of CNT in the presence of CTAB is being used, the highest extraction recovery could be achieved. Eventually, the developed MEPS technique in off-line combination with gas chromatography-mass spectrometry (GC-MS) was applied to the analysis of some pesticides including triazine, organophosphorous, organochlorine and aryloxyphenoxy propionic acid pesticides. Important parameters influencing the extraction and desorption processes were optimized and a 25 cycles of draw-eject gave maximum peak area, when desorption was performed using 200 MUL of n-hexane. Limits of detection (LODs) were in the range of 0.01-0.1 ngmL(-1) and 0.02-0.1 ngmL(-1) for distilled water and river water respectively, using time scheduled selected ion monitoring (SIM) mode. The method precision (RSD %) with four replicates was in the range of 1.6-14.6% for distilled water and 1.5-16.2% for river water at the concentration level of 5 ngmL(-1) while the linearity of method was in the range of 0.15-100 and 0.5-500 ngmL(-1). The developed method was successfully applied to different river water samples and the matrix factor for the spiked river water samples were found to be in the range of 0.74-1.09. PMID- 22204936 TI - Polymeric ionic liquid modified organic-silica hybrid monolithic column for capillary electrochromatography. AB - A polymeric ionic liquid (PIL) modified hybrid monolithic column for CEC was synthesized on the basis of mercaptopropy-functionalized (MP-silica) hybrid monolithic column which was prepared by the in situ co-condensation of tetramethoxysilane and 3-mercaptopropyltrimethoxysilane via a sol-gel process. The PIL modified (PImC8-silica) hybrid monolithic column, which was characterized by FT-IR and X-ray Photoelectron spectroscopy (XPS), generated a strong reversed and relatively stable EOF in a wide range of pH (3.0-8.0). The PImC8-silica hybrid monolithic column was evaluated by the separation of three aromatic hydrocarbons (AHs), four alkylbenzenes and five phenols, respectively, with phosphate buffers containing different ratios of acetonitrile as mobile phase. Reproducibilities of the column were also investigated by measuring RSDs of the migration time for AHs. RSDs of run-to-run (n=5), day-to-day (n=3) and column-to column (n=3) were in the range of 0.26-0.87%, 0.90-3.2% and 1.5-5.7%, respectively. PMID- 22204937 TI - Molecular-shape selective high-performance liquid chromatography: stabilization effect of polymer main chain by alternating copolymerization. AB - This work aims to clarify that stabilization or increased rigidity of polymer main chains as an organic stationary phase can lead the selectivity enhancement in high-performance liquid chromatography (HPLC). For this purpose, the alternating copolymer of octadecyl acrylate (ODA) with a cyclic monomer (N octadecylmaleimide, OMI) as a rigid segment was synthesized and compared with the ODA homopolymer. Both of the polymer-grafted silicas (Sil-poly(ODA-alt-OMI) and Sil-poly(ODA), respectively) were prepared by radical polymerization on 3 mercaptopropyltrimethoxysilane-modified silica. The characterizations were carried out by elemental analyses, diffuse reflectance infrared Fourier transform (DRIFT), and solid-state (13)C cross-polarization magic angle spinning nuclear magnetic resonance (CP-MAS-NMR) spectroscopies. Chromatographic behaviors were evaluated by the retention studies of shape-constrained isomers of polycyclic aromatic hydrocarbons (PAHs), isomers of tocopherol and carotenoids. Higher molecular-linearity selectivity toward PAHs was obtained on Sil-poy(ODA-alt-OMI) regardless of temperature changes but at temperature below 40 degrees C, Sil poly(ODA) showed better planarity selectivity than that of Sil-poy(ODA-alt-OMI). As a result, the higher separation ability toward tocopherols and carotenoids was obtained on Sil-poy(ODA-alt-OMI). These results indicate that the stabilization in the polymer main chain by alternating copolymerization and the stabilization in the side chains by a disordered-to-ordered phase transition were effective to enhance the molecular-shape selectivity. PMID- 22204938 TI - Towards the determination of an optimal scale for stormwater quality management: micropollutants in a small residential catchment. AB - Stormwater and atmospheric deposits were collected on a small residential urban catchment (0.8 ha) near Paris in order to determine the levels of certain micropollutants (using a preliminary scan of 69 contaminants, followed by a more detailed quantification of PAHs, PCBs, alkylphenols and metals). Atmospheric inputs accounted for only 10%-38% of the stormwater contamination (except for PCBs), thus indicating substantial release within the catchment. On this small upstream catchment however, stormwater contamination is significantly lower than that observed downstream in storm sewers on larger adjacent urban catchments with similar land uses. These results likely stem from cross-contamination activity during transfers inside the sewer system and underscore the advantages of runoff management strategies at the source for controlling stormwater pollutant loads. Moreover, it has been shown that both contamination levels and contaminant speciation evolve with the scale of the catchment, in correlation with a large fraction of dissolved contaminants in upstream runoff, which differs from what has been traditionally assumed for stormwater. Consequently, the choice of treatment device/protocol must be adapted to the management scale as well as to the targeted type of contaminant. PMID- 22204939 TI - Impact of sulfate pollution on anaerobic biogeochemical cycles in a wetland sediment. AB - The impact of sulfate pollution is increasingly being seen as an issue in the management of inland aquatic ecosystems. In this study we use sediment slurry experiments to explore the addition of sulfate, with or without added carbon, on the anaerobic biogeochemical cycles in a wetland sediment that previously had not been exposed to high levels of sulfate. Specifically we looked at the cycling of S (sulfate, dissolved and particulate sulfide--the latter measured as acid volatile sulfide; AVS), C (carbon dioxide, bicarbonate, methane and the short chain volatile fatty acids formate, acetate, butyrate and propionate), N (dinitrogen, ammonium, nitrate and nitrite) and redox active metals (Fe(II) and Mn(II)). Sulfate had the largest effects on the cycling of S and C. All the added S at lower loadings were converted to AVS over the course of the experiment (30 days). At the highest loading (8 mmol) less than 50% of consumed S was converted to AVS, however this is believed to be a kinetic effect. Although sulfate reduction was occurring in sediments with added sulfate, dissolved sulfide concentrations remained low throughout the study. Sulfate addition affected methanogenesis. In the absence of added carbon, addition of sulfate, even at a loading of 1 mmol, resulted in a halving of methane formation. The initial rate of formation of methane was not affected by sulfate if additional carbon was added to the sediment. However, there was evidence for anaerobic methane oxidation in those sediments with added sulfate and carbon, but not in those sediments treated only with carbon. Surprisingly, sulfate addition had little apparent impact on N dynamics; previous studies have shown that sulfide can inhibit denitrification and stimulate dissimilatory nitrate reduction to ammonia. We propose that because most of the reduced sulfur was in particulate form, levels of dissolved sulfide were too low to interfere with the N cycle. PMID- 22204940 TI - Cylindrospermopsin degradation in sediments--the role of temperature, redox conditions, and dissolved organic carbon. AB - One possible consequence of increasing water temperatures due to global warming in middle Europe is the proliferation of cylindrospermopsin-producing species from warmer regions. This may lead to more frequent and increased cylindrospermopsin (CYN) concentrations in surface waters. Hence, efficient elimination of CYN is important where contaminated surface waters are used as a resource for drinking water production via sediment passage. Sediments are often characterized by a lack of oxygen and low temperature (i.e. approx. 10 degrees C). The presence of dissolved organic carbon (DOC) is not only known to enhance but also to retard contaminant degradation by influencing the extent of lag phases. So far CYN degradation has only been investigated under oxic conditions and at room temperature. Therefore, the aim of our experiments was to understand CYN degradation, focusing on the effects of i) anoxic conditions, ii) low temperature (i.e. 10 degrees C) in comparison to room temperature (23+/-4 degrees C) and iii) DOC on lag phases. We used two natural sandy sediments (virgin and preconditioned) and surface water to conduct closed-loop column experiments. Anoxic conditions either inhibited CYN degradation completely or retarded CYN breakdown in comparison to oxic conditions (T(1/2) (oxic)=2.4 days, T(1/2) (anoxic)=23.6 days). A decrease in temperature from 20 degrees C to 10 degrees C slowed down degradation rates by a factor of 10. The presence of DOC shortened lag phases in virgin sediments at room temperature but induced a lag phase in preconditioned sediments at 10 degrees C, indicating potential substrate competition. These results show that information on physico-chemical conditions in sediments is crucial to assess the risk of CYN breakthrough. PMID- 22204941 TI - Evaluation of the Abraxis Strip Test for MicrocystinsTM for use with wastewater effluent and reservoir water. AB - Rapid tests for the microcystin-type cyanobacterial toxins that are designed to be able to be used in the field have recently become available. The tests provide a semi-quantitative result over a relatively narrow concentration range (10-fold) and are available with detection limits relevant for drinking water and recreational water compliance testing (1 MUg/L and 10 MUg/L, respectively). The aim of this research was to assess the applicability of these tests for the determination of microcystin-related toxicity in treated effluent from the Western Treatment Plant and potable source water from Tarago Reservoir, both near Melbourne, Australia. Accuracy, precision, cross-reactivity, matrix effects and inter-operator variability were assessed. The claimed mLR concentration response range of the tests was confirmed within reasonable limits, although the false negative and false positive rates were significant for spike concentrations below 2.5 MUg/L (Recreational Strip Test). Inter-operator variability was reasonably high (CV=23%) and this was exacerbated by the use of untrained scorers. Contributing to this was significant inter-assay variability in test band intensity (CV=28%). The strip tests responded to all 8 microcystin analogues tested and also to a mixture of another 7 analogues contained in a Certified Bloom Material. Cross-reactivity was always greater than 50%. Matrix effects due to the test waters or to cyanobacterial cell material were also relatively minor, being of the order of 2-fold at the maximum. Overall, these Strip Tests were found to be reliable for relatively rapid detection of microcystins around the upper limits of their response ranges, as recommended by the manufacturer. While the Recreational Water Strip test was less reliable in the lower ranges, it can be used in conjunction with the Drinking Water Strip test to reduce uncertainty around the 1 MUg/L concentration. Despite limitations, both strip tests provide near real-time information which can assist with day to day operational decisions. When results indicate microcystin concentrations near compliance limits it is recommended that use of the test kits should be supported by accurate quantitative toxin testing together with traditional algal cell counts, and possibly emerging qPCR methods for species and toxin gene detection. PMID- 22204942 TI - Temperature effect on nitrogen removal performance and bacterial community in culture of marine anammox bacteria derived from sea-based waste disposal site. AB - Anaerobic ammonium oxidation (anammox) bacteria have been detected in variety of marine environment in recent years, however, there have been only a few studies on their characteristics in the culture. The aim of this study is to reveal the effect of temperature on nitrogen removal ability and bacterial community in a culture of marine anammox bacteria (MAAOB). The MAAOB were cultured from the sediment of a sea-based waste disposal site at the North Port of Osaka Bay in Japan. The maximum nitrogen removal rate (NRR) was observed at 25 degrees C in the MAAOB culture, and it decreased both at below 20 degrees C and over 33 degrees C. The activation energy of the MAAOB culture was calculated to be 54.6 kJ mol(-1) in the 5 degrees C to 30 degrees C range. No significant change in bacterial community according with temperature (5-37 degrees C) was confirmed in the results of polymerase chain reaction and denaturing gradient gel electrophoresis (PCR-DGGE). Meanwhile, a number of bacteria related to the oxidation-reduction reaction of sulfur were confirmed and it is speculated that they involved in the activity of MAAOB and nitrogen removal ability in the culture. PMID- 22204943 TI - Coordination chemistry of copper proteins: how nature handles a toxic cargo for essential function. AB - Biological copper is coordinated predominantly by just three ligand types: the side chains of histidine, cysteine, and methionine, with of course some exceptions. The arrangement of these components, however, is fascinating. The diversity provided by just these three ligands provides choices of nitrogen vs. sulfur, neutral vs. charged, hydrophilic vs. hydrophobic, susceptibility to oxidation, and degree of pH-sensitivity. In this review we examine how the total number of ligands, their spatial arrangement and solvent accessibility, the various combinations of imidazole, thiolate, and thioether donors, all work together to provide binding sites that either enable copper to carry out a function, or safely transport it in a way that prevents toxic reactivity. We separate copper proteins into two broad classes, those that utilize the metal as a cofactor, or those that traffic the metal. Enzymes and proteins that utilize copper as a cofactor use high affinity sites of high coordination numbers of 4-5 that prevent loss of the metal during redox cycling. Copper trafficking proteins, on the other hand, promote metal transfer either by having low affinity binding sites with moderate coordination number ~4, or by having lower coordinate binding sites of 2-3 ligands that bind with high affinity. Both strategies retain the metal but allow transfer under appropriate conditions. Analysis of studies from our own lab on model peptides, combined with those from other labs, raises an interesting hypothesis that various methionine/histidine/cysteine combinations provide organisms with dynamic, multifunctional domains on copper trafficking proteins that facilitate copper transfer under different extracellular, subcellular, and tissue-specific scenarios of pH, redox environment, and presence of other copper carriers or target proteins. PMID- 22204944 TI - Efficacy and tolerance of gastrostomy feeding in Japanese muscular dystrophy patients. AB - Although muscular dystrophy patients often have feeding difficulty and need long term enteral nutrition, only a few reports have described gastrostomy feeding in these patients. This study was designed to evaluate the efficacy and tolerance of gastrostomy feeding in patients with muscular dystrophy. We performed a retrospective, multicenter study on 144 patients with muscular dystrophy who received gastrostomy feeding between 2007 and 2009 in 25 neuromuscular centers in Japan. There were 77 Duchenne muscular dystrophy (median age at gastrostomy placement 26 years, range 13-47 years), 40 myotonic dystrophy (median age 54.5 years, range 13-70 years), 11 Fukuyama congenital muscular dystrophy (median age 22 years, range 13-29 years), 5 limb girdle muscular dystrophy (median age 62 years, range 43-78 years), and 5 facioscapulohumeral muscular dystrophy (median age 52 years, range 28-67 years) patients. Many benefits including amelioration of malnutrition, swallowing difficulty and respiratory status were observed after the introduction of gastrostomy feeding. Especially in patients with Duchenne muscular dystrophy, mean body weight significantly increased after gastrostomy placement. Although most complications, which are commonly observed in other populations, were tolerable, respiratory failure and peritonitis were important concerns. These findings suggest that gastrostomy placement at an appropriate time is advisable in patients with muscular dystrophy. PMID- 22204945 TI - The relationship between social support and adolescent dating violence: a comparison across genders. AB - Although much research has focused on the function of social support in adult intimate partner violence, little is known about the role of social support in adolescent dating violence. This study is an exploratory analysis of the independent impact of social support from friends and family on the risk of adolescent dating violence perpetration and victimization among a large sample of youth (n = 970). Approximately, 21% of the sample reported experiencing victimization in a dating relationship whereas 23% indicated perpetrating dating violence. Male youth reported significantly more involvement in dating violence as both perpetrators and victims. Negative binomial regression modeling indicated that increased levels of support from friends was associated with significantly less dating violence perpetration and victimization; however, when gendered models were explored, the protective role of social support was only maintained for female youth. Family support was not significantly related to dating violence in any model. Implications for dating violence curriculum and future research are addressed. PMID- 22204946 TI - Dating violence perpetration and/or victimization and associated sexual risk behaviors among a sample of inner-city African American and Hispanic adolescent females. AB - The purpose of this study is to examine the prevalence of physical and psychological dating violence victimization and perpetration reported by inner city African American and Hispanic adolescent girls as well as associated risky sexual behaviors among this population. Participants in this study were 10th- and 11th-grade female students from seven inner-city Chicago public high schools. Participants were administered with the Safe Dates measures of physical violence victimization, physical violence perpetration, psychological abuse victimization, and psychological perpetration. Approximately half of the sample reported some psychological dating violence victimization and perpetration, and approximately one third reported some physical victimization and perpetration. Hispanic adolescents were significantly more likely to report psychological victimization, whereas African American adolescents were significantly more likely to report physical dating violence perpetration. Victimization was found to predict perpetration in this population, and adolescents who acknowledged being both victims and perpetrators of dating violence were more likely to report having had vaginal sex and a higher number of past-year sexual partners. Inner-city African American and Hispanic adolescent girls may be particularly vulnerable to dating violence victimization and perpetration, which may be due to a number of other social factors not explored within this study. Furthermore, African American adolescent girls continue to engage in behaviors that increase their risk for negative health outcomes, predominantly STIs, highlighting the need for effective interventions with this population. PMID- 22204947 TI - Insomnia, nightmare frequency, and nightmare distress in victims of sexual abuse: the role of perceived social support and abuse characteristics. AB - In this study of victims of sexual abuse, the aim was to investigate the role of perceived social support and abuse characteristics in self-reported insomnia, nightmare frequency, and nightmare distress. Four hundred sixty Norwegian victims of sexual abuse completed a questionnaire assessing perceived social support, abuse characteristics, insomnia, nightmare frequency, and nightmare distress. Results show that higher levels of perceived social support were related to lower scores on all symptom outcome measures. Abuse involving oral, genital, or anal penetration was related to more insomnia symptoms. Longer duration of abuse and threatening conducted by the perpetrator were related to higher nightmare frequency, while threats and abuse involving penetration were related to higher degrees of distress associated with nightmares. In conclusion, the present study provides preliminary data indicating that perceived social support may affect the nature of sleep difficulties in sexual abuse victims. Also, more severe forms of sexual abuse are related to higher levels of sleep difficulties. PMID- 22204948 TI - A brief program improves counseling of mothers with children who have persistent aggression. AB - OBJECTIVE: To assess whether a multimedia program can affect counseling behavior related to one of the strongest risk factors for violence later in life, persistent early childhood aggression. METHOD: The design was a controlled trial with unobtrusive measurement in a clinic setting. A researcher, pretending to be the mother of a 2 1/2 year old boy, called 19 pediatric residents during clinic hours and requested advice on how to manage her child's persistently hurtful behavior. The intervention was a 40-min lecture focusing on a multimedia program, Play Nicely, which teaches accepted strategies for managing aggression in young children ages 1-7 years. Residents' responses were blindly assessed to determine the treatment effect of the intervention. RESULTS: Compared with the control group (C), residents in the intervention (I) group were more likely to recommend setting the rule (I: 100% vs. C: 31%, p = .01), redirecting (I: 83% vs. C: 8%, p = .003), promoting empathy (I: 50% vs. C: 0%, p = .02), and more likely to discourage the use of physical punishment (I: 83% vs. C: 31%). These are the primary strategies encouraged by the intervention. The magnitude of the effect size was very large for each of these three strategies, ranging from d = 1.1 to 2.3. CONCLUSIONS: A brief intervention can improve the counseling behavior of primary care physicians regarding persistent childhood aggression. The findings have implications for child abuse prevention, violence prevention, medical education, and how to improve anticipatory guidance within primary care. PMID- 22204950 TI - Medial prefrontal cortex endocannabinoid system modulates baroreflex activity through CB(1) receptors. AB - Neural reflex mechanisms, such as the baroreflex, are involved in the regulation of cardiovascular system activity. Previous results from our group (Resstel LB, Correa FM. Medial prefrontal cortex NMDA receptors and nitric oxide modulate the parasympathetic component of the baroreflex. Eur J Neurosci 23: 481-488, 2006) have shown that glutamatergic synapses in the ventral portion of the medial prefrontal cortex (vMPFC) modulate baroreflex activity. Moreover, glutamatergic neurotransmission in the vMPFC can be modulated by the endocannabinoids system (eCBs), particularly the endocannabinoid anandamide, through presynaptic CB(1) receptor activation. Therefore, in the present study, we investigated eCBs receptors that are present in the vMPFC, and more specifically whether CB(1) receptors modulate baroreflex activity. We found that bilateral microinjection of the CB(1) receptor antagonist AM251 (100 or 300 pmol/200 nl) into the vMPFC increased baroreflex activity in unanesthetized rats. Moreover, bilateral microinjection of either the anandamide transporter inhibitor AM404 (100 pmol/200 nl) or the inhibitor of the enzyme fatty acid amide hydrolase that degrades anandamide, URB597 (100 pmol/200 nl), into the MPFC decreased baroreflex activity. Finally, pretreatment of the vMPFC with an ineffective dose of AM251 (10 pmol/200 nl) was able to block baroreflex effects of both AM404 and URB597. Taken together, our results support the view that the eCBs in the vMPFC is involved in the modulation of baroreflex activity through the activation of CB(1) receptors, which modulate local glutamate release. PMID- 22204949 TI - Relationships among alcohol outlet density, alcohol use, and intimate partner violence victimization among young women in the United States. AB - Greater access to alcohol has been widely found to be associated with many negative outcomes including violence perpetration. This study examines the relationship between alcohol outlet density, alcohol use, and intimate partner violence (IPV) victimization among young women in the United States. A direct association between alcohol outlet density in one's neighborhood and the likelihood of IPV victimization was examined. Data were from Wave III of the National Longitudinal Study of Adolescent Health (Add Health), which followed a nationally representative sample of adolescents into adulthood. Participants were young adult females age 18 to 26 at Wave III. Of the 4,571 female respondents who reported a current heterosexual relationship and had IPV data, 13.2% reported having been the victim of physical violence only and 6.5% experienced sexual only or physical and sexual violence in the relationship during the past year. In the regression models tested, there was no significant direct association between neighborhood alcohol outlet density and IPV victimization nor was there an association between outlet density and drinking behaviors, thus eliminating the possibility of an indirect association. Results of fully adjusted models indicate females who drank heavily, whether infrequently or frequently, were at significant risk for experiencing sexual only IPV or sexual and physical IPV. Asians and Native Americans were at significantly greater odds of experiencing sexual only or sexual and physical IPV compared with non-Hispanic Whites, while non-Hispanic Blacks were at significantly greater odds for physical only IPV. We conclude that a continuous measure of alcohol outlet density was not associated with IPV in models controlling for individual and other neighborhood characteristics. Young women who drink heavily, whether infrequently or frequently, have greater odds of experiencing sexual only or sexual and physical compared to abstainers. Similar to previous study findings, young women living with or married to their partner were at far greater risk of experiencing physical only and/or sexual only or sexual and physical IPV. The study adds to the growing body of literature that examines how community characteristics such as outlet density influence the likelihood of IPV. PMID- 22204952 TI - Potassium excretion through ROMK potassium channel expressed in gill mitochondrion-rich cells of Mozambique tilapia. AB - Despite recent progress in physiology of fish ion homeostasis, the mechanism of plasma K+ regulation has remained unclear. Using Mozambique tilapia, a euryhaline teleost, we demonstrated that gill mitochondrion-rich (MR) cells were responsible for K+ excretion, using a newly invented technique that insolubilized and visualized K+ excreted from the gills. For a better understanding of the molecular mechanism of K+ excretion in the gills, cDNA sequences of renal outer medullary K+ channel (ROMK), potassium large conductance Ca(2+)-activated channel, subfamily M (Maxi-K), K(+)-Cl(-) cotransporters (KCC1, KCC2, and KCC4) were identified in tilapia as the candidate molecules that are involved in K+ handling. Among the cloned candidate molecules, only ROMK showed marked upregulation of mRNA levels in response to high external K+ concentration. In addition, immunofluorescence microscopy revealed that ROMK was localized in the apical opening of gill MR cells, and that the immunosignals were most intense in the fish acclimated to the environment with high K+ concentration. To confirm K+ excretion via ROMK, K+ insolubilization-visualization technique was applied again in combination with K+ channel blockers. The K+ precipitation was prevented in the presence of Ba2+, indicating that ROMK has a pivotal role in K+ excretion. The present study is the first to demonstrate that the fish excrete K+ from the gill MR cells, and that ROMK expressed in the apical opening of the MR cells is a main molecular pathway responsible for K+ excretion. PMID- 22204951 TI - Modulation of cardiopulmonary depressor reflex in nucleus ambiguus by electroacupuncture: roles of opioids and gamma-aminobutyric acid. AB - Stimulation of cardiopulmonary receptors with phenylbiguanide (PBG) elicits depressor cardiovascular reflex responses, including decreases in blood pressure and heart rate mediated in part by the brain stem parasympathetic cardiac neurons in the nucleus ambiguus (NAmb). The present study examined NAmb neurotransmitter mechanisms underlying the influence of electroacupuncture (EA) on the PBG-induced hypotension and bradycardia. We hypothesized that somatic stimulation during EA modulates PBG responses through opioid and gamma-aminobutyric acid (GABA) modulation in the NAmb. Anesthetized and ventilated cats were studied during repeated stimulation with PBG or cardiac vagal afferents while low-frequency EA (2 Hz) was applied at P5-6 acupoints overlying the median nerve for 30 min and NAmb neuronal activity, heart rate, and blood pressure were recorded. Microinjection of kainic acid into the NAmb attenuated the PBG-induced bradycardia from -60 +/- 11 to -36 +/- 11 beats/min. Likewise, EA reduced the PBG induced depressor and bradycardia reflex by 52 and 61%, respectively. Cardiac vagal afferent evoked preganglionic cellular activity in the NAmb was reduced by EA for about 60 min. Blockade of opioid or GABA(A) receptors using naloxone and gabazine reversed the EA-related modulation of the evoked cardiac vagal activity by 73 and 53%, respectively. Similarly, naloxone and gabazine reversed EA modulation of the negative chronotropic responses from -11 +/- 5 to -23 +/- 6 and -13 +/- 4 to -24 +/- 3 beats/min, respectively. Thus EA at P5-6 decreases PBG evoked hypotension and bradycardia as well as the NAmb PBG-sensitive preganglionic cardiac vagal outflow through opioid and GABA neurotransmitter systems. PMID- 22204953 TI - Fish oil prevents high-saturated fat diet-induced impairments in adiponectin and insulin response in rodent soleus muscle. AB - High saturated fatty acid (SFA) diets contribute to the development of insulin resistance, whereas fish oil-derived n-3 polyunsaturated fatty acids (PUFA) increase the secretion of adiponectin (Ad), an adipocyte-derived protein that stimulates fatty acid oxidation (FAO) and improves skeletal muscle insulin response. We sought to determine whether fish oil could prevent and/or restore high SFA diet-induced impairments in Ad and insulin response in soleus muscle. Sprague-Dawley rats were fed 1) a low-fat control diet (CON group), 2) high-SFA diet (SFA group), or 3) high SFA with n-3 PUFA diet (SFA/n-3 PUFA group). At 4 wk, CON and SFA/n-3 PUFA animals were terminated, and SFA animals were either terminated or fed SFA or SFA/n-3 PUFA for an additional 2 or 4 wk. The effect of diet on Ad-stimulated FAO, insulin-stimulated glucose transport, and expression of Ad, insulin and inflammatory signaling proteins was determined in the soleus muscle. Ad stimulated FAO in CON and 4 wk SFA/n-3 PUFA (+36%, +39%, respectively P <= 0.05) only. Insulin increased glucose transport in CON, 4 wk SFA/n-3 PUFA, and 4 wk SFA + 4 wk SFA/n-3 PUFA (+82%, +33%, +25%, respectively P <= 0.05); this effect was lost in all other groups. TLR4 expression was increased with 4 wk of SFA feeding (+24%, P <= 0.05), and this was prevented in 4 wk SFA/n-3 PUFA. Suppressor of cytokine signaling-3 expression was increased in SFA and SFA/n-3 PUFA (+33 and +18%, respectively, P <= 0.05). Our results demonstrate that fish oil can prevent high SFA diet-induced impairments in both Ad and insulin response in soleus muscle. PMID- 22204954 TI - Proteins regulating cap-dependent translation are downregulated during total knee arthroplasty. AB - Total knee arthroplasty (TKA) utilizes a tourniquet to reduce blood loss, maintain a clear surgical "bloodless" field, and to ensure proper bone-implant cementing. In 2007, over 600,000 TKAs were performed in the United States, and this number is projected to increase to 3.48 million procedures performed annually by 2030. The acute effects of tourniquet-induced ischemia-reperfusion (I/R) on human skeletal muscle cells are poorly understood and require critical investigation, as muscle atrophy following this surgery is rapid and represents the most significant clinical barrier to long-term normalization of physical function. To determine the acute effects of I/R on skeletal muscle cells, biopsies were obtained at baseline, maximal ischemia (prior to tourniquet release), and reperfusion (following tourniquet release). Quadriceps volume was determined before and 2 wk post-TKA by MRI. We measured a 36% decrease in phosphorylation of Akt Ser(473) during ischemia and 37% during reperfusion (P < 0.05). 4E-BP1 Thr(37/46) phosphorylation decreased 29% during ischemia and 22% during reperfusion (P < 0.05). eEF2 Thr(56) phosphorylation increased 25% during ischemia and 43% during reperfusion (P < 0.05). Quadriceps volume decreased 12% in the TKA leg (P < 0.05) and tended to decrease (6%) in the contralateral leg (P = 0.1). These data suggest cap-dependent translation initiation, and elongation may be inhibited during and after TKA surgery. We propose that cap-dependent translational events occurring during surgery may precipitate postoperative changes in muscle cells that contribute to the etiology of muscle atrophy following TKA. PMID- 22204956 TI - Permeability properties of the teleost gill epithelium under ion-poor conditions. AB - Permeability properties of the goldfish gill epithelium were examined in vivo and in vitro following exposure to ion-poor water (IPW) conditions. In gill tissue of IPW-acclimated goldfish, transcript abundance of tight junction (TJ) proteins occludin, claudin-b, -d, -e, -h, -7, and -8d increased, whereas ZO-1 and claudin 12 mRNA decreased and claudin-c was unaltered. In association with these changes, TJ depth increased among gill pavement cells (PVCs) and gill PVCs and mitochondria-rich cells (MRCs). PVC and MRC gill cell fractions were isolated using Percoll. Transcripts encoding for occludin, claudin-b, -c, -d, -e, -h, -7, 8d, -12, and ZO-1 were present in both fractions. After IPW acclimation, occludin, claudin-b and -e, and ZO-1 mRNA abundance increased in both fractions. In contrast, claudin-8d mRNA abundance increased in PVCs only while claudin-h decreased in MRCs. Gill permeability was examined using primary cultured goldfish PVC epithelia supplemented with serum derived from IPW-acclimated goldfish. IPW serum supplementation increased transepithelial resistance, reduced [(3)H]PEG 4000 permeability, and enhanced epithelial integrity during in vitro IPW exposure. IPW serum increased mRNA abundance of occludin, claudin-8d and -e in vitro. Using small interfering RNA, we found that occludin abundance was decreased in cultured gill epithelia, resulting in an increase in [(3)H]PEG-4000 flux. As occludin increased in the gills of IPW-acclimated fish as well as cultured gill epithelia exposed to IPW serum, results suggest that occludin is a barrier-forming TJ protein in fish gill epithelia. These studies support the idea that TJ proteins play an important role in regulating gill permeability in IPW. PMID- 22204955 TI - Detrusor expulsive strength is preserved, but responsiveness to bladder filling and urinary sensitivity is diminished in the aging mouse. AB - The prevalence of urinary symptoms increases with age and is a significant source of distress, morbidity, and expense in the elderly. Recent evidence suggests that symptoms in the aged may result from sensory dysfunction, rather than abnormalities of detrusor performance. Therefore, we employed a pressure/flow multichannel urethane-anesthetized mouse cystometry model to test the hypothesis that in vivo detrusor performance does not degrade with aging. Secondarily, we sought to evaluate sensory responsiveness to volume using pressure-volume data generated during bladder filling. Cystometric data from 2-, 12-, 22-, and 26-mo old female C57BL6 mice were compared. All 2- and 12-mo-old mice, 66% of 22-mo-old mice, and 50% of 26-mo-old mice responded to continuous bladder filling with periodic reflex voiding. Abdominal wall contraction with voiding had a minimal contribution to expulsive pressure, whereas compliance pressure was a significant contributor. Maximum bladder pressure, estimated detrusor pressure, detrusor impulse (pressure-time integral), as well as indices of detrusor power and work, did not decrease with aging. Bladder precontraction pressures decreased, compliance increased, and nonvoiding contraction counts did not change with increasing age. Intervoid intervals, per-void volumes, and voiding flow rates increased with age. Calculations approximating wall stress during filling suggested loss of bladder volume sensitivity with increasing age. We conclude that aging is associated with an impaired ability to respond to the challenge of continuous bladder filling with cyclic voiding, yet among responsive animals, voiding detrusor contraction strength does not degrade with aging in this murine model. Furthermore, indirect measures suggest that bladder volume sensitivity is diminished. Thus, changes in homeostatic reserve and peripheral and/or central sensory mechanisms may be important contributors to aging-associated changes in bladder function. PMID- 22204958 TI - Influence of hyperglycemia during and after pregnancy on postpartum vascular function. AB - Endothelial dysfunction is commonly observed in women with a previous diagnosis of gestational diabetes mellitus (GDM). Whether arterial stiffness is also related to pregnancy and/or postpartum glucose intolerance has not been determined. We examined the influence of GDM during pregnancy and hyperglycemia in the postpartum period on arterial function. Thirty postpartum women were stratified into one of three groups: 1) normoglycemic pregnancy, normoglycemic postpartum (NORM), 2) GDM during pregnancy, normoglycemic postpartum (GDM-N); and 3) GDM during pregnancy, hyperglycemic postpartum (GDM-H). Ten never-pregnant controls were also recruited (Control). All measures were made at 2 mo postpartum or in the early follicular phase in Control women. Arterial stiffness was assessed by pulse wave velocity (PWV) and brachial and carotid artery distensibility. Endothelial function was determined by flow-mediated dilation (FMD). PWV was not different between the four groups. Distensibility of the brachial and carotid arteries was lower in GDM-N women (brachial: 1.1 * 10(-3) mmHg(-1) +/- 3.6 * 10(-4); carotid: 2.0 * 10(-3) +/- 3.3 * 10(-4)) and GDM-H (brachial: 1.4 * 10(-3) mmHg(-1) +/- 4.1 * 10(-4); carotid: 1.8 * 10(-3) mmHg(-1) +/- 5.0 * 10(-4)) compared with NORM women (brachial: 3.4 * 10(-3) mmHg(-1) +/- 7.0 * 10(-4); carotid: 3.9 * 10(-3) +/- 7.4 * 10(-4)). However, only brachial artery distensibility returned to Control levels by 2 mo postpartum in the NORM women. FMD was lower in previously GDM women (GDM-N: 4.1% +/- 2.3; GDM-H: 4.4% +/ 0.9) compared with NORM women (10.8% +/- 1.3; P < 0.01). These findings suggest that the vascular function of women in the early postpartum period is influenced by GDM during pregnancy and the persistence of clinical and/or subclinical hyperglycemia after delivery. PMID- 22204957 TI - Activation of the central melanocortin system contributes to the increased arterial pressure in obese Zucker rats. AB - We have previously demonstrated that leptin-mediated activation of the central nervous system (CNS) melanocortin system reduces appetite and increases sympathetic activity and blood pressure (BP). In the present study we examined whether endogenous melanocortin system activation, independent of leptin's actions, contributes to the regulation of BP and metabolic functions in obese Zucker rats, which have mutated leptin receptors. The long-term cardiovascular and metabolic effects of central melanocortin-3/4 receptor (MC3/4R) antagonism with SHU-9119 were assessed in lean (n = 6) and obese (n = 8) Zucker rats. BP and heart rate (HR) were measured 24-h/day by telemetry and an intracerebroventricular cannula was placed in the brain lateral ventricle. After stable control measurements, SHU-9119 was infused intracerebroventricularlly (1 nmol/h) for 10 days followed by a 10-day recovery period. Chronic CNS MC3/4R antagonism significantly increased food intake and body weight in lean (20 +/- 1 to 45 +/- 2 g and 373 +/- 11 to 432 +/- 14 g) and obese (25 +/- 2 to 35 +/- 2 g and 547 +/- 10 to 604 +/- 11 g) rats. No significant changes were observed in plasma glucose levels in lean or obese rats, whereas plasma leptin and insulin levels markedly increased in lean Zucker rats during CNS MC3/4R antagonism. Chronic SHU-9119 infusion in obese Zucker rats reduced mean arterial pressure (MAP) and HR by 6 +/- 1 mmHg and 24 +/- 5 beats/min, whereas in lean rats SHU 9119 infusion reduced HR by 31 +/- 9 beats/min while causing only a transient decrease in MAP. These results suggest that in obese Zucker rats the CNS melanocortin system contributes to elevated BP independent of leptin receptor activation. PMID- 22204959 TI - Chronic intermittent hypoxia alters glutamatergic control of sympathetic and respiratory activities in the commissural NTS of rats. AB - Sympathetic overactivity and altered respiratory control are commonly observed after chronic intermittent hypoxia (CIH) exposure. However, the central mechanisms underlying such neurovegetative dysfunctions remain unclear. Herein, we hypothesized that CIH (6% O(2) every 9 min, 8 h/day, 10 days) in juvenile rats alters glutamatergic transmission in the commissural nucleus tractus solitarius (cNTS), a pivotal site for integration of peripheral chemoreceptor inputs. Using an in situ working heart-brain stem preparation, we found that l-glutamate microinjections (1, 3, and 10 mM) into the cNTS of control rats (n = 8) evoked increases in thoracic sympathetic nerve (tSN) and central vagus nerve (cVN) activities combined with inhibition of phrenic nerve (PN) activity. Besides, the ionotropic glutamatergic receptor antagonism with kynurenic acid (KYN; 250 mM) in the cNTS of control group (n = 7) increased PN burst duration and frequency. In the CIH group (n = 10), the magnitude of l-glutamate-induced cVN excitation was smaller, and the PN inhibitory response was blunted (P < 0.05). In addition, KYN microinjections into the cNTS of CIH rats (n = 9) did not alter PN burst duration and produced smaller increases in its frequency compared with controls. Moreover, KYN microinjections into the cNTS attenuated the sympathoexcitatory response to peripheral chemoreflex activation in control but not in CIH rats (P < 0.05). These functional CIH-induced alterations were accompanied by a significant 10% increase of N-methyl-D-aspartate receptor 1 (NMDAR1) and glutamate receptor 2/3 (GluR2/3) receptor subunit density in the cNTS (n = 3-8, P < 0.05), evaluated by Western blot analysis. These data indicate that glutamatergic transmission is altered in the cNTS of CIH rats and may contribute to the sympathetic and respiratory changes observed in this experimental model. PMID- 22204961 TI - Nonlipidized juvenile xanthogranuloma: an unusual variant with a potential diagnostic pitfall. AB - Juvenile xanthogranuloma (JXG) is a histiocytic inflammatory disorder that can present different histologic patterns. Classic JXG consists of sheets of foamy histiocytes and numerous multinucleated Touton giant cells. Nonlipidized JXG (NJXG) is one of the unusual variants of JXG, consisting of a diffuse monomorphic infiltrate of mononuclear histiocytes, suggesting an aggressive or malignant tumor due the high mitotic index. However, NJXG behaves clinically as classic JXG. We present an unusual case of a 6-year-old boy who presented an exophytic ulcerated nodule on the lower lip diagnosed as NJXG. The boy is currently well without recurrence three years after surgical excision. PMID- 22204960 TI - Acoustic brainstem implant in a post-meningitis deafened child-Lessons learned. AB - We report a case of a deafened child with advanced labyrinthitis ossificans resulting from meningo-encephalitis. She received a cochlear implant in the right ear, following a drill-out procedure. Post-implant hearing outcomes were satisfactory initially, but deteriorated over time as a result of partial electrode migration. The child subsequently received a left auditory brainstem implantation with improvement of hearing outcomes. Post-operatively, a sub-dural hematoma developed not on the side of the operation but on the opposite side. Simultaneous use of the cochlear implant on one side and the acoustic brainstem on the other, aggravated the non-auditory side effects of the ABI and compromised its potential for optimal hearing results. PMID- 22204962 TI - [Malaria imported into Spain]. PMID- 22204963 TI - Congenital fistula of palate. PMID- 22204964 TI - Vitamin D and incidence of diabetes: a prospective cohort study. AB - BACKGROUND & AIMS: To investigate the relationship between levels of 25 hydroxyvitamin D and the incidence of type 2 diabetes in a Spanish population. METHODS: We undertook a population-based prospective study in a population from southern Spain. The first phase of the study (1996-1998) included 1226 individuals. Of this original cohort, 988 persons were reassessed in 2002-2004 and 961 in 2005-2007. Measurements were made of 25-hydroxyvitamin D and intact parathyroid hormone in 2002-2004 and an oral glucose tolerance test was done in three time points. RESULTS: The incidence of diabetes in subjects with 25 hydroxyvitamin D levels <= 18.5 ng/mL (percentile 25) was 12.4% vs 4.7% in subjects with levels >18.5 ng/mL. The likelihood of having diabetes during the four years of follow-up was significantly lower in the subjects with higher levels of 25-hydroxyvitamin D [OR = 0.17 (0.05-0.61)]. None of the subjects with levels higher than 30 ng/mL developed diabetes. CONCLUSION: In this prospective study, we found a significant inverse association between serum 25-hydroxyvitamin D levels and the risk for type 2 diabetes in a population from the south of Spain. PMID- 22204965 TI - The RhoA GTPase-activating protein DLC2 modulates RhoA activity and hyperalgesia to noxious thermal and inflammatory stimuli. AB - Deleted in liver cancer 2 (DLC2) is a novel Rho GTPase-activating protein that regulates RhoA activity. DLC2 is ubiquitously expressed in most tissues, including the brain, spinal cord and peripheral nerves, and is thought to be involved in actin cytoskeletal reorganization. Unlike DLC1-deficient mice, DLC2 deficient mice (DLC2(-/-)) are viable and without gross anatomical abnormalities. Interestingly, DLC2(-/-) mice exhibit hyperalgesia to noxious thermal stimuli and inflammation-inducing chemicals, such as formalin and acetic acid. There was no difference in the structure or morphology of cutaneous or sural nerves between DLC2(+/+) and DLC2(-/-) mice. However, sensory nerve conduction velocity in DLC2( /-) mice was significantly higher than that in DLC2(+/+) mice, whereas motor nerve conduction velocity was not affected. After formalin injection, DLC2(-/-) mice showed increased RhoA activity in the spinal cord and an increased number of phosphorylated ERK1/2-positive cells. The inflammatory hyperalgesia in DLC2(-/-) mice appeared to be mediated through the activation of RhoA and ERK1/2. Taken together, DLC2 plays a key role in pain modulation during inflammation by suppressing the activation of RhoA and ERK to prevent an exaggerated pain response, and DLC2(-/-) mice provide a valuable tool for further understanding the regulation of inflammatory pain. PMID- 22204966 TI - Outcome of twin reversed arterial perfusion sequence following treatment with interstitial laser: a retrospective study. AB - OBJECTIVES: To determine the outcome of twin reversed arterial perfusion (TRAP) sequence treated with or scheduled for treatment with interstitial laser therapy. METHODS: This is a retrospective study on ten pregnancies diagnosed with TRAP sequence. Seven of the ten pregnancies were treated with interstitial laser therapy, and two pregnancies were scheduled for later treatment. One pregnancy was treated with fetoscopic laser ablation and excluded from analysis. The delivery reports of all pregnancies were collected, the neonatal health status recorded and the median time of delivery and the treatment to delivery interval calculated. RESULTS: Six of seven pump fetuses in TRAP pregnancies treated with interstitial laser therapy at a median of 16+2 (range 13+1 to 20+3) gestational weeks were born healthy at a median of 38+0 (range 34+3 to 40+6) gestational weeks. One fetus treated with interstitial laser died after the procedure at 20+3 weeks. Two pump twins scheduled for later treatment died before the gestational age of 16 weeks. The median treatment to delivery interval for the surviving fetuses was 153 days (range 128-194). CONCLUSION: Treatment of TRAP sequence by interstitial laser therapy is feasible from the 13th week of gestation and has a good outcome. PMID- 22204967 TI - Electrophoretic deposition of TiO2 nanoparticles using organic dyes. AB - Electrophoretic deposition method has been developed for the deposition of TiO(2) nanoparticles modified with organic dyes. Alizarin red, alizarin yellow and pyrocatechol violet dyes were used for the dispersion and charging of TiO(2) in ethanol and anodic electrophoretic deposition of TiO(2) films. The deposition yield was varied by the variation of dye concentration in suspensions and deposition time. Aurintricarboxylic acid dye was used for the deposition of TiO(2) from aqueous suspensions. It was found that thin films of pure aurintricarboxylic acid and composite aurintricarboxylic acid TiO(2) films can be obtained. The deposition yield was studied by quartz crystal microbalance. Dye film thickness was varied in the range of 0.1-2 MUm by variation in the deposition time at a constant voltage. The composition of the films and the amount of the deposited material can be varied by the variation of TiO(2) and dye concentration in suspensions and deposition time. The films were studied by Fourier transform infrared spectroscopy, thermogravimetric analysis, differential thermal analysis and electron microscopy. The deposition mechanisms were discussed. The electrophoretic deposition method offers advantages for the fabrication of dye-sensitized TiO(2) films. PMID- 22204968 TI - Fe-ions modified mesoporous Bi2WO6 nanosheets with high visible light photocatalytic activity. AB - Fe-ions modified mesoporous Bi(2)WO(6) nanosheets (Fe-Bi(2)WO(6)) were successfully synthesized via a simple two-step method, which involved a template free hydrothermal process and a following impregnation treatment. The resultant products were characterized by XRD, TEM, XPS, EDX, ESR, UV-Vis, PL, and visible light photocatalytic measurements. Experimental results indicated that the addition of a small amount Fe-ions (optimized content at 0.1 wt.%) could evidently improve the activity of Bi(2)WO(6). The apparent reaction rate of Fe Bi(2)WO(6)-0.1% (k, 0.099 min(-1)) was 3.2 times higher than that of Fe Bi(2)WO(6)-0% (k, 0.031 min(-1)). The Fe-ions mainly existed as Fe(3+) and Fe(2+) ions, which were uniformly distributed on the surface of Bi(2)WO(6) nanosheets and some Fe(3+)-ions substituted Bi(3+)-ions in Bi(2)O(2) layers. Both of the concentration and state of Fe-ions played vital factors for the improved visible light photocatalytic activities. PMID- 22204969 TI - Interactions between surfactants and silver nanoparticles of varying charge. AB - The interaction between silver nanoparticles (Ag NPs) of different surface charge and surfactants relevant to the laundry cycle has been investigated to understand changes in speciation, both in and during transport from the washing machine. Ag NPs were synthesized to exhibit either a positive or a negative surface charge in solution conditions relevant for the laundry cycle (pH 10 and pH 7). These particles were characterized in terms of size and surface charge and compared to commercially laser ablated Ag NPs. The surfactants included anionic sodium dodecylbenzenesulfonate (LAS), cationic dodecyltrimethylammoniumchloride (DTAC) and nonionic Berol 266 (Berol). Surfactant-Ag NP interactions were studied by means of dynamic light scattering, Raman spectroscopy, zeta potential, and Quartz Crystal Microbalance. Mixed bilayers of CTAB and LAS were formed through a co operative adsorption process on positively charged Ag NPs with pre-adsorbed CTAB, resulting in charge reversal from positive to negative zeta potentials. Adsorption of DTAC on negatively charged synthesized Ag NPs and negatively charged commercial Ag NPs resulted in bilayer formation and charge reversal. Weak interactions were observed for nonionic Berol with all Ag NPs via hydrophobic interactions, which resulted in decreased zeta potentials for Berol concentrations above its critical micelle concentration. Differences in particle size were essentially not affected by surfactant adsorption, as the surfactant layer thicknesses did not exceed more than a few nanometers. The surfactant interaction with the Ag NP surface was shown to be reversible, an observation of particular importance for hazard and environmental risk assessments. PMID- 22204970 TI - Synthesis and self-assembly of amphiphilic gradient copolymer via RAFT emulsifier free emulsion polymerization. AB - The amphiphilic gradient copolymers of 2,2,2-trifluoroethyl methacrylate (TFEMA) and acrylic acid (AA) have been synthesized by using amphiphilic RAFT agent via emulsifier-free emulsion polymerization with a starved feed method of adding TFEMA. Different cosolvents are added into polymerization system to inhibit AA's homopolymerization of in aqueous phase. RAFT polymerization kinetics under different reaction conditions are discussed in detail. (1)H NMR results indicate that the obtained copolymer has a chain structure with AA segments gradually changing to TFEMA segments. The copolymer latexes exhibit good pH stability (pH value from 5 to 14) and Ca(2+) stability. The self-assembly behavior of gradient copolymers in selective solvents are observed and studied by transmission electron microscopy. All the copolymers can form spherical micelles, but the homogeneity and size of micelles are different. PMID- 22204971 TI - Facile control of surface wettability in TiO2/poly(methyl methacrylate) composite films. AB - A facile method to produce very hydrophobic surface was developed simply using the mixture of TiO(2) nanoparticles and poly(methyl methacrylate) (PMMA). When the volume ratio of TiO(2) to PMMA is between 35 vol.% and 50 vol.%, the mixture of two hydrophilic materials became very hydrophobic. Analysis of the molecular structure by infrared spectroscopy shows that the preferential orientation and attachment of a carbonyl group of a polymer molecule to the surface of TiO(2) nanoparticles play a critical role in the appearance of the strong hydrophobicity. When this composite was exposed to UV light, PMMA on the surface of the mixture film was decomposed through a photocatalytic reaction and the very hydrophobic surface turned to the superhydrophilic one. The superhydrophilic property of UV-irradiated composite lasts as long as several months. This long lasting superhydrophilicity is ascribed to the porous structure, which provides high roughness and strong capillary interaction. Easy transition from strong hydrophobicity to superhydrophilicity in TiO(2)/PMMA composites could be applied to designing high contrast hydrophilic/hydrophobic patterns. PMID- 22204972 TI - Interactions of gemini surfactants with two model proteins: NMR, CD, and fluorescence spectroscopies. AB - Gemini surfactants have two polar head groups and two hydrocarbon tails. Compared with conventional surfactants, geminis have much lower (MUM vs. mM) critical micelle concentrations and possess slower (ms vs. MUs) monomer <-- / --> micelle kinetics. The structure of the gemini surfactants studied is [HOCH(2)CH(2)-, CH(3)-, CH(3)(CH(2))(15)-N(+)-(CH(2))(s)-N(+)-(CH(2))(15)CH(3),-CH(3), CH(2)CH(2)OH].2Br(-) where s=4, 5, or 6. Our objective is to reveal the effect of these cationic gemini surfactants on the structure and stability of two model proteins: Ribonuclease A (RNase A) and Hen Egg White Lysozyme (HEWL). 2D (1)H NMR and Circular Dichroism (CD) spectroscopies show that the conformation of RNase A and HEWL is unaffected at low to neutral pH where these proteins are positively charged, although hydrogen exchange shows that RNase A's conformational stability is slightly lowered. At alkaline pH, where these proteins lose their net positive charge, fluorescence and CD spectroscopies and ITC experiments show that they do interact with gemini surfactants, and multiple protein*gemini complexes are observed. Based on the results, we conclude that these cationic gemini surfactants neither interact strongly with nor severely destabilize these well folded proteins in physiological conditions, and we advance that they can serve as useful membrane mimetics for studying the interactions between membrane components and positively charged proteins. PMID- 22204973 TI - Pickering emulsions stabilized by cellulose nanocrystals grafted with thermo responsive polymer brushes. AB - Cellulose nanocrystals (CNCs) from ramie fibers are studied as stabilizers of oil in-water emulsions. The phase behavior of heptane and water systems is studied, and emulsions stabilized by CNCs are analyzed by using drop sizing (light scattering) and optical, scanning, and freeze-fracture electron microscopies. Water-continuous Pickering emulsions are produced with cellulose nanocrystals (0.05-0.5 wt%) grafted with thermo-responsive poly(NIPAM) brushes (poly(NIPAM)-g CNCs). They are observed to be stable during the time of observation of 4 months. In contrast, unmodified CNCs are unable to stabilize heptane-in-water emulsions. After emulsification, poly(NIPAM)-g-CNCs are observed to form aligned, layered structures at the oil-water interface. The emulsions stabilized by poly(NIPAM)-g CNCs break after heating at a temperature above the LCST of poly(NIPAM), which is taken as indication of the temperature responsiveness of the brushes installed on the particles and thus the responsiveness of the Pickering emulsions. This phenomenon is further elucidated via rheological measurements, in which viscosities of the Pickering emulsions increase on approach of the low critical solution temperature of poly(NIPAM). The effect of temperature can be counterbalanced with the addition of salt which is explained by the reduction of electrostatic and steric interactions of poly(NIPAM)-g-CNCs at the oil-water interface. PMID- 22204974 TI - Preparation of rhenium nanoparticles via pulsed-laser decomposition and catalytic studies. AB - Rhenium (Re) nanoparticles have been synthesized by pulsed-laser decomposition of ammonium perrhenate (NH(4)ReO(4)) or dirhenium decacarbonyl (Re(2)(CO)(10)) in the presence of 3-mercaptopropionic acid (MPA) as capping agent, in both aqueous and organic media. Preliminary studies showed that the MPA-capped Re nanoparticles are capable of catalyzing the isomerization of 10-undecen-1-ol to internal alkenols via long chain migration of the C=C double bond at ca. 200 degrees C. A one-pot synthesis of graphite-coated Re nanoparticles has also been achieved by pulsed-laser decomposition of Re(2)(CO)(10), due to photo-induced catalytic graphitization of the phenyl groups of PPh(3) on the surface of rhenium nanoparticles. PMID- 22204975 TI - Application of supercritical CO2 and ionic liquids for the preparation of fluorinated nanocomposites. AB - This work is focused on the tailoring of dispersions of layered silicates, such as MICA SOMASIF (ME-100) within a fluoride matrix (polytetrafluoroethylene) through two strategies: the physicochemical interactions between filler and matrix and the processing of materials. The interactions in these complex systems are modified by new environmentally friendly thermally stable surfactants. The ionic liquids used are based on alkyltriphenyl phosphonium and perfluorinated alkylpyridinium cations. The influences of the cation-anion combination and functionalization were investigated. The use of the supercritical carbon dioxide (ScCO(2)) as a solvent is relevant to generate structuring within the material based on ionic liquid phase separation. The tunability of ionic liquids and their combination with the supercritical carbon dioxide enables to design materials with optimized thermal and mechanical properties. PMID- 22204976 TI - Parkin: much more than a simple ubiquitin ligase. AB - Parkin is mainly a cytosolic protein involved in a subset of Parkinson's disease (PD) cases referred to as autosomal juvenile recessive forms of PD. Most studies have established as a dogma that parkin function could be resumed as an ubiquitin ligase activity. Accordingly, several cellular functions ascribed to parkin derive from its ability to ubiquitinate a series of proteins, thereby rendering them prone to proteasomal degradation. Several lines of data indicated that parkin could display antiapoptotic properties and we demonstrated that indeed, parkin could downregulate the p53-dependent pathway. However, we showed that such function remained independent of parkin's ability to act as an ubiquitin ligase. Thus, we established that parkin repressed p53 transcription by physically interacting with its promoter. Here, we describe this novel parkin-associated transcription factor function and we speculate on putative additional transcriptional targets. PMID- 22204977 TI - Fast, easy ethanomethanolysis of Jatropha curcus oil for biodiesel production due to the better solubility of oil with ethanol in reaction mixture assisted by ultrasonication. AB - Biodiesel was obtained by transesterification of Jatropha curcus oil with anhydrous methanol, ethanol, and various mixtures of methanol/ethanol system. The present research work ultrasonic assisted transesterification of J. curcus oil was carried out in the presence of various mixtures of methanol/ethanol system and potassium hydroxide (KOH) as a catalyst, keeping the molar ratio of oil to alcohol 1:6. The methodology allows for the reaction to be run under atmospheric conditions. The ethanomethanolysis and ultrasonic mixing promote the rate of transesterification reaction due to the better solubility of oil with ethanol in reaction mixture and obtained methyl esters as well as ethyl esters. PMID- 22204978 TI - Dense coating of surface mounted CuBTC Metal-Organic Framework nanostructures on silk fibers, prepared by layer-by-layer method under ultrasound irradiation with antibacterial activity. AB - The growth of Cu(3)(BTC)(2) (BTC=1,3,5-benzenetricarboxylate), also known as CuBTC and HKUST-1, Metal-Organic Framework (MOF) nanostructures on silk fibers were achieved by layer-by-layer technique in alternating bath of Cu(OAc)(2) . 2H(2)O and H(3)BTC solutions under ultrasound irradiation. The effect of pH, reaction time, ultrasound irradiation and sequential dipping steps in growth of the CuBTC Metal-Organic Framework nanostructures has been studied. These systems depicted a decrease in the size accompanying a decrease in the sequential dipping steps. In addition, dense coating of silk fibers with CuBTC MOF results in decrease the emission intensity of silk fibers. The silk fibers containing CuBTC Metal-Organic Framework exhibited high antibacterial activity against Escherichia coli and Staphylococcus aureus. The samples were characterized with powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) spectra and scanning electron microscopy (SEM). XRD analyses indicated that the prepared CuBTC MOF nanostructures on silk fibers were crystalline. PMID- 22204979 TI - The role of endothelial cell-bound Jagged1 in Notch3-induced human coronary artery smooth muscle cell differentiation. AB - Phenotype regulation of vascular smooth muscle cells (VSMC) is an important requirement in both tissue engineering and balloon angioplasty strategies. In recent years, it has become increasingly evident that the Notch signalling pathway plays a critical role in regulating vascular morphogenesis during development and the transcription of differentiated VSMC and its maturation. In arteries, Notch3 is the predominant receptor on VSMC and, signalling is initiated upon binding to its ligand, Jagged1. However, little is known on how ligand presenting strategies affect Notch signalling and subsequently upregulation of smooth muscle cell differentiation. In this study, using human coronary artery smooth muscle cells (HCASMC) and human coronary artery endothelial cells (HCAEC), we show several lines of evidence that direct heterocellular cell-cell contact is necessary for VSMC differentiation via Notch3 signalling. First, neither the addition of soluble Jagged1 nor Jagged1 immobilized to protein G beads induced HCASMC differentiation in culture. Second, despite the upregulation of Notch3 expression, EC-conditioned medium failed to induce HCASMC differentiation. However, when HCASMC and HCAEC were co-cultured either on opposite sides of porous membrane or when these cells were co-cultured directly, both Notch3 and VSMC differentiation marker proteins were upregulated. These upregulations were abrogated by Jagged1-specific siRNA. This study provides the first direct evidence that contact of HCASMC and HCAEC is required for regulating smooth muscle cell differentiation. These findings may have clinical importance and therapeutic potential for modulating vascular SMC phenotype during various cardiovascular disease states and in tissue engineering. PMID- 22204980 TI - Effects of micropitted/nanotubular titania topographies on bone mesenchymal stem cell osteogenic differentiation. AB - Micro/nanotopographical modification of biomaterials constitutes a promising approach to direct stem cell osteogenic differentiation to promote osseointegration. In this work, titania nanotubes (NTs) 25 and 80 nm in size with the acid-etched Ti topography (AcidTi) and hierarchical hybrid micropitted/nanotubular topographies (Micro/5VNT and Micro/20VNT) are produced to mimic the structure of the natural bone extracellular matrix (ECM). The effects on bone mesenchymal stem cell (MSC) osteogenic differentiation are studied systematically by various microscopic and biological characterization techniques. Cell adhesion is assayed by nucleus fluorescence staining and cell proliferation is studied by CCK-8 assay and flow cytometry. Osteogenic differentiation is assayed by alkaline phosphatase (ALP) expression, collagen secretion, matrix mineralization, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis on the osteogenesis related gene expression. All the topographies are observed to induce MSC osteogenic differentiation in the absence of osteogenic supplements. The nanotube surfaces significantly promote cell attachment and spread, collagen secretion and ECM mineralization, as well as osteogenesis-related gene expression. Among them, Micro/20VNT shows the best ability to simultaneously promote MSC proliferation and osteogenic differentiation. Our results unambiguously demonstrate their excellent ability to support MSC proliferation and induce MSC osteogenic differentiation, especially those with the micropitted topography. PMID- 22204981 TI - Multifunctional pH-disintegrable micellar nanoparticles of asymmetrically functionalized beta-cyclodextrin-based star copolymer covalently conjugated with doxorubicin and DOTA-Gd moieties. AB - We report on a novel type of multifunctional pH-disintegrable micellar nanoparticles fabricated from asymmetrically functionalized beta-cyclodextrin (beta-CD) based star copolymers covalently conjugated with doxorubicin (DOX), folic acid (FA), and DOTA-Gd moieties for integrated cancer cell-targeted drug delivery and magnetic resonance (MR) imaging contrast enhancement. Asymmetrically functionalized beta-CD, (N(3))(7)-CD-(Br)(14), which possesses 7 azide functionalities and 14 alpha-bromopropionate moieties in the upper and lower rim of rigid toroidal beta-CD core, respectively, was synthesized at first. The subsequent atom transfer radical polymerization (ATRP) of N-(2-hydroxypropyl) methacrylamide (HPMA), conjugation with DOX and FA, and click reaction with alkynyl-(DOTA-Gd) complex afforded (DOTA-Gd)(7)-CD-(PHPMA-FA-DOX)(14) star copolymer comprising of 7 DOTA-Gd complex moieties and 14 PHPMA arms covalently anchored with DOX and FA via acid-labile carbamate linkages and ester bonds, respectively. The covalent conjugation with ~13 DOX molecules onto PHPMA arms per star copolymer (~14 wt% loading content) endows the initially hydrophilic one with amphiphilicity, leading to the self-assembly into micellar nanoparticles of several tens of nanometers in aqueous solution at pH 7.4. In vitro DOX release profile from micellar nanoparticles is highly pH-dependent, and over a time period of 42 h, cumulative releases of ~10%, 53%, and 89% conjugated DOX at pH 7.4, 5.0, and 4.0, respectively, were observed. Most importantly, the pH modulated release of conjugated DOX from micellar nanoparticles is accompanied with the micelle disintegration due to the loss of amphiphilicity of the star copolymer scaffold. In vitro cell viability assays revealed that (DOTA-Gd)(7)-CD (PHPMA(15))(14) star copolymer is almost non-cytotoxic up to a concentration of 0.5 g/L, whereas DOX-conjugated micellar nanoparticles of (DOTA-Gd)(7)-CD-(PHPMA FA-DOX)(14) can effectively enter and kill HeLa cells at a concentration higher than ~80 mg/L. In vitro MR imaging experiments indicated a considerably enhanced T(1) relaxivity (r(1) = 11.4 s(-1) mM(-1)) for micellar nanoparticles compared to that for the small molecule counterpart, alkynyl-DOTA-Gd (r(1) = 3.1 s(-1) mM( 1)). In vivo MR imaging assay in rats revealed considerable accumulation of micellar nanoparticles within rat liver and kidney and prominent positive contrast enhancement. The integrated design of diagnostic and therapeutic functions of multifunctional pH-disintegrable micellar nanoparticles augurs well for their practical applications in the field of image-guided cancer chemotherapy. PMID- 22204982 TI - First general methods toward aldehyde enolphosphates. AB - We herein report two innovative methods toward aldehyde enolphosphates and the first saccharidic aldehyde enolphosphates. Aldehyde enolphosphate function is worthwhile to be considered as a good phosphoenolpyruvate analogue. PMID- 22204983 TI - Campylobacter spp. distribution in biofilms on different surfaces in an agricultural watershed (Elk Creek, British Columbia): using biofilms to monitor for Campylobacter. AB - Despite its relevance to public health, presence and concentrations of Campylobacter spp. in biofilms in natural aquatic environments has not been investigated. This study examined the occurrence of Campylobacter spp. in biofilms on a variety of surfaces (river rock, slate rock, wood, LexanTM, sandpaper, and sediment) and in water from December 2005 to December 2006 to find a substratum that facilitated campylobacters detection in natural aquatic environments. Samples were collected at four sites in an agricultural watershed (Elk Creek, British Columbia). Campylobacter spp. presence was determined using culturing methods. Correlations between chemical, physical and microbiological water quality parameters and Campylobacter spp. distribution on different surface types were also investigated. Campylobacter spp. had a prevalence of 13% in the wet season, but was not recovered in the dry season. Its prevalence was highest in sediment (27%), followed by slate rock (22%), Lexan and wood (13%), river rock (9%) and water (8%), respectively. No Campylobacter spp. was found in sandpaper biofilms. Several other criteria were used to assess substrata effectiveness, such as correlation amongst Campylobacter spp., indicator bacteria and water quality parameters, cost and availability of substratum, potential for standardizing substratum, ease of biofilm removal and probability of substratum loss in situ. Results show that sediment, slate rock or wood could be used as substrata for Campylobacter spp. monitoring. The study also highlights the potential use of nitrates and enterococci as faecal contamination indicators to protect public health. PMID- 22204984 TI - Genotoxicity of uranium contamination in embryonic zebrafish cells. AB - Uranium is a metal used in the nuclear industry and for military applications. Studies on mammals have shown that uranium is genotoxic. However the molecular and cellular mechanisms responsible for the genotoxicity of uranium are poorly known for other types of vertebrates such as fish. Since unrepaired DNA double strand breaks (DSBs) are considered to be key lesions in cell lethality, the activity of one of the major DSB-repair pathways, i.e. non-homologous end-joining (NHEJ), has been evaluated in embryonic zebrafish cells (ZF4) exposed to uranium. Genotoxicity of uranium in ZF4 cells was further assessed by comet and micronucleus assays. Exposure to uranium results in the production of DSBs a few hours after incubation. These breaks trigger the phosphorylation of H2AX proteins. We showed that the DNA-PK kinase activity, essential for NHEJ, is altered by the presence of uranium. The presence of uranium in cells disturbs but does not inhibit the repair rate of DSBs. Such a result suggests an impact of uranium upon the reparability of DSBs and the potential activation of alternative DSBs repair pathway leading to the propagation of possible misrepaired DSBs. In parallel, we performed a transmission electron microscopy analysis of cells exposed to uranium and were able to localize internalized uranium using an Energy Dispersive X-ray microanalyser. We observed the formation of precipitates in lysosome-like vesicles for 250 MUM of uranium in the medium. The appearance of these precipitates is concomitant with the decrease of the number of DSBs per cell. This process might be a part of a defence system whose role in counteracting cytotoxicity calls for further dedicated research. PMID- 22204985 TI - Cytochrome P450 1C1 complementary DNA cloning, sequence analysis and constitutive expression induced by benzo-a-pyrene in Nile tilapia (Oreochromis niloticus). AB - CYP1C is the newest member of the CYP1 family of P450s; however, its physiological significance, inducers, and metabolic functions are unknown. In this study, a new complementary DNA of the CYP1C subfamily encoding CYP1C1 was isolated from Nile tilapia (Oreochromis niloticus) liver after intracoelomic injection with benzo-a-pyrene (BaP). The full-length cDNA was 2223 base pair (bp) long and contained an open reading frame of 1581 bp encoding a protein of 526 amino acids and a stop codon. The sequence exhibited 3' non-coding region of 642 bp. The deduced amino acid sequence of O. niloticus CYP1C1 shows similarities of 86, 82.5, 79.7, 78.7, 77.8, 75.5, 69.6 and 61.3% with scup CYP1C1, killifish CYP1C1,1C2, Japanese eel CYP1C1, zebra fish CYP1C1, common carp CYP1C1, scup CYP1C2, common carp CYP1C2 and zebra fish CYP1C2, respectively. Phylogenetic tree based on the amino acids sequences clearly shows tilapia CYP1C1 and scup CYP1C1 to be more closely related to each other than to CYP1C genes from other species. Furthermore, for measuring BaP induction of CYP1C1 mRNA in different organs of tilapia (O. niloticus), beta-actin gene as internal control was selected based on previous studies to assess their expression variability. Real time RCR results revealed that there was a large increase in CYP1C1 mRNA in liver (43.1), intestine (5.1) and muscle (2.4). PMID- 22204986 TI - Adaptation of microalgae to lindane: a new approach for bioremediation. AB - Lindane is especially worrisome because its persistence in aquatic ecosystems, tendency to bioaccumulation and toxicity. We studied the adaptation of freshwater cyanobacteria and microalgae to resist lindane using an experimental model to distinguish if lindane-resistant cells had their origin in random spontaneous pre selective mutations (which occur prior to the lindane exposure), or if lindane resistant cells arose by a mechanism of physiological acclimation during the exposure to the selective agent. Although further research is needed to determine the different mechanisms contributing to the bio-elimination of lindane, this study, however, provides an approach to the bioremediation abilities of the lindane-resistant cells. Wild type strains of the experimental organisms were exposed to increasing lindane levels to estimate lethal concentrations. Growth of wild-type cells was completely inhibited at 5mg/L concentration of lindane. However, after further incubation in lindane for several weeks, occasionally the growth of rare lindane-resistant cells was found. A fluctuation analysis demonstrated that lindane-resistant cells arise only by rare spontaneous mutations that occur randomly prior to exposure to lindane (lindane-resistance did not occur as a result of physiological mechanisms). The rate of mutation from lindane sensitivity to resistance was between 1.48 * 10(-5) and 2.35 * 10(-7) mutations per cell per generation. Lindane-resistant mutants exhibited a diminished fitness in the absence of lindane, but only these variants were able to grow at lindane concentrations higher than 5mg/L (until concentrations as high as 40 mg/L). Lindane-resistant mutants may be maintained in uncontaminated waters as the result of a balance between new resistant mutants arising from spontaneous mutation and resistant cells eliminated by natural selection waters via clone selection. The lindane-resistant cells were also used to test the potential of microalgae to remove lindane. Three concentrations (4, 15 and 40 mg/L) were chosen as a model. In these exposures the lindane-resistant cells showed a great capacity to remove lindane (until 99% lindane was eliminated). Apparently, bioremediation based on lindane-resistant cells could be a great opportunity for cleaning up of lindane- and other chlorinated organics-polluted habitats. PMID- 22204987 TI - The interactive effects of ammonia exposure, nutritional status and exercise on metabolic and physiological responses in gold fish (Carassius auratus L.). AB - This study aimed to elucidate the physiological effects of high environmental ammonia (HEA) following periods of feeding (2% body weight) and starvation (unfed for 7 days prior to sampling) in gold fish (Carassius auratus). Both groups of fish were exposed to HEA (1 mg/L; Flemish water quality guideline) for 0 h (control), 3 h, 12 h, 1 day, 4 days, 10 days, 21 days and 28 days. Measurements of weight gain (%), oxygen consumption (MO2), ammonia excretion rate, ammonia quotient (AQ), critical swimming speeds (Ucrit), plasma and muscle ammonia accumulation, plasma lactate, liver and muscle glycogen, lipid and protein content were done at various time intervals during the experimental periods. Overall, ammonia excretion rates, plasma ammonia accumulation and AQ were significantly affected by food regime in ammonia free water. HEA, the additional challenge in the present study, significantly altered all the studied parameters among fed and starved groups in days-dependent manner. Results show that weight gain (%), MO2, Ucrit, protein content in liver and muscle, and glycogen content in muscle among starved fish under HEA were considerably reduced compared to control and fed fish. Additionally a remarkable increase in plasma ammonia level, muscle ammonia, lactate accumulation and AQ was seen. However in fed fish, MO2, ammonia excretion rate, AQ and lactate level augmented after exposure to HEA. These results indicate that starved fish appeared more sensitive to HEA than fed fish. Furthermore, as expected, the toxic effect of ammonia exposure in both feeding treatments was exacerbated when imposed to exhaustive swimming (swum at 3/4th Ucrit). Such effects were more pronounced in starved fish. This suggests that starvation can instigate fish more vulnerable to external ammonia during exercise. Therefore, it was evident from our study that feeding ameliorates ammonia handling and reduces its toxicity during both routine and exhaustive swimming. Moreover, recovery was observed for some physiological parameters (e.g. MO2, ammonia excretion, Ucrit, plasma ammonia) during the last exposure periods (21-28 days) while for others (e.g. growth, tissue glycogen and protein content, muscle ammonia) effects only became apparent at this time. In the future, these results need to be considered in ecological context as fish in ammonia polluted may experience different phenomenon (starvation and exercise) simultaneously. PMID- 22204988 TI - Effects of the anti-thyroidal compound potassium-perchlorate on the thyroid system of the zebrafish. AB - The increasing pollution of aquatic habitats with anthropogenic compounds has led to various test strategies to detect hazardous chemicals. However, information on effects of pollutants in the thyroid system in fish, which is essential for growth, development and parts of reproduction, is still scarce. Other vertebrate groups such as amphibians or mammals are well-studied; so the need for further knowledge especially in fish as a favored vertebrate model test organism is evident. Modified early life-stage tests were carried out with zebrafish exposed to the known thyroid inhibitor potassium perchlorate (0, 62.5, 125, 250, 500 and 5000 MUg/L) to identify adverse effects on the hypothalamic-pituitary-thyroid axis. Especially higher perchlorate concentrations led to conspicuous alterations in thyroidal tissue architecture and to effects in the pituitary. In the thyroid, severe hyperplasia at concentrations >= 500 MUg/L together with an increase in follicle number could be detected. The most sensitive endpoint was the colloid, which showed alterations at >= 250 MUg/L. The tinctorial properties and the texture of the colloid changed dramatically. Interestingly, effects on epithelial cell height were minor. The pituitary revealed significant proliferations of TSH producing cells resulting in alterations in the ratio of adeno- to neurohypophysis. The liver as the main site of T4 deiodination showed severe glycogen depletion at concentrations >= 250 MUg/L. In summary, the thyroid system in zebrafish showed effects by perchlorate from concentrations >= 250 MUg/L, thus documenting a high sensitivity of the zebrafish thyroid gland for goitrogens. In the future, such distinct alterations could lead to a better understanding and identification of potential thyroid-disrupting chemicals. PMID- 22204989 TI - Intracellular chromium localization and cell physiological response in the unicellular alga Micrasterias. AB - Various contaminants like metals and heavy metals are constantly released into the environment by anthropogenic activities. The heavy metal chromium has a wide industrial use and exists in two stable oxidation states: trivalent and hexavalent. Chromium can cause harm to cell metabolism and development, when it is taken up by plants instead of necessary micronutrients such as for example iron. The uptake of Cr VI into plant cells has been reported to be an active process via carriers of essential anions, while the cation Cr III seems to be taken up inactively. Micrasterias denticulata, an unicellular green alga of the family Desmidiaceae is a well-studied cell biological model organism. Cr III and VI had inhibiting effects on its cell development, while cell division rates were only impaired by Cr VI. Transmission electron microscopy (TEM) revealed ultrastructural changes such as increased vacuolization, condensed cytoplasm and dark precipitations in the cell wall after 3 weeks of Cr VI treatment. Electron energy loss spectroscopy (EELS) and electron spectroscopic imaging (ESI) were applied to measure intracellular chromium distribution. Chromium was only detected after 3 weeks of 10 MUM Cr VI treatment in electron dense precipitations found in bag-like structures along the inner side of the cell walls together with iron and elevated levels of oxygen, pointing toward an accumulation respectively extrusion of chromium in form of an iron-oxygen compound. Atomic emission spectroscopy (EMS) revealed that Micrasterias cells are able to accumulate considerable amounts of chromium and iron. During chromium treatment the Cr:Fe ratio shifted in favor of chromium, which implied that chromium may be taken up instead of iron. Significant and rapid increase of ROS production within the first 5 min of treatment confirms an active Cr VI uptake. SOD and CAT activity after Cr VI treatment did not show a response, while the glutathione pool determined by immuno-TEM decreased significantly in chromium treated cells, showing that glutathione is playing a major role in intracellular ROS and chromium detoxification. PMID- 22204990 TI - Responses of Pacific oyster Crassostrea gigas populations to abiotic stress in environmentally contrasted estuaries along the Atlantic coast of France. AB - Genetic and ecophysiological responses of oyster, Crassostrea gigas, populations to environmental stress were investigated in three highly contaminated French estuaries (the Gironde, Loire and Vilaine) and compared to a control, the Belon estuary. A strong response in both metallothionein CgMT4 mRNA expression, as determined by semi-quantitative RT-PCR, and amount of protein, as determined by ELISA tests, was demonstrated in estuarine populations subjected to differential contamination, with an inhibition in the area most highly contaminated with metals. In these same estuarine populations, we found polymorphisms of the metallothionein CgMT4 gene and three other genes (glutamine synthetase--GS, delta 9 desaturase--D9 and phosphoglucomutase--PGM) involved in stress response of C. gigas. We showed that genetic differentiation was observed for MT4 and PGM genes in the Gironde estuary which is highly contaminated with metals. A strong seasonal effect was observed. Phenotype-genotype coupling revealed that one particular MT4 allele and one PGM allele seemed to be associated with metal sensitivity expressed as lower detoxification efficiency and higher metal bioaccumulation. The MT4 gene is a good physiological and genetic marker of stress response and susceptibility. PMID- 22204991 TI - Clarifying the natural history of the doubly committed ventricular septal defect. PMID- 22204992 TI - Intra-abdominal hypertension: a potent silent killer of cardiac arrest survivors. PMID- 22204993 TI - Effects of antithrombin and gabexate mesilate on disseminated intravascular coagulation: a preliminary study. AB - PURPOSE: We hypothesized that antithrombin is more effective for disseminated intravascular coagulation (DIC) than is gabexate mesilate, which is a protease inhibitor, suggested from the previous studies. Initially, we compared the effects of antithrombin and gabexate mesilate for treating infection-related DIC. METHODS: Sixteen adult patients with a diagnosis of DIC with infection who were assessed with an acute DIC score 4 or higher at the admission to the intensive care unit were divided into antithrombin-treated and gabexate mesilate-treated groups. White blood cell counts, C-reactive protein, platelet counts, antithrombin, fibrin and fibrinogen degradation product, D-dimer, fibrinogen, thrombin antithrombin complex, plasmin plasminogen complex, prothrombin time, and activated partial thrombin time were measured on the day of admission and on days 1, 3, 5, and 7 thereafter. Mortality over 28 days was also compared. RESULTS: Platelet counts and antithrombin were significantly higher in the antithrombin group on day 7 and on days 5 and 7, respectively. Antithrombin increased to the normal level on day 1 in the antithrombin group but on day 7 in the gabexate mesilate group. C-reactive protein, fibrinogen degradation product, D-dimer, thrombin antithrombin complex, plasmin plasminogen complex, and prothrombin time were lower in the antithrombin group; but the differences were not significant. The 28-day mortality was 2 of 8 in the antithrombin group and 3 of 8 in the gabexate mesilate group, but they were not significantly different. CONCLUSIONS: Antithrombin may be a more effective treatment for coagulation and fibrinolysis disorders than gabexate mesilate in infection-related DIC, but there was no difference in 28-day mortality. PMID- 22204994 TI - Diagnosis of spontaneous urinary bladder rupture in the ED. PMID- 22204995 TI - Incidence of tricyclic antidepressant-like complications after cyclobenzaprine overdose. PMID- 22204996 TI - Takotsubo-pericarditis association. PMID- 22204997 TI - ED identification of patients with severe sepsis/septic shock decreases mortality in a community hospital. AB - STUDY OBJECTIVES: Our objective was to quantify the mortality difference between patients with severe sepsis/septic shock (SS/SS) identified in the emergency department (EDI) vs those not identified in the emergency department (NEDI) within our community hospital. METHODS: We conducted a retrospective review of all patients with SS/SS from July 2007 to January 2010 who were admitted to the intensive care unit within our community hospital. Our primary outcome measure was the difference in mortality rates of patients with SS/SS between the EDI and NEDI cohorts. Our secondary outcome measures included the final disposition, the length of stay, and direct cost (DC) for both groups. The data were analyzed using a 2 * 2 contingency table and the Fisher exact test for significance to compare the mortality rates between groups. Lengths of stay and DC between both groups were reported as medians, and significance was calculated using the Mann Whitney U test. RESULTS: A total of 267 patients with SS/SS were identified during the 31-month study period. Of these patients, 155 were EDI patients with a mortality rate of 27.7%, and 112 were NEDI patients with a mortality rate of 41.1%. This represents an absolute difference in mortality rates of 13.4% between the 2 groups (P = .0257). The median length of stay between both groups was 7 days for the EDI group and 12.5 days for the NEDI group, translating to median DCs of $9861.01 vs $16 031.07. CONCLUSIONS: Emergency department identification of patients with SS/SS in the community hospital significantly improves mortality. PMID- 22204998 TI - Optic nerve ultrasound for the detection of elevated intracranial pressure in the hypertensive patient. AB - PURPOSE: We sought to determine whether dilation of the optic nerve sheath diameter (ONSD), as detected at the bedside by emergency ultrasound (US), could reliably correlate with patient blood pressure and whether there was a blood pressure cutoff point where you would start to see abnormal dilation in the ONSD. METHODS: This was a single-blinded, prospective, observational trial from September 2010 to April 2011. One hundred fifty patients presenting to the emergency department were enrolled. There were 3 arms to the study with 50 patients in each arm: (1) ONSD in normotensive/asymptomatic patients; (2) ONSD in hypertensive/asymptomatic patients; and (3) ONSD in hypertensive/symptomatic patients. Ocular US was conducted on all subjects. RESULTS: Neither the number of symptoms nor the type of symptom present in the hypertensive/symptomatic group was able to significantly predict the average ONSD before treatment (P = .818 and .288, respectively). There was a significant correlation between both systolic blood pressure (SBP) and diastolic blood pressure (DBP) with the ONSD in all hypertensive patients. The best SBP and DBP cutoff point for abnormal ONSD was 166/82 mm Hg. Decrease in ONSD observed after blood pressure treatment was not statistically significant (P = .073). CONCLUSIONS: In conclusion, our study shows that practitioners can use bedside ocular US and a blood pressure cutoff point to help predict whether patients require more aggressive management of their symptomatic hypertension. Knowing the SBP and DBP readings that lead to increased ONSD and increased intracranial pressure can help guide management and treatment decisions at the bedside. PMID- 22204999 TI - Blood ammonia is a predictive biomarker of neurologic outcome in cardiac arrest patients treated with therapeutic hypothermia. AB - PURPOSE: The aim of this study was to investigate the value of commonly examined laboratory measurements, including ammonia and lactate, in predicting neurologic outcome of out-of-hospital cardiac arrest (OHCA) patients treated with therapeutic hypothermia (TH). METHODS: This was a retrospective cohort study of patients with a return of spontaneous circulation after OHCA who were treated with TH between February 2007 and July 2010. We measured typical blood measurements on arrival at the emergency department. The subjects were classified into 2 groups: the good neurologic outcome group (Cerebral Performance Category [CPC] 1-2 at 1 month) and the poor neurologic outcome group (Cerebral Performance Category 3-5). We compared blood biomarker levels and basal characteristics between the 2 groups. Logistic regression analyses were performed to determine independent biomarkers that predict poor neurologic outcome. RESULTS: A total of 117 patients were included. Between the 2 groups, significantly different levels of blood measurements included hemoglobin level, pH, Pao(2), Paco(2), base excess, albumin, glucose, potassium, chloride, bilirubin, phosphorous, and ammonia. In multivariate analyses, blood ammonia level (>96 mg/dL; odds ratio [OR], 7.240; 95% confidence interval [CI], 1.718-30.512), noncardiac causes (OR, 46.215; 95% CI, 9.670-220.873), and time interval from collapse to return of spontaneous circulation (>33 min; OR, 5.943; 95% CI, 1.543-22.886) were significantly related to poor neurologic outcome. CONCLUSION: Among the blood measurements on emergency department arrival, blood ammonia (>96 mg/dL) was the only independent predictive biomarker of poor neurologic outcome. Thus, higher blood ammonia level was associated with poor neurologic outcome in OHCA patients treated with TH. PMID- 22205000 TI - Blood-fluid level on computed tomography head: a sign of warfarin-associated intraparenchymal hemorrhage. AB - "Blood/fluid level" represents interface between the plasma and sedimented blood and is defined radiologically as presence of area of low computed tomography (CT) attenuation above and high CT attenuation below a discrete line of separation in an area of intraparenchymal hemorrhage. It is a rare finding seen in association with large clot volume of intraparenchymal hemorrhage. We present a case of warfarin-related intraparenchymal hemorrhage presenting with a classic sign of "blood/fluid level" on CT head with small clot volume. PMID- 22205001 TI - Regarding "unresponsive ventricular tachycardia associated with aluminum phosphide poisoning". PMID- 22205002 TI - Prospective evaluation of an ED observation unit protocol for trauma activation patients. AB - BACKGROUND: The University of Utah emergency department (ED) observation unit (EDOU) cares for over 2500 patients each year, with a significant portion of these patients being trauma activation patients. We evaluated the safety and efficacy of our EDOU trauma protocol and described patient characteristics and outcomes of trauma patients managed in an EDOU. METHODS: We performed a prospective observational study of all trauma patients admitted to the EDOU over a 1-year period. Patient disposition, interventions, and adverse events during observation were recorded. Thirty-day follow-up was performed by telephone and chart review to evaluate for missed injuries, repeat hospitalizations, or repeat traumatic events. RESULTS: A total of 259 trauma patients were admitted to the EDOU during the study period and were contacted at least 30 days after discharge. There were no deaths, intubations, or other adverse events. At 30-day follow-up, there was 1 missed injury, which did not result in an adverse outcome. Ten patients were reevaluated in the ED or required hospitalization for events occurring after their initial EDOU stay but related to their initial trauma evaluation. The inpatient admission rate from the EDOU was 10.4%, and 3.1% of patients reported another traumatic event during the 30-day follow-up period. CONCLUSIONS: There were no adverse outcomes in trauma patients admitted to the EDOU, and our inpatient admission rate was within the generally accepted admission rate for patients in observation status. The EDOU appears to be a safe alternative to inpatient admission for the evaluation of minimally injured trauma activation patients. PMID- 22205003 TI - Prospective study of computed tomography in patients with suspected acute appendicitis and low Alvarado score. AB - BACKGROUND: Computed tomography (CT) has been used in diagnosing acute appendicitis since late 1990s. Appropriate use of CT has not been studied prospectively in patients with suspected acute appendicitis and relative low Alvarado score. METHODS: Sixty participants with suspected acute appendicitis and an Alvarado score of 4 to 7 points were enrolled for analysis. Clinical and laboratory differences were compared between patients with histologically proven acute appendicitis (AA group) and patients without evidence of acute appendicitis (non-AA group) in the first part of the analysis. In the second part of the analysis, participants were divided into 2 groups: leukocytosis (LK group) and nonleukocytosis (non-LK group). RESULTS: In the first phase of the analysis, there were statistically significant differences in white blood cell count (13.5 K vs 10.9 K per MUL), neutrophilia (81.5% vs 73.5%), and hospital stay (4.9 vs 3.5 days) between the 2 groups. Disease spectrum between LK and non-LK groups was obtained in second part of analysis. CONCLUSION: Computed tomography scan is necessary for patients with relatively low Alvarado score when leukocytosis is noted. In female patients without leukocytosis, further large-scale prospective studies are necessary to change the current diagnostic strategy. PMID- 22205004 TI - Early embolic events complicating intravenous thrombolysis for acute ischemic stroke. AB - Intravenous recombinant tissue plasminogen activator (IV rt-PA) is the only established thrombolytic therapy for acute ischemic stroke. However, secondary embolism after IV rt-PA for acute ischemic stroke is recognized as an uncommon complication, and the pathophysiology is unclear. We describe a 72-year-old man with acute infarction in the territory of left anterior cerebral artery who developed new infarction in the territory of right middle cerebral artery and acute peripheral arterial occlusion after IV rt-PA therapy. It suggested a central embolic source. Because the patient has paroxysmal atrial fibrillation (Af), the possible embolic sources may come from fragmentation of pre-existing intra-atrial clot. Although Af and the presence of cardiac thrombus are not contraindication for IV rt-PA in acute ischemic stroke, our case and review suggested that the administration of IV rt-PA to patients with known Af and intracardiac thrombus could represent a particular risk situation and should be carefully evaluated. PMID- 22205005 TI - An example of extreme cardiology: chest pain on the high seas and helicoptered medical evacuations: the French Navy experience. AB - Medicalized high sea rescue is very different from prehospital medical evacuation. It requires specifically trained medical teams because the difficulties are marine, aerial, and medically related. The French Navy provides medical evacuations by helicopter on the Atlantic coast, up to 320 km offshore and under all weather conditions. The epidemiology of acute chest pain in the high seas has been poorly described. Therefore, in this retrospective study, we aimed to assess the prevalence and constraints found in the management of these emergencies. From January 1, 2000, to April 30, 2009, 286 medical evacuations by helicopter were performed, 132 of which were due to traumatological emergencies, and 154 to medical emergencies. Acute chest pain, with 36 missions, was the leading cause of medical evacuation. All evacuated patients were men who were either professional sailors or ferry passengers. The median age was 48 years (range, 26-79). The most common prehospital diagnosis was coronary chest pain in 23 patients (64%), including 11 patients with acute coronary syndrome with ST segment elevation. Thirty-two patients were airlifted by helicopter. All patients benefited from monitoring, electrocardiogram, peripheral venous catheter, and medical management as soon as the technical conditions allowed it. PMID- 22205006 TI - Continuous chest compressions improve survival and neurologic outcome in a swine model of prolonged ventricular fibrillation. AB - INTRODUCTION: Evidence suggests that any interruptions, including those of rescue breaths, during cardiopulmonary resuscitation (CPR) have significant, detrimental effects on survival. The 2010 International Liaison Committee on Resuscitation guidelines strongly emphasized on the importance of minimizing interruptions during chest compressions. However, those guidelines also stress the need for ventilations in the case of prolonged cardiac arrest (CA), and it is not at present clear at which point of CA the necessity of providing ventilations overcomes the hemodynamic compromise caused by chest compressions' interruption. METHODS: Ventricular fibrillation was electrically induced in 20 piglets (19 +/- 2 kg) and left untreated for 8 minutes. Animals were randomized to receive 2 minutes of either chest compression-only CPR (group CC) or standard 30:2 compressions/ventilations CPR (group S) before defibrillation. Resuscitated animals were monitored under anesthesia for 4 hours and then were awakened and placed in a maintenance facility for 24 hours. RESULTS: There was no significant difference among groups for both return of spontaneous circulation and 1-hour survival. There was a significant difference in 24-hour survival (group CC, 7/10 vs group S, 2/10; P = .025). Blood lactate levels were significantly lower in group CC compared with group S in both 1 (P = .019) and 4 hours (P = .034) after return of spontaneous circulation. Furthermore, group CC animals exhibited significantly higher mean Neurologic Alertness Score (58 +/- 42.4 vs 8 +/- 16.9) (P < .05). CONCLUSION: In this swine CA model, where defibrillation was first attempted at 10 minutes of untreated ventricular fibrillation, uninterrupted chest compressions resulted in significantly higher survival rates and higher 24 hour neurologic scores, compared with standard 30:2 CPR. PMID- 22205007 TI - Hospital-level variation in the percentage of admissions originating in the emergency department. AB - PURPOSE: Well over half of all US hospital patients are now admitted directly through the emergency department (ED) rather than scheduled through the admissions department by a referring member of the medical staff. This study sought to understand hospital-level variation in the percentage of admissions originating in the ED. BASIC PROCEDURES: This was a retrospective, cross sectional analysis of 5 748 375 ED visits and 2 265 478 inpatient discharge occurring in 192 short-term acute Florida hospitals in calendar year 2005. MAIN FINDINGS: Hospitals with increasing percentages of patients admitted through the ED are smaller in scale with fewer admissions, beds, and smaller medical staffs but admit a higher percentage of their ED visits to the hospital. Patients in these hospitals are increasingly Hispanic, older, Medicare insured, and likely to represent a preventable ambulatory sensitive condition. CONCLUSIONS: The increasing rate of admissions from the ED department is a national trend, but there is substantial variation at the hospital level. In Florida, measures of hospital scale and an older population with some limitations in access to, or the quality of, primary care are the factors influencing hospital-level variation. Factors implicated in increased ED use such as ED visit acuity, lack of insurance, and race are not important contributory variables. The process of admission and, particularly, the role of the organized medical staff in this process are evolving, and the consequences of these changes require further research. PMID- 22205008 TI - Lung ultrasound associated to capnography to verify correct endotracheal tube positioning in prehospital. AB - Endotracheal intubation is the "gold standard" of the control of airway patency but is associated with nonnegligible morbidity rates. A rapid detection of esophageal intubation is essential. Capnography is considered the reference technique for correct endotracheal tube (ETT) positioning confirmation. However, capnography can provide false-positive and false-negative results in some situations. Recently, the ultrasound assessment has been studied for confirming ETT placement. Despite of few trials, the ultrasound procedure may enhance physician confidence and decision making in airway management. We report the case of a 52-year-old female patient presenting cardiorespiratory failure. During cardiopulmonary resuscitation, there was a sudden absence of end-tidal CO2 capnographic detection. Correct tube positioning could not be ascertained by auscultation because the environment had become extremely noisy. However, TM-mode (Time Motion--mode) lung ultrasound revealed bilateral pleural sliding during insufflation with the self-filling balloon, thus confirming correct ETT positioning. PMID- 22205009 TI - Subcutaneous emphysema: an immediate call for chest computed tomographic scan or ultrasonography. PMID- 22205010 TI - Neurogenic stunned myocardium as a manifestation of encephalitis involving cerebellar tonsils. AB - Neurogenic stunned myocardium is defined as a myocardial injury or dysfunction after neurological insults. It is most commonly reported in patients with subarachnoid hemorrhage, and the presenting symptoms may mimic an acute myocardial infarction or myocarditis. In severe cases, cardiogenic shock and acute pulmonary edema may occur and lead to a devastating event. Therefore, it requires prompt recognition and proper intervention. We herein report the case of a 25-year-old woman who presented to our hospital with the symptoms of acute pulmonary edema, shock, and consciousness disturbance. The diagnosis of encephalitis of cerebellar tonsils complicated with acute hydrocephalus and neurogenic stunned myocardium was made. Detailed neurologic examinations, neuroimaging studies, and characteristic echocardiographic changes expedite the correct diagnosis and treatment. PMID- 22205011 TI - Emergent cricothyroidotomies for trauma: training considerations. AB - BACKGROUND: Emergent cricothyroidotomy remains an uncommon, but life-saving, core procedural training requirement for emergency medicine (EM) physician training. We hypothesized that although most cricothyroidotomies for trauma occur in the emergency department (ED), they are usually performed by surgeons. METHODS: We conducted a retrospective analysis of all emergent cricothyroidotomies for trauma presentations performed at 2 large level I trauma centers over 10 years. Operators and assistants for all procedures were identified, as well as mechanism of injury and patient demographics were examined. RESULTS: Fifty-four cricothyroidotomies were analyzed. Patients had a mean age of 50 years, 80% were male, and 90% presented as a result of blunt trauma. The most common primary operator was a surgeon (n = 47, 87%), followed by an emergency medical services (EMS) provider (n = 6, 11%) and an EM physician (n = 1, 2%). In all cases, except those performed by EMS, the operator or assistant was an attending surgeon. All EMS procedures resulted in serious complications compared with in-hospital procedures (P < .0001). CONCLUSIONS: (1) Prehospital cricothyroidotomy results in serious complications. (2) Despite the ubiquitous presence of EM physicians in the ED, all cricothyroidotomies were performed by a surgeon, which may present opportunities for training improvement. PMID- 22205012 TI - Assessing prognosis of sepsis in the ED: do we have a magic ball? PMID- 22205013 TI - A before- and after-intervention trial for reducing unexpected events during the intrahospital transport of emergency patients. AB - BACKGROUND: This study was aimed to explore the effect of intervention in safe intrahospital transport on the incidence of unexpected events (UEs) occurring during the transport of emergency patients. METHODS: This study was performed in an urban tertiary teaching hospital emergency department (ED) from May 17 to October 30, 2010. Patients older than 15 years who were transported to general wards; intensive care units; and magnetic resonance imaging, intervention, or operation rooms were enrolled. Demographics and data on all UEs related to the devices, clinical situations, and tubes or lines were measured by registered nurses at pre- and postintervention period. The intervention was that acting nurses were required to use a designed transport checklists before the patients were transported. Primary outcomes were the rate of all and serious UEs during the pre- and postintervention periods. Serious UEs were defined as any worsening of a patient's clinical status. Statistical values were measured with 95% confidence intervals (CIs) and compared using Student t tests or chi(2) tests. RESULTS: In total, there were 680 transports before interventions and 605 transports after interventions. Overall, UEs decreased significantly from a value of 36.8% (95% CI, 33.1-40.5) in the preintervention period to a value of 22.1% (95% CI, 18.9-25.7) in the postintervention period (P = .001). Serious UEs in clinical status also decreased significantly from 9.1% (95% CI, 7.1-11.5) in the preintervention period to a value of 5.2% (95% CI, 3.6-7.4) in the postintervention period (P = .005). CONCLUSION: A significant reduction in the rate of total and serious UEs during intrahospital transport from the ED was found through using transport checklists. PMID- 22205014 TI - Prospective evaluation of the treatment of pain in the ED using computerized physician order entry. AB - BACKGROUND: Treatment of pain in the emergency department (ED) is a significant area of focus, as previous studies have noted generally inadequate treatment of pain in ED patients. Previous studies have not evaluated the impact of computerized physician order entry (CPOE) on the treatment of pain in the ED. We sought to evaluate treatment of pain before and after implementation of CPOE in an academic ED. METHODS: We prospectively enrolled a convenience sample of patients presenting to the ED with a pain-related complaint in 4-month periods before and after CPOE implementation. We compared numbers who received pain medications, time from registration to administration of pain medication, and repeat dosing of pain medication. RESULTS: Six hundred forty-six ED patients participated in the pre-CPOE period, whereas 592 patients participated post-CPOE. Similar numbers of patients received pain medications in the pre-CPOE and post CPOE periods (55% vs 59%; P = .139), whereas those in the post-CPOE period were more likely to receive a repeat dose of pain medications (10.5% vs 17.6%; P < .001). CONCLUSION: The use of CPOE in the ED may offer modest benefits in the treatment of patients with pain-related complaints. PMID- 22205015 TI - Impact of inappropriate empirical antibiotic therapy on outcome of bacteremic adults visiting the ED. AB - OBJECTIVES: To investigate the clinical impact of inappropriate empirical antibiotics on patient outcome and determine the risk factors for mortality in bacteremic adults who visited the emergency department (ED). METHODS: Bacteremic adults visiting the ED from January 2007 to June 2008 were identified retrospectively. Demographic characteristics, clinical conditions, bacteremic pathogens, antimicrobial agents, and outcomes were determined from chart records. RESULTS: The total of 454 eligible bacteremic adults were included in the analysis; excluded from the study were another 261 patients with contaminated blood cultures and 64 patients with ED stays of less than 24 hours. Among the included individuals, the mean age was 64.6 years, with a small predominance of males (230 patients, 50.7%). Of a total 494 bacteremic isolates, Escherichia coli (206, 41.7%) and Klebsiella species (81, 16.4%) were the most frequently encountered microorganisms. A lower 28-day mortality rate was demonstrated in bacteremic patients treated with appropriate antibiotics than that in those with inappropriate antibiotics or that in those with no antibiotic therapy, as judged by Kaplan-Meier survival curves (P = .01). Moreover, the differences among these three groups achieved higher significance (P = .002) in critically ill patients (Pittsburgh bacteremia scores of >= 4 points). In multivariate analyses, inappropriate antibiotic therapy in the ED was associated independently with mortality at 28 days (odds ratio, 2.26; 95% confidence interval, 1.01-5.13; P = .04). CONCLUSIONS: For bacteremic adults visiting the ED, their outcomes were favorable following appropriate antibiotics, compared to treatment with inappropriate antibiotics or no antibiotics. PMID- 22205016 TI - Cerebrospinal fluid biochemistry reflects effects of therapeutic hypothermia after cardiac arrest in a porcine model. AB - BACKGROUND: Mild induced hypothermia (MIH) is recommended to treat neurologic injury after cardiac arrest (CA). However, clinical trials to assess MIH benefit after CA have been largely inconclusive. We investigated the subsequent changes in cerebrospinal fluid (CSF) biochemistry after MIH (33 degrees C-34 degrees C for 12 hours) and evaluated the importance of ongoing fever control. METHODS: Thirty-two male Wuzhishan inbred mini pigs (n = 16/group) underwent ventricular fibrillation followed by cardiopulmonary resuscitation and were randomized into 2 groups: hypothermic and control. Upon resumption of spontaneous circulation (ROSC) from CA, the hypothermic group was treated with MIH by endovascular cooling. The control group received no temperature intervention. Core temperatures were continually monitored. At various points throughout the procedure, CSF samples were obtained to measure glutamate, lactate, and pyruvate levels. RESULTS: The core temperature of the hypothermic group was found to have increased postrewarming and reached levels comparable with those of the control group at ROSC 72 hours. In both groups, glutamate increased significantly after ROSC, but the glutamate levels in the hypothermic group were lower than those in the control group, except at ROSC 1 hour. The lactate-pyruvate ratio increased in the control group at ROSC 1 hour and was significantly lower in the hypothermic group (P < .05). CONCLUSIONS: Mild induced hypothermia mitigated and delayed the CA-induced increase of CSF glutamate. Therefore, our results suggest that clinically inducing hypothermia as soon as possible after CA, or prolonging the time of MIH in combination with controlling ongoing fever, may enhance hypothermic protective effects. PMID- 22205017 TI - Amiodarone-induced T-U fusion. AB - Amiodarone is a widely used antiarrythmic drug for various atrial and ventricular arrhythmias. It has the potential to cause prolongation of the QT interval, which, in turn, can increases the incidence of torsade de pointes. Amiodarone is also one of the causes of prominent U waves. The presented case exemplifies the phenomenon of amiodarone-induced T-U fusion and QT prolongation. Other causes of QT prolongation as electrolyte abnormalities or administration of other drugs that prolong the QT interval were excluded. Awareness of this phenomenon and method of calculation of QT interval in this scenario is of utmost importance. PMID- 22205018 TI - Head to head comparisons as an alternative to placebo-controlled trials. AB - Head to head trials have been proposed as an alternative to the ethical and methodological concerns related to placebo-controlled trials. While those studies may be particularly informative from the clinical and cost-effectiveness point-of view, avoiding placebo poses several regulatory concerns: for superiority designs, the choice of the trial population, outcomes, dose and escalation of the comparator, as well as the comparator itself may be an issue; for non-inferiority studies, issues related to uncertain assay sensitivity and exposure of large samples to potentially ineffective or unsafe drugs make them inappropriate, in the absence of a previous positive superiority trial, for regulatory purposes. The inclusion of active comparators in regulatory trials should not be seen as an alternative, but as a useful complement to the information that can be obtained from placebo-controlled studies. PMID- 22205019 TI - Urinary red blood cells: not only glomerular or nonglomerular. AB - Two main types of red blood cells, isomorphic and dysmorphic, are found in the urine sediment, indicating nonglomerular and glomerular hematuria, respectively. Occasionally, however, other types of red blood cells such as sickle cells, anisocytes, poikilocytes, elliptocytes and dacryocytes can be seen in the urine sediment of patients with hematuria. This paper describes such cases reported in the literature in which such unusual urinary red blood cells have been found and the experience of the authors on this subject. PMID- 22205020 TI - A tribute to Ralph M. Steinman. PMID- 22205022 TI - No-loss gambling shows the speed of the unconscious. AB - This paper investigates the time it takes unconscious vs. conscious knowledge to form by using an improved "no-loss gambling" method to measure awareness of knowing. Subjects could either bet on a transparently random process or on their grammaticality judgment in an artificial grammar learning task. A conflict in the literature is resolved concerning whether unconscious rather than conscious knowledge is especially fast or slow to form. When guessing (betting on a random process), accuracy was above chance and RTs were longer than when feeling confident (betting on the grammaticality decision). In a second experiment, short response deadlines only interfered with the quality of confident decisions (betting on grammaticality). When people are unaware of their knowledge, externally enforced decisions can be made rapidly with little decline in quality; but if given ample time, they await a metacognitive process to complete. The dissociation validates no-loss gambling as a measure of conscious awareness. PMID- 22205023 TI - IL-27 promotes IL-10 production by effector Th1 CD4+ T cells: a critical mechanism for protection from severe immunopathology during malaria infection. AB - Infection with the malaria parasite, Plasmodium, is characterized by excessive inflammation. The establishment of a precise balance between the pro- and anti inflammatory responses is critical to guarantee control of the parasite and survival of the host. IL-10, a key regulatory cytokine produced by many cells of the immune system, has been shown to protect mice against pathology during acute Plasmodium0 chabaudi chabaudi AS model of malaria. However, the critical cellular source of IL-10 is still unknown. In this article, we demonstrate that T cell derived IL-10 is necessary for the control of pathology during acute malaria, as mice bearing specific deletion of Il10 in T cells fully reproduce the phenotype observed in Il10(-)(/)(-) mice, with significant weight loss, decline in temperature, and increased mortality. Furthermore, we show that IFN-gamma(+) Th1 cells are the main producers of IL-10 throughout acute infection, expressing high levels of CD44 and ICOS, and low levels of CD127. Although Foxp3(+) regulatory CD4(+) T cells produce IL-10 during infection, highly activated IFN-gamma(+) Th1 cells were shown to be the essential and sufficient source of IL-10 to guarantee protection against severe immune-mediated pathology. Finally, in this model of malaria, we demonstrate that the generation of protective IL10(+)IFN-gamma(+) Th1 cells is dependent on IL-27 signaling and independent of IL-21. PMID- 22205024 TI - Ifih1 gene dose effect reveals MDA5-mediated chronic type I IFN gene signature, viral resistance, and accelerated autoimmunity. AB - Type I IFNs (IFN-I) are normally produced during antiviral responses, yet high levels of chronic IFN-I expression correlate with autoimmune disease. A variety of viral sensors generate IFN-I in their response, but other than TLRs, it is not fully known which pathways are directly involved in the development of spontaneous immune pathologies. To further explore the link between IFN-I induced by viral pathways and autoimmunity, we generated a new transgenic mouse line containing multiple copies of Ifih1, a gene encoding the cytoplasmic dsRNA sensor MDA5 with proven linkage to diabetes and lupus. We show that MDA5 overexpression led to a chronic IFN-I state characterized by resistance to a lethal viral infection through rapid clearance of virus in the absence of a CD8(+) or Ab response. Spontaneous MDA5 activation was not sufficient to initiate autoimmune or inflammatory pathology by itself, even though every immune cell population had signs of IFN activation. When combined with the lupus-susceptible background of the FcgammaR2B deficiency, MDA5 overexpression did accelerate the production of switched autoantibodies, the incidence of glomerulonephritis, and early lethality. Thus, MDA5 transgenic mice provide evidence that chronic elevated levels of IFN-I are not sufficient to initiate autoimmunity or inflammation although they might exacerbate an ongoing autoimmune pathology. PMID- 22205025 TI - Discovery and characterization of secretory IgD in rainbow trout: secretory IgD is produced through a novel splicing mechanism. AB - The gene encoding IgH delta has been found in all species of teleosts studied to date. However, catfish (Ictalurus punctatus) is the only species of fish in which a secretory form of IgD has been characterized, and it occurs through the use of a dedicated delta-secretory exon, which is absent from all other species examined. Our studies have revealed that rainbow trout (Oncorhynchus mykiss) use a novel strategy for the generation of secreted IgD. The trout secretory delta transcript is produced via a run-on event in which the splice donor site at the end of the last constant domain exon (D7) is ignored and transcription continues until a stop codon is reached 33 nt downstream of the splice site, resulting in the production of an in-frame, 11-aa secretory tail at the end of the D7 domain. In silico analysis of several published IgD genes suggested that this unique splicing mechanism may also be used in other species of fish, reptiles, and amphibians. Alternative splicing of the secretory delta transcript resulted in two delta-H chains, which incorporated CMU1 and variable domains. Secreted IgD was found in two heavily glycosylated isoforms, which are assembled as monomeric polypeptides associated with L chains. Secretory delta mRNA and IgD(+) plasma cells were detected in all immune tissues at a lower frequency than secretory IgM. Our data demonstrate that secretory IgD is more prevalent and widespread across taxa than previously thought, and thus illustrate the potential that IgD may have a conserved role in immunity. PMID- 22205026 TI - Role of C3a receptors, C5a receptors, and complement protein C6 deficiency in collagen antibody-induced arthritis in mice. AB - The complement system, especially the alternative pathway, plays essential roles in the induction of injury in collagen Ab-induced arthritis (CAIA) in mice. The goal of the current study was to directly compare the roles of receptors for C3a and C5a, as well as the membrane attack complex, as effector mechanisms in the pathogenesis of CAIA. Clinical disease activity in C3aR(-/-), C5aR(-/-), and C6 deficient (C6-def) mice was decreased by 52, 94, and 65%, respectively, as compared with wild-type mice. Decreases in histopathologic injury as well as in IgG and C3 deposition paralleled the clinical disease activity. A decrease in the percentage of synovial neutrophils was observed in C3aR(-/-), C5aR(-/-), and C6 def mice, and a decrease in macrophages was observed in C3aR(-/-) and C5aR(-/-), but not in C6-def, mice. Synovial mRNA obtained by laser capture microdissection exhibited a decrease in TNF-alpha in C5aR(-/-) mice and in IL-1beta in both C5aR( /-) and C6-def mice, whereas C3aR(-/-) mice demonstrated no change in either cytokine. Our findings show that absent C3aR-, C5aR-, or membrane attack complex initiated effector mechanisms each decrease susceptibility to CAIA, with clinical effects most pronounced in C5aR-deficient mice. Although the absence of C3aR, C5aR, or C6 led to differential deficiencies in effector mechanisms, decreased proximal joint IgG and C3 deposition was common to all three genotypes in comparison with wild-type mice. These data suggest the existence of positive feedback amplification pathways downstream of all three effectors that promote additional IgG deposition and C3 activation in the joint. PMID- 22205027 TI - Class B scavenger receptor types I and II and CD36 mediate bacterial recognition and proinflammatory signaling induced by Escherichia coli, lipopolysaccharide, and cytosolic chaperonin 60. AB - Class B scavenger receptors (SR-B) are lipoprotein receptors that also mediate pathogen recognition, phagocytosis, and clearance as well as pathogen-induced signaling. In this study we report that three members of the SR-B family, namely, CLA-1, CLA-2, and CD36, mediate recognition of bacteria not only through interaction with cell wall LPS but also with cytosolic chaperonin 60. HeLa cells stably transfected with any of these SR-Bs demonstrated markedly (3- to 5-fold) increased binding and endocytosis of Escherichia coli, LPS, and chaperonin 60 (GroEL) as revealed by both FACS analysis and confocal microscopy imaging. Increased pathogen (E. coli, LPS, and GroEL) binding to SR-Bs was also associated with the dose-dependent stimulation of cytokine secretion in the order of CD36 > CLA-2 > CLA-1 in HEK293 cells. Pathogen-induced IL-6-secretion was reduced in macrophages from CD36- and SR-BI/II-null mice by 40-50 and 30-40%, respectively. Intravenous GroEL administration increased plasma IL-6 and CXCL1 levels in mice. The cytokine responses were 40-60% lower in CD36(-/-) relative to wild-type mice, whereas increased cytokine responses were found in SR-BI/II(-/-) mice. While investigating the discrepancy of in vitro versus in vivo data in SR-BI/II deficiency, SR-BI/II(-/-) mice were found to respond to GroEL administration without increases in either plasma corticosterone or aldosterone as normally seen in wild-type mice. SR-BI/II(-/-) mice with mineralocorticoid replacement demonstrated an ~40-50% reduction in CXCL1 and IL-6 responses. These results demonstrate that, by recognizing and mediating inflammatory signaling of both bacterial cell wall LPS and cytosolic GroEL, all three SR-B family members play important roles in innate immunity and host defense. PMID- 22205028 TI - The inference of phased haplotypes for the immunoglobulin H chain V region gene loci by analysis of VDJ gene rearrangements. AB - The existence of many highly similar genes in the lymphocyte receptor gene loci makes them difficult to investigate, and the determination of phased "haplotypes" has been particularly problematic. However, V(D)J gene rearrangements provide an opportunity to infer the association of Ig genes along the chromosomes. The chromosomal distribution of H chain genes in an Ig genotype can be inferred through analysis of VDJ rearrangements in individuals who are heterozygous at points within the IGH locus. We analyzed VDJ rearrangements from 44 individuals for whom sufficient unique rearrangements were available to allow comprehensive genotyping. Nine individuals were identified who were heterozygous at the IGHJ6 locus and for whom sufficient suitable VDJ rearrangements were available to allow comprehensive haplotyping. Each of the 18 resulting IGHV?IGHD?IGHJ haplotypes was unique. Apparent deletion polymorphisms were seen that involved as many as four contiguous, functional IGHV genes. Two deletion polymorphisms involving multiple contiguous IGHD genes were also inferred. Three previously unidentified gene duplications were detected, where two sequences recognized as allelic variants of a single gene were both inferred to be on a single chromosome. Phased genomic data brings clarity to the study of the contribution of each gene to the available repertoire of rearranged VDJ genes. Analysis of rearrangement frequencies suggests that particular genes may have substantially different yet predictable propensities for rearrangement within different haplotypes. Together with data highlighting the extent of haplotypic variation within the population, this suggests that there may be substantial variability in the available Ab repertoires of different individuals. PMID- 22205029 TI - Humoral and cellular cross-reactivity between Amb a 1, the major ragweed pollen allergen, and its mugwort homolog Art v 6. AB - Ragweed and mugwort are closely related weeds that represent the major cause of pollen allergy in late summer. Concomitant sensitization and clinical cross reactivity frequently occur in subjects who are coexposed to both pollen species, and have implications for diagnosis and specific immunotherapy. Molecules involved in this cross-reactivity might be Amb a 1, the major ragweed pollen allergen, and Art v 6, a highly homologous allergen from mugwort. Therefore, we investigated the IgE and T cell response to Art v 6 of 60 weed pollen-allergic patients and assessed its immunological cross-reactivity with Amb a 1. Results of ELISA inhibition experiments suggested that both allergens are largely cross reactive, but Amb a 1 possesses more IgE epitopes than Art v 6. In patients with IgE to both allergens, Amb a 1-induced T cell lines and clones responded weakly to Art v 6. Moreover, Art v 6-induced T cell lines responded stronger to Amb a 1. T cell epitope mapping of Art v 6 revealed that it contains only a few cross reactive epitopes, which is opposed to the multiple T cell-activating regions present in Amb a 1. In summary, Amb a 1 can elicit more diverse allergen-specific IgE and T cell responses than Art v 6 and dominates the cross-reactivity with its homolog. Nevertheless, Art v 6 can act as a primary sensitizing allergen in areas with high mugwort pollen exposure, and consequently may facilitate sensitization to Amb a 1 by epitope cross-recognition of T and B cells. PMID- 22205030 TI - Lymph node hypertrophy following Leishmania major infection is dependent on TLR9. AB - Control of the protozoan parasite Leishmania major is dependent on establishing a robust T cell response. An early event in the development of an effective T cell response is the expansion (or hypertrophy) of the lymph node draining the site of infection, although the mechanisms involved in this response are not completely understood. In this study, we show that lymph node hypertrophy following L. major infection in mice is associated with increased recruitment of lymphocytes to the lymph node from the blood, and that CD62L-deficient mice, which are unable to recruit cells to the lymph node, develop a chronic infection with L. major. Injection of L. major-activated dendritic cells promoted lymph node hypertrophy, and this correlated with an increase in the expression of CCR7 on dendritic cells, although the upregulation of CCR7 occurred on the bystander (uninfected) dendritic cells rather than those containing parasites. We found that increased CCR7 expression was TLR9-dependent, that TLR9(-/-) dendritic cells migrated less efficiently to the draining lymph node, and that TLR9(-/-) mice exhibited a deficit in lymph node expansion following L. major infection, as well as increased susceptibility. Taken together, to our knowledge, these results are the first to demonstrate that activation of dendritic cells via TLR9 is essential for the induction of lymph node hypertrophy in leishmaniasis. PMID- 22205032 TI - Splenic stroma-educated regulatory dendritic cells induce apoptosis of activated CD4 T cells via Fas ligand-enhanced IFN-gamma and nitric oxide. AB - Stromal microenvironments of bone marrow, lymph nodes, and spleen have been shown to be able to regulate immune cell differentiation and function. Our previous studies demonstrate that splenic stroma could drive mature dendritic cells (DC) to further proliferate and differentiate into regulatory DC subset that could inhibit T cell response via NO. However, how splenic stroma-educated regulatory DC release NO and whether other molecules are involved in the suppression of T cell response remain unclear. In this study, we show that splenic stroma educates regulatory DC to express high level of Fas ligand (FasL) by TGF-beta via ERK activation. The findings, that inhibition of CD4 T cell proliferation by regulatory DC required cell-to-cell contact and FasL deficiency impaired inhibitory effect of regulatory DC, indicate that regulatory DC inhibit CD4 T cell proliferation via FasL. Then, regulatory DC have been found to be able to induce apoptosis of activated CD4 T cells via FasL in caspase 8- and caspase 3 dependent manner. Interestingly, FasL on regulatory DC enhanced IFN-gamma production from activated CD4 T cells, and in turn T cell-derived IFN-gamma induced NO production from regulatory DC, working jointly to induce apoptosis of activated CD4 T cells. Blockade of IFN-gamma and NO could reduce the apoptosis induction. Therefore, our results demonstrated that splenic stroma-educated regulatory DC induced T cell apoptosis via FasL-enhanced T cell IFN-gamma and DC NO production, thus outlining a new way for negative regulation of T cell responses and maintenance of immune homeostasis by regulatory DC and splenic stromal microenvironment. PMID- 22205031 TI - Population dynamics of naive and memory CD8 T cell responses after antigen stimulations in vivo. AB - The extent to which the progeny of one primary memory CD8 T cell differs from the progeny of one naive CD8 T cell of the same specificity remains an unresolved question. To explore cell-autonomous functional differences between naive and memory CD8 T cells that are not influenced by differences in the priming environment, an experimental model has been developed in which physiological numbers of both populations of cells were cotransferred into naive hosts before Ag stimulation. Interestingly, naive CD8 T cells undergo greater expansion in numbers than do primary memory CD8 T cells after various infections or immunizations. The intrinsic ability of one naive CD8 T cell to give rise to more effector CD8 T cells than one memory CD8 T cell is independent of the number and quality of primary memory CD8 T cells present in vivo. The sustained proliferation of newly activated naive CD8 T cells contributed to their greater magnitude of expansion. Additionally, longitudinal analyses of primary and secondary CD8 T cell responses revealed that on a per-cell basis naive CD8 T cells generate higher numbers of long-lived memory cells than do primary memory CD8 T cells. This enhanced "memory generation potential" of responding naive CD8 T cells occurred despite the delayed contraction of secondary CD8 T cell responses. Taken together, the data in this study revealed previously unappreciated differences between naive and memory CD8 T cells and will help further define the functional potential for both cell types. PMID- 22205033 TI - Anergic CD8+ T lymphocytes have impaired NF-kappaB activation with defects in p65 phosphorylation and acetylation. AB - Because of the cytotoxic potential of CD8(+) T cells, maintenance of CD8(+) peripheral tolerance is extremely important. A major peripheral tolerance mechanism is the induction of anergy, a refractory state in which proliferation and IL-2 production are inhibited. We used a TCR transgenic mouse model to investigate the signaling defects in CD8(+) T cells rendered anergic in vivo. In addition to a previously reported alteration in calcium/NFAT signaling, we also found a defect in NF-kappaB-mediated gene transcription. This was not due to blockade of early NF-kappaB activation events, including IkappaB degradation and NF-kappaB nuclear translocation, as these occurred normally in tolerant T cells. However, we discovered that anergic cells failed to phosphorylate the NF-kappaB p65 subunit at Ser(311) and also failed to acetylate p65 at Lys(310). Both of these modifications have been implicated as critical for NF-kappaB transactivation capacity, and thus, our results suggest that defects in key phosphorylation and acetylation events are important for the inhibition of NF kappaB activity (and subsequent T cell function) in anergic CD8(+) T cells. PMID- 22205034 TI - A comparison of dequalinium chloride vaginal tablets (Fluomizin(r)) and clindamycin vaginal cream in the treatment of bacterial vaginosis: a single blind, randomized clinical trial of efficacy and safety. AB - AIMS: To investigate if vaginal application of dequalinium chloride (DQC, Fluomizin(r)) is as effective as vaginal clindamycin (CLM) in the treatment of bacterial vaginosis (BV). METHODS: This was a multinational, multicenter, single blind, randomized trial in 15 centers, including 321 women. They were randomized to either vaginal DQC tablets or vaginal CLM cream. Follow-up visits were 1 week and 1 month after treatment. Clinical cure based on Amsel's criteria was the primary outcome. Secondary outcomes were rate of treatment failures and recurrences, incidence of post-treatment vulvovaginal candidosis (VVC), lactobacillary grade (LBG), total symptom score (TSC), and safety. RESULTS: Cure rates with DQC (C1: 81.5%, C2: 79.5%) were as high as with CLM (C1: 78.4%, C2: 77.6%). Thus, the treatment with DQC had equal efficacy as CLM cream. A trend to less common post-treatment VVC in the DQC-treated women was observed (DQC: 2.5%, CLM: 7.7%; p = 0.06). Both treatments were well tolerated with no serious adverse events occurring. CONCLUSION: Vaginal DQC has been shown to be equally effective as CLM cream, to be well tolerated with no systemic safety concerns, and is therefore a valid alternative therapy for women with BV [ClinicalTrials.gov, Med380104, NCT01125410]. PMID- 22205035 TI - Early short-term application of high-frequency percussive ventilation improves gas exchange in hypoxemic patients. AB - BACKGROUND: Hypoxemia in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) patients represents a common finding in the intensive care unit (ICU) and frequently does not respond to standard ventilatory techniques. OBJECTIVE: To study whether the early short-term application of high-frequency percussive ventilation (HFPV) can improve gas exchange in hypoxemic patients with ALI/ARDS or many other conditions in comparison to conventional ventilation (CV) using the same mean airway pressure (P(aw)), representing the main determinant of oxygenation and hemodynamics, irrespective of the mode of ventilation. METHODS: Thirty-five patients not responding to CV were studied. During the first 12 h after admission to the ICU the patients underwent CV. Thereafter HFPV was applied for 12 h with P(aw) kept constant. They were then returned to CV. Gas exchange was measured at: 12 h after admission, every 4 h during the HFPV trial, 1 h after the end of HFPV, and 12 h after HFPV. Thirty-five matched patients ventilated with CV served as the control group (CTRL). RESULTS: PaO(2)/FiO(2) and the arterial alveolar ratio (a/A PO(2)) increased during HFPV treatment and a PaO(2)/FiO(2) steady state was reached during the last 12 h of CV, whereas both did not change in CTRL. PaCO(2) decreased during the first 4 h of HFPV, but thereafter it remained unaltered; PaCO(2) did not vary in CTRL. Respiratory system compliance increased after HFPV. CONCLUSIONS: HFPV improved gas exchange in patients who did not respond to conventional treatment. This improvement remained unaltered until 12 h after the end of HFPV. PMID- 22205036 TI - B-cell lymphoma presenting as acute pancreatitis. AB - BACKGROUND: Pancreatic lymphoma is uncommon, representing less than 0.5% of pancreatic tumors, with diffuse large B-cell lymphoma being the predominant histotype. Acute pancreatitis associated with pancreatic lymphoma is rare. CASE REPORT: We describe a case of synchronous pancreatic and pulmonary localizations of non-Hodgkin's lymphoma in a 42-year-old man who presented with acute pancreatitis. Acute pancreatitis resolved after standard treatment with a fasting regimen, gabexate mesilate and parenteral nutrition. However, ultrasound scan and abdominal computed tomography revealed two hypoechogenic areas within the pancreas, and chest X-ray film showed a pulmonary infiltrate in the right basal field. A percutaneous fine-needle aspiration biopsy of the pulmonary infiltrate under computed tomography guidance demonstrated a diffuse infiltration by atypical lymphoid cells positive for leukocyte common antigen, CD20 and CD30. Percutaneous fine-needle aspiration biopsy under ultrasound guidance of the pancreatic mass confirmed the diagnosis of diffuse large B-cell lymphoma. The patient was classified as stage IV-A, low-intermediate risk and received 6 cycles of chemotherapy. CONCLUSION: This is the first case of large B-cell lymphoma presenting with concomitant primary pancreatic and pulmonary involvement. Pancreatic lymphoma is uncommon and represents a rare cause of acute pancreatitis. The discovery of a pancreatic mass needs pathologic diagnosis to distinguish lymphoma from carcinoma or autoimmune pancreatitis. and IAP. PMID- 22205037 TI - Research and development on a public attitude instrument for stuttering. AB - This paper summarizes research associated with the development of the Public Opinion Survey of Human Attributes-Stuttering (POSHA-S), a survey instrument designed to provide a worldwide standard measure of public attitudes toward stuttering. Pilot studies with early experimental prototypes of the POSHA-S are summarized that relate to questionnaire rating scale prototypes, test-retest reliability, construct validity, item analysis and final item selection, translation to other languages, internal consistency, sampling procedures, manner of administration, and sample size. Future research and public service uses of the POSHA-S are discussed, especially for comparisons using its growing database archive. LEARNING OUTCOMES: Readers of this article should be able to: (1) describe the purposes of the International Project on Attitudes Toward Human Attributes (IPATHA) initiative, (2) describe procedures to determine reliability and validity of the Public Opinion Survey of Human Attributes-Stuttering (POSHA S), (3) describe factor analysis and other strategies to select items from the POSHA-E1 and POSHA-E2 pilot studies for the final POSHA-S, and (4) describe uses of the POSHA-S database archive in studies of public attitudes toward stuttering. PMID- 22205038 TI - Parenting styles and attachment in school-aged children who stutter. AB - Parental input has been described as influential in early childhood stuttering yet the exact nature of this influence remains equivocal. The present study aimed to examine whether quantitative measures of parenting styles, parent and peer attachment patterns, and parent- and self-reported child behaviour could differentiate between school-aged children who stutter (CWS) (n=10) and their fluent peers (n=10). In addition, qualitative individual semi-structured interviews with all CWS were conducted to gain insight into their life experiences and reflections in relation to stuttering. The interviews were classified into ancillary themes of school, peers and parents. Quantitative findings revealed that CWS perceived their parents with significantly lower attachment, particularly in relation to trust, and parents of CWS perceived their children with significantly higher maladjustments than fluent counterparts. Qualitative themes emerged pertaining to attitudes, perceptions and relationships with teachers, peers and parents, with consistent experiences of teasing and bullying reported as a consequence of the stutter. The majority of participants recounted frustration with the nature in which their parents attempted to remediate their stuttering. Collectively, these findings highlight imperative management considerations for school-aged CWS and their parents. The usefulness of quantitative and qualitative research paradigms is also emphasised. LEARNING OUTCOMES: The reader will be able to: (1) identify themes associated with the impact a childhood stutter has on parent and peer relationships; (2) identify how the quality of the parent child relationship is influenced by parenting styles and attachment; and (3) discuss the clinical implications of the results for children who stutter and their families. PMID- 22205039 TI - Towards defining a rigidity-associated pathogenic pathway in idiopathic parkinsonism. AB - Helicobacter pylori eradication has a differential effect on the facets of idiopathic parkinsonism (IP): brady/hypokinesia improves, but rigidity worsens. Small intestinal bacterial overgrowth is common in IP and has been described as a sequel to Helicobacter eradication. The hyperhomocysteinaemia of IP is, in part, explained by serum vitamin B(12), but the concentration is not explained by Helicobacter status. Moreover, Helicobacter-associated gastric atrophy is uncommon in IP. However, overgrowth both increases B(12) utilization and provides a source of inflammation to drive homocysteine production. It is not a bystander event in IP: clouds of lysosomes are seen in duodenal enterocytes. Its candidature for causality of a rigidity-associated pathway is circumstantial: there are biological gradients of rigidity on natural killer and T-helper blood counts, both being higher with hydrogen breath test positivity for overgrowth. PMID- 22205040 TI - Grasping soft tissue by means of vacuum technique. AB - INTRODUCTION: A notable characteristic of bariatric surgery is the frequent manipulation of the bowel. The bowel is large, delicate, flexible, and has a natural lubricant on the tissue surface. Therefore the bowel is difficult to grasp and manipulate. Vacuum technique is commonly used in industry for all types of grasping and manipulation. Two types of nozzles that differed slightly in geometry (NT1 and NT2), were reviewed in an experimental set up for pull tests on pig bowels. MATERIALS AND METHODS: An experimental set-up was used to conduct a series of pull tests on pig bowel tissue. The basic principle of the measurements was a Newton's force balance; F(Pmax)=Deltap*A. Student t-tests, two-way ANOVA and Wilcoxon signed rank tests were conducted for the statistical analysis of NT1 and NT2 with regard to the maximum pull force (F(Pmax)). RESULTS: Concerning NT1 the Newton's force balance could not be confirmed. Concerning NT2 the Newton's force balance could partly be confirmed. For both nozzle types the effect of Deltap on F(Pmax) was significant. F(Pmax) increases linear in proportion as Deltap increases. This relation between F(Pmax) and Deltap was confirmed by the Newton's force balance. DISCUSSION: The results confirm that vacuum technique can be used as a grasp technique for soft organs, particularly the bowels. By means of a clever design of the nozzle a firm grip can be obtained on the bowel segments. Therefore vacuum technique should be studied for further development of instruments, graspers and retractors, to be used in the abdominal area. PMID- 22205041 TI - Experimental investigation of the reciprocating ball pump (RBP). AB - This paper presents experimental investigations of a novel miniature reciprocating ball pump (RBP) as a potential infusion pump or drug delivery system. The objectives of this study are to validate the RBP's operational principle and to evaluate its performance. In the tests, the basic functionality of the pump has been established at different pumping frequencies ranging from 1.667 Hz (100 rpm) to 4.167 Hz (250 rpm) against different pressure heads ranging from 0 mmH(2)O and 100 mmH(2)O. In addition, experimental results show that the RBP can deliver a higher flow rate with a volumetric efficiency of 120% as compared to a conventional single acting reciprocating pump running under the same operating conditions. PMID- 22205042 TI - Comparison of plantar pressure distribution in adolescent runners at low vs. high running velocity. AB - This study aimed to compare foot plantar pressure distribution while jogging and running in highly trained adolescent runners. Eleven participants performed two constant-velocity running trials either at jogging (11.2 +/- 0.9 km/h) or running (17.8 +/- 1.4 km/h) pace on a treadmill. Contact area (CA in cm(2)), maximum force (F(max) in N), peak pressure (PP in kPa), contact time (CT in ms), and relative load (force time integral in each individual region divided by the force time integral for the total plantar foot surface, in %) were measured in nine regions of the right foot using an in-shoe plantar pressure device. Under the whole foot, CA, F(max) and PP were lower in jogging than in running (-1.2% [p<0.05], -12.3% [p<0.001] and -15.1% [p<0.01] respectively) whereas CT was higher (+20.1%; p<0.001). Interestingly, we found an increase in relative load under the medial and central forefoot regions while jogging (+6.7% and +3.7%, respectively; [p<0.05]), while the relative load under the lesser toes (-8.4%; p<0.05) was reduced. In order to prevent overloading of the metatarsals in adolescent runners, excessive mileage at jogging pace should be avoided. PMID- 22205043 TI - Protocadherin-12 deficiency leads to modifications in the structure and function of arteries in mice. AB - We studied the role of protocadherin-12 on arterial function. This protein belongs to the cadherin superfamily and is located at the intercellular junctions of endothelial cells where it promotes homotypic cellular adhesion. We previously showed that mice deficient for PCDH12 exhibited developmental growth retardation owing to placenta defects without altering neither survival nor fertility. Here, we investigated the effects of PCDH12 deficiency on the structural, mechanical properties and functionality of arteries from adult mice. Histological studies of the PCDH12(-/-) mouse arteries have shown age-independent modifications such as ramifications of medial elastic lamellae, accompanied by the appearance of radial fibers linking together two successive concentric elastic lamellae. Mechanical studies also revealed some age-independent modifications in the PCDH12(-/-) mice arteries such as an increase in inner-diameter and circumferential mid-wall stress. Moreover, the PCDH12(-/-) mice exhibited a mild reduction of blood pressure, thus maintaining the inner-diameter close to its normal value and a normal circumferential wall stress for vascular cells. This is likely a compensation mechanism enabling normal blood flow in the arteries. The vascular phenotypic differences observed between PCDH12(-/-) and wild type mice arteries did not seem to be age-dependent, except for some results regarding the carotid artery: the reactivity to acetylcholine and the circumferential mid-wall stress decreased with ageing in the PCDH12(-/-) mice, as opposed to the increase observed in the wild types. In conclusion, deficiency in one specific interendothelial junction component leads to significant changes in the structure and function of the vascular wall. Possible explanations for the observed modifications are discussed. PMID- 22205044 TI - Residues of chlorantraniliprole in rice field ecosystem. AB - The fate of chlorantraniliprole was studied in rice field ecosystem, and a simple and reliable analytical method was developed for determination of chlorantraniliprole in soil, rice straw, paddy water and brown rice. Chlorantraniliprole residues were extracted from samples with acetonitrile. The extract was cleaned up with QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method, and determined by high-performance liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). The average recoveries were 76.9-82.4% from soil, 83.6-89.3% from rice straw, 95.2-103.1% from paddy water and 84.9-87.7% from brown rice. The relative standard deviation was less than 15%. The limits of detection (LODs) of chlorantraniliprole calculated as a sample concentration (S/N ratio of 3) were 0.012 MUg L(-1) for paddy water, 0.15 MUg kg(-1) for soil, brown rice and rice straw. The results of the kinetics study of chlorantraniliprole residue showed that chlorantraniliprole degradation in soil, water and rice straw coincided with C=0.01939e(-0.0434t), C=0.01425e(-0.8111t), and C=1.171e(-0.198t), respectively; the half-lives were about 16.0 d, 0.85 d and 3.50 d, respectively. The degradation rate of chlorantraniliprole in water was the fastest, followed by rice straw. The final residues of chlorantraniliprole on brown rice were lower than maximum residue limit (MRL) of 0.02 mg kg(-1) after 14 d Pre-Harvest Interval (PHI). Therefore, a dosage of 150 mL a.i.hm(-2) was recommended, which could be considered as safe to human beings and animals. PMID- 22205045 TI - Comparison of in vitro and in vivo acute toxicity assays in Etroplus suratensis (Bloch, 1790) and its three cell lines in relation to tannery effluent. AB - Cell lines of Etroplus suratensis established in our laboratory were evaluated for their potential use as screening tools for the ecotoxicological assessment of tannery effluent. The cytotoxic effect of tannery effluent in three cell lines derived from eye, kidney and gill tissue of E. suratensis was assessed using multiple endpoints such as Neutral Red (NR) assay, Coomassie Blue (CB) protein assay and Alamar Blue (AB) assay. Acute toxicity tests on fish were conducted by exposing E. suratensis for 96 h to tannery effluent under static conditions. The toxic effect of tannery effluent on the survival of fish was found to be concentration and time dependent. The tannery effluent at the concentration of 15% caused 100% mortality at 96 h whereas the lower concentration (0.5%) caused 13.33% mortality. The cytotoxicity of tannery effluent was found to be similar in the three cell lines tested, independent of the toxic endpoints employed. EC(50) values, the effective concentration of tannery effluent resulting in 50% inhibition of cytotoxicity parameters after 48 h exposure to tannery effluent were calculated for eye, kidney and gill cell lines using NR uptake, AB and cell protein assays. Statistical analysis revealed good correlation with r(2)=0.95 0.99 for all combinations between endpoints employed. Linear correlations between each in vitro EC(50) and the in vivo LC(50) data, were highly significant p<0.001 with r(2)=0.977, 0.968 and 0.906 for AB(50), NR(50), and CB(50), respectively. PMID- 22205046 TI - Complete mineralization of benzene by a methanogenic enrichment culture and effect of putative metabolites on the degradation. AB - Microbial degradation of benzene under anaerobic conditions plays an important role in remediation of contaminated sites but the microorganisms and metabolic pathways involved remain poorly understood. In this study, we evaluated degradation of benzene by a methanogenic enrichment culture obtained from non contaminated lotus field soil, alone and in the presence of several putative metabolic intermediates, that is, toluene, benzoate and phenol. Using stable isotope ((13)C) labeled substrate, benzene was shown to be degraded almost completely to equimolar concentrations of methane and carbon dioxide, without detectable accumulation of extracellular metabolites. Concurrently, toluene, benzoate and phenol were also effectively mineralized, but probably by microorganisms other than the benzene degraders. The latter included Hasda-A, which is putative benzene-degrading deltaproteobacterium present in the culture. While toluene and benzoate did not affect benzene degradation, phenol had a moderate inhibitory effect although it was not a major metabolic intermediate of benzene in our culture. Finally, 4-hydroxycoumarin was detected as a compound formed from phenol but further experiments are required to elucidate its relationship to degradation of phenol. PMID- 22205047 TI - Photocatalytic oxidation of monuron in the suspension of WO3 under the irradiation of UV-visible light. AB - A comprehensive study of the degradation of monuron, one of the phenylurea herbicides, was conducted by UV-Vis/WO(3) process. It was found that hydroxyl radicals played a major role in the decay of monuron while other radicals (e.g. superoxide) and hole might also contribute to the decomposition of monuron. The oxidation path likely plays a major role in the generation of hydroxyl radicals. The effects of initial pH level, initial concentration of monuron, and inorganic oxidants on the performance of UV-Vis/WO(3) process were also investigated and optimized. Comparison between monuron decay pathways by UV-Vis/WO(3) and UV/TiO(2) was conducted. The decay mechanisms, including N-terminus demethylation, dechlorination and direct hydroxylation on benzene ring, were observed to be involved in the oxidation of monuron in these two processes. Sixteen intermediates were identified during the photodegradation of monuron and degradation pathways were proposed accordingly. PMID- 22205048 TI - Influence of releases of I-129 from reprocessing plants on the marine environment of the North Adriatic Sea. AB - Compared to the pre-nuclear era, large amounts of (129)I have been released to the marine environment, especially as liquid and gaseous discharges from two European reprocessing plants located at Sellafield and La Hague. Their liquid discharges influence Northern Europe and most research was conducted in the area of the North Atlantic Ocean and the Baltic Sea. In this article data on (129)I content and (129)I/(127)I ratios observed in the North Adriatic Sea, which is a rather enclosed basin of the Mediterranean Sea, are presented. To the best of our knowledge no data on (129)I in the Mediterranean Sea have previously been reported. As this area is isolated from direct liquid discharges, the main transport pathway is probably gaseous releases from reprocessing plants. Surface sea water, the marine alga Fucus virsoides, an iodine accumulator, and the Mediterranean mussel Mytilus galloprovincialis collected in 2009 and 2010, and marine sediment collected in 2005 and 2009 were analysed. The (129)I/(127)I isotopic ratios observed were in the range from 0.8 to 3.0*10(-08) for seawater, from 0.06 to 0.35*10(-08) for marine sediment, from 0.05 to 0.10*10(-08) for F. virsoides and from 0.3 to 0.9*10(-08) for M. galloprovincialis. PMID- 22205049 TI - Liver histopathology of the sharptooth catfish Clarias gariepinus as a biomarker of aquatic pollution. AB - This paper reports on a comparative perspective of liver histopathological data of the sharptooth catfish Clarias gariepinus. The data was collected from a spectrum of relatively un-impacted and isolated, to polluted, eutrophic freshwater ecosystems. Results were compared between regional areas, by combining data from freshwater systems which has a similar pollution status and/or is located within the same geographical region. Measurements included necropsy observations, semi-quantitative liver histopathology (Liver Index), and selected biometrical indices. The aim was to establish whether the results of these measurements would differ between, and/or reflect the pollution status of, the different freshwater aquatic ecosystems. The histopathological analysis showed a higher prevalence of toxicopathic non-neoplastic, and pre-neoplastic alterations in C. gariepinus from the polluted sites. We also found a significant difference between the Liver Index, hepatosomatic index, and condition factor values of fish inhabiting impoundments known to be polluted, compared to the same species from the selected reference sites. Fish from polluted sites also had more macroscopic liver abnormalities. The results suggest that the liver histopathology of this bio-indicator fish species could be a useful biomarker of freshwater aquatic pollution. PMID- 22205050 TI - Ozone-biological activated carbon integrated treatment for removal of precursors of halogenated nitrogenous disinfection by-products. AB - Pilot-scale tests were performed to reduce the formation of several nitrogenous and carbonaceous disinfection by-products (DBPs) with an integrated ozone and biological activated carbon (O(3)-BAC) treatment process following conventional water treatment processes (coagulation-sedimentation-filtration). Relative to the conventional processes alone, O(3)-BAC significantly improved the removal of turbidity, dissolved organic carbon, UV(254), NH(4)(+) and dissolved organic nitrogen from 98-99%, 58-72%, 31-53%, 16-93% and 35-74%, respectively, and enhanced the removal efficiency of the precursors for the measured DBPs. The conventional process was almost ineffective in removing the precursors of trichloronitromethane (TCNM) and dichloroacetamide (DCAcAm). Ozonation could not substantially reduce the formation of DCAcAm, and actually increased the formation potential of TCNM; it chemically altered the molecular structures of the precursors and increased the biodegradability of N-containing organic compounds. Consequently, the subsequent BAC filtration substantially reduced the formation of the both TCNM and DCAcAm, thus highlighting a synergistic effect of O(3) and BAC. Additionally, O(3)-BAC was effective at controlling the formation of the total organic halogen, which can be considered as an indicator of the formation of unidentified DBPs. PMID- 22205051 TI - Review: Placenta, evolution and lifelong health. AB - The intrauterine environment has an important influence on lifelong health, and babies who grew poorly in the womb are more likely to develop chronic diseases in later life. Placental function is a major determinant of fetal growth and is therefore also a key influence on lifelong health. The capacity of the placenta to transport nutrients to the fetus and regulate fetal growth is determined by both maternal and fetal signals. The way in which the placenta responds to these signals will have been subject to evolutionary selective pressures. The responses selected are those which increase Darwinian fitness, i.e. reproductive success. This review asks whether in addition to responding to short-term signals, such as a rise in maternal nutrient levels, the placenta also responds to longer-term signals representing the mother's phenotype as a measure of environmental influences across her life course. Understanding how the placenta responds to maternal signals is therefore not only important for promoting optimal fetal growth but can also give insights into how human evolution affected developmental history with long-term effects on health and disease. PMID- 22205052 TI - Synthetic grass cricket pitches and ball bounce characteristics. AB - The use of synthetic grass cricket pitches is becoming more common at club and sub-elite levels which constitute the majority of cricket participants but there is sparse data on ball bounce characteristics on these surfaces. OBJECTIVES: To compare the speed, angle and consistency of ball bounce on two types of synthetic cricket surfaces, the Traditional and the All-Seasons, and compare these ball bounce characteristics with published data for natural turf pitches. DESIGN: Group-based comparison. METHODS: High speed motion analysis was used to capture data from balls projected onto the cricket pitches from a bowling machine at three speeds: slow (47 km h(-1)), medium (72 km h(-1)) and fast (104 km h(-1)). Both ends of the cricket pitches were assessed and two types of balls were used: 2-piece and 4-piece leather cricket balls. Digitisation was used to determine the ball speed and angle pre and post bounce and then to calculate the ratios of ball speed and angle. Consistency was determined by the coefficient of variation. RESULTS: The All-Seasons synthetic surface generated a lower speed ratio and a higher angle ratio than the Traditional synthetic surface. The speed ratio for the Traditional surface fell within the range reported for natural turf, whilst the value for the All-Seasons surface was outside the range. Both synthetic surfaces produced angle ratios greater than those for natural turf surfaces. CONCLUSIONS: Differences were detected between the different synthetic cricket surfaces and also when compared to natural turf. This variability may have implications for skill development as well as safety. PMID- 22205053 TI - Doubly committed ventricular septal defect: single-centre experience and midterm follow-up. AB - BACKGROUND: Doubly committed ventricular septal defect (dcVSD) is the least common type of VSD. Because published studies are rather scarce, this study aimed at evaluating the midterm outcome of dcVSDs. METHODS: The records of all patients registered in the database of Paediatric and Congenital Cardiology, University Hospitals Leuven, with a dcVSD at 16 years of age were reviewed. Clinical, electrocardiographic and transthoracic echocardiographic changes from baseline, defined as of the age of 16 years, until the latest follow-up were compared. RESULTS: Thirty-three patients (20 males, median age 26 years, interquartile range 12) were followed for a median time of 7.9 years (interquartile range 9.8, time range 2-25.9). No deaths occurred. In 15 patients (45%), the defect remained patent at baseline. During follow-up, two spontaneous closures (13%) occurred. Eighteen patients (55%) required closure before the age of 16 years. Five (28%) needed reoperation. In the dcVSD closure group, left ventricular ejection fraction decreased from 69 +/- 12 to 61 +/- 6% (p = 0.028). No significant changes in pulmonary arterial hypertension were noticed. CONCLUSIONS: Patients with persistently patent dcVSD remained nearly event free during follow-up. Event free survival after dcVSD closure was markedly lower. These patients developed reduced left ventricular function and had a high risk of reintervention. PMID- 22205054 TI - Survival after starting renal replacement treatment in patients with autosomal dominant polycystic kidney disease: a single-centre 40-year study. AB - BACKGROUND/AIMS: Adult polycystic kidney disease (ADPKD) has a predictable natural history and the relative lack of co-morbidity allows a relatively unconfounded assessment of survival. We examined whether survival on renal replacement treatment (RRT) has improved over the last four decades compared to that in the general population. METHODS: We conducted a retrospective cohort study of all patients with ADPKD who received RRT between 1971 and 2000 at the Oxford Kidney Unit. The main exposure was period of start of treatment (1971-1985 vs. 1986-2000) and the key outcome was overall survival. Standard Cox regression techniques were used to assess the association between these baseline variables and survival. RESULTS: Age at start of RRT (HR per 1 year 1.08; 95% CI 1.06-1.10) and presence of a functioning transplant (HR 0.22; 95% CI 0.16-0.31) were associated with improved survival in unadjusted analyses. After adjustment for age the period of treatment also became a significant predictor of overall survival (HR 0.67; 95% CI 0.47-0.97). CONCLUSIONS: Survival on RRT appears to have improved and exceeds that observed in the general population, such that RRT now provides almost two-thirds of the life expectancy of the general population, compared to about half in earlier decades. PMID- 22205055 TI - Current challenges of behavior change talk for medical professionals and trainees. AB - OBJECTIVE: To explore medical professionals' and trainees' experiences and views of behavior change talk in various health care settings to develop current understanding of the challenges that underlie this phenomenon. METHODS: Qualitative, semi-structured interviews were conducted with medical professionals and trainees (n=29). Grounded theory principles informed sampling, data collection and analysis. To achieve maximum variance, participants with different levels of experience were purposively sampled from a range of primary and secondary care settings. Analysis was iterative, involving a constant comparative approach allowing emergent ideas to be tested in subsequent interviews until thematic saturation was reached. RESULTS: Three emergent themes described reasons for not engaging in behavior change talk with patients: (1) 'personal challenges'; (2) 'somebody else's responsibility' and (3) 'prioritizing the doctor-patient relationship'. CONCLUSION: Despite increasingly being recognized as a core aspect of medical practice and education, medical professionals and trainees remain unprepared to discuss health-related behavior change with patients and unclear of their roles within contemporary health care. PRACTICE IMPLICATIONS: Formal training in theory-based behavior change techniques is likely to help empower doctors and mitigate many of the barriers found, particularly in relation to socially and emotionally uncomfortable topics that are perceived to threaten the doctor-patient relationship. PMID- 22205056 TI - Supracondylar humerus fractures in children: a comparison of experiences. AB - The most common elbow lesions found in pediatric practice are supracondylar fractures. We compared two groups of 34 patients each with a supracondylar humerus fracture grade III (Gartland classification). The first group was treated with percutaneous pinning with Kirschner wires, with patients in a supine position, sometimes preceded by transkeletal traction. The second group was treated with percutaneous pinning with Kirschner wires, with patients in a prone position, within 6 h of the trauma. No statistically significant differences with regard to clinical outcomes and neurovascular complications were revealed in the comparison. Therefore, we can state that both treatment techniques used are valid. PMID- 22205057 TI - The 2011 Southern Society of Clinical Investigation President's Symposium: sexually transmitted infections-evolving concepts. PMID- 22205058 TI - Gender differences in risk for sexually transmitted diseases. PMID- 22205059 TI - The 2011 Joint Plenary Session Symposium: current strategies and evolving paradigms of treatment for type 2 diabetes. PMID- 22205060 TI - Pathophysiology of the metabolic syndrome: implications for the cardiometabolic risks associated with type 2 diabetes. AB - The worldwide obesity epidemic has brought to the author's attention the cardiometabolic risk factors and cardiovascular disease associated with the metabolic syndrome. The emphasis on diagnosing and treating the individual risk factors should help in the prevention of the cardiovascular disease associated with obesity, the metabolic syndrome and type 2 diabetes. PMID- 22205061 TI - Benefits and risks for intensive glycemic control in patients with diabetes mellitus. AB - Overweight, obesity, pre-diabetes and diabetes have become epidemic in most of Western society. An estimated 25.8 million United States adults have diabetes and some 79 million have prediabetes and are thus at high risk for future development of diabetes. Appropriate treatment of the ABCs of diabetes [A1C, blood pressure and cholesterol (dyslipidemia)] can reduce the risk for the development and progression of diabetic complications. This paper reviews some of the research studies that support treatment goals established by the American Association of Clinical Endocrinologists/American College of Endocrinology and the American Diabetes Association. Multiple studies have demonstrated that intensive glycemic control will reduce the risk for diabetes microvascular and neuropathic disease, but none showed decreased macrovascular disease events during the initial phase of the trials, although benefit was seen in long-term follow-up of the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study. The American Association of Clinical Endocrinologists/American College of Endocrinology and the American Diabetes Association goals for glycemia informed by these studies indicate the importance of individualizing targets for patients based on factors including the duration of diabetes, presence of acute and chronic complications and life expectancy. Writing groups convened by these organizations have also developed treatment algorithms to help clinicians appropriately use both lifestyle and pharmacotherapy interventions to safely achieve glycemic targets. PMID- 22205062 TI - Evolving treatment strategies for the management of type 2 diabetes. AB - It is well known that improved metabolic control significantly reduces both micro and macrovascular complications in diabetes. As it relates to specific treatment of type 2 diabetes mellitus, clinicians have traditionally initiated lifestyle intervention and progressed therapy using various drug treatments first as monotherapy and then as combination therapy throughout the course of the disease. This "stepwise" strategy has not always achieved the desired outcome of normal glycemic control; consequently, several clinical problems, such as hypoglycemia, weight gain and postprandial hyperglycemia, persist. However, new therapies that improve glycemic control and have favorable effects to address the unmet clinical problems have recently been developed or are still in development. These therapies include 2 classes of incretin-directed therapy, the dipeptidyl peptidase-4 inhibitors and the glucagon-like peptide-1 agonists, which help restore physiologic levels and activity of the incretin glucagon-like peptide-1. Also in development are additional therapies that have effects on the kidney to promote glucose excretion. These therapies are proposed to treat the key metabolic abnormalities associated with type 2 diabetes mellitus and minimize the side effects noted with conventional therapies. PMID- 22205063 TI - Influence of 1-D silica nanotubes as drug adsorbent on release behaviors of tulobuterol-loaded porous microcapsules. AB - Porous poly(epsilon-caprolactone) (PCL)/Eudragit RS 100 (ERS-100) microcapsules containing tulobuterol-adsorbed silica nanotubes (S-NTs) were prepared using a solvent evaporation method. The release behaviors of the PCL/ERS-100 microcapsules were investigated as a function of S-NT content. The PCL/ERS-100 microcapsules showed a stable and porous surface compared to the PCL microcapsules prepared without ERS-100. The drug loading and encapsulation efficiencies of the microcapsules were increased slightly by the addition of S NTs due to the adsorption of the drugs on the S-NTs. In an acidic release medium, the PCL/ERS-100 microcapsules containing the tulobuterol-loaded S-NTs showed a slow drug release, which was dependent on the S-NT content. These behaviors are most likely due to the reduced diffusion rate of the drug from the hydrated microcapsules, which results from the strong interaction between the porous S-NTs and the drug. PMID- 22205064 TI - Acaricidal, insecticidal, and larvicidal efficacy of aqueous extract of Annona squamosa L peel as biomaterial for the reduction of palladium salts into nanoparticles. AB - In recent years the utilization of secondary metabolites from plant extract has emerged as a novel technology for the synthesis of various nanoparticles. In this paper we studied the potential of nanocrystalline palladium nanoparticles production using acaricidal, insecticidal and larvicidal efficacy of Annona squamosa L aqueous peel extract as the biomaterial for the first time. The synthesized nanoparticles were characterized and confirmed as palladium nanoparticles by using UV-visible spectroscopy, XRD and TEM analysis. The results clearly showed that the compounds containing -OH as a functional group played a critical role in capping the nanoparticles. Also the results highlight the possibility of green pathways to produce palladium nanoparticles. PMID- 22205066 TI - A novel vesicular carrier, transethosome, for enhanced skin delivery of voriconazole: characterization and in vitro/in vivo evaluation. AB - This study describes a novel carrier, transethosome, for enhanced skin delivery of voriconazole. Transethosomes (TELs) are composed of phospholipid, ethanol, water and edge activator (surfactants) or permeation enhancer (oleic acid). Characterization of the TELs was based on results from recovery, particle size, transmission electron microscopy (TEM), zeta potential and elasticity studies. In addition, skin permeation profile was obtained using static vertical diffusion Franz cells and hairless mouse skin treated with TELs containing 0.3% (w/w) voriconazole, and compared with those of ethosomes (ELs), deformable liposomes (DLs), conventional liposomes (CLs) and control (polyethylene glycol, PG) solutions. The recovery of the studied vesicles was above 90% in all vesicles, as all of them contained ethanol (7-30%). There was no significant difference in the particles size of all vesicles. The TEM study revealed that the TELs were in irregular spherical shape, implying higher fluidity due to perturbed lipid bilayer compared to that of other vesicles which were of spherical shape. The zeta potential of vesicles containing sodium taurocholate or oleic acid showed higher negative value compared to other vesicles. The elasticities of ELs and TELs were much higher than that of CLs and DLs. Moreover, TELs dramatically enhanced the skin permeation of voriconazole compared to the control and other vesicles (p<0.05). Moreover, the TELs enhanced both in vitro and in vivo skin deposition of voriconazole in the dermis/epidermis region compared to DLs, CLs and control. Therefore, based on the current study, the novel carrier TELs could serve as an effective dermal delivery for voriconazole. PMID- 22205065 TI - Bicellar systems as a new colloidal delivery strategy for skin. AB - The presented work evaluates the use of bicellar systems as new delivery vectors for controlled release of compounds through the skin. Two different active principles were introduced into the bicellar systems: diclofenac diethylamine (DDEA) and flufenamic acid (Ffa). Bicellar systems are discoidal aggregates formed by long and short alkyl chain phospholipids. Characterization of the bicellar systems by dynamic light scattering (DLS) and cryogenic transmission electron microscopy (Cryo-TEM) showed that particle size decreased when DDEA was encapsulated and increased when Ffa was included in the bicellar systems. Percutaneous absorption studies demonstrated a lower penetration of DDEA and Ffa through the skin when the drugs were included in the bicellar systems than when the drugs were applied in an aqueous solution (DDEA) and in an ethanolic solution (Ffa); the reduction in penetration was more pronounced with Ffa. These bicellar systems may have retardant effects on percutaneous absorption, which result in a promising strategy for future drug or cosmetic delivery applications. PMID- 22205067 TI - Fractures as an independent predictor of functional decline in older people: a population-based study with an 8-year follow-up. AB - BACKGROUND: Fractures among older people are common, but there is scant evidence about the impact of fractures on functional decline in an unselected older population. OBJECTIVE: The objective of this study was to analyze the impact of lower and upper body fractures on functional performance among older adults during an 8-year follow-up. METHODS: A population-based cohort of 616 Finnish persons aged 65 and over was followed for up to 8 years, and the association between fractures and the risk of short-term (0-2 years) and long-term (up to 8 years) functional decline was analyzed. Fractures were categorized according their functional influence on mobility and activities of daily living (ADL) into lower and upper body fractures. Multivariate cumulative logistic regression model was used in the analyses. RESULTS: During the 8-year follow-up, 112 (18%) persons sustained at least one fracture. In the multivariate analyses, lower body fractures predicted both short-term and long-term decline in mobility [cumulative odds ratio (COR) 4.7, 95% confidence interval (95% CI) 1.9-11.7 and COR 2.6, 95% CI 1.1-6.2, respectively] and in ADL performance (COR 3.1, 95% CI 1.3-7.6 and COR 4.7, 95% CI 2.0-11.4, respectively). Upper body fractures predicted decline in ADL performance during the long-term follow-up (COR 2.5, 95% CI 1.3-4.8). Pre fracture functional decline and inactivity in leisure time physical exercise were independently associated with the risk of decline in extensive activities. CONCLUSION: Fractures have an independent influence on the development of functional decline in older persons regardless of the pre-fracture health. Prevention of falls and fractures and improvement of treatment, rehabilitation and follow-up process after fractures are needed. PMID- 22205086 TI - Road to Alzheimer's disease: the pathomechanism underlying. AB - Alzheimer's disease (AD), the most common cause of dementia, results from the interplay of various deregulated mechanisms triggering a complex pathophysiology. The neurons suffer from and slowly succumb to multiple irreversible damages, resulting in cell death and thus memory deficits that characterize AD. In spite of our vast knowledge, it is still unclear as to when the disease process starts and how long the perturbations continue before the disease manifests. Recent studies provide sufficient evidence to prove amyloid beta (Abeta) as the primary cause initiating secondary events, but Abeta is also known to be produced under normal conditions and to possess physiological roles, hence, the questions that remain are: What are the factors that lead to abnormal Abeta production? When does Abeta turn into a pathological molecule? What is the chain of events that follows Abeta? The answers are still under debate, and further insight may help us in creating better diagnostic and therapeutic options in AD. The present article attempts to review the current literature regarding AD pathophysiology and proposes a pathophysiologic cascade in AD. PMID- 22205087 TI - p53, a pivotal effector of a functional cross-talk linking presenilins and Pen-2. AB - The gamma-secretase is a multiprotein complex responsible for the ultimate cut yielding amyloid-beta peptides and their N-terminal truncated species. This complex is composed of at least four distinct entities, namely presenilin-1 (PS1) or PS2, anterior pharynx defective-1, presenilin enhancer-2 (Pen-2) and nicastrin. Very few studies examined the transcriptional regulation of this complex, and more precisely, whether some of the members functionally interact. Here, we summarize our previous data documenting the fact that Pen-2 controls cell death in a p53-dependent manner and our recent demonstration of a pivotal role of p53 as a regulator of Pen-2 transcription. As PS trigger amyloid precursor protein intracellular domain-dependent regulation of p53, our studies delineate a feedback control mechanism by which PS and Pen-2 functionally interact in a p53-dependent manner. PMID- 22205088 TI - The Journal of Comparative Pathology Educational Trust 2011 awards. PMID- 22205090 TI - Practical synthesis of hydroxychromenes and evaluation of their biological activity. AB - A simple and efficient seven steps synthesis of brodifacoum and difethialone from phenylacetyl chloride is described. The key synthetic strategies involve Friedel Crafts acylation, intramolecular ring cyclization and condensation reaction in the presence of Bronsted-Lowry acids. It was found that brodifacoum showed favorable inhibiting activities on LPS-stimulated nitrite production in BV-2 microglia cells. Brodifacoum exhibited superior anti-inflammatory effects than difethialone. We expect that an efficient linear synthesis of 4-hydroxycoumarin derivatives and key fragments that are useful agents for the modulation of inflammation as well as inhibition of coagulation will be of practical use. PMID- 22205089 TI - Synthesis and biological activity of some 3-(4-(substituted)-piperazin-1 yl)cinnolines. AB - A new series of 6-substituted-4-methyl-3-(4-arylpiperazin-1-yl)cinnolines 8-10 were synthesized as potential antifungal agents via intramolecular cyclization of the respective 1-(2-arylhydrazono)-1-(4-arylpiperazin-1-yl)propan-2-ones 5-7, mediated by polyphosphoric acid (PPA). The amidrazones themselves were synthesized via direct interaction of the appropriate hydrazonoyl chlorides 4a-d with the corresponding N-substituted piperazine in the presence of triethylamine. The structures of the new prepared compounds were confirmed by elemental analyses, (1)H-NMR, (13)C-NMR, and ESI-HRMS spectral data. The antitumor, antibacterial, and antifungal activity of the newly synthesized compounds was evaluated. PMID- 22205091 TI - Oligosaccharides might contribute to the antidiabetic effect of honey: a review of the literature. AB - Evidence shows that honey improves glycemic control in diabetes mellitus. Besides its hypoglycemic effect, studies indicate that honey ameliorates lipid abnormalities in rats and humans with diabetes. The majority of these studies do not examine the mechanisms by which honey ameliorates glycemic and/or lipid derangements. The gut microbiota is now recognized for its ability to increase energy harvest from the diet and alter lipid metabolism of the host. Recently available data implicate a causal role of these gut microbes in the pathophysiology of obesity, insulin resistance, and diabetes mellitus. In this review, we present some of the latest findings linking gut microbiota to pathogenesis of obesity, insulin resistance, and diabetes mellitus. The review also underlines data that demonstrate the beneficial effects of oligosaccharides on various abnormalities commonly associated with these disorders. Based on the similarities of some of these findings with those of honey, together with the evidence that honey contains oligosaccharides, we hypothesize that oligosaccharides present in honey might contribute to the antidiabetic and other health-related beneficial effects of honey. We anticipate that the possibility of oligosaccharides in honey contributing to the antidiabetic and other health related effects of honey will stimulate a renewed research interest in this field. PMID- 22205092 TI - Neonaucline, a new indole alkaloid from the leaves of Ochreinauclea maingayii (Hook. f.) Ridsd. (Rubiaceae). AB - A new indole alkaloid; neonaucline (1), along with six known compounds-Cadamine (2), naucledine (3), harmane, benzamide, cinnamide and blumenol A-were isolated from the leaves of Ochreinauclea maingayii (Rubiaceae). In addition to that of compound 1, (13)C-NMR data of cadamine (2) and naucledine (3) were also reported. Structural elucidations of these alkaloids were performed using spectroscopic methods especially 1D- and 2D-NMR, IR, UV and LCMS-IT-TOF. The excellent vasorelaxant activity on isolated rat aorta was observed for the alkaloids 1-3 after injection of each sample at 1 * 10(-5) M. PMID- 22205093 TI - Estimation of dermatological application of creams with St. John's Wort oil extracts. AB - Oleum Hyperici, the oil extract of St. John's Wort (SJW), is one of the oldest folk remedies, traditionally used in the topical treatment of wounds, bruises, ulcers, cuts, burns, hemorrhoids and also as an antiseptic. Considering the advantageous characteristics of emulsion applications, in the present study we have formulated three O/W creams containing 15% (w/v) of SJW oil extract as an active ingredient. The aim was to estimate dermatological application of the prepared creams for the abovementioned indications. The extracts were prepared according to the prescriptions from traditional medicine, however with different vegetable oils used as an extractant, namely: Olive, palm and sunflower oil. The investigated O/W creams demonstrated significant antiinflammatory effects in an in vivo double-blind randomized study, using a sodium lauryl sulphate test. Both skin parameters assessed in the study (electrical capacitance and erythema index), were restored to the baseline value after a seven-day treatment with the tested creams. Almost all investigated SJW oil extracts and corresponding creams displayed the same antimicrobial activity against the most of the investigated microorganisms with obtained minimal inhibitory concentrations values of 1,280 ug/mL, 2,560 ug/mL or >2,560 ug/mL. PMID- 22205094 TI - Relationship between the tibial anteroposterior axis and the surgical epicondylar axis in varus and valgus knees. AB - PURPOSE: Proper rotational alignment in total knee arthroplasty (TKA) is essential for successful outcomes. The surgical epicondylar axis (SEA) has been frequently used to determine the femoral rotational alignment, and the anteroposterior (AP) axis of the tibia described in previous study has been introduced as a line perpendicular to the SEA in healthy knees. However, the rotational relationship between the distal femur and the proximal tibia would vary between normal and osteoarthritic knees, and a question remains whether the rotational relationship between the SEA and the AP axis of the tibia would be the same between normal and osteoarthritic knees. This study aims to determine whether the AP axis of the tibia is actually perpendicular to the SEA and useful for the tibial rotational alignment also in osteoarthritic knees. METHODS: Preoperative computed tomography scans on 25 varus and 25 valgus knees undergoing TKA were studied. The SEA and the AP axis of the tibia were identified using a three-dimensional software, and the angle between the line perpendicular to the projected SEA and the AP axis was measured. RESULTS: The AP axis of the tibia was 1.7 degrees +/- 4.3 degrees and 2.0 degrees +/- 4.0 degrees internally rotated relative to the line perpendicular to the SEA in the varus and valgus groups, respectively. CONCLUSIONS: The AP axis of the tibia was, on average, perpendicular to the SEA in both varus and valgus knees. The AP axis would be useful for setting the tibial component with minimal rotational mismatch. LEVEL OF EVIDENCE: IV. PMID- 22205095 TI - Isolated ischaemic contracture of medial head of gastrocnemius. AB - A 47-year-old woman presented with a disabling fixed flexion deformity of the knee and an equinus deformity of the ankle following treatment in a cast for a minor flexion deformity following a tibial plateau fracture. Two years later, the cause was identified as an isolated ischaemic contracture involving the medial head of gastrocnemius. She made a good recovery following extensive corrective surgery and rehabilitation. PMID- 22205096 TI - Standardized pivot shift test improves measurement accuracy. AB - PURPOSE: The variability of the pivot shift test techniques greatly interferes with achieving a quantitative and generally comparable measurement. The purpose of this study was to compare the variation of the quantitative pivot shift measurements with different surgeons' preferred techniques to a standardized technique. The hypothesis was that standardizing the pivot shift test would improve consistency in the quantitative evaluation when compared with surgeon specific techniques. METHODS: A whole lower body cadaveric specimen was prepared to have a low-grade pivot shift on one side and high-grade pivot shift on the other side. Twelve expert surgeons performed the pivot shift test using (1) their preferred technique and (2) a standardized technique. Electromagnetic tracking was utilized to measure anterior tibial translation and acceleration of the reduction during the pivot shift test. The variation of the measurement was compared between the surgeons' preferred technique and the standardized technique. RESULTS: The anterior tibial translation during pivot shift test was similar between using surgeons' preferred technique (left 24.0 +/- 4.3 mm; right 15.5 +/- 3.8 mm) and using standardized technique (left 25.1 +/- 3.2 mm; right 15.6 +/- 4.0 mm; n.s.). However, the variation in acceleration was significantly smaller with the standardized technique (left 3.0 +/- 1.3 mm/s(2); right 2.5 +/- 0.7 mm/s(2)) compared with the surgeons' preferred technique (left 4.3 +/- 3.3 mm/s(2); right 3.4 +/- 2.3 mm/s(2); both P < 0.01). CONCLUSION: Standardizing the pivot shift test maneuver provides a more consistent quantitative evaluation and may be helpful in designing future multicenter clinical outcome trials. LEVEL OF EVIDENCE: Diagnostic study, Level I. PMID- 22205097 TI - Relationship of native tibial plateau anatomy with stability testing in the anterior cruciate ligament-deficient knee. AB - PURPOSE: Recent attention has been drawn to tibial plateau slope and depth with relation to both risk of anterior cruciate ligament (ACL) tear and kinematics in the cruciate-deficient knee. The purpose was to evaluate the relationship between native proximal tibial anatomy and knee kinematics in the anterior cruciate deficient knee. METHODS: Twenty-two cadaveric knees underwent CT scanning to measure proximal tibia anatomy. Translation was measured during Lachman and mechanized pivot-shift tests on the intact knee and then after resection of the ACL. Pearson's correlation was calculated to assess the relationship between tibial translation of the ACL-deficient knee and tibial plateau anatomic parameters. RESULTS: No significant correlation was found between ACL-deficient kinematic testing and tibial slope or depth (n.s.). Lateral compartment translation on Lachman and pivot-shift testing correlated with lateral compartment AP length (P = 0.007 and P = 0.033, respectively). The ratio of lateral AP length to medial AP length correlated with lateral compartment translation during the pivot shift (P = 0.002). CONCLUSION: There was a poor correlation between native tibial slope and kinematic testing. There were, however, increases in translation during pivot-shift and Lachman testing with increased AP length of the lateral compartment. In addition, the finding of increased pivot-shift magnitude when the lateral compartment was relatively wide in the AP plane compared to the medial compartment suggests that patients with a "dominant" lateral compartment may be prone to a greater magnitude of instability after ACL injury. PMID- 22205098 TI - Treatment of osteochondral lesions of the talus with microfracture technique and postoperative hyaluronan injection. AB - PURPOSE: The aim of this study is to report the outcomes of the treatment of talar osteochondral lesions with arthroscopic microfracture technique and postoperative intra-articular hyaluronan injection. METHOD: Fifty-seven patients (29 men, 28 women) with osteochondral lesions of the talus were included in this prospective randomized clinical study between the years 2003 and 2009. The patients were treated with arthroscopic debridement and microfracture technique. Randomly selected 41 patients were injected intra-articular hyaluronan (injection group). The remaining 16 patients did not receive postoperative injection (non injection group). Assessment of the pain and functional outcomes was performed using the Freiburg and AOFAS ankle/hindfoot scoring systems. RESULTS: In the injection group, the mean postoperative Freiburg functional and pain scores were significantly higher compared to preoperative functional and pain scores (P < 0.001). Similarly, for the patients in non-injection group, the mean postoperative Freiburg functional and pain scores were significantly higher compared to preoperative functional and pain scores (P < 0.001). The AOFAS functional and pain scores of the patients in the injection group were significantly higher (P < 0.001) postoperatively compared to preoperative scores. Scoring the patients in the non-injection group according to AOFAS system also revealed significantly higher (P < 0.001) postoperative functional and pain scores over preoperative scores. The increase in the postoperative scores was found to be significantly higher in the injection group compared to non-injection group in both Freiburg and AOFAS systems (P < 0.001). CONCLUSION: Treatment of osteochondral lesions of the talus using microfracture technique significantly improved functional and pain scores postoperatively. Additional treatment with intra-articular hyaluronan injection as an adjunct to microfracture technique may offer better clinical outcomes over microfracture technique alone. LEVEL OF EVIDENCE: Randomized, controlled trial, Level I. PMID- 22205099 TI - Early osteoarthritis. PMID- 22205100 TI - Diagnostic accuracy of C-reactive protein and white blood cell counts in the early detection of inflammatory complications after open resection of colorectal cancer: a retrospective study of 1,187 patients. PMID- 22205101 TI - Prevalence and risk factors for colonic perforation during colonoscopy in hospitalized end-stage renal disease patients on hemodialysis. AB - BACKGROUND AND AIMS: Colonic perforation is a rare complication during colonoscopy. A recent single center study reported a high incidence of colonic perforation in end-stage renal disease (ESRD) patients on hemodialysis (HD) who underwent colonoscopy. We sought to determine nationwide, population-based prevalence in rates of colonic perforation during colonoscopy among ESRD inpatients on HD in the US, and to assess risk factors for colonic perforation in this patient population. METHODS: We obtained patient data from the Nationwide Inpatient Sample and used the International Classification of Diseases, the 9th revision, clinical modification codes, to identify ESRD patients on HD who had undergone colonoscopy in 2006. The control group consisted of inpatients who had colonoscopy without ESRD. RESULTS: Colonic perforations occurred in 51/17,000 ESRD hospitalizations on HD (0.3%) and 3,951/564,428 controls without ESRD (0.7%). The risk of colonic perforation among the study group was not significantly higher than the control group even after adjusting for patient demographics like age, gender and comorbid conditions (adjusted odds ratio [aOR] 0.55; 95% confidence interval [CI], 0.30-0.97). Older age (OR -1.007; 95% CI, 1.002-1.011) and female gender (OR -1.18; 95% CI, 1.03-1.36) were identified as independent risk factors for the risk of perforation in this population group. CONCLUSIONS: There appeared no increased risk of colonic perforation during colonoscopy among inpatients who received HD in our study. Increasing age and female patients appeared to be associated with procedure-related colonic perforation. PMID- 22205102 TI - Age and CD4 count at initiation of antiretroviral therapy in HIV-infected children: effects on long-term T-cell reconstitution. AB - BACKGROUND: Effective therapies and reduced AIDS-related morbidity and mortality have shifted the focus in pediatric human immunodeficiency virus (HIV) from minimizing short-term disease progression to maintaining optimal long-term health. We describe the effects of children's age and pre-antiretroviral therapy (ART) CD4 count on long-term CD4 T-cell reconstitution. METHODS: CD4 counts in perinatally HIV-infected, therapy-naive children in the Paediatric European Network for the Treatment of AIDS 5 trial were monitored following initiation of ART for a median 5.7 years. In a substudy, naive and memory CD4 counts were recorded. Age-standardized measurements were analyzed using monophasic, asymptotic nonlinear mixed-effects models. RESULTS: One hundred twenty-seven children were studied. Older children had lower age-adjusted CD4 counts in the long term and at treatment initiation (P < .001). At all ages, lower counts before treatment were associated with impaired recovery (P < .001). Age-adjusted naive CD4 counts increased on a timescale comparable to overall CD4 T-cell reconstitution, whereas age-adjusted memory CD4 counts increased less, albeit on a faster timescale. CONCLUSIONS: It appears the immature immune system can recover well from HIV infection via the naive pool. However, this potential is progressively damaged with age and/or duration of infection. Current guidelines may therefore not optimize long-term immunological health. PMID- 22205103 TI - Statins in unconventional secretion of insulin-degrading enzyme and degradation of the amyloid-beta peptide. AB - Population-based studies demonstrated that statins might decrease the risk of developing Alzheimer's disease (AD). Statins inhibit the 3-hydroxy-3-methyl glutaryl-coenzyme-A reductase and thereby de novo synthesis of cholesterol. Cell culture and animal studies indicated that cholesterol affects the proteolytic processing of the amyloid precursor protein and the generation of amyloid-beta (Abeta). Recently, we have demonstrated that statins can also stimulate the degradation of Abeta. The statin-induced clearance of Abeta could be attributed to increased release of the insulin-degrading enzyme (IDE) via an exosome-related unconventional secretory pathway. Interestingly, this statin-induced secretion of exosome-associated IDE was independent of cellular cholesterol concentrations, but rather caused by impairment of isoprenoid biosynthesis and protein prenylation. We further identified a new hexapeptide sequence in the C-terminal region of IDE, named the SlyX motif that is critically involved in IDE secretion. Taken these findings together, the increased clearance of Abeta by stimulated secretion of IDE might contribute to the protective effects of statins against AD. PMID- 22205104 TI - RB1 mutations and second primary malignancies after hereditary retinoblastoma. AB - Survivors of hereditary retinoblastoma have a high risk of second primary malignancies, but it has not been investigated whether specific RB1 germline mutations are associated with greater risk of second primary malignancies in a large cohort. We conducted a retrospective cohort study of 199 survivors of hereditary retinoblastoma with a documented RB1 germline mutation diagnosed between 1905 and 2005. In total, 44 hereditary retinoblastoma survivors developed a second primary malignancy after a median follow-up of 30.2 years (range 1.33 76.0). A significantly increased risk of second primary malignancy was observed among carriers of one of the 11 recurrent CGA>TGA nonsense RB1 mutations (hazard ratio (HR) = 3.53; [95% confidence interval (CI) = 1.82-6.84]; P = .000), and there was a significantly lower risk for subjects with a low penetrance mutation (HR = .19; [95% CI = .05-.81]; P = .025). Our findings suggest a genotype phenotype correlation for second primary cancers of retinoblastoma survivors and may impact on long-term surveillance protocols of patients with hereditary retinoblastoma, if confirmed by future studies. PMID- 22205105 TI - Impact of clinical and pathohistological characteristics on the incidence of recurrence and survival in elderly patients with gastric cancer. AB - BACKGROUND: Gastric cancer is one of the most frequent malignant tumors worldwide. Despite improvements in diagnostic procedures, as well as the introduction of multimodal treatment strategies, the overall prognosis remains poor. The role of gastric resection in elderly patients with gastric cancer has not been clearly defined as yet. The goal of the present study was to assess whether specific pathohistological features result in different outcomes for younger patients and elderly patients. METHODS: A total of 272 patients with advanced gastric cancer treated surgically in our hospital between 1998 and 2009 were included in the study. Data were analyzed from a prospectively maintained database. RESULTS: Median overall survival was 84 months in the younger subgroup and 37 months in the elderly subgroup (P = 0.038), whereas local recurrence occurred more frequently in younger patients (33% vs. 23%). We identified positive lymph nodes at the contralateral curvature, perilymphonodular tumor cells, and positive lymph node conglomerates as strong negative prognostic factors. There were few pathohistological characteristics that affected survival and the incidence of tumor recurrence differently in elderly and younger patients. Although only a few elderly patients underwent chemotherapy plus gastric resection (7% vs. 28% of the younger patients), there was a trend toward longer survival for those who received multimodal treatment. CONCLUSIONS: Our results suggest that there is no tumor-related prognostic difference between young and elderly patients that would preclude radical surgery in elderly patients, as long as they are generally fit for surgery. PMID- 22205106 TI - Technical feasibility of a robotic-assisted ventral hernia repair. PMID- 22205107 TI - Multiple lymphatic basin drainage from cutaneous melanoma as a prognostic factor. AB - BACKGROUND: There is some controversy in the literature regarding the possible prognostic value of cases of multiple lymphatic basin drainage (MLBD). The purpose of this work was to study the differences in prognosis depending on whether there is MLBD from primary cutaneous melanoma. METHODS: We conducted a cohort analysis from a prospective database, and 112 consecutive patients with cutaneous melanoma were included. Sentinel lymph node biopsy (SLNB) was done in all of them. MLBD was defined as the occurrence of two or more different nodal basins from the same lesion. The demographic and clinical data for cases with a single nodal drainage basin and MLBD were statistically compared using Fisher's exact test, the chi(2) test, or Mann-Whitney's test according to the type of variables studied. Multivariate analysis also was performed on the disease-free survival rate using logistic regression analysis. The distribution of disease free survival was determined using a Cox proportional risk model. RESULTS: Only gender (27% men and 8% women; P = 0.01) and the localization of the primary tumor in the trunk (P < 0.001) were associated with the presence of MLBD. It also was observed that the cases with a high Breslow thickness or with MLBD were only associated with a worse disease-free survival rate in cases with positive (P < 0.01 and P = 0.047, respectively) and negative (P < 0.011 and P = 0.019, respectively) SLNB. CONCLUSIONS: This study suggests that both Breslow thickness and the presence of MLBD are statistically significant independent prognostic factors of disease-free survival in patients with cutaneous melanoma. PMID- 22205109 TI - Bioabsorbable staple-line reinforcement for pancreatectomy in a porcine model: a preliminary study. AB - BACKGROUND: We conducted an exploratory study to assess the use of FOREseal(r) bioabsorbable reinforcement sleeves in stapling of the pancreatic parenchyma. METHODS: A left pancreatectomy was carried out with linear stapler on 12 pigs: in the FOREseal group (n = 6), the stapling was reinforced with FOREseal, while in the control group (n = 6), simple stapling was applied. RESULTS: The mean operating time was not different between the two groups. No additional haemostasis of the stapling transection was necessary with FOREseal, while in the control group, four pigs required additional haemostasis (p = 0.03). The mean postoperative drainage volume and the mean duration of drainage were, respectively, in the FOREseal group versus the control group: 82 versus 204 ml (p = 0.2) and 3.2 versus 4.7 days (p = 0.3). No adverse event occurred in the FOREseal group. There was no anatomopathological difference between the two groups. CONCLUSION: A good tolerance of FOREseal was observed when used on the pancreatic stump. In this study, it was demonstrated a better haemostatic control of the pancreatic stump with FOREseal which also tends to reduce the volume of postoperative drainage liquid. PMID- 22205108 TI - Thoracoscopic removal of mediastinal parathyroid lesions: selection of surgical approach and pitfalls of preoperative and intraoperative localization. AB - BACKGROUND: Thoracoscopic surgery has replaced conventional sternotomy or thoracotomy for resection of mediastinal parathyroid lesions. We review our experience with this type of surgery with reference to selection of the appropriate approach and the pitfalls of lesion localization before and during surgery. METHODS: During a 14-year period, we treated 14 patients with hyperparathyroidism, in whom a mediastinal lesion had been localized preoperatively by sestamibi scan. Primary hyperparathyroidism was present in 12 patients (single adenoma in 11, associated with MEN 1 in one) and secondary hyperparathyroidism in 2. Thoracoscopic procedures were performed by the three port method. RESULTS: The thoracoscopic procedure was successful in eight patients who were shown preoperatively to have a deep-seated (5 anterior, 3 middle) mediastinal lesions. Intraoperative visual confirmation of parathyroid adenoma was difficult only in a 19-year-old patient with a tumor embedded in the thymus, necessitating partial thymectomy. One of the eight mediastinal lesions resected thoracoscopically was a sestamibi-positive thymoma. Secondary hyperparathyroidism recurred 4 years after thoracoscopic mediastinal parathyroidectomy in one patient, necessitating additional thoracoscopic removal of this supernumerary lesion. However, seven patients with mediastinal parathyroid lesions localized at the aortic arch or upper region were treated successfully via a cervical approach. None of the patients suffered any surgical complications. CONCLUSIONS: Thoracoscopic surgery is safe and feasible for resection of deep mediastinal parathyroid lesions. Such lesions localized preoperatively at the aortic arch or upper region can be treated via a cervical approach. Preoperative sestamibi scan can sometimes give a false-positive result in cases of concurrent thymoma. PMID- 22205110 TI - Immunohistochemical diagnosis of Fabry nephropathy and localisation of globotriaosylceramide deposits in paraffin-embedded kidney tissue sections. AB - Fabry disease (FD) is a rare X-linked lysosomal storage disorder of glycosphingolipids, mostly globotriaosylceramide (Gb3). Proteinuric chronic kidney disease develops frequently, and recognition of Fabry nephropathy on a kidney biopsy may be the first clue to the underlying diagnosis. Since the accumulated glycosphingolipids are largely extracted by the paraffin-embedding procedure, the most characteristic feature of Fabry nephropathy on routine light microscopy (LM) is nonspecific cell vacuolization. To test whether residual Gb3 in kidney tissue might be exploited for the specific diagnosis of Fabry nephropathy, paraffin-embedded kidney biopsies of nine FD patients (one boy, four men, four women) and of a female carrier of a mild genetic mutation, with no evidence of Fabry nephropathy, were immunostained with an anti-Gb3 antibody. The adult biopsies were additionally co-stained with a lysosomal marker (anti lysosomal-associated membrane protein 2 (anti-LAMP2) antibody). The distribution of Gb3 deposits was scored per cell type and compared to the histological scorings of glycosphingolipid inclusions on semi-thin sections. FD patients had residual Gb3 in all types of glomerular, tubular, interstitial and vascular kidney cells. The highest expression of LAMP2 was seen in tubular cells, but there were no meaningful associations between LAMP2 expression and prevalence of Gb3 deposits on different kidney cell types. The histological scorings of glycosphingolipid inclusions were relatively higher than the corresponding immunohistochemical scorings of Gb3 deposits. In the mildly affected female, Gb3 expression was limited to tubular cells, a pattern similar to controls. Gb3 immunostaining allows the specific diagnosis of Fabry nephropathy even in kidney biopsies routinely processed for LM. PMID- 22205111 TI - Association of aureolic acid antibiotic, chromomycin A3 with Cu2+ and its negative effect upon DNA binding property of the antibiotic. AB - Here we have examined the association of an aureolic acid antibiotic, chromomycin A3 (CHR), with Cu(2+). CHR forms a high affinity 2:1 (CHR:Cu(2+)) complex with dissociation constant of 0.08 * 10(-10) M(2) at 25 degrees C, pH 8.0. The affinity of CHR for Cu(2+) is higher than those for Mg(2+) and Zn(2+) reported earlier from our laboratory. CHR binds preferentially to Cu(2+) in presence of equimolar amount of Zn(2+). Complex formation between CHR and Cu(2+) is an entropy driven endothermic process. Difference between calorimetric and van't Hoff enthalpies indicate the presence of multiple equilibria, supported from biphasic nature of the kinetics of association. Circular dichroism spectroscopy show that [(CHR)(2):Cu(2+)] complex assumes a structure different from either of the Mg(2+) and Zn(2+) complex reported earlier. Both [(CHR)(2):Mg(2+)] and [(CHR)(2):Zn(2+)] complexes are known to bind DNA. In contrast, [(CHR)(2):Cu(2+)] complex does not interact with double helical DNA, verified by means of Isothermal Titration Calorimetry of its association with calf thymus DNA and the double stranded decamer (5'-CCGGCGCCGG-3'). In order to interact with double helical DNA, the (antibiotic)(2) : metal (Mg(2+) and Zn(2+)) complexes require a isohelical conformation. Nuclear Magnetic Resonance spectroscopy shows that the Cu(2+) complex adopts a distorted octahedral structure, which cannot assume the required conformation to bind to the DNA. This report demonstrates the negative effect of a bivalent metal upon the DNA binding property of CHR, which otherwise binds to DNA in presence of metals like Mg(2+) and Zn(2+). The results also indicate that CHR has a potential for chelation therapy in Cu(2+) accumulation diseases. However cytotoxicity of the antibiotic might restrict the use. PMID- 22205112 TI - Biomechanical evaluation of a posterior non-fusion instrumentation of the lumbar spine. AB - PURPOSE: Numerous posterior non-fusion systems have been developed within the past decade to resolve the disadvantages of rigid instrumentations and preserve spinal motion. The aim of this study was to investigate the effect of a new dynamic stabilization device, to measure the screw anchorage after flexibility testing and compare it with data reported in the literature. METHODS: Six human lumbar spine motion segments (L2-5) were loaded in a spine tester with pure moments of 7.5 Nm in lateral bending, flexion/extension and axial rotation. Specimens were tested intact, after instrumentation of the intact segment, after destabilization by a nucleotomy and after instrumentation of the destabilised segment with the new non-fusion device (Elaspine). After flexibility testing all screws were subjected to a pull-out test. RESULTS: Instrumentation of the intact segment significantly reduced the RoM (p < 0.002) in flexion, extension and lateral bending to 49.7, 44.6 and 53% of the intact state, respectively. In axial rotation, the instrumentation resulted in a non-significant RoM reduction to 95% of the intact state. Compared to the intact segment, instrumentation of the destabilized segment significantly (p < 0.05) reduced the RoM to 69.8, 62.3 and 79.1% in flexion, extension and lateral bending, respectively. In axial rotation, the instrumented segment showed a significantly higher RoM than the intact segment (137.6% of the intact state (p < 0.01)). The pull-out test showed a maximum pull-out force of 855.1 N (+/-334) with a displacement of 6.1 mm (+/-2.8) at maximum pull-out force. CONCLUSIONS: The effect of the investigated motion preservation device on the RoM of treated segments is in the range of other devices reported in the literature. Compared to the most implanted and investigated device, the Dynesys, the Elaspine has a less pronounced motion restricting effect in lateral bending and flexion/extension, while being less effective in limiting axial rotation. The pull-out force of the pedicle screws demonstrated anchorage comparable to other screw designs reported in the literature. PMID- 22205113 TI - Cage subsidence does not, but cervical lordosis improvement does affect the long term results of anterior cervical fusion with stand-alone cage for degenerative cervical disc disease: a retrospective study. AB - OBJECTIVE: Clinical outcomes of the stand-alone cage have been encouraging when used in anterior cervical discectomy and fusion (ACDF), but concerns remain regarding its complications, especially cage subsidence. This retrospective study was undertaken to investigate the long-term radiological and clinical outcomes of the stand-alone titanium cage and to evaluate the incidence of cage subsidence in relation to the clinical outcome in the surgical treatment of degenerative cervical disc disease. METHODS: A total of 57 consecutive patients (68 levels) who underwent ACDF using a titanium box cage for the treatment of cervical radiculopathy and/or myelopathy were reviewed for the radiological and clinical outcomes. They were followed for at least 5 years. Radiographs were obtained before and after surgery, 3 months postoperatively, and at the final follow-up to determine the presence of fusion and cage subsidence. The Cobb angle of C2-C7 and the vertebral bodies adjacent to the treated disc were measured to evaluate the cervical sagittal alignment and local lordosis. The disc height was measured as well. The clinical outcomes were evaluated using the Japanese Orthopaedic Association (JOA) score for cervical myelopathy, before and after surgery, and at the final follow-up. The recovery rate of JOA score was also calculated. The Visual Analogue Scale (VAS) score of neck and radicular pain were evaluated as well. The fusion rate was 95.6% (65/68) 3 months after surgery. RESULTS: Successful bone fusion was achieved in all patients at the final follow-up. Cage subsidence occurred in 13 cages (19.1%) at 3-month follow-up; however, there was no relation between fusion and cage subsidence. Cervical and local lordosis improved after surgery, with the improvement preserved at the final follow-up. The preoperative disc height of both subsidence and non-subsidence patients was similar; however, postoperative posterior disc height (PDH) of subsidence group was significantly greater than of non-subsidence group. Significant improvement of the JOA score was noted immediately after surgery and at the final follow-up. There was no significant difference of the recovery rate of JOA score between subsidence and non-subsidence groups. The recovery rate of JOA score was significantly related to the improvement of the C2-C7 Cobb angle. The VAS score regarding neck and radicular pain was significantly improved after surgery and at the final follow-up. There was no significant difference of the neck and radicular pain between both subsidence and non-subsidence groups. CONCLUSIONS: The results suggest that the clinical and radiological outcomes of the stand alone titanium box cage for the surgical treatment of one- or two-level degenerative cervical disc disease are satisfactory. Cage subsidence does not exert significant impact upon the long-term clinical outcome although it is common for the stand-alone cages. The cervical lordosis may be more important for the long-term clinical outcome than cage subsidence. PMID- 22205114 TI - Quantitative histological analysis of SM22alpha (transgelin) in an adriamycin induced focal segmental glomerulosclerosis model. AB - BACKGROUND/AIMS: SM22alpha, transgelin, has been revealed to be specifically expressed in glomerular epithelial cells and interstitial cells, according to the nature of the renal injury. In this study, quantitative analyses of SM22alpha positivity were performed to investigate the pathological significance of its expression. METHODS: Kidney samples of adriamycin nephropathy underwent immunohistochemistry with a newly established anti-SM22alpha monoclonal antibody. The SM22alpha positivity was quantified by an image analyzer. The correlation of the histological values with biochemical data was investigated statistically. Microstructural localization of SM22alpha was studied by immunoelectron microscopy. RESULTS: SM22alpha was expressed along the dense basal microfilaments of degenerating podocytes, and diffusely in interstitial cells. Both the extent and intensity of SM22alpha expression in glomerular and tubulointerstitial area were correlated with the deterioration of renal function and the severity of proteinuria. Stepwise multiple linear regression analysis revealed that the extent of its positivity in glomerular or tubulointerstitial area was the determinant of the amount of proteinuria or the deterioration of creatinine clearance (Ccr), respectively. Inversely, the deterioration of Ccr was the most important predictor of SM22alpha expression. CONCLUSION: SM22alpha expression in podocytes and interstitial cells represented the severity of proteinuria and the deterioration of renal function. SM22alpha expression in renal tissues might be a hallmark of kidney diseases. PMID- 22205115 TI - On-demand chest radiographs for hypoxia: impact on clinical care. AB - PURPOSE: To determine the therapeutic yield of on-demand chest radiographs in intubated patients experiencing acute oxygen desaturation/hypoxia. MATERIALS AND METHODS: A retrospective study was conducted examining all intubated intensive care unit patients over a 2 1/2-year period. Subjects were included only if the patient had undergone a comparison radiograph while intubated and if the word hypoxia or an equivalent alternative had been listed in the requisition. Radiographic findings were categorized into 3 groups: no change, minor new finding, or major new finding. A major new finding was defined as one that could result in a direct change in clinical management. Therapeutic yield was defined as any new clinical intervention documented in the electronic medical record occurring within the proximate timeframe after performing an on-demand radiograph. Interventions were recorded as appropriate or not appropriate to the expected therapy for each radiographic finding. RESULTS: A total of 676 radiographic reports were studied. 55.3%, 20.4%, and 24.3% of the radiographic findings were categorized into no change, minor new finding, and major new finding groups. A major radiographic finding was more likely to have new interventions compared with a no-change radiograph [odds ratio, 6.44 (4.16 9.78)]. Most interventions were deemed appropriate for the radiographic findings. CONCLUSIONS: On-demand radiographs performed for acute hypoxic clinical events yield a high percentage of major findings, with nearly half of them potentially influencing or resulting in new therapeutic interventions. Interventions were more likely in the major finding group, with most being appropriate. These results support the efficacy of the on-demand radiograph by providing evidence of its utility in patient management decisions. PMID- 22205116 TI - Atypical hyperplasia on core biopsy: is further surgery needed? AB - INTRODUCTION: Percutaneous core needle biopsy (CNB) has been widely performed as a standard technique for initial histological diagnosis of suspicious breast lesions. There have been an increased number of atypical lesions diagnosed on CNB as a consequence of the advances in breast imaging techniques. The authors aim to identify if any of the radiological and histopathological criteria evaluated in this study can predict the presence of malignancy associated with atypical hyperplasia (AH) diagnosed on CNB. METHODS: The authors retrospectively reviewed the medical records of 450 patients diagnosed with AH. Surgical excision was then performed and pathology revealed carcinoma or benign lesions. Patient age, imaging features, number of CNB samples taken, biopsy needle gauge, presence of additional proliferative diseases and calcification on CNB or excision were evaluated in both groups. RESULTS: Fifty-one (11.3%) patients were found to have malignancy on surgical excision; 74.5% had ductal carcinoma in situ only and 25.6% had invasive cancer. In subgroup analysis, pure atypical ductal hyperplasia lesions were upgraded in 11.5%, pure atypical lobular hyperplasia lesions were upgraded in 8.1% and mixed lesions were upgraded in 17.6% (P > 0.05) of patients. The majority of the patients were older than 50 years, and calcification was the main reason for biopsy in both groups. The presence of additional proliferative lesions and needle gauge were not found to be statistically significant (P > 0.05). CONCLUSION: Upgrade rate to cancer after surgical excision was 11.3% of AH patients diagnosed on CNB. However, none of the variables are significant in determining the presence of malignancy associated with AH diagnosed by CNB. PMID- 22205118 TI - Whole-body fluorodeoxyglucose positron emission tomography/computed tomography in patients with active polymyalgia rheumatica: evidence for distinctive bursitis and large-vessel vasculitis. AB - OBJECTIVES: To investigate fluorodeoxyglucose (FDG) accumulation in large joints, bursas, and large vessels in patients with polymyalgia rheumatica (PMR) using 18 FDG positron emission tomography/computed tomography (PET/CT) and to differentiate PMR from similar diseases. METHODS: Fourteen untreated patients with active PMR and 17 control patients with rheumatoid arthritis (n = 11) or other active rheumatic diseases (n = 6) underwent 18-FDG PET/CT. FDG uptake in large joints, bursas and vertebral spinous processes was evaluated by calculating maximum standardised uptake values and by visual scoring (scale 0-4). PET scan images were scored in seven vascular regions, and total vascular scores (range 0 21) were calculated. RESULTS: Polymyalgia rheumatica patients showed increased FDG uptake in ischial tuberosities, greater trochanters, and lumbar spinous processes. Positive results at two or more of these sites showed high sensitivity (85.7%) and specificity (88.2%) for the diagnosis of PMR, and shoulder or hip joint involvement showed low disease specificity. High FDG accumulations were found in the aortas and subclavian arteries of two PMR patients who were asymptomatic for temporal arteritis and scanty synovium and perisynovium, based on FDG uptake. PET/CT images of the 12 PMR patients without apparent vascular involvement showed synovitis and/or perisynovitis. CONCLUSIONS: Fluorodeoxyglucose-PET/CT may be useful for the detection of PMR lesions, which are difficult to identify using other methods. PMID- 22205117 TI - A multicenter, open-label, efficacy, pharmacokinetic, and safety study of adalimumab in Japanese patients with ankylosing spondylitis. AB - We evaluated the efficacy, pharmacokinetics, and safety of adalimumab in Japanese patients with active ankylosing spondylitis (AS) who had an inadequate response to, or who were intolerant of, treatment with >=1 nonsteroidal anti-inflammatory drugs (NSAIDs). This phase 3, multicenter, open-label trial assessed the percentage of patients with a 20% response in the Assessment of SpondyloArthritis international society working group criteria (ASAS20) at week 12 as the primary endpoint. Secondary outcome measures included assessments of disease activity, clinical response, functionality, and spinal mobility at weeks 12 and 60. Serum trough adalimumab concentrations were summarized using descriptive statistics. The adverse event profile was summarized for patients who received at least one dose of the study drug during the assessment period. At week 12, 73.2% (30/41) achieved an ASAS20 response and nearly 40% met ASAS partial remission criteria; proportions were maintained after up to 60 weeks of therapy. Mean adalimumab concentrations reached steady-state between weeks 12 and 20. Adalimumab was generally safe and well tolerated, with approximately 90% of adverse events considered to be mild. These results support the use of adalimumab as a safe and effective therapy for Japanese patients with active AS. PMID- 22205119 TI - Characterization of the lung epithelium of wild-type and TLR9(-/-) mice after single and repeated exposures to chicken barn air. AB - Exposure to chicken barn air causes lung injury resulting in lower and upper respiratory symptoms in the poultry workers, and mechanisms of which are not fully understood. The lung injury can initiate modifications such as proliferation of the airway epithelial cells such as Clara cells, type II alveolar (T2) cells and mucus producing goblet cells as part of the innate immune response. Toll-like receptors (TLR) have been suggested to play a role in cell division and proliferation. To understand the effect of TLR9 on Clara cells, T2 and mucus-producing goblet cells, we quantified the numbers of these cells in the lungs of wild-type (WT) and TLR9(-/-) mice exposed to chicken barn air. The mice were exposed for either one day or five or 20 days for 8 h/day. Clara cells and T2 cells were labelled with antibodies, and the mucus cells were identified with Periodic-acid Schiff stain, and quantified in per unit tissue section area. The data show decrease in the number of Clara cells and increase in mucus-producing goblet cells after exposure to chicken barn air in both WT and TLR9(-/-) mice. Numbers of T2 cells increased and decreased in WT and TLR9(-/-) mice, respectively, after exposure to poultry barn air. These data show that exposure to chicken barn air can affect major lung epithelial cells, and allude to the role of TLR9 in regulation of some of these responses. PMID- 22205120 TI - Amelioration of CCl(4)-induced nephrotoxicity by Oxalis corniculata in rat. AB - CCl(4) induces oxidative stress in various tissues by altering antioxidant enzymes defense system. In this study we investigated the chemical composition and protective role of Oxalis corniculata methanol extract (OCME) on CCl(4) induced nephrotoxicity in rat. Presence of flavonoids, alkaloids, terpenoids, saponins, cardiac glycosides, phlobatannins and steroids was determined in OCME while tannins were absent. Total phenolic contents estimated were 7.76 +/- 0.36 (mg gallic acid equivalents/g extract) while total flavonoid contents recorded were 6.92 +/- 0.52 (mg rutin equivalents/g extract). Intraperitoneal injection of CCl(4) (1 ml/kg b.w., 20% in olive oil) once a day for seven days caused nephrotoxicity as evident by elevated levels of urinary specific gravity, RBCs, WBCs, creatinine, protein, urobilinogen and nitrite. Serum level of creatinine, urea, blood urea nitrogen were significantly increased while protein and creatinine clearance was decreased by CCl(4) treatment in kidney samples. Activity of antioxidant enzymes; catalase, peroxidase, superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and glutathione concentration was decreased whereas lipid peroxidation and protein contents were increased along with histopathological injuries. Treatment with OCME caused significant recovery in changed parameters. It could be concluded that OCME has a protective role against CCl(4)-induced oxidative stress in rat, due to antioxidant effects of phenolics. PMID- 22205121 TI - Phosphorylation of ERK1/2 in dorsal root ganglia following sequential mustard oil and thermal stimulation of the rat hind paw. AB - The effect of a sequential stimulation by mustard oil and noxious heat or cold on the phosphorylation of ERK1/2 in sensory afferents was investigated. The stimuli were applied to the rat hind paw and phospho-ERK1/2 (p-ERK1/2) was measured by fluorescence-immunohistochemistry in the lumbar dorsal root ganglia (DRGs) neurons. All stimuli lead to a significant increase in the number of small size DRG cells displaying cytoplasmic staining for p-ERK1/2. The combination of mustard oil with cold significantly increased the number of cells with cytoplasmic staining above the level obtained with cold stimulus alone, however this was not observed with the combination of mustard oil and heat. Nuclear staining was weak and was found increased by mustard oil combined with cold stimulation. Mustard oil is known to activate TRPA1 and TRPV1 channels, heat TRPV1, and cold TRPA1 and TRPM8. The present findings shed new light on the DRG cell populations reacting with cytoplasmic and nuclear staining for p-ERK1/2 following sequential irritant chemical and thermal stimuli to the skin. PMID- 22205122 TI - Long-term follow-up of persistent truncus arteriosus: Kuwait experience. AB - OBJECTIVE: To evaluate the long-term results of patients in Kuwait who were operated for persistent truncus arteriosus (PTA). SUBJECTS AND METHODS: The following data were collected for retrospective analysis from 24 medical records of consecutive patients with PTA in Kuwait between August 1993 and August 2009: demographics, morphology, management and outcome. Major associated abnormalities included interrupted aortic arch in 1 patient and abnormal coronary artery anatomy in 2. RESULTS: Of the 24 patients, 16 underwent total intracardiac repair. The age at operation ranged from 15 days to 5 years (mean 166.19 +/- 438.63 days) and weight ranged from 2.5 to 15 kg (mean 4.3 +/- 3.01 kg). The right ventricle to pulmonary artery continuity was established with aortic homograft in 11, pulmonary homograft in 4 and by implantation of a Contegra conduit in 1 patient. Four patients had moderate truncal valve regurgitation requiring concomitant truncal valve repair. After a mean follow-up period of 81.81 +/- 61.58 months (range 3-166) there was no death. Eight of the 16 (50%) patients underwent redo homograft operations. One patient who had concomitant truncal valve repair subsequently underwent aortic valve replacement. CONCLUSION: The data showed that complete repair of PTA in the neonatal and early infancy period was the treatment with the best potential for survival. The homograft remained one of the conduits of choice to establish continuity between the right ventricle and the pulmonary artery in spite of the high incidence of conduit redo operations. PMID- 22205133 TI - Inactivation of microorganisms within collagen gel biomatrices using pulsed electric field treatment. AB - Pulsed electric field (PEF) treatment was examined as a potential decontamination method for tissue engineering biomatrices by determining the susceptibility of a range of microorganisms whilst within a collagen gel. High intensity pulsed electric fields were applied to collagen gel biomatrices containing either Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, Candida albicans, Saccharomyces cerevisiae or the spores of Aspergillus niger. The results established varying degrees of microbial PEF susceptibility. When high initial cell densities (10(6)-10(7) CFU ml(-1)) were PEF treated with 100 pulses at 45 kV cm(-1), the greatest log reduction was achieved with S. cerevisiae (~6.5 log(10) CFU ml(-1)) and the lowest reduction achieved with S. epidermidis (~0.5 log(10) CFU ml(-1)). The results demonstrate that inactivation is influenced by the intrinsic properties of the microorganism treated. Further investigations are required to optimise the microbial inactivation kinetics associated with PEF treatment of collagen gel biomatrices. PMID- 22205134 TI - From Morris Water Maze to computer tests in the prediction of Alzheimer's disease. AB - BACKGROUND: Spatial navigation performance in the Hidden Goal Task (HGT), a real space human analogue of the Morris Water Maze, can identify amnestic mild cognitive impairment (aMCI) patients with memory impairment of the hippocampal type, a known indicator of incipient Alzheimer's disease (AD). OBJECTIVE: Contrast results from computer versus real-space versions of the HGT. METHODS: A total of 42 aMCI patients were clinically and neuropsychologically classified into: (1) memory impairment of the hippocampal type--the hippocampal aMCI (HaMCI; n = 10) and (2) isolated retrieval impairment--the nonhippocampal aMCI (NHaMCI; n = 32). Results were compared to the control (n = 28) and AD (n = 21) groups. RESULTS: The HaMCI group, although similar to the NHaMCI group with respect to overall cognitive impairment, performed poorer on the computer version of the HGT and yielded parallel results to the real-space version. The two versions were strongly correlated. CONCLUSIONS: Both versions of the HGT can reliably identify aMCI with pronounced memory impairment of the hippocampal type. The computer version of the HGT may be a useful, relatively inexpensive screening tool for early detection of individuals at a high risk of AD. PMID- 22205135 TI - Trends in health-related quality of life and health service use associated with body mass index and comorbid major depression in South Australia, 1998-2008. AB - PURPOSE: To investigate 10-year trends in health-related quality of life and health service use associated with body mass index (BMI) and comorbid major depression in South Australia. METHODS: Data were obtained from 9,059 people aged >= 15 years who participated in representative surveys of the South Australian population in 1998, 2004, and 2008. Major depression was determined using the mood module of the PRIME-MD. Health-related quality of life was assessed using the SF-36 and 15-item AQoL instruments. RESULTS: Mean health-related quality-of life scores were 8-55% lower (worse), and health service use was 58-85% higher in all unhealthy BMI groups (underweight, overweight, and obesity) with major depression than in the healthy weight group independent of all covariates (socio demographic and chronic medical conditions), consistently over the 10-year period. In contrast, only some unhealthy BMI groups without major depression had worse SF-36 physical component scores (overweight/obesity), AQoL scores (underweight/obesity), and health service use outcomes (overweight/obesity), and by only 2-6%. CONCLUSION: Comorbid major depression explained most of the excess health-related quality of life and health service use in people with unhealthy BMI, consistently from 1998 to 2008. Interventions and policies that can mitigate the persistent excess population health and economic burden of major depression are needed. PMID- 22205136 TI - Health-related quality of life of doctors and nurses in China: findings based on the latest open-access data. AB - OBJECTIVE: To assess the health-related quality of life (QOL) of doctors and nurses using the recent free-access data. METHODS: The health-related QOL data of doctors and nurses came from a sub-survey of the Fourth National Health Services Survey (NHSS) of China in 2008, which used the European Quality of Life-5 Dimensions 3 level version (EQ-5D-3L) to measure the QOL. We used logistic regression to compare the percentage of respondents reporting any problems for each dimension of the EQ-5D-3L descriptive system between inhabitants aged 15-64 years and doctors and nurses. RESULTS: Fewer doctors and nurses reported problems in mobility (1.9%) than inhabitants aged 15-64 years (2.9%) (odds ratio = 0.65). No difference was detected in self-care problem. Compared with inhabitants aged 15-64 years, a relatively large proportion of doctors and nurses reported problems in usual activities (3.4% vs. 2.7%; odds ratio = 1.27), pain/discomfort (18.1% vs. 6.7%; odds ratio = 3.08), and anxiety/depression (24.6% vs. 5.1%; odds ratio = 6.07). The EQ-VAS score mean of doctors and nurses approached that of inhabitants aged 15-64 years (82 vs. 79). CONCLUSION: Compared with inhabitants aged 15-64 years, doctors and nurses have relatively poor health in usual activities, self-reporting pain/discomfort, and anxiety/depression. PMID- 22205137 TI - Neuroticism and extraversion personality traits, health behaviours, and subjective well-being: the Fukuoka Study (Japan). AB - PURPOSE: We evaluated personality dimensions captured by an abbreviated 8-item questionnaire and examined associations of the personality traits with health behaviours and subjective well-being (SWB) measures. METHODS: The subjects were 11,554 participants in the Kyushu University Fukuoka Cohort Study who completed a self-administered questionnaire inquiring health behaviours, morbidity, personality, and SWB. Personality was assessed by using a questionnaire appeared to capture neuroticism and extraversion traits, and SWB-related variables were assessed with 3 single-item questions. RESULTS: Neuroticism was negatively and extraversion was positively associated with BMI. Extraversion, but not neuroticism, was positively associated with smoking and alcohol drinking. After multivariate adjustment, neuroticism was strongly associated with each of 3 SWB measures. The multivariate-adjusted odds ratios for the highest versus lowest quintile of neuroticism were 6.09 (95% confidence interval [CI], 5.05-7.33) for perceived stress; 0.21 (95% CI, 0.18-0.25) for good health condition; and 0.26 (95% CI, 0.22-0.31) for life satisfaction. Extraversion showed no clear association with the SWB measures. CONCLUSIONS: The neuroticism and extraversion scales were associated with health behaviours and BMI differently. The neuroticism scale, but not the extraversion scale, was strongly associated with higher perception of stress, poorer perceived health, and lower satisfaction with life in a Japanese population. PMID- 22205139 TI - The cytotoxic effect of combined hyperthermia and taxane chemotherapy on ovarian cancer cells: results of an in vitro study. AB - PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) is under continuous evaluation as a potential treatment for ovarian cancer. The purpose of this study was to evaluate the effect of chemotherapy, drug concentration and temperature. MATERIALS AND METHODS: We examined the combined effects of hyperthermia and taxane chemotherapy on the clonogenic survival of the human ovarian carcinoma SHIN-3 cell line in vitro. RESULTS: When hyperthermia was combined with chemotherapy, the median lethal dose (LD50) was equivalent regardless of the duration of exposure, and was independent of the exposure temperature. Taxanes showed a similar LD50 over the temperature range tested. CONCLUSIONS: In our study, hyperthermia does not increase the cytotoxic effects of taxanes, at least for the concentrations and durations tested. PMID- 22205138 TI - Imaging thrombus in cancer patients with FDG PET-CT. AB - The incidence of thrombosis in patients with underlying primary malignancy is high. The thrombus may be the more common venous thromboembolism (VTE) or the rare tumour thrombus. VTE is a common entity in cancer patients and is managed with anticoagulant therapy, while tumour thrombosis requires aggressive multimodality management. Conventional imaging modalities, including ultrasonography, venography, contrast-enhanced computed tomography, and magnetic resonance imaging, are used routinely in such cases. With its increasing use in oncology, more and more such thrombi are encountered on 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT). Accurate characterisation of these lesions is of utmost importance owing to complementary functional information which it provides. FDG PET-CT has been found to be helpful in this context. This pictorial review discusses and illustrates the imaging features of thrombosis on FDG PET-CT. PMID- 22205140 TI - Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy. AB - A limited number of studies have associated adjuvant chemotherapy with structural brain changes. These studies had small sample sizes and were conducted shortly after cessation of chemotherapy. Results of these studies indicate local gray matter volume decrease and an increase in white matter lesions. Up till now, it is unclear if non-CNS chemotherapy is associated with long-term structural brain changes. We compared focal and total brain volume (TBV) of a large set of non-CNS directed chemotherapy-exposed breast cancer survivors, on average 21 years post treatment, to that of a population-based sample of women without a history of cancer. Structural MRI (1.5T) was performed in 184 chemotherapy-exposed breast cancer patients, mean age 64.0 (SD = 6.5) years, who had been diagnosed with cancer on average 21.1 (SD = 4.4) years before, and 368 age-matched cancer-free reference subjects from a population-based cohort study. Outcome measures were: TBV and total gray and white matter volume, and hippocampal volume. In addition, voxel based morphometry was performed to analyze differences in focal gray matter. The chemotherapy-exposed breast cancer survivors had significantly smaller TBV (-3.5 ml, P = 0.019) and gray matter volume (-2.9 ml, P = 0.003) than the reference subjects. No significant differences were observed in white matter volume, hippocampal volume, or local gray matter volume. This study shows that adjuvant chemotherapy for breast cancer is associated with long-term reductions in TBV and overall gray matter volume in the absence of focal reductions. The observed smaller gray matter volume in chemotherapy-exposed survivors was comparable to the effect of almost 4 years of age on gray matter volume reduction. These volume differences might be associated with the slightly worse cognitive performance that we observed previously in this group of breast cancer survivors. PMID- 22205141 TI - Triple-negative breast cancer: the impact of guideline-adherent adjuvant treatment on survival--a retrospective multi-centre cohort study. AB - Triple-negative breast cancer (TNBC) (ER-/PGR-/erb-2-) constitutes an aggressive subtype in breast cancer because it is accompanied by a significant decrease in overall survival (OAS) and recurrence-free survival (RFS) compared with hormone receptor positive breast cancers. This retrospective cohort study investigates the following issues: (1) Is there an impact of guideline-adherent treatment on RFS and OAS in TNBC? (2) Which adjuvant treatment has the most important impact on RFS and OAS in TNBC? This German retrospective multi-centre cohort study included 3,658 patients with primary breast cancer recruited from 2000 to 2005. The definition of guideline adherence was based on the German national S3 guideline for diagnosis and treatment of breast cancer (2004). A total of 371 patients (10.1%) had TNBC. Compared with HR+/erb-2- breast cancer (P = 0.001; HR = 1.75; 95% CI: 1.27-2.40), the recurrence rate of TNBC was significantly higher (P < 0.001; HR = 2.86; 95% CI: 2.17-3.76). Furthermore, the 5-year RFS and OAS was significantly lower in TNBC (RFS: 74.8% [95% CI: 68.8-80.8%] vs. 86.5% [95% CI: 84.6-88.4%] [log-rank P = 0.0001]) (OAS: 75.8% [95% CI: 69.9-81.8%] vs. 86.0% [95% CI: 84.1-87.9%] [log-rank P = 0.0001]). The most important parameters predicting RFS and OAS in TNBC after receiving guideline-conform chemotherapy are guideline-adherent surgery, radiotherapy, nodal status and grading. Overall, 66.8% TNBC were found with one or more (18%) guideline violations, which subsequently impaired OAS and RFS. The most important impact on OAS and RFS in TNBC patients was because of guideline violations (GV) concerning adjuvant radiotherapy and GV concerning adjuvant chemotherapy. Patients with TNBC primarily have a worse prognosis in terms of RFS and OAS than patients of a primarily non-TNBC phenotype. There is a strong association between guideline adherent adjuvant treatment and improved survival outcome in TNBC. The outcome significantly decreases with the number of guideline violations. PMID- 22205145 TI - Genotyping cytomegalovirus UL97 mutations by high-resolution melting analysis with unlabeled probe. AB - Human cytomegalovirus (CMV) is an opportunistic pathogen, and infections with this virus can be treated with ganciclovir (GCV). Most GCV-resistant clinical CMV isolates contain a mutation in the UL97 gene. Genotypic assays for diagnostic screening of GCV-resistant CMV have been developed. High-resolution melting analysis (HRMA) with unlabeled probe is considered a perfect tool for this purpose. In this study, we have developed an HRMA-based genotypic test for the detection of UL97 mutations. Wild type and M460V/I mutants of UL97 were constructed. HRMA with unlabeled probe was used as a genotyping method for the detection of M460V/I mutations. The melting peaks obtained directly from PCR products did not enable us to distinguish the wild type from M460 mutants. The sensitivity and accuracy of HRMA were dramatically improved by using unlabeled probe. HRMA with unlabeled probe successfully distinguished M460V from M460I and served well for the detection of M460V/I mutations in clinical samples. HRMA with unlabeled probe proves to be a sensitive and cost-effective genotyping method for the detection of M460 mutations. PMID- 22205146 TI - Neurorescue effect of rosmarinic acid on 6-hydroxydopamine-lesioned nigral dopamine neurons in rat model of Parkinson's disease. AB - Rosmarinic acid (RA) is a naturally occurring polyphenolic compound. It has been reported that RA possessed antioxidant and anti-inflammatory properties. Our previous study showed that RA could protect MES23.5 dopaminergic cells against 6 hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro. The purpose of this study was to explore the neuroreparative (neurorescue) effect of RA on 6-OHDA lesioned rat model of Parkinson's disease (PD) in vivo. In this study, the rats were given RA orally after intrastriatal 6-OHDA lesion. Results showed that the dopamine content in the striatum decreased and the numbers of tyrosine hydroxylase-immunoreactive neurons reduced after 6-OHDA treatment. RA treatment after 6-OHDA administration could restore these changes. Further studies demonstrated that 6-OHDA treatment increased the iron-staining positive cells, which were markedly decreased by RA treatment. Moreover, RA suppressed the increased ratio of Bax/Bcl-2 at gene level induced by 6-OHDA. This indicates that the neurorescue effects of RA against 6-ODHA-induced degeneration of the nigrostriatal dopaminergic system were achieved by decreasing nigral iron levels and regulating the ratio of Bcl-2/Bax gene expression. PMID- 22205147 TI - The relationship between blood mercury level and osteoporosis in postmenopausal women. AB - OBJECTIVE: Postmenopausal women have a higher prevalence of osteoporosis compared with premenopausal women. Postmenopause status has been found to be an independent risk factor for osteoporosis. Several studies have reported that heavy metals, including lead (Pb), mercury (Hg), cadmium (Cd), and arsenic (As), have detrimental effects on bone. The aim of this study was to evaluate the association among heavy metals, including Pb, Hg, Cd, and As, bone mineral density, and osteoporosis in postmenopausal Korean women. METHODS: We conducted a cross-sectional study of 481 postmenopausal women, all of whom were enrolled in the Korean National Health and Nutrition Examination Survey in 2008. Bone mineral density was measured using dual-energy x-ray absorptiometry. Blood Pb, Hg, and Cd and urinary As levels were measured. RESULTS: Postmenopausal women with higher blood Hg levels were more likely to be younger and have higher vitamin D levels, fish consumption, and prevalence of osteoporosis. On multivariate logistic regression analysis, postmenopausal women with blood Hg levels in the fourth quartile had a 0.36-fold decreased risk of having osteoporosis compared with those with levels in the first quartile, after adjustments for age, body mass index, alcohol intake, smoking history, exercise, use of oral contraceptive pills, hormone therapy, intake of caloric energy and calcium, fish consumption, and vitamin D level. However, there was no association between other heavy metals and osteoporosis. CONCLUSIONS: High blood Hg levels were associated with a lower risk of having osteoporosis in postmenopausal women. Because biomarkers of all four metals measured in this study reflect recent exposures, further studies are necessary to clarify the association of osteoporosis with the level of heavy metals in biomarkers for long-term exposure such as hair or fingernail. PMID- 22205148 TI - Systemic and topical hormone therapies reduce vaginal innervation density in postmenopausal women. AB - OBJECTIVE: Menopause is often accompanied by vaginal discomfort including burning, itching, dryness, and spontaneous or provoked pain. Although the direct effects of estrogen withdrawal on vaginal cells are implicated, surgical menopause in rodents causes autonomic and sensory nerves to proliferate, suggesting that indirect effects mediated by changes in vaginal innervation may contribute. We assessed whether postmenopausal women display hormone-dependent changes in vaginal innervation. METHODS: Vaginal biopsies from 20 postmenopausal women undergoing surgery for stress urinary incontinence and pelvic organ prolapse were fixed and immunostained for the pan-neuronal marker protein gene product 9.5, sympathetic marker tyrosine hydroxylase, parasympathetic marker vasoactive intestinal polypeptide, and sensory nociceptor marker calcitonin gene related peptide. Innervation density was measured as an apparent percentage of the section area occupied by immunofluorescent axons. Specimens were grouped according to whether participants received systemic hormone therapy (HT), topical (vaginal) HT, or no HT. RESULTS: Women not receiving HT showed relatively high levels of total innervation, with most axons expressing tyrosine hydroxylase or vasoactive intestinal polypeptide immunoreactivity. In women receiving systemic HT, overall innervation was reduced, as were presumptive parasympathetic, sympathetic, and sensory axon populations. Topical HT elicited more dramatic reductions in innervation than in systemic HT. CONCLUSIONS: Hormone therapy reduces autonomic and sensory vaginal innervation density, which may, in part, contribute to relief from vaginal discomfort. Moreover, topical therapy is more effective than systemic therapy, which may help explain the greater improvement reported with topical compared with systemic HT. PMID- 22205149 TI - Treatment with hormone therapy and calcitriol did not affect depression in older postmenopausal women: no interaction with estrogen and vitamin D receptor genotype polymorphisms. AB - OBJECTIVE: The aim of this study was to examine the effect of hormone therapy and calcitriol on depression in older postmenopausal women and to determine whether the response was associated with polymorphisms of estrogen receptor alpha and vitamin D receptor. METHODS: In a double-blind placebo-controlled prospective trial involving 489 postmenopausal older women, a secondary analysis of depression was done. The Geriatric Depression Scale was used to screen for depression. We used binary logistic regression to examine the effect of treatment on depression and one-way analysis of variance to find a relationship between gene polymorphisms and depression. RESULTS: There was no effect of hormone therapy (odds ratio [OR], 1.65; 95% CI, 0.66-4.12; P = 0.277), calcitriol (OR, 1.15; 95% CI, 0.43-3.11; P = 0.772), or hormone therapy with calcitriol (OR, 1.01; 95% CI, 0.36-2.80; P = 0.979) on depression. Neither the polymorphisms of estrogen receptor alpha (XbaI-beta = 0.093; CI, -0.337 to 1.350; P = 0.239 and PvuII-beta = -0.064; CI, -1.171 to 0.491, P = 0.421) nor those of vitamin D receptor (BsmI-beta = 0.044, CI -2.546 to 3.030, P = 0.865 and TaqI-beta = 0.015, CI -2.900 to 2.738, P = 0.955) were associated with depression. CONCLUSION: In older postmenopausal women, there was no effect of hormone therapy and calcitriol either individually or in combination with depression. Estrogen receptor alpha and vitamin D receptor polymorphisms are not associated with depression or the response to intervention in older postmenopausal women. Additional trials are required to confirm these findings. PMID- 22205150 TI - Metanephros transplantation inhibits the progression of vascular calcification in rats with adenine-induced renal failure. AB - BACKGROUND/AIM: Recent research has shown that transplanted metanephroi form primitive vascularized kidneys with histologically recognizable renal features. The aim of the present study was to determine the metabolic function of transplanted metanephroi in rats with chronic renal failure (CRF), with particular reference to secondary hyperparathyroidism and vascular calcification. METHODS: CRF was induced in 11-week-old male Wistar rats by maintaining them on a 0.75% adenine diet for 4 weeks, followed by normal diet for an additional 2 weeks. At the end of adenine loading, whole metanephroi from embryonic day 15 rats were transplanted into the omentum and epididymis of the transplantation group. Vascular calcification was evaluated 2 weeks after metanephroi transplantation. RESULTS: Metanephros transplantation significantly reduced vascular calcium and phosphorus content and suppressed the progression of vascular calcification as indicated by von Kossa staining of the media of the thoracic aorta. However, no significant differences between the adenine-fed control and transplantation groups were found regarding the serum levels of 1,25(OH)2D3, calcium or phosphorus or the calcium * phosphorus product. CONCLUSION: The present study has shown that transplantation of metanephroi suppresses the progression of vascular calcification via a mechanism that is independent of calcium-phosphorus dynamics. PMID- 22205151 TI - Chronic lymphocytic leukemia and prolymphocytic leukemia with MYC translocations: a subgroup with an aggressive disease course. AB - Translocations involving MYC are rare in chronic lymphocytic leukemia (CLL), and up to now, their prognostic significance remains unclear. We report the characteristics of 21 patients with CLL and nine patients with prolymphocytic leukemia (PLL), diagnosed in multiple centers (n = 13), which showed an MYC translocation demonstrated by fluorescence in situ hybridization. The prevalence was estimated to be <1%. Advanced age and male predominance were observed. Morphological analysis frequently revealed the presence of prolymphocytes. A typical "CLL-immunophenotype" was found in four of nine cases with PLL. Moreover, CD5 and CD23 were frequently expressed in PLL. The latter findings are atypical for PLL and may suggest transformation or progression of an underlying CLL. MYC translocations were frequently observed with concomitant adverse cytogenetic markers, such as del(11q) (n = 8/30) and/or del(17p)/monosomy 17 (n = 7/30). In addition, the presence of unbalanced translocations (n = 24 in 13/30 cases) and complex karyotype (n = 16/30) were frequent in cases with MYC translocations. Altogether, del(17p)/monosomy 17, del(11q), and/or complex karyotype were observed in 22 of 30 patients. Survival outcome was poor: the median time to treatment was only 5 months, and overall survival (OS) from clinical diagnosis and from genetic detection was 71 and 19 months, respectively. In conclusion, CLL/PLL with MYC translocations is a rare entity, which seems to be associated with adverse prognostic features and unfavorable outcome. PMID- 22205152 TI - Role of structural factors of antitumour anthraquinone derivatives and analogues in the ability to undergo bioreductive activation by NADPH cytochrome P450 reductase: implications for increasing the activity against sensitive and multidrug-resistant leukaemia HL60 cells. AB - The aim of this study was to examine the role of structural factors of antitumour anthraquinone derivatives and analogues in the ability to undergo bioreductive activation by NADPH cytochrome P450 reductase (CPR) and determine the impact of this activation on increasing the activity especially with regard to multidrug resistant (MDR) tumour cells. It was found that at a high NADPH concentration (500 MUmol/l), the anthracenedione agent ametantrone, with an unmodified quinone structure, was susceptible to CPR-dependent reductive activation. In contrast, it was shown that compounds with modified quinone grouping (benzoperimidine BP1, anthrapyridone CO1 and pyrazolopyrimidoacridine PPAC2) did not undergo reductive activation by CPR. This suggests that the presence of a modified quinone function is the structural factor excluding reductive activation of antitumour anthraquinone derivatives and analogues by CPR. In the second part of the work, the ability of antitumour anthraquinone derivatives and analogues to inhibit the growth of the human promyelocytic, sensitive leukaemia HL60 cell line as well as its MDR sublines exhibiting two different phenotypes of MDR related to the overexpression of P-glycoprotein (HL60/VINC) or MRP1 (HL60/DOX) was studied in the presence of exogenously added CPR. A significant increase in the activity of ametantrone with an unmodified quinone structure after its reductive conversion by CPR was observed against HL60 as well as HL60/VINC and HL60/DOX cells, whereas in the case of quinone-modified compounds (BP1, CO1 and PPAC2), the presence of the activation system had no effect on their activity against the sensitive and MDR tumour cells examined. PMID- 22205153 TI - Methylated chrysin reduced cell proliferation, but antagonized cytotoxicity of other anticancer drugs in acute lymphoblastic leukemia. AB - The efficacy of 5,7-dimethoxyflavone (DMF), a methylated analog of chrysin, as a therapeutic agent to treat acute lymphoblastic leukemia (ALL) was investigated. Using a panel of ALL cell lines, the IC50 (half-maximal inhibitory concentration) of DMF varied between 2.8 and 7.0 MUg/ml. DMF induced G0/G1 cell cycle arrest, concomitant with a decreased expression of phosphorylated retinoblastoma associated protein 1. DMF increased the rate of apoptosis, although it was apparent only after a long period of exposure (96 h). The accumulation of oxidative stress was not involved in the growth-inhibitory effects of DMF. As DMF reduced the intracellular levels of glutathione, the combination effects of DMF with other anticancer drugs were evaluated using the improved Isobologram and the combination index method. In the simultaneous drug combination assay, DMF antagonized the cytotoxicity of 4-hydroperoxy-cyclophosphamide, cytarabine, vincristine, and L-asparaginase in all tested ALL cells. This study demonstrated that DMF, a methylated flavone, was an effective chemotherapy agent that could inhibit cell cycle arrest and induce apoptosis in ALL cell lines. However, combination therapy with DMF and other anticancer drugs is not recommended. PMID- 22205154 TI - Antitumor efficacy of the scFv-based fusion protein and its enediyne-energized analogue directed against epidermal growth factor receptor. AB - Epidermal growth factor receptor (EGFR), overexpressed in many epithelial tumors, plays important roles in the formation and the development of tumors, and thus it is regarded as a promising target for cancer therapy. Single-chain variable fragment (scFv), an engineered antibody fragment, is generally used for constructing antibody-targeted drugs, owing to its low immunogenicity and high penetration capability into solid tumors. A fusion protein ER(Fv-LDP), consisting of an anti-EGFR scFv and the apoprotein (LDP) of lidamycin (LDM), was prepared and then assembled with the active chomophore [active enediyne (AE)] of LDM to generate enediyne-energized analogue ER(Fv-LDP-AE). The fusion protein ER(Fv-LDP) bound specifically to EGFR-overexpressing cancer cells and internalized into the cytoplasm through receptor-mediated endocytosis. ER(Fv-LDP) possessed cytotoxicity against carcinoma cell lines, which was hundreds of times more potent than the separate moiety of ER(Fv) and LDP. The enediyne-energized fusion protein ER(Fv-LDP-AE) also showed stronger cytotoxicity to target-relevant cancer cells than LDM in vitro. In human epidermoid carcinoma A431 xenografts, ER(Fv LDP) presented higher antitumor efficacy than that of ER(Fv), LDP, and their mixture, with tumor growth inhibition rates of 63.6, 46.7, 48.5, and 49.9%, respectively. The enediyne-energized fusion protein ER(Fv-LDP-AE) at a dose of 0.4 mg/kg inhibited tumor growth by 89.2%, while no significant body weight loss was seen in treated animals. The results show that an anti-EGFR scFv-based fusion protein and its enediyne-energized analogue can be prepared by DNA recombination and molecular reconstitution. Both ER(Fv-LDP) and ER(Fv-LDP-AE) are effective against EGFR-overexpressing cancer xenograft in athymic mice. An integrated technical platform for scFv-based enediyne-energized fusion proteins has been established. PMID- 22205155 TI - Pharmacological ascorbate induces cytotoxicity in prostate cancer cells through ATP depletion and induction of autophagy. AB - Recent studies have revealed the scientific basis for the use of intravenous (i.v.) vitamin C or ascorbic acid (ascorbate) in treating cancers, and raised the possibility of using i.v. ascorbate as a prooxidant anticancer therapy. Through the production of H2O2, pharmacologic ascorbate can induce some cancer cell death in vitro and inhibit a number of types of tumor growth in animal models. However, the mechanism of cell death triggered by ascorbate is not well understood. In this study, we investigated the cytotoxicity of pharmacological concentrations of ascorbate to human prostate cancer cells and the mechanisms involved. The results showed that ascorbate in the millimolar range induced cytotoxicity in five of the six tested prostate cancer cell lines. The IC50 values in the sensitive prostate cancer cells ranged from 1.9 to 3.5 mmol/l, concentrations clinically achievable with i.v. ascorbate use. All tested androgen-independent cells were sensitive to ascorbate treatment. The ascorbate-insensitive cell line LaPC4 is hormonally dependent. Whereas the reasons for sensitivity/resistance to ascorbate treatment need to be investigated further, cell death in sensitive cells was dependent on H2O2. Ascorbate treatment depleted ATP and induced autophagy in sensitive prostate cancer cells, resulting in cell death. Taken together with previous studies, high-dose ascorbate has the potential to be a novel treatment option to hormone-refractory prostate cancer. PMID- 22205157 TI - Salvage of recurrence after failed surgical treatment of hallux valgus. AB - Recurrence of the deformity is unfortunately a common occurrence following surgical treatment of hallux valgus. The underlying reason for recurrence is multifactorial and includes surgeon's factor, patient's factor, and deformity components that were not addressed at the index procedure. Salvage of recurrence can be challenging for both the patient and the surgeon. Successful treatment requires understanding the underlying reason for the failure of initial treatment and correcting bony alignment, restoring the joint congruity, and balancing soft tissues. We present an algorithmic approach to revision hallux valgus surgery. PMID- 22205156 TI - Delineation of apoptotic genes for synergistic apoptosis of lexatumumab and anthracyclines in human renal cell carcinoma cells by polymerase chain reaction array. AB - Lexatumumab, a human agonistic monoclonal antibody against tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor-2 (TRAIL-R2), is a promising molecular-targeted therapeutic agent. Our past study indicated that low concentrations of doxorubicin sensitized renal cell carcinoma (RCC) cells to lexatumumab-mediated apoptosis. The present study was designed to examine the cellular and molecular effects of lexatumumab and anthracyclines in RCC cells. The treatment of human RCC cells with lexatumumab in combination with anthracyclines, epirubicin, and pirarubicin had a synergistic cytotoxicity. A marked synergistic apoptosis was induced by lexatumumab in combination with epirubicin or pirarubicin. Epirubicin and pirarubicin significantly increased the TRAIL-R2 expression at both the mRNA and the protein levels. The combination induced cytotoxicity was significantly suppressed by the human recombinant DR5:Fc chimeric protein. To further explore the molecular mechanisms in this synergistic cytotoxicity with lexatumumab and anthracyclines, the changes in 84 apoptosis related genes were evaluated by a quantitative polymerase chain reaction (PCR) array. Among these genes, 18 (CD40LG, FASLG, LTA, TNSF7, FAS, BAG3, BAK1, BAX, BID, BIK, BCL10, caspase-1, caspase-5, caspase-6, caspase-10, TNF receptor associated factor 1, PYCARD, and CIDEA) were significantly upregulated and eight (TNF receptor-associated factor 4, TNFRSF11B, TNF, BCL2, BCL2L1, BNIP3L, caspase 9, and DAPK1) were downregulated at mRNA levels in RCC cells cotreated with lexatumumab and epirubicin. Furthermore, the upregulation of mRNA levels of PYCARD and CIDEA was confirmed using real-time reverse transcriptase-PCR analysis. The present study demonstrates that anthracylines sensitize RCC cells to lexatumumab-mediated apoptosis by inducing TRAIL-R2 expression, and the utility of PCR array to elucidate the mechanism of synergistic apoptosis. PMID- 22205158 TI - Age-dependent effects of chronic fluoxetine treatment on the serotonergic system one week following treatment. AB - RATIONALE: Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are increasingly used for the treatment of depression in children. Limited data are, however, available on their effects on brain development and their efficacy remains debated. Moreover, previous experimental studies are seriously hampered in their clinical relevance. OBJECTIVES: The aim of the present study was to investigate putative age-related effects of a chronic treatment with fluoxetine (5 mg/kg, either orally or i.p. for 3 weeks, 1 week washout) using conventional methods (behavioral testing and binding assay using [(123)I]beta-CIT) and a novel magnetic resonance imaging (MRI) approach. METHODS: Behavior was assessed, as well as serotonin transporter (SERT) availability and function through ex vivo binding assays and in vivo pharmacological MRI (phMRI) with an acute fluoxetine challenge (10 mg/kg oral or 5 mg/kg i.v.) in adolescent and adult rats. RESULTS: Fluoxetine caused an increase in anxiety-like behavior in treated adult, but not adolescent, rats. On the binding assays, we observed increased SERT densities in most cortical brain regions and hypothalamus in adolescent, but not adult, treated rats. Finally, reductions in brain activation were observed with phMRI following treatment, in both adult and adolescent treated animals. CONCLUSION: Collectively, our data indicate that the short-term effects of fluoxetine on the 5-HT system may be age-dependent. These findings could reflect structural and functional rearrangements in the developing brain that do not occur in the matured rat brain. phMRI possibly will be well suited to study this important issue in the pediatric population. PMID- 22205159 TI - Brainpeps: the blood-brain barrier peptide database. AB - Peptides are able to cross the blood-brain barrier (BBB) through various mechanisms, opening new diagnostic and therapeutic avenues. However, their BBB transport data are scattered in the literature over different disciplines, using different methodologies reporting different influx or efflux aspects. Therefore, a comprehensive BBB peptide database (Brainpeps) was constructed to collect the BBB data available in the literature. Brainpeps currently contains BBB transport information with positive as well as negative results. The database is a useful tool to prioritize peptide choices for evaluating different BBB responses or studying quantitative structure-property (BBB behaviour) relationships of peptides. Because a multitude of methods have been used to assess the BBB behaviour of compounds, we classified these methods and their responses. Moreover, the relationships between the different BBB transport methods have been clarified and visualized. PMID- 22205171 TI - Investigative clinical study on prostate cancer part VI: Follicle-stimulating hormone and the pituitary-testicular-prostate axis at the time of initial diagnosis and subsequent cluster selection of the patient population. AB - AIM: To evaluate the physiopathology of follicle-stimulating hormone (FSH) along the pituitary-testicular-prostate axis at the time of initial diagnosis of prostate cancer in relation to the available clinical variables and to the subsequent cluster selection of the patient population. PATIENTS AND METHODS: The study included 98 patients who were diagnosed with prostate cancer. Age, percentages of positive cores (P+) at transrectal ultrasound scan biopsy, biopsy Gleason score (bGS), luteinizing hormone (LH), FSH, total testosterone, free testosterone (FT) and prostate-specific antigen (PSA) were the continuous clinical variables. All patients had not previously received hormonal manipulations. FSH correlation and multiple linear analyses were computed in the population. The FSH/PSA ratio was computed and then ranked for clustering the population as groups A (0.13<=FSH/PSA<=0.57), B (0.57=1950) demonstrated heterogeneity in the association for having been breastfed between the two birth year groups (p for interaction = 0.0006); having been breastfed was significantly associated with a decreased risk among subjects who were born before 1950 (OR = 0.59; 95% CI: 0.35-0.99), whereas no such risk reduction was observed for subjects born after 1950 (OR = 1.60; 95% CI: 0.88-2.90). CONCLUSION: Although having been breastfed is not related to overall risk, birth year may modify the association between having been breastfed in infancy and breast cancer risk. In Japan, sociodemographic changes have occurred since the end of World War II. The use of standard formula supplement began to spread around 1950. The difference of breast cancer risk between birth-year groups may be attributable to these environmental changes. PMID- 22205178 TI - Renal intervention to treat hypertension. AB - Renal artery intervention to treat hypertension is one of the frontiers of ongoing research in combating this epidemic. This article focuses on recent data regarding PTRS and catheter-based renal sympathetic denervation. Despite progress in this field large multicenter, randomized trials that compare these treatment modalities with medical therapy for hypertension are lacking. PMID- 22205177 TI - The influence of insulin resistance, obesity, and diabetes mellitus on vascular tone and myocardial blood flow. AB - Among individuals with cardiovascular risk factors, reductions in coronary vasodilator capacity with or without diabetes mellitus (DM) carry important diagnostic and prognostic information. Positron emission tomography (PET) myocardial perfusion imaging in concert with tracer kinetic modeling allows the assessment of absolute regional myocardial blood flow (MBF) at rest and its response to various forms of vasomotor stress. Such noninvasive evaluation of myocardial flow reserve (MFR) or the vasodilator capacity of the coronary circulation expands the possibilities of conventional scintigraphic myocardial perfusion imaging from identifying flow-limiting epicardial coronary artery lesions to understanding the underlying pathophysiology of diabetic vasculopathy, microcirculatory dysfunction, and its atherothrombotic sequelae. Invaluable mechanistic insights were recently reported with PET by unraveling important effects of insulin resistance, obesity, and DM on the function of the coronary circulation. Such noninvasive assessment of coronary circulatory dysfunction enables monitoring its response to antidiabetic medication and/or behavioral interventions related to weight, diet, and physical activity that may evolve as a promising tool for an image-guided and personalized preventive diabetic vascular care. Whether PET-guided improvement or normalization of hyperemic MBF and/or MFR will translate into improved patient outcome in DM is a laudable goal to pursue next. PMID- 22205180 TI - Disturbed cytokine production at the systemic level in difficult-to-control atopic asthma: evidence for raised interleukin-4 and decreased interferon-gamma release following lipopolysaccharide stimulation. AB - BACKGROUND: Disturbed cytokine production is thought to govern inflammation in asthma, which, in its turn, may lead to uncontrolled disease. The aim of this study was to assess the relationship between cytokine production from blood leucocytes and the level of asthma control. METHODS: We compared the production of interleukin (IL)-4, IL-6, IL-10, interferon (IFN)-gamma and tumour necrosis factor-alpha from peripheral blood leucocytes in non-atopic healthy subjects (n = 22), atopic non-asthmatics (n = 10), well-controlled asthmatics [Juniper asthma control questionnaire (ACQ) score <1.5; n = 20] and patients with uncontrolled asthma despite inhaled or oral corticoids (ACQ score >=1.5; n = 20). Fifty microlitres of peripheral blood was incubated for 24 h with RPMIc, lipopolysaccharide (LPS; 1 ng/ml) or phytohaemagglutinin (1 MUg/ml), and cytokines were measured by immunotrapping (ELISA). RESULTS: Both controlled and uncontrolled asthmatics as well as atopic non-asthmatics spontaneously produced more IL-4 than non-atopic healthy subjects (p < 0.001). IL-4 production induced by LPS was significantly greater (p < 0.05) in both asthma groups compared to atopic non-asthmatics and non-atopic healthy subjects. By contrast, IFN-gamma release induced by LPS was lower in uncontrolled asthmatics than in non-atopic healthy subjects (p < 0.05) and controlled asthmatics (p < 0.05). IL-10 release after LPS was greater in uncontrolled asthmatics than in atopic non-asthmatics (p < 0.05). No difference was observed regarding other cytokines. CONCLUSION: Blood cells from patients with difficult-to-control atopic asthma display highly skewed Th2 cytokine release following LPS stimulation. PMID- 22205182 TI - Surface-enhanced Raman spectroscopy (SERS): progress and trends. AB - Surface-enhanced Raman spectroscopy (SERS) combines molecular fingerprint specificity with potential single-molecule sensitivity. Therefore, the SERS technique is an attractive tool for sensing molecules in trace amounts within the field of chemical and biochemical analytics. Since SERS is an ongoing topic, which can be illustrated by the increased annual number of publications within the last few years, this review reflects the progress and trends in SERS research in approximately the last three years. The main reason why the SERS technique has not been established as a routine analytic technique, despite its high specificity and sensitivity, is due to the low reproducibility of the SERS signal. Thus, this review is dominated by the discussion of the various concepts for generating powerful, reproducible, SERS-active surfaces. Furthermore, the limit of sensitivity in SERS is introduced in the context of single-molecule spectroscopy and the calculation of the 'real' enhancement factor. In order to shed more light onto the underlying molecular processes of SERS, the theoretical description of SERS spectra is also a growing research field and will be summarized here. In addition, the recording of SERS spectra is affected by a number of parameters, such as laser power, integration time, and analyte concentration. To benefit from synergies, SERS is combined with other methods, such as scanning probe microscopy and microfluidics, which illustrates the broad applications of this powerful technique. PMID- 22205181 TI - Acute promyelocytic leukemia associated with the PLZF-RARA fusion gene: two additional cases with clinical and laboratorial peculiar presentations. AB - Acute promyelocytic leukemia (APL) is characterized by the presence of the t(15;17) and PML-RARa rearrangement, with good response to treatment with retinoids. However, few cases of variant APL involving alternative chromosomal aberrations have been reported, including t(11;17)(q23;q21) (Wells et al. in Nat Genet 17:109-113, 1; Arnould et al. in Hum Mol Genet 8:1741-1749, 2) t(5;17)(q35;q12-21), t(11;17)(q13;q21) (Grimwade et al in Blood 96:1297-1308, 3) and der(17) (Rego et al. in Blood (ASH Annual Meeting Abstracts)114:Abstract 6, 4), whereby RARa is fused to the PLZF, NPM, NuMA, and STAT5b genes, respectively, have been described. These cases are characterized by distinct morphology, clinical presentation, and in respect to PLZF, a lack of differentiation response to retinoids leading to the need of different approaches concerning diagnostic methods and therapeutics. This paper describes two cases of APL associated with the PLZF-RARA fusion gene enrolled in the IC-APL trial that is a non-randomized, multicenter study conducted in Brazil, Mexico, Chile and Uruguay with the aim to improve the treatment outcome of APL patients in developing countries. These cases, although rare, offer a challenge to its early recognition and proper conduction. PMID- 22205183 TI - Occurrence of residual water within disk-based solid-phase extraction and its effect on GC-MS measurement of organic extracts of environmental samples. AB - Solid-phase extraction (SPE) is a widespread and powerful sample preparation technique in many analytical areas. Many of the used methods reduce residual water during sample preparation by drying the phase material. Despite the importance of this step, hardly any study deals specifically with the drying process, and if so, only few aspects are mentioned. The present study is the first systematic investigation of the drying process using SPE disks, including the influence of process parameters on the amount of residual water and its consequences for subsequent elution and gas chromatography-mass spectrometry (GC MS) analysis. The following points were investigated in detail: (1) the change of pressure and volume flow during the drying process, (2) the remaining amount of water at different drying times for different SPE materials, (3) the influence of suspended particulate matter on the drying process and (4) the effects of the residual water on the elution step by using different organic solvents. The study shows that the volume of residual water in the SPE disk is affected by the fixation of the sorbent, the phase material, the amount of sorbent, the pumping settings and the duration of the drying process. Furthermore, systematic investigations demonstrate the influence of residual water on the GC-MS analysis and show analytical interferences only for a few of the investigated analytes. All results suggest that more problems in SPE GC-MS methods are caused by residual water than previously assumed. PMID- 22205184 TI - Introduction : emotions, feelings and rational discourse. PMID- 22205185 TI - Melatonin ameliorates oxidative stress and induces cellular proliferation of lymphoid tissues of a tropical rodent, Funambulus pennanti, during reproductively active phase. AB - Effect of melatonin treatment on free radical production was assessed with simultaneous investigation of hormonal level (melatonin and testosterone), blastogenic response, stimulation index, and histological observation of lymphoid organs (spleen, thymus, and bone marrow) in male Indian palm squirrel (Funambulus pennanti) during reproductively active phase (RAP). Low endogenous melatonin and high testosterone level were noted during RAP. Daily subcutaneous injection of melatonin (25 MUg/100 g B wt.) at 17.30-18.00 h to squirrels for 60 consecutive days during May-June significantly decreased the thiobarbituric acid reactive substances (TBARS) level compared to control squirrels. Melatonin treatment significantly increased % stimulation ratio (%SR) of splenocytes and thymocytes against T cell mitogen concanavalin A. Pinealectomy (Px) led to a significant increase in TBARS level whereas a significant decrease was observed in blastogenic response and stimulation index was noted. Melatonin injection to Px squirrels showed restoration in %SR of thymocytes and splenocytes with a significant decrease in the TBARS level of the lymphoid tissues. Further, free radical load was induced by lipopolysaccharide (LPS; 400 MUg/ml) in lymphatic tissue homogenates and noted that melatonin supplementation (2 mM/ml) led to a significant decrease in TBARS level compared to the control and LPS-supplemented groups. Histological observation showed dense cellularity of thymocytes and splenocytes. Acridine orange staining technique shows a significant increase in thymocyte apoptosis Px squirrels when compared with melatonin-treated squirrels. These findings suggest that endogenous and exogenous melatonin might be responsible for the maintenance of immune system to adapt this seasonal breeder for the rigors of the environmental changes. PMID- 22205186 TI - Comparison of uterine exteriorization and in situ repair during cesarean sections. AB - PURPOSE: To compare the peri- and postoperative complication rates of two cesarean delivery techniques. METHODS: Medical records from 1,087 patients who had a cesarean delivery with regional anesthesia between 2008 and 2010 were reviewed retrospectively. Seven hundred and thirty-two patients had an in situ uterine repair, and 355 patients had an exterior uterine repair. Patients who had chorioamnionitis, preeclampsia, a bleeding disorder, or abnormal placentation were excluded from the study. The following outcomes were compared between the two groups: mean operative time, intraoperative blood loss, perioperative nausea, tachycardia, hypotension, hemoglobin level, hematocrit level, the time to the first recognized bowel movement, postoperative analgesic dose, nausea, length of hospital stay, surgical site infection rate and endometritis rate. RESULTS: No clinically significant differences were found between the exteriorization and in situ uterine repair groups for mean hematocrit differences, intraoperative blood loss, perioperative nausea, tachycardia, hypotension and postoperative analgesic doses. However, the mean operative time, time to the first recognized bowel movement, surgical site infection rate and length of hospital stay were significantly lower in the in situ repair group (p < 0.05). CONCLUSION: Although the techniques are similar in most scenarios, in situ uterine repair during cesarean sections appears to be more advantageous than exteriorization with respect to the mean operative time, time to the first recognized bowel movement, surgical site infection rate and length of hospital stay. PMID- 22205187 TI - Pregnancy after bariatric surgery: a current view of maternal, obstetrical and perinatal challenges. AB - With the increase in the number of bariatric surgeries being performed in women of childbearing age, physicians must have concerns regarding the safety of pregnancy after bariatric surgery. The aim of this review is to summarize the literature reporting on maternal, obstetrical and perinatal implications of pregnancy following BS. METHODS: English, Spanish and Portuguese-language articles were identified in a PUBMED search from 2005 to February 2011 using the keywords for pregnancy and bariatric surgery or gastric bypass or gastric banding. RESULTS: The studies show improved fertility and a reduced risk of gestational diabetes, pregnancy-induced hypertension and pre-eclampsia, macrosomia in pregnant women after bariatric surgery. The incidence of intrauterine growth restriction and small for gestational age are increased. No conclusions can be drawn concerning the risk for cesarean delivery and the best surgery-to-conception interval. Deficiencies in iron, vitamin A, vitamin B12, vitamin K, folate and calcium can result in maternal and fetal complications. CONCLUSIONS: Pregnancy outcome of women who delivered after BS, as compared to obese populations, is better and safer and comparable to the general population. Close supervision before, during and after pregnancy following bariatric surgery and nutrient supplementation adapted to the patient's individual requirements can prevent nutrition-related complications and improve maternal and fetal health. PMID- 22205190 TI - Ketamine as a novel antidepressant: from synapse to behavior. AB - Recent reports of a rapid antidepressant effect of the glutamate N-methyl-D aspartate (NMDA) receptor antagonist ketamine, even in treatment-resistant populations, have spurred translational therapeutic and neuroscience research aimed at elucidating ketamine's mechanism of action. This article provides a concise overview of research findings that pertain to the effects of low-dose ketamine at the cellular, neurocircuitry, and behavioral levels and describes an integrated model of the action of ketamine in the treatment of depression. PMID- 22205191 TI - Mineralocorticoid receptor blocker eplerenone improves endothelial function and inhibits Rho-associated kinase activity in patients with hypertension. AB - Hypertension is associated with endothelial dysfunction and activated Rho associated kinases (ROCKs). The purpose of this study was to evaluate the effects of the selective mineralocorticoid receptor blocker, eplerenone, on endothelial function and ROCK activity in patients with hypertension. The study was carried out over 48 weeks in 60 untreated patients with hypertension who were randomly assigned to eplerenone, nifedipine, and losartan groups. We evaluated the effects of each treatment on flow-mediated vasodilation (FMD) and ROCK activity in peripheral leukocytes. Eplerenone increased FMD and decreased leukocyte ROCK activity. Nifedipine decreased ROCK activity but did not alter FMD. Losartan increased FMD but did not alter ROCK activity. Hypotensive effects were similar in the three groups, as was nitroglycerin-induced vasodilation during the follow up period. There were no significant differences between the groups with respect to other parameters. The study results show that eplerenone improves endothelial function and inhibits ROCK activity in patients with essential hypertension. PMID- 22205193 TI - Uncoupling the dopamine D1-D2 receptor complex: a novel target for antidepressant treatment. AB - Depression, or major depressive disorder (MDD), is a serious mental illness that causes substantial worldwide disability. Current antidepressant medications mostly target the serotonin and norepinephrine neurotransmitter systems. These drugs are ineffective in many patients, and there are limited options for treatment-resistant depression. The dopamine neurotransmitter system has recently been identified as another modulator of mood and depressive symptoms, and a recently discovered interaction between the dopamine D1 and D2 receptor may be a novel antidepressant target. PMID- 22205192 TI - Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. AB - Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an analgesic are governed by CYP2D6 polymorphisms. Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher in ultrarapid metabolizers. The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine. PMID- 22205194 TI - Rational opioid dosing in the elderly: dose and dosing interval when initiating opioid therapy. AB - Opioids are the mainstay of treatment for moderate to severe pain. However, opioid therapy in the elderly is often associated with significant morbidity because of excessive ventilatory depression. The large amount of interindividual variability in opioid dose-response relationships makes it difficult to individualize the dose and dosing interval to provide safe and effective analgesia. By examining how aging affects the pharmacokinetics (PK) and pharmacodynamics (PD) of opioids, it is possible to provide a rational basis for age adjustment in opioid dosing. PMID- 22205195 TI - The use of modeling and simulation to guide clinical development of olmesartan medoxomil in pediatric subjects. AB - Modeling and simulation were used extensively in the development of an indication for the use of olmesartan medoxomil in pediatric patients with hypertension. Simulations based on models developed in adult patients indicated that two dose groups were sufficient to estimate a dose-response relationship, thereby reducing by one-third the number of subjects required for the phase III pediatric study. Model-based predictions for blood pressure reduction agreed with the observed results of the subsequent phase III study, showing statistically significant dose response relationships with respect to both systolic and diastolic blood pressure. Previously established pharmacokinetic and exposure-response relationships in adults, adjusted for the influence of body weight on clearance (wt(0.80)), were confirmed in the pediatric population. Together, these findings support an olmesartan dosing recommendation in pediatric subjects aged 6 to 16 years of 10 mg for subjects weighing <35 kg and 20 mg for those weighing >=35 kg. PMID- 22205196 TI - Pharmacokinetic similarity of biologics: analysis using nonlinear mixed-effects modeling. AB - Our objective was to show, using two examples, that a pharmacokinetic (PK) similarity analysis can be performed using nonlinear mixed-effects models (NLMEM). We used two studies that compared different biosimilars: a three-way crossover trial with somatropin and a parallel-group trial with epoetin-alpha. For both data sets, the results of NLMEM-based analysis were compared with those of noncompartmental analysis (NCA). For the latter analysis, we performed an NLMEM-based equivalence Wald test on secondary parameters of the model: the area under the curve and the maximal concentration. Somatropin PK was described by a one-compartment model and epoetin-alpha PK by a two-compartment model with linear and Michaelis-Menten elimination. For both studies, similarity of PK was demonstrated by means of both NCA and NLMEM, and both methods led to similar results. Therefore, for establishing similarity, PK data can be analyzed by either of the methods. NCA is an easier approach because it does not require data modeling; however, NLMEM leads to a better understanding of the underlying biological system. PMID- 22205197 TI - The cost-effectiveness of drug regulation: the example of thorough QT/QTc studies. AB - We analyzed the cost-effectiveness of the International Conference on Harmonisation (ICH) E14 guideline that requires a thorough QT/QTc (TQT) study for all drugs under development. We compared two pharmacoeconomic scenarios: the health effects and costs resulting from implementing ICH E14 ("regulation" scenario) vs. not implementing ICH E14 ("no regulation" scenario). We used a dynamic population model to calculate the cost-effectiveness of ICH E14 for a prototype QT-prolonging antipsychotic drug entering the US and European markets. The incremental cost-effectiveness ratios of regulation vs. no regulation were ~?2.4 million per sudden cardiac death prevented and ~?187,000 per quality adjusted life year (QALY) gained in users of antipsychotic drugs. The main driver of cost was the requirement for electrocardiogram (ECG) monitoring of users of QTc-prolonging drugs. Even when several of the assumptions in the model were varied, there were no results in favor of regulation. Our study shows that cost effectiveness analysis of drug regulatory measures is feasible and should be considered before developing such measures. PMID- 22205198 TI - The roles of neurotrophic factor and Wnt signaling in depression. AB - Depression is a debilitating disease with a lifetime prevalence of ~16% in the American population. In addition to the monoamine hypothesis, altered expressions of neurotrophic factors, growth factors, and Wnt signaling are implicated in the pathophysiology and treatment of depression. This review focuses on intracellular signaling cascades that underlie depression and treatment response. PMID- 22205199 TI - Pathways to drug development for autism spectrum disorders. AB - Autism spectrum disorders (ASDs) are neurodevelopmental disorders whose prevalence has risen over the past two decades. Current drug treatments for ASDs and the related disorders--fragile X syndrome (FXS) and Rett syndrome--target specific symptoms but do not address the basic underlying etiologies. However, based partly on an improved understanding of the neurochemical underpinnings of FXS, pharmacotherapy for this syndrome has progressed to the point of clinical trials of several novel drug treatments. By contrast, our overall understanding of the neuropathophysiology of ASDs is still rudimentary. There is hope in the field that knowledge and experience gained in the study of fragile X and Rett syndromes may be applicable to the larger autism patient population. In this review, we discuss how recent advances in our understanding of the biochemistry and neuropathology of these disorders could lead to new more effective treatments for ASDs. PMID- 22205200 TI - The epigenetic code in depression: implications for treatment. AB - Major depressive disorder (MDD) is a common and disabling disorder that carries both a substantial personal burden as well as a social one. A better understanding of the epigenetic mechanisms in depression might provide a new framework for individually tailored pharmacologic treatment options. In this review we highlight current knowledge about the role of epigenetic mechanisms in the pathogenesis of depression and treatment implications. PMID- 22205201 TI - Visualization of microbodies in Chlamydomonas reinhardtii. AB - In Chlorophycean algal cells, these organelles are generally called microbodies because they lack the enzymes found in the peroxisomes of higher plants. Microbodies in some algae contain fewer enzymes than the peroxisomes of higher plants, and some unicellular green algae in Chlorophyceae such as Chlamydomonas reinhardtii do not possess catalase, an enzyme commonly found in peroxisomes. Thus, whether microbodies in Chlorophycean algae are similar to the peroxisomes of higher plants, and whether they use a similar transport mechanism for the peroxisomal targeting signal (PTS), remain unclear. To determine whether the PTS is present in the microbodies of Chlorophycean algae, and to visualize the microbodies in Chlamydomonas cells, we examined the sub-cellular localization of green fluorescent proteins (GFP) fused to several PTS-like sequences. We detected GFP compartments that were spherical with a diameter of 0.3-1.0 MUm in transgenic Chlamydomonas. Comparative analysis of the character of GFP-compartments observed by fluorescence microscopy and that of microbodies by electron microscopy indicated that the compartments were one and the same. The result also showed that the microbodies in Chlorophycean cells have a similar transport mechanism to that of peroxisomes of higher plants. PMID- 22205202 TI - Gene therapy with RNAi targeting UHRF1 driven by tumor-specific promoter inhibits tumor growth and enhances the sensitivity of chemotherapeutic drug in breast cancer in vitro and in vivo. AB - UHRF1, also known as ICBP90 (inverted CCAAT box binding protein 90) in human, is a nuclear protein that acts as a fundamental regulator in cell proliferation and maintains DNA methylation. It is reported that UHRF1 is obviously upregulated in various human malignancies, but unchanged in differentiated tissues, suggesting that UHRF1 plays a crucial role in carcinogenesis and can be a useful anticancer drug target. In this study, we explored whether UHRF1 can be a therapeutic target for human breast carcinoma. We successfully constructed the tumor-specific shRNA expression vector driven by survivin promoter targeting UHRF1 gene. The tumor specific RNA interference system efficiently and specifically knocked down UHRF1 expression, induced the apoptosis of tumor cells, and enhanced chemosensitivity of tumor cells to cisplatinum, but not in normal cells in vitro and in vivo. Therefore, the survivin promoter-driving shRNA expression system targeting UHRF1 may play a vital and potential role for the treatment of specificity and high efficacy in human breast carcinomas. PMID- 22205203 TI - Age-stratified phase I trial of a combination of bortezomib, gemcitabine, and liposomal doxorubicin in patients with advanced malignancies. AB - BACKGROUND: Preclinical data suggest synergistic activity of bortezomib, gemcitabine, and liposomal doxorubicin. Because tolerance to therapy may be attenuated in elderly patients, we performed an age-stratified phase I trial of this combination. PATIENTS AND METHODS: Two parallel age-stratified arms (< 65 and >= 65 years old) were accrued (3 + 3 design). Starting doses included bortezomib 0.7 mg/m(2) (days 1 and 8), gemcitabine 500 mg/m(2) (days 1 and 8), and liposomal doxorubicin 20 mg/m(2) (day 1). RESULTS: In the < 65-year-old group, 65 patients were treated; the maximum-tolerated dose was bortezomib 1.3 mg/m(2), gemcitabine 800 mg/m(2), and liposomal doxorubicin 35 mg/m(2). In the >= 65-year-old group, 28 patients were treated; the recommended phase II dose was bortezomib 1.0 mg/m(2), gemcitabine 800 mg/m(2), and liposomal doxorubicin 20 mg/m(2). Dose-limiting toxicities included thrombocytopenia and neutropenia. The most common toxicities were mild cytopenias, fatigue, and neuropathy. Ten patients achieved partial responses (6 of 7 patients with cutaneous T-cell lymphoma; 4 of 16 patients with small cell carcinomas, including lung, prostate, ovarian, and nasopharyngeal). CONCLUSION: Combination of bortezomib, gemcitabine, and liposomal doxorubicin is well tolerated, but with a lower recommended phase II dose in elderly patients, and demonstrated antitumor activity, especially in T cell and small cell histology malignancies. PMID- 22205204 TI - Influence of maternal hyperglycemia on IL-10 and TNF-alpha production: the relationship with perinatal outcomes. AB - AIMS: This study was conducted to evaluate maternal and placental concentrations of interleukin 10 (IL-10) and tumor necrosis factor-alpha (TNF-alpha) in pregnant women with glycemic mean (GM) < or >=100 mg/dL, as well as correlate IL-10 and TNF-alpha placental concentrations with perinatal outcomes. METHODS: One hundred eighty-six pregnant women were distributed in groups determined by a GM <100 mg/dL or a GM >=100 mg/dL. The GM, HbA1c levels, maternal and placental concentrations of IL-10 and TNF-alpha, and the correlation of placental cytokines with perinatal outcomes were evaluated. RESULTS: In maternal blood, the lowest concentrations of IL-10 (p = 0.0019) and TNF-alpha (p = 0.0185) were observed in the GM >=100-mg/dL group. The placentas from GM >=100 mg/dL group exhibited higher TNF-alpha concentrations (p = 0.0385). Placental IL-10 directly correlated with hemoglobin (r = 0.63; p = 0.02) and insulin (r = 0.78; p = 0.01) levels in the umbilical cord and with 1-min (r = 0.53; p = 0.0095) and 5-min (r = 0.69; p = 0.0003) Apgar scores. Placental TNF-alpha displayed a tendency to inversely correlate with fetal weight (r = -0.41; p = 0.05). CONCLUSION: Compared to GM <100 mg/dL, GM >=100 mg/dL was associated with a reduction in maternal IL-10 and TNF-alpha concentrations and increased placental TNF-alpha production. Placental IL-10 production was similar in both groups studied and directly correlated with hemoglobin and umbilical cord insulin levels, as well as with the 1- and 5-min Apgar scores. PMID- 22205205 TI - Survival and predictors of death among primary immunodeficient patients: a registry-based study. AB - PURPOSES: The aims of this study were to investigate survival among patients with primary immunodeficiency disorders (PID) in Kuwait and to determine whether certain variables were associated with increased risk of death. METHODS: The data of 176 patients (98 males and 78 females) were extracted from the Kuwait National Primary Immunodeficiency Disorders Registry and the observation period was from January 2004 to July 2011. RESULTS: The distribution of the reported patients was combined T- and B-cell immunodeficiencies (30.1%), predominantly antibody immunodeficiency (19.9%), other well-defined immunodeficiencies (25%), diseases of immune dysregulation (14.8%), congenital defects of phagocyte number, function or both (6.25%), and complement deficiencies (4.0%). In a total of 619.1 patient years at risk, 48 patients died (mortality incidence rate 77.53 per 1,000 person years). The overall survival in the studied cohort was 72.7% (72.4% for males and 73.1% for females). The most common cause of death was sepsis (46%) followed by pneumonia (29%). The probabilities that a patient survived 2, 4, and 6 years after onset of symptoms were 76%, 73%, and 69%, respectively. The variables that were found to be predictors for death are parental consanguinity, sepsis, adenovirus and CMV infections, failure to thrive, PID category, and onset age <6 months. CONCLUSIONS: Patients with PID have decreased probabilities of survival that are variable between PID categories. Early diagnosis and aggressive therapeutic interventions specifically of patients with history of the variables associated with increased risk of death may help increase their chance of survival. PMID- 22205206 TI - Targeting SKP1, an ubiquitin E3 ligase component found decreased in sporadic Parkinson's disease. AB - Microarray-derived transcriptomic studies in human substantia nigra pars compacta (SNpc) samples from sporadic Parkinson's disease (SPD) cases have opened an avenue to concentrate on potential gene intersections or cross-talks along the dopaminergic (DAergic) neurodegenerative cascade in SPD. One emerging gene candidate identified by our group was SKP1A (p19, S-phase kinase-associated protein 1A), found significantly decreased in the SNpc. It is part of the SCF (Skp1, Cullin 1, F-box protein) complex, the largest class of sophisticated ubiquitin-proteasome/E3 ligases, and can directly interact with Fbxo7, a gene defective in PARK15-linked PD. In vitro target validation by viral-mediated RNA interference revealed that the deficiency of Skp1 in a mouse SN-derived DAergic neuronal cell line potentiated the damage caused by exogenous insults implicated in PD pathology and caused the death of neurons undergoing differentiation, which developed Lewy body-like, alpha-synuclein-positive inclusions preceding cell death. Furthermore, recent animal studies show that site-directed intranigral stereotaxic injections of lentiviruses targeting SKP1A induce pathological and behavioral deficits in mice, supporting a significant role of Skp1 in SN DAergic neuronal survival in SPD. Thus, strategies aimed at increasing the activity or content of Skp1 may represent a novel therapeutic approach that has the potential to treat PD. PMID- 22205207 TI - Diagnosis of neonatal sepsis by broad-range 16S real-time polymerase chain reaction. AB - BACKGROUND: The standard diagnostic test (blood culture) for suspected neonatal sepsis has limitations in sensitivity and specificity, and 16S polymerase chain reaction (PCR) has been suggested as a new diagnostic tool for neonatal sepsis. OBJECTIVES: To develop and evaluate a new real-time PCR method for detection of bacterial DNA in blood samples collected from infants with suspected neonatal sepsis. METHODS: Immediately after blood culture, a study sample of 0.5-1.0 ml whole blood was collected and used for a novel 16S real-time PCR assay. All positive samples were sequenced. Detailed case studies were performed in all cases with conflicting results, to verify if PCR could detect pathogens in culture negative sepsis. RESULTS: 368 samples from 317 infants were included. When compared with blood culture, the assay yielded a sensitivity of 79%, a specificity of 90%, a positive predictive value of 59%, and a negative predictive value of 96%. Seven of the 31 samples with a positive PCR result and a negative blood culture had definite or suspected bacterial sepsis. In five samples, PCR (but not blood culture) could detect a pathogen that was present in a blood culture collected more than 24 h prior to the PCR sample. CONCLUSIONS: This study presents an evaluation of a new real-time PCR technique that can detect culture positive sepsis, and suggests that PCR has the potential to detect bacteria in culture-negative samples even after the initiation of intravenous antibiotics. PMID- 22205208 TI - Changes in growth hormone receptor gene expression during therapy in children with juvenile idiopathic arthritis. AB - BACKGROUND: High levels of cytokines in juvenile idiopathic arthritis (JIA) can alter target cell sensitivity to growth hormone (GH) leading to short stature in adulthood. We hypothesized that the down-regulation of GH receptor (GHR) gene expression could be involved in growth failure of children with JIA. METHODS: In 18 (12 F and 6 M) prepubertal JIA patients and 13 age- and sex-matched healthy children, we evaluated serum growth-promoting factors and inflammatory indexes. We also measured GHR gene expression, by real-time PCR, in lymphocytes of patients and controls. All parameters were evaluated in patients before and after treatment of JIA. RESULTS: The most interesting (p = 0.007) result was the increase in GHR mRNA expression in all JIA patients. Moreover, we observed a significant (p = 0.0156) decrease in IL-6 levels in JIA patients after 2 years of therapy (19.37 +/- 41.01) with respect to basal values (90.84 +/- 124.71). On the contrary, IGF-I significantly (p = 0.0005) increased to a mean SDS value of 0 (range -1.69 to +1.70 SDS) with respect to values at disease onset (-0.64 SDS). CONCLUSIONS: Our preliminary data suggest that the restoration of both GHR gene expression and IGF-I secretion correlate with inactive disease in JIA children. PMID- 22205209 TI - Perinatal network consensus guidelines on the resuscitation of extremely preterm infants born at <27 weeks' gestation. AB - In spite of recent advances in perinatal care and an increase in survival of extremely preterm infants over the last few years, there remains a lack of consensus about practical aspects of resuscitation of extremely preterm infants born before 27 weeks' gestation. With this in the background, the working group of one of the Perinatal Networks in London, UK, set out to conduct a survey to explore the opinions of the doctors and nurses on resuscitation practices of infants born before 27 weeks' gestation, with the aim of developing consensus guidelines. The working group emailed a questionnaire to all neonatal units within the Perinatal Network to seek the views of paediatric medical and nursing staff on resuscitation of infants born at <27 weeks' gestation. The questionnaire was returned anonymously by post. The responses highlighted the difference of opinion that currently exists amongst the clinicians and nurses across the world around the resuscitation practices of extremely preterm infants; yet at the same time, there seemed to be some consensus on certain issues. Based on the survey (questionnaire) results and already existing literature, the working group of the North West London Perinatal Network (NWLPN) produced and implemented specific consensus guidelines on practical aspects of resuscitation for infants born before 27 weeks' gestation for the network. The network plans to audit these guidelines in future and also produce a parent information leaflet explaining the relevance of these guidelines. PMID- 22205210 TI - Breastfeeding may improve nocturnal sleep and reduce infantile colic: potential role of breast milk melatonin. AB - Melatonin is secreted during the night in adults but not in infants. It has a hypnotic effect as well as a relaxing effect on the smooth muscle of the gastrointestinal tract. It is plausible that breast milk, which consists of melatonin, may have an effect on improving infants' sleep and reducing infantile colic. Our first goal was to assess the differences in the prevalence and severity of infantile colic and nocturnal sleep between breast-fed infants and supplement-fed infants. The second was to characterize the profile of melatonin secretion in human breast milk compared to artificial formulas. Ninety-four mothers of healthy 2 to 4-month-old infants filled a questionnaire regarding irritability/potential infantile colic and sleep characteristics. For the second part, we measured melatonin levels in breast milk of five women every 2 h during 24 h and in three samples of commonly used artificial formulas. Exclusively breast-fed infants had a significantly lower incidence of colic attacks (p = 0.04), lower severity of irritability attacks (p = 0.03), and a trend for longer nocturnal sleep duration (p = 0.06). Melatonin in human milk showed a clear circadian curve and was unmeasurable in all artificial milks. CONCLUSIONS: Exclusive breastfeeding is associated with reduced irritability/colic and a tendency toward longer nocturnal sleep. Breast milk (nocturnal) consists of substantial melatonin levels, whereas artificial formulas do not. We speculate that melatonin which is supplied to the infant via breast milk plays a role in improving sleep and reducing colic in breast-fed infants compared to formula-fed ones. PMID- 22205211 TI - The potency of fluvoxamine to reduce ethanol self-administration decreases with concurrent availability of food. AB - The selective serotonin reuptake inhibitor fluvoxamine reduces responding for ethanol at lower doses than responding for food when each is available in separate components or separate groups of rats. However, when both are available concurrently and deliveries earned per session are equal, this apparent selectivity inverts and food-maintained behavior is more sensitive than ethanol maintained behavior to rate-decreasing effects of fluvoxamine. Here, we investigated further the impact that concurrent access to both food and ethanol has on the potency of fluvoxamine. Fluvoxamine (5.6-17.8 mg/kg) potency was assessed under conditions in which food and ethanol were available concurrently and response rates were equal [average variable intervals (VIs) 405 and 14 s for food and ethanol, respectively], as well as when density of food delivery was increased (average VI 60 s for food and VI 14 s for ethanol). The potency of fluvoxamine was also determined when only ethanol was available (food extinction and average VI 14 s for ethanol) and under multiple VIs (VI 30 s for food and ethanol) wherein either food or ethanol was the only programmed reinforcement available during each component. Fluvoxamine was less potent at decreasing ethanol self-administration when food was available concurrently {ED50 [95% confidence limit (CL): 8.2 (6.5-10.3) and 10.7 (7.9-14.4)]} versus when ethanol was available in isolation [ED50: 4.0 (2.7-5.9) and 5.1 (4.3-6.0)]. Effects on food were similar under each condition in which food was available. The results demonstrate that the potency of fluvoxamine in reducing ethanol-maintained behavior depends on whether ethanol is available in isolation or in the context of concurrently scheduled food reinforcement. PMID- 22205212 TI - Myelin-associated proteins block the migration of olfactory ensheathing cells: an in vitro study using single-cell tracking and traction force microscopy. AB - Newly generated olfactory receptor axons grow from the peripheral to the central nervous system aided by olfactory ensheathing cells (OECs). Thus, OEC transplantation has emerged as a promising therapy for spinal cord injuries and for other neural diseases. However, these cells do not present a uniform population, but instead a functionally heterogeneous population that exhibits a variety of responses including adhesion, repulsion, and crossover during cell cell and cell-matrix interactions. Some studies report that the migratory properties of OECs are compromised by inhibitory molecules and potentiated by chemical gradients. Here, we demonstrated that rodent OECs express all the components of the Nogo receptor complex and that their migration is blocked by myelin. Next, we used cell tracking and traction force microscopy to analyze OEC migration and its mechanical properties over myelin. Our data relate the decrease of traction force of OEC with lower migratory capacity over myelin, which correlates with changes in the F-actin cytoskeleton and focal adhesion distribution. Lastly, OEC traction force and migratory capacity is enhanced after cell incubation with the Nogo receptor inhibitor NEP1-40. PMID- 22205223 TI - Multivariate analysis of sexual size dimorphism in local turkeys (Meleagris gallopavo) in Nigeria. AB - Sexual size dimorphism is a key evolutionary feature that can lead to important biological insights. To improve methods of sexing live birds in the field, we assessed sexual size dimorphism in Nigerian local turkeys (Meleagris gallopavo) using multivariate techniques. Measurements were taken on 125 twenty-week-old birds reared under the intensive management system. The body parameters measured were body weight, body length, breast girth, thigh length, shank length, keel length, wing length and wing span. Univariate analysis revealed that toms (males) had significantly (P < 0.05) higher mean values than hens (females) in all the measured traits. Positive phenotypic correlations between body weight and body measurements ranged from 0.445 to 0.821 in toms and 0.053-0.660 in hens, respectively. Three principal components (PC1, PC2 and PC3) were extracted in toms, each accounting for 63.70%, 19.42% and 5.72% of the total variance, respectively. However, four principal components (PC1, PC2, PC3 and PC4) were extracted in hens, which explained 54.03%, 15.29%, 11.68% and 6.95%, respectively of the generalised variance. A stepwise discriminant function analysis of the eight morphological traits indicated that body weight, body length, tail length and wing span were the most discriminating variables in separating the sexes. The single discriminant function obtained was able to correctly classify 100% of the birds into their source population. The results obtained from the present study could aid future management decisions, ecological studies and conservation of local turkeys in a developing economy. PMID- 22205224 TI - Feeding of tropical trees and shrub foliages as a strategy to reduce ruminal methanogenesis: studies conducted in Cuba. AB - The aim of this paper was to present the main results obtained in Cuba on the effects of feeding tropical trees and shrubs on rumen methanogenesis in animals fed with low quality fibrous diets. More than 20 tree and shrub foliages were screened for phytochemicals and analyzed for chemical constituents. From these samples, seven promising plants (Samanea saman, Albizia lebbeck, Tithonia diversifolia, Leucaena leucocephala, Trichantera gigantea, Sapindus saponaria, and Morus alba) were evaluated for methane reduction using an in vitro rumen fermentation system. Results indicated that the inclusion levels of 25% of Sapindo, Morus, or Trichantera foliages in the foliages/grass mixtures (grass being Pennisetum purpureum) reduced (P < 0.01) methane production in vitro when compared to Pennisetum alone (17.0, 19.1, and 18.0 versus 26.2 mL CH(4)/g fermented dry matter, respectively). It was demonstrated that S. saman, A. lebbeck, or T. diversifolia accession 23 foliages when mixed at the rate of 30% in Cynodon nlemfuensis grass produced lower methane compared to the grass alone. Inclusion levels of 15% and 25% of a ruminal activator supplement containing 29% of L. leucocehala foliage meal reduced methane by 37% and 42% when compared to the treatment without supplementation. In vivo experiment with sheep showed that inclusion of 27% of L. leucocephala in the diet increased the DM intake but did not show significant difference in methane production compared to control diet without this foliage. The results of these experiments suggest that the feeding of tropical tree and shrub foliages could be an attractive strategy for reduction of ruminal methanogenesis from animals fed with low-quality forage diets and for improving their productivity. PMID- 22205213 TI - The battle against immunopathology: infectious tolerance mediated by regulatory T cells. AB - Infectious tolerance is a process whereby one regulatory lymphoid population confers suppressive capacity on another. Diverse immune responses are induced following infection or inflammatory insult that can protect the host, or potentially cause damage if not properly controlled. Thus, the process of infectious tolerance may be critical in vivo for exerting effective immune control and maintaining immune homeostasis by generating specialized regulatory sub-populations with distinct mechanistic capabilities. Foxp3(+) regulatory T cells (T(regs)) are a central mediator of infectious tolerance through their ability to convert conventional T cells into induced regulatory T cells (iT(regs)) directly by secretion of the suppressive cytokines TGF-beta, IL-10, or IL-35, or indirectly via dendritic cells. In this review, we will discuss the mechanisms and cell populations that mediate and contribute to infectious tolerance, with a focus on the intestinal environment, where tolerance induction to foreign material is critical. PMID- 22205225 TI - Dual RAS blockade normalizes angiotensin-converting enzyme-2 expression and prevents hypertension and tubular apoptosis in Akita angiotensinogen-transgenic mice. AB - We investigated the effects of dual renin-angiotensin system (RAS) blockade on angiotensin-converting enzyme-2 (Ace2) expression, hypertension, and renal proximal tubular cell (RPTC) apoptosis in type 1 diabetic Akita angiotensinogen (Agt)-transgenic (Tg) mice that specifically overexpress Agt in their RPTCs. Adult (11 wk old) male Akita and Akita Agt-Tg mice were treated with two RAS blockers (ANG II receptor type 1 blocker losartan, 30 mg.kg(-1).day(-1)) and angiotensin-converting enzyme (ACE) inhibitor perindopril (4 mg.kg(-1).day(-1)) in drinking water. Same-age non-Akita littermates and Agt-Tg mice served as controls. Blood pressure, blood glucose, and albuminuria were monitored weekly. The animals were euthanized at age 16 wk. The left kidneys were processed for immunohistochemistry and apoptosis studies. Renal proximal tubules were isolated from the right kidneys to assess gene and protein expression. Urinary ANG II and ANG 1-7 were quantified by ELISA. RAS blockade normalized renal Ace2 expression and urinary ANG 1-7 levels (both of which were low in untreated Akita and Akita Agt-Tg), prevented hypertension, albuminuria, tubulointerstitial fibrosis and tubular apoptosis, and inhibited profibrotic and proapoptotic gene expression in RPTCs of Akita and Akita Agt-Tg mice compared with non-Akita controls. Our results demonstrate the effectiveness of RAS blockade in preventing intrarenal RAS activation, hypertension, and nephropathy progression in diabetes and support the important role of intrarenal Ace2 expression in modulating hypertension and renal injury in diabetes. PMID- 22205226 TI - The renal transcriptome of db/db mice identifies putative urinary biomarker proteins in patients with type 2 diabetes: a pilot study. AB - We sought to identify novel urinary biomarkers of kidney function in type 2 diabetes. We screened the renal transcriptome of db/db and db/m mice for differentially expressed mRNA transcripts that encode secreted proteins with human orthologs. Whether elevated urine levels of the orthologous proteins correlated with diminished glomerular filtration rate was tested in a cross sectional study of n = 56 patients with type 2 diabetes. We identified 36 putative biomarker genes in db/db kidneys: 31 upregulated and 5 downregulated. Urinary protein levels of six selected candidates (endothelin-1, lipocalin-2, transforming growth factor-beta, growth and differentiation factor-15, interleukin-6, and macrophage chemoattractant protein-1) were elevated in type 2 diabetic patients with subnormal glomerular filtration rate (i.e., <90 ml.min( 1).1.73 m(-2)), independent of microalbuminuria, age, sex, race, and use of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists. In contrast, urinary levels of fibroblast growth factor were not increased. A composite variable of urine albumin and any of the six candidate markers was associated with subnormal estimated glomerular filtration rate more closely than albumin alone. In addition, urinary endothelin-1, growth and differentiation factor-15, and interleukin-6 were associated with a marker of proximal tubule damage, N-acetyl-beta-d-glucosaminidase activity. These results suggest that gene expression profiling in diabetic mouse kidney can complement existing proteomic based approaches for renal biomarker discovery in humans. PMID- 22205227 TI - Adjustable passive stiffness in mouse bladder: regulated by Rho kinase and elevated following partial bladder outlet obstruction. AB - Detrusor smooth muscle (DSM) contributes to bladder wall tension during filling, and bladder wall deformation affects the signaling system that leads to urgency. The length-passive tension (L-T(p)) relationship in rabbit DSM can adapt with length changes over time and exhibits adjustable passive stiffness (APS) characterized by a L-T(p) curve that is a function of both activation and strain history. Muscle activation with KCl, carbachol (CCh), or prostaglandin E(2) at short muscle lengths can increase APS that is revealed by elevated pseudo-steady state T(p) at longer lengths compared with prior T(p) measurements at those lengths, and APS generation is inhibited by the Rho Kinase (ROCK) inhibitor H 1152. In the current study, mouse bladder strips exhibited both KCl- and CCh induced APS. Whole mouse bladders demonstrated APS which was measured as an increase in pressure during passive filling in calcium-free solution following CCh precontraction compared with pressure during filling without precontraction. In addition, CCh-induced APS in whole mouse bladder was inhibited by H-1152, indicating that ROCK activity may regulate bladder compliance during filling. Furthermore, APS in whole mouse bladder was elevated 2 wk after partial bladder outlet obstruction, suggesting that APS may be relevant in diseases affecting bladder mechanics. The presence of APS in mouse bladder will permit future studies of APS regulatory pathways and potential alterations of APS in disease models using knockout transgenetic mice. PMID- 22205228 TI - Collecting duct cells that lack normal cilia have mislocalized vasopressin-2 receptors. AB - Polycystic kidney disease (PKD) is a ciliopathy characterized by renal cysts and hypertension. These changes are presumably due to altered fluid and electrolyte transport in the collecting duct (CD). This is the site where vasopressin (AVP) stimulates vasopressin-2 receptor (V2R)-mediated aquaporin-2 (AQP2) insertion into the apical membrane. Since cysts frequently occur in the CD, we studied V2R and AQP2 trafficking and function in CD cell lines with stunted and normal cilia [cilia (-), cilia (+)] derived from the orpk mouse (hypomorph of the Tg737/Ift88 gene). Interestingly, only cilia (-) cells grown on culture dishes formed domes after apical AVP treatment. This observation led to our hypothesis that V2R mislocalizes to the apical membrane in the absence of a full-length cilium. Immunofluorescence indicated that AQP2 localizes to cilia and in a subapical compartment in cilia (+) cells, but AQP2 levels were elevated in both apical and basolateral membranes in cilia (-) cells after apical AVP treatment. Western blot analysis revealed V2R and glycosylated AQP2 in biotinylated apical membranes of cilia (-) but not in cilia (+) cells. In addition, apical V2R was functional upon apical desmopressin (DDAVP) treatment by demonstrating increased cAMP, water transport, and benzamil-sensitive equivalent short-circuit current (I(sc)) in cilia (-) cells but not in cilia (+) cells. Moreover, pretreatment with a PKA inhibitor abolished DDAVP stimulation of I(sc) in cilia (-) cells. Thus we propose that structural or functional loss of cilia leads to abnormal trafficking of AQP2/V2R leading to enhanced salt and water absorption. Whether such apical localization contributes to enhanced fluid retention and hypertension in PKD remains to be determined. PMID- 22205229 TI - Induction of hemeoxygenase-1 reduces glomerular injury and apoptosis in diabetic spontaneously hypertensive rats. AB - Induction of hemeoxygenase-1 (HO-1) lowers blood pressure and reduces organ damage in hypertensive animal models; however, a potential protective role for HO 1 induction against diabetic-induced glomerular injury remains unclear. We hypothesize that HO-1 induction will protect against diabetes-induced glomerular injury by maintaining glomerular integrity and inhibiting renal apoptosis, inflammation, and oxidative stress. Diabetes was induced with streptozotocin in spontaneously hypertensive rats (SHR) as a model where the coexistence of hypertension and diabetes aggravates the progression of diabetic renal injury. Control and diabetic SHR were randomized to receive vehicle or the HO-1 inducer cobalt protoporphyrin (CoPP). Glomerular albumin permeability was significantly greater in diabetic SHR compared with control, consistent with an increase in apoptosis and decreased glomerular nephrin and alpha(3)beta(1)-integrin protein expression in diabetic SHR. CoPP significantly reduced albumin permeability and apoptosis and restored nephrin and alpha(3)beta(1)-integrin protein expression levels in diabetic SHR. Glomerular injury in diabetic SHR was also associated with increases in NF-kappaB-induced inflammation and oxidative stress relative to vehicle-treated SHR, and CoPP significantly blunted diabetes-induced increases in glomerular inflammation and oxidative stress in diabetic SHR. These effects were specific to exogenous stimulation of HO-1, since incubation with the HO inhibitor stannous mesoporphyrin alone did not alter glomerular inflammatory markers or oxidative stress yet was able to prevent CoPP-mediated decreases in these parameters. These data suggest that induction of HO-1 reduces diabetic induced glomerular injury and apoptosis and these effects are associated with decreased NF-kappaB-induced inflammation and oxidative stress. PMID- 22205230 TI - Acute calcineurin inhibition with tacrolimus increases phosphorylated UT-A1. AB - UT-A1, the urea transporter present in the apical membrane of the inner medullary collecting duct, is crucial to the kidney's ability to concentrate urine. Phosphorylation of UT-A1 on serines 486 and 499 is important for plasma membrane trafficking. The effect of calcineurin on dephosphorylation of UT-A1 was investigated. Inner medullary collecting ducts from Sprague-Dawley rats were metabolically labeled and treated with tacrolimus to inhibit calcineurin or calyculin to inhibit protein phosphatases 1 and 2A. UT-A1 was immunoprecipitated, electrophoresed, blotted, and total UT-A1 phosphorylation was assessed by autoradiography. Total UT-A1 was determined by Western blotting. A phospho specific antibody to pser486-UT-A1 was used to determine whether serine 486 can be hyperphosphorylated by inhibiting phosphatases. Inhibition of calcineurin showed an increase in phosphorylation per unit protein at serine 486. In contrast, inhibition of phosphatases 1 and 2A resulted in an increase in UT-A1 phosphorylation but no increase in pser486-UT-A1. In vitro perfusion of inner medullary collecting ducts showed tacrolimus-stimulated urea permeability consistent with stimulated urea transport. The location of phosphorylated UT-A1 in rats treated acutely and chronically with tacrolimus was determined using immunohistochemistry. Inner medullary collecting ducts of the acutely treated rats showed increased apical membrane association of phosphorylated UT-A1 while chronic treatment reduced membrane association of phosphorylated UT-A1. We conclude that UT-A1 may be dephosphorylated by multiple phosphatases and that the PKA-phosphorylated serine 486 is dephosphorylated by calcineurin. This is the first documentation of the role of phosphatases and the specific site of phosphorylation of UT-A1, in response to tacrolimus. PMID- 22205231 TI - Human adipose tissue-derived mesenchymal stem cells protect kidneys from cisplatin nephrotoxicity in rats. AB - Cisplatin has multiple cellular targets and modes of action that lead to nephrotoxicity. This suggests novel therapies that act at multiple cisplatin target sites may be effective. We tested whether human adipose tissue-derived mesenchymal stem cells (Ad-MSCs) can affect multiple target sites and protect against cisplatin-induced kidney damage. Rats were divided into four groups: control, infused with Ad-MSCs, injected with cisplatin, and cisplatin followed by infusion of Ad-MSCs. Animal survival and renal function were decreased and histological damage was increased in cisplatin-treated rats at day 3. Infusion of Ad-MSCs ameliorated renal dysfunction and tissue injury caused by cisplatin, leading to increased survival. Apoptotic cell death in the kidney was significantly reduced by infusion of Ad-MSCs. Activation of p53, JNK, and ERK and the expression of inflammation-related molecules were also decreased in the kidney that received Ad-MSCs. Very few Ad-MSCs were detected in the kidney. Conditioned medium from cultured Ad-MSCs had renal-protective functions in vivo and in vitro. Renal dysfunction and tissue damage caused by cisplatin were significantly reduced in rats treated with Ad-MSCs-conditioned medium. The viability of cultured renal proximal tubular cells exposed to cisplatin was also improved by coculture with Ad-MSCs or with conditioned medium. Release of proinflammatory mediators induced by cisplatin was inhibited in coculture with Ad MSCs. Our results show that human Ad-MSCs exert a paracrine-protective effect on cisplatin nephrotoxicity at multiple target sites and suggest that human Ad-MSCs might be a new therapeutic approach for patients with acute kidney injury. PMID- 22205232 TI - Do we use a priori knowledge of gravity when making elbow rotations? AB - In this study, we aim to investigate whether motor commands, emanating from movement planning, are customized to movement orientation relative to gravity from the first trial on. Participants made fast point-to-point elbow flexions and extensions in the transverse plane. We compared movements that had been practiced in reclined orientation either against or with gravity with the same movement relative to the body axis made in the upright orientation (neutral compared to gravity). For each movement type, five rotations from reclined to upright orientation were made. For each rotation, we analyzed the first trial in upright orientation and the directly preceding trial in reclined orientation. Additionally, we analyzed the last five trials of a 30-trial block in upright position and compared these trials with the first trials in upright orientation. Although participants moved fast, gravitational torques were substantial. The change in body orientation affected movement planning: we found a decrease in peak angular velocity and a decrease in amplitude for the first trials made in the upright orientation, regardless of whether the previous movements in reclined orientation were made against or with gravity. We found that these decreases disappeared after participants familiarized themselves with moving in upright position in a 30-trial block. These results indicate that participants used a general strategy, corresponding to the strategy observed in situations with unreliable or limited information on external conditions. From this, we conclude that during movement planning, a priori knowledge of gravity was not used to specifically customize motor commands for the neutral gravity condition. PMID- 22205233 TI - Evidence for vestibular dysfunction in orthostatic hypotension. AB - There is little definitive evidence of the clinical significance of the vestibular-cardiovascular reflex in humans, despite the fact that the vestibular system is known to contribute to cardiovascular control in animals. The present study involved 248 dizzy patients (127 male patients and 121 female patients) aged 65 years and younger. We classified all participants into three groups based on their vestibular evoked myogenic potential (VEMP) responses; absent VEMP, asymmetry VEMP and normal VEMP. To investigate the effect of the otolith disorder, which was estimated by the VEMP, on the orthostatic blood pressure responses, the subjects' systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate were monitored during the orthostatic test after they actively stood up. The male patients in the absent VEMP group had a significant drop in their DBP at 1 min after active standing up (P < 0.05) without any change in their SBP. Conversely, male patients in the asymmetry VEMP and normal VEMP groups showed a significant increase in the SBP at 1 min after active standing up (P < 0.05). Female patients in the absent VEMP group did not show any significant drop in their blood pressure after standing up (P > 0.05). In the entire group of participants, a total of 19.6% of the patients in the absent VEMP group fulfilled the criteria for orthostatic hypotension (OH), which was significantly > the 8.6% of patients in the normal VEMP group and the 7.2% in the asymmetry VEMP group (P < 0.05). Our results suggest that vestibular disorders due to the dysfunction of otolith organs provoke OH. PMID- 22205234 TI - Rice-induced anaphylaxis: IgE-mediated allergy against a 56-kDa glycoprotein. AB - BACKGROUND: Although rice (Oryza sativa) is one of the most common cereals produced and consumed around the world, there have been only a few reports on immediate hypersensitivity reactions after ingestion of rice. Few clinical studies on rice allergy in Asia have been reported concerning rhinitis, asthma and atopic dermatitis. In this case study, we identify allergens presumably responsible for anaphylaxis after ingestion of rice in a German patient. METHODS: Prick-to-prick tests, determination of specific IgE and the basophil activation test (BAT) were performed to confirm IgE-mediated allergy. IgE reactivity was further analyzed by immunoblotting of protein extracts from cooked commercial rice products. Rice allergens were purified, subjected to N-terminal sequencing and characterized by IgE binding and IgE inhibition assays using additional sera from 8 subjects with sensitization to rice and/or a history of hypersensitivity symptoms after rice ingestion. RESULTS: Prick-to-prick tests were positive to raw and cooked rice (basmati rice and long-grain rice) and preparations of different rice extracts. Specific IgE against rice (f9) was 1.87 kU(A)/l. The BAT showed specific IgE-mediated activation of basophils after stimulation with rice extracts. Four IgE-reactive rice proteins with an apparent molecular weight of 49, 52, 56 and 98 kDa were identified. Interestingly, only binding to the 56-kDa glycoprotein was at least partially independent from cross-reactive carbohydrate determinants (CCD), whereas IgE binding to the other rice proteins was completely inhibited by pre-incubation with the CCD MUXF derived from bromelain. CONCLUSIONS: Yet unidentified high-molecular-weight allergens from rice seeds, predominantly a 56-kDa glycoprotein, seem to be responsible for anaphylaxis after consumption of rice in a German patient. PMID- 22205235 TI - Recent advances in diagnostic strategies for giant cell arteritis. AB - Giant cell arteritis (GCA) is a systemic vasculitis that affects the aorta and its major branches. Involvement of the ciliary artery can result in ischemic optic neuropathy and subsequent blindness, which is typically irreversible. If GCA is suspected, treatment with glucocorticoids should be initiated promptly to prevent further vision loss. However, given the need for prolonged therapy with glucocorticoids and the morbidity associated with their use, diagnosis should be confirmed. Clinical features and laboratory findings are neither sensitive nor specific for GCA. The mainstay of diagnosis remains histopathologic examination of a section of the superficial temporal artery. Several imaging studies have been used to evaluate the temporal artery but, at present, their utility as alternatives to a temporal artery biopsy is limited. Recent advances in imaging modalities have allowed detailed noninvasive imaging of the large arteries and are a useful adjunct for the diagnosis of GCA, particularly in patients with primarily large-vessel involvement in whom temporal artery biopsy is often negative. PMID- 22205236 TI - Syndromes predisposing to pediatric central nervous system tumors: lessons learned and new promises. AB - Central nervous system (CNS) neoplasms are a leading cause of morbidity and mortality among children with cancer. In contrast to adults, a genetic basis for brain tumors is relatively common in children. A child harboring a germline mutation in a cancer-related gene will be predisposed to develop CNS tumors. These cancer predisposition syndromes are rare but pose overwhelming clinical and psychosocial challenges to families and the treating team. Recent significant advances in our understanding of the biological processes that govern these genetic conditions combined with international efforts to define and treat clinical aspects of these tumors are transforming the lives of these individuals. In this article, we summarize recent progress made for each of the major CNS tumor syndromes. We discuss the biological and clinical relevance of such advances, and suggest a comprehensive approach to a child affected by a predisposition to brain tumors. PMID- 22205237 TI - Depression and anxiety in perinatal period: prevalence and risk factors in an Italian sample. AB - Accumulating evidence suggests that pregnancy does not protect women from mental illness. The aim of this study was to assess the prevalence, sociodemographic correlates, and the risks factors for perinatal depression and anxiety. Five hundred ninety women between 28th and the 32nd gestational weeks were recruited and submitted to a sociodemographic, obstetric, and psychological interview. The Edinburgh Postnatal Depression Scale (EPDS) and the state-trait anxiety inventory (STAI-Y) were also administered in antenatal period and 3 months postnatally. The Structured Clinical Interview for DSM-IV (SCID-I) was used to diagnose mood and anxiety disorders. Three months after delivery, EPDS was administered by telephone interview. Women with an EPDS score >=10 were 129 in antenatal period (21.9%) and 78 in postnatal period (13.2%). During pregnancy 121 women (20.5%) were positive for STAI-Y state and 149 women (25.3%) for STAI-Y trait. The most important risk factors for antenatal depression are: foreign nationality, conflictual relationship with family and partner, and lifetime psychiatric disorders. The principal risk factors for postnatal depression are: psychiatric disorders during pregnancy and artificial reproductive techniques. Psychiatric disorders, during and preceding pregnancy, are the strongest risk factors for antenatal state and trait anxiety. Antenatal depressive and anxiety symptoms appear to be as common as postnatal symptoms. These results provide clinical direction suggesting that early identification and treatment of perinatal affective disorders is particularly relevant to avoid more serious consequences for mothers and child. PMID- 22205238 TI - The efficiency of a urotensin II antagonist in an experimental lung fibrosis model. AB - Pulmonary fibrosis is a chronic disease. Urotensin II (U-II) is a new peptide with angiogenic and profibrotic features. Therefore, we aim to evaluate the antagonism of U-II with palosuran in an animal model and plan to measure U-II, endothelin-1 (ET-1), and transforming growth factor-beta1 (TGF-beta1) and their association with lung fibrosis. Thirty Wistar male rats were used in the study and were divided into three groups: group 1, control; group 2, bleomycin-induced lung fibrosis group; and group 3, bleomycin-induced lung fibrosis with treatment palosuran group. U-II level (nanograms per milliliter) was 2.957 +/- 0.159 in group1, 3.188 +/- 0.122 in group 2, and 2.970 +/- 0.165 in group 3 (p = 0.002). The ET-1 level (picograms per milliliter) was 4.486 +/- 0.376 in group 1, 9.086 +/- 1.850 in group 2, and 4.486 +/- 0.376 in group 3 (p < 0.001). The TGF-beta1 (nanograms per milliliter) level was 73.143 +/- 9.96 in group 1, 84.81 +/- 4.73 in group 2, and 77.86 +/- 5.77 in group 3 (p = 0.006). Finally, the fibrosis score was 0.7 +/- 0.48 in group 1, 4.4 +/- 1.34 in group 2, and 3.2 +/- 0.63 in group 3 (p < 0.001). There is a statistically significant positive relationship between fibrosis scores and the UT-II, ET-1, and TGF-beta1 levels of the experimental lung fibrosis model. We believe U-II is an important mediator in lung fibrosis models, and its antagonism with palosuran could be a new treatment choice for interstitial lung fibrosis, but further studies need to be conducted to verify the findings of the current study. PMID- 22205239 TI - Sound levels and their effects on children in a German primary school. AB - Considerable sound levels are produced in primary schools by voices of children and resonance effects. As a consequence, hearing loss and mental impairment may occur. In a Cologne primary school, sound levels were measured in three different classrooms, each with 24 children, 8-10 years old, and one teacher. Sound dosimeters were positioned in the room and near the teacher's ear. Additional measurements were done in one classroom fully equipped with sound-absorbing materials. A questionnaire containing 12 questions about noise at school was distributed to 100 children, 8-10 years old. Measurements were repeated after children had been taught about noise damage and while "noise lights" were used. Mean sound levels of 5-h per day measuring period were 78 dB (A) near the teacher's ear and 70 dB (A) in the room. The average of all measured maximal sound levels for 1 s was 105 dB (A) for teachers, and 100 dB (A) for rooms. In the soundproofed classroom, Leq was 66 dB (A). The questionnaire revealed certain judgment of the children concerning situations with high sound levels and their ability to develop ideas for noise reduction. However, no clear sound level reduction was identified after noise education and using "noise lights" during lessons. Children and their teachers are equally exposed to high sound levels at school. Early sensitization to noise and the possible installation of sound absorbing materials can be important means to prevent noise-associated hearing loss and mental impairment. PMID- 22205240 TI - Differentiation of liver transplantation complications by quantitative analysis of dynamic hepatobiliary scintigraphy. AB - OBJECTIVE: We retrospectively investigated the value of dynamic Tc-diisopropyl iminodiacetic acid hepatobiliary scintigraphy (HBS) in discriminating postsurgical complications following liver transplantation (LT). METHODS: Dynamic HBS was performed for suspected post-LT complications in 201 cases. Hepatic uptake and excretion was visually graded. The portal perfusion index (PPI) and kinetic parameters were quantitatively analyzed. RESULTS: HBS findings were normal in all 119 (59%) cases without complications. Complications were confirmed in 82 cases: 24 had graft rejection, 48 had biliary obstruction, and 10 had hepatitis. Visual grades of uptake and excretion were abnormal for all three types of complications and showed no discriminative value. The PPI level was significantly higher for grafts with rejection (0.83 +/- 0.07) compared with no complication (0.57 +/- 0.08), biliary obstruction (0.69 +/- 0.06), and hepatitis (0.65 +/- 0.07; all P<0.0001). Receiver operating characteristic curve analysis confirmed PPI to be highly accurate for discerning rejection from no rejection (area under the curve, 0.97; sensitivity, 95.8%; specificity, 91.7%) or biliary obstruction (area under the curve, 0.93; sensitivity, 95.8%; specificity, 79.2%). CONCLUSION: PPI measured from dynamic HBS offers a highly accurate method for identifying post-LT rejection and distinguishing it from biliary obstruction or hepatitis. PMID- 22205241 TI - Comparison of 800 and 3700 MBq iodine-131 for the postoperative ablation of thyroid remnant in patients with low-risk differentiated thyroid cancer. AB - INTRODUCTION: The initial treatment of differentiated thyroid cancer is thyroidectomy, followed by remnant ablation with iodine-131 (I-131) in some patients. However, controversy exists concerning the appropriate radioiodine dose. The aim of the study is to compare the success rate of low and high activities of I-131 for postoperative remnant ablation. PATIENTS AND METHODS: A total of 108 nonmetastatic low-risk patients (mean age: 46, 85% women) with papillary and follicular carcinoma had I-131 ablation for the postoperative thyroid remnant. Fifty-three patients received a low dose (L) (800 MBq) and 55 patients received a high dose (H) (3700 MBq) of I-131. After total thyroidectomy, thyroid bed I-131 uptake (RAIU) and neck ultrasonography (USG) were performed to determine the remnant volume and the iodine avidity, which were used to calculate the dose delivered to the remnant tissue. The success rate of I-131 ablation was assessed with four different criteria based on serum thyroglobulin (Tg) and USG with and without the utilization of I-131 diagnostic whole-body scintigraphy (DxWBS). Ablation was considered to be successful if patients fulfilled all of the following criteria. (a) Strict criteria based on three tests: (i) USG negative, (ii) no tracer uptake or less than twice the background activity in the thyroid bed on DxWBS and/or up to 0.2% RAIU, and (iii) Tg < 0.2 ng/ml; (b) lax criteria based on three tests: (i) USG negative, (ii) no tracer uptake or less than twice the background activity in the thyroid bed on DxWBS and/or <= 0.2% RAIU, and (iii) Tg < 2 ng/ml; (c) strict criteria based on two tests: (i) USG negative and (ii) Tg < 0.2 ng/ml; (d) lax criteria based on two test: (i) USG negative and (ii) Tg < 2 ng/ml. RESULTS: When three tests were used to define successful ablation, in group L, 32 out of 53 (60%) and 43 out of 53 (81%) patients were successfully treated versus 35 out of 55 (64%) and 42 out of 55 (76%) for group H on the basis of strict and lax criteria, respectively (P=NS). The differences were not statistically significant between the two groups when only two tests were used to define ablation success (62 vs. 69% with strict and 89 vs. 87% with lax criteria, respectively). CONCLUSION: Our findings suggest that remnant thyroid tissue in patients with low-risk, well-differentiated thyroid cancer after total thyroidectomy can be ablated with 800 MBq of I-131. The success rate is not different from that obtained with 3700 MBq I-131. PMID- 22205243 TI - Threshold conditions for integrated pest management models with pesticides that have residual effects. AB - Impulsive differential equations (hybrid dynamical systems) can provide a natural description of pulse-like actions such as when a pesticide kills a pest instantly. However, pesticides may have long-term residual effects, with some remaining active against pests for several weeks, months or years. Therefore, a more realistic method for modelling chemical control in such cases is to use continuous or piecewise-continuous periodic functions which affect growth rates. How to evaluate the effects of the duration of the pesticide residual effectiveness on successful pest control is key to the implementation of integrated pest management (IPM) in practice. To address these questions in detail, we have modelled IPM including residual effects of pesticides in terms of fixed pulse-type actions. The stability threshold conditions for pest eradication are given. Moreover, effects of the killing efficiency rate and the decay rate of the pesticide on the pest and on its natural enemies, the duration of residual effectiveness, the number of pesticide applications and the number of natural enemy releases on the threshold conditions are investigated with regard to the extent of depression or resurgence resulting from pulses of pesticide applications and predator releases. Latin Hypercube Sampling/Partial Rank Correlation uncertainty and sensitivity analysis techniques are employed to investigate the key control parameters which are most significantly related to threshold values. The findings combined with Volterra's principle confirm that when the pesticide has a strong effect on the natural enemies, repeated use of the same pesticide can result in target pest resurgence. The results also indicate that there exists an optimal number of pesticide applications which can suppress the pest most effectively, and this may help in the design of an optimal control strategy. PMID- 22205244 TI - Animal models of erectile dysfunction (ED): potential utility of non-human primates as a model of atherosclerosis-induced vascular ED. AB - Erectile dysfunction (ED) is a prevalent medical condition affecting 18 million men and their sexual partners in the United States alone. In the majority of patients, ED is related to alterations in the flow of blood to or from the penis. Undeniably, significant progress has been made in understanding the multifactorial mechanisms that modulate erectile capacity and predispose one to ED, and this, in turn, has led to the availability of more effective treatment options. Nonetheless, all current therapies have untoward side effects, and moreover, there are still no satisfactory treatments for many patients with ED. Further enhancements in the treatment of ED would logically result from both early intervention and more detailed mechanistic insight into the characteristics of the disease process per se. This fact underscores the importance of improved understanding of the initiation, development and progression of ED. However, to do so requires longitudinal studies on animal models that more closely approximate the corresponding clinical features and time course of human disease. The goal of this report is twofold. First, to provide a brief general overview of the applicability of commonly used animal models for the study of ED. The second and primary goal is to highlight the scientific rationale for using non-human primates to evaluate the impact of atherosclerosis-induced vascular disease on the penile and systemic circulatory systems. This latter goal seems especially relevant in light of the recent literature documenting a link between ED and systemic vascular disease, a finding that has major implications in an aging US male population consuming a high fat diet. PMID- 22205242 TI - Isolation, characterization, and structure analysis of a non-TIR-NBS-LRR encoding candidate gene from MYMIV-resistant Vigna mungo. AB - Yellow mosaic disease of Vigna mungo caused by Mungbean yellow mosaic India virus (MYMIV) is still a major threat in the crop production. A candidate disease resistance (R) gene, CYR1 that co-segregates with MYMIV-resistant populations of V. mungo has been isolated. CYR1 coded in silico translated protein sequence comprised of 1,176 amino acids with coiled coil structure at the N-terminus, central nucleotide binding site (NBS) and C-terminal leucine-rich repeats (LRR) that belongs to non-TIR-NBS-LRR subfamily of plant R genes. CYR1 transcript was unambiguously expressed during incompatible plant virus interactions. A putative promoter-like sequence present upstream of this candidate gene perhaps regulates its expression. Enhanced transcript level upon MYMIV infection suggests involvement of this candidate gene in conferring resistance against the virus. In silico constructed 3D models of NBS and LRR regions of this candidate protein and MYMIV-coat protein (CP) revealed that CYR1-LRR forms an active pocket and successively interacts with MYMIV-CP during docking, like that of receptor-ligand interaction; indicating a critical role of CYR1 as signalling molecule to protect V. mungo plants from MYMIV. This suggests involvement of CYR1 in recognizing MYMIV-effector molecule thus contributing to incompatible interaction. This study is the first stride to understand molecular mechanism of MYMIV resistance. PMID- 22205245 TI - Therapeutic effect of combination of alagebrium (ALT-711) and sildenafil on erectile function in diabetic rats. AB - Recently, the relationship between advanced glycation end products (AGEs) and erectile dysfunction (ED) has been reported. The present study aimed to investigate whether a combination of an AGE cross-link breaker (alagebrium/ALT 711) and sildenafil could enhance the erectile capacity in streptozotocin (STZ) diabetic rats. Additionally, we assessed the effect of that treatment option on some molecules that have been suggested to have crucial roles in AGE-related ED pathways. Four groups of animals were utilized: (1) age-matched control rats, (2) STZ-induced diabetic rats (40 mg kg(-1) i.p.), (3) STZ rats+sildenafil (5 mg kg( 1) p.o.), (4) STZ rats treated with a combination of sildenafil (5 mg kg(-1) p.o)+alagebrium/ALT-711 (10 mg kg(-1) p.o.) for the final 1 month of the 2 months of diabetes period. At 2 months after i.p. injection of STZ, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Penile tissue AGEs, MDA (malondialdehyde), cyclic guanosine monophosphate (cGMP) (ELISA), endothelial nitric oxide (NO) synthase (eNOS), inducible NO synthase (iNOS) (western blot), nuclear factor (NF)-kappaB, mitogen-activated protein (MAP) kinase (immunohistochemistry) and apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling) analyses were performed in all groups of rats. STZ diabetic rats had a significant decrease in erectile function as determined by the peak intracavernosal pressure (ICP) and total ICP (area under the erectile curve) after CNS when compared with control rats (P<0.05). The increase in both ICP and area under the erectile curve of STZ diabetic rats treated with a combination of sildenafil+alagebrium/ALT-711 as well as in STZ diabetic rats treated with sildenafil alone was significantly greater than STZ diabetic rats. Additionally, combination treatment decreased AGE, MDA, iNOS, NF-kappaB, MAP kinase and apoptosis levels, whereas it preserved cGMP contents in diabetic penile tissue. Decreased AGE, MDA, iNOS, NF-kappaB, MAP kinase and increased cGMP levels at the combination (sildenafil+alagebrium/ALT 711) therapy group increased both the peak ICP and total ICP to CNS in the STZ diabetic rats, which was similar to the response observed in control rats. These results may explain the role of AGEs in diabetes-related ED and the effect of an AGE cross-link breaker alagebrium/ALT-711+sildenafil therapy on some critical molecules related to AGE-related ED pathways. PMID- 22205246 TI - Synthesis and luminescent properties of M2V2O7: Eu (M=Sr, Ba) nanophosphors. AB - A solution combustion route for the synthesis of Eu(3+)-activated M(2)V(2)O(7) (M = Sr, Ba) and their luminescent properties have been investigated. Structure and luminescent characteristics of Sr(2)V(2)O(7):Eu(3+) and Ba(2)V(2)O(7):Eu(3+) nanophosphors have been studied by x-ray diffraction, scanning electron microscopy, transmission electron microscopy, fluorescence spectrometry and Fourier transform infra-red spectroscopy. The incorporation of Eu(3+) activator in these nanoparticles has been checked by luminescence characteristics. These nanoparticles have displayed red color under a UV source which is due to characteristics transition of Eu(3+) from (5)D(0) -> (7)F(2) at 613 nm in both Sr(2)V(2)O(7):Eu(3+) and Ba(2)V(2)O(7):Eu(3+) nanophosphors. In addition, the optimal Eu(3+) - doped contents of Sr(2(1-x))Eu(2x)V(2)O(7) and Ba(2(1 x))Eu(2x)V(2)O(7) nanophosphors for both were 4 mol%. PMID- 22205247 TI - Influence of catalyses on the preparation of YVO4:Eu 3+ phosphors by the sol-gel methodology. AB - YVO(4):Eu(3+) phosphors have been prepared by the hydrolytic sol-gel methodology, with and without alkaline catalyst. The solid powder was obtained by reaction between yttrium III chloride and vanadium alkoxides; the europium III chloride was used as structural probe. The powder was treated at 100, 400, 600, or 800 degrees C for 4 h. The samples were characterized by X-ray diffraction, thermal analysis, and photoluminescence. The XRD patterns revealed YVO(4) crystalline phase formation for the sample prepared without the catalyst and heat-treated at 600 degrees C and for the sample prepared in the presence of ammonium as catalyst and heat-treated at 100 degrees C. The average nanosized crystallites were estimated by the Scherrer equation. The sample which was produced via alkaline catalysis underwent weight loss in two stages, at 100 and 400 degrees C, whereas the sample obtained without catalyst presented four stages of weight loss, at 150, 250, 400, and 650 degrees C. The excitation spectra of the samples treated at different temperatures displayed the charge transfer band (CTB) at 320 nm. PL data of all the samples revealed the characteristic transition bands arising from the (5)D(0) -> (5)F(J) (J = 0, 1, 2, 3, and 4) manifolds under maximum excitation at 320, 394, and 466 nm in all cases. The (5)D(0) -> (7)F(2) transition often dominates the emission spectra, indicating that the Eu(3+) ion occupies a site without inversion center. The long lifetime suggests that the matrix can be applied as phosphors. In conclusion, the sol-gel methodology is a very efficient approach for the production of phosphors at low temperature. PMID- 22205248 TI - Variability in isopter position and fatigue during semi-automated kinetic perimetry. AB - BACKGROUND: Assessment of factors influencing response variability to repeat presentations of III4e stimuli and the fatigue effect during semi-automated kinetic perimetry (SKP). DESIGN: Prospective case series; setting: university hospital. PARTICIPANTS: 58 patients with severe visual field loss: 21 with glaucoma, 18 with retinitis pigmentosa, and 19 with postchiasmal visual pathway lesions. METHODS: Following initial testing with three isopters (I2e or V4e, I4e and III4e), presentations of the III4e stimulus were repeated four times during the same session along identical vectors. MAIN OUTCOME MEASURES: Variability in III4e-isopter position (scatter of kinetic threshold) and the difference of isopter area between the first and four subsequent sessions (fatigue effect) of SKP were analyzed by diagnosis, age, visual acuity and reaction time (RT). RESULTS: The mean scatter of the kinetic threshold was 2.5 degrees (deg) in the glaucoma group, 1.5 deg in the group with retinitis pigmentosa, and 1.7 deg in the group of patients with postchiasmal lesions. The difference in the isopter area between a single examination and four times repeated examination was 656 square degrees (deg(2)) in the glaucoma group, 104 deg(2) in the retinitis pigmentosa group and 227 deg(2) in the group of patients with postchiasmal lesions. Post-hoc regression analysis revealed that the variability of isopter position increased as the RT increased. CONCLUSION: The variability of III4e isopter positionand fatiguewere most pronounced among glaucoma patients. RT is the most important factor influencing the variability of responses and fatigue during SKP, thus we propose that it can be used as a reliability indicator of SKP. PMID- 22205259 TI - Discrimination of healthy and glaucomatous eyes based on the ocular pulse amplitude: a diagnostic case-control study. AB - By measuring the ocular pulse amplitude (OPA), the dynamic contour tonometer (DCT) assesses intraocular pressure (IOP). Hypothesizing that OPA is characteristic for the IOP when considered with the systemic arterial blood pressure, we assumed the ratio of ocular and arterial pulsation amplitudes is larger in glaucoma patients. Bi-ocular DCT-OPA assessment was synchronized with arterial pulsations using Finapres(r) technology, thereby enabling blood pressure determination for each corresponding IOP value every 0.01 s for 12 s. Based on measurements and calculations in 10 healthy subjects and 11 glaucoma patients, we conclude that the ratio of the OPA and blood pressure variances is a strong glaucoma diagnostic indicator, thereby justifying further investigation. PMID- 22205264 TI - Temporal changes in total serum immunoglobulin E levels in East German children and the effect of potential predictors. AB - BACKGROUND: Elevated total serum immunoglobulin E (IgE) levels are a prominent feature of allergic and parasitic diseases. An epidemiologic study was conducted in East German children to describe trends in the development of total serum IgE levels and analyze the impact of potential determinants. METHODS: The study consisted of three cross-sectional surveys in 1992-1993, 1995-1996 and 1998-1999 and was conducted in three areas of the former German Democratic Republic. In total, 8,051 questionnaires were completed by the parents of children aged 5-14 years, supplying information on allergic symptoms and potential risk factors. A total of 5,918 measurements of total serum IgE and specific IgE to 5 common aeroallergens were available from 4,353 schoolchildren. Generalized estimating equations were applied to data from all children and stratified for atopic and nonatopic children to identify trends and estimate the effect of potential determinants on total IgE. RESULTS: Total serum IgE levels decreased significantly with a linear trend in East German schoolchildren between 1992 and 1999, the effect being stronger in nonatopic children. The following factors were associated with lower total serum IgE levels: female gender, living in a household with fewer than 4 people, no history of helminth infestation, younger age group (5-7 years), no parental allergy and high socioeconomic status. No association was seen for 'smoking at home' and close contact to pets. CONCLUSION: Total serum IgE declined parallel to helminth infestation; however, the latter explained the decrease only in part. Furthermore, total IgE developed in an opposite direction to specific IgE, indicating that it has determinants other than allergic sensitization. PMID- 22205265 TI - The functional MDM2 T309G genetic variant but not P53 Arg72Pro polymorphism is associated with risk of sarcomas: a meta-analysis. AB - PURPOSE: The P53-MDM2 pathway plays a central role in sarcoma pathogenesis. Functional P53 Arg72Pro and MDM2 T309G single-nucleotide polymorphisms (SNP) are considered to have significant effects on risk of sarcomas. METHODS: Several molecular epidemiology studies have evaluated how these genetic variants are involved in sarcoma development, but the conclusions are inconsistent. Therefore, we conducted this meta-analysis to systematically examine the association between these functional SNPs and sarcoma risk. RESULTS: There are four studies eligible for P53 Arg72Pro SNP (466 sarcoma patients and 552 controls), and three studies for MDM2 T309G SNP (355 sarcoma patients and 645 controls). Pooled odds ratios were appropriately calculated using either fixed-effect model or random-effect model. We did not find a significant association between P53 Arg72Pro polymorphism and sarcoma risk. However, in a stratified analysis, a statistically significant correlation between this SNP and osteosarcoma risk was observed. For MDM2 T309G variant, pooled results from the meta-analysis indicate that carriers of TG and GG genotypes showed a 34% increased risk to develop sarcomas compared to TT carriers. CONCLUSION: These results suggest that the functional MDM2 T309G genetic variant may play a more important role in carcinogenesis of sarcoma. PMID- 22205267 TI - Probiotic Lactobacillus paracasei effect on cariogenic bacterial flora. PMID- 22205266 TI - Antimyeloma activity of the sesquiterpene lactone cnicin: impact on Pim-2 kinase as a novel therapeutic target. AB - Despite recent advances in therapy, multiple myeloma, the second most common hematologic tumor in the Western world, is still incurable. Identification of substances that display a wide range of tumor-killing activities and target cancer-specific pathways constitute a basis for the development of novel therapies. In this study, we investigate the cytotoxic effect of the natural substance cnicin in multiple myeloma. Cnicin treatment reveals potent antiproliferative effects and induces cell death in cell lines and primary myeloma cells even in the presence of survival cytokines and the tumor microenvironment. Other cell lines of hematopoietic origin also succumb to cell death whereas stromal cells and endothelial cells are unaffected. We show that activation of caspases, accumulation of reactive oxygen species and downregulation of nuclear factor kappa-light-chain-enhancer of activated B cell contribute to the cytotoxic effects of cnicin. Microarray analysis reveals downregulation of Pim-2, a serine/threonine kinase. We provide evidence that Pim 2 constitutes a new survival kinase for myeloma cells in vitro and is highly expressed in malignant but not in normal plasma cells in vivo. Combining cnicin with current standard or experimental therapeutics leads to enhanced cell death. Thus, our data indicate that cnicin induces myeloma cell death via several pathways and reveals Pim-2 as a novel target. These findings provide a rational for further evaluation of cnicin as a new anti-tumor drug and underline the potential of sesquiterpene lactones in tumor therapy. PMID- 22205268 TI - Long-term outcome of primary non-surgical root canal treatment. AB - AIM: The aim of this study is to examine the survival distributions of primary root canal treatment using interval-censored data and to assess the factors affecting the outcome of primary root canal treatment, in terms of periapical healing and tooth survival. MATERIALS AND METHODS: About one tenth of primary root canal treatment performed between January 1981 and December 1994 in a dental teaching hospital were systematically sampled for inclusion in this study. Information about the patients' personal particulars, medical history, pre operative status, treatment details, and previous review status of the treated teeth, were obtained from dental records. Patients were recalled for examination clinically and radiographically. Treatment outcomes were categorized according to the status for periapical healing and tooth survival. The event time was interval censored and subjected to survival analysis using the Weibull accelerated failure time model. RESULTS: A total of 889 teeth were suitable for analysis. Survival curves of both outcome measures (periapical healing and tooth survival) declined in a non-linear fashion with time. Median survival of the treated teeth was 119 months (periapical healing) and 252 months (tooth survival). Age, tooth type, pre operative periapical status, occlusion, type of final restoration, and condition of the tooth/restoration margin were significant factors affecting both periapical healing and tooth survival. Apical extent and homogeneity of root canal fillings had a significant impact towards periapical healing (p < 0.05), but not tooth survival. CONCLUSION: The longevity of treated teeth based on tooth survival was considerably greater than that of periapical healing. Both outcome measures were affected by a number of socio-demographic, pre-, intra-, and post operative factors. CLINICAL RELEVANCE: Root canal-treated teeth may continue to function for a considerable period of time even though there may be radiographic periapical lesion present. Decision for extraction may be due to reasons other than a failure of the periapical tissues to heal. PMID- 22205270 TI - Intentional homicide: Italy and the United States. PMID- 22205269 TI - Investigation of trefoil factor expression in saliva and oral mucosal tissues of patients with oral squamous cell carcinoma. AB - OBJECTIVES: The aims of our study were to determine levels of trefoil factor (TFF) peptides in saliva and oral mucosal tissues from patients with oral squamous cell carcinoma (OSCC), and to evaluate whether individual members of TFFs (TFF1, TFF2, and TFF3) might act as biomarkers of disease. MATERIALS AND METHODS: Saliva samples were from 23 healthy subjects and 23 OSCC patients. Tissue samples were collected from 32 normal oral mucosa (NOM) and 32 OSCC biopsy specimens. ELISA and immunohistochemical methods were used to evaluate the expression of TFF1, TFF2, and TFF3 in saliva and oral mucosal tissues, respectively. RESULTS: Expression of TFF2 and TFF3 in oral mucosal tissues of OSCC patients was strongly downregulated when compared to healthy subjects (p < 0.001 and p = 0.002, respectively). However, there were no differences in levels of salivary TFF concentrations between OSCC patients and healthy subjects. CONCLUSIONS: The present study extends previous observations, demonstrating the reduction of TFF2 and TFF3 expression in oral mucosal tissues of OSCC patients. CLINICAL RELEVANCE: These findings suggest the clinical significance of TFF2 and TFF3 molecules as negative markers of tumor progression in OSCC. Quantification of TFF levels in saliva may not be optimal in terms of diagnostic or predictive value for OSCC derived from oral mucosa. PMID- 22205271 TI - Targeting leukocyte migration and adhesion in Crohn's disease and ulcerative colitis. AB - Crohn's disease and ulcerative colitis are two chronic inflammatory bowel diseases. Current biologic therapies are limited to blocking tumor necrosis factor alpha. However, some patients are primary non-responders, experience a loss of response, intolerance or side effects defining the urgent unmet need for novel treatments. The rapid recruitment and inappropriate retention of leukocytes is a hallmark of chronic inflammation and a potentially promising therapeutic target. We discuss the immunological mechanisms of leukocyte homing and adhesion in the gut mucosa. The interaction of lymphocytes (CD4+ T-cells, CD8+ T-cells, T(REG), T(H)1, T(H)17, B-cells), monocytes, macrophages, dendritic cells and granulocytes with endothelial and epithelial cells through integrins [alpha4beta7 (LPAM-1), alpha(E)beta7 (HML1 Human Mucosal Lymphocyte Antigen 1), alpha4beta1 (VLA-4), alpha(L)beta7, (LFA-1)] and their ligands immunoglobulin superfamily cellular adhesion molecules (CAM) (MAdCAM-1 Mucosal Addressin Cellular Adhesion Molecule 1, ICAM-1 Intercellular Cell Adhesion Molecule, VCAM-1 Vascular Cell Adhesion Molecule), fibronectin as well as chemokine receptors (CCR2, CCR4, CCR5, CCR7, CCR9, CCR10, CXCR3, CX3CR1) and chemokines [CCL5, CCL25 (TECK Thymus Expressed Chemokine), CCL28, CX3CL1, CXCL10, CXCL12] in the process of gut homing is critically reviewed and summarized in scientific cartoons. Moreover, we discuss the clinical trial results of approved and investigational antibodies and small molecules including natalizumab (anti-alpha4 Tysabri(r), Antegren(r)), AJM300 (anti-alpha4), etrolizumab (anti-beta7, rhuMAb-Beta7), vedolizumab (anti alpha4beta7, LDP-02, MLN-02, MLN0002), PF-00547659 (anti-MAdCAM), Alicaforsen (anti-ICAM-1), and CCX282-B (anti-CCR9, GSK-1605786, Traficet-ENTM) and their risks such as PML reported for natalizumab. Hopefully, the newer gut specific drug designs discussed in this article will have an impact on both efficacy and safety. PMID- 22205272 TI - Autoimmune hepatitis induced by adalimumab with successful switch to abatacept. PMID- 22205273 TI - Role of p38 inhibition in cardiac ischemia/reperfusion injury. AB - The p38 mitogen-activated protein kinases (p38s) are Ser/Thr kinases that are activated as a result of cellular stresses and various pathological conditions, including myocardial ischemia/reperfusion. p38 activation has been shown to accentuate myocardial injury and impair cardiac function. Inhibition of p38 activation and its activity has been proposed to be cardioprotective by slowing the rate of myocardial damage and improving cardiac function. The growing body of evidence on the use of p38 inhibitors as therapeutic means for responding to heart problems is controversial, since both beneficial as well as a lack of protective effects on the heart have been reported. In this review, the outcomes from studies investigating the effect of p38 inhibitors on the heart in a wide range of study models, including in vitro, ex vivo, and in vivo models, are discussed. The correlations of experimental models with practical clinical usefulness, as well as the need for future studies regarding the use of p38 inhibitors, are also addressed. PMID- 22205274 TI - Suspected unexpected adverse effect of sugammadex: hypotension. PMID- 22205275 TI - Do Parkinson's disease patients disclose their adverse events spontaneously? AB - BACKGROUND: Underreporting of adverse drug reactions is common but has been rarely studied in Parkinson's disease (PD). OBJECTIVE: To compare the prevalence of adverse events (AEs) in relation to antiparkinsonian drugs in PD patients using two different data collection methods: patient's spontaneous reporting versus a predefined investigator-driven structured interview. Secondary objectives were to assess factors related to spontaneous reporting and to compare the rate of AE reporting in PD patients with that of a group of non-parkinsonian post-stroke patients. STUDY DESIGN: Cross-sectional study. PATIENTS: Ambulatory, cognitively intact PD or post-stroke outpatients. INTERVENTIONS: None. OUTCOME MEASURES: Patients were first asked by means of an an open question to disclose any unpleasant effects in connection with their current medications that had occurred during the previous week. Afterwards, a predefined questionnaire listing the most common AEs known to be related to antiparkinsonian drugs was used to question the same patients in a systematic manner about the presence of any AE during the same week. Chronological and semiological criteria were used to classify the reported AEs as "unrelated" or "possibly/plausibly related" to the antiparkinsonian treatment. RESULTS: A total of 203 PD and 52 post-stroke patients of comparable age and sex were recruited. Eighty-five PD and five post stroke patients reported spontaneously at least one AE (42 vs. 10%, p < 0.01), while 203 PD and 47 post-stroke patients reported at least one AE following the structured questionnaire (100 vs. 90%, p < 0.001). In PD patients, there were a total of 112 spontaneously reported AEs as compared with 1,574 according to the structured questionnaire (7%). Spontaneous disclosure of AEs was associated with experiencing >2 AEs [OR = 1.2 (1.1-3.2)], logistic regression). Seventy-four percent of PD patients had >=1 AE possibly/plausibly related to antiparkinsonian drugs. CONCLUSIONS: Results showed that only 7% of AEs were reported spontaneously by patients, thus underscoring the importance of systematically asking about AEs in PD patients. PMID- 22205276 TI - Acute toxicity associated with the recreational use of the ketamine derivative methoxetamine. AB - PURPOSE: Long-term regular use of ketamine has been reported to be associated with severe symptomatic urinary tract problems. Methoxetamine, an arylcyclohexylamine derivative of ketamine, is marketed as a "bladder safe" derivative of ketamine, and no cases of acute toxicity following analytically confirmed methoxetamine use have been reported to date. We report here a case series of three individuals with acute toxicity related to the analytically confirmed use of methoxetamine. CASE SERIES: Three patients aged between 28 and 42 years presented to the Emergency Department (ED) on unrelated occasions having used methoxetamine. Clinical features were suggestive of a "dissociative/catatonic" state similar to that seen with ketamine; in addition, they had clinical features of acute sympathomimetic toxicity with significant tachycardia and hypertension. All were managed with low-dose benzodiazepines and discharged home once their symptoms/signs had settled. TOXICOLOGICAL SCREENING: Serum collected at the time of presentation to the ED was analysed qualitatively and quantitatively by gas chromatography-mass spectrometry. Serum concentrations ranged from 0.09 to 0.2 mg/L; in addition, detectable levels of 6-APB/5-APB were found in one of the patients. CONCLUSIONS: These three analytically confirmed cases demonstrate that acute methoxetamine-related toxicity is associated with both "dissociative" and "sympathomimetic" clinical features. The information from these three cases is useful to clinical pharmacologists, not only in managing individuals with acute methoxetamine toxicity but also in advising the appropriate legislative authorities on the risk of acute harm related to methoxetamine use. Further work is needed to determine whether methoxetamine is more "bladder friendly" than ketamine, as has been suggested by those marketing methoxetamine. PMID- 22205277 TI - Protective effects of piperine against corticosterone-induced neurotoxicity in PC12 cells. AB - Hyperactivation of the hypothalamic-pituitary-adrenal axis and the associated hippocampal atrophy were observed in patients with depression, which could be ameliorated by the treatment with antidepressants. Therefore, neuroprotection has been proposed to be one of the acting mechanisms of antidepressant. Our previous studies have showed that treating mice with piperine produced antidepressant-like effect in animal models of behavioral despair. This study aimed to examine the protective effect of piperine treatment on corticosterone-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. The results showed that piperine co-treatment revealed a differential effect on the cytotoxicity of corticosterone and had its maximum inhibitory effect at 1 MUM. Piperine (1 MUM) co-treatment also significantly decreased intracellular reactive oxygen species level, and enhanced superoxide dismutase activity and total glutathione level in corticosterone-treated PC12 cells. In addition, piperine (1 MUM) co-treatment was found to reverse the decreased brain-derived neurotrophic factor (BDNF) mRNA level caused by corticosterone in PC12 cells. The results suggest that piperine exerts a neuroprotective effect on corticosterone-induced neurotoxicity in PC12 cells, at least in part, via the inhibition of oxidative stress and the upregulation of BDNF mRNA expression. This neuroprotective effect may be one of the acting mechanisms accounts for the in vivo antidepressant activity of piperine. PMID- 22205278 TI - STK31(TDRD8) is dynamically regulated throughout mouse spermatogenesis and interacts with MIWI protein. AB - Tudor-domain-containing proteins (TDRDs) are suggested to be critical regulators of germinal granules assembly involved in Piwi-interacting RNAs (piRNAs)-mediated pathways, of which associated components and the underlying functional mechanisms, however, remain to be elucidated. We herein characterized the expression pattern of STK31, a member of TDRDs subfamily (also termed as TDRD8), throughout spermatogenesis during mouse postnatal development. RT-PCR and Western blot verified its preferential expression in testis, but not in any other somatic tissues, in addition to embryonic stem cells. Immunofluorescent staining demonstrated that STK31 was confined to granules-like structures in mid-to-late spermatocyte cytoplasm and to acrosomal cap starting at steps 7-8 of spermatids. Furthermore, STK31 retained its localization to equatorial segment of acrosome during epididymal maturation, capacitation, and acrosome reaction. Co immunoprecipitation assay in vivo and in vitro confirmed MIWI is a bona fide partner of STK31 in mice testes, in combination with LC/MS identification. We also discovered a group of heat shock proteins specifically associated with STK31 in vivo. Our findings suggest mouse STK31 could be a potential nuage-associated protein in the cytoplasm of mid-to-late spermatocytes and play pivotal roles related to fertilization. PMID- 22205279 TI - Comparative analysis of Neph gene expression in mouse and chicken development. AB - Neph proteins are evolutionarily conserved members of the immunoglobulin superfamily of adhesion proteins and regulate morphogenesis and patterning of different tissues. They share a common protein structure consisting of extracellular immunoglobulin-like domains, a transmembrane region, and a carboxyl terminal cytoplasmic tail required for signaling. Neph orthologs have been widely characterized in invertebrates where they mediate such diverse processes as neural development, synaptogenesis, or myoblast fusion. Vertebrate Neph proteins have been described first at the glomerular filtration barrier of the kidney. Recently, there has been accumulating evidence suggesting a function of Neph proteins also outside the kidney. Here we demonstrate that Neph1, Neph2, and Neph3 are expressed differentially in various tissues during ontogenesis in mouse and chicken. Neph1 and Neph2 were found to be amply expressed in the central nervous system while Neph3 expression remained localized to the cerebellum anlage and the spinal cord. Outside the nervous system, Neph mRNAs were also differentially expressed in branchial arches, somites, heart, lung bud, and apical ectodermal ridge. Our findings support the concept that vertebrate Neph proteins, similarly to their Drosophila and C. elegans orthologs, provide guidance cues for cell recognition and tissue patterning in various organs which may open interesting perspectives for future research on Neph1-3 controlled morphogenesis. PMID- 22205280 TI - A case of spontaneous intra-amniotic hemorrhage in an asymptomatic patient at near term pregnancy. AB - A spontaneous intra-amniotic hemorrhage is a very rare condition, which has been previously described in symptomatic patients. We report a case of an asymptomatic spontaneous intra-amniotic hemorrhage at 38 weeks of gestation, resulting in a favorable maternal and neonatal outcome following sonographic antenatal detection of an intra-amniotic blood clot. This pathology should be acknowledged, since a good clinical outcome depends on early diagnosis. PMID- 22205300 TI - Brain insulin signaling and Alzheimer's disease: current evidence and future directions. AB - Insulin receptors in the brain are found in high densities in the hippocampus, a region that is fundamentally involved in the acquisition, consolidation, and recollection of new information. Using the intranasal method, which effectively bypasses the blood-brain barrier to deliver and target insulin directly from the nose to the brain, a series of experiments involving healthy humans has shown that increased central nervous system (CNS) insulin action enhances learning and memory processes associated with the hippocampus. Since Alzheimer's disease (AD) is linked to CNS insulin resistance, decreased expression of insulin and insulin receptor genes and attenuated permeation of blood-borne insulin across the blood brain barrier, impaired brain insulin signaling could partially account for the cognitive deficits associated with this disease. Considering that insulin mitigates hippocampal synapse vulnerability to amyloid beta and inhibits the phosphorylation of tau, pharmacological strategies bolstering brain insulin signaling, such as intranasal insulin, could have significant therapeutic potential to deter AD pathogenesis. PMID- 22205299 TI - Synaptic protein alterations in Parkinson's disease. AB - Alterations occur within distal neuronal compartments, including axons and synapses, during the course of neurodegenerative diseases such as Parkinson's disease (PD). These changes could hold important implications for the functioning of neural networks, especially since research studies have shown a loss of dendritic spines locating to medium spiny projection neurons and impaired axonal transport in PD-affected brains. However, despite ever-increasing awareness of the vulnerability of synapses and axons, inadequate understanding of the independent mechanisms regulating non-somatic neurodegeneration prevails. This has resulted in limited therapeutic strategies capable of targeting these distinct cellular compartments. Deregulated protein synthesis, folding and degrading proteins, and protein quality-control systems have repeatedly been linked with morphological and functional alterations of synapses in the PD affected brains. Here, we review current understanding concerning the proteins involved in structural and functional changes that affect synaptic contact-points in PD. The collection of studies discussed emphasizes the need for developing therapeutics aimed at deregulated protein synthesis and degradation pathways operating at axonal and dendritic synapses for preserving "normal" circuitry and function, for as long as possible. PMID- 22205301 TI - The validity of a reference gene is highly dependent on the experimental conditions in green alga Ulva linza. AB - Normalization based on inappropriate reference gene may lead to the reduction of the accuracy of RT-qPCR. Although determination of suitable reference genes is essential to RT-qPCR studies, reports on the evaluation of reference genes in Ulva linza, a ubiquitous green-tide forming alga, are lacking. The expression levels of ten candidate reference genes were analyzed in U. linza across different experimental treatments, and the best-ranked reference genes differed across the treatments. The most suitable reference genes were tubulin2 (TUB2) among different salinity and UV treatments. Histone 2 (H2) was stably expressed in different temperature and desiccation stress treatments. 18S rRNA exhibited better expression stability in different light intensity treatments. While all tested samples were considered, none of single gene was widely applicable as a reference gene. Moreover, using a combination of two genes as reference genes might improve the reliability of gene expression by RT-qPCR, and the combination of TUB1 and TUB2 was selected as ideal for all tested samples. The results suggest that assessing the stability of reference gene expression patterns, determining candidates, and testing their suitability are required for each experimental investigation. The results will guide the selection of reference genes for gene expression studies in U. linza. PMID- 22205302 TI - Identification of HnRNP-A2/B1 as a target antigen of anti-endothelial cell IgA antibody in Behcet's disease. AB - Behcet's disease (BD) is a chronic, multisystemic vasculitis that theoretically affects all sizes and types of blood vessels. Although pathogenesis remains enigmatic, endothelial cells are believed to be the primary target in this disease. We detected the target protein using western blotting and immunoprecipitation and determined the amino-acid sequence of the peptide by liquid chromatography-matrix assisted laser desorption/ionization-tandem time-of flight analysis (LC-MALDI-TOF/TOF). Serum reactivity against the recombinant target protein was analyzed by immunoblotting. Serum reactivity against streptococcal 65-kD heat shock protein (hsp-65) and the recombinant target protein was investigated by ELISA. The 36-40-kD protein band that was obtained from immunoprecipitation, which was analyzed by LC-MALDI-TOF/TOF, exhibited the amino-acid sequences of heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1). Reactivity of serum IgA against human recombinant hnRNP-A2/B1 was detected in 25 of 30 BD patients (83.3%), 4 of 30 systemic lupus erythematosus patients (13.3%), 8 of 30 rheumatoid arthritis patients (26.7%), 9 of 30 Takayasu's arteritis patients (30%), 6 of 30 healthy controls (20%), and none of 30 IgA nephropathy patients. Optical densities obtained from ELISAs against the recombinant human hnRNP-A2/B1 were correlated with those against the recombinant streptococcal hsp-65.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub. PMID- 22205303 TI - Histone deacetylase 2 is upregulated in normal and keloid scars. PMID- 22205304 TI - Identification of rare, disease-associated variants in the promoter region of the RNF114 psoriasis susceptibility gene. PMID- 22205305 TI - Physical and mental impact of psoriasis severity as measured by the compact Short Form-12 Health Survey (SF-12) quality of life tool. AB - The Short Form-12 Health Survey (SF-12) is used to assess the patient's quality of life (QoL) using the physical component score (PCS) and the mental component score (MCS). The purpose of this study was to determine whether the SF-12 PCS and MCS are associated with psoriasis severity and to compare QoL between Murdough Family Center for Psoriasis (MFCP) patients and patients with other major chronic diseases included in the National Survey of Functional Health Status data. We used data from 429 adult patients enrolled in MFCP. Psoriasis Area Severity Index (PASI) was used to assess psoriasis severity at the time of completion of the SF 12 questionnaire. Other variables included age, sex, body mass index, psoriatic arthritis, psychiatric disorders, and comorbidities. Linear regression models were used to estimate effect sizes +/- 95% confidence intervals. For every 10 point increase in PASI, there was a 1.1 +/- 1.3 unit decrease in MCS (P=0.100) and a 2.4 +/- 1.3 unit decrease in PCS (P<0.001). Psoriasis severity was associated with PCS and MCS after adjusting for variables, although the strength of the relationship was attenuated in some models. Psoriasis severity is associated with decreased QoL. SF-12 may be a useful tool for assessing QoL among psoriasis patients. PMID- 22205307 TI - Effect of reducing the n-6:n-3 long-chain PUFA ratio during pregnancy and lactation on infant adipose tissue growth within the first year of life: an open label randomized controlled trial. AB - BACKGROUND: The composition of long-chain PUFAs (LCPUFAs) in the maternal diet may affect obesity risk in the mother's offspring. OBJECTIVE: We hypothesized that a reduction in the n-6 (omega-6):n-3 (omega-3) LCPUFA ratio in the diet of pregnant women and breastfeeding mothers may prevent expansive adipose tissue growth in their infants during the first year of life. DESIGN: In a randomized controlled trial, 208 healthy pregnant women were randomly assigned to an intervention (1200 mg n-3 LCPUFAs as a supplement per day and a concomitant reduction in arachidonic acid intake) or a control diet from the 15th wk of pregnancy to 4 mo of lactation. The primary outcome was infant fat mass estimated by skinfold thickness (SFT) measurements at 4 body sites at 3-5 d, 6 wk, and 4 and 12 mo postpartum. Secondary endpoints included sonographic assessment of abdominal subcutaneous and preperitoneal fat, fat distribution, and child growth. RESULTS: Infants did not differ in the sum of their 4 SFTs at <=1 y of life [intervention: 24.1 +/- 4.4 mm (n = 85); control: 24.1 +/- 4.1 mm (n = 80); mean difference: -0.0 mm (95% CI: -1.3, 1.3 mm)] or in growth. Likewise, longitudinal ultrasonography showed no significant differences in abdominal fat mass or fat distribution. CONCLUSIONS: We showed no evidence that supplementation with n-3 fatty acids and instructions to reduce arachidonic acid intake during pregnancy and lactation relevantly affects fat mass in offspring during the first year of life. Prospective long-term studies are needed to explore the efficacy of this dietary approach for primary prevention. This trial was registered at clinicaltrials.gov as NCT00362089. PMID- 22205308 TI - Flavonoids [corrected] and blood pressure. PMID- 22205306 TI - 25 years of epidermal stem cell research. AB - This is a chronicle of concepts in the field of epidermal stem cell biology and a historic look at their development over time. The past 25 years have seen the evolution of epidermal stem cell science, from first fundamental studies to a sophisticated science. The study of epithelial stem cell biology was aided by the ability to visualize the distribution of stem cells and their progeny through lineage analysis studies. The excellent progress we have made in understanding epidermal stem cell biology is discussed in this article. The challenges we still face in understanding epidermal stem cells include defining molecular markers for stem and progenitor sub-populations, determining the locations and contributions of the different stem cell niches, and mapping regulatory pathways of epidermal stem cell proliferation and differentiation. However, our rapidly evolving understanding of epidermal stem cells has many potential uses that promise to translate into improved patient therapy. PMID- 22205309 TI - Differential effects of polyphenols and alcohol of red wine on the expression of adhesion molecules and inflammatory cytokines related to atherosclerosis: a randomized clinical trial. AB - BACKGROUND: Few clinical studies have focused on the alcohol-independent cardiovascular effects of the phenolic compounds of red wine (RW). OBJECTIVE: We aimed to evaluate the effects of ethanol and phenolic compounds of RW on the expression of inflammatory biomarkers related to atherosclerosis in subjects at high risk of cardiovascular disease. DESIGN: Sixty-seven high-risk, male volunteers were included in a randomized, crossover consumption trial. After a washout period, all subjects received RW (30 g alcohol/d), the equivalent amount of dealcoholized red wine (DRW), or gin (30 g alcohol/d) for 4 wk. Before and after each intervention period, 7 cellular and 18 serum inflammatory biomarkers were evaluated. RESULTS: Alcohol increased IL-10 and decreased macrophage-derived chemokine concentrations, whereas the phenolic compounds of RW decreased serum concentrations of intercellular adhesion molecule-1, E-selectin, and IL-6 and inhibited the expression of lymphocyte function-associated antigen 1 in T lymphocytes and macrophage-1 receptor, Sialil-Lewis X, and C-C chemokine receptor type 2 expression in monocytes. Both ethanol and phenolic compounds of RW downregulated serum concentrations of CD40 antigen, CD40 ligand, IL-16, monocyte chemotactic protein-1, and vascular cell adhesion molecule-1. CONCLUSION: The results suggest that the phenolic content of RW may modulate leukocyte adhesion molecules, whereas both ethanol and polyphenols of RW may modulate soluble inflammatory mediators in high-risk patients. The trial was registered in the International Standard Randomized Controlled Trial Number Register at http://www.isrctn.org/ as ISRCTN88720134. PMID- 22205310 TI - Maternal phenylketonuria and hyperphenylalaninemia in pregnancy: pregnancy complications and neonatal sequelae in untreated and treated pregnancies. AB - BACKGROUND: Untreated maternal phenylketonuria or hyperphenylalaninemia may result in nonphenylketonuric offspring with neonatal sequelae, especially intellectual disability, microcephaly, and congenital heart disease (CHD). Dietary treatment to control phenylalanine concentrations can prevent these sequelae. OBJECTIVE: We aimed to present an overview of reported pregnancy complications and neonatal sequelae of maternal phenylketonuria or hyperphenylalaninemia in untreated and treated pregnancies. DESIGN: A MEDLINE and EMBASE search was conducted for case reports and case series that assessed maternal phenylketonuria or hyperphenylalaninemia during pregnancy. Pregnancy complications (spontaneous abortion, intrauterine-fetal-death, and preterm delivery) and neonatal sequelae [small for gestational age (SGA), microcephaly, CHD, intellectual or developmental disabilities (IDDs), and facial dysmorphism (FD)] were analyzed. Fifteen unpublished pregnancies from our clinic were added. RESULTS: We retrieved 196 pregnancies, of which 126 pregnancies were untreated and 70 pregnancies were treated. The occurrence of pregnancy complications was not significantly different between untreated and treated pregnancies. Except for SGA, all neonatal sequelae were more frequent in untreated pregnancies. Moreover, the occurrence of SGA, microcephaly, and IDDs was significantly related to the mean phenylalanine concentration in each trimester, whereas the occurrence of FD was related only to the first trimester. CONCLUSIONS: We present the largest cohort of untreated pregnant women with phenylketonuria or hyperphenylalaninemia since 1980. The results follow the general pattern reported by other researchers. We underline that the treatment of pregnant women with phenylketonuria or hyperphenylalaninemia is of great importance to prevent neonatal sequelae. We strongly recommend starting treatment before conception because we showed the deleterious effect of an increased mean first-trimester phenylalanine concentration on FD. PMID- 22205311 TI - Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: a 6-mo randomized intervention study. AB - BACKGROUND: The consumption of sucrose-sweetened soft drinks (SSSDs) has been associated with obesity, the metabolic syndrome, and cardiovascular disorders in observational and short-term intervention studies. Too few long-term intervention studies in humans have examined the effects of soft drinks. OBJECTIVE: We compared the effects of SSSDs with those of isocaloric milk and a noncaloric soft drink on changes in total fat mass and ectopic fat deposition (in liver and muscle tissue). DESIGN: Overweight subjects (n = 47) were randomly assigned to 4 different test drinks (1 L/d for 6 mo): SSSD (regular cola), isocaloric semiskim milk, aspartame-sweetened diet cola, and water. The amount of intrahepatic fat and intramyocellular fat was measured with (1)H-magnetic resonance spectroscopy. Other endpoints were fat mass, fat distribution (dual-energy X-ray absorptiometry and magnetic resonance imaging), and metabolic risk factors. RESULTS: The relative changes between baseline and the end of 6-mo intervention were significantly higher in the regular cola group than in the 3 other groups for liver fat (132-143%, sex-adjusted mean; P < 0.01), skeletal muscle fat (117-221%; P < 0.05), visceral fat (24-31%; P < 0.05), blood triglycerides (32%; P < 0.01), and total cholesterol (11%; P < 0.01). Total fat mass was not significantly different between the 4 beverage groups. Milk and diet cola reduced systolic blood pressure by 10-15% compared with regular cola (P < 0.05). Otherwise, diet cola had effects similar to those of water. CONCLUSION: Daily intake of SSSDs for 6 mo increases ectopic fat accumulation and lipids compared with milk, diet cola, and water. Thus, daily intake of SSSDs is likely to enhance the risk of cardiovascular and metabolic diseases. This trial is registered at clinicaltrials.gov as NCT00777647. PMID- 22205312 TI - Dietary patterns and ethnicity are associated with distinct plasma proteomic groups. AB - BACKGROUND: High-abundance plasma proteins are involved in disease-associated pathways and are useful in the diagnosis of nutritional and disease states. However, little is known about how concentrations of many plasma proteins vary between individuals from different ethnocultural groups with different dietary habits. OBJECTIVE: We explored the association between plasma proteomic groups, dietary patterns, and ethnicity in the Toronto Nutrigenomics and Health Study, an ethnically diverse population of healthy young adults. DESIGN: Concentrations of 54 high-abundance plasma proteins were measured simultaneously by liquid chromatography/multiple-reaction monitoring-mass spectrometry in 1090 individuals. Principal components analysis was used to identify plasma proteomic groups. Linear regression was used to investigate relations between proteomic groups and previously identified dietary patterns (Western, prudent, Eastern). Differences in individual protein concentrations between ethnocultural groups were tested by using general linear models. RESULTS: Four independent principal components representative of proteomic groups were identified. Principal components 1 and 2 included proteins from multiple pathways. Component 3 was inflammatory, and component 4 included coagulation cascade proteins. East Asians and South Asians had lower component 1 scores, and East Asians had higher component 2 scores. South Asians had higher average scores for component 3. Individual protein concentrations also varied across ethnocultural groups. Principal component 1 was positively associated with the Western dietary pattern and inversely associated with the Eastern pattern. Component 3 was positively associated with the Eastern pattern. CONCLUSIONS: Plasma proteomic groups differ between young adults of diverse ethnocultural groups with different dietary habits. These differences may partly account for different rates of cardiometabolic disease later in life. PMID- 22205313 TI - Dietary magnesium intake and risk of stroke: a meta-analysis of prospective studies. AB - BACKGROUND: Prospective studies of dietary magnesium intake in relation to risk of stroke have yielded inconsistent results. OBJECTIVE: We conducted a dose response meta-analysis to summarize the evidence regarding the association between magnesium intake and stroke risk. DESIGN: Relevant studies were identified by searching PubMed and EMBASE from January 1966 through September 2011 and reviewing reference lists of retrieved articles. We included prospective studies that reported RRs with 95% CIs of stroke for >=3 categories of magnesium intake. Results from individual studies were combined by using a random-effects model. RESULTS: Seven prospective studies, with 6477 cases of stroke and 241,378 participants, were eligible for inclusion in the meta-analysis. We observed a modest but statistically significant inverse association between magnesium intake and risk of stroke. An intake increment of 100 mg Mg/d was associated with an 8% reduction in risk of total stroke (combined RR: 0.92; 95% CI: 0.88, 0.97), without heterogeneity among studies (P = 0.66, I(2) = 0%). Magnesium intake was inversely associated with risk of ischemic stroke (RR: 0.91; 95% CI: 0.87, 0.96) but not intracerebral hemorrhage (RR: 0.96; 95% CI: 0.84, 1.10) or subarachnoid hemorrhage (RR: 1.01; 95% CI: 0.90, 1.14). CONCLUSION: Dietary magnesium intake is inversely associated with risk of stroke, specifically ischemic stroke. PMID- 22205314 TI - Exploration of the safe upper level of iodine intake in euthyroid Chinese adults: a randomized double-blind trial. AB - BACKGROUND: The beneficial health effects associated with Universal Salt Iodization are well known. Yet, little is known about the possible adverse health effects in people with high iodine intake and the safe daily intake upper limit in the Chinese population. OBJECTIVE: The objective of this study was to explore the safe upper level of total daily iodine intake among adults in China. DESIGN: A 4-wk, double-blind, placebo-controlled, randomized controlled trial was conducted in 256 euthyroid adults. Participants were randomly assigned to 12 intervention groups with various iodine supplement doses ranging from 0 to 2000 MUg/d. Total iodine intake included iodine from both supplements and diet. Multiple outcome measures were used to evaluate possible adverse effects, including thyroid function, thyroid size, and urinary iodine. RESULTS: The mean iodine intake from the diets and salt intake of the participants were 105 +/- 25 and 258 +/- 101 MUg/d, respectively. In comparison with the placebo group, all iodide-supplemented groups responded with significant increases in median urinary iodine concentrations (P < 0.05) and in thyroid-stimulating hormone concentration (P < 0.05). Thyroid volume decreased after 4 wk in the high-iodine intervention groups (1500-2000 MUg). Subclinical hypothyroidism appeared in the groups that received 400 MUg I (5%) and 500-2000 MUg I (15-47%). CONCLUSIONS: This study showed that subclinical hypothyroidism appeared in the participants who took the 400-MUg I supplement, which provided a total iodine intake of ~800 MUg/d. Thus, we caution against a total daily iodine intake that exceeds 800 MUg/d in China and recommend further research to determine a safe daily upper limit. PMID- 22205315 TI - Serving smaller age-appropriate entree portions to children aged 3-5 y increases fruit and vegetable intake and reduces energy density and energy intake at lunch. AB - BACKGROUND: Previous portion size research in children has focused on the impact of large entree portions on children's intake, but less attention has been given to how intake at a meal is affected across a broader range of entree portions. OBJECTIVE: The objective was to assess the effect of serving a range of entree portions on children's ad libitum intake and energy density consumed at the meal. DESIGN: A within-subject design was used to examine the effect of varying entree portions (ie, 100, 160, 220, 280, 340, and 400 g) on children's ad libitum energy intake of macaroni and cheese and fixed portions of unsweetened applesauce, green beans, and whole-wheat roll served with the entree. Seventeen children (10 girls), aged 3 to 6 y, were served a series of 6 lunches, which varied only in entree portion size, once per week. Weight, height, and weighed food intake were measured. RESULTS: Increasing portion size increased children's entree intake (P < 0.01) and decreased intake of other foods served with the entree, including fruit and vegetables (P < 0.0001). As a result, children consumed a more-energy dense (kcal/g) lunch as portion size increased (P < 0.0001). Further examination showed that BMI percentile moderated the positive association between portion size and entree intake (P < 0.01); overweight children showed greater increases in entree intake with increasing entree portion. CONCLUSION: Serving smaller age appropriate entree portions may be one strategy to improve children's nutritional profile by decreasing intake of energy-dense foods and by promoting intake of fruit and vegetables served with the entree. PMID- 22205316 TI - Intact sensory function in anorexia nervosa. AB - BACKGROUND: In anorexia nervosa (AN), taste and smell are believed to be anhedonic, hunger and pain are muted, and body-image distortion obscures wasting, which together facilitate self-starvation. However, the emphasis on these deficits may be biased because other sensory systems have been sparsely investigated. OBJECTIVES: Objectives of the study were to clarify whether these dysfunctions are specific or part of a pattern of sensory-perceptual deficits in AN patients and to test the gustatory senses dissociated from ingestion to clarify whether any deficit is sensory or affective. DESIGN: In 15 adolescent, first-episode, hospitalized, restrictive AN patients and 15 matched healthy controls who responded to gustatory stimuli (intensity and hedonics of 5 basic tastes and tastes and odors of foods and nonfoods), size estimation (manual and oral judgment of size and shape, kinesthesia, and body size and esthetics), cold pain, and auditory and visual processing were compared. RESULTS: AN patients did not differ on most tests, were better at odor recognition, were less successful in central auditory processing and oral assessment of size and shape, and may have been more sensitive to cold. Body-image dissatisfaction in AN patients was not related to dysfunctional size estimation. CONCLUSIONS: There is no systematic sensory-perceptual deficit in AN patients, and specifically, not in gustatory function. The few differences shown might be due to fear of food-related stimuli or comorbidity. PMID- 22205317 TI - Effect of titrated parenteral nutrition on body composition after allogeneic hematopoietic stem cell transplantation in children: a double-blind, randomized, multicenter trial. AB - BACKGROUND: Children undergoing hematopoietic stem cell transplantation (HSCT) often require parenteral nutrition (PN) to optimize caloric intake. Standard approaches to nutritional supplementation provide 130-150% of estimated energy expenditure, but resting energy expenditure (REE) may be lower than expected after HSCT. Provision of PN exceeding energy needs may lead to overfeeding and associated complications. OBJECTIVE: We conducted a blinded, randomized, controlled, multicenter trial in children undergoing HSCT to determine the effect on body composition of 2 different approaches of nutrition support: standard amounts of energy from PN (130-150% of REE) compared with PN titrated to match measured REE. DESIGN: Twenty-six children undergoing HSCT were randomly assigned to standard or titrated PN. Energy intake was monitored until day 30 after HSCT. Body-composition and anthropometric measures were obtained through day 100. The primary outcome variable was percentage body fat (%BF) measured by dual energy X ray absorptiometry. RESULTS: The estimated change in %BF from baseline to day 30 was 1.2 +/- 0.5% in the standard group and 0.1 +/- 0.5% in the experimental group, but the overall time course of %BF did not differ significantly by treatment (P = 0.39 for time * treatment interaction). A profound loss of lean body mass (LBM) occurred in both groups during the intervention period and persisted through day 100. CONCLUSIONS: Parenteral energy intake titrated to energy expenditure does not result in a lower accumulation of BF than does standard energy intake. Neither titrated nor standard PN regimens during HSCT preserve LBM. Alternative approaches to preserve LBM are needed. This trial is registered at clinicaltrials.gov as 00115258. PMID- 22205318 TI - What do we really know about the health effects of natural sources of trans fatty acids? PMID- 22205319 TI - Randomized controlled study of the effect of a butter naturally enriched in trans fatty acids on blood lipids in healthy women. AB - BACKGROUND: Whereas the negative effect of consuming trans fatty acids found in partially hydrogenated vegetable oils on cardiovascular disease (CVD) risk is well established, the effect of trans fatty acids from ruminant sources (rTFAs) on CVD risk factors has not yet been established, particularly among women. OBJECTIVE: We investigated the effects of a butter naturally enriched in rTFAs, of which vaccenic acid is the predominant isomer, on plasma lipid concentrations among healthy women. DESIGN: In a double-blind, randomized, crossover controlled study, 61 healthy women aged 19-70 y were fed 2 isoenergetic diets lasting 4 wk each. The 2 diets were defined as moderately high in rTFAs (3.7 g/d, 1.5% of daily energy) and control (0.9 g/d, 0.3% of daily energy). RESULTS: No significant effect of the rTFA diet was found on total plasma cholesterol, LDL cholesterol, apolipoprotein B, apolipoprotein A-I, and triglyceride concentrations compared with the control diet. There was a small yet statistically significant reduction in plasma HDL-cholesterol concentrations with the rTFA diet (-2.8%; P = 0.004), which was significant (P for the BMI * treatment interaction = 0.006) among women with a BMI (in kg/m(2)) >=25 (-5.2%; P = 0.004; n = 18) but not among women with a BMI <25 (-1.2%; P = 0.13; n = 43). CONCLUSIONS: These results suggest that an increase in dietary rTFAs equivalent to ~1% of daily energy has no significant effect on LDL but may be associated with a reduction in plasma HDL-cholesterol concentrations, particularly in overweight women. This trial is registered at clinicaltrials.gov as NCT00930137. PMID- 22205320 TI - Isolation of thermo-stable and solvent-tolerant Bacillus sp. lipase for the production of biodiesel. AB - This study presents the production of biodiesel from algae oil by transesterification using thermophilic microorganism. The microorganism used in this study was isolated from the soil sample obtained near the furnace. The organism was identified as Bacillus sp., and the lipase obtained was purified by ammonium sulfate precipitation and ion exchange chromatography leading to 8.6 fold purification and 13% recovery. Molecular weight of the enzyme was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and it was found to be 45 kDa. The effect of pH, temperature, and solvent addition on lipase activity was investigated. The enzyme showed maximum activity at 55 degrees C and at pH 7 and was also found to be highly active in the presence of organic solvents such as hexane and t-butanol. The isolated lipase was successfully used for the production of biodiesel. The transesterification activity of the isolated lipase showed 76% of fatty acid methyl esters yield in 40 h, which indicated that this enzyme can be used as a potential biocatalyst for the biodiesel production. PMID- 22205321 TI - Amentoflavone inhibits UVB-induced matrix metalloproteinase-1 expression through the modulation of AP-1 components in normal human fibroblasts. AB - Amentoflavone is a well-known biflavonoid that has diverse biological effects. Previously, we reported that amentoflavone suppressed UVB-induced matrix metalloproteinase-1 (MMP-1) expression in normal human fibroblasts (NHF). We investigated the effects of amentoflavone on UVB-induced MMP-1 expression in order to elucidate its mode of action. NHF were treated with amentoflavone for indicated times and doses with UVB irradiation. The expressions of MMP-1 gene and protein were determined by RT-PCR and ELISA, respectively. MAP kinase phosphorylation and the expression of c-Fos protein were determined by Western blot. The treatment of amentoflavone completely blocked the upregulation of MMP-1 which is induced by UVB irradiation in HaCaT-NHF co-culture in a dose-dependent manner as well as in NHF monoculture. Also, amentoflavone inhibited UVB-induced activation of extracellular signal-regulated kinase (ERK) without changing total ERK protein level, and did not affect p38 or JNK activation. Finally, AP-1 transcription factor components, phospho-c-Jun and c-Fos protein expressions were decreased by amentoflavone treatment. The major finding of this study shows that amentoflavone inhibits intracellular cell signaling ERK pathway leading to the prevention of MMP-1 expression in human skin fibroblasts. Therefore, these results strongly suggest that amentoflavone should be investigated as a potential agent for the prevention and the treatment of skin photoaging. PMID- 22205322 TI - Biogas production potential and kinetics of microwave and conventional thermal pretreatment of grass. AB - Pretreatment methods play an important role in the improvement of biogas production from the anaerobic digestion of energy grass. In this study, conventional thermal and microwave methods were performed on raw material, namely, Pennisetum hybrid, to analyze the effect of pretreatment on anaerobic digestion by the calculation of performance parameters using Logistic function, modified Gompertz equation, and transference function. Results indicated that thermal pretreatment improved the biogas production of Pennisetum hybrid, whereas microwave method had an adverse effect on the performance. All the models fit the experimental data with R (2) > 0.980, and the Reaction Curve presented the best agreement in the fitting process. Conventional thermal pretreatment showed an increasing effect on maximum production rate and total methane produced, with an improvement of around 7% and 8%, respectively. With regard to microwave pretreatment, maximum production rate and total methane produced decreased by 18% and 12%, respectively. PMID- 22205323 TI - Rapid establishment of p-nitrophenol biodegradation in acetate-fed aerobic granular sludge. AB - The aim of the study was to investigate the acclimation of precultivated acetate fed aerobic granular sludge to a toxic xenobiotic biodegradation. Establishment of p-nitrophenol (PNP) biodegradation in acetate-fed aerobic granular sludge and concomitant changes in the microstructure and bacterial community were determined. Rapid establishment of PNP utilization was observed in the granular sludge when fed with PNP as the sole carbon source. The specific PNP removal was 36-mg h(-1) g(-1) granular biomass at an initial PNP concentration of 50 mg L( 1). The presence of PNP resulted in significant membrane damage in a subpopulation of the bacterial consortium, as shown by BacLight viability staining. This was coincided with a significant decrease in the culturable bacterial diversity of the granular biomass. PCR-DGGE analysis revealed a shift and decrease in number of bands during the establishment of PNP biodegradation. Scanning electron microscopy showed the dominance of rod-shaped bacteria in the PNP-utilizing microbial granules. Our results suggest that acetate-fed granular sludge could be quickly adapted for PNP biodegradation. PMID- 22205324 TI - Rural residence and adoption of a novel HIV therapy in a national, equal-access healthcare system. AB - Rural persons with HIV face barriers to care that may influence adoption of advances in therapy. We performed a retrospective cohort study to determine rural urban variation in adoption of raltegravir-the first HIV integrase inhibitor-in national Veterans Affairs (VA) healthcare. There were 1,222 veterans with clinical indication for raltegravir therapy at time of its FDA approval in October 2007, of whom 223 (19.1%) resided in rural areas. Urban persons were more likely than rural to initiate raltegravir within 180 days (17.3% vs. 11.2%, P = 0.02) and 360 days (27.5% vs. 19.7%, P = 0.02), but this gap narrowed slightly at 720 days (36.3% vs. 31.8%, P = 0.19). In multivariable analysis adjusting for patient characteristics, urban residence predicted raltegravir adoption within 180 days (odds ratio 1.72, 95% CI 1.09-2.70) and 360 days (OR 1.63, 95% CI 1.13 2.34), but not 720 days (OR 1.26, 95% CI 0.84-1.87). Efforts are needed to reduce geographic variation in adoption of advances in HIV therapy. PMID- 22205325 TI - The difference in self-reported and biological measured HIV prevalence: implications for HIV prevention. AB - In Australia, HIV prevalence estimates among gay men have been mainly based on self-reported HIV status collected in annual behavioural surveys. We measured biological HIV prevalence among gay men in Melbourne, Australia, using a facility based sampling method. We calculated HIV prevalence and used logistic regression to assess correlates of a positive HIV test. A total of 639 gay men were recruited completed a survey and provided oral fluid for HIV testing from seven venues in 2008. The median age of the participants was 35 years (range 18-75 years). Overall biological HIV prevalence was 9.5% (95% CI 7.5-12.0%) compared with 6.3% (95% CI 4.5-8.4%) for self-reported HIV positive status. We found a significant discrepancy between test detected biological and self-report HIV status in our study, with 19 men (31.1%) unaware of their HIV infection. These results highlight the importance of repeatable biological estimates to inform and evaluate HIV prevention strategies. PMID- 22205327 TI - Organizing and investing to expand primary care availability with nurse practitioners. PMID- 22205326 TI - Risk factors for disease progression in advanced jejunoileal neuroendocrine tumors. AB - BACKGROUND: Knowledge of clinical course in advanced jejunoileal neuroendocrine tumors (NETs) is poor. AIM: To investigate progression-free survival (PFS), overall survival (OS), and possible predictors for disease progression (DP) in advanced jejunoileal NETs. PATIENTS AND METHODS: We carried out a multicenter, retrospective analysis of incoming patients with sporadic advanced jejunoileal NETs. PFS and OS were assessed by Kaplan-Meier analysis. Risk factors for progression were analyzed by the Cox proportional hazards method. RESULTS: Of the 114 patients enrolled, 46.5% had functioning tumors, 93.9% had stage IV disease, and 57.3 and 42.7% were G1 and G2 tumors, respectively. During a median follow-up of 48 months (interquartile range 29-84 months), DP occurred in 61.4% of patients, after 19 months (interquartile range 10-41 months) from diagnosis. Median PFS was 36 months. The 2-year and 5-year PFS were 59 and 33%, respectively, while 5-year OS was 77.5%. Ki67 was the sole strong independent risk factor for unfavorable outcome according to multivariate analysis, being significantly associated with both PFS and OS. CONCLUSIONS: DP occurred in the majority of patients with advanced jejunoileal NETs, with median PFS being 36 months. Ki67 was a significant predictor of DP and should be considered in determining appropriate treatments and planning follow-up for these patients. PMID- 22205338 TI - Bifidobacterium bifidum NCC 453 promotes tolerance induction in murine models of sublingual immunotherapy. AB - BACKGROUND: Enhancing clinical efficacy remains a major goal in allergen-specific immunotherapy. In this study, we tested three strains of bifidobacteria as candidate adjuvants for sublingual allergy vaccines. METHODS: Probiotic candidates were evaluated in human monocyte-derived dendritic cell (h-DC) maturation and CD4(+) T-cell polarization in vitro models and further tested in murine models of sublingual immunotherapy in BALB/c mice sensitized to either ovalbumin or birch pollen. RESULTS: Bifidobacterium adolescentis, B. bifidum and B. longum induced h-DC maturation and polarized naive CD4(+) T cells toward interferon-gamma and interleukin-10 production. B. bifidum increased CD25(high), Foxp3(+) cells within CD4(+) T lymphocytes and was the most potent inducer of interferon-gamma in Th2-skewed peripheral blood mononuclear cells and h-DC T-cell cocultures. It also induced a significant decrease in airway hyperresponsiveness in BALB/c mice sensitized to ovalbumin. Sublingual administration of B. bifidum together with recombinant Bet v 1 enhanced tolerance induction in BALB/c mice sensitized to birch pollen, with a downregulation of both airway hyperresponsiveness, lung inflammation and Bet v 1-specific Th2 responses. CONCLUSIONS: Due to its capacity to reorient established Th2 responses toward Th1/regulatory T-cell profiles, B. bifidum represents a valid candidate adjuvant for specific immunotherapy of type I allergies. PMID- 22205339 TI - Semi-automatic quantitative measurements of intracranial internal carotid artery stenosis and calcification using CT angiography. AB - INTRODUCTION: Intracranial carotid artery atherosclerotic disease is an independent predictor for recurrent stroke. However, its quantitative assessment is not routinely performed in clinical practice. In this diagnostic study, we present and evaluate a novel semi-automatic application to quantitatively measure intracranial internal carotid artery (ICA) degree of stenosis and calcium volume in CT angiography (CTA) images. METHODS: In this retrospective study involving CTA images of 88 consecutive patients, intracranial ICA stenosis was quantitatively measured by two independent observers. Stenoses were categorized with cutoff values of 30% and 50%. The calcification in the intracranial ICA was qualitatively categorized as absent, mild, moderate, or severe and quantitatively measured using the semi-automatic application. Linear weighted kappa values were calculated to assess the interobserver agreement of the stenosis and calcium categorization. The average and the standard deviation of the quantitative calcium volume were calculated for the calcium categories. RESULTS: For the stenosis measurements, the CTA images of 162 arteries yielded an interobserver correlation of 0.78 (P < 0.001). Kappa values of the categorized stenosis measurements were moderate: 0.45 and 0.58 for cutoff values of 30% and 50%, respectively. The kappa value for the calcium categorization was 0.62, with a good agreement between the qualitative and quantitative calcium assessment. CONCLUSIONS: Quantitative degree of stenosis measurement of the intracranial ICA on CTA is feasible with a good interobserver agreement ICA. Qualitative calcium categorization agrees well with quantitative measurements. PMID- 22205340 TI - Trans-radial embolization of epistaxis in patients with end-stage liver disease. AB - INTRODUCTION: Endovascular treatment of epistaxis in patients with bleeding disorders is challenging due to the intrinsic risk of hemorrhagic complication related to the arterial access. We describe the use of trans-radial approach for the endovascular embolization of epistaxis due to end-stage liver disease and resultant severe coagulopathy. METHODS: Two patients waiting for liver transplant continued to have epistaxis despite the aggressive correction of the coagulopathy and nose packing. After performing the Allen's test, trans-radial embolization of the epistaxis was performed in both patients. RESULTS: The complete cessation of epistaxis was achieved after the trans-radial embolization of bilateral maxillary arteries with particles. The radial access sites were manually compressed for 1 h, followed by a compression dressing for 12 h. The cessation of the epistaxis helped the subsequent treatment of correcting the coagulopathy. There was no complication related to the arterial puncture. CONCLUSION: Trans-radial embolization for epistaxis was a safe and effective method for the patient with end-stage liver disease and resultant severe coagulopathy. PMID- 22205341 TI - Mental health and patterns of work-related coping behaviour in a German sample of student teachers: a cross-sectional study. AB - PURPOSE: The aim of this cross-sectional study was to evaluate the mental health of student teachers, to analyse the extent to which they feel prepared for their profession by the university curriculum and to investigate patterns of coping with occupational stress. METHODS: A sample of 481 German student teachers was investigated using two standardised instruments: GHQ-12 (General Health Questionnaire) and AVEM (Arbeitsbezogenes Verhaltens- und Erlebensmuster), an occupational stress and coping questionnaire describing four patterns of work related coping behaviour. In addition, we asked how well the student teachers felt that the curriculum prepared them for their profession. RESULTS: Forty-four per cent of the student teachers report impaired mental health in the second teacher training period, indicated by a GHQ value equal to or over the cut-off of four. The AVEM responses revealed more than 40% showing risk patterns (A or B) compared to only 26.3% displaying a healthy coping style (G), while 32.8% demonstrate an unambitious style (S). These GHQ values are inversely correlated with the extent to which student teachers feel prepared for their work by the university curriculum. CONCLUSIONS: Our data indicate a problematic stress level for student teachers in the second training phase (high exposure to health risks and unfavourable coping styles). Since teaching is clearly an extremely demanding job, it is vital that teacher training systems contribute towards protecting the health of teachers by focusing on fostering healthy personal attitudes and equipping young teachers with coping styles and skills that will better prepare them for the challenges facing them in their daily work. Self-care health management should also be part of the teacher training curriculum. PMID- 22205342 TI - The role of tyramine and octopamine in the regulation of reproduction in queenless worker honeybees. AB - In honeybees, workers under queenless condition compete for reproduction and establish reproductive dominance hierarchy. Ovary activation is generally accompanied by the expression of queen-like pheromones. Biogenic amines (BAs), in particular dopamine, are believed to be involved in this process by regulating ovarian development. However, the role of BAs in establishing reproductive dominance or their effect on queen-like pheromone production was not investigated. Here, we explored the effect of octopamine (OA) and tyramine (TA) oral treatments on the propensity of treated bees to become reproductively dominant and produce queen-like pheromones in Dufour's and mandibular glands. One bee in a pair was treated with either OA or TA while the other was fed sugar solution. TA was found to enhance ovary development and the production of esters in the Dufour's gland and 9HDA (queen component) in the mandibular glands, thus facilitating worker reproductive dominance. OA, on the other hand, did not enhance ovarian development or ester production, but increased the production of 10HDA (worker major component) in the mandibular glands of their sugar-paired mates. OA is known to induce foraging behavior by workers, while increased production of 10HDA characterizes nursing workers. Therefore, we suggest that TA induces reproductive division of labor, while OA treatment results in caste differentiation of workers to foragers and nurses. PMID- 22205343 TI - Prevalence of the insulin receptor substrate-1(IRS-1) Gly972Arg and the insulin receptor substrate-2(IRS-2) Gly1057Asp polymorphisms in PCOS patients and non diabetic healthy women. AB - OBJECTIVE: The aim of our study was to investigate the frequency and compare the prevalence of IRS-1Gly972Arg and IRS-2 Gly1057Asp polymorphisms in PCOS patients and non-diabetic healthy women. MATERIAL(S) AND METHOD(S): Forty eight Iranian women diagnosed with PCOS were enrolled in this study. Fifty two non-diabetics, non-PCOS women were enrolled as the control group. HemoglobinA1c (HbA1c), fasting blood glucose (FBS), fasting insulin levels (FIL) and 2 h post-prandial blood glucose(2hpp BS) were evaluated from blood samples. Insulin resistance sample was estimated with Homeostasis Model Assessment index for insulin resistance (HOMA IR). Genotyping of allelic variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 was conducted using PCR. RESULTS: No statistically significant differences in the prevalence of IRS-1 Gly972Arg or IRS-2 Gly1057Asp polymorphisms or any combination of both were observed between controls and PCOS patients (P > 0.02). Control subjects with the IRS-1 polymorphism had higher levels of 2hpp BS compared with those with the Gly/Gly genotype (P = 0.037). CONCLUSIONS: Considering that no association between the IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymorphisms and PCOS were found, the results confirm that these polymorphisms should not be considered as major contributors to the pathogenesis of this disorder. PMID- 22205344 TI - Ovarian stimulation and embryo banking for fertility preservation in a woman with severe mixed connective tissue disease: Is it safe? AB - OBJECTIVE: To report the first case of using assisted reproductive technologies (ART) for fertility preservation in a patient with mixed connective tissue disease (MCTD), secondary pulmonary hypertension (PH) and antiphospholipid syndrome (APS). DESIGN: Case-report and review of the literature. SETTING: Academic infertility practice and tertiary care center. PATIENT(S): A 25-year-old woman with MCTD, complicated with PH and APS, who was scheduled for gonadotoxic therapy INTERVENTION(S): Controlled ovarian hyperstimulation, egg retrieval, embryo banking. MAIN OUTCOME MEASURE(S): Successful ART cycle leading to embryo banking without worsening her underlying disease. RESULT(S): Following successful embryo cryopreservation, the patient experienced respiratory failure and other severe complications, resulting in a prolonged hospital stay. CONCLUSION(S): Controlled ovarian hyperstimulation for embryo banking in women with MCTD, PH and APS may pose a risk for potentially catastrophic complications. A multidisciplinary approach to these patients is necessary to optimize the outcomes of such procedures. More data are needed regarding the safety of fertility preservation technologies in patients with complex medical diseases. PMID- 22205345 TI - New brain-specific beta-synuclein isoforms show expression ratio changes in Lewy body diseases. AB - Lewy body diseases (LBDs) include dementia with Lewy bodies (DLB) and Parkinson disease (PD). Alpha-synuclein (AS) aggregation is a key event in the pathogenesis of LBDs and beta-synuclein (BS) inhibits AS aggregation in vitro and in vivo. Recently, BS has been shown to interact directly with AS regulating its functionality and preventing its oligomerization, and a molecular subgroup of pure DLB lacks BS in cortical regions. In this study, we characterized four new BS transcript variants and analyzed their expression in neuronal and non-neuronal tissue, and their differential expression in frozen samples of three areas from brains of patients with pure Lewy body pathology (LBP), common LBP, Alzheimer pathology, and of controls. Relative mRNA expression was determined by real-time PCR with neuron-specific enolase 2 and synaptophysin as housekeeping genes, and expression changes were evaluated by the DeltaDeltaCt method. Two main findings are in concordance with earlier studies. First, all BS isoforms are drastically diminished in the cortex of patients with pure LBP that had presented clinically as DLB but not PD with dementia. Second, an important shift of the isoform expression ratio was observed in the temporal cortex of all LBD cases, and the minor isoforms, normally absent in the midbrain, were detected in the caudate nucleus of all DLB samples. Our results provide further evidence for the role of minor transcript variants in the development of complex diseases and provide new insights into the pathogenesis of LBDs that may be important for the understanding of molecular mechanisms involved in these complex diseases. PMID- 22205346 TI - Retinal micropseudocysts in diabetic retinopathy: prospective functional and anatomic evaluation. AB - AIM: To evaluate the prevalence, progression and functional predictive value of retinal micropseudocysts (MPCs) in diabetic patients. METHODS: Prospective controlled observational study. From among all the type 2 diabetic patients evaluated during a period of 5 months between September 2009 and January 2010, we enrolled all patients with retinal MPCs at spectral-domain scanning laser ophthalmoscope/optical coherence tomography (SD-SLO/OCT) not previously treated for diabetic retinopathy. Forty diabetic patients without MPCs served as the control group. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), macular sensitivity and stability of fixation at SD-SLO/OCT microperimetry were measured monthly for 12 months. RESULTS: 22/156 patients with type 2 diabetes (14.1%, 32 eyes) met the inclusion criteria. The 95% confidence interval for the prevalence estimate of MPCs was 12.3-16.6%. Mean BCVA, CRT and central retinal sensitivity at baseline were 77.53 +/- 2.2 Early Treatment Diabetic Retinopathy Study letters, 242.31 +/- 31.0 um and 15.95 +/- 0.61 dB, respectively. Fixation was stable in all cases. Compared to the control group, eyes with MPCs had similar BCVA but greater CRT (p = 0.01) and reduced macular sensitivity (p = 0.001) at baseline and at each follow-up visit. Over time, CRT remained stable in eyes with MPCs, whereas macular sensitivity progressively decreased. CONCLUSION: MPCs in diabetic retinopathy are associated, temporally or causally, with a progressive reduction of macular sensitivity despite a stable BCVA, CRT and fixation. PMID- 22205347 TI - Molluscicidal activity of some marine substances against the snail Biomphalaria glabrata (Mollusca, Planorbidae). AB - Freshwater snails of the genus Biomphalaria play a major role as intermediate hosts of Schistosoma mansoni, the etiologic agent of schistosomiasis. While Biomphalaria spp. control by molluscicides is one of the main strategies to reduce the snail population in infected areas, there are few effective molluscicides commercially available. Natural products may be considered as potentially useful and safe molluscicides. We have evaluated the molluscicidal activity of 12 extracts from ten marine organisms on adult and embryonic stages of Biomphalaria glabrata. Only extracts of the red algae Liagora farinosa and of the sponge Amphimedon viridis presented molluscicidal activity. Lethal concentration (LC)(50) values obtained were 120 MUg/mL for L. farinosa CH(2)Cl(2) extract (apolar fraction) and 20 MUg/mL for A. viridis extract and halitoxin. The polar alga fraction and halitoxin had no effect on B. glabrata embryos. The algae apolar fraction was active on B. glabrata in all embryonic development stages, with LC(50) values for blastulae at 42 MUg/mL, gastrulae at 124 MUg/mL, trochophore at 180 MUg/mL, and veliger at 222 MUg/mL. This is the first report of extracts from marine organisms which presented molluscicidal activity. PMID- 22205348 TI - The effects of flumethrin (Bayticol(r) pour-on) on European ticks exposed to treated hairs of cattle and sheep. AB - Tick infestations in cattle and sheep pose serious health problems when agents of diseases are transmitted. In addition, blood feeding of ticks induces enormous economic losses due to reduced weight gain of infested animals. The present study was designed to investigate the effects of exposure to hairs clipped from cattle and sheep treated with flumethrin (Bayticol(r)) on European ticks. The dose used was 10 ml/100 kg body weight for both animal species. At intervals of 7 days (days 7, 14, 21, 28 and 35), hairs were cut off from treated and untreated animals along the backline and from the feet just above the claws. These hairs were mingled with stages of the tick species Ixodes ricinus, Dermacentor reticulatus and Rhipicephalus sanguineus. It was found that in the cases of I. ricinus and D. reticulatus, all specimens died within 5-12 h when coming into contact with cattle hair from the feet or back of animals treated 3 weeks ago and within 6 to 9 h after contact to sheep hair from back or feet. After 4 weeks, the specimens of both tick species that had contact with hair of treated sheep and cattle, independent from the origin backline or feet, were dead after 8 h except for one tick that had contact to hair from feet of cattle. It remained fully motile after a 12-h contact even for the observation time on another 5 days. When having contact to hair of animals treated 5 weeks before, several specimens of Ixodes and Dermacentor survived an exposition of 12 h. There were more survivors in the case of ticks tested on hair of the feet than in the case of contacts with hair of the backline. The exposure of R. sanguineus to hair obtained from animals treated 2 weeks earlier resulted in death in 2-4 h. However, most R. sanguineus ticks when coming in contact with treated hairs (collected from animals treated 3, 4 or 5 weeks earlier) from back or feet survived for atleast 5 days even after exposure for 12 h. These experiments confirmed the positive protection results obtained in former studies with typical cattle ticks in the tropics and/or subtropics. In addition to the killing effects described above, it was noted that flumethrin had a significant repellent effect. If ticks were mingled with treated hair, they tried to flee away and did not seek shelter inside the hair as the controls did in untreated hair. PMID- 22205349 TI - Analysis of the course and treatment of toxocariasis in children-a long-term observation. AB - Toxocariasis is a helminthozoonotic disease caused by ascarid larvae of Toxocara genus: Toxocara canis and Toxocara cati. In the reported study, the clinical course of toxocariasis and administered therapy were evaluated in 103 children. The majority of the children (68.9%) were from the rural environment, with a prevalence of boys (62.1%). At diagnosis of infection, 36 (35%) children reported recurrent abdominal pain, 19 (18.4%) headache, 6 (5.8%) loss of appetite, 2 subfebrile conditions, and 2 arthralgia, Moreover, 23 (22.3%) children demonstrated symptoms of atopic diseases; in 30 (29.1%) children, moderate enlargement of lymphatic nodes was noted. In five children (4.9%), ophthalmic examination revealed unilateral changes in the eye: in two cases retinitis; in one case fibrotic lesions in the vitreous body, complicated 1 year from diagnosis by retinal detachment; and in other children parafoveal lesions and cataract. Only two children with ocular changes at diagnosis reported visual disorders. In 64.3% of children, eosinophilia was observed. A covert form of the disease was diagnosed in 95.1% of the children and an ocular form in 4.9%. In all the children, antiparasitic treatment was implemented, repeated several times in some of them. After therapy, the mean titer of specific antibodies, the number of children with abdominal pains and enlarged lymphatic nodes were decreased, while headaches maintained at unchanged levels. In approximately one fourth of the children with negative results of antibodies after the therapy, the symptoms of the disease were still reported. Evaluation of the efficacy of treatment is not easy due to non-characteristic symptoms and low kinetics of specific anti Toxocara IgG decrease; however, high IgG titers suggest non-effective treatment of concomitant infection requiring subsequent therapy. Due to risk of ocular form, which may develop in any stage of the disease, irrespectively of specific antibodies concentrations, it seems justified to implement antiparasitic treatment in all children infected with T. canis. PMID- 22205350 TI - Unusual presentation of Plasmodium vivax: a neglected human malaria parasite. AB - Severe and complicated malaria is usually caused by Plasmodium falciparum malaria (PF) but it has been increasingly observed that Plasmodium vivax malaria (PV), which was otherwise considered to be benign malaria, with a low case-fatality ratio, can also occasionally result in severe disease as with PF malaria. There is an urgent need to re-examine the clinical spectrum and burden of PV so that adequate control measures can be implemented against this emerging but neglected disease. We report a case of severe PV malaria with multi-organ dysfunction. Patients exhibited acute kidney injury, severe anemia/thrombocytopenia, jaundice, hypoglycemia, hyponatremia, and pulmonary edema. Peripheral blood microscopy by trained and expert pathologist and rapid diagnostic test showed the presence of PV and absence of PF. The patient recovered completely with anti-malarial drugs, supportive measures, and hemodialysis.Recent microrheologic research that analyzed malaria severity in PV clearly demonstrated enhanced aggregation, erythrocyte clumping, and reduced deformability affecting microcirculation. Our case report highlights the fact that PV malaria is benign by name but not always by nature. PV can lead to unusual and potentially life-threatening complications. Further large-scale multi-centric studies are needed to define this less known entity. PMID- 22205351 TI - RAPD-SCAR marker and genetic relationship analysis of three Demodex species (Acari: Demodicidae). AB - For a long time, classification of Demodex mites has been mainly based on their hosts and phenotype characteristics. The study was the first to conduct molecular identification and genetic relationship analysis for six isolates of three Demodex species by random amplified polymorphic DNA (RAPD) and sequence characterized amplified region (SCAR) marker. Totally, 239 DNA fragments were amplified from six Demodex isolates with 10 random primers in RAPD, of which 165 were polymorphic. Using a single primer, at least five fragments and at most 40 in the six isolates were amplified, whereas within a single isolate, a range of 35-49 fragments were amplified. DNA fingerprints of primers CZ 1-9 revealed intra and interspecies difference in six Demodex isolates, whereas primer CZ 10 only revealed interspecies difference. The genetic distance and dendrogram showed the intraspecific genetic distances were closer than the interspecific genetic distances. The interspecific genetic distances of Demodex folliculorum and Demodex canis (0.7931-0.8140) were shorter than that of Demodex brevis and D. canis (0.8182-0.8987). The RAPD-SCAR marker displayed primer CZ 10 could be applied to identify the three Demodex species. The 479-bp fragment was specific for D. brevis, and the 261-bp fragment was specific for D. canis. The conclusion was that the RAPD-SCAR multi-marker was effective in molecular identification of three Demodex species. The genetic relationship between D. folliculorum and D. canis was nearer than that between D. folliculorum and D. brevis. PMID- 22205352 TI - First report of anti-Trichomonas vaginalis activity of the medicinal plant Polygala decumbens from the Brazilian semi-arid region, Caatinga. AB - Trichomonosis, caused by the flagellate protozoan Trichomonas vaginalis, is the most common non-viral sexually transmitted disease worldwide. Actually, the infection treatment is based on 5-nitroimidazole drugs. However, an emergent number of resistant isolates makes important the search for new therapeutic arsenal. In this sense, the investigation of plants and their metabolites is an interesting approach. In the present study, the anti-T. vaginalis activity of 44 aqueous extracts from 23 Caatinga plants used in folk medicine was evaluated. After screening 44 aqueous extracts from 23 distinct plants against two isolates from ATCC and four fresh clinical isolates, only the Polygala decumbens root extract was effective in reducing significantly the trophozoite viability. The MIC value against all isolates tested, including the metronidazole resistant, was 1.56 mg/mL. The kinetic growth assays showed that the extract was able to completely abolish the parasite density in the first hours of incubation, confirmed by microscopy. In summary, this study describes the first report on the activity of P. decumbens from Caatinga against T. vaginalis, being directly related to the popular knowledge and use. PMID- 22205353 TI - Multiple effects of pepstatin A on Trypanosoma cruzi epimastigote forms. AB - Herein, we have aimed to explore the effects of pepstatin A, a powerful aspartic protease inhibitor, on Trypanosoma cruzi, the etiologic agent of Chagas' disease. Pepstatin A arrested the proliferation of epimastigotes of T. cruzi (clone Dm28c, TcI lineage), in both dose- and time-dependent manner. The IC(50) value was calculated to be 36.2 MUM after 96 h of parasite-drug contact. The parasite treatment with pepstatin A resulted in significant morphological alterations, including parasites becoming round in shape, reduction (~25%) of the parasite size, and parasites presenting parts or the whole flagellum detached from the cell body. Cell lysis was not observed, resulting in a trypanostatic effect. The treatment of different T. cruzi strains, belonging to distinct phylogenetic lineages, with pepstatin A at 36.2 MUM resulted in growth inhibition as follows: 28% to Y (TcII), 45% to CL Brener (TcII), 45.4% to 4167 (Z3), and 26.4% to 3663 (Z3) strains. The hydrolysis of a cathepsin D fluorogenic substrate (7 methoxycoumarin-4-acetyl-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(DNP)-D: -Arg amide) by T. cruzi epimastigote extract was inhibited (~65%) by pepstatin A at 10 MUM, suggesting that an aspartic protease may be the intracellular target of this inhibitor. Curiously, pepstatin A induced an increase of 54% and 98%, respectively, in the surface expression of gp63- and calpain-related molecules in epimastigotes, but not in the cruzipain level, as well as stimulated the epimastigote-to-trypomastigote differentiation in a dose-dependent manner. However, approximately 45% of the trypomastigotes had their flagellum detached from the cell body. These results contribute to understand the possible role of aspartic proteases in the physiology of T. cruzi cells, adding new in vitro insights into the possibility of exploiting aspartic protease as promising targets to treat Chagas' disease. PMID- 22205354 TI - Bietti crystalline dystrophy: a morpho-functional evaluation. AB - We report the clinical findings and macular function of a patient with Bietti crystalline dystrophy. A 39-year-old woman reported visual loss in both eyes and nyctalopia. A complete ophthalmological evaluation, retromode imaging, SD-OCT acquisition, MP1 microperimetry, and multifocal electroretinogram (mfERG) were performed. Microcrystalline deposits in the cornea and the retina with retinal pigment epithelial atrophy were observed. Retromode imaging revealed visualization of normal large choroidal vessels, cystoid macular edema, and small defined glistening lesions. SD-OCT showed changes in the outer retina with numerous microcrystalline deposits. Microperimetry showed an absolute scotoma involving the perimacular area but sparing of the fovea. In both eyes, mfERG analysis suggests a dysfunction of pre-ganglionic retinal elements detectable in the 20 central retinal degrees. The genetic characterization showed an homozygous mutation c.772C > T[p.Leu258Phe] in exon 6. Retromode imaging and SD-OCT were useful tools to determine the extent and the localization of the crystals. Microperimetry should allow evaluation of the progression of the macular changes. PMID- 22205356 TI - Vitamin D deficiency is common in children and adolescents with chronic kidney disease. AB - Here we determined if vitamin D deficiency is more common in children with chronic kidney disease compared to healthy children. In addition, we sought to identify disease-specific risk factors for this deficiency, as well as its metabolic consequences. We found that nearly half of 182 patients (ages 5 to 21) with kidney disease (stages 2 to 5) and a third of age-matched 276 healthy children were 25-hydroxyvitamin D deficient (<20 ng/ml). The risk of deficiency was significantly greater in advanced disease. Focal segmental glomerulosclerosis and low albumin were significantly associated with lower 25-hydroxyvitamin D, which, in turn, was associated with significantly higher intact parathyroid hormone levels. We found that 25-hydroxyvitamin D levels were positively associated with 1,25-dihydroxyvitamin D, the relationship being greatest in advanced disease (significant interaction), and inversely related to those of inflammatory markers C-reactive protein and IL-6. The association with C-reactive protein persisted when adjusted for the severity of kidney disease. Thus, lower 25-hydroxyvitamin D may contribute to hyperparathyroidism, inflammation, and lower 1,25-dihydroxyvitamin D in children and adolescents, especially those with advanced kidney disease. PMID- 22205357 TI - Endogenous Tim-1 (Kim-1) promotes T-cell responses and cell-mediated injury in experimental crescentic glomerulonephritis. AB - The T-cell immunoglobulin mucin 1 (Tim-1) modulates CD4(+) T-cell responses and is also expressed by damaged proximal tubules in the kidney where it is known as kidney injury molecule-1 (Kim-1). We sought to define the role of endogenous Tim 1 in experimental T-cell-mediated glomerulonephritis induced by sheep anti-mouse glomerular basement membrane globulin acting as a planted foreign antigen. Tim-1 is expressed by infiltrating activated CD4(+) cells in this model, and we studied the effects of an inhibitory anti-Tim-1 antibody (RMT1-10) on immune responses and glomerular disease. Crescentic glomerulonephritis, proliferative injury, and leukocyte accumulation were attenuated following treatment with anti-Tim-1 antibodies, but interstitial foxp3(+) cell accumulation and interleukin-10 mRNA were increased. T-cell proliferation and apoptosis decreased in the immune system along with a selective reduction in Th1 and Th17 cellular responses both in the immune system and within the kidney. The urinary excretion and renal expression of Kim-1 was reduced by anti-Tim-1 antibodies reflecting diminished interstitial injury. The effects of anti-Tim-1 antibodies were not apparent in the early phase of renal injury, when the immune response to sheep globulin was developing. Thus, endogenous Tim-1 promotes Th1 and Th17 nephritogenic immune responses and its neutralization reduces renal injury while limiting inflammation in cell-mediated glomerulonephritis. PMID- 22205355 TI - Analysis of baseline parameters in the HALT polycystic kidney disease trials. AB - HALT PKD consists of two ongoing randomized trials with the largest cohort of systematically studied patients with autosomal dominant polycystic kidney disease to date. Study A will compare combined treatment with an angiotensin-converting inhibitor and receptor blocker to inhibitor alone and standard compared with low blood pressure targets in 558 early-stage disease patients with an eGFR over 60 ml/min per 1.73 m(2). Study B will compare inhibitor-blocker treatment to the inhibitor alone in 486 late-stage patients with eGFR 25-60 ml/min per 1.73 m(2). We used correlation and multiple regression cross-sectional analyses to determine associations of baseline parameters with total kidney, liver, or liver cyst volumes measured by MRI in Study A and eGFR in both studies. Lower eGFR and higher natural log-transformed urine albumin excretion were independently associated with a larger natural log-transformed total kidney volume adjusted for height (ln(HtTKV)). Higher body surface area was independently associated with a higher ln(HtTKV) and lower eGFR. Men had larger height-adjusted total kidney volume and smaller liver cyst volumes than women. A weak correlation was found between the ln(HtTKV) and natural log-transformed total liver volume adjusted for height or natural log liver cyst volume in women only. Women had higher urine aldosterone excretion and lower plasma potassium. Thus, our analysis (1) confirms a strong association between renal volume and functional parameters, (2) shows that gender and other factors differentially affect the development of polycystic disease in the kidney and liver, and (3) suggests an association between anthropomorphic measures reflecting prenatal and/or postnatal growth and disease severity. PMID- 22205358 TI - Sleep-related epilepsy in a Long-Evans hooded rat model of depression. AB - INTRODUCTION: Neonatal treatment with clomipramine (CLI) has been shown to have reliable behavioral and biological changes that mimic major symptomatic and biochemical changes found in depression. This paper further explores a common feature of depression, the comorbidity of seizure activity and depressive behaviors in this mode. METHODS: Rat pups were neonatally treated with 40 mg/kg/day of CLI from postnatal day 8 through 21. In adulthood, they were instrumented with electroencephalographic (EEG) and electromyographic (EMG) electrodes for 24 h of polysomnogram (PSG) recordings. PSG data were analyzed for: (1) sleep-wake cycle; (2) spectral power; and (3) epileptiform activity, including NREM-to-REM transition (NRT) bursts. RESULTS: Neonatal treatment with CLI reliably produces enhanced levels of REM (p < 0.01) and reduced sexual activity (p < 0.05). Theta power was enhanced during NREM sleep in the CLI group (p = 0.02). CLI-treated animals experienced increased frequency at the NRT (p < 0.01), as well as additional epileptiform activity of continuous (CTS; p < 0.05) and petite-continuous (P-CTS; p < 0.01) types, across the sleep-wake cycle. There is a strong temporal correlation with increased REM sleep duration, increased frequency of NRT bursts, and increased theta power during NREM sleep in CLI treated animals. DISCUSSION: Neonatal CLI-treated animals experienced significantly more epileptiform activity as a whole, in addition to comorbid features of depression in adulthood. Neonatal exposure to CLI will not only produce depressive phenotype but may also enhance risk for epilepsy in some individuals. This warrants further investigation into currently acceptable medicinal use in humans. PMID- 22205359 TI - Effects of aluminum on immune functions of cultured splenic T and B lymphocytes in rats. AB - The effects of Aluminum (Al) exposure on immune functions of cultured splenic T and B lymphocytes of rats were studied. The lymphocytes were isolated from spleen of healthy male Wistar rats weighing 110-120 g. The cultured cells in RPMI-1640 medium were exposed to 0 (control group), 0.035 (low-dose group), 0.07 (medial dose group), and 0.14 (high-dose group) mg/mL Al(3+) as aluminum trichloride (AlCl(3)) in an incubator under 5% CO(2) at 37 degrees C for 24 h. The T and B lymphocyte proliferation was measured with a tetrazolium dye colorimetric assay. The levels of interleukin (IL)-2, IL-6, and tumor necrosis factor (TNF)-alpha were determined by iodine [(125)I] IL-2, IL-6, and TNF-alpha radioimmunoassay kits, respectively. The proportions of CD3(+), CD4(+), and CD8(+) T lymphocytes were measured with a flow cytometer. The results showed that the T and B lymphocyte proliferation, the levels of IL-2, IL-6, TNF-alpha, the proportions of CD3(+) and CD4(+) T lymphocytes, and the ratio of CD4(+)/CD8(+) T lymphocytes were lowered by Al treatments, while the proportion of CD8(+) T lymphocytes was increased. These findings indicate that Al exposure can inhibit the immune functions of splenic T and B lymphocytes of rats in vitro. PMID- 22205374 TI - Mineralocorticoid receptor-dependent proximal tubule injury is mediated by a redox-sensitive mTOR/S6K1 pathway. AB - BACKGROUND/AIMS: The mammalian target of rapamycin (mTOR) is a serine kinase that regulates phosphorylation (p) of its target ribosomal S6 kinase (S6K1), whose activation can lead to glomerular and proximal tubular cell (PTC) injury and associated proteinuria. Increased mTOR/S6K1 signaling regulates signaling pathways that target fibrosis through adherens junctions. Recent data indicate aldosterone signaling through the mineralocorticoid receptor (MR) can activate the mTOR pathway. Further, antagonism of the MR has beneficial effects on proteinuria that occur independent of hemodynamics. METHODS: Accordingly, hypertensive transgenic TG(mRen2)27 (Ren2) rats, with elevated serum aldosterone and proteinuria, and age-matched Sprague-Dawley rats were treated with either a low dose (1 mg/kg/day) or a conventional dose (30 mg/kg/day) of spironolactone (MR antagonist) or placebo for 3 weeks. RESULTS: Ren2 rats displayed increases in urine levels of the PTC brush border lysosomal enzyme N-acetyl-beta aminoglycosidase (beta-NAG) in conjunction with reductions in PTC megalin, the apical membrane adherens protein T-cadherin and basolateral alpha-(E)-catenin, and fibrosis. In concert with these abnormalities, Ren2 renal cortical tissue also displayed increased Ser2448 (p)/activation of mTOR and Thr389 (p)-S6K1 and increased 3-nitrotyrosine (3-NT) content, a marker for peroxynitrite. Low-dose spironolactone had no effect on blood pressure but decreased proteinuria and beta NAG comparable to a conventional dose of this MR antagonist. Both doses of spironolactone attenuated ultrastructural maladaptive alterations and led to comparable reductions in (p)-mTOR/(p)-S6K1, 3-NT, fibrosis, and increased expression of alpha-(E)-catenin, T- and N-cadherin. CONCLUSIONS: Thereby, MR antagonism improves proximal tubule integrity by targeting mTOR/S6K1 signaling and redox status independent of changes in blood pressure. PMID- 22205375 TI - Rufibacter tibetensis gen. nov., sp. nov., a novel member of the family Cytophagaceae isolated from soil. AB - A red-pigmented, Gram-negative, strictly aerobic, rod-shaped bacterium which was motile by gliding, designated strain 1351(T), was isolated from the soil of Lengduo, Tibet in China and subjected to a polyphasic taxonomic analysis. The isolate grows optimally at 30 degrees C and pH 7. It grows with NaCl tolerated up to 1.5% (optimum, 0.5%). Phylogenetic analysis based on the 16S rRNA gene sequence shows that strain 1351(T) is closely related to members of the family 'Cytophagaceae' closest sequence similarity was observed with similarity with Adhaeribacter terreus (91.8%). The major whole-cell fatty acids are summed feature 4 (containing anteiso-C(17:1) B and/or iso-C(17:1) I, 29.2%), summed feature 3 (containing C(16:1)omega6c and/or C(16:1)omega7c, 13.0%) and iso C(15:0) (12.0%). The predominant menaquinone of strain 1351(T) is menaquinone-7 (MK-7) and the G+C content of the DNA is 46.8 mol%. According to the phylogenetic evidence and phenotypic data, strain 1351(T) is considered to represent a new genus and species of the family 'Cytophagaceae' for which the name Rufibacter tibetensis gen nov., sp. nov. is proposed. The type species is R. tibetensis and the type strain is 1351(T) (=CCTCC AB 208084(T) = NRRL B-51285(T)). PMID- 22205376 TI - Vibrio zhanjiangensis sp. nov., isolated from sea water of shrimp farming pond. AB - A Gram-negative, facultatively anaerobic, motile by means of single polar flagellum, rod-shaped marine bacterium, designated strain E414, was isolated from sea water collected from a farming pond rearing marine shrimp Litopenaeus vannamei in Zhanjiang, Guangdong province, PRC. The strain was able to grow in the presence of 0.5-6% (w/v) NaCl (optimally in 3-6% (w/v) NaCl), between pH 6 and 9 (optimally at pH 7-8), between 15 and 37 degrees C (optimally at 25-30 degrees C). Phylogenetic analysis based on 16S rRNA gene sequences locate strain E414 in the vicinity of the coralliilyticus clade within the genus Vibrio. DNA DNA relatedness data and multigene phylogenetic analysis based on the concatenated sequences of four genes (16S rRNA, rpoA, recA and pyrH) clearly differentiated strain E414 from its closest phylogenetic neighbours. Analysis of phenotypic features, including enzyme activities and utilization and fermentation of various carbon sources, further revealed discrimination between strain E414 and phylogenetically related Vibrio species. The major fatty acid components are C(16:1)omega6c and/or C(16:1)omega7c (27.4%), C(18:1)omega7c and/or C(18:1)omega6c (19.3%) and C(16:0) (18.2%). The DNA G+C content of strain E414 was 38.7 mol%. Based on phenotypic, chemotaxonomic, phylogenetic and DNA-DNA relatedness values, it can be concluded that E414 should be placed in the genus Vibrio as representing a novel species, for which the name Vibrio zhanjiangensis sp. nov. is proposed, with the type strain E414 (=CCTCC AB 2011110(T) = NBRC 108723(T) = DSM 24901). PMID- 22205377 TI - Some aspects of social exclusion: do they influence suicide mortality? AB - BACKGROUND: The current study is aimed to assess the relationship between the 'economic/employment' and 'social/welfare' dimensions of social exclusion and suicide mortality in Europe. METHODS: Suicide rates for 26 countries were obtained from the WHO. Data on social expenditure were obtained from the OECD database. Employment rates and GDP were obtained from the Total Economy Database. Questions about citizens' attitudes towards different aspects of social exclusion were taken from the European Social Survey. Structural equation modelling was applied to research the theoretical structure of the variables. RESULTS: All variables are statistically significant in male and female models except of the relationships between 'economic/employment' and 'social/welfare' dimensions and female suicides; and the relationship between 'employment rates' and 'economic/employment' dimension. Suicide mortality rates among both males and females are influenced negatively by 'economic/employment' and 'social/welfare' dimensions. Among females, the influence of 'social/welfare' dimension is stronger compared to the 'economic/employment' dimension. The remaining influence of GDP is positive in both models. CONCLUSIONS: Both 'economic/employment' and 'social/welfare' dimensions of social exclusion significantly influence suicide mortality among males. The influence of 'economic/employment' and 'social/welfare' dimensions of social exclusion on female suicide mortality is controversial. Social exclusion might be considered as a risk factor for suicide mortality in Europe. PMID- 22205378 TI - Transfusion related acute lung injury in a neonate. AB - Transfusion related acute lung injury (TRALI) is a life threatening and potentially fatal complication of blood component transfusion, which largely remains under- diagnosed and under-reported, especially in neonates. The present case aims to emphasize that TRALI should be kept as a differential diagnosis in all groups of patients, including neonates, who develop acute respiratory distress and fresh lung infiltrations in the chest radiograph within 6 h of blood component transfusion in the absence of evidence of volume overload or cardiac dysfunction. Its recognition is important in view of the associated illness and death, for instituting correct management, and for eliminating implicated donors from donor panels. PMID- 22205379 TI - Emergence of ceftriaxone resistant Shigella. AB - Shigellosis is endemic in many resource-poor countries due to feco-oral transmission, resulting in considerable morbidity and mortality. There is rapid emergence of multi-drug resistant (MDR) Shigella spp. resulting in poor reliability of first line antibiotics like quinolones, co-trimoxazole and ampicillin. Ceftriaxone has been used as a reserved antibiotic for treatment of MDR Shigella spp. The authors report a case of ceftriaxone resistant Shigella flexneri successfully managed with meropenem. As occurrence of ceftriaxone resistant Shigella is still rare, the objective of reporting this case is to highlight the possible failure of ceftriaxone in treating shigellosis which if not detected timely can result in mortality. PMID- 22205380 TI - Vertically transmitted HIV infection having first clinical manifestations at 13 y of age. AB - Untreated vertically transmitted human immunodeficiency virus (HIV) infection progresses rapidly with 50% mortality at 1 y and most of the remainder dying before 5 y of age. The authors present a case of a 13-y-old boy, a paternal orphan with vertically transmitted HIV infection, lost to follow up after diagnosis in infancy, surviving to date without any major illness or medical intervention, till the present episode of full blown AIDS. The boy presented with shock, pneumocystis jirovecii pneumonia (PJP), disseminated tuberculosis, Herpes Simplex Type 1 (HSV-1) infection, anemia, malnutrition and oral candidiasis. Later he developed systemic candidiasis, transient renal and respiratory failure. CD4 counts were 41 cells/MUl. He was managed with sulphamethoxazole/trimethoprim (SXTM) combination, anti tubercular therapy, fluconazole, anti-retroviral therapy (ART) and supportive measures with full recovery at 2 mo. Thus, better ART during antenatal care and immediately after birth are likely to see more of such children survive to teenage and adulthood. PMID- 22205381 TI - The clinical significance of anti-cyclic citrullinated peptide antibody in primary Sjogren syndrome. AB - Anti-cyclic citrullinated peptide antibody (anti-CCP) is a specific marker for the diagnosis of rheumatoid arthritis. However, this antibody can be detected in other rheumatic diseases and even in healthy people. This study aims to determine the prevalence and the clinical significance of anti-CCP in patients with primary Sjogren syndrome (pSS). We analyzed the clinical and laboratory data of 95 patients with pSS by retrospective review of their medical records. Anti-CCP was measured by ELISA kit. Anti-CCP, rheumatoid factor (RF), anti-nuclear antibody, anti-Ro and anti-La antibodies, and clinical data were investigated. We analyzed clinical and serologic characteristics of anti-CCP-positive patients. Twenty-one patients (22.1%) had positive anti-CCP (mean titer 61.6 +/- 15.6 U/ml) and 40 patients (42.1%) had positive RF (mean titer 98.8 +/- 22.7 IU/ml). Seventy-nine patients (83.1%) had arthralgia, and 31 patients (32.6%) had non-erosive arthritis on physical examination and radiologic images. Anti-CCP-positive patients had more frequently positive RF (71.4% vs. 41.8%, P = 0.01) and anti-Ro antibody (85.7% vs. 60.8%, P = 0.03). Anti-CCP-positive patients had non-erosive arthritis more frequently than anti-CCP-negative patients (76.1% vs. 21.6%, P < 0.01). The prevalence of anti-CCP was 22.1% in pSS, and anti-CCP was associated with non-erosive arthritis, and positivity of RF and anti-Ro antibody. PMID- 22205382 TI - Psychometric evaluation of the Arabic version of the multidimensional assessment of fatigue scale (MAF) for use in patients with ankylosing spondylitis. AB - Fatigue is a frequent symptom during ankylosing spondylitis (AS) often under estimated which needs to be measured properly with respect to its intensity by appropriate measures, such as the multidimensional assessment of fatigue (MAF). The aims of this study were to translate into the classic Arabic version of the MAF questionnaire and to validate its use for assessing fatigue in Moroccan patients with AS. The MAF contains 16 items with a global fatigue index (IGF). The MAF was translated and back-translated to arabic, pretested and reviewed by a committee following the Guillemin criteria (J Clin Epidemiol 46:1417-1432, 1993). It was then validate on 110 Moroccan patients with AS. Reliability for the 3-day test-retest was assessed using internal consistency by Cronbach's alpha coefficient and the intra-class correlation coefficient (ICC). External construct validity was assessed by correlation with pain, activity of disease and other keys variable. The reproducibility of the 15 items was satisfactory with a kappa statistics of agreement superior to 0.6. The ICC for IGF score reproducibility was good and reached 0.98 (IC 95%, 0.96-0.99). The internal consistency was at 0.991 with Cronbach's alpha coefficient. The construct validity showed a positive correlation between MAF and the axial (r = 0.34) and peripheral (r = 0.32) visual analogical scale, the Bath ankylosing spondylitis disease activity index (BASDAI) (r = 0.77), the first item of BASDAI (r = 0.85), the functional disability by the Bath ankylosing spondylitis functional index (r = 0.64), the erythrocyte sedimentation rate (r = 0.43) and the C reactive protein (r = 0.30) (for all P < 0.001). There was no statistical correlation between MAF and the other variables. The Arabic version of the MAF has good comprehensibility, internal consistency, reliability and validity for the evaluation of Arabic speaking patients with AS. PMID- 22205383 TI - Emergency healthcare process automation using mobile computing and cloud services. AB - Emergency care is basically concerned with the provision of pre-hospital and in hospital medical and/or paramedical services and it typically involves a wide variety of interdependent and distributed activities that can be interconnected to form emergency care processes within and between Emergency Medical Service (EMS) agencies and hospitals. Hence, in developing an information system for emergency care processes, it is essential to support individual process activities and to satisfy collaboration and coordination needs by providing readily access to patient and operational information regardless of location and time. Filling this information gap by enabling the provision of the right information, to the right people, at the right time fosters new challenges, including the specification of a common information format, the interoperability among heterogeneous institutional information systems or the development of new, ubiquitous trans-institutional systems. This paper is concerned with the development of an integrated computer support to emergency care processes by evolving and cross-linking institutional healthcare systems. To this end, an integrated EMS cloud-based architecture has been developed that allows authorized users to access emergency case information in standardized document form, as proposed by the Integrating the Healthcare Enterprise (IHE) profile, uses the Organization for the Advancement of Structured Information Standards (OASIS) standard Emergency Data Exchange Language (EDXL) Hospital Availability Exchange (HAVE) for exchanging operational data with hospitals and incorporates an intelligent module that supports triaging and selecting the most appropriate ambulances and hospitals for each case. PMID- 22205384 TI - Complications associated with arthroscopic rotator cuff repair: a literature review. AB - The aim of this literature review was to report complications associated with arthroscopic rotator cuff repair (RCR). A computerized search of articles published between 200 and 2009 was performed using MEDLINE and PubMed. We included clinical studies (Level 1-4): (a) investigating patients with rotator cuff tears, managed by a completely arthroscopic RCR technique; (b) reported data about complications. Data about arthroscopic-assisted techniques were excluded. Articles that meet criteria inclusion were analytically examined. Complications were classified into general complications and specific complications related to arthroscopic RCR. We found 414 complications in 2,890 patients; most of them were specific complications related to arthroscopic RCR. Re-rupture was the most frequently encountered complication: re-tear rate ranged between 11.4 and 94%. Stiffness and hardware-related complications were observed in 74 and 12 patients, respectively. Eleven less common complications were also reported: 5 neurovascular, 3 septic, 2 thromboembolic events, and 1 anesthesiological complication. This review stated that arthroscopic RCR is a low-risk surgical procedure. Anatomical failure of the repair is the most common complication encountered in the literature. PMID- 22205386 TI - Democratization of computational chemistry and chem(o)informatics. PMID- 22205385 TI - Surgical management of adrenal metastases. AB - PURPOSE: This paper aims to review controversies in the management of adrenal gland metastasis and to reach an evidence-based consensus. MATERIALS AND METHODS: A review of English-language studies addressing the management of adrenal metastasis, including indications for surgery, diagnostic imaging, fine-needle aspiration, surgical approach, and outcome was carried out. Results were discussed at the 2011 Workshop of the European Society of Endocrine Surgeons devoted to adrenal malignancies and a consensus statement agreed. RESULTS: Patients should be managed by a multidisciplinary team. Positron emission tomography coupled with computed tomography (PET/CT) scanning is the technique of choice for suspected adrenal metastasis. When PET/CT is not available or results are inconclusive, the CT scan or magnetic resonance imaging can be used. Patients should undergo complete hormonal evaluation. Adrenal biopsy should be reserved for cases in which the results of non-invasive techniques are equivocal. If malignancy has been reliably ruled out, patients with adrenal incidentalomas should be managed like noncancer patients. CONCLUSIONS: A patient with suspected adrenal metastasis should be considered a candidate for adrenalectomy when: (a) control of extra-adrenal disease can be accomplished, (b) metastasis is isolated to the adrenal gland(s), (c) adrenal imaging is highly suggestive of metastasis or the patient has a biopsy-proven adrenal malignancy, (d) metastasis is confined to the adrenal gland as assessed by a recent imaging study, and (e) the patient's performance status warrants an aggressive approach. In properly selected patients, laparoscopic (or retroperitoneoscopic) adrenalectomy is a feasible and safe option. PMID- 22205387 TI - Testing the semi-explicit assembly solvation model in the SAMPL3 community blind test. AB - We report here a test of the Semi-Explicit Assembly (SEA) model in the solvation free energy category of the SAMPL3 blind prediction event (summer 2011). We tested how dependent the SEA results are on the chosen force field by performing calculations with both the General Amber and OPLS force fields. We compared our SEA results with full molecular dynamics simulations in explicit solvent. Of the 20 submissions, our SEA/OPLS results gave the second smallest RMS errors in free energies compared to experiments. SEA gives results that are very similar to those of its underlying force field and explicit solvent model. Hence, while the SEA water modeling approach is much faster than explicit solvent simulations, its predictions appear to be just as accurate. PMID- 22205388 TI - Influence of aerobic fitness on thermoregulation during exercise in the heat. AB - It is believed that the adaptations induced by aerobic training would prevent athletes from overheating while retaining body electrolytes during exercise in the heat. Data from our laboratory suggest that aerobic training is not enough to induce these adaptations. This review considers the factors that can lead to hyperthermia in trained and untrained populations when exercising in the heat. PMID- 22205390 TI - Studies in a consanguineous family reveal a novel locus for stuttering on chromosome 16q. PMID- 22205389 TI - LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin. AB - We describe a severe form of congenital myasthenic syndrome (CMS) caused by two heteroallelic mutations: a nonsense and a missense mutation in the gene encoding agrin (AGRN). The identified mutations, Q353X and V1727F, are located at the N terminal and at the second laminin G-like (LG2) domain of agrin, respectively. A motor-point muscle biopsy demonstrated severe disruption of the architecture of the neuromuscular junction (NMJ), including: dispersion and fragmentation of endplate areas with normal expression of acetylcholinesterase; simplification of postsynaptic membranes; pronounced reduction of the axon terminal size; widening of the primary synaptic cleft; and, collection of membranous debris material in the primary synaptic cleft and in the subsynaptic cytoplasm. Expression studies in heterologous cells revealed that the Q353X mutation abolished expression of full-length agrin. Moreover, the V1727F mutation decreased agrin-induced clustering of the acetylcholine receptor (AChR) in cultured C2 muscle cells by >100-fold, and phosphorylation of the MuSK receptor and AChR beta subunit by ~tenfold. Surprisingly, the V1727F mutant also displayed increased binding to alpha-dystroglycan but decreased binding to a neural (z+) agrin-specific antibody. Our findings demonstrate that agrin mutations can associate with a severe form of CMS and cause profound distortion of the architecture and function of the NMJ. The impaired ability of V1727F agrin to activate MuSK and cluster AChRs, together with its increased affinity to alpha-dystroglycan, mimics non neural (z-) agrin and are important determinants of the pathogenesis of the disease. PMID- 22205391 TI - Lipoxin A4 inhibits immune cell binding to salivary epithelium and vascular endothelium. AB - Lipoxins are formed by leukocytes during cell-cell interactions with epithelial or endothelial cells. Native lipoxin A(4) (LXA(4)) binds to the G protein-coupled lipoxin receptors formyl peptide receptor 2 (FPR2)/ALX and CysLT1. Furthermore, LXA(4) inhibits recruitment of neutrophils, by attenuating chemotaxis, adhesion, and transmigration across vascular endothelial cells. LXA(4) thus appears to serve as an endogenous "stop signal" for immune cell-mediated tissue injury (Serhan CN; Annu Rev Immunol 25: 101-137, 2007). The role of LXA(4) has not been addressed in salivary epithelium, and little is known about its effects on vascular endothelium. Here, we determined that interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) receptor activation in vascular endothelium and salivary epithelium upregulated the expression of adhesion molecules that facilitates the binding of immune cells. We hypothesize that the activation of the ALX/FPR2 and/or CysLT1 receptors by LXA(4) decreases this cytokine-mediated upregulation of cell adhesion molecules that enhance lymphocyte binding to both the vascular endothelium and salivary epithelium. In agreement with this hypothesis, we observed that nanomolar concentrations of LXA(4) blocked IL-1beta- and TNF-alpha-mediated upregulation of E-selectin and intercellular cell adhesion molecule-1 (ICAM-1) on human umbilical vein endothelial cells (HUVECs). Binding of Jurkat cells to stimulated HUVECs was abrogated by LXA(4). Furthermore, LXA(4) preincubation with human submandibular gland cell line (HSG) also blocked TNF-alpha-mediated upregulation of vascular cell adhesion molecule-1 (VCAM-1) in these cells, and it reduced lymphocyte adhesion. These findings suggest that ALX/FPR2 and/or CysLT1 receptor activation in endothelial and epithelial cells blocks cytokine-induced adhesion molecule expression and consequent binding of lymphocytes, a critical event in the pathogenesis of Sjogren's syndrome (SS). PMID- 22205393 TI - Clustering is a feature of the spiral ganglion in the basal turn. AB - OBJECTIVE: To demonstrate the organization of the spiral ganglion in the mammalian species. METHODS: Temporal bone (TB) specimens from man (n = 2), monkey (n = 2), lion (n = 2) and cat (n = 20) were stained, decalcified and dissected according to the Sudan black B method of Rasmussen. These TB specimens were examined under a Zeiss operating microscope and photographed with a Canon 100 camera interfaced with the microscope. RESULTS: Spiral ganglion cells occurred in clusters within Rosenthal's canal in all four species. The location of the clusters was marked by the interface between axon and dendritic bundles as well as groups of ganglion cells. In monkey and man the clusters were more separated than in lion and cat. CONCLUSIONS: These observations indicate that the spiral ganglion forms clusters of neurons within Rosenthal's canal at the basal cochlear turn in the mammals investigated here. The formation of clusters may be related to the principles of neurogenesis. PMID- 22205392 TI - Chronic hypoxia upregulates pulmonary arterial ASIC1: a novel mechanism of enhanced store-operated Ca2+ entry and receptor-dependent vasoconstriction. AB - Acid-sensing ion channel 1 (ASIC1) is a newly characterized contributor to store operated Ca(2+) entry (SOCE) in pulmonary vascular smooth muscle (VSM). Since SOCE is implicated in elevated basal VSM intracellular Ca(2+) concentration ([Ca(2+)](i)) and augmented vasoconstriction in chronic hypoxia (CH)-induced pulmonary hypertension, we hypothesized that ASIC1 contributes to these responses. To test this hypothesis, we examined effects of the specific pharmacologic ASIC1a inhibitor, psalmotoxin 1 (PcTX1), on vasoconstrictor and vessel wall [Ca(2+)](i) responses to UTP and KCl (depolarizing stimulus) in fura 2-loaded, pressurized small pulmonary arteries from control and CH (4 wk at 0.5 atm) Wistar rats. PcTX1 had no effect on basal vessel wall [Ca(2+)](i), but attenuated vasoconstriction and increases in vessel wall [Ca(2+)](i) to UTP in arteries from control and CH rats; normalizing responses between groups. In contrast, responses to the depolarizing stimulus, KCl, were unaffected by CH exposure or PcTX1. Upon examining potential Ca(2+) influx mechanisms, we found that PcTX1 prevented augmented SOCE following CH. Exposure to CH resulted in a significant increase in pulmonary arterial ASIC1 protein. This study supports a novel role of ASIC1 in elevated receptor-stimulated vasoconstriction following CH which is likely mediated through increased ASIC1 expression and SOCE. PMID- 22205394 TI - Identification of a chicken CLEC-2 homologue, an activating C-type lectin expressed by thrombocytes. AB - Receptors on natural killer (NK) cells are classified as C-type lectins or as Ig like molecules, and many of them are encoded by two genomic clusters designated natural killer gene complex (NKC) and leukocyte receptor complex, respectively. Here, we describe the analysis of an NKC-encoded chicken C-type lectin, previously annotated as homologue to CD94 and NKG2 and thus designated chicken CD94/NKG2. To further elucidate its potential function on NK cells, we produced a specific mab by immunizing with stably transfected HEK293 cells expressing this lectin. Staining of various chicken tissues revealed minimal reactivity with bursal, or thymus cells. In peripheral blood mononuclear cell and spleen, however, the mab reacted with virtually all thrombocytes, whereas most NK cells in organs such as embryonic spleen, lung and intestine were found to be negative. These findings indicate that the gene may not resemble CD94/NKG2, but rather a CLEC-2 homologue, a claim further supported by sequence features such as an additional extracellular cysteine residue and the presence of a cytoplasmic motif known as a hem immunoreceptor tyrosine-based activation motif, found in C-type lectins such as Dectin-1, CLEC-2, but not CD94/NKG2. The biochemical analyses demonstrated that CLEC-2 is present on the cell surface as heavily glycosylated homodimer, which upon mab crosslinking induced thrombocyte activation, as measured by CD107 expression. These analyses reveal that the chicken NKC may not encode NK cell receptor genes, in particular not CD94 or NKG2 genes, and identifies a chicken CLEC-2 homologue. PMID- 22205396 TI - Mechanism-based therapeutics for autosomal dominant polycystic kidney disease: recent progress and future prospects. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, accounting for up to 10% of patients on renal replacement therapy. There are presently no proven treatments for ADPKD and an effective disease-modifying drug would have significant implications for patients and their families. Since the identification of PKD1 and PKD2, there has been an explosion in knowledge identifying new disease mechanisms and testing new drugs. Currently, the three major treatment strategies are to: (1) reduce cAMP levels; (2) inhibit cell proliferation, and (3) reduce fluid secretion. Several compounds shown to be effective in preclinical models have already undergone clinical trials and more are planned. In addition, a whole raft of other compounds have been developed from preclinical studies. The purpose of this paper is to evaluate the results of recent published trials, review current trials and highlight the most promising compounds in the pipeline. There appears to be no shortage of potential candidates, but several key issues need to be addressed to facilitate clinical translation. PMID- 22205395 TI - Genome-wide associated loci influencing interleukin (IL)-10, IL-1Ra, and IL-6 levels in African Americans. AB - Interleukins (ILs) are key mediators of the immune response and inflammatory process. Plasma levels of IL-10, IL-1Ra, and IL-6 are associated with metabolic conditions, show large inter-individual variations, and are under strong genetic control. Therefore, elucidation of the genetic variants that influence levels of these ILs provides useful insights into mechanisms of immune response and pathogenesis of diseases. We conducted a genome-wide association study (GWAS) of IL-10, IL-1Ra, and IL-6 levels in 707 non-diabetic African Americans using 5,396,780 imputed and directly genotyped single nucleotide polymorphisms (SNPs) with adjustment for gender, age, and body mass index. IL-10 levels showed genome wide significant associations (p < 5 * 10(-8)) with eight SNPs, the most significant of which was rs5743185 in the PMS1 gene (p = 2.30 * 10(-10)). We tested replication of SNPs that showed genome-wide significance in 425 non diabetic individuals from West Africa, and successfully replicated rs17365948 in the YWHAZ gene (p = 0.02). IL-1Ra levels showed suggestive associations with two SNPs in the ASB3 gene (p = 2.55 * 10(-7)), ten SNPs in the IL-1 gene family (IL1F5, IL1F8, IL1F10, and IL1Ra, p = 1.04 * 10(-6) to 1.75 * 10(-6)), and 23 SNPs near the IL1A gene (p = 1.22 * 10(-6) to 1.63 * 10(-6)). We also successfully replicated rs4251961 (p = 0.009); this SNP was reported to be associated with IL-1Ra levels in a candidate gene study of Europeans. IL-6 levels showed genome-wide significant association with one SNP (RP11-314E23.1; chr6:133397598; p = 8.63 * 10(-9)). To our knowledge, this is the first GWAS on IL-10, IL-1Ra, and IL-6 levels. Follow-up of these findings may provide valuable insight into the pathobiology of IL actions and dysregulations in inflammation and human diseases. PMID- 22205399 TI - The modulation of the excitability of primary sensory neurons by Ca2+-CaM-CaMKII pathway. AB - Ca(2+)-calmodulin (CaM) dependent protein kinase II (CaMKII) is an important intracellular signal transduction pathway. CaMKII is rich in the primary sensory neurons and specifically presents in the small- and medium-sized neurons. It remains unclear about the modulation on the excitability of primary sensory neurons by Ca(2+)-CaM-CaMKII pathway. By current clamp recording, we found that the excitability of capsaicin-sensitive small and medium trigeminal ganglion (TG) neurons was significantly reduced by a CaM specific antagonist (W-7) and a CaMKII antagonist (KN-93). The inhibition is represented as the reduction of numbers of action potential (AP), decrease of the amplitude of AP, increase of threshold, and prolongation of duration of AP. Consistently, by voltage clamp recording, we found that both voltage-gated sodium channels (VGSCs) and voltage-gated potassium channels (VGPCs) were inhibited by W-7 and KN-93 in the order of total sodium (Na(+)) current (INa-T) > sustained potassium (K(+)) current (IK) > A-type K(+) current (IA). In addition, AIP (a selective CaMKII peptide inhibitor) and KN-93 caused a similar inhibition of INa-T and IK. Those evidences show that the excitability of capsaicin sensitive small and medium TG neurons can be regulated by Ca(2+)-CaM-CaMKII pathway through modulating VGSCs and VGPCs. Considering the specific distribution of CaMKII and its susceptibility to many analgesic stimuli, Ca(2+)-CaM-CaMKII pathway may play an important role in the peripheral sensory transduction, especially in nociception. PMID- 22205409 TI - Accelerated protein evolution analysis reveals genes and pathways associated with the evolution of mammalian longevity. AB - The genetic basis of the large species differences in longevity and aging remains a mystery. Thanks to recent large-scale genome sequencing efforts, the genomes of multiple species have been sequenced and can be used for cross-species comparisons to study species divergence in longevity. By analyzing proteins under accelerated evolution in several mammalian lineages where maximum lifespan increased, we identified genes and processes that are candidate targets of selection when longevity evolves. We identified several proteins with longevity specific selection patterns, including COL3A1 that has previously been related to aging and proteins related to DNA damage repair and response such as DDB1 and CAPNS1. Moreover, we found that processes such as lipid metabolism and cholesterol catabolism show such patterns of selection and suggest a link between the evolution of lipid metabolism, cholesterol catabolism, and the evolution of longevity. Lastly, we found evidence that the proteasome-ubiquitin system is under selection specific to lineages where longevity increased and suggest that its selection had a role in the evolution of longevity. These results provide evidence that natural selection acts on species when longevity evolves, give insights into adaptive genetic changes associated with the evolution of longevity in mammals, and provide evidence that at least some repair systems are selected for when longevity increases. PMID- 22205423 TI - Social and institutional factors that affect breastfeeding duration among WIC participants in Los Angeles County, California. AB - Hospital practices and early maternal return to work are associated with breastfeeding duration; however, research has not documented the long-term effects of many hospital policies or the effect of early return to work on breastfeeding outcomes of WIC participants. This study investigated the impact of in-hospital breastfeeding, receipt of a formula discharge pack, and maternal return to work on the long-term breastfeeding outcomes of 4,725 WIC participants in Los Angeles County, California. Multivariate logistic regression analyses were used to assess determinants of exclusive breastfeeding at 6 months and breastfeeding at 6, 12, and 24 months. In-hospital initiation of breastfeeding, exclusive breastfeeding in the hospital, receipt of a formula discharge pack, and maternal return to work before 3 months were all significantly associated with breastfeeding outcomes after controlling for known confounders. Mothers who exclusively breastfed in the hospital were eight times as likely as mothers who did not breastfeed in the hospital to reach the AAP recommendation of breastfeeding for 12 months or longer (P < .01). Only 6.9% of the sample reported exclusively breastfeeding for 6 months or more, and just one-third reported any breastfeeding at 12 months. Nine in ten respondents received a formula discharge pack in the hospital. Mothers who received a discharge pack were half as likely to exclusively breastfeed at 6 months as those who did not receive one (P < .01). Medical providers should educate, encourage, and support WIC mothers to breastfeed in the hospital and refrain from giving formula discharge packs. PMID- 22205424 TI - Heart rate variability profiles and exposure therapy treatment outcome in flight phobia. AB - The goal of this study was to explore why certain patients in a previous study on exposure therapy for flight phobia did not experience an improvement in their conditions. Participants from a treatment study (N = 45) were selected according to post-treatment results and divided into two groups: the unsatisfactory treatment outcome group (UTO, N = 10) and the satisfactory treatment outcome group (STO, N = 10). The differences between these two groups prior to receiving exposure therapy were analyzed at the behavioral, physiological, and cognitive levels. The UTO participants had been avoiding flying longer than the STO phobics. Following Thayer and Lane's neurovisceral model of emotion regulation, heart rate variability was analyzed at two levels: tonic and phasic. Low frequency and high frequency (HF) power were calculated in the frequency domain and Sample Entropy was computed in the time domain. The tonic HF power of the UTO group was higher than the STO group's tonic HF power. In the phasic level, while the STO group's HF power decreased under exposure and subsequently returned to baseline level, the UTO group demonstrated a more rigid pattern. Finally, the STO group reported higher emotional involvement than the UTO group when they were shown a sample of the therapy. Based on these results, the challenge of matching exposure therapy to each patient's profile is discussed. PMID- 22205425 TI - What are the values of using QTc and N-terminal fragment of B-type natriuretic peptide as markers for early detection of acute antipsychotic drugs-induced cardiotoxicity? PMID- 22205426 TI - Induction of potato steroidal glycoalkaloid biosynthetic pathway by overexpression of cDNA encoding primary metabolism HMG-CoA reductase and squalene synthase. AB - Potato steroidal glycoalkaloids (SGAs) are toxic secondary metabolites whose total content in tubers must be regulated. SGAs are biosynthesized by the sterol branch of the mevalonic acid/isoprenoid pathway. In a previous study, we showed a correlation between SGA levels and the abundance of transcript coding for HMG-CoA reductase 1 (HMG1) and squalene synthase 1 (SQS1) in potato tissues and potato genotypes varying in SGA content. Here, Solanum tuberosum cv. Desiree (low SGA producer) was transformed with a gene construct containing the coding region of either HMG1 or SQS1 of Solanum chacoense Bitt. clone 8380-1, a high SGA producer. SGA levels in transgenic HMG-plants were either greater than (in eight of 14 plants) or no different from untransformed controls, whereas only four of 12 SQS transgenics had greater SGA levels than control, as determined by HPLC. Quantitative real-time PCR was used to estimate relative steady-state transcript levels of isoprenoid-, steroid-, and SGA-related genes in leaves of the transgenic plants compared to nontransgenic controls. HMG-transgenic plants exhibited increased transcript accumulation of SQS1, sterol C24-methyltransferase type1 (SMT1), and solanidine glycosyltransferase 2 (SGT2), whereas SQS-transgenic plants, had consistently lower transcript levels of HMG1 and variable SMT1 and SGT2 transcript abundance among different transgenics. HMG-transgenic plants exhibited changes in transcript accumulation for some sterol biosynthetic genes as well. Taken together, the data suggest coordinated regulation of isoprenoid metabolism and SGA secondary metabolism. PMID- 22205427 TI - The changing impact of the AIDS epidemic on older-age parents in the era of ART: evidence from Thailand. AB - Previous research makes clear that before antiretroviral therapy (ART), when HIV led to disabling illness and certain death, many older persons as parents of infected adults experienced adverse emotional, material and social consequences. The present study examines how widespread access to ART is transforming the situation in Thailand. Interviews with parents of adult ART recipients reveal that major improvements in the health of their adult children under treatment is associated with major reductions in parental caregiving and expenses associated with their HIV-infected child although parents continue to provide psychological support. Parents own worry about their child's health also declines. Most adult children on ART are able to continue or resume economic activity and many contribute to support of the parental household. ART appears to reduce negative community reaction. Nevertheless, given uncertainty surrounding how long ART can protect against fatal illnesses, whether the adverse impacts of the AIDS epidemic on parents are being eliminated or only postponed remains an open question. PMID- 22205430 TI - Cysteamine therapy: a treatment for cystinosis, not a cure. AB - Cystinosis as a clinical entity is a progressive dysfunction of multiple organs caused by the accumulation of cystine in the tissues, leading, for example, to end-stage renal failure, diabetes, hypothyroidism, myopathy, and central nervous system deterioration. Brodin-Sartorius and colleagues present a long-term study on the impact of cysteamine therapy on these complications. The data show that cysteamine improves the outcome and complications of cystinosis but does not prevent them. PMID- 22205432 TI - Unilateral renal cystic disease. PMID- 22205431 TI - Recipe for a new imaging biomarker: carefully combine target, reagent, and technology. AB - A careful combination of biological targeting moieties (C3 fragments), imaging reagents (a small particle of iron oxide), and appropriate technology (T2 weighted magnetic resonance imaging) is the key to the successful development of an imaging agent for glomerulonephritis. This recipe applies to virtually any molecular imaging probe for the kidney and throughout the body. However, each organ and disease requires a unique combination of these three components in order to achieve success. PMID- 22205433 TI - The case ? intractable diuretic resistance in a young woman. PMID- 22205434 TI - Evaluating a dichotomized measure of self-reported hearing loss against gold standard audiometry: prevalence estimates and age bias in a pooled national data set. AB - OBJECTIVES: To evaluate a harmonized binary measure of self-reported hearing loss against gold standard audiometry in an older adult population. METHOD: Seven nationally representative population-based studies were harmonized and pooled (n = 23,001). Self-report items were recoded into a dichotomous format. Audiometric hearing loss was defined by averaged pure-tone thresholds greater than 25-decibel hearing level in the better ear. We compared age and sex stratified prevalence rates of hearing loss estimated by self-report and audiometric measures. RESULTS: Overall, 56% of men and 43% of women had audiometric hearing loss. There were moderate associations between self-reported and audiometric hearing loss. However, prevalence based on self-report was overestimated for adults aged below 70 years and underestimated for adults aged above 75. DISCUSSION: Self-report of hearing loss is insensitive to age effects and does not provide a reliable basis for estimating prevalence of age-related hearing loss, although may indicate perceived hearing disability. PMID- 22205435 TI - Interpretation of the association between beta-blockers and hip/femur fracture. PMID- 22205438 TI - The development of PROQOL-HIV: an international instrument to assess the health related quality of life of persons living with HIV/AIDS. AB - OBJECTIVES: Health-related quality of life (HRQL) is an important outcome in HIV/AIDS infection and treatment. However, most existing HIV-HRQL instruments miss important issues (eg, sleeping problems, lipodystrophy). They were developed before highly active antiretroviral therapy (pre-HAART), and in a single language. We sought to develop a contemporary HIV-HRQL instrument (PROQOL-HIV) in multiple languages that accounts for HAART treatment and side effects. This article details the 3-stage content validation phase of PROQOL-HIV. METHODS: In stage 1, we developed a conceptual model of HIV-HRQL and questionnaire item bank from thematic analysis of 152 patient interviews conducted simultaneously across 9 countries. In stage 2, pilot items were selected by an expert panel to form the pilot instrument. Stage 3 involved linguistic validation and harmonization of selected items to form an equivalent instrument in 9 target languages. RESULTS: Analysis of 3375 pages of interview text revealed 11 underlying themes: general health perception, social relationships, emotions, energy/fatigue, sleep, cognitive functioning, physical and daily activity, coping, future, symptoms, and treatment. Seven issues new to HIV-HRQL measurement were subsumed by these themes: infection fears, future concerns, satisfaction with care, self-esteem problems, sleep problems, work disruption, and treatment issues. Of the 442 theme related items banked, 70 items met the retention criteria and formed the pilot PROQOL-HIV instrument. CONCLUSIONS: HIV patients across 11 countries attributed a wide range of physical, mental, and social issues to their condition, many of which were not measured by existing HIV-HRQL instruments. The pilot PROQOL-HIV instrument captures these issues, is sensitive to sociocultural context, disease stage, and HAART. PMID- 22205436 TI - Body fat abnormality in HIV-infected children and adolescents living in Europe: prevalence and risk factors. AB - OBJECTIVES: To estimate the prevalence of and identify risk factors for lipodystrophy syndrome (LS) and body fat abnormality in a population of HIV infected children and adolescents. DESIGN: Cross-sectional observational study. METHODS: HIV-infected subjects aged 2-18 years were recruited from 15 HIV centers in Belgium, Italy, and Poland between January 2007 and December 2008. Standardized assessments by the patient's long-term clinician were performed to establish the presence of abnormality. Risk factors were explored in logistic regression models for fat abnormality outcomes and LS (abnormality plus dyslipidemia). RESULTS: Among 426 subjects (70% white), median age was 12.2 years (interquartile range: 9.0-15.0 years) and median duration of antiretroviral therapy was 5.2 years (interquartile range: 2.2-8.8 years). Prevalence was 57% (n = 235) for LS and 42% (n = 176) for fat abnormality; 90 subjects with abnormality were affected in >=3 locations. Lipoatrophy occurred in 28% (n = 117) of subjects and lipohypertrophy in 27% (n = 115), most commonly in the face and trunk, respectively. In multivariable analysis, white ethnicity, body mass index, ritonavir/lopinavir, and nonnucleoside reverse transcriptase inhibitors were each associated with an increased risk of LS (P < 0.05). White ethnicity, history of Centers for Disease Control and Prevention-defined disease, and stavudine were associated with risk of lipoatrophy (P < 0.05). Increased risk of lipohypertrophy was associated with body mass index and prior HIV disease. CONCLUSIONS: Fat abnormality was prevalent in close to half of children and adolescents, who had accumulated long treatment durations. Risk of fat abnormality was associated with specific drugs, including stavudine and ritonavir, and other variables. Our results underline the importance of continued surveillance of children treated with antiretroviral therapy. PMID- 22205437 TI - Uptake and outcome of combination antiretroviral therapy in men who have sex with men according to ethnic group: the UK CHIC Study. AB - BACKGROUND: We investigated differences in retention in HIV care and uptake of combination antiretroviral therapy (cART) and treatment outcomes between different ethnic men who have sex with men (MSM) groups. METHODS: MSM subjects with known ethnicity and >=1 day follow-up from 1996 to 2009 in the UK Collaborative HIV Cohort Study were included. Black and minority ethnic (BME) men were categorized as: black; Indian/Pakistani/Bangladeshi; other Asian/Oriental; and other/mixed. Logistic regression was used to identify factors associated with treatment initiation within the 6 months after each CD4 count. HIV viral load, CD4 counts, discontinuation/switch of a drug in the initial cART regimen, and development of a new AIDS event/death at 6 and 12 months were also analyzed. RESULTS: Of 16,406 MSM, 1818 (11.0%) were BME; 892 (49.1%) black, 139 (7.6%) Indian/Pakistani/Bangladeshi, 254 (13.9%) other Asian/Oriental, 532 (29.2%) other/mixed. The proportion of MSM with no follow-up after HIV diagnosis was higher among BME than white MSM (3.4% vs. 2.2%, P = 0.002). Permanent loss to follow-up was highest in the other/mixed and lowest in Indian/Pakistani/Bangladeshi groups (P = 0.02). Six thousand three hundred thirty eight MSM initiated first cART from January 1, 2000, to January 1, 2009. In multivariable analyses, BME MSM were 18% less likely to initiate cART than white MSM with similar CD4 counts [adjusted odds ratio 0.82 (95% confidence interval: 0.74 to 0.91), P = 0.0001]. However, once on cART, there were no differences in virological, immunological, and clinical outcomes. CONCLUSIONS: This study demonstrates that despite BME MSM being a "minority within a minority" for those HIV infected, there are few ethnic disparities in access to and treatment outcomes in our setting. PMID- 22205440 TI - Ataxia and HIV: clinicopathologic correlations in a case of HIV-associated cerebellar leukoencephalopathy. PMID- 22205439 TI - Vaccination against trypanosomiasis: can it be done or is the trypanosome truly the ultimate immune destroyer and escape artist? AB - To date, human African trypanosomiasis (HAT) still threatens millions of people throughout sub-Sahara Africa, and new approaches to disease prevention and treatment remain a priority. It is commonly accepted that HAT is fatal unless treatment is provided. However, despite the well-described general symptoms of disease progression during distinct stages of the infection, leading to encephalitic complications, coma and death, a substantial body of evidence has been reported suggesting that natural acquired immunity could occur. Hence, if under favorable conditions natural infections can lead to correct immune activation and immune protection against HAT, the development of an effective anti-HAT vaccine should remain a central goal in the fight against this disease. In this review, we will (1) discuss the vaccine candidates that have been proposed over the past years, (2) highlight the main obstacles that an efficient anti-trypanosomiasis vaccine needs to overcome and (3) critically reflect on the validity of the widely used murine model for HAT. PMID- 22205441 TI - Surface display of monkey metallothionein alpha tandem repeats and EGFP fusion protein on Pseudomonas putida X4 for biosorption and detection of cadmium. AB - Monkey metallothionein alpha domain tandem repeats (4mMTalpha), which exhibit high cadmium affinity, have been displayed for the first time on the surface of a bacterium using ice nucleation protein N-domain (inaXN) protein from the Xanthomonas campestris pv (ACCC-10049) as an anchoring motif. The shuttle vector pIME, which codes for INAXN-4mMTalpha-EGFP fusion, was constructed and used to target 4mMTalpha and EGFP on the surface of Pseudomonas putida X4 (CCTCC-209319). The surface location of the INAXN-4mMTalpha-EGFP fusion was further verified by western blot analysis and immunofluorescence microscopy. The growth of X4 showed resistance to cadmium presence. The presence of surface-exposed 4mMTalpha on the engineered strains was four times higher than that of the wild-type X4. The Cd2+ accumulation by X4/pIME was not only four times greater than that of the original host bacterial cells but was also remarkably unaffected by the presence of Cu2+ and Zn2+. Moreover, the surface-engineered strains could effectively bind Cd2+ under a wide range of pH levels, from 4 to 7. P. putida X4/pIME with surface expressed 4mMTalpha-EGFP had twice the cadmium binding capacity as well as 1.4 times the fluorescence as the cytoplasmic 4mMTa-EGFP. These results suggest that P. putida X4 expressing 4mMTalpha-EGFP with the INAXN anchor motif on the surface would be a useful tool for the remediation and biodetection of environmental cadmium contaminants. PMID- 22205442 TI - Enhancement of sialylation on humanized IgG-like bispecific antibody by overexpression of alpha2,6-sialyltransferase derived from Chinese hamster ovary cells. AB - Improvement of glycosylation is one of the most important topics in the industrial production of therapeutic antibodies. We have focused on terminal sialylation with alpha-2,6 linkage, which is crucial for anti-inflammatory activity. In the present study, we have successfully cloned cDNA of beta galactosyl alpha-2,6 sialyltransferase (ST6Gal I) derived from Chinese hamster ovary (CHO) cells regardless of reports that stated this was not endogenously expressed in CHO cells. After expressing cloned ST6Gal I in Escherichia coli, the transferase activity was confirmed by HPLC and lectin binding assay. Then, we applied ST6Gal I to alpha-2,6 sialylation of the recombinant antibody; the ST6Gal I expression vector was transfected into the CHO cell line producing a bispecific antibody. The N-glycosylation pattern of the antibody was estimated by HPLC and sialidase digestion. About 70% of the total N-linked oligosaccharide was alpha 2,6 sialylated in the transfected cell line whereas no sialylation was observed in the non-transfected cell line. The improvement of sialylation would be of practical importance for the industrial production of therapeutic antibodies. PMID- 22205443 TI - Changes in functional diversity of soil microbial community with addition of antibiotics sulfamethoxazole and chlortetracycline. AB - Potential effects of antibiotics on agricultural soil microflora have recently become increasing concerns with antibiotic-contaminated biosolid now being used in agricultural land. However, changes of soil microbial community function caused by the antibiotic-associated disturbance are less addressed. This paper investigated the changes in microbial functional diversity by spiking sulfamethoxazole (SMX) and chlortetracycline (CTC) in a loam paddy soil and then incubating for 21 days. The dose-effect and time-dependent changes of antibiotic associated disturbance on soil microbial community were analyzed with the soils sampled at 7 and 21 days using Biolog EcoPlate. At day 7 following treatment, SMX decreased functional diversity of soil microbial community, and the treatment of 100 mg SMX kg-1 dry soil had a significant inhibition of average well color development (AWCD) and Shannon index as compared to the control (p < 0.05). The SMX changed to improve soil microbial community function at day 21. CTC had less effect on soil microbial community function during the whole incubation period. Antibiotic dissipation and adsorption in soil, which may decrease their microbial bioavailability, led to the temporary change of antibiotic effect on functional diversity of soil microbial community. Principal component analysis clearly revealed the difference of antibiotic dose-effects on the soil microbial community function. The findings demonstrated that soil microbial community showed more sensitivity to SMX than CTC, and soil microbial community function could recover or improve due to antibiotic dissipation in soil. PMID- 22205444 TI - Lung neovascularity in pulmonary arterial hypertension associated with congenital heart defects and idiopathic pulmonary arterial hypertension: study of 198 patients. AB - OBJECTIVES: To correlate the severity of lung neovascularity (Sheehan vessels) with the cause and haemodynamic severity of pulmonary arterial hypertension (PAH), pulmonary artery (PA) size and heart disease type in patients with PH associated with congenital heart diseases (PAH-CHD) and idiopathic PH (IPAH). METHODS: We reviewed the HRCT and CT pulmonary angiography studies of 87 patients with PAH-CHD and 111 with IPAH; all had undergone right heart catheterisation. We evaluated the PA size and severity of neovascularity on CT. RESULTS: Neovascularity, which was found in 72% of PAH-CHD (56% with Eisenmenger's syndrome) and in 22% of IPAH patients, is significantly related to the severity of PH and all patients with severe neovascularity had intermediate or high PH. All PAH-CHD patients had a dilated PA with a greater risk of developing severe dilatation (diameter >5 cm). The neovascularity correlated with the PA size only in IPAH. CONCLUSIONS: Neovascularity even if not pathognomonic for PAH-CHD, is significantly more common in these patients, especially in Eisenmenger's syndrome. It is often the first CT sign to indicate the severity of PH in PAH-CHD and IPAH. A neovascularity >=5 on CT indicates a intermediate or high PH. KEY POINTS: * Large retrospective studying specific lung disorders in patients with pulmonary arterial hypertension. * Neovascularity is often the first CT sign indicating the severity of pulmonary hypertension Alterations of lung parenchyma on CT in pulmonary hypertension are described * The first study to assess the severity of pulmonary hypertension by CT * If substantiated, CT might eventually replace some cardiac catheterisation for evaluating PH. PMID- 22205445 TI - The role of breast MR imaging in pre-operative determination of invasive disease for ductal carcinoma in situ diagnosed by needle biopsy. AB - OBJECTIVES: To evaluate whether magnetic resonance (MR) imaging features can predict the presence of occult invasion in cases of biopsy-proven pure ductal carcinoma in situ (DCIS). METHODS: We retrospectively reviewed 92 biopsy-proven pure DCIS in 92 women who underwent MR imaging. The following MR imaging findings were compared between confirmed DCIS and invasive breast cancer (IBC): lesion size, type, morphological and kinetic assessments by ACR BI-RADS MRI, and findings of fat-suppressed T2-weighted (FS-T2W) imaging. RESULTS: Sixty-eight of 92 (74%) were non-mass-like enhancements (NMLE) and 24 were mass lesions on MR imaging. Twenty-one of 68 (31%) NMLE and 13 of 24 (54%) mass lesions were confirmed as IBC. In NMLE lesions, large lesions (P = 0.007) and higher signal intensities (SI) on FS-T2W images (P = 0.032) were significantly associated with IBC. Lesion size remained a significant independent predictor of invasion in multivariate analysis (P = 0.032), and combined with FS-T2W SIs showed slightly higher observer performances (area under the curve, AUC, 0.71) than lesion size alone (AUC 0.68). There were no useful findings that enabled the differentiation of mass-type lesions. CONCLUSIONS: Breast MR imaging is potentially useful to predict the presence of occult invasion in biopsy-proven DCIS with NMLE. KEY POINTS: MR mammography permits more precise lesion assessment including ductal carcinoma in situ A correct diagnosis of occult invasion before treatment is important for clinicians This study showed the potential of MR mammography to diagnose occult invasion Treatment and/or aggressive biopsy can be given with greater confidence MR mammography can lead to more appropriate management of patients. PMID- 22205446 TI - Prospective ECG triggering reduces prosthetic heart valve-induced artefacts compared with retrospective ECG gating on 256-slice CT. AB - OBJECTIVES: Multidetector computed tomography (MDCT) has diagnostic value for the evaluation of prosthetic heart valve (PHV) dysfunction but it is hampered by artefacts. We hypothesised that image acquisition using prospective triggering instead of retrospective gating would reduce artefacts related to pulsating PHV. METHODS: In a pulsatile in vitro model, a mono- and bileaflet PHV were imaged using 256 MDCT at 60, 75 and 90 beats per minute (BPM) with either retrospective gating (120 kV, 600 mAs, pitch 0.2, CTDI(vol) 39.8 mGy) or prospective triggering (120 kV, 200 mAs, CTDI(vol) 13.3 mGy). Two thresholds (>175 and <-45HU), derived from the density of surrounding structures, were used for quantification of hyper and hypodense artefacts. Image noise and artefacts were compared between protocols. RESULTS: Prospective triggering reduced hyperdense artefacts for both valves at every BPM (P = 0.001 all comparisons). Hypodense artefacts were reduced for the monoleaflet valve at 60 (P = 0.009), 75 (P = 0.016) and 90 BPM (P = 0.001), and for the bileaflet valves at 60 (P = 0.001), 90 (P = 0.001) but not at 75 BPM (P = 0.6). Prospective triggering reduced image noise at 60 (P = 0.001) and 75 (P < 0.03) but not at 90 BPM. CONCLUSIONS: Compared with retrospective gating, prospective triggering reduced most artefacts related to pulsating PHV in vitro. KEY POINTS: * Computed tomographic images are often degraded by prosthetic heart valve-induced artefacts * Prospective triggering reduces prosthetic heart valve-induced artefacts in vitro * Artefact reduction at 90 beats per minute occurs without image noise reduction * Prospective triggering may improve CT image quality of moving hyperdense structures. PMID- 22205447 TI - Backbone and side chain 1H, 13C and 15N resonance assignments of the catalytic domain of diphtheria toxin. AB - Diphtheria is a serious upper respiratory tract disease caused by the diphtheria toxin (DT) secreted from the bacteria Corynebacterium diphtheriae. Vaccination is the best way to protect against this infectious disease. Diphtheria vaccines are prepared by isolating, purifying and chemically deactivating DT. Although toxoids have been used for decades in immunization, there is still little understanding at the molecular level of the process of toxoid preparation, and how chemical treatment enhances their immunogenicity. We have undertaken an NMR study of the catalytic domain as a first step in understanding the molecular details involved in vaccine antigen preparation. Here we report a near complete assignment for the backbone and side chain resonances of the diphtheria toxin catalytic domain. PMID- 22205448 TI - [Choice of surgical procedures for refractory constipation]. AB - Refractory constipations are mostly mixed constipations. Surgery is only reserved as the last option when conservative treatments have failed. Colectomy or stapbed transanal rectal resection (STARR) represents the procedure of choice in patients with pure slow transmit constipation (STC) or obstructive defecation syndrome (ODS). However, its clinical outcome is unsatisfactory. Jinling procedure, a new surgical innovation for mixed constipation, aims to correct the coexistence of STC and ODS in severe refractory constipation. It combines subtotal colectomy and side to side cecorectal anastomosis, which shows a promising clinical outcome in over 500 refractory constipation patients. In our department, there is no significant difference in operation time, mortality and complications between the laparoscopic assisted and open Jinling procedures. Jinling procedure is also appropriate for secondary Hirschsprung's disease. Stoma is described in the treatment of some adult constipation patients, which has not been supported by the evidence-based medicine at present. Anastomosis leakage is a severe complication after constipation surgery. Fecal diversion is indicated once it happened. Colon irrigation may be used in patients who failed after surgery or children who refused definitive operation. It has showed a good short-term functional recovery but becomes invalid after a long-term follow-up. PMID- 22205449 TI - [Surgical innovation for refractory constipation (Jinling procedure): a long-term follow-up of its safety and efficacy]. AB - OBJECTIVE: To propose a novel surgical procedure for refractory constipation, namely Jinling procedure, and to explore its safety and efficacy through long term follow-up. METHODS: A total of 614 patients with refractory constipation were admitted to the Department of General Surgery between February 2000 and June 2011. Five hundred and fifty-four patients received Jinling procedure and were included in this study. The general clinical data, complications after Jinling procedure, gastrointestinal quality of life index (GIQLI), Wexner constipation scale and satisfaction rate during follow-up were collected. RESULTS: No operation-associated death occurred. Increased bowel movement frequency was observed during the perioperative period. Temporary difficulty in urination occurred in 24.5% of the patients. Other complications included small bowel obstruction (9.6%), anastomotic bleeding (8.1%), anastomotic leakage (3.1%), sexual dysfunction (3.1%), and wound infection (3.1%). Most postoperative complications were managed conservatively. The most recent follow-up was on August 2011, and the follow-up rate was 100%, 88.8%, 75.1%, 56.3% at 3, 6, 12, and 24 months after surgery. GIQLI temporarily increased from 78.1+/-9.4 preoperatively to 92.0+/-9.5 at 3 months follow-up, but continued to decrease during the follow-up at the 6 months (48.4+/-14.1), 12 months (21.0+/-4.3), and 24 months (20.0+/-3.4). Wexner constipation scale decreased from 19.9+/-4.3 preoperatively to 8.4+/-2.1 at 3 months follow-up (P<0.01). The low Wexner scale sustained until 24 months after operation. The satisfaction rate at the 3, 6,12 and 24 months follow-up was 78.1%, 91.1%, 94.2% and 94.6%, respectively. CONCLUSION: Jinling procedure provides refractory constipation patients with a novel, safe and effective surgical option. PMID- 22205450 TI - [Changes of defecography pre- and post-Jinling procedure for mixed constipation: a prospective single center study]. AB - OBJECTIVE: To evaluate the anatomy and functional changes of pelvis before and after Jinling procedure (subtotal colectomy and side-to-side colorectal anastomosis) using defecography. METHODS: Fifty patients with refractory mixed constipation received Jinling procedure in the Jinling Hospital between March 2009 and December 2010 and were included in this prospective study. The defecography was performed at one week before surgery and 6 months after Jinling procedure. Longo outlet obstructed score, Wexner constipation score and Wexner incontinence score were also recorded before and after the procedure. RESULTS: After 6 months follow-up, defecography showed that anterior rectocele, prolapse, intussusception, and descending perineum were significantly improved (P<0.01). Anterior rectoceles were significantly reduced in depth from 22.0+/-1.8 mm to 2.4+/-0.4 mm (P<0.01). Intussusception decreased from 1.9+/-0.4 cm to 0.4+/-0.5 cm (P<0.01). Compared with preoperative score, Longo score and Wexner constipation score were significantly improved from 17.6+/-3.8 to 5.3+/-2.0 and from 19.5+/-4.8 to 5.5+/-2.4, respectively (P<0.01). CONCLUSIONS: Jinling procedure can correct the anatomy and functional pelvic disorders in mixed constipation. Clinical improvement of obstructed defecation syndrome after Jinling procedure correlates well with morphologic correction of the rectal redundancy. PMID- 22205451 TI - [Complications after stapled transanal rectal resection for obstructed defecation]. AB - OBJECTIVE: To evaluate the safety of stapled transanal rectal resection (STARR) for the treatment of obstructed defecation syndrome(ODS). METHODS: A retrospective study was performed in 112 female patients with ODS eligible for STARR. The short-lerm and long-term postoperative complications were recorded and assessed. RESULTS: Short-term postoperative complications and adverse events were reported in 18 patients (16.1%) including fecal incontinence (4.5%), anastomotic bleeding (2.7%), staple line partial dehiscence (0.9%), anal fissure (2.7%), acute urinary retention (1.8%), thrombosed external hemorrhoid (1.8%), hematoma of the rectovaginal septum (0.9%) and fecal impaction (0.9%). Reoperation was required in 2 patients (1.8%) due to the short-term postoperative complications. The median length of follow-up was 24 months. There were 6 patients with long term postoperative complications (5.4%) including fecal incontinence (1.8%), defecatory urgency (0.9%), chronic pain due to anastomotic inflammation (1.8%), and chronic pain due to anal rectal diverticulum (0.9%). Three patients (2.7%) were reoperated. CONCLUSION: STARR appears to be a safe technique for patients with obstructed defecation. PMID- 22205452 TI - [Influence of fiberform on defecation condition after surgery for benign anorectal lesion]. AB - OBJECTIVE: To explore the influence of fiberform on the defecation condition after surgery for benign anorectal lesion. METHODS: A total of 121 cases undergoing surgery for benign anorectal lesion at the Third Affiliated Hospital of Nanjing University of Traditional Chinese Medicine from October 2009 to February 2010 were randomly divided into the treatment group (n=61) and the control group (n=60) according to random number table. Patients in the treatment group received fiberform granule for 2 weeks while patients in the control group did not receive any medication to promote defecation. Postoperative defecation symptom scores and patient satisfaction were compared between the two groups. RESULTS: On postoperative day 7, patients in the treatment group had a lower defecation smoothness score (62.1% decrease), lower fecal character score (74.3% decrease), lower defecation interval score (80.2% decrease), lower defecation pain score (77.5% decrease), the differences were statistically significant. On postoperative day 14, the degree of decrease of the abovementioned score were 58.3%, 88.5%, 82.8% and 83.1%, respectively. Postoperative patient satisfaction rate in the treatment group was significantly higher than that in the control group(P<0.05). No patient in the treatment group experienced any adverse events such as abdominal pain, diarrhea, and drug dependence. CONCLUSION: Fiberform can effectively prevent defecation disorders such as dry stool, unsmooth defecation, and anorectal pain. PMID- 22205453 TI - [Diagnosis and treatment of slow transit constipation complicated with adult megacolon]. AB - OBJECTIVE: To summarize the experience in the management of slow transit constipation complicated with adult megacolon. METHODS: The clinical data of 32 above patients admitted between October 2007 and June 2011 were retrospectively studied. RESULTS: Thirty-two patients were diagnosed as slow transit constipation according to the Roman III criteria. There were 15 males and 17 females aging from 18 to 56 years old. Sitz marker study showed prolonged colon transit time. Barium enema and defecography suggested bowel stricture locating in the transverse colon (n=3), descending colon (n=4), rectum (n=20), and concurrent transverse colon or descending colon and rectum (n=5). Anal manometry showed that anorectal inhibitory reflex was absent in 23 patients, while the other 9 patients were normal. Procedures performed included segmental colectomy and side-to-side anastomosis (n=1), subtotal colectomy and modified Duhamel anastomosis (n=16), total colectomy and ileal J-pouch Duhamel anastomosis (n=9). There were no postoperative complications. During the follow-up ranging from 3 to 47 months, defacatory function was excellent in 18, good in 9, and moderate in 5 patients. CONCLUSIONS: Adult megacolon should be considered differential diagnosis of slow transit constipation. Detailed history taking and thorough evaluation of testing is the key to obviate misdiagnosis. Extent of resection should include the diseased dilated colon and slow transit colon. PMID- 22205454 TI - [Neutrophil-lymphocyte ratio as a prognostic factor in gastric cancer]. AB - OBJECTIVE: To explore whether neutrophil-lymphocyte ratio (NLR) is an effective prognostic marker in gastric cancer. METHODS: Clinical data of 775 patients with gastric cancer in the First Affiliated Hospital of Sun Yat-sen University from 1994 to 2006 were analyzed retrospectively. According to preoperative NLR, the patients were divided into the low NLR group (NLR<=3.79, n=652) and the high NLR group (NLR>3.79, n=123). The 5-year survival rates of two groups of different TNM stage, different surgical intervention were separately analyzed. RESULTS: The 5 year survival rates in the low NLR group and high NLR group were 44.0% and 12.2% respectively (P<0.01). In different TNM stages: stage I (97.8% vs 33.3%), stage II (55.4% vs 32.0%), stage IIIA (30.2% vs 11.1%), stage IIIB (15.5% vs 8.3%), stage IV (10.7% vs 2.1%), and in different surgical intervention: D1 curative gastrectomy (93.3% 33.3%), D2 group (51.3% vs 20.4%), D3 group (42.4% vs 10.5%), D4 group (14.3% vs 2.0%), and in palliative operation group (8.3% vs 2.2%). There were significant differences of 5-year survival rate in TNM staging and surgical procedures between the high and low NLR groups (all P<0.05). CONCLUSION: Preoperative NLR may be a prognostic marker in patients with gastric cancer. PMID- 22205455 TI - [Association of metabolic syndrome and colorectal cancer]. AB - OBJECTIVE: To evaluate the association between metabolic syndrome and colorectal cancer. METHODS: A multicenter case-control study was conducted. A total of 1506 cases of colorectal cancer (936 males and 570 females), whose clinical data were complete and aged from 30 to 75, were collected in the Third, First and Second People's Hospital of Jingdezhen between 2000 and 2009. A total of 3354 controls (1766 males and 1588 females) were subjects admitted to the above 3 hospitals as cases with acute non-malignant non-digestive diseases. Multiple logistic regression models were used to analyze the association between metabolic syndrome and its components and colorectal cancer. RESULTS: Forty-eight cases of colorectal cancer (3.2%) and 59 controls (1.8%) were diagnosed as metabolic syndrome. Colorectal cancer risk was increased in cases with metabolic syndrome (OR=1.64, 95% CI:1.14-2.49, P<0.05) and in men with metabolic syndrome (OR=1.92, 95% CI:1.27-3.78, P<0.05), but not in women (P>0.05). As the number of component of metabolic syndrome increased, the risk of colorectal cancer increased in men (P<0.01), but not in women (P>0.05). CONCLUSION: Association between metabolic syndrome and colorectal cancer exists in men, but not in women. PMID- 22205456 TI - [Value of the laparoscopy combined with double-balloon enteroscopy in diagnosis and treatment of intestinal diseases]. AB - OBJECTIVE: To evaluate the value of laparoscopy combined with double-balloon enteroscopy (DBE) for the diagnosis and treatment of intestinal diseases. METHODS: Clinical data of 69 cases with suspected small bowel diseases undergoing laparoscopic and DBE for the diagnosis and treatment were retrospectively analyzed. RESULTS: The lesions were found in 48 cases by laparoscopy. DBE was required in the remaining 21 patients to identify the underlying condition. All the operations were successfully completed using the laparoscopic approach, including totally laparoscopic bowel resection (n=11), and laparoscopic-assisted bowel resection (n=58). There were no anastomotic leakage, postoperative bleeding, intestinal obstruction, or wound infection. All the patients were discharged within 7 to 9 days after surgery. Postoperative pathological examination showed vascular abnormally (n=10), gastrointestinal stromal tumor (n=20), intestinal adenocarcinoma (n=5), intestinal neurofibroma (n=2), diverticulum (n=5), intestinal mucosal ulceration (n=8), intestinal tuberculosis (n=3), postoperative pouch bleeding (n=1), intestinal polyp (n=6), Crohn's disease (n=5), Meckel diverticulum (n=2), metastatic kidney cancer (n=1), and metastatic lung cancer (n=1). Length of follow up ranged from 3 months to 4 years, during which no re-bleeding occurred, 2 patients with gastrointestinal stromal tumor died of local recurrence and liver metastasis, 1 patient with adenocarcinoma died of local recurrence involving pancreatic head, duodenum, and mesenteric vessels, 2 patients with metastatic disease died of peritoneal recurrence and liver metastasis. CONCLUSION: Laparoscopic combined with DBE has a high detection rate for small intestinal disease with accurate localization, less trauma, and quicker recovery. PMID- 22205457 TI - [Diagnosis, treatment and prognosis of neuroendocrine carcinoma of the colorectum]. AB - OBJECTIVE: To investigate the diagnosis, treatment and prognosis of colorectal neuroendocrine carcinoma. METHODS: Clinical data of 39 patients with colorectal neuroendocrine carcinoma from Jan 1995 to Jan 2010 were analyzed retrospectively and the related literatures were reviewed. RESULTS: There were 27 males and 12 females. No patients presented endocrinal dysfunction symptoms. Fourteen patients were diagnosed as neuroendocrine cancer by preoperative pathological examination. All the patients received postoperative adjuvant chemotherapy including cis platinum and etoposide. Twenty-two patients underwent curative resection, while 14 underwent palliative resection and 3 underwent biopsy alone. Of the 36 surgical resection specimens, vascular invasion was found in 27 patients (75.0%) and regional lymph node metastasis was found in 29 patients (80.6%). Length of follow-up ranged from 4 to 67 months. The 1-year, 3-year and 5-year survival rates were 48.2%, 16.5% and 6.8%, respectively. Statistically significant differences in survival were observed and associated with tumor staging, vascular invasion and surgery type (P<0.05), but not related to gender, age, tumor location, or diameter (P>0.05). CONCLUSIONS: Clinical symptoms and signs of colorectal neuroendocrine carcinoma are nonspecific with poor prognosis. Tumor staging, vascular invasion and surgical type have potential impact on survival. PMID- 22205458 TI - [Analysis on human papillomavirus 16 and 18 types infection among 805 patients with common anorectal lesions]. AB - OBJECTIVE: To analyze the infection condition of human papillomavirus (HPV) type 16 and 18 in the squamous cells and columnar cells of patients with common anorecatal lesions. METHODS: Infections of HPV type 16 and 18 were determined with real-time fluorescent quantitative PCR in the wax-embedded surgical specimen of 805 patients with common anorectal diseases. RESULTS: The overall infection rate among 805 patients with anorecatal lesions was 66.1% (532/805). The infection rate was 82.6% (95/115) in patients with mixed hemorrhoids, 76.5% (88/115) in anal papillary fibromas, 74.8% (86/115) in internal hemorrhoids, 72.2% (83/115) in fistulas, 69.6% (80/115) in external hemorrhoids, 47.8% (55/115) in anal perianal abscesses, and 39.1% (45/115) in anal fissures. CONCLUSION: Infection rate of HPV type 16, 18 in common anorectal lesions is high. PMID- 22205459 TI - [Association between primary tumor regression and lymph node status after neoadjuvant chemoradiotherapy in mid and low rectal cancer]. AB - OBJECTIVE: To analyze the association between the response of primary tumor to neoadjuvant chemoradiotherapy (CRT) and lymph node status in mid and low rectal cancer. METHODS: Seventy-one patients with locally advanced mid and low rectal cancer underwent preoperative CRT followed by surgery. Surgical specimens were examined by surgeons and pathologists to obtain more lymph nodes and the histological sections were examined. Tumor responses to preoperative CRT were assessed in terms of tumor downstaging and tumor regression. Statistical analyses were performed to investigate the relationship between tumor regression and lymph node status. RESULTS: All the patients completed the neoadjuvant CRT. Twelve patients achieved pathological complete response, of whom one was not operated and on surveillance. Pathological examination of the remaining 70 patients showed that the tumor was downstaged to T 0-2 group in 39 patients, among whom 5 patients (12.8%) had positive lymph nodes. Tumor was not downstaged in 31 patients, of whom 10 patients (32.3%) had positive nodes. The difference between the two groups was statistically significant (P=0.029). CONCLUSION: Tumor regression is consistent with the reduction of lymph node metastasis after preoperative CRT. PMID- 22205460 TI - [Study of healing mechanism of acellular dermal matrix in the treatment of anal fistula]. AB - OBJECTIVE: To evaluate the efficacy of acellular dermal matrix(ADM) in the closure of anal fistula in an experimental porcine model, and to explore its healing mechanism. METHODS: The fistula-in-ano model was created and treated with ADM in the porcine model (n=14). Fistula specimens were obtained at hour 12, 24 and day 3, 7, 14, 28, 60 respectively with 2 pigs in each time point. Hematoxylin and eosin staining and immunohistochemical staining for the alpha smooth muscle actin (alpha-SMA) were performed. RESULTS: At 12 hours after implantation, neutrophils and scattered cells with a fibroblastic appearance were present at the interface and began to infiltrate into the ADM. The cell density increased from hour 12 (218.2+/-58.2) to day 7(998.7+/-128.0) (P<0.01), and decreased from day 7 to day 28. Mature vessels and myofibroblasts stained with alpha-SMA were identified at the edge of ADM at day 7. The density of vessels (11.2+/-3.3 vs. 30.5+/-5.2, P<0.01) and myofibroblasts (3.8+/-0.8 vs. 6.8+/-0.4, P<0.01) increased from day 7 to day 14. Partially organized bundles of muscle were found at day 60. CONCLUSIONS: ADM is a reasonable new option for the closure of anal fistula. The ability of ADM to become vascularized and remodeled by autologous cells may be advantageous for anal fistula healing and other chronic septic wound. PMID- 22205461 TI - [Association of the changes of central serotonin and peripheral blood free amino acids with postoperative fatigue after abdominal surgery]. AB - OBJECTIVE: To explore the mechanism of postoperative fatigue syndrome(POFS) by detecting the change of central monoamine neurotransmitters in a rat model after major abdominal surgery. METHOD: Eighty-four rats were randomly divided into fatigue assessment groups (including model group and sham group) and experimental groups (including postoperative day 1, 3, 5, 7, and 14 recovery groups and the corresponding control groups). Postoperative fatigue was evaluated after surgery. The brains were removed thereafter to detect the levels of 5-hydroxytryptamine (5 HT), norepinephrine (NE), dopamine (DA) in the hippocampus, midbrain, hypothalamus by high performance liquid chromatography. Serum free tryptophan (f Trp) and branched-chain amino acids (BCAA) were measured. RESULTS: The level of 5 HT increased to the highest at postoperative day 3, but reduced rapidly to the minimum at postoperative day 5, and then gradually recovered to the preoperative level. There was significant difference of 5-HT among experimental groups (P<0.05), also between the postoperative 24 hrs group and control groups (P<0.05). f-Trp and the ratio of f-Trp/BCAA increased in the early postoperative period, reduced to minimum at postoperative day 5. f-Trp was still lower compared to the control group at postoperative day 14, while the ratio of f-Trp/BCAA and BCAA restored to control level. Both of them were significantly different among experimental groups (P<0.05), also between the experimental groups and control groups (P<0.05). CONCLUSION: Changes of f-Trp, the ratio of f-Trp/BCAA, and central 5-HT may play an important role in the development of POFS. PMID- 22205462 TI - [Preparation of carbon nanoparticle paclitaxel suspension and pharmacokinetic study of intraperitoneal chemotherapy]. AB - OBJECTIVE: To prepare carbon nanoparticle-paclitaxel suspension(CNPS) and to study the pharmacokinetics of intraperitoneal chemotherapy with CNPS. METHODS: Saturated absorption capacity of carbon nanoparticle suspension (CNS) and paclitaxel were detected by high performance liquid chromatography in order to prepare the above suspension. Wistar rats were randomly divided into the experimental group (A) and the control group (B), to which intraperitoneal injections of CNPS and paclitaxel were given respectively. At different time points, measure the blood samples, mesenteric lymph nodes, and intraperitoneal lavage fluid were collected to measure the concentration of paclitaxel. RESULTS: One ml CNS could absorb 7 mg paclitaxel by maximum. The ratio of area under the curve (AUC) in the plasma of group A to group B was 0.63. The ratio of AUC in lymph nodes of group A to group B was 0.75 and that in intraperitoneal lavage fluid was 1.25. The metabolic half-life (t1/2) of paclitaxel in the plasma of group A was 1.61 times as long as that of group B. The t1/2 of paclitaxel in intraperitoneal lavage fluid of group A was 0.88 as long as that of Group B. The t1/2 of paclitaxel in lymph nodes of group A was 1.10 as long as that of Group B. CONCLUSIONS: CNS has a high absorption capacity with paclitaxel. Intraperitoneal chemotherapy by CNPS is characterized by low drug concentration in the blood, high drug concentration in the peritoneal cavity and high safety. However, the targeting and lymphatic retention effect are not significant. The mechanism warrants further investigation. PMID- 22205465 TI - Functional voice and swallowing outcomes after robotic thyroidectomy by a gasless unilateral axillo-breast approach: comparison with open thyroidectomy. AB - BACKGROUND: Voice and swallowing alterations are common complaints after thyroidectomy, even in the absence of laryngeal nerve impairment. However, voice and swallowing functions after robotic thyroidectomy have not been thoroughly investigated. This study compared the functional outcomes for voice and swallowing after robotic thyroidectomy and conventional open thyroidectomy. METHODS: The study prospectively analyzed the voice and swallowing functions of patients with thyroid nodules who underwent robotic thyroidectomy by a gasless unilateral axillo-breast (GUAB) approach (50 cases) or by conventional open thyroidectomy (61 cases) from September 2009 to October 2010. Videolaryngostroboscopy or flexible laryngoscopy was performed pre- and postoperatively. Subjective voice and swallowing alterations were assessed by questionnaire preoperatively and then 1 day, 1 week, 1 month, 3 months, and 6 months postoperatively. In addition, objective acoustic voice analysis was performed using a Multidimensional Voice Program, with Voice Range Profiles and maximum phonation times measured preoperatively and then 1 week, 1 month, 3 months, and 6 months postoperatively. RESULTS: Subjective postoperative voice function was significantly better in the robotic group at 1 day, 1 month, and 3 months postoperatively than in the open group. The mean values of fundamental frequency, jitter, shimmer and noise-to-harmonic ratio before and after surgery did not differ between the two groups. However, the frequency range and the highest frequency were significantly better in the robotic group than in the open group at 3 months postoperatively. Subjective swallowing function did not differ between the two groups. CONCLUSION: Postoperative voice function is better with robotic thyroidectomy using the GUAB approach than with conventional open thyroidectomy. This is an advantage of robotic thyroidectomy by the GUAB approach in addition to the excellent cosmesis. PMID- 22205467 TI - Supervision in behavioral health: implications for students, interns, and new professionals. AB - Behavioral health providers (BHPs) are trained by their respective programs and professions on the importance of communicating with other professionals around patient care, yet few are trained on how to provide collaborative care and work as part of a team. New clinical innovation models, such as integrated care, punctuate the need to further develop training methods to best equip the next generation of BHPs to work in collaborative settings. Supervision is a tool that students, interns, and new professionals can use to help them navigate new and unfamiliar territory in health care settings. This manuscript will describe the steps of choosing a supervisor, provide elements that must be considered when developing a supervision contract, offer a template for crafting a document that will assist with assessing fidelity to one's practice and maximize consistency and productivity in the supervision process, and detail the potential supervision dynamics in different levels of clinical collaboration. Supervision that is tailored to the BHPs level of clinical collaboration in their given practice setting can provide a structure for the supervision process. PMID- 22205469 TI - Neodymium:YAG laser treatment of lower leg telangiectasia: a new minimally invasive approach. AB - The aim of this study was to validate the safety and effectiveness of a new therapeutic procedure for the treatment of lower leg telangiectasia without clinical vein insufficiency. A group of 20 healthy women aged between 24 and 47 years (mean+/-sem 37.05 +/- 1.47) with lower leg telangiectasia without clinical vein insufficiency, previously investigated by echo colour Doppler sonography, were recruited and were treated with neodymium:YAG laser (mean+/-sem 2.5 +/- 0.11 sessions). Good or excellent results were obtained in 16 patients and the improvements were statistically significant (p < 0.01). Out of the 20 patients, 16 were satisfied with the procedure. We strongly support laser treatment of lower leg telangiectasia since it allows injection of chemicals to be avoided, and changes the stromal microarchitecture rearranging the fibroblast network into a more resistant pattern reducing the likelihood of relapse. PMID- 22205468 TI - Hospitalizations for chronic pancreatitis in Allegheny County, Pennsylvania, USA. AB - BACKGROUND/AIMS: Population-based estimates for chronic pancreatitis (CP) are scarce. We determined incident CP hospitalization rates and the risk of pancreatitis-related readmissions in Allegheny County, Pennsylvania, USA. METHODS: We used Pennsylvania Health Care Cost Containment Council (PHC4) dataset to identify all unique White and Black Allegheny County residents with incident hospitalization for CP from years 1996-2005. We noted presence of alcoholism codes (from one year before index hospitalization until last contact) and pancreatitis-related readmissions until the third quarter of 2007. Age-, sex-, and race-adjusted (to US 2000 population) rates/100,000 were calculated. RESULTS: 988 unique County residents with incident hospitalization for CP were identified. Of these, 37.6% also received alcoholism codes. Overall hospitalization rate was 7.75/100,000 (95% CI 7.26-8.24), which remained stable throughout the study period. Patients with alcoholism codes were significantly younger (47.2 vs. 58.0 years), more likely to be male (71.4 vs. 36.6%), and Black (38.5 vs. 17.7%). Hospitalization rates were significantly higher (2.4-fold) in Blacks (vs. Whites), particularly for those with alcoholism codes. During follow-up (median 45 months), pancreatitis-related readmissions were common, significantly more so for patients with alcoholism codes. CONCLUSIONS: CP hospitalization rates over a one-decade period were stable. Readmissions were highest among patients with a diagnosis of alcoholism. and IAP. PMID- 22205470 TI - Laser biomodulation of normal and neoplastic cells. AB - This study was designed to determine the laser dose for the stimulation, zero bioactivation, and inhibition of normal and neoplastic cells in vitro. The medical use of laser biomodulation has been occurring for decades in the area of tissue healing and inflammatory conditions. The potential to modulate the regeneration and differentiation of early cellular precursors by laser photons is a valuable endeavor searching for novel and efficient methods. A 35-mW HeNe (632.8-nm) laser and power density of 1.25 mW/cm(2) was used to irradiate tissue culture dishes seeded with 400 cells/dish of normal cells (CHO, CCL-226, 3 T3, and HSF) and neoplastic cells (EMT-6 and RIF-1). All cell lines were cultured using DMEM supplemented with 10% and 5% FBS, 2 mM glutamine and 100 U pen-strep antibiotic. Irradiation times of 16, 32, 48, 64, 80, 96, 112, 128, 144, and 160 s for three consecutive days to deliver cumulative doses of 60, 120, 180, 240, 300, 360, 420, 480, 540, and 600 mJ/cm(2) were done, respectively. Cell cultures were stained and colony-forming efficiency was determined. Data analysis was done using Student's t test, alpha = 0.05. A trend of stimulation, zero-bioactivation, and inhibition in all cell lines was observed except for CCL-226 which gave a pattern of inhibition, zero-bioactivation, and inhibition. The optimum biostimulatory dose was at 180 mJ/cm(2) and bioinhibitory doses were from 420-600 mJ/cm(2) cumulative doses. This study established the dose-dependency of cell growth to laser treatments, that the extent of cellular proliferation is influenced by the type of cells involved, and the risk when laser irradiation is performed on patients with undiagnosed neoplasms and during pregnancy. On the other hand, the ability of laser irradiation to regulate embryonic fibroblasts and human skin fibroblast in vitro suggests possible laser biomodulatory effects on embryonic and adult stem cells directed for tissue regeneration. Studies on the effects of light treatments exploring different laser parameters for the clonal expansion and differentiation of stem cells are recommended. PMID- 22205471 TI - Assessment of metal pollution in soils from a former Havana (Cuba) solid waste open dump. AB - Concentrations of cobalt, nickel, cooper, zinc and lead in the top-soils (0-10 cm) from a former Havana solid waste open dump were estimated by X-ray fluorescence analysis. The mean metal contents in the dump topsoil samples (in mg kg(-1): 8.4 +/- 2.7 for cobalt, 50 +/- 27 for nickel, 252 +/- 80 for copper, 489 +/- 230 for zinc and 276 +/- 140 for lead) were compared with mean concentrations from Havana urban soils and from other solid waste disposals around the world. The comparison with Dutch soil quality guidelines showed a serious cooper contamination and a slight contamination with the rest of determined metals. The values of the integrated pollution index (mean index = 3.5) indicated that dump soils are highly contaminated by metals, and the enrichment index values shows that metal concentrations on the studied locations are above the permissible levels for urban agriculture. PMID- 22205472 TI - Assessing natural isothiocyanate air emissions after field incorporation of mustard cover crop. AB - A regional air assessment was performed to characterize volatile natural isothiocyanate (NITC) compounds in air during soil incorporation of mustard cover crops in Washington State. Field air sampling and analytical methods were developed specific to three NITCs known to be present in air at appreciable concentrations during/after field incorporation. The maximum observed concentrations in air for the allyl, benzyl, and phenethyl isothiocyanates were respectively 188, 6.1, and 0.7 MUg m(-3) during mustard incorporation. Based on limited inhalation toxicity information, airborne NITC concentrations did not appear to pose an acute human inhalation exposure concern to field operators and bystanders. PMID- 22205494 TI - Measuring the allocation of attention in the Stroop task: evidence from eye movement patterns. AB - Attention plays a crucial role in the Stroop task, which requires attending to less automatically processed task-relevant attributes of stimuli and the suppression of involuntary processing of task-irrelevant attributes. The experiment assessed the allocation of attention by monitoring eye movements throughout congruent and incongruent trials. Participants viewed two stimulus arrays that differed regarding the amount of items and their numerical value and judged by manual response which of the arrays contained more items, while disregarding their value. Different viewing patterns were observed between congruent (e.g., larger array of numbers with higher value) and incongruent (e.g., larger array of numbers with lower value) trials. The direction of first saccades was guided by task-relevant information but in the incongruent condition directed more frequently towards task-irrelevant information. The data further suggest that the difference in the deployment of attention between conditions changes throughout a trial, likely reflecting the impact and resolution of the conflict. For instance, stimulus arrays in line with the correct response were attended for longer and fixations were longer for incongruent trials, with the second fixation and considering all fixations. By the time of the correct response, this latter difference between conditions was absent. Possible mechanisms underlying eye movement patterns are discussed. PMID- 22205495 TI - Detecting perturbations in polyrhythms: effects of complexity and attentional strategies. AB - Jones et al. in Journal of Experimental Psychology Human Perception and Performance 21:293-307, 1995, showed that a temporal perturbation is easier to detect in a 3:2 polyrhythm than in a single-stream isochronous baseline condition if the two isochronous pulse streams forming the polyrhythm are perceptually integrated: integration creates shorter inter-onset interval (IOI) durations that facilitate perturbation detection. The present study examined whether this benefit of integration outweighs the potential costs imposed by the greater IOI heterogeneity and memory demands of more complex polyrhythms. In "Experiment 1", musically trained participants tried to detect perturbations in 3:5, 4:5, 6:5, and 7:5 polyrhythms having one of two different pitch separations between pulse streams, as well as in an isochronous baseline condition. "Experiment 2" included an additional 2:5 polyrhythm, additional pitch separations, and instructions to integrate or segregate the two pulse streams. In both experiments, perturbation detection scores for polyrhythms were below baseline, decreased as polyrhythm complexity increased, and tended to be lower at a smaller pitch separation, with little effect of instructions. Clearly, polyrhythm complexity was the main determinant of detection performance, which is attributed to the interval heterogeneity and/or memory demands of the pattern formed by the integrated pulse streams. In this task, perceptual integration was disadvantageous, but apparently could not be avoided. PMID- 22205497 TI - Characteristics and distribution of complex fractionated atrial electrograms and the dominant frequency during atrial fibrillation: relationship to the response and outcome of circumferential pulmonary vein isolation. AB - BACKGROUND: Although sites of complex fractionated electrograms (CFAEs) and dominant frequency (DF) are known to be critical for the maintenance of atrial fibrillation (AF), spatial distribution of CFAEs and DF and their impact on the outcome of AF ablation remain unclear. METHODS: We created CFAE and DF maps of the left atrium (LA), right atrium, and pulmonary veins (PVs) with a NavX mapping system and simultaneously calculated the DF values with a Bard LabSystem Pro in 40 patients with AF (nonparoxysmal, n = 16). RESULTS: In 19 patients in whom circumferential PV isolation (CPVI) terminated AF, there was a high DF in the PVs (Bard-based DF value, 6.70 +/- 1.01 Hz), low DF in the LA body (5.94 +/- 0.75 Hz), and a significant PV-to-LA body DF gradient (0.76 +/- 0.65 Hz), and the CFAEs were located mainly in the PV antrum. In the 21 patients not responding to CPVI, a high DF was located in both the PVs (7.04 +/- 0.81 Hz) and LA body (6.75 +/- 0.81 Hz), and therefore, the PV-to-LA body DF gradient was smaller than that in the CPVI responders (0.29 +/- 0.52 Hz, P = 0.0160), and the CFAEs extended to the LA body. The higher DF in the LA body, nonparoxysmal AF, and longer AF duration remained as independent predictors of a post-ablation AF recurrence by using a multivariate analysis. CONCLUSIONS: A higher LA-DF value, smaller PV-to LA DF gradient, and wider LA-CFAE distribution were noted more often in the nonresponders to CPVI than in the responders. This suggested the presence of an arrhythmogenic substrate in the LA beyond the PVs in patients whose AF persisted after CPVI, which was further associated with post-ablation AF recurrence. PMID- 22205496 TI - A randomized trial of budiodarone in paroxysmal atrial fibrillation. AB - OBJECTIVE: The aim of this study was to investigate the preliminary safety and efficacy of three doses of budiodarone in patients with paroxysmal atrial fibrillation. BACKGROUND: Budiodarone is a chemical analogue of amiodarone and shares its mixed ion channel electrophysiological properties. It has a shorter half-life than amiodarone. METHODS: Patients with paroxysmal atrial fibrillation and a previously implanted dual-chamber pacemaker capable of storing electrograms for at least 4 weeks were enrolled. Pacemaker memories were used to quantify atrial tachycardia/atrial fibrillation burden (AT/AFB). All antiarrhythmic drugs were stopped for greater than five half-lives and amiodarone greater than 3 months prior to enrollment. Following a 4-week baseline period to assess AT/AFB off antiarrhythmic drugs, patients with AT/AFB between 3% and 70% were blindly randomized to placebo, 200, 400, or 600 mg BID of budiodarone for 12 weeks followed by a 4-week washout period. Pacemakers were interrogated and safety assessed every 4 weeks. Pacemaker-derived electrograms were adjudicated blinded to treatment assignment. The primary study endpoint was percent change from baseline AT/AFB over 12 weeks of treatment compared to placebo. RESULTS: Of 72 randomized patients, 61 completed the study. The median reduction of AT/AFB for the 400 and 600 mg BID groups vs. placebo was 54% and 74% (p = 0.01 and 0.001), respectively. The budiodarone dose-response was statistically significant (p < 0.001). Number and duration of AT/AF episodes were reduced. CONCLUSIONS: In this preliminary study, budiodarone at both higher doses significantly reduced AT/AFB. The study is novel because dual-chamber pacemakers, previously placed for standard clinical indications, were successfully used to monitor AT/AFB. PMID- 22205499 TI - Functional assessment of adipose stem cells for xenotransplantation using myocardial infarction immunocompetent models: comparison with bone marrow stem cells. AB - Recently, preclinical studies have shown that allogeneic adipose-derived stem cells (ASCs), like bone marrow-derived mesenchymal stem cell (BMSCs) have significant clinical benefits in treating cardiovascular diseases, such as ischemic/infarcted heart. In this study, we tested whether ASCs are also immune tolerant, such that they can be used as universal donor cells for myocardial regenerative therapy. The study also focuses on investigating the potential therapeutic effects of human ASCs (hASCs) for myocardial infarction in xenotransplant model, and compares its effects with that of hBMSCs. The in vitro study confirms the superior proliferation potential and viability of hASCs under normoxic and stressed hypoxic conditions compared with hBMSCs. hASCs also show higher potential in adopting cardiomyocyte phenotype. The major findings of the in vivo study are that (1) both hASCs and hBMSCs implanted into immunocompetent rat hearts with acute myocardial infarction survived the extreme environment of xenogeneic mismatch for 6 weeks; (2) both hASCs and hBMSCs showed significant improvement in myocardial pro/anti-inflammatory cytokine levels with no detectable inflammatory reaction, despite the lack of any immunosuppressive therapy; and (3) hASCs contributed to the remarkable improvement in cardiac function and reduced infarction which was significantly better than that of hBMSC and untreated control groups. Thus, our findings suggest the feasibility of using ASCs, instead of BMSCs, as universal donor cells for xenogeneic or allogeneic cell therapy. PMID- 22205500 TI - Azithromycin attenuates fibroblast growth factors induced vascular endothelial growth factor via p38(MAPK) signaling in human airway smooth muscle cells. AB - The airways in asthma and COPD are characterized by an increase in airway smooth muscle (ASM) mass and bronchial vascular changes associated with increased expression of pro-angiogenic growth factors, such as fibroblast growth factors (FGF-1 and FGF-2) and vascular endothelial growth factor (VEGF). We investigated the contribution of FGF-1/-2 in VEGF production in ASM cells and assessed the influence of azithromycin and dexamethasone and their underlying signaling mechanisms. Growth-synchronized human ASM cells were pre-treated with MAPK inhibitors, U0126 for ERK1/2(MAPK) and SB239063 for p38(MAPK) as well as with dexamethasone or azithromycin, 30 min before incubation with FGF-1 or FGF-2. Expression of VEGF (VEGF-A, VEGF121, and VEGF165) was assessed by quantitative PCR, VEGF release by ELISA and MAPK phosphorylation by Western blotting. Both FGF 1 and FGF-2 significantly induced mRNA levels of VEGF-A, VEGF121, and VEGF165. The VEGF protein release was increased 1.8-fold (FGF-1) and 5.5-fold (FGF-2) as compared to controls. Rapid transient increase in ERK1/2(MAPK) and p38(MAPK) phosphorylation and subsequent release of VEGF from FGF-1 or FGF-2-treated ASM cells were inhibited by respective blockers. Furthermore, azithromycin and dexamethasone significantly reduced both the VEGF release and the activation of p38(MAPK) pathway in response to FGF-1 or FGF-2 treatment. Our Results demonstrate that FGF-1 and FGF-2 up-regulate VEGF production via ERK1/2(MAPK) and p38(MAPK) pathways. Both azithromycin and dexamethasone elicited their anti angiogenic effects via p38(MAPK) pathway in vitro, thereby suggesting a possible therapeutic approach to tackle VEGF-mediated vascular remodeling. PMID- 22205502 TI - Differences in salinity tolerance and gene expression between two populations of Atlantic cod (Gadus morhua) in response to salinity stress. AB - Populations of marine fish, even from contrasting habitats, generally show low genetic differentiation at neutral genetic markers. Nevertheless, there is increasing evidence for differences in gene expression among populations that may be ascribed to adaptive divergence. Studying variation in salinity tolerance and gene expression among Atlantic cod (Gadus morhua) from two populations distributed across a steep salinity gradient, we observed high mortality (45% North Sea cod and 80% Baltic Sea cod) in a reciprocal common garden setup. Quantitative RT-PCR assays for expression of hsp70 and Na/K-ATPase alpha genes demonstrated significant differences in gene regulation within and between populations and treatment groups despite low sample sizes. Most interesting are the significant differences observed in expression of the Na/K-ATPase alpha gene in gill tissue between North Sea and Baltic cod. The findings strongly suggest that Atlantic cod are adapted to local saline conditions, despite relatively low levels of neutral genetic divergence between populations. PMID- 22205501 TI - Dysregulation of PTEN in cardiopulmonary vascular remodeling induced by pulmonary hypertension. AB - Pulmonary hypertension (PH) is a disorder of lung vasculature characterized by arterial narrowing. Phosphatase-and-tensin homolog on chromosome 10 (PTEN), associated in the progression of multiple cancers, is implicated in arterial remodeling. However, the involvement of PTEN in PH remains unclear. The objective of the present study was to determine the role of PTEN in pulmonary vascular remodeling using established models of PH. The study used rat models of PH, induced by monocrotaline (MCT) administration (60 mg/kg) or continuous hypoxic exposure (10% oxygen) for 3 weeks. Pulmonary artery smooth muscle cells (SMCs) were used for in vitro confirmation. Development of PH was verified by hemodynamic, morphological and histopathology analyses. PTEN and key downstream proteins in pulmonary and cardiac tissues were analyzed by western blotting and RT-PCR. PTEN was significantly decreased (MCT, 53%; Hypoxia, 40%), pAkt was significantly increased (MCT, 42%; Hypoxia, 55%) in tissues of rats with PH. Similar results were observed in SMCs exposed to hypoxia (1% oxygen) for 48 h. Ubiquitination assay showed that PTEN degradation occurs via proteasomal degradation pathway. Western blotting demonstrated a significant downregulation of cell-cycle regulatory proteins p53 and p27, and upregulation of cyclin-D1 in the lungs of both models. The results showed that PTEN-mediated modulation of PI3K pathway was independent of the focal adhesion kinase and fatty acid synthase. The study, for the first time, established that PTEN plays a key role in the progression of pulmonary hypertension. The findings may have potential for the treatment of pulmonary hypertension using PTEN as a target. PMID- 22205503 TI - Reduced difference of alpha2-plasmin inhibitor levels between plasma and serum in patients with severe factor XIII deficiency, including autoimmune hemorrhaphilia due to anti-factor XIII antibodies. AB - Coagulation factor XIII/13 (FXIII/13) stabilizes fibrin molecules by creating crosslinks with other fibrin molecules as well as with alpha2-plasmin inhibitor (alpha2-PI). "Hemorrhagic acquired FXIII/13 deficiency" was formerly considered rare, but has been increasing recently in Japan. During the 10 months of our nationwide campaign, we diagnosed five new patients with "acquired hemorrhaphilia due to anti-FXIII/13 autoantibodies," after examining 20 newly suspected cases of "hemorrhagic acquired FXIII/13 deficiency." When FXIII/13 activity was reduced to less than 50% of normal, it was proportional to the difference in alpha2-PI levels between plasma and serum (plasma-serum alpha2-PI), likely due to its cross linking to fibrin by activated FXIII/13. Accordingly, decreased amounts of the plasma-serum alpha2-PI ex vivo may reflect reduced FXIII/13 activity in vivo. The plasma-serum alpha2-PI may thus also be a useful diagnostic marker for severe FXIII/13 deficiency. PMID- 22205504 TI - Prognostic significance of absolute lymphocyte count at diagnosis of diffuse large B-cell lymphoma: a meta-analysis. AB - The prognostic value of absolute lymphocytic count (ALC) has been a recent matter of debate in the study of non-Hodgkin-lymphoma. To evaluate the prognostic value of ALC at diagnosis in patients with diffuse large B-cell lymphoma (DLBCL), we performed a meta-analysis of published studies that provided survival information with reference to ALC at diagnosis. Six studies covering a total of 1,206 subjects were included in this analysis. The summary hazard ratios of low ALC for overall survival were 2.72 (95% confidence interval (CI) 2.15-3.45, P < 0.001) in the entire population, 2.96 (95% CI 2.04-4.29, P < 0.001) in the population that received CHOP, and 2.78 (95% CI 1.87-4.13, P < 0.001) in the population that received R-CHOP. The corresponding ratios for progression-free survival were 2.79 (95% CI 1.90-4.11, P < 0.001) in the entire population, and 2.56 (95% CI 1.66 3.96, P < 0.001) in the population that received R-CHOP. In conclusion, our systematic analysis suggests that low ALC has an adverse effect on outcome in DLBCL. Although it should be borne in mind that this meta-analysis was mainly based on data abstracted from observational studies, these results may justify risk-adapted therapeutic strategies for DLBCL to account for ALC at diagnosis. PMID- 22205505 TI - Lateral epicondylitis and beyond: imaging of lateral elbow pain with clinical radiologic correlation. AB - The diagnosis of lateral epicondylitis is often straightforward and can be made on the basis of clinical findings. However, radiological assessment is valuable where the clinical picture is less clear or where symptoms are refractory to treatment. Demographics, aspects of clinical history, or certain physical signs may suggest an alternate diagnosis. Knowledge of the typical clinical presentation and imaging findings of lateral epicondylitis, in addition to other potential causes of lateral elbow pain, is necessary. These include entrapment of the posterior interosseous and lateral antebrachial cutaneous nerves, posterolateral rotatory instability, posterolateral plica syndrome, Panner's disease, osteochondritis dissecans of the capitellum, radiocapitellar overload syndrome, occult fractures and chondral-osseous impaction injuries, and radiocapitellar arthritis. Knowledge of these potential masquerades of lateral epicondylitis and their characteristic clinical and imaging features is essential for accurate diagnosis. The goal of this review is to provide an approach to the imaging of lateral elbow pain, discussing the relevant anatomy, various causes, and discriminating factors, which will allow for an accurate diagnosis. PMID- 22205506 TI - The spectrum of HIV-related nephropathy in children. AB - BACKGROUND: Despite the burden of human immunodeficiency virus (HIV) disease in Southern Africa, there have been few reports of HIV-related nephropathy in children. This study outlines the spectrum of HIV-1-related kidney diseases of children in KwaZulu-Natal, South Africa. METHODS: A review of the clinical presentation, laboratory and histopathological findings of children diagnosed with HIV-related nephropathy. RESULTS: Forty-nine out of 71 children (1-16 years old) with HIV-1 related nephropathy underwent kidney biopsy. The most common histopathological finding was focal segmental glomerulosclerosis (FSGS), which was present in 32 (65.3%) children; 13 (26.5%) having collapsing glomerulopathy and 19 (38.8%) classic FSGS. The majority of patients showed haematological (86.4%) and electrolyte abnormalities (69.4%). Renal impairment was present in 41% of patients on initial presentation. However, end-stage kidney disease was present in only 4% of these patients. All patients were treated with highly active anti-retroviral therapy (HAART), the majority (79.6%) showed decreased proteinuria with 38.8% having complete remission. CONCLUSIONS: This study, one of the largest series of children reported from Africa, demonstrates that nephrotic syndrome due to HIV-associated nephropathy (HIVAN) is the commonest presentation of HIV-related nephropathy in childhood. Highly active anti-retroviral therapy in combination with angiotensin-converting enzyme antagonists is highly effective in decreasing proteinuria and preserving renal function. PMID- 22205507 TI - Vascular access: choice and complications in European paediatric haemodialysis units. AB - BACKGROUND: European and U.S. guidelines emphasise that permanent vascular access in the form of arteriovenous fistulae (AVF) or grafts (AVG) are preferable to central venous catheters (CVC) in paediatric patients on long-term haemodialysis. We report vascular access choice and complication rates in 13 European paediatric nephrology units. METHODS: A survey of units participating in the European Pediatric Dialysis Working Group requesting data on type of vascular access, routine care and complications in patients on chronic haemodialysis between March 2010 and February 2011. RESULTS: Information was complied on 111 patients in 13 participating centres with a median age of 14 (range 0.25-20.2) years. Central venous catheters were used in 67 of 111 (60%) patients, with 42 patients (38%) having an AVF and two patients (2%) having an AVG. Choice of vascular access was significantly related to patient age, with patients with AVF/AVG having a median age of 16 years compared to 12 years for patients with CVCs (p < 0.001). Routine CVC exit site care and catheter lock solution use differed between centres. CVC infections requiring intravenous antibiotics were reported at a rate of 1.9 and exit site infections at a rate of 1.8 episodes/1000 catheter days. Overall infective complications necessitating CVC change occurred at a rate of 0.9 episodes/1000 catheter days. No infective complications were reported in patients with AVF/AVG access. The rate of CVC infections requiring intravenous antibiotics was significantly lower in patients in whom CVC exit sites were cleaned weekly as opposed to every dialysis session (relative risk with every session cleaning vs. weekly cleaning 2.58, 95% confidence interval 1.17-5.69). Catheter malfunction (inadequate blood flow) was a more prevalent complication necessitating 22.4 thrombolytic interventions/1000 catheter days and 2.1 CVC changes/1000 catheter days. CONCLUSIONS: Central venous catheters remain the predominant choice of vascular access in Europe despite problems of malfunction and infection. AVF/AVG were predominantly used in adolescents without reported complications. More regular exit site cleaning may predispose to CVC infection, but this observation requires prospective evaluation. PMID- 22205508 TI - Linear nevus sebaceous syndrome with hypophosphatemic rickets with elevated FGF 23. AB - BACKGROUND: Linear nevus sebaceous syndrome (LNSS) is a rare congenital neuroectodermal disorder characterized by involvement of the skeleton and central nervous system. CASE: We report the case of a 5-year-old girl who had LNSS with hypophosphatemic rickets and multiple fractures of her extremities. Biochemical tests revealed a high serum level of fibroblast growth factor-23 (FGF-23) but normal levels of immunoglobulin E (IgE) and parathormone (PTH). FGF-23 mRNA expression in the skin lesions of our patient's skin was found to be below the limit of detection in all samples tested by quantitative-PCR analysis. CONCLUSIONS: It is possible that an as-yet unidentified substance increases FGF 23 expression LNS lesions. PMID- 22205509 TI - GeneProf: analysis of high-throughput sequencing experiments. PMID- 22205510 TI - Gene expression deconvolution in linear space. PMID- 22205512 TI - Optimal enzymes for amplifying sequencing libraries. PMID- 22205513 TI - Gene editing: not just for translation anymore. PMID- 22205514 TI - Zinc-finger nucleases: how to play two good hands. PMID- 22205516 TI - Running in reverse: rhodopsins sense voltage. PMID- 22205517 TI - Tracking genomic hydroxymethylation by the base. PMID- 22205518 TI - Power tools for gene expression and clonal analysis in Drosophila. AB - The development of two-component expression systems in Drosophila melanogaster, one of the most powerful genetic models, has allowed the precise manipulation of gene function in specific cell populations. These expression systems, in combination with site-specific recombination approaches, have also led to the development of new methods for clonal lineage analysis. We present a hands-on user guide to the techniques and approaches that have greatly increased resolution of genetic analysis in the fly, with a special focus on their application for lineage analysis. Our intention is to provide guidance and suggestions regarding which genetic tools are most suitable for addressing different developmental questions. PMID- 22205521 TI - Contemporary neurotoxins and injectable fillers. PMID- 22205519 TI - A guide to analysis of mouse energy metabolism. AB - We present a consolidated view of the complexity and challenges of designing studies for measurement of energy metabolism in mouse models, including a practical guide to the assessment of energy expenditure, energy intake and body composition and statistical analysis thereof. We hope this guide will facilitate comparisons across studies and minimize spurious interpretations of data. We recommend that division of energy expenditure data by either body weight or lean body weight and that presentation of group effects as histograms should be replaced by plotting individual data and analyzing both group and body composition effects using analysis of covariance (ANCOVA). PMID- 22205522 TI - The use of poly-L-lactic acid filler in facial aesthetics. AB - The use of poly-L-lactic acid in facial aesthetic surgery has been utilized for over a decade. More recently approved by the Food and Drug Administration as a stimulatory filler for the correction of shallow to deep facial lines, it is gaining popularity in the United States. The advantages of its use include its stimulatory action on collagen formation, the longevity of its effect, and the low side effect profile. Despite these advantages, meticulous preparation practices and injection techniques are paramount to achieving a satisfactory outcome. We review poly-L-lactic acid as a filler, along with its associated side effects, indications of use, and techniques of injection. PMID- 22205523 TI - Calcium hydroxyapatite fillers. AB - Calcium hydroxyapatite fillers have unique advantages over other fillers in regards to duration of action and volume of product required for augmentation, especially in the midface and lower face. In this article, we describe our experience with calcium hydroxyapatite fillers and compare them with other available filler products. PMID- 22205524 TI - Neuromodulators: available agents, physiology, and anatomy. AB - Neuromodulators have risen to the forefront of aesthetic medicine. By reversibly relaxing target muscles, neuromodulators exhibit their effect by softening hyperfunctional lines. An understanding of their physiology, relevant facial anatomy, and current agents is imperative for a successful aesthetic practice. PMID- 22205525 TI - Hyaluronic acid fillers: history and overview. AB - Hyaluronic acid (HA) fillers have many favorable characteristics that make it a popular injectable filler device. Its minimal immunogenicity and relative ease of use has helped HA become the most commonly used injectable filler today. A brief history of injectable fillers, the various injection techniques, and legal ramifications are discussed. A review of the most recent literature compares the efficacy and safety of HA to other injectable filler substances. PMID- 22205526 TI - Botulinum toxin: clinical techniques, applications, and complications. AB - This article outlines practice routines, clinical techniques, applications, and complications of botulinum toxin type A treatment of mimetic facial and neck muscles. Detailed descriptions are provided for each clinical indication that maximize the treatment of the intended muscle groups while minimizing potential complications. PMID- 22205527 TI - Permanent soft tissue fillers. AB - As our youth-oriented society ages, interest in nonsurgical aesthetic techniques has generated a dramatic rise in the use of filling agents for facial rejuvenation. Backed by multiple published studies documenting safety and efficacy, soft tissue fillers are often viewed as treatments with minimal recovery time and limited risk of complications when compared with traditional surgical interventions. This has led to a genuine demand for fillers with similar safety profiles but ever increasing longevity in their aesthetic corrections. This review addresses many of the permanent soft tissue fillers that are commercially available worldwide as well as important concerns regarding their complications. PMID- 22205528 TI - Future trends and new materials. AB - The variety of products available as injectable fillers and neuromodulators continues to increase. New products are soon to be introduced in the United States that will enable the clinician to treat a greater array of esthetic problems and concerns. In addition, existing materials are being modified to allow for less painful treatments and easier product handling. PMID- 22205529 TI - Lip augmentation utilizing allogenic acellular dermal graft. AB - There are many options available to increase the volume and enhance the contours of the lip, as well as the perioral region. This article outlines an easy application of an allogenic, acellular dermal graft into the lips for this purpose. This material is readily available, easy to use, biocompatible, and nonimmunogenic; it exhibits a natural look and feel, and it has a low rate of infection. Our experience with this material has provided excellent cosmetic outcomes. PMID- 22205530 TI - Use of UTF1 genetic control elements as iPSC reporter. AB - The reprogramming of adult somatic cells into an embryonic stem cell (ESC) state by various means has opened a new chapter in basic and applied life science. While this technology will create great opportunities for regenerative medicine, the more immediate impact is likely to be found in human disease modeling and drug testing/development. An important aspect in the latter contexts is the ability to reliably monitor the pluripotent stem cell state, in particular with respect to human cell reprogramming using patient-specific somatic cells and high throughput screens. Undifferentiated transcription factor 1 (UTF1) belongs to the core transcriptional network characterizing pluripotency. UTF1 is involved in ESC specific chromatin organization, and its expression pattern during cell reprogramming and subsequent differentiation appears to be tightly connected with the pluripotent stem cell state. Here, we capitalized on these features and generated a reliable reporter system that was used to monitor induced pluripotent stem cell (iPSC) formation and subsequent differentiation. Our reporter cassette comprises less than 2.3 kb and remains functional during many cell passages after genomic integration. The fact that the human UTF1 genetic control elements work in a mouse background and the demonstrated functionality of the reporter in an epigenetic state further qualifies this system as a versatile new tool for iPSC research. PMID- 22205531 TI - Intrauterine myelomeningocele repair postnatal results and follow-up at 3.5 years of age--initial experience from a single reference service in Brazil. AB - PURPOSE: Present the outcomes of six cases submitted to intrauterine myelomeningocele (MMC) repair. METHODS: Descriptive observational study of six children submitted to antenatal surgical repair of MMC between 26 and 27 weeks gestation. All deliveries were through cesarean section. The following neonatal variables were assessed: gestational age at delivery, birth weight, Apgar scores, need for intubation, duration of hospital stay and need for postnatal shunt procedures. After 3.5 years, the children were evaluated using the Columbia Mental Maturity Scale or Denver II tests and the Hoffer Ambulation Scale. RESULTS: All deliveries were preterm at a mean gestational age of 32 + 4 weeks and mean birth weight was 1,942 g. Two infants had Apgar scores <7 at 1 min and 1 at 5 min. Ventricular-peritoneal shunts were placed in two cases. All six children are alive: five have normal cognitive development and one has a neuropsychomotor developmental delay. Two children had normal leg movements, a sacral functional level and are community ambulators. Three children had upper lumbar anatomical level lesions and one had a lower thoracic level lesion at the time of fetal surgery. One child, with an L1-L2 anatomical level lesion, in noambulatory and fully dependent on a wheelchair for mobility. CONCLUSION: Antenatal surgical repair of MMC reduced the need for postnatal shunt placements. Despite preterm delivery, the cognitive development of most children at 3.5 years was normal. Antenatal surgery seemed to improve lower limb motor function in these cases. PMID- 22205532 TI - Multi-cystic white matter enlarged Virchow Robin spaces in a 5-year-old boy. PMID- 22205533 TI - Low-pressure valves in hydrocephalic children: a retrospective analysis. AB - PURPOSE: A series of 100 children under 2 years of age treated for hydrocephalus is described. All patients received a standard differential low-pressure (SD low) valve as the first cerebrospinal fluid (CSF) shunt treatment. The performance of this group during follow-up is analysed. METHODS: A retrospective cohort study was performed using the intern electronic health record from our hospital. Children younger than 2 years who underwent initial CSF shunt treatment with a SD low valve between 1998 and 2008 were eligible. RESULTS: Mean follow-up was 7 years. The majority of 81% (81 of 100) of the children did not receive an upgrade of pressure profile throughout follow-up. The first revision was done after a mean of 456 days (median, 64 days; min, 3; and max, 4,183). The 1-year survival rate of the CSF shunt in this cohort was 42%. In the relatively large group of myelomeningocele patients (37 of 100), only one patient developed symptomatic overdrainage. A total of 9% (9 of 100) of the children presented with symptoms of overdrainage. In 3% (3 out of 100) of these children, symptoms of overdrainage persisted, in spite of multiple valve mutations. During the total follow-up, 26% (26 of 100) of the patients had never received shunt revision surgery. Fifteen percent (15 of 100) of the children developed a shunt infection within the first year. CONCLUSIONS: The use of SD low valves in the youngest age group is effective in the majority of children. The aetiology of myelomeningocele appears to protect the patient from symptomatic overdrainage. PMID- 22205534 TI - Treatment of glioblastoma multiforme with high doses of carmustine intracavitary, in an infant. PMID- 22205535 TI - Pediatric diseases in Juan Carreno de Miranda's paintings. AB - Pediatric obesity has become a widespread problem of health in developed countries. Overweight in the pediatric population obeys to a variety of causes. A few of Carreno de Miranda's paintings show pathological conditions occurring in children of his epoch. We briefly illustrate the significance of Carreno's paintings that portray some of these diseases. Two of his best-known works constitute an artistic representation of childhood obesity. PMID- 22205536 TI - Randomized, prospective study of TissuGlu(r) surgical adhesive in the management of wound drainage following abdominoplasty. AB - BACKGROUND: Wound drainage and seroma formation following abdominoplasty remain significant concerns to both surgeons and patients due to the resulting increased need for patient follow-up and delays in returning to normal function. While a number of approaches are used to reduce wound drainage and seroma formation, there is still no definitive solution. A promising strategy to reduce these complications is the development of an effective method for closing dead space between tissue layers in order to achieve improved patient outcomes. METHODS: We conducted a multicenter, prospective, randomized trial assessing the use of a lysine-derived urethane adhesive (TissuGlu(r), Cohera Medical) in patients undergoing abdominoplasty. Twenty patients were randomized to a treatment group and a control group, with the adhesive applied to the abdominal wall prior to closure of the abdominoplasty flap in the treatment group. Control patients underwent an identical procedure but without application of TissuGlu. Outcome measures included time to drain removal, total wound drainage prior to drain removal, and surgical complications. RESULTS: The use of TissuGlu was associated with a trend toward decreased time to drain removal compared to the control group (2.9+/-1.4 vs. 3.7+/-1.5 days; P=0.13). Mean total drain volume also tended to be lower in the treatment versus the control group (208.7+/-138.2 vs. 303.5+/-240.8 ml; P=0.14). There were no differences in adverse events or complication rates between the two study groups. CONCLUSION: The application of TissuGlu in abdominoplasty is safe and may decrease wound drainage and the length of time required for postsurgical drains in abdominoplasty patients. PMID- 22205537 TI - Ptcorp gene induced by cold stress was identified by proteomic analysis in leaves of Poncirus trifoliata (L.) Raf. AB - A proteomic approach was employed to investigate the cold stress-responsive proteins in trifoliate orange (Poncirus trifoliata (L.) Raf.), which is a well known cold tolerant citrus relative and widely used as rootstock in China. Two year-old potted seedlings were exposed to freezing temperature (-6 degrees C) for 50 min (nonlethal) and 80 min (lethal), and the total proteins were isolated from leaves of the treated plants. Nine differentially accumulated proteins over 2 fold changes in abundance were identified by two-dimensional gel electrophoresis and mass spectrometry. Among these proteins, a resistance protein induced by the nonlethal cold treatment (protein spot #2 from P. trifoliata) was selected as target sequence for degenerated primer design. By using the designed primers, a PCR product of about 700 bp size was amplified from P. trifoliata genomic DNA, which was further cloned and sequenced. A nucleotide sequence of 676 bp was obtained and named Ptcorp. Blast retrieval showed that Ptcorp shared 88% homology with an EST of cold acclimated Bluecrop (Vaccinium corymbosum) library (Accession number: CF811080), indicating that Ptcorp had association with cold acclimation. Semiquantitative RT-PCR analysis demonstrated that Ptcorp gene was up-regulated by cold stress which was consistent with the former result of protein expression profile. As the resistance protein (NBS-LRR disease resistance protein family) gene was up-regulated by cold stress in trifoliate orange and satsuma mandarin, it may imply that NBS-LRR genes might be associated with cold resistance in citrus. PMID- 22205538 TI - The significance of Exonuclease 1 K589E polymorphism on hepatocellular carcinoma susceptibility in the Turkish population: a case-control study. AB - Exonuclease 1 (Exo 1) is an important nuclease involved in mismatch repair system that contributes to maintain genomic stability, to modulate DNA recombination, and to mediate cell cycle arrest. A guanine (G)/adenine (A) common single nucleotide polymorphism at first position of codon 589 in Exo 1 gene determines a glutamic acid (Glu, E) to lysine (Lys, K) (K589E) aminoacidic substitution which may alter cancer risk by influencing the activity of Exo 1 protein. Exo 1 K589E polymorphism has been studied in various cancers, but its association with hepatocellular carcinoma (HCC) has yet to be investigated. To determine the association of the Exo 1 K589E polymorphism with the risk of HCC development in a Turkish population, a hospital-based case-control study was designed consisting of 224 subjects with HCC and 224 cancer-free control subjects matched for age, gender, smoking and alcohol status. The genotype frequency of the Exo 1 K589E polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. Our data shows that the Lys/Lys genotype of the Exo 1 K589E polymorphism is associated with increased risk of HCC development in this Turkish population [odds ratio (OR) = 2.15, 95% confidence interval (CI): 1.13-4.09, P = 0.02]. Furthermore, according to stratified analysis, a significant association was observed between the homozygote Lys/Lys genotype and HCC risk in the subgroups of male gender (OR = 2.67, 95% CI: 1.27-5.61, P = 0.009) and patients with non-viral-related HCC (OR = 3.14, 95% CI: 1.09-8.99, P = 0.03). Because our results suggest for the first time that the Lys/Lys homozygote genotype of Exo 1 K589E polymorphism may be a genetic susceptibility factor for HCC in the Turkish population, further independent studies are required to validate our findings in a larger series, as well as in patients of different ethnic origins. PMID- 22205539 TI - Expression of connective tissue growth factor and interleukin-11 in intratumoral tissue is associated with poor survival after curative resection of hepatocellular carcinoma. AB - In the present study, we evaluated the prognostic value of intratumoral and peritumoral expression of connective tissue growth factor (CTGF), transforming growth factor-beta 1 (TGF-beta1), and interleukin-11 (IL-11) in patients with hepatocellular carcinoma (HCC) after curative resection. Expression of CTGF, TGF beta1, and IL-11 was assessed by immunohistochemical staining of tissue microarrays containing paired tumor and peritumoral liver tissue from 290 patients who had undergone hepatectomy for histologically proven HCC. The prognostic value of these and other clinicopathologic factors were evaluated. The median follow-up time was 54.3 months (range, 4.3-118.3 months). High intratumoral CTGF expression was associated with vascular invasion (P = 0.015), intratumoral IL-11 expression correlated with higher tumor node metastasis (TNM) stage (P = 0.009), and peritumoral CTGF overexpression correlated with lack of tumor encapsulation (P = 0.031). Correlation analysis of these proteins revealed that intratumoral CTGF and IL-11 correlated with high intratumoral TGF-beta1 expression (r = 0.325, P < 0.001; and r = 0.273, P < 0.001, respectively). TNM stage (P < 0.001), high intratumoral CTGF levels (P = 0.010), and intratumoral IL 11 expression (P = 0.015) were independent prognostic factors for progression free survival (PFS). Vascular invasion (P = 0.032), TNM stage (P < 0.001), high intratumoral CTGF levels (P = 0.036), and intratumoral IL-11 expression (P = 0.013) were independent prognostic factors for overall survival (OS). High intratumoral CTGF and intratumoral IL-11 expression were associated with PFS and OS after hepatectomy, and the combination of intratumoral CTGF with IL-11 may be predictive of survival. PMID- 22205540 TI - Effect of mechanical stretch on the expressions of elastin, LOX and Fibulin-5 in rat BMSCs with ligament fibroblasts co-culture. AB - The occurrence of PFD is closely related with elasticity, toughness, and functional changes of the connective tissue of the pelvic support tissue. This study aims to evaluate the effect of mechanical stretch on the differentiation of BMSCs with a co-culture with pelvic ligament fibroblasts. BMSCs was isolated and identified from 7 day SPF SD rats. Rat pelvic ligament fibroblasts were obtained from rat pelvic ligament. The fourth passage of fibroblasts was subjected to 10% deformation with 1 Hz, 12 h periodic one-way mechanical stretch stimulation, and the cells were then co-cultured with BMSCs. The longer co-culture and co-culture with mechanical stretch (i.e. 6 and 12 days) induced more expression of elastin, LOX, and Fibulin-5, compared to the groups without stimulation. Compared to co culture group each, Co-culture with mechanical stretch stimulation group induced significant expression of elastin, LOX, and Fibulin-5, both in 3, 6 and 12 days co-culture groups (P < 0.05). However, there were no significant differences among 3, 6, and 12 days control groups. These results suggest that in an indirect co-culture system, pelvic ligament fibroblasts with mechanical stretch stimulation can promote BMSCs differentiation, reflecting in the increased expression of elastin, LOX, and Fibulin-5. PMID- 22205541 TI - Risk stratification of spontaneous bacterial peritonitis in cirrhosis with ascites based on classification and regression tree analysis. AB - Risk stratification for spontaneous bacterial peritonitis (SBP) in patients with cirrhosis and ascites helps guide care. Existing prediction models, such as end stage liver disease (MELD) score, are accurate but controversial in clinical practice. We developed and validated a practical user-friendly bedside tool for SBP risk stratification of patients with cirrhosis and ascites. Using classification and regression tree (CART) analysis, a model was developed for prediction of SBP in cirrhosis with ascites. The CART model was derived on data collected from 676 patients admitted from January 2007 to December 2009 retrospectively, and then was prospectively tested in another independent 198 inpatients between January 2010 and December 2010. The accuracy of CART model was evaluated using the area under the receiver operating characteristic curve. The performance of the model was further validated by comparing its predictive accuracy with that of the MELD score. Furthermore, the model was used to stratify SBP among patients with MELD scores under 15. CART analysis identified four variables for prediction of SBP: creatinine, total bilirubin, prothrombin time and white blood cell count, and three risk groups: low (2.0%), intermediate (27.5 33.3%) and high (60.6-86.4%) risk. The accuracy of CART model (0.881) exceeded that of MELD (0.791). Subjects in the intermediate risk and high risk groups had 22.21-fold (95% confident interval (CI), 9.98-49.45) and 173.50-fold (95% CI, 77.68-634.33) increased risk of SBP, respectively, comparing with the low risk group. Similar results were found when this risk stratification was applied to the validation cohort. Cirrhotic patients with ascites at low, intermediate, and high risk for SBP can be easily identified using CART model, which provides clinicians with a validated, practical bedside tool for SBP risk stratification. PMID- 22205543 TI - Relationship between clinical efficacy for pulmonary MAC and drug-sensitivity test for isolated MAC in a recent 6-year period. AB - There are a few recent reports about the relationship between the clinical effect and drug-sensitivity test. We investigated the relationship between the clinical efficacy of treatment for pulmonary Mycobacterium avium complex (MAC) and drug sensitivity test for isolated MAC by comparison between data from 2005 to 2007 and from 2008 to 2010. We studied 60 patients who satisfied diagnostic criteria of nontuberculous mycobacterial infection established by the American Thoracic Society in 2007 and who received combination therapy using rifampicin (RFP), ethambutol (EB), streptomycin (SM), and clarithromycin (CAM). Average CAM dosage was increased from the early (517 mg/day) to the later (800 mg/day) period. Sputum conversion rate increased from 63% in the early period to 83% in the later period. Clinical improvement also increased from 38% in the early period to 53% in the later period. The causative microorganisms isolated were M. avium in 35 patients and M. intracellulare in 25. In both periods, isolated MAC strains showed excellent minimum inhibitory concentration (MIC) for CAM. Regarding the relationship between clinical efficacy and MICs of RFP, EB, CAM, and SM, most patients with good clinical effects showed low MIC for CAM in both periods. Good clinical efficacy, including the sputum conversion rate, was obtained with an increased dose of CAM in the later period. We speculate that the increased dose of CAM influenced the good clinical effect in both periods. PMID- 22205542 TI - Low-dose memantine attenuated morphine addictive behavior through its anti inflammation and neurotrophic effects in rats. AB - Opioid abuse and dependency are international problems. Studies have shown that neuronal inflammation and degeneration might be related to the development of opioid addiction. Thus, using neuroprotective agents might be beneficial for treating opioid addiction. Memantine, an Alzheimer's disease medication, has neuroprotective effects in vitro and in vivo. In this study, we evaluated whether a low dose of memantine prevents opioid-induced drug-seeking behavior in rats and analyzed its mechanism. A conditioned-place-preference test was used to investigate the morphine-induced drug-seeking behaviors in rats. We found that a low-dose (0.2-1 mg/kg) of subcutaneous memantine significantly attenuated the chronic morphine-induced place-preference in rats. To clarify the effects of chronic morphine and low-dose memantine, serum and brain levels of cytokines and brain-derived neurotrophic factor (BDNF) were measured. After 6 days of morphine treatment, cytokine (IL-1beta, IL-6) levels had significantly increased in serum; IL-1beta and IL-6 mRNA levels had significantly increased in the nucleus accumbens and medial prefrontal cortex, both addiction-related brain areas; and BDNF levels had significantly decreased, both in serum and in addiction-related brain areas. Pretreatment with low-dose memantine significantly attenuated chronic morphine-induced increases in serum and brain cytokines. Low-dose memantine also significantly potentiated serum and brain BDNF levels. We hypothesize that neuronal inflammation and BDNF downregulation are related to the progression of opioid addiction. We hypothesize that the mechanism low-dose memantine uses to attenuate morphine-induced addiction behavior is its anti inflammatory and neurotrophic effects. PMID- 22205544 TI - Sulfate-reducing anaerobic ammonium oxidation as a potential treatment method for high nitrogen-content wastewater. AB - After sulfate-reducing ammonium oxidation (SRAO) was first assumed in 2001, several works have been published describing this process in laboratory-scale bioreactors or occurring in the nature. In this paper, the SRAO process was performed using reject water as a substrate for microorganisms and a source of NH(4) (+), with SO(4) (2-) being added as an electron acceptor. At a moderate temperature of 20 degrees C in a moving bed biofilm reactor (MBBR) sulfate reduction along with ammonium oxidation were established. In an upflow anaerobic sludge blanket reactor (UASBR) the SRAO process took place at 36 degrees C. Average volumetric TN removal rates of 0.03 kg-N/m3/day in the MBBR and 0.04 kg N/m3/day in the UASBR were achieved, with long-term moderate average removal efficiencies, respectively. Uncultured bacteria clone P4 and uncultured planctomycete clone Amx-PAn30 were detected from the biofilm of the MBBR, from sludge of the UASBR uncultured Verrucomicrobiales bacterium clone De2102 and Uncultured bacterium clone ATB-KS-1929 were found also. The stoichiometrical ratio of NH(4) (+) removal was significantly higher than could be expected from the extent of SO(4) (2-) reduction. This phenomenon can primarily be attributed to complex interactions between nitrogen and sulfur compounds and organic matter present in the wastewater. The high NH(4) (+) removal ratio can be attributed to sulfur-utilizing denitrification/denitritation providing the evidence that SRAO is occurring independently and is not a result of sulfate reduction and anammox. HCO(3) (-) concentrations exceeding 1,000 mg/l were found to have an inhibiting effect on the SRAO process. Small amounts of hydrazine were naturally present in the reaction medium, indicating occurrence of the anammox process. Injections of anammox intermediates, hydrazine and hydroxylamine, had a positive effect on SRAO process performance, particularly in the case of the UASBR. PMID- 22205545 TI - Effect of cigarette smoking on paraoxonase 1 activity according to PON1 L55M and PON1 Q192R gene polymorphisms. AB - OBJECTIVE: This study aims to investigate the effect of cigarette smoking on paraoxonase 1 (PON1) activity according to PON1 L55M and PON1 Q192R gene polymorphisms. MATERIALS AND METHODS: Our sample included 300 voluntary subjects: 138 nonsmokers and 162 current smokers aged 38.47 +/- 21.91 and 35.55 +/- 16.03 years, respectively. PON1 activity was determined by kinetic methods. L55M and Q192R gene polymorphisms of PON1 were determined by multiplex polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). RESULTS: We found in smokers a significant decrease of PON1 activity before and after adjustment. We noted a significant association between smoking status and lower PON1 activity [odds ratio (OR) = 3.03, confidence interval 95% = 1.5-5.9, p = 0.001]. In smokers, there was significant association between PON1 activity and PON1 L55M polymorphisms (p = 0.01). Also, the 55MM genotype presented the lowest paraoxonase activity, while the 55LL genotype showed the highest one. After adjustment for confounding variables, smokers with PON1 L55M polymorphism had the highest risk for lower PON1 activity; however, PON1 Q192R genotype might protect smokers from decrease in PON1 activity. We found significant interaction between the effect of cigarette smoking and both PON1 L55M and PON1 Q192R polymorphisms on lower PON1 activity. CONCLUSIONS: Cigarette smoking was significantly associated with decrease in PON1 activity. Moreover, PON1 L55M polymorphism predisposes smokers to decreased PON1 activity in contrast to PON1 Q192R genotype. PMID- 22205546 TI - Factors in genetic susceptibility in a chemical sensitive population using QEESI. AB - OBJECTIVES: Inherited impairment of xenobiotic metabolism is a postulated mechanism underlying environmentally associated pathogeneses such as multiple chemical sensitivity (MCS). Using the Quick Environmental Exposure and Sensitivity Inventory (QEESI), we defined people who have a strong response to chemical substances as "chemical sensitive populations (CSP)." The aim of this study is to evaluate the condition of subjects sensitive to chemicals and to analyze their genotypes in order to identify susceptibility factors in CSPs in Japanese populations. METHODS: A total of 1,084 employees of Japanese companies were surveyed using the QEESI, history of MCS, and sick house syndrome. The common genotypes of the participants were analyzed for glutathione S-transferase (GST) M1, GSTT1, aldehyde dehydrogenase2 (ALDH2), and paraoxonase1 (PON1) in order to identify factors in the susceptibility to sensitivity to chemicals. RESULTS: Four subjects had history of diagnosis of MCS; no subjects had diagnosis of sick house syndrome. The subjects were divided into four levels according to scores of 0, 1-19, 20-39, and 40 or more on three of the QEESI subscales. In addition, we used the MCS criteria by Hojo to differentiate between cases (CSP) and controls. No significant differences in the allelic distribution of genetic polymorphisms in the GSTM1, GSTT1, ALDH2 or PON1 genes were found among the four levels of each subscale, or between cases and controls. CONCLUSIONS: Our findings suggest that the common genotypes of GSTM1, GSTT1, ALDH2, and PON1 are of little importance to CSP in a Japanese population. PMID- 22205547 TI - Levels of neural progenitors in the hippocampus predict memory impairment and relapse to drug seeking as a function of excessive methamphetamine self administration. AB - Methamphetamine affects the hippocampus, a brain region crucial for learning and memory, as well as relapse to drug seeking. Rats self-administered methamphetamine for 1 h twice weekly (intermittent-short-I-ShA), 1 h daily (limited-short-ShA), or 6 h daily (extended-long-LgA) for 22 sessions. After 22 sessions, rats from each access group were withdrawn from self-administration and underwent spatial memory (Y-maze) and working memory (T-maze) tests followed by extinction and reinstatement to methamphetamine seeking or received one intraperitoneal injection of 5-bromo-2'-deoxyuridine (BrdU) to label progenitors in the hippocampal subgranular zone (SGZ) during the synthesis phase. Two-hour old and 28-day-old surviving BrdU-immunoreactive cells were quantified. I-ShA rats performed better on the Y-maze and had a greater number of 2-h-old SGZ BrdU cells than nondrug controls. LgA rats, but not ShA rats, performed worse on the Y and T-maze and had a fewer number of 2-h-old SGZ BrdU cells than nondrug and I ShA rats, suggesting that new hippocampal progenitors, decreased by methamphetamine, were correlated with impairment in the acquisition of new spatial cues. Analyses of addiction-related behaviors after withdrawal and extinction training revealed methamphetamine-primed reinstatement of methamphetamine-seeking behavior in all three groups (I-ShA, ShA, and LgA), and this effect was enhanced in LgA rats compared with I-ShA and ShA rats. Protracted withdrawal from self-administration enhanced the survival of SGZ BrdU cells, and methamphetamine seeking during protracted withdrawal enhanced Fos expression in the dentate gyrus and medial prefrontal cortex in LgA rats to a greater extent than in ShA and I-ShA rats. These results indicate that changes in the levels of the proliferation and survival of hippocampal neural progenitors and neuronal activation of hippocampal granule cells predict the effects of methamphetamine self-administration (limited vs extended access) on cognitive performance and relapse to drug seeking and may contribute to the impairments that perpetuate the addiction cycle. PMID- 22205549 TI - Chemotherapy line-associated differences in quality of life in patients with advanced cancer. AB - PURPOSE: The aim of this study was to investigate quality of life (QOL) differences between patients receiving first, second, or third-line palliative chemotherapy (CT).Furthermore, QOL was also compared to a sex- and age-matched sample of healthy controls. METHODS: Patients with different metastatic cancers receiving palliative CT were approached to complete the EORTC QLQ-C30 questionnaire by means of touch-screen computers before the start of CT, after 3 cycles and at the end of cytostatic treatment. RESULTS: One hundred four patients were recruited for QOL assessment (56.9% of patients in first, 22.5% second and 20.6% third- or above-line palliative CT). Compared to healthy controls, they suffered from substantial QOL impairments in all EORTC QLQ-C30 sub-domains. In regard to CT lines, patients with first-line CT reached better scores in emotional and social functioning than second-line patients and less financial difficulties than third-line patients. Despite the high level of impairment in the patient sample, electronic data collection proved to be feasible and well accepted. CONCLUSIONS: The results indicate that patients receiving third- or above-line palliative CT are confronted with stronger QOL impairments than first- and second-line patients. Supported by its feasibility and acceptance of by patients, electronic QOL data capture is an attractive method to screen for symptoms and track their course within clinical routine. PMID- 22205548 TI - Swallowing dysfunction in cancer patients. AB - PURPOSE: Dysphagia (swallowing dysfunction) is a debilitating, depressing, and potentially life-threatening complication in cancer patients that is likely underreported. The present paper is aimed to review relevant dysphagia literature between 1990 and 2010 with a focus on assessment tools, prevalence, complications, and impact on quality of life in patients with a variety of different cancers, particularly in those treated with curative chemoradiation for head and neck cancer. METHODS: The literature search was limited to the English language and included both MEDLINE/PubMed and EMBASE. The search focused on papers reporting dysphagia as a side effect of cancer and cancer therapy. We identified relevant literature through the primary literature search and by articles identified in references. RESULTS: A wide range of assessment tools for dysphagia was identified. Dysphagia is related to a number of factors such as direct impact of the tumor, cancer resection, chemotherapy, and radiotherapy and to newer therapies such as epidermal growth factor receptor inhibitors. Concomitant oral complications such as xerostomia may exacerbate subjective dysphagia. Most literature focuses on head and neck cancer, but dysphagia is also common in other types of cancer. CONCLUSIONS: Swallowing impairment is a clinically relevant acute and long-term complication in patients with a wide variety of cancers. More prospective studies on the course of dysphagia and impact on quality of life from baseline to long-term follow-up after various treatment modalities, including targeted therapies, are needed. PMID- 22205551 TI - Parenteral nutrition remains a lifeline. PMID- 22205550 TI - Empirical evidence of the validity of the Spanish version of the pain vigilance awareness questionnaire. AB - BACKGROUND: The Spanish version of the Pain Vigilance and Awareness Questionnaire has not been validated. PURPOSE: The aims of this study were to examine the factor structure of the Spanish version of the Pain Vigilance and Awareness Questionnaire and present empirical evidence regarding its validity. METHOD: A sample of 468 chronic back pain patients completed a battery of instruments to assess fear-avoidance beliefs, pain anxiety, pain catastrophizing, pain vigilance and awareness, pain acceptance, depression, anxiety, disability, and pain intensity. RESULTS: Confirmatory factor analysis supported the validity of a nine item version with two subscales: Active Vigilance and Passive Awareness. Both subscales and the total score were positively and significantly correlated with other fear-related constructs: fear-avoidance beliefs, pain anxiety, and pain catastrophizing. Regression analyses showed that Active Vigilance and the two subscales of the Fear-Avoidance Beliefs Questionnaire were significantly associated with higher anxiety and that the Acceptance Activity Engagement subscale was significantly associated with lower anxiety. The Fear-Avoidance Beliefs Questionnaire-Physical subscale was associated with higher disability and the Acceptance Pain Willingness subscale was associated with lower disability. The Fear-Avoidance Beliefs Questionnaire-Work subscale was significantly associated with higher pain intensity and depression; the Acceptance Activity Engagement and Pain Willingness subscales were significantly associated with lower pain intensity and depression. CONCLUSION: The Spanish version of the Pain Vigilance and Awareness Questionnaire is a reliable and valid instrument. Pain Acceptance and Fear Avoidance beliefs are better predictors of adjustment to pain than pain hypervigilance. PMID- 22205552 TI - Immune-modulating formulas: who wins the meta-analysis race? AB - Most agree that enteral nutrition is the ideal way to feed critically ill patients who have a functional gastrointestinal tract, but selecting the appropriate enteral formula can be difficult. Specifically, the use of immune modulating diets has brought much excitement as well as debate. Literature to date presents both positive and potential adverse effects. To aid the clinician in the decision-making process, this article reviews the current research and recommendations regarding the use of immune-modulating diets. PMID- 22205553 TI - National clinical guidelines and home parenteral nutrition. AB - Research-based guidelines provide the best evidence and are the cornerstones of achieving quality outcomes for home parenteral nutrition (HPN) patients and their families. However, evidence about the implementation of HPN guideline recommendations is rarely reported. The purpose of this clinical practice project was to compare HPN clinical guidelines with baseline data reported by HPN patients from 1990-2010 and to explore possible facilitators or barriers to the implementation of guidelines in clinical practice. Methods included PubMed literature searches for HPN clinical guidelines and comparison of the retrieved guidelines with HPN clinical data reported by HPN patients from 3 separate studies conducted in the United States from 1990-2010. Results of reviewing published HPN guidelines found recommendations based primarily on expert opinion and included the appropriate use of HPN, coordination of care by teams of experts, use of dedicated ports, salvaging catheters when possible, and bowel transplantation. Comparison of baseline data over the 2 decades indicated that guidelines for the appropriate use and types of central venous catheters were being implemented, but there was little evidence that most HPN patients had their care coordinated by multidisciplinary teams. Conclusions are that most HPN guideline recommendations were being implemented in practice except for the care delivered by multidisciplinary experts. To ensure quality HPN outcomes, multidisciplinary teams of HPN experts are needed as are large data sets that will provide indicators of guideline use and outcomes. Furthermore, research is needed so that recommendations are not based totally on expert consensus. PMID- 22205554 TI - Comparison of the effects of different intravenous fat emulsions in patients with systemic inflammatory response syndrome and sepsis. AB - BACKGROUND: In this study, the authors aimed to compare the effects that a medium and long-chain triglyceride (MCT/LCT) fat infusion and a fish oil-based (omega 3) fat infusion for parenteral nutrition (PN) had on systemic inflammation, cytokine response, and hepatic steatosis in mixed intensive care unit (ICU) patients. METHODS: This was a single-center, placebo-controlled, randomized clinical trial in a university hospital. Four patient groups, including systemic inflammatory response syndrome (SIRS) and sepsis patients, were assigned to receive PN employing the MCT/LCT fat infusion or the fish oil-based fat infusion over 7 days. Blood biochemistry and liver steatosis were evaluated. RESULTS: Twenty sepsis and 20 SIRS patients were included in this study. There was no statistically significant difference in terms of biochemical values and Acute Physiology and Chronic Health Evaluation II scores between the different feeding groups. Sepsis groups who received MCT/LCT revealed higher grades of liver steatosis by ultrasound on days 7 and 10 (P < .05). Tumor necrosis factor (TNF) alpha and interleukin (IL)-6 values in sepsis group 1 (S1) were higher than in sepsis group (S2) on day 7, whereas IL-1 values were higher on days 3, 7, and 10 in group S1 than in group S2. Conversely, IL-10 values on days 3 and 7 were significantly higher in group S2. CONCLUSION: Fish oil-based fat emulsions might have anti-inflammatory and hepatoprotective effects in hyperinflammatory disease such as sepsis. PMID- 22205556 TI - Plasma citrulline concentration as a biomarker for bowel loss and adaptation in hospitalized pediatric patients requiring parenteral nutrition. AB - BACKGROUND: Citrulline is a nonessential amino acid produced solely in the enterocyte. Plasma citrulline concentration has been proposed as a noninvasive biomarker for bowel length, function, and dependency on parenteral nutrition (PN). The purpose of this study was to determine if citrulline concentrations differed between pediatric patients with and without small bowel loss requiring specialized nutrition support. METHODS: This was a retrospective categorical analysis of citrulline concentrations from previously published studies. Patients were included if they were receiving PN, more than 30 days of age, and if they had at least 2 plasma citrulline concentrations. Patients with renal insufficiency and who received outpatient PN treatment were excluded. Patients were categorized as either having or not having small bowel loss. RESULTS: Thirty six patients were included for analysis (18 per category). The median citrulline concentration was significantly lower in the group with bowel loss, 8.4 umol/L vs 10.5 umol/L (P < .0005), and undetectable citrulline concentrations occurred more often in the bowel loss group, 40% vs 8% (P < .0005). In 13 patients who received enteral nutrition during the study periods, plasma citrulline concentrations increased only in patients without bowel loss. CONCLUSIONS: These data confirm previous studies and identify decreased citrulline concentrations in pediatric patients with bowel dysfunction in the absence of bowel loss. These data also represent the first serial citrulline concentrations over a 21-day period. The increase in citrulline concentrations only in fed patients without bowel loss suggests that citrulline concentrations could provide a biomarker for bowel function and adaptation. PMID- 22205557 TI - Early enteral nutrition improves outcomes of open abdomen in gastrointestinal fistula patients complicated with severe sepsis. AB - BACKGROUND: Although nutrition therapy is favorably considered as an assistant therapeutic measure in critical illness, little data evaluate its role in gastrointestinal fistula patients with severe sepsis after an open abdomen. The purpose of this study is to evaluate the role of early nutrition therapy in that population. METHODS: This is a retrospective review of patients who underwent open abdomen management for gastrointestinal fistula and severe sepsis from January 2001 to June 2009. Nutrition therapy, fistula, abdominal closure, and demographics were noted. Succus entericus reinfusion (SER) was performed for high output volume or multiple fistulae. Patients were divided into two groups based on whether enteral nutrition (EN) was initiated within 14 days after admission. Delivery route of nutrients, mortality, complications, and time to abdominal closure were compared among groups. RESULTS: Eighty-two patients were included. Fifty-six (68.3%) patients survived to discharge. Forty-one (50%) patients received SER. EN was initiated within 14 days in 36 patients, with a mean initiation time at 8.3 +/- 3.4 days; 46 patients did not start any EN within 14 days (29.9 +/- 20.9 days). The mean age, BMI, APACHE II score, and fistula characteristics were similar between groups. The abdominal closure was accomplished more rapidly in patients fed within 14 days (142.8 vs 184.5 days, P = .017), with decreased mortality (11.1% vs 47.8%, P < .001). CONCLUSIONS: Nutrition therapy plays an important role in the management of gastrointestinal fistula with severe sepsis. Early EN could be successfully delivered for that population, with improved mortality risk. PMID- 22205558 TI - Monitoring parenteral nutrition in hospitalized patients: issues related to spurious bloodwork. AB - BACKGROUND: Monitoring hospitalized patients receiving parenteral nutrition requires regular bloodwork. However, blood specimens, if not drawn appropriately, may be contaminated by parenteral nutrition, leading to spurious results and unnecessary medical interventions. The objective was to determine, in a large academic center, the frequency of spurious bloodwork, unnecessary medical interventions, and contributing factors. METHODS: This was a 1-year prospective cohort study monitoring hospitalized patients receiving parenteral nutrition and their bloodwork. Sudden unexplained changes in serum levels of glucose, potassium, and sodium were identified. Subsequent medical interventions were tracked. Factors affecting blood collection, such as technique, shifts, nursing units, nursing, and patient demography, were assessed and compared with those of a control group. RESULTS: Out of 201 patients, 34 had 63 incidents of spurious bloodwork. This led to 23 medical interventions. The most frequent problem was the failure to clamp the parenteral nutrition infusion prior to blood collection or too short a time between clamping and drawing. There was an increased occurrence of spurious bloodwork drawn by nurses with < 10 years of experience due to failure in following blood collection policy. Cost of spurious bloodwork and subsequent interventions for 63 incidents was approximately $3480 (CAD) per year. This excluded physician time. CONCLUSIONS: Spurious bloodwork was due to parenteral nutrition contamination by incorrect blood draw techniques. This led to a policy amendment to incorporate a "wait time" between stopping the parenteral nutrition infusion and drawing blood and to an institution-wide nursing reeducation. PMID- 22205555 TI - Use of parenteral lipid emulsions in French neonatal ICUs. AB - OBJECTIVE: To determine the types of parenteral lipid emulsions currently used for preterm infants, their mode of delivery, and the main disease conditions that are considered by neonatologists as contraindications. DESIGN: National survey using a questionnaire. SETTING: 155 neonatal departments in France. RESULTS: 100 (65%) neonatal departments participated in the survey. The most widely used lipid emulsion was the 20% soybean oil/coconut oil-based emulsion (68% of the units), followed by the soybean oil-based emulsion (28.5%) and the soybean oil/olive oil based emulsion (3.5%). Peripheral venous access was considered to be a possible route for the infusion of lipid emulsions in only 58 (63.7%) of the units. In 80% 90% of the units, sepsis, hemodynamic failure, thrombocytopenia, disseminated intravascular coagulation, and hyperbilirubinemia were considered to be relative or absolute contraindications, whereas only hemodynamic failure, disseminated intravascular coagulation, and to a lesser extent sepsis were most often perceived as absolute contraindications. CONCLUSIONS: Neonatologists are somewhat reluctant to use parenteral lipids when only peripheral venous access is available, despite the low osmolarity of the emulsions. This may impair, at least temporarily, the adequate supply of energy and/or essential fatty acids in infants who do not have central venous access. This study also shows a large heterogeneity of responses with regard to the contraindications for parenteral lipids. PMID- 22205559 TI - Practice-based validation of calcium and phosphorus solubility limits for pediatric parenteral nutrition solutions. AB - In an effort to maximize the precipitation-free delivery of calcium and phosphorus to neonates, Fitzgerald and MacKay published in 1986 the results of empirical determination of calcium-phosphate saturation curves for a number of parenteral nutrition (PN) solutions. The saturation curves generated from these investigations have been used to formulate thousands of PN solutions. The curves were developed testing only calcium and phosphate without other components added to PN solutions. The authors reviewed 38,019 PN orders from 2007-2010 and plotted the calcium and phosphate concentrations for each solution in relation to the published curves to assess the practical validity of the curves. The solutions reviewed were compounded using standard weight ranges for electrolytes, trace minerals, and vitamins. The solutions were evaluated for precipitation using standards for visual compatibility against a black and white background. There were no visual precipitates found in the 38,019 PN solutions. All calcium and phosphorus concentrations plotted below the precipitation limits predicted by the published curves despite a large range of concentrations of electrolytes and minerals. There has always been concern about extrapolating data from solubility curves that were developed empirically from a limited number of test solutions based on the few variables of calcium, phosphorus, amino acid concentration, and presence of cysteine HCl and/or fat emulsion. This experience validates the calcium and phosphorus solubility limits represented by published curves. Moreover, the findings support the concept that principal variables governing calcium and phosphorus precipitation in PN solutions are calcium, phosphorus, amino acid concentrations, temperature, and pH. PMID- 22205560 TI - Comparison of 70/30 biphasic insulin with glargine/lispro regimen in non critically ill diabetic patients on continuous enteral nutrition therapy. AB - Despite significant advances in inpatient diabetes management, it is still a challenge to choose the safest and most efficacious subcutaneous insulin regimen for diabetic patients on continuous enteral nutrition (EN) therapy. The authors conducted a retrospective analysis of glycemic control in 22 non-critically ill diabetic patients, receiving at least 3 days of continuous EN. Patients received different insulin regimens while on continuous EN, including a basal/bolus glargine/lispro regimen (group 1, n = 8), 70/30 biphasic insulin twice daily (group 2, n = 8), and 70/30 biphasic insulin 3 times a day (group 3, n = 6). The glucose data from 72 hours from the initiation of EN were analyzed (12 point-of contact glucose measurements per patient). Overall, the degree of control was comparable in all groups, with target range maintained more consistently in group 3 (70/30 insulin administered 3 times daily). In this group, 69% of values were in the target range (140-180 mg/dL) as compared with 24% in glargine/lispro group and 22% in the 70/30 insulin bid group. Eight hypoglycemic episodes occurred among the 3 groups: 5 episodes in group 1 (5.4%), 2 episodes in group 2 (2.1%), and 1 episode in group 3 (1.4%) (P = .05, groups 2 and 3 vs group 1). Administration of 70/30 biphasic insulin 3 times daily is a safe therapeutic regimen in diabetic patients on continuous EN as it maintains glycemia in the target range and might produce fewer episodes of hypoglycemia. PMID- 22205561 TI - Red wine, grapes, and better health--resveratrol. PMID- 22205562 TI - Current nutrition guidelines may overestimate energy requirements in critically ill obese cancer patients. PMID- 22205564 TI - Protective barrier reduces central venous catheter infection. PMID- 22205565 TI - Unstable angina and non-ST elevation myocardial infarction. AB - Non-ST elevation acute coronary syndromes are responsible for approximately 1 million admissions to U.S. hospitals and twice as many to European hospitals each year. Thus, they are among the most common serious illnesses in adults, and are associated with an in-hospital mortality of approximately 5%. The most common cause is rupture of an atherosclerotic coronary plaque, resulting in subtotal coronary occlusion. Diagnosis is based on the clinical picture of retrosternal chest pain, aided by electrocardiographic findings of ST segment deviations and biomarker abnormalities (elevation of troponin and natriuretic peptides) and cardiac imaging (myocardial scans showing perfusion defects). Treatment involves antiischemic agents (nitrates and beta blockers), antiplatelet drugs (aspirin, P2Y(12), and glycoprotein IIb/IIIa receptor blockers), and anticoagulants (unfractionated and low-molecular-weight heparins). Patients should undergo risk stratification, and those with high-risk factors should undergo coronary arteriography promptly with the intent to carry out coronary revascularization. Those at low risk should continue to receive intensive antiischemic and antithrombotic therapy. At discharge, patients should receive intensive lipid lowering therapy with high doses of a statin, as tolerated. PMID- 22205566 TI - A potential role for the myeloid lineage in leptin-regulated bone metabolism. AB - Leptin influences bone formation centrally through the hypothalamus and peripherally by acting on osteoblasts or their precursors. However, neither mechanism explains the divergent, gender-specific correlation between leptin and bone mineral density in humans. Although leptin is a potent regulator of pro inflammatory immune responses, a potential role for leptin as an osteoimmunologic intermediate in bone metabolism has not been tested. Mice with myeloid-specific ablation of the long-form leptin receptor (ObRb) were generated using mice expressing cre-recombinase from the lysoszyme M promoter. At 12 weeks of age, the conditional knockout mice did not display any appreciable phenotype. However, at 52 weeks 2 changes were noted. First, there was a mild increase in liver inflammation. Second, a gender-specific, divergent bone phenotype was observed. Female mice displayed a consistent trend toward decreased trabecular bone parameters including reductions in bone volume fraction, trabecular number, and bone mineral content as well as a significant increase in marrow adipogenesis. Conversely, male mice lacked trabecular changes, but had statistically significant increases in cortical bone volume, thickness, and bone mineral density with equivalent total cortical volume. Since the year 2000, over 25 studies on more than 10,000 patients have sought to determine the correlation between leptin and bone mineral density. The results revealed a gender-specific correlation similar to that observed in our LysM transgenic animals. We hypothesize and show new evidence that regulation of myeloid lineage cells by leptin may facilitate their actions as an osteoimmunologic intermediate and contribute to leptin-regulated bone formation and metabolism in a gender-specific manner. PMID- 22205567 TI - The metabolic role of retinol binding protein 4: an update. AB - Retinol binding protein 4 (RBP(4)) is regarded as a novel cardiometabolic risk factor, which is secreted mainly by the hepatocytes and also by the adipose tissue. RBP(4) has been shown to induce insulin resistance, and plasma RBP(4) values are increased in type 2 diabetes mellitus, obesity, metabolic syndrome, and cardiovascular disease. Moreover, it has been found that circulating RBP(4) decreases during medical interventions that result in amelioration of the metabolic profile, such as diet, exercise, oral antidiabetic drugs, and hypolipidemic agents. However, only few of the RBP(4)-related studies have investigated whether RBP(4) constitutes a causal factor of the above-mentioned metabolic conditions. Importantly, circulating RBP(4) is influenced by some nonmetabolic conditions, such as renal failure, acute illness, injury, and liver failure. Thus, further studies investigating the metabolic roles of RBP(4) should be carefully planned, taking into account the effects of nonmetabolic conditions on circulating RBP(4). PMID- 22205568 TI - Carbenoxolone alters the morphology of adipose tissues and downregulates genes involved in adipogenesis, glucose transport and lipid metabolism in high-fat diet fed mice. AB - Glucocorticoid (GC) excess promotes adipose tissue accumulation, and 11beta hydroxysteroid dehydrogenase type 1 (11beta-HSD1) plays an important role in the local amplification of GC. Therefore, in this study, we investigated the effects of carbenoxolone (CBX), an 11beta-HSD1 inhibitor, on morphological changes in visceral fat, and the expression of genes involved in adipogenesis and lipid metabolism in high-fat (HF) diet-fed mice. Mice were fed a HF diet from 5 weeks of age. At 10 weeks of age, the mice received an intraperitoneal injection of CBX or vehicle every day for 2 weeks. CBX decreased body weight and visceral fat mass, and improved insulin sensitivity in HF-fed mice. This was accompanied by reduced adipocyte size and a decrease in large-sized adipocytes in visceral fat. The expression of adipogenesis (PPARgamma and C/EBPalpha), glucose transport (GLUT4) and lipid metabolism (LPL, ATGL, and HSL)-related genes were suppressed in CBX mice. CBX treatment induced beneficial morphological changes in visceral fat and decreased the expression of adipogenesis, glucose transport and lipid metabolism-related genes. These findings reveal a potential mechanism underling the effects of CBX on reduced fat accumulation and improved insulin sensitivity. PMID- 22205569 TI - Glycerol metabolism alteration in adipocytes from n3-PUFA-depleted rats, an animal model for metabolic syndrome. AB - Aquaglyceroporin 7 (AQP7) is a glycerol transporter expressed in adipocytes. Its expression has been shown to be modulated in obesity. Metabolic syndrome is characterized by abdominal obesity, insulin resistance, dyslipidemia, and hypertension. An animal model displaying several features of metabolic syndrome was used to study the AQP7 expression at both mRNA and protein level and glycerol flux in adipocytes. Second generation n3-PUFA depleted female rats is a good animal model for metabolic syndrome as it displays characteristic features such as liver steatosis, visceral obesity, and insulin resistance. Our data show a reduced expression of AQP7 at the protein level in adipose tissue from n3-PUFA depleted rats, without any changes at the mRNA levels. [U-(14)C]-Glycerol uptake was not modified in adipocytes from n3-PUFA-depleted animals. PMID- 22205570 TI - Antihyperglycemic effect of ginsenoside Rh2 by inducing islet beta-cell regeneration in mice. AB - The present study was designed to determine the antihyperglycemic function of ginsenoside Rh2 (GS-Rh2) by the regeneration of beta-cells in mice that underwent 70% partial pancreatectomy (PPx), and to explore the mechanisms of GS-Rh2-induced beta-cell proliferation. Adult C57BL/6J mice were subjected to PPx or a sham operation. Within 14 days post-PPx, mice that underwent PPx received GS-Rh2 (1 mg/kg body weight) or saline injection. GS-Rh2-treated mice exhibited an improved glycemia and glucose tolerance, an increased serum insulin levels, and beta-cell hyperplasia. Meanwhile, increased beta-cell proliferation percentages and decreased beta-cell apoptosis percentages were also observed in GS-Rh2-treated mice. Further studies on the Akt/Foxo1/PDX-1 signaling pathway revealed that GS Rh2 probably induced beta-cell proliferation via activation of Akt and PDX-1 and inactivation of Foxo1. Studies on the abundance and activity of cell cycle proteins suggested that GS-Rh2-induced beta-cell proliferation may ultimately be achieved through the regulation of cell cycle proteins. These findings demonstrate that GS-Rh2 administration could inhibit the tendency of apoptosis, and reverse the impaired beta-cell growth potential by modulating Akt/Foxo1/PDX-1 signaling pathway and regulating cell cycle proteins. Induction of islet beta cell proliferation by GS-Rh2 suggests its therapeutic potential in the treatment of diabetes. PMID- 22205571 TI - Disturbances of basal and postprandial insulin secretion and clearance in obese patients with type 2 diabetes mellitus. AB - Hyperinsulinemia of nondiabetic overweight and obese subjects is associated with weight-dependent increased insulin secretion and decreased insulin clearance. The present analysis examines whether similar effects can be observed in overweight and obese patients with type 2 diabetes mellitus (DM2). Additionally basal and postprandial insulin secretion and clearance were analyzed in relation to duration of disease. In a random sample of 348 DM2 patients basal plasma insulin concentrations were significantly higher in most BMI groups compared to matched nondiabetic (ND) controls. The weight-dependent increase of basal insulin in DM2 was primarily the result of reduced clearance rather than augmented secretion. Postprandial insulin concentrations were lower in DM2 patients and did not show any BMI-related increase. The weight-dependent reduction of postprandial insulin clearance was absent in DM2. At the time of diagnosis basal insulin concentration was higher and secretion was comparable to ND subjects and this did not change with duration of diabetes. The early postprandial insulin response was still comparable between DM2 and ND subjects at the time of diagnosis but deteriorated with longer duration of disease. The later postprandial response at diagnosis (AUC 90-180) was characterized by significantly greater insulin secretion and concentration while later on the 3-fold higher secretion was paralleled by comparable peripheral plasma concentrations due to a significantly greater postprandial insulin clearance in DM2. In conclusion, the present data indicate that apart from disturbances of insulin secretion substantial changes of insulin clearance contribute to inadequate peripheral insulin concentrations in obese DM2 patients. PMID- 22205572 TI - Autoantibodies against serotoninergic 5-HT(4) receptor in patients with heart failure. AB - Serotoninergic 5-HT(4) receptors have been detected in several tissues including the heart. An autoimmune mechanism may underline the pathogenesis of heart failure. The aim of this work was to look for autoantibodies to the 5-HT(4) receptor in patients with heart failure. We looked for the presence of autoantibodies against 5-HT(4) receptor as well as angiotensin II type (AT1), beta(1)-adrenoceptor, and muscarinic M2 receptors in the sera of 176 patients with heart failure (female: n=96, male: n=80) and in 108 controls (female: n=69; male: n=39). The prevalence of 5-HT(4) receptor autoantibodies was 18.8% (n=33) in the group of patients with heart failure and 4.6% (n=5) in the control group (p<0.002). The prevalence of autoantibodies against AT1 was 1.7 (n=3), beta(1) adrenoreceptor 0.6 (n=1), and muscarinic-receptor M2 4.2 (n=5). Female patients with diabetes and heart failure had a positive trend (p=0.07) to the presence of 5-HT(4) receptor autoantibodies. In the group of female heart failure patients we found a significant correlation with the presence of coronary heart disease (p=0.05). The clinical relevance of 5-HT(4) receptor autoantibodies has to be further studied. The prevalence of 5-HT(4) receptor autoantibodies was highly significant in patients with chronic heart failure. It was also a significant correlation between these autoantibodies and the female subgroup with coronary heart disease. It is conceivable that the increased prevalence of autoantibodies against the 5-HT(4) receptor in patients with heart failure is more than just an epiphenomenon. PMID- 22205573 TI - Brain serum amyloid P levels are reduced in individuals that lack dementia while having Alzheimer's disease neuropathology. AB - The neuropathological signs of Alzheimer's disease (AD) include beta amyloid plaques and neurofibrillary tangles. There is a significant population of individuals that have these key hallmarks but show no signs of cognitive impairment, termed non-demented with AD neuropathology (NDAN). The protective mechanism allowing these individuals to escape dementia is unknown. Serum amyloid P (SAP) is a serum protein associated with wound repair that is elevated in the brains of Alzheimer's patients and binds to amyloid plaques. Using immunoblotting and immunohistochemistry, we evaluated SAP levels in postmortem samples of hippocampus and frontal cortex in age-matched controls, AD, and NDAN individuals. AD individuals had significantly increased SAP levels compared to normal controls, while NDAN samples had no significant difference in SAP levels compared to normal controls. Our results suggest that low levels of SAP in plaques marks the brains of individuals that escape dementia despite the presence of beta amyloid plaques and tangles. PMID- 22205574 TI - Characterisation of the iterative integral parameter identification method. AB - Parameter identification methods are used to find optimal parameter values to fit models to measured data. The single integral method was defined as a simple and robust parameter identification method. However, the method did not necessarily converge to optimum parameter values. Thus, the iterative integral method (IIM) was developed. IIM will be compared to a proprietary nonlinear-least-squares based Levenberg-Marquardt parameter identification algorithm using a range of reasonable starting values. Performance is assessed by the rate and accuracy of convergence for an exemplar two parameters insulin pharmacokinetic model, where true values are known a priori. IIM successfully converged to within 1% of the true values in all cases with a median time of 1.23 s (IQR 0.82-1.55 s; range 0.61-3.91 s). The nonlinear-least-squares method failed to converge in 22% of the cases and had a median (successful) convergence time of 3.29 s (IQR 2.04-4.89 s; range 0.42-44.9 s). IIM is a stable and relatively quick parameter identification method that can be applied in a broad variety of model configurations. In contrast to most established methods, IIM is not susceptible to local minima and is thus, starting point and operator independent. PMID- 22205575 TI - Laser speckle contrast imaging of the skin: interest in processing the perfusion data. AB - Laser speckle contrast imaging (LSCI) is a recent clinical powerful tool to obtain full-field images of microvascular blood perfusion. The technique relies on laser speckle obtained by the interactions between coherent monochromatic radiations and the tissues under study. From these speckle images, contrast values are determined and instantaneous map of the perfusion are computed. LSCI has gained increased attention in the last years and is now additional to laser Doppler flowmetry (LDF). In spite of the growing interest for LSCI in skin clinical research, very few LSCI perfusion data processing have been published from now to extract physiologically-linked indices. By opposition, numerous signal processing works have been dedicated to the processing of LDF signals. The latter works proposed methodological processing procedures to extract information reflecting underlying microvascular mechanisms such as myogenic, neurogenic and endothelial activities. Our goal herein is to report on the potentialities of studies dedicated to the processing of LSCI perfusion data. Linear and nonlinear analyses could be of interest to improve the understanding of LSCI images. PMID- 22205576 TI - Transumbilical laparoendoscopic single-site pyeloplasty in infants and children: initial experience and short-term outcome. AB - BACKGROUND: Scar-free abdominal wall surgery is a research hotspot in recent years. This study presented surgical skills of transumbilical laparoendoscopic single-site pyeloplasty (LESS-P) for pediatric patients with ureteropelvic junction obstruction (UPJO) and its clinical application. METHODS: Twenty-four pediatric patients with UPJO had transumbilical LESS-P performed by the same surgeon from June to December 2010. Among them, 16 were males and 8 females aged from 2 to 62 months with average of 14 months. Eighteen patients had obstruction on the left ureteropelvic junction and six on the right. The renal pelvis and ureter were anastomosed using 5-0 absorbable sutures and a double-J ureteric stent was placed through the anastomotic stoma. RESULTS: All operations were successful. None was converted to open surgery and no additional sheath tube or incision besides umbilicus was needed. No intraoperative complications occurred. Ectopic blood vessels were found in two cases during surgery. The mean operative time was 145 min, and the average blood loss about 10 ml. Abdominal drainage tubes were remained for 2-9 days after surgery. The mean postoperative hospital time was 7 days. Two patients had postoperative urinary fistula, which naturally disappeared at 4 and 7 days of postoperation, respectively. Ultrasound and diuretic renal scintigraphy in follow-up found 23 patients had significantly decreased renal pelvis diameter. Although the other one showed no obvious change, but diuretic renography showed significantly improved excretion as indicated by increased glomerular filtration rate from 29 ml/min before surgery to 46 ml/min 6 months after surgery. CONCLUSION: Pediatric transumbilical LESS-P is not only safe and effective but also can well meet patient's aesthetic desire for scar free abdominal wall. PMID- 22205577 TI - Expression levels of microRNA-192 and -215 in gastric carcinoma. AB - MicroRNAs (miRNAs) are small, non-coding RNAs of endogenous origin. Accumulating studies have shown aberrant miRNA expression plays an important role in many tumor types. miR-192 and -215, which have the same "seed region", have not been comprehensively investigated using a large number of cases in gastric cancer. The total RNA was extracted from 118 gastric cancer tissues and three gastric cancer cell lines as well as matched non-tumor adjacent tissues (NATs). After polyadenylation and reverse transcription, expression levels of miR-192 and -215 were determined by real-time PCR and calculation using the 2(-??CT) method for evaluation of the association between miR-192, and -215 expression levels and clinicopathological characteristics. There were no significant differences in miR 192 and -215 expression levels between gastric cancer tissues and non-tumor counterparts (both p > 0.05, paired t-test). Interestingly, miR-192 and -215 were down-regulated in MGC-803 cells, BGC-823 cells and SGC-7901 cells (all p < 0.01, paired t-test). Also, the down-regulation of miR-192 and -215 was demonstrated to be associated with increased tumor sizes (both p = 0.003, Mann-Whitney U test) and advanced Borrmann type tumors (p = 0.015 and p = 0.044, respectively, Kruskal Wallis H test). Moreover, the expression of miR-192 was significantly lower in the pT4 stage of gastric cancer than in pT1, pT2 and pT3 stages (p = 0.026). Furthermore, there was a strong correlation between miR-192 and -215 in gastric cancer tissues (p < 0.001, Pearson regressions). miR-192 and -215 might be related to the proliferation and invasion of gastric cancer. Potentially, they could become important biomarkers. PMID- 22205578 TI - Preconception care and genetic risk: ethical issues. AB - Preconception care to address genetic risks in reproduction may be offered either individually to couples with a known or suspected increased risk of having a child with a genetic disorder, or systematically to couples or individuals of reproductive age. The identification of couples at risk of transmitting a (serious) genetic disorder allows those couples to refrain from having children or to adapt their reproductive plans (using prenatal or preimplantation diagnosis, donor gametes, or adoption). Ethical issues concern the possible objectives of providing these options through preconception genetic counseling or screening, objections to abortion and embryo-selection, concerns about eugenics and medicalization, and issues arising in the professional-client relationship and/or in the light of the normative framework for population screening. Although enhancing reproductive autonomy rather than prevention should be regarded as the primary aim of preconception care for genetic risks, directive counseling may well be acceptable in exceptional cases, and prevention in the sense of avoiding serious suffering may be an appropriate objective of specific community-based preconception screening programmes. The seemingly unavoidable prospect of comprehensive preconception screening raises further ethical issues. PMID- 22205579 TI - Endovenous laser ablation for the treatment of varicose veins. AB - Lower extremity venous insufficiency secondary to saphenous vein insufficiency is a common medical condition that decreases a patient's quality of life. Traditionally treated with high ligation and stripping, minimally invasive procedures using endovenous thermal ablation techniques, such as endovenous laser ablation, have evolved. The use of detailed imaging and advances in the understanding of the anatomy of truncal vein insufficiency are important for performing the endovenous laser ablation procedure successfully. Endovenous laser ablation eliminates reflux with less morbidity, faster recovery, and improved cosmetic results with high patient satisfaction. As such, it has become the preferred treatment method for varicose veins since it was first introduced a decade ago. PMID- 22205580 TI - Ethanol lock therapy in reducing catheter-related bloodstream infections in adult home parenteral nutrition patients: results of a retrospective study. AB - BACKGROUND: Equivocal data demonstrate the efficacy of ethanol lock therapy (ELT) in preventing catheter-related bloodstream infections (CRBSIs) in home parenteral nutrition (HPN) patients, but it is not currently a standard of practice. The objective of this study is to investigate the efficacy of ELT in reducing the incidence of CRBSIs in HPN patients. METHODS: Medical records from the Cleveland Clinic database of adult HPN patients with CRBSIs placed on prophylactic ELT were retrospectively studied from January 2006 to August 2009 (n = 31). Outcomes were compared pre- and post-ELT with the patients serving as their own controls. Medical-grade (70%) ethanol was instilled daily into each lumen of the central venous catheter (CVC) between PN infusion cycles. Comparative analysis was performed using McNemar's test and Wilcoxon ranked tests. RESULTS: Thirty-one patients had 273 CRBSI-related admissions prior to ELT in comparison to 47 CRBSI related admissions post-ELT. Adjusted data for only tunneled CVC pre- and post ELT showed a similar reduction of CRBSI-related admissions from 10.1 to 2.9 per 1000 catheter days (P < .001). There was also a statistically significant reduction in culture-positive CRBSIs and number of catheters changed pre- and post-ELT. There were no reported side effects or complications in any patient undergoing ELT. CONCLUSIONS: This study supports the efficacy and safety of ELT in reducing CRBSI-related admissions in HPN patients and potentially helps reduce the burden of CRBSI-related healthcare costs. This novel technique shows great promise as a standard prophylaxis for CRBSI in HPN patients and must be incorporated in routine practice. PMID- 22205581 TI - Autophagic response to a single bout of moderate exercise in murine skeletal muscle. AB - The effect of a single bout of exercise on autopahgy in murine gastrocnemius muscle was investigated. Autophagy is a process for the degradation system of cytoplasmic components, which may help maintain intracellular quality control of cell survival and turnover under normal conditions. The present study investigated the changes of autophagy-related proteins including microtubule associated protein 1b light chain 3 (LC3), Beclin-1, Atg7 (autophagy-related gene 7), conjugation form of Atg12 to Atg5, lysosome-associated membrane protein (LAMP2a), and muscle-specific RING finger protein-1 (MURF-1) protein level in gastrocnemius muscle after a single bout of treadmill exercise. Mice exercised on a treadmill for 50 min at a speed of 12.3 m/min with a slope of 5 degrees . The animals were sacrificed by cervical dislocation 0, 3, 6, or 12 h after exercise, and muscle samples were collected immediately. Western blot analysis demonstrated that the autophagy marker LC3-II was significantly decreased during the recovery period (3, 6, and 12 h) whereas there was no decrease immediately after exercise (0 h). To identify factors related to this decrease, autophagosome component proteins were examined in murine gastrocnemius muscle. A decrease in Beclin-1, Atg7, and LAMP2a during recovery period was concomitant with the decreased level of LC3-II. Additionally, MuRF-1 expression was significantly increased after a single bout of exercise. This study is the first to demonstrate autophasic related protein expression after a single bout of treadmill exercise and our results suggest that a single bout of treadmill exercise attenuates the autophagic response in murine skeletal muscle. PMID- 22205582 TI - Evaluation of blood antioxidant defense and apoptosis in peripheral lymphocytes on exogenous administration of pineal proteins and melatonin in rats. AB - In view of the significant health impact of oxidative stress and apoptosis dysfunction, and further, because of suggestions that administration of antioxidants might reduce apoptosis rate through up-regulation of body antioxidant defense systems, therefore the purpose of this study was to compare the effect of buffalo (Bubalus bubalis) pineal proteins (PP at 100 MUg/kg BW, i.p.) with melatonin (MEL at 10 mg/kg BW, i.p.) on blood (erythrocytes) antioxidant defense system and apoptosis in isolated peripheral blood lymphocytes of female Wistar albino rats. The cell viability index (%) and apoptosis index (%), which are directly related to the apoptosis rate of the cells, were used as dependent measures for inferring PP and MEL activity. The total cell viability index did not differ between rats treated with MEL and PP from control animals. The percentage of apoptotic cell death through fluorescence microscopy also did not change in MEL and PP groups as compared with control. DNA fragmentation as an index of apoptosis was detected with propidium iodide staining and assessed by flow cytometry. Pineal proteins and MEL administration caused significant (p < 0.05) reduction in lipid peroxidation and increased level of catalase, superoxide dismutase, glutathione peroxidase, and glutathione in erythrocytes as compared with control. Interestingly, we did not observe increase in the non-viable cells and percentage of apoptotic cell death in PP-treated group, controls or in animals in which MEL had been administered. Therefore, the present study confirmed the up-regulation of erythrocytes (blood) antioxidant defense systems and absence of adverse effect on rate of apoptosis in PP and MEL-administered rats under absence of stress or toxicant exposure. Hence, these test agents can be tested for further therapeutic values against adverse apoptosis rate under stress or toxicants exposures. PMID- 22205583 TI - Effect of soybean oil on atherogenic metabolic risks associated with estrogen deficiency in ovariectomized rats: dietary soybean oil modulate atherogenic risks in overiectomized rats. AB - The aim of the present study was to investigate the cardiac biomarker changes in experimental bilateral ovariectomized (OVX) rats in addition to evaluating the role of soybean oil-supplemented diet to attenuate these alterations. Female rats were divided into four groups and treated for 2 months as follows: groups 1 and 2 fed with standard diet with or without 15% soybean oil. Groups 3 and 4 were bilateral OVX and received the standard diet with or without 15% soybean oil. The results revealed that rats subjected to ovariectomy exhibited an inhibition in estrogen and high-density lipoprotein cholesterol levels and marked increase of lipid profile, low-density lipoprotein cholesterol, and VLDL-C accompanied with a marked elevation in atherogenic index, cardiac enzyme activity, tumor necrosis factor-alpha, and C-reactive protein. Signs of cardiovascular injury which included an increase in cardiac thiobarbituric acid-reactive substances were concomitantly noticed with a reduction in the reduced glutathione, total antioxidant capacity, and superoxide dismutase. However, supplementation of soybean oil resulted in the restoration of the changed lipid profile and improved cardiac biomarkers near to normal values as well as improved inflammatory and antioxidant status. It was concluded that consumption of soybean oil may have a role in retarding atherosclerosis and risk of cardiovascular disorders associated with estrogen deficiency in ovariectomy status. PMID- 22205584 TI - Varicella zoster virus-induced pain and post-herpetic neuralgia in the human host and in rodent animal models. AB - Pain and post-herpetic neuralgia (PHN) are common and highly distressing complications of herpes zoster that remain a significant public health concern and in need of improved therapies. Zoster results from reactivation of the herpesvirus varicella zoster virus (VZV) from a neuronal latent state established at the primary infection (varicella). PHN occurs in some one fifth to one third of zoster cases with severity, incidence, and duration of pain increasing with rising patient age. While VZV reactivation and the ensuing ganglionic damage trigger the pain response, the mechanisms underlying protracted PHN are not understood, and the lack of an animal model of herpes zoster (reactivation) makes this issue more challenging. A recent preclinical rodent model has developed that opens up the potential to allow the exploration of the underlying mechanisms and treatments for VZV-induced pain. Rats inoculated with live cell-associated human VZV into the hind paw reliably demonstrate thermal hyperalgesia and mechanical allodynia for extended periods and then spontaneously recover. Dorsal root ganglia express a limited VZV gene subset, including the IE62 regulatory protein, and upregulate expression of markers suggesting a neuropathic pain state. The model has been used to investigate treatment modalities and aspects of pain signaling and is under investigation by the authors to delineate VZV genetics involved in the induction of pain. This article compares human zoster-associated pain and PHN to the pain indicators in the rat and poses important questions that, if answered, could be the basis for new treatments. PMID- 22205586 TI - Mechanisms and networks of motoneuronal control during sleep: introduction. PMID- 22205585 TI - Accelerated aging and human immunodeficiency virus infection: emerging challenges of growing older in the era of successful antiretroviral therapy. AB - HIV-infected patients are living longer as a result of potent antiretroviral therapy. Immuno-inflammatory phenomena implicated in the normal aging process, including immune senescence, depreciation of the adaptive immune system, and heightened systemic inflammation are also pathophysiologic sequelae of HIV infection, suggesting HIV infection can potentiate the biological mechanisms of aging. Aging HIV-infected patients manifest many comorbidities at earlier ages, and sometimes with more aggressive phenotypes compared to seronegative counterparts. In this review, we describe relevant biologic changes shared by normal aging and HIV infection and explore the growing spectrum of clinical manifestations associated with the accelerated aging phenotype in HIV-infected individuals. PMID- 22205587 TI - Brainstem neurons responsible for postural, masseter or pharyngeal muscle atonia during paradoxical sleep in freely-moving cats. AB - In this mini review, we summarize our findings regarding the brainstem neurons responsible for the postural, masseter, or pharyngeal muscle atonia observed during paradoxical sleep (PS) in freely moving cats. Both the pons and medulla contain neurons showing tonic activation selective to PS and atonia, referred to as PS/atonia-on-neurons. The PS/atonia-on neurons, characterized by their most slow conducting property and located in the peri-locus coeruleus alpha (peri-LCa) and adjacent LCa of the mediodorsal pontine tegmentum, play a critical executive role in the somatic and orofacial muscle atonia observed during PS. Slow conducting medullary PS/atonia-on neurons located in the nuclei reticularis magnocellularis (Mc) and parvocellularis (Pc) may play a critical executive role in the generation of, respectively, antigravity or orofacial muscle atonia during PS. In addition, either tonic or phasic cessation of activity of medullary serotonergic neurons may play an important role in the atonia of genioglossus muscles during PS via a mechanism of disfacilitation. PMID- 22205588 TI - Muscle tone regulation during REM sleep: neural circuitry and clinical significance. AB - Rapid eye movement (REM) sleep is a distinct behavioral state characterized by an activated cortical and hippocampal electroencephalogram (EEG) and concurrent muscle atonia. Research conducted over the past 50 years has revealed the neuronal circuits responsible for the generation and maintenance of REM sleep, as well as the pathways involved in generating the cardinal signs of REM sleep such as cortical activation and muscle atonia. The generation and maintenance of REM sleep appear to involve a widespread network in the pons and medulla. The caudal laterodorsal tegmental nucleus (cLDT) and sublaterodorsal nucleus (SLD) within the dorsolateral pons contain REM-on neurons, and the ventrolateral periaqueductal grey (vlPAG) contains REM-off neurons. The interaction between these structures is proposed to regulate REM sleep amounts. The cLDT-SLD neurons project to the basal forebrain via the parabrachial-precoeruleus (PB-PC) complex, and this pathway may be critical for the EEG activation seen during REM sleep. Descending SLD glutamatergic projections activate the ventromedial medulla, and spinal cord interneurons mediate muscle atonia and suppress phasic muscle twitches in spinal musculature. In contrast, phasic muscle twitches in the masseter muscles may be driven by glutamatergic neurons in the rostral parvicellular reticular nucleus (PCRt); however, the brain region responsible for generating phasic twitches in the other cranial muscles including facial muscles and tongue are not clear. PMID- 22205589 TI - The 'scanning hypothesis' of rapid eye movements during REM sleep: a review of the evidence. AB - Rapid eye movements (REMs) and visual dreams are salient features of REM sleep. However, it is unclear whether the eyes scan dream images. Several lines of evidence oppose the scanning hypothesis: REMs persist in animals and humans without sight (pontine cats, foetus, neonates, born-blinds), some binocular REMs are not conjugated (no focus point), REMs occur in parallel (not in series) with the stimulation of the visual cortex by ponto-geniculo-occipital spikes, and visual dreams can be obtained in non REM sleep. Studies that retrospectively compared the direction of REMs to dream recall recorded after having awakened the sleeper yielded inconsistent results, with a concordance varying from 9 to 80%. However, this method was subject to methodological flaws, including the bias of retrospection and neck atonia that does not allow the determination of the exact direction of gaze. Using the model of RBD (in which patients are able to enact their dreams due to the absence of muscle atonia) in 56 patients, we directly determined if the eyes moved in the same directions as the head and limbs. When REMs accompanied goal-oriented motor behaviour during RBD (e.g., framing something, greeting with the hand, climbing a ladder), 90% were directed towards the action of the patient (same plane and direction). REMs were however absent in 38% of goal-oriented behaviours. This directional coherence between limbs, head and eye movements during RBD suggests that, when present, REMs imitate the scanning of the dream scene. Because REMs index and complexity were similar in patients with RBD and controls, this concordance can be extended to normal REM sleep. These results are consistent with the model of a brainstem generator activating simultaneously images, sounds, limbs movements and REMs in a coordinated parallel manner, as in a virtual reality. PMID- 22205590 TI - The tongue and its control by sleep state-dependent modulators. AB - The neural networks controlling vital functions such as breathing are embedded in the brain, the neural and chemical environment of which changes with state, i.e., wakefulness, non-rapid eye movement (non-REM) sleep and REM sleep, and with commonly administered drugs such as anaesthetics, sedatives and ethanol. One particular output from the state-dependent chemical brain is the focus of attention in this paper; the motor output to the muscles of the tongue, specifically the actions of state-dependent modulators acting at the hypoglossal motor pool. Determining the mechanisms underlying the modulation of the hypoglossal motor output during sleep is relevant to understanding the spectrum of increased upper airway resistance, airflow limitation, hypoventilation and airway obstructions that occur during natural and drug-influenced sleep in humans. Understanding the mechanisms underlying upper airway dysfunction in sleep disordered breathing is also important given the large and growing prevalence of obstructive sleep apnea syndrome which constitutes a major public health problem with serious clinical, social and economic consequences. PMID- 22205591 TI - Control of motoneuron function and muscle tone during REM sleep, REM sleep behavior disorder and cataplexy/narcolepsy. AB - REM sleep triggers a potent suppression of postural muscle tone - i.e., REM atonia. However, motor control during REM sleep is paradoxical because overall brain activity is maximal, but motor output is minimal. The skeletal motor system remains quiescent during REM sleep because somatic motoneurons are powerfully inactivated. Determining the mechanisms triggering loss of motoneuron function during REM sleep is important because breakdown in REM sleep motor control underlies sleep disorders such as REM sleep behavior disorder (RBD) and cataplexy/narcolepsy. For example, RBD is characterized by dramatic REM motor activation resulting in dream enactment and subsequent patient injury. In contrast, cataplexy a pathognomonic symptom of narcolepsy - is caused by the involuntary onset of REM-like atonia during wakefulness. This review highlights recent work from my laboratory that examines how motoneuron function is lost during normal REM sleep and it also identifies potential biochemical mechanisms underlying abnormal motor control in both RBD and cataplexy. First, I show that both GABAB and GABAA/glycine mediated inhibition of motoneurons is required for generating REM atonia. Next, I show that impaired GABA and glycine neurotransmission triggers the cardinal features of RBD in a transgenic mouse model. Last, I show that loss of an excitatory noradrenergic drive onto motoneurons is, at least in part, responsible for the loss of postural muscle tone during cataplexy in narcoleptic mice. Together, this research indicates that multiple transmitters systems are responsible for regulating postural muscle tone during REM sleep, RBD and cataplexy. PMID- 22205592 TI - Bruxism and nocturnal groaning. AB - Sleep bruxism (SB) is a sleep-related movement disorder, characterized by tooth grinding and/or clenching. The causes of SB range from psychosocial factors to an excessive sleep arousal response. Some studies showed that SB episodes during sleep are under the influences of transient activity of the brainstem arousal. Nocturnal groaning (NG) is a parasomnia characterized by an expiratory monotonous vocalization occurring during sleep, especially in REM sleep and during the second half of the night. The pathogenesis of NG remains still unclear and many hypotheses arose, ranging from the persistence of a vestigial ventilatory pattern rather than an expiratory upper airways' obstruction. Sleep microstructure fluctuation might modulate the NG, since the end of the NG episode usually is synchronized with a cortical arousal and an autonomic activation. Further studies should clarify the pathophysiology of SB and NG, especially when the two phenomena are associated. PMID- 22205593 TI - Masseter EMG activity during sleep and sleep bruxism. AB - The masseter muscle is involved in the complex and coordinated oromotor behaviors such as mastication during wakefulness. The masseter electromyographic (EMG) activity decreases but does not disappear completely during sleep: the EMG activity is generally of low level and inhomogeneous for the duration, amplitude and intervals. The decreased excitability of the masseter motoneurons can be determined by neural substrates for NREM and REM sleep. The masseter EMG activity is increased in association with the level of arousal fluctuations within either sleep state. In addition, there are some motor events such as REM twitches, swallowing and rhythmic masticatory muscle activity (RMMA), whose generation might involve the additional activation of specific neural circuits. Sleep bruxism (SB) is characterized by exaggerated occurrence of RMMA. In SB, the rhythmic activation of the masseter muscle can reflect the rhythmic motor inputs to motoneurons through, at least in part, common neural circuits for generating masticatory rhythm under the facilitatory influences of transient arousals. However, it remains elusive as to which neural circuits determine the genesis of sleep bruxism. Based on the available knowledge on the masseter EMG activity during sleep, this review presents that the variety of the masseter EMG phenotypes during sleep can result from the combinations of the quantitative, spatial and temporal neural factors eventually sending net facilitatory inputs to trigeminal motoneurons under sleep regulatory systems. PMID- 22205594 TI - Noradrenergic modulation of hypoglossal motoneuron excitability: developmental and putative state-dependent mechanisms. AB - Hypoglossal (XII) motoneurons (MNs) contribute to diverse behaviors. Their innervation of the genioglossus muscle, a tongue protruder, plays a critical role in maintaining upper airway patency during breathing. Indeed, reduced activity in these motoneurons is implicated in sleep related disorders of breathing such as obstructive sleep apnea (OSA). The excitability of these MNs is modulated by multiple neurotransmitter systems. The focus of this review is on the modulation of XII MN excitability by norepinephrine (NE), which increases MN excitability through a variety of mechanisms. The level of noradrenergic drive, however, is very dynamic, varying on developmental, sleep-wake and even millisecond timescales relevant to transitions between behaviours. Here we review and provide new data on the maturation of the noradrenergic modulatory system, focusing on those elements specifically relevant to XII MN excitability including the: i) ontogeny of the noradrenergic cell group that provides the majority of the noradrenergic innervation to the XII nucleus, the Locus subcoeruleus (LsC); ii) time course over which the XII nucleus is innervated by noradrenergic nerve fibres, and; iii) ontogeny of XII MN sensitivity to NE. In the context of state dependent changes in noradrenergic cell activity, we review mechanisms of NE action most relevant to its role in the muscle atonia of REM sleep. We conclude with a discussion of the hypothesis that the dynamics of MN modulation by NE extend to the spatial domain and recent data suggesting that noradrenergic modulation of the dendritic tree is not uniform but compartmentalized. Implications for information processing are discussed. PMID- 22205595 TI - Cerebrospinal fluid hypocretin (orexin) levels are elevated by play but are not raised by exercise and its associated heart rate, blood pressure, respiration or body temperature changes. AB - Hypocretin (Hcrt) has been implicated in the control of motor activity and in respiration and cardiovascular changes. Loss of Hcrt in narcolepsy is linked to sleepiness and to cataplexy, a sudden loss of muscle tone which is triggered by sudden strong emotions. In the current study we have compared the effects of treadmill running, to yard play on cerebrospinal fluid (CSF) Hcrt level in normal dogs. We find that treadmill locomotion, at a wide range of speeds, does not increase Hcrt level beyond baseline, whereas yard play produces a substantial increase in Hcrt, even though both activities produce comparable increases in heart rate, respiration and body temperature. We conclude that motor and cardiovascular changes are not sufficient to elevate CSF levels of Hcrt and we hypothesize that the emotional aspects of yard play account for the observed increase in Hcrt. PMID- 22205596 TI - Quantitative differences among EMG activities of muscles innervated by subpopulations of hypoglossal and upper spinal motoneurons during non-REM sleep - REM sleep transitions: a window on neural processes in the sleeping brain. AB - In the rat, a species widely used to study the neural mechanisms of sleep and motor control, lingual electromyographic activity (EMG) is minimal during non rapid eye movement (non-REM) sleep and then phasic twitches gradually increase after the onset of REM sleep. To better characterize the central neural processes underlying this pattern, we quantified EMG of muscles innervated by distinct subpopulations of hypoglossal motoneurons and nuchal (N) EMG during transitions from non-REM sleep to REM sleep. In 8 chronically instrumented rats, we recorded cortical EEG, EMG at sites near the base of the tongue where genioglossal and intrinsic muscle fibers predominate (GG-I), EMG of the geniohyoid (GH) muscle, and N EMG. Sleep-wake states were identified and EMGs quantified relative to their mean levels in wakefulness in successive 10 s epochs. During non-REM sleep, the average EMG levels differed among the three muscles, with the order being N>GH>GG-I. During REM sleep, due to different magnitudes of phasic twitches, the order was reversed to GG-I>GH>N. GG-I and GH exhibited a gradual increase of twitching that peaked at 70-120 s after the onset of REM sleep and then declined if the REM sleep episode lasted longer. We propose that a common phasic excitatory generator impinges on motoneuron pools that innervate different muscles, but twitching magnitudes are different due to different levels of tonic motoneuronal hyperpolarization. We also propose that REM sleep episodes of average durations are terminated by intense activity of the central generator of phasic events, whereas long REM sleep episodes end as a result of a gradual waning of the tonic disfacilitatory and inhibitory processes. PMID- 22205597 TI - Modulatory effects of the GABAergic basal ganglia neurons on the PPN and the muscle tone inhibitory system in cats. AB - Pedunculopontine tegmental nucleus (PPN) contributes to the control muscle tone by modulating the activities of pontomedullary reticulospinal systems during wakefulness and rapid eye movement (REM) sleep. The PPN receives GABAergic projection from the substantia nigra pars reticulata (SNr), an output nucleus of the basal ganglia. Here we examined how GABAergic SNr-PPN projection controls the activity of the pontomedullary reticulospinal tract that constitutes muscle tone inhibitory system. Intracellular recording was made from 121 motoneurons in the lumbosacral segments in decerebrate cats (n=14). Short train pulses of stimuli (3 pulses with 5 ms intervals, 10-40 mA) applied to the PPN, where cholinergic neurons were densely distributed, evoked eye movements toward to the contralateral direction and bilaterally suppressed extensor muscle activities. The identical PPN stimulation induced IPSPs, which had a peak latency of 40-50 ms with a duration of 40-50 ms, in extensor and flexor motoneurons. The late-latency IPSPs were mediated by chloride ions. Microinjection of atropine sulfate (20 mM, 0.25 ml) into the pontine reticular formation (PRF) reduced the amplitude of the IPSPs. Although conditioning stimuli applied to the SNr (40-60 mA and 100 Hz) alone did not induce any postsynaptic effects on motoneurons, it reduced the amplitude of the PPN-induced IPSPs. Subsequent injection of bicuculline (5 mM, 0.25 ml) into the PPN blocked the SNr effects. Microinjections of NMDA (5 mM, 0.25 ml) and muscimol (5 mM, 0.25 ml) into the SNr reduced and increased the amplitude of the PPN-induced IPSPs, respectively. These results suggest that GABAergic basal ganglia output controls postural muscle tone by modulating the activity of cholinergic PPN neurons which activate the muscle tone inhibitory system. The SNr-PPN projection may contribute to not only control of muscle tone during movements in wakefulness but also modulation of muscular atonia of REM sleep. Dysfunction of the SNr-PPN projection may therefore be involved in sleep disturbances in basal ganglia disorders. PMID- 22205598 TI - Noninvasive in vivo assessment of soft contact lens type on tear film surface quality. AB - PURPOSE: To evaluate the effect of soft contact lens type on the in vivo tear film surface quality (TFSQ) on daily disposable lenses and to establish whether two recently developed techniques for noninvasive measurement of TFSQ can distinguish between different contact lens types. METHODS: Thirteen subjects wearing four different types of daily soft contact lenses participated in the study. Dynamic area high-speed videokeratoscopy (HSV) and lateral shearing interferometry (LSI) were used to quantitatively assess TFSQ in natural blinking conditions in the morning soon after lens insertion and in the afternoon following 8 hours of lens wear. RESULTS: All considered contact lenses caused a significant reduction in TFSQ compared with bare eye measures. Significant differences (P < 0.05) in the average TFSQ were also observed between all contact lens materials in LSI measurements and in the majority of dynamic area HSV measurements. The potential relationship between the contact lens parameters and the observed decline in the prelens TFSQ was explored. CONCLUSIONS: Noninvasive techniques of tear film surface assessment have the potential to discriminate contact lens type/material on eye. LSI was found to more effectively perform this discrimination than the dynamic area HSV technique. PMID- 22205599 TI - Imaging and evaluation of corneal vascularization using fluorescein and indocyanine green angiography. AB - PURPOSE: To evaluate indocyanine green angiography (ICGA) and fluorescein angiography (FA) in imaging and quantifying corneal neovascularization (CNV). METHODS: Patients with CNV were studied using a standardized protocol of color digital photography, FA, and ICGA. Images were graded independently by two observers and assessed for quality, phases of fluorescence, and leakage. Areas of CNV and vasculature geometric properties were analyzed and quantified by an automated program. RESULTS: Twenty-three patients with good quality images were included. Mean times to appearance of ICG and fluorescein were 17 and 20 seconds (P = 0.10). Best images for analysis were obtained at 64 seconds for ICGA and 47 seconds for FA. CNV not apparent on color or FA, particularly in the presence of scarring, was well delineated by ICGA. Leakage of ICGA did not occur. Fluorescein leakage from apical CNV images occurred significantly earlier (32 seconds) in patients with CNV of <6-month duration than those of >1-year (50 seconds) duration (P = 0.04). Mean area of CNV and vessel diameter were similar with ICGA (8.79 mm(2), 0.058 mm) or FA (7.74 mm(2), 0.054 mm) but significantly larger than on color (1.94 mm(2), 0.026 mm) images (P < 0.01). Vessel tortuosity was similar on ICGA (1.16), FA (1.17), and color (1.15) (P = 0.27). CONCLUSIONS: Combined use of FA and ICGA are valuable tools with which to assess CNV and provide better vessel delineation than can be obtained with only color images. Parameters used to assess CNV, such as leakage, area, diameter, and tortuosity, may be useful measures for evaluating treatment. Videography is useful for detecting early leakage. PMID- 22205600 TI - Microkeratome-assisted preparation of ultrathin grafts for descemet stripping automated endothelial keratoplasty. AB - PURPOSE: To compare three microkeratome-assisted techniques for the preparation of ultrathin (UT) grafts for Descemet stripping automated endothelial keratoplasty. METHODS: After dissection with a 300-MUm microkeratome head in 40 donor tissues, a second cut was performed with a 130-MUm head either after manual stromal hydration (group A, n = 10) or osmotic hydration at the eye bank (group B, n = 10) or with a 50- or 90-MUm head, depending on residual bed thickness (group C, n = 10); no further dissection was performed in the control group (group D, n = 10). Corneal thickness and endothelial cell (EC) count were determined at all appropriate stages. Statistical analysis was performed using a Fisher exact test. RESULTS: Final graft thicknesses in groups A (89.1 +/- 34.1MUm), B (84.1 +/- 18.6 MUm), and C (72.1 +/- 10.1 MUm) were significantly lower than in group D (201.9 +/- 25.3 MUm) (P < 0.001). EC loss did not differ significantly among the groups. Multiple areas of Descemet detachment were seen in 4 of 10 corneas of group A. CONCLUSIONS: All methods proved equally efficient in producing UT grafts, but stromal hydration induced tissue structural changes. EC loss was unaffected by the additional manipulation required to prepare UT grafts. PMID- 22205602 TI - Spliceosome protein (SRp) regulation of glucocorticoid receptor isoforms and glucocorticoid response in human trabecular meshwork cells. AB - PURPOSE: Glaucoma is a leading cause of visual impairment and blindness, with elevated intraocular pressure (IOP) as a major causative risk factor. Glucocorticoid (GC) therapy causes morphologic and biochemical changes in the trabecular meshwork (TM), an ocular tissue involved in regulating IOP, which can lead to the development of glaucoma in susceptible individuals (steroid responders). Steroid responders comprise 40% of the general population and are at higher risk of developing glaucoma. In addition, a majority of glaucoma patients are steroid responders. Differential distribution of various isoforms of GC receptor (GR) may be responsible for this heterogeneity in the steroid response. The alternatively spliced GRbeta isoform acts as dominant negative regulator of classical GRalpha transcriptional activity. mRNA splicing is mediated by spliceosomes, which include serine-arginine rich proteins (SRps). The purpose of this study was to determine whether specific SRps regulate levels of these isoforms and thereby GC response in TM cells. METHODS: Quantitative RT-PCR, Western blot analysis, and immunocytochemistry were used to determine the differential expression of different SRps (SRp20, 30c, and 40) in human normal and glaucomatous TM cell strains. Bioinformatics was used to find putative binding sites for SRp20 and SRp40 on exon 9 of the GR gene. A peptide modulator of splicing (bombesin) and SRp expression vectors were used to modulate SRp levels and determine their effects on GRalpha/GRbeta ratios as well as dexamethasone (DEX) responsiveness via GRE- luciferase reporter activity, fibronectin, and myocilin induction in TM cells. RESULTS: SRp20, SRp30c, and SRp40 regulate GR splicing and the GC response in TM cells. Modulation of SRp levels altered the GRbeta/alpha ratio that correlated with DEX responsiveness. Bombesin decreased SRp20; increased SRp30c, SRp40 levels, and GRbeta/alpha ratio, and suppressed DEX response in TM cells. CONCLUSIONS: Relative levels of SRp20, SRp30c, and SRp40 in TM cells control differential expression of the two alternatively spliced isoforms of the GR and thereby regulate GC responsiveness. Different levels and/or activities of these SRps may account for differential GC sensitivity among the normal and glaucoma populations. PMID- 22205603 TI - Relationship between air pollution and outpatient visits for nonspecific conjunctivitis. AB - PURPOSE: Past studies present evidence of associations between air pollution and human ocular symptoms; however, to the knowledge of the authors, research investigating the hazardous effects of air pollution on nonspecific conjunctivitis is nonexistent. This study investigates the relationship between air pollution and outpatient visits for nonspecific conjunctivitis in Taiwan. A multiarea analysis was conducted to examine and assess the risks of short-term effects of particulate matter (PM), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and carbon monoxide on nonspecific conjunctivitis. METHODS: Data were collected from outpatient visits for nonspecific conjunctivitis from seven air quality-monitoring areas. To find immediate and lag effects of air pollution, an area-specific, case-crossover analysis was performed and a meta-analysis with random effects was used to combine the area-specific RESULTS: Results. The effects on outpatient visits for nonspecific conjunctivitis are strongest for O3 and NO2, with a 2.5% increase (95% confidence interval [CI], 0.9-4.1) for a 16.4 ppb (parts per billion) concentration rise in O3 and a 2.3% increase (95% CI, 0.7 3.9) for an 11.47 ppb concentration rise in NO2. Effects are also found for particulate matter with an aerodynamic diameter <= 10 MUm (PM10) and SO2. Effects are more prominent in winter because the analysis was stratified according to season. CONCLUSIONS: The air pollutants NO2, SO2, O3, and PM10 increase the chances of outpatient visits for nonspecific conjunctivitis and have no evident lag effects. PMID- 22205604 TI - A randomized trial using progressive addition lenses to evaluate theories of myopia progression in children with a high lag of accommodation. AB - PURPOSE: To compare the effect of wearing, then ceasing to wear, progressive addition lenses (PALs) versus single vision lenses (SVLs) on myopia progression in children with high accommodative lag to evaluate accommodative lag and mechanical tension as theories of myopia progression. METHODS: Eighty-five children (age range, 6-11 years) with spherical equivalent (SE) cycloplegic autorefraction between -0.75 D and -4.50 D were randomly assigned to wear SVLs or PALs for 1 year; all children wore SVLs a second year. Children had high accommodative lag and also had near esophoria if their myopia was greater than 2.25 D SE. The primary outcome after each year was the previous year's change in SE. RESULTS: When the children were randomly assigned to SVLs or PALs, the adjusted 1-year changes in SE were -0.52 D (SVL group) and -0.35 D (PAL group; treatment effect = 0.18 D; P = 0.01). When all children wore SVLs the second year, there was no difference in myopia progression between SVL and former PAL wearers (0.06 D; P = 0.50). Accommodative lag was not associated with myopia progression. CONCLUSIONS: The statistically significant, but clinically small, PAL effect suggests that treatments aimed at reducing foveal defocus may not be as effective as previously thought in myopic children with high accommodative lag. Finding no evidence of treatment loss after discontinuing PAL wear supports hyperopic defocus-based theories such as accommodative lag; however, not finding an association between accommodative lag and myopia progression is inconsistent with the PAL effect being due to decreased foveal blur during near work. (Clinical Trials.gov number, NCT00335049.). PMID- 22205601 TI - Natural history of age-related retinal lesions that precede AMD in mice fed high or low glycemic index diets. AB - PURPOSE: Epidemiologic data indicate that people who consume low glycemic index (GI) diets are at reduced risk for the onset and progression of age-related macular degeneration (AMD). The authors sought corroboration of this observation in an animal model. METHODS: Five- and 16-month-old C57BL/6 mice were fed high or low GI diets until they were 17 and 23.5 months of age, respectively. Retinal lesions were evaluated by transmission electron microscopy, and advanced glycation end products (AGEs) were evaluated by immunohistochemistry. RESULTS: Retinal lesions including basal laminar deposits, loss of basal infoldings, and vacuoles in the retinal pigment epithelium were more prevalent in the 23.5- than in the 17-month-old mice. Within each age group, consumption of a high GI diet increased the risk for lesions and the risk for photoreceptor abnormalities and accumulation of AGEs. CONCLUSIONS: Consuming high GI diets accelerates the appearance of age-related retinal lesions that precede AMD in mice, perhaps by increasing the deposition of toxic AGEs in the retina. The data support the hypothesis that consuming lower GI diets, or simulation of their effects with nutraceuticals or drugs, may protect against AMD. The high GI-fed C57BL/6 mouse is a new model of age-related retinal lesions that precede AMD and mimic the early stages of disease and may be useful for drug discovery. PMID- 22205605 TI - Cyclosporine immunomodulation retards regeneration of surgically transected corneal nerves. AB - PURPOSE: To determine whether immunomodulation with cyclosporine (CsA) affects reinnervation after surgical transection of stromal nerves. METHODS: Thy1-YFP+ neurofluorescent mice underwent lamellar corneal surgery and 3 days later, received artificial tears or CsA eye drops for 6 weeks. Serial in vivo wide-field stereofluorescent microscopy was performed to determine changes in nerve fiber density (NFD). Real-time quantitative PCR was performed to determine the expression of neurotrophins and cytokines (IL6 and TNF-alpha). Compartmental culture of trigeminal ganglion neurons was performed in Campenot devices to determine whether CsA directly affects neurite outgrowth. RESULTS: Yellow fluorescent protein (YFP)-positive cells significantly increased at 3 and 7 days after surgery. The number of YFP-positive cells in the cornea was significantly lower in the CsA group than that in the control group. The percentage increase in NFD between 2 to 6 weeks was greater in the control group (80% +/- 10%, P = 0.05) than that in the CsA group (39% +/- 21%). The CsA group also exhibited lower expression of IL6 and TNF-alpha (P = 0.01). In compartmental culture experiments, neurite outgrowth toward side compartments containing CsA was significantly less (2.29 +/- 0.4 mm, P = 0.01) than that toward side compartments containing vehicle (3.97 +/- 0.71 mm). CONCLUSIONS: Immunomodulation with CsA reduces the expression of cytokines (IL6) in the cornea and retards regenerative sprouting from transected corneal stromal nerve trunks. In addition, CsA has a direct growth inhibitory action on neurites as well. PMID- 22205606 TI - JAK2 and STAT3 polymorphisms in a Han Chinese population with Behcet's disease. AB - PURPOSE: Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) polymorphisms have been demonstrated as a common risk factor for a number of autoimmune diseases. The aim of this study was to investigate the association of JAK2 and STAT3 polymorphisms with Behcet's disease (BD) in a Han Chinese population. METHODS: A case-control study was performed in 503 Chinese patients with BD and 615 healthy controls. The genotypes of three single-nucleotide polymorphisms (SNPs) (rs10758669, rs7857730, rs10119004) in the JAK2 and four SNPs (rs6503695, rs744166, rs2293152, and rs12948909) in the STAT3 gene were analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). In all, 10% of the samples were sequenced to validate the result of PCR-RFLP. The chi(2) test was performed to compare allele and genotype distributions and Bonferroni correction was applied for multiple comparisons. RESULTS: A deviation from the Hardy-Weinberg equilibrium was not found in all controls tested. A significantly increased frequency of the GG genotype of the STAT3 rs2293152 was observed in patients with BD (Bonferroni corrected P value = 0.021). None of the tested SNPs of JAK2 was associated with BD. Stratification analysis according to oral ulceration, genital ulceration, skin lesions, and arthritis for BD did not reveal an association. CONCLUSIONS: These results suggest that a STAT3 genetic polymorphism is associated with the susceptibility to BD. PMID- 22205607 TI - Elevated blood pressure is associated with rarefaction of the retinal vasculature in children. AB - PURPOSE: Retinal vascular fractal dimension (D(f)) is a measure of the geometric complexity of the retinal microvasculature, and has been associated with diabetic retinopathy. In this study, the authors examined the relationship between blood pressure and retinal D(f) in children. METHODS: Among 1174 children aged 10 to 14 years who participated in the Singapore Cohort Study of Risk Factors for Myopia, retinal D(f) was measured from digital fundus images using a computer-based program following a standardized protocol. Blood pressure was calculated from the average of three separate measurements in a seated position. RESULTS: The analysis shows that retinal D(f) was normally distributed, with a mean of 1.4619 (SD, 0.0144). After adjusting for age, sex, height, and retinal arteriolar and venular caliber, smaller retinal D(f) was correlated with elevated mean arterial blood pressure (P = 0.02), diastolic blood pressure (P = 0.02), and possibly systolic blood pressure (P = 0.06). CONCLUSIONS: Higher blood pressure in children is associated with smaller retinal D(f), reflecting rarefaction of the retinal microvasculature. Retinal fractal analysis detects early subtle microvascular effects of elevated blood pressure, and may further the understanding of the genesis of ocular and systemic vascular complications of hypertension. PMID- 22205608 TI - Depth-dependent transverse shear properties of the human corneal stroma. AB - PURPOSE: To measure the transverse shear modulus of the human corneal stroma and its profile through the depth by mechanical testing, and to assess the validity of the hypothesis that the shear modulus will be greater in the anterior third due to increased interweaving of lamellae. METHODS: Torsional rheometry was used to measure the transverse shear properties of 6 mm diameter buttons of matched human cadaver cornea pairs. One cornea from each pair was cut into thirds through the thickness with a femtosecond laser and each stromal third was tested individually. The remaining intact corneas were tested to measure full stroma shear modulus. The shear modulus from a 1% shear strain oscillatory test was measured at various levels of axial compression for all samples. RESULTS: After controlling for axial compression, the transverse shear moduli of isolated anterior layers were significantly higher than central and posterior layers. Mean modulus values at 0% axial strain were 7.71 +/- 6.34 kPa in the anterior, 1.99 +/ 0.45 kPa in the center, 1.31 +/- 1.01 kPa in the posterior, and 9.48 +/- 2.92 kPa for full thickness samples. A mean equilibrium compressive modulus of 38.7 +/ 8.6 kPa at 0% axial strain was calculated from axial compression measured during the shear tests. CONCLUSIONS: Transverse shear moduli are two to three orders of magnitude lower than tensile moduli reported in the literature. The profile of shear moduli through the depth displayed a significant increase from posterior to anterior. This gradient supports the hypothesis and corresponds to the gradient of interwoven lamellae seen in imaging of stromal cross-sections. PMID- 22205609 TI - gamma-Secretase inhibition of murine choroidal neovascularization is associated with reduction of superoxide and proinflammatory cytokines. AB - PURPOSE: This study aimed to determine whether upregulation of gamma-secretase could inhibit laser-induced choroidal neovascularization (CNV) and if this was associated with a reduction in both oxidative stress and proinflammatory cytokines. METHODS: gamma-Secretase, or its catalytic subunit presenilin 1 (PS1), were upregulated by exposure to either pigment epithelial derived factor (PEDF) or an AAV2 vector containing a PS1 gene driven by a vascular endothelial-cadherin promoter. Retinal endothelial cells were infected with AAV2 or exposed to PEDF in the presence or absence of VEGF and in vitro angiogenesis determined. Mouse eyes either received intravitreal injection of PEDF, DAPT (a gamma-secretase inhibitor) or PEDF + DAPT at the time of laser injury, or AAV2 infection 3 weeks before receiving laser burns. Lesion volume was determined 14 days post laser injury. Superoxide generation, antioxidant activity and the production of proinflammatory mediators were assessed. Knockdown of gamma-secretase was achieved using siRNA. RESULTS: gamma-Secretase upregulation and PS1 overexpression suppressed VEGF-induced in vitro angiogenesis and in vivo laser induced CNV. This was associated with a reduction in the expression of VEGF and angiogenin 1 together with reduced superoxide anion generation and an increase in MnSOD compared with untreated CNV eyes. PS1 overexpression reduced proinflammatory factors and microglial activation in eyes with CNV compared with control. siRNA inhibition of gamma-secretase resulted in increased angiogenesis. CONCLUSIONS: gamma-Secretase, and in particular PS1 alone, are potent regulators of angiogenesis and this is due in part to stabilizing endogenous superoxide generation and reducing proinflammatory cytokine expression during CNV. PMID- 22205610 TI - Sildenafil accelerates anterior chamber refilling after paracentesis in sheep and rabbits. AB - PURPOSE: Sildenafil increases ocular blood flow. Thus, the authors investigated if it also increases anterior chamber (AC) refilling after paracentesis. METHODS: Corriedale sheep and albino rabbits were used as animal models. Intraocular pressure (IOP) was measured, paracentesis performed on one eye, and AC refilling followed by observation using oblique illumination. IOP measurements continued as the AC formed. After IOP stabilization, sildenafil (100 mg) was orally administered. Forty to 60 minutes later, AH was withdrawn from the contralateral eye. The point at which IOP recovered was used to determine refilling time. Paracentesis volumes were either 60, 120, or 300 MUL in sheep, and 50 or 100 MUL in rabbits. RESULTS: IOP recovered in approximately 49, 56, and 50 minutes after the 60, 120, and 300 MUL withdrawals in sheep. The refilling times of the contralateral eye after sildenafil ingestion were approximately 19, 26, and 37 minutes for the respective AH withdrawals. With rabbits, IOP recovered in approximately 13 minutes after the 50 and 100 MUL AH withdrawals. After sildenafil, the IOP recovery times of the fellow eye were approximately 6 minutes. AH refilling rates were estimated by dividing the paracentesis volume by IOP recovery time. After sildenafil, such rates were larger than the AH formation rate attributed to secretion by the ciliary epithelium. CONCLUSIONS: Sildenafil accelerates the rate of AC refilling and might have beneficial utility as an agent enhancing fluid entry into the AC of patients who experienced AH loss during eye surgery, as well as in some cases of ocular hypotony. PMID- 22205611 TI - The impact of diabetic retinopathy and diabetic macular edema on health-related quality of life in type 1 and type 2 diabetes. AB - PURPOSE: To assess the impact of diabetic retinopathy (DR) and diabetic macular edema (DME) on health-related quality of life (HRQoL) in type 1 and type 2 diabetes using the EuroQoL EQ-5D generic multi-attribute utility instrument (MAUI). METHODS: In this cross-sectional study, 577 patients with diabetes were recruited from specialized eye clinics in Melbourne, Australia. Each patient underwent clinical, biochemical, and anthropometric assessments. The severity of combined DR and DME (no DR/DME; mild NPDR [nonproliferative DR (NPDR)] and/or mild DME; moderate NPDR and/or moderate DME; and vision-threatening DR (VTDR) (severe NPDR or PDR and/or severe DME) in the worse eye was calculated. EQ-5D utility measures were the main outcome. Because the distribution of the utility measures was skewed, independent associations were explored using multivariate quantile regression models (five quintiles, namely 15th, 30th, 45th, 60th, 75th) ranging from poorest to highest HRQoL. RESULTS: Median age of the participants was 66 years (range, 26-90 years). Of the 577 participants, 223 (38.7%) had no DR/DME, 35 (6.1%) had mild NPDR/DME, 127 (22.0%) had moderate NPDR/DME, and 192 (33.3%) had VTDR. In adjusted models, neither presence nor severity of DR/DME was significantly associated with any quantile of the EQ-5D. In contrast, the presence of diabetic complications (other than DR) (beta = -0.153; SE = 0.052; P < 0.001), other nonocular comorbidities (beta = -0.115; SE = 0.038; P < 0.01), and higher body mass index (beta = -0.007; SE = 0.002; P < 0.001) were all associated with worse HRQoL. CONCLUSIONS: Using a generic MAUI, the EQ-5D, the authors found that the presence or severity of DR/DME and concomitant vision loss were not associated with any quantile of HRQoL. These findings suggest that the EQ-5D lacks sensitivity in assessing the impact of the severity of DR/DME on HRQoL parameters and that condition-specific instruments may better capture the full impact of the association. PMID- 22205613 TI - A short-lived face alert during inhibition of return. AB - In the present study, we explored the role of faces in oculomotor inhibition of return (IOR) using a tightly controlled spatial cuing paradigm. We measured saccadic response latency to targets following peripheral cues that were either faces or objects of lesser sociobiological salience. A recurring influence from cue content was observed across numerous methodological variations. Faces versus other object cues briefly reduced saccade latencies toward subsequently presented targets, independently of attentional allocation and IOR. The results suggest a short-lived priming effect or social facilitation effect from the mere presence of a face. In the present study, we further showed that saccadic responses were unaffected by face versus nonface objects in double-cue presentations. Our findings indicate that peripheral face cues do not influence attentional orienting processes involved in IOR any differently from other objects in a tightly controlled oculomotor IOR paradigm. PMID- 22205612 TI - Magnetic resonance imaging indicates decreased choroidal and retinal blood flow in the DBA/2J mouse model of glaucoma. AB - PURPOSE: This study tests the hypothesis that reduced retinal and choroidal blood flow (BF) occur in the DBA/2J mouse model of glaucoma. METHODS: Quantitative BF magnetic resonance imaging (MRI) with a resolution of 42 * 42 * 400 MUm was performed on DBA/2J mice at 4, 6, and 9 months of age and C57BL/6 age-matched controls under isoflurane anesthesia. BF MRI images were acquired with echo planar imaging using an arterial spin labeling technique and a custom-made eye coil at 7 Tesla. Automated profile analysis was performed to average layer specific BF along the length of the retina and choroid. In separate experiments, servo-null micropressure measurements of iliac arterial pressure were performed in old mice of both strains. RESULTS: Choroidal BF was lower in DBA/2J mice than in age-matched C57BL/6 control mice at 4, 6, and 9 months of age (P < 0.01 for all age-matched groups). Retinal BF was lower in DBA/2J mice than in C57BL/6 mice at the 9-month time point (P < 0.01). Mean arterial pressure was not significantly different in aged C57BL/6 mice compared with aged DBA/2J mice. CONCLUSIONS: The reduced ocular blood flow in DBA/2J mice compared with C57BL/6 control mice suggests that ischemia or hypoxia should be considered as a possible contributing factor in the optic neuropathy in the DBA/2J mouse model of glaucoma. PMID- 22205614 TI - Different sperm sources and parameters can influence intracytoplasmic sperm injection outcomes before embryo implantation. AB - To evaluate the effects of sperm with different parameters and sources on the outcomes of intracytoplasmic sperm injection (ICSI), 1972 ICSI cycles were analyzed retrospectively. Groups 1 to 5 were composed of cycles using ejaculated sperm and were grouped according to sperm quantity, quality, and morphology into normal (288 cycles), or mild (329 cycles), moderate (522 cycles), severe (332 cycles), and extremely severe (171 cycles) oligozoospermia and/or asthenozoospermia and/or teratozoospermia (OAT) groups. Group 6 was composed of 250 cycles using testicular or epididymal sperm, and Group 7 consisted of 80 cycles using frozen-thawed sperm. We found that fertilization rates were gradually reduced from Groups 1 to 6, and reached statistical difference in Groups 5 and 6 (P<0.05). The high-quality embryo rate was higher in Group 1 than in Groups 2, 3, 5, 6, and 7 (P<0.05). No statistical differences were observed in the rates of embryo cleavage, clinical pregnancy, miscarriage, live-birth, premature birth, low birth weight, weeks of premature birth, average birth weight, or sex ratio for all seven groups (P>0.05). A total of nine cases of malformation were observed, with a malformation rate of 1.25% (9/719). In conclusion, different sperm sources and parameters can affect ICSI outcomes before embryo implantation. A full assessment of offspring malformation will require further study using a larger sample size. PMID- 22205615 TI - Induced pluripotent stem cell-related genes influence biological behavior and 5 fluorouracil sensitivity of colorectal cancer cells. AB - OBJECTIVE: We aimed to perform a preliminary study of the association between induced pluripotent stem cell (iPS)-related genes and biological behavior of human colorectal cancer (CRC) cells, and the potential for developing anti-cancer drugs targeting these genes. METHODS: We used real-time reverse transcriptase polymerase chain reaction (RT-PCR) to evaluate the transcript levels of iPS related genes NANOG, OCT4, SOX2, C-MYC and KLF4 in CRC cell lines and cancer stem cells (CSCs)-enriched tumor spheres. NANOG was knockdowned in CRC cell line SW620 by lentiviral transduction. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, plate colony formation, and a mouse xenograft model were used to evaluate alterations in biological behavior in NANOG-knockdown SW620 cells. Also, mock-knockdown and NANOG-knockdown cells were treated with 5 fluorouracil (5-FU) and survival rate was measured by MTT assay to evaluate drug sensitivity. RESULTS: A significant difference in the transcript levels of iPS related genes between tumor spheres and their parental bulky cells was observed. NANOG knockdown suppressed proliferation, colony formation, and in vivo tumorigenicity but increased the sensitivity to 5-FU of SW620 cells. 5-FU treatment greatly inhibited the expression of the major stemness-associated genes NANOG, OCT4, and SOX2. CONCLUSIONS: These results collectively suggest an overlap between iPS-related genes and CSCs in CRC. Quenching a certain gene NANOG may truncate the aggressiveness of CRC cells. PMID- 22205616 TI - Effects of insulin-like growth factor-1 on the properties of mesenchymal stem cells in vitro. AB - OBJECTIVE: To explore the effects of insulin-like growth factor-1 (IGF-1) on migration, proliferation and differentiation of mesenchymal stem cells (MSCs). METHODS: MSCs were obtained from Sprague-Dawley rats by a combination of gradient centrifugation and cell culture techniques and treated with IGF-1 at concentrations of 5-20 ng/ml. Proliferation of MSCs was determined as the mean doubling time. Expression of CXC chemokine receptor 4 (CXCR4) and migration property were determined by flow cytometry and transwell migration essay, respectively. mRNA expression of GATA-4 and collagen II was determined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The mean doubling time of MSC proliferation was decreased, and the expression of CXCR4 on MSCs and migration of MSCs were increased by IGF-1, all in a dose-dependent manner, while the optimal concentration of IGF-1 on proliferation and migration was different. IGF-1 did not affect the expression of GATA-4 or collagen II mRNA. CONCLUSIONS: IGF-1 dose-dependently stimulated the proliferation of MSCs, upregulated the expression of CXCR4, and accelerated migration. There was no apparent differentiation of MSCs to cardiomyocytes or chondrocytes after culturing with IGF-1 alone. PMID- 22205617 TI - Early effects of oral administration of omeprazole and roxatidine on intragastric pH. AB - OBJECTIVE: The ideal medication for the treatment of acid-related diseases, e.g., peptic ulcers, stress-related gastric bleeding, functional dyspepsia, and gastroesophageal reflux disease, should have a rapid onset of action to promote hemostasis and relieve the symptoms. The aim of our study was to investigate the inhibitory effects on gastric acid secretion of a single oral administration of a proton pump inhibitor, omeprazole 20 mg, and an H(2)-receptor antagonist, roxatidine 75 mg. METHODS: Ten Helicobacter pylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 6 h after single oral administration of omeprazole 20 mg and roxatidine 75 mg. Each administration was separated by a 7-d washout period. RESULTS: During the 6-h study period, the average pH after administration of roxatidine was higher than that after administration of omeprazole (median: 4.45 vs. 2.65; P=0.0367). Also during the 6-h study period, a longer duration of maintenance at pH above 2, 5, and 6 was observed after administration of roxatidine 75 mg than after administration of omeprazole 20 mg (median: 90.6% vs. 55.2%, P=0.0284; 43.7% vs. 10.6%, P=0.0125; 40.3% vs. 3.3%, P=0.0125; respectively). CONCLUSIONS: In Helicobacter pylori-negative healthy male subjects, oral administration of roxatidine 75 mg increased the intragastric pH more rapidly than that of omeprazole 20 mg. PMID- 22205618 TI - Assessment of ghrelin and leptin receptor levels in postmenopausal women who received oral or transdermal menopausal hormonal therapy. AB - OBJECTIVE: In postmenopausal women, an increased leptin concentration and reduced levels of ghrelin and adiponectin were observed. The aim of this study was to evaluate the concentrations of the active form of ghrelin, total ghrelin, leptin receptor, lipoprotein(a) (Lp(a)), and plasminogen activator inhibitor type 1 (PAI 1) in postmenopausal women who received oral or transdermal menopausal hormonal therapy (MHT). METHODS: The study involved 76 healthy women: 46 women aged from 44 to 58 years who received oral (26) or transdermal (20) MHT; the control group consisted of 30 women aged from 44 to 54 years who did not receive MHT. The plasma concentrations of total ghrelin, the active form of ghrelin, Lp(a), and PAI-1:Ag were measured by enzyme-linked immunosorbent assay (ELISA). The concentration of the leptin receptor was measured by enzyme immunometric assay (EIA). RESULTS: We observed a significantly higher concentration of total ghrelin and the active form of ghrelin in women who received transdermal MHT in comparison with those who took oral MHT. We also found a significantly lower concentration of total ghrelin in women who received oral MHT compared with the control group. A higher concentration of PAI-1:Ag was found in the group of women who took transdermal MHT in comparison with those who took oral MHT and with the control group. The differences were statistically significant. Additionally, we found a significant negative correlation between the concentrations of total ghrelin and PAI-1:Ag and a positive correlation between the concentrations of total ghrelin and leptin receptor in women who received transdermal MHT. CONCLUSIONS: The study showed that women who used transdermal MHT had higher levels of total ghrelin than women who took oral MHT. This indicates a beneficial effect of the transdermal route of MHT. However, transdermal therapy was associated with adverse effects with regard to the observed higher levels of PAI 1:Ag, which in turn, can lead to a reduction in fibrinolytic activity. PMID- 22205619 TI - Management of traumatic hemothorax by closed thoracic drainage using a central venous catheter. AB - OBJECTIVE: To evaluate the efficacy and safety of the treatment of traumatic hemothorax by closed pleural drainage using a central venous catheter (CVC), compared with using a conventional chest tube. METHODS: A prospective controlled study with the Ethics Committee approval was undertaken. A total of 407 patients with traumatic hemothorax were involved and they were randomly assigned to undergo closed pleural drainage with CVCs (n=214) or conventional chest tubes (n=193). The Seldinger technique was used for drainage by CVC, and the conventional technique for drainage by chest tube. If the residual volume of the hemothorax was less than 200 ml after the daily volume of drainage decreased to below 100 ml for two consecutive days, the treatment was considered successful. The correlative data of efficacy and safety between the two groups were analyzed using t or chi-squared tests with SPSS 13.0. A P value of less than 0.05 was taken as indicating statistical significance. RESULTS: Compared with the chest tube group, the operation time, fraction of analgesic treatment, time of surgical wound healing, and infection rate of surgical wounds were significantly decreased (P<0.05) in the CVC group. There were no significant differences between the two groups in the success rate of treatment and the incidence of serious complications (P>0.05), or in the mean catheter/tube indwelling time and mean medical costs of patients treated successfully (P>0.05). CONCLUSIONS: Management of medium or large traumatic hemothoraxes by closed thoracic drainage using CVC is minimally invasive and as effective as using a conventional large-bore chest tube. Its complications can be prevented and it has the potential to replace the large-bore chest tube. PMID- 22205620 TI - Clinical characteristics of critical patients with pandemic influenza A (H1N1) virus infection in Chengdu, China. AB - OBJECTIVE: The critical illness of pandemic influenza A (H1N1) virus infection may be associated with relatively poor outcomes. The objective of this study is to describe clinical features and factors associated with the deaths of critical patients. METHODS: Medical records of 26 critical patients with H1N1 infection admitted from Sept. 1 to Dec. 31, 2009, were retrospectively reviewed. Diagnosis was established by real-time reverse transcriptase-polymerase chain reaction (RT PCR) assay. RESULTS: The mean age of the patients was (40.4 +/- 18.4) years and 73.1% of them were male. Clinical manifestations included fever, cough, and sputum production. The laboratory findings included leukocytosis, lymphopenia, C reaction protein, and lactic dehydrogenase elevation. In this series, 17 subjects survived and 9 died. The parameters between the deaths and survivors were compared, which included acute physiology and chronic health evaluation II (APACHE II) scores (23.8 +/- 10.1 vs. 14.3 +/- 6.6, P<0.05), sequential organ failure assessment (SOFA) scores (13.3 +/- 3.0 vs. 6.6 +/- 3.3, P<0.05), and multiple organ dysfunction syndrome (MODS) scores (7.4 +/- 2.5 vs. 3.3 +/- 1.7, P<0.05). The cases of deaths had higher incidences of cardiovascular failure (100% vs. 41.2%, P<0.05), renal failure (55.6% vs. 11.7%, P<0.05), encephalopathy (44.4% vs. 5.9%, P<0.05), hepatic failure (33.3% vs. 5.9%, P<0.05), and septic shock (33.3% vs. 17.6%, P<0.05). CONCLUSIONS: The critical patients with H1N1 infection have high APACHE II, SOFA, and MODS scores, which may be associated with an increased risk of death and complex clinical courses. PMID- 22205621 TI - New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy. AB - Infection with hepatitis C virus (HCV) affects approximately 170 million people worldwide. However, no vaccine or immunoglobulin is currently available for the prevention of HCV infection. The standard of care (SOC) involving pegylated interferon-alpha (PEG-IFN alpha) plus ribavirin (RBV) for 48 weeks results in a sustained virologic response in less than 50% of patients with chronic hepatitis C genotype 1, the most prevalent type of HCV in North America and Europe. Recently, reliable in vitro culture systems have been developed for accelerating antiviral therapy research, and many new specifically targeted antiviral therapies for hepatitis C (STAT-C) and treatment strategies are being evaluated in clinical trials. These new antiviral agents are expected to improve present treatment significantly and may potentially shorten treatment duration. The aim of this review is to summarize the current developments in new anti-HCV drugs. PMID- 22205623 TI - Understanding the better than average effect: motives (still) matter. AB - People evaluate themselves more positively than they evaluate most other people. Although this better than average (BTA) effect was originally thought to represent a motivated bias, several cognitively oriented theorists have questioned whether this is the case. In support of a motivational model, the author reports five studies showing that the BTA effect is stronger for important attributes than unimportant ones (all five studies) and that once attribute importance is taken into account, the effect occurs when self-evaluations are compared with a single peer (Study 2) and when self is specified as the referent rather than the target (Study 4). Finally, Study 5 shows that the BTA effect increases in magnitude after participants experience a threat to their feelings of self-worth. Collectively, these findings establish that motivational processes underlie the BTA effect. PMID- 22205622 TI - Delayed matching to sample: reinforcement has opposite effects on resistance to change in two related procedures. AB - The effects of reinforcement on delayed matching to sample (DMTS) have been studied in two within-subjects procedures. In one, reinforcer magnitudes or probabilities vary from trial to trial and are signaled within trials (designated signaled DMTS trials). In the other, reinforcer probabilities are consistent for a series of trials produced by responding on variable-interval (VI) schedules within multiple-schedule components (designated multiple VI DMTS). In both procedures, forgetting functions in rich trials or components are higher than and roughly parallel to those in lean trials or components. However, during disruption, accuracy has been found to decrease more in rich than in lean signaled DMTS trials and, conversely, to decrease more in lean than in rich multiple VI DMTS components. In the present study, we compared these procedures in two groups of pigeons. In baseline, forgetting functions in rich trials or components were higher than and roughly parallel to those in lean trials or components, and were similar between the procedures. During disruption by prefeeding or extinction, accuracy decreased more in rich signaled DMTS trials, whereas accuracy decreased more in lean multiple VI DMTS components. These results replicate earlier studies and are predicted by a model of DMTS from Nevin, Davison, Odum, and Shahan (2007). PMID- 22205624 TI - Hanging in the balance: the role of self-construal abstractness in navigating self-relevant uncertainty. AB - People inevitably face moments of uncertainty as they await feedback regarding self-relevant life outcomes, but they react to this uncertainty with varying amounts of anxiety. Self-construal abstractness (SCA) may be one key predictor of anxiety in the face of uncertain outcomes. SCA refers to a broad self-concept based on generalizations rather than a detailed, low-level self-concept that is based on specific behaviors or events. The current studies examined SCA and anxiety over self-relevant uncertainty. Studies 1 and 2 measured naturally occurring levels of SCA and found that reflecting on an abstract self-construal buffered people from anxiety when upcoming evaluative feedback was highly self relevant (Study 1) and immediate (Study 2). Study 3 revealed that SCA is equally effective as a buffer against anxiety when manipulated with a subtle prime. The potential for SCA to serve as the target for anxiety-reduction interventions in uncertain situations is discussed. PMID- 22205625 TI - When do counterstereotypic ingroup members inspire versus deflate? The effect of successful professional women on young women's leadership self-concept. AB - Three experiments tested whether and when exposure to counterstereotypic ingroup members enhances women's implicit leadership self-concept. Participants read about professional women leaders framed as similar to versus different from most women (Experiment 1) or having the same versus different collegiate background as participants (Experiment 3). Experiment 2 manipulated similarity by giving false feedback about participants' similarity to women leaders. In all cases, seeing women leaders reduced implicit self-stereotyping relative to controls but only when they were portrayed as similar to one's ingroup (Experiment 1) and oneself (Experiments 2-3). Leaders portrayed as dissimilar either had no effect on self beliefs (Experiment 1 and 3) or increased implicit self-stereotyping (Experiment 2). Dissimilar leaders also deflated participants' career goals and explicit leadership beliefs (Experiment 3). Finally, implicit self-beliefs became less stereotypic regardless of whether women believed the similarity feedback, but explicit self-beliefs changed only when they believed the feedback to be true (Experiment 2). PMID- 22205626 TI - Stepwise age-related outcomes of elective endovascular abdominal aortic aneurysm repair: 11-year institutional review. AB - OBJECTIVE: Endovascular repair of abdominal aortic aneurysms (EVAR) has largely supplanted open surgery over the past 2 decades. Faced with an aging population, the outcomes of EVAR among various age groups were examined. METHOD: Retrospective review of elective EVAR cases was performed at a single institution from 1998 to 2009. Patients were separated into 4 age groups for easy comparison. Perioperative data were analyzed using Fisher's exact test. RESULTS: Demographics were similar among the groups except for sex, BMI, and smoking status. The 30-day morbidity and mortality data were not statistically different among groups. From EVAR to end of the study, there was a 10.9% all-cause mortality rate (with no difference among groups) and an 8.0% reintervention rate (with the oldest age group having a lower reintervention rate; P < .03). CONCLUSIONS: EVAR remains a good treatment option for elective aneurysm repair despite advanced age, which alone does not appear to be an independent predictor of outcome. PMID- 22205627 TI - A perspective on the determination of mitochondrial biogenesis. AB - The measurement of mitochondrial biogenesis is important in the determination of aging and disease processes and the assessment of countermeasurements to them. We argue that the frequently used assessments of cell signaling, mitochondrial protein mRNA, mitochondrial protein expression or enzyme activity, and mitochondrial density are not measurements that can lead to conclusions about mitochondrial biogenesis. Instead, we propose that only measurements of mitochondrial synthesis are indicative of biogenesis. Clarification of this issue will hopefully result in further differentiation of the processes important for morphological and functional changes of mitochondria. PMID- 22205628 TI - A major prolactin-binding complex on human milk fat globule membranes contains cyclophilins A and B: the complex is not the prolactin receptor. AB - Prolactin (PRL) in milk influences maturation of gastrointestinal epithelium and development of both the hypothalamo-pituitary and immune systems of offspring. Here, we demonstrate that most PRL in human milk is part of a novel, high affinity, multicomponent binding complex found on the milk fat globule membrane and not in whey. To examine properties of the complex, a sensitive ELISA was developed such that human PRL (hPRL) binding to the complex was measured by loss of hPRL detectability; thus, as much as 50 ng of hPRL was undetectable in the presence of 10 MUl of human milk. Using the same methodology, no comparable complex formation was observed with human serum or amniotic fluid. hPRL complexation in milk was rapid, time dependent, and cooperative. Antibodies to or competitors of the hPRL receptor (placental lactogen and growth hormone) showed the hPRL receptor was not involved in the complex. However, hPRL complexation was antagonized by cyclosporine A and anti-cyclophilins. The complex was very stable, resisting dissociation in SDS, urea, and dithiothreitol. Western analysis revealed an ~75-kDa complex that included hPRL, cyclophilins A and B, and a 16 kDa cyclophilin A. Compared with noncomplexed hPRL, complexed hPRL in whole milk showed similar activation of STAT5 but markedly delayed activation of ERK. Alteration of signaling suggests that complex formation may alter hPRL biological activity. This is the first report of a unique, multicomponent, high-capacity milk fat reservoir of hPRL; all other analyses of milk PRL have utilized defatted milk. PMID- 22205629 TI - Insight into molecular pathways of retinal metabolism, associated with vitellogenesis in zebrafish. AB - Retinal is the main retinoid stored in oviparous eggs of fish, amphibians, and reptiles, reaching the oocytes in association with vitellogenins, the yolk precursor proteins. During early presegmentation stages of zebrafish embryos, retinal is metabolized to retinoic acid (RA), which regulates genes involved in cell proliferation, differentiation, and tissue function and is therefore essential for normal embryonic development. While synthesis of vitellogenin and its regulation by 17beta-estradiol (E(2)) were extensively investigated, pathways for retinal synthesis remain obscure. We determined the expression pattern of 46 candidate genes, aiming at identifying enzymes associated with retinal synthesis, ascertaining whether they were regulated by E(2), and finding pathways that could fulfill the demand for retinoids during vitellogenesis. Genes associated with retinal synthesis were upregulated in liver (rdh10, rdh13, sdr) and surprisingly also in intestine (rdh13) and ovary (rdh1, sdr), concomitantly with higher gene expression and synthesis of vitellogenins in liver but also in extrahepatic tissues, shown here for the first time. Vitellogenin synthesis in the ovary was regulated by E(2). Gene expression studies suggest that elevated retinal synthesis in liver, intestine, and ovary also depends on cleavage of carotenoids (by Bcdo2 or Bmco1), but in the ovary it may also be contingent on higher uptake of retinol from the circulatory system (via Stra6) and retinol synthesis from retinyl esters (by Lpl). Decrease in oxidation (by Raldh2 or Raldh3) of retinal to RA and/or degradation of RA (by Cyp26a1) may also facilitate higher hepatic retinal levels. Together, these processes enable meeting the putative demands of retinal for binding to vitellogenins. Bioinformatic tools reveal multiple hormone response elements in the studied genes, suggesting complex and intricate regulation of these processes. PMID- 22205630 TI - Contribution of FSH and triiodothyronine to the development of circadian clocks during granulosa cell maturation. AB - The involvement of FSH and triiodothyronine (T(3)) in circadian clocks was investigated using immature granulosa cells of ovaries during the progress of cell maturation. Granulosa cells were prepared from preantral follicles of mouse Period2 (Per2)-dLuc reporter gene transgenic rats injected subcutaneously with the synthetic nonsteroidal estrogen diethylstilbestrol. Analysis of the cellular clock of the immature granulosa cells was performed partly using a serum-free culture system. Several bioluminescence oscillations of Per2-dLuc promoter activity were generated in the presence of FSH + fetal bovine serum, but not in the presence of either FSH or serum. As revealed by bioluminescence recording and analysis of clock gene expression, the granulosa cells lack the functional cellular clock at the immature stage, although Lhr was greatly expressed during the period of cell maturation. The granulosa cells gained a strong circadian rhythm of bioluminescence during stimulation with FSH, whereas LH reset the cellular clock of matured granulosa cells. During strong circadian rhythms of clock genes, the Star gene showed significant expression in matured granulosa cells. In contrast, T(3) showed an inhibitory effect on the development of the functional cellular clock during the period of cell maturation. These results indicate that FSH provides a cue for the development of the functional cellular clock of the immature granulosa cells, and T(3) blocks the development of the cellular clock. PMID- 22205633 TI - Regulatory T cells induced by mucosal B cells alleviate allergic airway hypersensitivity. AB - Asthma is one of the most common chronic airway inflammatory diseases. The induction of immunologic tolerance via mucosa has been used for treating allergic diseases. B cells, which comprise the major cell population in Peyer's patches, were shown to induce the development of regulatory T (Treg) cells. This study investigated the role of B cells in Peyer's patches regarding the induction of tolerance and Treg cell functions. An in vitro suppressive assay and ELISA were used to evaluate the function of T cells stimulated by Peyer-patch B cells (Treg of-B cells). The therapeutic potential of Treg-of-B cells was then evaluated by an animal model of airway inflammation. Treg-of-B cells were found to exert a suppressive function on T-cell proliferation. Antigen-loaded B cells isolated from Peyer's patches were more tolerogenic, and had the potential to generate more suppressive Treg-of-B cells via the production of IL-10 and cell-cell contacts. Treg-of-B cells expressed cytotoxic T lymphocyte antigen 4, inducible costimulator, OX40 (CD134), programmed death 1, and TNF-RII, and produced lower concentrations of IL-2 and higher concentrations of IL-10. In a murine model of asthma, an adoptive transfer of Treg-of-B cells before or after immunization sufficiently suppressed Th2 cytokine production and eosinophilic infiltration, and alleviated asthmatic symptoms. B cells isolated from gut-associated lymphoid tissues can generate regulatory T cells that may be important in oral tolerance, and that may be applicable to the alleviation of allergic symptoms. PMID- 22205631 TI - Negative control of TLR3 signaling by TICAM1 down-regulation. AB - Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 (TICAM1, also called TRIF) is an important adaptor protein in TLR3 and TLR4 signaling pathways that mediate proinflammatory cytokine and IFN responses. Negative regulation of TICAM1 by exogenous viral protease or by endogenous caspase and proteasome have been reported to shut down TICAM1-mediated signaling. In this study, we discovered that down-regulation of TICAM1, but not other components in this signaling pathway, occurred in a natural process of TLR3 activation induced by double-stranded RNA or human rhinovirus (RV) infection in airway epithelial cells and various other cell types. TICAM1 was essential for IFN expression, and the loss of TICAM1 significantly elevated RV production. The low level of TICAM1 protein expression, caused by the prior double-stranded RNA treatment, led to a lack of IFN production upon additional treatment, suggesting receptor desensitization. In follow-up studies, TICAM1 down-regulation was found to be dependent on TLR3 but not RIG1, MDA5, or PKR and appeared to be regulated post translationally. Neither proteasome nor caspase inhibitors could prevent TICAM1 down-regulation. Instead, a lysosome-mediated process appeared to be involved, suggesting a novel mechanism that is different from previous reports. In conclusion, TICAM1 down-regulation is an essential step in TLR3 activation, and its function is to stop TLR3-mediated IFN production. PMID- 22205632 TI - LPS-stimulated cytokine production in type I cells is modulated by the renin angiotensin system. AB - The alveolar epithelium serves as a barrier to the entry of potential respiratory pathogens. Alveolar Type II (TII) cells have immunomodulatory functions, but whether Type I (TI) cells, which comprise approximately 95% of the alveolar epithelium, also play a role in immunity is unknown. Because the renin angiotensin system (RAS) is emerging as an important mediator of inflammation, and angiotensin-converting enzyme 2 (ACE2), an element of the RAS, has been implicated in lung injury, we hypothesize that TI cells can produce cytokines in response to LPS stimulation, and that this inflammation can be modulated by the RAS. Alveolar TI cells were isolated from adult Sprague-Dawley rat lungs that had been injured with an intratracheal instillation of LPS. PCR was performed to determine whether TI cells expressed transcripts for TNF-alpha, IL-6, or IL-1beta at baseline and after lung injury. Immunocytochemical and protein analysis detected angiotensin II (Ang II) and ACE2, as well as angiotensin Type 1 receptor (AT1R) and Type 2 receptor (AT2R), in TI cells. To separate cell-specific responses, primary TI cells were isolated, cultured, and exposed to LPS, Ang II, or specific inhibitors of AT1R or AT2R. Cytokine production was assayed by ELISA. LPS stimulated the production of all cytokines, whereas ACE2 and losartan, an AT1R inhibitor, blocked elements of the LPS-induced cytokine response. Primary TI cells produce cytokines when treated with LPS, contain important components of the RAS, and can modulate LPS-induced cytokine production via the RAS, suggesting a role for TI cells in the innate immune response of the lung. PMID- 22205634 TI - Socio-economic inequality in oral healthcare coverage: results from the World Health Survey. AB - The objective of this study was to assess socio-economic inequality in oral healthcare coverage among adults with expressed need living in 52 countries. Data on 60,332 adults aged 18 years or older were analyzed from 52 countries participating in the 2002-2004 World Health Survey. Oral healthcare coverage was defined as the proportion of individuals who received any medical care from a dentist or other oral health specialist during a period of 12 months prior to the survey, among those who expressed any mouth and/or teeth problems during that period. In addition to assessment of the coverage across wealth quintiles in each country, a wealth-based relative index of inequality was used to measure socio economic inequality. The index was adjusted for sex, age, marital status, education, employment, overall health status, and urban/rural residence. Pro-rich inequality in oral healthcare coverage was observed within most of the countries, although lower income countries showed greater levels of relative inequality than higher income countries. Overall, lowest coverage and highest relative inequality were found in the low-income countries. The findings of this study may inform policies for oral health at global and national levels. To achieve universal coverage in oral healthcare, relevant interventions should reach the poorest population groups. PMID- 22205636 TI - Mastication suppresses initial gastric emptying by modulating gastric activity. AB - Because various mastication-related factors influence gastric activity, the functional relationship between mastication and gastric function has not been fully elucidated. To investigate the influence of mastication on gastric emptying and motility, we conducted a randomized trial to compare the effects of mastication on gastric emptying and gastric myoelectrical activity under conditions that excluded the influences of food comminution, taste, and olfaction. A (13)C-acetate breath test with electrogastrography and electrocardiography was performed in 14 healthy men who ingested a test meal with or without chewing gum. Autonomic nerve activity was evaluated by fluctuation analysis of heart rate. Gastric emptying was significantly delayed in the 'ingestion with mastication' group. Gastric myoelectrical activity was significantly suppressed during mastication and increased gradually in the post mastication phase. A decrease in the high-frequency power of heart rate variability was observed coincidentally with gastric myoelectrical activity suppression. These findings suggest that initial gastric emptying is suppressed by mastication, and that the suppression is caused by mastication-induced inhibition of gastric activity (UMIN Clinical Trial Registration no. UMIN000005351). PMID- 22205635 TI - Reliability of reduced-thickness and thinly veneered lithium disilicate crowns. AB - The present investigation hypothesized that the reliability of reduced-thickness monolithic lithium disilicate crowns is high relative to that of veneered zirconia (Y-TZP) and comparable with that of metal ceramic (MCR) systems. CAD/CAM first mandibular molar full-crown preparations were produced with uniform thicknesses of either 1.0-mm or 2.0-mm occlusal and axial reduction, then replicated in composite for standard crown dies. Monolithic 1.0-mm (MON) and 2.0 mm CAD/CAM lithium disilicate crowns, the latter with a buccal thin veneer (BTV) of 0.5 mm, were fabricated and then sliding-contact-fatigued (step-stress method) until failure or suspension (n = 18/group). Crack evolution was followed, and fractography of post mortem specimens was performed and compared with that of clinical specimens. Use level probability Weibull calculation (use load = 1,200 N) showed interval overlaps between MON and BTV. There was no significant difference between the Weibull characteristic failure loads of MON and BTV (1,535 N [90% CI 1,354-1,740] and 1,609 N [90% CI 1,512-1,712], respectively), which were significantly higher than that of Y-TZP (370 N [90% CI 322-427]) and comparable with that of MCR (1,304 N [90% CI 1,203-1,414]), validating the study hypothesis. PMID- 22205637 TI - Altered expression of diacylglycerol kinase isozymes in regenerating liver. AB - The liver possesses the capacity to restore its function and mass after injury. Liver regeneration is controlled through complicated mechanisms, in which the phosphoinositide (PI) cycle is shown to be activated in hepatocytes. Using a rat partial hepatectomy (PH) model, the authors investigated the expression of the diacylglycerol kinase (DGK) family, a key enzyme in the PI cycle, which metabolizes a lipid second-messenger diacylglycerol (DG). RT-PCR analysis shows that DGKzeta and DGKalpha are the major isozymes in the liver. Results showed that in the process of regeneration, the DGKzeta protein, which is detected in the nucleus of a small population of hepatocytes in normal liver, is significantly increased in almost all hepatocytes. However, the mRNA levels remain largely unchanged. Double labeling with bromodeoxyuridine (BrdU), an S phase marker, reveals that DGKzeta is expressed independently of DNA synthesis or cell proliferation. However, DGKalpha protein localizes to the cytoplasm in normal and regenerating livers, but immunoblot analysis reveals that the expected (80 kDa) and the lower (70 kDa) bands are detected in normal liver, whereas at day 10 after PH, the expected band is solely recognized, showing a different processing pattern of DGKalpha in liver regeneration. These results suggest that DGKzeta and DGKalpha are involved, respectively, in the nucleus and the cytoplasm of hepatocytes in regenerating liver. PMID- 22205646 TI - Distributed sensitivity for movement amplitude in directionally tuned neuronal populations. AB - Neurons in macaque primary motor cortex and dorsal premotor cortex are tuned to movement direction. In humans, neuronal populations tuned to movement direction have recently been described using multivoxel pattern analysis and functional magnetic resonance imaging adaptation. It is unclear, however, to what extent directionally tuned neuronal populations are sensitive to movement amplitude. Here we used functional magnetic resonance imaging adaptation to determine whether directionally tuned neuronal populations are modulated by movement amplitude. In different blocks, participants were adapted to small- or large amplitude hand-reaching movements. On occasional test trials, we parametrically varied the angular difference between adaptation and test direction and the congruency between adapted and tested amplitude (same or different). We predicted that the blood oxygen level-dependent signal in directionally tuned regions should be adapted in proportion to the angular difference between adaptation and test direction. Directionally tuned regions insensitive to movement amplitude should show a transfer of adaptation from the adapted to the nonadapted amplitude. In contrast, regions sensitive to the specific combination of movement direction and amplitude should show directional tuning only for the adapted amplitude. We identified a network of parietal and frontal regions tuned to movement direction. We found that parietal areas contain neuronal populations sensitive to specific combinations of movement direction and amplitude, while frontal areas show transfer from the adapted to the nonadapted amplitude during small-amplitude movements after adaptation to large amplitude, but not vice versa. Our results thus imply different processing of movement amplitude in directionally tuned frontal and parietal areas. PMID- 22205645 TI - Domain III regulates N-type (CaV2.2) calcium channel closing kinetics. AB - Ca(V)2.2 (N-type) and Ca(V)1.2 (L-type) calcium channels gate differently in response to membrane depolarization, which is critical to the unique physiological functions mediated by these channels. We wondered if the source for these differences could be identified. As a first step, we examined the effect of domain exchange between N-type and L-type channels on activation-deactivation kinetics, which were significantly different between these channels. Kinetic analysis of chimeric channels revealed N-channel-like deactivation for all chimeric channels containing N-channel domain III, while activation appeared to be a more distributed function across domains. This led us to hypothesize that domain III was an important regulator of N-channel closing. This idea was further examined with R-roscovitine, which is a trisubstituted purine that slows N channel deactivation by exclusively binding to activated N-channels. L-channels lack this response to roscovitine, which allowed us to use N-L chimeras to test the role of domain III in roscovitine modulation of N-channel deactivation. In support of our hypothesis, all chimeric channels containing the N-channel domain III responded to roscovitine with slowed deactivation, while those chimeric channels with L-channel domain III did not. Thus a combination of kinetic and pharmacological evidence supports the hypothesis that domain III is an important regulator of N-channel closing. Our results support specialization of gating functions among calcium channel domains. PMID- 22205647 TI - Covert attention regulates saccadic reaction time by routing between different visual-oculomotor pathways. AB - Covert attention modulates saccadic performance, e.g., the abrupt onset of a task irrelevant visual stimulus grabs attention as measured by a decrease in saccadic reaction time (SRT). The attentional advantage bestowed by the task-irrelevant stimulus is short-lived: SRT is actually longer ~200 ms after the onset of a stimulus than it is when no stimulus appears, known as inhibition of return. The mechanism by which attention modulates saccadic reaction is not well-understood. Here, we propose two possible mechanisms: by selective routing of the visuomotor signal through different pathways (routing hypothesis) or by general modulation of the speed of visuomotor transformation (shifting hypothesis). To test them, we designed a cue gap paradigm in which a 100-ms gap was introduced between the fixation point disappearance and the target appearance to the conventional cued visual reaction time paradigm. The cue manipulated the location of covert attention, and the gap interval resulted in a bimodal distribution of SRT, with an early mode (express saccade) and a late mode (regular saccade). The routing hypothesis predicts changes in the proportion of express saccades vs. regular saccades, whereas the shifting hypothesis predicts a shift of SRT distribution. The addition of the cue had no effect on mean reaction time of express and regular saccades, but it changed the relative proportion of two modes. These results demonstrate that the covert attention modification of the mean SRT is largely attributed to selective routing between visuomotor pathways rather than general modulation of the speed of visuomotor transformation. PMID- 22205648 TI - Synaptic pathways that shape the excitatory drive in an OFF retinal ganglion cell. AB - Different types of retinal ganglion cells represent distinct spatiotemporal filters that respond selectively to specific features in the visual input. Much about the circuitry and synaptic mechanisms that underlie such specificity remains to be determined. This study examines how N-methyl-d-aspartate (NMDA) receptor signaling combines with other excitatory and inhibitory mechanisms to shape the output of small-field OFF brisk-sustained ganglion cells (OFF-BSGCs) in the rabbit retina. We used voltage clamp to separately resolve NMDA, alpha-amino 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and inhibitory inputs elicited by stimulation of the receptive field center. Three converging circuits were identified. First is a direct glutamatergic input, arising from OFF cone bipolar cells (CBCs), which is mediated by synaptic NMDA and AMPA receptors. The NMDA input was saturated at 10% contrast, whereas the AMPA input increased monotonically up to 60% contrast. We propose that NMDA inputs selectively enhance sensitivity to low contrasts. The OFF bipolar cells, mediating this direct excitatory input, express dendritic kainate (KA) receptors, which are resistant to the nonselective AMPA/KA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4 tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt (NBQX), but are suppressed by a GluK1- and GluK3-selective antagonist, (S)-1-(2-amino-2 carboxyethyl)-3-(2-carboxy-thiophene-3-yl-methyl)-5-methylpyrimidine-2,4-dione (UBP-310). The second circuit entails glycinergic crossover inhibition, arising from ON-CBCs and mediated by AII amacrine cells, which modulate glutamate release from the OFF-CBC terminals. The third circuit also comprises glycinergic crossover inhibition, which is driven by the ON pathway; however, this inhibition impinges directly on the OFF-BSGCs and is mediated by an unknown glycinergic amacrine cell that expresses AMPA but not KA receptors. PMID- 22205649 TI - Glial-derived adenosine modulates spinal motor networks in mice. AB - The activation of purinergic receptors modulates central pattern generators controlling rhythmic motor behaviors, including respiration in rodents and swimming in frog tadpoles. The present study aimed to determine whether purinergic signaling also modulates the mammalian locomotor central pattern generator. This was investigated by using isolated spinal cord preparations obtained from neonatal mice in which locomotor-related activity can be induced pharmacologically. The application of either ATP or adenosine led to a reduction in the frequency of locomotor activity recorded from ventral roots. ATP had no effect when applied in the presence of both the adenosine receptor antagonist theophylline and the ectonucleotidase inhibitor ARL67156, demonstrating that the effects of ATP application result from the breakdown of ATP to adenosine and subsequent activation of adenosine receptors. The application of theophylline or the A(1)-specific antagonist cyclopentyl dipropylxanthine, but not the A(2A) receptor antagonist SCH58261, caused an increase in locomotor burst frequency, demonstrating that endogenously derived adenosine activates A(1) receptors during locomotor network activity. Furthermore, theophylline had no effect in the presence of the ectonucleotidase inhibitor ARL67156 or the glial toxins methionine sulfoximine or ethyl fluoracetate, suggesting that endogenous adenosine is derived from ATP, which is released from glia. Finally, adenosine had no effect on slow rhythmic activity recorded upon blockade of all inhibitory transmission, suggesting that adenosine may act via the modulation of inhibitory transmission. Together, these data highlight endogenous purinergic gliotransmission, involving activation of A(1) receptors, as an important intrinsic modulatory system controlling the frequency of activity generated by spinal locomotor circuitry in mammals. PMID- 22205650 TI - Ifenprodil reduces excitatory synaptic transmission by blocking presynaptic P/Q type calcium channels. AB - Ifenprodil is a selective blocker of NMDA receptors that are heterodimers composed of GluN1/GluN2B subunits. This pharmacological profile has been extensively used to test the role of GluN2B-containing NMDA receptors in learning and memory formation. However, ifenprodil has also been reported to have actions at a number of other receptors, including high voltage-activated calcium channels. Here we show that, in the basolateral amygdala, ifenprodil dose dependently blocks excitatory transmission to principal neurons by a presynaptic mechanism. This action of ifenprodil has an IC(50) of ~10 MUM and is fully occluded by the P/Q type calcium channel blocker omega-agatoxin. We conclude that ifenprodil reduces synaptic transmission in the basolateral amygdala by partially blocking P-type voltage-dependent calcium channels. PMID- 22205651 TI - Linear and nonlinear auditory response properties of interneurons in a high-order avian vocal motor nucleus during wakefulness. AB - Motor-related forebrain areas in higher vertebrates also show responses to passively presented sensory stimuli. However, sensory tuning properties in these areas, especially during wakefulness, and their relation to perception, are poorly understood. In the avian song system, HVC (proper name) is a vocal-motor structure with auditory responses well defined under anesthesia but poorly characterized during wakefulness. We used a large set of stimuli including the bird's own song (BOS) and many conspecific songs (CON) to characterize auditory tuning properties in putative interneurons (HVC(IN)) during wakefulness. Our findings suggest that HVC contains a diversity of responses that vary in overall excitability to auditory stimuli, as well as bias in spike rate increases to BOS over CON. We used statistical tests to classify cells in order to further probe auditory responses, yielding one-third of neurons that were either unresponsive or suppressed and two-thirds with excitatory responses to one or more stimuli. A subset of excitatory neurons were tuned exclusively to BOS and showed very low linearity as measured by spectrotemporal receptive field analysis (STRF). The remaining excitatory neurons responded well to CON stimuli, although many cells still expressed a bias toward BOS. These findings suggest the concurrent presence of a nonlinear and a linear component to responses in HVC, even within the same neuron. These characteristics are consistent with perceptual deficits in distinguishing BOS from CON stimuli following lesions of HVC and other song nuclei and suggest mirror neuronlike qualities in which "self" (here BOS) is used as a referent to judge "other" (here CON). PMID- 22205653 TI - The evolving options for endovascular repair of complex aortic aneurysms. Foreword. PMID- 22205652 TI - Anion size modulates salt taste in rats. AB - The purpose of this study was to investigate the influence of anion size and the contribution of the epithelial sodium channel (ENaC) and the transient receptor potential vanilloid-1 (TRPV1) channel on sodium-taste responses in rat chorda tympani (CT) neurons. We recorded multiunit responses from the severed CT nerve and single-cell responses from intact, narrowly tuned and broadly tuned, salt sensitive neurons in the geniculate ganglion simultaneously with stimulus-evoked summated potentials to signal when the stimulus contacted the lingual epithelium. Artificial saliva served as the rinse and solvent for all stimuli (0.3 M NH(4)Cl, 0.5 M sucrose, 0.03-0.5 M NaCl, 0.01 M citric acid, 0.02 M quinine hydrochloride, 0.1 M KCl, and 0.03-0.5 M Na-gluconate). We used the pharmacological antagonist benzamil to assess NaCl responses mediated by ENaC, and SB-366791 and cetylpyridinium chloride to assess responses mediated by TRPV1. CT nerve responses were greater to NaCl than Na-gluconate at each concentration; this was attributed mostly to broadly tuned, acid-generalist neurons that responded with higher frequency and shorter latency to NaCl than Na-gluconate. In contrast, narrowly tuned NaCl-specialist neurons responded more similarly to the two salts, but with subtle differences in temporal pattern. Benzamil reduced CT nerve and single-cell responses only of narrowly tuned neurons to NaCl. Surprisingly, SB 366791 and cetylpyridinium chloride were without effect on CT nerve or single cell NaCl responses. Collectively, our data demonstrate the critical role that apical ENaCs in fungiform papillae play in processing information about sodium by peripheral gustatory neurons; the role of TRPV1 channels is an enigma. PMID- 22205654 TI - Standardized off-the-shelf components for multibranched endovascular repair of thoracoabdominal aortic aneurysms. AB - Endovascular techniques have been slow to assume a primary role in the management of thoracoabdominal aortic aneurysms (TAAAs) because of the high cost of multiple components, regulatory challenges, manufacturing delays, and the complexity of multibranched stent graft insertion. Standardized off-the-shelf stent grafts have the potential to lower all these barriers to the widespread application of multibranched endovascular technology. Despite the desire for a single design to accommodate all variations of thoracoabdominal aneurysms, different approaches are likely required for patients with extensive aneurysmal disease compared with disease that is more localized to the infradiaphragmatic region or that which does not extend below the renals. This article summarizes the basic concepts and stent graft designs for repair of TAAA using off-the-shelf fenestrated and branched endografts. PMID- 22205655 TI - YB-1, the E2F pathway, and regulation of tumor cell growth. AB - BACKGROUND: Y-box binding factor 1 (YB-1) has been associated with prognosis in many tumor types. Reduced YB-1 expression inhibits tumor cell growth, but the mechanism is unclear. METHODS: YB-1 mRNA levels were compared with tumor grade and histology using microarray data from 771 breast cancer patients and with disease-free survival and distant metastasis-free survival using data from 375 of those patients who did not receive adjuvant therapy. Microarrays were further searched for genes that had correlated expression with YB-1 mRNA. Small interfering RNA (siRNA) was used to study the effects of reduced YB-1 expression on growth of three tumor cell lines (MCF-7 breast, HCT116 colon, and A549 lung cancer cells), on tumorigenesis by A549 cells in nude mice, and on global transcription in the three cancer cell lines. Reporter gene assays were used to determine whether YB-1 siRNAs affected the expression of E2F1, and chromatin immunoprecipitation was used to determine whether YB-1 bound to various E2F promoters as well as E2F1-regulated promoters. All P values were from two-sided tests. RESULTS: YB-1 levels were elevated in more aggressive tumors and were strongly associated with poor disease-free survival and distant metastasis-free survival. YB-1 expression was often associated with the expression of genes with E2F sites in their promoters. Cells expressing YB-1 siRNA grew substantially more slowly than control cells and formed tumors less readily in nude mice. Transcripts that were altered in cancer cell lines with YB-1 siRNA included 32 genes that are components of prognostic gene expression signatures. YB-1 regulated expression of an E2F1 promoter-reporter construct in A549 cells (eg, relative E2F1 promoter activity with control siRNA = 4.04; with YB-1 siRNA = 1.40, difference= -2.64, 95% confidence interval = -3.57 to -1.71, P < .001) and bound to the promoters of several well-defined E2F1 target genes. CONCLUSION: YB 1 expression is associated with the activity of E2F transcription factors and may control tumor cell growth by this mechanism. PMID- 22205656 TI - Immunological correlates of vaccination and infection for equine herpesvirus 1. AB - Equine herpesvirus 1 (EHV-1) induces a variety of disease manifestations, including respiratory disease, abortions, and myeloencephalopathy. Several vaccines are commercially available but could not previously be distinguished by serologic testing from infection with EHV-1 (or the closely related EHV-4). Currently available vaccines are not reliably protective against the severe manifestations of the disease, including fatal myeloencephalopathy. We determined immunological parameters that can differentiate vaccinated from previously infected animals by comparing humoral and cellular EHV-1-specific responses in clinically healthy horses 10 months after vaccination. Forty-seven horses with known histories of vaccination and infection were studied, including a group of horses that survived a severe neurological outbreak 5 years prior to vaccination. Results of serum virus neutralization (SN), serum IgG isotyping, and cytokine profiling of lymphocyte subsets were compared. IgG4/7 levels strongly correlated with virus neutralization (P < 0.0001). IgG1/3 and SN values distinguished vaccinated/outbreak-exposed (vacc/outbreak) horses from vaccinated horses (P < 0.05). EHV-1-specific gamma interferon (IFN-gamma)-producing CD4(+) (but not CD8(+)) T-cell numbers were also increased in vacc/outbreak horses, which distinguished them from vaccinated horses (P < 0.01). IFN-alpha secretion was similar between all groups and independent of previous exposure or vaccination. Our data suggest that IgG isotype responses to EHV-1 are more diverse under field conditions than is revealed by experimental studies and that the current modified live virus (MLV) vaccine induces a more restricted IgG isotype response than does natural exposure to EHV-1. Since these parameters can be assessed in a high throughput manner, they may prove useful in screening future vaccine candidates and assessing levels of protection. PMID- 22205657 TI - Human endogenous retrovirus K(HML-2) Gag- and Env-specific T-cell responses are infrequently detected in HIV-1-infected subjects using standard peptide matrix based screening. AB - T-cell responses to human endogenous retrovirus (HERV) K(HML-2) Gag and Env were mapped in HIV-1-infected subjects using 15 mer peptides. Small peptide pools and high concentrations were used to maximize sensitivity. In the 23 subjects studied, only three bona fide HERV-K(HML-2)-specific responses were detected. At these high peptide concentrations, we detected false-positive responses, three of which were mapped to an HIV-1 Gag peptide contaminant. Thus, HERV-K(HML-2) Gag- and Env-specific T-cell responses are infrequently detected by 15 mer peptide mapping. PMID- 22205658 TI - Immunological response to parenteral vaccination with recombinant hepatitis B virus surface antigen virus-like particles expressing Helicobacter pylori KatA epitopes in a murine H. pylori challenge model. AB - Virus-like particles (VLPs) based on the small envelope protein of hepatitis B virus (HBsAg-S) are immunogenic at the B- and T-cell level. In this study, we inserted overlapping sequences encoding the carboxy terminus of the Helicobacter pylori katA gene product into HBsAg-S. The HBsAg-S-KatA fusion proteins were able to assemble into secretion-competent VLPs (VLP-KatA). The VLP-KatA proteins were able to induce KatA-specific antibodies in immunized mice. The mean total IgG antibody titers 41 days post-primary immunization with VLP-KatA (2.3 * 10(3)) were significantly greater (P < 0.05) than those observed for vaccination with VLP alone (5.2 * 10(2)). Measurement of IgG isotypes revealed responses to both IgG1 and IgG2a (mean titers, 9.0 * 10(4) and 2.6 * 10(4), respectively), with the IgG2a response to vaccination with VLP-KatA being significantly higher than that for mice immunized with KatA alone (P < 0.05). Following challenge of mice with H. pylori, a significantly reduced bacterial load in the gastric mucosa was observed (P < 0.05). This is the first report describing the use of VLPs as a delivery vehicle for H. pylori antigens. PMID- 22205660 TI - Single nucleotide polymorphisms in the Toll-like receptor 3 and CD44 genes are associated with persistence of vaccine-induced immunity to the serogroup C meningococcal conjugate vaccine. AB - The rate of decay of antibody concentration following serogroup C meningococcal (MenC) polysaccharide-protein conjugate vaccination varies between individuals. This depends partly on vaccination age but may be influenced by human genetics. We studied 721 single nucleotide polymorphisms (SNPs) across 131 candidate genes in a first cohort of 905 Caucasians (11 to 21 years old; mean time after vaccination, 4.9 years) and 30 SNPs across 17 genes in a replication study using 155 children, aged 6 to 12 years (mean time after vaccination, 6.7 years), and 196 infants (1 year old; mean time after vaccination, 8 months). Individuals were classified as responders or nonresponders for total MenC IgG concentration and MenC serum bactericidal antibody (SBA) measurements. Associated genes were examined further for quantitative outcome measures. Fifty-nine SNPs in 37 genes were associated with IgG persistence (adjusted for age at measurement), and 56 SNPs in 36 genes were associated with SBA persistence (adjusted for age at measurement and vaccine used). Three SNPs each within the Toll-like receptor 3 (TLR3) (rs3775291, rs3775292, and rs5743312) and CD44 (rs11033013, rs353644, and rs996076) genes were associated with IgG (adjusted for age at measurement) or SBA (adjusted for age at measurement and vaccine used) persistence in the initial genetic study (P, 0.02 to 0.04). Single SNPs within the TLR3 (rs7657186) (P = 0.004 [unadjusted]) and CD44 (rs12419062) (P = 0.01 [unadjusted]) genes were associated with IgG persistence in the replication study. These results suggest that genetic polymorphisms in the TLR3 and CD44 genes are associated with the persistence of the immune response to MenC vaccines 1 to 6 years after vaccination. PMID- 22205659 TI - Anti-Toxoplasma antibody prevalence, primary infection rate, and risk factors in a study of toxoplasmosis in 4,466 pregnant women in Japan. AB - Toxoplasmosis is a zoonosis caused by infection with Toxoplasma gondii and is prevalent worldwide under various climatic conditions. It is usually asymptomatic, but infection in pregnant women can pose serious health problems for the fetus. However, epidemiological information regarding toxoplasmosis in Japanese pregnant women is limited. This study aimed to determine the prevalence of anti-Toxoplasma antibodies, the primary infection rate, and the risk factors for toxoplasmosis in Japanese pregnant women. We measured anti-Toxoplasma antibody titers in 4,466 pregnant women over a period of 7.5 years and simultaneously conducted interviews to identify the risk factors for toxoplasmosis. The overall prevalence of anti-Toxoplasma antibodies was 10.3%, and it was significantly higher in women aged above 35 years. The rate of primary Toxoplasma infection during pregnancy was estimated to be 0.25%. A possibility of infection in the later stages of pregnancy was identified for those women who were not infected in the early stages. A history of raw meat intake was identified to be a risk factor related to toxoplasmosis. Therefore, to lower the risk of toxoplasmosis, pregnant women should refrain from eating raw and undercooked meat and maintain personal hygiene. PMID- 22205661 TI - Effects of pretreating serum samples on the performance of a latex agglutination test for serodiagnosis of paracoccidioidomycosis. AB - Paracoccidioidomycosis (PCM) is a fungal disease caused by Paracoccidioides brasiliensis, and Brazil is one of the principal countries where it is endemic. Diagnosis is based on the observation of budding P. brasiliensis yeast in clinical specimens from patients; however, the sensitivity of the visualization of fungi is low, indicating that serological tests are used for early diagnosis. The double-immunodiffusion test (ID) is the "gold standard" test for serology in PCM, although the execution of this test requires the availability of laboratorial infrastructure. We report the improved performance of a latex agglutination test (LAT) by pretreating 30 serum samples from PCM patients and 71 controls (histoplasmosis and aspergillosis patients, patients with bacterial infections, and normal human sera) with a dilution buffer incubated at 37 degrees C for 30 min. The sensitivity and specificity of the LAT test in the nonpretreated samples were 73% and 79%, respectively. However, when samples were pretreated, the sensitivity and specificity of the test increased to 90%. In this study, we did not observe cross-reactivity with histoplasmosis patient sera, but some reactions to sera from patients with aspergillosis and bacterial infections were noted. Normal human sera were not reactive in our tests. These results indicate the need for the elimination of heterologous reactions so that we can adequately use this method for screening cases of PCM. PMID- 22205662 TI - Evidence for a major QTL associated with host response to porcine reproductive and respiratory syndrome virus challenge. AB - Porcine reproductive and respiratory syndrome (PRRS) causes decreased reproductive performance in breeding animals and increased respiratory problems in growing animals, which result in significant economic losses in the swine industry. Vaccination has generally not been effective in the prevention of PRRS, partially because of the rapid mutation rate and evolution of the virus. The objective of the current study was to discover the genetic basis of host resistance or susceptibility to the PRRS virus through a genome-wide association study using data from the PRRS Host Genetics Consortium PRRS-CAP project. Three groups of approximately 190 commercial crossbred pigs from 1 breeding company were infected with PRRS virus between 18 and 28 d of age. Blood samples and BW were collected up to 42 d post infection (DPI). Pigs were genotyped with the Illumina Porcine 60k Beadchip. Whole-genome analysis focused on viremia at each day blood was collected and BW gains from 0 to 21 DPI (WG21) or 42 DPI (WG42). Viral load (VL) was quantified as area under the curve from 0 to 21 DPI. Heritabilities for WG42 and VL were moderate at 0.30 and litter accounted for an additional 14% of phenotypic variation. Genomic regions associated with VL were found on chromosomes 4 and X and on 1, 4, 7, and 17 for WG42. The 1-Mb region identified on chromosome 4 influenced both WG and VL, exhibited strong linkage disequilibrium, and explained 15.7% of the genetic variance for VL and 11.2% for WG42. Despite a genetic correlation of -0.46 between VL and WG42, genomic EBV for this region were favorably and nearly perfectly correlated. The favorable allele for the most significant SNP in this region had a frequency of 0.16 and estimated allele substitution effects were significant (P < 0.01) for each group when the SNP was fitted as a fixed covariate in a model that included random polygenic effects with overall estimates of -4.1 units for VL (phenotypic SD = 6.9) and 2.0 kg (phenotypic SD = 3 kg) for WG42. Candidate genes in this region on SSC4 include the interferon induced guanylate-binding protein gene family. In conclusion, host response to experimental PRRS virus challenge has a strong genetic component, and a QTL on chromosome 4 explains a substantial proportion of the genetic variance in the studied population. These results could have a major impact in the swine industry by enabling marker-assisted selection to reduce the impact of PRRS but need to be validated in additional populations. PMID- 22205663 TI - Triennial Lactation Symposium: Prolactin: The multifaceted potentiator of mammary growth and function. AB - At face value there are clear and established roles for prolactin (PRL) in the regulation of mammary gland growth, lactogenesis, and galactopoiesis. These actions of PRL do not occur in isolation; rather, they are finely attuned to and coordinated with many local, reproductive, and metabolic events in the female. Hence, to understand PRL action at the level of the mammary gland is to understand the systemic and local contexts in which it acts and functions. Herein we review the functions of PRL, its receptors, and the pathways leading to the phenotypes it evokes within the mammary glands, including growth and lactation, across a variety of species. At one level, the actions of PRL are mediated by several PRL receptor (PRLR) isoforms, including its long form and various short PRLR variants that are generated by alternative splicing in a species- and tissue dependent manner. In turn, these PRLR activate a variety of intracellular signaling cascades. We also focus on how PRL coordinates with other endocrine cues to impart its effects on the mammary glands, where the ovarian hormones can independently and substantially modulate PRL action. Many of these effects of PRL are also realized at the local level of the mammary gland, either through the autocrine or paracrine synthesis of a multitude of molecules and transcription factors or through its effects on adjacent supporting tissues, including the mammary vasculature. Taken together, it is clear that PRL directs a variety of mechanisms during growth and function of the mammary gland and is deserving of its classification as the master hormone. PMID- 22205664 TI - Predicting water intake by yearling feedlot steers. AB - Data from 4 separate beef cattle feedlot experiments, which were conducted at the Southeast Colorado Research Center (SECRC) in Lamar, CO, in 2001, 2003, 2004, and 2007, were utilized in a retrospective longitudinal study investigating possible relationships between daily water consumption (WC), DMI, and weather variables. The data set consisted of 8,209 records from 2001, 2003, 2004, and 2007, with pen based daily WC (L*animal(-1)) and DMI measurements and calculated daily steer BW from April to October in each year. Daily weather data were obtained from the weather station located at Lamar Municipal Airport located approximately 1.9 km from SECRC. Data collected consisted of daily high, low, and mean temperature; high, low, and mean humidity; high, low, and mean sea level pressure; mean wind speed; total precipitation; and average daily wind direction (cosine of radians from due north). Univariate analysis demonstrated that the continuous variables of BW, humidity, and sea level pressure were negatively related (P < 0.0001), whereas DMI, temperature the previous day, daily temperature, change in temperature from the previous day, average wind speed, and the temperature humidity index (THI) were positively related (P < 0.001) to daily WC. There was a trend (P < 0.06) for the cosine of wind direction (1 = due north and -1 = due south) to be negatively related to WC. The multivariate, parsimonious model predicting average daily WC included (P < 0.05) average humidity, average humidity squared, high temperature squared, high humidity squared, low temperature, low temperature squared, low humidity, average sea level pressure, average wind speed, average daily BW, high sea level pressure, low sea level pressure, high humidity, and low humidity. The generalized R(2) of the parsimonious multivariate model was 0.32. These results indicate that BW and numerous weather factors are related to WC by yearling feedlot steers. Dry matter intake had minimal impact on WC for yearling feedlot steers consuming steam flaked corn-based high concentrate diets from mid-spring to early fall. PMID- 22205665 TI - Ruminant Nutrition Symposium: ruminant production and metabolic responses to heat stress. AB - Heat stress compromises efficient animal production by marginalizing nutrition, management, and genetic selection efforts to maximize performance endpoints. Modifying farm infrastructure has yielded modest success in mitigating heat stress-related losses, yet poor production during the summer remains arguably the costliest issue facing livestock producers. Reduced output (e.g., milk yield and muscle growth) during heat stress was traditionally thought to result from decreased nutrient intake (i.e., a classic biological response shared by all animals during environmental-induced hyperthermia). Our recent observations have begun to challenge this belief and indicate heat-stressed animals employ novel homeorhetic strategies to direct metabolic and fuel selection priorities independently of nutrient intake or energy balance. Alterations in systemic physiology support a shift in carbohydrate metabolism, evident by increased basal and stimulated circulating insulin concentrations. Perhaps most intriguing given the energetic shortfall of the heat-stressed animal is the apparent lack of basal adipose tissue mobilization coupled with a reduced responsiveness to lipolytic stimuli. Thus, the heat stress response markedly alters postabsorptive carbohydrate, lipid, and protein metabolism independently of reduced feed intake through coordinated changes in fuel supply and utilization by multiple tissues. Interestingly, the systemic, cellular, and molecular changes appear conserved amongst different species and physiological states. Ultimately, these changes result in the reprioritization of fuel selection during heat stress, which appears to be primarily responsible for reduced ruminant animal productivity during the warm summer months. PMID- 22205667 TI - Comparison of linear, skewed-linear, and proportional hazard models for the analysis of lambing interval in Ripollesa ewes. AB - Lambing interval is a relevant reproductive indicator for sheep populations under continuous mating systems, although there is a shortage of selection programs accounting for this trait in the sheep industry. Both the historical assumption of small genetic background and its unorthodox distribution pattern have limited its implementation as a breeding objective. In this manuscript, statistical performances of 3 alternative parametrizations [i.e., symmetric Gaussian mixed linear (GML) model, skew-Gaussian mixed linear (SGML) model, and piecewise Weibull proportional hazard (PWPH) model] have been compared to elucidate the preferred methodology to handle lambing interval data. More specifically, flock by-flock analyses were performed on 31,986 lambing interval records (257.3 +/- 0.2 d) from 6 purebred Ripollesa flocks. Model performances were compared in terms of deviance information criterion (DIC) and Bayes factor (BF). For all flocks, PWPH models were clearly preferred; they generated a reduction of 1,900 or more DIC units and provided BF estimates larger than 100 (i.e., PWPH models against linear models). These differences were reduced when comparing PWPH models with different number of change points for the baseline hazard function. In 4 flocks, only 2 change points were required to minimize the DIC, whereas 4 and 6 change points were needed for the 2 remaining flocks. These differences demonstrated a remarkable degree of heterogeneity across sheep flocks that must be properly accounted for in genetic evaluation models to avoid statistical biases and suboptimal genetic trends. Within this context, all 6 Ripollesa flocks revealed substantial genetic background for lambing interval with heritabilities ranging between 0.13 and 0.19. This study provides the first evidence of the suitability of PWPH models for lambing interval analysis, clearly discarding previous parametrizations focused on mixed linear models. PMID- 22205669 TI - Influence of increasing slaughter age of chickens on meat quality, welfare, and technical and economic results. AB - Because of the increasing demand for raw cuts and processed products, there is a trend to producing very heavy broilers. Breeds that are used for such kinds of production have been intensively selected for growth rate and breast meat yield, and birds are reared for a longer period than standard broilers. This study was to evaluate the effects of increasing slaughter age on technical and economic factors, including production efficiency and environmental costs, bird welfare, and breast meat quality in a modern heavy broiler line. Five groups of 300 male Ross 708 chickens were reared until slaughter ages of 35, 42, 49, 56, or 63 d. Increasing age at slaughter from 35 to 63 d resulted in a 7.4-fold increase (P < 0.01) in mortality rate (5.21 vs. 0.70%). It also increased (P < 0.001) the slaughter weight and ADFI of birds 2.5- and 1.4-fold, respectively, without affecting their G:F. Under our experimental conditions, economic profit evaluated through the net gain reached a maximum at 42 d. The moisture and ammonium content of litter increased (P < 0.05 and P < 0.01, respectively) rapidly during rearing concomitantly with increased (P < 0.05) occurrence and severity of contact dermatitis and decreased (P < 0.05) walking ability and activity of birds. Thermal comfort also decreased (P < 0.05) greatly as early as 42 d of age. Changes in carcass quality occurred mainly between 35 and 56 d of age, with a progressive increase (P < 0.001) in breast and leg yield, whereas body fatness was barely affected by age. Major changes in breast meat traits were observed between 35 and 49 d of age, with an increase in muscle pH at 15 min (P < 0.01) and 24 h (P < 0.001) postmortem and reduced (P < 0.001) lightness and drip loss. The protein and lipid content of raw breast meat also increased (P < 0.05 and P < 0.01, respectively) with age. Taking into account the main aspects of sustainability, we could recommend slaughtering chickens of heavy line at 42 d of age. PMID- 22205668 TI - Triennial Lactation Symposium: A local affair: How the mammary gland adapts to changes in milking frequency. AB - Regular removal of milk from the mammary gland is critical to maintaining milk secretion. Early studies in rodents demonstrated that changes in milking frequency influenced mammary blood flow, as well as mammary cell number and activity. Later studies in ruminants confirmed those observations and that the response was regulated locally within the mammary gland. In addition, it was discovered that increased milking frequency (IMF) during early lactation stimulated an increase in milk production that partially persisted through late lactation, indicating long-term effects on mammary function. The local mechanisms regulating the mammary response to IMF are poorly understood, although several have been proposed. To gain insight into the mechanisms underlying the mammary response to IMF, and to identify genes associated with the response, we used a functional genomics approach and conducted experiments on dairy cows exposed to unilateral frequent milking [UFM; twice daily milking (2X) of the left udder half and 4-times daily milking (4X) of the right udder half]. Across multiple experiments, we were unable to detect an effect of UFM on mammary cell proliferation or apoptosis. We have, however, identified distinct transcriptional signatures associated with the mammary response to milk removal and to UFM during early lactation. Sequential sampling of mammary tissue revealed that when UFM was imposed during early lactation, at least 2 sets of genes were coordinately regulated with changes in differential milk production of 4X vs. 2X udder halves. Moreover, some genes were persistently differentially expressed in 4X vs. 2X udder halves after UFM and were associated with the persistent increase in milk yield. We conclude that a coordinated transcriptional response is associated with the increase in milk yield elicited by IMF during early lactation and that the 2 sets of differentially expressed genes may be a marker for the autocrine up regulation of milk production. Moreover, we propose that we have identified a novel form of imprinting associated with persistent alteration of mammary function, which we term "lactational imprinting." PMID- 22205670 TI - Kinetics and disposition of orally dosed sodium chlorate in sheep. AB - Experiments were conducted in sheep to determine excretory characteristics of sodium chlorate after a single oral dose. In Exp. 1, lambs (n = 16; age = 8.1 +/- 1.7 d; BW = 8.2 +/- 1.1 kg; mean +/- SD) were dosed orally with 0, 30, 60, or 90 mg/kg BW of sodium chlorate. Twenty-four hours after exposure chlorate residues were dose dependent (P < 0.05) in small intestinal contents, serum, and urine, but chlorate residues were not consistently detected in cecal or colonic contents. In Exp. 2, non-pregnant yearling ewes (BW = 74.8 +/- 5.6 kg; mean +/- SD) were orally dosed with 0, 150, 300, or 450 mg/kg BW of sodium chlorate. Across dose, chlorate residues averaged from 47 to 114, 0.6 to 4.5, and were not detectable to 0.2 MUg/mL at 24, 48, and 72 h, respectively, in serum of treated animals; in feces, residues averaged 29 to 82, 0.8 to 14, and were not detectable to 1.2 MUg/mL at the same respective time periods. In Exp. 3, six lactating ewes (BW = 76.3 +/- 8.0 kg) were dosed orally with 450 mg/kg BW of sodium chlorate; residues were measured in serum, milk, urine and feces in periods encompassing 0 to 8, 8 to 16, 16 to 24, 24 to 32, 32 to 40, and 40 to 48 h. Chlorate residues in milk were detectable at all time periods with concentrations averaging from 287 +/- 67 to 26 +/- 13 MUg/mL during the first and last collection periods, respectively. Urine contained the greatest concentration of chlorate at each time point and averaged 480 +/- 268 MUg/mL at 40 to 48 h. Depletion half-lives in serum, milk, urine, and feces were estimated to be 6.2, 27, 19, and 10 h, respectively; milk, urinary and fecal half-lives are likely overestimated due to the fact that 8-h sample pools were used in half-life estimations. In Exp. 4, three wethers (BW = 87.1 +/- 5.3 kg) each were orally dosed with 14 or 42 mg/kg BW of sodium chlorate; blood samples were serially collected for 48 h, and urine samples were collected at 0 to 8, 8 to 16, 16 to 24, 24 to 36, and 36 to 48 h. Estimates of absorption and elimination half-lives based on serum chlorate concentrations were about 0.4 and 2.5 h, respectively. Urine collected during the 6 h immediately following dosing contained the greatest concentrations of chlorate residues relative to subsequent collection periods. Rapid removal of chlorate from the gastrointestinal lumen suggests that effects of chlorate on colonic and fecal gastrointestinal bacteria may occur through mechanisms other than direct luminal contact between microbe and chlorate salts. PMID- 22205671 TI - Effect of polymorphism in egg white lysozyme on muramidase and antibacterial activities as well as hatchability in the Japanese quail (Coturnix japonica). AB - Lysozyme is one of the best characterized antimicrobial proteins in egg white. Three phenotypes of egg white lysozyme in Japanese quail, Coturnix japonica, (namely fast; slow; and the combination, FS) were observed by acid polyacrylamide gel electrophoresis. The fast phenotype showed faster mobility on Acid-PAGE than the slow phenotype. Comparison of the coding sequences for lysozyme derived from the slow and fast phenotypes revealed a nonsynonymous SNP at nucleotide position 115 from the translation initiation site, which alters AA sequence of lysozyme. This nonsynonymous SNP converted glutamine (Q) in the slow phenotype to lysine (K) in the fast phenotype at AA residue 21 of mature lysozyme (Q21K). Here, we investigated the effect of these phenotypes on muramidase activity, antibacterial activity, and hatchability. Muramidase activity toward isolated cell walls of Micrococcus lysodeikticus was in the order: fast allozyme > slow allozyme > chicken (Gallus gallus), but no significant difference was found among the 3 (P > 0.05). Antibacterial activity against live Staphylococcus aureus cells was significantly greater for the fast allozyme than the slow allozyme from 20 h after incubation (P < 0.05). For the antibacterial effects against live Escherichia coli cells, the activity of fast was significantly higher than that of slow at 16 h after incubation (P < 0.05). Hatchability was estimated for reciprocal crosses of Japanese quail with the FF (fast) and SS (slow) genotypes. Hatchability was 92.5% in FF male * SS female crosses and 87.2% in SS male * FF female crosses. A Cochran-Mantel-Haenszel test revealed a significant difference between the crosses (P < 0.05) and indicated that the female-derived slow phenotype led to improved rates of hatching. Our results suggest that the nonsynonymous SNP in Japanese quail lysozyme influences the electrophoretic migration, muramidase activity, and antibacterial activity of the protein, in addition to the hatchability of the eggs. These results demonstrate, for the first time, a significant difference in antibacterial activity and hatchability between 2 lysozyme phenotypes in Japanese quail. PMID- 22205672 TI - Optimizing the use of sex-sorted sperm in timed artificial insemination programs for suckled beef cows. AB - Three experiments were designed to evaluate methods to optimize the use of sex sorted sperm in timed AI (TAI) programs for suckled beef cows. In all 3 experiments, suckled Bos indicus cows were synchronized using an intravaginal progesterone (P4) device during 8 d and a 2.0-mg injection of intramuscular estradiol benzoate (EB) at device insertion. The females received PG and eCG (300 IU) at P4 device removal and 1.0 mg of EB 24 h later. The cows were inseminated 60 to 64 h after P4 device withdrawal. All cows had their ovaries scanned by transrectal ultrasound at TAI to indentify and to measure the largest follicle (LF) present. In Exp. 1, a total of 853 cows had their LF classified as <9 mm or >=9 mm at the time of TAI; these cows were then randomly assigned to 4 groups according to their LF diameter (<9 mm or >=9 mm) and the type of sperm used (sex sorted or non-sex-sorted). There was an interaction (P = 0.02) between the type of sperm and LF diameter beginning at TAI[non-sex-sorted >=9 mm = 58.9%a (126/214); non-sex-sorted <9 mm = 49.5%b (106/214);sex-sorted >=9 mm = 56.8%ab (134/236); and sex-sorted <9 mm = 31.2%c (59/189), a?b?c = P < 0.05]. In Exp. 2, suckled cows (n = 491) were classified immediately before TAI as having displayed estrus or not (estrus or no estrus) between P4 device removal and TAI. These cows were randomly assigned to 4 groups according to the occurrence of estrus and the type of sperm (sex-sorted or non-sex-sorted). There were effects of the occurrence of estrus (P = 0.0003) and the type of sperm (P = 0.05) on pregnancy per AI [P/AI; no estrus, non-sex-sorted = 43.6% (27/62); estrus, non-sex-sorted = 58.5%; (107/183); no estrus, sex-sorted = 33.9% (21/62), and estrus, sex-sorted = 50.0% (92/184)]; however, no interaction between the occurrence of estrus and type of sperm was observed (P = 0.87). In Exp. 3, a total of 200 suckled cows presenting LF >=9 mm at TAI were randomly assigned to receive sex-sorted sperm deposited into the uterine body (n = 100) or into the uterine horn ipsilateral to the recorded LF (n = 100). No effect of deeper AI on P/AI was found (P = 0.57). Therefore, the LF diameter at TAI and the occurrence of estrus can be used as selection criteria to identify cows with greater odds of pregnancy to receive sex sorted sperm in TAI programs. In addition, performing TAI with sex-sorted sperm deeper into the uterus did not alter the pregnancy results. PMID- 22205673 TI - 9-cis Retinoic acid inhibits cumulus cell apoptosis during the maturation of bovine cumulus-oocyte-complexes. AB - Cumulus cell (CC) apoptosis is inversely correlated with embryonic development in vitro. Therefore, inhibition of CC apoptosis is important for proper embryonic development and quality. Retinoic acids (all-transRA and 9-cisRA) are natural components of retinoids, and 9-cisRA is the physiologically active metabolite of retinoic acid in vitro. During in vitro maturation, 9-cisRA enhances oocyte competence through multiple mechanisms affecting the oocyte and preimplantation embryo; however, the effect of 9-cisRA on CC apoptosis has yet to be elucidated. The aim of the present study was to evaluate the effect of 9-cisRA on CC apoptosis and to identify the molecular mechanism underlying that effect. Bovine slaughterhouse cumulus-oocyte complexes (COC) were matured in vitro in the absence or presence of 5 nM 9-cisRA. Cumulus cells were collected from immature and matured COC for the detection of apoptosis and gene expression analysis. Results showed that 9-cisRA reduced the number of apoptotic CC by about 2.7 fold (P < 0.023), compared with control. However, apoptosis is rare in CC of immature COC (0.01% +/- 0.001). Transcripts involved in the caspase cascade were down regulated upon exposure to 9-cisRA, including tumor necrosis factor alpha (TNF alpha, 11.1 fold, P < 0.001), tumor necrosis factor alpha receptor 1 (TNFR1, 2.3 fold, P < 0.01), caspase 9 (CASP9, 2.0 fold, P < 0.031), caspase 8 (CASP8, 2.2 fold, P < 0.012), and caspase 3 (CASP3, 2.1 fold, P < 0.006), while antiapoptotic B-cell lymphoma 2 (BCL2) transcript was increased (3.1 fold, P < 0.004), compared with control. In addition, 9-cisRA inhibited mitogen activated protein kinase mRNA expression in CC, including extracellular signal-regulated kinase 1/2 (ERK1, 2.7 fold, P < 0.02; ERK2, 2.7 fold, P < 0.03), and c-Jun N-terminal kinase (JNK, 1.6 fold, P < 0.044), as well as the activator protein-1 (AP1) family members c jun (1.6 fold, P < 0.041) and c-fos (2.0 fold, P < 0.06). The transcript abundances of TNF-alpha, TNFR1, CASP9, CASP8, CASP3, ERK1, ERK1, JNK, and BCL2 were increased, while c-fos and c-jun mRNA expression was decreased in the matured CC. On the basis of the data, we suggest that 9-cisRA inhibits CC apoptosis during in vitro maturation of bovine COC. PMID- 22205674 TI - Free ferulic acid uptake in ram lambs. AB - The objective of this research was to investigate the fate of free ferulic acid (FA) in sheep. Ferulic acid is normally present in plants, bound to the indigestible cell wall. If the FA present in a ruminant diet is released from the cell wall with feed pretreatment methods, FA may be released into the rumen for digestion or absorption into the bloodstream or both. Eight male Dorset * Finn lambs were randomly assigned to 1 of 4 treatment (trt) concentrations, 0 (control), 3, 6, or 9 g/d free FA as part of a replicated 4 * 4 Latin square design. Lambs were housed individually and consumed chopped alfalfa hay (Medicago sativa; 22.8% CP, 39.3% NDF, 0.73 Mcal/kg NE(g)) ad libitum and 350 g corn grain (Zea mays L.; 9.1% CP, 11.2% NDF, 1.52 Mcal/kg NE(g)) once daily at 0800 h. Basal concentrations of FA in hay, grain, blood, feces, and urine were established following a 14-d adjustment to diet and housing. An oral dose of free FA was administered for 5 d via bolus after each morning feeding, after which hay, grain, blood, feces, and urine were sampled. Body weights were recorded at the beginning and end of each trt, and DMI was measured daily during trt periods. In addition to trt, each lamb ingested a daily average of 3.78 g FA in its bound form via the offered hay (2.67 mg/g FA; 1.0 kg/d DMI) and corn (3.17 mg/g FA; 0.35 kg/d DMI). The FA administered had a quadratic effect on average hay DMI (1.25, 1.41, 1.41, and 1.29 kg/d for 0, 3, 6, or 9 g/d FA trt; P < 0.01; SE = 58.9 g), but lamb BW did not change as a result of FA trt (P = 0.28). The NDF content and amount of FA in refusals were not affected by trt, (P = 0.30; P = 0.82, respectively). Fecal FA did not differ among trt or when compared with basal FA (P = 0.53), while urine FA increased as FA dose increased (P < 0.01), indicating that free FA was absorbed and transferred into urine. No free FA was found in the plasma analyzed, suggesting that disappearance from the blood of absorbed free FA occurred within the 5 h that passed between bolus dosage and blood collection. An in vitro analysis was conducted to assess the degree of inhibition of microbial NDF digestion caused by FA supplementation. In vitro, NDF disappearance was not inhibited as a result of FA treatment (P = 0.80). These data in combination with the results of the lamb study indicate that free FA as 0.24, 0.43, and 0.70% of DMI in lambs is absorbed and excreted in the urine as opposed to the feces with no apparent effects on rumen microbial NDF digestion. PMID- 22205676 TI - Long term follow-up of deep brain stimulation of the caudal zona incerta for essential tremor. AB - PURPOSE: The ventral intermediate nucleus of thalamus is the standard target for deep brain stimulation (DBS) in essential tremor (ET). However, favourable data have recently highlighted the caudal zona incerta (cZi) as an alternative target. Reports concerning the long-term results are however lacking, and we have therefore evaluated the long-term effects in our patients with ET and cZi DBS. METHODS: 18 patients were evaluated using the Essential Tremor Rating Scale (ETRS) before and on-/off-stimulation at 1 and 3-5 years after surgery (mean 48.5+/-10.6 months). Two patients were operated on bilaterally but all electrodes were evaluated separately. The stimulation parameters were recorded and the stimulation strength calculated. RESULTS: A baseline total ETRS mean score of 46.0 decreased to 21.9 (52.4%) at the final evaluation. On the treated side, tremor of the upper extremity (item 5 or 6) improved from 6.1 to 0.5 (91.8%) and hand function (items 11-14) improved from 9.3 to 2.0 (78.0%). Activities of daily living improved by 65.8%. There was no increase in stimulation strength over time. CONCLUSION: cZi DBS is a safe and effective treatment for the long term suppression of ET. PMID- 22205675 TI - The Kurtzke EDSS rank stability increases 4 years after the onset of multiple sclerosis: results from the MSBase Registry. AB - BACKGROUND: The Expanded Disability Status Scale (EDSS) is widely used to rate multiple sclerosis (MS) disability, but lack of disease duration information limits utility in assessing severity. EDSS ranking at specific disease durations was used to devise the MS Severity Score, which is gaining popularity for predicting outcomes. As this requires validation in longitudinal cohorts, we aimed to assess the utility of EDSS ranking as a predictor of 5-year outcome in the MSBase Registry. METHODS: Rank stability of EDSS over time was examined in the MSBase Registry, a large multicentre MS cohort. Scores were ranked for 5-year intervals, and correlation of rank across intervals was assessed using Spearman's rank correlation. EDSS progression outcomes at 10 years were disaggregated by 5 year EDSS scores. RESULTS: Correlation coefficients for EDSS rank over 5-year intervals increased with MS duration: years 1-6=0.55, years 4-9=0.74, years 7 12=0.80 and years 10-15=0.83. EDSS progression risk at 10 years after onset was highly dependent on EDSS at 5 years; one-point progression risk was greater for EDSS score of >2 than <=2. Two-point progression was uncommon for EDSS score of <2 and more common at EDSS score of 4. CONCLUSIONS: EDSS rank stability increases with disease duration, probably due to reduced relapses and less random variation in later disease. After 4 years duration, EDSS rank was highly predictive of EDSS rank 5 years later. Risk of progression by 10 years was highly dependent on EDSS score at 5 years duration. We confirm the utility of EDSS ranking to predict 5 year outcome in individuals 4 years after disease onset. PMID- 22205677 TI - Breast and ovarian cancers: a survey and possible roles for the cell surface heparan sulfate proteoglycans. AB - Tumor markers are widely used in pathology not only for diagnostic purposes but also to assess the prognosis and to predict the treatment of the tumor. Because tumor marker levels may change over time, it is important to get a better understanding of the molecular changes during tumor progression. Occurrence of breast and ovarian cancer is high in older women. Common known risk factors of developing these cancers in addition to age are not having children or having children at a later age, the use of hormone replacement therapy, and mutations in certain genes. In addition, women with a history of breast cancer may also develop ovarian cancer. Here, the authors review the different tumor markers of breast and ovarian carcinoma and discuss the expression, mutations, and possible roles of cell surface heparan sulfate proteoglycans during tumorigenesis of these carcinomas. The focus is on two groups of proteoglycans, the transmembrane syndecans and the lipid-anchored glypicans. Both families of proteoglycans have been implicated in cellular responses to growth factors and morphogens, including many now associated with tumor progression. PMID- 22205678 TI - Immunolocalization of myostatin (GDF-8) following musculoskeletal injury and the effects of exogenous myostatin on muscle and bone healing. AB - The time course and cellular localization of myostatin expression following musculoskeletal injury are not well understood; therefore, the authors evaluated the temporal and spatial localization of myostatin during muscle and bone repair following deep penetrant injury in a mouse model. They then used hydrogel delivery of exogenous myostatin in the same injury model to determine the effects of myostatin exposure on muscle and bone healing. Results showed that a "pool" of intense myostatin staining was observed among injured skeletal muscle fibers 12 24 hr postsurgery and that myostatin was also expressed in the soft callus chondrocytes 4 days following osteotomy. Hydrogel delivery of 10 or 100 ug/ml recombinant myostatin decreased fracture callus cartilage area relative to total callus area in a dose-dependent manner by 41% and 80% (p<0.05), respectively, compared to vehicle treatment. Myostatin treatment also decreased fracture callus total bone volume by 30.6% and 38.8% (p<0.05), with the higher dose of recombinant myostatin yielding the greatest decrease in callus bone volume. Finally, exogenous myostatin treatment caused a significant dose-dependent increase in fibrous tissue formation in skeletal muscle. Together, these findings suggest that early pharmacological inhibition of myostatin is likely to improve the regenerative potential of both muscle and bone following deep penetrant musculoskeletal injury. PMID- 22205679 TI - beta4 integrin marks interstitial myogenic progenitor cells in adult murine skeletal muscle. AB - Skeletal muscle growth and its regeneration following injury rely on myogenic progenitor cells, a heterogeneous population that includes the satellite cells and other interstitial progenitors. The present study demonstrates that surface expression of beta4 integrin marks a population of vessel-associated interstitial muscle progenitor cells. Muscle beta4 integrin-positive cells do not express myogenic markers upon isolation. However, they are capable of undergoing myogenic specification in vitro and in vivo: beta4 integrin cells differentiate into multinucleated myotubes in culture dishes and contribute to muscle regeneration upon delivery into diseased mice. Subfractionation of beta4 integrin-expressing cells based on CD31 expression does not further enrich for myogenic precursors. These findings support the expression of beta4 integrin in interstitial, vessel associated cells with myogenic activity within adult skeletal muscle. PMID- 22205680 TI - The porcine chloride channel calcium-activated family member pCLCA4a mirrors lung expression of the human hCLCA4. AB - Pig models of cystic fibrosis (CF) have recently been established that are expected to mimic the human disease closer than mouse models do. The human CLCA (originally named chloride channels, calcium-activated) member hCLCA4 is considered a potential modifier of disease severity in CF, but its murine ortholog, mCLCA6, is not expressed in the mouse lung. Here, we have characterized the genomic structure, protein processing, and tissue expression patterns of the porcine ortholog to hCLCA4, pCLCA4a. The genomic structure and cellular protein processing of pCLCA4a were found to closely mirror those of hCLCA4 and mCLCA6. Similar to human lung, pCLCA4a mRNA was strongly expressed in porcine lungs, and the pCLCA4a protein was immunohistochemically detected on the apical membranes of tracheal and bronchial epithelial cells. This stands in sharp contrast to mouse mCLCA6, which has been detected exclusively in intestinal epithelia but not the murine lung. The results may add to the understanding of species-specific differences in the CF phenotype and support the notion that the CF pig model may be more suitable than murine models to study the role of hCLCA4. PMID- 22205681 TI - Roles of collagen and periostin expression by cranial neural crest cells during soft palate development. AB - The tissue in the palatal region can be divided into the hard and the soft palates, each having a specialized function such as occlusion, speech, or swallowing. Therefore, an understanding of the mechanism of palatogenesis in relation to the function of each region is important. However, in comparison with the hard palate, there is still a lack of information about the mechanisms of soft palate development. In this study, the authors investigated the contribution of cranial neural crest (CNC) cells to development of both hard and soft palates. They also demonstrated a unique pattern of periostin expression during soft palate development, which was closely related to that of collagen type I (Col I) in palatine aponeurosis. Furthermore, organ culture analysis showed that exogenous transforming growth factor-beta (TGF-beta) induced the expression of both periostin and Col I. These novel patterns of expression in the extracellular matrix (ECM) induced by CNC cells suggest that these cells may help to determine the character of both the hard and soft palates through ECM induction. TGF-beta signaling appears to be one of the mediators of Col I and periostin expression in the formation of functional structures during soft palate development. PMID- 22205683 TI - Combined endocardial and epicardial catheter ablation in arrhythmogenic right ventricular dysplasia incorporating scar dechanneling technique. AB - BACKGROUND: Ventricular tachycardia (VT) ablation in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) has a low success rate. A more extensive epicardial (Epi) arrhythmogenic substrate could explain the low efficacy. We report the results of combined endocardial (Endo) and Epi VT ablation and conducting channel (CC) elimination. METHODS AND RESULTS: Eleven consecutive patients with ARVD/C were included in the study. A high-density 3D Endo (321+/-93 sites mapped) and Epi (302+/-158 sites mapped) electroanatomical voltage map was obtained during sinus rhythm to define scar areas (<1.5 mV) and CCs inside the scars, between scars, or between the tricuspid annulus and a scar. The end point of the ablation procedure was the elimination of all identified CCs (scar dechanneling) and the abolition of all inducible VTs. The mean procedure and fluoroscopy time were 177+/-63 minutes and 20+/-8 minutes, respectively. Epi scar area was larger in all cases (26+/-18 versus 94+/-45 cm(2), P<0.01). The combined Endo and Epi VT ablation eliminated all clinical and induced VTs, and the addition of scar dechanneling resulted in noninducibility in all cases. Seven patients continued on sotalol. During a median follow-up of 11 months (6-24 months), only 1 (9%) patient had a VT recurrence. There was a single major bleeding event that did not preclude a successful procedure. CONCLUSIONS: Combined Endo and Epi mapping reveals a wider Epi VT substrate in patients with ARVD/C with clinical VTs. As a first-line therapy, combined Endo and Epi VT ablation incorporating scar dechanneling achieves a very good short- and midterm success rate. PMID- 22205682 TI - Widespread expression of gamma-glutamyl cyclotransferase suggests it is not a general tumor marker. AB - gamma-Glutamyl cyclotransferase (GGCT) contributes to the gamma-glutamyl cycle that regulates glutathione metabolism. Although GGCT has been implicated in several studies as a possible cancer marker, little is known about its distribution in cells and tissues. The authors investigated GGCT expression in normal tissues and tumors using Western blots and immunohistochemistry with a novel anti-GGCT monoclonal antibody. GGCT was detected in most organs and was mainly found in epithelial cells. Although the intracellular distribution was mainly cytoplasmic, in some situations, nuclear staining was strong. A significant increase in the expression of GGCT was found in tumors of the lung, esophagus, stomach, bile duct, and uterine cervix. In contrast, there was a significant decrease in expression in renal and urothelial tumors. These results suggest that GGCT may be a biomarker of tumors in a limited range of organs. PMID- 22205684 TI - Ventricular arrhythmias among implantable cardioverter-defibrillator recipients for primary prevention: impact of chronic total coronary occlusion (VACTO Primary Study). AB - BACKGROUND: An implantable cardioverter-defibrillator (ICD) is the therapy of choice for primary prevention in patients with ischemia who are at risk for sudden cardiac death (SCD). One third of patients with significant coronary disease have chronic total coronary occlusion (CTO), which is associated with long-term mortality in patients with previous myocardial infarction. However, the impact of CTO on the occurrence of ventricular arrhythmias and long-term mortality in ICD recipients remains unknown. METHODS AND RESULTS: All consecutive patients with coronary artery disease receiving ICD therapy for the prevention of SCD were included in the study. Among other characteristics, the existence of CTO was assessed. During follow-up, the occurrence of appropriate device delivery because of ventricular arrhythmias as well as mortality were noted. A total of 162 patients (mean age, 62+/-9 years; 93% men) with an ICD were included and followed for a median of 26 months (interquartile range, 12-42). At least 1 CTO was present in 71 (44%) patients. Appropriate device therapy was detected in 18% of the patients during the follow-up. The presence of CTO was associated with higher ventricular arrhythmia and mortality rates (log-rank test, <0.01). Multivariable analysis revealed that CTO was independently associated with appropriate ICD intervention (hazard ratio, 3.5; P=0.003). CONCLUSIONS: In patients with ischemic heart disease receiving ICDs for primary prevention of SCD, CTO is an independent predictor for the occurrence of ventricular arrhythmias and has an adverse impact on long-term mortality. PMID- 22205685 TI - Motion transparency: depth ordering and smooth pursuit eye movements. AB - When two overlapping, transparent surfaces move in different directions, there is ambiguity with respect to the depth ordering of the surfaces. Little is known about the surface features that are used to resolve this ambiguity. Here, we investigated the influence of different surface features on the perceived depth order and the direction of smooth pursuit eye movements. Surfaces containing more dots, moving opposite to an adapted direction, moving at a slower speed, or moving in the same direction as the eyes were more likely to be seen in the back. Smooth pursuit eye movements showed an initial preference for surfaces containing more dots, moving in a non-adapted direction, moving at a faster speed, and being composed of larger dots. After 300 to 500 ms, smooth pursuit eye movements adjusted to perception and followed the surface whose direction had to be indicated. The differences between perceived depth order and initial pursuit preferences and the slow adjustment of pursuit indicate that perceived depth order is not determined solely by the eye movements. The common effect of dot number and motion adaptation suggests that global motion strength can induce a bias to perceive the stronger motion in the back. PMID- 22205687 TI - Molecular pathways: hypoxia response in immune cells fighting or promoting cancer. AB - Both malignant and stromal components in tumors are influenced by the physiologic conditions of the microenvironment. Hypoxia is a prominent feature of solid tumors as a result of defective vascularization and intense metabolic activity. The gene-expression control mechanisms that adapt tissues to hypoxia are exploited by tumors to promote angiogenesis and vasculogenesis. The functions of infiltrating immune cells (macrophages and lymphocytes) and other stromal components are also influenced by a limited O(2) supply. Hypoxia-inducible factors (HIF) are the main molecular transcriptional mediators in the hypoxia response. The degradation and activity of HIF-1alpha and HIF-2alpha are tightly controlled by the fine-tuned action of oxygen-sensing prolyl and asparaginyl hydroxylase enzymes. Recent evidence indicates that hypoxia can modulate the differentiation and function of T lymphocytes and myeloid cells, skewing their cytokine-production profiles and modifying the expression of costimulatory receptors. This conceivably includes tumor-infiltrating lymphocytes. Hypoxia not only directly affects tumor-infiltrating leukocytes but also exerts effects on tumor cells and vascular cells that indirectly cause selective chemokine-mediated recruitment of suppressive and proangiogenic T-cell subsets. This review focuses on changes induced by hypoxia in immune cells infiltrating solid malignancies. Such changes may either promote or fight cancer, and thus are important for immunotherapy. PMID- 22205686 TI - Blocking epidermal growth factor receptor activation by 3,3'-diindolylmethane suppresses ovarian tumor growth in vitro and in vivo. AB - Genetic alterations, including the overexpression of epidermal growth factor receptor (EGFR) (in approximately 70% of ovarian tumors), play a crucial role in the signal transduction pathways that regulate key cellular functions, such as cell survival and proliferation, and are responsible for compromising traditional chemotherapy. 3,3'-Diindolylmethane (DIM) is an indole compound present in Brassica vegetables. In our previous studies, we demonstrated that BR-DIM, a formulated version of DIM, suppressed the growth of ovarian cancer cells by causing cell cycle arrest and apoptosis. In the present study, we delineated the mechanism by which DIM suppressed the growth of SKOV-3, OVCAR-3, and TOV-21G human ovarian cancer cells. DIM treatment caused significant down-regulation of the constitutive EGFR protein level as well as phosphorylation of EGFR at Tyr1068, Tyr992, Tyr845, and Tyr1173 in various ovarian cancer cells. To determine whether DIM suppressed the activation of EGFR by activating phosphorylation, cells were treated with epidermal growth factor. Epidermal growth factor treatment significantly blocked the DIM-mediated inhibition of EGFR activation and apoptosis in both SKOV-3 and OVCAR-3 cells. In addition, DIM treatment drastically reduced the phosphorylation of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK), which are downstream to EGFR, without affecting their protein levels. DIM treatment also inhibited the kinase activity of ERK, as observed by the down-regulation of phospho-E twenty-six like transcription factor 1 (p-ELK1) in all three ovarian cancer cell lines. DIM significantly suppressed the growth of ovarian tumors in vivo. Tumor growth suppressive effects of DIM in SKOV-3 tumor xenografts were associated with reduced phosphorylation of EGFR, MEK, and ERK. These results indicate that DIM induces apoptosis in ovarian cancer cells by inhibiting the EGFR-ERK pathway in vitro and in vivo. PMID- 22205688 TI - Increasing potential of HER3 signaling in colon cancer progression and therapy. AB - HER3 protein levels at the cancer cell plasma membrane are directly correlated with reduced survival in patients with colorectal cancer. In colorectal cancer cells, HER3 blockade restricted cellular growth (G(2)-M arrest), survival, migration, and invasion, and potentiated the chemotherapeutic effect of 5-FU, supporting strategies that target HER3 in subsets of patients with colorectal cancer. PMID- 22205689 TI - Molecular pathways: involvement of Helicobacter pylori-triggered inflammation in the formation of an epigenetic field defect, and its usefulness as cancer risk and exposure markers. AB - Infection-associated cancers account for a large proportion of human cancers, and gastric cancer, the vast majority of which is associated with Helicobacter pylori infection, is a typical example of such cancers. Epigenetic alterations are known to occur frequently in gastric cancers, and H. pylori infection has now been shown to induce aberrant DNA methylation in gastric mucosae. Accumulation of aberrant methylation in gastric mucosae produces a field for cancerization, and methylation levels correlate with gastric cancer risk. H. pylori infection induces methylation of specific genes, and such specificity is determined by the epigenetic status in normal cells, including the presence of H3K27me3 and RNA polymerase II (active or stalled). Specific types of inflammation, such as that induced by H. pylori infection, are important for methylation induction, and infiltration of monocytes appears to be involved. The presence of an epigenetic field defect is not limited to gastric cancers and is observed in various types of cancers. It provides translational opportunities for cancer risk diagnosis incorporating life history, assessment of past exposure to carcinogenic factors, and cancer prevention. PMID- 22205690 TI - Circulating epithelial cells in patients with benign colon diseases. AB - BACKGROUND: Detection of circulating tumor cells (CTCs) in the peripheral blood is a rapidly developing research field with clear clinical implications for the staging and monitoring of cancer patients. Current CTC assays, including the US Food and Drug Administration-cleared CellSearch(r) system, typically use markers [e.g., cytokeratins (CKs), the transmembrane protein EpCAM (epithelial cell adhesion molecule)] that are expressed on normal and malignant epithelial cells but not on the surrounding normal leukocytes. METHODS: We enrolled 53 patients with benign colon diseases (e.g., diverticulosis, benign polyps, Crohn disease, ulcerative rectocolitis, colonic endometriosis) and analyzed their peripheral blood with 2 previously validated CTC assays: the epithelial immunospot (EPISPOT) assay and the CellSearch system. The EPISPOT assay detects only viable, CK19 releasing CTCs that were enriched by depletion of CD45(+) leukocytes, whereas the CellSearch system detects CK-positive CTCs after positive EpCAM-based immunomagnetic enrichment. RESULTS: In patients with benign colon diseases, positive events that met the criteria for "tumor cells" were detected with both the CellSearch system (11.3%) and the CK19-EPISPOT assay (18.9%), whereas no positive events were detected in samples from healthy volunteers. Positive events were detected most frequently in patients with diverticulosis and Crohn disease. All positive events lacked expression of CD45, a common leukocyte antigen. CONCLUSIONS: These results indicate that patients with benign inflammatory colon diseases in particular can harbor viable circulating epithelial cells that are detectable with current CTC assays. This finding points to the need for further molecular characterization of circulating epithelial cells and has important implications for the use of CTC testing. PMID- 22205691 TI - Multiplex immunoassays of peptide hormones extracted from formalin-fixed, paraffin-embedded tissue accurately subclassify pituitary adenomas. AB - BACKGROUND: The current gold standard for diagnostic classification of many solid tissue neoplasms is immunohistochemistry (IHC) performed on formalin-fixed, paraffin-embedded (FFPE) tissue. Although IHC is commonly used, there remain important issues related to preanalytic variability, nonstandard methods, and operator bias that may contribute to clinically significant error. To increase the quantitative accuracy and reliability of FFPE tissue-based diagnosis, we sought to develop a clinical proteomic method to characterize protein expression in pathologic tissue samples rapidly and quantitatively. METHODS: We subclassified FFPE tissue from 136 clinical pituitary adenoma samples according to hormone translation with IHC and then extracted tissue proteins and quantified pituitary hormones with multiplex bead-based immunoassays. Hormone concentrations were normalized and compared across diagnostic groups. We developed a quantitative classification scheme for pituitary adenomas on archived samples and validated it on prospectively collected clinical samples. RESULTS: The most abundant relative hormone concentrations differentiated sensitively and specifically between IHC-classified hormone-expressing adenoma types, correctly predicting IHC-positive diagnoses in 85% of cases overall, with discrepancies found only in cases of clinically nonfunctioning adenomas. Several adenomas with clinically relevant hormone-expressing phenotypes were identified with this assay yet called "null" by IHC, suggesting that multiplex immunoassays may be more sensitive than IHC for detecting clinically meaningful protein expression. CONCLUSIONS: Multiplex immunoassays performed on FFPE tissue extracts can provide diagnostically relevant information and may exceed the performance of IHC in classifying some pituitary neoplasms. This technique is simple, largely amenable to automation, and likely applicable to other diagnostic problems in molecular pathology. PMID- 22205692 TI - Exploring the initial steps of the testing process: frequency and nature of pre preanalytic errors. AB - BACKGROUND: Few data are available on the nature of errors in the so-called pre preanalytic phase, the initial steps of the testing process. We therefore sought to evaluate pre-preanalytic errors using a study design that enabled us to observe the initial procedures performed in the ward, from the physician's test request to the delivery of specimens in the clinical laboratory. METHODS: After a 1-week direct observational phase designed to identify the operating procedures followed in 3 clinical wards, we recorded all nonconformities and errors occurring over a 6-month period. Overall, the study considered 8547 test requests, for which 15 917 blood sample tubes were collected and 52 982 tests undertaken. RESULTS: No significant differences in error rates were found between the observational phase and the overall study period, but underfilling of coagulation tubes was found to occur more frequently in the direct observational phase (P = 0.043). In the overall study period, the frequency of errors was found to be particularly high regarding order transmission [29 916 parts per million (ppm)] and hemolysed samples (2537 ppm). The frequency of patient misidentification was 352 ppm, and the most frequent nonconformities were test requests recorded in the diary without the patient's name and failure to check the patient's identity at the time of blood draw. CONCLUSION: The data collected in our study confirm the relative frequency of pre-preanalytic errors and underline the need to consensually prepare and adopt effective standard operating procedures in the initial steps of laboratory testing and to monitor compliance with these procedures over time. PMID- 22205693 TI - Estimating glomerular filtration rates by use of both cystatin C and standardized serum creatinine avoids ethnicity coefficients in Asian patients with chronic kidney disease. AB - BACKGROUND: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is most accurate for estimating glomerular filtration rate (GFR) but requires an adjustment for African-American patients. Estimation equations are also improved with the use of serum cystatin C combined with standardized creatinine. Combination equations have been derived by the CKD-EPI and Chinese investigators. We investigated whether these cystatin C-based equations improve estimation adequately, so that adjustments for ethnicity are not required in a multiethnic Asian population with chronic kidney disease (CKD). METHODS: This was a cross-sectional study of 232 stable CKD patients who underwent GFR measurements using 3-sample plasma clearances of (99m)Tc-DTPA, and for whom serum cystatin C and creatinine were quantified. RESULTS: For all patients, the median biases with cystatin C equations were generally greater than with the CKD-EPI equation, and precision and root mean square error (RMSE) were not significantly better. However, the combination serum creatinine and cystatin C equation improved the precision, RMSE, and percentage of estimated GFR to within 15% and 30% of the measured GFR (57.3% vs 50.0%, 88.4% vs 82.8%, respectively). The derived ethnicity coefficients for the combination equation were all >1 (1.009-1.082) but small, suggesting that coefficients are not required. The Chinese-specific equations were more biased and performed more poorly than the CKD-EPI equation. CONCLUSIONS: The use of a cystatin C and creatinine combination equation for estimating GFR in a multiethnic Asian population with CKD does not require ethnicity coefficients because the derived coefficients are very close to each other. PMID- 22205694 TI - Fetal laboratory medicine: on the frontier of maternal-fetal medicine. AB - BACKGROUND: Emerging antenatal interventions and care delivery to the fetus require diagnostic support, including laboratory technologies, appropriate methodologies, establishment of special algorithms, and interpretative guidelines for clinical decision-making. CONTENT: Fetal diagnostic and therapeutic interventions vary in invasiveness and are associated with a spectrum of risks and benefits. Fetal laboratory assessments are well served by miniaturized diagnostic methods for blood analysis. Expedited turnaround times are mandatory to support invasive interventions such as cordocentesis and intrauterine transfusions. Health-associated reference intervals are required for fetal test interpretation. Fetal blood sampling by cordocentesis carries substantial risk and is therefore performed only when fetal health is impaired, or at risk. When the suspected pathology is not confirmed, however, normative fetal data can be collected. Strategies for assurance of sample integrity from cordocenteses and confirmation of fetal origin are described. After birth, definitive assessment of prenatal environmental and/or drug exposures to the fetus can be retrospectively assessed by analysis of meconium, hair, and other alternative matrices. A rapidly advancing technology for fetal assessment is the use of fetal laboratory diagnostic techniques that use cell-free fetal DNA collected from maternal plasma, and genetic analysis based on molecular counting techniques. SUMMARY: Developmental changes in fetal biochemical and hematologic parameters in health and disease are continually delineated by analysis of our collective outcome based experience. Noninvasive technologies for fetal evaluation are realizing the promise of lower risk yet robust diagnostics; examples include sampling and analysis of free fetal DNA from maternal blood, and analysis of fetal products accessible at maternal sites. Application of diagnostic technologies for nonmedical purposes (e.g., sex selection) underscores the importance of ethical guidelines for new technology implementation. PMID- 22205696 TI - Heightened pro-inflammatory effect of preeclamptic placental microvesicles on peripheral blood immune cells in humans. AB - Normal pregnancy is associated with the presence of circulating placental microvesicles (MVs). Increased MV shedding and altered immune activation are seen in patients with preeclampsia, suggesting that placental MVs may play a role in the pathophysiology of this disease. Therefore, the aim of this study was to investigate the activation of peripheral blood mononuclear cells (PBMCs) by MVs shed by first-trimester, normal term, and preeclamptic term placenta. First trimester and preeclamptic term, but not normal term, placental-derived MVs activated PBMCs, as evidenced by elevated IL1B. Significant changes were also seen with several other cytokines and chemokines, and in general when compared to normal term MVs, preeclamptic MVs induced a greater pro-inflammatory response in PBMCs. Pretreatment of PBMCs with first-trimester or normal term placental MVs resulted in a dampened IL1B response to a subsequent lipopolysaccharide (LPS) challenge. In contrast, treatment of PBMCs with preeclamptic term placental MVs exacerbated the LPS response. This was also the case for several other cytokines and chemokines. These studies suggest that placental MVs can modulate basal peripheral immune cell activation and responsiveness to LPS during normal pregnancy, and that in preeclampsia this effect is exacerbated. PMID- 22205695 TI - Growth differentiation factor-15 in the early diagnosis and risk stratification of patients with acute chest pain. AB - BACKGROUND: Growth differentiation factor-15 (GDF-15) is a stress-responsive marker that might aid in the early diagnosis and risk stratification of patients with suspected acute myocardial infarction (AMI). METHODS: In a prospective, international multicenter study, GDF-15, high-sensitivity cardiac troponin T (hs cTnT), and B-type natriuretic peptide (BNP) were measured in 646 unselected patients presenting to the emergency department with acute chest pain. The final diagnosis was adjudicated by 2 independent cardiologists. The primary prognostic end point was all-cause mortality during a median follow-up of 26 months. RESULTS: AMI was the adjudicated final diagnosis in 115 patients (18%). GDF-15 concentrations at presentation were significantly higher in AMI patients compared to patients with other diagnoses. The diagnostic accuracy of GDF-15 at presentation for the diagnosis of AMI as quantified by the area under the ROC curve (AUC) was lower (AUC 0.69, 95% CI 0.64-0.74) compared to hs-cTnT (AUC 0.96, 95% CI 0.94-0.98, P < 0.001) and BNP (AUC 0.74, 95% CI 0.69-0.80, P = 0.02). A total of 55 deaths occurred during follow-up. GDF-15 predicted all-cause mortality independently of and more accurately than hs-cTnT [AUC 0.85 (95% CI 0.81-0.90) vs 0.77 (95% CI 0.72-0.83), P = 0.002] and BNP (AUC 0.75, 95% CI 0.68 0.82, P = 0.007). Net reclassification improvement was 0.15 (P = 0.01), and the absolute integrated discrimination improvement was 0.07, yielding a relative integrated discrimination improvement of 0.36 (P = 0.07). CONCLUSIONS: GDF-15 predicts all-cause mortality in unselected patients with acute chest pain independently of and more accurately than hs-cTnT and BNP. However, GDF-15 does not seem to help in the early diagnosis of AMI. PMID- 22205697 TI - Inhibition of follicular development induced by chronic unpredictable stress is associated with growth and differentiation factor 9 and gonadotropin in mice. AB - Chronic psychosocial stress negatively affects ovarian function. Ovarian follicular development is regulated by both pituitary-derived gonadotropins and intraovarian regulatory factors. To date, the suppressive effects of chronic stress on the ovary have been observed to be manifested mainly as an inhibition of gonadotropin release. It is not clear whether there are any other intraovarian regulatory mechanisms involved in this process. Growth and differentiation factor 9 (GDF9) is an important, oocyte-specific paracrine regulator required for follicular development. In this study, the chronic unpredictable mild stress model was used to produce psychosocial stress in mice. The number of different developmental stages of follicles was counted on ovarian sections stained with hematoxylin and eosin. Real-time PCR and Western blotting were used to detect the mRNA and protein levels, respectively, of GDF9. The results show that chronic unpredictable stress inhibits follicular development, increases follicular atresia, and suppresses GDF9 expression. Exogenous gonadotropin treatment partly restores the repressed antral follicular development, but has no effect on the repressed secondary follicular development associated with chronic stress. Treatment with recombinant GDF9 restores secondary follicular development. Cotreatments with GDF9 and gonadotropins restore both secondary and antral follicular development in stressed mice. These findings demonstrate that inhibition of follicular development induced by chronic unpredictable stress is associated with GDF9 and gonadotropin. PMID- 22205698 TI - Endometrial HSD11B1 and cortisol regeneration in the ovine uterus: effects of pregnancy, interferon tau, and prostaglandins. AB - In ruminants, the elongating conceptus secretes interferon tau (IFNT), the pregnancy recognition signal, and prostaglandins (PGs). Progesterone from the ovary induces prostaglandin synthase two (PTGS2) and hydroxysteroid (11-beta) dehydrogenase 1 (HSD11B1) in the endometrial epithelia, and PTGS2-derived PGs regulate endometrial functions and conceptus elongation. The enzyme HSD11B1 interconverts inactive cortisone and active cortisol. These studies determined the effects of pregnancy, IFNT, and PGs on endometrial HSD11B1 expression and activity in the ovine uterus. Study one found that HSD11B1 activity was present in both the endometrium and conceptus during early pregnancy. In study two, ewes received intrauterine infusions of vehicle as a control (CX) or meloxicam (MEL), a PTGS2 inhibitor, from Days 8 to 14 of pregnancy. Endometrial HSD11B1 activity and cortisol in the uterine lumen were substantially lower in MEL-infused ewes. In study three, cyclic ewes received intrauterine infusions of vehicle as a CX, MEL, recombinant ovine IFNT, or IFNT and MEL. Infusion of IFNT increased endometrial HSD11B1 expression and activity and cortisol in the uterine lumen, and this effect was diminished by coinfusion of MEL. In study four, cyclic ewes were infused with vehicle as a CX, IFNT, PGE2, PGF2 alpha, or PGI2. Infusion of all the PGs and IFNT increased endometrial HSD11B1 expression and activity, and IFNT and PGI2 infusion increased cortisol in the uterine lumen. These studies support the idea that IFNT and PGs from the conceptus regulate endometrial HSD11B1 expression and activity that regenerates bioactive cortisol in the ovine uterus during early pregnancy to influence endometrial functions and conceptus elongation. PMID- 22205699 TI - Acclimation of Chlamydomonas reinhardtii to different growth irradiances. AB - We report on the changes the photosynthetic apparatus of Chlamydomonas reinhardtii undergoes upon acclimation to different light intensity. When grown in high light, cells had a faster growth rate and higher biomass production compared with low and control light conditions. However, cells acclimated to low light intensity are indeed able to produce more biomass per photon available as compared with high light-acclimated cells, which dissipate as heat a large part of light absorbed, thus reducing their photosynthetic efficiency. This dissipative state is strictly dependent on the accumulation of LhcSR3, a protein related to light-harvesting complexes, responsible for nonphotochemical quenching in microalgae. Other changes induced in the composition of the photosynthetic apparatus upon high light acclimation consist of an increase of carotenoid content on a chlorophyll basis, particularly zeaxanthin, and a major down regulation of light absorption capacity by decreasing the chlorophyll content per cell. Surprisingly, the antenna size of both photosystem I and II is not modulated by acclimation; rather, the regulation affects the PSI/PSII ratio. Major effects of the acclimation to low light consist of increased activity of state 1 and 2 transitions and increased contributions of cyclic electron flow. PMID- 22205700 TI - Divergence of Pumilio/fem-3 mRNA binding factor (PUF) protein specificity through variations in an RNA-binding pocket. AB - mRNA control networks depend on recognition of specific RNA sequences. Pumilio fem-3 mRNA binding factor (PUF) RNA-binding proteins achieve that specificity through variations on a conserved scaffold. Saccharomyces cerevisiae Puf3p achieves specificity through an additional binding pocket for a cytosine base upstream of the core RNA recognition site. Here we demonstrate that this chemically simple adaptation is prevalent and contributes to the diversity of RNA specificities among PUF proteins. Bioinformatics analysis shows that mRNAs associated with Caenorhabditis elegans fem-3 mRNA binding factor (FBF)-2 in vivo contain an upstream cytosine required for biological regulation. Crystal structures of FBF-2 and C. elegans PUF-6 reveal binding pockets structurally similar to that of Puf3p, whereas sequence alignments predict a pocket in PUF-11. For Puf3p, FBF-2, PUF-6, and PUF-11, the upstream pockets and a cytosine are required for maximal binding to RNA, but the quantitative impact on binding affinity varies. Furthermore, the position of the upstream cytosine relative to the core PUF recognition site can differ, which in the case of FBF-2 originally masked the identification of this consensus sequence feature. Importantly, other PUF proteins lack the pocket and so do not discriminate upstream bases. A structure-based alignment reveals that these proteins lack key residues that would contact the cytosine, and in some instances, they also present amino acid side chains that interfere with binding. Loss of the pocket requires only substitution of one serine, as appears to have occurred during the evolution of certain fungal species. PMID- 22205701 TI - Stimulation of unprimed macrophages with immune complexes triggers a low output of nitric oxide by calcium-dependent neuronal nitric-oxide synthase. AB - Immune complexes composed of IgG-opsonized pathogens, particles, or proteins are phagocytosed by macrophages through Fcgamma receptors (FcgammaRs). Macrophages primed with IFNgamma or other pro-inflammatory mediators respond to FcgammaR engagement by secreting high levels of cytokines and nitric oxide (NO). We found that unprimed macrophages produced lower levels of NO, which required efficient calcium (Ca(2+)) flux as demonstrated by using macrophages lacking selenoprotein K, which is required for FcgammaR-induced Ca(2+) flux. Thus, we further investigated the signaling pathways involved in low output NO and its functional significance. Evaluation of inducible, endothelial, and neuronal nitric-oxide synthases (iNOS, eNOS, and nNOS) revealed that FcgammaR stimulation in unprimed macrophages caused a marked Ca(2+)-dependent increase in both total and phosphorylated nNOS and slightly elevated levels of phosphorylated eNOS. Also activated were three MAP kinases, ERK, JNK, and p38, of which ERK activation was highly dependent on Ca(2+) flux. Inhibition of ERK reduced both nNOS activation and NO secretion. Finally, Transwell experiments showed that FcgammaR-induced NO functioned to increase the phagocytic capacity of other macrophages and required both NOS and ERK activity. The production of NO by macrophages is conventionally attributed to iNOS, but we have revealed an iNOS-independent receptor/enzyme system in unprimed macrophages that produces low output NO. Under these conditions, FcgammaR engagement relies on Ca(2+)-dependent ERK phosphorylation, which in turn increases nNOS and, to a lesser extent, eNOS, both of which produce low levels of NO that function to promote phagocytosis. PMID- 22205702 TI - Roles of STAT3 and ZEB1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial-mesenchymal transition. AB - The progression of colorectal carcinoma (CRC) to invasive and metastatic disease may involve localized occurrences of epithelial-mesenchymal transition (EMT). However, mechanisms of the EMT process in CRC progression are not fully understood. We previously showed that knockdown of signal transducer and activator of transcription 3 (STAT3) up-regulated E-cadherin (a key component in EMT progression) in CRC. In this study, we examined the roles of STAT3 in CRC EMT and ZEB1, an EMT inducer, in STAT3-induced down-regulation of E-cadherin. Knockdown of STAT3 significantly increased E-cadherin and decreased N-cadherin and vimentin expressions in highly invasive LoVo CRC cells. Meanwhile, overexpression of STAT3 significantly reduced E-cadherin and enhanced N-cadherin and vimentin expressions in weakly invasive SW1116 CRC cells. Activation of STAT3 significantly increased CRC cell invasiveness and resistance to apoptosis. Knockdown of STAT3 dramatically enhanced chemosensitivity of CRC cells to fluorouracil. STAT3 regulated ZEB1 expression in CRC cells, and the STAT3-induced decrease in E-cadherin and cell invasion depended on activation of ZEB1 in CRC cells. Additionally, pSTAT3(Tyr-705) and ZEB1 expressions were significantly correlated with TNM (tumor, lymph node, and metastasis stages) (p < 0.01). In conclusion, STAT3 may directly mediate EMT progression and regulate ZEB1 expression in CRC. ZEB1 may participate in STAT3-induced cell invasion and E cadherin down-regulation in CRC cells. The expressions of pSTAT3(Tyr-705) and ZEB1 may be positively associated with CRC metastasis. Our data may provide potential targets to prevent and/or treat CRC invasion and metastasis. PMID- 22205703 TI - Retagging identifies dendritic cell-specific intercellular adhesion molecule-3 (ICAM3)-grabbing non-integrin (DC-SIGN) protein as a novel receptor for a major allergen from house dust mite. AB - Dendritic cells (DCs) have been shown to play a key role in the initiation and maintenance of immune responses to microbial pathogens as well as to allergens, but the exact mechanisms of their involvement in allergic responses and Th2 cell differentiation have remained elusive. Using retagging, we identified DC-SIGN as a novel receptor involved in the initial recognition and uptake of the major house dust mite and dog allergens Der p 1 and Can f 1, respectively. To confirm this, we used gene silencing to specifically inhibit DC-SIGN expression by DCs followed by allergen uptake studies. Binding and uptake of Der p 1 and Can f 1 allergens was assessed by ELISA and flow cytometry. Intriguingly, our data showed that silencing DC-SIGN on DCs promotes a Th2 phenotype in DC/T cell co-cultures. These findings should lead to better understanding of the molecular basis of allergen-induced Th2 cell polarization and in doing so paves the way for the rational design of novel intervention strategies by targeting allergen receptors on innate immune cells or their carbohydrate counterstructures on allergens. PMID- 22205704 TI - Initial insights into structure-activity relationships of avian defensins. AB - Numerous beta-defensins have been identified in birds, and the potential use of these peptides as alternatives to antibiotics has been proposed, in particular to fight antibiotic-resistant and zoonotic bacterial species. Little is known about the mechanism of antibacterial activity of avian beta-defensins, and this study was carried out to obtain initial insights into the involvement of structural features or specific residues in the antimicrobial activity of chicken AvBD2. Chicken AvBD2 and its enantiomeric counterpart were chemically synthesized. Peptide elongation and oxidative folding were both optimized. The similar antimicrobial activity measured for both L- and D-proteins clearly indicates that there is no chiral partner. Therefore, the bacterial membrane is in all likelihood the primary target. Moreover, this work indicates that the three dimensional fold is required for an optimal antimicrobial activity, in particular for gram-positive bacterial strains. The three-dimensional NMR structure of chicken AvBD2 defensin displays the structural three-stranded antiparallel beta sheet characteristic of beta-defensins. The surface of the molecule does not display any amphipathic character. In light of this new structure and of the king penguin AvBD103b defensin structure, the consensus sequence of the avian beta defensin family was analyzed. Well conserved residues were highlighted, and the potential strategic role of the lysine 31 residue of AvBD2 was emphasized. The synthetic AvBD2-K31A variant displayed substantial N-terminal structural modifications and a dramatic decrease in activity. Taken together, these results demonstrate the structural as well as the functional role of the critical lysine 31 residue in antimicrobial activity. PMID- 22205706 TI - The idolatry of the surrogate. PMID- 22205705 TI - Notch signal suppresses Toll-like receptor-triggered inflammatory responses in macrophages by inhibiting extracellular signal-regulated kinase 1/2-mediated nuclear factor kappaB activation. AB - Multiple signaling pathways are involved in the tight regulation of Toll-like receptor (TLR) signaling, which is important for the tailoring of inflammatory response to pathogens in macrophages. It is widely accepted that TLR signaling can activate Notch pathway; however, whether full activation of Notch signaling can feedback modulate TLR signaling pathway so as to control inflammation response remains unclear. Here, we demonstrated that stimulation with TLR ligands up-regulated Notch1 and Notch2 expression in macrophages. The expression of Notch target genes including Hes1 and Hes5 was also induced in macrophages by LPS, suggesting that TLR4 signaling enhances the activation of Notch pathway. Importantly, overexpression of constituted active form of Notch1 (NICD1) and Notch2 (NICD2) suppressed production of TLR4-triggered proinflammatory cytokines such as TNF-alpha and IL-6 but promoted production of antiinflammatory cytokine IL-10, which is dependent on the PEST domain of NICD. In addition, NICD1 and NICD2 suppressed TLR-triggered ERK phosphorylation, which is indispensable for Notch-mediated inhibition of TLR4-triggered proinflammatory cytokine production. Furthermore, activation of Notch signaling inhibited NF-kappaB transcription activity by MyD88/TRAF6 and TRIF pathways, which was dependent on ERK activity. Therefore, our results showed that Notch signaling negatively regulates TLR triggered inflammation responses, revealing a new mechanism for negative regulation of TLR signaling via Notch pathway. PMID- 22205707 TI - What is the most effective way to maintain weight loss in adults? PMID- 22205708 TI - Progress in global access to medicines threatened by funding shortfalls, warns charity. PMID- 22205709 TI - In vitro studies of novel PRKAR1A mutants that extend the predicted RIalpha protein sequence into the 3'-untranslated open reading frame: proteasomal degradation leads to RIalpha haploinsufficiency and Carney complex. AB - BACKGROUND: Carney complex (CNC) is a multiple endocrine neoplasia syndrome due to inactivating mutations in the PRKAR1A gene that codes for type Ialpha regulatory (RIalpha) subunit of protein kinase A. Most PRKAR1A mutations are subject to nonsense mRNA decay (NMD) and, thus, lead to haploinsufficiency. METHODS AND SETTING: Patient phenotyping for CNC features and DNA, RNA, protein, and transfection studies were carried out at a research center. RESULTS: We describe in unrelated kindreds with CNC four naturally occurring PRKAR1A mutations (1055del4, 1067del4ins5, 1076delTTins13, and 1142del4) that are predicted to escape NMD because they are located in the last coding exon of the gene. The phenotype of CNC was not different from that in other patients with the condition, although the number of patients was small. Each of the mutations caused a frameshift that led to a new stop codon into the 3' untranslated open reading frame, predicting an elongated protein that, however, was absent in patient-derived cells. After site-directed mutagenesis, in vitro transcription, and cell-free translation experiments, the expected size mutant proteins were present. However, when the mutant constructs were transfected in adrenal (NCI 295), testicular (N-TERA), and embryonic (HEK293) cells and despite the presence of the mutant mRNA, Western blot analysis indicated that there were no longer proteins. The subsequent application of proteasome inhibitors to cells transfected with the mutant constructs led to the detection of the aberrant proteins, although a compound that affects protein folding had no effect. The wild-type protein was also decreased in both patient-derived cells and/or tissues as well as in the in vitro systems used in this study. CONCLUSIONS: This was the first demonstration of proteasomal degradation of RIalpha protein variants leading to PRKAR1A haploinsufficiency and CNC, adding protein surveillance to NMD in the cellular mechanisms overseeing RIalpha synthesis. In agreement with the molecular data, CNC patients bearing PRKAR1A defects that extend the open reading frame did not have a different phenotype, although this has to be confirmed in a larger number of patients. PMID- 22205710 TI - Latent autoimmune diabetes of adults is phenotypically similar to type 1 diabetes in a minority population. AB - CONTEXT: Latent autoimmune diabetes of adults (LADA) is a form of autoimmune diabetes that has been classified as part of type 1 diabetes or as a distinct clinical entity. Its precise place as a disease category is therefore controversial. OBJECTIVE: The objective of this study was to further examine this issue by comparing the phenotypes of LADA and type 1 diabetes in a predominately minority population. PATIENTS AND METHODS: We studied 126 subjects who were anti glutamic acid decarboxylase antibody-positive in two separate studies--63 subjects in an outpatient study (study 1), and 63 inpatients after resolution of ketoacidosis (study 2). Clinical and biochemical phenotyping was performed in all patients in each group. RESULTS: Few significant differences were found in the clinical or biochemical phenotypes in patients classified as LADA when compared with type 1 diabetes. Adiposity, body mass index, waist/hip ratio, fasting plasma C-peptide, serum high-density lipoprotein cholesterol, and triglycerides were all similar. The only distinguishing feature was a history of hypertension (study 1) or systolic blood pressure (study 2). Also, a history of ketoacidosis did not influence the phenotype of LADA in the outpatients in any discernable way. CONCLUSIONS: We conclude that LADA and type 1 diabetes are phenotypically indistinguishable in this predominantly minority population with a mean duration of glutamic acid decarboxylase antibody-positive diabetes of about 8 yr. PMID- 22205711 TI - Misconception and concerns about bioidentical hormones used for custom-compounded hormone therapy. PMID- 22205712 TI - Update in lipid alterations in subclinical hypothyroidism. AB - Thyroid hormone has multiple effects on the regulation of lipid synthesis, absorption, and metabolism. Studies consistently demonstrate elevated levels of serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, lipoprotein(a), and possibly triglycerides in individuals with overt hypothyroidism, all of which are reversible with levothyroxine therapy. Although it is estimated that 1 to 11% of all patients with dyslipidemia have subclinical hypothyroidism, the effects of subclinical hypothyroidism on serum lipid values are less clear. Apolipoprotein B levels may be increased in patients with subclinical hypothyroidism. Although some studies have demonstrated that total cholesterol and LDL-C levels are elevated in patients with subclinical hypothyroidism, others have not shown any effect of subclinical hypothyroidism on these lipid measurements. Serum triglycerides, lipid subparticle size, and LDL-C oxidizability may be altered in subclinical hypothyroidism, but these studies have also been inconsistent. The preponderance of evidence suggests that HDL-C and lipoprotein(a) levels are not altered in subclinically hypothyroid patients. Smoking and insulin resistance may modify the effects of subclinical hypothyroidism on serum lipid values. Clinical trials to date have not consistently shown a beneficial effect of levothyroxine treatment on serum lipid levels in subclinically hypothyroid patients. PMID- 22205713 TI - Serum thyroid-stimulating hormone levels are associated with blood pressure in children and adolescents. AB - OBJECTIVE: It is currently unclear whether subclinical thyroid dysfunction is associated with blood pressure. Furthermore, data on the potential relation of thyroid function with blood pressure in children and adolescents are sparse. We investigated the association between serum TSH levels and blood pressure in a population-based study conducted in children aged 3-10 yr and adolescents aged 11 17 yr. MATERIAL AND METHODS: Data from 6435 children and 5918 adolescents of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) were analyzed. Two readings of systolic and diastolic blood pressure were taken in a sitting position after 5 min of rest. Hypertension was defined by an increased systolic or an increased diastolic blood pressure using age-, sex-, and height-specific reference values from the KiGGS study. Serum TSH levels were measured with the electrochemiluminescence method. High and low serum TSH levels were defined according to age-specific reference limits for the assay. Continuous and categorized serum TSH levels were associated with hypertension by multivariable logistic regression. RESULTS: Serum TSH levels were significantly associated with hypertension in children (odds ratio=1.12; 95% confidence interval=1.00-1.25; P=0.045) and adolescents (odds ratio=1.19; 95% confidence interval=1.12-1.26; P<0.001). High serum TSH levels were positively associated with systolic and diastolic blood pressure, but not with hypertension in children and adolescents. CONCLUSION: There is a positive relationship between serum TSH levels and hypertension in children and adolescents, suggesting that subclinical hypothyroidism is associated with an increased risk of hypertension. PMID- 22205714 TI - Resistance to selective BRAF inhibition can be mediated by modest upstream pathway activation. AB - A high percentage of patients with BRAF(V600E) mutant melanomas respond to the selective RAF inhibitor vemurafenib (RG7204, PLX4032) but resistance eventually emerges. To better understand the mechanisms of resistance, we used chronic selection to establish BRAF(V600E) melanoma clones with acquired resistance to vemurafenib. These clones retained the V600E mutation and no second-site mutations were identified in the BRAF coding sequence. Further characterization showed that vemurafenib was not able to inhibit extracellular signal-regulated kinase phosphorylation, suggesting pathway reactivation. Importantly, resistance also correlated with increased levels of RAS-GTP, and sequencing of RAS genes revealed a rare activating mutation in KRAS, resulting in a K117N change in the KRAS protein. Elevated levels of CRAF and phosphorylated AKT were also observed. In addition, combination treatment with vemurafenib and either a MAP/ERK kinase (MEK) inhibitor or an AKT inhibitor synergistically inhibited proliferation of resistant cells. These findings suggest that resistance to BRAF(V600E) inhibition could occur through several mechanisms, including elevated RAS-GTP levels and increased levels of AKT phosphorylation. Together, our data implicate reactivation of the RAS/RAF pathway by upstream signaling activation as a key mechanism of acquired resistance to vemurafenib, in support of clinical studies in which combination therapy with other targeted agents are being strategized to combat resistance. PMID- 22205715 TI - CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. AB - Cytotoxic T cells that are present in tumors and capable of recognizing tumor epitopes are nevertheless generally impotent in eliciting tumor rejection. Thus, identifying the immune escape mechanisms responsible for inducing tumor-specific CD8(+) T-cell dysfunction may reveal effective strategies for immune therapy. The inhibitory receptors PD-1 and Tim-3 are known to negatively regulate CD8(+) T cell responses directed against the well-characterized tumor antigen NY-ESO-1. Here, we report that the upregulation of the inhibitory molecule BTLA also plays a critical role in restricting NY-ESO-1-specific CD8(+) T-cell expansion and function in melanoma. BTLA-expressing PD-1(+)Tim-3(-) CD8(+) T cells represented the largest subset of NY-ESO-1-specific CD8(+) T cells in patients with melanoma. These cells were partially dysfunctional, producing less IFN-gamma than BTLA(-) T cells but more IFN-gamma, TNF, and interleukin-2 than the highly dysfunctional subset expressing all three receptors. Expression of BTLA did not increase with higher T-cell dysfunction or upon cognate antigen stimulation, as it does with PD 1, suggesting that BTLA upregulation occurs independently of functional exhaustion driven by high antigen load. Added with PD-1 and Tim-3 blockades, BTLA blockade enhanced the expansion, proliferation, and cytokine production of NY-ESO 1-specific CD8(+) T cells. Collectively, our findings indicate that targeting BTLA along with the PD-1 and Tim-3 pathways is critical to reverse an important mechanism of immune escape in patients with advanced melanoma. PMID- 22205716 TI - Rate of evolution and molecular epidemiology of tick-borne encephalitis virus in Europe, including two isolations from the same focus 44 years apart. AB - Tick-borne encephalitis virus (TBEV) is a member of the family Flaviviridae. It is transmitted by Ixodes spp. ticks in a cycle involving rodents and small mammals. TBEV has three subtypes: European, Siberian and Far Eastern. The virus causes thousands of cases of meningoencephalitis in Europe annually, with an increasing trend. The increase may be attributed to a complex network of elements, including climatic, environmental and socio-economic factors. In an attempt to understand the evolutionary history and dispersal of TBEV, to existing genetic data we add two novel complete ORF sequences of TBEV strains from northern Europe and the completion of the genome of four others. Moreover, we provide a unique measure for the natural rate of evolution of TBEV by studying two isolations from the same forest on an island in Aland archipelago 44 years apart. For all isolates, we analysed the phylogeny, rate of evolution and probable time of radiation of the different TBEV strains. The results show that the two lineages of TBEV in different Ixodes species have evolved independently for approximately 3300 years. Notably, rapid radiation of TBEV-Eur occurred approximately 300 years ago, without the large-scale geographical clustering observed previously for the Siberian subtype. The measurements from the natural rate of evolution correlated with the estimates done by phylogenetic programs, demonstrating their robustness. PMID- 22205717 TI - Early activation of the host complement system is required to restrict central nervous system invasion and limit neuropathology during Venezuelan equine encephalitis virus infection. AB - Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne RNA virus of the genus Alphavirus, family Togaviridae, that is responsible for sporadic outbreaks in human and equid populations in Central and South America. In order to ascertain the role that complement plays in resolving VEEV-induced disease, complement-deficient C3(-/-) mice were infected with a VEEV mutant (V3533) that caused mild, transient disease in immunocompetent mice. In the absence of a functional complement system, peripheral inoculation with V3533 induced much more severe encephalitis. This enhanced pathology was associated with a delay in clearance of infectious virus from the serum and more rapid invasion of the central nervous system in C3(-/-) mice. If V3533 was inoculated directly into the brain, however, disease outcome in C3(-/-) and wild-type mice was identical. These findings indicate that complement-dependent enhancement of peripheral virus clearance is critical for protecting against the development of severe VEEV induced encephalitis. PMID- 22205719 TI - Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension. AB - The authors review the basic pharmacology and potential for adverse drug-drug interactions (DDIs) of bosentan and ambrisentan, the 2 endothelin receptor antagonists currently approved for pulmonary arterial hypertension (PAH) treatment. Bosentan, an endothelin (ET) receptor-type ET(A) and ET(B) antagonist, is metabolized to active metabolites by and an inducer of cytochrome P450 (CYP)2C9 and CYP3A. Ambrisentan, a selective ET(A) receptor antagonist, is metabolized primarily by uridine 5'diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S and, to a lesser extent, by CYP3A and CYP2C19. Drug interactions observed with bosentan DDI studies have demonstrated a potential for significant clinical implications during PAH management: bosentan is contraindicated with cyclosporine A and glyburide, and additional monitoring/dose adjustments are required when coadministered with hormonal contraceptives, simvastatin, lopinavir/ritonavir, and rifampicin. As bosentan carries a boxed warning regarding risks of liver injury and showed dose-dependant increases in serum aminotransferase abnormalities, drug interactions that increase bosentan exposure are of particular clinical concern. Ambrisentan DDI studies performed to date have shown only one clinically relevant DDI, an interaction with cyclosporine A that requires ambrisentan dose reduction. As the treatment of PAH moves toward multimodal combination therapy, scrutiny should be placed on ensuring that drug combinations achieve maximal clinical benefit while minimizing side effects. PMID- 22205718 TI - Co-circulation of diverse paramyxoviruses in an urban African fruit bat population. AB - Bats constitute a reservoir of zoonotic infections and some bat paramyxoviruses are capable of cross-species transmission, often with fatal consequences. Determining the level of viral diversity in reservoir populations is fundamental to understanding and predicting viral emergence. This is particularly relevant for RNA viruses where the adaptive mutations required for cross-species transmission can be present in the reservoir host. We report the use of non invasively collected, pooled, neat urine samples as a robust sample type for investigating paramyxoviruses in bat populations. Using consensus PCR assays we have detected a high incidence and genetic diversity of novel paramyxoviruses in an urban fruit bat population over a short period of time. This may suggest a similarly unique relationship between bats and the members of the family Paramyxoviridae as proposed for some other viral families. Additionally, the high rate of bat-human contact at the study site calls for the zoonotic potential of the detected viruses to be investigated further. PMID- 22205720 TI - Complete genome sequence of a double-stranded RNA virus from avocado. AB - A number of avocado (Persea americana) cultivars are known to contain high molecular-weight double-stranded RNA (dsRNA) molecules for which a viral nature has been suggested, although sequence data are not available. Here we report the cloning and complete sequencing of a 13.5-kbp dsRNA virus isolated from avocado and show that it corresponds to the genome of a new species of the genus Endornavirus (family Endornaviridae), tentatively named Persea americana endornavirus (PaEV). PMID- 22205721 TI - Complete genome sequence of Salmonella enterica serovar typhimurium bacteriophage SPN1S. AB - To understand the interaction between the host of pathogenic Salmonella enterica serovar Typhimurium and its bacteriophage, we isolated the bacteriophage SPN1S. It is a lysogenic phage in the Podoviridae family and uses the O-antigen of lipopolysaccharides (LPS) as a host receptor. Comparative genomic analysis of phage SPN1S and the S. enterica serovar Anatum-specific phage epsilon15 revealed different host specificities, probably due to the low homology of host specificity-related genes. Here we report the complete circular genome sequence of S. Typhimurium-specific bacteriophage SPN1S and show the results of our analysis. PMID- 22205722 TI - Complete genome sequence of a novel species of Porcine Bocavirus, PBoV5. AB - Porcine bocavirus 5 is a novel porcine bocavirus species found in a pig with clinical diarrhea from a farm in China. Here, we report the complete genome sequence of strain PBoV5/JS677, which will help toward understanding the molecular and evolutionary characteristics of the porcine bocavirus. PMID- 22205723 TI - Complete genomic sequence of bluetongue virus serotype 1 from China. AB - We report here the complete genomic sequence of the Chinese bluetongue virus serotype 1 (BTV1) strain SZ97/1. This work is the first to document the complete genomic sequence of a BTV1 strain from China and represents the second complete sequence of BTV1 in the world. The sequence information provided here will help determine the geographic origin of Chinese BTV1 and provide data to facilitate future analyses of the genetic diversity and phylogenetic relationships of BTV strains. PMID- 22205725 TI - Peroxisome proliferator-activated receptors modulate proliferation and angiogenesis in human endometrial carcinoma. AB - Peroxisome proliferator-activated receptors (PPAR) and retinoid X receptors (RXR) are implicated in the development of several obesity-related cancers. Little is known of either the expression or function of PPARs and RXRs in endometrial cancer although this increasingly common disease is highly associated with both obesity and insulin resistance. We investigated the expression of PPAR and RXR subtypes in human endometrial cancers and normal endometrium with immunoblotting and immunohistochemistry and subsequently showed PPAR/RXR binding preferences by coimmunoprecipitation. To determine the functions of PPARs within the endometrium, we investigated proliferation, apoptosis, PTEN expression, and secretion of vascular endothelial growth factor (VEGF) in endometrial cell lines after reducing the expression of PPARalpha and PPARgamma with antisense RNA. The functional effects of PPAR ligands were also investigated in vitro. We identified differential expression of PPAR and RXR subtypes in endometrial cancers and discovered that PPARgamma expression correlated with expression of PTEN. PPARalpha activation influences endometrial cell growth and VEGF secretion. PPARgamma activation reduces proliferation of endometrial cells via regulation of PTEN and appears to reduce VEGF secretion. We conclude that the PPAR/RXR pathway contribute to endometrial carcinogenesis by control of PTEN expression and modulation of VEGF secretion. We propose that PPAR ligands should be considered for clinical investigation in early phase studies of women with endometrial cancer. PMID- 22205724 TI - Systems kinomics demonstrates Congo Basin monkeypox virus infection selectively modulates host cell signaling responses as compared to West African monkeypox virus. AB - Monkeypox virus (MPXV) is comprised of two clades: Congo Basin MPXV, with an associated case fatality rate of 10%, and Western African MPXV, which is associated with less severe infection and minimal lethality. We thus postulated that Congo Basin and West African MPXV would differentially modulate host cell responses and, as many host responses are regulated through phosphorylation independent of transcription or translation, we employed systems kinomics with peptide arrays to investigate these functional host responses. Using this approach we have demonstrated that Congo Basin MPXV infection selectively down regulates host responses as compared with West African MPXV, including growth factor- and apoptosis-related responses. These results were confirmed using fluorescence-activated cell sorting analysis demonstrating that West African MPXV infection resulted in a significant increase in apoptosis in human monocytes as compared with Congo Basin MPXV. Further, differentially phosphorylated kinases were identified through comparison of our MPXV data sets and validated as potential targets for pharmacological inhibition of Congo Basin MPXV infection, including increased Akt S473 phosphorylation and decreased p53 S15 phosphorylation. Inhibition of Akt S473 phosphorylation resulted in a significant decrease in Congo Basin MPXV virus yield (261-fold) but did not affect West African MPXV. In addition, treatment with staurosporine, an apoptosis activator resulted in a 49-fold greater decrease in Congo Basin MPXV yields as compared with West African MPXV. Thus, using a systems kinomics approach, our investigation demonstrates that West African and Congo Basin MPXV differentially modulate host cell responses and has identified potential host targets of therapeutic interest. PMID- 22205727 TI - Ovary cryopreservation and transplantation for fertility preservation. AB - The aim of this review is to summarize the state-of-the-art of ovarian transplantation and cryopreservation. This field has progressed over the last half century from simple animal experiments to sophisticated application in humans. The initial poor results in humans began to improve when a series of nine monozygotic (MZ) twin pairs discordant for premature ovarian failure (POF) underwent ovary transplantation at one center. All of these fresh ovary transplants were successful, resulting in 11 healthy babies in 7 of the 9 recipients. The same surgical techniques were then applied to 3 frozen ovary tissue transplants, up to 14 years after the ovary had been frozen, resulting in 3 more healthy babies. Around the world, the number of healthy babies has now risen to 28. Even ovary allotransplantation is being attempted in the not so uncommon situation where a previous bone marrow donor is now willing to donate ovarian tissue to the same recipient. Recipients routinely reinitiated ovulatory menstrual cycles and normal Day 3 serum FSH levels by 4.5 months. Most conceived naturally (three of them twice or three times from the same graft). The duration of function of fresh ovarian grafts, contrary to initial expectations, indicated minimal oocyte loss from ischemia time. Grafts of just modest portions of ovarian tissue have lasted >7 years. In vitro studies suggest that vitrification of ovarian tissue may be an improvement over the 70% oocyte viability loss from slow freeze. PMID- 22205726 TI - The ATM substrate KAP1 controls DNA repair in heterochromatin: regulation by HP1 proteins and serine 473/824 phosphorylation. AB - The repair of DNA damage in highly compact, transcriptionally silent heterochromatin requires that repair and chromatin packaging machineries be tightly coupled and regulated. KAP1 is a heterochromatin protein and co-repressor that binds to HP1 during gene silencing but is also robustly phosphorylated by Ataxia telangiectasia mutated (ATM) at serine 824 in response to DNA damage. The interplay between HP1-KAP1 binding/ATM phosphorylation during DNA repair is not known. We show that HP1alpha and unmodified KAP1 are enriched in endogenous heterochromatic loci and at a silent transgene prior to damage. Following damage, gammaH2AX and pKAP1-s824 rapidly increase and persist at these loci. Cells that lack HP1 fail to form discreet pKAP1-s824 foci after damage but levels are higher and more persistent. KAP1 is phosphorylated at serine 473 in response to DNA damage and its levels are also modulated by HP1. Unlike pKAP1-s824, pKAP1-s473 does not accumulate at damage foci but is diffusely localized in the nucleus. While HP1 association tempers KAP1 phosphorylation, this interaction also slows the resolution of gammaH2AX foci. Thus, HP1-dependent regulation of KAP1 influences DNA repair in heterochromatin. PMID- 22205728 TI - A functional variant in ANGPT1 and the risk of pregnancies with hypertensive disorders and small-for-gestational-age infants. AB - Pregnancies complicated by pre-eclampsia and small-for-gestational-age (SGA) infants demonstrate impaired placental vascular remodelling. Angiopoietin-1 (ANG 1) is an angiogenic growth factor which regulates vascular integrity and remodelling. The TT genotype of angiopoietin 1 (ANGPT1) rs2507800 polymorphism has been associated with increased plasma ANG-1 levels compared with the AA genotype. We aimed to investigate the association between ANGPT1 rs2507800 polymorphism and pregnancies complicated by gestational hypertensive disorders and SGA infants. We also aimed to investigate whether the polymorphism was associated with abnormal uterine artery Doppler as a surrogate marker of impaired placental vascular remodelling. Genotyping data of 1361 nulliparous pregnant women, 1226 partners and 1190 infants were analysed. The prevalence of ANGPT1 rs2507800 TT genotype was reduced in women with pre-eclampsia [P = 0.01, adjusted odds ratio (aOR), 0.5; 95% confidence interval (CI), 0.3-0.9], hypertensive SGA (P = 0.04, aOR, 0.5; 95% CI, 0.2-0.9) and SGA with abnormal uterine artery Doppler (P = 0.009, aOR, 0.4. 95% CI, 0.2-0.8) compared with women with uncomplicated pregnancy. The prevalence of maternal ANGPT1 rs2507800 TT genotype was reduced in women with increased uterine artery resistance index (P = 0.03, aOR, 0.7; 95% CI, 0.5-0.9) and bilateral notching of the uterine arteries (P = 0.004, aOR, 0.6; 95% CI, 0.4-0.9). These results remained significant after correcting for multiple testing. Maternal ANGPT1 rs2507800 TT genotype is associated with a reduced risk for pre-eclampsia, hypertensive SGA and abnormal uterine artery Doppler. These findings suggest that the TT genotype may protect against these pregnancy disorders by increasing ANG-1 production at the maternal fetal interface. The ANGPT1 rs2507800 polymorphism may have a potential role in screening women to predict the risk of these pregnancy complications. TRIAL REGISTRY NAME: Screening nulliparous women to identify the combinations of clinical risk factors and/or biomarkers required to predict pre-eclampsia, SGA babies and spontaneous preterm birth. PMID- 22205730 TI - Influenza A virus infection results in a robust, antigen-responsive, and widely disseminated Foxp3+ regulatory T cell response. AB - Foxp3(+) CD4(+) regulatory T cells (Tregs) represent a highly suppressive T cell subset with well-characterized immunosuppressive effects during immune homeostasis and chronic infections, although the role of these cells in acute viral infections is poorly understood. The present study sought to examine the induction of Foxp3(+) CD4(+) Tregs in a nonlethal murine model of pulmonary viral infection by the use of the prototypical respiratory virus influenza A. We establish that influenza A virus infection results in a robust Foxp3(+) CD4(+) T cell response and that regulatory T cell induction at the site of inflammation precedes the effector T cell response. Induced Foxp3(+) CD4(+) T cells are highly suppressive ex vivo, demonstrating that influenza virus-induced Foxp3(+) CD4(+) T cells are phenotypically regulatory. Influenza A virus-induced regulatory T cells proliferate vigorously in response to influenza virus antigen, are disseminated throughout the site of infection and primary and secondary lymphoid organs, and retain Foxp3 expression in vitro, suggesting that acute viral infection is capable of inducing a foreign-antigen-specific Treg response. The ability of influenza virus-induced regulatory T cells to suppress antigen-specific CD4(+) and CD8(+) T cell proliferation and cytokine production correlates closely to their ability to respond to influenza virus antigens, suggesting that virus induced Tregs are capable of attenuating effector responses in an antigen dependent manner. Collectively, these data demonstrate that primary acute viral infection is capable of inducing a robust, antigen-responsive, and suppressive regulatory T cell response. PMID- 22205729 TI - Natural occurrence and characterization of two internal ribosome entry site elements in a novel virus, canine picodicistrovirus, in the picornavirus-like superfamily. AB - Dicistroviridae and Picornaviridae are two phylogenetically related families of positive-sense single-stranded RNA viruses in the picornavirus-like superfamily with similar gene contents but different genome organizations and hosts. In a surveillance study involving 1,472 samples from 368 dogs over a 22-month period, we identified a novel picornavirus-like virus from 47 fecal and urine samples by the use of reverse transcription-PCR (RT-PCR). Sequencing and phylogenetic analysis of three complete genomes revealed that, although it seemed that the virus was most closely related to other picornaviruses, P1, P2, and P3 of the virus possessed very low amino acid identities of <30% to those of all other known picornaviruses and that the amino acid identities between the 3D(pol) and 2C of the virus and the RNA-dependent RNA polymerases and helicases of all other picornaviruses were <35%. Distinct from other picornaviruses, the genomes of the virus contain two putative internal ribosome entry sites (IRESs) and two open reading frames, encoding two polyprotein precursors (844 and 1,406 amino acids), separated by an intergenic region (IGR) of 588 bases. A dual-luciferase activity assay using DNA and RNA transfection revealed that both IRESs were functional. Quantitative RT-PCR showed that numbers of viral RNAs ranged from 7.55 * 10(6) to 1.26 * 10(9) copies/ml of urine and 1.82 * 10(6) to 4.97 * 10(10) copies/ml of fecal sample. This is the first report of the natural occurrence of two functional IRESs in nondicistroviruses. Based on our results, we have proposed a novel species, canine picodicistrovirus (CPDV), to describe this novel member of the picornavirus-like superfamily, which could represent a novel family of viruses. PMID- 22205731 TI - Self-assembly of viral capsid protein and RNA molecules of different sizes: requirement for a specific high protein/RNA mass ratio. AB - Virus-like particles can be formed by self-assembly of capsid protein (CP) with RNA molecules of increasing length. If the protein "insisted" on a single radius of curvature, the capsids would be identical in size, independent of RNA length. However, there would be a limit to length of the RNA, and one would not expect RNA much shorter than native viral RNA to be packaged unless multiple copies were packaged. On the other hand, if the protein did not favor predetermined capsid size, one would expect the capsid diameter to increase with increase in RNA length. Here we examine the self-assembly of CP from cowpea chlorotic mottle virus with RNA molecules ranging in length from 140 to 12,000 nucleotides (nt). Each of these RNAs is completely packaged if and only if the protein/RNA mass ratio is sufficiently high; this critical value is the same for all of the RNAs and corresponds to equal RNA and N-terminal-protein charges in the assembly mix. For RNAs much shorter in length than the 3,000 nt of the viral RNA, two or more molecules are assembled into 24- and 26-nm-diameter capsids, whereas for much longer RNAs (>4,500 nt), a single RNA molecule is shared/packaged by two or more capsids with diameters as large as 30 nm. For intermediate lengths, a single RNA is assembled into 26-nm-diameter capsids, the size associated with T=3 wild-type virus. The significance of these assembly results is discussed in relation to likely factors that maintain T=3 symmetry in vivo. PMID- 22205732 TI - Differential transmission of HIV traversing fetal oral/intestinal epithelia and adult oral epithelia. AB - While human immunodeficiency virus (HIV) transmission through the adult oral route is rare, mother-to-child transmission (MTCT) through the neonatal/infant oral and/or gastrointestinal route is common. To study the mechanisms of cell free and cell-associated HIV transmission across adult oral and neonatal/infant oral/intestinal epithelia, we established ex vivo organ tissue model systems of adult and fetal origin. Given the similarity of neonatal and fetal oral epithelia with respect to epithelial stratification and density of HIV-susceptible immune cells, we used fetal oral the epithelium as a model for neonatal/infant oral epithelium. We found that cell-free HIV traversed fetal oral and intestinal epithelia and infected HIV-susceptible CD4(+) T lymphocytes, Langerhans/dendritic cells, and macrophages. To study the penetration of cell-associated virus into fetal oral and intestinal epithelia, HIV-infected macrophages and lymphocytes were added to the surfaces of fetal oral and intestinal epithelia. HIV-infected macrophages, but not lymphocytes, transmigrated across fetal oral epithelia. HIV infected macrophages and, to a lesser extent, lymphocytes transmigrated across fetal intestinal epithelia. In contrast to the fetal oral/intestinal epithelia, cell-free HIV transmigration through adult oral epithelia was inefficient and virions did not infect intraepithelial and subepithelial HIV-susceptible cells. In addition, HIV-infected macrophages and lymphocytes did not transmigrate through intact adult oral epithelia. Transmigration of cell-free and cell associated HIV across the fetal oral/intestinal mucosal epithelium may serve as an initial mechanism for HIV MTCT. PMID- 22205733 TI - Adenovirus E4orf3 targets transcriptional intermediary factor 1gamma for proteasome-dependent degradation during infection. AB - The ability of adenovirus early region proteins, E1B-55K and E4orf6, to usurp control of cellular ubiquitin ligases and target proteins for proteasome dependent degradation during infection is well established. Here we show that the E4 gene product, E4orf3 can, independently of E1B-55K and E4orf6, target the transcriptional corepressor transcriptional intermediary factor 1gamma (TIF1gamma) for proteasome-mediated degradation during infection. Initial mass spectrometric studies identified TIF1 family members-TIF1alpha, TIF1beta, and TIF1gamma-as E1B-55K-binding proteins in both transformed and infected cells, but analyses revealed that, akin to TIF1alpha, TIF1gamma is reorganized in an E4orf3 dependent manner to promyelocytic leukemia protein-containing nuclear tracks during infection. The use of a number of different adenovirus early region mutants identified the specific and sole requirement for E4orf3 in mediating TIF1gamma degradation. Further analyses revealed that TIF1gamma is targeted for degradation by a number of divergent human adenoviruses, suggesting that the ability of E4orf3 to regulate TIF1gamma expression is evolutionarily conserved. We also determined that E4orf3 does not utilize the Cullin-based ubiquitin ligases, CRL2 and CRL5, or the TIF1alpha ubiquitin ligase in order to promote TIF1gamma degradation. Further studies suggested that TIF1gamma possesses antiviral activity and limits adenovirus early and late gene product expression during infection. Indeed, TIF1gamma knockdown accelerates the adenovirus-mediated degradation of MRE11, while TIF1gamma overexpression delays the adenovirus mediated degradation of MRE11. Taken together, these studies have identified novel adenovirus targets and have established a new role for the E4orf3 protein during infection. PMID- 22205735 TI - Characterization of the R263K mutation in HIV-1 integrase that confers low-level resistance to the second-generation integrase strand transfer inhibitor dolutegravir. AB - Integrase (IN) strand transfer inhibitors (INSTIs) have been developed to inhibit the ability of HIV-1 integrase to irreversibly link the reverse-transcribed viral DNA to the host genome. INSTIs have proven their high efficiency in inhibiting viral replication in vitro and in patients. However, first-generation INSTIs have only a modest genetic barrier to resistance, allowing the virus to escape these powerful drugs through several resistance pathways. Second-generation INSTIs, such as dolutegravir (DTG, S/GSK1349572), have been reported to have a higher resistance barrier, and no novel drug resistance mutation has yet been described for this drug. Therefore, we performed in vitro selection experiments with DTG using viruses of subtypes B, C, and A/G and showed that the most common mutation to emerge was R263K. Further analysis by site-directed mutagenesis showed that R263K does confer low-level resistance to DTG and decreased integration in cell culture without altering reverse transcription. Biochemical cell-free assays performed with purified IN enzyme containing R263K confirmed the absence of major resistance against DTG and showed a slight decrease in 3' processing and strand transfer activities compared to the wild type. Structural modeling suggested and in vitro IN-DNA binding assays show that the R263K mutation affects IN-DNA interactions. PMID- 22205734 TI - Targeting HIV-1 envelope glycoprotein trimers to B cells by using APRIL improves antibody responses. AB - An HIV-1 vaccine remains elusive, in part because various factors limit the quantity and quality of the antibodies raised against the viral envelope glycoprotein complex (Env). We hypothesized that targeting Env vaccines directly to B cells, by fusing them to molecules that bind and activate these cells, would improve Env-specific antibody responses. Therefore, we fused trimeric Env gp140 to A PRoliferation-Inducing Ligand (APRIL), B-cell Activating Factor (BAFF), and CD40 Ligand (CD40L). The Env-APRIL, Env-BAFF, and Env-CD40L gp140 trimers all enhanced the expression of activation-induced cytidine deaminase (AID), the enzyme responsible for inducing somatic hypermutation, antibody affinity maturation, and antibody class switching. They also triggered IgM, IgG, and IgA secretion from human B cells in vitro. The Env-APRIL trimers induced higher anti Env antibody responses in rabbits, including neutralizing antibodies against tier 1 viruses. The enhanced Env-specific responses were not associated with a general increase in total plasma antibody concentrations, indicating that the effect of APRIL was specific for Env. All the rabbit sera raised against gp140 trimers, irrespective of the presence of CD40L, BAFF, or APRIL, recognized trimeric Env efficiently, whereas sera raised against gp120 monomers did not. The levels of trimer-binding and virus-neutralizing antibodies were strongly correlated, suggesting that gp140 trimers are superior to gp120 monomers as immunogens. Targeting and activating B cells with a trimeric HIV-1 Env-APRIL fusion protein may therefore improve the induction of humoral immunity against HIV-1. PMID- 22205736 TI - The human cytomegalovirus protein TRS1 inhibits autophagy via its interaction with Beclin 1. AB - Human cytomegalovirus modulates macroautophagy in two opposite directions. First, HCMV stimulates autophagy during the early stages of infection, as evident by an increase in the number of autophagosomes and a rise in the autophagic flux. This stimulation occurs independently of de novo viral protein synthesis since UV inactivated HCMV recapitulates the stimulatory effect on macroautophagy. At later time points of infection, HCMV blocks autophagy (M. Chaumorcel, S. Souquere, G. Pierron, P. Codogno, and A. Esclatine, Autophagy 4:1-8, 2008) by a mechanism that requires de novo viral protein expression. Exploration of the mechanisms used by HCMV to block autophagy unveiled a robust increase of the cellular form of Bcl-2 expression. Although this protein has an anti-autophagy effect via its interaction with Beclin 1, it is not responsible for the inhibition induced by HCMV, probably because of its phosphorylation by c-Jun N-terminal kinase. Here we showed that the HCMV TRS1 protein blocks autophagosome biogenesis and that a TRS1 deletion mutant is defective in autophagy inhibition. TRS1 has previously been shown to neutralize the PKR antiviral effector molecule. Although phosphorylation of eIF2alpha by PKR has been described as a stimulatory signal to induce autophagy, the PKR-binding domain of TRS1 is dispensable to its inhibitory effect. Our results show that TRS1 interacts with Beclin 1 to inhibit autophagy. We mapped the interaction with Beclin 1 to the N-terminal region of TRS1, and we demonstrated that the Beclin 1-binding domain of TRS1 is essential to inhibit autophagy. PMID- 22205737 TI - Epstein-Barr virus downregulates microRNA 203 through the oncoprotein latent membrane protein 1: a contribution to increased tumor incidence in epithelial cells. AB - The Epstein-Barr virus (EBV) is highly associated with nasopharyngeal carcinoma (NPC), and it regulates some microRNAs (miRNAs) that are involved in the development of cancer. The role of EBV in the deregulation of cellular miRNAs and how this affects the progression of NPC remain to be investigated. An analysis of the miRNA profile in an EBV-infected cell line revealed that miRNA 203 (miR-203) was downregulated. miR-203 is expressed specifically in epithelial cells. This downregulation of miR-203 was further verified and functionally analyzed. miR-203 was downregulated substantially in epithelial cells and NPC tissues that were latently infected with EBV. Downregulation of miR-203 also occurred during the early stage of EBV infection. Furthermore, the viral oncoprotein, latent membrane protein 1 (LMP1), was responsible for downregulation of miR-203. Removal of the latent EBV genome or suppression of LMP1 resulted in restoration of miR-203 expression. EBV-LMP1 mediated the downregulation of miR-203 at the primary transcript level. E2F3 and CCNG1 were identified as target genes of miR-203. Ectopic expression of miR-203 inhibited EBV-induced S-phase entry and transformation in vivo. Overexpression of the targets overcame the effects of miR 203 mimics on the cell cycle, and the expression of target genes in tumor models was inhibited by miR-203. Inhibitors of Jun N-terminal protein kinase (JNK) and NF-kappaB blocked miR-203 downregulation. These results imply that EBV promotes malignancy by downregulating cellular miR-203, which contributes to the etiology of NPC. PMID- 22205738 TI - Equine herpesvirus type 1-mediated oncolysis of human glioblastoma multiforme cells. AB - The cytolytic animal virus equine herpesvirus type 1 (EHV-1) was evaluated for its oncolytic potential against five human glioblastoma cell lines. EHV-1 productively infected four of these cell lines, and the degree of infection was positively correlated with glioma cell death. No human major histocompatibility complex class 1 (MHC-I) was detected in the resistant glioma line, while infection of the susceptible glioma cell lines, which expressed human MHC-I, were blocked with antibody to MHC-I, indicating that human MHC-I acts as an EHV-1 entry receptor on glioma cells. PMID- 22205740 TI - A leucine zipper motif of a tegument protein triggers final envelopment of human cytomegalovirus. AB - The product of the human cytomegalovirus (HCMV) UL71 gene is conserved throughout the herpesvirus family. During HCMV infection, protein pUL71 is required for efficient virion egress and is involved in the final steps of secondary envelopment leading to infectious viral particles. We found strong indications for oligomerization of pUL71 under native conditions when recombinant pUL71 was negatively stained and analyzed by electron microscopy. Oligomerization of pUL71 during infection was further verified by native and reducing polyacrylamide gel electrophoresis (PAGE). By in silico analyses of the pUL71 sequence, we noticed a basic leucine zipper (bZIP)-like domain, which might serve as an oligomerization domain. We demonstrated the requirement of the bZIP-like domain for pUL71 oligomerization by coimmunoprecipitation and bimolecular fluorescence complementation using a panel of pUL71 mutants. These studies revealed that the mutation of two leucine residues is sufficient to abrogate oligomerization but that intracellular localization of pUL71 was unaffected. To investigate the relevance of the bZIP domain in the viral context, recombinant viruses carrying mutations identical to those in the panel of pUL71 mutants were generated. bZIP defective viral mutants showed impaired viral growth, a small-plaque phenotype, and an ultrastructural phenotype similar to that of the previously described UL71 stop mutant virus. The majority of virus particles within the viral assembly compartment exhibited various stages of incomplete envelopment, which is consistent with the growth defect for the bZIP mutants. From these data we conclude that the bZIP-like domain is required for oligomerization of pUL71, which seems to be essential for correct envelopment of HCMV. PMID- 22205741 TI - CD4 T cells promote CD8 T cell immunity at the priming and effector site during viral encephalitis. AB - CD4 T cell activation during peripheral infections not only is essential in inducing protective CD8 T cell memory but also promotes CD8 T cell function and survival. However, the contributions of CD4 T cell help to antiviral CD8 T cell immunity during central nervous system (CNS) infection are not well established. Encephalitis induced by the sublethal coronavirus JHMV was used to identify when CD4 T cells regulate CD8 T cell responses following CNS infection. Peripheral expansion of virus-specific CD8 T cells was impaired when CD4 T cells were ablated prior to infection but not at 4 days postinfection. Delayed CD4 T cell depletion abrogated CD4 T cell recruitment to the CNS but only slightly diminished CD8 T cell recruitment. Nevertheless, the absence of CNS CD4 T cells was associated with reduced gamma interferon (IFN-gamma) and granzyme B expression by infiltrating CD8 T cells, increased CD8 T cell apoptosis, and impaired control of infectious virus. CD4 T cell depletion subsequent to CD4 T cell CNS migration restored CD8 T cell activity and virus control. Analysis of gammac-dependent cytokine expression indicated interleukin-21 (IL-21) as a primary candidate optimizing CD8 T cell activity within the CNS. These results demonstrate that CD4 T cells play critical roles in both enhancing peripheral activation of CD8 T cells and prolonging their antiviral function within the CNS. The data highlight the necessity for temporally and spatially distinct CD4 T cell helper functions in sustaining CD8 T cell activity during CNS infection. PMID- 22205739 TI - The association of recombination events in the founding and emergence of subgenogroup evolutionary lineages of human enterovirus 71. AB - Enterovirus 71 (EV71) is responsible for frequent large-scale outbreaks of hand, foot, and mouth disease worldwide and represent a major etiological agent of severe, sometimes fatal neurological disease. EV71 variants have been classified into three genogroups (GgA, GgB, and GgC), and the latter two are further subdivided into subgenogroups B1 to B5 and C1 to C5. To investigate the dual roles of recombination and evolution in the epidemiology and transmission of EV71 worldwide, we performed a large-scale genetic analysis of isolates (n = 308) collected from 19 countries worldwide over a 40-year period. A series of recombination events occurred over this period, which have been identified through incongruities in sequence grouping between the VP1 and 3Dpol regions. Eleven 3Dpol clades were identified, each specific to EV71 and associated with specific subgenogroups but interspersed phylogenetically with clades of coxsackievirus A16 and other EV species A serotypes. The likelihood of recombination increased with VP1 sequence divergence; mean half-lives for EV71 recombinant forms (RFs) of 6 and 9 years for GgB and GgC overlapped with those observed for the EV-B serotypes, echovirus 9 (E9), E30, and E11, respectively (1.3 to 9.8 years). Furthermore, within genogroups, sporadic recombination events occurred, such as the linkage of two B4 variants to RF-W instead of RF-A and of two C4 variants to RF-H. Intriguingly, recombination events occurred as a founding event of most subgenogroups immediately preceding their lineage expansion and global emergence. The possibility that recombination contributed to their subsequent spread through improved fitness requires further biological and immunological characterization. PMID- 22205742 TI - Macrophage internal HIV-1 is protected from neutralizing antibodies. AB - In macrophages, HIV-1 accumulates in intracellular vesicles designated virus containing compartments (VCCs). These might play an important role in the constitution of macrophages as viral reservoirs and allow HIV-1 to evade the immune system by sequestration in an internal niche, which is difficult to access from the exterior. However, until now, evidence of whether internal virus accumulations are protected from the host's humoral immune response is still lacking. In order to be able to study the formation and antibody accessibility of VCCs, we generated HIV-1 with green fluorescent protein (GFP)-tagged Gag replicating in primary macrophages. Live-cell observations revealed faint initial cytosolic Gag expression and subsequent large intracellular Gag accumulations which stayed stable over days. Taking advantage of the opportunity to study the accessibility of intracellular VCCs via the cell surface, we demonstrate that macrophage internal HIV-1-containing compartments cannot be targeted by neutralizing antibodies. Furthermore, HIV-1 was efficiently transferred from antibody-treated macrophages to T cells. Three-dimensional reconstruction of electron microscopic slices revealed that Gag accumulations correspond to viral particles within enclosed compartments and convoluted membranes. Thus, although some VCCs were connected to the plasma membrane, the complex membrane architecture of the HIV-1-containing compartment might shield viral particles from neutralizing antibodies. In sum, our study provides evidence that HIV-1 is sequestered into a macrophage internal membranous web, posing an obstacle for the elimination of this viral reservoir. PMID- 22205743 TI - Evidence for a common evolutionary origin of coronavirus spike protein receptor binding subunits. AB - Among different coronavirus genera, the receptor-binding S1 subunits of their spike proteins differ in primary, secondary, and tertiary structures. This study identified shared structural topologies (connectivity of secondary structural elements) in S1 domains of different coronavirus genera. The results suggest that coronavirus S1 subunits share a common evolutionary origin but have attained diverse sequences and structures following extensive divergent evolution. The results also increase understanding of the structures and functions of coronavirus S1 domains whose tertiary structures are currently unknown. PMID- 22205744 TI - Identification of a pyridopyrimidinone inhibitor of orthopoxviruses from a diversity-oriented synthesis library. AB - Orthopoxviruses include the prototypical vaccinia virus, the emerging infectious agent monkeypox virus, and the potential biothreat variola virus (the causative agent of smallpox). There is currently no FDA-approved drug for humans infected with orthopoxviruses. We screened a diversity-oriented synthesis library for new scaffolds with activity against vaccinia virus. This screen identified a nonnucleoside analog that blocked postreplicative intermediate and late gene expression. Viral genome replication was unaffected, and inhibition could be elicited late in infection and persisted upon drug removal. Sequencing of drug resistant viruses revealed mutations predicted to be on the periphery of the highly conserved viral RNA polymerase large subunit. Consistent with this, the compound had broad-spectrum activity against orthopoxviruses in vitro. These findings indicate that novel chemical synthesis approaches are a potential source for new infectious disease therapeutics and identify a potentially promising candidate for development to treat orthopoxvirus-infected individuals. PMID- 22205745 TI - DNA-binding activity of adeno-associated virus Rep is required for inverted terminal repeat-dependent complex formation with herpes simplex virus ICP8. AB - Herpes simplex virus (HSV) helper functions for (AAV) replication comprise HSV ICP8 and helicase-primase UL5/UL52/UL8. Here we show that N-terminal amino acids of AAV Rep78 that contact the Rep-binding site within the AAV inverted terminal repeat (ITR) are required for ternary-complex formation with infected-cell protein 8 (ICP8) on AAV single-strand DNA (ssDNA) in vitro and for colocalization in nuclear replication domains in vivo. Our data suggest that HSV-dependent AAV replication is initiated by Rep contacting the AAV ITR and by cooperative binding of ICP8 on AAV ssDNA. PMID- 22205746 TI - Vif proteins of human and simian immunodeficiency viruses require cellular CBFbeta to degrade APOBEC3 restriction factors. AB - HIV-1 requires the cellular transcription factor CBFbeta to stabilize its accessory protein Vif and promote APOBEC3G degradation. Here, we demonstrate that both isoforms of CBFbeta allow for increased steady-state levels of Vif, enhanced APOBEC3G degradation, and increased viral infectivity. This conserved functional interaction enhances the steady-state levels of Vif proteins from multiple HIV-1 subtypes and is required for the degradation of all human and rhesus Vif sensitive APOBEC3 proteins by their respective lentiviral Vif proteins. PMID- 22205747 TI - Noncatalytic ions direct the RNA-dependent RNA polymerase of bacterial double stranded RNA virus phi6 from de novo initiation to elongation. AB - RNA-dependent RNA polymerases (RdRps) are key to the replication of RNA viruses. A common divalent cation binding site, distinct from the positions of catalytic ions, has been identified in many viral RdRps. We have applied biochemical, biophysical, and structural approaches to show how the RdRp from bacteriophage phi6 uses the bound noncatalytic Mn(2+) to facilitate the displacement of the C terminal domain during the transition from initiation to elongation. We find that this displacement releases the noncatalytic Mn(2+), which must be replaced for elongation to occur. By inserting a dysfunctional Mg(2+) at this site, we captured two nucleoside triphosphates within the active site in the absence of Watson-Crick base pairing with template and mapped movements of divalent cations during preinitiation. These structures refine the pathway from preinitiation through initiation to elongation for the RNA-dependent RNA polymerization reaction, explain the role of the noncatalytic divalent cation in 6 RdRp, and pinpoint the previously unresolved Mn(2+)-dependent step in replication. PMID- 22205748 TI - Coordinate deletion of N-glycans from the heptad repeats of the fusion F protein of Newcastle disease virus yields a hyperfusogenic virus with increased replication, virulence, and immunogenicity. AB - The role of N-linked glycosylation of the Newcastle disease virus (NDV) fusion (F) protein in viral replication and pathogenesis was examined by eliminating potential acceptor sites using a reverse genetics system for the moderately pathogenic strain Beaudette C (BC). The NDV-BC F protein contains six potential acceptor sites for N-linked glycosylation at residues 85, 191, 366, 447, 471, and 541 (sites Ng1 to Ng6, respectively). The sites at Ng2 and Ng5 are present in heptad repeat (HR) domains HR1 and HR2, respectively, and thus might affect fusion. Each N-glycosylation site was eliminated individually by replacing asparagine (N) with glutamine (Q), and a double mutant (Ng2 + 5) involving the two HR domains was also made. Each mutant was successfully recovered by reverse genetics except for the one involving Ng6, which is present in the cytoplasmic domain. All of the F proteins expressed by the recovered mutant viruses were efficiently cleaved and transported to the infected-cell surface. None of the individual mutations affected viral fusogenicity, but the double mutation at Ng2 and Ng5 in HR1 and HR2 increased fusogenicity >12-fold. The single mutations at sites Ng1, Ng2, and Ng5 resulted in modestly reduced multicycle growth in vitro. These three single mutations were also the most attenuating in eggs and 1-day-old chicks and were associated with decreased replication and spread in 2-week-old chickens. In contrast, the combination of the mutations at Ng2 and Ng5 yielded a virus that, compared to the BC parent, replicated >100-fold more efficiently in vitro, was more virulent in eggs and chicks, replicated more efficiently in chickens with enhanced tropism for the brain and gut, and elicited stronger humoral cell responses. These results illustrate the effects of N-glycosylation of the F protein on NDV pathobiology and suggest that the N-glycans in HR1 and HR2 coordinately downregulate viral fusion and virulence. PMID- 22205749 TI - Regulation of cyclin T1 and HIV-1 Replication by microRNAs in resting CD4+ T lymphocytes. AB - The replication of integrated human immunodeficiency virus type 1 (HIV-1) is dependent on the cellular cofactor cyclin T1, which binds the viral Tat protein and activates the RNA polymerase II transcription of the integrated provirus. The activation of resting CD4(+) T cells upregulates cyclin T1 protein levels independently of an increase in cyclin T1 mRNA levels, suggesting a translational repression of cyclin T1 in resting CD4(+) T cells. Hypothesizing that microRNAs (miRNAs) repress cyclin T1 translation in resting CD4(+) T cells and that this inhibition is lifted upon cell activation, we used microarray expression analysis to identify miRNAs miR-27b, miR-29b, miR-150, and miR-223 as being significantly downregulated upon CD4(+) T cell activation. The overexpression of these miRNAs decreased endogenous cyclin T1 protein levels, while treatment with the corresponding antagomiRs increased cyclin T1 protein levels. An miR-27b binding site within the cyclin T1 3' untranslated region (3'UTR) was identified and confirmed to be functional after the mutation of key resides abrogated the ability of miR-27b to decrease the expression of a luciferase reporter upstream of the cyclin T1 3'UTR. Ago2 immunoprecipitation revealed an association with cyclin T1 mRNA that was decreased following treatment with miR-27b and miR-29b antagomiRs. Cells overexpressing miR-27b showed decreased viral gene expression levels of the HIV-1 reporter virus and a decreased replication of strain NL4.3; a partial rescue of viral transcription could be seen following the transfection of cyclin T1. These results implicate miR-27b as a novel regulator of cyclin T1 protein levels and HIV-1 replication, while miR-29b, miR-223, and miR-150 may regulate cyclin T1 indirectly. PMID- 22205750 TI - Stimulation of BK virus DNA replication by NFI family transcription factors. AB - BK polyomavirus (BKV) establishes persistent, low-level, and asymptomatic infections in most humans and causes polyomavirus-associated nephropathy (PVAN) and other pathologies in some individuals. The activation of BKV replication following kidney transplantation, leading to viruria, viremia, and, ultimately, PVAN, is associated with immune suppression as well as inflammation and stress from ischemia-reperfusion injury of the allograft, but the stimuli and molecular mechanisms leading to these pathologies are not well defined. The replication of BKV DNA in cell cultures is regulated by the viral noncoding control region (NCCR) comprising the core origin and flanking sequences, to which BKV T antigen (Tag), cellular proteins, and small regulatory RNAs bind. Six nuclear factor I (NFI) binding sites occur in sequences flanking the late side of the core origin (the enhancer) of the archetype virus, and their mutation, either individually or in toto, reduces BKV DNA replication when placed in competition with templates containing intact BKV NCCRs. NFI family members interacted with the helicase domain of BKV Tag in pulldown assays, suggesting that NFI helps recruit Tag to the viral core origin and may modulate its function. However, Tag may not be the sole target of the replication-modulatory activities of NFI: the NFIC/CTF1 isotype stimulates BKV template replication in vitro at low concentrations of DNA polymerase-alpha primase (Pol-primase), and the p58 subunit of Pol-primase associates with NFIC/CTF1, suggesting that NFI also recruits Pol-primase to the NCCR. These results suggest that NFI proteins (and the signaling pathways that target them) activate BKV replication and contribute to the consequent pathologies caused by acute infection. PMID- 22205751 TI - The multibasic cleavage site of the hemagglutinin of highly pathogenic A/Vietnam/1203/2004 (H5N1) avian influenza virus acts as a virulence factor in a host-specific manner in mammals. AB - Highly pathogenic avian influenza (HPAI) viruses of the H5 and H7 subtypes typically possess multiple basic amino acids around the cleavage site (MBS) of their hemagglutinin (HA) protein, a recognized virulence motif in poultry. To determine the importance of the H5 HA MBS as a virulence factor in mammals, recombinant wild-type HPAI A/Vietnam/1203/2004 (H5N1) viruses that possessed (H5N1) or lacked (DeltaH5N1) the H5 HA MBS were generated and evaluated for their virulence in BALB/c mice, ferrets, and African green monkeys (AGMs) (Chlorocebus aethiops). The presence of the H5 HA MBS was associated with lethality, significantly higher virus titers in the respiratory tract, virus dissemination to extrapulmonary organs, lymphopenia, significantly elevated levels of proinflammatory cytokines and chemokines, and inflammation in the lungs of mice and ferrets. In AGMs, neither H5N1 nor DeltaH5N1 virus was lethal and neither caused clinical symptoms. The H5 HA MBS was associated with mild enhancement of replication and delayed virus clearance. Thus, the contribution of H5 HA MBS to the virulence of the HPAI H5N1 virus varies among mammalian hosts and is most significant in mice and ferrets and less remarkable in nonhuman primates. PMID- 22205752 TI - The amino acid linker between the endonuclease and helicase domains of adeno associated virus type 5 Rep plays a critical role in DNA-dependent oligomerization. AB - The adeno-associated virus (AAV) genome encodes four Rep proteins, all of which contain an SF3 helicase domain. The larger Rep proteins, Rep78 and Rep68, are required for viral replication, whereas Rep40 and Rep52 are needed to package AAV genomes into preformed capsids; these smaller proteins are missing the site specific DNA-binding and endonuclease domain found in Rep68/78. Other viral SF3 helicases, such as the simian virus 40 large T antigen and the papillomavirus E1 protein, are active as hexameric assemblies. However, Rep40 and Rep52 have not been observed to form stable oligomers on their own or with DNA, suggesting that important determinants of helicase multimerization lie outside the helicase domain. Here, we report that when the 23-residue linker that connects the endonuclease and helicase domains is appended to the adeno-associated virus type 5 (AAV5) helicase domain, the resulting protein forms discrete complexes on DNA consistent with single or double hexamers. The formation of these complexes does not require the Rep binding site sequence, nor is it nucleotide dependent. These complexes have stimulated ATPase and helicase activities relative to the helicase domain alone, indicating that they are catalytically relevant, a result supported by negative-stain electron microscopy images of hexameric rings. Similarly, the addition of the linker region to the AAV5 Rep endonuclease domain also confers on it the ability to bind and multimerize on nonspecific double-stranded DNA. We conclude that the linker is likely a key contributor to Rep68/78 DNA-dependent oligomerization and may play an important role in mediating Rep68/78's conversion from site-specific DNA binding to nonspecific DNA unwinding. PMID- 22205753 TI - Contribution of intra- and interhost dynamics to norovirus evolution. AB - Norovirus (NoV) is an emerging RNA virus that has been associated with global epidemics of gastroenteritis. Each global epidemic arises with the emergence of novel antigenic variants. While the majority of NoV infections are mild and self limiting, in the young, elderly, and immunocompromised, severe and prolonged illness can result. As yet, there is no vaccine or therapeutic treatment to prevent or control infection. In order to design effective control strategies, it is important to understand the mechanisms and source of the new antigenic variants. In this study, we used next-generation sequencing (NGS) technology to investigate genetic diversification in three contexts: the impact of a NoV transmission event on viral diversity and the contribution to diversity of intrahost evolution over both a short period of time (10 days), in accordance with a typical acute NoV infection, and a prolonged period of time (288 days), as observed for NoV chronic infections of immunocompromised individuals. Investigations of the transmission event revealed that minor variants at frequencies as low as 0.01% were successfully transmitted, indicating that transmission is an important source of diversity at the interhost level of NoV evolution. Our results also suggest that chronically infected immunocompromised subjects represent a potential reservoir for the emergence of new viral variants. In contrast, in a typical acute NoV infection, the viral population was highly homogenous and relatively stable. These results indicate that the evolution of NoV occurs through multiple mechanisms. PMID- 22205756 TI - Facet arthrography in an unusual presentation of a lumbar hemorrhagic synovial cyst. AB - An 84-year-old man experienced right buttock pain that radiated gradually to his right lower extremity over a few months before admission. MRI revealed a space occupying intraspinal lesion that was close to the right-sided L4-L5 facet joint and an extraspinal lesion posterior to the right-sided L5 lamina. The lesions appeared as hyperintense areas on T1 weighted images and heterogeneous areas on T2 weighted images. Facet arthrography under CT guidance revealed peripheral infiltration of the contrast medium only in the intraspinal lesion at early stages; subsequently, the contrast medium diffused into the extraspinal lesion, establishing a continuity of the right L4-L5 facet joint with both lesions, which were connected through the interlaminar space. A connection between the intraspinal and extraspinal lesions at the right-sided interlaminar space at the L4-L5 level was clearly noted during intraoperative examination. Histological examination revealed a hemorrhagic synovial cyst. PMID- 22205754 TI - Bovine herpesvirus type 4 glycoprotein L is nonessential for infectivity but triggers virion endocytosis during entry. AB - The core entry machinery of mammalian herpesviruses comprises glycoprotein B (gB), gH, and gL. gH and gL form a heterodimer with a central role in viral membrane fusion. When archetypal alpha- or betaherpesviruses lack gL, gH misfolds and progeny virions are noninfectious. However, the gL of the rhadinovirus murid herpesvirus 4 (MuHV-4) is nonessential for infection. In order to define more generally what role gL plays in rhadinovirus infections, we disrupted its coding sequence in bovine herpesvirus 4 (BoHV-4). BoHV-4 lacking gL showed altered gH glycosylation and incorporated somewhat less gH into virions but remained infectious. However, gL(-) virions showed poor growth associated with an entry deficit. Moreover, a major part of their entry defect appeared to reflect impaired endocytosis, which occurs upstream of membrane fusion itself. Thus, the rhadinovirus gL may be more important for driving virion endocytosis than for incorporating gH into virions, and it is nonessential for membrane fusion. PMID- 22205755 TI - An inducible cytochrome P450 3A4-dependent vitamin D catabolic pathway. AB - Vitamin D(3) is critical for the regulation of calcium and phosphate homeostasis. In some individuals, mineral homeostasis can be disrupted by long-term therapy with certain antiepileptic drugs and the antimicrobial agent rifampin, resulting in drug-induced osteomalacia, which is attributed to vitamin D deficiency. We now report a novel CYP3A4-dependent pathway, the 4-hydroxylation of 25-hydroxyvitamin D(3) (25OHD(3)), the induction of which may contribute to drug-induced vitamin D deficiency. The metabolism of 25OHD(3) was fully characterized in vitro. CYP3A4 was the predominant source of 25OHD(3) hydroxylation by human liver microsomes, with the formation of 4beta,25-dihydroxyvitamin D(3) [4beta,25(OH)(2)D(3)] dominating (V(max)/K(m) = 0.85 ml . min(-1) . nmol enzyme(-1)). 4beta,25(OH)(2)D(3) was found in human plasma at concentrations comparable to that of 1alpha,25-dihydroxyvitamin D(3), and its formation rate in a panel of human liver microsomes was strongly correlated with CYP3A4 content and midazolam hydroxylation activity. Formation of 4beta,25(OH)(2)D(3) in primary human hepatocytes was induced by rifampin and inhibited by CYP3A4-specific inhibitors. Short-term treatment of healthy volunteers (n = 6) with rifampin selectively induced CYP3A4-dependent 4beta,25(OH)(2)D(3), but not CYP24A1-dependent 24R,25 dihydroxyvitamin D(3) formation, and altered systemic mineral homeostasis. Our results suggest that CYP3A4-dependent 25OHD(3) metabolism may play an important role in the regulation of vitamin D(3) in vivo and in the etiology of drug induced osteomalacia. PMID- 22205757 TI - Focal hand dystonia: lack of evidence for abnormality of motor representation at rest. AB - OBJECTIVE: To examine whether the corticospinal system emanating from the primary motor cortex may be organized to facilitate generation of dystonic movements. METHODS: In this cross-sectional observational study, finger movement (FM) representations were assessed in 10 patients with focal hand dystonia (FHD) and 10 matched healthy controls by transcranial magnetic stimulation during rest. Evoked finger movements of the right hand were recorded using an instrumented data glove. Patterns of finger joint movements were analyzed using cluster analysis. Principal component analysis and centers of gravity for finger movement representations and motor evoked potentials recorded from the abductor pollicis brevis and abductor digiti minimi muscles were computed. For comparison, high resolution somatosensory evoked potentials (SSEP) were recorded after electrical stimulation of the thumb (D1) or little finger (D5) in the same patients. Source reconstruction for the N20 SSEP component was performed using a dual-dipole model. RESULTS: Stimulation of the resting motor cortex did not reveal overt abnormalities in FHD, neither with respect to finger joint movement patterns nor with respect to the topologic organization of finger movements or intrinsic hand muscle representations. However, in line with previous reports, the distance between the dipole sources of D1 and D5 in the somatosensory cortex (S1) was smaller in patients with FHD, suggesting disruption of homuncular finger representations in S1. CONCLUSIONS: Our findings may imply that abnormality of motor organization in focal hand dystonia arises principally only during activation, when abnormal somatosensory representations are functionally integrated. PMID- 22205758 TI - Cost comparison between the atraumatic and cutting lumbar puncture needles. AB - OBJECTIVE: The aim of this study was to determine which type of spinal needle is preferred from a cost perspective, taking into account costs of the spinal needle and treatment of postlumbar puncture headache. METHODS: A decision-analytic model was created to determine the cost of diagnostic lumbar punctures using atraumatic and cutting needles. We assumed a health care system perspective and based the analysis on the treatment of a patient facing event probabilities derived from prior studies. The economic outcome measure was the difference in estimated costs between the 2 needles. One-way and probabilistic sensitivity analyses tested the robustness of the model. RESULTS: Lumbar puncture performed with the atraumatic needle is associated with an average cost savings of $26.07 per patient. Average total health care costs are $166.08 with the atraumatic needle, compared to $192.15 with the cutting needle. There is 94% certainty that the atraumatic needle is cost-saving compared to the cutting needle based on probabilistic sensitivity analysis. Use of the atraumatic needle over the cutting needle by neurologists alone may result in $10.4 million in cost savings to the US health care system per year. CONCLUSION: The atraumatic spinal needle is associated with an overall cost savings to the US health care system. The balance of costs and benefits favors the use of the atraumatic needle over the cutting needle for diagnostic lumbar puncture. PMID- 22205759 TI - Mapping thalamocortical network pathology in temporal lobe epilepsy. AB - OBJECTIVE: Although experimental work has provided evidence that the thalamus is a crucial relay structure in temporal lobe epilepsy (TLE), the relation of the thalamus to neocortical pathology remains unclear. To assess thalamocortical network pathology in TLE, we mapped pointwise patterns of thalamic atrophy and statistically related them to neocortical thinning. METHODS: We studied cross sectionally 36 patients with drug-resistant TLE and 19 age- and sex-matched healthy control subjects using high-resolution MRI. To localize thalamic pathology, we converted manual labels into surface meshes using the spherical harmonic description and calculated local deformations relative to a template. In addition, we measured cortical thickness by means of the constrained Laplacian anatomic segmentation using proximity algorithm. RESULTS: Compared with control subjects, patients with TLE showed ipsilateral thalamic atrophy that was located along the medial surface, encompassing anterior, medial, and posterior divisions. Unbiased analysis correlating the degree of medial thalamic atrophy with cortical thickness measurements mapped bilateral frontocentral, lateral temporal, and mesiotemporal cortices. These areas overlapped with those of cortical thinning found when patients were compared with control subjects. Thalamic atrophy intensified with a longer duration of epilepsy and was more severe in patients with a history of febrile convulsions. CONCLUSION: The degree and distribution of thalamic pathology relates to the topography and extent of neocortical atrophy, lending support to the concept that the thalamus is an important hub in the pathologic network of TLE. PMID- 22205760 TI - Recovery after spinal cord infarcts: long-term outcome in 115 patients. AB - OBJECTIVE: To investigate the long-term outcome of patients with spinal cord infarct (SCI) and identify prognostic predictors. METHODS: We reviewed 115 patients with SCI treated between 1990 and 2007. Severity of impairment was defined using the American Spinal Injury Association (ASIA) scoring. Functional outcome endpoints were ambulatory status, need for bladder catheterization, and pain. RESULTS: Mean age was 64 years; 72 (62.6%) patients were men. A total of 45% of infarcts were perioperative (69% aortic surgeries). A total of 68% reached maximal deficit within 1 hour (mean = 5 hours). Impairment at nadir was ASIA A 23%, B 26%, C 14%, and D 37%. A total of 75/93 (81%) patients studied with MRI had cord signal abnormality. At nadir, 81% required wheelchair, 86% required catheterization, and 32% had pain. At last follow-up (mean = 3 years), 23% had died. Among survivors, 42% required a wheelchair, 54% required catheterization, and 29% had pain upon last follow-up. Of 74 patients using a wheelchair at hospital dismissal, 41% were walking by final follow-up. Of 83 patients catheterized at dismissal, 33% were catheter-free at last follow-up. Older age (p < 0.0001), increased severity of impairment at nadir (p = 0.02), and peripheral vascular disease (p = 0.003) were independent risk factors for mortality. Severe impairment (ASIA A/B) at nadir predicted wheelchair use (p < 0.0001) and bladder catheterization (p < 0.0001) at last follow-up. CONCLUSIONS: Gradual improvement in not uncommon after spinal cord infarction and it may continue long after hospital dismissal. While severe impairment at nadir is the strongest predictor of poor functional outcome, meaningful recovery is also possible in a substantial minority of these patients. PMID- 22205761 TI - Thalamic astasia from isolated centromedian thalamic infarction. PMID- 22205762 TI - The good, bad, and ugly? How blood nutrient concentrations may reflect cognitive performance. PMID- 22205763 TI - Nutrient biomarker patterns, cognitive function, and MRI measures of brain aging. AB - OBJECTIVE: To examine the cross-sectional relationship between nutrient status and psychometric and imaging indices of brain health in dementia-free elders. METHODS: Thirty plasma biomarkers of diet were assayed in the Oregon Brain Aging Study cohort (n = 104). Principal component analysis constructed nutrient biomarker patterns (NBPs) and regression models assessed the relationship of these with cognitive and MRI outcomes. RESULTS: Mean age was 87 +/- 10 years and 62% of subjects were female. Two NBPs associated with more favorable cognitive and MRI measures: one high in plasma vitamins B (B1, B2, B6, folate, and B12), C, D, and E, and another high in plasma marine omega-3 fatty acids. A third pattern characterized by high trans fat was associated with less favorable cognitive function and less total cerebral brain volume. Depression attenuated the relationship between the marine omega-3 pattern and white matter hyperintensity volume. CONCLUSION: Distinct nutrient biomarker patterns detected in plasma are interpretable and account for a significant degree of variance in both cognitive function and brain volume. Objective and multivariate approaches to the study of nutrition in brain health warrant further study. These findings should be confirmed in a separate population. PMID- 22205765 TI - Accurate van der Waals coefficients from density functional theory. AB - The van der Waals interaction is a weak, long-range correlation, arising from quantum electronic charge fluctuations. This interaction affects many properties of materials. A simple and yet accurate estimate of this effect will facilitate computer simulation of complex molecular materials and drug design. Here we develop a fast approach for accurate evaluation of dynamic multipole polarizabilities and van der Waals (vdW) coefficients of all orders from the electron density and static multipole polarizabilities of each atom or other spherical object, without empirical fitting. Our dynamic polarizabilities (dipole, quadrupole, octupole, etc.) are exact in the zero- and high-frequency limits, and exact at all frequencies for a metallic sphere of uniform density. Our theory predicts dynamic multipole polarizabilities in excellent agreement with more expensive many-body methods, and yields therefrom vdW coefficients C(6), C(8), C(10) for atom pairs with a mean absolute relative error of only 3%. PMID- 22205764 TI - Air quality implications of the Deepwater Horizon oil spill. AB - During the Deepwater Horizon (DWH) oil spill, a wide range of gas and aerosol species were measured from an aircraft around, downwind, and away from the DWH site. Additional hydrocarbon measurements were made from ships in the vicinity. Aerosol particles of respirable sizes were on occasions a significant air quality issue for populated areas along the Gulf Coast. Yields of organic aerosol particles and emission factors for other atmospheric pollutants were derived for the sources from the spill, recovery, and cleanup efforts. Evaporation and subsequent secondary chemistry produced organic particulate matter with a mass yield of 8 +/- 4% of the oil mixture reaching the water surface. Approximately 4% by mass of oil burned on the surface was emitted as soot particles. These yields can be used to estimate the effects on air quality for similar events as well as for this spill at other times without these data. Whereas emission of soot from burning surface oil was large during the episodic burns, the mass flux of secondary organic aerosol to the atmosphere was substantially larger overall. We use a regional air quality model to show that some observed enhancements in organic aerosol concentration along the Gulf Coast were likely due to the DWH spill. In the presence of evaporating hydrocarbons from the oil, NO(x) emissions from the recovery and cleanup operations produced ozone. PMID- 22205767 TI - More with less Xist. PMID- 22205768 TI - The connection between selective referrals for radical cystectomy and radical prostatectomy and volume-outcome effects: an instrumental variables analysis. AB - This study delineates the roles of "selective referrals" and "practice makes perfect" in the hospital procedure volume and in-hospital mortality association for radical cystectomy and radical prostatectomy. This is a retrospective analysis of the Nationwide Inpatient Sample (years 2000-2004). All hospitalizations with primary procedure codes for radical cystectomy and radical prostatectomy were selected. The association between hospital procedure volume and in-hospital mortality was examined using generalized estimating equations and by instrumental variables approaches. There was an inverse association between hospital procedure volume and in-hospital mortality for radical cystectomy (odds ratio = 0.57; 95% confidence interval = 0.38-0.87; P < .05). Results from the 2 stages least squares regression approach suggested that receiving treatment in high-volume hospitals decreased the probability of in-hospital mortality by 0.02 points, compared with 0.01 points using the ordinary least squares regression approach. Outcomes following radical cystectomy appear to be driven by "practice makes perfect." PMID- 22205769 TI - Variation in diabetes care quality among medicare advantage plans: understanding the role of case mix. AB - This study investigates whether variation in Medicare Advantage plan performance on comprehensive diabetes care is explained by the case mix of plans. Using data on 513 Medicare Advantage plan-year observations for 2007 and 2008, the authors estimate multivariate regressions for 3 diabetes care quality measures: (1) hemoglobin screening, (2) low-density lipoprotein screening, and (3) retinal eye exam. Plan case mix is measured with the percentage of a plan's enrollees who have type 1 diabetes with and without comorbidities and the percentage of a plan's enrollees who have type 2 diabetes with and without comorbidities. Plans with a higher percentage of enrollees with type 1 diabetes with comorbidity and plans with a higher percentage of enrollees with type 2 diabetes without comorbidity have lower performance, on average. Finding evidence of a relationship between case mix and Healthcare Effectiveness Data and Information Set performance reinforces the argument for developing standardized risk adjustment or stratification methods in public reporting and pay-for-performance efforts. PMID- 22205770 TI - Commentary: establishing safety and quality as core values: a hospital road map. PMID- 22205771 TI - Differential impact of a crew resource management program according to professional specialty. AB - Adverse events occur in 3% to 16% of hospital patients, half of these during surgery and related to human error. The authors' objective was to determine the impact of a crew resource management program in collaboration with Swiss International Airlines. Participants included operating room personnel: surgeons, anesthesiologists, nurses, and technicians. Outcome measures were a 10-item questionnaire evaluating participants' satisfaction and a 32-item survey to analyze participants' learning. Nine seminars included 99 participants: 22% surgeons, 19% anesthesiologists, 29% nurses, and 30% nurse's aides/technicians. Satisfaction was very high for course organization (91%), group dynamics (74%), and teaching methods (68%). Significant improvements in learning were observed after the course in 17 out of 32 questions. Surgeons demonstrated the greatest improvement in knowledge (P = .018), specifically teamwork and safety-related issues. Less improvement was seen for all specialties in stress recognition areas. Crew resource management is valuable in improving operating room staff knowledge regarding teamwork, safety climate, and stress recognition. However, program impact varies with participant specialty. PMID- 22205772 TI - Interpreting changes in troponin--clinical judgment is essential. PMID- 22205773 TI - Commentary. PMID- 22205774 TI - Commentary. PMID- 22205775 TI - Biomarkers in cardiovascular clinical trials: past, present, future. AB - BACKGROUND: Cardiovascular (CV) clinical trials are instrumental in understanding treatment effects and offer insights into the natural progression of CV disease. Biomarkers are a critical component of patient selection, end point definition, and safety monitoring, and clinical trials provide a platform for the discovery and validation of new biomarkers that may augment the understanding of disease mechanisms, risk stratification, and/or clinical decision-making. CONTENT: We review the roles that biomarkers have played in CV clinical trials and roles that CV clinical trials have played and will continue to play in the discovery and validation of biomarkers and their implementation in clinical practice. Large biobanks containing multiple specimen types are increasingly being created from patients enrolled in clinical trials, and such biobanks, when coupled with advances in molecular techniques and bioinformatics, promise to accelerate our understanding of CV disease mechanisms and to help fuel the discovery and development of novel therapeutic targets and biomarkers of risk and treatment response. SUMMARY: The past, present, and future of biomarkers and clinical trials have been and will remain intertwined. Biomarkers were once the workhorses of patient selection and end point definition in clinical trials; more recently, clinical trials have been the proving ground for individual biomarkers. Attention to biobanking and the application of modern informatics and molecular techniques to samples collected within clinical trials will usher in the era of stratified and personalized medicine. PMID- 22205778 TI - Development of an in vitro system with human liver microsomes for phenotyping of CYP2C9 genetic polymorphisms with a mechanism-based inactivator. AB - Polymorphisms in cytochrome P450 enzymes can significantly alter the rate of drug metabolism, as well as the extent of drug-drug interactions. Individuals who homozygotically express the CYP2C9*3 allele (I359L) of CYP2C9 exhibit ~70 to 80% reductions in the oral clearance of drugs metabolized through this pathway; the reduction in clearance is ~40 to 50% for heterozygotic individuals. Although these polymorphisms result in a decrease in the activity of individual enzyme molecules, we hypothesized that decreasing the total number of active enzyme molecules in an in vitro system (CYP2C9*1/*1 human liver microsomes) by an equivalent percentage could produce the same net change in overall metabolic capacity. To this end, the selective CYP2C9 mechanism-based inactivator tienilic acid was used to reduce irreversibly the total CYP2C9 activity in human liver microsomes. Tienilic acid concentrations were effectively titrated to produce microsomal preparations with 43 and 73% less activity, mimicking the CYP2C9*1/*3 and CYP2C9*3/*3 genotypes, respectively. With probe substrates specific for other major cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), no apparent changes in the rate of metabolism were noted for these enzymes after the addition of tienilic acid, which suggests that this model is selective for CYP2C9. In lieu of using rare human liver microsomes from CYP2C9*1/*3 and CYP2C9*3/*3 individuals, a tienilic acid-created knockdown in human liver microsomes may be an appropriate in vitro model to determine CYP2C9 mediated metabolism of a given substrate, to determine whether other drug metabolizing enzymes may compensate for reduced CYP2C9 activity, and to predict the extent of genotype-dependent drug-drug interactions. PMID- 22205779 TI - Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro. AB - Cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs used in the majority of patients with solid organ transplants, generally in combination with a wide range of drugs. CsA and Tac seem not only to be substrates of CYP3A but have also been described as inhibitors of CYP3A. For CsA, in particular, inhibition of CYP3A has been suggested as the main mechanism of interactions seen clinically with various drugs. The aim of this study was to investigate the inhibitory effect and inhibition characteristics of CsA and Tac on CYP3A4 and CYP3A5 in vitro and to evaluate its clinical relevance. Inhibition by CsA and Tac was studied using midazolam as the probe substrate in coincubation and preincubation investigations using human liver microsomes (HLMs) as well as specific CYP3A4- and CYP3A5-expressing insect microsomes (Supersomes). In vitro in vivo extrapolations (IVIVEs) were performed to evaluate the clinical relevance of the inhibition. Both CsA and Tac competitively inhibited CYP3A in HLMs, showing inhibition constants (K(i)) of 0.98 and 0.61 MUM, respectively. Experiments in Supersomes revealed that Tac inhibited both CYP3A4 and CYP3A5, whereas CsA only inhibited CYP3A4. In contrast to the HLM experiments, studies in Supersomes showed inhibition by Tac to be NADPH- and time-dependent, with a 5 fold reduction in IC(50) after preincubation, supporting a time-dependent inhibition mechanism in recombinant microsomes. By application of HLM data, IVIVE estimated the area under the concentration versus time curve of midazolam to increase by 73 and 27% with CsA and Tac, respectively. The inhibitory effect was predominantly on the intestinal level, whereas hepatic intrinsic clearance seemed unaffected. PMID- 22205780 TI - Does the death rate of Hong Kong Chinese change during the lunar ghost month? AB - BACKGROUND: Most cultures believe in ghosts and for the Chinese, the seventh lunar month-the ghost month-causes particular concern. 'The gates of hell' are open for the first 14 days of the month which allows the restless ghosts of people who were hungry when they died to haunt the living. In this study, it was hypothesised that if the notion that ghosts are out to harm the living could affect the Chinese, this may be reflected in death statistics. METHODS: Because the Chinese believe death is more likely during the ghost month, male and female deaths from all causes and from four common causes of death in the first and second fortnights of the seventh lunar months of 1995-2000 were compared in Hong Kong Chinese. Deaths in two consecutive fortnights 30 days before each year's seventh lunar month were used as controls. Death data were compared using the binomial test with a null hypothesis probability of 0.5 between the first and second fortnights. RESULTS: There was no difference in male deaths between the first and second fortnights of the control and seventh lunar months. While there were no significant differences in female deaths during the control month periods, fewer women died overall in the first fortnight of the seventh lunar month (p=0.026). CONCLUSION: To protect their family, the Chinese women postpone death until after the hungry ghosts have been fed and hopefully banished forever. PMID- 22205781 TI - Bloody tears. PMID- 22205782 TI - Potentially avoidable emergency department attendance: interview study of patients' reasons for attendance. AB - OBJECTIVES: To explore the reasons for attendance at the emergency department (ED) by patients who could have been managed in an alternative service and the rate of acute admissions to one acute hospital. DESIGN: Interview study. SETTING: One acute hospital (University Hospitals of Leicester) in the East Midlands. PARTICIPANTS: 23 patients and/or their carers. METHODS: A purposive sample of patients attending the ED and the linked urgent care centre was identified and recruited. Patients in the sample were approached by a clinician and a researcher and invited to take part in an interview. Patients of different ethnicities and from different age groups, arriving at the ED via different referral routes (self referral, emergency ambulance, GP referral, out-of-hours services) and attending at different times of the day and night were included. The interviews were recorded and transcribed with the individuals' permission and analysed using the framework analysis approach. RESULTS: Patients' anxiety or concern about the presenting problem, the range of services available to the ED and the perceived efficacy of these services, patients' perceptions of access to alternative services including general practice and lack of alternative pathways were factors that influenced the decision to use the ED. CONCLUSIONS: Access to general practice, anxiety about the presenting problem, awareness and perceptions of the efficacy of the services available in the ED and lack of alternative pathways are important predictors of attendance rates. PMID- 22205783 TI - The ABC of handover: impact on shift handover in the emergency department. AB - INTRODUCTION: A study was undertaken to test the impact of a new tool for shift handover, 'The ABC of Handover', in the emergency department (ED). The impact on shift handover following implementation of this structured tool, the effect on clinical and organisational aspects of the subsequent shift and the opinions of users of this new tool are reported. METHODS: A prospective observational before and after study was performed to explore the effect of implementing 'The ABC of Handover' on clinical and organisational practice using a questionnaire. RESULTS: 41 handovers were observed before implementation of 'The ABC of Handover' and 42 were observed after. The new tool was successfully implemented and resulted in a change of practice which led to a significant increase in the operational issues mentioned at handover from a mean of 34% to a mean of 86% of essential items with the ABC method. Over the study period, middle-grade staff demonstrated improved situational awareness as they adopted proactive management of operational issues such as staffing or equipment shortages. All participants reported that 'The ABC of Handover' improved handover regardless of the seniority of the doctor giving it, and found the ABC method easy to learn. CONCLUSIONS: Successful implementation of 'The ABC of Handover' led to a change of practice in the ED. Improving handover resulted in better organisation of the shift and heightened awareness of potential patient safety issues. The ABC method provides a framework for organising the shift and preparing for events in the subsequent shift. PMID- 22205784 TI - Highly efficient method of preparing human catalytic antibody light chains and their biological characteristics. AB - The ultimate goal of catalytic antibody research is to develop new patient therapies that use the advantages offered by human catalytic antibodies. The establishment of a high-throughput method for obtaining valuable candidate catalytic antibodies must be accelerated to achieve this objective. In this study, based on our concept that we can find antibody light chains with a high probability of success if they include a serine protease-like catalytic triad composed of Ser, His, and Asp on a variable region of the antibody structure, we amplified and cloned DNAs encoding human antibody light chains from germline genes of subgroup II by seminested PCR using two primer sets designed for this purpose. Seven DNA fragments encoding light chains in 17 clones were derived from germline gene A18b, 6 DNA fragments from A3/A19, 2 DNA fragments from A17, and a clone DNA fragment from A5 and O11/O1. All light chains expressed in Escherichia coli and highly purified under nondenaturing conditions exhibited amidolytic activity against synthetic peptides. Some of the light chains exhibited unique features that suppressed the infectious activity of the rabies virus. Furthermore, the survival rate of mice in which a lethal level of the rabies virus was coinoculated directly into the brain with light chain 18 was significantly improved. In the case of humans, these results demonstrate that high-throughput selection of light chains possessing catalytic functions and specificity for a target molecule can be attained from a light-chain DNA library amplified from germline genes belonging to subgroup II. PMID- 22205785 TI - Actinomucor elegans as an emerging cause of Mucormycosis. AB - We report an invasive mucormycosis caused by Actinomucor elegans in a patient with refractory aplastic anemia. The organism was isolated from a necrotic skin lesion on the patient's left arm and demonstrated angioinvasive features on histopathology examination. In contrast to three cases described previously, we describe the first case of A. elegans invasive fungal infection in an immunocompromised patient. This report, along with the three previously reported cases, is convincing evidence that A. elegans is an emerging fungal pathogen capable of causing invasive mucormycosis in humans. PMID- 22205786 TI - Molecular and microbiological characterization of Clostridium difficile isolates from single, relapse, and reinfection cases. AB - In this study, we investigated the correlation between the microbiological characteristics of Clostridium difficile clinical isolates and the recurrence of C. difficile-associated disease (CDAD). Twenty C. difficile isolates recovered from 20 single infection cases and 53 isolates from 20 recurrent cases were analyzed by pulsed-field gel electrophoresis (PFGE) and PCR ribotyping, and the cytotoxicity, antimicrobial susceptibility, and sporulation/germination rates of the isolates were examined. Recurrent cases were divided into relapse or reinfection cases by the results of C. difficile DNA typing. Among the 20 recurrent cases, 16 cases (80%) were identified to be relapse cases caused by the initial strain and the remaining 4 cases (20%) were identified to be reinfection cases caused by different strains. All 73 isolates were susceptible to both vancomycin and metronidazole, but resistance against clindamycin, ceftriaxone, erythromycin, and ciprofloxacin was found in 87.7%, 93.2%, 87.7%, and 100% of the isolates, respectively. No correlations between DNA typing group, cytotoxicity, and sporulation rate of isolates and infection status, i.e., single, relapse, or reinfection, were observed. However, the isolates recovered from relapse cases showed a significantly higher germination rate when incubated in medium lacking the germination stimulant sodium taurocholate. These results indicate that the germination ability of C. difficile may be a potential risk factor for the recurrence of CDAD. PMID- 22205787 TI - Molecular epidemiology of avian leukosis virus subgroup J in layer flocks in China. AB - Avian leukosis virus subgroup J (ALV-J) was first isolated from meat-type chickens in 1988. No field cases of ALV-J infection or tumors in layer chickens were observed worldwide until 2004. However, layer flocks in China have experienced outbreaks of this virus in recent years. The molecular epidemiology of ALV-J strains isolated from layer flocks was investigated. The env genes of 77.8% (21/27) of the ALV-J layer isolates with a high degree of genetic variation were significantly different from the env genes of the prototype strain of ALV-J (HPRS-103) and American and Chinese strains from meat-type chickens (designated ALV-J broiler isolates). A total of 205 nucleotides were deleted from the 3' untranslated region of 89.5% (17/19) of the ALV-J layer isolates. Approximately 94.7% (16/17) of the layer isolates contained a complete E element of 146 to 149 residues. The U3 sequences of 84.2% (16/19) of the ALV-J layer isolates displayed less than 92.5% sequence homology to those of the ALV-J broiler isolates, although the transcriptional regulatory elements that are typical of avian retroviruses were highly conserved. Several unique nucleotide substitutions in the env gene, the U3 region, and the E element of most of the ALV-J layer isolates were detected. These results suggested that the env gene, E element, and U3 region in the ALV-J layer isolates have evolved rapidly and were significantly different from those of the ALV-J broiler isolates. These findings will contribute to a better understanding of the pathogenic mechanism of layer tumor diseases induced by ALV-J. PMID- 22205789 TI - Distinctive Epstein-Barr virus variants associated with benign and malignant pediatric pathologies: LMP1 sequence characterization and linkage with other viral gene polymorphisms. AB - The ubiquitous Epstein-Barr virus (EBV) is related to the development of lymphoma and is also the etiological agent for infectious mononucleosis (IM). Sequence variations in the gene encoding LMP1 have been deeply studied in different pathologies and geographic regions. Controversial results propose the existence of tumor-related variants, while others argued in favor of a geographical distribution of these variants. Reports assessing EBV variants in IM were performed in adult patients who displayed multiple variant infections. In the present study, LMP1 variants in 15 pediatric patients with IM and 20 pediatric patients with EBV-associated lymphomas from Argentina were analyzed as representatives of benign and malignant infections in children, respectively. A 3 month follow-up study of LMP1 variants in peripheral blood cells and in oral secretions of patients with IM was performed. Moreover, an integrated linkage analysis was performed with variants of EBNA1 and the promoter region of BZLF1. Similar sequence polymorphisms were detected in both pathological conditions, IM and lymphoma, but these differ from those previously described in healthy donors from Argentina and Brazil. The results suggest that certain LMP1 polymorphisms, namely, the 30-bp deletion and high copy number of the 33-bp repeats, are associated with EBV-related pathologies, either benign or malignant, instead of just being tumor related. Additionally, this is the first study to describe the Alaskan variant in EBV-related lymphomas that previously was restricted to nasopharyngeal carcinomas from North America. PMID- 22205790 TI - Peripheral blood buffy coat smear: a promising tool for diagnosis of visceral leishmaniasis. AB - Confirmative diagnosis of visceral leishmaniasis (VL) is still a challenge at the primary health care facilities in most of the rural areas of endemicity in the Indian subcontinent. Conventional methods for parasitological confirmation are risky and require skilled personnel, and hence they are unavailable to the poor people in the regions of endemicity. Buffy coat smear microscopy, as a minimally invasive, simple alternative for the parasitological diagnosis of VL, was evaluated in this prospective study. One hundred twelve VL patients were enrolled in this study. The buffy coat was separated from peripheral blood of all enrolled subjects using Histopaque-1119 solution. Leishman-stained buffy coat smears were examined for Leishmania donovani bodies, and buffy coat was also utilized for detection of parasite DNA by Leishmania nested PCR (LnPCR) for all cases. Concomitant splenic smears could be examined for L. donovani bodies in 66 cases, and the parasite load was graded on a scale of 1+ to 6+ for L. donovani-positive smears. All splenic smear-positive cases were also found to be positive by LnPCR. Of 112 enrolled VL cases, 103 (92%) were found to be positive for L. donovani bodies in buffy coat smear microscopy, which is promising as a confirmative diagnosis tool. We have also found a significant association of the buffy coat smear positivity with parasitic burden in the spleen smear. In this preliminary observation in Bangladesh, buffy coat smear microscopy has been found to be very simple, minimally invasive, and risk-free method of parasitological diagnosis of VL with a good diagnostic accuracy and potential for field use. PMID- 22205791 TI - Individual Plasmodium vivax msp1 variants within polyclonal P. vivax infections display different propensities for relapse. AB - Using a newly developed Plasmodium vivax merozoite surface protein 1 gene (Pvmsp1) heteroduplex tracking assay, we genotyped 107 P. vivax infections in individuals from Cambodia, 45 of whom developed recurrent parasitemia within 42 days. The majority of isolates were polyclonal, but recurrent parasitemias displayed fewer variants compared to initial parasitemias. Two Pvmsp1 gene variants occurred more frequently in the initial genotypes of those who developed recurrent parasitemia, representing the first time P. vivax variants associated with a higher risk of relapse have been described. PMID- 22205792 TI - Genotype 3 diversity and quantification of hepatitis E virus RNA. AB - Genotype 3 hepatitis E viruses (HEVs) are distributed across the world and are now considered to be an emerging public health concern in industrialized countries. At least 10 genotype 3 subtypes have been identified in humans and animals worldwide. It was recently reported that the sensitivities of HEV RNA assays differ greatly. We have assessed the influence of genotype 3 diversity on the performances of two HEV RNA assays: one targeting the ORF3 gene and the other targeting the ORF2 gene. We tested a panel of 5 HEV-positive reference samples of genotypes 3a, 3b, 3c, 3e, and 3f at 10-fold serial dilutions. The HEV RNA concentrations obtained with both reverse transcription (RT)-PCRs were correlated, but the RT-PCR based on ORF2 underestimated the HEV RNA concentrations. The mean [ORF3 - ORF2] difference was 1.41 log copies/ml. We also tested 34 clinical specimens of genotypes 3c (n = 15), 3e (n = 4), and 3f (n = 15), representing the most prevalent subtypes in Europe. The mean [ORF3 - ORF2] differences were 1.41 log copies/ml for genotype 3c, 0.96 log copies/ml for genotype 3e, and 0.70 log copies/ml for genotype 3f. The bias between the 2 RT PCR assays was significantly greater for genotype 3c than for genotype 3f (P = 0.007). We therefore recommend the use of an RT-PCR protocol based on ORF3 to quantify HEV RNA of genotype 3 strains. PMID- 22205793 TI - The geographic origin of Helicobacter pylori influences the association of the homB gene with gastric cancer. AB - We found that South Korean Helicobacter pylori isolates predominantly carry homB at locus B and that there is no association between the homB allele and the cagA allele or the development of gastric cancer within this population. Uniquely, several East Asian strains carried multiple copies of the hom genes. PMID- 22205794 TI - Leptotrichia bacteremia in patients receiving high-dose chemotherapy. AB - Leptotrichia spp. are anaerobic, pencil-shaped, Gram-negative rods that are part of the normal oral and intestinal human flora. Although not typically considered pathogenic, invasive Leptotrichia infections have been reported in immunosuppressed patients. A perceived rise in the identification of Leptotrichia spp. at our institution prompted a retrospective evaluation of these infections. Laboratory and clinical records were reviewed to identify Leptotrichia culture positive patients. Over a 5-year period, 68 Leptotrichia-positive specimens were identified. Of these, 21% (14/68) were identified in original samples submitted from 13 different patients at our institution, and the remainder (79% [54/68]) were unknown isolates referred from outside hospitals for molecular identification. All in-house Leptotrichia were identified from blood cultures. Only 64% (9/14) of these grew on solid media, and 5 were a part of polymicrobial bacteremias containing other enteric pathogens. All local patients were receiving chemotherapy and a majority received hematopoietic stem cell transplant (HSCT) (11/13). All had neutropenic fever with symptoms of mucositis and/or enteritis. Most of the HSCT patients (73% [8/11]) were autologous recipients hospitalized after recent high-dose chemotherapy for multiple myeloma. L. hongkongensis, a novel species, was found in the majority of myeloma cases (63% [5/8]). In conclusion, we suggest that Leptotrichia spp. may be an underappreciated cause of bacteremia, particularly in multiple myeloma patients receiving cytotoxic chemotherapy for autologous HSCT. In our cohort, these infections were associated with neutropenic fever from an enteric source, and most isolates remained sensitive to standard antibiotics. PMID- 22205795 TI - Pediococcus acidilactici endocarditis successfully treated with daptomycin. AB - This report describes the first case of persistent bacteremia with endocarditis caused by Pediococcus acidilactici in a 32-year-old male with a history of short gut syndrome following a small bowel transplant. The results showed the utility of sequencing the intergenic spacer region for species identification and successful treatment using daptomycin. PMID- 22205796 TI - First report of sepsis caused by Rhodococcus corynebacterioides in a patient with myelodysplastic syndrome. AB - We report a case of sepsis caused by Rhodococcus corynebacterioides, identified using 16S rRNA gene sequencing, in a myelodysplastic syndrome patient who had undergone hematopoietic stem cell transplantation. This is the first report of R. corynebacterioides infection in a human. PMID- 22205797 TI - Presence of genes encoding panton-valentine leukocidin is not the primary determinant of outcome in patients with hospital-acquired pneumonia due to Staphylococcus aureus. AB - The impact of Panton-Valentine leukocidin (PVL) on the outcome in Staphylococcus aureus pneumonia is controversial. We genotyped S. aureus isolates from patients with hospital-acquired pneumonia (HAP) enrolled in two registrational multinational clinical trials for the genetic elements carrying pvl and 30 other virulence genes. A total of 287 isolates (173 methicillin-resistant S. aureus [MRSA] and 114 methicillin-susceptible S. aureus [MSSA] isolates) from patients from 127 centers in 34 countries for whom clinical outcomes of cure or failure were available underwent genotyping. Of these, pvl was detected by PCR and its product confirmed in 23 isolates (8.0%) (MRSA, 18/173 isolates [10.4%]; MSSA, 5/114 isolates [4.4%]). The presence of pvl was not associated with a higher risk for clinical failure (4/23 [17.4%] versus 48/264 [18.2%]; P = 1.00) or mortality. These findings persisted after adjustment for multiple potential confounding variables. No significant associations between clinical outcome and (i) presence of any of the 30 other virulence genes tested, (ii) presence of specific bacterial clone, (iii) levels of alpha-hemolysin, or (iv) delta-hemolysin production were identified. This study suggests that neither pvl presence nor in vitro level of alpha-hemolysin production is the primary determinant of outcome among patients with HAP caused by S. aureus. PMID- 22205798 TI - New species of Madurella, causative agents of black-grain mycetoma. AB - A new species of nonsporulating fungus, isolated in a case of black-grain mycetoma in Sudan, is described as Madurella fahalii. The species is characterized by phenotypic and molecular criteria. Multigene phylogenies based on the ribosomal DNA (rDNA) internal transcribed spacer (ITS), the partial beta tubulin gene (BT2), and the RNA polymerase II subunit 2 gene (RPB2) indicate that M. fahalii is closely related to Madurella mycetomatis and M. pseudomycetomatis; the latter name is validated according to the rules of botanical nomenclature. Madurella ikedae was found to be synonymous with M. mycetomatis. An isolate from Indonesia was found to be different from all known species based on multilocus analysis and is described as Madurella tropicana. Madurella is nested within the order Sordariales, with Chaetomium as its nearest neighbor. Madurella fahalii has a relatively low optimum growth temperature (30 degrees C) and is less susceptible to the azoles than other Madurella species, with voriconazole and posaconazole MICs of 1 MUg/ml, a ketoconazole MIC of 2 MUg/ml, and an itraconazole MIC of >16 MUg/ml. Since eumycetoma is still treated only with azoles, correct species identification is important for the optimal choice of antifungal therapy. PMID- 22205799 TI - No evidence for an association between persistent measles virus infection and otosclerosis among patients with otosclerosis in Japan. AB - Otosclerosis, which is characterized by disordered bone remodeling, occurs exclusively in the human temporal bone. The etiology of the disease is unknown, but a popular hypothesis is that it is caused by persistent measles virus (MV) infection. Paramyxovirus-like filamentous structures were found in otosclerotic lesions of stapes footplates from patients with otosclerosis. Although MV RNAs have been detected in otosclerotic samples by using reverse transcription-PCR, no complete MV mRNA sequence has been reported, nor has infectious virus been isolated from clinical samples. Furthermore, one study failed to obtain evidence of MV infection in otosclerotic bone samples. In this study, we tested, by three different protocols, for the presence of MV in clinical samples from patients with otosclerosis in Japan. We used a highly sensitive reverse transcription quantitative PCR method which is able to detect viral mRNA in cells infected with MV at around one infectious unit per well. We obtained no evidence of MV infection in bone samples, primary cell cultures derived from stapes bones, or MV susceptible cell lines (Vero/hSLAM and II-18 cells) cocultured with bone samples or primary cell cultures derived from them. Thus, our results do not support the hypothesis that persistent MV infection is involved in the pathoetiology of otosclerosis. PMID- 22205800 TI - Distribution of Mycobacterium leprae strains among cases in a rural and urban population of Maharashtra, India. AB - The elimination of leprosy continues to be a challenge, with the disease remaining endemic in several countries. India accounts for the highest number of cases, and the identification of child cases indicates recent transmission. Genetic markers, like variable-number tandem repeats (VNTRs) and single nucleotide polymorphisms (SNPs), have been identified to track transmission of the pathogen Mycobacterium leprae. They were used to describe M. leprae strains detected in 48 skin biopsy specimens from leprosy patients in the state of Maharashtra in western India in rural and urban areas near Mumbai. Ninety-three percent of strains across both settings belonged to the SNP type 1D, with three of SNP type 1B being identified in patients living within 3 km of each other. The VNTR profiles of the Maharashtra strains clustered with those from Southern India reported previously and a few other Asian strains, indicating that the Indian strains are genotypically conserved at the level of many VNTR loci. Taken together, SNP and VNTR markers are sufficiently reliable and suitable for both localized and broad geographical genotype associations. VNTR profiles of additional cases may aid in distinguishing the SNP type 1B and 1D strains. PMID- 22205801 TI - Combination of single nucleotide polymorphism and variable-number tandem repeats for genotyping a homogenous population of Mycobacterium tuberculosis Beijing strains in China. AB - The standard 15- and 24-locus variable-number tandem repeat (VNTR) genotyping methods have demonstrated adequate discriminatory power and a small homoplasy effect for tracing tuberculosis (TB) transmission and predicting Mycobacterium tuberculosis lineages in European and North American countries. However, its validity for the definition of transmission in homogenous M. tuberculosis populations in settings with high TB burdens has been questioned. Here, we genotyped a population-based collection of 191 Beijing strains based on standard 15-locus VNTR (VNTR-15) and 8 single nucleotide polymorphisms (SNPs) in Shanghai, China. Limited discriminatory power and high rates of VNTR homoplasy were observed in the homogenous population of evolutionarily "modern" Beijing strains. Additional typing of three hypervariable loci (VNTR3820, VNTR4120, and VNTR3232) was performed for VNTR-15-based clusters. High variations of hypervariable alleles were observed in clusters with inconsistent SNP sublineages. We concluded that SNPs and hypervariable VNTR loci are helpful to enhance the discriminatory power and decrease the VNTR homoplasy effect for defining clusters. We recommend the combination of standard VNTR-15 and SNPs as first-line typing methods and the hypervariable loci for second-line typing of clustered strains for molecular epidemiology studies of homogenous M. tuberculosis populations. PMID- 22205802 TI - Probiotic mechanism of Lactobacillus gasseri OLL2716 strain against Helicobacter pylori. PMID- 22205803 TI - Detection of negative-sense RNA in packaged hepatitis E virions by use of an improved strand-specific reverse transcription-PCR method. AB - Current hepatitis E virus (HEV) negative-sense RNA detection assays have the drawback of false positivity. cDNA synthesis using tag-based primer and Superscript RT-III followed by exonuclease I treatment increased the specificity. Assays could detect as few as 10 copies of negative-sense RNA and could be used in detecting low levels of HEV replication in cells. Virus particles in stool samples of hepatitis E patients showed encapsidation of negative-sense RNA along with HEV genomic RNA. PMID- 22205804 TI - Novel real-time simultaneous amplification and testing method to accurately and rapidly detect Mycobacterium tuberculosis complex. AB - The aim of this study was to establish and evaluate a simultaneous amplification and testing method for detection of the Mycobacterium tuberculosis complex (SAT TB assay) in clinical specimens by using isothermal RNA amplification and real time fluorescence detection. In the SAT-TB assay, a 170-bp M. tuberculosis 16S rRNA fragment is reverse transcribed to DNA by use of Moloney murine leukemia virus (M-MLV) reverse transcriptase, using specific primers incorporating the T7 promoter sequence, and undergoes successive cycles of amplification using T7 RNA polymerase. Using a real-time PCR instrument, hybridization of an internal 6 carboxyfluorescein-4-[4-(dimethylamino)phenylazo] benzoic acid N-succinimidyl ester (FAM-DABCYL)-labeled fluorescent probe can be used to detect RNA amplification. The SAT-TB assay takes less than 1.5 h to perform, and the sensitivity of the assay for detection of M. tuberculosis H37Rv is 100 CFU/ml. The TB probe has no cross-reactivity with nontuberculous mycobacteria or other common respiratory tract pathogens. For 253 pulmonary tuberculosis (PTB) specimens and 134 non-TB specimens, the SAT-TB results correlated with 95.6% (370/387 specimens) of the Bactec MGIT 960 culture assay results. The sensitivity, specificity, and positive and negative predictive values of the SAT TB test for the diagnosis of PTB were 67.6%, 100%, 100%, and 62.0%, respectively, compared to 61.7%, 100%, 100%, and 58.0% for Bactec MGIT 960 culture. For PTB diagnosis, the sensitivities of the SAT-TB and Bactec MGIT 960 culture methods were 97.6% and 95.9%, respectively, for smear-positive specimens and 39.2% and 30.2%, respectively, for smear-negative specimens. In conclusion, the SAT-TB assay is a novel, simple test with a high specificity which may enhance the detection rate of TB. It is therefore a promising tool for rapid diagnosis of M. tuberculosis infection in clinical microbiology laboratories. PMID- 22205805 TI - Differences in methicillin-resistant Staphylococcus aureus strains isolated from pediatric and adult patients from hospitals in a large county in California. AB - Studies of U.S. epidemics of community- and health care-associated methicillin resistant Staphylococcus aureus (MRSA) suggested differences in MRSA strains in adults and those in children. Comprehensive population-based studies exploring these differences are lacking. We conducted a prospective cohort study of inpatients in Orange County, CA, collecting clinical MRSA isolates from 30 of 31 Orange County hospitals, to characterize differences in MRSA strains isolated from children compared to those isolated from adults. All isolates were characterized by spa typing. We collected 1,124 MRSA isolates from adults and 159 from children. Annual Orange County population estimates of MRSA inpatient clinical cultures were 119/100,000 adults and 22/100,000 children. spa types t008, t242, and t002 accounted for 83% of all isolates. The distribution of these three spa types among adults was significantly different from that among children (chi(2) = 52.29; P < 0.001). Forty-one percent of adult isolates were of t008 (USA300), compared to 69% of pediatric isolates. In multivariate analyses, specimens from pediatric patients, wounds, non-intensive care unit (ICU) wards, and hospitals with a high proportion of Medicaid-insured patients were significantly associated with the detection of t008 strains. While community- and health care-associated MRSA reservoirs have begun to merge, significant differences remain in pediatric and adult patient populations. Community associated MRSA spa type t008 is significantly more common in pediatric patients. PMID- 22205806 TI - Thymidine auxotrophic Staphylococcus aureus small-colony variant endocarditis and left ventricular assist device infection. AB - We describe a thymidine-dependent small-colony variant of Staphylococcus aureus associated with left ventricular assist device infection and prosthetic valve and pacemaker endocarditis. PMID- 22205807 TI - Severity of human rhinovirus infection in immunocompromised adults is similar to that of 2009 H1N1 influenza. AB - This retrospective chart review of patients at a tertiary referral center compares characteristics and clinical features of patients diagnosed with human rhinovirus (HRV) infection to those of patients with 2009 H1N1 influenza A (pH1N1) during the pandemic respiratory season of 2009 to 2010. Hospital admission rates, intensive care unit (ICU) admissions, and mortality were not statistically different between the HRV and pH1N1 groups; however, more patients in the HRV group were considered immunocompromised. PMID- 22205808 TI - Molecular diagnosis of subcutaneous Pythium insidiosum infection by use of PCR screening and DNA sequencing. AB - Pythium insidiosum is an emerging human pathogen classified among brown algae and diatoms that can cause significant morbidity and mortality in otherwise healthy individuals. Here we describe a pediatric patient with pythiosis acquired in the southern United States, diagnosed by molecular screening and DNA sequencing of internal transcribed spacer region 1. PMID- 22205809 TI - Genetic diversity and drug susceptibility of Mycobacterium tuberculosis isolates from Zunyi, one of the highest-incidence-rate areas in China. AB - Mycobacterium tuberculosis isolates from Zunyi were found more diversified but clustered less frequently to the Beijing family compared to isolates from other areas of China. These observations, on top of the fact that the Zunyi area has a high prevalence of multidrug-resistant tuberculosis (MDR-TB), support the notion that Beijing family isolates may not be linked to MDR-TB. PMID- 22205810 TI - Evaluation of swabs, transport media, and specimen transport conditions for optimal detection of viruses by PCR. AB - Depletion of swabs and viral transport medium during epidemics may prompt the use of unvalidated alternatives. Swabs collected and transported dry or in saline were compared to commercially available swab/medium combinations for PCR detection of influenza, enterovirus, herpes simplex virus, and adenovirus. Each was detected at an ambient temperature (22 degrees C) and 4 degrees C for 7 days. Detection of influenza on dry or saline swabs is important because of its capacity to cause outbreaks involving large numbers of cases. PMID- 22205811 TI - Recurrent urinary infection with Bifidobacterium scardovii. AB - Bifidobacterium species are difficult to identify and may be underreported or not recovered by many laboratories because of their slow growth. We emphasize the importance of the Gram stain in urine samples and the addition of enriched media and enhanced atmosphere over time for urine cultures with pyuria. This is the first report of a Bifidobacterium scardovii recurrent urinary infection in an elderly woman. PMID- 22205812 TI - Matrix-assisted laser desorption ionization-time of flight mass spectrometry based functional assay for rapid detection of resistance against beta-lactam antibiotics. AB - Resistance against beta-lactam antibiotics is a growing challenge for managing severe bacterial infections. The rapid and cost-efficient determination of beta lactam resistance is an important prerequisite for the choice of an adequate antibiotic therapy. beta-Lactam resistance is based mainly on the expression/overexpression of beta-lactamases, which destroy the central beta lactam ring of these drugs by hydrolysis. Hydrolysis corresponds to a mass shift of +18 Da, which can be easily detected by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Therefore, a MALDI TOF MS-based assay was set up to investigate different enterobacteria for resistance against different beta-lactam antibiotics: ampicillin, piperacillin, cefotaxime, ceftazidime, ertapenem, imipenem, and meropenem. beta-Lactamases are enzymes that have a high turnover rate. Therefore, hydrolysis can be detected by MALDI-TOF MS already after a few hours of incubation of the bacteria to be tested with the given antibiotic. The comparison of the MS-derived data with the data from the routine procedure revealed identical classification of the bacteria according to sensitivity and resistance. The MALDI-TOF MS-based assay delivers the results on the same day. The approved routine procedures require at least an additional overnight incubation. PMID- 22205813 TI - Genetic relationships of phage types and single nucleotide polymorphism typing of Salmonella enterica Serovar Typhimurium. AB - Salmonella enterica serovar Typhimurium is one of the leading causes of gastroenteritis in humans. Phage typing has been used for the epidemiological surveillance of S. Typhimurium for over 4 decades. However, knowledge of the evolutionary relationships between phage types is very limited. In this study, we used single nucleotide polymorphisms (SNPs) as molecular markers to determine the relationships between common S. Typhimurium phage types. Forty-four SNPs, including 24 identified in a previous study and 20 from 6 available whole-genome sequences, were used to analyze 215 S. Typhimurium isolates belonging to 45 phage types. Altogether, 215 isolates and 6 genome strains were differentiated into 33 SNP profiles and four distinctive phylogenetic clusters. Fourteen phage types, including DT9, one of the most common phage types in Australia, were differentiated into multiple SNP profiles. These SNP profiles were distributed into different phylogenetic clusters, indicating that they have arisen independently multiple times. This finding suggests that phage typing may not be useful for long-term epidemiological studies over long periods (years) and diverse localities (different countries or continents). SNP typing provided a discriminative power similar to that of phage typing. However, 12 SNP profiles contained more than one phage type, and more SNPs would be needed for further differentiation. SNP typing should be considered as a replacement for phage typing for the identification of S. Typhimurium strains. PMID- 22205814 TI - Comprehensive multicenter evaluation of a new line probe assay kit for identification of Mycobacterium species and detection of drug-resistant Mycobacterium tuberculosis. AB - We evaluated a new line probe assay (LiPA) kit to identify Mycobacterium species and to detect mutations related to drug resistance in Mycobacterium tuberculosis. A total of 554 clinical isolates of Mycobacterium tuberculosis (n = 316), Mycobacterium avium (n = 71), Mycobacterium intracellulare (n = 51), Mycobacterium kansasii (n = 54), and other Mycobacterium species (n = 62) were tested with the LiPA kit in six hospitals. The LiPA kit was also used to directly test 163 sputum specimens. The results of LiPA identification of Mycobacterium species in clinical isolates were almost identical to those of conventional methods. Compared with standard drug susceptibility testing results for the clinical isolates, LiPA showed a sensitivity and specificity of 98.9% and 97.3%, respectively, for detecting rifampin (RIF)-resistant clinical isolates; 90.6% and 100%, respectively, for isoniazid (INH) resistance; 89.7% and 96.0%, respectively, for pyrazinamide (PZA) resistance; and 93.0% and 100%, respectively, for levofloxacin (LVX) resistance. The LiPA kit could detect target species directly in sputum specimens, with a sensitivity of 85.6%. Its sensitivity and specificity for detecting RIF-, PZA-, and LVX-resistant isolates in the sputum specimens were both 100%, and those for detecting INH-resistant isolates were 75.0% and 92.9%, respectively. The kit was able to identify mycobacterial bacilli at the species level, as well as drug-resistant phenotypes, with a high sensitivity and specificity. PMID- 22205815 TI - Do differences in Panton-Valentine leukocidin production among international methicillin-resistant Staphylococcus aureus clones affect disease presentation and severity? AB - Panton-Valentine leukocidin (PVL) production by methicillin-resistant Staphylococcus aureus (MRSA) was determined in vitro using the enzyme-linked immunosorbent assay (ELISA), and associations with clinical presentation and bacterial genetic characteristics were examined. PVL production ranged from 0.02 to 4.865 MUg/ml and correlated with a multilocus sequence type (MLST) clonal complex associated with specific PVL phage types. A relationship between PVL production and clinical presentation or patient demographics could not be demonstrated. PMID- 22205816 TI - Use of illumina deep sequencing technology to differentiate hepatitis C virus variants. AB - Hepatitis C virus (HCV) is a positive-strand enveloped RNA virus that shows diverse viral populations even in one individual. Though Sanger sequencing has been used to determine viral sequences, deep sequencing technologies are much faster and can perform large-scale sequencing. We demonstrate the successful use of Illumina deep sequencing technology and subsequent analyses to determine the genetic variants and amino acid substitutions in both treatment-naive (patient 1) and treatment-experienced (patient 7) isolates from HCV-infected patients. As a result, almost the full nucleotide sequence of HCV was detectable for patients 1 and 7. The reads were mapped to the HCV reference sequence. The coverage was 99.8% and the average depth was 69.5* for patient 7, with values of 99.4% (coverage) and 51.1* (average depth) for patient 1. In patient 7, amino acid (aa) 70 in the core region showed arginine, with methionine at aa 91, by Sanger sequencing. Major variants showed the same amino acid sequence, but minor variants were detectable in 18% (6/34 sequences) of sequences, with replacement of methionine by leucine at aa 91. In NS3, 8 amino acid positions showed mixed variants (T72T/I, K213K/R, G237G/S, P264P/S/A, S297S/A, A358A/T, S457S/C, and I615I/M) in patient 7. In patient 1, 3 amino acid positions showed mixed variants (L14L/F/V, S61S/A, and I586T/I). In conclusion, deep sequencing technologies are powerful tools for obtaining more profound insight into the dynamics of variants in the HCV quasispecies in human serum. PMID- 22205817 TI - Genes encoding OXA-134-like enzymes are found in Acinetobacter lwoffii and A. schindleri and can be used for identification. AB - bla(OXA-134) genes and variants were sought in 21 species of Acinetobacter and found in A. lwoffii, genomic species 9 (regarded as synonyms), and A. schindleri. Sequencing revealed a 9-bp deletion in the gene in the type strain of genomic species 9 (ATCC 9957) relative to the gene in the type strain of A. lwoffii (ATCC 15309). Primers based on the gene without the deletion gave specific amplification of 29 of 30 clinical isolates of A. lwoffii/genomic species 9. PMID- 22205818 TI - Cross-reactivity of Fusarium spp. in the Aspergillus Galactomannan enzyme-linked immunosorbent assay. AB - Nine of 11 hematological patients with disseminated/deep-seated Fusarium infection tested at least twice for Aspergillus galactomannan (GM) had repeated positive results in the absence of Aspergillus isolation in culture. The centrifuged supernatants of 12 Fusarium isolates were tested by a GM enzyme linked immunosorbent assay (EIA). All the isolates produced positive reactions when tested undiluted. These results show cross-reactivity of Fusarium spp. with Aspergillus GM that may constitute a drawback with respect to the specificity of the Platelia EIA. PMID- 22205819 TI - Legionella pneumophila sequence type 1/Paris pulsotype subtyping by spoligotyping. AB - Endemic strains of Legionella pneumophila sequence type 1 (ST1), in particular the ST1/Paris pulsotype, are dispersed worldwide and represent about 10% of culture-proven clinical cases of Legionnaires' disease in France. The high rate of isolation of this strain from both clinical and environmental samples makes identification of the source of infection difficult during epidemiological investigations. The full-length genome sequence of this strain was recently determined, and it revealed the presence of a CRISPR/cas complex. The aim of this study was to develop and evaluate a spoligotyping tool based on the diversity of this CRISPR locus that would allow the accurate subtyping of the L. pneumophila serogroup 1 ST1/Paris pulsotype. The CRISPR loci of 28 L. pneumophila ST1/Paris pulsotype isolates were sequenced, and 42 different spacers regions were characterized. A membrane-based spoligotyping method was developed and used to determine the subtypes of 406 L. pneumophila isolates, including 233 with the ST1/Paris pulsotype profile that were collected in France from 2000 to 2011. A total of 46 different spoligotypes were detected, and 41 of these were specifically identified in the ST1/Paris pulsotype isolates. In 27 of 33 epidemiological investigations, the environmental source of contamination was confirmed by comparing spoligotypes of clinical isolates with those of environmental isolates. With an index of discrimination of 79.72% (95% confidence interval, 75.82 to 83.63), spoligotyping of the L. pneumophila ST1/Paris pulsotype has the potential to be a useful complementary genotyping tool for discriminating isolates with undistinguishable pulsed-field gel electrophoresis (PFGE) and ST genotypes, which could help to identify environmental sources of infection. PMID- 22205820 TI - Pooling nasopharyngeal/throat swab specimens to increase testing capacity for influenza viruses by PCR. AB - Real-time PCR methodology can be applied to rapidly and accurately detect influenza viruses. During times of surge testing or enhanced pandemic surveillance, public health laboratories (PHLs) may experience overwhelming demand for testing, even while the prevalence of positive specimens remains low. To improve laboratory capacity and testing efficiency during surges, we evaluated whether nasopharyngeal (NP)/throat swab specimens can be pooled and tested for the presence of the 2009 H1N1 influenza virus without a reduction in sensitivity. Pools of 10 specimens were extracted and concentrated upon elution on the MagNA Pure LC instrument, and real-time PCR was performed on the Applied Biosystems 7500 Fast platform, using the CDC swine influenza virus real-time RT-PCR detection panel (rRT-PCR swine flu panel). Specimens in positive pools were singly re-extracted and retested by PCR to identify individual positive samples. Initial studies showed that spiking a pool of nine negative specimens (100 MUl each) or 900 MUl of virus transport medium with 100 MUl of a positive clinical specimen caused no loss of sensitivity by rRT-PCR testing. Pools containing either multiple positive specimens or specimens positive for other respiratory viruses also showed no negative effect on crossing threshold (C(T)) values. To test the robustness of the pooling protocol, a panel of 50 blinded samples was sent to three PHLs and tested in five pools of 10. All PHLs correctly identified the positive specimens. This study demonstrates the feasibility of using a pooling strategy to increase capacity and conserve resources during surge testing and periods of enhanced influenza surveillance when the prevalence is low. PMID- 22205821 TI - Evidence of diversity among epidemiologically related carbapenemase-producing Acinetobacter baumannii strains belonging to international clonal lineage II. AB - Carbapenem-resistant Acinetobacter baumannii strains belonging to international clonal lineage II (ICL-II) have become predominant in intensive care units (ICUs) throughout Italy. Between 2005 and 2009, the carbapenem-hydrolyzing class D beta lactamase (CHDL) bla(OXA-23) gene became more prevalent than bla(OXA-58) among epidemic ICL-II strains showing extensive genetic similarity. These findings posed the question of whether CHDL gene replacement occurred in the homogeneous ICL-II population or a new OXA-23 clone(s) emerged and spread in ICUs. In this study, the changes in the ICL-II A. baumannii population and CHDL gene carriage were investigated in 30 genetically related isolates collected during the bla(OXA 58)-to-bla(OXA-23) transition period. Pulsotyping, randomly amplified polymorphic DNA (RAPD) analysis, and multilocus sequence typing (MLST) results were combined with multilocus variable-number tandem-repeat (VNTR) analysis (MLVA-8), siderotyping, and plasmid profiling to improve genotype-based discrimination between isolates. Pulsotyping, RAPD analysis, and MLST clustered isolates into a single type. MLVA-8 identified 19 types that clustered into three complexes. All OXA-23-producing isolates formed a single complex, while OXA-58 producers were split into two complexes. Southern blot analysis of the physical localization and genetic context of the CHDL genes showed that bla(OXA-58) was invariably located on plasmids, while bla(OXA-23) was present within Tn2006 on the chromosome or both the chromosome and plasmids. These data indicate that the apparently homogeneous population of CHDL-producing ICL-II strains was composed of several independent strains and that, between 2005 and 2009, distinct OXA-23 producers displaced the preexisting OXA-58 producers. Thus, MLVA-8 appears to be a suitable tool not only for investigating A. baumannii population structure but also for high-resolution epidemiological typing. PMID- 22205822 TI - Characterization of isolates of Salmonella enterica serovar Stanley, a serovar endemic to Asia and associated with travel. AB - Salmonella enterica serovar Stanley (S. Stanley) is a common serovar in Southeast Asia and was the second most common serovar implicated in human salmonellosis in Thailand in the years 2002 to 2007. In contrast, this serovar is relatively uncommon in Europe. The objective of this study was to characterize a collection of S. Stanley strains isolated from Thai (n = 62), Danish (n = 39), and French (n = 24) patients to gain a broader understanding of the genetic diversity, population dynamics, and susceptibility to antimicrobials. All isolates were characterized by pulsed-field gel electrophoresis and antimicrobial susceptibility testing. The molecular mechanisms of resistance to extended spectrum cephalosporins and plasmid-mediated resistance to quinolones were characterized by PCR and sequencing. Plasmid profiling, replicon typing, and microarray analysis were used to characterize the genetic mechanisms of antimicrobial resistance in 10 extended-spectrum cephalosporinase-producing isolates. Considerable genetic diversity was observed among the isolates characterized with 91 unique XbaI pulsed-field gel electrophoresis (PFGE) patterns, including 17 distinct clusters consisting of two to seven indistinguishable isolates. We found some of the S. Stanley isolates isolated from patients in Europe were acquired during travel to Southeast Asia, including Thailand. The presence of multiple plasmid lineages carrying the extended spectrum cephalosporinase-encoding bla(CMY-2) gene in S. Stanley isolates from the central part of Thailand was confirmed. Our results emphasize that Thai authorities, as well as authorities in other countries lacking prudent use of antimicrobials, should improve the ongoing efforts to regulate antimicrobial use in agriculture and in clinical settings to limit the spread of multidrug resistant Salmonella isolates and plasmids among humans and pigs in Thailand and abroad. PMID- 22205823 TI - Application of a 16S rRNA PCR-high-resolution melt analysis assay for rapid detection of Salmonella Bacteremia. AB - Current culture and phenotypic protocols for diagnosing Salmonella infections can be time-consuming. Here, we describe the application of a 16S rRNA PCR coupled to high-resolution melt analysis (HRMA) for species and serotype identification within 6 h of blood sample collection from a patient with Salmonella enterica serotype Enteritidis bacteremia. PMID- 22205824 TI - "Candidatus Neoehrlichia mikurensis," Anaplasma phagocytophilum, and lyme disease spirochetes in questing european vector ticks and in feeding ticks removed from people. AB - To estimate the likelihood of people coming into contact with the recently described tick-borne agent "Candidatus Neoehrlichia mikurensis," we compared its prevalence to those of Lyme disease spirochetes and Anaplasma phagocytophilum in questing adult Ixodes ricinus ticks collected in various Central European sites and examined ticks, which had been removed from people, for the presence of these pathogens. Whereas spirochetes infected questing adult ticks most frequently (22.3%), fewer than a third as many ticks were infected by "Ca. Neoehrlichia mikurensis" (6.2%), and about a sixth harbored A. phagocytophilum (3.9%). On average, every twelfth encounter of a person with an I. ricinus tick (8.1%) may bear the risk of acquiring "Ca. Neoehrlichia mikurensis." Although a fifth of the people (20%) had removed at least one tick infected by "Ca. Neoehrlichia mikurensis," none displayed symptoms described for this pathogen, suggesting that its transmission may not be immediate and/or that immunocompetent individuals may not be affected. Because immunosuppressed patients may be at a particular risk of developing symptoms, it should be considered that "Ca. Neoehrlichia mikurensis" appears to be the second most common pathogen in I. ricinus ticks. In our survey, only Borrelia afzelii appears to infect Central European vector ticks more frequently. PMID- 22205825 TI - Cell-associated hemolysis induced by Helicobacter pylori is mediated by phospholipases with mitogen-activated protein kinase-activating properties. AB - Pathogenic Helicobacter pylori strains can selectively activate epithelial mitogen-activated protein kinase (MAPK) signaling pathways linked with disease. We now demonstrate that H. pylori-induced hemolysis is strain specific and is mediated by phospholipases PldA1 and PldD. Inactivation of PldD inhibited activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), indicating that H. pylori hemolytic phospholipases also harbor MAPK-activating properties. PMID- 22205826 TI - Photochemical Preparation of a Novel Low Molecular Weight Heparin. AB - Commercial low molecular weight heparins (LMWHs) are prepared by several methods including peroxidative cleavage, nitrous acid cleavage, chemical beta elimination, and enzymatic beta-elimination. The disadvantages of these methods are that strong reaction conditions or harsh chemicals are used and these can result in decomposition or modification of saccharide units within the polysaccharide backbone. These side-reactions reduce product quality and yield. Here we show the partial photolysis of unfractionated heparin can be performed in distillated water using titanium dioxide (TiO(2)). TiO(2) is a catalyst that can be easily removed by centrifugation or filtration after the photochemical reaction takes place, resulting in highly pure products. The anticoagulant activity of photodegraded LMWH (pLMWH) is comparable to the most common commercially available LMWHs (i.e., Enoxaparin and Dalteparin). (1)H NMR spectra obtained show that pLMWH maintains the same core structure as unfractionated heparin. This photochemical reaction was investigated using liquid chromatography/mass spectrometry (LC/MS) and unlike other processes commonly used to prepare LMWHs, photochemically preparation affords polysaccharide chains of reduced length having both odd and even of saccharide residues. PMID- 22205827 TI - Barcoding allows immediate downloading of PowerPoint presentations by smart phones. PMID- 22205828 TI - Trabeculectomy with double low dose of mitomycin C - two years of follow-up. AB - PURPOSE: To evaluate the efficacy and the safety of a surgical technique in which classic trabeculectomy ab externo is performed with a double application of low dose mitomycin C (MMC) in uncontrolled open-angle glaucoma (OAG) patients. METHOD: A consecutive series of 43 white patients (43 eyes) with uncontrolled primary OAG underwent trabeculectomy surgery. A double application of MMC (0.1%) was performed: the first under the Tenon's capsule for 3 minutes, and the second below the scleral flap for 1 or 2 minutes, according to the risk factors. Complete success was defined as intraocular pressure (IOP) <14 mmHg without any additional glaucoma surgery or medication. Qualified success was defined as IOP <14 mmHg with additional needling revision. RESULTS: Mean preoperative IOP was 29.9 mmHg (SD 3.8) for all eyes evaluated. At 1 day postoperative, mean IOP was 6.7 mmHg (SD 1.26). At the end of the first 2 weeks postoperative, mean IOP was 8.6 mmHg (SD 1.7), at 12 months mean IOP was 11.3 mmHg (SD 1.4; P < 0.0001) and at 24 months mean IOP was 11.4 mmHg (SD 1.5; P < 0.0001). At 3 months, two eyes (5.4%) underwent needling of the bleb for cystic blebs formation. CONCLUSION: In this study we presented the results after 2 years of follow-up of OAG undergoing trabeculectomy with dual administration of MMC (0.1 mg/mL). After 24 months, complete success was achieved in 93% of patients and a qualified success in 100% of patients. PMID- 22205830 TI - Asymmetric severity of diabetic retinopathy in Waardenburg syndrome. AB - A 30-year-old female patient was referred to our institution due to vitreous hemorrhage. Best corrected visual acuity of her right and left eyes at her initial visit was 10/20 and 20/20, respectively. Although hypochromic iris was observed in the superior iris between the 10 and 2 o'clock positions in her right eye, her entire left eye exhibited hypochromic iris. Hypopigmentation of the fundus was seen in the superior part of her right eye. This eye also had a huge neovascularization on the optic disc that was 7 discs in diameter. Conversely, her left fundi showed hypopigmentation of the fundus in the entire region of the left eye, and dot hemorrhages were observed all over the left fundi, although no neovascularization could be seen microscopically. Fluorescein angiography showed a huge neovascularization in the right eye and a tiny neovascularization in the left eye. Gene analysis revealed the presence of the PAX3 gene homeobox domain mutation, which led to her being diagnosed as Waardenburg syndrome type 1. Magnetic resonance angiography showed there was no obstructive region at either of the internal carotid arteries and ophthalmic arteries. The severity of the diabetic retinopathy appeared to be correlated with the degree of hypopigmentation in the posterior fundus. We speculate that hypopigmentation of the fundus in Waardenburg syndrome may be responsible for the reduction in retinal metabolism, which led to a reduction in oxygen consumption and prevented further aggravation of the diabetic retinopathy. Only laser treatments using short wavelengths was effective in this case. While the extinction coefficient for hemoglobin when using green light is higher than when using yellow light, the differences between these wavelengths tend to disappear when oxygenated hemoglobin is present. To the best of the authors' knowledge, this is the first case report of a patient with Waardenburg syndrome and diabetic retinopathy. PMID- 22205829 TI - Correlation between contrast sensitivity and higher-order aberration based on pupil diameter after cataract surgery. AB - BACKGROUND: The purpose of this study was to evaluate the correlation between contrast sensitivity and calculated higher-order aberrations based on individual natural pupil diameter after cataract surgery. METHODS: This prospective study included 120 eyes from 92 patients who were randomized to receive one of four lenses, including three aspheric lenses (Acrysof SN60WF, Tecnis ZA9000, and Hoya Py60AD) and one spherical lens (Acrysof SN60AT). Contrast sensitivity, higher order aberrations of the whole eye, and pupil diameter under photopic and mesopic conditions were measured 1 month postoperatively. Higher-order aberrations were decomposed into Zernike coefficients, calculated according to individual pupil diameter. The correlation between higher-order aberrations and contrast sensitivity was evaluated. RESULTS: There were no significant differences in contrast sensitivity function between the four types of lenses under photopic conditions. However, the contrast sensitivity function and area under log contrast sensitivity function in the aspheric lenses were significantly better than in the spherical lens under mesopic conditions. Under mesopic conditions, spherical aberration in eyes with aspheric lenses was significantly lower than in eyes with spherical lenses (P < 0.05). Under photopic conditions, coma aberration had a significant negative correlation with contrast sensitivity at 12 cycles/degree. Under mesopic conditions, spherical aberration had a significant negative correlation with contrast sensitivity at 3, 6, and 12 cycles/degree with glare, and with contrast sensitivity at 6 and 18 cycles/degree without glare. CONCLUSION: In terms of influence on visual function, coma aberration may be more significant under photopic conditions and spherical aberration under mesopic conditions. PMID- 22205831 TI - Significant correlations between optic nerve head microcirculation and visual field defects and nerve fiber layer loss in glaucoma patients with myopic glaucomatous disk. AB - BACKGROUND: Eyes with glaucoma are characterized by optic neuropathy with visual field defects in the areas corresponding to the optic disk damage. The exact cause for the glaucomatous optic neuropathy has not been determined. Myopia has been shown to be a risk factor for glaucoma. The purpose of this study was to determine whether a significant correlation existed between the microcirculation of the optic disk and the visual field defects and the retinal nerve fiber layer thickness (RNFLT) in glaucoma patients with myopic optic disks. METHODS: Sixty eyes of 60 patients with myopic disks were studied; 36 eyes with glaucoma (men:women = 19:17) and 24 eyes with no ocular diseases (men:women = 14:10). The mean deviation (MD) determined by the Humphrey field analyzer, and the peripapillary RNFLT determined by the Stratus-OCT were compared between the two groups. The ocular circulation was determined by laser speckle flowgraphy (LSFG), and the mean blur rate (MBR) was compared between the two groups. The correlations between the RNFLT and MBR of the corresponding areas of the optic disk and between MD and MBR of the optic disk in the glaucoma group were determined by simple regression analyses. RESULTS: The average MBR for the entire optic disk was significantly lower in the glaucoma group than that in the control group. The differences of the MBR for the tissue in the superior, inferior, and temporal quadrants of the optic disk between the two groups were significant. The MBR for the entire optic disk was significantly correlated with the MD (r = 0.58, P = 0.0002) and the average RNFLT (r = 0.53, P = 0.0008). The tissue MBR of the optic disk was significantly correlated with the RNFLT in the superior, inferior, and temporal quadrants. CONCLUSIONS: Our study suggests that there is a causal relationship between the thinner RNFLT that led to the MD and reduction in the microcirculation in the optic nerve head. PMID- 22205832 TI - Over 10 years follow-up of Coats' disease in adulthood. AB - Coats' disease diagnosed in adulthood is rare; therefore, the treatment options and longer clinical course are not well established. We report on two cases of adult onset Coats' disease, which have been observed for more than 10 years after conventional treatment. In the first case, a 76-year-old man with 9 years of diabetic retinopathy noticed a visual field defect in his left eye. Yellowish subretinal exudation with serous retinal detachment in his superior peripheral retina, and telangiectatic vessels with fluorescein leakage, numerous microaneurysms, and areas of capillary nonperfusion observed in a fluorescein angiography indicated adult Coats' disease, and retinal photocoagulation was applied. Within 1 year, subretinal exudation was regressed and visual acuity was improved from 20/50 to 20/20, and was maintained for the next 11 years. In the second case, a 71-year-old man presented with decreased vision in his right eye. The fundus of his right eye showed multiple telangiectasic vessels and subretinal exudates extended to the fovea, which is diagnosed as adult Coats' disease. Despite retinal photocoagulation, an increase of exudation and an enlargement of retinal detachment was observed within 1 month, and subsequently, additional treatment of cryotherapy was performed. Two months after these therapies, the exudation was regressed without retinal detachment, and visual acuity was improved to 20/200 which was maintained for the next 10 years. Even with adult Coats' disease, conventional therapies of retinal photocoagulation and cryotherapy are effective and are the initial choice for improving or maintaining visual function. PMID- 22205833 TI - Iritis and iris atrophy after eyebrow epilation with alexandrite laser. AB - PURPOSE: To report a case of bilateral iritis and transillumination defects after laser hair removal of the eyebrows with an alexandrite laser. METHODS: A 41-year old male presented with bilateral eye pain and mild photophobia 2 days after receiving alexandrite (755 nm) laser epilation of both eyebrows. Examination showed visual acuity of 20/20 in both eyes, 2+ conjunctival injection in both eyes, 1+ cells in the anterior chamber of right eye and trace cells in left eye, poor right pupil dilation, and left pupil without movement. Intraocular pressure and fundus examination were normal. He was diagnosed with iritis and iris atrophy, associated with laser epilation. Topical steroids and cycloplegic drops were prescribed for 1 month. RESULTS: After 1 month of treatment, transillumination defects remained in both eyes, but greater in right. In dim light, the right pupil was 4 mm and oval and the left pupil was 6 mm and round. Visual acuity remained 20/20 in both eyes. CONCLUSION: Laser hair removal of the eyebrows can lead to permanent ocular damage even with eye protection, and should be avoided. PMID- 22205834 TI - 23-gauge pars plana vitrectomy for management of posteriorly dislocated crystalline lens. AB - PURPOSE: Management of posteriorly dislocated crystalline lens has traditionally been performed with a standard 20-gauge vitrectomy system. This study demonstrates the use of a 23-gauge vitrectomy system for removal of retained lens fragments secondary to spontaneous dislocation or complicated cataract extraction. METHODS: A retrospective, noncomparative, interventional consecutive case series at a single university medical center. RESULTS: Fourteen eyes of 14 patients underwent a 23-gauge vitrectomy for removal of retained lens. Mean age was 75 years. Mean logMAR (logarithm of minimum angle of resolution) visual acuity was 1.47 (Snellen equivalent 20/600) preoperatively and 0.37 (Snellen equivalent 20/50) postoperatively. A 20-gauge fragmatome was used in 64% of cases. The mean time to the best post-vitrectomy acuity was 4.9 weeks. The mean healing time was 25 days (6-48 days). Post- vitrectomy complications included choroidal detachment (two patients), vitreous hemorrhage (two patients), and acute ocular hypertension (two patients). The mean length of follow-up was 6.2 months (1-13 months). CONCLUSION: A 23-gauge vitrectomy system alone or in combination with the 20-gauge fragmatome is a safe and efficacious option for removal of dense posteriorly dislocated crystalline lens material. PMID- 22205835 TI - Addition of a fixed combination of brinzolamide 1%/timolol 0.5% to prostaglandin monotherapy in patients with glaucoma or ocular hypertension. AB - BACKGROUND: This study was conducted to evaluate the safety and efficacy of adding a fixed combination of brinzolamide 1%/timolol 0.5% to prostaglandin analog (PGA) monotherapy in patients with primary open-angle glaucoma, pigment dispersion glaucoma, or ocular hypertension who require additional intraocular pressure (IOP) reduction. METHODS: This was a prospective, multicenter (n = 5), open-label, single-arm, Phase IV clinical trial in which patients currently being treated with a PGA but requiring additional IOP reduction were administered brinzolamide 1%/timolol 0.5% twice daily as adjunctive therapy to their current PGA monotherapy regimen. The primary objective was to examine the IOP-lowering efficacy of brinzolamide-timolol when used as adjunctive therapy. RESULTS: Forty seven patients enrolled in and completed the study. After 12 weeks of adjunctive brinzolamide-timolol therapy, the mean IOP of the total patient population decreased from 22.1 mmHg at baseline to 16.7 mmHg. The mean IOP reduction of 5.4 mmHg (24.4%) was both clinically and statistically significant (P < 0.001). This significant decrease in mean IOP at week 12 was maintained across all PGA groups (P < 0.05). No significant differences were observed in symptom frequency between baseline and week 12 for any of the six solicited symptoms. A total of 17 adverse events from six patients was reported, of which ten were drug-related. Most (n = 7) of the drug-related adverse events were mild or moderate in intensity. None of the adverse events required any treatment or resulted in treatment interruption or discontinuation. Of the 90 eligible eyes, 85.6% had a decrease in IOP of at least 3 mmHg from baseline and 98% of patients had a decrease in IOP of >=1 mmHg. CONCLUSION: This study suggests that a fixed combination of brinzolamide 1%/timolol 0.5% can provide additional IOP reduction effectively and safely when used as adjunctive therapy for patients receiving insufficient IOP reduction from PGA monotherapy. PMID- 22205836 TI - Kinetics of central macular thickness reduction in patients with macular edema after intravitreal drug therapy. AB - BACKGROUND: The purpose of this study was to characterize central macular thickness and retinal volume following intravitreal injections using time domain and spectral domain optical coherence tomography (TD-OCT and SD-OCT, respectively). METHODS: Nine patients with macular edema secondary to diabetes or retinal vein occlusion treated with intravitreal triamcinolone 4.0 mg and/or bevacizumab 1.25 mg were enrolled. Central macular thickness and volume was measured by SD-OCT and TD-OCT scan at baseline, and 1, 3, 6, 24, 48 hours, and 1 week postinjection. RESULTS: Equations were derived to describe central macular thickness and volume reduction in the hours following intravitreal injection. Measurements of central macular thickness by SD-OCT were significantly reduced by 3 hours (P = 0.03) and retinal volume by 6 hours (P = 0.03). Central macular thickness measured 40.9 (28.6-53.2) MUm thicker on the SD-OCT instrument while volume measured 3.47 (3.27-3.66) mm(3) higher. CONCLUSION: Significant central macular thickness and volume reductions occur in the first hours after injection with triamcinolone and/or bevacizumab. PMID- 22205839 TI - Is the low-thalidomide dose MPT regimen beneficial? PMID- 22205837 TI - Recent advances in mechanisms and treatments of airway remodeling in asthma: a message from the bench side to the clinic. AB - Airway remodeling in asthma is a result of persistent inflammation and epithelial damage in response to repetitive injury. Recent studies have identified several important mediators associated with airway remodeling in asthma, including transforming growth factor-beta, interleukin (IL)-5, basic fibroblast growth factor, vascular endothelial growth factor, LIGHT, tumor necrosis factor (TNF) alpha, thymic stromal lymphopoietin, IL-33, and IL-25. In addition, the epithelium mesenchymal transformation (EMT) induced by environmental factors may play an important role in initiating this process. Diagnostic methods using sputum and blood biomarkers as well as radiological interventions have been developed to distinguish between asthma sub-phenotypes. Human clinical trials have been conducted to evaluate biological therapies that target individual inflammatory cells or mediators including anti IgE, anti IL-5, and anti TNF alpha. Furthermore, new drugs such as c-kit/platelet-derived growth factor receptor kinase inhibitors, endothelin-1 receptor antagonists, calcium channel inhibitors, and HMG-CoA reductase inhibitors have been developed to treat asthma related symptoms. In addition to targeting specific inflammatory cells or mediators, preventing the initiation of EMT may be important for targeted treatment. Interestingly, bronchial thermoplasty reduces smooth muscle mass in patients with severe asthma and improves asthma-specific quality of life, particularly by reducing severe exacerbation and healthcare use. A wide range of different therapeutic approaches has been developed to address the immunological processes of asthma and to treat this complex chronic illness. An important future direction may be to investigate the role of mediators involved in the development of airway remodeling to enhance asthma therapy. PMID- 22205838 TI - Endoscopic therapy in chronic pancreatitis. AB - Chronic pancreatitis (CP) is a debilitating disease that can result in chronic abdominal pain, malnutrition, and other related complications. The main aims of treatment are to control symptoms, prevent disease progression, and correct any complications. A multidisciplinary approach involving medical, endoscopic, and surgical therapy is important. Endoscopic therapy plays a specific role in carefully selected patients as primary interventional therapy when medical measures fail or in patients who are not suitable for surgery. Endoscopic therapy is also used as a bridge to surgery or as a means to assess the potential response to pancreatic surgery. This review addresses the role of endoscopic therapy in relief of obstruction of the pancreatic duct (PD) and bile du ct, closure of PD leaks, and drainage of pseudocysts in CP. The role of endoscopic ultrasound-guided celiac plexus block for pain in chronic pancreatitis is also discussed. PMID- 22205840 TI - A combination of melphalan, prednisone, and 50 mg thalidomide treatment in non transplant-candidate patients with newly diagnosed multiple myeloma. AB - BACKGROUND/AIMS: The clinical efficacy and safety of a three-drug combination of melphalan, prednisone, and thalidomide were assessed in patients with multiple myeloma who were not candidates for high-dose therapy as a first-line treatment. Because the side effects of thalidomide at a dose of >= 100 mg daily can be a barrier to effective treatment for these patients, we evaluated the efficacy and safety of a reduced dose of thalidomide, 50 mg, for non-transplant candidates. METHODS: Twenty-one patients were treated in 4-week cycles, receiving 4 mg/m(2) melphalan and 40 mg/m(2) prednisone on days 1-7 and 50 mg thalidomide daily. The primary efficacy outcome was the overall response rate. Aspirin (100 mg daily) was also provided as prophylactic treatment for thromboembolism. RESULTS: The overall response rate was 57.1%; a complete response was seen in 23.8% of patients, a partial response in 33.3%, and stable disease in 9.5%. After a median follow-up time of 16.1 months, the median time to progression was 11.4 months (95% confidence interval, 2.1 to 20.6); the median overall survival was not reached. Grades 3 and 4 adverse events included infection (10%), peripheral neuropathy (5%), diarrhea (5%), thrombosis (10%), and loss of consciousness (10%). Two patients discontinued treatment due to loss of consciousness and neuropathy. CONCLUSIONS: Low-dose thalidomide (50 mg) plus melphalan and prednisone is an effective combination drug therapy option for newly diagnosed myeloma patients who are ineligible for high-dose chemotherapy. PMID- 22205841 TI - Alteration of left ventricular function with dobutamine challenge in patients with myocardial bridge. AB - BACKGROUND/AIMS: The aim of this study was to identify changes in left ventricular (LV) performance in patients with a myocardial bridge (MB) in the left anterior descending coronary artery during resting and in an inotropic state. METHODS: Myocardial strain measurement by speckle-tracking echocardiography and conventional LV wall-motion scoring was performed in 18 patients with MB (mean age, 48.1 +/- 1.7 years, eight female) during resting and intravenous dobutamine challenge (10 and 20 ug/kg/min). RESULTS: Conventional LV wall-motion scoring was normal in all patients during resting and in an inotropic state. Peak regional circumferential strain increased dose dependently upon dobutamine challenge. Longitudinal strains of the anterior and anteroseptal segments were, however, reduced at 20 ug/kg/min and showed a dyssynchronous pattern at 20 ug/kg/min. Although there were no significant differences in radial strain and displacement of all segments at rest compared with under 10 ug/kg/min challenge, radial strain and displacement of anterior segments at 20 ug/kg/min were significantly reduced compared with posterior segments at the papillary muscle level (44.8 +/- 14.9% vs. 78.4 +/- 20.1% and 5.3 +/- 2.3 mm vs. 8.5 +/- 1.8 mm, respectively; all p < 0.001), and showed plateau (40%) or biphasic (62%) patterns. CONCLUSIONS: Reduced LV strain of patients with MB after inotropic stimulation was identified. Speckle-tracking strain echocardiography identified a LV myocardial dyssynchrony that was not demonstrated by conventional echocardiography in patients with MB. PMID- 22205842 TI - Sound analysis in an in vitro endotracheal tube model. AB - BACKGROUND/AIMS: Complete endotracheal tube obstruction is a medical emergency, and partial occlusion causes increased breathing rates and failure to wean off mechanical ventilation. Partial occlusion may be underestimated due to the lack of proper detection methods. We tested whether the sound of an endotracheal tube could be used to detect an endotracheal tube obstruction using an in vitro model. METHODS: An endotracheal tube was connected to a ventilator on one end and a test lung on the other. Sounds were recorded with a microphone located inside the endotracheal tube via a connector. During mechanical ventilation, we changed the endotracheal tube internal diameter from 5.0 to 8.0 mm and different grades of obstruction at different sites were used along the tube. Sound energy was compared among the different conditions. RESULTS: The energy of endotracheal tube sounds was positively correlated with the internal diameter and negatively correlated with the degree of obstruction. The rate of decline in energy differed with obstruction location. When the obstruction was more distal, the rate of decline in endotracheal sound energy was more rapid. CONCLUSIONS: Changes in the sound of an endotracheal tube can be used to detect an obstruction. Further studies are needed for clinical application. PMID- 22205843 TI - Gender differences in susceptibility to smoking among patients with lung cancer. AB - BACKGROUND/AIMS: To determine whether female smokers are more or less susceptible to the detrimental pulmonary-function effects of smoking when compared to male smokers among patients with lung cancer. METHODS: Pack-years and pulmonary function indices were compared between 1,594 men and women with lung cancer who were smokers or had a history of smoking. Differences in individual susceptibility to smoking were estimated using a susceptibility index formula. RESULTS: Of the patients, 959 (92.8%) men and 74 (7.2%) women were current smokers. Common histological types of lung cancer were squamous cell carcinoma, adenocarcinoma, and small cell carcinoma, among others. Women had a lower number of pack-years, forced expiratory volume in 1 second (FEV(1), liters), forced vital capacity (FVC, liters), and total lung capacity (TLC, liters) compared to those of men (25.0 +/- 19.2 vs. 42.9 +/- 21.7 for pack-years; 1.4 +/- 0.5 vs. 2.0 +/- 0.6 for FEV(1); 3.0 +/- 0.7 vs. 2.0 +/- 0.6 for FVC; 4.5 +/- 0.8 vs. 5.7 +/- 1.0 for TLC; all p < 0.001). The susceptibility index for women was significantly higher compared to that of men (1.1 +/- 4.1 vs. 0.7 +/- 1.1; p = 0.001). A significant inverse association was shown between the susceptibility index and TLC and FVC (r = -0.200 for TLC, -0.273 for FVC; all p < 0.001). CONCLUSIONS: The results suggest that the detrimental effects of smoking on pulmonary function are greater in women, as compared to those in men, among patients with lung cancer. PMID- 22205844 TI - Serum TSH level in healthy Koreans and the association of TSH with serum lipid concentration and metabolic syndrome. AB - BACKGROUND/AIMS: The proper treatment of subclinical hypothyroidism and the normal range of serum thyroid stimulating hormone (TSH) concentration are intensely debated. However, few reports have investigated TSH concentrations in Asian ethnic groups. Therefore, the present study was designed to define the TSH reference range in a Korean population and to investigate the metabolic significance of TSH concentration. METHODS: We enrolled patients who underwent medical examination at the CHA Bundang Medical Center. Anthropometric data were evaluated, and serum TSH, free T4, and lipid profiles were assayed. RESULTS: A total of 7,270 subjects were included. Mean TSH concentration of the study population was 1.82 +/- 0.95 mU/L, and we observed a sex-related difference in TSH concentration (male, 1.67 +/- 0.87 mU/L; female, 2.02 +/- 1.01 mU/L; p < 0.01). When the 2.5 and 97.5 percentiles were calculated, 95% TSH reference limits were 0.52-4.29 mU/L. TSH concentration was higher in elderly subjects, during winter, in postmenopausal women, and in obese males. Moreover, TSH showed significantly positive correlations with serum total cholesterol, triglyceride, and low density lipoprotein cholesterol regardless of sex, age, season, obesity, or menopausal status (all p < 0.01). Finally, TSH concentration was positively related to the prevalence of metabolic syndrome. CONCLUSIONS: We demonstrated the association between TSH concentration within the normal reference range and serum lipid levels. TSH concentration varies according to sex, age, season, and body mass index (only in males). Moreover, high normal TSH levels were significantly associated with an increased prevalence of metabolic syndrome, which may be of importance when evaluating subjects with high normal TSH concentration. PMID- 22205845 TI - Causes of different estimates of the prevalence of metabolic syndrome in Korea. AB - BACKGROUND/AIMS: Reports of the prevalence of and trends in metabolic syndrome in Korea have been inconsistent. Thus, we investigated the reasons underlying these inconsistencies. METHODS: We estimated the prevalence of metabolic syndrome using different diagnostic criteria, exclusion criteria, and sampling weights among 5,509 respondents, aged 20-79, who participated in the 2001 Korean National Health and Nutrition Examination Surveys (KNHANES). Trends in metabolic syndrome were assessed by examining the 1998 (n = 6,747), 2001 (n = 4,337), and 2005 (n = 5,139) KNHANES. RESULTS: The estimated prevalence of metabolic syndrome in 2001 ranged from 1.6 to 29.6% in males and from 10.1 to 32.8% in females, depending on the diagnostic criteria used. The exclusion criteria and sampling weights did not significantly affect the prevalence estimates. The prevalence of metabolic syndrome first significantly increased and then decreased between 1998, 2001, and 2005 in males (26.2, 29.6, and 27.2%, respectively) and females (29.2, 32.8, and 24.7%, respectively). Among the individual metabolic variables, triglyceride levels in 2001 were significantly higher than in 1998 and 2005, whereas other variables remained relatively constant during the same period. The exceptionally high triglyceride levels in 2001 might have contributed to the increased prevalence of metabolic syndrome between 1998 and 2001. CONCLUSIONS: Different diagnostic criteria for metabolic syndrome represent a major cause of the inconsistent estimates of prevalence, and the absence of standardized laboratory methods might have affected the trend estimates. PMID- 22205847 TI - Takotsubo cardiomyopathy: a case of persistent apical ballooning complicated by an apical mural thrombus. AB - Takotsubo cardiomyopathy (TTC) is an infrequent cardiac syndrome characterized by acute onset chest pain with apical ballooning on echocardiography. It is often triggered by severe emotional or physical stress, and in contrast to acute myocardial infarction (AMI), the regional wall motion abnormality returns to normal within days. Here, we describe a 62-year-old female who presented with acute onset chest pain during treatment for a liver abscess. We presumed a diagnosis of AMI because of ST segment elevation on electrocardiography and elevated cardiac enzyme levels. However, the patient's coronary arteries were normal on angiography, and apical ballooning was seen on echocardiography. A diagnosis of TTC was made, and the patient was managed with intensive cardiopulmonary support using vasopressors in our hospital's medical intensive care unit. The patient's symptoms improved, but persistent severe left ventricular dysfunction was detected on follow-up echocardiography. After 5 weeks, a new apical mural thrombus appeared, and anticoagulation therapy was started. The apical ballooning persisted 3 months later, although the patient's overall ejection fraction was slightly improved. The apical thrombus was completely resolved without any embolic event. Non-adrenergic inotropics can be recommended in TTC with shock, and clinicians should keep in mind the potential risk of thrombus formation and cardioembolism. PMID- 22205846 TI - Clinical implications of elevated antiphospholipid antibodies in adult patients with primary immune thrombocytopenia. AB - BACKGROUND/AIMS: Antiphospholipid antibodies (aPL) have been detected in various proportions of patients with primary immune thrombocytopenia (ITP), but the clinical significance of this is debatable. The present study aimed to determine the frequency and clinical implications of elevated aPL in adult patients with ITP. METHODS: We prospectively studied newly diagnosed adult patients with ITP who were enrolled between January 2003 and December 2008 at Chungnam National University Hospital. They were evaluated for the presence of lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) at diagnosis and were followed for the development of thrombosis. RESULTS: Seventy consecutive patients with ITP (median age, 48 years; range, 18 to 79) were enrolled. Twenty patients (28.5%) were positive for aPL at the time of diagnosis: aCL alone in 15 (75%), aCL and LA in two (10%), and LA alone in three (15%). Patients who had platelet counts < 50,000/uL were administered oral prednisolone with or without intravenous immune globulin. No difference was found between the aPL-positive and -negative groups regarding gender, initial platelet count, and response to the therapy. After a median follow-up of 20 months (range, 2 to 68), two of 20 patients who were aPL positive (10%) developed thrombosis, whereas no thrombotic event was found among those who were aPL-negative. CONCLUSIONS: Our data suggest that aPL levels should be determined at the initial presentation of ITP and that patients found to be aPL-positive should receive closer follow-up for thrombotic events. PMID- 22205848 TI - Central venous stenosis caused by traction of the innominate vein due to a tuberculosis-destroyed lung. AB - We report a case of central venous stenosis due to a structural deformity caused by a tuberculosis-destroyed lung in a 65-year-old woman. The patient presented with left facial edema. She had a history of pulmonary tuberculosis, and the chest X-ray revealed a collapsed left lung. Angiography showed leftward deviation of the innominate vein leading to kinking and stenosis of the internal jugular vein. Stent insertion improved her facial edema. PMID- 22205849 TI - Acute kidney injury due to sodium bromate intoxication: a report of two cases. AB - Sodium bromate is a strong oxidant used as a neutralizing solution in hair permanents, as well as an auxiliary agent in printing and dyeing. Accidental or deliberate ingestion of bromate solution has rarely been reported in Korea. The clinical manifestations of bromate intoxication are vomiting, diarrhea, central nervous system symptoms, oliguric or non-oliguric acute kidney injury, hemolytic anemia, and deafness; most of these manifestations are reversible, with the exception of renal failure and deafness. Here, we report on two patients who demonstrated distinct clinical progressions. In the first case, a 16-year-old woman was successfully treated with hemodialysis and recovered renal function without hearing loss. However, in the second case, delayed hemodialysis resulted in persistent renal failure and hearing loss in a 77-year-old woman. This suggests that emergency therapeutic measures, including hemodialysis, should be taken as soon as possible, as the rapid removal of bromate may be essential to preventing severe intoxication and its sequelae. PMID- 22205850 TI - An adult case of chronic active Epstein-Barr virus infection with interstitial pneumonitis. AB - Chronic active Epstein-Barr virus (CAEBV) infection is characterized by persistent infectious mononucleosis-like symptoms, an unusual pattern of Epstein Barr virus (EBV) antibodies, detection of the EBV genome in affected tissues or peripheral blood, and chronic illness that cannot be attributed to any other known disease. This is the first reported Korean case of an immunocompetent adult with CAEBV-associated interstitial pneumonitis. A 28-year-old female was admitted with a fever that persisted for 3 weeks. She had multiple lymphadenopathy, hepatosplenomegaly, pancytopenia, and elevated serum aminotransferase levels. Serology for antibodies was positive and chest computed tomography showed diffuse ground glass opacities in both lungs. Histopathology of the lung tissue showed lymphocyte infiltration, and EBV DNA was detected in those lymphocytes using in situ hybridization with an EBV-encoded RNA probe. After 1 month of hospitalization, she improved without specific treatment. PMID- 22205851 TI - A case of minimal change disease treated successfully with mycophenolate mofetil in a patient with systemic lupus erythematosus. AB - The World Health Organization classifies lupus nephritis as class I to V or VI. However, a few cases of minimal change glomerulopathy have been reported in association with systemic lupus erythematosus (SLE). Mycophenolate mofetil has been shown to be effective for treatment of minimal change disease and lupus nephritis. A 24-year-old woman diagnosed with SLE five years prior to presentation complained of a mild generalized edema. The urinalysis showed microscopic hematuria and proteinuria. The assessed amount of total proteinuria was 1,618 mg/24 hours. A renal biopsy demonstrated diffuse fusion of the foot processes of podocytes on electron microscopy. Mycophenolate mofetil was started in addition to the maintenance medications of prednisolone 10 mg/day and hydroxychloroquine 400 mg/day. After six months of treatment, the microscopic hematuria and proteinuria resolved, and the total urine protein decreased to 100 mg/24 hours. PMID- 22205852 TI - Two cases of scrub typhus presenting with Guillain-Barre syndrome with respiratory failure. PMID- 22205853 TI - Nododuodenal fistula caused by tuberculosis. PMID- 22205854 TI - Excretion of urine mixed with air and fecal material. PMID- 22205855 TI - Observation and measurement of negative differential resistance on PtSi Schottky junctions on porous silicon. AB - Nanosize porous Si is made by two step controlled etching of Si. The first etching step is carried on the Si surface and the second is performed after deposition of 75 A of platinum on the formed surface. A platinum silicide structure with a size of less than 25 nm is formed on the porous Si surface, as measured with an Atomic Forced Microscope (AFM). Differential resistance curve as a function of voltage in 77 K and 100 K shows a negative differential resistance and indicates the effect of quantum tunneling. In general form, the ratio of maximum to minimum tunneling current (PVR) and the number of peaks in I-V curves reduces by increasing the temperature. However, due to accumulation of carriers behind the potential barrier and superposition of several peaks, it is observed that the PVR increases at 100 K and the maximum PVR at 100 K is 189.6. PMID- 22205856 TI - CENet: a cabinet environmental sensing network. AB - For data center cooling and intelligent substation systems, real time cabinet environmental monitoring is a strong requirement. Monitoring data, such as temperature, humidity, and noise, is important for operators to manage the facilities in cabinets. We here propose a sensing network, called CENet, which is energy efficient and reliable for cabinet environmental monitoring. CENet achieves above 93% reliable data yield and sends fewer beacons compared to periodic beaconing. It does so through a data-aided routing protocol. In addition, based on B-MAC, we propose a scheduling scheme to increase the lifetime of the network by reducing unnecessary message snooping and channel listening, thus it is more energy efficient than B-MAC. The performance of CENet is evaluated by simulations and experiments. PMID- 22205857 TI - A multiscale region-based motion detection and background subtraction algorithm. AB - This paper presents a region-based method for background subtraction. It relies on color histograms, texture information, and successive division of candidate rectangular image regions to model the background and detect motion. Our proposed algorithm uses this principle and combines it with Gaussian mixture background modeling to produce a new method which outperforms the classic Gaussian mixture background subtraction method. Our method has the advantages of filtering noise during image differentiation and providing a selectable level of detail for the contour of the moving shapes. The algorithm is tested on various video sequences and is shown to outperform state-of-the-art background subtraction methods. PMID- 22205858 TI - Evaluation of three electronic noses for detecting incipient wood decay. AB - Tree assessment methodologies, currently used to evaluate the structural stability of individual urban trees, usually involve a visual analysis followed by measurements of the internal soundness of wood using various instruments that are often invasive, expensive, or inadequate for use within the urban environment. Moreover, most conventional instruments do not provide an adequate evaluation of decay that occurs in the root system. The intent of this research was to evaluate the possibility of integrating conventional tools, currently used for assessments of decay in urban trees, with the electronic nose-a new innovative tool used in diverse fields and industries for various applications such as quality control in manufacturing, environmental monitoring, medical diagnoses, and perfumery. Electronic-nose (e-nose) technologies were tested for the capability of detecting differences in volatile organic compounds (VOCs) released by wood decay fungi and wood from healthy and decayed trees. Three e noses, based on different types of operational technologies and analytical methods, were evaluated independently (not directly compared) to determine the feasibility of detecting incipient decays in artificially-inoculated wood. All three e-nose devices were capable of discriminating between healthy and artificially-inoculated, decayed wood with high levels of precision and confidence. The LibraNose quartz microbalance (QMB) e-nose generally provided higher levels of discrimination of sample unknowns, but not necessarily more accurate or effective detection than the AromaScan A32S conducting polymer and PEN3 metal-oxide (MOS) gas sensor e-noses for identifying and distinguishing woody samples containing different agents of wood decay. However, the conducting polymer e-nose had the greater advantage for identifying unknowns from diverse woody sample types due to the associated software capability of utilizing prior developed, application-specific reference libraries with aroma pattern recognition and neural-net training algorithms. PMID- 22205859 TI - Using fuzzy logic to enhance stereo matching in multiresolution images. AB - Stereo matching is an open problem in computer vision, for which local features are extracted to identify corresponding points in pairs of images. The results are heavily dependent on the initial steps. We apply image decomposition in multiresolution levels, for reducing the search space, computational time, and errors. We propose a solution to the problem of how deep (coarse) should the stereo measures start, trading between error minimization and time consumption, by starting stereo calculation at varying resolution levels, for each pixel, according to fuzzy decisions. Our heuristic enhances the overall execution time since it only employs deeper resolution levels when strictly necessary. It also reduces errors because it measures similarity between windows with enough details. We also compare our algorithm with a very fast multi-resolution approach, and one based on fuzzy logic. Our algorithm performs faster and/or better than all those approaches, becoming, thus, a good candidate for robotic vision applications. We also discuss the system architecture that efficiently implements our solution. PMID- 22205860 TI - Development of a fingertip glove equipped with magnetic tracking sensors. AB - In this paper, we present the development of a data glove system based on fingertip tracking techniques. To track the fingertip position and orientation, a sensor module and two generator coils are attached on the fingertip and metacarpal of the corresponding finger. By tracking the fingertip, object manipulation tasks in a virtual environment or teleoperation system can be carried out more precisely, because fingertips are the foremost areas that reach the surface of an object in most of grasping processes. To calculate the bending angles of a finger, we also propose a method of constructing the shape of the finger. Since the coils are installed on the fingertips and metacarpals, there is no contact point between the sensors and finger joints. Hence, the shape of the sensors does not change as the fingers are bending, and both the quality of measurement and the lifetime of the sensors will not decrease in time. For the convenience of using this glove, a simple and efficient calibration process consisting of only one calibration gesture is also provided, so that all required parameters can be determined automatically. So far, the experimental results of the sensors performing linear movement and bending angle measurements are very satisfactory. It reveals that our data glove is available for a man-machine interface. PMID- 22205861 TI - System interface for an integrated intelligent safety system (ISS) for vehicle applications. AB - This paper deals with the interface-relevant activity of a vehicle integrated intelligent safety system (ISS) that includes an airbag deployment decision system (ADDS) and a tire pressure monitoring system (TPMS). A program is developed in LabWindows/CVI, using C for prototype implementation. The prototype is primarily concerned with the interconnection between hardware objects such as a load cell, web camera, accelerometer, TPM tire module and receiver module, DAQ card, CPU card and a touch screen. Several safety subsystems, including image processing, weight sensing and crash detection systems, are integrated, and their outputs are combined to yield intelligent decisions regarding airbag deployment. The integrated safety system also monitors tire pressure and temperature. Testing and experimentation with this ISS suggests that the system is unique, robust, intelligent, and appropriate for in-vehicle applications. PMID- 22205862 TI - Machine learning methods for classifying human physical activity from on-body accelerometers. AB - The use of on-body wearable sensors is widespread in several academic and industrial domains. Of great interest are their applications in ambulatory monitoring and pervasive computing systems; here, some quantitative analysis of human motion and its automatic classification are the main computational tasks to be pursued. In this paper, we discuss how human physical activity can be classified using on-body accelerometers, with a major emphasis devoted to the computational algorithms employed for this purpose. In particular, we motivate our current interest for classifiers based on Hidden Markov Models (HMMs). An example is illustrated and discussed by analysing a dataset of accelerometer time series. PMID- 22205863 TI - Cooperative anchor-free position estimation for hierarchical wireless sensor networks. AB - This paper proposes a distributed algorithm for establishing connectivity and location estimation in cluster-based wireless sensor networks. The algorithm exploits the information flow while coping with distributed signal processing and the requirements of network scalability. Once the estimation procedure and communication protocol are performed, sensor clusters can be merged to establish a single global coordinate system without GPS sensors using only distance information. In order to adjust the sensor positions, the refinement schemes and cooperative fusion approaches are applied to reduce the estimation error and improve the measurement accuracy. This paper outlines the technical foundations of the localization techniques and presents the tradeoffs in algorithm design. The feasibility of the proposed schemes is shown to be effective under certain assumptions and the analysis is supported by simulation and numerical studies. PMID- 22205864 TI - ZnO-based amperometric enzyme biosensors. AB - Nanostructured ZnO with its unique properties could provide a suitable microenvironment for immobilization of enzymes while retaining their biological activity, and thus lead to an expanded use of this nanomaterial for the construction of electrochemical biosensors with enhanced analytical performance. ZnO-based enzyme electrochemical biosensors are summarized in several tables for an easy overview according to the target biosensing analyte (glucose, hydrogen peroxide, phenol and cholesterol), respectively. Moreover, recent developments in enzyme electrochemical biosensors based on ZnO nanomaterials are reviewed with an emphasis on the fabrications and features of ZnO, approaches for biosensor construction (e.g., modified electrodes and enzyme immobilization) and biosensor performances. PMID- 22205865 TI - A finite element model of a MEMS-based surface acoustic wave hydrogen sensor. AB - Hydrogen plays a significant role in various industrial applications, but careful handling and continuous monitoring are crucial since it is explosive when mixed with air. Surface Acoustic Wave (SAW) sensors provide desirable characteristics for hydrogen detection due to their small size, low fabrication cost, ease of integration and high sensitivity. In this paper a finite element model of a Surface Acoustic Wave sensor is developed using ANSYS12(c) and tested for hydrogen detection. The sensor consists of a YZ-lithium niobate substrate with interdigital electrodes (IDT) patterned on the surface. A thin palladium (Pd) film is added on the surface of the sensor due to its high affinity for hydrogen. With increased hydrogen absorption the palladium hydride structure undergoes a phase change due to the formation of the beta-phase, which deteriorates the crystal structure. Therefore with increasing hydrogen concentration the stiffness and the density are significantly reduced. The values of the modulus of elasticity and the density at different hydrogen concentrations in palladium are utilized in the finite element model to determine the corresponding SAW sensor response. Results indicate that with increasing the hydrogen concentration the wave velocity decreases and the attenuation of the wave is reduced. PMID- 22205866 TI - Secure adaptive topology control for wireless ad-hoc sensor networks. AB - This paper presents a secure decentralized clustering algorithm for wireless ad hoc sensor networks. The algorithm operates without a centralized controller, operates asynchronously, and does not require that the location of the sensors be known a priori. Based on the cluster-based topology, secure hierarchical communication protocols and dynamic quarantine strategies are introduced to defend against spam attacks, since this type of attacks can exhaust the energy of sensor nodes and will shorten the lifetime of a sensor network drastically. By adjusting the threshold of infected percentage of the cluster coverage, our scheme can dynamically coordinate the proportion of the quarantine region and adaptively achieve the cluster control and the neighborhood control of attacks. Simulation results show that the proposed approach is feasible and cost effective for wireless sensor networks. PMID- 22205867 TI - Direct electrochemistry and electrocatalysis of hemoglobin at mesoporous carbon modified electrode. AB - The novel highly ordered mesoporous carbon (known as FDU-15), prepared by the organic-organic self-assembly method was been used for first time for the immobilization of hemoglobin (Hb) and its bioelectrochemical properties were studied. The resulting Hb/FDU-15 film provided a favorable microenvironment for Hb to perform direct electron transfers at the electrode. The immobilized Hb also displayed its good electrocatalytic activity for the reduction of hydrogen peroxide. The results demonstrate that mesoporous carbon FDU-15 can improve the Hb loading with retention of its bioactivity and greatly promote the direct electron transfer, which can be attributed to its high specific surface area, uniform ordered porous structure, suitable pore size and biocompatibility. Our present study may provide an alternative way for the construction of nanostructure biofunctional surfaces and pave the way for its application to biosensors. PMID- 22205868 TI - Evaluating the consistency of the 1982-1999 NDVI trends in the Iberian Peninsula across four time-series derived from the AVHRR sensor: LTDR, GIMMS, FASIR, and PAL-II. AB - Successive efforts have processed the Advanced Very High Resolution Radiometer (AVHRR) sensor archive to produce Normalized Difference Vegetation Index (NDVI) datasets (i.e., PAL, FASIR, GIMMS, and LTDR) under different corrections and processing schemes. Since NDVI datasets are used to evaluate carbon gains, differences among them may affect nations' carbon budgets in meeting international targets (such as the Kyoto Protocol). This study addresses the consistency across AVHRR NDVI datasets in the Iberian Peninsula (Spain and Portugal) by evaluating whether their 1982-1999 NDVI trends show similar spatial patterns. Significant trends were calculated with the seasonal Mann-Kendall trend test and their spatial consistency with partial Mantel tests. Over 23% of the Peninsula (N, E, and central mountain ranges) showed positive and significant NDVI trends across the four datasets and an additional 18% across three datasets. In 20% of Iberia (SW quadrant), the four datasets exhibited an absence of significant trends and an additional 22% across three datasets. Significant NDVI decreases were scarce (croplands in the Guadalquivir and Segura basins, La Mancha plains, and Valencia). Spatial consistency of significant trends across at least three datasets was observed in 83% of the Peninsula, but it decreased to 47% when comparing across the four datasets. FASIR, PAL, and LTDR were the most spatially similar datasets, while GIMMS was the most different. The different performance of each AVHRR dataset to detect significant NDVI trends (e.g., LTDR detected greater significant trends (both positive and negative) and in 32% more pixels than GIMMS) has great implications to evaluate carbon budgets. The lack of spatial consistency across NDVI datasets derived from the same AVHRR sensor archive, makes it advisable to evaluate carbon gains trends using several satellite datasets and, whether possible, independent/additional data sources to contrast. PMID- 22205869 TI - Fabrication and characterization of CMOS-MEMS thermoelectric micro generators. AB - This work presents a thermoelectric micro generator fabricated by the commercial 0.35 MUm complementary metal oxide semiconductor (CMOS) process and the post-CMOS process. The micro generator is composed of 24 thermocouples in series. Each thermocouple is constructed by p-type and n-type polysilicon strips. The output power of the generator depends on the temperature difference between the hot and cold parts in the thermocouples. In order to prevent heat-receiving in the cold part in the thermocouples, the cold part is covered with a silicon dioxide layer with low thermal conductivity to insulate the heat source. The hot part of the thermocouples is suspended and connected to an aluminum plate, to increases the heat-receiving area in the hot part. The generator requires a post-CMOS process to release the suspended structures. The post-CMOS process uses an anisotropic dry etching to remove the oxide sacrificial layer and an isotropic dry etching to etch the silicon substrate. Experimental results show that the micro generator has an output voltage of 67 MUV at the temperature difference of 1 K. PMID- 22205871 TI - Characterization of thick and thin film SiCN for pressure sensing at high temperatures. AB - Pressure measurement in high temperature environments is important in many applications to provide valuable information for performance studies. Information on pressure patterns is highly desirable for improving performance, condition monitoring and accurate prediction of the remaining life of systems that operate in extremely high temperature environments, such as gas turbine engines. A number of technologies have been recently investigated, however these technologies target specific applications and they are limited by the maximum operating temperature. Thick and thin films of SiCN can withstand high temperatures. SiCN is a polymer-derived ceramic with liquid phase polymer as its starting material. This provides the advantage that it can be molded to any shape. CERASETTM also yields itself for photolithography, with the addition of photo initiator 2, 2 Dimethoxy-2-phenyl-acetophenone (DMPA), thereby enabling photolithographical patterning of the pre-ceramic polymer using UV lithography. SiCN fabrication includes thermosetting, crosslinking and pyrolysis. The technology is still under investigation for stability and improved performance. This work presents the preparation of SiCN films to be used as the body of a sensor for pressure measurements in high temperature environments. The sensor employs the phenomenon of drag effect. The pressure sensor consists of a slender sensitive element and a thick blocking element. The dimensions and thickness of the films depend on the intended application of the sensors. Fabrication methods of SiCN ceramics both as thin (about 40-60 MUm) and thick (about 2-3 mm) films for high temperature applications are discussed. In addition, the influence of thermosetting and annealing processes on mechanical properties is investigated. PMID- 22205870 TI - A lanthanide-based chemosensor for bioavailable Fe3+ using a fluorescent siderophore: an assay displacement approach. AB - The measurement of trace analytes in aqueous systems has become increasingly important for understanding ocean primary productivity. In oceanography, iron (Fe) is a key element in regulating ocean productivity, microplankton assemblages and has been identified as a causative element in the development of some harmful algal blooms. The chemosenor developed in this study is based on an indicator displacement approach that utilizes time-resolved fluorescence and fluorescence resonance energy transfer as the sensing mechanism to achieve detection of Fe3+ ions as low as 5 nM. This novel approach holds promise for the development of photoactive chemosensors for ocean deployment. PMID- 22205872 TI - Design strategies of fluorescent biosensors based on biological macromolecular receptors. AB - Fluorescent biosensors to detect the bona fide events of biologically important molecules in living cells are increasingly demanded in the field of molecular cell biology. Recent advances in the development of fluorescent biosensors have made an outstanding contribution to elucidating not only the roles of individual biomolecules, but also the dynamic intracellular relationships between these molecules. However, rational design strategies of fluorescent biosensors are not as mature as they look. An insatiable request for the establishment of a more universal and versatile strategy continues to provide an attractive alternative, so-called modular strategy, which permits facile preparation of biosensors with tailored characteristics by a simple combination of a receptor and a signal transducer. This review describes an overview of the progress in design strategies of fluorescent biosensors, such as auto-fluorescent protein-based biosensors, protein-based biosensors covalently modified with synthetic fluorophores, and signaling aptamers, and highlights the insight into how a given receptor is converted to a fluorescent biosensor. Furthermore, we will demonstrate a significance of the modular strategy for the sensor design. PMID- 22205873 TI - Whole-cell fluorescent biosensors for bioavailability and biodegradation of polychlorinated biphenyls. AB - Whole-cell microbial biosensors are one of the newest molecular tools used in environmental monitoring. Such biosensors are constructed through fusing a reporter gene such as lux, gfp or lacZ, to a responsive promoter. There have been many reports of the applications of biosensors, particularly their use in assaying pollutant toxicity and bioavailability. This paper reviews the basic concepts behind the construction of whole-cell microbial biosensors for pollutant monitoring, and describes the applications of two such biosensors for detecting the bioavailability and biodegradation of polychlorinated biphenyls (PCBs). PMID- 22205874 TI - Neurological tremor: sensors, signal processing and emerging applications. AB - Neurological tremor is the most common movement disorder, affecting more than 4% of elderly people. Tremor is a non linear and non stationary phenomenon, which is increasingly recognized. The issue of selection of sensors is central in the characterization of tremor. This paper reviews the state-of-the-art instrumentation and methods of signal processing for tremor occurring in humans. We describe the advantages and disadvantages of the most commonly used sensors, as well as the emerging wearable sensors being developed to assess tremor instantaneously. We discuss the current limitations and the future applications such as the integration of tremor sensors in BCIs (brain-computer interfaces) and the need for sensor fusion approaches for wearable solutions. PMID- 22205876 TI - eBird: engaging birders in science and conservation. AB - How do you successfully engage an audience in a citizen-science project? The processes developed by eBird (www.ebird.org), a fast-growing web-based tool that now gathers millions of bird observations per month, offers a model. PMID- 22205877 TI - Recognition and degradation of plant cell wall polysaccharides by two human gut symbionts. AB - Symbiotic bacteria inhabiting the human gut have evolved under intense pressure to utilize complex carbohydrates, primarily plant cell wall glycans in our diets. These polysaccharides are not digested by human enzymes, but are processed to absorbable short chain fatty acids by gut bacteria. The Bacteroidetes, one of two dominant bacterial phyla in the adult gut, possess broad glycan-degrading abilities. These species use a series of membrane protein complexes, termed Sus like systems, for catabolism of many complex carbohydrates. However, the role of these systems in degrading the chemically diverse repertoire of plant cell wall glycans remains unknown. Here we show that two closely related human gut Bacteroides, B. thetaiotaomicron and B. ovatus, are capable of utilizing nearly all of the major plant and host glycans, including rhamnogalacturonan II, a highly complex polymer thought to be recalcitrant to microbial degradation. Transcriptional profiling and gene inactivation experiments revealed the identity and specificity of the polysaccharide utilization loci (PULs) that encode individual Sus-like systems that target various plant polysaccharides. Comparative genomic analysis indicated that B. ovatus possesses several unique PULs that enable degradation of hemicellulosic polysaccharides, a phenotype absent from B. thetaiotaomicron. In contrast, the B. thetaiotaomicron genome has been shaped by increased numbers of PULs involved in metabolism of host mucin O glycans, a phenotype that is undetectable in B. ovatus. Binding studies of the purified sensor domains of PUL-associated hybrid two-component systems in conjunction with transcriptional analyses demonstrate that complex oligosaccharides provide the regulatory cues that induce PUL activation and that each PUL is highly specific for a defined cell wall polymer. These results provide a view of how these species have diverged into different carbohydrate niches by evolving genes that target unique suites of available polysaccharides, a theme that likely applies to disparate bacteria from the gut and other habitats. PMID- 22205878 TI - Coupled motions direct electrons along human microsomal P450 Chains. AB - Protein domain motion is often implicated in biological electron transfer, but the general significance of motion is not clear. Motion has been implicated in the transfer of electrons from human cytochrome P450 reductase (CPR) to all microsomal cytochrome P450s (CYPs). Our hypothesis is that tight coupling of motion with enzyme chemistry can signal "ready and waiting" states for electron transfer from CPR to downstream CYPs and support vectorial electron transfer across complex redox chains. We developed a novel approach to study the time dependence of dynamical change during catalysis that reports on the changing conformational states of CPR. FRET was linked to stopped-flow studies of electron transfer in CPR that contains donor-acceptor fluorophores on the enzyme surface. Open and closed states of CPR were correlated with key steps in the catalytic cycle which demonstrated how redox chemistry and NADPH binding drive successive opening and closing of the enzyme. Specifically, we provide evidence that reduction of the flavin moieties in CPR induces CPR opening, whereas ligand binding induces CPR closing. A dynamic reaction cycle was created in which CPR optimizes internal electron transfer between flavin cofactors by adopting closed states and signals "ready and waiting" conformations to partner CYP enzymes by adopting more open states. This complex, temporal control of enzyme motion is used to catalyze directional electron transfer from NADPH->FAD->FMN->heme, thereby facilitating all microsomal P450-catalysed reactions. Motions critical to the broader biological functions of CPR are tightly coupled to enzyme chemistry in the human NADPH-CPR-CYP redox chain. That redox chemistry alone is sufficient to drive functionally necessary, large-scale conformational change is remarkable. Rather than relying on stochastic conformational sampling, our study highlights a need for tight coupling of motion to enzyme chemistry to give vectorial electron transfer along complex redox chains. PMID- 22205880 TI - How bacteria turn fiber into food. PMID- 22205879 TI - Mechanotransduction in vivo by repeated talin stretch-relaxation events depends upon vinculin. AB - Mechanotransduction is a critical function for cells, in terms of cell viability, shaping of tissues, and cellular behavior. In vitro, cellular level forces can stretch adhesion proteins that link extracellular matrix to the actin cytoskeleton exposing hidden binding sites. However, there is no evidence that in vivo forces produce significant in vivo stretching to cause domain unfolding. We now report that the adhesion protein, talin, is repeatedly stretched by 100-350 nm in vivo by myosin contraction of actin filaments. Using a functional EGFP-N Talin1-C-mCherry to measure the length of single talin molecules, we observed that the C-terminal mCherry was normally displaced in the direction of actin flow by 90 to >250 nm from N-EGFP but only by 50-60 nm (talin's length in vitro) after myosin inhibition. Individual talin molecules transiently stretched and relaxed. Peripheral, multimolecular adhesions had green outside and red proximal edges. They also exhibited transient, myosin-dependent stretching of 50-350 nm for 6-16 s; however, expression of the talin-binding head of vinculin increased stretching to about 400 nm and suppressed dynamics. We suggest that rearward moving actin filaments bind, stretch, and release talin in multiple, stochastic stick-slip cycles and that multiple vinculin binding and release cycles integrate pulling on matrices into biochemical signals. PMID- 22205883 TI - Worldwide incidence of malaria in 2009: estimates, time trends, and a critique of methods. AB - BACKGROUND: Measuring progress towards Millennium Development Goal 6, including estimates of, and time trends in, the number of malaria cases, has relied on risk maps constructed from surveys of parasite prevalence, and on routine case reports compiled by health ministries. Here we present a critique of both methods, illustrated with national incidence estimates for 2009. METHODS AND FINDINGS: We compiled information on the number of cases reported by National Malaria Control Programs in 99 countries with ongoing malaria transmission. For 71 countries we estimated the total incidence of Plasmodium falciparum and P. vivax by adjusting the number of reported cases using data on reporting completeness, the proportion of suspects that are parasite-positive, the proportion of confirmed cases due to each Plasmodium species, and the extent to which patients use public sector health facilities. All four factors varied markedly among countries and regions. For 28 African countries with less reliable routine surveillance data, we estimated the number of cases from model-based methods that link measures of malaria transmission with case incidence. In 2009, 98% of cases were due to P. falciparum in Africa and 65% in other regions. There were an estimated 225 million malaria cases (5th-95th centiles, 146-316 million) worldwide, 176 (110 248) million in the African region, and 49 (36-68) million elsewhere. Our estimates are lower than other published figures, especially survey-based estimates for non-African countries. CONCLUSIONS: Estimates of malaria incidence derived from routine surveillance data were typically lower than those derived from surveys of parasite prevalence. Carefully interpreted surveillance data can be used to monitor malaria trends in response to control efforts, and to highlight areas where malaria programs and health information systems need to be strengthened. As malaria incidence declines around the world, evaluation of control efforts will increasingly rely on robust systems of routine surveillance. PMID- 22205884 TI - Estimating the burden of malaria: the need for improved surveillance. PMID- 22205885 TI - The toxic effects of cigarette additives. Philip Morris' project mix reconsidered: an analysis of documents released through litigation. AB - BACKGROUND: In 2009, the promulgation of US Food and Drug Administration (FDA) tobacco regulation focused attention on cigarette flavor additives. The tobacco industry had prepared for this eventuality by initiating a research program focusing on additive toxicity. The objective of this study was to analyze Philip Morris' Project MIX as a case study of tobacco industry scientific research being positioned strategically to prevent anticipated tobacco control regulations. METHODS AND FINDINGS: We analyzed previously secret tobacco industry documents to identify internal strategies for research on cigarette additives and reanalyzed tobacco industry peer-reviewed published results of this research. We focused on the key group of studies conducted by Phillip Morris in a coordinated effort known as "Project MIX." Documents showed that Project MIX subsumed the study of various combinations of 333 cigarette additives. In addition to multiple internal reports, this work also led to four peer-reviewed publications (published in 2001). These papers concluded that there was no evidence of substantial toxicity attributable to the cigarette additives studied. Internal documents revealed post hoc changes in analytical protocols after initial statistical findings indicated an additive-associated increase in cigarette toxicity as well as increased total particulate matter (TPM) concentrations in additive-modified cigarette smoke. By expressing the data adjusted by TPM concentration, the published papers obscured this underlying toxicity and particulate increase. The animal toxicology results were based on a small number of rats in each experiment, raising the possibility that the failure to detect statistically significant changes in the end points was due to underpowering the experiments rather than lack of a real effect. CONCLUSION: The case study of Project MIX shows tobacco industry scientific research on the use of cigarette additives cannot be taken at face value. The results demonstrate that toxins in cigarette smoke increase substantially when additives are put in cigarettes, including the level of TPM. In particular, regulatory authorities, including the FDA and similar agencies elsewhere, could use the Project MIX data to eliminate the use of these 333 additives (including menthol) from cigarettes. PMID- 22205886 TI - A comprehensive framework for human resources for health system development in fragile and post-conflict states. PMID- 22205887 TI - Sex-specific immunization for sexually transmitted infections such as human papillomavirus: insights from mathematical models. AB - BACKGROUND: Sex-specific differences regarding the transmissibility and the course of infection are the rule rather than the exception in the epidemiology of sexually transmitted infections (STIs). Human papillomavirus (HPV) provides an example: disease outcomes differ between men and women, as does the potential for transmission to the opposite sex. HPV vaccination of preadolescent girls was recently introduced in many countries, and inclusion of boys in the vaccination programs is being discussed. Here, we address the question of whether vaccinating females only, males only, or both sexes is the most effective strategy to reduce the population prevalence of an STI like HPV. METHODS AND FINDINGS: We use a range of two-sex transmission models with varying detail to identify general criteria for allocating a prophylactic vaccine between both sexes. The most effective reduction in the population prevalence of infection is always achieved by single-sex vaccination; vaccinating the sex with the highest prevaccine prevalence is the preferred strategy in most circumstances. Exceptions arise only when the higher prevaccine prevalence is due to a substantially lower rate of natural immunity, or when natural immunity is lifelong, and a prolonged duration of infectiousness coincides with increased transmissibility. Predictions from simple models were confirmed in simulations based on an elaborate HPV transmission model. Our analysis suggests that relatively inefficient genital transmission from males to females might render male vaccination more effective in reducing overall infection levels. However, most existing HPV vaccination programs have achieved sufficient coverage to continue with female-only vaccination. CONCLUSIONS: Increasing vaccine uptake among preadolescent girls is more effective in reducing HPV infection than including boys in existing vaccination programs. As a rule, directing prophylactic immunization at the sex with the highest prevaccine prevalence results in the largest reduction of the population prevalence. PMID- 22205888 TI - Non-cell-autonomous RNA interference in mammalian cells: Implications for in vivo cell-based RNAi delivery. AB - RNA interference (RNAi) is a post-transcriptional pathway in which double stranded RNA (dsRNA) triggers the degradation of complementary mRNA in the cytoplasm of eukaryotic cells. In plants and in some animals, including Caenorhabditis elegans, initiation of RNAi in one cell can lead to sequence specific RNA silencing in another cell, a phenomenon referred to as non-cell autonomous RNAi. Until recently, this phenomenon had not been observed in mammalian cells. Here, we review emerging data demonstrating that non-cell autonomous RNAi occurs in cultured mammalian cells. We discuss possible mechanisms for the transfer of RNAi between mammalian cells and highlight the implications of this phenomenon for the development of in vivo cell-based RNAi delivery. PMID- 22205889 TI - Genetic biomarkers for neoplastic colorectal cancer in peripheral lymphocytes. AB - BACKGROUND: Loss of genomic stability appears as a key step in colorectal carcinogenesis. Micronucleus (MN) designates a chromosome fragment or an entire chromosme which lags behind mitosis. MN may be noticed as an additional nucleus within the cytoplasm cell during the intermediate mitosis phases. We tested the hypothesis that MN and its related anomalies may be associated with the presence of neoplastic colorectal lesions. METHOD: Peripheral blood lymphocytes were cultured and microscopically examined. The frequency of micronuclei (FMN) and the presence of nucleoplasmic bridges (NPB) in binucleated cells were compared in patients with of without colorectal neoplastic lesions. RESULTS: We included 45 patients undergoing colonoscopy, 23 males and 22 females, with a median age of 59. 17 patients had polyps, 11 colorectal cancer (CRC) and 17 had a normal colonoscopy. The FMN was significantly higher in women than in men (8.14 vs 4.17, p=0.008); NPB were significantly less frequent in patients with advanced adenomas (>10mm or vilous) or CRC (p=0.044) when compared with patients with normal colonoscopy, hiperplastic polyps or non-advanced adenomas. CONCLUSION: Micronuclei are more frequent in women, but its frequency was not significantly different in patients with advanced adenomas or CRC. Null or low frequency values for nucleoplasmic bridges presence in peripheral lymphocyte may be predictive for advanced adenomas and colorectal cancer. PMID- 22205891 TI - Immunotherapy with rituximab in follicular lymphomas. AB - BACKGROUND: Non-Hodgkin Lymphomas (NHL) represent a recent and fascinating domain of hemato-oncology, in which remarkable progress has been made. The conventional treatments of indolent lymphomas do not extend the survival rate, nor do they cure. Recent directions are centered on using several new drugs that are capable of overcoming the mechanisms that are resistant to recovery. The initiation of immunotherapy (Rituximab in 1997) seems to have changed the natural evolution of follicular lymphomas (FL). It is possible that resistance to healing in follicular lymphomas may be neutralized with Rituximab by suppressing STAT-1 positive macrophages that are present in the cellular microenvironment.Thereinafter, the re-evaluation of recent models of prognostic and therapeutic paradigmas that were used in FL became compulsory.The purpose of the paper is to compare the evolution of patients with follicular lymphoma and the period of response, according to the treatments. MATERIAL AND METHOD: The study group consisted of the 71 patients diagnosed with follicular lymphoma, out of a total of 767 malignant lymphatic proliferations with B cells, for a period of 7 years (2002-2008), at the Hematology Department, Hospital Coltea, Bucharest and Hematology Department, Universitary Hospital, BucharestResults and conclusions: Combining chemotherapy with Rituximab had better results compared to the same chemotherapy, administered alone, both in induction and in case of relapse. The overall response rate in our study group was 74.7%, out of which 42.3% complete remissions. The overall response rate was 84.61% in the Rituximab group, compared to 68.88% in patients without Rituximab. PMID- 22205890 TI - Predictive Factors of Obesity and their Relationships to Dietary Intake in Schoolchildren in Western Algeria. AB - BACKGROUND: Obesity has reached epidemic proportions world-wide. Its risk factors are poorly studied, especially among children in developing countries such as Algeria. OBJECTIVES: The purpose of this study was therefore to determine the prevalence and risk factors of obesity in Algerian schoolchildren 6 to 8 years aged by conducting a school-site retrospective cohort study in Tlemcen Department (western Algeria).Material and Mthods: From 2008 to 2010, socio-demographic characteristics, body mass index (BMI), physical activity categories, lifestyle and nutritional habits of 1520 children (839 boys and 681 girls), at entrance into primary school, were recorded using a self-administered questionnaire. RESULTS: Among the 1520 participants, 99 (6.5%) were obese. Birthweight <= 2.5 kg and >= 4 kg, early introduction of solid foods and low physical activity were significantly associated with obesity (p<0.001). Additionally, mother's and grandmother's BMI >=30 kg/m(2), fewer children in the household, higher parental education, household income and the presence of familial obesity may predispose significantly to childhood obesity (p<0.001). Furthermore, child's BMI was significant positively correlated with total energy, fat and saturated fatty acid (SFA) intakes (p<0.01). Mother's and grandmother's BMI were significant positively correlated with child total energy, fat and SFA intakes. Physical activity score was significant negatively correlated with child total energy, fat and SFA (p<0.01) intakes in obese children. CONCLUSIONS: Mother's and grandmother's obesity, excess energy and fat intakes and low physical activity are the strong predictors of childhood obesity in Algeria. Preventive measures should focus on the promotion of physical activity and maternal and children nutritional education. PMID- 22205892 TI - The advantage of arthroscopic anterior cruciate ligament reconstruction with autograft from the tendons of the semitendinosus - gracilis muscles for the recovery of the stability of the knee. AB - Anterior cruciate ligament (ACL) injuries remain a common orthopaedic disease, particularly in young adults. The treatment of choice for ACL injuries is ACL reconstruction (ligamentoplasty). ACL reconstruction is the surgical intervention used to replace the damaged ACL with a bone-patella tendon-bone (BTB) graft or with soft parts (semitendinosus - gracilis muscles (ST-G) - a method more frequently used nowadays). MATERIALS AND METHOD: In the Clinic of Orthopedics and Traumatology of the University Emergency Hospital of Bucharest, during the period 01.01.2009 - 01.03.2011, a number of 37 arthroscopic ACL reconstructions with ST G were studied, performed to treat ACL isolated injuries or injuries associated with complex trauma of the knee. RESULTS: Clinical studies have shown that ACL reconstruction is highly superior to ACL repair (suturing). Arthroscopy was the main method of diagnosis in 28 cases, whereas the remaining ACL injuries were diagnosed using the MRI. CONCLUSIONS: The rehabilitation of the patients who underwent arthroscopic ACL reconstructions with ST-G was easier and faster in comparison with that following the surgical interventions performed with BTB graft during the previous years. PMID- 22205893 TI - Difficulties in achieving arterial hypertension control. AB - OBJECTIVE: Our study aims to examine the effectiveness of arterial hypertension treatment on arterial pressure values in a group of people, by gender and age. MATERIAL AND METHODS: We performed an analytical prospective study, from 2007 to 2009, that included 2266 people; 674 subjects (397 women and 277 men) were diagnosed with essential systemic arterial hypertension, according to ESH (European Society of Hypertension) criteria. Medium age was 49 years. Therapy applied to all diagnosed patients consisted in: general measures (lifestyle modifications) and pharmacological treatment. Medication regimens implied: one agent (single drug therapy: inhibitors of angiotensin converting enzyme or angiotensin receptors blockers), two, three or more combined drugs (we used a combination of inhibitors of angiotensin converting enzyme or angiotensin receptors blockers and diuretics, beta-blockers, calcium channel blockers). Patients were followed up at 1 month, 3 and 6 month from the beginning of the study. Statistics used was EpiInfo6. RESULTS: Hypertension control was obtained for 33.38% of all patients; a better control was noticed for feminine gender (35.52%) over masculine gender (30.33%); distribution on age group showed the best control of the disease for the group aged 41 to 60 years old (19.92%) over those aged under 40 years (1.93%) and over 60 years (12.17%). CONCLUSIONS: Patient's poor compliance to treatment generates a suboptimal hypertension control, emphasizing that efforts for achieving goal blood pressure should continue. PMID- 22205894 TI - The Role of 4D Ultrasound in the Assessment of Fetal Behaviour. AB - Fetal behavior is defined as any fetal action seen by the mother or fetus diagnosed by objective methods such as cardiotocography (CTG) or ultrasound. Analysis of the dynamics of the fetal behavior with morphological studies has lead to the conclusion that fetal behavior patterns are directly reflecting development and maturation of the central nervous system. The assessment of fetal behavior by 4D ultrasound could allow distinction between normal and abnormal fetal behavior patterns which might make possible the early recognition of fetal brain impairment. AIM: Assessment of fetal movements throughout the pregnancy using 4D ultrasound. MATERIAL AND METHOD: The study group included 144 healthy pregnant women with single pregnancies between 7-38 weeks of gestation. For the first trimester of pregnancy we assessed eight types of fetal movements and for the second and third trimesters 14 types of fetal movements and facial expressions. The analyzed parameters for each trimester of pregnancy can be used for performing antenatal neurodevelopment test, used the first time by Professor Kurjak. RESULTS: After 15-20 minutes 4D ultrasound examination, we found a pattern of fetal behavior for each trimester of pregnancy. CONCLUSIONS: Dynamic evaluation of fetal behavior reflects directly the processes of maturation and development of the central nervous system. This can make the difference between normal and abnormal brain development and may be used for early diagnosis of neurological disorders that become manifest in perinatal and postnatal periods. PMID- 22205895 TI - Myositis ossificans traumatica of the neck - a pediatric case. AB - Myositis ossificans circumscripta (MOC) is an extra-osseous non- neoplastic growth of a new bone. It occurs most commonly in the second and the third decade of life, while it is rare in children. The etiology of MOC is unknown and the quadriceps and brachials are the most affected. The occurrence of traumatic MOC in tissues of the neck is uncommon. We are presenting below a rare case of traumatic myositis ossificans occurring in sternocleidomastoid and trapezius muscles in a 17-year-old girl. PMID- 22205896 TI - A rare chromosomal disorder - isochromosome 18p syndrome. AB - BACKGROUND: Tetrasomy 18p is a very rare chromosomal disorder and is the result of a spontaneous mutation early in embryonic development in most of the cases. This condition is characterised by the presence of a supernumerary 18p isochromosome (i(18p)) in all or some cells of the affected individual. It has a prevalence of 1/180000 live births and affects both genders equally. MATERIALS AND METHODS: In this paper we report a de novo tetrasomy 18p in a 3 months old female dysmorphic child. The clinical features were distinctive with a particular facies, strabismus, microcephaly, growth delay, neonatal hypertonia and talipes varus. An additional small metacentric marker chromosome has been identified after standard cytogenetic analysis, without recognized parental origin of the supplementary genetic material. The child's parents were also tested and their karyotype results were normal. The characterization of the marker chromosome was performed in our genetics laboratory using conventional cytogenetic methods and Fluorescence in Situ Hybridization (FISH) analysis. Also, our patient was compared with other published cases with the same diagnosis. CONCLUSION: Cytogenetic investigation is an essential step towards the accurate diagnosis of individuals with clinical suspicion of a genetic anomaly. Also, this type of investigation could offer critical information to the practitioner for prognosis of patient and the correct appreciation of the recurrence risk of a certain genetic condition.With current advances in preventive and interventional procedures, patients with rare chromosomal disorders can live longer. Therefore, proper medical and behavioural management of each case is important for the enhancement of the quality of life for the patients and their families. PMID- 22205897 TI - The role of uterine artery embolization in cervical cancer - single case report. AB - Massive vaginal bleeding represents one of the emergencies that the gynecologists have to deal with. When unresponsive to the haemostatic treatment (local or iv), the bleeding can be stopped by using the uterine artery embolization. It provides visualization of the bleeding site and enables targeted, minimally invasive therapy to achieve hemostasis. We present a case of a patient with cervical cancer associated with massive vaginal bleeding and the beneficial effects of the uterine artery embolization in the therapy management. PMID- 22205898 TI - Associated pulmonary arterial hypertension in connective tissue diseases. AB - In recent years, major advances have been achieved in the understanding of pulmonary arterial hypertension (PAH) patho-physiology. Associated pulmonary arterial hypertension (APAH) can occur in a variety of other conditions and circumstances including a number of systemic autoimmune diseases. As with PAH in general, clinical symptoms of APAH in systemic autoimmune diseases are unspecific. In addition, there is a long standing association between autoimmunity and APAH. It has been postulated that autoimmunity may play a role in the pathogenesis of APAH. This argument has been based on frequent coexisting clinical and serological rheumatic findings. There is no experimental model of immune mechanism-dependent severe APAH. The loss of self-tolerance could initiate a process which ultimately results in APAH. It is possible that T-cell deficiencies (in either function or number) may contribute to pulmonary vascular injury or disease. These conditions are often associated with autoantibodies as well as defects in the CD4 T-cell compartiment. However, it remains uncertain how autoimmune mechanisms contribute to the pathogenesis of APAH. There are data that show a significant association between APAH and connective tissue diseases (CTD). In this regard, systemic sclerosis, mixed connective tissue disease, systemic lupus erythematosus, dermato/polymyositis and primary Sjogren's syndrome are associated with APAH. The study of APAH in the systemic autoimmune diseases and its relation to basic immunologic disturbances may yet bring effective therapies in the future. APAH can be a severe complication attracting a high excess mortality in autoimmune diseases. The present review will focus on what is known about autoimmune phenomena in APAH patients. PMID- 22205899 TI - Ocular changes and approaches of ophthalmopathy in basedow - graves- parry- flajani disease. AB - Basedow-Graves disease is an autoimmune condition with multiple local and systemic aspects. Among these, oculopathy has a major impact on patient's life from both functional and esthetic point of view. Basedow-Graves oculopathy requires an appropriate positive and differential diagnosis using clinical and imagistic approaches. Treatment is always required in moderate or severe forms and it begins with simple general points and continues with medical and surgical therapies. Current article stresses upon the most characteristic clinical signs of thyroidian ophthalmopathy and the required current therapeutic approaches. PMID- 22205900 TI - Update in cardiology. PMID- 22205901 TI - Update in gastroenterology. PMID- 22205902 TI - Update in anesthesia and intensive care. PMID- 22205903 TI - Update in pediatrics: to take or not to take soft drinks, sports or energy drinks? PMID- 22205904 TI - Update in immunology. PMID- 22205905 TI - Update in physical medicine and rehabilitation: new technologies and robots versus classical training in gait rehabilitation after stroke. PMID- 22205906 TI - Update in stomatology: assuring dental student head and neck cancer screening competency. PMID- 22205907 TI - GMA Annual Conference 2011 in Munich - Conference Report. PMID- 22205908 TI - Academisation of the health professions - achievements and future prospects. PMID- 22205909 TI - The Munich Declaration - Key points for the establishment teaching in the new cross-disciplinary area 13: palliative medicine at German faculties. PMID- 22205910 TI - Breaking bad news - an interdisciplinary curricular teaching-concept. AB - BACKGROUND: The concerns of patients suffering from life-threatening disease and end-of-life care aspects have gained increasing attention in public perception. The increasing focus on palliative medicine questions can be considered to be paradigmatic for this development. Palliative medicine became a compulsory subject of the undergraduate curriculum in Germany to be implemented until 2013. The preexisting conditions and qualifications at the medical faculties vary, though. We describe the conceptual process, didactic background, and first experiences with the new interdisciplinary course "Delivering bad news" as a compulsory part of the palliative medicine curriculum. METHODS: Since autumn 2009, this course has been taught at the University Medical Center Gottingen, consisting of two double lessons in the final year of medical education. Considering the curriculum-based learning goals in Gottingen, the focus of this course is to impart knowledge, attitudes and communication skills relating to "bad news". RESULTS: Although the seminar requires adequate staff and is time consuming, students have accepted it and gave high marks in evaluations. In particular, the teachers' performance and commitment was evaluated positively. DISCUSSION AND CONCLUSIONS: We describe the first experiences with a new course. Didactic structure, theoretical contents, role-plays and usage of media (film, novel) are well- suited to communicate topics such as "bad news". Additional experiences and evaluations are necessary. According to the progressive nature of learning, it might be worthwhile to repeat communication- centered questions several times during medical studies. PMID- 22205911 TI - Leadership and cooperation at the general medicine department of LMU Munich: Good grades despite difficult conditions. AB - The relevance of general medicine at German universities will increase over the next few years. Consequently, the discussion of teaching content and even more the improvement of the structures within the still small and dependent departments of general medicine are of major importance. The example of our department at LMU Munich shows which challenges for leadership and cooperation result from lack of financial and personnel structure. The project "cooperation culture" that the department has conducted in collaboration with the LMU Center for Leadership and People Management is presented as a means to promote leadership and cooperation. This project can serve as an inspiration for the coordinators of smaller departments of general medicine at other German universities that are also striving to improve their structure and their position within the university. PMID- 22205912 TI - The communication skills course for second year medical students at Hannover Medical School: An evaluation study based on students' self-assessments. AB - In the model medical curriculum HannibaL at Hannover Medical School (MHH, Hannover, Germany), communication skills in taking case histories and disclosing diagnoses (breaking bad news) are assessed through an objective structured clinical examination (OSCE). This is part of the examinations which at the MHH represent the equivalent to the First Part of the Medical Examinations. The second year doctor-patient communication course preparing for these examinations was evaluated during the 2009/10 academic year.Using questionnaires specific to the learning objectives, learning needs were assessed, pre-post comparisons of self-assessed competencies were performed and key teaching methods were evaluated (5-point Likert scales, "5"=fully agree). At T0 (start of the course) 267 students participated (response rate: 93.7%), of which 180 filled out the T1 questionnaire during the last session of the course (67.4%). Within-subject analyses of variance and paired t-tests were conducted.The highest learning needs were found for the "to show how"-items regarding history taking and disclosing diagnoses (M=4.4). The T1-T0 comparisons showed the greatest improvements for history taking ("to know how": mean difference = +1.7, "to show how": +1.8, p<.0001 as with all tests) and the "to know how"-item regarding the disclosure of diagnoses (+1.6), followed by the "to show how"-items on disclosing a diagnosis (+1.4), shared decision making (+1.2), self-assessing one's own strengths/weaknesses (+1.0) and confidently approaching new patients (+0.7). Students with T0 values of 1 or 2 on the respective scales improved on average by 2.2 points across all items, students with the value of 3 by 1.1, and from 4 or 5 by 0.1. Methodically, the use of simulated patients was rated the most helpful (M=4.8, 87% with the scale value 5). This doctor-patient communication course is associated with substantial improvements regarding all key learning objectives. Regarding methods, the deployed simulated patients (2-4 per 10-student-course group in 3 of the 7 course sessions, respectively) were rated the most helpful. The present evaluation calls for both further development of the doctor-patient communication curriculum at the MHH and joint activities across medical schools, which are discussed at the end of the paper. PMID- 22205913 TI - Cost analysis for computer supported multiple-choice paper examinations. AB - INTRODUCTION: Multiple-choice-examinations are still fundamental for assessment in medical degree programs. In addition to content related research, the optimization of the technical procedure is an important question. Medical examiners face three options: paper-based examinations with or without computer support or completely electronic examinations. Critical aspects are the effort for formatting, the logistic effort during the actual examination, quality, promptness and effort of the correction, the time for making the documents available for inspection by the students, and the statistical analysis of the examination results. METHODS: Since three semesters a computer program for input and formatting of MC-questions in medical and other paper-based examinations is used and continuously improved at Wuerzburg University. In the winter semester (WS) 2009/10 eleven, in the summer semester (SS) 2010 twelve and in WS 2010/11 thirteen medical examinations were accomplished with the program and automatically evaluated. For the last two semesters the remaining manual workload was recorded. RESULTS: The cost of the formatting and the subsequent analysis including adjustments of the analysis of an average examination with about 140 participants and about 35 questions was 5-7 hours for exams without complications in the winter semester 2009/2010, about 2 hours in SS 2010 and about 1.5 hours in the winter semester 2010/11. Including exams with complications, the average time was about 3 hours per exam in SS 2010 and 2.67 hours for the WS 10/11. DISCUSSION: For conventional multiple-choice exams the computer-based formatting and evaluation of paper-based exams offers a significant time reduction for lecturers in comparison with the manual correction of paper-based exams and compared to purely electronically conducted exams it needs a much simpler technological infrastructure and fewer staff during the exam. PMID- 22205914 TI - Student Evaluation Scale for Medical Courses with Simulations of the Doctor Patient Interaction (SES-Sim). AB - OBJECTIVE: Simulations of doctor-patient interactions have become a popular method for the training of medical skills, primarily communication skills. A new questionnaire for the measurement of students' satisfaction with medical courses using this technique is presented, the Student Evaluation Scale for Medical Courses with Simulations of the Doctor-Patient Interaction (SES-Sim). METHOD: A set of items focusing on the course quality and the core elements of simulations was created and presented to 220 medical students who had been trained with this method. RESULTS: Based on factor-analyses 18 items were selected for the final version of the scale, which represent five dimensions: learning success, actors, premises, tutors and students. The five dimensions are all significantly correlated with a 1-item-measure of the general satisfaction with the course. CONCLUSION: The SES-Sim enables tutors to assess in an economic way whether the course has met the students' needs and what can be done better. PMID- 22205915 TI - Interactive versus reproductive learning, a comparison of medical school graduates with participants of a postgraduate CPD session. AB - AIMS: In order to develop the e-learning teaching material for medical professionals who are not physicians, we compared solution-based interactive and reading-based reproductive learning with regard to the increase of knowledge. Furthermore we tried to identify additional factors influencing learning. METHODS: We used a quasi-experimental double-stage study design with pre-test (point of time t(1)), intervention and post-test (point of time t(2)). The classification into three comparable groups was carried out according to the pre test results. The interactive and reproductive group participated in the intervention but not the control group. All three groups consisted of graduates of medical schools (N=150) and more experienced physiotherapists during continuing training (N=66). The increase of knowledge was assessed by the post test. The analysis of variance was the most important statistical tool. RESULTS: Interactive learning generated a higher increase of knowledge than reproductive learning but was more time consuming. The two groups which participated in the intervention obtained better results than the control group. The level of education and the prior knowledge also influenced the post-test results. CONCLUSION: We recommend combining interactive and reproductive approaches for designing the e-learning platform. PMID- 22205917 TI - Regulation of emotions in the community: suppression and reappraisal strategies and its psychometric properties. AB - OBJECTIVE: The German Version of the Emotion Regulation Questionnaire (ERQ) has recently been published. The questionnaire investigates two common emotion regulation strategies (10 items) on two scales (suppression, reappraisal). Major aims of the study were to assess the reliability and factor structure of the ERQ, to determine population based norms and to investigate relations of suppression and reappraisal to anxiety, depression and demographic characteristics. METHODS: In a representative community study (N=2524) we assessed emotion regulation strategies, anxiety, depression (Hospital Anxiety and Depression Scale), and demographic variables. The mean age of the participants was 49.4 (SD 18.2) years. 55.5% were female. The age-groups were represented in comparable proportions. The representativeness of the sample was ensured by drawings of ADM (Arbeitskreis Deutscher Marktforscher) samples und by comparison with the data of German Federal Statistical Office. RESULTS: Confirmatory factor analysis could not fully confirm the original factor structure, we kept the original scaling, except a modification regarding item 8. Internal consistencies were acceptable for the original and the modified version: reappraisal (Cronbach's alpha = 0.82) and suppression (alpha = 0.76). Norms are presented as percentile scores for age groups and gender. Reappraisal correlated negative with anxiety and depression, whereas we could find a positive relationship of suppression with anxiety and depression. In a linear regression model suppression was predicted by depression, a lower level of education, male gender, and lower income. CONCLUSIONS: The ERQ is a short instrument to assess emotion regulation strategies economically, e.g. in larger community based studies. We could demonstrate sufficient psychometric properties of the German version of the ERQ: reliability, factor structure and indicators for construct validity. Because of the cross sectional character of our study it remains unclear whether reappraisal is protective and suppression is unfavourable regarding mental health or whether life circumstances and psychic symptoms lead to a suppression of emotions. PMID- 22205916 TI - A consensus statement on practical skills in medical school - a position paper by the GMA Committee on Practical Skills. AB - INTRODUCTION: Encouraged by the change in licensing regulations the practical professional skills in Germany received a higher priority and are taught in medical schools therefore increasingly. This created the need to standardize the process more and more. On the initiative of the German skills labs the German Medical Association Committee for practical skills was established and developed a competency-based catalogue of learning objectives, whose origin and structure is described here. Goal of the catalogue is to define the practical skills in undergraduate medical education and to give the medical schools a rational planning basis for the necessary resources to teach them. METHODS: Building on already existing German catalogues of learning objectives a multi-iterative process of condensation was performed, which corresponds to the development of S1 guidelines, in order to get a broad professional and political support. RESULTS: 289 different practical learning goals were identified and assigned to twelve different organ systems with three overlapping areas to other fields of expertise and one area of across organ system skills. They were three depths and three different chronological dimensions assigned and the objectives were matched with the Swiss and the Austrian equivalent. DISCUSSION: This consensus statement may provide the German faculties with a basis for planning the teaching of practical skills and is an important step towards a national standard of medical learning objectives. LOOKING AHEAD: The consensus statement may have a formative effect on the medical schools to teach practical skills and plan the resources accordingly. PMID- 22205918 TI - Percutaneous coronary intervention with optimal medical therapy vs. optimal medical therapy alone for patients with stable angina pectoris. AB - SCIENTIFIC BACKGROUND: Stable Angina Pectoris (AP) is a main syndrome of chronic coronary artery disease (CAD), a disease with enormous epidemiological and health economic relevance. Medical therapy and percutaneous coronary interventions (PCI) are the most important methods used in the treatment of chronic CAD. RESEARCH QUESTIONS: The evaluation addresses questions on medical efficacy, incremental cost-effectiveness as well as ethic, social and legal aspects in the use of PCI in CAD patients in comparison to optimal medical therapy alone. METHODS: A systematic literature search was conducted in June 2010 in the electronic databases (MEDLINE, EMBASE etc.) and was completed by a hand search. The medical analysis was initially based on systematic reviews of randomized controlled trials (RCT) and was followed by the evaluation of RCT with use of current optimal medical therapy. The results of the RCT were combined using meta analysis. The strength and the applicability of the determined evidence were appraised. The health economic analysis was initially focused on the published studies. Additionally, a health economic modelling was performed with clinical assumptions derived from the conducted meta-analysis and economic assumptions derived from the German Diagnosis Related Groups 2011. RESULTS: Seven systematic reviews (applicability of the evidence low) and three RCT with use of optimal medical therapy (applicability of the evidence for the endpoints AP and revascularisations moderate, for further endpoints high) were included in the medical analysis. The results from RCT are used as a base of the evaluation. The routine use of the PCI reduces the proportion of patients with AP attacks in the follow-up after one and after three years in comparison with optimal medical therapy alone (evidence strength moderate); however, this effect was not demonstrated in the follow-up after five years (evidence strength low). The difference in effect in the follow-up after four to five years was not found for the further investigated clinical endpoints: death, cardiac death, myocardial infarction and stroke (evidence strength high) as well as for severe heart failure (evidence strength moderate). Two studies were included in the health economic analysis. The costs estimations from these studies are not directly transferable to the corresponding costs in Germany. The average difference in the total costs for PCI in comparison with optimal medical therapy alone, which was calculated in the modelling, was found to be 4,217 Euro per patient. The incremental cost-effectiveness ratio per life-year of a patient with avoided AP attacks was estimated to be 24,805 Euro (evidence strength moderate). No publication was identified concerning ethical, social or legal aspects. DISCUSSION: Important methodical problems of the studies are a lack of blinding of the patients and incomplete data for several endpoints in the follow-up. The determined incremental cost-effectiveness ratio per life-year of a patient with avoided AP attacks was appraised not to be cost-effective. CONCLUSIONS: From a medical point of view the routine use of PCI in addition to the optimal medicinal therapy in patients with stable AP can be recommended for the reduction of the proportion of patients with AP attacks after one year and after three years (recommendation degree weak). Otherwise, PCI is to be performed in patients with refractory or progressing AP despite of optimal medical therapy use; in this case PCI is expected to be applied in 27% to 30% of patients in five years. From the health economic view the routine use of PCI in addition to an optimal medical therapy in patients with stable AP cannot be recommended. No special considerations can be made concerning special ethical, social or legal aspects in the routine use of PCI in addition to optimal medical therapy in patients with stable AP. PMID- 22205919 TI - Prognostic factors of resected node-positive lung cancer: location, extent of nodal metastases, and multimodal treatment. AB - OBJECTIVE: To investigate the prognostic significance of location and extent of lymph node metastasis in resected non-small cell lung cancer (NSCLC), and to weigh up the influence of treatment modalities on survival. PATIENTS AND METHOD: On exploratory analysis, patients were grouped according to location and time of diagnosis of nodal metastasis: group I, pN2-disease in the aortopulmonary region (N=14); group II, pN2-disease at other level (N=30); group III, cN2-disease with response to induction treatment (ypN0; N=21); group IV, cN2-disease without response to induction treatment (ypN1-2; N=27); group V, pN1-disease (N=66). RESULTS: From 1999 to 2005, 158 patients (median age: 64 years) with node positive NSCLC were treated at our institution either by neoadjuvant chemo radiotherapy plus surgery or by surgery plus adjuvant therapy (chemotherapy, radiotherapy, or both). Operative mortality and major morbidity rates were 2% and 15%. Five-year survival rates were 19% for group I, 12% for group II, 66% for group III, 15% for group IV, and 29% for group V (P<.05). On multivariate analysis, time of N+-diagnosis, extent of nodal involvement and therapy approach were significantly linked to prognosis. CONCLUSION: The survival of patients with node-positive NSCLC does not depend on anatomical location of nodal disease, but strongly correlates to extent of nodal metastases and treatment modality. Combined therapy approaches including chemotherapy and surgery may improve long term survival. PMID- 22205920 TI - A simple negative interaction in the positive transcriptional feedback of a single gene is sufficient to produce reliable oscillations. AB - Negative and positive transcriptional feedback loops are present in natural and synthetic genetic oscillators. A single gene with negative transcriptional feedback needs a time delay and sufficiently strong nonlinearity in the transmission of the feedback signal in order to produce biochemical rhythms. A single gene with only positive transcriptional feedback does not produce oscillations. Here, we demonstrate that this single-gene network in conjunction with a simple negative interaction can also easily produce rhythms. We examine a model comprised of two well-differentiated parts. The first is a positive feedback created by a protein that binds to the promoter of its own gene and activates the transcription. The second is a negative interaction in which a repressor molecule prevents this protein from binding to its promoter. A stochastic study shows that the system is robust to noise. A deterministic study identifies that the dynamics of the oscillator are mainly driven by two types of biomolecules: the protein, and the complex formed by the repressor and this protein. The main conclusion of this paper is that a simple and usual negative interaction, such as degradation, sequestration or inhibition, acting on the positive transcriptional feedback of a single gene is a sufficient condition to produce reliable oscillations. One gene is enough and the positive transcriptional feedback signal does not need to activate a second repressor gene. This means that at the genetic level an explicit negative feedback loop is not necessary. The model needs neither cooperative binding reactions nor the formation of protein multimers. Therefore, our findings could help to clarify the design principles of cellular clocks and constitute a new efficient tool for engineering synthetic genetic oscillators. PMID- 22205923 TI - Analysis of inducible nitric oxide synthase gene polymorphisms in vitiligo in Han Chinese people. AB - BACKGROUND: Vitiligo is a chronic depigmented skin disorder with regional melanocytes depletion. The pathogenesis was not completely clarified. Recently, more and more evidence suggested that polymorphisms of some genes are associated with vitiligo risk. Here, we want to examine the association between the inducible nitric oxide synthase (iNOS) gene polymorphisms and the risk of vitiligo in Chinese populations. METHODS AND PRINCIPAL FINDINGS: In a hospital based case-control study of 749 patients with vitiligo and 763 age- and sex matched healthy controls, three polymorphisms of iNOS gene were genotyped by using the PCR-restriction fragment length polymorphism (PCR-RFLP) and mutagenically separated PCR (MS-PCR) methods, respectively. We found the iNOS-954 polymorphism was associated with a significantly higher risk of vitiligo (adjusted OR = 1.36, 95% CI = 1.02-1.81). Furthermore, this association is more pronounced in vulgaris vitiligo, active vitiligo and vitiligo without other autoimmune diseases in the stratification study. Analysis of haplotypes showed increased risk for the C-1173C-954C(Ex16+14) (OR = 1.44, 95% CI = 1.01-1.74). In addition, the serum iNOS activity is significantly associated with iNOS-954 combined genotype (GC+CC) and is much higher in vitiligo patients than in the controls (P<0.01). Logistic regression analysis of iNOS activity showed increased risk between higher activity and iNOS-954 G->C variant genotype carriers (P(trend)<0.001). CONCLUSIONS AND SIGNIFICANCE: INOS gene polymorphisms may play an important role in the genetic susceptibility to the development of vitiligo. PMID- 22205924 TI - The role of pre-existing diabetes mellitus on hepatocellular carcinoma occurrence and prognosis: a meta-analysis of prospective cohort studies. AB - BACKGROUND: The impact of pre-existing diabetes mellitus (DM) on hepatocellular carcinoma (HCC) occurrence and prognosis is complex and unclear. The aim of this meta-analysis is to evaluate the association between pre-existing diabetes mellitus and hepatocellular carcinoma occurrence and prognosis. METHODS: We searched PubMed, Embase and the Cochrane Library from their inception to January, 2011 for prospective epidemiological studies assessing the effect of pre-existing diabetes mellitus on hepatocellular carcinoma occurrence, mortality outcomes, cancer recurrence, and treatment-related complications. Study-specific risk estimates were combined by using fixed effect or random effect models. RESULTS: The database search generated a total of 28 prospective studies that met the inclusion criteria. Among these studies, 14 reported the risk of HCC incidence and 6 studies reported risk of HCC specific mortality. Six studies provided a total of 8 results for all-cause mortality in HCC patients. Four studies documented HCC recurrence risks and 2 studies reported risks for hepatic decomposition occurrence in HCC patients. Meta-analysis indicated that pre existing diabetes mellitus (DM) was significantly associated with increased risk of HCC incidence [meta-relative risk (RR) = 1.87, 95% confidence interval (CI): 1.15-2.27] and HCC-specific mortality (meta-RR = 1.88, 95%CI: 1.39-2.55) compared with their non-DM counterparts. HCC patients with pre-existing DM had a 38% increased (95% CI: 1.13-1.48) risk of death from all-causes and 91% increased (95%CI: 1.41-2.57) risk of hepatic decomposition occurrence compared to those without DM. In DM patients, the meta-RR for HCC recurrence-free survival was 1.93(95%CI: 1.12-3.33) compared with non-diabetic patients. CONCLUSION: The findings from the current meta-analysis suggest that DM may be both associated with elevated risks of both HCC incidence and mortality. Furthermore, HCC patients with pre-existing diabetes have a poorer prognosis relative to their non diabetic counterparts. PMID- 22205925 TI - Innate structure of DNA foci restricts the mixing of DNA from different chromosome territories. AB - The distribution of chromatin within the mammalian nucleus is constrained by its organization into chromosome territories (CTs). However, recent studies have suggested that promiscuous intra- and inter-chromosomal interactions play fundamental roles in regulating chromatin function and so might define the spatial integrity of CTs. In order to test the extent of DNA mixing between CTs, DNA foci of individual CTs were labeled in living cells following incorporation of Alexa-488 and Cy-3 conjugated replication precursor analogues during consecutive cell cycles. Uniquely labeled chromatin domains, resolved following random mitotic segregation, were visualized as discrete structures with defined borders. At the level of resolution analysed, evidence for mixing of chromatin from adjacent domains was only apparent within the surface volumes where neighboring CTs touched. However, while less than 1% of the nuclear volume represented domains of inter-chromosomal mixing, the dynamic plasticity of DNA foci within individual CTs allows continual transformation of CT structure so that different domains of chromatin mixing evolve over time. Notably, chromatin mixing at the boundaries of adjacent CTs had little impact on the innate structural properties of DNA foci. However, when TSA was used to alter the extent of histone acetylation changes in chromatin correlated with increased chromatin mixing. We propose that DNA foci maintain a structural integrity that restricts widespread mixing of DNA and discuss how the potential to dynamically remodel genome organization might alter during cell differentiation. PMID- 22205926 TI - Defects of protein phosphatase 2A causes corticosteroid insensitivity in severe asthma. AB - BACKGROUND: Corticosteroid insensitivity is a major barrier of treatment for some chronic inflammatory diseases, such as severe asthma, but the molecular mechanism of the insensitivity has not been fully elucidated. The object of this study is to investigate the role of protein phosphate 2A (PP2A), a serine/threonine phosphatase, on corticosteroid sensitivity in severe asthma. METHODOLOGY/PRINCIPAL FINDINGS: Corticosteroid sensitivity was determined by the dexamethasone ability to inhibit TNFalpha-induced IL-8 or LPS-induced TNFalpha production. PP2A expression, glucocorticoid receptor (GR) nuclear translocation defined as the nuclear/cytoplasmic GR ratio and phosphorylation of GR-Ser226, c Jun N-terminal kinase 1 (JNK1) and PP2A were analysed by Western-blotting. Phosphatase activity was measured by fluorescence-based assay. Okadaic acid (OA), a PP2A inhibitor, reduced corticosteroid sensitivity with reduced GR nuclear translocation and increased GR phosphorylation in U937 monocytic cells. PP2A knockdown by RNA interference showed similar effects. IL-2/IL-4 treatment to U937 reduced corticosteroid sensitivity, and PP2A expression/activity. In peripheral blood mononuclear cells (PBMCs) from severe asthma, the PP2A expression and activity were significantly reduced with concomitant enhancement of PP2A(C) Tyr307 phosphorylation compared with those in healthy volunteers. As the results, GR-Ser226 and JNK1 phosphorylation were increased. The expression and activity of PP2A were negatively correlated with phosphorylation levels of GR-Ser226. Furthermore, co-immunoprecipitation assay in U937 cells revealed that PP2A associated with GR and JNK1 and IL-2/IL-4 exposure caused dissociation of each molecule. Lastly, PP2A overexpression increased corticosteroid sensitivity in U937 cells. CONCLUSIONS/SIGNIFICANCE: PP2A regulates GR nuclear translocation and corticosteroid sensitivity possibly by dephosphorylation of GR-Ser226 via dephosphorylation of upstream JNK1. This novel mechanism will provide new insight for the development of new therapy for severe asthma. PMID- 22205927 TI - Community-based values for 2009 pandemic influenza A H1N1 illnesses and vaccination-related adverse events. AB - OBJECTIVE: To evaluate community-based values for avoiding pandemic influenza (A) H1N1 (pH1N1) illness and vaccination-related adverse events in adults and children. METHODS: Adult community members were randomly selected from a nationally representative research panel to complete an internet survey (response rate = 65%; n = 718). Respondents answered a series of time trade-off questions to value four hypothetical health state scenarios for varying ages (1, 8, 35, or 70 years): uncomplicated pH1N1 illness, pH1N1 illness-related hospitalization, severe allergic reaction to the pH1N1 vaccine, and Guillain-Barre syndrome. We calculated descriptive statistics for time trade-off amounts and derived quality adjusted life year losses for these events. Multivariate regression analyses evaluated the effect of scenario age, as well as respondent socio-demographic and health characteristics on time trade-off amounts. RESULTS: Respondents were willing to trade more time to avoid the more severe outcomes, hospitalization and Guillain-Barre syndrome. In our adjusted and unadjusted analyses, age of the patient in the scenario was significantly associated with time trade-off amounts (p-value<0.05), with respondents willing to trade more time to prevent outcomes in children versus adults. Persons who had received the pH1N1 vaccination were willing to trade significantly more time to avoid hospitalization, severe allergic reaction, and Guillain-Barre syndrome, controlling for other variables in adjusted analyses.(p-value<0.05) CONCLUSIONS: Community members placed the highest value on preventing outcomes in children, compared with adults, and the time trade-off values reported were consistent with the severity of the outcomes presented. Considering these public values along with other decision-making factors may help policy makers improve the allocation of pandemic vaccine resources. PMID- 22205928 TI - Using amino acid correlation and community detection algorithms to identify functional determinants in protein families. AB - Correlated mutation analysis has a long history of interesting applications, mostly in the detection of contact pairs in protein structures. Based on previous observations that, if properly assessed, amino acid correlation data can also provide insights about functional sub-classes in a protein family, we provide a complete framework devoted to this purpose. An amino acid specific correlation measure is proposed, which can be used to build networks summarizing all correlation and anti-correlation patterns in a protein family. These networks can be submitted to community structure detection algorithms, resulting in subsets of correlated amino acids which can be further assessed by specific parameters and procedures that provide insight into the relationship between different communities, the individual importance of community members and the adherence of a given amino acid sequence to a given community. By applying this framework to three protein families with contrasting characteristics (the Fe/Mn-superoxide dismutases, the peroxidase-catalase family and the C-type lysozyme/alpha lactalbumin family), we show how our method and the proposed parameters and procedures are related to biological characteristics observed in these protein families, highlighting their potential use in protein characterization and gene annotation. PMID- 22205929 TI - Detection of herpes simplex virus type-1 in patients with fibrotic lung diseases. AB - The current study intends to investigate i) the incidence of herpes viruses including Herpes Simplex Virus type-1 (HSV-1), Cytomegalovirus (CMV) and Human Herpes Virus -6, -7, -8 (HHV6, HHV7, HHV8) in two biological samples, bronchoalveolar lavage fluid (BALF) and lung tissue biopsy, in different forms of pulmonary fibrosis, and ii) the induction of molecular pathways involved in fibrosis by herpesvirus infection in primary cell cultures. PCR was employed for the detection of CMV, HHV6-8 and HSV-1 DNA in lung specimens (4 controls and 11 IPF specimens) and BALF pellet [6 controls and 20 fibrotic Idiopathic Intestitial Pneumonias (f-IIPs) samples: 13 idiopathic pulmonary fibrosis (IPF) and 7 nonspecific idiopathic interstitial pneumonia (NSIP)] samples. Among all herpesviruses tested, HSV-1 was detected in 1/11 (9%) specimens from IPF lung tissue and in 2/20 (10%) samples of f-IIPs BALF whereas the control group was negative. Primary cell cultures from BALF of patients with IPF and healthy controls were infected in vitro with wild-type HSV-1 virus and Real Time PCR was employed for the detection of gene transcription of specific axes implicated in lung fibrosis. Primary cell cultures were permissive to HSV-1, resulting in an upregulation of the fibrotic growth factors TGFbeta1 and FGF, the angiogenetic markers SDF1a, SDF1b, VEGF, FGF and the regulators of tissue wound healing MMP9 and CCR7. Downregulation was noted for the CXCR4 and MMP2 genes, while a different response has been detected in healthy donors regarding the expression of the aforementioned markers. These results implicate for the first time the HSV 1 with Fibrotic Idiopathic Interstitial Pneumonias since the virus presented similar incidence in two different biological samples. PMID- 22205930 TI - Safety and reactogenicity of canarypox ALVAC-HIV (vCP1521) and HIV-1 gp120 AIDSVAX B/E vaccination in an efficacy trial in Thailand. AB - BACKGROUND: A prime-boost vaccination regimen with ALVAC-HIV (vCP1521) administered intramuscularly at 0, 4, 12, and 24 weeks and gp120 AIDSVAX B/E at 12 and 24 weeks demonstrated modest efficacy of 31.2% for prevention of HIV acquisition in HIV-uninfected adults participating in a community-based efficacy trial in Thailand. METHODOLOGY/PRINCIPAL FINDINGS: Reactogenicity was recorded for 3 days following vaccination. Adverse events were monitored every 6 months for 3.5 years, during which pregnancy outcomes were recorded. Of the 16,402 volunteers, 69% of the participants reported an adverse event any time after the first dose. Only 32.9% experienced an AE within 30 days following any vaccination. Overall adverse event rates and attribution of relatedness did not differ between groups. The frequency of serious adverse events was similar in vaccine (14.3%) and placebo (14.9%) recipients (p = 0.33). None of the 160 deaths (85 in vaccine and 75 in placebo recipients, p = 0.43) was assessed as related to vaccine. The most common cause of death was trauma or traffic accident. Approximately 30% of female participants reported a pregnancy during the study. Abnormal pregnancy outcomes were experienced in 17.1% of vaccine and 14.6% (p = 0.13) of placebo recipients. When the conception occurred within 3 months (estimated) of a vaccination, the majority of these abnormal outcomes were spontaneous or elective abortions among 22.2% and 15.3% of vaccine and placebo pregnant recipients, respectively (p = 0.08). Local reactions occurred in 88.0% of vaccine and 61.0% of placebo recipients (p<0.001) and were more frequent after ALVAC-HIV than AIDSVAX B/E vaccination. Systemic reactions were more frequent in vaccine than placebo recipients (77.2% vs. 59.8%, p<0.001). Local and systemic reactions were mostly mild to moderate, resolving within 3 days. CONCLUSIONS/SIGNIFICANCE: The ALVAC-HIV and AIDSVAX B/E vaccine regimen was found to be safe, well tolerated and suitable for potential large-scale use in Thailand. TRIAL REGISTRATION: ClinicalTrials.govNCT00223080. PMID- 22205931 TI - A comparison of initial antiretroviral therapy in the Swiss HIV Cohort Study and the recommendations of the International AIDS Society-USA. AB - BACKGROUND: In order to facilitate and improve the use of antiretroviral therapy (ART), international recommendations are released and updated regularly. We aimed to study if adherence to the recommendations is associated with better treatment outcomes in the Swiss HIV Cohort Study (SHCS). METHODS: Initial ART regimens prescribed to participants between 1998 and 2007 were classified according to IAS USA recommendations. Baseline characteristics of patients who received regimens in violation with these recommendations (violation ART) were compared to other patients. Multivariable logistic and linear regression analyses were performed to identify associations between violation ART and (i) virological suppression and (ii) CD4 cell count increase, after one year. RESULTS: Between 1998 and 2007, 4189 SHCS participants started 241 different ART regimens. A violation ART was started in 5% of patients. Female patients (adjusted odds ratio aOR 1.83, 95%CI 1.28-2.62), those with a high education level (aOR 1.49, 95%CI 1.07-2.06) or a high CD4 count (aOR 1.53, 95%CI 1.02-2.30) were more likely to receive violation ART. The proportion of patients with an undetectable viral load (<400 copies/mL) after one year was significantly lower with violation ART than with recommended regimens (aOR 0.54, 95% CI 0.37-0.80) whereas CD4 count increase after one year of treatment was similar in both groups. CONCLUSIONS: Although more than 240 different initial regimens were prescribed, violations of the IAS-USA recommendations were uncommon. Patients receiving these regimens were less likely to have an undetectable viral load after one year, which strengthens the validity of these recommendations. PMID- 22205932 TI - Respiratory infections precede adult-onset asthma. AB - BACKGROUND: Respiratory infections in early life are associated with an increased risk of developing asthma but there is little evidence on the role of infections for onset of asthma in adults. The objective of this study was to assess the relation of the occurrence of respiratory infections in the past 12 months to adult-onset asthma in a population-based incident case-control study of adults 21 63 years of age. METHODS/PRINCIPAL FINDINGS: We recruited all new clinically diagnosed cases of asthma (n = 521) during a 2.5-year study period and randomly selected controls (n = 932) in a geographically defined area in South Finland. Information on respiratory infections was collected by a self-administered questionnaire. The diagnosis of asthma was based on symptoms and reversible airflow obstruction in lung function measurements. The risk of asthma onset was strongly increased in subjects who had experienced in the preceding 12 months lower respiratory tract infections (including acute bronchitis and pneumonia) with an adjusted odds ratio (OR) 7.18 (95% confidence interval [CI] 5.16-9.99), or upper respiratory tract infections (including common cold, sinusitis, tonsillitis, and otitis media) with an adjusted OR 2.26 (95% CI 1.72-2.97). Individuals with personal atopy and/or parental atopy were more susceptible to the effects of respiratory infections on asthma onset than non-atopic persons. CONCLUSIONS/SIGNIFICANCE: This study provides new evidence that recently experienced respiratory infections are a strong determinant for adult-onset asthma. Reducing such infections might prevent onset of asthma in adulthood, especially in individuals with atopy or hereditary propensity to it. PMID- 22205934 TI - Multi-cellular logistics of collective cell migration. AB - During development, the formation of biological networks (such as organs and neuronal networks) is controlled by multicellular transportation phenomena based on cell migration. In multi-cellular systems, cellular locomotion is restricted by physical interactions with other cells in a crowded space, similar to passengers pushing others out of their way on a packed train. The motion of individual cells is intrinsically stochastic and may be viewed as a type of random walk. However, this walk takes place in a noisy environment because the cell interacts with its randomly moving neighbors. Despite this randomness and complexity, development is highly orchestrated and precisely regulated, following genetic (and even epigenetic) blueprints. Although individual cell migration has long been studied, the manner in which stochasticity affects multi-cellular transportation within the precisely controlled process of development remains largely unknown. To explore the general principles underlying multicellular migration, we focus on the migration of neural crest cells, which migrate collectively and form streams. We introduce a mechanical model of multi-cellular migration. Simulations based on the model show that the migration mode depends on the relative strengths of the noise from migratory and non-migratory cells. Strong noise from migratory cells and weak noise from surrounding cells causes "collective migration," whereas strong noise from non-migratory cells causes "dispersive migration." Moreover, our theoretical analyses reveal that migratory cells attract each other over long distances, even without direct mechanical contacts. This effective interaction depends on the stochasticity of the migratory and non-migratory cells. On the basis of these findings, we propose that stochastic behavior at the single-cell level works effectively and precisely to achieve collective migration in multi-cellular systems. PMID- 22205933 TI - Estimating loss to follow-up in HIV-infected patients on antiretroviral therapy: the effect of the competing risk of death in Zambia and Switzerland. AB - BACKGROUND: Loss to follow-up (LTFU) is common in antiretroviral therapy (ART) programmes. Mortality is a competing risk (CR) for LTFU; however, it is often overlooked in cohort analyses. We examined how the CR of death affected LTFU estimates in Zambia and Switzerland. METHODS AND FINDINGS: HIV-infected patients aged >=18 years who started ART 2004-2008 in observational cohorts in Zambia and Switzerland were included. We compared standard Kaplan-Meier curves with CR cumulative incidence. We calculated hazard ratios for LTFU across CD4 cell count strata using cause-specific Cox models, or Fine and Gray subdistribution models, adjusting for age, gender, body mass index and clinical stage. 89,339 patients from Zambia and 1,860 patients from Switzerland were included. 12,237 patients (13.7%) in Zambia and 129 patients (6.9%) in Switzerland were LTFU and 8,498 (9.5%) and 29 patients (1.6%), respectively, died. In Zambia, the probability of LTFU was overestimated in Kaplan-Meier curves: estimates at 3.5 years were 29.3% for patients starting ART with CD4 cells <100 cells/ul and 15.4% among patients starting with >= 350 cells/uL. The estimates from CR cumulative incidence were 22.9% and 13.6%, respectively. Little difference was found between naive and CR analyses in Switzerland since only few patients died. The results from Cox and Fine and Gray models were similar: in Zambia the risk of loss to follow-up and death increased with decreasing CD4 counts at the start of ART, whereas in Switzerland there was a trend in the opposite direction, with patients with higher CD4 cell counts more likely to be lost to follow-up. CONCLUSIONS: In ART programmes in low-income settings the competing risk of death can substantially bias standard analyses of LTFU. The CD4 cell count and other prognostic factors may be differentially associated with LTFU in low-income and high-income settings. PMID- 22205935 TI - The glial scar-monocyte interplay: a pivotal resolution phase in spinal cord repair. AB - The inflammatory response in the injured spinal cord, an immune privileged site, has been mainly associated with the poor prognosis. However, recent data demonstrated that, in fact, some leukocytes, namely monocytes, are pivotal for repair due to their alternative anti-inflammatory phenotype. Given the pro inflammatory milieu within the traumatized spinal cord, known to skew monocytes towards a classical phenotype, a pertinent question is how parenchymal-invading monocytes acquire resolving properties essential for healing, under such unfavorable conditions. In light of the spatial association between resolving (interleukin (IL)-10 producing) monocytes and the glial scar matrix chondroitin sulfate proteoglycan (CSPG), in this study we examined the mutual relationship between these two components. By inhibiting the de novo production of CSPG following spinal cord injury, we demonstrated that this extracellular matrix, mainly known for its ability to inhibit axonal growth, serves as a critical template skewing the entering monocytes towards the resolving phenotype. In vitro cell culture studies demonstrated that this matrix alone is sufficient to induce such monocyte polarization. Reciprocal conditional ablation of the monocyte derived macrophages concentrated at the lesion margins, using diphtheria toxin, revealed that these cells have scar matrix-resolving properties. Replenishment of monocytic cell populations to the ablated mice demonstrated that this extracellular remodeling ability of the infiltrating monocytes requires their expression of the matrix-degrading enzyme, matrix metalloproteinase 13 (MMP-13), a property that was found here to be crucial for functional recovery. Altogether, this study demonstrates that the glial scar-matrix, a known obstacle to regeneration, is a critical component skewing the encountering monocytes towards a resolving phenotype. In an apparent feedback loop, monocytes were found to regulate scar resolution. This cross-regulation between the glial scar and monocytes primes the resolution of this interim phase of spinal cord repair, thereby providing a fundamental platform for the dynamic healing response. PMID- 22205936 TI - Systematic drug repositioning based on clinical side-effects. AB - Drug repositioning helps fully explore indications for marketed drugs and clinical candidates. Here we show that the clinical side-effects (SEs) provide a human phenotypic profile for the drug, and this profile can suggest additional disease indications. We extracted 3,175 SE-disease relationships by combining the SE-drug relationships from drug labels and the drug-disease relationships from PharmGKB. Many relationships provide explicit repositioning hypotheses, such as drugs causing hypoglycemia are potential candidates for diabetes. We built Naive Bayes models to predict indications for 145 diseases using the SEs as features. The AUC was above 0.8 in 92% of these models. The method was extended to predict indications for clinical compounds, 36% of the models achieved AUC above 0.7. This suggests that closer attention should be paid to the SEs observed in trials not just to evaluate the harmful effects, but also to rationally explore the repositioning potential based on this "clinical phenotypic assay". PMID- 22205937 TI - Mirror adaptation in sensory-motor simultaneity. AB - BACKGROUND: When one watches a sports game, one may feel her/his own muscles moving in synchrony with the player's. Such parallels between observed actions of others and one's own has been well supported in the latest progress in neuroscience, and coined "mirror system." It is likely that due to such phenomena, we are able to learn motor skills just by observing an expert's performance. Yet it is unknown whether such indirect learning occurs only at higher cognitive levels, or also at basic sensorimotor levels where sensorimotor delay is compensated and the timing of sensory feedback is constantly calibrated. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that the subject's passive observation of an actor manipulating a computer mouse with delayed auditory feedback led to shifts in subjective simultaneity of self mouse manipulation and auditory stimulus in the observing subjects. Likewise, self adaptation to the delayed feedback modulated the simultaneity judgment of the other subjects manipulating a mouse and an auditory stimulus. Meanwhile, subjective simultaneity of a simple visual disc and the auditory stimulus (flash test) was not affected by observation of an actor nor self-adaptation. CONCLUSIONS/SIGNIFICANCE: The lack of shift in the flash test for both conditions indicates that the recalibration transfer is specific to the action domain, and is not due to a general sensory adaptation. This points to the involvement of a system for the temporal monitoring of actions, one that processes both one's own actions and those of others. PMID- 22205938 TI - Statin-associated muscular and renal adverse events: data mining of the public version of the FDA adverse event reporting system. AB - OBJECTIVE: Adverse event reports (AERs) submitted to the US Food and Drug Administration (FDA) were reviewed to assess the muscular and renal adverse events induced by the administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) and to attempt to determine the rank order of the association. METHODS: After a revision of arbitrary drug names and the deletion of duplicated submissions, AERs involving pravastatin, simvastatin, atorvastatin, or rosuvastatin were analyzed. Authorized pharmacovigilance tools were used for quantitative detection of signals, i.e., drug-associated adverse events, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Myalgia, rhabdomyolysis and an increase in creatine phosphokinase level were focused on as the muscular adverse events, and acute renal failure, non-acute renal failure, and an increase in blood creatinine level as the renal adverse events. RESULTS: Based on 1,644,220 AERs from 2004 to 2009, signals were detected for 4 statins with respect to myalgia, rhabdomyolysis, and an increase in creatine phosphokinase level, but these signals were stronger for rosuvastatin than pravastatin and atorvastatin. Signals were also detected for acute renal failure, though in the case of atorvastatin, the association was marginal, and furthermore, a signal was not detected for non acute renal failure or for an increase in blood creatinine level. CONCLUSIONS: Data mining of the FDA's adverse event reporting system, AERS, is useful for examining statin-associated muscular and renal adverse events. The data strongly suggest the necessity of well-organized clinical studies with respect to statin associated adverse events. PMID- 22205939 TI - Malaria infections do not compromise vaccine-induced immunity against tuberculosis in mice. AB - BACKGROUND: Given the considerable geographic overlap in the endemic regions for malaria and tuberculosis, it is probable that co-infections with Mycobacterium tuberculosis and Plasmodium species are prevalent. Thus, it is quite likely that both malaria and TB vaccines may be used in the same populations in endemic areas. While novel vaccines are currently being developed and tested individually against each of these pathogens, the efficacy of these vaccines has not been evaluated in co-infection models. To further assess the effectiveness of these new immunization strategies, we investigated whether co-infection with malaria would impact the anti-tuberculosis protection induced by four different types of TB vaccines in a mouse model of pulmonary tuberculosis. PRINCIPAL FINDINGS: Here we show that the anti-tuberculosis protective immunity induced by four different tuberculosis vaccines was not impacted by a concurrent infection with Plasmodium yoelii NL, a nonlethal form of murine malaria. After an aerogenic challenge with virulent M. tuberculosis, the lung bacterial burdens of vaccinated animals were not statistically different in malaria infected and malaria naive mice. Multi parameter flow cytometric analysis showed that the frequency and the median fluorescence intensities (MFI) for specific multifunctional T (MFT) cells expressing IFN-gamma, TNF-alpha, and/or IL-2 were suppressed by the presence of malaria parasites at 2 weeks following the malaria infection but was not affected after parasite clearance at 7 and 10 weeks post-challenge with P. yoelii NL. CONCLUSIONS: Our data indicate that the effectiveness of novel TB vaccines in protecting against tuberculosis was unaffected by a primary malaria co-infection in a mouse model of pulmonary tuberculosis. While the activities of specific MFT cell subsets were reduced at elevated levels of malaria parasitemia, the T cell suppression was short-lived. Our findings have important relevance in developing strategies for the deployment of new TB vaccines in malaria endemic areas. PMID- 22205940 TI - The influence of feature selection methods on accuracy, stability and interpretability of molecular signatures. AB - Biomarker discovery from high-dimensional data is a crucial problem with enormous applications in biology and medicine. It is also extremely challenging from a statistical viewpoint, but surprisingly few studies have investigated the relative strengths and weaknesses of the plethora of existing feature selection methods. In this study we compare 32 feature selection methods on 4 public gene expression datasets for breast cancer prognosis, in terms of predictive performance, stability and functional interpretability of the signatures they produce. We observe that the feature selection method has a significant influence on the accuracy, stability and interpretability of signatures. Surprisingly, complex wrapper and embedded methods generally do not outperform simple univariate feature selection methods, and ensemble feature selection has generally no positive effect. Overall a simple Student's t-test seems to provide the best results. PMID- 22205941 TI - Anatomic brain asymmetry in vervet monkeys. AB - Asymmetry is a prominent feature of human brains with important functional consequences. Many asymmetric traits show population bias, but little is known about the genetic and environmental sources contributing to inter-individual variance. Anatomic asymmetry has been observed in Old World monkeys, but the evidence for the direction and extent of asymmetry is equivocal and only one study has estimated the genetic contributions to inter-individual variance. In this study we characterize a range of qualitative and quantitative asymmetry measures in structural brain MRIs acquired from an extended pedigree of Old World vervet monkeys (n = 357), and implement variance component methods to estimate the proportion of trait variance attributable to genetic and environmental sources. Four of six asymmetry measures show pedigree-level bias and one of the traits has a significant heritability estimate of about 30%. We also found that environmental variables more significantly influence the width of the right compared to the left prefrontal lobe. PMID- 22205942 TI - You know what it is: learning words through listening to hip-hop. AB - Music listeners have difficulty correctly understanding and remembering song lyrics. However, results from the present study support the hypothesis that young adults can learn African-American English (AAE) vocabulary from listening to hip hop music. Non-African-American participants first gave free-response definitions to AAE vocabulary items, after which they answered demographic questions as well as questions addressing their social networks, their musical preferences, and their knowledge of popular culture. Results from the survey show a positive association between the number of hip-hop artists listened to and AAE comprehension vocabulary scores. Additionally, participants were more likely to know an AAE vocabulary item if the hip-hop artists they listen to use the word in their song lyrics. Together, these results suggest that young adults can acquire vocabulary through exposure to hip-hop music, a finding relevant for research on vocabulary acquisition, the construction of adolescent and adult identities, and the adoption of lexical innovations. PMID- 22205943 TI - miR451 and AMPK mutual antagonism in glioma cell migration and proliferation: a mathematical model. AB - Glioblastoma multiforme (GBM) is the most common and the most aggressive type of brain cancer; the median survival time from the time of diagnosis is approximately one year. GBM is characterized by the hallmarks of rapid proliferation and aggressive invasion. miR-451 is known to play a key role in glioblastoma by modulating the balance of active proliferation and invasion in response to metabolic stress in the microenvironment. The present paper develops a mathematical model of GBM evolution which focuses on the relative balance of growth and invasion. In the present work we represent the miR-451/AMPK pathway by a simple model and show how the effects of glucose on cells need to be "refined" by taking into account the recent history of glucose variations. The simulations show how variations in glucose significantly affect the level of miR-451 and, in turn, cell migration. The model predicts that oscillations in the levels of glucose increase the growth of the primary tumor. The model also suggests that drugs which upregulate miR-451, or block other components of the CAB39/AMPK pathway, will slow down glioma cell migration. The model provides an explanation for the growth-invasion cycling patterns of glioma cells in response to high/low glucose uptake in microenvironment in vitro, and suggests new targets for drugs, associated with miR-451 upregulation. PMID- 22205944 TI - Health newscasts for increasing influenza vaccination coverage: an inductive reasoning game approach. AB - Both pandemic and seasonal influenza are receiving more attention from mass media than ever before. Topics such as epidemic severity and vaccination are changing the way in which we perceive the utility of disease prevention. Voluntary influenza vaccination has been recently modeled using inductive reasoning games. It has thus been found that severe epidemics may occur because individuals do not vaccinate and, instead, attempt to benefit from the immunity of their peers. Such epidemics could be prevented by voluntary vaccination if incentives were offered. However, a key assumption has been that individuals make vaccination decisions based on whether there was an epidemic each influenza season; no other epidemiological information is available to them. In this work, we relax this assumption and investigate the consequences of making more informed vaccination decisions while no incentives are offered. We obtain three major results. First, individuals will not cooperate enough to constantly prevent influenza epidemics through voluntary vaccination no matter how much they learned about influenza epidemiology. Second, broadcasting epidemiological information richer than whether an epidemic occurred may stabilize the vaccination coverage and suppress severe influenza epidemics. Third, the stable vaccination coverage follows the trend of the perceived benefit of vaccination. However, increasing the amount of epidemiological information released to the public may either increase or decrease the perceived benefit of vaccination. We discuss three scenarios where individuals know, in addition to whether there was an epidemic, (i) the incidence, (ii) the vaccination coverage and (iii) both the incidence and the vaccination coverage, every influenza season. We show that broadcasting both the incidence and the vaccination coverage could yield either better or worse vaccination coverage than broadcasting each piece of information on its own. PMID- 22205945 TI - Mesenchymal stromal cells primed with paclitaxel provide a new approach for cancer therapy. AB - BACKGROUND: Mesenchymal stromal cells may represent an ideal candidate to deliver anti-cancer drugs. In a previous study, we demonstrated that exposure of mouse bone marrow derived stromal cells to Doxorubicin led them to acquire anti proliferative potential towards co-cultured haematopoietic stem cells (HSCs). We thus hypothesized whether freshly isolated human bone marrow Mesenchymal stem cells (hMSCs) and mature murine stromal cells (SR4987 line) primed in vitro with anti-cancer drugs and then localized near cancer cells, could inhibit proliferation. METHODS AND PRINCIPAL FINDINGS: Paclitaxel (PTX) was used to prime culture of hMSCs and SR4987. Incorporation of PTX into hMSCs was studied by using FICT-labelled-PTX and analyzed by FACS and confocal microscopy. Release of PTX in culture medium by PTX primed hMSCs (hMSCsPTX) was investigated by HPLC. Culture of Endothelial cells (ECs) and aorta ring assay were used to test the anti angiogenic activity of hMSCsPTX and PTX primed SR4987(SR4987PTX), while anti tumor activity was tested in vitro on the proliferation of different tumor cell lines and in vivo by co-transplanting hMSCsPTX and SR4987PTX with cancer cells in mice. Nevertheless, despite a loss of cells due to chemo-induced apoptosis, both hMSCs and SR4987 were able to rapidly incorporate PTX and could slowly release PTX in the culture medium in a time dependent manner. PTX primed cells acquired a potent anti-tumor and anti-angiogenic activity in vitro that was dose dependent, and demonstrable by using their conditioned medium or by co-culture assay. Finally, hMSCsPTX and SR4987PTX co-injected with human cancer cells (DU145 and U87MG) and mouse melanoma cells (B16) in immunodeficient and in syngenic mice significantly delayed tumor takes and reduced tumor growth. CONCLUSIONS: These data demonstrate, for the first time, that without any genetic manipulation, mesenchymal stromal cells can uptake and subsequently slowly release PTX. This may lead to potential new tools to increase efficacy of cancer therapy. PMID- 22205946 TI - Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebrafish. AB - A major obstacle in treating drug addiction is the severity of opiate withdrawal syndrome, which can lead to unwanted relapse. Mitragynine is the major alkaloid compound found in leaves of Mitragyna speciosa, a plant widely used by opiate addicts to mitigate the harshness of drug withdrawal. A series of experiments was conducted to investigate the effect of mitragynine on anxiety behavior, cortisol level and expression of stress pathway related genes in zebrafish undergoing morphine withdrawal phase. Adult zebrafish were subjected to two weeks chronic morphine exposure at 1.5 mg/L, followed by withdrawal for 24 hours prior to tests. Using the novel tank diving tests, we first showed that morphine-withdrawn zebrafish display anxiety-related swimming behaviors such as decreased exploratory behavior and increased erratic movement. Morphine withdrawal also elevated whole-body cortisol levels, which confirms the phenotypic stress-like behaviors. Exposing morphine-withdrawn fish to mitragynine however attenuates majority of the stress-related swimming behaviors and concomitantly lower whole body cortisol level. Using real-time PCR gene expression analysis, we also showed that mitragynine reduces the mRNA expression of corticotropin releasing factor receptors and prodynorphin in zebrafish brain during morphine withdrawal phase, revealing for the first time a possible link between mitragynine's ability to attenuate anxiety during opiate withdrawal with the stress-related corticotropin pathway. PMID- 22205947 TI - Outbreak of beriberi among African Union troops in Mogadishu, Somalia. AB - CONTEXT AND OBJECTIVES: In July 2009, WHO and partners were notified of a large outbreak of unknown illness, including deaths, among African Union (AU) soldiers in Mogadishu. Illnesses were characterized by peripheral edema, dyspnea, palpitations, and fever. Our objectives were to determine the cause of the outbreak, and to design and recommend control strategies. DESIGN, SETTING, AND PARTICIPANTS: The illness was defined as acute onset of lower limb edema, with dyspnea, chest pain, palpitations, nausea, vomiting, abdominal pain, or headache. Investigations in Nairobi and Mogadishu included clinical, epidemiologic, environmental, and laboratory studies. A case-control study was performed to identify risk factors for illness. RESULTS: From April 26, 2009 to May 1, 2010, 241 AU soldiers had lower limb edema and at least one additional symptom; four patients died. At least 52 soldiers were airlifted to hospitals in Kenya and Uganda. Four of 31 hospitalized patients in Kenya had right-sided heart failure with pulmonary hypertension. Initial laboratory investigations did not reveal hematologic, metabolic, infectious or toxicological abnormalities. Illness was associated with exclusive consumption of food provided to troops (not eating locally acquired foods) and a high level of insecurity (e.g., being exposed to enemy fire on a daily basis). Because the syndrome was clinically compatible with wet beriberi, thiamine was administered to ill soldiers, resulting in rapid and dramatic resolution. Blood samples taken from 16 cases prior to treatment showed increased levels of erythrocyte transketolase activation coefficient, consistent with thiamine deficiency. With mass thiamine supplementation for healthy troops, the number of subsequent beriberi cases decreased with no further deaths reported. CONCLUSIONS: An outbreak of wet beriberi caused by thiamine deficiency due to restricted diet occurred among soldiers in a modern, well-equipped army. Vigilance to ensure adequate micronutrient intake must be a priority in populations completely dependent upon nutritional support from external sources. PMID- 22205948 TI - Binding of tetracycline and chlortetracycline to the enzyme trypsin: spectroscopic and molecular modeling investigations. AB - Tetracycline (TC) and chlortetracycline (CTC) are common members of the widely used veterinary drug tetracyclines, the residue of which in the environment can enter human body, being potentially harmful. In this study, we establish a new strategy to probe the binding modes of TC and CTC with trypsin based on spectroscopic and computational modeling methods. Both TC and CTC can interact with trypsin with one binding site to form trypsin-TC (CTC) complex, mainly through van der Waals' interactions and hydrogen bonds with the affinity order: TC>CTC. The bound TC (CTC) can result in inhibition of trypsin activity with the inhibition order: CTC>TC. The secondary structure and the microenvironment of the tryptophan residues of trypsin were also changed. However, the effect of CTC on the secondary structure content of trypsin was contrary to that of TC. Both the molecular docking study and the trypsin activity experiment revealed that TC bound into S1 binding pocket, competitively inhibiting the enzyme activity, and CTC was a non-competitive inhibitor which bound to a non-active site of trypsin, different from TC due to the Cl atom on the benzene ring of CTC which hinders CTC entering into the S1 binding pocket. CTC does not hinder the binding of the enzyme substrate, but the CTC-trypsin-substrate ternary complex can not further decompose into the product. The work provides basic data for clarifying the binding mechanisms of TC (CTC) with trypsin and can help to comprehensively understanding of the enzyme toxicity of different members of tetracyclines in vivo. PMID- 22205949 TI - Comparison of strategies to detect epistasis from eQTL data. AB - Genome-wide association studies have been instrumental in identifying genetic variants associated with complex traits such as human disease or gene expression phenotypes. It has been proposed that extending existing analysis methods by considering interactions between pairs of loci may uncover additional genetic effects. However, the large number of possible two-marker tests presents significant computational and statistical challenges. Although several strategies to detect epistasis effects have been proposed and tested for specific phenotypes, so far there has been no systematic attempt to compare their performance using real data. We made use of thousands of gene expression traits from linkage and eQTL studies, to compare the performance of different strategies. We found that using information from marginal associations between markers and phenotypes to detect epistatic effects yielded a lower false discovery rate (FDR) than a strategy solely using biological annotation in yeast, whereas results from human data were inconclusive. For future studies whose aim is to discover epistatic effects, we recommend incorporating information about marginal associations between SNPs and phenotypes instead of relying solely on biological annotation. Improved methods to discover epistatic effects will result in a more complete understanding of complex genetic effects. PMID- 22205950 TI - Nothing a hot bath won't cure: infection rates of amphibian chytrid fungus correlate negatively with water temperature under natural field settings. AB - Dramatic declines and extinctions of amphibian populations throughout the world have been associated with chytridiomycosis, an infectious disease caused by the pathogenic chytrid fungus Batrachochytrium dendrobatidis (Bd). Previous studies indicated that Bd prevalence correlates with cooler temperatures in the field, and laboratory experiments have demonstrated that Bd ceases growth at temperatures above 28 degrees C. Here we investigate how small-scale variations in water temperature correlate with Bd prevalence in the wild. We sampled 221 amphibians, including 201 lowland leopard frogs (Rana [Lithobates] yavapaiensis), from 12 sites in Arizona, USA, and tested them for Bd. Amphibians were encountered in microhabitats that exhibited a wide range of water temperatures (10-50 degrees C), including several geothermal water sources. There was a strong inverse correlation between the water temperature in which lowland leopard frogs were captured and Bd prevalence, even after taking into account the influence of year, season, and host size. In locations where Bd was known to be present, the prevalence of Bd infections dropped from 75-100% in water <15 degrees C, to less than 10% in water >30 degrees C. A strong inverse correlation between Bd infection status and water temperature was also observed within sites. Our findings suggest that microhabitats where water temperatures exceed 30 degrees C provide lowland leopard frogs with significant protection from Bd, which could have important implications for disease dynamics, as well as management applications.There must be quite a few things a hot bath won't cure, but I don't know many of them--Sylvia Plath, "The Bell Jar" (1963). PMID- 22205951 TI - Genome-wide association study in bipolar patients stratified by co-morbidity. AB - BACKGROUND: Bipolar disorder is a severe psychiatric disorder with high heritability. Co-morbid conditions are common and might define latent subgroups of patients that are more homogeneous with respect to genetic risk factors. METHODOLOGY: In the Caucasian GAIN bipolar disorder sample of 1000 cases and 1034 controls, we tested the association of single nucleotide polymorphisms with patient subgroups defined by co-morbidity. RESULTS: Bipolar disorder with psychosis and/or substance abuse in the absence of alcohol dependence was associated with the rare variant rs1039002 in the vicinity of the gene phosphodiesterase 10A (PDE10A) on chromosome 6q27 (p = 1.7*10-8). PDE10A has been implicated in the pathophysiology of psychosis. Antagonists to the encoded protein are currently in clinical testing. Another rare variant, rs12563333 (p = 5.9*10-8) on chromosome 1q41 close to the MAP/microtubule affinity-regulating kinase 1 (MARK1) gene, approached the genome-wide level of significance in this subgroup. Homozygotes for the minor allele were present in cases and absent in controls. Bipolar disorder with alcohol dependence and other co-morbidities was associated with SNP rs2727943 (p = 3.3*10-8) on chromosome 3p26.3 located between the genes contactin-4 precursor (BIG-2) and contactin 6 (CNTN6). All three associations were found under the recessive genetic model. Bipolar disorder with low probability of co-morbid conditions did not show significant associations. CONCLUSION: Conceptualizing bipolar disorder as a heterogeneous disorder with regard to co-morbid conditions might facilitate the identification of genetic risk alleles. Rare variants might contribute to the susceptibility to bipolar disorder. PMID- 22205952 TI - Fetal movement counting improved identification of fetal growth restriction and perinatal outcomes--a multi-centre, randomized, controlled trial. AB - BACKGROUND: Fetal movement counting is a method used by the mother to quantify her baby's movements, and may prevent adverse pregnancy outcome by a timely evaluation of fetal health when the woman reports decreased fetal movements. We aimed to assess effects of fetal movement counting on identification of fetal pathology and pregnancy outcome. METHODOLOGY: In a multicentre, randomized, controlled trial, 1076 pregnant women with singleton pregnancies from an unselected population were assigned to either perform fetal movement counting from gestational week 28, or to receive standard antenatal care not including fetal movement counting (controls). Women were recruited from nine Norwegian hospitals during September 2007 through November 2009. Main outcome was a compound measure of fetal pathology and adverse pregnancy outcomes. Analysis was performed by intention-to-treat. PRINCIPAL FINDINGS: The frequency of the main outcome was equal in the groups; 63 of 433 (11.6%) in the intervention group, versus 53 of 532 (10.7%) in the control group [RR: 1.1 95% CI 0.7-1.5)]. The growth-restricted fetuses were more often identified prior to birth in the intervention group than in the control group; 20 of 23 fetuses (87.0%) versus 12 of 20 fetuses (60.0%), respectively, [RR: 1.5 (95% CI 1.0-2.1)]. In the intervention group two babies (0.4%) had Apgar scores <4 at 1 minute, versus 12 (2.3%) in the control group [RR: 0.2 (95% CI 0.04-0.7)]. The frequency of consultations for decreased fetal movement was 71 (13.1%) and 57 (10.7%) in the intervention and control groups, respectively [RR: 1.2 (95% CI 0.9-1.7)]. The frequency of interventions was similar in the groups. CONCLUSIONS: Maternal ability to detect clinically important changes in fetal activity seemed to be improved by fetal movement counting; there was an increased identification of fetal growth restriction and improved perinatal outcome, without inducing more consultations or obstetric interventions. TRIAL REGISTRATION: ClinicalTrials.govNCT00513942. PMID- 22205953 TI - Structural and functional studies of a bothropic myotoxin complexed to rosmarinic acid: new insights into Lys49-PLA2 inhibition. AB - Snakebite envenoming is an important public health problem in many tropical and subtropical countries, and is considered a neglected tropical disease by the World Health Organization. Most severe cases are inflicted by species of the families Elapidae and Viperidae, and lead to a number of systemic and local effects in the victim. One of the main problems regarding viperidic accidents is prominent local tissue damage whose pathogenesis is complex and involves the combined actions of a variety of venom components. Phospholipases A2 (PLA2s) are the most abundant muscle-damaging components of these venoms. Herein, we report functional and structural studies of PrTX-I, a Lys49-PLA2 from Bothops pirajai snake venom, and the influence of rosmarinic acid (RA) upon this toxin's activities. RA is a known active component of some plant extracts and has been reported as presenting anti-myotoxic properties related to bothopic envenomation. The myotoxic activity of Lys49-PLA2s is well established in the literature and although no in vivo neurotoxicity has been observed among these toxins, in vitro neuromuscular blockade has been reported for some of these proteins. Our in vitro studies show that RA drastically reduces both the muscle damage and the neuromuscular blockade exerted by PrTX-I on mice neuromuscular preparations (by ~80% and ~90%, respectively). These results support the hypothesis that the two effects are closely related and lead us to suggest that they are consequences of the muscle membrane-destabilizing activity of the Lys49-PLA2. Although the C terminal region of these proteins has been reported to comprise the myotoxic site, we demonstrate by X-ray crystallographic studies that RA interacts with PrTX-I in a different region. Consequently, a new mode of Lys49-PLA2 inhibition is proposed. Comparison of our results with others in the literature suggests possible new ways to inhibit bothropic snake venom myotoxins and improve serum therapy. PMID- 22205954 TI - Plasma biomarkers of brain atrophy in Alzheimer's disease. AB - Peripheral biomarkers of Alzheimer's disease (AD) reflecting early neuropathological change are critical to the development of treatments for this condition. The most widely used indicator of AD pathology in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with brain atrophy in AD. Using gel based proteomics we previously identified seven plasma proteins that were significantly associated with hippocampal volume in a combined cohort of subjects with AD (N = 27) and MCI (N = 17). In the current report, we validated this finding in a large independent cohort of AD (N = 79), MCI (N = 88) and control (N = 95) subjects using alternative complementary methods-quantitative immunoassays for protein concentrations and estimation of pathology by whole brain volume. We confirmed that plasma concentrations of five proteins, together with age and sex, explained more than 35% of variance in whole brain volume in AD patients. These proteins are complement components C3 and C3a, complement factor I, gamma-fibrinogen and alpha-1-microglobulin. Our findings suggest that these plasma proteins are strong predictors of in vivo AD pathology. Moreover, these proteins are involved in complement activation and coagulation, providing further evidence for an intrinsic role of these pathways in AD pathogenesis. PMID- 22205955 TI - The Plasmodium falciparum malaria M1 alanyl aminopeptidase (PfA-M1): insights of catalytic mechanism and function from MD simulations. AB - Malaria caused by several species of Plasmodium is major parasitic disease of humans, causing 1-3 million deaths worldwide annually. The widespread resistance of the human parasite to current drug therapies is of major concern making the identification of new drug targets urgent. While the parasite grows and multiplies inside the host erythrocyte it degrades the host cell hemoglobin and utilizes the released amino acids to synthesize its own proteins. The P. falciparum malarial M1 alanyl-aminopeptidase (PfA-M1) is an enzyme involved in the terminal stages of hemoglobin digestion and the generation of an amino acid pool within the parasite. The enzyme has been validated as a potential drug target since inhibitors of the enzyme block parasite growth in vitro and in vivo. In order to gain further understanding of this enzyme, molecular dynamics simulations using data from a recent crystal structure of PfA-M1 were performed. The results elucidate the pentahedral coordination of the catalytic Zn in these metallo-proteases and provide new insights into the roles of this cation and important active site residues in ligand binding and in the hydrolysis of the peptide bond. Based on the data, we propose a two-step catalytic mechanism, in which the conformation of the active site is altered between the Michaelis complex and the transition state. In addition, the simulations identify global changes in the protein in which conformational transitions in the catalytic domain are transmitted at the opening of the N-terminal 8 A-long channel and at the opening of the 30 A-long C-terminal internal chamber that facilitates entry of peptides to the active site and exit of released amino acids. The possible implications of these global changes with regard to enzyme function are discussed. PMID- 22205956 TI - Modeling the population-level effects of male circumcision as an HIV-preventive measure: a gendered perspective. AB - BACKGROUND: Evidence from biological, epidemiological, and controlled intervention studies has demonstrated that male circumcision (MC) protects males from HIV infection, and MC is now advocated as a public-health intervention against HIV. MC provides direct protection only to men, but is expected to provide indirect protection to women at risk of acquiring HIV from heterosexual transmission. How such indirect protection interacts with the possibility that MC campaigns will lead to behavior changes, however, is not yet well understood. Our objective here is to investigate the link between individual-level effects of MC campaigns and long-term population-level outcomes resulting from disease dynamics, looking at both genders separately, over a broad range of parameters. METHODS AND FINDINGS: We use simple mathematical models of heterosexual transmission to investigate the potential effects of a circumcision scale-up, combined with possible associated behavioral disinhibition. We examine patterns in expected long-term prevalence using a simple equilibrium model based on transmission factors, and validate our results with ODE-based simulations, focusing on the link between effects on females and those on males.We find that the long-term population-level effects on females and males are not strongly linked: there are many possible ways in which an intervention which reduces prevalence in males might nonetheless increase prevalence in females. CONCLUSIONS: Since an intervention that reduces long-term male prevalence could nonetheless increase long-term female prevalence, MC campaigns should explicitly consider both the short-term and long-term effects of MC interventions on females. Our findings strongly underline the importance of pairing MC programs with education, support programs and HIV testing and counseling, together with other prevention measures. PMID- 22205957 TI - Assessment of objectively measured physical activity levels in individuals with intellectual disabilities with and without Down's syndrome. AB - OBJECTIVE: To investigate, using accelerometers, the levels of physical activity being undertaken by individuals with intellectual disabilities with and without Down's syndrome. METHODS: One hundred and fifty two individuals with intellectual disabilities aged 12-70 years from East and South-East England. Physical activity levels in counts per minute (counts/min), steps per day (steps/day), and minutes of sedentary, light, moderate, vigorous, and moderate to vigorous physical activity (MVPA) measured with a uni-axial accelerometer (Actigraph GT1M) for seven days. RESULTS: No individuals with intellectual disabilities met current physical activity recommendations. Males were more active than females. There was a trend for physical activity to decline and sedentary behaviour to increase with age, and for those with more severe levels of intellectual disability to be more sedentary and less physically active, however any relationship was not significant when adjusted for confounding variables. Participants with Down's syndrome engaged in significantly less physical activity than those with intellectual disabilities without Down's syndrome and levels of activity declined significantly with age. CONCLUSIONS: Individuals with intellectual disabilities, especially those with Down's syndrome may be at risk of developing diseases associated with physical inactivity. There is a need for well-designed, accessible, preventive health promotion strategies and interventions designed to raise the levels of physical activity for individuals with intellectual disabilities. We propose that there are physiological reasons why individuals with Down's syndrome have particularly low levels of physical activity that also decline markedly with age. PMID- 22205958 TI - Common variation in vitamin D pathway genes predicts circulating 25 hydroxyvitamin D Levels among African Americans. AB - Vitamin D is implicated in a wide range of health outcomes, and although environmental predictors of vitamin D levels are known, the genetic drivers of vitamin D status remain to be clarified. African Americans are a group at particularly high risk for vitamin D insufficiency but to date have been virtually absent from studies of genetic predictors of circulating vitamin D levels. Within the Southern Community Cohort Study, we investigated the association between 94 single nucleotide polymorphisms (SNPs) in five vitamin D pathway genes (GC, VDR, CYP2R1, CYP24A1, CYP27B1) and serum 25-hydroxyvitamin D (25(OH)D) levels among 379 African American and 379 Caucasian participants. We found statistically significant associations with three SNPs (rs2298849 and rs2282679 in the GC gene, and rs10877012 in the CYP27B1 gene), although only for African Americans. A genotype score, representing the number of risk alleles across the three SNPs, alone accounted for 4.6% of the variation in serum vitamin D among African Americans. A genotype score of 5 (vs. 1) was also associated with a 7.1 ng/mL reduction in serum 25(OH)D levels and a six-fold risk of vitamin D insufficiency (<20 ng/mL) (odds ratio 6.0, p = 0.01) among African Americans. With African ancestry determined from a panel of 276 ancestry informative SNPs, we found that high risk genotypes did not cluster among those with higher African ancestry. This study is one of the first to investigate common genetic variation in relation to vitamin D levels in African Americans, and the first to evaluate how vitamin D-associated genotypes vary in relation to African ancestry. These results suggest that further evaluation of genetic contributors to vitamin D status among African Americans may help provide insights regarding racial health disparities or enable the identification of subgroups especially in need of vitamin D-related interventions. PMID- 22205959 TI - Catastrophic floods may pave the way for increased genetic diversity in endemic artesian spring snail populations. AB - The role of disturbance in the promotion of biological heterogeneity is widely recognised and occurs at a variety of ecological and evolutionary scales. However, within species, the impact of disturbances that decimate populations are neither predicted nor known to result in conditions that promote genetic diversity. Directly examining the population genetic consequences of catastrophic disturbances however, is rarely possible, as it requires both longitudinal genetic data sets and serendipitous timing. Our long-term study of the endemic aquatic invertebrates of the artesian spring ecosystem of arid central Australia has presented such an opportunity. Here we show a catastrophic flood event, which caused a near total population crash in an aquatic snail species (Fonscochlea accepta) endemic to this ecosystem, may have led to enhanced levels of within species genetic diversity. Analyses of individuals sampled and genotyped from the same springs sampled both pre (1988-1990) and post (1995, 2002-2006) a devastating flood event in 1992, revealed significantly higher allelic richness, reduced temporal population structuring and greater effective population sizes in nearly all post flood populations. Our results suggest that the response of individual species to disturbance and severe population bottlenecks is likely to be highly idiosyncratic and may depend on both their ecology (whether they are resilient or resistant to disturbance) and the stability of the environmental conditions (i.e. frequency and intensity of disturbances) in which they have evolved. PMID- 22205960 TI - Multiplexed quantum dot labeling of activated c-Met signaling in castration resistant human prostate cancer. AB - The potential application of multiplexed quantum dot labeling (MQDL) for cancer detection and prognosis and monitoring therapeutic responses has attracted the interests of bioengineers, pathologists and cancer biologists. Many published studies claim that MQDL is effective for cancer biomarker detection and useful in cancer diagnosis and prognosis, these studies have not been standardized against quantitative biochemical and molecular determinations. In the present study, we used a molecularly characterized human prostate cancer cell model exhibiting activated c-Met signaling with epithelial to mesenchymal transition (EMT) and lethal metastatic progression to bone and soft tissues as the gold standard, and compared the c-Met cell signaling network in this model, in clinical human prostate cancer tissue specimens and in a castration-resistant human prostate cancer xenograft model. We observed c-Met signaling network activation, manifested by increased phosphorylated c-Met in all three. The downstream survival signaling network was mediated by NF-kappaB and Mcl-1 and EMT was driven by receptor activator of NF-kappaB ligand (RANKL), at the single cell level in clinical prostate cancer specimens and the xenograft model. Results were confirmed by real-time RT-PCR and western blots in a human prostate cancer cell model. MQDL is a powerful tool for assessing biomarker expression and it offers molecular insights into cancer progression at both the cell and tissue level with high degree of sensitivity. PMID- 22205961 TI - Temporal integration of movement: the time-course of motion streaks revealed by masking. AB - Temporal integration in the visual system causes fast-moving objects to leave oriented 'motion streaks' in their wake, which could be used to facilitate motion direction perception. Temporal integration is thought to occur over ~100 ms in early cortex, although this has never been tested for motion streaks. Here we compare the ability of fast-moving ('streaky') and slow-moving fields of dots to mask briefly flashed gratings either parallel or orthogonal to the motion trajectory. Gratings were presented at various asynchronies relative to motion onset (from -200 to +700 ms) to sample the time-course of the accumulating streaks. Predictions were that masking would be strongest for the fast parallel condition, and would be weak at early asynchronies and strengthen over time as integration rendered the translating dots more streaky and grating-like. The asynchrony where the masking function reached a plateau would correspond to the temporal integration period. As expected, fast-moving dots caused greater masking of parallel gratings than orthogonal gratings, and slow motion produced only modest masking of either grating orientation. Masking strength in the fast, parallel condition increased with time and reached a plateau after 77 ms, providing an estimate of the temporal integration period for mechanisms encoding motion streaks. Interestingly, the greater masking by fast motion of parallel compared with orthogonal gratings first reached significance at 48 ms before motion onset, indicating an effect of backward masking by motion streaks. PMID- 22205962 TI - E-cadherin is transcriptionally activated via suppression of ZEB1 transcriptional repressor by small RNA-mediated gene silencing. AB - RNA activation has been reported to be induced by small interfering RNAs (siRNAs) that act on the promoters of several genes containing E-cadherin. In this study, we present an alternative mechanism of E-cadherin activation in human PC-3 cells by siRNAs previously reported to possess perfect-complementary sequences to E cadherin promoter. We found that activation of E-cadherin can be also induced via suppression of ZEB1, which is a transcriptional repressor of E-cadherin, by seed dependent silencing mechanism of these siRNAs. The functional seed-complementary sites of the siRNAs were found in the coding region in addition to the 3' untranslated region of ZEB1 mRNA. Promoter analyses indicated that E-boxes, which are ZEB1-binding sites, in the upstream promoter region are indispensable for E cadherin transcription by the siRNAs. Thus, the results caution against ignoring siRNA seed-dependent silencing effects in genome-wide transcriptional regulation. In addition, members of miR-302/372/373/520 family, which have the same seed sequences with one of the siRNAs containing perfect-complementarity to E-cadherin promoter, are also found to activate E-cadherin transcription. Thus, E-cadherin could be upregulated by the suppression of ZEB1 transcriptional repressor by miRNAs in vivo. PMID- 22205963 TI - Impact of immunization technology and assay application on antibody performance- a systematic comparative evaluation. AB - Antibodies are quintessential affinity reagents for the investigation and determination of a protein's expression patterns, localization, quantitation, modifications, purification, and functional understanding. Antibodies are typically used in techniques such as Western blot, immunohistochemistry (IHC), and enzyme-linked immunosorbent assays (ELISA), among others. The methods employed to generate antibodies can have a profound impact on their success in any of these applications. We raised antibodies against 10 serum proteins using 3 immunization methods: peptide antigens (3 per protein), DNA prime/protein fragment-boost ("DNA immunization"; 3 per protein), and full length protein. Antibodies thus generated were systematically evaluated using several different assay technologies (ELISA, IHC, and Western blot). Antibodies raised against peptides worked predominantly in applications where the target protein was denatured (57% success in Western blot, 66% success in immunohistochemistry), although 37% of the antibodies thus generated did not work in any of these applications. In contrast, antibodies produced by DNA immunization performed well against both denatured and native targets with a high level of success: 93% success in Western blots, 100% success in immunohistochemistry, and 79% success in ELISA. Importantly, success in one assay method was not predictive of success in another. Immunization with full length protein consistently yielded the best results; however, this method is not typically available for new targets, due to the difficulty of generating full length protein. We conclude that DNA immunization strategies which are not encumbered by the limitations of efficacy (peptides) or requirements for full length proteins can be quite successful, particularly when multiple constructs for each protein are used. PMID- 22205964 TI - Evaluation of cellular phenotypes implicated in immunopathogenesis and monitoring immune reconstitution inflammatory syndrome in HIV/leprosy cases. AB - BACKGROUND: It is now evident that HAART-associated immunological improvement often leads to a variety of new clinical manifestations, collectively termed immune reconstitution inflammatory syndrome, or IRIS. This phenomenon has already been described in cases of HIV coinfection with Mycobacterium leprae, most of them belonging to the tuberculoid spectrum of leprosy disease, as observed in leprosy reversal reaction (RR). However, the events related to the pathogenesis of this association need to be clarified. This study investigated the immunological profile of HIV/leprosy patients, with special attention to the cellular activation status, to better understand the mechanisms related to IRIS/RR immunopathogenesis, identifying any potential biomarkers for IRIS/RR intercurrence. METHODS/PRINCIPAL FINDINGS: Eighty-five individuals were assessed in this study: HIV/leprosy and HIV-monoinfected patients, grouped according to HIV-viral load levels, leprosy patients without HIV coinfection, and healthy controls. Phenotypes were evaluated by flow cytometry for T cell subsets and immune differentiation/activation markers. As expected, absolute counts of the CD4+ and CD8+ T cells from the HIV-infected individuals changed in relation to those of the leprosy patients and controls. However, there were no significant differences among the groups, whether in the expression of cellular differentiation phenotypes or cellular activation, as reflected by the expression of CD38 and HLA-DR. Six HIV/leprosy patients identified as IRIS/RR were analyzed during IRIS/RR episodes and after prednisone treatment. These patients presented high cellular activation levels regarding the expression of CD38 in CD8+ cells T during IRIS/RR (median: 77,15%), dropping significantly (p<0,05) during post IRIS/RR moments (median: 29,7%). Furthermore, an increase of cellular activation seems to occur prior to IRIS/RR. CONCLUSION/SIGNIFICANCE: These data suggest CD38 expression in CD8+ T cells interesting tool identifying HIV/leprosy individuals at risk for IRIS/RR. So, a comparative investigation to leprosy patients at RR should be conducted. PMID- 22205965 TI - The endocrine disruptor mono-(2-ethylhexyl) phthalate affects the differentiation of human liposarcoma cells (SW 872). AB - Esters of phthalic acid (phthalates) are largely used in industrial plastics, medical devices, and pharmaceutical formulations. They are easily released from plastics into the environment and can be found in measurable levels in human fluids. Phthalates are agonists for peroxisome proliferator-activated receptors (PPARs), through which they regulate translocator protein (TSPO; 18 kDa) transcription in a tissue-specific manner. TSPO is a drug- and cholesterol binding protein involved in mitochondrial respiration, steroid formation, and cell proliferation. TSPO has been shown to increase during differentiation and decrease during maturation in mouse adipocytes. The purpose of this study was to establish the effect of mono-(2-ethylhexyl) phthalate (MEHP) on the differentiation of human SW 872 preadipocyte cells, and examine the role of TSPO in the process. After 4 days of treatment with 10 uM MEHP, we observed changes in the transcription of acetyl-CoA carboxylase alpha, adenosine triphosphate citrate lyase, glucose transporters 1 and 4, and the S100 calcium binding protein B, all of which are markers of preadipocyte differentiation. These observed gene expression changes coincided with a decrease in cellular proliferation without affecting cellular triglyceride content. Taken together, these data suggest that MEHP exerts a differentiating effect on human preadipocytes. Interestingly, MEHP was able to temporarily increase TSPO mRNA levels through the PPAR-alpha and beta/delta pathways. These results suggest that TSPO can be considered an important player in the differentiation process itself, or alternatively a factor whose presence is essential for adipocyte development. PMID- 22205966 TI - Polyvalent DNA vaccines expressing HA antigens of H5N1 influenza viruses with an optimized leader sequence elicit cross-protective antibody responses. AB - Highly pathogenic avian influenza A (HPAI) H5N1 viruses are circulating among poultry populations in parts of Asia, Africa, and the Middle East, and have caused human infections with a high mortality rate. H5 subtype hemagglutinin (HA) has evolved into phylogenetically distinct clades and subclades based on viruses isolated from various avian species. Since 1997, humans have been infected by HPAI H5N1 viruses from several clades. It is, therefore, important to develop strategies to produce protective antibody responses against H5N1 viruses from multiple clades or antigenic groups. In the current study, we optimized the signal peptide design of DNA vaccines expressing HA antigens from H5N1 viruses. Cross reactivity analysis using sera from immunized rabbits showed that antibody responses elicited by a polyvalent formulation, including HA antigens from different clades, was able to elicit broad protective antibody responses against multiple key representative H5N1 viruses across different clades. Data presented in this report support the development of a polyvalent DNA vaccine strategy against the threat of a potential H5N1 influenza pandemic. PMID- 22205967 TI - Escherichia coli bacteriocins: antimicrobial efficacy and prevalence among isolates from patients with bacteraemia. AB - Bacteriocins are antimicrobial peptides generally active against bacteria closely related to the producer. Escherichia coli produces two types of bacteriocins, colicins and microcins. The in vitro efficacy of isolated colicins E1, E6, E7, K and M, was assessed against Escherichia coli strains from patients with bacteraemia of urinary tract origin. Colicin E7 was most effective, as only 13% of the tested strains were resistant. On the other hand, 32%, 33%, 43% and 53% of the tested strains exhibited resistance to colicins E6, K, M and E1. Moreover, the inhibitory activity of individual colicins E1, E6, E7, K and M and combinations of colicins K, M, E7 and E1, E6, E7, K, M were followed in liquid broth for 24 hours. Resistance against individual colicins developed after 9 hours of treatment. On the contrary, resistance development against the combined action of 5 colicins was not observed. One hundred and five E. coli strains from patients with bacteraemia were screened by PCR for the presence of 5 colicins and 7 microcins. Sixty-six percent of the strains encoded at least one bacteriocin, 43% one or more colicins, and 54% one or more microcins. Microcins were found to co-occur with toxins, siderophores, adhesins and with the Toll/Interleukin-1 receptor domain-containing protein involved in suppression of innate immunity, and were significantly more prevalent among strains from non-immunocompromised patients. In addition, microcins were highly prevalent among non-multidrug resistant strains compared to multidrug-resistant strains. Our results indicate that microcins contribute to virulence of E. coli instigating bacteraemia of urinary tract origin. PMID- 22205968 TI - Selective cytotoxicity against human osteosarcoma cells by a novel synthetic C-1 analogue of 7-deoxypancratistatin is potentiated by curcumin. AB - The natural compound pancratistatin (PST) is a non-genotoxic inducer of apoptosis in a variety of cancers. It exhibits cancer selectivity as non-cancerous cells are markedly less sensitive to PST. Nonetheless, PST is not readily synthesized and is present in very low quantities in its natural source to be applied clinically. We have previously synthesized and evaluated several synthetic analogues of 7-deoxypancratistatin, and found that JC-TH-acetate-4 (JCTH-4), a C 1 acetoxymethyl analogue, possessed similar apoptosis inducing activity compared to PST. In this study, notoriously chemoresistant osteosarcoma (OS) cells (Saos 2, U-2 OS) were substantially susceptible to JCTH-4-induced apoptosis through mitochondrial targeting; JCTH-4 induced collapse of mitochondrial membrane potential (MMP), increased reactive oxygen species (ROS) production in isolated mitochondria, and caused release of apoptosis inducing factor (AIF) and endonuclease G (EndoG) from isolated mitochondria. Furthermore, JCTH-4 selectively induced autophagy in OS cells. Additionally, we investigated the combinatory effect of JCTH-4 with the natural compound curcumin (CC), a compound found in turmeric spice, previously shown to possess antiproliferative properties. CC alone had no observable effect on Saos-2 and U-2 OS cells. However, when present with JCTH-4, CC was able to enhance the cytotoxicity of JCTH-4 selectively in OS cells. Such cytotoxicity by JCTH-4 alone and in combination with CC was not observed in normal human osteoblasts (HOb) and normal human fetal fibroblasts (NFF). Therefore, this report illustrates a new window in combination therapy, utilizing a novel synthetic analogue of PST with the natural compound CC, for the treatment of OS. PMID- 22205970 TI - Towards the establishment of a porcine model to study human amebiasis. AB - BACKGROUND: Entamoeba histolytica is an important parasite of the human intestine. Its life cycle is monoxenous with two stages: (i) the trophozoite, growing in the intestine and (ii) the cyst corresponding to the dissemination stage. The trophozoite in the intestine can live as a commensal leading to asymptomatic infection or as a tissue invasive form producing mucosal ulcers and liver abscesses. There is no animal model mimicking the whole disease cycle. Most of the biological information on E. histolytica has been obtained from trophozoite adapted to axenic culture. The reproduction of intestinal amebiasis in an animal model is difficult while for liver amebiasis there are well described rodent models. During this study, we worked on the assessment of pigs as a new potential model to study amebiasis. METHODOLOGY/PRINCIPAL FINDINGS: We first co-cultured trophozoites of E. histolytica with porcine colonic fragments and observed a disruption of the mucosal architecture. Then, we showed that outbred pigs can be used to reproduce some lesions associated with human amebiasis. A detailed analysis was performed using a washed closed-jejunal loops model. In loops inoculated with virulent amebas a severe acute ulcerative jejunitis was observed with large hemorrhagic lesions 14 days post-inoculation associated with the presence of the trophozoites in the depth of the mucosa in two out four animals. Furthermore, typical large sized hepatic abscesses were observed in the liver of one animal 7 days post-injection in the portal vein and the liver parenchyma. CONCLUSIONS: The pig model could help with simultaneously studying intestinal and extraintestinal lesion development. PMID- 22205971 TI - Immunoassays based on Penicillium marneffei Mp1p derived from Pichia pastoris expression system for diagnosis of penicilliosis. AB - BACKGROUND: Penicillium marneffei is a dimorphic fungus endemic in Southeast Asia. It can cause fatal penicilliosis in humans, particularly in HIV-infected people. Diagnosis of this infection is difficult because its clinical manifestations are not distinctive. Specialized laboratory tests are necessary to establish a definitive diagnosis for successful management. We have demonstrated previously that a cell wall mannoprotein Mp1p, abundant in P. marneffei, is a potential biomarker for diagnosis of P. marneffei infections. In the present study, we describe immunoassays based on Mp1p derived from the yeast Pichia pastoris expression system. METHODOLOGY/PRINCIPAL FINDINGS: We generated monoclonal antibodies (MAbs) and rabbit polyclonal antibodies (PAbs) against Mp1p expressed in P. pastoris. Subsequently, we developed two Mp1p antigen capture ELISAs which employed MAbs for both the capture and detecting antibodies (MAb-MAb pair) or PAbs and MAbs as the capture and detecting antibodies (PAbs-MAb pair) respectively. The two Mp1p antigen ELISAs detected Mp1p specifically in cultures of P. marneffei yeast phase at 37-40 degrees C and had no cross-reaction with other tested pathogenic fungi. The sensitivities and specificities of the two antigen assays were found to be 55% (11/20) and 99.6% (538/540) for MAb-MAb Mp1p ELISA, and 75% (15/20) and 99.4% (537/540) for PAbs-MAb Mp1p ELISA performed using 20 sera with culture-confirmed penicilliosis, and 540 control sera from 15 other mycosis patients and 525 healthy donors. Meanwhile, we also developed an anti-Mp1p IgG antibody ELISA with an evaluated sensitivity of 30% (6/20) and a specificity of 98.5% (532/540) using the same sera. Furthermore, combining the results of Mp1p antigen and antibody detection improved the sensitivity of diagnosis to 100% (20/20). CONCLUSIONS/SIGNIFICANCE: Simultaneous detection of antigen and antibody using the immunoassays based on Mp1p derived from P. pastoris greatly improves detection sensitivity. The procedures should be useful for the routine diagnosis of penicilliosis. PMID- 22205969 TI - ACSL6 is associated with the number of cigarettes smoked and its expression is altered by chronic nicotine exposure. AB - Individuals with schizophrenia tend to be heavy smokers and are at high risk for tobacco dependence. However, the nature of the comorbidity is not entirely clear. We previously reported evidence for association of schizophrenia with SNPs and SNP haplotypes in a region of chromosome 5q containing the SPEC2, PDZ-GEF2 and ACSL6 genes. In this current study, analysis of the control subjects of the Molecular Genetics of Schizophrenia (MGS) sample showed similar pattern of association with number of cigarettes smoked per day (numCIG) for the same region. To further test if this locus is associated with tobacco smoking as measured by numCIG and FTND, we conducted replication and meta-analysis in 12 independent samples (n>16,000) for two markers in ACSL6 reported in our previous schizophrenia study. In the meta-analysis of the replication samples, we found that rs667437 and rs477084 were significantly associated with numCIG (p = 0.00038 and 0.00136 respectively) but not with FTND scores. We then used in vitro and in vivo techniques to test if nicotine exposure influences the expression of ACSL6 in brain. Primary cortical culture studies showed that chronic (5-day) exposure to nicotine stimulated ACSL6 mRNA expression. Fourteen days of nicotine administration via osmotic mini pump also increased ACSL6 protein levels in the prefrontal cortex and hippocampus of mice. These increases were suppressed by injection of the nicotinic receptor antagonist mecamylamine, suggesting that elevated expression of ACSL6 requires nicotinic receptor activation. These findings suggest that variations in the ACSL6 gene may contribute to the quantity of cigarettes smoked. The independent associations of this locus with schizophrenia and with numCIG in non-schizophrenic subjects suggest that this locus may be a common liability to both conditions. PMID- 22205972 TI - Gentle masking of low-complexity sequences improves homology search. AB - Detection of sequences that are homologous, i.e. descended from a common ancestor, is a fundamental task in computational biology. This task is confounded by low-complexity tracts (such as atatatatatat), which arise frequently and independently, causing strong similarities that are not homologies. There has been much research on identifying low-complexity tracts, but little research on how to treat them during homology search. We propose to find homologies by aligning sequences with "gentle" masking of low-complexity tracts. Gentle masking means that the match score involving a masked letter is min(0,S), where S is the unmasked score. Gentle masking slightly but noticeably improves the sensitivity of homology search (compared to "harsh" masking), without harming specificity. We show examples in three useful homology search problems: detection of NUMTs (nuclear copies of mitochondrial DNA), recruitment of metagenomic DNA reads to reference genomes, and pseudogene detection. Gentle masking is currently the best way to treat low-complexity tracts during homology search. PMID- 22205973 TI - Farnesol-induced apoptosis in Candida albicans is mediated by Cdr1-p extrusion and depletion of intracellular glutathione. AB - Farnesol is a key derivative in the sterol biosynthesis pathway in eukaryotic cells previously identified as a quorum sensing molecule in the human fungal pathogen Candida albicans. Recently, we demonstrated that above threshold concentrations, farnesol is capable of triggering apoptosis in C. albicans. However, the exact mechanism of farnesol cytotoxicity is not fully elucidated. Lipophilic compounds such as farnesol are known to conjugate with glutathione, an antioxidant crucial for cellular detoxification against damaging compounds. Glutathione conjugates act as substrates for ATP-dependent ABC transporters and are extruded from the cell. To that end, this current study was undertaken to validate the hypothesis that farnesol conjugation with intracellular glutathione coupled with Cdr1p-mediated extrusion of glutathione conjugates, results in total glutathione depletion, oxidative stress and ultimately fungal cell death. The combined findings demonstrated a significant decrease in intracellular glutathione levels concomitant with up-regulation of CDR1 and decreased cell viability. However, addition of exogenous reduced glutathione maintained intracellular glutathione levels and enhanced viability. In contrast, farnesol toxicity was decreased in a mutant lacking CDR1, whereas it was increased in a CDR1-overexpressing strain. Further, gene expression studies demonstrated significant up-regulation of the SOD genes, primary enzymes responsible for defense against oxidative stress, with no changes in expression in CDR1. This is the first study describing the involvement of Cdr1p-mediated glutathione efflux as a mechanism preceding the farnesol-induced apoptotic process in C. albicans. Understanding of the mechanisms underlying farnesol-cytotoxicity in C. albicans may lead to the development of this redox-cycling agent as an alternative antifungal agent. PMID- 22205974 TI - CCL5 neutralization restricts cancer growth and potentiates the targeting of PDGFRbeta in colorectal carcinoma. AB - Increased CCL5 levels are markers of an unfavourable outcome in patients with melanoma, breast, cervical, prostate, gastric or pancreatic cancer. Here, we have assessed the role played by CCL5/CCR5 interactions in the development of colon cancer. To do so, we have examined a number of human colorectal carcinoma clinical specimens and found CCL5 and its receptors over-expressed within primary as well as liver and pulmonary metastases of patients compared to healthy tissues. In vitro, CCL5 increased the growth and migratory responses of colon cancer cells from both human and mouse origins. In addition, systemic treatment of mice with CCL5-directed antibodies reduced the extent of development of subcutaneous colon tumors, of liver metastases and of peritoneal carcinosis. Consistently, we found increased numbers of CD45-immunoreactive cells within the stroma of the remaining lesions as well as at the interface with the healthy tissue. In contrast, selective targeting of CCR5 through administration of TAK 779, a CCR5 antagonist, only partially compromised colon cancer progression. Furthermore, CCL5 neutralization rendered the tumors more sensitive to a PDGFRbeta-directed strategy in mice, this combination regimen offering the greatest protection against liver metastases and suppressing macroscopic peritoneal carcinosis. Collectively, our data demonstrate the involvement of CCL5 in the pathogenesis of colorectal carcinoma and point to its potential value as a therapeutic target. PMID- 22205975 TI - Differences in genotype and virulence among four multidrug-resistant Streptococcus pneumoniae isolates belonging to the PMEN1 clone. AB - We report on the comparative genomics and characterization of the virulence phenotypes of four S. pneumoniae strains that belong to the multidrug resistant clone PMEN1 (Spain(23F) ST81). Strains SV35-T23 and SV36-T3 were recovered in 1996 from the nasopharynx of patients at an AIDS hospice in New York. Strain SV36 T3 expressed capsule type 3 which is unusual for this clone and represents the product of an in vivo capsular switch event. A third PMEN1 isolate - PN4595-T23 - was recovered in 1996 from the nasopharynx of a child attending day care in Portugal, and a fourth strain - ATCC700669 - was originally isolated from a patient with pneumococcal disease in Spain in 1984. We compared the genomes among four PMEN1 strains and 47 previously sequenced pneumococcal isolates for gene possession differences and allelic variations within core genes. In contrast to the 47 strains - representing a variety of clonal types - the four PMEN1 strains grouped closely together, demonstrating high genomic conservation within this lineage relative to the rest of the species. In the four PMEN1 strains allelic and gene possession differences were clustered into 18 genomic regions including the capsule, the blp bacteriocins, erythromycin resistance, the MM1-2008 prophage and multiple cell wall anchored proteins. In spite of their genomic similarity, the high resolution chinchilla model was able to detect variations in virulence properties of the PMEN1 strains highlighting how small genic or allelic variation can lead to significant changes in pathogenicity and making this set of strains ideal for the identification of novel virulence determinants. PMID- 22205976 TI - Histopathology of growth anomaly affecting the coral, Montipora capitata: implications on biological functions and population viability. AB - Growth anomalies (GAs) affect the coral, Montipora capitata, at Wai'opae, southeast Hawai'i Island. Our histopathological analysis of this disease revealed that the GA tissue undergoes changes which compromise anatomical machinery for biological functions such as defense, feeding, digestion, and reproduction. GA tissue exhibited significant reductions in density of ova (66.1-93.7%), symbiotic dinoflagellates (38.8-67.5%), mesenterial filaments (11.2-29.0%), and nematocytes (28.8-46.0%). Hyperplasia of the basal body wall but no abnormal levels of necrosis and algal or fungal invasion was found in GA tissue. Skeletal density along the basal body wall was significantly reduced in GAs compared to healthy or unaffected sections. The reductions in density of the above histological features in GA tissue were collated with disease severity data to quantify the impact of this disease at the colony and population level. Resulting calculations showed this disease reduces the fecundity of M. capitata colonies at Wai'opae by 0.7 49.6%, depending on GA severity, and the overall population fecundity by 2.41+/ 0.29%. In sum, GA in this M. capitata population reduces the coral's critical biological functions and increases susceptibility to erosion, clearly defining itself as a disease and an ecological threat. PMID- 22205977 TI - Idebenone and resveratrol extend lifespan and improve motor function of HtrA2 knockout mice. AB - Heterozygous loss-of-function mutation of the human gene for the mitochondrial protease HtrA2 has been associated with increased risk to develop mitochondrial dysfunction, a process known to contribute to neurodegenerative disorders such as Huntington's disease (HD) and Parkinson's disease (PD). Knockout of HtrA2 in mice also leads to mitochondrial dysfunction and to phenotypes that resemble those found in neurodegenerative disorders and, ultimately, lead to death of animals around postnatal day 30. Here, we show that Idebenone, a synthetic antioxidant of the coenzyme Q family, and Resveratrol, a bioactive compound extracted from grapes, are both able to ameliorate this phenotype. Feeding HtrA2 knockout mice with either compound extends lifespan and delays worsening of the motor phenotype. Experiments conducted in cell culture and on brain tissue of mice revealed that each compound has a different mechanism of action. While Idebenone acts by downregulating the integrated stress response, Resveratrol acts by attenuating apoptosis at the level of Bax. These activities can account for the delay in neuronal degeneration in the striata of these mice and illustrate the potential of these compounds as effective therapeutic approaches against neurodegenerative disorders such as HD or PD. PMID- 22205978 TI - Asymmetric proteome equalization of the skeletal muscle proteome using a combinatorial hexapeptide library. AB - Immobilized combinatorial peptide libraries have been advocated as a strategy for equalization of the dynamic range of a typical proteome. The technology has been applied predominantly to blood plasma and other biological fluids such as urine, but has not been used extensively to address the issue of dynamic range in tissue samples. Here, we have applied the combinatorial library approach to the equalization of a tissue where there is also a dramatic asymmetry in the range of abundances of proteins; namely, the soluble fraction of skeletal muscle. We have applied QconCAT and label-free methodology to the quantification of the proteins that bind to the beads as the loading is progressively increased. Although some equalization is achieved, and the most abundant proteins no longer dominate the proteome analysis, at high protein loadings a new asymmetry of protein expression is reached, consistent with the formation of complex assembles of heat shock proteins, cytoskeletal elements and other proteins on the beads. Loading at different ionic strength values leads to capture of different subpopulations of proteins, but does not completely eliminate the bias in protein accumulation. These assemblies may impair the broader utility of combinatorial library approaches to the equalization of tissue proteomes. However, the asymmetry in equalization is manifest at either low and high ionic strength values but manipulation of the solvent conditions may extend the capacity of the method. PMID- 22205979 TI - Evaluation of microorganisms cultured from injured and repressed tissue regeneration sites in endangered giant aquatic Ozark Hellbender salamanders. AB - Investigation into the causes underlying the rapid, global amphibian decline provides critical insight into the effects of changing ecosystems. Hypothesized and confirmed links between amphibian declines, disease, and environmental changes are increasingly represented in published literature. However, there are few long-term amphibian studies that include data on population size, abnormality/injury rates, disease, and habitat variables to adequately assess changes through time. We cultured and identified microorganisms isolated from abnormal/injured and repressed tissue regeneration sites of the endangered Ozark Hellbender, Cryptobranchus alleganiensis bishopi, to discover potential causative agents responsible for their significant decline in health and population. This organism and our study site were chosen because the population and habitat of C. a. bishopi have been intensively studied from 1969-2009, and the abnormality/injury rate and apparent lack of regeneration were established. Although many bacterial and fungal isolates recovered were common environmental organisms, several opportunistic pathogens were identified in association with only the injured tissues of C.a. bishopi. Bacterial isolates included Aeromonas hydrophila, a known amphibian pathogen, Granulicetella adiacens, Gordonai terrae, Stenotrophomonas maltophilia, Aerococcus viridans, Streptococcus pneumoniae and a variety of Pseudomonads, including Pseudomonas aeruginosa, P. stutzeri, and P. alcaligenes. Fungal isolates included species in the genera Penicillium, Acremonium, Cladosporium, Curvularia, Fusarium, Streptomycetes, and the Class Hyphomycetes. Many of the opportunistic pathogens identified are known to form biofilms. Lack of isolation of the same organism from all wounds suggests that the etiological agent responsible for the damage to C. a. bishopi may not be a single organism. To our knowledge, this is the first study to profile the external microbial consortia cultured from a Cryptobranchid salamander. The incidence of abnormalities/injury and retarded regeneration in C. a. bishopi may have many contributing factors including disease and habitat degradation. Results from this study may provide insight into other amphibian population declines. PMID- 22205980 TI - Inhibitors of alphavirus entry and replication identified with a stable Chikungunya replicon cell line and virus-based assays. AB - Chikungunya virus (CHIKV), an alphavirus, has recently caused epidemic outbreaks and is therefore considered a re-emerging pathogen for which no effective treatment is available. In this study, a CHIKV replicon containing the virus replicase proteins together with puromycin acetyltransferase, EGFP and Renilla luciferase marker genes was constructed. The replicon was transfected into BHK cells to yield a stable cell line. A non-cytopathic phenotype was achieved by a Pro718 to Gly substitution and a five amino acid insertion within non-structural protein 2 (nsP2), obtained through selection for stable growth. Characterization of the replicon cell line by Northern blotting analysis revealed reduced levels of viral RNA synthesis. The CHIKV replicon cell line was validated for antiviral screening in 96-well format and used for a focused screen of 356 compounds (natural compounds and clinically approved drugs). The 5,7-dihydroxyflavones apigenin, chrysin, naringenin and silybin were found to suppress activities of EGFP and Rluc marker genes expressed by the CHIKV replicon. In a concomitant screen against Semliki Forest virus (SFV), their anti-alphaviral activity was confirmed and several additional inhibitors of SFV with IC50 values between 0.4 and 24 uM were identified. Chlorpromazine and five other compounds with a 10H phenothiazinyl structure were shown to inhibit SFV entry using a novel entry assay based on a temperature-sensitive SFV mutant. These compounds also reduced SFV and Sindbis virus-induced cytopathic effect and inhibited SFV virion production in virus yield experiments. Finally, antiviral effects of selected compounds were confirmed using infectious CHIKV. In summary, the presented approach for discovering alphaviral inhibitors enabled us to identify potential lead structures for the development of alphavirus entry and replication phase inhibitors as well as demonstrated the usefulness of CHIKV replicon and SFV as biosafe surrogate models for anti-CHIKV screening. PMID- 22205981 TI - A case control association study and cognitive function analysis of neuropilin and tolloid-like 1 gene and schizophrenia in the Japanese population. AB - BACKGROUND: Using a knock-out mouse model, it was shown that NETO1 is a critical component of the NMDAR complex, and that loss of Neto1 leads to impaired hippocampal long term potentiation and hippocampal-dependent learning and memory. Moreover, hemizygosity of NETO1 was shown to be associated with autistic-like behavior in humans. PURPOSE OF THE RESEARCH: We examined the association between schizophrenia and the neuropilin and tolloid-like 1 gene (NETO1). First, we selected eight single nucleotide polymorphisms (SNPs) within the NETO1 locus, based on the Japanese schizophrenia genome wide association study (JGWAS) results and previously conducted association studies. These SNPs were genotyped in the replication sample comprised of 963 schizophrenic patients and 919 healthy controls. We also examined the effect of associated SNPs on scores in the Continuous Performance Test and the Wisconsin Card Sorting Test Keio version (schizophrenic patients 107, healthy controls 104). RESULTS: There were no significant allele-wise and haplotype-wise associations in the replication analysis after Bonferroni correction. However, in meta-analysis (JGWAS and replication dataset) three association signals were observed (rs17795324: p = 0.028, rs8098760: p = 0.017, rs17086492: p = 0.003). These SNPs were followed up but we could not detect the allele-specific effect on cognitive performance measured by the Continuous performance test (CPT) and Wisconsin Card Sorting test (WCST). MAJOR CONCLUSIONS: We did not detect evidence for the association of NETO1 with schizophrenia in the Japanese population. Common variants within the NETO1 locus may not increase the genetic risk for schizophrenia in the Japanese population. Additionally, common variants investigated in the current study did not affect cognitive performance, as measured by the CPT and WCST. PMID- 22205982 TI - Indicators measuring the performance of malaria programs supported by the global fund in Asia, progress and the way forward. AB - INTRODUCTION: In 2010, the Global Fund provided more than 75% of external international financing for malaria control. The Global Fund uses performance based funding in the grants it finances. This paper analyses the indicators used to measure the performance of Global Fund supported malaria grants in Asia. METHODS: Indicators used in the performance frameworks for all Global Fund supported malaria grants in Asia were retrieved from grant database and grouped into impact, outcome, output and input categories and categorized by service delivery areas. Indicators of each group were compared over rounds. Indicators used in performance frameworks were compared with internationally adopted indicators included in the Monitoring and Evaluation Toolkit developed by the Global Fund and international technical agencies. RESULTS: Between 2002 and 2010, 1,434 indicators were included in the performance frameworks of the 48 malaria grants awarded in Asia, including 229 impact and 227 outcome indicators, 437 output and 541 input indicators, with an average of 29.9 indicators per grant. The proportion of impact and outcome indicators increased over rounds, with that of input indicators declining from 44.1% in Round 1 to 22.7% in Round 9. CONCLUSIONS: Input indicators, which have predominated the performance frameworks of the Global Fund supported malaria programs in Asia have declined between Rounds 1 and 9. However, increased alignment with internationally adopted indicators included in the Monitoring and Evaluation Toolkit is needed to improve the validity of reported results. PMID- 22205984 TI - Resource selection and its implications for wide-ranging mammals of the brazilian cerrado. AB - Conserving animals beyond protected areas is critical because even the largest reserves may be too small to maintain viable populations for many wide-ranging species. Identification of landscape features that will promote persistence of a diverse array of species is a high priority, particularly, for protected areas that reside in regions of otherwise extensive habitat loss. This is the case for Emas National Park, a small but important protected area located in the Brazilian Cerrado, the world's most biologically diverse savanna. Emas Park is a large mammal global conservation priority area but is too small to protect wide-ranging mammals for the long-term and conserving these populations will depend on the landscape surrounding the park. We employed novel, noninvasive methods to determine the relative importance of resources found within the park, as well as identify landscape features that promote persistence of wide-ranging mammals outside reserve borders. We used scat detection dogs to survey for five large mammals of conservation concern: giant armadillo (Priodontes maximus), giant anteater (Myrmecophaga tridactyla), maned wolf (Chrysocyon brachyurus), jaguar (Panthera onca), and puma (Puma concolor). We estimated resource selection probability functions for each species from 1,572 scat locations and 434 giant armadillo burrow locations. Results indicate that giant armadillos and jaguars are highly selective of natural habitats, which makes both species sensitive to landscape change from agricultural development. Due to the high amount of such development outside of the Emas Park boundary, the park provides rare resource conditions that are particularly important for these two species. We also reveal that both woodland and forest vegetation remnants enable use of the agricultural landscape as a whole for maned wolves, pumas, and giant anteaters. We identify those features and their landscape compositions that should be prioritized for conservation, arguing that a multi-faceted approach is required to protect these species. PMID- 22205983 TI - Suppression and regression of choroidal neovascularization in mice by a novel CCR2 antagonist, INCB3344. AB - PURPOSE: To investigate the effect of an intravitreally administered CCR2 antagonist, INCB3344, on a mouse model of choroidal neovascularization (CNV). METHODS: CNV was induced by laser photocoagulation on Day 0 in wild type mice. INCB3344 or vehicle was administered intravitreally immediately after laser application. On Day 14, CNV areas were measured on retinal pigment epithelium (RPE)-choroid flat mounts and histopathologic examination was performed on 7 um thick sections. Macrophage infiltration was evaluated by immunohistochemistry on RPE-choroid flat mounts and quantified by flow cytometry on Day 3. Expression of vascular endothelial growth factor (VEGF) protein in RPE-choroid tissue was examined by immunohistochemistry and ELISA, VEGF mRNA in sorted macrophages in RPE-choroid tissue was examine by real-time PCR and expression of phosphorylated extracellular signal-regulated kinase (p-ERK 1/2) in RPE-choroid tissue was measured by Western blot analysis on Day 3. We also evaluated the efficacy of intravitreal INCB3344 to spontaneous CNV detected in Cu, Zn-superoxide dismutase (SOD1) deficient mice. Changes in CNV size were assessed between pre- and 1week post-INCB3344 or vehicle administration in fundus photography and fluorescence angiography (FA). RESULTS: The mean CNV area in INCB3344-treated mice decreased by 42.4% compared with the vehicle-treated control mice (p<0.001). INCB3344 treatment significantly inhibited macrophage infiltration into the laser irradiated area (p<0.001), and suppressed the expression of VEGF protein (p = 0.012), VEGF mRNA in infiltrating macrophages (p<0.001) and the phosphorylation of ERK1/2 (p<0.001). The area of spontaneous CNV in Sod1-/- mice regressed by 70.35% in INCB3344-treated animals while no change was detected in vehicle treated control mice (p<0.001). CONCLUSIONS: INCB3344 both inhibits newly forming CNV and regresses established CNV. Controlling inflammation by suppressing macrophage infiltration and angiogenic ability via the CCR-2/MCP-1 signal may be a useful therapeutic strategy for treating CNV associated with age-related macular degeneration. PMID- 22205985 TI - The DNA repair gene APE1 T1349G polymorphism and risk of gastric cancer in a Chinese population. AB - BACKGROUND: Apurinic/apyrimidinic endonuclease 1 (APE1) has a central role in the repair of apurinic apyrimidic sites through both its endonuclease and its phosphodiesterase activities. A common APE1 polymorphism, T1349G (rs3136820), was previously shown to be associated with the risk of cancers. OBJECTIVE: We hypothesized that the APE1 T1349G polymorphism is also associated with risk of gastric cancer. METHODS: In a hospital-based case-control study of 338 case patients with newly diagnosed gastric cancer and 362 cancer-free controls frequency-matched by age and sex, we genotyped the T1349G polymorphism and assessed its associations with risk of gastric cancer. RESULTS: Compared with the APE1 TT genotype, individuals with the variant TG/GG genotypes had a significantly increased risk of gastric cancer (odds ratio = 1.69, 95% confidence interval = 1.19-2.40), which was more pronounced among subgroups of aged <= 60 years, male, ever smokers, and ever drinkers. Further analyses revealed that the variant genotypes were associated with an increased risk for diffuse-type, low depth of tumor infiltration (T1 and T2), and lymph node metastasis gastric cancer. CONCLUSIONS: The APE1 T1349G polymorphism may be a marker for the development of gastric cancer in the Chinese population. Larger studies are required to validate these findings in diverse populations. PMID- 22205986 TI - High-frequency dynamics of ocean pH: a multi-ecosystem comparison. AB - The effect of Ocean Acidification (OA) on marine biota is quasi-predictable at best. While perturbation studies, in the form of incubations under elevated pCO(2), reveal sensitivities and responses of individual species, one missing link in the OA story results from a chronic lack of pH data specific to a given species' natural habitat. Here, we present a compilation of continuous, high resolution time series of upper ocean pH, collected using autonomous sensors, over a variety of ecosystems ranging from polar to tropical, open-ocean to coastal, kelp forest to coral reef. These observations reveal a continuum of month-long pH variability with standard deviations from 0.004 to 0.277 and ranges spanning 0.024 to 1.430 pH units. The nature of the observed variability was also highly site-dependent, with characteristic diel, semi-diurnal, and stochastic patterns of varying amplitudes. These biome-specific pH signatures disclose current levels of exposure to both high and low dissolved CO(2), often demonstrating that resident organisms are already experiencing pH regimes that are not predicted until 2100. Our data provide a first step toward crystallizing the biophysical link between environmental history of pH exposure and physiological resilience of marine organisms to fluctuations in seawater CO(2). Knowledge of this spatial and temporal variation in seawater chemistry allows us to improve the design of OA experiments: we can test organisms with a priori expectations of their tolerance guardrails, based on their natural range of exposure. Such hypothesis-testing will provide a deeper understanding of the effects of OA. Both intuitively simple to understand and powerfully informative, these and similar comparative time series can help guide management efforts to identify areas of marine habitat that can serve as refugia to acidification as well as areas that are particularly vulnerable to future ocean change. PMID- 22205987 TI - APC/C(Cdh1)-mediated degradation of the F-box protein NIPA is regulated by its association with Skp1. AB - NIPA (Nuclear Interaction Partner of Alk kinase) is an F-box like protein that targets nuclear Cyclin B1 for degradation. Integrity and therefore activity of the SCF(NIPA) E3 ligase is regulated by cell-cycle-dependent phosphorylation of NIPA, restricting substrate ubiquitination to interphase. Here we show that phosphorylated NIPA is degraded in late mitosis in an APC/C(Cdh1)-dependent manner. Binding of the unphosphorylated form of NIPA to Skp1 interferes with binding to the APC/C-adaptor protein Cdh1 and therefore protects unphosphorylated NIPA from degradation in interphase. Our data thus define a novel mode of regulating APC/C-mediated ubiquitination. PMID- 22205988 TI - A honey bee hexamerin, HEX 70a, is likely to play an intranuclear role in developing and mature ovarioles and testioles. AB - Insect hexamerins have long been known as storage proteins that are massively synthesized by the larval fat body and secreted into hemolymph. Following the larval-to-pupal molt, hexamerins are sequestered by the fat body via receptor mediated endocytosis, broken up, and used as amino acid resources for metamorphosis. In the honey bee, the transcript and protein subunit of a hexamerin, HEX 70a, were also detected in ovaries and testes. Aiming to identify the subcellular localization of HEX 70a in the female and male gonads, we used a specific antibody in whole mount preparations of ovaries and testes for analysis by confocal laser-scanning microscopy. Intranuclear HEX 70a foci were evidenced in germ and somatic cells of ovarioles and testioles of pharate-adult workers and drones, suggesting a regulatory or structural role. Following injection of the thymidine analog EdU we observed co-labeling with HEX 70a in ovariole cell nuclei, inferring possible HEX 70a involvement in cell proliferation. Further support to this hypothesis came from an injection of anti-HEX 70a into newly ecdysed queen pupae where it had a negative effect on ovariole thickening. HEX 70a foci were also detected in ovarioles of egg laying queens, particularly in the nuclei of the highly polyploid nurse cells and in proliferating follicle cells. Additional roles for this storage protein are indicated by the detection of nuclear HEX 70a foci in post-meiotic spermatids and spermatozoa. Taken together, these results imply undescribed roles for HEX 70a in the developing gonads of the honey bee and raise the possibility that other hexamerins may also have tissue specific functions. PMID- 22205989 TI - N-glycans of human protein C inhibitor: tissue-specific expression and function. AB - Protein C inhibitor (PCI) is a serpin type of serine protease inhibitor that is found in many tissues and fluids in human, including blood plasma, seminal plasma and urine. This inhibitor displays an unusually broad protease specificity compared with other serpins. Previous studies have shown that the N-glycan(s) and the NH2-terminus affect some blood-related functions of PCI. In this study, we have for the first time determined the N-glycan profile of seminal plasma PCI, by mass spectrometry. The N-glycan structures differed markedly compared with those of both blood-derived and urinary PCI, providing evidence that the N-glycans of PCI are expressed in a tissue-specific manner. The most abundant structure (m/z 2592.9) had a composition of Fuc3Hex5HexNAc4, consistent with a core fucosylated bi-antennary glycan with terminal Lewis(x). A major serine protease in semen, prostate specific antigen (PSA), was used to evaluate the effects of N-glycans and the NH2-terminus on a PCI function related to the reproductive tract. Second order rate constants for PSA inhibition by PCI were 4.3+/-0.2 and 4.1+/-0.5 M-1 s 1 for the natural full-length PCI and a form lacking six amino acids at the NH2 terminus, respectively, whereas these constants were 4.8+/-0.1 and 29+/-7 M-1 s-1 for the corresponding PNGase F-treated forms. The 7-8-fold higher rate constants obtained when both the N-glycans and the NH2-terminus had been removed suggest that these structures jointly affect the rate of PSA inhibition, presumably by together hindering conformational changes of PCI required to bind to the catalytic pocket of PSA. PMID- 22205990 TI - Revisiting G3BP1 as a RasGAP binding protein: sensitization of tumor cells to chemotherapy by the RasGAP 317-326 sequence does not involve G3BP1. AB - RasGAP is a multifunctional protein that controls Ras activity and that is found in chromosomal passenger complexes. It also negatively or positively regulates apoptosis depending on the extent of its cleavage by caspase-3. RasGAP has been reported to bind to G3BP1 (RasGAP SH3-domain-binding protein 1), a protein regulating mRNA stability and stress granule formation. The region of RasGAP (amino acids 317-326) thought to bind to G3BP1 corresponds exactly to the sequence within fragment N2, a caspase-3-generated fragment of RasGAP, that mediates sensitization of tumor cells to genotoxins. While assessing the contribution of G3BP1 in the anti-cancer function of a cell-permeable peptide containing the 317-326 sequence of RasGAP (TAT-RasGAP317-326), we found that, in conditions where G3BP1 and RasGAP bind to known partners, no interaction between G3BP1 and RasGAP could be detected. TAT-RasGAP317-326 did not modulate binding of G3BP1 to USP10, stress granule formation or c-myc mRNA levels. Finally, TAT RasGAP317-326 was able to sensitize G3BP1 knock-out cells to cisplatin-induced apoptosis. Collectively these results indicate that G3BP1 and its putative RasGAP binding region have no functional influence on each other. Importantly, our data provide arguments against G3BP1 being a genuine RasGAP-binding partner. Hence, G3BP1-mediated signaling may not involve RasGAP. PMID- 22205991 TI - An 11p15 imprinting centre region 2 deletion in a family with Beckwith Wiedemann syndrome provides insights into imprinting control at CDKN1C. AB - We report a three generation family with Beckwith Wiedemann syndrome (BWS) in whom we have identified a 330 kb deletion within the KCNQ1 locus, encompassing the 11p15.5 Imprinting Centre II (IC2). The deletion arose on the paternal chromosome in the first generation and was only associated with BWS when transmitted maternally to subsequent generations. The deletion on the maternal chromosome was associated with a lower median level of CDKN1C expression in the peripheral blood of affected individuals when compared to a cohort of unaffected controls (p<0.05), however was not significantly different to the expression levels in BWS cases with loss of methylation (LOM) within IC2 (p<0.78). Moreover the individual with a deletion on the paternal chromosome did not show evidence of elevated CDKN1C expression or features of Russell Silver syndrome. These observations support a model invoking the deletion of enhancer elements required for CDKN1C expression lying within or close to the imprinting centre and importantly extend and validate a single observation from an earlier study. Analysis of 94 cases with IC2 loss of methylation revealed that KCNQ1 deletion is a rare cause of loss of maternal methylation, occurring in only 3% of cases, or in 1.5% of BWS overall. PMID- 22205992 TI - Clag9 is not essential for PfEMP1 surface expression in non-cytoadherent Plasmodium falciparum parasites with a chromosome 9 deletion. AB - BACKGROUND: The expression of the clonally variant virulence factor PfEMP1 mediates the sequestration of Plasmodium falciparum infected erythrocytes in the host vasculature and contributes to chronic infection. Non-cytoadherent parasites with a chromosome 9 deletion lack clag9, a gene linked to cytoadhesion in previous studies. Here we present new clag9 data that challenge this view and show that surface the non-cytoadherence phenotype is linked to the expression of a non-functional PfEMP1. METHODOLOGY/PRINCIPAL FINDINGS: Loss of adhesion in P. falciparum D10, a parasite line with a large chromosome 9 deletion, was investigated. Surface iodination analysis of non-cytoadherent D10 parasites and COS-7 surface expression of the CD36-binding PfEMP1 CIDR1alpha domain were performed and showed that these parasites express an unusual trypsin-resistant, non-functional PfEMP1 at the erythrocyte surface. However, the CIDR1alpha domain of this var gene expressed in COS-7 cells showed strong binding to CD36. Atomic Force Microscopy showed a slightly modified D10 knob morphology compared to adherent parasites. Trafficking of PfEMP1 and KAHRP remained functional in D10. We link the non-cytoadherence phenotype to a chromosome 9 breakage and healing event resulting in the loss of 25 subtelomeric genes including clag9. In contrast to previous studies, knockout of the clag9 gene from 3D7 did not interfere with parasite adhesion to CD36. CONCLUSIONS/SIGNIFICANCE: Our data show the surface expression of non-functional PfEMP1 in D10 strongly indicating that genes other than clag9 deleted from chromosome 9 are involved in this virulence process possibly via post-translational modifications. PMID- 22205993 TI - The dynamin chemical inhibitor dynasore impairs cholesterol trafficking and sterol-sensitive genes transcription in human HeLa cells and macrophages. AB - Intracellular transport of cholesterol contributes to the regulation of cellular cholesterol homeostasis by mechanisms that are yet poorly defined. In this study, we characterized the impact of dynasore, a recently described drug that specifically inhibits the enzymatic activity of dynamin, a GTPase regulating receptor endocytosis and cholesterol trafficking. Dynasore strongly inhibited the uptake of low-density lipoprotein (LDL) in HeLa cells, and to a lower extent in human macrophages. In both cell types, dynasore treatment led to the abnormal accumulation of LDL and free cholesterol (FC) within the endolysosomal network. The measure of cholesterol esters (CE) further showed that the delivery of regulatory cholesterol to the endoplasmic reticulum (ER) was deficient. This resulted in the inhibition of the transcriptional control of the three major sterol-sensitive genes, sterol-regulatory element binding protein 2 (SREBP-2), 3 hydroxy-3-methyl-coenzymeA reductase (HMGCoAR), and low-density lipoprotein receptor (LDLR). The sequestration of cholesterol in the endolysosomal compartment impaired both the active and passive cholesterol efflux in HMDM. Our data further illustrate the importance of membrane trafficking in cholesterol homeostasis and validate dynasore as a new pharmacological tool to study the intracellular transport of cholesterol. PMID- 22205995 TI - Detection of murine leukemia virus or mouse DNA in commercial RT-PCR reagents and human DNAs. AB - The xenotropic murine leukemia virus (MLV)-related viruses (XMRV) have been reported in persons with prostate cancer, chronic fatigue syndrome, and less frequently in blood donors. Polytropic MLVs have also been described in persons with CFS and blood donors. However, many studies have failed to confirm these findings, raising the possibility of contamination as a source of the positive results. One PCR reagent, Platinum Taq polymerase (pol) has been reported to contain mouse DNA that produces false-positive MLV PCR results. We report here the finding of a large number of PCR reagents that have low levels of MLV sequences. We found that recombinant reverse-transcriptase (RT) enzymes from six companies derived from either MLV or avian myeloblastosis virus contained MLV pol DNA sequences but not gag or mouse DNA sequences. Sequence and phylogenetic analysis showed high relatedness to Moloney MLV, suggesting residual contamination with an RT-containing plasmid. In addition, we identified contamination with mouse DNA and a variety of MLV sequences in commercially available human DNAs from leukocytes, brain tissues, and cell lines. These results identify new sources of MLV contamination and highlight the importance of careful pre-screening of commercial specimens and diagnostic reagents to avoid false-positive MLV PCR results. PMID- 22205994 TI - Mechanochemical modeling of dynamic microtubule growth involving sheet-to-tube transition. AB - Microtubule dynamics is largely influenced by nucleotide hydrolysis and the resultant tubulin configuration changes. The GTP cap model has been proposed to interpret the stabilizing mechanisms of microtubule growth from the view of hydrolysis effects. Besides, the growth of a microtubule involves the closure of a curved sheet at its growing end. The curvature conversion from the longitudinal direction to the circumferential direction also helps to stabilize the successive growth, and the curved sheet is referred to as the conformational cap. However, there still lacks theoretical investigation on the mechanical-chemical coupling growth process of microtubules. In this paper, we study the growth mechanisms of microtubules by using a coarse-grained molecular method. First, the closure process involving a sheet-to-tube transition is simulated. The results verify the stabilizing effect of the sheet structure and predict that the minimum conformational cap length that can stabilize the growth is two dimers. Then, we show that the conformational cap and the GTP cap can function independently and harmoniously, signifying the pivotal role of mechanical factors. Furthermore, based on our theoretical results, we describe a Tetris-like growth style of microtubules: the stochastic tubulin assembly is regulated by energy and harmonized with the seam zipping such that the sheet keeps a practically constant length during growth. PMID- 22205997 TI - Lyso-GM2 ganglioside: a possible biomarker of Tay-Sachs disease and Sandhoff disease. AB - To find a new biomarker of Tay-Sachs disease and Sandhoff disease. The lyso-GM2 ganglioside (lyso-GM2) levels in the brain and plasma in Sandhoff mice were measured by means of high performance liquid chromatography and the effect of a modified hexosaminidase (Hex) B exhibiting Hex A-like activity was examined. Then, the lyso-GM2 concentrations in human plasma samples were determined. The lyso-GM2 levels in the brain and plasma in Sandhoff mice were apparently increased compared with those in wild-type mice, and they decreased on intracerebroventricular administration of the modified Hex B. The lyso-GM2 levels in plasma of patients with Tay-Sachs disease and Sandhoff disease were increased, and the increase in lyso-GM2 was associated with a decrease in Hex A activity. Lyso-GM2 is expected to be a potential biomarker of Tay-Sachs disease and Sandhoff disease. PMID- 22205996 TI - Transcriptional response of zebrafish embryos exposed to neurotoxic compounds reveals a muscle activity dependent hspb11 expression. AB - Acetylcholinesterase (AChE) inhibitors are widely used as pesticides and drugs. Their primary effect is the overstimulation of cholinergic receptors which results in an improper muscular function. During vertebrate embryonic development nerve activity and intracellular downstream events are critical for the regulation of muscle fiber formation. Whether AChE inhibitors and related neurotoxic compounds also provoke specific changes in gene transcription patterns during vertebrate development that allow them to establish a mechanistic link useful for identification of developmental toxicity pathways has, however, yet not been investigated. Therefore we examined the transcriptomic response of a known AChE inhibitor, the organophosphate azinphos-methyl (APM), in zebrafish embryos and compared the response with two non-AChE inhibiting unspecific control compounds, 1,4-dimethoxybenzene (DMB) and 2,4-dinitrophenol (DNP). A highly specific cluster of APM induced gene transcripts was identified and a subset of strongly regulated genes was analyzed in more detail. The small heat shock protein hspb11 was found to be the most sensitive induced gene in response to AChE inhibitors. Comparison of expression in wildtype, ache and sop(fixe) mutant embryos revealed that hspb11 expression was dependent on the nicotinic acetylcholine receptor (nAChR) activity. Furthermore, modulators of intracellular calcium levels within the whole embryo led to a transcriptional up-regulation of hspb11 which suggests that elevated intracellular calcium levels may regulate the expression of this gene. During early zebrafish development, hspb11 was specifically expressed in muscle pioneer cells and Hspb11 morpholino-knockdown resulted in effects on slow muscle myosin organization. Our findings imply that a comparative toxicogenomic approach and functional analysis can lead to the identification of molecular mechanisms and specific marker genes for potential neurotoxic compounds. PMID- 22205998 TI - Identifying priority areas for conservation: a global assessment for forest dependent birds. AB - Limited resources are available to address the world's growing environmental problems, requiring conservationists to identify priority sites for action. Using new distribution maps for all of the world's forest-dependent birds (60.6% of all bird species), we quantify the contribution of remaining forest to conserving global avian biodiversity. For each of the world's partly or wholly forested 5-km cells, we estimated an impact score of its contribution to the distribution of all the forest bird species estimated to occur within it, and so is proportional to the impact on the conservation status of the world's forest-dependent birds were the forest it contains lost. The distribution of scores was highly skewed, a very small proportion of cells having scores several orders of magnitude above the global mean. Ecoregions containing the highest values of this score included relatively species-poor islands such as Hawaii and Palau, the relatively species rich islands of Indonesia and the Philippines, and the megadiverse Atlantic Forests and northern Andes of South America. Ecoregions with high impact scores and high deforestation rates (2000-2005) included montane forests in Cameroon and the Eastern Arc of Tanzania, although deforestation data were not available for all ecoregions. Ecoregions with high impact scores, high rates of recent deforestation and low coverage by the protected area network included Indonesia's Seram rain forests and the moist forests of Trinidad and Tobago. Key sites in these ecoregions represent some of the most urgent priorities for expansion of the global protected areas network to meet Convention on Biological Diversity targets to increase the proportion of land formally protected to 17% by 2020. Areas with high impact scores, rapid deforestation, low protection and high carbon storage values may represent significant opportunities for both biodiversity conservation and climate change mitigation, for example through Reducing Emissions from Deforestation and Forest Degradation (REDD+) initiatives. PMID- 22205999 TI - A Chitinase from Aeromonas veronii CD3 with the potential to control myxozoan disease. AB - BACKGROUND: The class Myxosporea encompasses about 2,400 species, most of which are parasites of fish and cause serious damage in aquaculture. Due to the concerns about food safety issues and limited knowledge of Myxozoa life cycle and fish immune system, no chemicals, antibiotics or immune modulators are available to control myxozoa infection. Therefore, little can be done once Myxozoa establishment has occurred. METHODOLOGY/PRINCIPAL FINDINGS: In this paper we isolated Aeromonas veronii CD3 with significant myxospore shell valve-degrading ability from pond sediment. A 3,057-bp full-length chitinase gene was consequently cloned, and the corresponding mature, recombinant chitinase (ChiCD3) produced by Escherichia coli had substantial chitinase activity. The deduced sequence of ChiCD3 contained one catalytic domain, two chitin-binding domains, and one putative signal peptide. ChiCD3 had an optimal activity at 50 degrees C and pH 6.0, and retained more than 50% of its optimal activity under warm water aquaculture conditions (~30 degrees C and pH ~7.0). After incubation with ChiCD3, 38.0+/-4.8% of the myxospores had damaged shell valves, whereas myxospores incubated with commercially available chitinases remained intact. CONCLUSION/SIGNIFICANCE: This study reveals a new strategy to control myxozoan disease. ChiCD3 that has capacity to damage the shell valve of myxospores can be supplemented into fish feed and used to control Myxozoa-induced diseases specifically. PMID- 22206000 TI - Mechanisms of MEOX1 and MEOX2 regulation of the cyclin dependent kinase inhibitors p21 and p16 in vascular endothelial cells. AB - Senescence, the state of permanent cell cycle arrest, has been associated with endothelial cell dysfunction and atherosclerosis. The cyclin dependent kinase inhibitors p21(CIP1/WAF1) and p16(INK4a) govern the G(1)/S cell cycle checkpoint and are essential for determining whether a cell enters into an arrested state. The homeodomain transcription factor MEOX2 is an important regulator of vascular cell proliferation and is a direct transcriptional activator of both p21(CIP1/WAF1) and p16(INK4a). MEOX1 and MEOX2 have been shown to be partially functionally redundant during development, suggesting that they regulate similar target genes in vivo. We compared the ability of MEOX1 and MEOX2 to activate p21(CIP1/WAF1) and p16(INK4a) expression and induce endothelial cell cycle arrest. Our results demonstrate for the first time that MEOX1 regulates the MEOX2 target genes p21(CIP1/WAF1) and p16(INK4a). In addition, increased expression of either of the MEOX homeodomain transcription factors leads to cell cycle arrest and endothelial cell senescence. Furthermore, we show that the mechanism of transcriptional activation of these cyclin dependent kinase inhibitor genes by MEOX1 and MEOX2 is distinct. MEOX1 and MEOX2 activate p16(INK4a) in a DNA binding dependent manner, whereas they induce p21(CIP1/WAF1) in a DNA binding independent manner. PMID- 22206001 TI - Chromatin remodeling, cell proliferation and cell death in valproic acid-treated HeLa cells. AB - BACKGROUND: Valproic acid (VPA) is a potent anticonvulsant that inhibits histone deacetylases. Because of this inhibitory action, we investigated whether VPA would affect chromatin supraorganization, mitotic indices and the frequency of chromosome abnormalities and cell death in HeLa cells. METHODOLOGY/PRINCIPAL FINDINGS: Image analysis was performed by scanning microspectrophotometry for cells cultivated for 24 h, treated with 0.05, 0.5 or 1.0 mM VPA for 1-24 h, and subjected to the Feulgen reaction. TSA-treated cells were used as a predictable positive control. DNA fragmentation was investigated with the TUNEL assay. Chromatin decondensation was demonstrated under TSA and all VPA treatments, but no changes in chromosome abnormalities, mitotic indices or morphologically identified cell death were found with the VPA treatment conditions mentioned above, although decreased mitotic indices were detected under higher VPA concentration and longer exposure time. The frequency of DNA fragmentation identified with the TUNEL assay in HeLa cells increased after a 24-h VPA treatment, although this fragmentation occurred much earlier after treatment with TSA. CONCLUSIONS/SIGNIFICANCE: The inhibition of histone deacetylases by VPA induces chromatin remodeling in HeLa cells, which suggests an association to altered gene expression. Under VPA doses close to the therapeutic antiepileptic plasma range no changes in cell proliferation or chromosome abnormalities are elicited. The DNA fragmentation results indicate that a longer exposure to VPA or a higher VPA concentration is required for the induction of cell death. PMID- 22206002 TI - C-terminal di-leucine motif of dopamine D1 receptor plays an important role in its plasma membrane trafficking. AB - The dopamine D1 receptor (D1R), a G protein-coupled receptor, plays a critical role in regulating blood pressure through its actions on renal hemodynamics and epithelial ion transport, which are highly linked to its intracellular trafficking. In this study, we generated a series of C-terminal mutants of D1R that were tagged with or without enhanced yellow fluorescent protein, and analyzed the consequences of these mutants on the plasma membrane trafficking of D1R and cyclic AMP response to D1R stimulation. D1R with mutations within the endocytic recycling signal (amino acid residues 360-382) continued to be functional, albeit decreased relative to wild-type D1R. Mutation of the palmitoylation site (347C>S) of D1R did not impair its trafficking to the plasma membrane, but abolished its ability to increase cyclic AMP accumulation. In contrast, replacement of di-leucines (344-345L>A) by alanines resulted in the retention of D1R in the early endosome, decreased its glycosylation, and prevented its targeting to the plasma membrane. Our studies suggest that di-L motif at the C-terminus of D1R is critical for the glycosylation and cell surface targeting of D1R. PMID- 22206003 TI - Comparative genomics of the anopheline glutathione S-transferase epsilon cluster. AB - Enzymes of the glutathione S-transferase (GST) family play critical roles in detoxification of xenobiotics across many taxa. While GSTs are ubiquitous both in animals and plants, the GST epsilon class (GSTE) is insect-specific and has been associated with resistance to chemical insecticides. While both Aedes aegypti and Anopheles gambiae GSTE clusters consist of eight members, only four putative orthologs are identifiable between the species, suggesting independent expansions of the class in each lineage. We used a primer walking approach, sequencing almost the entire cluster from three Anopheles species (An. stephensi, An. funestus (both Cellia subgenus) and An. plumbeus (Anopheles subgenus)) and compared the sequences to putative orthologs in An. gambiae (Cellia) in an attempt to trace the evolution of the cluster within the subfamily Anophelinae. Furthermore, we measured transcript levels from the identified GSTE loci by real time reverse transcription PCR to determine if all genes were similarly transcribed at different life stages. Among the species investigated, gene order and orientation were similar with three exceptions: (i) GSTE1 was absent in An. plumbeus; (ii) GSTE2 is duplicated in An. plumbeus and (iii) an additional transcriptionally active pseudogene (psiAsGSTE2) was found in An. stephensi. Further statistical analysis and protein modelling gave evidence for positive selection on codons of the catalytic site in GSTE5 albeit its origin seems to predate the introduction of chemical insecticides. Gene expression profiles revealed differences in expression pattern among genes at different life stages. With the exception of GSTE1, psiAsGSTE2 and GSTE2b, all Anopheles species studied share orthologs and hence we assume that GSTE expansion generally predates radiation into subgenera, though the presence of GSTE1 may also suggest a recent duplication event in the Old World Cellia subgenus, instead of a secondary loss. The modifications of the catalytic site within GSTE5 may represent adaptations to new habitats. PMID- 22206004 TI - Executive functioning in daily life in Parkinson's disease: initiative, planning and multi-task performance. AB - Impairments in executive functioning are frequently observed in Parkinson's disease (PD). However, executive functioning needed in daily life is difficult to measure. Considering this difficulty the Cognitive Effort Test (CET) was recently developed. In this multi-task test the goals are specified but participants are free in their approach. This study applies the CET in PD patients and investigates whether initiative, planning and multi-tasking are associated with aspects of executive functions and psychomotor speed. Thirty-six PD patients with a mild to moderate disease severity and thirty-four healthy participants were included in this study. PD patients planned and demonstrated more sequential task execution, which was associated with a decreased psychomotor speed. Furthermore, patients with a moderate PD planned to execute fewer tasks at the same time than patients with a mild PD. No differences were found between these groups for multi tasking. In conclusion, PD patients planned and executed the tasks of the CET sequentially rather than in parallel presumably reflecting a compensation strategy for a decreased psychomotor speed. Furthermore, patients with moderate PD appeared to take their impairments into consideration when planning how to engage the tasks of the test. This compensation could not be detected in patients with mild PD. PMID- 22206005 TI - Tau reduction does not prevent motor deficits in two mouse models of Parkinson's disease. AB - Many neurodegenerative diseases are increasing in prevalence and cannot be prevented or cured. If they shared common pathogenic mechanisms, treatments targeting such mechanisms might be of benefit in multiple conditions. The tau protein has been implicated in the pathogenesis of diverse neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Tau reduction prevents cognitive deficits, behavioral abnormalities and other pathological changes in multiple AD mouse models. Here we examined whether tau reduction also prevents motor deficits and pathological alterations in two mouse models of PD, generated by unilateral striatal injection of 6-hydroxydopamine (6 OHDA) or transgene-mediated neuronal expression of human wildtype alpha synuclein. Both models were evaluated on Tau(+/+), Tau(+/-) and Tau(-/-) backgrounds in a variety of motor tests. Tau reduction did not prevent motor deficits caused by 6-OHDA and slightly worsened one of them. Tau reduction also did not prevent 6-OHDA-induced loss of dopaminergic terminals in the striatum. Similarly, tau reduction did not prevent motor deficits in alpha-synuclein transgenic mice. Our results suggest that tau has distinct roles in the pathogeneses of AD and PD and that tau reduction may not be of benefit in the latter condition. PMID- 22206006 TI - tRNA gene identity affects nuclear positioning. AB - The three-dimensional organization of genomes is dynamic and plays a critical role in the regulation of cellular development and phenotypes. Here we use proximity-based ligation methods (i.e. chromosome conformation capture [3C] and circularized chromosome confrmation capture [4C]) to explore the spatial organization of tRNA genes and their locus-specific interactions with the ribosomal DNA. Directed replacement of one lysine and two leucine tRNA loci shows that tRNA spatial organization depends on both tRNA coding sequence identity and the surrounding chromosomal loci. These observations support a model whereby the three-dimensional, spatial organization of tRNA loci within the nucleus utilizes tRNA gene-specific signals to affect local interactions, though broader organization of chromosomal regions are determined by factors outside the tRNA genes themselves. PMID- 22206007 TI - Dendritic cells take up and present antigens from viable and apoptotic polymorphonuclear leukocytes. AB - Dendritic cells (DC) are endowed with the ability to cross-present antigens from other cell types to cognate T cells. DC are poised to meet polymorphonuclear leukocytes (PMNs) as a result of being co-attracted by interleukin-8 (IL-8), for instance as produced by tumor cells or infected tissue. Human monocyte-derived and mouse bone marrow-derived DC can readily internalize viable or UV-irradiated PMNs. Such internalization was abrogated at 4 degrees C and partly inhibited by anti-CD18 mAb. In mice, DC which had internalized PMNs containing electroporated ovalbumin (OVA) protein, were able to cross-present the antigen to CD8 (OT-1) and CD4 (OT-2) TCR-transgenic T cells. Moreover, in humans, tumor cell debris is internalized by PMNs and the tumor-cell material can be subsequently taken up from the immunomagnetically re-isolated PMNs by DC. Importantly, if human neutrophils had endocytosed bacteria, they were able to trigger the maturation program of the DC. Moreover, when mouse PMNs with E. coli in their interior are co-injected in the foot pad with DC, many DC loaded with fluorescent material from the PMNs reach draining lymph nodes. Using CT26 (H-2(d)) mouse tumor cells, it was observed that if tumor cells are intracellularly loaded with OVA protein and UV-irradiated, they become phagocytic prey of H-2(d) PMNs. If such PMNs, that cannot present antigens to OT-1 T cells, are immunomagnetically re-isolated and phagocytosed by H-2(b) DC, such DC productively cross-present OVA antigen determinants to OT-1 T cells. Cross-presentation to adoptively transferred OT-1 lymphocytes at draining lymph nodes also take place when OVA-loaded PMNs (H-2(d)) are coinjected in the footpad of mice with autologous DC (H-2(b)). In summary, our results indicate that antigens phagocytosed by short-lived PMNs can be in turn internalized and productively cross-presented by DC. PMID- 22206008 TI - Prevalence of 2009 pandemic influenza A (H1N1) virus antibodies, Tampa Bay Florida--November-December, 2009. AB - BACKGROUND: In 2009, a novel influenza virus (2009 pandemic influenza A (H1N1) virus (pH1N1)) caused significant disease in the United States. Most states, including Florida, experienced a large fall wave of disease from September through November, after which disease activity decreased substantially. We determined the prevalence of antibodies due to the pH1N1 virus in Florida after influenza activity had peaked and estimated the proportion of the population infected with pH1N1 virus during the pandemic. METHODS: During November-December 2009, we collected leftover serum from a blood bank, a pediatric children's hospital and a pediatric outpatient clinic in Tampa Bay Florida. Serum was tested for pH1N1 virus antibodies using the hemagglutination-inhibition (HI) assay. HI titers >=40 were considered seropositive. We adjusted seroprevalence results to account for previously established HI assay specificity and sensitivity and employed a simple statistical model to estimate the proportion of seropositivity due to pH1N1 virus infection and vaccination. RESULTS: During the study time period, the overall seroprevalence in Tampa Bay, Florida was 25%, increasing to 30% after adjusting for HI assay sensitivity and specificity. We estimated that 5.9% of the population had vaccine-induced seropositivity while 25% had seropositivity secondary to pH1N1 virus infection. The highest cumulative incidence of pH1N1 virus infection was among children aged 5-17 years (53%) and young adults aged 18-24 years (47%), while adults aged >=50 years had the lowest cumulative incidence (11-13%) of pH1N1 virus infection. CONCLUSIONS: After the peak of the fall wave of the pandemic, an estimated one quarter of the Tampa Bay population had been infected with the pH1N1 virus. Consistent with epidemiologic trends observed during the pandemic, the highest burdens of disease were among school-aged children and young adults. PMID- 22206009 TI - Regulation of glucose homeostasis by KSR1 and MARK2. AB - Protein scaffolds control the intensity and duration of signaling and dictate the specificity of signaling through MAP kinase pathways. KSR1 is a molecular scaffold of the Raf/MEK/ERK MAP kinase cascade that regulates the intensity and duration of ERK activation. Relative to wild-type mice, ksr1-/- mice are modestly glucose intolerant, but show a normal response to exogenous insulin. However, ksr1-/- mice also demonstrate a three-fold increase in serum insulin levels in response to a glucose challenge, suggesting a role for KSR1 in insulin secretion. The kinase MARK2 is closely related to C-TAK1, a known regulator of KSR1. Mice lacking MARK2 have an increased rate of glucose disposal in response to exogenous insulin, increased glucose tolerance, and are resistant to diet-induced obesity. mark2-/-ksr1-/- (DKO) mice were compared to wild type, mark2-/-, and ksr1-/- mice for their ability to regulate glucose homeostasis. Here we show that disruption of KSR1 in mark2-/- mice reverses the increased sensitivity to exogenous insulin resulting from MARK2 deletion. DKO mice respond to exogenous insulin similarly to wild type and ksr1-/- mice. These data suggest a model whereby MARK2 negatively regulates insulin sensitivity in peripheral tissue through inhibition of KSR1. Consistent with this model, we found that MARK2 binds and phosphorylates KSR1 on Ser392. Phosphorylation of Ser392 is a critical regulator of KSR1 stability, subcellular location, and ERK activation. These data reveal an unexpected role for the molecular scaffold KSR1 in insulin-regulated glucose metabolism. PMID- 22206010 TI - Distinct characteristics of circulating vascular endothelial growth factor-a and C levels in human subjects. AB - The mechanisms that lead from obesity to atherosclerotic disease are not fully understood. Obesity involves angiogenesis in which vascular endothelial growth factor-A (VEGF-A) plays a key role. On the other hand, vascular endothelial growth factor-C (VEGF-C) plays a pivotal role in lymphangiogenesis. Circulating levels of VEGF-A and VEGF-C are elevated in sera from obese subjects. However, relationships of VEGF-C with atherosclerotic risk factors and atherosclerosis are unknown. We determined circulating levels of VEGF-A and VEGF-C in 423 consecutive subjects not receiving any drugs at the Health Evaluation Center. After adjusting for age and gender, VEGF-A levels were significantly and more strongly correlated with the body mass index (BMI) and waist circumference than VEGF-C. Conversely, VEGF-C levels were significantly and more closely correlated with metabolic (e.g., fasting plasma glucose, hemoglobin A1c, immunoreactive insulin, and the homeostasis model assessment of insulin resistance) and lipid parameters (e.g., triglycerides, total cholesterol (TC), low-density-lipoprotein cholesterol (LDL C), and non-high-density-lipoprotein cholesterol (non-HDL-C)) than VEGF-A. Stepwise regression analyses revealed that independent determinants of VEGF-A were the BMI and age, whereas strong independent determinants of VEGF-C were age, triglycerides, and non-HDL-C. In apolipoprotein E-deficient mice fed a high-fat diet (HFD) or normal chow (NC) for 16 weeks, levels of VEGF-A were not significantly different between the two groups. However, levels of VEGF-C were significantly higher in HFD mice with advanced atherosclerosis and marked hypercholesterolemia than NC mice. Furthermore, immunohistochemistry revealed that the expression of VEGF-C in atheromatous plaque of the aortic sinus was significantly intensified by feeding HFD compared to NC, while that of VEGF-A was not. In conclusion, these findings demonstrate that VEGF-C, rather than VEGF-A, is closely related to dyslipidemia and atherosclerosis. PMID- 22206011 TI - Identification of Eps15 as antigen recognized by the monoclonal antibodies aa2 and ab52 of the Wuerzburg Hybridoma Library against Drosophila brain. AB - The Wuerzburg Hybridoma Library against the Drosophila brain represents a collection of around 200 monoclonal antibodies that bind to specific structures in the Drosophila brain. Here we describe the immunohistochemical staining patterns, the Western blot signals of one- and two-dimensional electrophoretic separation, and the mass spectrometric characterization of the target protein candidates recognized by the monoclonal antibodies aa2 and ab52 from the library. Analysis of a mutant of a candidate gene identified the Drosophila homolog of the Epidermal growth factor receptor Pathway Substrate clone 15 (Eps15) as the antigen for these two antibodies. PMID- 22206012 TI - Analytical processing of binary mixture information by olfactory bulb glomeruli. AB - Odors are rarely composed of a single compound, but rather contain a large and complex variety of chemical components. Often, these mixtures are perceived as having unique qualities that can be quite different than the combination of their components. In many cases, a majority of the components of a mixture cannot be individually identified. This synthetic processing of odor information suggests that individual component representations of the mixture must interact somewhere along the olfactory pathway. The anatomical nature of sensory neuron input into segregated glomeruli with the bulb suggests that initial input of odor information into the bulb is analytic. However, a large network of interneurons within the olfactory bulb could allow for mixture interactions via mechanisms such as lateral inhibition. Currently in mammals, it is unclear if postsynaptic mitral/tufted cell glomerular mixture responses reflect the analytical mixture input, or provide the initial basis for synthetic processing with the olfactory system. To address this, olfactory bulb glomerular binary mixture representations were compared to representations of each component using transgenic mice expressing the calcium indicator G-CaMP2 in olfactory bulb mitral/tufted cells. Overall, dorsal surface mixture representations showed little mixture interaction and often appeared as a simple combination of the component representations. Based on this, it is concluded that dorsal surface glomerular mixture representations remain largely analytical with nearly all component information preserved. PMID- 22206013 TI - The mutational spectrum in a cohort of Charcot-Marie-Tooth disease type 2 among the Han Chinese in Taiwan. AB - BACKGROUND: Charcot-Marie-Tooth disease type 2 (CMT2) is a clinically and genetically heterogeneous group of inherited axonal neuropathies. The aim of this study was to extensively investigate the mutational spectrum of CMT2 in a cohort of patients of Han Chinese. METHODOLOGY AND PRINCIPAL FINDINGS: Genomic DNA from 36 unrelated Taiwanese CMT2 patients of Han Chinese descent was screened for mutations in the coding regions of the MFN2, RAB7, TRPV4, GARS, NEFL, HSPB1, MPZ, GDAP1, HSPB8, DNM2, AARS and YARS genes. Ten disparate mutations were identified in 14 patients (38.9% of the cohort), including p.N71Y in AARS (2.8%), p.T164A in HSPB1 (2.8%), and p.[H256R]+[R282H] in GDAP1 (2.8%) in one patient each, three NEFL mutations in six patients (16.7%) and four MFN2 mutations in five patients (13.9%). The following six mutations were novel: the individual AARS, HSPB1 and GDAP1 mutations and c.475-1G>T, p.L233V and p.E744M mutations in MFN2. An in vitro splicing assay revealed that the MFN2 c.475-1G>T mutation causes a 4 amino acid deletion (p.T159_Q162del). Despite an extensive survey, the genetic causes of CMT2 remained elusive in the remaining 22 CMT2 patients (61.1%). CONCLUSIONS AND SIGNIFICANCE: This study illustrates the spectrum of CMT2 mutations in a Taiwanese CMT2 cohort and expands the number of CMT2-associated mutations. The relevance of the AARS and HSPB1 mutations in the pathogenesis of CMT2 is further highlighted. Moreover, the frequency of the NEFL mutations in this study cohort was unexpectedly high. Genetic testing for NEFL and MFN2 mutations should, therefore, be the first step in the molecular diagnosis of CMT2 in ethnic Chinese. PMID- 22206014 TI - The combination of early and rapid type I IFN, IL-1alpha, and IL-1beta production are essential mediators of RNA-like adjuvant driven CD4+ Th1 responses. AB - There is a growing need for novel vaccine adjuvants that can provide safe and potent T-helper type 1 (Th1) activity. RNA-like immune response modifiers (IRMs) are candidate T-cell adjuvants that skew acquired immune responses towards a Th1 phenotype. We set out to delineate the essential signaling pathways by which the RNA-like IRMs, resiquimod (R-848) and polyinosinic:polycytidylic acid (poly I:C), augment CD4+ T-helper 1 (Th1) responses. Highly purified murine conventional dendritic cells (cDCs) and conventional CD4+ T-cells were co-cultured in allogeneic and MHC congenic mixed leukocyte reactions. The activation of CD4+ Th1 cells was examined utilizing cells from mice deficient in specific RNA-sensing pattern recognition receptors and signaling mediators. R-848 and poly I:C stimulation of Type I interferon production and signaling in cDCs was essential but not sufficient for driving CD4+ Th1 responses. The early and rapid production of IL-1alpha and IL-1beta was equally critical for the optimal activation of Th1 CD4+ T-cells. R-848 activation of Toll-like receptor 7/MyD88-dependent signaling in cDCs led to a rapid upregulation of pro-IL-1alpha and pro-IL-1beta production compared to poly I:C activation of MyD88-independent signaling pathways. The in vitro data show that CD4+ T-cell adjuvant activity of RNA-like IRMs is mediated by a critical combination of early and rapid Type I interferon, IL-1alpha and IL 1beta production. These results provide important insights into the key signaling pathways responsible for RNA-like IRM CD4+ Th1 activation. A better understanding of the critical signaling pathways by which RNA-like IRMs stimulate CD4+ Th1 responses is relevant to the rational design of improved vaccine adjuvants. PMID- 22206015 TI - Collagen XXVII organises the pericellular matrix in the growth plate. AB - In order to characterise the function of the novel fibrillar type XXVII collagen, a series of mice expressing mutant forms of the collagen were investigated. Mice harboring a glycine to cysteine substitution in the collagenous domain were phenotypically normal when heterozygote and displayed a mild disruption of growth plate architecture in the homozygous state. Mice expressing an 87 amino acid deletion in the collagenous domain of collagen XXVII were phenotypically normal as heterozygotes whereas homozygotes exhibited a severe chondrodysplasia and died perinatally from a lung defect. Animals expressing the 87 amino acid deletion targeted specifically to cartilage were viable but severely dwarfed. The pericellular matrix of proliferative chondrocytes was disrupted and the proliferative cells exhibited a decreased tendency to flatten and form vertical columns. Collagen XXVII plays an important structural role in the pericellular extracellular matrix of the growth plate and is required for the organisation of the proliferative zone. PMID- 22206016 TI - Multiple analytical approaches reveal distinct gene-environment interactions in smokers and non smokers in lung cancer. AB - Complex disease such as cancer results from interactions of multiple genetic and environmental factors. Studying these factors singularly cannot explain the underlying pathogenetic mechanism of the disease. Multi-analytical approach, including logistic regression (LR), classification and regression tree (CART) and multifactor dimensionality reduction (MDR), was applied in 188 lung cancer cases and 290 controls to explore high order interactions among xenobiotic metabolizing genes and environmental risk factors. Smoking was identified as the predominant risk factor by all three analytical approaches. Individually, CYP1A1*2A polymorphism was significantly associated with increased lung cancer risk (OR = 1.69;95%CI = 1.11-2.59,p = 0.01), whereas EPHX1 Tyr113His and SULT1A1 Arg213His conferred reduced risk (OR = 0.40;95%CI = 0.25-0.65,p<0.001 and OR = 0.51;95%CI = 0.33-0.78,p = 0.002 respectively). In smokers, EPHX1 Tyr113His and SULT1A1 Arg213His polymorphisms reduced the risk of lung cancer, whereas CYP1A1*2A, CYP1A1*2C and GSTP1 Ile105Val imparted increased risk in non-smokers only. While exploring non-linear interactions through CART analysis, smokers carrying the combination of EPHX1 113TC (Tyr/His), SULT1A1 213GG (Arg/Arg) or AA (His/His) and GSTM1 null genotypes showed the highest risk for lung cancer (OR = 3.73;95%CI = 1.33-10.55,p = 0.006), whereas combined effect of CYP1A1*2A 6235CC or TC, SULT1A1 213GG (Arg/Arg) and betel quid chewing showed maximum risk in non-smokers (OR = 2.93;95%CI = 1.15-7.51,p = 0.01). MDR analysis identified two distinct predictor models for the risk of lung cancer in smokers (tobacco chewing, EPHX1 Tyr113His, and SULT1A1 Arg213His) and non-smokers (CYP1A1*2A, GSTP1 Ile105Val and SULT1A1 Arg213His) with testing balance accuracy (TBA) of 0.6436 and 0.6677 respectively. Interaction entropy interpretations of MDR results showed non-additive interactions of tobacco chewing with SULT1A1 Arg213His and EPHX1 Tyr113His in smokers and SULT1A1 Arg213His with GSTP1 Ile105Val and CYP1A1*2C in nonsmokers. These results identified distinct gene-gene and gene environment interactions in smokers and non-smokers, which confirms the importance of multifactorial interaction in risk assessment of lung cancer. PMID- 22206018 TI - Expression pattern of Kv11 (Ether a-go-go-related gene; erg) K+ channels in the mouse retina. AB - In response to light, most retinal neurons exhibit gradual changes in membrane potential. Therefore K+ channels that mediate threshold currents are well-suited for the fine-tuning of signal transduction. In the present study we demonstrate the expression of the different Kv11 (ether-a-go-go related gene; erg) channel subunits in the human and mouse retina by RT PCR and quantitative PCR, respectively. Immunofluorescence analysis with cryosections of mouse retinae revealed the following local distribution of the three Kv11 subunits: Kv11.1 (m erg1) displayed the most abundant expression with the strongest immunoreactivity in rod bipolar cells. In addition, immunoreactivity was found in the inner part of the outer plexiform layer (OPL), in the inner plexiform layer (IPL) and in the inner segments of photoreceptors. Immunoreactivity for Kv11.2 (m-erg2) was observed in the outer part of the OPL and throughout the IPL. Double-labeling for vGluT1 or synaptophysin indicated a mainly presynaptic localization of Kv11.2. While no significant staining for Kv11.3 (m-erg3) was detected in the neuronal retina, strong Kv11.3 immunoreactivity was present in the apical membrane of the retinal pigment epithelium. The different expression levels were confirmed by real-time PCR showing almost equal levels of Kv11.1 and Kv11.2, while Kv11.3 mRNA expression was significantly lower. The two main splice variants of Kv11.1, isoforms a and b were detected in comparable levels suggesting a possible formation of cGMP/cGK-sensitive Kv11.1 channels in photoreceptors and rod bipolar cells. Taken together, the immunohistological results revealed different expression patterns of the three Kv11 channels in the mouse retina supposing distinct physiological roles. PMID- 22206017 TI - Neonatal androgenization exacerbates alcohol-induced liver injury in adult rats, an effect abrogated by estrogen. AB - Alcoholic liver disease (ALD) affects millions of people worldwide and is a major cause of morbidity and mortality. However, fewer than 10% of heavy drinkers progress to later stages of injury, suggesting other factors in ALD development, including environmental exposures and genetics. Females display greater susceptibility to the early damaging effects of ethanol. Estrogen (E2) and ethanol metabolizing enzymes (cytochrome P450, CYP450) are implicated in sex differences of ALD. Sex steroid hormones are developmentally regulated by the hypothalamic-pituitary-gonadal (HPG) axis, which controls sex-specific cycling of gonadal steroid production and expression of hepatic enzymes. The aim of this study was to determine if early postnatal inhibition of adult cyclic E2 alters ethanol metabolizing enzyme expression contributing to the development of ALD in adulthood. An androgenized rat model was used to inhibit cyclic E2 production. Control females (Ctrl), androgenized females (Andro) and Andro females with E2 implants were administered either an ethanol or isocalorically-matched control Lieber-DeCarli diet for four weeks and liver injury and CYP450 expression assessed. Androgenization exacerbated the deleterious effects of ethanol demonstrated by increased steatosis, lipid peroxidation, profibrotic gene expression and decreased antioxidant defenses compared to Ctrl. Additionally, CYP2E1 expression was down-regulated in Andro animals on both diets. No change was observed in CYP1A2 protein expression. Further, continuous exogenous administration of E2 to Andro in adulthood attenuated these effects, suggesting that E2 has protective effects in the androgenized animal. Therefore, early postnatal inhibition of cyclic E2 modulates development and progression of ALD in adulthood. PMID- 22206019 TI - A fly in the ointment: evaluation of traditional use of plants to repel and kill blowfly larvae in fermented fish. AB - INTRODUCTION: In rural areas in Laos, fly larvae infestations are common in fermenting fish. Blowflies (Chrysomya megacephala, Diptera: Calliphoridae) are attracted to oviposit (and/or larviposit) onto fermenting fish which results in infestations with fly larvae. Knowledge of traditional use of plants to repel larvae during the production of fermented fish is common and widespread in Lao PDR. RESEARCH QUESTIONS: How effective are the most salient species in repelling, and killing fly larvae in fermenting fish? MATERIAL AND METHODS: The three plant species most frequently reported to repel fly larvae during an ethnobotanical survey throughout Lao PDR were tested for repellence and larvicidal activity of fly larvae infesting fermented fish. The lethality and repellence of Tadehagi triquetrum (L.) H. Ohashi (Fabaceae), Uraria crinita (L.) Desv. ex DC. (Fabaceae) and Bambusa multiplex (Lour.) Raeusch. ex Schult. & Schult. f. (Poaceae) were tested in an experimental design using fermenting fish in Vientiane, Lao PDR. RESULTS: The repellent effect of fresh material of T. triquetrum and U. crinita, and the larvicidal effect of fresh B. multiplex, is significantly more effective than that of dried material of the same species, and the total effect (repellence and larvicidal effect combined) for each of the three species was significantly more effective for fresh than for dry material. Fresh material of T. triquetrum, U. crinita, or B. multiplex added on top of the fermenting fish repelled 50%, 54%, 37%, and killed 22%, 28%, and 40% of fly larvae. The total effect was not significantly different per species at 72%, 82%, and 77%, respectively. DISCUSSION AND CONCLUSIONS: The three most salient species are effective in repelling and killing fly larvae in the production of fermented fish, and may be essential to augment food safety during traditional fermentation in open jars. PMID- 22206020 TI - An interfaith dialogue on the neglected tropical diseases. PMID- 22206021 TI - Population dynamics of Aedes aegypti and dengue as influenced by weather and human behavior in San Juan, Puerto Rico. AB - Previous studies on the influence of weather on Aedes aegypti dynamics in Puerto Rico suggested that rainfall was a significant driver of immature mosquito populations and dengue incidence, but mostly in the drier areas of the island. We conducted a longitudinal study of Ae. aegypti in two neighborhoods of the metropolitan area of San Juan city, Puerto Rico where rainfall is more uniformly distributed throughout the year. We assessed the impacts of rainfall, temperature, and human activities on the temporal dynamics of adult Ae. aegypti and oviposition. Changes in adult mosquitoes were monitored with BG-Sentinel traps and oviposition activity with CDC enhanced ovitraps. Pupal surveys were conducted during the drier and wetter parts of the year in both neighborhoods to determine the contribution of humans and rains to mosquito production. Mosquito dynamics in each neighborhood was compared with dengue incidence in their respective municipalities during the study. Our results showed that: 1. Most pupae were produced in containers managed by people, which explains the prevalence of adult mosquitoes at times when rainfall was scant; 2. Water meters were documented for the first time as productive habitats for Ae. aegypti; 3. Even though Puerto Rico has a reliable supply of tap water and an active tire recycling program, water storage containers and discarded tires were important mosquito producers; 4. Peaks in mosquito density preceded maximum dengue incidence; and 5. Ae. aegypti dynamics were driven by weather and human activity and oviposition was significantly correlated with dengue incidence. PMID- 22206022 TI - Evaluation of amoebicidal potential of Paneth cell cryptdin-2 against Entamoeba histolytica. AB - BACKGROUND: Amoebiasis is a major public health problem in tropical and subtropical countries. Currently, metronidazole is the gold choice medication for the treatment of this disease. However, reports have indicated towards the possibility of development of metronidazole-resistance in Entamoeba strains in near future. In view of the emergence of this possibility, in addition to the associated side effects and mutagenic ability of the currently available anti amoebic drugs, there is a need to explore newer therapeutics against this disease. In this context, the present study evaluated the amoebicidal potential of cryptdin-2 against E. histolytica. METHODS/PRINCIPAL FINDINGS: In the present study, cryptdin-2 exhibited potent in-vitro amoebicidal activity against E. histolytica in a concentration dependent manner at a minimum amoebicidal concentration (MAC) of 4 mg/L. Scanning electron microscopy as well as phase contrast microscopic investigations of cryptdin-2 treated trophozoites revealed that the peptide was able to induce significant morphological alterations in terms of membrane wrinkling, leakage of the cytoplasmic contents and damaged plasma membrane suggesting a possible membrane dependent amoebicidal activity. N phenyl napthylamine (NPN) uptake assay in presence of sulethal, lethal as well as twice the lethal concentrations further confirmed the membrane-dependent mode of action of cryptdin-2 and suggested that the peptide could permeabilize the plasma membrane of E. histolytica. It was also found that cryptdin-2 interfered with DNA, RNA as well as protein synthesis of E. histolytica exerting the highest effect against DNA synthesis. Thus, the macromolecular synthesis studies correlated well with the observations of membrane permeabilization studies. SIGNIFICANCE/CONCLUSIONS: The amoebicidal efficacy of cryptdin-2 suggests that it may be exploited as a promising option to combat amoebiasis or, at least, may act as an adjunct to metronidazole and/or other available anti-amoebic drugs. PMID- 22206023 TI - Tropheryma whipplei: a common bacterium in rural Senegal. AB - BACKGROUND: Tropheryma whipplei is known as the cause of Whipple's disease, but it is also an emerging pathogen, detected in stool, that causes various chronic localized infections without histological digestive involvement and is associated with acute infections, including gastroenteritis and bacteremia. METHODS/PRINCIPAL FINDINGS: We conducted a study in 2008 and 2009 using 497 non diarrheic and diarrheic stool samples, 370 saliva samples, 454 sera samples and 105 samples obtained from water samples in two rural Sine-Saloum villages (Dielmo and Ndiop) in Senegal. The presence of T. whipplei was investigated by using specific quantitative PCR. Genotyping was performed on positive samples. A serological analysis by western blotting was performed to determine the seroprevalence and to detect seroconversion. Overall, T. whipplei was identified in 31.2% of the stool samples (139/446) and 3.5% of the saliva samples (13/370) obtained from healthy subjects. The carriage in the stool specimens was significantly (p<10(-3)) higher in children who were between 0 and 4 years old (60/80, 75%) compared to samples obtained from individuals who were between 5 to 10 years old (36/119, 30.2%) or between 11 and 99 years old (43/247, 17.4%). The carriage in the stool was also significantly more common (p = 0.015) in subjects with diarrhea (25/51, 49%). We identified 22 genotypes, 16 of which were new. Only one genotype (#53) was common to both villages. Among the specific genotypes, one (#52) was epidemic in Dielmo (15/28, 53.4%, p<10(-3)) and another (#49) in Ndiop (27.6%, p = 0.002). The overall seroprevalence was estimated at 72.8% (291/400). Seroconversion was detected in 66.7% (18/27) of children for whom PCR became positive in stools between 2008 and 2009. CONCLUSIONS/SIGNIFICANCE: T. whipplei is a common bacterium in the Sine-Saloum area of rural Senegal that is contracted early in childhood. Epidemic genotypes suggest a human transmission of the bacterium. PMID- 22206024 TI - Tools to support policy decisions related to treatment strategies and surveillance of Schistosomiasis japonica towards elimination. AB - BACKGROUND: Appropriate diagnostics to monitor disease trends and assess the effectiveness and impact of interventions are essential for guiding treatment strategies at different thresholds of schistosomiasis transmission and for certifying elimination. Field validation of these assays is urgently needed before they can be adopted to support policy decisions of the national programme for control and elimination of schistosomiasis in P.R. China. We compared the efficacy and utility of different immunoassays in guiding control strategies and monitoring the endemic status of S. japonicum infections towards elimination. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional survey was conducted in seven villages with different transmission intensities settings to assess the performance and utility of three immunoassays, e.g., an indirect hemagglutination assay (IHA_JX), an enzyme linked immunosorbent assay (ELISA_SZ), and a dot immunogold filtration assay (DIGFA_SH). 6,248 individuals aged 6-65 years old who gave consent and supplied their stool and blood samples were included for data analysis. Results showed that ELISA_SZ performed significantly higher sensitivity (95.45%, 95%CI: 92.94-97.97%) than IHA_JX (87.59%, 95%CI: 83.51-91.49%) and DIGFA_SH (79.55%, 95%CI: 74.68-84.41%), especially in subgroups with very low infection intensity. The specificity of ELISA_SZ, IHA_JX, DIGFA_SH in 6-9 year olds with occasional exposure was nearly 90%. DIGFA_SH performed the highest screening efficacy for patients among three assays with overall positive predicative value of 13.07% (95%CI: 11.42-14.72%). We found a positive correlation of antibody positive rate of IHA_JX with results of stool examination in age strata (r = 0.70, P<0.001). Seropositivity of IHA_JX in children aged 6-9 years old showed an excellent correlation with prevalence of schistosome infection in the seven communities (r = 0.77, P<0.05). CONCLUSIONS/SIGNIFICANCE: Studies suggest that ELISA_SZ could be used to guide selective chemotherapy in moderate or low endemic regions. IHA_JX could be used to as a surveillance tool and for certifying elimination of schistosomiasis through monitoring children as a sentinel population. PMID- 22206025 TI - Activation of the innate immune response against DENV in normal non-transformed human fibroblasts. AB - BACKGROUND: When mosquitoes infected with DENV are feeding, the proboscis must traverse the epidermis several times ("probing") before reaching a blood vessel in the dermis. During this process, the salivary glands release the virus, which is likely to interact first with cells of the various epidermal and dermal layers, cells which could be physiologically relevant to DENV infection and replication in humans. However, important questions are whether more abundant non hematopoietic cells such as fibroblasts become infected, and whether they play any role in antiviral innate immunity in the very early stages of infection, or even if they might be used by DENV as primary replication cells. METHODOLOGY/PRINCIPAL FINDINGS: Fibroblasts freshly released from healthy skin and infected 12 hours after their isolation show a positive signal for DENV. In addition, when primary skin fibroblast cultures were established and subsequently infected, we showed DENV-2 antigen-positive intracellular signal at 24 hours and 48 hours post-infection. Moreover, the fibroblasts showed productive infection in a conventional plaque assay. The skin fibroblasts infected with DENV-2 underwent potent signaling through both TLR3 and RIG- 1, but not Mda5, triggering up regulation of IFNbeta, TNFalpha, defensin 5 (HB5) and beta defensin 2 (HbetaD2). In addition, DENV infected fibroblasts showed increased nuclear translocation of interferon (IFN) regulatory factor 3 (IRF3), but not interferon regulatory factor 7 (IRF7), when compared with mock-infected fibroblasts. CONCLUSIONS/SIGNIFICANCE: In this work, we demonstrated the high susceptibility to DENV infection by primary fibroblasts from normal human skin, both in situ and in vitro. Our results suggest that these cells may contribute to the pro-inflammatory and anti viral microenvironment in the early stages of interaction with DENV-2. Furthermore, the data suggest that fibroblast may also be used as a primary site of DENV replication and provide viral particles that may contribute to subsequent viral dissemination. PMID- 22206026 TI - An unexpected recurrent transmission of Rift Valley fever virus in cattle in a temperate and mountainous area of Madagascar. AB - Rift Valley fever is an acute, zoonotic viral disease of domestic ruminants, caused by a phlebovirus (Bunyaviridae family). A large outbreak occurred in Madagascar in 2008-2009. The goal of the present study was to evaluate the point prevalence of antibodies against Rift Valley Fever Virus (RVFV) in cattle in the Anjozorobe district, located in the wet and temperate highland region of Madagascar and yet heavily affected by the disease, and analyse environmental and trade factors potentially linked to RVFV transmission. A serological study was performed in 2009 in 894 bovines. For each bovine, the following variables were recorded: age, location of the night pen, minimum distance from the pen to the nearest water point and the forest, nearest water point type, and herd replacement practices. The serological data were analyzed using a generalized linear mixed model. The overall anti-RVFV IgG seroprevalence rate was 28% [CI95% 25-31]. Age was statistically linked to prevalence (p = 10(-4)), being consistent with a recurrent RVFV circulation. Distance from the night pen to the nearest water point was a protective factor (p = 5.10(-3)), which would be compatible with a substantial part of the virus transmission being carried out by nocturnal mosquito vectors. However, water point type did not influence the risk of infection: several mosquito species are probably involved. Cattle belonging to owners who purchase animals to renew the herd were significantly more likely to have seroconverted than others (p = 0.04): cattle trade may contribute to the introduction of the virus in this area. The minimum distance of the night pen to the forest was not linked to the prevalence. This is the first evidence of a recurrent transmission of RVFV in such an ecosystem that associates a wet, temperate climate, high altitude, paddy fields, and vicinity to a dense rain forest. Persistence mechanisms need to be further investigated. PMID- 22206027 TI - Multiplicity and diversity of Plasmodium vivax infections in a highly endemic region in Papua New Guinea. AB - Plasmodium vivax is highly endemic in the lowlands of Papua New Guinea and accounts for a large proportion of the malaria cases in children less than 5 years of age. We collected 2117 blood samples at 2-monthly intervals from a cohort of 268 children aged 1 to 4.5 years and estimated the diversity and multiplicity of P. vivax infection. All P. vivax clones were genotyped using the merozoite surface protein 1 F3 fragment (msp1F3) and the microsatellite MS16 as molecular markers. High diversity was observed with msp1F3 (H(E) = 88.1%) and MS16 (H(E) = 97.8%). Of the 1162 P. vivax positive samples, 74% harbored multi clone infections with a mean multiplicity of 2.7 (IQR = 1-3). The multiplicity of P. vivax infection increased slightly with age (P = 0.02), with the strongest increase in very young children. Intensified efforts to control malaria can benefit from knowledge of the diversity and MOI both for assessing the endemic situation and monitoring the effects of interventions. PMID- 22206028 TI - Economic impact of dengue illness and the cost-effectiveness of future vaccination programs in Singapore. AB - BACKGROUND: Dengue illness causes 50-100 million infections worldwide and threatens 2.5 billion people in the tropical and subtropical regions. Little is known about the disease burden and economic impact of dengue in higher resourced countries or the cost-effectiveness of potential dengue vaccines in such settings. METHODS AND FINDINGS: We estimate the direct and indirect costs of dengue from hospitalized and ambulatory cases in Singapore. We consider inter alia the impacts of dengue on the economy using the human-capital and the friction cost methods. Disease burden was estimated using disability-adjusted life years (DALYs) and the cost-effectiveness of a potential vaccine program was evaluated. The average economic impact of dengue illness in Singapore from 2000 to 2009 in constant 2010 US$ ranged between $0.85 billion and $1.15 billion, of which control costs constitute 42%-59%. Using empirically derived disability weights, we estimated an annual average disease burden of 9-14 DALYs per 100 000 habitants, making it comparable to diseases such as hepatitis B or syphilis. The proportion of symptomatic dengue cases detected by the national surveillance system was estimated to be low, and to decrease with age. Under population projections by the United Nations, the price per dose threshold for which vaccines stop being more cost-effective than the current vector control program ranged from $50 for mass vaccination requiring 3 doses and only conferring 10 years of immunity to $300 for vaccination requiring 2 doses and conferring lifetime immunity. The thresholds for these vaccine programs to not be cost effective for Singapore were $100 and $500 per dose respectively. CONCLUSIONS: Dengue illness presents a serious economic and disease burden in Singapore. Dengue vaccines are expected to be cost-effective if reasonably low prices are adopted and will help to reduce the economic and disease burden of dengue in Singapore substantially. PMID- 22206030 TI - Post-kala-azar dermal leishmaniasis in Nepal: a retrospective cohort study (2000 2010). AB - INTRODUCTION: Post-kala-azar dermal leishmaniasis (PKDL) is a cutaneous complication appearing after treatment of visceral leishmaniasis, and PKDL patients are considered infectious to sand flies and may therefore play a role in the transmission of VL. We estimated the risk and risk factors of PKDL in patients with past VL treatment in south-eastern Nepal. METHODS: Between February and May 2010 we traced all patients who had received VL treatment during 2000 2009 in five high-endemic districts and screened them for PKDL-like skin lesions. Suspected cases were referred to a tertiary care hospital for confirmation by parasitology (slit skin smear (SSS)) and/or histopathology. We calculated the risk of PKDL using Kaplan-Meier survival curves and exact logistic regression for risk factors. RESULTS: Out of 680 past-treated VL patients, 37(5.4%) presented active skin lesions suspect of PKDL during the survey. Thirty-three of them underwent dermatological assessment, and 16 (2.4%) were ascertained as probable (2) or confirmed (14) PKDL. Survival analysis showed a 1.4% risk of PKDL within 2 years of VL treatment. All 16 had been previously treated with sodium stibogluconate (SSG) for their VL. In 5, treatment had not been completed (<= 21 injections). Skin lesions developed after a median time interval of 23 months [interquartile range (IQR) 16-40]. We found a higher PKDL rate (29.4%) in those inadequately treated compared to those who received a full SSG course (2.0%). In the logistic regression model, unsupervised treatment [odds ratio (OR) = 8.58, 95% CI 1.21-374.77], and inadequate SSG treatment for VL in the past (OR = 11.68, 95% CI 2.71-45.47) were significantly associated with PKDL. CONCLUSION: The occurrence of PKDL after VL treatment in Nepal is low compared to neighboring countries. Supervised and adequate treatment of VL seems essential to reduce the risk of PKDL development and active surveillance for PKDL is needed. PMID- 22206029 TI - Potentiating effects of MPL on DSPC bearing cationic liposomes promote recombinant GP63 vaccine efficacy: high immunogenicity and protection. AB - BACKGROUND: Vaccines that activate strong specific Th1-predominant immune responses are critically needed for many intracellular pathogens, including Leishmania. The requirement for sustained and efficient vaccination against leishmaniasis is to formulate the best combination of immunopotentiating adjuvant with the stable antigen (Ag) delivery system. The aim of the present study is to evaluate the effectiveness of an immunomodulator on liposomal Ag through subcutaneous (s.c.) route of immunization, and its usefulness during prime/boost against visceral leishmaniasis (VL) in BALB/c mice. METHODOLOGY/PRINCIPAL FINDINGS: Towards this goal, we formulated recombinant GP63 (rGP63)-based vaccines either with monophosphoryl lipid A-trehalose dicorynomycolate (MPL-TDM) or entrapped within cationic liposomes or both. Combinatorial administration of liposomes with MPL-TDM during prime confers activation of dendritic cells, and induces an early robust T cell response. To investigate whether the combined formulation is required for optimum immune response during boost as well, we chose to evaluate the vaccine efficacy in mice primed with combined adjuvant system followed by boosting with either rGP63 alone, in association with MPL-TDM, liposomes or both. We provide evidences that the presence of either liposomal rGP63 or combined formulations during boost is necessary for effective Th1 immune responses (IFN-gamma, IL-12, NO) before challenge infection. However, boosting with MPL-TDM in conjugation with liposomal rGP63 resulted in a greater number of IFN-gamma producing effector T cells, significantly higher levels of splenocyte proliferation, and Th1 responses compared to mice boosted with liposomal rGP63, after virulent Leishmania donovani (L. donovani) challenge. Moreover, combined formulations offered superior protection against intracellular amastigote replication in macrophages in vitro, and hepatic and splenic parasite load in vivo. CONCLUSION: Our results define the immunopotentiating effect of MPL-TDM on protein Ag encapsulated in a controlled release system against experimental VL. PMID- 22206031 TI - Novel, meso-substituted cationic porphyrin molecule for photo-mediated larval control of the dengue vector Aedes aegypti. AB - BACKGROUND: Control of the mosquito vector population is the most effective strategy currently available for the prevention of dengue fever and the containment of outbreaks. Photo-activated oxidants may represent promising tools for developing effective, safe and ecofriendly novel larvicides. The purpose of this study was to evaluate the potential of the synthetic meso-substituted porphyrin meso-tri(N-methylpyridyl), meso-mono(N-tetradecylpyridyl)porphine (C14) as a photoactivatable larvicide against the dengue vector Aedes (Stegomyia) aegypti. METHODOLOGY: The photophysical and photochemical properties of the C14 molecule were assessed spectrophotometrically. Photomediated larvicidal efficacy, route of intake and site of action were determined on Ae. aegypti larvae by laboratory bioassays and fluorescence microscopy. Using powdered food pellet for laboratory rodents (a common larval food used in the laboratory) as a carrier for C14, loading-release dynamics, larvicidal efficacy and residual activity of the C14-carrier complex were investigated. MAIN FINDINGS: The C14 molecule was found to exert a potent photosensitizing activity on Ae. aegypti larvae. At irradiation intervals of 12 h and 1 h, at a light intensity of 4.0 mW/cm(2), which is 50-100 times lower than that of natural sunlight, LC(50) values of 0.1 uM (0.15 mg/l) and 0.5 uM (0.77 mg/l) were obtained, respectively. The molecule was active after ingestion by the larvae and caused irreversible, lethal damage to the midgut and caecal epithelia. The amphiphilic nature of C14 allowed a formulate to be produced that not only was as active against the larvae as C14 in solution, but also possessed a residual activity of at least two weeks, in laboratory conditions. CONCLUSIONS: The meso-substituted synthetic porphyrin C14, thanks to its photo-sensitizing properties represents an attractive candidate for the development of novel photolarvicides for dengue vector control. PMID- 22206033 TI - Cytoplasmic incompatibility as a means of controlling Culex pipiens quinquefasciatus mosquito in the islands of the south-western Indian Ocean. AB - The use of the bacterium Wolbachia is an attractive alternative method to control vector populations. In mosquitoes, as in members of the Culex pipiens complex, Wolbachia induces a form of embryonic lethality called cytoplasmic incompatibility, a sperm-egg incompatibility occurring when infected males mate either with uninfected females or with females infected with incompatible Wolbachia strain(s). Here we explore the feasibility of the Incompatible Insect Technique (IIT), a species-specific control approach in which field females are sterilized by inundative releases of incompatible males. We show that the Wolbachia wPip(Is) strain, naturally infecting Cx. p. pipiens mosquitoes from Turkey, is a good candidate to control Cx. p. quinquefasciatus populations on four islands of the south-western Indian Ocean (La Reunion, Mauritius, Grande Glorieuse and Mayotte). The wPip(Is) strain was introduced into the nuclear background of Cx. p. quinquefasciatus mosquitoes from La Reunion, leading to the LR[wPip(Is)] line. Total embryonic lethality was observed in crosses between LR[wPip(Is)] males and all tested field females from the four islands. Interestingly, most crosses involving LR[wPip(Is)] females and field males were also incompatible, which is expected to reduce the impact of any accidental release of LR[wPip(Is)] females. Cage experiments demonstrate that LR[wPip(Is)] males are equally competitive with La Reunion males resulting in demographic crash when LR[wPip(Is)] males were introduced into La Reunion laboratory cages. These results, together with the geographic isolation of the four south-western Indian Ocean islands and their limited land area, support the feasibility of an IIT program using LR[wPip(Is)] males and stimulate the implementation of field tests for a Cx. p. quinquefasciatus control strategy on these islands. PMID- 22206032 TI - Identification of loci controlling restriction of parasite growth in experimental Taenia crassiceps cysticercosis. AB - Human neurocysticercosis (NC) caused by Taenia solium is a parasitic disease of the central nervous system that is endemic in many developing countries. In this study, a genetic approach using the murine intraperitoneal cysticercosis caused by the related cestode Taenia crassiceps was employed to identify host factors that regulate the establishment and proliferation of the parasite. A/J mice are permissive to T. crassiceps infection while C57BL/6J mice (B6) are comparatively restrictive, with a 10-fold difference in numbers of peritoneal cysticerci recovered 30 days after infection. The genetic basis of this inter-strain difference was explored using 34 AcB/BcA recombinant congenic strains derived from A/J and B6 progenitors, that were phenotyped for T. crassiceps replication. In agreement with their genetic background, most AcB strains (A/J-derived) were found to be permissive to infection while most BcA strains (B6-derived) were restrictive with the exception of a few discordant strains, together suggesting a possible simple genetic control. Initial haplotype association mapping using >1200 informative SNPs pointed to linkages on chromosomes 2 (proximal) and 6 as controlling parasite replication in the AcB/BcA panel. Additional linkage analysis by genome scan in informative [AcB55xDBA/2]F1 and F2 mice (derived from the discordant AcB55 strain), confirmed the effect of chromosome 2 on parasite replication, and further delineated a major locus (LOD = 4.76, p<0.01; peak marker D2Mit295, 29.7 Mb) that we designate Tccr1 (T. crassiceps cysticercosis restrictive locus 1). Resistance alleles at Tccr1 are derived from AcB55 and are inherited in a dominant fashion. Scrutiny of the minimal genetic interval reveals overlap of Tccr1 with other host resistance loci mapped to this region, most notably the defective Hc/C5 allele which segregates both in the AcB/BcA set and in the AcB55xDBA/2 cross. These results strongly suggest that the complement component 5 (C5) plays a critical role in early protective inflammatory response to infection with T. crassiceps. PMID- 22206035 TI - Multifaceted population structure and reproductive strategy in Leishmania donovani complex in one Sudanese village. AB - Leishmania species of the subgenus Leishmania and especially L. donovani are responsible for a large proportion of visceral leishmaniasis cases. The debate on the mode of reproduction and population structure of Leishmania parasites remains opened. It has been suggested that Leishmania parasites could alternate different modes of reproduction, more particularly clonality and frequent recombinations either between related individuals (endogamy) or between unrelated individuals (outcrossing) within strongly isolated subpopulations. To determine whether this assumption is generalized to other species, a population genetics analysis within Leishmania donovani complex strains was conducted within a single village. The results suggest that a mixed-mating reproduction system exists, an important heterogeneity of subsamples and the coexistence of several genetic entities in Sudanese L. donovani. Indeed, results showed significant genetic differentiation between the three taxa (L. donovani, L. infantum and L. archibaldi) and between the human or canine strains of such taxa, suggesting that there may be different imbricated transmission cycles involving either dogs or humans. Results also are in agreement with an almost strict specificity of L. donovani stricto sensu to human hosts. This empirical study demonstrates the complexity of population structure in the genus Leishmania and the need to pursue such kind of analyses at the smallest possible spatio-temporal and ecological scales. PMID- 22206034 TI - Novel structural components of the ventral disc and lateral crest in Giardia intestinalis. AB - Giardia intestinalis is a ubiquitous parasitic protist that is the causative agent of giardiasis, one of the most common protozoan diarrheal diseases in the world. Giardia trophozoites attach to the intestinal epithelium using a specialized and elaborate microtubule structure, the ventral disc. Surrounding the ventral disc is a less characterized putatively contractile structure, the lateral crest, which forms a continuous perimeter seal with the substrate. A better understanding of ventral disc and lateral crest structure, conformational dynamics, and biogenesis is critical for understanding the mechanism of giardial attachment to the host. To determine the components comprising the ventral disc and lateral crest, we used shotgun proteomics to identify proteins in a preparation of isolated ventral discs. Candidate disc-associated proteins, or DAPs, were GFP-tagged using a ligation-independent high-throughput cloning method. Based on disc localization, we identified eighteen novel DAPs, which more than doubles the number of known disc-associated proteins. Ten of the novel DAPs are associated with the lateral crest or outer edge of the disc, and are the first confirmed components of this structure. Using Fluorescence Recovery After Photobleaching (FRAP) with representative novel DAP::GFP strains we found that the newly identified DAPs tested did not recover after photobleaching and are therefore structural components of the ventral disc or lateral crest. Functional analyses of the novel DAPs will be central toward understanding the mechanism of ventral disc-mediated attachment and the mechanism of disc biogenesis during cell division. Since attachment of Giardia to the intestine via the ventral disc is essential for pathogenesis, it is possible that some proteins comprising the disc could be potential drug targets if their loss or disruption interfered with disc biogenesis or function, preventing attachment. PMID- 22206036 TI - IFN-gamma production depends on IL-12 and IL-18 combined action and mediates host resistance to dengue virus infection in a nitric oxide-dependent manner. AB - Dengue is a mosquito-borne disease caused by one of four serotypes of Dengue virus (DENV-1-4). Severe dengue infection in humans is characterized by thrombocytopenia, increased vascular permeability, hemorrhage and shock. However, there is little information about host response to DENV infection. Here, mechanisms accounting for IFN-gamma production and effector function during dengue disease were investigated in a murine model of DENV-2 infection. IFN-gamma expression was greatly increased after infection of mice and its production was preceded by increase in IL-12 and IL-18 levels. In IFN-gamma(-/-) mice, DENV-2 associated lethality, viral loads, thrombocytopenia, hemoconcentration, and liver injury were enhanced, when compared with wild type-infected mice. IL-12p40(-/-) and IL-18(-/-) infected-mice showed decreased IFN-gamma production, which was accompanied by increased disease severity, higher viral loads and enhanced lethality. Blockade of IL-18 in infected IL-12p40(-/-) mice resulted in complete inhibition of IFN-gamma production, greater DENV-2 replication, and enhanced disease manifestation, resembling the response seen in DENV-2-infected IFN-gamma( /-) mice. Reduced IFN-gamma production was associated with diminished Nitric Oxide-synthase 2 (NOS2) expression and NOS2(-/-) mice had elevated lethality, more severe disease evolution and increased viral load after DENV-2 infection. Therefore, IL-12/IL-18-induced IFN-gamma production and consequent NOS2 induction are of major importance to host resistance against DENV infection. PMID- 22206037 TI - Metabolic variation during development in culture of Leishmania donovani promastigotes. AB - The genome sequencing of several Leishmania species has provided immense amounts of data and allowed the prediction of the metabolic pathways potentially operating. Subsequent genetic and proteomic studies have identified stage specific proteins and putative virulence factors but many aspects of the metabolic adaptations of Leishmania remain to be elucidated. In this study, we have used an untargeted metabolomics approach to analyze changes in the metabolite profile as promastigotes of L. donovani develop during in vitro cultures from logarithmic to stationary phase. The results show that the metabolomes of promastigotes on days 3-6 of culture differ significantly from each other, consistent with there being distinct developmental changes. Most notable were the structural changes in glycerophospholipids and increase in the abundance of sphingolipids and glycerolipids as cells progress from logarithmic to stationary phase. PMID- 22206038 TI - Mosquito host selection varies seasonally with host availability and mosquito density. AB - Host selection by vector mosquitoes is a critical component of virus proliferation, particularly for viruses such as West Nile (WNV) that are transmitted enzootically to a variety of avian hosts, and tangentially to dead end hosts such as humans. Culex tarsalis is a principal vector of WNV in rural areas of western North America. Based on previous work, Cx. tarsalis utilizes a variety of avian and mammalian hosts and tends to feed more frequently on mammals in the late summer than during the rest of the year. To further explore this and other temporal changes in host selection, bloodfed females were collected at a rural farmstead and heron nesting site in Northern California from May 2008 through May 2009, and bloodmeal hosts identified using either a microsphere-based array or by sequencing of the mitochondrial cytochrome c oxidase I (COI) gene. Host composition during summer was dominated by four species of nesting Ardeidae. In addition, the site was populated with various passerine species as well as domestic farm animals and humans. When present, Cx. tarsalis fed predominantly (>80%) upon the ardeids, with Black-crowned Night-Herons, a highly competent WNV host, the most prevalent summer host. As the ardeids fledged and left the area and mosquito abundance increased in late summer, Cx. tarsalis feeding shifted to include more mammals, primarily cattle, and a high diversity of avian species. In the winter, Yellow-billed Magpies and House Sparrows were the predominant hosts, and Yellow-billed Magpies and American Robins were fed upon more frequently than expected given their relative abundance. These data demonstrated that host selection was likely based both on host availability and differences in utilization, that the shift of bloodfeeding to include more mammalian hosts was likely the result of both host availability and increased mosquito abundance, and that WNV-competent hosts were fed upon by Cx. tarsalis throughout the year. PMID- 22206039 TI - High prevalence of drug resistance in animal trypanosomes without a history of drug exposure. AB - BACKGROUND: Trypanosomosis caused by Trypanosoma congolense is a major constraint to animal health in sub-Saharan Africa. Unfortunately, the treatment of the disease is impaired by the spread of drug resistance. Resistance to diminazene aceturate (DA) in T. congolense is linked to a mutation modifying the functioning of a P2-type purine-transporter responsible for the uptake of the drug. Our objective was to verify if the mutation was linked or not to drug pressure. METHODOLOGY/PRINCIPAL FINDINGS: Thirty-four T. congolense isolates sampled from tsetse or wildlife were screened for the DA-resistance linked mutation using DpnII-PCR-RFLP. The results showed 1 sensitive, 12 resistant and 21 mixed DpnII PCR-RFLP profiles. This suggests that the mutation is present on at least one allele of each of the 33 isolates. For twelve of the isolates, a standard screening method in mice was used by (i) microscopic examination, (ii) trypanosome-specific 18S-PCR after 2 months of observation and (iii) weekly trypanosome-specific 18S-PCR for 8 weeks. The results showed that all mice remained microscopically trypanosome-positive after treatment with 5 mg/kg DA. With 10 and 20 mg/kg, 8.3% (n = 72) and 0% (n = 72) of the mice became parasitologically positive after treatment. However, in these latter groups the trypanosome-specific 18S-PCR indicated a higher degree of trypanosome-positivity, i.e., with a unique test, 51.4% (n = 72) and 38.9% (n = 72) and with the weekly tests 79.2% (n = 24) and 66.7% (n = 24) for 10 and 20 mg/kg respectively. CONCLUSION/SIGNIFICANCE: The widespread presence of the DA-resistance linked mutation in T. congolense isolated from wildlife suggests that this mutation is favourable to parasite survival and/or its dissemination in the host population independent from the presence of drug. After treatment with DA, those T. congolense isolates cause persisting low parasitaemias even after complete elimination of the drug and with little impact on the host's health. PMID- 22206040 TI - The Connection between the Presence of Melanoma and Changes in Fibre Diffraction Patterns. AB - An accurate diagnosis of melanomas at an early stage correlates directly with a better prognosis. However the incidence of melanoma is still increasing along with the number of related deaths. Melanoma cells grow extremely fast, with the result that many patients present after metastasis has occurred, too late for effective treatment. This paper describes the changes in the fibre diffraction patterns of skin that indicate the presence of a melanoma. Identification of these changes would provide an alternative early low-cost, totally reliable diagnostic test which could be conducted on a regular basis in local radiology facilities using rotating anode x-ray generators or as a mass screening test using suitable small angle x-ray beam-lines at synchrotrons. PMID- 22206041 TI - Extremely Early Diagnostic Test for Prostate Cancer. AB - PURPOSE: This article reports the results of a blinded fibre diffraction study of skin samples taken from TRAMP mice and age-matched controls to determine whether changes noted in fibre diffraction studies of human skin were present in these TRAMP mice studies. These mice are bred to progress to Gleeson Type 3 to Type 5 prostate cancer. METHODS: Small strips, 1mm*5mm, cut from the mouse skin samples were loaded into cells in the same way as human samples and slightly stretched to remove the crimp. They remained completely hydrated throughout exposure to the synchrotron beam. RESULTS: The added change that was reported for prostate cancer in 2009 was obtained for all TRAMP mice samples, indicating that this change can be read as High Grade Cancer in human diagnostic tests. DISCUSSION: These changes were evident for all 3 and 7 week old TRAMP mice samples but not for any of the control samples. This indicates that the changes in the fibre diffraction patterns appear much earlier than in any other available prostate cancer diagnostic test which cannot verify the presence of prostate cancer before 10 weeks of age. The fibre diffraction test is therefore the most accurate and earliest test for high grade prostate cancer. PMID- 22206042 TI - Infrared spectroscopy and microscopy in cancer research and diagnosis. AB - Since the middle of 20(th) century infrared (IR) spectroscopy coupled to microscopy (IR microspectroscopy) has been recognized as a non destructive, label free, highly sensitive and specific analytical method with many potential useful applications in different fields of biomedical research and in particular cancer research and diagnosis. Although many technological improvements have been made to facilitate biomedical applications of this powerful analytical technique, it has not yet properly come into the scientific background of many potential end users. Therefore, to achieve those fundamental objectives an interdisciplinary approach is needed with basic scientists, spectroscopists, biologists and clinicians who must effectively communicate and understand each other's requirements and challenges. In this review we aim at illustrating some principles of Fourier transform (FT) Infrared (IR) vibrational spectroscopy and microscopy (microFT-IR) as a useful method to interrogate molecules in specimen by mid-IR radiation. Penetrating into basics of molecular vibrations might help us to understand whether, when and how complementary information obtained by microFT-IR could become useful in our research and/or diagnostic activities. MicroFT-IR techniques allowing to acquire information about the molecular composition and structure of a sample within a micrometric scale in a matter of seconds will be illustrated as well as some limitations will be discussed. How biochemical, structural, and dynamical information about the systems can be obtained by bench top microFT-IR instrumentation will be also presented together with some methods to treat and interpret IR spectral data and applicative examples. The mid-IR absorbance spectrum is one of the most information-rich and concise way to represent the whole "... omics" of a cell and, as such, fits all the characteristics for the development of a clinically useful biomarker. PMID- 22206043 TI - HCG variants, the growth factors which drive human malignancies. AB - The term human chorionic gonadotropin (hCG) refers to a group of 5 molecules, each sharing the common amino acid sequence but each differing in meric structure and carbohydrate side chain structure. The 5 molecules are each produced by separate cells and each having separate biological functions. hCG and sulfated hCG are hormones produced by placental syncytiotrophoblast cells and pituitary gonadotrope cells. Hyperglycosylated hCG is an autocrine produced by placental cytotrophoblast cells. Hyperglycosylated hCG drives malignancy in placental cancers, and in testicular and ovarian germ cell malignancies. hCGbeta and hyperglycosylated hCGbeta are autocrines produce by most advanced malignancies. These molecules, particularly the malignancy promoters are presented in this review on hCG and cancer. hCGbeta and hyperglycosylated hCGbeta are critical to the growth and invasion, or malignancy of most advanced cancers. In many ways, while hCG may appear like a nothing, a hormone associated with pregnancy, it is not, and may be at the center of cancer research. PMID- 22206044 TI - The warts gene as a novel target of the Drosophila DRE/DREF transcription pathway. AB - The Hippo tumor suppressor pathway in Drosophila represses expression of DIAP1 and Cyclin E via inactivation of the transcription co-activator Yorkie, resulting in cell cycle arrest and induction of apoptosis. The warts (wts) gene is well known as a core kinase in this pathway, but its transcriptional regulation has yet to be clarified. In Drosophila, DREF binds to a target sequence named DRE (5' TATCGATA) and regulates transcription of cell proliferation-related genes containing the DRE sequence in their promoter regions. Here we found half reduction of the wts gene dose to enhance the DREF-induced rough eye phenotype, suggesting a DREF genetic interaction with the Hippo pathway in vivo. Three DREs indentified in the wts gene promoter region exhibited strong promoter activity with a luciferase transient expression assay in Drosophila S2 cells, this decreasing under DREF-RNAi conditions. In addition, knockdown of DREF in S2 cells reduced the level of endogenous wts mRNA. Chromatin immunoprecipitation assays with anti-DREF antibody revealed that DREF binds specifically to the wts gene promoter region containing DREs in vivo. These results indicate that the DRE/DREF pathway is required for transcriptional regulation of the wts gene, indicating a novel link between the DRE/DREF and the Hippo pathways. PMID- 22206045 TI - TRAIL receptor signaling and therapeutic option in bone tumors: the trap of the bone microenvironment. AB - Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL/TNFSF10) has been reported to specifically induce malignant cell death being relatively nontoxic to normal cells. Since its identification 15 years ago, the antitumor activity and therapeutic value of TRAIL have been extensively studied. Five receptors quickly emerged, two of them being able to induce programmed cell death in tumor cells. This review takes a comprehensive look at this ligand and its receptors, and its potential role in primary bone tumors (osteosarcoma and Ewing's sarcoma) therapy. The main limit of clinical use of TRAIL being the innate or acquired resistance mechanisms, different possibilities to sensitize resistant cells are discussed in this review, together with the impact of bone microenvironment in the regulation of TRAIL activity. PMID- 22206046 TI - Understanding the role of miRNA in regulating NF-kappaB in blood cancer. AB - MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by binding to complementary sequences in mRNAs encoding downstream target genes. A large variety of cellular processes, including differentiation, development, apoptosis and cell cycle progression, are dependent on miRNA-mediated suppression of gene expression for their regulation. As such, it is unsurprising that these small RNA molecules are associated with signaling networks that are often altered in various diseases, including many blood cancers. One such network is the nuclear factor-kappaB (NF-kappaB) pathways that universally stimulate transcription of proteins which generally promote cell survival, inhibit apoptosis, allow cellular growth, induce angiogenesis and generate many pro inflammatory responses. The NF-kappaB signalling pathway is often constitutively activated in blood cell cancers including myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), lymphomas and in multiple myeloma (MM). This review focuses on the function of miRNAs that directly target NF-kappaB signaling cascade. Recent findings that connect this pathway through various miRNA families to human blood cancers are reviewed, and support for using miRNA-based therapy as a novel method to counteract this tumour-promoting signalling event is discussed. PMID- 22206048 TI - Molecular signature and pathway analysis of human primary squamous and adenocarcinoma lung cancers. AB - Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with a poor response to chemotherapy and low survival rate. This unfavorable treatment response is likely to derive from both late diagnosis and from complex, incompletely understood biology, and heterogeneity among NSCLC subtypes. To define the relative contributions of major cellular pathways to the biogenesis of NSCLC and highlight major differences between NSCLC subtypes, we studied the molecular signatures of lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), based on analysis of gene expression and comparison of tumor samples with normal lung tissue. Our results suggest the existence of specific molecular networks and subtype-specific differences between lung ADC and SCC subtypes, mostly found in cell cycle, DNA repair, and metabolic pathways. However, we also observed similarities across major gene interaction networks and pathways in ADC and SCC. These data provide a new insight into the biology of ADC and SCC and can be used to explore novel therapeutic interventions in lung cancer chemoprevention and treatment. PMID- 22206047 TI - Targeted ovarian cancer treatment: the TRAILs of resistance. AB - Ovarian cancer (OC) is the leading cause of death from gynecological malignancies. Although most patients respond to the initial therapy when presenting with advanced disease, only 10-15% maintain a complete response following first-line therapy. Recurrence defines incurable disease in most cases. Despite improvements with conventional chemotherapy combinations, the overall cure rate remained mostly stable over the years. Increased long-term survival in OC patients will only be achieved through a comprehensive understanding of the basic mechanisms of tumor cell resistance. Such knowledge will translate into the development of new targeted strategies. In addition, because OC is considered to be a heterogeneous group of diseases with distinct gene expression profiles, it is likely that different approaches to treatment for distinct sub-types will be required to optimize response. One of the new promising anti-cancer therapies is the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL has the ability to selectively induce apoptosis in tumor cells with little toxicity to normal cells. Death receptor ligands such as TRAIL rely on the activation of the apoptotic signaling pathway to destroy tumor cells. TRAIL induces the formation of a pro-apoptotic death-inducing signaling complex (DISC) via its death receptors, TRAIL receptor 1 (TRAIL R1) and TRAIL receptor 2 (TRAIL R2). The formation of the DISC activates caspase-8 which requires further signal amplification through the mitochondrial pathway for an efficient activation of effector caspases in OC cells. The initial enthusiasm for TRAIL has been hampered by accumulating data demonstrating TRAIL resistance in various tumor types including OC cells. There is, therefore, a need to identify markers of TRAIL resistance, which could represent new hits for targeted therapy that will enhance TRAIL efficacy. In addition, the identification of patients that are more likely to respond to TRAIL therapy would be highly desirable. In this review, we discuss the different molecular and cellular mechanisms leading to TRAIL resistance in OC. In particular, we address the mechanisms involved in intrinsic, acquired and environment-mediated TRAIL resistance, and their potential implication in the clinical outcome. PMID- 22206049 TI - Expression of FOXO1 is associated with GATA3 and Annexin-1 and predicts disease free survival in breast cancer. AB - PURPOSE: To determine the prognostic value of FOXO1, GATA3 and Annexin-1 expression in breast cancer. METHODS: Tissue microarray and individual paraffin tissue slides from 131 patients were used for the study. The association of FOXO1, GATA3 and Annexin-1 expression with clinicopathological features of breast cancer and disease outcome was examined in retrospective samples. Kaplan-Meier survival curves and Cox regression with multivariate analysis were used for assessing the relative risk (RR) and disease-free survival (DFS). The expression of FOXO1, GATA3 and Annexin-1 were determined by immunohistochemistry and the association among the three proteins was analyzed by Logistic regression analysis. RESULTS: The nuclear expression of FOXO1 was observed in most of the normal breast tissues and 51.3% of the malignant breast tissues. GATA3 and Annexin-1 were expressed at 73% and 24.6% respectively in breast cancer tissues. The expression of FOXO1, GATA3 and Annexin-1 were all inversely correlated with lymph node-positive tumors. Both FOXO1 and Annexin-1 expression were also inversely associated with HER2-overexpressing tumors. FOXO1 expression was significantly associated with both GATA3 and Annexin-1 expression. In addition, Multivariate analyses confirm that only FOXO1 levels independently predict DFS. CONCLUSION: FOXO1 expression in breast cancer is regulated by the PI3K/Akt pathway. The expression of FOXO1 is also associated with GATA3 and/or Annexin-1. Restoring or targeting FOXO1 to the cell nucleus in breast cancer tissues may improve response to therapy and disease outcome. Further clinical studies are warranted to test this hypothesis. PMID- 22206050 TI - Prognostic significance of aberrant gene methylation in gastric cancer. AB - Promoter methylation acts as an important alternative to genetic alterations for gene inactivation in gastric carcinogenesis. Although a number of gastric cancer associated genes have been found to be methylated in gastric cancer, valuable methylation markers for early diagnosis and prognostic evaluation of this cancer remain largely unknown. In the present study, we used methylation-specific PCR (MSP) to analyze promoter methylation of 9 gastric cancer-associated genes, including MLF1, MGMT, p16, RASSF2, hMLH1, HAND1, HRASLS, TM, and FLNc, and their association with clinicopathological characteristics and clinical outcome in a large cohort of gastric cancers. Our data showed that all of these genes were aberrantly methylated in gastric cancer, ranging from 8% to 51%. Moreover, gene methylation was strongly associated with certain clinicopathological characteristics, such as tumor differentiation, lymph node metastasis, and cancer related death. Of interest, methylation of MGMT, p16, RASSF2, hMLH1, HAND1, and FLNc was closely associated with poor survival in gastric cancer, particularly MGMT, p16, RASSF2 and FLNc. Thus, our findings suggested these epigenetic events may contribute to the initiation and progression of gastric cancer. Importantly, methylation of some genes were closely relevant to poor prognosis in gastric cancer, providing the strong evidences that these hypermethylated genes may be served as valuable biomarkers for prognostic evaluation in this cancer. PMID- 22206051 TI - A timely investment: coordinated care for depression and anxiety disorders. PMID- 22206052 TI - Changing epidemiological patterns of hepatitis A infection in Singapore. AB - INTRODUCTION: Singapore has experienced remarkable socioeconomic progress over the last few decades, with a corresponding rise in standards of sanitation and living conditions. We undertook a study to describe its epidemiological trends of hepatitis A over the last 2 decades. MATERIALS AND METHODS: We analysed the epidemiological data on all laboratory-confirmed cases of hepatitis A from 1990 to 2009. We also described 3 outbreaks which occurred in 1991, 1992 and 2002. To determine the changing prevalence of hepatitis A virus (HAV) infection, we compared the findings from a seroepidemiological study conducted in 1993 with earlier surveys in 1975 and 1984/1985. RESULTS: The incidence of indigenous hepatitis A cases per 100,000 population declined significantly from 1.8 in 1989 to 0.7 in 2009, and more than half were imported. While majority of the imported cases were Singapore residents, the proportion of imported cases among Singapore residents had decreased significantly. Most of the Singapore residents contracted the disease from Southeast Asia and the Indian subcontinent. The overall prevalence of HAV infection in the population declined from 31.8% in 1984/85 to 25.9% in 1993. CONCLUSION: The incidence and seroprevalence of hepatitis A in Singapore are comparable to other developed countries. As Singapore is situated in a region highly endemic for HAV, it is very vulnerable to the introduction of the disease because of the high volume of regional travel and import of food, especially shellfish. While we note that there have been no further shellfish associated outbreaks since 2002, sustained vigilance, strict control of food import by the authorities and public health education on the risk of consuming shellfish, especially cockles, raw and half-cooked, should be maintained. PMID- 22206053 TI - Evaluation of the dried blood spot (DBS) collection method as a tool for detection of HIV Ag/Ab, HBsAg, anti-HBs and anti-HCV in a Malaysian tertiary referral hospital. AB - INTRODUCTION: Dried blood spot (DBS) collection is an appealing alternative to whole blood or plasma sampling, as it has technical and economic advantages over the latter. MATERIALS AND METHODS: A prospective cross-sectional study was conducted at a Malaysian tertiary referral hospital from November 2009 to March 2010. One hundred and fifty paired specimens of DBS and plasma were analysed by the standard assays for HIV Ag/Ab, HBsAg, anti-HBS and anti-HCV, separately (total 600 paired specimens). DBS sample titres were then compared to the results of plasma testing, which was used as the gold standard. RESULTS: For the HIV Ag/Ab assay with a cut-off point of 0.35 Relative Light Units (RLUs), the sensitivity and specificity were both 100%. For the HBsAg assay, the sensitivity was 96.5% and the specificity was 97.8%, with a cut-off point of 1.72 RLUs. Sensitivity for the anti-HBs test was 74.2% and the specificity was 86.9%, using a cut-off point of 0.635 RLUs. For the anti-HCV assay, the sensitivity was 97.3% and the specificity was 100%, with a cut-off point of 0.10 RLUs. CONCLUSION: DBS is an ideal choice to be used as a screening tool for the detection of HIV, Hepatitis B and Hepatitis C virus infections. However, different cut-off values need to be used for the validation of test positivity in DBS samples because the small amount of blood in the DBS specimens leads to lower assay titres. PMID- 22206054 TI - Atypical enhancement pattern of hepatocellular carcinoma with portal vein thrombosis on multiphasic CT. AB - INTRODUCTION: The 2005 American Association for Study of Liver Diseases (AASLD) diagnostic criteria allow non-invasive diagnosis of hepatocellular carcinoma (HCC) based on their enhancement pattern but we have observed a high incidence of atypical enhancement characteristics in HCC associated with portal vein thrombosis. This study seeks to examine the radiological features of this particular subgroup. MATERIALS AND METHODS: Patients with HCC and portal vein thrombosis who underwent pre-treatment multiphasic CT imaging were drawn from a surgical database. The arterial, portal venous and delayed phase images were assessed qualitatively and quantitatively (with region of interest [ROI] analysis) for lesion hypervascularity and washout. The background enhancement of the left and right lobes of the liver was also quantifi ed by ROI analysis. RESULTS: Twenty-fi ve lesions in 25 patients were selected for analysis. Qualitative analysis showed that 10/25 (40%) lesions demonstrated arterial hypervascularity while 16/25 (64%) lesions showed washout. Ten out of 25 (40%) lesions demonstrated both arterial hypervascularity and washout. Quantitative analysis showed that the average absolute lesion enhancement from precontrast to arterial phases was 49.1 (+/- 17.1) HU for hypervascular lesions compared to 23.8 (+/- 16.6) HU for non-hypervascular lesions (P <0.01). The mean absolute enhancement of the background liver parenchyma in the arterial phase was 13.79 (+/- 7.9) HU for hypervascular lesions compared to 36.6 (+/- 30.6) HU for non hypervascular lesions (P = 0.03). CONCLUSION: A large proportion of HCC with portal vein thrombosis lack characteristic arterial hypervascularity, which may be secondary to compensatory increased arterial supply to the background liver. This is a potential pitfall when applying imaging criteria for diagnosis of HCC. PMID- 22206055 TI - Robot-assisted rectal surgery for malignancy: a review of current literature. AB - Laparoscopic colorectal surgery is rapidly gaining acceptance for the management of colorectal cancer. However, laparoscopic colorectal surgery is technically more challenging than conventional surgery. This challenge is more profound for laparoscopic rectal cancer, where there is a need to perform a total mesorectal excision (TME), in the confines of the pelvis, with the limitations of the laparoscopic system. The Da Vinci robotic surgical system was designed to overcome the pitfalls of laparoscopic surgery, hence the use of this novel system in colorectal surgery seems logical, in particular with regards to rectal cancer surgery. Recently, there have been an increasing number of reports in the literature on robotic colorectal surgery. The advantages of the robotic surgical system include; 7 degrees of movement, 3 dimensional views, tremor filtration, motion scaling and superior ergonomics. These advantages when applied to robotic TME for rectal cancer surgery may potentially translate to better outcomes. The aim of this review is to summarise the current evidence on clinical and oncological outcomes of robotic rectal cancer surgery. PMID- 22206056 TI - Salmonella related mycotic aneurysm with psoas and paraortic abscess treated conservatively. PMID- 22206057 TI - Simple innovative measures for ease of corneal foreign body removal. PMID- 22206058 TI - Full thickness burns over bilateral patella tendons - adjunctive Hyperbaric Oxygen Therapy and Negative Pressure Wound Therapy for wound bed preparation and improved graft take. PMID- 22206059 TI - Salivary duct carcinoma in the neck. PMID- 22206060 TI - Swallowed fish bone expelled spontaneously after perforating the small bowel. PMID- 22206061 TI - Intraocular cilia in retinal detachment. PMID- 22206062 TI - The diabetes dilemma: how do we deal with it? PMID- 22206063 TI - Clinical outcome following treatment of stable and unstable intertrochanteric fractures with dynamic hip screw. AB - INTRODUCTION: Intertrochanteric (IT) fractures are associated with significant morbidity and mortality in the elderly population. We aim to compare the clinical outcome of unstable with stable IT fractures after treatment with dynamic hip screw (DHS). MATERIALS AND METHODS: Patients with IT fractures treated with DHS at National University Hospital between 2003 and 2005 were included in the study. Patients were divided into 2 groups: stable and unstable IT fractures. Clinical outcome parameters include perioperative complications, functional outcomes, and incidence of morbidity and mortality. RESULTS: One hundred and thirty-six patients were analysed. Mean age was 77 years. There were 61 stable and 78 unstable fractures. Average length of follow-up was 30 months. The rates of local complications were not significantly different between the 2 groups. The incidence of malunion and excessive impaction were significantly higher in the unstable group. The ambulatory status at one year post-surgery was not significantly different between the 2 groups. In terms of general postoperative complications and one year mortality rate, there was no significant difference between the 2 groups. The need for blood transfusion was significantly higher in the unstable group. CONCLUSION: In summary, DHS fixation provides comparable postoperative outcomes in unstable IT fractures with relatively low rates of complications. Although it was associated with a higher incidence of malunion and excessive impaction in the unstable fracture group, there was no difference in functional status at one-year compared to the stable group. PMID- 22206064 TI - KCNQ1 variants associate with type 2 diabetes in Malaysian Malay subjects. AB - INTRODUCTION: Type 2 diabetes (T2D) candidate gene: potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) was suggested by conducting a genome wide association study (GWAS) in Japanese population. Association studies have been replicated among East Asian populations; however, the association between this gene and T2D in Southeast Asian populations still needs to be studied. This study aimed to investigate the association of KCNQ1 common variants with type 2 diabetes in Malaysian Malay subjects. MATERIALS AND METHODS: The KCNQ1 single nucleotide polymorphisms (SNPs): rs2237892, rs2283228, and rs2237895 were genotyped in 234 T2D and 177 normal Malay subjects. RESULTS: The risk allele of the rs2283228 (A) was strongly associated with T2D (OR = 1.7, P = 0.0006) while the rs2237892 (C) was moderately associated with T2D (OR = 1.45, P = 0.017). The recessive genetic models showed that rs2283228 was strongly associated with T2D (OR = 2.35, P = 0.00005) whereas rs2237892 showed a moderate association with T2D (OR = 1.69, P = 0.01). The haplotype block (TCA), which contained the protective allele, correlated with a protection from T2D (OR = 0.5, P = 0.003). Furthermore, the diplotype (CAA-TCA) that contained the protective haplotype was protected against T2D (OR = 0.46, P = 0.006). CONCLUSION: The KCNQ1 SNPs, haplotypes and diplotypes are associated with T2D in the Malaysian Malay subjects. PMID- 22206065 TI - High prevalence of hearing loss in Down syndrome at first year of life. AB - INTRODUCTION: Infants with Down syndrome (DS) are at higher risk of hearing loss (HL). Normal hearing at one year of age plays an important part in language development. An audit was conducted to determine the impact of the newborn hearing screening program on the incidence, type and timing of diagnosis of HL during first year of life. MATERIALS AND METHODS: Infants with DS were scheduled for Universal Newborn Hearing Screening (UNHS) within 4 weeks of life. If they passed, they had a high-risk screen at 3 to 6 months. They were referred to the otolaryngology department if they did not pass the UNHS or the high-risk screen. Information was obtained from the computerised data tracking system and case notes. Infants born from April 2002 to January 2005 and referred to the DS clinic of our hospital were analysed. RESULTS: Thirty-seven (82.2%) of 45 infants underwent UNHS, of which 12 (32.4%) infants did not pass. Of remaining 33 infants, 27 had high-risk screen done of which 14 (51.8%) did not pass. Twenty eight infants were referred to the ear, nose, throat (ENT) clinic: 12 from UNHS, 14 from high-risk screens and 2 from the DS clinic. Eleven (39.2%) defaulted follow-up. Fourteen (82.3%) of 17 infants who attended the ENT Clinic had HL. Twelve (85.7%) were conductive, and 2 (14.2%) mixed. Nine (64.2%) had mild moderate HL and 3 (21%) had severe HL. The mean age of diagnosis was 6.6 +/- 3.3 months. All were treated medically, plus surgically if indicated. By 12 months of age, the hearing had normalised in 4 (28.6%) infants and remained the same in 3 (21.4%). Five (35.7%) defaulted follow-up. Thirty-five out of 45 (77.8%) underwent complete hearing screen in the first year of life (UNHS & High-risk screen). Six out of 45 (13.3%) had incomplete screening. Fourteen out of 41 (34.1%) had HL of varying degrees. Four out of 45 (8.8%) did not have any audiological assessment in first year of life. CONCLUSION: The incidence of HL in the first year of life was high (34.1%). Eighty-five percent were conductive with 64.2% in mild-moderate range. One third of infants hearing normalized after treatment, one third remained unaltered and one third of infants did not attend follow-up. An aggressive approach involving early screening after birth and continued surveillance and early referral to appropriate agencies are essential for establishing timely diagnosis and treatment. Measures to reduce the high default rate during long-term follow-up are needed. Parent education and integrated multidisciplinary follow-up clinic may be useful. PMID- 22206066 TI - How can we improve clinical research in clinical practice with better research outcome? AB - This paper explains some of the difficulties doctors face when taking up a career in research. It describes the efforts by the government and the Ministry of Health (MOH) to nurture the Clinician Scientist Programme. The nature of research and the mindset of clinicians who are passionate about research are explored and the reasons which drive some of them to pursue a research career. It discusses the need to have structured training for research and how continuing research education is necessary for the researcher. The paper discusses the goals for research and how we can achieve better research outcomes and the importance of good mentorship. It suggests ways to engage more doctors in research in the restructured hospitals by overcoming some of the problems they encounter. Finally, it relates the Biomedical Science initiative of the government through the National Research Foundation and the various programmes in Translational Clinical Research available for clinicians who are keen on a research career. PMID- 22206067 TI - Ophthalmoplegia in a patient with breast cancer. PMID- 22206068 TI - Stevens-Johnson syndrome due to strontium ranelate. PMID- 22206069 TI - Migrated brachiocephalic venous stent into the right atrium - can it be left alone? A case report and review of the literature. PMID- 22206070 TI - Enterobius vermicularis infestation of the endometrium - a cause of menstrual irregularity and review of literature. PMID- 22206071 TI - Delayed neuropsychiatric sequelae and recovery following carbon monoxide poisoning. PMID- 22206072 TI - Large lymphangioma presenting like irreducible inguinal hernia: a rare presentation and literature review. PMID- 22206073 TI - Two randomized, controlled, comparative studies of the stratum corneum integrity benefits of two cosmetic niacinamide/glycerin body moisturizers vs. conventional body moisturizers. AB - BACKGROUND AND OBJECTIVE: Despite numerous body moisturizers being available, cosmetic xerosis continues to be a leading skin problem for consumers. We performed two 35-day studies to evaluate the ability of a variety of body moisturizers containing various levels of oils/lipids, humectants, as well as other ingredients (e.g., niacinamide) to improve stratum corneum integrity. METHODS: 63 and 58 female subjects were enrolled and randomized in an incomplete block design to six of nine products (eight moisturizers or no treatment control) in studies 1 and 2, respectively. The primary endpoints included visual dryness by a qualified skin grader, skin hydration as measured by Corneometer, and barrier integrity as measured by transepidermal water loss (TEWL). The primary comparisons for the two niacinamide/glycerin moisturizers were to the other six moisturizers and to the no treatment control for each endpoint. RESULTS: The two niacinamide/glycerin moisturizers demonstrated an overall better solution towards rapid and prolonged improvement of cosmetic xerosis due to functional improvement of stratum corneum barrier function compared to no treatment and the other moisturizers tested. CONCLUSIONS: These studies establish the benefit of including niacinamide in a body moisturizer to improve the integrity of the stratum corneum and thus reduce cosmetic xerosis over time. PMID- 22206074 TI - Application of a topical biomimetic electrical signaling technology to photo aging: a randomized, double-blind, placebo-controlled trial of a galvanic zinc copper complex. AB - BACKGROUND: The first signs of facial skin photo-aging often occur in the skin of the periorbital area and include sagging, loss of firmness and definition, and sallowness. Epidermal wounds have been shown to alter the trans-epithelial electrical potential creating an electric signal that directs cell migration in epithelial wound healing; this electric field declines sharply with age. A topical galvanic zinc-copper complex, which couples elemental zinc and copper to create a biomimetic electric field, has demonstrated anti-inflammatory activity and extracellular matrix improvement in vitro, including collagen and elastin production. OBJECTIVES: To evaluate the efficacy and tolerability of a galvanic zinc-copper complex on photo-aging parameters in a randomized, double-blind, placebo-controlled clinical trial. MATERIALS AND METHODS: In this eight-week study, women (40-65 years) with mild to moderate photo-aging were randomized to use placebo or 1 of 3 galvanic zinc-copper complex compositions (gel and activating moisturizer). Efficacy evaluations included clinical grading, specialized clinical imaging, and subject self-assessments performed at baseline, 15-30 minutes after product application and after 1, 2, 4, and 8 weeks. Tolerability was based on adverse events and clinical grading of irritation. Significance was set at P?0.05 versus baseline and between treatment groups. RESULTS: The study was completed by 124 women. Compositions containing the galvanic zinc-copper complex showed statistically significant clinical improvements versus placebo and baseline rapidly (15-30 min) after application and through week 8. Clinical grading showed significant improvement versus placebo in skin radiance and under-eye dark circles 15-30 minutes after first application with continued improvement through week 8, and in overall photo damage, fine lines, lifted appearance of the eyes, and under-eye wrinkles starting after two weeks and continuing through week 8. Test compositions were well tolerated. CONCLUSION: This galvanic zinc-copper complex provided rapid and lasting improvements versus placebo in photo-aged skin, supporting its use in topical anti-aging formulations. PMID- 22206075 TI - Results of a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of a botulinum toxin type A topical gel for the treatment of moderate-to-severe lateral canthal lines. AB - BACKGROUND: Injections of botulinum toxin type A are commonly used to treat facial wrinkles; however, undesirable effects are associated with injections (e.g., pain, bruising, ptosis, immunogenicity, and needle aversion). To address these issues, RT001 Botulinum Toxin Type A Topical Gel is being developed for the treatment of lateral canthal lines. OBJECTIVES: To assess the safety and efficacy of RT001 for the treatment of lateral canthal lines in a randomized, double blind, placebo-controlled study. MATERIALS & METHODS: Adult subjects were enrolled to receive a single treatment of RT001 (n=45) or placebo (n=45) applied topically in the lateral canthal area. The primary endpoint was the composite of the Investigator Global Assessment of Lateral Canthal Line Severity (IGA-LCL) and the Patient Severity Assessment of lateral canthal line severity (PSA) defined as a 2-point or greater improvement on both scales. RESULTS: At four weeks, 44.4 percent of subjects treated with RT001 achieved a 2-point or greater improvement on a rigorous composite of both the IGA-LCL and PSA scales compared to 0.0% for the placebo subjects (P<0.0001). At four weeks, 88.9 percent of subjects achieved clinically relevant improvement by investigator assessment. Adverse events were mild in severity and unrelated to study treatment. CONCLUSIONS: RT001 appears to be a safe and well-tolerated treatment for improvement of lateral canthal lines. PMID- 22206076 TI - Nonanatomic free cartilage batten grafting with second intention healing for defects on the distal nose. AB - BACKGROUND: Defects of the distal nose, particularly the nasal ala, pose a reconstructive challenge due to the lack of loose adjacent tissue and proximity to a free margin. OBJECTIVE: We report our experience using nonanatomic free cartilage batten grafts in combination with second intention healing for nasal ala defects. METHODS: A retrospective study of distal nose defects repaired using nonanatomic free cartilage batten grafting with second intention healing was performed. Detailed data on the quality of the scar, post-operative complications, free margin distortion, functional impairments, and patient satisfaction were recorded. Digital images were also shown to an experienced fellowship-trained Mohs surgeon to assess the overall aesthetic outcome using a 5 point score ranging from poor to excellent. RESULTS: Sixteen subjects were included in the study. Complications were common, but minor. Five (~31%) subjects had subtle contour depressions, three (~18%) subjects had excessive granulation tissue, two (~12%) subjects had post-operative ear pain at the donor site lasting up to 10 days, and one (~6%) subject had a hypertrophic scar at the recipient site. There were two occurrences (~12%) of mild alar notching but no occurrences of significant alar margin distortion or nasal valve dysfunction. In terms of aesthetic outcome, seven (~43%) were assessed by an independent fellowship trained Mohs surgeon as having excellent aesthetic outcomes, six (~38%) were very good, and three (~19%) were good. All sixteen subjects reported satisfaction on follow-up evaluation. CONCLUSIONS: Nonanatomic free cartilage grafting with second intention healing allows for facile, single-step repair of nasal ala defects with high patient satisfaction and aesthetically pleasing results. This provides an attractive alternative to other flap techniques, skin grafting, and healing via secondary intention. PMID- 22206077 TI - Split-face study of topical 23.8% L-ascorbic acid serum in treating photo-aged skin. AB - BACKGROUND: L-ascorbic acid has been widely used to treat photo-aged skin. However, its aqueous formula is prone to oxidation. Therefore, a new formula that contains 23.8% L-ascorbic acid and a chemical penetration enhancer was developed. OBJECTIVE: Observe the efficacy and safety of topical 23.8% L-ascorbic acid serum on photo-aged skin. METHODS: Twenty Chinese women with photo-aged skin were enrolled in this split-face study. They were treated with topical L-ascorbic acid serum with iontophoresis on one side of the face once a day for 2 weeks; the other side of the face was spared treatment through participants' self-control. Changes in photo-aged skin were evaluated using a global evaluation, an overall self-assessment, a spectrophotometer, the phase-shift rapid in vivo measurement of skin (PRIMOS) 3D, and a corneometer. RESULTS: Sixteen of 20 patients (80%) experienced a score decrease of 2 or 3 grades, according to the dermatologist. Fifteen patients (75%) rated their overall satisfaction as excellent or good. Dyspigmentation, surface roughness, and fine lines on the treated side improved significantly. CONCLUSION: Topical 23.8% L-ascorbic acid serum is effective for the treatment of photo-aged skin and does not cause any obvious side effects. PMID- 22206078 TI - Treatment of focal axillary hyperhidrosis using a long-pulsed Nd:YAG 1064 nm laser at hair reduction settings. AB - BACKGROUND AND OBJECTIVE: Axillary hyperhidrosis is a rather common idiopathic disorder of the eccrine sweat glands, which can interfere with daily activities and cause significant social distress. The effects of 1064 nm laser hair reduction on sweat production in a pilot study in patients with focal axillary hyperhidrosis are described. STUDY DESIGN/MATERIALS AND METHODS: In a prospective, case-controlled, randomized pilot study, one axilla from six different subjects with axillary hyperhidrosis was treated with monthly laser hair reduction sessions using the 1064 nm Nd:YAG laser at typical settings. The contralateral axilla acted as a control. Subjects were asked to subjectively classify improvement of axillary sweating using a Global Assessment Questionnaire (GAQ) weekly after each treatment. Qualitative evaluation of sweating was also performed using a modified starch iodine test monthly after each treatment. In addition, prior to the first treatment and at one month following the final treatment, a punch biopsy was performed on the treatment axilla to assess for histologic changes to the eccrine gland and surrounding structures. RESULTS: Statistically significant improvements in subjective ratings of sweating using the GAQ compared to baseline were observed. Objective improvements in sweating with modified starch iodine testing comparing treated versus non-treated axillae were also seen for at least nine months in selected subjects. No significant differences in pre- and post-treatment biopsies were noted on routine histology. CONCLUSIONS: Laser hair reduction using the 1064 nm Nd:YAG at laser hair removal settings provides subjective and objective improvements in patients with focal axillary hyperhidrosis. PMID- 22206079 TI - A randomized, double-blind, controlled comparative trial of the anti-aging properties of non-prescription tri-retinol 1.1% vs. prescription tretinoin 0.025%. AB - Vitamin A and its derivatives (commonly termed retinoids) are widely used in topical anti-aging products. Certain retinoids such as retinol and its esters are available without a prescription, while others such as tretinoin are available only via prescription. A randomized, double-blind, controlled clinical study was conducted to compare the efficacy and tolerability of a tri-retinol 1.1% gradual release cream vs. tretinoin 0.025% cream in females with mild-to-moderate facial photodamage. Subjects applied the test product to the entire face in the evening after cleansing in a progressively increasing frequency starting twice weekly for the first week, followed by three times weekly during the second week and then daily as tolerated for the third week and beyond. Treatment was continued for a total of three months. Clinical evaluations and standardized digital photographs were performed at baseline and after four, eight, and 12 weeks of treatment. Self assessment questionnaires were completed by the subjects at four, eight, and 12 weeks to assess perceived efficacy of the test products. Thirty-four subjects (16: tri-retinol and 18: tretinoin) completed the study. Both test products significantly improved signs of photodamage, including fine and coarse periocular wrinkles, skin firmness, skin tone, mottled pigmentation, tactile roughness, overall photodamage and global photodamage improvement. There were no significant differences in efficacy between the two products for these assessments. The adverse effects (which were graded as mild or less) were those typically seen with topical retinoids. Subjects reported >93 percent overall satisfaction with both products at weeks 8 and 12. PMID- 22206080 TI - Use of blunt tipped cannulas for soft tissue fillers. AB - In the US, soft tissue fillers are currently administered using sharp, hypodermic needles. The choice in length and gauge of needle is determined by the injector's preferences, as well as the physical properties of the filler itself. While some adverse events are injector-dependent, others may be due to risks inherent to using sharp needles. The use of new, flexible cannulas with blunt tips may potentially both lower these risks and change the techniques by which fillers are administered in the future. PMID- 22206081 TI - Comparison of the effects of Contractubex(r) gel in an experimental model of scar formation in rats: an immunohistochemical and ultrastructural study. AB - BACKGROUND: Contractubex(r) gel, a commercial treatment for scars, consists of a mixture of onion extract (cepea extract), heparin sodium, and allantoin. It exerts a softening and smoothing effect on indurated, hypertrophic, painful, and cosmetically-disfiguring scar tissue. AIM: To compare and discuss the immunohistochemical and ultrastructural effects of treatment of an experimental scar in a rat model with Contractubex gel. METHODS: Thirty-two Sprague-Dawley rats were divided into four groups. Skin biopsies were taken to develop full thickness wounds. After 10 days, Contractubex gel, heparin, and allantoin were topically applied daily to groups 2, 3, and 4, respectively. Group 1 was the control group. On the 30th day, scar tissues were excised to investigate the immunohistochemical and ultrastructural effects of these agents. For this purpose we used TGF-beta, laminin, and fibronectin primary antibodies. RESULTS: Increased immunoreactivities of laminin, fibronectin, and TGF-beta in control group, moderate immunoreactivities in heparin and allantoin groups, and mild immunoreactivities in the Contractubex gel group were observed. In semi-thin sections, Group 2 showed the thinnest epidermis of the four groups. In electron micrographs of Group 2, completely keratinized and normally appearing cells could be seen. CONCLUSIONS: Immunohistochemical and ultrastructural observations demonstrated that the Contractubex gel significantly improved the quality of wound healing and reduction of scar formation. Also, it was a more appropriate treatment choice than heparin monotherapy and allantoin monotherapy in keloidal and hypertrophic scars. PMID- 22206082 TI - Safety and efficacy evaluation of tretinoin cream 0.02% for the reduction of photodamage: a pilot study. AB - BACKGROUND: Clinical studies as well as histologic data maintain that tretinoin improves the appearance of photodamage; however, the long-term benefits of tretinoin 0.02% in moderate to severe photodamage have not been established. OBJECTIVE: We performed independent assessments to demonstrate the long-term safety and efficacy of tretinoin emollient cream 0.02% for moderate to severe facial photodamage. METHODS: A single-center, open-label, single-group observational study followed 19 patients over 52 weeks. Efficacy assessments consisted of the Glogau Photodamage Classification Scale and severity grading of photodamage signs and symptoms. Facial photography and biopsies were taken from three subjects at baseline and final visits. Tolerability was assessed by the investigator. RESULTS: Twelve patients completed 52 weeks of treatment. Mean change in Glogau photodamage demonstrated statistically significant differences at 3, 6, 9, and 12 months (P<.0005). All patients with moderate to severe photodamage had improved to mild photodamage status by 9 months. Statistically significant improvements (P<.05) were observed at all time points for fine wrinkling, tactile roughness, and mottled hyperpigmentation as well as for lentigines at 6, 9, and 12 months and telangiectasia at 12 months. Biopsy samples revealed microscopic improvement in photodamage. Tretinoin cream 0.02% was generally well-tolerated, with few subjects experiencing adverse events. LIMITATIONS: Our pilot study is limited by lack of control and the small study sample. CONCLUSIONS: Tretinoin cream 0.02% was safe and effective for moderate to severe photodamage of facial skin and demonstrated sustainable benefits over an entire year based on the clinically validated Glogau classification system and expert visual grading analysis. PMID- 22206083 TI - A review of protocols for 308 nm excimer laser phototherapy in psoriasis. AB - BACKGROUND: 308 nm excimer laser phototherapy is efficacious in the treatment of localized psoriasis. Different approaches regarding dose fluency, number of treatments, and maintenance have been utilized, and there is yet to be a consensus on standard protocol. OBJECTIVE: To characterize treatment parameters for 308 nm excimer laser phototherapy. METHODS: We performed a PubMed search for studies describing excimer laser treatment protocol with particular attention to dosage determination, dose adjustment, dose fluency, number of treatments, and maintenance. RESULTS: Seven prospective studies were found describing the excimer efficacy for psoriasis. All studies determined the initial treatment dose using either the minimal erythema dose (MED) or induration. Fluency ranged from 0.5 MED (low) to 16 MED (high); one study demonstrated that medium to high fluencies yielded better improvement in fewer number of treatments. Fluency adjustments during the course of treatment were important to minimize phototherapy-associated side effects. The use of higher fluencies was reported to result in higher occurrences of blistering. One study implemented a maintenance tapering of dose frequency phase to better manage psoriasis flare-ups. CONCLUSION: The 308 nm excimer laser is an effective therapy for psoriasis regardless of the method used to determine initial dosage, dose fluency, or number of treatments. As its usage as a targeted monotherapy increases, future trials should consider evaluating and modifying these parameters to determine the most optimal management of localized psoriasis. Based on our reviewed studies, there is no consensus for a single excimer laser therapy protocol and as a result, patient preferences should continue to be an important consideration for phototherapy regimen planning. PMID- 22206084 TI - The hatchet and bilobed flaps revisited: shedding new light on traditional concepts. AB - BACKGROUND: The bilobed and hatchet flaps are well-accepted reconstructive options for the correction of defects of the lower third of the nose. Optimal utilization of these flaps depends on understanding the characteristics of each flap as well as anatomic considerations related to the distal nasal area. Disregarding the limitations of either method may lead to flap failure and unacceptable aesthetic results. OBJECTIVE: We present three original ideas: 1) a bilobed flap may be considered as a hatchet flap with a Z-plasty; 2) the trap door deformity (TDD) associated with a bilobed flap can be used as an advantage; and 3) an easy method for preoperative planning of a bilobed flap. METHODS: We collected data from patients who underwent excision of basal cell carcinoma (BCC) of the distal third of the nose and reconstruction with a hatchet or a bilobed flap within the last 20 years. RESULTS: Favorable cosmetic results were achieved when a hatchet flap was used to reconstruct defects of the inferior third of the nasal side wall, above or bordered with the alar crease, and when a bilobed flap was used to reconstruct nasal tip para-medial defects above the lower lateral cartilage convexity. CONCLUSIONS: We suggest choosing between the hatchet and bilobed flaps for nasal reconstruction according to the defect location as outlined by our findings. PMID- 22206085 TI - Topical bimatoprost for the treatment of eyebrow hypotrichosis. AB - Topical bimatoprost was FDA approved in December of 2008 for the treatment of eyelash hypotrichosis. Since its approval, some physicians have advocated the use of bimatoprost "off label" for hair growth in other areas, such as the scalp or eyebrows, but there has yet to be published scientific evidence to support this use. We report one of the first cases of significant eyebrow hair growth in a patient after use of topical bimatoprost for eyebrow hypotrichosis. PMID- 22206086 TI - Persistent erythematous lesion of the vulva: a diagnostic and treatment challenge. AB - The painful, erythematous and eroded vulva often proves to be a diagnostic problem both clinically and histologically. Its differential diagnosis includes both non-neoplastic and neoplastic diseases like Bowen's disease and squamous cell carcinoma (SCC). We report the case of a 62-year-old woman diagnosed, after considerable delay, with Bowen's disease of the vulva that eventually progressed to invasive SCC, despite the treatment with imiquimod 5% cream. Our case indicates, on one hand, that dermoscopy could contribute to the accuracy of the pre-operative clinical diagnosis. On the other hand it confirms the fact that treatment of Bowen's disease of the vulva could be rather intriguing. Although imiquimod 5% cream is an effective, non-invasive treatment option for large lesions or poor healing sites, it should be administered with great consideration in carefully selected cases. PMID- 22206087 TI - Transient improvement in chronic psoriasis after treatment of TNF-alpha blocker induced disseminated M. tuberculosis infection. AB - Improvement in psoriasis after treatment of reactivated latent tuberculosis following initiation of TNF-alpha inhibitor therapy has yet to be described in the literature. The authors present a case of transient, yet significant, improvement in chronic plaque psoriasis after antibiotic therapy for reactivated TB. PMID- 22206088 TI - Necrobiotic xanthogranuloma of the extremities. PMID- 22206089 TI - Truth or fiction: risk factors for childhood atopic dermatitis. AB - Atopic dermatitis is increasing in prevalence throughout the developed world, in parallel with asthma and hay fever. The reasons for the increase remain unclear. As a practical question, it is valuable to understand which interventions might decrease risk for childhood atopic disease. Prospective studies among infants and children are challenging to design and to execute. Fortunately, several large studies from Europe and the United States are better characterizing whether behavioral interventions such as breastfeeding, delayed introduction of solid foods, hydrolyzed protein infant formulas, or pets in the home might be protective or impart increased risk of developing atopic dermatitis. As this body of literature grows, physicians will be able to recommend behavioral interventions that can prevent atopic dermatitis in individuals and ideally decrease prevalence over the population. PMID- 22206090 TI - Memories of the pioneering days of kidney transplantation. PMID- 22206091 TI - [Non-prescription antibiotics use]. PMID- 22206092 TI - Applied neurodynamics: from neural dynamics to neural engineering. PMID- 22206093 TI - International disease monitoring, July to September 2011. PMID- 22206094 TI - Characteristics of law enforcement officers' fatalities in motor vehicle crashes. PMID- 22206095 TI - Thread of idealism a lifeline to developing countries: emergency physician heads global effort to teach emergency care. PMID- 22206096 TI - Value over volume: value-based purchasing brings financial incentives for 13 core quality measures. PMID- 22206097 TI - Localized epidermolysis bullosa simplex (Weber-Cockayne type). PMID- 22206098 TI - Adolescents' fertility concerns: "I'm not trying to get pregnant, but if I did.". PMID- 22206099 TI - From nuclear physics to bone cell biology--Maureen Owen--1927-2011. PMID- 22206100 TI - Consensus report: E. coli O104:H4 (HUSEC041) and the potential threat to European water supplies. AB - Among the 3rd Seminar for PhD students working on Water and Health which was held in Cannes on 27-29 June 2011, experts from a number of universities and research institutes took the opportunity to discuss the emergence of Escherichia coli O104:H4 in Europe. Especially, possible threats for European water suppliers were considered. The consensus is summarized in this report. The main conclusion was that E. coli O104:H4 would not pose a substantial risk to well managed water supplies, especially where regular monitoring of indicator E. coli is negative. However, this may not apply for small and very small water systems which are quite common in Europe. New strategies like the Water Safety Plan approach are needed to protect also small scale drinking water systems and private wells in Europe. Water used in the processing of foods likely to be eaten raw, especially sprouts, should be of drinking water quality. PMID- 22206102 TI - Fluorous chemistry. Preface. PMID- 22206101 TI - Retraction notice to "From single neuron-firing to consciousness - towards the true solution of the binding problem" [Neurosci. Behav. Rev. 34 (2010) 993-1011]. PMID- 22206103 TI - Identification, diagnosis and treatment of wound infection. AB - The early identification of the subtle signs of increased bioburden in a wound enables timely and appropriate treatment and therefore improved patient outcomes. The rising costs of antimicrobial dressings and the growth in antibiotic resistant organisms increase the need for correct diagnosis. Indiscriminate use of antibiotics is a significant contributory factor in bacterial resistance. This article describes a new tool devised by a professional working group of tissue viability nurse specialists which is designed to help healthcare professionals to identify and manage bacterial burden in wounds. It is hoped that this will assist prompt diagnosis and help to reduce patient morbidity with appropriate and timely interventions. PMID- 22206115 TI - [The imagined city - ideologicoemblematic context and functionality: an essay in interpreting the city]. PMID- 22206116 TI - Fleeing dictatorship: socialism, sexuality and the history of science in the life of Aldo Mieli. PMID- 22206117 TI - Air hunger: the 1930 Johannesburg Conference and the politics of silicosis. PMID- 22206118 TI - Blacks and Gypsies in Nazi Germany: the limits of the "racial state". PMID- 22206119 TI - The administration of gender identity in Nazi Germany. PMID- 22206121 TI - President's message: history and heritage: forging the future. PMID- 22206122 TI - "The Trinite is our everlasting lover": marriage and Trinitarian love in the later Middle Ages. PMID- 22206123 TI - The regulation of sexuality in the late Middle Ages: England and France. PMID- 22206126 TI - Retraction of an original article in whole. PMID- 22206128 TI - Retraction notice. Investigating the needle dynamic response during insertion into soft tissue. PMID- 22206129 TI - Retraction notice. Controlling force variations during soft-tissue grasping. PMID- 22206130 TI - Fall in nurses but doctors increase. PMID- 22206131 TI - "Think outside the tick box to ensure equality in your trust". PMID- 22206132 TI - "If only a rub down with rose petals could cure ill health". PMID- 22206133 TI - "Why do nurses believe they are management material"? PMID- 22206134 TI - Improving person-centred care in dementia. AB - Failings in dementia care in acute hospitals have been reported to the Scottish Public Services Ombudsman and other scrutiny bodies in Scotland and the UK. This article sets out key knowledge and resources to help nurses provide compassionate and person-centred care. PMID- 22206135 TI - "Extending choice will let us set standards for children". PMID- 22206136 TI - Behaviour change to treat overactive bladder syndrome. AB - Overactive bladder syndrome has a negative impact on quality of life. This article discusses a definition of the condition and its the prevalence and aetiology, as well as some of the more common behavioural therapies. Although there is a good evidence base for bladder retraining, there is often conflicting research to support other interventions including caffeine reduction, the amount and types of fluid recommended, smoking cessation and weight reduction. A standardised approach from a national level is needed; nurses also need to demonstrate more robustly the effectiveness of their interventions. PMID- 22206137 TI - Faecal incontinence in critical illness. AB - Diarrhoea is a common problem in ICUs, occurring in as many as half of patients who are critically ill. There is a lack of specific guidance on the management of faecal incontinence in these patients. A literature review was used to identify best practice of faecal incontinence in patients in critical care and draw up local guidelines. A specific focus was put on the management of faecal incontinence to protect and heal damaged skin. Nurses are ideally placed to support patients with this condition. PMID- 22206138 TI - An infant with intussusception. PMID- 22206139 TI - Military matron. PMID- 22206140 TI - Area of desensitization following mental nerve block in dogs. AB - Regional nerve blocks are commonly used to provide analgesia for dental and oral surgical procedures. The purpose of this study was to demarcate the areas of the mandible that would be desensitized by application of the mental nerve block. Seven healthy mixed-breed dogs were anesthetized for an annual dental examination and professional teeth cleaning procedure. Bupivacaine HCl (0.4 ml/ m2) was administered at one middle mental foramen based on previously described techniques for the mental nerve block. A noxious stimulus was applied at 23 predetermined ipsilateral mandibular locations using pressure from a mosquito hemostat on the mucocutaneous junction (MCJ) and a dental curette on the vestibular mucogingival line (MGL) at the incisor canine, and premolar teeth; and, the mesial and distal aspects of the first molar tooth. A thermal stimulus using a refrigerant spray on a cotton ball was applied to the ipsilateral canine, third premolar and fourth premolar teeth; and, the mesial and distal aspects of the first molar tooth. Demonstration of nociception or anesthesia was noted and the responses tabulated. The area of desensitized tissues was smaller than expected and highly variable within the study group. In conclusion, the unilateral mental nerve block does not reliably provide generalized desensitization to tissues of the incisive and rostral regions of the mandible. Although the mental nerve block is recommended, other modes of analgesia should be emphasized for surgical and dental procedures involving these areas. PMID- 22206141 TI - Lingual lesions in the dog and cat: recognition, diagnosis, and treatment. AB - The tongue plays many vital roles in the oral cavity of the dog and cat. Consequently, lingual lesions can have devastating effects on an animal's overall health. This article provides a review of tongue anatomy as well as a review of the etiology, gross appearance, and diagnostic procedures indicated for a wide variety of lingual lesions. Lingual pathologic conditions that are reviewed include traumatic, metabolic, idiopathic, infectious, immune-mediated, hereditary, and neoplastic lesions. This article also describes current concepts in the medical management of lingual lesions. PMID- 22206142 TI - Sublingual reactive histiocytosis in a dog. AB - Lingual lesions are relatively uncommon in dogs and are mostly represented by neoplasms and glossitis secondary to trauma or infections. Reactive histiocytosis is an uncommon, poorly understood, reactive disorder characterized by proliferation of activated, interstitial, dendritic, antigen-presenting cells associated with lymphocytes and neutrophils with a specific angiocentric orientation and occasional angioinvasion and angiodestruction. Clinically, the disease has a waxing and waning behavior with possible response to treatment and regression, or progression to multiple lesions and internal organ involvement. This case report describes an unusual sublingual presentation of reactive histiocytosis in a Miniature Pinscher dog. The diagnosis was obtained by clinical and histopathological exclusion of other causes, detection of the characteristic microscopic growth pattern, and by immunocytochemistry. Histiocytic cells were vimentin, CD18, CD11c, and CD1c positive consistent with a dendritic cell origin. Anti-BCG stain (Bacillus Calmette and Guerin) was negative for etiological agents. The dog was treated with oral administration of tetracycline and niacinamide during an 8-month period. There was no indication of recurrence of the sublingual mass 2-years following treatment. PMID- 22206143 TI - Comparison of radiography and CT to identify changes in the skulls of four rabbits with dental disease. AB - Four domestic pet rabbits with dental pathology were presented at a university clinic. In addition to conducting physical examinations of the rabbits, radiographic and computed tomographic (CT) images of the rabbits' heads were obtained. Three rabbits were euthanized at the owners' request, and anatomic sections of the skulls were made. The observations of the anatomic sections, radiographs, and CT images are described. The abnormalities found on the radiographs and CT images were very similar to the findings on the anatomic sections. Compared to radiography, the CT images provided more details about the extent of the dental pathology, which is likely to be important for establishing a more precise prognosis and a more informed decision making process. PMID- 22206144 TI - Interceptive extraction of a persistent deciduous incisor tooth in a young horse. PMID- 22206145 TI - Essential considerations for equine oral examination, diagnosis, and treatment. AB - Equine dentistry should no longer be thought of as art over science. To be an effective equine dental clinician requires considerable investment in knowledge beyond the basic veterinary degree. It requires current scientific dental knowledge and adherence to the fundamental principles of medicine, dentistry, and surgery. Knowledge and principles will provide clinicians with the necessary information to make more evidence-based decisions as the scientific literature continues to evolve. Diagnosis and therapy should be seen as journeys with a destination, keeping in mind the values of the Hippocratic oath. Equine dentistry no longer needs to be seen as hard physical work with considerable risk to all involved. There is a demand for providers of equine dental care to be appropriately trained veterinarians and for veterinarians to further develop the science of equine dentistry. The rewards to the horse, client, and clinician are likely to be evident to those who make the investment. PMID- 22206146 TI - Major glossectomy in the dog. PMID- 22206147 TI - Our issues are global concerns. PMID- 22206148 TI - Ward's pressure ulcer care system 'priceless' for patients. PMID- 22206149 TI - Loss of Parkinson's role would 'cost NHS pound 42m'. PMID- 22206150 TI - Specialist nurses save money and improve care. PMID- 22206151 TI - Call bell response times. PMID- 22206152 TI - Telehealth. PMID- 22206153 TI - Management of osteoarthritis. AB - Many older people are affected by osteoarthritis (OA). The main symptoms of this chronic disease are pain, stiffness and potentially reduced function of affected joints. In severe OA the ability to engage in functional and social activities may be restricted and, as a consequence, quality of life may be affected. Nurses have an important role in pain assessment, education and support of people with OA in many different healthcare settings. PMID- 22206154 TI - Improving nursing home practice: an international concern. AB - The International Association of Gerontology and Geriatrics, in association with the World Health Organization, set up a task force in response to the urgent need to improve long-term care, and address the variations in standards of nursing home care worldwide. This task force was charged with identifying the main clinical, quality and research concerns and actions that would enhance the care provided in nursing homes. As a result, recommendations have been developed. The authors argue that nurses worldwide have a responsibility to support and implement the international nursing home development agenda. PMID- 22206155 TI - Caring for older adults with hearing loss. AB - This article discusses hearing impairment and the frequency with which it occurs in older adults. Anatomy and physiology of the ear are examined. Categories of hearing loss, causes, assessment and management are explored, including hearing aids, auditory implants and approaches to communication with hearing-impaired patients. PMID- 22206156 TI - A comparison of elderly care nursing in the UK and Japan. AB - AIM: The aim of this study was to gain insight into registered nurses' experiences of caring for older people in the UK and Japan. METHOD: Critical incident technique was used because of its ability to capture actual incidents from practice. Written, anonymous self-report data were collected during 2010. Participants were asked to recall two critical incidents where they had felt either rewarded or challenged at work. Data were analysed using thematic analysis. FINDINGS: Analysis revealed striking similarities in the experiences of nurses from both countries. Four main themes emerged: the challenges of a complex work environment; the challenges of resolving ethical conflicts; the rewards of establishing meaningful relationships; and the rewards of achieving excellence in individual patient care. CONCLUSION: The study provides new evidence from two different countries that although there are some challenges, nurses reap many rewards from working with older people. PMID- 22206157 TI - Cultural shift. PMID- 22206158 TI - Join our campaign to enable the best care. PMID- 22206159 TI - Nurse leaders set out their top ten objectives in bid to improve care. PMID- 22206160 TI - Health chiefs and unions draw up plans for mass pensions walk out. PMID- 22206161 TI - Passion and pride of new recruits revitalises permanent employees. PMID- 22206162 TI - Call for nurse leaders to be vetted by a national competency system. PMID- 22206163 TI - Join our drive to make quality care universal. PMID- 22206164 TI - Speaking up for change. PMID- 22206165 TI - It is time to address unfair attacks. PMID- 22206166 TI - Failures in care. PMID- 22206167 TI - Quality watch. PMID- 22206168 TI - Success in sight. AB - Staff working for a macular disease service in a London eye hospital have won an award for their work in providing a one-stop service. PMID- 22206169 TI - "There will be terrible casualties". AB - Royal College of Midwives general secretary Cathy Warwick is urging the government to act now to save UK maternity services from deteriorating further. PMID- 22206170 TI - VERA framework: communicating with people who have dementia. AB - This article presents a communication framework, devised by the authors, that could be used by healthcare professionals who come into contact with people who have dementia. The framework is based on four key concepts: validation, emotion, reassure and activity (VERA). It describes a stage-by-stage process of communication that guides nurses towards providing compassionate and caring responses. The framework was developed in response to students who said they find it useful to have structured guidance on how to interact with people who have dementia. The VERA framework offers a means of interpreting communication and responding appropriately. PMID- 22206171 TI - Experiences of home detoxification for alcohol dependency. AB - AIM: To identify the experiences of service users, family members and staff involved with a community alcohol service that provided home detoxification and psychosocial support. METHOD: Semi-structured interviews were conducted with service users, family members and staff (n=35). Comment sheets were sent to all service users and 22 were returned. Data were analysed using thematic analysis. FINDINGS: Participants were positive about the detoxification service and particularly valued the therapeutic relationship with nursing staff. Service users also valued the availability of psychosocial services. Contradictory views from service users and staff were identified regarding some aspects of the service. CONCLUSION: Service users were very satisfied with the community alcohol service and valued the support offered by nurses. PMID- 22206172 TI - Pelvic fractures: classification and nursing management. AB - Fractures to the pelvis can occur as a result of low-energy or high-energy trauma. Pelvic fractures may be associated with significant internal bleeding and injury to the organs within the pelvis. Patients with pelvic fractures often have complex healthcare needs; fractures resulting from high-energy trauma may be associated with multiple injuries, whereas fractures resulting from low-energy trauma, such as falls, may be associated with multiple patient comorbidities. Nurses have a fundamental role in the assessment and observation of the patient following pelvic fracture and are crucial in identifying any changes or deterioration in the patient's condition that require prompt intervention. This article focuses on the relevant anatomy of the pelvis, epidemiology and classification of pelvic fractures, and outlines the management and complications of pelvic fractures. PMID- 22206173 TI - Children's travel health. PMID- 22206174 TI - "Bombings and killings are routine". PMID- 22206175 TI - Crossing borders. PMID- 22206176 TI - Taking a practical approach. PMID- 22206177 TI - Bridging community dental practitioners to research: the South Texas Oral Health Network (STOHN). AB - Dental practice-based research networks (PBRNs) are a consortia of practices committed to supporting research projects aimed at improving clinical care. Participation in a PBRN provides investigative experience for dental practitioners as they contribute to the evidence base for dental practice, and it returns the information gained from the network back to the practices with the goal of improving the quality of care. The South Texas Oral Health Network (STOHN), affiliated with the University of Texas Health Science Center in San Antonio, was established through the Clinical Translational Science Award funded by the National Institutes of Health in May 2008. STOHN provides a centralized university-based infrastructure, a link to research resources, and an engine to move projects forward. This infrastructure allows dental practitioners and faculty to easily participate actively in research leading to collaborative community partnerships. STOHN's 31 members are very committed to participating in research activities and have contributed to research at each stage of its development. This article outlines an approach to building a research network, and it provides examples of clinical achievements from the dental practice-based research. PMID- 22206178 TI - Necrotizing ulcerative gingivitis: a discussion of four dissimilar presentations. AB - BACKGROUND: Necrotizing ulcerative gingivitis (NUG) is a periodontal disease characterized by pain, bleeding, and necrosis of interdental papillae. This series details treatment of four cases, followed by a discussion of the disease. CASE DESCRIPTION: Four patients presented to four practitioners for treatment of severe gingival pain, each eventually being diagnosed with NUG. All patients in this series were successfully treated using accepted protocols, and though each was different with regard to presenting signs and symptoms, all responded similarly to treatment. Similar to the patients described in this series, NUG cases in general can present with varying degrees of involvement from barely noticeable to starkly severe. CLINICAL IMPLICATIONS: The most severe cases of NUG are often more destructive in appearance than those most commonly seen in textbooks, while in the mildest cases the appearance can almost be mistaken for health. PMID- 22206179 TI - An interview with Dr Kenneth Kornman. Interview by David W Richards. AB - Inflammation is recognized as the major underlying contributor to a number of chronic diseases, amongst them periodontitis and cardiovascular diseases. The relationship between these diseases is explored and commented on in this question and-answer session between Ken Kornman, D.D.S., Ph.D., the editor of the Journal of Periodontology and David Richards, D.D.S., Ph.D., a former student of Dr. Kornman's. Practical suggestions and guidelines for the dentist are also examined. PMID- 22206180 TI - The Texas business margins tax--falling short of revenue expectations. PMID- 22206181 TI - The new "HHSC Texas Dental Program". PMID- 22206182 TI - The Texas Head Start Dental Home Initiative: Making a difference in the smiles of Head Start children. PMID- 22206183 TI - Texas' dental public health safety net. PMID- 22206184 TI - In the primary care setting, the value of adjunctive aids for oral cancer examinations remains unanswered (UT CAT #265). PMID- 22206185 TI - Perishing peridontal paradigms. PMID- 22206186 TI - Oral and maxillofacial pathology case of the month. Buccal bifurcation cyst. PMID- 22206187 TI - Changes in the credit card processing industry may affect you. PMID- 22206188 TI - Break the cycle of environmental health disparities in vulnerable children. PMID- 22206189 TI - Environmental health disparities in children. PMID- 22206190 TI - Environmental victims: environmental injustice issues that threaten the health of children living in poverty. AB - Children living in poverty are disproportionately at risk from and affected by environmental hazards. According to the National Center for Children in Poverty, 13 million children in America live in poverty. Thus, not only are millions of children living in poverty but are also living in environments that are hazardous to their health. Impoverished children are more likely to live in environments with heavily polluting industries, hazardous waste sites, contaminated water and soil, in old housing with deteriorating lead-based paint, in areas with limited access to healthy food, and more. Poor children residing in these toxic environments are either at risk or suffer from a myriad of health disparities, such as asthma, cancer, lead poisoning, obesity, and hyperactivity. This unfortunate reality is better known as environmental injustice. Environmental injustice recognizes that economically disadvantaged groups are adversely affected by environmental hazards more than other groups. To remedy this dilemma, environmental justice seeks to address these unfair burdens of environmental health hazards on poor communities. The purpose of this article is to (a) examine the environmental living conditions of children living in poverty, (b) examine the environmental health disparities of children living in poverty, (c) discuss environmental justice legislation, (d) describe government initiatives to improve environmental health, and (e) propose recommendations that executes measures to protect the health of children. PMID- 22206191 TI - Planning for the North Carolina healthy homes initiative. AB - Substandard housing conditions have been linked to widespread childhood environmental health ailments, including two of the leading causes of childhood morbidity: lead poisoning and asthma. In 2009, the United States Surgeon General called for action around healthy homes. Improving home health environments can alleviate the cycle of childhood morbidity and mortality. The North Carolina (NC) Department of Environment and Natural Resources Children's Environmental Health Branch is working to build capacity at the State level to expand the childhood lead poisoning prevention program to respond to additional in-home environmental health issues. To achieve this objective, North Carolina must consider recommendations for assessment, management, and evaluation. This paper will situate healthy homes on the national public health agenda; discuss ways that healthy homes programs address children's environmental health disparities; introduce the NC Healthy Homes Initiative; explore current healthy housing efforts in North Carolina through an examination of the Guilford County Healthy Homes Initiative; and provide recommendations for the NC Healthy Homes Initiative to address children's environmental health disparities. PMID- 22206192 TI - Combating childhood obesity: a survey of laws affecting the built environments of low-income and minority children. AB - Childhood overweight and obesity have reached epidemic proportions, with nearly one of every three children in the USA being affected. That factors in the built environment are closely correlated to childhood obesity has become increasingly evident. Negative built environment factors disproportionately affect poor and minority children. This paper examines the current research on the state of childhood overweight and obesity and surveys the built environment factors that have been linked to the problem. Analyzing the built environment from a legal perspective, this paper identifies how zoning, legislation, public/private partnerships, and contracts are being used at the local, state, and federal levels to combat the epidemic of childhood obesity. Using these tools, local, state, and federal government agencies are increasing access to healthy food, decreasing the density of unhealthy food sources, and increasing physical activity resources for children. Whereas some of the programs are geared toward minority and low-income children, many apply to children across the socioeconomic and demographic spectrum. PMID- 22206193 TI - The role of physical environment on student health and education in green schools. AB - The role of physical school environment on student health and education is becoming better understood. A growing body of literature indicates that improved physical environments in schools (e.g., indoor air quality, lighting, and acoustic conditions) can enhance student health outcomes. In parallel, the green building movement centers around designing buildings, including schools, that are more sustainable to decrease energy consumption, minimize environmental impact, and create healthier spaces for occupants. This paper synthesizes the findings from both green design studies and school outcomes studies to provide a systematic evaluation of the potential impacts of green school design features on student health outcomes. Three inter-related topics are covered in detail: (i) overview of the "green" concept, including existing guidelines for "greening" schools, attitudes toward green schools, and condition of the physical environments in non-green schools; (ii) potential effects of the physical environment on school children, including documentation of national statistics and summary of findings from school research studies; (iii) synthesis of findings, including a discussion of the knowledge gaps in the field of green school research and conclusions. PMID- 22206194 TI - The relationship between the built environment and birthweight. AB - A growing body of research has broadened the study of the relationship between the built environment and health from individual housing conditions, to include the larger neighborhood environment and its subsequent effects on the health outcomes of its residents. Research has connected measures of neighborhood quality to changes in health outcomes for residents, yet little work has been done to develop measures that capture and quantify the physical features of the neighborhood's manmade surroundings, also known as the built environment. This paper investigates the current literature detailing the relationship between the built environment and low birthweight and suggests potential interventions. Interventions developed at the county, neighborhood, and individual levels could aid community leaders and policymakers in breaking the cycle of low birthweight. PMID- 22206195 TI - Second hand smoke exposure in children: environmental factors, physiological effects, and interventions within pediatrics. AB - BACKGROUND: Second hand smoke (SHS) exposure has long been correlated with many adverse disease processes, particularly in children. For children growing up with socioeconomic disadvantages and increased exposure to SHS, exposure can have far reaching consequences. OBJECTIVE: The purpose of this review was to examine the literature assessing the effects of SHS exposure in children, as well as the perspectives of both parents and providers regarding current practices in cessation counseling. The review also sought out recommendations on ways to increase the influence of pediatricians on parental smoking. STUDY GROUP: Children under the age of 18 years. METHODS: PubMed and MEDLINE were searched systematically. A narrative approach was used because the studies differed in methods and data. RESULTS: The studies showed correlations between SHS exposure and sudden infant death syndrome (SIDS), asthma, altered respiratory function, infection, cardiovascular effects, behavior problems, sleep difficulties, increased cancer risk, and a higher likelihood of smoking initiation. Questionnaires of both parents and pediatricians showed that pediatricians are not consistently carrying out the recommended smoking cessation interventions, with lack of training as a primary barrier. Nevertheless, interventions targeting improved cessation training for both residents and practicing pediatricians have been studied and show promising results. CONCLUSIONS: SHS exposure has many detrimental effects on children's health, particularly for those in low socioeconomic circumstances, for which factors in the built environment accentuated a higher baseline risk. By counseling parents, expanding residency education, and continuing advocacy work, pediatricians can have a significant positive impact on children's health as related to SHS exposure. PMID- 22206196 TI - Mercury exposure education provided by women's health clinics in Duval County, Florida. AB - Duval County (Jacksonville, FL, USA) has a long history of environmental health hazards, especially prevalent within its urban core, referred to as Health Zone 1. In 2009, the Duval County Health Department conducted a survey of awareness of and actual exposure to methylmercury among women in the county. The survey found that women with more education or higher incomes had a higher awareness of potential mercury exposures. Furthermore, women in the urban core were less aware and had higher exposure than those in more affluent areas. This study assesses the mercury-exposure awareness and education by healthcare providers serving women of child-bearing age. We surveyed 28 women's health clinic offices. Sixty one percent (17/28) indicated that they provide mercury exposure education to female patients, either written or verbal. Of these, only half (8/17) provide written education materials. Ninety-three percent of the providers indicated that a benefit to providing education on mercury exposure, is having "healthier developing fetuses and young children in the community". Two barriers identified by providers to offering information on mercury exposure and risk were (a) a lack of interest among patients, and (b) a lack of clear, understandable educational materials. The long-term goal of our * -8project is to develop and distribute culturally effective, low literacy materials for distribution by health clinics, to document the increased awareness of mercury exposure risks, and to lessen the adverse health outcomes that may result from mercury exposure among vulnerable population groups in Duval County. PMID- 22206197 TI - Crawl spaces as reservoirs for transmission of mold to the livable part of the home environment. AB - BACKGROUND: Recent studies suggest that exposure to mold in damp buildings is an important environmental risk factor for childhood respiratory illness. One potential source of a damp home, is crawl space construction. A poorly constructed crawl space not only presents the possibility of contributing to a 'damp' home but can also become a reservoir for fungal growth. OBJECTIVES: Fungal levels in the livable indoor environment have been characterized in other studies, but little has been done to assess the potential for mold growth in the crawl space. This study examines the potential for mold growth and subsequent transmission from the crawl space into the home environment. METHODS: In this study, we assessed mold contamination levels within crawl spaces from 238 study homes in North Carolina. We determined whether air leakage from the heating, ventilation, and air conditioning (HVAC) system and associated ductwork, transmitted viable mold spores from the crawl space into the living spaces within the home. RESULTS: The results indicate that 19% of the homes demonstrated transmission of mold spores from the crawl space into the indoor environment, 45% of the homes displayed no transmission, and 36% of the homes were indeterminate. CONCLUSIONS: The results support the hypothesis that the HVAC system can serve as a conduit for the transmission of mold spores from the crawl space to the indoor environment of a home. This transmission likely affects children's health, given the significant amount of time they spend in the home environment. For low-income families, the HVAC system may contribute an additional source of childhood exposure and highlights the importance of the assessment of indoor environmental hazards. PMID- 22206198 TI - The association between urinary concentrations of dichlorophenol pesticides and obesity in children. AB - BACKGROUND: Increasing prevalence of childhood obesity has been seen in the United States and other parts of the world. Environmental chemical exposures might play a role in the worldwide obesity epidemic. OBJECTIVE: This study was conducted to assess the association of exposure to environmental pesticides with childhood obesity. METHODS: A total of 6770 subjects aged 6-19 years were selected from the 2003-2004 and 2005-2006 National Health and Nutrition Examination Survey (NHANES). Exposure to environmental pesticides was determined based on the concentrations of pesticide residues in urine. Multivariate logistic regression was performed using SAS 9.1.3 to assess the association between pesticide levels in urine and childhood obesity with the adjustment of potential confounders, including age, gender, race, income, and total fat intake. RESULTS: A dose-dependent increase in prevalence of obesity was observed in the groups with inter-quartile urinary concentrations of 2,5-dichlorophenol (2,5-DCP). Logistic regression revealed a significant association between adjusted third (Q3) (AOR: 1.47; 95% CI: 1.09, 1.97) and fourth (Q4) (AOR: 1.44; 95% CI: 1.06, 1.95) inter-quartile urinary 2,5-DCP levels and childhood obesity. However, urinary concentrations of 2,4-dichlorophenol were not shown to be significantly associated with childhood obesity. CONCLUSION: This study suggests a possible relationship between exposure to 2,5-DCP and obesity in children. PMID- 22206199 TI - Socioeconomic differences and the impact of being small for gestational age on neurodevelopment among preschool-aged children. AB - BACKGROUND: Studies of small for gestational age (SGA) birth and subsequent childhood cognitive outcomes are inconsistent. Few studies have assessed whether effects varied by socioeconomic status (SES). OBJECTIVE: To assess child cognitive and behavioral outcomes according to SGA and severe SGA (<10th and <5th percentiles) and SES. METHODS: We followed 474 infants initially selected for a case-control study assessing SGA vs. appropriate-for-gestational age (AGA). The infants were born at two hospitals: a public hospital serving a low-income, African-American population and a private hospital serving a predominantly white, middle-class population. At age 54 months, a psychologist administered the Differential Abilities Scales (DAS), and Vineland Adaptive Behavior Scales (VABS). The mother completed the Child Behavior Checklist (CBCL). Associations were analyzed using multiple linear regression. RESULTS: Among AGA children, the mean DAS score was >1 standard deviation lower for children born at the public vs. the private hospital (75.2 vs. 95.7 among boys; 76.3 vs. 101.8 among girls). Being SGA had a weaker effect on DAS scores, overall. Severe SGA had a significant effect on DAS scores of children born at the private hospital (average reduction 8.0 +/- 2.5 points), but not on children born at the public hospital (average reduction 1.1 +/- 2.2 points). In the latter group, severe SGA was associated with a lower VABS score (average reduction 9.2 +/- 2.5 points). CONCLUSIONS: Poor fetal growth influences neurodevelopment, but this influence is modified by postnatal environment. Adverse effects associated with low SES might mask or attenuate associations between prenatal exposures and developmental outcomes in some populations. PMID- 22206200 TI - [New national program for the prevention of suicide]. PMID- 22206201 TI - [Work which is making us ill]. AB - Whether they are the result of increased sensitivity or a real deterioration in working conditions, concerns regarding occupational health question the effects of managerial and technical innovations on the body and mind. While the explosion of occupational illnesses reveals an increased exposure of employees, all workers are not concerned in the same way. Will our ways of working be questioned by the emergence of psychosocial risks? PMID- 22206202 TI - [The added value of a nurse in the face of musculoskeletal problems]. AB - In a furniture factory in the Vendee, more and more employees, during their medical check-ups, were complaining of pain in their upper body. A study, carried out by a team, identified the main biomechanical factors at risk. Taking into account safety regulations and the ergonomics of the work stations, solutions were found to reduce the risks. PMID- 22206203 TI - [Psychosocial risks, symbols of uneasiness and suffering at work]. AB - The reality of psychosocial risks concerns all companies, all sectors and all professions, including freelancers and farmers. Employees, public sector workers, supervisors, managers, directors, no profile is spared from these new forms of suffering at work. The situation is especially worrying as the reality of this occupational health issue is almost certainly under-estimated. PMID- 22206204 TI - [Assessing the impact of psychological and organizational constraints on caregivers]. AB - Through a national cohort of more than 4000 nurses and nursing assistants in 14 university hospital centres, a study has developed a tool to assess the health of nursing staff within nursing units. This tool enables the general health condition of caregivers, as well as their working conditions, to be gauged. On this basis, preventative measures in terms of work organisation can be drawn up. PMID- 22206205 TI - [A psychologist's insight to understand the suffering of caregivers at work]. AB - During their interviews with the staff psychologist, caregivers evoke numerous reasons for their unease. Difficulties relating to their work are the first to be mentioned: a search for a sense of purpose, a lack of communication with their colleagues and time with their patients. However, sometimes, this suffering felt by caregivers may be linked to deep-rooted personal issues which can reappear at work, disconcerting them in their professional practice. PMID- 22206206 TI - [Occupational health nursing, a new aspect of a profession under construction]. AB - Being an occupational health nurse means having chosen prevention. Aside from practising in large companies, more and more professionals are providing intercompany services. This enables employees in small and very small companies to benefit from interviews and essential nursing advice which highlight the strong links between work and health. Occupational health teams must be able to fulfil their role of informing employees and putting forward proposals. PMID- 22206207 TI - [I wish the younger nurses as much pleasure as I've had in my career]. PMID- 22206208 TI - [The components of an ethical approach]. AB - A new bi-monthly feature in La revue de l'Infirmiere on the theme of ethics and the resulting dilemmas, so often encountered in nursing contexts. Far from being prescriptive and giving turnkey solutions, we will open the debate on ethical questioning. One which envisages the scope of possibilities and searches for the best decision for each particular situation. This first article offers elements of methodology. PMID- 22206209 TI - [Measuring pulse oximetry at the patient's bedside]. AB - Pulse oximetry, or oxygen saturation, reflects the quantity of oxygen fixed to the haemoglobin. It is commonly measured in a non invasive way, with the aid of a digital sensor oximeter. The results can be distorted by a number of parameters, it is therefore necessary to eliminate the risk of errors and to check the results against clinical data. PMID- 22206210 TI - [Home-based care in Senegal]. AB - Kine Sow is a home caregiver in the Senegalese village of Ndienne. With no initial connection with the medical world, she has been trained to fight against malaria. She carries out quick diagnostic tests and hands out medicines. A unique system set up by Dakar to fight against the disease in rural areas. PMID- 22206211 TI - [A cyber lounge to reinforce elderly people's social ties]. AB - Contact with family and friends is essential for elderly people. A multi professional working group studied ways in which these social and family ties could be reinforced in nursing homes. By using new communication technologies, a "cyber lounge" project using the internet has been established in Fontainebleau's hospital centre. PMID- 22206212 TI - [Clinical approach in vulvar cancer surgery]. AB - Vulva cancer is rare. It is mainly treated through surgery. Recurrent scarring complications can prolong the period of hospitalisation. To reduce scar dihiscence, the nursing team of the Oscar Lambret Centre in Lille treats scars by negative pressure as a preventative measure. It also integrates into its clinical approach the prevention of pain and malnutrition. PMID- 22206213 TI - Preventing the elderly from choking on food. PMID- 22206214 TI - [The nurse and the care of the craniocerebral trauma patient]. PMID- 22206215 TI - [Nervous system diseases with psychiatric manifestations]. PMID- 22206216 TI - [Interprofessional collaboration on campus]. PMID- 22206217 TI - [Ascites puncture]. PMID- 22206218 TI - Evolution of dynamic combinatorial chemistry. AB - Since its inception in the mid-1990s, dynamic combinatorial chemistry (DCC), the chemistry of complex systems under thermodynamic control, has proved valuable in identifying unexpected molecules with remarkable binding properties and in providing effective synthetic routes to complex species. Essentially, in this approach, one designs the experiment rather than the molecule. DCC has also provided us with insights into how some chemical systems respond to external stimuli. Using examples from the work of our laboratory and others, this Account shows how the concept of DCC, inspired by the evolution of living systems, has found an increasing range of applications in diverse areas and has evolved conceptually and experimentally. A dynamic combinatorial library (DCL) is a thermodynamically controlled mixture of interconverting species that can respond to various stimuli. The Cambridge version of dynamic combinatorial chemistry was initially inspired by the mammalian immune system and was conceived as a way to create and identify new unpredictable receptors. For example, an added template can select and stabilize a strongly binding member of the library which is then amplified at the expense of the unsuccessful library members, minimizing the free energy of the system. But researchers have exploited DCC in a variety of other ways: over the past two decades, this technique has contributed to the evolution of chemistry and to applications in the diverse fields of catalysis, fragrance release, and responsive materials. Among these applications, researchers have built intricate and well-defined architectures such as catenanes or hydrogen bonded nanotubes, using the ability of complex chemical systems to reach a high level of organization. In addition, DCC has proved a powerful tool for the study of complex molecular networks and systems. The use of DCC is improving our understanding of chemical and biological systems. The study of folding or self replicating macrocycles in DCLs has served as a model for appreciating how complex organisations such as life can emerge from a pool of simple chemicals. Today, DCC is no longer restricted to thermodynamic control, and new systems have recently appeared in which kinetic and thermodynamic control coexist. Expanding the realm of DCC to unexplored and promising new territories, these hybrid systems show that the concept of dynamic combinatorial chemistry continues to evolve. PMID- 22206219 TI - Triarylboron-functionalized Cu(II) carboxylate paddlewheel complexes. AB - The assembly of two copper(II)-carboxylate dimer complexes appended with four peripheral triarylborane functionalities has been achieved. Complex stabilities in the presence of fluoride are examined. PMID- 22206222 TI - Glass transition temperature and beta relaxation temperature around chain end of polystyrene determined by site specific spin labeling. AB - A glass transition temperature, T(g), and a beta relaxation temperature, T(beta), of spin-labeled polystyrene (PS) having a number average molecular weight (M(n)) of ca. 25 kDa were determined by the microwave power saturation (MPS) method of electron spin resonance (ESR). Spin labeling was selectively carried out at chain ends or midchain segments. This method allowed us to determine the local T(g) and the local T(beta) around the spin-labeled sites, selectively. The T(g) determined by the ESR, T(g,ESR), was in good agreement with that determined by differential scanning calorimetry, T(g,DSC); the T(g,ESR) decreased with decreasing M(n) with blending oligomers as well as the T(g,DSC). The T(g,ESR) for the end-labeled PS (PS-E) was equal to that for the midchain-labeled PS (PS-M) irrespective of the M(n). However, we previously reported that the PS-E showed distinctly higher segmental mobility than the PS-M in the temperature range 423-463 K (above T(g)). Therefore, we conclude that the chain ends intrinsically have higher segmental mobility than midchain segments due to the discontinuity of repeat units; however, the mobilities of chain ends and midchain segments are averaged out in the vicinity of T(g) due to the cooperativities with neighboring numerous chain segments. Concerning the beta relaxation, the T(beta) determined by the MPS was in good agreement with those determined by dielectric and dynamic mechanical spectroscopies and dilatometry. The T(beta) of the PS-E was the same with that of the PS-M within experimental uncertainties; the T(beta) was insensitive to the M(n) in contrast to the T(g). Therefore, we conclude that the effect of chain end is little on the beta relaxation of PS due to its local character. In addition, the effect of annealing at 353 K was found to be the same for the T(beta)s of the PS-E and PS-M. PMID- 22206223 TI - HIV risk behaviors among a sample of heterosexually identified men who occasionally have sex with another male and/or a transwoman. AB - Discordance between sexual identity and sexual behavior is not new; however, little is known about the HIV risk behaviors of heterosexually identified men who have occasional sex with a male and/or a male-to-female transgender woman. Open ended qualitative interviews were conducted with 31 heterosexually identified men who reported at least one sexual encounter with a male and/or a transwoman in the previous 12 months. Sixty-one percent were African American/Black, the mean age was 38.9 years (SD = 8.4), 58.1% reported current substance use, and 58.1% were HIV infected. Among those who had a sexual encounter with a transwoman, the majority (81.3%) were the insertive partner during anal sex. In comparison, among those who had a sexual encounter with a male partner, almost one-half (42.9%) were the receptive partner during anal sex. HIV-infected participants were more likely to use a condom with a biological female partner than with a male or transwoman partner. HIV-uninfected participants reported limited condom use with any partner type, highlighting their potential role in the diffusion of HIV and other sexually transmitted infections. Participants' HIV status, partner type, substance use, and cultural factors influenced sexual decision-making and HIV risk behaviors. PMID- 22206225 TI - Insights into the mechanistic dichotomy of the protein farnesyltransferase peptide substrates CVIM and CVLS. AB - Protein farnesyltransferase (FTase) catalyzes farnesylation of a variety of peptide substrates. (3)H alpha-secondary kinetic isotope effect (alpha-SKIE) measurements of two peptide substrates, CVIM and CVLS, are significantly different and have been proposed to reflect a rate-limiting S(N)2-like transition state with dissociative characteristics for CVIM, while, due to the absence of an isotope effect, CVLS was proposed to have a rate-limiting peptide conformational change. Potential of mean force quantum mechanical/molecular mechanical studies coupled with umbrella sampling techniques were performed to further probe this mechanistic dichotomy. We observe the experimentally proposed transition state (TS) for CVIM but find that CVLS has a symmetric S(N)2 TS, which is also consistent with the absence of a (3)H alpha-SKIE. These calculations demonstrate facile substrate-dependent alterations in the transition state structure catalyzed by FTase. PMID- 22206226 TI - Tidally driven export of dissolved organic carbon, total mercury, and methylmercury from a mangrove-dominated estuary. AB - The flux of dissolved organic carbon (DOC) from mangrove swamps accounts for 10% of the global terrestrial flux of DOC to coastal oceans. Recent findings of high concentrations of mercury (Hg) and methylmercury (MeHg) in mangroves, in conjunction with the common co-occurrence of DOC and Hg species, have raised concerns that mercury fluxes may also be large. We used a novel approach to estimate export of DOC, Hg, and MeHg to coastal waters from a mangrove-dominated estuary in Everglades National Park (Florida, USA). Using in situ measurements of fluorescent dissolved organic matter as a proxy for DOC, filtered total Hg, and filtered MeHg, we estimated the DOC yield to be 180 (+/-12.6) g C m(-2) yr(-1), which is in the range of previously reported values. Although Hg and MeHg yields from tidal mangrove swamps have not been previously measured, our estimated yields of Hg species (28 +/- 4.5 MUg total Hg m(-2) yr(-1) and 3.1 +/- 0.4 MUg methyl Hg m(-2) yr(-1)) were five times greater than is typically reported for terrestrial wetlands. These results indicate that in addition to the well documented contributions of DOC, tidally driven export from mangroves represents a significant potential source of Hg and MeHg to nearby coastal waters. PMID- 22206228 TI - Phylogenetic analysis of human immunodeficiency virus type 1 subtype C env gp120 sequences among four drug-naive families following subsequent heterosexual and vertical transmissions. AB - To characterize phylogenetic relatedness of plasma HIV-1 RNA subtype C env gp120 viral variants capable of establishing an infection following heterosexual and subsequent vertical transmission events a 650-base pair fragment within the C2-V5 subregion was sequenced from four HIV-1-infected families each consisting of biological parent(s), index children (first), and subsequent (second) siblings. None of the family members had received antiretroviral therapy at the time of sample collection. Sequence alignment and analysis were done using Gene Doc, Clustal X, and MEGA software programs. Second siblings' sequences were homogeneous and clustered in a single branch while first siblings' sequences were more heterogeneous, clustering in separate branches, suggestive of more than one donor variants responsible for the infection or evolution from founder variant(s) could have occurred. While the directionality for heterosexual transmission could not be determined, homogeneous viral variants were a unique characteristic of maternal variants as opposed to the more heterogeneous paternal variants. Analysis of families' sequences demonstrated a localized expansion of the subtype C infection. We demonstrated that families' sequences clustered quite closely with other regional HIV-1 subtype C sequences supported by a bootstrap value of 86%, confirming the difficulty of classifying subtype C sequences on a geographic basis. Data are indicative of several mechanisms that may be involved in both vertical and heterosexual transmission. Larger studies are warranted to address the caveats of this study and build on the strengths. Our study could be the beginning of family-based HIV-1 intervention research in Zimbabwe. PMID- 22206231 TI - Ugi-Smiles couplings of 4-substituted pyridine derivatives: a fast access to chloroquine analogues. AB - 4-Hydroxy and mercapto pyridines were successfully tested in Ugi-Smiles couplings. Such multicomponent reactions applied to quinoline derivatives afford a very convenient and short synthesis of antimalarial analogues. PMID- 22206232 TI - Yield of single- and double-strand breaks and nucleobase lesions in fully hydrated plasmid DNA films irradiated with high-LET charged particles. AB - We measured the yield and spectrum of strand breaks and nucleobase lesions produced in fully hydrated plasmid DNA films to determine the linear energy transfer (LET) dependence of DNA damage induced by ion-beam irradiation in relation to the change in the atomic number of ions. The yield of isolated damage was revealed as a decrease in prompt SSBs with increasing LET of He(2+), C(5+,6+) and Ne(8+,10+) ions. On the other hand, the yields of prompt DSBs increased with increasing ion LET. SSBs were additionally induced in ion-irradiated DNA film by treatment with two kinds of base excision repair proteins (glycosylases), Nth and Fpg, indicating that base lesions are produced in the hydrated DNA film. This result shows that nucleobase lesions are produced via both chemical reactions with diffusible water radicals, such as OH radicals, and direct energy deposition onto DNA and the hydrated water layer. Nth-sensitive sites deduced to be pyrimidine lesions, such as 5,6-dihydrothymine (DHT), showed a relatively larger yield than Fpg-sensitive sites deduced to be purine lesions, such as 7,8-dihydro 8-oxo-2'deoxyguanine (8-oxoGua), for all ion exposures tested. The yield of SSBs or DSBs observed by enzyme treatment decreased noticeably with increasing LET for all tested ions. These results indicated that higher-LET ions preferentially produce a complex type of damage that might compromise the activities of the glycosylases used in this study. These findings are biologically important since, under cell mimicking conditions, persistent DNA damage occurs in part due to direct energy deposition on the DNA or hydrated water shell that is specifically induced by dense ionization in the track. PMID- 22206233 TI - Risk of lung cancer mortality in relation to lung doses among French uranium miners: follow-up 1956-1999. AB - The aim of this study was to assess the risk of lung cancer death associated with cumulative lung doses from exposure to alpha-particle emitters, including radon gas, radon short-lived progeny, and long-lived radionuclides, and to external gamma rays among French uranium miners. The French "post-55" sub-cohort included 3,377 uranium miners hired from 1956, followed up through the end of 1999, and contributing to 89,405 person-years. Lung doses were calculated with the ICRP Human Respiratory Tract Model (Publication 66) for 3,271 exposed miners. The mean "absorbed lung dose" due to alpha-particle radiation was 78 mGy, and that due to the contribution from other types of radiation (gamma and beta-particle radiation) was 56 mGy. Radon short-lived progeny accounted for 97% of the alpha particle absorbed dose. Out of the 627 deaths, the cause of death was identified for 97.4%, and 66 cases were due to lung cancer. A significant excess relative risk (ERR) of lung cancer death was associated with the total absorbed lung dose (ERR/Gy = 2.94, 95% CI 0.80, 7.53) and the alpha-particle absorbed dose (4.48, 95% CI 1.27, 10.89). Assuming a value of 20 for the relative biological effectiveness (RBE) of alpha particles for lung cancer induction, the ERR/Gy-Eq for the total weighted lung dose was 0.22 (95% CI: 0.06, 0.53). PMID- 22206234 TI - Early and extensive CD55 loss from red blood cells supports a causal role in malarial anaemia. AB - BACKGROUND: Levels of complement regulatory proteins (CrP) on the surface of red blood cells (RBC) decrease during severe malarial anaemia and as part of cell ageing process. It remains unclear whether CrP changes seen during malaria contribute to the development of anaemia, or result from an altered RBC age distribution due to suppressive effects of malaria on erythropoiesis. METHODS: A cross sectional study was conducted in the north-east coast of Tanzania to investigate whether the changes in glycosylphosphatidylinositol (GPI)-anchored complement regulatory proteins (CD55 and CD59) contributes to malaria anaemia. Blood samples were collected from a cohort of children under intensive surveillance for Plasmodium falciparum parasitaemia and illness. Levels of CD55 and CD59 were measured by flow cytometer and compared between anaemic (8.08 g/dl) and non- anaemic children (11.42 g/dl). RESULTS: Levels of CD55 and CD59 decreased with increased RBC age. CD55 levels were lower in anaemic children and the difference was seen in RBC of all ages. Levels of CD59 were lower in anaemic children, but these differences were not significant. CD55, but not CD59, levels correlated positively with the level of haemoglobin in anaemic children. CONCLUSION: The extent of CD55 loss from RBC of all ages early in the course of malarial anaemia and the correlation of CD55 with haemoglobin levels support the hypothesis that CD55 may play a causal role in this disorder. PMID- 22206237 TI - Publisher's Notes. PMID- 22206235 TI - Influenza A/H1N1 septic shock in a patient with systemic lupus erythematosus. A case report. AB - BACKGROUND: Immunocompromised patients, such as systemic lupus erythematosus (SLE) sufferers have an increased risk of mortality, following influenza infection. In the recent pandemic, influenza A H1NI virus caused 18449 deaths, mainly because of adult respiratory distress syndrome or bacterial co-infections. CASE PRESENTATION: In this case report, an SLE patient with viral-induced septic shock, without overt pulmonary involvement, is discussed. The patient was administered oseltamivir and supportive treatment, including wide-spectrum antibiotics, vasopressors and steroids, according to the guidelines proposed for bacterial sepsis and septic shock. She finally survived and experienced a lupus flare soon after intensive care unit (ICU) discharge. CONCLUSIONS: To our knowledge, this is the first case to report severe septic shock from influenza A/H1N1 virus, without overt pulmonary involvement. PMID- 22206238 TI - Reducing cancer risk with vitamins C, e, and selenium. AB - Abstract Current research has provided evidence that nearly 90 percent of all cancers may be related to diet, environment, and lifestyle. Of this number, 30 to 40 percent of cancers in men and up to 60 percent of cancers in women may be related to diet and nutrition. The two-stage process in the formation of many cancers, defined as initiation and promotion, is influenced by many dietary components. Vitamins C, E, and the mineral selenium are nutrients that function as antioxidants, reducing potential cancer-causing chemicals in the body. These natural anticarcinogens are thought to alter the cancer process and are currently under study for their cancer prevention properties. The functions, Recommended Dietary Allowances, food sources, research evidence for cancer prevention, and recommendations for supplementation are presented for these three nutrients. Research suggests that the proper and prudent use of nutrients, along with a healthy diet and lifestyle, may offer protection against this devastating disease. PMID- 22206239 TI - Physical characteristics related to coronary heart disease risk factors: comparison of hispanics and navajo, acoma and laguna indians in new Mexico. AB - Abstract The Checkerboard Cardiovascular Curriculum (CCC) project was designed to develop a culturally-oriented educational program for reducing coronary heart disease (CHD) risk factors in rural American Indians and Hispanics in the state of New Mexico. Because so little information is available on children from these ethnic groups, the purposes of this paper are: 1) to describe and compare some physical characteristics of Hispanics and Navajo, Laguna and Acoma Indians which are associated with CHD risk factors; and 2) to assess the short-term effectiveness of the CCC in altering these CHD risk factors. Body weight, height, blood pressure, one mile walk/run data, and triceps, subscapula, and calf skinfold thicknesses were collected for 97 boys and 79 girls from the four ethnic groups. Results of analyses of covariance (ANCOVA), controlling for age, indicated ethnic differences for all dependent variables. The average body mass index of all Indian children exceeded the median values reported in the second National Health and Nutrition Examination Survey (NHANES-II). The average sum of the triceps and subscapula skinfolds of the children from all ethnic groups failed to meet acceptable standards established by The National Children and Youth Fitness Study (NCYFS). The results of the CCC project suggest that these children are in need of health promotion and physical fitness programs that emphasize obesity and cardiovascular fitness and provide for ethnic and cultural differences. PMID- 22206240 TI - Exercise adherence research: future directions. PMID- 22206241 TI - Business aspects of health promotion. PMID- 22206242 TI - Networking. PMID- 22206244 TI - Resource reviews. PMID- 22206245 TI - Perspectives beyond health promotion. PMID- 22206247 TI - Developing independent investigators for clinical research relevant for Africa. AB - Sustainable research capacity building requires training individuals at multiple levels within a supportive institutional infrastructure to develop a critical mass of independent researchers. At many African medical institutions, a PhD is important for academic promotion and is, therefore, an important focal area for capacity building programs. We examine the training at the Infectious Diseases Institute (IDI) as a model for in-country training based on systems capacity building and attention to the academic environment. PhD training in Africa should provide a strong research foundation for individuals to perform independent, original research and to mentor others. Training the next generation of researchers within excellent indigenous academic centers of excellence with strong institutional infrastructure will empower trainees to ask regionally relevant research questions that will benefit Africans. PMID- 22206248 TI - The type XIV family of C-type lectin-like domain (CTLD) containing proteins. PMID- 22206249 TI - CD248: reviewing its role in health and disease. AB - CD248, also known as endosialin or tumor endothelial marker-1 (TEM-1), is a C type lectin-like domain (CTLD) containing cell surface glycoprotein that is expressed by stromal cells of proliferating tissues during embryogenesis and postnatally in tumors and inflammatory lesions. Loss-of-function studies in mice support the notion that CD248 promotes tumor growth and inflammation, observations that are stimulating interest in evaluating this molecule as a therapeutic target. In spite of these advances, the mechanisms by which CD248 modulates cancer and inflammation remain largely enigmatic. This review highlights our current understanding of CD248, its structure, pattern of expression, regulation and function in various disease processes. PMID- 22206250 TI - Thrombomodulin links coagulation to inflammation and immunity. AB - Thrombomodulin (TM) is a type 1 membrane bound glycoprotein that has a C-type lectin domain at its Nterminus, 6 copies of the epidermal growth factor-like (EGF) motif and serine/threonine rich domain carrying a glycosoaminoglycan external to the membrane. TM binds thrombin changing thrombin's substrate specificity from procoagulant and pro-inflammatory to anti-coagulant and anti inflammatory because of the activation of protein C (PC) and thrombin-activatable fibrinolysis inhibitor (TAFI). Thrombin's anion binding site 1 binds to TM's EGF domains 5 and 6. EGF4 is required for PC activation and EGF3 and 4 for TAFI activation in addition to EGF56. The X-ray structure of thrombin bound to TM has been solved and shows few major alterations in the active site of thrombin. The lectin domain can bind high mobility group box protein 1 (HMGB1) and a sugar, Lewis Y. TM's lectin domain behaves as an antagonist to HMGB1 endowing it with intrinsic anti-inflammatory activity. Treatment of dendritic cells with TM converts them from immunogenic to tolerogenic. TM is necessary for maintenance of pregnancy as well as prevention of coagulation throughout life. Soluble TM has been developed as an anticoagulant possessing favorable pharmacokinetics that has been approved for treatment of disseminated intravascular coagulation in Japan. PMID- 22206251 TI - CD93: recent advances and implications in disease. AB - While it has been known for some time that CD93 regulates several processes involved in innate immunity and inflammation including phagocytosis and adhesion, the function of CD93 in disease progression is only now being elucidated. Recent in vivo studies in mice, and genome wide studies in mice and humans, have provided clues about its molecular function. Following a comprehensive review of CD93 expression patterns, this review will focus on recent findings over the last three years that address the putative function of CD93 in inflammation and innate immunity. PMID- 22206252 TI - Bacterial virulence and the development of novel antimicrobial approaches. PMID- 22206253 TI - The role of streptokinase as a virulence determinant of Streptococcus pyogenes- potential for therapeutic targeting. AB - Streptococcus pyogenes is a major human pathogen responsible for numerous diseases ranging from uncomplicated skin and throat infections to severe, life threatening invasive disease such as necrotising fasciitis and streptococcal toxic shock syndrome. These severe invasive infections progress rapidly and produce high rates of morbidity and mortality despite the implementation of aggressive treatment plans. The activation of plasminogen and the acquisition of plasmin activity at the bacterial cell surface is critical for the invasive pathogenesis of this organism. To facilitate this process, S. pyogenes secrete streptokinase, a potent plasminogen activating protein. Here, we describe the role of streptokinase in invasive pathogenesis and discuss some potentially useful strategies for disruption of streptokinase mediated plasminogen activation which could be employed to treat severe invasive S. pyogenes infections. PMID- 22206254 TI - Knowing is half the battle: targeting virulence factors of group A Streptococcus for vaccine and therapeutics. AB - Group A Streptococcus (GAS) is a leading human pathogen that causes a multitude of diseases from pharyngitis, and impetigo, to more severe outcomes such as rheumatoid arthritis and necrotizing fasciitis. GAS remains a global burden as currently no vaccine exists that is completely effective. In this review we highlight recent studies on the virulence of GAS and present several approaches that have extended those findings into aims at combating GAS disease. These and other studies such as recent genome-wide efforts into host-pathogen relationships of GAS disease will likely reveal new targets of intervention. Given the recent rise in GAS strains that have acquired resistance to several types of antibiotics, it is crucial that we continue to increase our knowledge of the mechanisms underlying GAS disease. PMID- 22206255 TI - Combat pneumococcal infections: adhesins as candidates for protein-based vaccine development. AB - Streptococcus pneumoniae (pneumococcus) is an asymptomatic colonizer of the upper respiratory tract in humans. However, these apparently harmless bacteria have also a high virulence potential and are known as the etiologic agent of respiratory and life-threatening invasive diseases. Dissemination of pneumococci from the nasopharynx into the lungs or bloodstream leads to community-acquired pneumonia, septicaemia and meningitis. Traditionally, pneumococcal diseases are treated with antibiotics and prevented with polysaccharide-based vaccines. However, due to the dramatic increase in antibiotic resistance and limitations of the current available vaccines, the burden of diseases remains high. Thus, combating pneumococcal transmission and infections has emphasized the need for a new generation of protein-based vaccines. Interactions of pneumococci with soluble host proteins or cellular receptors are crucial for adherence, colonization, transmigration of host barriers and immune evasion. Therefore, surface-exposed proteins involved in these pathogenic processes and virtually expressed by all pneumococcal strains and serotypes are the prime potential targets for an immunogenic and highly protective pneumococcal-derived carrier protein of a vaccine. In this review, we will address the state of the art in deciphering, i). the conservation, distribution and pathogenic role of recently discovered pneumococcal adhesins in colonization and invasive diseases, ii). the interactions of these virulence factors with host-proteins and receptors, iii). the subversion of the host immune and cellular responses, and iv). the potential of pneumococcal adhesins as vaccine candidates. PMID- 22206256 TI - The type III secretion system as a source of novel antibacterial drug targets. AB - Type III Secretion Systems (T3SSs) are highly organized multi-protein nanomachines which translocate effector proteins from the bacterial cytosol directly into host cells. These systems are required for the pathogenesis of a wide array of Gram-negative bacterial pathogens, and thus have attracted attention as potential antibacterial drug targets. A decade of research has enabled the identification of natural products, conventional small molecule drug like structures, and proteins that inhibit T3SSs. The mechanism(s) of action and molecular target(s) of the majority of these inhibitors remain to be determined. At the same time, structural biology methods are providing an increasingly detailed picture of the functional arrangement of the T3SS component proteins. The confluence of these two research areas may ultimately identify non-classical drug targets and facilitate the development of novel therapeutics. PMID- 22206258 TI - Screening strategies to identify new antibiotics. AB - The emergence of multi-drug resistant bacteria is one of the most critical medical problems currently facing humankind, which will only get worse if no new antibacterial drugs are launched. This article will first review commonly used screening strategies used to identify potential new antibiotics and then discuss novel screening methods. In addition, new assays, methods, biological targets and compounds with novel modes of action undergoing pre-clinical or clinical development are briefly discussed. PMID- 22206259 TI - Applications of biophysical tools to target-based discovery of novel antibacterial leads. AB - New antibacterial drugs are urgently needed to combat the growing problem of multidrug resistant bacterial infections. Major advances in bacterial genomics have uncovered many unexploited targets, leading to the possibility of discovering new antibacterials with novel mechanisms that would circumvent resistance. Many of these targets are soluble enzymes that vary in their degrees of mechanistic complexity. Protein crystallography as well as solution based biophysical methods are playing an increasingly important role in selecting, characterizing and validating promising targets as well as identifying and optimizing lead compounds that inhibit their functions. Advances made in recent years in sensitivity, resolution and throughput of biophysical tools are allowing multiple approaches to screening for hits and rational design of leads based on a deeper understanding of structure-activity relationships. However, the path from a lead compound to a safe and efficacious antibacterial drug still remains challenging. Structural and biophysical approaches have had less of an impact on this later phase of discovery than on the lead generation phase. PMID- 22206260 TI - High-throughput graphene imaging on arbitrary substrates with widefield Raman spectroscopy. AB - Raman spectroscopy has been used extensively to study graphene and other sp(2) bonded carbon materials, but the imaging capability of conventional micro-Raman spectroscopy is limited by the technique's low throughput. In this work, we apply an existing alternative imaging mode, widefield Raman imaging (WRI), to image and characterize graphene films on arbitrary substrates with high throughput. We show that WRI can be used to image graphene orders of magnitude faster than micro Raman imaging allows, while still obtaining detailed spectral information about the sample. The advantages of WRI allow characterization of graphene under conditions that would be impossible or prohibitively time-consuming with other techniques, such as micro-Raman imaging or reflected optical microscopy. To demonstrate these advantages, we show that WRI enables graphene imaging on a large variety of substrates (copper, unoxidized silicon, suspended), large-scale studies of defect distribution in CVD graphene samples, and real-time imaging of dynamic processes. PMID- 22206261 TI - One building block, two different nanoporous self-assembled monolayers: a combined STM and Monte Carlo study. AB - With the use of a single building block, two nanoporous patterns with nearly equal packing density can be formed upon self-assembly at a liquid-solid interface. Moreover, the formation of both of these porous networks can be selectively and homogenously induced by changing external parameters like solvent, concentration, and temperature. Finally, their porous properties are exploited to host up to three different guest molecules in a spatially resolved way. PMID- 22206264 TI - Crystal growth, structure, and physical properties of LnCu2(Al,Si)5 (Ln = La and Ce). AB - LnCu(2)(Al,Si)(5) (Ln = La and Ce) were synthesized and characterized. These compounds adopt the SrAu(2)Ga(5) structure type and crystallize in the tetragonal space group P4/mmm with unit cell dimensions of a ~ 4.2 A and c ~ 7.9 A. Herein, we report the structure as obtained from single crystal X-ray diffraction. Additionally, we report the magnetic susceptibility, magnetization, resistivity, and specific heat capacity data obtained for polycrystalline samples of LnCu(2)(Al,Si)(5) (Ln = La and Ce). PMID- 22206262 TI - High prevalence of Pneumocystis jirovecii colonization in Brazilian cystic fibrosis patients. AB - A high rate of Pneumocystis jirovecii colonization was observed in Brazilian cystic fibrosis (CF) patients (13 out of 34; 38.2%) who underwent bronchoscopy between March 2006 and August 2009 at the Hospital de Clinicas de Porto Alegre, Brazil. Bronchoalveolar lavage samples were collected from these patients and studied by nested PCR amplification of the mitochondrial gene coding for the large subunit ribosomal RNA (mtLSUrDNA). The observed rate of colonization was higher than that reported in European populations. Genotypic characterization of the mtLSUrDNA locus revealed a predominance of the polymorphisms 85C/248C (genotype 1) and 85T/248C (genotype 3), with all samples possessing the wild-type genotype of dihydropteroate synthase. These findings suggest that cystic fibrosis patients could be an important reservoir and source of P. jirovecii infection. Further studies are required to elucidate the role of this common fungal colonization in the evolution of CF patients. PMID- 22206257 TI - Architecture and conservation of the bacterial DNA replication machinery, an underexploited drug target. AB - New antibiotics with novel modes of action are required to combat the growing threat posed by multi-drug resistant bacteria. Over the last decade, genome sequencing and other high-throughput techniques have provided tremendous insight into the molecular processes underlying cellular functions in a wide range of bacterial species. We can now use these data to assess the degree of conservation of certain aspects of bacterial physiology, to help choose the best cellular targets for development of new broad-spectrum antibacterials. DNA replication is a conserved and essential process, and the large number of proteins that interact to replicate DNA in bacteria are distinct from those in eukaryotes and archaea; yet none of the antibiotics in current clinical use acts directly on the replication machinery. Bacterial DNA synthesis thus appears to be an underexploited drug target. However, before this system can be targeted for drug design, it is important to understand which parts are conserved and which are not, as this will have implications for the spectrum of activity of any new inhibitors against bacterial species, as well as the potential for development of drug resistance. In this review we assess similarities and differences in replication components and mechanisms across the bacteria, highlight current progress towards the discovery of novel replication inhibitors, and suggest those aspects of the replication machinery that have the greatest potential as drug targets. PMID- 22206266 TI - Algal uptake of hydrophobic and hydrophilic dissolved organic nitrogen in effluent from biological nutrient removal municipal wastewater treatment systems. AB - Dissolved organic nitrogen (DON) accounts for a large fraction of the total nitrogen discharged to surface waters by municipal wastewater treatment plants designed for biological nutrient removal (BNR). Previous research indicates that some but not all of the DON in wastewater effluent is available to bacteria and algae over time scales that are relevant to rivers and estuaries. To separate bioavailable DON from nitrate and less reactive DON species, an XAD-8 resin coupled with an anion exchange treatment was employed prior to chemical analysis and algal bioassays. Analysis of effluent samples from a range of municipal BNR plants (total DON concentrations ranging from 0.7 to 1.8 mg N/L) employing a range of technologies indicated that hydrophilic DON, which typically accounted for approximately 80% of the total DON, stimulated algal growth, whereas hydrophobic DON, which accounted for the remaining DON, remained at nearly constant concentrations and had little or no effect on algal growth during a 14 day incubation period. The hydrophobic DON exhibits characteristics of humic substances, and is likely to persist for long periods in the aquatic environment. The distinct differences between these two classes of DON may provide a basis for considering them separately in water quality models and effluent discharge regulations. PMID- 22206265 TI - Workshop summary: Novel biomarkers for HIV incidence assay development. AB - Reliable methods for measuring human immunodeficiency virus (HIV) incidence are a high priority for HIV prevention. They are particularly important to assess the population-level effectiveness of new prevention strategies, to evaluate the community-wide impact of ongoing prevention programs, and to assess whether a proposed prevention trial can be performed in a timely and cost-efficient manner in a particular population and setting. New incidence assays and algorithms that are accurate, rapid, cost-efficient, and can be performed on easily-obtained specimens are urgently needed. On May 4, 2011, the Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), sponsored a 1-day workshop to examine strategies for developing new assays to distinguish recent from chronic HIV infections. Participants included leading investigators, clinicians, public health experts, industry, regulatory specialists, and other stakeholders. Immune-based parameters, markers of viral sequence diversity, and other biomarkers such as telomere length were evaluated. Emerging nanotechnology and chip-based diagnostics, including algorithms for performing diverse assays on a single platform, were also reviewed. This report summarizes the presentations, panel discussions, and the consensus reached for pursuing the development of a new generation of HIV incidence assays. PMID- 22206269 TI - Influence of the chemical functionalities of a molecularly imprinted conducting polymer on its sensing properties: electrochemical measurements and semiempirical DFT calculations. AB - Starting from thiophene-based functional monomers (FM), namely, TMA, TAA, TMeOH, EDOT, and Th, bonded to atrazine (ATZ) target molecules into FM/ATZ prepolymerization dimers in acetonitrile solutions, differently functionalized molecularly imprinted conducting polymers (FM-MICP) are electrosynthesized and then washed and used as sensitive layers for ATZ recognition. Sensitivity of these layers toward ATZ, which is quantified by cyclic voltammetric measurements, decreases in the following order of functional monomers: TMA, TAA, TMeOH, EDOT, and Th. Absolute values of the FM-ATZ dimerization free energies are calculated with the help of DFT/PCM calculations and of an empirical correction of the entropy effects, using a modified Wertz formula. A strong correlation is found between FM-MICP sensitivity and the amount of FM/ATZ prepolymerization complexes. PMID- 22206270 TI - Dynamics of pyrophosphate ion release and its coupled trigger loop motion from closed to open state in RNA polymerase II. AB - Pyrophosphate ion (PP(i)) release after nucleotide incorporation is a necessary step for RNA polymerase II (pol II) to enter the next nucleotide addition cycle during transcription elongation. However, the role of pol II residues in PP(i) release and the mechanistic relationship between PP(i) release and the conformational change of the trigger loop remain unclear. In this study, we constructed a Markov state model (MSM) from extensive all-atom molecular dynamics (MD) simulations in the explicit solvent to simulate the PP(i) release process along the pol II secondary channel. Our results show that the trigger loop has significantly larger intrinsic motion after catalysis and formation of PP(i), which in turn aids PP(i) release mainly through the hydrogen bonding between the trigger loop residue H1085 and the (Mg-PP(i))(2-) group. Once PP(i) leaves the active site, it adopts a hopping model through several highly conserved positively charged residues such as K752 and K619 to release from the pol II pore region of the secondary channel. These positive hopping sites form favorable interactions with PP(i) and generate four kinetically metastable states as identified by our MSM. Furthermore, our single-mutant simulations suggest that H1085 and K752 aid PP(i) exit from the active site after catalysis, whereas K619 facilitates its passage through the secondary channel. Finally, we suggest that PP(i) release could help the opening motion of the trigger loop, even though PP(i) release precedes full opening of the trigger loop due to faster PP(i) dynamics. Our simulations provide predictions to guide future experimental tests. PMID- 22206271 TI - The effects of varying protein and energy intakes on the growth and body composition of very low birth weight infants. AB - OBJECTIVE: To determine the effects of high dietary protein and energy intake on the growth and body composition of very low birth weight (VLBW) infants. STUDY DESIGN: Thirty-eight VLBW infants whose weights were appropriate for their gestational ages were assessed for when they could tolerate oral intake for all their nutritional needs. Thirty-two infants were included in a longitudinal, randomized clinical trial over an approximate 28-day period. One control diet (standard preterm formula, group A, n = 8, 3.7 g/kg/d of protein and 129 kcal/kg/d) and two high-energy and high-protein diets (group B, n = 12, 4.2 g/kg/d and 150 kcal/kg/d; group C, n = 12, 4.7 g/kg/d and 150 kcal/kg/d) were compared. Differences among groups in anthropometry and body composition (measured with bioelectrical impedance analysis) were determined. An enriched breast milk group (n = 6) served as a descriptive reference group. RESULTS: Groups B and C displayed greater weight gains and higher increases in fat-free mass than group A. CONCLUSION: An intake of 150 kcal/kg/d of energy and 4.2 g/kg/d of protein increases fat-free mass accretion in VLBW infants. PMID- 22206272 TI - Electrospun core-shell fibers for robust silicon nanoparticle-based lithium ion battery anodes. AB - Because of its unprecedented theoretical capacity near 4000 mAh/g, which is approximately 10-fold larger compared to those of the current commercial graphite anodes, silicon has been the most promising anode for lithium ion batteries, particularly targeting large-scale energy storage applications including electrical vehicles and utility grids. Nevertheless, Si suffers from its short cycle life as well as the limitation for scalable electrode fabrication. Herein, we develop an electrospinning process to produce core-shell fiber electrodes using a dual nozzle in a scalable manner. In the core-shell fibers, commercially available nanoparticles in the core are wrapped by the carbon shell. The unique core-shell structure resolves various issues of Si anode operations, such as pulverization, vulnerable contacts between Si and carbon conductors, and an unstable sold-electrolyte interphase, thereby exhibiting outstanding cell performance: a gravimetric capacity as high as 1384 mAh/g, a 5 min discharging rate capability while retaining 721 mAh/g, and cycle life of 300 cycles with almost no capacity loss. The electrospun core-shell one-dimensional fibers suggest a new design principle for robust and scalable lithium battery electrodes suffering from volume expansion. PMID- 22206274 TI - Contact of oil with solid surfaces in aqueous media probed using sum frequency generation spectroscopy. AB - We have studied the interface between hexadecane droplets and sapphire substrates in water using infrared-visible sum frequency generation spectroscopy (SFG). At high pH and above the isoelectric point of the sapphire substrate, the hexadecane drop is repelled due to electrostatic forces. The SFG measurements are consistent with the observation that a thick layer of water is present between the oil and the sapphire substrate. Below the isoelectric point of the sapphire substrate, the hexadecane drops stick to the sapphire surface. Surprisingly, the SFG results show the presence of a thin layer of water between hexadecane drop and the sapphire substrate. At this contact interface, we observe contributions to the SFG signal from both the hexadecane/water and water/sapphire interfaces. The reasons for the presence of a thin water layer with adhesive contact can be explained due to weaker repulsive double layer and the attractive van der Waals interactions. PMID- 22206275 TI - Nucleic acid templated uncaging of fluorophores using Ru-catalyzed photoreduction with visible light. AB - Hybridization-based reactions have attracted significant attention. The nucleic acid templated photocatalyzed azide reduction using catalytic amounts of a [Ru(bpy)(2)phen](2+) conjugate is reported. The reaction could be performed with as little as 2% of the Ru nucleic acid probe and was shown to productively unquench 7-azido-coumarin as well as uncage a small molecule. PMID- 22206276 TI - Diffusion and adsorption of uranyl carbonate species in nanosized mineral fractures. AB - Atomistic simulations were performed to study the diffusion and adsorption of Ca(2)UO(2)(CO3)3 and of some of its constituent species, i.e., UO(2)2+, CO(3)2-, and UO(2)CO3, in feldspar nanosized fractures. Feldspar is important to uranium remediation efforts at the U.S. Department of Energy Hanford site as it has been found in recent studies to host contaminants within its intragrain fractures. In addition, uranyl carbonate species are known to dominate U(VI) speciation in conditions relevant to the Hanford site. Molecular dynamics (MD) simulations showed that the presence of the feldspar surface diminishes the diffusion coefficients of all of the species considered in this work and that the diffusion coefficients do not reach their bulk aqueous solution values in the center of a 2.5 nm fracture. Moreover, the MD simulations showed that the rate of decrease in the diffusion coefficients with decreasing distance from the surface is greater for larger adsorbing species. Free energy profiles of the same species adsorbing on the feldspar surface revealed a large favorable free energy of adsorption for UO(2)2+ and UO(2)CO3, which are able to adsorb to the surface with their uranium atom directly bonded to a surface hydroxyl oxygen, whereas adsorption of CO(3)2- and Ca(2)UO(2)(CO3)3, which attach to the surface via hydrogen bonding from a surface hydroxyl group to a carbonate oxygen, was calculated to be either only slightly favorable or unfavorable. PMID- 22206279 TI - Publisher's Notes. PMID- 22206277 TI - Binding of phthalate plasticizers to human serum albumin in vitro: a multispectroscopic approach and molecular modeling. AB - As endocrine-disrupting chemicals, a few frequently used phthalate plasticizers were banned or restricted for use as additives in food in some countries. The interaction mechanisms between three phthalate plasticizers with human serum albumin (HSA) were studied by fluorescence (quenching, synchronous, and three dimensional), UV-vis absorption, circular dichroism (CD), and Fourier transform infrared (FT-IR) spectroscopy, in combination with molecular modeling under simulative physiological conditions, respectively. The results obtained from fluorescence quenching data revealed that the plasticizers-HSA interaction altered the conformational strcture of HSA. Meanwhile, the alterations of HSA secondary structure in the presence of phthalate plasticizers were investigated. The binding distances for the plasticizers-HSA system were provided by the efficiency of fluorescence resonance energy transfer. Furthermore, the thermodynamic analysis implied that hydrophobic forces were the main interaction for the plasticizers-HSA system, which agreed well with the results from the molecular modeling study. PMID- 22206280 TI - Beyond blood pressure screening: a rationale for promoting the primary prevention of hypertension. AB - Abstract High blood pressure is a major public health problem in the United States. However, the underlying reasons for the chronic elevation of blood pressure (BP) are unknown in most cases of hypertension (HT), and medical care has focused on lowering already elevated BP, primarily by pharmacologic means. Although an important factor in the development of HT appears to be a genetic predisposition, other potentially modifiable lifestyle risk factors associated with elevated BP have been identified. This article describes the scientific rationale for encouraging health promotion specialists to focus on the primary prevention of abnormally elevated blood pressure. Nonbehavioral risk factors such as increasing age, history of HT, Black ancestry, and consistent BP readings in the higher range of normality, and behavioral factors including dietary excesses and deficiencies, excessive body fat, a sedentary life style, and frequent episodes of unmanageable emotional stress are addressed. Recommendations are made based on scientific evidence supporting the relationships between these risk factors and the development of HT. PMID- 22206281 TI - Dietary factors related to physical fitness among navy shipboard men. AB - Abstract This study examines the relationship between habitual dietary practices and performance on the physical readiness test required of active duty Navy personnel. Participants were 1,013 men (mean age = 26.2 years) stationed aboard nine Navy ships. The men completed a self-report survey of lifestyle and dietary habits and were evaluated on four tests of physical fitness: 1.5-mile Run, Sit-ups, Sit-reach, and Percent Body Fat. A standardized Overall Fitness score was also computed for each person. Results indicated that the participants tended to skip breakfast, ingest moderate amounts of caffeine, and favor a high fat, low-fiber diet. Fitness scores were associated with a number of dietary variables, including caffeine intake, between-meal snacking, and overeating (all negatively related to fitness, p <.01), and having a general "nutrition orientation" (positively related to fitness, p <.001). The relationships were confounded by the influence of age, exercise, and smoking, but even after controlling for these, diet was a significant predictor of fitness (p <.001). PMID- 22206282 TI - Validity of a Children's Health Locus of Control Measure: A "Heart Smart" Study. AB - Abstract Questionnaires used in health promotion programs are too rarely subjected to tests of reliability and validity prior to their use. Without such tests, any information gathered must be suspect. The complexity of such tests is illustrated by the investigation of the validity of a revised version of the Multidimensional Health Locus of Control (MHLC) Scales. Confirmatory maximum likelihood factor analysis was used to analyze data from 519 elementary school students. The concurrent validity of the revised MHLC was also evaluated by conducting an interbattery factor analysis that included data from selected "marker" items from the measure developed by Parcel and his colleagues. The results supported the validity of the revised MLHC Scales when used with children. PMID- 22206284 TI - Business aspects of health promotion. PMID- 22206283 TI - Research and evaluation results. PMID- 22206285 TI - Networking. PMID- 22206287 TI - Resource reviews. PMID- 22206288 TI - Perspectives beyond health promotion. PMID- 22206291 TI - The role of ALOX5AP, LTA4H and LTB4R polymorphisms in determining baseline lung function and COPD susceptibility in UK smokers. AB - BACKGROUND: We have previously shown evidence that polymorphisms within genes controlling leukotriene B4 (LTB4) production (ALOX5AP and LTA4H) are associated with asthma susceptibility in children. Evidence also suggests a potential role of LTB4 in COPD disease mechanisms including recruitment of neutrophils to the lung. The aim of the current study was to see if these SNPs and those spanning the receptor genes for LTB4 (LTB4R1 and LTB4R2) influence baseline lung function and COPD susceptibility/severity in smokers. METHODS: Eight ALOX5AP, six LTA4H and six LTB4R single nucleotide polymorphisms (SNPs) were genotyped in a UK Smoking Cohort (n = 992). Association with baseline lung function (FEV1 and FEV1/FVC ratio) was determined by linear regression. Logistic regression was used to compare smoking controls (n = 176) with spirometry-defined COPD cases (n = 599) and to more severe COPD cases (GOLD stage 3 and 4, n = 389). RESULTS: No association with ALOX5AP, LTA4H or LTB4R survived correction for multiple testing. However, we showed modest association with LTA4H rs1978331C (intron 11) with increased FEV1 (p = 0.029) and with increased FEV1/FVC ratio (p = 0.020). CONCLUSIONS: These data suggest that polymorphisms spanning ALOX5AP, LTA4H and the LTB4R locus are not major determinants of baseline lung function in smokers, but provide tentative evidence for LTA4H rs1978331C (intron 11) in determining baseline FEV1 and FEV1/FVC ratio in Caucasian Smokers in addition to our previously identified role in asthma susceptibility. PMID- 22206293 TI - Genomic sequencing in clinical trials. AB - Human genome sequencing is the process by which the exact order of nucleic acid base pairs in the 24 human chromosomes is determined. Since the completion of the Human Genome Project in 2003, genomic sequencing is rapidly becoming a major part of our translational research efforts to understand and improve human health and disease. This article reviews the current and future directions of clinical research with respect to genomic sequencing, a technology that is just beginning to find its way into clinical trials both nationally and worldwide. We highlight the currently available types of genomic sequencing platforms, outline the advantages and disadvantages of each, and compare first- and next-generation techniques with respect to capabilities, quality, and cost. We describe the current geographical distributions and types of disease conditions in which these technologies are used, and how next-generation sequencing is strategically being incorporated into new and existing studies. Lastly, recent major breakthroughs and the ongoing challenges of using genomic sequencing in clinical research are discussed. PMID- 22206294 TI - Canada's Physical Activity Guide: examining print-based material for motivating physical activity in the workplace. AB - The authors conducted a secondary analysis on 202 adults from the Physical Activity Workplace Study. The aim of this analysis was to examine demographic characteristics associated with reading Canada's Physical Activity Guide (CPAG), being motivated by the guide, and whether participants in the Physical Activity Workplace Study who read the CPAG increased their physical activity levels over 1 year. Results revealed that less than 50% of participants read the full version of CPAG, and less than 10% were motivated by it. The CPAG also appears to be more appealing to and effective for women than for men. Although the CPAG had some influence in increasing mild physical activity levels in a workplace sample, there was also a decrease in physical activity levels among some members of the group. Overall, the effectiveness of CPAG was not substantial, and the findings of this analysis could help guide future targeted intervention materials and programs. PMID- 22206295 TI - Formation of phosphino-substituted isocyanate by reaction of CO2 with group 2 complexes based on the (Me3Si)(i-Pr2P)NH ligand. AB - The group 2 complexes [(Me(3)Si)(i-Pr(2)P)N](2)M(THF)(x) (M = Mg, x = 1; M = Ca/Sr, x = 2) as well as an unusual dimagnesium complex {[(Me(3)Si)(i Pr(2)P)N](3)Mg}Mg(n-C(4)H(9)) have been prepared and characterized by multinuclear NMR spectroscopy and single crystal X-ray diffraction. Each complex was shown to react with CO(2) under extremely mild conditions (15 min, 1 atm, room temperature) to give the isocyanate (i-Pr)(2)P-N?C?O. The independent syntheses of (i-Pr)(2)P-N?C?O and the carbodiimide dimer [(i-Pr)(2)PNCNP(i Pr)(2)](2) are also reported. PMID- 22206297 TI - Formation of one-dimensional electronic states along the step edges of CeO2(111). AB - Scanning tunneling microscopy (STM) combined with density functional theory (DFT) are used to analyze the structural and electronic properties of step edges on the surface of CeO(2)(111) films grown on Ru(0001). Depending on the preparation conditions, 211 or 110-oriented steps develop on the surface, which results in the formation of ceria ad-islands with hexagonal or triangular shapes. STM conductance spectroscopy reveals pronounced differences in the electronic properties of the step edges, as reflected in different onset positions of the ceria conduction band. The band shifts are related to the development of distinct edge electronic states that split-off from the ceria conduction band, as shown with DFT calculations. The separation of the edge states from the main band is governed by the atom-coordination and local charge-distribution along the edge, the latter giving rise to the development of electrostatic dipoles. We expect that the observed edge morphologies determine not only the electronic properties but also the adsorption behavior of step edges on the CeO(2)(111) surface. PMID- 22206299 TI - Microsecond time-scale conformational exchange in proteins: using long molecular dynamics trajectory to simulate NMR relaxation dispersion data. AB - With the advent of ultra-long MD simulations it becomes possible to model microsecond time-scale protein dynamics and, in particular, the exchange broadening effects (R(ex)) as probed by NMR relaxation dispersion measurements. This new approach allows one to identify the exchanging species, including the elusive "excited states". It further helps to map out the exchange network, which is potentially far more complex than the commonly assumed 2- or 3-site schemes. Under fast exchange conditions, this method can be useful for separating the populations of exchanging species from their respective chemical shift differences, thus paving the way for structural analyses. In this study, recent millisecond-long MD trajectory of protein BPTI (Shaw et al. Science 2010, 330, 341) is employed to simulate the time variation of amide (15)N chemical shifts. The results are used to predict the exchange broadening of (15)N lines and, more generally, the outcome of the relaxation dispersion measurements using Carr Purcell-Meiboom-Gill sequence. The simulated R(ex) effect stems from the fast (~10-100 MUs) isomerization of the C14-C38 disulfide bond, in agreement with the prior experimental findings (Grey et al. J. Am. Chem. Soc. 2003, 125, 14324). PMID- 22206301 TI - Underdiagnosis of malnutrition in infants and young children in Rwanda: implications for attainment of the Millennium Development Goal to end poverty and hunger. AB - Progress towards the first Millennium Development Goal (MDG1) to end poverty and hunger has lagged behind attainment of other MDGs due to chronic poverty and worldwide inequity in access to adequate health care, food, clean water, and sanitation. Despite ongoing challenges, Rwanda has experienced economic progress and the expansion of the national public health system during the past 20 years. However, protein-energy malnutrition in children under five is still a major concern for physicians and government officials in Rwanda. Approximately 45% of children under the age of five in Rwanda suffer from chronic malnutrition, and one in four is undernourished. For years, health facilities in Rwanda have used incorrect growth references for measuring nutritional status of children despite the adoption of new standards by the World Health Organization in 2006. Under incorrect growth references used in Rwanda, a number of children under five who were severely underweight were not identified, and therefore were not treated for malnutrition, thus potentially contributing to the under five mortality rate. Given that one in ten children suffer from malnutrition worldwide, it is imperative that all countries with a burden of malnutrition adopt the most up-to date international standards for measuring malnutrition, and that the problem is brought to the forefront of international public health initiatives. For low income countries in the process of improving economic conditions, as Rwanda is, increasing the identification and treatment of malnutrition can promote the advancement of MDG1 as well as physical and cognitive development in children, which is imperative for advancing future economic progress. PMID- 22206302 TI - Synthesis and characterization of a lithium-doped fullerane (Li(x)-C60-H(y)) for reversible hydrogen storage. AB - Herein, we present a lithium-doped fullerane (Li(x)-C(60)-H(y)) that is capable of reversibly storing hydrogen through chemisorption at elevated temperatures and pressures. This system is unique in that hydrogen is closely associated with lithium and carbon upon rehydrogenation of the material and that the weight percent of H(2) stored in the material is intimately linked to the stoichiometric ratio of Li:C(60) in the material. Characterization of the material (IR, Raman, UV-vis, XRD, LDI-TOF-MS, and NMR) indicates that a lithium-doped fullerane is formed upon rehydrogenation in which the active hydrogen storage material is similar to a hydrogenated fullerene. Under optimized conditions, a lithium-doped fullerane with a Li:C(60) mole ratio of 6:1 can reversibly desorb up to 5 wt % H(2) with an onset temperature of ~270 degrees C, which is significantly less than the desorption temperature of hydrogenated fullerenes (C(60)H(x)) and pure lithium hydride (decomposition temperature 500-600 and 670 degrees C respectively). However, our Li(x)-C(60)-H(y) system does not suffer from the same drawbacks as typical hydrogenated fullerenes (high desorption T and release of hydrocarbons) because the fullerene cage remains mostly intact and is only slightly modified during multiple hydrogen desorption/absorption cycles. We also observed a reversible phase transition of C(60) in the material from face centered cubic to body-centered cubic at high levels of hydrogenation. PMID- 22206304 TI - Uranyl and/or rare-earth mellitates in extended organic-inorganic networks: a unique case of heterometallic cation-cation interaction with U(VI)?O-Ln(III) bonding (Ln = Ce, Nd). AB - A series of uranyl and lanthanide (trivalent Ce, Nd) mellitates (mel) has been hydrothermally synthesized in aqueous solvent. Mixtures of these 4f and 5f elements also revealed the formation of a rare case of lanthanide-uranyl coordination polymers. Their structures, determined by XRD single-crystal analysis, exhibit three distinct architectures. The pure lanthanide mellitate Ln(2)(H(2)O)(6)(mel) possesses a 3D framework built up from the connection of isolated LnO(6)(H(2)O)(3) polyhedra (tricapped trigonal prism) through the mellitate ligand. The structure of the uranyl mellitate (UO(2))(3)(H(2)O)(6)(mel).11.5H(2)O is lamellar and consists of 8-fold coordinated uranium atoms linked to each other through the organic ligand giving rise to the formation of a 2D 3(6) net. The third structural type, (UO(2))(2)Ln(OH)(H(2)O)(3)(mel).2.5H(2)O, involves direct oxygen bondings between the lanthanide and uranyl centers, with the isolation of a heterometallic dinuclear motif. The 9-fold coordinated Ln cation, LnO(5)(OH)(H(2)O)(3), is linked to the 7-fold coordinated uranyl (UO(2))O(4)(OH) (pentagonal bipyramid) via one MU(2)-hydroxo group and one MU(2)-oxo group. The latter is shared between the uranyl bonding (U?O = 1.777(4)/1.779(6) A) and a long Ln-O bonding (Ce-O = 2.822(4) A; Nd-O = 2.792(6) A). This unusual linkage is a unique illustration of the so-called cation-cation interaction associating 4f and 5f metals. The dinuclear motif is then further connected through the mellitate ligand, and this generates organic-inorganic layers that are linked to each other via discrete uranyl (UO(2))O(4) units (square bipyramid), which ensure the three-dimensional cohesion of the structure. The mixed U-Ln carboxylate is thermally decomposed from 260 to 280 degrees C and then transformed into the basic uranium oxide (U(3)O(8)) together with U-Ln oxide with the fluorite structural type ("(Ln,U)O(2)"). At 1400 degrees C, only fluorite type "(Ln,U)O(2)" is formed with the measured stoichiometry of U(0.63)Ce(0.37)O(2) and U(0.60)Nd(0.40)O(2 delta). PMID- 22206305 TI - Calixarene-based surfactants: evidence of structural reorganization upon micellization. AB - The self-aggregation of five amphiphilic p-sulfonatocalix[n]arenes bearing alkyl chains at the lower rim was investigated by NMR spectroscopy and electrical conductivity. The critical micelle concentration was determined, and the tendency of this special class of surfactants to self-aggregate in aqueous solution was analyzed as a function of the alkyl chain length and the number of aromatic units in the macrocyclic ring. The structure of the surfactants in the monomeric and micellized states was elucidated by means of (1)H NMR and, in the case of the calix[6]arene derivative, with 2D NMR experiments. While all amphiphilic calix[4]arenes studied here are blocked in the cone conformation, in the monomeric state the calix[6]arene adopts a pseudo-1,2,3-alternate conformation and the calix[8]arene is conformationally mobile. These calixarenes undergo an aggregation-induced conformational change, adopting the cone conformation in the micelles. The structure and size of the aggregates were studied by diffusion ordered spectroscopy (DOSY) experiments, and the results indicate that these surfactants self-assemble into ellipsoidal micelles. PMID- 22206328 TI - Publisher's Notes. PMID- 22206306 TI - Colorimetric sensing of fluoride ion by new expanded calix[4]pyrrole through anion-pi interaction. AB - Three new expanded calix[4]pyrroles were synthesized, where the two dialkylldipyrromethane units are linked via C-C double bonds. One of them, calix[2]bispyrrolylethene, colorimetrically senses fluoride ion only, owing to anion-pi interaction in polar aprotic solvents. PMID- 22206329 TI - Incidence and reasons for medical referral in a worksite health promotion program. AB - Abstract The purpose of this study was to examine incidence and reasons for medical referral as a result of screening performed in a worksite health promotion program. Screening consisted of a medical history questionnaire, blood lipid profile, a submaximal treadmill stress test to 85% of age-predicted maximal heart rate, and other fitness measures. Overall, 11.5% of participants were referred to their personal physician for medical reasons following testing. Males (rate = 23.3%) were significantly more likely to be referred than females (rate = 8.8%). No significant difference was found in the percent of male (89.3%) or female (78.5%) referrals who were subsequently cleared to actively participate in the worksite program by their personal physician. These findings have important practical applications for worksite health promotion programs that conduct health screening. PMID- 22206330 TI - A randomized trial of physician training for smoking cessation. AB - Abstract This randomized controlled trial investigated the effects of a smoking cessation workshop on physician practices and on patients' smoking behavior. Eighty-three community family physicians were randomly allocated by practice to either 1) a Usual Care condition, 2) a group in which physicians were not trained but were asked to address smoking cessation with specific patients, or 3) a condition which included physician training as well as printed resources and in which specific patients were identified as smokers. The intervention taught to the physicians through a four hour training workshop included providing advice about stopping smoking, the setting of a date for stopping, the offer of nicotine gum, take-home materials, and the offer of follow-up visits. The intervention was described, demonstrated, and the physicians practiced with simulated patients. The outcome of the intervention was assessed in terms of physician behavior and patient smoking behavior. Exit interviews with patients demonstrated that patients of trained physicians did not differ from patients of untrained physicians on how willing they were to try to stop smoking nor on their receptiveness to nicotine gum. However, there was a small but statistically significant difference favoring the patients from the trained physician group who successfully stopped smoking. PMID- 22206331 TI - Employee stress claims: increasing implications for health promotion programming. AB - Abstract Characterized as "the Nation's fastest growing occupational disease" by the National Council on Compensation Insurance, stress has become a major issue for corporate leaders today. With the recent rise in high cost stress claims, organizations have become interested in preventing potential stress problems. This article discusses types of stress claims, individual and occupational risks, reasons given for filing claims, efforts aimed at prevention, and future outlooks. Finally, the implications for health promotion programming in providing a multi-dimensional approach to preventing the physical, psychological and economic impact of stress, are discussed. PMID- 22206333 TI - Health promotion in the workplace: suggested directions for research. PMID- 22206332 TI - Health locus of control and participation in physical activity. AB - Abstract The purpose of this study was to determine the physical activity participation patterns of college students when defined by their Health Locus of Control orientation. One thousand thirty-three college-aged students completed the Wellness Activity Profile, a questionnaire that yielded data on Health Locus of Control and self-reported frequency of participation in physical activities. Discriminant analyses indicated that the combination of physical activities associated with internally and externally oriented students were different for both males and females. Participation in high caloric expenditure activities was more frequent among internal subjects (Male: bicycling, volleyball, other individual sports, and snorkel/scuba diving; Female: basketball, weight training, tennis, fast walking/jogging/running, and judo/karate), while low caloric expenditure activities were associated with an external orientation (Male: baseball/softball, sailing, fishing, golf, and other recreational sports; Female: track and field jumping and fishing). PMID- 22206335 TI - Business aspects of health promotion. PMID- 22206334 TI - Research and evaluation results. PMID- 22206336 TI - Networking. PMID- 22206340 TI - Resource reviews. PMID- 22206339 TI - Report of the conference on fear communications. PMID- 22206341 TI - Perspectives beyond health promotion. PMID- 22206342 TI - Optimization of microwave-assisted extraction for the characterization of olive leaf phenolic compounds by using HPLC-ESI-TOF-MS/IT-MS(2). AB - In the present work, a simple and rapid method for the extraction of phenolic compounds from olive leaves, using microwave-assisted extraction (MAE) technique, has been developed. The experimental variables that affect the MAE process, such as the solvent type and composition, microwave temperature, and extraction time, were optimized using a univariate method. The obtained extracts were analyzed by using high-performance liquid chromatography (HPLC) coupled to electrospray time of-flight mass spectrometry (ESI-TOF-MS) and electrospray ion trap tandem mass spectrometry (ESI-IT-MS(2)) to prove the MAE extraction efficiency. The optimal MAE conditions were methanol:water (80:20, v/v) as extracting solvent, at a temperature equal to 80 degrees C for 6 min. Under these conditions, several phenolic compounds could be characterized by HPLC-ESI-MS/MS(2). As compared to the conventional method, MAE can be used as an alternative extraction method for the characterization of phenolic compounds from olive leaves due to its efficiency and speed. PMID- 22206343 TI - Structural coupling between the Rho-insert domain of Cdc42 and the geranylgeranyl binding site of RhoGDI. AB - The small GTPase proteins are components of the intracellular signaling system, alternating between active (membrane-bound and GTP-loaded) and inactive (GDP loaded and cytosolic) states. In the inactive state, the proteins are soluble in the cytoplasm. To compensate for the energetic penalty of extraction of the hydrophobic moiety from the membrane phase, the inactive state is stabilized via formation of a complex with the RhoGDI proteins that provide a hydrophobic pocket for the binding of the hydrophobic moieties. The signals delivered by the Rho subfamily involve a specific, short, highly exposed alpha-helix (Rho-insert), located close to the GDP binding site. Upon simulating the complex in solution, we observed that the Rho-insert domain of Cdc42 can assume two basic orientations. One is the canonical one, as detected in both crystals and NMR spectra of concentrated protein solutions. The second orientation appears only in the RhoGDI-Cdc42 complex where the GER moiety of Cdc42 is properly inserted into the specific binding site of RhoGDI. Any impairment of the GER-RhoGDI interactions, such as insertion of specific mutations in the hydrophobic binding site, abolished the coupling between the proteins and the Rho-insert domain, preserving its canonical orientation as in the crystalline structure. The noncanonical conformation of the Rho-insert domain is not a simulation artifact, as it appears in crystals of plant Rho proteins (ROP4, ROP5, and ROP7). In accord with the notion that the Rho-insert domain participates in downstream signaling, we propose that the deformation of the Rho-insert is part of the signal transmissions. PMID- 22206345 TI - Developing a patient-centered outcome measure for complementary and alternative medicine therapies I: defining content and format. AB - BACKGROUND: Patients receiving complementary and alternative medicine (CAM) therapies often report shifts in well-being that go beyond resolution of the original presenting symptoms. We undertook a research program to develop and evaluate a patient-centered outcome measure to assess the multidimensional impacts of CAM therapies, utilizing a novel mixed methods approach that relied upon techniques from the fields of anthropology and psychometrics. This tool would have broad applicability, both for CAM practitioners to measure shifts in patients' states following treatments, and conventional clinical trial researchers needing validated outcome measures. The US Food and Drug Administration has highlighted the importance of valid and reliable measurement of patient-reported outcomes in the evaluation of conventional medical products. Here we describe Phase I of our research program, the iterative process of content identification, item development and refinement, and response format selection. Cognitive interviews and psychometric evaluation are reported separately. METHODS: From a database of patient interviews (n = 177) from six diverse CAM studies, 150 interviews were identified for secondary analysis in which individuals spontaneously discussed unexpected changes associated with CAM. Using ATLAS.ti, we identified common themes and language to inform questionnaire item content and wording. Respondents' language was often richly textured, but item development required a stripping down of language to extract essential meaning and minimize potential comprehension barriers across populations. Through an evocative card sort interview process, we identified those items most widely applicable and covering standard psychometric domains. We developed, pilot tested, and refined the format, yielding a questionnaire for cognitive interviews and psychometric evaluation. RESULTS: The resulting questionnaire contained 18 items, in visual analog scale format, in which each line was anchored by the positive and negative extremes relevant to the experiential domain. Because of frequent informant allusions to response set shifts from before to after CAM therapies, we chose a retrospective pretest format. Items cover physical, emotional, cognitive, social, spiritual, and whole person domains. CONCLUSIONS: This paper reports the success of a novel approach to the development of outcome instruments, in which items are extracted from patients' words instead of being distilled from pre-existing theory. The resulting instrument, focused on measuring shifts in patients' perceptions of health and well-being along pre specified axes, is undergoing continued testing, and is available for use by cooperating investigators. PMID- 22206347 TI - Protein supplementation in strength and conditioning adepts: knowledge, dietary behavior and practice in Palermo, Italy. AB - BACKGROUND: It is known that supplement use is a widespread and accepted practice by athletes and people who attend commercial gyms. Little is known about protein supplement amongst people undertaking strength training in commercial gyms in Italy when compared to the US. OBJECTIVE: The purpose of this study was to examine the use of protein supplementation, alone or in association with other supplements, and dietary behavior amongst regular fitness center attendees in Palermo, Italy. DESIGN: Resistance training information have been collected from 800 regular fitness center attendees for the initial analysis. A specific questionnaire was generated for the experimentation. Data were collected using a face-to-face interview method. Supplement users were then compared to the non users and analyzed using a one-way ANOVA, Kruskall-Wallis, chi-square test or exact test of Fisher when appropriate. RESULTS: 30.1% of the respondents use dietary supplements during their training as a believe it is the "way to gain muscles and strength". Whey protein shakes (50.0%) mixed with creatine and amino acids (48.3%) were the most frequent choices amongst the users. A majority of the subjects (34.0%) appeared to rely on their gym instructors' advice for their intake; a lower proportion (13.0%) consulted physicians, while none of them consulted nutritionists. A high consumption of milk has been noticed in both users (67,7%) and non-users (52,8%); supplement non-users consumed significantly more snacks and bakery products than users per week (P < 0.001), while users consumed significantly more protein-rich foods (P < 0.01) with a particular preference for meat (48.0%). CONCLUSIONS: A considerable number of regular strength training adepts consume protein supplements mixed with other products (mainly creatine and amino-acids). Limited numbers consult "dietary specialists" and rely mainly on their instructors. We emphasize on the importance of the dissemination of scientifically based information about supplementation in this environment and the promotion of updated educational programs for the instructors. PMID- 22206348 TI - Efficacy of child abuse and neglect prevention messages in the Florida Winds of Change campaign. AB - Public awareness campaigns have been included in universal, communitywide, and programmatic approaches aimed at preventing child abuse and neglect. More evaluation of campaign effects is needed to identify their place on the continuum of evidence-based programs. This article reports on an efficacy study of the Florida Winds of Change campaign using a randomized experimental design. Investigators conducted an online survey of a web-based panel of Florida residents with children 18 years of age or younger living in the home. Six outcomes were measured at baseline and a 30-day follow-up. Three outcomes referred to knowledge of child development, child disciplinary techniques, and community resources for parents. Prevention attitudes or beliefs, motivation, and action were also assessed. Respondents were exposed to three public service announcements and a selection of parent resource material. Logistic regression models revealed that exposure to campaign messages was associated with significant increases in all but one of the campaign outcomes. PMID- 22206350 TI - Tuning of redox potentials by introducing a cyclometalated bond to bis-tridentate ruthenium(II) complexes bearing bis(N-methylbenzimidazolyl)benzene or -pyridine ligands. AB - A series of asymmetrical bis-tridentate cyclometalated complexes including [Ru(Mebib)(Mebip)](+), [Ru(Mebip)(dpb)](+), [Ru(Mebip)(Medpb)](+), and [Ru(Mebib)(tpy)](+) and two bis-tridentate noncyclometalated complexes [Ru(Mebip)(2)](2+) and [Ru(Mebip)(tpy)](2+) were prepared and characterized, where Mebib is bis(N-methylbenzimidazolyl)benzene, Mebip is bis(N methylbenzimidazolyl)pyridine, dpb is 1,3-di-2-pyridylbenzene, Medpb is 4,6 dimethyl-1,3-di-2-pyridylbenzene, and tpy is 2,2':6',2"-terpyridine. The solid state structure of [Ru(Mebip)(Medpb)](+) is studied by X-ray crystallographic analysis. The electrochemical and spectroscopic properties of these ruthenium complexes were studied and compared with those of known complexes [Ru(tpy)(dpb)](+) and [Ru(tpy)(2)](2+). The change of the supporting ligands and coordination environment allows progressive modulation of the metal-associated redox potentials (Ru(II/III)) from +0.26 to +1.32 V vs Ag/AgCl. The introduction of a ruthenium cyclometalated bond in these complexes results in a significant negative potential shift. The Ru(II/III) potentials of these complexes were analyzed on the basis of Lever's electrochemical parameters (E(L)). Density functional theory (DFT) and time-dependent DFT calculations were carried out to elucidate the electronic structures and spectroscopic spectra of complexes with Mebib or Mebip ligands. PMID- 22206349 TI - Three routes to modulate the pore size of the MscL channel/nanovalve. AB - MscL is a bacterial mechanosensitive channel that protects cells from lysis upon acute decrease in external osmotic environment. It is one of the best characterized mechanosensors known, thus serving as a paradigm of how such molecules sense and respond to stimuli. In addition, the fact that it can be genetically modified, expressed, isolated, and manipulated has led to its proposed use as a triggered nanovalve for various functions including sensors within microelectronic array chips, as well as vesicular-based targeted drug release. X-ray crystallography reveals a homopentameric complex with each subunit containing two transmembrane alpha-helices (TM1 and TM2) and a single carboxyl terminal alpha-helix arranging within the complex to form a 5-fold cytoplasmic bundle (CB), whose function and stability remain unclear. In this study, we show three routes that throttle the open channel conductance. When the linker between the TM2 and CB domain is shortened by deletions or constrained by either cross linking or heavy metal coordination, the conductance of the channel is reduced; in the later two cases, even reversibly. While they have implications for the stability of the CB, these data also provide routes for engineering MscL sensors that are more versatile for potential nanotech devices. PMID- 22206352 TI - Low-molecular-weight oxidants involved in disulfide bond formation. AB - SIGNIFICANCE: The biogenesis of most secreted and outer membrane proteins involves the formation of structure stabilizing disulfide bonds. Hence knowledge of the mechanisms for their formation is critical for understanding a myriad of cellular processes and associated disease states. RECENT ADVANCES: Until recently it was thought that members of the Ero1 sulfhydryl oxidase family were responsible for catalyzing the majority of disulfide bond formation in the endoplasmic reticulum. However, multiple eukaryotic organisms are now known to show no or minor phenotypes when these enzymatic pathways are disrupted, suggesting that other pathways can catalyze disulfide bond formation to an extent sufficient to maintain normal physiology. CRITICAL ISSUES AND FUTURE DIRECTIONS: This lack of a strong phenotype raises multiple questions regarding what pathways are acting and whether they themselves constitute the major route for disulfide bond formation. This review critically examines the potential low molecular oxidants that maybe involved in the catalyzed or noncatalyzed formation of disulfide bonds, with an emphasis on the mammalian endoplasmic reticulum, via an examination of their thermodynamics, kinetics, and availability and gives pointers to help guide future experimental work. PMID- 22206354 TI - Application of the PROJECT concept for suppression of J modulation to DEPT for 13C-multilabeled analytes. AB - Incorporation of the PROJECT element for suppression of J modulation into the DEPT pulse sequence resulted in near-distortionless signals, thus realizing spectra more amenable to quantitative evaluation, a potential valuable aid in cases where (13)C-multilabeled compounds arise, e.g. as a result of feeding experiments in biosynthetic studies. PMID- 22206353 TI - Correlating changes in lung function with patient outcomes in chronic obstructive pulmonary disease: a pooled analysis. AB - BACKGROUND: Relationships between improvements in lung function and other clinical outcomes in chronic obstructive pulmonary disease (COPD) are not documented extensively. We examined whether changes in trough forced expiratory volume in 1 second (FEV(1)) are correlated with changes in patient-reported outcomes. METHODS: Pooled data from three indacaterol studies (n = 3313) were analysed. Means and responder rates for outcomes including change from baseline in Transition Dyspnoea Index (TDI), St. George's Respiratory Questionnaire (SGRQ) scores (at 12, 26 and 52 weeks), and COPD exacerbation frequency (rate/year) were tabulated across categories of DeltaFEV(1). Also, generalised linear modelling was performed adjusting for covariates such as baseline severity and inhaled corticosteroid use. RESULTS: With increasing positive DeltaFEV(1), TDI and DeltaSGRQ improved at all timepoints, exacerbation rate over the study duration declined (P < 0.001). Individual-level correlations were 0.03-0.18, but cohort level correlations were 0.79-0.95. At 26 weeks, a 100 ml increase in FEV(1) was associated with improved TDI (0.46 units), DeltaSGRQ (1.3-1.9 points) and exacerbation rate (12% decrease). Overall, adjustments for baseline covariates had little impact on the relationship between DeltaFEV(1) and outcomes. CONCLUSIONS: These results suggest that larger improvements in FEV(1) are likely to be associated with larger patient-reported benefits across a range of clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00393458, NCT00463567, and NCT00624286. PMID- 22206356 TI - Chemical vapor deposition of highly adherent diamond coatings onto co-cemented tungsten carbides irradiated by high power diode laser. AB - The present investigation deals with the definition of a new eco-friendly alternative to pretreat Co-cemented tungsten carbide (WC-Co) substrates before diamond deposition by hot filament chemical vapor deposition (HFCVD). In particular, WC-5.8 wt %Co substrates were submitted to a thermal treatment by a continuous wave-high power diode laser to reduce surface Co concentration and promote the reconstruction of the WC grains. Laser pretreatments were performed both in N(2) and Ar atmosphere to prevent substrate oxidation. Diamond coatings were deposited onto the laser pretreated substrates by HFCVD. For comparative purpose, diamond coatings were also deposited on WC-5.8 wt %Co substrates chemically etched by the well-known two-step pretreatment employing Murakami's reagent and Caro's acid. Surface morphology, microstructure, and chemical composition of the WC-5.8 wt %Co substrates after the different pretreatments and the deposition of diamond coatings were assessed by surface profiler, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and X-ray diffraction analyses. Wear performance of the diamond coatings was checked by dry sliding linear reciprocating tribological tests. The worn volume of the diamond coatings deposited on the laser pretreated substrates was always found lower than the one measured on the chemically etched substrates, with the N(2) atmosphere being particularly promising. PMID- 22206357 TI - Adsorption of polyvinylpyrrolidone on Ag surfaces: insight into a structure directing agent. AB - We use density functional theory to resolve the role of polyvinylpyrrolidone (PVP) in the shape-selective synthesis of Ag nanostructures. At the segment level, PVP binds more strongly to Ag(100) than Ag(111) because of a surface sensitive balance between direct binding and van der Waals attraction. At the chain level, correlated segment binding leads to a strong preference for PVP bind to Ag(100). Our study underscores differences between small-molecule and polymeric structure-directing agents. PMID- 22206355 TI - Spatially explicit multi-criteria decision analysis for managing vector-borne diseases. AB - The complex epidemiology of vector-borne diseases creates significant challenges in the design and delivery of prevention and control strategies, especially in light of rapid social and environmental changes. Spatial models for predicting disease risk based on environmental factors such as climate and landscape have been developed for a number of important vector-borne diseases. The resulting risk maps have proven value for highlighting areas for targeting public health programs. However, these methods generally only offer technical information on the spatial distribution of disease risk itself, which may be incomplete for making decisions in a complex situation. In prioritizing surveillance and intervention strategies, decision-makers often also need to consider spatially explicit information on other important dimensions, such as the regional specificity of public acceptance, population vulnerability, resource availability, intervention effectiveness, and land use. There is a need for a unified strategy for supporting public health decision making that integrates available data for assessing spatially explicit disease risk, with other criteria, to implement effective prevention and control strategies. Multi criteria decision analysis (MCDA) is a decision support tool that allows for the consideration of diverse quantitative and qualitative criteria using both data driven and qualitative indicators for evaluating alternative strategies with transparency and stakeholder participation. Here we propose a MCDA-based approach to the development of geospatial models and spatially explicit decision support tools for the management of vector-borne diseases. We describe the conceptual framework that MCDA offers as well as technical considerations, approaches to implementation and expected outcomes. We conclude that MCDA is a powerful tool that offers tremendous potential for use in public health decision-making in general and vector-borne disease management in particular. PMID- 22206385 TI - Temperature dependence of molecular interactions involved in defining stability of glutamine binding protein and its complex with L-glutamine. AB - The temperature dependence of dynamic parameters derived from nuclear magnetic resonance (NMR) relaxation data is related to conformational entropy of the system under study. This provides information such as macromolecules stability and thermodynamics of ligand binding. We studied the temperature dependence of NMR order parameter of glutamine binding protein (GlnBP), a periplasmic binding protein (PBP) highly specific to L-glutamine associated with its ABC transporter, with the goal of elucidating the dynamical differences between the respective ligand bound and free forms. We found that the protein-ligand interaction, which is stabilized at higher temperature, has a striking effect on the stability of the hydrophobic core of the large domain of GlnBP. Moreover, in contrast to what was found for less specific PBPs, the decreasing backbone motion of the hinge region at increasing temperature supports the idea that the likelihood that GlnBP can adopt a ligand free closed conformation in solution diminishes at higher temperatures. Our results support the induced-fit model as mode of action for GlnBP. In addition, we found that the backbones of residues involved in a salt bridge do not necessarily become more rigid as the temperature rises as it was previously suggested [Vinther, J. M., et al. (2011) J. Am. Chem. Soc., 133, 271 278]. Our results show that for this to happen these residues have to also directly interact with a region of the protein that is becoming more rigid as the temperature increases. PMID- 22206389 TI - Publisher's Notes. PMID- 22206387 TI - Quantitative analysis of the role played by poly(vinylpyrrolidone) in seed mediated growth of Ag nanocrystals. AB - This article presents a quantitative analysis of the role played by poly(vinylpyrrolidone) (PVP) in seed-mediated growth of Ag nanocrystals. Starting from Ag nanocubes encased by {100} facets as the seeds, the resultant nanocrystals could take different shapes depending on the concentration of PVP in the solution. If the concentration was above a critical value, the seeds simply grew into larger cubes still enclosed by {100} facets. When the concentration fell below a critical value, the seeds would evolve into cuboctahedrons enclosed by a mix of {100} and {111} facets and eventually octahedrons completely covered by {111} facets. We derived the coverage density of PVP on Ag(100) surface by combining the results from two measurements: (i) cubic seeds were followed to grow at a fixed initial concentration of PVP to find out when {111} facets started to appear on the surface, and (ii) cubic seeds were allowed to grow at reduced initial concentrations of PVP to see at which concentration {111} facets started to appear from the very beginning. We could calculate the coverage density of PVP from the differences in PVP concentration and the total surface area of Ag nanocubes between these two samples. The coverage density was found to be 140 and 30 repeating units per nm(2) for PVP of 55,000 and 10,000 g/mol in molecular weight, respectively, for cubic seeds of 40 nm in edge length. These values dropped slightly to 100 and 20 repeating units per nm(2), respectively, when 100 nm Ag cubes were used as the seeds. PMID- 22206390 TI - Worksite health promotion: feasibility testing of repeated weight control and smoking cessation classes. AB - Abstract This paper describes a study examining the feasibility of a worksite health promotion program that was repealed twice in one year. Weight control and smoking cessation classes, which included a supporting incentive component, were made available at a worksite of 485 white-collar employees continuously throughout one year. Identical education programs were offered twice at six-month intervals. Results suggest that this model of program implementation is attractive to employees. Total participation over 12 months included an estimated 53% of overweight employees in the weight program and 23% of smokers in the smoking cessation program. The two series of classes, run back to back, generated similar participation. Thirty-nine percent of weight control participants and six percent of smoking cessation participants who enrolled in the first program also enrolled in the second. Weight losses and smoking cessation rates were comparable for the two cycles, with a mean weight loss of about seven pounds and a smoking cessation rate at six months of about 33%. Surveys of a random sample of employees at baseline and again at 12 months showed a 28% reduction in the prevalence of cigarette smoking, but no change in average weight or the prevalence of overweight. This study suggests that health promotion programs at worksites which offer repeated opportunities for employee participation are promising and deserve further study. PMID- 22206391 TI - Social marketing and communication: changing health behavior in the third world. AB - Abstract Development communication, particularly within the health sector, is relatively new and still shrouded in mystique. Many health planners and policy makers in developing countries and elsewhere do not yet fully appreciate the role communication plays in primary health care interventions. Nevertheless, communication theory, embracing diffusion of innovations and social marketing, can make a significant contribution in improving health status. This paper explores, through an examination of the literature and the experience of a worldwide research and development project, the synthesis of development communication, diffusion, social marketing, and primary health care. It attempts to demonstrate the value of integrating these paradigms within the context of a public health communication model. Focusing on the use of radio and interpersonal communication, the paper describes model projects in India and Honduras and reveals through their example the role of communication in changing health behavior in Third World settings. PMID- 22206392 TI - Montana state university: an employee wellness program financed by a self insurance group health plan. PMID- 22206393 TI - How to institutionalize health promotion programs. AB - Abstract This article presents six implications for practice that suggest how to optimize the institutionalization of health promotion programs. These six implications were derived from a study of ten health promotion programs funded by the Virginia State Health Department and operated by local schools and community health agencies. Institutionalization refers to the long-term survival of health promotion programs, i.e., survival well beyond an initial grant funding period. To generate the implications for practice, a multiple case design for cross-case comparisons was applied to the ten health promotion programs. In brief, the six practice implications are: 1) cultivating a "program champion"; 2) favoring organizations with mature "subsystems"; 3) favoring organizations in which health promotion "fits" with the organization's mission; 4) avoiding brokering relationships; 5) altering lengths of funding periods; and 6) funding existing worthy programs. The significance of these practice implications for both funding and implementing agencies is briefly discussed. PMID- 22206394 TI - Comment: is institutionalization the proper goal of grantmaking? PMID- 22206395 TI - Robert f. Allen memorial scholarship awards. PMID- 22206397 TI - Research and evaluation results. PMID- 22206396 TI - Health promotion for older adults: directions for research. PMID- 22206398 TI - Business aspects of health promotion. PMID- 22206399 TI - Networking. PMID- 22206400 TI - Professional association profiles. PMID- 22206402 TI - Resource reviews. PMID- 22206403 TI - Perspectives beyond health promotion. PMID- 22206406 TI - There is more than one way to turn a spherical cellular monolayer inside out: type B embryo inversion in Volvox globator. AB - BACKGROUND: Epithelial folding is a common morphogenetic process during the development of multicellular organisms. In metazoans, the biological and biomechanical processes that underlie such three-dimensional (3D) developmental events are usually complex and difficult to investigate. Spheroidal green algae of the genus Volvox are uniquely suited as model systems for studying the basic principles of epithelial folding. Volvox embryos begin life inside out and then must turn their spherical cell monolayer outside in to achieve their adult configuration; this process is called 'inversion.' There are two fundamentally different sequences of inversion processes in Volvocaceae: type A and type B. Type A inversion is well studied, but not much is known about type B inversion. How does the embryo of a typical type B inverter, V. globator, turn itself inside out? RESULTS: In this study, we investigated the type B inversion of V. globator embryos and focused on the major movement patterns of the cellular monolayer, cell shape changes and changes in the localization of cytoplasmic bridges (CBs) connecting the cells. Isolated intact, sectioned and fragmented embryos were analyzed throughout the inversion process using light microscopy, confocal laser scanning microscopy, scanning electron microscopy and transmission electron microscopy techniques. We generated 3D models of the identified cell shapes, including the localizations of CBs. We show how concerted cell-shape changes and concerted changes in the position of cells relative to the CB system cause cell layer movements and turn the spherical cell monolayer inside out. The type B inversion of V. globator is compared to the type A inversion in V. carteri. CONCLUSIONS: Concerted, spatially and temporally coordinated changes in cellular shapes in conjunction with concerted migration of cells relative to the CB system are the causes of type B inversion in V. globator. Despite significant similarities between type A and type B inverters, differences exist in almost all details of the inversion process, suggesting analogous inversion processes that arose through parallel evolution. Based on our results and due to the cellular biomechanical implications of the involved tensile and compressive forces, we developed a global mechanistic scenario that predicts epithelial folding during embryonic inversion in V. globator. PMID- 22206407 TI - Nanoporous piezo- and ferroelectric thin films. AB - Nanoporous barium titanate and lead titanate thin films (~100 nm calculated from ellipsometric data) are prepared starting from sol-gel solutions modified with a commercially available block-copolymer and evaporation-induced self-assembly methodology. The tuning of the thermal treatment followed by in situ ellipsometry allows the decomposition of the organic components and of the structuring agent leading to the formation of porous tetragonal crystalline perovskite structures as observed by XRD, HRTEM, SEM, and ellipsoporosimetry. Both nanoporous barium titanate and lead titanate thin films present local piezoelectric and ferroelectric behavior measured by piezoresponse force microscopy (PFM), being promising platforms for the preparation of the generation of new multifunctional systems. PMID- 22206409 TI - Developing a patient-centered outcome measure for complementary and alternative medicine therapies II: refining content validity through cognitive interviews. AB - BACKGROUND: Available measures of patient-reported outcomes for complementary and alternative medicine (CAM) inadequately capture the range of patient-reported treatment effects. The Self-Assessment of Change questionnaire was developed to measure multi-dimensional shifts in well-being for CAM users. With content derived from patient narratives, items were subsequently focused through interviews on a new cohort of participants. Here we present the development of the final version in which the content and format is refined through cognitive interviews. METHODS: We conducted cognitive interviews across five iterations of questionnaire refinement with a culturally diverse sample of 28 CAM users. In each iteration, participant critiques were used to revise the questionnaire, which was then re-tested in subsequent rounds of cognitive interviews. Following all five iterations, transcripts of cognitive interviews were systematically coded and analyzed to examine participants' understanding of the format and content of the final questionnaire. Based on this data, we established summary descriptions and selected exemplar quotations for each word pair on the final questionnaire. RESULTS: The final version of the Self-Assessment of Change questionnaire (SAC) includes 16 word pairs, nine of which remained unchanged from the original draft. Participants consistently said that these stable word pairs represented opposite ends of the same domain of experience and the meanings of these terms were stable across the participant pool. Five pairs underwent revision and two word pairs were added. Four word pairs were eliminated for redundancy or because participants did not agree on the meaning of the terms. Cognitive interviews indicate that participants understood the format of the questionnaire and considered each word pair to represent opposite poles of a shared domain of experience. CONCLUSIONS: We have placed lay language and direct experience at the center of questionnaire revision and refinement. In so doing, we provide an innovative model for the development of truly patient-centered outcome measures. Although this instrument was designed and tested in a CAM specific population, it may be useful in assessing multi-dimensional shifts in well-being across a broader patient population. PMID- 22206410 TI - Intravenous sedation for implant surgery: midazolam, butorphanol, and dexmedetomidine versus midazolam, butorphanol, and propofol. AB - We compared the amnesic action, recovery process, and satisfaction of patients and surgeons after the use of 2 different sedation regimens for 40 patients undergoing scheduled implant surgery. Butorphanol, midazolam, dexmedetomidine (BMD) was administered to 20 patients who were maintained with continuous infusion of dexmedetomidine after the induction with butorphanol and midazolam, and butorphanol, midazolam, propofol (BMP) was administered to 20 patients who were maintained with continuous infusion of propofol after the induction with butorphanol and midazolam. To assess the amnesic action, the memory of local anesthesia, auditory memory, and visual memory were evaluated. The Trieger Dot Test (TDT) was applied during the recovery process. A questionnaire regarding the patient's feelings of the management of sedation was taken from each patient and was also filled out by the surgeon. The comparison between groups was analyzed by the Mann-Whitney U test. No significant differences in the amnesic action and the TDT were noted. Both methods also satisfied the patients and surgeons, as determined by the questionnaire results. In conclusion, both sedation regimens are appropriate for implant surgery. PMID- 22206411 TI - Parent-teen communication about sex in urban Thai families. AB - This study describes sexual communication among Thai parents and their teens and identifies variables related to communication about sex in urban Thai families. Data were derived from 420 families whose teenage children ages 13-14 years were randomly selected using the probability proportional to size technique. Interviews were conducted with 1 parent and 1 teenage child in each family. In depth interviews were also conducted in 30 parents and teens drawn from the same 420 families. Results showed that parents were most likely to talk with their teens about body changes and dating; however, less discussion about sex-related issues, birth control, and HIV/AIDS occurred. More daughters than sons reported frequent discussions with their parents about sex. Parents who believed their teens had been involved in sexual activity were more likely to talk about HIV/AIDS and the difficulty of teenagers having babies, instead of talking about sexual intercourse or when to start having sex. Multiple regression analysis indicated that gender of the child (female), parental religiosity, and parental perception of teen sexual activity were significant predictors of increased sexual communication in Thai families. The findings suggest a need for approaches designed to facilitate communication skills about sex-related issues among Thai parents. PMID- 22206414 TI - Toward healthy aging through empowering self-care during the climacteric stage. AB - BACKGROUND: While they progress through the climacteric stage, women often develop physical and psychological health needs, calling for innovative health care services that can be translated into preventive programs and empowerment towards self-care. OBJECTIVE: To identify the changes in women's discourse regarding their concerns and needs about the climacteric stage and self-care after they had participated in an integrative women-centered health-care model with empowerment for self-care. METHODS: Women's narratives during counseling group sessions were analyzed using qualitative inductive thematic analysis. RESULTS: A total of 121 women between 45 and 59 years of age participated. At the beginning of the counseling group sessions, we identified the following themes: (1) Lack of information about changes during the climacteric stage and self-care; (2) Tradition: the climacteric stage as a taboo subject; (3) Life's changes and transitions: the complexity of the climacteric experience; (4) Stigma of menopause; (5) Relationship between the traditional gender role and the lack of self-care. At the end of the counseling group sessions, the themes were: (1) The climacteric as a natural stage; (2) Expectations for old age; (3) Empowerment and the change of awareness for self-care; (3) De-medicalization of the climacteric; (4) The richness of group work; (5) Empowerment as motivation to convey acquired knowledge. CONCLUSION: Women in the climacteric stage require more information about their physical, psychological and social needs, as well as the potential impact on their health during old age. Empowerment during the climacteric can contribute to improving the perception about this stage as well as the importance of self-care. PMID- 22206413 TI - Thyroid hormone-regulated gene expression in juvenile mouse liver: identification of thyroid response elements using microarray profiling and in silico analyses. AB - BACKGROUND: Disruption of thyroid hormone signalling can alter growth, development and energy metabolism. Thyroid hormones exert their effects through interactions with thyroid receptors that directly bind thyroid response elements and can alter transcriptional activity of target genes. The effects of short-term thyroid hormone perturbation on hepatic mRNA transcription in juvenile mice were evaluated, with the goal of identifying genes containing active thyroid response elements. Thyroid hormone disruption was induced from postnatal day 12 to 15 by adding goitrogens to dams' drinking water (hypothyroid). A subgroup of thyroid hormone-disrupted pups received intraperitoneal injections of replacement thyroid hormones four hours prior to sacrifice (replacement). An additional group received only thyroid hormones four hours prior to sacrifice (hyperthyroid). Hepatic mRNA was extracted and hybridized to Agilent mouse microarrays. RESULTS: Transcriptional profiling enabled the identification of 28 genes that appeared to be under direct thyroid hormone-regulation. The regulatory regions of the genome adjacent to these genes were examined for half-site sequences that resemble known thyroid response elements. A bioinformatics search identified 33 thyroid response elements in the promoter regions of 13 different genes thought to be directly regulated by thyroid hormones. Thyroid response elements found in the promoter regions of Tor1a, 2310003H01Rik, Hect3d and Slc25a45 were further validated by confirming that the thyroid receptor is associated with these sequences in vivo and that it can bind directly to these sequences in vitro. Three different arrangements of thyroid response elements were identified. Some of these thyroid response elements were located far up-stream (> 7 kb) of the transcription start site of the regulated gene. CONCLUSIONS: Transcriptional profiling of thyroid hormone disrupted animals coupled with a novel bioinformatics search revealed new thyroid response elements associated with genes previously unknown to be responsive to thyroid hormone. The work provides insight into thyroid response element sequence motif characteristics. PMID- 22206416 TI - Heterocycle synthesis via direct C-H/N-H coupling. AB - A method for five- and six-membered heterocycle formation by palladium-catalyzed C-H/N-H coupling is presented. The method employs a picolinamide directing group, PhI(OAc)(2) oxidant, and toluene solvent at 80-120 degrees C. Cyclization is effective for sp(2) as well as aliphatic and benzylic sp(3) C-H bonds. PMID- 22206417 TI - Concept to estimate regional inhalation dose of industrially synthesized nanoparticles. AB - The use of nanoparticles (NPs) in industry is increasing rapidly, but knowledge of the occupational health and safety aspects of NPs is still limited. This is because quantitative NP exposure levels are scarce, and the metrics to describe doses are unclear. This study presents one method for estimating workers' calculated regional inhalation dose of deposited particles from size-fractionated concentrations. It was applied to estimate workers' regional inhalation dose rates and doses separately for NPs and NPs with background particles during NP synthesis. Dose analysis was performed in units of particle number (particles and particles min(-1)), active surface area (MUm(2) and MUm(2) min(-1)), and mass (ng and ng min(-1)) for three respiratory regions: head airways, tracheobronchial, and alveolar. It was found that in NP synthesis NPs were deposited mainly in the alveolar region in all units. However, when the dose of all particles was examined, it was found that dose and the main deposition region were mainly defined by the synthesized NPs for particle number, as active surface area was described by both NPs and background particles, and mass by background particles. This study provides fundamental data for NP inhalation exposure risk assessment, regulations, dose metrics for NP synthesis, and a basis for defining metrics of dose-biological response and helps us understand the magnitude of doses in NP synthesis. It also illustrates the necessity to obtain size-fractionated measurements of NP concentrations to support accurate dose estimation. PMID- 22206418 TI - Do capsular pressure and implant motion interact to cause high pressure in the periprosthetic bone in total hip replacement? AB - When there is a debonding at the bone-implant interface, the difference in stiffness between the implant and the bone can result in micromotion, allowing existing gaps to open further or new gaps to be created during physiological loading. It has been suggested that periprosthetic fluid flow and high pressure may play an important role in osteolysis development in the proximity of these gaps. To explain this phenomenon, the concepts of "effective joint space" and "pumping stem" have been cited in many studies. However, there is no clear understanding of the factors causing, or contributing to, these mechanisms. It is likely that capsular pressure, gap dimensions, and micromotion of the gap during cyclic loading of an implant can play a defining role in inducing periprosthetic flow. In order to obtain a better understanding of the main influences on periprosthetic flows and the development of osteolysis, steady state and transient 2D computational fluid dynamic simulations were performed for the joint capsule of the lateral side of a stem-femur system, and a gap in communication with the capsule and the surrounding bone. It was shown that high capsular pressure may be the main driving force for high fluid pressure and flow in the bone surrounding the gap, while micromotion of only very long and narrow gaps can cause significant pressure and flow in the bone. At low capsular pressure, micromotion induced large flows in the gap region; however, the flow in the bone tissue was almost unaffected. The results also revealed the existence of high velocity spikes in the bone region at the bottom of the gap. These velocity spikes can exert excessive fluid shear stress on the bone cells and disturb the local biological balance of the surrounding interstitial fluid which can result in osteolysis development. High capsular pressure was observed to be the main cause of these velocity spikes whereas, at low capsular pressure, gap micromotion of only very long and narrow gaps generated significant velocity spikes in the bone at the bottom of the gaps. PMID- 22206420 TI - Study of the velocity and strain fields in the flow through prosthetic heart valves. AB - A comparative experimental study of the velocity field and the strain field produced down-stream of biological and mechanical artificial valves is presented. In order to determine the spatial and temporal distributions of these fields, a phase-locked stereoscopic particle image velocimetry (or 3D-PIV) technique was implemented. Emphasis was placed on the identification of the fundamental differences between the extensional and the shear components of the strain tensor. The analysis of the characteristic flows reveal that the strains in every direction may reach high values at different times during the cardiac cycle. It was found that elevated strain levels persist throughout the cardiac cycle as a result of all these contributions. Finally, it is suggested that the frequency with which the strain variations occur at particular instants and locations could be associated to the cumulative damage process of the blood constituents and should be taken into account in the overall assessment of existing valve types, as well as in future design efforts. PMID- 22206419 TI - Static and dynamic error of a biplanar videoradiography system using marker-based and markerless tracking techniques. AB - The use of biplanar videoradiography technology has become increasingly popular for evaluating joint function in vivo. Two fundamentally different methods are currently employed to reconstruct 3D bone motions captured using this technology. Marker-based tracking requires at least three radio-opaque markers to be implanted in the bone of interest. Markerless tracking makes use of algorithms designed to match 3D bone shapes to biplanar videoradiography data. In order to reliably quantify in vivo bone motion, the systematic error of these tracking techniques should be evaluated. Herein, we present new markerless tracking software that makes use of modern GPU technology, describe a versatile method for quantifying the systematic error of a biplanar videoradiography motion capture system using independent gold standard instrumentation, and evaluate the systematic error of the W.M. Keck XROMM Facility's biplanar videoradiography system using both marker-based and markerless tracking algorithms under static and dynamic motion conditions. A polycarbonate flag embedded with 12 radio-opaque markers was used to evaluate the systematic error of the marker-based tracking algorithm. Three human cadaveric bones (distal femur, distal radius, and distal ulna) were used to evaluate the systematic error of the markerless tracking algorithm. The systematic error was evaluated by comparing motions to independent gold standard instrumentation. Static motions were compared to high accuracy linear and rotary stages while dynamic motions were compared to a high accuracy angular displacement transducer. Marker-based tracking was shown to effectively track motion to within 0.1 mm and 0.1 deg under static and dynamic conditions. Furthermore, the presented results indicate that markerless tracking can be used to effectively track rapid bone motions to within 0.15 deg for the distal aspects of the femur, radius, and ulna. Both marker-based and markerless tracking techniques were in excellent agreement with the gold standard instrumentation for both static and dynamic testing protocols. Future research will employ these techniques to quantify in vivo joint motion for high-speed upper and lower extremity impacts such as jumping, landing, and hammering. PMID- 22206421 TI - Tortuosity triggers platelet activation and thrombus formation in microvessels. AB - Tortuous blood vessels are often seen in humans in association with thrombosis, atherosclerosis, hypertension, and aging. Vessel tortuosity can cause high fluid shear stress, likely promoting thrombosis. However, the underlying physical mechanisms and microscale processes are poorly understood. Accordingly, the objectives of this study were to develop and use a new computational approach to determine the effects of venule tortuosity and fluid velocity on thrombus initiation. The transport, collision, shear-induced activation, and receptor ligand adhesion of individual platelets in thrombus formation were simulated using discrete element method. The shear-induced activation model assumed that a platelet became activated if it experienced a shear stress above a relative critical shear stress or if it contacted an activated platelet. Venules of various levels of tortuosity were simulated for a mean flow velocity of 0.10 cm s(-1), and a tortuous arteriole was simulated for a mean velocity of 0.47 cm s( 1). Our results showed that thrombus was initiated at inner walls in curved regions due to platelet activation in agreement with experimental studies. Increased venule tortuosity modified fluid flow to hasten thrombus initiation. Compared to the same sized venule, flow in the arteriole generated a higher amount of mural thrombi and platelet activation rate. The results suggest that the extent of tortuosity is an important factor in thrombus initiation in microvessels. PMID- 22206422 TI - One-dimensional model for propagation of a pressure wave in a model of the human arterial network: comparison of theoretical and experimental results. AB - Pulse wave evaluation is an effective method for arteriosclerosis screening. In a previous study, we verified that pulse waveforms change markedly due to arterial stiffness. However, a pulse wave consists of two components, the incident wave and multireflected waves. Clarification of the complicated propagation of these waves is necessary to gain an understanding of the nature of pulse waves in vivo. In this study, we built a one-dimensional theoretical model of a pressure wave propagating in a flexible tube. To evaluate the applicability of the model, we compared theoretical estimations with measured data obtained from basic tube models and a simple arterial model. We constructed different viscoelastic tube set-ups: two straight tubes; one tube connected to two tubes of different elasticity; a single bifurcation tube; and a simple arterial network with four bifurcations. Soft polyurethane tubes were used and the configuration was based on a realistic human arterial network. The tensile modulus of the material was similar to the elasticity of arteries. A pulsatile flow with ejection time 0.3 s was applied using a controlled pump. Inner pressure waves and flow velocity were then measured using a pressure sensor and an ultrasonic diagnostic system. We formulated a 1D model derived from the Navier-Stokes equations and a continuity equation to characterize pressure propagation in flexible tubes. The theoretical model includes nonlinearity and attenuation terms due to the tube wall, and flow viscosity derived from a steady Hagen-Poiseuille profile. Under the same configuration as for experiments, the governing equations were computed using the MacCormack scheme. The theoretical pressure waves for each case showed a good fit to the experimental waves. The square sum of residuals (difference between theoretical and experimental wave-forms) for each case was <10.0%. A possible explanation for the increase in the square sum of residuals is the approximation error for flow viscosity. However, the comparatively small values prove the validity of the approach and indicate the usefulness of the model for understanding pressure propagation in the human arterial network. PMID- 22206423 TI - The impact of simplified boundary conditions and aortic arch inclusion on CFD simulations in the mouse aorta: a comparison with mouse-specific reference data. AB - Computational fluid dynamics (CFD) simulations allow for calculation of a detailed flow field in the mouse aorta and can thus be used to investigate a potential link between local hemodynamics and disease development. To perform these simulations in a murine setting, one often needs to make assumptions (e.g. when mouse-specific boundary conditions are not available), but many of these assumptions have not been validated due to a lack of reference data. In this study, we present such a reference data set by combining high-frequency ultrasound and contrast-enhanced micro-CT to measure (in vivo) the time-dependent volumetric flow waveforms in the complete aorta (including seven major side branches) of 10 male ApoE -/- deficient mice on a C57Bl/6 background. In order to assess the influence of some assumptions that are commonly applied in literature, four different CFD simulations were set up for each animal: (i) imposing the measured volumetric flow waveforms, (ii) imposing the average flow fractions over all 10 animals, presented as a reference data set, (iii) imposing flow fractions calculated by Murray's law, and (iv) restricting the geometrical model to the abdominal aorta (imposing measured flows). We found that - even if there is sometimes significant variation in the flow fractions going to a particular branch - the influence of using average flow fractions on the CFD simulations is limited and often restricted to the side branches. On the other hand, Murray's law underestimates the fraction going to the brachiocephalic trunk and strongly overestimates the fraction going to the distal aorta, influencing the outcome of the CFD results significantly. Changing the exponential factor in Murray's law equation from 3 to 2 (as suggested by several authors in literature) yields results that correspond much better to those obtained imposing the average flow fractions. Restricting the geometrical model to the abdominal aorta did not influence the outcome of the CFD simulations. In conclusion, the presented reference dataset can be used to impose boundary conditions in the mouse aorta in future studies, keeping in mind that they represent a subsample of the total population, i.e., relatively old, non-diseased, male C57Bl/6 ApoE -/- mice. PMID- 22206424 TI - Assessment of hindlimb locomotor strength in spinal cord transected rats through animal-robot contact force. AB - Robotic locomotor training devices have gained popularity in recent years, yet little has been reported regarding contact forces experienced by the subject performing automated locomotor training, particularly in animal models of neurological injury. The purpose of this study was to develop a means for acquiring contact forces between a robotic device and a rodent model of spinal cord injury through instrumentation of a robotic gait training device (the rat stepper) with miniature force/torque sensors. Sensors were placed at each interface between the robot arm and animal's hindlimb and underneath the stepping surface of both hindpaws (four sensors total). Twenty four female, Sprague-Dawley rats received mid-thoracic spinal cord transections as neonates and were included in the study. Of these 24 animals, training began for 18 animals at 21 days of age and continued for four weeks at five min/day, five days/week. The remaining six animals were untrained. Animal-robot contact forces were acquired for trained animals weekly and untrained animals every two weeks while stepping in the robotic device with both 60 and 90% of their body weight supported (BWS). Animals that received training significantly increased the number of weight supported steps over the four week training period. Analysis of raw contact forces revealed significant increases in forward swing and ground reaction forces during this time, and multiple aspects of animal-robot contact forces were significantly correlated with weight bearing stepping. However, when contact forces were normalized to animal body weight, these increasing trends were no longer present. Comparison of trained and untrained animals revealed significant differences in normalized ground reaction forces (both horizontal and vertical) and normalized forward swing force. Finally, both forward swing and ground reaction forces were significantly reduced at 90% BWS when compared to the 60% condition. These results suggest that measurement of animal-robot contact forces using the instrumented rat stepper can provide a sensitive and reliable measure of hindlimb locomotor strength and control of flexor and extensor muscle activity in neurologically impaired animals. Additionally, these measures may be useful as a means to quantify training intensity or dose-related functional outcomes of automated training. PMID- 22206425 TI - Hemodynamics of the mouse abdominal aortic aneurysm. AB - The abdominal aortic aneurysm (AAA) is a significant cause of death and disability in the Western world and is the subject of many clinical and pathological studies. One of the most commonly used surrogates of the human AAA is the angiotensin II (Ang II) induced model used in mice. Despite the widespread use of this model, there is a lack of knowledge concerning its hemodynamics; this study was motivated by the desire to understand the fluid dynamic environment of the mouse AAA. Numerical simulations were performed using three subject-specific mouse models in flow conditions typical of the mouse. The numerical results from one model showed a shed vortex that correlated with measurements observed in vivo by Doppler ultrasound. The other models had smaller aneurysmal volumes and did not show vortex shedding, although a recirculation zone was formed in the aneurysm, in which a vortex could be observed, that elongated and remained attached to the wall throughout the systolic portion of the cardiac cycle. To link the hemodynamics with aneurysm progression, the remodeling that occurred between week one and week two of the Ang II infusion was quantified and compared with the hemodynamic wall parameters. The strongest correlation was found between the remodeled distance and the oscillatory shear index, which had a correlation coefficient greater than 0.7 for all three models. These results demonstrate that the hemodynamics of the mouse AAA are driven by a strong shear layer, which causes the formation of a recirculation zone in the aneurysm cavity during the systolic portion of the cardiac waveform. The recirculation zone results in areas of quiescent flow, which are correlated with the locations of the aneurysm remodeling. PMID- 22206426 TI - Muscle tension estimation in the presence of neuromuscular impairment. AB - Static optimization approaches to estimating muscle tensions rely on the assumption that the muscle activity pattern is in some sense optimal. However, in the case of individuals with a neuromuscular impairment, this assumption is likely not to hold true. We present an approach to muscle tension estimation that does not rely on any optimality assumptions. First, the nature of the impairment is estimated by reformulating the relationship between the muscle tensions and the external forces produced in terms of the deviation from the expected activation in the unimpaired case. This formulation allows the information from several force production tasks to be treated as a single coupled system. In a second step, the identified impairments are used to obtain a novel cost function for the muscle tension estimation task. In a simulation study of the index finger, the proposed method resulted in muscle tension errors with a mean norm of 23.3 +/- 26.8% (percentage of the true solution norm), compared to 52.6 +/- 24.8% when solving the estimation task using a cost function consisting of the sum of squared muscle stresses. Performance was also examined as a function of the amount of error in the kinematic and muscle Jacobians and found to remain superior to the performance of the squared muscle stress cost function throughout the range examined. PMID- 22206427 TI - Sequential structural and fluid dynamic numerical simulations of a stented bifurcated coronary artery. AB - Despite their success, stenting procedures are still associated to some clinical problems like sub-acute thrombosis and in-stent restenosis. Several clinical studies associate these phenomena to a combination of both structural and hemodynamic alterations caused by stent implantation. Recently, numerical models have been widely used in the literature to investigate stenting procedures but always from either a purely structural or fluid dynamic point of view. The aim of this work is the implementation of sequential structural and fluid dynamic numerical models to provide a better understanding of stenting procedures in coronary bifurcations. In particular, the realistic geometrical configurations obtained with structural simulations were used to create the fluid domains employed within transient fluid dynamic analyses. This sequential approach was applied to investigate the final kissing balloon (FKB) inflation during the provisional side branch technique. Mechanical stresses in the arterial wall and the stent as well as wall shear stresses along the arterial wall were examined before and after the FKB deployment. FKB provoked average mechanical stresses in the arterial wall almost 2.5 times higher with respect to those induced by inflation of the stent in the main branch only. Results also enlightened FKB benefits in terms of improved local blood flow pattern for the side branch access. As a drawback, the FKB generates a larger region of low wall shear stress. In particular, after FKB the percentage of area characterized by wall shear stresses lower than 0.5 Pa was 79.0%, while before the FKB it was 62.3%. For these reasons, a new tapered balloon dedicated to bifurcations was proposed. The inclusion of the modified balloon has reduced the mechanical stresses in the proximal arterial vessel to 40% and the low wall shear stress coverage area to 71.3%. In conclusion, these results show the relevance of the adopted sequential approach to study the wall mechanics and the hemodynamics created by stent deployment. PMID- 22206428 TI - Targeted particle tracking in computational models of human carotid bifurcations. AB - A significant and largely unsolved problem of computational fluid dynamics (CFD) simulation of flow in anatomically relevant geometries is that very few calculated pathlines pass through regions of complex flow. This in turn limits the ability of CFD-based simulations of imaging techniques (such as MRI) to correctly predict in vivo performance. In this work, I present two methods designed to overcome this filling problem, firstly, by releasing additional particles from areas of the flow inlet that lead directly to the complex flow region ("preferential seeding") and, secondly, by tracking particles both "downstream" and "upstream" from seed points within the complex flow region itself. I use the human carotid bifurcation as an example of complex blood flow that is of great clinical interest. Both idealized and healthy volunteer geometries are investigated. With uniform seeding in the inlet plane (in the common carotid artery (CCA)) of an idealized bifurcation geometry, approximately half the particles passed through the internal carotid artery (ICA) and half through the external carotid artery. However, of those particles entering the ICA, only 16% passed directly through the carotid bulb region. Preferential seeding from selected regions of the CCA was able to increase this figure to 47%. In the second method, seeding of particles within the carotid bulb region itself led to a very high proportion (97%) of pathlines running from CCA to ICA. Seeding of particles in the bulb plane of three healthy volunteer carotid bifurcation geometries led to much better filling of the bulb regions than by particles seeded at the inlet alone. In all cases, visualization of the origin and behavior of recirculating particles led to useful insights into the complex flow patterns. Both seeding methods produced significant improvements in filling the carotid bulb region with particle tracks compared with uniform seeding at the inlet and led to an improved understanding of the complex flow patterns. The methods described may be combined and are generally applicable to CFD studies of fluid and gas flow and are, therefore, of relevance in hemodynamics, respiratory mechanics, and medical imaging science. PMID- 22206429 TI - Theoretical study on temperature dependence of cellular uptake of QDs nanoparticles. AB - Cellular uptake kinetics of nanoparticles is one of the key issues determining the design and application of the particles. Models describing nanoparticles intrusion into the cell mostly take the endocytosis process into consideration, and the influences of electrical charges, sizes, concentrations of the particles have been investigated. In this paper, the temperature effect on the cellular uptake of Quantum Dots (QDs) is studied experimentally. QDs are incubated with the SPCA-1 human lung tumor cells, and the nanoparticles on the cell membrane and inside the cell are quantified according to the fluorescence intensities recorded. It is found that the amounts of nanoparticles attached onto the cell membrane and inside the cell both increase with temperature. Based on the experimental results, a model is proposed to describe the cellular uptake dynamic process of nanoparticles. The process consists of two steps: nanoparticles adsorption onto the cell membrane and the internalization. The dynamic parameters are obtained through curve fitting. The simulated results show that the internalization process can be categorized into different phases. The temperature dependent internalization rate constant is very small when below 14 degrees C. It increases distinctly when temperature rises from 14 degrees C to 22 degrees C, but there is no evident increase as temperature further increases above 22 degrees C. Results show that by incorporating a temperature-independent internalization factor, the model predictions well fit the experimental results. PMID- 22206430 TI - Nanostructural alteration in bone quantified in terms of orientation distribution of mineral crystals: a possible tool for fracture risk assessment. AB - There may be different causes of failures in bone; however, their origin generally lies at the lowest level of structural hierarchy, i.e., at the mineral collagen composite. Any change in the nanostructure affects the affinity or bonding effectiveness between and within the phases at this level, and hence determines the overall strength and quality of bone. In this study, we propose a novel concept to assess change in the nanostructure and thereby change in the bonding status at this level by revealing change in the orientation distribution characteristics of mineral crystals. Using X-ray diffraction method, a parameter called Degree of Orientation (DO) has been quantified. The DO accounts for the azimuthal distribution of mineral crystals and represents their effective amount along any direction. Changes in the DOs in cortical bone samples from bovine femur with different preferential orientations of mineral crystals were estimated under external loads. Depending on the applied loads, change in the azimuthal distribution of the DOs and the degree of reversibility of the crystals was observed to vary. The characteristics of nanostructural change and thereby possible affect on the strength of bone was then predicted from the reversible or irreversible characteristics of distributed mineral crystals. Significant changes in the organization of mineral crystals were observed; however, variations in the applied stresses and elastic moduli were not evinced at the macroscale level. A novel concept to assess the alteration in nanostructure on the basis of mineral crystals orientation distribution has been proposed. The importance of nanoscale level information obtained noninvasively has been emphasized, which acts as a precise tool to estimate the strength and predict the possible fracture risks in bone. PMID- 22206432 TI - Template-free fabrication of TiO2 hollow spheres and their photocatalytic properties. AB - Submicrometer-sized anatase TiO(2) hollow spheres were fabricated through a template-free solvothermal route using TiCl(4) as a raw material and a mixture of alcohols-acetone as solvent. Control of the hollow spheres' size was achieved by adjusting the ratio of alcohols to acetone. Products were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), high resolution TEM, X-ray photoelectron spectra (XPS), X-ray diffraction (XRD), Fourier transform infrared (FT-IR), and thermogravimetric (TG) analysis. It was found that the formation process of the TiO(2) hollow spheres might include the hydrolysis of Ti(IV) with the water formed from the solvothermal etherification reaction, the aggregation of the anatase TiO(2) nanoparticles, and the Ostwald ripening. Furthermore, the as-prepared TiO(2) hollow nanostructures exhibited good photocatalytic activity for the degradation of phenol. PMID- 22206433 TI - Mechanisms of pH-dependent activity for water oxidation to molecular oxygen by MnO2 electrocatalysts. AB - Manganese oxides function as efficient electrocatalysts for water oxidation to molecular oxygen in strongly alkaline conditions, but are inefficient at neutral pH. To provide new insight into the mechanism underlying the pH-dependent activity of the electrooxidation reaction, we performed UV-vis spectroelectrochemical detection of the intermediate species for water oxidation by a manganese oxide electrode. Layered manganese oxide nanoparticles, delta MnO(2) (K(0.17)[Mn(4+)(0.90)Mn(3+)(0.07)?(0.03)]O(2).0.53H(2)O) deposited on fluorine-doped tin oxide electrodes were shown to catalyze water oxidation at pH from 4 to 13. At this pH range, a sharp rise in absorption at 510 nm was observed with a concomitant increase of anodic current for O(2) evolution. Using pyrophosphate as a probe molecule, the 510 nm absorption was attributable to Mn(3+) on the surface of delta-MnO(2). The onset potential of the water oxidation current was constant at approximately 1.5 V vs SHE from pH 4 to pH 8, but sharply shifted to negative at pH > 8. Strikingly, this behavior was well reproduced by the pH dependence of the onset of 510 nm absorption, indicating that Mn(3+) acts as the precursor of water oxidation. Mn(3+) is unstable at pH < 9 due to the disproportionation reaction resulting in the formation of Mn(2+) and Mn(4+), whereas it is effectively stabilized by the comproportionation of Mn(2+) and Mn(4+) in alkaline conditions. Thus, the low activity of manganese oxides for water oxidation under neutral conditions is most likely due to the inherent instability of Mn(3+), whose accumulation at the surface of catalysts requires the electrochemical oxidation of Mn(2+) at a potential of approximately 1.4 V. This new model suggests that the control of the disproportionation and comproportionation efficiencies of Mn(3+) is essential for the development of Mn catalysts that afford water oxidation with a small overpotential at neutral pH. PMID- 22206434 TI - Synthesis of platinum(II) metallocycles using microwave-assisted heating. AB - An efficient microwave-assisted self-assembly of dinuclear platinum metallocycles is reported. The reactions proceed to afford the products with high purity and yields within 3-4 h. We have used this methodology to synthesize a new 14.75 A * 14.75 A molecular square. The solid-state structure showed a perfect alignment of the squares along the c axis. PMID- 22206437 TI - Fat-1 transgenic cattle as a model to study the function of omega-3 fatty acids. AB - omega-3 polyunsaturated fatty acids have been shown to play an important role in health. Enriched with omega-3 polyunsaturated fatty acids modulate expression of a number of genes with such broad functions as cell proliferation, growth and apoptosis and cell signaling and transduction, these effects, seem to regulate coronary artery disease, hypertension, atherosclerosis, psychiatric disorders and various cancer. In this context, fat-1 transgenic cattle was designed to convert omega-6 to omega-3 fatty acids could form an ideal model to study the effect of omega-3 fatty acids on the above functions. This study focuses on the total genomic difference of gene expression between fat-1 transgenic cattle and wild type using cDNA microarrays, several genes were found to be overexpressed or suppressed in transgenic cattle relative to wild-type, these discrepancy genes related with lipid metabolism, immunity, inflammation nervous development and fertility. PMID- 22206438 TI - Chinese herb mix Tiao-Geng-Tang possesses antiaging and antioxidative effects and upregulates expression of estrogen receptors alpha and beta in ovariectomized rats. AB - BACKGROUND: Herb mixtures are widely used as an alternative to hormonal therapy in China for treatment of the menopausal syndrome. However, composition of these herb mixtures are complex and their working mechanism is often unknown. This study investigated the effect of Tiao-Geng-Tang (TG-decoction), a Chinese herbal mixture extract, in balancing female hormones, regulating expression of estrogen receptors (ERs), and preventing aging-related tissue damage. METHODS: Ovariectomized 5-month-old female rats were used to model menopause and treated with either TG-decoction or conjugated estrogen for 8 weeks. Estradiol (E2), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured in serum and in the hypothalamus. Hypothalamic expression of estrogen receptor (ER) alpha and beta were studied by real-time PCR and western blotting. Total antioxidant capacity (T-AOC), oxidation indicator superoxide dismutase (SOD) activity and tissue damage parameter malondialdehyde (MDA) were measured using standard assays. Aging-related ultrastructural alterations in mitochondria were studied in all animals by transmission electron microscopy. RESULTS: TG-decoction treatment elevated E2 and lowered FSH in serum of ovariectomized rats. The potency and efficacy of TG-decoction on the hypothalamus was generally weaker than that of conjugated estrogens. However, TG-decoction was superior in upregulating expression of ERalpha and beta. TG-decoction increased hypothalamic SOD and T-AOC levels and decreased MDAlevels and mitochondrial damage in hypothalamic neurons. CONCLUSIONS: TG-decoction balances female hormones similarly to conjugated estrogens but less effectively. However, it is superior in up regulating ERalpha and beta and exhibits antioxidative antiaging activities. Whilst it shares similar effects with estrogen, TG-decoction also seems to have distinctive and more complex functions and activities. PMID- 22206439 TI - The bending of cell sheets--from folding to rolling. AB - The bending of cell sheets plays a major role in multicellular embryonic morphogenesis. Recent advances are leading to a deeper understanding of how the biophysical properties and the force-producing behaviors of cells are regulated, and how these forces are integrated across cell sheets during bending. We review work that shows that the dynamic balance of apical versus basolateral cortical tension controls specific aspects of invagination of epithelial sheets, and recent evidence that tissue expansion by growth contributes to neural retinal invagination in a stem cell-derived, self-organizing system. Of special interest is the detailed analysis of the type B inversion in Volvox reported in BMC Biology by Hohn and Hallmann, as this is a system that promises to be particularly instructive in understanding morphogenesis of any monolayered spheroid system. PMID- 22206440 TI - Performance of conventional and antimicrobial-treated filtering facepiece respirators challenged with biological aerosols. AB - This study evaluated the filtration performance of four commercially available models of National Institute of Occupational Safety and Health (NIOSH)-certified filtering facepiece respirators (FFR) against both biological and inert aerosols at a flow rate of 85 L/min. Conventional N95 and P100 FFRs and two antimicrobial (AM)-treated FFRs (an N95 and a P95, both with iodine-based AM treatments) were tested for both physical penetration (PEN(P)) and viable penetration (PEN(V)) with three different bioaerosols, including MS2 bacteriophage virus, and the spores and vegetative cells of Bacillus atrophaeus bacteria, in addition to inert sodium chloride (NaCl) aerosol. For each FFR model, the PEN(P) measured with NaCl was predictive of its MS2 PEN(P), and it was observed that spores and bacteria aerosols were also filtered similarly to the inert aerosol. For both conventional FFRs, up to a 1-log reduction in PEN(V) in comparison with PEN(P) was observed and attributed to the experimental variability of the test system. For both models of AM-FFRs, no statistically significant differences between PEN(V) and PEN(P) for any of the three different bioaerosol challenges were observed. Thus, no bioaerosol filtration enhancement over the conventional FFRs was detected for either iodine-based AM-FFR. In the absence of any standardized test methods, we recommend that future studies evaluating the filtration performance of AM-treated FFRs incorporate the experimental best practices described herein. PMID- 22206442 TI - Community-engaged research to identify house parent perspectives on support and risk within the House and Ball scene. AB - This article describes a community-engaged study with the Los Angeles House and Ball scene in which the perspectives of the leaders of these communities are captured to better understand how the House and Ball communities may protect or increase its members' risks for HIV infection. Data were collected through in depth interviews with House parents (N = 26). This study identified key features of both support (e.g., family and support, acceptance, and validation and recognition) and risk (e.g., members' struggles to maintain status in the Ballroom scene, sex work, substance use, danger of becoming too involved in the Ball community, and perception and stigma of the Ballroom scene within the larger gay community) within these communities. Findings are discussed in relation to framing how to leverage the supportive aspects of the House and Ball communities to design relevant HIV-prevention interventions. PMID- 22206443 TI - Expression divergence measured by transcriptome sequencing of four yeast species. AB - BACKGROUND: The evolution of gene expression is a challenging problem in evolutionary biology, for which accurate, well-calibrated measurements and methods are crucial. RESULTS: We quantified gene expression with whole transcriptome sequencing in four diploid, prototrophic strains of Saccharomyces species grown under the same condition to investigate the evolution of gene expression. We found that variation in expression is gene-dependent with large variations in each gene's expression between replicates of the same species. This confounds the identification of genes differentially expressed across species. To address this, we developed a statistical approach to establish significance bounds for inter-species differential expression in RNA-Seq data based on the variance measured across biological replicates. This metric estimates the combined effects of technical and environmental variance, as well as Poisson sampling noise by isolating each component. Despite a paucity of large expression changes, we found a strong correlation between the variance of gene expression change and species divergence (R2 = 0.90). CONCLUSION: We provide an improved methodology for measuring gene expression changes in evolutionary diverged species using RNA Seq, where experimental artifacts can mimic evolutionary effects.GEO Accession Number: GSE32679. PMID- 22206445 TI - Is there still a place for the cemented titanium femoral stem? 10,108 cases from the Norwegian Arthroplasty Register. AB - BACKGROUND AND PURPOSE: Despite the fact that there have been some reports on poor performance, titanium femoral stems intended for cemented fixation are still used at some centers in Europe. In this population-based registry study, we examined the results of the most frequently used cemented titanium stem in Norway. PATIENTS AND METHODS: 11,876 cases implanted with the cemented Titan stem were identified for the period 1987-2008. Hybrid arthroplasties were excluded, leaving 10,108 cases for this study. Stem survival and the influence of age, sex, stem offset and size, and femoral head size were evaluated using Cox regression analyses. Questionnaires were sent to the hospitals to determine the surgical technique used. RESULTS: Male sex, high stem offset, and small stem size were found to be risk factors for stem revision, (adjusted RR = 2.5 (1.9-3.4), 3.3 (2.3-4.8), and 2.2 (1.4-3.5), respectively). Patients operated in the period 2001 2008 had an adjusted relative risk (RR) of 4.7 (95% CI: 3.0-7.4) for stem revision due to aseptic stem loosening compared to the period 1996-2000. Changes in broaching technique and cementing technique coincided with deterioration of the results in some hospitals. INTERPRETATION: The increased use of small stem sizes and high-offset stems could only explain the deterioration of results to a certain degree since the year 2000. The influence of discrete changes in surgical technique over time could not be fully evaluated in this registry study. We suggest that this cemented titanium stem should be abandoned. The results of similar implants should be carefully evaluated. PMID- 22206446 TI - Patient-reported outcome after rheumatoid arthritis-related surgery in the lower extremities: a report from the Swedish National Register of Rheuma Surgery (RAKIR). AB - BACKGROUND AND PURPOSE: Although decreasing with the development of effective pharmacological regimes, joint surgery has improved the function and quality of life of patients with rheumatoid arthritis (RA). Few studies have assessed patient-reported outcomes after RA surgery to the lower extremities. Here we report patient-relevant outcome after RA-related surgery based on the first data from the Swedish National Register of Rheuma Surgery (RAKIR). PATIENTS AND METHODS: 258 RA patients (212 women) who had joint surgery performed at the Department of Orthopaedics, Spenshult Hospital between September 2007 and June 2009 were included. Mean age at surgery was 64 (20-86) years. The patients completed the SF-36 and HAQ questionnaires preoperatively and 6 months postoperatively, and 165 patients completed them after 12 months. RESULTS: Improvement was seen as early as at 6 months. At 12 months, 165 patients (141 women)-including hip (n = 15), knee (n = 27), foot (n = 102), and ankle (n = 21) patients-reported statistically significant improvements from preoperatively to 12 months postoperatively in HAQ (mean change: -0.11) and SF-36 subscales physical function (11), role physical (12), bodily pain (13), social functioning (6.4), and role emotional (9.4). Hip and knee patients reported the greatest improvements. INTERPRETATION: Orthopedic RA-related surgery of the lower extremities has a strong effect on pain and physical function. Improvement is evident as early as 6 months postoperatively and remains after 12 months. PMID- 22206447 TI - Continued stabilization of trabecular metal tibial monoblock total knee arthroplasty components at 5 years-measured with radiostereometric analysis. AB - BACKGROUND AND PURPOSE: The trabecular metal tibial monoblock component (TM) is a relatively new option available for total knee arthroplasty. We have previously reported a large degree of early migration of the trabecular metal component in a subset of patients. These implants all appeared to stabilize at 2 years. We now present 5-year RSA results of the TM and compare them with those of the NexGen Option Stemmed cemented tibial component (Zimmer, Warsaw IN). PATIENTS AND METHODS: 70 patients with osteoarthritis were randomized to receive either the TM implant or the cemented component. RSA examination was done postoperatively and at 6 months, 1 year, 2 years, and 5 years. RSA outcomes were translations, rotations, and maximum total point motion (MTPM) of the components. MTPM values were used to classify implants as "at risk" or "stable". RESULTS: At the 5-year follow-up, 45 patients were available for analysis. There were 27 in the TM group and 18 in the cemented group. MTPM values were similar in the 2 groups (p = 0.9). The TM components had significantly greater subsidence than the cemented components (p = 0.001). The proportion of "at risk" components at 5 years was 2 of 18 in the cemented group and 0 of 27 in the TM group (p = 0.2). INTERPRETATION: In the previous 2-year report, we expressed our uncertainty concerning the long-term stability of the TM implant due to the high initial migration seen in some cases. Here, we report stability of this implant up to 5 years in all cases. The implant appears to achieve solid fixation despite high levels of migration initially. PMID- 22206449 TI - Surgery of skeletal metastases in 306 patients with prostate cancer. AB - PURPOSE: Skeletal metastases are common in patients with prostate cancer, and they can be a source of considerable morbidity. We analyzed patient survival after surgery for skeletal metastases and identified risk factors for reoperation and complications. PATIENTS AND METHODS: This study included 306 patients with prostate cancer operated for skeletal metastases during 1989-2010. Kaplan-Meier analysis was used to calculate survival. Cox multiple regression analysis was performed to study risk factors, and results were expressed as hazard ratios (HRs). RESULTS: The median age at surgery was 72 (49-94) years. The median survival after surgery was 0.5 (0-16) years. The cumulative 1-, 2-, and 3-year survival after surgery was 29% (95% CI: 24-34), 14% (10-18), and 8% (5-11). Age over 70 years (HR 1.4), generalized metastases (HR 2.4), and multiple skeletal metastases (HR 2.3) resulted in an increased risk of death after surgery. Patients with lesions in the humerus (HR 0.6) had a lower death rate. The reoperation rate was 9% (n = 31). The reasons for reoperation were deep wound infection (n = 10), hematoma (n = 7), material (implant) failure (n = 3), wound dehiscence (n = 3), increasing neurological symptoms (n = 2), prosthetic dislocation (n = 2), and others (n = 4). INTERPRETATION: This study involves the largest reported cohort of patients operated for skeletal lesions from prostate cancer. Our survival data and analysis of predictors for survival help to set appropriate expectations for the patients, families, and medical staff. PMID- 22206448 TI - Interleukin-7 levels in synovial fluid increase with age and MMP-1 levels decrease with progression of osteoarthritis. AB - BACKGROUND AND PURPOSE: Little is known about biochemical mediators that correlate with the initiation and progression of knee osteoarthritis (OA). We therefore valuated the roles of cytokines and metalloenzymes in knee OA in relation to OA grading, age, and BMI. PATIENTS AND METHODS: A multiplex ELISA based immunoassay (Luminex technology) was used to measure biochemical mediators in the synovial fluid (SF) of 82 patients undergoing knee surgery. All patients were classified according to age, BMI, and OA grade. 24 patients had no signs of OA (knee reconstruction surgeries). The mediators that were tested for included interleukins (IL-1Ra, IL-6, IL-7, and IL-18), chemokines (CCL2 (MCP-1), CCL3 (MIP 1a), and CXCL8 (IL-8)), growth factors (HGF and VEGF), and matrix metalloproteinases (MMP-1, MMP-2, MMP-9, and MMP-13). RESULTS: There was a correlation between IL-7 levels in SF and age (p < 0.01). The 11 highest IL-7 levels were seen in patients who were aged between 59 and 72 but had different OA grades. In contrast, all patients who had severe OA in all 3 knee compartments (pan-OA) had only low or medium IL-7 levels. There was a negative correlation between MMP-1 levels in synovial fluid and grade of OA (p < 0.001). Correlation studies between pairs of mediators revealed two groups of mediators that are important in OA progression, dominated by MCP-1 and IL-1Ra. INTERPRETATION: IL-7 levels in SF are elevated in elderly people suffering from OA of different grades, but they are depressed in patients with severe 3-compartment OA, possibly due to widely impaired chondrocytes embedded in the affected cartilage tissue. The observed decrease in MMP-1 levels in SF, which is dependent on the severity of OA, may be caused by deterioration of superficial cartilage layers during progression of OA. PMID- 22206451 TI - In vitro digestion kinetics of excipients for lipid-based drug delivery and introduction of a relative lipolysis half life. AB - BACKGROUND: Lipid-based drug delivery systems are widely used for enhancing the solubility of poorly water soluble drugs in the gastro-intestinal tract. Following oral intake, lipid systems undergo digestion in the stomach as well as the intestine. Lipolysis is here a complex process at the oil/water interface, influenced by numerous factors. PURPOSE: To study the digestibility of nine excipients often used in lipid-based drug delivery systems. In addition, we introduced a mathematical model to describe in vitro lipolysis kinetics. A relative lipolysis half life was defined using the reference excipient medium chain triglycerides. METHODS: Using pH-stat equipment, the NaOH consumption was determined in an in vitro lipolysis assay. RESULTS: We identified two classes of excipients. Some additives were partially hydrolysed, whereas other excipients displayed complete lipolysis. For the latter class, a simplified mathematical model provided a good first approximation of initial lipolysis kinetics. CONCLUSIONS: Digestion characterization of excipients is important for the development of lipid-based delivery systems. The applied kinetic model and the concept of a relative lipolysis half life seemed to be promising tools for comparing in vitro lipolysis results. PMID- 22206453 TI - Constant flow-driven microfluidic oscillator for different duty cycles. AB - This paper presents microfluidic devices that autonomously convert two constant flow inputs into an alternating oscillatory flow output. We accomplish this hardware embedded self-control programming using normally closed membrane valves that have an inlet, an outlet, and a membrane-pressurization chamber connected to a third terminal. Adjustment of threshold opening pressures in these 3-terminal flow switching valves enabled adjustment of oscillation periods to between 57 and 360 s with duty cycles of 0.2-0.5. These values are in relatively good agreement with theoretical values, providing the way for rational design of an even wider range of different waveform oscillations. We also demonstrate the ability to use these oscillators to perform temporally patterned delivery of chemicals to living cells. The device only needs a syringe pump, thus removing the use of complex, expensive external actuators. These tunable waveform microfluidic oscillators are envisioned to facilitate cell-based studies that require temporal stimulation. PMID- 22206454 TI - Krill oil attenuates left ventricular dilatation after myocardial infarction in rats. AB - BACKGROUND: In the western world, heart failure (HF) is one of the most important causes of cardiovascular mortality. Supplement with n-3 polyunsaturated fatty acids (PUFA) has been shown to improve cardiac function in HF and to decrease mortality after myocardial infarction (MI). The molecular structure and composition of n-3 PUFA varies between different marine sources and this may be of importance for their biological effects. Krill oil, unlike fish oil supplements, contains the major part of the n-3 PUFA in the form of phospholipids. This study investigated effects of krill oil on cardiac remodeling after experimental MI. Rats were randomised to pre-treatment with krill oil or control feed 14 days before induction of MI. Seven days post-MI, the rats were examined with echocardiography and rats in the control group were further randomised to continued control feed or krill oil feed for 7 weeks before re examination with echocardiography and euthanization. RESULTS: The echocardiographic evaluation showed significant attenuation of LV dilatation in the group pretreated with krill oil compared to controls. Attenuated heart weight, lung weight, and levels of mRNA encoding classical markers of LV stress, matrix remodeling and inflammation reflected these findings. The total composition of fatty acids were examined in the left ventricular (LV) tissue and all rats treated with krill oil showed a significantly higher proportion of n-3 PUFA in the LV tissue, although no difference was seen between the two krill oil groups. CONCLUSIONS: Supplement with krill oil leads to a proportional increase of n-3 PUFA in myocardial tissue and supplement given before induction of MI attenuates LV remodeling. PMID- 22206455 TI - Immunolocalization of aquaporin 7 in human sperm and its relationship with semen parameters. AB - Aquaporins (AQPs) are a family of 13 small hydrophobic trans-membrane proteins expressed in numerous tissues and cells. Some AQPs work as strict water channels, others are permeable to a range of substances, including glycerol. In the male reproductive system their localization in testis, efferent ducts, epididymis, and spermatozoa has been described. We studied the distribution of AQP7 in ejaculated human sperm and the relationship between AQP7 labeling and sperm characteristics. Semen samples from 33 men were examined by light and transmission electron microscopy (TEM). TEM data were quantified using a mathematical formula that calculates a fertility index (FI) and the percentages of sperm apoptosis, immaturity, and necrosis. Immunocytochemistry with a polyclonal antibody anti AQP7 was performed on the sperm samples. Normal sperm were labeled in the pericentriolar area, midpiece, equatorial segment, and weakly in the tail (grade 1). Abnormal sperm showed a diffuse low intensity of fluorescence evident in the cytoplasmic residues, coiled tails, in the entire head, and acrosome (grade 2). A high number of motile sperm obtained by swim up were labeled in a dotted manner in the mitochondria. A significant positive correlation was found between the spermatozoa with AQP7 grade 1 labeling and the percentage of normal form (P<0.008), progressive motility and FI (P<0.005); a negative correlation was noted with the percentages of cytoplasmic residues (P<0.010) and immaturity (P<0.006) and coiled tails (P<0.012). The link between AQP7 distribution and sperm morphology and the particular dotted labeling in swim up selected motile sperm are novel and deserve additional studies. PMID- 22206456 TI - Stereochemistry-dependent, mechanoresponsive supramolecular host assemblies for fullerenes: a guest-induced enhancement of thixotropy. AB - Self-assembly behaviors of a series of systems (G1, G2, and G3) possessing same organic building blocks based on a substituted anthracene have been investigated in decalin. G2 and G3 are dominated by head-to-tail (ht) and head-to-head (hh) type dimers of G1, respectively. G1 gives a thermoresponsive gel that behaves ideally, showing frequency-independent elastic and viscous moduli. Interestingly, G2 produces a thixotropic gel that shows the signature of structural relaxation, signifying the dynamic nature of the system. In contrast, G3 remains fluidlike. As investigated by scanning electron microscopy (SEM), in the assembly process of G2, first disklike nanoaggregates are formed, and in the second step these aggregates interact to construct the densely packed secondary assembly. A transition from secondary assembly to primary assembly under shear initiates the mechanoresponsive destruction of the gel. In the self-assembly process, G1 propagates in a one-dimensional fashion, whereas G2 and G3 can propagate in a two dimensionional fashion. The same side orientation of the substituents in G3 facilitates the formation of a compact closed-shell-type structure, which results in the generation of isolated nanocrystals. The long-range weak interaction together with the capability of propagating in two dimensions is found to be essential for the construction of such a mechanoresponsive assembly. C(60) and C(70) could be incorporated successfully in G2 assembly to develop mechanoresponsive fullerene assemblies. The presence of fullerenes not only enhances the elastic properties of G2 but also intensifies the thixotropy. C(70) appears to be a superior guest in terms of property enhancement due to its better size fitting with the concave-shaped host. PMID- 22206457 TI - Silica nanoparticles and frameworks from rice husk biomass. AB - Biogenic silica nanoparticles (25-30 nm in diameter) were synthesized from rice husks. The characterizations revealed that the silica nanoparticles were composed of smaller primary particles (ca. 4.2 nm in diameter), and their clustering led to a porous structure with a surface area of 164 m(2)/g. Under the controlled melting catalyzed by K(+), such silica nanoparticle clusters can gradually fuse to form semicrystalline porous silica frameworks with tunable pore size and structural integrity. PMID- 22206462 TI - Difficult phylogenetic questions: more data, maybe; better methods, certainly. AB - Contradicting the prejudice that endosymbiosis is a rare phenomenon, Husnik and co-workers show in BMC Biology that bacterial endosymbiosis has occured several times independently during insect evolution. Rigorous phylogenetic analyses, in particular using complex models of sequence evolution and an original site removal procedure, allow this conclusion to be established after eschewing inference artefacts that usually plague the positioning of highly divergent endosymbiont genomic sequences. PMID- 22206463 TI - Rhenium-catalyzed regiodivergent addition of indoles to terminal alkynes. AB - An efficient rhenium-catalyzed site-switchable addition of indoles to terminal alkynes is described. A variety of bisindolylalkane derivatives are expeditiously synthesized in high yields with excellent regioselectivity. Preliminary mechanistic study sheds light on the observed regiodivergent addition. PMID- 22206464 TI - Development and validation of the endorsement of the hookup culture index. AB - Although researchers have examined the predictors and outcomes of the behavioral aspect of "hooking up," typically defined as casual, commitment-free sexual encounters, research has not yet examined the extent to which young people endorse the culture associated with hooking up. Based on the argument that there is a set of understood rules and assumptions associated with hooking up, this article describes the development of an instrument to measure college students' endorsement of the hookup culture. Results from two studies found that five factors represent endorsement of the hookup culture: (a) a belief that hooking up is harmless and best without emotional commitment, (b) a belief that hooking up is fun, (c) a belief that hooking up will enhance one's status in one's peer group, (d) a belief that hooking up allows one to assert control over one's sexuality, and (e) a belief that hooking up is a reflection of one's sexual freedom. The index also had acceptable internal reliability, and performed well on the tests of construct validity. Taken together, the results suggest that the Endorsement of the Hookup Culture Index is suitable for use by researchers interested in the social phenomenon of hooking up. PMID- 22206465 TI - Apparent clearance of valproic acid in elderly epileptic patients: estimation of the confounding effect of albumin concentration. AB - BACKGROUND: Valproic acid (VPA) apparent clearance (CL) estimated from total serum concentrations is analogous in elderly and non-elderly adult patients. As drug-protein binding decreases in old age, the aim of our study was to evaluate the confounding effect of the serum albumin concentration on the VPA apparent CL in elderly patients. METHODS: In 102 epileptic out-patients treated with VPA in monotherapy, serum total steady-state trough concentrations (Css) were determined. Css concentrations were normalized for a 42 g/L albumin concentration (Css(N)), and the apparent CL and normalized apparent CL(N) were calculated. RESULTS: A poor concordance of 53% was found in the classification of Css and Css(N) levels of VPA as subtherapeutic, therapeutic, or supratherapeutic dose. In the elderly (>=65 years) and non-elderly adult patients, the VPA apparent CL was similar; however, normalized apparent CL(N) was significantly lower in older patients (P < 0.01), with a 40% median decrease. CONCLUSIONS: Total VPA concentrations should be interpreted with caution, mainly in older patients, in which determination of unbound or normalized total drug concentrations may be clinically useful. Normalization of total concentrations permits an estimation of the masking effect of serum albumin concentrations on the VPA apparent CL in elderly patients. PMID- 22206466 TI - Ectopic liver within the umbilical cord in a very preterm infant from a multiple gestation. AB - A 29 weeks' gestational age newborn, the product of a multiple gestation, was found to have a round mass in the umbilical cord; the resected lesion was an ectopic liver tissue (3 * 2 cm). She also had an imperforated hymen; otherwise, no other abnormalities were seen. The infant survived. Some possible mechanisms that may be associated with an ectopic liver tissue are presented. PMID- 22206467 TI - GIS-based regionalized life cycle assessment: how big is small enough? Methodology and case study of electricity generation. AB - We describe a new methodology for performing regionalized life cycle assessment and systematically choosing the spatial scale of regionalized impact assessment methods. We extend standard matrix-based calculations to include matrices that describe the mapping from inventory to impact assessment spatial supports. Uncertainty in inventory spatial data is modeled using a discrete spatial distribution function, which in a case study is derived from empirical data. The minimization of global spatial autocorrelation is used to choose the optimal spatial scale of impact assessment methods. We demonstrate these techniques on electricity production in the United States, using regionalized impact assessment methods for air emissions and freshwater consumption. Case study results show important differences between site-generic and regionalized calculations, and provide specific guidance for future improvements of inventory data sets and impact assessment methods. PMID- 22206470 TI - Selective dehydrogenative silylation-hydrogenation reaction of divinyldisiloxane with hydrosilane catalyzed by an iron complex. AB - A hydride and a silyl group of hydrosilane is introduced into 1,3 divinyldisiloxane in the presence of a catalytic amount of (eta(5) C(5)H(5))Fe(CO)(2)Me. Instead of the product expected from the well-known hydrosilylation reaction, the product obtained is that characteristic of dehydrogenative silylation at one vinyl group and hydrogenation at the other vinyl group of 1,3-divinyldisiloxane. Based on deuterium labeling experiments, a catalytic cycle for this new reaction has been proposed. PMID- 22206469 TI - Formulation and evaluation of novel coated floating tablets of bergenin and cetirizine dihydrochloride for gastric delivery. AB - A novel coated gastric floating drug-delivery system (GFDDS) of bergenin (BN) and cetirizine dihydrochloride (CET) was developed. First, the pharmacodynamic studies were performed and the results revealed that the new compounds of bergenin/cetirizine dihydrochloride had comparative efficacy as commercial products (bergenin/chlorphenamine maleate) but with fewer side effects on central nervous system (CNS). Subsequently, bergenin was formulated as an extended release core tablet while cetirizine dihydrochloride was incorporated into the gastric coating film for immediate release. The formulation of GFDDS was optimized by CET content uniformity test, in vitro buoyancy and drug release. Herein, the effects of sodium bicarbonate (effervescent), hydroxypropyl methylcellulose (HPMC, matrix polymer) and coating weight gain were investigated respectively. The optimized GFDDS exhibited good floating properties (buoyancy lag time < 2 min; floating duration > 10 h) and satisfactory drug-release profiles (immediate release of CET in 10 min and sustained release of BN for 12 h). In vivo gamma scintigraphy proved that the optimized GFDDS could retain in the stomach with a prolonged gastric retention time (GRT) of 5 h, and the coating layer showed no side effect for gastric retention. The novel coated gastric floating drug-delivery system offers a new approach to enhance BN's absorption at its absorption site and the efficacy of both CET and BN. PMID- 22206471 TI - A survey of engagement and competence levels in interventions and activities in a community mental health workforce in England. AB - BACKGROUND: National Health Service (NHS) mental health workforce configuration is at the heart of successful delivery, and providers are advised to produce professional development strategies. Recent policy changes in England have sharpened the focus on competency based role development. We determined levels of intervention activities, engagement and competence and their influencing factors in a community-setting mental health workforce. METHODS: Using a modified questionnaire based on the Yorkshire Care Pathways Model we investigated 153 mental health staff working in Coventry and Warwickshire NHS Trust. A median score of competence was computed across 10 cluster activities. Low engagement and competence levels were examined in a logistic regression model. RESULTS: In 220 activities, Monitoring risk was the highest rate of engagement (97.6%) and Group psychological therapy/Art/Drama therapy was the lowest engagement (3.6%). The median competence level based on all activities was 3.95 (proficient). There were significant differences in the competence level among professional groups; non qualified support group (3.00 for competent), Counsellor/Psychologist/Therapist (3.38), Occupational therapists (3.76), Nurses (4.01), Medical staff (4.05), Social workers (4.25) and Psychologists (4.62 for proficient/expert). These levels varied with activity clusters; the lowest level was for Counsellor/Psychologist/Therapist in the accommodation activity (1.44 novice/advance beginner) and the highest for Occupational therapists in personal activity (4.94 expert). In a multivariate analysis, low competence was significantly related to non-qualified community support professions, late time of obtaining first qualification, more frequencies of clinical training, and training of cognitive behavioural therapy. The associations were similar in the analysis for 10 activity clusters respectively. CONCLUSIONS: There was a reasonable competence level in the community-setting mental health workforce, but competence varied with professional groups and cluster activities. New staff and other non-qualified support professions need to receive efficient training, and the training content is more important than frequency to increase level of competence. PMID- 22206472 TI - Employing machine learning for reliable miRNA target identification in plants. AB - BACKGROUND: miRNAs are ~21 nucleotide long small noncoding RNA molecules, formed endogenously in most of the eukaryotes, which mainly control their target genes post transcriptionally by interacting and silencing them. While a lot of tools has been developed for animal miRNA target system, plant miRNA target identification system has witnessed limited development. Most of them have been centered around exact complementarity match. Very few of them considered other factors like multiple target sites and role of flanking regions. RESULT: In the present work, a Support Vector Regression (SVR) approach has been implemented for plant miRNA target identification, utilizing position specific dinucleotide density variation information around the target sites, to yield highly reliable result. It has been named as p-TAREF (plant-Target Refiner). Performance comparison for p-TAREF was done with other prediction tools for plants with utmost rigor and where p-TAREF was found better performing in several aspects. Further, p-TAREF was run over the experimentally validated miRNA targets from species like Arabidopsis, Medicago, Rice and Tomato, and detected them accurately, suggesting gross usability of p-TAREF for plant species. Using p TAREF, target identification was done for the complete Rice transcriptome, supported by expression and degradome based data. miR156 was found as an important component of the Rice regulatory system, where control of genes associated with growth and transcription looked predominant. The entire methodology has been implemented in a multi-threaded parallel architecture in Java, to enable fast processing for web-server version as well as standalone version. This also makes it to run even on a simple desktop computer in concurrent mode. It also provides a facility to gather experimental support for predictions made, through on the spot expression data analysis, in its web-server version. CONCLUSION: A machine learning multivariate feature tool has been implemented in parallel and locally installable form, for plant miRNA target identification. The performance was assessed and compared through comprehensive testing and benchmarking, suggesting a reliable performance and gross usability for transcriptome wide plant miRNA target identification. PMID- 22206474 TI - Natural cycle is superior to hormone replacement therapy cycle for vitrificated preserved frozen-thawed embryo transfer. AB - We undertook this retrospective variables-control analysis to compare the reproductive outcomes of frozen-thawed embryo transfer using endometrial preparation with either natural cycle or hormone replacement therapy cycle. Patients were divided into three subgroups. Subgroup A (n = 32) consisted of patients having three 8-cell post-thawed embryos transferred. Subgroup B (n = 404) consisted of patients having three good quality post-thawed embryos transferred. Subgroup C (n = 578) consisted of patients having two or three all intact and mitosis resumption post-thawed embryos transferred. Implantation rate, biochemical pregnancy rate, and clinical pregnancy rate were measured. In subgroup A, significantly higher implantation rate, clinical pregnancy rate ongoing pregnancy rate, and lower biochemical pregnancy rate were observed in the natural cycle compared with hormone replacement therapy (HRT) cycle. Subgroup B, had a significantly higher rate of implantation, ongoing pregnancy, and a significantly lower rate of biochemical pregnancy in natural cycle compared with HRT cycle. The natural cycle had a higher trend of clinical pregnancy rate without reaching statistical significance. No statistical difference in reproductive outcomes between natural cycle and HRT cycle was observed in subgroup C. The results suggest the superiority of the natural cycle as compared with the HRT cycle under certain circumstances in a selected population of patients. PMID- 22206476 TI - Three-dimensional graphene oxide nanostructure for fast and efficient water soluble dye removal. AB - In this study, we demonstrated the potential of graphene nanomaterials as environmental pollutant adsorbents by utilizing the characteristics of ultralarge surface area and strong pi-pi interaction on the surface. We generated a three dimensional (3D) graphene oxide sponge (GO sponge) from a GO suspension through a simple centrifugal vacuum evaporation method, and used them to remove both the methylene blue (MB) and methyl violet (MV) dyes which are main contaminants from the dye manufacturing and textile finishing. The efficiency and speed of dye adsorption on a GO sponge was investigated under various parameters such as contact time, stirring speed, temperature, and pH. The adsorption process shows that 99.1% of MB and 98.8% of MV have been removed and the equilibrium status has been reached in 2 min. The 3D GO sponge displays adsorption capacity as high as 397 and 467 mg g(-1) for MB and MV dye, respectively, and the kinetic data reveal that the adsorption process of MB and MV dyes is well-matched with the pseudo second-order model. The MB and MV adsorption on the 3D GO sponge involved in endothermic chemical adsorption through the strong pi-pi stacking and anion cation interaction with the activation energy of 50.3 and 70.9 kJ mol(-1), respectively. The 3D GO sponge has demonstrated its high capability as an organic dye scavenger with high speed and efficiency. PMID- 22206473 TI - The effect of endogenously released glucose, insulin, glucagon-like peptide 1, ghrelin on cardiac output, heart rate, stroke volume, and blood pressure. AB - BACKGROUND: Ingestion of a meal increases the blood flow to the gastrointestinal organs and affects the heart rate (HR), blood pressure and cardiac output (CO), although the mechanisms are not known. The aim of this study was to evaluate the effect of endogenously released glucose, insulin, glucagon-like peptide 1 (GLP 1), ghrelin on CO, HR, stroke volume (SV), and blood pressure. METHODS: Eleven healthy men and twelve healthy women ((mean +/- SEM) aged: 26 +/- 0.2 y; body mass index: 21.8 +/- 0.1 kg/m(2))) were included in this study. The CO, HR, SV, systolic and diastolic blood pressure, antral area, gastric emptying rate, and glucose, insulin, GLP-1 and ghrelin levels were measured. RESULTS: The CO and SV at 30 min were significantly higher, and the diastolic blood pressure was significantly lower, than the fasting in both men and women (P < 0.05). In men, significant correlations were found between GLP-1 level at 30 min and SV at 30 min (P = 0.015, r = 0.946), and between ghrelin levels and HR (P = 0.013, r = 0.951) at 110 min. Significant correlations were also found between the change in glucose level at 30 min and the change in systolic blood pressure (P = 0.021, r = -0.681), and the change in SV (P = 0.008, r = -0.748) relative to the fasting in men. The insulin 0-30 min AUC was significantly correlated to the CO 0-30 min AUC (P = 0.002, r = 0.814) in men. Significant correlations were also found between the 0-120 min ghrelin and HR AUCs (P = 0.007, r = 0.966) in men. No statistically significant correlations were seen in women. CONCLUSIONS: Physiological changes in the levels of glucose, insulin, GLP-1 and ghrelin may influence the activity of the heart and the blood pressure. There may also be gender-related differences in the haemodynamic responses to postprandial changes in hormone levels. The results of this study show that subjects should not eat immediately prior to, or during, the evaluation of cardiovascular interventions as postprandial affects may affect the results, leading to erroneous interpretation of the cardiovascular effects of the primary intervention. TRIAL REGISTRATION NUMBER: NCT01027507. PMID- 22206477 TI - Lubricated biodegradable polymer networks for regulating nerve cell behavior and fabricating nerve conduits with a compositional gradient. AB - We present a method of tuning surface chemistry and nerve cell behavior by photo cross-linking methoxy poly(ethylene glycol) monoacrylate (mPEGA) with hydrophobic, semicrystalline poly(epsilon-caprolactone) diacrylate (PCLDA) at various weight compositions of mPEGA (o(m)) from 2 to 30%. Improved surface wettability is achieved with corresponding decreases in friction, water contact angle, and capability of adsorbing proteins from cell culture media because of repulsive PEG chains tethered in the network. The responses of rat Schwann cell precursor line (SpL201), rat pheochromocytoma (PC12), and E14 mouse neural progenitor cells (NPCs) to the modified surfaces are evaluated. Nonmonotonic or parabolic dependence of cell attachment, spreading, proliferation, and differentiation on o(m) is identified for these cell types with maximal values at o(m) of 5-7%. In addition, NPCs demonstrate enhanced neuronal differentiated lineages on the mPEGA/PCLDA network at o(m) of 5% with intermediate wettability and surface energy. This approach lays the foundation for fabricating heterogeneous nerve conduits with a compositional gradient along the wall thickness, which are able to promote nerve cell functions within the conduit while inhibiting cell attachment on the outer wall to prevent potential fibrous tissue formation following implantation. PMID- 22206480 TI - Development and validation of HIV-related dyadic measures for men who have sex with men. AB - The purpose of this study was to develop and assess the psychometric properties of several scales that measure dyadic constructs derived from an integrated model of interdependence theory and communal coping perspectives. The scales are specific to HIV risk and men who have sex with men who are in an intimate relationship. These scales are newly developed measures of perceived severity of HIV, preferences for sexual health outcomes, outcome and couple efficacy to avoid HIV, and communal coping strategies. Scale items were created based on theoretical definitions and results from six focus groups with men who have sex with men. Face and content validity of the scales were assessed with a panel of six experts in the field of HIV prevention. Revised scales were subsequently administered to an online sample of 638 men who have sex with men, who indicated being in a relationship for at least three months. All scales showed adequate reliability, and evidence for construct validity was obtained for all scales, except for perceived severity of HIV. The results indicate that these dyadic scales are psychometrically sound and can be used in future HIV prevention research and practice with men who have sex with men couples. PMID- 22206481 TI - Preparation and characterization of mosapride citrate inclusion complexes with natural and synthetic cyclodextrins. AB - The aim of this work was to investigate the inclusion complexes between mosapride citrate and SBE7beta-CD in comparison with the natural beta-CD to enhance its bioavailability by improving the solubility and dissolution rate. The complexation efficiency value of SBE7beta-CD was higher than that for beta-CD. Solid binary systems of mosapride citrate with CDs were prepared by physical mixing, kneading and freeze-drying techniques at molar ratio of 1:1(drug:CD). Physicochemical characterization of the prepared systems was studied using X-ray diffractometry, differential scanning calorimetry, Fourier-transform infrared spectroscopy and scanning electron microscopy (SEM). Amorphous drug was detectable to large extent in inclusion complexes prepared using the freeze drying technique. From the dissolution study of different inclusion complexes in simulated saliva solution (pH 6.8), we could concluded that irrespective of the preparation technique, the systems prepared using SBE7beta-CD showed better performance than the corresponding ones prepared using beta-CD. In addition, the freeze-drying technique showed superior dissolution enhancement than other methods especially when combined with the SBE7beta-CD. PMID- 22206482 TI - Copper-catalyzed aerobic oxidative intramolecular C-H amination leading to imidazobenzimidazole derivatives. AB - A highly efficient copper-catalyzed aerobic oxidative intramolecular C-H amination has been developed using substituted 2-(1H-imidazol-1-yl)-N alkylbenzenamines as the starting materials, and the corresponding imidazobenzimidazole derivatives were obtained in excellent yields. This is an economical and practical method for the construction of N-heterocycles. PMID- 22206484 TI - Scalable method for the reductive dissolution, purification, and separation of single-walled carbon nanotubes. AB - As synthesized, bulk single-walled carbon nanotube (SWNT) samples are typically highly agglomerated and heterogeneous. However, their most promising applications require the isolation of individualized, purified nanotubes, often with specific optoelectronic characteristics. A wide range of dispersion and separation techniques have been developed, but the use of sonication or ultracentrifugation imposes severe limits on scalability and may introduce damage. Here, we demonstrate a new, intrinsically scalable method for SWNT dispersion and separation, using reductive treatment in sodium metal-ammonia solutions, optionally followed by selective dissolution in a polar aprotic organic solvent. In situ small-angle neutron scattering demonstrates the presence of dissolved, unbundled SWNTs in solution, at concentrations reaching at least 2 mg/mL; the ability to isolate individual nanotubes is confirmed by atomic force microscopy. Spectroscopy data suggest that the soluble fraction contains predominately large metallic nanotubes; a potential new mechanism for nanotube separation is proposed. In addition, the G/D ratios observed during the dissolution sequence, as a function of metal:carbon ratio, demonstrate a new purification method for removing carbonaceous impurities from pristine SWNTs, which avoids traditional, damaging, competitive oxidation reactions. PMID- 22206485 TI - Low ficolin-3 levels in early follow-up serum samples are associated with the severity and unfavorable outcome of acute ischemic stroke. AB - BACKGROUND: A number of data indicate that the lectin pathway of complement activation contributes to the pathophysiology of ischemic stroke. The lectin pathway may be triggered by the binding of mannose-binding lectin (MBL), ficolin 2 or ficolin-3 to different ligands. Although several papers demonstrated the significance of MBL in ischemic stroke, the role of ficolins has not been examined. METHODS: Sera were obtained within 12 hours after the onset of ischemic stroke (admission samples) and 3-4 days later (follow-up samples) from 65 patients. The control group comprised 100 healthy individuals and 135 patients with significant carotid stenosis (patient controls). The concentrations of ficolin-2 and ficolin-3, initiator molecules of the lectin complement pathway, were measured by ELISA methods. Concentration of C-reactive protein (CRP) was also determined by a particle-enhanced immunturbidimetric assay. RESULTS: Concentrations of both ficolin-2 and ficolin-3 were significantly (p < 0.001) decreased in both the admission and in the follow-up samples of patients with definite ischemic stroke as compared to healthy subjects. Concentrations of ficolin-2 and ficolin-3 were even higher in patient controls than in healthy subjects, indicating that the decreased levels in sera during the acute phase of stroke are related to the acute ischemic event. Ficolin-3 levels in the follow-up samples inversely correlated with the severity of stroke indicated by NIH scale on admission. In follow-up samples an inverse correlation was observed between ficolin-3 levels and concentration of S100beta, an indicator of the size of cerebral infarct. Patients with low ficolin-3 levels and high CRP levels in the follow up samples had a significantly worse outcome (adjusted ORs 5.6 and 3.9, respectively) as measured by the modified Rankin scale compared to patients with higher ficolin-3 and lower CRP concentrations. High CRP concentrations were similarly predictive for worse outcome, and the effects of low ficolin-3 and high CRP were independent. CONCLUSIONS: Our findings indicate that ficolin-mediated lectin pathways of complement activation contribute to the pathogenesis of ischemic stroke and may be additive to complement-independent inflammatory processes. PMID- 22206487 TI - Design, synthesis, and biological evaluation of potent quinoline and pyrroloquinoline ammosamide analogues as inhibitors of quinone reductase 2. AB - A variety of ammosamide B analogues have been synthesized and evaluated as inhibitors of quinone reductase 2 (QR2). The potencies of the resulting series of QR2 inhibitors range from 4.1 to 25,200 nM. The data provide insight into the structural parameters necessary for QR2 inhibitory activity. The natural product ammosamide B proved to be a potent QR2 inhibitor, and the potencies of the analogues generally decreased as their structures became more distinct from that of ammosamide B. Methylation of the 8-amino group of ammosamide B was an exception, resulting in an increase in quinone reductase 2 inhibitory activity from an IC(50) of 61 nM to IC(50) 4.1 nM. PMID- 22206488 TI - Phosphorus dendrimers affect Alzheimer's (Abeta1-28) peptide and MAP-Tau protein aggregation. AB - Alzheimer's disease (AD) is characterized by pathological aggregation of beta amyloid peptides and MAP-Tau protein. beta-Amyloid (Abeta) is a peptide responsible for extracellular Alzheimer's plaque formation. Intracellular MAP-Tau aggregates appear as a result of hyperphosphorylation of this cytoskeletal protein. Small, oligomeric forms of Abeta are intermediate products that appear before the amyloid plaques are formed. These forms are believed to be most neurotoxic. Dendrimers are highly branched polymers, which may find an application in regulation of amyloid fibril formation. Several biophysical and biochemical methods, like circular dichroism (CD), fluorescence intensity of thioflavin T and thioflavin S, transmission electron microscopy, spectrofluorimetry (measuring quenching of intrinsic peptide fluorescence) and MTT-cytotoxicity assay, were applied to characterize interactions of cationic phosphorus-containing dendrimers of generation 3 and generation 4 (CPDG3, CPDG4) with the fragment of amyloid peptide (Abeta(1-28)) and MAP-Tau protein. We have demonstrated that CPDs are able to affect beta-amyloid and MAP-Tau aggregation processes. A neuro-2a cell line (N2a) was used to test cytotoxicity of formed fibrils and intermediate products during the Abeta(1-28) aggregation. It has been shown that CPDs might have a beneficial effect by reducing the system toxicity. Presented results suggest that phosphorus dendrimers may be used in the future as agents regulating the fibrilization processes in Alzheimer's disease. PMID- 22206489 TI - Emil Kraepelin's habilitation and his thesis: a pioneer work for modern systematic reviews, psychoimmunological research and categories of psychiatric diseases. AB - OBJECTIVES: Although Kraepelin and his oeuvre have been in scientific focus over the past decades, main aspects have still been neglected. Thus the exact circumstances under which and on what topic Kraepelin wrote his habilitation thesis and qualified as university lecturer (in Germany the prerequisite to be appointed as professor) are still widely unknown. METHODS: This study reconstructs his habilitation at the Medical Faculty of Leipzig University in 1882. RESULTS: The study reveals the difficulties he had to habilitate on a topic from Wilhelm Wundt's experimental psychology and the opposition he faced from Paul Flechsig. Yet Kraepelin succeeded, mainly due to a positive review by neurologist Wilhelm Erb on his study "On the Influence of Acute Diseases on the Development of Mental Illnesses" (1881/82). CONCLUSIONS: This work must be regarded as his actual habilitation thesis. It provides an update of organic psychiatric disorders following acute inflammatory diseases and a meta-analysis on the basis of raw data. In addition it discusses possibilities to categorize and understand the pathophysiological mechanism of these disorders and to classify them into those appearing when the fever rises and those occurring when it falls, which has a high impact from a very modern psychoimmunological viewpoint. PMID- 22206490 TI - Improving accuracy of medication identification in an older population using a medication bottle color symbol label system. AB - BACKGROUND: The purpose of this pilot study was to evaluate and refine an adjuvant system of color-specific symbols that are added to medication bottles and to assess whether this system would increase the ability of patients 65 years of age or older in matching their medication to the indication for which it was prescribed. METHODS: This study was conducted in two phases, consisting of three focus groups of patients from a family medicine clinic (n = 25) and a pre-post medication identification test in a second group of patient participants (n = 100). Results of focus group discussions were used to refine the medication label symbols according to themes and messages identified through qualitative triangulation mechanisms and data analysis techniques. A pre-post medication identification test was conducted in the second phase of the study to assess differences between standard labeling alone and the addition of the refined color specific symbols. The pre-post test examined the impact of the added labels on participants' ability to accurately match their medication to the indication for which it was prescribed when placed in front of participants and then at a distance of two feet. RESULTS: Participants appreciated the addition of a visual aid on existing medication labels because it would not be necessary to learn a completely new system of labeling, and generally found the colors and symbols used in the proposed labeling system easy to understand and relevant. Concerns were raised about space constraints on medication bottles, having too much information on the bottle, and having to remember what the colors meant. Symbols and colors were modified if they were found unclear or inappropriate by focus group participants. Pre-post medication identification test results in a second set of participants demonstrated that the addition of the symbol label significantly improved the ability of participants to match their medication to the appropriate medical indication at a distance of two feet (p < 0.001) and approached significant improvement when placed directly in front of participants (p = 0.07). CONCLUSIONS: The proposed medication symbol label system provides a promising adjunct to national efforts in addressing the issue of medication misuse in the home through the improvement of medication labeling. Further research is necessary to determine the effectiveness of the labeling system in real-world settings. PMID- 22206492 TI - Ageing prolongs inflammatory marker expression in regenerating rat skeletal muscles after injury. AB - BACKGROUND: Some of the most serious consequences of normal ageing relate to its effects on skeletal muscle, particularly significant wasting and associated weakness, termed "sarcopenia". The underlying mechanisms of sarcopenia have yet to be elucidated completely but an altered muscle inflammatory response after injury is a likely contributing factor. In this study we investigated age-related changes in the expression of numerous inflammatory markers linked to successful muscle regeneration. METHODS: Right extensor digitorum longus (EDL) muscles from young (3 month), adult (12 month) and old (24 month) male F344 rats were injected with bupivacaine hydrochloride to cause complete muscle fibre degeneration, then excised 12, 24, 36, and 72 hours later (n = 5/age group/time point). We used qRT PCR to quantify the mRNA expression levels of the inflammatory markers TNFalpha, IFNgamma, IL1, IL18, IL6, and CD18 as well as regenerative markers MyoD and myogenin. RESULTS: Inflammatory markers were all increased significantly in all age groups after myotoxic injury. There was a trend for expression of inflammatory markers to be higher in uninjured muscles of old rats, especially at 72 hours post injury where the expression levels of several markers was significantly higher in old compared with young and adult rats. There was also a decrease in the expression of regenerative markers in old rats at 72 hours post injury. CONCLUSION: Our findings identify a prolonged inflammatory signature in injured muscles from old compared with young and adult rats together with a blunted expression of key markers of regeneration in muscles of old rats. Importantly, our findings identify potential targets for future therapeutic strategies for improving the regenerative capacity of skeletal muscle during ageing. PMID- 22206493 TI - Earlier surgical intervention in congenital heart disease results in better outcome and resource utilization. AB - BACKGROUND: Congenital heart disease (CHD) accounts for a major proportion of disease in the pediatric age group. The objective of the study was to estimate the cost of illness associated with CHD pre, intra and postoperatively; among patients referred to a tertiary care hospital in Karachi, Pakistan. This is the first study conducted to estimate the cost of managing CHD in Pakistan. METHODS: A prevalence based cost of illness study design was used to estimate the cost of cardiac surgery (corrective & palliative) for congenital heart defects in children <= 5 years of age from June 2006 to June 2009. A total of 120 patients were enrolled after obtaining an informed consent and the data was collected using a pre-tested questionnaire. RESULTS: The mean age at the time of surgery in group A (1-12 mo age) was 6.08 +/- 2.80 months and in group B (1-5 yrs) was 37.10 +/- 19.94 months. The cost of surgical admission was found to be significantly higher in the older group, p = 0.001. The total number and cost of post-operative outpatient visits was also higher in group B, p = 0.003. Pre and post operative hospital admissions were not found to be significantly different among the two groups, p = 0.166 and 0.627, respectively. The number of complications were found to be different between the two groups (p = 0.019). Majority of these were contributed by hemorrhage and post-operative seizures. CONCLUSION: This study concluded that significant expenditure is incurred by people with CHD; with the implication that resources could be saved by earlier detection and awareness campaigns. PMID- 22206494 TI - Knowledge mobilization regarding activity and exercise after spinal cord injury: a Canadian undergraduate curriculum scan. AB - PURPOSE: The purpose of this study was to conduct a curriculum scan of Canadian undergraduate university programs to determine the relative emphasis placed on the activity and exercise after spinal cord injury (SCI), in the context of physical disability studies. METHOD: Eighty-three Canadian Universities were evaluated for courses discussing: (i) general information about SCI, (ii) physical activity and exercise after SCI, (iii) general information about other physical disabilities and (iv) physical activity and exercise for such disabilities. Online course calendars (2009) were scanned, and their accuracy was verified by instructors or administrative assistants. RESULTS: The curriculum scan revealed 113 courses that discuss physical disability. Seventy-four of these courses cover information regarding SCI, 47 of which include content relating to activity and exercise. In comparison, 104 courses discuss other physical disabilities, 76 of which cover material related to activity and exercise. Further, the 47 courses that cover activity and exercise after SCI are only offered in 22 Canadian Universities, and only 31 are mandatory for a degree. CONCLUSIONS: A substantial number of future healthcare professionals lack exposure to material regarding activity and exercise after SCI during their undergraduate education. This curricular oversight likely contributes to ineffective exercise strategies and the relative inactivity of the SCI population. [ IMPLICATIONS FOR REHABILITATION: * Individuals with spinal cord injury are relatively inactive due to the many physical, psychological and social barriers they face regarding activity and exercise participation.* Effective knowledge mobilization regarding activity and exercise after SCI to future healthcare providers is an essential step in promoting participation.* This undergraduate curriculum scan showed that students lack exposure to issues regarding the activity and exercise after SCI in Canadian Universities.* The lack of effective knowledge mobilization in this area likely contributes to the low levels of activity and exercise participation in the SCI population.] PMID- 22206495 TI - Intermolecular interaction between CO or CO2 and ethylene oxide or ethylene sulfide in a complex, investigated by Fourier transform microwave spectroscopy and ab initio calculations. AB - The rotational spectra of the CO-ethylene oxide (EO), CO-ethylene sulfide (ES), CO(2)-EO, and CO(2)-ES complexes were measured by Fourier transform microwave spectroscopy in the frequency region from 4 up to 31 GHz. The isotopologues with a single (13)C atom in the EO or ES, (18)O in the EO, (34)S in the ES, and (13)C in the CO(2) moiety, respectively, were observed in natural abundance, and enriched samples, (13)CO or C(18)O in the CO-EO or CO-ES complex and C(18)OO and C(18)O(2) in the CO(2)-EO or CO(2)-ES complex, were employed to record respective rotational transitions. The rotational spectra observed for the CO-EO, CO-ES, CO(2)-EO, and CO(2)-ES complexes were analyzed by using an asymmetric-rotor S reduced Hamiltonian to determine rotational and centrifugal distortion constants. The r(s) coordinates of the atoms in the four complexes, which were calculated from the observed rotational constants, led to a structure in which the CO or CO(2) moiety is located in a plane perpendicular to the EO or ES skeletal plane and bisecting the COC or CSC angle. We have also carried out ab initio molecular orbital calculations at the level of MP2 with basis sets 6-311++G(d,p) and aug-cc pVDZ using the Gaussian 09 package. The MP2/6-311++G(d,p) calculations yield rotational constants in better agreement with the experimental values than with the other basis set; in other words, the molecular structures calculated using this basis set are close to those experimentally found for the ground state. The estimated dissociation energies of the complexes, including the zero-point vibrational energy corrections DeltaZPV and the basis set superposition errors (BSSE) calculated with the counterpoise correction (CP), are in good agreement with the experimentally obtained binding energies E(B). We have applied an NBO analysis to the complexes to calculate the stabilization energy CT (=DeltaE(sigmasigma*)), which we found are closely correlated with the binding energies E(B). We have thus achieved a consistent overview on the intermolecular interaction in the complexes under consideration. It is to be noted that the spectral intensities of the inner OC(18)O-EO and OC(18)O-ES complexes were larger by a factor of 2 than those of the outer (18)OCO-EO/ES complexes. This observation was explained by the zero-point energy of the inner conformer being a little smaller than that of the outer one. PMID- 22206499 TI - Thermoreversible gel for delivery of activin receptor-like kinase 5 inhibitor SB 505124 for glaucoma filtration surgery. AB - The purpose of this study is to investigate a thermoreversible gel using Pluronic F-127 to deliver an activin receptor-like kinase 5 (ALK-5) inhibitor SB-505124 in glaucoma filtration surgery (GFS). The gel was characterized for in vitro drug release and viscosity studies. Cytotoxicity of Pluronic F-127 was examined by MTT assay using cultured rabbit subconjunctival fibroblasts. In addition, Pluronic F 127 gel (18% w/v) containing 5 mg of SB-505124 was applied at the surgical site in an in vivo rabbit GFS model. In the in vitro viscosity study, the gel showed a change in viscosity (from 1000 cps to 45,000 cps) from low temperature (10 degrees C) to body temperature (37 degrees C). The in vitro drug release study demonstrated 100% drug release within 12 h. The gel did not show cytotoxicity to the cultured rabbit subconjunctival cells by MTT assay. In the in vivo rabbit GFS model, the drug was successfully delivered by injection and no severe post surgical complications were observed. A thermoreversible gel system with SB 505124 was successfully prepared and delivered for the rabbit GFS model, and it may provide a novel delivery system in GFS. PMID- 22206500 TI - Interfacially treated dye-sensitized solar cell with in situ photopolymerized iodine doped polythiophene. AB - A thin film of iodine doped polythiophene was grown photoelectrochemically around the dye-sensitized TiO(2) nanoparticles in a Gratzel cell, and the effect of iodine doping level on the cell performance was investigated using X-ray photoelectron spectroscopy, electrochemical impedance spectroscopy, and photovoltage decay. At an optimum doping level, the cell demonstrated the enhanced energy conversion efficiency by 27.52% compared to the cell without polythiophene. PMID- 22206501 TI - A test of an adapted multiple domain model in predicting sexual behaviors among unmarried young adults in India. AB - Theory-based, scientific research examining sexual behaviors of young adults is sparse in India, even though pre-marital sex among unmarried young people has been rising in recent years. At the same time, young people aged 15 to 24 are disproportionately affected by HIV/AIDS. This has been attributed in part to rising pre-marital sexual behaviors, coupled with a lack of sex education. The objective of this study was to advance an understanding of the determinants of sexual behavior among unmarried young adults in northern India. An adaptation of a comprehensive model of health behavior, the Multiple Domain Model, was employed to study the effects of environmental/cultural influences (parental and media), structural determinants (sex, socioeconomic status, age, caste, and place of residence), personality factors (sensation-seeking and impulsive decision making), gender role identity, psychosocial variables (attitudes, norms, and self efficacy), contextual influences (relationship status and alcohol/drug use) and preparatory behaviors (frequency of being in sexual situations) on adolescents' sexual behaviors. Results of path analysis indicated that key predictors of ever having had vaginal sex included preparatory behaviors, masculine gender role identity, attitudes toward having sex and peer norms regarding sex. Implications of these findings for future research and intervention are discussed. PMID- 22206502 TI - Diisobutylaluminum hydride reductions revitalized: a fast, robust, and selective continuous flow system for aldehyde synthesis. AB - A continuous flow system for the multiparameter (flow rate, temperature, residence time, stoichiometry) optimization of the DIBALH reduction of esters to aldehydes is described. Incorporating an in-line quench (MeOH), these transformations are generally complete in fewer than 60 s. Mixing of the DIBALH and ester solutions was observed to be an exceptionally critical parameter for optimum results. This system thus provides general guidelines based on the structure of the ester for selective reduction of an ester without overreduction. PMID- 22206503 TI - Explicitly correlated electrons in molecules. PMID- 22206505 TI - Time scales of slow motions in ubiquitin explored by heteronuclear double resonance. AB - Understanding how proteins function at the atomic level relies in part on a detailed characterization of their dynamics. Ubiquitin, a small single-domain protein, displays rich dynamic properties over a wide range of time scales. In particular, several regions of ubiquitin show the signature of chemical exchange, including the hydrophobic patch and the beta4-alpha2 loop, which are both involved in many interactions. Here, we use multiple-quantum relaxation techniques to identify the extent of chemical exchange in ubiquitin. We employ our recently developed heteronuclear double resonance method to determine the time scales of motions that give rise to chemical exchange. Dispersion profiles are obtained for the backbone NH(N) pairs of several residues in the hydrophobic patch and the beta4-alpha2 loop, as well as the C-terminus of helix alpha1. We show that a single time scale (ca. 50 MUs) can be used to fit the data for most residues. Potential mechanisms for the propagation of motions and the possible extent of correlation of these motions are discussed. PMID- 22206504 TI - Efficacy and safety outcomes among treatment-experienced women and men treated with etravirine in gender, race and clinical experience. AB - The GRACE (Gender, Race and Clinical Experience) trial enrolled treatment experienced, HIV-1-infected patients, mainly women, in North America, to assess outcomes with a darunavir/ritonavir-based regimen, which could include etravirine (ETR). We present outcomes at week 48 for men and women receiving ETR. Virologic response (HIV-1 RNA <50 copies/ml) and safety were assessed; descriptive statistics are reported. To evaluate the independent contribution of ETR treatment, a post hoc analysis including a multivariate model assessed factors predictive of virologic response for the entire GRACE population (429 patients). Of 207 patients who received ETR (women, 57.5%; black or Hispanic, 81.7%), 71.4% of women and 79.5% of men completed the study. Week 48 virologic response rates in women and men (intent-to-treat population) were 58.0% and 61.4%, respectively. After censoring patients who discontinued treatment for reasons other than virologic failure, response rates were 79.3% and 73.0%, respectively. Overall, ETR was well tolerated. Women experienced more nausea (24.4% vs. 11.4%) and rash related events (21.0% vs. 15.9%), but less diarrhea (15.1% vs. 21.6%), compared with men. Grade 3-4 hypertriglyceridemia was more common in men (9.3%) than women (1.1%). In total, 11 (9.2%) women and 7 (8.0%) men discontinued ETR due to adverse events. In the multivariate model of the entire GRACE population, ETR use was independently associated with improved virologic response. ETR is effective and well tolerated in treatment-experienced patients with HIV-1, with similar outcomes among women and men. PMID- 22206507 TI - Identification and determination of selenosulfate and selenocyanate in flue gas desulfurization waters. AB - In this work, 13 selenium species in flue gas desulfurization (FGD) waters from coal-fired power plants were separated and quantified using anion-exchange chromatography coupled to inductively coupled plasma mass spectrometry. For the first time, we identified both selenosulfate (SeSO(3)(2-)) and selenocyanate (SeCN(-)) in such waters, using retention time matching and confirmation by electrospray mass spectrometry. Besides selenite and selenate, selenosulfate was the most frequently occurring selenium species. It occurred in most samples and constituted a major fraction (up to 63%) of the total selenium concentration in waters obtained from plants employing inhibited oxidation scrubbers. Selenocyanate occurred in about half of the tested samples, but was only a minor species (up to 6% of the total selenium concentration). Nine additional Se containing compounds were found in FGD waters, but they remain unidentified at this point. PMID- 22206506 TI - Interleukin-1alpha expression precedes IL-1beta after ischemic brain injury and is localised to areas of focal neuronal loss and penumbral tissues. AB - BACKGROUND: Cerebral ischemia is a devastating condition in which the outcome is heavily influenced by inflammatory processes, which can augment primary injury caused by reduced blood supply. The cytokines interleukin-1alpha (IL-1alpha) and IL-1beta are key contributors to ischemic brain injury. However, there is very little evidence that IL-1 expression occurs at the protein level early enough (within hours) to influence brain damage after stroke. In order to determine this we investigated the temporal and spatial profiles of IL-1alpha and IL-1beta expression after cerebral ischemia. FINDINGS: We report here that in mice, as early as 4 h after reperfusion following ischemia induced by occlusion of the middle cerebral artery, IL-1alpha, but not IL-1beta, is expressed by microglia like cells in the ischemic hemisphere, which parallels an upregulation of IL 1alpha mRNA. 24 h after ischemia IL-1alpha expression is closely associated with areas of focal blood brain barrier breakdown and neuronal death, mostly near the penumbra surrounding the infarct. The sub-cellular distribution of IL-1alpha in injured areas is not uniform suggesting that it is regulated. CONCLUSIONS: The early expression of IL-1alpha in areas of focal neuronal injury suggests that it is the major form of IL-1 contributing to inflammation early after cerebral ischemia. This adds to the growing body of evidence that IL-1alpha is a key mediator of the sterile inflammatory response. PMID- 22206508 TI - Reagentless biosensor based on glucose oxidase wired by the mediator freely diffusing in enzyme containing membrane. AB - Wiring glucose oxidase in the membrane with an immobilized mediator is possible due to the diffusion ability of the latter, if the enzyme containing membrane is formed according to the proposed protocol, including exposing proteins to water organic mixtures with the high content of organic solvent. In the course of the study, the new glucose oxidase mediator, unsubstituted phenothiazine, was discovered. The diffusion coefficient of the mediator in the resulting membrane is independent of the presence of enzyme. The cyclic voltammograms of the enzyme electrode after appearance of the only glucose in solution obtain a well-defined catalytic shape, which is normally observed for both the enzyme and the mediator in solution. Analytical performances of the resulting biosensor are comparable to the advanced second generation ones, which, however, require covalent linking of the mediator either to the membrane forming polymer or to the enzyme. Even without such covalent linking, the reported biosensor is characterized by an appropriate long-term operational stability allowing reagentless sensing. PMID- 22206509 TI - Aggression exhibited by older dementia clients toward staff in Japanese long-term care. AB - This study examined the experiences of staff members from seven Japanese hospitals who had been treated aggressively by older dementia clients. Altogether, 170 questionnaires were analyzed. In the past year, 75.3% and 63.5% of staff members had experienced physical and verbal aggression, respectively. Working numerous night shifts, working shifts other than 3-shifts, and being allotted assignments with clients who had a lower average level of physical capacity were the factors associated with recurrent client aggression. Those staff members who spent adequate time caring for their clients, who gained client consent before providing care, and who tried to build a trusting relationship with their clients were found to have experienced less aggression. Burnout, which is likely to enhance the risk of the staff mistreatment and neglect of older clients, was found to be higher among those who experienced aggression. PMID- 22206510 TI - Health care professionals' perspectives on barriers to elder abuse detection and reporting in primary care settings. AB - The purpose of this study was to explore health care professionals' perspectives on elder abuse to achieve a better understanding of the problems of reporting and to generate ideas for improving the detection and reporting process. Through a mailed survey, nurses, physicians, and social workers were invited to participate in an interview. Nine nurses, 8 physicians, and 6 social workers were interviewed, and thematic analysis was used to identify the following core themes: preconceptions, assessment, interpretation, systems, and knowledge and education. Participants suggested a reorganization of the external reporting system. More frequent and pragmatic education is necessary to strengthen practical knowledge about elder abuse. PMID- 22206511 TI - Adult protective services and animal welfare: should animal abuse and neglect be assessed during adult protective services screening? AB - Past research has examined links among animal abuse, child maltreatment, and intimate partner violence and demonstrated the importance of addressing the needs of both human and animal victims. We hypothesized that there might be a similar link between animal abuse and older adult welfare issues. As a first step in the earlier research was the development of a screening protocol that shed light on the link between domestic violence and animal abuse, we decided to follow a similar route to explore this new topic by asking state government representatives about their experiences, if any, with this topic. Here we report the results of a national survey of state Adult Protective Services agencies regarding their protocols for assessing animal welfare issues in the context of older adult maltreatment. We also describe a model assessment protocol we developed in collaboration with the Utah Division of Aging and Adult Services. PMID- 22206512 TI - Elder abuse and oral health care providers: an intervention to increase knowledge and self-perceived likelihood to report. AB - The objective of this study was to ascertain whether a symposium on elder abuse raises the level of knowledge and the self-reported likelihood to report elder abuse among licensed oral health care providers. 130 dentists, hygienists, and assistants voluntarily attended a 4-hour training symposium and completed both pre- and postsurveys testing their level of knowledge. Results by statistical analyses, using repeated measurements, Wilcoxon signed-rank test for nonparametric data, showed increases in awareness of reporting process, knowledge/awareness of elder abuse, knowledge of mandated reporter requirements, and comfort levels with recognizing signs and symptoms of elder abuse and neglect. In conclusion, a symposium can increase the self-reported likelihood of reporting elder abuse. PMID- 22206515 TI - How toxic are toxic chemicals in soil? PMID- 22206513 TI - Physical abuse of older adults in nursing homes: a random sample survey of adults with an elderly family member in a nursing home. AB - Few empirical studies have focused on elder abuse in nursing home settings. The present study investigated the prevalence and risk factors of staff physical abuse among elderly individuals receiving nursing home care in Michigan. A random sample of 452 adults with elderly relatives, older than 65 years, and in nursing home care completed a telephone survey regarding elder abuse and neglect experienced by this elder family member in the care setting. Some 24.3% of respondents reported at least one incident of physical abuse by nursing home staff. A logistic regression model was used to estimate the importance of various risk factors in nursing home abuse. Limitations in activities of daily living (ADLs), older adult behavioral difficulties, and previous victimization by nonstaff perpetrators were associated with a greater likelihood of physical abuse. Interventions that address these risk factors may be effective in reducing older adult physical abuse in nursing homes. Attention to the contextual or ecological character of nursing home abuse is essential, particularly in light of the findings of this study. PMID- 22206517 TI - Solute transport in porous media with sorption-site heterogeneity. PMID- 22206516 TI - Dynamic polluted atmosphere generator at low ppbv levels for validating VOC sampling methods. PMID- 22206518 TI - Decomposition of Tetrachloro-1,4-benzoquinone (p-Chloranil) in Aqueous Solution. PMID- 22206519 TI - Methanotrophic Chloroethene Transformation Capacities And 1,1-dichloroethene Transformation Product Toxicity. PMID- 22206520 TI - Catalytic supercritical water oxidation: phenol conversion and product selectivity. PMID- 22206521 TI - Determination of pentachlorophenol in water and soil by a magnetic particle-based enzyme immunoassay. PMID- 22206522 TI - Hydroxylated atrazine degradation products in a small missouri stream. PMID- 22206523 TI - Size-dependent bioconcentration kinetics of hydrophobic organic chemicals in fish based on diffusive mass transfer and allometric relationships. PMID- 22206524 TI - Rapid toluene mineralization by aquifer microorganisms at adak, alaska: implications for intrinsic bioremediation in cold environments. PMID- 22206525 TI - Polycyclic aromatic hydrocarbons and polychlorinated biphenyls in air at an urban and a rural site near lake michigan. PMID- 22206527 TI - Measurement of atmospheric methyl bromide using gravimetric gas standards. PMID- 22206526 TI - Sonochemical degradation of p-nitrophenol in a parallel-plate near-field acoustical processor. PMID- 22206528 TI - Identification and Quantification of Monobromopolychlorobiphenyls in Baltic Ringed Seal and a Technical PCB (Clophen A50). PMID- 22206529 TI - Patterns of herbicide contamination in selected vermont streams detected by enzyme immunoassay and gas chromatography/mass spectrometry. PMID- 22206530 TI - Modeling the photochemical degradation of ethylenediaminetetraacetate in the River Glatt. PMID- 22206531 TI - Effects of light intensity on the phototoxicity of fluoranthene to a benthic macroinvertebrate. PMID- 22206532 TI - Stability of organophosphorus pesticides on disposable solid-phase extraction precolumns. PMID- 22206533 TI - Use of methyldibenzothiophenes as markers for differentiation and source identification of crude and weathered oils. PMID- 22206534 TI - Sorption of trichloroethylene and tetrachloroethylene in a batch reactive metallic iron-water system. PMID- 22206535 TI - Cobalamin-enhanced anaerobic biotransformation of carbon tetrachloride. PMID- 22206536 TI - Byproducts of anaerobic alkylbenzene metabolism useful as indicators of in situ bioremediation. PMID- 22206537 TI - Survival of Polycyclic Aromatic Hydrocarbons during Diesel Combustion. PMID- 22206538 TI - Persistent organochlorine residues and their accumulation kinetics in Baikal seal (Phoca sibirica) from Lake Baikal, Russia. PMID- 22206539 TI - Use of the Semipermeable Membrane Device as an in Situ Sampler of Waterborne Bioavailable PCDD and PCDF Residues at Sub-Parts-per-Quadrillion Concentrations. PMID- 22206540 TI - Great Lakes Herring Gull Egg PCB Concentrations Indicate Approximate Steady-State Conditions. PMID- 22206541 TI - Rapid dechlorination of polychlorinated biphenyls on the surface of a pd/fe bimetallic system. PMID- 22206542 TI - Absorption of Formaldehyde by Oleander (Nerium indicum). PMID- 22206543 TI - Atmospheric washout of polycyclic aromatic hydrocarbons in the southern chesapeake bay region. PMID- 22206545 TI - Gastric transit and small intestinal transit time and motility assessed by a magnet tracking system. AB - BACKGROUND: Tracking an ingested magnet by the Magnet Tracking System MTS-1 (Motilis, Lausanne, Switzerland) is an easy and minimally-invasive method to assess gastrointestinal transit. The aim was to test the validity of MTS-1 for assessment of gastric transit time and small intestinal transit time, and to illustrate transit patterns detected by the system. METHODS: A small magnet was ingested and tracked by an external matrix of 16 magnetic field sensors (4 * 4) giving a position defined by 5 coordinates (position: x, y, z, and angle: theta, phi). Eight healthy subjects were each investigated three times: (1) with a small magnet mounted on a capsule endoscope (PillCam); (2) with the magnet alone and the small intestine in the fasting state; and (3) with the magnet alone and the small intestine in the postprandial state. RESULTS: Experiment (1) showed good agreement and no systematic differences between MTS-1 and capsule endoscopy when assessing gastric transit (median difference 1 min; range: 0-6 min) and small intestinal transit time (median difference 0.5 min; range: 0-52 min). Comparing experiments (1) and (2) there were no systematic differences in gastric transit or small intestinal transit when using the magnet-PillCam unit and the much smaller magnetic pill. In experiments (2) and (3), short bursts of very fast movements lasting less than 5% of the time accounted for more than half the distance covered during the first two hours in the small intestine, irrespective of whether the small intestine was in the fasting or postprandial state. The mean contraction frequency in the small intestine was significantly lower in the fasting state than in the postprandial state (9.90 min-1 vs. 10.53 min-1) (p = 0.03). CONCLUSION: MTS-1 is reliable for determination of gastric transit and small intestinal transit time. It is possible to distinguish between the mean contraction frequency of small intestine in the fasting state and in the postprandial state. PMID- 22206546 TI - Nonquaternary reactivators for organophosphate-inhibited cholinesterases. AB - A new class of amidine-oxime reactivators of organophosphate (OP)-inhibited cholinesterases (ChE) was synthesized and tested in vitro and in vivo. Compared with 2-PAM, the most promising cyclic amidine-oxime (i.e., 12e) showed comparable or greater reactivation of OP-inactivated AChE and OP-inactivated BChE. To the best of our knowledge, this is the first report of a nonquaternary oxime that has, comparable to 2-PAM, in vitro potency for reactivation of Sarin (GB) inhibited AChE and BChE. Amidine-oximes were tested in vitro, and reactivation rates for OP-inactivated butyrylcholinesterase (BChE) were greater than those for 2-PAM or MINA. Amidine-oxime reactivation rates for OP-inactivated acetylcholinesterase (AChE) were lower compared to 2-PAM but greater compared with MINA. Amidine-oximes were tested in vivo for protection against the toxicity of nerve agent model compounds. (i.e., a model of Sarin). Post-treatment (i.e., 5 min after OP exposure, i.p,) with amidine oximes 7a-c and 12a, 12c, 12e, 12f, and 15b (145 MUmol/kg, i.p.) protected 100% of the mice challenged with the sarin model compound. Even at 25% of the initial dose of amidine-oxime (i.e., a dose of 36 MUmol/kg, i.p.), 7b and 12e protected 100% of the animals challenged with the sarin nerve agent model compound that caused lethality in 6/11 animals without amidine-oxime. PMID- 22206548 TI - The spectrum of readership of the journal. PMID- 22206552 TI - How to treat patients with obstructive sleep apnea syndrome during an altitude sojourn. AB - Considering the high prevalence of the obstructive sleep apnea syndrome (OSA), it is expected that many patients with the disorder are traveling to altitude. However, this may expose them to the risk of pronounced hypoxemia, exacerbation of nocturnal breathing disturbances by frequent central apneas, impaired daytime performance, and high blood pressure. Recently, randomized studies specifically investigated the effects of altitude (1630-2590 m) in OSA patients and the optimal treatment in this setting. The results indicate that patients should continue to use continuous positive airway pressure therapy (CPAP) when sleeping at altitude. Since CPAP alone does not control central sleep apnea emerging at altitude, combined treatment with acetazolamide and CPAP should be considered, in particular, in patients with severe OSA and co-morbidities. Supplemental oxygen combined with CPAP might be advantageous in patients with OSA and concomitant cardiopulmonary disease by preventing hypoxemia and central sleep apnea. In patients unable to use CPAP or if electrical power is not available, an optimally fitted mandibular advancement device might be an alternative treatment option that can be combined with acetazolamide during altitude sojourns. Acetazolamide alone is also beneficial and better than no treatment at all, since it improves oxygen saturation, breathing disturbances, and the excessive blood pressure elevation in OSA patients traveling to altitude. PMID- 22206547 TI - S100A10 protein expression is associated with oxaliplatin sensitivity in human colorectal cancer cells. AB - BACKGROUND: Individual responses to oxaliplatin (L-OHP)-based chemotherapy remain unpredictable. The objective of our study was to find candidate protein markers for tumor sensitivity to L-OHP from intracellular proteins of human colorectal cancer (CRC) cell lines. We performed expression difference mapping (EDM) analysis of whole cell lysates from 11 human CRC cell lines with different sensitivities to L-OHP by using surface-enhanced laser desorption/ionization time of-flight mass spectrometry (SELDI-TOF MS), and identified a candidate protein by liquid chromatography/mass spectrometry ion trap time-of-flight (LCMS-IT-TOF). RESULTS: Of the qualified mass peaks obtained by EDM analysis, 41 proteins were differentially expressed in 11 human colorectal cancer cell lines. Among these proteins, the peak intensity of 11.1 kDa protein was strongly correlated with the L-OHP sensitivity (50% inhibitory concentrations) (P < 0.001, R2 = 0.80). We identified this protein as Protein S100-A10 (S100A10) by MS/MS ion search using LCMS-IT-TOF. We verified its differential expression and the correlation between S100A10 protein expression levels in drug-untreated CRC cells and their L-OHP sensitivities by Western blot analyses. In addition, S100A10 protein expression levels were not correlated with sensitivity to 5-fluorouracil, suggesting that S100A10 is more specific to L-OHP than to 5-fluorouracil in CRC cells. S100A10 was detected in cell culture supernatant, suggesting secretion out of cells. CONCLUSIONS: By proteomic approaches including SELDI technology, we have demonstrated that intracellular S100A10 protein expression levels in drug untreated CRC cells differ according to cell lines and are significantly correlated with sensitivity of CRC cells to L-OHP exposure. Our findings provide a new clue to searching predictive markers of the response to L-OHP, suggesting that S100A10 is expected to be one of the candidate protein markers. PMID- 22206553 TI - Pro: Hypoxic pulmonary vasoconstriction is a limiting factor of exercise at high altitude. PMID- 22206554 TI - Con: Hypoxic pulmonary vasoconstriction is not a limiting factor of exercise at high altitude. PMID- 22206555 TI - Pro: Rebuttal. PMID- 22206556 TI - Con: Rebuttal. PMID- 22206557 TI - No correlation between plasma levels of vascular endothelial growth factor or its soluble receptor and acute mountain sickness. AB - Increased plasma levels of vascular endothelial growth factor (VEGF) due to lower levels of its soluble receptor (sFlt-1) had been suggested to cause vasogenic brain edema and thereby to cause the symptoms of acute mountain sickness (AMS). We tested this hypothesis after active ascent to high altitude. Plasma was collected from 31 subjects at low altitude (100 m) before (LA1) and after (LA2) 4 weeks of aerobic exercise training in normobaric hypoxia or normoxia, and one night after ascent to high altitude (4559 m). Training modalities (hypoxia or normoxia) did not influence VEGF- and sFlt-1-levels. Therefore, data of both training groups were analyzed together. After one night at 4559 m, 18 subjects had AMS (AMS+), 13 had no AMS (AMS-). In AMS+ and AMS-, VEGF was 110 +/- 75 (SD) pg/ml vs. 104 +/- 82 (p = 0.74) at LA1, 63 +/- 40 vs. 73 +/- 50 (p = 0.54) at LA2, and 88 +/- 62 vs. 104 +/- 81 (p = 0.54) at 4559 m, respectively. Corresponding values for sFlt-1 in AMS+ and AMS- were 81 pg/ml +/- 13.1 vs. 82 +/ 17 (p = 0.97), 79 +/- 11 vs. 80 +/- 16 (p = 0.92) and 139 +/- 28 vs. 135 +/- 31 (p = 0.70), respectively. Absolute values or changes of VEGF were not correlated and those of sFlt-1 slightly correlated with AMS scores. These data provide no evidence for a role of plasma VEGF and sFlt-1 in the pathophysiology of AMS. They do, however, not exclude paracrine effects of VEGF in the brain. PMID- 22206558 TI - Visual analogue scores in assessment of acute mountain sickness. AB - Acute mountain sickness (AMS) is common on ascent to high altitude, with self assessment being the current method used to assess symptoms. The Lake Louise Self Report Score (LLSRS) and the Environmental Symptoms Questionnaire (ESQ) are widely used and validated. A Visual Analogue Scale (VAS) may be used as a simpler alternative for AMS assessment. Our aims were to compare a VAS using lines of length 100 mm, for both individual symptoms of AMS and self-assessed overall AMS with both LLSRS and a shortened Environmental Symptoms Questionnaire (ESQc) on ascent to 4392 m. We set out to suggest a specific score as a cut off point for diagnosis of AMS when using the VAS. There were significant positive correlations (p<0.01), between VAS and both LLSRS and ESQc scores for overall AMS and a composite AMS score derived from the individual symptom scores at 4392 m. The sensitivity and specificity of the VAS were calculated as 0.67 and 0.98, respectively, when using the LLSRS as the standard test for comparison, and 0.91 and 0.96, respectively, when using the ESQc for comparison. The cut off point for diagnosis of AMS was calculated to be 22 mm or above when using a VAS for overall AMS or 15 mm or above when using the VAS composite score, when using LLSRS as the comparative test. Our results show significant correlations between the VAS and the LLSRS and ESQc, when assessing AMS at 4392 m. Our study suggests that a VAS could provide a simple alternative method of assessing AMS at high altitude. PMID- 22206559 TI - Medical standards for mountain rescue operations using helicopters: official consensus recommendations of the International Commission for Mountain Emergency Medicine (ICAR MEDCOM). AB - The purpose of this article is to establish medical recommendations for safe and effective Helicopter Emergency Medical Systems (HEMS) in countries with a dedicated mountain rescue service. A nonsystematic search was undertaken and a consensus among members of International Commission for Mountain Emergency Medicine (ICAR Medcom) was reached. For the severely injured or ill patient, survival depends on approach time and quality of medical treatment by high-level providers. Helicopters can provide significant shortening of the times involved in mountain rescue. Safety is of utmost importance and everything possible should be done to minimize risk. Even in the mountainous environment, the patient should be reached as quickly as possible (optimally<20 min) and provided with on-site and en-route medical treatment according to international standards. The HEMS unit should be integrated into the Emergency Medical System of the region. All dispatchers should be aware of the specific problems encountered in mountainous areas. The nearest qualified HEMS team to the incident site, regardless of administrative boundaries, should be dispatched. The 'air rescue optimal crew' concept with its flexibility and adaptability of crewmembers ensures that all HEMS tasks can be performed. The helicopter and all equipment should be appropriate for the conditions and specific for mountain related emergencies. These recommendations, agreed by ICAR Medcom, establish recommendations for safe and effective HEMS in mountain rescue. PMID- 22206560 TI - Equipment of medical backpacks in mountain rescue. AB - We conducted a survey of equipment in medical backpacks for mountain rescuers and mountain emergency physicians. The aim was to investigate whether there are standards for medical equipment in mountain rescue organizations associated with the International Commission for Mountain Emergency Medicine (ICAR MEDCOM). A questionnaire was completed by 18 member organizations from 14 countries. Backpacks for first responders are well equipped to manage trauma, but deficiencies in equipment to treat medical emergencies were found. Paramedic and physicians' backpacks were well equipped to provide advanced life support and contained suitable drugs. We recommend that medical backpacks should be equipped in accordance with national laws, the medical emergencies in a given region, and take into account the climate, geography, medical training of rescuers, and funding of the organization. Automated external defibrillator provision should be improved. The effects of temperature on the drugs and equipment should be considered. Standards for training in the use and maintenance of medical tools should be enforced. First responders and physicians should only use familiar tools and drugs. PMID- 22206561 TI - Preparation and medical outcomes of Nepalese staff and porters compared with foreign nationals on the Annapurna trekking circuit. AB - This cross-sectional study investigates preparedness and medical problems in Nepalese staff and porters compared with foreign nationals trekking at altitude in the Nepal Himalaya. 331 Nepalese and 338 foreign nationals in 61 trekking groups were surveyed over 4 weeks on the Annapurna trekking circuit. Foreign nationals reported that 92% of trekking groups received altitude illness information and carried a medical kit. However, fewer than 30% knew the evacuation insurance status of the Nepalese staff and porters on their trek, 39% would not pay for an ill Nepalese national's helicopter evacuation, and 41% reported insufficient resources to carry an individual. Medical problems occurred in 44% of groups. A significantly higher proportion of Nepalese staff and porters were evacuated compared with foreign nationals. No significant differences in Nepalese and foreign national preparation were found between groups with and without medical problems. Medical problems were commonly encountered, yet many groups lacked resources to evacuate someone dangerously ill. Foreign and Nepalese nationals have a duty of care towards each other; recognizing that preparedness relies not only on a first aid kit, but also on knowledge of acclimatization and individuals' insurance is an important part of health and safety for individuals trekking at altitude. PMID- 22206562 TI - Cardiopulmonary response and body composition changes after prolonged high altitude exposure in women. AB - Weight loss in men is commonly observed during prolonged high altitude exposure as a result of a daily negative energy balance. Its amount depends mainly on duration of exposure, altitude reached, and level of physical activity. This reduction in body weight often comes with a loss of muscular mass, likely contributing to the decreased physical performance generally reported. Limited data is, however, available on body composition, functional capacity, and cardiopulmonary response to exercise after high altitude exposure in women. The aim of this study was to evaluate the effects of prolonged high altitude exposure on body composition and on cardiopulmonary response to maximal exercise in a group of young, moderately active women. Twelve female subjects, aged 21.5 +/- 3.1 (mean +/- SD), BMI 22.1 +/- 1.9 kg . m(-2) and Vo(2max) 33.8 +/- 3.5 mL . kg( 1) . min(-1), participated in this study, by residing for 21 days at high altitude (5050 m, Pyramid, EV-K(2)-CNR laboratory). Before and after high altitude exposure, all subjects underwent both a body composition evaluation using two methods (bioimpedance analysis and DEXA) and a functional evaluation based on a maximal exercise test on a cycle ergometer with breath-by-breath gas analysis. After high altitude exposure, data showed a slight, nonsignificant reduction in body weight, with an average 3:2 reduction ratio between fat and fat free mass evaluated by DEXA, in addition to a significant decrease in Vo(2max) on the cycle ergometer test (p<0.01). Changes in Vo(2max) correlated to changes of leg muscle mass, evaluated by DEXA (r(2) = 0.72; p<0.0001). No changes were observed in the maximal heart rate, work capacity, and ventilatory thresholds, while the Vo(2)/W slope was significantly reduced (p<0.05). Finally, Ve/Vo(2) and VE/Vco(2max) slopes were increased (p<0.01), suggesting a possible long-term modulation of the exercise ventilatory response after prolonged high altitude exposure. PMID- 22206563 TI - The effects of altitude training on the AMPK-related glucose transport pathway in the red skeletal muscle of both lean and obese Zucker rats. AB - INTRODUCTION: The skeletal muscle AMP-activated protein kinase (AMPK)-related glucose transport pathway is involved in glucose homeostasis. AIM: In this study, we examined whether obese control Zucker rats had abnormal expression of proteins in the LKB1-AMPK-AS160-GLUT4 pathway in red gastrocnemius muscle compared to that in lean (normal) control Zucker rats. We also compared the chronic training effects of exercise, hypoxia, and altitude training on this pathway in lean and obese rats. METHODS: At sea level, lean and obese rats were divided into 4 groups for 6 weeks training as follows: 1) control; 2) exercise (progressive daily swimming-exercise training with comparable exercise signals between the two groups); 3) hypoxia (8 hours of daily 14% O2 exposure); and 4) exercise plus hypoxia (also called altitude training). Seven animals were used for each group. RESULTS: The obese rats in the control group had higher body weights, elevated fasting insulin and glucose levels, and higher baseline levels of muscle AMPK and AS160 phosphorylation compared with those of lean control rats. For obese Zucker rats in the exercise or hypoxia groups, the muscle AMPK phosphorylation level was significantly decreased compared with that of the control group. For obese Zucker rats in the altitude training group, the levels of AMPK, AS160 phosphorylation, fasting insulin, and fasting glucose were decreased concomitant with an approximate 50% increase in the muscle GLUT4 protein level compared with those of the control group. In lean rats, the altitude training efficiently lowered fasting glucose and insulin levels and increased muscle AMPK and AS160 phosphorylation as well as GLUT4 protein levels. CONCLUSION: Our results provide evidence that long-term altitude training may be a potentially effective nonpharmacological strategy for treating and preventing insulin resistance based on its effects on the skeletal muscle AMPK-AS160-GLUT4 pathway. PMID- 22206564 TI - Prior altitude experience of climbers attempting to summit Aconcagua. AB - Aconcagua (6962 m) is one of the seven summits and the highest mountain outside of Asia. Climbers of varying experience are drawn to its nontechnical route. Our objective was to detail the prior altitude experience of climbers attempting to summit Aconcagua. We asked all climbers on the normal route of Aconcagua to complete questionnaires with demographics and prior high altitude experience while acclimatizing at Plaza de Mulas base camp during 9 nonconsecutive days in January 2009. 127 volunteers from 22 countries were enrolled. Mean age was 39.8 years and 88.2% were male. Median altitude at place of residence was 200 m (IQR: 30, 700). Median previous maximum altitude reached was 5895 m (IQR: 5365, 6150). 7.1% of climbers had never been above 4000 m. Median previous maximum sleeping altitude was 4800 m (IQR: 4300, 5486). 12.6% of climbers had never slept above 4000 m. Climbers who performed acclimatization treks spent a mean of 3.6 (2.5, 4.7) days at>3000 m in the previous 2 months. However, 50.4% of climbers performed no acclimatization treks. Although the majority of mountaineers who attempt Aconcagua have prior high altitude experience, a substantial minority has never been above 4000 m. PMID- 22206565 TI - Retinal vein occlusion in high altitude. AB - Staying at high altitude has been reported to be associated with thrombosis in lowlanders. We report 3 cases of retinal vein occlusion in high altitude. Two were males 31 and 37 years of age, who developed nonischemic central retinal vein occlusion while staying at high altitude. The former developed central retinal vein occlusion after 90 days at 6309 m, while the latter was affected at an altitude of 3353 m where he had been for the past 1 year and had recurrence of central retinal vein occlusion in the other eye on re-entry to the same altitude. The third case is that of a 40-year-old female who developed inferotemporal branch retinal vein occlusion on the second day after entry into high altitude (3353 m) by air, while ascending further in a vehicle at an altitude of approximately 4572 m. All three did not have any systemic disease and showed complete recovery on descent to a lower altitude. PMID- 22206566 TI - The quest for evidence-based medicine in mountain areas. PMID- 22206568 TI - Is depression the link between suicide and high altitude? PMID- 22206570 TI - Hemodynamics and metabolism at low versus moderate altitudes. PMID- 22206572 TI - Dexamethasone improves maximal exercise capacity of individual's susceptible to high altitude pulmonary edema at 4559 m. PMID- 22206574 TI - Multi-tyrosine kinase inhibitors in preclinical studies for pediatric CNS AT/RT: Evidence for synergy with Topoisomerase-I inhibition. AB - BACKGROUND: Currently, Atypical Teratoid Rhabdoid Tumor (AT/RT) constitutes one of the most difficult to treat malignancies in pediatrics. Hence, new knowledge of potential targets for therapeutics and the development of novel treatment approaches are urgently needed. We have evaluated the presence of cytokine pathways and the effects of two clinically available multi-tyrosine kinase inhibitors for cytotoxicity, target modulation and drug combinability against AT/RT cell lines. RESULTS: AT/RT cell lines expressed measurable quantities of VEGF, FGF, PDGF and SDF-1, although the absolute amounts varied between the cell lines. The targeted receptor tyrosine kinase inhibitor sorafenib inhibited the key signaling molecule Erk, which was activated following the addition of own conditioned media, suggesting the existence of autocrine/paracrine growth stimulatory pathways. The multi-tyrosine kinase inhibitors sorafenib and sunitinib also showed significant growth inhibition of AT/RT cells and their activity was enhanced by combination with the topoisomerase inhibitor, irinotecan. The loss of cytoplasmic NF-kappa-B in response to irinotecan was diminished by sorafenib, providing evidence for a possible benefit for this drug combination. CONCLUSIONS: In addition to previously described involvement of insulin like growth factor (IGF) family of cytokines, a multitude of other growth factors may contribute to the growth and survival of AT/RT cells. However, consistent with the heterogeneous nature of this tumor, quantitative and qualitative differences may exist among different tumor samples. Multi-tyrosine kinase inhibitors appear to have effective antitumor activity against all cell lines studied. In addition, the target modulation studies and drug combinability data provide the groundwork for additional studies and support the evaluation of these agents in future treatment protocols. PMID- 22206576 TI - "Having sex" as a graded and hierarchical construct: a comparison of sexual definitions among heterosexual and lesbian emerging adults in the U.K. AB - Research into definitions of "having sex" has tended to employ a dichotomous response design (following Sanders & Reinisch, 1999). However, conceptions of sexual activity may be far less clear-cut (c.f. Faulkner, 2003 ; Peterson & Muehlenhard, 2007). More refinement is also needed regarding the impact of sexual orientation on the construction of what counts as sex. This research employed a continuous response design, asking 124 emerging adults (40 male heterosexuals, 42 female heterosexuals, & 42 lesbians) to judge 13 sexual acts using a graded, six point scale. Overall, there was substantial agreement that intercourse (vaginal and anal) was "definitely," and kissing "definitely not," sex. However, across the various acts, participants also consistently made use of options between these extremes, such that a clear hierarchy of sexual behaviors emerged. The lesbian group considered a range of forms of genital stimulation to be significantly more constitutive of sex than either heterosexual group, while judgments by male and female heterosexuals did not significantly differ for any listed act. The implications of graded definitions of sex, a hierarchy of sexual behaviors, and the role of sexual behaviors in hetero- and homosexual identity management are explored. PMID- 22206578 TI - Leupeptin reduces impulse noise induced hearing loss. AB - BACKGROUND: Exposure to continuous and impulse noise can induce a hearing loss. Leupeptin is an inhibitor of the calpains, a family of calcium-activated proteases which promote cell death. The objective of this study is to assess whether Leupeptin could reduce the hearing loss resulting from rifle impulse noise. METHODS: A polyethelene tube was implanted into middle ear cavities of eight fat sand rats (16 ears). Following determination of auditory nerve brainstem evoked response (ABR) threshold in each ear, the animals were exposed to the noise of 10 M16 rifle shots. Immediately after the exposure, saline was then applied to one (control) ear and non-toxic concentrations of leupeptin determined in the first phase of the study were applied to the other ear, for four consecutive days. RESULTS: Eight days after the exposure, the threshold shift (ABR) in the control ears was significantly greater (44 dB) than in the leupeptin ears (27 dB). CONCLUSION: Leupeptin applied to the middle ear cavity can reduce the hearing loss resulting from exposure to impulse noise. PMID- 22206579 TI - Three ring posttranslational circuses: insertion of oxazoles, thiazoles, and pyridines into protein-derived frameworks. AB - Nitrogen heterocycles are the key functional and structural elements in both RNA and DNA, in half a dozen of the most important coenzymes, and in many synthetic drug scaffolds. On the other hand, only 3 of 20 proteinogenic amino acids have nitrogen heterocycles: proline, histidine, and tryptophan. This inventory can be augmented in microbial proteins by posttranslational modifications downstream of leader peptide regions that convert up to 10 serine, threonine, and cysteine residues, side chains and peptide backbones, into oxazoles, thiazoles, and pyridine rings. Subsequent proteolysis releases these heterocyclic scaffolds in both linear and macrocyclic frameworks as bioactive small molecules. PMID- 22206581 TI - 17-Hydroxyprogesterone caproate to prolong pregnancy after preterm rupture of the membranes: early termination of a double-blind, randomized clinical trial. AB - BACKGROUND: Progestational agents may reduce the risk of preterm birth in women with various risk factors. We sought to test the hypothesis that a weekly dose of 17-hydroxyprogesterone caproate (17P) given to women with preterm rupture of the membranes (PROM) will prolong pregnancy and thereby reduce neonatal morbidity. METHODS: Double-blind, placebo-controlled randomized clinical trial. Women with PROM at 23.0 to 31.9 weeks of gestation were randomly assigned to receive a weekly intramuscular injection of 17P (250 mg in 1 mL castor oil) or placebo (1 mL castor oil). The primary outcome was the rate of continuing the pregnancy until 34.0 weeks of gestation or until documentation of fetal lung maturity at 32.0 to 33.9 weeks of gestation. Planned secondary outcomes were duration of latency period and rate of composite neonatal morbidity. Enrollment of 111 participants per group, 222 total, was planned to yield 80% power to detect an increase in the primary outcome from 30% with placebo to 50% with 17P. RESULTS: Twelve women were enrolled of whom 4 were randomly assigned to receive 17P and 8 to receive placebo. The trial was terminated prematurely because of two separate issues related to the supply of 17P. No adverse events attributable to 17P were identified. CONCLUSION: Because of premature termination, the trial does not have adequate statistical power to evaluate efficacy or safety of 17P in women with PROM. Nonetheless, ethical principles dictate that we report the results, which may contribute to possible future metaanalyses and systematic reviews. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01119963Supported by a research grant from the Center for Research, Education, and Quality, Pediatrix Medical Group, Sunrise, FL. PMID- 22206582 TI - Access to dienophilic ene-triketone synthons by oxidation of diketones with an oxoammonium salt. AB - Here we describe the oxidation of 1,3-cyclohexanediones with 4-acetamido-2,2,6,6 tetramethylpiperidine-1-oxoammonium tetrafluoroborate (Bobbitt's salt) to generate 5-ene-1,2,4-triones in moderate-to-good (40-80%) yields. This inexpensive oxidant facilitated an unprecedented cascade of oxidation and elimination to yield novel ene-triketones. The reactivity of these products was explored in the Diels-Alder reaction and provided moderate-to-good yields of cycloaddition products. The products described in this study represent unique, densely functionalized, and versatile building blocks for the synthesis of more complex molecules. PMID- 22206583 TI - Prevalence of xenotropic murine leukemia virus-related virus infection in different risk populations in Spain. AB - Human infection with the xenotropic murine leukemia virus-related virus (XMRV) has been associated controversially with prostate cancer and chronic fatigue syndrome. Information is lacking about the mechanisms of transmission and potential risk groups for XMRV infection. Plasma and peripheral blood mononuclear cells (PBMCs) from individuals with retroviral infections, chronic viral hepatitis, autoimmune diseases, prostate cancer, chronic fatigue syndrome, and blood donors were tested for XMRV markers. Antibodies to XMRV proteins p15E and gp70 were examined using research assays. DNA extracted from PBMCs was tested for the presence of XMRV gag and env sequences. A total of 1103 specimens belonging to individuals with chronic fatigue syndrome and/or fibromyalgia (437), prostate cancer (69), HIV-1 (149), HTLV-1/2 (31), chronic hepatitis B (81), chronic hepatitis C (72), autoimmune diseases (18), and blood donors (246) were examined. Overall, three samples (0.3%) were p15E seroreactive (two HTLV-1 and one HCV patient). Another 15 (1.4%) were gp70 seroreactive (six chronic fatigue syndrome fibromyalgia, four blood donors, two HIV-1, one prostate cancer, one HBV, and one HCV). Four specimens were initially positive for XMRV gag sequences, but none could be confirmed by repeated testing. In summary, no evidence of XMRV infection was found in populations with retroviral and viral hepatitis infections in Spain. Likewise, XMRV was not recognized in patients with autoimmune diseases, chronic fatigue syndrome-fibromyalgia, prostate cancer, or healthy blood donors. PMID- 22206584 TI - Coherent transport through spin-crossover single molecules. AB - Coherent quantum transport calculations were performed for high- and low-spin states of a mononuclear Fe(II) complex showing spin-crossover behavior using density functional theory methods combined with the non-equilibrium Green functions procedure. The high-spin state has a larger conductivity than the low spin state; furthermore, it behaves as a spin filter, giving a beta-polarized current. PMID- 22206586 TI - Making enhancers from spare parts of the genome. AB - New studies show that novel long-range enhancers of developmental genes can emerge by exaptation of protein-coding sequences with no previous regulatory function. PMID- 22206588 TI - Historical perspective fifty years of particles: a personal retrospect. PMID- 22206590 TI - The relationship between apolipoprotein (apo) E polymorphism and lipid changes: An 8-year cohort study in Beijing elderly persons. AB - This study aimed to investigate the influence of apoE genetic polymorphism on serum lipid changes in a community-based elderly population in China in an 8-year period, in which 746 individual, aged 65.29 +/- 6.85 years (mean +/- standard deviation (SD)) were enrolled and serum lipid parameters were checked at baseline. After 8 years, serum lipids as well as apoE genotypes were measured. The frequencies of apoE allele were 9.4%, 81.7%, and 8.9% for E2, E3 and E4, respectively. After the population was divided into 3 groups by different apoE allele carriers, the apoE allele carriers for E2, E3 and E4 were 121 (16.2%), 513 (68.8%) and 112 (15.0%), respectively. Levels of total cholesterol (TC) and low density lipoprotein (LDL) in E2 carriers were lower comparing with that of E3 allele carriers at baseline. 8 years later, TC and high density lipoprotein (HDL) elevated and LDL decreased with aging in this population (p<0.01). The changes of TC levels were smaller in E2 allele carriers as compared to that of E3 allele carriers. The difference was still statistically significant after controlling for age, sex, smoking status, drinking habit, body mass index (BMI) and baseline TC level. The same trend of changes was noted for LDL between E2 and E3 allele carriers. However, no significant differences were noted between E4 and E3 allele carriers on lipid changes. This community-based study shows that E2 allele is helpful on lipid changes. The effect of E4 allele on lipid change is not strong in this elderly population. Genetic and environmental factors maybe co-operate on lipid metabolism in elderly persons. PMID- 22206591 TI - The effects of group reminiscence therapy on depression, self-esteem, and affect balance of Chinese community-dwelling elderly. AB - OBJECTIVES: To study the effects of group reminiscence therapy on depressive symptoms, self-esteem, and affect balance among community dwelling elderly. METHODS: Eight communities were randomly selected from 372 eligible communities in Changsha city. They were randomly divided into four experimental groups and four control group. Geriatric Depression Scale (GDS) was used to screen entire 478 older adults living in these 8 communities. One hundred and sixty five of them had a GDS score between 11 and 25; among them, 125 participated in the study finally. The elderly group who were in the control group received health education, while the intervention group received both health education and group reminiscence therapy for 6 weeks. Both groups were assessed with the GDS, Self Esteem Scale (SES), and Affect Balance Scale (ABS) before and after the 6-week intervention. The results were analyzed using a mixed effect model with fixed effect of the intervention and random effect of the community, incorporating the structured randomness at the community level. RESULTS: After 6 weeks' therapy, the GDS scores in the intervention group decreased significantly compared to those in the control group (p<0.001). Scores on the positive affect subscale and affect balance in the intervention group increased significantly higher than control group, and scores on the negative affect subscale decreased significantly lower than control group (p<0.01). After the intervention, there were no statistically significant differences in self-esteem scores between intervention and control groups. CONCLUSIONS: Group reminiscence therapy was effective in reducing symptoms of depression, improving affect balance, and promoting mental health of community-dwelling elderly. PMID- 22206592 TI - An improved protocol for efficient transformation and regeneration of diverse indica rice cultivars. AB - BACKGROUND: Rice genome sequencing projects have generated remarkable amount of information about genes and genome architecture having tremendous potential to be utilized in both basic and applied research. Success in transgenics is paving the way for preparing a road map of functional genomics which is expected to correlate action of a gene to a trait in cellular and organismal context. However, the lack of a simple and efficient method for transformation and regeneration is a major constraint for such studies in this important cereal crop. RESULTS: In the present study, we have developed an easy, rapid and highly efficient transformation and regeneration protocol using mature seeds as explants and found its successful applicability to a choice of elite indica rice genotypes. We have optimized various steps of transformation and standardized different components of the regeneration medium including growth hormones and the gelling agent. The modified regeneration medium triggers production of large number of shoots from smaller number of calli and promotes their faster growth, hence significantly advantageous over the existing protocols where the regeneration step requires maximum time. Using this protocol, significantly higher transformation efficiency (up to 46%) and regeneration frequency (up to 92% for the untransformed calli and 59% for the transformed calli) were achieved for the four tested cultivars. We have used this protocol to produce hundreds of independent transgenic lines of different indica rice genotypes. Upon maturity, these transgenic lines were fertile thereby indicating that faster regeneration during tissue culture did not affect their reproductive potential. CONCLUSIONS: This speedy, yet less labor-intensive, protocol overcomes major limitations associated with genetic manipulation in rice. Moreover, our protocol uses mature seeds as the explant, which can easily be obtained in quantity throughout the year and kept viable for a long time. Such an easy, efficient and generalized protocol has the potential to be a major tool for crop improvement and gene function studies on the model monocot plant rice. PMID- 22206593 TI - The cytocompatability of polyhydroxyalkanoates coated with a fusion protein of PHA repressor protein (PhaR) and Lys-Gln-Ala-Gly-Asp-Val (KQAGDV) polypeptide. AB - Microbial polyhydroxyalkanoates (PHAs) are a family of polyesters with biodegradability, biocompatibility and adjustable mechanical properties that are under intensive development for bioimplant applications. In this research, a fusion protein of PHA repressor protein (PhaR) and Lys-Gln-Ala-Gly-Asp-Val (KQAGDV) oligopeptide (PhaR-KQAGDV) was utilized to enhance the PHA cytocompatability via a mechanism of PhaR hydrophobically binding to PHA coupled with KQAGDV oligopeptide, a specific ligand to the integrins on the cell surface, for promotion of cell adhesion. The PhaR-KQAGDV fusion protein successfully produced and purified from recombinant E. coli was used to coat the surfaces of several PHA including poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly(3 hydroxybutyrate-co-4-hydroxybutyrate) (P3HB4HB) and poly(3-hydroxybutyrate-co-3 hydroxyhexanoate) (PHBHHx), respectively. The PhaR was observed to bind efficiently on all PHA surfaces measured by the fluorescence intensity of PhaR EGFP as compared to the uncoated (PhaR negative) PHA films. The PHA surface hydrophilicity measured by water contact angles was significantly improved after PhaR-KQAGDV coating. Observations under confocal microscope and scanning electron microscopy, together with CCK-8 assays clearly demonstrated that adhesion and proliferation of human vascular smooth muscle cells (HvSMCs) inoculated on PHA films were much better on PhaR-KQAGDV coated surfaces than the non-coated control ones. The convenient physical coating approach for enhanced PHA cytocompatibility provides an advantage for PHA based tissue engineering. PMID- 22206594 TI - The use of magnetic resonance cell tracking to monitor endothelial progenitor cells in a rat hindlimb ischemic model. AB - A water-soluble magnetic resonance imaging (MRI) contrast agent, Dextran mono-N succinimidyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate-gadolinium(3+) (Dex-DOTA-Gd(3+)), was shown to enable monitoring of the anatomical migration and the survival period of transplanted stem cells for up to 1 month. Gadolinium molecules in the cells were rapidly eliminated from the site and excreted upon cell death. Endothelial progenitor cells (EPCs) transplanted into the inguinal femoral muscle of rats migrated distally through the knee in rats after hindlimb ischemia but did not migrate in non-ischemic rats. Interestingly, the survival period of transplanted EPCs was notably prolonged in the ischemic limb, indicating that EPCs are required by the ischemic tissues and that the fate of transplanted EPCs was affected by the disease. Compared to the commonly used particle type of MRI contrast agents, the system described in this study is expected to be invaluable to help clarifying the process of stem cell transplantation therapy. PMID- 22206595 TI - Functional delivery of DNAzyme with iron oxide nanoparticles for hepatitis C virus gene knockdown. AB - DNAzyme is an attractive therapeutic oligonucleotide which enables cleavage of mRNA in a sequence-specific manner and thus, silencing target gene. A particularly important challenge in achieving the successful down-regulation of gene expression is to efficiently deliver DNAzymes to disease sites and cells. Here, we report the nanoparticle-assisted functional delivery of therapeutic DNAzyme for the treatment of hepatitis C by inducing knockdown of hepatitis C virus (HCV) gene, NS3. HCV NS3 gene encodes helicase and protease which are essential for the virus replication. The nanocomplex showed efficient NS3 knockdown while not evoking undesired immune responses or notable cytotoxicity. We also demonstrated the DNAzyme conjugated nanoparticle system could be applicable in vivo by showing the accumulation of the nanoparticles in liver, and more specifically, in hepatocytes. We believe that the present work is a successful demonstration of effective, functional, non-immunostimulatory DNAzyme delivery system based on inorganic nanoparticles with high potential for further therapeutic application of DNAzyme in the treatment of hepatitis C. PMID- 22206596 TI - Multi-functional graphene as an in vitro and in vivo imaging probe. AB - A strategy has been developed for the synthesis of multi-functional graphene (MFG) using green synthetic approach and explored its biomedical application as a promising fluorescent marker for in vitro and in vivo imaging. In-situ microwave assisted reduction and magnetization process was adopted to convert the graphene oxide into magnetic graphene within 1 min, which was further covalently modified to build a polyacrylic acid (PAA) bridge for linking the fluorescein o methacrylate (FMA) to yield MFG with water-dispersibility (~2.5 g/l) and fluorescence property (emission maximum at 526 nm). The PAA bridges also functions to prevent graphene-induced fluorescence quenching of conjugated FMA. The extent of reduction, magnetization, and functionalization was confirmed with TEM, AFM, Raman, XPS, FT-IR, TGA, and SQUID measurements. In vitro cytotoxicity study of HeLa cells reveal that MFG could stand as a biocompatible imaging probe with an IC(50) value of ~100 MUg/ml; whereas in vivo zebrafish study does not induce any significant abnormalities nor affects the survival rate after microinjection of MFG. Confocal laser scanning microscopy images reveals that MFG locates only in the cytoplasm region and exhibits excellent co-localization and biodistribution from the head to tail in the zebrafish. Our results demonstrate the applicability of graphene based fluorescence marker for intracellular imaging and, more significantly, as well as whole-animal imaging. Hence, MFG could preferentially serve as a dual functional probe in biomedical diagnostics. PMID- 22206597 TI - The effectiveness and perception of the use of sulphadoxine-pyrimethamine in intermittent preventive treatment of malaria in pregnancy programme in Offinso district of Ashanti region, Ghana. AB - BACKGROUND: Malaria in pregnant women has been shown to be associated with low birth weight, stillbirth and mortality in newborns. The WHO has adopted the use of sulphadoxine-pyrimethamine (SP) to control malaria, a disease which worsens the plight of pregnant women leading to low birth weight, stillbirths and increased neonatal mortality. The present study assessed the effectiveness of SP and perception of its use in pregnant women in Offinso district (Ashanti Region), Ghana. METHOD: Pregnant women, gestational age 32 weeks prior to term, were studied from November 2006 to October 2007. Their haemoglobin levels (Hb), parasitaemia and other quantitative determinants were assessed. In-depth interviews (IDIs) and focus group discussions (FGDs) were used to assess the perception of SP usage and its effectiveness. RESULTS: Of the 306 study participants, 92 (30%) took one dose, 100 (33%) two doses and 114 (37%) three doses of SP, respectively. There was significant association between gravidity and SP dosage taken (Pearson chi2 = 18.9, p < 0.001). Although adverse effects were produced in 113 (i.e. 37%) of the pregnant women, no significant difference was observed with regard to the dosage of SP taken (Pearson's chi2 = 2.3, p >= 0.32). Peripheral parasitaemia was present in 47 (15%) of the subjects. There was a poor negative relationship of doses of SP with parasitaemia (r = -0.07, p >= 0.24). Mean Hb was 11.3 +/- 1.6 g/dl, with 118 (39%) of the subjects anaemic (Hb < 11.0 g/dl), whilst 187 (61%) were normal (Hb >=11.0 g/dl). Significant positive correlation of SP use with Hb level (r = 0.15, p < 0.008) was observed. SP use reduced malaria and anaemia prevalence, contributed to reduced maternal morbidity with mild side effects being reported. CONCLUSIONS: This study points to the effectiveness of IPTp using SP as an evidence-based measure for control of malaria and malaria-related anaemia in pregnancy. Therefore, the Ghana Health Service should improve current programme strategies to increase the proportion of pregnant women who take three doses of SP, paying attention to improved face-to face health education, focussed antenatal care and better social mobilization. PMID- 22206598 TI - The management impact of clinically significant incidental lesions detected on staging FDG PET-CT in patients with non-small cell lung cancer (NSCLC): an analysis of 649 cases. AB - To evaluate FDG PET-CT in the detection of unexpected pre-malignancy or second malignancy at the initial staging of patients with histologically proven non small cell lung cancer (NSCLC) and its impact on management. METHODS: Staging FDG PET-CT scans acquired between February 2006 and July 2010 in 649 patients (M=389; F=260) with NSCLC were reviewed for the presence of unexpected pre-malignancy or second primary. A "True-Positive" lesion represented a second primary or pre malignant lesion. A "False-Positive" lesion was due to benign causes or an atypical site of metastasis from NSCLC. RESULTS: 77 (12%) patients were identified on PET-CT as having a potential pre-malignancy or second primary. 39 out of 77 (51%) patients had diagnostic verification where histopathology served as reference standard in 33 patients (85%) and the rest had endoscopy and progress PET-CT scans. 20 patients (3.1%) had a second primary (n=11) or pre malignant lesions comprising dysplastic colorectal polyps (n=9), and additional therapy and/or management change for the index tumour was instigated in 17 patients (85%). In patients with a second primary, 3 (27%) patients had a high impact change in management from an initial curative intent to palliative. CONCLUSION: Staging FDG PET-CT is highly valuable in identifying second primary cancers or pre-malignant lesions in patients with NSCLC. When a second primary is detected on PET-CT, there is a high impact change in management in 27% of patients. PMID- 22206599 TI - Home mechanical ventilation monitoring software: measure more or measure better? AB - In recent years, there has been an increasing interest in knowing the consequences of the patient-ventilator interaction in non-invasive mechanical ventilation. Therefore, several ventilator manufacturers have incorporated into their devices the possibility to monitor ventilation on-line and download the data stored in their internal memories. However, there is not a consensus as to how these data should be presented, and said devices have still not been sufficiently validated to be used systematically in clinical practice. The objective of the present study is to develop a critical, argumentative analysis of the technical characteristics for determining the monitor variables used in the different software programs incorporated in commercial ventilators. Likewise, the study contemplates the presentation of the measurements on the screen display, emphasizing the advantages and defects of each one and analyzing their behavior in common clinical practice situations, such as changes in the interface or the presence of accidental leaks. In addition, solution mechanisms are proposed for establishing future directives for the parameters that are important for clinicians, as well as the manner for providing and interpreting said information. PMID- 22206600 TI - Effect of sample tilt on PEEM resolution. AB - In electron microscopy design, the systems are usually assumed to be perfectly aligned or that possible small imperfections can be eliminated by simple multipole correctors (centering deflectors, stigmators) without loss of resolution. However, in some cases, like in the cathode lens between the sample and the objective lens in the photoemission electron microscope, even a small imperfection can impair the resolution significantly. Because of the strong field between the sample and the objective lens, even a small tilt of the sample generates a parasitic dipole field, which decreases resolution and causes image deformations. We present a simulation of the influence of a small sample tilt on the system resolution based on modern computational methods that enable simulation of the whole system including the parasitic fields, proper setting of centering deflectors and stigmators. The resolution is determined by simulating the point spread function and finding the size of its significant part. The procedure is shown on realistic data from the literature. We found out that the resolution becomes worse mainly in the direction of the parasitic dipole field. PMID- 22206601 TI - A surprise in the first Born approximation for electron scattering. AB - A standard textbook derivation for the scattering of electrons by a weak potential under the first Born approximation suggests that the far-field scattered wave should be in phase with the incident wave. However, it is well known that waves scattered from a weak phase object should be phase-shifted by pi/2 relative to the incident wave. A disturbing consequence of this missing phase is that, according to the Optical Theorem, the total scattering cross section would be zero in the first Born approximation. We resolve this mystery pedagogically by showing that the first Born approximation fails to conserve electrons even to first order. Modifying the derivation to conserve electrons introduces the correct phase without changing the scattering amplitude. We also show that the far-field expansion for the scattered waves used in many texts is inappropriate for computing an exit wave from a sample, and that the near-field expansion also give the appropriately phase-shifted result. PMID- 22206602 TI - Localization of inelastic electron scattering in the low-loss energy regime. AB - The spatial resolution and contrast level in electron energy-loss spectroscopy (EELS) imaging depend on the delocalization of the inelastic electron scattering cross sections. Theoretical calculations within the dipole approximation provide the lower limit for the delocalization of low loss signals, and suggest that atomic resolution EELS imaging in the low loss energy regime (<50 eV) should be possible. Here, we directly measure the localization of the inelastic electron scattering at different energy loss in the low loss regime using a clean open edge of monolayer graphene. Our results demonstrate that the delocalization depends both on the energy loss and the specific electron excitation mode contributing to the energy loss. While the plasmons are delocalized over 1.2 nm, sub-nm enhancement is observed at the edge for the low-loss signal at 11 eV, indicating the possible formation of a one-dimensional plasmon (or inter-band transition) at the edge of monolayer graphene. Our results also suggest that if the initial states or final states are atomically localized, atomic resolution EELS imaging could be obtained even in the low loss region of the spectra. PMID- 22206603 TI - Aberrations in asymmetrical electron lenses. AB - Starting from well established knowledge in light-optics we explore the question if electron-optical aberration can be improved in asymmetrical electron lenses. We show that spherical as well as chromatic aberration coefficients are reduced in asymmetric electrostatic einzel lenses when the center electrode is moved away from the center position towards the entrance electrode. Relative improvements up to 40% for both the chromatic and the spherical aberration coefficients can be obtained. We use analytical and numerical calculations to confirm this result for exemplary cases of a lens with fixed length and working distance. The agreement of the two calculation methods is very good. We then derive an estimate for the electron-optical aberration coefficients from light-optics. The derived expressions for chromatic and spherical aberrations are somewhat simpler than the ones derived from electron-optics as they involve integrals only over the electrostatic potential, not over the electron paths. The estimated formulas still agree well with the electron optical calculations. Overall, we are tempted to suggest that the enormous knowledge base of light optics can provide considerable guidance for electron-optical applications. PMID- 22206604 TI - Modularity detection in protein-protein interaction networks. AB - BACKGROUND: Many recent studies have investigated modularity in biological networks, and its role in functional and structural characterization of constituent biomolecules. A technique that has shown considerable promise in the domain of modularity detection is the Newman and Girvan (NG) algorithm, which relies on the number of shortest-paths across pairs of vertices in the network traversing a given edge, referred to as the betweenness of that edge. The edge with the highest betweenness is iteratively eliminated from the network, with the betweenness of the remaining edges recalculated in every iteration. This generates a complete dendrogram, from which modules are extracted by applying a quality metric called modularity denoted by Q. This exhaustive computation can be prohibitively expensive for large networks such as Protein-Protein Interaction Networks. In this paper, we present a novel optimization to the modularity detection algorithm, in terms of an efficient termination criterion based on a target edge betweenness value, using which the process of iterative edge removal may be terminated. RESULTS: We validate the robustness of our approach by applying our algorithm on real-world protein-protein interaction networks of Yeast, C.Elegans and Drosophila, and demonstrate that our algorithm consistently has significant computational gains in terms of reduced runtime, when compared to the NG algorithm. Furthermore, our algorithm produces modules comparable to those from the NG algorithm, qualitatively and quantitatively. We illustrate this using comparison metrics such as module distribution, module membership cardinality, modularity Q, and Jaccard Similarity Coefficient. CONCLUSIONS: We have presented an optimized approach for efficient modularity detection in networks. The intuition driving our approach is the extraction of holistic measures of centrality from graphs, which are representative of inherent modular structure of the underlying network, and the application of those measures to efficiently guide the modularity detection process. We have empirically evaluated our approach in the specific context of real-world large scale biological networks, and have demonstrated significant savings in computational time while maintaining comparable quality of detected modules. PMID- 22206605 TI - [Vitamin D and autoimmunity. First part: Fundamental aspects]. AB - The effects of vitamin D on calcium homeostasis and bone metabolism are well known. In recent years, suboptimal vitamin D status has been recognized as a pandemic. Meanwhile, extra-skeletal effects of vitamin D are becoming better documented, particularly its effects on immunity. The authors present their actions on myeloid dendritic cells, T cells, B cells, as well as on the synthesis of antimicrobial peptides and autophagy, and the potential beneficial effects in autoimmune and inflammatory diseases. PMID- 22206606 TI - Educational attainment is not a good proxy for cognitive function in methamphetamine dependence. AB - BACKGROUND: We sought to test the hypothesis that methamphetamine use interferes with both the quantity and quality of one's education, such that the years of education obtained by methamphetamine dependent individuals serves to underestimate general cognitive functioning and overestimate the quality of academic learning. METHODS: Thirty-six methamphetamine-dependent participants and 42 healthy comparison subjects completed cognitive tests and self-report measures in Los Angeles, California. An overall cognitive battery score was used to assess general cognition, and vocabulary knowledge was used as a proxy for the quality of academic learning. Linear regression procedures were used for analyses. RESULTS: Supporting the hypothesis that methamphetamine use interferes with the quantity of education, we found that (a) earlier onset of methamphetamine use was associated with fewer years of education (p<.01); (b) using a normative model developed in healthy participants, methamphetamine-dependent participants had lower educational attainment than predicted from their demographics and performance on the cognitive battery score (p<.01); and (c) greater differences between methamphetamine-dependent participants' predicted and actual educational attainment were associated with an earlier onset of MA use (p<=.01). Supporting the hypothesis that methamphetamine use interferes with the quality of education, years of education received prior to the onset of methamphetamine use was a better predictor of a proxy for academic learning, vocabulary knowledge, than was the total years of education obtained. CONCLUSION: Results support the hypothesis that methamphetamine use interferes with the quantity and quality of educational exposure, leading to under- and overestimation of cognitive function and academic learning, respectively. PMID- 22206607 TI - Novel potent 2,5-pyrrolidinedione peptidomimetics as aminopeptidase N inhibitors. Design, synthesis and activity evaluation. AB - A series of novel aminopeptidase N inhibitors with 2,5-pyrrolidinedione scaffold were chemically synthesized. Their preliminary biological activities in enzyme kinetics and cell assay in vitro and anti-metastasis profile in vivo were also evaluated. The results indicated that all the compounds displayed potent inhibitory activity against aminopeptidase N. Compound 8f inhibited aminopeptidase N activity with IC(50) value of 1.0MUM and displayed better activity profile in vivo than that of bestatin. PMID- 22206608 TI - Phenotypic characteristics and proliferative activity of hyperplastic ductule cells in cholangiofibrosis induced by thioacetamide in rats. AB - The oral administration of thioacetamide to rats induces cholangiofibrosis characterized by hyperplasia of ductules surrounded by fibrous tissue. In the present study, we examined the expression of markers of cholangiocyte and hepatocyte phenotypes in these hyperplastic ductule cells and their proliferative activity immunohistochemically. The oral administration of thioacetamide to 21 day-old male Fisher 344 rats for 12 weeks induced multiple areas of various sizes with hyperplastic ductules. The ductules consisted of two types of ductules; ductules composed of cholangiocyte-like cuboidal cells with transparent nuclei and cytoplasm, and of intestinal epithelium-like (IE-like) cells of basophilic nuclei and cytoplasm, and the transition of these two types of cells in the same ductule was sometimes observed. The cholangiocyte-like cells expressed cytokeratin (CK)-7, CK-19 and OV-6 (cholangiocyte phenotype markers) but not Hep Par-1 antigen or HNF4alpha (hepatocyte phenotype markers). In contrast, the IE like cells expressed Hep Par-1 antigen and HNF4alpha but not CK-7, CK-19 or OV-6. The examination of Ki-67 expression showed a much higher proliferative activity for the IE-like cells compared to the cholangiocyte-like cells. The present results show that the hyperplastic ductules induced by thioacetamide are composed of IE-like cells with a high proliferative activity expressing the hepatocyte phenotype markers and of cholangiocyte-like cells with a low proliferative activity expressing the cholangiocyte phenotype markers. PMID- 22206609 TI - Comparison of standard- and low-tube voltage 320-detector row volume CT angiography in detection of intracranial aneurysms with digital subtraction angiography as gold standard. AB - RATIONALE AND OBJECTIVES: The aim of this study was to prospectively assess the effect of low-tube voltage (80 kVp) 320-detector row volume computed tomographic (CT) angiography (L-VCTA) in the detection of intracranial aneurysms, with three dimensional (3D) spin digital subtraction angiography (DSA) as the gold standard. MATERIALS AND METHODS: Forty-eight patients with clinically suspected subarachnoid hemorrhages were divided into two groups. One group underwent L-VCTA and DSA, while the other group underwent conventional-tube voltage (120 kVp) volume CT angiography (C-VCTA) and DSA. Vascular enhancement, image quality, detection accuracy of aneurysms, and radiation dose were compared between the two groups. RESULTS: For objective image quality, the L-VCTA group had higher mean vessel attenuation, correlated with higher image noise and lower signal-to-noise ratio, than the C-VCTA group. For subjective image quality, there were no significant differences between the two groups regarding scores for arterial enhancement, depiction of small arterial detail, interference of venous structures, and overall image quality scores. The mean effective dose for the L VCTA group was significantly lower than for the C-VCTA group (0.56 +/- 0.25 vs 1.84 +/- 0.002 mSv), with a reduction of radiation dose of 69.73%. With 3D DSA as the reference standard, the sensitivity, specificity, and accuracy in the L-VCTA and C-VCTA groups were 94.12%, 100%, 94.4% and 100%, 100%, and 100%, respectively. In both groups, there were significant correlations for maximum aneurysm diameter measurements between volume CT angiography and 3D DSA; no statistical difference in the mean maximum diameter of each aneurysm was measured between volume CT angiography and 3D DSA. CONCLUSIONS: L-VCTA is helpful in detecting intracranial aneurysms, with results similar to those of 3D DSA, but at a lower radiation dose than C-VCTA. PMID- 22206611 TI - The analysis of PS II photochemical activity using single and multi-turnover excitations. AB - Paper describes chlorophyll a fluorescence measurements in algal cells, and intact plant leaves and isolated chloroplasts. It focuses on amplitude and 10 MUs resolved kinetics of variable fluorescence responses upon excitation with fluorescence-saturating pulses (SP) and with 25 MUs saturating single turnover flashes (STF) which are exposed before, during and after a 100 s actinic illumination (AL) of low and high intensity. In addition to the amply documented suppression of the maximal variable fluorescence from F(m) to F(m)('), the relative proportion of the distinguished O-J-, J-I- and I-P-phases of an SP induced response is shown to be distinctly different in dark- and light-adapted leaves. The O-J-phase in the 0.01-1 ms time range is much less sensitive to light adaptation than the other phases in the 1-200 ms range. In algae and chloroplasts, the amplitude F(m)(STF) of the STF-induced response is hardly affected by a shift from the dark- to the light-activated steady state. The results support the hypothesis that the maximal variable fluorescence F(m) induced by a multiple-turnover, fluorescence-saturating pulse (SP), is associated with the release of photochemical and photoelectrochemical quenching. It is argued that the OJIPMT- or Kautsky induction curve of variable chlorophyll fluorescence in the 0-100 s time range is the reflection of the release of photochemical quenching supplemented with a temporary Photosystem I (PSI) dependent photoelectric stimulation and transient release of photoelectrochemical quenching of radiative energy loss in the Photosystem II (PSII) antennas, rather than solely of a decrease in PSII photochemical activity as is usually concluded. PMID- 22206610 TI - Hematopoietic stem cells, hematopoiesis and disease: lessons from the zebrafish model. AB - The zebrafish model is rapidly gaining prominence in the study of development, hematopoiesis, and disease. The zebrafish provides distinct advantages over other vertebrate models during early embryonic development by producing transparent, externally fertilized embryos. Embryonic zebrafish are easily visualized and manipulated through microinjection, chemical treatment, and mutagenesis. These procedures have contributed to large-scale chemical, suppressor, and genetic screens to identify hematopoietic gene mutations. Genomic conservation and local synteny between the human and zebrafish genomes make genome-scale and epigenetic analysis of these mutations (by microarray, chromatin immunoprecipitation sequencing, and RNA sequencing procedures) powerful methods for translational research and medical discovery. In addition, large-scale screening techniques have resulted in the identification of several small molecules capable of rescuing hematopoietic defects and inhibiting disease. Here, we discuss the contributions of the zebrafish model to the understanding of hematopoiesis, hematopoietic stem cell development, and disease-related discovery. We also highlight the recent discovery of small molecules with clinical promise, such as dimethyl prostaglandin E2, 3F8, and thiazole-carboxamide 10A. PMID- 22206612 TI - Comment on: Effects of surgically-induced weight loss via Roux-en-Y gastric bypass on cardiovascular autonomic nerve function. PMID- 22206613 TI - Comment on: cognitive function predicts weight loss following bariatric surgery. PMID- 22206614 TI - Comment on: Early prediction of the failure to lose weight after obesity surgery. PMID- 22206615 TI - Innovations in plastic surgery using cheap readily available materials in a resource poor environment - from CoRSU Uganda. PMID- 22206618 TI - Heterologous expression and mechanistic investigation of a fungal cytochrome P450 (CYP5150A2): involvement of alternative redox partners. AB - A fungal cytochrome P450 monooxygenase (CYP5150A2) from the white-rot basidiomycete Phanerochaete chrysosporium was heterologously expressed in Escherichia coli and purified as an active form. The purified CYP5150A2 was capable of hydroxylating 4-propylbenzoic acid (PBA) with NADPH-dependent cytochrome P450 oxidoreductase (CPR) as the single redox partner; the reaction efficiency was improved by the addition of electron transfer protein cytochrome b5 (Cyt-b5). Furthermore, CYP5150A2 exhibited substantial activity with redox partners Cyt-b5 and NADH-dependent Cyt-b5 reductase (CB5R) even in the absence of CPR. These results indicated that a combination of CB5R and Cyt-b5 may be capable of donating both the first and the second electrons required for the monooxygenation reaction. Under reaction conditions in which the redox system was associated with the CB5R-dependent Cyt-b5 reduction system, the exogenous addition of CPR and NADPH had no effect on the PBA hydroxylation rate or on coupling efficiency, indicating that the transfer of the second electron from Cyt b5 was the rate-limiting step in the monooxygenase system. In addition, the rate of PBA hydroxylation was significantly dependent on Cyt-b5 concentration, exhibiting Michaelis-Menten kinetics. This study provides indubitable evidence that the combination of CB5R and Cyt-b5 is an alternative redox partner facilitating the monooxygenase reaction catalyzed by CYP5150A2. PMID- 22206616 TI - Donation after cardiocirculatory death: a call for a moratorium pending full public disclosure and fully informed consent. AB - Many believe that the ethical problems of donation after cardiocirculatory death (DCD) have been "worked out" and that it is unclear why DCD should be resisted. In this paper we will argue that DCD donors may not yet be dead, and therefore that organ donation during DCD may violate the dead donor rule. We first present a description of the process of DCD and the standard ethical rationale for the practice. We then present our concerns with DCD, including the following: irreversibility of absent circulation has not occurred and the many attempts to claim it has have all failed; conflicts of interest at all steps in the DCD process, including the decision to withdraw life support before DCD, are simply unavoidable; potentially harmful premortem interventions to preserve organ utility are not justifiable, even with the help of the principle of double effect; claims that DCD conforms with the intent of the law and current accepted medical standards are misleading and inaccurate; and consensus statements by respected medical groups do not change these arguments due to their low quality including being plagued by conflict of interest. Moreover, some arguments in favor of DCD, while likely true, are "straw-man arguments," such as the great benefit of organ donation. The truth is that honesty and trustworthiness require that we face these problems instead of avoiding them. We believe that DCD is not ethically allowable because it abandons the dead donor rule, has unavoidable conflicts of interests, and implements premortem interventions which can hasten death. These important points have not been, but need to be fully disclosed to the public and incorporated into fully informed consent. These are tall orders, and require open public debate. Until this debate occurs, we call for a moratorium on the practice of DCD. PMID- 22206617 TI - Stem cell therapy for retinal diseases: update. AB - Distinct stem cell types have been established from embryos and identified in the fetal tissues and umbilical cord blood as well as in specific niches in many adult mammalian tissues and organs such as bone marrow, brain, skin, eyes, heart, kidneys, lungs, gastrointestinal tract, pancreas, liver, breast, ovaries, and prostate. All stem cells are undifferentiated cells that exhibit unlimited self renewal and can generate multiple cell lineages or more restricted progenitor populations that can contribute to tissue homeostasis by replenishing the cells or to tissue regeneration after injury. The remarkable progress of regenerative medicine in the last few years indicates promise for the use of stem cells in the treatment of ophthalmic disorders. Experimental and human studies with intravitreal bone marrow-derived stem cells have begun. This paper reviews recent advances and potential sources of stem cells for cell therapy in retinal diseases. PMID- 22206619 TI - Adoption of electronic health records in Korean tertiary teaching and general hospitals. AB - PURPOSE: This study examined the current prevalence of electronic health records (EHRs) in Korea and identified the factors that impede or facilitate the adoption of EHRs. METHODS: We surveyed all tertiary teaching and general hospitals in Korea. The degree to which EHR systems were adopted was evaluated using the previously defined definitions of 'comprehensive' and 'basic' EHRs based on their electronic functionality. The effects of teaching status, size, and location of hospitals on EHR adoption were examined. We also investigated factors that impeded or facilitated the adoption of EHR systems. RESULTS: The response rate was 39.0% (122/313), and 37.2% (95% confidence interval [CI] 31.9-42.6%) of Korean tertiary teaching and general hospitals had either basic or comprehensive EHR systems (50.2% of tertiary teaching hospitals, 35.0% of general hospitals). However, only 5.0% (CI 2.6-7.4%) had comprehensive EHR systems. Most Korean tertiary teaching and general hospitals, i.e., 87.0% (95% CI, 83.3-90.7%), have implemented computerized provider order-entry (CPOE) systems for medications, with larger hospitals more likely than smaller ones to have adopted some sort of EHRs (p-value<0.001). However, the prevalence of these systems did not differ according to the location of the hospital (metropolitan vs. non-metropolitan). According to the survey data, the capital requirements and high maintenance costs of EHR systems were the major barriers to their adoption, and government reimbursement or incentives were the most requested facilitators of their adoption. CONCLUSION: The rate at which EHR and CPOE for medications systems have been adopted by Korean tertiary teaching and general hospitals was higher than the rate of adoption by US hospitals. Financial aspects are reported to be the most important facilitators of and barriers to EHR adoption. Government financial support, especially to small hospitals, seems to be essential to promoting the adoption of EHRs by Korean hospitals. PMID- 22206620 TI - Adjuvant chemotherapy for resected non-small-cell lung cancer: future perspectives for clinical research. AB - Adjuvant chemotherapy for non-small-cell lung carcinoma (NSCLC) is a debated issue in clinical oncology. Although it is considered a standard for resected stage II-IIIA patients according to the available guidelines, many questions are still open. Among them, it should be acknowledged that the treatment for stage IB disease has shown so far a limited (if sizable) efficacy, the role of modern radiotherapies requires to be evaluated in large prospective randomized trials and the relative impact of age and comorbidities should be weighted to assess the reliability of the trials' evidences in the context of the everyday-practice. In addition, a conclusive evidence of the best partner for cisplatin is currently awaited as well as a deeper investigation of the fading effect of chemotherapy over time. The limited survival benefit since first studies were published and the lack of reliable prognostic and predictive factors beyond pathological stage, strongly call for the identification of bio-molecular markers and classifiers to identify which patients should be treated and which drugs should be used. Given the disappointing results of targeted therapy in this setting have obscured the initial promising perspectives, a biomarker-selection approach may represent the basis of future trials exploring adjuvant treatment for resected NSCLC. PMID- 22206621 TI - A comparison of leg length and femoral offset discrepancies in hip resurfacing, large head metal-on- metal and conventional total hip replacement: a case series. AB - BACKGROUND: A discrepancy in leg length and femoral offset restoration is the leading cause of patient dissatisfaction in hip replacement surgery and has profound implications on patient quality of life. The aim of this study is to compare biomechanical hip reconstruction in hip resurfacing, large-diameter femoral head hip arthroplasty and conventional total hip replacement. METHOD: Sixty patient's post-operative radiographs were reviewed; 20 patients had a hip resurfacing (HR), 20 patients had a Large Head Metal-on-metal (LHM) hip replacement and 20 patients had a conventional small head Total Hip Replacement (THR). The leg length and femoral offset of the operated and unoperated hips were measured and compared. RESULTS: Hip resurfacing accurately restored hip biomechanics with no statistical difference in leg length (P = 0.07) or femoral offset (P = 0.95) between the operated and non-operative hips. Overall HR was superior for reducing femoral offset discrepancies where it had the smallest bilateral difference (-0.2%, P = 0.9). The traditional total hip replacement was least effective at restoring the hip anatomy. CONCLUSION: The use of a larger diameter femoral head in hip resurfacing does not fully account for the superior biomechanical restoration, as LHM did not restore femoral offset as accurately. We conclude that restoration of normal hip biomechanics is best achieved with hip resurfacing. PMID- 22206623 TI - Folic acid supplementary reduce the incidence of adenocarcinoma in a mouse model of colorectal cancer: microarray gene expression profile. AB - BACKGROUND: Whether Folic acid is a potential drug that may prevent the progression of colorectal carcinoma and when to use are important healthy issues we focus on. Our study is to examine the effect of folic acid on the development of the CRC and the optimal time folic acid should be provided in a mouse-ICR model induced by 1, 2-Dimethylhydrazine. Also, we investigated the gene expression profile of this model related to folic acid. METHOD: Female ICR mouse (n=130) were divided into 7 groups either with the treatment of 1, 2 Dimethylhydrazine (20 mg/kg bodyweight) weekly or folic acid (8 mg/kg bodyweight) twice a week for 12 or 24 weeks. Using a 4 x 44 K Agilent whole genome oligo microarray assay, different gene expression among groups (NS, DMH, FA2, FA3) were identified and selected genes were validated by real-time polymerase chain reaction. RESULTS: Animals with a supplementary of folic acid showed a significant decrease in the incidence, the maximum diameter and multiplicity of adenocarcinomas (P<0.05). Furthermore, there were fewer adenomas or adenocarcinomas developed in the group of folic acid supplementation in pre adenoma stage compared to group of post-adenoma stage. Meanwhile, about 1070 genes that were changed by 1, 2-Dimethylhydrazine can be reversed by folic acid and 172 differentially genes were identified between the groups of pre- and post- adenoma stage using microarray gene expression analysis. CONCLUSION: Our study demonstrated that folic acid supplementary was significantly associated with the decrease risk of CRC. And the subgroup of providing folic acid without precancerous lesions was more effective than that with precancerous lesions. PMID- 22206622 TI - Effects of Marathi-Hindi bilingualism on neuropsychological performance. AB - The present study aimed to examine if bilingualism affects executive functions and verbal fluency in Marathi and Hindi, two major languages in India, with a considerable cognate (e.g., activity is actividad in Spanish) overlap. A total of 174 native Marathi speakers from Pune, India, with varying levels of Hindi proficiency were administered tests of executive functioning and verbal performance in Marathi. A bilingualism index was generated using self-reported Hindi and Marathi proficiency. After controlling for demographic variables, the association between bilingualism and cognitive performance was examined. Degree of bilingualism predicted better performance on the switching (Color Trails-2) and inhibition (Stroop Color-Word) components of executive functioning; but not for the abstraction component (Halstead Category Test). In the verbal domain, bilingualism was more closely associated with noun generation (where the languages share many cognates) than verb generation (which are more disparate across these languages), as predicted. However, contrary to our hypothesis that the bilingualism "disadvantage" would be attenuated on noun generation, bilingualism was associated with an advantage on these measures. These findings suggest distinct patterns of bilingualism effects on cognition for this previously unexamined language pair, and that the rate of cognates may modulate the association between bilingualism and verbal performance on neuropsychological tests. PMID- 22206624 TI - Improving the accuracy and precision of cognitive testing in mild dementia. AB - The CAMCOG, ADAS-cog, and MMSE, designed to grade global cognitive ability in dementia have inadequate precision and accuracy in distinguishing mild dementia from normal ageing. Adding neuropsychological tests to their scale might improve precision and accuracy in mild dementia. We, therefore, pooled neuropsychological test-batteries from two memory clinics (ns = 135 and 186) with CAMCOG data from a population study and 2 memory clinics (n = 829) and ADAS-cog data from 3 randomized controlled trials (n = 713) to estimate a common dimension of global cognitive ability using Rasch analysis. Item difficulties and individuals' global cognitive ability levels were estimated. Difficulties of 57 items (of 64) could be validly estimated. Neuropsychological tests were more difficult than the CAMCOG, ADAS-cog, and MMSE items. Most neuropsychological tests had difficulties in the ability range of normal ageing to mild dementia. Higher than average ability levels were more precisely measured when neuropsychological tests were added to the MMSE than when these were measured with the MMSE alone. Diagnostic accuracy in mild dementia was consistently better after adding neuropsychological tests to the MMSE. We conclude that extending dementia specific instruments with neuropsychological tests improves measurement precision and accuracy of cognitive impairment in mild dementia. PMID- 22206625 TI - Management Impacts on Forest Floor and Soil Organic Carbon in Northern Temperate Forests of the US. AB - BACKGROUND: The role of forests in the global carbon cycle has been the subject of a great deal of research recently, but the impact of management practices on forest soil dynamics at the stand level has received less attention. This study used six forest management experimental sites in five northern states of the US to investigate the effects of silvicultural treatments (light thinning, heavy thinning, and clearcutting) on forest floor and soil carbon pools. RESULTS: No overall trend was found between forest floor carbon stocks in stands subjected to partial or complete harvest treatments. A few sites had larger stocks in control plots, although estimates were often highly variable. Forest floor carbon pools did show a trend of increasing values from southern to northern sites. Surface soil (0-5 cm) organic carbon content and concentration were similar between treated and untreated plots. Overall soil carbon (0-20 cm) pool size was not significantly different from control values in sites treated with partial or complete harvests. No geographic trends were evident for any of the soil properties examined. CONCLUSIONS: Results indicate that it is unlikely that mineral soil carbon stocks are adversely affected by typical management practices as applied in northern hardwood forests in the US; however, the findings suggest that the forest floor carbon pool may be susceptible to loss. PMID- 22206626 TI - Clinicopathological characteristics and treatment strategies in early gastric cancer: a retrospective cohort study. AB - BACKGROUND: Both endoscopic and surgical approaches are employed in the treatment of early gastric cancer (EGC). The aim of this study was to establish appropriate treatment strategies for early gastric cancer. METHODS: We retrospectively examined clinicopathological data of EGC patients who had undergone surgery. RESULTS: A total of 327 patients (204 males and 123 females, mean age 63.2 years) were eligible for inclusion in the study. The median follow-up period was 31 months. Of 161 mucosal (pT1a) tumors, 87 were mainly undifferentiated and 110 had an undifferentiated component. Four patients with pT1a tumors had lymph node metastases; all these tumors were signet-ring cell carcinomas and were macroscopic type 0-IIc with ulceration, and only one of them had lymphatic invasion. Among patients with submucosal tumors, four of 43 patients with pT1b1 tumors and 37 of 123 patients with pT1b2 tumors had nodal metastases. Lymph node metastases were significantly higher in mixed undifferentiated type group than differentiated type group for both groups, pT1a-pT1b1 (p = 0.0251) and pT1b2 (p = 0.0430) subgroups. Only four of 45 patients with nodal metastases were diagnosed preoperatively by computed tomography (sensitivity 8.9%, specificity 96.2%). Nine patients with pT1b tumors had recurrence after surgery, and died. The sites of initial recurrence were liver, bone, peritoneum, distant nodes, and the surgical anastomosis. CONCLUSIONS: The incidence of nodal metastases was approximately 5% in undifferentiated type mucosal (pT1a) tumors, and higher in submucosal (pT1b) tumors. The sensitivity of preoperative diagnosis of nodal metastases in EGC using computed tomography was relatively low in this study. Therefore at present surgery with adequate lymphadenectomy should be performed as curative treatment for undifferentiated type EGC. PMID- 22206627 TI - Smaller prostate gland size and older age predict Gleason score upgrading. AB - OBJECTIVES: Gleason score is important for prostate cancer (CaP) risk stratification and prognostication but has a significant rate of upgrading. We examined the effect of prostate size and age on upgrading of Gleason 6 CaP. MATERIALS AND METHODS: A retrospective review was performed of patients with Gleason 6 CaP who underwent radical prostatectomy from 2001 through 2010. Preoperative clinical and pathologic variables were assessed to determine association with risk of upgrading at prostatectomy. RESULTS: A total of 1,836 patients were identified with Gleason 6 on prostate biopsy. Upgrading was observed in 543 (29.6%) patients with a final Gleason score of 3+4 in 463 (25.2%), 4+3 in 49 (2.7%), and 8-10 in 31 (1.7%). On univariate logistic regression, age, prostate weight, and PSA were significant predictors of Gleason score upgrading and remained significant on multiple logistic regression. Prostate weight was inversely related to risk of upgrading. To further explore this effect, we performed multiple logistic regression to examine risk of Gleason 6, 7, or 8-10 disease in 2,493 patients with Gleason 6-10 at prostatectomy. After controlling for age and PSA, there was a progressively increased risk of Gleason 6, 7, and 8-10 disease with decreasing prostate weight. CONCLUSIONS: Older age, higher PSA, and smaller prostate gland size are associated with increased risk of Gleason score upgrading. The inverse relationship of prostate weight to risk of Gleason upgrading may be related to increased high-grade disease in smaller glands. PMID- 22206628 TI - A modified squeeze-out mechanism for generating high surface pressures with pulmonary surfactant. AB - The exact mechanism by which pulmonary surfactant films reach the very low surface tensions required to stabilize the alveoli at end expiration remains uncertain. We utilized the nanoscale sensitivity of atomic force microscopy (AFM) to examine phospholipid (PL) phase transition and multilayer formation for two Langmuir-Blodgett (LB) systems: a simple 3 PL surfactant-like mixture and the more complex bovine lipid extract surfactant (BLES). AFM height images demonstrated that both systems develop two types of liquid condensed (LC) domains (micro- and nano-sized) within a liquid expanded phase (LE). The 3 PL mixture failed to form significant multilayers at high surface pressure (pi while BLES forms an extensive network of multilayer structures containing up to three bilayers. A close examination of the progression of multilayer formation reveals that multilayers start to form at the edge of the solid-like LC domains and also in the fluid-like LE phase. We used the elemental analysis capability of time-of flight secondary ion mass spectrometry (ToF-SIMS) to show that multilayer structures are enriched in unsaturated PLs while the saturated PLs are concentrated in the remaining interfacial monolayer. This supports a modified squeeze-out model where film compression results in the hydrophobic surfactant protein-dependent formation of unsaturated PL-rich multilayers which remain functionally associated with a monolayer enriched in disaturated PL species. This allows the surface film to attain low surface tensions during compression and maintain values near equilibrium during expansion. PMID- 22206629 TI - The human OCTN1 (SLC22A4) reconstituted in liposomes catalyzes acetylcholine transport which is defective in the mutant L503F associated to the Crohn's disease. AB - The organic cation transporter (OCTN1) plays key roles in transport of selected organic cations, but understanding of its biological functions remains limited by restricted knowledge of its substrate targets. Here we show capacity of human OCTN1-reconstituted proteoliposomes to mediate uptake and efflux of [(3)H]acetylcholine, the Km of transport being 1.0mM with V(max) of 160nmol?mg( 1)protein?min(-1). OCTN1-mediated transport of this neurotransmitter was time dependent and was stimulated by intraliposomal ATP. The transporter operates as uniporter but translocates acetylcholine in both directions. [(3)H]acetylcholine uptake was competitively inhibited by tetraethylammonium, gamma-butyrobetaine and acetylcarnitine, and was also inhibited by various polyamines. Decreasing intraliposomal ATP concentrations increased OCTN Km for acetylcholine, but V(max) was unaffected. Evaluation of the acetylcholine transporter properties of a variant form of OCTN1, the Crohn's disease-associated 503F variant, revealed time course, Km and V(max) for acetylcholine uptake to be comparable to that of wild type OCTN1. Km for acetylcholine efflux was also comparable for both OCTN1 species, but V(max) of OCTN1 503F-mediated acetylcholine efflux (1.9nmol?mg( 1)protein?min(-1)) was significantly lower than that of wild-type OCTN1 (14nmol?mg(-1)protein?min(-1)). These data identify a new transport role for OCTN1 and raise the possibility that its involvement in the non-neuronal acetylcholine system may be relevant to the pathogenesis of Crohn's disease. PMID- 22206630 TI - Further assessment to determine the additive effect of botulinum toxin type A on an upper extremity exercise program to enhance function among individuals with chronic stroke but extensor capability. AB - OBJECTIVE: To determine whether dose-specified botulinum toxin type A (BTX-A) and a standardized exercise protocol produce better upper extremity function than placebo and the same exercise program. DESIGN: Double-blind randomized trial. SETTING: A rehabilitation research center. PARTICIPANTS: A convenience sample of patients (N=25, age range, 23-76 y) who sustained a stroke 3 to 24 months previously but could initiate wrist extension. INTERVENTIONS: Participants were randomly selected to receive either BTX-A (maximum 300 U) or saline, followed by 12 to 16 exercise sessions. MAIN OUTCOME MEASURES: The primary outcome was the Wolf Motor Function Test (WMFT). Secondary outcome measures included the Modified Ashworth Scale (MAS), active range of motion, and the Stroke Impact Scale (SIS; quality of life). RESULTS: There were no group-by-time interactions for changes in the WMFT and no treatment difference (P=.86), although the BTX-A group could complete more tasks governing proximal joint motions. MAS scores improved for the BTX-A group and worsened for the control group after injection (P=.02), as did the SIS emotion domain (P=.035). CONCLUSIONS: Among chronic stroke survivors, BTX A did not impact function, movement, or tone more than a standardized exercise program. PMID- 22206632 TI - Pure coronary ectasia differs from atherosclerosis: morphological and risk factors analysis. PMID- 22206633 TI - Cryoballoon in AF ablation: impact of PV ovality on AF recurrence. AB - INTRODUCTION: Complete occlusion of the pulmonary veins (PV) is crucial for successful PV isolation. While two different sizes of cryoballoons (23 and 28 mm) are available, complete occlusion is not always achieved in any given PV. We investigated the role of PV ostial anatomy during cryoballoon PV occlusion grading and atrial fibrillation (AF) recurrence rate. METHODS: PV ostial diameter was analyzed in 168 consecutive patients (111 men, 61 +/- 10 years, 124 paroxysmal (px) and 44 persistent AF) using cardiac computed tomography (CT) prior to procedure. The ovality index at the PV ostial level was calculated in any given PV. During follow-up, 7-day holter monitors were performed at 1, 3, 6, 9, 12, 18 and 24 months post-ablation. RESULTS: The success rate at 12 +/- 6 months follow-up was 69% including a 3-month blanking period (px AF: 66%; persistent AF 77%). The ovality index of the left-sided PVs was significantly larger ("more oval") than that of the right-sided PVs (p<0.001). An optimized PV occlusion in all individual PVs (complete occlusion, grading 4/4) was achieved during ablation in 49% of patients with AF recurrence and in 73% of patients without AF recurrence (p=0.004). Patients with AF recurrence had "more oval" left sided PVs compared to patients free from AF recurrence (LSPV 0.40 +/- 0.2 vs. 0.33 +/- 0.2; p=0.04 and LIPV 0.41 +/- 0.3 vs. 0.32 +/- 0.2; p=0.03), whereas no significant association was found for right sided PVs. CONCLUSION: The ostial PV anatomy seems to have an important impact on clinical outcome and should be considered when planning and performing cryoballoon AF ablation procedures. PMID- 22206631 TI - Do 12-step meeting attendance trajectories over 9 years predict abstinence? AB - This study grouped treatment-seeking individuals (n = 1825) by common patterns of 12-step attendance using 5 waves of data (75% interviewed Year 9) to isolate unique characteristics and use-related outcomes distinguishing each class profile. The "high" class reported the highest attendance and abstention. The "descending" class reported high baseline alcohol severity, long treatment episodes, and high initial attendance and abstinence, but by Year 5, their attendance and abstinence dropped. The "early-drop" class, which started with high attendance and abstinence but with low problem severity, reported no attendance after Year 1. The "rising" class, with fairly high alcohol and psychiatric severity throughout, reported initially low attendance, followed by increasing attendance paralleling their abstention. Last, the "low" and "no" classes, which reported low problem severity and very low/no attendance, had the lowest abstention. Female gender and high alcohol severity predicted attendance all years. Consistent with a sustained benefit for 12-step exposure, abstinence patterns aligned much like attendance profiles. PMID- 22206634 TI - Immigrant status and disparities in health care delivery in patients with myocardial infarction. AB - BACKGROUND: We investigated the differences in socioeconomic status and quality health care between Singapore-born citizens and immigrants presenting with ST segment elevation myocardial infarction (STEMI). METHODS: In a prospective study, patients admitted with STEMI were recruited for a questionnaire survey. The recruited patients were categorized based on their immigration status into Singapore-born citizens (SBC), foreign-born citizens (FBC), permanent residents (PR) and non-residents (NR). RESULTS: Among the 374 recruited patients, 286 (76.5%) patients were categorized as SBC, and the remaining 88 (23.5%) as immigrants. Further breakdown of the immigrants revealed that 33 were FBC (median duration of living in Singapore, 53 years), 22 were PR (18 years), and 33 were NR (11 years). Significant differences in socioeconomic status among SBC, FBC, PR and NR were detected. NR were in the lowest, while PR in the highest, socioeconomic class based on occupation (p=0.003), education level (p<0.001), and average monthly household income (p=0.020). There were no disparities in the proportion of patients treated with primary PCI (SBC 88%, FBC 82%, PR 91%, NR 79%, p=0.555). Median door-to-balloon times were similar among the four groups (56, 52, 60, 56min, p=0.614). Compared with SBC, PR was associated with longer symptom-to-balloon times (median difference 54.1 min; 95% CI 9.0 to 99.2). CONCLUSION: There were major differences in the socioeconomic status among SBC, FBC, PR and NR who presented with STEMI. Although there were no major disparities in access to high quality health care to these patients with different immigration status, symptom-to-balloon time differed substantially among the different migrant classes. PMID- 22206635 TI - A contribution for validation of ECG criteria for interatrial conduction delay. PMID- 22206636 TI - Changes in cardiorespiratory fitness in cardiac rehabilitation patients: a meta analysis. AB - BACKGROUND/OBJECTIVES: Improving patients' cardiorespiratory fitness is an important therapeutic outcome in cardiac rehabilitation. The ability of cardiac rehabilitation to reduce mortality and morbidity has been evidenced through several meta-analyses. Whether cardiac rehabilitation can increase cardiorespiratory fitness and which factors may influence such gains are less well quantified. METHODS: We performed detailed literature searches of electronic databases and manually searched papers concerning changes in cardiorespiratory fitness in cardiac rehabilitation patients. We performed random-effects meta analysis of mean improvements in cardiorespiratory fitness and subgroup analyses to determine potential sources of heterogeneity. RESULTS: Data from 31 studies produced 48 groups (n=3827) with a mean improvement of 1.55 (95% CI 1.21-1.89) METs, (p<0.001); equivalent to standardised effect size of ES=0.97 (95% CI 0.80 1.13). As this value was highly heterogeneous (Q=852, p<0.001) we performed subgroup analyses on the effect size data. Gains in fitness were highest in patients receiving >36 exercise sessions in studies where fitness was assessed using the Naughton Protocol. Patient characteristics associated with the highest fitness gains were age (being young) and sex (being male training in a male-only exercise group). Changes in fitness were unrelated to programme type (comprehensive or exercise-only), duration or study design. There was no association with patient's baseline fitness levels. CONCLUSION: This is the first meta-analysis of changes in cardiovascular fitness in cardiac rehabilitation patients and shows clinically significant improvements in a large sample of patients from a variety of rehabilitation programmes. This analysis helps describe the characteristics of cardiac rehabilitation programmes which can increase patients' cardiorespiratory fitness. PMID- 22206637 TI - In-hospital death while awaiting cardioverter/defibrillator in neuromuscular disease. PMID- 22206638 TI - Hyperglycemia in patients with hypertensive crisis: response to "Hypertensive crisis: Comparison between diabetics and non-diabetics". PMID- 22206639 TI - Osteogenesis Imperfecta: the audiological phenotype lacks correlation with the genotype. AB - BACKGROUND: Osteogenesis Imperfecta (OI) is a heritable connective tissue disorder mainly caused by mutations in the genes COL1A1 and COL1A2 and is associated with hearing loss in approximately half of the cases. The hearing impairment usually starts between the second and fourth decade of life as a conductive hearing loss, frequently evolving to mixed hearing loss thereafter. A minority of patients develop pure sensorineural hearing loss. The interindividual variability in the audiological characteristics of the hearing loss is unexplained. METHODS: With the purpose of evaluating inter- and intrafamilial variability, hearing was thorougly examined in 184 OI patients (type I: 154; type III: 4; type IV: 26), aged 3-89 years, with a mutation in either COL1A1 or COL1A2 and originating from 89 different families. Due to the adult onset of hearing loss in OI, correlations between the presence and/or characteristics of the hearing loss and the underlying mutation were investigated in a subsample of 114 OI patients from 64 different families who were older than 40 years of age or had developed hearing loss before the age of 40. RESULTS: Hearing loss was diagnosed in 48.4% of the total sample of OI ears with increasing prevalence in the older age groups. The predominant type was a mixed hearing loss (27.5%). A minority presented a pure conductive (8.4%) or pure sensorineural (12.5%) loss. In the subsample of 114 OI subjects, no association was found between the nature of the mutation in COL1A1 or COL1A2 genes and the occurrence, type or severity of hearing loss. Relatives originating from the same family differed in audiological features, which may partially be attributed to their dissimilar age. CONCLUSIONS: Our study confirms that hearing loss in OI shows a strong intrafamilial variability. Additional modifications in other genes are assumed to be responsible for the expression of hearing loss in OI. PMID- 22206640 TI - Electromyographic indices, orofacial myofunctional status and temporomandibular disorders severity: A correlation study. AB - This study examined whether there is an association between surface electromyography (EMG) of masticatory muscles, orofacial myofunction status and temporomandibular disorder (TMD) severity scores. Forty-two women with TMD (mean 30 years, SD 8) and 18 healthy women (mean 26 years, SD 6) were examined. According to the Research Diagnostic Criteria for TMD (RDC/TMD), all patients had myogenous disorders plus disk displacements with reduction. Surface EMG of masseter and temporal muscles was performed during maximum teeth clenching either on cotton rolls or in intercuspal position. Standardized EMG indices were obtained. Validated protocols were used to determine the perception severity of TMD and to assess orofacial myofunctional status. TMD patients showed more asymmetry between right and left muscle pairs, and more unbalanced contractile activities of contralateral masseter and temporal muscles (p<0.05, t-test), worse orofacial myofunction status and higher TMD severity scores (p<0.05, Mann-Whitney test) than healthy subjects. Spearman coefficient revealed significant correlations between EMG indices, orofacial myofunctional status and TMD severity (p<0.05). In conclusion, these methods will provide useful information for TMD diagnosis and future therapeutic planning. PMID- 22206641 TI - N-Acetylcysteine treatment of dystrophic mdx mice results in protein thiol modifications and inhibition of exercise induced myofibre necrosis. AB - Oxidative stress is implicated as a factor that increases necrosis of skeletal muscles in Duchenne Muscular Dystrophy (DMD) and the dystrophic mdx mouse. Consequently, drugs that minimize oxidative stress are potential treatments for muscular dystrophy. This study examined the in vivo benefits to mdx mice of an antioxidant treatment with the cysteine precursor N-acetylcysteine (NAC), administered in drinking water. NAC was completely effective in preventing treadmill exercise-induced myofibre necrosis (assessed histologically) and the increased blood creatine kinase levels (a measure of sarcolemma leakiness) following exercise were significantly lower in the NAC treated mice. While NAC had no effect on malondialdehyde level or protein carbonylation (two indicators of irreversible oxidative damage), treatment with NAC for one week significantly decreased the oxidation of glutathione and protein thiols, and enhanced muscle protein thiol content. These data provide in vivo evidence for protective benefits of NAC treatment on dystropathology, potentially via protein thiol modifications. PMID- 22206642 TI - Exotic pets: health and safety issues for children and parents. PMID- 22206643 TI - A developmental staging series for the African house snake, Boaedon (Lamprophis) fuliginosus. AB - Embryonic staging series are important tools in the study of morphological evolution as they establish a common standard for future studies. In this study, we describe the in ovo embryological development of the African house snake (Boaedon fuliginosus), a non-venomous, egg-laying species within the superfamily Elapoidea. We develop our staging series based on external morphology of the embryo including the head, eye, facial prominences, pharyngeal slits, heart, scales, and endolymphatic ducts. An analysis of embryonic growth in length and mass is presented, as well as preliminary data on craniofacial skeletal development. Our results indicate that B. fuliginosus embryos are well into organogenesis but lack well-defined facial prominences at the time of oviposition. Mandibular and maxillary processes extend rostrally within 8 days (stage 3), corresponding to the first appearance of Meckel's cartilages. Overall, the development of the craniofacial skeleton in B. fuliginosus appears similar to that of other snake species with intramembraneous bones (e.g., dentary and compound bones) ossifying before most of the endochondral bones, the first of which to ossify are the quadrate and the otic capsule. Our staging series is the first to describe the post-ovipositional development of a non-venomous elapoid based on external morphology. This species is an extremely tractable captive that can produce large clutches of eggs every 45 days throughout the year. As such, B. fuliginosus should be a good model for evolutionary developmental biologists focusing on the craniofacial skeleton, loss of limbs, generational teeth, and venom delivery systems. PMID- 22206644 TI - Evaluation of the pharmacokinetic profile of artesunate, artemether and their metabolites in sheep naturally infected with Fasciola hepatica. AB - The pharmacokinetic (PK) parameters of artesunate, artemether and their metabolites dihydroartemisinin (DHA) and dihydroartemisinin-glucuronide (DHA glucuronide) were determined in sheep naturally infected with Fasciola hepatica. Sheep were treated either with artesunate (intramuscular (i.m.): 40 and 60 mg/kg) or artemether (i.m.: 40 and 160 mg/kg; oral: 80 mg/kg). Blood samples were withdrawn at selected time points post treatment and the artemisinins were quantified in plasma by liquid chromatography and tandem mass spectrometry (LC MS/MS). The in vitro effect of the metabolites against F. hepatica was investigated using a phenotype-based assay and scanning electron microscopy (SEM). Following artesunate applications (40 and 60 mg/kg), comparable C(max) (maximal plasma concentration) and AUCs (area under the plasma concentration-time curve) were observed for artesunate (C(max): 8.4*10(3) and 9.4*10(3)ng/ml; AUC: 6.9*10(5) and 9.7*10(5) ng min/ml), DHA (C(max): both 2.4*10(3)ng/ml; AUC: 3.7*10(5) and 5.0*10(5) ng min/ml), and DHA-glucuronide (C(max): 1.7*10(4) and 1.6*10(4)ng/ml; AUC: 2.6*10(6) and 3.3*10(6) ng min/ml). Mean elimination half lifes (t(1/2)) of artesunate, DHA and DHA-glucuronide ranged between 58 and 63 min, 94 and 113min, and 89 and 98 min, respectively. The i.m. oil-based drug formulation liberated artemether slowly and constant levels of artemether and its metabolites were observed during the entire sampling period (24 h). The AUCs of all analytes were significantly higher for the i.m. 160 mg/kg dose compared to i.m. 40 and oral 80 mg/kg doses (P=0.018). Mean C(max) of artemether (2126 and 426 ng/ml) and DHA-glucuronide (3477 and 1587 ng/ml) were higher following oral compared to i.m. (160 mg/kg) treatments (P>0.068), whereas C(max) of DHA was significantly higher following i.m. applications (P=0.0062). DHA rapidly reduced the viability of F. hepatica in vitro, whereas DHA-glucuronide showed no activity. SEM observations revealed only minor and focal tegumental alterations in few of the DHA treated worms. The calculated PK parameters reflect the anthelmintic activity of artesunate and artemether following different routes of application and will aid in the design of future studies with these drugs. PMID- 22206645 TI - Evaluation of Cymbopogon schoenanthus essential oil in lambs experimentally infected with Haemonchus contortus. AB - Hematophagous gastrointestinal parasites cause significant economic losses in small ruminant grazing systems. The growing reports of multi-drug resistant parasites call for intensive research on alternative treatments for anthelmintics to help small ruminants cope with these parasites. Two-month-old lambs with mean body weight (BW) of 22.5 kg were experimentally infected with a multidrug resistant Haemonchus contortus strain. Infected animals were dosed orally with Cymbopogon schoenanthus essential oil to evaluate its anthelmintic potential. Eighteen animals were allocated into three groups of six animals, and each received one of the following treatments: Group 1 - control (10 mL of water), Group 2 - C. schoenanthus essential oil (180 mg/kg BW); and Group 3 - C. schoenanthus essential oil (360 mg/kg BW). Animals received the oil once a day for 3 consecutive days. Lambs were evaluated clinically for blood biochemistry before, at 1, 5, 10, 15 and 20 days after treatment, and then were euthanized to assess the total worm burden. No statistically significant reduction in fecal egg count, packed cell volume or total worm count was observed after treatments. Also, no statistical difference among group means for blood levels of urea, creatinine, albumin, alkaline phosphatase, aspartate aminotransferase and gamma glutamyl transferase was found. Larval development assay (LDA) and egg hatch assay (EHA) were performed from feces of treated animals at 1, 5, 10 and 15 days after essential oil administration. An inhibition in LDA was observed 1 day after the 3-day treatment in larvae from feces of animals treated with 360 mg/kg essential oil. In conclusion, the essential oil at the doses of 180 mg/kg and 360 mg/kg was safe to sheep, but failed as an anthelmintic treatment when applied to young sheep artificially infected with a multidrug-resistant H. contortus strain. PMID- 22206646 TI - Sorption, desorption, and degradation of (4-chloro-2-methylphenoxy)acetic acid in representative soils of the Danubian Lowland, Slovakia. AB - Herbicide leaching through soil into groundwater greatly depends upon sorption desorption and degradation phenomena. Batch adsorption, desorption and degradation experiments were performed with acidic herbicide MCPA and three soil types collected from their respective soil horizons. MCPA was found to be weakly sorbed by the soils with Freundlich coefficient values ranging from 0.37 to 1.03 mg(1-1/)(n) kg(-1) L(1/)(n). It was shown that MCPA sorption positively correlated with soil organic carbon content, humic and fulvic acid carbon contents, and negatively with soil pH. The importance of soil organic matter in MCPA sorption by soils was also confirmed by performing sorption experiments after soil organic matter removal. MCPA sorption in these treated soils decreased by 37-100% compared to the original soils. A relatively large part of the sorbed MCPA was released from soils into aqueous solution after four successive desorption steps, although some hysteresis occurred during desorption of MCPA from all soils. Both sorption and desorption were depth-dependent, the A soil horizons exhibited higher retention capacity of the herbicide than B or C soil horizons. Generally, MCPA sorption decreased in the presence of phosphate and low molecular weight organic acids. Degradation of MCPA was faster in the A soil horizons than the corresponding B or C soil horizons with half-life values ranging from 4.9 to 9.6 d in topsoils and from 11.6 to 23.4 d in subsoils. PMID- 22206647 TI - Store operated Ca2+ entry dependent contraction of coronary artery smooth muscle: inhibition by peroxide pretreatment. AB - The sarco/endoplasmic reticulum (SER) Ca(2+) pool is refilled by the SER Ca(2+) pump (SERCA) using cytosolic Ca(2+) and/or extracellular Ca(2+) entering the cell. The effects of the SERCA pump inhibitor cyclopiazonic acid (CPA) were studied in pig coronary artery smooth muscle using two protocols. In protocol A, the SERCA pump was inhibited by adding CPA to cells/tissues in Ca(2+)-containing solution, whereas in protocol B, CPA was added to cells/tissues in Ca(2+)-free solution, followed by reintroduction of extracellular Ca(2+). Addition of CPA increased cytosolic Ca(2+) in cultured smooth muscle cells and elicited contraction in de-endothelialized coronary arteries in both protocols. Based on pharmacological experiments, the CPA-induced contraction of de-endothelialized arteries in protocol B resulted from store operated Ca(2+) entry (SOCE). Reactive oxygen species such as peroxides are known to damage the SERCA pump in this tissue. Consistently, CPA-induced contractions were decreased in arteries pre treated with hydrogen peroxide in protocol A. However, this pretreatment also decreased the force of contraction due to SOCE in protocol B, suggesting that it closed SOCE. We propose that the closure of SOCE triggered by exposure to reactive oxygen species may be a protective mechanism, so that Ca(2+) entry by this pathway is disallowed when SERCA is damaged in pathologies such as ischemia reperfusion. PMID- 22206648 TI - Ultrasound imaging for the rheumatologist XXXVI. Sonographic assessment of the foot in gout patients. AB - OBJECTIVES: This study aims to investigate the relationship between clinical and US findings together with the prevalence and distribution of US findings indicative of monosodium urate (MSU) crystal deposition within the foot in patients with gout. METHODS: A total of 50 patients with gout attending the in patient and the out-patient clinics of the Rheumatology Departments were prospectively enrolled in this multi-centre study. Multiplanar examination of the following 15 joints was performed: talo-navicular, navicular-cuneiform (medial, intermediate and lateral), calcaneo-cuboid, medial, intermediate and lateral cuneiform-metatarsal, cuboid-4th metatarsal, cuboid-5th metatarsal and all five metatarsophalangeal (MTP) joints. RESULTS: The following US findings were indicative of gout: enhancement of the superficial margin of the hyaline cartilage, intra-articular tophus, and extraarticular tophus. In 46 patients, a total of 1380 foot joints were investigated. In 1309 joints that were not clinically involved, US detected signs indicative of joint inflammation in 9% (121/1309). Talo-navicular joint and the first MTP joint were the joints in which the highest number of US findings were found at mid-foot and fore-foot, respectively. At MTP joint level, dorsal scans allowed the detection of a higher number of US findings indicative of joint inflammation, and MSU crystal deposits rather than on the volar plane. CONCLUSIONS: This study demonstrated that US detected a higher number of inflamed foot joints than clinical examination, and that the first MTP and the talo-navicular joints were the anatomic sites with the highest prevalence of US signs of MSU crystal aggregates. PMID- 22206649 TI - Association of mannose-binding lectin 2 gene polymorphic variants with susceptibility and clinical progression in systemic lupus erythematosus. AB - OBJECTIVES: This study investigates the role of mannose-binding lectin (MBL) in susceptibility and clinical expression of systemic lupus erythematosus (SLE), through the analysis of promoter region and exon 1 polymorphisms of the MBL2 gene. METHODS: We analysed 325 SLE patients from the Hospital de Clinicas de Porto Alegre and 344 controls. All individuals were grouped according to ethnic origin. Genotyping of the promoter and exon 1 variants were performed by PCR-SSP and PCR-RFLP, respectively. Polymorphisms frequencies between patients and controls were compared by Chi-square or Fisher's exact tests. RESULTS: A statistically significant difference was observed among the frequencies of both promoter haplotypes (p=0.005) and haplotypic combinations (p=0.004) in African derived patients, with a higher incidence of HY haplotype and LY/HY combination in SLE patients when compared to controls. These results showed a tendency to higher frequencies of genotypes related to high MBL levels in African-derived patients. A joint analysis of data from the promoter and exon 1 polymorphisms showed an increased frequency of genotypes conferring a deficient of MBL levels in European-derived patients (p<0.001). CONCLUSIONS: Our data suggest a possible influence of MBL deficiency in SLE European-derived although we did not observe any involvement of MBL2 variants in SLE clinical progression. The conflicting results shown by the analysis of patients grouped by ethnicity emphasise the need for studies considering this variable. PMID- 22206650 TI - Ultrasound assessment of the posterior sacroiliac ligaments. AB - OBJECTIVES: Posterior ligaments of the sacroiliac joints (SIJ) are comprised of the long and the short posterior sacroiliac ligaments. They are recognised as a potential source of aspecific low back pain or peripartum pelvic pain. The aim of this study was to assess the characteristics of these ligaments using high resolution ultrasonography (HRUS). METHODS: The features of the ligaments was first studied in a formalin-preserved intact cadaver. US characteristics were then recorded in 20 volunteers with a Philips HD11 XE unit using a multifrequency linear transducer (5-12 Mhz). RESULTS: US was performed in 8 men and 12 women, with a mean age of 45+/-15 year and mean body mass index (BMI) of 25.45 (+/ 3.57). Ligaments were identified in all the volunteers. The short posterior sacroiliac ligament (median length 2.17 cm and 2.31 cm in the right and left SIJ respectively) was described as a fibrilar structure attached to the posterior tuberosity of the ilium and the sacrum. The long posterior sacroiliac ligament (median length 3.42 cm and 3.56 cm in the right and left SIJ, respectively) was a fibrilar structure attached superiorly to the posterior superior iliac spine and inferiorly to the third sacral transverse tubercle. CONCLUSIONS: Our study shows that US can be used to identify the posterior ligaments of the sacroiliac joint. US could be useful to detect any pathological change associated with pain and to guide steroid injection in these ligaments. PMID- 22206653 TI - [Traumatic pancreatic pseudocyst as an unusual cause of left portal hypertension]. PMID- 22206655 TI - [Surgery, internet and social networks: is the way we communicate obsolete?]. PMID- 22206654 TI - [Measurement of lactic acid in multiple injury patients and its usefulness as a predictor of multiorgan failure and mortality]. AB - INTRODUCTION: The use of lactic acid as marker of occult hyperfusion and its relationship with multiorgan failure (MOF) and/or mortality is a subject of debate. MATERIAL AND METHOD: A prospective study was conducted on multiple injury patients over 16 years of age in critical care areas. The lactic acid was measured at the beginning and at 24 hours of the trauma and associating it with the patient morbidity and mortality. RESULTS: A total of 342 patients, with a mean injury severity score of 24.1, were included. The patients who survived had an initial, and 24 hours after the trauma, lactic acid of 27.8 mg/dl and 17.9 mg/dl, respectively, (normal values less than 22 mg/dl), increasing to 36.5mg/dl and 40.2mg/dl, respectively, in those who died. There were no differences between the initial lactic acid in patients with and without MOF, being increased at 24 hours in those who had MOF (17.8 vs 26.7). The patients with a lactic acid that got worse or remained abnormal at 24 hours had a higher mortality than those in which it remained the same or improved (25% - 17.1% vs 6.3% - 0.8%), with the percentage of patients with MOF also increasing (40.6% - 32.8% vs 14.9% - 11.1%). In haemodynamically stable patients, there was also a higher mortality when the lactic acid got worse or remained abnormal in the first 24 hours (23.8% - 19.2% vs 8.8% - 0%), as well as a higher percentage of MOF (38.1% - 26.9% vs 10.9% - 7.6%). CONCLUSIONS: The lactic acid results in the first 24 hours of the multiple injury patient are associated with mortality and MOF, even when the patient is haemodynamically stable. PMID- 22206656 TI - [Caecal lipoma as a cause of a presacral mass]. PMID- 22206657 TI - [Intestinal obstruction due to Meckel's diverticulum enterolithiasis]. PMID- 22206658 TI - [Carcinosarcoma of the colon: presentation of a case]. PMID- 22206661 TI - Staying afloat in the sensor data deluge. AB - Developments in sensor design, electronics, computer technology and networking have converged to provide new ways of collecting environmental data at rates hitherto impossible to achieve. To translate this 'data deluge' into scientific knowledge requires comparable advances in our ability to integrate, process and analyze massive data sets. We review the experience of one large project in ingesting and analyzing sensor data from global lakes and provide a synopsis of innovative approaches being used to confront the information management and analytical challenges posed by massive volumes of data. PMID- 22206663 TI - Targeting receptor for advanced glycation end products (RAGE) expression induces apoptosis and inhibits prostate tumor growth. AB - Expression of receptor for advanced glycation end products (RAGE) plays a key role in the progression of prostate cancer. However, the therapeutic potential of targeting RAGE expression in prostate cancer is not yet evaluated. Therefore in this study, we have investigated the effects of silencing the expression of RAGE by RNAi approach both in vitro and in vivo. The results of this study showed that down regulation of RAGE expression by RNAi inhibited the cell proliferation of androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells. Furthermore, targeting RAGE expression resulted in apoptotic elimination of these prostate cancer cells by activation of caspase-8 and caspase-3 death signaling. Of note, the levels of prostate specific antigen (PSA) were also reduced in LNCaP cells transfected with RAGE RNAi constructs. Importantly, the RAGE RNAi constructs when administered in nude mice bearing prostate tumors, inhibited the tumor growth by targeting the expression of RAGE, and its physiological ligand, HMGB1 and by up regulating death receptors DR4 and DR5 expression. Collectively, the results of this study for the first time show that targeting RAGE by RNAi may be a promising alternative therapeutic strategy for treating prostate cancer. PMID- 22206662 TI - Zinc, ferritin, magnesium and copper in a group of Egyptian children with attention deficit hyperactivity disorder. AB - BACKGROUND: Attention deficit hyperactivity disorder is a behavioral syndrome of childhood characterized by inattention, hyperactivity and impulsivity. There were many etiological theories showed dysfunction of some brain areas that are implicated in inhibition of responses and functions of the brain. Minerals like zinc, ferritin, magnesium and copper may play a role in the pathogenesis and therefore the treatment of this disorder. OBJECTIVE: This study aimed to measure levels of zinc, ferritin, magnesium and copper in children with attention deficit hyperactivity disorder and comparing them to normal. METHODS: This study included 58 children aged 5-15 years with attention deficit hyperactivity disorder attending Minia University Hospital from June 2008 to January 2010. They were classified into three sub-groups: sub-group I included 32 children with in attentive type, sub-group II included 10 children with hyperactive type and sub group III included 16 children with combined type according to the DSM-IV criteria of American Psychiatric Association, 2000. The control group included 25 apparently normal healthy children. RESULTS: Zinc, ferritin and magnesium levels were significantly lower in children with attention deficit hyperactivity disorder than controls (p value 0.04, 0.03 and 0.02 respectively), while copper levels were not significantly different (p value 0.9). Children with inattentive type had significant lower levels of zinc and ferritin than controls (p value 0.001 and 0.01 respectively) with no significant difference between them as regards magnesium and copper levels (p value 0.4 and 0.6 respectively). Children with hyperactive type had significant lower levels of zinc, ferritin and magnesium than controls (p value 0.01, 0.02 and 0.02 respectively) with no significant difference between them as regards copper levels (p value 0.9). Children with combined type had significant lower levels of zinc and magnesium than controls (p value 0.001 and 0.004 respectively) with no significant difference between them as regards ferritin and copper levels (p value 0.7 and 0.6 respectively). CONCLUSIONS: Children with attention deficit hyperactivity disorder had lower levels of zinc, ferritin and magnesium than healthy children but had normal copper levels. PMID- 22206664 TI - The Nogo receptor 2 is a novel substrate of Fbs1. AB - Members of the Nogo66 receptor family (NgR) are closely associated with nerve growth inhibition and plasticity in the CNS. All three members, NgR1, NgR2 and NgR3, are GPI anchored and highly glycosylated proteins. The binding and signaling properties of NgR1 are well described, but largely unknown for NgR2. At present the only known ligands are myelin associated glycoprotein (MAG) and amyloid beta precursor protein (APP). Despite the requirement of co-receptors for signaling no other binding partner has been uncovered. To learn more about the interactome of NgR2 we performed pull down experiments and were able to identify F-box protein that recognizes sugar chain 1 (Fbs1) as binding partner. We confirmed this finding with co-immunoprecipitations and in vitro binding assays and showed that the binding is mediated by the substrate recognition domain of Fbs1. As a substrate recognition protein of the SCF complex, Fbs1 binding leads to polyubiquitination and finally degradation of its substrates. This is the first time a member of the Nogo receptor family has been connected with an intracellular degradation pathway, which has not only implications for its production, but also for amyloid deposition in Alzheimer's disease. PMID- 22206665 TI - ETS1 promotes chemoresistance and invasion of paclitaxel-resistant, hormone refractory PC3 prostate cancer cells by up-regulating MDR1 and MMP9 expression. AB - ETS1, which belongs to the ETS transcription factor family, plays important roles in diverse aspects of cancer such as drug resistance and metastasis. In the present study, we examined the functional roles of ETS1 in paclitaxel resistance and invasion using human prostate cancer PC3 cells and paclitaxel-resistant PC3PR cells established from PC3 cells. Our results showed that ETS1mRNA and protein expression was markedly up-regulated in paclitaxel-resistant PC3PR cells compared with paclitaxel-sensitive PC3 cells. The mRNA levels of MDR1 as well as MMP1, MMP3, MMP9 and uPA were positively correlated with that of ETS1. In PC3PR cells, silencing of ETS1 expression by siRNAs inhibited the activity of the MDR1 promoter containing ETS binding sites, reduced the mRNA and protein levels of MDR1 and suppressed paclitaxel resistance. Furthermore, ETS1 knockdown decreased secretion of MMP9 as well as its intracellular mRNA level, and dramatically inhibited invasion of PC3PR cells. Our results suggest that ETS1 promotes paclitaxel resistance and invasion in part by up-regulating MDR1 and MMP9 expression. Taken together, a novel therapeutic strategy targeting the ETS1 gene could be designed to overcome chemoresistance and metastasis of taxane-resistant, hormone-refractory prostate cancer. PMID- 22206666 TI - The sclerostin-bone protein interactome. AB - The secreted glycoprotein, sclerostin alters bone formation. To gain insights into the mechanism of action of sclerostin, we examined the interactions of sclerostin with bone proteins using a sclerostin affinity capture technique. Proteins from decalcified rat bone were captured on a sclerostin-maltose binding protein (MBP) amylose column, or on a MBP amylose column. The columns were extensively washed with low ionic strength buffer, and bound proteins were eluted with buffer containing 1M sodium chloride. Eluted proteins were separated by denaturing sodium-dodecyl sulfate gel electrophoresis and were identified by mass spectrometry. Several previously unidentified full-length sclerostin-interacting proteins such as alkaline phosphatase, carbonic anhydrase, gremlin-1, fetuin A, midkine, annexin A1 and A2, and collagen alpha1, which have established roles in bone formation or resorption processes, were bound to the sclerostin-MBP amylose resin but not to the MBP amylose resin. Other full-length sclerostin-interacting proteins such as casein kinase II and secreted frizzled related protein 4 that modulate Wnt signaling were identified. Several peptides derived from proteins such as Phex, asporin and follistatin that regulate bone metabolism also bound sclerostin. Sclerostin interacts with multiple proteins that alter bone formation and resorption and is likely to function by altering several biologically relevant pathways in bone. PMID- 22206667 TI - Mechanosensitive behavior of bacterial cyclic nucleotide gated (bCNG) ion channels: Insights into the mechanism of channel gating in the mechanosensitive channel of small conductance superfamily. AB - We have recently identified and characterized the bacterial cyclic nucleotide gated (bCNG) subfamily of the larger mechanosensitive channel of small conductance (MscS) superfamily of ion channels. The channel domain of bCNG channels exhibits significant sequence homology to the mechanosensitive subfamily of MscS in the regions that have previously been used as a hallmark for channels that gate in response to mechanical stress. However, we have previously demonstrated that three of these channels are unable to rescue Escherichiacoli from osmotic downshock. Here, we examine an additional nine bCNG homologues and further demonstrate that the full-length bCNG channels are unable to rescue E. coli from hypoosmotic stress. However, limited mechanosensation is restored upon removal of the cyclic nucleotide binding domain. This indicates that the C terminal domain of the MscS superfamily can drive channel gating and further highlight the ability of a superfamily of ion channels to be gated by multiple stimuli. PMID- 22206668 TI - About and beyond the Henri-Michaelis-Menten rate equation for single-substrate enzyme kinetics. AB - For more than a century the simple single-substrate enzyme kinetics model and related Henri-Michaelis-Menten (HMM) rate equation have been thoroughly explored in various directions. In the present paper we are concerned with a possible generalization of this rate equation recently proposed by F. Kargi (BBRC 382 (2009) 157-159), which is assumed to be valid both in the case that the total substrate or enzyme is in excess and the quasi-steady-state is achieved. We demonstrate that this generalization is grossly inadequate and propose another generalization based on application of the quasi-steady-state condition and conservation equations for both enzyme and substrate. The standard HMM equation is derived by (a) assuming the quasi-steady-state condition, (b) applying the conservation equation only for the enzyme, and (c) assuming that the substrate concentration at quasi-steady-state can be approximated by the total substrate concentration [S](0). In our formula the rate is already expressed through [S](0), and we only assume that when quasi-steady-state is achieved the amount of product formed is negligible compared to [S](0). Numerical simulations show that our formula is generally more accurate than the HMM formula and also can provide a good approximation when the enzyme is in excess, which is not the case for the HMM formula. We show that the HMM formula can be derived from our expression by further assuming that the total enzyme concentration is negligible compared to [S](0). PMID- 22206669 TI - Two G-protein-coupled-receptor candidates, Cand2 and Cand7, are involved in Arabidopsis root growth mediated by the bacterial quorum-sensing signals N-acyl homoserine lactones. AB - Many Gram-negative bacteria use N-acyl-homoserine lactones (AHLs) as quorum sensing (QS) signaling molecules to coordinate their group behavior. Recently, it was shown that plants can perceive and respond to these bacterial AHLs. However, little is known about the molecular mechanism underlying the response of plants to bacterial QS signals. In this study, we show that the promotion of root elongation in wild type Arabidopsis thaliana induced by the AHLs N-3-oxo-hexanoyl homoserine lactone (3OC6-HSL) or N-3-oxo-octanoyl-homoserine lactone (3OC8-HSL) was completely abolished in plants with loss-of-function mutations in two candidate G-protein Coupled Receptors (GPCRs), Cand2 and Cand7. Furthermore, real time PCR analysis revealed that the expression levels of Cand2 and Cand7 were elevated in plants treated with 3OC6-HSL or 3OC8-HSL. These results suggest that Cand2 and Cand7 are involved in the regulation of root growth by bacterial AHLs and that GPCRs play a role in mediating interactions between plants and microbes. PMID- 22206670 TI - Thymoquinone inhibits growth and augments 5-fluorouracil-induced apoptosis in gastric cancer cells both in vitro and in vivo. AB - Thymoquinone (TQ), a component derived from the bioactive constituent of black seed (Nigella sativa), has been shown to exert biological activity on various types of human cancers. However, there are few studies addressing its effects on gastric cancer. Here, we present the first report describing the chemosensitizing effect of thymoquinone and 5-fluorouracil (5-FU) on gastric cancer cells both in vitro and in vivo. Studies have shown that pretreatment with TQ significantly increased the apoptotic effects induced by 5-FU in gastric cancer cell lines in vitro. Moreover, we found that TQ enhanced the 5-FU-induced killing of gastric cancer cells by mediating the downregulation of the anti-apoptotic protein bcl-2, the upregulation of the pro-apoptotic protein bax, and the activation of both caspase-3 and caspase-9. In addition to the in vitro results, it has been shown that the combined treatment of TQ with 5-FU represents a significantly more effective antitumor agent than either agent alone in a xenograft tumor mouse model. These data suggest that the TQ/5-FU combined treatment induces apoptosis by enhancing the activation of both caspase-3 and caspase-9 in gastric cancer cells. These results, which provide molecular evidence both in vitro and in vivo, support our conclusion that thymoquinone can activate caspase-3 and caspase-9 and thus result in the chemosensitisation of gastric cancer cells to 5-FU-induced cell death. PMID- 22206671 TI - Ellagic acid in pomegranate suppresses resistin secretion by a novel regulatory mechanism involving the degradation of intracellular resistin protein in adipocytes. AB - Resistin, an adipocytokine, is considered the link between obesity and type 2 diabetes. Pomegranate is a rich source of compounds used to treat metabolic diseases including type 2 diabetes. In this study, we found that consumption of pomegranate fruit extract (PFE) predominantly reduced the serum resistin levels in ovariectomized mice, an animal model with elevated resistin levels in serum and upregulated resistin mRNA expression in white adipose tissue. Moreover, the PFE significantly reduced the secretion and intracellular protein levels of resistin in differentiated murine 3T3-L1 adipocytes, but it did not alter resistin mRNA expression. When de novo protein synthesis was inhibited by the protein synthesis inhibitor cycloheximide, the intracellular resistin protein levels were drastically reduced by the PFE, suggesting that the PFE promoted the degradation of resistin at the protein level. We also found that ellagic acid (EA), a main component of pomegranate, had the same effects on the secretion and intracellular protein level of resistin. These results suggest that EA in pomegranate suppresses resistin secretion by a novel mechanism involving the degradation of intracellular resistin protein in adipocytes. PMID- 22206672 TI - SPARC expression induces cell cycle arrest via STAT3 signaling pathway in medulloblastoma cells. AB - Dynamic cell interaction with ECM components has profound influence in cancer progression. SPARC is a component of the ECM, impairs the proliferation of different cell types and modulates tumor cell aggressive features. We previously reported that SPARC expression significantly impairs medulloblastoma tumor growth in vivo. In this study, we demonstrate that expression of SPARC inhibits medulloblastoma cell proliferation. MTT assay indicated a dose-dependent reduction in tumor cell proliferation in adenoviral mediated expression of SPARC full length cDNA (Ad-DsRed-SP) in D425 and UW228 cells. Flow cytometric analysis showed that Ad-DsRed-SP-infected cells accumulate in the G2/M phase of cell cycle. Further, immunoblot and immunoprecipitation analyses revealed that SPARC induced G2/M cell cycle arrest was mediated through inhibition of the Cyclin-B regulated signaling pathway involving p21 and Cdc2 expression. Additionally, expression of SPARC decreased STAT3 phosphorylation at Tyr-705; constitutively active STAT3 expression reversed SPARC induced G2/M arrest. Ad-DsRed-SP significantly inhibited the pre-established orthotopic tumor growth and tumor volume in nude-mice. Immunohistochemical analysis of tumor sections from mice treated with Ad-DsRed-SP showed decreased immunoreactivity for pSTAT3 and increased immunoreactivity for p21 compared to tumor section from mice treated with mock and Ad-DsRed. Taken together our studies further reveal that STAT3 plays a key role in SPARC induced G2/M arrest in medulloblastoma cells. These new findings provide a molecular basis for the mechanistic understanding of the effects of SPARC on medulloblastoma tumor cell proliferation. PMID- 22206673 TI - Mechanical stimulation of cyclic tensile strain induces reduction of pluripotent related gene expressions via activation of Rho/ROCK and subsequent decreasing of AKT phosphorylation in human induced pluripotent stem cells. AB - Mechanical stimulation has been shown to regulate the proliferation and differentiation of stem cells. However, the effects of the mechanical stress on the stemness or related molecular mechanisms have not been well determined. Pluripotent stem cells such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are used as good materials for cell transplantation therapy and research of mammalian development, since they can self-renew infinitely and differentiate into various cell lineages. Here we demonstrated that the mechanical stimulation to human iPS cells altered alignment of actin fibers and expressions of the pluripotent related genes Nanog, POU5f1 and Sox2. In the mechanically stimulated iPS cells, small GTPase Rho was activated and interestingly, AKT phosphorylation was decreased. Inhibition of Rho-associated kinase ROCK recovered the AKT phosphorylation and the gene expressions. These results clearly suggested that the Rho/ROCK is a potent primary effector of mechanical stress in the pluripotent stem cells and it participates to pluripotency-related signaling cascades as an upper stream regulator. PMID- 22206674 TI - PMA induces GCMa phosphorylation and alters its stability via the PKC- and ERK dependent pathway. AB - The glial cells missing a (GCMa) transcription factor plays a pivotal role in the placental development by regulating the expression of several genes in the placenta that are responsible for the proper formation of the syncytiotrophoblast. It is well known that the function of GCMa is regulated at both transcriptional and post-translational levels by the cyclic AMP (cAMP)/protein kinase A (PKA)-dependent pathway, the activation of which increases the GCMa protein level and leads to trophoblast differentiation into the syncytiotrophoblast. However, little is known about the regulatory control of GCMa by PKC-dependent signaling mechanism(s). To investigate whether GCMa is regulated by PKC-dependent pathway, we treated the human choriocarcinoma JEG-3 cells with phorbol 12-myristate 13-acetate (PMA) and studied its effect on the GCMa protein using a monoclonal anti-GCMa antibody we prepared. PMA caused a transient decrease in the endogenous GCMa protein level in JEG-3 cells that was accompanied by an increase in GCMa phosphorylation. The phosphorylation and degradation of GCMa by PMA treatment was effectively reduced by pretreatment with protein kinase C (PKC) inhibitors and a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor, indicating a PKC- and MEK-dependent mechanism. Furthermore, we identified the serine residues 328, 378 and 383 to be the phosphorylation sites on GCMa that are involved in the PMA-induced degradation of GCMa. Our data demonstrate for the first time that GCMa is phosphorylated by the PKC- and MEK/extracellular signal-regulated kinase (ERK)-dependent mechanism, and that this phosphorylation is involved in its degradation process. PMID- 22206675 TI - Luteolin enhances TNF-related apoptosis-inducing ligand's anticancer activity in a lung cancer xenograft mouse model. AB - Sensitization of cancer cells to apoptosis induced by tumor necrosis factor related apoptosis-inducing ligand (TRAIL) by luteolin has been suggested by in vitro studies. However, no in vivo experiment has been reported to validate the potentiation effect of luteolin on TRAIL's anticancer activity. In this report, we first confirmed that luteolin potentiates TRAIL-induced cytotoxicity in A549 cells and HeLa cells in association with increased activation of apoptosis. Then we performed an in vivo experiment with a non-small cell lung cancer xenograft mouse model, which showed for the first time that the in vivo anticancer activity of TRAIL was greatly enhanced by luteolin. Compared with that in untreated control or treatment with TRAIL or luteolin alone, inhibition of tumor growth and apoptotic cell death in xenograft tumors were significantly increased in animals receiving combination treatment with TRAIL and luteolin. Data from this study thus provide strong in vivo evidence supporting that luteolin is a potential sensitizer for TRAIL in anticancer therapy. PMID- 22206676 TI - Decidual spiral artery remodeling during early post-implantation period in mice: investigation of associations with decidual uNK cells and invasive trophoblast. AB - Circumferential remodeling of spiral arteries (SAs) during pregnancy is crucial for regulating maternal blood flow into the placenta and clinically important. However its mechanism is still ill defined in humans and mice. In mice, several important aspects of decidual SA remodeling (SAR) remain unexplored and were addressed here using morphometrics by examining SAs within the mesometrial half of the decidua basalis between embryonic day 6.5 (E6.5) and midgestation (E10.5). The data presented here provide evidence that supports the following novel conclusions about SAR: (a) SAs (defined by their muscular walls) appear between E6.5 and E7.5, undergo 'outward hypertrophic' SAR (SA lumen widening with muscular wall thickening) during the E7.5-E8.5 and E9.5-E10.5 periods, and 'outward hypotrophic' SAR (SA lumen widening with muscular wall thinning) during the E8.5-E9.5 interval. (b) 'Outward hypotrophic' SAR is associated with decreases in the overall number, but not density, of SA media nuclei, suggesting loss of SA muscular wall cells. Proximity of placenta-derived invasive trophoblast to SAs appears not be involved in SAR, as these cells were undetectable in the mesometrial region of decidua basalis throughout the E6.5 E10.5 period. Although the maternally derived lymphocytes of the decidual uterine natural killer (uNK) cell type are required for decidual SAR, the timing of this, the uNK cell parameter involved and the type of SAR they influence have not been adequately explored. Evidence is presented here that not all decidual SAR during this period is uNK cell-dependent. Rather, the data suggest that uNKs only influence 'outward hypotrophic' SAR during the E8.5-E9.5 period. Evidence is presented that the uNK cell parameter involved is the attainment of a certain maturation state (based on uNK cell size) by SA wall uNKs of the Dolichos biflorus agglutinin (DBA) lectin-positive uNK cell subset. This work also suggests that the previously shown loss of contractile mural cell character from the SA wall does not depend on either uNKs or trophoblast proximity. The novel implications of the present data for early mouse pregnancy are discussed. PMID- 22206677 TI - Mouse transient receptor potential channel 6: role in hemostasis and thrombogenesis. AB - Although changes in the intracellular levels of calcium (Ca(2+)) are a central step in platelet activation, the underlying mechanism of Ca(2+) entry is still unclear. Previous studies have demonstrated that TRPC6, a member of the canonical transient receptor potential channel (TRPC) family is expressed in platelets in a significant amount, and is predominantly found on the plasma membrane. Based on these considerations, we hypothesized that TRPC6 plays a critical role in platelet function. To characterize the role of TRPC6 in platelet function in vivo, we employed a genetic approach, subjecting TRPC6 knockout mice to the tail bleeding time test and a carotid artery injury thrombosis model. We found that TRPC6-deficient animals displayed a prolonged bleeding time, and an increased time for occlusion of the injured carotid artery, compared to their wild-type littermates. Taken together, our data demonstrate for the first time, that TRPC6 deletion in mice results in defects in hemostasis and protection against thrombogenesis, suggesting a vital role in platelet function. Furthermore, TRPC6 may define a new therapeutic target for managing multiple thrombosis-based disorders. PMID- 22206678 TI - Abnormal DNA methylation of ITGAL (CD11a) in CD4+ T cells from infants with biliary atresia. AB - Recent evidence indicates that alterations to epigenetic DNA methylation patterns contribute to many autoimmune diseases. Biliary atresia (BA) is a virus-induced autoimmune disease characterized by impaired T cells, which may be due to aberrant DNA methylation. CD11a, a subunit of the beta2-integrin LFA-1 (CD11a/CD18) with costimulatory functions, is overexpressed due to hypomethylation of its promoter regulatory elements in CD4+ T cells from patients with many autoimmune diseases. However, it is unknown whether aberrant expression and methylation of CD11a occur in T cells from infants with BA. We aimed to compare the CD11a expression level and the methylation status of the CD11a promoter region in CD4+ T cells from BA infants and healthy controls (HC). We used real-time quantitative reverse transcriptase-polymerase chain reaction (qRT PCR) to examine CD11a mRNA levels in CD4+ T cells from BA and HC infants. Bisulfite sequencing was used to determine the methylation status of the CD11a promoter and flanking regions in CD4+ T cells from BA and HC infants, and in CD4+ T cells with DNA methylation inhibitors. We found that CD11a expression is significantly decreased in BA CD4+ T cells (P=0.007). This was associated with hypermethylation of the CD11a promoter region in CD4+ T cells from infants with BA. Treatment with a DNA methylation inhibitor decreased CD11a promoter methylation and increased CD11a mRNA. Therefore, DNA hypermethylation at the CD11a locus contributes to the lowered expression of CD11a in BA CD4+ T cells. PMID- 22206679 TI - The role of autophagy in cytotoxicity induced by new oncogenic B-Raf inhibitor UI 152 in v-Ha-ras transformed fibroblasts. AB - In human cancers, B-Raf is the most frequently mutated protein kinase in the MAPK signaling cascade, making it an important therapeutic target. We recently discovered a potent and selective B-Raf inhibitor, UI-152, by using a structure based drug design strategy. In this study, we examined whether B-Raf inhibition by UI-152 may be an effective therapeutic strategy for eliminating cancer cells transformed with v-Ha-ras (Ras-NIH 3T3). UI-152 displayed selective cytotoxicity toward Ras-NIH 3T3 cells while having little to no effect on non-transformed NIH 3T3 cells. We found that treatment with UI-152 markedly increased autophagy and, to a lesser extent, apoptosis. However, inhibition of autophagy by addition of 3 MA failed to reverse the cytotoxic effects of UI-152 on Ras-NIH 3T3 cells, demonstrating that apoptosis and autophagy can act as cooperative partners to induce growth inhibition in Ras-NIH 3T3 cells treated with UI-152. Most interestingly, cell responses to UI-152 appear to be paradoxical. Here, we showed that although UI-152 inhibited ERK, it induced B-Raf binding to Raf-1 as well as Raf-1 activation. This paradoxical activation of Raf-1 by UI-152 is likely to be coupled with the inhibition of the mTOR pathway, an intracellular signaling pathway involved in autophagy. We also showed for the first time that, in multi drug resistant cells, the combination of UI-152 with verapamil significantly decreased cell proliferation and increased autophagy. Thus, our findings suggest that the inhibition of autophagy, in combination with UI-152, offers a more effective therapeutic strategy for v-Ha-ras-transformed cells harboring wild-type B-Raf. PMID- 22206680 TI - Percutaneous transluminal angioplasty and stenting in patients with proximal vertebral artery stenosis. AB - BACKGROUND: Atherosclerotic occlusive disease of the proximal vertebral artery is an important cause of cerebrovascular ischemic events with a significant associated morbidity and mortality. Endovascular treatment has emerged as a promising tool of the therapeutic armamentarium, along with medical therapy and surgical reconstruction. Our objective was to systemically review the pertinent evidence on the endovascular management of proximal vertebral artery disease and perform an analysis of the published outcomes. METHODS: A systematic review of the literature identified all studies reporting percutaneous transluminal angioplasty or stenting, or both, for proximal vertebral artery stenosis. Web based search engines were searched using the Medical Subject Headings terms "vertebral artery," "angioplasty," and "stents" in all possible combinations. Studies comprising a series of at least five patients were considered for analysis. Periprocedural transient ischemic attack and stroke and death from any cause <=30 days of treatment were defined as the primary outcome end points. RESULTS: One randomized controlled trial comparing angioplasty and stenting of the proximal vertebral artery and medical therapy was identified. No comparative studies of endovascular treatment and open surgical repair were found. Forty-two selected studies reported endovascular treatment (angioplasty or stenting, or both) of 1117 vertebral arteries in 1099 patients. The weighted mean technical success rate was 97% (range, 36%-100%). Periprocedural transient ischemic attack occurred in 17 patients (1.5%). The combined stroke and death rate was 1.1%. Recurrent symptoms of vertebrobasilar insufficiency developed in 65 of 967 patients (8%) within a reported follow-up of 6 to 54 months. Restenosis developed in 183 of 789 patients (23%) who underwent follow-up imaging (range, 0%-58%). Reintervention for recurrent disease during follow-up occurred in 86 patients (9%; range, 0%-35%). CONCLUSIONS: There is limited comparative evidence on the efficacy of medical, surgical, and endovascular treatment of proximal vertebral artery disease. Percutaneous transluminal angioplasty and stenting has low periprocedural neurologic adverse events and mortality. PMID- 22206681 TI - Interactions between selected bile salts and Triton X-100 or sodium lauryl ether sulfate. AB - BACKGROUND: In order to develop colloidal drug carriers with desired properties, it is important to determine physico-chemical characteristics of these systems. Bile salt mixed micelles are extensively studied as novel drug delivery systems. The objective of the present investigation is to develop and characterize mixed micelles of nonionic (Triton X-100) or anionic (sodium lauryl ether sulfate) surfactant having oxyethylene groups in the polar head and following bile salts: cholate, deoxycholate and 7-oxodeoxycholate. RESULTS: The micellization behaviour of binary anionic-nonionic and anionic-anionic surfactant mixtures was investigated by conductivity and surface tension measurements. The results of the study have been analyzed using Clint's, Rubingh's, and Motomura's theories for mixed binary systems. The negative values of the interaction parameter indicate synergism between micelle building units. It was noticed that Triton X-100 and sodium lauryl ether sulfate generate the weakest synergistic interactions with sodium deoxycholate, while 7-oxodeoxycholate creates the strongest attractive interaction with investigated co-surfactants. CONCLUSION: It was concluded that increased synergistic interactions can be attributed to the larger number of hydrophilic groups at alpha side of the bile salts. Additionally, 7-oxo group of 7-oxodeoxycholate enhance attractive interactions with selected co-surfactants more than 7-hydroxyl group of sodium cholate. PMID- 22206682 TI - Effect of excess estrogen on breast and external genitalia development in growth hormone deficiency. AB - BACKGROUND: The progress of sexual maturation and development in cases with growth hormone (GH) and insulin-like growth factor-I (IGF-I) deficiency is not well documented in females. CASE: We observed breast and genitalia development in a 2-year-old girl with GH deficiency following neonatal asphyxia; this girl later developed central precocious puberty. Markedly pigmented stimulated areolas and nipples without an apparent breast mound, and non-enlarged labia minora in the external genitalia were observed as features of sexual maturation in the patient. The hormonal condition was characterized by increased circulating estradiol levels and extremely low IGF-I levels. SUMMARY AND CONCLUSION: This case indicates that IGF-I is necessary for exerting the full effect of estrogen on the development of breasts and maturation of external genitalia. PMID- 22206683 TI - The clinical presentation and surgical management of adnexal torsion in the pediatric and adolescent population. AB - STUDY OBJECTIVE: To determine the history, clinical presentation, physical exam, and laboratory findings of ovarian and/or tubal torsion in the pediatric and adolescent population and to examine the surgical management of adnexal torsion. DESIGN: Descriptive, retrospective chart review. SETTING: Academic children's hospital. PARTICIPANTS: Children and adolescents, aged 3-21 years, with the surgical diagnosis of ovarian and/or tubal torsion. MAIN OUTCOME MEASURES: Pain, physical exam, and laboratory characteristics and surgical outcomes. RESULTS: Of the 82 cases, there was a higher rate of right-sided adnexal torsion (64%). The most commonly reported duration of pain was 24 hours. Most (91%) stated the pain has sudden onset and 69% qualified the pain as severe. Eighty-three percent complained of nausea and 67% had vomiting. There was a higher rate of tachycardia in younger patients (P = 0.003). On exam, 91% of subjects presented with tenderness, usually in the right lower quadrant (61%). A longer duration of pain was associated with a higher rate of oophorectomy and/or salpingectomy. There was no difference in the rates of the removal of adnexal structures between gynecologists and pediatric surgeons. CONCLUSIONS: Most pediatric or adolescent patients with adnexal torsion present with acute onset of severe, intermittent pain lasting for 24 hours. Nausea and vomiting, as well as abdominal tenderness were common. Our findings will facilitate the accurate diagnosis of adnexal torsion and may contribute to more expedient surgical management. PMID- 22206684 TI - An adolescent affliction: nephrectomy and persistent severe pains due to misdiagnosed non-communicating "retroperitoneal" uterine horn. AB - STUDY OBJECTIVE: To report the existence and management of retroperitoneal functioning uterine horn in a case with unicornuate uterus and to emphasis the significance of its misdiagnosis. STUDY DESIGN: Case report. SETTING: Assiut University, Woman's Health Hospital. PARTICIPANTS: An adolescent female with progressive pains related to menstruation. INTERVENTIONS: Extraperitoneal resection of the obstructed uterine horn. MAIN OUTCOME MEASURE: Operative time, complications and postoperative pains. RESULTS: A patient aged 11 years presented with severe lower abdominal pains, history of correction of ectopia vesicae in infancy, and recent history of nephrectomy for ipsilateral obstructed pelvic kidney. MRI and transrectal ultrasonography showed a pelvic mass with thick wall. Laparoscopy showed unicornuate uterus with only the left horn was being visualized. Hysteroscopy showed normal vagina and cervical canal communicating with normal left hemi-cavity. Extraperitoneal approach via extending the incision of previous nephrectomy was done under laparoscopic monitoring. Excision of the horn was done totally extraperitoneal without puncturing its covering parietal peritoneum within 65 min. No operative or postoperative complications were reported. Menstrual pains showed dramatic improvement after the procedure. CONCLUSIONS: The present report is the first to describe the existence of a retroperitoneal functioning uterine horn with description of a successful extraperitoneal approach for its excision. Nephrectomy in the present case might be attributed to misdiagnosis of this problem. PMID- 22206685 TI - Rett syndrome and menstruation. AB - OBJECTIVE: Describe the experience that girls with Rett syndrome have with menstruation including menstrual hygiene, dysmenorrhea, premenstrual syndrome (PMS), and attempts at treatment. DESIGN: Anonymous web-based survey. SETTING: Convenience sample recruited from Rett syndrome LISTSERV in July of 2009. PARTICIPANTS: Mothers of girls with Rett syndrome between the ages of 10-25 who have had at least one menses. MAIN OUTCOME MEASURES: Prevalence, frequency, and severity of dysmenorrhea and PMS; hygiene concerns; and treatments attempts and perceived effectiveness. RESULTS: Dysmenorrhea and PMS are common problems among young women with Rett syndrome. Despite their frequency and severity they do not routinely limit activities. Multiple treatment attempts are common. Hormonal contraception is used mostly for menstrual cycle control with oral contraceptive pills the most commonly used method. CONCLUSIONS: Young women with Rett syndrome have standard symptoms of dysmenorrhea and PMS as well as autism spectrum specific PMS symptoms. Hormonal contraception is commonly used for menstrual management. PMID- 22206686 TI - Can von Willebrand disease be investigated on combined hormonal contraceptives? AB - STUDY OBJECTIVE: To review the medical literature and determine whether testing for von Willebrand disease can be performed in adolescents using combined hormonal contraceptives (CHC). DESIGN: Literature review where Embase and Medline were searched using the key words "von Willebrand factor," "von Willebrand disease," "contraceptive agents," and "menorrhagia." Articles were included in the review if they were controlled trials comparing a current form of CHC versus a control group and testing for von Willebrand factor was performed and reported. MAIN OUTCOME MEASURES: Impact of combined hormonal contraceptives on von Willebrand factor antigen. Secondary outcomes included effects on Factor VIII and von Willebrand factor activity known as the Ristocetin cofactor. RESULTS: Seven articles met inclusion criteria. All seven assessed VWF Ag with CHC use; six of the seven demonstrated no change and one, Gevers Leuven, demonstrated a significant decrease after CHC use. Three studies measured Factor VIII and showed no significant change with use. One study by Kadir assessed the Ristocetin cofactor and also failed to demonstrate change on CHC. CONCLUSION: From the literature it appears that adolescents, assessed for menorrhagia and already on combined hormonal contraceptives, can be tested for von Willebrand disease if this diagnosis is suspected by the physician. By allowing adolescents to remain on combined hormonal contraceptives during testing, one avoids the risk of recurrent and severe menorrhagia which could result in admission and transfusion. PMID- 22206687 TI - Sexual health behavior interventions for U.S. Latino adolescents: a systematic review of the literature. AB - STUDY OBJECTIVE: To identify sexual health behavior interventions targeting U.S. Latino adolescents. DESIGN: A systematic literature review. SETTING: Peer reviewed articles published between 1993 and 2011, conducted in any type of setting. PARTICIPANTS: Male and female Latino adolescents ages 11-21 years. INTERVENTIONS: Interventions promoting sexual abstinence, pregnancy prevention, sexually transmitted infection (STI) prevention, and/or HIV/AIDS prevention. MAIN OUTCOME MEASURES: Changes in knowledge, attitudes, engagement in risky sexual behaviors, rates of STIs, and/or pregnancy. RESULTS: Sixty-eight articles were identified. Fifteen were included in this review that specifically addressed Latino adolescent sexual health behavior. Among the reviewed interventions, most aimed to prevent or reduce STI and HIV/AIDS incidence by focusing on behavior change at two levels of the social ecological model: individual and interpersonal. Major strengths of the articles included addressing the most critical issues of sexual health; using social ecological approaches; employing different strategies to deliver sexual health messages; and employing different intervention designs in diverse geographical locations with the largest population of Latino communities. Most of the interventions targeted female adolescents, stressing the need for additional interventions that target Latino adolescent males. CONCLUSIONS: Latino adolescent sexual health is a new research field with gaps that need to be addressed in reducing negative sexual health outcomes among this population. More research is needed to produce new or validate existing, age-specific, and culturally-sensitive sexual health interventions for Latino male and female adolescents. Further, this research should also be conducted in areas of the U.S. with the newest Latino migration (e.g., North Carolina). PMID- 22206688 TI - Untangling a web: an unusual case of labial necrosis in an adolescent female. AB - BACKGROUND: Hair tourniquets are commonly described in the pediatric literature. Prompt recognition of a hair tourniquet and treatment with complete removal of the hair by pediatricians, pediatric emergency room physicians, or gynecologists is essential to prevent ischemia and necrosis of affected tissue. CASE: Herein we present the case of a 12-year-old female referred to the pediatric surgery clinic for labial pain and swelling. She was found to have a hair tourniquet of the labia minora caused by pubic hair. The patient was taken to the operating room for examination under anesthesia and removal of the hair. Her post-operative course was unremarkable and she was discharged home the following day. On follow up visit to the clinic her labial edema had completely resolved and she was pain free. SUMMARY AND CONCLUSIONS: Unlike previous case reports that describe hair tourniquets as originating from hair on the head, our patient had a hair tourniquet caused by pubic hair. In adolescents where personal hygiene of the perineum is difficult, clinicians need to be aware of the possibility of a hair tourniquet forming from pubic hair. PMID- 22206689 TI - Triacylglycerols and body fat mass are possible independent predictors of C3 in apparently healthy young Brazilian adults. AB - OBJECTIVE: To evaluate the association between serum concentrations of complement factor-3 (C3) with anthropometric, biochemical, and lifestyle features in healthy young adults. METHODS: From 157 young healthy adults 18 to 35 y old, anthropometric measurements and body composition, systolic and diastolic blood pressures, and lifestyle data were collected and analyzed. Blood samples were collected after a 12-h fast for the determination of glucose, triacylglycerols, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, insulin, C3, ceruloplasmin, and uric acid. RESULTS: Complement factor-3 correlated directly with body mass index (r = 0.23417, P = 0.0032), body fat mass (bioelectrical impedance analysis; r = 0.33407, P < 0.0001), percentage of body fat (bioelectrical impedance analysis; r = 0.26873, P = 0.0007), waist circumference (r = 0.21266, P = 0.0075), insulin (r = 0.26152, P = 0.0009), homeostasis model assessment of insulin resistance (r = 0.24831, P = 0.0017), total cholesterol (r = 0.23335, P = 0.0033), triacylglycerols (r = 0.38435, P < 0.0001), and other outcome measurements. In the multiple linear regression analysis, triacylglycerols (r(2) = 0.1379, P < 0.0001) and body fat mass (bioelectrical impedance analysis; r(2) = 0.0621, P = 0.0010) were independently associated with the C3 concentration after adjusting for age, gender, smoking status, and physical activity. CONCLUSION: Complement factor-3 seems to be related to several anthropometric and biochemical measurements in healthy young adults. These results demonstrate an independent role of triacylglycerols, a component of the metabolic syndrome, and body fat mass as possible predictors of C3 concentrations. Thus, C3 can be used as an early marker for metabolic syndrome manifestations. PMID- 22206690 TI - Chronic trauma-induced neck pain impairs the neural control of the deep semispinalis cervicis muscle. AB - OBJECTIVE: The deep cervical extensors show structural changes in patients with neck pain however their activation has never been investigated in patients. This study is the first to present neurophysiological data from the deep semispinalis cervicis muscle in patients. METHODS: Ten women with chronic neck pain and 10 healthy controls participated. Activity of the semispinalis cervicis was measured as subjects performed isometric contractions at 15 and 30 N force with continuous change in force direction in the range 0-360 degrees . Tuning curves of the EMG amplitude (average rectified value, ARV) were computed and the mean point of the ARV curves defined a directional vector, which determined the directional specificity of the muscle activity. RESULTS: Patients displayed reduced directional specificity of the semispinalis cervicis (P < 0.05). Furthermore, the EMG amplitude during the circular contraction was lower for the patients (86.3 +/ 38.0 and 104.4 +/- 47.0 MUV for 15 and 30N, respectively) compared to controls (226.4 +/- 128.5 and 315.8 +/- 205.5 MUV; P<0.05). CONCLUSIONS: The activity of the semispinalis cervicis muscle is reduced and less defined in patients with neck pain confirming a disturbance in the neural control of this muscle. SIGNIFICANCE: This finding suggests that exercises that target the deep semispinalis cervicis muscle may be relevant to include in the management of patients with neck pain. PMID- 22206691 TI - Contralateral glossoplegia in a lower pontine infarction. AB - A 65-year old man developed sudden dysarthria, dysphagia, right-sided weakness, and sensory loss. The neurologic examination revealed left-sided tongue deviation caused by right glossoplegia. A magnetic resonance imaging scan revealed an elongated acute infarction from the left ventromedial portion of the lower pons extending to the dorsal pontine tegmentum area. The ipsilateral tongue deviation of the patient may result from interruption of the contralateral crossed corticohtpoglossal projection. This finding suggests that the possibility of the corticohypoglossal decussation may exist just above the pontomedullary junction, with individual variability. PMID- 22206692 TI - Vertebral artery stenting for the treatment of bow hunter's syndrome: report of 4 cases. AB - Bow hunter's syndrome (BHS) is a rare condition resulting from vertebrobasilar insufficiency secondary to mechanical occlusion or stenosis of the vertebral artery (VA) due to head rotation. Traditionally, surgical intervention with C1-C2 fusion or VA decompression was the mainstay of therapy. Endovascular intervention was rarely performed to treat BHS. We reviewed the neurointerventional database from July 2005 to October 2010 to identify all cases of BHS treated with VA stenting. Here we report clinical, technical, and outcome data for 4 patients with BHS who were treated with VA stenting. In all 4 of these patients, stenting was performed in the V2 segment (C2-C6) of the VA without significant technical difficulties. All patients reported symptomatic relief, and only minor or no residual stenosis was detected by dynamic digital subtraction angiography. Our findings indicate that VA stenting for the treatment of BHS is feasible, safe, and clinically effective. Endovascular techniques might offer an alternative, minimally invasive therapy for the treatment of BHS. PMID- 22206693 TI - "Code stroke": hospitalized versus emergency department patients. AB - Stroke rapid-response ("code stroke") teams facilitate the evaluation and treatment of patients presenting to emergency departments (EDs). Little is known about the usefulness of code stroke systems for patients hospitalized primarily for other conditions. We hypothesized that the yield of code stroke evaluations would be lower in hospitalized than in ED patients, and sought to identify potential targets for quality improvement efforts. Diagnoses and management of in hospital and ED code stroke patients were assessed retrospectively in a Joint Commission-certified primary stroke center over a 1-year period. A total of 93 in hospital and 204 ED code strokes were identified during this period. Compared with the ED patients, the hospitalized patients were less likely to have had a stroke/transient ischemic attack (26.8% vs 51.4%; P < .0001) and less likely to have been treated with a thrombolytic agent (odds ratio, 0.27; 95% confidence interval, 0.07-0.97: P = .03). Conditions not necessitating immediate neurologic care accounted for 63.4% of in-hospital strokes, compared with 31.3% of ED code strokes (P < .0001). "Altered mental status" was the sole presenting symptom in 48% of the hospitalized patients, compared with only 10% of ED patients (P < .0001), and was the only clinical feature independently associated with a stroke mimic in the hospitalized patients (odds ratio, 63.52; 95% confidence interval, 7.37-547.69; P = .0002). There was no association between a final diagnosis of a stroke mimic and patient age, sex or race-ethnicity or nursing shift. The proportions of patients with acute ischemic stroke and patients treated with thrombolytics after activation of in-hospital code stroke were small, and were lower than those of patients with ED code stroke in the same hospital over the same time period. Developing a standardized assessment protocol for hospitalized patients with altered mental status may improve the efficacy of care. PMID- 22206694 TI - Intracranial hemorrhage as the initial presentation of disseminated intravascular coagulation in association with malignancy. AB - A 76-year-old man presented with a sudden disturbance of consciousness and right hemiplegia. An initial computed tomographic examination revealed multiple hematomas. The laboratory studies were highly suggestive of disseminated intravascular coagulation, although the underlying diseases were unknown at the time of admission. Despite various attempts at management, including replacement therapy, bleeding was not controlled and the patient died on day 5. An autopsy revealed the presence of prostate and rectal cancers. This case illustrates the fact that a fatal intracranial hemorrhage can be the first manifestation of disseminated intravascular coagulation in association with malignancy. PMID- 22206695 TI - No correlation between plasma D-dimer levels and lymph node involvement in operable breast cancer. PMID- 22206696 TI - A new NOTCH3 mutation presenting as primary intracerebral haemorrhage. AB - Primary intracerebral haemorrhages (PICH) are defined as haemorrhages within the brain parenchyma in the absence of readily identifiable causes. CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary vascular disease and its mainly clinical manifestations are early-onset infarcts. Spontaneous lobar haematomas are a rare occurrence. We report a very unusual presentation of CADASIL in a 65 year-old man carrying a new NOTCH3 mutation. The clinical onset of the disease was related to an intracerebral haematoma following colon surgery and causing a delirium. In brief, our report suggests that CADASIL must be considered in patient with PICH. PMID- 22206697 TI - Patterns of metal composition and biological condition and their association in male common carp across an environmental contaminant gradient in Lake Mead National Recreation Area, Nevada and Arizona, USA. AB - There is a contaminant gradient in Lake Mead National Recreation Area (LMNRA) that is partly driven by municipal and industrial runoff and wastewater inputs via Las Vegas Wash (LVW). Adult male common carp (Cyprinus carpio; 10 fish/site) were collected from LVW, Las Vegas Bay (receiving LVW flow), Overton Arm (OA, upstream reference), and Willow Beach (WB, downstream) in March 2008. Discriminant function analysis was used to describe differences in metal concentrations and biological condition of fish collected from the four study sites, and canonical correlation analysis was used to evaluate the association between metal and biological traits. Metal concentrations were determined in whole-body extracts. Of 63 metals screened, those initially used in the statistical analysis were Ag, As, Ba, Cd, Co, Fe, Hg, Pb, Se, Zn. Biological variables analyzed included total length (TL), Fulton's condition factor, gonadosomatic index (GSI), hematocrit (Hct), and plasma estradiol-17beta and 11 ketotestosterone (11kt) concentrations. Analysis of metal composition and biological condition both yielded strong discrimination of fish by site (respective canonical model, p<0.0001). Compared to OA, pairwise Mahalanobis distances between group means were WB500 nm particles from Caelyx confirmed the presence of SVS, providing independent evidence for their stable existence. Based on a rough estimation, the amount of SVS in Caelyx is some 60 billionth part of all liposomes. These observations raise the possibility that the presence of an exceedingly small fraction of >500 nm particles may be an intrinsic property of PEGylated small unilamellar liposomes, and that the described FACS analysis may be developed further as a quality assay for liposomal homogeneity. PMID- 22206710 TI - Melatonin concentration as a marker of the circadian phase in patients with obstructive sleep apnoea. AB - OBJECTIVE: The effects of obstructive sleep apnoea (OSA) on the markers of glucose metabolism and other hormones are of interest, particularly since there is growing evidence that OSA may be a risk factor for disorders such as insulin resistance. However, interpreting these studies depends on the target hormone not having a diurnal rhythm and the circadian rhythm not being altered by the sleep fragmentation that occurs in OSA. Therefore, the aim of our study was to test the hypothesis that OSA displaces the circadian rhythm. METHODS: We carried out a prospective, observational, controlled, parallel study in 22 OSA patients (mean [SD] age: 45.1 [8.8]years; apnoea/hypopnoea index (AHI): 37 [24] events/h) and 22 age matched healthy subjects (age: 47.9 [7.9]years; AHI: 3 [1] events/h). Saliva samples for the measurement of melatonin were collected from participants resting in dim light at 30 min intervals between 19:30 and 22:30 h. Dim light melatonin onset (DLMO), a marker of the circadian phase, was taken at the end of the 30 min interval in which the greatest rise in melatonin occurred. RESULTS: The group median (interquartile range) DLMO did not differ in OSA patients compared to healthy subjects (OSA patients: 90 [60-150]min; healthy subjects: 135 [90 150]min, p=0.19). CONCLUSION: The circadian phase is the same in OSA patients and healthy subjects using salivary melatonin concentration as a marker of the circadian phase. PMID- 22206711 TI - Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders. AB - INTRODUCTION: To improve the understanding of psychotic abnormalities and their non-Mendelian inheritance patterns, the epigenetic regulation of the psychotic disorder-associated GABRB2, gene for the type A gamma-aminobutyric acid receptor beta(2)-subunit, was investigated. METHODS: Expression of GABRB2, and the epigenetic regulatory enzymes histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) in mouse and postmortem human brains was analyzed using real-time PCR. RESULTS: Results showed that expression of GABRB2 isoforms significantly increased over time in both mouse and human, especially for the long splicing isoform. In the brains of non-psychiatric controls (CON), a significant positive correlation of GABRB2 expression with age was observed in individuals with MM genotypes of the single nucleotide polymorphisms (SNPs) rs187269 and rs1816072. This was reversed to a significant negative correlation in schizophrenics (SCZ). A similar reversal was also displayed by bipolar disorder (BPD) patients. In parallel, a significant co-variation of HDAC1 with GABRB2 expression observed in CON remained significant in BPD but not in SCZ; comparably, a significant co-variation of HDAC2 with GABRB2 expression observed in CON became non-significant in both SCZ and BPD. Moreover, co-variations of DNMT1 and DNMT3B with GABRB2, not observable in CON, became significant in BPD. CONCLUSION: These findings demonstrated that GABRB2 expression was under epigenetic regulation that varied with development, genotype and disease status, and these regulatory mechanisms were observably disrupted in SCZ and BPD. This study provided insight into the complex inheritance patterns of psychiatric disorders, and pointed to the involvement of epigenetic dysregulation in the disease process of major psychotic disorders. PMID- 22206712 TI - Volatile anesthetics reduce biochemical markers of brain injury and brain magnesium disorders in patients undergoing coronary artery bypass graft surgery. AB - OBJECTIVES: Neuropsychological disorders are some of the most common complications of coronary artery bypass graft (CABG) surgery. The early diagnosis of postoperative brain damage is difficult and mainly based on the observation of specific brain injury markers. The aim of this study was to analyze the effects of volatile anesthesia (VA) on plasma total and ionized arteriovenous magnesium concentrations in the brain circulation (a-vtMg and a-viMg), plasma matrix metalloproteinase-9 (MMP-9), and glial fibrillary acidic protein (GFAP) in adult patients undergoing CABG surgery. DESIGN: An observational study. SETTING: The Department of Cardiac Surgery in a Medical University Hospital. PATIENTS AND METHODS: Studied parameters were measured during surgery and in the early postoperative period. Patients were assigned to 3 groups: group O, patients who did not receive VA; group ISO, patients who received isoflurane; and group SEV, patients who received sevoflurane. RESULTS: Ninety-two patients were examined. CABG surgery increased MMP-9 and GFAP. The highest MMP-9, GFAP, and the most dramatic disorders in a-vtMg and a-viMg were noted in group O. CONCLUSIONS: Cardiac surgery increased plasma MMP-9 and GFAP concentrations. Changes in MMP-9, GFAP, and arteriovenous tMg and iMg were significantly higher in group O. Volatile anesthetics, such as ISO or SEV, reduced plasma MMP-9, GFAP concentrations, and disturbances in a-vtMg and a-viMg. PMID- 22206713 TI - Drug policy in Vietnam: a decade of change? AB - BACKGROUND: Driven by the rapid spread of HIV, Vietnam's response to drug use has undergone significant transformation in the past decade. This paper seeks to identify and analyse factors that prompted these changes and to investigate their impact on the lives of people who use drugs. METHOD: This policy analysis is based on a review of Vietnamese Government documents, peer-reviewed publications and the authors' knowledge of and involvement in drug policy in Vietnam. RESULTS: The last decade has witnessed a progressive change in the mindset of political leaders in Vietnam around illicit drug use and HIV issues. This has led to adoption of evidence-based interventions and the evolution of drug policy that support the scale up of these interventions. However, HIV prevalence among drug users at 31.5% remains high due to limited access to effective interventions and impediments caused by the compulsory treatment centre system. CONCLUSIONS: The twin epidemics of HIV and illicit drug use have commanded high-level political attention in Vietnam. Significant policy changes have allowed the implementation of HIV prevention and drug dependence treatment services. Nevertheless, inconsistencies between policies and a continued commitment to compulsory treatment centres remain as major impediments to the provision of effective services to drug users. It is critical that Vietnamese government agencies recognise the social and health consequences of policy conflicts and acknowledge the relative ineffectiveness of centre-based compulsory treatment. In order to facilitate practical changes, the roles of the three ministries directly charged with HIV and illicit drug use need to be harmonised to ensure common goals. The participation of civil society in the policymaking process should also be encouraged. Finally, stronger links between local evidence, policy and practice would increase the impact on HIV prevention and drug addiction treatment programming. PMID- 22206714 TI - Estimation of age at death from the pubic symphysis and the auricular surface of the ilium using a smoothing procedure. AB - We discuss here the estimation of age at death from two indicators (pubic symphysis and the sacro-pelvic surface of the ilium) based on four different osteological series from Portugal, Great-Britain, South Africa or USA (European origin). These samples and the scoring system of the two indicators were used by Schmitt et al. (2002), applying the methodology proposed by Lucy et al. (1996). In the present work, the same data was processed using a modification of the empirical method proposed by Lucy et al. (2002). The various probability distributions are estimated from training data by using kernel density procedures and Jackknife methodology. Bayes's theorem is then used to produce the posterior distribution from which point and interval estimates may be made. This statistical approach reduces the bias of the estimates to less than 70% of what was obtained by the initial method. This reduction going up to 52% if knowledge of sex of the individual is available, and produces an age for all the individuals that improves age at death assessment. PMID- 22206715 TI - Do century-specific equations provide better estimates of stature? A test of the 19-20th century boundary for the stature estimation feature in Fordisc 3.0. AB - A sample (n=28) from the Terry Collection was selected to include only White males who were born and had their entire growth and development period before 1900 to assess the effects year of birth have on accuracy and precision when estimating stature. Using the computer application Fordisc 3.0, stature was estimated using the humerus, radius, femur, and tibia equations developed from White males born in the 19th Century and the 20th Century. The 19th Century White male equations did not consistently provide the most precise and accurate estimates of stature. The 20th Century equations provide results that were as good as or slightly better than the 19th Century equations for the humerus, radius and femur. The 20th Century equations provided notably better results for the tibia. There is a great deal of evidence that there are clear positive secular changes in most of North America in the last 100-125 years, but the division commonly advocated in a forensic context at the year 1900 has no positive effect on accuracy or precision when estimating stature. PMID- 22206716 TI - Current status of temporomandibular joint arthroscopy in the United Kingdom. AB - In an era during which minimally invasive procedures are increasingly becoming the norm, arthroscopy of the temporomandibular joint (TMJ) seems to be infrequently used for diagnosis and treatment of disorders of the TMJ. The reasons for this are not clear. The purpose of this study was to find out the current state of arthroscopy of the TMJ in the UK and, more specifically, how often it is used, the indications for its use, the level of experience of practising surgeons, and the reasons for not using it. Information was gathered between 2009 and 2010 from a postal and e-mail questionnaire to all oral and maxillofacial consultants in the UK. Of the 346 consultants, 215 (60%) responded to the questionnaire. Forty-two said that they currently used arthroscopy of the TMJ, and 33 of those (81%) have more than 5 years' experience. During the past year, a total of 8 consultants nationally have done 20 arthroscopies or more. Thirty-three of the procedures (81%) were done for both diagnosis and treatment. Lack of perceived need of patients and lack of interest in this specialty were the main reasons given for not doing arthroscopy, lack of training being a key secondary reason. The Storz and Olympus systems were the most commonly used within the UK. Results seem to support the opinion that arthroscopy of the TMJ is under-used, and consideration should be given to ensuring that trainees are instructed in its use, which is important in the diagnosis and treatment of disorders of the TMJ. PMID- 22206717 TI - Comparative biomechanical evaluation of mono-cortical osteosynthesis systems for condylar fractures using photoelastic stress analysis. AB - Fractures of the condyle account for 20-30% of all mandibular fractures, and are therefore one of the most common facial injuries. Precise evaluation of the mechanical stresses that develop in a fractured mandible is essential, particularly for the testing of systems currently used for stabilisation of the condylar fragment. Photoelastic stress analysis can be used to visualise alterations in the strain that is induced in the mandible by a fracture, and in the osteosynthesis materials used to stabilise it. This method, used on currently used osteosynthesis materials, showed that stabilisation of a subcondylar fracture with a single miniplate does not provide enough stability, whereas the use of two miniplates - properly positioned - offers sufficient stability in all loading conditions. A microplate may be used as a tension-resisting plate with equally good results. PMID- 22206718 TI - Acute cervico-facial infection in Scotland 2010: patterns of presentation, patient demographics and recording of systemic involvement. AB - Acute bacterial cervicofacial infection is a common problem that is most often secondary to dental infection. Most cases present as localised abscesses but some may be associated with serious morbidity including scarring, embarrassment of the airway, SIRS (systemic inflammatory response syndrome), and sepsis syndrome. Fourteen oral surgery or maxillofacial surgery units in Scotland took part in a clinical audit of acute infection during two four-week cycles (August and November) in 2010. Information regarding the patients, signs and symptoms, and management was recorded. Training material was distributed between cycles with information on SIRS, sepsis, and the prescription of antibiotics. Overall, 140 patients presented with acute infection. There was an equal sex distribution and ages ranged from 5 to 87 years. There was an association with deprivation and 36% of patients were from the lowest socioeconomic quintile. Most infections were dental (n=120, 86%), and patients presented with pain and swelling (n=120, 86% and n=134, 96%, respectively) Twenty-three patients (16%) met the criteria for SIRS. A further 23 (16%) had at least one positive SIRS marker with incomplete recording of the remaining markers. Twenty-six patients (19%) had no recorded SIRS markers. Cervicofacial infection can be associated with serious morbidity and mortality, which may be better managed if the systemic signs and symptoms of sepsis are recognised and recorded at presentation. This study showed that the recording of signs of sepsis was variable even with training. Further training of junior staff to recognise severe acute bacterial infection may improve management. PMID- 22206719 TI - Isolated greater tuberosity fracture: Short-term functional outcome following a specific rehabilitation program. AB - BACKGROUND: Evaluate the functional outcome of a specific program of rehabilitation during conservative treatment of fracture of the greater tuberosity. METHODS: We retrospectively studied the records of 22 patients, with minimally displaced greater tuberosity fracture, according to inclusion criteria. All patients have received an early (one week after the injury) rehabilitation program based on physical analgesic therapy means, techniques for recovering range of motion, strengthening exercises, proprioceptive stabilization exercises and usability advices. The evaluation was done at baseline, one, two and three months of the end of physical treatment. RESULTS: Pain, perceived disability and range of motion were improved significantly since the end of rehabilitation. The improvement of function (Constant score) was significant at different evaluation times. The functional result seems to be poor when patients are aged and pain is severe at baseline. CONCLUSION: During conservative treatment of fracture of the greater tuberosity, earlier rehabilitation allows rapid range of motion and functional recovery limiting care duration. After fracture healing, the rehabilitation program becomes similar to that advocated in rotator cuff disease. Whatever the initial treatment choice, rehabilitation must be considered at the waning of the first week. PMID- 22206720 TI - Blushing-fearful individuals overestimate the costs and probability of their blushing. AB - It has been proposed that blushing-fearful individuals overestimate both the probability and the interpersonal costs of blushing. To study these judgmental biases, we presented a treatment-seeking sample of blushing-fearful individuals a series of vignettes describing social events and tested whether this clinical sample would overestimate the costs and probability of blushing compared to non fearful controls. To test if blushing-fearfuls overestimate and/or low-fearful individuals underestimate the cost of displaying a blush, a second experiment examined the effects of blushing in these situations on observers' judgments. Experiment 1 showed that blushing-fearfuls indeed have judgmental biases for the probability and costs of blushing. Experiment 2 showed that the observers' judgments were very similar to the judgments anticipated by the low-fear group in Experiment 1. Thus the judgmental biases that were evident in the high-fearfuls can be best interpreted as an overestimation of the social costs of displaying a blush. These findings help improving our understanding of the mechanisms that may drive blushing phobia and also point to the clinical implication that it might be worthwhile to challenge blushing-fearfuls' judgmental biases. PMID- 22206721 TI - Geochemical behavior of 210Pb and 210Po in the nearshore waters off western Taiwan. AB - Dissolved and particulate (210)Pb and (210)Po were determined at 15 stations along the coastline off western Taiwan in April 2007. The (210)Pb activities in dissolved and particulate phases fell within a relatively small range of 2.4-5.2 dpm 100 L(-1) and 1.0-3.2 dpm 100 L(-1), respectively. The dissolved and particulate (210)Po activities also fell within a small range of 0.8-3.4 dpm 100 L(-1) and 1.1-2.9 dpm 100 L(-1), respectively. The correlation of the distribution coefficients (K(d)) of (210)Pb and (210)Po with particle concentration in turbid waters are not as evident as in the open ocean. The mass balance calculation shows that the residence times of (210)Pb and (210)Po with respect to particle removal from the nearshore waters ranges from 3 to 15 days and from 14 to 125 days, respectively. The flux of particulate organic carbon was estimated by (210)Po proxy and ranged from 4.8 to 33.7 mmol-C m(-2) d(-1). PMID- 22206722 TI - Oxidative stress, genotoxicity and histopathology biomarker responses in mullet (Mugil cephalus) and sea bass (Dicentrarchus labrax) liver from Bizerte Lagoon (Tunisia). AB - The aim of the study was to evaluate the impact of environmental contaminants on oxidative stress, genotoxic and histopathologic biomarkers in liver of mullet (Mugil cephalus) and sea bass (Dicentrarchus labrax) collected from a polluted coastal lagoon (Bizerte Lagoon) in comparison to a reference site (the Mediterranean Sea). Antioxidant enzyme activities were lower in fish from the polluted site compared with fish from the reference site, suggesting deficiency of the antioxidant system to compensate for oxidative stress. DNA damage was higher in both fish species from the contaminated site indicating genotoxic effects. The liver histopathological analysis revealed alterations in fish from Bizerte Lagoon. Hepatocytes from both fish species featured extensive lipid-type vacuolation and membrane disruption. Results suggest that the selected biomarkers in both fish species are useful for the assessment of pollution impacts in coastal environments influenced by multiple pollution sources. PMID- 22206724 TI - Quantifying potential propagule pressure of aquatic invasive species from the commercial shipping industry in Canada. AB - We quantify and compare different measures of potential propagule pressure (PPP) of aquatic invasive species (AIS) from commercial vessels in Canada. We used ship arrivals and ballast water discharge volumes as proxies for PPP from ballast water organisms, and wetted surface area (WSA) as a proxy for hull fouling PPP, to determine their relative contributions to total PPP. For three regions studied, PPP proxies correlated significantly across ports and some vessel categories. Relative contributions of ship arrivals, ballast discharge, and WSAs to PPP, evidenced by non-significant correlations across these measures, varied across regions, ports, vessel types, and seasons. Flow-through (dominant on east and west coasts) and empty-refill (in Great Lakes-St. Lawrence region) were the major ballast water exchange methods employed by the vessels surveyed. These methods have different biological efficacy for AIS removal, influencing PPP. Our study illustrates benefits and limitations of using different PPP proxies to estimate invasion risk. PMID- 22206725 TI - Modelling the environmental behaviour of pollutants in Algeciras Bay (south Spain). AB - An environmental study of Algeciras Bay is carried out through numerical modelling. First, a 2D barotropic model is applied to calculate tides and mean circulation. Results of this model are used by a sediment transport model which provides suspended matter concentrations and sedimentation rates in the Bay. It includes three particle classes. An effective diffusion coefficient has been calibrated simulating temperature distribution inside the Bay. An additional validation is obtained from an independent nitrate dispersion simulation. Then heavy metal dispersion patterns are investigated using a model which includes water-sediment metal interactions and uses the outputs of the hydrodynamic and sediment transport models. The metal transport model has been applied to simulate the dispersion of Zn, Cu and Ni. Results from the hydrodynamic, sediment and metal transport models have been compared with measurements. Model results also indicate that transport inside the Bay is relatively weak. Numerical experiments have been carried out to determine flushing times for conservative and non conservative pollutants. Flushing time is about 20 days for a conservative tracer, and this value is mainly due to the M(2) residual current. Tides are not effective in removing pollutants. PMID- 22206726 TI - Fabrication of conductive electrospun silk fibroin scaffolds by coating with polypyrrole for biomedical applications. AB - Scaffolds constituted by micro and nanofibers of silk fibroin were obtained by electrospinning. Fibers of fibroin meshes were coated with polypyrrole (pPy) by chemical polymerization; chemical linkages between polymers were observed by SEM and IR spectroscopy. Mechanical resistance of the meshes was improved by polypyrrole coating. Furthermore, coated meshes present a high electroactivity allowing anion storage and delivery during oxidation/reduction reactions in aqueous solutions. Uncoated and pPy coated materials support the adherence and proliferation of adult human mesenchymal stem cells (ahMSCs) or human fibroblasts (hFb). The bioactivity of fibroin mesh overcomes that of the polypyrrole coated meshes. PMID- 22206727 TI - Biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and noninflamed patients. AB - INTRODUCTION: Delirium occurs frequently in critically ill patients and is associated with disease severity and infection. Although several pathways for delirium have been described, biomarkers associated with delirium in intensive care unit (ICU) patients is not well studied. We examined plasma biomarkers in delirious and nondelirious patients and the role of these biomarkers on long-term cognitive function. METHODS: In an exploratory observational study, we included 100 ICU patients with or without delirium and with ("inflamed") and without ("noninflamed") infection/systemic inflammatory response syndrome (SIRS). Delirium was diagnosed by using the confusion-assessment method-ICU (CAM-ICU). Within 24 hours after the onset of delirium, blood was obtained for biomarker analysis. No differences in patient characteristics were found between delirious and nondelirious patients. To determine associations between biomarkers and delirium, univariate and multivariate logistic regression analyses were performed. Eighteen months after ICU discharge, a cognitive-failure questionnaire was distributed to the ICU survivors. RESULTS: In total, 50 delirious and 50 nondelirious patients were included. We found that IL-8, MCP-1, procalcitonin (PCT), cortisol, and S100-beta were significantly associated with delirium in inflamed patients (n = 46). In the noninflamed group of patients (n = 54), IL-8, IL-1ra, IL-10 ratio Abeta1-42/40, and ratio AbetaN-42/40 were significantly associated with delirium. In multivariate regression analysis, IL-8 was independently associated (odds ratio, 9.0; 95% confidence interval (CI), 1.8 to 44.0) with delirium in inflamed patients and IL-10 (OR 2.6; 95% CI 1.1 to 5.9), and Abeta1-42/40 (OR, 0.03; 95% CI, 0.002 to 0.50) with delirium in noninflamed patients. Furthermore, levels of several amyloid-beta forms, but not human Tau or S100-beta, were significantly correlated with self-reported cognitive impairment 18 months after ICU discharge, whereas inflammatory markers were not correlated to impaired long-term cognitive function. CONCLUSIONS: In inflamed patients, the proinflammatory cytokine IL-8 was associated with delirium, whereas in noninflamed patients, antiinflammatory cytokine IL-10 and Abeta1-42/40 were associated with delirium. This suggests that the underlying mechanism governing the development of delirium in inflamed patients differs from that in noninflamed patients. Finally, elevated levels of amyloid-beta correlated with long-term subjective cognitive-impairment delirium may represent the first sign of a (subclinical) dementia process. Future studies must confirm these results.The study was registered in the Clinical Trial Register (NCT00604773). PMID- 22206728 TI - Differences in dietary pattern between obese and eutrophic children. AB - BACKGROUND: Excessive consumption of energy is a decisive factor of obesity, but a simple quantitative assessment of consumption between obese and eutrophic individuals not always explains the problem, raising questions about the importance of the qualitative aspects of food. Therefore, the purpose of this study was to evaluate the differences in nutrient composition and meal patterns between eutrophic and obese schoolchildren. METHODS: The diet of 83 children (42 obese and 41 eutrophic), aged between 7 and 11 years of age, was assessed by two non-consecutive dietary recalls. After the software analysis of macro and micronutrients composition, the different types and amount of legumes, fruits and vegetables were analyzed to verify the dietary patterns. RESULTS: No differences were verified in energy consumption between the groups (eutrophic = 1934.2 +/- 672.7 kcal, obese = 1835.8 +/- 621.2 kcal). In general, children showed consumption within the recommended ranges of carbohydrates, lipids and proteins. The average consumption of fiber was higher in the eutrophic group (20.7 g) when compared to the obese group (14.8 g). The dietary fiber was strongly correlated with the number of servings of beans (r = 0.77), when compared to fruits (r = 0.44) and leafy vegetables (r = 0.13). It was also observed that the higher the consumption of fiber and beans, the lower the proportion of dietary fat (r = 0.22) in the diet. Generally, there was a low consumption of fiber (20.7 g = eutrophic group/14.8 g = obese group), beans (1.1 portions in the eutrophic and obese groups), fruits (0.7 portions eutrophic group and 0.6 obese group) and vegetables (1.3 eutrophic group and 1.1 obese group). CONCLUSIONS: It is concluded that the obesity was more related to a dietary pattern of low intake of dietary fiber than excessive energy consumption and macronutrients imbalance. PMID- 22206729 TI - Inversin, Wnt signaling and primary cilia. AB - Mutations of the ankyrin-repeat protein Inversin, a member of a diverse family of more than 12 proteins, cause nephronophthisis (NPH), an autosomal recessive cystic kidney disease associated with extra-renal manifestations such as retinitis pigmentosa, cerebellar aplasia and situs inversus. Most NPH gene products (NPHPs) localize to the cilium, and appear to control the transport of cargo protein to the cilium by forming functional networks. Inversin interacts with NPHP1 and NPHP3, and shares with NPHP4 the ability to antagonize Dishevelled stimulated canonical Wnt signaling, potentially through recruitment of the Anaphase Promoting Complex (APC/C). However, Dishevelled antagonism may be confined towards the basal body, thereby polarizing motile cilia on the cells of the ventral node and respiratory tract. Inversin is essential for recruiting Dishevelled to the plasma membrane in response to activated Frizzled, a crucial step in planar cell polarity signaling. During vertebrate pronephros development, the Inversin-mediated translocation of Dishevelled appears to orchestrate the migration of cells and differentiation of segments that correspond to the mammalian loop of Henle. Thus, defective tubule migration and elongation may contribute to concentration defects and cause cyst formation in patients with NPH. PMID- 22206730 TI - Increased adenosine concentration in bronchoalveolar lavage fluid of horses with lower airway inflammation. AB - Several reports have suggested a role for adenosine in the pathogenesis of chronic airway conditions and this has led to new therapeutic strategies to limit airway inflammation. In this study, detectable levels of adenosine in bronchoalveolar lavage (BAL) samples from 11 horses with non-infectious lower airway inflammation and 14 healthy controls are reported, with significantly higher values in horses with airway inflammation. Although these increased levels did not correlate with changes in neutrophil percentage in BAL, a positive association between adenosine levels and signs of lower airway inflammation (clinical score) was observed. These novel findings support the hypothesis that adenosine may contribute to bronchoconstriction and also act as a pro inflammatory mediator in the bronchoalveolar milieu of horses with airway inflammation. Further investigation of this axis could lead to new approaches for the treatment of highly prevalent lower airway inflammatory conditions in the horse. PMID- 22206731 TI - [Out-of-hospital management of elderly patients for trauma injury]. AB - Elderly patients should benefit from maximum care in cases of serious trauma, starting with pre-hospital care. A proper evaluation of the gravity of the trauma is an essential element in the management. The elderly are at risk of "under triage", which can result in inappropriate hospital admission and delayed trauma care. Particular attention must be paid to "common" trauma, because such trauma is often associated with a potentially serious outcome in elderly patients. The Vittel criteria offer an important tool to estimate the level of gravity and to help in patient triage. The kinetic of the accident is important in identifying serious trauma. Emergency medical services with physicians on board must be the norm in cases of severe trauma, irrespective of the age of the patient. The literature clearly indicates the benefit of an aggressive strategy in elderly trauma patients, thus justifying direct admission in a trauma center in cases of real or potentially serious trauma. There is no difference in pre-hospital care management between elderly and younger trauma patients. Analgesia must be a priority. When a self-assessment of pain intensity is impossible, specific scales for pain can be used, such as Algoplus((r)). Morphine titration is the recommended strategy for analgesia in the pre-hospital setting and the same protocol must be used for both the elderly and younger patients. Locoregional anaesthesia should be used when possible in this setting, in particular the ilio facial block. Age is not a criterion for a non-resuscitation order in trauma patients. The decisions of limitation of therapeutic, if they were not anticipated, will be discussed after admission, according to the principles of the current legislation. PMID- 22206732 TI - Preparation and characterization of succinic acid deamidated wheat gluten microspheres for encapsulation of fish oil. AB - Succinic acid deamidated wheat gluten (SDWG) microspheres for encapsulation of fish oil (FO) via O/W/O double-emulsion followed by heat-polymerization of emulsified SDWG was reported. Different SWDG concentrations (16.8-67.2 mg/ml) and FO/SDWG ratios (1:3-4:3, w/w) were studied. To optimize the process, particle size and Zeta potential of SDWG-FO emulsion and encapsulation efficiency (EE) of FO were analyzed. The most efficient condition was obtained at 50.4 mg/ml for SDWG and 3:3 (w/w) for FO/SDWG ratio, with an EE of 81.8%. In this condition, confocal microscopy showed FO well encapsulated in SDWG microspheres. Scanning electron microscope (SEM) showed sunken pores and fractures inside microspheres after FO was extracted, confirming the presence of FO in microspheres. FTIR and electrophoresis showed during microspheres formation dramatically elevated SWDG aggregation resulted in intermolecular-crosslinking and enhanced interactions (hydrogen bonds and hydrophobic interactions) between SDWG and FO. In the evaluations of in vitro experiments in simulated gastric fluid and oxidation stability during storage, results indicated that SDWG matrix protected it from both oxygen and gastric fluid, resulting in improved storage stability and release property. Therefore, it is foreseen that SDWG can be used to encapsulate FO or other sensitive nutraceuticals in the applications of supplementation and functional foods. PMID- 22206733 TI - On the likelihood of SCN1A microdeletions or duplications in Dravet syndrome with missense mutation. AB - This study examines whether microdeletions and duplications of the gene encoding alpha1 subunit of the sodium channel (SCN1A) are underlying causes in Dravet syndrome (DS) with SCN1A missense mutation. Multiple exonic deletions were identified in 8/84 patients without mutation and 0/41 patients with missense mutations. Our findings indicate that while microdeletions are not rare in SCN1A negative patients, they are not likely to be present simultaneously with other SCN1A mutations. PMID- 22206734 TI - Unicommissural aortic valves: gross, histological, and immunohistochemical analysis of 52 cases (1978-2008). AB - BACKGROUND: Unicommissural aortic valves (UAVs) are rare anomalies in which adjacent cusps of two commissures are congenitally fused. Currently, features of UAVs are poorly characterized. METHODS: Fifty-two surgical and autopsy cases of UAV at Mayo Clinic were evaluated for various clinicopathologic features. Histology and immunohistochemistry (IHC) were used in 30 UAVs to identify biomarkers important to developing aortic stenosis. RESULTS: In 52 UAV patients (58% were male, 42% were female), their ages ranged from 18 weeks' gestation to 80 years (mean, 28 years). Functional status was pure stenosis in 20, pure regurgitation in 9, combined in 22, and normal in 1. Common additional cardiovascular disorders included left ventricular hypertrophy (56%) and ascending aortopathies (42%). The position of the true commissure was determined in 30 UAVs and was left posterior in 73%. Gross calcification increased exponentially with age, starting as early as 16 years. Microscopically, the values of the 3 youngest patients showed dysplasia. Other UAVs exhibited fibrous thickening (93%), ventricular pads (89%), aortic pads (81%), and thickened spongy layer (74%). Macrophages were the most common leukocyte by IHC. Bone morphogenetic protein-2 was positive in 27 IHC cases; osteopontin was positive in 15, and matrix metalloproteinase (MMP) 2, MMP-9, and MMP-14 were positive in 1, 6, and 4 cases, respectively. CONCLUSION: The functional status of UAVs typically involves stenosis but can vary in type and degree or rarely be normal. In early stenosis (<16 years), the pathology is primarily fibrosis with minimal calcification. UAVs show more calcification compared with age-matched bicuspid or tricuspid aortic valves. The molecular mechanisms of calcification and fibrosis in UAVs remain incompletely understood. PMID- 22206735 TI - The association between urinary cadmium and frontal T wave axis deviation in the US adults. AB - The association between environmental cadmium exposure and frontal T wave axis deviation, a valuable and easily detected subclinical marker of ventricular arrhythmias in individuals without heart disease is unexplored and unknown. The objective of the study was to test the hypothesis that cadmium exposure predicts frontal T-wave axis deviation. US adults 40 years of age or older from NHANES III were included in the analysis. The participants' creatinine-corrected urinary cadmium concentrations expressed as micrograms per gram were determined. Frontal T-wave axis deviations were measured from the standard 12-lead electrocardiogram. Multivariable regression analyses adjusting for age, race, smoking, metabolic syndrome, left ventricular mass, QRS duration and heart rate were performed. The odds ratio of borderline and abnormal frontal T wave axis deviations due to cadmium exposure and their corresponding 95% confidence intervals (CIs) were 1.25 (1.10-1.54) and 1.64 (1.27-2.12), respectively. This study documents a positive graded relationship between environmental cadmium exposure and the risk for frontal T-wave axis deviation. Screening individuals with large body burden of cadmium to identify frontal T-wave axis deviation is warranted. PMID- 22206736 TI - Differential proteomic analysis of bronchoalveolar lavage fluid from lung transplant patients with and without chronic graft dysfunction. AB - BACKGROUND: Biomarkers are urgently needed for diagnosis, prognosis and monitoring of lung transplant chronic graft dysfunction. Bronchoalveolar lavage fluid (BAL) has been used in the past as proximal fluid for biomarker discovery in various lung diseases including chronic graft dysfunction (CGD). The current study describes the proteomic analysis of BAL fluids collected from 4 asymptomatic post-transplant patients and 3 patients with symptoms of CGD. METHODS: BAL proteome was fractionated by size-exclusion chromatography at protein level and reverse-phase-chromatography at peptide level followed by Orbitrap mass spectrometry detection. RESULTS: Our in-depth proteomic analysis identified 531 proteins, the largest catalog of BAL proteins reported to date in the context of CGD. A total of 30 and 39 proteins detected exclusively in CGD and non-CGD samples, respectively, are potential candidates for verification phase. CONCLUSIONS: A new protocol was developed to enhance the sensitivity of detecting less abundant proteins in BAL. PMID- 22206737 TI - Immobilization of barley oxalate oxidase onto gold-nanoparticle-porous CaCO3 microsphere hybrid for amperometric determination of oxalate in biological materials. AB - OBJECTIVES: The use of Au nanoparticles (AuNPs)-CaCO(3) porous microsphere hybrid as a matrix for enzyme immobilization to increase the performance of an amperometric biosensor. DESIGN AND METHODS: A method is described for construction of an amperometric oxalate biosensor by immobilizing a barley root oxalate oxidase (OxOx) onto AuNPs-CaCO(3) porous microsphere hybrid encapsulated in silica sol and deposited on Au electrode. RESULTS: The biosensor showed optimum response within 4s at pH 5.0 and 30 degrees C, when polarized at +0.4V vs. Ag/agCl. The biosensor possesses high sensitivity and measures oxalate concentrations as low as 1.0 MUmol/L. The working linear range was from 1.0 to 1000 MUmol/L of oxalate. The biosensor measured urinary and plasma oxalate of normal persons and stone formers. CONCLUSION: The use of AuNPs-CaCO(3) porous microsphere hybrid as a support for immobilization of OxOx has resulted into an improved amperometric oxalate biosensor. PMID- 22206738 TI - Inflammatory marker levels in obese adolescents with glucose intolerance: increased chitotriosidase activity. AB - OBJECTIVES: Existence of low grade persistent inflammation in obese children may increase the risk of metabolic and cardiovascular events. The aim was to determine whether glucose intolerance has an influence on inflammatory markers in obese adolescents. DESIGNS AND METHODS: 45 obese adolescents (mean BMI: 30.34+/ 5.42 kg/m2) were grouped as normal or impaired glucose tolerance. IL-6 and CRP levels were analyzed by commercially available kits. Chitotriosidase activity was measured by a fluorescence method and neopterin levels were determined by ELISA. Data were expressed as mean+/-SD. RESULTS: IL-6 and CRP levels were similar in the two groups. Serum neopterin levels were not different between the groups. The chitotriosidase activity was significantly higher in the IGT group than NGT (124.33+/-51.97 MUmol/L/h vs 84.50+/-53.99 MUmol/L/h, p=0.04). CONCLUSION: Serum chitotriosidase activity is increased in obese adolescents with impaired glucose tolerance. PMID- 22206739 TI - HDL-associated enzymes and proteins in hemodialysis patients. AB - OBJECTIVES: To evaluate HDL-associated proteins and enzymes and their relation with lipoprotein profile and inflammatory markers in chronic renal patients on hemodialysis. DESIGN AND METHODS: We studied 53 patients under hemodialysis and 32 healthy subjects as controls. We compared plasma lipids, Apoprotein-AI and hs CRP, as a marker of chronic inflammation. We evaluated proteins and enzymes associated to HDL, involved in several points of lipoprotein metabolism: CETP, paraoxonase and LpPLA2 activities. Hepatic lipase was measured in postheparin plasma. RESULTS: Patients showed higher triglycerides and lower LDL-, HDL- and total-cholesterol than controls (p<0.05). Also, in comparison with controls, Apoprotein-AI, paraoxonase and hepatic lipase were lower, while CETP was higher (p<0.03). LpPLA2 did not show changes between groups. CONCLUSION: Beyond plasma lipid-lipoprotein profile, other factors could contribute to induce a pro oxidative and pro-inflammatory status. The protective role of HDL does not only depend on its concentration, but also on its functionality. PMID- 22206740 TI - Determination of mercury distribution inside spent compact fluorescent lamps by atomic absorption spectrometry. AB - In this study, spent compact fluorescent lamps were characterized to determine the distribution of mercury. The procedure used in this research allowed mercury to be extracted in the vapor phase, from the phosphor powder, and the glass matrix. Mercury concentration in the three phases was determined by the method known as cold vapor atomic absorption spectrometry. Median values obtained in the study showed that a compact fluorescent lamp contained 24.52+/-0.4ppb of mercury in the vapor phase, 204.16+/-8.9ppb of mercury in the phosphor powder, and 18.74+/-0.5ppb of mercury in the glass matrix. There are differences in mercury concentration between the lamps since the year of manufacture or the hours of operation affect both mercury content and its distribution. The 85.76% of the mercury introduced into a compact fluorescent lamp becomes a component of the phosphor powder, while more than 13.66% is diffused through the glass matrix. By washing and eliminating all phosphor powder attached to the glass surface it is possible to classified the glass as a non-hazardous waste. PMID- 22206741 TI - Effect of frozen storage on urinary concentration of kidney damage markers. PMID- 22206742 TI - Risk factors for ESRD in HIV-infected individuals: traditional and HIV-related factors. AB - BACKGROUND: Despite improvements in survival with human immunodeficiency virus (HIV) infection, kidney disease remains an important complication. Few studies have evaluated risk factors associated with the development of end-stage renal disease (ESRD) in HIV-infected individuals. We sought to identify traditional and HIV-related risk factors for ESRD in HIV-infected individuals and compare ESRD risk by estimated glomerular filtration rate (eGFR) and proteinuria levels. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 22,156 HIV-infected veterans without pre-existing ESRD receiving health care in the Veterans' Affairs medical system between 1996 and 2004. PREDICTORS: Hypertension, diabetes, cardiovascular disease, hypoalbuminemia (serum albumin <3.5 mg/dL), CD4 lymphocyte count, HIV viral load, hepatitis C virus coinfection, proteinuria, and eGFR were identified using the Veterans' Affairs electronic record system. OUTCOMES: ESRD was ascertained by the US Renal Data System. RESULTS: 366 cases of ESRD occurred, corresponding to 3 cases/1,000 person-years. Hypertension (HR, 1.9; 95% CI, 1.5-2.4), diabetes (HR, 1.7; 95% CI, 1.3-2.2), and cardiovascular disease (HR, 2.2; 95% CI, 1.7-2.7) were associated independently with ESRD risk in multivariate-adjusted models, as were CD4 lymphocyte count <200 cells/MUL (HR, 1.5; 95% CI, 1.2-2.0), HIV viral load >=30,000 copies/mL (HR, 2.0; 95% CI, 1.5 2.8), hepatitis C virus coinfection (HR, 1.9; 95% CI, 1.5-2.4), and hypoalbuminemia (HR, 2.1; 95% CI, 1.8-2.5). Compared with persons without chronic kidney disease, defined as eGFR >60 mL/min/1.73 m(2) and no proteinuria, lower eGFR and higher proteinuria categories were associated jointly with exponentially higher ESRD rates, ranging from 6.6 events/1,000 person-years for persons with urine protein excretion of 30-100 mg/dL and eGFR >60 mL/min/1.73 m(2) to 193 events/1,000 person-years for persons with urine protein excretion >=300 mg/dL and eGFR <30 mL/min/1.73 m(2). LIMITATIONS: Results may not be generalizable to female and nonveteran populations. CONCLUSIONS: In HIV-infected persons, ESRD risk appears attributable to a combination of traditional and HIV-related risk factors for kidney disease. Combining eGFR and proteinuria for chronic kidney disease staging is most effective for stratifying the risk of ESRD. PMID- 22206743 TI - Utilization and costs of cardiovascular disease medications in dialysis patients in Medicare Part D. AB - BACKGROUND: Cardiovascular disease (CVD) is a major source of mortality and morbidity in dialysis patients. Population-level descriptions of CVD medication use are lacking in this population. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adult dialysis patients in the United States, alive on December 31, 2006, with Medicare Parts A and B and enrollment in Medicare Part D continuously in 2007. PREDICTOR: CVDs and demographic characteristics. OUTCOME: >=1 prescription fill during follow-up (2007). MEASUREMENTS: Average out-of pocket costs per user per month and average total drug costs per member per month were calculated. RESULTS: Of 225,635 dialysis patients who met inclusion criteria during the entry period, 70% (n = 158,702) had continuous Part D coverage during follow-up. Of these, 76% received the low-income subsidy. beta-Blockers were the most commonly used CVD medication (64%), followed by renin-angiotensin system inhibitors (52%), calcium channel blockers (51%), lipid-lowering agents (44%), and alpha-agonists (23%). Use varied by demographics, geographic region, and low income subsidy status. For CVD medications, mean out-of-pocket costs per user per month were $3.44 and $49.59 and mean total costs per member per month were $124.02 and $110.32 for patients with and without the low-income subsidy, respectively. LIMITATIONS: Information was available for only filled prescriptions under the Part D benefit; information for clinical contraindications was lacking, information for over-the-counter medications was unavailable, and medication adherence and persistence were not examined. CONCLUSIONS: Most Medicare dialysis patients in 2007 were enrolled in Part D, and most enrollees received the low-income subsidy. beta-Blockers were the most used CVD medication. Total costs of CVD medications were modestly higher for low income subsidy patients, but out-of-pocket costs were much higher for patients not receiving the subsidy. Further study is warranted to delineate sources of variation in the use and costs of CVD medications across subgroups. PMID- 22206744 TI - Long-term risk of CKD in children surviving episodes of acute kidney injury in the intensive care unit: a prospective cohort study. AB - BACKGROUND: The development of standardized acute kidney injury (AKI) definitions has allowed for a better understanding of AKI epidemiology, but the long-term renal outcomes of AKI in the pediatric critical care setting have not been well established. This study was designed to: (1) determine the incidence of chronic kidney disease (CKD) in children 1-3 years after an episode of AKI at a tertiary care pediatric intensive care unit (ICU), (2) identify the proportion of patients at risk of CKD, and (3) compare ICU admission characteristics in those with and without CKD. DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Patients admitted to the British Columbia Children's Hospital pediatric ICU from 2006-2008 with AKI, as defined by AKI Network (AKIN) criteria. Surviving patients, most with short-term recovery from their AKI, were assessed at 1, 2, or 3 years after AKI. PREDICTORS: Severity of AKI as defined by AKIN and several ICU admission characteristics, including demographics, diagnosis, severity of illness, and ventilation data. OUTCOMES & MEASUREMENTS: CKD was defined as the presence of albuminuria and/or glomerular filtration rate (GFR) < 60 mL/min/1.73 m2. Being at risk of CKD was defined as having a mildly decreased GFR (60-90 mL/min/1.73 m2), hypertension, and/or hyperfiltration (GFR >= 150 mL/min/1.73 m2). RESULTS: The proportion of patients with AKI stages 1, 2, and 3 were 44 of 126 (35%), 47 of 126 (37%), and 35 of 126 (28%), respectively. The number of patients with CKD 1-3 years after AKI was 13 of 126 (10.3% overall; 2 of 44 [4.5%] with stage 1, 5 of 47 [10.6%] with stage 2, and 6 of 35 [17.1%] with stage 3; P = 0.2). In addition, 59 of 126 (46.8%) patients were identified as being at risk of CKD. LIMITATIONS: Several patients identified with AKI were lost to follow-up, with the potential of underestimating the incidence of CKD. CONCLUSIONS: In tertiary-care pediatric ICU patients, ~10% develop CKD 1-3 years after AKI. The burden of CKD in this population may be higher with further follow-up because several patients were identified as being at risk of CKD. Regardless of the severity of AKI, all pediatric ICU patients should be monitored regularly for long-term kidney damage. PMID- 22206745 TI - Predictive models for acute kidney injury following cardiac surgery. AB - BACKGROUND: Accurate prediction of cardiac surgery-associated acute kidney injury (AKI) would improve clinical decision making and facilitate timely diagnosis and treatment. The aim of the study was to develop predictive models for cardiac surgery-associated AKI using presurgical and combined pre- and intrasurgical variables. STUDY DESIGN: Prospective observational cohort. SETTINGS & PARTICIPANTS: 25,898 patients who underwent cardiac surgery at Cleveland Clinic in 2000-2008. PREDICTOR: Presurgical and combined pre- and intrasurgical variables were used to develop predictive models. OUTCOMES: Dialysis therapy and a composite of doubling of serum creatinine level or dialysis therapy within 2 weeks (or discharge if sooner) after cardiac surgery. RESULTS: Incidences of dialysis therapy and the composite of doubling of serum creatinine level or dialysis therapy were 1.7% and 4.3%, respectively. Kidney function parameters were strong independent predictors in all 4 models. Surgical complexity reflected by type and history of previous cardiac surgery were robust predictors in models based on presurgical variables. However, the inclusion of intrasurgical variables accounted for all explained variance by procedure-related information. Models predictive of dialysis therapy showed good calibration and superb discrimination; a combined (pre- and intrasurgical) model performed better than the presurgical model alone (C statistics, 0.910 and 0.875, respectively). Models predictive of the composite end point also had excellent discrimination with both presurgical and combined (pre- and intrasurgical) variables (C statistics, 0.797 and 0.825, respectively). However, the presurgical model predictive of the composite end point showed suboptimal calibration (P < 0.001). LIMITATIONS: External validation of these predictive models in other cohorts is required before wide-scale application. CONCLUSIONS: We developed and internally validated 4 new models that accurately predict cardiac surgery-associated AKI. These models are based on readily available clinical information and can be used for patient counseling, clinical management, risk adjustment, and enrichment of clinical trials with high risk participants. PMID- 22206746 TI - Emergency gastroduodenal artery embolization by sandwich technique for angiographically obvious and oblivious, endotherapy failed bleeding duodenal ulcers. AB - AIM: To determine the feasibility, safety, and efficacy of adopting a standardized protocol for emergency transarterial embolization (TAE) of the gastroduodenal artery (GDA) with a uniform sandwich technique in endotherapy failed bleeding duodenal ulcers (DU). MATERIALS AND METHODS: Between December 2009 and December 2010, 15 patients with endotherapy-failed bleeding DU were underwent embolization. Irrespective of active extravasation, the segment of the GDA supplying the bleeding DU as indicated by endoscopically placed clips was embolized by a uniform sandwich technique with gelfoam between metallic coils. The clinical profile of the patients, re-bleeding, mortality rates, and response time of the intervention radiology team were recorded. The angioembolizations were reviewed for their technical success, clinical success, and complications. Mean duration of follow-up was 266.5 days. RESULTS: Active contrast-medium extravasation was seen in three patients (20%). Early re-bleeding was noted in two patients (13.33%). No patient required surgery. There was 100% technical success, while primary and secondary clinical success rates for TAE were 86.6 and 93.3%, respectively. Focal pancreatitis was the single major procedure-related complication. There was no direct bleeding-DU-related death. The response time of the IR service averaged 150 min (range 60-360 min) with mean value of 170 min. CONCLUSION: Emergency embolization of the GDA using the sandwich technique is a safe and highly effective therapeutic option for bleeding DUs refractory to endotherapy. A prompt response from the IR service can be ensured with an institutional protocol in place for such common medical emergencies. PMID- 22206747 TI - Nonsteroidal antiinflammatory drugs and progestins synergistically enhance cell death in ovarian epithelial cells. AB - OBJECTIVE: There is growing evidence that progestins and nonsteroidal antiinflammatory drugs (NSAIDs) may prevent ovarian cancer. Because both induce apoptosis, we investigated the potential for synergistic impact of combined drug treatment on cell death. STUDY DESIGN: Using normal and malignant human ovarian epithelial cells and an NSAID-sensitive human colon cancer cell line, we evaluated the effects of progestins and NSAIDs alone and in combination on apoptosis. RESULTS: Both progestins and NSAIDs dose dependently inhibited cell growth (P < .0001). Doses of NSAIDs or progestins that independently reduced cell viability by less than 30% synergistically reduced cell viability by 70-95% when combined. Similarly, the NSAID/progestin combination conferred 4- to 18-fold (P < .05) increased apoptosis over either treatment alone. CONCLUSION: Our results suggest it may be possible to combine progestins and NSAIDs to achieve ovarian cancer prevention at lower doses of each than are required for single administration, thereby lessening the risk of side effects posed by these agents. PMID- 22206748 TI - Pulsatile versus continuous administration of oxytocin for induction and augmentation of labor: two randomized controlled trials. AB - OBJECTIVE: To determine whether pulsatile oxytocin infusion improves delivery outcome in women requiring induction or augmentation of labor. STUDY DESIGN: Two related randomized controlled trials undertaken in 2 inner-city United Kingdom university hospitals (ISRCTN72773405; http://www.isrctn.org/). Women were randomly assigned to a pulsatile or continuous infusion protocol. PRIMARY OUTCOME: cesarean section rate (induction trial); operative delivery rate (augmentation trial). RESULTS: For induction, cesarean section rates were similar in women receiving pulsatile (n = 264, 38.3%) vs continuous infusion of oxytocin (n = 257; 37.7%; risk ratio, 1.01; 95% confidence interval, 0.81-1.26; P = .903), but associated with increased "infusion to time of delivery" intervals (P < .001) in the pulsatile group. For augmentation, pulsatile infusion resulted in higher operative delivery rates (70.1%, n = 251) vs continuous infusion (62.7%, n = 249; risk ratio, 1.12; 95% confidence interval, 0.99-1.27; P = .077) and increased neonatal morbidity. CONCLUSION: For induction, pulsatile infusion of oxytocin is effective, but conferred little clinical benefit. Pulsatile infusion is not recommended for augmentation. PMID- 22206749 TI - Impact of socioeconomic determinants on psychosocial factors and lifestyle--for health service: the Swedish experience. PMID- 22206750 TI - The surprising empathic abilities of rodents. AB - Many believe empathy and related pro-social behaviors to be the sole province of humans. The evolutionary antecedents of such phenomena, however, have been observed in lower mammals. By demonstrating empathy-based helping behavior in rats, a recently published study has provided clear-cut evidence that pro-social behaviors are not limited to humans. PMID- 22206752 TI - Culture and education: new frontiers in brain plasticity. AB - Cognitive neuroscience has started to probe cross-cultural differences in the neuronal mechanisms underlying cognitive, perceptual and social domains. Moreover, brain imaging has revealed how education changes the brain. Such research opens up a new frontier in brain plasticity research, breaking down the boundaries between neuroscience and other traditionally non-biological disciplines, resulting in many conceptual and practical implications. PMID- 22206753 TI - Embodied simulation, an unproductive explanation: comment on Gallese and Sinigaglia. PMID- 22206754 TI - Social impressions while drinking account for the relationship between alcohol related problems and social anxiety. AB - Individuals with elevated social anxiety appear particularly vulnerable to experiencing alcohol-related problems; yet we know little about factors that may account for this relationship. One possibility is that socially anxious individuals hold beliefs about the impressions they make on others while drinking and these beliefs play an important role in their drinking behaviors. The present study used exploratory factor analysis among participants with clinically elevated social anxiety (n=166) to develop a measure, the Social Impressions while Drinking Scale (SIDS), to assess beliefs regarding others' impressions of drinking behaviors that may be particularly relevant to socially anxious individuals. A valuations scale was also developed to assess the importance of each belief. Empirically-derived subscales were identified with adequate reliability. Among socially anxious participants, the Gregarious and Sexual Facilitation subscales were uniquely related to drinking problems and frequency respectively. Individuals with clinically meaningful social anxiety achieved higher scores on all SIDS subscales compared to those with lower social anxiety (n=166). Several SIDS scales mediated the relations between social anxiety group status and drinking problems (Interaction Fears, Observation Fears, Aggression, Gregariousness). Results highlight the importance of examining beliefs specific to high-risk populations in assessing their alcohol-related behaviors. PMID- 22206755 TI - Thromboxane A(2) receptor signaling promotes liver tissue repair after toxic injury through the enhancement of macrophage recruitment. AB - It is thought that thromboxane A(2) (TxA(2)) contributes to the progression of inflammation during acute hepatic injury; however, it is still unknown whether TxA(2) is involved in liver repair. The objective of the present study was to examine the role of TxA(2) receptor (TP) signaling in liver injury and repair in response to toxic injury. Carbon tetrachloride (CCl(4)) was used to induce liver injury in TP knockout (TP(-/-)) mice and wild-type (WT) mice. In WT mice, serum levels of alanine aminotransferase (ALT) and the size of the necrotic area peaked at 24 and 48h, respectively, and then declined. In TP(-/-) mice, the changes in ALT levels were similar to WT mice, but liver regeneration was impaired as evidenced by remained elevated levels of hepatic necrosis and by delayed hepatocyte proliferation, which was associated with the reduced expression of growth factors including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), and hepatocyte growth factor (HGF). In TP(-/-) mice, the accumulation of hepatic CD11b(+)/F4/80(+) macrophages in injured livers was attenuated, and the hepatic expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and its receptor, the C-C chemokine receptor (CCR2), was reduced compared to WT. Additionally, the application of the TP receptor agonist, U-46619, enhanced the expression of MCP-1/CCL2 and CCR2 in peritoneal macrophages, which was associated with increased levels of IL-6, TNFalpha and HGF. These results suggested that TP receptor signaling facilitates liver recovery following CCl(4)-induced hepatotoxicity by affecting the expression of hepatotrophic growth factors, and through the recruitment of macrophages mediated by MCP-1/CCL2-CCR2 expression. PMID- 22206756 TI - Elucidating the mechanisms of nickel compound uptake: a review of particulate and nano-nickel endocytosis and toxicity. AB - Nickel (Ni) is a worldwide pollutant and contaminant that humans are exposed to through various avenues resulting in multiple toxic responses - most alarming is its clear carcinogenic nature. A variety of particulate Ni compounds persist in the environment and can be distinguished by characteristics such as solubility, structure, and surface charge. These characteristics influence cellular uptake and toxicity. Some particulate forms of Ni are carcinogenic and are directly and rapidly endocytized by cells. A series of studies conducted in the 1980s observed this process, and we have reanalyzed the results of these studies to help elucidate the molecular mechanism of particulate Ni uptake. Originally the process of uptake observed was described as phagocytosis, however in the context of recent research we hypothesize that the process is macropinocytosis and/or clathrin mediated endocytosis. Primary considerations in determining the route of uptake here include calcium dependence, particle size, and inhibition through temperature and pharmacological approaches. Particle characteristics that influenced uptake include size, charge, surface characteristics, and structure. This discussion is relevant in the context of nanoparticle studies and the emerging interest in nano-nickel (nano-Ni), where toxicity assessments require a clear understanding of the parameters of particulate uptake and where establishment of such parameters is often obscured through inconsistencies across experimental systems. In this regard, this review aims to carefully document one system (particulate nickel compound uptake) and characterize its properties. PMID- 22206757 TI - betaPix plays a dual role in cerebral vascular stability and angiogenesis, and interacts with integrin alphavbeta8. AB - The growth of new blood vessels by angiogenesis and their stabilization by the recruitment of perivascular mural cells are thought to be two sequential, yet independent events. Here we identify molecular links between both processes through the betaPix and integrin alpha(v)beta(8) proteins. Bubblehead (bbh) mutants with a genetic mutation in betaPix show defective vascular stabilization. betaPix is a guanine nucleotide exchange factor and scaffold protein that binds many proteins including Git1, which bridges betaPix to integrins at focal adhesions. Here we show that the ability of betaPix to stabilize vessels requires Git1 binding residues. Knockdown of Git1 leads to a hemorrhage phenotype similar to loss of integrin alpha(v), integrin beta(8) or betaPix, suggesting that vascular stabilization through betaPix involves interactions with integrins. Furthermore, double loss of function of betaPix and integrin alpha(v) shows enhanced hemorrhage rates. Not only is vascular stability impaired in these embryos, but we also uncover a novel role of both betaPix and integrin alpha(v)beta(8) in cerebral angiogenesis. Downregulation of either betaPix or integrin alpha(v)beta(8) results in fewer and morphologically abnormal cerebral arteries penetrating the hindbrain. We show that this is coupled with a significant reduction in endothelial cell proliferation in bbh mutants or integrin alpha(v)beta(8) morphants. These data suggest that a complex involving betaPix, GIT1 and integrin alpha(v)beta(8) may regulate vascular stability, cerebral angiogenesis and endothelial cell proliferation in the developing embryo. PMID- 22206760 TI - Untapped targets in multiple sclerosis. AB - Multiple sclerosis is a chronic inflammatory disease of the white and grey matter which results in irrevocable axonal and neuronal damage. Grey matter injury is widespread and reflects disability to a greater extent than do white matter lesions. Growing understanding of the immunopathology of multiple sclerosis is leading the way to the identification and testing of untapped targets that may offer new and more specific ways to treat the disease. For example, data from animal models support a two-step pathological process in multiple sclerosis, whereby T cells initially induce inflammation and open up the blood-brain barrier, which then allows access to antibodies which aggravate tissue damage. Determination of the specificity of the invading T cells and the autoantibodies that cause disease is a major focus of current research. The discovery of anti aquaporin-4 autoantibodies in patients with neuromyelitis optica and of anti-MOG antibodies in a subset of children with paediatric autoimmune demyelinating disease are promising steps in this direction. Recently, the axoglial antigens neurofascin and contactin-2/TAG-1, which are localised around the node of Ranvier, were identified as targets of an autoimmune response in multiple sclerosis. Such an autoimmune response might induce axonal injury and direct the immunopathological response to the grey matter. It is to be hoped that the outcome of such investigations will lead to the identification of patient subgroups based on their autoreactivity and new ways to treat them safely and effectively. PMID- 22206759 TI - Oocyte specific oolemmal SAS1B involved in sperm binding through intra-acrosomal SLLP1 during fertilization. AB - Molecular mechanisms by which fertilization competent acrosome-reacted sperm bind to the oolemma remain uncharacterized. To identify oolemmal binding partner(s) for sperm acrosomal ligands, affinity panning was performed with mouse oocyte lysates using sperm acrosomal protein, SLLP1 as a target. An oocyte specific membrane metalloproteinase, SAS1B (Sperm Acrosomal SLLP1 Binding), was identified as a SLLP1 binding partner. cDNA cloning revealed six SAS1B splice variants, each containing a zinc binding active site and a putative transmembrane domain, with signal peptides in three variants. SAS1B transcripts were ovary specific. SAS1B protein was first detected in early secondary follicles in day 3 ovaries. Immunofluorescence localized SAS1B to the microvillar oolemma of M2 oocytes. After fertilization, SAS1B decreased on the oolemma and became virtually undetectable in blastocysts. In transfected CHO-K1 cells SAS1B localized to the surface of unpermeabilized cells. Recombinant and native SLLP1 co-localized with SAS1B to the microvillar domain of ovulated M2 oocytes. Molecular interactions between mouse SLLP1 and SAS1B were demonstrated by surface plasmon resonance, far western, yeast two-hybrid, recombinant- and native-co-IP analyses. SAS1B bound to SLLP1 with high affinity. SAS1B had protease activity, and SAS1B protein or antibody significantly inhibited fertilization. SAS1B knockout female mice showed a 34% reduction in fertility. The study identified SAS1B-SLLP1 as a pair of novel sperm-egg binding partners involving the oolemma and intra-acrosomal compartment during fertilization. PMID- 22206758 TI - Sin3a is essential for the genome integrity and viability of pluripotent cells. AB - The Sin3a/HDAC co-repressor complex is a critical regulator of transcription networks that govern cell cycle control and apoptosis throughout development. Previous studies have identified Sin3a as essential for embryonic development around the time of implantation, during which the epiblast cell cycle is uniquely structured to achieve very rapid divisions with little tolerance of DNA damage. This study investigates the specific requirement for Sin3a in the early mouse embryo and shows that embryos lacking Sin3a suffer unresolved DNA damage and acute p53-independent apoptosis specifically in the E3.5-4.5 epiblast. Surprisingly, Myc and E2F targets in Sin3a-null ICMs are downregulated, suggesting a central but non-canonical role for Sin3a in regulating the pluripotent embryonic cell cycle. ES cells deleted for Sin3a mount a DNA damage response indicative of unresolved double-strand breaks, profoundly arrest at G2, and undergo apoptosis. These results indicate that Sin3a protects the genomic integrity of pluripotent embryonic cells and governs their unusual cell cycle. PMID- 22206761 TI - MRI measures of neuroprotection and repair in multiple sclerosis. AB - Magnetic resonance imaging (MRI) has had an enormous impact on multiple sclerosis, enabling early diagnosis and providing surrogate markers for monitoring treatment response in clinical trials. Despite these advantages, conventional MRI is limited by lack of pathological specificity and lack of sensitivity to grey matter lesions and to microscopic damage in normal appearing tissue. Quantitative MRI techniques such as measures of parenchymal volume loss, magnetisation transfer imaging, diffusion tensor imaging, and proton magnetic resonance spectroscopy have enhanced our understanding of the nature and mechanism of tissue injury and repair in multiple sclerosis, and provided more specific correlates of neurological deficits and disability accrual. Some of these techniques may be of potential use in clinical trials as surrogate outcome measures for measuring treatment effects on neurodegenerative injury, which is currently difficult to quantify in clinical trials. In this respect, measures of brain volume, T1 hypointensity and magnetisation transfer ratio, and optical coherence tomography appear to be the most promising in the short term. The evidence for a role of neurodegeneration in the pathogenesis of multiple sclerosis, and particularly in the accumulation of irreversible disability, has become increasingly strong over recent years. This has prompted the search for new treatments that can effectively slow down, halt or even reverse such neurodegenerative processes, and in this way restore nervous system function. For this reason, there has been much interest in the development and validation of surrogate markers of neurodegeneration and neuroprotection for use in clinical trials. Advances in magnetic resonance imaging (MRI) technology have allowed the development and implementation of a number of methods that may be promising in this respect. To assess the utility of these methods and to identify needs for further research, sixty experts in neuropathology, clinical measurement, imaging and statistics participated in a meeting held in Amsterdam in 2008 under the aegis of the National Multiple Sclerosis Society. In the proceedings of the meeting, published in 2009 [1], brain volume changes, T1 hypointensity, magnetisation transfer ratio and optical coherence tomography were deemed the most promising measures for screening the neuroprotective capacity of new agents. Other MRI techniques, such as DTI, (1)H-MRS and functional MRI, although potentially useful, require more observational data to help determine the optimal trial design. This article will review some of the issues that were discussed at this meeting, and present some of the imaging techniques that were considered to be the most promising. PMID- 22206762 TI - Early treatment in multiple sclerosis. AB - There is now a consensus that early treatment of patients with relapsing remitting multiple sclerosis is desirable, mainly because early treatment may delay the accumulation of disability, but also because disease-modifying treatments seem to be more effective when started early in the course of the disease. In particular, all current first-line disease-modifying treatments have also been shown to be effective in treating clinically isolated syndrome. The evidence for this comes from extensive experience in randomised controlled Phase III clinical trials. While many patients presenting a clinically isolated syndrome are at high risk of experiencing a second attack, early treatment with all disease-modifying treatments has been shown to delay conversion to clinically definite multiple sclerosis when compared to late treatment. Some of these trials have completed five years of follow-up. While the evidence for early intervention is stronger than ever, it is worthwhile to consider its relevance to everyday clinical practice. In particular, it is important to determine which patients are the best candidates for early therapy and to evaluate the anticipated risks and benefits of choosing a given therapy for a given patient. PMID- 22206763 TI - Balancing the benefits and risks of disease-modifying therapy in patients with multiple sclerosis. AB - Balancing efficacy versus burden of therapy is essential for the choice of disease-modifying therapy in every MS patient. The first-line therapies, interferon-? and glatiramer acetate, have well-established efficacy and present no major safety concerns. Certain second-line therapies, such as natalizumab, offer potentially greater efficacy, but are associated with an increased level of risk. Over the last year, the first two oral treatments of relapsing-remitting multiple sclerosis, cladribine and fingolimod, have been marketed in certain countries, although cladribine was subsequently withdrawn. In the Phase III clinical development programme, both drugs appeared effective and reasonably safe. However, there were cases of serious adverse events (malignancies and fatal infections) whose relationship with treatment was unclear. Specific postmarketing studies will be necessary to assess the risks of these new oral therapies. Indeed, both natalizumab and mitoxantrone are known today to be associated with rare adverse drug reactions (progressive multifocal leukoencephalopathy for natalizumab and treatment-related leukaemia for mitoxantrone), which were not identified before the treatments were approved. The use of therapies carrying potential serious risks is justified in patients who cannot be treated effectively with safe first-line therapies, but probably not in the average relapsing-remitting multiple sclerosis or clinical isolated syndrome patient. Pivotal Phase III clinical trials, on which basis drug approval is generally granted, are designed to demonstrate clinical efficacy and reveal frequently occurring adverse effects of a new drug. However, post-approval trials with extensive patient exposure are needed to generate knowledge of more patient specific clinical effectiveness and long-term safety, in particular with respect to rare adverse reactions. Other post-approval measures, such as risk management programmes, pharmacovigilance studies, or phased launch of the drug, may be useful to ensure that risks associated with new treatments are identified and minimised. The final evaluation of the benefits to risks balance of a drug should be made in every patient by weighing benefits in disease activity and progression, quality of life and health economy against both commonly occurring mild side-effects and rare potentially life-threatening adverse drug effects. This decision should be shared between the physician and patient, who may not share the same perceptions of acceptable risk. PMID- 22206764 TI - Autoimmune disease in the brain--how to spot the culprits and how to keep them in check. AB - Current concepts attribute an early and central role for auto-aggressive, myelin specific T-lymphocytes in the pathogenesis of multiple sclerosis. This view emerged from immunological and pathological findings in experimental autoimmune encephalitis, an animal model characterised by pathological lesions closely resembling the ones found in multiple sclerosis. Furthermore, therapeutic strategies targeting the functions of these encephalitogenic T cells which attenuate their pathogenicity such as glatiramer acetate or anti-VLA4 antibody treatments represent proven approaches in multiple sclerosis. Nonetheless, all therapies evaluated to date either insufficiently dampen down inflammation or completely block immune processes. For this reason, there is a need to identify new therapeutic targets. We have employed live intravital two-photon microscopy to learn more about the behaviour of T cells during the preclinical phase of EAE, when T cells acquire the properties required to invade their target organ. Furthermore, we were able to identify an unexpected locomotive behaviour of T cells at the blood-brain barrier, which occurs immediately before diapedesis and the induction of paralytic disease. Such studies might open new avenues for the treatment of CNS autoimmune diseases. Multiple sclerosis is considered to be an autoimmune disease in which self-reactive T cells enter the central nervous system (CNS) and create an inflammatory milieu that destroys myelin and neurons. Immunomodulatory strategies for the treatment of multiple sclerosis target this process by attempting to inactivate these auto-aggressive T cells. However, so far, these strategies have failed to extinguish disease activity completely. For this reason, there is a need to understand in more detail the mechanisms by which T cells become encephalitogenic, how they enter the nervous system, and what the signals are that guide them along this path. If these processes could be better understood, it may be possible to design more effective and specific therapies for multiple sclerosis. This article will give a brief overview about our recent findings obtained using intravital imaging of autoaggressive effector T cells in an experimental model of multiple sclerosis. This new technological approach might help to fill some gaps in the understanding of autoimmune pathogenesis of multiple sclerosis. PMID- 22206765 TI - Review of methodological issues of clinical trials in multiple sclerosis. AB - There are currently six approved disease-modifying therapies available to the physician for the treatment of multiple sclerosis. Their efficacy on clinical and radiological parameters has been demonstrated in Phase III pivotal clinical trials over the past two decades. Perceptions of the relative potency of these treatments have been driven principally by the response measured relative to a placebo group. However, efficacy comparisons between trials is of limited value because of differences in study methodology, in characteristics of the patient populations included, in the behaviour of the placebo group during the trial and in the time at which the trial was conducted. Moreover, and most importantly, the assumption that the efficacy observed in clinical trial settings is the same as that achievable in everyday clinical practice is inevitably flawed. Impressions of the relative efficacy of two treatments may differ dramatically depending on whether absolute or relative differences with respect to placebo are compared. Randomised direct comparative trials are therefore the only objective way to evaluate the relative efficacy of two therapies. It is clear that between treatment differences are difficult to quantify in short-term studies and require large numbers of patients. Long-term outcome is increasingly important to monitor in spite of the inherent methodological limitations in order to establish the safety profile of a potentially lifelong treatment. New disease-modifying treatments for multiple sclerosis will soon be available. Although these are eagerly awaited, their risk-benefit profile, and their place in therapy, will only be adequately understood once real-life and long-term use has been documented as well as it has been for current treatments. Over the last two decades, considerable advances have been made in the methodology of clinical trials in multiple sclerosis. Consensual standardised protocols have been designed and validated for Phase II and Phase III trials, with standardised definitions for short-term clinical and radiological outcome measures. The elaboration and implementation of this methodology were possible through international collaborations, and this has enabled extensive experience to be gained throughout the world. These trials have laid the foundation for an evidence-based medicine approach to the treatment of multiple sclerosis. Clinical trials in multiple sclerosis have to some extent become a victim of their own success, with more and more trials competing for a limited pool of patients and limited resources. Modern trials require large number of patients to generate adequate statistical power and this in turn entails recruitment in many countries across different continents. This increases the complexity and cost of the study, and contract research organisations now play a dominant role in the logistics and administration of these trials. The challenge in conducting trials on a global basis involving large numbers of countries is to ensure that this heterogeneity does not impinge on the reliability of the findings. This may happen due to differences in the patient populations included in different countries, access to or experience with methods in evaluation, for example certain magnetic resonance imaging (MRI) protocols, and also due to ethical considerations. In addition, whether disease-modifying treatments are reimbursed in a given country or not will influence what sort of patients are likely to get included in clinical trial protocols. PMID- 22206766 TI - Rehabilitation and multiple sclerosis: hot topics in the preservation of physical functioning. AB - In a chronic and disabling disease like multiple sclerosis, rehabilitation becomes of major importance in the preservation of physical, psychological and social functioning. Approximately 80% of patients have multiple sclerosis for more than 35 years and most will develop disability at some point of their lives, emphasising the importance of rehabilitation in order to maintain quality of life. An important aspect of multiple sclerosis rehabilitation is the preservation of physical functioning. Hot topics in the rehabilitation of physical function include (1) exercise therapy, (2) robot-assisted training and (3) pharmacological interventions. Exercise therapy has for many years been a controversial issue in multiple sclerosis rehabilitation and the advice generally given to patients was not to participate in physical exercise, since it was thought to lead to a worsening of symptoms or fatigue. However, a paradigm shift is taking place and it is now increasingly acknowledged that exercise therapy is both safe and beneficial. Robot-assisted training is also attracting attention in multiple sclerosis rehabilitation. Several sophisticated commercial robots exist, but so far the number of scientific studies that have evaluated these is limited, although some promising results have been reported. Finally, recent studies have shown that certain pharmacological interventions have the potential to improve functional capacity substantially, with the potassium channel blocker fampridine being one of the most promising. This drug has been shown to improve walking ability in some patients with multiple sclerosis, associated with a reduction of patients' self-reported ambulatory disability. Rehabilitation strategies involving these different approaches, or combinations of them, may be of great use in improving everyday functioning and quality of life in patients with MS. PMID- 22206767 TI - Symptom management in patients with multiple sclerosis. AB - Multiple sclerosis is a complex disease associated with a wide variety of different symptoms that can affect the ability of multiple sclerosis patients to carry out normal activities of daily living. Although a myriad of symptoms can afflict these patients, the most commonly reported include fatigue, mood disorders, changes in cognitive function or memory, sensory changes (numbness, pain, vibrations), motor changes (loss of balance, poor coordination, muscle weakness or stiffness), vision changes (double vision, blurred vision, loss of vision) and bladder or bowel dysfunction. Treatments are available that can help minimise some of these symptoms and relieve patient distress. After the diagnosis has been established and a decision taken regarding initiation of immunomodulatory treatments, the majority of management decisions with which the physician will be confronted will concern symptom management. Whereas some symptoms are relatively easily treated, others are more difficult to manage. Management involves rehabilitation, pharmacological treatments and surgical procedures. Successful symptom management is a key determinant of quality of life for the patient and is the basis for improving physical and psychological function. PMID- 22206768 TI - Multiple sclerosis in childhood and adolescence. AB - Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system, typically manifesting in young adults. However, it can be identified in children in all age groups, including children and adolescents below the age of eighteen years. It has been reported that at least five percent of patients with multiple sclerosis experience the clinical onset of disease prior to the age of eighteen. The majority of children initially present with a relapsing-remitting disease course. Paediatric multiple sclerosis poses a number of challenges to the physician. In particular, the initial presenting clinical and radiological features may be difficult to distinguish from other white matter diseases with a higher prevalence in children than in adults, notably acute disseminated encephalomyelitis. This can lead to difficulties establishing an early diagnosis and considering appropriate investigations. Long-term follow-up of patients with paediatric-onset multiple sclerosis reveals transition to a secondary progressive course, as well as development of significant neurological deficits, at a much younger age compared to adult-onset patients. There is growing evidence that certain disease-modifying therapies are well tolerated and probably of benefit in paediatric multiple sclerosis. Studies with prolonged follow-up are still needed to determine the long-term tolerability and benefits of different treatment approaches in paediatric multiple sclerosis. In view of the potentially devastating long-term consequences of the disease, treatment should not be delayed. Early initiation of disease-modifying therapy, as advocated in the adult multiple sclerosis population, will, it is hoped, translate into improved long-term outcomes in children and adolescents with multiple sclerosis. PMID- 22206769 TI - High-resolution absorptive intermolecular multiple-quantum coherence NMR spectroscopy under inhomogeneous fields. AB - Intermolecular multiple-quantum coherence (iMQC) is capable of improving NMR spectral resolution using a 2D shearing manipulation method. A pulse sequence termed CT-iDH, which combines intermolecular double-quantum filter (iDQF) with a modified constant-time (CT) scheme, is designed to achieve fast acquisition of high-resolution intermolecular zero-quantum coherences (iZQCs) and intermolecular double-quantum coherences (iDQCs) spectra without strong coupling artifacts. Furthermore, double-absorption lineshapes are first realized in 2D intermolecular multi-quantum coherences (iMQCs) spectra under inhomogeneous fields through a combination of iZQC and iDQC signals to double the resolution without loss of sensitivity. Theoretically the spectral linewidth can be further reduced by half compared to original iMQC high-resolution spectra. Several experiments were performed to test the feasibility of the new method and the improvements are evaluated quantitatively. The study suggests potential applications for in vivo spectroscopy. PMID- 22206770 TI - Genetic diversity and comparative analysis of gene expression between Heterorhabditis bacteriophora Az29 and Az36 isolates: uncovering candidate genes involved in insect pathogenicity. AB - Entomopathogenic nematode Heterorhabditis bacteriophora Az29 and Az36 isolates with different virulence against Popillia unipuncta and soil survival time were isolated from the Azorean archipelago (Portugal) and used for the study. RAPD analysis revealed a very low-level of genetic diversity (GD(axenic Az36 isolate)(axenic Az29 isolate)=0.2338+/-0.0541) between axenic Az29 and Az36 isolates, and a relative low-level of diversity (GD(Az36 isolate)(Az29 isolate)=0.3366+/-0.0471) between Az29 and Az36 isolates. To unravel the molecular differences, a suppressive subtractive hybridization library was constructed from the parasitic stage. Assembling 150 high quality ESTs produced 70 singletons and 17 contigs. BLAST analysis revealed that 48 ESTs showed significant similarity to known protein and 39 ESTs had no significant hits in the database, perhaps representing novel genes. Functional annotation revealed some of these genes to be involved in metabolism, cellular process and signaling, information storage and processing, stress response and host-parasite interactions. Genes with a role in the parasitism process were identified including lectin, metalloprotease, enolase, chitinase, surface-associated antigen, and as well as genes (aquaporin, Hsp70A, Hsp10 and Hsp20) essential for stresses tolerance. The work described here provides the molecular data necessary for investigating the fundamental molecular aspects of host-parasite interactions. Future investigations should be focused on determining the molecular mechanism of those genes in entomopathogenic nematode life cycle. PMID- 22206771 TI - European Lipoprotein Club: Report of the 34th ELC annual conference, Tutzing, 5-8 September 2011. PMID- 22206772 TI - PGD2 induces eotaxin-3 via PPARgamma from sebocytes: a possible pathogenesis of eosinophilic pustular folliculitis. AB - BACKGROUND: Eosinophilic pustular folliculitis (EPF) is a chronic intractable pruritic dermatosis characterized by massive eosinophil infiltrates involving the pilosebaceous units. Recently, EPF has been regarded as an important clinical marker of HIV infection, and its prevalence is increasing in number. The precise mechanism by which eosinophils infiltrate into the pilosebaceous units remains largely unknown. Given that indomethacin, a COX inhibitor, can be successfully used to treat patients with EPF, we can assume that COX metabolites such as prostaglandins (PGs) are involved in the etiology of EPF. OBJECTIVE: To determine the involvement of PGs in the pathogenesis of EPF. METHODS: We performed immunostaining for PG synthases in EPF skin lesions. We examined the effect of PGD(2) on induction of eotaxin, a chemoattractant for eosinophils, in human keratinocytes, fibroblasts, and sebocytes and sought to identify its responsible receptor. RESULTS: Hematopoietic PGD synthase was detected mainly in infiltrating inflammatory cells in EPF lesions, implying that PGD(2) was produced in the lesions. In addition, PGD(2) and its immediate metabolite 15-deoxy-Delta 12,14 PGJ(2) (15d-PGJ(2)) induced sebocytes to produce eotaxin-3 via peroxisome proliferator-activated receptor gamma. Consistent with the above findings, eotaxin-3 expression was immunohistochemically intensified in sebaceous glands of the EPF lesions. CONCLUSION: The PGD(2)/PGJ(2)-peroxisome proliferator-activated receptor gamma pathway induces eotaxin production from sebocytes, which may explain the massive eosinophil infiltrates observed around pilosebaceous units in EPF. PMID- 22206773 TI - The mediating effect of microbial colonization on the effect of cesarean section delivery. PMID- 22206774 TI - Molecular profiles of IgE to Phleum pratense in children with grass pollen allergy: implications for specific immunotherapy. AB - BACKGROUND: The so-called component-resolved immunotherapy of allergies proposes an immunization tailored to the molecular sensitization profiles of individual patients. OBJECTIVES: We sought (1) to investigate the profiles of IgE sensitization to Phleum pratense in children with grass pollen allergy and (2) to define the compatibility of these profiles with a mixture of recombinant allergenic molecules of P pratense previously proposed for specific immunotherapy. METHODS: We examined 200 children (age, 4-18 years; 126 boys) with allergic rhinitis, asthma, or both ascertained through validated questionnaires. Each child underwent skin prick testing (ALK-Abello) and serum IgE assays (ImmunoCAP, Phadia) with 9 pollen extracts. Sera reacting against P pratense were tested for the individual molecules (rPhl p 1, rPhl p 2, rPhl p 4, nPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11, and Phl p 12). Through a combinatorial approach, the IgE individual sensitization profiles were matched against an experimental allergen-specific immunotherapy (SIT) preparation containing Phl p 1, Phl p 2, Phl p 5, and Phl p 6. RESULTS: Among the 176 of 200 children with IgE sensitization to P pratense extract, 39 profiles of sensitization to the 8 allergenic molecules tested (cutoff, 0.35 kU/L) were identified. This high heterogeneity was reduced by considering only 6 or 4 P pratense molecules but not by increasing the cutoff levels of IgE positivity. The molecular profile of the experimental SIT preparation matched that of 7 (4%) of 176 patients only; the remaining 169 patients were classified in 4 mismatch categories: underpowered (29%), overpowered (32%), underpowered/overpowered (32%), and unrelated (3%). CONCLUSIONS: IgE sensitization profiles to P pratense are highly heterogeneous. Molecularly designed SIT preparations tailored to patients' needs should consider this high heterogeneity and be driven by locally performed population studies. PMID- 22206775 TI - Airway TGF-beta1 and oxidant stress in children with severe asthma: association with airflow limitation. AB - BACKGROUND: TGF-beta1 is thought to play a role in airway remodeling in asthmatic subjects. TGF-beta1 expression might be mediated by an excessive burden of reactive oxygen species and oxidant stress. OBJECTIVE: Given the profound airway oxidant stress we have previously observed in children with severe asthma, we sought to (1) quantify TGF-beta1 protein and mRNA gene expression in the airways of children with mild-to-moderate and severe atopic asthma and (2) determine the relationship of airway TGF-beta1 concentrations to oxidant burden (ie, lipid peroxidation), T(H)2-mediated eosinophilic inflammation, and airflow limitation. METHODS: Bronchoalveolar lavage fluid was collected from 68 atopic children with asthma (severe asthma, n = 28) and 12 atopic adult control subjects. Airway TGF beta1 expression and activation were assessed in relation to airway IL-13, 8 isoprostane, and malondialdehyde concentrations. The relationship of airway TGF beta1 expression to airflow limitation in children with asthma was also assessed. RESULTS: Children with severe asthma had higher total airway concentrations of TGF-beta1 that were associated with increased protein and mRNA expression of TGF beta1 in airway macrophages and an increase in concentrations of the lipid peroxidation biomarkers 8-isoprostanes and malondialdehyde. TGF-beta1 activation was also greater in children with severe asthma and was associated with higher airway 8-isoprostane, malondialdehyde, and IL-13 concentrations. Total airway TGF beta1 concentrations were further associated with airflow limitation. CONCLUSIONS: Children with severe asthma have increased airway TGF-beta1 expression and activation associated with an increased airway oxidant burden. Oxidant stress might mediate the effects of TGF-beta1 and promote airway remodeling in children with severe asthma. PMID- 22206776 TI - Fungal disease of the nose and paranasal sinuses. AB - Fungal infections of the nose and paranasal sinuses represent a spectrum of diseases ranging from colonization to invasive rhinosinusitis. Clinical manifestations are largely dependent on the immune status of the host, and given the ubiquitous nature of these organisms, exposure is unavoidable. Noninvasive disease includes asymptomatic fungal colonization, fungus balls, and allergic fungal rhinosinusitis. Invasive disease includes indolent chronic rhinosinusitis, granulomatous fungal sinusitis, and acute fulminant fungal rhinosinusitis. A differentiation of these somewhat overlapping syndromes and the disparate treatment regimens required for effective management are the focus of this review. PMID- 22206777 TI - Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial. AB - BACKGROUND: Eosinophilic esophagitis is a chronic allergic disease with insufficient treatment options. Results from animal studies suggest that IL-5 induces eosinophil trafficking in the esophagus. OBJECTIVE: We sought to evaluate the effect of reslizumab, a neutralizing antibody against IL-5, in children and adolescents with eosinophilic esophagitis. METHODS: Patients with symptom severity scores of moderate or worse and an esophageal biopsy specimen with 24 or more intraepithelial eosinophils per high-power field were randomly assigned to receive infusions of 1, 2, or 3 mg/kg reslizumab or placebo at weeks 0, 4, 8, and 12. The coprimary efficacy measures were changes in peak esophageal eosinophil count and the physician's global assessment score at week 15 (end of therapy). RESULTS: Two-hundred twenty-six patients received study medication. Median reductions from baseline to the end of therapy in peak esophageal eosinophil counts were 59%, 67%, 64%, and 24% in the 1, 2, and 3 mg/kg reslizumab (all P < .001) and placebo groups, respectively. All treatment groups, including the placebo group, showed improvements in physician's global assessment scores; the differences between the reslizumab and placebo groups were not statistically significant. The most common adverse events in the reslizumab groups were headache, cough, nasal congestion, and upper respiratory tract infection. One patient in each reslizumab group and 2 in the placebo group had serious adverse events; none were considered related to the study medication. CONCLUSION: Reslizumab significantly reduced intraepithelial esophageal eosinophil counts in children and adolescents with eosinophilic esophagitis. However, improvements in symptoms were observed in all treatment groups and were not associated with changes in esophageal eosinophil counts. PMID- 22206778 TI - Increased risk of pertussis in patients with asthma. AB - BACKGROUND: The recent pertussis outbreak in California highlights the effect of pertussis on public health. In 2004, a pertussis outbreak occurred in Olmsted County, Minnesota, despite a high vaccine uptake. This outbreak provided a natural experiment to assess the relationship between asthma and pertussis. OBJECTIVE: We sought to determine whether asthmatic subjects have a higher risk of pertussis than nonasthmatic subjects. METHODS: We conducted a population-based case-control study. There were 223 pertussis cases identified by means of PCR in 2004 and 2005. We identified age- and sex-matched control subjects from 5537 patients with negative test results for pertussis. We conducted a comprehensive medical record review and applied predetermined criteria to ascertain asthma status. Conditional logistic regression was fit to assess the effect of asthma status on the risk of pertussis. RESULTS: Of the 223 subjects, 164 were eligible for the study, and 328 matched control subjects (1:2 matching) were enrolled. Of these 164 subjects, 50% were male, and 82% were white. The median age at the index date of pertussis was 14 years. Sixty-two (38%) of the 164 cases had asthma before the index date of pertussis compared with 85 (26%) of the 328 control subjects (odds ratio, 1.73; 95% CI, 1.12-2.67; P = 013). The population attributable risk percentage of asthma for risk of pertussis was 17%. CONCLUSIONS: Given the high prevalence of asthma and the ongoing risk of pertussis throughout the United States, consideration of defining asthmatic subjects as a target group for pertussis vaccination (eg, replacing decennial tetanus-diphtheria booster with tetanus, diphtheria, and acellular pertussis vaccine for adolescents and adults) should be given. PMID- 22206779 TI - Advances in basic and clinical immunology in 2011. AB - Investigations of basic immunologic mechanisms and clinical studies of primary immunodeficiencies were most prevalent in 2011. Significant progress was achieved in the characterization of T(H)17 cell differentiation and associated cytokines in the setting of inflammatory disorders, HIV infection, and immunodysregulation disorders. The role of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) mutations in the pathogenesis of CVID was further described and reported to be likely mediated by impaired TACI expression affecting B-cell function. The frequency of autoimmunity in patients with partial DiGeorge syndrome was estimated at 8.5%, predominantly resulting in blood cytopenias and hypothyroidism. Several reports emphasized the presentation of neoplasias, most often lymphomas, as the first manifestation of several primary immunodeficiencies. Novel strategies for newborn screening of B-cell lymphopenia by measuring immunoglobulin kappa chain-deletion recombinant excision circles and for adenosine deaminase deficiency using tandem mass spectrometry were demonstrated to be feasible at a large scale. Progress in the treatment of primary immunodeficiencies included increased success with unrelated HLA compatible donors for hematopoietic stem cell transplantation and the development of new gene therapy approaches with improved safety features. Induced pluripotent stem cells were developed from patients with primary immunodeficiencies, providing a virtually unlimited resource for pathophysiology and gene correction studies. New findings in several of the uncommon immunodeficiencies, such as the increased susceptibility to severe viral infections caused by defects in the activation of the Toll-like receptor 3 pathway, overall contributed to the understanding of their immunologic basis and provided for the design of effective diagnostic and therapeutic strategies. PMID- 22206781 TI - Study II: mechanoreceptive sensation is of increased importance for human postural control under alcohol intoxication. AB - Standing postural stability relies on input from visual, vestibular, proprioceptive and mechanoreceptive sensors. When the information from any of these sensors is unavailable or disrupted, the central nervous system maintains postural stability by relying more on the contribution from the reliable sensors, termed sensory re-weighting. Alcohol intoxication is known to affect the integrity of the vestibular and visual systems. The aim was to assess how mechanoreceptive sensory information contributed to postural stability at 0.00% (i.e. sober), 0.06% and 0.10% blood alcohol concentration (BAC) in 25 healthy subjects (mean age 25.1 years). The subjects were assessed with eyes closed and eyes open under quiet standing and while standing was perturbed by repeated, random-length, vibratory stimulation of the calf muscles. Plantar cutaneous mechanoreceptive sensation was assessed for both receptor types: slowly adapting (tactile sensitivity) and rapidly adapting (vibration perception). The correlation between recorded torque variance and the sensation from both mechanoreceptor types was calculated. The recorded stability during alcohol intoxication was significantly influenced by both the tactile sensation and vibration perception of the subjects. Moreover, the study revealed a fluctuating association between the subjects' vibration perception and torque variance during balance perturbations, which was significantly influenced by the level of alcohol intoxication, vision and adaptation. Hence, one's ability to handle balance perturbations under the influence of alcohol is strongly dependent on accurate mechanoreceptive sensation and efficient sensory re-weighting. PMID- 22206782 TI - Vision and agility training in community dwelling older adults: incorporating visual training into programs for fall prevention. AB - This study aimed to examine the effect of visual training on obstacle course performance of independent community dwelling older adults. Agility is the ability to rapidly alter ongoing motor patterns, an important aspect of mobility which is required in obstacle avoidance. However, visual information is also a critical factor in successful obstacle avoidance. We compared obstacle course performance of a group that trained in visually driven body movements and agility drills, to a group that trained only in agility drills. We also included a control group that followed the American College of Sports Medicine exercise recommendations for older adults. Significant gains in fitness, mobility and power were observed across all training groups. Obstacle course performance results revealed that visual training had the greatest improvement on obstacle course performance (22%) following a 12 week training program. These results suggest that visual training may be an important consideration for fall prevention programs. PMID- 22206783 TI - Compressive tibiofemoral force during crouch gait. AB - Crouch gait, a common walking pattern in individuals with cerebral palsy, is characterized by excessive flexion of the hip and knee. Many subjects with crouch gait experience knee pain, perhaps because of elevated muscle forces and joint loading. The goal of this study was to examine how muscle forces and compressive tibiofemoral force change with the increasing knee flexion associated with crouch gait. Muscle forces and tibiofemoral force were estimated for three unimpaired children and nine children with cerebral palsy who walked with varying degrees of knee flexion. We scaled a generic musculoskeletal model to each subject and used the model to estimate muscle forces and compressive tibiofemoral forces during walking. Mild crouch gait (minimum knee flexion 20-35 degrees ) produced a peak compressive tibiofemoral force similar to unimpaired walking; however, severe crouch gait (minimum knee flexion>50 degrees ) increased the peak force to greater than 6 times body-weight, more than double the load experienced during unimpaired gait. This increase in compressive tibiofemoral force was primarily due to increases in quadriceps force during crouch gait, which increased quadratically with average stance phase knee flexion (i.e., crouch severity). Increased quadriceps force contributes to larger tibiofemoral and patellofemoral loading which may contribute to knee pain in individuals with crouch gait. PMID- 22206784 TI - Positive blood culture in hospital: notification methods and impact of recommendations by an infectious disease specialist. AB - OBJECTIVE: The study's objective was to describe the notification methods of positive blood cultures and analyse the impact of recommendations made by an infectious disease specialist on the appropriateness of antibiotherapy. METHOD: We included all patients with positive blood cultures, from 12 different hospitals (including six with mobile infectious disease teams: MIDT) during a seven-day period. Medical records were retrospectively analysed to determine the delivered antibiotic treatment and the notification method of positive blood culture. We considered that the antibiotic treatment was appropriate if the antibiotic was effective on the isolated bacterium, whatever its spectrum. We assessed the impact of recommendations on appropriateness of antibiotherapy. RESULTS: One hundred and eighty-six patients were included. 44% (n=86) were considered as contamination cases. In true infections (n=104), Staphylococcus aureus and enterobacteria accounted for 51% of isolated bacteria. The Medical Unit was notified of blood culture positivity the day of positivity in 98% of cases (n=182). Antibiotic recommendations were given on the same day in 71% of cases. The antibiotic treatment was appropriate if recommendations were given in 92% of bacteremia, and only in 79% in without any recommendations (P=0.1). CONCLUSION: Antibiotic treatment seems to be more appropriate when antibiotic recommendations are given. This suggests that the MIDT has a key role in improving antibiotic prescriptions, whether for effectiveness, cost, or bacterial ecology. PMID- 22206785 TI - Rapid, sensitive and label-free detection of Shiga-toxin producing Escherichia coli O157 using carbon nanotube biosensors. AB - An electronic platform to detect very small amounts of genomic DNA from bacteria without the need for PCR amplification and molecular labeling is described. The system uses carbon nanotube field-effect transistor (FET) arrays whose electrical properties are affected by minute electrical charges localized on their active regions. Two pathogenic strains of E. coli are used to evaluate the detection properties of the transistor arrays. Described herein are the results for detection of synthetic oligomers, unpurified and highly purified genomic DNA at various concentrations and their comparison against non-specific binding. In particular, the capture of genomic DNA of E. coli O157:H7 by a specific oligonucleotide probe coated onto the transistor array results in a significant shift in the threshold (gate-source) voltage (V(th)). By contrast the signal under the same procedure using a different strain, E. coli O45 that is non complementary to the probe remained nearly constant. This work highlights the detection sensitivity and efficacy of this biosensor without stringent requirement for DNA sample preparation. PMID- 22206786 TI - A biosensor for cholesterol based on gold nanoparticles-catalyzed luminol electrogenerated chemiluminescence. AB - A novel cholesterol biosensor was prepared based on gold nanoparticles-catalyzed luminol electrogenerated chemiluminescence (ECL). Firstly, l-cysteine-reduced graphene oxide composites were modified on the surface of a glassy carbon electrode. Then, gold nanoparticles (AuNPs) were self-assembled on it. Subsequently, cholesterol oxidase (ChOx) was adsorbed on the surface of AuNPs to construct a cholesterol biosensor. The stepwise fabrication processes were characterized with cyclic voltammetry and atomic force microscopy. The ECL behaviors of the biosensor were also investigated. It was found that AuNPs not only provided larger surface area for higher ChOx loading but also formed the nano-structured interface on the electrode surface to improve the analytical performance of the ECL biosensor for cholesterol. Besides, based on the efficient catalytic ability of AuNPs to luminol ECL, the response of the biosensor to cholesterol was linear range from 3.3 MUM to 1.0 mM with a detection limit of 1.1 MUM (S/N=3). In addition, the prepared ECL biosensor exhibited satisfying reproducibility, stability and selectivity. Taking into account the advantages of ECL, we confidently expect that ECL would have potential applications in biotechnology and clinical diagnosis. PMID- 22206787 TI - [Adrenal tuberculosis: case report]. AB - Isolated adrenal tuberculosis is rare, and represents between 1-2% of the etiologies of adrenal masses called incidentalomas. A 32-year-old woman, without notable medical history, was hospitalized for pain in the left hypochondrium, lasting for two months in a context of apyrexia and weight loss amounted to 5 kg. Clinical examination was normal, but abdominopelvic CT objectified bilateral adrenal hypertrophy predominantly left with bilateral linear calcifications. The chest radiograph was normal, adrenal hormones were normal. The research of BK in sputum and urine were negative on direct examination and culture. The tuberculin was 12 mm and HIV status was negative. A left adrenal biopsy was done and histopathological study of tuberculous lesions was found confirming caseofolliculaire adrenal tuberculosis. The patient has been treated with antibacillaire with favorable evolution. In light of this observation, the authors make the point on this rare disease. PMID- 22206788 TI - [Acute respiratory distress syndrome secondary to influenza A (H1N1) infection: a report of a case]. AB - Through a clinical case of acute respiratory distress syndrome after infection with influenza virus H1N1 and a review of the literature the authors discuss treatment options, prognostic factors and the problems raised in support this pathology in Moroccan center. PMID- 22206789 TI - [Clinical characteristics, microbiologic findings and outcome of non-tuberculous purulent pleural effusion in HIV-infected and non HIV-infected adult patients in Yaounde, Cameroon]. AB - OBJECTIVE: To investigate the impact of HIV infection on clinical presentation, etiologic features and outcome of non-tuberculous purulent pleural effusion in adult patients in Yaounde. METHODS: We prospectively studied 55 consecutive patients aged 15 years and above, hospitalized in chest clinic of Yaounde Jamot Hospital for non-tuberculous purulent pleural effusion from August 2007 to September 2010. RESULTS: Twenty (36.4%) of the 55 patients were HIV-positive and 35 (63.6%) were HIV-negative. The mean age of HIV-positive patients was 37.5+/ 11.7 years compare to 43.2 +/-18.5 years on HIV-negative patients (P=0.159). Twelve (60%) HIV-positive patients were females compared to eight (22.6%) of HIV negative patients (P=0.006). No significant differences were found between the two groups of patients in regard to clinical and radiological features. The mean hemoglobin level was 10.5+/-2.8g/L in HIV-negative patients and 8.8+/-2.2g/L in HIV-positive patients (P=0.031). Streptococcus pneumoniae was the most common single bacterial etiology in the two groups with four (50%) cases in HIV-positive and eight (38.1%) cases in HIV-negative. Poor outcome (failure of thoracocenthesis or chest tube drainage and death) was observed in eight (40%) HIV-infected patients and only in four (11.4%) non-infected-HIV patients (P=0.019). CONCLUSION: The prevalence of HIV infection among adult patients with non-tuberculous purulent pleural effusion in Yaounde is high. HIV infection does not seem to have any impact on clinical, radiological and bacteriologic characteristics of patients suffering from purulent pleural effusion, but it seems to modify hematologic parameters of these patients. Failure of thoracocenthesis or chest tube drainage was significantly most frequent in HIV infected patients. PMID- 22206790 TI - [Doege-Potter syndrome. about one new case]. AB - Syndrome Doege-Potter is a paraneoplastic syndrome in which hypoglycemia is the result of tumors producing insulin growth factor-like (IGF-II) it is most often solitary fibrous tumor of the pleura (TFSP). These are rare and may be discovered incidentally, during non-specific respiratory symptoms or during hypoglycemia. Hypoglycemia occurs in tumors of large volume and it disappears after surgery, which is the treatment of choice for a permanent cure in most cases. We present a case of Doege-Potter syndrome whose interest is to consider the TFSP as a cause of hypoglycemia in patients with pleural tumors. PMID- 22206791 TI - The columnist manifesto. PMID- 22206792 TI - Three different LDL apheresis columns efficiently and equally reduce lipoprotein(a) concentrations in patients with familial hypercholesterolemia and small apolipoprotein(a) particles. AB - INTRODUCTION: High levels of lipoprotein(a) [Lp(a)] and apolipoprotein(a) [apo(a)] are associated with cardiovascular disease. In this study we determined apo(a) particle size and compared the Lp(a) reducing efficacy of three different LDL apheresis columns; DL-75, LA-15 and EC-50W in patients with familial hypercholesterolemia (FH). RESULTS: Average Lp(a) concentration was reduced by 70%, 74% and 75% (all p<0.0001) for DL-75, LA-15 and EC-50W, respectively. No significant changes in the relative proportion of the isoforms of 14 and 32K 4 domains were observed after apheresis. CONCLUSION: Three different LDL apheresis columns reduced Lp(a) efficiently with preserved ratio between apo(a) isoforms. PMID- 22206793 TI - Associations among birth weight, placental weight, gestational period and product quality indicators of umbilical cord blood units. AB - INTRODUCTION: Numbers of CD34+ cell and total nucleated cell (TNC) and cord blood volume are commonly used as indicators for haematopoietic potential of umbilical cord blood (UCB) units. The purpose of this study was to investigate the relationship between donor-related factors and the quality indicators of UCB. METHODS: Obstetric and neonatal clinical laboratory data of a total of 1549 UCB units were obtained from Buddhist Tzu Chi Stem Cells Center (BTCSCC) Cord Blood Bank. A retrospective multivariate analysis was conducted to analyze the data. RESULTS: Our results showed that birth weight had positive correlations with each of the clinical features of CD34+ cell number, TNC count and unit volume of UCB, followed by the placental weight. Longer gestational period would decrease CD34+ cell number and volume of UCB. Female baby and mode of vaginal delivery of neonates were found to have larger amount of TNC in UCB. CONCLUSION: Our results would be helpful and beneficial in building up standard criteria for evaluating stored UCB units. PMID- 22206794 TI - Clinical pharmacokinetics of gabapentin after administration of gabapentin enacarbil extended-release tablets in patients with varying degrees of renal function using data from an open-label, single-dose pharmacokinetic study. AB - BACKGROUND: Gabapentin enacarbil, a transported acyloxyalkylcarbamate prodrug of gabapentin, provides predictable and dose-proportional gabapentin exposure (AUC). Gabapentin is cleared via renal excretion, and its elimination is proportional to creatinine clearance (CrCL); CrCL can, therefore, be used as a predictor of gabapentin renal clearance. Gabapentin produced from hydrolysis of gabapentin enacarbil is also eliminated via the renal clearance pathway. It was, therefore, anticipated that the pharmacokinetics of gabapentin derived from gabapentin enacarbil would also be affected by renal function. OBJECTIVE: The objective of this study was to describe a population pharmacokinetic analysis of gabapentin enacarbil in patients with varying degrees of renal function, using data from an open-label study of gabapentin enacarbil in patients with renal impairment (XenoPort, Inc. protocol XP066), to determine whether dosage adjustments are necessary in patients with renal impairment. METHODS: Men and women >18 years of age with a body mass index <=34 kg/m(2) and who were, in general, healthy with the exception of renal impairment were enrolled All patients received a single 600-mg gabapentin enacarbil extended-release tablet under fed conditions. After dosing, plasma, urine, and dialysate samples were analyzed. Safety profile evaluations included adverse events, vital signs, ECGs, and laboratory values. Pharmacokinetic data were compared with those from Phase I-III studies in subjects with normal renal function to evaluate the relationship between gabapentin oral clearance (CL/F) and CrCL. RESULTS: Fifteen patients (11 men and 4 women) were enrolled. One patient had moderate renal impairment (CrCL 30-59 mL/min), 7 patients had severe renal impairment (CrCL <30 mL/min), and 7 patients had end-stage renal disease (CrCL <15 mL/min). Ten patients were white, 4 were African American, and 1 was American Indian or Alaskan Native. Their mean (range) age was 55 (28-76) years, weight was 85.6 (62-134) kg, and body mass index was 28.3 (22-34) kg/m(2). Mean maximum plasma gabapentin concentration was 5.77 MUg/mL in patients with moderate and severe renal impairment, and 5.59 MUg/mL in patients with end-stage renal disease who were undergoing hemodialysis. Based on the population pharmacokinetic analysis, gabapentin CL/F after administration of gabapentin enacarbil was proportionally related to CrCL, with an approximately 1.6-fold decrease in CL/F for every 2-fold decrease in CrCL. The most frequent adverse event was dizziness (4 of 15 patients). Other adverse events that were assessed as possibly or probably related to treatment were defecation urgency, extremity pain, feeling of relaxation, and muscle weakness; each occurred in 1 patient only. All events were mild or moderate and resolved without sequelae. CONCLUSIONS: The data suggest that dosage adjustment for gabapentin enacarbil is necessary in patients with impaired renal function. Gabapentin enacarbil, 600 mg, seemed to be well tolerated in this small selected population. PMID- 22206796 TI - [Relation between myocardial infarction and circadian rhythm in patients attended in a prehospital emergency service]. AB - BACKGROUND AND OBJECTIVES: The aim of this study is to analyze the presence of circadian rhythm in the time of onset of symptoms of acute myocardial infarction treated by a prehospital emergency system and the influence of modifiable cardiovascular risk factors and non-modifiable as modulators of that circadian rhythm. PATIENTS AND METHODS: Retrospective analysis of 709 patients clinically diagnosed with acute myocardial infarction on-site in the prehospital setting. The variables were time to onset of symptoms, age, sex, previous ischemic heart disease, hypertension, diabetes mellitus, hyperlipidemia and smoking. We analyzed the rhythm with cosinor multiple sinusoid method, with 3 harmonics (24, 12 and 8h) for the adjustment. RESULTS: The time of onset of pain showed circadian rhythm (P <,001), peaking at 10.39 and a valley at 4.28, showing a sinusoidal curve fitting bimodal aspect with a predominant morning peak and another evening one of lower amplitude. All subgroups categorized by the study variables showed circadian rhythm, with a cosine curve similar to the global infarction. Smokers had a predominantly evening peak. CONCLUSIONS: Acute myocardial infarction shows a circadian rhythm. Smoking and diabetes mellitus can modify the standard incidence rate of occurrence of myocardial infarction. PMID- 22206795 TI - Pharmacokinetics of vandetanib: three phase I studies in healthy subjects. AB - BACKGROUND: Vandetanib is an orally available inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor and is rearranged during transfection tyrosine kinase activity. Development has included studies in non-small cell lung cancer and other tumor types. Accurate elimination kinetics were not determined in patient studies, and so the current human volunteer studies were performed to derive detailed kinetic data. OBJECTIVE: The aim of this study was to investigate pharmacokinetics, metabolism, excretion, and elimination kinetics after single oral doses of vandetanib in healthy subjects. METHODS: Three studies were conducted. In Study A (n = 23), cohorts of 8 subjects were randomized to receive double-blind, ascending doses of vandetanib (300-1200 mg) or placebo (6:2). Study B had a crossover design; subjects (n = 16) received vandetanib 300 mg under fed and fasted conditions. In Study C, subjects (n = 4) received [(14)C] vandetanib 800 mg. Blood samples were collected for pharmacokinetic analysis for up to 28 days after the dose (Studies A and B) and 42 days after the dose (Study C). Plasma (all studies) and urine (Study A only) samples were collected for determination of vandetanib concentrations. In Study C radioactivity was measured in plasma, blood, urine, and feces, and metabolites were identified chromatographically. Tolerability was evaluated by recording of adverse events, clinical chemistry, hematology and urinalysis parameters, vital signs, and ECGs (all studies). RESULTS: Study A: mean (SD) age 34.4 (6.9) years; 23/23 male; mean (SD; range) weight 80.6 (8.1; 62-97) kg. Study B: mean (SD) age 35.3 (8.4) years; 15/16 male; mean (SD; range) weight 80.7 (11.2; 57-100) kg. Study C: mean (SD) age 60.3 (7.4) years; 4/4 male; mean (SD; range) weight 78.0 (7.7l; 72-87) kg. Pharmacokinetic parameters were consistent across all studies (Studies A and C, vandetanib 800 mg: geometric mean CL/F, 13.1-13.3 L/h; geometric mean apparent volume of distribution at steady state [V(SS)/F], 3592 4103 L; mean t(1/2), 215.8-246.6 hours). Vandetanib was absorbed and eliminated slowly after single oral doses. AUC(0-infinity) and C(max) were not significantly affected by ingestion of food. Median (range) T(max) was 8 (3-18) hours after food and 6 (5-18) hours after fasting. In plasma, concentrations of total radioactivity were higher than vandetanib concentrations at all time points, indicating the presence of circulating metabolites. Unchanged vandetanib and 2 anticipated metabolites (N-desmethylvandetanib and vandetanib N-oxide) were detected in plasma, urine, and feces. A further trace minor metabolite (glucuronide conjugate) was found in urine and feces. Approximately two thirds of the dose was recovered in feces (44%) and urine (25%) over 21 days, underlining the importance of both routes of elimination. Adverse events were reported by all subjects in Study A apart from 2 at a vandetanib dose of 300 mg; 12/15 (80%) and 14/16 (88%) subjects who took vandetanib under fed and fasted conditions, respectively, in Study B; and 2/4 (50%) subjects in Study C. No serious adverse events were reported. Increasing doses of vandetanib, in Study A, were associated with variable increases in systolic and diastolic blood pressures and variable increases from baseline in QTc interval. Hematuria was reported by 3 subjects (vandetanib 300 mg) in Study A. Small but consistent increases from baseline in serum creatinine were noted in subjects who received vandetanib in these studies. No other clinically important changes were observed in clinical chemistry, hematology and urinalysis parameters, vital signs, and ECGs in any of the studies. CONCLUSIONS: The pharmacokinetics of vandetanib after single oral doses to healthy subjects were defined and the metabolic pathway was proposed. Vandetanib was absorbed and eliminated slowly with a t(1/2) of ~10 days after single oral doses. The extent of absorption was not significantly affected by the presence of food. Approximately two thirds of the dose was recovered in feces (44%) and urine (25%) over 21 days. Unchanged vandetanib and N-desmethyl and N oxide metabolites were detected in plasma, urine, and feces. Vandetanib appeared to be was well tolerated in the populations studied. PMID- 22206797 TI - [Usefulness of endoscopic biopsy in Barrett's esophagus]. AB - BACKGROUND AND OBJECTIVE: Endoscopy with random biopsies is the standard technique for the diagnosis of Barrett's esophagus (BE). We studied the usefulness of endoscopic biopsies in the diagnosis and surveillance of patients with BE. PATIENTS: We reviewed all patients with BE controlled at the Hospital Clinic from February 2002 to March 2010. RESULTS: During the study period, 493 endoscopies were performed in 206 patients. We excluded 86 patients who had undergone one endoscopy only, hence the final sample consisted of 117 patients (mean age 61 [12] years, 73% men) with 407 endoscopies and a mean follow-up of 45 (38) months. Fifty-seven patients had a short-BE (49%), 28 a long-BE (24%) and 32 (27%) could not be inferred from the report. In 25 cases (21%), intestinal metaplasia (IM) was not detected at the endoscopic index. During follow-up, biopsies were negative for IM at some point in 45 patients (38.4%) and there was a change in the histologic grade in 100 cases (24.6%). The presence of a short-BE (43% in short-BE vs 7% in long-BE, P=.001) and few biopsies (3 [1.5] vs 6.2 [4.5]; P=.005) were associated with a higher frequency of negative biopsies for IM. CONCLUSION: Random endoscopic biopsies are not a good tool for diagnosis and surveillance of patients with BE. PMID- 22206798 TI - Variables affecting long-term maintenance of renal function following ileal based urinary diversion. PMID- 22206799 TI - Re: Sven van den Bosch, J. Alfred Witjes. Long-term cancer-specific survival in patients with high-risk, non-muscle-invasive bladder cancer and tumour progression: a systematic review. Eur Urol 2011;60:493-500. PMID- 22206800 TI - Perioperative outcomes of robot-assisted radical prostatectomy compared with open radical prostatectomy: results from the nationwide inpatient sample. AB - BACKGROUND: Prior to the introduction and dissemination of robot-assisted radical prostatectomy (RARP), population-based studies comparing open radical prostatectomy (ORP) and minimally invasive radical prostatectomy (MIRP) found no clinically significant difference in perioperative complication rates. OBJECTIVE: Assess the rate of RARP utilization and reexamine the difference in perioperative complication rates between RARP and ORP in light of RARP's supplanting laparoscopic radical prostatectomy (LRP) as the most common MIRP technique. DESIGN, SETTING, AND PARTICIPANTS: As of October 2008, a robot-assisted modifier was introduced to denote robot-assisted procedures. Relying on the Nationwide Inpatient Sample between October 2008 and December 2009, patients treated with radical prostatectomy (RP) were identified. The robot-assisted modifier (17.4x) was used to identify RARP (n=11 889). Patients with the minimally invasive modifier code (54.21) without the robot-assisted modifier were classified as having undergone LRP and were removed from further analyses. The remainder were classified as ORP patients (n=7389). INTERVENTION: All patients underwent RARP or ORP. MEASUREMENTS: We compared the rates of blood transfusions, intraoperative and postoperative complications, prolonged length of stay (pLOS), and in-hospital mortality. Multivariable logistic regression analyses of propensity score-matched populations, fitted with general estimation equations for clustering among hospitals, further adjusted for confounding factors. RESULTS AND LIMITATIONS: Of 19 462 RPs, 61.1% were RARPs, 38.0% were ORPs, and 0.9% were LRPs. In multivariable analyses of propensity score-matched populations, patients undergoing RARP were less likely to receive a blood transfusion (odds ratio [OR]: 0.34; 95% confidence interval [CI], 0.28-0.40), to experience an intraoperative complication (OR: 0.47; 95% CI, 0.31-0.71) or a postoperative complication (OR: 0.86; 95% CI, 0.77-0.96), and to experience a pLOS (OR: 0.28; 95% CI, 0.26-0.30). Limitations of this study include lack of adjustment for tumor characteristics, surgeon volume, learning curve effect, and longitudinal follow-up. CONCLUSIONS: RARP has supplanted ORP as the most common surgical approach for RP. Moreover, we demonstrate superior adjusted perioperative outcomes after RARP in virtually all examined outcomes. PMID- 22206801 TI - Re: Ben J. Challacombe, Bernard H. Bochner, Prokar Dasgupta, et al. The role of laparoscopic and robotic cystectomy in the management of muscle-invasive bladder cancer with special emphasis on cancer control and complications. Eur Urol 2011;60:767-75. PMID- 22206802 TI - Toward a better understanding of the savant brain. AB - OBJECTIVE: The objectives of this study are to investigate the neuroanatomy, regional brain connectivity, and neurochemistry of a prodigious artistic savant; to place these findings within the context of existing neuroimaging literature of savant syndrome; and to discuss the utility of newer imaging modalities to extend our current understanding of mechanisms underlying savant skills. METHODS: High resolution magnetic resonance (MR) imaging, J-resolved MR spectroscopy, and diffusion tensor imaging data were acquired during a single scanning session for a 63-year-old male autistic savant with prodigious artistic skills. Regional and compartmental brain volumes, N-acetyl aspartate, choline, creatine, glutamate and gamma-aminobutyric acid concentrations, fractional anisotropy values, and white matter bundle volumes as well as axial, radial, and mean diffusivities were calculated. RESULTS: No gross anatomical differences were observed. By morphological assessment, cerebral volume (1362 mL) was larger than normative literature values for adult males. The corpus callosum was intact and did not exhibit abnormal structural features. The right cerebral hemisphere was 1.9% larger than the left hemisphere; the right amygdala and right caudate nuclei were 24% and 9.9% larger, respectively, compared with the left side. In contrast, the putamen was 8.3% larger on the left side. Fractional anisotropy was increased on the right side as compared with the left for 4 of the 5 bilateral regions studied (the amygdala, caudate, frontal lobe, and hippocampus). Fiber tract bundle volumes were larger on the right side for the amygdala, hippocampus, frontal lobe, and occipital lobe. Both the left and the right hippocampi had substantially increased axial and mean diffusivities as compared with those of a comparison sample of nonsavant adult males. The corpus callosum and left amygdala also exhibited high axial, radial, and mean diffusivities. MR spectroscopy revealed markedly decreased gamma-aminobutyric acid and glutamate in the parietal lobe. CONCLUSIONS: Although examination of brain gross morphometry demonstrated no clinically remarkable abnormalities, utilization of conventional as well as newer MR imaging technologies revealed several atypical structural and chemical features that may be involved in the special skills of this prodigious savant. The multimodal imaging approach presented in this study is suitable for the evaluation of larger samples of savants with a diverse range of talents to investigate common brain features that may underlie the exceptional cognitive capabilities characteristic of savant syndrome. Given the high co-occurrence of the two syndromes, elucidating the underlying neurophysiologic basis of savant syndrome may also lead to a better understanding of autism spectrum disorder. PMID- 22206803 TI - Identifying attentional deficits in people with first-episode psychosis with the Scale for the Assessment of Negative Symptoms attention subscale: is it possible? AB - OBJECTIVE: The aim of this study was to examine the correspondence between clinical ratings of inattention problems in the early course of a psychotic disorder and concurrent neuropsychological data for sustained attention and speed of processing/executive functioning (SP/EF) derived from a comprehensive neuropsychological test battery. METHOD: A sample of 131 patients with first episode psychosis (FEP) was clinically rated after clinical stabilization with the attention subscale of the Scale for the Assessment of Negative Symptoms (SANS) and a completed neuropsychological test battery, which included measurements of sustained attention and SP/EF. To test the associations of the clinical ratings and objective data, correlations and regression analyses were conducted. RESULTS: Clinical ratings of inattention showed only weak correlations with the global score of SP/EF and with the clinical ratings of negative symptoms (rho < 0.25). None of the independent variables entered in the logistic regression model were significant (all P values > .05). Percentages of agreement between clinical judgment and neuropsychological measures were unacceptably low (ranged from 53% to 68%). kappa values indicate only slight agreement (kappa < 0.2). CONCLUSIONS: Clinical ratings based on the SANS attention subscale do not reliably match neuropsychological test measures of attention or other related cognitive processes in FEP. Even for those cognitive domains more pronouncedly impaired, mental health professionals will likely need to rely on psychometric testing or, alternatively, specific guidelines and also, probably, to collect data from different sources to adequately identify cognitive impairments. PMID- 22206804 TI - Lower dose dexamethasone/thalidomide and zoledronic acid every 3 weeks in previously untreated multiple myeloma. AB - BACKGROUND: Physicians in Asia have anecdotally reported that Asian patients with multiple myeloma (MM) are frequently intolerant of conventional doses of dexamethasone (Dex) and/or thalidomide (Thal). Since zoledronic acid (Zol) has an anti-MM effect in preclinical studies, we investigated whether the approved 3 times-weekly Zol combined with lower dose Dex/Thal could be an effective and better tolerated regimen in Asian patients. PATIENTS AND METHODS: In this first Asian cooperative multicenter phase II study, previously untreated patients with MM (N = 44) received up to 6 cycles of 3-times-weekly low-dose Dex/Thal and 4 mg Zol (the dtZ regimen). Response was graded using Blade criteria. RESULTS: The average doses of Dex and Thal administered were 185.2 mg/month; and 87.5 mg/day, respectively. Thirty-nine (88.6%) patients demonstrated at least a partial response (PR), including 18.2% very good partial response (VGPR), 15.9% near complete response (nCR) and 18.2% complete response (CR). Achievement of CR/nCR was related to significant (P < .05), rapid, and sustained inhibition of osteoclasts (OCs) and OC precursors (pOCs) by Zol. Sepsis was the most frequently reported serious toxicity, contributing to 3 of 4 deaths. Importantly, there was no peripheral neuropathy, osteonecrosis of the jaw, or nephrotoxicity. CONCLUSION: We conclude that the dtZ regimen is an effective and well-tolerated regimen for Asian patients with newly diagnosed MM. The high rate of VGPR/nCR/CR suggests that Zol could have a clinically relevant anti-MM effect. Since infections are the most frequent adverse event, it is probably wise to further lower the dose of Dex in future studies. PMID- 22206805 TI - Long-term Outcomes of Undercorrection Versus Full Correction After Unilateral Intraocular Lens Implantation in Children. AB - PURPOSE: To evaluate the impact of full correction vs undercorrection on the magnitude of the myopic shift and postoperative visual acuity after unilateral intraocular lens (IOL) implantation in children. DESIGN: Retrospective case control study. METHODS: The medical records of 24 children who underwent unilateral cataract surgery and IOL implantation at 2 to <6 years of age were reviewed. The patients were divided into 2 groups based on their 1-month postoperative refraction: Group 1 (full correction) -1.0 to +1.0 diopter (D) and Group 2 (undercorrection) >=+2.0 D. The main outcome measures included the change in refractive error per year and visual acuity for the pseudophakic eyes at last follow-up visit. The groups were compared using the independent groups t test and Wilcoxon rank sum test. RESULTS: The mean age at surgery (Group 1, 4.2+/-0.9 years, n=12; Group 2, 4.5+/-1.0 years, n=12; P=.45) and mean follow-up (Group 1, 5.8+/-3.7 years; Group 2, 6.1+/-3.5 years; P=.69) were similar for the 2 groups. The change in refractive error (Group 1, -0.4+/-0.5 D/y; Group 2, -0.3+/-0.2 D/y; P=.70) and last median logMAR acuity (Group 1, 0.4; Group 2, 0.4; P=.54) were not significantly different between the 2 groups. CONCLUSIONS: We did not find a significant difference in the myopic shift or the postoperative visual acuity in children aged 2 to <6 years of age following unilateral cataract surgery and IOL implantation if the initial postoperative refractive error was near emmetropia or undercorrected by 2 diopters or more. PMID- 22206806 TI - Bisphosphonate stimulation of osteoblasts and osteoblastic metastasis as a mechanism of hypocalcaemia. AB - Bisphosphonates are used in the oncological setting to treat and prevent skeletal related events and preserve bone mineral density. Bisphosphonates also possess a hypocalcaemic effect. When undesired, hypocalcaemia can result in increased morbidity and complications. The currently understood mechanism of bisphosphonate induced hypocalcaemia is by osteoclast inhibition. The effect of bisphosphonates on osteoblasts is less well understood. Laboratory studies demonstrate that bisphosphonates increase osteoblast and osteoblastic metastases maturation, activity and bone mineralization. We hypothesize that where large populations of osteoblasts exist increased mineralization may result in hypocalcaemia. Consequently patients with bone-metastatic prostate cancer may be more susceptible to symptomatic hypocalcaemia following bisphosphonate therapy. We are currently designing a study to investigate our hypothesis and to identify the risk factors of hypocalcaemia. PMID- 22206807 TI - A phase II study of pemetrexed combined with cisplatin in patients with recurrent or metastatic nanopharyngeal carcinoma. AB - Pemetrexed is a novel chemotherapy agent with good efficacy and toxicity profiles. This phase II study aimed at evaluating its use in combination with cisplatin for recurrent or metastatic nasopharyngeal carcinoma (NPC). All participating patients had metastatic or recurrent NPC with prior treatment by platinum-based chemotherapy. The study regimen comprised of pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2), repeated 3-weekly for 4 cycles. Efficacy evaluation was based on both radiological and biochemical responses. Patients with no progressive disease and good tolerance were given another 2-4 cycles. Fifteen patients were treated for a total of 4-8 cycles (median, 6 cycles); 9 had distant metastases and 6 had loco-regional recurrences only. Reduction of DNA copies of EB virus by >=50% was observed in 93% accessible patients, with 21% of them being biochemical complete response (CR). Radiologically, 1 (7%) patient achieved CR, 2 (13%) achieved partial response and 8 (53%) had stable diseases. The median time to progression was 30 weeks. Treatment was well tolerated with only 1 (7%) patient developing grade 4 toxicity (of anemia). The most common grade 3 toxicities were neutropenia (27%) and anemia (20%). The baseline mean total QOL scores (as measured with FACT-H&N version 4) was 100.4 and showed no significant change after the fourth cycle (95.6, p=0.20) and sixth cycle (91.9, p=0.15). Pemetrexed in combination with cisplatin is a well tolerated regimen with encouraging efficacy for metastatic and recurrent NPC. Further evaluation of its role in the management of NPC is warranted. PMID- 22206809 TI - Brain activation during spatial updating and attentive tracking of moving targets. AB - Keeping aware of the locations of objects while one is moving requires the updating of spatial representations. As long as the objects are visible, attentional tracking is sufficient, but knowing where objects out of view went in relation to one's own body involves an updating of spatial working memory. Here, multiple object tracking was employed to study spatial updating and its neural correlates. In a dynamic 3D-scene, targets moved among visually indistinguishable distractors. The targets and distractors either stayed visible during continuous viewpoint changes or they turned invisible. The parametric variation of tracking load revealed load-dependent activations of the intraparietal sulcus, the superior parietal lobule, and the lateral occipital cortex in response to the attentive tracking task. Viewpoint changes with invisible objects that demanded retention and updating produced load-dependent activation only in the precuneus in line with its presumed involvement in updating spatial working memory. PMID- 22206808 TI - Review of drug treatment of oral submucous fibrosis. AB - This study undertook a review of the literature on drug treatment of oral submucous fibrosis. An electronic search was carried out for articles published between January 1960 to November 2011. Studies with high level of evidence were included. The levels of evidence of the articles were classified after the guidelines of the Oxford Centre for Evidence-Based Medicine. The main outcome measures used were improvement in oral ulceration, burning sensation, blanching and trismus. Only 13 publications showed a high level of evidence (3 randomized controlled trials and 10 clinical trials/controlled clinical trials), with a total of 1157 patients. Drugs like steroids, hyaluronidase, human placenta extracts, chymotrypsin and collagenase, pentoxifylline, nylidrin hydrochloride, iron and multivitamin supplements including lycopene, have been used. Only systemic agents were associated with few adverse effects like gastritis, gastric irritation and peripheral flushing with pentoxifylline, and flushingly warm skin with nylidrin hydrochloride; all other side-effects were mild and mainly local. Few studies with high levels of evidence were found. The drug treatment that is currently available for oral submucous fibrosis is clearly inadequate. There is a need for high-quality randomized controlled trials with carefully selected and standardized outcome measures. PMID- 22206810 TI - Artifacts in wearable photoplethysmographs during daily life motions and their reduction with least mean square based active noise cancellation method. AB - Signal distortion of photoplethysmographs (PPGs) due to motion artifacts has been a limitation for developing real-time, wearable health monitoring devices. The artifacts in PPG signals are analyzed by comparing the frequency of the PPG with a reference pulse and daily life motions, including typing, writing, tapping, gesturing, walking, and running. Periodical motions in the range of pulse frequency, such as walking and running, cause motion artifacts. To reduce these artifacts in real-time devices, a least mean square based active noise cancellation method is applied to the accelerometer data. Experiments show that the proposed method recovers pulse from PPGs efficiently. PMID- 22206812 TI - Humoral immune responses to venom and antivenom of patients bitten by Bothrops snakes. AB - Snake envenomation and its treatment cause the entry of two kind of foreign antigens into the human body: snake toxins and antivenom from animal origin. Samples of patients bitten by snakes in Uruguay were assayed to determine levels of human antibodies against venom and antivenom. The ELISA results showed that most of the patients presented an important increase of IgG and IgM antibodies against antivenom at day 15 post accident. Antibodies were reactive against both equine immunoglobulin chains by western blot assay. In the case of the response against the venom, increase in titre at day 15 was of a minor degree as compared with the antivenom by ELISA. Only one of the patients showed an important increase of IgG and IgM levels against Bothropoides pubescens and only of IgG level against Rhinocerophis alternatus. This patient also showed an extensive reactivity against B. pubescens by western blot. PMID- 22206813 TI - Assessing the neurotoxic effects of palytoxin and ouabain, both Na+/K+-ATPase inhibitors, on the myelinated sciatic nerve fibres of the mouse: an ex vivo electrophysiological study. AB - Palytoxin (PlTX) is a marine toxin originally isolated from the zoantharians of the genus Palythoa. It is considered to be one of the most lethal marine toxins that block the Na+/K+-ATPase. This study was designed to investigate the acute effects of PlTX and ouabain, also an Na+/K+-ATPase blocker, on the mammalian peripheral nervous system using an ex vivo electrophysiological preparation: the isolated mouse sciatic nerve. Amplitude of the evoked nerve compound action potential (nCAP) was used to measure the proper functioning of the sciatic nerve fibres. The half-vitality time of the nerve fibres (the time required to inhibit the nCAP to 50% of its initial value: IT50) incubated in normal saline was 24.5 +/- 0.40 h (n = 5). Nerves incubated continuously in 50.0, 10.0, 1.0, 0.5, 0.250 and 0.125 nM of PlTX had an IT50 of 0.06 +/- 0.00, 0.51 +/- 0.00, 2.1 +/- 0.10, 8.9 +/- 0.30, 15.1 +/- 0.30 h, and 19.5 +/- 0.20 h, respectively (n = 5, 3, 4, 4, 10). PlTX was extremely toxic to the sciatic nerve fibres, with a minimum effective concentration (mEC) of 0.125 nM (n = 5) and inhibitory concentration to 50% (IC50) of 0.32 +/- 0.08 nM (incubation time 24 h). Ouabain was far less toxic, with a mEC of 250.0 MUM (n = 5) and IC50 of 370.0 +/- 18.00 MUM (incubation 24.5 h). Finally, when the two compounds were combined--e.g. pre incubation of the nerve fibre in 250.0 MUM ouabain for 1 h and then exposure to 1.0 nM PlTX--ouabain offered minor a neuroprotection of 9.1-17.6% against PlTX induced neurotoxicity. Higher concentrations of ouabain (500.0 MUM) offered no protection. The mouse sciatic nerve preparation is a simple and low-cost bioassay that can be used to assess and quantify the neurotoxic effects of standard PlTX or PlTX-like compounds, since it appears to have the same sensitivity as the haemolysis of erythrocytes assay--the standard ex vivo test for PlTX toxicity. PMID- 22206814 TI - Activation of a tunicate (Ciona intestinalis) xenobiotic receptor orthologue by both natural toxins and synthetic toxicants. AB - Vertebrate xenobiotic receptors are ligand-activated nuclear receptors (NRs) that bind exogenous biologically active chemicals before activating the transcription of genes involved in xenobiotic metabolism and excretion. Typically, xenobiotic receptors have ligand binding domains (LBDs) that can accommodate a structurally diverse array of molecules and in addition display high levels of inter-taxa sequence diversity suggestive of positive selection. Pursuing the idea that xenobiotic receptors may adaptively evolve to bind toxic chemicals commonly present in an organism's environment/diet, we examined ligand binding by a xenobiotic receptor orthologue of a marine filter-feeding organism. The solitary tunicate Ciona intestinalis (Phylum Chordata) genome encodes an orthologue of the vertebrate pregnane X receptor (PXR) and vitamin D receptor (VDR), here denoted CiVDR/PXRalpha. In a luciferase reporter assay the CiVDR/PXRalpha was activated, at nanomolar concentrations, by two of four natural marine microalgal biotoxins tested (okadaic acid, EC50 = 18.2 +/- 0.9 nM and pectenotoxin-2, EC50 = 37.0 +/- 3.5 nM) along with 1 of 11 synthetic toxicants (esfenvalerate: EC50 = 0.59 +/- 0.7 MUM). Two related C. intestinalis NRs, orthologous to vertebrate farnesoid X receptor and liver X receptors, respectively, along with the PXR of a freshwater fish (zebrafish, Danio rerio), were not activated by any of the 15 chemicals tested. In contrast, human PXR was activated by okadaic acid at similar concentrations to CiVDR/PXRalpha (EC50 = 7.2 +/- 1.1 nM) but not by pectenotoxin 2. A common features pharmacophore developed for the CiVDR/PXRalpha ligand consisted of an off-center hydrogen bond acceptor flanked by two hydrophobic regions. The results of this study are consistent with the original hypothesis that natural toxins, present in the diet of filter-feeding marine invertebrates, may have acted as selective agents in the molecular evolution of tunicate xenobiotic receptors. Bioassays based on tunicate xenobiotic receptor activation may find application in marine environmental monitoring and bioprospecting. PMID- 22206815 TI - Pramipexole is active in depression tests and modulates monoaminergic transmission, but not brain levels of BDNF in mice. AB - The dopamine D(2)/D(3) receptor agonist pramipexole exerts antidepressive capacities in patients with Parkinson's disease with little evidence for patients with affective diseases only. Little is known about the neurobiological basis of these antidepressive effects. In this study, C57BL/6N mice received acute or chronic (3 weeks) treatment with pramipexole in different dosages (0.1, 0.3, 1, and 3mg/kg b.w.) and imipramine or saline serving as positive and negative controls. To characterize antidepressant-like effects mice underwent behavioral characterization. In a second experiment dosages of pramipexole shown to be effective were used and candidate brain regions including hippocampus, frontal cortex and striatum were analyzed for levels of 5-hydroxytryptamine (5-HT), noradrenaline and dopamine and their metabolites as well as brain-derived neurotrophic factor (BDNF) to investigate possible neurochemical correlates of behavioral changes. Whereas acute treatment with pramipexole resulted in antidepressive-like effects in the Porsolt Forced Swim Test, Novel Cage Test, Openfield Test and Dark-light-Box Test and a tendency but insignificant effect in the Tail Suspension Test, chronic treatment did not show significant effects in any of the behavioral analyses. Neurochemical analyses revealed a highly significant effect on dopaminergic metabolites in the striatum as well as a moderate transient modulation of the serotonergic system in the hippocampus. BDNF levels were not affected by any dosage and treatment regime in any brain region investigated. In conclusion, the present data substantiate antidepressive effects of pramipexole and indicate a contribution of the dopaminergic and serotonergic metabolism in these effects, but argue against an eminent role of BDNF. PMID- 22206816 TI - Riluzole and gabapentinoids activate glutamate transporters to facilitate glutamate-induced glutamate release from cultured astrocytes. AB - We have recently demonstrated that the glutamate transporter activator riluzole paradoxically enhanced glutamate-induced glutamate release from cultured astrocytes. We further showed that both riluzole and the alpha(2)delta subunit ligand gabapentin activated descending inhibition in rats by increasing glutamate receptor signaling in the locus coeruleus and hypothesized that these drugs share common mechanisms to enhance glutamate release from astrocytes. In the present study, we examined the effects of riluzole and gabapentin on glutamate uptake and release and glutamate-induced Ca(2+) responses in primary cultures of astrocytes. Riluzole and gabapentin facilitated glutamate-induced glutamate release from astrocytes and significantly increased glutamate uptake, the latter being completely blocked by the non-selective glutamate transporter blocker DL-threo beta-benzyloxyaspartic acid (DL-TBOA). Riluzole and gabapentin also enhanced the glutamate-induced increase in intracellular Ca(2+) concentrations. Some alpha(2)delta subunit ligands, pregabalin and L-isoleucine, enhanced the glutamate-induced Ca(2+) response, whereas another, 3-exo aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (ABHCA), did not. The enhancement of glutamate-induced intracellular Ca(2+) response by riluzole and gabapentin was blocked by the DL-TBOA and an inhibitor of Na(+)/Ca(2+) exchange, 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiurea (KB-R7943). Gabapentin's enhancement of Ca(2+) increase was specific to glutamate stimulation, as it was not mimicked with stimulation by ATP. These results suggest that riluzole and gabapentin enhance Na(+)-glutamate co-transport through glutamate transporters, induce subsequent Ca(2+) influx via the reverse mode of Na(+)/Ca(2+) exchange, and thereby facilitate Ca(2+)-dependent glutamate release by glutamate in astrocytes. The present study also demonstrates a novel target of gabapentinoid action in astrocytes other than alpha(2)delta subunits in neurons. PMID- 22206817 TI - Systemic paracetamol-induced analgesic and antihyperalgesic effects through activation of descending serotonergic pathways involving spinal 5-HT7 receptors. AB - Although some studies have shown the essential role of descending serotonergic pathways and spinal 5-HT(1A), 5-HT(2A), or 5-HT(3) receptors in the antinociceptive effects of paracetamol, other studies have presented conflicting results, and the particular subtype of spinal 5-HT receptors involved in paracetamol-induced analgesia remains to be clarified. Recent studies have demonstrated the importance of spinal 5-HT(7) receptors in descending serotonergic pain inhibitory pathways. In this study, we investigated the role of descending serotonergic pathways and spinal 5-HT(7) receptors compared with 5 HT(3) and 5-HT(2A) receptors in the antinociceptive and antihyperalgesic effects of paracetamol. Tail-flick, hot plate and plantar incision tests were used to determine nociception in male BALB/c mice. Lesion of serotonergic bulbospinal pathways was performed by intrathecal (i.th.) injection of 5,7 dihydroxytryptamine (5,7-DHT), and spinal 5-HT levels were measured by HPLC. To evaluate the particular subtypes of the spinal 5-HT receptors, the selective 5 HT(7), 5-HT(3) and 5-HT(2A) receptor antagonists SB 269970, ondansetron and ketanserin, respectively, were given i.th. after oral administration of paracetamol. Oral paracetamol (200, 400 and 600 mg/kg) elicits dose-dependent antinociceptive and antihyperalgesic effects. I.th. pretreatment with 5,7-DHT (50 MUg) sharply reduced 5-HT levels in the spinal cord. Depletion of spinal 5-HT totally abolished the antinociceptive and antihyperalgesic effects of paracetamol. I.th. injection of SB 2669970 (10 MUg) blocked the antinociceptive and antihyperalgesic effects of paracetamol, but ondansetron and ketanserin (10 MUg) did not. Our findings suggest that systemic administration of paracetamol may activate descending serotonergic pathways and spinal 5-HT(7) receptors to produce a central antinociceptive and antihyperalgesic effects. PMID- 22206818 TI - Genes and molecular mechanisms involved in the epileptogenesis of idiopathic absence epilepsies. AB - Idiopathic absence epilepsies (IAE), that have high prevalence particularly among children and adolescents, are complex disorders mainly caused by genetic factors. Childhood absence epilepsy and juvenile absence epilepsy are among the most common subtypes of IAEs. While the role of ion channels has been the primary focus of epilepsy research, the analysis of mutation and association in both patients with absence epilepsies and animal models revealed the involvement of GABA receptors and calcium channels, but also of novel non-ion channel proteins in inducing spike wave discharges (SWD). Functional studies on a mutated variant of these proteins also support their role in the epileptogenesis of absence seizures. Studies in animal models point to both the thalamus and cortex as the origin of SWDs: the abnormalities in the components of these circuits leading to seizure activity. This review examines the current research on mutations and susceptibility alleles determined in the genes that code for the subunits of GABA receptors (GABRG2, GABRA1, GABRB3, GABRA5, GABA(B1) and GABA(B2)), calcium channels (CACNA1A, CACNA1G, CACNA1H, CACNA1I, CACNAB4, CACNAG2 and CACNG3), and novel non-ion channel proteins, taking into account the results of functional studies on these variants. PMID- 22206819 TI - Longistatin is an unconventional serine protease and induces protective immunity against tick infestation. AB - Classical serine proteases use the conserved Ser/His/Asp catalytic triad to hydrolyze substrates. Here, we show that longistatin, a salivary gland protein with two EF-hand domains from the vector tick Haemaphysalis longicornis, does not have the conserved catalytic triad, but still functions as a serine protease. Longistatin was synthesized in and secreted from the salivary glands of ticks, and is injected into host tissues during the acquisition of blood-meals. Longistatin hydrolyzed fibrinogen, an essential plasma protein in the coagulation cascade, and activated plasminogen, into its active form plasmin, a serine protease that dissolves fibrin clots. Longistatin efficiently hydrolyzed several serine protease-specific substrates showing its specificity to the amide bond of Arg. Longistatin did not hydrolyze synthetic substrates specific for other groups of proteases. The enzyme was active at a wide range of temperatures and pHs, with the optimum at 37 degrees C and pH 7. Its activity was efficiently inhibited by various serine protease inhibitors such as phenylmethanesulfonyl fluoride (PMSF), aprotinin, antipain, and leupeptin with the estimated IC(50) of 278.57 MUM, 0.35 MUM, 41.56 MUM and 198.86 MUM, respectively. In addition, longistatin was also potently inhibited by Zinc (Zn(2+)) in a concentration-dependent manner with an IC(50) value of 275 MUM, and the inhibitory effect of Zn(2+) was revived by ethylenediaminetetra acetic acid (EDTA). Immunization studies revealed that longistatin sharply induced high levels of protective IgG antibodies against ticks. Immunization with longistatin reduced repletion of ticks by about 54%, post engorgement body weight by >11% and molting of nymphs by approximately 34%; thus, the vaccination trial was approximately 73% effective against tick infestation. Taken together, our results suggest that longistatin is a new potent atypical serine protease, and may be an interesting candidate for the development of anti-tick vaccines. PMID- 22206820 TI - Effect of tibial component varus on wear in total knee arthroplasty. AB - INTRODUCTION: Malalignment can result in poor clinical outcomes and increased wear. However, component malalignment can occur even when overall limb mechanical axis is within the normal anatomic range. We studied the effect of component malalignment in the presence of acceptable knee alignment in knee arthroplasty. METHODS: Sixteen tibial inserts retrieved at revision surgery were laser-mapped to measure wear. Average implantation duration was 7.7 years (range, 1 to 13). Early (postprimary) and final (prerevision) radiographs were analyzed for overall alignment (limb, femoral and tibial components) and osteolysis. RESULTS: The tibial components were initially aligned in a mean of 1.3 +/- 1.7 degrees varus (range, -1.5 to 4.5 degrees ), which increased to 3.2 +/- 2.9 degrees (range, 2.0 to 8.0 degrees ) at the time of revision (p=0.05). Tibial components initially placed in greater than 3 degrees varus were associated with almost twice the volumetric penetration rate. Anatomic knee angles were 5.4 +/- 0.9 degrees valgus (range, 4.0 to 7.0 degrees ) in the post-primary radiographs and decreased in prerevision radiographs to 3.8 +/- 2.6 degrees (range, -1.0 to 7.5 degrees ), (p=0.04). DISCUSSION: Tibial varus was associated with increased medial compartment wear and total wear, thus affecting osteolysis in addition to local destruction of the bearing surface. Varus malalignment as low as 3 degrees may result in accelerated wear, even if overall limb alignment is nearly ideal. These results indicate that tibial component alignment is an important factor associated with tibial tray subsidence and polyethylene wear even when limb alignment is neutral. PMID- 22206821 TI - Almanac 2011: acute coronary syndromes. The national society journals present selected research that has driven recent advances in clinical cardiology. PMID- 22206822 TI - Brain levels of arginine-vasotocin and isotocin in dominant and subordinate males of a cichlid fish. AB - The nonapeptides arginine-vasotocin (AVT) and isotocin (IT), which are the teleost homologues of arginine-vasopressin and oxytocin in mammals, have well established peripheral effects on osmoregulation and stress response, and central effects on social behavior. However, all studies that have looked so far into the relationship between these nonapeptides and social behavior have used indirect measures of AVT/IT activity (i.e. immunohistochemistry of AVT/IT immunoreactive neurons, or AVT/IT or their receptors mRNA expression with in situ hybridization or qPCR) and therefore direct measures of peptide levels in relation to social behavior are still lacking. Here we use a recently developed high-performance liquid chromatography analysis with fluorescence detection (HPLC-FL) method to quantify the levels of both AVT and IT in macro-dissected brain areas [i.e. olfactory bulbs, telencephalon, diencephalon, optic tectum, cerebellum, and hindbrain (= rhombencephalon minus cerebellum)] and pituitary of dominant and subordinate male cichlid fish (Oreochromis mossambicus). The pituitary shows higher levels of both peptides than any of the brain macroareas, and the olfactory bulbs have the highest AVT among all brain areas. Except for IT in the telencephalon there is a lack of correlations between central levels and pituitary peptide levels, suggesting an independent control of hypophysial and CNS nonapeptide secretion. There were also no correlations between AVT and IT levels either for each brain region or for the pituitary gland, suggesting a decoupled activity of the AVT and IT systems at the CNS level. Subordinate AVT pituitary levels are significantly higher than those of dominants, and dominant hindbrain IT levels are significantly higher than those of subordinates, suggesting a potential involvement of AVT in social stress in subordinate fish and of IT in the regulation of dominant behavior at the level of the hindbrain. Since in this species dominant males use urine to communicate social status and since AVT is known to have an antidiuretic effect, we have also investigated the effect of social status on urine storage. As predicted, dominant males stored significantly more urine than subordinates. Given these results we suggest that AVT/IT play a key role in orchestrating social phenotypes, acting both as central neuromodulators that promote behavioral plasticity and as peripheral hormones that promote integrated physiological changes. PMID- 22206824 TI - Development of an antigen-capture enzyme-linked immunosorbent assay using monoclonal antibodies for detecting H6 avian influenza viruses. AB - The H6 subtype of avian influenza virus (AIV) infection occurs frequently in wild and domestic birds. AIV antigen detection is preferred for controlling AIV as birds are infected before they produce antibodies. The purpose of this study was to develop an early diagnostic method for AIV detection. Six monoclonal antibodies (mAbs) developed from a field H6N1 AIV strain were tested for their ability to bind to viruses. The two that showed the greatest binding ability to AIVs were used for antigen detection. An antigen-capture enzyme-linked immunosorbent assay (ELISA) to detect H6 AIVs was developed using these mAbs. One mAb was coated onto an ELISA plate as the capture antibody. The other mAb was used as the detector antibody after labeling with horseradish peroxidase. The antigen-capture ELISA detected H6N1 AIVs but not H5 AIVs, human H1N1, H3N2 influenza or other viruses. This antigen-capture ELISA could be used to specifically detect H6N1 AIV. PMID- 22206825 TI - Emergence of complex partial epilepsy-like experiences following closed head injuries: personality variables and neuropsychological profiles. AB - To pursue Richard Roberts' epileptic spectrum disorder (ESD) and the emergence of complex partial epilepsy-like experiences, items and total scores for the ESD Inventory were examined for 185 patients who had sustained mechanical impacts (and were diagnosed with or without neuropsychological impairment) and a reference group (n=68) of university students. Results from neuropsychological, personality, neurological screening, and interview data supported the role of temporal lobe origins for these experiences. The incidences of these experiences were sufficient to adversely affect adaptation and to produce psychiatric profiles. Although only 70% of the patients who were impaired versus not impaired could be differentiated by items from the ESD Inventory, >95% of the patients with scores >100 on the ESD Inventory displayed abnormal scores on more than four Minnesota Multiphasic Personality Inventory scales. These results support Roberts' ESD concept and strongly suggest that persistent, subclinical occurrence of these experiences could be the cause or major correlate of neuropsychological impairment for these patients. PMID- 22206823 TI - The oxytocin system in drug discovery for autism: animal models and novel therapeutic strategies. AB - Animal models and behavioral paradigms are critical for elucidating the neural mechanism involved in complex behaviors, including social cognition. Both genotype and phenotype based models have implicated the neuropeptide oxytocin (OT) in the regulation of social behavior. Based on the findings in animal models, alteration of the OT system has been hypothesized to play a role in the social deficits associated with autism and other neuropsychiatric disorders. While the evidence linking the peptide to the etiology of the disorder is not yet conclusive, evidence from multiple animal models suggest modulation of the OT system may be a viable strategy for the pharmacological treatment of social deficits. In this review, we will discuss how animal models have been utilized to understand the role of OT in social cognition and how those findings can be applied to the conceptualization and treatment of the social impairments in ASD. Animal models with genetic alterations of the OT system, like the OT, OT receptor and CD38 knock-out mice, and those with phenotypic variation in social behavior, like BTBR inbred mice and prairie voles, coupled with behavioral paradigms with face and construct validity may prove to have predictive validity for identifying the most efficacious methods of stimulating the OT system to enhance social cognition in humans. The widespread use of strong animal models of social cognition has the potential yield pharmacological, interventions for the treatment social impairments psychiatric disorders. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID- 22206826 TI - Characterization of a large genomic deletion in four Irish families with C7 deficiency. AB - Inherited deficiency of the seventh complement component (C7) is associated with increased susceptibility to Neisseria meningitidis infections. The disease is rare in most Western countries. Here we report new investigations of a large, but incompletely characterized genomic deletion of exons 8 and 9 [c.739-?_1093+?del], previously identified in three unrelated Irish families with C7 deficiency. We have analysed DNA from one individual, who is homozygous for the deletion, by PCR using primers progressively proximal to the deleted exons. Thus we were able to map the deletion boundaries. Amplification across the breakpoint and sequencing revealed an indel mutation that included a 6.4kb deletion together with an insertion of a novel 8bp sequence [c.739+1262_1270-2387delinsGCAGGCCA]. We demonstrated the same defect in the C7 deficient patients from each family and developed a duplex PCR method to enable the detection of alleles containing the deletion in heterozygotes. A member of a fourth family was found to be homozygous for the deletion defect. Thus, the deletion defect may be a more commonly distributed cause of C7 deficiency in Ireland. PMID- 22206827 TI - Wear-induced loss of mass in reversed total shoulder arthroplasty with conventional and inverted bearing materials. AB - The notching phenomenon is one of the major concerns with reversed total shoulder arthroplasty. Repetitive contact between the humeral implant and the scapula (mechanical notching) produces progressive abrasion of the implant if the moving part is made of polyethylene. Its debris may then lead to active osteolysis (biological notching). Inversion of bearing materials, i.e. Glenosphere made of polyethylene and humeral Inlay made of metal, aims at the reduction of this phenomenon. However, the question arises if the tribological behavior would then be different. On an experimental setup, the gravimetric wear of both material configurations was measured after loading and moving over 500,000 cycles. The abrasion of the polyethylene Inlay due to mechanical notching was calculated by means of 3D CAD models with different notching stages. The loss of mass due to gravimetric wear was compared to the loss of mass caused by mechanical notching. After 500,000 cycles the measured amount of wear of the polyethylene components was between 8 and 10 mg for both tribological pairings. The calculated loss of mass of the polyethylene Inlay caused by mechanical notching ranged from 73 to 3881 mg. The results of this study indicate that the gravimetric polyethylene wear in the estimated life-time is very low and not significantly different between both material configurations. However, the polyethylene abrasion due to mechanical notching in the configuration with polyethylene Inlay is by far more important than any gravimetric wear. These results support the continued use of inverted bearings in reversed total shoulder arthroplasty. PMID- 22206828 TI - Dependence of cyclic stretch-induced stress fiber reorientation on stretch waveform. AB - Cyclic uniaxial stretching of adherent nonmuscle cells induces the gradual reorientation of their actin stress fibers perpendicular to the stretch direction to an extent dependent on stretch frequency. By subjecting cells to various temporal waveforms of cyclic stretch, we revealed that stress fibers are much more sensitive to strain rate than strain frequency. By applying asymmetric waveforms, stress fibers were clearly much more responsive to the rate of lengthening than the rate of shortening during the stretch cycle. These observations were interpreted using a theoretical model of networks of stress fibers with sarcomeric structure. The model predicts that stretch waveforms with fast lengthening rates generate greater average stress fiber tension than that generated by fast shortening. This integrated approach of experiment and theory provides new insight into the mechanisms by which cells respond to matrix stretching to maintain tensional homeostasis. PMID- 22206829 TI - Hyperosmolaric contrast agents in cartilage tomography may expose cartilage to overload-induced cell death. AB - In clinical arthrographic examination, strong hypertonic contrast agents are injected directly into the joint space. This may reduce the stiffness of articular cartilage, which is further hypothesized to lead to overload-induced cell death. We investigated the cell death in articular cartilage while the tissue was compressed in situ in physiological saline solution and in full strength hypertonic X-ray contrast agent Hexabrix(TM). Samples were prepared from bovine patellae and stored in Dulbecco's Modified Eagle's Medium overnight. Further, impact tests with or without creep were conducted for the samples with contact stresses and creep times changing from 1 MPa to 10 MPa and from 0 min to 15 min, respectively. Finally, depth-dependent cell viability was assessed with a confocal microscope. In order to characterize changes in the biomechanical properties of cartilage as a result of the use of HexabrixTM, stress-relaxation tests were conducted for the samples immersed in HexabrixTM and phosphate buffered saline (PBS). Both dynamic and equilibrium modulus of the samples immersed in HexabrixTM were significantly (p<0.05) lower than those of the samples immersed in PBS. Cartilage samples immersed in physiological saline solution showed load-induced cell death primarily in the superficial and middle zones. However, under high 8-10 MPa contact stresses, the samples immersed in full strength HexabrixTM showed significantly (p<0.05) higher number of dead cells than the samples compressed in physiological saline, especially in the deep zone of cartilage. In conclusion, excessive loading stresses followed by tissue creep might increase the risk for chondrocyte death in articular cartilage when immersed in hypertonic X-ray contrast agent, especially in the deep zone of cartilage. PMID- 22206830 TI - Imaging of a bone tumour for the non-radiologist. PMID- 22206831 TI - Mammographic features of screening detected pT1 (a-b) invasive breast cancer using BI-RADS lexicon. AB - AIM: To describe mammographic features in screening detected invasive breast cancer less than or equal to 10mm using Breast Imaging Reporting and Data System lexicon in full-field digital mammography. PATIENTS AND METHODS: A retrospective analysis of 123 pT1 (a-b) invasive breast cancers in women aged 50-69 years from our screening program. Radiologic patterns were: masses, calcifications, distortions, asymmetries and mixed. Masses: shape, margins and density, and calcifications: morphology, number of flecks and size of the cluster were taken into account, following Breast Imaging Reporting and Data System terminology. RESULTS: We found 61 masses (49.6%), 8 masses with calcifications (6.5%), 30 groups of calcifications (24.4%), 19 architectural distortions (15.4%), 1 architectural distortion with calcifications (0.8%), 4 asymmetries (3.2%). Sixty out of 69 masses were irregular in shape, 6 lobular, 2 ovals and 1 round. Thirty four showed ill-defined margins, 29 spiculated and 6 microlobulated. Most of them showed a density similar to surrounding fibroglandular tissue. Calcifications were pleomorphic or fine linear in 24 of 30 (80%). Most of cases showed more than 10 flecks and a size greater than 1cm. CONCLUSION: The predominant radiologic finding is an irregular, isodense mass those margins tend to share different descriptors, being ill-defined margins the most constant finding. Calcifications representing invasive cancer are predominantly pleomorphic with more than 10 flecks per cm. Architectural distortion and invasive tubular carcinoma are more common than reported in general series. PMID- 22206832 TI - Identification of receptors and enzymes for endocannabinoids in NSC-34 cells: relevance for in vitro studies with cannabinoids in motor neuron diseases. AB - NSC-34 cells, a hybridoma cell line derived from the fusion of neuroblastoma cells with mice spinal cord cells, have been widely used as an in vitro model for the study of motor neuron diseases [i.e. amyotrophic lateral sclerosis (ALS)]. In the present study, they were used to characterize different elements of the cannabinoid signaling system, which have been reported to serve as targets for the neuroprotective action of different natural and synthetic cannabinoid compounds. Using RT-PCR, Western blotting and immunocytochemistry, we first identified the presence of the cannabinoid CB(1) receptor in these cells. As expected, CB(2) receptor is not expressed in this neuronal cell line, a result that is concordant with the idea that this receptor type is preferentially expressed in glial elements. Diacylglycerol-lipase (DAGL) and N arachidonoylphosphatidylethanolamine-phospholipase D (NAPE-PLD), the enzymes that synthesize endocannabinoids, have also been detected in these cells using RT-PCR, and the same happened with the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol-lipase (MAGL). The presence of the CB(1) receptor in these cells supports the idea that this receptor may play a role in the regulation of cellular survival face to excitotoxic injury. Interestingly, the expression of CB(1) receptor (and also the FAAH enzyme) was strongly up regulated after differentiation of these cells, as previously reported with glutamate receptors. No changes were found for NAPE-PLD, DAGL and MAGL. Assuming that glutamate toxicity is one of the major causes of neuronal damage in ALS and other motor neurons diseases, the differentiated NSC-34 cells might serve as a useful model for studying neuroprotection with cannabinoids in conditions of excitotoxic injury, mitochondrial malfunctioning and oxidative stress. PMID- 22206833 TI - The effects of different phenotype astrocytes on neural stem cells differentiation in co-culture. AB - Astrocytes were reported to show neuroprotective effects on neurons, but there was no direct evidence for a functional relationship between astrocytes and neural stem cells (NSCs). In this experiments, we examined neuronal differentiation of NSCs induced by protoplasmic and fibrous astrocytes in a co culture model respectively. Two types of astrocytes and NSCs were isolated from E13 to 15 cortex of rats. The neuronal differentiation of NSCs was examined after co-culture with two kinds of astrocytes. There were more neuronal marker beta tublin III positive cells from NSCs co-cultured with protoplasmic astrocytes. However the differentiated neurons, whether co-cultured with protoplasmic astrocytes or fibrous astrocytes, both expressed glutamate AMPA receptor subunit GluR2 protein and exhibited biological electrical reactivity after stimulated by glutamine. Therefore, these findings indicated that two types of astrocytes could induce the differentiation of NSCs and also possibly induce functional maturation of differentiated neurons, among which protoplasmic astrocytes have the ability to promote neuronal differentiation of NSCs compared with fibrous astrocytes. PMID- 22206834 TI - Volumetric variation in subregions of the cerebellum correlates with working memory performance. AB - We aimed to investigate the relationship between structural variations in the cerebellum and individual differences in working memory performance as assessed by average reaction time (RT) and correction rate (CR) on a 3-back task. High resolution T1-weighted magnetic resonance images were acquired in 311 healthy young adults. Voxel-based morphometry (VBM) was used to identify cerebellar areas with volumes correlated to working memory performance when controlling for age, gender, years of education and handedness. We found that RT was positively correlated with the grey matter volume (GMV) bilaterally in cerebellar lobules IV/V, VI and VIII, in vermis VII/VIII and in left Crus I; CR was positively correlated with the GMV in the left lobule VI and Crus I. These findings suggest that RT on a working memory task is related to structural variation in both motor and cognitive subregions of the cerebellum, while CR is mainly associated with the cognitive subregions. Our findings provide further evidence that the cerebellum contributes to working memory function. PMID- 22206835 TI - Cocaine-taking and cocaine-seeking behaviors in rats remain stable after systemic administration of GYKI 52466: a non-competitive AMPA receptor antagonist. AB - Given the posited role of enhanced AMPA-mediated synaptic transmission in relapse to drug seeking, we investigated whether systemic administration of the AMPA receptor antagonist GYKI 52466 inhibits cocaine-taking and cocaine-seeking behavior in rats. Rats were trained to self-administer cocaine until stable self administration was achieved. Effects of GYKI 52466 (1, 3, or 10mg/kg, i.v.) on cocaine self-administration were assessed. Animals were allowed to re-establish stable cocaine self-administration and were then behaviorally extinguished from drug taking. The effects of GYKI 52466 (3, 10mg/kg, i.v.) on cocaine-induced reinstatement of drug-seeking behavior were assessed. We found that GYKI 52466 failed to inhibit cocaine-taking and cocaine-seeking in both the self administration and reinstatement paradigms. We suggest that although AMPA receptors may be involved in cocaine reward and addiction, the AMPA receptor antagonist GYKI 52466 has low therapeutic potential for cocaine addiction treatment. PMID- 22206836 TI - The human execution/observation matching system investigated with a complex everyday task: a functional near-infrared spectroscopy (fNIRS) study. AB - The investigation of brain areas involved in the human execution/observation matching system (EOM) has been limited to restricted motor actions when using common neuroimaging techniques such as functional magnetic resonance imaging (fMRI). A method which overcomes this limitation is functional near-infrared spectroscopy (fNIRS). In the present study, we explored the cerebral responses underlying action execution and observation during a complex everyday task. We measured brain activation of 39 participants during the performance of object related reaching, grasping and displacing movements, namely setting and clearing a table, and observation of the same task from different perspectives. Observation of the table-setting task activated parts of a network matching those activated during execution of the task. Specifically, observation from an egocentric perspective led to a higher activation in the inferior parietal cortex than observation from an allocentric perspective, implicating that the viewpoint also influences the EOM during the observation of complex everyday tasks. Together these findings suggest that fNIRS is able to overcome the restrictions of common imaging methods by investigating the EOM with a naturalistic task. PMID- 22206837 TI - Effects of hindlimb unloading on neurogenesis in the hippocampus of newly weaned rats. AB - Effects of hindlimb suspension (HS) and ambulation recovery on hippocampal neurogenesis of newly weaned rats were studied by using immunohistochemical techniques. The number of proliferating cell nuclear antigen-positive (PCNA(+)) cells in the subgranular zone (SGZ) markedly decreased during normal growth. However, neither HS nor subsequent recovery caused additional changes in the number of PCNA(+) cells. The number of doublecortin-positive (DCX(+)) neurons decreased gradually during normal growth. HS resulted in a further decrease in these neurons. However, DCX(+) cell numbers became identical to the levels in age matched controls after 14 days of recovery. PCNA and DCX-double positive cells in the SGZ were also observed, and their cell numbers were not affected by HS and 14 day ambulation. Thus, HS suppressed the generation of DCX(+) neurons without affecting PCNA(+) cells in the SGZ of weaned rats. Taken together, hippocampal neurogenesis in weaned rats was not severely affected by HS while it decreased significantly as they had grown. PMID- 22206838 TI - Effects of l-dopa methyl ester on visual cortex injury induced by amblyopia and its underlying mechanism. AB - Amblyopia is related to the impairment of visual system, especially visual cortex. l-Dopa has been reported to treat the disease, but the effect of its derived methyl ester has not been investigated. Therefore this study assessed the anatomic and physiologic effects of 30 days' treatment of l-dopa methyl ester at different doses on visual cortex area 17 in feline model with amblyopia induced by monocular vision deprivation. Immunohistochemical staining and Western blot were used to examine the structural changes of nerve cells and the expression of nerve growth factor (NGF), respectively. Comparing to the control, l-dopa methyl ester intervention significantly increased the number and density of NGF immunoreactive cells, elevated endogenous NGF expression in visual cortex and promoted neural regeneration. The results suggest that l-dopa methyl ester can effectively inhibit amblyopia process via a mechanism that may involve increasing endogenous NGF expression and promoting neural repairment in visual cortex area 17. PMID- 22206839 TI - Macrophage migration inhibitory factor reduces apoptosis in cerebral arteriovenous malformations. AB - PURPOSE: To investigate the expression of macrophage migration inhibitory factor (MIF) in human brain arteriovenous malformations (AVM). MATERIALS AND METHODS: Twelve AVM specimens were obtained from patients who did not received preoperative embolization. MIF levels were measured by Western blot and matrix metalloproteinase 9 (MMP9) levels were measured by reverse transcription PCR. The expression of MIF in brain AVMs was also evaluated by immunohistochemistry and was correlated with apoptosis and the expression of cleaved caspase-3 and MMP9. RESULTS: The expression of MIF, MMP9, and cleaved caspase-3 was elevated in brain AVM vessels. High levels of MIF were primarily found in the endothelium and adventitia, whereas apoptotic cells were concentrated in the smooth muscle layer. CONCLUSIONS: Abnormal apoptosis may be involved in the pathogenesis of brain AVM. In addition, increased MIF expression could play an important role regulating the homeostasis of AVM vessels. PMID- 22206840 TI - Soft-food diet induces oxidative stress in the rat brain. AB - Decreased dopamine (DA) release in the hippocampus may be caused by dysfunctional mastication, although the mechanisms involved remain unclear. The present study examined the effects of soft- and hard-food diets on oxidative stress in the brain, and the relationship between these effects and hippocampal DA levels. The present study showed that DA release in the hippocampus was decreased in rats fed a soft-food diet. Electron spin resonance studies using the nitroxyl spin probe 3 methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl directly demonstrated a high level of oxidative stress in the rat brain due to soft-food diet feeding. In addition, we confirmed that DA directly react with reactive oxygen species such as hydroxyl radical and superoxide. These observations suggest that soft-food diet feeding enhances oxidative stress, which leads to oxidation and a decrease in the release of DA in the hippocampus of rats. PMID- 22206841 TI - Does conscious intention to perform a motor act depend on slow prefrontal (de)oxyhemoglobin oscillations in the resting brain? AB - Characteristically within the resting brain there are slow fluctuations (around 0.1Hz) of EEG and NIRS-(de)oxyhemoglobin ([deoxy-Hb], [oxy-Hb]) signals. An interesting question is whether such slow oscillations can be related to the intention to perform a motor act. To obtain an answer we analyzed continuous blood pressure (BP), heart rate (HR), prefrontal [oxy-Hb], [deoxy-Hb] and EEG signals over sensorimotor areas in 10 healthy subjects during 5min of rest and during 10min of voluntary finger movements. Analyses of prefrontal [oxy Hb]/[deoxy-Hb] oscillations around 0.1Hz and central EEG band power changes in the beta (alpha) band revealed that the positive [oxy-Hb] peaks preceded the central EEG beta (alpha) power peak by 3.6+/-0.9s in the majority of subjects. A similar relationship between prefrontal [oxy-Hb] and central EEG beta power was found during voluntary movements whereby the post movement beta power increase (beta rebound) is known to coexist with a decreased excitability of cortico spinal neurons. Therefore, we speculate that the beta power increase ~3s after slow fluctuating [oxy-Hb] peaks during rest is indicative for a slow excitability change of central motor cortex neurons. This work provides the first evidence that initiation of finger movements at free will in relatively constant intervals around 10s could be temporally related to slow oscillations of prefrontal [oxy Hb] and autonomic blood pressure in the resting brain. PMID- 22206842 TI - Mild dopaminergic lesions are accompanied by robust changes in subthalamic nucleus activity. AB - The subthalamic nucleus (STN) is a major player in the input and output of the basal ganglia motor circuitry. The neuronal regular firing pattern of the STN changes into a pathological bursting mode in both advanced Parkinson's disease (PD) and in PD animals models with severe dopamine depletion. One of the current hypothesis, based on clinical and experimental evidence, is that this typical burst activity is responsible for some of the principal motor symptoms. In the current study we tested whether mild DA depletion, mimicking early stages of PD, induced deficits in motor behaviour and changes in STN neuronal activity. The present study demonstrated that rats with a mild lesion (20-40% loss of DA neurons) and a slowed motor response, but without gross motor abnormalities already have an increased number of bursty STN neurons under urethane anaesthesia. These findings indicate that the early increase in STN burst activity is a compensatory mechanism to maintain the dopamine homeostasis in the basal ganglia. PMID- 22206843 TI - Improving emotional prosody detection in the attending ear by cathodal tDCS suppression of the competing channel. AB - Currently it is assumed that cathodal stimulation (in transcranial direct current stimulation, tDCS) degrades the neural firing rate, and thus it is believed to degrade cognitive performance. Here we challenge this assumption by predicting that under high competition the cathodal stimulation might act as a noise filter, leading to an improved performance. We presented auditory targets with different emotional valence using a dichotic listening paradigm. We found that cathodal, but not anodal stimulation of the right IFG generated better prosody comprehension. Cathodal stimulation in competitive situations, such as the dichotic listening paradigm, can act like a noise filter, and may in fact enhance cognitive performance. This study contributes to understanding the way the IFG is engaged with prosody functions, and explains the cathodal effects of tDCS. This might lead to the development of more efficient brain stimulation protocols. PMID- 22206844 TI - Emotional valence modulates putative mirror neuron activity. AB - Mirror neurons are thought to facilitate emotion processing, but it is unclear whether the valence of an emotional presentation (positive or negative) can influence subsequent mirror neuron activity. Participants completed a transcranial magnetic stimulation experiment that involved stimulation of the primary motor cortex, and electromyography recording from contralateral hand muscles. This was performed while participants viewed videos of either a static hand or a transitive hand action preceded by either a positive or negative stimulus. Corticospinal excitability facilitation during action observation was significantly greater following the presentation of negative (relative to positive) stimuli; this was evident for the first dorsal interosseous muscle (which was central to the observed grasp), but not for the abductor digiti minimi muscle. This study provides evidence that emotional valence can modulate mirror neuron activity, which may reflect an adaptive mechanism. PMID- 22206845 TI - A new neuronal target for beta-amyloid peptide in the rat hippocampus. AB - In Alzheimer's disease, amyloid beta peptide (Abeta) accumulation is associated with hippocampal network dysfunction. Intrahippocampal injections of Abeta induce aberrant inhibitory septohippocampal (SH) network activity in vivo and impairment of memory processing. In the present study, we observed, after hippocampal Abeta treatment, a selective loss of neurons projecting to the medial septum (MS) and containing calbindin (CB) and/or somatostatin (SOM). Other GABAergic neuronal subpopulations were not altered. Thus, the present study identifies hippocamposeptal neuron populations as specific targets for Abeta deposits. We observed that in Abeta-treated rats but not in controls, glutamate agonist application induced rhythmic bursting in 55% of the slow-firing neurons in the medial septum. This suggests that hippocampal Abeta can trigger modifications of the septohippocampal pathway via the alteration of a specific neuronal population. Long-range hippocamposeptal GABA/calbindin neurons, targets of hippocampal amyloid deposits, are implicated in supporting network synchronization. By identifying this target, we contribute to the understanding of the mechanisms underlying deleterious effects of Abeta, one of the main agents of dementia in Alzheimer's disease. PMID- 22206846 TI - Calpastatin modulates APP processing in the brains of beta-amyloid depositing but not wild-type mice. AB - We report that neuronal overexpression of the endogenous inhibitor of calpains, calpastatin (CAST), in a mouse model of human Alzheimer's disease (AD) beta amyloidosis, the APP23 mouse, reduces beta-amyloid (Abeta) pathology and Abeta levels when comparing aged, double transgenic (tg) APP23/CAST with APP23 mice. Concurrent with Abeta plaque deposition, aged APP23/CAST mice show a decrease in the steady-state brain levels of the amyloid precursor protein (APP) and APP C terminal fragments (CTFs) when compared with APP23 mice. This CAST-dependent decrease in APP metabolite levels was not observed in single tg CAST mice expressing endogenous APP or in younger, Abeta plaque predepositing APP23/CAST mice. We also determined that the CAST-mediated inhibition of calpain activity in the brain is greater in the CAST mice with Abeta pathology than in non-APP tg mice, as demonstrated by a decrease in calpain-mediated cytoskeleton protein cleavage. Moreover, aged APP23/CAST mice have reduced extracellular signal regulated kinase 1/2 (ERK1/2) activity and tau phosphorylation when compared with APP23 mice. In summary, in vivo calpain inhibition mediated by CAST transgene expression reduces Abeta pathology in APP23 mice, with our findings further suggesting that APP metabolism is modified by CAST overexpression as the mice develop Abeta pathology. Our results indicate that the calpain system in neurons is more responsive to CAST inhibition under conditions of Abeta pathology, suggesting that in the disease state neurons may be more sensitive to the therapeutic use of calpain inhibitors. PMID- 22206848 TI - Age- and genotype-related neurophysiologic reactivity to oxidative stress in healthy adults. AB - The epsilon4 allele of the apolipoprotein E gene (ApoE), as well as aging increase the risk of Alzheimer's and vascular diseases. Electroencephalogram (EEG) reactivity to hyperventilation (HV) depends on hypocapnia-induced cerebral vasoconstriction, which may be impaired in subjects with subclinical cerebrovascular disease. Quantitative EEG at rest and under 3-minute HV was examined in 125 healthy subjects divided into younger (age range 28-50) and older (age range 51-82) cohorts and stratified by ApoE genotype. The younger ApoE epsilon4 carriers had excessive EEG reactivity to HV characterized by the manifestation of high-voltage delta, theta activity and sharp waves, and larger HV-induced changes in EEG relative powers than in the younger ApoE-epsilon4 noncarriers. EEG reactivity to HV decreased with aging, and in the ApoE-epsilon4 carriers the decrease was more pronounced than in the ApoE-epsilon4 noncarriers. The older ApoE-epsilon4 carriers had smaller HV-induced changes in EEG relative powers than the older ApoE-epsilon4 noncarriers. A marked decline of EEG reactivity to HV in the older ApoE-epsilon4 carriers suggests the possible impact of vascular factors on the pathogenesis of ApoE-induced Alzheimer disease. PMID- 22206847 TI - Synaptic protein deficits are associated with dementia irrespective of extreme old age. AB - Recent evidence shows that despite high incidence of dementia in the very old, they exhibit significantly lower levels of Alzheimer's disease (AD) neuropathology relative to younger persons with dementia. The levels and distributions of some synaptic proteins have been found to be associated with dementia severity, even in the oldest-old, but the molecular and functional nature of these deficits have not been studied in detail. The objective of this study was to assess the relationship of dementia with gene and protein expression of a panel of synaptic markers associated with different synaptic functions in young-, middle-, and oldest-old individuals. The protein and messenger RNA (mRNA) levels of 7 synaptic markers (complexin-1, complexin-2, synaptophysin, synaptobrevin, syntaxin, synaptosomal-associated protein 25 (SNAP-25), and septin 5) were compared in the brains of nondemented and demented individuals ranging from 70 to 103 years of age. One hundred eleven brains were selected to have either no significant neuropathology or only AD-associated pathology (neuritic plaques [NPs] and neurofibrillary tangles [NFTs]). The cohort was then stratified into tertiles as young-old (70-81 years old), middle-old (82-88), and oldest-old (89-103). The brains of persons with dementia evidenced significantly lower levels of gene and protein expression of synaptic markers regardless of age. Importantly, dementia was associated with reductions in all measured synaptic markers irrespective of their role(s) in synaptic function. Although other dementia-associated hallmarks of AD neuropathology (neuritic plaques and neurofibrillary tangles) become less prominent with increasing age, synaptic marker abnormalities in dementia remain constant with increasing age and may represent an independent substrate of dementia spanning all ages. PMID- 22206849 TI - Auto-antibodies in autoimmune hepatitis: anti-smooth muscle antibodies (ASMA). PMID- 22206850 TI - Nodule within nodule. PMID- 22206851 TI - A HCO3-umbrella protects human cholangiocytes against bile salt-induced injury. PMID- 22206852 TI - Effects of vitamin D deficiency in critically ill surgical patients. AB - BACKGROUND: The incidence of vitamin D deficiency in critically ill patients is reported to be up to 50%, with a 3-fold increase in predicted mortality, but limited data exist concerning vitamin D deficiency in critically ill surgical patients. METHODS: Sixty-six adult surgical intensive care unit patients who had 25-hydroxyvitamin D serum levels evaluated from January 2010 to February 2011 were prospectively identified. Patients were divided into groups according to vitamin D level (<20 vs >=20 ng/mL). RESULTS: Of the 66 patients evaluated, 49 (74%) had vitamin D levels < 20 ng/mL, and 17 (26%) had vitamin D levels >= 20 ng/mL. Patients with vitamin D levels < 20 versus >= 20 ng/mL had longer lengths of hospital stay. Lengths of intensive care unit stay were clinically longer, although not significant. Infection rates tended to be higher (P = .09), and a higher incidence of sepsis was seen in the patients with vitamin D levels < 20 ng/mL. CONCLUSIONS: Vitamin D levels < 20 ng/mL have a significant impact on length of stay, organ dysfunction, and infection rates. More data are needed on the value of supplementation to improve these outcomes. PMID- 22206854 TI - Control charts to identify adverse outcomes in elective colon resection. AB - BACKGROUND: Control charts have been proposed for the measurement of quality in surgical care. METHODS: For each of 181 study hospitals in the 2005 National Inpatient Sample of the Healthcare Cost and Utilization Project database, an average moving range control chart for risk-adjusted postoperative length of stay (RApoLOS) was created for patients discharged alive after elective colectomy. RApoLOS outliers using upper control limits of 2.0sigma, 2.5sigma, and 3.0sigma were correlated to coded complications (CCs). Hospital costs were correlated to RApoLOS outliers and CCs. RESULTS: Of 13,118 live discharges, 902 (6.9%) were outliers using a 3.0sigma upper control limit, 1,350 (10.3%) were 2.5sigma outliers, and 2,053 (15.7%) were 2.0sigma outliers. CCs were identified in 92.7% of 3.0sigma outliers, in 81.3% of 2.5sigma outliers, and 70.6% of 2.0sigma outliers. Increased costs were associated with RApoLOS outliers and poorly with CCs. CONCLUSIONS: Average moving range control charts for RApoLOS outliers are valid tools for measurement of surgical quality and costs. PMID- 22206853 TI - Surgery via natural orifices in human beings: yesterday, today, tomorrow. AB - BACKGROUND: We performed an evaluation of models, techniques, and applicability to the clinical setting of natural orifice surgery (mainly natural orifice transluminal endoscopic surgery [NOTES]) primarily in general surgery procedures. NOTES has attracted much attention recently for its potential to establish a completely alternative approach to the traditional surgical procedures performed entirely through a natural orifice. Beyond the potentially scar-free surgery and abolishment of dermal incision-related complications, the safety and efficacy of this new surgical technology must be evaluated. METHODS: Studies were identified by searching MEDLINE, EMBASE, Cochrane Library, and Entrez PubMed from 2007 to February 2011. Most of the references were identified from 2009 to 2010. There were limitations as far as the population that was evaluated (only human beings, no cadavers or animals) was concerned, but there were no limitations concerning the level of evidence of the studies that were evaluated. RESULTS: The studies that were deemed applicable for our review were published mainly from 2007 to 2010 (see Methods section). All the evaluated studies were conducted only in human beings. We studied the most common referred in the literature orifices such as vaginal, oral, gastric, esophageal, anal, or urethral. The optimal access route and method could not be established because of the different nature of each procedure. We mainly studied procedures in the field of general surgery such as cholecystectomy, intestinal cancers, renal cancers, appendectomy, mediastinoscopy, and peritoneoscopy. All procedures were feasible and most of them had an uneventful postoperative course. A number of technical problems were encountered, especially as far as pure NOTES procedures are concerned, which makes the need of developing new endoscopic instruments, to facilitate each approach, undeniable. CONCLUSIONS: NOTES is still in the early stages of development and more robust technologies will be needed to achieve reliable closure and overcome technical challenges. Well-designed studies in human beings need to be conducted to determine the safety and efficacy of NOTES in a clinical setting. Among these NOTES approaches, the transvaginal route seems less complicated because it virtually eliminates concerns for leakage and fistulas. The transvaginal approach further favors upper-abdominal surgeries because it provides better maneuverability to upper-abdominal organs (eg, liver, gallbladder, spleen, abdominal esophagus, and stomach). The stomach is considered one of the most promising targets because this large organ, once adequately mobilized, can be transected easily with a stapler. The majority of the approaches seem to be feasible even with the equipment used nowadays, but to achieve better results and wider applications to human beings, the need to develop new endoscopic instruments to facilitate each approach is necessary. PMID- 22206856 TI - Laparoendoscopic single-site gastric bands versus standard multiport gastric bands: a comparison of technical learning curve measured by surgical time. AB - BACKGROUND: We aimed to evaluate our learning curve comparing surgical time of laparoendoscopic single-site (LESS) banding with multiport laparoscopy. METHODS: We performed a retrospective analysis of prospectively collected data comparing our first 48 LESS bands with our first 50 multiport laparoscopic bands at our institution. We then compared the first 24 LESS bands with the last 24 bands. RESULTS: The average body mass index for the LESS group was significantly lower than for the laparoscopic group (43.19 vs 48.3; P < .0001). The surgical time was much faster toward the second half of our experience performing the LESS procedure (85.34 vs 68.8; P = .0055). LESS banding took significantly longer than our early traditional laparoscopic adjustable gastric banding (76.85 vs 64.4; P = .0015). CONCLUSIONS: We conclude that in experienced hands, single-incision banding is feasible and safe to perform. Long-term data are needed to prove that LESS banding is as good a surgery as traditional laparoscopic surgery. PMID- 22206855 TI - Receptor changes in metachronous breast tumors--our experience of 10 years. AB - INTRODUCTION: Patients with primary breast cancer (PBC) are at 2 to 6 times higher risk for developing synchronous and metachronous breast cancer (MBC). The pathology and behavior of MBC still remains unclear. METHODS: We reviewed the charts of 108 women with MBC at our hospital over the past 10 years. Profile patterns of the estrogen receptor (ER), the progesterone receptor (PR), and Her2/neu receptors were explored. RESULTS: Of 33 patients with ER(+)/PR(+) in the primary tumor, 23 (70%) retained the status in MBC. Forty-five (92%) of 49 patients with ER(-)/PR(-) in the primary tumor remained the same in MBC. Most Her2(-) tumors (22/31, 71%) remained negative, but 50% (8/16) of Her2(+) tumors became negative. CONCLUSIONS: Most MBC retained the ER/PR expression patterns irrespective of the treatment for the primary tumor, thus suggesting a common origin. Because MBCs tend to be triple negative and thus more aggressive, early detection and close surveillance techniques must be devised. PMID- 22206857 TI - Outcome prediction by amplitude-integrated EEG in adults with hypoxic ischemic encephalopathy. AB - INTRODUCTION: Amplitude-integrated electroencephalography (aEEG) had been widely used in predicting outcome in infants with hypoxic ischemic encephalopathy (HIE). We aimed to evaluate the use of aEEG as a quantitative predictor of outcome in adult patients with HIE. METHODS: aEEG and Glasgow coma scale (GCS) were recorded for patients with HIE within 72 h of onset. aEEG traces were categorized as Grade I (normal amplitude): upper margin of aEEG activity >10 MUV, lower margin >5 MUV; Grade II (moderately abnormal amplitude): upper margin of aEEG activity >10 MUV, lower margin <=5 MUV, or with suppressed amplitude, upper margin <=10 MUV, lower margin >5MUV; Grade III (mild abnormality): either upper margin <10 MUV, lower margin <5 MUV. GCS was graded as I (9-14), grade II (4-8), or grade III (3). Cerebral performance category scores (CPCs) were determined 1 and 3 month after clinical evolution. CPC 1,2 were defined as favorable outcome; CPC 3,4,5 were considered as poor outcome. RESULTS: 30 cases met inclusion criteria. Both the aEEG grade and GCS scores correlated significantly with short-term outcome, and cases with a worse aEEG grade were more likely to have an unfavorable short-term outcome. Since the number of patients is really too small for long-term outcome analysis, we did not perform the analysis of aEEG, GCS and longer-term outcome. There was significant difference of clinical findings among aEEG classifications, while no statistical difference was found of causes of HIE. CONCLUSIONS: aEEG is a reliable predictor of short-term outcome in HIE, and aEEG results within 72h after onset were associated with neurodevelopmental outcome at 1 mo following clinical evolution. PMID- 22206858 TI - Spinal epidural abscess in adults caused by Staphylococcus aureus: clinical characteristics and prognostic factors. AB - OBJECTIVE: Spinal epidural abscess (SEA) is a devastating infectious disease, which may result in neurologic sequelae. Staphylococcus (S.) aureus is a common pathogen of SEA. Here, we analyzed the clinical characteristics and laboratory data of adult patients with S. aureus SEA and compared the clinical characteristics of methicillin-sensitive S. aureus (MSSA) and methicillin resistant S. aureus (MRSA) infections. METHODS: Between 2003 and 2008, we collected data regarding 29 adult cases of S. aureus SEA and analyzed the clinical presentations, magnetic resonance (MR) imaging features, therapeutic outcome, and prognostic factors. Antibiotic susceptibility test results of 11 implicated MRSA strains were also further analyzed. RESULTS: We identified 17 MSSA strains and 12 MRSA strains. Lumbar and lumbosacral spine segments were the most commonly involved segments. All 29 patients had back pain. Other findings included sensory abnormalities (25), motor weakness (21), fever (16), bladder dysfunction (16), and altered consciousness (3). Disease onset at admission was acute in 6 cases and chronic in 23. The stages of disease severity were early stage in 9 and late stage in 20. After therapy, 21 patients had a good prognosis and 8 had a poor prognosis. Significant prognostic factors included older age (>70years), presence of diabetes mellitus, adrenal insufficiency, and MRSA infection. The prognosis alone was clinically different between patients with MSSA and MRSA infections. CONCLUSIONS: Patients with localized back pain, particularly those with a fever and compromised immune system, should undergo MR imaging to ensure an early diagnosis and management. PMID- 22206859 TI - Correlational study of the serum levels of the glial fibrillary acidic protein and neurofilament proteins in Parkinson's disease patients. AB - OBJECTIVE: To investigate changes in the serum levels of the glial fibrillary acidic protein (GFAP) and neurofilament proteins (NFs) in patients with Parkinson's disease (PD) and to determine their clinical significance. METHODS: In this study, 82 subjects were divided into 3 groups: the PD group, the acute cerebral infarction (ACI) group, and a normal control group. The serum levels of GFAP and NFs were measured using a sandwich ELISA assay. RESULTS: The serum levels of GFAP and NFs were significantly higher in the PD and the ACI groups than in the normal control group (P<0.05). There was no significant difference between the PD group and the ACI group (P>0.05). The serum level of GFAP in the PD group had no significant correlation with duration of the disease or age (P>0.05). The serum level of NFs in the PD group was significantly correlated with duration of the disease and age (P<0.05). CONCLUSIONS: The serum levels of GFAP and NFs were significantly higher in the PD group than in the normal group, indicating that astrocytic activity may remain elevated during the axonal degeneration that occurs over duration of the disease, although this activity is not specific to the disease. PMID- 22206860 TI - Group B Streptococcus surface proteins as major determinants for meningeal tropism. AB - Streptococcus agalactiae (group B Streptococcus, GBS), a normal constituent of the intestinal microbiota is the major cause of human neonatal infections and a worldwide spread 'hypervirulent' clone, GBS ST-17, is strongly associated with neonatal meningitis. Adhesion to epithelial and endothelial cells constitutes a key step of the infectious process. Therefore GBS surface-anchored proteins are obvious potential adhesion mediators of barrier crossing and determinant of hypervirulence. This review addresses the most recent molecular insights gained from studies on GBS surface proteins proven to be involved in the crossing of the brain-blood barrier and emphasizes on the specificity of a hypervirulent clone that displays meningeal tropism. PMID- 22206862 TI - Survival from childhood acute lymphoblastic leukaemia: the impact of social inequality in the United Kingdom. AB - BACKGROUND: Survival from childhood acute lymphoblastic leukaemia (ALL) has continued to improve in economically-developed regions of the world, but 20% of patients still die within 5-years of diagnosis. Treatment is prolonged and complex; and as survival rates plateau, factors relating to socio-economic status and/or treatment adherence are increasingly scrutinised as potentially important determinants of outcome. METHODS: Predicated on the frame-work of the United Kingdom (UK) NHS, the relationship between socio-demographic factors and ALL survival is examined here using data from a large follow-up study conducted in the 1990s. One thousand five hundred and fifty nine children (0-14 years) diagnosed in England, Scotland &Wales during the era of the national UKALL XI randomized-controlled trial (RCT) were followed-up for an average of 15.9 years (20,826.3 person-years). Area-based deprivation scores and father's occupational social class at the time of the child's birth were used as markers of socio economic status. Information on deaths was obtained from the NHS Information Centre for Health and Social Care. All children were included in the analyses, irrespective of RCT enrolment or participation in the founding epidemiological study (www.UKCCS.org).Survival effects were assessed using proportional hazards regressions models. RESULTS: Survival varied with both area-based deprivation at diagnosis (hazard ratio (HR) 1.29; 95% confidence interval (CI) 1.05-1.57) and fathers occupational social class at birth (HR 1.12; 95% CI 0.97-1.29); the divergence beginning 6-9 months after diagnosis, and widening thereafter during home-administered therapy. The findings became more marked when analyses were restricted to those enrolled in UKALL XI (n = 1341). As expected, survival differences were also observed with sex, and age at diagnosis. CONCLUSION: The existence of significant social disparities in ALL survival, which are not due to treatment accessibility, is of major clinical importance. Trends should be monitored and further research into potentially modifiable risk factors conducted. PMID- 22206861 TI - The role of upregulated miRNAs and the identification of novel mRNA targets in prostatospheres. AB - TICs are characterized by their ability to self-renew, differentiate and initiate tumor formation. miRNAs are small noncoding RNAs that bind to mRNAs resulting in regulation of gene expression and biological functions. The role of miRNAs and TICs in cancer progression led us to hypothesize that miRNAs may regulate genes involved in TIC maintenance. Using whole genome miRNA and mRNA expression profiling of TICs from primary prostate cancer cells, we identified a set of up regulated miRNAs and a set of genes down-regulated in PSs. Inhibition of these miRNAs results in a decrease of prostatosphere formation and an increase in target gene expression. This study uses genome-wide miRNA profiling to analyze expression in TICs. We connect aberrant miRNA expression and deregulated gene expression in TICs. These findings can contribute to a better understanding of the molecular mechanisms governing TIC development/maintenance and the role that miRNAs have in the fundamental biology of TICs. PMID- 22206863 TI - Role of EBNA1 in NPC tumourigenesis. AB - EBNA1 is expressed in all NPC tumours and is the only Epstein-Barr virus protein needed for the stable persistence of EBV episomes. EBNA1 binds to specific sequences in the EBV genome to facilitate the initiation of DNA synthesis, ensure the even distribution of the viral episomes to daughter cells during mitosis and to activate the transcription of other viral latency genes important for cell immortalization. In addition, EBNA1 has been found to alter cellular pathways in multiple ways that likely contribute to cell immortalization and malignant transformation. This chapter discusses the known functions and cellular effects of EBNA1, especially as pertains to NPC. PMID- 22206864 TI - ARDEN2BYTECODE: a one-pass Arden Syntax compiler for service-oriented decision support systems based on the OSGi platform. AB - Patient empowerment might be one key to reduce the pressure on health care systems challenged by the expected demographic changes. Knowledge based systems can, in combination with automated sensor measurements, improve the patients' ability to review their state of health and make informed decisions. The Arden Syntax as a standardized language to represent medical knowledge can be used to express the corresponding decision rules. In this paper we introduce ARDEN2BYTECODE, a newly developed open source compiler for the Arden Syntax. ARDEN2BYTECODE runs on Java Virtual Machines (JVM) and translates Arden Syntax directly to Java Bytecode (JBC) executable on JVMs. ARDEN2BYTECODE easily integrates into service oriented architectures, like the Open Services Gateway Initiative (OSGi) platform. Apart from an evaluation of compilation performance and execution times, ARDEN2BYTECODE was integrated into an existing knowledge supported exercise training system and recorded training sessions have been used to check the implementation. PMID- 22206865 TI - Kruppel-like factor 4 regulates membranous and endochondral ossification. AB - Kruppel-like factor 4 (KLF4/GKLF/EZF) is a zinc finger type of transcription factor highly expressed in the skin, intestine, testis, lung and bone. The role played by Klf4 has been studied extensively in normal epithelial development and maintenance; however, its role in bone cells is unknown. Previous reports showed that Klf4 is expressed in the developing flat bones but its expression diminishes postnatally. We now show that in the developing long bones, Klf4 is expressed in the perichondrium, trabecular osteoblasts and prehypertrophic chondrocytes. In contrast, osteoblasts lining at the surface of the bone collar showed extremely low levels of Klf4 expression. To investigate the possible roles played by Klf4 during skeletal development, we generated transgenic mice expressing Klf4 under mouse type I collagen regulatory sequence. Transgenic mice exhibited severe skeletal deformities and died soon after birth. Transgenic mice showed delayed formation of the calvarial bones; and over-expressing Klf4 in primary mouse calvarial osteoblasts in culture resulted in strong repression of mineralization indicating that this regulation of Klf4 is through an osteoblast-autonomous effect. Surprisingly, long bones of the transgenic mice exhibited delayed marrow cavity formation. Even at E18.5, the presumptive marrow space was occupied by cartilage anlage and invasion of the vascular endothelial cells and osteoclasts were seldom observed. Instead of entering the cartilage anlage, osteoclasts accumulated at the periosteum in the transgenic mice. Significantly, osteocalcin, which is known to chemotact osteoclasts, was up-regulated at the perichindrium as early as E14.5 in the mutants. In vitro studies showed that this induction of osteocalcin by Klf4 was regulated at its transcriptional level. Our results demonstrate that Klf4 regulates normal skeletal development through coordinating the differentiation and migration of osteoblasts, chondrocytes, vascular endothelial cells and osteoclasts. PMID- 22206866 TI - Spontaneous transformation of cynomolgus mesenchymal stem cells in vitro: further confirmation by short tandem repeat analysis. AB - It remains a highly debatable issue whether mesenchymal stem cells (MSCs) can undergo spontaneous transformation in culture. Recently, two groups retracted their previous publications due to the finding that the claimed transformed cells are actually contaminating cancer cells, which calls for a more stringent identification of transformed cells in the field. In this study, we continued with our previous finding of spontaneous transformation of cynomolgus MSCs and provided further evidence using short tandem repeat analysis that the transformed mesenchymal stem cells were indeed derived from cynomolgus MSCs. PMID- 22206867 TI - Molecular cloning and characterization of Toll-like receptor 3 in Japanese flounder, Paralichthys olivaceus. AB - Mammalian Toll-like receptor 3 (TLR3) recognizes extracellular and intracellular viral dsRNA, and then initiates signaling cascades leading to NF-kappaB activation and interferon (IFN) production. To understand the roles of TLR3 in the fish immune system, TLR3 gene (JfTLR3) was identified from Japanese flounder (Paralichthys olivaceus), which consisted of 4 exons and 3 introns. Its expression in peripheral blood leukocytes increased upon stimulation with poly I:C and CpG ODN 1668. Exposure to viral hemorrhagic septicemia virus increased expression of JfTLR3 in the blood, liver, head kidney and spleen. Intracellular poly I:C stimulation in JfTLR3-overexpressing YO-K cells significantly induced IFN-inducible and NF-kappaB-regulated genes. NF-kappaB activity in JfTLR3 overexpressing YO-K cells was significantly induced by intracellular poly I:C while expression of IFN-inducible genes and NF-kappaB reporter activity in JfTLR3 overexpressing HINAE cells increased upon stimulation by extracellular poly I:C. These results suggest that JfTLR3 plays an important role in the induction of antiviral immune response. PMID- 22206869 TI - Semisynthetic neoboutomellerone derivatives as ubiquitin-proteasome pathway inhibitors. AB - The interesting pharmacological properties of neoboutomellerones 1 and 2 were the basis for the assembly of a small library of analogues consisting of natural products isolated from the plant Neoboutonia melleri and of semisynthetic derivatives. As the two enone systems (C23-C24a and C1-C3) and the two hydroxyls groups (C22 and C26) of neoboutomellerones are required for activity, modifications were focused on these functional groups. Biological evaluation by using a cellular assay for proteasome activity provided clues regarding the mechanism of action of these natural products and synthetic derivatives. Certain neoboutomellerone derivatives inhibited the proliferation of human WM-266-4 melanoma tumor cells at submicromolar concentration and warrant evaluation as anticancer agents. PMID- 22206868 TI - A two-dimensional ERK-AKT signaling code for an NGF-triggered cell-fate decision. AB - Growth factors activate Ras, PI3K, and other signaling pathways. It is not well understood how these signals are translated by individual cells into a decision to proliferate or differentiate. Here, using single-cell image analysis of nerve growth factor (NGF)-stimulated PC12 cells, we identified a two-dimensional phospho-ERK (pERK)-phospho-AKT (pAKT) response map with a curved boundary that separates differentiating from proliferating cells. The boundary position remained invariant when different stimuli were used or upstream signaling components perturbed. We further identified Rasa2 as a negative feedback regulator that links PI3K to Ras, placing the stochastically distributed pERK pAKT signals close to the decision boundary. This allows for uniform NGF stimuli to create a subpopulation of cells that differentiates with each cycle of proliferation. Thus, by linking a complex signaling system to a simpler intermediate response map, cells gain unique integration and control capabilities to balance cell number expansion with differentiation. PMID- 22206870 TI - Switchable MRI contrast agents based on morphological changes of pH-responsive polymers. AB - Magnetic resonance imaging (MRI) contrast agents are effective tools in both medical diagnosis and life science research. Various smart contrast agents have been developed for the visualization of biological phenomena. These contrast agents have molecular switches that increase or reduce MRI signal intensity in response to the target biological reaction. Therefore, novel approaches to the design of molecular switches for versatile in vivo studies using MRI are eagerly anticipated. Here, we report one such approach for the development of molecular switches based on morphological changes of pH-responsive polymers. We designed and synthesized three types of contrast agents based on a linear homopolymer or spherical copolymers with two different cross-linking degrees. The relaxivity measurements showed that these agents have molecular switches that respond to pH changes, and fluorescence studies indicated that these switches are based on the alteration of the molecular tumbling caused by pH-responsive morphological changes. As a result, the spherical polymers possess promising characteristics for the development of switchable MRI contrast agents. PMID- 22206871 TI - Role of PCDH10 and its hypermethylation in human gastric cancer. AB - Epigenetic changes of genomic DNA are involved in the development and progression of many cancers. Aberrant methylation of CpG islands in the promoter regions of certain tumor-suppressor genes (TSG) is frequently observed in cancer cells. Protocadherin 10 (PCDH10), a member of the cadherin superfamily, is a recently identified putative TSG. PCDH10 is frequently silenced in many solid tumors. However, the role of PCDH10 in gastric cancer is largely unknown. In this study, we examined the expression and methylation status of PCDH10 in gastric cancer cells and tissues by real time PCR and methylation-specific PCR (MSP), and then investigated the biological function of PCDH10. We found that the expression of PCDH10 was markedly reduced in gastric cancer cells and tissues. The reduced expression correlated with hypermethylation of this gene in its promoter region, as demonstrated by MSP and bisulfite genomic sequencing (BGS) analysis. In addition, pharmacological demethylation using 5-Aza restored the expression of PCDH10 in gastric cancer cells. Over-expression of PCDH10 in gastric cancer cells suppressed cell proliferation and migration, but did not cause marked apoptosis. Over-expression of PCDH10 also suppressed growth of xenograft tumors in nude mice. Thus, PCDH10 functions as a TSG in gastric cancer, and might be a useful target for cancer therapy. PMID- 22206872 TI - Stopping speech suppresses the task-irrelevant hand. AB - Some situations require one to quickly stop an initiated response. Recent evidence suggests that rapid stopping engages a mechanism that has diffuse effects on the motor system. For example, stopping the hand dampens the excitability of the task-irrelevant leg. However, it is unclear whether this 'global suppression' could apply across wider motor modalities. Here we tested whether stopping speech leads to suppression of the task-irrelevant hand. We used Transcranial Magnetic Stimulation over the primary motor cortex with concurrent electromyography from the hand. We found that when speech was successfully stopped the motor evoked potential from the task-irrelevant hand was significantly reduced compared to when the participant failed to stop speaking, or responded on non stop signal trials, or compared to baseline. This shows that when speech is quickly stopped, there is a broad suppression across the motor system. This has implications for the neural basis of speech control and stuttering. PMID- 22206873 TI - The risk of skin rash and stomatitis with the mammalian target of rapamycin inhibitor temsirolimus: a systematic review of the literature and meta-analysis. AB - OBJECTIVE: We conducted a systematic review of the literature and performed a meta-analysis to determine the risk of developing skin rash and stomatitis among patients receiving temsirolimus. METHODS: Databases from PubMed and Web of Science from January, 1998 until June, 2011 and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through 2011 were searched to identify relevant studies. The incidence and relative risk (RR) of skin rash and stomatitis were calculated using random-effects or fixed-effects model depending on the heterogeneity of included studies. RESULTS: A total of 779 patients from 10 clinical trials were included in this analysis. The overall incidence of all-grade rash was 45.8% (95% confidence interval (CI): 35.6-56.3%), with a RR of 7.6 (95%CI: 4.4-13.3; p<0.001). The overall incidence of high-grade rash was 3.3% (95%CI: 1.9-5.6%), with a RR of 13.70 (95%CI: 0.82-227.50, p=0.07). The overall incidence of all-grade stomatitis was 44.3% (CI: 32.1-57.1%), with a RR of 11.10, 95%CI: 5.60-22.00; p<0.001). The overall incidence of high-grade stomatitis was 3.2% (95%CI: 1.9-5.4%), with a RR of 13.2 (95%CI: 0.80-218.50, p=0.07). CONCLUSION: There is a significant risk of developing skin rash and stomatitis in cancer patients receiving temsirolimus. The risk is independent of underlying tumour. Adequate monitoring and early intervention are recommended to prevent debilitating toxicity and suboptimal dosing. PMID- 22206874 TI - Neurobiology of emotional dysfunction in schizophrenia: new directions revealed through meta-analyses. PMID- 22206877 TI - Functional magnetic resonance imaging correlates of emotional word encoding and recognition in depression and anxiety disorders. AB - BACKGROUND: Major depressive disorder (MDD), panic disorder, and social anxiety disorder are among the most prevalent and frequently co-occurring psychiatric disorders in adults and may be characterized by a common deficiency in processing of emotional information. METHODS: We used functional magnetic resonance imaging during the performance of an emotional word encoding and recognition paradigm in patients with MDD (n = 51), comorbid MDD and anxiety (n = 59), panic disorder and/or social anxiety disorder without comorbid MDD (n = 56), and control subjects (n = 49). In addition, we studied effects of illness severity, regional brain volume, and antidepressant use. RESULTS: Patients with MDD, prevalent anxiety disorders, or both showed a common hyporesponse in the right hippocampus during positive (>neutral) word encoding compared with control subjects. During negative encoding, increased insular activation was observed in both depressed groups (MDD and MDD + anxiety), whereas increased amygdala and anterior cingulate cortex activation during positive word encoding were observed as depressive state dependent effects in MDD only. During recognition, anxiety patients showed increased inferior frontal gyrus activation. Overall, effects were unaffected by medication use and regional brain volume. CONCLUSIONS: Hippocampal blunting during positive word encoding is a generic effect in depression and anxiety disorders, which may constitute a common vulnerability factor. Increased insular and amygdalar involvement during negative word encoding may underlie heightened experience of, and an inability to disengage from, negative emotions in depressive disorders. Our results emphasize a common neurobiological deficiency in both MDD and anxiety disorders, which may mark a general insensitiveness to positive information. PMID- 22206878 TI - Multiple clinical traits predict clinical diagnosis of depersonalization disorder: implications for DSM-V. PMID- 22206876 TI - Neural activation during facial emotion processing in unmedicated bipolar depression, euthymia, and mania. AB - BACKGROUND: Studies incorporating direct comparisons across all phases of bipolar (BP) disorder are needed to elucidate the pathophysiology of bipolar disorder. However, functional neuroimaging studies that differentiate bipolar mood states from each other and from healthy subjects are few and have yielded inconsistent findings. METHODS: One hundred five unmedicated adults were recruited: 30 with current bipolar depression (BPD), 30 with current bipolar hypomania or mania (BPM), 15 bipolar euthymic (BPE), and 30 healthy control subjects (HC). All subjects were diagnosed with DSM-IV BP (type I or II) using a structured clinical interview. Groups were age- and gender-ratio matched. In 3T functional magnetic resonance imaging experiments, subjects completed a negative facial emotion matching task. RESULTS: Bipolar euthymic and BPD groups exhibited increased amygdala activation compared with HCs in response to the negative faces; however, in the BPM group, this increase was not seen. Conversely, both BPE and BPM groups had increased activation in the insula relative to HCs, but in the BPD group, this effect was not seen. All three BP groups exhibited increased activation of the putamen compared with HCs. In the cortical areas, the BPM group exhibited decreased left lateral orbitofrontal cortex activation compared with both BPEs and HCs, increased dorsal anterior cingulate cortex activation compared with the BPD group, and increased dorsolateral prefrontal cortical activation compared with all other groups. CONCLUSIONS: Both state- and trait-related abnormalities in corticolimbic activation were seen in response to the negative facial emotion processing in a large sample of unmedicated adults across BP mood states. PMID- 22206879 TI - [Hypoglycaemia due to persistent hyperinsulinism in a patient with Sotos syndrome]. PMID- 22206880 TI - [Spontaneous subgaleal haematoma presenting as an alteration in platelet function]. PMID- 22206881 TI - [A new mutation in the GLDC gene in non-ketotic hyperglycinaemia]. PMID- 22206882 TI - [Helicobacter pylori infection; a rarely suspected and treatable cause of chronic urticaria]. PMID- 22206883 TI - [Hemicerebellitis associated with rotavirus gastroenteritis]. PMID- 22206884 TI - Effects of a methanolic extract of the plant Haplophyllum tuberculatum and of teflubenzuron on female reproduction in the migratory locust, Locusta migratoria (Orthoptera: Oedipodinae). AB - The effects of a methanolic extract of the plant Haplophyllum tuberculatum (ME Ht) and of teflubenzuron (TFB) were compared on several reproductive variables and ecdysteroid titers in the females of Locusta migratoria. The test products were administered orally to newly emerged females at doses of 1500 (ME-Ht) and 10MUg/female (TFB). The methanolic extract and TFB had comparable effects on several of the variables examined. Both significantly delayed the first oviposition and reduced fecundity and fertility. ME-Ht and TFB also displayed similar effects on ovarian growth, vitellogenesis and ecdysteroid titers. Both treatments induced a drop in hemolymph protein levels as well as a reduction in vitellogenin uptake by oocytes. This delay in oogenesis was accompanied by a resorption of terminal oocytes. However, whereas TFB completely blocked egg hatch, ME-Ht only had a modest inhibitory effect on this variable. Hemolymph and ovarian ecdysteroid titers, as measured by radioimmunoassay, were similar and low in both control and treated females, except for a peak observed only in control females at the end of vitellogenesis. We discuss the functional significance of the observed effects in the context of the putative modes of action of the methanolic plant extract and TFB. PMID- 22206885 TI - Recent experiments towards a model for fluid secretion in Rhodnius Upper Malpighian Tubules (UMT). AB - Three different methods have been used to improve a model for fluid secretion in Upper Malpighian Tubules (UMT) of the blood sucking insect Rhodnius prolixus. (I) In the first, UMT double perfusions in 5th instar Rhodnius were used to measure their fluid secretion rate. They were stimulated to secrete with 5-HT. Double perfusions allowed access separately to the basolateral and the apical cell membranes with pharmacological agents known to block different ion transport functions, namely ATPases, cotransporters and/or countertransporters and ion and water channels: ouabain, bafilomycin A1, furosemide, bumetanide, SITS, acetazolamide, amiloride, DPC, BaCl(2), pCMBS and DTT. The basic assumption is that changes in water movement reflect changes in ion transport mechanisms. (II) Intracellular Na(+) concentrations were measured with a fluorometric method in dissected R. prolixus UMT, under several experimental conditions. (III) ATPase activities were measured in R. prolixus UMT. A tentative model for the function of the UMT cell is presented. We find that (a) at the basolateral cell membrane, fundamental is a Na(+)-K(+)-2Cl(-) cotransporter; of intermediate importance are the Na(+)-K(+)-ATPase and a ouabain-insensitive Na(+)-ATPase, ion channels and Rp MIP water channels. (b) At the apical cell membrane, most important are a V-H(+) ATPase; and a K(+) and/or Na(+)-H(+) exchanger. PMID- 22206886 TI - Ontogenetic changes in immunity and susceptibility to fungal infection in Mormon crickets Anabrus simplex. AB - Insects have innate immunity that may be weakened by resource allocation to growth. I measured enzymatic immunity, encapsulation response, and susceptibility to fungal infection in Mormon crickets of known age. Although the concentrations of circulating spontaneous and total phenoloxidase (PO) increased with age from the most recent molt in late instar nymphs (5th, 6th, and 7th) and 0-5 day old adults, mean values did not differ between stadia, indicating that circulating PO titers are knocked back with each molt. In contrast, encapsulation rate increased throughout nymphal development and adult maturation. No longer required to molt, adult PO titers increased steadily with age. Survivorship also increased with the age at which Metarhizium acridum fungus was applied to adults. I conclude that immunity relevant to defense against fungi continues to develop well into the adult stage. With each molt setting the insects back in circulating PO titers, very young adults are much like nymphs in enzymatic immunity. PMID- 22206887 TI - Localization of two Na+- or K+-H+ antiporters, AgNHA1 and AgNHA2, in Anopheles gambiae larval Malpighian tubules and the functional expression of AgNHA2 in yeast. AB - The newly identified metazoan Na(+)/H(+) antiporter (NHA) family is represented by two paralogues, AgNHA1 and AgNHA2, in the genome of the African malaria mosquito, Anopheles gambiae. Both antiporters are postulated to be electrophoretic i.e. voltage-driven. AgNHA1 was first cloned from An. gambiae larvae and immunolocalized with respect to the H(+) V-ATPase by the Harvey laboratory. Little is known about the properties of NHA1s; attempts to characterize AgNHA1 in Na(+)/H(+) exchanger (NHE)-lacking Chinese hamster ovary cells and in yeast cells or frog oocytes were unsuccessful. Even less is known about AgNHA2. It is predicted to have a relative molecular mass of ~60 kDa and shares 30.5% amino acid identity with AgNHA1. Immunolocalization images show AgNHA2 on the apical plasma membrane of stellate cells in Malpighian tubules of An. gambiae larvae and adults. When heterologously expressed in a mutant strain of the yeast, Saccharomyces cerevisiae, which lacks endogenous cation/proton antiporters and pumps, AgNHA2 enhanced repression of growth by the alkali metal cations, Li(+), Na(+), or K(+) and enhanced Li(+) accumulation. The yeast growth studies invite the speculation that AgNHA2 is an electrophoretic antiporter with a stoichiometry of nNa(+) to 1H(+) with n > 1. Immunolocalization images provide direct evidence that H(+) V-ATPase is co-localized with AgNHA1 on the apical membrane of principal cells but it is not present in the stellate cells where AgNHA2 is localized apically. These results are consistent with the notion that the outside positive voltage that the H(+) V-ATPase generates across the apical membrane of principal cells appears with but little attenuation across the apical membrane of stellate cells. This immunolocalization pattern is consistent with the hypothesis that the voltage acts via AgNHA1 to drive nH(+) into the principal cells and Na(+) out to the lumen and acts via AgNHA2 to drive nNa(+) into the stellate cells and H(+) out to the lumen. Precious Na(+) is then retained by ejection into the blood via a basal Na(+)/K(+)-ATPase. Localizations of anion transporters and their functions in stellate and principal cells are described by Linser, Romero and associates in this volume. The role that the electrogenic H(+) V-ATPase and the electrophoretic cationic and anionic transporters play in ion homeostasis is incorporated into a model for Malpighian tubule cells of larval mosquitoes. PMID- 22206888 TI - Downregulation of the dopamine D2-like receptor in corpus allatum affects juvenile hormone synthesis in Drosophila melanogaster females. AB - In Drosophila, juvenile hormone (JH) is synthesized de novo in the specialized endocrine gland, corpusallatum (CA). Dopamine (DA) controls JH levels by either stimulating or inhibiting its synthesis and degradation depending on the developmental stage. The present study focuses on the role of D2-like receptors in the regulation of JH synthesis by dopamine. We show that D2-like receptors (DD2R) are expressed in CA cells of Drosophila melanogaster females. In addition, the level of JH production was analyzed in D. melanogaster females with decreased DD2R expression in CA (vs. corresponding control flies) by assessing multiple indices of JH synthesis (JH-hydrolyzing activity and stress reactivity of the system of JH metabolism, activity and stress reactivity of the alkaline phosphatase, activity and stress reactivity of the tyrosine decarboxylase). The differential value obtained for each index suggests increased JH production in female flies that downregulate DD2R. Based on these findings, we postulate that the DA inhibiting effect on the JH synthesis in D. melanogaster is mediated at least in part via D2-like receptors. PMID- 22206889 TI - Isolation and characterisation of degradant impurities in dipyridamole formulation. AB - Dipyridamole is an antithrombotic drug. In the stability study of drug product of Dipyridamole, two unknown impurities (referred as DP-I and DP-II) were detected at levels of 0.25% and 0.54% by gradient reverse phase HPLC method. The drug product was subjected to stress to enhance the level of these impurities. An elegant isocratic preparative method was employed using a Reprosil CN column with a short run time of 14 min to isolate these impurities. The DP-I and DP-II were isolated with purities of 99.1% and 99.8% respectively. Structural studies of these impurities were undertaken using spectroscopic techniques such as IR, NMR and Mass. Based on the spectral data, the structures of DP-I and DP-II have been characterised to be 2,2',2",2'"-(4-hydroxy-8-(piperidin-1-yl) pyrimido [5,4 d]pyrimidine-2,6 diyl) bis(azanetriyl) tetraethanol, 4-(2-((6-(bis (2 hydroxyethyl) amino)-4, 8-di (piperidin-1-yl) pyrimido [5,4-d] pyrimidin-2-yl) (2 hydroxyethyl) amino) ethoxy)-2, 3-dihydroxy-4-oxobutanoic acid, respectively. A detailed elucidation of the structure is presented in this article. PMID- 22206890 TI - Libraries, classifiers, and quantifiers: a comparison of chemometric methods for the analysis of Raman spectra of contaminated pharmaceutical materials. AB - In this study, pharmaceutical grade sorbitol was used as a model system for comparison of Raman based library spectral correlation methods with more sophisticated methods of chemometric data analysis. Both crystallizing sorbitol (CS) and non-crystallizing sorbitol (NCS) from several manufacturers were examined. The Raman spectrum of each sample was collected and identified by correlation with a spectral library that included the CS spectrum but not the NCS spectrum. The average hit quality index (HQI) for the measured NCS spectra and the library CS spectrum was 0.966 whereas the average HQI for the measured CS spectra was 0.991. Both HQIs exceeded the 0.950 threshold that is commonly used for material verification. To enhance the discrimination between CS and NCS, a CS/NCS classification model was constructed using soft independent modeling of class analogies (SIMCA). SIMCA was able to positively identify CS and NCS solutions with no misclassifications. When CS was adulterated with low levels (0 5%) of ethylene glycol (EG) and diethylene glycol (DEG), the HQI values of the measured spectra and the CS library spectrum were still above 0.950. When the CS SIMCA model was applied to adulterated CS spectra, it determined that CS samples with adulterant levels as low as 2% were outside of the CS class. A quantitative PLS model was also applied to EG adulterated CS and resulted in a detection limit of 0.9% for EG. The results obtained from these studies highlight the importance of selecting an appropriate data analysis process for the detection of low level adulterants in pharmaceutical raw materials using Raman spectroscopic screening methods. PMID- 22206891 TI - [Consumption of fruit juices and fruit drinks: impact on the health of children and teenagers, the dentist's point of view]. AB - OBJECTIVES: The French dietary guidelines published in 2001 recommend daily consumption of 5 portions of fruit or vegetable. Despite this advice, the consumption of fruit in France, especially in the north of France, is low, whereas sale of 100% fruit juices, fruit drinks, and fruit-flavored beverages is increasing. The impact of contemporary changes in beverage patterns on dental caries has received less attention than the impact on childhood obesity. Nevertheless, the cariogenic potential of soft drinks is known. Drinking fruit juices, fruit drinks, or fruit-flavored beverages over a long period of time and continuous sipping could therefore be harmful for the teeth. The aim of this study was to examine the sugar content of such beverages. METHODOLOGY: Four different major supermarkets were visited to select a representative sample of beverages for sale. Fruit juices, nectars, fruit drinks (water and fruit juices) and fruit-flavored waters were included. Lemonades, teas, and drinks containing artificial sweetener were not included. The data were collected in April 2010 by reading nutrition labels. The variables studied were the sugar content (g/100mL), the presence of added sugar, and the percentage of fruit juices. A descriptive analysis of the variables studied was conducted. The mean sugar content of the French population's favorite juices (orange, grapefruit, pineapple, apple, and grape) was compared to the sugar content of a corresponding 100-g portion of fresh fruit. The data were processed using Microsoft Excel. RESULTS: Hundred and eighty-seven different beverages were analyzed: 89 fruit juices, 26 nectars, 51 fruit drinks (sparkling or flat), and 21 fruit-flavored waters. Unlike fruit flavored waters, nectars and fruit drinks contained fruit juices. Nectars and fruit drinks contained an average of 44.5% (+/- 10.7%) and 10.5% (+/- 3.8%) fruit juice, respectively. The sugar content varied from 0 g/100mL to 17.5 g/100mL. The average sugar content was 2.4 (+/- 2.1) g/100mL, 8.8 (+/- 2.3) g/100mL, 10.7 (+/- 1.9) g/100mL, and 10.8 (+/- 1) g/100mL for fruit-flavored waters, fruit drinks, fruit juices, and nectars, respectively. High sugar content was reported for grape juice, with an average of 15.6 (+/- 1.9) g/100mL. Nectars, fruit drinks, and 71.4% of fruit-flavored waters contained added sugar. CONCLUSION: These beverages are rich in sugar and labels should better inform consumers on the sugar content. Dental caries is a chronic disease of childhood, which has common risk factors with obesity. General practitioners, dieticians, and dentists must work together to provide preventive guidance: fruit juice intake has to be limited and other beverages restricted to occasional use; fruit juice may contribute to only one portion of the recommended five a day. PMID- 22206892 TI - Infant responding to joint attention, executive processes, and self-regulation in preschool children. AB - Infant joint attention is related to behavioral and social outcomes, as well as language in childhood. Recent research and theory suggests that the relations between joint attention and social-behavioral outcomes may reflect the role of executive self-regulatory processes in the development of joint attention. To test this hypothesis two studies were conducted. The first, cross-sectional study examined the development of responding to joint attention (RJA) skill in terms of increasing executive efficiency of responding between 9 and 18 months of age. The results indicated that development of RJA was characterized by a decreased latency to shift attention in following another person's gaze and head turn, as well as an increase in the proportion of correct RJA responses exhibited by older infants. The second study examined the longitudinal relations between 12-month measures of responding to joint attention and 36-month attention regulation in a delay of gratification task. The results indicated that responding to joint attention at 12-months was significantly related to children's use of three types of self-regulation behaviors while waiting for a snack reward at 36 months of age. These observations are discussed in light of a developmental theory of attention regulation and joint attention in infancy. PMID- 22206893 TI - Distribution of mono-, di- and trisialo gangliosides in the brain of Actinopterygian fishes. AB - BACKGROUND: Mono-, di- and trisialo gangliosides are major glycosphingolipids in the brain of higher vertebrates involved in lipid raft assembly. In contrast, the fish brain is abundant in polisialo-gangliosides, whose function is implicated in the modulation of repulsive and attractive intercellular interactions during embryonic development and a temperature adaptation process. The histological distribution of gangliosides is usually studied in rodent and mammalian brains, but to date it has not been described in the case of fish brain. METHODS: Gangliosides were extracted from adult brains of trout, carp and zebrafish and separated by TLC. High-affinity anti-ganglioside (GM1, GD1a, GD1b, GT1b) IgG antibodies were used for immunohistochemistry. RESULTS: In trout and carp brains GM1 and GT1b are expressed in the same neuronal cell bodies from the telencephalon to the spinal cord. In zebrafish brain GM1 was not detected, whereas GT1b is a general neuropil staining. GD1a is specific for unmyelinated parallel fibers in carp and zebrafish brains as well as parallel fibers in the molecular layer of all cerebellar divisions. In trout brain GD1b is found in parallel fibers of the cerebellum, but not in the tectum mesencephali. GD1b is expressed in zebrafish neuronal cell bodies. CONCLUSIONS: Each studied species has a different expression of complex gangliosides. GT1b is widely present, whereas GD1a and GD1b appear in a specific group of unmyelinated fibers and could be used as their specific marker. GENERAL SIGNIFICANCE: This is the first report on mono-, di- and trisialo ganglioside (GM1, GD1a, GD1b and GT1b) distribution in the brain of adult Actinopterygian fishes. This article is part of a Special Issue entitled Glycoproteomics. PMID- 22206894 TI - New oxo-bridged calix[2]arene[2]triazine stationary phase for high performance liquid chromatography. AB - A new oxo-bridged calix[2]arene[2]triazine bonded stationary phase (OCATS) for high performance liquid chromatography (HPLC) was prepared using 3 aminopropyltriethoxysilane as coupling reagent. The structure of new material was characterized by infrared spectroscopy, elemental analysis and thermogravimetric analysis. The chromatographic performance and retention mechanism of the new stationary phase were evaluated in reversed-phase mode compared with ODS using different solute probes including polycyclic aromatic hydrocarbons (PAHs), mono substituted benzenes, disubstituted benzene isomers. The new OCATS stationary phase could provide various interactions for different solutes, such as hydrophobic, hydrogen bonding, pipi and inclusion interactions. The synergistic effects resulting from aromatic rings, bridging oxygen atoms and triazine nitrogen atoms and alkyl linkers in the new material improved the separation selectivity by multiple retention mechanisms. The retention behaviors of the analytes on OCATS column were explained with the assistance of quantum chemistry calculation results using DFT-B3LYP/STO-3G* base group. The OCATS column was successfully employed for the analysis of melamine in infant formula. PMID- 22206895 TI - [Comment to: "Increased expression of hypoxia-inducible factor-1alpha and connective tissue growth factor accompanied by fibrosis in the rat testis of varicocele"]. PMID- 22206896 TI - Study on the structure and vibrational spectra of efavirenz conformers using DFT: comparison to experimental data. AB - Efavirenz, (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H 3,1-benzoxazin-2-one, is an anti HIV agent belonging to the class of the non nucleoside inhibitors of the HIV-1 virus reverse transcriptase. A systematic quantum chemical study of the possible conformations, their relative stabilities and vibrational spectra of efavirenz has been reported. Structural and spectral characteristics of efavirenz have been studied by vibrational spectroscopy and quantum chemical methods. Density functional theory (DFT) calculations for potential energy curve, optimized geometries and vibrational spectra have been carried out using 6-311++G(d,p) basis sets and B3LYP functionals. Based on these results, we have discussed the correlation between the vibrational modes and the crystalline structure of the most stable form of efavirenz. A complete analysis of the experimental infrared and Raman spectra has been reported on the basis of wavenumber of the vibrational bands and potential energy distribution. The infrared and the Raman spectra of the molecule based on DFT calculations show reasonable agreement with the experimental results. The calculated HOMO and LUMO energies shows that charge transfer occur within the molecule. PMID- 22206897 TI - The JNK inhibitor D-JNKI-1 blocks apoptotic JNK signaling in brain mitochondria. AB - Kainic acid (KA) induced seizures provokes an extensive neuronal degeneration initiated by c-Jun N-terminal kinases (JNK) as central mediators of excitotoxicity. However, the actions of their individual isoforms in cellular organelles including mitochondria remain to be elucidated. Here, we have studied the activation of JNK1, JNK2 and JNK3 and their activators, mitogen-activated protein kinase kinase (MKK) 4/7, in brain mitochondria, cytosolic and nuclear fractions after KA seizures. In the mitochondrial fraction, KA significantly increased the presence of JNK1, JNK3 and MKK4 and stimulated their phosphorylation i.e. activation. The pro-apoptotic proteins, Bim and Bax were induced and, consequently, the ratio Bcl-2-Bax decreased. These changes were paralleled by the release of cytochrome c and cleavage of poly(ADP-ribose) polymerase (PARP). The JNK peptide inhibitor, D-JNKI-1 (XG-102) reversed these pathological events in the mitochondria and almost completely abolished cytochrome c release and PARP cleavage. Importantly, JNK3, but not JNK1 or JNK2, was associated with Bim in mitochondria and D-JNKI-1 prevented the formation of this apoptotic complex. Apart from of the attenuation of c-Jun phosphorylation in the nucleus, D-JNKI-1 did not affect the level of JNK3 isoform in the nuclear and cytosolic fractions. These findings provide novel insights into the mode of action of individual JNK isoforms in cell organelles and points to the JNK3 pool in mitochondria as a target of the JNK inhibitor D-JNKI-1 to confer neuroprotection. PMID- 22206898 TI - [Anterior medial cervicoplasty]. AB - Submental skin and fat excess are common with aging. Real cutaneous crop in pronounced forms, may be felt with difficulty by patients, which leads them to consult. The proposal of a conventional face-lift is not always suitable or accepted by a predominantly male population. Therefore, an anterior medial cervicoplasty with elliptical excision of excess skin and a medial platysmaplasty will be an interesting alternative. The authors offer a new description of this technique by simplifying, compared to the previously described techniques. Two clinical cases are reported, with both types of recommended incisions. This procedure is performed under local anesthesia. The results obtained by this technique were considered good to excellent by all operated patients in our unit. The final scar that may appear significant and sometimes unacceptable for some surgeons remains in fact very inconspicuous. The anterior medial cervicoplasty is an easy technique that allows responding gracefully to a frequent request, with good cosmetic results and few complications. PMID- 22206899 TI - [Biometric and morphometric analyse of the umbilicus: about 70 cases]. AB - PURPOSE OF THE STUDY: More than the first scar present from the birth, the umbilicus is the original and fundamental element, which characterizes the abdomen. It can be analyzed under various aspects: symbolic, artistic, anatomical and morphometric. Its place takes on all its importance in frame of the abdominal plastic surgery. We tried to measure how the position of the umbilicus varies with the age, the weight or the sex... to optimize our abdominoplasties. PATIENTS AND METHOD: We realized a study on the umbilicus from 70 persons to determine its abdominal position in the general population. Some objective measurements between bones projections and umbilicus were realized and analyzed with various parameters (weight, age especially...). Depth of the umbilicus, its situation compared the median line, its dimensions, were noted for each patient. RESULTS: Population was composed of 39 women and 31 men, 35.4 years on average. The umbilicus was measured one centimeter under the line joining the top of the iliac crest. In the group of men, its situated lower. We noted a positive correlation between body mass index (BMI) and height of the umbilicus. More the BMI increases, lower is the umbilicus (R=0,72, P<10(-5)). Similarly, the umbilicus is lower when the age increases (R=0,36, P=0,0022). Its average depth was 15 mm, correlated to BMI (R=0,60, P<10(-7)). Some data about dimensions and form were precised. CONCLUSION: This anatomical and morphometric study could allow a more precise determination of the position, dimensions and form of the umbilicus during abdominoplasty. PMID- 22206900 TI - From natural geometry to spatial cognition. AB - A review of selected works on spatial memory in animals and humans is presented, and some ideas about the encoding of geometry and its role in evolution are presented, based on recently accumulated evidence from psychology, ethology and the neurosciences. It is argued that comparative analyses at the level of both spatial navigation behaviors and their underlying neural mechanisms may provide a solid foundation for the biological origins of organisms' spontaneous ability in dealing with geometric concepts. To this aim, the representations of space underlying memory tasks involving discrete (i.e., landmark arrays) or continuous elements (i.e., enclosed environments) are evaluated and compared as regards the impact of their geometric arrangement. PMID- 22206901 TI - The reciprocal interaction between serotonin and social behaviour. AB - Serotonin (5-HT) is an ancient molecule directing behavioural responses to environmental stimuli. The social environment is the most powerful environmental factor. It is well recognized that 5-HT plays a key role in shaping social responses, and that the serotonergic system itself is highly responsive to social influences. This review aims to provide an overview of a selection of representative papers that significantly contribute to a coherent view on the role of serotonin in reciprocal social interactions. The studies here reviewed, selected using the pubmed search terms "social behaviour" and "serotonin", describe the effects of serotonergic gene variation and pharmacological manipulations in humans, monkeys, and rodents, and involve parental attachment and caregiving, social play, aggressiveness, cooperation, and sexual behaviour. We conclude that serotonin is positively correlated with sensitivity to social factors and modulates social behaviour in a 'for-better-and-for-worse' manner, depending on the nature of social factors. Simultaneously, these behavioural responses influence the serotonergic system, leading to highly complex bidirectional serotonin*environment interaction. PMID- 22206902 TI - Late gestational maternal serum cortisol is inversely associated with fetal brain growth. AB - To analyze the association between fetal brain growth and late gestational blood serum cortisol in normal pregnancy.Blood total cortisol was quantified at delivery in 432 Chinese mother/child pairs. Key inclusion criteria of the cohort were: no structural anomalies of the newborn, singleton pregnancy, no alcohol abuse, no drug abuse or history of smoking no hypertensive disorders and no impairment of glucose tolerance and no use of steroid medication during pregnancy. Differential ultrasound examination of the fetal body was done in early (gestational day 89.95 +/- 7.31), middle (gestational day 160.17 +/- 16.12) and late pregnancy (gestational day 268.89 +/- 12.42). Newborn's cortisol was not correlated with any of the ultrasound measurements during pregnancy nor with birth weight. Multivariable regression analysis, considering timing of the ultrasound examination, the child's sex, maternal BMI, maternal age, maternal body weight at delivery, the timing of cortisol measurement and maternal uterine contraction states, revealed that maternal serum total cortisol was significantly negative correlated with ultrasound parameters describing the fetal brain: late biparietal diameter (R2=0.512, p=0.009), late head circumference (R2=0.498, p=0.001), middle biparietal diameter (R2=0.819, p=0.013), middle cerebellum transverse diameter R2=0.76, p=0.014) and early biparietal diameter(R2=0.819, p=0.013). The same analysis revealed that birth weight as well as ultrasound parameters such as abdominal circumference and femur length were not correlated to maternal cortisol levels. In conclusion, our study demonstrates that maternal cortisol secretion within physiological ranges may be inversely correlated to fetal brain growth but not to birth weight. It remains to be demonstrated whether maternal cortisol secretion negatively influencing fetal brain growth translates to adverse neurological outcomes in later life. PMID- 22206903 TI - A new insight into the field of physical exercises to employ neuroimmunological constituents as an outcome measure for depression. PMID- 22206904 TI - Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. AB - CD8(+) T cells undergo major metabolic changes upon activation, but how metabolism influences the establishment of long-lived memory T cells after infection remains a key question. We have shown here that CD8(+) memory T cells, but not CD8(+) T effector (Teff) cells, possessed substantial mitochondrial spare respiratory capacity (SRC). SRC is the extra capacity available in cells to produce energy in response to increased stress or work and as such is associated with cellular survival. We found that interleukin-15 (IL-15), a cytokine critical for CD8(+) memory T cells, regulated SRC and oxidative metabolism by promoting mitochondrial biogenesis and expression of carnitine palmitoyl transferase (CPT1a), a metabolic enzyme that controls the rate-limiting step to mitochondrial fatty acid oxidation (FAO). These results show how cytokines control the bioenergetic stability of memory T cells after infection by regulating mitochondrial metabolism. PMID- 22206905 TI - False belief and verb non-factivity: a common neural basis? AB - Using fMRI, the present study compares the brain activation underlying false belief thinking induced by pictorial, nonverbal material to that instigated by strong non-factive verbs in a sample of adult Chinese speakers. These verbs obligatorily negate their complements which describe the mind content of the sentence agent, and thus may activate part of the false belief network. Some previous studies have shown a behavioral correlation between verb non factivity/false complementation and conventional false belief but corresponding neural evidence is lacking. Our results showed that the non-factive grammar and false belief commonly implicated the right temporo-parietal junction (TPJ), which had been shown by past studies to play a role in general mentalizing. Regions that were unique to nonverbal false belief were the left TPJ and right middle frontal gyrus (MFG), whereas the unique regions for the non-factive grammar were the left inferior frontal gyrus (IFG) and right superior temporal gyrus (STG). Hence, conventional nonverbal false belief and verb non-factivity have both shared and unique neural representations. PMID- 22206906 TI - Cortical correlate of spatial presence in 2D and 3D interactive virtual reality: an EEG study. AB - The present study is the first that examined neuronal underpinnings of spatial presence using multi-channel EEG in an interactive virtual reality (VR). We compared two VR-systems: a highly immersive Single-Wall-VR-system (three dimensional view, large screen) and a less immersive Desktop-VR-system (two dimensional view, small screen). Twenty-nine participants performed a spatial navigation task in a virtual maze and had to state their sensation of "being there" on a 5-point rating scale. Task-related power decrease/increase (TRPD/TRPI) in the Alpha band (8-12Hz) and coherence analyses in different frequency bands were used to analyze the EEG data. The Single-Wall-VR-system caused a more intense presence experience than the Desktop-VR-system. This increased feeling of presence in the Single-Wall-VR-condition was accompanied by an increased parietal TRPD in the Alpha band, which is associated with cortical activation. The lower presence experience in the Desktop-VR-group was accompanied by a stronger functional connectivity between frontal and parietal brain regions indicating that the communication between these two brain areas is crucial for the presence experience. Hence, we found a positive relationship between presence and parietal brain activation and a negative relationship between presence and frontal brain activation in an interactive VR-paradigm, supporting the results of passive non-interactive VR-studies. PMID- 22206907 TI - Viscoelastic stability of resin-composites under static and dynamic loading. AB - OBJECTIVES: To compare the viscoelastic behavior (creep) of dental resin composites under both static and cyclic loading in compression. METHODS: Ten cylindrical specimens (4 mm * 6 mm), divided into two subgroups (n = 5) were prepared from each of four commercial resin-composites, using a divisible stainless steel mold. They were thoroughly cured from all sides. Groups 1 and 2 were loaded statically and dynamically respectively after 1d of fabrication and dry storage. Group 1 was loaded with a constant static load of 35 MPa and it was applied for 2 h followed by 2 h of strain recovery to obtain the static creep (%) and permanent set (%) respectively. To Group 2 a cyclic load between 1 MPa and 50 MPa was applied at a frequency of 0.25 Hz for 30 min to obtain the "dynamic" creep strain (%). Regression and correlation analysis (alpha = 0.05) was performed to examine possible correlations between static and "dynamic" creep. RESULTS: For the resin-composite investigated, a good correlation was found between "dynamic" creep strain (%) and maximum static creep strain (%) (r = 0.92) and a strong correlation was also found between "dynamic" creep strain (%) and permanent set (%) (r = 0.97), SIGNIFICANCE: Maximum static creep was significantly higher than "dynamic" creep. A direct numerical equivalence was not expected between static and "dynamic" creep values, as in the case of "dynamic" creep, loading was cyclic and was applied for a shorter overall period. Nevertheless a strong correlation was found between the static and dynamic creep measurement. PMID- 22206908 TI - Automation of clip localization in Digital Tomosynthesis for setup of breast cancer patients. AB - The objective of this study is to develop an automatic clip localization procedure for breast cancer patient setup based on Digital Tomosynthesis (DTS) and to characterize its performance with respect to the overall registration accuracy and robustness. The study was performed under an IRB-approved protocol for 12 breast cancer patients with surgical clips implanted around the tumor cavity. The registration of DTS images to planning CTs was performed using an automatic algorithm developed to overcome specific challenges of localization and registration of clips in the breast setup images. The automatic method consisted of auto-segmentation (intensity-based thresholding with a priori knowledge about clip size and location to distinguish clips from bony features) and auto registration of the segmented clip clusters. To determine the inherent accuracy and robustness of the registration algorithm, additional simulated DTS data was analyzed. The developed algorithm is efficient in removing false positives and negatives and provides an accuracy of better than 2.3mm for 60 degrees and 3.3mm for 40 degrees DTS. When incorporated in clinical software, this algorithm helps to facilitate fast and accurate setup evaluation with minimal dose delivered to patients. PMID- 22206909 TI - Elemental distribution images in prostate samples by X-ray fluorescence microtomography. AB - An X-ray transmission microtomography (CT) system combined with an X-ray fluorescence microtomography (XRFMUCT) system was implemented in the Brazilian Synchrotron Light Laboratory (LNLS), in order to determine the elemental distribution in prostate samples aiming at establishing a correlation between the concentration of some elements and the characteristics and pathology of the tissues. The CT images were reconstructed using a filtered-back projection algorithm and the XRFMUCT images were reconstructed using a filtered-back projection algorithm with absorption corrections. PMID- 22206910 TI - Bone quality analysis using X-ray microtomography and microfluorescence. AB - Bone quality is an evaluation index often applied in order to interpret clinical observations made upon bone health, such as bone mineral density, micro and macro architecture, and mineral content. Conventional inspection techniques do not provide full information on trabecular bone quality. This study shows the high resolution potential and the non-destructive character of X-ray microtomography and microfluorescence upon the application of such techniques for evaluating bone quality. The mineral content assessment was performed by two-dimensional concentration mappings of calcium, zinc, and strontium. The results showed significant changes in bone morphology. PMID- 22206911 TI - Coverage intervals according to MARLAP, Bayesian statistics and the new ISO 11929 for ionising radiation measurements. AB - The coverage intervals stipulated by ISO 11929 (2010) for estimating the uncertainty from ionising radiation measurements of replicate samples are compared with those of MARLAP (=Multi-Agency Radiological Laboratory Analytical Protocols Manual) and of Bayesian statistics. The latter two intervals agree well despite their different concepts. Whereas for either of them the ratio of the length of the coverage interval and MARLAP's standard uncertainty grows when the number of samples decreases, no such growth arises for the interval mandated by ISO 11929 (2010). It may therefore be too short (e.g. for three samples by a factor of approximately 2). PMID- 22206912 TI - Mechanisms by which pesticides affect insect immunity. AB - The current state of knowledge regarding the effect of pesticides on insect immunity is reviewed here. A basic understanding of these interactions is needed for several reasons, including to improve methods for controlling pest insects in agricultural settings, for controlling insect vectors of human diseases, and for reducing mortality in beneficial insects. Bees are particularly vulnerable to sublethal pesticide exposures because they gather nectar and pollen, concentrating environmental toxins in their nests in the process. Pesticides do have effects on immunity. Organophosphates and some botanicals have been found to impact hemocyte number, differentiation, and thus affect phagocytosis. The phenoloxidase cascade and malanization have also been shown to be affected by several insecticides. Many synthetic insecticides increase oxidative stress, and this could have severe impacts on the production of some antimicrobial peptides in insects, but research is needed to determine the actual effects. Pesticides can also affect grooming behaviors, rendering insects more susceptible to disease. Despite laboratory data documenting pesticide/pathogen interactions, little field data is available at the population level. PMID- 22206913 TI - Effect of organic loading rate on organic matter and foulant characteristics in membrane bio-reactor. AB - In this study, the influence of organic loading rate (OLR) on the performance of a membrane bio-reactor (MBR) was investigated. The MBR was operated with 6 different OLRs between 0.5 and 3.0 kg COD/m(3)d. The hydrodynamic parameters of the MBR were kept constant. The hydraulic retention time and sludge retention time were kept at 8h and 40 d respectively. From the experimental investigation, it was found that the removal efficiency of DOC, COD and NH(4)-N decreased when OLRs were increased from 0.5 to 3.0 kg COD/m(3)d. Higher OLRs of 2.75-3.0 kg COD/m(3)d resulted in a higher transmembrane pressure development. The fractionation of organic matters showed more hydrophilic substances with higher OLRs. A detailed organic matter characterization of membrane foulant, soluble microbial product and extracellular polymeric substances showed that bio-polymers type substances together with humic acid and lower molecular neutral and acids were responsible for membrane fouling. PMID- 22206914 TI - Biological treatment and ozone oxidation: Integration or coupling? AB - Wastewaters generated by many economically relevant industrial activities contain recalcitrant organic compounds which pass unaltered through biological stage of the treatment plant making it difficult to meet the discharge limits currently in force. Therefore, an additional treatment is usually required to remove these compounds. In this study, the application of ozonation together with biological treatment was investigated. In particular, the effectiveness of biological degradation followed by or integrated with ozonation for treating the effluents produced by three environmentally relevant activities (i.e., leather and textile processing and municipal waste landfilling) are compared in the present paper. The results show that biological treatment followed by ozonation does not guarantee depurative levels sufficient for discharge for landfill leachates and tannery wastewater. On the contrary, thanks to the synergy between biological degradation and ozonation, integrated treatment significantly improves the process performance for all the investigated wastewaters, thus allowing the discharge limits to be met. PMID- 22206915 TI - Stoichiometric conversion of biodiesel derived crude glycerol to hydrogen: Response surface methodology study of the effects of light intensity and crude glycerol and glutamate concentration. AB - Photofermentation by the photosynthetic bacterium Rhodopseudomonas palustris has been used to convert the crude glycerol fraction from biodiesel production to hydrogen as a means of converting this large resource to useful energy. In the present study response surface methodology was applied to investigate the interactive effects among several important process parameters; light intensity, and the concentrations of crude glycerol and glutamate, on the stoichiometric conversion of crude glycerol to hydrogen. Under optimal conditions, a light intensity of 175W/m(2), 30mM glycerol, and 4.5mM glutamate, 6.69mol hydrogen/mole of crude glycerol were obtained, a yield 96% of theoretical. Determination of nitrogenase activity and expression levels showed that there was relatively little variation in levels of nitrogenase protein with changes in process variables whereas nitrogenase activity varied considerably, with maximal nitrogenase activity (228nmol of C(2)H(4)/ml/min) at the optimal central point. PMID- 22206916 TI - Kinetics studies of synthesis of biodiesel from waste frying oil using a heterogeneous catalyst derived from snail shell. AB - Waste frying oil was used to produce biodiesel using calcined snail shell as a heterogeneous base catalyst. Trans esterification reactions were carried out and the yield and conversion of the product were optimized by varying the methanol to oil molar ratio, catalyst amount, reaction temperature, and time. A biodiesel conversion of 99.58% was obtained with a yield of 87.28%. The reaction followed first order kinetics. The activation energy (E(A)) was 79kJ/mol and the frequency factor (A) was 2.98*10(10)min(-1). The fuel properties of the biodiesel were measured according to ASTM D 6751 and found to be within the specifications. Snail shell is a novel source for the production of heterogeneous base catalyst that can be successfully utilized for synthesis of biodiesel of high purity. PMID- 22206917 TI - Effect of continuous oleate addition on microbial communities involved in anaerobic digestion process. AB - In the present study, the microbial diversity in anaerobic reactors, continuously exposed to oleate, added to a manure reactor influent, was investigated. Relative changes in archaeal community were less remarkable in comparison to changes in bacterial community indicating that dominant archaeal composition remained relatively stable. Majority of the analyzed bacterial amplicons were phylogenetically affiliated with uncultured bacteria belonging to Firmicutes, Bacteroidetes, Proteobacteria and Thermotogae phyla. Bacterial community changes in response to oleate addition resulted in a less diverse bacterial consortium related to functional specialization of the species towards oleate degradation. For the archaeal domain, the sequences were affiliated within Euryarchaeota phylum with three major groups (Methanosarcina, Methanosaeta and Methanobacterium genera). Results obtained in this study deliver a comprehensive picture on oleate degrading microbial communities in high organic strength wastewater. The findings might be utilized for development of strategies for biogas production from lipid riched wastes. PMID- 22206918 TI - Mathematical modeling of process liquid flow and acetoclastic methanogenesis under mesophilic conditions in a two-phase biogas reactor. AB - Acetoclastic methanogenesis in the second stage of a two-phase biogas reactor is investigated. A mathematical model coupling chemical reactions with transport of process liquid and with the variation of population of the microorganisms living on the plastic tower packing of the reactor is proposed. The evolution of the liquid is described by an advection-diffusion-reaction equation, while a monod type kinetic is used for the reactions. Moreover, a new inhibition factor MO(max) is introduced, which hinders the growth of microorganisms when the plastic tower packing is overpopulated. After estimating the reaction parameters, the acetate outflow measured experimentally is in good agreement with that predicted by simulations. For coupling liquid transport with reaction processes, a spatial discretization of the reactor is performed. This yields essential information about the distribution of acetate and the production of methane in the reactor. This information allows for defining a measure of the effectiveness of the reactor. PMID- 22206919 TI - Knowledge-based control module for start-up of flat sheet MBRs. AB - In start-up periods low MLSS concentration may lead to fouling phenomena and uncommon frequency of chemical cleanings using membrane bioreactors. A knowledge based control module for the optimisation of start-up procedures in membrane bioreactors is presented and validated in this paper. The main objective of the control module is to accelerate the growth of MLSS and the achievement of the design flux while minimising the fouling phenomenon during start-up periods. The module was validated in a pilot-scale membrane bioreactor with the University of Cape Town configuration and submerged flat sheet microfiltration membranes. The knowledge of the control system was represented as a decision tree before being implemented. A fully satisfactory start-up, both for the filtration and the biological phase, was obtained in 20 days, saving time and preserving the membrane integrity. PMID- 22206920 TI - Investigations into the biodegradation of microcystin-LR mediated by the biofilm in wintertime from a biological treatment facility in a drinking-water treatment plant. AB - The potential of winter biofilm for microcystin-LR (MCLR) biodegradation was comparatively evaluated under various nutrient conditions. Results indicated that MCLR was completely biodegraded by Day 7 without nutrient addition. MCLR biodegradation was inhibited in the presence of phosphate or glucose addition, with complete MCLR removal observed by Day 10. MCLR was totally biodegraded by Day 7 with dual nutrients comprising glucose and nitrate, suggesting that additional nitrate alleviated the inhibitory effect of glucose alone on the biodegradation. Simultaneously, MCLR-degrading gene (mlrA) abundance were detected to increase with increasing amount of MCLR being degraded under the respective conditions, implying that MCLR-biodegradation depended on the population of indigenous MCLR-degrading bacteria (MCLRDB), which was related to the population of non-degrading bacteria in the biofilm. MCLRDB was found to primarily use MCLR for proliferation rather than other nutrients. This is the first report verifying MCLR as a primary substrate for bacteria under various nutrient conditions. PMID- 22206921 TI - New miniature stirred-tank bioreactors for parallel study of enzymatic biomass hydrolysis. AB - Many factors strongly influence the enzymatic hydrolysis of biomass to fermentable sugars (feedstock composition, pretreatment, enzymes and enzyme loading). In order to optimize the reaction conditions for the hydrolysis of biomass, an accurate high-throughput bioprocess development tool is mandatory, which enables a parallelization and an easy scale-up. New S-shaped impellers were developed for magnetically inductive driven stirred-tank bioreactors at a 10mL scale. An efficient and reproducible homogenization was shown at 20% w/w solids loading of microcrystalline cellulose and at, 4-10% with wheat straw in 48 parallel operated stirred-tank bioreactors. The scale-up was successfully validated for the enzymatic hydrolysis of wheat straw suspensions and microcrystalline cellulose mixtures by application of a cellulase complex at a milliliter- and liter-scale. As an example, the parallel stirred-tank bioreactor system was applied for the evaluation of enzymatic batch hydrolyses of plant materials with varying pretreatments. PMID- 22206922 TI - Effectiveness of liver metastasectomies in patients with metastatic colorectal cancer treated with FIr-B/FOx triplet chemotherapy plus bevacizumab. AB - BACKGROUND: Intensive medical treatment increases resection rate of liver metastases in patients with metastatic colorectal cancer (MCRC). The effectiveness of liver metastasectomies was evaluated in patients with MCRC who were treated with previously reported FIr-B/FOx (triplet chemotherapy plus bevacizumab). PATIENTS AND METHODS: Fifty patients with MCRC enrolled in the reported phase II study were classified according to involved metastatic sites (liver-only metastatic site, multiple metastatic sites) and the extent of liver metastases (single, multiple). Surgical resectability of liver metastases was evaluated at baseline and every 3 cycles of FIr-B/FOx treatment. The resection rate of liver metastases, activity, and efficacy were evaluated; progression-free survival (PFS) and overall survival (OS) were compared by using the log-rank test. RESULTS: Patients with liver MCRC were 33 of 50 consecutive unselected patients with MCRC: liver limited, 22 patients; multiple metastatic sites, 11 patients. Liver metastasectomies were performed in 13 patients: 26% of 50 patients with MCRC, 39% of 33 patients with liver MCRC. In patients with liver only MCRC, a secondary liver surgery was performed in 54%: 6 of 9 single and 6 of 13 multiple liver metastases. Also, 1 liver and lung metastasectomy was performed. Pathologic complete responses were achieved in 2 patients (15%). The conversion rate of unresectable liver metastases was 83%. Objective response rate, PFS, OS were, respectively: 84%, 11 and 23 months in 33 liver MCRC; 86%, 17 and 44 months in 22 liver-limited patients. PFS and OS were significantly increased in patients with liver-limited metastases compared with multiple metastatic sites and single compared with multiple liver metastases. CONCLUSION: The FIr-B/FOx regimen may increase the resection rate of liver metastases and improve clinical outcome of patients with liver-only MCRC. PMID- 22206923 TI - IB4-saporin attenuates acute and eliminates chronic muscle pain in the rat. AB - The function of populations of nociceptors in muscle pain syndromes remain poorly understood. We compared the contribution of two major classes, isolectin B4 positive (IB4(+)) and IB4-negative (IB4(-)) nociceptors, in acute and chronic inflammatory and ergonomic muscle pain. Baseline mechanical nociceptive threshold was assessed in the gastrocnemius muscle of rats treated with IB4-saporin, which selectively destroys IB4(+) nociceptors. Rats were then submitted to models of acute inflammatory (intramuscular carrageenan)- or ergonomic intervention (eccentric exercise or vibration)-induced muscle pain, and each of the three models also evaluated for the transition from acute to chronic pain, manifest as prolongation of prostaglandin E2 (PGE(2))-induced hyperalgesia, after recovery from the hyperalgesia induced by acute inflammation or ergonomic interventions. IB4-saporin treatment did not affect baseline mechanical nociceptive threshold. However, compared to controls, IB4-saporin treated rats exhibited shorter duration mechanical hyperalgesia in all three models and attenuated peak hyperalgesia in the ergonomic pain models. And, IB4-saporin treatment completely prevented prolongation of PGE(2)-induced mechanical hyperalgesia. Thus, IB4(+) and IB4(-) neurons contribute to acute muscle hyperalgesia induced by diverse insults. However, only IB4+ nociceptors participate in the long term consequence of acute hyperalgesia. PMID- 22206925 TI - Effect of chronic intracerebroventricular insulin administration in rats on the peripheral glucose metabolism and synaptic plasticity of CA1 hippocampal neurons. AB - In this study we examined the effects of sustained intracerebroventricular insulin infusion on hippocampal synaptic plasticity in rats. Insulin was infused intracerebroventricularly in male Wistar rats (n=12) for 3 months using osmotic minipumps. A control group (n=12) received a sham operation. Insulin infusion led to an initial reduction in food intake and body weight gain, but these differences attenuated over 12 weeks. Insulin infusion did not affect fasting or non-fasting blood glucose levels. Field synaptic potentials recording from the hippocampus demonstrated a defect in the expression of long-term potentiation. Sharp electrode current-clamp recording showed that CA1 pyramidal cells fire action potentials in response to prolonged depolarizing current injection and those action potentials showed progressive broadening. The action potential broadening in the insulin-perfused animals were significantly longer than the control. The amplitude of slow after hyperpolarization (sAHP) was measured after manually "clamping" the cells at -65 mV and injecting currents to evoke a train of four APs. The sAHP amplitude was significantly longer than in the control animals. We conclude that local insulin infusion into the brain of rats had significant effects on synaptic plasticity in the absence of marked effects on systemic glucose levels. These results indicate that long-term elevation of insulin levels can have adverse effects directly on the brain. PMID- 22206924 TI - Calcium dependence of damage to mouse motor nerve terminals following oxygen/glucose deprivation. AB - Motor nerve terminals are especially sensitive to an ischemia/reperfusion stress. We applied an in vitro model of this stress, oxygen/glucose deprivation (OGD), to mouse neuromuscular preparations to investigate how Ca(2+) contributes to stress induced motor terminal damage. Measurements using an ionophoretically-injected fluorescent [Ca(2+)] indicator demonstrated an increase in intra-terminal [Ca(2+)] following OGD onset. When OGD was terminated within 20-30min of the increase in resting [Ca(2+)], these changes were sometimes reversible; in other cases [Ca(2+)] remained high and the terminal degenerated. Endplate innervation was assessed morphometrically following 22min OGD and 120min reoxygenation (32.5 degrees C). Stress-induced motor terminal degeneration was Ca(2+)-dependent. Median post-stress endplate occupancy was only 26% when the bath contained the normal 1.8mM Ca(2+), but increased to 81% when Ca(2+) was absent. Removal of Ca(2+) only during OGD was more protective than removal of Ca(2+) only during reoxygenation. Post-stress endplate occupancy was partially preserved by pharmacological inhibition of various routes of Ca(2+) entry into motor terminals, including voltage-dependent Ca(2+) channels (omega-agatoxin-IVA, nimodipine) and the plasma membrane Na(+)/Ca(2+) exchanger (KB-R7943). Inhibition of a Ca(2+)-dependent protease with calpain inhibitor VI was also protective. These results suggest that most of the OGD-induced motor terminal damage is Ca(2+)-dependent, and that inhibition of Ca(2+) entry or Ca(2+)-dependent proteolysis can reduce this damage. There was no significant difference between the response of wild-type and presymptomatic superoxide dismutase 1 G93A mutant terminals to OGD, or in their response to the protective effect of the tested drugs. PMID- 22206927 TI - Temporal dynamics of trustworthiness perception. AB - Behavioral and neuroimaging studies suggest that the attribution of trustworthiness to faces relies on emotional and structural cues. Attributions happen spontaneously and very rapidly but the precise temporal dynamics of the underlying processes are not known. We investigated the temporal dynamics of trustworthiness perception by employing scalp recorded event related potentials and evaluating effects on components previously implicated in face processing: P1 (positive component ~100 ms post-stimulus), N170 (negative deflection sensitive to faces) and a posterior-occipital negativity~230 to 280 ms (early posterior negativity-EPN). Participants judged the gender and trustworthiness of female and male images manipulated to look either more or less trustworthy. The results indicated that facilitated behavioral processing of socially important stimuli-in particular males that looked untrustworthy (and should be avoided) but also females that looked trustworthy (and who might therefore be useful in cooperative ventures)-was reflected in an increased negativity of N170 amplitude over the right hemisphere. Additionally, trustworthiness continued to modulate the amplitude of the negative deflection~230 to 280 ms post-stimulus during explicit judgments of trustworthiness but not during gender judgments. The results suggest that negativity accompanies the relevance of the faces (female trustworthy and male untrustworthy) that are important to remember for future social interactions. PMID- 22206926 TI - Kcna1-mutant rats dominantly display myokymia, neuromyotonia and spontaneous epileptic seizures. AB - Mutations in the KCNA1 gene, which encodes for the alpha subunit of the voltage gated potassium channel Kv1.1, cause episodic ataxia type 1 (EA1). EA1 is a dominant human neurological disorder characterized by variable phenotypes of brief episodes of ataxia, myokymia, neuromyotonia, and associated epilepsy. Animal models for EA1 include Kcna1-deficient mice, which recessively display severe seizures and die prematurely, and V408A-knock-in mice, which dominantly exhibit stress-induced loss of motor coordination. In the present study, we have identified an N-ethyl-N-nitrosourea-mutagenized rat, named autosomal dominant myokymia and seizures (ADMS), with a missense mutation (S309T) in the voltage sensor domain, S4, of the Kcna1 gene. ADMS rats dominantly exhibited myokymia, neuromyotonia and generalized tonic-clonic seizures. They also showed cold stress induced tremor, neuromyotonia, and motor incoordination. Expression studies of homomeric and heteromeric Kv1.1 channels in HEK cells and Xenopus oocytes, showed that, although S309T channels are transferred to the cell membrane surface, they remained non-functional in terms of their biophysical properties, suggesting a dominant-negative effect of the S309T mutation on potassium channel function. ADMS rats provide a new model, distinct from previously reported mouse models, for studying the diverse functions of Kv1.1 in vivo, as well as for understanding the pathology of EA1. PMID- 22206928 TI - Terpenoids from root bark of Celastrus orbiculatus. AB - Phytochemical investigation of root bark of Celastrusorbiculatus afforded 10 terpenoids and eight known compounds. Their structures were established on the basis of spectroscopic and chemical methods. Celastrol and its dimers and adducts displayed moderate inhibitory activity against T cell proliferation. The reaction of celastrol under acidic conditions was undertaken, and a mechanism is presented, which may help towards modification of its structure and elucidation of the biogenetic routes to natural celastrol derivatives. PMID- 22206929 TI - Vertebral osteonecrosis as a complication of corticosteroid therapy: the intravertebral vacuum cleft sign. PMID- 22206930 TI - [Lung cancer: changes in epidemiology and survival]. AB - BACKGROUND AND OBJECTIVE: In the last decades, variations have been described in the epidemiology of lung cancer. In our study, we have analyzed if changes have occurred in the epidemiology and survival of lung cancer. PATIENTS AND METHODS: All the cases with the diagnosis of lung cancer having cytohistological confirmation between May 1997 and December 2008 were included. To compare the variables, the study period was divided into three cohorts, respectively including the years 1997-2000, 2001-2004 and 2005-2008. RESULTS: A total of 905 patients, 776 males (85.7%) were included with a mean age (+/- SD) of 64.4 +/- 11.6 years. The number of cases in females went from 11.2% in 1997-2000 to 16.2% in 2005-2008, and adenocarcinoma from 29.3% to 34.5% (P=.2). Survival was associated independently with the performance status, treatment, comorbidity and weight loss. CONCLUSIONS: In our area, there is been an increasing number of cases of lung cancer in females. The histological type of adenocarcinoma has increased and we have observed a slight increase in survival. PMID- 22206931 TI - Referral of discharged emergency department patients to primary and specialty care follow-up. AB - BACKGROUND: Emergency department (ED) patients often need urgent primary or specialty care follow-up, but access is particularly difficult for those without insurance. OBJECTIVE: To characterize follow-up options for uninsured ED patients and to evaluate differences based on ED characteristics. METHODS: We mailed a survey to all ED Directors in Colorado, Georgia, Massachusetts, and Oregon (n = 351 EDs). Typical referrals for urgent primary and specialty care follow-up for uninsured patients were classified as: a) private physician or clinic affiliated with the same hospital; b) external public clinic or university hospital; or c) no referral system/policy. RESULTS: Of the 298 (85%) responding EDs, 215 (72%) reported primary care referral to private physicians or clinics at the same hospital and 231 (78%) for specialty care. Twenty (7%) and 27 (9%) EDs had no referral system for primary and specialty care, respectively. Factors associated with typical referral to primary care follow-up at the same hospital were: lower visit volume (85% for EDs with < 1 patient per hour vs. 67% for EDs with >= 3 patients per hour); rural area (79% for rural vs. 68% for urban areas), and critical access hospital status (81% critical access vs. 69% non-critical access). Conversely, higher visit volume (87% vs. 58%), urban (81% vs. 72%), and non-critical access hospitals (83% vs. 53%) were more likely to refer for specialty care follow-up at the same hospital. CONCLUSION: Referral of uninsured ED patients to local follow-up was high for primary and specialty care. Smaller, rural EDs referred within their own hospital more often for primary care but less often for specialty care. PMID- 22206932 TI - Man with tongue deviation. PMID- 22206933 TI - Splenic abscesses. PMID- 22206934 TI - Quantification of protein posttranslational modifications using stable isotope and mass spectrometry I: principles and applications. AB - With the increased attention to quality by design (QbD) for biopharmaceutical products, there is a demand for accurate and precise quantification methods to monitor critical quality attributes (CQAs). To address this need we have developed a mass spectrometry (MS) based method to quantify a wide range of posttranslational modifications (PTMs) in recombinant proteins using stable isotope-labeled internal standard (SILIS). The SILIS was produced through metabolic labeling where 15N was uniformly introduced at every nitrogen atom in the studied proteins. To enhance the accuracy of the method, the levels of PTMs in SILIS were quantified using orthogonal analytical techniques. Digestion of an unknown sample mixed with SILIS generates a labeled and a nonlabeled version of each peptide. The nonlabeled and labeled counterparts coelute during RP-HPLC separation but exhibit a sufficient mass difference to be distinguished by MS detection. With the application of SILIS, numerous PTMs can be quantified in a single analysis based on the measured MS signal ratios of 15N-labeled versus the nonlabeled pairs. Several examples using microbial and mammalian-expressed recombinant proteins demonstrated the principle and utility of this method. The results indicate that SILIS is a valuable methodology in addressing CQAs for the QbD paradigm. PMID- 22206935 TI - Development of iodoacetic acid-based cysteine mass tags: detection enhancement for cysteine-containing peptide by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - We developed and characterized 6 new cysteine mass tags for high-sensitivity peptide analysis. The structural features are: (1) iodoacetyl group for thiol tagging, (2) hydrophilic character for reducing sample loss, (3) tertiary amino, quaternary ammonium, or guanidino group for high proton affinity, and (4) no amide bonding for minimizing fragmentation of tag moiety in collision-induced dissociation. By using these tags, 2- to 200-fold MS sensitivity was achieved, compared to control peptide with carbamydomethylation. PMID- 22206936 TI - 18O-Labeled nitrous acid and nitrite: Synthesis, characterization, and oxyhemoglobin-catalyzed oxidation to 18O-labeled nitrate. AB - We describe a simple laboratory method for specific labeling of nitrite with 18O for use in chemical and biochemical studies in the area of nitric oxide research. NaNO2 (0.1 mmol) is diluted in H218O (45 MUl) and acidified with HCl (1 MUl, 5 M), and the solution is allowed to equilibrate. Subsequently, the sample is mixed by vortexing with ethyl acetate (500 MUl), and the organic phase is dried over anhydrous Na2SO(4). Ethyl acetate is evaporated to dryness, and the residue is reconstituted in phosphate-buffered saline. In human blood hemolysate, oxyhemoglobin (HbFe16O2) was shown to oxidize N18O2- to 16ON18O2-. PMID- 22206937 TI - A versatile method to measure the binding to basic proteins by surface plasmon resonance. AB - Biomolecular interaction is a fundamental mechanism involved in many critical biological processes including gene transcription, translation, and cell signaling networks. Many basic proteins, such as histones, transcription factors, and ribosomal proteins, participate in the interaction of these processes. Surface plasmon resonance (SPR) has been used as a "gold" standard to measure biomolecular interactions. One key issue in SPR assay is how to immobilize ligand without affecting its conformation and biological activity. In this study, we developed a novel method for measuring bindings to basic proteins by SPR, wherein the naturally positive charge of basic protein was utilized to immobilize ligand. The electrostatic interaction between the basic proteins and the negatively charged C1 chip surface (Biacore, GE) generated a specific and stable immobilization without any modification; sodium dodecyl sulfate was identified to be efficient enough for the complete regeneration that allows fresh ligand to be immobilized in each cycle for an optimal kinetic assay. With those parameters determined, an efficient, fast, and reversible method was established to measure bindings to basic proteins under physiological conditions. This new method is widely applicable to the study of binding kinetics between protein-, DNA-, or RNA and basic protein. PMID- 22206938 TI - Fast and reliable method for simultaneous zymographic detection of glucoamylase and alpha-amylase in fungal fermentation. AB - Detection of alpha-amylase and glucoamylase in crude fermentation extracts using a single native electrophoresis gel and zymogram is described in this article. Proteins were printed on substrate gel and simultaneously onto a membrane in a three-sandwich gel. alpha-Amylase was detected on the substrate gel with copolymerized beta-limit dextrins and iodine reagent. Glucoamylases were detected on the membrane using a coupled assay for glucose detection. Both amylases were detected in native gel using starch and iodine reagent. The described technique can be a helpful tool for monitoring and control of fermentation processes because fungal amylase producers almost always synthesize both amylases. PMID- 22206939 TI - Vapor conjugation of toluene diisocyanate to specific lysines of human albumin. AB - Exposure to toluene diisocyanate (TDI), an industrially important crosslinking agent used in the production of polyurethane products, can cause asthma in sensitive workers. Albumin has been identified as a major reaction target for TDI in vivo, and TDI-albumin reaction products have been proposed to serve as exposure biomarkers and to act as asthmagens, yet they remain incompletely characterized. In the current study, we used a multiplexed tandem mass spectrometry (MS/MS) approach to identify the sites of albumin conjugation by TDI vapors, modeling the air/liquid interface of the lung. Vapor phase TDI was found to react with human albumin in a dose-dependent manner, with up to 18 potential sites of conjugation, the most susceptible being Lys351 and the dilysine site Lys413-414. Sites of vapor TDI conjugation to albumin were quantitatively limited compared with those recently described for liquid phase TDI, especially in domains IIA and IIIB of albumin. We hypothesize that the orientation of albumin at the air/liquid interface plays an important role in vapor TDI conjugation and, thus, could influence biological responses to exposure and the development of in vitro assays for exposure and immune sensitivity. PMID- 22206941 TI - Machine learning for improved pathological staging of prostate cancer: a performance comparison on a range of classifiers. AB - OBJECTIVES: Prediction of prostate cancer pathological stage is an essential step in a patient's pathway. It determines the treatment that will be applied further. In current practice, urologists use the pathological stage predictions provided in Partin tables to support their decisions. However, Partin tables are based on logistic regression (LR) and built from US data. Our objective is to investigate a range of both predictive methods and of predictive variables for pathological stage prediction and assess them with respect to their predictive quality based on U.K. data. METHODS AND MATERIAL: The latest version of Partin tables was applied to a large scale British dataset in order to measure their performances by mean of concordance index (c-index). The data was collected by the British Association of Urological Surgeons (BAUS) and gathered records from over 1700 patients treated with prostatectomy in 57 centers across UK. The original methodology was replicated using the BAUS dataset and evaluated using concordance index. In addition, a selection of classifiers, including, among others, LR, artificial neural networks and Bayesian networks (BNs) was applied to the same data and compared with each other using the area under the ROC curve (AUC). Subsets of the data were created in order to observe how classifiers perform with the inclusion of extra variables. Finally a local dataset prepared by the Aberdeen Royal Infirmary was used to study the effect on predictive performance of using different variables. RESULTS: Partin tables have low predictive quality (c-index=0.602) when applied on UK data for comparison on patients with organ confined and extra prostatic extension conditions, patients at the two most frequently observed pathological stages. The use of replicate lookup tables built from British data shows an improvement in the classification, but the overall predictive quality remains low (c-index=0.610). Comparing a range of classifiers shows that BNs generally outperform other methods. Using the four variables from Partin tables, naive Bayes is the best classifier for the prediction of each class label (AUC=0.662 for OC). When two additional variables are added, the results of LR (0.675), artificial neural networks (0.656) and BN methods (0.679) are overall improved. BNs show higher AUCs than the other methods when the number of variables raises CONCLUSION: The predictive quality of Partin tables can be described as low to moderate on U.K. data. This means that following the predictions generated by Partin tables, many patients would received an inappropriate treatment, generally associated with a deterioration of their quality of life. In addition to demographic differences between U.K. and the original U.S. population, the methodology and in particular LR present limitations. BN represents a promising alternative to LR from which prostate cancer staging can benefit. Heuristic search for structure learning and the inclusion of more variables are elements that further improve BN models quality. PMID- 22206940 TI - Fluorescent reporters of thrombin, heparin cofactor II, and heparin binding in a ternary complex. AB - Thrombin inactivation by heparin cofactor II (HCII) is accelerated by ternary complex formation with heparin. The novel active-site-labeled thrombins, [4'F]FPR T and [6F]FFR-T, and the exosite I probe, Hir-(54-65)(SO3-), characterized thrombin exosite I and II interactions with HCII and heparin in the complex. HCII binding to exosite I of heparin-bound [4'F]FPR-T caused a saturable fluorescence increase, absent with antithrombin. Heparin binding to exosite II and a second weaker site caused fluorescence quenching of [6F]-FFR-T, attenuated by simultaneous Hir-(54-65)(SO3-) binding. Stopped-flow analysis demonstrated ordered assembly of HCII and the [6F]FFR-T.heparin complex, in agreement with tighter heparin binding to thrombin than to HCII. Saturating HCII dependences and bell-shaped heparin dependences of the fluorescence change reported ternary complex formation, consistent with a template mechanism in which the thrombin.heparin complex binds HCII and allowing for interaction of thrombin.(heparin)2 complexes with HCII. Hir-(54-65)(SO3-) displacement in reactions with FPR-blocked and active thrombin indicated a concerted action of the active site and exosite I during ternary complex formation. These studies demonstrate that binding of HCII to the thrombin.heparin complex is dramatically enhanced compared with heparin binding alone and that exosite I is still available for ligand or HCII binding when both heparin binding sites on thrombin are saturated. PMID- 22206942 TI - Caffeic acid phenethyl ester extends survival of a mouse model of amyotrophic lateral sclerosis. AB - There is currently very limited effective pharmacological treatment for amyotrophic lateral sclerosis. Recent evidence suggests that caffeic acid phenethyl ester has strong anti-inflammatory, anti-oxidative, and anti-neuronal death properties; thus, the present study tested the effects of caffeic acid phenethyl ester in mice expressing a mutant superoxide dismutase (SOD1(G93A)) linked to human amyotrophic lateral sclerosis. Administration of caffeic acid phenethyl ester after symptom onset significantly increased the post-onset survival and lifespan of SOD1(G93A) mice. Moreover, immunohistochemical analysis detected less activation of microglia and astrocytes and higher motor neuron counts at an early symptomatic stage (7 days following onset) in the spinal cords of SOD1(G93A) mice given caffeic acid phenethyl ester treatment. Additionally, lower levels of phosphorylated p38, a mitogen-activated protein kinase that is involved in both inflammation and neuronal death, were observed in the spinal cords of SOD1(G93A) mice treated with caffeic acid phenethyl ester for 7 days. These results indicate that caffeic acid phenethyl ester may represent a novel and effective therapeutic for the treatment of amyotrophic lateral sclerosis, and these significant neuroprotective effects observed in a commonly used amyotrophic lateral sclerosis mouse model validate the therapeutic potential of caffeic acid phenethyl ester for slowing disease progression by attenuating the neuroinflammation and motor neuron cell death associated with clinical amyotrophic lateral sclerosis pathology. PMID- 22206943 TI - Deletion of forebrain glucocorticoid receptors impairs neuroendocrine stress responses and induces depression-like behavior in males but not females. AB - Dysfunction in central glucocorticoid signaling is implicated in hypothalamic pituitary-adrenocortical (HPA) axis dysregulation and major depression. In comparison with men, women are twice as likely to suffer from depression and have heightened HPA axis responses to stress. We hypothesized that this striking increase in stress vulnerability in females may be because of sex differences in central glucocorticoid signaling. The current study tests the role of the forebrain type II glucocorticoid receptor (GR) on HPA axis function in female mice and depression-like behavior in both female and male mice. This was accomplished by using mice with selective deletion of GR in forebrain cortico limbic sites including the prefrontal cortex, hippocampus, and basolateral amygdala (forebrain glucocorticoid receptor knockout mouse (FBGRKO)). In order to examine HPA axis function in female FBGRKO, we measured nadir, peak circadian and restraint-induced corticosterone concentrations in female FBGRKO. The data indicate that unlike male FBGRKO, basal and stress-induced corticosterone concentrations are not increased in female FBGRKO. Given the pronounced effect of central glucocorticoid signaling on mood, we also examined the necessity of corticolimbic GR on depression-like behavior with the sucrose preference and forced swim tests (FST) in male and female FBGRKO mice. Consistent with previous studies, male FBGRKO displayed increased depression-like behavior as indicated by greater immobility in the FST and decreased sucrose preference compared with littermate controls, effects that were not observed in females. Overall the findings indicate a marked sex difference in the function of forebrain GR on HPA axis regulation and depression-like behaviors, and may have implications for therapeutic approaches using GR-modulating drugs. PMID- 22206944 TI - Albumin coupled lipid nanoemulsions of diclofenac for targeted delivery to inflammation. AB - Diclofenac lipid nanoemulsions (DLNEs) were prepared with different compositions. Based on size, PDI, zeta potential, and in vitro drug release, the optimized DLNEs (DLNE-4 and DLNE-7) were developed and evaluated for drug content, entrapment efficiencies, and stability in comparison to the control formulation (DLNE-1). The albumin was coupled to DLNE-7 globules (DLNE-8) by water soluble carbodiimide (EDC) method, purified, and quantified by modified Bradford method. The pharmacokinetic study was conducted in inflammation (granuloma air pouch model) induced rats. The maximum peak concentration of DLNE-8 was almost fourfold to fivefold in comparison to drug solution in granuloma air pouch fluid (GAPF). The therapeutic availability (TA) of DLNE-8 was 2.89, 2.34, and 1.66 times that of drug solution, DLNE-4 and DLNE-7, respectively. The GAPF/serum ratio of diclofenac from DLNE-8 was above one at all time points indicating the targeting potential of albumin ligated LNEs to inflammatory sites. FROM THE CLINICAL EDITOR: This study demonstrates targeted delivery of diclofenac to an inflammatory environment using the granuloma air pouch model and diclofenac nanoemulsions with different compositions. PMID- 22206945 TI - Preclinical evaluation of a pulmonary delivered paclitaxel-loaded lipid nanocarrier antitumor effect. AB - Lung cancer remains a leading cause of death due to the low efficacy of chemotherapy, mainly related to the administration route used. Therefore, alternative administration routes are needed. Paclitaxel (PTX) is an insoluble anticancer drug active against solid tumors, such as those found in lung cancer, that has stimulated an intense research effort over recent years. Solid lipid nanoparticles (SLNs) are potential carriers for poorly soluble drugs, being biodegradable systems that served as alternatives to the usual colloidal carriers. That system was used to deliver PTX to the lungs and seem to fulfill the requirements for an optimum particulate carrier. Furthermore, PTX-loaded SLN pulmonary administration provided a target administration, which is expected to avoid high concentration of the drug at nontarget tissues, reducing toxicity, and increasing the drug's therapeutic index. The rationale of this study was to deliver a colloidal system to the lung lymphatics through a pulmonary route for cancer therapy. FROM THE CLINICAL EDITOR: Paclitaxel-loaded solid lipid nanoparticles were used to target tumors in a murine lung cancer model enabling high PTX concentration in the target with reduced systemic toxicity and increased therapeutic index. PMID- 22206946 TI - Activation of TrkB receptors by NGFbeta mimetic peptide conjugated polymersome nanoparticles. AB - Activation of tyrosine kinase receptor B (TrkB), a neurotrophin receptor, has been shown to increase neuronal cell survival and promote regeneration. Stimulation of the TrkB receptor by neurotrophic growth factors has been identified as a possible therapeutic target for the treatment of neurodegenerative disorders. However, growth factor delivery is problematic because of a short half-life in vivo. We have conjugated hNgf-EE, a short peptide mimetic of NGFbeta to the surface of polymersome nanoparticles and shown that they are capable of activating the TrkB receptor in vitro in the SHSY-G7 cell line. We propose that polymersomes could act as a scaffold for the delivery of TrkB activating moieties and that the polymersome size and polyethylene glycol surface have been shown to increase in vivo retention time. These multifunctional nanoparticles have potential for the treatment of neurodegenerative disorders by TrkB activation. From the ClinicaL Editor: Tyrosine kinase receptor B activation has been shown to promote regeneration and survival of neurons. However, growth factor delivery to stimulate these receptors remains problematic. The authors demonstrate that a peptide mimetic of NGFbeta conjugated to the surface of polymersome nanoparticles is capable of activating the TrkB receptors. These nanoparticles may offer a novel treatment strategy for a variety of neurodegenerative disorders. PMID- 22206947 TI - [Costs associated with nosocomial bacteraemias in a University Hospital]. AB - OBJECTIVE: To describe the increase in costs due to patients who had any episode of nosocomial bacteraemia (NB) in a University Hospital, compared to the costs of patients with the same illness who did not. METHODS: Descriptive and retrospective study. POPULATION: all hospitalisation episodes between January 2005 and December 2007. We compared the patients who suffered some episode of NB, with the patients who did not. Dependent variable: cost of the hospitalisation episode. Main explanatory variable: presence of nosocomial bacteraemia. A generalized linear model was adjusted, with Gamma distribution and link logarithm function, given the distribution of the costs. RESULTS: There were 640 hospital episodes with NB and 28,459 with no NB. The average incremental cost for the hospitalisations with NB was 14,735.5?, adjusted for the disease. The impact on the costs for the hospital due to patients with NB was 9,430,713?. The most frequent source of infection was the catheter (35.5%), with an average increase in cost of 18,078?. In the multivariable model, the cost of patients with NB and involving a Gram(+) microorganism was 2.1 times more than that of patients without bacteraemia (95% CI; 1.96-2.23), if the microorganism was Gram(-) it was 1.8 times more (95% CI; 1.70-1.93), and for a fungus it was 2.4 time more (95% CI; 1.95-2.89). CONCLUSIONS: This analysis shows the significant impact in the financial costs due to NB, and gives a measure of the cost-benefit of investing in resources to prevent them. Knowing the source cause of the bacteraemia allows priority to be given to these areas and to promote the necessary actions designed to prevent them. PMID- 22206948 TI - [Invasive fungal disease: conventional or molecular mycological diagnosis?]. AB - Diagnosis of invasive mycoses is a difficult challenge due to the limitations and low sensitivity of traditional microbiology methods which lead to diagnostic and therapeutic delays. The aim of this review is to summarise the state of the art of the molecular diagnosis of invasive fungal disease and to clarify its current role in the clinical practice. Conventional microbiological methods could be complemented with molecular methods in the rapid and definitive identification of fungal isolates. Biomarkers (beta-glucan, galactomannan) are very useful in immunocompromised patients and have been included as probable invasive mycoses by the EORTC/MSG. Nucleic acid detection is currently used as a complementary tool for diagnosis. However, PCR can be very useful in mould invasive mycoses. Finally, the combined detection using biomarkers can improve the diagnosis. However, their applicability in the microbiology laboratory is not so easy and further studies are required for the appropriate evaluation of its clinical usefulness. PMID- 22206949 TI - [Analysis of publications on infectious diseases. A comparative study of ten countries in the period 2000-2009]. AB - OBJECTIVE: We analyse the productivity and visibility of Spanish publications on the subject category of infectious diseases in the period 2000-2009 and compared with the corresponding nine other countries. METHODS: We used the database Web of Science. Analysis (annual and five-year) was restricted to the citable documents. The bibliometric indicators used were the number of publications, the amount of citations, median and interquartile range of the citations and the h-index Hirsch. RESULTS: There were 76,491 publications (84.1% were original articles) with a percentage increase of 20% between the two periods. The ten countries with over 50,000 citations were the United States, United Kingdom, France, Germany, Canada, Holland, Spain, Italy, Switzerland and Australia. 24.8% of publications in international collaboration was made and received 29.9% of the total citations. 47.1% of the publications corresponding to the first quartile journals and received 68.1% of the total citations. The median of citations for all publications was 9 (interquartile range: 4-21). Spain was the fifth country in the world by number of publications, the seventh by citations received, and the eighth by the h index. Spain was the country with the lowest percentage of publications in the first quartile (40.2%), and international collaboration (26.7%). CONCLUSIONS: In the period 2000-2009 analysed we observed a high production of publications by Spanish authors, with a high growth rate, and a prominent position in the total number of citations received by publications. PMID- 22206950 TI - Human papillomavirus (HPV) genotype distribution in women with abnormal cervical cytology in the Basque Country, Spain. AB - INTRODUCTION: The aim of this study was to analyze the distribution of human papillomavirus (HPV) genotypes in cytologically abnormal cervical samples from 106 women living in a region of the north of Spain. METHODS: Cytological classification was reported according to the 2001 Bethesda System and HPV genotyping was performed by Roche Linear Array. RESULTS: The overall HPV prevalence was 69.8% with 30 different HPV genotypes detected. The prevalence of HR (high-risk) HPV types and pHR (probable high-risk) HPV types in positive samples was 94.3%, 78.1% and 100% in patients with ASCUS, LSIL and HSIL/CC, respectively, with no significant differences. The most frequent type was the HPV 16, present in 29.7% of all positive samples, followed by HPV 51 (17.5%), HPV 53 and 42 (16%), HPV 52 (12%), HPV 39 (10.8%), HPV 18 and 58 (9.4%) and HPV 66 (8.1%). No significant differences in the percentage of any HPV genotype with the grade of the cytological lesion were detected. The prevalence of HPV co-infection was 58.1% of HPV positive. CONCLUSIONS: This study confirms the high prevalence of high-risk genotypes in women with abnormal cytology living in our geographical area. This information may be useful for the formulation of algorithms for patient management according to the different risks associated with specific high risk genotypes. PMID- 22206951 TI - Patients' radiation doses during thoracic stent-graft implantation: the problem of long-lasting procedures. AB - BACKGROUND: This article investigates patient radiation doses during implantation of thoracic stent-graft. Aortic stengraft implantation can be disturbed by many factors, which, in turn, lead to prolongation of the procedure time and, as a consequence, increase the radiation dose. METHODS: Measurements of radiation length (fluoroscopy and exposure), air kerma (AK) in grays, and dose-area product in grays.square centimeters were conducted simultaneously in 100 patients. The patients were analyzed retrospectively, regarding their body mass index (BMI), type of aneurysms, number of stent-graft parts, angulation of aorta, and coverage of the left subclavian artery. RESULTS: Mean total dose-area product value for this kind of treatment was 361 Gy.cm2. This was caused by the fact that total mean AK was high for the cohort analyzed and reached 797 mGy. For 23 patients total AK was between 1 and 2 Gy, and for 3 it exceeded 2 Gy. In the remaining group, the maximal radiation dose was very high and exceeded 3 Gy. The total AK of patients with BMI within the range of 25 to 29.9 kg/m2 and with BMI greater than 30 kg/m2 significantly increased in comparison with the group of patients with BMI between 18 and 24.9 kg/m2 (p=0.00005 and 0.000001, respectively). During the study, a good correlation between AK and fluoroscopy time (r=0.6) and for AK (or dose-area product) and exposure time (r=0.66 or 0.81, respectively) was observed. CONCLUSIONS: The main factors contributing to a high radiation dose being acquired by patients during thoracic stent-graft were BMI greater than 25 kg/m2, number of parts of the stent-graft, and angulation of the neck of aneurysm exceeding 60 degrees. PMID- 22206952 TI - Determinants of acute kidney injury duration after cardiac surgery: an externally validated tool. AB - BACKGROUND: Acute kidney injury (AKI) duration after cardiac surgery is associated with poor survival in a dose-dependent manner. However, it is not known what perioperative risk factors contribute to prolonged AKI and delayed recovery. We sought to identify perioperative risk factors that predict duration of AKI, a complication that effects short and long-term survival. METHODS: We studied 4,987 consecutive cardiac surgery patients from 2002 through 2007. Acute kidney injury was defined as a 0.3 or greater (mg/dL) or 50% or greater increase in serum creatinine from baseline. Duration of AKI was defined by the number of days AKI was present. Stepwise multivariable negative binomial regression analysis was conducted using perioperative risk factors for AKI duration. The c index was estimated by Kendall's tau. RESULTS: Acute kidney injury developed in 39% of patients with a median duration of AKI at 3 days and ranged from 1 to 108 days. Patients without AKI had a duration of 0 days. Independent predictors of AKI duration included baseline patient and disease characteristics, and operative and postoperative factors. Prediction for mean duration of AKI was developed using coefficients from the regression model and externally validated the model on 1,219 cardiac surgery patients in a separate cardiac surgery cohort (Translational Research Investigating Biomarker Endpoints-AKI). The c-index was 0.65 (p<0.001) for the derivation cohort and 0.62 (p<0.001) for the validation cohort. CONCLUSIONS: We identified and externally validated perioperative predictors of AKI duration. These risk factors will be useful to evaluate a patient's risk for the tempo of recovery from AKI after cardiac surgery and subsequent short and long-term survival. The levels of awareness created by working with these risk factors have implications regarding positive changes in processes of care that have the potential to decrease the incidence and mitigate AKI. PMID- 22206953 TI - Outcomes after surgical treatment of native and prosthetic valve infective endocarditis. AB - BACKGROUND: The risk of death and complications of infective endocarditis (IE) treated medically has to be balanced against those from surgery in constructing a therapeutic approach. Recent literature has drawn conflicting conclusions on the benefit of surgery for IE. We reviewed patients treated surgically for IE at the Cleveland Clinic from 2003 to 2007 to examine their outcomes. METHODS: A retrospective review of consecutive patients who underwent surgery for native and prosthetic valve endocarditis between January 1, 2003, and December 31, 2007, was conducted. Surgical outcomes were reviewed to include survival and postoperative complications. Survival was evaluated at end of hospital stay, 30 days, 1 year, and at last follow-up. RESULTS: Four hundred twenty-eight patients underwent surgery for IE during the study period: 248 (58%) had native valve endocarditis and 180 (42%) had prosthetic valve endocarditis. Overall 90% of patients survived to hospital discharge. When compared with patients with native valve infection, patients with prosthetic infection had significantly higher 30-day mortality (13% versus 5.6%; p<0.01), but long-term survival was not significantly different (35% versus 29%; p=0.19). Patients with IE caused by Staphylococcus aureus had significantly higher hospital mortality (15% versus 8.4%; p<0.05), 6-month mortality (23% versus 15%; p=0.05), and 1-year mortality (28% versus 18%; p=0.02) compared with non-S aureus IE. CONCLUSIONS: Surgical treatment of IE was associated with 90% hospital survival. Outcomes within the 30 days were better for native valve than for prosthetic valve endocarditis. Long-term outcomes were similar. Finally, S aureus was associated with significantly higher mortality compared with other pathogens. PMID- 22206954 TI - High-pressure distention of the saphenous vein during preparation results in increased markers of inflammation: a potential mechanism for graft failure. AB - BACKGROUND: Coronary artery disease is the single leading cause of death in the United States. Commonly it is treated with coronary bypass grafting using the saphenous vein (SV) or internal mammary artery (IMA) as a conduit. Unfortunately, the SV has much lower patency rates compared with the IMA. Several hypotheses exist as to why occlusion occurs more commonly in SV grafts than in IMA grafts. However detailed studies in this area have been limited. This study investigates the effects of pressure distention on inflammation in SV conduit used in coronary artery bypass grafting (CABG). METHODS: Saphenous vein distention pressure was measured intraoperatively during 48 CABG procedures. A segment of SV was excised from the conduit before distention. Because the vein was used for coronary artery grafting, sequential pieces were archived for evaluation. Real-time polymerase chain reaction (RT-PCR) and immunohistochemical analyses were performed to investigate a change in the expression of biomarkers. RESULTS: Upregulation of various biomarkers occurred. These biomarkers included scavenger receptors A and B (SR-A, SR-B), toll-like receptors 2 and 4 (TLR2, TLR4), platelet endothelial cell adhesion molecule (PECAM), vascular cell adhesion molecule (VCAM), and intercellular cell adhesion molecule (ICAM) in segments of SV that were subjected to distention. Immunohistochemical results mirrored RT-PCR findings. A significant correlation was observed between biomarkers and pressure values. CONCLUSIONS: These studies demonstrate that markers of inflammation are upregulated in response to SV distention. The data suggest that the pressure used in graft preparation procedures should be regulated to avoid inflammation and its potential to induce graft failure. PMID- 22206955 TI - Reoperation after surgical correction of acute type A aortic dissection: risk factor analysis. AB - BACKGROUND: Aortic dissection is an evolving process that may require one or several reoperations after its initial repair. We conducted a study to evaluate risk factors and define the incidence and locations of reoperations after surgical correction of acute type A aortic dissection (AAD). METHODS: Between 1998 and 2008, 250 consecutive patients (mean age 62.5+/-12.4 years) underwent surgery for AAD at our institution. Replacement of the ascending aorta was done in 173 cases, composite graft replacement in 61 cases, separate aortic valve and ascending aorta replacement in 2 cases, and arch replacement required by distal repair in 14 cases. Mean follow-up time was 4.7+/-5.6 years. RESULTS: Freedom from reoperation was 99%, 82%, and 79% at 1, 5, and 10 years, respectively. Twenty-five patients required 25 reoperations at a mean interval of 4.7 years after initial surgery for the correction of AAD. Reoperations included 21 procedures on the proximal aorta (ascending aorta, aortic root, or valve) and 4 procedures on the distal aorta (arch or descending aorta). Cox regression analysis identified the use of gelatin-resorcinol-formaldehyde (GRF) glue (p=0.0270), and nonreplacement of the aortic root at the time of initial AAD repair (p=0.0004), as a significant risk factor for proximal reoperation, and a patent false lumen (p=0.0107) as a significant risk factor for distal reoperation. CONCLUSIONS: A patent false lumen, the use of GRF glue, and aortic root preservation at initial operation influence the risk for surgical correction in patients undergoing surgery for AAD. These patients need long-term follow-up. PMID- 22206956 TI - Molecular detection of microorganisms in distal airways of patients undergoing lung cancer surgery. AB - BACKGROUND: Whereas proximal airways of patients undergoing lung cancer surgery are known to present specific microbiota incriminated in the occurrence of postoperative respiratory complications, little attention has been paid to distal airways and lung parenchyma considered to be free from bacteria. We have hypothesized that molecular culture-independent techniques applied to distal airways should allow identification of uncultured bacteria, virus, or emerging pathogens and predict the occurrence of postoperative respiratory complications. METHODS: Microbiological assessments were obtained from the distal airways of resected lung specimens from a prospective cohort of patients undergoing major lung resections for cancer. Microorganisms were detected using real-time polymerase chain reaction (PCR) assays targeting the bacterial 16s ribosomal RNA gene and Herpesviridae, cytomegalovirus (CMV), and herpesvirus simplex. All postoperative microbiological assessments were compared with the PCR results. RESULTS: In all, 240 samples from 87 patients were investigated. Colonizing agents were exclusively Herpesviridae (CMV, n=13, and herpesvirus simplex, n=1). All 16s ribosomal RNA PCR remained negative. Thirteen patients (15%) had a positive CMV PCR (positive-PCR group), whereas the remaining 74 patients constituted the negative-PCR group. Postoperative pneumonia occurred in 24% of the negative-PCR group and in 69% of the positive-PCR group (p=0.003). Upon stepwise logistic regression, performance status, percent of predicted diffusion lung capacity for carbon monoxide, and positive PCR were the risk factors of postoperative respiratory complications. The CMV PCR had a positive predictive value of 0.70 in prediction of respiratory complications. CONCLUSIONS: When tested by molecular techniques, lung parenchyma and distal airways are free of bacteria, but CMV was found in a high proportion of the samples. Molecular CMV detection in distal airways should be seen as a reliable marker to identify patients at risk for postoperative respiratory complications. PMID- 22206957 TI - Refractory spasm of coronary arteries and grafted conduits after isolated coronary artery bypass surgery. AB - BACKGROUND: Refractory vascular spasm (RVS) concomitantly involving the entire coronary artery system and grafted conduits after coronary artery bypass grafting (CABG) surgery is a rare, but dreadful event. No consensus exists in terms of appropriate management. METHODS: Between 1986 and 2009, 5,762 patients underwent isolated CABG at our institution, and 7 patients experienced RVS involving the coronary arteries and implanted conduits. Mean age was 65.6 years and 3 were female. All patients received from 3 to 5 distal anastomoses, including use of the left internal mammary artery. During the same time period, 18 patients experienced perioperative vasospasm of a single coronary artery or of a grafted conduit. RESULTS: All diffuse RVS events occurred between 3 and 8 hours after surgery. All patients had diffuse ischemic-like electrocardiographic changes, and 5 patients rapidly developed cardiogenic shock in the intensive care unit. Angiography was quickly performed in all patients and showed diffuse RVS involving either the native coronary arteries or the anastomosed arterial and venous conduits. The first 5 patients of this series died in the catheterization lab due to rapidly evolving refractory cardiogenic shock and unresponsive cardiac arrest, despite intraaortic counterpulsation and aggressive pharmacologic interventions (selective vasodilators and systemic inotropes). In the last 2 patients, extracorporeal membrane oxygenation was quickly instituted (1 in the catheterization lab, 1 in the operating room) and RVS could be successfully managed with complete resolution of ongoing vasospasm. In the single vascular spasm, there was only 1 death for refractory cardiac arrest, whereas all the other patients were successfully treated with direct infusion of vasodilators. CONCLUSIONS: Diffuse RVS after CABG is a rare but lethal condition. Our experience, although limited, indicates that in such cases an aggressive treatment, that is, prompt extracorporeal membrane oxygenation institution and controlled cardiocirculatory assistance, represents the preferred solution to face such a dramatic event and may save patient lives. PMID- 22206958 TI - Maximal standardized uptake value on FDG-PET is correlated with cyclooxygenase-2 expression in patients with lung adenocarcinoma. AB - BACKGROUND: Cyclooxygenase-2 (COX-2) is constitutively overexpressed in a variety of epithelial malignancies and is usually associated with a poor prognosis. Fluorodeoxyglucose positron emission tomography (FDG-PET) has become an important tool for the diagnosis and staging of non-small-cell lung cancer. The maximal standardized uptake values (SUVmax) of primary tumors on FDG-PET have been shown to be correlated with some clinicopathologic factors. In this study, we investigated the prediction of intratumoral COX-2 expression by FDG-PET in cases of lung adenocarcinoma. METHODS: We conducted a retrospective review of the data of 60 patients with lung adenocarcinoma measuring less than 3 cm in diameter. Immunohistochemical staining for COX-2 and other biological factors that might influence cancer progression was performed, and the correlations of the selective tumor marker expression with the SUVmax were evaluated. RESULTS: A significant correlation was observed between the SUVmax and the expressions of COX-2, Ki-67, and vascular endothelial growth factor (VEGF). Multiple stepwise regression analysis revealed significant relationships between the SUVmax and the expression of COX-2 (p<0.001) and Ki-67 (p=0.016). Of the 2, COX-2 expression was the stronger determinant of the SUVmax, which increased in proportion to the score for COX-2 expression. The recurrence-free survival of patients with elevated COX 2 expression was significantly worse than that of patients not showing COX-2 expression. CONCLUSIONS: The expression of COX-2 in primary tumors is as strongly correlated with a worse clinical outcome as is increased FDG uptake in cases of lung adenocarcinoma. These findings indicate that the SUVmax of primary tumors might reflect the biological malignant potential in lung adenocarcinomas. PMID- 22206959 TI - Local extension at the hilum region is associated with worse long-term survival in stage I non-small cell lung cancers. AB - BACKGROUND: The prognostic significance of hilar structures invasion, which remains undefined for non-small cell lung cancer (NSCLC), may have potential application for cancer staging. Tumor extension along the bronchus and pulmonary vessels was examined for survival significance. METHODS: In all, 213 pathologically proved central-type stage I NSCLC cases were enrolled. Four study groups were assigned based on the extent of resections: standard lobectomy (group L, n=32), bronchoplastic procedures (group B, n=94), standard lobectomy combined with pulmonary angioplasty (group A, n=48), and bronchial sleeve resection combined with pulmonary artery angioplasty (group BA, n=39). Univariate and multivariate analysis were performed by the Kaplan-Meier method and the Cox regression model. RESULTS: There were 2 postoperative deaths (pulmonary embolism and serious pulmonary infection). Complications were noted in 39 patients (18.3%). Among these patients, the overall 5-year survival rate was 60.2%+/ 0.05%, with a median survival time of 75.0+/-7.5 months. The 5-year survival rates of subgroups were 79.5%, 59.7%, 59.0%, and 47.9%, respectively for groups L, B, A, and BA. Univariate analysis indicated tumor size, bronchial invasion, arterial involvement, and type of operation as closely associated with long-term survival. Multivariate analysis indicated that type of operation and tumor size were the most prominent prognostic factors of 5-year survival. CONCLUSIONS: Proximal tumor extension into bronchus, invasions into extrapericardial pulmonary vessels, and tumor size were the most important risk factors for 5-year survival with central-type stage I NSCLC. Tumor extension in the hilum was highly related to prognosis and might provide pertinent information to accurately define a tumor ("T") subclass. PMID- 22206961 TI - Aortic valve replacement with the Medtronic Mosaic bioprosthesis: a 13-year follow-up. AB - BACKGROUND: This study evaluated the long-term clinical performance of the Mosaic bioprosthesis (Medtronic Inc, Minneapolis, MN) after aortic valve replacement. METHODS: From 1995 to 2008, 178 patients (48 women; mean age, 74+/-6 years) had aortic valve replacement. Mean functional class was 2.3+/-0.5, and 157 patients (88%) were in sinus rhythm. Prosthetic sizes were 23 mm in 98 patients and 25 mm in 66. Follow-up was completed in December 2009 with a cumulative duration of 1,015 patient/years (mean, 5.7+/-3.5 years, maximum, 13.7 years). RESULTS: Early mortality was 4%, none being valve-related; of 38 late deaths 7 were valve related. Actuarial survival at 13 years was 48%+/-8%. Mean functional class of current survivors was 1.2+/-0.6. Six embolic episodes occurred and four cases of endocarditis, with respective actuarial freedom of 92%+/-5% for embolism and 97%+/-2% for endocarditis at 13 years. Four patients required reoperations for endocarditis and 2 for structural deterioration. Actuarial freedom from structural deterioration and from reoperation for all causes was 89%+/-7% and 86%+/-7% at 13 years, with an actuarial freedom from prosthesis-related deaths of 86%+/-5%. Results of echocardiographic evaluation at 1 year were mean peak gradient, 20+/-6 mm Hg and mean effective orifice area index, 1.07+/-0.21 cm2/m2 for size 23 mm and 22+/-6 mm Hg and 1.11+/-0.26 cm2/m2 for size 25 mm; at 10 years, mean peak gradient and mean effective orifice area index were 28+/-13 mm Hg and 1.01+/-0.19 cm2/m2 for size 23 mm and 26+/-8 mm Hg and 1.08+/-0.18 cm2/m2 for size 25 mm. CONCLUSIONS: The Mosaic bioprosthesis showed good overall performance, with low incidence of structural valve deterioration and hemodynamic stability in the long-term. Expected increased durability of this device should be verified at longer follow-up intervals. PMID- 22206960 TI - Aortic dilatation with bicuspid aortic valves: cusp fusion correlates to matrix metalloproteinases and inhibitors. AB - BACKGROUND: Congenital bicuspid aortic valves (BAVs) result from fusion of 2 valve cusps, resulting in left-noncoronary (L-N), right-left (R-L), and right noncoronary (R-N) morphologic presentations. BAVs predispose to ascending thoracic aortic aneurysms (ATAAs). This study hypothesized that ATAAs with each BAV morphologic group possess unique signatures of matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of metalloproteinases (TIMPs). METHODS: Ascending thoracic aortic aneurysm tissue from 46 patients with BAVs was examined for MMP/TIMP abundance, and global MMP activity was compared with normal aortic specimens (n=15). Proteolytic balance was calculated as the ratio of MMP abundance to a composite TIMP score. Results were stratified by valve morphologic group (L-N [n=6], R-L [n=31], and R-N [n=9]). RESULTS: The BAV specimens (p<0.05 versus normal aorta, 100%) displayed elevated global MMP activity (273%+/-63%), MMP-9 (263%+/-47%), and decreased MMP-7 (56%+/-10%), MMP-8 (58%+/-11%), TIMP-1 (63%+/-7%), and TIMP-4 (38%+/-3%). The R-L group showed increased global MMP activity (286%+/-89%) and MMP-9 (267%+/-55%) with reduced MMP-7 (45%+/-7%), MMP-8 (68%+/-15%), TIMP-1 (58%+/-7%), and TIMP-4 (35%+/-3%). The L-N group showed elevated global MMP activity (284%+/-71%) and decreased MMP-8 (37%+/-17%) and TIMP-4 (48%+/-14) activity. In the R-N group, MMP-7 (46%+/-13%) and MMP-8 (36%+/ 17%) and TIMP-1 (59%+/-10%) and TIMP-4 (42%+/-5%) were decreased. The R-L group demonstrated an increased proteolytic balance for MMP-1, MMP-9, and MMP-12 relative to L-N and R-N. CONCLUSIONS: Each BAV morphologic group possesses a unique signature of MMPs and TIMPs. MMP/TIMP score ratios suggest that the R-L group may be more aggressive, justifying earlier surgical intervention. PMID- 22206962 TI - Surgical results for functional univentricular heart with total anomalous pulmonary venous connection over a 25-year experience. AB - BACKGROUND: Surgical results for functional univentricular heart with total anomalous pulmonary venous connection (TAPVC) have been unsatisfactory to date. METHODS: During a 25-year period until December 2009, 207 TAPVC patients underwent surgical repair at our institute, including 56 with a univentricular heart. The 10-year survival rate was 51.1% with univentricular heart and 84.7% with biventricular heart (p<0.0001; log-rank, 27.6). Surgical outcomes and risk factors for early and late death after TAPVC repair in univentricular hearts were retrospectively analyzed. RESULTS: Patients were aged 3.8+/-4.3 years and weighed 12.3+/-10.7 kg at operation. Preoperative diagnoses included heterotaxy syndrome in 55, asplenia in 48, preoperative pulmonary venous obstruction in 35, and pulmonary atresia in 20. TAPVC was classified as I in 22, II in 26, III in 5, and IV in 3. Concomitant procedures included Fontan procedure in 29, bidirectional Glenn procedure in 5, systemic-pulmonary shunt in 11, and pulmonary artery banding in 5. There were 17 hospital deaths and 11 late deaths. Fontan completion was undertaken in 31 (55.3%). Postoperative pulmonary venous obstruction was found in 15. Multivariate analysis identified TAPVC III and IV and pulmonary atresia as risk factors for hospital death. Univariate analysis identified postoperative pulmonary venous obstruction and concomitant systemic-pulmonary shunt as risk factors for hospital and late death. CONCLUSIONS: TAPVC III, IV, and pulmonary atresia are risk factors for early postoperative death. Intensive intervention, including perioperative management and operation, is required in these complex patients. PMID- 22206963 TI - Postprandial plasma PYY concentrations are associated with increased regional gray matter volume and rCBF declines in caudate nuclei--a combined MRI and H2(15)O PET study. AB - The anorexigenic gastrointestinal hormone Peptide YY plays an important role in the communication between the gastrointestinal tract and the central nervous system. PYY has been shown to modulate brain activity in regions implicated in reward and food related behavior. Its effects on brain structure however, remain unknown. Voxel-based morphometry was used to investigate the relationship between fasting and postprandial plasma PYY concentrations and regional gray matter volume (GMV). For this analysis twenty adult, non diabetic Caucasians were included (18F/2M, age 31+/-9 y, percentage of body fat [PFAT] 32+/-8%) who had volumetric brain magnetic resonance images and underwent H(2)(15)O positron emission tomographic (PET) measurements of regional cerebral blood flow (rCBF), a marker of local neuronal activity, and measurements of plasma total PYY, prior to (fasting) and following a satiating liquid meal. Voxel-wise analysis revealed a regional positive association between postprandial PYY and gray matter volume bilaterally in the caudate nuclei. These associations remained significant (p<0.05) after small volume correction for multiple comparisons. Based on these findings we investigated whether postprandial PYY is associated with PET measured rCBF of the caudate nucleus. We found a significant negative association between average postprandial caudate rCBF and postprandial plasma PYY concentrations (r= 0.60, p<0.02, age, sex and PFAT adjusted). Average postprandial caudate rCBF was also negatively associated with rCBF in the right medial orbitofrontal cortex and the right hippocampal formation (p<0.05, corrected for multiple comparisons). Total PYY is positively associated with gray matter but negatively with postprandial activity in the caudate nuclei while caudate activity is negatively associated with rCBF in prefrontal and paralimbic regions implicated in reward behavior. Thus, PYY may act centrally to modulate eating behavior via striatal networks. PMID- 22206964 TI - Inflection in action: Semantic motor system activation to noun- and verb containing phrases is modulated by the presence of overt grammatical markers. AB - A recent breakthrough in understanding brain-language mechanisms is the discovery of local motor cortex activations that index specific meaning features of words, phrases and sentences. The words "talk" and "walk" activate different parts of the motor cortex, reflecting the body part relationship of actions the linguistic items are typically used to speak about. It has been suggested that such semantic motor mapping can be explained by behaviorist theories, based on conditioning mechanisms also effective in Pavlov's dog when it salivates to bell sounds. In contrast, a neurobiological approach to language predicts modulation of semantic activation by grammatical, including inflectional-morphological, information. Here, we test these competing predictions by putting action words into different phrasal contexts invoking morphosyntactic and morphophonological processes and demonstrate that semantic motor mappings are modulated by grammatical sentence properties, especially the presence of overtly realized inflectional affixes on nouns or verbs embedded in grammatical phrases. Mechanistic neuroscience theories taking into account both meaning and grammar, including morphology and syntax, are required to explain these observations. A direct comparison between phrases containing nouns and verbs revealed a tendency towards greater activation to noun phrases in left-inferior premotor cortex and posterior Broca's region (BA 44), thus questioning previous suggestions that left inferiorfrontal areas might be dedicated to verb processing per se. PMID- 22206966 TI - Memory coding in plastic neuronal subpopulations within the amygdala. AB - Specific neuronal subpopulations within specific brain areas are responsible for learning and memory. A fear memory engages a subset of lateral amygdala neurons, but whether multiple contextual fear memories engage the same or different subsets of lateral amygdala neurons remains unclear. Here, we demonstrate the representation of multiple contextual fear memories in the amygdala with cellular and temporal resolution using a large-scale imaging method. Mice were conditioned with a footshock in 2 separate chambers. They were then re-exposed to either the same conditioning chamber twice or 2 different conditioning chambers. The activities of individual neurons related to the re-exposures were determined by the subcellular distribution of Arc/Arg3.1 RNA. Reactivation of different memories activated partially (about 50%) overlapping neurons, whereas reactivation of the same memory activated more overlapping (about 65%) neurons. These findings indicate that lateral amygdala neurons related to different fear memories are partly common, and that a small but significant neuronal population (2.7% of total lateral amygdala neurons) encodes differences in individual fear memories. Moreover, memory retrieval increased the size of the neuronal subpopulation activated during subsequent retrieval. Taken together, our findings indicate that small plastic subsets of neurons encode fear memories from individual contexts. PMID- 22206965 TI - Neural substrates of smoking cue reactivity: a meta-analysis of fMRI studies. AB - Reactivity to smoking-related cues may be an important factor that precipitates relapse in smokers who are trying to quit. The neurobiology of smoking cue reactivity has been investigated in several fMRI studies. We combined the results of these studies using activation likelihood estimation, a meta-analytic technique for fMRI data. Results of the meta-analysis indicated that smoking cues reliably evoke larger fMRI responses than neutral cues in the extended visual system, precuneus, posterior cingulate gyrus, anterior cingulate gyrus, dorsal and medial prefrontal cortex, insula, and dorsal striatum. Subtraction meta analyses revealed that parts of the extended visual system and dorsal prefrontal cortex are more reliably responsive to smoking cues in deprived smokers than in non-deprived smokers, and that short-duration cues presented in event-related designs produce larger responses in the extended visual system than long-duration cues presented in blocked designs. The areas that were found to be responsive to smoking cues agree with theories of the neurobiology of cue reactivity, with two exceptions. First, there was a reliable cue reactivity effect in the precuneus, which is not typically considered a brain region important to addiction. Second, we found no significant effect in the nucleus accumbens, an area that plays a critical role in addiction, but this effect may have been due to technical difficulties associated with measuring fMRI data in that region. The results of this meta-analysis suggest that the extended visual system should receive more attention in future studies of smoking cue reactivity. PMID- 22206968 TI - Fabrication of hierarchical structures by unconventional two-step imprinting. AB - We present a simple sequential imprinting lithography method to fabricate micro/nanoscale hierarchical structures. This method involves hot embossing and capillary force lithography with two stamps of different microscales, which avoids using nanoscale stamps. By varying the experimental conditions in the capillary force lithography process, the morphology of the resulting structures can be controlled. This method may provide a facile and low-cost route for fabricating large area patterns of hierarchical structures. PMID- 22206969 TI - Hydrodynamic and interparticle potential effects on aggregation of colloidal particles. AB - The effects of both hydrodynamic interaction and the form of the interparticle potential on the aggregation process for dispersed spherical particles are investigated by computational simulation. The simulation methods of Brownian Dynamics (BD) and Stokesian Dynamics (SD) are applied, over a range of solid volume fraction of 0.04<=phi<=0.12. The interparticle potential is a combination of a generalized Lennard-Jones form and a Yukawa potential, the latter of which describes a screened electrostatic repulsion at longer range. The combined potential is parameterized to include a roughly constant primary minimum near contact, along with a variable repulsive barrier at slightly larger separation. The microstructure is characterized through the pair distribution function, g(r), and the static structure factor. The repulsive barrier reduces the rate of aggregation and is also seen to affect the structure, with a large repulsion associated with a more tenuous structure. This is reflected in the potential having a strong effect on the evolution of 'bonds' per particle. Hydrodynamic interactions were found to reduce the solid fraction required for percolation, with the influence depending upon the form of the potential; the difference in percolation threshold was significant, with phi(c,SD)?0.06 and phi(c,BD)>=0.08 a typical difference for moderate repulsion barriers. These results are for 864 particles in a cubic unit cell. To address the mechanism for this influence of hydrodynamic interactions, a complementary analysis of the evolution of numerous independent three-particle aggregates was performed. The analysis shows that hydrodynamic interaction slows the evolution toward a condensed aggregate of lowest potential energy in a way which cannot be explained by a simple rescaling of the drag due to uncorrelated particle motions. PMID- 22206967 TI - Functional brain networks and abnormal connectivity in the movement disorders. AB - Clinical manifestations of movement disorders, such as Parkinson's disease (PD) and dystonia, arise from neurophysiological changes within the cortico-striato pallidothalamocortical (CSPTC) and cerebello-thalamo-cortical (CbTC) circuits. Neuroimaging techniques that probe connectivity within these circuits can be used to understand how these disorders develop as well as identify potential targets for medical and surgical therapies. Indeed, network analysis of (18)F fluorodeoxyglucose (FDG) positron emission tomography (PET) has identified abnormal metabolic networks associated with the cardinal motor symptoms of PD, such as akinesia and tremor, as well as PD-related cognitive dysfunction. More recent task-based and resting state functional magnetic resonance imaging studies have reproduced several of the altered connectivity patterns identified in these abnormal PD-related networks. A similar network analysis approach in dystonia revealed abnormal disease related metabolic patterns in both manifesting and non manifesting carriers of dystonia mutations. Other multimodal imaging approaches using magnetic resonance diffusion tensor imaging in patients with primary genetic dystonia suggest abnormal connectivity within the CbTC circuits mediate the clinical manifestations of this inherited neurodevelopmental disorder. Ongoing developments in functional imaging and future studies in early patients are likely to enhance our understanding of these movement disorders and guide novel targets for future therapies. PMID- 22206971 TI - Uncoupling of ATP-depletion and cell death in human dopaminergic neurons. AB - The mitochondrial inhibitor 1-methyl-4-phenylpyridinium (MPP(+)) is the toxicologically relevant metabolite of 1-methyl-4-phenyltetrahydropyridine (MPTP), which causes relatively selective degeneration of dopaminergic neurons in the substantia nigra. Dopaminergic LUHMES cells were used to investigate whether ATP-depletion can be uncoupled from cell death as a downstream event in these fully post-mitotic human neurons. Biochemical assays indicated that in the homogeneously differentiated cell cultures, MPP(+) was taken up by the dopamine transporter (DAT). MPP(+) then triggered oxidative stress and caspase activation, as well as ATP-depletion followed by cell death. Enhanced survival of the neurons in the presence of agents interfering with mitochondrial pathology, such as the fission inhibitor Mdivi-1 or a Bax channel blocker suggested a pivotal role of mitochondria in this model. However, these compounds did not prevent cellular ATP depletion. To further investigate whether cells could be rescued despite respiratory chain inhibition by MPP(+), we have chosen a diverse set of pharmacological inhibitors well-known to interfere with MPP(+) toxicity. The antioxidant ascorbate, the iron chelator desferoxamine, the stress kinase inhibitor CEP1347, and different caspase inhibitors reduced cell death, but allowed ATP-depletion in protected cells. None of these compounds interfered with MPP(+) accumulation in the cells. These findings suggest that ATP-depletion, as the initial mitochondrial effect of MPP(+), requires further downstream processes to result in neuronal death. These processes may form self-enhancing signaling loops, that aggravate an initial energetic impairment and eventually determine cell fate. PMID- 22206972 TI - Titanium dioxide-gold nanocomposite materials embedded in silicate sol-gel film catalyst for simultaneous photodegradation of hexavalent chromium and methylene blue. AB - Aminosilicate sol-gel supported titanium dioxide-gold (EDAS/(TiO(2)-Au)(nps)) nanocomposite materials were synthesized by simple deposition-precipitation method and characterized. The photocatalytic oxidation and reduction activity of the EDAS/(TiO(2)-Au)(nps) film was evaluated using hexavalent chromium (Cr(VI)) and methylene blue (MB) dye under irradiation. The photocatalytic reduction of Cr(VI) to Cr(III) was studied in the presence of hole scavengers such as oxalic acid (OA) and methylene blue (MB). The photocatalytic degradation of MB was investigated in the presence and absence of Cr(VI). Presence of Au(nps) on the (TiO(2))(nps) surface and its dispersion in the silicate sol-gel film (EDAS/(TiO(2)-Au)(nps)) improved the photocatalytic reduction of Cr(VI) and oxidation of MB due to the effective interfacial electron transfer from the conduction band of the TiO(2) to Au(nps) by minimizing the charge recombination process when compared to the TiO(2) and (TiO(2)-Au)(nps) in the absence of EDAS. The EDAS/(TiO(2)-Au)(nps) nanocomposite materials provided beneficial role in the environmental remediation and purification process through synergistic photocatalytic activity by an advanced oxidation-reduction processes. PMID- 22206973 TI - Graphene oxide adsorption enhanced by in situ reduction with sodium hydrosulfite to remove acridine orange from aqueous solution. AB - Graphene oxide (GO) is a highly effective adsorbent, and its absorbing capability is further enhanced through its in situ reduction with sodium hydrosulfite as the reductant. Acridine orange is the selected target to eliminate with GO as the adsorbent. Under identical conditions, GO without the in situ reduction showed a maximum adsorption capacity of 1.4 g g(-1), and GO with the in situ reduction provided a maximum adsorption capacity of 3.3 g g(-1). Sodium hydrosulfite converts carbonyl groups on GO into hydroxyl groups, which function as the key sites for the adsorption enhancement. PMID- 22206970 TI - Methylmercury: a potential environmental risk factor contributing to epileptogenesis. AB - Epilepsy or seizure disorder is one of the most common neurological diseases in humans. Although genetic mutations in ion channels and receptors and some other risk factors such as brain injury are linked to epileptogenesis, the underlying cause for the majority of epilepsy cases remains unknown. Gene-environment interactions are thought to play a critical role in the etiology of epilepsy. Exposure to environmental chemicals is an important risk factor. Methylmercury (MeHg) is a prominent environmental neurotoxicant, which targets primarily the central nervous system (CNS). Patients or animals with acute or chronic MeHg poisoning often display epileptic seizures or show increased susceptibility to seizures, suggesting that MeHg exposure may be associated with epileptogenesis. This mini-review highlights the effects of MeHg exposure, especially developmental exposure, on the susceptibility of humans and animals to seizures, and discusses the potential role of low level MeHg exposure in epileptogenesis. This review also proposes that a preferential effect of MeHg on the inhibitory GABAergic system, leading to disinhibition of excitatory glutamatergic function, may be one of the potential mechanisms underlying MeHg-induced changes in seizure susceptibility. PMID- 22206974 TI - Separation and recovery of lead from a low concentration solution of lead(II) and zinc(II) using the hydrolysis production of poly styrene-co-maleic anhydride. AB - The PbZn separation/preconcentration technique, based on the complex formation reaction of Pb(II) and Zn(II), using a copolymer poly(styrene-co-maleic anhydride) (PSMA), without adding any carrier element was developed. The effects of several experimental parameters such as solution pH, temperature and adsorption time were studied. The experimental results show that the PSMA resin Pb equilibrium was achieved in 2 min and the Pb(II) loading capacity is up to 641.62 mg g(-1) in aqueous solution under optimum conditions, which is much higher than the Zn(II) loading capacity within 80 min. The adsorption test for Pb(II) indicates that PSMA can recover Pb(II) from a mixed solution of Pb(II), Zn(II) and light metals such as Ca(II) and Mg(II) with higher adsorption rate and larger selective coefficient. A further study indicates that PSMA as chelating resins recovering Pb(II) can be regenerated via mineral acid (6M H(2)SO(4)). PSMA was synthesized by radical polymerization and tested as an adsorbent for the selective recovery of Pb(II). In addition, the formation procedure and structure of Pb-PSMA complex were also studied. Both the PSMA and the Pb-PSMA complex were characterized by means of FTIR spectroscopy, elemental analysis, gel permeation chromatography (GPC) and atomic absorption spectrometry (AAS). PMID- 22206975 TI - Preparation and application of poly(2-amino thiophenol)/MWCNTs nanocomposite for adsorption and separation of cadmium and lead ions via solid phase extraction. AB - A new method which utilizes a multiwalled carbon nanotubes/poly(2-amino thiophenol) nanocomposites as an effective sorbents in solid-phase extraction has been developed for separation and preconcentration of Cd(II) and Pb(II) trace levels in environmental samples. The method is based on the adsorption of heavy metals on macromolecular chains due to sharing an electron pair of N and S groups of conducting polymer with cadmium and lead ions. The results indicate the novel nanocomposite presents a high affinity for heavy metals due to the presence of several good extractive sites (S and N) which are introduced to the synthesized nanocomposite. Some parameters including sample condition such as: pH, flow rate, sample volume, and eluent condition such as: type, volume, and concentration: moreover adsorption capacity of matrix ions was investigated on the recovery of Cd(II) and Pb(II). The maximum adsorption capacity of MWCNTs/P2AT nanocomposite as sorbents at optimum conditions for cadmium and lead ions was found to be 178.7 mg g(-1) and 186.4 mg g(-1), respectively. The detection limits of this method were 0.3 and 1 ng mL(-1) for Cd(II) and Pb(II), respectively. The validation of the presented procedure was checked by reference material analysis. Finally, the presented procedure was applied for determination of Cd(II) and Pb(II) in some environmental samples. PMID- 22206976 TI - Removal of nalidixic acid and its degradation products by an integrated MBR ozonation system. AB - Chemical-biological degradation of a widely spread antibacterial (nalidixic acid) was successfully obtained by an integrated membrane bioreactor (MBR)-ozonation process. The composition of the treated solution simulated the wastewater from the production of the target pharmaceutical, featuring high salinity and a relevant concentration of sodium acetate. Aim of treatment integration was to exploit the synergistic effects of chemical oxidation and bioprocesses, by adopting the latter to remove most of the COD and the ozonation biodegradable products. Integration was achieved by placing ozonation in the recirculation stream of the bioreactor effluent. The recirculation flow rate was three-fold the MBR feed, and the performance of the integrated system was compared to the standard polishing configuration (single ozonation step after the MBR). Results showed that the introduction of the ozonation step did not cause relevant drawbacks to both biological and filtration processes. nalidixic acid passed undegraded through the MBR and was completely removed in the ozonation step. Complete degradation of most of the detected ozonation products was better achieved with the integrated MBR-ozonation process than using the sequential treatment configuration, i.e. ozone polishing after MBR, given the same ozone dosage. PMID- 22206977 TI - Aldehyde dehydrogenases and cell proliferation. AB - Aldehyde dehydrogenases (ALDHs) oxidize aldehydes to the corresponding carboxylic acids using either NAD or NADP as a coenzyme. Aldehydes are highly reactive aliphatic or aromatic molecules that play an important role in numerous physiological, pathological, and pharmacological processes. ALDHs have been discovered in practically all organisms and there are multiple isoforms, with multiple subcellular localizations. More than 160 ALDH cDNAs or genes have been isolated and sequenced to date from various sources, including bacteria, yeast, fungi, plants, and animals. The eukaryote ALDH genes can be subdivided into several families; the human genome contains 19 known ALDH genes, as well as many pseudogenes. Noteworthy is the fact that elevated activity of various ALDHs, namely ALDH1A2, ALDH1A3, ALDH1A7, ALDH2*2, ALDH3A1, ALDH4A1, ALDH5A1, ALDH6, and ALDH9A1, has been observed in normal and cancer stem cells. Consequently, ALDHs not only may be considered markers of these cells, but also may well play a functional role in terms of self-protection, differentiation, and/or expansion of stem cell populations. The ALDH3 family includes enzymes able to oxidize medium chain aliphatic and aromatic aldehydes, such as peroxidic and fatty aldehydes. Moreover, these enzymes also have noncatalytic functions, including antioxidant functions and some structural roles. The gene of the cytosolic form, ALDH3A1, is localized on chromosome 17 in human beings and on the 11th and 10th chromosome in the mouse and rat, respectively. ALDH3A1 belongs to the phase II group of drug metabolizing enzymes and is highly expressed in the stomach, lung, keratinocytes, and cornea, but poorly, if at all, in normal liver. Cytosolic ALDH3 is induced by polycyclic aromatic hydrocarbons or chlorinated compounds, such as 2,3,7,8 tetrachlorodibenzo-p-dioxin, in rat liver cells and increases during carcinogenesis. It has been observed that this increased activity is directly correlated with the degree of deviation in hepatoma and lung cancer cell lines, as is the case in chemically induced hepatoma in rats. High ALDH3A1 expression and activity have been correlated with cell proliferation, resistance against aldehydes derived from lipid peroxidation, and resistance against drug toxicity, such as oxazaphosphorines. Indeed, cells with a high ALDH3A1 content are more resistant to the cytostatic and cytotoxic effects of lipidic aldehydes than are those with a low content. A reduction in cell proliferation can be observed when the enzyme is directly inhibited by the administration of synthetic specific inhibitors, antisense oligonucleotides, or siRNA or indirectly inhibited by the induction of peroxisome proliferator-activated receptor gamma (PPARgamma) with polyunsaturated fatty acids or PPARgamma transfection. Conversely, cell proliferation is stimulated by the activation of ALDH3A1, whether by inhibiting PPARgamma with a specific antagonist, antisense oligonucleotides, siRNA, or a medical device (i.e., composite polypropylene prosthesis for hernia repair) used to induce cell proliferation. To date, the mechanisms underlying the effects of ALDHs on cell proliferation are not yet fully clear. A likely hypothesis is that the regulatory effect is mediated by the catabolism of some endogenous substrates deriving from normal cell metabolism, such as 4-hydroxynonenal, which have the capacity to either stimulate or inhibit the expression of genes involved in regulating proliferation. PMID- 22206978 TI - Metabolic activation of sulfur mustard leads to oxygen free radical formation. AB - We recently published electron paramagnetic resonance (EPR) spin trapping results that demonstrated the enzymatic reduction of sulfur mustard sulfonium ions to carbon-based free radicals using an in vitro system containing sulfur mustard, cytochrome P450 reductase, NADPH, and the spin trap alpha-(4-pyridyl-1-oxide)-N tert-butylnitrone (4-POBN) in buffer (A.A. Brimfield et al., 2009, Toxicol. Appl. Pharmacol. 234:128-134). Carbon-based radicals have been shown to reduce molecular oxygen to form superoxide and, subsequently, peroxyl and hydroxyl radicals. In some cases, such as with the herbicide paraquat, a cyclic redox system results, leading to magnified oxygen free radical concentration and sustained tissue damage. Low mustard carbon radical concentrations recorded by EPR in our in vitro system, despite a robust (4.0mM) sulfur mustard starting concentration, led us to believe a similar oxygen reduction and redox cycling process might be involved with sulfur mustard. A comparison of the rate of mustard radical-POBN adduct formation in our in vitro system by EPR at atmospheric and reduced oxygen levels indicated a sixfold increase in 4-POBN adduct formation (0.5 to 3.0 MUM) at the reduced oxygen concentration. That result suggested competition between oxygen and POBN for the available carbon based mustard radicals. In parallel experiments we found that the oxygen radical specific spin trap 5-tert-butoxycarbonyl-5-methylpyrroline-N-oxide (BMPO) detected peroxyl and hydroxyl radicals directly when it was used in place of POBN in the in vitro system. Presumably these radicals originated from O(2) reduced by carbon-based mustard radicals. We also showed that reactive oxygen species (ROS) BMPO EPR signals were reduced or eliminated when mustard carbon radical production was impeded by systematically removing system components, indicating that carbon radicals were a necessary precursor to ROS production. ROS EPR signals were completely eliminated when superoxide dismutase and catalase were included in the complete in vitro enzymatic system, providing additional proof of oxygen radical participation. The redox cycling hypothesis was supported by density functional theory calculations and frontier molecular orbital analysis. PMID- 22206979 TI - Genetic variants in antioxidant genes are associated with sperm DNA damage and risk of male infertility in a Chinese population. AB - To test the hypothesis that polymorphisms in antioxidant genes are more susceptible to sperm DNA damage and male infertility, we examined 11 single nucleotide polymorphisms from six antioxidant genes (GPX1, CAT, PON1, NQO1, SOD2/MnSOD, and SOD3) in 580 infertility cases and 580 controls from a Chinese population-based case-control study (NJMU Infertility Study). Genotypes were determined using the OpenArray platform. Sperm DNA fragmentation was detected using the Tdt-mediated dUTP nick-end labeling assay, and the level of 8 hydroxydeoxyguanosine (8-OHdG) in sperm DNA was measured using immunofluorescence. The adjusted odds ratio and 95% confidence interval (CI) were estimated using unconditional logistic regression. The results indicated that the PON1 Arg192Glu (rs662) and SOD2 Val16Ala (rs4880) variant genotypes were associated with a significantly higher risk of male infertility. In addition, subjects carrying variant genotypes of both loci had a twofold (95% CI, 1.42 2.90) increase in the risk of male infertility, indicating a significant gene gene interaction between these two loci (P for multiplicative interaction=0.045). Moreover, linear regression analysis showed that individuals carrying the PON1 Arg192Glu (rs662) or SOD2 Val16Ala (rs4880) variants have significantly higher levels of sperm DNA fragmentation and 8-OHdG. These data suggest that genetic variations in antioxidant genes may contribute to oxidative sperm DNA damage and male infertility. PMID- 22206980 TI - The combination of a synthetic promoter and a CMV promoter improves foreign gene expression efficiency in myocytes. AB - Skeletal muscle is becoming an attractive target tissue for gene therapy. Nevertheless, the low level of gene therapeutic expression in this tissue is the major limitation to it becoming an ideal target for gene transfer. The promoter is important element for gene transcription; however, the gene expression efficiencies and specificities of viral promoters and skeletal muscle-specific promotors are in themselves limiting factors. In this study, we established a dual-promoters system in skeletal muscle using a cytomegalovirus (CMV) promoter and a skeletal muscle-specific synthetic promoter. Mouse myoblast cell line C2C12 cells were transfected with the system. We demonstrated that the dual-promoters system could significantly improve exogenous gene expression rate in vitro when compared with a single CMV promoter system and a skeletal muscle-specific synthetic promoter system in C2C12 cell line, by 69.48% and 41.93%, respectively. Next, we evaluated the system efficiency in vivo, the results showed that the dual-promoters system increased gene expression in mice 1.23-fold and 1.60-fold, respectively compared with expression controlled by the two single promoter vectors. Finally, we tested the dual-promoters system in growth hormone-releasing hormone (GHRH) gene therapy, and revealed that when these two promoters co-drove the GHRH gene expression in vivo animal growth was enhanced significantly. All these results indicate that use of the dual-promoter vector was more efficient for gene expression in skeletal muscle tissue than use of the single promoter vectors. These finding could, hopefully, lead to the development of a high efficiency expression system in myocytes and form an ideal approach for gene therapy. PMID- 22206982 TI - Scale-up of microbial processes: impacts, tools and open questions. AB - Industrial biotechnological production is developing rapidly worldwide. Consequently, more and novel bioprocesses need to perform optimally not only in small lab- but also in large production scales. This article shortly reviews typical impacts found when cells are exposed to micro environmental heterogeneities typically occurring in poorly mixed large scale production reactors. The current state-of-the-art of tool development is presented for analyzing these phenomena. Finally, still open questions are formulated and needs for future research are outlined to further support the expansion of biotech industries by successful research results. PMID- 22206981 TI - Production and characterization of a recombinant single-chain antibody (scFv) for tracing the sigma54 factor of Pseudomonas putida. AB - The number of alternative sigma factor molecules per bacterial cell determines either stochasticity or evenness of transcription of cognate promoters. An approach for examining the abundance of sigmas in any sample of bacterial origin is explained here which relies on the production of a recombinant highly specific, high-affinity single-chain variable Fv domain (scFv) targeted towards unique protein sites of the factor. Purposely, a super-binder scFv recognizing a distinct epitope of the less abundant sigma sigma(54) of Pseudomonas putida (also known as sigma(N)) was obtained and its properties examined in detail. To this end, an scFv library was generated from mRNA extracted from lymphocytes of mice immunized with the purified sigma(54) protein of this bacterium. The library was displayed on a phage system and subjected to various rounds of panning with purified sigma(54) for capturing extreme binders. The resulting high-affinity anti-sigma(54) phage antibody (Phab) clone named C2 strongly attached a small region located between positions 172 and 183 of the primary amino acid sequence of sigma(54) that overlaps its core RNA polymerase-binding region. The purified scFv-C2 detected minute amounts of sigma(54) in whole cell protein extracts not only of P. putida but also Escherichia coli cells and putatively in other bacteria as well. The affinity constant of the purified antibody was measured by surface plasmon resonance (SPR) and found to have a K(D) (k(off)/k(on)) in the range of 2*10(-9)M. The considerable affinity and specificity of this recombinant antibody makes it a tool of choice for quantitative studies on gene expression of sigma(54)-dependent promoters in P. putida and other Gram-negative bacteria. PMID- 22206983 TI - Using outreach to involve the hard-to-reach in a health check: what difference does it make? AB - OBJECTIVES: Mortality from coronary heart disease remains higher in Scotland than the European average. Primary prevention programmes, such as Keep Well, aim to tackle the associated risk factors within deprived communities. In Lanarkshire, the problem of non-attendance amongst 'hard-to-reach' groups was addressed by an outreach team, but there was a need to understand the methods employed to achieve health screening attendance. STUDY DESIGN: Qualitative interviews with a typical sample of those who initially failed to attend for health screening but were subsequently appointed after outreach intervention. METHODS: Semi-structured interviews (n = 30) were conducted following clinic attendance. Transcripts were subjected to a form of content analysis and concepts were arranged into themes. RESULTS: The group often referred to as 'hard-to-reach' are more accurately defined as either 'hard-to-contact' or 'hard-to-engage'. Non-attenders reported that outreach staff were effective in engaging them partly because of their personalities, but also because some of the contacts occurred at an opportune time. CONCLUSIONS: Not all non-attenders for screening appointments are negatively disposed towards health screening, and defining them all as 'hard-to reach' does them a disservice. The majority appeared to need outreach staff to convert them into attenders, but the costs of this need to be balanced against the benefits realized. PMID- 22206984 TI - The obesity pandemic: implementing the evidence for children in Scottish families. AB - BACKGROUND: Increasing obesity levels arise from multiple causes, which require understanding as a whole system. Co-ordinated action from heterogeneous groups with differing interests and perspectives is required to tackle rising obesity. To be effective, this must be targeted at identifying, agreeing and modifying the critical drivers. OBJECTIVES: To illustrate an application of an environmental health systems modelling approach (as adapted in Scotland) to a particularly important Scottish topic: the rising obesity levels in Scottish children. DISCUSSION: The model was able to capture an integration of the closely coupled causal chains around excessive energy intake and physical inactivity in children in their domestic environment. The model was able to incorporate action at different strategic levels. CONCLUSIONS: Applying the Drivers, Pressures, State, Exposure, Effects, Actions (DPSEEA) model to the public health problem of child obesity allowed a clear view of a number of multiple causal chains involved in a particular environment. That clarity may be a necessary condition for co ordinated action to create change. PMID- 22206985 TI - The multicenter AIDS Cohort Study, 1983 to .... AB - The Multicenter AIDS Cohort (MACS), initiated in 1983 at the Johns Hopkins School of Public Health, the University of Pittsburgh School of Public Health, Northwestern University School of Medicine, and the UCLA School of Public Health, continues to conduct studies and publish key papers on the natural history of untreated and treated HIV infection in 6972 men-who-have-sex-with-men. Through May 2011, 1,490,995 specimens have been collected, 86,883 person-years of data accrued and 1195 scientific papers published in international journals. PMID- 22206986 TI - Molecular structure and peptidoglycan recognition of Mycobacterium tuberculosis ArfA (Rv0899). AB - Mycobacterium tuberculosis ArfA (Rv0899) is a membrane protein encoded by an operon that is required for supporting bacterial growth in acidic environments. Its C-terminal domain (C domain) shares significant sequence homology with the OmpA-like family of peptidoglycan-binding domains, suggesting that its physiological function in acid stress protection may be related to its interaction with the mycobacterial cell wall. Previously, we showed that ArfA forms three independently structured modules, and we reported the structure of its central domain (B domain). Here, we describe the high-resolution structure and dynamics of the C domain, we identify ArfA as a peptidoglycan-binding protein and we elucidate the molecular basis for its specific recognition of diaminopimelate-type peptidoglycan. The C domain of ArfA adopts the characteristic fold of the OmpA-like family. It exhibits pH-dependent conformational dynamics (with significant heterogeneity at neutral pH and a more ordered structure at acidic pH), which could be related to its acid stress response. The C domain associates tightly with polymeric peptidoglycan isolated from M. tuberculosis and also associates with a soluble peptide intermediate of peptidoglycan biosynthesis. This enabled us to characterize the peptidoglycan binding site where five highly conserved ArfA residues, including two key arginines, establish the specificity for diaminopimelate- but not Lys-type peptidoglycan. ArfA is the first peptidoglycan-binding protein to be identified in M. tuberculosis. Its functions in acid stress protection and peptidoglycan binding suggest a link between the acid stress response and the physicochemical properties of the mycobacterial cell wall. PMID- 22206987 TI - Sensitivity of amyloid formation by human islet amyloid polypeptide to mutations at residue 20. AB - Islet amyloid polypeptide (IAPP, amylin) is responsible for amyloid formation in type 2 diabetes and in islet cell transplants. The only known natural mutation found in mature human IAPP is a Ser20-to-Gly missense mutation, found with small frequency in Chinese and Japanese populations. The mutation appears to be associated with increased risk of early-onset type 2 diabetes. Early measurements in the presence of organic co-solvents showed that S20G-IAPP formed amyloid more quickly than the wild type. We confirm that the mutant accelerates amyloid formation under a range of conditions including in the absence of co-solvents. Ser20 adopts a normal backbone geometry, and the side chain makes no steric clashes in models of IAPP amyloid fibers, suggesting that the increased rate of amyloid formation by the mutant does not result from the relief of steric incompatibility in the fiber state. Transmission electronic microscopy, circular dichroism, and seeding studies were used to probe the structure of the resulting fibers. The S20G-IAPP peptide is toxic to cultured rat INS-1 (transformed rat insulinoma-1) beta-cells. The sensitivity of amyloid formation to the identity of residue 20 was exploited to design a variant that is much slower to aggregate and that inhibits amyloid formation by wild-type IAPP. An S20K mutant forms amyloid with an 18-fold longer lag phase in homogeneous solution. Thioflavin T binding assays, together with experiments using a p-cyanophenylalanine (p-cyanoPhe) variant of human IAPP, show that the designed S20K mutant inhibits amyloid formation by human IAPP. The experiments illustrate how p-cyanoPhe can be exploited to monitor amyloid formation even in the presence of other amyloidogenic proteins. PMID- 22206988 TI - Molecular basis of the functional divergence of fatty acyl-AMP ligase biosynthetic enzymes of Mycobacterium tuberculosis. AB - Activation of fatty acids as acyl-adenylates by fatty acyl-AMP ligases (FAALs) in Mycobacterium tuberculosis is a variant of a classical theme that involves formation of acyl-CoA (coenzyme A) by fatty acyl-CoA ligases (FACLs). Here, we show that FAALs and FACLs possess similar structural fold and substrate specificity determinants, and the key difference is the absence of a unique insertion sequence in FACL13 structure. A systematic analysis shows a conserved hydrophobic anchorage of the insertion motif across several FAALs. Strikingly, mutagenesis of two phenylalanine residues, which are part of the anchorage, to alanine converts FAAL32 to FACL32. This insertion-based in silico analysis suggests the presence of FAAL homologues in several other non-mycobacterial genomes including eukaryotes. The work presented here establishes an elegant mechanism wherein an insertion sequence drives the functional divergence of FAALs from canonical FACLs. PMID- 22206989 TI - Key structural features of the actin filament Arp2/3 complex branch junction revealed by molecular simulation. AB - We investigated the structure, properties and dynamics of the actin filament branch junction formed by actin-related protein (Arp) 2/3 complex using all-atom molecular dynamics (MD) simulations based on a model fit to a reconstruction from electron tomograms. Simulations of the entire structure consisting of 31 protein subunits together with solvent molecules containing ~3 million atoms were performed for an aggregate time of 175 ns. One 75-ns simulation of the original reconstruction was compared to two 50-ns simulations of alternate structures, showing that the hypothesized branch junction structure is very stable. Our simulations revealed that the interface between Arp2/3 complex and the mother actin filament features a large number of salt bridges and hydrophobic contacts, many of which are dynamic and formed/broken on the timescale of the simulation. The simulations suggest that the DNase binding loops in Arp3, and possibly Arp2, form stabilizing contacts with the mother filament. Unbiased comparison of models sampled from the MD simulation trajectory with the primary experimental electron tomography data identified regions were snapshots from the simulation provide atomic details of the model structures and also pinpoints regions where the initial modeling based on the electron tomogram reconstruction may be suboptimal. PMID- 22206991 TI - Behavioral mechanisms of male sterilization on plateau pika in the Qinghai-Tibet plateau. AB - Fertility control is an alternative non-lethal method in the management of rodents. Previous modeling suggests that the efficacy of male sterilization depends on mating systems of animals, but behavioral mechanisms of male sterilization have not been investigated. Here we investigated the behavioral mechanism of the sterilant quinestrol in reducing the fertility of plateau pika (Ochotona curzoniae) inhabiting the Qinghai-Tibet plateau. Male pikas treated with quinestrol showed reduced aggression compared to control males, but they showed significantly higher levels of territorial behavior such as long-calls and long-chases. Levels of long-call and long-chase were negatively correlated with the number of newborn pikas in the family. Single-baiting of quinestrol effectively sterilized male pikas and reduced the pregnancy rate of female pikas; this was likely achieved by increased territorial behavior of sterilized pikas which resulted in unsuccessful invasions by fertile adult male pikas. Our study reveals a novel behavioral mechanism, increased territoriality in sterilized males, in the fertility control of plateau pikas. PMID- 22206992 TI - Captive spider monkeys (Ateles geoffroyi) arm-raise to solicit allo-grooming. AB - Old World monkeys solicit allo-grooming from conspecifics. However, there are relatively few studies of allo-grooming among spider monkeys, and descriptions of allo-grooming solicitation among spider monkeys are anecdotal. In this study, eighty-one hours of video, shot over eight weeks, captured 271 allo-grooming bouts among small groups of captive spider monkeys. Six of eight monkeys made heretofore unreported arm-raises that solicited higher than normal rates of allo grooming. Allo-grooming bout durations following arm-raises also tended to be longer than bouts not preceded by arm-raises. The efficacy of the arm-raise at soliciting allo-grooming suggests spider monkeys are capable of intentional communication. PMID- 22206993 TI - Freshwater pearl mussels show plasticity of responses to different predation risks but also show consistent individual differences in responsiveness. AB - Animals often show behavioural plasticity with respect to predation risk but also show behavioural syndromes in terms of consistency of responses to different stimuli. We examine these features in the freshwater pearl mussel. These bivalves often aggregate presumably to reduce predation risk to each individual. Predation risk, however, will be higher in the presence of predator cues. Here we use dimming light, vibration and touch as novel stimuli to examine the trade-off between motivation to feed and motivation to avoid predation. We present two experiments that each use three sequential novel stimuli to cause the mussels to close their valves and hence cease feeding. We find that mussels within a group showed shorter closure times than solitary mussels, consistent with decreased vulnerability to predation in group-living individuals. Mussels exposed to the odour of a predatory crayfish showed longer closures than control mussels, highlighting the predator assessment abilities of this species. However, individuals showed significant consistency in their closure responses across the trial series, in line with behavioural syndrome theory. Our results show that bivalves trade-off feeding and predator avoidance according to predation risk but the degree to which this is achieved is constrained by behavioural consistency. PMID- 22206994 TI - Effect of testosterone and melatonin on social dominance and agonistic behavior in male Tscheskia triton. AB - Social dominance and agonistic behavior play important roles in animal societies. Melatonin and testosterone are closely related to social dominance and agonistic behavior in rodents, but interactions between both of them remain unknown. In this study we investigated the effects of testosterone and melatonin by manipulating photoperiod and castration on social dominance and agonistic behavior in male Tscheskia triton. Castration significantly decreases social dominance of both short- and long-day males, suggesting that testosterone benefits social dominance of males in both breeding and non-breeding seasons. In intact conditions, long-day males tended to dominate short-day males, suggesting that the effect of testosterone on social dominance was a little stronger than melatonin. However, castrated short-day males became dominant over their castrated long-day opponents meaning that high melatonin levels obviously benefit social dominance in males. Hormone implantation indicated that testosterone had no effect on non-breeding condition, but that melatonin was important during the breeding season. Our results indicate that both testosterone and melatonin are important in determining social dominance in male hamsters, and the effect of testosterone appears to be stronger than melatonin. Testosterone is responsible for aggression and social dominance in male hamsters during the breeding season, while melatonin regulates behavior during non-breeding, probably due to the different seasonal secretory patterns of the hormones. PMID- 22206995 TI - Behavioral differentiation during collective building in wild mice Mus spicilegus. AB - Although well documented in social insects, the possibility of behavioral differentiation during collective building has been poorly studied in mammals. In this context, the mound-building mouse Mus spicilegus is an interesting model. Under natural conditions, juveniles from different litters gather vegetal material and build a sophisticated structure, the mound, under which the mice will spend winter. The first steps of this complex building process may be elicited under laboratory conditions by offering cotton balls as building material. Spatio-temporal distribution of both animals and cotton balls was automatically recorded by RFID (Radio-Frequency Identification Device) technique. Our results revealed a behavioral differentiation during a collective building task. In a group of six individuals, only two mice (called carriers) transported 80% of the building material whereas the contribution of the remaining mice was weak or even non-existent. The proportion of carriers was constant in all of the six groups studied. This behavioral differentiation was implemented immediately after the building material was made available and remained stable during the 4 days of experiment. The high contribution level of carriers did not result from resource monopolization, nor did it depend on the gender or parental origin of the mice. PMID- 22206997 TI - Transfer of metabolites across the peroxisomal membrane. AB - Peroxisomes perform a large variety of metabolic functions that require a constant flow of metabolites across the membranes of these organelles. Over the last few years it has become clear that the transport machinery of the peroxisomal membrane is a unique biological entity since it includes nonselective channels conducting small solutes side by side with transporters for 'bulky' solutes such as ATP. Electrophysiological experiments revealed several channel forming activities in preparations of plant, mammalian, and yeast peroxisomes and in glycosomes of Trypanosoma brucei. The properties of the first discovered peroxisomal membrane channel - mammalian Pxmp2 protein - have also been characterized. The channels are apparently involved in the formation of peroxisomal shuttle systems and in the transmembrane transfer of various water soluble metabolites including products of peroxisomal beta-oxidation. These products are processed by a large set of peroxisomal enzymes including carnitine acyltransferases, enzymes involved in the synthesis of ketone bodies, thioesterases, and others. This review discusses recent data pertaining to solute permeability and metabolite transport systems in peroxisomal membranes and also addresses mechanisms responsible for the transfer of ATP and cofactors such as an ATP transporter and nudix hydrolases. PMID- 22207001 TI - Mental health disorders in children of non-drug-abusing parents: a sample from a rural community devastated by methamphetamine. AB - A representative sample of 58 preschoolers (aged 4 and 5) and 78 school-age children (aged 8 and 9) from methamphetamine-producing (MP) and non-producing (NP) homes was drawn from a rural county in Tennessee, for two separate studies. The researchers assessed the psychological functioning of the children using age appropriate Behavior Assessment System for Children (BASC) forms, and compared the scores of children with NP status with population-based data. The results indicate that in this rural sample, the prevalence of internalizing and externalizing disorders in children from NP homes was higher than in population based norms. Specifically, the preschoolers showed a higher rate of depression, and the school-age children had higher rates of anxiety, depression, and atypical behaviors than their population-based peers. The results are interpreted in terms of low SES and accessibility to mental health services in rural communities. The authors suggest nurse practitioners include brief psychological screenings in their assessment protocols for this population. PMID- 22207000 TI - Synthesis, thermal properties, and cytotoxicity evaluation of hydrocarbon and fluorocarbon alkyl beta-D-xylopyranoside surfactants. AB - Alkyl beta-d-xylopyranosides are highly surface active, biodegradable surfactants that can be prepared from hemicelluloses and are of interest for use as pharmaceuticals, detergents, agrochemicals, and personal care products. To gain further insights into their structure-property and structure-activity relationships, the present study synthesized a series of hydrocarbon (-C(6)H(13) to -C(16)H(33)) and fluorocarbon (-(CH(2))(2)C(6)F(13)) alkyl beta-d xylopyranosides in four steps from d-xylose by acylation or benzoylation, bromination, Koenigs-Knorr reaction, and hydrolysis, with the benzoyl protecting group giving better yields compared to the acyl group in the Koenigs-Knorr reaction. All alkyl beta-d-xylopyranosides formed thermotropic liquid crystals. The phase transition of the solid crystalline phase to a liquid crystalline phase increased linearly with the length of the hydrophobic tail. The clearing points were near constant for alkyl beta-d-xylopyranosides with a hydrophobic tail ?8, but occurred at a significantly lower temperature for hexyl beta-d xylopyranoside. Short and long-chain alkyl beta-d-xylopyranosides displayed no cytotoxicity at concentration below their aqueous solubility limit. Hydrocarbon and fluorocarbon alkyl beta-d-xylopyranosides with intermediate chain length displayed some toxicity at millimolar concentrations due to apoptosis. PMID- 22206998 TI - Antioxidants in Down syndrome. AB - Individuals with Down syndrome (DS) have high levels of oxidative stress throughout the lifespan. Mouse models of DS share some structural and functional abnormalities that parallel findings seen in the human phenotype. Several of the mouse models show evidence of cellular oxidative stress and have provided a platform for antioxidant intervention. Genes that are overexpressed on chromosome 21 are associated with oxidative stress and neuronal apoptosis. The lack of balance in the metabolism of free radicals generated during processes related to oxidative stress may have a direct role in producing the neuropathology of DS including the tendency to Alzheimer disease (AD). Mitochondria are often a target for oxidative stress and are considered to be a trigger for the onset of the AD process in DS. Biomarkers for oxidative stress have been described in DS and in AD in the general population. However, intervention trials using standard antioxidant supplements or diets have failed to produce uniform therapeutic effect. This chapter will examine the biological role of oxidative stress in DS and its relationship to abnormalities in both development and aging within the disorder. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. PMID- 22207002 TI - Interferon-gamma release assay and Rifampicin therapy for household contacts of tuberculosis. AB - OBJECTIVES: Longitudinal studies in household contacts to identify subgroups at risk of active tuberculosis are lacking. METHODS: Household contacts of pulmonary tuberculosis patients were prospectively enrolled to receive chest radiography, sputum studies, and T-SPOT.TB assay at initial visit. Repeat examinations every 6 months for 3 years, and 4-month rifampin preventive therapy for T-SPOT.TB positive contacts were provided. We investigated factors predicting T-SPOT.TB positivity and active pulmonary tuberculosis. RESULTS: 583 contacts were enrolled with a follow-up duration of 20.7 +/- 9.4 months. 176 (30.2%) were T-SPOT.TB positive initially and 32 (18.2%) of them received preventive therapy. Old age, living in the same room/house with the index case, the index case having a high smear grade (3+ ~ 4+) and pulmonary cavitation were associated with T-SPOT.TB positivity. Active tuberculosis developed in 9 T-SPOT.TB-positive contacts; risk factors included T-SPOT.TB-positivity without preventive therapy, living in the same room, and the index case being <=50 years or female. 108 (61.4%) T-SPOT.TB positive contacts had repeat examinations. Forty-five had T-SPOT.TB reversion and none of them developed active tuberculosis. CONCLUSION: Household contacts who are T-SPOT.TB-positive and live in the same room as the index case are at risk of active tuberculosis and require preventive therapy and close follow-up. PMID- 22206999 TI - Oxidative stress and cerebral endothelial cells: regulation of the blood-brain barrier and antioxidant based interventions. AB - While numerous lines of evidence point to increased levels of oxidative stress playing a causal role in a number of neurodegenerative conditions, our current understanding of the specific role of oxidative stress in the genesis and/or propagation of neurodegenerative diseases remains poorly defined. Even more challenging to the "oxidative stress theory of neurodegeneration" is the fact that many antioxidant-based clinical trials and therapeutic interventions have been largely disappointing in their therapeutic benefit. Together, these factors have led researchers to begin to focus on understanding the contribution of highly localized structures, and defined anatomical features, within the brain as the sites responsible for oxidative stress-induced neurodegeneration. This review focuses on the potential for oxidative stress within the cerebrovascular architecture serving as a modulator of neurodegeneration in a variety of pathological settings. In particular, this review highlights important implications for vascular-derived oxidative stress in the initiating and promoting pathophysiology in the brain, identifying new roles for cerebrovascular oxidative stress in a variety of brain disorders. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. PMID- 22207003 TI - Apoptosis markers soluble Fas (sFas), Fas Ligand (FasL) and sFas/FasL ratio in patients with bacteremia: a prospective cohort study. AB - BACKGROUND: Recent studies have shown that immunoparalysis and lymphocyte apoptosis play a critical role in severe bacteremia. Monitoring apoptosis on a routine basis in septic patients has proved challenging. We here studied the prognostic value of apoptosis markers human soluble Fas (sFas), Fas ligand (FasL) and sFas/FasL ratio in patients with bacteremia. METHODS: sFas (ng/ml) and FasL (ng/ml) concentrations in plasma were determined using commercial quantitative enzyme immunoassays (Quantikine(r), R&D Systems Inc., Minneapolis, MN, USA) in 132 patients with bacteremia caused by Staphylococcus aureus, Streptococcus pneumoniae, beta-hemolytic streptococcae or Escherichia coli. RESULTS: Maximum sFas, minimum FasL and high sFas/FasL ratio predicted high SOFA score in bacteremic patients (p < 0.001, p = 0.003 and p < 0.001, respectively). AUC(ROC)'s in the prediction of high SOFA score for sFas, FasL and sFas/FasL ratio were 0.70 (CI 0.61-0.79), 0.65 (CI 0.56-0.75) and 0.72 (CI 0.63-0.80), respectively. High sFas concentrations and sFas/aFasL ratio, assessed using ROC curve as regards high SOFA (>=4) score, were associated with hypotension (p = 0.001 and p = 0.039, respectively). All of these markers predicted a high SOFA score independently in a logistic regression model. Maximum sFas, sFas/FasL ratio or minimum FasL during days 1-4 after blood culture were not associated with increased case fatality. CONCLUSIONS: Apoptosis markers sFas, FasL or sFas/FasL ratio are associated with high SOFA score in bacteremia. PMID- 22207004 TI - Altered CSF orexin and alpha-synuclein levels in dementia patients. AB - Neurodegenerative dementia, most frequently represented by Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), is often accompanied by altered sleeping patterns and excessive daytime sleepiness. Studies showing an association between the neuropeptide orexin and AD/DLB-related processes such as amyloid-beta (Abeta)1-42 plaque formation, alpha-synuclein accumulation and inflammation indicate that orexin might play a pathogenic role similar to the situation in narcolepsy. Our study of patients with AD (n = 26), DLB (n = 18), and non-demented controls (n = 24) shows a decrease in cerebrospinal fluid (CSF) orexin concentrations in DLB versus AD patients and controls. The observed differences in orexin levels were found to be specific to female DLB patients. We also show that the female DLB patients exclusively displayed lower levels of alpha-synuclein compared to AD patients and controls. Orexin was linked to alpha synuclein and total-tau in female non-demented controls whereas associations between orexin and Abeta1-42 concentrations were absent in all groups regardless of gender. Thus, the proposed links between orexin, Abeta, and alpha-synuclein pathology could not be monitored in CSF protein concentrations. Interestingly, alpha-synuclein was strongly correlated to the CSF levels of total-Tau in all groups, suggesting alpha-synuclein to be an unspecific marker of neurodegeneration. We conclude that lower levels of CSF orexin are specific to DLB versus AD and appear unrelated to Abeta1-42 and alpha-synuclein levels in AD and DLB. Alterations in CSF orexin and alpha-synuclein levels may be related to gender which warrants further investigation. PMID- 22207006 TI - Behavioral and psychological symptoms in moderate to severe Alzheimer's disease: a palliative care approach emphasizing recognition of personhood and preservation of dignity. AB - The assessment and management of behavioral and psychological symptoms of dementia (BPSD) in moderate to severe Alzheimer's disease (AD) can be challenging, and ethical dilemmas often arise. Clinicians often perceive a disconnect between evidence-based guidelines and the challenges of treating BPSD in moderate to severe AD. Reconciliation of salient ethical issues can help bridge this disconnect. In view of the fact that AD is a progressive and ultimately fatal disease, and given that there are often competing considerations when managing BPSD in moderate to severe AD, we propose a palliative care approach that prioritizes the recognition of personhood and the preservation of dignity. We present case illustrations, discuss the concepts of dignity and personhood during palliative care in AD, and encourage the use of the bioethical grid in navigating complex clinical challenges. PMID- 22207005 TI - Genomic and nongenomic signaling induced by 1alpha,25(OH)2-vitamin D3 promotes the recovery of amyloid-beta phagocytosis by Alzheimer's disease macrophages. AB - Brain clearance of amyloid-beta (Abeta42) by innate immune cells is necessary for maintenance of normal brain function. Phagocytosis of soluble Abeta42 by Alzheimer's disease (AD) macrophages is defective, recovered in all "Type I and Type II" AD patients by 1alpha,25(OH)2-vitamin D3 (1,25D3) and blocked by the nuclear vitamin D receptor (VDR) antagonist (23S)-25-dehydro-1alpha(OH)-vitamin D3-26,23-lactone (MK). Bisdemethoxycurcumin (BDC) is a VDR ligand and additive with 1,25D3 in promoting Abeta42 phagocytosis by Type I, but not by Type II macrophages. Here, we define the following intracellular mechanisms regulated by 1,25D3 that are associated with recovery of phagocytosis and consistent with the selectivity of BDC: 1) 1,25D3 potentiates a 4,4-diisothiocyanostilbene-2,2 disulfonic acid-sensitive chloride channel (i.e., ClC-3) currents in both Type I and II AD macrophages, but curcumin only potentiates the currents in Type I cells; 2) 1,25D3 is particularly effective in upregulating ClC-3 mRNA expression in Type II peripheral blood mononuclear cells (PBMCs) while both 1,25D3 and the BDC analog, C180, upregulate VDR mRNA, repressed by Abeta42 in Type II PBMCs; and 3) 1,25D3-induced Abeta42 phagocytosis is attenuated by the calcium-dependent ClC 3 blocker, inositol 3,4,5,6-tetraphosphate (IP4), in both AD Types and by the MEK1/2 inhibitor U0126 only in Type II macrophages. VDR hydrogen/deuterium exchange coupled mass spectrometry and computational results show differences between the abilities of 1,25D3 and curcuminoids to stabilize VDR helices associated with the regulation of gene transcription. The structure-function results provide evidence that 1,25D3 activation of VDR-dependent genomic and nongenomic signaling, work in concert to recover dysregulated innate immune function in AD. PMID- 22207007 TI - Cobalt(II) complexes with non-steroidal anti-inflammatory drug tolfenamic acid: Structure and biological evaluation. AB - Cobalt(II) complexes with the non-steroidal anti-inflammatory drug tolfenamic acid in the presence or absence of nitrogen-donor heterocyclic ligands (2,2' bipyridine, 1,10-phenanthroline, 2,2'-bipyridylamine or pyridine) have been synthesized and characterized with physicochemical and spectroscopic techniques. The deprotonated tolfenamato ligands are coordinated to Co(II) ion through carboxylato oxygen atoms. The crystal structures of complexes [bis(2,2' bipyridine) bis(methanol)bis(tolfenamato)cobalt(II)] 2 and [bis(2,2' bipyridylamine)bis(tolfenamato)cobalt(II)] 4 have been determined by X-ray crystallography. UV studies of the interaction of the complexes with calf-thymus DNA (CT DNA) have shown that the complexes can bind to CT DNA and [bis(methanol)(1,10-phenanthroline)bis(tolfenamato)cobalt(II)] exhibits the highest binding constant to CT DNA. The cyclic voltammograms of the complexes recorded in DMSO solution and in the presence of CT DNA in 1/2 DMSO/buffer (containing 150 mM NaCl and 15 mM trisodium citrate at pH 7.0) solution have shown that they can bind to CT DNA by the intercalative binding mode which has also been verified by DNA solution viscosity measurements. Competitive study with ethidium bromide (EB) has shown that the complexes can displace the DNA-bound EB indicating that they bind to DNA in strong competition with EB. Tolfenamic acid and its cobalt(II) complexes exhibit good binding propensity to human or bovine serum albumin protein having relatively high binding constant values. PMID- 22207008 TI - Sleep enhances memory consolidation in the hippocampus-dependent object-place recognition task in rats. AB - The positive impact of sleep on memory consolidation has been shown for human subjects in numerous studies, but there is still sparse knowledge on this topic in rats, one of the most prominent model species in neuroscience research. Here, we examined the role of sleep in the object-place recognition task, a task closely comparable to tasks typically applied for testing human declarative memory: It is a one-trial task, hippocampus-dependent, not stressful and can be repeated within the same animal. A test session consisted of the Sample trial, followed by a 2-h retention interval and a Test trial, the latter examining the memory the rat had for the places of two objects presented at the Sample trial. In Experiment 1, each rat was tested twice, with the retention interval taking place either in the morning or evening, i.e., in the inactive or active phase, respectively. Rats showed significantly (p<0.01) better memory for object place after the Morning session. To control for confounding circadian factors, in Experiment 2 rats were tested four times, i.e., in the morning or in the evening while sleep was or was not deprived. Sleep during the retention interval was recorded polysomnographically. Rats only showed significant memory for the target object place in the Test trial after the Morning retention interval in the absence of sleep deprivation, and recognition performance in this condition was significantly superior to that in the three other conditions (p<0.05). EEG recordings during spontaneous morning sleep revealed increased slow oscillation (0.85-2.0 Hz) and upper delta (2.0-4.0 Hz), but reduced spindle band (10.5-13.5 Hz) activity, as compared to evening sleep. However, spindle band power was increased in the Morning retention interval in comparison to a Morning Baseline period (p<0.05). We conclude that consolidation of object-place memory depends on sleep, and presumably requires NonREM sleep rich in both slow wave and spindle activity. PMID- 22207009 TI - Relaxing music counters heightened consolidation of emotional memory. AB - Emotional events tend to be retained more strongly than other everyday occurrences, a phenomenon partially regulated by the neuromodulatory effects of arousal. Two experiments demonstrated the use of relaxing music as a means of reducing arousal levels, thereby challenging heightened long-term recall of an emotional story. In Experiment 1, participants (N=84) viewed a slideshow, during which they listened to either an emotional or neutral narration, and were exposed to relaxing or no music. Retention was tested 1 week later via a forced choice recognition test. Retention for both the emotional content (Phase 2 of the story) and material presented immediately after the emotional content (Phase 3) was enhanced, when compared with retention for the neutral story. Relaxing music prevented the enhancement for material presented after the emotional content (Phase 3). Experiment 2 (N=159) provided further support to the neuromodulatory effect of music by post-event presentation of both relaxing music and non relaxing auditory stimuli (arousing music/background sound). Free recall of the story was assessed immediately afterwards and 1 week later. Relaxing music significantly reduced recall of the emotional story (Phase 2). The findings provide further insight into the capacity of relaxing music to attenuate the strength of emotional memory, offering support for the therapeutic use of music for such purposes. PMID- 22207010 TI - Artin M enhances TNF-alpha production and phagocytosis of Candida albicans mediated by dectin-1 and mannose receptors. AB - The activities of dectin-1 and mannose receptors on phagocytosis of Candida albicans and the production of TNF-alpha by macrophages from mice pretreated for 3 days with extract of Artocarpus intergrifolia seeds (jack extract), Artin M or jacalin were studied. Macrophages from these mice were coincubated with C. albicans CR15 (yeast), in the presence of mannose (50mM) plus mannan (100 MUg) or laminarin (1mg). Phagocytosis was significantly enhanced to 52% in macrophages from mice pretreated intraperitoneally for 3 days with jack extract (500 MUg/250 MUl PBS). Reduction in phagocytosis from 52% to 34% (P<0.05) occurred in the presence of mannose receptor inhibitors and from 52% to 16% (P<0.01) in the presence of dectin-1 inhibitor laminarin, whereas only 20% of control macrophages phagocytosed blastoconidia. Similar results were verified for pretreatment of mice with Artin M (2.5 MUg/250 MUl PBS), but not for jacalin (25 MUg/250 MUl PBS). Macrophages from mice pretreated 3 days previously with jack extract or Artin M and then coincubated for 2h with C. albicans presented a significant increase in TNF-alpha production, correlating with significantly less transition of yeast to filamentous forms compared to pretreatment with jacalin. These results suggest that Artin M, but not jacalin present in jack extract significantly increased TNF-alpha production and the activity of mannose and dectin-1 receptors. PMID- 22207011 TI - Measuring and evaluating the level of quality in organized health care. PMID- 22207012 TI - Comment on Rangachari and colleagues, "Using the "customer service framework" to successfully implement patient- and family-centered care". PMID- 22207013 TI - Why do we worship P < .05? AB - The headlines shout "medical breakthrough." The study results are significant. Regulatory approval, billions of dollars in drug sales, publications in high impact journals, promotions, tenure and fame, all because P < .05. How did the P value get to play such a prominent role in how medicine is practiced? PMID- 22207014 TI - Feasibility of real-time satisfaction surveys through automated analysis of patients' unstructured comments and sentiments. AB - This article shows how sentiment analysis (an artificial intelligence procedure that classifies opinions expressed within the text) can be used to design real time satisfaction surveys. To improve participation, real-time surveys must be radically short. The shortest possible survey is a comment card. Patients' comments can be found online at sites organized for rating clinical care, within e-mails, in hospital complaint registries, or through simplified satisfaction surveys such as "Minute Survey." Sentiment analysis uses patterns among words to classify a comment into a complaint, or praise. It further classifies complaints into specific reasons for dissatisfaction, similar to broad categories found in longer surveys such as Consumer Assessment of Healthcare Providers and Systems. In this manner, sentiment analysis allows one to re-create responses to longer satisfaction surveys from a list of comments. To demonstrate, this article provides an analysis of sentiments expressed in 995 online comments made at the RateMDs.com Web site. We focused on pediatrician and obstetrician/gynecologist physicians in District of Columbia, Maryland, and Virginia. We were able to classify patients' reasons for dissatisfaction and the analysis provided information on how practices can improve their care. This article reports the accuracy of classifications of comments. Accuracy will improve as the number of comments received increases. In addition, we ranked physicians using the concept of time-to-next complaint. A time-between control chart was used to assess whether time-to-next complaint exceeded historical patterns and therefore suggested a departure from norms. These findings suggest that (1) patients' comments are easily available, (2) sentiment analysis can classify these comments into complaints/praise, and (3) time-to-next complaint can turn these classifications into numerical benchmarks that can trace impact of improvements over time. The procedures described in the article show that real-time satisfaction surveys are possible. PMID- 22207015 TI - Reduction in hypoglycemic events in critically ill patients on continuous insulin following implementation of a treatment guideline. AB - BACKGROUND: Hyperglycemia is common in critically ill children and appears to be associated with poor outcomes. However, the incidence of hypoglycemia while attempting glycemic control using an insulin infusion may be as high as 25% and hypoglycemia may be an independent risk factor for mortality in critically ill children. METHODS: An improvement team developed a guideline for initiation and maintenance of insulin infusions for hyperglycemia in critically ill, nondiabetic patients in the pediatric intensive care unit. The guideline included an insulin infusion algorithm that provided an initiating dose, titration instructions, and discontinuation parameters. Guideline recommendations addressed the frequency of bedside blood glucose monitoring and management of symptomatic hypoglycemia while on insulin infusion. The guideline was implemented in late January 2007 and revised in September 2007. RESULTS: Hypoglycemic events in at-risk patients decreased significantly following implementation of the guideline, from 36% to 3%, despite an increase in the total number of patient days on insulin infusion. The average days between hypoglycemic events increased from 21 to 186. CONCLUSIONS: Implementation of a guideline to manage critical illness hyperglycemia in nondiabetic, critically ill pediatric patients resulted in a reduction in hypoglycemic events and a sustained increase in the days between such events. PMID- 22207016 TI - Using quality improvement methods at the system level to improve hospital emergency department treatment times. AB - Because the reason for long waits in emergency departments often arises outside the emergency department, addressing the problem of long waits requires a system or hospital-wide response. This, in turn, requires mobilization of management and clinicians from across a hospital and often from outside the hospital. This article describes how the causes of long waits were presented to obtain "buy-in" from a wide variety of stakeholders and how strategies to address causes were linked in a large multihospital system. PMID- 22207017 TI - What happened to the no-wait hospital? A case study of implementation of operational plans for reduced waits. AB - BACKGROUND: Both research and practice show that waiting lists are hard to reduce. Implementing complex interventions for reduced waits is an intricate and challenging process that requires special attention for surrounding factors helping and hindering the implementation. This article reports a case study of a hospital implementation of operational plans for reduced waits, with an emphasis on the process of change. METHODS: A case study research design, theoretically informed by the Pettigrew and Whipp model of strategic change, was applied. Data were gathered from individual and focus group interviews with informants from different organizational levels at different times and from documents and plans. FINDINGS: The findings revealed arrangements both helping and hindering the implementation work. Helping factors were the hospital's contemporary savings requirements and experiences from similar change initiatives. Those hindering the actions to plan and agree the changes were unclear support functions and unclear task prioritization. CONCLUSIONS AND PRACTICE IMPLICATIONS: One contribution of this study is to demonstrate the advantages, disadvantages, and challenges of a contextualized case study for increased understanding of factors influencing organizational change implementation. One lesson for current policy is to regard context factors that are critical for successful implementation. PMID- 22207018 TI - Early return visits by pediatric primary care patients with otitis media: a retail nurse practitioner clinic versus standard medical office care. AB - PURPOSE: To compare outpatient return visits within 2 weeks experienced by pediatric patients diagnosed with otitis media using retail nurse practitioner clinics to similar patients using standard medical office clinics. BACKGROUND: The impact of retail clinics on return visit rates has not been extensively studied. DATA SOURCE: Electronic medical records of pediatric primary care patients seen in a large group practice in Minnesota in 2009 for otitis media. SAMPLE: Patients seen in retail walk-in clinics staffed by nurse practitioners (N = 627) or regular office clinics (N = 2353). OUTCOME MEASURE: A return visit to any site within 2 weeks. RESULTS: The percentage returning was higher in standard care patients than in retail medicine patients (21.0 vs 11.2, P < .001). The odds of a return visit within 2 weeks were higher in standard care patients than in retail medicine patients after adjusting for propensity to use services, age, and gender (odds ratio = 1.54, P < 0.01). CONCLUSION: In this group practice, the odds of return visits within 2 weeks for pediatric patients treated for otitis media were lower in retail medicine clinics than in standard office clinics. PMID- 22207019 TI - An exploration of the leadership attributes and methods associated with successful lean system deployments in acute care hospitals. AB - The lean system has been shown to be a viable and sustainable solution for the growing number of cost, quality, and efficiency issues in the health care industry. While there is a growing body of evidence to support the outcomes that can be achieved as a result of the successful application of the lean system in hospital organizations, there is not a complete understanding of the leadership attributes and methods that are necessary to achieve successful widespread mobilization and sustainment. This study was an exploration of leadership and its relevant association with successful lean system deployments in acute care hospitals. This research employed an exploratory qualitative research design encompassing a research questionnaire and telephonic interviews of 25 health care leaders in 8 hospital organizations across the United States. The results from this study identified the need to have a strong combination of personal characteristics, learned behaviors, strategies, tools, and tactics that evolved into a starting adaptable framework for health care leaders to leverage when starting their own transformational change journeys using the lean system. Health care leaders could utilize the outcomes reported in this study as a conduit to enhance the effective deployment, widespread adoption, and sustainment of the lean system in practice. PMID- 22207020 TI - James Reason: patient safety, human error, and Swiss cheese. Interview by Karolina Peltomaa and Duncan Neuhauser. PMID- 22207023 TI - Dengue virus infection induces upregulation of hn RNP-H and PDIA3 for its multiplication in the host cell. AB - The pathogenic mechanism of Dengue virus (DENV) infection is related to the host responses within target cells and therefore, we assessed intracellular changes in host cell proteins following DENV infection. This study provides evidence that heterogeneous nuclear ribonucleoprotein H (hnRNP-H) and protein disulfide isomerase A3 (PDIA3) helps in DENV multiplication by suppressing TNF-alpha production in human monocytic THP1 cells. Proteomic analysis of infected cells, identified upregulation of the host cell proteins PDIA3 and hnRNP-H in comparison to mock infected cells. The functional role of hnRNP-H and PDIA3 in DENV infection was identified by down regulating hnRNP-H and PDIA3 genes with their specific siRNA duplexes which lead to decreased intracellular viral load. It also resulted in increased TNF-alpha level which mediates antiviral effect. This is the first study, which reports the role of PDIA3 and hnRNP-H in TNF-alpha production in DENV infected cells. Collectively, these results suggest that increased level of hnRNP-H and PDIA3 expression in DENV infected THP1 cells assist in the viral replication by suppressing the TNF-alpha production. PMID- 22207024 TI - Emervel(r): full-face rejuvenation with a range of customized hyaluronic acid fillers. PMID- 22207025 TI - Spatial dynamics of airborne infectious diseases. AB - Disease outbreaks, such as those of Severe Acute Respiratory Syndrome in 2003 and the 2009 pandemic A(H1N1) influenza, have highlighted the potential for airborne transmission in indoor environments. Respirable pathogen-carrying droplets provide a vector for the spatial spread of infection with droplet transport determined by diffusive and convective processes. An epidemiological model describing the spatial dynamics of disease transmission is presented. The effects of an ambient airflow, as an infection control, are incorporated leading to a delay equation, with droplet density dependent on the infectious density at a previous time. It is found that small droplets (~0.4MUm) generate a negligible infectious force due to the small viral load and the associated duration they require to transmit infection. In contrast, larger droplets (~4MUm) can lead to an infectious wave propagating through a fully susceptible population or a secondary infection outbreak for a localized susceptible population. Droplet diffusion is found to be an inefficient mode of droplet transport leading to minimal spatial spread of infection. A threshold air velocity is derived, above which disease transmission is impaired even when the basic reproduction number R(0) exceeds unity. PMID- 22207027 TI - Combined gracilis tendon autograft reconstruction and discus repair of a chronic anterior-superior sternoclavicular joint dislocation. AB - A case of an 18-year-old gardener who sustained an anterior-superior dislocation of the sternoclavicular joint while playing handball and falling on his right shoulder is presented. Non-surgical treatment failed, and the patient could willingly dislocate the right clavicle while abduction and external rotation of the arm. This painful condition was finally treated with surgical reconstruction of the sternoclavicular joint using gracilis tendon autograft and repair of the discus. Level of evidence Therapeutic study, case report and technical note, Level IV. PMID- 22207026 TI - Subacromial patient-controlled analgesia with ropivacaine provides effective pain control after arthroscopic rotator cuff repair. AB - PURPOSE: To investigate the postoperative analgesic effect of subacromial patient controlled analgesia (SA-PCA) with ropivacaine in comparison with intravenous patient-controlled analgesia (IV-PCA) after arthroscopic rotator cuff repair. METHODS: Sixty patients were prospectively randomized into one of the two types of analgesics for 48 h after the operation. In the SA-PCA group, patients received 0.5% ropivacaine at a rate of 2 ml/h with a patient-controlled bolus dose of 2 ml. In the IV-PCA group, patients received intravenous patient controlled analgesia. Pain relief was regularly assessed using visual analog scale (VAS) for 48 h, and side effects were noted. RESULTS: The postoperative pain VAS at 1 h after the operation was lower for the SA-PCA group (4.3 +/- 2.7) than for the IV-PCA group (6.3 +/- 2.6, P = 0.009). The frequency of requested bolus doses by patients in the IV-PCA (19 +/- 19) was higher than in the SA-PCA (7 +/- 10, P = 0.04). Rescue opioid or NSAID requirements were not different. More patients in the IV-PCA (17/30) experienced nausea than in the SA-PCA (7/30, P = 0.03). Patient satisfaction was higher in the SA-PCA than in the IV-PCA [6.7 (3-10) vs. 5.6 (0-8), P = 0.04]. The mean total venous plasma concentration of ropivacaine at 8 and 24 h was below the maximum tolerated venous plasma concentration, and symptoms of systemic toxicity were not noted during 48 h in the SA-PCA. CONCLUSIONS: The analgesic effect of subacromial patient-controlled analgesia with ropivacaine was better than intravenous analgesia during the immediate postoperative period with fewer side effects. LEVEL OF EVIDENCE: Therapeutic study, Level I. PMID- 22207028 TI - Rotatory knee laxity tests and the pivot shift as tools for ACL treatment algorithm. AB - The goal of anterior cruciate ligament (ACL) reconstruction surgery is to eliminate the pivot shift phenomenon. Different injury mechanisms and injury patterns may lead to specific knee laxity patterns. Computer navigation is helpful for the surgeon during examination under anesthesia. Surgical treatment may have to be altered if high-grade laxity is detected preoperatively for example by utilizing a computer navigation that is a helpful adjunct for surgeons during examination under anesthesia. A typical case for revision ACL reconstruction is presented. This article describes several techniques of laxity assessments. Based on the type and degree of pathologic laxity, a treatment algorithm has been developed. LEVEL OF EVIDENCE: V. PMID- 22207029 TI - A phase I study for adjuvant chemotherapy of gemcitabine plus S-1 in curatively resected patients with biliary tract cancer: adjusting the dose of adjuvant chemotherapy according to the surgical procedures. AB - PURPOSE: We conducted a phase I study for adjuvant chemotherapy of gemcitabine (GEM) plus S-1 in order to determine the maximum tolerated dose and the recommended dose (RD) and to evaluate the efficacy and toxicity of the regimen in curatively resected patients with biliary cancer. METHODS: The study included 34 patients with adequate organ functions, Eastern Cooperative Oncology Group PS 0 1, under 80 years of age, who had curative resection after August, 2007. Patients received GEM on day 1 and day 15, and S-1 from day 1 to day 14. Dose-limiting toxicities were determined during first two treatment cycles. After determining RD, a feasibility study was continued in the following four treatment cycles. RESULTS: Hematological toxicity, particularly neutropenia and thrombocytopenia, was the most pronounced toxic effect of gemcitabine and S-1 adjuvant combination chemotherapy. The RD after pancreatoduodenectomy is GEM 1,000 mg/m(2) + S-1 80 mg/m(2), and RD after hemihepatectomy is GEM 800 mg/m(2) + S-1 60 mg/m(2). CONCLUSIONS: The pharmacokinetics of GEM and S-1 indicate that changing the dose of adjuvant chemotherapy based on the operation method for biliary cancers is reasonable. We believe that this regimen will be established as an effective adjuvant chemotherapy for biliary cancer in the future. PMID- 22207030 TI - Peak stepping cadence in free-living adults: 2005-2006 NHANES. AB - BACKGROUND: Analysis of the 2005-2006 National Health and Nutrition Examination Survey (NHANES) accelerometer data provides the descriptive epidemiology of peak 30-minute cadence (defined as the average steps/min recorded for the 30 highest, but not necessarily consecutive, minutes in a day) and peak 1-minute cadence (defined as the steps/min recorded for the highest single minute in a day) by sex, age, and body mass index (BMI). METHODS: Minute-by-minute step data were rank ordered each day to identify the peak 30-minute and 1-minute cadences for 3522 adults (20+ years of age) with complete sex, age, and BMI data and at least 1 valid day (ie, 10/24 hours of accelerometer wear) of accelerometer data. Peak values were averaged across days within participants by sex, age, and BMI-defined categories. RESULTS: U.S. adults average a peak 30-minute cadence of 71.1 (men: 73.7, women: 69.6, P < .0001) steps/min and a peak 1-minute cadence of 100.7 (men: 100.9, women: 100.5, P = .54) steps/min. Both peak cadence indicators displayed significant and consistent declines with age and increasing levels of obesity. CONCLUSIONS: Peak cadence indicators capture the highest intensity execution of naturally occurring ambulatory activity. Future examination of their relationship with health parameters using cross-sectional, longitudinal, and intervention designs is warranted. PMID- 22207031 TI - Response rate of catatonia to electroconvulsive therapy and its clinical correlates. AB - Electroconvulsive therapy (ECT) is an important treatment for catatonia. We aimed to study the response rate of catatonia treated with ECT and its clinical correlates in a large sample of inpatients. The ECT parameters of all patients (n = 63) admitted with catatonia between the months of January and December 2007 were examined. The number of ECTs administered, seizure threshold, failure to achieve adequate seizures and clinical signs pertaining to catatonia were analyzed. Response was considered as complete resolution of catatonic symptoms with Bush Francis Catatonia Rating Scale (BFCRS) score becoming zero. ECT was mostly started after failed lorazepam treatment except in 6 patients where ECT was the first choice. Patients who responded in 4 ECT sessions were considered fast responders (mean session number for response is 4 sessions) and response with 5 or more ECTs was considered slow response. Fast responders had significantly lower duration of catatonia (19.67 +/- 21.66 days, P = 0.02) and higher BFCRS score at presentation (17.25 +/- 6.21, P = 0.03). Presence of waxy flexibility and gegenhalten (22.60% vs. 0%, P = 0.01) predicted faster response, whereas presence of echophenomena (3.2% vs. 24.0%) predicted slow response. The response rate to catatonia appears to be associated with the severity and duration of catatonia, and the presence of certain catatonic signs. PMID- 22207032 TI - Significant associations of the rs2943634 (2q36.3) genetic polymorphism with adiponectin, high density lipoprotein cholesterol and ischemic stroke. AB - BACKGROUND: rs2943634 C/A single nucleotide polymorphism (SNP), located in a non coding region of chromosome 2q36.3, has been associated with coronary artery disease in two genome wide association studies. Our goal was to investigate its relation with myocardial infarction (MI) and ischemic stroke (IS), as well as with 12 intermediate risk phenotypes, in a population-based prospective cohort study. METHODS: rs2943634 was genotyped in a case-cohort study including a random sample of 1891 individuals (subcohort) and all incident MI (n=211) and IS (n=144) cases during a mean follow-up of 8.2+/-2.2years, nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort comprising 27,548 middle-aged men and women. RESULTS: rs2943634 minor allele (A) was associated in an additive fashion with lower risk of IS but not with MI [hazard ratio (HR)=0.66; 95% confidence interval (CI): 0.50-0.87; P=0.003; HR=1.02; 95% CI: 0.82-1.28; P=0.83 respectively, for the age and sex adjusted model]. Furthermore, it was related to slightly higher levels of plasma adiponectin [CC 6.94, CA 7.27, AA 7.86MUg/ml, P=0.0002] and high density lipoprotein (HDL)-cholesterol (CC 52.08, CA 53.05 and AA 55.27mg/dl, P=0.002), based on additive models. Adjustment for adiponectin and HDL-cholesterol did not attenuate the association between the SNP and IS risk. In contrast, adjustment for adiponectin abolished the association between the SNP and HDL-cholesterol and adjustment for HDL-cholesterol attenuated the association between the SNP and adiponectin. CONCLUSIONS: Our findings suggest that rs2943634 is associated with IS risk and with plasma levels of HDL-cholesterol and adiponectin in this German population. Further investigations are needed to confirm these results and to clarify the mechanisms underlying the association. PMID- 22207034 TI - Lack of association between glutathione S-transferase T1 gene polymorphism and laryngeal cancer susceptibility: a meta-analysis based on 2,124 cases and 2,059 controls. AB - Studies investigating the association between glutathione S-transferase T1 (GSTT1) gene polymorphism and laryngeal cancer susceptibility have reported conflicting results. The aim of the present study was to conduct a meta-analysis assessing the possible association of GSTT1 gene polymorphism with laryngeal cancer risk. The relevant studies were identified through a search of PubMed, Embase, ISI Web of Knowledge and Chinese National Knowledge Infrastructure until May 2011. Twelve studies were included in the present meta-analysis, which described a total of 2124 laryngeal cancer cases and 2059 controls. The overall odds ratio (OR) for GSTT1 null genotype was 1.40 (95% CI=0.90-2.16). When stratifying for race, the pooled ORs for GSTT1 null genotype were 1.07 (95% CI=0.81-1.41) in Caucasians and 5.63 (95% CI=1.00-31.83) in Asians. The pooled ORs for GSTT1 null genotype were 1.03 (95% CI=0.71-1.49) in population-based studies and 2.39 (95% CI=0.73-7.86) in hospital-based studies, stratifying for study design. This meta-analysis suggested that there was lack of association between GSTT1 gene polymorphism and laryngeal cancer risk. However, larger scale primary studies are still required to further evaluate the interaction of GSTT1 gene polymorphism with laryngeal cancer risk. PMID- 22207033 TI - A regulatory cascade of three transcription factors in a single specific neuron, DVC, in Caenorhabditis elegans. AB - Homeobox proteins are critical regulators of developmental gene transcription and cell specification. Many insights into transcriptional regulation have been gained from studies in the nematode Caenorhabditis elegans. We investigated the expression and regulation of the C. elegans homeobox gene ceh-63, which encodes a single-homeodomain transcription factor of 152 amino acids. ceh-63 is expressed in the interneuron DVC in both sexes, from late embryogenesis through adulthood, and two pairs of uterine cells in reproductive hermaphrodites only. A reporter gene fusion, encoding GFP fused to the full-length CEH-63, also drove weak inconsistent expression in additional unidentified cells in the head and tail. A potential ceh-63 null mutant had no obvious abnormalities, except for a possible increase in subtle defects of the DVC axon projection. No behavioural responses were observed upon either laser ablation of DVC or activation of DVC through light stimulation of channelrhodopsin-2 specifically expressed in this neuron. The function of DVC therefore remains enigmatic. A transcriptional regulatory cascade operating in DVC was defined from the LIM-homeodomain protein CEH-14 through CEH-63 to the helix-turn-helix transcription factor MBR-1. Both CEH-14 and CEH-63 individually bound the mbr-1 promoter in a yeast one-hybrid assay. A model is proposed suggesting that CEH-14 activates ceh-63 and then along with CEH 63 co-ordinately activates mbr-1. PMID- 22207036 TI - Step-defined physical activity and cardiovascular risk among middle-aged Japanese: the National Health and Nutrition Survey of Japan 2006. AB - BACKGROUND: Pedometers are becoming widely accepted for physical activity measurement. To use step data effectively, an index which categorizes steps/day by < 5000, >= 5000, >= 7500, >= 10,000, and >= 12,500 steps/day has been previously proposed. However, evidence is insufficient to validate this index compared with health outcomes. This study examined the association of steps/day categories with cardiovascular (CVD) risk. METHODS: Cross-sectional data from the National Health and Nutrition Survey of Japan 2006, including 1166 men and 1453 women aged 40-64 years, were analyzed to calculate odds ratios (OR) for having CVD risk including overweight/obesity, blood pressure, high density lipoprotein cholesterol, hemoglobin A1c, and clustered risk factors by steps/day categories. RESULTS: Among men, inverse gradient associations between steps/day categories and CVD risk (overweight/obesity, blood pressure, HbA1c, and clustered risk factors) were observed. Among women, those taking >= 5000 steps/day had substantially lower risk of overweight/obesity and high blood pressure compared with those taking < 5000 steps/day. However, additional decreases of OR by taking more steps were modest among women. CONCLUSIONS: CVD risk was generally lower with higher steps/day categories. Given the limitations of cross-sectional design, further studies, especially using longitudinal designs, are needed to precisely calibrate the association between steps/day and CVD risk. PMID- 22207035 TI - A further study on chromosome minimization by protoplast fusion in Aspergillus oryzae. AB - Our goal in this work was to develop a method to minimize the chromosomes of Aspergillus oryzae, to arrive at a deeper understanding of essential gene functions that will help create more efficient industrially useful strains. In a previous study, we successfully constructed a highly reduced chromosome 7 using multiple large-scale chromosomal deletions (Jin et al. in Mol Genet Genomics 283:1-12, 2010). Here, we have created a further reduced chromosome A. oryzae mutant harboring a reduced chromosome 7 and a reduced chromosome 8 both of which contain a large number of non-syntenic blocks. These are the smallest A. oryzae chromosomes that have been reported. Protoplast fusion between the two distinct chromosome-reduced mutants produced a vigorous and stable fusant which was isolated. PCR and flow cytometry confirmed that two kinds of nuclei, derived from the parent strains, existed in this fusant and that the chromosome DNA per nucleus was doubled, suggesting that the fusant was a heterozygous diploid strain. By treating the cell with 1 MUg/ml benomyl, cell nuclei haploidization was induced in the stable diploid strain. Array comparative genomic hybridization and pulsed-field gel electrophoresis confirmed that the reduced chromosomes 7 and 8 co-existed in the haploid fusant and that no other chromosomal modifications had occurred. This method provides a useful tool for chromosome engineering in A. oryzae to construct an industry-useful strain. PMID- 22207037 TI - Similarities and differences of innate immune responses elicited by smooth and rough LPS. AB - The lipopolysaccharide is the major component of Gram-negative bacteria outer membrane. LPS comprises three covalently linked regions: the lipid A, the rough core oligosaccharide, and the O-antigenic side chain determining serotype specificity. Wild-type LPS (sLPS) contains the O-antigenic side chain and is referred to as smooth. Rough LPS (rLPS) does not contain the O-side chain. Most wt bacteria and especially wt Enterobacteriaceae express prevalently the sLPS form although some truncated rLPS molecules always reach the external membrane. The two sLPS and rLPS forms are used almost indistinctly to study the effects on innate immune cells. Nevertheless, there is evidence that their mechanism of action may be different. For instance, while sLPS requires CD14 for the initiation of both MyD88-dependent and independent signal transduction pathways at least at low doses, rLPS leads to MyD88-dependent responses in the absence of CD14 even at low doses. Here we have identified additional differences in the signaling capacity of the two LPS species in the mouse. We have found that rLPS, diversely from sLPS, is capable of activating in dendritic cells (DCs) the Ca(2+)/calcineurin and NFAT pathway in a CD14-independent manner, moreover it is also capable per se of activating the inflammasome and eliciting IL-1beta secretion independent of the presence of additional stimuli required instead for sLPS. The ability of rLPS of activating the inflammasome in vitro has as a direct consequence a higher efficiency of rLPS-exposed DCs in activating natural killer (NK) cells compared to sLPS-exposed DCs. However, diversely from possible predictions, we found that the different efficiencies of the two LPS species in eliciting innate responses are almost nullified in vivo. Therefore, sLPS and rLPS induce nearly similar in vivo innate responses but with different mechanisms of signaling. PMID- 22207038 TI - Rho GTPases: masters of T lymphocyte migration and activation. AB - Rho GTPases are key signal transducer elements activated in T cells by both chemokine and antigen receptors. These two signalling pathways control the two main functions of T lymphocytes: motility and activation. Rho GTPases are thus crucial for the development of an adequate immune response. In this review, we mostly focus on the roles of RhoA, Rac1 and Cdc42 in T cells. We show their importance in phenomena such as adhesion, morphological polarization, migration and antigen recognition. PMID- 22207039 TI - Structural elucidation of degradation products of a benzopyridooxathiazepine under stress conditions using electrospray orbitrap mass spectrometry - study of degradation kinetic. AB - 1-(4-Methoxyphenylethyl)-11H-benzo[f]-1,2-dihydro pyrido[3,2,c][1,2,5]oxathiazepine 5,5 dioxide (BZN) is a cytotoxic derivative with very promising in vitro activity. Regulatory authority for registration of pharmaceuticals for human use requires to evaluate the stability of active compound under various stress conditions. Forced degradation of BZN was investigated under hydrolytic (0.1M NaOH, 0.1M HCl, neutral), oxidative (3.3% H(2)O(2)), photolytic (visible light) and thermal (25 degrees C, 70 degrees C) settings. Relevant degradation took place under thermal acidic (0.1M HCl, 70 degrees C) and oxidative (3.3% H(2)O(2)) conditions. Liquid chromatography-mass spectrometry (LC-MS) analyses revealed the presence of ten degradation products whose structures were characterized by electrospray ionization-orbitrap mass spectrometry. The full scan accurate mass analysis of degradation products was confirmed or refuted using three tools furnished by the MS software: (1) predictive chemical formula and corresponding mass error; (2) double bond equivalent (DBE) calculation; and (3) accurate mass product ion spectra of degradation products. The structural elucidation showed that the tricycle moiety was unstable under thermal acidic and oxidative conditions since four degradation products possess an opened oxathiazepine ring. Then, a simple and fast HPLC-UV method was developed and validated for the determination of the degradation kinetic of BZN under acidic and oxidative conditions. The method was linear in the 5-100 MUg mL(-1) concentration range with a good precision (RSD=2.2% and 2.7% for the repeatability and the intermediate precision, respectively) and a bias which never exceeded 1.6%, whatever the quality control level. With regards to the BZN concentration, a first-order degradation process was determined, with t(1/2)=703 h and 1140 h, under oxidative and acidic conditions, respectively. PMID- 22207040 TI - Biochemical response of diverse organs in adult Danio rerio (zebrafish) exposed to sub-lethal concentrations of microcystin-LR and microcystin-RR: a balneation study. AB - The present study was carried out to examine the dose-response of microcystin-LR (MC-LR) and microcystin-RR (MC-RR) toxicity in adult Danio rerio (zebrafish) under balneation conditions at various time points. The differential responses of superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) as biomarkers were assessed for oxygen mediated toxicity in liver, gills, intestine and brain tissues of zebrafish exposed to dissolved MC-LR and MC-RR (0.1-10.0 MUgl(-1)). To investigate the time related response of biomarkers, fish were sampled after 4, 7 and 15 days of exposure. Responses varied (i) between MC-LR and MC-RR (for certain groups), (ii) for different enzymes at all time points, and (iii) for different tissues. In general, most of the enzymes followed a bell shaped curve, with an abrupt increase in activity at a particular concentration. It was observed that upon exposure to MC-LR and MC-RR, some enzymes showed an adaptive response after the first time point wherein the enzyme activity increased in some tissues. The increase in enzyme activity is suggestive of their cellular and metabolic adaptations to the continued stress and toxin exposure. Enzyme activities in general increased at lower concentrations (<= 5.0 MUgl(-1)) and decreased at higher concentrations (>= 5.0 MUgl(-1)). An abrupt change in enzyme activities was observed at a particular concentration in all the tissue enzymes. For GPx and GR, there was a differential response in the case of fish exposed to MC-LR and MC RR, which could be due to the difference in toxicity potentials of these cyanotoxins. In general, initial stress conditions were observed in most of the tissue enzymes following the exposure to microcystins (MCs). This observation suggests that MCs found in trace levels are likely to have deleterious effects on aquatic organisms and can trigger a variety of biochemical responses depending on their specific toxicity. PMID- 22207041 TI - Structural, electronic, and elastic properties of K-As compounds: a first principles study. AB - First-principle calculations are performed to investigate the structural, elastic and electronic properties of K-As compounds (KAs in NaP, LiAs and AuCu-type structures, KAs(2) in MgCu(2)-type structure, K(3)As in Na(3)As, Cu(3)P and Li(3)Bi-type structures, and K(5)As(4) in A(5)B(4)-type structure). The lattice parameters, cohesive energy, formation energy, bulk modulus, and the first derivative of bulk modulus (to fit to the Murnaghan's equation of state) of the considered structures are calculated and reasonable agreement is obtained, and the phase transition pressure is also predicted. The repeated calculations on the electronic band structures and the related partial density of states are also given. The calculated second-order elastic constants based on the stress-strain method and the other related quantities such as Young's modulus, shear modulus, Poisson's ratio, sound velocities, Debye temperature, and shear anisotropy factors for considered structures are presented, and trends are discussed. PMID- 22207042 TI - Laparoscopic colorectal surgery. PMID- 22207043 TI - Managing research misconduct: is anyone getting it right? PMID- 22207044 TI - French women to have PIP breast implants removed for free. PMID- 22207045 TI - High intersystem variability for the prediction of additional axillary non sentinel lymph node involvement in individual patients with sentinel node positive breast cancer. AB - PURPOSE: To compare the outcomes of the available systems that predict the risk of non-sentinel lymph node (non-SLN) metastasis and to evaluate the variability within a group of SLN-positive breast cancer patients. METHODS: Predicted probabilities and scores for non-SLN metastasis were calculated with nine predictive systems for 120 SLN-positive patients who underwent a completion axillary lymph node dissection. The number of patients was calculated that were considered low risk or had a probability of <= 10% by at least one of the systems. For each nomogram, a box plot was constructed. All patients with a predicted probability of <= 10% according to the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram were selected, and a comparison was made with the probabilities predicted by the other systems. RESULTS: Nearly two-thirds (64.2%, n = 77) of patients with SLN-positive breast cancer were allocated to a low-risk or low-probability group by at least one of the predictive systems. No patients were uniformly classified as low risk by all nine prediction models. At the group level, a considerable variation in the distribution of the predicted probabilities was observed. At the individual level, calculation of the predicted probabilities for the selected patients who were considered low risk (<= 10%) according to the MSKCC nomogram, showed even larger variations, ranging from 4 to 94%. CONCLUSIONS: This study shows that there is an unacceptably high variability in individual predictions when the predictive systems that are currently available are used to predict non-SLN metastasis in patients with SLN-positive breast cancer. PMID- 22207046 TI - Repeat hepatectomy for metastatic colorectal cancer is safe but marginally effective. AB - BACKGROUND: Although hepatectomy for metastatic colorectal cancer (mCRC) offers prolonged survival in up to 40% of people, recurrence rates are high, approaching 70%. Many patients experience recurrent disease in the liver after initial hepatectomy. We examined our experience with repeat hepatectomy for mCRC. METHODS: After Institutional Review Board approval, we reviewed the records of all patients at a single institution who underwent hepatectomy for mCRC. Repeat hepatectomy was defined as partial liver resection any time after the initial hepatectomy for recurrent mCRC. We estimated time to recurrence and survival by using the Kaplan-Meier method and compared outcomes between groups by using the log-rank test. RESULTS: From 1998 to 2008, 405 patients underwent hepatectomy for mCRC, and 215 (53%) experienced disease recurrence at a median of 13 months. Of 150 patients with liver-only or liver-predominant recurrence, 52 (35%) underwent repeat hepatectomy. The median time to recurrence after repeat hepatectomy was 10 months, and median overall survival was 19 months. There was one (1.9%) perioperative death, and there were 14 (27%) major complications. The median overall survival in the repeat hepatectomy group from the time of recurrence after initial hepatectomy was 22 months, compared with 15 months in the 98 patients with liver recurrence who were not selected for repeat hepatectomy (P=0.02). CONCLUSIONS: Repeat hepatectomy for mCRC is feasible in highly selected patients, with acceptable perioperative morbidity and mortality. Although repeat hepatectomy should be considered, recurrence rates are high. Although the initial hepatectomy for mCRC is potentially curative, recurrence of metastatic disease in the liver is unlikely to be cured. PMID- 22207047 TI - Feasibility of sentinel node biopsy in head and neck melanoma using a hybrid radioactive and fluorescent tracer. AB - PURPOSE: This study was designed to examine the feasibility of combining lymphoscintigraphy and intraoperative sentinel node identification in patients with head and neck melanoma by using a hybrid protein colloid that is both radioactive and fluorescent. METHODS: Eleven patients scheduled for sentinel node biopsy in the head and neck region were studied. Approximately 5 h before surgery, the hybrid nanocolloid labeled with indocyanine green (ICG) and technetium-99m ((99m)Tc) was injected intradermally in four deposits around the scar of the primary melanoma excision. Subsequent lymphoscintigraphy and single photon emission computed tomography with computed tomography (SPECT/CT) were performed to identify the sentinel nodes preoperatively. In the operating room, patent blue dye was injected in 7 of the 11 patients. Intraoperatively, sentinel nodes were acoustically localized with a gamma ray detection probe and visualized by using patent blue dye and/or fluorescence-based tracing with a dedicated near infrared light camera. A portable gamma camera was used before and after sentinel node excision to confirm excision of all sentinel nodes. RESULTS: A total of 27 sentinel nodes were preoperatively identified on the lymphoscintigraphy and SPECT/CT images. All sentinel nodes could be localized intraoperatively. In the seven patients in whom blue dye was used, 43% of the sentinel nodes stained blue, whereas all were fluorescent. The portable gamma camera identified additional sentinel nodes in two patients. Ex vivo, all radioactive lymph nodes were fluorescent and vice versa, indicating the stability of the hybrid tracer. CONCLUSIONS: ICG-(99m)Tc-nanocolloid allows for preoperative sentinel node visualization and concomitant intraoperative radio- and fluorescence guidance to the same sentinel nodes in head and neck melanoma patients. PMID- 22207048 TI - VEGF-A/VEGFR-2 signaling plays an important role for the motility of pancreas cancer cells. AB - BACKGROUND: Pancreatic cancer is one of the most lethal solid tumors. Vascular endothelial growth factor receptors (VEGFRs) are expressed not only by endothelial cells but also by pancreatic cancer cells. VEGFRs might play an important role for the development of pancreatic cancer cells. The purpose of this study was to evaluate the efficacy of VEGF/VEGFR-2-targeted therapy in pancreatic carcinoma. METHODS: Five pancreatic carcinoma cell lines were used. The expression level of VEGFR-2 of cancer cells was examined by RT-PCR and Western blot. The effects of VEGFs, bevacizumab as an anti-VEGF antibody, sunitinib as a tyrosine kinase inhibitor against VEGFRs, and VEGF-R2 siRNA on the motility activity of pancreatic cancer cells were examined by invasion assay and wound healing assay. The effect of VEGF, bevacizumab, and sunitinib on the phosphorylation of VEGFR-2 and downstream effecter molecules, MAPK and PI3K, was examined by western blot. RESULTS: Pancreatic cancer cell lines expressed VEGFR 2. VEGF-A significantly increased the motility of pancreas cancer cells, which was inhibited by VEGFR-2 siRNA. Conditioned medium from pancreas cancer cells significantly stimulated the motility of pancreas cancer cells. VEGF/VEGFR inhibitors, bevacizumab and sunitinib, significantly decreased the motility of pancreas cancer cells. VEGFR-2 phosphorylation level of pancreas cancer cells was increased by VEGF-A. Bevacizumab and sunitinib decreased the level of VEGFR-2 phosphorylation, p-ERK, and p-Akt expression. VEGF-A decreased zonula occludens (ZO-1) or ZO-2 expression in pancreas cancer cells. CONCLUSIONS: VEGF-A/VEGFR-2 signaling plays an important role in inducing invasion and migration of pancreatic cancer cells. PMID- 22207049 TI - A comparison of outcomes for younger and older adult patients undergoing surgery for primary hyperparathyroidism. AB - BACKGROUND: In adolescents and young adults, primary hyperparathyroidism (PHPT) is an uncommon diagnosis. We compared the clinical characteristics of these patients to those of older adult patients with PHPT. We hypothesized that PHPT in adolescents and young adults is more often caused by single-gland disease and is amenable to minimally invasive parathyroidectomy (MIP). METHODS: We retrospectively reviewed the medical records of 452 consecutive patients who had surgery for PHPT. Patients ranged in age from 13 to 94 years and were dichotomized into younger (age <30 years, n = 17, 3.8%) and older (age >= 30 years, n = 435, 96.2%) patients. Continuous baseline and intraoperative and postoperative measures were not normally distributed and were summarized with medians and interquartile ranges (IQRs). Groups were compared using Wilcoxon rank sum test or Fisher exact test, and significance was set at P < .05. RESULTS: Median [IQR] age was 24 [23-27] years for the younger group and 58 [51-66] years for the older group. Though not statistically significant, a smaller proportion of the younger patients compared with the older patients had a positive (99m)Tc sestamibi scan (71%; 95% confidence interval [95% CI] = 44-90% vs. 83%; 95% CI = 79-86%) and showed a suspected parathyroid adenoma on ultrasound (65%; 95% CI = 38-86% vs. 80%; 95% CI = 76-83%). The younger and older age groups did not significantly differ on preoperative serum PTH levels (median [IQR]: 111 [76-145] pg/ml vs 110 [84-152] pg/ml; P = .73 respectively). The younger group had higher serum calcium levels (11.6 [11.1-12.2] mg/dl) compared with the older group (11.1 [10.7-11.5] mg/dl; P = .01). MIP was performed less frequently on the younger patients (70.6%) compared with older patients (88.7%; P = 0.04). Though the incidence of a single adenoma was somewhat more frequent in older patients (90%; 95% CI = 87-93%) than in younger patients (82%; 95% CI = 57-96%) it was the most frequent cause of PHPT in the younger patients. The younger and older groups did not significantly differ on percent drop from baseline for intraoperative PTH monitoring (81.7 vs 79.3%; P = .46), respectively. CONCLUSIONS: Younger patients with PHPT present with significantly higher serum calcium levels than older patients. However, younger patients are less likely to localize abnormal parathyroid glands on sestamibi or ultrasound. Though younger patients appear to have a higher incidence of hyperplasia compared with older patients, single gland disease is still the overall most frequent cause. Our data suggest that MIP should be more frequently considered in younger patients because of the high incidence of single gland disease. PMID- 22207050 TI - Development and evaluation of a checklist to support decision making in cancer multidisciplinary team meetings: MDT-QuIC. AB - BACKGROUND: The quality of decision-making in cancer multidisciplinary team (MDT) meetings is variable, which can result in suboptimal clinical decision making. We developed MDT-QuIC, an evidence-based tool to support clinical decision making by MDTs, which was evaluated by key users. METHODS: Following a literature review, factors important for high-quality clinical decision making were listed and then converted into a preliminary checklist by clinical and safety experts. Attitudes of MDT members toward the tool were evaluated via an online survey, before adjustments were made giving rise to a final version: MDT-QuIC. RESULTS: The checklist was evaluated by 175 MDT members (surgeons = 38, oncologists = 40, specialist nurses = 62, and MDT coordinators = 35). Attitudes toward the checklist were generally positive (P < 0.001, 1-sample t test), although nurses were more positive than other groups regarding whether the checklist would improve their contribution in MDT meetings (P < 0.001, Mann-Whitney U test). Participants thought that the checklist could be used to prepare cases for MDT meetings, to structure and guide case discussions, or as a record of MDT discussion. Regarding who could use the checklist, 70% thought it should be used by the MDT chair, 54% by the MDT coordinator, and 38% thought all MDT members should use it. CONCLUSION: We have developed and validated an evidence-based tool to support the quality of MDT decision making. MDT members were positive about the checklist and felt it may help to structure discussion, improve inclusivity, and patient centeredness. Further research is needed to assess its effect on patient care and outcomes. PMID- 22207051 TI - Prognostic value of number of removed lymph nodes, number of involved lymph nodes, and lymph node ratio in 7502 breast cancer patients enrolled onto trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG). AB - PURPOSE: The number of removed axillary lymph nodes and the ratio of involved to removed lymph nodes are described as independent prognostic factors beside the absolute number of involved lymph nodes in breast cancer patients. The correlation between these factors and prognosis were investigated in trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG). METHODS: This retrospective analysis is based on the data of 7052 patients with endocrine responsive breast cancer who were randomized in four trials of the ABCSG in the years 1990-2006 and underwent axillary lymph node dissection. The prognostic value of number of removed nodes (NRN), number of involved nodes (NIN), and ratio of involved to removed nodes (lymph node ratio, LNR) concerning recurrence-free survival and overall survival was analyzed. RESULTS: A total of 2718 patients had node-positive disease. No correlation was found between NRN and prognosis. Increasing NIN and LNR were significantly associated with worse recurrence-free survival and overall survival in univariate and multivariate analyses (P < .001). Only in the subgroup of patients with one to three positive lymph nodes and treated with mastectomy (n = 728) was LNR an additional prognostic factor in univariate and multivariate analyses. CONCLUSIONS: For breast cancer patients stringently medicated in the framework of prospective adjuvant clinical trials and requiring a mandatory minimum of removed nodes, NRN does not influence prognosis, and LNR is not superior to NIN as prognostic factor. In patients with one to three positive lymph nodes and mastectomy, LNR could play a role as an additional prognostic factor. PMID- 22207052 TI - The combination of surgery and imatinib in GIST: a reality for localized tumors at high risk, an open issue for metastatic ones. PMID- 22207053 TI - Unique metabolic pathway of [(14)C]lenvatinib after oral administration to male cynomolgus monkey. AB - Lenvatinib, a potent inhibitor of multiple tyrosine kinases, including vascular endothelial growth factor receptors 2 and 3, generated unique metabolites after oral administration of [(14)C]lenvatinib (30 mg/kg) to a male cynomolgus monkey. Lenvatinib was found to be transformed to a GSH conjugate, through displacement of an O-aryl moiety, at the quinoline part of the molecule in the liver and kidneys. The GSH conjugate underwent further hydrolysis by gamma glutamyltranspeptidase and dipeptidases, followed by intramolecular rearrangement, to form N-cysteinyl quinoline derivatives, which were dimerized to form disulfide dimers and also formed an N,S-cysteinyl diquinoline derivative. In urine, a thioacetic acid conjugate of the quinoline was also observed as one of the major metabolites of lenvatinib. Lenvatinib is a 4-O-aryl quinoline derivative, and such compounds have been known to undergo conjugation with GSH, accompanied by release of the O-aryl moiety. Because of intramolecular rearrangement in the case of lenvatinib, hydrolysis of the GSH conjugate yielded N-cysteinylglycine and N-cysteine conjugates instead of the corresponding S conjugates. Because the N-substituted derivatives possess free sulfhydryl groups, dimerization through disulfide bonds and another nucleophilic substitution reaction with lenvatinib resulted in the formation of disulfanyl dimers and an N,S-cysteinyl diquinoline derivative, respectively. Characteristic product ions at m/z 235 and m/z 244, which were associated with thioquinoline and N ethylquinoline derivatives, respectively, were used to differentiate S- and N derivatives in this study. On the basis of accurate mass and NMR measurements, a unique metabolic pathway for lenvatinib in monkey and the proposed formation mechanism have been elucidated. PMID- 22207054 TI - Species differences in tissue distribution and enzyme activities of arylacetamide deacetylase in human, rat, and mouse. AB - Human arylacetamide deacetylase (AADAC) is a major esterase responsible for the hydrolysis of clinical drugs such as flutamide, phenacetin, and rifampicin. Thus, AADAC is considered to be a relevant enzyme in preclinical drug development, but there is little information about species differences with AADAC. This study investigated the species differences in the tissue distribution and enzyme activities of AADAC. In human, AADAC mRNA was highly expressed in liver and the gastrointestinal tract, followed by bladder. In rat and mouse, AADAC mRNA was expressed in liver at the highest level, followed by the gastrointestinal tract and kidney. The expression levels in rat tissues were approximately 7- and 10 fold lower than those in human and mouse tissues, respectively. To compare the catalytic efficiency of AADAC among three species, each recombinant AADAC was constructed, and enzyme activities were evaluated by normalizing with the expression levels of AADAC. Flutamide and phenacetin hydrolase activities were detected by the recombinant AADAC of all species. In flutamide hydrolysis, liver microsomes of all species showed similar catalytic efficiencies, despite the lower AADAC mRNA expression in rat liver. In phenacetin hydrolysis, rat liver microsomes showed approximately 4- to 6.5-fold lower activity than human and mouse liver microsomes. High rifampicin hydrolase activity was detected only by recombinant human AADAC and human liver and jejunum microsomes. Taken together, the results of this study clarified the species differences in the tissue distribution and enzyme activities of AADAC and facilitate our understanding of species differences in drug hydrolysis. PMID- 22207055 TI - Comparative analysis of gingival wetness at natural teeth and dental implant sites. AB - BACKGROUND: "Gingival Wetness (GW)," which is the thickness of residual saliva on gingiva, functions as a moisture retainer and a protective barrier for microbial colonization. Whether dental implant (DI) treatment affects GW scores and whether gingival inflammation has the capacity to alter GW remains unknown. Thus, this study was designed to evaluate the potential impact of DI treatment on GW. METHODS: A total of 118 DIs and natural teeth (NT) sites were comparatively analyzed. Clinical periodontal and periimplant status were determined. Sites were classified into 2 subgroups based on the clinical inflammatory status as inflamed or noninflamed. GW was measured by standardized paper strips and quantified by micromoisture meter. RESULTS: Gingival index, clinical attachment loss, plaque index, and gingival bleeding time index scores were generally lower at DI sites. Significant differences were seen in clinical attachment loss, plaque index, and gingival bleeding time index in inflamed sites, presenting higher scores for NT. Comparable values were observed for DI and NT regarding GW for all sites. No differences were noticed in GW scores between the noninflamed NT and DI sites and also wheninflamed sites were concerned. CONCLUSIONS: DI treatment does not seem to result in any apparent reduction in GW. Thus, it can be speculated that similar protective processes may occur at dental implant and NT sites. Furthermore, GW does not seem to depend on the local inflammatory status of the soft tissues. PMID- 22207056 TI - Functional annotation and characterization of 3-hydroxybenzoate 6-hydroxylase from Rhodococcus jostii RHA1. AB - The genome of Rhodococcus jostii RHA1 contains an unusually large number of oxygenase encoding genes. Many of these genes have yet an unknown function, implying that a notable part of the biochemical and catabolic biodiversity of this Gram-positive soil actinomycete is still elusive. Here we present a multiple sequence alignment and phylogenetic analysis of putative R. jostii RHA1 flavoprotein hydroxylases. Out of 18 candidate sequences, three hydroxylases are absent in other available Rhodococcus genomes. In addition, we report the biochemical characterization of 3-hydroxybenzoate 6-hydroxylase (3HB6H), a gentisate-producing enzyme originally mis-annotated as salicylate hydroxylase. R. jostii RHA1 3HB6H expressed in Escherichia coli is a homodimer with each 47kDa subunit containing a non-covalently bound FAD cofactor. The enzyme has a pH optimum around pH 8.3 and prefers NADH as external electron donor. 3HB6H is active with a series of 3-hydroxybenzoate analogues, bearing substituents in ortho- or meta-position of the aromatic ring. Gentisate, the physiological product, is a non-substrate effector of 3HB6H. This compound is not hydroxylated but strongly stimulates the NADH oxidase activity of the enzyme. PMID- 22207058 TI - Etiology of the post-concussion syndrome: Physiogenesis and Psychogenesis revisited. AB - In his seminal article, Physiogenesis and Psychogenesis in the 'Post-Concussional Syndrome,' Lishman (1988) proposed that neurobiological factors account for the development of the post-concussion syndrome and psychological factors become primarily responsible for maintaining it in the chronic phase. Over the 20 years that followed, researchers have advanced our understanding of the etiology of the post-concussion syndrome. Our review of this evidence suggests that neurobiological and psychological factors play a causal role in post-concussion symptoms from the outset, and thus, Lishman's causal model should be updated. If we can clinically identify individuals on a trajectory of poor recovery in the acute post-injury stage, then we can direct secondary prevention towards modifiable risk factors. PMID- 22207059 TI - A conceptual framework for interpreting neuroimaging studies of brain neuroplasticity and cognitive recovery. AB - Functional neuroimaging technologies are increasingly being used to predict cognitive/behavioral outcomes after the initiation of clinical interventions such as resective surgery or cognitive rehabilitation. We provide a conceptual model and a case example to explain how the results from various neuroimaging techniques can be integrated to answer important questions about clinical recovery such as whether neural reorganization has occurred and, if so, the type of adaptive cognitive mechanism driving this reorganization. This proposed framework and its use in interpreting neuroimaging outcomes studies should help uncover the principles that govern neural reorganization, and be of use to any patient for whom the risk, or potential benefit, of brain-based interventions is unknown. PMID- 22207057 TI - Resting-state oscillatory activity in autism spectrum disorders. AB - Neural oscillatory anomalies in autism spectrum disorders (ASD) suggest an excitatory/inhibitory imbalance; however, the nature and clinical relevance of these anomalies are unclear. Whole-cortex magnetoencephalography data were collected while 50 children (27 with ASD, 23 controls) underwent an eyes-closed resting-state exam. A Fast Fourier Transform was applied and oscillatory activity examined from 1 to 120 Hz at 15 regional sources. Associations between oscillatory anomalies and symptom severity were probed. Children with ASD exhibited regionally specific elevations in delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), and high frequency (20-120 Hz) power, supporting an imbalance of neural excitation/inhibition as a neurobiological feature of ASD. Increased temporal and parietal alpha power was associated with greater symptom severity and thus is of particular interest. PMID- 22207060 TI - Diffusion tensor imaging studies on corticospinal tract injury following traumatic brain injury: a review. AB - The corticospinal tract (CST) is the most important neural tract for motor function in the human brain. Therefore, clarification of CST injury would be an important topic in traumatic brain injury (TBI) rehabilitation. In this review, I reviewed diffusion tensor imaging (DTI) studies on CST injuries in terms of etiology and recovery in patients with TBI. Although DTI has several unique advantages for research on CST injury in TBI, only a dozen DTI studies on this topic have been reported: etiology of CST injury (9 studies), recovery of CST injury (3 studies). As for the etiology of CST injury in TBI, the previous studies have demonstrated the usefulness of DTI in diagnosis of CST injury in cases of diffuse axonal injury, transtentorial herniation, cerebral hemorrhage, and cortical contusion; moreover, according to the severity of TBI. The three studies on recovery of CST injury focused on recovery of a CST injured by diffuse axonal injury. In the future, we suggest an increase in the total number of DTI studies on this topic. In particular, research on recovery of CST injury should be encouraged. Moreover, studies of the various recovery mechanisms related to the CST are necessary. PMID- 22207061 TI - Successful treatment of severe abulia with co-beneldopa. AB - Abulia is a disorder of the executive and frontal lobe function. It is characterised by severe psychomotor slowing that is not due to depressive illness or catatonic schizophrenia. Abulia is thought to be due to disruption of the meso cortico-limbic dopaminergic system. Preliminary evidence suggests that patients with abulia may respond to treatment with dopaminergic drugs. We extend this evidence by reporting a significant and sustained functional improvement in a severely abulic patient after treatment with co-beneldopa (Madopar). PMID- 22207062 TI - Brown-Sequard-plus syndrome after a stab injury. AB - STUDY DESIGN: Case report. OBJECTIVE: To describe a patient presenting with Brown Sequard-plus syndrome treated in a conservative manner and to discuss the possible physiopathological mechanisms causing the injury. METHODS: The case study of a 35-year-old woman who entered the hospital with a knife that had penetrated her neck through the left upper thoracic aperture and with a rising, back, right oblique trajectory. This patient developed Brown-Sequard-plus syndrome on the right side of her body. RESULTS: The initial computerized tomography (CT) demonstrated that the tip of the knife was inside the right C7 vertebral foramen, which not dissected the vertebral artery. The initial magnetic resonance imaging (MRI) and the MRI done 3 weeks later showed the presence of spinal cord ischemia on the right side at the C6-C7 level. This spinal cord ischemia was most likely caused after a vessel spasm of the vertebral artery. After conservative treatment, the patient evolved from a C rating on the ASIA scale to a D rating. CONCLUSION: In our department, spinal cord injuries after stab wounds are very rare, and they usually cause incomplete lesions that eventually lead to Brown-Sequard syndrome. In our patient, the spinal cord injury was due to a vasospasm of the vertebral artery, which was accompanied by good functional prognosis. MRI helped to define the physiopathologic mechanism of the injury and guided the appropriate treatment decision. PMID- 22207063 TI - Ipsilateral motor cortex activation by unaffected hand movements in patients with cerebral infarct. AB - Many studies have reported that stroke patients can be accompanied by motor deficit of the unaffected extremities as well as the affected extremities. This suggests that neural control of motor function of unaffected extremities might be changed following stroke. However, very little is known about this topic. Using functional MRI (fMRI), we investigated changes in neural control of motor function of the unaffected hand in hemiparetic patients with cerebral infarct. Thirty-five hemiparetic stroke patients were recruited for this study. fMRI was performed at 1.5T during either affected or unaffected hand flexion-extension movements. We evaluated motor function of the affected upper extremity using the upper Motricity index (UMI) and the medical research council (MRC) scale for finger extensor. From fMRI, LI (laterality index) was calculated for assessment of relative activity in the ipsilateral versus the contralateral primary sensorimotor cortex. Positive correlation between LIs was observed during affected and unaffected hand movements (r=0.670, p=0.000). LI of unaffected hand movements was also correlated with the affected UMI (r=0.408, p=0.015) and MRC of the affected hand extensor (r=0.362, p=0.033). We demonstrated that the ipsilateral (affected) motor cortex was recruited by unaffected hand movements in proportion to poor motor function of the affected upper extremity. PMID- 22207064 TI - Application of combined 6-Hz primed low-frequency rTMS and intensive occupational therapy for upper limb hemiparesis after stroke. AB - INTRODUCTION: The purpose of this study was to clarify the safety, feasibility and efficacy of 6-Hz primed low-frequency repetitive transcranial magnetic stimulation (rTMS) applied with intensive occupational therapy (OT) for upper limb hemiparesis after stroke. SUBJECTS AND METHODS: Eleven patients with history of stroke and upper limb hemiparesis (age at intervention: 61.0 +/- 13.7 years, time after stroke onset: 70.2 +/- 39.8 months) were studied. Each patient received 22 sessions of 6-Hz primed low-frequency rTMS (10-min 6-Hz priming stimulation followed by 20-min low-frequency rTMS of 1-Hz) applied to the non lesional hemisphere plus intensive OT comprising 60-min one-to-one training and 60-min self-training during 15-day hospitalization. The motor function of the affected upper limb was evaluated by Fugl-Meyer Assessment (FMA) and Wolf Motor Function Test (WMFT) on the days of admission and discharge. RESULTS: All patients completed the 15-day protocol without any adverse effects. The treatment increased the FMA score (from 42.2 +/- 6.9 to 45.6 +/- 7.2 points, p< 0.005) and shortened the log performance time of WMFT (from 3.26 +/- 1.21 to 2.81 +/- 1.26 sec, p< 0.05). CONCLUSIONS: The 15-day protocol of 6-Hz primed low-frequency rTMS combined with intensive OT seems safe and a potentially useful therapeutic modality for upper limb hemiparesis after stroke. PMID- 22207065 TI - The correlation of cognitive capacity with recovery of hand sensibility after peripheral nerve injury of upper extremity. AB - INTRODUCTION: The aim of this study is to determine the correlation of cognitive ability with functional sensibility. METHOD: 130 patients with median and ulnar nerve repair at the distal forearm level and wrist level were included. Mean time since surgery and age were 44.35 months (range 23-68) and, 33.44 years (range 18 71), respectively. The patients underwent an assessment of sensory function of the hand and a battery of specific tests for cognitive capacity. RESULTS: A multiple linear regression analysis demonstrated a significant correlation between functional sensibility and cognitive capacity [Block design test (Beta=0.40, p=0.00); Reaction time (Beta=-0.32, p=0.00); The Stroop color word test (Beta=0.16, p=0.04)]. DISCUSSION: The results suggested that, cognitive capacity factors are associated with functional sensibility after nerve repair. These results may be mentioned cognitive rehabilitation programs would enhanced functional outcome following nerve repair. PMID- 22207066 TI - Efficacy and tolerance of a neurological restoration program in stroke patients. AB - The present paper shows the result of an open prospective study performed to evaluate the tolerance and efficacy of a program for neurological restoration (PRN) in stroke patients. The PRN is organized 4 weeks cycles - 39 hours per week - and applied by a team of physical, occupational, and speech therapists, physiatrists, psychologists, clinicians and nurses; directed by a neurologist. The first phase of treatment aims to increase the physical capacity and tolerance to exercise. The second phase trains specific abilities (balance, posture, gait and handling). Drugs were only used to modulate physical or mood disorders, spasticity, or pain. The study was performed in 80 stroke patients attended in our institution (2005-2007). Only patients with a confirmed diagnosis of stroke in the carotid territories, over 15 years old, and not least than 6 months post ictal evolution were included. Tolerance to treatment was very good, with only 4 adverse events not related to treatment. The neurological condition was evaluated using the Scandinavian Stroke Scale (SSS), and the functional condition using the Barthel Index (BI). The results show significant improvements both in the neurological (113.45 +/- 1.59%) and functional (130.11 +/- 5.17%) condition after one treatment cycle, which improved further when therapy continued for a second cycle (233.71 +/- 7.76% and 207.62 +/- 27.16% respectively). Severity of the impairment was not a negative predictor of the outcome. Age correlated negatively with the initial condition, but does not prevent improvement. Sex, time of evolution, affected hemisphere or interactions among them did not influence the outcome. These results demonstrate that the PRN is well tolerated and effective promoting recovery even in chronic stroke patients. PMID- 22207067 TI - Functional electrical stimulation of dorsiflexor muscle: effects on dorsiflexor strength, plantarflexor spasticity, and motor recovery in stroke patients. AB - OBJECTIVE: To evaluate the therapeutic effects of Functional Electrical Stimulation (FES) of the tibialis anterior muscle on plantarflexor spasticity, dorsiflexor strength, voluntary ankle dorsiflexion, and lower extremity motor recovery with stroke survivors. DESIGN: We conducted a prospective interventional study. SETTING: Rehabilitation ward, physiotherapy unit and gait analysis laboratory. PARTICIPANTS: Fifty-one patients with foot drop resulting from stroke. INTERVENTION: The functional electrical stimulation (FES) group (n=27) received 20-30 minutes of electrical stimulation to the peroneal nerve and anterior tibial muscle of the paretic limb along with conventional rehabilitation program (CRP). The control group (n=24) treated with CRP only. The subjects were treated 1 hr per day, 5 days a week, for 12 weeks. MAIN OUTCOME MEASURES: Plantarflexor spasticity measured by modified ashworth scale (MAS), dorsiflexion strength measured by manual muscle test (MMT), active/passive ankle joint dorsiflexion range of motion, and lower-extremity motor recovery by Fugl-Meyer assessment (FMA) scale. RESULTS: After 12 weeks of treatment, there was a significant reduction in a plantarflexor spasticity by 38.3% in the FES group and 21.2% in control group (P< 0.05), between the beginning and end of the trial. Dorsiflexor muscle strength was increased significantly by 56.6% and 27.7% in the FES group and control group, respectively. Similarly, voluntary ankle dorsiflexion and lower-extremity motor function improved significantly in both the groups. No significant differences were found in the baseline measurements among groups. When compared with control group, a significant improvement (p< 0.05) was measured in all assessed parameters in the FES group at post-treatment assessment, thus FES therapy has better effect on recovery process in post-stroke rehabilitation. CONCLUSIONS: Therapy combining FES and conventional rehabilitation program was superior to a conventional rehabilitation program alone, in terms of reducing spasticity, improving dorsiflexor strength and lower extremity motor recovery in stroke patients. PMID- 22207068 TI - Excellent recovery of aphasia in a patient with complete injury of the arcuate fasciculus in the dominant hemisphere. AB - The arcuate fasciculus (AF) is the neural tract that connects Wernicke's area and Broca's area. The main role of the AF is speech repetition; therefore, injury to the AF typically causes conduction aphasia. We report on a patient who showed excellent recovery of aphasia despite complete injury of the AF due to a cerebral infarct. A 54-year-old, right-handed male presented with aphasia and right hemiparesis. Brain MRI showed an infarct in the left centrum semiovale and corona radiata. Diffusion tensor tractography for the AF was reconstructed using DTI studio software. The Korean-Western Aphasia Battery (K-WAB) was used for measurement of language function. On K-WAB at 1 week after onset, his aphasia type was compatible with global aphasia (aphasia quotient: 120/00, fluency: 50/00, comprehension: 240/00, repetition: 150/00, and naming: 310/00). The patient underwent rehabilitative therapy, including language therapy and medication, which is known to facilitate recovery from aphasia, for a period of 24 months. His aphasia had improved to a nearly normal state at 30 months after onset; aphasia quotient: 930/00 (fluency: 910/00, comprehension: 920/00, repetition: 850/00, and naming: 960/00). The left AF showed a complete disruption on 27-month diffusion tensor tractography. Findings from this study suggest the possibility that aphasia might show good recovery, even in cases of severe injury of the AF. PMID- 22207069 TI - Strength and activation of the knee musculature in Parkinson's disease: effect of medication. AB - The specific neuromuscular mechanisms for compromised muscle strength with PD, and the improvement that occurs with medication, have not been clearly delineated. This study assessed knee extension and flexion strength of PD patients whilst on and off medication and examined the neural mechanisms responsible for any changes. Ten idiopathic PD patients were assessed whilst on and off medication (>= 12-h after drug withdrawal), ~ 7 days apart. Isometric strength of the knee extensors and flexors was assessed, and the interpolated twitch technique used to measure activation of the knee extensors. Surface EMG was also used to measure neural drive to the agonists and antagonists. Without medication isometric strength of the knee extensors (7%) and flexors (11%) was impaired and the interpolated twitch technique revealed activation of the knee extensors was reduced (8%, P=0.005). Maximum agonist amplitudes for nkee extension and flexion were unchanged off-medication (0.59 P< 0.77). The agonist and antagonist EMG-force relationships, and the maximum antagonist EMG, were unaffected by medication withdrawal. The decrease in knee extension strength when PD patients were off medication was due to reduced activation of the agonist muscle, rather than any change in antagonist co-activation, and these changes were associated with reduced locomotory performance. PMID- 22207070 TI - Radial extracorporeal shock wave therapy (rESWT) in the treatment of spasticity in cerebral palsy: a randomized, placebo-controlled clinical trial. AB - AIM: The aim of this study was to evaluate the efficacy and safety of radial extracorporeal shock wave therapy (rESWT) in the treatment of spasticity in patients with cerebral palsy. METHODS: Fifteen patients with spastic cerebral palsy, 12 men and 3 women, aged 10-46 years (mean age 31). The 15 patients presented 40 spastic muscles that were divided in three groups using a computerized random-number generator. The first group, received rESWT in spastic muscle. The second group received rESWT in spastic muscle + rESWT in antagonist muscle. The third group received placebo. Range of motion and Ashworth Scale were performed. This study is a randomized, placebo-controlled clinical trial. The patients were treated in 3 sessions at intervals of one week. RESULTS: There are significant differences between groups treated with rESWT and group placebo. A significant decrease in the Ashworth Scale, an increase in the range of motion, were observed in all patients that were treated with rESWT. Positive results were maintained for at least 2 months after treatment. INTERPRETATION: The treatment with rESWT is more effective than placebo in decreasing spasticity of patients with CP. PMID- 22207074 TI - Turing instabilities and spatio-temporal chaos in ratio-dependent Holling-Tanner model. AB - In this paper we consider a modified spatiotemporal ecological system originating from the temporal Holling-Tanner model, by incorporating diffusion terms. The original ODE system is studied for the stability of coexisting homogeneous steady states. The modified PDE system is investigated in detail with both numerical and analytical approaches. Both the Turing and non-Turing patterns are examined for some fixed parametric values and some interesting results have been obtained for the prey and predator populations. Numerical simulation shows that either prey or predator population do not converge to any stationary state at any future time when parameter values are taken in the Turing-Hopf domain. Prey and predator populations exhibit spatiotemporal chaos resulting from temporal oscillation of both the population and spatial instability. With help of numerical simulations we have shown that Turing-Hopf bifurcation leads to onset of spatio-temporal chaos when predator's diffusivity is much higher compared to prey population. Our investigation reveals the fact that Hopf-bifurcation is essential for the onset of spatiotemporal chaos. PMID- 22207073 TI - Linearized oncolytic adenoviral plasmid DNA delivered by bioreducible polymers. AB - As an effort to overcome limits of adenovirus (Ad) as a systemic delivery vector for cancer therapy, we developed a novel system using oncolytic Ad plasmid DNA with two bioreducible polymers: arginine-grafted bioreducible poly(disulfide amine)polymer (ABP) and PEG5k-conjugated ABP (ABP5k) in expectation of oncolytic effect caused by progeny viral production followed by replication. The linearized Ad DNAs for active viral replication polyplexed with each polymer were able to replicate only in human cancer cells and produce progeny viruses. The non immunogenic polymers delivering the DNAs markedly elicited to evade the innate and adaptive immune response. The biodistribution ratio of the polyplexes administered systemically was approximately 99% decreased in liver when compared with naked Ad. Moreover, tumor-to-liver ratio of the Ad DNA delivered by ABP or ABP5k was significantly elevated at 229- or 419-fold greater than that of naked Ad, respectively. The ABP5k improved the chance of the DNA to localize within tumor versus liver with 1.8-fold increased ratio. In conclusion, the innovative and simple system for delivering oncolytic Ad plasmid DNA with the bioreducible polymers, skipping time-consuming steps such as generation and characterization of oncolytic Ad vectors, can be utilized as an alternative approach for cancer therapy. PMID- 22207076 TI - Activation of nuclear factor-kappaB pathway is responsible for tumor necrosis factor-alpha-induced up-regulation of endothelin B2 receptor expression in vascular smooth muscle cells in vitro. AB - The endothelin B2 (ET(B2)) receptors are induced in vascular smooth muscle cells (VSMCs) in cardiovascular diseases. We tested if in vitro short-term exposure to the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) could up regulate ET(B2) receptors in rat mesenteric arteries, and if this effect is through activation of intracellular nuclear factor-kappaB (NF-kappaB) pathway. The mesenteric arteries were dissected from male Sprague-Dawley rats and the endothelium was removed. The arteries were co-incubated with TNF-alpha in serum free Dulbecco's modified Eagle's medium. Real-time reverse transcription-PCR, Western blot and immunohistochemical staining were employed to assess the mRNA/protein expression of ET(B2) receptors and activation of NF-kappaB pathway. The results showed that, during organ culture, TNF-alpha concentration dependently enhanced ET(B2) receptors expression at both mRNA and protein levels, paralleled with activation of NF-kappaB pathway in VSMC. The up-regulated ET(B2) receptor expression and NF-kappaB activation could be effectively suppressed by general transcriptional inhibitor actinomycin D, or either of the selective IkappaB kinase inhibitors wedelolactone and IMD-0354. Conclusively, the activation of intracellular NF-kappaB pathway is responsible for the up regulation of ET(B2) receptors induced by short-term exposure to TNF-alpha. This could partly explain the toxic effects of TNF-alpha on VSMCs that account for cardiovascular diseases. PMID- 22207075 TI - EPR studies on hydroxyl radical-scavenging activities of pravastatin and fluvastatin. AB - Statins are known clinically by their cholesterol reduction properties through the inhibition of HMG-CoA reductase. There is mounting evidence suggesting a protective role of statins in certain types of cancer, cardiac, and vascular disease through a mechanism that extends beyond their lipid lowering ability. The root mechanism of damage likely involves the inflammatory cascade, specifically compounds known as reactive oxygen species such as the hydroxyl radical. However, direct evidence for the hydroxyl-scavenging capacity of pravastatin and fluvastatin, two forms of statins being widely used to lower LDL cholesterol, is still lacking in literature. In this study, electron paramagnetic resonance spectroscopy in combination with 5,5-dimethyl-1-pyrroline N-oxide (DMPO)-spin trapping technique was utilized to determine the abilities of pravastatin and fluvastatin in scavenging hydroxyl radical generated from Fe(II) with H(2)O(2) system. In addition, we examined the effects of pravastatin and fluvastatin on oxidative-induced phiX-174 RF I plasmid DNA damage. We have demonstrated here for the first time that pravastatin and fluvastatin at physiologically relevant concentrations significantly decreased formation of DMPO-OH adduct indicating that both compounds could directly scavenge hydroxyl radicals. However, pravastatin and fluvastatin were not able to directly protect against oxidative DNA plasmid damage. The hydroxyl radical sequestering ability of pravastatin and fluvastatin reported in this study may contribute to their beneficial use in certain types of cancer and in cardiovascular disease. PMID- 22207077 TI - Physical activity among Canadian children on school days and nonschool days. AB - BACKGROUND: Schools are frequently cited as a favorable venue to promote physical activity (PA), however little data exist describing times when students are least active. Our objective was to overcome this limitation and describe time periods when students are least active. METHODS: We used a cross-sectional design to assess patterns of PA in 923 grade 5 students [mean age: 10.9 (+/- 0.4) years] from 30 schools in Alberta, Canada. Students wore time-stamped pedometers for 9 consecutive days, providing 7 full days of data. We compared step counts adjusted for nonwear time between school days and nonschool days as well as during school hours and after school hours. RESULTS: 689 (75%) students provided complete data. The average daily step count was higher on school days (boys 13,476 +/- 4123 step/day; girls 11,436 +/- 3158 steps/day) than nonschool days (boys 11,009 +/- 5542 steps/day; girls 10,256 +/- 5206 steps/day). More steps were also taken during school hours than nonschool hours (boys +206 +/- 420 steps/hour, P < .001; girls 210 +/- 347, P < .001 steps/hour). CONCLUSIONS: PA levels of children are below Canadian recommended levels for optimal growth and health. Health promotion should emphasize PA particularly among girls, outside school hours, and weekends. PMID- 22207079 TI - Intra-laboratory validation of chronic bee paralysis virus quantitation using an accredited standardised real-time quantitative RT-PCR method. AB - Chronic bee paralysis virus (CBPV) is responsible for chronic bee paralysis, an infectious and contagious disease in adult honey bees (Apis mellifera L.). A real time RT-PCR assay to quantitate the CBPV load is now available. To propose this assay as a reference method, it was characterised further in an intra-laboratory study during which the reliability and the repeatability of results and the performance of the assay were confirmed. The qPCR assay alone and the whole quantitation method (from sample RNA extraction to analysis) were both assessed following the ISO/IEC 17025 standard and the recent XP U47-600 standard issued by the French Standards Institute. The performance of the qPCR assay and of the overall CBPV quantitation method were validated over a 6 log range from 10(2) to 10(8) with a detection limit of 50 and 100 CBPV RNA copies, respectively, and the protocol of the real-time RT-qPCR assay for CBPV quantitation was approved by the French Accreditation Committee. PMID- 22207080 TI - Development of an immunochromatographic strip for rapid detection of antibodies against classical swine fever virus. AB - The genes encoding the Erns and E2 antigen epitopes of classical swine fever virus (CSFV) were expressed as a chimeric protein in Escherichia coli BL21 by pET expression system. The antigenicity of the expressed protein CnC2 was identified by indirect enzyme-linked immunoabsorbant assay (ELISA) and immunoblot with anti CSFV antibodies. Based on the CnC2 protein, an immunochromatographic strip was developed to evaluate the antibody titer of serum samples from swine vaccinated with CSFV vaccine rapidly. The chimeric protein used as a detector was labeled with colloidal gold. Staphylococcal protein A (SPA) and anti-CnC2 monoclonal antibodies (mAbs) were blotted onto the nitrocellulose membrane as the test and control lines, respectively. The strip assay could be performed within 5min, which did not require any special equipment or skills. Through testing sera against various strains of CSFV, the sensitivity of the strip was determined to be 97.0% (65/67) and the specificity was 100% (98/98). The strip results were consistent with those of the existing commercial ELISA kit, and their correlation coefficient was 0.935. In conclusion, the immunochromatographic strip was an acceptable method for surveying CSFV-antibody titers in pigs. PMID- 22207081 TI - Optimisation of a triplex real time RT-PCR for detection of hepatitis E virus RNA and validation on biological samples. AB - The aim of this study was to optimise a two-tube reverse transcription triplex quantitative real time PCR (qRT-PCR) combining amplification of two loci with an internal amplification control (IAC) for detection and quantitation of hepatitis E virus (HEV) RNA and to validate its performance on a pool of biological samples. Optimisation was performed on serially diluted "home-made" RNA standards. The limit of detection was determined experimentally as 10 copies/MUl of the RNA standard for both amplification targets. The qRT-PCR was validated on a cohort of samples originating from 48 wild boars (Sus scrofa), 17 fallow deer (Dama dama) and 28 mouflons (Ovis musimon), with nested RT-PCR used as a reference method. qRT-PCR was found to be more specific for the detection of HEV RNA in examined samples. HEV RNA was detected in samples of five more animals (one wild boar and four mouflons) in comparison with nested RT-PCR. PMID- 22207082 TI - Development of an indirect ELISA for serological detection of reticuloendotheliosis virus using the gp90 protein expressed in Pichia pastoris. AB - The present study was undertaken to express the gp90 protein of reticuloendotheliosis virus (REV) in Pichia pastoris and evaluate its potential use as a diagnostic antigen in ELISA. The full-length gp90 gene of REV was cloned into pPIC9k vector and then integrated into the chromosome of P. pastoris for induced expression. SDS-PAGE and western blot assay demonstrated that gp90 protein was expressed and secreted into the culture medium at about 100mg/L of culture under optimized condition. An indirect ELISA was then established by using the recombinant gp90 protein as the coating antigen. The optimal concentration of coated antigen was 0.1 MUg/well at a serum dilution of 1:200 and the optimal positive threshold value of the assay was 0.409. Cross-reactivity assay showed that this antigen was REV specific. The reproducibility experiment displayed good consistency. Furthermore, the gp90 protein based indirect ELISA showed good correlation rates of 96.3% and 97.5% with virus neutralization test and a commercially whole virus based indirect ELISA, respectively. This study demonstrates the efficacy of recombinant gp90 protein as an antigen in ELISA for seroepidemiological study of REV infection on a large scale. PMID- 22207084 TI - Rapid membrane responses to dihydrotestosterone are sex dependent in growth plate chondrocytes. AB - Sex steroids are important regulators for longitudinal growth, bone mass accrual, and sexual dimorphism of the skeleton. 17beta-Estradiol regulates proliferation and differentiation of female chondrocytes via a membrane-associated signaling pathway in addition to its estrogen receptor (ER) mediated effects. In contrast, testosterone does not elicit a similar membrane response, either in male or female cells. Whereas female rat growth plate chondrocytes convert testosterone to 17beta-estradiol, male chondrocytes produce 5alpha-dihydrotestosterone (DHT). Previously DHT was found to mediate sex-specific effects of testosterone in male cells, but it is not known if a membrane-signaling pathway is involved. In this study, we hypothesized that DHT can induce sex-specific rapid membrane effects similar to other steroid hormones. Confluent cultures of chondrocytes isolated from resting zones of growth plates of both male and female rats were treated with 10(-10)-10(-7)M testosterone or DHT for 3, 9, 90 and 270min and protein kinase C (PKC) and phospholipase A2 (PLA2) activities were measured. To examine potential signaling pathways involved in PKC activation, male chondrocytes were treated with 10(-7)M DHT for 9min in the presence or absence of the phospholipase C (PLC) inhibitor U73122, the secretory PLA2 inhibitor quinacrine or the cytosolic PLA2 inhibitor AACOCF3; the Galphai inhibitor pertussis toxin (PTX) or Galphas activator cholera toxin (CTX), and the general G-protein inhibitor GDPbetaS; thapsigargin, an inhibitor of a Ca-ATPase pump in the endoplasmic reticulum; verapamil and nifedipine, inhibitors of specific L type Ca2+ channels on the cell membrane; and cyproterone acetate (CPA), which is an inhibitor of the classical androgen receptor (AR); as well as the transcription inhibitor actinomycin D, or the translation inhibitor cycloheximide. DHT induced a dose dependent increase in PKC and PLA2 activity in male cells with the highest increase at 10(-7)M DHT (p<0.05), whereas testosterone had no effect. PKC activity was augmented at 9 and 90 min, and then decreased to baseline at 270min. Neither testosterone nor DHT affected PKC in female cells. U73122, quinacrine, and AACOCF3 inhibited DHT-induced activation of PKC. DHT treatment for 9 min had no effect in [(3)H]-thymidine incorporation in quiescent confluent cultures but caused a dose dependent increase in alkaline phosphatase specific activity. Inhibition of PLC reduced the response of to DHT in a dose dependent manner, indicating that PLC is involved. In conclusion, our study indicates that DHT, but not testosterone, has sex-specific rapid membrane effects in male growth plate chondrocytes involving PLC and PLA2-mediated PKC signaling pathways. Together with previous observations showing that male cells convert testosterone to DHT, these results suggest that DHT might act in the membrane through an autocrine/paracrine mechanism. PMID- 22207083 TI - The EPI bioassay identifies natural compounds with estrogenic activity that are potent inhibitors of androgenic pathways in human prostate stromal and epithelial cells. AB - The reactive stromal phenotype is an important factor for prostate cancer progression and may be a new target for treatment and prevention. A new high efficiency preclinical protocol, the EPI bioassay, reflects the interaction of endocrine, paracrine and immune, (EPI) factors on induced androgen metabolism in human prostate reactive stroma. The bioassay is based on co-culturing human primary prostate stromal cells and LAPC-4 prostatic adenocarcinoma cells in a downscaled format of 96-well-plates for testing multiple doses of multiple target compounds. Metabolism of dehydroepiandrosterone (DHEA) with or without TGFbeta1 induced stimulation (D+T) of the reactive stroma phenotype was assessed by increased testosterone in the media and PSA production of the epithelial prostate cancer cells. Using the non-metabolizable androgen R1881, effects from direct androgen action were distinguished from stromal androgen production from DHEA. Stromal cell androgenic bioactivity was confirmed using conditioned media from D+T-treated stromal cell monocultures in an androgen-inducible AR screening assay. We further showed that both agonists to estrogen receptor (ER), DPN (ERbeta) and PPT (ERalpha), as well as estrogenic natural compounds including soy isoflavones attenuated D+T-induced PSA production. Studies with the pure ER agonists showed that activating either ERalpha or ERbeta could inhibit both D+T mediated and R1881-mediated PSA production with the D+T effect being more pronounced. In conclusion, natural compounds with estrogenic activity and pure ER agonists are very potent inhibitors of stromal conversion of DHEA to androgenic metabolites. More studies are needed to characterize the mechanisms involved in estrogenic modulation of the endocrine-immune-paracrine balance of the prostate microenvironment. PMID- 22207085 TI - Attenuation of glomerular filtration barrier damage in adriamycin-induced nephropathic rats with bufalin: an antiproteinuric agent. AB - Proteinuria is an important risk factor for the progression and prognosis of chronic kidney disease. Bufalin, a cardiotonic steroid, has been shown to posses a variety of biological activities including cardiotonic, anaesthetic and antineoplastic activities, and regulate the immune response. This study investigated the effects of bufalin against proteinuria and glomerular filtration barrier damage in rats with adriamycin (ADR)-induced nephropathy. We compared the blood and urine biochemical indices and the histologic and ultrastructure of the glomerulus in ADR rats with and without the intervention of bufalin or prednisone. The transcription, expression and distribution of the podocyte associated molecules were compared utilising RT-PCR, western blotting and immunohistochemical staining. We found that bufalin reduced the urinary protein excretion and optimised the lipidaemia of the ADR rats. Bufalin alleviated the removal of podocyte foot processes and attenuated the changes in nephrin, podocin and integrin-linked kinase (ILK) stainings in the glomerulus of the ADR rats. Bufalin notably decreased the expression of nephrin and ILK but inhibited the down-regulation of podocin in protein levels on the renal cortex of the ADR rats. Additionally, bufalin inhibited the up-regulation of podocin and ILK in mRNA levels but did not affect nephrin mRNA levels. These results suggest that bufalin could alleviate ADR-induced proteinuria by protecting the glomerular filtration barrier and may be a novel potential therapeutic agent for proteinuria-associated kidney disease. PMID- 22207086 TI - Presurgical (neoadjuvant) endocrine therapy is a useful model to predict response and outcome to endocrine treatment in breast cancer patients. AB - Endocrine therapy of breast cancer has been improved continuously during the last decades. Currently, aromatase inhibitors are dominating treatment algorithms for postmenopausal women with hormone-receptor positive breast cancer while tamoxifen still is the most widely used drug for premenopausal women. Several research tools and study designs have been used to challenge established drugs and develop the field of antihormonal therapy. One pivotal study option has been the observation of clinical responses during presurgical/neoadjuvant endocrine therapy (PSET/NET). This strategy has several major advantages. First, the breast tumor, still present in the patient's breast during therapy, can be followed by clinical observations and radiological measurements and any treatment effect will be immediately registered. Second, tumor biopsies may be obtained before initiation and following therapy allowing intra-patient comparisons. These tumor biopsies may be used for the evaluation of intra-tumor changes associated with drug treatment. As examples, presurgical breast cancer trials have been used to evaluate intra-tumor estrogen levels during therapy with aromatase inhibitors and also to study mechanisms involved in the adaptation processes to estrogen suppression. Biomarker studies have provided information that may be used for patient selection in the future. Finally, recently published results from presurgical trials testing combinations of classical endocrine drugs and novel targeted therapies have produced promising results. PMID- 22207087 TI - Influence of depleted uranium on hepatic cholesterol metabolism in apolipoprotein E-deficient mice. AB - Depleted uranium (DU) is uranium with a lower content of the fissile isotope U 235 than natural uranium. It is a radioelement and a waste product from the enrichment process of natural uranium. Because of its very high density, it is used in the civil industry and for military purposes. DU exposure can affect many vital systems in the human body, because in addition to being weakly radioactive, uranium is a toxic metal. It should be emphasized that, to be exposed to radiation from DU, you have to eat, drink, or breathe it, or get it on your skin. This particular study is focusing on the health effects of DU for the cholesterol metabolism. Previous studies on the same issue have shown that the cholesterol metabolism was modulated at molecular level in the liver of laboratory rodents contaminated for nine months with DU. However, this modulation was not correlated with some effects at organs or body levels. It was therefore decided to use a "pathological model" such as hypercholesterolemic apolipoprotein E-deficient laboratory mice in order to try to clarify the situation. The purpose of the present study is to assess the effects of a chronic ingestion (during 3 months) of a low level DU-supplemented water (20 mg L(-1)) on the above mentioned mice in order to determine a possible contamination effect. Afterwards the cholesterol metabolism was studied in the liver especially focused on the gene expressions of cholesterol-catabolising enzymes (CYP7A1, CYP27A1 and CYP7B1), as well as those of associated nuclear receptors (LXRalpha, FXR, PPARalpha, and SREBP 2). In addition, mRNA levels of other enzymes of interest were measured (ACAT 2, as well as HMGCoA Reductase and HMGCoA Synthase). The gene expression study was completed with SRB1 and LDLr, apolipoproteins A1 and B and membrane transporters ABC A1, ABC G5. The major effect induced by a low level of DU contamination in apo-E deficient mice was a decrease in hepatic gene expression of the enzyme CYP7B1 ( 23%) and nuclear receptors LXRalpha (-24%), RXR (-32%), HNF4alpha (-21%) when compared to unexposed ones. These modifications on cholesterol metabolism did not lead to increased disturbances that are specific for apolipoprotein E-deficient mice, suggesting that chronic DU exposure did not worsen the pathology in this experimental model. In conclusion, the results of this study indicate that even for a sensitive pathologic model the exposure to a low dose of DU has no relevant impact. The results confirm the results of our first study carried out on healthy laboratory rodents where a sub-chronic contamination with low dose DU did not affect in vivo the metabolism of cholesterol. PMID- 22207088 TI - The independent effect of traditional cardiac rehabilitation and the LEARN program on weight loss: a comparative analysis. AB - INTRODUCTION: Despite its numerous other benefits, cardiac rehabilitation (CR) has not consistently proven to be an effective, although much needed, intervention for weight loss in the cardiovascular disease (CVD) population. Comparatively, the LEARN (Lifestyle, Exercise, Attitudes, Relationships, Nutrition) program appears to be an effective intervention for weight loss. The purpose of the present investigation was to compare changes in body weight in a CVD cohort consecutively participating in traditional CR and the LEARN program. METHODS: Forty-four patients diagnosed with CVD (22 men/22 women) participated in a 12-week multidisciplinary CR program. All patients successfully completed the LEARN program following CR. Body mass index (BMI) and body weight were recorded immediately prior to and following both CR and LEARN. RESULTS: The peak metabolic equivalents were significantly higher following CR (7.3 +/- 1.6 vs 8.5 +/- 1.6, P < .001), while body weight (203.5 +/- 32.6 vs 201.8 +/- 32.5 lbs, P > .10) and BMI (32.1 +/- 4.0 vs 31.8 +/- 3.9 kg/m, P > .05) were unchanged. All subjects then successfully completed the LEARN program, participating in an average of 10 sessions. There was a significant reduction in body weight (203.3 +/- 30.7 vs 190.1 +/- 30.4 lbs, P < .001) and BMI (32.0 +/- 3.9 vs 29.5 +/- 3.8 kg/m, P < .001) following the LEARN program. DISCUSSION: Our results support the independent value of the LEARN program in eliciting weight loss for CR patients. Clinicians delivering CR services should consider integrating a focused weight loss program, such as LEARN, into their usual CR programs. PMID- 22207090 TI - Pandemic H1N1 influenza virus-like particles are immunogenic and provide protective immunity to pigs. AB - The outbreak of the 2009 influenza pandemic underscored the important role of swine in influenza virus evolution and the emergence of novel viruses with pandemic potential. Vaccination is the most common practice to control swine influenza in swine industry. Influenza virus-like particle (VLP) vaccines are an alternative approach and have been demonstrated to be immunogenic and confer protection against influenza virus challenge in chickens, mice and ferrets. In this study, we generated VLPs consisting of HA, NA and M1 proteins derived from pandemic virus A/California/04/2009 in insect cells. The immunogenicity and efficacy following vaccination of VLPs were evaluated in swine. Our data showed that vaccination using VLPs elicited robust levels of serum IgG, mucosal IgA, and viral neutralizing antibodies against A/Sw/Manitoba/MAFRI32/2009 H1N1. Following challenge with pandemic H1N1 2009, vaccinated pigs were protected, displaying reduced lung lesions, virus shedding and inhibition of virus replication in the lungs compared to non-vaccinated control pigs. Thus, VLPs can serve as a promising vaccination strategy to control influenza in swine. PMID- 22207091 TI - Clinical disease in sheep caused by bluetongue virus serotype 8, and prevention by an inactivated vaccine. AB - The ability to reduce clinical signs, induce neutralizing antibodies, and perhaps most importantly, to prevent or reduce viraemia (and therefore virus transmission), represent primary criteria for assessment of bluetongue virus (BTV) vaccine efficacy. Identification of BTV challenge-strains that reliably induce viraemia and clinical signs comparable to those in naturally infected animals, is therefore important for vaccine evaluation. Texel cross-breed and Dorset Poll sheep vaccinated with inactivated BTV-8 vaccine ('Bovilis((r)) BTV8' from MSD Animal Health), were challenged with low-passage BTV-8 (Northern European strain) grown in either insect (Culicoides) or mammalian cell-cultures. The severity of clinical signs was recorded (using a modified numerical scoring system, which is described) along with viraemia and serum neutralizing (SN) antibody levels. Low level SN-antibodies were detected at the time of challenge (three weeks after vaccination). All unvaccinated control animals became infected after challenge, developing high SN-antibody titres by 21 days post challenge (dpc). Vaccinees showed faster increases in SN-antibody titres ('booster' response), with significantly higher titres at 6 dpc than unvaccinated controls. Although only limited clinical-signs could be attributed to BTV in younger animals infected with the mammalian-cell-culture derived virus, both BTV-8 challenge preparations induced severe clinical signs comparable to 'bluetongue' observed during natural outbreaks in older unvaccinated animals. Challenge with BTV-8 grown in Culicoides cell-cultures seemed to induce greater severity of clinical-scores and 'post-mortem lesions' than the mammalian-derived BTV-8 strain. Vaccination reduced clinical signs, fever, and viraemia equally well after challenge with either virus preparation. PMID- 22207093 TI - Is arthrodesis the end in spastic hip disease? AB - INTRODUCTION: The purpose of this study was to evaluate the long term results of 19 painful dislocated hips in patients with spastic cerebral palsy (CP) who were treated with hip arthrodesis and internal fixation. PATIENTS AND METHODS: The study included 19 patients with spastic CP with a mean age of 17 years and five months (min 10+11 and max 30+8) at the time of surgery. There were 11 tetraplegics, 5 diplegics, 2 diplegics with athetosis, and one hemiplegic. Functionally, 4 patients were community ambulators, 2 were household, and 13 were non-ambulators. Six patients had previous hip procedures prior to arthrodesis. The main surgical indications were pain and too much joint destruction to reconstruct the hip. The mean follow-up period was 11 years and one month. RESULTS: All patients showed bone union and pain relief, and postural improvement was seen in almost all patients. Four patients needed revision, with implant change and bone graft for delayed union. In two cases, the hip arthrodesis ended up being converted into a Castle procedure due to difficulties in positioning and/or increasing spinal deformity. CONCLUSION: Hip arthrodesis is a reasonable option in treating painful spastic subluxated and dislocated hips in CP, primarily in unilateral cases and in patients with ambulatory ability. PMID- 22207094 TI - The development of Australian Standards of Care for Hip Surveillance in Children with Cerebral Palsy: how did we reach consensus? AB - Progressive hip displacement is the second most common deformity in children with cerebral palsy (CP). For many decades, the methods of monitoring hip health and development in children with CP varied widely between facilities. Recently, systematic population based studies have identified some of the factors and characteristics of children with CP who would most benefit from hip surveillance. Health services providing hip surveillance within Australia identified a need for clinical guidelines to assist in provision of comprehensive and best practice health care for children with CP across all patient demographics. Guidelines providing clear, evidence based information on specific timing for commencement, frequency, and discharge have not previously been published. This article analyses the supportive evidence for comprehensive hip surveillance, discusses the development of draft guidelines in Australia, and describes the process for achieving national consensus resulting in the Consensus Statement on Hip Surveillance for Children with Cerebral Palsy: Australian Standards of Care. These standards of care are being followed in clinical facilities across Australia and are endorsed by the Australasian Academy of Cerebral Palsy and Developmental Medicine (AusACPDM). PMID- 22207095 TI - The Consensus Statement on Hip Surveillance for Children with Cerebral Palsy: Australian Standards of Care. AB - The 'Consensus Statement on Hip Surveillance for Children with Cerebral Palsy: Australian Standards of Care' ('Standards of Care') provides a clear and concise guideline for inclusion of hip surveillance into current services. The 'Standards of Care' have been developed by a multidisciplinary working group for the education and information of all health professionals working with children with CP and their families. The 'Standards of Care' were developed through extensive review of the literature and garnering of expert opinion from professionals working in the area within Australia and New Zealand. A formalized external consensus process was conducted from 2007 to 2008 and the 'Consensus Statement on Hip Surveillance for Children with Cerebral Palsy: Australian Standards of Care' became the basis for best practice around Australia in 2008. It has been endorsed by The Australasian Academy of Cerebral Palsy and Developmental Medicine (AusACPDM). Prospective longitudinal study will evaluate both effectiveness and cost/benefit outcomes of this recommended hip surveillance standard of care. PMID- 22207096 TI - Hip displacement and overall function in severe cerebral palsy. AB - OBJECTIVE: The aim of this study was to investigate the relationship between hip displacement (HD) in individuals with severe cerebral palsy with function and quality of life (QOL). The second aim was to identify differences in these outcomes when comparing surgical and non-surgical management for HD. DESIGN: Cross-sectional study of 26 participants born between 1988 and 1998 who had hip displacement on their most recent hip radiograph. METHOD: Caregivers completed the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD(c)) questionnaire. Hip migration percentage and a validated hip classification were used. RESULTS: Significant positive correlation coefficients (CC) were found for mobility and comfort (CC=0.620, rho = 0.001) as well as for QOL and comfort (CC=0.683, rho < 0.001). Orthopedic hip surgery was associated with better scores for mobility (median [95% CI]); surgery vs. none; (36.1 [27.7, 44.4]) vs. (25.6 [22.2, 29.8]) and personal care, (32.1 [27.1, 43.2]) vs. (25.9 [22.7, 30.8]). Severity of HD had no significant association with comfort or QOL. CONCLUSION: Mobility and personal care scores were significantly better in children who had undergone reconstructive hip surgery. However, QOL and pain scores were not associated with the severity of hip displacement or undertaking reconstructive hip surgery. PMID- 22207097 TI - Five-year outcome of state-wide hip surveillance of children and adolescents with cerebral palsy. AB - This study reports the five-year outcomes of a prospective population-based study of clinical hip surveillance for children with cerebral palsy (CP) according to evidence-based standards of care. Systematic hip surveillance commenced in Queensland, Australia as a state-wide program in 2005. Queensland represents a dispersed population across a large geographical area, creating unique challenges in terms of service delivery. Over five years, 1,115 children with CP were recruited, representing 73% of the expected population based on 1.9 to 2.1 per 1,000 live births. Standardized clinical and radiological assessments have been provided, with a median follow-up of 1.2 years (range 1 month -5(+8) yrs). Of the 1,115 children, 423 (38%) have been discharged and 692 (62%) remain on surveillance with 314 (28%) identified as having hip displacement with Migration Percentage (MP) equal to or greater than 30% (>= 30). The incidence of marked hip displacement (MP >= 30) was directly related to gross motor function, classified according to the gross motor function classification system (GMFCS), with distribution of GMFCS I=10, (3%), II=40 (13%), III=53 (43%), IV=96 (59%), and V=115 (64%). This state-wide surveillance program has been successful in correctly identifying children with hip displacement (MP >= 30), fast tracking children for orthopedic review and discharging those at minimal risk. No child has progressed to dislocation while on surveillance without orthopedic review. PMID- 22207098 TI - Daily care activities and hip pain in non-ambulatory children and young adults with cerebral palsy. AB - Hip movement pain was identified in 13 (32.5%) of 40 children and young adults with cerebral palsy who were in residential care. All of the participants were non-ambulatory (Level IV and V of the GMFCS), and their ages ranged from 8 to 26 years (median 16.5 years). Ten of the 13 participants had unilateral hip dislocation and three had bilateral dislocations. Degenerative hip changes were identified on radiographs of the painful dislocated hips. The occurrence of pain during a daily episode of washing, dressing, and transfer was recorded using non verbal indicators. Washing of the lower body elicited significantly more pain responses than dressing (p=0.008) and transfer (p<0.001). None of the participants had daily pain during all of the care activities. Pain was present in 1/3 of the patients and was intermittent in nature, indicating that conservative management can be considered for persons with cerebral palsy at Levels IV and V of the GMFCS who have established hip dislocations and this type of pain. This management could include medication, attention to seating and positioning, and careful handling during daily care activities. PMID- 22207099 TI - A comparison of the changes in the energy cost of walking between children with cerebral palsy and able-bodied peers over one year. AB - For ambulatory children with cerebral palsy, the assessment of walking energy efficiency is utilized to determine functional changes following surgical, pharmacologic, or orthotic interventions. While the assessment of energy efficiency is considered a useful outcome tool, minimal information exists about the changes in energy efficiency over one year in children with cerebral palsy at different gross motor function classification system (GMFCS) levels and whether the patterns of change are similar to their able-bodied peers. The purpose of this study was to determine whether energy efficiency variables change similarly over one year in children with cerebral palsy by GMFCS level and whether they differ from their age-matched peers. Forty-five able-bodied children and 34 children with cerebral palsy, GMFCS levels I-III participated in the study. Energy efficiency variables were measured at baseline and at 12 months using a Cosmed K4b2. All subjects walked at their self-selected velocity for testing around a 33 m track. Baseline velocity and net non-dimensional cost (NNcost) differed by GMFCS level and between the able-bodied peers and all GMFCS levels. Children in GMFCS level III had the highest cost and the slowest velocity. When controlling for age and baseline values, significant differences in the magnitude of change were seen in velocity between children in GMFCS level III and children in GMFCS level I and II and their able-bodied peers. In comparison to their able bodied peers, all GMFCS levels had an increase in NNcost over one year when controlling for age and baseline NNcost, with the difference in magnitude increasing by GMFCS level. Consistent with the literature, children with cerebral palsy had an increase in NNcost over one year in comparison to their able-bodied peers, which increased with GMFCS level. This finding demonstrates that when evaluating the change in walking energy efficiency with maturation and therapeutic intervention, comparisons should be made by GMFCS level. PMID- 22207100 TI - Hip surveillance for children with cerebral palsy: are the Australian standards the gold standard? PMID- 22207102 TI - The indirect effect of radiation reduces the repair fidelity of NHEJ as verified in repair deficient CHO cell lines exposed to different radiation qualities and potassium bromate. AB - The complexity of DNA lesions induced by ionizing radiation is mainly dependent on radiation quality, where the indirect action of radiation may contribute to different extent depending on the type of radiation under study. The effect of indirect action of radiation can be investigated by using agents that induce oxidative DNA damage or by applying free radical scavengers. The aim of this study was to investigate the role of the indirect effect of radiation for the repair fidelity of non-homologous end-joining (NHEJ), homologous recombination repair (HRR) and base excision repair (BER) when DNA damage of different complexity was induced by gamma radiation, alpha particles or from base damages (8-oxo-dG) induced by potassium bromate (KBrO(3)). CHO cells lines deficient in XRCC3 (HRR) irs1SF, XRCC7 (NHEJ) V3-3 and XRCC1 (BER) EM9 were irradiated in the absence or presence of the free radical scavenger dimethyl sulfoxide (DMSO). The endpoints investigated included rate of cell proliferation by the DRAG assay, clonogenic cell survival and the level of primary DNA damage by the comet assay. The results revealed that the indirect effect of low-LET radiation significantly reduced the repair fidelity of both NHEJ and HRR pathways. For high-LET radiation the indirect effect of radiation also significantly reduced the repair fidelity for the repair deficient cell lines. The results suggest further that the repair fidelity of the error prone NHEJ repair pathway is more impaired by the indirect effect of high-LET radiation relative to the other repair pathways studied. The response to bromate observed for the two DSB repair deficient cell lines strongly support earlier studies that bromate induces complex DNA damages. The significantly reduced repair fidelity of irs1SF and V3-3 suggests that NHEJ as well as HRR are needed for the repair, and that complex DSBs are formed after bromate exposure. PMID- 22207103 TI - The effect of a neighborhood built environment on physical activity behaviors. AB - BACKGROUND: The ability to design or reconfigure communities to be more supportive of physical activity has broad public health implications. Assessing the context and locations of specific behaviors will lead to a better understanding of how neighborhood attributes influence overall physical activity. METHODS: A cross-sectional survey was used to assess physical activity before and after residents moved to Mueller, a New Urbanist-inspired community in Austin, Texas. Context-specific physical activity and the locations where these activities took place were examined. RESULTS: Overall, residents reported that they increased their physical activity by 66.4 minutes (95% CI: 32.8-100.1) per week after moving to Mueller. For recreational walking, residents reported an average of 159.8 minutes inside Mueller after moving, an increase from 91.7 minutes before their move (P < .001). Correspondingly, residents walked 18.6 fewer minutes per week outside Mueller (P < .001). For transport-related walking, the mean number of minutes spent walking outside Mueller remained constant, but the time spent walking inside the neighborhood decreased an average of 10.8 minutes per week after moving (P = .02). CONCLUSIONS: The most notable increase was seen in walking for recreation inside the neighborhood. Results of this natural experiment strongly suggest the environmental impact on physical activity and underscore the importance of investigating the context and locations where different types of physical activity occur. PMID- 22207104 TI - A new oral otoprotective agent. Part 1: Electrophysiology data from protection against noise-induced hearing loss. AB - BACKGROUND: Data from animal studies show that antioxidants can compensate against noise-induced stress and sensory hair cell death. The aim of this study was to evaluate the otoprotection efficacy of various versions of orally administered Acuval 400 against noise damage in a rat animal model. MATERIAL/METHODS: Fifty-five Sprague Dawley rats were divided into 4 groups: A) noise-exposed animals; B) animals exposed to noise and treated with the Acuval; C) animals exposed to noise and treated with a combination of Coenzyme Q10 and Acuval; D) animals treated only with Acuval and Coenzyme Q10 and with no exposure to noise. All solutions were administered orally 5 times: 24 and 2 hrs prior to noise exposure, and then daily for 3 days. The auditory function was assessed by measuring auditory brainstem responses (ABR) in the range from 2 to 32 kHz at times =1, 7, 14 and 21 days after noise exposure. RESULTS: At low frequencies (click and 4 kHz) animals from both A and B groups showed significant threshold shifts in the majority of the tested frequencies and tested times. For the same frequencies, animals from group C presented threshold levels similar to those from group D. At frequencies >= 8 kHz the protective performance of the 2 Acuval groups is more clearly distinguished from the noise group A. At 32 kHz the 2 Acuval groups perform equally well in terms of otoprotection. Animals in Group D did not show any significant differences in the hearing threshold during the experiment. CONCLUSIONS: The data of this study suggest that a solution containing Coenzyme Q10 and Acuval 400, administered orally, protects from noise induced hearing loss. PMID- 22207105 TI - Osteopontin and integrin are involved in cholesterol gallstone formation. AB - BACKGROUND: This study aimed to investigate the role of osteopontin and its receptor, integrin alphav, in gallstone formation using human tissue specimens and a guinea pig lithogenic model. MATERIAL/METHODS: The nucleation role of osteopontin was determined in patients' and normal gallbladder bile samples in vitro. Normal gallbladder was the control, and gallstone gallbladders were divided into group I (with normal epithelia) and group II (with degenerated epithelia) based on pathology change. Immunostaining, mRNA and protein expressions of osteopontin and integrin alphav were analyzed. The animals were randomly divided into a lithogenic diet group and a normal diet group; the osteopontin mRNA expression in gallbladder and liver and osteopontin concentrations were determined. RESULTS: Osteopontin prolonged nucleation time and inhibited the pro-nucleating role induced by calcium in human bile in vitro. Immunostaining for osteopontin and integrin alphav in human gallbladder tissues showed a higher reactivity in Group I than control group and Group II. The immunostaining in Group II was weaker than control group; similar results were observed for mRNA and protein expression of osteopontin and integrin alphav. In the animal assay, the mRNA expression and concentration of osteopontin in gallbladder and liver gradually increased at initial stages and decreased in later stages. The concentrations of osteopontin in bile and serum of guinea pig showed similar trends. CONCLUSIONS: Our results suggest that osteopontin is involved in cholesterol gallstone formation, and the role of osteopontin might correlate with integrin alphav and calcium. PMID- 22207106 TI - 18alpha-Glycyrrhizin induces apoptosis and suppresses activation of rat hepatic stellate cells. AB - BACKGROUND: To investigate the potential mechanisms underlying the protective effects of 18alpha Glycyrrhizin (GL) on rat hepatic stellate cells (HSCs) and hepatocytes in vivo and in vitro. MATERIAL/METHODS: Sprague-Dawley (SD) rats were randomly divided into 5 groups: normal control group, liver fibrosis group, high dose 18alpha GL group (25 mg/ kg/d), intermediate-dose 18alpha GL group (12.5 mg/kg/d) and low-dose 18alpha GL group (6.25 mg/ kg/d). The rat liver fibrosis model was induced by carbon tetrachloride (CCl4). The expressions of alpha-smooth muscle actin (alphaSMA) and NF-kappaB were determined by real-time PCR and immunohistochemistry. RESULTS: 18alphaGL dose-dependently inhibited the CCl4 induced liver fibrosis. There were significant differences in the mRNA and protein expressions of alphaSMA between the fibrosis group and 18alpha-GL treatment groups, suggesting that 18alpha GL can suppress the proliferation and activation of HSCs. Few HSCs were apoptotic in the portal area and fibrous septum in the liver fibrosis group. However, the double-color staining of a-SMA and TUNEL showed that 18alpha-GL treatment groups increased HSC apoptosis. NF-kappaB was mainly found in the nucleus in the fibrosis group, while cytoplasmic expression of NF-kappaB was noted in the 18alphaGL groups. In the in vitro experiments, 18alpha GL promoted the proliferation of hepatocytes, but inhibited that of HSCs. HSCs were arrested in the G2/M phase following 18alpha GL treatment and were largely apoptotic. CONCLUSIONS: 18alpha-GL can suppress the activation of HSCs and induce the apoptosis of HSCs by blocking the translocation of NF kappaB into the nucleus, which plays an important role in the protective effect of 18alpha-GL on liver fibrosis. PMID- 22207107 TI - Hypermethylation of IGSF4 gene for noninvasive prenatal diagnosis of thalassemia. AB - BACKGROUND: For patients with pregnancy-induced thalassemia, fetal cord blood or amniotic fluid is invasively collected in the traditional diagnosis and prediction of thalassemia. However, there is no specific molecular target in the diagnosis of thalassemia using fetal DNA from the plasma of pregnant women. MATERIAL/METHODS: The promoter of cell surface adhesion molecule (IGSF4) gene was found to be down-regulated in patients with homozygous thalassemia, and the expression of IGSF4 was closely associated with the methylation of its promoter. In the present study, mass spectrometric sequencing of methylation was performed using MassARRAY to detect the 12 CpG sites in the promoter of IGSF4 gene. RESULTS: The methylation degree of these 12 CpG sites was significantly higher than that in healthy subjects (P<0.05). Hierarchical clustering was done in 23 patients with thalassemia and 5 healthy individuals. Results revealed the promoter of IGSF4 gene was highly methylated in thalassemia patients, which was dramatically different from that in healthy subjects (P<0.05). Methylation specific PCR (MSP) was employed to confirm the methylation of the promoter of IGSF4 gene and results were consistence with those obtained in sequencing with MassARRAY. Real-time PCR showed, when compared with heterozygous subjects, the expression of IGSF4 was significantly down-regulated in thalassemia patients (ratio=0.18). CONCLUSIONS: The expression of IGSF4 was closely related to the methylation of its promoter, suggesting the methylation of IGSF4 gene is tissue specific for thalassemia. These findings provide evidence for the non-invasive prenatal diagnosis of thalassemia in terms of epigenetics. PMID- 22207108 TI - Preventive effect of Teucrium polium on learning and memory deficits in diabetic rats. AB - BACKGROUND: Cognitive impairment occurs in diabetes mellitus. Teucrium polium L. (Lamiaceae) has been used in folk medicine to improve mental performance. Here we hypothesized that chronic treatment with an aqueous extract of Teucrium polium (100, 200 and 400 mg/kg, p.o.) would have an effect on passive avoidance learning (PAL) and memory in control and streptozocin-induced diabetic rats. MATERIAL/METHODS: Treatments were begun at the onset of hyperglycemia, and PAL was assessed 30 days later. A retention test was performed 24 h (hours) after training. After PAL and memory assessment, animals were weighed and blood samples were drawn for plasma glucose measurement. RESULTS: Diabetes caused impairment in acquisition of PAL and retrieval of memory. Teucrium polium treatment (200 and 400 mg/kg) improved learning and memory in control rats and reversed learning and memory deficits in diabetic rats. The 100 mg/kg dose did not affect cognitive function. Teucrium polium treatment partially improved the reduced body weight and hyperglycemia of treated diabetic rats, although the differences were not significant compared to non-treated diabetic rats. CONCLUSIONS: These results show that Teucrium polium prevented the deleterious effects of diabetes on PAL and memory. Antioxidant, anticholinesterase and hypoglycemic effects of Teucrium may be involved in the obtained effects. Therefore, Teucrium polium appears to be a promising candidate for memory improvement in diabetes, but this needs confirmation by future clinical studies. PMID- 22207109 TI - Chlorin-based photodynamic therapy enhances the effect of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) in bladder cancer cells. AB - BACKGROUND: Photodynamic therapy (PDT) is an attractive, emerging therapeutic procedure suitable for the treatment of non-muscle-invasive bladder cancer. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand that belongs to the TNF superfamily of cytokines. The ability of TRAIL to selectively induce apoptosis in cancer cells but not in normal cells promotes the development of TRAIL-based cancer therapy. However, many tumor cells are resistant to TRAIL induced apoptosis. The purpose of the study was to overcome TRAIL-resistance in bladder cancer cells by photodynamic therapy (PDT). MATERIAL/METHODS: Three human bladder transitional cancer cell lines - T24, 647V and SW780 - were treated with TRAIL and/or chlorin-based PDT. The cytotoxicity was measured by MTT and LDH assays and apoptosis was detected using annexin V by flow cytometry. RESULTS: Our test confirmed that T24 and 647V bladder cancer cells are resistant to TRAIL, whereas SW780 cells are sensitive to TRAIL. Then we examined the cytotoxic and apoptotic effects of TRAIL in combination with chlorin e6-polyvinylpyrrolidone (Ce6-PVP)-mediated PDT on bladder cancer cells. We showed for the first time that pretreatment with a low dose of PDT significantly sensitizes bladder cancer cells to TRAIL-induced apoptosis. Chlorin-based PDT augments the effect of TRAIL on bladder cancer cells. CONCLUSIONS: PDT with Ce6-PVP photosensitizer enhances the cytotoxic and apoptotic effects of TRAIL on bladder cancer cells. The obtained results suggest that combined treatment by TRAIL and PDT may provide the basis for a new therapeutic approach to induce cell death in bladder cancer. PMID- 22207110 TI - The role of Interleukin-17A and Interleukin-17E in multiple myeloma patients. AB - BACKGROUND: Tumor growth in multiple myeloma (MM) is regulated by the cytokine networks which are produced by myeloma cells and the microenvironment of the bone marrow. Interleukin-17 (IL-17) is implicated in the increased angiogenesis in the bone marrow of MM. Recent studies reported elevated levels of interleukin 17A (IL 17A) in the sera of patients with advanced stages according to Durie-Salmon classification. MATERIAL/METHODS: We compared the concentration of IL-17A and IL 17E in the blood serum of 34 newly diagnosed MM patients with healthy subjects' sera. We also evaluated the concentration of IL-17A and IL-17E in the blood serum of MM patients and the relation to the percentage of plasma cells and other clinical parameters. The concentration of IL-17E and IL-17A of healthy subjects and patients with MM was assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our data confirm that IL-17A and IL-17E serum levels were significantly higher in all MM patients and also in patients with advanced stage compared with healthy subjects. We found the correlation between serum levels of IL-17A in MM patients and percentage of plasma cells. Our results also showed that if serum levels of IL-17E were higher in MM patients, the percentage of plasma cells and beta-2-microglobulin levels were lower. CONCLUSIONS: The IL-17 family of cytokines may suppress or promote tumor growth. There seems to be some balance between the effects of IL-17A and IL-17E. The role of increased levels of IL-17E needs further investigation to understand its role in the pathobiology of MM. PMID- 22207111 TI - Apoptosis - associated genes and their role in predicting responses to neoadjuvant breast cancer treatment. AB - BACKGROUND: Neoadjuvant chemotherapy is used in the treatment of breast carcinoma because it substantially reduces the size of the primary tumor and lymph node metastases. The present study investigated biomarkers that can predict a pathologic response to the therapy. MATERIAL/METHODS: The role of apoptosis in regression of the tumors after neoadjuvant chemotherapy was determined by TUNEL and anti-active caspase 3 assay. The transcriptional profile of 84 key apoptosis genes was evaluated in both pre-therapeutically obtained tumor tissue by core needle biopsy and in specimens removed by final surgery, using a pathway-specific real-time PCR assay. Obtained data were analyzed by hierarchical cluster analysis and correlation analysis. The immunohistochemical profile of each tumor was determined using the standard ABC method. RESULTS: On the basis of a hierarchical cluster analysis of 13 significantly changed genes, we divided patients into good and poor prognosis groups, which correlate well with progression-free survival. In the good prognosis group, we found a statistically significant down-regulation of the expression of MCL1 and IGF1R genes after neoadjuvant treatment. We also found a statistically significant overexpression of BCL2L10, BCL2AF1, CASP8, CASP10, CASP14, CIDEB, FADD, HRK, TNFRSF25, TNFSF8 and CD70 genes. In contrast, we found up-regulation of IGF1R after the treatment in the group with poor prognosis. CONCLUSIONS: Gene expression profiling using real-time PCR assay is a valuable research tool for the investigation of molecular markers, which reflect tumor biology and treatment response. PMID- 22207112 TI - Orally administered L-arginine and glycine are highly effective against acid reflux esophagitis in rats. AB - BACKGROUND: Reflux esophagitis is caused mainly by excessive exposure of the mucosa to gastric contents. In the present study, we examined the effect of several amino acids on acid reflux esophagitis in rats. MATERIAL/METHODS: After 18 h of fasting, acid reflux esophagitis was induced by ligating both the pylorus and the transitional region between the forestomach and the corpus under ether anesthesia, and the animals were killed 4 h later. The severity of esophagitis was reduced by the oral administration of omeprazole, a proton pump inhibitor, or pepstatin, a specific pepsin inhibitor. RESULTS: The development of esophageal lesions was dose-dependently prevented by L-arginine and glycine, given intragastrically (i.g.) after the ligation, with complete inhibition obtained at 250 mg/kg and 750 mg/kg, respectively, and these effects were not influenced by the prior s.c. administration of indomethacin or L-NAME. By contrast, both L alanine and L-glutamine given i.g. after the ligation aggravated these lesions in a dose-dependent manner. These amino acids had no effect on acid secretion but increased the pH of the gastric contents to 1.8~2.3 due to their buffering action. CONCLUSIONS: The results confirmed an essential role for acid and pepsin in the pathogenesis of acid reflux esophagitis in the rat model and further suggested that various amino acids affect the severity of esophagitis in different ways, due to yet unidentified mechanisms; L-alanine and L-glutamine exert a deleterious effect on the esophagitis, while L-arginine and glycine are highly protective, independent of endogenous prostaglandins and nitric oxide. PMID- 22207113 TI - Reduced endothelial function in the skin in Southeast Asians compared to Caucasians. AB - BACKGROUND: The reaction of vascular endothelial cells to occlusion and heat in Southeast Asian Indians (SAI) compared to Caucasians (C) has not been studied, although genetic differences are found in endothelial cells between the races. MATERIAL/METHODS: Ten C and Ten SAI (<35 years old) male and female subjects participated. There was no difference in the demographics of the subjects except that the SAI group had been in the United States for 6 months; C was natives to the US. Endothelial function was assessed by the response of the circulation (BF) to local heating and the response to vascular occlusion. The effects of local heat on circulation in the skin on the forearm was assessed by applying heat for 6 minutes at temperatures, 38, 40 and 42 degrees C on 3 separate days. On different days, vascular occlusion was applied for 4 minutes to the same arm and skin blood flow was measured for 2 minutes after occlusion; skin temperature was either 31 degrees C or 42 degrees C. RESULTS: When occlusion was applied at a skin temperature of 31 degrees C, the BF response to occlusion was significantly lower in the SAI cohort compared to C (peak BF C = 617 +/- 88.2 flux, SAE = 284 +/- 73 flux). The same effect was seen at skin temperatures of 42 degrees C. The circulatory response to heat was also significantly less in SAI compared to C at each temperature examined (p<0.05)(for temperatures of 38, 40 and 42 degrees C, peak blood flow for C was 374.7 +/- 81.2, 551.9 +/- 91.3 and 725.9 +/- 107 flux respectively and 248.5 +/- 86.2, 361.4 +/- 104.3 and 455.3 +/- 109.7 flux respectively for SAI. (p<0.05). CONCLUSIONS: Thus there seems to be big differences in these 2 populations in endothelial response to these stressors. The difference may be due to genetic variations between the 2 groups of subjects. PMID- 22207114 TI - Selected surgical managements in snoring and obstructive sleep apnea patients. AB - BACKGROUND: The diagnostic process and the surgical procedures in patients with snoring and obstructive sleep apnea syndrome (OSAS) are crucial. The aim of this study was to assess the efficacy of surgical treatment in snoring and OSAS patients. MATERIAL/METHODS: A precise laryngological examination and screening polysomnography (Poly-Mesam) were performed in all patients with mild, moderate and severe OSAS before and 6 months after surgery. The patients completed questionnaires concerning their complaints. We included patients qualified to septoplasty, laser-assisted uvulopalatoplasty (LAUP), uvulopalatopharyngoplasty (UPPP) and radiofrequency-induced thermotherapy of the tongue base (RITT). Outcome evaluation of surgery was performed on the basis of data received from follow-up laryngological examinations, selected parameters obtained from the Poly Mesam test and follow-up questionnaires. RESULTS: In most cases we observed improvement, defined as decreasing some sleep parameters, such as a respiratory disturbance index (RDI), by more than 50%, decreasing the loudness of snoring, decreasing the number of hypopneas, and obtaining better blood saturation values. After UPPP we noticed changes in retropalatal space, soft palate dimensions and uvula-posterior pharyngeal wall distance. In the postoperative period we did not observe severe complications. In some cases we found short-lived palatal deficiency after UPPP. Patients after RITT experienced discomfort and throat pain lasting from 2 to 4 days. In 2 patients we observed swelling of the tongue base, which decreased after few days. CONCLUSIONS: Surgery in OSAS contributes to normalization of some sleep parameters. The majority of patients experienced improvement after surgery. PMID- 22207115 TI - Platelet glycoprotein IIb/IIIa polymorphism HPA-3 b/b is associated with increased risk of ischemic stroke in patients under 60 years of age. AB - BACKGROUND: The role of genetic risk factors in ischemic stroke is unclear. Platelet glycoprotein IIb/IIIa (GpIIb-IIIa) has been implicated in the pathogenesis of ischemic stroke. We sought to evaluate the relationship between the GpIIb/IIIa complex gene polymorphism and ischemic stroke. MATERIAL/METHODS: We investigated the association of the GpIIb/IIIa complex gene polymorphism with stroke risk in 306 patients with acute ischemic stroke and 266 control subjects by determining the GpIIb and GpIIIa genotype from leukocyte DNA by polymerase chain reaction (PCR) followed by FokI and ScrFI digestion, respectively. RESULTS: Compared with controls, more patients presented with coronary heart disease, hypertension, smoking history, and diabetes. In addition, the patients had higher levels of cholesterol and glucose compared with the control subjects. All donors in the GpIIIa (n=572) group expressed the GpIIIa PlA1 (HPA-1 aa) phenotype. There were no significant differences between the HPA-3 genotype (GpIIb) patient distribution (aa=39.9%, ab=41.4%, bb=28.7%) and healthy control subjects (aa=36.1%, ab=35.0%, bb=28.9%) (P=0.580). Among study participants <60 years, there was a significant difference in the HPA-3 genotype distributions of patients (aa=42.9%, ab=19.8%, bb=37.4%) and healthy control subjects (aa=43.3%, ab=38.8%, bb=17.9%) (P=0.007). Furthermore, HPA-3 b/b increased the risk of ischemic stroke >2-fold (P=0.008). CONCLUSIONS: The GpIIb Ile/Ser843 gene polymorphism is associated with ischemic stroke among young and middle-aged adults (<60 years), especially males. The GpIIIa PlA1 phenotype has no relationship to ischemic stroke. PMID- 22207116 TI - Cardiotrophin-1 plasma levels are increased in patients with diastolic heart failure. AB - BACKGROUND: Cardiotrophin-1 (CT-1) is a member of the interleukin (IL-6) family of cytokines and is increased in various cardiovascular diseases, including chronic heart failure. The aim of the study was to determine if plasma CT-1 is associated with diastolic heart failure (DHF) and to investigate the relationship between CT-1 and echocardiographic parameters. MATERIAL/METHODS: Fifty-seven consecutive patients (mean age 57 +/- 8 years, 24 males) diagnosed with DHF in our clinic and 33 controls (mean age 55 +/- 7 years, 12 males) were included in the study. All study participants underwent echocardiographic evaluation and blood samples were obtained. RESULTS: CT-1 and NT-proBNP values were significantly higher in DHF subjects than in controls (11.30 [8.09-16.51] vs. 17.5 [8.95-28.74] fmol/mL, P=0.017 and 64 [27.5-95] vs. 82 [55.5-241] pg/mL, P=0.009, respectively). The mitral peak velocity of early diastolic filling (E), mean ratio of E to early diastolic mitral annular velocity (E/Em), and the pulmonary capillary wedge pressure (PCWP) estimated from E/Em measurements were all significantly higher in the patient group (62.27 +/- 14.69 vs. 75.67 +/- 18.85 cm/sec, 6.40 +/- 1.48 vs. 10.30 +/- 3.48, and 10 [9-11] vs. 14[12-16] mmHg, P <= 0.001 for all). Lateral and septal Em were significantly lower in the patient group (10.69 +/- 1.87 vs. 8.69 +/- 2.00 cm/sec and 8.91 +/- 1.22 vs. 6.65 +/- 1.58 cm/sec, P<0.001 for both). CT-1 positively correlated with NT-proBNP (P=0.001, r=0.349), mean E/Em (P=0.003, r=0.307), and estimated mean PCWP (P=0.001, r=0.308). CONCLUSIONS: CT-1 is elevated in patients with DHF and is associated with NT-proBNP and estimated left ventricular filling pressures. PMID- 22207117 TI - Retinal pigment epithelial tears following ranibizumab therapy for fibrovascular retinal pigment epithelial detachment due to occult age-related macular degeneration. AB - BACKGROUND: The aim of this paper is to report the incidence of retinal pigment epithelial (RPE) tears in patients treated with ranibizumab for subfoveal fibrovascular retinal pigment epithelial detachment (FVPED) due to occult age related macular degeneration (AMD). MATERIAL/METHODS: Thirty patients were treated according to the following schedule: saturation phase, further treatment was based on activity of the degeneration process. Visual acuity (VA), optical coherence tomography (OCT) and fluorescein angiography (FA) parameters were evaluated and compared. RESULTS: Patients had a mean improvement of +4.7 +/- 8.1 letters at month 12. The mean number of needed injections was 6.8 +/- 1.8 (range, 3 to 9). RPE tears in fovea occurred in 8 cases (27% of all patients). Analysis of variance revealed significant upper mean values of ETDRS letters for the subgroup without RPE tears. Mean values of PED height were significant upper for RPE tears without baseline. Statistical analysis revealed that in the subgroup without RPE tears mean values of VA significantly differed in succeeding periods compare to baseline (P<0.001). Visual improvement or stabilization was observed in 90.9% of patients without RPE tears (significant improvement of 15 or more letters in 22.7% - 5/22) and in 87.5% of patients with RPE tears (significant improvement was not observed). Baseline leakage parameters, lesion and leakage parameters at month 12 were significantly higher in patients with RPE tears. The chi-square test revealed statistically significant associations between RPE tears and subretinal fluid in OCT (P<0.05) at month 12. CONCLUSIONS: In eyes with FVPED and RPE tears treated with ranibizumab, stabilization of visual acuity without significant improvement is predictable. One of the risk factors common to RPE tears may be baseline leakage parameters and pretreatment distorted RPE contour in OCT. During ranibizumab therapy in eyes with RPE tears, upper parameters of FVPED height may occur without significant differences in fovea and macula volume compare to eyes without RPE tears. PMID- 22207118 TI - Level of optimism and health behavior in athletes. AB - BACKGROUND: Persons with an optimistic attitude do not give up despite obstacles and failures. Optimistic athletes compete more out of hope for success than out of fear of defeat. The purpose of my research was to determine if optimism also promotes good health behavior in athletes. MATERIAL/METHODS: In order to measure the role of optimism in shaping the health behavior of athletes, I examined a group of women (N=147) and men (N=385) who were currently in training for athletic competition. The control group consisted of women (N=262) and men (N=435) who were not and had never been competitive athletes. The "O-P" Attitude Questionnaire was used to measure optimism, while health behavior was measured with the Juczynski Health Behavior Inventory, which measures proper nutrition habits, preventive behavior, positive attitude, and healthy practices. RESULTS: The level of pessimism in these athletes was average. The female athletes were less pessimistic than the female controls. A similar, highly significant difference occurred between the male athletes and non-athletes. Gender did not differentiate the level of optimism in either group. Among the women, optimism correlated with healthy practices, such as daily sleep and recreation habits, or physical activity. The greater the pessimism increased, positive attitudes declined in the female controls, the female athletes, and the male controls. CONCLUSIONS: The athletes displayed greater optimism than the controls. Among the women, optimism correlated with good health practices. PMID- 22207119 TI - Attentional and emotional functioning in schizophrenia patients treated with conventional and atypical antipsychotic drugs. AB - BACKGROUND: Effectiveness of antipsychotics in treating emotional and cognitive deficits in schizophrenia still remains controversial. The aim of our study was to assess emotional and cognitive functioning in schizophrenic inpatients currently treated with typical antipsychotics (perphenazine, perazine, fluphenazine, and haloperidol) and in another group of schizophrenic inpatients currently on atypical antipsychotics (olanzapine, risperidone, amisulpride, and quetiapine). MATERIAL/METHODS: One hundred patients with DSM-IV schizophrenia or schizoaffective disorders (39 treated using typical antipsychotics and 61 treated with atypical antipsychotics) under naturalistic treatment conditions, and 50 healthy controls were given the following: Test of Everyday Attention, Facial Emotion Recognition Test, Facial Memory Recognition Test, and "Reading the mind in the eyes" Test. RESULTS: Patients with a diagnosis of schizophrenia revealed the following deficits: facial emotion perception, empathy /theory of mind, visual selective attention/speed, attentional switching, and auditory-verbal working memory. Our results show a significant difference between schizophrenic and healthy controls in all tasks, with schizophrenic patients performing worse than controls. Interestingly, our patients on atypical neuroleptics performed similarly compared to schizophrenic patients treated with conventional neuroleptics on all tasks provided. There were some significant relationships between emotional and cognitive deficits and clinical variables. CONCLUSIONS: Our findings remain consistent with other recent studies in which atypical antipsychotics did not show a clear advantage over typical antipsychotics on both emotional and cognitive functioning. PMID- 22207120 TI - Immediate speech fluency improvement after application of the Digital Speech Aid in stuttering patients. AB - BACKGROUND: The Digital Speech Aid (DSA) is a pocket-sized device used for speech correction in stutterers. The device modifies the patient's auditory feedback with the use of Delayed Auditory Feedback (DAF) and Frequency-shifted Auditory Feedback (FAF). Both methods are well-known to improve speech fluency in stuttering persons. The aim of this study was to assess immediate disfluency reduction after application of the DSA. MATERIAL/METHODS: The study included 335 patients aged 6-64 years with speech disfluency. DSA fitting was performed during 3-day hospitalization. Speech disfluency was assessed during reading, in dialogue and in monologue before fitting and after selection of optimal DAF and FAF parameters. Fluency improvement was assessed statistically with Student's t test for logarithms of the odds of disfluency presence without the DSA and with the DSA. RESULTS: For all speaking situations, statistically significant improvement was achieved, with p<0.005. Immediate fluency improvement was observed in 82.1% of patients during reading, in 84.5% during dialogue, and in 81.2% during monologue. Values different from placebo (reliable improvement) were obtained in 66.9% of patients during reading, in 66.6% during dialogue, and in 63.9% during monologue. CONCLUSIONS: The results show that the DSA is an effective tool for immediate disfluency reduction in stutterers. PMID- 22207121 TI - A delayed diagnosis that altered the professional orientation of an athlete with upper limb chronic arterial embolization. AB - BACKGROUND: Vascular disorders of the upper extremity in young and physically active patients present a complex and challenging problem for the treating physician. Initial presentation may often be subtle and the consequences of misdiagnosis, delayed diagnosis or mistreatment can be severe. CASE REPORT: In this report, we discuss a case of a young woman with chronic upper limb ischemia due to an arterial thoracic outlet syndrome in whom even though symptoms persisted over a number of years during which she frequently sought medical consultation, remained undiagnosed until finally presenting with limb-threatening ischemia. Furthermore, due to this delay, the patient was forced to withdraw from her professional carrier in athletics. CONCLUSIONS: A thoughtful and through approach combining the history, physical findings, and use of appropriate diagnostic aids will provide the physician and patient with the greatest opportunity for a satisfactory outcome. Furthermore, a delay in definitive treatment may not only cause health deterioration, but may also incur social, economic and occupational consequences. PMID- 22207123 TI - Is lipoxins A4 a better alternative to anti-VEGF and anti-TNF-alpha antibody to prevent and treat age-related macular degeneration, diabetic macular edema and retinopathy? PMID- 22207122 TI - Early intervention with psychostimulants or antidepressants to increase methyl CpG-binding protein 2 (MeCP2) expressions: a potential therapy for Rett syndrome. AB - Rett syndrome (RTT) is a severe X-linked postnatal neurodevelopmental disorder. The syndrome is caused primarily by mutations in the methyl CpG binding protein 2 (MeCP2) gene on Xq28. Most individuals with RTT are female, and female RTT is normally heterozygous for mutations in MeCP2. Patients with RTT display a normal period of development prior to the onset of symptoms, at which point they undergo a period of regression. Currently, no effective medication is available for this disorder, although animal studies have suggested that RTT symptoms are potentially reversible. For females with RTT, the severity of symptoms and progression of the disease varies a great deal, despite its homogenous genetic origin. These differences could be attributed to differences in the mutation points of MeCP2 and the skew caused by X-chromosome inactivation. Thus, the increased expression in the normal MeCP2 gene could decrease the severity of the disease. Based on findings from studies on animals indicating that fluoxetine (an antidepressant) and cocaine (a psychostimulant) can increase MeCP2 expression in the brain, it is suggested that early intervention with antidepressants or psychostimulants could increase the normal MeCP2 expression in females with RTT, who are normally heterozygous. This therapeutic hypothesis could be tested in an RTT animal model. Following the identification of the antidepressants or psychostimulants with the greatest influence on MeCP2 expression, a combination of early detection of the disorder with early intervention may result in improved therapeutic outcomes. Furthermore, a trial investigating the effects of antidepressants or psychostimulants on MeCP2 expression in lymphocyte culture from patients with RTT is suggested for clinical therapeutic prediction. PMID- 22207124 TI - Optical topography recording of cortical activity during high frequency yoga breathing and breath awareness. Comment to: Non-invasive assessment of hemispheric language dominance by optical topography during a brief passive listening test: a pilot study. Stefano Bembich, Sergio Demarini, Andrea Clarici, Stefano Massaccesi, Domenico Grasso. Med Sci Monit 2011; 17(12): CR692-697. PMID- 22207125 TI - Cranioplasty prosthesis manufacturing based on reverse engineering technology. AB - BACKGROUND: Most patients with large focal skull bone loss after craniectomy are referred for cranioplasty. Reverse engineering is a technology which creates a computer-aided design (CAD) model of a real structure. Rapid prototyping is a technology which produces physical objects from virtual CAD models. The aim of this study was to assess the clinical usefulness of these technologies in cranioplasty prosthesis manufacturing. MATERIAL/METHODS: CT was performed on 19 patients with focal skull bone loss after craniectomy, using a dedicated protocol. A material model of skull deficit was produced using computer numerical control (CNC) milling, and individually pre-operatively adjusted polypropylene polyester prosthesis was prepared. In a control group of 20 patients a prosthesis was manually adjusted to each patient by a neurosurgeon during surgery, without using CT-based reverse engineering/rapid prototyping. In each case, the prosthesis was implanted into the patient. The mean operating times in both groups were compared. RESULTS: In the group of patients with reverse engineering/rapid prototyping-based cranioplasty, the mean operating time was shorter (120.3 min) compared to that in the control group (136.5 min). The neurosurgeons found the new technology particularly useful in more complicated bone deficits with different curvatures in various planes. CONCLUSIONS: Reverse engineering and rapid prototyping may reduce the time needed for cranioplasty neurosurgery and improve the prosthesis fitting. Such technologies may utilize data obtained by commonly used spiral CT scanners. The manufacturing of individually adjusted prostheses should be commonly used in patients planned for cranioplasty with synthetic material. PMID- 22207126 TI - Results of the AcrySof Toric intraocular lenses implantation. AB - BACKGROUND: The expectations of post-removal cataract surgery patients are extremely high, and best vision acuity is expected. The best refractive results are influenced by two factors - cataract surgical removal and the corneal astigmatism correction. Currently, the two most often applied corneal astigmatism removal methods are laser surgery and toric intraocular lens implantation, with the latter method being both more stable and more reversible. This study aimed to estimate the surgical astigmatism correction efficiency after AcrySof Toric intraocular lens implantation in patients with corneal astigmatism. MATERIAL/METHODS: We used the AcrySof Toric IOL 1-part hydrophobic acrylic lenses. The retrospective research covered 30 eyeballs in 28 cataract and corneal astigmatism patients, with the AcrySof Toric lens implanted by one surgeon. RESULTS: In our test group 92.31% of post-surgical patients (phacoemulsification and toric lenses implantation) gained the best uncorrected visual acuity, range 0.6-1.0; and in 7.69% of patients the acuity was 0.4-0.6. Lens rotation was examined three weeks after the surgical procedure and a 3.24 +/- 3.41 degree axial displacement was observed; however, this lens rotation was clinically unimportant. Based on the analysis of post-surgical results, the corneal astigmatism was 84.2% lower than before the procedure. CONCLUSIONS: We noticed clinically and statistically important vision acuity improvement in the corneal astigmatism patients. The patients' high satisfaction was conditioned by proper pre-surgery qualification. Astigmatism correction by cataract removal surgery is a safe and effective surgical solution. In the future, we expect the use of toric intraocular lenses will become widespread and significant. PMID- 22207127 TI - The mechanism of vascular calcification - a systematic review. AB - Calcification of vessels reduces their elasticity, affecting hemodynamic parameters of the cardiovascular system. The development of arterial hypertension, cardiac hypertrophy, ischemic heart disease or peripheral arterial disease significantly increases mortality in patients over 60 years of age. Stage of advancement and the extent of accumulation of calcium deposits in vessel walls are key risk factors of ischemic events. Vascular calcification is an active and complex process that involves numerous mechanisms responsible for calcium depositions in arterial walls. They lead to increase in arterial stiffness and in pulse wave velocity, which in turn increases cardiovascular disease morbidity and mortality. In-depth study and thorough understanding of vascular calcification mechanisms may be crucial for establishing an effective vasculoprotective therapy. The aim of this study was to present a comprehensive survey of current state-of-the-art research into the impact of metabolic and hormonal disorders on development of vascular calcification. Due to strong resemblance to the processes occurring in bone tissue, drugs used for osteoporosis treatment (calcitriol, estradiol, bisphosphonates) may interfere with the processes occurring in the vessel wall. On the other hand, drugs used to treat cardiovascular problems (statins, angiotensin convertase inhibitors, warfarin, heparins) may have an effect on bone tissue metabolism. Efforts to optimally control calcium and phosphate concentrations are also beneficial for patients with end-stage renal disease, for whom vessel calcification remains a major problem. PMID- 22207128 TI - E2F1: a potential negative regulator of hTERT transcription in normal cells upon activation of oncogenic c-Myc. AB - Previous studies have revealed that the link between c-Myc and E2F1 pathway plays a pivotal role in regulating cell growth and death. Human telomerase reverse transcriptase (hTERT), activation of which is required for cell immortalization and transformation, has been confirmed to be a direct transcriptional target of c Myc. It is of note that E2F1, which is also a direct transcriptional target of c Myc, can bind the hTERT promoter and repress its expression. Thus, although oncogene c-Myc can be activated in normal cells, for the subsequent induction of E2F1, it may still be insufficient to trigger the expression of hTERT. This negative feedback regulation, if it exists, may be another mechanism for normal cells to control the transmission of c-Myc-mediated oncogenic signals. In this article, we reviewed current knowledge about the crosstalk among c-Myc, E2F1 and hTERT, with an emphasis on the hypothesis that E2F1 negatively regulates c-Myc induced hTERT transcription. Additionally, we postulated that the miR-17-92 cluster-mediated regulation of c-Myc and E2F1 expression may be of particular importance for the repression of hTERT transcription. PMID- 22207129 TI - Use of individual auto-injector kits 'IZAS-05' on the contemporary battlefield. AB - In crisis situations, such as transportation catastrophes, terrorist attacks or contamination with chemical warfare agents, it is crucial to properly organize and sensibly conduct rescue operations. Among chemical warfare agents, the most toxic ones are the derivatives of organophosphorus compounds. An individual auto injector kit 'IZAS-05' contains auto-injectors, which are devices designed for intramuscular administration of drugs in self-aid or buddy-aid on the battlefield. This paper describes in detail the components of the 'IZAS-05' kit, as well as its mode of use and possible contraindications. PMID- 22207130 TI - IL-17 and IL-22 enhance skin inflammation by stimulating the secretion of IL 1beta by keratinocytes via the ROS-NLRP3-caspase-1 pathway. AB - BACKGROUND: The pathogenesis of inflammatory skin disease involves the release of cytokines from keratinocytes, and one of these, IL-1beta, has been previously implicated in inflammatory skin disease. T(h)17 cells, a subset of T(h) cells involved in autoimmunity and inflammation, possess IL-1beta receptors and secrete cytokines such as IL-17 and IL-22 in response to IL-1beta stimulation. A mutation in the inflammasome protein NLRP3 (NACHT, LRR and PYD domains-containing protein 3) causes excess production of IL-1beta, resulting in an augmentation of T(h)17 dominant pathology. METHODS: To determine the feedback effect, if any, of IL-17 and/or IL-22 on the secretion of IL-1beta from keratinocytes, we stimulated the human keratinocyte cell line HaCaT, as well as caspase-1-deficient mice, with IL 17 or IL-22. RESULTS: We found that treatment with IL-17 and IL-22 causes an increase in IL-1beta via the activation of NLRP3 by a process that involves the generation of reactive oxygen species. Moreover, skin inflammation induced by IL 17 and IL-22 was lower in caspase-1 knockout (KO) mice relative to that induced by IL-1beta treatment. Additionally, skin inflammation induced by the drug imiquimod was lower in caspase-1 KO mice than in wild-type mice. CONCLUSION: These results indicate that cytokines from T(h)17 cells may potentiate IL-1beta mediated skin inflammation and result in phenotypic alterations of keratinocytes via a feedback mechanism. PMID- 22207131 TI - Dynamic regulation of Th17 differentiation by oxygen concentrations. AB - Naive CD4(+) T cells are activated by antigen-presenting cells (APCs) and differentiate into distinct types of helper T (T(h)) cells in the lymph node or spleen. Oxygen (O(2)) tension is generally low in these secondary lymphoid tissues compared with the bloodstream or atmosphere. However, the effect of changes in O(2) concentration on the differentiation of T(h) cells remains unclear. Here, we established a novel model of T(h)-cell differentiation, which mimics physiological O(2) conditions. We primed naive CD4(+) T cells under 5% O(2), which has been observed in the lymph node or spleen and reoxygenated under normoxia that mimicked the O(2) concentration in blood. In this model, the differentiation of T(h)17 cells, but not T(h)1 or iTreg cells, was enhanced. Under the condition of 5% O(2), mammalian target of rapamycin complex 1 (mTORC1) was activated and led to the stabilization of hypoxia-inducible factor 1alpha (HIF-1alpha) in T(h)17 cells. The activation of mTORC1 and the acceleration of T(h)17-cell differentiation, which occurred when cells were primed under 5% O(2), were not observed in the absence of HIF-1alpha but were accelerated in the absence of von Hippel-Lindau tumor suppressor protein (vHL), a factor critical for HIF-1alpha degradation. Thus, a positive feedback loop between HIF-1alpha and mTORC1 induced by hypoxia followed by reoxygenation accelerates T(h)17-cell differentiation. PMID- 22207132 TI - Efficient capture of Candida albicans and zymosan by SIGNR1 augments TLR2 dependent TNF-alpha production. AB - SIGNR1, a mouse C-type lectin, binds various pathogens, including Candida albicans. In this study, we explore the impact of SIGNR1 in the recognition of C. albicans/zymosan and the subsequent tumor necrosis factor (TNF)-alpha production using SIGNR1-transfected RAW264.7 (RAW-SIGNR1) cells and resident peritoneal macrophages. Compared with RAW-control cells, RAW-SIGNR1 cells dramatically enhanced TNF-alpha production upon the stimulation with heat-killed C. albicans and zymosan. Recognition of microbes via carbohydrate recognition domain (CRD) of SIGNR1 was crucial for the enhanced TNF-alpha production. Consistently, such an enhancement was significantly decreased by anti-SIGNR1 mAb. Laminarin, antagonistic Dectin-1 ligand, cooperated to further diminish the response, although no effect was observed by itself in RAW-SIGNR1 cells. However, it moderately reduced the response of RAW-control cells. Zymosan depleted of toll like receptor (TLR) ligands decreased the response, even though it was recognized by SIGNR1 and Dectin-1. Moreover, antagonistic anti-TLR2 abolished the response, suggesting that TNF-alpha production largely relies on TLR2-mediated signaling. Resident peritoneal macrophages expressing SIGNR1 predominantly captured zymosan injected intra-peritoneally and produced TNF-alpha, which was dependent on TLR2 and partly inhibited by anti-SIGNR1 mAb. Finally, physical association of SIGNR1 with the extracellular portion of TLR2 through CRD was confirmed by immunoprecipitation using various deletion mutants. These results suggest that SIGNR1 recognizing microbes participates in the enhanced TNF-alpha production by Mphi in cooperation with TLR2. PMID- 22207133 TI - Sublingual immunization with adenovirus F protein-based vaccines stimulates protective immunity against botulinum neurotoxin A intoxication. AB - Sublingual (s.l.) vaccination is an efficient way to induce elevated levels of systemic and mucosal immune responses. To mediate mucosal uptake, ovalbumin (OVA) was genetically fused to adenovirus 2 fiber protein (OVA-Ad2F) to assess whether s.l. immunization was as effective as an alternative route of vaccination. Ad2F delivered vaccines were efficiently taken up by dendritic cells and migrated mostly to submaxillary gland lymph nodes, which could readily stimulate OVA specific CD4(+) T cells. OVA-Ad2F + cholera toxin (CT)-immunized mice elicited significantly higher OVA-specific serum IgG, IgA and mucosal IgA antibodies among the tested immunization groups. These were supported by elevated OVA-specific IgG and IgA antibody-forming cells. A mixed T(h)-cell response was induced as evident by the enhanced IL-4, IL-10, IFN-gamma and TNF-alpha-specific cytokine-forming cells. To assess whether this approach can stimulate neutralizing antibodies, immunizations were performed with the protein encumbering the beta-trefoil domain of C-terminus heavy chain (Hcbetatre) from botulinum neurotoxin A (BoNT/A) as well as when fused to Ad2F. Hcbetatre-Ad2F + CT-dosed mice showed the greatest serum IgG, IgA and mucosal IgA titers among the immunization groups. Hcbetatre Ad2F alone also induced elevated antibody production in contrast to Hcbetatre alone. Plasma from Hcbetatre + CT- and Hcbetatre-Ad2F + CT-immunized groups neutralized BoNT/A and protected mice from BoNT/A intoxication. Most importantly, Hcbetatre-Ad2F + CT-immunized mice were protected from BoNT/A intoxication relative to Hcbetatre + CT-immunized mice, which only showed ~60% protection. This study shows that s.l. immunization with Ad2F-based vaccines is effective in conferring protective immunity. PMID- 22207134 TI - Fine-tuning of proximal TCR signaling by ZAP-70 tyrosine residues in Jurkat cells. AB - Zeta-chain-associated protein kinase of 70kDa (ZAP-70) kinase is a key regulator in the early steps of TCR signaling but some aspects of its fine regulation are still unclear. From its 31 tyrosine (Y) residues, 11 phosphorylation sites have been identified, some with activator (Y315 and Y493) or inhibitory (Y292 and Y492) and others with unknown function (Y069, Y126 and Y178). In our present work, we aimed to elucidate the role of different Y residues of ZAP-70, especially those with unknown function, in calcium signaling and the autoregulation of the kinase. ZAP-70-deficient Jurkat cells (P116) were stably reconstituted with point-mutated ZAP-70 constructs where tyrosine residues 069, 126, 178, 238, 292, 315, 492 or 493 were replaced with phenylalanine (F). The anti-CD3-elicited calcium signal increased in F069-, F292- and F492-ZAP-70 expressing cell lines but decreased in the F126-, F315- and F493-ZAP-70 expressing cell lines. ZAP-70 point mutations led to phosphorylation changes predominantly in SH2 domain containing leukocyte protein of 76kDa (SLP-76) but not linker of activated T cells (LAT) during CD3-activation; moreover, we detected basal hyperphosphorylation of SLP-76 Y128 in the F126-, F178- and F492 ZAP-70-expressing cell lines. In summary, Y069, Y178, Y292 and Y492 have inhibitory, while Y126, Y315 and Y493 activator role in anti-CD3-induced T-cell activation. Phosphorylation changes in LAT and SLP-76 suggest that fine regulation of ZAP-70 on calcium signaling is rather transmitted through SLP-76 not LAT. Additionally, negative or positive autoregulatory function of Y292 and Y493 or Y315, respectively, was revealed in ZAP-70. These data indicate that previously not characterized Y069, Y126 and Y178 in ZAP-70 participate in the fine regulation of TCR signaling. PMID- 22207135 TI - Characterization of a model of tracheal plasma extravasation in passively sensitized rats using anti-allergic and anti-inflammatory drugs by oral and intratracheal route. AB - The aim of the following study was to characterize a passive systemic anaphylaxis rat model of dinitrophenyl (DNP)-induced plasma extravasation in the trachea to determine if the model is appropriate for the evaluation of new drugs targeting airway mast cells by oral and intratracheal (i.t.) route. To this purpose we have used fluticasone and a range of anti-allergic drugs including compounds either active on mast cell activation, such as cromoglycate and the Syk inhibitor R406, or active on mast cell mediators, such as cetirizine and montelukast. To further characterize the model, the effect of fluticasone, cromoglycate and R406 on rat tracheal mast cell degranulation was also assessed histologically. DNP-induced tracheal plasma extravasation was inhibited by cromoglycate (i.v. and i.t.) and R406 (p.o.), but not by fluticasone (i.t.), cetirizine or montelukast (p.o.). Cromoglycate and R406 also showed inhibition of tracheal mast cell degranulation, whereas fluticasone was inactive. These results suggest that the DNP-induced tracheal plasma extravasation model constitutes a useful animal model for the evaluation, by oral and i.t. route, of new anti-allergic drugs intended to target airway mast cells. PMID- 22207137 TI - Steroid-responsive encephalopathy associated with Hashimoto thyroiditis. AB - An 11-year-old girl presented with sudden sensory disturbance and left-sided muscle weakness. MRI revealed ischaemic change in the right lateral thalamus and the right internal capsule. During sonographic work-up of the cervical arteries, inflammation of the thyroid gland was noted. The results of the thyroid function tests and antibody titers confirmed Hashimoto thyroidits. Under high-dose corticosteroids, the girl had a full neurological recovery. PMID- 22207138 TI - RICH depuis la lettre. PMID- 22207139 TI - VCUG and the recurring question of sedation: preparation and catheterization technique are the key. PMID- 22207140 TI - VCUG and the question of sedation. PMID- 22207141 TI - Sedation and the VCUG. PMID- 22207142 TI - Appearance of gas collections after scuba diving death: a computed tomography study in a porcine model. AB - INTRODUCTION: Postmortem computed tomography can easily demonstrate gas collections after diving accidents. Thus, it is often used to support the diagnosis of air embolism secondary to barotrauma. However, many other phenomenons (putrefaction, resuscitation maneuvers, and postmortem tissue offgassing) can also cause postmortem gas effusions and lead to a wrong diagnosis of barotrauma. OBJECTIVES: The aim of this study is to determine topography and time of onset of postmortem gas collections respectively due to putrefaction, resuscitation maneuvers, and tissue offgassing. MATERIALS AND METHODS: A controlled experimental study was conducted on nine pigs. Three groups of three pigs were studied postmortem by CT from H0 to H24: one control group of nonresuscitated nondivers, one group of divers exposed premortem to an absolute maximal pressure of 5 b for 16 min followed by decompression procedures, and one group of nondivers resuscitated by manual ventilation and thoracic compression for 20 min. The study of intravascular gas was conducted using CT scan and correlated with the results of the autopsy. RESULTS: The CT scan reveals that, starting 3 h after death, a substantial amount of gas is observed in the venous and arterial systems in the group of divers. Arterial gas appears 24 h after death for the resuscitated group and is absent for the first 24 h for the control group. Concerning the putrefaction gas, this provokes intravenous and portal gas collections starting 6 h after death. Subcutaneous emphysema was observed in two of the three animals from the resuscitated group, corresponding to the thoracic compression areas. CONCLUSION: In fatal scuba diving accidents, offgassing appears early (starting from the first hour after death) in the venous system then spreads to the arterial system after about 3 h. The presence of intra arterial gas is therefore not specific to barotrauma. To affirm a death by barotrauma followed by a gas embolism, a postmortem scanner should be conducted very early. Subcutaneous emphysema should not be mistaken as diagnostic criteria of barotrauma because it can be caused by the resuscitation maneuvers. PMID- 22207145 TI - Efficient formation of cell spheroids using polymer nanofibers. AB - Spheroid culture has been used for suspension cultures of anchorage-dependent cells. In this study, we developed a new method for the suspension cultures of anchorage-dependent animal cells using polymer nanofibers. Poly(lactic-co glycolic acid) nanofibers (785 nm in average fiber-diameter, 88 MUm in average fiber-length) fabricated by the electrospinning method were added to each suspension culture of human embryonic kidney 293 cells and human dermal fibroblasts. As compared to no addition of nanofibers to the suspension cultures, nanofibers enhanced cell spheroid formation, thereby reducing cell death resulting from a lack of cell adhesion. Efficient formation of spheroids in the presence of polymer nanofibers may be useful for the suspension cultures of anchorage-dependent cells. PMID- 22207146 TI - Improved lycopene production by Blakeslea trispora with isopentenyl compounds and metabolic precursors. AB - The highest lycopene production in mated cultures of Blakeslea trispora was 578 mg/l by adding 42 mg geraniol/l to the medium after 48 h of growth. The control gave 317 mg/l. Adding isopentenyl alcohol at 40 mg/l, mevalonic acid at 17.5 mg/l or dimethyl allyl alcohol at 150 mg, each after 36 h growth, gave lycopene yields 62, 45 and 47%, respectively, higher than the control. PMID- 22207147 TI - Removing human immunodeficiency virus (HIV) from human blood using immobilized heparin. AB - Heparin covalently attached to a water-insoluble resin suspended in HIV-infected aqueous buffer or whole blood captures the virus; subsequent physical separation of the immobilized heparin reduced the viral titers by over 80 and 50%, respectively. The detoxification concept has been validated by both circulating an HIV-1 solution through a column packed with the heparin-sepharose beads and successively mixing an HIV-1 solution with fresh beads. PMID- 22207148 TI - Dominant lethal mutations of topoisomerase II inhibitors etoposide and merbarone in male mice: a mechanistic study. AB - Two topoisomerase II inhibitors, etoposide and merbarone, were tested for the induction of dominant lethal mutations in male mice. Etoposide was administered at a dosage of 30 or 60 mg/kg. Merbarone was administered at a dosage of 40 or 80 mg/kg. These males were mated at weekly intervals to virgin females for 6 weeks. In the present experiments, regardless of the agent, spermatids appeared to be the most sensitive germ-cell stage to dominant lethal induction. Etoposide and merbarone clearly induced dominant lethal mutations in the early spermatid stage only with the highest tested doses. The mutagenic effects were also directly correlated with reactive oxygen species accumulation as an obvious increase in 2',7'-dichlorofluorescein fluorescence level was noted in the sperm of animals treated with higher doses of etoposide and merbarone. Treatment of male mice with N-acetylcysteine significantly protected mice from etoposide- and merbarone induced dominant lethality. Moreover, N-acetylcysteine treatment had no antagonizing effect on etoposide- and merbarone-induced topoisomerase II inhibition. Overall, this study provides for the first time that etoposide and merbarone induce dominant lethal mutations in the early spermatid stage through a mechanism that involves increases in oxidative stress. The demonstrated mutagenicity profile of etoposide and merbarone may support further development of effective chemotherapy with less mutagenicity. PMID- 22207149 TI - Disentangling the spermatozoon's transcriptome. PMID- 22207144 TI - Recent advances in the pharmacogenetics of clopidogrel. AB - Clopidogrel has been used to prevent recurrent ischemic events after acute coronary syndrome and/or coronary stent implantation. An impaired platelet response to this drug (residual high platelet reactivity) has been identified as a risk factor for recurrent ischemic events. The platelet response to clopidogrel is highly heritable (73%) suggesting a substantial genetic component. Two sequential cytochrome P450-dependent oxidative steps are required to convert clopidogrel to its active metabolite. The first step leads to the formation of 2 oxo-clopidogrel, which is then metabolized to the active metabolite. Cytochrome P450s are large highly polymorphic family of mono-oxygenases. Many alleles have been reported, and some of these are able to modify the activity of proteins, reducing or increasing the concentration of active metabolites and the drug effect. Loss-of-function variants in the hepatic cytochrome 2C19 (mainly *2 allele) system have been found to be the predominant genetic mediators of clopidogrel response. Variant carriers have higher treatment platelet reactivity and higher risk of adverse cardiac events including stent thrombosis, myocardial infarction, and death. Although value of CYP2C19 genotyping has been demonstrated in ACS population treated with PCI, there is still a wide interindividual variability within each genotype to systematically advocate this genetic testing in clinical practice. The CYP2C19*2 variant only explained 12% of the platelet response to clopidogrel. In the near future, it is highly probable that additional gene variants or epigenetic phenomenon will emerge as significant contributors to clopidogrel response that will allow recommending genetic testing for routine use. The purpose of this review is to discuss the contribution of individual genetic differences responsible for variations of action and clopidogrel efficacy. PMID- 22207143 TI - Zebrafish: a model for the study of addiction genetics. AB - Drug abuse and dependence are multifaceted disorders with complex genetic underpinnings. Identifying specific genetic correlates is challenging and may be more readily accomplished by defining endophenotypes specific for addictive disorders. Symptoms and syndromes, including acute drug response, consumption, preference, and withdrawal, are potential endophenotypes characterizing addiction that have been investigated using model organisms. We present a review of major genes involved in serotonergic, dopaminergic, GABAergic, and adrenoreceptor signaling that are considered to be directly involved in nicotine, opioid, cannabinoid, and ethanol use and dependence. The zebrafish genome encodes likely homologs of the vast majority of these loci. We also review the known expression patterns of these genes in zebrafish. The information presented in this review provides support for the use of zebrafish as a viable model for studying genetic factors related to drug addiction. Expansion of investigations into drug response using model organisms holds the potential to advance our understanding of drug response and addiction in humans. PMID- 22207150 TI - Can the IPAQ-long be used to assess occupational physical activity? AB - BACKGROUND: To be able to draw any conclusions regarding the health effects of occupational physical activity (OPA), more information is needed regarding valid measures to assess OPA. Aims were to compare OPA as assessed with the International Physical Activity Questionnaire long version (IPAQ-L) with OPA assessed with an accelerometer and to assess the contribution of OPA to total PA. METHODS: Working adults (n = 441; mean age = 49.4 yrs; 44% males) wore an accelerometer for 7 days in free-living situations and completed the IPAQL. Comparisons were made between IPAQ-L-work and accelerometer data limited to working time (Moderate and Vigorous PA (accelerometer-MVPA-work) and average intensity). Subgroup analyses were performed. RESULTS: Spearman correlation was r = .46 (P < .01) between IPAQ-L-work and accelerometer-MVPA-work. Correlations ranged from r = .27 to r = .55 in respectively obese and overweight subjects. The contribution of IPAQ-L-work to IPAQ-total was 24.7%. CONCLUSIONS: The IPAQ-L work domain is a moderately good measure of time spent on MVPA at work and can be used to assess the contribution of OPA to total PA. This study provides valuable information regarding the use of the IPAQ-L in assessing work domain specific PA, and underscores the importance of assessing OPA, as it can contribute for a substantial part to total PA. PMID- 22207151 TI - Functional amyloids in insect immune response. AB - The innate immune system of insects consists of humoural and cellular responses that provide protection against invading pathogens and parasites. Defence reactions against these latter include encapsulation by immune cells and targeted melanin deposition, which is usually restricted to the surface of the foreign invader, to prevent systemic damage. Here we show that a protein produced by haemocytes of Heliothis virescens (Lepidoptera, Noctuidae) larvae, belonging to XendoU family, generates amyloid fibrils, which accumulate in large cisternae of the rough endoplasmic reticulum and are released upon immune challenge, to form a layer coating non-self objects entering the haemocoel. This amyloid layer acts as a molecular scaffold that promotes localised melanin synthesis and the adhesion of immune cells around the non-self intruder during encapsulation response. Our results demonstrate a new functional role for these protein aggregates that are commonly associated with severe human diseases. We predict that insects will offer new powerful experimental systems for studying inducible amyloidogenesis, which will likely provide fresh perspectives for its prevention. PMID- 22207152 TI - Posthysterectomy cytology screening: indications and clinical implications. AB - OBJECTIVE: To review the results of patients who were referred for posthysterectomy of abnormal cytology based on screening indications. MATERIALS AND METHODS: We performed a retrospective review of 64 patients who have been referred for posthysterectomy vaginal colposcopy to the gynecologic oncology service. Patients' demographics, clinical features, reason for screening, and final diagnosis were recorded. Patients were divided into 2 groups based on posthysterectomy screening guidelines. Group A was considered to have undergone unnecessary screening based on national guidelines, and group B had risk factors that appropriately called for continued surveillance. The number of colposcopic examinations and the incidence of neoplasia were recorded for each group. RESULTS: The mean age of the patients was 65 years (range = 35-95 y). Group A included 22 patients with history of abnormal cytology posthysterectomy for benign disease. Of the 22 abnormal cytology results, 21 were low-grade squamous intraepithelial lesion (n = 14) or atypical squamous cells of undetermined significance (n = 7) with 1 high-grade squamous intraepithelial lesion. After referral and colposcopy of this group, no neoplasia was found. Group B included 42 total patients. Of these 42 patients, 20 (48%) had a history of cervical intraepithelial neoplasia, 12 (28%) had a history of vaginal intraepithelial neoplasia, 6 (14%) had history of cervical cancer, 2 (5%) had history of diethylstilbestrol exposure, and 2 (5%) had a history of radiation therapy. In group B, 8 (9%) and 1 (2%) of the patients had vaginal intraepithelial neoplasia 2/3 and squamous cell carcinoma, respectively. CONCLUSIONS: Current national guidelines are appropriate. Adherence to these guidelines will decrease intervention and not affect the detection of vaginal neoplasia. Patients with risk factors for lower genital tract neoplasia warrant continued screening after hysterectomy. PMID- 22207153 TI - Rapid spontaneous regression of acute-onset vulvar intraepithelial neoplasia 3 in young women: a case series. AB - OBJECTIVE: Vulvar intraepithelial neoplasia 3 (VIN 3)/vulvar carcinoma in situ is currently treated by surgical excision, laser ablation, or topically with 5 fluorouracil or imiquimod. The rate of progression of untreated VIN 3/vulvar carcinoma in situ to invasive cancer is significant, although difficult to assess, because most patients undergo treatment. The peak incidence of invasive carcinoma of the vulva occurs in the sixth decade, which may indicate that human papillomavirus (HPV)-related preinvasive disease in the younger population has a lower progression rate. However, the risk of invasive disease cannot be disregarded. METHODS: This is a case series of complete spontaneous resolution of untreated VIN 3/vulvar carcinoma in situ in 5 healthy women aged 20 to 36 years from a single community gynecologic oncologist practice from 2006 to 2010. RESULTS: Complete spontaneous regression of acute VIN 3/vulvar carcinoma in situ was reported in 6 healthy young women aged 20 to 36 years. New sexual partners were reported in 2 of the 6 patients preceding the onset of vulvar lesions within 6 months. All patients were nonsmokers, healthy without known immunocompromise, and noted the acute onset of vulvar lesions. Vulvar intraepithelial neoplasia 3/vulvar carcinoma in situ was diagnosed on biopsy and confirmed on independent review. All lesions were multifocal in nature. Time to spontaneous regression was 6, 6, 8, 12, 18, and 20 weeks after initial biopsy. No patient received the HPV vaccine. Recurrence has not been noted in any of the patients within the follow up period of 6 to 60 months. CONCLUSIONS: Short-term follow-up with conservative management of acute-onset VIN 3/vulvar carcinoma in situ in this young patient population correlates with similar treatment strategies for HPV-related cervical intraepithelial neoplasia of the cervix and may prevent disfigurement, pain, and complications associated with the current recommended therapeutic modalities. The timing of intervention for VIN 3/vulvar carcinoma in situ in the young population needs clarification. Future studies are in order. PMID- 22207154 TI - Spontaneous neural activity of the anterodorsal lobe and entopeduncular nucleus in adult zebrafish: a putative homologue of hippocampal sharp waves. AB - Spontaneous neural activity is instrumental in the formation and maintenance of neural circuits that govern behavior. In mammals, spontaneous activity is observed in the spinal cord, brainstem, diencephalon, and neocortex, and has been most extensively studied in the hippocampus. Using whole-brain in vitro recordings we establish the presence of spontaneous activity in two regions of the zebrafish telenchephalon: the entopeduncular nucleus (EN) and the anterodorsal lobe (ADL). The ADL is part of the lateral telencephalic pallium, an area hypothesized to be functionally equivalent to the mammalian hippocampus. In contrast, the EN has been hypothesized to be equivalent to the mammalian basal ganglia. The observed spontaneous activity is GABA modulated, sensitive to glutamate and chloride transporter antagonists, and is abolished by sodium pump blockers; moreover, the spontaneous activity in the ADL is a slow multiband event (~100 ms) characterized by an embedded fast ripple wave (~150-180 Hz). Thus, the spontaneous activity in the ADL shares physiological features of hippocampal sharp waves in rodents. We suggest that this spontaneous activity is important for the formation and maintenance of neural circuits in zebrafish and argue that applying techniques unique to the fish may open novel routes to understand the function of spontaneous activity in mammals. PMID- 22207155 TI - Evidence for a new post-translational modification in Staphylococcus aureus: hydroxymethylation of asparagine and glutamine. AB - Staphylococcus aureus is an opportunistic pathogen whose infectious capacity depends on surface proteins, which enable bacteria to colonize and invade host tissues and cells. We analyzed "trypsin-shaved" surface proteins of S. aureus cultures by high resolution LC-MS/MS at different growth stages and culture conditions. Some modified peptides were identified, with a mass shift corresponding to the addition of a CH2O group (+30.0106 u). We present evidence that this shift corresponds to a hyxdroxymethylation of asparagine and glutamine residues. This known but poorly documented post-translational modification was only found in a few proteins of S. aureus grown under specific conditions. This specificity seemed to exclude the hypothesis of an artifact due to sample preparation. Altogether hydroxymethylation was observed in 35 peptides from 15 proteins in our dataset, which corresponded to 41 modified sites, 35 of them being univocally localized. While no function can currently be assigned to this post-translational modification, we hypothesize that it could be linked to modulation of virulence factors, since it was mostly found on some surface proteins of S. aureus. PMID- 22207156 TI - Effects of growth hormone on the salmon pituitary proteome. AB - Growth hormone 1 (GH1), a pituitary hormone, plays a key role in the regulation of growth. Both excess GH1 treatment and overexpression of a GH1 transgene promote growth of salmon, but these animals exhibit physiological abnormalities in viability, fertility and metabolism, which might be related to pituitary function. However, the molecular dynamics induced in the pituitary by excess GH1 remain unknown. In this study, we performed iTRAQ proteome analysis of the amago salmon pituitary, with and without excess GH1 treatment, and found that the expression levels of proteins related to endocrine systems, metabolism, cell growth and proliferation were altered in the GH1-treated pituitary. Specifically, pituitary hormone prolactin (2.29 fold), and somatolactin alpha (0.14 fold) changed significantly. This result was confirmed by proteome and transcriptome analyses of pituitary from the GH1-transgenic (GH1-Tg) amago salmon. The dynamics of protein and gene expression in the pituitary of GH1-Tg amago salmon were similar to those of pituitary treated with excess GH1. Our findings suggest that not only excess GH1 hormone, but also the quantitative changes in other pituitary hormones, might be essential for the abnormal growth of amago salmon. These data will be useful in future attempts to increase the productivity of fish farming. PMID- 22207157 TI - Clozapine administration reverses behavioral, neuronal, and nitric oxide disturbances in the neonatal ventral hippocampus rat. AB - Clozapine is widely used in the treatment of schizophrenia; however its complete mechanism of action is not fully established. The neonatal ventral hippocampal lesion (nVHL) has emerged as a model of schizophrenia-related behavior. Our group has previously shown hyperresponsiveness to novel environment, neuronal atrophy in prefrontal cortex (PFC) and nucleus accumbens (NAcc) neurons as well as abnormal levels of nitric oxide (NO) in the PFC of the nVHL rat. In the present study, we aimed to investigate the role of repeated clozapine administration (2 mg/kg/day for 21 days) in a novel environment, neuronal rearrangement in PFC, NAcc and basolateral amygdala (BLA) as well as NO levels in this model. Clozapine administration reversed the hyperlocomotion observed in a novel environment in the nVHL rat with no effect on locomotion in sham animals. Quantitative morphological analysis demonstrated a retracted neuronal arborization and decreased spinogenesis in the NAcc, PFC and BLA in nVHL rat. Interestingly, clozapine administration also rescued neuronal atrophy in these brain regions. The nVHL also displayed increased NO levels in PFC, striatum and occipital cortex. Clozapine administration selectively reversed these abnormal levels of NO in striatum in nVHL rat while NO levels were increased in the PFC of sham animals. Our results further extend the usefulness of the nVHL as a model of schizophrenia-related behavior and suggest that clozapine reverses behavioral deficits in these animals by modulating neuronal reorganization and NO levels in the brain. PMID- 22207158 TI - Rash and dyspnoea in a 39 year old man. PMID- 22207159 TI - US agency seeks to censor influenza research amid biosecurity fears. PMID- 22207160 TI - One in four hospital patients should be cared for out of hospital. PMID- 22207161 TI - Evaluation of intracellular trafficking and clearance from HeLa cells of doxorubicin-bound block copolymers. AB - New technologies are needed to deliver medicines safely and effectively. Polymeric nanoparticulate carriers are one such technology under investigation. We examined the intracellular trafficking of doxorubicin-bound block copolymers quantitatively and by imaging doxorubicin-derived fluorescence using confocal microscopy. The polymers were internalized by endocytosis and distributed in endosomal/lysosomal compartments and the endoplasmic reticulum; unlike free doxorubicin, the polymers were not found in the nucleus. Moreover, the ATP binding cassette protein B1 (ABCB1) transporter may be involved in the efflux of the polymer from cells. This drug delivery system is attractive because the endogenous transport system is used for the uptake and delivery of the artificial drug carrier to the target as well as for its efflux from cells to medium. Our results show that a drug delivery system strategy targeting this endogenous transport pathway may be useful for affecting specific molecular targets. PMID- 22207162 TI - Predicting hydrophilic drug encapsulation inside unilamellar liposomes. AB - A mathematical model has been developed to predict the encapsulation efficiency of hydrophilic drugs in unilamellar liposomes, and will be useful in formulation development to rapidly achieve optimized formulations. This model can also be used to compare drug encapsulation efficiencies of liposomes prepared via different methods, and will assist in the development of suitable process analytical technologies to achieve real-time monitoring and control of drug encapsulation during liposome manufacturing for hydrophilic molecules. Liposome particle size as well as size distribution, lipid concentration, lipid molecular surface area, and bilayer thickness were used in constructing the model. Most notably, a Log-Normal probability function was utilized to account for sample particle size distribution. This is important to avoid significant estimation error. The model-generated predictions were validated using experimental results as well as literature data, and excellent correlations were obtained in both cases. A Langmuir balance study provided insight regarding the effect of media on the liposome drug encapsulation process. The results revealed an inverse correlation between media ionic strength and lipid average molecular area, which helps to explain the phenomenon of inverse correlation between media ionic strength and drug encapsulation efficiency. Finally, a web application has been written to facilitate use of the model allowing calculations to be easily performed. This model will be useful in formulation development to rapidly achieve optimized formulation. PMID- 22207163 TI - In vitro evaluation of powders for inhalation: the effect of drug concentration on particle detachment. AB - Limited information on the effect of the drug concentration on the performance of powders for inhalation is currently published. The aim of this work was to study the influence of drug concentration on the adhesion between drug and carrier and on the drug detachment from the carrier. The study was done with formoterol fumarate and fluticasone propionate blended with lactose Lactohale 200. To assess the adhesion of respirable-sized drug to carrier particles, a simple method was developed based on aspiration and considering the whole blend as it is used in dry powder inhalers. Adhesion characteristics were evaluated by submitting the mixtures to a sieving action by air depression with an Alpine air-jet sieve. Aerodynamic evaluation of fine particle dose and emitted dose was obtained using a Twin Stage Impinger (TSI). Drug concentration of powder blends used in dry powder inhalers influenced adhesion, content uniformity and in vitro deposition of the drug. For the higher concentration of formoterol, it seemed that a lower quantity of drug adhered to the lactose. This was confirmed by the aerosolization assays done in the TSI. The fine particle fraction increased linearly with the formoterol concentration. A correlation was observed between adhesion characteristics and inertial impaction. In the case of fluticasone, the influence of the concentration was different. First, the fine particle fraction increased with the concentration and then decreased with a further increase of the fluticasone concentration. This could be explained by the lack of homogeneity when the fluticasone concentration was high because of agglomerates of pure drug which can not be redispersed, or by the physico-chemical characteristics of this drug. PMID- 22207164 TI - Bonding of acrylic denture teeth to MMA/PMMA and light-curing denture base materials: the role of conditioning liquids. AB - OBJECTIVES: The connection between resin denture teeth and the denture base is essential for the integrity of partial and full dentures. The aim of the present study was to analyse the bond strength of acrylic denture teeth to two light curing denture base materials compared to the gold-standard (MMA/PMMA) using different conditioning liquids. METHODS: The ridge laps of 220 identical denture teeth were ground and pre-treated using different conditioning liquids (MMA, an experimental conditioning liquid as well as the two commercially available liquids Palabond and Versyo.bond). The denture base materials (PalaXpress, Versyo.com, Eclipse) were applied using a split mould to obtain tensile bond strength specimens of identical shape. Ten specimens per test group were either stored in water for 24h or thermocycled (5000*, 5-55 degrees C) prior to tensile bond strength testing (cross-head speed 10mm/min). Data was subjected to parametric statistics (alpha=0.05). RESULTS: The three-way ANOVA revealed a significant influence of the material, pre-treatment as well as the storage. PalaXpress showed the highest bond strength (24.3MPa) of all materials tested after TC, whereas the use of MMA led to the most constant results. Lower values were recorded for Versyo.com (17.5MPa) and Eclipse (10.4MPa) bonded with Versyo.bond. CONCLUSIONS: The results indicate that MMA/PMMA based denture base resins provide reliable and durable bond strength to acrylic denture teeth. Using light-curing denture base materials requires the application of appropriate conditioning liquids to obtain acceptable bond strength. The use of MMA affects bond strength to light-curing denture base materials. CLINICAL SIGNIFICANCE: The pre-treatment of denture teeth is critical regarding their bond-strength to denture base materials and in turn for the integrity of removable full and partial dentures. Light-curing denture base resins are more sensitive to the correct tooth pre-treatment compared to conventional MMA/PMMA materials, requiring specific conditioning liquids. PMID- 22207166 TI - Gene regulation: Resolving transcription factor binding. PMID- 22207167 TI - Large omental metastases of a gastrointestinal stromal tumor. AB - Gastrointestinal stromal tumors are rare tumors, originating from the interstitial cells of Cajal. They are the most common mesenchymal tumors of the gastrointestinal tract. Metastatic tumor is treated with imatinib mesylate. A case of large metastases of a gastrointestinal stromal tumor to the omentum, diagnosis and treatment principles are presented in this case report. PMID- 22207165 TI - Crop genomics: advances and applications. AB - The completion of reference genome sequences for many important crops and the ability to perform high-throughput resequencing are providing opportunities for improving our understanding of the history of plant domestication and to accelerate crop improvement. Crop plant comparative genomics is being transformed by these data and a new generation of experimental and computational approaches. The future of crop improvement will be centred on comparisons of individual plant genomes, and some of the best opportunities may lie in using combinations of new genetic mapping strategies and evolutionary analyses to direct and optimize the discovery and use of genetic variation. Here we review such strategies and insights that are emerging. PMID- 22207168 TI - Carcinoma of two parathyroid glands caused by a novel MEN1 gene mutation - a rare feature of the MEN 1 syndrome. AB - Multiple endocrine neoplasia type 1 (MEN 1) is a rare syndrome inherited in an autosomal dominant pattern, characterized by combinations of tumors of the parathyroid glands, pituitary gland, and pancreatic islet cells and more rare tumors of endocrine organs and nonendocrine tissues. Germline mutations in the MEN1 gene are responsible for the MEN 1 syndrome, leading to an inactive form of menin protein. Benign lesions of the parathyroid glands are characteristic in patients with the MEN 1 syndrome; however, patients can develop parathyroid carcinomas very rarely. This report presents a clinical case of the MEN 1 syndrome: a 39-year-old woman underwent surgery for carcinoma of two parathyroid glands as well as was treated for pituitary prolactinoma, which caused infertility, and malignant insulinoma; the patient had multiple subcutaneous lipomas as well. Genetic analysis revealed a novel germline mutation in the MEN1 gene - a nucleotide insertion at codon 43 in exon 2 (c.129insA), which caused the occurrence of the MEN1 syndrome. The clinical case of the MEN 1 syndrome presented here is relevant in gathering the data on etiopathogenesis of not only MEN 1 syndrome, but an extremely rare pathology - parathyroid carcinoma - as well. PMID- 22207169 TI - Inhibition of matrine against gastric cancer cell line MNK45 growth and its anti tumor mechanism. AB - Anti-tumor activity and mechanism of matrine is evaluated and investigated. MTT assay showed that the matrine was able to inhibit gastric cancer cell line MNK45 in a dose-dependent manner. The concentration required for 50% inhibition (IC50) was found to be 540 MUg/ml. This anti-tumor function was achieved through modulation of the NF-kappaB, XIAP, CIAP, and p-ERK proteins expression in cell line MNK45. By western blot analysis, we found that expression of NF-kappaB, XIAP, CIAP, and p-ERK proteins in cell line MNK45 would vary with varying concentration of matrine. These protein interactions possibly play a pivotal role in the regulation of apoptosis, for which further detailed analyzes are need. These results overall indicate that matrine can be used as an effective anti tumor agent in therapy of gastric cancer. PMID- 22207170 TI - The complete mitochondrial genome analysis of the tiger (Panthera tigris). AB - The complete mitochondrial genomes of five tiger samples from three subspecies (P. t. sumatrae, P. t. altica, and P. t. tigris) were successfully obtained by using 26 specifically designed Panthera-specific primer sets. The genome organization and gene arrangement of the five tiger samples were similar to each other; however polymorphic tandem repeat sequences were observed in the control region (CR). This led to a difference in the genome lengths obtained from these five samples with an average size of 16,994 bp for the five tiger mitochondrial genomes. The nucleotide base composition was on average as follows: A, 31.8%; T, 27.0%; C, 26.6%; G, 14.6% and exhibited compositional asymmetry. Most of tiger mitochondrial genome characteristics are similar to those of other common vertebrate species; however, some distinctive features were observed in the CR. First, the repetitive sequence 2 (RS 2) contained two repeat units of 80 bp and the first 15 bp of what would be the third repeat motif. The repetitive sequence 3 (RS 3) contained 47-50 repeat motifs of a shorter 8 bp (ACGTAYAC)(n). Second, length heteroplasmy polycystosine (poly-C) stretches was observed at the end of the HV I locus in all tiger samples. PMID- 22207171 TI - The porcine Gpr3 gene: molecular cloning, characterization and expression level in tissues and cumulus-oocyte complexes during in vitro maturation. AB - G protein-coupled receptor 3 (Gpr3) is a member of G protein-coupled receptor rhodopsin family, which is present throughout the follicle within the ovary and functions as a critical factor for the maintenance of meiotic prophase arrest in oocytes by a Gs protein-mediated pathway. In the current paper, attempts were made to clone and characterize a gene encoding Gpr3 from pigs and investigate its expression pattern in tissues and the whole cumulus-oocyte complexes (COCs) in vitro maturation (IVM). Rapid amplification of cDNA ends and RT-PCR gave rise to the full sequence of Gpr3 gene with its length being 2101 bp nucleotides, including an open reading frame of 993 bp, encoding a 331 amino acid polypeptide with the molecular weight of 35.2 kDa. Homology search and sequence multi alignment demonstrated that the putative porcine Gpr3 protein sequence shared a high identity with other animal Gpr3 orthologs, including several highly conservative motifs and amino acids. Real-time PCR analysis showed that the Gpr3 gene was expressed in tissues of cerebrum, cerebellum, hypothalamus, pituitary, ovary, oviduct, uterus, heart, liver, spleen, lung, kidney, muscle, fat, testis, thymus and granulosa cell, oocyte and COCs at different expression levels. The expression levels of this gene in oocyte, uterus, liver, fat, pituitary and brain were higher than that in other tissues. Interestingly, the mRNA and protein levels of Gpr3 in the whole COCs were down-regulated, and its mRNA expression levels were significantly and negatively correlated with the degrees of cumulus expansion (r = -0.937, P < 0.01) during IVM, suggesting its important roles in cumulus expansion and oocyte maturation. PMID- 22207172 TI - Gene expression profiling of Sinapis alba leaves under drought stress and rewatering growth conditions with Illumina deep sequencing. AB - Sinapis alba has many desirable agronomic traits including tolerance to drought. In this investigation, we performed the genome-wide transcriptional profiling of S. alba leaves under drought stress and rewatering growth conditions in an attempt to identify candidate genes involved in drought tolerance, using the Illumina deep sequencing technology. The comparative analysis revealed numerous changes in gene expression level attributable to the drought stress, which resulted in the down-regulation of 309 genes and the up-regulation of 248 genes. Gene ontology analysis revealed that the differentially expressed genes were mainly involved in cell division and catalytic and metabolic processes. Our results provide useful information for further analyses of the drought stress tolerance in Sinapis, and will facilitate molecular breeding for Brassica crop plants. PMID- 22207173 TI - Co-expression of Oct-4 and Nestin in human breast cancers. AB - The aim is to investigate the clinical implications of the Oct-4 and Nestin protein in human breast cancers. A total of 346 cases including 26 fresh and 320 paraffin-embedded tumor tissues were selected for characterizing the frequency of CD44(+)CD24(-) tumor cells by flow cytometry and the differential expression of the stem cell-related genes between CD44(+)CD24(-) and non-CD44(+)CD24(-) tumor cells was analyzed by PCR Array and immunofluorescence. In comparison with the non-CD44(+)CD24(-) tumor cells, the CD44(+)CD24(-), particularly for those with high percentage of Oct-4(+) and Nestin(+), tumor cells had higher tumorigenicity by forming mammospheres in vitro. More importantly, 42 (13.125%) out of 320 tumor tissues were positive for Oct-4 and Nestin staining. Universal analysis and multivariate analysis revealed that the expression of Oct-4 and Nestin was associated significantly with younger age, pathogenic degrees, lymph node metastasis and triple-negative breast cancer independently (P < 0.05) as well as shorter survival (P = 0.001). Oct-4 and Nestin were important regulators of the development of breast cancer, and Oct-4 and Nestin may be used as predictors for the prognosis of breast cancers. PMID- 22207175 TI - Development of EST derived SSRs and SNPs as a genomic resource in Indian catfish, Clarias batrachus. AB - Clarias batrachus, an Indian catfish species, is endemic to the Indian subcontinent and potential cultivable species. The genomic resources in C. batrachus in the form of ESTs containing microsatellite repeats (EST-SSR) and single nucleotide polymorphisms (SNPs) that are associated with the expressed genes from spleen were mined. From a total of 1,937 ESTs generated, 1,698 unique sequences were obtained, out of which 221 EST-SSRs were identified and 54% could be functionally annotated by similarity searches. A total of 23 contigs containing 3 or more ESTs were found to contain 31 SNP loci, out of which 8 ESTs showed similarity to genes of known function and 1 for hypothetical protein. Nine ESTs with SSRs and/or SNPs identified in this study were reported to be associated with diseases in human and animals. These identified loci can be developed into markers in C. batrachus, which can be useful in linkage mapping, comparative genomics studies and for its genetic improvement programmes. PMID- 22207174 TI - Development of ESTs and data mining of pineapple EST-SSRs. AB - Improving the quality of the non-climacteric fruit, pineapple, is possible with information on the expression of genes that occur during the process of fruit ripening. This can be made known though the generation of partial mRNA transcript sequences known as expressed sequence tags (ESTs). ESTs are useful not only for gene discovery but also function as a resource for the identification of molecular markers, such as simple sequence repeats (SSRs). This paper reports on firstly, the construction of a normalized library of the mature green pineapple fruit and secondly, the mining of EST-SSRs markers using the newly obtained pineapple ESTs as well as publically available pineapple ESTs deposited in GenBank. Sequencing of the clones from the EST library resulted in 282 good sequences. Assembly of sequences generated 168 unique transcripts (UTs) consisting of 34 contigs and 134 singletons with an average length of ~500 bp. Annotation of the UTs categorized the known proteins transcripts into the three ontologies as: molecular function (34.88%), biological process (38.43%), and cellular component (26.69%). Approximately 7% (416) of the pineapple ESTs contained SSRs with an abundance of trinucleotide SSRs (48.3%) being identified. This was followed by dinucleotide and tetranucleotide SSRs with frequency of 46 and 57%, respectively. From these EST-containing SSRs, 355 (85.3%) matched to known proteins while 133 contained flanking regions for primer design. Both the ESTs were sequenced and the mined EST-SSRs will be useful in the understanding of non-climacteric ripening and the screening of biomarkers linked to fruit quality traits. PMID- 22207176 TI - Alternative splicing, expression patterns and promoter characters of vasa-like gene from the silkworm, Bombyx mori. AB - VASA is considered to be one of the most reliable molecular marker of germ cells. In order to study the Bombyx mori vasa-like gene (Bmvlg), the cDNAs of Bmvlg were cloned and sequenced, and the results showed that the Bmvlg gene from the fifth instar larval testes had four alternative splicing isoforms. The open reading frame (ORF) of the longest isoform was composed of 1,806 nucleotides encoding 601 amino acid residues and contained some known conserved domains. The other three isoforms had complete ORF, suggesting that the Bmvlg gene had several alternative splicing forms, completely different from that of Drosophila melanogaster. The results of sequencing demonstrated that the Bmvlg gene promoter had several elements conserved in eukaryotic and gonadal tissue-specific promoters. To detect the specificity of the Bmvlg promoter, a transient expression vector pSK-vlg DsRed-polyA with a red fluorescent protein gene (DsRed), controlled by the Bmvlg promoter and a vector pIZT/V5-His-vlg-DsRed containing a Bmvlg fused with DsRed driven by the Bmvlg promoter, was constructed, respectively. Red fluorescence could be observed in some transfected BmN cells derived from silkworm ovaries and in the eggs injected with the vector pSK-vlg-DsRed-polyA, but red fluorescence could not be detected in the tissues of silkworm larva, after the transient expression vector was injected into blood, suggesting the Bmvlg promoter had gonadal tissue specificity. The transcription levels of Bmvlg in gonads of the fourth and fifth instar larvae were determined by fluorescent quantitative PCR, and the results revealed that the expression level of the Bmvlg gene in testes was slightly higher than that in ovaries. The expression levels of Bmvlg were lower in the fourth instar larva than that in the fifth instar larvae. Moreover, subcellular localization experiments showed that Bmvlg mainly existed in cytoplasm. These results provided new clues for understanding the function of the Bmvlg gene. PMID- 22207177 TI - Association between GSTM1, GSTT1, and GSTP1 polymorphisms and lung cancer risk in a Turkish population. AB - Several studies focused on investigating genetic polymorphisms in order to estimate genetic contribution to lung cancer often showed conflicting results. In this study, we investigated the role of GSTM1, GSTT1, GSTP1 exon 5 and exon 6 polymorphisms on developing lung cancer and histological subtypes in 213 lung cancer patients and 231 controls. GSTM1 null, GSTT1 null, and GSTP1 exon 5 variant genotypes did not show a significant risk for developing lung cancer overall. Significant association was noted between GSTP1 exon 6 variant genotypes and overall lung cancer risk (OR 2.17, 95% CI 1.25-3.78; P = 0.006). These results show that GSTP1 exon 6 polymorphism might be an important factor in determining lung cancer susceptibility in a Turkish population. PMID- 22207178 TI - Lack of association between Glu298Asp polymorphism and coronary artery disease in North Indians. AB - Nitric Oxide (NO) is an important molecule carrying number of different functions in humans. Published studies suggest that it may inhibit several key steps involved in the pathogenesis of atherosclerosis. Inhibition or reduction of NO due to Glu298Asp polymorphism may accelerate atherosclerosis. The aim of this study was to determine whether Glu298Asp polymorphism is implicated in the pathogenesis of coronary artery disease (CAD) among North Indian population from the state of Uttar Pradesh, India. We selected 253 CAD patients and 174 healthy, normotensive, non-diabetic controls, which were matched for gender and ethnicity. The Glu298Asp (rs1799983) variant was detected by genotyping subjects, using a polymerase chain reaction followed by restriction fragment length polymorphism. There was no significant difference found in the genotypic and allelic frequencies between patients and controls. Our study indicated that Glu298Asp polymorphism does not play any critical role in the pathogenesis of CAD, at least in North Indian population. PMID- 22207179 TI - Induction of toll-like receptor (TLR) 2, and MyD88-dependent TLR- signaling in response to ligand stimulation and bacterial infections in the Indian major carp, mrigal (Cirrhinus mrigala). AB - Toll-like receptor 2 (TLR2) is a member of TLR family. It recognizes a wide range of bacteria and their products, and is involved in inducing innate immune responses. In this article, we reported inductive expression of TLR2 and myeloid differentiation primary response gene 88 (MyD88)-dependent signaling in the Indian major carp, mrigal (Cirrhinus mrigala) which is highly commercially important fish species in the Indian subcontinent. Ontogeny analysis of TLR2, MyD88 and TRAF6 (TNF receptor associated factor 6) genes by quantitative real time PCR (qRT-PCR) revealed constitutive expression of these genes in all embryonic developmental stages, indicating their involvement in embryonic innate immune defense system in fish. Tissue specific expression analysis of these genes by qRT-PCR showed their wide distribution in various organs and tissues. Highest expression of TLR2 was in gill, MyD88 in liver and TRAF6 was in kidney. Inductive expression of TLR2, MyD88 and TRAF6 genes were observed following peptidoglycan (PGN)-treatment, and Streptococcus uberis and Aeromonas hydrophila infections. Expression of interleukin (IL)-8 and TNF-alpha in various organs were significantly enhanced by PGN-treatment and bacterial infections, and were closely associated with TLR2 induction. These findings together highlighted the contribution of TLR2 in augmenting innate immunity in fish, and indicated it's important role in immune surveillance of various organs during pathogenic invasion. This study will enrich the information in understanding the innate immune mechanism in fish, and will be helpful in developing preventive measures against infectious diseases in fish. PMID- 22207180 TI - Dissection of genetic overlap of drought and low-temperature tolerance QTLs at the germination stage using backcross introgression lines in soybean. AB - Northeast of China is the main soybean production area, drought and low temperature tolerance are both main factors involved in reducing soybean yield and limiting planting regions, the most effective way to solve this problem is to breed cultivars with drought and low-temperature tolerance. A set of the BC(2)F(3) lines was constructed with Hongfeng 11 as recurrent parent and Harosoy as donor parent, and screened in drought and low-temperature condition at the germination stage. Related QTLs were obtained by Chi-test and ANOVA analysis with genotypic and phenotypic data. Eighteen QTLs of drought tolerance and 23 QTLs of low-temperature tolerance were detected. Among them, 12 QTLs were correlated with both drought and low-temperature tolerance, which showed a partial genetic overlap between drought and low-temperature tolerance at the germination stage in soybean. Among the 12 genetic overlap QTLs, Satt253, Satt513, Satt693, Satt240, Satt323, and Satt255 were detected by at least one method for both drought and low-temperature tolerance. Satt557, Satt452, Sat_331, Satt338, Satt271, and Satt588 were detected by only one analysis method. The QTLs detected above were significant loci for drought or low-temperature tolerance in soybean. This will play an important role in MAS for development of both drought and low-temperature tolerance variety. PMID- 22207181 TI - Epigenetic and genetic analysis of WNT signaling pathway in sporadic colorectal cancer patients from Iran. AB - The WNT signaling is deregulated in most human colorectal cancers (CRC). Promoter methylation has been proposed as an alternative mechanism to inactivate genes in tumors. To gain insight into the methylation silencing of the WNT pathway during colorectal carcinogenesis, we examined the aberrant methylation profile of four genes, APC, Axin1, Axin2, and GSK3beta in an unselected series of 112 sporadic colorectal tumors by methylation specific PCR. It has been suggested that the Axin2 C148T SNP is associated with the risk of developing certain types of cancers. To assess the contribution of Axin2 SNP to CRC susceptibility, we examined the Axin2 C148T genotype in CRC patients and 170 healthy controls by PCR RFLP. The frequency of CRCs with at least one gene methylated was 18.75%. Promoter methylation of Axin2 and APC genes was detected in 7.1 and 11.9% of tumors, respectively. No aberrant methylation was found in Gsk3beta and Axin1 gene in these tumor series. The methylation status of APC had no significant association with clinical parameters. But, promoter methylation of Axin2 was sex related, occurring more frequently in females (P = 0.002). The frequency of Axin2 C148T genotypes were similar in patients and controls. Moreover, we observed no association between the Axin2 SNP and risk of CRC in patients stratified by age, sex, and smoking status. However, the heterozygote CT genotype was associated with a reduced CRC risk in distal patients compared with proximal patients (OR = 0.3; 95% CI 0.1-0.9, P = 0.04). Our findings indicate that Axin1 and GSK3beta methylation play a minor role in colorectal carcinogenesis. PMID- 22207182 TI - Comparison of aneuploidy frequencies between in vitro matured and unstimulated cycles oocytes by metaphase comparative genomic hybridization (mCGH). AB - A common observation after in vitro matured oocyte is that they yield poorer embryo quality compared to their in vivo counterparts. This study was designed to assess chromosomal status with metaphase comparative genomic hybridization after in vitro maturation (IVM) in unstimulated cycles and compare the results with those obtained after in vivo maturation. Patients without any obstetrical or gynecological pathology were admitted into the study. IVM oocytes were collected 36 h post hCG and matured in vitro at 37 degrees C in 5% O(2), 6% CO(2), and 89% air for 36 h. All matured (metaphase II) oocytes were subject to polar body 1 (PB 1) biopsy and vitrified individually. PB-1 samples were transferred into 0.25 cc PCR tubes containing 2.5 MUl of PBS. PB-1 samples from 12 IVM patients were studied. Twenty-six out of 63 PB-1 samples (41%) were determined as euploid and 37 samples (59%) were aneuploid, whereas these values were 42% euploid and 58% aneuploid in the control group (in vivo matured oocytes). No statistical differences were found between the IVM and the control groups for euploid aneuploid samples (P = 0.900). More aneuploidy was observed on chromosomes 11, 13, 15, 21, and 22 after IVM. Results show a non-significant rate of abnormal PB 1 formation after IVM compared to in vivo maturation. More aneuploidy was observed in chromosomes 11, 13, 15, 21, and 22 in the IVM group. PMID- 22207183 TI - Evaluating MEFV mutation frequency in Turkish familial Mediterranean fever suspected patients and gender correlation: a retrospective study. AB - Familial Mediterranean fever (FMF) is the most frequent hereditary inflammatory disease. FMF causes different clinical manifestations in different ethnic groups and countries. In this study, we retrospectively reviewed the records of 1,152 FMF suspected patients (673 female and 479 male) from November 2006 to December 2010. A commercial kit assay for the identification of MEFV (Mediterranean fever) gene mutations based on PCR and reverse-hybridization was used to investigate 12 mutations of the MEFV gene. 52.17% of 1,152 FMF suspected patients had MEFV mutation and 45.25% of them were male. The rate of MEFV mutation among male and female patients were 56.78 and 48.88%, respectively. These results were statistically significant and might support the suggestion that FMF had much more penetrance in male patients (P = 0.009). Not any significant difference was observed between the male and female patients in terms of heterozygote and homozygote mutation carriage rate (P = 0.071). Also not any significant difference was observed between the male and female patients in terms of compound heterozygote mutation carriage rate (P = 0.058). PMID- 22207184 TI - Use of the Internet for the surveillance and prevention of sexually transmitted diseases. AB - The Internet is a relatively new tool in the surveillance and prevention of sexually transmitted infections, and this review examines its global use in this regard. Much use has been made in the form of information collection and dissemination; targeted population engagement through chat rooms, partner notification and other mechanisms; and the provision of testing services and other products. Internet users may need education concerning reputable websites, and public health practitioners need proficiency in the use of social media and marketing. PMID- 22207186 TI - Mass transport enhancement in annular-shaped lid-driven bioreactor. AB - The current study investigated numerically the two-dimensional (2D) incompressible flow and mass transfer in a lid-driven cavity of annular geometry accompanied by enzymatic surface-reactions. The lid-driven bioreactor had a square cross-section of (H * H) and a radius of curvature of r (c). This flow configuration gives the opportunity to evaluate effects of curvature as well as operational parameters on the bioreactor performance. For forced-convection, conservation equations were solved numerically, using fourth-order finite volume schemes, to identify the 2D flow structure and concentration distribution of substrate within the bioreactor. For pure diffusion, analytical solution was obtained. Substrate transfer rates were presented in terms of Sherwood number. While, effectiveness factor was computed to evaluate the force-convection contribution over pure molecular diffusion. Mass-transfer against surface reaction resistance was estimated via Damkohler number. Results indicate the positive role of increasing Peclet number, Reynolds number, and radius of curvature in enhancing the substrate transport process. PMID- 22207185 TI - Anthrax and the inflammasome. AB - Anthrax lethal toxin (LT), a major virulence determinant of anthrax disease, induces vascular collapse in mice and rats. LT activates the Nlrp1 inflammasome in macrophages and dendritic cells, resulting in caspase-1 activation, IL-1beta and IL-18 maturation and a rapid cell death (pyroptosis). This review presents the current understanding of LT-induced activation of Nlrp1 in cells and its consequences for toxin-mediated effects in rodent toxin and spore challenge models. PMID- 22207187 TI - Excess protein synthesis in FXS patient lymphoblastoid cells can be rescued with a p110beta-selective inhibitor. AB - The fragile X mental retardation protein (FMRP) plays a key role for neurotransmitter-mediated signaling upstream of neuronal protein synthesis. Functional loss of FMRP causes the inherited intellectual disability fragile X syndrome (FXS), and leads to increased and stimulus-insensitive neuronal protein synthesis in FXS animal models. Previous studies suggested that excess protein synthesis mediated by dysregulated signal transduction contributes to the majority of neurological defects in FXS, and might be a promising target for therapeutic strategies in patients. However, possible impairments in receptor dependent protein synthesis have not been evaluated in patient cells so far. Using quantitative fluorescent metabolic labeling, we demonstrate that protein synthesis is exaggerated and cannot be further increased by cytokine stimulation in human fragile X lymphoblastoid cells. Our previous work suggested that loss of FMRP-mediated regulation of protein expression and enzymatic function of the PI3K catalytic subunit p110beta contributes to dysregulated protein synthesis in a mouse model of FXS. Here, we demonstrate that these molecular mechanisms are recapitulated in FXS patient cells. Furthermore, we show that treatment with a p110beta-selective antagonist rescues excess protein synthesis in synaptoneurosomes from an FXS mouse model and in patient cells. Our work suggests that dys-regulated protein synthesis and PI3K activity in patient cells might be suitable biomarkers to quantify the efficacy of drugs to ameliorate molecular mechanisms underlying FXS, and could be used for drug screens to refine treatment strategies for individual patients. Moreover, we provide rationale to pursue p110beta-targeting treatments as potential therapy in FXS, and possibly other autism spectrum disorders. PMID- 22207188 TI - Policy-makers' responses to neighborhood focus group outcomes on physical activity. AB - BACKGROUND: Neighborhood environment and resources affect physical activity. This study examined the relationships between San Francisco residents' perceived barriers to physical activity and policy-maker perspectives of conditions in neighborhoods that are under-served for physical activity. METHODS: Nine focus groups comprised of primarily African American, Chinese American, and Latino populations were constructed from 6 low-income neighborhoods to respond to questions based on the social-ecological model about neighborhood recreational opportunities and to offer policy and intervention strategies to increase physical activity. A tenth focus group was conducted with staff members from 7 city departments to respond to neighborhood focus groups outcomes. The transcribed videotaped discussions were analyzed using qualitative content analysis. RESULTS: Both residents and policy-makers highlighted neighborhood disparities that reduce physical activity including unsafe and unhealthy environments and difficulty accessing available resources. Residents reported fewer available free or low-cost resources than those identified by policy makers. CONCLUSIONS: Findings suggest that policy-makers would benefit from consideration of neighborhood-level affects of policies on physical activity and local residents' recommendations for policies affecting physical activity. Concordance between residents' perceptions and policy-maker perceptions of neighborhood conditions for physical activity was greater than reported in previous literature. PMID- 22207189 TI - Unbalance of CB1 receptors expressed in GABAergic and glutamatergic neurons in a transgenic mouse model of Huntington's disease. AB - Cannabinoid CB1 receptors (CB1Rs) are known to be downregulated in patients and in animal models of Huntington's disease (HD). However, the functional meaning of this reduction, if any, is still unclear. Here, the effects of the cannabinoid receptor agonist WIN 55,212-2 (WIN) were investigated on striatal synaptic transmission and on glutamate and GABA release in symptomatic R6/2 mice, a genetic model of HD. The expression levels of CB1Rs in glutamatergic and GABAergic synapses were also evaluated. We found that in R6/2 mice, WIN effects on synaptic transmission and glutamate release were significantly increased with respect to wild type mice. On the contrary, a decrease in WIN-induced reduction of GABA release was found in R6/2 versus WT mice. The expression of CB1Rs in GABAergic neurons was drastically reduced, while CB1Rs levels in glutamatergic neurons were unchanged. These results demonstrate that the expression and functionality of CB1Rs are differentially affected in GABAergic and glutamatergic neurons in R6/2 mice. As a result, the balance between CB1Rs expressed by the two neuronal populations and, thus, the net effect of CB1R stimulation, is profoundly altered in HD mice. PMID- 22207190 TI - MicroRNA dysregulation in schizophrenia. AB - Schizophrenia is a complex neuropsychiatric disorder that involves disturbances in neural circuitry and synaptic function. The exquisite network architecture and capacity for discreet post-synaptic remodeling of neurons requires coordination by an elaborate intracellular network of molecular signal transduction systems. The redundancy of these networks means that many combinations of gene variants have the potential to cause system dysfunction that manifest as related neurobehavioural syndromes. Recent investigation has revealed that posttranscriptional gene regulation and associated small non-coding microRNA (miRNA), are likely to be important factors shaping the topography of these networks. miRNA display complex temporospatial expression patterns in the mammalian brain and have the potential to regulate thousands of target genes by functioning as the specificity factor for intracellular gene-silencing machinery. They are emerging as key regulators of many neurodevelopmental and neurological processes as their dysregulation could lead to pervasive changes in the network structure during development and in the mature brain that are highly significant in the pathophysiology of schizophrenia. This review looks at mounting evidence that mature miRNA levels are altered in both the cerebral cortex and peripheral blood mononuclear cells (PBMCs) in schizophrenia. It also examines compelling evidence that the underlying miRNA biogenesis machinery and miRNA genes themselves are subject to disease-associated genetic mutation and epigenetic influence. Significantly, these changes in miRNA expression and associated machinery may represent new targets for pharmaceutical development, and the identification of miRNA signatures in PBMCs suggest that miRNA biomarkers of schizophrenia may also provide the basis for new clinical diagnostics. These developments have tremendous potential and highlight the significance of this avenue of research. PMID- 22207192 TI - Effects of surgery and/or remifentanil administration on the expression of pERK1/2, c-Fos and dynorphin in the dorsal root ganglia in mice. AB - Tissue injury and/or opioids induce plastic changes in the spinal cord resulting in pain hypersensitivity; the contribution of the dorsal root ganglia (DRG) is poorly understood. We evaluated DRG phenotypic changes induced by surgery and/or remifentanil in a mice model of postoperative pain using as neuronal markers ERK1/2 and c-Fos; prodynorphin mRNA and dynorphin levels were also determined. We hypothesized that a correlation between nociception and DRG reactivity would occur. Surgery and/or remifentanil induced mechanical hypersensitivity, correlated with ERK1/2 phosphorylation and c-Fos expression in the DRG; changes were greater in the remifentanil + incision group and still present on day 14 (p < 0.01 vs. control). Intrathecal PD98059 (ERK1/2 inhibitor) partially reversed the mechanical hypersensitivity (44%, p < 0.05) observed in the remifentanil + incision group. In this group, significant increases in prodynorphin mRNA (at 2, 7, and 14 days, p < 0.01) roughly coincided with increases in dynorphin (days 2 and 14, p < 0.001) in the DRG. Remifentanil or incision (alone) also induced an up-regulation in prodynorphin mRNA expression on days 7 and 14 (p < 0.01, p < 0.05, respectively), partially correlating with dynorphin levels. On day 21, all molecular changes returned to control levels in all experimental conditions, concurring with the complete recovery of nociceptive thresholds. Surgery and/or remifentanil induce up-regulation of c-Fos and pERK in the DRG, approximately correlating with nociceptive behavior, also associated with an increased expression of prodynorphin/dynorphin. These changes support the role of the DRG in the development and maintenance of pain hypersensitivity after surgery. The findings could contribute to the development of new therapeutic agents focused on peripheral targets. PMID- 22207193 TI - Of possible cheminformatics futures. AB - For over a decade, cheminformatics has contributed to a wide array of scientific tasks from analytical chemistry and biochemistry to pharmacology and drug discovery; and although its contributions to decision making are recognized, the challenge is how it would contribute to faster development of novel, better products. Here we address the future of cheminformatics with primary focus on innovation. Cheminformatics developers often need to choose between "mainstream" (i.e., accepted, expected) and novel, leading-edge tools, with an increasing trend for open science. Possible futures for cheminformatics include the worst case scenario (lack of funding, no creative usage), as well as the best case scenario (complete integration, from systems biology to virtual physiology). As " omics" technologies advance, and computer hardware improves, compounds will no longer be profiled at the molecular level, but also in terms of genetic and clinical effects. Among potentially novel tools, we anticipate machine learning models based on free text processing, an increased performance in environmental cheminformatics, significant decision-making support, as well as the emergence of robot scientists conducting automated drug discovery research. Furthermore, cheminformatics is anticipated to expand the frontiers of knowledge and evolve in an open-ended, extensible manner, allowing us to explore multiple research scenarios in order to avoid epistemological "local information minimum trap". PMID- 22207194 TI - Epileptogenic networks in two patients with hypothalamic hamartoma. AB - Hypothalamic hamartomas (HH) are typically associated with gelastic seizures but also implicated in the genesis of other seizure types. In order to identify networks involved in seizure generation, we performed EEG-fMRI in two adult patients with HH, the first with predominantly gelastic seizures and the second with complex partial and no typical gelastic seizures. The ictal and interictal analysis of the patient with gelastic seizures revealed the involvement of the HH, the cingulate gyrus, the precuneus and the prefrontal cortex. The interictal analysis of the patient with complex partial seizures, showed changes in blood oxygen-level dependent signal over the temporal lobes, the base of the frontal lobe, the cingulate, the precuneus and the prefrontal cortex, but not the HH. The differences in the neural networks implicated may account for differences in clinical manifestation of seizures owing to HH. PMID- 22207197 TI - Reduction in sickness absence in patients with rheumatoid arthritis receiving adalimumab: data from a German noninterventional study. AB - The aim of this noninterventional study (NIS) was to analyze the changes in sickness absence, disease activity, and functional capacity in employed rheumatoid arthritis (RA) patients during adalimumab treatment. RA patients receiving adalimumab according to label instructions (40 mg every other week) were evaluated at regular intervals in a multicenter prospective NIS. Patients provided information on sickness absence in the 12 months preceding treatment initiation (baseline) and at months 6 and 12. Disease activity was assessed by the Disease Activity Score using 28 joints, and physical function was assessed via the Hannover Functional Ability Questionnaire, a patient self-questionnaire comparable with the Health Assessment Questionnaire-Disability Index. We present data on 1,157 patients who were employed (part time or full time) at baseline. Patients were categorized by the length of sickness absence at baseline. At baseline, patients with absences of 6 weeks or more in the previous year (n = 226 [19.5%]) accounted for 77% of the documented weeks of sickness absence, and patients with absences of more than 12 weeks (n = 98 [8.5%]) accounted for 54% of sickness absence weeks. During 12 months of adalimumab treatment, disease activity decreased, functional capacity improved, and sickness absence was reduced. The greatest decrease in sickness absence was observed in patients with more than 12 weeks of sick leave in the year prior to adalimumab therapy. These patients also showed gains in function comparable with those observed in other employed patients. We conclude that sustaining and improving functional capacity represent the key to preservation of work capability. PMID- 22207198 TI - Comment on: is Still's disease still one disease? A case of adult-onset Still's disease showing accumulation in the carotids and the large vessels of the legs on positron emission tomography: CT images. PMID- 22207199 TI - Sustained hypogammaglobulinemia under rituximab maintenance therapy could increase the risk for serious infections: a report of two cases. AB - We report two patients with granulomatosis with polyangiitis in remission with rituximab maintenance therapy with sustained hypogammaglobulinemia. Both patients had serious infections and were admitted to the intensive therapy unit. The patients had at least low IgM levels prior to the initiation of rituximab. They received cyclophosphamide and prednisolone at induction and at maintenance. They had lung affection, low level of both IgM and IgG and a cumulative dose of rituximab over 7 g at the time of the severe infection. Our patients have features similar to common variable immunodeficiency patients, and therefore prolonged very low levels of immunoglobulins could heighten the risk for severe infections. PMID- 22207200 TI - Trajectories of physical activity in Montreal adolescents from age 12 to 17 years. AB - BACKGROUND: Despite the benefits of physical activity, many Canadian adolescents are inactive and rates of inactivity increase with age. Few studies describe the pattern of change in physical activity as a function of age during adolescence. METHODS: Data were drawn from the Nicotine Dependence in Teens Study. The analytic sample included 1206 adolescents who completed a 7-day physical activity recall up to 4 times per year over 5 years. Individual growth models, analyzed using multilevel models for change, were developed separately by sex controlling for season. RESULTS: Physical activity levels through adolescence were best described by a cubic function. Levels increased from age 12 to a peak at approximately age 13.5, decreased to age 16.5, and increased again to age 17. Activity participation was highest in the spring and lowest during fall and winter. Substantial within- and between-subject heterogeneity in the trajectories was evident. CONCLUSION: Adolescent physical activity follows a complex, curvilinear pattern in both males and females, with considerable variation within and between-persons. PMID- 22207201 TI - Discovering genome regulation with 3C and 3C-related technologies. AB - It has been known for some time that eukaryotic genomic DNA is packaged in the form of highly organized chromatin in vivo. This organization is important not only to reduce the length of chromosomes during interphase but also because it represents a type of higher-order genome regulation mechanism. Indeed, spatial chromatin architecture is known to be important for transcription, DNA replication and repair. Chromosome structure can be observed at different scales and studied with a variety of complementary techniques. For example, microscopy can provide single cell information while technologies such as the chromosome conformation capture (3C) method and its derivatives can yield higher-resolution data from cell populations. In this review, we report on the biological questions addressed with 3C and 3C-related techniques and what has been uncovered to date. We also explore what these methods may further reveal about the regulation of genomic DNA activities. PMID- 22207195 TI - Regulation of reactive oxygen species generation in cell signaling. AB - Reactive oxygen species (ROS) including superoxide anion and hydrogen peroxide (H(2)O(2)) are thought to be byproducts of aerobic respiration with damaging effects on DNA, protein, and lipid. A growing body of evidence indicates, however, that ROS are involved in the maintenance of redox homeostasis and various cellular signaling pathways. ROS are generated from diverse sources including mitochondrial respiratory chain, enzymatic activation of cytochrome p450, and NADPH oxidases further suggesting involvement in a complex array of cellular processes. This review summarizes the production and function of ROS. In particular, how cytosolic and membrane proteins regulate ROS generation for intracellular redox signaling will be detailed. PMID- 22207202 TI - Mapping acetylation sites in E2A identifies a conserved lysine residue in activation domain 1 that promotes CBP/p300 recruitment and transcriptional activation. AB - E-proteins are basic helix-loop-helix transcription factors that function in cell type specification. The gene E2A encodes two E-proteins, E12 and E47, which are required in B-lymphopoiesis. E2A proteins can interact directly with the transcriptional co-activators and lysine acetyltranferases (KATs) CBP, p300 and PCAF to induce target gene transcription. Prior investigations have shown that the E2A-encoded isoform E2-5 is acetylated by CBP, p300 or PCAF in vitro or in vivo. However, E2-5 lacks the important N-terminal activation domain AD1. Furthermore, the acetylated residues in E-proteins have not been mapped, and the functional consequences of acetylation are largely unknown. Here, we use mutagenesis to show that a lysine residue at position 34 within AD1 of E12/E47 is acetylated by CBP/p300 and PCAF. Lys34 lies adjacent to a conserved helical LXXLL motif that interacts directly with the KIX domain of CBP/p300. We show that acetylation at Lys34 increases the affinity of AD1 for the KIX domain and enhances AD1-driven transcriptional induction. Our results illustrate for the first time that AD1 can both recruit, and be acetylated by, KATs and that KAT recruitment may promote transcriptional induction in part through acetylation of AD1 itself. PMID- 22207203 TI - New clues to understand the role of THO and other functionally related factors in mRNP biogenesis. AB - Coupling of transcription with mRNA processing and export has been shown to be relevant to efficient gene expression. A number of studies have determined that THO/TREX, a nuclear protein complex conserved from yeast to humans, plays an important role in mRNP biogenesis connecting transcription elongation, mRNA export and preventing genetic instability. Recent data indicates that THO could be relevant to different mRNA processing steps, including the 3'-end formation, transcript release and export. Novel connections of THO to proteins related to the splicing machinery, provide new views about possible functions of THO in mRNP biogenesis. In this review, we summarize the previous and new results concerning the impact of THO in transcription and its biological implications, with a special emphasis on the relationship with THSC/TREX-2 and other functionally related factors involved in mRNA biogenesis and export. The emerging picture presents THO as a dynamic complex interacting with the nascent RNA and with different factors connecting nuclear functions necessary for mRNP biogenesis with genome integrity, cellular homeostasis and development. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing. PMID- 22207205 TI - Relationship of cortical thickness of the proximal humerus and pullout strength of a locked plate and screw construct. AB - BACKGROUND: No study to date has evaluated cortical thickness as it relates to locking plate failure or screw pullout in the proximal humerus. The purpose of this study is to determine the relationship between proximal humerus cortical thickness and locked plate hardware failure in a cadaveric proximal humerus fracture model. METHODS: Twelve humerus specimens were placed into two groups based on the proximal humerus cortical thickness on an anteroposterior radiograph: less than 4 mm and greater than 4 mm. The specimens were plated with a six-hole proximal humerus locking plate and a 15-mm resection osteotomy at the surgical neck was performed. The specimens were tested in a materials testing machine at a displacement of 5 mm/min to failure. RESULTS: Load at failure, stiffness, maximum load, failure, and fracture gap closure were all statistically similar (P > 0.05) between the groups. CONCLUSION: Our biomechanical study used modern locked plate-screw construct fixation of a simulated two-part proximal humerus fracture. The mechanical strength was unaffected based on a threshold combined proximal humerus cortical thickness of 4 mm. PMID- 22207206 TI - Staged posterior tibial plating for the treatment of Orthopaedic Trauma Association 43C2 and 43C3 tibial pilon fractures. AB - OBJECTIVE: Obtaining an accurate reduction of the posterior malleolar fragment in high-energy pilon fractures can be difficult through standard anterior or medial incisions, resulting in a less than optimal articular reduction. The purpose of this study was to report on our results using a direct approach with posterior malleolar plating in combination with staged anterior fixation in high-energy pilon fractures. DESIGN: Prospective clinical cohort. SETTING: A Level I trauma and tertiary referral center. PATIENTS/PARTICIPANTS: From January 1, 2005, to December 31, 2008, 19 Orthopaedic Trauma Association 43C pilon fractures (16 C3 and 3 C2) with a separate, displaced, posterior malleolar fragment were treated by the authors. Nine patients were treated with posterior plating of the tibia (PL) through a posterolateral approach followed by a staged direct anterior approach. Ten patients with similar fracture patterns were treated using standard anterior or anteromedial incisions (A) with indirect reduction of the posterior fragment. All 19 patients were available for follow-up at an average of 40 months (range, 28-54 months). INTERVENTION: All patients were treated with open reduction and internal fixation for their pilon fractures. MAIN OUTCOME MEASUREMENTS: Quality of reduction was assessed using postoperative plain radiographs and computed tomography. Serial radiographs were taken during the postoperative course to assess the progression of healing and the development of joint arthrosis. Clinical follow-up included physical examination and evaluation of the ankle using the American Orthopaedic Foot and Ankle Society Ankle & Hindfoot score, Maryland Foot Score as well as noting all complications. RESULTS: There were no differences in injury pattern or time to surgery between groups. Of the 10 patients who were in the A group, 4 (40%) had more than 2 mm of joint incongruity at the posterior articular fracture edge as compared with no patients in the PL group as measured on postoperative computed tomography scans. At latest follow-up, 7 (70%) patients in the A group had radiographic evidence of joint space narrowing compared with 3 (33%) in the PL group. Ankle range of motion for the A group was 35.8 degrees versus 34.2 degrees for the PL group (nonsignificant). There were 2 delayed wound healing complications in the A group with one deep infection in the PL group. Two patients in the A group required arthrodesis procedures resulting from posttraumatic arthrosis compared with none in the PL group. No significant difference was seen in postoperative complications across both groups. The average Maryland Foot Score and American Orthopaedic Foot and Ankle Society/Ankle & Hindfoot score for the PL group was 86.4/85.2 compared with 69.4/76.4 for the A group. CONCLUSIONS: The addition of a posterior lateral approach offers direct visualization for reduction of the posterior distal fragment of the tibial pilon. Although the joint surface itself cannot be visualized, this reduction allows the anterior components to be secured to a stable posterior fragment at a later date. This technique improved our ability to subsequently obtain an anatomic articular reduction based on computed tomography scans and preservation of the tibiotalar joint space at a minimum 1 year follow-up. Furthermore, it correlated with an improvement in clinical outcomes with increases in Maryland Foot Score and Ankle & Hindfoot score for the posterior plating group. Although promising, continued follow-up will be needed to determine the long-term outcome using this technique for treating tibial pilon fractures. PMID- 22207204 TI - The interface of transcription and DNA replication in the mitochondria. AB - DNA replication of the mitochondrial genome is unique in that replication is not primed by RNA derived from dedicated primases, but instead by extension of processed RNA transcripts laid down by the mitochondrial RNA polymerase. Thus, the RNA polymerase serves not only to generate the transcripts but also the primers needed for mitochondrial DNA replication. The interface between this transcription and DNA replication is not well understood but must be highly regulated and coordinated to carry out both mitochondrial DNA replication and transcription. This review focuses on the extension of RNA primers for DNA replication by the replication machinery and summarizes the current models of DNA replication in mitochondria as well as the proteins involved in mitochondrial DNA replication, namely, the DNA polymerase gamma and its accessory subunit, the mitochondrial DNA helicase, the single-stranded DNA binding protein, topoisomerase I and IIIalpha and RNaseH1. This article is part of a Special Issue entitled: Mitochondrial Gene Expression. PMID- 22207207 TI - Optimizing adenoviral transduction of endothelial cells under flow conditions. AB - PURPOSE: To target adenoviral vectors to cells of the vasculature and shielding vectors from inactivation by the immune system. METHODS: Complexes of reporter gene expressing adenoviral vectors with positively charged magnetic nanoparticles were formed by electrostatic interaction in presence or absence of additional negatively charged poly(ethylene glycol)-based polymer. Transduction of HUVEC was analyzed in vitro under flow. Protection from inactivation by the immune system was analyzed by pre-incubation of AdV and complexes with neutralizing antibodies and subsequent reporter protein analysis of infected cells. RESULTS: Physical association of AdV with MNP and polymers was demonstrated by radioactive labelling of components and co-sedimentation in a magnetic field. Ad-MNP+/ polymer resulted in efficient transduction of HUVEC, depending on MOI and flow rate in presence of magnetic field, whereas no transduction was observed without complex formation with MNP or in absence of magnetic field. Association with MNP did result in protection from neutralizing antibodies, with slightly increased protection provided by the polymer. CONCLUSIONS: Complex formation of AdV with MNP is a viable means for targeting of vectors to areas of magnetic field gradient. Additional coating with polymer might proof useful in protection from inactivation by the immune system. PMID- 22207208 TI - Local gene targeting and cell positioning using magnetic nanoparticles and magnetic tips: comparison of mathematical simulations with experiments. AB - PURPOSE: Magnetic nanoparticles (MNPs) and magnets can be used to enhance gene transfer or cell attachment but gene or cell delivery to confined areas has not been addressed. We therefore searched for an optimal method to simulate and perform local gene targeting and cell delivery in vitro. METHODS: Localized gene transfer or cell positioning was achieved using permanent magnets with newly designed soft iron tips and MNP/lentivirus complexes or MNP-loaded cells, respectively. Their distribution was simulated with a mathematical model calculating magnetic flux density gradients and particle trajectories. RESULTS: Soft iron tips generated strong confined magnetic fields and could be reliably used for local (~500 MUm diameter) gene targeting and positioning of bone marrow cells or cardiomyocytes. The calculated distribution of MNP/lentivirus complexes and MNP-loaded cells concurred very well with the experimental results of local gene expression and cell attachment, respectively. CONCLUSION: MNP-based gene targeting and cell positioning can be reliably performed in vitro using magnetic soft iron tips, and computer simulations are effective methods to predict and optimize experimental results. PMID- 22207209 TI - Extract of Ganoderma lucidum prolongs sleep time in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (Ling Zhi) is a basidiomycete white-rot macrofungus that has been used as a tranquilizing agent (i.e., An-Shen effect) for the treatment of restlessness, insomnia, and palpitation in China for hundreds of years. AIM OF THE STUDY: The present study aimed to investigate whether Ganoderma lucidum extract (GLE) influences the sleep of freely moving rats and the potential mechanism. MATERIALS AND METHODS: Ganoderma lucidum extract was extracted from fruiting bodies of Ganoderma lucidum. Rats were treated with GLE orally for 3 days, and on the third day, electroencephalographic and electromyographic recordings were made for 6h from 9:00 p.m. to 3:00 a.m. in freely moving rats. Sleep parameters were analyzed using SleepSign software. Tumor necrosis factor-alpha (TNF-alpha) levels were measured using the enzyme linked immunosorbent assay. RESULTS: Three-day administration of GLE significantly increased total sleep time and non-rapid eye movement (NREM) sleep time at a dose of 80 mg/kg (i.g.) without influencing slow-wave sleep or REM sleep in freely moving rats. TNF-alpha levels were significantly increased concomitantly in serum, the hypothalamus, and dorsal raphe nucleus. The hypnotic effect of GLE (80 mg/kg, i.g.) was significantly inhibited by intracerebroventricular injection of TNF-alpha antibody (2.5 MUg/rat). Co administration of GLE (40 mg/kg, i.g.) and TNF-alpha (12.5 ng/rat, i.c.v.), both at ineffective doses, revealed an additive hypnotic effect. CONCLUSION: These results suggest that GLE has hypnotic effects in freely moving rats. The mechanism by which the extract promoted sleep remains unclear, but this effect appears to be primarily related to the modulation of cytokines such as TNF-alpha. Furthermore, these data at least partially support the ethnomedical use of Ganoderma lucidum. PMID- 22207210 TI - Role of cinnabar and realgar of WSHFD in protecting against LPS-induced neurotoxicity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Wan-Sheng-Hua-Feng-Dan (WSHFD) is a traditional Chinese medicine used for the treatment of neurological disorders. Cinnabar (HgS) and realgar (As(4)S(4)) are included in WSHFD. Are they remedies or poisons? AIM OF STUDY: To investigate the role of cinnabar and realgar in the protective effects of WSHFD on lipopolysaccharide (LPS)-induced neurotoxicity. MATERIALS AND METHODS: Rat primary midbrain neuron-glia cultures were used to explore the effects of WSHFD on LPS-induced dopamine (DA) neurodegeneration. The experiment was randomly divided into control, LPS, LPS+removed (cinnabar and realgar in WSHFD were removed), LPS+reduced (cinnabar and realgar in WSHFD were reduced by 65%) and LPS+original (10% cinnabar and 10% realgar in WSHFD) groups. Dopaminergic neurotoxicity was assessed by [(3)H]DA uptake assay and the quantification of tyrosine hydroxylase (TH)-positive neurons. Microglial activation was evaluated using an anti-OX-42 antibody. The release of intracellular reactive oxygen species (ROS) was quantified via the DCFH-DA probe. The transcripts and production of pro-inflammatory factors were examined by real time RT-PCR analysis and ELISA, respectively. RESULTS: WSHFD (original) significantly attenuated LPS-induced decrease of DA uptake capacity and TH positive neuron number, inhibited microglial activation, decreased LPS-induced ROS production, ameliorated LPS-induced elevations of the mRNA expressions of TNFalpha, iNOS, IL-1beta and COX-2 and the subsequent production of TNFalpha, NO, IL-1beta and PGE(2) in neuron-glia cultures. However, WSHFD (removed) and (reduced) failed to protect against LPS-induced neurotoxicity. CONCLUSION: Cinnabar and realgar were active ingredients of WSHFD in producing protective effects against LPS-induced neurotoxicity. PMID- 22207211 TI - Synergistic protective effect of astragaloside IV-tetramethylpyrazine against cerebral ischemic-reperfusion injury induced by transient focal ischemia. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Astragaloside IV and tetramethylpyrazine have been extensively used in the cardio-cerbrovascular diseases of medicine as a chief ingredient of glycoside or alkaloid formulations for the treatment of stroke and myocardial ischemia diseases. AIM OF THE STUDY: To investigate the effects of astragaloside IV (ASG IV) and tetramethylpyrazine (TMPZ) on cerebral ischemia-reperfusion (IR) injury model in rat model. MATERIALS AND METHODS: Rats were randomly divided into the following five groups: sham group, IR group and treatment group including ASG IV, ASG IV-TMPZ and nimodipine treatment. The therapeutic effect was evaluated by micro-positron emission tomography (Micro PET) using (18)F-fluoro-2-deoxy-d-glucose. The neurological examination, infarct volume and the levels of oxidative stress- and cell apoptosis-related molecules were assessed. RESULTS: Micro-PET imaging showed that glucose metabolism in the right hippocampus was significantly decreased in the IR group compared to the sham group (P<0.01). ASG IV and ASG IV-TMPZ treatments reversed the decreased glucose metabolism in the model group (P<0.05 and P<0.01, respectively). IR induced the increase of Caspase-3 mRNA levels, MDA content and iNOS activity, but it caused the decrease of SOD activity and Bcl-2 expression compared the sham group (P<0.01). ASG IV-TMPZ and ASG IV reversed the IR-induced changes of these parameters, i.e. the down regulation of Caspase-3 mRNA, MDA content and iNOS activity, and the up regulation of SOD activity and Bcl-2 expression (P<0.05). CONCLUSION: This study showed that ASG IV-TMPZ played a pivotal synergistic protective role against focal cerebral ischemic reperfusion damage in a rat experimental model. PMID- 22207212 TI - Overexpression of the PHO84 gene causes heavy metal accumulation and induces Ire1p-dependent unfolded protein response in Saccharomyces cerevisiae cells. AB - Pho84p, the protein responsible for the high-affinity uptake and transport of inorganic phosphate across the plasma membrane, is also involved in the low affinity uptake of heavy metals in the Saccharomyces cerevisiae cells. In the present study, the effect of PHO84 overexpression upon the heavy metal accumulation by yeast cells was investigated. As PHO84 overexpression triggered the Ire1p-dependent unfolded protein response, abundant plasma membrane Pho84p could be achieved only in ire1Delta cells. Under environmental surplus, PHO84 overexpression augmented the metal accumulation by the wild type, accumulation that was exacerbated by the IRE1 deletion. The pmr1Delta cells, lacking the gene that encodes the P-type ATPase ion pump that transports Ca(2+) and Mn(2+) into the Golgi, hyperaccumulated Mn(2+) even from normal medium when overexpressing PHO84, a phenotype which is rather restricted to metal-hyperaccumulating plants. PMID- 22207213 TI - Selection of a whole-cell biocatalyst for methyl parathion biodegradation. AB - Whole-cell biocatalyst has the potential to become a cost-effective alternative to conventional enzyme methods for solving ecological and energy issues. However, cytosolic-expressing biocatalyst systems are critically disadvantaged due to the low permeability of the cell membrane. To overcome substrate transport barrier, periplasmic secretion and surface display biocatalysts were developed by expressing signal peptides or anchor proteins in Escherichia coli. In this work, six carriers were compared in regard to whole-cell activity of methyl parathion hydrolase (MPH). Our results indicate that the surface display systems yielded one to three times whole-cell activity than the periplasmic secretion systems. Although periplasmic secretion systems showed generally more stable than surface display systems, surface display appeared more suitable for whole-cell biocatalyst. It should note that the applicability of the DsbA/PhoA/AIDA-I leader to MPH expression is shown here for the first time. In addition, the result provided a useful reference for other whole-cell biocatalyst selection. PMID- 22207214 TI - Production of bioactive, SUMO-modified, and native-like TNF-alpha of the rhesus monkey, Macaca mulatta, in Escherichia coli. AB - Biotechnologically produced tumor necrosis factor alpha (TNF-alpha) neutralizing agents have proven efficient in patients suffering from disparate autoimmune diseases. The rhesus monkey (Macaca mulatta) could be developed as a model for human autoimmune disease. Consequently, a large amount of M. mulatta TNF-alpha (mmTNFalpha) is required to further understand TNF-alpha-related pathogenesis and evaluate novel human TNF-alpha (hTNFalpha) neutralizing agents. We therefore attempted to express mmTNFalpha by using a small ubiquitin-like modifier (SUMO) fusion system. The synthetic gene, encoding the fusion protein SUMO-mmTNFalpha, was inserted into a pQE30 plasmid and was transformed into Escherichia coli M15. The fusion protein was expressed as both soluble and insoluble protein in E. coli. Approximately 10-12 mg of SUMO-mmTNFalpha was obtained from the soluble fraction of 1 L of bacterial culture. Cleavage of the fusion protein with SUMO protease produced native-like mmTNFalpha. Both native-like and SUMO-modified mmTNFalpha formed functional trimers and showed excellent cytotoxicity (ED(50), 0.05-0.1 ng/ml) in standard L929 cells. In addition, SUMO-mmTNFalpha and mmTNFalpha also exhibited cytotoxicity in human cancer cell types, such as, breast, lung, and liver cancer cells. The hTNFalpha neutralizing agents, including soluble receptors of hTNFalpha and antibodies against hTNFalpha, interacted with the mmTNFalpha. These results demonstrate that the bioactive mmTNFalpha produced with the SUMO fusion system is useful for further research, especially for the in vitro preclinical evaluation of biological hTNFalpha neutralizing agents. PMID- 22207215 TI - An ELISA based on the repeated foot-and-mouth disease virus 3B epitope peptide can distinguish infected and vaccinated cattle. AB - To develop a strategy of differentiating infected from vaccinated animals (DIVA) with foot-and-mouth disease virus (FMDV), a short (27aa) peptide containing three conserved linear B cell epitopes of the FMDV 3B nonstructural protein was designed. This novel BF peptide was synthesized using a gene splicing by overlap extension protocol with preferred codons for Escherichia coli. The resultant eight tandem repeat multimer (1, 2, 4, 6, 8, 16, 24, and 32BF) were expressed as soluble fusion proteins in E. coli. An indirect ELISA was developed based on the recombinant 8BF protein with the aim of specifically distinguishing antibodies induced by FMDV infection but not those induced by vaccination. Using the cut-off value of 0.3, the sensitivity of the assay was 96.8% and the specificities for naive and vaccinated cattle were 99.8 and 99.0%, respectively. The performance of the newly developed epitope-based ELISA was compared with three commercial NSP ELISA kits. The 8BF-ELISA appears to be a promising DIVA test for FMD control and eradication. PMID- 22207216 TI - Genes involved in alkane degradation in the Alcanivorax hongdengensis strain A-11 3. AB - Alcanivorax hongdengensis A-11-3 is a newly identified type strain isolated from the surface water of the Malacca and Singapore Straits that can degrade a wide range of alkanes. To understand the degradation mechanism of this strain, the genes encoding alkane hydroxylases were obtained by PCR screening and shotgun sequencing of a genomic fosmid library. Six genes involved in alkane degradation were found, including alkB1, alkB2, p450-1, p450-2, p450-3 and almA. Heterogeneous expression analysis confirmed their functions as alkane oxidases in Pseudomonas putida GPo12 (pGEc47DeltaB) or Pseudomonas fluorescens KOB2Delta1. Q PCR revealed that the transcription of alkB1 and alkB2 was enhanced in the presence of n-alkanes C(12) to C(24); three p450 genes were up-regulated by C(8) C(16) n-alkanes at different levels, whereas enhanced expression of almA was observed when strain A-11-3 grew with long-chain alkanes (C(24) to C(36)). In the case of branched alkanes, pristane significantly enhanced the expression of alkB1, p450-3 and almA. The six genes enable strain A-11-3 to degrade short (C(8)) to long (C(36)) alkanes that are straight or branched. The ability of A. hongdengensis A-11-3 to thrive in oil-polluted marine environments may be due to this strain's multiple systems for alkane degradation and its range of substrates. PMID- 22207217 TI - Performances of two biotrickling filters in treating H2S-containing waste gases and analysis of corresponding bacterial communities by pyrosequencing. AB - Two identical biotrickling filters named BTFa and BTFb were run in parallel to examine their performances in removing hydrogen sulfide. BTFa was filled with ceramic granules, and BTFb was filled with volcanic rocks. The results showed that BTFb was more robust than BTFa under acidic conditions. At empty bed residence times (EBRTs) of 20 and 15 s, the removal efficiency of BTFa was close to 100%. At EBRTs of 10 and 5 s, the removal efficiency of BTFa slightly decreased. The removal efficiencies of BTFa decreased by different degrees at the end of each stage, dropping to 94%, 81%, 60%, and 71%, respectively. However, the H(2)S removal efficiency in BTFb consistently reached 99% throughout the experiment. Pyrosequencing analyses indicated that members of Thiomonas dominated in both BTFs, but the relative abundance of Acidithiobacillus was higher in BTFb than in BTFa. PMID- 22207218 TI - Selenium-enriched probiotics improves murine male fertility compromised by high fat diet. AB - A total of 75 male mice were allotted to five groups of 15 each in a completely randomized experimental design to study the effects of probiotics, inorganic selenium, and selenium-enriched probiotics on male fertility in hyperlipidemic status. The mice in group 1 were fed a normal basal diet and served as negative control. The mice in group 2 were fed a high fat diet and served as positive control. The mice in groups 3, 4, and 5 were fed the high fat diet supplemented with probiotics, inorganic selenium, and selenium-enriched probiotics, respectively. The high fat diet was composed of 15% lard, 1% cholesterol, 0.3% cholic acid, and 83.7% basal diet. Over 90% of the selenium in the selenium enriched probiotics was present in forms of organic selenium. After the mice were fed these diets for 75 days, serumal total cholesterol, triglycerides, low density lipoprotein, high density lipoprotein, and testosterone levels, plus sperm index (count, motility and abnormalities), penis length, and weight and histopathology of testes were measured. The results showed that in the mice fed the high fat diet were significant (P < 0.01) elevations of serumal total cholesterol, triglycerides and low density lipoprotein, and decreases of high density lipoprotein. The high fat diet caused a decline in serumal testosterone level, reduced semen quality, and atrophy and degeneration of seminiferous tubules. No effects on penis length or relative weight of testis were observed. Supplementation of probiotics, inorganic selenium, or selenium-enriched probiotics to the high fat diet significantly alleviated (P < 0.05) the adverse effects of hyperlipidemia by reducing testicular tissue injury, increasing serumal testosterone level, and improving sperm indexes. It was concluded that hyperlipidemia had significant adverse effects on male fertility, which could be ameliorated at various degrees by feeding the diets supplemented with probiotics, inorganic selenium, or selenium-enriched probiotics. Selenium-enriched probiotics or inorganic selenium supplementation gave better results than probiotics supplementation and may be used to improve animal and human male fertility compromised by hyperlipidemia or obesity. PMID- 22207219 TI - Effects of chicken selenoprotein W on H2O2-induced apoptosis in CHO-K1 cells. AB - Selenoprotein W (SelW) is expressed in various tissues of many animals and acts as an oxidoreductase in mammals. However, little is known about the role of the SelW in birds. To investigate the role of the chicken SelW on H(2)O(2)-induced apoptosis in CHO-K1 cells, overexpression of a chicken SelW cell lines (CHO K1/SelW) were constructed. Using acridine orange/ethidium bromide (AO/EB) double staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assays, as well as WST-1 cell viability assay, we monitored the extent of the H(2)O(2)-induced apoptosis and detected the abundance of the caspase-3, caspase-8, and fas mRNA by real-time quantitative reverse transcription PCR (qPCR). We here found that overexpression of SelW cells, compared with the wild-type cells, resulted in a markedly decrease in sensitivity to H(2)O(2)-induced oxidative stress and had a lower apoptotic cell death in AO/EB and TUNEL assays. Cell viability revealed that overexpression of SelW cells had higher cell viability than wild-type cells. qPCR results found that overexpression of SelW cells had a lower levels of caspase-3, caspase-8, and fas mRNA than wild-type cells. Taken together, our findings suggested that SelW could reduce the oxidative damage induced by H(2)O(2) and had an important protective function in against oxidative damage. PMID- 22207221 TI - Targeting cancer metabolism--aiming at a tumour's sweet-spot. AB - Targeting cancer metabolism has emerged as a hot topic for drug discovery. Most cancers have a high demand for metabolic inputs (i.e. glucose/glutamine), which aid proliferation and survival. Interest in targeting cancer metabolism has been renewed in recent years with the discovery that many cancer-related (e.g. oncogenic and tumour suppressor) pathways have a profound effect on metabolism and that many tumours become dependent on specific metabolic processes. Considering the recent increase in our understanding of cancer metabolism and the increasing knowledge of the enzymes and pathways involved, the question arises: could metabolism be cancer's Achilles heel? During recent years, interest into the possible therapeutic benefit of targeting metabolic pathways in cancer has increased dramatically with academic and pharmaceutical groups actively pursuing this aspect of tumour physiology. Therefore, what has fuelled this revived interest in targeting cancer metabolism and what are the major advances and potential challenges faced in the race to develop new therapeutics in this area? This review will attempt to answer these questions by summarising recent developments in this field. We aim to illustrate why we, and others, believe that targeting metabolism in cancer presents such a promising therapeutic rationale. PMID- 22207220 TI - The ratio of sTfR/ferritin is associated with the expression level of TfR in rat bone marrow cells after endurance exercise. AB - Currently, it is unclear which index of haematological parameters could be used to most easily monitor iron deficiency during endurance training. To address this question, 16 male Wistar rats were randomly assigned to two groups: a sedentary group (n = 8) and an exercised group (n = 8). Initially, animals in the exercise group started running on a treadmill at a rate of 30 m/min, on a 0% grade, for 1 min/session. Running time was gradually increased by 2 min/day. The training plan was one session per day during the initial 2 weeks and two sessions per day during the third to ninth week. At the end of the 9-week experiment, we analysed the blood of the experimental animals for haemoglobin levels, erythrocyte numbers, haematocrit, serum iron levels, total iron binding capacity, transferrin saturation, serum ferritin levels and soluble transferrin receptor (sTfR) levels, and we calculated the ratio of sTfR/ferritin. Erythrocyte numbers, haemoglobin levels and haematocrit values were decreased after 9 weeks of exercise, but sTfR and sTfR/ferritin values were increased (P < 0.01 or P < 0.05). The training regime significantly increased TfR mRNA levels in the bone marrow cells of the exercised rats compared with the sedentary group (1.8 +/- 0.5 vs. 1.1 +/- 0.2, P < 0.01). These results revealed a significant correlation between TfR levels in the bone marrow cells and the ratio of sTfR/ferritin (r = 0.517; P < 0.01) and sTfR levels (r = 0.206; P < 0.05) in sedentary and exercised rats. In conclusion, we show that sTfR indices and the ratio of sTfR/ferritin could be useful indicators for monitoring iron deficiency during endurance training. PMID- 22207222 TI - New regulatory framework for cancer drug development. AB - Recent changes to non-clinical cancer guidelines offer a golden opportunity to expedite the translation of new anticancer drugs into the clinic. In this review we look at how these guidelines can be implemented and how they can be integrated with non-clinical and clinical study design to produce robust and safe clinical trials. PMID- 22207224 TI - It's time to say goodbye... (to the first-generation drug-eluting stent era). PMID- 22207225 TI - Repetita iuvant (repeating helps): why another paper on a new stent is important. PMID- 22207226 TI - Young interventionalists. PMID- 22207227 TI - Five-year clinical follow-up from the MISSION! Intervention Study: sirolimus eluting stent versus bare metal stent implantation in patients with ST-segment elevation myocardial infarction, a randomised controlled trial. AB - AIMS: To evaluate the clinical outcomes of sirolimus-eluting stent (SES) versus bare metal stent (BMS) implantation in patients with ST-segment elevation myocardial infarction (STEMI) at long-term follow-up. METHODS AND RESULTS: After five years, 310 STEMI patients randomly assigned to implantation of either SES or BMS, were compared. Survival rates were comparable between groups (SES 94.3% vs. BMS 92.8%, p=0.57), as were the rates of reinfarction (10.6% vs. 13.7%, p=0.40), freedom of death/re-MI (84.4% vs. 79.8%, p=0.29) and target vessel failure (14.9% vs. 21.7%, p=0.11). Likewise, rates of overall stent thrombosis (ST) (5.4% vs. 2.7%, p=0.28) and very late ST (4.1% vs. 0.7%, p=0.07) did not significantly differ between the SES- and BMS-group. In 184 patients with IVUS data, definite and definite/probable VLST was more common in those with late stent malapposition versus those without late stent malapposition (4.3% and 6.6% vs. no events [p=0.018 and p=0.004], respectively). The cumulative incidences of target vessel and target lesion revascularisation (TVR and TLR) were not significantly lower in the SES-group (11.2% vs. 17.9%, p=0.09 and 7.2% vs. 12.9%, p=0.08), as was the rate of clinically driven TLR (6.6% vs. 9.5%, p=0.30). CONCLUSIONS: SES implantation was neither associated with increased rates of major adverse cardiac events, nor with a reduction in re-intervention, compared to implantation of a BMS in patients with STEMI after five years. However, a trend of more very late stent thrombosis was observed after SES implantation (ISRCTN62825862). PMID- 22207228 TI - Predictors of early and late outcomes after everolimus and paclitaxel-eluting coronary stents. AB - AIMS: To evaluate whether the improved outcomes with newer generation drug eluting stents (DES) utilising thin-strut stents are consistent among different patient and angiographic subgroups. METHODS AND RESULTS: Clinical outcomes over three years were collected in the SPIRIT III trial comparing the XIENCE V(r) everolimus-eluting stents (EES) (Abbott Vascular, Santa Clara, CA, USA) to the TAXUS(r) paclitaxel-eluting stents (PES) (Boston Scientific, Natick, MA, USA). Potential predictors of adverse clinical outcomes were assessed using demographic, clinical, and procedural variables by logistic and Cox regression analyses. For three-year target vessel failure, the independent predictors identified by Cox regression were number of vessels treated (HR=2.19 [1.50, 3.19], p<0.0001), HbA1c (%) (HR=1.17 [1.05, 1.29], p=0.004), total cholesterol (>200 mg/dl) (HR=1.63 [1.13, 2.36], p=0.009), and female gender (HR=1.42 [1.01, 2.01], p=0.05). Logistic regression analysis identified the same predictors except for the female gender. The clinical results with EES compared to PES were consistent among the multiple subgroups examined with the possible exception of patients with diabetes. CONCLUSIONS: Clinical factors and stent type were the most important multivariable predictors of adverse clinical outcomes in this contemporary trial of first versus second generation DES. The benefit of the EES compared to the PES was consistent across a wide range of patient and angiographic subgroups with the possible exception of patients with diabetes. PMID- 22207229 TI - A comparative analysis of major clinical outcomes with drug-eluting stents versus bare metal stents in male versus female patients. AB - AIMS: To conduct a risk-adjusted gender-based analysis of clinical outcomes following drug-eluting stent (DES) versus bare metal stent (BMS) implantation in patients with coronary artery disease. METHODS AND RESULTS: We compared risk adjusted total mortality rate, myocardial infarction, and event-free survival (defined as freedom from death, myocardial infarction and/or repeat revascularisation) in a consecutive cohort of 7,662 patients undergoing percutaneous coronary intervention at our institution, including 1,835 (25.4%) women. Follow-up was six months to 6.2 years (mean: 3.5 years; median: 3.6 years). The women were older than men and more likely to suffer from diabetes, hypertension or congestive heart failure. Smokers were more often men, and men were more likely to have had prior coronary bypass surgery compared to women. A DES was used in 39.9% of males and 39.5% of females. Both genders derived a significant long-term clinical benefit from DES compared to BMS; advantages were observed for mortality (men: HR=0.78, 95% CI: 0.64-0.96, p=0.016; women: HR=0.62, 95% CI: 0.45-0.85, p=0.003) and major adverse cardiac events (men: HR=0.73, 95% CI: 0.63-0.84, p<0.001; women: HR=0.76, 95% CI: 0.52-0.84, p=0.001). Among BMS treated patients, women had worse cumulative clinical outcomes than men. DES eliminated the gender differences in cardiac prognosis. CONCLUSIONS: Our analysis indicated a profound prognostic advantage for DES versus BMS among both genders, though female patients appeared to derive the greatest benefit. PMID- 22207230 TI - Safety and effectiveness of the Catania Polyzene-F coated stent in real world clinical practice: 12-month results from the ATLANTA 2 registry. AB - AIMS: The pivotal ATLANTA first-in-man study showed the promising safety and efficacy profile of the novel CataniaTM stent in a population with ~20% American College of Cardiology/American Heart Association (ACC/AHA) type C coronary lesions. The ATLANTA 2 registry was designed to evaluate the 12-month safety and efficacy of the Catania stent in a broader real world scenario. METHODS AND RESULTS: The ATLANTA 2 registry was a prospective, non-randomised, single-arm study of patients with symptomatic ischaemic heart disease and de novo lesions of native coronary arteries. A total of 300 patients (396 lesions) were recruited and 482 Catania stents were implanted. At 12 months, major adverse cardiac events were 8.8%, mainly driven by target lesion revascularisation (6.5%). Cardiac death and non-fatal myocardial infarction occurred in 2.5% and 0.7% of patients, respectively. Subacute definite or probable stent thrombosis was 0.7%. No late stent thrombosis was recorded. Compared with patients treated with drug-eluting stents or bare metal stents in the study period, those treated with Catania stents experienced similar outcomes at one year. CONCLUSIONS: The 12-month results of the ATLANTA 2 registry confirmed the positive results of the ATLANTA first-in-man trial in a more complex population. A randomised trial is needed to assess the comparative value of the Catania stent over currently-used drug eluting stents or bare metal stents. PMID- 22207231 TI - Brain tumours among interventional cardiologists: a cause for alarm? Report of four new cases from two cities and a review of the literature. AB - AIMS: Interventional cardiologists who work in cardiac catheterisation laboratories are exposed to low doses of ionising radiation that could pose a health hazard. DNA damage is considered to be the main initiating event by which radiation damage to cells results in development of cancer. METHODS AND RESULTS: We report on four interventional cardiologists, all with brain malignancies in the left hemisphere. In a literature search, we found five additional cases and thus present data on six interventional cardiologist and three interventional radiologists who were diagnosed with brain tumours. All worked for prolonged periods with exposure to ionising radiation in the catheterisation laboratory. CONCLUSIONS: In interventional cardiologists and radiologists, the left side of the head is known to be more exposed to radiation than the right. A connection to occupational radiation exposure is biologically plausible, but risk assessment is difficult due to the small population of interventional cardiologists and the low incidence of these tumours. This may be a chance occurrence, but the cause may also be radiation exposure. Scientific study further delineating occupational risks is essential. Since interventional cardiologists have the highest radiation exposure among health professionals, major awareness of radiation safety and training in radiological protection are essential and imperative, and should be used in every procedure. PMID- 22207232 TI - How should I treat an iatrogenic aortic dissection as a complication of complex PCI? PMID- 22207233 TI - Tools & techniques: Above the knee angioplasty by transradial access. PMID- 22207234 TI - Tools & techniques: Below the knee interventions. PMID- 22207235 TI - Catheter-induced coronary dissection during optical coherence tomography investigation. PMID- 22207236 TI - Heterocatalytic Fenton oxidation process for the treatment of tannery effluent: kinetic and thermodynamic studies. AB - BACKGROUND, AIM, SCOPE: Treatment of wastewater has become significant with the declining water resources. The presence of recalcitrant organics is the major issue in meeting the pollution control board norms in India. The theme of the present investigation was on partial or complete removal of pollutants or their transformation into less toxic and more biodegradable products by heterogeneous Fenton oxidation process using mesoporous activated carbon (MAC) as the catalyst. MATERIALS AND METHODS: Ferrous sulfate (FeSO(4).7H(2)O), sulfuric acid (36 N, specific gravity 1.81, 98% purity), hydrogen peroxide (50% v/v) and all other chemicals used in this study were of analytical grade (Merck). Two reactors, each of height 50 cm and diameter 6 cm, were fabricated with PVC while one reactor was packed with MAC of mass 150 g and other without MAC served as control. RESULTS AND DISCUSSION: The oxidation process was presented with kinetic and thermodynamic constants for the removal of COD, BOD, and TOC from the wastewater. The activation energy (Ea) for homogeneous and heterogeneous Fenton oxidation processes were 44.79 and 25.89 kJ/mol, respectively. The thermodynamic parameters DeltaG, DeltaH, and DeltaS were calculated for the oxidation processes using Van't Hoff equation. Furthermore, the degradation of organics was confirmed through FTIR and UV-visible spectroscopy, and cyclic voltammetry. CONCLUSIONS: The heterocatalytic Fenton oxidation process efficiently increased the biodegradability index (BOD/COD) of the tannery effluent. The optimized conditions for the heterocatalytic Fenton oxidation of organics in tannery effluent were pH 3.5, reaction time-4 h, and H(2)O(2)/FeSO(4).7H(2)O in the molar ratio of 2:1. PMID- 22207237 TI - Assessing the removal of pharmaceuticals and personal care products in a full scale activated sludge plant. AB - PURPOSE: This study aimed to investigate the removal mechanisms of pharmaceutical active compounds (PhACs) and musks in a wastewater treatment plant (WWTP). Biological removal and adsorption in the activated sludge tank as well as the effect of UV radiation used for disinfection purposes were considered when performing a mass balance on the WWTP throughout a 2-week sampling campaign. METHODS: Solid-phase extraction (SPE) was carried out to analyse the PhACs in the influent and effluent samples. Ultrasonic solvent extraction was used before SPE for PhACs analysis in sludge samples. PhAC extracts were analysed by LC-MS. Solid phase microextraction of liquid and sludge samples was used for the analysis of musks, which were detected by GC-MS. The fluxes of the most abundant compounds (13 PhACs and 5 musks) out of 79 compounds studied were used to perform the mass balance on the WWTP. RESULTS: Results show that incomplete removal of diclofenac, the compound that was found in the highest abundance, was observed via biodegradation and adsorption, and that UV photolysis was the main removal mechanism for this compound. The effect of adsorption to the secondary sludge was often negligible for the PhACs, with the exceptions of diclofenac, etofenamate, hydroxyzine and indapamide. However, the musks showed a high level of adsorption to the sludge. UV radiation had an important role in reducing the concentration of some of the target compounds (e.g. diclofenac, ibuprofen, clorazepate, indapamide, enalapril and atenolol) not removed in the activated sludge tank. CONCLUSIONS: The main removal mechanism of PhACs and musks studied in the WWTP was most often biological (45%), followed by adsorption (33%) and by UV radiation (22%). In the majority of the cases, the WWTP achieved >75% removal of the most detected PhACs and musks, with the exception of diclofenac. PMID- 22207238 TI - Removal of cyanotoxins from surface water resources using reusable molecularly imprinted polymer adsorbents. AB - INTRODUCTION: Microcystins (MCs; cyclic heptapeptides) are produced by freshwater cyanobacteria and cause public health concern in potable water supplies. There are more than 60 types of MCs identified to date, of which MC-LR is the most common found worldwide. For MC-LR, the WHO has established a threshold value of 1 MUg L(-1) for drinking water. The present MCs removal methods such as coagulation, flocculation, adsorption, and filtration showed low efficiency for removing dissolved MC fraction from surface waters to the stipulated limit prescribed by WHO based on MC health impacts. The search for cost-effective and efficient removal method is still warranted for remediation of dissolved MC-LR contaminated water resources. MATERIALS AND METHODS: Molecularly imprinted polymer (MIP) adsorbent has been prepared using non-covalent imprinting approach. Using MC-LR as a template, itaconic acid as a functional monomer, and ethylene glycol dimethacrylate as a cross-linking monomer, a MIP has been synthesized. Computer simulations were used to design effective binding sites for MC-LR binding in aqueous solutions. Batch binding adsorption assay was followed to determine binding capacity of MIP under the influence of environmental parameters such as total dissolved solids and pH. RESULTS AND DISCUSSION: The adsorptive removal of MC-LR from lake water has been investigated using MIPs. The MIP showed excellent adsorption potential toward MC-LR in aqueous solutions with a binding capacity of 3.64 MUg mg(-1) which is about 60% and 70% more than the commercially used powdered activated carbon (PAC) and resin XAD, respectively. Environmental parameters such as total organic carbon (represented as chemical oxygen demand (COD)) and total dissolved solids (TDS) showed no significant interference up to 300 mg L(-1) for MC-LR removal from lake water samples. It was found that the binding sites on PAC and XAD have more affinity toward COD and TDS than the MC LR. Further, the adsorption capacity of the MIP was evaluated rigorously by its repeated contact with fresh lake water, and it was found that the adsorption capacity of the MIP did not change even after seven adsorption/desorption cycles. The contaminated water of MC-LR (1.0 MUg L(-1)) of 3,640 L could be treated by 1 g of MIP with an estimated cost of US $1.5. CONCLUSIONS: The adsorption capacity of the MIP is 40% more than commercially used PAC and resins and also the polymer showed reusable potential which is one of the important criteria in selection of cyanotoxins remediation methods. PMID- 22207239 TI - The use of date palm as a potential adsorbent for wastewater treatment: a review. AB - BACKGROUND: In tropical countries, the palm tree is one of the most abundant and important trees. Date palm is a principal fruit grown in many regions of the world. It is abundant, locally available and effective material that could be used as an adsorbent for the removal of different pollutants from aqueous solution. REVIEW: This article presents a review on the role of date palm as adsorbents in the removal of unwanted materials such as acid and basic dyes, heavy metals, and phenolic compounds. Many studies on adsorption properties of various low cost adsorbent, such as agricultural waste and activated carbons based on agricultural waste have been reported in recent years. CONCLUSION: Studies have shown that date palm-based adsorbents are the most promising adsorbents for removing unwanted materials. No previous review is available where researchers can get an overview of the adsorption capacities of date palm-based adsorbent used for the adsorption of different pollutants. This review provides the recent literature demonstrating the usefulness of date palm biomass-based adsorbents in the adsorption of various pollutants. PMID- 22207240 TI - Increased motivation to eat in opiate-withdrawn mice. AB - RATIONALE: In drug-dependent individuals, the primary excessive motivation is for drugs. Studies also indicate altered interest for "natural" rewarding activities associated with motivational disorders that may be relevant to drug dependence. However, to date, the impact of drug dependence and withdrawal upon motivation for "natural" rewards remains unclear. METHODS AND OBJECTIVES: In the present study, we use a food-driven operant behavior paradigm to assess the impact of opiate intake and withdrawal upon the motivational properties of highly palatable food (HPF) in mice. RESULTS: Our findings indicate that early (8-h) opiate withdrawal does not affect either the motivational or the discriminative properties of HPF intake. However, starting 32 h after the last morphine injection, opiate withdrawal increases operant behavior aimed at obtaining HPF. The increased HPF-driven behavior lasts at least 12 days following opiate withdrawal, indicating long-lasting effects upon motivation. Using a paradigm of reward contingency reversal, we also address the impact of opiate withdrawal upon cognitive functions. Our results indicate that opiate withdrawal does not affect the ability to learn a new operant rule to obtain HPF. Indeed, opiate withdrawal ameliorates the acquisition of the new HPF-driven operant task, most probably due to the persistent and long-lasting increased motivation. Finally, analysis of ambulatory activity and body weight (BW) changes reveal that motivational and cognitive effects are totally independent of caloric and/or motor effects of opiate dosing and withdrawal. CONCLUSIONS: These results clearly demonstrate that excessive opiate intake and withdrawal produces dramatic and long-lasting motivational disorders relevant to drug dependence. PMID- 22207241 TI - Drug-related cues exacerbate decision making and increase craving in heroin addicts at different abstinence times. AB - RATIONALE: Relapse is a persistent problem in the management of addiction. Drug related cues are powerful instigators of relapse. Impulsive decision making may contribute to relapse through a poorly considered assessment of the consequences of drug use. Drug cues robustly increase subjective craving, which is frequently associated with relapse. OBJECTIVE: The present study explored the effects of drug-related cues on decision making and craving in heroin addicts at different abstinence times: 1, 3, 12, and 24 months. METHODS: The 75 male participants were given 5 min exposure to neutral and drug-associated cues while decision making performance, craving, blood pressure, heart rate, and emotional state pre- and post-exposure were assessed. The Iowa Gambling Task was used to evaluate decision making ability in heroin addicts. RESULTS: Drug-related cues exacerbated impulsive decision making and increased craving, heart rate, and systolic pressure in heroin addicts at all abstinence times. CONCLUSIONS: Drug-related cues aggravated decision making and increased craving in former heroin addicts who had been drug-free for 1-24 months, which might have significant clinical implications for the prevention of relapse. PMID- 22207242 TI - Sensitivity to apomorphine-induced yawning and hypothermia in rats eating standard or high-fat chow. AB - RATIONALE: Feeding conditions modify sensitivity to indirect- and direct-acting dopamine receptor agonists as well as the development of sensitization to these drugs. OBJECTIVES: This study examined whether feeding condition affects acute sensitivity to apomorphine-induced yawning or changes in sensitivity that occur over repeated drug administration. Quinpirole-induced yawning was also evaluated to see whether sensitization to apomorphine confers cross-sensitization to quinpirole. METHODS: Drug-induced yawning was measured in different groups of male Sprague Dawley rats (n = 6/group) eating high (34.3%) fat or standard (5.7% fat) chow. RESULTS: Five weeks of eating high-fat chow rendered otherwise drug naive rats more sensitive to apomorphine- (0.01-1.0 mg/kg, i.p.) and quinpirole- (0.0032-0.32 mg/kg, i.p.) induced yawning, compared with rats eating standard chow. In other rats, tested weekly with apomorphine, sensitivity to apomorphine induced yawning increased (sensitization) similarly in rats with free access to standard or high-fat chow; conditioning to the testing environment appeared to contribute to increased yawning in both groups of rats. Food restriction decreased sensitivity to apomorphine-induced yawning across five weekly tests. Rats with free access to standard or high-fat chow and sensitized to apomorphine were cross-sensitized to quinpirole-induced yawning. The hypothermic effects of apomorphine and quinpirole were not different regardless of drug history or feeding condition. CONCLUSIONS: Eating high-fat chow or restricting access to food alters sensitivity to direct-acting dopamine receptor agonists (apomorphine, quinpirole), although the relative contribution of drug history and dietary conditions to sensitivity changes appears to vary among agonists. PMID- 22207243 TI - Rosuvastatin elicits KDR-dependent vasculogenic response of human placental stem cells through PI3K/AKT pathway. AB - The growth and plasticity of engrafted human mesenchymal stem cells is regulated by external stimuli. Rosuvastatin (RSV) promotes myocardial neovascularization and limits myocardial remodeling in patients with chronic heart failure (CHF). While these non-lipid benefits may in part depend on the activation of stem cells, experimental evidence that RSV directly elicits vasculogenic differentiation of human mesenchymal stem cells is still lacking. We assessed whether RSV may drive a gene program of vascular commitment and the secretion of trophic mediators with antiapoptotic, angiogenic and antifibrotic activities in human mesenchymal stem cells from full-term placentas (FMhMSCs). With real-time RT-PCR, immunofluorescence, chemiluminescence, Western blot analysis, and in vitro vasculogenesis assays, we show that RSV enhanced expression of vascular endothelial growth factor (VEGF), kinase insert domain receptor (KDR), encoding a major VEGF receptor, hepatocyte growth factor (HGF), and platelet-derived growth factor-BB (PDGF-BB) in a time- and dose-dependent manner. GATA-4 and Nkx-2.5 transcription was not affected. RSV enhanced capillary-like formation in vitro, but capillary-embedded FMhMSCs lacked endothelial marker expression, suggesting a role of pericyte-like elements in tube formation. In HUVEC/FMhMSC cocultures, RSV increases PDGFRbeta expression in FMhMSCs, and enhanced capillary density and organizational efficiency, promoting a long-lasting survival of tubular networks. RSV also activated PI3K-Akt pathway; the vasculogenic effects of the statin were abrogated following PI3K inhibition by LY294002. In conclusion, RSV-induced increase in capillary formation was dependent on VEGF and KDR. RSV promotes the activation of paracrine signals for vascular commitment of FMhMSCs through PI3K Akt pathway. This observation may pave the way to the use of RSV as a pharmacological enhancer of stem cell potential for cardiovascular cell therapy. PMID- 22207244 TI - Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways. AB - Epithelial sodium channels (ENaCs) are located on the apical surface of cells and funnel Na(+) ions from the lumen into the cell. ENaC function also regulates extracellular fluid volume as water flows across membranes accompanying Na(+) ions to maintain osmolarity. To examine the sites of expression and intracellular localization of ENaC, we generated polyclonal antibodies against the extracellular domain of human alpha-ENaC subunit that we expressed in E. coli. Three-dimensional (3D) confocal microscopy of immunofluorescence using these antibodies for the first time revealed that ENaCs are uniformly distributed on the ciliary surface in all epithelial cells with motile cilia lining the bronchus in human lung and female reproductive tract, all along the fimbrial end of the fallopian tube, the ampulla and rare cells in the uterine glands. Quantitative analysis indicated that cilia increase cell surface area >70-fold and the amount of ENaC on cilia is >1,000-fold higher than on non-ciliated cell surface. These findings indicate that ENaC functions as a regulator of the osmolarity of the periciliary fluid bathing the cilia. In contrast to ENaC, cystic fibrosis transmembrane conductance regulator (CFTR) that channels chloride ions from the cytoplasm to the lumen is located mainly on the apical side, but not on cilia. The cilial localization of ENaC requires reevaluation of the mechanisms of action of CFTR and other modulators of ENaC function. ENaC on motile cilia should be essential for diverse functions of motile cilia, such as germ cell transport, fertilization, implantation, clearance of respiratory airways and cell migration. PMID- 22207245 TI - Coordination of tongue activity during swallowing in mouth-breathing children. AB - Habitual mouth breathing is often accompanied by habitual anterior tongue thrust, instead of a lip closure, in order to create the anterior seal necessary for the initiation of physiological deglutition. We tested the null hypothesis of no significant influence of oral maneuver and the use of oral screens on tongue coordination and position during deglutition in 29 subjects (age = 6-16; mean = 9.69 years; 13/16 female/male) with habitual open-mouth posture using intraoral polysensography. The target parameters for swallowing were swallowing-associated nasal airflow interruption (NAI) and coordination of tongue-palate contact during NAI. Conventional myofunctional maneuvers could be facilitated and made more efficient, in terms of increasing the numbers of favorable early tongue-palate contacts typical of somatic swallowing, if accompanied by the application of an oral screen. Habitual open-mouth breathing does not necessarily coincide with distinctively pronounced proportions of late tongue-palate contact. PMID- 22207246 TI - Pharyngeal dysphagia in inflammatory muscle diseases resulting from impaired suprahyoid musculature. AB - Dysphagia has previously been reported in the inflammatory myopathies (IMs): inclusion body myositis (IBM), dermatomyositis (DM), and polymyositis (PM). Patients report coughing, choking, and bolus sticking in the pharynx. Myotomy has been the treatment of choice, with variable success reported. We sought to determine underlying causes of dysphagia in IM patients using instrumental evaluation. Eighteen subjects participated in the study: four with DM, six with PM, and eight with IBM. They underwent simultaneous videofluoroscopy and manometry, yielding 214 swallows for analysis regarding function of the upper esophageal sphincter (UES), swallow initiation, hyolaryngeal excursion, and pharyngeal residue. Penetration and aspiration were also recorded. UES failed to relax in two participants. High incidence of pharyngeal dysphagia was noted; 72% of participants demonstrated abnormalities, including delayed swallow initiation (24%), decreased hyolaryngeal excursion (22%), pyriform residue (17%), and penetration (22%). Dysphagia in IM patients appears to be more due to impaired muscle contraction and reduced hyolaryngeal excursion than the often held belief of failed UES relaxation. The distinction between mechanisms causing patients' dysphagia should be examined, particularly if CP myotomy is being considered as it may be contraindicated for patients with normal UES relaxation. More studies investigating IM patients pre- and post-myotomy are needed. PMID- 22207247 TI - Resting cerebral metabolism correlates with skin conductance and functional brain activation during fear conditioning. AB - We investigated whether resting brain metabolism can be used to predict autonomic and neuronal responses during fear conditioning in 20 healthy humans. Regional cerebral metabolic rate for glucose was measured via positron emission tomography at rest. During conditioning, autonomic responses were measured via skin conductance, and blood oxygen level dependent signal was measured via functional magnetic resonance imaging. Resting dorsal anterior cingulate metabolism positively predicted differentially conditioned skin conductance responses. Midbrain and insula resting metabolism negatively predicted midbrain and insula functional reactivity, while dorsal anterior cingulate resting metabolism positively predicted midbrain functional reactivity. We conclude that resting metabolism in limbic areas can predict some aspects of psychophysiological and neuronal reactivity during fear learning. PMID- 22207249 TI - Chilblain lupus induced by TNF-alpha antagonists: a case report and literature review. AB - We report the case of a 72-year-old man with history of ankylosing spondylitis, who, during the treatment with infliximab, developed painful, erythematous violaceous plaques with later development of ulcers on his feet associated with cold exposure. Concomitantly with the appearance of these lesions, he presented increased antinuclear antibodies (ANA) titers, positivity for anti-DNA and IgM anticardiolipin antibodies, low complement levels, polyclonal hypergammaglobulinemia, and lymphopenia. He was diagnosed of chilblain lupus induced by infliximab, this agent was withdrawn and initiated treatment for chilblains with improvement of lesions. On reviewing of the literature, we found seven reported cases of tumor necrosis factor alpha (TNF-alpha) antagonists induced chilblain lupus, all in rheumatoid arthritis patients and four of them with clinical and immunological characteristics available are presented and compared with our case. Although it is infrequent, chilblain lupus forms part of the spectrum of TNF-alpha antagonists-induced lupus erythematosus; usually is limited to skin without progression to systemic lupus erythematosus; presents ANA, anti-DNA, and antinucleosome antibodies positivity as more frequent immunological alterations; and responds appropriately to the specific treatment, TNF-alpha antagonists withdrawal being not necessary in almost all cases. PMID- 22207250 TI - Effect of music on anxiety and pain during joint lavage for knee osteoarthritis. AB - Joint lavage for knee osteoarthritis is an invasive procedure that can be stressful and painful. We aimed to assess the impact of music therapy on perioperative anxiety, pain and tolerability of the procedure in patients undergoing joint lavage performed with two needles. We randomized all patients diagnosed with knee osteoarthritis and undergoing joint lavage in our department from November 2009 to October 2010 to an experimental group listening to recorded music or a control group receiving no music intervention. Perioperative anxiety and pain related to the procedure were self-reported on a visual analogic scale (0-100 mm visual analog scale [VAS]), and heart rate and blood pressure were measured during the procedure. Tolerability was assessed on a four-grade scale directly after the procedure. We included 62 patients (31 in each group). Mean age was 68.8 +/- 12.6 years (72% females). As compared with the control group, the music group had lower levels of perioperative anxiety (40.3 +/- 31.1 vs. 58.2 +/- 26.3 mm; p = 0.046) and pain related to the procedure (26.6 +/- 16.2 vs. 51.2 +/- 23.7 mm; p = 0.0005). Moreover, heart rate was lower in the music group (69.5 +/- 11.4 vs. 77.2 +/- 13.2; p = 0.043) but not diastolic or systolic blood pressure. Tolerability was higher in the music group (p = 0.002). Music is a simple and effective tool to alleviate pain and anxiety in patients undergoing joint lavage for knee osteoarthritis. PMID- 22207251 TI - Effects of socioeconomic status and acculturation on accelerometer-measured moderate-to-vigorous physical activity among Mexican American adolescents: findings from NHANES 2003-2004. AB - BACKGROUND: Socioeconomic status (SES) and acculturation are potential contributors of adolescent physical activity disparity among ethnic groups in the U.S. However, studies relying on self-report physical activity measures have reported inconsistent findings regarding sociocultural predictors of physical activity. Therefore, the current study examined the main and interactive effects of SES and acculturation on accelerometer-measured moderate-to-vigorous intensity physical activity (MVPA) among Mexican American adolescents. METHODS: The National Health and Nutrition Examination Survey 2003-2004 was analyzed. Samples of 153 and 169 Mexican American boys and girls, respectively, were analyzed. SES was indicated by poverty-to-income ratio (PIR); and acculturation was measured by 5-item English preference scales and adolescent and parental country of birth. Regression models were tested separately for boys and girls. RESULTS: U.S.-born boys compared with immigrants did more MVPA (beta = .48, P < .01). On the contrary, the effect of English preference on MVPA in boys was negative (beta = .05, P < .01) and amplified by higher SES (beta = -.02, P < .01). For girls, none of the tested variables were significant. CONCLUSIONS: Higher SES was a risk factor for physical inactivity in Mexican American adolescents, by a moderating mechanism. In addition, physical activity promotion efforts need to consider English speaking and immigrant Mexican American adolescent boys as a target population. PMID- 22207253 TI - Transitional cell carcinoma of the upper urinary tract: optimizing image interpretation with 3D reconstructions. AB - PURPOSE: This article reviews the pathophysiology of transitional cell carcinoma (TCC), CT urography (CTU) protocols, different possible 3D reconstruction techniques, and the importance of 3D reconstructions for appropriate interpretation. RESULTS/CONCLUSION: CTU has largely replaced conventional IV pyelography in the evaluation of the upper urinary tract for TCC. The majority of large lesions can be easily seen on standard axial images with multiplanar reformats. However, it is imperative to also use 3D reconstructions when interpreting these studies, as subtle lesions can be difficult to visualize on the more traditional images. In this pictorial essay, we present multiple cases of upper urinary tract TCC which illustrate the value of 3D reconstructions for increasing the conspicuity of lesions, particularly at the junction of the infundibulum and calyx and in the ureters. As these cases demonstrate, each of the three possible 3D reconstruction techniques (maximum intensity projection, volume rendering, and volume rendered "virtual ureteroscopy") has its own distinct advantages, although the pitfalls of each technique must also be kept in mind. PMID- 22207254 TI - Association between lifting weights and metabolic syndrome among U.S. Adults: 1999-2004 National Health and Nutrition Examination Survey. AB - The purpose of this cross-sectional study was to determine the proportion of U.S. adults who participate in the resistance exercise modality of lifting weights (LWs) by demographic characteristics and to investigate the impact of LWs on the prevalence and risk of metabolic syndrome (MetS) in a national representative sample of U.S. adults. The sample (n = 5,618) in this cross-sectional study included adults aged >=20 years who participated in the 1999-2004 National Health and Nutrition Examination Survey. Approximately twice as many men (11.2%; 95% confidence interval [CI] 9.5, 13.1) reported LWs as women did (6.3%; 95% CI 5.2, 7.6) with non-Hispanic Whites (9.6%; 95% CI 8.1, 11.4) reporting the highest levels and Mexican Americans reporting the lowest levels (5.6%; 95% CI 4.4, 7.2) of engaging in LWs. Additionally, higher levels of socioeconomic status were associated with greater levels of self-reported LWs. MetS prevalence was found to be significantly lower among U.S. adults reporting LWs (24.6%; 95% CI 19.3, 30.9) compared with adults not reporting LWs (37.3%; 95% CI 35.5, 39.2) with associated risk reductions of 58% (p < 0.001) and 37% (p < 0.01) in the unadjusted model and model adjusted for demographic variables, respectively. These findings suggest that LWs may play a role in reducing the prevalence and risk of MetS among U.S. adults. Therefore, exercise professionals should strongly encourage the activity of LWs among adults of all ages to promote metabolic health and focus programs designed to increase the adoption of LWs among the subgroups who report the lowest levels of LWs. PMID- 22207252 TI - Lessons learned from phagocytic function studies in a large cohort of patients with recurrent infections. AB - BACKGROUND: There is a paucity of data on the relationship between demographic characteristics, specific clinical manifestations, and neutrophil dysfunction, guiding physicians to decide which clinical signs and symptoms are a code for an underlying phagocytic disorder. METHODS: The data over a 21-year period of all adult and pediatric patients referred to our Laboratory for Leukocyte Functions with recurrent pyogenic infections were analyzed. Neutrophil function studies included chemotaxis, superoxide production (SOP), bactericidal activity (BA), and specific studies in case of suspected primary phagocytic disorder (PPD). RESULTS: Neutrophil dysfunction was found in 33.6% of 998 patients; chemotaxis in 16.6%, SOP in 6%, and BA in 24.5%. The younger the patient and the more organ systems involved, the greater the probability of finding phagocytic impairment. Impaired chemotaxis correlated with recurrent aphthous stomatitis, infections associated with elevated IgE, and purulent upper respiratory tract infections. Impaired SOP and BA correlated with deep-seated abscesses, recurrent lymphadenitis, sepsis, and bone and joint and central nervous system infections. PPDs were identified in 5.7%, chronic granulomatous disease in 4.8%, neutrophil glucose-6-phosphate dehydrogenase deficiency in 0.3%, leukocyte adhesion deficiency type 1 in 0.4%, and myeloperoxidase deficiency in 0.2%. Phagocytic evaluation contributed to the diagnosis of hyperimmunoglobulin-E syndrome (n = 21) and Chediak-Higashi syndrome (n = 3). CONCLUSIONS: PPDs are identified in 5.7% of patients with recurrent pyogenic infections; in the remainder, phagocytic dysfunction may be related to deleterious effects of persistent infection, drug consumption, or disorders not yet established. PMID- 22207255 TI - Comparison of two aerobic field tests in young tennis players. AB - This study compares the maximal responses of a new aerobic tennis field test, the NAVTEN to a known aerobic field test, often used with young tennis players, that is, the continuous multistage 20-m shuttle run test (20-m SRT). The NAVTEN is an intermittent (1-minute/1-minute) multistage test with side-to-side displacements and ball hitting. Ten young elite tennis players aged 12.9 +/- 0.3 (mean +/- SD) randomly performed both tests and were continuously monitored for heart rate (HR) and oxygen uptake (V[Combining Dot Above]O2) using the Vmax ST (Sensormedics). The 20-m SRT and NAVTEN show similar HRpeak (202 +/- 6.1 vs. 208 +/- 9.5, respectively) and V[Combining Dot Above]O2peak (54.2 +/- 5.9 vs. 54.9 +/- 6.0 ml.kg.min). Pearson correlations between both tests were 0.88 and 0.92 for V[Combining Dot Above]O2peak and maximal speed, respectively. The NAVTEN yielded V[Combining Dot Above]O2peak values that are typical for active subjects of that age and are similar to the 20-m SRT supporting its use to measure aerobic fitness of young tennis players in specific and entertaining field conditions. The fact that two-thirds of the tennis players achieved a different ranking (+/-1 rank) with the NAVTEN and the 20-m SRT suggests that the NAVTEN may be more specific than the 20-m SRT to assess aerobic fitness of tennis players. From a practical point of view, the NAVTEN test is more specific and pedagogical for young tennis players even though both tests yield similar maximal values. PMID- 22207256 TI - Transversus abdominis activation during a side-bridge exercise progression is similar in people with recurrent low back pain and healthy controls. AB - Low back pain (LBP) affects 70-80% of the population. The transversus abdominis (TrA) has been implicated as part of the cause of LBP. Prevention and rehabilitation of LBP often target the TrA using exercises such as the side bridge accompanied with the abdominal drawing-in maneuver (ADIM). However, it is unknown whether individuals with recurrent LBP, when they are in a period of no pain, are able to activate the TrA and healthy individuals during this exercise. The purpose of our study was to compare the activation ratio of the TrA during a 5-level side-bridge exercise progression. Twenty-three subjects with a history of recurrent, nonspecific LBP, but not experiencing an exacerbation of symptoms and 24 healthy controls volunteered. All the subjects performed the ADIM and side bridge exercises with clinician feedback (verbal cueing). Each participant performed the side-bridge exercise progression while ultrasound images were taken. The subjects were only progressed if they successfully completed the previous level. The thickness of the TrA was measured in rested and contracted states at each exercise level to find the activation ratio (TrA contracted/TrA rest). Separate analyses of covariance did not reveal a difference in activation ratios between groups (p > 0.40) when the ratio at the lowest level was used as the covariate. The results from this study indicate that both groups were able to contract the TrA with verbal cueing during a side-bridge exercise progression. Because the TrA contracted similarly during exercise in both groups, the association of LBP with the TrA may be because of another mechanism, such as delayed activation in the feed-forward mechanism during activity or a lack of endurance of the TrA. PMID- 22207257 TI - The relationship between short- and long-distance swimming performance and repeated sprint ability. AB - The purpose of this study was to determine indices of repeated sprint ability (RSA) during a repeated sprint swimming test (RST), to compare these with previous similar running and cycling RST, and to correlate these indices with the best short (100 m, as an index of anaerobic performance) and long (2,000 m, as an index of aerobic performance) distance swimming times in 20 elite, national team level, male swimmers. Indices of RSA included the ideal sprint time (IS), the total sprint time (TS), and the performance decrement (PD) recorded during an 8 * 15-m swimming RST. The PD during the present swimming RST (4.7 +/- 2.3%) was similar to that in previous running or cycling RSTs. However, the physiological responses after the swimming RST (heart rate 168 +/- 7 b.min(-1) and blood lactate concentration 5.5 +/- 2.0 mmol.L(-1)) were lower than typical responses after running or cycling RSTs. There was no significant relationship between any of the RST performance indices and either the 100-m or 2,000-m swimming results. Multiple regression analysis indicated that the 3 RST indices (IS, TS, and PD), contributed 36% of the variance of the 2,000-m, but not the 100-m, swimming time. A strong correlation was found between the 100- and 2,000-m swim times (r = 0.74, p < 0.05). The results suggest that RSA in swimmers is a specific quality that cannot predict short- or long-distance swim performance. The significantly strong relationship between the 100- and 2,000-m swim times is unique for swimming. PMID- 22207258 TI - Salivary hormonal responses and performance changes during 15 weeks of mixed aerobic and weight training in elite junior wrestlers. AB - To prepare efficiently for competition, wrestlers usually train physically for a period of approximately 12-20 weeks. Numerous physical qualities must be developed during this period of preparation: aerobic fitness, maximal strength, muscular endurance, power, and speed. However, numerous studies have concluded that it is difficult to concurrently develop strength and aerobic fitness for several reasons, in particular antagonistic endocrine variations. The study involved 15 elite junior wrestlers who trained at a sports training school for 15 weeks. To investigate the effects of long-term training and to assess the relationships between hormonal concentrations (salivary testosterone [T] and cortisol [C]) and performance changes during simultaneous strength and aerobic fitness training, 6 saliva samples and 3 physical tests and 2 measures of body composition were made during the training period. Wrestlers had a significant increase (+1.5 kg) in body weight without changes in percentage body fat. Apart from the 20-m maximal shuttle speed, all performances increased significantly during the 15 weeks of training: maximum mechanical power output (Pmax: +12.8%), mean power during 30 seconds (Pmean: +10.8%), bench press (+5.7%), squat (+23.1%), power clean (+6.1%), time to 3,000- and 30-m sprints (-3.6, -1.3% respectively). During the period that the C increased, there was no significant variation for the T. The T/C ratio followed a variation pattern contrary to that of the C. We found strong correlations between salivary T, C, and T/C and the variation in explosive strength. Our results suggest that data about subjects' salivary C, T, and T/C may be employed to optimize the training process for sports people who need to develop strength and aerobic fitness simultaneously. PMID- 22207259 TI - Physical fitness factors to predict female Olympic wrestling performance and sex differences. AB - To determine differences in anthropometric, body composition, physiological and neuromuscular markers between elite and amateur female wrestlers, 35 female wrestlers were assigned into 4 groups according to their body mass (light and middle weight) and their competitive level (elite and amateur): light weight (between 49 and 58 kg) in elite (n = 6) and amateur (n = 12) levels, and middle weight (between 58 and 67 kg) in elite (n = 7) and amateur (n = 10) levels. A binary logistic regression analysis was performed to identify which variables better predict female wrestling success. Elite female wrestlers were older (8 10%), had more training experience (27-29%), fat-free mass (3%), maximum strength in absolute and allometrically scaled values (13-33%), maximal muscle power (16 34%), mean and peak power during an arm crank Wingate testing in absolute and allometrically scaled values (17-23%), jumping height (2-9%) and grip (5-13%), and back isometric strength (10-13%) compared with amateur wrestlers (p < 0.05). When the results of the present research and those of a recent study performed in our laboratory with elite male wrestlers were compared, elite women presented lower (p < 0.05) maximum isometric and dynamic strength, muscle power output, and anaerobic metabolism values even when these data were normalized using allometric methods. PMID- 22207260 TI - Attack and serve performances according to the match period and quality of opposition in elite volleyball matches. AB - The purpose of this study was to examine attack and serve performances in the beginning and end of the initial and final sets of volleyball matches according to the quality of opposition. Six hundred rallies from the Men's World Cup 2007 were selectively sampled from a total of 5,117 rallies observed using video match analysis. Rally-by-rally double moving averages of serve and attack efficacy were plotted by 4 different match periods (first 15 rallies of the initial set; first 15 rallies of the final set; last 15 rallies of the initial set; and last 15 rallies of the final set). Approximate entropy values were calculated to analyze the amount of data randomness. The results were examined according to the quality of opposition in 2 types of games: higher level (HIGH) including the first 4 ranked teams and lower level (LOW) composed of the last 5 ranked teams. The results suggested that volleyball matches presented different profiles depending on the match period. Considering the teams' level, a greater adaptation was found within the HIGH * HIGH matches according to the match period and a more strategic use of the serve and attack tactics taking into account the type of the set (initial or final set) and the period (beginning or end of the set). The findings emphasize the need for coaches and players to perceive the most important points at the end of the set and to manage their effort throughout the match attempting to reach this period in optimal condition. Therefore, it might be beneficial to coaches to stress the need to perform at the highest level, particularly at the end of the training drills that simulate competition scenarios. PMID- 22207261 TI - Mechanical demands of kettlebell swing exercise. AB - The aims of this study were to establish mechanical demands of kettlebell swing exercise and provide context by comparing them to mechanical demands of back squat and jump squat exercise. Sixteen men performed 2 sets of 10 swings with 16, 24, and 32 kg, 2 back squats with 20, 40, 60, and 80% 1-repetition maximum (1RM), and 2 jump squats with 0, 20, 40, and 60% 1RM. Sagittal plane motion and ground reaction forces (GRFs) were recorded during swing performance, and GRFs were recorded during back and jump squat performances. Net impulse, and peak and mean propulsion phase force and power applied to the center of mass (CM) were obtained from GRF data and kettlebell displacement and velocity from motion data. The results of repeated measures analysis of variance showed that all swing CM measures were maximized during the 32-kg condition but that velocity of the kettlebell was maximized during the 16-kg condition; displacement was consistent across different loads. Peak and mean force tended to be greater during back and jump squat performances, but swing peak and mean power were greater than back squat power and largely comparable with jump squat power. However, the highest net impulse was recorded during swing exercise with 32 kg (276.1 +/- 45.3 N.s vs. 60% 1RM back squat: 182.8 +/- 43.1 N.s, and 40% jump squat: 231.3 +/- 47.1 N.s). These findings indicate a large mechanical demand during swing exercise that could make swing exercise a useful addition to strength and conditioning programs that aim to develop the ability to rapidly apply force. PMID- 22207262 TI - Neural contributions to concentric vs. eccentric exercise-induced strength loss. AB - The purpose of this study was to examine the strength, electromyographic (EMG), and mechanomyographic (MMG) responses after workouts designed to elicit fatigue and muscle damage vs. only fatigue. Thirteen men (mean +/- SD age = 23.7 +/- 2.2 years) performed 6 sets of 10 maximal concentric isokinetic (CONexercise) or eccentric isokinetic (ECCexercise) muscle actions of the dominant forearm flexors on 2 separate days. Before (PRE) and after (POST) these workouts, peak torque (PT), surface EMG, and MMG signals were measured during maximal concentric isokinetic, eccentric isokinetic, and isometric muscle actions of the forearm flexors. The subjects also visited the laboratory for a control (CTL) visit with quiet resting between the PRE and POST measurements, rather than performing the CONexercise or ECCexercise. The results showed that there were significant 26 and 25% decreases in PT after the CONexercise and ECCexercise, respectively, and these decreases were statistically equivalent for the concentric, eccentric, and isometric muscle actions. There were also 19 and 23% reductions in normalized EMG amplitude after the CONexercise and ECCexercise, respectively, but no changes in EMG mean frequency (MNF), MMG amplitude, or MMG MNF. These findings demonstrated a neural component(s) to the strength decrement after CONexercise and ECCexercise. It is possible that after these 2 types of exercise, activation of free nerve endings that are sensitive to muscle damage and pH changes resulted in inhibition of alpha motor neurons, causing decreased muscle activation and torque. These findings suggest that training programs designed to minimize strength loss during competition should consider the fact that at least some of this loss is because of neural factors. PMID- 22207263 TI - Moderate running and plyometric training during off-season did not show a significant difference on soccer-related high-intensity performances compared with no-training controls. AB - Several investigators have reported the effects of reduced training and interrupted training on athletic performance, but few reports are available for soccer players. The purpose of this study was to examine, using the Yo-Yo intermittent recovery level 2 (YoYoIR2) test and sprint performance, the effects on soccer players of a reduced training program consisting of either moderate running training, plyometric training. After the completion of a competitive season, 29 male soccer players were divided into 3 groups: the running group (n = 13), the plyometric group (n = 11), and the control group (n = 5). Both training groups completed either running or plyometric training sessions 2 d.wk(-1) for 3 weeks, whereas the control group was not allowed to perform any training. The subjects performed YoYoIR2 and 20-m sprint tests before (pre) and after (post) the experimental period. Neither training group showed any significant training effects on the YoYoIR2 performance or 20-m sprint times compared with the control group. This study suggests that neither endurance running nor plyometric training 2 d.wk(-1) for 3 weeks has a significant effect on high-intensity performance compared with a nontraining regimen. However, our results do not support complete inactivity. These results may have important implications for the management of training cessation for a few weeks. PMID- 22207265 TI - Homelessness and health care disparities among lesbian, gay, bisexual, and transgender youth. PMID- 22207266 TI - US healthcare executives hit pay jackpot. PMID- 22207267 TI - NHS hospitals will be able to raise up to half their income from private patients. PMID- 22207268 TI - Demonstration of intrahepatic accumulated microbubble on ultrasound represents the grade of hepatic fibrosis. AB - OBJECTIVES: To examine the feasibility of perflubutane-based ultrasound for grading hepatic fibrosis. METHODS: This prospective study included 202 subjects; main study (controls:33, F0-1:35, F2:26, F3:23, cirrhosis:29) and subsequent study (controls:16, F0-1:7, F2:20, F3:7, cirrhosis:6). Diagnostic abilities for assessing fibrosis grade were compared between contrast findings and FIB4 (age * AST/[platelet count * ALT(0.5)]). RESULTS: High-power emission produced an intrahepatic band-like structure, and the three-layer appearance was less frequent and monolayer appearance was more frequent in cirrhosis than controls/chronic hepatitis (P < 0.0001). Intensity difference at 15-min phase showed most significant correlation with fibrosis grade (rho = 0.79, P < 0.0001), and the best areas under the receiver operating characteristic curves are 0.88 for marked fibrosis, 0.95 for advanced fibrosis and 0.97 for cirrhosis, which were significantly higher than those of FIB4, 0.85 for marked fibrosis, 0.89 for advanced fibrosis and 0.90 for cirrhosis. Sensitivity, specificity and efficiency of the intensity difference were 88%, 72% and 81% for marked fibrosis, 85%, 91% and 89% for advanced fibrosis and 97%, 90% and 91% for cirrhosis, respectively. The subsequent study validated the main study results; significant correlation between the intensity difference and the fibrosis grade (rho = 0.73-0.77, P < 0.0001). CONCLUSIONS: Perflubutane-based ultrasound accurately predicts the grade of hepatic fibrosis. KEY POINTS: * The behaviour of intrahepatic microbubbles depends on the severity of hepatic fibrosis. * Layer enhancement pattern simply represents the degree of chronic liver disease. * Parenchymal intensity change due to high-power emission predicts the hepatic fibrosis grade. PMID- 22207269 TI - Interdependencies of aortic arch secondary flow patterns, geometry, and age analysed by 4-dimensional phase contrast magnetic resonance imaging at 3 Tesla. AB - OBJECTIVE: It was the aim to analyse the impact of age, aortic arch geometry, and size on secondary flow patterns such as helix and vortex flow derived from flow sensitive magnetic resonance imaging (4D PC-MRI). METHODS: 62 subjects (age range = 20-80 years) without circumscribed pathologies of the thoracic aorta (ascending aortic (AAo) diameter: 3.2 +/- 0.6 cm [range 2.2-5.1]) were examined by 4D PC-MRI after IRB-approval and written informed consent. Blood flow visualisation based on streamlines and time-resolved 3D particle traces was performed. Aortic diameter, shape (gothic, crook-shaped, cubic), angle, and age were correlated with existence and extent of secondary flow patterns (helicity, vortices); statistical modelling was performed. RESULTS: Helical flow was the typical pattern in standard crook-shaped aortic arches. With altered shapes and increasing age, helicity was less common. AAo diameter and age had the highest correlation (r = 0.69 and 0.68, respectively) with number of detected vortices. None of the other arch geometric or demographic variables (for all, P >= 0.177) improved statistical modelling. CONCLUSION: Substantially different secondary flow patterns can be observed in the normal thoracic aorta. Age and the AAo diameter were the parameters correlating best with presence and amount of vortices. Findings underline the importance of age- and geometry-matched control groups for haemodynamic studies. KEY POINTS: * Secondary blood flow patterns (helices, vortices) are commonly observed in the aorta * Secondary flow patterns predominantly depend on patient age and aortic diameter * Geometric factors show a lesser impact on blood flow patterns than age and diameter * Future analyses of flow patterns should incorporate age- and diameter dependencies. PMID- 22207270 TI - Impact of 64-slice coronary CT on the management of patients presenting with acute chest pain: results of a prospective two-centre study. AB - OBJECTIVE: Our two-centre prospective study evaluates the usefulness of 64-slice coronary computed tomography (CCT) to rule out significant coronary artery stenosis in patients admitted in emergency departments (ED) for acute coronary syndromes (ACS) with low-to-intermediate risk score. METHODS: Patients (175) admitted for acute chest pain (ACP), unmodified electrocardiogram and first troponin measurement within normal ranges were included. A second troponin measurement and a 64-slice CCT within 24 h were performed. Major adverse cardiac events (MACE) were recorded during follow-up (6 months +/- 2). RESULTS: 64-slice CCT was either normal or showed non-significant coronary stenosis in the majority of patients (78%). 64-slice CCT depicted significant stenosis (>50% diameter) in 22% of patient whereas initial clinical and biological evaluation was reassuring. For negative CCTs, elevated troponin at second measurement did not modify the strategy or treatment of patients. No MACEs were noted during follow up. In 12% of patients CCT identified unsuspected non-coronary abnormalities. CONCLUSION: Our study confirms 64-slice CCT utility to rule out significant coronary artery stenosis in 8/10 patients admitted in ED with ACP or ACS with low-to-intermediate risk score. Early discharge with a negative 64-slice CCT is associated with very low risk of cardiac events at 6 months. KEY POINTS: * 64-slice coronary computed tomography (CCT) offers a critical role in acute chest pain. * 64-slice CCT allows differentiation between significant and non-significant coronary artery stenosis. * Normal 64-slice CCT allows rapid discharge of patients with ACP. * 64 slice CCT helps make appropriate therapeutic decision in patients with ACP. PMID- 22207271 TI - The effect of medication reconciliation in elderly patients at hospital discharge. AB - OBJECTIVE: To assess the impact of medication reconciliation interventions on medication error rates when elderly patients are discharged from hospital to community care or nursing homes. SETTING: Elderly patients (>65 years) living in nursing homes or in their own homes with care provided by the community nursing system. METHOD: All medical records containing information on drug treatment were collected from hospital departments, the community care service and GPs. We then identified if there were any changes in the transfer of information i.e. if the drugs were not the same as before the transfer. Two different persons independently evaluated all information about the patients' drugs to identify medication errors for three different time periods. During all three periods structured discharge information was used. In period 2, electronic medication lists were introduced and in period 3 we introduced specific routines and support by a clinical pharmacist to ensure prescription in the specific medication dispensing system (ApoDos). Asymptotic Linear by-Linear Association Test was used to compare number of medication errors in period 1, 2 and 3 respectively. MAIN OUTCOME MEASURE: Number of medication errors per patient. RESULTS: A total of 123 patients were evaluated at discharge. For the 109 patients using the ApoDos system, there were significant differences in the number of medication errors between period 1 and 3 (P = 0.048), period 2 and 3 (P = 0.037 but not between period 1 and 2 (P = 0.41). The mean numbers of errors were 1.5, 1.1 and 0.5 for period 1, 2 and 3 respectively. The 14 patients not using the ApoDos system had on average 0.4 errors per patient. Among the 58 patients with medication errors, 34 were evaluated as having low clinical risk, 22 moderate, and 2 high clinical risk. CONCLUSION: Medication errors are still common when elderly patients are transferred from hospital to community/primary care. The main risk factor seems to be the specific medication dispensing system (ApoDos) or rather the process on how to use it. When this system was supported by clinical pharmacists, the error rate dropped to the same level as for patients without ApoDos. PMID- 22207272 TI - Clinical pharmacy services in the outpatient pediatric oncology clinics at a comprehensive cancer center. AB - BACKGROUND: There is a need to expand clinical pharmacy services to cover the ambulatory pediatric cancer patients. There is a paucity of published literature describing pharmacy services in this setting. OBJECTIVE: To describe the development, implementation and the reported interventions of a clinical pharmacy service in the outpatient pediatric hematology-oncology clinics at a comprehensive cancer center in Jordan. METHODS: A stepwise approach was followed to develop and implement the described service. Four goals were set for the service comprising (1) ensure safe medication use (2) improve patient and caregiver education (3) enhance efficiency in medication distribution (4) facilitate the continuity of care across the inpatient and outpatient settings. The interventions collected were categorized into four major classes: clarification, safety, therapeutic and education. RESULTS: A total of 939 interventions were reported. Safety interventions were the highest with 500 (53%), followed by education 247 (26%), clarification 113 (12%) and therapeutic 79 (9%). The most common single interventions were patient counseling 247 (26%) and chemotherapy evaluation 229 (24%). Less frequent interventions were drug interactions and adverse drug reactions with 10 (1%) each. CONCLUSION: Developing pediatric hematology-oncology clinical pharmacy services to cover the outpatient setting is essential to ensure continuity of care and to optimize therapeutics. PMID- 22207273 TI - Application of ATC/DDD methodology to evaluate perioperative antimicrobial prophylaxis. AB - OBJECTIVE: To evaluate quality of perioperative antibiotic prophylaxis (PAP) and to calculate the cost per procedure in a Turkish university hospital. SETTING: A 352-bed teaching hospital in Denizli, Turkey. METHOD: An prospective audit was performed between July and October 2010. All clean, clean-contaminated and contaminated elective surgical procedures in ten surgical wards were recorded. Antimicrobial use was calculated per procedure using the ATC-DDD system. The appropriateness of antibiotic use for each procedure was evaluated according to international guidelines on PAP. In addition, the cost per procedure was calculated. RESULTS: Overall, in 577 of the 625 (92.3%) of the studied procedures, PAP was used. PAP was indicated in 12.5% of the group where it was not used, and not indicated in 7.1% of the group where it was used. Unnecessarily prolonged antimicrobial prophylaxis was observed in 56.9% of the procedures, mean duration was 2.6 +/- 2.7 days. The most frequently used antimicrobials were cefazolin (117.9 DDD/100-operation) and sulbactam/ampicillin (102.2 DDD/100 operation). The timing of the starting dose was appropriate in 545 procedures (94.5%). In the group that received PAP, only 80 (13.7%) of the procedures were found to be fully appropriate and correct. The density of antimicrobial use per operation was 2.8 DDD. The mean cost of the use of prophylactic antimicrobials 18.6 per procedure. CONCLUSION: The density of antimicrobial use in PAP was found to be very high in our hospital. Antibiotic overuse extended into the postoperative period. PMID- 22207274 TI - Photo catalogue for the classification of cell colonies in the Syrian hamster embryo (SHE) cell transformation assay at pH 7.0. AB - This catalogue is a display of Syrian hamster embryo (SHE) cell colony photos representative of the cell transformation assay (CTA) carried out at pH 7.0. It is intended as a visual aid for the identification and the scoring of cell colonies in the conduct of the assay. A proper training from experienced personnel together with the protocol reported in this issue and the present photo catalogue will support method transfer and consistency in the assay results. PMID- 22207276 TI - Variations in vertebral body dimensions in women measured by 3D-XA: a longitudinal in vivo study. AB - Bone size and shape play an important role in bone strength, as shown by biomechanical testing and clinical studies. Vertebral body dimensions determine vertebral body strength even after adjustment for bone mineral density. We have recently proposed an in vivo method for 3D reconstruction of vertebral bodies using the whole spine imaging on a standard DXA device (3D-XA). The aim of our study was to measure in vivo vertebral body dimension changes by 3D-XA in women over a 6 year period. A total of 174 women were included in this study. They were divided into 3 groups: premenopausal (20-40 years; N=53), postmenopausal women (55-60 years; N=65) and elderly women (70-80 years; N=56). Thoracic and lumbar spine (T4-L4) were reconstructed using the 3D-XA method at baseline and 6 years later. Biochemical markers of bone remodeling were measured at baseline. In premenopausal women, there was an increase in minimal cross-sectional area (minCSA), vertebral body volume as well as end plate width of the lumbar vertebrae, without statistically significant change of these parameters at the thoracic spine; there was no change in anterior heights. In postmenopausal women, there was a decrease in vertebral body anterior height and depth, driven by results in the elderly group at both the thoracic and lumbar spine. Vertebral body width decreased at the thoracic spine but increased at the lumbar spine. MinCSA and volume decreased at the thoracic spine, in contrast with an increase of these 2 parameters at the lumbar spine in early postmenopausal women (55-60 years). In elderly women (70-80 years), the change in minCSA and volume of the lumbar spine was not statistically significant over 6 years. In postmenopausal women, there was no correlation between changes in vertebral dimensions and baseline biochemical markers of bone remodeling except for NTX/Cr and anterior height decrease. Our study confirms that an increase in geometric dimensions of lumbar vertebrae occurs through adult life. This could be related to a compensation for bone loss, aiming to maintain bone strength through increase in size. However, this phenomenon is not observed at all levels in the spine; since we do not confirm this increase at the thoracic spine. This might be one of the determinants of the higher risk of fractures in this part of the spine. PMID- 22207275 TI - Increased susceptibility to microdamage in Brtl/+ mouse model for osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is a genetic disease of collagen or collagen-related proteins that adversely impacts bone mass and fracture resistance. Little is known regarding the role that microdamage plays in OI and whether or not OI bone is more prone to damage accumulation than bone with unaffected collagen. The Brtl/+ mouse is a heterozygous model for OI which contains a Gly349Cys substitution in one COL1A1 allele, and demonstrates a low ductility phenotype. At 8 weeks of age, Brtl/+ demonstrates an increase in osteoclast number, which mimics the upregulated bone turnover often found in OI patients. We hypothesize that upregulated osteoclast activity in Brtl/+ is due, in part, to increased remodeling associated with microdamage repair. In the present study, we used Brtl/+ to investigate the susceptibility of OI bone to microdamage. The mouse ulnar loading model was used to induce microdamage and to test the hypothesis that Brtl/+ is more susceptible to damage accumulation than age-matched wild type (WT) counterparts. Linear elastic fracture mechanics (LEFM) was used to investigate the fracture toughness properties of both Brtl/+ and WT bones to determine if there is any correlation with toughness and the degree of microdamage. Results show that Brtl/+ ulnae subject to normal cage activity demonstrate an inherently larger amount of microdamage than WT controls. Following axial compressive loading, Brtl/+ ulnae are more prone to damage than WT counterparts despite demonstrating a greater resistance to whole-bone deformation. Fracture toughness results demonstrate that Brtl/+ specimens, despite not exhibiting a significant difference, display a trend toward lower fracture toughness values than their WT counterparts. Correlations show that microdamage levels tend to increase as fracture toughness decreases. Together, these findings may have strong clinical implications for explaining increased fragility and remodeling activity in OI patients. PMID- 22207278 TI - Primary and secondary angiosarcomas of the breast: a single institution experience. AB - Angiosarcomas of the breast (ASB) are rare, representing <1% of breast malignancies. They can develop as a primary or secondary malignancy, also called post-radiation angiosarcoma. The aim of the this study is to discuss diagnosis, treatment, and outcome of primary and secondary ASB patients, diagnosed and treated in a single institution, over a 10-year period and to further compare the two conditions. We retrieved 28 consecutive cases of ASB, diagnosed from 1999 to 2009 at the European Institute of Oncology. Clinical and pathologic findings and survival analyses were performed. Of the 28 cases (27 women and 1 man), eight were primary breast angiosarcomas (PBA) and 20 were secondary breast angiosarcomas (SBA). Median follow-up was 23 months (range 1-112 months). Type of treatment (conservative or radical surgery) did not affect survival in both types of angiosarcomas. The clinical course observed was characterized by a high rate of local recurrence rather than distant metastasis or death from disease. There was a correlation between histological grade and prognosis of angiosarcomas with high-grade tumors presenting worse prognosis. SBA had a poorer prognosis compared to PBA. Our data indicate that primary and secondary ASB are distinct clinical and pathological features. SBA showed worse prognosis and was more often diagnosed in the study period compared to PBA. Physicians who care for patients who have been treated with radiation must be aware of its potential to induce angiosarcoma and stay vigilant in its detection. PMID- 22207277 TI - Clinical and biomarker predictors of side effects from tamoxifen. AB - Tamoxifen decreases breast cancer recurrence, mortality, and breast cancer risk in high-risk women. Despite these proven benefits, tamoxifen use is often limited due to side effects. We identified predictors of tamoxifen-induced side effects based on clinical variables and serum tamoxifen metabolite biomarkers in a cross sectional study of patients taking tamoxifen. We enrolled 241 women and collected data on demographics, tamoxifen use and side effects, as well as potential clinical and serum predictors. We used logistic regression models and adjusted for age, body mass index, ethnicity, education, prior post-menopausal hormone therapy (HT), tamoxifen duration, and endoxifen levels to identify factors associated with side effects. Common tamoxifen attributed side effects were hot flashes (64%), vaginal dryness (35%), sleep problems (36%), weight gain (6%), and depression, irritability or mood swings (6%). In multi-variate models, tamoxifen duration, age, prior post-menopausal HT, and endoxifen levels all predicted side effects. Women who had been on tamoxifen for >12 months were less likely to report side effects (OR 0.15, 95% CI 0.04-0.58) or severe side effects (OR 0.05, 95% CI 0.005-0.58) compared to women on tamoxifen for <12 months. Compared to women younger than 50, women who were age 60-70 and older than 70 were less likely to report side effects (OR 0.22, 95% CI 0.03-1.35; OR 0.13, 95% CI 0.01 0.99; respectively). Women who previously took post-menopausal HT were more likely to report severe side effects. Women with higher endoxifen levels were more likely to report side effects (OR 1.67, 95% CI 1.01-2.77 per standard deviation increase in endoxifen). Clinicians should consider closely monitoring adherence in women taking tamoxifen, especially in younger women, and women who previously took HT. The association between endoxifen levels and side effects is consistent with the data that suggest that endoxifen is the most highly active metabolite of tamoxifen. PMID- 22207280 TI - Overview of aging research using nonhuman primate models. PMID- 22207279 TI - Acute and chronic response to CRT in narrow QRS patients. AB - Previous studies suggest that CRT may benefit narrow QRS patients with mechanical dyssynchrony (MD). We conducted an acute and chronic study, evaluating the response of heart failure patients with a narrow QRS to cardiac resynchronization therapy (CRT). ESTEEM-CRT was a multi-center, single-arm, feasibility study that evaluated ICD-indicated, medically-optimized patients with EF <= 35%, NYHA class III heart failure, QRS duration <120 ms, and MD as defined by the standard deviation of time to peak systolic velocity of 12 segments (Ts-SD). Sixty-eight patients received a CRT defibrillator, exercise testing, and echo exams, and 47 of these patients underwent invasive hemodynamic testing at implant. Follow-up was at 6 and 12 months. The average maximal improvement in LV dP/dt(max) was minor (2 +/- 2%). NYHA and quality of life scores were substantially improved at 6 and 12 months (P < 0.001), while exercise capacity and LV volumes were unchanged. The echo indices of MD were difficult to collect, discordant, and failed to predict clinical outcomes. ESTEEM-CRT patients with a narrow QRS and MD as defined in this study did not improve as measured by acute hemodynamics, chronic exercise performance, or reverse remodeling. These multi-center results support the notion that dyssynchrony indices are ineffective or at least require greater refinement for the selection of narrow QRS patients for CRT. PMID- 22207281 TI - Development of a UHPLC-MS/MS method for the measurement of chlortetracycline degradation in swine manure. AB - An ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC MS/MS) method was developed capable of simultaneously measuring chlortetracycline (CTC), epi-chlortetracycline, and isochlortetracycline (ICTC), as well as other structurally related tetracyclines in swine manure. A simple sample preparation was used consisting of extraction, dilution, centrifugation, and ultrafiltration. The concentrations of analyte were calculated using d(6)-tetracycline as an internal standard in the matrix-matched standard curve. A solvent gradient resolved the compounds in 3.5 min with an additional 1.5 min of re-equilibration allowing the analyses of a large number of samples in a short period of time. MS/MS was used as the detection method giving analyte confirmation in addition to a large dynamic range and low detection limit. The UHPLC-MS/MS method successfully resolved multiple degradation products of CTC from the complex manure matrix. The method detection limits ranged from 1.9 pg/MUL for CTC to 7.3 pg/MUL for ICTC, and the calibration curve was linear from 1 to 10,000 pg/MUL. The method was tested by measuring CTC and its degradation products as a function of time in incurred swine manure that had been incubated at three different temperatures (22 degrees C, 38 degrees C, and 55 degrees C). CTC concentration at 22 degrees C decreased 44% after 25 days; greater percentage decreases were observed when the manure was stored at elevated temperatures (96% and 98% for 38 degrees C and 55 degrees C, respectively). The concentration of the microbiologically inactivate isomer, ICTC, increased over the incubation period. At 22 degrees C, ICTC continued to increase through 25 days of incubation; at 38 degrees C, ICTC concentration plateaued on day 14 while at 55 degrees C ICTC concentration plateaued on day 7, with concentration increases of 198%, 374%, and 282% for 22 degrees C, 38 degrees C, and 55 degrees C, respectively. PMID- 22207282 TI - Determination of D-fagomine in buckwheat and mulberry by cation exchange HPLC/ESI Q-MS. AB - D-Fagomine is an iminosugar first found in buckwheat (Fagopyrum esculentum Moench) which if used as a dietary supplement or functional food component may reduce the risks of developing insulin resistance, becoming overweight and suffering from an excess of potentially pathogenic bacteria. As D-fagomine may become increasingly important to the food industry, a reliable analytical method for its determination in natural plant sources and foodstuffs is desirable. We have devised a method to separate D-fagomine from its diastereomers 3-epi fagomine and 3,4-di-epi-fagomine in a single run by cation exchange high performance liquid chromatography (HPLC) with detection and quantification by mass spectrometry using electrospray ionisation and a simple quadrupole analyser (ESI-Q-MS). The method is validated and applied to the determination of D fagomine in buckwheat groats (6.7-44 mg kg(-1)), leaves, bran and flour. We show that buckwheat contains 3,4-di-epi-fagomine (1.0-43 mg kg(-1)), which has not previously been reported in this source. The procedure is also applied to mulberry (Morus alba) leaves, which contain D-fagomine and 3-epi-fagomine as minor components. The new method provides a means for convenient and accurate determination of D-fagomine in plant samples and foodstuffs. PMID- 22207283 TI - Diversity analysis of pseudomonas in rice rhizosphere for multifaceted plant growth promotion. AB - This investigation was carried out based on the hypothesis that there may be some pseudomonad strains, which could exist in rhizosphere of plant species contributing multifaceted beneficial activities. For this purpose, 21 pseudomonad isolates from the rhizosphere of rice, cultivated in western parts of Tamil Nadu were screened. All the 21 isolates were authenticated as pseudomonads by a genus specific PCR screening. The molecular diversity of these isolates was investigated by Amplified Ribosomal DNA Restriction Analysis (ARDRA) and the dendrogram obtained from the analysis revealed that all the 21 isolates clustered into seven groups. Further, these isolates were screened for plant growth promoting activities such as diazotrophy (PCR amplification of nifH gene and acetylene reduction assay), Indole acetic acid (IAA) and siderophore production (spectrometrically), 1-Aminocyclopropane-1-carboxylic acid (ACC) deaminase for ethylene regulation (PCR screening), mineral solubilization (biochemically) and antagonistic potential against soil pathogenic fungi (dual culture assay). Based on the results, two elite Pseudomonas isolates (S9 and O3) were chosen as multi functional plant growth-promoting rhizobacteria, paving way for potential use as bioinoculants in rice. PMID- 22207284 TI - Evaluation of mammalian codon usage of fimH in DNA vaccine design. AB - Uropathogenic Escherichia coli (UPEC) bacteria are the principal cause of urinary tract infections (UTI). Because these bacteria propagate intracellularly, the cellular immune response is an important factor in UTIs. Therefore, we designed a genetic construct to induce a cellular immune response. In order to develop a genetic construct that induces strong cellular immunity against this pathogen, we used the fimH synthetic gene according to mammalian codon usage, and the gene expression was compared with wild type codon usage. Initially, we designed two constructs, pVAX/fimH mam and pVAX/fimH wt, which contain mammalian and wild type codon usage, respectively. The Cos-7 cell line was transfected separately with a complex of pVAX/fimH mam-ExGene 500 poly cationic polymer and pVAX/fimH wt-ExGene 500 poly cationic polymer. Expression of the fimH gene in both constructs in COS7 cells was confirmed by RT-PCR, SDS-PAGE, and Western blotting. Both of the pVAX/fimH cassettes expressed inserted fimH genes (mam and wt) in Cos-7 cells. Our results suggest that codon optimization successfully expressed the fimH gene because the fimH gene with mammalian codon usage is compatible with the eukaryotic expression system. Therefore, mammalian codon usage could be appropriate in a pVAX/fimH construct as a DNA vaccine. PMID- 22207285 TI - Antimicrobial susceptibility profiles associated with bacterial meningitis among children: a referral hospital-based study in Iran. AB - Bacterial meningitis continues to be associated with high morbidity and mortality rate worldwide, especially in the pediatric age group. This study was performed to identify the microbial etiologies of meningitis among 31 children, who were admitted in the Emergency Ward of a referral pediatric hospital in Iran. Culture identification showed that Streptococcus pneumoniae (12 subjects), Haemophilus influenzae (11 subjects) were the most common bacteria, followed by Escherichia coli (7 cases) and Neisseria meningitidis (only one case). Antibiotic susceptibility tests revealed that vancomycin had the best effect on S. pneumoniae in comparison with other antibiotics, whereas H. influenzae and E. coli were more susceptible to ceftriaxone, ceftazidime, and ceftizoxime than other antibiotics. In conclusion, despite the advances in antibiotic therapy and vaccine development, bacterial meningitis still is a health problem. S. pneumoniae, H. influenzae, and N. meningitidis are the main sources of bacterial meningitis, but other organisms such as E. coli should also be suspected, when a case is admitted to a referral pediatric hospital. PMID- 22207286 TI - The effects on immune response of levamisole treatment following infection of U 937 macrophages with Candida albicans. AB - The aim of this study was to investigate the effects on the immune response of levamisole alone and in conjunction with Candida albicans stimulation in human macrophage cell culture by determining the alterations in the levels of cytokine release. Levamisole treatment was performed before, during and after infecting U 937 human macrophage cells with C. albicans. In cell supernatants, interleukin (IL)-1b, IL-12, IL-18, tumour necrosis factor alpha (TNF-alpha) levels were measured by ELISA. In vitro levamisole treatment accompanied by C. albicans stimulation significantly increased IL-12, IL-1beta and IL-18 production in macrophage cells (p < 0.05). It was observed that when administered before C. albicans infection, levamisole significantly increased IL-12 and IL-1beta production in macrophage cells (p < 0.05). Another finding was that when applied to macrophage cells simultaneously with C. albicans infection, or before infection with C. albicans, levamisole suppressed the TNF-beta production stimulating effect of C. albicans (p < 0.05). These results indicated that levamisole could be useful in treating patients infected with C. albicans or in protecting individuals under the risk of being infected with this pathogen. There is a need for further experimental and clinical studies on this hypothesis. PMID- 22207287 TI - Aetiology of upper respiratory tract infections in children in Arak city: a community based study. AB - Viruses are frequent causes of upper respiratory tract infections in children. We investigated the viral aetiology of community-acquired upper respiratory tract infections (URIs) in young children treated as outpatients in community settings. During November 2008, nasal swab specimens were taken from children with recent onset of upper respiratory tract infections. The patients attended day care or primary schools; the specimens were randomly obtained by pediatricians from schools and childcare institutions and sent for identification by PCR method. A total of 300 specimens were collected. From all samples, 40.67% were positive for at least 1 virus, viz. adenovirus 11.76%, rhinovirus 9.8%, respiratory syncytial virus 6.08%, influenza virus 5.56%, parainfluenza virus 4.9%, enterovirus 2.94% and a combination of 2 viruses 2%. Clinical manifestations of the respiratory infections were as follows: 70.7% of the patients had coryza, 69.3% cough, 26% sneezing, 19.7% sore throat, 2.7% headache, 7.7% fever, 2.3% conjunctivitis, 1.3% abdominal pain and 1% hoarseness. The results of this study demonstrate that adenoviruses and rhinoviruses are the two most common viral agents isolated from pediatric outpatients with acute URIs in autumn in Arak City. Coryza and cough were the most common symptoms in children. Sore throat and hoarseness were more prevalent in infections caused by influenza virus, conjunctivitis in parainfluenza, and coryza in rhinovirus infections. PMID- 22207288 TI - Liver abscess as the presenting manifestation of chronic granulomatous disease. AB - Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease, affecting phagocytic blood cells, which predispose patients to recurrent infectious complications. Herein, an 11-year-old girl is described who presented with liver abscess at the age of 9 years. Positive dihydrorhodamine (DHR) and nitrobluetetrazolium (NBT) tests confirmed the diagnosis of CGD for the patient. Anti-tuberculosis drugs and parenteral antibiotic therapy were started. Unusual visceral abscess and recurrent infections should be considered as an alarm for primary immunodeficiency diseases, while early diagnosis and appropriate treatment could prevent severe complications and even death in this group of patients. PMID- 22207289 TI - Human cytomegalovirus induces MMP-1 and MMP-3 expression in aortic smooth muscle cells. AB - Human cytomegalovirus (HCMV) infection may be involved in the pathogenesis of atherosclerosis by modulating functions of smooth muscle cells (SMC). In this study, we performed an oligonucleotide microarray screening of 780 inflammation associated genes in HCMV-infected aortic SMC (AoSMC). The expression of 31 genes was stimulated and 24 genes were down-regulated following infection with HCMV strain DC-134. Following infection with HCMV strain AD-169 infection, we found 24 genes to be stimulated and 32 genes to be down-regulated. Among these were primarily genes encoding for CC and CXC chemokines, adhesion molecules, and tumor necrosis factor (TNF) receptor superfamily members, apoptosis-related factors, signal transduction molecules and transcription regulators. The up-regulated genes included matrix metalloproteinase (MMP)-1 and MMP-3 in HCMV infected cells. Using RT-PCR and enzyme immunoassay we found stimulated expression of MMP-1 (3.2 fold expression) and MMP-3 (334-fold expression) in HCMV strain DC-134-infected AoSMC at 72 h following infection.The findings of our study suggest that HCMV infection of AoSMC cause an activation of atherosclerosis-relevant factors in SMC. The increased expression of MMPs which have been shown to be involved in atherosclerotic plaque rupture and myocardial infarction is in agreement with the hypothesis that this pathogen might contribute to plaque inflammation in atherosclerotic disease. PMID- 22207290 TI - Comparison of diversity of torque teno virus 1 in different mucosal tissues and disorders. AB - Diversity of TTV1 was assessed in the head and neck region in patients with potentially malignant (oral lichen planus, oral leukoplakia) and malignant lesions (oral and laryngeal squamous cell cancers) and was compared to that found in the uterine cervix (cervical atypia and cervical cancer) by directly sequencing the NG061-063 segment of ORF1. These sequences were classified by the formerly used genogroup-genotype system as well as by the newly accepted species classification by aligning with the corresponding region of the type sequences of the 29 TTV species. All sequences obtained during the study clustered together with the TTV1 type sequence; to express diversity within TTV1, genotypes and subtypes of the former classification were used.The commonest subtypes were 2c followed by 2b, 1a and 1b. Subtypes 2b and 2c were evenly distributed among cervical samples; subtype 1a was more frequent in patients with cervical atypia or cancer. Subtypes 2c was more frequent than 2b in head and neck lesions. In conclusion, genotype and even subtype distribution may be important in association with diseases, therefore using this classification for characterization of intraspecies diversity of TTV1 is proposed. PMID- 22207291 TI - Optimization of production and reaction conditions of polygalacturonase from Byssochlamys fulva. AB - In the present study, the optimization of production and reaction conditions of polygalacturonase produced by a fungus Byssochlamys fulva MTCC 505 was achieved. The production of polygalacturonase with a considerable activity of 1.28 IU/ml was found when the culture was shaken at 30 degrees C for 5 days in 100 ml of medium containing (w/v) 10 g/l pectin, 2 g/l NaNO3, 1 g/l KH2PO4, 0.5 g/l KCl, 0.5 g/l MgSO4. 7H2O, 0.001 g/l FeSO4. 7H2O, 0.001 g/l CaCl2. The best carbon and nitrogen source for this enzyme were pectin (1%) and Ca(NO3)2 (0.1%), respectively. The enzyme gave maximum activity at incubation time of 72 h, temperature of 30 degrees C and pH 4.5. During the optimization of reaction conditions, the enzyme showed maximum activity in sodium citrate buffer (50 mM) of pH 5.5 at 50 degrees C reaction temperature for 15 minutes of incubation. The enzyme showed greater affinity for polygalacturonic acid as substrate (0.5%). Km and Vmax values were 0.15 mg/ml and 4.58 MUmol/ml/min. The effect of various phenolics, thiols, protein inhibitors and metal ions on the enzyme activity was investigated. The enzyme was quite stable at 4 degrees C and 30 degrees C. At 40 degrees C the half life of the enzyme was 6 h and at 60 degrees C it was 2 h. PMID- 22207292 TI - The role of IgG avidity determination in diagnosis of Epstein-Barr virus infection in immunocompetent and immunocompromised patients. AB - There is a high degree of variability in the serologic response to Epstein-Barr virus (EBV) infection, especially in viral capsid antigen (VCA)-IgM antibodies. Therefore, additional tests are needed to confirm primary infection. We evaluated the value of IgG avidity determination in diagnosis of EBV infection in immunocompetent and immunocompromised patients. A total of 236 serum samples from immunocompetent patients with symptoms suggestive of EBV infection were tested for the presence of VCA-IgM/IgG antibodies and IgG avidity. Using IgG avidity, acute primary infection was confirmed in 56.7% of the immunocompetent patients with positive and in 1.8% of patients with negative VCA-IgM. Recent primary infection was documented in 8.9% of the IgM positive and 3.5% of the IgM negative patients. In patients with indeterminate serology (equivocal IgM), 6.7% were classified by avidity index (AI) as acute primary infection, 10.0% as post-acute and 83.3% as past infection cases. Concerning the 32 immunocompromised patients, recent primary infection was documented in 3 of the 14 IgM positive patients. High AI was detected in 11 of these patients, indicating an IgM response due to reactivation. Determination of IgG avidity in combination with classical serologic markers seems to be a reliable method to confirm primary infection both in immunocompetent and immunocompromised patients. It may be especially useful to differentiate cases of primary infection in patients with undetectable VCA-IgM antibodies or indeterminate routine EBV serology. PMID- 22207293 TI - Diversity of aminoglycoside modifying enzyme genes among multidrug resistant Acinetobacter baumannii genotypes isolated from nosocomial infections in Tehran hospitals and their association with class 1 integrons. AB - The aim of the present study was to investigate, for the first time, the diversity of the genes encoding aminoglycoside-modifying enzymes (AME) and their association with class 1 integrons in Iranian Acinetobacter baumannii strains. A total of 100 multidrug resistant A. baumannii, isolated from eight distinct hospitals in Tehran, were enrolled in this study. Susceptibility of these isolates to antimicrobial agents including gentamicin and amikacin was determined by E-test. Aminoglycoside resistant isolates were then tested by PCR for AME genes, including aphA6, aacC1, aacC2, aacA4, aadB, aadA1, classes 1 integron, 5' CS-3' and typed by RAPD PCR. The rate of resistance to imipenem, meropenem, gentamicin and amikacin were 39%, 39%, 38% and 32%, respectively. Intermediate resistance phenotype to gentamicin and amikacin was observed in 2% and 5% of all the isolates, respectively. After aph6 with 90% (n = 36/40), aadA1, aacC1 and aadB with 82.5% (n = 33/40), 65% (n = 26/40) and 20% (n = 8/40) were the most prevalent AME genes among aminoglycosides resistant A. baumannii isolates. A combination of two to four different resistance genes was observed in 39 of 40 strains (97.5%), with a total of 7 different combinations. PCR of integrase genes revealed that AME gene was associated with 67% of class 1 integrons. RAPD analysis showed three predominant genotypes A (n = 20), B (n = 10) and 10 unrelated genotypes. The occurrence of identical resistance genes, gene combinations and class 1 integrons associated with these genes in clonally distinct strains indicates that horizontal gene transfer plays a major role in the dissemination of aminoglycoside resistance in A. baumannii. PMID- 22207294 TI - Bacterial communities in an ultrapure water containing storage tank of a power plant. AB - Ultrapure waters (UPWs) containing low levels of organic and inorganic compounds provide extreme environment. On contrary to that microbes occur in such waters and form biofilms on surfaces, thus may induce corrosion processes in many industrial applications. In our study, refined saltless water (UPW) produced for the boiler of a Hungarian power plant was examined before and after storage (sampling the inlet [TKE] and outlet [TKU] waters of a storage tank) with cultivation and culture independent methods. Our results showed increased CFU and direct cell counts after the storage. Cultivation results showed the dominance of aerobic, chemoorganotrophic alpha-Proteobacteria in both samples. In case of TKU sample, a more complex bacterial community structure could be detected. The applied molecular method (T-RFLP) indicated the presence of a complex microbial community structure with changes in the taxon composition: while in the inlet water sample (TKE) alpha-Proteobacteria (Sphingomonas sp., Novosphingobium hassiacum) dominated, in the outlet water sample (TKU) the bacterial community shifted towards the dominance of alpha-Proteobacteria (Rhodoferax sp., Polynucleobacter sp., Sterolibacter sp.), CFB (Bacteroidetes, formerly Cytophaga Flavobacterium-Bacteroides group) and Firmicutes. This shift to the direction of fermentative communities suggests that storage could help the development of communities with an increased tendency toward corrosion. PMID- 22207295 TI - Positive correlation between type 1 and 2 iodothyronine deiodinases activities in human goiters. AB - Type 1 (D1) and 2 (D2) iodothyronine deiodinases are selenocysteine-containing enzymes that catalyze the deiodination of T4 to T3 in the thyroid and in peripheral tissues. Despite their importance to the plasma T3 pool in human beings, there are few studies about their behavior in human thyroids. In order to better understand iodothyronine deiodinase regulation in the thyroid gland, we studied thyroid tissue samples from follicular adenoma (AD, n = 5), toxic diffuse goiter (TDG, n = 6), nontoxic multinodular goiter (NMG, n = 40), papillary thyroid carcinoma (PTC, n = 8), and surrounding normal tissues (NT, n = 7) from 36 patients submitted to elective thyroidectomy. D1 and D2 activities were determined by quantification of the radioiodine released by 125I-rT3 or 125I-T4 under standardized conditions, and expressed as pmol rT3 deiodinated per minute and mg protein (pmol rT3 min-1 mg-1 ptn) and fmol T4 deiodinated per minute and mg protein (fmol T4 min-1 mg-1 ptn), respectively. D1 activity detected in TDG and AD tissues were significantly higher than in NT, PTC or NMG samples. D2 activity was also significantly higher in TDG and AD samples than in PTC, NMG, or NT. There was great variability in D1 and D2 enzymatic activities from distinct patients as well as from different areas from the same goiter. There was a positive correlation (P < 0,0001, r = 0.4942) between D1 and D2 activities when all samples were taken into account, suggesting that-in the thyroid-these two iodothyronine deiodinases may have related regulatory mechanisms, even if conditioned by other as yet unknown factors. PMID- 22207296 TI - Atypical work schedules are associated with poor sleep quality and mental health in Taiwan female nurses. AB - PURPOSE: To investigate the effects of shift work schedules on sleep quality and mental health in female nurses in south Taiwan. METHODS: This study recruited 1,360 female registered nurses in the Kaohsiung area for the first survey, and among them, 769 nurses had a rotation shift schedule. Among the 769 rotation shift work nurses, 407 completed another second survey 6-10 months later. Data collection included demographic variables, work status, shift work schedule, sleep quality (Pittsburgh Sleep Quality Index), and mental health (Chinese Health Questionnaire-12). RESULTS: Nurses on rotation shift had the poor sleep quality and mental health compared to nurses on day shift. The nurses on rotation shift had a relatively higher OR of reporting poor sleep quality and poor mental health (OR, 2.26; 95% CI, 1.57-3.28; and OR, 1.91; 95% CI, 1.39-2.63, respectively). Additionally, rotation shift nurses who had >=2 days off after their most recent night shifts showed significantly improved sleep quality and mental health (PSQI decreased of 1.23 and CHQ-12 decreased of 0.86, respectively). Comparison of sleep quality between the first and second surveys showed aggravated sleep quality only in nurses who had an increased frequency of night shifts. CONCLUSION: Female nurses who have a rotation shift work schedule tend to experience poor sleep quality and mental health, but their sleep quality and mental health improve if they have >=2 days off after their most recent night shifts. This empirical information is useful for optimizing work schedules for nurses. PMID- 22207297 TI - The impact of thromboemboli histology on the performance of a mechanical thrombectomy device. AB - BACKGROUND AND PURPOSE: Recently we published a novel method of thrombus preparation for use in a swine model for evaluation of thrombectomy designs. The clot (fibrin rich clot) is characterized by its similarity in histologic characteristics to the thromboemboli recovered from stroke patients. The purpose of this latest study was to evaluate if the performance of a mechanical thrombectomy device was affected by the histologic characteristics of thromboembolus. Erythrocyte rich clot, which was created using exogenous thrombin, and the novel experimental clot with abundance of fibrin/cellular component were used for comparison. The Merci clot retriever was used for the evaluation and the angiographic outcomes were analyzed. MATERIALS AND METHODS: Two histologically different types of experimental clot, a conventionally used thrombin-induced clot (erythrocyte-rich clot) and a novel experimental clot that is similar in histologic characteristics to the thromboemboli recovered from patients with stroke (fibrin-rich clot), were prepared. Eight extracranial arteries in swine were occluded with erythrocyte-rich clot (group A), and 8 were occluded with fibrin-rich clot (group B), and MT by using the Merci clot retriever device was performed. Angiographic results in each group were evaluated. RESULTS: A total of 48 attempts at MT were made. The average number of attempts to achieve TIMI grade II or III recanalization was 2.75 times in group A and 4.5 times in group B (P < .001), respectively. The mean time to achieve recanalization was 15.5 minutes in group A and 81.5 minutes in group B (P < .01). Every vessel in group A showed recanalization (100%), whereas only 3 of 8 samples (37.5%) achieved recanalization in group B. CONCLUSIONS: In this model, arteries occluded by fibrin-rich clot demonstrated a significantly lower recanalization rate, lower final TIMI score, and a longer mean recanalization time than did arteries occluded by erythrocyte-rich clot. The angiographic outcome of MT by using the Merci clot retriever system was influenced by the histologic characteristics of the occluding thromboembolus. PMID- 22207298 TI - Safety and efficacy of CT-guided transforaminal cervical epidural steroid injections using a posterior approach. AB - BACKGROUND AND PURPOSE: Image-guided cervical transforaminal epidural injections play an important role in the management of cervical radicular pain syndromes. The safety and efficacy of these injections via an anterolateral approach has been well-studied. The goal of this retrospective review was to determine the safety and efficacy of CT-guided transforaminal epidural injections by using a posterior approach. MATERIALS AND METHODS: Retrospective review of patient records was used to define VNPS and RMDI of patients undergoing CT-guided transforaminal cervical epidural injections between 2006 and 2010. Pain scores were recorded preprocedure, immediately postprocedure, at 2 weeks, and at 2 months. The RMDI was recorded preprocedure, at 2 weeks, and at 2 months. Data analysis of 247 patients was completed. Differences in VNPS scores and the RMDI were then compared on the basis of a CT-guided approach (anterolateral versus posterior). RESULTS: There was no statistical difference in the degree of pain relief and improvement in the RMDI between the CT-guided transforaminal anterolateral approach and the posterior approach at 2 weeks and at 2 months. Both groups demonstrated a statistically significant improvement in pain scores and the RMDI. Approximately 35% of patients in both groups demonstrated >50% pain relief at 2 months. There were no serious complications in either group. CONCLUSIONS: CT-guided transforaminal cervical epidural injections by using a posterior approach are safe and effective. PMID- 22207299 TI - Cerecyte coil trial: procedural safety and clinical outcomes in patients with ruptured and unruptured intracranial aneurysms. AB - BACKGROUND AND PURPOSE: This study arose from a need to systematically evaluate the clinical and angiographic outcomes of intracranial aneurysms treated with modified coils. We report the procedural safety and clinical outcomes in a prospective randomized controlled trial of endovascular coiling for ruptured and unruptured intracranial aneurysms, comparing polymer-loaded Cerecyte coils with bare platinum coils in 23 centers worldwide. MATERIALS AND METHODS: Five hundred patients between 18 and 70 years of age with a ruptured or unruptured target aneurysm planning to undergo endovascular coiling were randomized to receive Cerecyte or bare platinum coils. Analysis was by intention to treat. RESULTS: Two hundred forty-nine patients were allocated to Cerecyte coils and 251 to bare platinum coils. Baseline characteristics were balanced. For ruptured aneurysms, in-hospital mortality was 2/114 (1.8%) with Cerecyte versus 0/119 (0%) bare platinum coils. There were 8 (3.4%) adverse procedural events resulting in neurological deterioration: 5/114 (4.4%) with Cerecyte versus 3/119 (2.5%) with bare platinum coils (P = .22). The 6-month mRS score of <=2 was not significantly different in 103/109 (94.5%) patients with Cerecyte and 110/112 (98.2%) patients with bare platinum coils. Poor outcome (mRS score of >=3 or death) was 6/109 (5.5%) with Cerecyte versus 2/112 (1.8%) with bare platinum coils (P = .070). For UIAs, there was no in-hospital mortality. There were 7 (2.7%) adverse procedural events with neurological deterioration, 5/133 (3.8%) with Cerecyte versus 2/131 (1.5%) with bare platinum coils (P = .13). There was a 6-month mRS score of <=2 in 114/119 (95.8%) patients with Cerecyte versus 123/123 (100%) patients with bare platinum coils. There was poor outcome (mRS >=3 and 1 death) in 5/119 (4.2%) patients with Cerecyte versus 0/123 (0%) patients with bare platinum coils (P = .011). CONCLUSIONS: There was a statistical excess of poor outcomes in the Cerecyte arm at discharge in the ruptured aneurysm group and at 6-month follow-up in the unruptured group. Overall adverse clinical outcomes and in-hospital mortality were exceptionally low in both groups. PMID- 22207300 TI - MR diagnosis of facial neuritis: diagnostic performance of contrast-enhanced 3D FLAIR technique compared with contrast-enhanced 3D-T1-fast-field echo with fat suppression. AB - BACKGROUND AND PURPOSE: Current MRI with the CE T1-weighted sequence plays a limited role in the evaluation of facial neuritis due to prominent normal facial nerve enhancement. Our purpose was to retrospectively investigate the usefulness of the CE 3D-FLAIR sequence compared with the CE 3D-T1-FFE sequence in facial neuritis patients. MATERIALS AND METHODS: We assessed 36 consecutive patients who underwent temporal bone MR imaging at 3T for idiopathic facial palsy. Two readers independently reviewed CE 3D-T1-FFE and CE 3D-FLAIR images to determine the degree of enhancement in each of 5 segments of the facial nerve. We compared AUCs using the Z-test, compared diagnostic performance of 2 MR techniques with the McNemar test, and evaluated interobserver agreement. The Pearson chi(2) test was used for each segment of the facial nerve. RESULTS: The AUC of CE 3D-FLAIR (reader 1, 0.754; reader 2, 0.746) was greater than that of CE 3D-T1-FFE (reader 1, 0.624; reader 2, 0.640; P < .001). The diagnostic sensitivities, specificities, and accuracies were 97.2%, 86.1%, and 91.7%, respectively, for CE 3D-FLAIR, and 100%, 56.9%, and 78.5%, respectively, for CE 3D-T1-FFE. The specificity and accuracy of CE 3D-FLAIR were greater than those of CE 3D-T1-FFE (specificity, P = .029; accuracy, P = .008). The interobserver agreements for CE 3D-FLAIR (kappa-value, 0.831) and CE 3D-T1-FFE (kappa-value, 0.694) were excellent. Enhancement of the canalicular and anterior genu segments on CE 3D FLAIR were significantly correlated with the occurrence of facial neuritis (P < .001 for canalicular; P = .032 and 0.020 for anterior genu by reader 1 and reader 2, respectively). CONCLUSIONS: CE 3D-FLAIR can improve the specificity and overall accuracy of MR imaging in patients with idiopathic facial palsy. PMID- 22207301 TI - Feasibility of cerebral blood volume mapping by flat panel detector CT in the angiography suite: first experience in patients with acute middle cerebral artery occlusions. AB - BACKGROUND AND PURPOSE: A new FPCT application offers the possibility of perfusion (FPCT CBV) and parenchymal (FPCT) imaging within the angiography suite. We tested the hypothesis that findings in FPCT CBV and FPCT would correlate with those obtained using MSCT and PCT. MATERIALS AND METHODS: In 16 patients with acute MCA occlusion, FPCT CBV was performed immediately posttreatment. The volume of tissue having abnormal CBV values was determined by FPCT CBV and PCT images. Stroke volume on follow-up MSCT was determined, CBV values in the effected parenchyma were measured, and FPCT images were reviewed. RESULTS: In 6 cases, we found a FPCT CBV value identical or higher (hyperemia) in comparison with the contralateral side. In 10 cases, we found CBV lesions with values lower (oligemia) than the contralateral brain tissue. We found a high correlation of CBV lesion volume on FPCT CBV images to stroke volume on follow-up MSCT (r = 0.9, P < .05) in the oligemia group. Absolute FPCT CBV and PCT CBV values were comparable and showed good correlation (r = 0.9, P < .05). In 8 patients, contrast medium extravasation was visible. CONCLUSIONS: The new FPCT application allows assessment of CBV in acute stroke patients. Our initial results indicate that these measurements may predict final infarct volume. The ability to assess this key parameter of cerebral perfusion within the angiographic suite may improve the management of these patients. PMID- 22207302 TI - Cranial CT with adaptive statistical iterative reconstruction: improved image quality with concomitant radiation dose reduction. AB - BACKGROUND AND PURPOSE: To safeguard patient health, there is great interest in CT radiation-dose reduction. The purpose of this study was to evaluate the impact of an iterative-reconstruction algorithm, ASIR, on image-quality measures in reduced-dose head CT scans for adult patients. MATERIALS AND METHODS: Using a 64 section scanner, we analyzed 100 reduced-dose adult head CT scans at 6 predefined levels of ASIR blended with FBP reconstruction. These scans were compared with 50 CT scans previously obtained at a higher routine dose without ASIR reconstruction. SNR and CNR were computed from Hounsfield unit measurements of normal GM and WM of brain parenchyma. A blinded qualitative analysis was performed in 10 lower-dose CT datasets compared with higher-dose ones without ASIR. Phantom data analysis was also performed. RESULTS: Lower-dose scans without ASIR had significantly lower mean GM and WM SNR (P = .003) and similar GM-WM CNR values compared with higher routine-dose scans. However, at ASIR levels of 20% 40%, there was no statistically significant difference in SNR, and at ASIR levels of >=60%, the SNR values of the reduced-dose scans were significantly higher (P < .01). CNR values were also significantly higher at ASIR levels of >=40% (P < .01). Blinded qualitative review demonstrated significant improvements in perceived image noise, artifacts, and GM-WM differentiation at ASIR levels >=60% (P < .01). CONCLUSIONS: These results demonstrate that the use of ASIR in adult head CT scans reduces image noise and increases low-contrast resolution, while allowing lower radiation doses without affecting spatial resolution. PMID- 22207303 TI - Proton MR spectroscopy-detectable major neurotransmitters of the brain: biology and possible clinical applications. AB - Neurotransmitters are chemical substances that, by definition, allow communication between neurons and permit most neuronal-glial interactions in the CNS. Approximately 80% of all neurons use glutamate, and almost all interneurons use GABA. A third neurotransmitter, NAAG, modulates glutamatergic neurotransmission. Concentration changes in these molecules due to defective synthetic machinery, receptor expression, or errors in their degradation and metabolism are accepted causes of several neurologic disorders. Knowledge of changes in neurotransmitter concentrations in the brain can add useful information in making a diagnosis, helping to pick the right drug of treatment, and monitoring patient response to drugs in a more objective manner. Recent advances in (1)H-MR spectroscopy hold promise in providing a more reliable in vivo detection of these neurotransmitters. In this article, we summarize the essential biology of 3 major neurotransmitters: glutamate, GABA, and NAAG. Finally we illustrate possible applications of (1)H-MR spectroscopy in neuroscience research. PMID- 22207305 TI - Trafficking: Effector T cells cross the line. PMID- 22207304 TI - The added value of apparent diffusion coefficient to cerebral blood volume in the preoperative grading of diffuse gliomas. AB - BACKGROUND AND PURPOSE: In cerebral gliomas, rCBV correlates with tumor grade and histologic findings of vascular proliferation. Moreover, ADC assesses water diffusivity and is inversely correlated with tumor grade. In the present work, we have studied whether combined rCBV and ADC values improve the diagnostic accuracy of MR imaging in the preoperative grading of gliomas. MATERIALS AND METHODS: One hundred sixty-two patients with histopathologically confirmed diffuse gliomas underwent DWI and DSC. Mean rCBV and ADC values were compared among the tumor groups with the Student t test or ANOVA. ROC analysis was used to determine rCBV and ADC threshold values for glioma grading. RESULTS: rCBV had significantly different values between grade II and IV gliomas and between grade III and IV tumors, but there were no significant differences between grade II and III gliomas (P > .05). Grade II and III tumors also did not differ when astrocytomas, oligodendrogliomas, and oligoastrocytomas were considered separately. ADC values were significantly different for all 3 grades. The ADC threshold value of 1.185 * 10(-3) mm(2)/s and the rCBV cutoff value of 1.74 could be used with high sensitivity in the characterization of high-grade gliomas. The area under the ROC curve for the maximum rCBV and minimum ADC was 0.72 and 0.75, respectively. The combination of rCBV and ADC values increased the area under the ROC curve to 0.83. CONCLUSIONS: ADC measurements are better than rCBV values for distinguishing the grades of gliomas. The combination of minimum ADC and maximum rCBV improves the diagnostic accuracy of glioma grading. PMID- 22207306 TI - Autoimmunity: Interfering with brain inflammation. PMID- 22207307 TI - Comparison of long-term results between laparoscopy-assisted gastrectomy and open gastrectomy with D2 lymph node dissection for advanced gastric cancer. AB - BACKGROUND: Laparoscopy-assisted gastrectomy (LAG) has been established as a low invasive surgery for early gastric cancer. However, it remains unknown whether it is applicable also for advanced gastric cancer, mainly because the long-term results of LAG with D2 lymph node dissection for advanced gastric cancer have not been well validated compared with open gastrectomy (OG). METHODS: A retrospective cohort study was performed to compare LAG and OG with D2 lymph node dissection. For this study, 167 patients (66 LAG and 101 OG patients) who underwent gastrectomy with D2 lymph node dissection for advanced gastric cancer were reviewed. Recurrence-free survival and overall survival time were estimated using Kaplan-Meier curves. Stratified log-rank statistical evaluation was used to compare the difference between the LAG and OG groups stratified by histologic type, pathologic T status, N status, and postoperative adjuvant chemotherapy. The adjusted Cox proportional hazards regression models were used to calculate the hazard ratios (HRs) of LAG. RESULTS: The 5-year recurrence-free survival rate was 89.6% in the LAG group and 75.8% in the OG group (nonsignificant difference; stratified log-rank statistic, 3.11; P = 0.0777). The adjusted HR of recurrence for LAG compared with OG was 0.389 [95% confidence interval (CI) 0.131-1.151]. The 5-year overall survival rate was 94.4% in the LAG group and 78.5% in the OG group (nonsignificant difference; stratified log-rank statistic, 0.4817; P = 0.4877). The adjusted HR of death for LAG compared with OG was 0.633 (95% CI 0.172-2.325). CONCLUSIONS: The findings show that LAG with D2 lymph node dissection is acceptable in terms of long-term results for advanced gastric cancer cases and may be applicable for advanced gastric cancer treatment. PMID- 22207309 TI - Single-incision laparoscopic Roux-en-Y hepaticojejunostomy using conventional instruments for children with choledochal cysts. AB - BACKGROUND: Single-incision laparoscopy has recently become popular in pediatric surgery. Yet there has been no report on its application in the management of choledochal cysts (CDC). The current series is the first study to evaluate the safety and efficacy of single-incision laparoscopic hepaticojejunostomy (SILH) for CDC in children. METHODS: We reviewed 19 children who underwent SILH between April and June 2011. Early postoperative and follow-up results were compared with our historical controls. RESULTS: The median follow-up period was 3 months. Two procedures were converted to the conventional four-port laparoscopic hepaticojejunostomies. SILH was successfully completed in 17 patients (median age: 3.00 years; F/M: 12/5). Early in the series, one patient developed bile leak, which stopped spontaneously after 10 days of drainage. The mean operative time of the SILH group did not differ from that of our conventional laparoscopic hepaticojejunostomy (CLH) controls (3.06 vs. 3.04 h, P = 0.909). The average postoperative hospital stay, time to full feed, and duration of drainage in the SILH group were comparable to our historical controls of CLH (P = 0.056, 0.472, 0.619, respectively). CONCLUSIONS: In experienced hands, SILH is safe and its short-term results are comparable to CLH. It potentially provides a viable surgical alternative for CDC. PMID- 22207310 TI - RSVP in orbit: identification of single and dual targets in motion. AB - Three experiments using rapid serial visual presentation (RSVP) tested participants' ability to detect targets in streams that are in motion. These experiments compared the ability to identify moving versus stationary RSVP targets and examined the attentional blink with pairs of targets that were moving or stationary. One condition presented RSVP streams in the center of the screen; a second condition used an RSVP that was orbiting in a circle, with participants instructed to follow the stream with their eyes; and a third condition had participants fixate in the middle while observing a circling RSVP stream. Relative to performance in stationary RSVP streams, participants were not markedly impaired in detecting single targets in RSVP streams that were moving, either with or without instructions to pursue the motion. In streams with two targets, a normal attentional blink effect was observed when participants were instructed to pursue the moving stream. When participants had to maintain central fixation as the RSVP stream moved, the attentional blink was nearly absent even when a trailing mask was added. We suggest that the reduction of the attentional blink for moving RSVP streams may reflect a reduced ability to perceive the temporal boundaries of the individual items. PMID- 22207311 TI - Sink positive: linguistic experience with th substitutions influences nonnative word recognition. AB - We used eyetracking, perceptual discrimination, and production tasks to examine the influences of perceptual similarity and linguistic experience on word recognition in nonnative (L2) speech. Eye movements to printed words were tracked while German and Dutch learners of English heard words containing one of three pronunciation variants (/t/, /s/, or /f/) of the interdental fricative /theta/. Irrespective of whether the speaker was Dutch or German, looking preferences for target words with /theta/ matched the preferences for producing /s/ variants in German speakers and /t/ variants in Dutch speakers (as determined via the production task), while a control group of English participants showed no such preferences. The perceptually most similar and most confusable /f/ variant (as determined via the discrimination task) was never preferred as a match for /theta/. These results suggest that linguistic experience with L2 pronunciations facilitates recognition of variants in an L2, with effects of frequency outweighing effects of perceptual similarity. PMID- 22207312 TI - All the stereotypes confirmed: differences in how Australian boys and girls use their time. AB - BACKGROUND: To influence adolescent health, a greater understanding of time use and covariates such as gender is required. PURPOSE: To explore gender-specific time use patterns in Australian adolescents using high-resolution time use data. METHOD: This study analyzed 24-hour recall time use data collected as part of the 2007 Australian National Children's Nutrition and Physical Activity Survey (n = 2,200). Univariate analyses to determine gender differences in time use were conducted. RESULTS: Boys spent more (p < .0001) time participating in screen based (17.7 % vs. 14.2% daily time) and physical activities (10.7% vs. 9.2%). Girls spent more (p < .0001) time being social (4.7% vs. 3.4% daily time), studying (2.0% vs. 1.7%), and doing household chores (4.7% vs. 3.4%). CONCLUSIONS: There are gender-specific differences in time use behavior among Australian adolescents. The results reinforce existing time use gender-based stereotypes. Implications. The gender-specific time use behaviors offer intervention design possibilities. PMID- 22207313 TI - Thunderclap headache as the primary clinical feature of a supratentorial embolic cerebral infarct. PMID- 22207314 TI - GSTT1 is upregulated by oxidative stress through p38-MK2 signaling pathway in human granulosa cells: possible association with mitochondrial activity. AB - We previously reported that GSTT1 was upregulated in human granulosa cells during aging and that activation and localization of p38 MAPK was changed in parallel. Although oxidative stress is responsible for these changes, the age-associated expression of GSTT1 regulated by MAPKs and the role of GSTT1 in aged granulosa cells remain unclear. Therefore, we examined the relationship between the expression of GSTT1 and MAPK signaling pathways using human granulosa-like KGN cells stimulated with H(2)O(2) in the presence or absence of various MAPK inhibitors. Interestingly, H(2)O(2)-induced GSTT1 was only inhibited by a p38 inhibitor. An inhibitor of MK2, a downstream regulator of p38, also diminished H(2)O(2)-induced GSTT1 upregulation. Notably, both p38 and MK2 were significantly inactivated in cells carrying an shRNA construct of GSTT1 (?GSTT1 cells), suggesting that the p38-MK2 pathway is essential for age-associated upregulation of GSTT1. The relevance of GSTT1 in mitochondrial activity was then determined. ?GSTT1 cells displayed enhanced polarization of mitochondrial membrane potential without increasing the apoptosis, suggesting that the age-associated upregulation of GSTT1 may influence the mitochondrial activity of granulosa cells. PMID- 22207315 TI - Validation of indirect calorimetry for measurement of energy expenditure in healthy volunteers undergoing pressure controlled non-invasive ventilation support. AB - The aim of this validation study was to assess the reliability of gas exchange measurement with indirect calorimetry among subjects who undergo non-invasive ventilation (NIV). Oxygen consumption (VO2) and carbon dioxide production (VCO2) were measured in twelve healthy volunteers. Respiratory quotient (RQ) and resting energy expenditure (REE) were then calculated from the measured VO2 and VCO2 values. During the measurement period the subjects were breathing spontaneously and ventilated using NIV. Two different sampling air flow values 40 and 80 l/min were used. The gas leakage from the measurement setup was assessed with a separate capnograph. The mean weight of the subjects was 93 kg. Their mean body mass index was 29 (range 22-40) kg/m2. There was no statistically significant difference in the measured values for VO2, VCO2, RQ and REE during NIV-supported breathing and spontaneous breathing. The change of sampling air flow had no statistically significant effect on any of the above parameters. We found that REE can be accurately measured with an indirect calorimeter also during NIV supported breathing and the change of sampling air flow does not distort the gas exchange measurement. A higher sampling air flow in indirect calorimetry decreases the possibility for air leakages in the measurement system and increases the reliability of REE measurement. PMID- 22207316 TI - Ex vivo enrichment of circulating anti-tumor T cells from both cutaneous and ocular melanoma patients: clinical implications for adoptive cell transfer therapy. AB - Tumor-infiltrating lymphocytes (TILs) have been successfully used for adoptive cell transfer (ACT) immunotherapy; however, due to their scarce availability, this therapy is possible for a limited fraction of cutaneous melanoma patients. We assessed whether an effective protocol for ex vivo T-cell expansion from peripheral blood mononuclear cells (PBMCs), suitable for ACT of both cutaneous and ocular melanoma patients, could be identified. PBMCs from both cutaneous and ocular melanoma patients were stimulated in vitro with autologous, irradiated melanoma cells (mixed lymphocyte tumor cell culture; MLTCs) in the presence of IL 2 and IL-15 followed by the rapid expansion protocol (REP). The functional activity of these T lymphocytes was characterized and compared with that of TILs. In addition, the immune infiltration in vivo of ocular melanoma lesions was analyzed. An efficient in vitro MLTC expansion of melanoma reactive T cells was achieved from all PBMC's samples obtained in 7 cutaneous and ocular metastatic melanoma patients. Large numbers of melanoma-specific T cells could be obtained when the REP protocol was applied to these MLTCs. Most MLTCs were enriched in non terminally differentiated T(EM) cells homogeneously expressing co-stimulatory molecules (e.g., NKG2D, CD28, CD134, CD137). A similar pattern of anti-tumor activity, in association with a more variable expression of co-stimulatory molecules, was detected on short-term in vitro cultured TILs isolated from the same patients. In these ocular melanoma patients, we observed an immune infiltrate with suppressive characteristics and a low rate of ex vivo growing TILs (28.5% of our cases). Our MLTC protocol overcomes this limitation, allowing the isolation of T lymphocytes with effector functions even in these patients. Thus, anti-tumor circulating PBMC-derived T cells could be efficiently isolated from melanoma patients by our novel ex vivo enrichment protocol. This protocol appears suitable for ACT studies of cutaneous and ocular melanoma patients. PMID- 22207317 TI - Using predictors of hormone therapy use to model the healthy user bias: how does healthy user status influence cognitive effects of hormone therapy? AB - OBJECTIVE: This study investigated the phenomenon known as the healthy user bias by equating hormone therapy (HT) use (past or current) with healthy user status. METHODS: Data from the Survey of Midlife in the United States were used to identify the predictors of HT use. The unique Survey of Midlife in the United States data include psychological, demographic, health-related, and behavioral variables as well as history of HT use. Predictors of HT use were combined to derive propensity scores, describing the likelihood that a woman was an HT user, based on her psychological, demographic, physical, and behavioral profile (ie, likelihood of being a healthy user) as opposed to her actual use of HT. Finally, cognitive performance on an executive function test was examined in women stratified by propensity score. RESULTS: Using a multiple logistic regression model, nine variables emerged as predictors of HT use. The nine variables were used to estimate the propensity or conditional probability of using HT for each subject; resultant propensity scores were ranked and divided into tertiles. Women in the highest tertile demonstrated shorter median response latencies on a test of executive function than did women who did not use HT. CONCLUSIONS: From an array of psychological, medical, and behavioral variables, nine emerged as predictors of HT use. If validated, these features may serve as a means of estimating the phenomenon known as healthy user bias. Moreover, these data suggest that the degree to which a woman fits a model of a healthy user may influence cognitive response to HT. PMID- 22207318 TI - Evolution of postmenopausal hormone therapy between 2002 and 2009. AB - OBJECTIVE: The results of the Women's Health Initiative led to a sharp decline in postmenopausal hormone therapy use. Subsequently, treatment guidelines were revised to recommend hormone therapy at the lowest effective dose for the shortest possible duration. The objective of this analysis was to assess trends in nationwide hormone therapy prescription claims from 2002 to 2009. METHODS: This study was a retrospective database analyses of pharmacy claims from MedImpact Healthcare Systems Inc. Data from women with claims for oral or transdermal hormone therapy were analyzed to assess trends in hormone therapy claims, including route of administration, dose, and physician specialty. RESULTS: By the end of 2002, the total number of hormone therapy claims dropped approximately 30% from 2002 second quarter claims. This trend continued during the next 7 years, and by 2009, hormone therapy claims were reduced by more than 70%. The proportion of low--dose oral claims rose fourfold, whereas the proportion of standard/high-dose claims decreased 30%. The proportion of claims for transdermal formulations more than doubled, and the proportion of claims for low-dose transdermal hormone therapy increased 10-fold. Although reductions in overall claims, routes of administration, and dose categories were similar between physician specialties, obstetrician/gynecologists prescribed transdermal hormone therapy nearly twice as often as all other types of providers. CONCLUSIONS: Since the publication of the Women's Health Initiative results, there has been a sustained decrease in hormone therapy claims. The proportional use of low-dose oral and transdermal formulations has increased, but as of 2009, claims for these formulations accounted for approximately one in four total hormone therapy claims. PMID- 22207319 TI - Adolescent pregnancy is associated with osteoporosis in postmenopausal women. AB - OBJECTIVE: Adolescence is a critical time of life to accumulate bone for peak bone mass. Factors that may interfere with bone mass accrual during this period may increase the risk of osteoporosis. Several studies have reported that pregnancy during adolescence has detrimental effects on bone mass measurements after pregnancy. However, less is known about how adolescent pregnancy affects bone mineral density (BMD) and osteoporosis after menopause. The aim of this study was to evaluate the association between adolescent pregnancy and osteoporosis in postmenopausal Korean women. METHODS: We conducted a cross sectional study of 719 postmenopausal women, all of whom were enrolled in the Korean National Health and Nutrition Examination Survey in 2008. BMD was measured using dual-energy x-ray absorptiometry. RESULTS: Postmenopausal women with histories of adolescent pregnancy had lower BMD of the total hip, femoral neck, and lumbar spine than did women without histories of adolescent pregnancy. Multivariate logistic regression analyses revealed that postmenopausal women with history of adolescent pregnancy were at increased risk of osteoporosis (odds ratio, 2.20; 95% CI, 1.12-4.30) compared with women without history of adolescent pregnancy after adjustments for age, body mass index, marital status, education level, household income, alcohol intake, smoking history, exercise, age at menarche, age at menopause, parity, hormone therapy use, intake of energy and calcium, and vitamin D level. CONCLUSIONS: Adolescent pregnancy may be a predictor of osteoporosis in postmenopausal women. PMID- 22207320 TI - Fish intake, cooking practices, and risk of prostate cancer: results from a multi ethnic case-control study. AB - PURPOSE: Studies conducted to assess the association between fish consumption and prostate cancer (PCA) risk are inconclusive. However, few studies have distinguished between fatty and lean fish, and no studies have considered the role of different cooking practices, which may lead to differential accumulation of chemical carcinogens. In this study, we investigated the association between fish intake and localized and advanced PCA taking into account fish types (lean vs. fatty) and cooking practices. METHODS: We analyzed data for 1,096 controls, 717 localized and 1,140 advanced cases from the California Collaborative Prostate Cancer Study, a multiethnic, population-based case-control study. We used multivariate conditional logistic regression to estimate odds ratios using nutrient density converted variables of fried fish, tuna, dark fish and white fish consumption. We tested for effect modification by cooking methods (high- vs. low-temperature methods) and levels of doneness. RESULTS: We observed that high white fish intake was associated with increased risk of advanced PCA among men who cooked with high-temperature methods (pan-frying, oven-broiling and grilling) until fish was well done (p (trend) = 0.001). No associations were found among men who cooked fish at low temperature and/or just until done (white fish x cooking method p (interaction) = 0.040). CONCLUSIONS: Our results indicate that consideration of fish type (oily vs. lean), specific fish cooking practices and levels of doneness of cooked fish helps elucidate the association between fish intake and PCA risk and suggest that avoiding high-temperature cooking methods for white fish may lower PCA risk. PMID- 22207322 TI - Effects of intravenous iron on mononuclear cells during the haemodialysis session. AB - BACKGROUND: This study analysed, in vivo and in vitro, the effects of four different intravenous iron preparations (iron gluconate, iron sucrose, iron dextran and ferric carboxymaltose) on activation and damage of mononuclear cells. METHODS: A randomized prospective study was conducted in 10 haemodialysis (HD) patients. Blood samples were collected at baseline (T0); 1 h after starting HD, just before the iron or saline administration (T1); 30 min after the iron or saline infusion (T2) and at the end of HD (T3). In addition, peripheral blood mononuclear cells from 10 healthy individuals and 9 chronic kidney disease Stage 5 (CKD-5) without HD treatment were cultured with the 4 iron preparations. RESULTS: Iron infusion during the HD session increased the percentage of mononuclear cells with reactive oxygen species (ROS) production, Inter-Cellular Adhesion Molecule-1 (ICAM-1) and apoptosis. There were no significant differences between the four iron preparations. Culture of mononuclear cells from healthy individuals and CKD-5 patients with the different iron preparations resulted in a significant increase in ROS, ICAM-1 and apoptosis as compared with control. In an additional study, the effect of original iron sucrose formulation on mononuclear cells was compared with that of one generic formulation. The generic formulation produced a greater increase in ROS, ICAM-1 and apoptosis than the original iron sucrose. CONCLUSIONS: Our results suggest that intravenous iron has deleterious effects on mononuclear cells. The four iron compounds evaluated produced similar effects on oxidative stress, cell activation and apoptosis. However, the effects of iron compounds with the same formulation were different, thus further investigation may be required to establish the safety of iron preparations that theoretically have the same composition. PMID- 22207321 TI - Genome-wide association mapping of loci for antipsychotic-induced extrapyramidal symptoms in mice. AB - Tardive dyskinesia (TD) is a debilitating, unpredictable, and often irreversible side effect resulting from chronic treatment with typical antipsychotic agents such as haloperidol. TD is characterized by repetitive, involuntary, purposeless movements primarily of the orofacial region. In order to investigate genetic susceptibility to TD, we used a validated mouse model for a systems genetics analysis geared toward detecting genetic predictors of TD in human patients. Phenotypic data from 27 inbred strains chronically treated with haloperidol and phenotyped for vacuous chewing movements were subject to a comprehensive genomic analysis involving 426,493 SNPs, 4,047 CNVs, brain gene expression, along with gene network and bioinformatic analysis. Our results identified ~50 genes that we expect to have high prior probabilities for association with haloperidol-induced TD, most of which have never been tested for association with human TD. Among our top candidates were genes regulating the development of brain motor control regions (Zic4 and Nkx6-1), glutamate receptors (Grin1 and Grin2a), and an indirect target of haloperidol (Drd1a) that has not been studied as well as the direct target, Drd2. PMID- 22207323 TI - Mineral and bone disorders and survival in hemodialysis patients with and without polycystic kidney disease. AB - BACKGROUND: Maintenance hemodialysis (MHD) patients with polycystic kidney disease (PKD) have better survival than non-PKD patients. Mineral and bone disorders (MBD) are associated with accelerated atherosclerosis and cardiovascular death in MHD patients. It is unknown whether the different MBD mortality association between MHD populations with and without PKD can explain the survival differential. METHODS: Survival models were examined to assess the association between different laboratory markers of MBD [such as serum phosphorous, parathyroid hormone (PTH), calcium and alkaline phosphatase] and mortality in a 6-year cohort of 60,089 non-PKD and 1501 PKD MHD patients. RESULTS: PKD and non-PKD patients were 57+/-13 and 62+/-15 years old and included 46 and 45% women and 14 and 32% Blacks, respectively. Whereas PKD individuals with PTH 150 to <300 pg/mL (reference) had the lowest risk for mortality, the death risk was higher in patients with PTH<150 [hazard ratio (HR): 2.16 (95% confidence interval 1.53-3.06)], 300 to <600 [HR: 1.30 (0.97-1.74)] and >=600 pg/mL [HR: 1.46 (1.02-2.08)], respectively. Similar patterns were found in non PKD patients. Fully adjusted death HRs of time-averaged serum phosphorous increments<3.5, 5.5 to <7.5 and >=7.5 mg/dL (reference: 3.5 to <5.5 mg/dL) for PKD patients were 2.82 (1.50-5.29), 1.40 (1.12-1.75) and 2.25 (1.57-3.22). The associations of alkaline phosphatase and calcium with mortality were similar in PKD and non-PKD patients. CONCLUSION: Bone-mineral disorder markers exhibit similar mortality trends between PKD and non-PKD MHD patients, although some differences are observed in particular in low PTH and phosphorus ranges. PMID- 22207324 TI - Uraemia disrupts the vascular niche in a 3D co-culture system of human mesenchymal stem cells and endothelial cells. AB - BACKGROUND: Recent studies identified mesenchymal stem cells (MSC) as major players in vascular remodelling and the sub-endothelial compartment as the stem cell niche. The uraemic microenvironment predisposes to increased levels of reactive oxygen species, accelerated ageing of endothelial cells (EC) and vascular sclerosis. METHODS: We generated an in vitro model of a vascular niche consisting of a three-dimensional collagen I/III gel containing MSC and EC. We recapitulated a uraemic microenvironment by supplementing the medium with 20% pooled sera from either healthy or uraemic patients. RESULTS: Under healthy conditions, MSC/EC co-culture in collagen gels resulted in vessel-like tube formation. In contrast, uraemic serum-induced expression of extracellular matrix proteins (real-time reverse transcription-polymerase chain reaction, immunohistochemistry) that was accompanied by significant collagen contraction and a myofibroblastic phenotype of MSC. Although the uraemic culture conditions stimulated EC proliferation (cell counting, BrdU assay) and did not induce apoptosis (7-amino-actinomycin, annexin V FACS analysis), the tube formation was disrupted in spite of significantly enhanced vascular endothelial growth factor-A messenger RNA expression. The excessive matrix synthesis and remodelling by uraemia-exposed MSC/EC was reminiscent of remodelling processes observed in arteries of 12 dialysis patients (using arteries from 10 children and 10 age matched non-dialysis patients as controls). CONCLUSION: Our data indicate a potential role of the sub-endothelial niche and its major cell types EC and MSC in the remodelling process of the vascular wall in CKD. PMID- 22207326 TI - Renal-limited 'lupus-like' nephritis. AB - In the setting of an IgG-dominant immune complex-mediated glomerulonephritis, there are multiple pathological findings that strongly suggest the diagnosis of lupus nephritis (LN) including (i) 'full-house' immunofluorescence staining for IgG, IgM, IgA, C3 and C1; (ii) extraglomerular immune deposits; (iii) combined mesangial, subendothelial and subepithelial immune deposits and (iv) the presence of endothelial tubuloreticular inclusions. We report four female adult patients with renal biopsy findings which are highly suggestive of LN but without extrarenal signs, symptoms or serologies of systemic lupus erythematosus at the time of biopsy or over a mean follow-up period of 3 years. Despite aggressive therapy, outcomes were poor in this small cohort. We refer to these cases as renal-limited 'lupus-like' nephritis. PMID- 22207327 TI - The impact of mycophenolate mofetil versus azathioprine as adjunctive therapy to cyclosporine on the rates of renal allograft loss due to glomerular disease recurrence. AB - BACKGROUND: Given the reported efficacy of mycophenolate mofetil (MMF) in the treatment of glomerular diseases, we question whether MMF can reduce the rate of renal allograft loss due to glomerular disease recurrence compared to azathioprine (AZA) as adjunctive therapy to cyclosporine (CSA)-based immunosuppression. METHODS: This is a retrospective study based on the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database designed to compare the Kaplan-Meier rates of graft loss due to disease recurrence stratified by primary renal diagnoses between recipients receiving CSA+AZA versus CSA+MMF. Recipients of primary kidney transplants (both deceased donor and living, related and unrelated) renal transplants performed between 1 January 1988 and 31 December 2007 with the primary renal diagnosis of IgA nephropathy (IgAN), membranous glomerulonephropathy (MGN), membranoproliferative glomerulonephropathy (MPGN), lupus nephritis (LN) or focal segmental glomerulosclerosis (FSGS) with a functioning allograft at discharge were included. RESULTS: Seven thousand eight hundred and twenty-six recipients of primary deceased donor kidney transplants (DDKT) [CSA + AZA: IgAN (890), MGN (380), MPGN (193), LN (1324), FSGS (1314) and CSA+MMF: IgAN (855), MGN (614), MPGN (116), LN (715), FSGS (1425)] and 5498 recipients of living donor kidney transplants (LDKT) [CSA+AZA: IgAN (694), MGN (229), MPGN (100), LN (592), FSGS (654) and CSA+MMF: IgAN (1066), MGN (435), MPGN (89), LN (530), FSGS (1109)] were included in the analysis. At 10-year follow-up (mean duration was 5.6 to 6.7+/ 1.8 years in DDKT and 6.2 to 7.4+/-1.7 years in LDKT), mean times of transplantation (era of transplantation) were: 1992+/-1.6 years and 2002+/-1.9 years for the CSA+AZA and CSA+MMF groups, respectively. There was no statistically significant difference in the Kaplan-Meier rates of graft loss due to disease recurrence of any glomerular disease studied between the CSA+AZA and CSA+MMF groups in either DDKT or LDKT recipients. Chi-square analysis revealed no statistically significant difference between the two immunosuppressive regimen groups in terms of age, gender and ethnic background. CONCLUSION: The OPTN/UNOS database revealed no difference in the rates of renal allograft loss due to disease recurrence of IgAN, MGN, MPGN, LN and FSGS among recipients receiving either CSA+AZA or CSA+MMF maintenance immunosuppressive therapy at 10-year follow up. PMID- 22207328 TI - Cystatin C as risk factor for cardiovascular events and all-cause mortality in the general population. The Tromso Study. AB - BACKGROUND: Glomerular filtration rate<60 mL/min/1.73 m2 is associated with increased cardiovascular risk. Cystatin C is believed to be a better tool than creatinine for detection of mild renal dysfunction (>60 mL/min/1.73 m2) and possibly a more sensitive marker for cardiovascular risk and all-cause mortality. We examined the association of cystatin C with cardiovascular morbidity and all cause mortality in a prospective population-based study. METHODS: Cystatin C was measured in 2852 men and 3153 women in the Tromso Study 1994/95. Gender-specific associations during 12 years of follow-up for all-cause mortality and 9.5 years for myocardial infarction (MI) and ischaemic stroke were assessed (Cox proportional hazard ratios, HRs). RESULTS: During follow-up, 591 MIs, 293 ischaemic strokes and 1262 deaths occurred. In women, HR for all-cause mortality was increased in the upper cystatin C quartile (>=0.93 mg/L) compared with the lowest quartile (<=0.73 mg/L); 1.38, 95% confidence interval 1.04-1.84. A significant interaction with gender was observed. One SD (0.17 mg/L) increase in cystatin C was associated with 9% higher risk of death in women, also when persons with a cancer history were excluded. Crude HRs for MI and ischaemic stroke were increased in both genders, but the associations did not persist after multivariable adjustments. No independent associations with end points were observed in non-gender-specific analyses. CONCLUSIONS: Cystatin C was not independently associated with fatal and non-fatal MI or ischaemic stroke in the general population. However, cystatin C was a risk factor for all-cause mortality in women. PMID- 22207325 TI - Prevalence and correlates of erectile dysfunction in men on chronic haemodialysis: a multinational cross-sectional study. AB - BACKGROUND: Factors associated with erectile dysfunction in men on haemodialysis are incompletely identified due to suboptimal existing studies. We determined the prevalence and correlates of erectile dysfunction and identified combinations of clinical characteristics associated with a higher risk of erectile dysfunction using recursive partitioning and amalgamation (REPCAM) analysis. METHODS: We conducted a multinational cross-sectional study in men on haemodialysis within a collaborative network. Erectile dysfunction and depressive symptoms were evaluated using the erectile function domain of the International Index of Erectile Function questionnaire and the Center for Epidemiological Studies Depression Scale, respectively. RESULTS: Nine hundred and forty-six (59%) of 1611 eligible men provided complete data for erectile dysfunction. Eighty-three per cent reported erectile dysfunction and 47% reported severe erectile dysfunction. Four per cent of those with erectile dysfunction were receiving pharmacological treatment. Depressive symptoms were the strongest correlate of erectile dysfunction [adjusted odds ratio 2.41 (95% confidence interval (CI) 1.57-3.71)]. Erectile dysfunction was also associated with age (1.06, 1.05-1.08), being unemployed (1.80, 1.17-2.79) or receiving a pension (2.05, 1.14-3.69) and interdialytic weight gain (1.9-2.87 kg, 1.92 [CI 1.19-3.09]; >2.87 kg, 1.57 [CI 1.00-2.45]). Married men had a lower risk of erectile dysfunction (0.49, 0.31 0.76). The prevalence of erectile dysfunction was highest (94%) in unmarried and unemployed or retired men who have depressive symptoms. CONCLUSIONS: Most men on haemodialysis experience erectile dysfunction and are untreated. Given the prevalence of this condition and the relative lack of efficacy data for pharmacological agents, we suggest that large trials of pharmacological and non pharmacological interventions for erectile dysfunction and depression are needed. PMID- 22207329 TI - The impact of type II diabetes mellitus in patients with autosomal dominant polycystic kidney disease. AB - BACKGROUND: The epidemic of obesity and diabetes is increasing within the USA and worldwide. We have previously shown that body mass index has increased significantly in autosomal dominant polycystic kidney disease (ADPKD) subjects seen at our center in more recent years. However, the impact of Type II diabetes in ADPKD patients has not been well studied. METHODS: This retrospective cohort study compared clinical characteristics in 44 pre-renal transplant patients with ADPKD and diabetes and 88 age- and sex-matched non-diabetic patients with ADPKD who were seen at the University of Colorado between 1977 and 2008. The primary outcomes in this study were renal volume determined by renal ultrasonography, renal function assessed by estimated glomerular filtration rate and time to onset of end-stage renal disease or death by Kaplan-Meier analyses. RESULTS: Diabetic patients had significantly larger kidney volumes than those with ADPKD alone [geometric mean (95% confidence interval (CI)]: 2456 (1510-3992) versus 1358 (1186-1556) cm3, P=0.02. Among those whose age at hypertension diagnosis was known, the diabetic ADPKD patients had earlier median (95% CI) age at onset of hypertension compared to those with ADPKD alone: 32.5 (28-40) versus 38 (35-42) years, P=0.04. Diabetic ADPKD patients tended to have an earlier median age of death than those with ADPKD alone. CONCLUSIONS: Patients with ADPKD and type II diabetes have larger renal volumes, earlier age at diagnosis of hypertension and may die at a younger age compared to those patients with ADPKD alone. This study emphasizes the importance of diabetes risk management in ADPKD. PMID- 22207330 TI - A predictive algorithm for the management of anaemia in haemodialysis patients based on ESA pharmacodynamics: better results for less work. AB - BACKGROUND: Many anaemia management algorithms recommend changes to erythropoiesis-stimulating agent (ESA) doses based on frequent measurement of haemoglobin levels in keeping with the ESA datasheets. We designed a predictive anaemia algorithm based on ESA pharmacodynamics, which we hoped would improve compliance with haemoglobin targets and reduce workload. METHODS: A new algorithm was designed which predicted the 3-month steady-state haemoglobin concentration following a change in ESA dose and only recommended a change if it was outside the range 10.5-12.5 g/dL. Data were collected prospectively for 3 months prior and 15 months subsequent to implementing the algorithm. RESULTS: A total of 214 prevalent dialysis patients were included in the audit. After 12 months, the haemoglobin concentration was 11.4 g/dL, near the midpoint of the target range, with a narrowing of the distribution (SD 1.46 to 1.25 g/dL, P < 0.0001). The proportion of patients with a haemoglobin level in the target range increased from 56% to 66% (P < 0.001) principally due to a reduction in the number of patients with high haemoglobin levels. There was no significant change in the ESA dose over the audit period. The number of prescription changes fell from 1/2.5 months to 1/6.1 months after 12 months (P < 0.001). CONCLUSIONS: Switching prevalent haemodialysis patients to a predictive anaemia management algorithm improved compliance with haemoglobin targets, reduced the number of patients with high haemoglobin levels and reduced the number of ESA dose changes required. PMID- 22207331 TI - The fallacy of the BUN:creatinine ratio in critically ill patients. AB - BACKGROUND AND OBJECTIVES: Acute kidney injury (AKI) is common in critically ill patients and is associated with a high mortality rate. Pre-renal azotemia, suggested by a high blood urea nitrogen to serum creatinine (BUN:Cr) ratio (BCR), has traditionally been associated with a better prognosis than other forms of AKI. Whether this pertains to critically ill patients is unknown. METHODS: We conducted a retrospective observational study of two cohorts of critically ill patients admitted to a single center: a derivation cohort, in which AKI was diagnosed, and a larger validation cohort. We analyzed associations between BCR and clinical outcomes: mortality and renal replacement therapy (RRT). RESULTS: Patients in the derivation cohort (N = 1010) with BCR >20 were older, predominantly female and white, and more severely ill. A BCR >20 was significantly associated with increased mortality and a lower likelihood of RRT in all patients, patients with AKI and patients at risk for AKI. Patients in the validation cohort (N = 10 228) with a BCR >20 were older, predominantly female and white, and more severely ill. A BCR >20 was associated with increased mortality and a lower likelihood of RRT in all patients and in those at risk for AKI, BUN correlated with age and severity of illness. CONCLUSIONS: A BCR >20 is associated with increased mortality in critically ill patients. It is also associated with a lower likelihood of RRT, perhaps because of misinterpretation of the BCR. Clinicians should not use a BCR >20 to classify AKI in critically ill patients. PMID- 22207332 TI - Timing of initiation of renal replacement therapy for acute kidney injury: a survey of nephrologists and intensivists in Canada. AB - BACKGROUND: Little is known about factors that influence the timing of initiation of renal replacement therapy (RRT) for acute kidney injury (AKI). We sought to better describe these factors for Canadian physicians that prescribe RRT for AKI. METHODS: A web-based survey was conducted of physicians involved in the decision to initiate RRT for critically ill patients in Canada. Participants were asked about the factors that prompt them to initiate RRT for AKI both directly and using scenario-based questions. RESULTS: Surveys completed by 180 physicians at 32 different sites were included for analysis. Serum potassium level and severity of pulmonary edema were the most commonly utilized factors for deciding when RRT should be started. For all clinical and laboratory factors inquired about, there was wide variation in the minimum severity that prompted respondents to indicate that they would initiate RRT. Additional factors that influenced the timing of initiation were the time-of-day that laboratory and clinical results became available, patient age and co-morbidity, responsiveness to a diuretic challenge and the specialty of the prescribing physician. Over 90% of respondents indicated that a randomized controlled trial to assess the optimal timing of initiation of RRT for AKI is ethically justified. CONCLUSIONS: These results provide insight into clinical and laboratory factors that influence the timing of initiation of RRT for AKI and may aid in the design of future trials. While most clinicians consider the degree of hyperkalemia and pulmonary edema in deciding when to initiate RRT for AKI, there is a wide range of clinical practice, uncertainty regarding the optimal timing of initiation and enthusiasm for prospective interventional studies to address this topic. PMID- 22207333 TI - Hepatic differentiation from human mesenchymal stem cells on a novel nanofiber scaffold. AB - The emerging fields of tissue engineering and biomaterials have begun to provide potential treatment options for liver failure. The goal of the present study is to investigate the ability of a poly L-lactic acid (PLLA) nanofiber scaffold to support and enhance hepatic differentiation of human bone marrow-derived mesenchymal stem cells (hMSCs). A scaffold composed of poly L-lactic acid and collagen was fabricated by the electrospinning technique. After characterizing isolated hMSCs, they were seeded onto PLLA nanofiber scaffolds and induced to differentiate into a hepatocyte lineage. The mRNA levels and protein expression of several important hepatic genes were determined using RT-PCR, immunocytochemistry and ELISA. Flow cytometry revealed that the isolated bone marrow-derived stem cells were positive for hMSC-specific markers CD73, CD44, CD105 and CD166 and negative for hematopoietic markers CD34 and CD45. The differentiation of these stem cells into adipocytes and osteoblasts demonstrated their multipotency. Scanning electron microscopy showed adherence of cells in the nanofiber scaffold during differentiation towards hepatocytes. Our results showed that expression levels of liver-specific markers such as albumin, alpha fetoprotein, and cytokeratins 8 and 18 were higher in differentiated cells on the nanofibers than when cultured on plates. Importantly, liver functioning serum proteins, albumin and alpha-1 antitrypsin were secreted into the culture medium at higher levels by the differentiated cells on the nanofibers than on the plates, demonstrating that our nanofibrous scaffolds promoted and enhanced hepatic differentiation under our culture conditions. Our results show that the engineered PLLA nanofibrous scaffold is a conducive matrix for the differentiation of MSCs into functional hepatocyte-like cells. This represents the first step for the use of this nanofibrous scaffold for culture and differentiation of stem cells that may be employed for tissue engineering and cell-based therapy applications. PMID- 22207334 TI - A new BSMV-based vector with modified beta molecule allows simultaneous and stable silencing of two genes. AB - Virus-induced gene silencing is an important tool for functional gene analysis and the vector based on Barley stripe mosaic virus (BSMV) is widely used for the purpose in monocots. Of the tripartite BSMV genome, currently the BSMV:gammaMCS molecule is used to clone a fragment of a target gene. As an alternative, the BSMV:beta molecule was engineered with a unique BamHI site between the open reading frame of betac (ORF betac) and poly(A). The mixture of RNA particles alpha, betaBamHI and gammaMCS was fully infectious. Barley phytoene desaturase and wheat phospholipase Dalpha fragments were cloned to betaBamHI and gammaMCS. Delivery of the target gene fragment in gammaMCS induced stronger silencing, while delivery in betaBamHI yielded more stable transcript reduction. A quantitative analysis (qRT-PCR) of the transcripts showed that the silencing induced with a fragment carried in both particles was stronger and more stable than that from a fragment placed in one particle. The modification of beta enables simultaneous silencing of two genes. Quantifying the beta and gamma particles in virus-inoculated plants revealed a 2.5-fold higher level of gamma than beta, while the stability of the insert was higher in beta compared with gamma. The possible influence of the relative quantity of beta and gamma particles in virus-inoculated plants on insert stability and gene silencing efficiency is discussed. PMID- 22207335 TI - Cloning and expression of a new inositol 1,4,5-trisphosphate receptor type 1 splice variant in adult rat atrial myocytes. AB - Inositol 1,4,5-trisphosphate receptor type 1 (IP(3)R1) is already known to be highly expressed in the brain, and is found in many other tissues, including the atrium of the heart. Although the complete primary structure of IP(3)R1 in the rat brain has been reported, the complete sequence of an IP(3)R1 clone from atrial myocytes has not been reported. We isolated an IP(3)R1 complementary DNA (cDNA) clone from isolated adult rat atrial myocytes, and found a new splice variant of IP(3)R1 that was different from a previously reported IP(3)R1 cDNA clone obtained from a rat brain (NCBI GenBank accession number: NM_001007235). Our clone had 99% similarity with the rat brain IP(3)R1 sequence; the exceptions were 39 amino acid deletions at the position of 1693-1731, and the deletion of phenylalanine at position 1372 that lay in the regulatory region. Compared with the rat brain IP(3)R1, in our clone proline was replaced with serine at residue 2439, and alanine was substituted for valine at residue 2445. These changes lie adjacent to or within the fifth transmembrane domain (2440-2462). Although such changes in the amino acid sequences were different from the rat brain IP3R1 clone, they were conserved in human or mouse IP3R1. We produced a plasmid construct expressing the atrial IP3R1 together with green fluorescent protein (GFP), and successfully overexpressed the atrial IP3R1 in the adult atrial cell line HL-1. Further investigation is needed on the physiological significance of the new splice variant in atrial cell function. PMID- 22207336 TI - Inhibition of biogenic membrane flippase activity in reconstituted ER proteoliposomes in the presence of low cholesterol levels. AB - Biogenic membranes or self-synthesizing membranes are the site of synthesis of new lipids such as the endoplasmic reticulum (ER) in eukaryotes. Newly synthesized phospholipids (PLs) at the cytosolic leaflet of ER need to be translocated to the lumen side for membrane biogenesis and this is facilitated by a special class of lipid translocators called biogenic membrane flippase. Even though ER is the major site of cholesterol synthesis, it contains very low amounts of cholesterol, since newly synthesized cholesterol in ER is rapidly transported to other organelles and is highly enriched in plasma membrane. Thus, only low levels of cholesterol are present at the biosynthetic compartment (ER), which results in loose packing of ER lipids. We hypothesize that the prevalence of cholesterol in biogenic membranes might affect the rapid flip-flop. To validate our hypothesis, detergent solubilized ER membranes from both bovine liver and spinach leaves were reconstituted into proteoliposomes with varying mol% of cholesterol. Our results show that (i) with increase in the cholesterol/PL ratio, the half-life time of PL translocation increased, suggesting that cholesterol affects the kinetics of flipping, (ii) flipping activity was completely inhibited in proteoliposomes reconstituted with 1 mol% cholesterol, and (iii) FRAP and DSC experiments revealed that 1 mol% cholesterol did not alter the bilayer properties significantly and that flippase activity inhibition is probably mediated by interaction of cholesterol with the protein. PMID- 22207337 TI - Developmental expression of P5 ATPase mRNA in the mouse. AB - P(5) ATPases (ATP13A1 through ATP13A5) are found in all eukaryotes. They are currently poorly characterized and have unknown substrate specificity. Recent evidence has linked two P(5) ATPases to diseases of the nervous system, suggesting possible importance of these proteins within the nervous system. In this study we determined the relative expression of mouse P5 ATPases in development using quantitative real time PCR. We have shown that ATP13A1 and ATP13A2 were both expressed similarly during development, with the highest expression levels at the peak of neurogenesis. ATP13A3 was expressed highly during organogenesis with one of its isoforms playing a more predominant role during the period of neuronal development. ATP13A5 was expressed most highly in the adult mouse brain. We also assessed the expression of these genes in various regions of the adult mouse brain. ATP13A1 to ATP13A4 were expressed differentially in the cerebral cortex, hippocampus, brainstem and cerebellum while levels of ATP13A5 were fairly constant between these brain regions. Moreover, we demonstrated expression of the ATP13A4 protein in the corresponding brain regions using immunohistochemistry. In summary, this study furthers our knowledge of P(5)-type ATPases and their potentially important role in the nervous system. PMID- 22207339 TI - DUBs' key to selectivity. PMID- 22207340 TI - Three-dimensional echocardiography in the management of parachute mitral valve. PMID- 22207341 TI - Multimodality imaging of iatrogenic pulmonary vein stenosis. PMID- 22207342 TI - Importance and inter-relationship of tissue Doppler variables for predicting adverse outcomes in high-risk patients: an analysis of 388 diabetic patients referred for coronary angiography. AB - AIMS: To investigate the relative importance of individual tissue Doppler imaging variables to predict adverse events in a high-risk population with diabetes, ischaemic heart disease, and/or systolic dysfunction. METHODS AND RESULTS: Transthoracic echocardiograms were analysed in 388 diabetic patients without significant valve disease, bundle branch block, and atrial fibrillation who underwent coronary angiography. Multivariable Cox's regression analyses were used to establish the association between peak systolic (s'), early diastolic (e'), and late diastolic (a') tissue velocities and outcomes (hospitalization for heart failure or death). The mean age and left ventricular ejection fraction (LVEF) was 66+/-10 years and 45+/-12%, respectively. During 2.3 (+/-1.0) years of follow-up, 91 patients (24%) met the combined endpoint. After adjustment for LVEF, coronary artery pathology, heart failure at baseline, age, and gender, each 1 cm/s decrease in s', e', and a' was associated with a hazard ratio (HR) of 1.18 (0.89 1.57), 1.03 (0.86-1.22), and 1.20 (1.05-1.37), respectively. A significant interaction was found between s' and a', P<0.01. In patients with lower than mean s', 1 cm/s decrease in a' was associated with HR 1.31 (1.10-1.55, P<0.01), whereas a' was without prognostic importance in patients with higher than mean s' [HR 0.99 (0.78-1.25, P=0.6)]. Patients having lower than mean values of both s' and a' had a poorer prognosis than patients having at least one of s' and a' high. CONCLUSION: Peak systolic and late diastolic tissue velocities add prognostic information beyond LVEF in high-risk patients. Variables should be considered together as they interact on prognosis. PMID- 22207343 TI - Influence of pre-infarction angina, collateral flow, and pre-procedural TIMI flow on myocardial salvage index by cardiac magnetic resonance in patients with ST segment elevation myocardial infarction. AB - BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI) pre-infarction angina, pre-procedural TIMI flow and collateral flow to the myocardium supplied by the infarct related artery are suggested to be cardioprotective. We evaluated the effect of these factors on myocardial salvage index (MSI) and infarct size adjusting for area at risk in patients with STEMI treated with primary percutaneous coronary intervention. METHODS AND RESULTS: Cardiac magnetic resonance (CMR) was used to measure myocardial area at risk within 1-7 days and final infarct size 90 +/- 21 days after the STEMI in 200 patients. MSI was calculated as (area-at-risk infarct size) / area-at-risk. Patients with pre-infarction angina had a median MSI of 0.80 (IQR 0.67 to 0.86) versus 0.72 (0.61 to 0.80) in those without pre-infarction angina, P = 0.004). In a regression analysis of the infarct size plotted against the area-at-risk there was a strong trend that the line for the pre-infarction angina group was below the one for the non-angina group (P = 0.05). Patients with pre-procedural TIMI flow 0/1, 2 and 3 had a median MSI of (0.69 (IQR 0.59 to 0.76), 0.78 (0.68 to 0.86) and 0.85 (0.77 to 0.91), respectively (P<0.001). Collateral flow did not change MSI (P = 0.45) nor area-at-risk (P = 0.40) and no significant difference in infarct size adjusted for area at risk (P = 0.25) was observed. CONCLUSIONS: Pre-infarction angina increases MSI in patients with STEMI supporting the theory that pre-infarction angina leads to ischemic preconditioning. As opposed to the presence of angiographically visible collateral flow to the infarct area pre procedural TIMI flow is strongly associated with MSI. PMID- 22207344 TI - Transoesophageal echocardiography: an unusual trigger to Takotsubo cardiomyopathy. PMID- 22207345 TI - A positive feedback signaling loop between ATM and the vitamin D receptor is critical for cancer chemoprevention by vitamin D. AB - Both epidemiologic and laboratory studies have shown the chemopreventive effects of 1alpha,25-dihydroxyvitamin D(3) (1,25-VD) in tumorigenesis. However, understanding of the molecular mechanism by which 1,25-VD prevents tumorigenesis remains incomplete. In this study, we used an established mouse model of chemical carcinogenesis to investigate how 1,25-VD prevents malignant transformation. In this model, 1,25-VD promoted expression of the DNA repair genes RAD50 and ATM, both of which are critical for mediating the signaling responses to DNA damage. Correspondingly, 1,25-VD protected cells from genotoxic stress and growth inhibition by promoting double-strand break DNA repair. Depletion of the vitamin D receptor (VDR) reduced these genoprotective effects and drove malignant transformation that could not be prevented by 1,25-VD, defining an essential role for VDR in mediating the anticancer effects of 1,25-VD. Notably, genotoxic stress activated ATM and VDR through phosphorylation of VDR. Mutations in VDR at putative ATM phosphorylation sites impaired the ability of ATM to enhance VDR transactivation activity, diminishing 1,25-VD-mediated induction of ATM and RAD50 expression. Together, our findings identify a novel vitamin D-mediated chemopreventive mechanism involving a positive feedback loop between the DNA repair proteins ATM and VDR. PMID- 22207346 TI - Development of common variable immunodeficiency in IgA- and IgG2-deficient patients with systemic lupus erythematosus. AB - BACKGROUND: There have been few reports on children who developed common variable immunodeficiency (CVID) in association with immunoglobulin A (IgA) and IgG2 deficiencies and systemic lupus erythematosus (SLE). CASE-DIAGNOSIS/TREATMENT: Our patient experienced nephrotic syndrome and acute respiratory distress syndrome (ARDS) caused by influenza A/H1N1 virus infection at 5 years of age. A diagnosis of IgA and IgG2 deficiency and SLE was made on the basis of severe proteinuria, hematuria, hypocomplementemia, high anti-DNA antibody and antinuclear antibody (ANA) titers, and malar rash. However, these clinical signs and symptoms and laboratory features disappeared after the administration of methylprednisolone pulse therapy and prednisolone. For the 5 years following the initial treatment for SLE, the patient experienced a number of infections and had a low serum total IgG level; she was eventually diagnosed with CVID. The administration of intravenous immunoglobulin (IVIG) was required to prevent subsequent infections, and no relapse of SLE was observed. CONCLUSION: We report the development of CVID in an IgA- and IgG2-deficient patient with SLE on the basis of multiple episodes of infection. To prevent the development of CVID in IgA- and IgG2-deficient patients with SLE, it is important to prevent immune dysregulation by the avoidance of infections through the use of IVIG therapy. PMID- 22207347 TI - Comparing cystatin C and creatinine in the diagnosis of pediatric acute renal allograft dysfunction. AB - BACKGROUND: Allograft function following renal transplantation is commonly monitored using serum creatinine. Multiple cross-sectional studies have shown that serum cystatin C is superior to creatinine for detection of mild to moderate chronic kidney dysfunction. Recent data in adults indicate that cystatin C might also be a more sensitive marker of acute renal dysfunction. This study aims to compare cystatin C and creatinine for detection of acute allograft dysfunction in children using pediatric RIFLE (risk of renal dysfunction, injury to the kidney, failure or loss of kidney function, end stage renal disease) criteria for acute kidney injury. METHODS: Retrospective chart review of post-transplant period in 24 patients in whom creatinine and cystatin C were measured every day. Allograft dysfunction was defined as a sustained rise in marker concentration above the mean of the three preceding measurements. RESULTS: In total, there were 13 episodes of allograft dysfunction. Maximum RIFLE stages with creatinine were 'R' in 7, 'I' in 4, and 'F' in 2, with cystatin C 'R' in 6, 'I' in 4 and 'F' in 3, respectively. In 9/13 cases, both markers rose simultaneously, in three, the rise in creatinine preceded cystatin C by 1-5 days (median 4). In one case, the rise in cystatin C preceded creatinine by 1 day. The time lag was not statistically different. The maximum relative rise of creatinine was significantly higher than cystatin C. By multiple linear regression analysis, the maximum rise of cystatin C was related to the maximum rise of creatinine, but independent of patient age, gender, steroid dose, and anthropometric data. CONCLUSIONS: In this pediatric population, cystatin C was not superior to creatinine for the detection of acute allograft dysfunction. PMID- 22207348 TI - Fulminant Hepatic Failure Secondary to Metastatic Transitional Cell Carcinoma Case Report and Review of the Literature. PMID- 22207349 TI - Recurrent Dedifferentiated Liposarcoma Arising from the Small Bowel Mesentery: A Case Report. PMID- 22207350 TI - Treatment with octreotide LAR in clinically non-functioning pituitary adenoma: results from a case-control study. AB - Surgical cure cannot be achieved in most patients with invasive non-functioning pituitary macroadenoma (NFPA). Short-term residual tumor treatment with somatostatin analogs has produced disappointing results. This prospective case control study assessed the efficacy of chronic treatment with long acting octreotide (octreotide LAR) on tumor volume in patients harboring post-surgical NFPA residue. The study population comprised 39 patients with NFPAs not cured by surgery. All patients underwent somatostatin receptor scintigraphy at least 6 months after the last surgery. Patients with a positive pituitary level octreoscan at (n = 26) received octreotide LAR (20 mg every 28 days) for >= 12 months (mean follow-up 37 +/- 18 months) (Treated group). Moreover, a fragment of tumor tissue from patients in the treated group was retrospectively collected to assess the immunohistochemical expression of somatostatin receptor subtypes (SSTRs). The patients with a negative octreoscan (n = 13) formed the control group (mean follow-up 37 +/- 16 months). Hormonal, radiological and visual field parameters were periodically assessed. In the treated group, all tumors expressed at least one SSTR subtype. The SSTR5 subtype was the most abundant, followed by SSTR3. The tumor residue increased in five of 26 patients (19%) in the treated group and in seven of 13 controls (53%). Visual field and pituitary function did not change in any patient. This study indicates that SSTR5 and SSTR3 are the most frequently expressed SSTR subtypes in NFPAs and supports a potential role of SSTR subtypes in stabilization of tumor remnant from NFPAs. PMID- 22207351 TI - Monozygotic twins discordant for constitutive BRCA1 promoter methylation, childhood cancer and secondary cancer. AB - We describe monozygotic twins discordant for childhood leukemia and secondary thyroid carcinoma. We used bisulfite pyrosequencing to compare the constitutive promoter methylation of BRCA1 and several other tumor suppressor genes in primary fibroblasts. The affected twin displayed an increased BRCA1 methylation (12%), compared with her sister (3%). Subsequent bisulfite plasmid sequencing demonstrated that 13% (6 of 47) BRCA1 alleles were fully methylated in the affected twin, whereas her sister displayed only single CpG errors without functional implications. This between-twin methylation difference was also found in irradiated fibroblasts and untreated saliva cells. The BRCA1 epimutation may have originated by an early somatic event in the affected twin: approximately 25% of her body cells derived from different embryonic cell lineages carry one epigenetically inactivated BRCA1 allele. This epimutation was associated with reduced basal protein levels and a higher induction of BRCA1 after DNA damage. In addition, we performed a genome-wide microarray analysis of both sisters and found several copy number variations, i.e., heterozygous deletion and reduced expression of the RSPO3 gene in the affected twin. This monozygotic twin pair represents an impressive example of epigenetic somatic mosaicism, suggesting a role for constitutive epimutations, maybe along with de novo genetic alterations in recurrent tumor development. PMID- 22207352 TI - Role of DNA methylation in the regulation of the RANKL-OPG system in human bone. AB - Osteoblasts are specialized cells that form new bone and also indirectly influence bone resorption by producing factors that modulate osteoclast differentiation. Although the methylation of CpG islands plays an important role in the regulation of gene expression, there is still scanty information about its role in human bone. The aim of this study was to investigate the influence of CpG methylation on the transcriptional levels of two osteoblast-derived critical factors in the regulation of osteoclastogenesis: the receptor activator of nuclear factor NF-kappaB ligand (RANKL) and its soluble decoy receptor osteoprotegerin (OPG). Quantitative methylation specific PCR (qMSP) and pyrosequencing analysis in various cell types showed that the methylation of regulatory regions of these genes, in the vicinity of the transcription start sites, repressed gene transcription, whereas an active transcription was associated with low levels of methylation. In addition, treatment with the DNA demethylating agent 5-azadeoxycitidine promoted a 170-fold induction of RANKL and a 20-fold induction of OPG mRNA expression in HEK-293 cells, which showed hypermethylation of the CpG islands and barely expressed RANKL and OPG transcripts at baseline. Transcriptional levels of both genes were also explored in bone tissue samples from patients with hip fractures and hip osteoarthritis. Although RANKL transcript abundance and the RANKL:OPG transcript ratio were significantly higher in patients with fractures than in those with osteoarthritis (RANKL: 0.76 +/- 0.23 vs. 0.24 +/- 0.08, p = 0.012; RANKL/OPG: 7.66 +/- 2.49 vs. 0.92 +/- 0.21, p = 0.002), there was no evidence for differential methylation across patient groups. In conclusion, the association between DNA methylation and the repression of RANKL and OPG expression strongly suggests that methylation dependent mechanisms influence the transcription of these genes, which play a critical role in osteoclastogenesis. However, other mechanisms appear to be involved in the increased RANKL/OPG ratio of patients with osteoporotic fractures. PMID- 22207353 TI - Role of DNMT3B in the regulation of early neural and neural crest specifiers. AB - The de novo DNA methyltransferase DNMT3B functions in establishing DNA methylation patterns during development. DNMT3B missense mutations cause immunodeficiency, centromere instability and facial anomalies (ICF) syndrome. The restriction of Dnmt3b expression to neural progenitor cells, as well as the mild cognitive defects observed in ICF patients, suggests that DNMT3B may play an important role in early neurogenesis. We performed RNAi knockdown of DNMT3B in human embryonic stem cells (hESCs) in order to investigate the mechanistic contribution of DNMT3B to DNA methylation and early neuronal differentiation. While DNMT3B was not required for early neuroepithelium specification, DNMT3B deficient neuroepithelium exhibited accelerated maturation with earlier expression, relative to normal hESCs, of mature neuronal markers (such as NEUROD1) and of early neuronal regional specifiers (such as those for the neural crest). Genome-wide analyses of DNA methylation by MethylC-seq identified novel regions of hypomethylation in the DNMT3B knockdowns along the X chromosome as well as pericentromeric regions, rather than changes to promoters of specific dysregulated genes. We observed a loss of H3K27me3 and the polycomb complex protein EZH2 at the promoters of early neural and neural crest specifier genes during differentiation of DNMT3B knockdown but not normal hESCs. Our results indicate that DNMT3B mediates large-scale methylation patterns in hESCs and that DNMT3B deficiency in the cells alters the timing of their neuronal differentiation and maturation. PMID- 22207354 TI - Aging and epigenetics: longitudinal changes in gene-specific DNA methylation. AB - DNA methylation has been associated with age-related disease. Intra-individual changes in gene-specific DNA methylation over time in a community-based cohort has not been well described. We estimated the change in DNA methylation due to aging for nine genes in an elderly, community-dwelling cohort of men. Seven hundred and eighty four men from the Veterans Administration Normative Aging Study who were living in metropolitan Boston from 1999-2009 donated a blood sample for DNA methylation analysis at clinical examinations repeated at approximately 3-5 year intervals. We used mixed effects regression models. Aging was significantly associated with decreased methylation of GCR, iNOS and TLR2 and with increased methylation of IFNgamma, F3, CRAT and OGG. Obstructive pulmonary disease at baseline modified the effect of aging on methylation of IFNgamma (interaction p = 0.04). For participants who had obstructive pulmonary disease at their baseline visit, the rate of change of methylation of IFNgamma was -0.05% 5 methyl-cytosine (5-mC) per year (95% CI: -0.22, 0.13), but was 0.14% 5-mC per year (95% CI: 0.05, 0.24) for those without this condition. Models with random slopes indicated significant heterogeneity in the effect of aging on methylation of GCR, iNOS and OGG. These findings suggest that DNA methylation may reflect differential biological aging. PMID- 22207356 TI - Local chromatin dynamics of transcription factors imply cell-lineage specific functions during cellular differentiation. AB - Chromatin dynamics across cellular differentiation states is an emerging perspective from which the mechanism of global gene expression regulation may be better understood. While the roles of some histone marks have been partially interpreted in terms of their association with gene transcription, the dynamics of histone marks from a loci-specific perspective during cellular differentiation is not well studied. We established a method to systematically assess the histone modification variations of genes across various cellular differentiation states. We calculated the histone modification variation scores of H3K4me3, H3K27me3 and H3K36me3 for over 1300 curated transcription factors (TFs) during human blood cell differentiation. Hematopoietic-specific TFs (identified by literature mining) were significantly overrepresented by TFs with higher histone modification variation scores. Hierarchical clustering of all TFs based on the histone modification variation scores defined a group of TFs where known or potential hematopoietic-specific TFs were remarkably enriched. Our results suggest that local chromatin state dynamics of transcription factors across cellular differentiation states could imply cell lineage-specific functions. More importantly, our method can be applied to broader systems, holding the promise to discover de novo, lineage-specific TFs by interrogating their histone modification dynamics across cell lineages. PMID- 22207355 TI - Current status and future prospects for epigenetic psychopharmacology. AB - Mounting evidence suggest that epigenetic regulation of brain functions is important in the etiology of psychiatric disorders. These epigenetic regulatory mechanisms, such as DNA methylation and histone acetylation, are influenced by many pharmaceutical compounds including psychiatric drugs. It is therefore of interest to investigate how psychiatric drugs are of influence and what the potential is of new epigenetic drugs for psychiatric disorders. With this targeted review we summarize the current state of knowledge in order to provide insight in this developing field. Several traditional psychiatric drugs have been found to alter the epigenome and in a variety of animal studies, experimental compounds with epigenetic targets have been investigated as potential psychiatric drugs. After discussion of the most relevant epigenetic mechanisms we present the evidence for epigenetic effects for the most relevant classes of drugs. PMID- 22207357 TI - Clinical and public health research using methylated DNA immunoprecipitation (MeDIP): a comparison of commercially available kits to examine differential DNA methylation across the genome. AB - The methylated DNA immunoprecipitation method (MeDIP) is a genome-wide, high resolution approach that detects DNA methylation with oligonucleotide tiling arrays or high throughput sequencing platforms. A simplified high-throughput MeDIP assay will enable translational research studies in clinics and populations, which will greatly enhance our understanding of the human methylome. We compared three commercial kits, MagMeDIP Kit TM (Diagenode), Methylated-DNA IP Kit (Zymo Research) and MethylampTM Methylated DNA Capture Kit (Epigentek), in order to identify which one has better reliability and sensitivity for genomic DNA enrichment. Each kit was used to enrich two samples, one from fresh tissue and one from a cell line, with two different DNA amounts. The enrichment efficiency of each kit was evaluated by agarose gel band intensity after Nco I digestion and by reaction yield of methylated DNA. A successful enrichment is expected to have a 1:4 to 10:1 conversion ratio and a yield of 80% or higher. We also evaluated the hybridization efficiency to genome-wide methylation arrays in a separate cohort of tissue samples. We observed that the MagMeDIP kit had the highest yield for the two DNA amounts and for both the tissue and cell line samples, as well as for the positive control. In addition, the DNA was successfully enriched from a 1:4 to 10:1 ratio. Therefore, the MagMeDIP kit is a useful research tool that will enable clinical and public health genome-wide DNA methylation studies. PMID- 22207358 TI - The 3D tissue microenvironment modulates DNA methylation and E-cadherin expression in squamous cell carcinoma. AB - The microenvironment plays a significant role in human cancer progression. However, the role of the tumor microenvironment in the epigenetic control of genes critical to cancer progression remains unclear. As transient E-cadherin expression is central to many stages of neoplasia and is sensitive to regulation by the microenvironment, we have studied if microenvironmental control of E cadherin expression is linked to transient epigenetic regulation of its promoter, contributing to the unstable and reversible expression of E-cadherin seen during tumor progression. We used 3D, bioengineered human tissue constructs that mimic the complexity of their in vivo counterparts, to show that the tumor microenvironment can direct the re-expression of E-cadherin through the reversal of methylation-mediated silencing of its promoter. This loss of DNA methylation results from the induction of homotypic cell-cell interactions as cells undergo tissue organization. E-cadherin re-expression is associated with multiple epigenetic changes including altered methylation of a small number of CpGs, specific histone modifications, and control of miR-148a expression. These epigenetic changes may drive the plasticity of E-cadherin-mediated adhesion in different tissue microenvironments during tumor cell invasion and metastasis. Thus, we suggest that epigenetic regulation is a mechanism through which tumor cell colonization of metastatic sites occurs as E-cadherin-expressing cells arise from E-cadherin-deficient cells. PMID- 22207359 TI - DNA replication, RNAi and epigenetic inheritance. AB - Epigenetic marks, such as histone methylation, play a central role in chromatin structure and gene expression. During DNA replication, chromatin undergoes a wave of disruption and reassembly. Little is known about how the epigenetic marks are faithfully inherited from one generation to the next. In fission yeast, the hallmark of heterochromatin, a condensed chromatin structure, is H3K9 methylation. This conserved epigenetic mark is mediated by small interference RNAs (siRNAs) in a cell cycle-dependent manner: at S phase, heterochromatin is briefly transcribed by RNAP II and the transcripts are subsequently processed into siRNAs. These small RNAs, together with other key silencing factors, including Dos1/Raf1/Clr8/Cmc1, Dos2/Raf2/Clr7/Cmc2 and Rik1, mediate H3K9 methylation by the histone H3K9 methyltransferase Clr4. Our recent findings indicate that the epsilon subunit of DNA polymerase, Cdc20, associates with the Dos2-Rik1 complex and is essential for H3K9 methylation and heterochromatin function. Moreover, Cdc20 regulates siRNA generation by promoting RNAP II transcription of heterochromatin. These data suggest that DNA polymerase components may play a key role in the inheritance of histone methylation by coordinating DNA replication, RNAi and histone methylation, and explain previously observed cell cycle-regulated RNAi-dependent heterochromatin silencing. We propose a model in which, at DNA replication forks, DNA polymerase subunits mediate the recruitment of epigenetic factors required for RNAi and histone modification to heterochromatin to promote the faithful transmission of histone methylation. PMID- 22207360 TI - Assembling pieces of the centromere epigenetics puzzle. AB - The centromere is a key region for cell division where the kinetochore assembles, recognizes and attaches to microtubules so that each sister chromatid can segregate to each daughter cell. The centromeric chromatin is a unique rigid chromatin state promoted by the presence of the histone H3 variant CENP-A, in which epigenetic histone modifications of both heterochromatin or euchromatin states and associated protein elements are present. Although DNA sequence is not regarded as important for the establishment of centromere chromatin, it has become clear that this structure is formed as a result of a highly regulated epigenetic event that leads to the recruitment and stability of kinetochore proteins. We describe an integrative model for epigenetic processes that conform regional chromatin interactions indispensable for the recruitment and stability of kinetochore proteins. If alterations of these chromatin regions occur, chromosomal instability is promoted, although segregation may still take place. PMID- 22207362 TI - A special method of dilating tracheal stenosis following tracheostomy. AB - Several methods can be used to manage tracheal stenosis. For patients unfit for surgery, frequent dilatation with stent placement is the most common treatment. We here describe a simple and effective method using Bakes common bile duct dilators to dilate a tracheal stenosis in a patient with a tracheostomy. PMID- 22207361 TI - Multisensory simultaneity recalibration: storage of the aftereffect in the absence of counterevidence. AB - Recent studies show that repeated exposure to an asynchrony between auditory and visual stimuli shifts the point of subjective simultaneity. Usually, the measurement stimuli used to assess this aftereffect are interleaved with short re exposures to the asynchrony. In a first experiment, we show that the aftereffect declines during measurement in spite of the use of re-exposures. In a second experiment, we investigate whether the observed decline is either due to a dissipation of the aftereffect with the passage of time, or the result of using measurement stimuli with a distribution of asynchronies different from the exposure stimulus. To this end, we introduced a delay before measuring the aftereffects and we compared the magnitude of the aftereffect with and without delay. We find that the aftereffect does not dissipate during the delay but instead is stored until new sensory information in the form of measurement stimuli is presented as counterevidence (i.e., stimuli with an asynchrony that differs from the one used during exposure). PMID- 22207363 TI - Low-volume, single-shot crystalloid cardioplegia is safe for isolated aortic valve replacement. AB - We report our experience with a low-volume (100 mL), single-shot crystalloid cardioplegia (Cardioplexol) in 61 consecutive patients undergoing isolated aortic valve replacement (AVR). Cardioplexol resulted in immediate cardiac arrest. Intraoperative courses were uneventful. Postoperative markers of myocardial damage, Troponin T and CK-MB levels, were low but steadily increased with longer cross-clamp time. Thirty-day mortality was 3% and all noncardiac. Cardioplexol not only simplifies and speeds up the procedure but also seems to be safe for patients undergoing AVR. PMID- 22207364 TI - The influence of the primary tumor on the long-term results of pulmonary metastasectomy for metastatic renal cell carcinoma. AB - OBJECTIVE: To investigate one of the primary tumor (PT) on pulmonary metastasectomy (PM) for metastatic renal cell carcinoma (RCC) and to define prognostic factors. METHODS: Retrospective review of patients with pulmonary metastases from RCC from January 1999 through December 2008 was performed. All patients underwent PM with curative intend. TNM-classification, tumor stage and PT grade, disease-free-interval (DFI) from nephrectomy to the diagnosis of metastasis, systemic chemotherapy before surgical intervention, surgical procedures, morbidity, mortality, and survival were investigated. RESULTS: One hundred seven consecutive patients (age 61.5 +/- 9.6 years) underwent PM. Morbidity and mortality rates were 15.0 and 0.9%, respectively. Thirty-six patients (33.6%) had systematic therapy before PM. Complete resections could be achieved in 104 patients (97.2%). Mean survival was 63.4 +/- 5.1 months. The overall 5- and 10-year survival rates were 47 and 9%, respectively. Advanced N Status (p < 0.001), grade (p < 0.001) and stage group (stage I/II vs. III/IV, p = 0.022) of the PT were associated with inferior survival in the univariate analysis. T-Status (p = 0.89) and M-Status (p = 0.96) of the PT had no significant impact on survival. In a multivariable Cox proportional hazards model, N-Status and tumor grade were the only significant prognostic factors. CONCLUSIONS: PM can be performed safely. Long-term survival is achievable in selected patients. Nodal disease and high tumor grade of the PT at the time of the initial nephrectomy were associated with worse survival after PM. These results might help to identify a high-risk group of patients who might benefit from enrollment in adjuvant therapy protocols after primary treatment of RCC. PMID- 22207365 TI - A modified Brompton technique for the treatment of giant bulla in patients with diffuse emphysema. AB - Four patients with diffuse emphysema and a giant bulla were treated by a modified Brompton technique using a mushroom catheter and low suction. There was no mortality although one patient developed a troublesome pulmonary infection. All the patients had significant symptomatic improvement with a mean dyspnoea index changing from 3.5 before operation to 2.25 afterwards. We concluded that the modified Brompton technique is a safe and simple alternative in treating a giant bulla associated with diffuse emphysema. PMID- 22207366 TI - Endobronchial foreign body removed by flexible bronchoscopy using the Trendelenburg position. AB - Foreign body (FB) aspiration causes various symptoms and sometimes leads to severe conditions. Therefore, its prompt diagnosis and removal are essential to avoid complications. Flexible bronchoscopy is both a safe and effective method to confirm suspected cases of FB aspiration and to facilitate FB removal. However, few articles have dealt with the proper techniques for removal of FB in younger versus older patients based on anatomical variation. We report FB aspiration in an old male patient in whom attempted removal with flexible bronchoscopy failed but was later achieved by repeated flexible bronchoscopy with the patient in the Trendelenburg position. PMID- 22207367 TI - Sleeve lobectomy for NSCLC treatment: a simple surgical choice or a mandatory need in high-risk patients? PMID- 22207368 TI - Acute renal dysfunction does not develop more frequently among octogenarians compared to septuagenarians after cardiac surgery. AB - BACKGROUND: We tested the hypothesis that octogenarians develop more frequently renal dysfunction compared with septuagenarians after cardiac surgery. METHODS: A retrospective, observational study on an age-, gender- and operation-matched cohort of 598 patients, (299 octogenarians vs. 299 septuagenarians) who underwent cardiac surgery between January 2006 and August 2009, was performed. Kidney function was estimated with the abbreviated Modification in Renal Disease equation and acute kidney injury was defined as a decrease of glomerular filtration rate >=50%. RESULTS: Operations included 246 coronary, 198 isolated valve, and 154 combined coronary and valve procedures. Mean logistic EuroSCORE was 8.5% in septuagenarians and 13.2% in octogenarians. Octogenarians had significantly more frequent and estimated GFR < 60 mL/min/1.73 m2 (44 vs. 34.4%, p = 0.02). The incidence of dialysis-dependent acute kidney failure did not differ between both groups (6.7 vs. 5.4%, p = 0.60). Postoperative decline of glomerular filtration rate <25% occurred significantly more often in septuagenarians (40 vs. 30%, p = 0.02). Septuagenarians with a preoperative GFR < 60 mL/min/1.73 m2 had a higher 30-day mortality compared with patients with a GFR > 60 mL/min/1.73 m2 (10.9 vs. 3.1%, p = 0.02). Overall, 30-day mortality in octogenarians was 7.7% without significant differences with respect to preoperative GFR. CONCLUSIONS: Octogenarians do not develop acute kidney failure more frequently than their matched septuagenarian counterparts. They can be operated on at an acceptable risk for morbidity and mortality. Preoperative impaired renal function is associated with higher risk for mortality in septuagenarians. PMID- 22207369 TI - Video-assisted approach combined with the open Brompton technique for intracavitary drainage of giant bullae. AB - The modified Monaldi procedure represents a nonexcisional treatment option for patients with giant bullous emphysema as an alternative to bullectomy. We want to highlight its role in the surgical treatment of emphysema and discuss changes made to the open-access Brompton approach through introduction of video-assisted thoracic surgical technique. PMID- 22207370 TI - Combined embolization and surgical resection of a giant mediastinal tumor. AB - Large mediastinal tumors typically have a rich blood supply derived from multiple arteries, and surgical resection can be associated with a large blood loss. Embolization is used to treat a variety of malignant and benign conditions preoperatively, as well as an alternative to surgery, however, the use of preoperative embolization of large mediastinal tumors has not been extensive. Herein, we report a case of a giant mediastinal tumor measuring >15 cm and extending into both chest cavities in which preoperative embolization was used to reduce the surgical blood loss and facilitate excision of the lesion. PMID- 22207371 TI - Unusual cause of acute back pain mimicking aortic dissection: a case report. AB - We report the case of a 62-year-old woman who initially presented with symptoms suggesting acute type A aortic dissection. Imaging studies revealed hemorrhagic pericardial fluid without the evidence of dissection. Foreign body material was noted floating in the inferior vena cava (IVC) and also piercing the right ventricular wall. Upon surgical exploration, the extracted material could be identified to be acrylic bone cement (palacos). The patient had reported a history of kyphoplasty in 2008. PMID- 22207372 TI - Prevention of alveolar air leakage after video-assisted thoracic surgery: comparison of the efficacy of methods involving the use of fibrin glue. AB - BACKGROUND: The aim of this study was to evaluate the appropriate condition of use of the fibrin glue plus polyglycolic acid (PGA) sheet combination to obtain the optimal sealing effect. METHODS: 126 consecutive patients underwent video assisted thoracic surgery (VATS) were divided into groups as follows: fibrin glue sprayed on the PGA sheet placed over the pleural defect (Method I); fibrinogen and thrombin solutions sprayed separately on the PGA sheet soaked in thrombin and placed over the pleural defect after rubbing of fibrinogen solution on the area (Method II); fibrin glue sprayed on the PGA sheet placed over the pleural defect after rubbing of fibrinogen solution on the area (Method III). Method II and Method III were also examined in an animal model. RESULTS: Postoperative air leakage was more effectively prevented by Method III than by the other two methods (p < 0.05). In the experimental study, a significantly higher seal breaking pressure was obtained for Method III than for Method II (p < 0.05). CONCLUSION: Method III was the most effective for preventing alveolar air leakage. PMID- 22207374 TI - [Role of chromatin conformation in eukaryotic gene regulation]. AB - Gene expression in eukaryotes is regulated at multiple levels, which involves various cis-regulatory elements and trans-acting factors at transcriptional level. In addition, DNA methylation and histone modifications also play crucial roles in epigenetic regulation of eukaryotic genes. It is pivotal for evaluating the regulation of gene expression to understand the structural properties and spatial organization of chromatin at 3-D level. The dynamic alternations of chromatin conformation can either activate gene expression by facilitating the interactions between enhancers or other cis-regulatory elements and their target genes or suppress gene expression by blocking the interactions due to steric hindrance. Although the precise molecular mechanisms underlying the gene regulation via conformational changes of chromatin remain obscure, epigenetic studies including histone modification, nucleosome positioning, chromosome territories as well as chromatin interactions, have provided accumulating evidence to demonstrate the significance of chromatin conformation in eukaryotic gene regulation. Here, we reviewed the recent advances on the role of dynamic alterations of chromatin in gene regulation , which occur at different levels from the primary structure to three dimensional conformation. PMID- 22207373 TI - Leisure-time physical activity in pregnancy and the birth weight distribution: where is the effect? AB - BACKGROUND: Leisure-time physical activity (LTPA) is recommended during pregnancy and has been associated with lower risk of delivering a large infant. We sought to characterize the effect of LTPA across the entire birth weight distribution. METHODS: Women enrolled in the Pregnancy Outcomes and Community Health (POUCH) Study (1998-2004) were followed-up in 2007. Follow-up efforts were extensive for a subcohort and minimal for the remainder (nonsubcohort). Thus, 596 subcohort and 418 nonsubcohort women who delivered at term participated. Offspring were categorized as small-, appropriate-, or large-for-gestational-age (SGA, AGA, and LGA, respectively) based on gender and gestational age-specific birth weight z scores (BWz). At follow-up, women recalled pregnancy LTPA and were classified as inactive, insufficiently active or meeting LTPA recommendations. Linear, logistic, and quantile regression analyses were conducted separately by subcohort status. RESULTS: Meeting LTPA recommendations decreased odds of LGA significantly among the nonsubcohort (aOR = 0.30, 95% CI: 0.14-0.64) and nonsignificantly among the subcohort (aOR = 0.68, 95% CI: 0.34-1.34). In quantile regression, meeting LTPA recommendations reduced BWz among the upper quantiles in the nonsubcohort. CONCLUSIONS: LTPA during pregnancy lowered odds of LGA and reduced BWz among the upper quantiles, without shifting the entire distribution. LTPA during pregnancy may be useful for reducing risks of large fetal size. PMID- 22207375 TI - [Regulation of gene expression during spermatogenesis at transcriptional level]. AB - Mammalian spermatogenesis is a highly complex cell division and differentiation process occurring in the seminiferous tubules of the testis. This processes are regulated at both transcriptional and post-transcriptional levels, any mistake in this process can lead to infertility. Unveiling the molecular mechanisms of spermatogenesis has important implications for exploring novel contraceptive approach and treatment of infertility. This review addresses recent progress towards understanding the regulation of androgen, estrogen and their receptors, transcription factors and chromatin-associated factors for spermatogenesis at transcriptional level. PMID- 22207376 TI - [Genomic selection and its application]. AB - Selective breeding is very important in agricultural production and breeding value estimation is the core of selective breeding. With the development of genetic markers, especially high throughput genotyping technology, it becomes available to estimate breeding value at genome level, i.e. genomic selection (GS). In this review, the methods of GS was categorized into two groups: one is to predict genomic estimated breeding value (GEBV) based on the allele effect, such as least squares, random regression - best linear unbiased prediction (RR BLUP), Bayes and principle component analysis, etc; the other is to predict GEBV with genetic relationship matrix, which constructs genetic relationship matrix via high throughput genetic markers and then predicts GEBV through linear mixed model, i.e. GBLUP. The basic principles of these methods were also introduced according to the above two classifications. Factors affecting GS accuracy include markers of type and density, length of haplotype, the size of reference population, the extent between marker-QTL and so on. Among the methods of GS, Bayes and GBLUP are usually more accurate than the others and least squares is the worst. GBLUP is time-efficient and can combine pedigree with genotypic information, hence it is superior to other methods. Although progress was made in GS, there are still some challenges, for examples, united breeding, long-term genetic gain with GS, and disentangling markers with and without contribution to the traits. GS has been applied in animal and plant breeding practice and also has the potential to predict genetic predisposition in humans and study evolutionary dynamics. GS, which is more precise than the traditional method, is a breakthrough at measuring genetic relationship. Therefore, GS will be a revolutionary event in the history of animal and plant breeding. PMID- 22207377 TI - [Application of next generation sequencing techniques in plant transcriptome]. AB - With the development of DNA sequencing techniques, the next-generation sequencing (NGS) techniques with the characteristics of high-throughput and low cost have become the first choice for more and more researchers to carry out the biological researches. Among the next-generation sequencing techniques, the 454 sequencing platform is the first commercially available and relatively mature one and widely used in various fields of biological research. Taking 454 sequencing platform as an example, we illustrate the advantages and disadvantages of NGS technical principles, review their applications in plant transcriptome, and outlook their future development and applications in plant research field. PMID- 22207378 TI - [T-DNA integration patterns in transgenic plants mediated by Agrobacterium tumefaciens]. AB - The genetic transformation mediated by Agrobacterium tumefaciens has been widely applied to research of transgenic plants. As the vector of the exotic genes, the integration patterns of T-DNA fragments affects not only transformation efficiency and stability, but also expression properties of the transgenes. This review summaries the two major patterns and the rules of T-DNA integration in Agrobacterim-mediated transformation, rules of T-DNA mediated by Agrobacterium tumefaciens, as well as research tools for flanking sequence amplification. It is attempted to provide references for researches on transformation and T-DNA integration mutation mediated by Agrobacterium tumefaciens. PMID- 22207379 TI - [Auxin response factors and plant growth and development]. AB - An important aspect of studies on auxin is auxin response factors (ARFs), which activate or repress the auxin response genes by binding to auxin response elements (AuxREs) on their promoters. In this review, we focused on molecular biological advances of plant ARF families, and discussed ARF structures, regulation of ARF gene expression, the roles of ARFs in regulating the development of plants and in signal transduction and the mechanisms involved in the target gene regulation by ARFs. The phylogenetic relationships of ARFs in plants are close and most of them have 4 domains. ARFs are expressed in various tissues. Their expressions are regulated at both transcriptional and post transcriptional levels. They play important roles in the interactions between auxin and other hormones. PMID- 22207380 TI - [Association of porcine ATF4 gene polymorphism and production traits and analysis of gene expression]. AB - In order to understand the function of gene ATF4 and identify new DNA markers involved in pig production traits, the cDNA fragment of porcine ATF4 was cloned and sequenced. Sequence comparison revealed an A159G substitution downstream of the initiation codon (ATG). We then carried out PCR-AluI-RFLP analysis in Large white, Landrace, Tongcheng and Meishan pigs, followed by association analysis in F2 "Large white *Meishan" resource family. In all the individuals tested, Large White and Landrace pigs possessed the AA genotype, while Meishan and Tongcheng pigs pos-sessed the GG genotype. Association analysis in F2 resource family showed that this site was highly associated with buttock fat thickness (BFT) (Pamp;0.01) and had significant effect on thorax-waist fat thickness (TFT), average backfat thickness (ABT), loin eye height (LEH), and loin eye area (LEA)(Pamp;0.05). Real-time PCR was used to analyze the expression patterns of porcine ATF4 gene in longissimus dorsi at different development stages of Large White and Meishan pigs. The results showed that the gene expression levels of ATF4 were low 65 days after conception and 3 days after birth, but no signifi cant differences were observed in both breeds. Meanwhile, the expression levels of porcine ATF4 gene were up-regulated 60 days and 120 days after birth in both breeds and the expression level in Meishan pigs was obviously higher than that in Large White pigs. These data could lay the foundation for further study on the molecular mechanism of porcine ATF4 gene in lipid metabolism. PMID- 22207381 TI - [Confirmation and expression analysis of three predicted genes in sheep MHC region]. AB - Previous DNA sequencing of BAC clones covering entire ovine MHC (OLA) region resulted in identification of approximately 130 functional genes in the region, of which 8 were predicted by computer software to be exclusively existed in sheep, but not in any other species known to date. In the present study, we successfully identified and cloned cDNA sequence of OaN2, OaN5, and OaN6 from representative sheep tissues, confirmed their existence in reality. The sequences obtained experimentally exactly identical to those predicted previously. The length of cDNA fragments for OaN2, OaN5, and OaN6 was 270 bp, 309 bp, and 205 bp, respectively, with GenBank accession number assigned as JF330782 (OaN2), JF330783 (OaN5), and JF330784 (OaN6). Northern analyses indicated that the mRNA transcripts of OaN2 were mainly seen in ovine mesenteric lymph nodes and spleen, while OaN5 was observed in only in mesenteric lymph nodes. In contrast, OaN6 transcripts were detected in all tissues except for liver and heart. Western blot showed that OaN2 protein expression level was detected in mesenteric lymph nodes, spleen, and liver, essentially consistent with that of mRNA transcripts. Immunohistochemistry analysis showed that OaN2 protein was highly expressed in ovine mesenteric lymph nodes, moderately expressed in, and not expressed in heart, liver, and pancreas, consistent with the results of Western blotting. The cloning and expression analysis of 3 novel genes provide a basis for revealing their specificities and would be helpful to further study of their expression profile and their potential functions. PMID- 22207382 TI - [Polymorphism of POU1F1 gene and PRL gene and their combined effects on milk performance traits in Chinese Holstein cattle]. AB - Three novel SNPs were found by DNA sequencing, PCR-RFLP and CRS-PCR methods were used for genotyping in 979 Chinese Holstein cattle. One SNP, G1178C, was identified in exon 2 of POU1F1 gene. Two novel SNPs, A906G and A1134G, were identified in 5'-flanking regulatory region (5'-UTR) of PRL gene. The association between polymorphisms of the two genes and milk performance traits were analyzed with PROC GLM of SAS. The results showed that GC genotype at 1178 locus of POU1F1 gene was advantageous for milk yield, milk protein yield, and milk fat yield. AG genotype at 906 locus was advantageous for milk yield. There was no significant difference between 1134 locus and milk performance traits of 5'-UTR of PRL gene. Analysis of genotype combination effect on milk production traits showed that the effect of combined genotype was not simple sum of single genotypes and the effects of gene pyramiding seemed to be more important in molecular breeding. PMID- 22207383 TI - [Quantitative trait locus analysis of standard length, body depth and body thickness in mirror carp (Cyprinus carpio L.)]. AB - Based on a full-sib family, the genetic linkage map was constructed with 246 microsatellite and 306 SNP markers, which was used to detect the QTLs for standard length (SL), body depth (H), body thickness (BT), and the ratio of standard length and body depth (SLH) in mirror carp by GridQTL software. The results indicated that a total of 14 related QTLs distributed on the 7 linkage groups were obtained. Seven QTLs were related to standard length, of which the linkage groups of LG6, LG17, LG21, LG23, and LG35 were at 5% significant level, and linkage group LG1 and LG28 were at 1% significant level, which explained 6.6% 12.6% of the phenotypic variance. Three QTLs were identified for body depth on the linkage groups of LG17, LG23 and LG28 (P amp; 0.01), accounting for 11.6%, 12.7%, and 15.6% of the phenotypic variance, respectively. Two QTLs were associated with body thickness on the linkage of LG23 and LG28 (P amp; 0.05), which explained 8.6% and 7.2% of the phenotypic variation, respectively. Two QTLs were responsible for the ratio of standard length and body depth on the linkage of LG21 and LG35 (P amp; 0.05), both of which explained 8.2% of the phenotypic variance. The results provide a useful reference for further candidate gene research and molecular marker assisted selection in mirror carp. PMID- 22207384 TI - [Genetic analysis and gene mapping of DDF1, a pleiotropic gene involving in both vegetable and reproductive growth in rice]. AB - There are many pleiotropic genes playing key roles in regulating both vegetative growth and reproductive development in plants. A dwarf mutant of rice with deformed flowers, named as ddf1, was identified from indica rice breeding lines. Genetic analysis indicated that ddf1 was resulted from the recessive mutation of a single gene, temporarily named as DDF1. This result suggested that DDF1 is a pleiotropic gene, which controls both vegetative growth and reproductive development in rice. To map this gene, an F2 population was developed by crossing the ddf1 heterozygote with the tropical japonica rice variety DZ60. By means of bulked segregant analysis and small population-based linkage analysis using the published RM-series rice SSR markers, DDF1 was preliminarily mapped in a region between markers RM588 and RM587 on chromosome 6 with the genetic distances of 3.8 cM and 2.4 cM to the two markers, respectively. By developing new SSR markers in this interval according to the published rice genome sequence, we further mapped DDF1 in a 165 kb interval. The results will facilitate cloning of DDF1. PMID- 22207385 TI - [Genetic improvement of breeding materials in tropical and sub- tropical maize]. AB - In the present study, 122 maize local cultivars and adapted exotic germplasm from Thailand were used to develop open pollinate varieties (OPVs) using modified ear to-row scheme, top-cross or test-cross programmes. Ten new maize OPVs with distinct characters were created based on the precise breeding objectives and directional design. The selection of breeding materials was based upon three factors: elite performance, broad adaptability, and genetic diversity. The synthesizing system provided four features: genetic mixing and recombination, equal comparable genetic contribution, mild selection pressure, and maximum intermating for genetic equilibrium (i.e., the female traits were close for the genetic com-positions). Subsequently, Suwan 1 composite and its deritives (Suwan 2, Suwan 3 composite, Suwan 5 and KS24 synthetics), KS6 and KS28 synthetics with the dent type of different origins, and Caripeno DMR composite, KS23, and KS27 synthetics with the dent type of Non-Suwan 1 origin were developed. These OPVs had been improved for 2~13 cycles using S1 recurrent selection method. About 50 inbred lines were developed from these OPVs, and 16 elite single (three-way) crosses were combined and released from these inbred lines. At present, at least one parental inbred line of all the tropical hybrids was derived from Suwan (KS) germplasm in Thailand. Based on the theory of the synthesizing OPVs and developing inbred lines, this paper discussed the genetic moderate diversity, relationship, heterotic group, and patterns for synthesizing OPVs, and inspiration for composed OPVs to heterosis breeding. PMID- 22207386 TI - [Gene mapping of an ultra-dwarf mutant in upland cotton]. AB - A ultra-dwarf mutant was newly found in upland cotton (Gossypium hirsutum L.). This mutant was controlled by single recessive gene du. Seventy pairs of polymorphic primers were selected from 1350 primers, which covered all the identified chromosomes by screening in parents and near-isogenic lines. Gene du was mapped using an F2 population derived from intraspecific crosses between "Ultra-dwarf 1" and "Xinluzao 16". Thirty-six primers were distributed in eight linkage groups, and du was linked to LG01. Seven co-dominant markers linked to du were NAU2679, NAU2749, NAU905, NAU2838, NAU5373, NAU2238, and NAU4946. Based on the known genetic map of tetraploid cotton, the markers NAU4946, NAU2238, NAU905, NAU5373, and NAU2679 were located on chromosome 6, and the target gene du was located between NAU2238 and NAU4946 with the genetic distances of 3.3 cM and 1.4 cM, respectively. Hence, gene du was located on chromosome 6. PMID- 22207387 TI - [Construction of a melon genetic map with fruit and seed QTLs]. AB - A genetic map of melon was constructed using 143 F2 population developed from a cross between two distant lines Ano2 of Japan and Hami melon K413. The map contains 12 linkage groups and 142 markers, including 121 AFLPs, 16 SSRs, 3 STSs, 2 trait markers and covers 1 014.2 cM. Composite interval mapping (CIM) method was used to detect QTLs involved in melon fruit and seed traits: fruit length (FL), fruit width (FW), fruit shape (length/width, FS), centre sugar (CS), edge sugar (ES), flesh texture (FT), seed length (SL), seed width (SW), seed shape (SS), and seed weight (SW). The result showed that Flesh was located between AFLP markers NDAA and NCFA on C9. A total of 25 QTLs were detected for other traits and some QTLs were co-located with each other. The QTLs Sl5.1, Sw5.1, and Swt5.1 located on linkage C5 between NCA and N73C explained a significant portion of associated phenotypic variation (R2=17%, 19%, 23%). The allele from Ano2 obviously suppressed the length, width, and weight of melon seed; the QTLs between N73A and NFDA on C8 were involved in seed width, shape, and weight; the QTL Fs8.1 on C8 was detected using both F2 and F3 fruit data and explained a significant portion of phenotypic variation 25% and 19%. Fs8.1 showed partly dominant, and the allele from Ano2 sup-pressed elongation of fruit to form round melon. The QTLs related to centre sugar, edge sugar, and fruit texture were also detected in this research. PMID- 22207388 TI - [Improving experimental teaching facilities and opening up of laboratories in order to raise experimental teaching quality of genetics]. AB - Advanced teaching facilities and the policy of opening laboratories to students play an important role in raising the quality in the experimental teaching of Genetics. This article introduces the superiority of some advanced instruments and equipment (such as digital microscope mutual laboratory system, flow cytometry, and NIRSystems) in the experimental teaching of genetics, and illustrates with examples the significance of exposing students to experiments in developing their creative consciousness and creative ability. This article also offers some new concepts on the further improvement upon teaching in the laboratory. PMID- 22207389 TI - Laparoscopic assisted sigmoid resection for diverticular disease. AB - PURPOSE: Laparoscopic assisted sigmoid resection (LASR) has become a widely accepted procedure in colorectal surgery. In the last decade, numerous variations of surgical details have been established. In order to demonstrate a feasible technique, this video is provided. METHODS: LASR is performed using four ports. The first port is inserted via open access by a minilaparotomy in the right paraumbilical region. Two ports are sited in the right lower abdomen, including one 12-mm port in the following incision above the pubic symphysis. The forth port is inserted in the left upper abdomen. The procedure starts with the removal of adhesions, the peritoneal incision is performed medially, and a medial to lateral approach to the mesocolon and the inferior mesenteric artery (IMA) is carried out. After identifying the left ureter, the IMA is either clipped or sealed about 1.5 to 2 cm from the origin in order to preserve the autonomous plexus. Then dissection is continued on Gerota's fascia. After lifting the rectosigmoid, dissection is continued in the avascular plane until the mesentery of the upper rectum is mobilized. Then the remaining lateral adhesions are dissected with preservation of the gonadal vessels and the left ureter. The distal resection line is always in the upper rectum, which is easily identified by the lack of tenia. After sealing the mesorectum, the rectum is dissected using a linear stapler. Thereafter, a minilaparotomy above the pubic symphysis is performed and a device for protection and retraction of the wound is inserted. Dissection of the mesosigmoid and the descending colon is carried out extracorporally. The anvil of a circular stapling device is inserted in the descending colon, which is then returned into the peritoneal cavity. Running sutures closes the incision, and the anastomosis is carried out laparoscopically in a "double stapling" technique. CONCLUSION: The video describes the efficacy and technical feasibility of laparoscopic surgery for diverticular disease and demonstrates its effect regarding perioperative morbidity and functional outcome. PMID- 22207390 TI - Polysaccharide-K (PSK) may suppress surgical stress-induced metastasis in rat colon cancer. AB - PURPOSE: We previously demonstrated that hepatic ischemia and reperfusion (I/R) injury increased liver metastasis and cancer growth of RCN-H4 cells. Using a rat model of hepatic I/R-induced liver metastasis, we investigated the metastasis suppressing effect of polysaccharide-K (PSK), a biological response modifier composed of protein-bound polysaccharide. METHODS: Fischer rats underwent 60 min of 70% partial hepatic ischemia. After 60 min of reperfusion, rat colon adenocarcinoma cells (RCN-H4) were inoculated intrasplenically. PSK was administered orally before I/R, after I/R, or before and after I/R. The weights of metastatic lesions of the liver or the numbers of liver metastatic nodules were determined on day 21. The effect of PSK on angiogenesis was studied by a rat cornea model using RCN-H4 cells or a vascular endothelial growth factor (VEGF) containing pellet and an in vitro VEGF-induced endothelial cell migration assay. RESULTS: PSK administration significantly (p < 0.05) suppressed the I/R-induced increase in hepatic metastasis of RCN-H4 cells. The suppression of I/R-promoted metastasis was observed irrespective of the timing of administration. Furthermore, PSK significantly suppressed angiogenesis induced by RCN-H4 cells (p < 0.05) and the VEGF pellet (p < 0.01). PSK significantly suppressed the VEGF induced migration of vascular endothelial cells (p < 0.05). CONCLUSION: PSK may suppress metastasis induced by hepatic I/R. The suppression of angiogenesis by PSK may be one of the mechanisms of the inhibition of hepatic metastasis. PMID- 22207392 TI - Increased plasma levels of heparin-binding protein in patients with shock: a prospective, cohort study. AB - OBJECTIVE: Heparin-binding protein (HBP) is a potent inducer of increased vascular permeability. The purpose of this study was to examine plasma levels of HBP in patients with shock. DESIGN: Fifty-three consecutive patients with septic and non-septic shock at a mixed-bed intensive care unit were included, as well as 20 age-matched controls. Patients with local infections but without signs of shock served as infectious controls. Enzyme-linked immunosorbent assay was used to determine plasma levels of HBP. RESULTS: There were no differences in serum HBP levels between healthy controls and those with local infections, including urinary tract infections, pneumonia and gastroenteritis, without shock. Levels of HBP were higher in patients with non-septic shock and septic shock than healthy controls. However, there was no difference in serum HBP levels between patients with septic shock and those with non-septic shock. Moreover, HBP levels were not different between patients with low and high APACHE II scores. Plasma levels of HBP were similar in surviving and non-surviving patients with shock. CONCLUSIONS: HBP is elevated in patients with shock from septic and non-septic etiologies. Future investigations are required to define the functional role of HBP in patients with shock. PMID- 22207391 TI - A modular strategy to prepare multivalent inhibitors of prostate-specific membrane antigen (PSMA). AB - We have developed a modular scaffold for preparing high-affinity, homo multivalent inhibitors of the prostate-specific membrane antigen (PSMA) for imaging and therapy of prostate cancer (PCa). Our system contains a lysine-based (u-, e-) dialkyne residue for incorporating a PSMA binding Lys-Glu urea motif exploiting click chemistry and a second lysine residue for subsequent modification with an imaging or therapeutic moiety. The utility of the multivalent scaffold was examined by synthesizing bivalent compounds 2 and 3 and comparing them with the monovalent analog 1. Determination of inhibition constants (Ki) revealed that bivalent 2 (0.2 nM) and 3 (0.08 nM) are significantly more potent (~ 5 fold and ~ 11 fold, respectively) inhibitors of PSMA than monovalent 1 (0.9 nM). A single photon emission computed tomography (SPECT)-CT imaging study of [111In]3 demonstrated high and specific uptake in PSMA+ PC-3 PIP tumor until at least 48 h post-injection, with rapid clearance from non-target tissues, including kidney. A biodistribution study revealed that [111In]3 demonstrated 34.0 +/- 7.5 percent injected dose per gram of tissue in PSMA+ tumor at 24 h post-injection and was capable of generating target-to-non target ratios of ~ 379 in PSMA+ PC-3 PIP tumors vs. isogenic PSMA-negative PC3 flu tumors in vivo. The click chemistry approach affords a convenient strategy toward multivalent PSMA inhibitors of enhanced affinity and superior pharmacokinetics for imaging. PMID- 22207393 TI - Status of proinflammatory and anti-inflammatory cytokines in different brain regions of a rat model of Japanese encephalitis. AB - OBJECTIVES: This study evaluated cytokines and chemokine in different regions of the rat brain at different time points following Japanese encephalitis virus (JEV) infection. DESIGN: Twelve-day-old Wistar rats were infected by intracerebral inoculation of 3 * 10(6) plaque-forming units of JEV 78668A strain. Expression of cytokines and chemokine was assayed using cytokine bead array in different regions of the brain at 3, 6, 10 and 20 days post-inoculation (dpi). Pathological changes including immunohistochemistry for JEV antigen were observed. RESULTS: The cytokine levels were increased in the acute stage and declined on follow-up. In the acute stage (6 dpi), the levels of TNF-alpha, IFN gamma, IL-6 and IL-10 were maximum in the cortex, whereas the level of IL-4 was maximum in the striatum. Lower levels of these cytokines were observed in mid brain and thalamus compared to other regions studied. Maximum expression of JEV antigen and histopathological changes as well as cytokines and chemokine were observed at 6 dpi in all the brain regions studied, but declined thereafter. CONCLUSION: This experimental study revealed maximum expression of cytokines and chemokine at 6 dpi of JEV infection which corresponded with histopathological changes in different brain regions. PMID- 22207394 TI - Long-term trends in the epidemiology and resistance of childhood bacterial enteropathogens in Crete. AB - In this study, we investigated the long-term trends in the epidemiology and susceptibility of bacterial enteropathogens among children in a well-defined area of adequate health standards. The study included all children younger than 14 years of age treated for enteritis at Heraklion University General Hospital on the island of Crete during the 18-year period from January 1993 to December 2010. Stool specimens were tested for Salmonella, Shigella, Campylobacter, enteropathogenic Escherichia coli (EPEC), Yersinia, and Aeromonas species. Of the 33,032 stool samples from patients of any age, 2,912 (8.82%) were positive for bacterial enteropathogens. The 1,597 isolates from children were identified as S. enterica (42.3%), Campylobacter spp. (33.6%), EPEC (17.4%), Y. enterocolitica (5.82%), A. hydrophila (0.44%), and Shigella spp. (0.38%). A decline in prevalence was observed for all bacterial enteropathogens. Taken as a total, enteropathogens were susceptible to gentamicin, ceftriaxone, ciprofloxacin, co trimoxazole, and amoxicillin in 98.8%, 88.0%, 83.0%, 67.1%, and 59.6%, respectively. During the study period, the susceptibility rates decreased for co trimoxazole (p<0.0001) and ciprofloxacin (p<0.001), and increased for amoxicillin (p<0.0001). Our findings suggest declining long-term trends in the prevalence of bacterial enteropathogens and changes in susceptibility rates to first-line antibacterial agents. These changing trends in the long-term morbidity and susceptibility call for ongoing surveillance and tailored management. PMID- 22207395 TI - Investigating the signal transduction pathways underlying remote ischemic conditioning in the porcine heart. AB - BACKGROUND: The mechanism underlying remote ischemic conditioning (RIC) remains unclear. We investigated whether RIC protects the heart through the activation of the adenosine receptor and the PI3K-Akt pathway at the onset of myocardial reperfusion. METHODS AND RESULTS: Domestic pigs (27-35 kg) were subjected to in situ left anterior descending coronary artery ischemia (60 min) followed by reperfusion (180 min) and randomised to the following: (1) Control- No additional intervention; (2) Remote ischemic preconditioning (RIPC)- Four-5 min cycles of lower limb ischemia/reperfusion were administered prior to myocardial ischemia; (3) RIPC + Wort or 8-SPT: Wortmannin (Wort 20 MUg/kg, a PI3K inhibitor) or 8 sulfophenyltheophylline (8-SPT 10 mg/kg, an adenosine receptor inhibitor) were administered intravenously 30 s before myocardial reperfusion to RIPC-treated animals; (4) Remote ischemic perconditioning (RIPerC)--Four-5 min cycles of lower limb ischemia/reperfusion were applied 1 min before myocardial reperfusion; (5) RIPerC + Wort or 8-SPT: Wort or 8-SPT were given 30 s before myocardial reperfusion to RIPerC-treated animals. Both RIPC and RIPerC reduced myocardial infarct size (13.3 +/- 2.2% with RIPC, 18.2 +/- 2.0% with RIPerC versus 48.8 +/- 4.2% in control:P < 0.05:N >= 5/group). Wortmannin abolished the infarct limiting effects of RIPC (33.2 +/- 6% with RIPC + Wort versus 13.3 +/- 2.2% with RIPC:P < 0.05:N >= 5/group) but not RIPerC (18.0 +/- 3.4% with RIPerC + Wort versus 18.2 +/- 2.0% with RIPerC:P > 0.05:N >= 5/group). 8-SPT did not influence the infarct-limiting effects of either RIPC or RIPerC. Western blot analysis confirmed Wortmannin-sensitive PI3K and Akt activation at myocardial reperfusion in RIPC-treated hearts. CONCLUSIONS: In the porcine heart, both RIPC and RIPerC both reduce myocardial infarct size and with RIPC but not RIPerC this cardioprotective effect is associated with the activation of the PI3K-Akt pathway at reperfusion. PMID- 22207396 TI - Celebrating the 20th anniversary of the Journal of Genetic Counseling. PMID- 22207397 TI - Educational needs of primary care physicians regarding direct-to-consumer genetic testing. AB - To assess the educational needs of North Carolina primary care physicians (PCPs) about direct-to-consumer (DTC) genetic testing, surveys were mailed to 2,402 family and internal medicine providers in North Carolina. Out of 382 respondents, 323 (85%) felt unprepared to answer patient questions and 282 (74%) reported wanting to learn about DTC genetic testing. A total of 148 (39%) were aware of DTC genetic testing. Among these, 63 (43%) thought DTC genetic testing was clinically useful. PCPs who felt either unprepared to answer patient questions (OR = 0.354, p = 0.01) or that DTC genetic testing was clinically useful (OR = 5.783, p = 0.00) were more likely to want to learn about DTC genetic testing. PCPs are interested in learning about DTC genetic testing, but are mostly unaware of DTC testing and feel unprepared to help patients with DTC testing results. Familiar and trusted channels that provide the information and tools PCPs need to help answer patient's questions and manage their care should be used when creating educational programs. PMID- 22207398 TI - Nonobstructive coronary artery disease on CT coronary angiography and abnormal coronary flow reserve: two sides of the same coin. PMID- 22207399 TI - Screening for mutation site on the type I neurofibromatosis gene in a family. AB - PURPOSE: The purpose of the study was to determine the sites and types of mutations associated with type I neurofibromatosis (NF1) in the NF1 gene in a family with NF1 patients. METHODS: The blood samples obtained from this family (four patients and one normal healthy individual) were analyzed by performing polymerase chain reaction (PCR) and DNA sequencing for mutation screening. RESULTS: We found synonymous mutations in exons 7, 38, 50, and 56 of the NF1 gene. This implied that the third codon had a new SNP that did not lead to a change in the amino acid coding. The exon 19 mutation was CAG homozygous, while it was C/TAG heterozygous in normal individuals. The stop codon led to nonsense codon-mediated decay of the mRNA (NMD), thus resulting in only one copy of the NF1 gene that encodes the normal protein in individuals. CONCLUSIONS: The synonymous mutations in the NF1 gene occur in exons 7, 38, 50, and 56. The CAG homozygous mutations may occur in exon 19, and the C/TAG heterozygous mutations may occur in the others. This mutation may be responsible for NF1 in patients in this family and may warrant extensive research on the NF1 gene. PMID- 22207400 TI - Clear cell ependymoma with trisomy 19 developing bone metastases. PMID- 22207404 TI - Japanese launch skin stem cell trials for dry AMD. PMID- 22207401 TI - The importance of very early decompressive craniectomy as a prevention to avoid the sudden increase of intracranial pressure in children with severe traumatic brain swelling (retrospective case series). AB - PURPOSE: The purpose of the retrospective case series of eight consecutive patients is to call our attention to the optimal timing of decompressive craniectomy (DC) in children. METHOD: We report the outcomes of eight children under the age of 12 with severe head injuries. DC was performed at different intracranial pressure (ICP; 20 and 25 mmHg) levels. RESULTS: Our results suggest that above 20 mmHg, very fast progression of ICP (within 15 min) can occur, which may limit the time available to plan and perform DC with a successful patient outcome. CONCLUSION: Considering the anamnestic data, it could be useful to perform DC at 20-22 mmHg ICP in young patients in order to prevent the potential of very fast brain swelling if there is no possibility to perform durotomy within 20 min after the onset of raising the ICP. It is especially considerable in poor countries where the emergency route could be less organized because of locations of building and extreme load of the staff. Further controlled trials are necessary to evaluate the indication and standardization of early decompressive craniectomy as a standard preventive therapy in pediatric severe traumatic brain swelling. PMID- 22207406 TI - Monitoring the one year postoperative infection rate after primary total hip replacement. AB - PURPOSE: Infection of a total hip replacement is potentially a devastating complication. Statistical process control methods have been generating interest as a means of improving the quality of healthcare, and we report our experience with the implementation of such a method to monitor the one year infection rate after primary total hip replacement. METHOD: Infection was defined as the growth of the same organism in cultures of at least two aspirates or intra-operative specimens, or growth of one pathogen in a patient with local signs of infection such as erythema, abscess or draining sinus tract. The cumulative summation test (CUSUM test) was used to continuously monitor the one year postoperative infection rate. The target performance was 0.5% and the test was set to detect twice that rate. RESULTS: Over the three year study period, 2006 primary total hip replacements were performed. Infection developed within one year after surgery in eight (0.4%) hips. The CUSUM test generated no alarms during the study period, indicating that there was no evidence that the process was out of control. CONCLUSION: The one year infection rate after primary total hip replacement was in control. The CUSUM test is a useful method to continuously ensure that performance is maintained at an adequate level. PMID- 22207407 TI - Laparoscopic sleeve gastrectomy: a first step for rapid weight loss in morbidly obese patients requiring a second non-bariatric procedure. AB - BACKGROUND: Laparoscopic sleeve gastrectomy is a viable option that is becoming common in the management of morbid obesity. The aim of this study was to examine the effectiveness and safety of laparoscopic sleeve gastrectomy as a primary step for rapid weight loss in patients who required a second non-bariatric procedure. METHODS: After Internal Review Board approval and with adherence to HIPAA guidelines, we conducted a retrospective review of a prospectively collected database of all patients who underwent laparoscopic sleeve gastrectomy as a primary procedure for a second non-bariatric operation from November 2004 to September 2008 at the Bariatric and Metabolic Institute at Cleveland Clinic Florida. The data was reviewed for age, gender, percentage of excess weight loss (%EWL), preoperative and postoperative body mass index (BMI), morbidity, and mortality. Mean follow-up time was 7 months (range, 2 weeks-12 months). RESULTS: Laparoscopic sleeve gastrectomy was performed in 18 patients who needed a second non-bariatric procedure such as knee replacement surgery, recurrent incisional hernia repair, laminectomy of the lumbar spine, kidney transplant, anterior cervical discectomy, and nephrectomy. Mean preoperative weight and BMI were 124.9 kg (range, 95.5-172.3 kg) and 44.87 kg/m2 (range, 33.36-58.87 kg/m2), respectively. Mean postoperative weight and BMI were 99.2 kg (range, 68.2-132.2 kg) and 35.79 kg/m2 (range, 23.46-48.97 kg/m2), respectively. There were no conversions to an open procedure in this series. There was no morbidity or mortality in this series. CONCLUSIONS: In this small group, laparoscopic sleeve gastrectomy appears to be an effective and safe first surgical approach for rapid weight loss in high-risk patients that require a second non-bariatric procedure. PMID- 22207408 TI - The Michel Benoist and Robert Mulholland yearly European Spine Journal review: a survey of the "surgical and research" articles in the European Spine Journal, 2011. PMID- 22207409 TI - Rapid Flush Technique for Donor Hepatectomy: Safety and Efficacy of an Improved Method of Liver Recovery for Transplantation. AB - Techniques for multiple organ procurement of the heart, liver, and kidneys were first described by Starzl1 and have been adopted throughout the world. Although this conventional technique provides usable organs in the majority of cases it has certain limitations principally due to the need for time-consuming dissection of the hepatic hilar structures. These limitations, which became critically evident in the unstable donor, have led to the evolution and refinement of this technique2 and its eventual standardization. The final simplified version, commonly referred to as the rapid flush technique, requires no preliminary hilar dissection and allows for rapid organectomy in a bloodless field after early in situ core cooling.3 This report describes a 2-year retrospective review of 437 donor hepatectomies comparing our experience with both the conventional and rapid flush techniques. PMID- 22207410 TI - Correlation of LAPTM4B polymorphisms with hepatocellular carcinoma in Chinese patients. AB - Hepatocellular carcinoma (HCC) is the leading cause of cancer mortality in many countries. Evaluation of new susceptibility risk factors is therefore warranted in order to explore means to improve the survival rate. Here, we report on a novel HCC-related gene known as lysosomal protein transmembrane 4 beta (LAPTM4B) that has two alleles designated LAPTM4B*1 and LAPTM4B*2. Allele *1 differs from allele *2 in that it contains one copy of a 19-bp sequence, whereas this sequence is duplicated in allele *2 in exon 1 of LAPTM4B. In this study, we aimed to investigate the relationship between LAPTM4B allelic variation and HCC susceptibility. The LAPTM4B genotype was analyzed in the blood samples from 102 HCC patients and 135 healthy individuals by PCR. The genotypic distribution of LAPTM4B was analyzed using the chi-squared test. The frequencies of allele *2 were 38.24 and 24.07% in the HCC group and control group, respectively, representing a significant difference between these two groups (P<0.001). Thus, allele *2 of LAPTM4B appears to be associated with genetic susceptibility of HCC and may therefore be considered as a risk factor. PMID- 22207411 TI - Heterogeneous friendship affiliation, problem behaviors, and emotional outcomes among high-risk adolescents. AB - Adolescent friendship groups are often heterogeneous and thus involve exposure to both deviant and nondeviant influences. This longitudinal study examined whether the addition of nondeviant peer influences in early high school protected against the negative socialization effects of deviant affiliation on both concurrent and future smoking, alcohol problems, and depressive symptomatology. Adolescents (9th and 10th grade students, N = 1,128) completed self-report questionnaires at both a baseline and 24-month assessment. Nondeviant affiliation consistently reduced the effects of deviant influences on smoking and alcohol problems but not on depressive symptoms. Findings reinforce the complexity of adolescent friendship influences and the notion that distinct mechanisms may drive the associations between deviant affiliations and behavioral and emotional outcomes throughout adolescence. Implications for prevention are also discussed. PMID- 22207412 TI - Clear cell sarcoma of the ileum: report of a case and review of the literature. AB - INTRODUCTION: Clear cell sarcoma of the gastrointestinal tract (CCS-GI) is an extremely rare and aggressive tumor, which often mimics other neoplastic processes. Because of this feature, its real incidence may have been underestimated, especially in the past when genetic tests were less available than nowadays. To date, less then 30 cases have been described in the literature on the GI tract. CASE PRESENTATION: We report the case of a 69-year-old woman who presented with active rectal bleeding. After a negative colonoscopy, the patient underwent a video-capsule endoscopy. The latter detected an ileal mass that was surgically resected. The microscopic appearance was consistent with a malignant mesenchymal neoplasm; immunohistochemistry was positive for S100 protein, CD56, and INI1. Fluorescence in situ hybridization showed a translocation involving the EWSR1 (Ewing sarcoma 1) gene region. All these findings were consistent with a CCS-GI. CONCLUSION: Herein we present a case of CCS-GI, discuss its clinical and pathological features, and review the literature on the subject. PMID- 22207413 TI - Exposure to physical activity resources by neighborhood sociodemographic characteristics in Copenhagen. AB - BACKGROUND: To investigate socioeconomic patterning of physical activity resources in Copenhagen. METHODS: We used multivariate logistic regression analysis to examine the association between physical activity-supportive resources [public open space (POS), cycling and walking paths, sports facilities, and intersection density] and neighborhood sociodemographic indicators (low education, recent immigrants, children under 15 yr, and household income). RESULTS: Neighborhoods with high proportions of residents with low education were most likely to have POS (OR = 2.63; CI: 2.10-3.29), paths (OR = 3.60; CI: 2.84 4.56) and sports facilities (OR = 5.96; CI: 4.31-8.24). Mid-to-low income areas were less likely to contain POS (OR = 67; CI: 0.49-0.90), paths (OR = 0.36; CI: 0.26-0.50), and sports facilities (OR = 0.48; CI: 0.30-0.77). Areas with children were less likely to have connected streets (OR = 0.51; CI: 0.31-0.83) but more likely to have POS (OR = 1.40; CI: 1.15-1.70) and paths (OR = 1.52; CI: 1.25 1.85). CONCLUSIONS: Residents living in areas with high proportions of low education or young children are likely to have high exposure to physical activity resources. Exposure to physical activity resources in Copenhagen may not explain the inequalities in physical activity behavior. Further examination of exposure to built environment resources is warranted. PMID- 22207414 TI - Mixed-effect circadian rhythm model for human erythrocyte acetylcholinesterase activity--application to the proof of concept of cholinesterase inhibition by acorn extract in healthy subjects with galantamine as positive control. AB - PURPOSE: The aim of this study was to develop a non-linear mixed effect circadian rhythm model of acetylcholinesterase (AChE) activity variation and to evaluate the inhibitory effect of acorn extract (2 g) and galantamine (16 mg), used as positive control, on human AChE in red blood cells (RBC). METHODS: This was an open-label, randomized, three-way crossover study involving 12 healthy subjects who received one of the treatments in each study period: no treatment, acorn extract, and galantamine. RBC AChE activity was measured in peripheral blood samples collected at 0 (pre-dose), 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16 and 24 h post-dose administration. Non-linear mixed effect modeling was performed using NONMEM (ver. 7.0). RESULTS: The circadian variation of AChE activity was best described using two mixed effect cosine functions, with periods of 24 and 12 h, respectively. When the inhibitory effect terms were added, the model was significantly improved for both acorn extract and galantamine. In terms of the effect, a 2-g single dose of acorn extract showed AChE inhibition (about 5%) similar to that of a 16-mg single dose of galantamine, in the first 24 h after administration. CONCLUSIONS: Based on the very pronounced inter- and intra-day variation in AChE activity in RBC, we conclude that the model-based approach is essential for the proof of concept and quantitation of AChE inhibition in human subjects. PMID- 22207417 TI - Topics in dementia: papers from the WFN-RGACD 2010 meeting. Introduction. PMID- 22207416 TI - Population pharmacokinetic and exposure-response analysis of nilotinib in patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase. AB - PURPOSE: We investigated the population pharmacokinetics and exposure-response relationship of nilotinib in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase. METHODS: Nilotinib was given at 300 mg or 400 mg twice daily. Serum concentration data (sparse and full pharmacokinetic profiles) were obtained from 542 patients over 12 months. A population pharmacokinetic analysis was performed using nonlinear mixed-effect modeling. Exposure-response relationships were explored graphically or using logistic regression models. RESULTS: Nilotinib concentrations were stable over 12 months. Patients in the 400 mg twice-daily arm had an 11.5% higher exposure than did those in the 300 mg twice-daily arm, and the relative bioavailability of nilotinib 400 mg twice daily was 0.84 times that of 300 mg twice daily. Patient demographics did not significantly affect nilotinib pharmacokinetics. The occurrence of all-grade total bilirubin elevation was significantly higher in patients with higher nilotinib exposure, and a positive correlation was also observed between nilotinib exposure and QTcF change on electrocardiograms from baseline. There was no significant relationship between nilotinib exposure and major molecular response at 12 months. CONCLUSIONS: There is a less than proportional dose exposure relationship between nilotinib 300 mg and 400 mg twice-daily doses. Blood level testing is unlikely to play an important role in the general management of patients with newly diagnosed CML treated with nilotinib. PMID- 22207415 TI - Managing hypertension among nursing-home residents and community-dwelling elderly in Germany: a comparative pharmacoepidemiological study. AB - PURPOSE: The purpose of this study was to investigate the adequacy of hypertension management in hypertensive elderly living in long-term-care facilities compared with home-living elderly. METHODS: This retrospective, cross sectional, pharmacoepidemiological study compared data from a community-dwelling population (CD) and from four nursing homes (NH) in Dresden, Germany. Individuals aged >= 65 with the diagnosis of arterial hypertension were included. Demographical, medical, and drug prescription data as well as blood pressure (BP) values were analyzed and compared descriptively after matching the populations by age and gender. RESULTS: Each population comprised 209 patients (mean age 80.4 years [+/- 6], 70.3% women). NH showed a higher number of diseases [7 (5-9) vs. 5 (3-7); p < 0.001]. BP (<140/90 mmHg) was better controlled in NH (61.0% vs. 48.1%; p = 0.015). The median number of BP-lowering drugs was three (2-4; CD) and two (1-3; NH) (range: 0-9). Most frequently used antihypertensives were diuretics and beta-blockers. Among renin-angiotensin system (RAS) blockers, angiotensin receptor blockers (ARBs) were preferred in CD and angiotensin-converting enzyme (ACE) inhibitors in NH. Drug treatment for secondary prevention of myocardial infarction or stroke [acetylsalicylic acid (ASA) 100, RAS-blocker, beta-blocker, statin] was low among both groups (CD 21.3%; NH 1.6%; p = 0.01). NH received more inappropriate drugs, especially tranquillizers (31.2% vs. 21.0%; p < 0.05) [according to the PRISCUS (Latin for "old and venerable") list for potentially inappropriate medications in the elderly (PIM)]. CONCLUSIONS: NH residents showed better BP control than CD elderly while receiving less antihypertensive drugs. The prescription of antihypertensives was assumed to be more cost effective in NH. Nevertheless, inappropriate drug use is still high (NH > CD), and there is an extended need for professional medication assessment in both groups of elderly. PMID- 22207418 TI - Auditory delta event-related oscillatory responses are decreased in Alzheimer's disease. AB - BACKGROUND: Visual delta event-related (ERO) and evoked oscillations (EO) of Alzheimer patients (AD) are different than healthy. In the present study, the analysis is extented to include auditory ERO and EO in AD. The rationale is to reveal whether the auditory ERO delta responses are also reduced, and whether this is a general phenomenon in Alzheimer patients upon applying stimuli with cognitive load. METHODS: Thirty-four mild AD subjects [17 de-novo and 17 medicated (cholinergic)] and seventeen healthy controls were included. Auditory oddball paradigm and sensory auditory stimuli were applied to the subjects. Oscillatory responses were analyzed by measuring maximum amplitudes in delta frequency range (0.5-3.5 Hz). RESULTS: Auditory delta ERO (0.5-3.5 Hz) responses of healthy controls were higher than either de-novo AD or medicated AD group, without a difference between two AD subgroups. Furthermore, the auditory EO after presentation of tone bursts yielded no group difference. CONCLUSION: Our findings imply that delta ERO is highly unstable in AD patients in comparison to age matched healthy controls only during the cognitive paradigm. Our results favor the hypothesis that neural delta networks are activated during cognitive tasks and that the reduced delta response is a general phenomenon in AD, due to cognitive impairment. PMID- 22207419 TI - Graph theory of tower tasks. AB - The appropriate mathematical model for the problem space of tower transformation tasks is the state graph representing positions of discs or balls and their moves. Graph theoretical quantities like distance, eccentricities or degrees of vertices and symmetries of graphs support the choice of problems, the selection of tasks and the analysis of performance of subjects whose solution paths can be projected onto the graph. The mathematical model is also at the base of a computerized test tool to administer various types of tower tasks. PMID- 22207420 TI - Unpicking the semantic impairment in Alzheimer's disease: qualitative changes with disease severity. AB - Despite a vast literature examining semantic impairment in Alzheimer's disease (AD), consensus regarding the nature of the deficit remains elusive. We re considered this issue in the context of a framework that assumes semantic cognition can break down in two ways: (1) core semantic representations can degrade or (2) cognitive control mechanisms can become impaired. We hypothesised and confirmed that the nature of semantic impairment in AD changes with disease severity. Patients at mild or severe stages of the disorder exhibited impairment across various semantic tasks but the nature of those deficits differed qualitatively for the two groups. Commensurate with early dysfunction of the cognitive control, temporoparietal-frontal-cingulate network, characteristics of deregulated semantic cognition were exhibited by the mild AD cases. In contrast, the severe AD group reproduced features of additional degradation of core semantic representations. These results suggest that spread of pathology into lateral anterior temporal lobes in later stage AD produces degradation of semantic representations, exacerbating the already deregulated system. Moreover, the dual nature of severe patients' impairment was highlighted by disproportionately poor performance on tasks placing high demand on both conceptual knowledge and control processes--e.g., category fluency. PMID- 22207421 TI - Famous people knowledge and the right and left temporal lobes. AB - It is generally accepted that the anterior temporal lobes support knowledge of famous people. The specific roles of the right and left temporal lobe remain a subject of debate, with some studies suggesting differential roles based on modality (visual versus verbal information) and others category (person knowledge versus general semantics). The present study re-examined performance of semantic dementia patients with predominantly right and predominantly left temporal lobe atrophy on famous face, famous name and general semantic tasks, with the specific aim of testing the hypothesis that the right temporal lobe has a privileged role for person knowledge and the left temporal lobe for general semantic knowledge. Comparisons of performance rankings across tasks showed no evidence to support this hypothesis. By contrast, there was robust evidence from naming, identification and familiarity measures for modality effects: right-sided atrophy being associated with relatively greater impairment for faces and visual tasks and left-sided atrophy for names and verbal tasks. A double dissociation in test scores in two patients reinforced these findings. The data present a challenge for the influential 'semantic hub' model, which views the anterior temporal lobes as an area of convergence in which semantic information is represented in amodal form. PMID- 22207422 TI - Decision making cognition in primary progressive aphasia. AB - We sought to investigate the decision making profile of Primary Progressive Aphasia (PPA) by assessing patients diagnosed with this disease (n = 10), patients diagnosed with behavioral variant frontotemporal dementia (bvFTD, n = 35), and matched controls (n = 14) using the Iowa Gambling Task, a widely used test that mimics real-life decision making. Participants were also evaluated with a complete neuropsychological battery. Patients with PPA were unable to adopt an advantageous strategy on the IGT, which resulted in a flat performance, different to that exhibited by both controls (who showed advantageous decision making) and bvFTD patients (who showed risk-appetitive behavior). The decision making profile of PPA patients was not associated with performance on language tasks and did not differ between sub-variants of the disease (namely, semantic dementia and progressive nonfluent aphasia). Investigating decision making in PPA is crucial both from a theoretical perspective, as it can shed light about the way in which language interacts with other cognitive functions, as well as a clinical standpoint, as it could lead to a more objective detection of impairments of decision making deficits in this condition. PMID- 22207423 TI - One size does not fit all: face emotion processing impairments in semantic dementia, behavioural-variant frontotemporal dementia and Alzheimer's disease are mediated by distinct cognitive deficits. AB - Patients with frontotemporal dementia (both behavioural variant [bvFTD] and semantic dementia [SD]) as well as those with Alzheimer's disease (AD) show deficits on tests of face emotion processing, yet the mechanisms underlying these deficits have rarely been explored. We compared groups of patients with bvFTD (n = 17), SD (n = 12) or AD (n = 20) to an age- and education-matched group of healthy control subjects (n = 36) on three face emotion processing tasks (Ekman 60, Emotion Matching and Emotion Selection) and found that all three patient groups were similarly impaired. Analyses of covariance employed to partial out the influences of language and perceptual impairments, which frequently co-occur in these patients, provided evidence of different underlying cognitive mechanisms. These analyses revealed that language impairments explained the original poor scores obtained by the SD patients on the Ekman 60 and Emotion Selection tasks, which involve verbal labels. Perceptual deficits contributed to Emotion Matching performance in the bvFTD and AD patients. Importantly, all groups remained impaired on one task or more following these analyses, denoting a primary emotion processing disturbance in these dementia syndromes. These findings highlight the multifactorial nature of emotion processing deficits in patients with dementia. PMID- 22207424 TI - Spatial and temporal variability of xylan distribution in differentiating secondary xylem of hybrid aspen. AB - Xylans occupy approximately one-third of the cell wall components in hardwoods and their chemical structures are well understood. However, the microdistribution of xylans (O-acetyl-4-O-methylglucuronoxylans, AcGXs) in the cell wall and their correlation with functional properties of cells in hardwood xylem is poorly understood. We demonstrate here the spatial and temporal distribution of xylans in secondary xylem cells of hybrid aspen using immunolocalization with LM10 and LM11 antibodies. Xylan labeling was detected earliest in fibers at the cell corner of the S1 layer, and then later in vessels and ray cells respectively. Fibers showed a heterogeneous labeling pattern in the mature cell wall with stronger labeling of low substituted xylans (lsAcGXs) in the outer than inner cell wall. In contrast, vessels showed uniform labeling in the mature cell wall with stronger labeling of lsAcGXs than fibers. Xylan labeling in ray cells was detected much later than that in fibers and vessels, but was also detected at the beginning of secondary cell wall formation as in fibers and vessels with uniform labeling in the cell wall regardless of developmental stage. Interestingly, pit membranes including fiber-, vessel- and ray-vessel pits showed strong labeling of highly substituted xylans (hsAcGXs) during differentiation, although this labeling gradually disappeared during pit maturation. Together our observations indicate that there are temporal and spatial variations of xylan deposition and chemical structure of xylans between cells in aspen xylem. Differences in xylan localization between aspen (hardwood) and cedar (softwood) are also discussed. PMID- 22207425 TI - Immunhistochemical expression of galectin-3 in cancer: a review of the literature. AB - Galectin-3 is a beta-galactoside-binding animal lectin that contains carbohydrate-recognition domains and displays multiple related functions. It has important roles in diverse biological events, such as embryogenesis, growth, cell adhesion, proliferation, differantiation, cell-cycle progression, apoptosis, mRNA splicing, and regulation of the immune system. Galectin-3 is expressed in various cells and tissues, such as activated macrophages, eosinophils, neutrophils, mast cells, epithelium of the gastrointestinal and respiratory tracts, kidneys and some sensory neurons, and is also involved in tumorigenesis, angiogenesis, and tumor metastasis. In this review of the literature, immunohistochemical Galectin-3 expression is investigated in numerous tumors and disorders of various organ systems. PMID- 22207426 TI - Evaluation of clinical and histopathologic/direct immunofluorescence diagnosis in autoimmune vesiculobullous dermatitis: utility of direct immunofluorescence. AB - OBJECTIVE: Autoimmune bullous diseases are heterogeneous diseases and the differentiation between the various bullous disease is important for treatment and prognosis. Direct immunofluorescence microscopy is still the gold standard in differentiating these diseases. Our aim was to determine the diagnostic accordance between clinical and histopathological/direct immunofluorescence diagnosis of patients with autoimmune vesicolulobullous skin diseases. MATERIAL AND METHOD: A total of 197 cases with clinical diagnosis of vesiculobullous dermatitis was included in the study. The slides stained with H&E were retrospectively re-evaluated for histopathological diagnosis, and had already been evaluated with direct immunofluorescence microscopy. Data were analyzed using the Scientific Package for Social Sciences software. Results were evaluated using Kappa statistics. RESULTS: The clinical and histopathological/direct immunofluorescence accordance for cases ranged from 0% to 100% (Kappa value=0.29). The accordance was 58.8% in pemphigus vulgaris, 53.8% in pemphigus foliaceus, 37.9% in bullous pemphigoid and, 5.2% in dermatitis herpetiformis. Cases of limited numbers in our study were linear IgA bullous dermatitis in 2 cases, Grover's disease in 1 case, epidermolysis bullosa acquisata in 5 cases and, Hailey-Hailey disease in 1 case. The percentages of accordance in these cases were 50%, 100%, 40% and, 0%, respectively. CONCLUSION: The accordance was good in pemphigus vulgaris, pemphigus foliaceus and bullous pemphigoid, but low in dermatitis herpetiformis. Based on our results, we recommend direct immunofluorescence microscopy to be added to light microscopy for the definitive diagnosis of autoimmune blistering disease. Only light microscopic findings are not sufficient and direct immunofluorescence microscopy is the gold standard. PMID- 22207427 TI - Grade of atypia in dysplastic nevi and relationship with dermal fibroplasia. AB - OBJECTIVE: Dysplastic nevus is described as an important factor in increasing the risk of melanoma. Many authors suggested dysplastic nevi should be graded according to architectural and cytological features. Dermal fibroplasia can be in concentric or lamellar fashion. In our study we aim to grade architectural and cytological atypia in dysplastic nevi and to assess the relationship between atypia and dermal fibroplasia. MATERIAL AND METHOD: Ninety-three biopsies obtained from 71 patients were included in the study group. Hematoxylin-eosin stained slides were evaluated and graded according to architectural and cytological features. A total score was obtained for both architectural and cytological atypia in each case. Masson Trichrome stained sections were used to assess dermal fibroplasia and evaluated semiquantitatively. RESULTS: Twenty-eight (30.1%) cases had mild, 48 (51.6%) cases moderate, and 17 (18.3%) cases had severe atypia regarding architectural features. Nine (9.7%) cases were scored having mild, 28 (30.1%) cases moderate, and 56 (60.2%) cases having severe atypia regarding cytologic features. There was a significant correlation between the degree of architectural and cytologic atypia. Six (21.4%) cases with mild, 31 (64.6%) cases with moderate,, and 12 cases (70.6%) with severe architectural atypia had dermal fibroplasia. One case (11.1%) with mild, 10 cases (% 35.7) with moderate, and 10 cases (67.9%) with severe cytological atypia had dermal fibroplasia. A significant relationship was found between the presence of fibroplasia and the degree of cytological and architectural atypia. CONCLUSION: A statistically significant relationship was revealed between the increase of architectural and cytological atypia and dermal fibroplasia. Detection and evaluation of stromal changes by histochemical methods, and scoring of atypia in dysplastic nevi may be helpful to distinguish dysplastic from other banal nevi. PMID- 22207428 TI - Childhood fibroblastic and myofibroblastic tumors: a multicenter documentation and review of the literature. AB - OBJECTIVE: In this study, we aimed to give a documentation of 37 cases of childhood fibroblastic/myofibroblastic tumors retrieved from the archives of 6 reference centers in Ankara along with a comprehensive review on the subject. MATERIAL AND METHOD: A retrospective archive search was carried out for the period between 2006-2010 in 6 reference centers in Ankara covering patients with ages ranging between 0-18 years. All the tumors categorized under fibroblastic and myofibroblastic group according to World Health Organization criteria were collected. RESULTS: The study comprised 407 soft tissue tumors in total. Fibroblastic/myofibroblastic tumors constituted 9,1 % (37 cases) of these tumors. According to histopathology; 16 cases were categorized as fibromatosis, 8 cases as inflammatory myofibroblastic tumor, 6 cases as infantile fibrous hamartoma, 3 cases as nodular fasciitis and 2 cases as infantile myofibroblastic tumor/myofibromatosis and 1 case as cranial fasciitis. The only malignant case was an infantile fibrosarcoma. CONCLUSION: Infantile fibrosarcoma was lower than reported series and a male predominance was noted. The low incidence of newly described entities as well suggests that these tumors may have been unrecognized. PMID- 22207429 TI - CD117 and CD34 staining patterns in childhood benign mammary lesions. AB - OBJECTIVE: CD117 and CD34 are markers that have both been implied in cancer progression in adult breast lesions. This study was conducted in order to create a retrospective documentation and to analyze the expression patterns of these markers on childhood benign lesions along with a comparison with adult breast lesions' staining patterns. MATERIAL AND METHOD: Nine fibroadenomas, 2 tubular adenomas, 1 mammary hamartoma, 2 gynecomastias, 1 benign phyllodes tumor were retrieved from pathology archives of two reference centers between 2005-2010. RESULTS: CD117 staining was identified in the epithelium of all cases in fibroadenoma/tubular adenoma group and focally positive in 1 mammary hamartoma, 2 gynecomastias, and 1 benign phyllodes tumor. CD117 staining was detected in the stroma of 8 cases. Three fibroadenomas, 1 mammary hamartoma, 2 gynecomastias and 1 benign phyllodes tumor lacked stromal labelling for this marker. All cases were strongly and diffusely positive for CD34 except the benign phyllodes tumor case. This case presented marked loss of stromal CD34 staining when compared to the surrounding stroma. Additionally, pseudoangiomatous stromal hyperplasia was noted in 2 gynecomastias and in the peritumoral stroma of benign phyllodes tumor case. CONCLUSION: Our study demonstrated that fibroadenoma was the most commonly encountered breast lesion in childhood and that adolescent fibroadenomas showed similar staining patterns for CD117 and CD34 as for adult counterparts. On the other hand, different expression patterns of CD117 and CD34 between adenoma group and the gynecomastias and benign phyllodes tumor group may implicate different mechanisms of development and tumorigenesis among these groups. PMID- 22207430 TI - Correlation of hormone receptors with Her-2 Neu protein expression and the histological grade in invasive breast cancers in a cohort of Saudi Arabia. AB - OBJECTIVE: Data on Hormone Receptor and Her-2/neu expression in breast cancers from Saudi Arabia and Gulf Region is sparse. We undertook this study to describe the patterns of hormone receptor and Her-2/neu protein expression in breast carcinoma and compared them with the histological grade at a University Hospital in Riyadh. MATERIAL AND METHOD: We conducted a retrospective study on 164 invasive ductal carcinoma of breast between the year 2002 and 2008. Immunohistochemical analysis for Estrogen and Progesterone Receptor and Her-2/neu was done in all the cases. Fluorescent in situ hybridization for Her-2/neu gene amplification was performed in all 2+ cases and few equivocal 1+ and 3+cases by immunohistochemistry. Correlation between Estrogen and Progesterone Receptor and Her-2/ neu amplification and grade of tumor was calculated. RESULTS: The expression of Estrogen Receptor, Progesterone Receptor were significantly correlated (p < 0.001). Also, there was a significant negative correlation between expression of hormone receptor and Her-2/neu amplification. The histologic grade of the tumor was significantly correlated to the expression of both Estrogen and Progesterone Receptor. However, the relationship between Her-2/ neu amplification and grade was not significant and many of the grade III tumor were Her-2/neu negative. In addition, Her-2/neu gene amplification by fluorescent in situ hybridization was observed in 84.6% of breast cancer that were 3+ and in 18.75 % cases that were 2+ by immunohistochemistry. CONCLUSION: Prevalence of Estrogen and Progesterone Receptor expression and Her-2/neu amplification in breast cancer in the Saudi Arabian population is similar to that reported internationally. There is a negative correlation between hormone receptors expression and Her-2/neu amplification. However not all of the high-grade breast cancers showed Her-2/neu positive status. PMID- 22207431 TI - Amyloidosis of seminal vesicles; incidence and pathologic characteristics. AB - OBJECTIVE: Amyloidosis is a rare disease with various etiologies with extracellular amyloid protein depositions. At present, at least 26 distinctive amyloid forms have been detected with different clinical importance and treatment. They have characteristic staning fetaures with Congo red. Amyloid may be detected in 2-10% of prostates that have been removed because of hyperplasia or carcinoma. Amyloidosis of seminal vesicles is accepted as senil amyloidosis and it is not accompanied by systemic amyloidosis or clinical symptoms. This condition is the most common form of localized amyloidosis. In this study we aimed to investigate incidence and histologic characteristics of amyloidosis of seminal vesicles in radical prostatectomy materials of the patients whose prostate carcinomas were treated surgically. MATERIAL AND METHOD: Amyloid depositions in seminal vesicles of 207 radical prostatectomy materials that prostates had been removed due to localized prostate carcinoma. Amyloid depositions were confirmed with Congo red staining and polarization microscope. RESULTS: Amyloidosis of seminal vesicles was detected in 10 (4.8%) of cases. Mean age of the patients is 66.2 years. Amyloid depositions tend to be nodular and bilateral in subepithelial region of affected seminal vesicles. Amyloid depositions were not detected in blood vessels in seminal vesicles or prostate parenchyma. CONCLUSION: Localized amyloidosis of seminal vesicles is not an unusual finding. amyloidosis of seminal vesicles incidence in Turkish patients included in this study and histopathologic characteristics of these patients are not different from the other studies. Systemic AA amyloidosis is the most common form of amyloidosis in our country. To be aware of amyloidosis of seminal vesicles is of importance in discrimination from the other forms of amyloidosis. PMID- 22207432 TI - Expressions of bax, bcl-2 and Ki-67 in odontogenic keratocysts (Keratocystic Odontogenic Tumor) in comparison with ameloblastomas and radicular cysts. AB - OBJECTIVE: The aim of the study was to determine the apoptotic features and proliferation potential of odontogenic keratocysts compared with ameloblastomas and radicular cysts by analysing the role of bax, bcl-2, and Ki-67. MATERIAL AND METHOD: The study material consisted of 20 odontogenic keratocysts, 20 radicular cysts, and 20 ameloblastomas. Immunohistochemically, bax, bcl-2 and Ki-67 were applied. The positive cells were evaluated in both neoplastic/nonneoplastic odontogenic epithelium and connective tissue cells. RESULTS: Ameloblastoma showed stronger bcl-2 expression than odontogenic keratocysts and radicular cysts. Bcl-2 expression in the whole thickness of epithelium and connective tissue of odontogenic keratocyst was significantly higher than radicular cyst. The expression of bax in the epithelium of radicular cyst was significantly higher than odontogenic keratocyst and ameloblastoma. The lining epithelium of odontogenic keratocyst showed stronger Ki-67 expression than ameloblastoma and radicular cyst. CONCLUSION: The proliferation potential of the epithelium and the overexpression of various anti-apoptotic proteins in odontogenic epithelial tumors are quite significant for their clinical behaviour. High expressions of bcl-2 and Ki-67 in odontogenic keratocysts accord with their aggressive clinical behaviour and a high recurrence rate. PMID- 22207433 TI - Pregnancy-related peritoneal ectopic decidua (deciduosis): morphological and clinical evaluation. AB - OBJECTIVE: Ectopic decidual reaction (deciduosis) can be seen rarely on the peritoneum during laparotomy for a cesarean section for pregnancy, in addition to the ovary and cervix. The aim of this study was to evaluate the clinical, histopathological, immunohistochemical characteristics of ectopic decidua cases that were incidentally found in the peritoneum during a cesarean section. MATERIAL AND METHOD: A total of seven cases where decidualization was found in the peritoneal biopsy taken during pregnancy at the Baskent University Medical Faculty Adana Teaching and Training Hospital Department of Pathology were included in this study. The clinical features of the cases were obtained from their clinical folders. The morphological findings were recorded and the peritoneal biopsies were analyzed with keratin Pan Ab-1, calretinin, vimentin, HMB-45 and progesterone receptor antibody for immunohistochemical analysis. RESULTS: The mean age for the seven cases was 36+/-4.16. The gestational age was 33 to 39 (mean 37.2) weeks. Microscopic evaluation revealed decidualized cells that were large polygonal and eosinophilic, some with vacuolated cytoplasm, that formed small nodules under the mesothelium of the peritoneum in all cases. Immunohistochemical staining showed positive staining of the cell cytoplasm with vimentin and positive staining of the cell nucleus with the progesterone receptor antibody in the decidual cells. Calretinin, keratin and HMB-45 stains were negative. CONCLUSION: Pregnancy-related peritoneal deciduosis develops with the effect of progesterone in pregnancy. It disappears without complication in the postpartum period. Immunohistochemistry may help the differential diagnosis of peritoneal deciduosis where problems are experienced differentiating the case from malignant mesothelioma or metastatic tumor. PMID- 22207434 TI - Tumor budding in colorectal carcinomas. AB - OBJECTIVE: In colorectal carcinomas, tumor budding has been defined as the presence of isolated single tumor cells or small cell clusters in the stroma at the invasive tumor margin. In this study, the relationship between tumor budding density at the invasive tumor margin and pathological parameters is investigated. MATERIAL AND METHOD: Haematoxylin and eosin stained slides of 73 cases with colorectal carcinoma were retrospectively evaluated for the presence and intensity of tumor budding by 2 observers. After the specimens were assessed, the highest density of tumor budding area was counted in a microscopic field of x200. Cases were separated into 2 groups according to tumor budding density as low grade ( < 10) and high grade (>=10). The relationship of these groups with depth of tumor invasion, histological grade, vascular invasion and lymph node involvement was investigated. RESULTS: Of the 73 colorectal carcinoma cases, 33 (45.2%) had low and 40 (54.8%) had high grade tumor budding density, respectively. There was a statistically significant relationship between high grade tumor budding density and histological grade (p=0.042), lymph node involvement (p=0.0001) and vascular invasion (p=0.0034). CONCLUSION: High grade tumor budding density is associated with aggressive phenotypical features in colorectal carcinoma. PMID- 22207435 TI - [Low grade sinonasal adenocarcinoma]. AB - Sinonasal adenocarcinoma is a rare neoplasm which is classified as 'intestinal' or 'nonintestinal' type, depending on its resemblance to gastrointestinal mucosa. These tumors are associated with occupational and environmental carcinogens. In this study, a fifty-year-old oil-painter male patient with a low-grade nonintestinal type sinonasal adenocarcinoma originating from the left middle concha and ethmoid sinus is presented. Microscopical examination revealed many infiltrative glandular structures, most of which were cystically dilated and some of which were smaller in diameter, arranged back to back in loose fibrous stroma as well as intraglandular papillary and micropapillary structures forming complex branches or a cribriform pattern. The glands were lined by epithelial cells that were faintly eosinophilic and relatively abundant cubical/ cylinderical cytoplasms and mildly pleomorphic round/oval nuclei, with rare mitotic figures. Intraluminal and focally intracytoplasmic mucin was demonstrated with Alcian Blue, mucicarmin and PAS stains. Immunohistochemically, tumor cells were strongly and diffusely positive with CK7; focally and weakly positive with CK20 and negative with CDX2 in accordance with the nonintestinal type. S-100, Actin and p63, applied for investigating the myoepithelial and salivary glandular origins, were all negative. Prognostic markers, TTF-1 and p53 were negative; while the Ki-67 index was 2%. The fact that intestinal type sinonasal adenocarcinomas are generally high grade, while nonintestinal tumors are histologically low grade makes this morphological and immunohistochemical-based classification valuable in predicting the prognosis of the disease. In addition to the morphological and immunohistochemical findings, clinical information stands out in the differentiation of the tumor from benign or malignant primary lesions or metastatic adenocarcinoma. PMID- 22207436 TI - [Cytopathologic features of pleomorphic carcinoma of the lung: case report]. AB - Pleomorphic carcinoma of the lung is a subtype of sarcomatoid carcinoma and essentially classified as a poorly-differentiated, non-small cell lung carcinoma. Being a very rare tumor, it constitutes 0.3-1.3% of all malignancies of the lung. Cytology reveals malignant fusiform and/or giant cells, accompanied by malignant epithelial elements like squamous cell, adeno or large cell carcinoma. Our case, a 76-year-old female patient, presented with chest and back pain. Thoracic CT showed a well-demarcated solid mass of 5x3 cm located peripherally in the left upper lobe of the lung. Trans-thoracic fine needle aspiration cytology showed atypical cells with a biphasic character in a myxoid matrix. It was noted that of these, some were poorly demarcated fusiform cells with oval nuclei and marked nucleoli, while others were epithelial cells with eccentrically placed nuclei, large cytoplasms and macronucleoli. The patient was diagnosed as pleomorphic carcinoma on the basis of these findings, and the cytological diagnosis was confirmed by histopathology. Pleomorphic carcinoma is a poorly-differentiated non-small cell lung carcinoma, which poses diagnostic difficulties. As it is rare, it lacks decisive diagnostic criteria and has cytological characteristics resembling those of other lung tumors. PMID- 22207437 TI - Myxoma of the renal sinus: case report and literature review. AB - Myxoma is a rare mesenchymal tumor and it is mainly seen in heart and skin. Renal myxoma is extremely rare. To date, eleven cases of kidney myxomas have been reported in the literature. One of them is myxoma of the renal sinus. Our case was an 82-year-old man admitted to our hospital symptoms related to the urinary tract obstruction. Abdominal computerized tomography revealed a solid, hypodense mass 9 cm in diameter infiltrating the renal parenchyma in the renal pelvis. The patient underwent nephrectomy. The resected kidney contained gelatinous tumor with indistinct borders. The tumor was composed of slender, bland, spindle-shaped cells with large amounts of mucoid material. Tumor cells were positively stained with vimentin, focally stained positive for smooth muscle actin and had negative reactivity for S-100 protein, epithelial membrane antigen and pancytokeratin. Herein we report the second case of renal myxoma arising from the renal sinus. PMID- 22207438 TI - Adult lymphangioma - a rare entity: a report of two cases. AB - OBJECTIVE: Lymphangiomas are rare congenital malformations commonly seen in children. Its occurrence in adults is uncommon with very scarce reports in the literature. It mainly occurs in infants or children younger than two years of age. We report these cases to emphasize the need to consider cystic lymphangiomas in differential diagnosis of neck masses in adults. CASE REPORTS: We describe two cases in adults, one a 27-year-old man and the other a 59-year-old male. The former presented with recurrent neck mass for 5 years, and the latter presented with asymptomatic neck mass of a short duration. Both were not associated with any pain, discoloration, discharge or sudden increase in size. CONCLUSION: The awareness of occurrence of cystic lymphangioma in adults is important for its proper management which includes complete surgical removal, to prevent recurrence. PMID- 22207439 TI - Gastric adenocarcinoma deposits presenting as multiple cutaneous nodules: a case report with review of literature. AB - Metastases to the skin from internal tumors are uncommon, yet they may be the first presentation of such malignancies. They usually arise from the breast, lung and large bowel. Cutaneous metastases from gastric adenocarcinoma are extremely rare. We report a case of gastric adenocarcinoma that at presentation had multiple clinically benign looking skin nodules. Fine needle aspiration cytology of the cutaneous nodule revealed metastatic deposits. The current literature on cutaneous metastases of gastric carcinoma is reviewed in this case report. PMID- 22207440 TI - [Melanocytosis of the oesophagus: case report]. AB - Esophageal melanocytosis is a benign clinicopathologic entity characterized by melanocytic proliferation in esophageal squamous epithelium and melanin deposition in the mucosa. Little is known about the etiology and natural course of this condition, although it has been suggested to be a precursor of primary esophageal melanoma by some authors. Following a search of the databases regarding esophageal melanocytosis and melanosis, thirty-four cases of isolated esophageal melanocytosis were found. The histopathologic features of esophageal melanocytosis are reviewed and its differential diagnosis with other pigmented esophageal lesions is discussed. PMID- 22207441 TI - Carcinosarcoma of the lung associated with neurofibromatosis type 1: a case report. AB - Neurofibromatosis or von Recklinghausen's disease is the most common inherited syndrome predisposing to neoplasia. Carcinosarcoma is a rare malignant mixed tumor of the lung. Association of carcinosarcoma of lung with Neurofibromatosis-1 is not common. A 57-year-old man presented with history of fever, cough, hemoptysis, breathlessness, weight loss, chest pain. Multiple cutaneous neurofibromas and cafe au lait spots were revealed by physical examination. A homogeneous opacity was found in the right middle and right upper zone on posterior-anterior chest radiography. A 8x8x7 cm mass that had irregular borders in right upper posterior and apical segment was seen on contrast enhanced chest computed tomography. On bronchoscopy, the lumen of right upper apical segment was obstructed with vegetating tumoral lesion. The biopsy taken from this region was diagnosed as carcinosarcoma by histopathological and immunohistochemical examination.A rare case with carcinosarcoma of the lung and Neurofibromatosis-1 was reported. PMID- 22207442 TI - Modern health worries, somatosensory amplification and subjective symptoms: a longitudinal study : a longitudinal study. AB - BACKGROUND: Modern health worries (MHWs; i.e., concerns about possibly harmful features of modern life) have been associated with somatic symptoms and somatosensory amplification in previous cross-sectional studies. Causal relationship among these variables is yet to be discovered. PURPOSE: The study investigates the temporal association among subjective symptoms, somatosensory amplification (SSA), and modern health worries (MHWs). METHOD: Baseline and follow-up questionnaires (somatic symptoms--PHQ-15, somatosensory amplification scale--SSAS, modern health worries scale--MHW, PANAS negative affect scale-NA) were completed by 366 undergraduate students in a 2-month longitudinal study. RESULTS: MHWs were predicted by baseline MHWs (beta = 0.721, p < 0.001) and by somatic symptoms (beta = 0.084, p < 0.05). Somatic symptoms were predicted by baseline symptoms (beta = 0.610, p < 0.001), NA (beta = 0.104, p < 0.05), and SSAS scores (beta = 0.089, p < 0.05). The only predictor of SSA was baseline SSAS score (beta = 0.628, p < 0.001). CONCLUSION: Based on the results, a linear model (proneness to somatosensory amplification leads to subjective symptoms which lead to MHWs) was proposed, where MHWs serve as explanations of physical symptoms or as possible environmental threats to avoid. PMID- 22207443 TI - P75 nerve growth factor receptor as a useful marker to distinguish spindle cell melanoma from other spindle cell neoplasms of sun-damaged skin. AB - P75 nerve growth factor receptor (p75 NGF-R) is a low-affinity receptor expressed on the surface of neural crest-derived cells and in a variety of neural tumors. Strong p75 NGF-R expression has been found in spindle cell melanoma (SCM). We studied spindle cell neoplasms of sun-damaged skin to determine whether this marker can reliably distinguish between SCM and other spindle cell malignancies. We evaluated the staining of p75 NGF-R, S100, and HMB-45 in 11 cases of SCM, 16 cases of spindle cell squamous cell carcinoma (SCSCC), 19 cases of spindle cell atypical fibroxanthoma, 6 cases of cutaneous leiomyosarcoma, and 20 scars. Staining with p75 NGF-R was positive in all 11 of 11 (100%) cases of SCM, whereas S100 stained 10 of 11 (91%) cases, and HMB-45 was negative in all SCMs. In addition, there was superior intensity of the staining for p75 NGF-R in comparison to S100. P75-NGF-R showed focal positivity in 3 of 16 (19%) cases of SCSCC. None of the rest of the cases of SCSCC, and none of the cases of spindle cell atypical fibroxanthoma, cutaneous leiomyosarcoma, and scars expressed p75 NGF-R, S100, or HMB-45. P75 NGF-R is a useful marker to distinguish SCM from other spindle cell neoplasms of sun-damaged skin. This marker exhibits greater sensitivity than S100 in identifying SCM and may be a useful diagnostic and ancillary stain especially in the setting of an S100 negative spindle cell neoplasm. PMID- 22207444 TI - Multiple tubulovillous adenomas of the vulva. AB - Enteric-type lesions are rare in the female genital tract. We report the first case of multiple vulvar tubulovillous adenomas with transformation into adenocarcinoma. A 31-year-old woman presented with recurrent vulvar polypoid lesions resembling condylomas that were excised. These tumors were characterized by their tubulovillous architecture and intestinal differentiation, with columnar epithelium, goblet cells, and Paneth cells. As in their colonic counterpart, the degree of dysplasia was evaluated. The lesions consisted of 3 low-grade adenomas and 1 adenocarcinoma with superficial invasion. After 15 months, there is no sign of recurrence. The clinical presentation, pathological findings, differential diagnoses, and pathogenesis are discussed. PMID- 22207445 TI - Granuloma annulare with prominent lymphoid infiltrates ("pseudolymphomatous" granuloma annulare). AB - Granuloma annulare (GA) is characterized histopathologically by 3 patterns: necrobiotic granuloma, interstitial incomplete form and, rarely, sarcoidal or tuberculoid granuloma. The amount of lymphoid infiltrate in GA is usually limited. We describe 10 cases of GA with prominent "pseudolymphomatous" lymphoid infiltrates mimicking cutaneous lymphoid hyperplasia. Patients were 6 males and 4 females (mean age 49.9 years, median age 47 years, age range 25-70). Lesions were localized to a limited area of the body (n = 6), or involved the entire trunk (n = 3), or were generalized (n = 1). The correct clinical diagnosis of GA was provided only in 30% of the cases. In all cases, histopathologic features were characterized by dense, nodular, superficial, and deep infiltrates of lymphocytes. Immunohistology revealed predominance of T lymphocytes in 7 of 7 tested cases. This "pseudolymphomatous" variant of GA represents a pitfall in the histopathologic diagnosis of the disease and may be misinterpreted as other types of cutaneous lymphoproliferative disorders. PMID- 22207446 TI - Two cases of male nipple leiomyoma: idiopathic leiomyoma and gynecomastia associated leiomyoma. AB - We describe 2 cases of male nipple leiomyoma. A 70-year-old man had a painful subcutaneous tumor on his left nipple of 6 months duration. Histopathology disclosed dermal spindle cells with oval-shaped nuclei forming interlacing bundles with irregular pattern. Glandular elements were absent. The spindle cells were positive to alpha-smooth muscle actin, desmin, and vimentin. Estrogen receptor (ER) and progesterone receptor (PrR) were negative. We diagnosed this case as male leiomyoma of the nipple. Another patient was a 61-year-old man with gynecomastia induced by spironolactone of 6 months duration. He also had a painful nodule on his left nipple and histopathology disclosed spindle-shaped tumor cells as in the previous patient. The tumor was accompanied by glandular elements in the deep dermis and subcutaneous tissue, which showed apocrine secretion and were positive for alpha-smooth muscle actin, ER, and PrR. These glandular elements were interpreted as mammary gland. But ER and PrR stain did not show positive results for leiomyoma in the upper dermis. To the best of our knowledge, this is the first report of male idiopathic and gynecomastia-induced leiomyoma with ER and PrR staining. PMID- 22207447 TI - Cigarettes and self-rated health among online university students. AB - An increasing number of university students are earning their degrees online. Thus far, the determinants of health among online university students have not been studied. The purpose of this cross-sectional internet survey was to test the association between behavioral risk factors and self-rated health in a diverse sample of online university students. Cigarette smoking was associated with lower odds of good self-rated health (OR = 0.27, P < 0.01). Compared to having zero days of mental distress, 14 or more days of mental distress was associated with lower odds of good self-rated health (OR = 0.08, P < 0.05). White students had lower odds of reporting good self-rated health compared to African-American students (OR = 0.35, P < 0.05). Health education, screening and health promotion programs should be developed for online students. PMID- 22207448 TI - Factors influencing healthcare utilization within a free community clinic. AB - The purpose was to explore the relationship between the presence of a free community clinic and factors associated with utilization of healthcare through a secondary data analysis. Using a descriptive correlational design, results were analyzed to explore relationships between potential utilization of healthcare, identification of a regular source of healthcare, and health insurance status. Most subjects would not seek healthcare if the free community clinic was not available. Subjects with health insurance were significantly more likely to have a regular source of healthcare and seek healthcare in the absence of the free community clinic. Subjects with a regular source of healthcare were significantly more likely to seek healthcare in the absence of the free community clinic. Emergency room utilization was not impacted by regular source of healthcare or health insurance. This study supports the need for free community clinics in areas with high percentages of uninsured, immigrant, and refugee populations. PMID- 22207450 TI - Effectiveness of acupressure on pruritus and lichenification associated with atopic dermatitis: a pilot trial. AB - BACKGROUND: Pruritus is a debilitating aspect of atopic dermatitis (AD). Acupuncture has been reported to diminish pruritus, but self-administered acupressure has not been previously evaluated. OBJECTIVES: To evaluate the effectiveness of acupressure on the severity of eczema in a pilot trial. METHODS: Adult patients with AD were randomised to an intervention group (acupressure with standard of care) or a control group (standard of care alone). Subjects in the intervention group performed acupressure using a 1.2 mm acupellet at the LI11 point, applying pressure for 3 min three times per week for 4 weeks. The severity of itching and AD at baseline and at 4 weeks were measured on a visual analogue scale (VAS), the Investigator's Global Assessment (IGA) and the Eczema Area and Severity Index (EASI). RESULTS: Fifteen subjects were enrolled, 12 of whom completed the study between November 2009 and May 2011. There was no significant change between baseline and follow-up survey scores within the control group. In the investigation group there was a decrease in the VAS score (p=0.05) and EASI lichenification (p=0.03), although without significant change in the overall EASI score. Comparison of the scores between groups showed a greater decrease in VAS in the experimental group than in the control group (p=0.04), and a decrease in the IGA (p=0.03) and EASI lichenification score (p=0.03). The overall EASI scores were unchanged. CONCLUSION: Subjects using acupressure at LI11 for 4 weeks had improvement in pruritus and lichenification. Acupressure may prove to be an easily administered alternative treatment, but larger-scale studies are needed to confirm these preliminary findings. PMID- 22207449 TI - LED (660 nm) and laser (670 nm) use on skin flap viability: angiogenesis and mast cells on transition line. AB - Skin flap procedures are commonly used in plastic surgery. Failures can follow, leading to the necrosis of the flap. Therefore, many studies use LLLT to improve flap viability. Currently, the LED has been introduced as an alternative to LLLT. The objective of this study was to evaluate the effect of LLLT and LED on the viability of random skin flaps in rats. Forty-eight rats were divided into four groups, and a random skin flap (10 * 4 cm) was performed in all animals. Group 1 was the sham group; group 2 was submitted to LLLT 660 nm, 0.14 J; group 3 with LED 630 nm, 2.49 J, and group 4 with LLLT 660 nm, with 2.49 J. Irradiation was applied after surgery and repeated on the four subsequent days. On the 7th postoperative day, the percentage of flap necrosis was calculated and skin samples were collected from the viable area and from the transition line of the flap to evaluate blood vessels and mast cells. The percentage of necrosis was significantly lower in groups 3 and 4 compared to groups 1 and 2. Concerning blood vessels and mast cell numbers, only the animals in group 3 showed significant increase compared to group 1 in the skin sample of the transition line. LED and LLLT with the same total energies were effective in increasing viability of random skin flaps. LED was more effective in increasing the number of mast cells and blood vessels in the transition line of random skin flaps. PMID- 22207451 TI - Trans fatty acids consumption in type 1 diabetic patients: evaluation by dietary records and measurement in serum phospholipids. AB - The consumption of foods containing trans fatty acids (TFA), especially those produced by food industries, induces pleiotropic negative effects on health. Therefore, it is important to assess the amount of TFA consumed, especially in age groups more exposed to the consumption of TFA-containing foods. The present pilot study evaluates TFA intake in 54 young people with and without type 1 diabetes (29 young subjects with type 1 diabetes and 25 healthy subjects) through both dietary records (7-day food record) and the measurement of TFA levels in serum phospholipids, a possibly more objective marker of TFA intake. The comparison between the two groups was made by the student t test for independent samples. The intake of synthetic TFA was low in both groups (type 1 diabetic patients: 0.25 +/- 0.25 g/day; healthy subjects 0.48 +/- 0.37 g/day), but significantly lower in diabetic patients vs controls (P < 0.05); TFA levels in serum phospholipids also confirmed a low intake of these fatty acids. These data indicate that the intake of trans fatty acids is relatively low in our population, i.e.,<1% of total calories in the diet, in line with what recommended by the World Health Organization. PMID- 22207452 TI - Type 1 diabetes is increasing in very young children, but is the real reason referable only to environmental factors? PMID- 22207453 TI - Risk assessment of aggression toward emergency health care workers. AB - BACKGROUND: Health care and social service workers face a significant risk of job related violence. AIMS: To develop a method for quantitative evaluation of the risk of violence, as required by Italian and European regulations, against extra hospital emergency health care workers employed by the Regional Emergency Healthcare Service (ARES 118) in the Lazio Region in Italy. METHODS: Violence to the ARES 118 workers during working hours was examined by analysing injuries reported by them between 2005 and 2007. The assessment method proposed should give a numerical indicator of the risk of violence for each homogeneous group. The quantitative risk was evaluated on the basis of variables such as the days off work for each episode, the total number of aggressive attacks, the type of health intervention involved, etc. RESULTS: The rate of accidents related to aggression during working hours at the ARES unit was 6.3%, which is significantly higher than the figure of 2% reported for the entire health care sector. CONCLUSIONS: The present evaluation is largely based on analysis of the Injury Register. To increase the sensitivity of the method so that it closely reflects active reporting of events, it would be necessary to implement a procedure for reporting events in a 'company register of acts of violence' and to make workers more aware of the need to report all such episodes. PMID- 22207454 TI - Is pre-employment health screening by questionnaire effective? AB - BACKGROUND: Following a job offer, many employers require the chosen candidate to undergo health screening by questionnaire before the applicant commences work. Despite their widespread use, the effectiveness of such questionnaires remains uncertain. AIMS: To systematically review the evidence for the effectiveness of pre-employment health questionnaires in predicting health and employment outcomes. METHODS: We used a sensitive search strategy to search electronic databases from 1985 to September 2009. The search included dissertations for Membership of the UK Faculty of Occupational Medicine (MFOM). The authors independently selected abstracts and papers for critical appraisal and inclusion in the review using methods based on guidelines produced by the National Health Service Centre for Reviews and Dissemination, University of York. RESULTS: Five hundred and three abstracts were identified; nine papers and two MFOM dissertations were critically appraised. Seven papers and two MFOM dissertations were included in the final review. Six studies explored pre-employment predictors of respiratory symptoms, one explored predictors of back pain in nurses, and two dissertations explored work outcomes including sickness absence and ill-health retirement. No papers addressing mental health outcomes met our inclusion criteria. Included studies either failed to identify pre-employment predictors of health and work outcomes or found very weak predictors. CONCLUSIONS: Pre employment health screening (PEHS) by questionnaire has a low predictive value in detecting future adverse health and occupational outcomes. Where PEHS takes place, the health standards required and criteria for rejection of applicants should be based on a full risk assessment of the prospective post. PMID- 22207455 TI - Vasoactive intestinal peptide enhances TNF-alpha-induced IL-6 and IL-8 synthesis in human proximal renal tubular epithelial cells by NF-kappaB-dependent mechanism. AB - Vasoactive intestinal polypeptide (VIP) is a 28-amino acid neuropeptide with vasodilator, bronchodilator, and anti-inflammatory effects. But little is known about its pro-inflammatory effects. We investigated the effect of VIP on the secretion of interleukin-6 (IL-6) and interleukin-8 (IL-8), two pro-inflammatory cytokines, in TNF-alpha-activated proximal renal tubular epithelial cell line (HK 2 cells). Cultured HK-2 cells were treated with TNF-alpha in the presence or absence of VIP with a dose range from 1 to 100 nM, followed by analysis of pro inflammatory cytokines (IL-6 and IL-8) induction and their signal events including activation of the NF-kappaB pathway. We report here that tumor necrosis factor-alpha (TNF-alpha) increased IL-6 and IL-8 production, and that these effects were potentiated by VIP at 10 nM in HK-2 cells. However, VIP at 1 and 100 nM did not display this function. Consistent with these observations, we were able to show that VIP at 10 nM upregulated TNF-alpha-induced phosphorylation of IkappaB-alpha, leading to IkappaB-alpha degradation and the subsequent nuclear translocation of NF-kappaB. Furthermore, VIP-enhanced activation of NF-kappaB transcription activity was demonstrated using a NF-kappaB reporter construct upon transient transfection into HK-2 cells. These results strongly suggest that VIP synergistically enhances TNF-alpha-stimulated IL-6 and IL-8 synthesis via activating the NF-kappaB pathway in HK-2 cells. PMID- 22207457 TI - Single scrotal incision for repair of bilateral inguinal hernias in boys. AB - PURPOSE: Single scrotal incision for repair of bilateral inguinal hernias in boys is a new and attractive approach. However, the advantages and drawbacks of this approach have not been fully discussed in the literature and it has not been widely accepted as a standard procedure for repair of bilateral inguinal hernias. We develop the median raphe approach and this study is aimed to clarify the outcomes of this new technique. METHODS: From January 2006 to December 2010, we studied 114 boys with bilateral inguinal hernias who underwent trans-scrotal repairs using median raphe incisions. The follow-up durations ranged from 12 to 36 months. The operation time and morbidity of this approach were compared to those of 91 boys who underwent conventional bilateral inguinal incision herniorrhaphy from January 2001 to December 2005. RESULTS: The operation times were equal in both approaches. The incidence of stitch abscesses was a little higher in scrotal incision group. All the boys with the scrotal approach had excellent cosmetic results. CONCLUSION: The median raphe approach for bilateral inguinal hernia repair is a good alternative to the conventional method for boys. PMID- 22207458 TI - Small bowel skip segment Hirschprung's disease presenting with perforated Meckel's diverticulum. AB - Skip segment Hirschprung's disease (SSHD) is an uncommon variant of Hirschprung's disease where normal intestine is interspersed proximally and distally by abnormal, aganglionated intestine. These segmental changes have no well-defined embryological explanation. We present a case of SSHD in the small bowel and concomitant perforated Meckel's diverticulum, with review of the literature relevant to SSHD. PMID- 22207456 TI - Expression and functional analysis of two osmotin (PR5) isoforms with differential antifungal activity from Piper colubrinum: prediction of structure function relationship by bioinformatics approach. AB - Osmotin, a pathogenesis-related antifungal protein, is relevant in induced plant immunity and belongs to the thaumatin-like group of proteins (TLPs). This article describes comparative structural and functional analysis of the two osmotin isoforms cloned from Phytophthora-resistant wild Piper colubrinum. The two isoforms differ mainly by an internal deletion of 50 amino acid residues which separates them into two size categories (16.4 kDa-PcOSM1 and 21.5 kDa-PcOSM2) with pI values 5.6 and 8.3, respectively. Recombinant proteins were expressed in E. coli and antifungal activity assays of the purified proteins demonstrated significant inhibitory activity of the larger osmotin isoform (PcOSM2) on Phytophthora capsici and Fusarium oxysporum, and a markedly reduced antifungal potential of the smaller isoform (PcOSM1). Homology modelling of the proteins indicated structural alterations in their three-dimensional architecture. Tertiary structure of PcOSM2 conformed to the known structure of osmotin, with domain I comprising of 12 beta-sheets, an alpha-helical domain II and a domain III composed of 2 beta-sheets. PcOSM1 (smaller isoform) exhibited a distorted, indistinguishable domain III and loss of 4 beta-sheets in domain I. Interestingly, an interdomain acidic cleft between domains I and II, containing an optimally placed endoglucanase catalytic pair composed of Glu-Asp residues, which is characteristic of antifungal PR5 proteins, was present in both isoforms. It is well accepted that the presence of an acidic cleft correlates with antifungal activity due to the presence of endoglucanase catalytic property, and hence the present observation of significantly reduced antifungal capacity of PcOSM1 despite the presence of a strong acidic cleft, is suggestive of the possible roles played by other structural features like domain I or/and III, in deciding the antifungal potential of osmotin. PMID- 22207459 TI - Opportunity and challenge. PMID- 22207460 TI - Motor activity in children with autism: a review of current literature. AB - Physical therapists have expanded their role and visibility in the treatment of children with autism spectrum disorders (ASD). Limitations in motor activity have not been considered in the assessments of core deficits of this population; however, physical therapists should be prepared to discuss and address these limitations in children with ASD. PURPOSE: The primary purposes of this review were to summarize current evidence for motor activity limitations in children with ASD and suggest further areas of research in physical therapy and autism while considering how physical therapy may benefit children with autism. METHOD: A literature search was carried out in 2009 and 2010 by using multiple search engines. RESULTS: Forty-nine articles met inclusion criteria and were included in the review. CONCLUSION: Findings indicate that limitations in motor activity may be present in individuals with ASD, and further research is needed to identify specific functional limitations. PMID- 22207461 TI - Motor characteristics of young children referred for possible autism spectrum disorder. AB - PURPOSE: To examine motor characteristics of children referred for evaluation for autism spectrum disorder (ASD) using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). METHODS: BSID-III scores were collected through retrospective chart review for 30 children (mean age = 31.57 +/- 6 months) admitted to an outpatient autism evaluation clinic. RESULTS: Children referred to an ASD clinic demonstrated a mean delay of 6 months for gross motor skills and 8 months for fine motor skills. There were no differences in total score or item analysis in group comparisons of motor characteristics in young children who did or did not receive a diagnosis of ASD. CONCLUSIONS: These results suggest that a delay in fine and gross motor skills at an early age is a characteristic of infants referred to an ASD clinic. Furthermore, the BSID-III may not be sensitive enough to distinguish between referred children with and without ASD. PMID- 22207462 TI - Commentary on "Motor characteristics of young children referred for possible autism spectrum disorder". PMID- 22207463 TI - Autism spectrum disorder: an emerging opportunity for physical therapy. AB - PURPOSE: A growing body of evidence from research on autism spectrum disorder (ASD) confirms a substantial sensory motor component to ASD. Yet, policy and practice lag behind in recognizing the potential contributions of physical therapists in research, practice, and education related to ASD. The objective of this commentary is to inform and encourage reflection and formal dialogue among pediatric physical therapists regarding the assumption of vital roles in research, education, and clinical practice in ASD. KEY POINTS: Selected studies representative of the type of work being carried out with respect to motor aspects of ASD is presented with selected older literature for those unfamiliar with the range of information available. CONCLUSION: Findings from research provide ample substantiation for physical therapists to join interdisciplinary efforts as researchers, scholars, educators, policy analysts, and advocates in ASD. Physical therapists have the potential and ability to play a much greater role in ASD. PMID- 22207464 TI - Volumetric MRI and MRS and early motor development of infants born preterm. AB - PURPOSE: To investigate the relationship between volumetric magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in infants born less than 30 weeks gestation and early motor development at 6 months adjusted age. METHODS: Twenty infants born preterm and 4 born at term (control) underwent MRI with volumetric analysis and MRS prior to neonatal intensive care unit discharge. Infants were assessed using the Bayley Scale of Infant Development at 6 months adjusted age. RESULTS: At 6 months, infants born preterm with low motor scores had a reduction in their subcortical gray matter. No differences were detected in other brain structures. N-acetylaspartate/choline correlated with white matter (R = 0.45, P = .03), gray matter (R = 0.43, P = .04), and cerebellar volume (R = 0.6, P = .002) but not with 6-month motor performance. CONCLUSION: There is an association between diminished subcortical gray matter volume and low motor scores. Our data suggest that volumetric MRI performed prior to hospital discharge may have some role in counseling parents about potential motor delays. PMID- 22207465 TI - Commentary on "Volumetric MRI and MRS and early motor development of infants born preterm". PMID- 22207466 TI - Are spatiotemporal gait characteristics reliable outcome measures in children with developmental coordination disorder? AB - PURPOSE: To evaluate the reliability of spatiotemporal gait parameters used in the clinical evaluation of children with developmental coordination disorder (DCD). METHODS: Participants recruited were asked to ambulate across a 4.5-meter GAITRite walkway (CIR Systems, Inc, Havertown, Pennsylvania) at a self-selected walking speed. The spatiotemporal parameters recorded for both limbs were: velocity (cm/sec), stance phase duration (%), swing phase duration (%), stride length (cm), double support duration (%), and single support duration (%). RESULTS: Intraclass correlation coefficient values attained in this study ranged from 0.24 to 0.73, with good reliability achieved for one parameter (cadence = 0.73), and moderate reliability for step length (0.55-0.58), stride length (0.57 0.61), and double support duration (0.56-0.59). CONCLUSION: The findings from this study indicate that the clinical evaluation of spatiotemporal gait parameters in children with DCD can yield reliable data for some parameters but further work on this is warranted. PMID- 22207467 TI - Commentary on "Are spatiotemporal gait characteristics reliable outcome measures in children with developmental coordination disorder?". PMID- 22207468 TI - Conservative treatment of clubfoot using modified Copenhagen method. AB - PURPOSE: To evaluate the efficacy of a modified Copenhagen physical therapy method in reducing surgery rates for congenital idiopathic clubfoot. METHODS: This research is a retrospective descriptive study of 82 patients (123 clubfeet). All patients were younger than 2 months at the beginning of the treatment and were initially evaluated to classify clubfoot severity using the Harrold and Walker scale. The study period included the years from 1980 to 2003, with an average monitoring of 14.5 years (range, 3-26 years). RESULTS: After 3 years of treatment, 55% of the involved feet did not need surgery, 2% needed percutaneous tenotomy of the Achilles tendon, and 43% had posterior release. At the end of monitoring, 34% feet did not need surgery, 2% had percutaneous tenotomy of the Achilles tendon, and 64% required posterior releases. CONCLUSION: The Copenhagen method may reduce the necessity of surgical intervention for idiopathic clubfoot. PMID- 22207469 TI - Commentary on "Conservative treatment of clubfoot using modified Copenhagen method". PMID- 22207470 TI - Bayley Scales of Infant Development Screening Test-Gross Motor Subtest: efficacy in determining need for services. AB - PURPOSE: To identify the efficacy of the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), Screening Test-Gross Motor Subtest (GMS) in identifying infants who are accepted for early intervention services. METHODS: This retrospective study included 93 infants with a neonatal intensive care experience who participated in a 6-month developmental assessment follow-up visit. All infants were examined using the BSID-III Screening Test-GMS and the Alberta Infant Motor Scale. A binary logical regression analysis was used to determine the best predictors of acceptance status in this sample. RESULTS: The BSID-III Screening Test-GMS accounted for a significant portion of the variance in acceptance status. CONCLUSION: The results suggest that the BSID-III Screening Test-GMS has great applicability for transdisciplinary/interdisciplinary teams as it effectively identified children who were eligible for early intervention. PMID- 22207471 TI - Commentary on "Bayley Scales of Infant Development Screening Test-Gross Motor Subtest: efficacy in determining need for services". PMID- 22207473 TI - Commentary on "Effects of constraint-induced movement therapy on gait, balance, and functional locomotor mobility". PMID- 22207472 TI - Effects of constraint-induced movement therapy on gait, balance, and functional locomotor mobility. AB - PURPOSE: This study reports the secondary effects of a constraint-induced movement therapy (CIMT) protocol on spatial temporal parameters of gait, balance, and functional locomotor mobility in children with cerebral palsy. METHODS: Sixteen children (4-12 years old) participated in a 3-week CIMT program. Participants were tested on the first and last day of the CIMT program using the Standardized Walking Obstacle Course (SWOC), the Pediatric Balance Scale (PBS) and the GAITRite Gold system (CIR Systems, Inc, Havertown, Pennsylvania). RESULTS: Wilcoxon signed rank tests were used on all pre- and posttests. Only the spatial temporal parameters of cadence and velocity differed significantly, with 12 subjects displaying a faster cadence (P = .02) and 10 subjects displaying a faster velocity (P = .05). CONCLUSION: In this pilot study, CIMT was found to promote changes in 2 spatial temporal parameters of gait. However, no changes were noted in the participant's measures on the SWOC and PBS. PMID- 22207474 TI - Care coordination for children with special health care needs and roles for physical therapists. AB - PURPOSE: The purpose of this article is to summarize the research on the possible benefits of care coordination for children with special health care needs and explore potential roles for physical therapists in care coordination, including roles as primary care coordinators, members of interprofessional teams, advocates, and researchers. KEY POINTS: The medical home model is described. Benefits of care coordination are reviewed. Potential roles for physical therapists in care coordination are outlined. The barriers to care coordination are reviewed and recommendations to reduce barriers and better prepare therapists for care coordination are offered. CONCLUSION: Therapists need to be aware of and adapt to change in care models to be the provider of choice. PMID- 22207475 TI - Motor control outcomes following Nintendo Wii use by a child with Down syndrome. AB - PURPOSE: The purpose of this work was to examine motor outcomes following an 8 week intervention period of family-supported Nintendo Wii use by a child with a diagnosis of Down syndrome (DS). SUMMARY OF KEY POINTS: A 12-year-old child with a diagnosis of DS and with limited Wii exposure was asked to play Wii games in the home 4 times each week for 20 minutes each session for 8 weeks. Family members were encouraged to participate. The participant chose what games to play and selected 4 different games. Repeatedly practicing the skills involved in these games resulted in improvements in the child's postural stability, limits of stability, and Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition balance, upper-limb coordination, manual dexterity, and running speed and agility standard scores. CONCLUSIONS: Wii game use by a child with DS may elicit improvements in highly practiced motor skills and postural control. PMID- 22207476 TI - Epidemiology of pelvic and acetabular trauma in a Dublin tertiary hospital: a 10 year experience. AB - BACKGROUND: Pelvic fractures are usually the result of high-energy trauma and may have associated soft tissue and organ damage resulting in significant morbidity and mortality in these patients. Currently, there is little data from Ireland regarding these injuries. OBJECTIVE: To study the epidemiology of pelvic fractures presenting to a tertiary referral centre in Dublin. METHODS: Patients referred with a pelvic fracture were identified using the Hospital Inpatient Enquiry System (HIPE) from 1998 to 2008. The patient's medical notes were reviewed for demographic data, type and mechanism of fracture and associated injuries. RESULTS: A total of 509 patients were identified over the 10-year period. 466 patients were included in the study. There was a significant male preponderance 76% (n = 354) as compared to females 24% (n = 112). Mean age was 36.5 years (range 16-83). Road traffic accidents (RTA) were the cause in 74% (n = 346) of the cases. CONCLUSION: From our study, the typical patient profile is one of a male in his 30's involved in an RTA requiring acetabular surgery. This is in accordance with previously published international data and highlights the need for specialised units, training in this subspecialty and allocation of resources. PMID- 22207477 TI - Recent cattail expansion and possible relationships to water management: changes in Upper Taylor Slough (Everglades National Park, Florida, USA). AB - Recent appearance of cattail (Typha domingensis) within a southern Everglades slough-Upper Taylor Slough (Everglades National Park)-suggests ecosystem eutrophication. We analyze water quality, nutrient enrichment, and water management operations as potential drivers of eutrophication in Upper Taylor Slough. Further, we attempt to determine why surface water phosphorus, a parameter used commonly to monitor ecosystem health in the Everglades, did not serve as an early warning for eutrophication, which has broader implication for other restoration efforts. We found that surface water total phosphorus concentrations generally were below a 0.01 mg L(-1) threshold determined to cause imbalances in flora and fauna, suggesting no ecosystem eutrophication. However, assessment of nutrient loads and loading rates suggest Upper Taylor Slough has experienced eutrophication and that continued total phosphorus loading through a point-source discharge was a major driver. These nutrient loads, combined with increases in hydroperiods, led to the expansion of cattail in Upper Taylor Slough. We recommend other metrics, such as nutrient loads, periphyton and arthropod community shifts, and sediment core analyses, for assessing ecosystem health. Monitoring surface water alone is not enough to indicate ecosystem stress. PMID- 22207478 TI - The nutritional effect of Moringa oleifera fresh leaves as feed supplement on Rhode Island Red hen egg production and quality. AB - This study aimed to evaluate the potential of Moringa oleifera fresh leaves (MOL) as feed supplement on the performance and egg quality of Rhode Island Red (RIR) hens under the tropical conditions of Yucatan, Mexico. Forty-eight RIR hens were allocated in 12 floor pen replicates each with four birds. Thereafter, the replicates were divided into three groups which were corresponded to ad libitum feed (control), ad libitum feed supplemented with MOL T1 (AL + MOL) and restricted feed amount (20% lower than control) with MOL T2 (RCD + MOL), respectively. T1 (AL + MOL) had higher egg laying rate (71.4% versus 66.6%), higher daily egg mass production (45.4 versus 41.9 g/day), lower feed intake (121.3 versus 127.5 g/day) and better feed conversion ratio (2.8 versus 3.2 g feed:g egg) versus control. T2 / (RCD + MOL) had lower values of body weight, egg laying rate, egg weight and egg mass, and recorded better feed conversion ratio than the control group. The control group recorded a higher percentage of pecked eggs versus T1 and T2 (6.5% versus 1.2% and 2.0 %). Similar intake of MOL (3.1 and 3.4 g DM/day) was recorded in T1 (AL + MOL) and T2 (RCD + MOL). Yolk color was improved significantly in T1 (AL + MOL) than both control and T2 (RCD + MOL), while T2 (RCD + MOL) had eggs with lower yolk and higher albumen percentages than the other two ad libitum groups. The results suggest that MOL could be used successfully as sustainable tropical feed resource for RIR hens. PMID- 22207479 TI - In vitro antimicrobial activity of Combretum molle (Combretaceae) against Staphylococcus aureus and Streptococcus agalactiae isolated from crossbred dairy cows with clinical mastitis. AB - Following the rapidly expanding dairy enterprise, mastitis has remained the most economically damaging disease. The objective of this study was mainly to investigate the in vitro antibacterial activities of ethanol extracts of Combretum molle (R.Br.Ex.G.Don) Engl & Diels (Combretaceae) against antibiotic resistant and susceptible Staphylococcus aureus and Streptococcus agalactiae isolated from clinical cases of bovine mastitis using agar disc diffusion method. The leaf and bark extracts showed antibacterial activity against S. aureus at concentrations of 3 mg/ml while the stem and seed extract did not show any bioactivity. Although both leaf and bark extracts were handled in the same manner, the antibacterial activity of the bark extract against the bacterial strains had declined gradually to a lower level as time advanced after extraction. The leaf extract had sustained bioactivity for longer duration. The susceptibility of the bacteria to the leaf extract is not obviously different between S. aureus and S. agalactiae. Also, there was no difference in susceptibility to the leaf extract between the antibiotic-resistant and antibiotic-sensitive bacteria. Further phytochemical and in vivo efficacy and safety studies are required to evaluate the therapeutic value of the plant against bovine mastitis. PMID- 22207481 TI - Radiological features and therapeutic responses of pulmonary nontuberculous mycobacterial disease in rheumatoid arthritis patients receiving biological agents: a retrospective multicenter study in Japan. AB - OBJECTIVE: This study was performed to evaluate the radiological features of and therapeutic responses to pulmonary disease caused by nontuberculous mycobacteria (NTM) in the setting of biological therapy for rheumatoid arthritis (RA). METHODS: We conducted a retrospective chart review of 13 patients from multiple centers who had developed pulmonary NTM disease during biological therapy for RA, including infliximab, etanercept, adalimumab, and tocilizumab. RESULTS: Most cases were asymptomatic or resulted in only common-cold-like symptoms. Abnormalities in computed tomography (CT) imaging were protean and frequently overlapped. The most predominant pattern was nodular/bronchiectatic disease (six cases), followed by alveolar infiltrate (three cases), cavitary disease (two cases), and pulmonary nodules (two cases). In most cases, pulmonary NTM disease had spread from a preexisting lesion; in particular, bronchial/bronchiolar abnormalities. In three cases, one or more nodular lesions with or without calcification were a focus of disease. Following the discontinuation of biological agents, most patients responded to anti-NTM therapy. Two patients showed no exacerbation in the absence of any anti-NTM therapy. In one patient, restarting tocilizumab therapy while continuing to receive adequate anti-NTM therapy produced a favorable outcome. In two other patients with a previous history of pulmonary NTM disease, introducing biological therapy led to recurrence, but anti-NTM therapy was effective in these patients. CONCLUSION: CT abnormalities of pulmonary NTM disease in RA patients receiving biological therapy were variable, but were not unique to this clinical setting. NTM disease can spread from preexisting structural abnormalities, even if they are minute. Contrary to our expectations, the therapeutic outcomes of pulmonary NTM disease were favorable in these patients. PMID- 22207482 TI - Human serum protein adsorption onto synthesis nano-hydroxyapatite. AB - Adsorption of human serum proteins (Albumin and total protein) onto high purity synthesis nano-hydroxyapatite (HA), Ca10(PO4)6(OH)2, has been studied in a wide temperature range by UV-visible spectrophotometer. Adsorption isotherm is basically important to describe how solutes interact with adsorbent, and is critical in optimizing the use of adsorbent. In the present study, the experimental results were fitted to the Langmuir, Freundlich, Temkin and Dubinin Radushkevich (DR) models to obtain the characteristic parameters of each model and square of the correlation coefficients (R2). According to the results, the DR isotherm model had the best agreement with the experimental data. The effect of temperature on adsorption of human serum proteins (HSP) onto the synthesized nano HA was studied. The experimental results indicated that temperature increase generally causes an increase in the adsorption of HSP onto the nano-HA. This is basically due to the effect of temperature on the HSP activity and its diffusion rate on HA surfaces. PMID- 22207480 TI - Functions of cholesterol and the cholesterol bilayer domain specific to the fiber cell plasma membrane of the eye lens. AB - The most unique feature of the eye lens fiber-cell plasma membrane is its extremely high cholesterol content. Cholesterol saturates the bulk phospholipid bilayer and induces formation of immiscible cholesterol bilayer domains (CBDs) within the membrane. Our results (based on EPR spin-labeling experiments with lens-lipid membranes), along with a literature search, have allowed us to identify the significant functions of cholesterol specific to the fiber-cell plasma membrane, which are manifest through cholesterol-membrane interactions. The crucial role is played by the CBD. The presence of the CBD ensures that the surrounding phospholipid bilayer is saturated with cholesterol. The saturating cholesterol content in fiber-cell membranes keeps the bulk physical properties of lens-lipid membranes consistent and independent of changes in phospholipid composition. Thus, the CBD helps to maintain lens-membrane homeostasis when the membrane phospholipid composition changes significantly. The CBD raises the barrier for oxygen transport across the fiber-cell membrane, which should help to maintain a low oxygen concentration in the lens interior. It is hypothesized that the appearance of the CBD in the fiber-cell membrane is controlled by the phospholipid composition of the membrane. Saturation with cholesterol smoothes the phospholipid-bilayer surface, which should decrease light scattering and help to maintain lens transparency. Other functions of cholesterol include formation of hydrophobic and rigidity barriers across the bulk phospholipid-cholesterol domain and formation of hydrophobic channels in the central region of the membrane for transport of small, nonpolar molecules parallel to the membrane surface. In this review, we provide data supporting these hypotheses. PMID- 22207483 TI - Glutathione and vitamin B12 cooperate in stabilization of a B12 trafficking chaperone protein. AB - The protein bCblC (bCblCpro) is a bovine homolog of a human B12 trafficking chaperone that is responsible for the processing of vitamin B12 and its escorted delivery in intracellular B12 metabolism. In this study, we found that bCblCpro is highly thermolabile with a T(m) = 42.0 +/- 0.2 degrees C as shown for the human homolog, suggesting thermal regulation of these proteins. Binding of the reduced form of glutathione (GSH) that is a predominant cellular thiol increased the T(m) of bCblCpro from 42 degrees C to ~45 degrees C (DeltaT(m max) = 3.1 +/ 0.2 degrees C and AC50 = 2.1 +/- 0.5 mM). Binding of vitamin B12 and its derivatives also stabilized bCblCpro increasing the T(m) to a different extent and vitamin B12 (cyanocobalamin, CNCbl) was the least efficient (DeltaT(m max) = 4.3 +/- 0.3 degrees C and AC50 = 291 +/- 36 MUM). However, the stabilizing effect of CNCbl was significantly greater for GSH-bound bCblCpro (DeltaT(m max) = 12.8 +/- 0.6 degrees C and AC50 = 9.3 +/- 1.6 MUM) than for GSH-free bCblCpro. In addition, the stabilizing effect of GSH was also greater for CNCbl-bound bCblCpro (DeltaT(m max) = 9.3 +/- 0.3 degrees C and AC50 = 57.0 +/- 6.8 MUM). Limited proteolysis revealed that thermal stabilization of bCblCpro is derived from conformational changes of the protein induced by binding of the ligands. The results in this study indicate that GSH cooperates with vitamin B12 in thermal stabilization of bCblCpro and is a positive regulator of the protein. PMID- 22207484 TI - Crystal structure analysis of a recombinant predicted acetamidase/formamidase from the thermophile Thermoanaerobacter tengcongensis. AB - The structure of acetamidase/formamidase (Amds/Fmds) from the archaeon Thermoanaerobacter tengcongensis has been determined by X-ray diffraction analysis using MAD data in a crystal of space group P21, with unit-cell parameters a = 41.23 (3), b = 152.88 (6), c = 100.26 (7) A, beta = 99.49 (3) degrees and been refined to a crystallographic R-factor of 17.4% and R-free of 23.7%. It contains two dimers in one asymmetric unit, in which native Amds/Fmds (TE19) contains of the 32 kDa native protein. The final model consists of 4 monomer (299 amino acids residues with additional 2 expression tag amino acids residues), 5 Ca2+, 4 Zn2+ and 853 water molecules. The monomer is composed by the following: an N-domain which is featuring by three-layers beta/beta/beta; a prominent excursion between N-terminal end of strand beta7 and beta11, which contains four-stranded antiparallel beta sheet; an C-domain which is formed by the last 82 amino acid residues with the feature of mixed alpha/beta structure. The protein contains ion-pair Ca2+-Zn2+. The portion of three-layer beta/beta/beta along with the loops provides four protein ligands to the tightly bound Ca2+, three water molecules complete the coordination; and provides five protein ligands to the tightly bound Zn2+, one water molecule complete the coordination. PMID- 22207486 TI - Orotracheal intubation facilitated with a GlideScope GVL(r) video laryngoscope in a patient with a large oronasopharyngeal rhinosporidiosis. PMID- 22207485 TI - Novel phosphatidylinositol 3-kinase inhibitor NVP-BKM120 induces apoptosis in myeloma cells and shows synergistic anti-myeloma activity with dexamethasone. AB - NVP-BKM120 is a novel phosphatidylinositol 3-kinase (PI3K) inhibitor and is currently being investigated in phase I clinical trials in solid tumors. This study aimed to evaluate the therapeutic efficacy of BKM120 in multiple myeloma (MM). BKM120 induces cell growth inhibition and apoptosis in both MM cell lines and freshly isolated primary MM cells. However, BKM120 only shows limited cytotoxicity toward normal lymphocytes. The presence of MM bone marrow stromal cells, insulin-like growth factor, or interleukin-6 does not affect BKM120 induced tumor cell apoptosis. More importantly, BKM120 treatment significantly inhibits tumor growth in vivo and prolongs the survival of myeloma-bearing mice. In addition, BKM120 shows synergistic cytotoxicity with dexamethasone in dexamethasone-sensitive MM cells. Low doses of BKM120 and dexamethasone, each of which alone has limited cytotoxicity, induce significant cell apoptosis in MM.1S and ARP-1. Mechanistic study shows that BKM120 exposure causes cell cycle arrest by upregulating p27 (Kip1) and downregulating cyclin D1 and induces caspase dependent apoptosis by downregulating antiapoptotic XIAP and upregulating expression of cytotoxic small isoform of Bim, BimS. In summary, our findings demonstrate the in vitro and in vivo anti-MM activity of BKM120 and suggest that BKM120 alone or together with other MM chemotherapeutics, particularly dexamethasone, may be a promising treatment for MM. PMID- 22207488 TI - Transient obstructive hydrocephalus by intraventricular fat migration after surgery of the posterior fossa. PMID- 22207487 TI - Characterization of the partial VP2 gene region of canine parvoviruses in domestic cats from Turkey. AB - Canine parvoviruses (CPVs) is a category comprising three closely related viruses, CPV, feline panleukopenia virus (FPLV), and mink enteritis virus, all of which cause serious diseases, especially in young cats. In this study, molecular detection and genetic analysis of a partial VP2 gene region of CPVs from domestic cats living in Turkey between 2006 and 2010 was performed by PCR amplification and sequence analysis. The results indicated that CPV-2a, CPV-2c, and FPLV were circulating in vaccinated and unvaccinated cats. This is the first description of molecular characterization of CPVs in domestic cats from Turkey. PMID- 22207489 TI - Clinical profile of diabetic ketoacidosis in Indian children. AB - OBJECTIVE: To study the clinical profile of the Indian children admitted with DKA. METHODS: This descriptive retrospective study was conducted in pediatric ICU of tertiary level care hospital at Delhi (between Jan 2008 and Jan 2010). The case records of 55 children admitted with DKA were reviewed and information with respect to the personal details, clinical features, laboratory parameters, management and outcome was recorded using a predesigned performa.The data was analyzed using SPSS version 16. RESULTS: The mean age of patients at presentation was 7.4+/-3.9 y; 27 boys and 28 girls were enrolled. Diabetes was newly diagnosed in 56.4% patients and 43.6% were known cases of diabetes. Polyuria and polydipsia (54.5%), persistent vomiting (52.7%), altered sensorium (50.9%), abdominal pains (47.3%) were common presenting symptoms. Most of the children had dehydration at admission, one fourth being severe. Hypernatremia, hypokalemia, cerebral edema and renal failure were observed in 20%, 14.5%, 14.5% and 7.2% , respectively. While 12.72% had fatal outcome, cerebral edema with or without renal failure and sepsis accounted for most of the deaths. CONCLUSIONS: Boys and girls were equally affected. Newly diagnosed diabetics constituted more >50% of total DKA admissions. Nearly two third presented with severe DKA. Renal failure, cerebral edema and sepsis contributed to adverse outcome. PMID- 22207491 TI - Hyperbilirubinemia in breastfed term neonates. PMID- 22207490 TI - Stress response and procedural pain in the preterm newborn: the role of pharmacological and non-pharmacological treatments. AB - Repeated invasive procedures occur routinely in neonates who require intensive care, causing pain at a time when it is developmentally unexpected. Multiple lines of evidence suggest that repeated and prolonged pain exposure alters their subsequent pain processing, long-term development, and behaviour. Primary outcome of this study was to evaluate the reduction of procedural pain induced by "heel lances" in preterm newborns with three different treatment [administration of fentanyl (FE, 1-2 MUg/kg), facilitated tucking (FT), sensorial saturation (SS)]. Secondary outcome was the measurement of the levels of cytokines as markers of stress correlated to pain. A prospective randomized controlled trial (RCT) comparing three different pharmacological or non-pharmacological treatments was performed involving 150 preterm newborn (gestational age 27-32 weeks). No other analgesic treatment was performed during the study. CRIES score was used to evaluate the procedural pain. The results showed that the reduction in the pain score was greater in FE and SS groups than FS group. The differences were statistically significant (p < 0.01). The levels of IL-6, IL-8, and TNF-alpha were higher in the FT individuals than in the FE or SS-treated infants at 1 day (p < 0.01), at 3 days (p < 0.01), and at 7 days (p < 0.01) of life. CONCLUSIONS: The findings of this study suggest that FE and SS provide a superior analgesia in preterm neonates during procedural pain. In particular, sensorial saturation seems to be an important non-pharmacological alternative treatment to prevent and reduce the procedural pain in preterm newborn. PMID- 22207493 TI - Lymph node recurrence in patients with N1b papillary thyroid carcinoma who underwent unilateral therapeutic modified radical neck dissection. AB - BACKGROUND: Therapeutic modified radical neck dissection (MND) is a mandatory surgical procedure for patients with papillary thyroid carcinoma (PTC) having clinical lateral node metastasis (N1b). However, N1b PTC is still likely to recur in regional lymph nodes after surgery. We investigated the clinicopathological features predicting recurrence in nodes in previously dissected compartments (ipsilateral lateral compartment or central compartment) and nodes in the contralateral lateral compartment for N1b patients who underwent unilateral therapeutic MND. METHODS: A total of 744 N1b PTC patients who underwent thyroidectomy with unilateral therapeutic MND between 1987 and 2004 were enrolled in the study. The patient ages ranged from 12 to 88 years (average 50.2 years). The average postoperative follow-up period was 113 months. RESULTS: To date, 87 (12%) and 49 (7%) patients showed recurrence in previously dissected compartments and the contralateral lateral compartment, respectively. On univariate analysis, age >55 years, node metastasis >3 cm, extranodal tumor extension, and extrathyroid extension affected recurrence in previously dissected compartments. Also, the former two were independent predictors on multivariate analysis (P = 0.0170 and <0.0001, respectively). In contrast, only extrathyroid extension and tumor size >4 cm influenced recurrence in the contralateral lateral compartment on univariate analysis. On multivariate analysis, the former was an independent predictor (P = 0.0015), and the latter was of marginal significance (P = 0.0909). To date, 13% of patients having both of these characteristics showed recurrence in the contralateral lateral compartment. CONCLUSIONS: Extremely careful therapeutic MND is required for N1b patients with age >55 years or node metastasis >3 cm because of the likelihood of recurrence in previously dissected compartments. Bilateral MND (therapeutic for ipsilateral side and prophylactic for contralateral side) may be a therapy option for N1b PTC >4 cm and having extrathyroid extension. PMID- 22207492 TI - Toilet training in daycare centers in Flanders, Belgium. AB - Several changes have occurred in the toilet training (TT) process in recent decades. There has been an increase in the use of daycare as both parents now often work outside the home. Most children attend daycare centers during the period TT usually takes place, and daytime training has shifted from home to daycare. This study is the first to evaluate the way TT is done in daycare centers. A questionnaire was sent to 1,500 daycare centers, of which 429 replied (response rate of 28.6%). The results show that half of the childcare workers base the decision to start TT on readiness signs. The combination of age and readiness signs is used by 44.5%. The majority of the respondents spent more than 1 h per day on TT (81.8%); 79.8% considered that daycare and parents should play an equal role in TT. However, more than a third of the respondents thought that parents pass the responsibility for TT on to daycare and that not enough attention was paid to TT in the home. Most respondents stated that daycare centers had the facilities and means to be able to give the children proper TT (88.5%). Other research indicated that the outcome of TT is not that good overall and that there is room for improvement in the methods used. More research is needed on the role division and on the interaction between daycare and parents and their combined influence on the process and outcome of TT. PMID- 22207494 TI - Fungating thyroid cancer: a complex clinical scenario. AB - BACKGROUND: Most research reporting the management of advanced thyroid cancer focuses on major aerodigestive system or vessel involvement. In the present study, we investigated patients with locally advanced thyroid cancers who presented with malignant skin infiltration. The term fungating thyroid cancer (fTC) has been used to describe such a condition. METHODS: The study was based on prospective collection of clinical, laboratory, imaging, and pathological data of all patients admitted to the head and neck and endocrine surgery unit, Main University Hospital, Alexandria School of Medicine, during the period April 2005 March 2011. RESULTS: Eleven patients were referred with fTC, eight of whom had undergone subtotal thyroidectomy for an undiagnosed well-differentiated thyroid cancer (DTC) in another institution. The final pathological diagnosis showed (DTC, n = 3), poorly differentiated thyroid cancer (n = 5), anaplastic cancer (n = 2), and medullary thyroid cancer (n = 1). Extensive resections and reconstruction using flaps (pectoralis major, n = 6; deltopectoral, n = 1; sternocleidomastoid, n = 1) were undertaken. Complete tumor clearance (R0) was achieved in one patient and the others had microscopic (R1, n = 6) or macroscopic (R2, n = 1) residual disease. The three patients who did not undergo operation died within one month of presentation. The latest review of the eight patients who did undergo operation ranged from 3 to 6 months, but their survival remains unknown as access for follow-up was limited. PMID- 22207495 TI - Breast radiation correlates with side of parathyroid adenoma. AB - BACKGROUND: Prior head and neck irradiation is a known risk factor for hyperparathyroidism. It is not clear whether irradiation for breast cancer, which may expose the neck to radiation, is also a risk factor for hyperparathyroidism. The present study analyzes the association between the side of radiation to the chest following breast surgery and the side of subsequent parathyroid adenoma development. METHODS: We analyzed a prospective database of 1,428 consecutive patients who underwent parathyroidectomy at our institution between November 2000 and August 2010. Patients who had previously undergone breast surgery were identified. Patients with multigland disease were excluded. Patients with bilateral breast surgery were counted as having had two separate procedures; one on each side. Patients who had radiation therapy following breast surgery (RadRx) were compared to those who had breast surgery without radiation treatment (No RadRx). RESULTS: A total of 146 breast procedures were performed in 121 patients. Forty procedures were in the RadRx group versus 106 cases in the No RadRx group. Patients with radiation therapy were older (68 +/- 1.8 years versus 63 +/- 1.2 years; P = 0.02) and had higher preoperative calcium levels (11.3 +/- 0.1 mg/dl versus 10.9 +/- 0.1 mg/dl; P = 0.001). However, there was no significant difference in either parathyroid hormone (PTH) level or gland weight. The latency period between breast irradiation and parathyroid surgery was 8 +/- 0.9 years. Interestingly, the side of radiation therapy was associated with the side of the parathyroid adenoma in 76% of cases, compared to only 44% in those who had breast surgery without radiation exposure (P = 0.0004). CONCLUSIONS: The present study demonstrates that, similar to prior head and neck radiation, prior breast irradiation correlates with the development of parathyroid disease. Specifically, there is a strong correlation between the side of the radiation therapy and the side of a subsequent parathyroid adenoma. Breast irradiation should therefore be considered a risk factor for the development of parathyroid adenomas. PMID- 22207496 TI - Analgesic and anti-inflammatory activity of beta-sitosterol isolated from Nyctanthes arbortristis leaves. AB - Nyctanthes arbortristis Linn. (Oleaceae) is one of the well-known Indian medicinal plant. Various extracts of leaves of the plant were screened for analgesic activity by hot plate test and acetic acid-induced writhings and anti inflammatory activity by carrageenan-induced hind paw edema method at the dose of 50 mg/kg, i.p. Petroleum ether extract was found to be most active and hence subjected to activity-guided fractionation. Results showed that beta-sitosterol (5, 10 and 20 mg/kg, i.p.) was responsible for the significant and dose-dependent activity comparable with the standard extract. beta-Sitosterol from N. arbortristis leaves might be responsible for analgesic and anti-inflammatory activity. PMID- 22207497 TI - Prevalence of plagiarism in recent submissions to the Croatian Medical Journal. AB - To assess the prevalence of plagiarism in manuscripts submitted for publication in the Croatian Medical Journal (CMJ). All manuscripts submitted in 2009-2010 were analyzed using plagiarism detection software: eTBLAST, CrossCheck, and WCopyfind. Plagiarism was suspected in manuscripts with more than 10% of the text derived from other sources. These manuscripts were checked against the Deja vu database and manually verified by investigators. Of 754 submitted manuscripts, 105 (14%) were identified by the software as suspicious of plagiarism. Manual verification confirmed that 85 (11%) manuscripts were plagiarized: 63 (8%) were true plagiarism and 22 (3%) were self-plagiarism. Plagiarized manuscripts were mostly submitted from China (21%), Croatia (14%), and Turkey (19%). There was no significant difference in the text similarity rate between plagiarized and self plagiarized manuscripts (25% [95% CI 22-27%] vs. 28% [95% CI 20-33%]; U = 645.50; P = 0.634). Differences in text similarity rate were found between various sections of self-plagiarized manuscripts (H = 12.65, P = 0.013). The plagiarism rate in the Materials and Methods (61% (95% CI 41-68%) was higher than in the Results (23% [95% CI 17-36%], U = 33.50; P = 0.009) or Discussion (25.5 [95% CI 15-35%]; U = 57.50; P < 0.001) sections. Three authors were identified in the Deja vu database. Plagiarism detection software combined with manual verification may be used to detect plagiarized manuscripts and prevent their publication. The prevalence of plagiarized manuscripts submitted to the CMJ, a journal dedicated to promoting research integrity, was 11% in the 2-year period 2009-2010. PMID- 22207498 TI - Diagnostic and prognostic value of procalcitonin in community-acquired pneumonia. AB - INTRODUCTION: The value of measuring procalcitonin (PCT) in patients with community-acquired pneumonia (CAP) is unclear. The aim of this study was to determine the value of PCT as a marker for microbial etiology and a predictor of outcome in CAP patients. METHODS: A single-center observational study was conducted with CAP patients. On admission, their leukocyte count, serum C reactive protein level, and serum PCT level were determined, and microbiological tests were performed. Patients were classified into 4 groups according to the A DROP scoring system, which assesses the severity of CAP. RESULTS: A total of 102 patients were enrolled. The pathogen was identified in 60 patients, and 31 patients had streptococcal pneumonia. The PCT levels were significantly higher in those patients with pneumococcal pneumonia than in those patients with other bacterial pneumonias (P < 0.0001). Multivariate regression analysis revealed that high PCT levels were associated with a pneumococcal etiology [odds ratio, 1.68; 95% confidence interval (CI): 1.02-2.81; P = 0.04] after adjustment for disease severity and demographic factors. The PCT levels were correlated with the A-DROP score (r = 0.49; P < 0.0001). The area under the curve for predicting mortality was highest for the A-DROP score (0.97; 95% CI: 0.92-0.99), followed by the area under the curve for PCT (0.82; 95% CI: 0.74-0.89) and C-reactive protein (0.77; 95% CI: 0.67-0.84). CONCLUSIONS: High PCT levels indicate that pneumococcal pneumonia and PCT levels depend on the severity of pneumonia. PCT measurements may provide important diagnostic and prognostic information for patients with CAP. PMID- 22207499 TI - Successful pregnancy following myomectomy of a giant uterine myoma: role of a combined surgical approach. AB - PURPOSE: There are very few reports in the literature about the conservative surgical approach of large uterine myoma. The individualization of the surgery approach, the technical expertise and skill of the surgeon, the use of modern technologies/facilities could offer the optimal individualized treatment. METHODS: We performed a conservative combined surgical approach consisting of open laparoscopy myomectomy followed by laparotomy for the treatment of a very large uterine myoma of the anterior uterine wall in a 27-year-old non-pregnant woman with a history of progressive abdominal distension and symptoms related to abdomen pressure and constipation. RESULTS: The myoma weighted 12.010 kg. The postoperative course was good and 20 months after surgery, the patients had a successful pregnancy with a spontaneous delivery at the 39th week of a healthy baby weighting 3.260 kg. CONCLUSIONS: In the case reported here, the careful pre surgical evaluation, the technical expertise and skill of the surgeon, the choice of a combined approach with laparoscopy and open surgery and the use of modern surgical instruments have enabled us to achieve a significant result: the preservation of the anatomical integrity of the uterus and adnexa which allowed a successful natural pregnancy with spontaneous delivery. PMID- 22207500 TI - Misexpression of testicular microRNA in sterile Xenopus hybrids points to tetrapod-specific microRNAs associated with male fertility. AB - Spermatogenesis is one of the most complex biological processes undergone by any organism, making it susceptible to perturbations that result in male sterility. Research has demonstrated that mutant phenotypes can be obtained from the disruption of epigenetic modifications, which are commonly microRNA guided. Employing the Xenopus system, whereby homogametic interspecies males are always sterile, thus violating Haldane's Rule, we deep-sequenced testes-specific small RNAs to identify microRNAs most frequently misexpressed between sterile hybrids and their fertile parental taxa. Using these data, we cross-referenced our expression information with previously published mouse (Mus musculus) data and identified a subset of seven microRNAs common to both (miR-338, miR-222, miR-18, miR-30, miR-10, miR-196, and miR-365). We propose that these microRNAs are likely critical for spermatogenesis in all tetrapods, having retained testicular expression across ~350 million years of evolution (Amphibian-Mammal split). Gene targets of six of these microRNAs are known, and all the six associate with zinc and zinc finger proteins (both previously found critical in male fertility), and three with Hox genes (some of which have also previously been deemed critical for testicular development and male fertility). Expression information for these targets revealed that all those associated with zinc have previously been found to express in mammalian testes. One Hox target has known mammalian testicular expression, two have close relatives with known mammalian testicular expression, and two more are associated with proteins known to have mammalian testicular expression. In addition, miR-222 has prior association with spermatogenesis, and miR-30 has been found to be abundantly expressed in both mouse and human testes. PMID- 22207501 TI - Spectrophotometric evaluation of a novel aesthetic composite resin with respect to different backgrounds in vitro. AB - Tooth colour matching of composite materials is often a common problem caused by a dark background from the oral cavity. Therefore, the aim of the study was to evaluate a novel aesthetic composite material and to assess the influence of white and black backgrounds. Tooth shades of 30 freshly extracted upper front teeth were determined using a spectrophotometer (SpectroShadeTM) both against a white and a black background. Two class IV cavities in each tooth were prepared and restored using three different composite resins: ArabeskTM (AB), SynergyTM (SE) and the novel material AmarisTM (AM). After water storage for 1 week, differences in hue, saturation and lightness were measured to assess changes from baseline. After thermocycling, teeth were evaluated once more to assess the reliability of the treatment outcomes. Compared to baseline, differences in hue were not statistically different for all restoration materials (p > 0.05) with respect to the white or black background. Delta values for saturation were not different in the AB and AM groups (p > 0.05) with higher values for SE (p < 0.05). Regarding lightness, values in the AB group were statistically higher (p < 0.05) than values for AM with no difference between AB and SE and with no difference between the AM and SE groups (p > 0.05). Employing the novel aesthetic composite resin, a minor impact of white and black backgrounds could be observed compared to conventional composites. Therefore, it might effectively mask the dark background from the oral cavity. PMID- 22207503 TI - Transient ischemic attack incidence in joinville, Brazil, 2010: a population based study. AB - BACKGROUND AND PURPOSE: There are scarce data on transient ischemic attack incidence in low- and middle-income countries. We aimed to measure transient ischemic attack incidence and the distribution of the ABCD2 risk score in Joinville, Brazil. METHODS: In 2009 to 2010, using a multiple overlapping sources, we ascertained all first ever probable and definite transient ischemic attacks. RESULTS: We recorded 74 definite and probable transient ischemic attacks. The crude incidence was 15 (12-18) per 100 000 population. Age adjusted to European population the incidence was 28 (22-35). One fourth was in the higher risk of stroke by the ABCD2 scale. CONCLUSIONS: The transient ischemic attack incidence in Joinville, Brazil, is lower than other well-designed studies. New studies could clarify whether the measured rates were due to underascertainment or reflect a truly low incidence. PMID- 22207502 TI - Phosphorylation of the insulin receptor by AMP-activated protein kinase (AMPK) promotes ligand-independent activation of the insulin signalling pathway in rodent muscle. AB - AIMS/HYPOTHESIS: Muscle may experience hypoglycaemia during ischaemia or insulin infusion. During severe hypoglycaemia energy production is blocked, and an increase of AMP:ATP activates the energy sensor and putative insulin-sensitiser AMP-activated protein kinase (AMPK). AMPK promotes energy conservation and survival by shutting down anabolism and activating catabolic pathways. We investigated the molecular mechanism of a unique glucose stress defence pathway involving AMPK-dependent, insulin-independent activation of the insulin signalling pathway. METHODS: Cardiac or skeletal myocytes were subjected to glucose and insulin-free incubation for increasing intervals up to 20 h. AMPK, and components of the insulin signalling pathway and their targets were quantified by western blot using phosphor-specific antibodies. Phosphomimetics were used to determine the function of IRS-1 Ser789 phosphorylation and in vitro [32P]ATP kinase assays were used to measure the phosphorylation of the purified insulin receptor by AMPK. RESULTS: Glucose deprivation increased Akt-Thr308 and Akt-Ser473 phosphorylation by almost tenfold. Phosphorylation of glycogen synthase kinase 3 beta increased in parallel, but phosphorylation of ribosomal 70S subunit-S6 protein kinase and mammalian target of rapamycin decreased. AMPK inhibitors blocked and aminoimidazole carboxamide ribonucleotide (AICAR) mimicked the effects of glucose starvation. Glucose deprivation increased the phosphorylation of IRS-1 on serine-789, but phosphomimetics revealed that this conferred negative regulation. Glucose deprivation enhanced tyrosine phosphorylation of IRS-1 and the insulin receptor, effects that were blocked by AMPK inhibition and mimicked by AICAR. In vitro kinase assays using purified proteins confirmed that the insulin receptor is a direct target of AMPK. CONCLUSIONS/INTERPRETATION: AMPK phosphorylates and activates the insulin receptor, providing a direct link between AMPK and the insulin signalling pathway; this pathway promotes energy conservation and survival of muscle exposed to severe glucose deprivation. PMID- 22207504 TI - Stenting versus surgery in patients with carotid stenosis after previous cervical radiation therapy: systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: Patients with both carotid stenosis and previously cervical radiation therapy are considered "high risk" for carotid endarterectomy (CEA). Carotid angioplasty and stenting (CAS) seems a reasonable alternative, but neither the operative risk for CEA nor the effectiveness of CAS has been proven. The purpose of this study was to evaluate perioperative and long-term outcome of both procedures in patients with radiation therapy. METHODS: A systematic search strategy with the synonyms "carotid artery stenosis" and "cervical irradiation" was conducted in MEDLINE and EMBASE databases. To provide and compare estimates of outcomes, pooled and metaregression analyses were performed. RESULTS: Twenty seven articles comprising 533 patients undergoing radiation therapy (361 CAS and 172 CEA) fulfilled our inclusion criteria. Pooled analysis showed perioperative risk for "any cerebrovascular adverse event" (CVE) of 3.9% (95% CI, 2.3%-6.7%) in CAS studies against 3.5% (95% CI, 1.5%-8.0%) in CEA studies (P=0.77). Risk for cranial nerve injury (CNI) after CEA was 9.2% (95% CI, 3.7%-21.1%) versus none after CAS. Late outcome showed rates of CVE favoring CEA (P=0.014). The rate of restenosis >50% was significantly higher in patients treated with CAS compared with CEA (P<0.003). CONCLUSIONS: Both CAS and CEA proved to be feasible revascularization techniques with low risk for CVE. Although patients undergoing CEA had more temporary CNI, higher rates of late CVE and restenosis were identified after CAS. PMID- 22207505 TI - Ischemic cerebral damage: an appraisal of synaptic failure. AB - In the human brain, ~30% of the energy is spent on synaptic transmission. Disappearance of synaptic activity is the earliest consequence of cerebral ischemia. The changes of synaptic function are generally assumed to be reversible and persistent damage is associated with membrane failure and neuronal death. However, there is overwhelming experimental evidence of isolated, but persistent, synaptic failure resulting from mild or moderate cerebral ischemia. Early failure results from presynaptic damage with impaired transmitter release. Proposed mechanisms include dysfunction of adenosine triphosphate-dependent calcium channels and a disturbed docking of glutamate-containing vesicles resulting from impaired phosphorylation. We review energy distribution among neuronal functions, focusing on energy usage of synaptic transmission. We summarize the effect of ischemia on neurotransmission and the evidence of long-lasting synaptic failure as a cause of persistent symptoms in patients with cerebral ischemia. Finally, we discuss the implications of synaptic failure in the diagnosis of cerebral ischemia, including the limited sensitivity of diffusion-weighted MRI in those cases in which damage is presumably limited to the synapses. PMID- 22207506 TI - Use of secondary medical prophylaxis and clinical outcome among patients with ischemic stroke: a nationwide follow-up study. AB - BACKGROUND AND PURPOSE: Although secondary medical prevention strategies in patients with stroke are well established, only sparse data exist regarding their effectiveness in routine care. We examined the effectiveness in a nationwide, population-based follow-up study. METHODS: Using data from the Danish National Indicator Project (DNIP), 28,612 patients hospitalized for ischemic stroke in 2003 to 2006 were identified. Information on drug use and outcomes was by individual-level record linkage with national medical databases. Hazard ratios were computed for death, myocardial infarction, and recurrent stroke according to drug use after hospital discharge. RESULTS: Treatment with antiplatelets, oral anticoagulants, antihypertensives, or statins was associated with a lower risk of the combined end point of death, myocardial infarction, or recurrent stroke during a mean follow-up period of 2.7 years (adjusted hazard ratios [HRs] from 0.44 [95% CI, 0.39-0.49] to 0.94 [95% CI, 0.89-0.99]). All drug classes were associated with lower risk of death (adjusted HRs from 0.36 [95% CI, 0.32-0.41] to 0.85 [95% CI, 0.80-0.90]), with oral anticoagulant treatment in patients with atrial fibrillation being particularly effective in elderly women (>80 years; adjusted HR, 0.35; 95% CI, 0.28-0.45). Oral anticoagulant treatment was associated with a lower risk of recurrent stroke (adjusted HR, 0.58; 95% CI, 0.47 0.73), and statins were associated with a lower risk of myocardial infarction (adjusted HR, 0.84; 95% CI, 0.73-0.97) and recurrent stroke (adjusted HR, 0.86; 95% CI, 0.79-0.92). CONCLUSIONS: Secondary medical prophylaxis after ischemic stroke was associated with improved outcome in routine settings. Although these findings are of an observational nature, they tend to support the results from previous randomized trials. PMID- 22207507 TI - Hippocampal neuronal atrophy and cognitive function in delayed poststroke and aging-related dementias. AB - BACKGROUND AND PURPOSE: We have previously shown delayed poststroke dementia in elderly (>=75 years old) stroke survivors is associated with medial temporal lobe atrophy; however, the basis of the structural and functional changes is unknown. METHODS: Using 3-dimensional stereological methods, we quantified hippocampal pyramidal neuronal volumes and densities in a total of 95 postmortem samples from demented and nondemented poststroke survivors within our prospective Cognitive Function after Stroke study and subjects pathologically diagnosed with vascular dementia, Alzheimer disease, and mixed Alzheimer disease and vascular dementia syndrome. RESULTS: Hippocampal CA1 but not CA2 subfield neuron density was affected in poststroke, Alzheimer disease, vascular dementia, and mixed dementia groups relative to control subjects (P<0.05). Neuronal volume was reduced in the poststroke dementia relative to poststroke nondemented group in both CA1 and CA2, although there were no apparent differences in neuronal density. Poststroke nondemented neuronal volumes were similar to control subjects but greater than in all dementias (P<0.05). Neuronal volumes positively correlated with global cognitive function and memory function in both CA1 and CA2 in poststroke subjects (P<0.01). Degrees of neuronal atrophy and loss were similar in the poststroke dementia and vascular dementia groups. However, in the entorhinal cortex layer V, neuronal volumes were only impaired in the mixed and Alzheimer disease groups (P<0.05). CONCLUSIONS: Our results suggest hippocampal neuronal atrophy is an important substrate for dementia in both cerebrovascular and neurodegenerative disease. PMID- 22207508 TI - Insufficient platelet inhibition is related to silent embolic cerebral infarctions after coronary angiography. AB - BACKGROUND AND PURPOSE: Considering that insufficient platelet inhibition is related to thrombotic complications after coronary angiography, we hypothesized that the extent of platelet inhibition by antiplatelet agents is related to the occurrence of silent embolic cerebral infarction (SECI) after coronary angiography. METHODS: Among the patients scheduled for coronary artery bypass surgery, we retrospectively analyzed the location of SECI on diffusion-weighted imaging of 272 patients, which was performed after coronary angiography, as a presurgical evaluation in Phase 1 study. In Phase 2 study, we have prospectively recruited 102 patients to compare the extent of platelet inhibition measured by the VerifyNow system among patients with and without SECI. RESULTS: SECI is observed in 45 patients (16.5%) in Phase 1 and 17 (16.7%) in Phase 2. The lesions were slightly more frequent in the right hemisphere. In the Phase 2 study, aspirin reaction units and P(2)Y(12) reaction units were higher in the patients with SECI than those without (aspirin reaction units: 490+/-72 versus 446+/-53, P=0.03; P(2)Y(12) reaction units: 352+/-65 versus 300+/-77, P=0.009). The incidence of SECI increased with the number of resistant antiplatelets; resistance to both antiplatelet agent (50%), resistance to 1 antiplatelet agent (22%), and no resistance (4%; P=0.023). From the result of logistic regression, higher aspirin reaction units, white blood cell count, low hemoglobin, and nonresponsiveness to antiplatelet agents were independent risk factors. CONCLUSIONS: Insufficient platelet inhibition after administration of antiplatelet agents is related with SECI appearing after coronary angiography. PMID- 22207509 TI - Asymmetric pattern of cerebrovascular lesions in patients after left ventricular assist device implantation. AB - BACKGROUND AND PURPOSE: Stroke is a major adverse event after left ventricular assist device (LVAD) surgery. The purpose of this study was to describe differences in hemispheric distribution of stroke in LVAD patients. METHODS: We reviewed 317 consecutive patients who underwent LVAD surgery between November 2000 and July 2011. Stroke during LVAD support was analyzed. RESULTS: In total, 46 strokes occurred at 76.0+/-96.8 days postoperatively. Among the 46 strokes, 27 events (58.7%) occurred in right hemisphere, 13 events (28.2%) in the left hemisphere, 3 events (8.7%) occurred bilaterally, and 2 events (4.3%) were vertebrobasilar lesions. The right hemispheric stroke was significantly more common in patients with postoperative infection compared with left hemispheric events. CONCLUSIONS: Stroke after LVAD implantation has a right hemispheric predominance. This finding suggests LVAD-related thrombus in the setting of infection and/or the anatomic configuration of LVAD outflow cannula-ascending aorta anastomosis to be highly associated with stroke after LVAD surgery. PMID- 22207510 TI - alpha7 nicotinic acetylcholine receptor agonism confers neuroprotection through GSK-3beta inhibition in a mouse model of intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Perihematomal edema formation and consequent cell death contribute to the delayed brain injury evoked by intracerebral hemorrhage (ICH). We aimed to evaluate the effect of alpha7 nicotinic acetylcholine receptor (alpha7nAChR) stimulation on behavior, brain edema, and neuronal apoptosis. Furthermore, we aimed to determine the role of the proapoptotic glycogen synthase kinase-3beta (GSK-3beta) after experimental ICH. METHODS: Male CD-1 mice (n=109) were subjected to intracerebral infusion of autologous blood (n=88) or sham surgery (n=21). ICH animals received vehicle administration, 4 or 12 mg/kg of alpha7nAChR agonist PHA-543613, 12 mg/kg of alpha7nAChR agonist PNU-282987, 6 mg/kg of alpha7nAChR antagonist methyllycaconitine (MLA), 15 MUg/kg of phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin, or PHA-543613 combined with MLA or wortmannin. Behavioral deficits and brain water content were evaluated at 24 and 72 hours after surgery. Western blotting and immunofluorescence staining were used for the quantification and localization of activated Akt (p-Akt), GSK-3beta (p-GSK-3beta), and cleaved caspase-3 (CC3). Neuronal cell death was quantified through terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL). RESULTS: alpha7nAChR stimulation improved neurological outcome and reduced brain edema at 24 and 72 hours after surgery (P<0.05 compared with vehicle). Furthermore, PHA-543613 treatment increased p-Akt and decreased p-GSK-3beta and CC3 expressions in the ipsilateral hemisphere (P<0.05, respectively), which was reversed by MLA and wortmannin. P Akt, p-GSK-3beta, and CC3 were generally localized in neurons. PHA-543613 reduced neuronal cell death in the perihematomal area (P<0.05). CONCLUSIONS: alpha7nAChR stimulation improved functional and morphological outcomes after experimental ICH in mice. PHA-543613 reduced the expression of proapoptotic GSK-3beta through the PI3K-Akt signaling pathway. PMID- 22207511 TI - Incremental value of biochemical and echocardiographic measures in prediction of ischemic stroke: the Strong Heart Study. AB - BACKGROUND AND PURPOSE: American Indians have high rates of stroke. Improved risk stratification could enhance prevention, but the ability of biochemical and echocardiographic markers of preclinical disease to improve stroke prediction is not well-defined. METHODS: We evaluated such markers as predictors of ischemic stroke in a community-based cohort of American Indians without prevalent cardiovascular or renal disease. Laboratory markers included C-reactive protein, fibrinogen, urine albumin-to-creatinine ratio, and glycohemoglobin (HbA1c), whereas echocardiographic parameters comprised left atrial diameter, left ventricular mass, mitral annular calcification, and the ratio of early to late mitral diastolic velocities. Predictive performance was judged by indices of discrimination, reclassification, and calibration. RESULTS: After adjustment for standard risk factors, only HbA1c, albuminuria, and left atrial diameter were significantly associated with first ischemic stroke. Addition of HbA1c, although not urine albumin-to-creatinine ratio, to a basic clinical model significantly improved the C-statistic (0.714 versus 0.695; P=0.044), whereas left atrial diameter modestly enhanced integrated discrimination improvement (0.90%; P=0.004), but not the C-statistic (0.701; P=0.528). When combined with HbA1c, left atrial diameter further increased integrated discrimination improvement (1.81%; P<0.001) but not the C-statistic (0.716). No marker achieved significant net reclassification improvement. CONCLUSIONS: In this cohort at high cardiometabolic risk, HbA1c emerged as the foremost predictor of ischemic stroke when added to traditional risk factors, affording substantially improved discrimination, with a more modest contribution for left atrial diameter. These findings bolster the role of HbA1c in cardiovascular risk assessment among persons with glycometabolic disorders and provide impetus for further study of the incremental value of echocardiography in high-risk populations. PMID- 22207512 TI - Dietary protein sources and the risk of stroke in men and women. AB - BACKGROUND AND PURPOSE: Few dietary protein sources have been studied prospectively in relation to stroke. We examined the relation between foods that are major protein sources and risk of stroke. METHODS: We prospectively followed 84 010 women aged 30 to 55 years at baseline and 43 150 men aged 40 to 75 years at baseline without diagnosed cancer, diabetes, or cardiovascular disease. Diet was assessed repeatedly by a standardized and validated questionnaire. We examined the association between protein sources and incidence of stroke using a proportional hazard model adjusted for stroke risk factors. RESULTS: During 26 and 22 years of follow-up in women and men, respectively, we documented 2633 and 1397 strokes, respectively. In multivariable analyses, higher intake of red meat was associated with an elevated risk of stroke, whereas a higher intake of poultry was associated with a lower risk. In models estimating the effects of exchanging different protein sources, compared with 1 serving/day of red meat, 1 serving/day of poultry was associated with a 27% (95% CI, 12%-39%) lower risk of stroke, nuts with a 17% (95% CI. 4%-27%) lower risk, fish with a 17% (95% CI, 0% 30%) lower risk, low-fat dairy with an 11% (95% CI, 5%-17%) lower risk, and whole fat dairy with a 10% (95% CI, 4%-16%) lower risk. We did not see significant associations with exchanging legumes or eggs for red meat. CONCLUSIONS: These data suggest that stroke risk may be reduced by replacing red meat with other dietary sources of protein. PMID- 22207513 TI - The use of intramedullary nails in tibiotalocalcaneal arthrodesis. AB - Tibiotalocalcaneal arthrodesis is a salvage procedure undertaken for hindfoot problems that affect both the ankle and subtalar joints (eg, two-joint arthritis, severe acute trauma, osteonecrosis of the talus, severe malalignment deformities, significant hindfoot bone loss). Methods of achieving fusion include Steinmann pins, screws, plates, external fixators, and retrograde intramedullary nailing. Retrograde intramedullary nailing provides a load-sharing fixation device with superior biomechanical properties and is an excellent choice for use in tibiotalocalcaneal arthrodesis. This technique can be performed through relatively small incisions. In addition, recent design modifications include the availability of dynamization and the choice of curved or straight nails. Contraindications to the technique include the presence of infection, severe vascular disease, and severe malalignment of the tibia. PMID- 22207514 TI - Variations in sacral morphology and implications for iliosacral screw fixation. AB - Posterior pelvic percutaneous fixation following either closed or open reduction is a popular procedure. Knowledge of the posterior pelvic anatomy, its variations, and related imaging is critical to performing reproducibly safe surgery. The dysmorphic sacrum has several key characteristics. The upper portion of the sacrum is relatively colinear with the iliac crests on the outlet radiographic view. Other characteristics include the presence of mammillary bodies (ie, underdeveloped transverse processes) at the sacral mid-alar area, anterior upper sacral foramina that are not circular, residual upper sacral disks, an acute alar slope oriented from cranial-posterior-central to caudal anterior-lateral on the outlet and lateral views of the sacrum, a tongue-in groove sacroiliac joint surface visualized on CT, and cortical indentation of the anterior ala on the inlet radiographic view. The surgeon must be knowledgeable about individual patient anatomy to ensure safe iliosacral screw placement. PMID- 22207515 TI - Hemiarthroplasty for three- and four-part proximal humerus fractures. AB - Displaced three- and four-part proximal humerus fractures are among the most challenging shoulder conditions to manage. Because of the risk of symptomatic malunion, nonunion, and humeral head osteonecrosis, surgical management is preferred. Locking plate technology has provided an alternative to hemiarthroplasty for certain three- and four-part fracture patterns, even in the setting of osteopenic bone. Prosthetic humeral head replacement has been advocated for head-splitting fractures and fracture-dislocations as well as four part fractures with significant initial varus displacement (>20 degrees ). Technical challenges, including obtaining proper humeral head height, retroversion, and optimal positioning and fixation of the tuberosities, have a substantial effect on patient outcomes. PMID- 22207516 TI - Psoriatic arthritis. AB - Psoriatic arthritis is a chronic inflammatory arthropathy that affects approximately 6% to 48% of patients with psoriasis. Arthritis is not correlated with the extent of skin disease. Classic radiographic findings of the involved joint include erosion, ankylosis, and fluffy periostitis. Site-specific characteristic deformities such as pencil-in-cup deformity of the phalanges also may be present. The disease typically follows a moderate course, but up to 47% of cases develop into destructive arthritis in which the inflammatory process leads to bony erosion and loss of joint architecture. The mainstay of treatment is biologic therapy (eg, tumor necrosis factor-alpha inhibitors) in conjunction with disease-modifying antirheumatic drugs. Patients with end-stage joint destruction may require surgery to alleviate pain and restore function. Orthopaedic surgeons should be cognizant of the risk factors (eg, increased risk of cardiovascular disease) and potential complications (eg, poor wound healing and increased risk of infection) associated with psoriatic arthritis. PMID- 22207517 TI - Brachial plexus blocks for upper extremity orthopaedic surgery. AB - Regional anesthesia of the upper extremity has several clinical applications and is reported to have several advantages over general anesthesia for orthopaedic surgery. These advantages, such as improved postoperative pain, decreased postoperative opioid administration, and reduced recovery time, have led to widespread acceptance of a variety of regional nerve blocks. Interscalene block is the most commonly used block for shoulder surgery. Other brachial plexus nerve blocks used for orthopaedic surgery of the upper extremity are supraclavicular, infraclavicular, and axillary. Several practical and theoretical aspects of regional nerve blocks must be considered to optimize the beneficial effects and minimize the risk of complications. PMID- 22207518 TI - Surgical exposures of the wrist and hand. AB - The neurovascular anatomy of the carpus and hand is complex. Therefore, precise exposures are required to avoid iatrogenic injury. In general, dorsal exposures are more forgiving than volar exposures because major neurovascular structures lie on the volar aspect of the hand and fingers; however, volar, ulnar, and radial approaches to the carpal bones are also commonly used. Exposure of the metacarpals and phalanges is relatively straightforward by comparison. Exposure of the carpus and hand is also complicated by the dense and often superficial innervation network. Therefore, a thorough knowledge of the pertinent anatomy is required for safe surgical approaches to the wrist and hand. PMID- 22207519 TI - Wnt, osteosarcoma, and future therapy. PMID- 22207520 TI - Nanotechnology in orthopaedics. PMID- 22207522 TI - Comparison of fixed combinations of dorzolamide/timolol and brimonidine/timolol in patients with primary open-angle glaucoma. AB - To compare the short-term effectiveness and ocular side-effects of fixed combinations of dorzolamide/timolol (DTFC) and brimonidine/timolol (BTFC) in patients with primary open-angle glaucoma (POAG). Forty-two eyes of 42 patients newly diagnosed with primary open-angle glaucoma were assessed prospectively. One of the two eyes was chosen randomly and treated with DTFC (2 * 1) for 4 weeks. The treatment was then stopped to allow a 4-week wash-out period. Following the wash-out period, the same eye was treated with BTFC (2 * 1) for 4 weeks. Intraocular pressure (IOP) values were measured before and after each treatment at 0800, 1,200 and 1,600 h. Tear function test results and ocular side-effects were also recorded. The mean baseline IOP values for DTFC and BTFC were 24.1 +/- 1.8 and 24.6 +/- 2.4 mmHg, respectively. The mean IOP values after 4 weeks of treatment with DTFC or BTFC were 17.1 +/- 2.9 and 16.9 +/- 2.5 mmHg, respectively. Both medications reduced IOP values significantly (P = 0.0000). The effectiveness of both medications was similar (P = 0.7363). Both combinations significantly reduced the amount of tear secretion and tear break-up time (P = 0.0000). Eye burning was more common with DTFC than with BTFC (P = 0.0182). Other adverse effects were observed at similar rates for both combinations. This study demonstrated that the IOP-reducing effects of DTFC and BTFC in patients with POAG are similar. The side-effect profile of BTFC is similar to that of DTFC. Lower occurrence of a burning sensation may improve patient compliance in the BTFC group. PMID- 22207521 TI - Metastatic papillary thyroid carcinoma to the maxilla: case report and literature review. AB - Metastatic tumors to the oral cavity are uncommon and a thyroid origin is considered exceedingly rare. A case of metastatic papillary thyroid carcinoma (PTC) presenting as a painful swelling in the right posterior maxilla of a 63 year-old male is reported here. The patient had been diagnosed with PTC 2 years ago and treated with thyroidectomy and radioactive iodine treatment. Radiographically, the metastatic lesion presented as a poorly-defined radiolucent lesion around an impacted maxillary third molar in the right maxilla. Histopathologic examination revealed features of PTC which was immunohistochemically positive for pancytokeratin, keratin 19 and thyroglobulin. Imaging studies revealed the presence of residual maxillary and neck disease as well as additional metastatic lesions in the sternum, ribs, and left tibia. A thorough review of the English language literature revealed only 36 previously published cases of thyroid cancer metastases to the oral cavity, the demographic and clinicopathologic features of which are summarized. PMID- 22207523 TI - Receptor for activated C kinase 1 (RACK1): a regulator for migration and invasion in oral squamous cell carcinoma cells. AB - PURPOSE: Receptor of activated protein kinase C 1 (RACK1) has been identified as an anchoring or adaptor protein in multiple intracellular signal transduction pathways. Our previous study has showed that the expression of RACK1 was paralleled with proliferation and correlated with metastasis and clinical outcome. However, the underlined mechanism has not been uncovered. MATERIALS AND METHODS: We first selected a most effective siRNA among three siRNAs (siRNA-1, siRNA-2 and siRNA-3) targeting different regions in the RACK1 mRNA and re evaluated the anticancer effect of RACK1 silencing on HSC-3 and Cal-27 cell lines by cell growth inhibition. And then, we investigated whether knockdown of RACK1 could inhibit cell adhesion, migration and invasion in these two cell lines. To further understand the molecular mechanism of RACK1 in these processes, the expressions of EGFR, pEGFR, HER2, MMP-2 and MMP-9 were detected by western blot. RESULTS: We verified that the silence of RACK1 gene in two OSCC cell lines could not only inhibit cell proliferation but also decrease the invasion, migration and adhesion capability of the tumor cells. Further, western blot analysis deduced that it might be related to the decrease in protein expression of EGFR, pEGFR, HER2, MMP-2 and MMP-9. CONCLUSION: Our results clearly showed the significance of RACK1-induced OSCC cell migration, invasion and adhesion, which could explain the underlined mechanism of the effect of the gene on metastasis and clinical outcome. Also, our results confirmed its role to be a prognostic indicator and a promising drug target for OSCC cell metastasis. PMID- 22207526 TI - The effect of allergic rhinitis on the degree of stress, fatigue and quality of life in OSA patients. AB - Both allergic rhinitis (AR) and obstructive sleep apnea (OSA) are known to increase stress and fatigue, but the result of their coexistence has not been studied. The objective of this study was to evaluate the amount of stress and fatigue when AR is combined with OSA. One hundred and twelve patients diagnosed with OSA by polysomnography were enrolled. Among them, 37 patients were diagnosed with AR by a skin prick test and symptoms (OSA-AR group) and 75 patients were classified into the OSA group since they tested negative for allergies. We evaluated the Epworth sleepiness scale (ESS), stress score, fatigue score, ability to cope with stress, and rhinosinusitis quality of life questionnaire (RQLQ) with questionnaires and statistically compared the scores of both groups. There were no significant differences in BMI and sleep parameters such as LSAT, AHI, and RERA between the two groups. However, the OSA-AR group showed a significantly higher ESS score compared to the OSA group (13.7 +/- 4.7 vs. 9.3 +/ 4.8). Fatigue scores were also significantly higher in the OSA-AR group than in the OSA group (39.8 +/- 11.0 vs. 30.6 +/- 5.4). The OSA-AR group had a significantly higher stress score (60.4 +/- 18.6 vs. 51.2 +/- 10.4). The ability to cope with stress was higher in the OSA group, although this difference was not statistically significant. RQLQ scores were higher in the OSA-AR group (60.2 +/- 16.7 compared to 25.1 +/- 13.9). In conclusion, management of allergic rhinitis is very important in treating OSA patients in order to eliminate stress and fatigue and to minimize daytime sleepiness and quality of life. PMID- 22207524 TI - MiR-181d acts as a tumor suppressor in glioma by targeting K-ras and Bcl-2. AB - PURPOSE: Recently, several microRNAs (miRNAs) were reported to be involved in the modulation of glioma development. The aim of our study was to determine the effect of miR-181d on the growth of glioma and to investigate whether this growth is modulated by targeting K-ras and Bcl-2. METHODS: Real-time PCR was used to analyze the expression of miR-181d in human glioma samples and glioma cell lines. Apoptosis, cell cycle, and proliferation (MTT) assays were performed to assess the phenotypic changes in glioma cells. Immunohistochemistry was used to determine the expression of K-ras and Bcl-2 in glioma tissues, and a luciferase reporter assay was carried out to confirm whether K-ras and Bcl-2 are direct targets of miR-181d. Western blotting was used to identify the potential signaling pathways affected glioma cell growth by miR-181d. In vivo, xenograft tumors were examined for an anti-glioma effect of miR-181d. RESULTS: MiR-181d was down-regulated in human glioma samples and up-regulated in transfected glioma cells. Ectopic expression of miR-181d suppressed proliferation and triggered cell cycle arrest and apoptosis in glioma cell lines. K-ras and Bcl-2 were identified as direct targets of miR-181d and were up-regulated in glioma samples. The results showed evidence linking the tumor suppressor activity of miR-181d in glioma cells with the K-ras-related PI3K/AKT and MAPK/ERK pathways. Furthermore, xenograft tumors from miR-181d-treated U251 cells were suppressed in vivo. CONCLUSION: MiR-181d may act as a glioma suppressor by targeting K-ras and Bcl-2. PMID- 22207527 TI - HPV infection and p16 expression in carcinomas of the minor salivary glands. AB - The correlation between p16 upregulation and high-risk HPV infection is well known in head and neck squamous cell cancer. However, no information is available on rare carcinomas of the minor salivary glands. We analyzed 38 samples of minor salivary gland malignancies. p16 expression was determined by immunohistochemistry, HPV DNA by using in situ hybridization to detect low (type 6 and 11) and high (type 16 and 18) risk HPV types. In 71% of samples p16 expression was found. Low-risk HPV DNA could not be detected in any of the samples, whereas high-risk HPV DNA was found in two samples of mucoepidermoid carcinoma, which also showed the highest immunoreactivity with p16. HPV infection does not seem to be a common event in minor salivary gland carcinoma. Upregulation of p16 is present in the majority of cases but only diffuse staining correlates with HPV 16 and 18 infections. PMID- 22207528 TI - Initial work-up for cervical lymphadenopathy: back to basics. AB - The aim of this study was to evaluate the value of FNA, Tb-PCR, and CBC as an initial work-up protocol for cervical lymphadenopathy to reiterate the importance of CBC in terms of predicting the clinical course. In this consecutive case series, 158 patients with cervical lymphadenopathy were enrolled. All patients underwent FNA and CBC, with or without Tb-PCR. The validity of combined FNA +/- Tb-PCR and CBC in the diagnosis of diseases requiring definitive treatment was evaluated. Final diagnoses were self-limiting disease in 110 (69.6%), malignancy in 19 (12.0%), and tuberculosis in 26 (16.5%). Sensitivity of FNA +/- Tb-PCR was 66.7% and of added CBC profile was 97.9%. Patients with neutropenia or lymphocytosis were found to have a higher chance of spontaneous recovery than patients with a normal WBC profile. FNA and Tb-PCR were found to be important in patients aged more than 20. The results indicate that FNA, Tb-PCR, and CBC are basic and essential in initial work-up for cervical lymphadenopathy. In particular, CBC was found to aid in detecting critical diseases and predicting the likelihood of open biopsy in patients with negative FNA and Tb-PCR. Patient age was also found to be an important determinant of the work-up protocol. PMID- 22207530 TI - Use of Floseal and effects on wound healing and pain in adults undergoing tonsillectomy: randomised comparison versus electrocautery. AB - The objective of this study was to evaluate the effect of FloSeal((r)) (FS, Baxter Healthcare, Deerfield, IL, USA) as a haemostatic matrix in comparison to bipolar electrocautery (EC) after tonsillectomy. Eligible patients were adults undergoing cold-knife tonsillectomy because of recurrent tonsillitis, tonsillar hypertrophy, or peritonsillar abscess (more than 3 months previously). Patients were randomly allocated, on a single-blind basis, to either FS or EC for haemostasis during tonsillectomy. Five experienced surgeons judged the handling of FS application using a five-point scale (very good, good, fair, poor, very poor). Postoperative pain scores were evaluated with a visual analogue scale for 20 days, and the duration under pain medication together with the consumption of pain medication was compared. Wound healing was documented on Days 1-5, 10, and 20. A total of 176 patients were enrolled. Overall, 76/77 (98.7%) of surgeon evaluations of FS handling were judged at least "good". FS-treated patients showed significantly improved wound healing (less thickness of wound plaques) throughout the postoperative observation period, a trend for less postoperative pain (cumulative pain intensity score; P = 0.074), and a significantly shorter duration of pain-medication use (9.5 vs. 11.6 days; P = 0.014) as well as reduced pain-medication consumption/demand (P = 0.032). No difference in the rate of postoperative haemorrhage was observed between the two treatment groups (4.9% for FS patients, 6.0% for EC patients, P = 0.76). In conclusion, this study demonstrates the easy handling of FS application in tonsillectomy. Its use instead of EC after cold-steel tonsillectomy shows beneficial effects on mucosal recovery, as assessed by a decrease in the thickness of wound coating. Furthermore, FS is associated with a significantly shortened duration of pain medication use and overall reduction in consumption/demand. PMID- 22207529 TI - Risk factors for failing the hearing screen due to otitis media in Dutch infants. AB - Hearing loss from otitis media (OM) can affect young children's development. Some children with persistent OM-related hearing loss and associated problems can benefit from treatment, but researchers and clinicians are still unclear on how to identify them best. The present study aims to determine which factors are most related to the hearing loss in OM, as a first step towards an effective case finding instrument for detecting infants with persistent OM-related hearing loss. The full PEPPER ('Persistent Ear Problems, Providing Evidence for Referral') item pool includes a wide range of risk factors for OM in a single questionnaire, and is easily completed by parents or guardians. The questionnaire was sent to all children invited for the universal hearing screen at age 9 months in Limburg, The Netherlands. Repeatedly failing of the hearing screen was used as outcome marker indicative of OM-related chronic hearing loss. Univariate analyses were conducted to determine statistically significant risk factors predicting 'fail' cases at this hearing screen. Five items were found as individually predictive of hearing screen failure and subsequent referral: 'having severe cold symptoms', 'attending day care with >4 children', 'having siblings', 'severe nasal congestion' and 'male gender'. Suitably worded parental questions document risk factors for OM related hearing loss in infants, broadly consistent with past general literature on OM risk factors, but more focused. The findings justify further optimising and evaluation of an additive or multiplicative combination of these questions as a means for selecting and routing an infant with diagnosed or suspected OM to further care. PMID- 22207532 TI - Stretching beyond your comfort zone. PMID- 22207533 TI - Tap into electronic networking to advance your career. PMID- 22207531 TI - Risk factors for laryngopharyngeal reflux. AB - The aim of this study was to evaluate the demographic and clinicopathologic characteristics of gastroesophageal reflux disease (GERD) with and without laryngopharyngeal reflux (LPR) to determine the risk factors for the occurrence of LPR in patients with GERD. This is a retrospective study of GERD patients with and without LPR. From the outpatient computer program of our hospital we randomly enrolled 45 GERD patients with LPR into the first group and another 45 GERD patients without LPR to the second group. Medical records of the patients in both groups were examined. All patients underwent upper gastrointestinal system endoscopy. LPR was confirmed by laryngoscopy, and LPR-related laryngoscopy scoring. Non-erosive GERD (NERD), erosive GERD (ERD) and Barrett's esophagus (BE) were diagnosed by endoscopy and histopathology. Various clinical parameters including status of Helicobacter pylori (H. pylori) infection, topography of gastritis were analyzed. For therapy, lansoprazole in a dosage of 30 mg BID for at least 8 weeks were given to all patients in both groups. GERD patients with and without LPR were compared according to demographic, clinic, endoscopic and histopathological parameters. The results revealed that patients with LPR were younger than the patients without LPR (38.7 +/- 10.2 years and 43.8 +/- 11.5 years; p = 0.08); however, there was no statistical significance. Patients without LPR showed no gender predilection (55% male) while LPR patients showed male preponderance (71% male). In LPR group, 11 patients (24%) had NERD, while 28 (62%) and 6 (13%) patients had ERD and BE, respectively. Twenty-seven (60%) patients without LPR were diagnosed as NERD, 15 patients (33%) without LPR had ERD and only 3 patients (6.6%) showed the histological findings of BE. The patients in LPR group had higher body mass index. Hiatal hernia was more frequent in the patients with LPR (53%) than in the patients without LPR (24%) (p = 0.005). LPR patients had longer duration of reflux symptoms than the patients without LPR (p = 0.04). H. pylori status was not different in both groups but the patients without LPR had more corpus gastritis than the patients with LPR. Eight weeks of lansoprazole treatment was successful in 71% of patients with LPR, and 86% of patients without LPR. We concluded that male gender, hiatal hernia, longer duration of symptoms, high BMI, having ERD and BE seems as risk factors for the occurrence of LPR in patients with GERD. H. pylori status did not have any effect on the development of LPR. Corpus dominant gastritis may have a protective role against the development of LPR. Proton pump inhibitor therapy is less effective in patients with LPR. PMID- 22207534 TI - Reap the benefits of certification. PMID- 22207535 TI - Increasing your professional net worth: tips for new nurses. PMID- 22207536 TI - Explore nursing abroad! Interview by Sandy Dancer. AB - International nursing allows nurses to experience a different culture of practice, to appreciate the variations in healthcare among countries, and to learn from each other. In this question-and-answer account, American nurse Donna Boyd shares her experience working as a nurse in the United Kingdom. PMID- 22207537 TI - Mentor and protege: a mutually beneficial relationship. PMID- 22207538 TI - Community health nursing: a partnership of care. PMID- 22207539 TI - Preparing successful grant proposals. PMID- 22207540 TI - Introducing the Nurse's Education Center! PMID- 22207541 TI - Striving for work-life balance. PMID- 22207545 TI - Multidisciplinary communication strategies for Magnet(r) success. PMID- 22207546 TI - Nomadic nursing: opportunities in travel nursing. PMID- 22207547 TI - Review of renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions with focus on pathobiological aspect. AB - The concept of Xp11.2 renal cell carcinoma (RCC) was recently established as a tumor affecting 15% of RCC patients <45 years. Many patients present with advanced stage with frequent lymph node metastases. Histologically, Xp11.2 RCC is characterized by mixed papillary nested/alveolar growth pattern and tumor cells with clear and/or eosinophilic, voluminous cytoplasm. Neoplastic cells show intense nuclear immunoreactivity to TFE3, while focal immunostaining for melanocytic markers, including melanosome-associated antigen or Melan A in some cases, are also noted. Alpha smooth muscle actin and TFEB are consistently negative. Ultrastructurally, the ASPL-TFE3 RCC variant contains rhomboid crystals in the cytoplasm, similar to that observed in alveolar soft part sarcoma. The fusion of the TFE3 gene with several different genes, including ASPL(17q25), PRCC(1q21), PSF(1q34), NonO (Xq12) and CLTC (17q23) have been identified to date. The behavior of Xp11.2 RCC in children and young adults is considered as indolent even when diagnosed at advanced stage, including lymph node metastasis. However, Xp11.2 RCC in older patients behaves in a more aggressive fashion. Therapy includes nephrectomy with extended lymphadenectomy. There may be a role for new protease inhibitors in advanced inoperable disease. Further research is required to correlate clinical behavior with the expanding genetic spectrum of this tumor, and to establish standard therapy protocols for primary and metastatic lesions. PMID- 22207548 TI - E-cadherin in oral SCC: an analysis of the confusing literature and new insights related to its immunohistochemical expression. AB - E-cadherin plays a crucial structural role in cell-cell contacts in epithelial tissues, and a functional role in signaling pathways that regulate cell proliferation, differentiation, and survival. Reduced immunoexpression of E cadherin adhesions is largely considered as being equivalent to defective functionality and malignancy, and has been used as a prognostic parameter. A critical analysis of studies on E-cadherin immunoexpression in oral carcinomas revealed a wide range of both technical and interpretational aspects. This paper highlights biological characteristics of E-cadherin with respect to its expression in normal and neoplastic epithelial cells and to its interrelations with the tumor microenvironment that can have an impact on immunohistochemical results and their application in the clinical setting. PMID- 22207550 TI - New models towards assessing anti-cancer therapeutics. AB - Cancer is the subject of intense research around the world, but many questions about how the disease works remain unanswered. How exactly does cancer start and how do tumours grow? In fact, at present there are ten times more anticancer drugs being tested in clinical trials than there were 15 years ago. However, many of the new anticancer agents are predicted to show clinical benefit in only small subpopulations of patients. The cancer stem cell model could explain not only how some cancers work but also why patients suffer relapses, providing a good opportunity to gain insight into the reasons why agents work or, more commonly, don't work, before going into a clinical trial. PMID- 22207549 TI - Notch: a key regulator of tumor angiogenesis and metastasis. AB - The Notch signaling pathway is critical for many developmental processes including physiologic angiogenesis. Notch is also implicated in having a key role in tumor angiogenesis. Preclinical and clinical experience with anti-angiogenic strategies indicates that they may be limited by tumor resistance and recurrence, which has led to the search for alternative angiogenic treatment strategies. Significant progress has been made in shedding light on the complex mechanisms by which Notch signaling can influence tumor growth by disrupting vasculature in an array of tumor models (Ridgway et al., 2006). These results have led to the consideration of Notch as an attractive target to block tumor angiogenesis and inhibit growth. However, studies of inhibition of Notch signaling in different tumor models have uncovered similarly variable results, and some unexpected adverse effects. The ability of Notch to function in a context-dependent manner as a determinant of cell fate, a tumor suppressor, and an oncogene may partially explain the complexity in interpreted the role of Notch signaling inhibitors in preclinical tumor studies. In addition, Notch may also play an important role in metastasis via its direct effects on the vasculature and by modulation of epithelial-mesenchymal transition in tumor cells. Here we present a current understanding of Notch signaling in tumor angiogenesis, and discuss recent work on the role of Notch in tumor metastatic progression. PMID- 22207552 TI - The incidence and clinical significance of lymph node micrometastases determined by immunohistochemical staining in stage I - lymph node negative endometrial cancer. AB - OBJECTIVE: Determine the incidence and clinical relevance of lymph node micrometastases found with immunohistochemical (IHC) staining in patients diagnosed with stage I lymph node-negative endometrial adenocarcinoma. METHODS: Eligible patients with endometrioid-type histology and negative lymph nodes by H&E were identified by a computerized database. After histologic confirmation, all paraffin-embedded pathologic specimens were freshly sliced and stained with IHC stains for pancytokeratin. Slides were interpreted by two pathologists and positive IHC staining for micrometastases was defined as positive staining of cells <2 mm in greatest dimension. Patient demographics, clinicopathologic factors, and follow-up data were abstracted. RESULTS: Fifty-one patients were included in our study. Most patients had stage IA (84%) tumors of grade 2/3 histology (51%), and 11 patients (22%) received adjuvant therapy. Mean number of lymph nodes was 12.2 per patient. Of 151 lymph node paraffin blocks evaluated for pancytokeratin, only two (1.3%) had IHC-positive micrometastases. The two lymph node-positive results occurred in separate patients, leading to 3.9% of all patients in our cohort. Both micrometastatic lymph node-positive patients had adjuvant radiation therapy for uterine high-risk factors and are currently without evidence of disease at 15 and 16 months, respectively. Three lymph node negative patients (6.1%) have developed recurrences within a median follow-up of 15 months. CONCLUSION: The incidence of IHC stain-positive micrometastases in H&E negative lymph nodes is low in surgically staged endometrial cancer and does not justify routine IHC staining. Additionally, as little evidence exists to support the clinical significance of IHC-stained micrometastases in endometrial cancer, further study is warranted. PMID- 22207551 TI - Ascorbic acid deficiency accelerates aging of hepatic stellate cells with up regulation of PPARgamma. AB - Senescent cells have been observed in certain aged or damaged tissues. However, the information about the effects of aging on liver cells is limited. In the present study, we have examined age-related histological changes in the livers of senescence marker protein knockout (SMP30-/-) mice, which are considered as a murine aging model due to the more sensitive response to apoptotic reagents and due to their shorter life span. In livers of old SMP30-/- mice, numerous hepatic stellate cells (HSCs) were hypertrophic and contained abundant microvesicular lipid droplets in cytoplasm. We have found that the expression of peroxisome proliferators-activated receptor gamma (PPARgamma), which is a protein related to lipid metabolism and HSC quiescence, was increased in hypertrophic HSCs by aging and vitamin C (VC) deficiency, whereas these phenomena were dramatically reduced by antioxidant treatment. Therefore, these prominent phenotypic changes can be considered as aging markers in the livers of animals which are subjected to antioxidant property evaluation. PMID- 22207553 TI - Local identification of porcine haptoglobin in salivary gland and diaphragmatic muscle tissues. AB - In order to clarify the origin of the haptoglobin (Hp) quantified in saliva and meat juice samples, the extrahepatic localization of Hp in salivary gland and in diaphragmatic muscle, as part of the systemic acute phase response in pigs, was studied by immunohistochemistry. For this purpose a specific monoclonal antibody (mAb) produced by immunising mice with purified porcine Hp was used. Reactivity of the mAb was assessed by direct ELISA and by western blot, which showed the ability and specificity of the mAb to identify porcine haptoglobin as a purified antigen or in porcine serum in a native or denatured but non-reduced state. Five healthy and five diseased pigs were sampled at slaughter for serum and tissue procurement. Hepatic immunohistochemical analysis was used as control of the acute phase reaction status. In the liver, cell immunostaining revealed a perinuclear, cytoplasmic localization of Hp within hepatocytes, following mainly a periacinar pattern. Extrahepatic immunohistochemical analysis revealed positive cells in the glandular acini and duct epithelial cells of the salivary gland and intrasarcoplasmic immunolabelling of random diaphragmatic myofibers. A possible role of both salivary gland and diaphragmatic muscle on local Hp production could be postulated based on the present immunohistochemical study, which supports the concept that other cells besides hepatocytes may have the potential to produce Hp in the pig. PMID- 22207555 TI - Thrombospondin-1 expression in breast cancer: prognostic significance and association with p53 alterations, tumour angiogenesis and extracellular matrix components. AB - Thrombospondin (TSP-1) is a 450-kd adhesive glycoprotein that was initially discovered in platelets and subsequently in a variety of cell types. Several reports suggest that TSP-1 possesses tumour suppressor function, through its ability to inhibit tumour neovascularization. In this study we investigated tissue sections from 124 breast carcinomas for the immuno-histochemical expression of TSP-1 protein and its relationship to several clinicopathological parameters. The possible relationship to hormone receptors content, p53 protein, proliferation associated indices, angiogenesis, VEGF expression and extracellular matrix components (tenascin, fibronectin, laminin, collagen type IV and syndecan 1) was also estimated. TSP-1 was detected in the perivascular tissue, at the epithelial-stromal junction, in the stroma and in the tumour cells. High tumour cell TSP-1 expression was observed in 9.7%, moderate in 17.7%, mild in 10.5%, while 62.1% of the cases were negative for TSP-1 expression. The survival analysis showed an increased risk of recurrence associated with low TSP-1 tumour cell expression. High stromal TSP-1 expression was observed in 3.2% of the cases, moderate in 3.3%, mild in 27.4%, while 63.6% of the cases showed absence of TSP-1 expression. This expression was higher in invasive lobular type of breast cancer and inversely correlated with the lymph node involvement and the estrogen receptor content. Stromal TSP-1 expression was also positively correlated with extracellular matrix components expression, tenascin, fibronectin, collagen type IV, laminin, and syndecan-1. The relationship of TSP-1 expression with tumor angiogenesis, growth fraction and p53 protein expression was not significant. Our data suggest that TSP-1 expression seems to be associated with favorable biological behavior and may have clinical value in terms of predicting the risk of recurrence. In addition, TSP-1 might not be a direct anti-angiogenic factor, although it seems to be implicated in the remodeling of breast cancer tissue through interaction with other extracellular matrix components. PMID- 22207554 TI - High MET copy number and MET overexpression: poor outcome in non-small cell lung cancer patients. AB - The aim of this study was to evaluate the prevalence and prognostic role of increased gene copy number and protein expression of MET and EGFR in non-small cell lung cancer (NSCLC) patients. Samples were collected from 380 patients with surgically resected NSCLC, and fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) were performed. EGFR amplification and high polysomy (EGFR FISH-positive) were observed in 9.7% and 17.4% of the patients, respectively. EGFR was overexpressed (EGFR IHC-positive) in 19.2% of the patients. Neither EGFR FISH-positive nor EGFR IHC-positive status affected survival after resection. Increased MET copy number (MET FISH-positive by University of Colorado Cancer Center criteria) was observed in 11.1% of the patients (high polysomy, 8.7%; gene amplification, 2.4%). According to the Cappuzzo system, 7.1% of the patients were MET FISH-positive. MET FISH positivity was a negative prognostic factor, especially in patients with adenocarcinoma histology (p=0.040), female gender (p=0.010), old age (p=0.084), and EGFR FISH negativity (p=0.020) at the univariate level but not at the multivariate level. MET was overexpressed (MET IHC-positive) in 13.7% of the patients and associated with shorter overall and disease-free survival (p=0.010 and p=0.056, respectively). Multivariate analysis revealed that MET IHC-positive patients had a significantly increased risk of death (hazard ratio, 1.618; 95% confidence interval, 1.066-2.456; p=0.024). Increased MET copy number and MET overexpression are negative prognostic factors for surgically resected NSCLCs. PMID- 22207556 TI - PCDH17 gene promoter demethylation and cell cycle arrest by genistein in gastric cancer. AB - Protocadherin 17 (PCDH17) is a member of the cadherin superfamily, but little is known about its functions. We focused on it as a candidate tumor suppressor gene (TSG) and hypothesized that PCDH17 may be susceptible to promoter methylation and gene silencing. Genistein has been reported to upregulate mRNA expression in many TSGs. We further tried to determine whether genistein could increase transcriptional PCDH17 by promoter demethylation. Gastric cancer cell line AGS and normal gastric cell line Ges-1 were treated with genistein and 5-aza-2' deoxycytidine (5Aza-C). Fluorescence-activated cell sorting was performed to analyze cell cycle and apoptosis, and cell proliferation was examined by cell viability assay. PCDH17 mRNA expression in pairs of gastric cancer and normal tissue samples and cell lines were determined by quantitative real-time polymerase chain reaction. Bisulfite-modified polymerase chain reaction, cloning and sequencing were used to examine promoter methylation. We found genistein has an anti-proliferative effect on cancer cell growth through induction of cell cycle arrest. PCDH17 mRNA expression was down-regulated in cancer tissues, and PCDH17 promoter in cancer tissues was hyper-methylated in comparison with normal ones. Genistein and 5Aza-C induced PCDH17 mRNA expression in AGS, but not in Ges 1. Furthermore, genistein and 5Aza-C treatment significantly decreased promoter methylation in putative methylation target regions in AGS, reactivating PCDH17 expression. These results suggest that silencing of PCDH17 expression through promoter hypermethylation leads to loss of its tumor-suppressive activity. Genistein showed similar effects to that of 5Aza-C. Our results indicate that genistein is a novel, advantageous therapeutic agent for treating gastric cancer. PMID- 22207557 TI - Synchronous and metachronous multiple gastrointestinal stromal tumors. AB - BACKGROUND & AIMS: Sporadic multiple gastrointestinal stromal tumors (GISTs) are rare events especially those developed metachronously. This study aimed to investigate the clinico-pathologic and genetic features defining multiple GISTs. METHODS: 624 cases of GISTs were retrieved for retrospective review. 15 cases were identified as multiple GISTs including 13 synchronous and 2 metachronous ones. 32 tumors and 15 normal tissues were obtained from these cases each containing 2-3 tumor nodules and the genomic DNA was extracted for mutational analysis of KIT and PDGFRA genes. The associated patients were recruited for clinical follow-up studies, including 5 males and 10 females at 49 to 84 years of age. RESULTS: Multiple GISTs comprised of 2.4% of GIST cases in our consecutive series. Twenty-six tumors showed mutations at KIT gene in exon 11 and one at PDGFRA gene in exon 18. In seven synchronous cases, different tumors from the same patients displayed different genotypes of KIT or PDGFRA, suggesting their polyclonal origin. In the two multiple GISTs occurring metachronously, the tumors from each patient showed different KIT mutations, suggesting that the second tumors were not the relapse or metastasis of the primary GISTs. CONCLUSIONS: Based on types of KIT or PDGFRA mutations and other pathological features, multiple primary GISTs can be differentiated from multiple GISTs resulting from recurrence or metastasis of a single primary tumor. Unlike recurrence or metastasis of GISTs that are malignant, most multiple GISTs are mostly benign and do not require aggressive adjuvant therapy. Therefore, correct diagnosis is critical for proper treatment. PMID- 22207558 TI - Histological features and immune cell changes in skin lesions of engraftment syndrome of children undergoing hematopoietic stem cell transplantation. AB - Various skin eruptions are encountered during hematopoietic stem cell transplantation (HSCT) of children with hematologic malignancies. Engraftment syndrome (ES) is a disease characterized by fever, weight gain, maculopapular skin rash and noncardiogenic pulmonary edema. ES occurs during neutrophil recovery without identifiable causes of infection. Early detection of ES is critical to reduce mortality and morbidity, but identical morphologic changes found in skin lesions from ES and graft-versus-host disease (GVHD) are a challenging problem for histology-based diagnosis. To resolve this issue, immunopathologic changes in skin lesions of ES were studied. Five skin biopsies from patients with symptoms clinically compatible with ES were retrieved and compared to 15 age- and sex-matched cases of acute GVHD with antibodies to CD3, CD4, CD8 and CD1a. Mean numbers of epidermal CD8+ cells and CD1a+ cells were lower in ES than in GVHD. However, there were no significant differences in mean score of GVHD grade, mean numbers of lymphoid cells, CD3+ cells, or CD4+ cells. In the setting of HSCT in children, the dominance of CD4+ cells and a decreased number of CD1a+ cells in the epidermis are specific features for the skin lesions of ES. PMID- 22207559 TI - Analysis of pituitary gonadotropin concentration in blood serum and immunolocalization and immunoexpression of follicle stimulating hormone and luteinising hormone receptors in ovaries of postmenopausal women. AB - The participation of gonadotropins in ovarian carcinogenesis is well known and is supported by studies with inhibition of pituitary gonadotropin secretion, which results in a diminished risk of cancer. However, there are few data on localization and expression of Follicle Stimulating Hormone and Luteinising Hormone Receptors (FSHR and LHR) in ovaries of healthy postmenopausal women, and their correlation with FSH and LH concentration in blood serum is unknown. The aim of our study was to analyze gonadotropin concentration in blood serum and the expression of FSHR and LHR in ovaries of 207 postmenopausal women. Patients included in the study were divided into three groups depending on the number of years since menopause. We analyzed the concentration of FSH and LH in blood serum and the expression of FSHR and LHR in ovaries. Ovaries of postmenopausal women showed numerous morphological changes in the cortex and medulla when compared to the structure of ovaries of women at reproductive age. In all groups of patients clefts in the surface epithelium and epithelial inclusion cysts were found. The concentration of FSH and LH in the blood serum of women studied increased significantly with time from menopause. Significant differences between analyzed menopausal groups were found. The highest FSH and LH concentration in blood serum were found in women with the longest period of time from menopause. Quantitatively similar expression of FSHR and LHR was found in ovarian surface epithelial cells, in epithelial inclusion cysts and in the connective tissue cells of ovarian stroma. The intensity of the immunohistochemical reaction decreased with time from menopause and with age. PMID- 22207560 TI - Less gelatinases is associated with apolipoprotein E accumulation in glomerulosclerosis rats. AB - BACKGROUND: Gelatinases include matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). The abnormal expressions of gelatinases are implicated in the pathogenesis of extracellular matrix (ECM) accumulation. Apolipo-protein E (apoE) is an important plasma protein in cholesterol homeostasis and plays a key role in the progression of glomerulosclerosis (GS). We conducted this investigation to explore whether gelatinases were associated with the apoE accumulation in the pathological process of GS. METHODS: 40 Wistar rats were divided into two groups at random: sham operation group (SHO) and glomerulosclerosis model group (GS); n=20, respectively. The disease of GS was established by uninephrectomy and adriamycin (5 mg/kg) injection. At the end of 13 weeks, the 20 rats in each group were killed and the relevant samples were collected and measured. RESULTS: Serum total protein (TP) and serum albumin (Alb) in GS group were reduced compared to those of the SHO group (P<0.01). Compared with the SHO group, values of 24-hour urine total protein (24UTP), 24-hour urine excretion for albumin (24Ualb), blood urea nitrogen (BUN), serum creatinine (Scr) and glomerulosclerosis index (GSI) in GS group were significantly increased (P<0.01). The protein of MMP-2 or MMP-9 in the glomerulus, and mRNA expression of MMP-2 or MMP-9 in renal tissue were reduced when compared with those in SHO (P<0.01). Protein expressions of apoE, collagen IV (Col-IV), fibronectin (FN), alpha-smooth muscle actin (alpha-SMA) and transforming growth factor-beta1 (TGF beta1) in the glomerulus and expression of apoE mRNA in renal tissue were significantly up-regulated in GS group when compared with those in the SHO group (P<0.01). CONCLUSIONS: Lower expression of gelatinases is associated with the increased expression of apoE in the glomerulus, and increases the accumulation of ECM and takes part in the pathological change of GS. PMID- 22207561 TI - CD4 count is associated with postoperative infection in patients with orthopaedic trauma who are HIV positive. AB - BACKGROUND: Since the advent of effective antiretroviral therapy, the number of people with AIDS has increased and a certain percentage of these patients will require emergent orthopaedic surgery. Little is known regarding orthopaedic infections and the association of CD4 counts with postoperative infection in patients with HIV infection who experience orthopaedic trauma. QUESTIONS/PURPOSES: We questioned whether the postoperative infection rate is higher after orthopaedic trauma surgery for patients who are HIV positive than for patients who are HIV negative undergoing similar surgery and aimed to identify preoperative variables that may be important in predicting postoperative infection in patients who are HIV positive. METHODS: We determined the postoperative infection rate in 64 patients who were HIV positive and who underwent orthopaedic surgery requiring instrumentation or an implant from January 2001 to May 2007. We compared this rate with historical control data from 2003 to 2007 for all orthopaedic procedures at Grady Memorial Hospital. We examined numerous preoperative variables for association with postoperative infection, including CD4 count, length of inpatient stay, polytrauma, and malnutrition. RESULTS: Of the 64 patients, 15 had postoperative infections develop with an infection rate of 23%, compared with the 3.9% rate for the historical control subjects. Analysis of the 64 patients who were HIV positive revealed CD4 counts less than 300 were associated with development of postoperative infection. Hospital stay, polytrauma, and low serum albumin also were found to be associated with postoperative infection. CONCLUSIONS: It is evident that patients who are HIV positive with low CD4 counts undergoing emergent orthopaedic intervention are a patient population at risk for infection. Further study is necessary to evaluate preoperative and perioperative interventions that may decrease infections in this population. LEVEL OF EVIDENCE: Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22207562 TI - Obituary: George Dewey Purvis Jr. MD (1920-2011). PMID- 22207563 TI - Arthroscopy: editorial comment. PMID- 22207564 TI - Biographical sketch: James Stephen Ewing, MD (1844-1943). PMID- 22207565 TI - Relationship between air pollution, NFE2L2 gene polymorphisms and childhood asthma in a Hungarian population. AB - Air pollution and subsequent increased oxidative stress have long been recognized as contributing factors for asthma phenotypes. Individual susceptibility to oxidative stress is determined by genetic variations of the antioxidant defence system. In this study, we analysed the association between environmental nitrogen dioxide (NO(2)) exposure and single nucleotide polymorphisms (SNP) in NFE2L2 and KEAP1 genes and their common impact on asthma risk. We genotyped 12 SNPs in a case-control study of 307 patients diagnosed with asthma and 344 controls. NO(2) concentration was collected from the period preceding the development of asthma symptoms. Multiple logistic regression was applied to evaluate the effects of the studied genetic variations on asthma outcomes in interaction with NO(2) exposure. Our data showed that genotypes of rs2588882 and rs6721961 in the regulatory regions of the NFE2L2 gene were inversely associated with infection-induced asthma (odds ratio (OR) = 0.290, p = 0.0015, and OR = 0.437, p = 0.007, respectively). Furthermore, case-only analyses revealed significant differences for these SNPs between asthma patients that lived in modestly or highly polluted environment (OR = 0.43 (0.23-0.82), p = 0.01, and OR = 0.51, p = 0.02, respectively, in a dominant model). In conclusion, our results throw some new light upon the impact of NFE2L2 polymorphisms on infection-induced asthma risk and their effect in gene-environment interactions. PMID- 22207566 TI - Optimization of injection dose based on noise-equivalent count rate with use of an anthropomorphic pelvis phantom in three-dimensional 18F-FDG PET/CT. AB - The optimal injection dose for imaging of the pelvic region in 3D FDG PET tests was investigated based on the noise-equivalent count (NEC) rate with use of an anthropomorphic pelvis phantom. Count rates obtained from an anthropomorphic pelvis phantom were compared with those of pelvic images of 60 patients. The correlation between single photon count rates obtained from the pelvic regions of patients and the doses per body weight was also evaluated. The radioactivity at the maximum NEC rate was defined as an optimal injection dose, and the optimal injection dose for the body weight was evaluated. The image noise of a phantom was also investigated. Count rates obtained from an anthropomorphic pelvis phantom corresponded well with those from the human pelvis. The single photon count rate obtained from the phantom was 9.9 Mcps at the peak NEC rate. The coefficient of correlation between the single photon count rate and the dose per weight obtained from patient data was 0.830. The optimal injection doses for a patient with weighing 60 kg were estimated to be 375 MBq (6.25 MBq/kg) and 435 MBq (7.25 MBq/kg) for uptake periods of 60 and 90 min, respectively. The image noise was minimal at the peak NEC rate. We successfully estimated the optimal injection dose based on the NEC rate in the pelvic region on 3D FDG PET tests using an anthropomorphic pelvis phantom. PMID- 22207567 TI - Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review. AB - BACKGROUND: Oral adverse events (OAEs) associated with multitargeted tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors (mTORIs) are underestimated but frequent and novel presentations of mucosal manifestations. Because optimal antitumor activity requires maintaining the optimal dose, it is essential to avoid unintended treatment delays or interruptions. METHODS: We review the reported prevalence and appearance of OAEs with TKIs and mTORIs and the current oral assessment tools commonly used in clinical trials. We discuss the correlations between OAEs and hand-foot skin reaction (HFSR) and rash. RESULTS: The reported prevalence of oral mucositis/stomatitis of any grade is 4% for pazopanib, 28% for sorafenib, 38% for sunitinib, 41% for temsirolimus, and 44% for everolimus. Oral lesions associated with these agents have been reported to more closely resemble aphthous stomatitis than OM caused by conventional agents. In addition, these agents may result in symptoms such as oral mucosal pain, dysgeusia, and dysphagia, in the absence of clinical lesions. Because of these factors, OAEs secondary to targeted agents may be underreported. In addition, a correlation between OAEs and HFSR was identified. CONCLUSIONS: OAEs caused by TKIs and mTORIs may represent dose limiting toxicities, especially considering the fact that even low grades of OAEs may be troubling to the patient. We discuss how these novel AEs can be assessed because current mucositis assessment tools have limitations. Prospective studies investigating the pathogenesis, risk factors, and management of OAEs are needed in order to minimize the impact on patient's health-related quality of life. PMID- 22207569 TI - Dissociation chemistry of hydrogen-deficient radical peptide anions. AB - The fragmentation chemistry of anionic deprotonated hydrogen-deficient radical peptides is investigated. Homolytic photodissociation of carbon-iodine bonds with 266 nm light is used to generate the radical species, which are subsequently subjected to collisional activation to induce further dissociation. The charges do not play a central role in the fragmentation chemistry; hence deprotonated peptides that fragment via radical directed dissociation do so via mechanisms which have been reported previously for protonated peptides. However, charge polarity does influence the overall fragmentation of the peptide. For example, the absence of mobile protons favors radical directed dissociation for singly deprotonated peptides. Similarly, a favorable dissociation mechanism initiated at the N-terminus is more notable for anionic peptides where the N-terminus is not protonated (which inhibits the mechanism). In addition, collisional activation of the anionic peptides containing carbon-iodine bonds leads to homolytic cleavage and generation of the radical species, which is not observed for protonated peptides presumably due to competition from lower energy dissociation channels. Finally, for multiply deprotonated radical peptides, electron detachment becomes a competitive channel both during the initial photoactivation and following subsequent collisional activation of the radical. Possible mechanisms that might account for this novel collision-induced electron detachment are discussed. PMID- 22207568 TI - Probing the 3-D structure, dynamics, and stability of bacterial collagenase collagen binding domain (apo- versus holo-) by limited proteolysis MALDI-TOF MS. AB - Pairing limited proteolysis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) to probe clostridial collagenase collagen binding domain (CBD) reveals the solution dynamics and stability of the protein, as these factors are crucial to CBD effectiveness as a drug-delivery vehicle. MS analysis of proteolytic digests indicates initial cleavage sites, thereby specifying the less stable and highly accessible regions of CBD. Modulation of protein structure and stability upon metal binding is shown through MS analysis of calcium-bound and cobalt-bound CBD proteolytic digests. Previously determined X-ray crystal structures illustrate that calcium binding induces secondary structure transformation in the highly mobile N-terminal arm and increases protein stability. MS-based detection of exposed residues confirms protein flexibility, accentuates N-terminal dynamics, and demonstrates increased global protein stability exported by calcium binding. Additionally, apo- and calcium-bound CBD proteolysis sites correlate well with crystallographic B factors, accessibility, and enzyme specificity. MS-observed cleavage sites with no clear correlations are explained either by crystal contacts of the X-ray crystal structures or by observed differences between Molecules A and B in the X ray crystal structures. The study newly reveals the absence of the betaA strand and thus the very dynamic N-terminal linker, as corroborated by the solution X ray scattering results. Cobalt binding has a regional effect on the solution phase stability of CBD, as limited proteolysis data implies the capture of an intermediate-CBD solution structure when cobalt is bound. PMID- 22207570 TI - Eleusine indica L. possesses antioxidant activity and precludes carbon tetrachloride (CCl4)-mediated oxidative hepatic damage in rats. AB - OBJECTIVES: The purpose of this study was to evaluate the ability of aqueous extract of Eleusine indica to protect against carbon tetrachloride (CCl4)-induced hepatic injury in rats. METHODS: The antioxidant activity of E. indica was evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay. The total phenolic content of E. indica was also determined. Biochemical parameters [e.g. alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), glutathione (GSH), catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase and quinone reductase] were used to evaluate hepatic damage in animals pretreated with E. indica and intoxicated with CCl4. CCl4-mediated hepatic damage was also evaluated by histopathologically. RESULTS: E. indica extract was able to reduce the stable DPPH level in a dose-dependent manner. The half maximal inhibitory concentration (IC50) value was 2350 MUg/ml. Total phenolic content was found to be 14.9 +/- 0.002 mg/g total phenolic expressed as gallic acid equivalent per gram of extract. Groups pretreated with E. indica showed significantly increased activity of antioxidant enzymes compared to the CCl4-intoxicated group (p < 0.05). The increased levels of serum ALT and AST were significantly prevented by E. indica pretreatment (p < 0.05). The extent of MDA formation due to lipid peroxidation was significantly reduced (p < 0.05), and reduced GSH was significantly increased in a dose-dependently manner (p < 0.05) in the E. indica-pretreated groups as compared to the CCl4-intoxicated group. The protective effect of E. indica was further evident through decreased histopathological alterations in the liver. CONCLUSION: The results of our study indicate that the hepatoprotective effects of E. indica might be ascribable to its antioxidant and free radical scavenging property. PMID- 22207571 TI - Characteristics of reactive oxygen metabolites in serum of early teenagers in Japan. AB - OBJECTIVES: The relationship between the incidence of cardiovascular disease and the state of oxidative stress in blood has been studied to some extent. Several lines of evidence underscore the importance of primary prevention of cardiovascular disease beginning in childhood. However, little is known about the current state of oxidative stress in childhood. This study was carried out to determine the current state of the level of reactive oxygen metabolites (ROM) in serum of early teenagers. METHODS: This study enrolled 595 healthy junior high school students from the town of Nanbu located in northern Japan. Oxidative stress was evaluated by measuring the serum level of ROM, and antioxidant capacity was evaluated by measuring the serum level of biological antioxidant potential (BAP). RESULTS: Although the ROM level in female students [308.6 +/- 63.1 Carratelli units (U.CARR)] was slightly higher than that in males (299.9 +/- 55.2 U.CARR), the difference was not statistically significant. The BAP level in males was significantly higher than that in females. The levels of ROM and BAP detected in males in the first grade were higher than those in the other grades. In females, only first-graders' BAP was higher than that in other grades. CONCLUSIONS: The current study found that the ROM level in males was negatively correlated with grade. These results suggest the presence of factor(s) that increase oxidative stress in Japanese puberty. PMID- 22207572 TI - Positive autoregulation of a KNOX gene is essential for shoot apical meristem maintenance in rice. AB - Self-maintenance of the shoot apical meristem (SAM), from which aerial organs are formed throughout the life cycle, is crucial in plant development. Class I Knotted1-like homeobox (KNOX) genes restrict cell differentiation and play an indispensable role in maintaining the SAM. However, the mechanism that positively regulates their expression is unknown. Here, we show that expression of a rice (Oryza sativa) KNOX gene, Oryza sativa homeobox1 (OSH1), is positively regulated by direct autoregulation. Interestingly, loss-of-function mutants of OSH1 lose the SAM just after germination but can be rescued to grow until reproductive development when they are regenerated from callus. Double mutants of osh1 and d6, a loss-of-function mutant of OSH15, fail to establish the SAM both in embryogenesis and regeneration. Expression analyses in these mutants reveal that KNOX gene expression is positively regulated by the phytohormone cytokinin and by KNOX genes themselves. We demonstrate that OSH1 directly binds to five KNOX loci, including OSH1 and OSH15, through evolutionarily conserved cis-elements and that the positive autoregulation of OSH1 is indispensable for its own expression and SAM maintenance. Thus, the maintenance of the indeterminate state mediated by positive autoregulation of a KNOX gene is an indispensable mechanism of self maintenance of the SAM. PMID- 22207573 TI - Plant oxygen sensing is mediated by the N-end rule pathway: a milestone in plant anaerobiosis. AB - Like all aerobic organisms, plants require molecular oxygen for respiratory energy production. In plants, hypoxic conditions can occur during natural events (e.g., flooding), during developmental processes (e.g., seed germination), and in cells of compact tissues with high metabolic rates. Plant acclimation responses to hypoxia involve a modulation of gene expression leading to various biochemical, physiological, and morphological changes that stave off eventual anoxia. In contrast with the animal kingdom, a direct oxygen-sensing mechanism in plants has been elusive so far. However, two recent independent studies show that oxygen sensing in plants operates via posttranslational regulation of key hypoxia response transcription factors by the N-end rule pathway. The N-end rule is an evolutionarily conserved pathway for protein degradation that relates the fate of a protein with the identity of its N-terminal residues. Results from these studies demonstrate that oxygen-dependent modification and targeted proteolysis of members of the ethylene response factor group VII transcription factor family regulate hypoxia-responsive gene expression in Arabidopsis thaliana. The discovery of this plant hypoxia-sensing mechanism sets the stage for further research on plant homeostatic response to oxygen, which could be relevant to understanding plant distributions in flood-prone ecosystems and improving hypoxia tolerance of crops. PMID- 22207574 TI - Increased leaf angle1, a Raf-like MAPKKK that interacts with a nuclear protein family, regulates mechanical tissue formation in the Lamina joint of rice. AB - Mitogen-activated protein kinase kinase kinases (MAPKKKs), which function at the top level of mitogen-activated protein kinase cascades, are clustered into three groups. However, no Group C Raf-like MAPKKKs have yet been functionally identified. We report here the characterization of a rice (Oryza sativa) mutant, increased leaf angle1 (ila1), resulting from a T-DNA insertion in a Group C MAPKKK gene. The increased leaf angle in ila1 is caused by abnormal vascular bundle formation and cell wall composition in the leaf lamina joint, as distinct from the mechanism observed in brassinosteroid-related mutants. Phosphorylation assays revealed that ILA1 is a functional kinase with Ser/Thr kinase activity. ILA1 is predominantly resident in the nucleus and expressed in the vascular bundles of leaf lamina joints. Yeast two-hybrid screening identified six closely related ILA1 interacting proteins (IIPs) of unknown function. Using representative IIPs, the interaction of ILA1 and IIPs was confirmed in vivo. IIPs were localized in the nucleus and showed transactivation activity. Furthermore, ILA1 could phosphorylate IIP4, indicating that IIPs may be the downstream substrates of ILA1. Microarray analyses of leaf lamina joints provided additional evidence for alterations in mechanical strength in ila1. ILA1 is thus a key factor regulating mechanical tissue formation at the leaf lamina joint. PMID- 22207576 TI - Activation of TRPA1 by luminal stimuli induces EP4-mediated anion secretion in human and rat colon. AB - In gastrointestinal (GI) physiology, anion and fluid secretion is an important function for host defense and is induced by changes in the luminal environment. The transient receptor potential A1 (TRPA1) channel is considered to be a chemosensor in several sensory tissues. Although the function of TRPA1 has been studied in GI motility, its contribution to the transepithelial ion transport system has rarely been discussed. In the present study, we investigated the secretory effect of the potential TRPA1 agonist allyl isothiocyanate (AITC) in rat and human colon using an Ussing chamber. The mucosal application of AITC (10( 6)-10(-3) M) induced Cl(-) and HCO(3)(-) secretion in a concentration-dependent manner, whereas the serosal application induced a significantly weaker effect. AITC-evoked anion secretion was attenuated by tissue pretreatment with piroxicam and prostaglandin (PG) E(2); however, this secretion was not affected by TTX, atropine, or extracellular Ca(2+) depletion. These experiments indicate that TRPA1 activation induces anion secretion through PG synthesis, independent of neural pathways in the colon. Further analysis also indicates that AITC-evoked anion secretion is mediated mainly by the EP(4) receptor subtype. The magnitude of the secretory response exhibited segmental heterogeneity in rat colon. Real time PCR analysis showed the segmental difference was corresponding to the differential expression of EP(4) receptor and cyclooxygenase-1 and -2. In addition, RT-PCR, in situ hybridization, and immunohistochemical studies showed TRPA1 expression in the colonic epithelia. Therefore, we conclude that the activation of TRPA1 in colonic epithelial cells is likely involved in the host defense mechanism through rapid anion secretion. PMID- 22207575 TI - Apolipoprotein A-IV regulates chylomicron metabolism-mechanism and function. AB - Dietary fat is an important mediator of atherosclerosis and obesity. Despite its importance in mediating metabolic disease, there is still much unknown about dietary fat absorption in the intestine and especially the detailed biological roles of intestinal apolipoproteins involved in that process. We were specifically interested in determining the physiological role of the intestinal apolipoprotein A-IV (A-IV) using A-IV knockout (KO) mice. A-IV is stimulated by fat absorption in the intestine and is secreted on nascent chylomicrons into intestinal lymph. We found that A-IV KO mice had reduced plasma triglyceride (TG) and cholesterol levels and that this hypolipidemia persisted on a high-fat diet. A-IV KO did not cause abnormal intestinal lipid absorption, food intake, or adiposity. Additionally, A-IV KO did not cause abnormal liver TG and cholesterol metabolism, as assessed by measuring hepatic lipid content, lipogenic and cholesterol synthetic gene expression, and in vivo VLDL secretion. Instead, A-IV KO resulted in the secretion of larger chylomicrons from the intestine into the lymph, and those chylomicrons were cleared from the plasma more slowly than wild type chylomicrons. These data suggest that A-IV has a previously unknown role in mediating the metabolism of chylomicrons, and therefore may be important in regulating plasma lipid metabolism. PMID- 22207577 TI - Metabolism of [13C5]hydroxyproline in vitro and in vivo: implications for primary hyperoxaluria. AB - Hydroxyproline (Hyp) metabolism is a key source of glyoxylate production in the body and may be a major contributor to excessive oxalate production in the primary hyperoxalurias where glyoxylate metabolism is impaired. Important gaps in our knowledge include identification of the tissues with the capacity to degrade Hyp and the development of model systems to study this metabolism and how to suppress it. The expression of mRNA for enzymes in the pathway was examined in 15 different human tissues. Expression of the complete pathway was identified in liver, kidney, pancreas, and small intestine. HepG2 cells also expressed these mRNAs and enzymes and were shown to metabolize Hyp in the culture medium to glycolate, glycine, and oxalate. [(18)O]- and [(13)C(5)]Hyp were synthesized and evaluated for their use with in vitro and in vivo models. [(18)O]Hyp was not suitable because of an apparent tautomerism of [(18)O]glyoxylate between enol and hydrated forms, which resulted in a loss of isotope. [(13)C(5)]Hyp, however, was metabolized to [(13)C(2)]glycolate, [(13)C(2)]glycine, and [(13)C(2)]oxalate in vitro in HepG2 cells and in vivo in mice infused with [(13)C(5)]Hyp. These model systems should be valuable tools for exploring various aspects of Hyp metabolism and will be useful in determining whether blocking Hyp catabolism is an effective therapy in the treatment of primary hyperoxaluria. PMID- 22207580 TI - Functional reentry and circus movement arrhythmias in the small intestine of normal and diabetic rats. AB - In a few recent studies, the presence of arrhythmias based on reentry and circus movement of the slow wave have been shown to occur in normal and diseased stomachs. To date, however, reentry has not been demonstrated before in any other part of the gastrointestinal system. No animals had to be killed for this study. Use was made of materials obtained during the course of another study in which 11 rats were treated with streptozotocin and housed with age-matched controls. After 3 and 7 mo, segments of duodenum, jejunum, and ileum were isolated and positioned in a tissue bath. Slow wave propagation was recorded with 121 extracellular electrodes. After the experiment, the propagation of the slow waves was reconstructed. In 10 of a total of 66 intestinal segments (15%), a circus movement of the slow wave was detected. These reentries were seen in control (n = 2) as well as in 3-mo (n = 2) and 7-mo (n = 6) diabetic rats. Local conduction velocities and beat-to-beat intervals during the reentries were measured (0.42 +/ 0.15 and 3.03 +/- 0.67 cm/s, respectively) leading to a wavelength of 1.3 +/- 0.5 cm and a circuit diameter of 4.1 +/- 1.5 mm. This is the first demonstration of a reentrant arrhythmia in the small intestine of control and diabetic rats. Calculations of the size of the circuits indicate that they are small enough to fit inside the intestinal wall. Extrapolation based on measured velocities and rates indicate that reentrant arrhythmias are also possible in the distal small intestine of larger animals including humans. PMID- 22207578 TI - Lactobacillus reuteri strains reduce incidence and severity of experimental necrotizing enterocolitis via modulation of TLR4 and NF-kappaB signaling in the intestine. AB - Necrotizing enterocolitis (NEC) is the leading gastrointestinal cause of mortality and morbidity in the premature infant. Premature infants have a delay in intestinal colonization by commensal bacteria and colonization with potentially pathogenic organisms. Lactobacillus reuteri is a probiotic that inhibits enteric infections, modulates the immune system, and may be beneficial to prevent NEC. In previous studies, L. reuteri strains DSM 17938 and ATCC PTA 4659 differentially modulated inflammation in vitro; however, the strains had equivalent anti-inflammatory responses in LPS feeding-induced ileitis in neonatal rats in vivo. The impact of these two strains in the prevention of NEC has not been previously investigated. NEC was induced in newborn rats by orogastric formula feeding and exposure to hypoxia. L. reuteri was added to the formula to prevent NEC. NEC score, Toll-like receptor (TLR)-signaling genes, phospho-IkappaB activity, and cytokine levels in the intestine were examined. Both strains significantly increased survival rate and decreased the incidence and severity of NEC, with optimal effects from DSM 17938. In response to probiotic, mRNA expression of IL-6, TNF-alpha, TLR4, and NF-kappaB was significantly downregulated, while mRNA levels of anti-inflammatory cytokine IL-10 were significantly upregulated. In parallel, L. reuteri treatment led to decrease intestinal protein levels of TLR4 and cytokine levels of TNF-alpha and IL-1beta in newborn rats with NEC. Both strains significantly inhibited not only intestinal LPS-induced phospho-IkappaB activity in an ex vivo study but also decreased the levels of phospho-IkappaB in the intestines of NEC rat model. Cow milk formula feeding produced a similar but milder proinflammatory profile in the intestine that was also ameliorated by 17938. Our studies demonstrate that each of the two L. reuteri strains has potential therapeutic value in our NEC model and in enteritis associated with cow milk feeding. These results support the concept that L. reuteri may represent a valuable treatment to prevent NEC. PMID- 22207579 TI - Role of myosin Va in purinergic vesicular neurotransmission in the gut. AB - We examined the hypothesis that myosin Va, by transporting purinergic vesicles to the varicosity membrane for exocytosis, plays a key role in purinergic vesicular neurotransmission. Studies were performed in wild-type (WT) and myosin Va deficient dilute, brown, nonagouti (DBA) mice. Intracellular microelectrode recordings were made in mouse antral muscle strips. Purinergic inhibitory junction potential (pIJP) was recorded under nonadrenergic noncholinergic conditions after masking the nitrergic junction potentials. DBA mice showed reduced pIJP but normal hyperpolarizing response to P2Y1 receptor agonist MRS 2365. To investigate the mechanism of reduced purinergic transmission in DBA mice, studies were performed in isolated varicosities obtained from homogenates of whole gut tissues by ultracentrifugation and sucrose cushion purification. Purinergic varicosities were identified in tissue sections and in isolated varicosities by immunostaining for the vesicular ATP transporter, the solute carrier protein SLC17A9. The varicosities were similar in WT and DBA mice. Myosin Va was markedly reduced in DBA varicosities compared with the WT varicosities. Proximity ligation assay showed that myosin Va was closely associated with SLC17A9. Vesicular exoendocytosis was examined by FM1-43 staining of varicosities, which showed that exoendocytosis after KCl stimulation was impaired in DBA varicosities compared with WT varicosities. These studies show that SLC17A9 identifies ATP-containing purinergic varicosities. Myosin Va associates with SLC17A9-stained vesicles and possibly transports them to varicosity membrane for exocytosis. In myosin Va-deficient mice, purinergic inhibitory neurotransmission is impaired. PMID- 22207582 TI - Validation of uniaxial and triaxial accelerometers for the assessment of physical activity in preschool children. AB - PURPOSE: Given the unique physical activity (PA) patterns of preschoolers, wearable electronic devices for quantitative assessment of physical activity require validation in this population. Study objective was to validate uniaxial and triaxial accelerometers in preschoolers. METHODS: Room calorimetry was performed over 3 hours in 64 preschoolers, wearing Actical, Actiheart, and RT3 accelerometers during play, slow, moderate, and fast translocation. Based on activity energy expenditure (AEE) and accelerometer counts, optimal thresholds for PA levels were determined by piecewise linear regression and discrimination boundary analysis. RESULTS: Established HR cutoffs in preschoolers for sedentary/light, light/moderate and moderate/vigorous levels were used to define AEE (0.015, 0.054, 0.076 kcal.kg-1.min-1) and PA ratio (PAR; 1.6, 2.9, 3.6) thresholds, and accelerometer thresholds. True positive predictive rates were 77%, 75%, and 76% for sedentary; 63%, 61%, and 65% for light; 34%, 52%, and 49% for moderate; 46%, 46%, and 49% for vigorous levels. Due to low positive predictive rates, we combined moderate and vigorous PA. Classification accuracy was improved overall and for the combined moderate-to-vigorous PA level (69%, 82%, 79%) for Actical, Actiheart, and RT3, respectively. CONCLUSION: Uniaxial and triaxial accelerometers are acceptable devices with similar classification accuracy for sedentary, light, and moderate-to-vigorous levels of PA in preschoolers. PMID- 22207581 TI - Significance of para-esophageal lymph nodes in food or aeroallergen-induced iNKT cell-mediated experimental eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disorder driven by food hypersensitivity; however, the specific foods and mechanisms involved are unclear. In patients with EoE, we have found that hypersensitivities to corn and peanuts are the most common. Accordingly, we sensitized and exposed mice either intranasally or intragastrically with corn or peanut extract or saline. Esophageal eosinophilia, the genes of eosinophil-directed cytokines, and allergen-induced antibodies were examined in mice challenged with corn or peanut extract or saline. A high number of esophageal lamina propria eosinophils as well as eosinophilic microabscesses, intraepithelial eosinophils, extracellular eosinophilic granules, thickened and disrupted epithelial mucosa, and mast cell hyperplasia were observed in the esophagus of peanut or corn allergen-challenged mice. Mechanistic analysis indicated that para-esophageal lymph nodes might be critical in the trafficking of eosinophils to the esophagus and in EoE association to airway eosinophilia. Furthermore, experimentation with gene targeted mice revealed that peanut allergen-induced EoE was dependent on eotaxin and invariant natural killer T (iNKT) cells, as CD1d and eotaxin-1/2 gene deficient mice were protected from disease induction. Thus we provide evidence that para-esophageal lymph nodes are involved in food- or aeroallergen-induced eosinophilia and patchy EoE pathogenesis, likely a mechanism dependent on eotaxins and iNKT cells. PMID- 22207583 TI - Failure to clear intra-monocyte HIV infection linked to persistent neuropsychological testing impairment after first-line combined antiretroviral therapy. AB - HIV-associated neurocognitive disorders (HAND) persist despite plasma HIV RNA suppression with antiretrovirals (ARV). Sequestered reservoirs in the central nervous system and circulating monocytes are theorized to contribute to persistent brain injury. We previously demonstrated that elevated intracellular HIV DNA from circulating cells was associated with HAND in ARV-treated and ARV naive subjects. We now report that failure to suppress intra-monocyte HIV DNA 3.5 years after initiating ARV is linked to persistent HAND and subjects with dementia are least likely to suppress intra-monocyte HIV DNA at 3.5 years. These findings suggest that antiviral strategies may need to target intra-monocyte HIV DNA. PMID- 22207586 TI - Investigation on ultrasound-assisted extraction and separation of enduracidin from Streptomyces sp. NJWGY3665. AB - Ultrasound-assisted extraction of enduracidin from Streptomyces sp. NJWGY3665 was studied. The effects of various factors on the yield of target components were investigated. The results showed that the extraction by ultrasound-assisted extraction is four times faster than those by conventional solvent extraction. The results also indicated that fast extraction rate was obtained in the first 30 min, and the maximum yield was obtained at the power of 150 W. The effects of other factors such as different solvents, solvent concentration, solvent to solid ratio, and extraction batches on the field were also discussed. The optimum conditions were found at solvent of methanol, time of 30 min, power of 150 W, pH of 7.0, solvent to solid ratio of 50 ml/g, solvent concentration of 70% and extraction batches of four times. PMID- 22207584 TI - The herpes simplex virus type 1 latency associated transcript locus is required for the maintenance of reactivation competent latent infections. AB - Herpes simplex virus (HSV) establishes latent infections in sensory neurons from which it can periodically reactivate and cause recurrent disease and transmission to new hosts. Little is known about the virally encoded mechanisms that influence the maintenance of HSV latent infectious and modulate the frequency of virus reactivation from the latent state. Here, we report that the latency associated transcript locus of HSV-1 is required for long-term maintenance of reactivation competent latent infections. PMID- 22207585 TI - Neuromuscular complications in HIV: effects of aging. AB - There has been speculation that chronic HIV infection is a condition of accelerated aging that may lead to early onset of disease in multiple organ systems. The neuromuscular disorders of HIV, in particular distal symmetric polyneuropathy and myopathies, are also seen in the general population among older patients. As the HIV-infected population ages, there may be deleterious synergistic effects of age and chronic HIV infection on the brain, peripheral nerve, and muscle. In this review, we explore commonalities between the clinical features and putative mechanisms of neuromuscular disorders and HIV. PMID- 22207587 TI - Exhausted jackknife validation exemplified by prediction of temperature optimum in enzymatic reaction of cellulases. AB - This was the continuation of our previous study along the same line with more focus on technical details because the data are usually divided into two datasets, one for model development and the other for model validation during the development of predictive model. The widely used validation method is the delete 1 jackknife validation. However, no systematical studies were conducted to determine whether the jackknife validation with different deletions works better because the number of validations with different deletions increases in a factorial fashion. Therefore it is only small dataset that can be used for such an exhausted study. Cellulase is an enzyme playing an important role in modern industry, and many parameters related to cellulase in enzymatic reactions were poorly documented. With increased interests in cellulases in bio-fuel industry, the prediction of parameters in enzymatic reactions is listed on agenda. In this study, two aims were defined (a) which amino acid property works better to predict the temperature optimum and (b) with which deletion the jackknife validation works. The results showed that the amino acid distribution probability works better in predicting the optimum temperature of catalytic reaction by cellulase, and the delete-4, more precisely one-fifth deletion, jackknife validation works better. PMID- 22207588 TI - Kinetics of alloxan-induced inhibition on delta-aminolevulinate dehydratase activity in mouse liver homogenates. AB - This study evaluated the effects of alloxan on the kinetics properties of the delta-aminolevulinate dehydratase (delta-ALA-D) using mouse liver homogenates. delta-ALA-D is an important sulfhydryl enzyme that catalyses the second step in heme biosynthesis and is commonly diminished in experimental and human diabetes. Despite the known effects of alloxan in models of experimental diabetes, there are no data in the literature demonstrating the effects of alloxan on the kinetics properties of the delta-ALA-D. The results showed that alloxan (1.25-20 MUM) caused a concentration-dependent inhibition of hepatic delta-ALA-D activity. The inhibition constant (K(i)) for alloxan-induced inhibition on delta-ALA-D was 3.64 MUM. The alloxan (5 MUM) caused a decrease in V(max) (65.8%) and in K(m) (53.1%), which is suggestive of an uncompetitive inhibition of enzyme. In addition, dithiothreitol (700 and 1,000 MUM) completely prevented the delta-ALA-D activity inhibition induced by 10 and 20 MUM alloxan. Similar protection was obtained in the presence of 2,000 MUM glutathione. Therefore, this work showed that the inhibition of hepatic delta-ALA-D activity can be obtained in vitro at low micromolar levels of alloxan, and can also be prevented by reducing agents. Moreover, these results may help to understand the abnormalities in heme pathway found in models of experimental diabetes in vivo. PMID- 22207589 TI - Brief physical activity-related psychosocial measures: reliability and construct validity. AB - BACKGROUND: Psychosocial factors have been related to physical activity (PA) and are used to evaluate mediation in PA interventions. METHODS: Brief theory-based psychosocial scales were compiled from existing measures and evaluated. Study 1 assessed factor structure and construct validity with self-reported PA and accelerometry in overweight/obese men (N = 441) and women (N = 401). Study 2 assessed 2-week reliability and internal consistency in 49 college students. RESULTS: Confirmatory factor analysis indicated good fit in men and women (CFI = .90; RMSEA = .05). Construct validity was supported for change strategies (r = .29-.46), self-efficacy (r = .19-.22) and enjoyment (r = .21-.33) in men and women, and for cons in women (r = -.19 to -.20). PA pros (r = -.02 to .11) and social support (r = -.01 to .12) were not supported for construct validity. Test retest reliability ICCs ranged from .49-.81. Internal consistency alphas ranged from .55-.90. Reliability was supported for most scales with further testing needed for cons (alphas = .55-.63) and enjoyment (ICC = .49). CONCLUSIONS: Many of the brief scales demonstrated adequate reliability and validity, while some need further development. The use of these scales could advance research and practice in the promotion of PA. PMID- 22207590 TI - Upregulation of osmo-mechanosensitive TRPV4 channel facilitates chronic hypoxia induced myogenic tone and pulmonary hypertension. AB - Chronic hypoxia causes pulmonary hypertension with vascular remodeling, increase in vascular tone, and altered reactivity to agonists. These changes involve alterations in multiple Ca(2+) pathways in pulmonary arterial smooth muscle cells (PASMCs). We have previously shown that vanilloid (TRPV)- and melastatin-related transient receptor potential (TRPM) channels are expressed in pulmonary arteries (PAs). Here we found that TRPV4 was the only member of the TRPV and TRPM subfamilies upregulated in PAs of chronic hypoxic rats. The increase in TRPV4 expression occurred within 1 day of hypoxia exposure, indicative of an early hypoxic response. TRPV4 in PASMCs were found to be mechanosensitive. Osmo mechanical stress imposed by hypotonic solution activated Ca(2+) transients; they were inhibited by TRPV4 specific short interfering RNA, the TRPV blocker ruthenium red, and the cytochrome P450 epoxygenase inhibitor N-(methylsulfonyl)-2 (2-propynyloxy)-benzenehexanamide. Consistent with TRPV4 upregulation, the Ca(2+) response induced by the TRPV4 agonist 4alpha-phorbol 12,13-didecanoate and hypotonicity was potentiated in hypoxic PASMCs. Moreover, a significant myogenic tone, sensitive to ruthenium red, was observed in pressurized endothelium denuded small PAs of hypoxic but not normoxic rats. The elevated basal intracellular Ca(2+) concentration in hypoxic PASMCs was also reduced by ruthenium red. In extension of these results, the development of pulmonary hypertension, right heart hypertrophy, and vascular remodeling was significantly delayed and suppressed in hypoxic trpv4(-/-) mice. These results suggest the novel concept that TRPV4 serves as a signal pathway crucial for the development of hypoxia induced pulmonary hypertension. Its upregulation may provide a pathogenic feed forward mechanism that promotes pulmonary hypertension via facilitated Ca(2+) influx, subsequently enhanced myogenic tone and vascular remodeling. PMID- 22207592 TI - The influence of neighborhood socioeconomic status and walkability on TV viewing time. AB - BACKGROUND: Influences on TV viewing time, which is associated with adverse health outcomes such as obesity and diabetes, need clarification. We assessed the relation of neighborhood socioeconomic status (SES) and walkability with TV viewing time in the Black Women's Health Study, a prospective study of African American women. METHODS: We created neighborhood SES and walkability scores using data from the U.S. census and other sources. We estimated odds ratios for TV viewing 5+ hours/day compared with 0-1 hours/day for quintiles of neighborhood SES and walkability scores. RESULTS: Neighborhood SES was inversely associated with TV viewing time. The odds ratio for watching 5+ hours/day in the highest compared with the lowest quintile of neighborhood SES was 0.66 (95% CI 0.54 0.81). Neighborhood walkability was not associated with TV viewing time. CONCLUSIONS: Neighborhood SES should be considered in devising strategies to combat the high levels of sedentariness prevalent in African American women. PMID- 22207591 TI - Altered lymphatics in an ovine model of congenital heart disease with increased pulmonary blood flow. AB - Abnormalities of the lymphatic circulation are well recognized in patients with congenital heart defects. However, it is not known how the associated abnormal blood flow patterns, such as increased pulmonary blood flow (PBF), might affect pulmonary lymphatic function and structure. Using well-established ovine models of acute and chronic increases in PBF, we cannulated the efferent lymphatic duct of the caudal mediastinal node and collected and analyzed lymph effluent from the lungs of lambs with acutely increased PBF (n = 6), chronically increased PBF (n = 6), and age-matched normal lambs (n = 8). When normalized to PBF, we found that lymph flow was unchanged following acute increases in PBF but decreased following chronic increases in PBF. The lymph:plasma protein ratio decreased with both acute and chronic increases in PBF. Lymph bioavailable nitric oxide increased following acute increases in PBF but decreased following chronic increases in PBF. In addition, we found perturbations in the transit kinetics of contrast material through the pleural lymphatics of lambs with chronic increases in PBF. Finally, there were structural changes in the pulmonary lymphatic system in lambs with chronic increases in PBF: lymphatics from these lambs were larger and more dilated, and there were alterations in the expression of vascular endothelial growth factor-C, lymphatic vessel endothelial hyaluronan receptor-1, and Angiopoietin-2, proteins known to be important for lymphatic growth, development, and remodeling. Taken together these data suggest that chronic increases in PBF lead to both functional and structural aberrations of lung lymphatics. These findings have important therapeutic implications that warrant further study. PMID- 22207594 TI - Prevalence of extended-spectrum cephalosporinase (ESC)-producing Escherichia coli in Danish slaughter pigs and retail meat identified by selective enrichment and association with cephalosporin usage. AB - OBJECTIVES: To investigate the prevalence of extended-spectrum cephalosporinase (ESC)-producing Escherichia coli in pigs at slaughter and retail meat, and possible associations with the consumption of third- and fourth-generation cephalosporins. METHODS: During 2009, faecal samples from Danish pigs (n=786) were collected at slaughter, and 866 meat samples [Danish: pork (153), broiler meat (121) and beef (142); and imported: pork (173), broiler meat (193) and beef (84)] were randomly collected in retail stores and outlets. E. coli was isolated after enrichment in MacConkey broth with ceftriaxone (1 mg/L). ESC genotypes were detected using PCR, microtube array and sequencing. The MIC of cefotaxime was determined for 150 E. coli from the pigs and 606 E. coli from meat isolated without selective enrichment. RESULTS: Eleven percent (86/786) of slaughter pigs contained ESC E. coli and a significantly higher prevalence was observed among pigs originating from farms with registered cephalosporin consumption in slaughter pigs (P=0.034). Among ESC E. coli from pigs, 66% contained bla(CTX-M 1). From meat, a high prevalence of ESC E. coli was found in imported broiler meat (36%) compared with 0.7%-3.3% in other meat types. ESC E. coli from imported broiler meat (n=69) contained bla(CMY-2) (48%), bla(CTX-M-1) (25%) and bla(SHV 12) (16%). Without selective enrichment, no ESC E. coli from pigs and only 4.1% from imported broiler meat were found. CONCLUSIONS: The usage of cephalosporins for slaughter pigs may increase the prevalence of ESC E. coli in slaughter pigs. Meat may be a source of ESCs in humans, especially imported broiler meat. Selective enrichment should be considered as a supplementary surveillance method. PMID- 22207595 TI - Differential genetic hitchhiking around mutant pfcrt alleles in the Indian Plasmodium falciparum population. AB - OBJECTIVES: To study the origin and spread of the chloroquine-resistant Plasmodium falciparum population in the Indian subcontinent. METHODS: Fourteen microsatellites spanning a ~120 kb region, flanking the P. falciparum chloroquine resistance transporter (pfcrt) gene, were analysed in 185 parasite isolates. RESULTS: The Indian P. falciparum population exhibited a selective valley of reduced genetic variation in the flanking microsatellites of the mutant pfcrt alleles (up to +/-29 kb) as compared with the wild-type allele. This valley is much narrower than the +/-200 kb valley reported from African and South-East Asian countries. The majority of the isolates showed asymmetry in the selective valley, where upstream microsatellites showed less genetic variation than the downstream microsatellites. Regional variation in the width and symmetry of the selective valley was noticed, which seems to be related to the number of pfcrt alleles present in the parasite population of a region. Forty-six different microsatellite haplotypes were observed among the P. falciparum isolates containing mutant pfcrt alleles. Parasite populations from different regions of mainland India shared microsatellite haplotypes between them, but they shared none with the isolates from the Andaman and Nicobar Islands, and vice versa. Indian isolates shared microsatellite haplotypes with the isolates from Papua New Guinea and Thailand. CONCLUSIONS: With regard to chloroquine there is regional variation in the selection pressure on the P. falciparum population in India. These findings will help the regional implementation of drug policy in India's malaria control programme. PMID- 22207596 TI - Enhanced gonococcal antimicrobial surveillance in the era of ceftriaxone resistance: a real-time PCR assay for direct detection of the Neisseria gonorrhoeae H041 strain. AB - OBJECTIVES: Recent emergence of the extensively drug-resistant Neisseria gonorrhoeae H041 strain in Japan raises concerns that gonorrhoea may soon become untreatable and emphasizes the need for enhanced surveillance. In this study we developed a real-time PCR assay for direct detection of the H041 strain. METHODS: Two real-time PCR assays for detection of the penA gene of the H041 strain, H041 PCR1 and H041-PCR2, were developed and evaluated in parallel. Assay performance was assessed using a panel of pathogenic and commensal Neisseria species (n = 167 strains) including the N. gonorrhoeae H041 strain and clinical specimens (n = 252) submitted for sexual health screening. The detection limits of the assays were compared with a standard N. gonorrhoeae real-time PCR method. RESULTS: Both the H041-PCR1 and H041-PCR2 assays correctly detected the N. gonorrhoeae H041 strain and provided negative results for all other N. gonorrhoeae strains. However, only the H041-PCR2 assay proved to be specific when applied to the non gonococcal Neisseria species and clinical samples. False-positive results in the H041-PCR1 included cross-reactions with two Neisseria subflava isolates and eight clinical specimens. DNA sequencing of these N. subflava strains revealed the presence of the penicillin-binding protein 2 Ala328Thr alteration previously only observed in the N. gonorrhoeae H041 strain. CONCLUSIONS: The H041-PCR2 assay is suitable for direct detection of the N. gonorrhoeae H041 ceftriaxone-resistant strain in cultured and non-cultured samples. PMID- 22207597 TI - More about the safety of tigecycline for the treatment of infectious diseases: the role of superinfection rates. PMID- 22207598 TI - Lack of effect of extracorporeal membrane oxygenation on tigecycline pharmacokinetics. PMID- 22207599 TI - Insight into antimicrobial susceptibility and population structure of contemporary human Enterococcus faecalis isolates from Europe. AB - OBJECTIVES: To investigate antimicrobial susceptibility and clonal relatedness of Enterococcus faecalis human isolates recovered recently (2006-09) in six European countries. METHODS: Antimicrobial susceptibility of 386 isolates from Denmark, Germany, Norway, Poland, Spain and The Netherlands, from hospital infections (223 isolates), carriage (82 isolates) and from colonization in the community (81 isolates) was determined by the broth microdilution method. Clonal relatedness of isolates was assessed by multilocus sequence typing. RESULTS: All isolates were susceptible to benzylpenicillin, ampicillin, linezolid, tigecycline and daptomycin. Non-susceptibility to tetracycline (77.6%), rifampicin (57.3%), ciprofloxacin (51.2%), aminoglycosides (43.3% high-level gentamicin resistance, 40.0% high-level streptomycin resistance) was frequent among hospital isolates, while non-susceptibility to glycopeptides was rare and associated mostly with vanA. Multidrug resistance was found in 59.7% of hospital isolates and 16.1% of community isolates. Isolates were classified into 105 sequence types (STs), of which 21 STs, representing more than half of the collected isolates (53.9%), grouped with 6 large E. faecalis clonal complexes (CCs; CC2, CC16, CC21, CC30, CC40 and CC87). Two of these, CC2 (frequently recovered in Spain and The Netherlands) and CC87 (prevalent in Poland), were found almost exclusively in hospitals and included the highest proportion of multiresistant isolates. CONCLUSIONS: While hospital-acquired E. faecalis in Europe remains susceptible to ampicillin and glycopeptides, the high prevalence of strains that are highly resistant to aminoglycosides excludes these antibiotics from combination therapies. Genotyping revealed that nosocomial infections by multiresistant E. faecalis are largely caused by only a few hospital-associated clones. PMID- 22207600 TI - Validation of secondary commercial data sources for physical activity facilities in urban and nonurban settings. AB - BACKGROUND: Secondary data are often necessary to assess the availability of commercial physical activity (PA) facilities and examine its association with individual behaviors and outcomes, yet the validity of such sources has been explored only in a limited number of studies. METHODS: Field data were collected on the presence and attributes of commercial PA facilities in a random sample of 30 urban, 15 suburban, and 15 rural Census tracts in the Chicago metropolitan statistical area and surrounding area. RESULTS: Approximately 40% of PA establishments in the field data were listed for both urban and nonurban tracts in both lists except for nonurban tracts in D&B (35%), which was significantly improved in the combined list of D&B and InfoUSA. Approximately one-quarter of the PA facilities listed in D&B were found on the ground, whereas 40% to 50% of PA facilities listed in InfoUSA were found on the ground. PA establishments that offered instruction programs or lessons or that had a court or pool were less likely to be listed, particularly in the nonurban tracts. CONCLUSIONS: Secondary commercial business lists on PA facilities should be used with caution in assessing the built environment. PMID- 22207602 TI - Optimization of composition, structure and mechanical strength of bioactive 3-D glass-ceramic scaffolds for bone substitution. AB - Fabrication of 3-D highly porous, bioactive, and mechanically competent scaffolds represents a significant challenge of bone tissue engineering. In this work, Bioglass(r)-derived glass-ceramic scaffolds actually fulfilling this complex set of requirements were successfully produced through the sponge replication method. Scaffold processing parameters and sintering treatment were carefully designed in order to obtain final porous bodies with pore content (porosity above 70 %vol), trabecular architecture and mechanical properties (compressive strength up to 3 MPa) analogous to those of the cancellous bone. Influence of the Bioglass(r) particles size on the structural and mechanical features of the sintered scaffolds was considered and discussed. Relationship between porosity and mechanical strength was investigated and modeled. Three-dimensional architecture, porosity, mechanical strength and in vitro bioactivity of the optimized Bioglass(r)-derived scaffolds were also compared to those of CEL2-based glass ceramic scaffolds (CEL2 is an experimental bioactive glass originally developed by the authors at Politecnico di Torino) fabricated by the same processing technique, in an attempt at understanding the role of different bioactive glass composition on the major features of scaffolds prepared by the same method. PMID- 22207601 TI - Effects of surface modification of PLGA-PEG-PLGA nanoparticles on loperamide delivery efficiency across the blood-brain barrier. AB - In this study, we developed a nanoparticle system for drug delivery across the blood-brain barrier (BBB). The nanoparticle consisting of loperamide and poly(lactide-co-glycolide)-poly(ethylene glycol)-poly(lactide-co-glycolide) (PLGA PEG-PLGA) triblock copolymer were prepared by the nanoprecipitation method; then the nanoparticles were coated with poloxamer 188 or polysorbate 80. The effects of poloxamer 188 or polysorbate 80 on the physicochemical and pharmaceutical properties of the coated nanoparticles were investigated. Loperamide, which does not cross the blood-brain barrier (BBB) but exerts antinociceptive effects after direct injection into the brain, was encapsulated by different polymeric materials and used as a model drug. The in vitro BBB penetration study shows that the surfactant-coated PLGA-PEG-PLGA nanoparticles could have penetration of 14.4 21.2%, which was better than the PLGA-PEG-PLGA nanoparticles (PEP) (8.2%) and the PLGA nanoparticles (PN) (4.3%). The biopsy studies also confirm that the PEP coated by surfactant could increase the penetration. The results of nanoparticles accumulation in brain tissue show that the PEP coated by surfactant had a much higher concentration than both the PEP and the PN. Moreover, the maximal possible antinociception effect (MPE) for the surfactant-coated PEP was 21-35% at 150 min after administering the drug intravenously, which was significantly better than just the PEP (MPE: 11.6%). The results of the formalin test show that the surfactant-coated PEP administered intravenously 150 min prior to the formalin injection could greatly reduce the pain response in the first phase. The results demonstrate that the surfactant-coated PEP could help to deliver loperamide across the BBB. PMID- 22207603 TI - Assessment of multicomponent hydrogel scaffolds of poly(acrylic acid-2-hydroxy ethyl methacrylate)/gelatin for tissue engineering applications. AB - The article describes the design of the multicomponent hydrogel system of poly(acrylic acid-HEMA)/gelatin for tissue engineering application. Derivative of polycaprolactone-diol (polycaprolactone diacrylate (PCL-DAr)) was used to cross link acrylate monomers whereas gelatin was kept free for cell proliferation. Epigallocatechin gallate (EGCG), an anti-oxidant phytochemical, was loaded by diffusion method. Its in vitro release study in PBS (pH 6.5) at 37 +/- 0.2 degrees C (75 rpm) revealed a sustained release profile upto 20 days. Fitting of drug release data in Korsmeyer-Peppas model equation revealed probable release mechanism through the value of release coefficient (n), which was found to depend on formulations composition. Drug-polymer interaction, thermal behavior, and surface morphology were investigated by attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, thermogravimetric analysis (TGA), and scanning electron microscopic (SEM). Swelling behavior of hydrogel in PBS (pH 6.5 and 7.4, 0.2 M) and in distilled water was found to increase with increasing AAc/HEMA ratio. Compression modulus decreased from 203 +/- 3.7 KPa to 11.6 +/- 1.1KPa, at 30% strain, whereas displacement values significantly increased from 3.2 +/- 0.2 to 4.7 +/- 0.6 mm at 20 N force (p < 0.05), with increasing AAc/HEMA ratio. Percentage cell viability was analyzed using indirect 3-[4, 5 dimethylthiazolyl-2]-2,5-diphenyltetrazo-liumbromide (MTT) assay with fibroblast L929 cells; showed >=92.3% cell viability after 24 h incubation. Cell proliferation on the scaffold surface was found to increase with incorporation of HEMA in P(AAc)/G cross-linked hydrogel matrix upto a certain extent. These biocompatible, elastic, and swellable hydrogels can serve as a matrix for drug delivery and tissue engineering applications. PMID- 22207604 TI - Ligation of the ovarian pedicles in dogs with a resorbable self-locking device--a long-term follow-up study. AB - A prospective clinical trial was performed to evaluate applicability, hemostatic efficiency, and long-term tissue reactions of a novel medical device. The device was made of polydioxanone and designed in principle as a cable-tie with a flexible band running through a locking case. It was tested for ligation of the ovarian pedicles during ovariohysterectomy in nine intact female dogs. The dogs were followed-up monthly by physical examination and ultrasonography of the abdomen for 5-12 months after surgery. Macroscopic and histological post mortem examinations were performed in two dogs 7 and 18 months after surgery. Hemostasis was achieved with the devices although 1 of the 18 devices needed further tightening during a reoperation. Ultrasonography revealed a hyperechoic device that caused acoustic shadowing, which decreased over time indicating gradual resorption. Post mortem examinations demonstrated adhesions and a local transient tissue reaction at site of the device. The results show that the device may be a future alternative for ligation of ovarian pedicles in dogs. PMID- 22207605 TI - Neomycin and carbodiimide crosslinking as an alternative to glutaraldehyde for enhanced durability of bioprosthetic heart valves. AB - Glutaraldehyde cross-linked porcine aortic valves, referred to as bioprosthetic heart valves (BHVs), are often used in heart valve replacements. Glutaraldehyde does not stabilize glycosaminoglycans (GAGs) and they are lost during preparation, in vivo implantation, cyclic fatigue, and storage. We report that binding of neomycin, a hyaluronidase inhibitor, to the tissues with carbodiimide cross-linking improves GAG retention without reducing collagen and elastin stability. It also led to improved biomechanical properties. Neomycin carbodiimide cross-linking did not significantly reduce calcification in a rat subdermal implantation model when they were stored in formaldehyde after cross linking. Removal of formaldehyde storage significantly reduced calcification. PMID- 22207606 TI - Influence of screw holes and gamma sterilization on properties of phosphate glass fiber-reinforced composite bone plates. AB - Polymers prepared from polylactic acid (PLA) have found a multitude of uses as medical devices. For a material that degrades, the main advantage is that an implant would not necessitate a second surgical event for removal. In this study, fibers produced from a quaternary phosphate-based glass (PBG) in the system 50P2O5-40CaO-5Na2O-5Fe2O3 were used to reinforce PLA polymer. The purpose of this study was to assess the effect of screw holes in a range of PBG-reinforced PLA composites with varying fiber layup and volume fraction. The flexural properties obtained showed that the strength and modulus values increased with increasing fiber volume fraction; from 96 MPa to 320 MPa for strength and between 4 GPa and 24 GPa for modulus. Furthermore, utilizing a larger number of thinner unidirectional (UD) fiber prepreg layers provided a significant increase in mechanical properties, which was attributed to enhanced wet out and thus better fiber dispersion during production. The effect of gamma sterilization via flexural tests showed no statistically significant difference between the sterilized and nonsterilized samples, with the exception of the modulus values for samples with screw holes. Degradation profiles revealed that samples with screw holes degraded faster than those without screw holes due to an increased surface area for the plates with screw holes in PBS up to 30 days. Scanning electron microscope (SEM) analysis revealed fiber pullout before and after degradation. Compared with various fiber impregnation samples, with 25% volume fraction, 8 thinner unidirectional prepreg stacked samples had the shortest fiber pull-out lengths in comparison to the other samples investigated. PMID- 22207607 TI - An evaluation of the processing conditions, structure, and properties (biaxial flexural strength and antibacterial efficacy) of sintered strontium-zinc-silicate glass ceramics. AB - The use of artificial bone grafts has increased in order to satisfy a growing demand for bone replacement materials. Initial mechanical stability of synthetic bone grafts is very advantageous for certain clinical applications. Coupled with the advantage of mechanical strength, a material with inherent antibacterial properties would be very beneficial. A series of strontium-doped zinc silicate (Ca-Sr-Na-Zn-Si) glass ceramics have been characterized in terms of their crystalline structure, biaxial flexural strength and antibacterial efficacy based on the identification of optimum sintering conditions. All three glass ceramics, namely, BT110, BT111, and BT112 were found to be fully crystalline, with BT111 and BT112 comprising of biocompatible crystalline phases. The biaxial flexural strengths of the three glass ceramics ranged from 70 to 149 MPa and were shown to be superior to those of clinically established ceramics in dry conditions and following incubation in simulated physiological conditions. The bacteriostatic effect for each glass ceramic was also established, where BT112 showed an inhibitory effect against three of the most common bacteria found at implantation sites, namely, Enterococcus faecalis, methicillin-resistant Staphylococcus aureus (MRSA), and Pseudomonas aeruginosa. The results of the evaluation suggest that the materials studied offer advantages over current clinical materials and indicate the potential suitability of the glass ceramics as therapeutic bone grafts. PMID- 22207608 TI - Long-term biocompatibility and osseointegration of electron beam melted, free form-fabricated solid and porous titanium alloy: experimental studies in sheep. AB - The purpose of the present study was to evaluate the long-term osseointegration and biocompatibility of electron beam melted (EBM) free-form-fabricated (FFF titanium grade 5 (Ti6Al4V) implants. Porous and solid machined cylindrical and disk-shaped implants were prepared by EBM and implanted bilaterally in the femur and subcutaneously in the dorsum of the sheep. After 26 weeks, the implants and surrounding tissue were retrieved. The tissue response was examined qualitatively and quantitatively using histology and light microscopic (LM) morphometry. Selected bone implants specimens were evaluated by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), and micro-computed tomography (mCT). The results showed that both porous and solid implants were osseointegrated and high bone-implant contact was observed throughout the porous implant. In the soft tissue, the porous implants showed thinner fibrous encapsulation while no signs of intolerance were observed for either implant type. Taken together, the present experimental results show that FFF Ti6Al4V with and without porous structures demonstrate excellent long-term soft tissue biocompatibility and a high degree of osseointegration. The present findings extend earlier, short-term experimental observations in bone and suggest that EBM, FFF Ti6Al4V implants possess valuable properties in bone and soft tissue applications. PMID- 22207609 TI - Positive charge of chitosan retards blood coagulation on chitosan films. AB - In this study, a series of chitosan films with different protonation degrees were prepared by deacidification with NaOH aqueous or ethanol solutions. The films were then used as a model to investigate the effects of the positive charge of chitosan on blood coagulation. The results showed that the positive charge of chitosan acted as a double-edged sword, in that it promoted erythrocyte adhesion, fibrinogen adsorption, and platelet adhesion and activation, but inhibited activation of the contact system. In contrast to prevailing views, we found that the positive charge of chitosan retarded thrombin generation and blood coagulation on these films. At least two reasons were responsible for this phenomenon. First, the positive charge inhibited the contact activation, and second, the positive charge could not significantly promote the activation of non adherent platelets in the bulk phase during the early stage of coagulation. The present findings improve our understanding of the events leading to blood coagulation on chitosan films, which will be useful for the future development of novel chitosan-based hemostatic devices. PMID- 22207610 TI - Cellular interactions with biodegradable polyurethanes formulated from L tyrosine. AB - L-Tyrosine polyurethanes (LTUs) have been synthesized by structural modification of the poly (amino acid) backbone to circumvent the problems associated with the processing of poly (amino acids) arising from their high crystallinity, insolubility in common organic solvents, and high glass-transition and melting temperatures. Additionally, problems such as unpredictable swelling characteristics, change in conformation, and uncontrolled enzymatic degradation have severely restricted the use of poly (amino acids). In contrast, LTUs are designed to retain their superior physico-chemical properties, while incorporating biodegradability through enzymatic, hydrolytic, and oxidative pathways. The aim of this study is to evaluate initially the biocompatibility of LTUs and their degradation products. Studies involving primary dermal human fibroblasts cultured in contact with LTU films or degradation products suggest a lack of toxicity (cell viabilities >93% with p < 0.05 compared to the control for all studies). The diversity of LTU polymer chemistry and the ability of LTUs to phase separate seem to present a heterogeneous surface with variable wettability. This phenomenon influences the adhesion and proliferation of human fibroblasts on polymeric surfaces, wherein fibroblast adhesion on polycaprolactone diol (PCL) based LTUs is characterized by higher cell counts (81,250 +/- 18,390 for PCL-C DTH (desaminotyrosine-tyrosyl hexyl, DTH), 58,360 +/- 7370 for PCL-L-DTH, 38,480 +/- 12,680 for PEG-C-DTH (polyethylene glycol, PEG), and 46,430 +/- 16,000 for PEG-L-DTH at 120 h with p < 0.001 for comparison between PCL-C-DTH and all other LTUs), more rapid cellular proliferation (doubling time of 37-49 h for PCL-based LTUs compared to 68-90 h for PEG-based LTUs), and a uniform cell distribution compared to PEG-based LTUs. However, immunofluorescence assay for F-actin suggests that the cells are well attached. Thus, the lack of cytotoxicity and the ability to control cellular adhesion through polymer chemistry make LTUs attractive candidates for tissue-engineering applications that require elastomeric, biodegradable, and biocompatible polymers. PMID- 22207611 TI - Molecular chaperoning by glucose-regulated protein 170 in the extracellular milieu promotes macrophage-mediated pathogen sensing and innate immunity. AB - Recognition of pathogen-associated molecular patterns by innate immune receptors is essential for host defense responses. Although extracellular stress proteins are considered as indicators of the stressful conditions (e.g., infection or cell injury), the exact roles of these molecules in the extracellular milieu remain less defined. We found that glucose-regulated protein 170 (Grp170), the largest stress protein and molecular chaperone, is highly efficient in binding CpG oligodeoxynucleotides (CpG-ODN), the microbial DNA mimetic sensed by toll-like receptor 9 (TLR9). Extracellular Grp170 markedly potentiates the endocytosis and internalization of CpG-ODN by mouse bone marrow-derived macrophages and directly interacts with endosomal TLR9 on cell entry. These molecular collaborations result in the synergistic activation of the MyD88-dependent signaling and enhanced production of proinflammatory cytokines and nitric oxide in mouse primary macrophages as well as human THP-1 monocyte-derived macrophages, suggesting that Grp170 released from injured cells facilitates the sensing of pathogen-associated "danger" signals by intracellular receptors. This CpG-ODN chaperone complex-promoted innate immunity confers increased resistance in mice to infection of Listeria monocytogenes compared with CpG-ODN treatment alone. Our studies reveal a previously unrecognized attribute of Grp170 as a superior DNA binding chaperone capable of amplifying TLR9 activation on pathogen recognition, which provides a conceptual advance in understanding the dynamics of ancient chaperoning functions inside and outside the cell. PMID- 22207612 TI - Effects of soil nutrient heterogeneity on intraspecific competition in the invasive, clonal plant Alternanthera philoxeroides. AB - BACKGROUND AND AIMS: Fine-scale, spatial heterogeneity in soil nutrient availability can increase the growth of individual plants, the productivity of plant communities and interspecific competition. If this is due to the ability of plants to concentrate their roots where nutrient levels are high, then nutrient heterogeneity should have little effect on intraspecific competition, especially when there are no genotypic differences between individuals in root plasticity. We tested this hypothesis in a widespread, clonal species in which individual plants are known to respond to nutrient heterogeneity. METHODS: Plants derived from a single clone of Alternanthera philoxeroides were grown in the greenhouse at low or high density (four or 16 plants per 27.5 * 27.5-cm container) with homogeneous or heterogeneous availability of soil nutrients, keeping total nutrient availability per container constant. After 9 weeks, measurements of size, dry mass and morphology were taken. KEY RESULTS: Plants grew more in the heterogeneous than in the homogeneous treatment, showing that heterogeneity promoted performance; they grew less in the high- than in the low-density treatment, showing that plants competed. There was no interactive effect of nutrient heterogeneity and plant density, supporting the hypothesis that heterogeneity does not affect intraspecific competition in the absence of genotypic differences in plasticity. Treatments did not affect morphological characteristics such as specific leaf area or root/shoot ratio. CONCLUSIONS: Results indicate that fine-scale, spatial heterogeneity in the availability of soil nutrients does not increase competition when plants are genetically identical, consistent with the suggestion that effects of heterogeneity on competition depend upon differences in plasticity between individuals. Heterogeneity is only likely to increase the spread of monoclonal, invasive populations such as that of A. philoxeroides in China. PMID- 22207613 TI - Restoration of tensile strength in bark samples of Ficus benjamina due to coagulation of latex during fast self-healing of fissures. AB - BACKGROUND AND AIMS: The functions of plant latex have been discussed for a long time. Today, many studies support a defence mechanism as being its main function. A role as a self-healing mechanism was never attributed to the coagulation of latex. In this study we quantified the contribution of the coagulation of Ficus benjamina (weeping fig) latex to a restoration of the mechanical properties of the bark after external lesions. METHODS: Tensile tests of F. benjamina bark were conducted either immediately after injury or at various latency times after injury. KEY RESULTS: A significant increase in the tensile strength of bark samples until 30 min after injury was found, and this effect could be attributed to the coagulation of plant latex alone. The tensile strength remains nearly constant until several hours or days after injury. Then, very probably due to other mechanisms such as cell growth and cell proliferation, the tensile strength begins to increase slightly again. CONCLUSIONS: The coagulation of latex seals lesions and serves as a quick and effective pre-step of subsequent, more effective, long-lasting self-healing mechanisms such as cell growth and proliferation. Thus, a fast self-healing effect can be included in the list of functions of plant latex. PMID- 22207614 TI - Ultraconserved elements are novel phylogenomic markers that resolve placental mammal phylogeny when combined with species-tree analysis. AB - Phylogenomics offers the potential to fully resolve the Tree of Life, but increasing genomic coverage also reveals conflicting evolutionary histories among genes, demanding new analytical strategies for elucidating a single history of life. Here, we outline a phylogenomic approach using a novel class of phylogenetic markers derived from ultraconserved elements and flanking DNA. Using species-tree analysis that accounts for discord among hundreds of independent loci, we show that this class of marker is useful for recovering deep-level phylogeny in placental mammals. In broad outline, our phylogeny agrees with recent phylogenomic studies of mammals, including several formerly controversial relationships. Our results also inform two outstanding questions in placental mammal phylogeny involving rapid speciation, where species-tree methods are particularly needed. Contrary to most phylogenomic studies, our study supports a first-diverging placental mammal lineage that includes elephants and tenrecs (Afrotheria). The level of conflict among gene histories is consistent with this basal divergence occurring in or near a phylogenetic "anomaly zone" where a failure to account for coalescent stochasticity will mislead phylogenetic inference. Addressing a long-standing phylogenetic mystery, we find some support from a high genomic coverage data set for a traditional placement of bats (Chiroptera) sister to a clade containing Perissodactyla, Cetartiodactyla, and Carnivora, and not nested within the latter clade, as has been suggested recently, although other results were conflicting. One of the most remarkable findings of our study is that ultraconserved elements and their flanking DNA are a rich source of phylogenetic information with strong potential for application across Amniotes. PMID- 22207615 TI - Comparative RNA sequencing reveals substantial genetic variation in endangered primates. AB - Comparative genomic studies in primates have yielded important insights into the evolutionary forces that shape genetic diversity and revealed the likely genetic basis for certain species-specific adaptations. To date, however, these studies have focused on only a small number of species. For the majority of nonhuman primates, including some of the most critically endangered, genome-level data are not yet available. In this study, we have taken the first steps toward addressing this gap by sequencing RNA from the livers of multiple individuals from each of 16 mammalian species, including humans and 11 nonhuman primates. Of the nonhuman primate species, five are lemurs and two are lorisoids, for which little or no genomic data were previously available. To analyze these data, we developed a method for de novo assembly and alignment of orthologous gene sequences across species. We assembled an average of 5721 gene sequences per species and characterized diversity and divergence of both gene sequences and gene expression levels. We identified patterns of variation that are consistent with the action of positive or directional selection, including an 18-fold enrichment of peroxisomal genes among genes whose regulation likely evolved under directional selection in the ancestral primate lineage. Importantly, we found no relationship between genetic diversity and endangered status, with the two most endangered species in our study, the black and white ruffed lemur and the Coquerel's sifaka, having the highest genetic diversity among all primates. Our observations imply that many endangered lemur populations still harbor considerable genetic variation. Timely efforts to conserve these species alongside their habitats have, therefore, strong potential to achieve long-term success. PMID- 22207616 TI - Relations among student attention behaviors, teacher practices, and beginning word reading skill. AB - The role of student attention for predicting kindergarten word reading was investigated among 432 students. Using Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Rating Scale behavior rating scores, the authors conducted an exploratory factor analysis, which yielded three distinct factors that reflected selective attention. In this study, the authors focused on the role of one of these factors, which they labeled attention-memory, for predicting reading performance. Teacher ratings of attention-memory predicted word reading above and beyond the contribution of phonological awareness and vocabulary knowledge. In addition, the relations between four teacher practices and attention ratings for predicting reading performance were examined. Using hierarchical linear modeling, the authors found significant interactions between student attention and teacher practices observed during literacy instruction. In general, as ratings of attention improved, better kindergarten word reading performance was associated with high levels of classroom behavior management. However, better word reading performance was not associated with high levels of teacher task orienting. A significant three-way interaction was also found among attention, individualized instruction, and teacher task redirections. The role of regulating kindergarten student attention to support beginning word reading skill development is discussed. PMID- 22207617 TI - Transcript and protein profiling analysis of OTA-induced cell death reveals the regulation of the toxicity response process in Arabidopsis thaliana. AB - Ochratoxin A (OTA) is a toxic isocoumarin derivative produced by various species of mould which mainly grow on grain, coffee, and nuts. Recent studies have suggested that OTA induces cell death in plants. To investigate possible mechanisms of OTA phytotoxicity, both digital gene expression (DGE) transcriptomic and two-dimensional electrophoresis proteomic analyses were used, through which 3118 genes and 23 proteins were identified as being up- or down regulated at least 2-fold in Arabidopsis leaf in response to OTA treatment. First, exposure of excised Arabidopsis thaliana leaves to OTA rapidly causes the hypersensitive reponse, significantly accelerates the increase of reactive oxygen species and malondialdehyde, and enhances antioxidant enzyme defence responses and xenobiotic detoxification. Secondly, OTA stimulation causes dynamic changes in transcription factors and activates the membrane transport system dramatically. Thirdly, a concomitant persistence of compromised photosynthesis and photorespiration is indicative of a metabolic shift from a highly active to a weak state. Finally, the data revealed that ethylene, salicylic acid, jasmonic acid, and mitogen-activated protein kinase signalling molecules mediate the process of toxicity caused by OTA. Profiling analyses on Arabidopsis in response to OTA will provide new insights into signalling transduction that modulates the OTA phytotoxicity mechanism, facilitate mapping of regulatory networks, and extend the ability to improve OTA tolerance in Arabidopsis. PMID- 22207618 TI - Genome-wide metabolic network reconstruction of the picoalga Ostreococcus. AB - The green picoalga Ostreococcus is emerging as a simple plant model organism, and two species, O. lucimarinus and O. tauri, have now been sequenced and annotated manually. To evaluate the completeness of the metabolic annotation of both species, metabolic networks of O. lucimarinus and O. tauri were reconstructed from the KEGG database, thermodynamically constrained, elementally balanced, and functionally evaluated. The draft networks contained extensive gaps and, in the case of O. tauri, no biomass components could be produced due to an incomplete Calvin cycle. To find and remove gaps from the networks, an extensive reference biochemical reaction database was assembled using a stepwise approach that minimized the inclusion of microbial reactions. Gaps were then removed from both Ostreococcus networks using two existing gap-filling methodologies. In the first method, a bottom-up approach, a minimal list of reactions was added to each model to enable the production of all metabolites included in our biomass equation. In the second method, a top-down approach, all reactions in the reference database were added to the target networks and subsequently trimmed away based on the sequence alignment scores of identified orthologues. Because current gap-filling methods do not produce unique solutions, a quality metric that includes a weighting for phylogenetic distance and sequence similarity was developed to distinguish between gap-filling results automatically. The draft O. lucimarinus and O. tauri networks required the addition of 56 and 70 reactions, respectively, in order to produce the same biomass precursor metabolites that were produced by our plant reference database. PMID- 22207619 TI - A nationwide survey of the prevalence of multiple sclerosis in immigrant populations of Sweden. AB - BACKGROUND: In 2008, immigrants constituted 14% of the population of Sweden, a high-risk area for multiple sclerosis (MS). We investigated the largest Swedish immigrant populations for the prevalence of MS. METHOD: Data on foreign-born MS patients were retrieved from Swedish national health and population registers. We calculated observed versus expected numbers of MS patients and gender- and age specific prevalence ratios (PR) between immigrant populations and the general population of Sweden and, where possible, of the countries of birth. RESULTS: The 19 largest immigrant populations included 1327 MS patients. The global variation in MS prevalence was reflected in Sweden. The prevalence in immigrant populations who had moved to Sweden from countries with a lower MS risk was however higher than in their countries of birth. Notably, the MS prevalence in the population born in Iran was at least as high as in the general population of Sweden (men: PR = 1.10, 95% CI 0.81-1.46, p = 0.537, women: PR = 1.18, 95% CI 0.97-1.44, p = 0.855) and more than twice as high as in Isfahan, Iran (men: PR = 3.06 (95% CI 2.26-4.06), p <0.001, women: PR = 2.21 (95% CI 1.81-2.68), p <0.001). CONCLUSIONS: The MS prevalence increased in migrants who moved to Sweden from countries with a lower MS risk. In the Iranian immigrant population the prevalence exceeded that in the general population of Sweden. This indicates that Iranians carry genetic factors that contribute to a higher MS risk when environmental-lifestyle MS risk factors change. PMID- 22207620 TI - 15-Lipoxygenase eicosanoids are the putative ligands for vanilloid receptors and peroxisome proliferator-activated receptors (PPARs). PMID- 22207622 TI - A tolerogenic role for Toll-like receptor 9 is revealed by B-cell interaction with DNA complexes expressed on apoptotic cells. AB - Intracellular protein complexes containing nucleic acids are common targets of autoantibodies in many autoimmune diseases. Central tolerance to these antigens is incomplete, yet nucleosomal DNA is expressed on the surface of cells dying by apoptosis. It is commonly believed that autoimmunity is prevented by the rapid uptake of apoptotic cells (ACs) by neighbors or professional phagocytes to which they deliver anti-inflammatory signals. Self-reactive, innate-like B cells contact and are selected by intracellular antigens expressed on ACs; however, how self-tolerance is maintained is not well understood. Here we report that IL-10 production by B cells, stimulated by contact with ACs, results from the engagement of Toll-like receptor 9 (TLR9) within the B cell after recognition of DNA-containing complexes on the surface of ACs. Until now, TLR9 ligation has been considered an inflammatory signal, but we have confirmed a hitherto unexpected immunoregulatory role by demonstrating the absence of the protective effect of ACs during experimental autoimmune encephalitis (EAE) in TLR9-deficient mice. Human circulating CD27(+) B cells also respond to DNA-bearing ACs, but not to DNase-treated cells, by secreting IL-10. Chronic autoimmune disease may arise if this tolerance mechanism is not reimposed after episodes of inflammation, or if the regulatory B-cell response is subverted. PMID- 22207623 TI - Structure and function of the small terminase component of the DNA packaging machine in T4-like bacteriophages. AB - Tailed DNA bacteriophages assemble empty procapsids that are subsequently filled with the viral genome by means of a DNA packaging machine situated at a special fivefold vertex. The packaging machine consists of a "small terminase" and a "large terminase" component. One of the functions of the small terminase is to initiate packaging of the viral genome, whereas the large terminase is responsible for the ATP-powered translocation of DNA. The small terminase subunit has three domains, an N-terminal DNA-binding domain, a central oligomerization domain, and a C-terminal domain for interacting with the large terminase. Here we report structures of the central domain in two different oligomerization states for a small terminase from the T4 family of phages. In addition, we report biochemical studies that establish the function for each of the small terminase domains. On the basis of the structural and biochemical information, we propose a model for DNA packaging initiation. PMID- 22207624 TI - Reducing system noise in copy number data using principal components of self-self hybridizations. AB - Genomic copy number variation underlies genetic disorders such as autism, schizophrenia, and congenital heart disease. Copy number variations are commonly detected by array based comparative genomic hybridization of sample to reference DNAs, but probe and operational variables combine to create correlated system noise that degrades detection of genetic events. To correct for this we have explored hybridizations in which no genetic signal is expected, namely "self self" hybridizations (SSH) comparing DNAs from the same genome. We show that SSH trap a variety of correlated system noise present also in sample-reference (test) data. Through singular value decomposition of SSH, we are able to determine the principal components (PCs) of this noise. The PCs themselves offer deep insights into the sources of noise, and facilitate detection of artifacts. We present evidence that linear and piecewise linear correction of test data with the PCs does not introduce detectable spurious signal, yet improves signal-to-noise metrics, reduces false positives, and facilitates copy number determination. PMID- 22207625 TI - High pressure ices. AB - H(2)O will be more resistant to metallization than previously thought. From computational evolutionary structure searches, we find a sequence of new stable and meta-stable structures for the ground state of ice in the 1-5 TPa (10 to 50 Mbar) regime, in the static approximation. The previously proposed Pbcm structure is superseded by a Pmc2(1) phase at p = 930 GPa, followed by a predicted transition to a P2(1) crystal structure at p = 1.3 TPa. This phase, featuring higher coordination at O and H, is stable over a wide pressure range, reaching 4.8 TPa. We analyze carefully the geometrical changes in the calculated structures, especially the buckling at the H in O-H-O motifs. All structures are insulating--chemistry burns a deep and (with pressure increase) lasting hole in the density of states near the highest occupied electronic levels of what might be component metallic lattices. Metallization of ice in our calculations occurs only near 4.8 TPa, where the metallic C2/m phase becomes most stable. In this regime, zero-point energies much larger than typical enthalpy differences suggest possible melting of the H sublattice, or even the entire crystal. PMID- 22207626 TI - End-Cretaceous marine mass extinction not caused by productivity collapse. AB - An asteroid impact at the end of the Cretaceous caused mass extinction, but extinction mechanisms are not well-understood. The collapse of sea surface to sea floor carbon isotope gradients has been interpreted as reflecting a global collapse of primary productivity (Strangelove Ocean) or export productivity (Living Ocean), which caused mass extinction higher in the marine food chain. Phytoplankton-dependent benthic foraminifera on the deep-sea floor, however, did not suffer significant extinction, suggesting that export productivity persisted at a level sufficient to support their populations. We compare benthic foraminiferal records with benthic and bulk stable carbon isotope records from the Pacific, Southeast Atlantic, and Southern Oceans. We conclude that end Cretaceous decrease in export productivity was moderate, regional, and insufficient to explain marine mass extinction. A transient episode of surface ocean acidification may have been the main cause of extinction of calcifying plankton and ammonites, and recovery of productivity may have been as fast in the oceans as on land. PMID- 22207627 TI - Structural basis for DNA recognition and loading into a viral packaging motor. AB - Genome packaging into preformed viral procapsids is driven by powerful molecular motors. The small terminase protein is essential for the initial recognition of viral DNA and regulates the motor's ATPase and nuclease activities during DNA translocation. The crystal structure of a full-length small terminase protein from the Siphoviridae bacteriophage SF6, comprising the N-terminal DNA binding, the oligomerization core, and the C-terminal beta-barrel domains, reveals a nine subunit circular assembly in which the DNA-binding domains are arranged around the oligomerization core in a highly flexible manner. Mass spectrometry analysis and four further crystal structures show that, although the full-length protein exclusively forms nine-subunit assemblies, protein constructs missing the C terminal beta-barrel form both nine-subunit and ten-subunit assemblies, indicating the importance of the C terminus for defining the oligomeric state. The mechanism by which a ring-shaped small terminase oligomer binds viral DNA has not previously been elucidated. Here, we probed binding in vitro by using EPR and surface plasmon resonance experiments, which indicated that interaction with DNA is mediated exclusively by the DNA-binding domains and suggested a nucleosome like model in which DNA binds around the outside of the protein oligomer. PMID- 22207628 TI - Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells. AB - Misregulation of a pluripotency-associated transcription factor network in adult tissues is associated with the expansion of rare, highly malignant tumor initiating stem cells (TISCs) through poorly understood mechanisms. We demonstrate that robust and selective expression of the receptor for the adipocyte-derived peptide hormone leptin (OB-R) is a characteristic feature of TISCs and of a broad array of embryonic and induced pluripotent stem cells and is mediated directly by the core pluripotency-associated transcription factors OCT4 and SOX2. TISCs exhibit sensitized responses to leptin, including the phosphorylation and activation of the pluripotency-associated oncogene STAT3 and induction of Oct4 and Sox2, thereby establishing a self-reinforcing signaling module. Exposure of cultured mouse embryonic stem cells to leptin sustains pluripotency in the absence of leukemia inhibitory factor. By implanting TISCs into leptin-deficient ob/ob mice or into comparably overweight Lepr(db/db) mice that produce leptin, we provide evidence of a central role for the leptin-TISC signaling axis in promoting obesity-induced tumor growth. Differential responses to extrinsic, adipocyte-derived cues may promote the expansion of tumor cell subpopulations and contribute to oncogenesis. PMID- 22207629 TI - Suppression of tumour-specific CD4+ T cells by regulatory T cells is associated with progression of human colorectal cancer. AB - BACKGROUND: There is indirect evidence that T cell responses can control the metastatic spread of colorectal cancer (CRC). However, an enrichment of CD4(+)Foxp3(+) regulatory T cells (Tregs) has also been documented. OBJECTIVE: To evaluate whether CRC promotes Treg activity and how this influences anti-tumour immune responses and disease progression. METHODS: A longitudinal study of Treg activity on a cohort of patients was performed before and after tumour resection. Specific CD4(+) T cell responses were also measured to the tumour associated antigens carcinoembryonic antigen (CEA) and 5T4. RESULTS: Tregs from 62 preoperative CRC patients expressed a highly significant increase in levels of Foxp3 compared to healthy age-matched controls (p=0.007), which returned to normal after surgery (p=0.0075). CD4(+) T cell responses to one or both of the tumour associated antigens, CEA and 5T4, were observed in approximately two thirds of patients and one third of these responses were suppressed by Tregs. Strikingly, in all patients with tumour recurrence at 12 months, significant preoperative suppression was observed of tumour-specific (p=0.003) but not control CD4(+) T cell responses. CONCLUSION: These findings demonstrate that the presence of CRC drives the activity of Tregs and accompanying suppression of CD4(+) T cell responses to tumour-associated antigens. Suppression is associated with recurrence of tumour at 12 months, implying that Tregs contribute to disease progression. These findings offer a rationale for the manipulation of Tregs for therapeutic intervention. PMID- 22207630 TI - TPX2 and AURKA promote 20q amplicon-driven colorectal adenoma to carcinoma progression. AB - BACKGROUND AND OBJECTIVE: Progression of a colorectal adenoma to invasive cancer occurs in a minority of adenomas and is the most crucial step in colorectal cancer pathogenesis. In the majority of cases, this is associated with gain of a substantial part of chromosome 20q, indicating that multiple genes on the 20q amplicon may drive carcinogenesis. The aim of this study was to identify genes located on the 20q amplicon that promote progression of colorectal adenoma to carcinoma. DESIGN: Functional assays were performed for 32 candidate driver genes for which a positive correlation between 20q DNA copy number and mRNA expression had been demonstrated. Effects of gene knockdown on cell viability, anchorage independent growth, and invasion were analysed in colorectal cancer cell lines with 20q gain. Colorectal tumour protein expression was examined by immunohistochemical staining of tissue microarrays. RESULTS: TPX2, AURKA, CSE1L, DIDO1, HM13, TCFL5, SLC17A9, RBM39 and PRPF6 affected cell viability and/or anchorage-independent growth. Chromosome 20q DNA copy number status correlated significantly with TPX2 and AURKA protein levels in a series of colorectal adenomas and carcinomas. Moreover, downmodulation of TPX2 and AURKA was shown to inhibit invasion. CONCLUSION: These data identify TPX2 (20q11) and AURKA (20q13.2) as two genes located on distinct regions of chromosome 20q that promote 20q amplicon-driven progression of colorectal adenoma to carcinoma. Therefore the selection advantage imposed by 20q gain in tumour progression is achieved by gain of-function of multiple cancer-related genes-knowledge that can be translated into novel tests for early diagnosis of progressive adenomas. PMID- 22207631 TI - The gender role motivation model of women's sexually submissive behavior and satisfaction in heterosexual couples. AB - Previous findings suggest that women are more likely than men to take on the submissive role during sexual activities (e.g., waiting for their partner to initiate and orchestrate sexual activities), often to the detriment of their sexual satisfaction. Extending previous research on gender role motivation, the authors recruited 181 heterosexual couples to examine scripted sexual behavior, motivation for such behavior, and relationship outcomes (sexual satisfaction, perceptions of closeness, and relationship satisfaction) for both women and their partners. Using the actor-partner interdependence model, path analyses revealed that women's submissive behavior had negative links to personal sexual satisfaction and their partner's sexual satisfaction but only when their submission was inconsistent with their sexual preferences. Moreover, the authors show there are negative downstream consequences of diminished sexual satisfaction on perceptions of closeness and overall relationship satisfaction for both partners in the relationship. PMID- 22207633 TI - Investigating the neural correlates of pathological cortical networks in Alzheimer's disease using heterogeneous neuronal models. AB - This paper describes an investigation into the pathophysiological causes of abnormal cortical oscillations in Alzheimer's disease (AD) using two heterogeneous neuronal network models. The effect of excitatory circuit disruption on the beta band power (13-30 Hz) using a conductance-based network model of 200 neurons is assessed. Then, the neural correlates of abnormal cortical oscillations in different frequency bands based on a larger network model of 1000 neurons consisting of different types of cortical neurons are also analyzed. EEG studies in AD patients have shown that beta band power (13-30 Hz) decreased in the early stages of the disease with a parallel increase in theta band power (4-7 Hz). This abnormal change progresses with the later stages of the disease but with decreased power spectra in other fast frequency bands plus an increase in delta band power (1-3 Hz). Our results show that, despite the heterogeneity of the network models, the beta band power is significantly affected by excitatory neural and synaptic loss. Second, the results of modeling a functional impairment in the excitatory circuit shows that beta band power exhibits the most decrease compared with other bands. Previous biological experiments on different types of cultural excitatory neurons show that cortical neuronal death is mediated by dysfunctional ionic behavior that might specifically contribute to the pathogenesis of beta-amyloid-peptide-induced neuronal death in AD. Our study also shows that beta band power was the first affected component when the modeled excitatory circuit begins to lose neurons and synapses. PMID- 22207632 TI - Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders--a systematic review and meta-analysis. AB - Individuals with schizophrenia have high levels of medical comorbidity and cardiovascular risk factors. The presence of 3 or more specific factors is indicative of metabolic syndrome, which is a significant influence upon future morbidity and mortality. We aimed to clarify the prevalence and predictors of metabolic syndrome (MetS) in adults with schizophrenia and related disorders, accounting for subgroup differences. A PRISMA systematic search, appraisal, and meta-analysis were conducted of 126 analyses in 77 publications (n = 25,692). The overall rate of MetS was 32.5% (95% CI = 30.1%-35.0%), and there were only minor differences according to the different definitions of MetS, treatment setting (inpatient vs outpatient), by country of origin and no appreciable difference between males and females. Older age had a modest influence on the rate of MetS (adjusted R(2) = .20; P < .0001), but the strongest influence was of illness duration (adjusted R(2) = .35; P < .0001). At a study level, waist size was most useful in predicting high rate of MetS with a sensitivity of 79.4% and a specificity of 78.8%. Sensitivity and specificity of high blood pressure, high triglycerides, high glucose and low high-density lipoprotein, and age (>38 y) are shown in supplementary appendix 2 online. Regarding prescribed antipsychotic medication, highest rates were seen in those prescribed clozapine (51.9%) and lowest rates of MetS in those who were unmedicated (20.2%). Present findings strongly support the notion that patients with schizophrenia should be considered a high-risk group. Patients with schizophrenia should receive regular monitoring and adequate treatment of cardio-metabolic risk factors. PMID- 22207634 TI - Assessment of cognitive decline through quantitative analysis of the timed up and go test. AB - Cognitive decline and dementia have emerged as major challenges in modern healthcare with enormous associated societal and economic costs. Shifting demographics, owing to increasing numbers of people aged over 65 have greatly increased the potential scale of this problem in years to come. We report a novel quantitative method for assessment of cognitive decline (defined as a decline in mini mental state examination (MMSE) score of three or more) using quantitative parameters derived from body-worn inertial sensors. We sought to determine if baseline quantitative parameters and changes from baseline at follow-up, in those parameters could be used to automatically classify participants as cognitively declined or intact. Quantitative movement parameters were obtained at a baseline clinical assessment and in a follow-up assessment approximately 2 years later, using shank mounted triaxial gyroscopes. Data were obtained from 189 community dwelling older adults (aged over 60, 59 male, 130 female, mean age: 70.43 +/- 6.57) while performing the timed up and go test. Nine participants who were deemed to be cognitively impaired at baseline (MMSE < 24) were excluded from analysis. Results suggest that quantitative parameters measured at baseline are 75.94% accurate in predicting cognitive decline in participants who were cognitively intact at baseline. A combination of baseline quantitative movement parameters and the change at follow-up (compared to baseline) in these parameters were 88.78% accurate in classifying final cognitive status in participants deemed cognitively intact at baseline. The reported method may be suitable for use as a portable cognitive screening tool, prompting further specialist clinical investigation and may also form part of a tool for longitudinal monitoring of cognitive function. PMID- 22207636 TI - A design of a high-speed and high-efficiency capsule endoscopy system. AB - This paper presents a high-speed and high-efficiency capsule endoscopy system. Both a transmitter and a receiver were optimized for its application through an analysis of the human body channel. ON-OFF keying modulation is utilized to achieve low power consumption of the in-body transmitter. A low drop output regulator is adopted to prevent performance degradation in the event of a voltage drop in the battery. The receiver adopts superheterodyne structure to obtain high sensitivity, considering the link budget from the previous analysis. The receiver and transmitter were fabricated using the CMOS 0.13-MUm process. The output power of the transmitter is -1.6 dB.m and its efficiency is 27.7%. The minimum sensitivity of the receiver is -80 dB.m at a bit error ratio (BER) of 3 * 10 ( 6). An outer wall loop antenna is adopted for the capsule system to ensure a small size. The integrated system is evaluated using a liquid human phantom and a living pig, resulting in clean captured images. PMID- 22207635 TI - An improved method for the estimation and visualization of velocity fields from gastric high-resolution electrical mapping. AB - High-resolution (HR) electrical mapping is an important clinical research tool for understanding normal and abnormal gastric electrophysiology. Analyzing velocities of gastric electrical activity in a reliable and accurate manner can provide additional valuable information for quantitatively and qualitatively comparing features across and within subjects, particularly during gastric dysrhythmias. In this study, we compared three methods of estimating velocities from HR recordings to determine which method was the most reliable for use with gastric HR electrical mapping. The three methods were 1) simple finite difference (FD) 2) smoothed finite difference (FDSM), and 3) a polynomial-based method. With synthetic data, the accuracy of the simple FD method resulted in velocity errors almost twice that of the FDSM and the polynomial-based method, in the presence of activation time error up to 0.5 s. With three synthetic cases under various noise types and levels, the FDSM resulted in average speed error of 3.2% and an average angle error of 2.0 degrees and the polynomial-based method had an average speed error of 3.3% and an average angle error of 1.7 degrees . With experimental gastric slow wave recordings performed in pigs, the three methods estimated similar velocities (6.3-7.3 mm/s), but the FDSM method had a lower standard deviation in its velocity estimate than the simple FD and the polynomial-based method, leading it to be the method of choice for velocity estimation in gastric slow wave propagation. An improved method for visualizing velocity fields is also presented. PMID- 22207637 TI - Fully automated colon segmentation for the computation of complete colon centerline in virtual colonoscopy. AB - Virtual colonoscopy detects polyps by navigating along a colon centerline. Complete colon segmentation based on computed tomography (CT) data is a prerequisite to the computation of complete colon centerline. There are two main problems impeding complete segmentation: overdistention/underdistention of colon and the use of oral contrast agents. Overdistention produces loops in the segmented colon, while underdistention may cause the segmented colon collapse into a series of disconnected segments. Use of oral contrast agents, which have high attenuation on CT, may add redundant structures (bones and small bowels) to the segmented colon. A fully automated colon segmentation method is proposed in this paper to address the two problems. We tested the proposed method in 170 cases, including 37 "moderate" and 133 "challenging" cases. Computer-generated centerlines were compared with human-generated centerlines (plotted by three radiologists). The proposed method achieved a 90.56% correct coverage rate with respect to the human-generated centerlines. We also compared the proposed method with two existing colon segmentation methods: Uitert's method and Nappi's method. The results of these two methods were 75.16% and 72.59% correct coverage rates, respectively. Our experimental results indicate that the proposed method could yield more complete colon centerlines than the existing methods. PMID- 22207638 TI - Tumor-Cut: segmentation of brain tumors on contrast enhanced MR images for radiosurgery applications. AB - In this paper, we present a fast and robust practical tool for segmentation of solid tumors with minimal user interaction to assist clinicians and researchers in radiosurgery planning and assessment of the response to the therapy. Particularly, a cellular automata (CA) based seeded tumor segmentation method on contrast enhanced T1 weighted magnetic resonance (MR) images, which standardizes the volume of interest (VOI) and seed selection, is proposed. First, we establish the connection of the CA-based segmentation to the graph-theoretic methods to show that the iterative CA framework solves the shortest path problem. In that regard, we modify the state transition function of the CA to calculate the exact shortest path solution. Furthermore, a sensitivity parameter is introduced to adapt to the heterogeneous tumor segmentation problem, and an implicit level set surface is evolved on a tumor probability map constructed from CA states to impose spatial smoothness. Sufficient information to initialize the algorithm is gathered from the user simply by a line drawn on the maximum diameter of the tumor, in line with the clinical practice. Furthermore, an algorithm based on CA is presented to differentiate necrotic and enhancing tumor tissue content, which gains importance for a detailed assessment of radiation therapy response. Validation studies on both clinical and synthetic brain tumor datasets demonstrate 80%-90% overlap performance of the proposed algorithm with an emphasis on less sensitivity to seed initialization, robustness with respect to different and heterogeneous tumor types, and its efficiency in terms of computation time. PMID- 22207640 TI - Soft object deformation monitoring and learning for model-based robotic hand manipulation. AB - This paper discusses the design and implementation of a framework that automatically extracts and monitors the shape deformations of soft objects from a video sequence and maps them with force measurements with the goal of providing the necessary information to the controller of a robotic hand to ensure safe model-based deformable object manipulation. Measurements corresponding to the interaction force at the level of the fingertips and to the position of the fingertips of a three-finger robotic hand are associated with the contours of a deformed object tracked in a series of images using neural-network approaches. The resulting model captures the behavior of the object and is able to predict its behavior for previously unseen interactions without any assumption on the object's material. The availability of such models can contribute to the improvement of a robotic hand controller, therefore allowing more accurate and stable grasp while providing more elaborate manipulation capabilities for deformable objects. Experiments performed for different objects, made of various materials, reveal that the method accurately captures and predicts the object's shape deformation while the object is submitted to external forces applied by the robot fingers. The proposed method is also fast and insensitive to severe contour deformations, as well as to smooth changes in lighting, contrast, and background. PMID- 22207639 TI - Discovering thematic objects in image collections and videos. AB - Given a collection of images or a short video sequence, we define a thematic object as the key object that frequently appears and is the representative of the visual contents. Successful discovery of the thematic object is helpful for object search and tagging, video summarization and understanding, etc. However, this task is challenging because 1) there lacks a priori knowledge of the thematic objects, such as their shapes, scales, locations, and times of re occurrences, and 2) the thematic object of interest can be under severe variations in appearances due to viewpoint and lighting condition changes, scale variations, etc. Instead of using a top-down generative model to discover thematic visual patterns, we propose a novel bottom-up approach to gradually prune uncommon local visual primitives and recover the thematic objects. A multilayer candidate pruning procedure is designed to accelerate the image data mining process. Our solution can efficiently locate thematic objects of various sizes and can tolerate large appearance variations of the same thematic object. Experiments on challenging image and video data sets and comparisons with existing methods validate the effectiveness of our method. PMID- 22207641 TI - Reaching unanimous agreements within agent-based negotiation teams with linear and monotonic utility functions. AB - In this article, an agent-based negotiation model for negotiation teams that negotiate a deal with an opponent is presented. Agent-based negotiation teams are groups of agents that join together as a single negotiation party because they share an interest that is related to the negotiation process. The model relies on a trusted mediator that coordinates and helps team members in the decisions that they have to take during the negotiation process: which offer is sent to the opponent, and whether the offers received from the opponent are accepted. The main strength of the proposed negotiation model is the fact that it guarantees unanimity within team decisions since decisions report a utility to team members that is greater than or equal to their aspiration levels at each negotiation round. This work analyzes how unanimous decisions are taken within the team and the robustness of the model against different types of manipulations. An empirical evaluation is also performed to study the impact of the different parameters of the model. PMID- 22207642 TI - Virtual active touch using randomly patterned intracortical microstimulation. AB - Intracortical microstimulation (ICMS) has promise as a means for delivering somatosensory feedback in neuroprosthetic systems. Various tactile sensations could be encoded by temporal, spatial, or spatiotemporal patterns of ICMS. However, the applicability of temporal patterns of ICMS to artificial tactile sensation during active exploration is unknown, as is the minimum discriminable difference between temporally modulated ICMS patterns. We trained rhesus monkeys in an active exploration task in which they discriminated periodic pulse-trains of ICMS (200 Hz bursts at a 10 Hz secondary frequency) from pulse trains with the same average pulse rate, but distorted periodicity (200 Hz bursts at a variable instantaneous secondary frequency). The statistics of the aperiodic pulse trains were drawn from a gamma distribution with mean inter-burst intervals equal to those of the periodic pulse trains. The monkeys distinguished periodic pulse trains from aperiodic pulse trains with coefficients of variation 0.25 or greater. Reconstruction of movement kinematics, extracted from the activity of neuronal populations recorded in the sensorimotor cortex concurrent with the delivery of ICMS feedback, improved when the recording intervals affected by ICMS artifacts were removed from analysis. These results add to the growing evidence that temporally patterned ICMS can be used to simulate a tactile sense for neuroprosthetic devices. PMID- 22207643 TI - Cortical shape adaptation transforms a circle into a hexagon: a novel afterimage illusion. AB - After viewing a colored figure on a uniform gray background, an observer will see a negative afterimage after the colored figure disappears. This study shows that the shapes of afterimages vary systematically according to the shape of the adaptation stimuli, a phenomenon that could be caused only by cortical shape adaptation. In the experiments reported here, participants typically saw a hexagonal afterimage after viewing a circle and sometimes saw a circular afterimage after viewing a hexagon. When observers were adapted to rotating circles or hexagons, which produced the same circular retinal painting, they reliably reported that afterimages of circles appeared as hexagons, and vice versa. Furthermore, the fact that this effect also arose through interocular transfer confirms that a cortical process with binocular inputs must have contributed to it. This novel finding reveals that afterimage formation is determined mainly by a cortical process, not by retinal bleaching, and that rival mechanisms detect corners and curves of shapes in cortical processing. PMID- 22207644 TI - Is the map in our head oriented north? AB - We examined how a highly familiar environmental space--one's city of residence- is represented in memory. Twenty-six participants faced a photo-realistic virtual model of their hometown and completed a task in which they pointed to familiar target locations from various orientations. Each participant's performance was most accurate when he or she was facing north, and errors increased as participants' deviation from a north-facing orientation increased. Pointing errors and latencies were not related to the distance between participants' initial locations and the target locations. Our results are inconsistent with accounts of orientation-free memory and with theories assuming that the storage of spatial knowledge depends on local reference frames. Although participants recognized familiar local views in their initial locations, their strategy for pointing relied on a single, north-oriented reference frame that was likely acquired from maps rather than experience from daily exploration. Even though participants had spent significantly more time navigating the city than looking at maps, their pointing behavior seemed to rely on a north-oriented mental map. PMID- 22207645 TI - Elimination of position-change alarms in an Alzheimer's and dementia long-term care facility. AB - In a long-term care facility, whose residents have been diagnosed with Alzheimer's disease or dementia, falls are a particularly prominent issue. Technology in health care has continued to evolve and play a larger role in how we care for our patients, even in preventing falls. However, overreliance on these types of technologies may have detrimental effects. In our facility, it was felt that staff reliance on position-change alarms was inappropriate due to the high rate of false alarms associated with these devices. We took a tiered approach to removing position-change alarms from our facility, monitoring the fall incidence rate for a period before, during, and after the elimination of these alarms. After discontinuing their use, we found a decrease in the rate of falls, and a decrease in the percentage of our residents who fell. Staff has easily adapted and reports a calmer, more pleasant environment. PMID- 22207646 TI - Functional decline associated with polypharmacy and potentially inappropriate medications in community-dwelling older adults with dementia. AB - This study provides empirical evidence on whether polypharmacy and potentially inappropriate prescription medications (PIRx, as defined by the 2003 Beers criteria) increase the likelihood of functional decline among community-dwelling older adults with dementia. Data were from the National Alzheimer's Coordinating Center, Uniform Data Set (9/2005-9/2009). Study sample included 1994 community dwelling participants aged >=65 with dementia at baseline. Results showed that participants having >=5 medications were more likely to have functional decline than participants having <5 medications. However, the increased likelihood was only apparent in participants who did not have PIRx. Instead of magnifying the associated risk as hypothesized, PIRx appeared to have a protective effect albeit marginally statistically significant. Therefore, increased medication burden may be associated with functional decline in community-dwelling older adults with dementia who are not prescribed with PIRx. More research is needed to understand which classes of medications have the most deleterious effect on this population. PMID- 22207647 TI - Antiviral activity of coxsackievirus B3 3C protease inhibitor in experimental murine myocarditis. AB - BACKGROUND: We investigated the efficacy of a 3C protease inhibitor (3CPI) in a murine coxsackievirus B3 (CVB3) myocarditis model. CVB3 is a primary cause of viral myocarditis. The CVB3 genome encodes a single polyprotein that undergoes a series of proteolytic events to produce several viral proteins. Most of this proteolysis is catalyzed by the 3C protease (3CP). METHODS AND RESULTS: By way of a micro-osmotic pump, each mouse received 50 mM 3CPI in 100 MUL of 100% dimethyl sulfoxide (DMSO) during a 72-hour period. On the day of pump implantation, mice (n = 40) were infected intraperitoneally with 10(6) plaque-forming units of CVB3. For the infected controls (n = 50), the pump was filled with 100% DMSO without 3CPI. The 3-week survival rate of 3CPI-treated mice was significantly higher than that of controls (90% vs 22%; P < .01). Myocardial inflammation, viral titers, and viral RNA levels were also reduced significantly in the 3CPI-treated group compared with these measures in the controls. CONCLUSIONS: The protein-based drug 3CPI inhibited the activity of 3CP of CVB3, significantly inhibited viral proliferation, and attenuated myocardial inflammations, subsequent fibrosis, and CVB3-induced mortality in vivo. Thus, this CVB3 3CPI has the potential to be a novel therapeutic agent for the treatment of acute viral myocarditis during the viremic phase. PMID- 22207648 TI - Sequestration and microvascular congestion are associated with coma in human cerebral malaria. AB - The pathogenesis of coma in severe Plasmodium falciparum malaria remains poorly understood. Obstruction of the brain microvasculature because of sequestration of parasitized red blood cells (pRBCs) represents one mechanism that could contribute to coma in cerebral malaria. Quantitative postmortem microscopy of brain sections from Vietnamese adults dying of malaria confirmed that sequestration in the cerebral microvasculature was significantly higher in patients with cerebral malaria (CM; n = 21) than in patients with non-CM (n = 23). Sequestration of pRBCs and CM was also significantly associated with increased microvascular congestion by infected and uninfected erythrocytes. Clinicopathological correlation showed that sequestration and congestion were significantly associated with deeper levels of premortem coma and shorter time to death. Microvascular congestion and sequestration were highly correlated as microscopic findings but were independent predictors of a clinical diagnosis of CM. Increased microvascular congestion accompanies coma in CM, associated with parasite sequestration in the cerebral microvasculature. PMID- 22207649 TI - Immune response following H1N1pdm09 vaccination: differences in antibody repertoire and avidity in young adults and elderly populations stratified by age and gender. AB - BACKGROUND: The H1N1 2009 influenza (H1N1pdm09) pandemic had unexpected features, including lower morbidity and mortality in elderly populations. METHODS: We performed in-depth elucidation of antibody responses generated post-H1N1pdm09 vaccination in elderly (aged 66-83 years) and younger (aged 18-45 or 46-65 years) adults using H1N1pdm09 whole-genome-fragment phage display library and measured antibody isotype and affinity to antigenic domains within hemagglutinin (HA). RESULTS: H1N1pdm09 vaccination induced 10-fold higher antibody levels in elderly compared with younger adults. These antibodies primarily targeted the HA1 globular domain, including neutralizing epitopes in the receptor-binding domain. Antibody epitope repertoire, isotype, and affinity maturation after H1N1pdm09 vaccination evolved independently for HA2, HA1, and HA1 N-terminus antigenic regions. Postvaccination serum samples from elderly subjects demonstrated substantially higher avidity than from younger subjects (>60% vs <30% resistance to 7 mol/L urea) and slower antibody dissociation rates using surface plasmon resonance. We also identified a gender difference in postvaccination antibody avidity (female < male subjects) in adults <65 years old. CONCLUSIONS: This is the first study in humans that provides evidence for a qualitatively superior antibody response in elderly adults after H1N1pdm09 vaccination. These findings may help explain the age-related mortality observed during the H1N1pdm09 pandemic. The difference in gender specific avidity merits further exploration. PMID- 22207650 TI - Respiratory syncytial virus in neutrophils. PMID- 22207651 TI - Detection of acute HIV infection: a field evaluation of the determine(r) HIV-1/2 Ag/Ab combo test. AB - BACKGROUND: Most human immunodeficiency virus (HIV) point-of-care tests detect antibodies (Ab) but not p24 antigen (Ag) or RNA. In the absence of antibodies, p24 antigen and RNA typically indicate acute HIV infection. We conducted a field evaluation of the Determine(r) HIV-1/2 Ag/Ab Combo rapid test (Combo RT). METHODS: The antigen portion of the Combo RT (for acute HIV infection) was compared with a Roche Monitor HIV RNA polymerase chain reaction assay. The antibody portion of Combo RT (for established HIV infection) was compared with rapid test algorithms. Participants were enrolled at a sexually transmitted infection clinic and HIV testing and counseling center in Lilongwe, Malawi. Rapid testing was conducted with parallel testing in the clinic and serial testing in the center. The Combo RT was performed in clinic participants with negative or discordant antibody results and in all center participants. RESULTS: Of the participants 838 were HIV negative, 163 had established HIV infection, and 8 had acute HIV infection. For detecting acute HIV infection, the antigen portion had a sensitivity of 0.000 and a specificity of 0.983. For detecting established HIV infection, the antibody portion had a sensitivity of 0.994 and a specificity of 0.992. CONCLUSIONS: Combo RT displayed excellent performance for detecting established HIV infection and poor performance for detecting acute HIV infection. In this setting, Combo RT is no more useful than current algorithms. PMID- 22207652 TI - Detection of acute HIV infection: we can't close the window. PMID- 22207654 TI - Peripheral vision and pattern recognition: a review. AB - We summarize the various strands of research on peripheral vision and relate them to theories of form perception. After a historical overview, we describe quantifications of the cortical magnification hypothesis, including an extension of Schwartz's cortical mapping function. The merits of this concept are considered across a wide range of psychophysical tasks, followed by a discussion of its limitations and the need for non-spatial scaling. We also review the eccentricity dependence of other low-level functions including reaction time, temporal resolution, and spatial summation, as well as perimetric methods. A central topic is then the recognition of characters in peripheral vision, both at low and high levels of contrast, and the impact of surrounding contours known as crowding. We demonstrate how Bouma's law, specifying the critical distance for the onset of crowding, can be stated in terms of the retinocortical mapping. The recognition of more complex stimuli, like textures, faces, and scenes, reveals a substantial impact of mid-level vision and cognitive factors. We further consider eccentricity-dependent limitations of learning, both at the level of perceptual learning and pattern category learning. Generic limitations of extrafoveal vision are observed for the latter in categorization tasks involving multiple stimulus classes. Finally, models of peripheral form vision are discussed. We report that peripheral vision is limited with regard to pattern categorization by a distinctly lower representational complexity and processing speed. Taken together, the limitations of cognitive processing in peripheral vision appear to be as significant as those imposed on low-level functions and by way of crowding. PMID- 22207655 TI - Cellular pharmacokinetic/pharmacodynamic relationship of platinum cytostatics in head and neck squamous cell carcinoma evaluated by liquid chromatography coupled to tandem mass spectrometry. AB - Cisplatin (diaminodichloroplatinum) is the favored platinum (Pt) drug for the treatment of head and neck squamous cell carcinoma (HNSCC). However, Pt drug alternatives such as carboplatin (diaminoplatinum-cyclobutan-1,1-dicarboxylate) or oxaliplatin [oxalato[(1R,2R)-cyclohexanediamino]platinum] have not been comprehensively investigated in HNSCC. Moreover, little data reveal the decisive efficacy determinant and whether Pt drug efficacy is truly concentration dependent. Using five human HNSCC cell lines, we determined the concentrations of cisplatin, carboplatin, and oxaliplatin leading to 50% inhibition of cell proliferation (IC(50)). Concurrently we quantified cellular drug uptake by liquid chromatography coupled to tandem mass spectrometry and evaluated mRNA expression of drug transporters involved in Pt drug uptake by quantitative real-time polymerase chain reaction. Mean IC(50) among the five cell lines was 6.2 +/- 1.9 MUM for cisplatin and 11.6 +/- 4.2 MUM for oxaliplatin, whereas carboplatin showed significantly lower proliferation inhibition (IC(50) 107.5 +/- 21.2 MUM). In agreement with this finding carboplatin poorly accumulated in HNSCC cells, compared with cisplatin and oxaliplatin. HNSCC cell lines expressed Pt drug transporters. Taken together, the results demonstrate: 1) carboplatin was less effective and was poorly taken up; 2) a high individuality among cell lines was found concerning the accumulation of cisplatin and oxaliplatin despite similar in vitro efficacy; and 3) distinct expression of SLC22A2 and ABCC2 accompanies strong uptake and cytotoxicity of Pt drugs. In conclusion, we demonstrate that in vitro efficacy of cisplatin and oxaliplatin in HNSCC is concentration-independent because they exhibited different uptake characteristics but similar efficacies, suggesting oxaliplatin as a promising alternative against HNSCC that needs further evaluation in clinical trials. PMID- 22207656 TI - Anti-inflammatory mechanism of compound K in activated microglia and its neuroprotective effect on experimental stroke in mice. AB - Microglial activation plays a pivotal role in the pathogenesis of various neurologic disorders, such as cerebral ischemia, Alzheimer's disease, and Parkinson's disease. Thus, controlling microglial activation is a promising therapeutic strategy for such brain diseases. In the present study, we found that a ginseng saponin metabolite, compound K [20-O-D-glucopyranosyl-20(S) protopanaxadiol], inhibited the expressions of inducible nitric-oxide synthase, proinflammatory cytokines, monocyte chemotactic protein-1, matrix metalloproteinase-3, and matrix metalloproteinase-9 in lipopolysaccharide (LPS) stimulated BV2 microglial cells and primary cultured microglia. Subsequent mechanistic studies revealed that compound K suppressed microglial activation via inhibiting reactive oxygen species, mitogen-activated protein kinases, and nuclear factor-kappaB/activator protein-1 activities with enhancement of heme oxygenase-1/antioxidant response element signaling. To address the anti inflammatory effects of compound K in vivo, we used two brain disease models of mice: sepsis (systemic inflammation) and cerebral ischemia. Compound K reduced the number of Iba1-positive activated microglia and inhibited the expressions of tumor necrosis factor-alpha and interleukin-1beta in the LPS-induced sepsis brain. Furthermore, compound K reduced the infarct volume of ischemic brain induced by middle cerebral artery occlusion and suppressed microglial activation in the ischemic cortex. The results collectively suggest that compound K is a promising agent for prevention and/or treatment of cerebral ischemia and other neuroinflammatory disorders. PMID- 22207657 TI - Public registration of clinical trials: good for patients, good for dentists. PMID- 22207658 TI - Vulnerable populations. PMID- 22207659 TI - Terminology. PMID- 22207661 TI - Periodontology and pregnancy. PMID- 22207663 TI - Assessing the association between receipt of dental care, diabetes control measures and health care utilization. AB - BACKGROUND: The literature contains few studies regarding the relationships between receipt of regular dental care and medical outcomes for people with type 2 diabetes. METHODS: The authors compared hemoglobin A(1c) (HbA(1c)) levels (< 7 percent versus < 7 percent), low-density lipoprotein cholesterol levels (< 100 milligrams/deciliter versus >= 100 mg/dL) and diabetes-specific hospital admissions and emergency department (ED) visits (one or more visits versus no visits) in 493 people with type 2 diabetes who received regular dental care (>= two prophylactic visits, periodontal treatment visits or both during a 12-month period) with measures in 493 people with type 2 diabetes who did not receive any dental care. The authors matched patients, all of whom had private medical and dental insurance benefits during the study period, with regard to age, sex and previous utilization of ED visits and hospital admissions, and they followed them for three years. RESULTS: The authors analyzed the data by using multiple logistic regression, which showed that receipt of regular dental care was associated with lower diabetes-specific ED utilization (odds ratio [OR] = 0.61, 95 percent confidence interval [CI] = 0.40-0.92) and hospital admissions (OR = 0.61, 95 percent CI, 0.39-0.95) after they adjusted for age, sex, previous hospital admissions, previous ED utilization, race, baseline HbA(1c) values, Charlson comorbidity index score, body mass index status, periodontal risk status and primary care utilization. The authors found no significant association between receipt of dental care and control of HbA(1c) levels. CONCLUSIONS: The study results show an association between regular receipt of dental care and reduced diabetes-specific medical care utilization (that is, ED visits and hospital admissions). CLINICAL IMPLICATIONS: Although the results of this study could not show causality, they suggest that receipt of dental care may reduce diabetes-specific health care utilization. Prospective studies are needed to better understand the relationship of receipt of dental care with diabetes control and health care utilization measures. PMID- 22207664 TI - Antibiotic use for treating dental infections in children: a survey of dentists' prescribing practices. AB - BACKGROUND: The authors conducted a study to examine the antibiotic prescribing practices of general and pediatric dentists in the management of odontogenic infections in children. METHODS: The authors relied on a cross-sectional study design to assess the antibiotic prescribing practices of general and pediatric dentists in North Carolina. The survey instrument consisted of five clinical case scenarios that included antibiotic-prescribing decisions in a self-administered questionnaire format. The participants were volunteers attending one of four continuing education courses. The authors invited all pediatric dentists in private practice to participate in the study, as well as general practitioners who treated children in general practice. The authors compared the practitioners' responses for each clinical case scenario with the prescribing guidelines of the American Academy of Pediatric Dentistry and the American Dental Association. RESULTS: A total of 154 surveys were completed and returned (55 percent response rate). The mean age of respondents was 47 years, and the mean number of years in practice was 19. Of the 154 overall, 106 (69 percent) were general practitioners and 48 (31 percent) were pediatric dentists. Across the three in-office clinical case scenarios, adherence to professional prescribing guidelines ranged from 10 to 42 percent. For the two weekend scenarios, overall adherence to the professional prescribing guidelines dropped to 14 and 17 percent. Dentists who had completed postgraduate education (n = 73 [51 percent]) were more likely (P < .05) to have adhered to published guidelines in prescribing antibiotics. CONCLUSIONS: The results of this survey show that dentists' adherence to professional guidelines for prescribing antibiotics for odontogenic infections in children was low. There appears to be a lack of concordance between recommended professional guidelines and the antibiotic prescribing practices of dentists. Clearer, more specific guidelines may lead to improved adherence among dentists. PMID- 22207665 TI - Hyposalivation after undergoing stapedectomy. AB - BACKGROUND: Treatment for otosclerosis involves patients' undergoing stapedectomy. Inadvertent damage to the chorda tympani nerve's (CTN's) secretory fibers during stapedectomy can result in inadequate secretory stimulation of the submandibular salivary glands (SMSGs) and sublingual salivary glands (SLSGs). Because most saliva originates from these glands, hyposalivation and subjective xerostomia manifest during resting periods when parotid gland secretions are minimal. Stimulation with food increases parotid gland salivation enough to overcome the subjective sense of dryness. CASE DESCRIPTION: The author examined a 52-year-old man who had undergone bilateral stapedectomy because of hearing loss; his rheumatologist referred him to the Salivary Gland Center (New York City) because of a complaint of dry mouth. After the author examined the patient, he concluded that the patient had decreased SMSG and SLSG secretion and recommended that the patient use sugarless chewing gum or sour candy frequently to stimulate his parotid glands and use oral lubricants and sip water as needed. CLINICAL IMPLICATIONS: Stimulation of parotid gland secretion is independent of SMSG and SLSG activation. Therefore, the dental practitioner must become aware of the innervation of the salivary glands and each gland's secretory production during periods of oral stimulation and of rest. PMID- 22207666 TI - A 57-year-old man with inflamed, enlarged gingivae and associated bone loss. PMID- 22207667 TI - Evaluation of the short-term effectiveness of education versus an occlusal splint for the treatment of myofascial pain of the jaw muscles. AB - BACKGROUND: The authors conducted a clinical trial to compare the effectiveness of an education program with that of an occlusal splint in treating myofascial pain of the jaw muscles across a short period. METHOD: The authors assigned 44 patients randomly to two treatment groups; 41 patients completed the study. The first group (four male, 19 female; mean [standard deviation {SD}] age, 31.4 [14.0] years) received information regarding the nature of temporomandibular disorder (TMD) and self-care measures, whereas the second group (five male, 13 female; mean [SD] age, 31.1 [8.8] years) received an occlusal splint. One of the authors evaluated each patient every three weeks during a three-month treatment period. Treatment outcomes included pain-free maximal mouth opening, spontaneous muscle pain, pain during chewing and headache. RESULTS: After three months, changes in spontaneous muscle pain differed significantly between the education and occlusal splint groups (P = .034; effect size = 0.33). Changes in pain-free maximal mouth opening did not differ significantly between groups (P = .528; effect size = 0.20). Changes of headache and pain on chewing did not differ significantly between groups (P >= .550, effect size <= 0.10). CONCLUSIONS: During a short period, education was slightly more effective than an occlusal splint delivered without education in reducing spontaneous muscle pain in patients with TMD. Pain-free mouth opening, headache and pain during chewing were not significantly different between the two treatments. PMID- 22207668 TI - A practitioner's guide to developing critical appraisal skills: the fundamentals of research. AB - BACKGROUND AND OVERVIEW: This is the first of a series of articles summarizing the basic principles and methods of research with an emphasis on clinical investigation. In today's environment of evidence-based practice, the prevention of, diagnosis of, prognosis for and treatment of oral diseases must be based on a critical evaluation of available research. The purpose of this series is to help practitioners understand research and develop skills in interpreting research published in the medical and dental literature. CONCLUSIONS AND PRACTICE IMPLICATIONS: Research involves systematic investigation and can be categorized in different ways. Primary research may take several forms and includes basic and applied research. Basic research seeks fundamental knowledge without having a specific application; applied research is conducted for the purpose of a specific application and often is predicated on basic research findings. Applied research may take several forms and includes clinical research, which seeks to inform patients, clinicians, public health workers and policymakers about methods of preventing and treating diseases. Secondary research involves the use of existing data and results of published scientific studies. Systematic literature reviews are a form of secondary research that attempt to remove bias often associated with narrative reviews. PMID- 22207669 TI - Combined antiviral-corticosteroid therapy for Bell palsy yields inconclusive benefit. PMID- 22207670 TI - Early childhood caries-related visits to emergency departments and ambulatory surgery facilities and associated charges in New York state. AB - BACKGROUND: The authors assessed the extent of early childhood caries- (ECC-) related visits to emergency departments (EDs) and ambulatory surgery facilities (ASFs) in children younger than 6 years and associated treatment charges in New York state from 2004 through 2008. METHODS: The authors obtained data from the New York state's Statewide Planning and Research Cooperative System (Albany) and calculated descriptive statistics and rates according to selected indicators, as well as total and average per-visit treatment charges. RESULTS: From 2004 through 2008, the number of ECC-related visits to EDs and ASFs increased by 349 and 1,039, respectively. Most ECC-related visits were to ASFs. The total annual treatment charges increased from $18.5 million to $31.3 million from 2004 to 2008, and average per-visit charges increased from $4,237 to $5,501 during the same period. CONCLUSIONS: ECC-related visits to EDs and ASFs by children younger than 6 years and the associated treatment charges increased substantially from 2004 through 2008 in New York state. Practice Implications. Dental professionals need to determine the reasons parents seek dental care for their children in EDs and ASFs and effective strategies for preventing ECC to avoid the subsequent need for seeking dental care in EDs and ASFs. PMID- 22207671 TI - Dealing with negative publicity. PMID- 22207672 TI - How can I manage my patient's oral care when her insurance will not provide coverage for the necessary treatments? PMID- 22207673 TI - Your child's growing smile. PMID- 22207674 TI - Radiologic imaging in cystic fibrosis: cumulative effective dose and changing trends over 2 decades. AB - OBJECTIVE: With the increasing life expectancy for patients with cystic fibrosis (CF), and a known predisposition to certain cancers, cumulative radiation exposure from radiologic imaging is of increasing significance. This study explores the estimated cumulative effective radiation dose over a 17-year period from radiologic procedures and changing trends of imaging modalities over this period. METHODS: Estimated cumulative effective dose (CED) from all thoracic and extrathoracic imaging modalities and interventional radiology procedures for both adult and pediatric patients with CF, exclusively attending a nationally designated CF center between 1992-2009 for > 1 year, was determined. The study period was divided into three equal tertiles, and estimated CED attributable to all radiologic procedures was estimated for each tertile. RESULTS: Two hundred thirty patients met inclusion criteria (2,240 person-years of follow-up; 5,596 radiologic procedures). CED was > 75 mSv for one patient (0.43%), 36 patients (15.6%) had a CED between 20 and 75 mSv, 56 patients (24.3%) had a CED between 5 and 20 mSv, and in 138 patients (60%) the CED was estimated to be between 0 and 5 mSv over the study period. The mean annual CED per patient increased consecutively from 0.39 mSv/y to 0.47 mSv/y to 1.67 mSv/y over the tertiles one to three of the study period, respectively (P < .001). Thoracic imaging accounted for 46.9% of the total CED and abdominopelvic imaging accounted for 42.9% of the CED, respectively. There was an associated 5.9-fold increase in the use of all CT scanning per patient (P < .001). CONCLUSIONS: This study highlights the increasing exposure to ionizing radiation to patients with CF as a result of diagnostic imaging, primarily attributable to CT scanning. Increased awareness of CED and strategies to reduce this exposure are needed. PMID- 22207675 TI - Indium lung disease. AB - BACKGROUND: Reports of pulmonary fibrosis, emphysema, and, more recently, pulmonary alveolar proteinosis (PAP) in indium workers suggested that workplace exposure to indium compounds caused several different lung diseases. METHODS: To better understand the pathogenesis and natural history of indium lung disease, a detailed, systematic, multidisciplinary analysis of clinical, histopathologic, radiologic, and epidemiologic data for all reported cases and workplaces was undertaken. RESULTS: Ten men (median age, 35 years) who produced, used, or reclaimed indium compounds were diagnosed with interstitial lung disease 4-13 years after first exposure (n = 7) or PAP 1-2 years after first exposure (n = 3). Common pulmonary histopathologic features in these patients included intraalveolar exudate typical of alveolar proteinosis (n = 9), cholesterol clefts and granulomas (n = 10), and fibrosis (n = 9). Two patients with interstitial lung disease had pneumothoraces. Lung disease progressed following cessation of exposure in most patients and was fatal in two. Radiographic data revealed that two patients with PAP subsequently developed fibrosis and one also developed emphysematous changes. Epidemiologic investigations demonstrated the potential for exposure to respirable particles and an excess of lung abnormalities among coworkers. CONCLUSIONS: Occupational exposure to indium compounds was associated with PAP, cholesterol ester crystals and granulomas, pulmonary fibrosis, emphysema, and pneumothoraces. The available evidence suggests exposure to indium compounds causes a novel lung disease that may begin with PAP and progress to include fibrosis and emphysema, and, in some cases, premature death. Prospective studies are needed to better define the natural history and prognosis of this emerging lung disease and identify effective prevention strategies. PMID- 22207677 TI - 24/7 in-house intensivist coverage and fellowship education: a cross-sectional survey of academic medical centers in the United States. AB - OBJECTIVES: The objectives of this study were to determine the current staffing models of practice and the frequency of 24/7 coverage in academic medical centers in the United States and to assess the perceptions of critical care trainees and program directors toward these models. METHODS: A cross-sectional national survey was conducted using an Internet-based survey platform. The survey was distributed to fellows and program directors of 374 critical care training programs in US academic medical centers. RESULTS: We received 518 responses: 138 from program directors (PDs) (37% of 374 programs) and 380 fellow responses. Coverage by a board-certified or board-eligible intensivist physician 24/7 was reported by 33% of PD respondents and was more common among pediatric and surgical critical care programs. Mandatory in-house call for critical care trainees was reported by 48% of the PDs. Mandatory call was also more common among pediatric-critical care programs compared with the rest (P < .001). Advanced nurse practitioners with critical care training were reported available by 27% of the PDs. The majority of respondents believed that 24/7 coverage would be associated with better patient care in the ICU and improved education for the fellows, although 65% of them believed this model would have a negative impact on trainees' autonomy. CONCLUSIONS: Intensivist coverage 24/7 was not commonly used in US academic centers responding to our survey. Significant differences in coverage models among critical care medicine specialties appear to exist. Program director and trainee respondents believed that 24/7 coverage was associated with better outcomes and education but also expressed concerns about the impact of this model on fellows' autonomy. PMID- 22207676 TI - The association between a Darc gene polymorphism and clinical outcomes in African American patients with acute lung injury. AB - BACKGROUND: Acute lung injury (ALI) mortality is increased among African Americans compared with Americans of European descent, and genetic factors may be involved. A functional T-46C polymorphism (rs2814778) in the promoter region of Duffy antigen/receptor for chemokines (Darc) gene, present almost exclusively in people of African descent, results in isolated erythrocyte DARC deficiency and has been implicated in ALI pathogenesis in preclinical and murine models, possibly because of an increase in circulating Duffy-binding, proinflammatory chemokines like IL-8. We sought to determine the effect of the functional rs2814778 polymorphism, C/C genotype (Duffy null state), on clinical outcomes in African Americans with acute lung injury. METHODS: Clinical data and biologic specimens from African American patients with ALI who enrolled in three randomized controlled trials were analyzed. Multivariate analysis accounted for proportion of African ancestry, sex, cirrhosis, and severity of illness on presentation. RESULTS: Among 132 subjects, 88 (67%) were Duffy null (C/C genotype). The Duffy null state was associated with a 17% absolute risk increase (95% CI, 1.4%-33%) in mortality at 60 days, a median of 8 fewer ventilator-free days (95% CI, 1-18.5), and 4.5 fewer organ failure-free days (95% CI, 0-18) compared with individuals with the C/T or T/T genotypes (all P values < .05). Estimates were similar on multivariate analysis. In African Americans without the null variant, clinical outcomes were similar to those in patients of European descent. A subgroup analysis suggested that plasma IL-8 levels are increased in Duffy null individuals. CONCLUSIONS: Our results provide evidence that the functional rs2814778 polymorphism in the gene encoding DARC is associated with worse clinical outcomes among African Americans with ALI, possibly via an increase in circulating IL-8. PMID- 22207678 TI - The complex relationship of serum adiponectin to COPD outcomes COPD and adiponectin. AB - BACKGROUND: COPD is a chronic inflammatory disorder with high risk of cardiovascular morbidity and mortality. Adiponectin is a hormone that has anti inflammatory, antidiabetic, and anti atherogenic activities. We investigated the relationship of serum adiponectin to health outcomes in COPD. METHODS: We measured adiponectin levels in serum samples from participants of the Lung Health Study, who were smokers with mild to moderate airflow limitation. We determined the relationship of serum adiponectin to hospitalization and mortality using a Cox proportional hazards model and to baseline lung function measurements and bronchial reactivity using multiple regression methods. RESULTS: Serum adiponectin concentrations were inversely related to hospitalizations and mortality from coronary heart disease (hazard ratio [HR], 0.73; 95% CI, 0.62 0.86) and to cardiovascular disease (HR, 0.83; 95% CI, 0.73-0.94) and positively related to deaths from respiratory causes (HR, 2.09; 95% CI, 1.41-3.11). However, serum adiponectin concentrations were not significantly related to total mortality (HR, 1.10; 95% CI, 0.93-1.29) or cancer-related mortality(HR, 1.11; 95% CI, 0.92-1.34). Serum adiponectin concentrations were significantly related to increased bronchial reactivity and an accelerated decline in lung function (both P , .0001). Smoking status had no material influence on serum adiponectin concentrations. CONCLUSIONS: Adiponectin is a complex serum biomarker in COPD that is associated with decreased risk of cardiovascular events but increased risk of respiratory mortality. Because serum adiponectin is not significantly influenced by smoking status, it is a very promising biomarker of cardiovascular outcomes in COPD. PMID- 22207679 TI - The impact of COPD on management and outcomes of patients hospitalized with acute myocardial infarction: a 10-year retrospective observational study. AB - BACKGROUND: There are limited data describing contemporary trends in the management and outcomes of patients with COPD who develop acute myocardial infarction (AMI). METHODS: The study population consisted of patients hospitalized with AMI at all greater Worcester, Massachusetts, medical centers between 1997 and 2007. RESULTS: Of the 6,290 patients hospitalized with AMI, 17% had a history of COPD. Patients with COPD were less likely to be treated with beta-blockers or lipid-lowering therapy or to have undergone interventional procedures during their index hospitalization than patients without COPD. Patients with COPD were at higher risk for dying during hospitalization (13.5% vs 10.1%) and at 30 days after discharge (18.7% vs 13.2%), and their outcomes did not improve during the decade-long period under study. After multivariable adjustment, the adverse effects of COPD remained on both in-hospital (OR, 1.25; 95% CI, 0.99-1.50) and 30-day all-cause mortality (OR, 1.31; 95% CI, 1.10-1.58). The use of evidence-based therapies for all patients with AMI increased between 1997 and 2007, with a particularly marked increase for patients with COPD. CONCLUSIONS: Our results suggest that the gap in medical care between patients with and without COPD hospitalized with AMI narrowed substantially between 1997 and 2007. Patients with COPD, however, remain less aggressively treated and are at increased risk for hospital adverse outcomes than patients without COPD in the setting of AMI. Careful consideration is necessary to ensure that these high-risk complex patients are not denied the benefits of effective cardiac therapies. PMID- 22207680 TI - Prevalence and prognostic value of left ventricular diastolic dysfunction in idiopathic and heritable pulmonary arterial hypertension. AB - BACKGROUND: Little is known about the association between left ventricular (LV) diastolic dysfunction and outcomes in patients with idiopathic or heritable pulmonary arterial hypertension (PAH). Our rationale was to investigate the prevalence of LV diastolic dysfunction, and its association with disease severity and outcomes, in patients with idiopathic or heritable PAH. METHODS: Using the Cleveland Clinic Pulmonary Hypertension Registry, we identified subjects with heritable or idiopathic PAH who underwent Doppler echocardiography and right sided heart catheterization. Echocardiographic diastolic parameters were assessed in each patient. RESULTS: A total of 61 patients met the inclusion criteria (idiopathic 85%, heritable 15%). The age at the time of echocardiography was 48.3 +/- 18 years, 84% of the subjects were women, and 48% were on PAH-targeted therapies. Normal LV diastolic function, impaired relaxation, and pseudonormalization were seen in 10%, 88%, and 2% of the patients, respectively. Peak early diastolic (peak E) velocity was directly associated with LV end diastolic volume and cardiac index and inversely associated with the degree of right ventricular dilation, right atrial pressure, and pulmonary vascular resistance. Peak E velocity was associated with mortality adjusted for age and sex (hazard ratio [HR], 1.5; 95% CI, 1.1-2 per 10 cm/s decrease; P = .015) and age, sex, 6-min walk distance, and cardiac output (HR, 1.8; 95% CI, 1.2-2.9 per 10 cm/s decrease; P = .01). CONCLUSIONS: LV diastolic dysfunction of the impaired relaxation type is observed in the majority of patients with advanced idiopathic or heritable PAH. A decrease in transmitral flow peak E velocity is associated with worse hemodynamics and outcome. PMID- 22207681 TI - Precursor B-acute lymphoblastic leukemia occurring in patients with a history of prior malignancies: is it therapy-related? AB - BACKGROUND: Precursor B-acute lymphoblastic leukemia occurring in patients with a history of malignancies is uncommon, and this condition is not well understood. DESIGN AND METHODS: A retrospective review of 457 adults with precursor B-acute lymphoblastic leukemia treated at our hospital identified 44 (9.6%) patients with prior malignancies. The clinical and genetic characteristics of this group of patients was compared with those of their counterparts with de novo disease and the relationship with prior chemoradiation therapy was assessed. RESULTS: Thirty of 44(6.2%) patients received cytotoxic therapies, whereas 14 patients did not. The former group showed a significantly shorter interval from prior malignancy to onset of precursor B-acute lymphoblastic leukemia (36 versus 144 months; P = 0.002). Compared with 413 de novo cases, the frequencies of t(4;11)(q21;q23) (P<0.001) and hypodiploidy (P = 0.009) with loss of chromosome 5, 7 or 17 were significantly higher in patients who received topoisomerase II inhibitor and/or alkylating agents. By contrast, Philadelphia-positive and normal karyotype were more frequent in patients who either did not receive chemotherapy or received only local radiation or nucleoside analogs. Patients with precursor B-acute lymphoblastic leukemia following prior malignancies and chemoradiation were older, had a lower complete remission rate and showed an inferior survival in univariate, but not multivariate analysis. CONCLUSIONS: The data support the interpretation that therapy-related precursor B-acute lymphoblastic leukemia does occur. In particular, cases associated with t(4;11)(q21;q23) or hypodiploidy with -5, -7, -17 are likely to be therapy-related and have a poor prognosis. The inferior outcome of these patients may be attributable to the high-risk cytogenetic abnormalities that are found in this group of patients. PMID- 22207682 TI - Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis. AB - BACKGROUND: Iron metabolism, regulated by the iron hormone hepcidin, and oxygen homeostasis, dependent on hypoxia-inducible factors, are strongly interconnected. We previously reported that in mice in which both liver hypoxia-inducible factors 1 and -2 are stabilized (the hepatocyte von Hippel-Lindau knockout mouse model), hepcidin expression was strongly repressed and we hypothesized that hypoxia inducible factor-2 could be the major regulatory component contributing to the hepcidin down-regulation. DESIGN AND METHODS: We generated and analyzed hepatocyte-specific knockout mice harboring either hypoxia-inducible factor 2alpha deficiency (Hif2a knockout) or constitutive hypoxia-inducible factor 2alpha stabilization (Vhlh/Hif1a knockout) and ex vivo systems (primary hepatocyte cultures). Hif2a knockout mice were fed an iron-deficient diet for 2 months and Vhlh/Hif1a knockout mice were treated with neutralizing erythropoietin antibody. RESULTS: We demonstrated that hypoxia-inducible factor-2 is dispensable in hepcidin gene regulation in the context of an adaptive response to iron deficiency anemia. However, its overexpression in the double Vhlh/Hif1a hepatocyte-specific knockout mice indirectly down-regulates hepcidin expression through increased erythropoiesis and erythropoietin production. Experiments in primary hepatocytes confirmed the non-autonomous role of hypoxia-inducible factor 2 in hepcidin regulation. CONCLUSIONS: While our results indicate that hypoxia inducible factor-2 is not directly involved in hepcidin repression, they highlight the contribution of hepatic hypoxia-inducible factor-2 to the repression of hepcidin through erythropoietin-mediated increased erythropoiesis, a result of potential clinical interest. PMID- 22207683 TI - Positron emission tomography/computed tomography surveillance in patients with Hodgkin lymphoma in first remission has a low positive predictive value and high costs. AB - BACKGROUND: The value of performing post-therapy routine surveillance imaging in patients with Hodgkin lymphoma is controversial. This study evaluates the utility of positron emission tomography/computed tomography using 2-[18F]fluoro-2 deoxyglucose for this purpose and in situations with suspected lymphoma relapse. DESIGN AND METHODS: We conducted a multicenter retrospective study. Patients with newly diagnosed Hodgkin lymphoma achieving at least a partial remission on first line therapy were eligible if they received positron emission tomography/computed tomography surveillance during follow-up. Two types of imaging surveillance were analyzed: "routine" when patients showed no signs of relapse at referral to positron emission tomography/computed tomography, and "clinically indicated" when recurrence was suspected. RESULTS: A total of 211 routine and 88 clinically indicated positron emission tomography/computed tomography studies were performed in 161 patients. In ten of 22 patients with recurrence of Hodgkin lymphoma, routine imaging surveillance was the primary tool for the diagnosis of the relapse. Extranodal disease, interim positron emission tomography-positive lesions and positron emission tomography activity at response evaluation were all associated with a positron emission tomography/computed tomography-diagnosed preclinical relapse. The true positive rates of routine and clinically indicated imaging were 5% and 13%, respectively (P = 0.02). The overall positive predictive value and negative predictive value of positron emission tomography/computed tomography were 28% and 100%, respectively. The estimated cost per routine imaging diagnosed relapse was US$ 50,778. CONCLUSIONS: Negative positron emission tomography/computed tomography reliably rules out a relapse. The high false positive rate is, however, an important limitation and a confirmatory biopsy is mandatory for the diagnosis of a relapse. With no proven survival benefit for patients with a pre-clinically diagnosed relapse, the high costs and low positive predictive value make positron emission tomography/computed tomography unsuitable for routine surveillance of patients with Hodgkin lymphoma. PMID- 22207684 TI - The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells. AB - BACKGROUND: Inhibitors of nicotinamide phosphoribosyltransferase have recently been validated as therapeutic targets in leukemia, but the mechanism of leukemogenic transformation downstream of this enzyme is unclear. DESIGN AND METHODS: Here, we evaluated whether nicotinamide phosphoribosyltransferase's effects on aberrant proliferation and survival of myeloid leukemic cells are dependent on sirtuin and delineated the downstream signaling pathways operating during this process. RESULTS: We identified significant upregulation of sirtuin 2 and nicotinamide phosphoribosyltransferase levels in primary acute myeloid leukemia blasts compared to in hematopoietic progenitor cells from healthy individuals. Importantly, specific inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 significantly reduced proliferation and induced apoptosis in human acute myeloid leukemia cell lines and primary blasts. Intriguingly, we found that protein kinase B/AKT could be deacetylated by nicotinamide phosphoribosyltransferase and sirtuin 2. The anti-leukemic effects of the inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 were accompanied by acetylation of protein kinase B/AKT with subsequent inhibition by dephosphorylation. This leads to activation of glycogen synthase kinase-3 beta via diminished phosphorylation and, ultimately, inactivation of beta-catenin by phosphorylation. CONCLUSIONS: Our results provide strong evidence that nicotinamide phosphoribosyltransferase and sirtuin 2 participate in the aberrant proliferation and survival of leukemic cells, and suggest that the protein kinase B/AKT/ glycogen synthase kinase-3 beta/beta-catenin pathway is a target for inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 and, thereby, leukemia cell proliferation. PMID- 22207685 TI - Multiple myeloma shows no intra-disease clustering of immunoglobulin heavy chain genes. AB - BACKGROUND: Characterization of the immunoglobulin gene repertoire has improved our understanding of the immunopathogenesis of lymphoid tumors. Early B lymphocyte precursors of multiple myeloma are known to exist and might be susceptible to antigenic drive. DESIGN AND METHODS: To verify this hypothesis, we collected a database of 345 fully readable multiple myeloma immunoglobulin sequences. We characterized the immunoglobulin repertoire, analyzed the somatic hypermutation load, and investigated for stereotyped receptor clusters. RESULTS: Compared to the normal immunoglobulin repertoire, multiple myeloma displayed only modest differences involving only a few genes, showing that the myeloma immunoglobulin repertoire is the least skewed among mature B-cell tumors. Median somatic hypermutation load was 7.8%; median length of complementarity determining region 3 was 15.5 amino acids. Clustering analysis showed the absence of myeloma specific clusters and no similarity with published chronic lymphocytic leukemia or lymphoma subsets. CONCLUSIONS: Analysis of multiple myeloma immunoglobulin repertoire does not support a pathogenetic role for antigen selection in this tumor. PMID- 22207686 TI - Physical contact with endothelial cells through beta1- and beta2- integrins rescues chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis and induces a peculiar gene expression profile in leukemic cells. AB - BACKGROUND: Chronic lymphocytic leukemia B cells display prolonged survival in vivo, but when cultured in vitro rapidly undergo spontaneous apoptosis. We hypothesize that interactions with endothelial cells in infiltrated tissues and during recirculation may have a pathogenic role in chronic lymphocytic leukemia. DESIGN AND METHODS: We evaluated apoptosis of leukemic cells after co-culture on a monolayer of human umbilical vein endothelial cells with addition of fludarabine and antibodies that block adhesion. Then, we compared microarray based gene expression profiles between leukemic cells at baseline and after co culture. RESULTS: We found that the endothelial layer protected leukemic cells from apoptosis inducing a 2-fold mean decrement in apoptotic cells after 2 days of co-culture. Moreover, the endothelial layer decreased the sensitivity of chronic lymphocytic leukemia B cells to fludarabine-induced apoptosis. Physical contact with endothelium mediated by both beta(1)- and beta(2)- integrins is essential for the survival advantage of leukemic cells. In particular, blocking CD106 on endothelial cells or CD18 on leukemic B cells led to the almost complete abrogation of the survival advantage (>70% inhibition of viability). However, a reduction of apoptosis was also measured in leukemic cells cultured in conditioned medium collected after 2 days of co-culture, implying that survival is partially mediated by soluble factors. Overall, the contact with endothelial cells modulated 1,944 genes in chronic lymphocytic leukemia B cells, establishing a peculiar gene expression profile: up-regulation of angiogenesis-related genes, an increase of genes involved in TGFbeta and Wnt signaling pathways, secretion of cytokines recruiting stromal cells and macrophages and up-regulation of anti apoptotic molecules such as Bcl2 and Survivin. CONCLUSIONS: Our study supports the notion that endothelial cells are major players in the chronic lymphocytic leukemia microenvironment. Adhesion to endothelium strongly supports survival, protects from drug-induced apoptosis and extensively modifies the gene expression profile of leukemic cells. PMID- 22207687 TI - Varicella-zoster virus glycoproteins B and E are major targets of CD4+ and CD8+ T cells reconstituting during zoster after allogeneic transplantation. AB - BACKGROUND: After allogeneic hematopoietic stem-cell transplantation patients are at increased risk for herpes zoster as long as varicella-zoster virus specific T cell reconstitution is impaired. This study aimed to identify immunodominant varicella-zoster virus antigens that drive recovery of virus-specific T cells after transplantation. DESIGN AND METHODS: Antigens were purified from a varicella-zoster virus infected cell lysate by high-performance liquid chromatography and were identified by quantitative mass spectrometric analysis. To approximate in vivo immunogenicity for memory T cells, antigen preparations were consistently screened with ex vivo PBMC of varicella-zoster virus immune healthy individuals in sensitive interferon-gamma ELISpot assays. Candidate virus antigens identified by the approach were genetically expressed in PBMC using electroporation of in vitro transcribed RNA encoding full-length proteins and were then analyzed for recognition by CD4(+) and CD8(+) memory T cells. RESULTS: Varicella-zoster virus encoded glycoproteins B and E, and immediate early protein 62 were identified in immunoreactive lysate material. Predominant CD4(+) T-cell reactivity to these proteins was observed in healthy virus carriers. Furthermore, longitudinal screening in allogeneic stem-cell transplantation patients showed strong expansions of memory T cells recognizing glycoproteins B and E after onset of herpes zoster, while immediate early protein 62 reactivity remained moderate. Reactivity to viral glycoproteins boosted by acute zoster was mediated by both CD4(+) and CD8(+) T cells. CONCLUSIONS: Our data demonstrate that glycoproteins B and E are major targets of varicella-zoster virus specific CD4(+) and CD8(+) T cell reconstitution occurring during herpes zoster after allogeneic stem-cell transplantation. Varicella-zoster virus glycoproteins B and E might form the basis for novel non-hazardous zoster subunit vaccines suitable for immunocompromised transplant patients. PMID- 22207688 TI - A20 inactivation in ocular adnexal MALT lymphoma. AB - Recent studies showed A20 inactivation by deletion, mutation and promoter methylation in ocular adnexal mucosa-associated lymphoid tissue lymphoma. However, the incidences of A20 abnormalities and their clinical impact remain for the most part unknown. It is also unknown whether ABIN-1 and ABIN-2, the components of the A20 NF-kappaB inhibitor complex, are inactivated by genetic changes in ocular adnexal mucosa-associated lymphoid tissue lymphoma. A total of 105 cases were investigated for A20 mutation/deletion, ABIN-1/2 mutation, MALT1 and IGH involved translocation. Somatic mutation was seen frequently in A20 (28.6%) but rarely in ABIN-1 (1%) and ABIN-2 (1%). A20 mutations were significantly associated with A20 heterozygous deletion, and both were mutually exclusive from the MALT1 or IGH involved translocations. A20 mutation/deletion was also significantly associated with increased expression of the NF-kappaB target genes CCR2, TLR6 and BCL2. The cases with A20 mutation/deletion required significantly higher radiation dosages to achieve complete remission than those without these abnormalities. PMID- 22207689 TI - Biogenesis of Weibel-Palade bodies in von Willebrand's disease variants with impaired von Willebrand factor intrachain or interchain disulfide bond formation. AB - BACKGROUND: Mutations of cysteine residues in von Willebrand factor are known to reduce the storage and secretion of this factor, thus leading to reduced antigen levels. However, one cysteine mutation, p.Cys2773Ser, has been found in patients with type 2A(IID) von Willebrand's disease who have normal plasma levels of von Willebrand factor. We hypothesize that disruption of either intra- or interchain disulfide bonds by cysteine mutations in von Willebrand factor has different effects on the biogenesis of Weibel-Palade bodies. DESIGN AND METHODS: The effect of specific cysteine mutations that either disrupt intrachain (p.Cys1130Phe and p.Cys2671Tyr) or interchain (p.Cys2773Ser) disulfide bonds on storage and secretion of von Willebrand factor was studied by transient transfection of human embryonic kidney cell line 293. Upon expression of von Willebrand factor these cells formed endothelial Weibel-Palade body-like organelles called pseudo-Weibel Palade bodies. Storage of von Willebrand factor was analyzed with both confocal immunofluorescence and electron microscopy. Regulated secretion of von Willebrand factor was induced by phorbol 12-myristate 13-acetate. RESULTS: p.Cys1130Phe and p.Cys2671Tyr reduced the storage of von Willebrand factor into pseudo-Weibel Palade bodies with notable retention of von Willebrand factor in the endoplasmic reticulum, whereas p.Cys2773Ser-von Willebrand factor was stored normally. As expected, wild-type von Willebrand factor formed proteinaceous tubules that were seen under electron microscopy as longitudinal striations in pseudo-Weibel-Palade bodies. p.Cys2773Ser caused severe defects in von Willebrand factor multimerization but the factor formed normal tubules. Furthermore, the basal and regulated secretion of von Willebrand factor was drastically impaired by p.Cys1130Phe and p.Cys2671Tyr, but not by p.Cys2773Ser. CONCLUSIONS: We postulate that natural mutations of cysteines involved in the formation of interchain disulfide bonds do not affect either the storage in Weibel-Palade bodies or secretion of von Willebrand factor, whereas mutations of cysteines forming intrachain disulfide bonds lead to reduced von Willebrand factor storage and secretion because the von Willebrand factor is retained in the endoplasmic reticulum. PMID- 22207690 TI - Chronic phase chronic myeloid leukemia patients with low OCT-1 activity randomized to high-dose imatinib achieve better responses and have lower failure rates than those randomized to standard-dose imatinib. AB - BACKGROUND: The functional activity of the organic cation transporter 1 (OCT-1) protein (OCT-1 activity) is an excellent predictor of molecular response and progression-free survival in patients with newly diagnosed chronic phase chronic myeloid leukemia treated with imatinib as front-line therapy. DESIGN AND METHODS: In this study the predictive value of OCT-1 activity in patients treated with imatinib 400 mg/day or 800 mg/day was evaluated in relation to trough imatinib plasma levels assessed in 100 patients enrolled in the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial. RESULTS: The rate of major molecular responses by 24 months in patients on imatinib 400 mg/day was significantly higher in those with high OCT-1 activity than in those with low OCT-1 activity (low OCT-1 activity, 57% of patients; high OCT-1 activity, 100%; P < 0.001); the corresponding difference in patients treated with imatinib 800 mg/day did not reach statistical significance (low OCT-1 activity, 68%; high OCT-1 activity, 95%; P = 0.073). In addition, the combination of low trough imatinib levels (< 1200 ng/mL) and low OCT-1 activity defined a group of patients who had the lowest rates of major molecular response (47%) by 24 months compared to all other patients (81%, P = 0.009). These patients were also at the highest risk of failed imatinib therapy when compared to all other patients (P<0.001). CONCLUSIONS: High dose imatinib leads to superior molecular responses in patients with low OCT-1 activity. In this group trough imatinib levels may define a group with inferior outcomes. Among patients with high OCT-1 activity, neither higher imatinib dose nor monitoring imatinib trough levels was found to be of significant clinical value. Hence OCT-1 activity determined prior to the start of therapy in newly diagnosed CML patients provides a valuable prognostic tool to determine the optimal up-front dose of imatinib in patients with newly diagnosed chronic phase chronic myeloid leukemia. PMID- 22207691 TI - NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL. AB - Trisomy 12, the third most frequent chromosomal aberration in chronic lymphocytic leukemia (CLL), confers an intermediate prognosis. In our cohort of 104 untreated patients carrying +12, NOTCH1 mutations occurred in 24% of cases and were associated to unmutated IGHV genes (P=0.003) and +12 as a sole cytogenetic abnormality (P=0.008). NOTCH1 mutations in +12 CLL associated with an approximately 2.4 fold increase in the risk of death, a significant shortening of survival (P<0.01) and proved to be an independent predictor of survival in multivariate analysis. Analogous to +12 CLL with TP53 disruption or del(11q), NOTCH1 mutations in +12 CLL conferred a significantly worse survival compared to that of +12 CLL with del(13q) or +12 only. The overrepresentation of cell cycle/proliferation related genes of +12 CLL with NOTCH1 mutations suggests the biological contribution of NOTCH1 mutations to determine a poor outcome. NOTCH1 mutations refine the intermediate prognosis of +12 CLL. PMID- 22207693 TI - Job satisfaction and career commitment among Alzheimer's care providers: addressing turnover and improving staff empowerment. AB - This study investigated the relation between job satisfaction and career commitment among 262 Alzheimer's care staff working in long-term and community based care settings. It was anticipated that the results would suggest whether career commitment could be enhanced to positively influence job satisfaction, and conversely, if improvements in job satisfaction might contribute to a deepened sense of vocational empowerment. Participants attended dementia-specific training and completed 2 short work-related questionnaires that measured job satisfaction and career commitment. The results of stepwise regression revealed interrelations between the 2 constructs. Congruence appeared to be reciprocal with respect to the overall scale scores and the intrinsic job satisfaction measure. Unexpected relations appeared in analyses of the extrinsic job satisfaction measure and the career planning subscale. Results are indicative of the fundamental distinction between job satisfaction and career commitment. Implications for efforts to reduce turnover and improve staff empowerment are also considered. PMID- 22207695 TI - Sternal wire-grip: a new device in the surgical armamentarium. AB - We describe a new wire-grip that enhances the surgeon's grip on sternal wires and facilitates their tightening with minimal risk of slips. This wire-grip should protect against operating room personnel injury during sternal re-approximation. PMID- 22207697 TI - Infants exposed to fluent natural speech succeed at cross-gender word recognition. AB - PURPOSE: To examine the possibility that early signal-to-word form mapping capabilities are robust enough to handle substantial indexical variation in the realization of words. METHOD: Two groups of 7.5-month-olds were tested with the Headturn Preference Procedure. Half of the infants were exposed to words embedded in passages spoken by their mothers and tested on lists of trained and novel isolated words spoken by their fathers. The other half of the infants were yoked pairs listening to unfamiliar speakers. RESULTS: In the test phase, infants listened longer to trained than to novel words, indicating that they successfully segmented the words from the passages. This result was not modulated by infants' familiarity with the speaker. CONCLUSIONS: Under more naturalistic listening conditions, 7.5-month-olds exhibit the ability to recognize words in the face of substantial indexical variation regardless of whether speakers are familiar. This suggests that early word representations are, at least to some extent, independent of the speaker's gender and may reflect sophisticated abstraction capabilities on the part of the infants, which would render extreme episodic models of early speech perception untenable. Additional research using similarly ecologically valid testing methods is called for to elucidate the precise nature of early word representations. PMID- 22207696 TI - Consequences of broad auditory filters for identification of multichannel compressed vowels. AB - PURPOSE: In view of previous findings (Bor, Souza, & Wright, 2008) that some listeners are more susceptible to spectral changes from multichannel compression (MCC) than others, this study addressed the extent to which differences in effects of MCC were related to differences in auditory filter width. METHOD: Listeners were recruited in 3 groups: listeners with flat sensorineural loss, listeners with sloping sensorineural loss, and a control group of listeners with normal hearing. Individual auditory filter measurements were obtained at 500 and 2000 Hz. The filter widths were related to identification of vowels processed with 16-channel MCC and with a control (linear) condition. RESULTS: Listeners with flat loss had broader filters at 500 Hz but not at 2000 Hz compared with listeners with sloping loss. Vowel identification was poorer for MCC compared with linear amplification. Listeners with flat loss made more errors than listeners with sloping loss, and there was a significant relationship between filter width and the effects of MCC. CONCLUSIONS: Broadened auditory filters can reduce the ability to process amplitude-compressed vowel spectra. This suggests that individual frequency selectivity is a factor that influences benefit of MCC when a high number of compression channels are used. PMID- 22207698 TI - Random versus blocked practice in treatment for childhood apraxia of speech. AB - PURPOSE: To compare the relative effects of random vs. blocked practice schedules in treatment for childhood apraxia of speech (CAS). Although there have been repeated suggestions in the literature to use random practice in CAS treatment, no systematic studies exist that have directly compared random with blocked practice in this population. METHOD: Using an alternating treatments single subject design with multiple baselines across behaviors, the authors compared random and blocked practice in 4 children diagnosed with CAS in terms of retention and transfer. Random and blocked practice were implemented in the context of a version of Dynamic Temporal and Tactile *Cueing treatment (Strand, Stoeckel, & Baas, 2006). Perceptual accuracy of target utterances was scored, and effect sizes were calculated to quantify the magnitude of treatment effects. RESULTS: Findings were mixed, with 2 children showing a blocked practice advantage, 1 child showing a random practice advantage, and 1 child showing no clear improvement in either condition. CONCLUSIONS: These findings suggest that the random practice advantage observed in the nonspeech motor learning literature may not extend to treatment for CAS. Furthermore, the findings add to the small body of literature indicating that integral stimulation treatment can lead to improvements in speech production for children with CAS. PMID- 22207699 TI - Lexical and phonological effects in early word production. AB - PURPOSE: This study examines the influence of word frequency, phonological neighborhood density (PND), age of acquisition (AoA), and phonotactic probability on production variability and accuracy of known words by toddlers with no history of speech, hearing, or language disorders. METHOD: Fifteen toddlers between 2;0 (years;months) and 2;5 produced monosyllabic target words varying in word frequency, PND, AoA, and phonotactic probability. Phonetic transcription was used to determine (a) whole-word variability and (b) proportion of whole-word proximity (PWP; Ingram, 2002) of each target word produced. RESULTS: Results show a significant effect of PND on PWP and variability (words from dense neighborhoods had higher PWP and lower variability than those from sparse neighborhoods), a significant effect of word frequency on variability (high frequency words were less variable) but not proximity, and a significant effect of AoA on proximity (earlier acquired words had lower PWP) but not variability. CONCLUSIONS: Results provide new information regarding the role that lexical and phonological factors play in the speech of young children; specifically, several factors are identified that influence variability of production. Additionally, by examining lexical and phonological factors simultaneously, the current study isolates differential effects of the individual factors. Implications for our understanding of emerging phonological representations are discussed. PMID- 22207700 TI - Animation of graphic symbols representing verbs and prepositions: effects on transparency, name agreement, and identification. AB - PURPOSE: The effects of animation on transparency, name agreement, and identification of graphic symbols for verbs and prepositions were evaluated in preschoolers of 3 age groups. Methods A mixed-group design was used; in each age group, half of the children were randomly allocated to 1 of 2 orders of symbol formats. The 52 children were asked to guess the meaning of symbols and to identify a target symbol among foils given the spoken label. RESULTS: Animated symbols were more transparent than static symbols, although this was more pronounced for verbs. Animated verbs were named more accurately than static verbs, but there was no difference between animated and static prepositions. Verbs were identified more accurately compared with prepositions, but there was no difference between symbol formats. Older children guessed, named, and identified symbols more effectively than younger children. CONCLUSION: Animation enhances transparency and name agreement, especially for verbs, which reduces the instructional burden that comes with nontransparent symbols. Animation does not enhance identification accuracy. Verbs are easier to identify than prepositions. A developmental effect was observed for each measure. Limitations and implications for future research are discussed. PMID- 22207701 TI - The effect of intertalker variations on acoustic-perceptual mapping in Cantonese and Mandarin tone systems. AB - PURPOSE: This study investigates the impact of intertalker variations on the process of mapping acoustic variations on tone categories in two different tone languages. METHOD: Pitch stimuli manipulated from four voice ranges were presented in isolation through a blocked-talker design. Listeners were instructed to identify the stimuli that they heard as lexical tones in their native language. RESULTS: Tone identification of Mandarin listeners exhibited relatively stable normalization regardless of the voice, whereas tone identification of Cantonese listeners was unstable and susceptible to the influence of intertalker variations. In the case of Cantonese listeners, intertalker variations had a larger effect on the perception of F0 height dimension than of F0 slope dimension. CONCLUSION: The comparison between Cantonese and Mandarin listeners' performances reveals an interaction of intertalker variations and the types of tone contrasts in each language. For Cantonese tones, which depend heavily on F0 height distinctions, intertalker variations result in F0 overlapping and, consequently, ambiguities among them in isolated tone perception. For Mandarin tones, which are distinctive in terms of their F0 contours, the differences in F0 contours alone seem sufficient to elicit reliable tone identification. Intertalker variations therefore have relatively limited effect on Mandarin tone perception. PMID- 22207702 TI - La autoantigen mediates oxidant induced de novo Nrf2 protein translation. AB - Nrf2 gene encodes a transcription factor that regulates the expression of a cluster of antioxidant and detoxification genes. Recent works from our laboratory indicate that oxidative stress causes rapid de novo synthesis of Nrf2 protein. We have found that 5' Untranslated Region (5'UTR) of Nrf2 allows the mRNA to undergo an Internal Ribosomal Entry Site (IRES) mediated protein translation. Using liquid chromatography tandem MS, we have discovered that La/SSB protein bound to Nrf2 5'UTR in response to oxidative stress. In vitro RNA binding and in vivo ribonucleoprotein immunoprecipitation showed H(2)O(2) dose and time dependent increases of La/SSB binding to Nrf2 5'UTR. La/SSB protein translocated from the nuclei to cytoplasm and distributed in the perinuclear space in cells treated with H(2)O(2). Isolation of ribosomal fractions indicated that oxidants caused an association of La/SSB with ribosomes. Physical interaction of La/SSB with representative proteins from the small or large subunits of ribosomes was found to increase in cells responding to H(2)O(2) treatment. Knocking down La/SSB gene with siRNA prevented Nrf2 protein elevation or Nrf2 5'UTR activation by oxidants. In contrast, overexpression of La/SSB gene was able to enhance Nrf2 5'UTR activation and Nrf2 protein increase. Our data suggest that oxidants cause nuclear export of La/SSB protein and subsequent association of La/SSB with Nrf2 5'UTR and ribosomes. These events contribute to de novo Nrf2 protein translation because of oxidative stress. PMID- 22207703 TI - Chronic pelvic pain syndrome and semen quality of Korean men in their fourth decade. AB - Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common condition that adversely affects men across a wide range of ages. A number of pharmacologic and nonpharmacologic therapies for CP/CPPS have been investigated. Our study aimed to evaluate the prevalence of CPPS in Korean men in their thirties and to investigate the effect of CPPS and medical treatment on semen quality. Of 314 men with prostatitis, 74 patients with CPPS class IIIA (23.6%) were eligible for the study; these patients underwent combined alpha-blocker and cyclo-oxygenase 2 inhibitor therapy. These 74 men were prospectively studied at a medical center in Seoul, Korea. A number of parameters, including ejaculations per month, semen variables, and the levels of hormones (such as follicle stimulating hormone, estradiol [E(2)], luteinizing hormone [LH], testosterone, and prolactin) were evaluated. The mean number of ejaculations per month, the mean number of daily hours spent sitting at work, smoking, body mass index, LH and E(2) levels, and semen parameters all showed significant differences (P < .0001) between the study patients and the controls. The combined regimen was effective in improving all aspects of semen quality except morphology (P < .05). CPPS class IIIA, which is notably prevalent among Korean men in the fourth decade of life, affects semen quality and poses a challenge to fertility. Proper treatment of CPPS class IIIA results in improved semen quality. Men with CPPS therefore require proper evaluation and treatment by andrologists/urologists before planning a natural conception. PMID- 22207704 TI - Epididymosome-mediated acquisition of MMSDH, an androgen-dependent and developmentally regulated epididymal sperm protein. AB - A differential proteomics approach led to the identification of several novel epididymal sperm proteins. One of the novel proteins was methylmalonate semialdehyde dehydrogenase (MMSDH). In the present study, we carried out an in depth characterization to study its regulation by androgen, its appearance during ontogeny, and the mechanism of its interaction with and acquisition by the sperm. Western blotting and immunohistochemical studies suggest that the protein is present in both tissue and sperm from all regions of the epididymis, indicating synthesis as well as acquisition of the protein in these regions. Androgen depletion resulted in reduction of the MMSDH protein level in the epididymis, which completely disappeared 1 week after castration. The protein reappeared after testosterone propionate injection, indicating that the protein is regulated by androgens. Ontogeny studies indicated that the protein appeared from day 10 postnatal with a gradual increase at day 30, which maximized at day 50, indicating that the protein is developmentally regulated and is probably involved in epididymal development. Sequential extraction of sperm proteins indicated that MMSDH exists both as a peripheral and integral form on the plasma membrane. We also found that the protein can be transferred from the epididymosomes to testicular sperm in vitro. The study provides evidence regarding the acquisition of this multidomain androgen and developmentally regulated protein in the epididymis via the epididymosomes. The molecule has generated enough interest and deserves to be investigated further for its physiological relevance. PMID- 22207705 TI - Nitric oxide may mediate nipple erection. AB - The nipple is a specialized structure that can become erect by cold, sexual arousal, breast-feeding, or other tactile stimulations, which can induce the milk ejection reflex and sexual arousal because of intense sensory innervation. The studies that have been conducted thus far to identify the mechanism of nipple erection (NE) are not sufficient. It has been stated that NE occurs via activation of the sympathetic nervous system and smooth muscle contraction. The purposes of this study were to investigate the existence of nitric oxide synthase (NOS) in the nipple-areola complex (NAC) to explain the NE mechanism. Considering that smooth muscle relaxation might be effective in NE, endothelial and neuronal NOS expression and localization were investigated via immunohistochemical methods on sagittal sections from 17 human NACs. The results of this study indicate that eNOS is expressed in the vascular endothelium, ductal epithelium, and smooth muscles, whereas nNOS is expressed in the neural fibers, smooth muscles, ductal epithelium, and vascular endothelium in the NAC. Sinusoidal spaces with endothelial layers similar to those found in penile cavernosal tissue are not found in the NAC. Various mediators are known to affect the function of the NAC smooth muscles; however, this study demonstrates that enzymes (eNOS and nNOS) that synthesize nitric oxide are expressed in the NAC. PMID- 22207706 TI - Use of human chorionic gonadotropin in a male Pacific walrus (Odobenus rosmarus divergens) to induce rut and achieve a pregnancy in a nulliparous female. AB - Walrus in US zoos have a very low reproductive rate of 11 births in 80 years, and little is known about Pacific walrus (Odobenus rosmarus divergens) reproductive biology. To address this, we initiated a program in which detailed biological data were recorded on captive walrus. As part of a 7-year study, 1 male and 1 female 16-year-old captive Pacific walrus were carefully monitored with weekly serum hormone analysis, daily glans penis smears for spermatozoa, and abdominal ultrasound for pregnancy. The female ovulated once annually from late December through mid-January and then exhibited 9 months of sustained elevated progesterone. This nonconceptive estrous cycle profile is consistent with reports from wild walrus females. In contrast, the male's seasonal rut routinely occurred in late February through May with a serum testosterone peak in March. This profile differed from the reported adult male cycle in wild walrus of November through March. During the period of the female's ovulation, the male had nadir testosterone levels and was consistently azoospermic. Likewise, during the male's spermatogenic rut in the spring, the female was anovulatory with elevated progesterone. On this basis, the male was treated for 14 weeks with human chorionic gonadotropin (hCG) in an attempt to increase testosterone levels in synchrony with the female's annual ovulation. The treatment successfully induced rut characterized by sustained elevated serum testosterone levels and production of spermatozoa. The male and female successfully bred, and the female became pregnant. Upon discontinuation of hCG treatment, the male resumed baseline testosterone levels. We theorize that the lack of synchronization of rut and ovulatory cycles is a primary reason for reproductive failure in these captive walrus. PMID- 22207707 TI - Prospective inverse associations of sex hormone concentrations in men with biomarkers of inflammation and oxidative stress. AB - The suggested associations between sex hormone concentrations and inflammatory biomarkers in men originate from cross-sectional studies and small-scale clinical trials. But prior studies have not investigated longitudinal associations. Overall, 1344 men aged 20-79 years from the population-based cohort Study of Health in Pomerania were followed up for 5.0 (median) years. We used multivariable regression models to analyze cross-sectional and longitudinal associations of serum sex hormone concentrations (total testosterone [TT], sex hormone-binding globulin [SHBG], calculated free testosterone [free T], and dehydroepiandrosterone sulfate [DHEAS]) with biomarkers of inflammation (fibrinogen, high-sensitive C-reactive protein [hsCRP], and white blood cell count [WBC]) and oxidative stress (gamma-glutamyl transferase [GGT]) using ordinary least square regression and generalized estimating equation models, respectively. Cross-sectional models revealed borderline associations of sex hormone concentrations with hsCRP, WBC, and GGT levels that were not retained after multivariable adjustment. Longitudinal multivariable analyses revealed an inverse association of baseline TT, free T, and DHEAS concentrations with change in fibrinogen levels (per SD decrement in TT, 0.25 [95% confidence interval, 0.04-0.45]; in free T, 0.30 [0.09-0.51]; and in DHEAS, 0.23 [0.11-0.36]). Furthermore, baseline DHEAS concentrations were inversely associated with change in WBC levels (per SD decrement, 0.53 [0.24-0.82]). Baseline TT, SHBG, free T, and DHEAS concentrations were also inversely associated with change in GGT after multivariable adjustment. The present study is the first to demonstrate prospective inverse associations between sex hormone concentrations and markers of inflammation and oxidative stress in men. Additional studies are warranted to elucidate potential mechanisms underlying the revealed associations. PMID- 22207708 TI - A new practical model of testes shield: the effectiveness during abdominopelvic computed tomography. AB - The goal of our prospective study was to measure the effect of a new standard model male gonad shield on the testicular radiation exposure during routine abdominopelvic computed tomography (CT). Two hundred male patients who underwent upper abdominal and pelvic CT examinations were included in our study. To prepare the testes shield (TS), 2 No. 8 fluoroscopy radiation-protection gloves made of bismuth (0.35 mm lead equivalent) were used. These gloves were invaginated into one another and their fingers were turned inside out. Scrotums of all patients were pushed into these lead-containing gloves. Upper abdominal CT (n = 6), pelvic CT (n = 9), and abdominopelvic scanning (n = 185) were performed. Immediately after the CT examinations and at postprocedural day 1, the scrotal examinations were repeated. None of the patients exhibited scrotal laceration, edema, eruption, erythema, tenderness, or pain. During the CT examinations, 22 patients (11%) felt unrest because of their exposed genital regions, without any adverse effect on the procedure. Dosimetric measurements of radioactivity inside the TS (dosimeter I) and outside it (dosimeter II) were 6.8 and 69.00 mSv, respectively. Accordingly, the TS we used in our study reduced the radiation exposure of the testes by 90.2% (10.1 times). We think that the use of this radioprotective TS during radiological diagnostic and therapeutic procedures is an appropriate approach from both a medical and legal perspective. Therefore, we recommend this userfriendly, practical, low-cost, and effective TS for all radiologic procedures. PMID- 22207709 TI - High-mobility group A1 protein: a new coregulator of peroxisome proliferator activated receptor-gamma-mediated transrepression in the vasculature. AB - RATIONALE: The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) is an important regulator of gene transcription in vascular cells and mediates the vascular protection observed with antidiabetic glitazones. OBJECTIVE: To determine the molecular mechanism of ligand-dependent transrepression in vascular smooth muscle cells and their impact on the vascular protective actions of PPARgamma. METHODS AND RESULTS: Here, we report a molecular pathway in vascular smooth muscle cells by which ligand-activated PPARgamma represses transcriptional activation of the matrix-degrading matrix metalloproteinase-9 (MMP-9) gene, a crucial mediator of vascular injury. PPARgamma-mediated transrepression of the MMP-9 gene was dependent on the presence of the high-mobility group A1 (HMGA1) protein, a gene highly expressed in vascular smooth muscle cells, newly identified by oligonucleotide array expression analysis. Transrepression of MMP-9 by PPARgamma and regulation by HMGA1 required PPARgamma SUMOylation at K367. This process was associated with formation of a complex between PPARgamma, HMGA1, and the SUMO E2 ligase Ubc9 (ubiquitin-like protein SUMO-1 conjugating enzyme). After PPARgamma ligand stimulation, HMGA1 and PPARgamma were recruited to the MMP-9 promoter, which facilitated binding of SMRT (silencing mediator of retinoic acid and thyroid hormone receptor), a nuclear corepressor involved in transrepression. The relevance of HMGA1 for vascular PPARgamma signaling was underlined by the complete absence of vascular protection through a PPARgamma ligand in HMGA1(-/-) mice after arterial wire injury. CONCLUSIONS: The present data suggest that ligand-dependent formation of HMGA1-Ubc9-PPARgamma complexes facilitates PPARgamma SUMOylation, which results in the prevention of SMRT corepressor clearance and induction of MMP-9 transrepression. These data provide new information on PPARgamma-dependent vascular transcriptional regulation and help us to understand the molecular consequences of therapeutic interventions with PPARgamma ligands in the vasculature. PMID- 22207710 TI - FRS2alpha-mediated FGF signals suppress premature differentiation of cardiac stem cells through regulating autophagy activity. AB - RATIONALE: Although the fibroblast growth factor (FGF) signaling axis plays important roles in heart development, the molecular mechanism by which the FGF regulates cardiogenesis is not fully understood. OBJECTIVE: To investigate the mechanism by which FGF signaling regulates cardiac progenitor cell differentiation. METHODS AND RESULTS: Using mice with tissue-specific ablation of FGF receptors and FGF receptor substrate 2alpha (Frs2alpha) in heart progenitor cells, we demonstrate that disruption of FGF signaling leads to premature differentiation of cardiac progenitor cells in mice. Using embryoid body cultures of mouse embryonic stem cells, we reveal that FGF signaling promotes mesoderm differentiation in embryonic stem cells but inhibits cardiomyocyte differentiation of the mesoderm cells at later stages. Furthermore, we also report that inhibiting FRS2alpha-mediated signals increases autophagy and that activating autophagy promotes myocardial differentiation and vice versa. CONCLUSIONS: The results indicate that the FGF/FRS2alpha-mediated signals prevent premature differentiation of heart progenitor cells through suppressing autophagy. The findings provide the first evidence that autophagy plays a role in heart progenitor differentiation. PMID- 22207711 TI - Inhalation of nitric oxide prevents ischemic brain damage in experimental stroke by selective dilatation of collateral arterioles. AB - RATIONALE: Stroke is the third most common cause of death in industrialized countries. The main therapeutic target is the ischemic penumbra, potentially salvageable brain tissue that dies within the first few hours after blood flow cessation. Hence, strategies to keep the penumbra alive until reperfusion occurs are needed. OBJECTIVE: To study the effect of inhaled nitric oxide on cerebral vessels and cerebral perfusion under physiological conditions and in different models of cerebral ischemia. METHODS AND RESULTS: This experimental study demonstrates that inhaled nitric oxide (applied in 30% oxygen/70% air mixture) leads to the formation of nitric oxide carriers in blood that distribute throughout the body. This was ascertained by in vivo microscopy in adult mice. Although under normal conditions inhaled nitric oxide does not affect cerebral blood flow, after experimental cerebral ischemia induced by transient middle cerebral artery occlusion it selectively dilates arterioles in the ischemic penumbra, thereby increasing collateral blood flow and significantly reducing ischemic brain damage. This translates into significantly improved neurological outcome. These findings were validated in independent laboratories using two different mouse models of cerebral ischemia and in a clinically relevant large animal model of stroke. CONCLUSIONS: Inhaled nitric oxide thus may provide a completely novel strategy to improve penumbral blood flow and neuronal survival in stroke or other ischemic conditions. PMID- 22207712 TI - Vascular bioactivation of nitroglycerin is catalyzed by cytosolic aldehyde dehydrogenase-2. AB - RATIONALE: According to general view, aldehyde dehydrogenase-2 (ALDH2) catalyzes the high-affinity pathway of vascular nitroglycerin (GTN) bioactivation in smooth muscle mitochondria. Despite having wide implications to GTN pharmacology and raising many questions that are still unresolved, mitochondrial bioactivation of GTN in blood vessels is still lacking experimental support. OBJECTIVE: In the present study, we investigated whether bioactivation of GTN is affected by the subcellular localization of ALDH2 using immortalized ALDH2-deficient aortic smooth muscle cells and mouse aortas with selective overexpression of the enzyme in either cytosol or mitochondria. METHODS AND RESULTS: Quantitative Western blotting revealed that ALDH2 is mainly cytosolic in mouse aorta and human coronary arteries, with only approximately 15% (mouse) and approximately 5% (human) of the enzyme being localized in mitochondria. Infection of ALDH2 deficient aortic smooth muscle cells or isolated aortas with adenovirus containing ALDH2 cDNA with or without the mitochondrial signal peptide sequence led to selective expression of the protein in mitochondria and cytosol, respectively. Cytosolic overexpression of ALDH2 restored GTN-induced relaxation and GTN denitration to wild-type levels, whereas overexpression in mitochondria (6-fold vs wild-type) had no effect on relaxation. Overexpression of ALDH2 in the cytosol of ALDH2-deficient aortic smooth muscle cells led to a significant increase in GTN denitration and cyclic GMP accumulation, whereas mitochondrial overexpression had no effect. CONCLUSIONS: The data indicate that vascular bioactivation of GTN is catalyzed by cytosolic ALDH2. Mitochondrial GTN metabolism may contribute to oxidative stress-related adverse effects of nitrate therapy and the development of nitrate tolerance. PMID- 22207713 TI - Burnout and connectedness in the job demands-resources model: studying palliative care volunteers and their families. AB - This study examined the role of burnout and connectedness in the job demands resources (JD-R) model among palliative care volunteers. It was hypothesized that (a) exhaustion mediates the relationship between demands and depression, and between demands and retention; (b) cynicism mediates the relationship between resources and retention; and (c) connectedness mediates the relationship between resources and retention. Hypotheses were tested in 2 separate analyses: structural equation modeling (SEM) and path analyses. The first was based on volunteer self-reports (N = 204), while the second analysis concerned matched data from volunteers and their family members (N = 99). While strong support was found for cynicism and connectedness as mediators in both types of analyses, this was not altogether the case for exhaustion. Implications of these findings for the JD-R model and volunteer organizations are discussed. PMID- 22207714 TI - Assessing attitudinal barriers toward end-of-life care. AB - Due to the rapid influx of Palliative care and Hospice services over the last decade, there has been an increase in the number of medical professionals interacting with terminal patients. One of the challenges with this growth becomes how to integrate these services into already busy practices along with providing physicians the education and tools they need to provide quality care. While there is no shortage of articles focusing on the educational needs of physicians related to end of life care, less is known about the level of anxiety physicians feel about interacting with dying patients and their families. PMID- 22207715 TI - Sirolimus as primary immunosuppression attenuates allograft vasculopathy with improved late survival and decreased cardiac events after cardiac transplantation. AB - BACKGROUND: We retrospectively analyzed the potential of sirolimus as a primary immunosuppressant in the long-term attenuation of cardiac allograft vasculopathy progression and the effects on cardiac-related morbidity and mortality. METHODS AND RESULTS: Forty-five cardiac transplant recipients were converted to sirolimus 1.2 years (0.2, 4.0) after transplantation with complete calcineurin inhibitor withdrawal. Fifty-eight control subjects 2.0 years (0.2, 6.5 years) from transplantation were maintained on calcineurin inhibitors. Age, sex, ejection fraction, and time from transplantation to baseline intravascular ultrasound study were not different (P>0.2 for all) between the groups; neither were secondary immunosuppressants and use of steroids. Three-dimensional intravascular ultrasound studies were performed at baseline and 3.1 years (1.3, 4.6 years) later. Plaque index progression (plaque volume/vessel volume) was attenuated in the sirolimus group (0.7+/-10.5% versus 9.3+/-10.8%; P=0.0003) owing to reduced plaque volume in patients converted to sirolimus early (<2 years) after transplantation (P=0.05) and improved positive vascular remodeling (P=0.01) in patients analyzed late (>2 years) after transplantation. Outcome analysis in 160 consecutive patients maintained on 1 therapy was performed regardless of performance of intravascular ultrasound examinations. Five-year survival was improved with sirolimus (97.4+/-1.8% versus 81.8+/-4.9%; P=0.006), as was freedom from cardiac-related events (93.6+/-3.2% versus 76.9+/-5.5%; P=0.002). CONCLUSIONS: Substituting calcineurin inhibitor with sirolimus as primary immunosuppressant attenuates long-term cardiac allograft vasculopathy progression and may improve long-term allograft survival owing to favorable coronary remodeling. Because of the lack of randomization and retrospective nature of our analysis, the differences in outcome should be interpreted cautiously, and prospective clinical trials are required. PMID- 22207716 TI - Intraovarian thrombin and activated protein C signaling system regulates steroidogenesis during the periovulatory period. AB - In addition to its role in blood coagulation, thrombin directly stimulates protease-activated receptors (PAR) or interacts with thrombomodulin (THBD) to activate membrane-bound protein C which stimulates PAR1 and PAR4 receptors to promote downstream pleiotropic effects. Our DNA microarray, RT-PCR, and immunostaining analyses demonstrated ovarian expression of THBD, activated protein C (APC) receptor [endothelial protein C receptor (EPCR)], as well as PAR1 and PAR4 receptors in mice. After treatment of gonadotropin-primed immature mice with an ovulatory dose of human chorionic gonadotropin (hCG) (a LH surrogate), major increases in the expression of THBD, EPCR, PAR1, and PAR4 were detected in granulosa and cumulus cells of preovulatory follicles. Immunoassay analyses demonstrated sustained increases in ovarian prothrombin and APC levels after hCG stimulation. We obtained luteinizing granulosa cells from mice treated sequentially with equine CG and hCG. Treatment of these cells with thrombin or agonists for PAR1 or PAR4 decreased basal and forskolin-induced cAMP biosynthesis and suppressed hCG-stimulated progesterone production. In cultured preovulatory follicles, treatment with hirudin (a thrombin antagonist) and SCH79797 (a PAR1 antagonist) augmented hCG-stimulated progesterone biosynthesis, suggesting a suppressive role of endogenous thrombin in steroidogenesis. Furthermore, intrabursal injection with hirudin or SCH79797 led to ipsilateral increases in ovarian progesterone content. Our findings demonstrated increased ovarian expression of key components of the thrombin-APC-PAR1/4 signaling system after LH/hCG stimulation, and this signaling pathway may allow optimal luteinization of preovulatory follicles. In addition to assessing the role of thrombin and associated genes in progesterone production by the periovulatory ovary, these findings provide a model with which to study molecular mechanisms underlying thrombin-APC-PAR1/4 signaling. PMID- 22207717 TI - Research resource: The estrogen receptor alpha cistrome defined by DamIP. AB - Gene expression is tightly regulated by transcription factors and cofactors that function by directly or indirectly interacting with DNA of the genome. Understanding how and where these proteins bind provides essential information to uncover genetic regulatory mechanisms. We have developed a new method to study DNA-protein interaction in vivo called DNA adenine methyltransferase (Dam)IP, which is based on fusing a protein of interest to a mutant form of Dam from Escherichia coli. We showed previously that DamIP can efficiently identify in vivo binding sites of Dam-tethered human estrogen receptor (hER)alpha. In current study, we present the cistrome of hERalpha determined by DamIP and high throughput sequencing (DamIP-seq). The DamIP-seq-defined hERalpha cistrome identifies many new binding regions and overlaps with those determined by chromatin immunoprecipitation (ChIP)-chip or ChIP-seq. Elements uniquely identified by DamIP-seq include a unique class of elements that show low, but persistent, hERalpha binding when reexamined by conventional ChIP. In contrast, DamIP-seq fails to detect some elements with very transient hERalpha binding. The methyl-adenine modifications introduced by Dam are stable and do not decrease over 12 d. In summary, the current study provides both an alternate view of the hERalpha cistrome to further understand the mechanism of hERalpha-mediated transcription and a new tool to explore other transcriptional factors and cofactors that is very different from conventional ChIP. PMID- 22207718 TI - The RANKL distal control region is required for the increase in RANKL expression, but not the bone loss, associated with hyperparathyroidism or lactation in adult mice. AB - Osteoclast-mediated bone resorption plays an essential role in calcium homeostasis and lactation. The cytokine receptor activator of nuclear factor kappaB ligand (RANKL) is one of a number of factors that controls the production, survival, and activity of osteoclasts. Calciotropic hormones, such as PTH, control RANKL transcription in part via an enhancer known as the distal control region (DCR), and mice lacking this enhancer have fewer osteoclasts under normal physiological conditions. Here, we have addressed the role of the DCR in situations in which activation of the PTH receptor is thought to stimulate bone resorption via elevation of RANKL expression. Dietary calcium deficiency stimulated RANKL expression in the bone of young (1 month old) wild-type, but not DCR knockout (KO), mice. Consistent with this, the cancellous bone loss and the increase in osteoclasts caused by dietary calcium deficiency were blunted in young KO mice. DCR deletion also prevented the increase in RANKL expression caused by dietary calcium deficiency in 6-month-old mice. However, the diet induced bone loss was similar in wild-type and KO mice at this age. The increase in RANKL expression caused by lactation was also blunted in DCR KO mice, but lactation-induced bone loss was similar in both genotypes. These results demonstrate that, even though the DCR is required for the increase in RANKL expression associated with hyperparathyroidism or lactation, this increase is not required for the bone loss caused by these conditions in adult mice, suggesting that changes in other factors, such as osteoprotegerin or estrogen levels, play a dominant role. PMID- 22207719 TI - Repression of the Arabidopsis thaliana jasmonic acid/ethylene-induced defense pathway by TGA-interacting glutaredoxins depends on their C-terminal ALWL motif. AB - Glutaredoxins are small heat-stable oxidoreductases that transfer electrons from glutathione (GSH) to oxidized cysteine residues, thereby contributing to protein integrity and regulation. In Arabidopsis thaliana, floral glutaredoxins ROXY1 and ROXY2 and pathogen-induced ROXY19/GRX480 interact with bZIP transcription factors of the TGACG (TGA) motif-binding family. ROXY1, ROXY2, and TGA factors PERIANTHIA, TGA9, and TGA10 play essential roles in floral development. In contrast, ectopically expressed ROXY19/GRX480 negatively regulates expression of jasmonic acid (JA)/ethylene (ET)-induced defense genes through an unknown mechanism that requires clade II transcription factors TGA2, TGA5, and/or TGA6. Here, we report that at least 17 of the 21 land plant-specific glutaredoxins encoded in the Arabidopsis genome interact with TGA2 in a yeast-two-hybrid system. To investigate their capacity to interfere with the expression of JA/ET induced genes, we developed a transient expression system. Activation of the ORA59 (OCTADECANOID-RESPONSIVE ARABIDOPSIS AP2/ERF-domain protein 59) promoter by transcription factor EIN3 (ETHYLENE INSENSITVE 3) was suppressed by co-expressed ROXY19/GRX480. Suppression depended on the L**LL motif in the C-terminus of ROXY19/GRX480. This putative protein interaction domain was recently described as being essential for the TGA/ROXY interaction. Ten of the 17 tested ROXY proteins suppressed ORA59 promoter activity, which correlated with the presence of the C terminal ALWL motif, which is essential for ROXY1 function in flower development. ROXY19/GRX480-mediated repression depended on the GSH binding site, suggesting that redox modification of either TGA factors or as yet unknown target proteins is important for the suppression of ORA59 promoter activity. PMID- 22207720 TI - Drought responses of leaf tissues from wheat cultivars of differing drought tolerance at the metabolite level. AB - Drought has serious effects on the physiology of cereal crops. At the cellular and specifically the metabolite level, many individual compounds are increased to provide osmoprotective functions, prevent the dissociation of enzymes, and to decrease the number of reactive oxygen species present in the cell. We have used a targeted GC-MS approach to identify compounds that differ in three different cultivars of bread wheat characterized by different levels of tolerance to drought under drought stress (Kukri, intolerant; Excalibur and RAC875, tolerant). Levels of amino acids, most notably proline, tryptophan, and the branched chain amino acids leucine, isoleucine, and valine were increased under drought stress in all cultivars. In the two tolerant cultivars, a small decrease in a large number of organic acids was also evident. Excalibur, a cultivar genotypically related to Kukri, showed a pattern of response that was more similar to Kukri under well-watered conditions. Under drought stress, Excalibur and RAC875 had a similar response; however, Excalibur did not have the same magnitude of response as RAC875. Here, the results are discussed in the context of previous work in physiological and proteomic analyses of these cultivars under drought stress. PMID- 22207721 TI - Respiratory mechanics during high-frequency oscillatory ventilation: a physical model and preterm infant study. AB - Accurate mechanics measurements during high-frequency oscillatory ventilation (HFOV) facilitate optimizing ventilator support settings. Yet, these are influenced substantially by endotracheal tube (ETT) contributions, which may dominate when leaks around uncuffed ETT are present. We hypothesized that 1) the effective removal of ETT leaks may be confirmed via direct comparison of measured vs. model-predicted mean intratracheal pressure [mPtr (meas) vs. mPtr (pred)], and 2) reproducible respiratory system resistance (Rrs) and compliance (Crs) may be derived from no-leak oscillatory Ptr and proximal flow. With the use of ETT test-lung models, proximal airway opening (Pao) and distal (Ptr) pressures and flows were measured during slow-cuff inflations until leaks are removed. These were repeated for combinations of HFOV settings [frequency, mean airway pressure (Paw), oscillation amplitudes (DeltaP), and inspiratory time (%t(I))] and varying test-lung Crs. Results showed that leaks around the ETT will 1) systematically reduce the effective distending pressures and lung-delivered oscillatory volumes, and 2) derived mechanical properties are increasingly nonphysiologic as leaks worsen. Mean pressures were systematically reduced along the ventilator circuit and ETT (Paw > Pao > Ptr), even for no-leak conditions. ETT size-specific regression models were then derived for predicting mPtr based on mean Pao (mPao), DeltaP, %t(I), and frequency. Next, in 10 of 11 studied preterm infants (0.77 +/- 0.24 kg), no-to-minimal leak was confirmed based on excellent agreement between mPtr (meas) and mPtr (pred), and consequently, their oscillatory respiratory mechanics were evaluated. Infant resistance at the proximal ETT (R(ETT); resistance airway opening = R(ETT) + Rrs; P < 0.001) and ETT inertance (P = 0.014) increased significantly with increasing DeltaP (50%, 100%, and 150% baseline), whereas Rrs showed a modest, nonsignificant increase (P = 0.14), and Crs was essentially unchanged (P = 0.39). We conclude that verifying no-leak conditions is feasible by comparison of model-derived vs. distending mPtr (meas). This facilitated the reliable and accurate assessment of physiologic respiratory mechanical properties that can objectively guide ventilatory management of HFOV treated preterm infants. PMID- 22207722 TI - Assessment of locomotion in chlorine exposed mice by computer vision and neural networks. AB - Assessment of locomotion following exposure of animals to noxious or painful stimuli can offer significant insights into underlying mechanisms of injury and the effectiveness of various treatments. We developed a novel method to track the movement of mice in two dimensions using computer vision and neural network algorithms. By using this system we demonstrated that mice exposed to chlorine (Cl(2)) gas developed impaired locomotion and increased immobility for up to 9 h postexposure. Postexposure administration of buprenorphine, a common analgesic agent, increased locomotion and decreased immobility times in Cl(2)- but not air exposed mice, most likely by decreasing Cl(2)-induced pain. This method can be adapted to assess the effectiveness of various therapies following exposure to a variety of chemical and behavioral noxious stimuli. PMID- 22207723 TI - Role of vitamin C and E supplementation on IL-6 in response to training. AB - Vitamin C and E supplementation has been shown to attenuate the acute exercise induced increase in plasma interleukin-6 (IL-6) concentration. Here, we studied the effect of antioxidant vitamins on the regulation of IL-6 expression in muscle and the circulation in response to acute exercise before and after high-intensity endurance exercise training. Twenty-one young healthy men were allocated into either a vitamin (VT; vitamin C and E, n = 11) or a placebo (PL, n = 10) group. A 1-h acute bicycling exercise trial at 65% of maximal power output was performed before and after 12 wk of progressive endurance exercise training. In response to training, the acute exercise-induced IL-6 response was attenuated in PL (P < 0.02), but not in VT (P = 0.82). However, no clear difference between groups was observed (group * training: P = 0.13). Endurance exercise training also attenuated the acute exercise-induced increase in muscle-IL-6 mRNA in both groups. Oxidative stress, assessed by plasma protein carbonyls concentration, was overall higher in the VT compared with the PL group (group effect: P < 0.005). This was accompanied by a general increase in skeletal muscle mRNA expression of antioxidative enzymes, including catalase, copper-zinc superoxide dismutase, and glutathione peroxidase 1 mRNA expression in the VT group. However, skeletal muscle protein content of catalase, copper-zinc superoxide dismutase, or glutathione peroxidase 1 was not affected by training or supplementation. In conclusion, our results indicate that, although vitamin C and E supplementation may attenuate exercise-induced increases in plasma IL-6 there is no clear additive effect when combined with endurance training. PMID- 22207724 TI - TRPV4 deficiency increases skeletal muscle metabolic capacity and resistance against diet-induced obesity. AB - Transient receptor potential channel V4 (TRPV4) functions as a nonselective cation channel in various cells and plays physiological roles in osmotic and thermal sensation. However, the function of TRPV4 in energy metabolism is unknown. Here, we report that TRPV4 deficiency results in increased muscle oxidative capacity and resistance to diet-induced obesity in mice. Although no difference in body weight was observed between wild-type and Trpv4(-/-) mice when fed a standard chow diet, obesity phenotypes induced by a high-fat diet were significantly improved in Trpv4(-/-) mice, without any change in food intake. Quantitative analysis of mRNA revealed the constitutive upregulation of many genes, including those for transcription factors such as peroxisome proliferator activated receptor alpha and for metabolic enzymes such as phosphoenolpyruvate carboxykinase. These upregulated genes were especially prominent in oxidative skeletal muscle, in which the activity of Ca(2+)-dependent phosphatase calcineurin was elevated, suggesting that other Ca(2+) channels function in the skeletal muscle of Trpv4(-/-) mice. Indeed, gene expressions for TRPC3 and TRPC6 increased in the muscles of Trpv4(-/-) mice compared with those of wild-type mice. The number of oxidative type I fiber also increased in the mutant muscles following myogenin gene induction. These results strongly suggested that inactivation of Trpv4 induces compensatory increases in TRPC3 and TRPC6 production, and elevation of calcineurin activity, affecting energy metabolism through increased expression of genes involved in fuel oxidation in skeletal muscle and thereby contributing to increased energy expenditure and protection from diet-induced obesity in mice. PMID- 22207725 TI - Anti-apoptotic and pro-survival effects of exercise training on hypertensive hearts. AB - BACKGROUND: Activated cardiac apoptosis was found in hearts from hypertensive animals, but little information regarding the effects of exercise training on cardiac apoptosis in hypertension is available. The purpose of this study was to evaluate the anti-apoptotic and pro-survival effects of exercise training on hypertensive hearts. METHODS: 28 spontaneously hypertensive rats were divided into sedentary group (SHR) or underwent running exercise on treadmill for 1 h/day, 5 sessions/wk, for 12 wk (SHR-EX). Fourteen age-matched Wistar Kyoto rats served as a sedentary normotensive group (WKY). After exercise training or sedentary status, the excised hearts were measured by hemotoxylin and eosin staining, terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) assay, and Western blotting. RESULTS: Fewer TUNEL-positive apoptotic cells were in SHR-EX groups than those in SHR. Protein levels of Fas ligand, Fas death receptor, tumor necrosis factor (TNF)-alpha, TNF receptor 1, Fas-associated death domain (FADD), activated caspase-8, and activated caspase-3 (Fas-dependent apoptotic pathways), as well as Bid, t-Bid, Bad, p-Bad, Bak, cytochrome c, activated caspase 9, and activated caspase-3 (mitochondria-dependent apoptotic pathways) were decreased in the SHR-EX group compared with the SHR group. Protein levels of IGF-1, IGF-1R, p-PI3K, p-Akt, p-Bad, and Bcl2 (cardiac pro-survival pathway) become more activated in SHR-EX groups than SHR and WKY. CONCLUSIONS: Exercise training prevented hypertension-enhanced cardiac Fas-dependent and mitochondria-dependent apoptotic pathways and enhanced cardiac pro-survival pathway in rat models. Our findings demonstrate new therapeutic effects of exercise training on hypertensive hearts for preventing apoptosis and enhancing survival. PMID- 22207726 TI - Canes for knee osteoarthritis: is a randomised trial necessary? PMID- 22207727 TI - Endogenous estrogens lower plasma PCSK9 and LDL cholesterol but not Lp(a) or bile acid synthesis in women. AB - OBJECTIVE: Cholesterol and lipoprotein metabolism display pronounced gender differences. Premenopausal women have lower LDL and higher HDL cholesterol, whereas men display higher synthetic rates of bile acids and cholesterol. The effects of the administration of exogenous hormones to humans and animals indicate that these gender differences can often be explained by estrogens. We evaluated how increased levels of endogenous estrogens modulate cholesterol and lipoprotein metabolism in women. METHODS AND RESULTS: We studied healthy women during initiation of in vitro fertilization using blood samples obtained when endogenous estrogens were low and high. Cholesterol in VLDL and LDL, but not in HDL, was reduced 20% when estrogens were high. Apolipoprotein B levels decreased 13%. Apolipoprotein A-I and triglyceride levels increased 8% and 37%, respectively, whereas lipoprotein(a) levels were unchanged. Circulating PCSK9, a suppressor of LDL receptors, was reduced 14% when estrogens were high. Serum markers of bile acid and cholesterol synthesis were unaltered. Growth hormone levels increased 3-fold when estrogens were high, whereas insulin-like growth factor-1 and fibroblast growth factor-21 concentrations were unaltered. CONCLUSION: In women, Apolipoprotein B-containing particles and circulating PCSK9 are reduced when endogenous estrogens are high, indicating that endogenous estrogens induce hepatic LDL receptors partly through a posttranscriptional mechanism. However, estrogens do not stimulate bile acid or cholesterol synthesis. PMID- 22207728 TI - Role for the guanine nucleotide exchange factor phosphatidylinositol-3,4,5 trisphosphate-dependent rac exchanger 1 in platelet secretion and aggregation. AB - OBJECTIVE: Recent studies have shown a role for Rac1 in regulating platelet functions, but how Rac1 is activated in platelets remains unclear. Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) was originally identified in neutrophils that regulates phagocyte functions. We sought to examine whether P-Rex1 plays a role in platelet activation. METHODS AND RESULTS: Western blotting showed P-Rex1 expression in mouse and human platelets. Mice lacking P-Rex1 exhibited prolonged bleeding time and increased rebleeding. When challenged with low doses of the G protein-coupled receptor (GPCR) agonists U46619 and thrombin, P-Rex1-/- platelets displayed significantly reduced secretion and aggregation compared with wild-type platelets. Increasing the concentration of these agonists could overcome the defect. Platelet aggregation induced by collagen, a non-GPCR agonist, was also compromised in the absence of P Rex1. Along with these phenotypic changes were impaired Rac1 activation; reduced ATP secretion; and decreased phosphorylation of Akt, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase in P-Rex1-/- platelets on agonist stimulation. CONCLUSION: These results demonstrate for the first time the presence of P-Rex1 in platelets as well as its role in platelet secretion and aggregation induced by low-dose agonists for GPCR and by collagen. PMID- 22207729 TI - Niacin in cardiovascular disease: recent preclinical and clinical developments. AB - Niacin has been used for more than 50 years in the treatment of cardiovascular disease, although its use has largely been superseded by better-tolerated lipid modulating interventions. There has been a renewed interest in the HDL cholesterol raising properties of niacin, with the appreciation that substantial cardiovascular risk remains despite effective treatment of LDL-cholesterol. This coincides with increasing evidence that the complex functional properties of HDL are not well reflected by measurement of HDL-cholesterol alone. In addition to favorable actions on lipoproteins, it is becoming apparent that niacin may also possess lipoprotein independent or pleiotropic effects including the inhibition of inflammatory pathways mediated by its receptor GPR109A, which is expressed by adipocytes and some leukocytes. In this article we consider emerging and prior clinical trial data relating to niacin. We review recent data in respect of mechanisms of action on lipoproteins, which remain complex and incompletely understood. We discuss the recent reports of anti-inflammatory effects of niacin in adipocytes and through bone marrow derived cells and vascular endothelium. These novel observations come at an interesting time, with current imaging and outcome studies leaving outstanding questions on niacin efficacy in statin treated patients. PMID- 22207731 TI - Regulation of lipid droplet cholesterol efflux from macrophage foam cells. AB - Cholesterol efflux from macrophages is the first and potentially most important step in reverse cholesterol transport, a process especially relevant to atherosclerosis and to the regression of atherosclerotic plaques. Increasingly, lipid droplet (LD) cholesteryl ester (CE) hydrolysis is being recognized as a rate-limiting step in cholesterol efflux. The traditional view on macrophage CE hydrolysis is that this pathway is entirely dependent on the action of neutral hydrolases, and numerous candidate CE hydrolases have been proposed to play a role in lipid hydrolysis in macrophages and atherogenesis. Although the exact identity of macrophage-specific CE hydrolases remains to be clarified, a common point to all of these studies is that enhancing LD-associated CE hydrolysis increases cholesterol efflux and is antiatherogenic. Understanding how cholesterol is mobilized from LDs offers new steps for modulating cholesterol efflux, and recently a role for autophagy and lysosomal acid lipase in macrophage lipolysis has emerged. Autophagy and lysosomal acid lipase thus represent novel therapeutic targets to enhance macrophage reverse cholesterol transport. This review discusses our current understanding of the relationship between macrophage LDs and atherosclerosis and presents recent insights into the mechanisms for LD CE hydrolysis in macrophage foam cells. PMID- 22207730 TI - Acute exposure to low glucose rapidly induces endothelial dysfunction and mitochondrial oxidative stress: role for AMP kinase. AB - OBJECTIVE: Hypoglycemia is associated with increased mortality. The reasons for this remain unclear, and the effects of low glucose exposure on vascular endothelial function remain largely unknown. We endeavored to determine the effects of low glucose on endothelial cells and intact human arterioles. METHODS AND RESULTS: We exposed human umbilical vein endothelial cells to low glucose conditions in a clinically relevant range (40-70 mg/dL) and found rapid and marked reductions in nitric oxide (NO) bioavailability (P<0.001). This was associated with concomitantly increased mitochondrial superoxide production (P<0.001) and NO-dependent mitochondrial hyperpolarization (P<0.001). Reduced NO bioavailability was rapid and attributable to reduced endothelial nitric oxide synthase activity and destruction of NO. Low glucose rapidly activated AMP kinase, but physiological activation failed to restore NO bioavailability. Pharmacological AMP kinase activation led to phosphorylation of endothelial nitric oxide synthase's Ser633 activation site, reversing the adverse effects of low glucose. This protective effect was prevented by L-NG-Nitroarginine methyl ester. Intact human arterioles exposed to low glucose demonstrated marked endothelial dysfunction, which was prevented by either metformin or TEMPOL. CONCLUSION: Our data suggest that moderate low glucose exposure rapidly impairs NO bioavailability and endothelial function in the human endothelium and that pharmacological AMP kinase activation inhibit this effect in an NO-dependent manner. PMID- 22207732 TI - Peroxisome proliferator-activated receptor-gamma activation induces 11beta hydroxysteroid dehydrogenase type 1 activity in human alternative macrophages. AB - OBJECTIVE: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the intracellular reduction of inactive cortisone to active cortisol, the natural ligand activating the glucocorticoid receptor (GR). Peroxisome proliferator- activated receptor-gamma (PPARgamma) is a nuclear receptor controlling inflammation, lipid metabolism, and the macrophage polarization state. In this study, we investigated the impact of macrophage polarization on the expression and activity of 11beta-HSD1 and the role of PPARgamma therein. METHODS AND RESULTS: 11beta-HSD1 gene expression is higher in proinflammatory M1 and anti inflammatory M2 macrophages than in resting macrophages, whereas its activity is highest in M2 macrophages. Interestingly, PPARgamma activation induces 11beta HSD1 enzyme activity in M2 macrophages but not in resting macrophages or M1 macrophages. Consequently, human M2 macrophages displayed enhanced responsiveness to the 11beta-HSD1 substrate cortisone, an effect amplified by PPARgamma induction of 11beta-HSD1 activity, as illustrated by an increased expression of GR target genes. CONCLUSION: Our data identify a positive cross-talk between PPARgamma and GR in human M2 macrophages via the induction of 11beta-HSD1 expression and activity. PMID- 22207733 TI - Prognostic value of monosomal karyotype in comparison to complex aberrant karyotype in acute myeloid leukemia: a study on 824 cases with aberrant karyotype. AB - In acute myeloid leukemia (AML) the subset with complex karyotype (CK) is traditionally regarded as the worst prognostic group. However, >= 3, >= 4, or >= 5 abnormalities have been variably used for its definition. Recently, monosomal karyotype (MSK) was suggested to indicate an even inferior outcome. We tested which definition fits best to identify the most unfavorable subgroup. After excluding patients with t(15;17)/PML-RARA, t(8;21)/RUNX1-RUNX1T1, inv (16)/t(16;16)/CBFB-MYH11, and normal karyotype, 824 patients with AML with cytogenetic abnormalities were analyzed. Patients with MSK or CK defined as >= 3, >= 4, or >= 5 abnormalities showed an inferior overall survival compared with the respective remaining patients not fulfilling these criteria (for all, P < .001). Hazard ratios were 1.93, 1.68, 1.94, and 1.92. CK >= 4 as a single parameter identified the largest proportion of patients with very poor risk. However, combining CK >= 4 and MSK detected an even larger number of patients with very unfavorable outcome (261 of 824; 31.7%). PMID- 22207734 TI - miR-27b controls venous specification and tip cell fate. AB - We discovered that miR-27b controls 2 critical vascular functions: it turns the angiogenic switch on by promoting endothelial tip cell fate and sprouting and it promotes venous differentiation. We have identified its targets, a Notch ligand Delta-like ligand 4 (Dll4) and Sprouty homologue 2 (Spry2). miR-27b knockdown in zebrafish and mouse tissues severely impaired vessel sprouting and filopodia formation. Moreover, miR-27b was necessary for the formation of the first embryonic vein in fish and controlled the expression of arterial and venous markers in human endothelium, including Ephrin B2 (EphB2), EphB4, FMS-related tyrosine kinase 1 (Flt1), and Flt4. In zebrafish, Dll4 inhibition caused increased sprouting and longer intersegmental vessels and exacerbated tip cell migration. Blocking Spry2 caused premature vessel branching. In contrast, Spry2 overexpression eliminated the tip cell branching in the intersegmental vessels. Blockade of Dll4 and Spry2 disrupted arterial specification and augmented the expression of venous markers. Blocking either Spry2 or Dll4 rescued the miR-27b knockdown phenotype in zebrafish and in mouse vascular explants, pointing to essential roles of these targets downstream of miR-27b. Our study identifies critical role of miR-27b in the control of endothelial tip cell fate, branching, and venous specification and determines Spry2 and Dll4 as its essential targets. PMID- 22207735 TI - Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis. AB - The tyrosine kinase inhibitor imatinib is highly effective in the treatment of chronic myelogenous leukemia (CML), but primary and acquired resistance of CML cells to the drug offset its efficacy. Molecular mechanisms for resistance of CML to tyrosine kinase inhibitors are not fully understood. In the present study, we show that BCR-ABL activates the expression of the mammalian stress response gene SIRT1 in hematopoietic progenitor cells and that this involves STAT5 signaling. SIRT1 activation promotes CML cell survival and proliferation associated with deacetylation of multiple SIRT1 substrates, including FOXO1, p53, and Ku70. Imatinib-mediated inhibition of BCR-ABL kinase activity partially reduces SIRT1 expression and SIRT1 inhibition further sensitizes CML cells to imatinib-induced apoptosis. Knockout of SIRT1 suppresses BCR-ABL transformation of mouse BM cells and the development of a CML-like myeloproliferative disease, and treatment of mice with the SIRT1 inhibitor tenovin-6 deters disease progression. The combination of SIRT1 gene knockout and imatinib treatment further extends the survival of CML mice. Our results suggest that SIRT1 is a novel survival pathway activated by BCR-ABL expression in hematopoietic progenitor cells, which promotes oncogenic transformation and leukemogenesis. Our findings suggest further exploration of SIRT1 as a therapeutic target for CML treatment to overcome resistance. PMID- 22207736 TI - Genome-wide analysis of histone H3 acetylation patterns in AML identifies PRDX2 as an epigenetically silenced tumor suppressor gene. AB - With the use of ChIP on microarray assays in primary leukemia samples, we report that acute myeloid leukemia (AML) blasts exhibit significant alterations in histone H3 acetylation (H3Ac) levels at > 1000 genomic loci compared with CD34(+) progenitor cells. Importantly, core promoter regions tended to have lower H3Ac levels in AML compared with progenitor cells, which suggested that a large number of genes are epigenetically silenced in AML. Intriguingly, we identified peroxiredoxin 2 (PRDX2) as a novel potential tumor suppressor gene in AML. H3Ac was decreased at the PRDX2 gene promoter in AML, which correlated with low mRNA and protein expression. We also observed DNA hypermethylation at the PRDX2 promoter in AML. Low protein expression of the antioxidant PRDX2 gene was clinically associated with poor prognosis in patients with AML. Functionally, PRDX2 acted as inhibitor of myeloid cell growth by reducing levels of reactive oxygen species (ROS) generated in response to cytokines. Forced PRDX2 expression inhibited c-Myc-induced leukemogenesis in vivo on BM transplantation in mice. Taken together, epigenome-wide analyses of H3Ac in AML led to the identification of PRDX2 as an epigenetically silenced growth suppressor, suggesting a possible role of ROS in the malignant phenotype in AML. PMID- 22207737 TI - The disulfide isomerase ERp57 mediates platelet aggregation, hemostasis, and thrombosis. AB - A close homologue to protein disulfide isomerase (PDI) called ERp57 forms disulfide bonds in glycoproteins in the endoplasmic reticulum and is expressed on the platelet surface. We generated 2 rabbit Abs to ERp57. One Ab strongly inhibited ERp57 in a functional assay and strongly inhibited platelet aggregation. There was minimal cross-reactivity of this Ab with PDI by Western blot or in the functional assay. This Ab substantially inhibited activation of the alphaIIbbeta3 fibrinogen receptor and P-selectin expression. Furthermore, adding ERp57 to platelets potentiated aggregation. In contrast, adding a catalytically inactive ERp57 inhibited platelet aggregation. When infused into mice the inactive ERp57 prolonged the tail bleeding times. We generated 2 IgG2a mAbs that reacted with ERp57 by immunoblot. One of these Abs inhibited both ERp57 activity and platelet aggregation. The other Ab did not inhibit ERp57 activity or platelet aggregation. The inhibitory Ab inhibited activation of alphaIIbbeta3 and P-selectin expression, prolonged tail bleeding times, and inhibited FeCl(3) induced thrombosis in mice. Finally, we found that a commonly used mAb to PDI also inhibited ERp57 activity. We conclude that a glycoprotein-specific member of the PDI family, ERp57, is required for platelet aggregation, hemostasis, and thrombosis. PMID- 22207738 TI - Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization. AB - VEGFs activate 3 receptor tyrosine kinases, VEGFR-1, VEGFR-2, and VEGFR-3, promoting angiogenic and lymphangiogenic signaling. The extracellular receptor domain (ECD) consists of 7 Ig-homology domains; domains 2 and 3 (D23) represent the ligand-binding domain, whereas the function of D4-7 is unclear. Ligand binding promotes receptor dimerization and instigates transmembrane signaling and receptor kinase activation. In the present study, isothermal titration calorimetry showed that the Gibbs free energy of VEGF-A, VEGF-C, or VEGF-E binding to D23 or the full-length ECD of VEGFR-2 is dominated by favorable entropic contribution with enthalpic penalty. The free energy of VEGF binding to the ECD is 1.0-1.7 kcal/mol less favorable than for binding to D23. A model of the VEGF-E/VEGFR-2 ECD complex derived from small-angle scattering data provided evidence for homotypic interactions in D4-7. We also solved the crystal structures of complexes between VEGF-A or VEGF-E with D23, which revealed comparable binding surfaces and similar interactions between the ligands and the receptor, but showed variation in D23 twist angles. The energetically unfavorable homotypic interactions in D4-7 may be required for re-orientation of receptor monomers, and this mechanism might prevent ligand-independent activation of VEGFR 2 to evade the deleterious consequences for blood and lymph vessel homeostasis arising from inappropriate receptor activation. PMID- 22207739 TI - Human virus-specific effector-type T cells accumulate in blood but not in lymph nodes. AB - It is believed that the size of the CD8(+) T-cell pool is fixed and that with every new viral challenge, the size of the pre-existing memory-cell population shrinks to make way for the new virus-specific cells. CMV-seropositive individuals have high numbers of CMV-specific resting-effector type CD8(+) T cells in their peripheral blood (PB). This prompted us to investigate whether CMV infection limits immunologic space at sites where immune reactions are initiated, such as in the lymph nodes (LNs). LN and paired PB samples were analyzed for CMV , EBV-, and influenza-specific CD8(+) T cells. In marked contrast to blood, LNs contained significantly lower numbers of CX3CR1-expressing effector-type CD8(+) T cells, whereas the CMV-specific cells that were found in the LNs resembled polyfunctional memory-type cells. In contrast, EBV- and influenza-specific CD8(+) T cells were highly similar between PB and LNs both in number and function. Therefore, it is unlikely that CMV-specific CD8(+) T cells in the LNs restrain the immunologic space of other virus-specific cells. PMID- 22207740 TI - Complete genome sequences of three Pseudomonas aeruginosa isolates with phenotypes of polymyxin B adaptation and inducible resistance. AB - Clinical "superbug" isolates of Pseudomonas aeruginosa were previously observed to be resistant to several antibiotics, including polymyxin B, and/or to have a distinct, reproducible adaptive polymyxin resistance phenotype, identified by observing "skipped" wells (appearance of extra turbid wells) during broth microdilution testing. Here we report the complete assembled draft genome sequences of three such polymyxin resistant P. aeruginosa strains (9BR, 19BR, and 213BR). PMID- 22207741 TI - Complete genome sequence of the rice pathogen Pantoea ananatis strain PA13. AB - Pantoea ananatis is the causative agent of sheath and grain rot in rice. Here, we present the complete genome sequence of P. ananatis strain PA13, originally isolated from a diseased rice grain. PMID- 22207742 TI - Complete sequences of plasmids from the hemolytic-uremic syndrome-associated Escherichia coli strain HUSEC41. AB - The complete and annotated sequences of four plasmids from a historical enteroaggregative Shiga toxin-producing Escherichia coli (HUSEC) serotype O104:H4 strain, HUSEC41/01-09591, isolated in 2001 in Germany are reported. PMID- 22207743 TI - Complete genome sequence of Sphingobium sp. strain SYK-6, a degrader of lignin derived biaryls and monoaryls. AB - Sphingobium sp. strain SYK-6 is able to grow on an extensive variety of lignin derived biaryls and monoaryls, and the catabolic genes for these compounds are useful for the production of industrially valuable metabolites from lignin. Here we report the complete nucleotide sequence of the SYK-6 genome which consists of the 4,199,332-bp-long chromosome and the 148,801-bp-long plasmid. PMID- 22207744 TI - Genome sequencing of Bacillus subtilis SC-8, antagonistic to the Bacillus cereus group, isolated from traditional Korean fermented-soybean food. AB - Bacillus subtilis SC-8 is a Gram-positive bacterium displaying narrow antagonistic activity for the Bacillus cereus group. B. subtilis SC-8 was isolated from Korean traditional fermented-soybean food. Here we report the draft genome sequence of B. subtilis SC-8, including biosynthetic genes for antibiotics that may have beneficial effects for control of food-borne pathogens. PMID- 22207745 TI - Genome sequence of the bacteriocin-producing Lactobacillus curvatus strain CRL705. AB - Lactobacillus curvatus is one of the most prevalent lactic acid bacteria found in fermented meat products. Here, we present the draft genome sequence of Lactobacillus curvatus CRL705, a bacteriocin producer strain isolated from an Argentinean artisanal fermented sausage, which consists of 1,833,251 bp (GC content, 41.9%) and two circular plasmids of 12,342 bp (pRC12; GC, 43.9%) and 18,664 bp (pRC18; GC, 34.4%). PMID- 22207746 TI - Draft genome sequence of Leucobacter chromiiresistens, an extremely chromium tolerant strain. AB - Here we present the draft genome of Leucobacter chromiiresistens. This is the first genome sequence of an organism belonging to the genus Leucobacter. L. chromiiresistens was sequenced due to its capability to tolerate up to 300 mM Cr(VI) in the medium, which is so far a unique feature for microorganisms. PMID- 22207747 TI - Shotgun genome sequence of a Yersinia enterocolitica isolate from the Philippines. AB - The first shotgun genome sequence of a microbial pathogen from the Philippines is reported. Yersinia enterocolitica subsp. palearctica strain PhRBD_Ye1 is the first Y. enterocolitica strain sequenced from an animal source, swine, which is a natural source of yersiniosis. The closest phylogenetic match is a human clinical isolate from Germany. PMID- 22207748 TI - Complete genome sequence of the BTEX-degrading bacterium Pseudoxanthomonas spadix BD-a59. AB - Pseudoxanthomonas spadix BD-a59, able to metabolize all six BTEX (benzene, toluene, ethylbenzene, and o-, m-, and p-xylene) compounds, was isolated from gasoline-contaminated sediment. Here, we report the complete 3.45-Mb genome sequence and annotation of strain BD-a59. These advance the understanding of strain BD-a59's genomic properties and pollutant metabolic versatility. PMID- 22207749 TI - Whole-genome sequences of Borrelia bissettii, Borrelia valaisiana, and Borrelia spielmanii. AB - It has been known for decades that human Lyme disease is caused by the three spirochete species Borrelia burgdorferi, Borrelia afzelii, and Borrelia garinii. Recently, Borrelia valaisiana, Borrelia spielmanii, and Borrelia bissettii have been associated with Lyme disease. We report the complete genome sequences of B. valaisiana VS116, B. spielmanii A14S, and B. bissettii DN127. PMID- 22207750 TI - Genome sequence of Mycoplasma iowae strain 695, an unusual pathogen causing deaths in turkeys. AB - Mycoplasma iowae is associated mainly with reduced hatchability in turkeys and is well known for the unusual ability of phenotypic variation in the Mycoplasma surface components as well as a relative resistance to heat, bile salts, and many antimicrobials. A subset of unique genes and a gene cluster responsible for these characteristics could be identified from the genome. Here, we report the first genome sequence of this species. PMID- 22207751 TI - Whole-genome sequence of the emerging pathogen Mycobacterium abscessus strain 47J26. AB - Mycobacterium abscessus is a rapidly growing environmental mycobacterium commonly found in soil and water which is often also associated with infections in humans, particularly of the lung. We report herein the draft genome sequence of M. abscessus strain 47J26. PMID- 22207752 TI - Draft genome sequence of Enterococcus mundtii CRL1656. AB - We report the draft genome sequence of Enterococcus mundtii CRL1656, which was isolated from the stripping milk of a clinically healthy adult Holstein dairy cow from a dairy farm of the northwestern region of Tucuman (Argentina). The 3.10-Mb genome sequence consists of 450 large contigs and contains 2,741 predicted protein-coding genes. PMID- 22207753 TI - Genome sequence of the haloalkaliphilic methanotrophic bacterium Methylomicrobium alcaliphilum 20Z. AB - Methylomicrobium strains are widespread in saline environments. Here, we report the complete genome sequence of Methylomicrobium alcaliphilum 20Z, a haloalkaliphilic methanotrophic bacterium, which will provide the basis for detailed characterization of the core pathways of both single-carbon metabolism and responses to osmotic and high-pH stresses. Final assembly of the genome sequence revealed that this bacterium contains a 128-kb plasmid, making M. alcaliphilum 20Z the first methanotrophic bacterium of known genome sequence for which a plasmid has been reported. PMID- 22207754 TI - Identification of in vivo disulfide conformation of TRPA1 ion channel. AB - TRPA1 (transient receptor potential ankyrin 1) is an ion channel expressed in the termini of sensory neurons and is activated in response to a broad array of noxious exogenous and endogenous thiol-reactive compounds, making it a crucial player in chemical nociception. A number of conserved cysteine residues on the N terminal domain of the channel have been identified as critical for sensing these electrophilic pungent chemicals, and our recent EM structure with modeled domains predicts that these cysteines form a ligand-binding pocket, allowing for the possibility of disulfide bonding between the cysteine residues. Here, we present a comprehensive mass spectrometry investigation of the in vivo disulfide bonding conformation and in vitro reactivity of 30 of the 31 cysteine residues in the TRPA1 ion channel. Four disulfide bonds were detected in the in vivo TRPA1 structure: Cys-666-Cys-622, Cys-666-Cys-463, Cys-622-Cys-609, and Cys-666-Cys 193. All of the cysteines detected were reactive to N-methylmaleimide (NMM) in vitro, with varying degrees of labeling efficiency. Comparison of the ratio of the labeling efficiency at 300 MUM versus 2 mM NMM identified a number of cysteine residues that were outliers from the mean labeling ratio, suggesting that protein conformation changes rendered these cysteines either more or less protected from labeling at the higher NMM concentrations. These results indicate that the activation mechanism of TRPA1 may involve N-terminal conformation changes and disulfide bonding between critical cysteine residues. PMID- 22207755 TI - The ubiquitin regulatory X (UBX) domain-containing protein TUG regulates the p97 ATPase and resides at the endoplasmic reticulum-golgi intermediate compartment. AB - p97/VCP is a hexameric ATPase that is coupled to diverse cellular processes, such as membrane fusion and proteolysis. How p97 activity is regulated is not fully understood. Here we studied the potential role of TUG, a widely expressed protein containing a UBX domain, to control mammalian p97. In HEK293 cells, the vast majority of TUG was bound to p97. Surprisingly, the TUG UBX domain was neither necessary nor sufficient for this interaction. Rather, an extended sequence, comprising three regions of TUG, bound to the p97 N-terminal domain. The TUG C terminus resembled the Arabidopsis protein PUX1. Similar to the previously described action of PUX1 on AtCDC48, TUG caused the conversion of p97 hexamers into monomers. Hexamer disassembly was stoichiometric rather than catalytic and was not greatly affected by the p97 ATP-binding state or by TUG N-terminal regions in vitro. In HeLa cells, TUG localized to the endoplasmic reticulum-to Golgi intermediate compartment and endoplasmic reticulum exit sites. Although siRNA-mediated TUG depletion had no marked effect on total ubiquitylated proteins or p97 localization, TUG overexpression caused an accumulation of ubiquitylated substrates and targeted both TUG and p97 to the nucleus. A physiologic role of TUG was revealed by siRNA-mediated depletion, which showed that TUG is required for efficient reassembly of the Golgi complex after brefeldin A removal. Together, these data support a model in which TUG controls p97 oligomeric status at a particular location in the early secretory pathway and in which this process regulates membrane trafficking in various cell types. PMID- 22207756 TI - Productive recognition of factor IX by factor XIa exosites requires disulfide linkage between heavy and light chains of factor XIa. AB - In the intrinsic pathway of blood coagulation factor XIa (FXIa) activates factor IX (FIX) by cleaving the zymogen at Arg(145)-Ala(146) and Arg(180)-Val(181) bonds releasing an 11-kDa activation peptide. FXIa and its isolated light chain (FXIa LC) cleave S-2366 at comparable rates, but FXIa-LC is a very poor activator of FIX, possibly because FIX undergoes allosteric modification on binding to an exosite on the heavy chain of FXIa (FXIa-HC) required for optimal cleavage rates of the two scissile bonds of FIX. However preincubation of FIX with a saturating concentration of isolated FXIa-HC did not result in any potentiation in the rate of FIX cleavage by FXIa-LC. Furthermore, if FIX binding via the heavy chain exosite of FXIa determines the affinity of the enzyme-substrate interaction, then the isolated FXIa-HC should inhibit the rate of FIX activation by depleting the substrate. However, whereas FXIa/S557A inhibited FIX activation of by FXIa, FXIa HC did not. Therefore, we examined FIX binding to FXIa/S557A, FXIa-HC, FXIa-LC, FXIa/C362S/C482S, and FXIa/S557A/C362S/C482S. The heavy and light chains are disulfide-linked in FXIa/S557A but not in FXIa/C362S/C482S and FXIa/S557A/C362S/C482S. In an ELISA assay only FXI/S557A ligated FIX with high affinity. Partial reduction of FXIa/S557A to produce heavy and light chains resulted in decreased FIX binding, and this function was regained upon reformation of the disulfide linkage between the heavy and the light chains. We therefore conclude that substrate recognition by the FXIa exosite(s) requires disulfide-linked heavy and light chains. PMID- 22207757 TI - Axonal gradient of arachidonic acid-containing phosphatidylcholine and its dependence on actin dynamics. AB - Phosphatidylcholine (PC) is the most abundant component of lipid bilayers and exists in various molecular forms, through combinations of two acylated fatty acids. Arachidonic acid (AA)-containing PC (AA-PC) can be a source of AA, which is a crucial mediator of synaptic transmission and intracellular signaling. However, the distribution of AA-PC within neurons has not been indicated. In the present study, we used imaging mass spectrometry to characterize the distribution of PC species in cultured neurons of superior cervical ganglia. Intriguingly, PC species exhibited a unique distribution that was dependent on the acyl chains at the sn-2 position. In particular, we found that AA-PC is enriched within the axon and is distributed across a proximal-to-distal gradient. Inhibitors of actin dynamics (cytochalasin D and phallacidin) disrupted this gradient. This is the first report of the gradual distribution of AA-PC along the axon and its association with actin dynamics. PMID- 22207758 TI - Amplification and demultiplexing in insulin-regulated Akt protein kinase pathway in adipocytes. AB - Akt plays a major role in insulin regulation of metabolism in muscle, fat, and liver. Here, we show that in 3T3-L1 adipocytes, Akt operates optimally over a limited dynamic range. This indicates that Akt is a highly sensitive amplification step in the pathway. With robust insulin stimulation, substantial changes in Akt phosphorylation using either pharmacologic or genetic manipulations had relatively little effect on Akt activity. By integrating these data we observed that half-maximal Akt activity was achieved at a threshold level of Akt phosphorylation corresponding to 5-22% of its full dynamic range. This behavior was also associated with lack of concordance or demultiplexing in the behavior of downstream components. Most notably, FoxO1 phosphorylation was more sensitive to insulin and did not exhibit a change in its rate of phosphorylation between 1 and 100 nm insulin compared with other substrates (AS160, TSC2, GSK3). Similar differences were observed between various insulin-regulated pathways such as GLUT4 translocation and protein synthesis. These data indicate that Akt itself is a major amplification switch in the insulin signaling pathway and that features of the pathway enable the insulin signal to be split or demultiplexed into discrete outputs. This has important implications for the role of this pathway in disease. PMID- 22207759 TI - Regulation of adipocyte formation by GLP-1/GLP-1R signaling. AB - Increased nutrient intake leads to excessive adipose tissue accumulation, obesity, and the development of associated metabolic disorders. How the intestine signals to adipose tissue to adapt to increased nutrient intake, however, is still not completely understood. We show here, that the gut peptide GLP-1 or its long-lasting analog liraglutide, function as intestinally derived signals to induce adipocyte formation, both in vitro and in vivo. GLP-1 and liraglutide activate the GLP-1R, thereby promoting pre-adipocyte proliferation and inhibition of apoptosis. This is achieved at least partly through activation of ERK, PKC, and AKT signaling pathways. In contrast, loss of GLP-1R expression causes reduction in adipogenesis, through induction of apoptosis in pre-adipocytes, by inhibition of the above mentioned pathways. Because GLP-1 and liraglutide are used for the treatment of type 2 diabetes, these findings implicate GLP-1 as a regulator of adipogenesis, which could be an alternate pathway leading to improved lipid homeostasis and controlled downstream insulin signaling. PMID- 22207760 TI - Glutathione peroxidase 4 is required for maturation of photoreceptor cells. AB - Oxidative stress is implicated in the pathologies of photoreceptor cells, and the protective role of antioxidant enzymes for photoreceptor cells have been well understood. However, their essentiality has remained unknown. In this study we generated photoreceptor-specific conditional knock-out (CKO) mice of glutathione peroxidase 4 (GPx4) and showed the critical role of GPx4 for photoreceptor cells. In the wild-type retina the dominant GPx4 expression was in the mitochondria, indicating the mitochondrial variant was the major GPx4 in the retina. In the GPx4-CKO mice, although photoreceptor cells developed and differentiated into rod and cone cells by P12, they rapidly underwent drastic degeneration and completely disappeared by P21. The photoreceptor cell death in the GPx4-CKO mice was associated with the nuclear translocation of apoptosis-inducing factor (AIF) and TUNEL-positive cells. Photoreceptor cells before undergoing apoptosis (P11) exhibited decreased mitochondrial biomass, decreased number of connecting cilia, as well as disorganized structure of outer segments. These findings indicate that GPx4 is a critical antioxidant enzyme for the maturation and survival of photoreceptor cells. PMID- 22207761 TI - Synergistic roles for G-protein gamma3 and gamma7 subtypes in seizure susceptibility as revealed in double knock-out mice. AB - The functions of different G-protein alphabetagamma subunit combinations are traditionally ascribed to their various alpha components. However, the discovery of similarly diverse gamma subtypes raises the possibility that they may also contribute to specificity. To test this possibility, we used a gene targeting approach to determine whether the closely related gamma(3) and gamma(7) subunits can perform functionally interchangeable roles in mice. In contrast to single knock-out mice that show normal survival, Gng3(-/-)Gng7(-/-) double knock-out mice display a progressive seizure disorder that dramatically reduces their median life span to only 75 days. Biochemical analyses reveal that the severe phenotype is not due to redundant roles for the two gamma subunits in the same signaling pathway but rather is attributed to their unique actions in different signaling pathways. The results suggest that the gamma(3) subunit is a component of a G(i/o) protein that is required for gamma-aminobutyric acid, type B, receptor-regulated neuronal excitability, whereas the gamma(7) subunit is a component of a G(olf) protein that is responsible for A(2A) adenosine or D(1) dopamine receptor-induced neuro-protective response. The development of this mouse model offers a novel experimental framework for exploring how signaling pathways integrate to produce normal brain function and how their combined dysfunction leads to spontaneous seizures and premature death. The results underscore the critical role of the gamma subunit in this process. PMID- 22207762 TI - Lack of kinase regulation of canonical transient receptor potential 3 (TRPC3) channel-dependent currents in cerebellar Purkinje cells. AB - Canonical transient receptor potential (TRPC) channels are widely expressed in the brain and play several roles in development and normal neuronal function. In the cerebellum, Purkinje cell TRPC3 channels underlie the slow excitatory postsynaptic potential observed after parallel fiber stimulation. In these cells TRPC3 channel opening requires stimulation of metabotropic glutamate receptor 1, activation of which can also lead to the induction of long term depression (LTD), which underlies cerebellar motor learning. LTD induction requires protein kinase C (PKC) and protein kinase G (PKG) activation, and although PKC phosphorylation targets are well established, virtually nothing is known about PKG targets in LTD. Because TRPC3 channels are inhibited after phosphorylation by PKC and PKG in expression systems, we examined whether native TRPC3 channels in Purkinje cells are a target for PKG or PKC, thereby contributing to cerebellar LTD. We find that in Purkinje cells, activation of TRPC3-dependent currents is not inhibited by conventional PKC or PKG to any significant extent and that inhibition of these kinases does not significantly impact on TRPC3-mediated currents either. Based on these and previous findings, we propose that TRPC3-dependent currents may differ significantly in their regulation from those overexpressed in expression systems. PMID- 22207763 TI - Regulation of the ATP-sensitive potassium channel subunit, Kir6.2, by a Ca2+ dependent protein kinase C. AB - The activity of ATP-sensitive potassium (K(ATP)) channels is governed by the concentration of intracellular ATP and ADP and is thus responsive to the metabolic status of the cell. Phosphorylation of K(ATP) channels by protein kinase A (PKA) or protein kinase C (PKC) results in the modulation of channel activity and is particularly important in regulating smooth muscle tone. At the molecular level the smooth muscle channel is composed of a sulfonylurea subunit (SUR2B) and a pore-forming subunit Kir6.1 and/or Kir6.2. Previously, Kir6.1/SUR2B channels have been shown to be inhibited by PKC, and Kir6.2/SUR2B channels have been shown to be activated or have no response to PKC. In this study we have examined the modulation of channel complexes formed of the inward rectifier subunit, Kir6.2, and the sulfonylurea subunit, SUR2B. Using a combination of biochemical and electrophysiological techniques we show that this complex can be inhibited by protein kinase C in a Ca(2+)-dependent manner and that this inhibition is likely to be as a result of internalization. We identify a residue in the distal C terminus of Kir6.2 (Ser-372) whose phosphorylation leads to down regulation of the channel complex. This inhibitory effect is distinct from activation which is seen with low levels of channel activity. PMID- 22207764 TI - Target of rapamycin complex 2 signals to downstream effector yeast protein kinase 2 (Ypk2) through adheres-voraciously-to-target-of-rapamycin-2 protein 1 (Avo1) in Saccharomyces cerevisiae. AB - The conserved Ser/Thr kinase target of rapamycin (TOR) serves as a central regulator in controlling cell growth-related functions. There exist two distinct TOR complexes, TORC1 and TORC2, each coupling to specific downstream effectors and signaling pathways. In Saccharomyces cerevisiae, TORC2 is involved in regulating actin organization and maintaining cell wall integrity. Ypk2 (yeast protein kinase 2), a member of the cAMP-dependent, cGMP-dependent, and PKC (AGC) kinase family, is a TORC2 substrate known to participate in actin and cell wall regulation. Employing avo3(ts) mutants with defects in TORC2 functions that are suppressible by active Ypk2, we investigated the molecular interactions involved in mediating TORC2 signaling to Ypk2. GST pulldown assays in yeast lysates demonstrated physical interactions between Ypk2 and components of TORC2. In vitro binding assays revealed that Avo1 directly binds to Ypk2. In avo3(ts) mutants, the TORC2-Ypk2 interaction was reduced and could be restored by AVO1 overexpression, highlighting the important role of Avo1 in coupling TORC2 to Ypk2. The interaction was mapped to an internal region (amino acids 600-840) of Avo1 and a C-terminal region of Ypk2. Ypk2(334-677), a truncated form of Ypk2 containing the Avo1-interacting region, was able to interfere with Avo1-Ypk2 interaction in vitro. Overexpressing Ypk2(334-677) in yeast cells resulted in a perturbation of TORC2 functions, causing defective cell wall integrity, aberrant actin organization, and diminished TORC2-dependent Ypk2 phosphorylation evidenced by the loss of an electrophoretic mobility shift. Together, our data support the conclusion that the direct Avo1-Ypk2 interaction is crucial for TORC2 signaling to the downstream Ypk2 pathway. PMID- 22207766 TI - A simultaneous d-optimal designed study for population pharmacokinetic analyses of mycophenolic Acid and tacrolimus early after renal transplantation. AB - Mycophenolic acid (MPA) and tacrolimus (TAC) are immunosuppressive agents used in combination with corticosteroids for the prevention of acute rejection after solid organ transplantation. Their pharmacokinetics (PK) show considerable unexplained intraindividual and interindividual variability, particularly in the early period after transplantation. The main objective of the present work was to design a study based on D-optimality to describe the PK of the 2 drugs with good precision and accuracy and to explain their variability by means of patients' demographics, biochemical test results, and physiological characteristics. Pharmacokinetic profiles of MPA and TAC were obtained from 65 stable adult renal allograft recipients on a single occasion (ie, day 15 after transplantation). A sampling schedule was estimated based on the D-optimality criterion with the POPED software, using parameter values from previously published studies on MPA and TAC modeling early after transplantation. Subsequently, a population PK model describing MPA and TAC concentrations was developed using nonlinear mixed-effects modeling. Optimal blood-sampling times for determination of MPA and TAC concentrations were estimated to be at 0 (predose) and at 0.24, 0.64, 0.98, 1.37, 2.38, and 11 hours after oral intake of mycophenolate and TAC. The PK of MPA and TAC were best described by a 2-compartment model with first-order elimination. For MPA, the absorption was best described by a transit compartment model, whereas first-order absorption with a lag time best described TAC transfer from the gastrointestinal tract. Parameters were estimated with good precision and accuracy. While hematocrit levels and CYP3A5 genetic polymorphism significantly influenced TAC clearance, the pharmaceutical formulation and MRP2 genetic polymorphism were retained as significant covariates on MPA absorption and elimination, respectively. The prospective use of the simultaneous D-optimal design approach for MPA and TAC has allowed good estimation of MPA and TAC PK parameters in the early period after transplantation characterized by a very high unexplained variability. The influence of some relevant covariates could be shown. PMID- 22207765 TI - Structural dynamics of C-domain of cardiac troponin I protein in reconstituted thin filament. AB - The regulatory function of cardiac troponin I (cTnI) involves three important contiguous regions within its C-domain: the inhibitory region (IR), the regulatory region (RR), and the mobile domain (MD). Within these regions, the dynamics of regional structure and kinetics of transitions in dynamic state are believed to facilitate regulatory signaling. This study was designed to use fluorescence anisotropy techniques to acquire steady-state and kinetic information on the dynamic state of the C-domain of cTnI in the reconstituted thin filament. A series of single cysteine cTnI mutants was generated, labeled with the fluorophore tetramethylrhodamine, and subjected to various anisotropy experiments at the thin filament level. The structure of the IR was found to be less dynamic than that of the RR and the MD, and Ca(2+) binding induced minimal changes in IR dynamics: the flexibility of the RR decreased, whereas the MD became more flexible. Anisotropy stopped-flow experiments showed that the kinetics describing the transition of the MD and RR from the Ca(2+)-bound to the Ca(2+)-free dynamic states were significantly faster (53.2-116.8 s(-1)) than that of the IR (14.1 s(-1)). Our results support the fly casting mechanism, implying that an unstructured MD with rapid dynamics and kinetics plays a critical role to initiate relaxation upon Ca(2+) dissociation by rapidly interacting with actin to promote the dissociation of the RR from the N-domain of cTnC. In contrast, the IR responds to Ca(2+) signals with slow structural dynamics and transition kinetics. The collective findings suggested a fourth state of activation. PMID- 22207768 TI - Challenging Incommensurability: What We Can Learn from Ludwik Fleck for the Analysis of Configurational Innovation. AB - This paper argues that Ludwik Fleck's concepts of thought collectives and proto ideas are surprisingly topical to tackle some conceptual challenges in analyzing contemporary innovation. The objective of this paper is twofold: First, it strives to establish Ludwik Fleck as an important classic on the map of innovation analysis. A systematic comparison with Thomas Kuhn's work on paradigms, a concept highly influential in various branches of innovation studies, suggests a number of pronounced yet under-researched advantages of a Fleckian perspective in the context of technological change and innovation. Secondly, the paper links these advantages to some recent changes in the organization of innovation. Due to the rising pervasiveness of Information and Communication Technologies (ICTs), configurational innovation has become commonplace that cuts across the boundaries of established trajectories of knowledge generation. Fleck's graded understanding of the closedness of thought collectives and his weak notion of incommensurability provide powerful metaphors to grasp the peculiarities of configurational innovation. PMID- 22207767 TI - Continuous distribution model for the investigation of complex molecular architectures near interfaces with scattering techniques. AB - Biological membranes are composed of a thermally disordered lipid matrix and therefore require non-crystallographic scattering approaches for structural characterization with x-rays or neutrons. Here we develop a continuous distribution (CD) model to refine neutron or x-ray reflectivity data from complex architectures of organic molecules. The new model is a flexible implementation of the composition-space refinement of interfacial structures to constrain the resulting scattering length density profiles. We show this model increases the precision with which molecular components may be localized within a sample, with a minimal use of free model parameters. We validate the new model by parameterizing all-atom molecular dynamics (MD) simulations of bilayers and by evaluating the neutron reflectivity of a phospholipid bilayer physisorbed to a solid support. The determination of the structural arrangement of a sparsely tethered bilayer lipid membrane (stBLM) comprised of a multi-component phospholipid bilayer anchored to a gold substrate by a thiolated oligo(ethylene oxide) linker is also demonstrated. From the model we extract the bilayer composition and density of tether points, information which was previously inaccessible for stBLM systems. The new modeling strategy has been implemented into the ga_refl reflectivity data evaluation suite, available through the National Institute of Standards and Technology (NIST) Center for Neutron Research (NCNR). PMID- 22207769 TI - Reaching a Consensus: Terminology and Concepts Used in Coordination and Decision Making Research. AB - Research on coordination and decision-making in humans and nonhuman primates has increased considerably throughout the last decade. However, terminology has been used inconsistently, hampering the broader integration of results from different studies. In this short article, we provide a glossary containing the central terms of coordination and decision-making research. The glossary is based on previous definitions that have been critically revised and annotated by the participants of the symposium "Where next? Coordination and decision-making in primate groups" at the XXIIIth Congress of the International Primatological Society (IPS) in Kyoto, Japan. We discuss a number of conceptual and methodological issues and highlight consequences for their implementation. In summary, we recommend that future studies on coordination and decision-making in animal groups do not use the terms "combined decision" and "democratic/despotic decision-making." This will avoid ambiguity as well as anthropocentric connotations. Further, we demonstrate the importance of 1) taxon-specific definitions of coordination parameters (initiation, leadership, followership, termination), 2) differentiation between coordination research on individual level process and group-level outcome, 3) analyses of collective action processes including initiation and termination, and 4) operationalization of successful group movements in the field to collect meaningful and comparable data across different species. PMID- 22207770 TI - Communication and Cognition in Primate Group Movement. AB - We here review the communicative and cognitive processes underpinning collective group movement in animals. Generally, we identify 2 major axes to explain the dynamics of decision making in animal or human groups or aggregations: One describes whether the behavior is largely determined by simple rules such as keeping a specific distance from the neighbor, or whether global information is also factored in. The second axis describes whether or not the individual constituents of the group have overlapping or diverging interests. We then review the available evidence for baboons, which have been particularly well studied, but we also draw from further studies on other nonhuman primate species. Baboons and other nonhuman primates may produce specific signals in the group movement context, such as the notifying behavior of male hamadryas baboons at the departure from the sleeping site, or clear barks that are given by chacma baboons that have lost contact with the group or specific individuals. Such signals can be understood as expressions of specific motivational states of the individuals, but there is no evidence that the subjects intend to alter the knowledge state of the recipients. There is also no evidence for shared intentionality. The cognitive demands that are associated with decision making in the context of group coordination vary with the amount of information and possibly conflicting sources of information that need to be integrated. Thus, selective pressures should favor the use of signals that maintain group cohesion, while recipients should be selected to be able to make the decision that is in their own best interest in light of all the available information. PMID- 22207771 TI - Coordination of Group Movements in Wild Red-fronted Lemurs (Eulemur rufifrons): Processes and Influence of Ecological and Reproductive Seasonality. AB - Group-living species have to coordinate collective actions to maintain cohesion. In primates, spatial movements represent a meaningful model to study group coordination processes across different socio-ecological contexts. We studied 4 groups of red-fronted lemurs (Eulemur rufifrons) in Kirindy Forest, Madagascar, between 2008 and 2010 across different ecological and reproductive seasons. We collected data on ranging patterns using GPS collars and observational data on different predefined parameters of group movements, including initiation, leadership, followership, overtaking events, termination, and travel distances. Cohesion of these relatively small, egalitarian lemur groups was high year-round, but daily path length and home range size varied considerably between ecological seasons, presumably due to long-distance migrations of some groups at the beginning of the rainy season. Individuals of different age and sex classes successfully initiated group movements. However, stable female leadership prevailed year-round, irrespective of ecological and reproductive season, which might be due to higher or more specific energetic requirements of reproduction. In contrast to lemur species with a more despotic social structure, female red fronted lemurs did not recruit more followers than males. Adult leaders recruited more followers than subadult ones. Further, recruitment success was higher during the peak of the dry season, when predation risk appeared to be higher. Distances of single group movements did not depend on the initiator's sex and age or on ecological seasons. Our results provide new insights into seasonal variability of coordination processes and the role of social dominance in lemur group movements, thereby contributing to a comparative perspective from a primate radiation that evolved group living independently of anthropoids. PMID- 22207772 TI - Out of Sight but Not Out of Mind? Behavioral Coordination in Red-Tailed Sportive Lemurs (Lepilemur ruficaudatus). AB - Many animals are organized into social groups and have to synchronize their activities to maintain group cohesion. Although activity budgets, habitat constraints, and group properties may impact on behavioural synchrony, little is known regarding how members of a group reach a consensus on the timing of activities such as foraging bouts. Game theory predicts that pair partners should synchronize their activities when there is an advantage of foraging together. As a result of this synchronization, differences in the energetic reserves of the two players develop spontaneously and the individual with lower reserves emerges as a pacemaker of the synchrony. Here, we studied the behavioral synchrony of pair-living, nocturnal, red-tailed sportive lemurs (Lepilemur ruficaudatus). We observed 8 pairs continuously for >=1 annual reproductive cycle in Kirindy Forest, Western Madagascar. During focal observations, one observer followed the female of a pair and, simultaneously, another observer followed the male. We recorded the location and behavioral state of the focal individual every 5 min via instantaneous sampling. Although behavioral synchrony of pair partners appeared to be due mainly to endogenous activity patterns, they actively synchronized when they were in visual contact (<10 m). Nevertheless, red-tailed sportive lemurs benefit from synchronizing their activity only for 15% of the time, when they are close together. The lack of an early warning system for predators and weak support for benefits via social information transfer in combination with energetic constraints may explain why red-tailed sportive lemurs do not spend more time together and thus reap the benefits of behavioral synchrony. PMID- 22207773 TI - Spreading order: religion, cooperative niche construction, and risky coordination problems. AB - Adaptationists explain the evolution of religion from the cooperative effects of religious commitments, but which cooperation problem does religion evolve to solve? I focus on a class of symmetrical coordination problems for which there are two pure Nash equilibriums: (1) ALL COOPERATE, which is efficient but relies on full cooperation; (2) ALL DEFECT, which is inefficient but pays regardless of what others choose. Formal and experimental studies reveal that for such risky coordination problems, only the defection equilibrium is evolutionarily stable. The following makes sense of otherwise puzzling properties of religious cognition and cultures as features of cooperative designs that evolve to stabilise such risky exchange. The model is interesting because it explains lingering puzzles in the data on religion, and better integrates evolutionary theories of religion with recent, well-motivated models of cooperative niche construction. PMID- 22207774 TI - Cooperative feeding and breeding, and the evolution of executive control. AB - Dubreuil (Biol Phil 25:53-73, 2010b, this journal) argues that modern-like cognitive abilities for inhibitory control and goal maintenance most likely evolved in Homo heidelbergensis, much before the evolution of oft-cited modern traits, such as symbolism and art. Dubreuil's argument proceeds in two steps. First, he identifies two behavioral traits that are supposed to be indicative of the presence of a capacity for inhibition and goal maintenance: cooperative feeding and cooperative breeding. Next, he tries to show that these behavioral traits most likely emerged in Homo heidelbergensis. In this paper, I show that neither of these steps are warranted in light of current scientific evidence, and thus, that the evolutionary background of human executive functions, such as inhibition and goal maintenance, remains obscure. Nonetheless, I suggest that cooperative breeding might mark a crucial step in the evolution of our species: its early emergence in Homo erectus might have favored a social intelligence that was required to get modernity really off the ground in Homo sapiens. PMID- 22207775 TI - Capturing Community Context of Human Response to Forest Disturbance by Insects: A Multi-Method Assessment. AB - The socioeconomic and environmental features of local places (community context) influence the relationship between humans and their physical environment. In times of environmental disturbance, this community context is expected to influence human perceptual and behavioral responses. Residents from nine Colorado communities experiencing a large outbreak of mountain pine beetles (Dendroctonus ponderosae) were surveyed in 2007. Multiple analytic methods including ordinary least squares regression and multilevel modeling techniques were used to evaluate a community-context conceptual model of factors influencing individual actions in response to forest disturbance by beetles. Results indicated that community biophysical and socioeconomic characteristics had important impacts on participation in beetle-related actions and influenced the relationships of individual-level variables in the conceptual model with beetle-related activities. Our findings have implications for natural resource management and policy related to forest disturbances, and for developing a methodology appropriate to measure the general community context of human-environment interactions. PMID- 22207776 TI - Rural-to-Urban Labor Migration, Household Livelihoods, and the Rural Environment in Chongqing Municipality, Southwest China. AB - Rural migration and its relationship to the rural environment have attracted increasing research interest in recent decades. Rural migration constitutes a key component of human population movement, while rural areas contain most of the world's natural resources such as land and forests. This study empirically evaluates a conceptual framework incorporating rural household livelihoods as an integrative mediating factor between rural migration and the rural environment in the context of rural-to-urban labor migration in Chongqing Municipality, Southwest China. The analysis draws on data collected through household surveys and key informant interviews from four villages. Results confirm the hypothesis that labor-migrant and non-labor-migrant households differ significantly in livelihood activities including agricultural production, agricultural technology use, income and consumption, and resource use and management. Implications for the subsequent environmental outcomes of rural labor out-migration and corresponding natural resource management and policy in rural origin areas are discussed. PMID- 22207777 TI - Cross-National Measurement Invariance of the Teacher and Classmate Support Scale. AB - The cross-national measurement invariance of the teacher and classmate support scale was assessed in a study of 23202 Grade 8 and 10 students from Austria, Canada, England, Lithuania, Norway, Poland, and Slovenia, participating in the Health Behaviour in School-aged Children (HBSC) 2001/2002 study. A multi-group means and covariance analysis supported configural and metric invariance across countries, but not full scalar equivalence. The composite reliability was adequate and highly consistent across countries. In all seven countries, teacher support showed stronger associations with school satisfaction than did classmate support, with the results being highly consistent across countries. The results indicate that the teacher and classmate support scale may be used in cross cultural studies that focus on relationships between teacher and classmate support and other constructs. However, the lack of scalar equivalence indicates that direct comparison of the levels support across countries might not be warranted. PMID- 22207778 TI - Comparing the Well-Being of Older Europeans: Introduction. PMID- 22207780 TI - Cross-Country Differentials in Work Disability Reporting Among Older Europeans. AB - Descriptive evidence shows that there is large cross-country variation in self reported work disability rates of the elderly in Europe. In this paper we analyse whether these differences are genuine or they just reflect heterogeneity in reporting styles. To shed light on the determinants of work-disability differentials across countries, we combine a wide set of individuals' socioeconomic and health status characteristics with macro-economic indicators describing the institutional background of the country of residence. PMID- 22207781 TI - Satisfaction with Social Contacts of Older Europeans. AB - This paper analyses the determinants of an important component of well-being among individuals aged 50 years or older in eleven European countries: satisfaction with social contacts. We use data from the Survey of Health, Ageing and Retirement in Europe and anchoring vignettes to correct for potential differences in responses scales across countries and socio-demographic groups. On average, older Europeans report being satisfied with their social contacts, but there exist substantial differences across countries: respondents from Northern countries tend to be more satisfied than individuals from Central or Mediterranean countries. Our analysis shows that correcting for response scale differentials alters the country ranking for of satisfaction with social contacts, while it has much less effect on the estimates of what drives within country determinants. PMID- 22207779 TI - Can Reporting Heterogeneity Explain Differences in Depressive Symptoms Across Europe? AB - Depression is one of the leading causes of disability in the developed world. Previous studies have shown varying depression prevalence rates between European countries, and also within countries, between socioeconomic groups. However, it is unclear whether these differences reflect true variations in prevalence or whether they are attributable to systematic differences in reporting styles (reporting heterogeneity) between countries and socioeconomic groups. In this study, we examine the prevalence of three depressive symptoms (mood, sleeping and concentration problems) and their association with educational level in 10 European countries, and examine whether these differences can be explained by differences in reporting styles. We use data from the first and second waves of the COMPARE study, comprising a sub-sample of 9,409 adults aged 50 and over in 10 European countries covered by the Survey of Health, Ageing and Retirement in Europe. We first use ordered probit models to estimate differences in the prevalence of self-reported depressive symptoms by country and education. We then use hierarchical ordered probit models to assess differences controlling for reporting heterogeneity. We find that depressive symptoms are most prevalent in Mediterranean and Eastern European countries, whereas Sweden and Denmark have the lowest prevalence. Lower educational level is associated with higher prevalence of depressive symptoms in all European regions, but this association is weaker in Northern European countries, and strong in Eastern European countries. Reporting heterogeneity does not explain these cross-national differences. Likewise, differences in depressive symptoms by educational level remain and in some regions increase after controlling for reporting heterogeneity. Our findings suggest that variations in depressive symptoms in Europe are not attributable to differences in reporting styles, but are instead likely to result from variations in the causes of depressive symptoms between countries and educational groups. PMID- 22207782 TI - Age, Health and Life Satisfaction Among Older Europeans. AB - In this paper we investigate how age affects the self-reported level of life satisfaction among the elderly in Europe. By using a vignette approach, we find evidence that age influences life satisfaction through two counterbalancing channels. On the one hand, controlling for the effects of all other variables, the own perceived level of life satisfaction increases with age. On the other hand, given the same true level of life satisfaction, older respondents are more likely to rank themselves as "dissatisfied" with their life than younger individuals. Detrimental health conditions and physical limitations play a crucial role in explaining scale biases in the reporting style of older individuals. PMID- 22207783 TI - Fungal root endophyte associations of plants endemic to the Pamir Alay Mountains of Central Asia. AB - The fungal root endophyte associations of 16 species from 12 families of plants endemic to the Pamir Alay Mountains of Central Asia are presented. The plants and soil samples were collected in Zeravshan and Hissar ranges within the central Pamir Alay mountain system. Colonization by arbuscular mycorrhizal fungi (AMF) was found in 15 plant species; in 8 species it was of the Arum type and in 4 of the Paris type, while 3 taxa revealed intermediate arbuscular mycorrhiza (AM) morphology. AMF colonization was found to be absent only in Matthiola integrifolia, the representative of the Brassicaceae family. The AM status and morphology are reported for the first time for all the species analyzed and for the genera Asyneuma, Clementsia, and Eremostachys. Mycelia of dark septate endophytes (DSE) accompanied the AMF colonization in ten plant species. The frequency of DSE occurrence in the roots was low in all the plants, with the exception of Spiraea baldschuanica. However, in the case of both low and higher occurrence, the percentage of DSE root colonization was low. Moreover, the sporangia of Olpidium spp. were sporadically found inside the root epidermal cells of three plant species. Seven AMF species (Glomeromycota) found in the trap cultures established with soils surrounding roots of the plants being studied were reported for the first time from this region of Asia. Our results provide information that might well be of use to the conservation and restoration programmes of these valuable plant species. The potential application of beneficial root-inhabiting fungi in active plant protection projects of rare, endemic and endangered plants is discussed. PMID- 22207784 TI - Dubinectes infirmus, a new species of deep-water Munnopsidae (Crustacea, Isopoda, Asellota) from the Argentine Basin, South Atlantic Ocean. AB - Dubinectes infirmussp. n., Munnopsidae, is described from the Argentine Basin, southwest Atlantic, at depths between 4586-4607 m. The new species is distinguished by a narrow rim of the pleotelson posterior margin which is not raising over its dorsal surface; article 3 of the antennula is subequal in length to article 2; distomedial lobes of male pleopod 1 are of same size as distolateral lobes; stylet of male pleopod 2 is subequal in length to protopod; uropod exopod is more than a half of endopod length. Some generic characters which are weakly pronounced in the new species or have different state are defined more precisely in the revised diagnosis of Dubinectes. The modified diagnosis of the genus, a key to the species of Dubinectes as well as the distribution of the genus are presented. PMID- 22207785 TI - Integrating field surveys and remote sensing data to study distribution, habitat use and conservation status of the herpetofauna of the Comoro Islands. AB - We studied the non-marine reptile and amphibian species of the volcanic Comoro archipelago in the Western Indian Ocean, a poorly known island herpetofauna comprising numerous microendemic species of potentially high extinction risk and widespread, non-endemic and often invasive taxa. According to our data, the Comoro islands are inhabited by two amphibian species and at least 28 species of reptiles although ongoing genetic studies and unconfirmed historical records suggest an even higher species diversity. 14 of the 28 currently recognized species of terrestrial reptiles (50%) and the two amphibians are endemic to a single island or to the Comoro archipelago. The majority of species are most abundant at low elevation. However, a few endemic species, like the gekkonid lizards Paroedura sanctijohannis and Phelsuma nigristriata, are more common in or even confined to higher altitudes. We created habitat maps from remotely sensed data in combination with detailed species distribution maps produced using comprehensive data from field surveys between 2000 and 2010, literature, and historical locality records based on specimens in zoological collections. Using these data, we assessed the conservation status of the endemic terrestrial reptiles and amphibians according to the IUCN Red List criteria. Our results show that although little area of natural forest remains on the Comoros, many species are abundant in degraded forest or plantations. Competition and predation by invasive species appears to be the most important threat factor for the endemic herpetofauna, together with habitat degradation and destruction, which further favours invasive species. We propose the status Endangered for three species, Vulnerable for one species, Near Threatened for six species, Least Concern for four and Data Deficient for two species. The endemic subspecies Oplurus cuvieri comorensis is proposed for the status Critically Endangered. Based on the results of this study, seven areas of importance for reptile and amphibian conservation on the Comoros are identified. This study shows how remote sensing data can contribute to increasing accuracy and objectiveness of conservation assessments. PMID- 22207786 TI - Redescription of the poorly known Central Asian Titanoeca lehtineni Fet, 1986 (Araneae, Titanoecidae). AB - A poorly known spiders species, Titanoeca lehtineni Fet, 1986, from southwestern Central Asia is redescribed and diagnosed. PMID- 22207787 TI - Redescription of the rare amphipod crustacean Pseudaeginella montoucheti (Quitete, 1971) from Brazil. AB - Pseudaeginella montoucheti (Quitete, 1971) is redescribed based on newly collected specimens from red and brown algae and tubiculous polychaete colony that were obtained from shallow waters at Tamboretes Archipelago, Balneario Barra do Sul and Sepultura Beach, Bombinhas, Santa Catarina State, Brazil. Of 10 species of Pseudaeginella so far reported, Pseudaeginella montoucheti is closest to Pseudaeginella sanctipauli Laubitz, 1995, but differs from the latter by having more numerous body spines including ventro-lateral ones over gills on pereonites 3 and 4, and the antenna 1 length measuring half body length. An identification key for Pseudaeginella species and a checklist of Caprellidea occurring along the Brazilian coasts are also presented. PMID- 22207788 TI - Protura of Italy, with a key to species and their distribution. AB - The Italian Protura were studied basing on 5103 specimens from 198 sampling areas, along with bibliographic data from 49 collecting sites. 17 out of the 20 Italian regions are covered. As a result, 40 species have been identified (belonging to 8 genera and 4 families), 6 of which are new records for the Italian fauna.A key to the Italian species is reported, followed by a series of distribution maps and brief remarks for some of them. A preliminary biogeographical overview allowed us to delineate the chorological categories of these species, 10 of which are actually known only in Italy. The comparison with the species richness known for some best studied Central and Eastern European Countries leads us to speculate that widening our research, Italian Protura check list will be much implemented. PMID- 22207789 TI - Contributions to the systematics of New World macro-moths III. PMID- 22207790 TI - A new species of Herpetogramma (Lepidoptera, Crambidae, Spilomelinae) from eastern North America. AB - Herpetogramma sphingealissp. n., a new species of Crambidae (Lepidoptera), is described from Quebec, Canada. The species is included in the genus Herpetogramma Led., 1863, a genus in the subfamily Spilomelinae. Adults and genitalia of this species are described and illustrated, as well as those of Herpetogramma aeglealis (Walker, 1859) and Herpetogramma thestealis (Walker, 1859), and adults of the semi-melanic form of Herpetogramma aeglealis are illustrated. PMID- 22207791 TI - Two new species of the Hagnagora anicata complex (Geometridae, Larentiinae) from Costa Rica. AB - Examination of the lectotype (here designated) reveals that Hagnagora anicata (Felder & Rogenhofer) does not occur in Costa Rica. Instead two new species are described, Hagnagora eliannesp. n. and Hagnagora unniasp. n., and their distribution is discussed. The previous treatment of Hagnagora anicata as a single widespread species ranging from Jamaica and Mexico to Bolivia needs to be critically evaluated. PMID- 22207793 TI - The genus Neotherina Dognin (Geometridae, Ennominae) in Costa Rica. AB - So far, two species of Neotherina Dognin have been recorded in Costa Rica. Neotherina imperilla (Dognin) occurs primarily at altitudes between 1100 and 1700 meters and Neotherina callas (Druce) which is widely distributed above 1100 meters. A third, new species, Neotherina xanthosa Sullivan and Chacon is described from altitudes above 2400 meters. Heterogeneity of the genus is discussed. PMID- 22207792 TI - Pterospoda nigrescens (Hulst), a synonym of Ixala klotsi Sperry (Lepidoptera, Geometridae, Ennominae). AB - Comparison of the types of Ixala klotsi (Sperry) and Pterospoda nigrescens (Hulst) shows that they are the same species, with Ixala klotsi a synonym of Pterospoda nigrescens. A lectotype of Selidosema nigrescens is designated, and the types of Selidosema nigrescens and Ixala klotsi are illustrated. Male and female habitus and genitalia of Pterospoda nigrescens are illustrated. PMID- 22207794 TI - A new species of Elasmia Moschler from New Mexico and Texas, and a new subspecies of Elasmia mandela (Druce) from Texas and Oklahoma (Lepidoptera, Notodontidae, Nystaleinae). AB - Hippia packardii (Morrison) and Hippia insularis (Grote) are moved to the genus Elasmia Moschler as comb. n.Elasmia cave Metzler,sp. n. is described from New Mexico and Texas, and Elasmia mandela santaana Metzler & Knudson,ssp. n. is described from Texas and Oklahoma. A key to the species of Elasmia of southwestern U.S. is provided. Adult male and female moths of Elasmia from southwestern U.S. and their genitalia are illustrated. PMID- 22207795 TI - Generic placement of the Neotropical species of " Phragmatobia" (Erebidae, Arctiinae), with a remarkable matrivorous species from the Peruvian Andes. AB - Phragmatobia Stephens is briefly reviewed and a diagnosis is provided. The South American species currently placed in Phragmatobia Stephens are revised to two new genera, Andesobia Schmidt and De Freina, gen. n., and Patagobia Schmidt and De Freina, gen. n. (subtribe Spilosomina). Both Andesobia and Patagobia exhibit adaptations to high altitude habitats, including micropterous females in Andesobia (Patagobia females are unknown) and diurnal flight of males. The adults, immature stages, and mating behaviour of Andesobia jelskii (Oberthur, 1881) are described. Males of Andesobia jelskii enter the female cocoon to mate, and the micropterous, flightless females remain in the cocoon following oviposition where newly hatched larvae feed initially on the female's body.Four species are included in Andesobia, Andesobia jelskiicomb. n. (= Paracles imitatrix Rothschild, 1922, syn. n.), Andesobia flavata (Hampson, 1901), comb. n., Andesobia boliviana (Gaede, 1923), comb. n. (=Turuptiana flavescens Rothschild, 1933, syn. n.), and Andesobia sanguinea (Hampson, 1907), comb. n.Patagobia includes only Patagobia thursbyi (Rothschild, 1910), comb. n., and Patagobia thursbyi pluto Toulgoet is relegated to its synonymy. Patagobia shows affinities to Phaos Walker, 1855 of Australia, Metacrias Meyrick, 1886 of New Zealand, and Pseudophragmatobia Kruger, 2009 of South Africa, suggesting a common ancestry of circumantarctic origin. Phragmatobia karsholti Toulgoet, 1991 is transferred to Venedictoffia Toulgoet, comb. n., an unrelated genus that is removed from subtribe Arctiina and provisionally placed in the Phaegopterina. Phragmatobia oberthueri Rothschild, 1910, described from Tibet, is a synonym of Lachana alpherakii (Grum-Grzhimailo, 1891) [Erebidae: Lymantriinae], syn. n., comb. n. PMID- 22207796 TI - A new Zanclognatha from eastern North America and a preliminary key to the larvae of the genus (Lepidoptera, Erebidae, Herminiinae). AB - The adult of a widespread but previously undescribed species of Zanclognatha Lederer is described from eastern North America. Images of the mature larva and life history datafor Zanclognathadentatasp. n. are included, along with a preliminary key to the larvae of ten eastern North American Zanclognatha species. PMID- 22207797 TI - Gondysia preceded Neadysgonia (Lepidoptera, Erebidae, Erebinae), a new generic synonymy from southeastern United States. AB - The recently proposed genus Neadysgonia Sullivan, 2010, was preceded in the literature by Gondysia Berio, 1955, a monotypic genus based on specimens without locality labels but presumed to be from Madagascar. The genus Gondysia replaces Neadysgonia and the species Gondysia pertorrida Berio, 1955, becomes a junior synonym of Gondysia consobrina (Guenee, 1852). PMID- 22207798 TI - New synonymies and combinations in Argyrostrotis Hubner (Lepidoptera, Erebidae, Erebinae, Poaphilini). AB - After examining the type specimens of species in the eastern North American genus Argyrostrotis the number of known species in the genus is reduced from 10 to six through synonymy. A key to species is included along with illustrations of the adults and genitalia of each species. Three Neotropical species currently included in Argyrostrotis (Argyrostrotis eurysaces Schaus, 1914; Argyrostrotis quadrata Dognin, 1910; and Celiptera surrufula Dyar, 1913) are transferred to other genera as Argyrosticta eurysaces (Schaus, 1914), comb. n. [Noctuidae: Bagisarinae], Heterochroma quadrata (Dognin, 1910), comb. n. [Noctuidae: Amphipyrinae], and Ptichodis surrufula (Dyar, 1913), comb. n. [Erebidae: Erebinae: Euclidiini]. PMID- 22207799 TI - The Lepidoptera of White Sands National Monument, Otero County, New Mexico, USA 2. Rediscovery and description of Sparkia immacula (Grote, 1883) (Noctuidae, Noctuinae, Hadenini). AB - In 2006 the U.S. National Park Service initiated a long term study of the Lepidoptera at White Sands National Monument, Otero County, New Mexico. Sparkia immacula (Grote, 1883), previously known only from historical specimens collected in Arizona and New Mexico, was discovered in the Monument in 2007 during the second year of the study. The adult moths and male and female genitalia are illustrated for the first time. PMID- 22207800 TI - The Lepidoptera of White Sands National Monument, Otero County, New Mexico, USA 3. A new species of Aleptina Dyar, 1902 (Lepidoptera, Noctuidae, Amphipyrinae, Psaphidini). AB - In 2006 the US National Park Service initiated a long-term study of the Lepidoptera at White Sands National Monument, Otero County, New Mexico. Aleptina arenariasp. n., described here, was discovered in 2008, the second year of the study. The adult moths and male and female genitalia are illustrated. PMID- 22207801 TI - The Lepidoptera of White Sands National Monument, Otero County, New Mexico, USA 4. A new species of Schinia Hubner, 1818 (Lepidoptera, Noctuidae, Heliothinae). AB - In 2006 the U.S. National Park Service initiated a long term study of the Lepidoptera at White Sands National Monument, Otero County, New Mexico. Schinia pogueisp. n., described here, was discovered in 2007, the second year of the study. The male and female adult moths and genitalia are illustrated. PMID- 22207803 TI - Collaborative electronic infrastructures to accelerate taxonomic research. PMID- 22207802 TI - Additions and corrections to the check list of the Noctuoidea (Insecta, Lepidoptera) of North America north of Mexico. AB - A total of 115 additions and corrections are listed and discussed for the check list of the Noctuoidea of North America north of Mexico published in 2010. Thirty two of these are changes in authorship and/or date of publication or spelling. Taxonomic changes are 33 new or revised synonymies, three new combinations, and six revisions in status from synonymy to valid species. PMID- 22207804 TI - ZooKeys 150: Three and a half years of innovative publishing and growth. PMID- 22207806 TI - Scratchpads 2.0: a Virtual Research Environment supporting scholarly collaboration, communication and data publication in biodiversity science. AB - The Scratchpad Virtual Research Environment (http://scratchpads.eu/) is a flexible system for people to create their own research networks supporting natural history science. Here we describe Version 2 of the system characterised by the move to Drupal 7 as the Scratchpad core development framework and timed to coincide with the fifth year of the project's operation in late January 2012. The development of Scratchpad 2 reflects a combination of technical enhancements that make the project more sustainable, combined with new features intended to make the system more functional and easier to use. A roadmap outlining strategic plans for development of the Scratchpad project over the next two years concludes this article. PMID- 22207805 TI - Data issues in the life sciences. AB - We review technical and sociological issues facing the Life Sciences as they transform into more data-centric disciplines - the "Big New Biology". Three major challenges are: 1) lack of comprehensive standards; 2) lack of incentives for individual scientists to share data; 3) lack of appropriate infrastructure and support. Technological advances with standards, bandwidth, distributed computing, exemplar successes, and a strong presence in the emerging world of Linked Open Data are sufficient to conclude that technical issues will be overcome in the foreseeable future. While motivated to have a shared open infrastructure and data pool, and pressured by funding agencies in move in this direction, the sociological issues determine progress. Major sociological issues include our lack of understanding of the heterogeneous data cultures within Life Sciences, and the impediments to progress include a lack of incentives to build appropriate infrastructures into projects and institutions or to encourage scientists to make data openly available. PMID- 22207807 TI - Biodiversity information platforms: From standards to interoperability. AB - One of the most serious bottlenecks in the scientific workflows of biodiversity sciences is the need to integrate data from different sources, software applications, and services for analysis, visualisation and publication. For more than a quarter of a century the TDWG Biodiversity Information Standards organisation has a central role in defining and promoting data standards and protocols supporting interoperability between disparate and locally distributed systems.Although often not sufficiently recognized, TDWG standards are the foundation of many popular Biodiversity Informatics applications and infrastructures ranging from small desktop software solutions to large scale international data networks. However, individual scientists and groups of collaborating scientist have difficulties in fully exploiting the potential of standards that are often notoriously complex, lack non-technical documentations, and use different representations and underlying technologies. In the last few years, a series of initiatives such as Scratchpads, the EDIT Platform for Cybertaxonomy, and biowikifarm have started to implement and set up virtual work platforms for biodiversity sciences which shield their users from the complexity of the underlying standards. Apart from being practical work-horses for numerous working processes related to biodiversity sciences, they can be seen as information brokers mediating information between multiple data standards and protocols.The ViBRANT project will further strengthen the flexibility and power of virtual biodiversity working platforms by building software interfaces between them, thus facilitating essential information flows needed for comprehensive data exchange, data indexing, web-publication, and versioning. This work will make an important contribution to the shaping of an international, interoperable, and user-oriented biodiversity information infrastructure. PMID- 22207808 TI - XML schemas and mark-up practices of taxonomic literature. AB - We review the three most widely used XML schemas used to mark-up taxonomic texts, TaxonX, TaxPub and taXMLit. These are described from the viewpoint of their development history, current status, implementation, and use cases. The concept of "taxon treatment" from the viewpoint of taxonomy mark-up into XML is discussed. TaxonX and taXMLit are primarily designed for legacy literature, the former being more lightweight and with a focus on recovery of taxon treatments, the latter providing a much more detailed set of tags to facilitate data extraction and analysis. TaxPub is an extension of the National Library of Medicine Document Type Definition (NLM DTD) for taxonomy focussed on layout and recovery and, as such, is best suited for mark-up of new publications and their archiving in PubMedCentral. All three schemas have their advantages and shortcomings and can be used for different purposes. PMID- 22207809 TI - Supporting Red List threat assessments with GeoCAT: geospatial conservation assessment tool. AB - GeoCAT is an open source, browser based tool that performs rapid geospatial analysis to ease the process of Red Listing taxa. Developed to utilise spatially referenced primary occurrence data, the analysis focuses on two aspects of the geographic range of a taxon: the extent of occurrence (EOO) and the area of occupancy (AOO). These metrics form part of the IUCN Red List categories and criteria and have often proved challenging to obtain in an accurate, consistent and repeatable way. Within a familiar Google Maps environment, GeoCAT users can quickly and easily combine data from multiple sources such as GBIF, Flickr and Scratchpads as well as user generated occurrence data. Analysis is done with the click of a button and is visualised instantly, providing an indication of the Red List threat rating, subject to meeting the full requirements of the criteria. Outputs including the results, data and parameters used for analysis are stored in a GeoCAT file that can be easily reloaded or shared with collaborators. GeoCAT is a first step toward automating the data handling process of Red List assessing and provides a valuable hub from which further developments and enhancements can be spawned. PMID- 22207810 TI - Creative Commons licenses and the non-commercial condition: Implications for the re-use of biodiversity information. AB - The Creative Commons (CC) licenses are a suite of copyright-based licenses defining terms for the distribution and re-use of creative works. CC provides licenses for different use cases and includes open content licenses such as the Attribution license (CC BY, used by many Open Access scientific publishers) and the Attribution Share Alike license (CC BY-SA, used by Wikipedia, for example). However, the license suite also contains non-free and non-open licenses like those containing a "non-commercial" (NC) condition. Although many people identify "non-commercial" with "non-profit", detailed analysis reveals that significant differences exist and that the license may impose some unexpected re-use limitations on works thus licensed. After providing background information on the concepts of Creative Commons licenses in general, this contribution focuses on the NC condition, its advantages, disadvantages and appropriate scope. Specifically, it contributes material towards a risk analysis for potential re users of NC-licensed works. PMID- 22207811 TI - Towards the bibliography of life. AB - This paper discusses how we intend to take forward the vision of a Bibliography of Life in the ViBRANT project. The underlying principle of the Bibliography is to provide taxonomists and others with a freely accessible bibliography covering the whole of life. Such a bibliography has been achieved for specific study areas within taxonomy, but not for "life" as a whole.The creation of such a comprehensive tool has been hindered by various social and technical issues. The social concerns focus on the willingness of users to contribute to the Bibliography. The technical concerns relate to the architecture required to deliver the Bibliography. These issues are discussed in the paper and approaches to addressing them within the ViBRANT project are described, to demonstrate how we can now seriously consider building a Bibliography of Life. We are particularly interested in the potential of the resulting tool to improve the quality of bibliographic references. Through analysing the large number of references in the Bibliography we will be able to add metadata by resolving known issues such as geographical name variations. This should result in a tool that will assist taxonomists in two ways. Firstly, it will be easier for them to discover relevant literature, especially pre-digital literature; and secondly, it will be easier for them to identify the canonical form for a citationThe paper also covers related issues relevant to building the tool in ViBRANT, including implementation and copyright, with suggestions as to how we could address them. PMID- 22207812 TI - Data standards, sense and stability: Scratchpads, the ICZN and ZooBank. AB - The International Commission of Zoological Nomenclature has used the Scratchpads platform (currently being developed and maintained by ViBRANT) as the foundation for its redesigned website and as a platform for engaging with its users. The existing Scratchpad tools, with extensions to provide additional functions, have allowed for a major transformation in presentation of linked nomenclatural tools. Continued development of the new website will act as a springboard for the ICZN to participate more fully in the wider community of biodiversity informatics. PMID- 22207813 TI - Who learns from whom? Supporting users and developers of a major biodiversity e infrastructure. AB - Support systems play an important role for the communication between users and developers of software. We studied two support systems, an issues tracker and an email service available for Scratchpads, a Web 2.0 social networking tool that enables communities to build, share, manage and publish biodiversity information on the Web. Our aim was to identify co-learning opportunities between users and developers of the Scratchpad system by asking which support system was used by whom and for what type of questions. Our results show that issues tracker and emails cater to different user mentalities as well as different kind of questions and suggest ways to improve the support system as part of the development under the EU funded ViBRANT programme. PMID- 22207814 TI - Studying the effects of virtual biodiversity research infrastructures. AB - The research environment of scholars is increasingly web-based. This makes it urgent to study the effects of moving to the Web on research practices, scholarly output and innovation. We propose a theoretical framework and a methodology to study these effects. In a pilot study, we apply theory and method on an online community in biodiversity research, to demonstrate the feasibility of the approach. We also indicate the practical relevance of this kind of analysis for improving the quality of virtual research environments. In the last section, directions for further research are suggested. PMID- 22207815 TI - Engaging the broader community in biodiversity research: the concept of the COMBER pilot project for divers in ViBRANT. AB - This paper discusses the design and implementation of a citizen science pilot project, COMBER (Citizens' Network for the Observation of Marine BiodivERsity, http://www.comber.hcmr.gr), which has been initiated under the ViBRANT EU e infrastructure. It is designed and implemented for divers and snorkelers who are interested in participating in marine biodiversity citizen science projects. It shows the necessity of engaging the broader community in the marine biodiversity monitoring and research projects, networks and initiatives. It analyses the stakeholders, the industry and the relevant markets involved in diving activities and their potential to sustain these activities. The principles, including data policy and rewards for the participating divers through their own data, upon which this project is based are thoroughly discussed. The results of the users analysis and lessons learned so far are presented. Future plans include promotion, links with citizen science web developments, data publishing tools, and development of new scientific hypotheses to be tested by the data collected so far. PMID- 22207816 TI - Bush Blitz aids description of three new species and a new genus of Australian beeflies (Diptera, Bombyliidae, Exoprosopini). AB - Bush Blitz is a three-year multimillion dollar program to document the plants and animals in hundreds of properties across Australia's National Reserve System. The core focus is on nature discovery - identifying and describing new species of plants and animals. The Bush Blitz program has enabled the collection and description of beeflies (Diptera, Bombyliidae) from surveys in Western Australia and Queensland. Three new species of Australian beeflies belonging to the Exoprosopini are described; Palirika mackenziei Lambkin sp. n., Palirika culgoafloodplainensis Lambkin sp. n., and Larrpana bushblitz Lambkin sp. n. Phylogenetic analysis of 40 Australian exoprosopine species belonging to the Balaana generic-group Lambkin & Yeates 2003 supports the placement of the three new species into existing genera, and the erection and description of the new genus Ngalki Lambkin gen. n. for Ngalki trigonium (Lambkin & Yeates 2003) comb. n. Revised keys are provided for the genera of the Australian Balaana genus-group and the species of Palirika Lambkin & Yeates, 2003 and Larrpana Lambkin & Yeates 2003. With the description of the three new species and the transferral of Munjua trigona Lambkin & Yeates 2003 into the new genus Ngalki Lambkin gen. n., three genera are rediagnosed; Munjua Lambkin & Yeates 2003, Palirika and Larrpana. PMID- 22207818 TI - Cambrian archaeocyathan metazoans: revision of morphological characters and standardization of genus descriptions to establish an online identification tool. AB - Archaeocyatha represent the oldest calcified sponges and the first metazoans to build bioconstructions in association with calcimicrobes. They are a key group in biology, evolutionary studies, biostratigraphy, paleoecology and paleogeography of the early Cambrian times. The establishing of a new standardized terminology for archaeocyathans description has permitted the creation of the first knowledge base in English including descriptions of all archaeocyathan genera. This base, using the XPER2 software package, is an integral part of the -Archaeocyatha- a knowledge base website, freely available at url http://www.infosyslab.fr/archaeocyatha. The website is composed of common information about Archaeocyatha, general remarks about the knowledge base, the description of the 307 genera recognized with images of type-specimens of type species for each genus, as well as additional morphological data, an interactive free access key and its user guide.The automatic analysis and comparison of the digitized descriptions have identified some genera with highly similar morphology. These results are a great help for future taxonomic revisions and suggest a number of possible synonymies that require further study. PMID- 22207819 TI - The future of the past in the present: biodiversity informatics and geological time. AB - The biological and palaeontological communities have approached the problem of informatics separately, creating a divide between communities that is both technological and sociological in nature. In this paper we describe one new advance towards solving this problem - expanding the Scratchpads platform to deal with geological time. In creating this system we have attempted to make our work open to existing communities by providing a webservice of geological time data via the GBIF Vocabularies site. We have also ensured that our system can adapt to changes in the definition of geological time intervals and is capable of querying datasets independently of the format of geological age data used. PMID- 22207817 TI - An account of the taxonomy and distribution of Syllidae (Annelida, Polychaetes) in the eastern Mediterranean, with notes on the genus Prosphaerosyllis San Martin, 1984 in the Mediterranean. AB - The syllid fauna of three locations in Crete and Israel (eastern Mediterranean Sea) was studied, yielding 82 syllid species, many of which were found for the first time in the respective areas: Seventeen species were recorded for the first time on the Israeli coasts and 20 in Greek waters. Perkinsyllis augeneri (Hartmann-Schroder, 1979) and Prosphaerosyllis chauseyensis Olivier et al., 2011 are new records for the Mediterranean Sea. Detailed information is given on the morphology, ecology and distribution of the species recorded for the first time in the studied areas. In addition, an update on the distribution of the genus Prosphaerosyllis San Martin, 1984 in the Mediterranean is given and an identification key to the Mediterranean species is provided. PMID- 22207820 TI - Literature based species occurrence data of birds of northeast India. AB - The northeast region of India is one of the world's most significant biodiversity hotspots. One of the richest bird areas in India, it is an important route for migratory birds and home to many endemic bird species. This paper describes a literature-based dataset of species occurrences of birds of northeast India. The occurrence records documented in the dataset are distributed across eleven states of India, viz.: Arunachal Pradesh, Assam, Bihar, Manipur, Meghalaya, Mizoram, Nagaland, Sikkim, Tripura, Uttar Pradesh and West Bengal. The geospatial scope of the dataset represents 24 to 29 degree North latitude and 78 to 94 degree East longitude, and it comprises over 2400 occurrence records. These records have been collated from scholarly literature published between1915 and 2008, especially from the Journal of the Bombay Natural History Society (JBNHS). The temporal scale of the dataset represents bird observations recorded between 1909 and 2007. The dataset has been developed by employing MS Excel. The key elements in the database are scientific name, taxonomic classification, temporal and geospatial details including geo-coordinate precision, data collector, basis of record and primary source of the data record. The temporal and geospatial quality of more than 50% of the data records has been enhanced retrospectively. Where possible, data records are annotated with geospatial coordinate precision to the nearest minute. This dataset is being constantly updated with the addition of new data records, and quality enhancement of documented occurrences. The dataset can be used in species distribution and niche modeling studies. It is planned to expand the scope of the dataset to collate bird species occurrences across the Indian peninsula. PMID- 22207821 TI - Electrochemical synthesis of magnetic iron oxide nanoparticles with controlled size. AB - We present a novel and facile method enabling synthesis of iron oxide nanoparticles, which are composed mainly of maghemite according to X-ray diffraction (XRD) and Mossbauer spectroscopy studies. The proposed process is realized by anodic iron polarization in deaerated LiCl solutions containing both water and ethanol. Water seems to play an important role in the synthesis. Morphology of the product was studied by means of transmission electron microscopy and XRD. In the solution containing almost 100% of water a black suspension of round shaped maghemite nanoparticles of 20-40 nm size is obtained. Regulating water concentration allows to control nanoparticle size, which is reduced to 4-6 nm for 5% of water with a possibility to reach intermediate sizes. For 3% or lower water concentration nanoparticles are of a needle-like shape and form a reddish suspension. In this case phase determination is problematic due to a small particle size with the thickness of roughly 3 nm. However, XRD studies indicate the presence of ferrihydrite. Coercivities of the materials are similar to those reported for nanoparticle magnetite powders, whereas the saturation magnetization values are considerably smaller. PMID- 22207823 TI - A Dual-Microphone Speech Enhancement Algorithm Based on the Coherence Function. AB - A novel dual-microphone speech enhancement technique is proposed in the present paper. The technique utilizes the coherence between the target and noise signals as a criterion for noise reduction and can be generally applied to arrays with closely-spaced microphones, where noise captured by the sensors is highly correlated. The proposed algorithm is simple to implement and requires no estimation of noise statistics. In addition, it offers the capability of coping with multiple interfering sources that might be located at different azimuths. The proposed algorithm was evaluated with normal hearing listeners using intelligibility listening tests and compared against a well-established beamforming algorithm. Results indicated large gains in speech intelligibility relative to the baseline (front microphone) algorithm in both single and multiple noise source scenarios. The proposed algorithm was found to yield substantially higher intelligibility than that obtained by the beamforming algorithm, particularly when multiple noise sources or competing talker(s) were present. Objective quality evaluation of the proposed algorithm also indicated significant quality improvement over that obtained by the beamforming algorithm. The intelligibility and quality benefits observed with the proposed coherence-based algorithm make it a viable candidate for hearing aid and cochlear implant devices. PMID- 22207822 TI - Role of histone tails in structural stability of the nucleosome. AB - Histone tails play an important role in nucleosome structure and dynamics. Here we investigate the effect of truncation of histone tails H3, H4, H2A and H2B on nucleosome structure with 100 ns all-atom molecular dynamics simulations. Tail domains of H3 and H2B show propensity of alpha-helics formation during the intact nucleosome simulation. On truncation of H4 or H2B tails no structural change occurs in histones. However, H3 or H2A tail truncation results in structural alterations in the histone core domain, and in both the cases the structural change occurs in the H2Aalpha3 domain. We also find that the contacts between the histone H2A C terminal docking domain and surrounding residues are destabilized upon H3 tail truncation. The relation between the present observations and corresponding experiments is discussed. PMID- 22207826 TI - Probing technoscience. PMID- 22207825 TI - Experienced discrimination amongst European old citizens. AB - This study analyses the experienced age discrimination of old European citizens and the factors related to this discrimination. Differences in experienced discrimination between old citizens of different European countries are explored. Data from the 2008 ESS survey are used. Old age is defined as being 62 years or older. The survey data come from 28 European countries and 14,364 old-age citizens. Their average age is 72 years. Factor analysis is used to construct the core variable 'experienced discrimination'. The influence of the independent variables on experienced discrimination is analysed using linear regression analysis. About one-quarter of old European citizens sometimes or frequently experience discrimination because of their age. Gender, education, income and belonging to a minority are related to experienced age discrimination. Satisfaction with life and subjective health are strongly associated with experienced age discrimination, as is trust in other people and the seriousness of age discrimination in the country. Large, significant differences in experienced discrimination due to old age exist between European countries. A north-west versus south-east European gradient is found in experienced discrimination due to old age. The socio-cultural context is important in explaining experienced age discrimination in old European citizens. Old-age discrimination is experienced less frequently in countries with social security arrangements. Further research is needed to understand the variation in (old) age discrimination between European countries. Measures recommended include increasing public awareness about the value of ageing for communities and changing public attitudes towards the old in a positive way. PMID- 22207827 TI - The "technoscientization" of medicine and its limits: technoscientific identities, biosocialities, and rare disease patient organizations. AB - The fact that the emergence of "technoscience," resulting from the coalescing of science and technology, may have serious social and cultural impact has been debated in recent years particularly with regard to the field of medicine. The present article is exploring the scope and limits of the "technoscientization" of medicine using the example of rare disease patient associations. It is investigated whether and to what extent these organizations adopt technoscientific illness identities and subscribe to the research priorities and objectives of biomedicine. In addition, it is analyzed whether Paul Rabinow's highly influential concept of biosociality entails a technoscientific model of identity or, quite to the contrary, offers a framework for contesting biomedical ascriptions of identities. As the article shows, patient associations do refer to technoscientific definitions of diseases yet constantly modify and transform them based on their everyday illness experiences. Likewise, the "biosociality" of rare disease patients emerges from the shared experience of having been neglected by mainstream medical research rather than from supposedly objective biomedical classifications. PMID- 22207828 TI - When does the co-evolution of technology and science overturn into technoscience? AB - In this paper, the relations between science and technology, intervention and representation, the natural and the artificial are analysed on the background of the formation of modern science in the sixteenth century. Due to the fact that technique has been essential for modern science from its early beginning, modern science is characterised by a hybridisation of knowledge and intervention. The manipulation of nature in order to measure its properties has steadily increased until artificial things have been produced, such as laser beams, chemical compounds, elementary particles. Furthermore, the structural bracing of natural science, technological development, and industrial exploitation of nature go also back to the foundation of modern science. In order to strengthen the debate on technoscience against this background, the specific characteristics of technoscientific objects have to be clarified as have the specific characteristics of the social organisation of technoscience and its performance. PMID- 22207824 TI - A review on herbal antiasthmatics. AB - In traditional systems of medicine, many plants have been documented to be useful for the treatment of various respiratory disorders including asthma. In the last two decades the use of medicinal plants and natural products has been increased dramatically all over the world. Current synthetic drugs used in pharmacotherapy of asthma are unable to act at all the stages and targets of asthma. However some herbal alternatives employed in asthma are proven to provide symptomatic relief and assist in the inhibition of disease progression also. The herbs have shown interesting results in various target specific biological activities such as bronchodilation, mast cell stabilization, anti-anaphylactic, anti-inflammatory, anti-spasmodic, anti-allergic, immunomodulatory and inhibition of mediators such as leukotrienes, lipoxygenase, cyclooxygenase, platelet activating, phosphodiesterase and cytokine, in the treatment of asthma. This paper is an attempt to classify these pharmacological and clinical findings based on their possible mechanism of action reported. It also signifies the need for development of polyherbal formulations containing various herbs acting at particular sites of the pathophysiological cascade of asthma for prophylaxis as well as for the treatment of asthma. PMID- 22207829 TI - Toward an epistemology of nano-technosciences: Probing technoscience from a historical perspective: on today's surprising prevalence and relevance of Francis Bacon. AB - This paper aims to contribute to the attempts to clarify and classify the vague notion of "technosciences" from a historical perspective. A key question that is raised is as follows: Does Francis Bacon, one of the founding fathers of the modern age, provide a hitherto largely undiscovered programmatic position, which might facilitate a more profound understanding of technosciences? The paper argues that nearly everything we need today for an ontologically well-informed epistemology of technoscience can be found in the works of Bacon-this position will be called epistemological real-constructivism. Rather than realist or constructivist, empiricist or rationalist, Bacon's position can best be understood as real-constructivist since it challenges modern dichotomies. Reflection upon the contemporary relevance of Bacon could contribute to the expanding and critical discussion on technoscience. In the following I will reconstruct the term "technoscience". My finding is that at least four different understandings or types of the term "technoscience" co-exist. In a second step, I will analyze and elaborate on Bacon's epistemological position. I will identify central elements of the four different understandings in Bacon's work. Finally, I will conclude that the epistemology of technoscience is, indeed, very old-it is the epistemological position put forward by Bacon. PMID- 22207830 TI - Technoscientia est Potentia?: Contemplative, interventionist, constructionist and creationist idea(l)s in (techno)science. AB - Within the realm of nano-, bio-, info- and cogno- (or NBIC) technosciences, the 'power to change the world' is often invoked. One could dismiss such formulations as 'purely rhetorical', interpret them as rhetorical and self-fulfilling or view them as an adequate depiction of one of the fundamental characteristics of technoscience. In the latter case, a very specific nexus between science and technology, or, the epistemic and the constructionist realm is envisioned. The following paper focuses on this nexus drawing on theoretical conceptions as well as empirical material. It presents an overview of different technoscientific ways to 'change the world'-via contemplation and representation, intervention and control, engineering, construction and creation. It further argues that the hybrid character of technoscience makes it difficult (if not impossible) to separate knowledge production from real world interventions and challenges current science and technology policy approaches in fundamental ways. PMID- 22207831 TI - Diffracting the rays of technoscience: a situated critique of representation. AB - This essay focuses on the possibility of adopting a representational approach for technoscience, in which representation is considered as a situated process of dynamic "intra-action" (Barad 2007). Re-elaborating the recent critiques of representationalism (Thrift 2008), my analysis begins by analysing Hayles's situated model of representation from an early essay where she explains her definition of constrained constructivism (Hayles [1991] 1997). The essay then discusses the notions of figuration and diffraction and the way they are employed by Haraway in many of her writings for her critique of technoscience (Haraway 1991, 1997). Finally, after considering diffraction through Barad's reading of this practice in the context of her theory of agential realism (2007), it shows the links that relate constrained constructivism, situated knowledge and agential realism, and the way all of them work at "diffract[ing] the rays of technoscience" (Haraway 1997: 16) through an alternative representational practice. PMID- 22207832 TI - Neural network models of learning and categorization in multigame experiments. AB - Previous research has shown that regret-driven neural networks predict behavior in repeated completely mixed games remarkably well, substantially equating the performance of the most accurate established models of learning. This result prompts the question of what is the added value of modeling learning through neural networks. We submit that this modeling approach allows for models that are able to distinguish among and respond differently to different payoff structures. Moreover, the process of categorization of a game is implicitly carried out by these models, thus without the need of any external explicit theory of similarity between games. To validate our claims, we designed and ran two multigame experiments in which subjects faced, in random sequence, different instances of two completely mixed 2 * 2 games. Then, we tested on our experimental data two regret-driven neural network models, and compared their performance with that of other established models of learning and Nash equilibrium. PMID- 22207833 TI - The appropriateness of unbiased optical fractionators to assess cell proliferation in the adult hippocampus. AB - Optical fractionators have dominated the field of neural cell counting for two decades. These unbiased stereological techniques are often used for the quantification of hippocampal cell proliferation in neurogenesis experiments. However, the heterogeneous distribution of labeled cells, especially in the form of clusters, confounds the application of these techniques. A critical evaluation of the applicability of the optical fractionator suggests that absolute counting achieves higher efficiency in the quantification of cell proliferation than unbiased estimations. PMID- 22207834 TI - Depolarization-mediated regulation of alternative splicing. AB - Alternative splicing in eukaryotes plays an important role in regulating gene expression by selectively including alternative exons. A wealth of information has been accumulated that explains how alternative exons are selected in a developmental stage- or tissue-specific fashion. However, our knowledge of how cells respond to environmental changes to alter alternative splicing is very limited. For example, although a number of alternative exons have been shown to be regulated by calcium level alterations, the underlying mechanisms are not well understood. As calcium signaling in neurons plays a crucial role in essential neuronal functions such as learning and memory formation, it is important to understand how this process is regulated at every level in gene expression. The significance of the dynamic control of alternative splicing in response to changes of calcium levels has been largely unappreciated. In this communication, we will summarize the recent advances in calcium signaling-mediated alternative splicing that have provided some insights into the important regulatory mechanisms. In addition to describing the cis-acting RNA elements on the pre-mRNA molecules that respond to changes of intracellular calcium levels, we will summarize how splicing regulators change and affect alternative splicing in this process. We will also discuss a novel mode of calcium-mediated splicing regulation at the level of chromatin structure and transcription. PMID- 22207835 TI - Optimization of a 96-Well Electroporation Assay for Postnatal Rat CNS Neurons Suitable for Cost-Effective Medium-Throughput Screening of Genes that Promote Neurite Outgrowth. AB - Following an injury, central nervous system (CNS) neurons show a very limited regenerative response which results in their failure to successfully form functional connections with their original target. This is due in part to the reduced intrinsic growth state of CNS neurons, which is characterized by their failure to express key regeneration-associated genes (RAGs) and by the presence of growth inhibitory molecules in CNS environment that form a molecular and physical barrier to regeneration. Here we have optimized a 96-well electroporation and neurite outgrowth assay for postnatal rat cerebellar granule neurons (CGNs) cultured upon an inhibitory cellular substrate expressing myelin associated glycoprotein or a mixture of growth inhibitory chondroitin sulfate proteoglycans. Optimal electroporation parameters resulted in 28% transfection efficiency and 51% viability for postnatal rat CGNs. The neurite outgrowth of transduced neurons was quantitatively measured using a semi-automated image capture and analysis system. The neurite outgrowth was significantly reduced by the inhibitory substrates which we demonstrated could be partially reversed using a Rho Kinase inhibitor. We are now using this assay to screen large sets of RAGs for their ability to increase neurite outgrowth on a variety of growth inhibitory and permissive substrates. PMID- 22207836 TI - Virally mediated gene manipulation in the adult CNS. AB - Understanding how the CNS functions poses one of the greatest challenges in modern life science and medicine. Studying the brain is especially challenging because of its complexity, the heterogeneity of its cellular composition, and the substantial changes it undergoes throughout its life-span. The complexity of adult brain neural networks results also from the diversity of properties and functions of neuronal cells, governed, inter alia, by temporally and spatially differential expression of proteins in mammalian brain cell populations. Hence, research into the biology of CNS activity and its implications to human and animal behavior must use novel scientific tools. One source of such tools is the field of molecular genetics-recently utilized more and more frequently in neuroscience research. Transgenic approaches in general, and gene targeting in rodents have become fundamental tools for elucidating gene function in the CNS. Although spectacular progress has been achieved over recent decades by using these approaches, it is important to note that they face a number of restrictions. One of the main challenges is presented by the temporal and spatial regulation of introduced genetic manipulations. Viral vectors provide an alternative approach to temporally regulated, localized delivery of genetic modifications into neurons. In this review we describe available technologies for gene transfer into the adult mammalian CNS that use both viral and non-viral tools. We discuss viral vectors frequently used in neuroscience, with emphasis on lentiviral vector (LV) systems. We consider adverse effects of LVs, and the use of LVs for temporally and spatially controllable manipulations. Especially, we highlight the significance of viral vector-mediated genetic manipulations in studying learning and memory processes, and how they may be effectively used to separate out the various phases of learning: acquisition, consolidation, retrieval, and maintenance. PMID- 22207837 TI - Environmental enrichment decreases GABAergic inhibition and improves cognitive abilities, synaptic plasticity, and visual functions in a mouse model of Down syndrome. AB - Down syndrome (DS) is the most common genetic disorder associated with mental retardation. It has been repeatedly shown that Ts65Dn mice, the prime animal model for DS, have severe cognitive and neural plasticity defects due to excessive inhibition. We report that increasing sensory-motor stimulation in adulthood through environmental enrichment (EE) reduces brain inhibition levels and promotes recovery of spatial memory abilities, hippocampal synaptic plasticity, and visual functions in adult Ts65Dn mice. PMID- 22207838 TI - Laws of conservation as related to brain growth, aging, and evolution: symmetry of the minicolumn. AB - Development, aging, and evolution offer different time scales regarding possible anatomical transformations of the brain. This article expands on the perspective that the cerebral cortex exhibits a modular architecture with invariant properties in regards to these time scales. These properties arise from morphometric relations of the ontogenetic minicolumn as expressed in Noether's first theorem, i.e., that for each continuous symmetry there is a conserved quantity. Whenever minicolumnar symmetry is disturbed by either developmental or aging processes the principle of least action limits the scope of morphometric alterations. Alternatively, local and global divergences from these laws apply to acquired processes when the system is no longer isolated from its environment. The underlying precepts to these physical laws can be expressed in terms of mathematical equations that are conservative of quantity. Invariant properties of the brain include the rotational symmetry of minicolumns, a scaling proportion or "even expansion" between pyramidal cells and core minicolumnar size, and the translation of neuronal elements from the main axis of the minicolumn. It is our belief that a significant portion of the architectural complexity of the cerebral cortex, its response to injury, and its evolutionary transformation, can all be captured by a small set of basic physical laws dictated by the symmetry of minicolumns. The putative preservations of parameters related to the symmetry of the minicolumn suggest that the development and final organization of the cortex follows a deterministic process. PMID- 22207839 TI - Modeling accuracy and variability of motor timing in treated and untreated Parkinson's disease and healthy controls. AB - Parkinson's disease (PD) is characterized by difficulty with the timing of movements. Data collected using the synchronization-continuation paradigm, an established motor timing paradigm, have produced varying results but with most studies finding impairment. Some of this inconsistency comes from variation in the medication state tested, in the inter-stimulus intervals (ISI) selected, and in changeable focus on either the synchronization (tapping in time with a tone) or continuation (maintaining the rhythm in the absence of the tone) phase. We sought to re-visit the paradigm by testing across four groups of participants: healthy controls, medication naive de novo PD patients, and treated PD patients both "on" and "off" dopaminergic medication. Four finger tapping intervals (ISI) were used: 250, 500, 1000, and 2000 ms. Categorical predictors (group, ISI, and phase) were used to predict accuracy and variability using a linear mixed model. Accuracy was defined as the relative error of a tap, and variability as the deviation of the participant's tap from group predicted relative error. Our primary finding is that the treated PD group (PD patients "on" and "off" dopaminergic therapy) showed a significantly different pattern of accuracy compared to the de novo group and the healthy controls at the 250-ms interval. At this interval, the treated PD patients performed "ahead" of the beat whilst the other groups performed "behind" the beat. We speculate that this "hastening" relates to the clinical phenomenon of motor festination. Across all groups, variability was smallest for both phases at the 500-ms interval, suggesting an innate preference for finger tapping within this range. Tapping variability for the two phases became increasingly divergent at the longer intervals, with worse performance in the continuation phase. The data suggest that patients with PD can be best discriminated from healthy controls on measures of motor timing accuracy, rather than variability. PMID- 22207840 TI - Using DREADDs to Isolate Internal Clocks. PMID- 22207841 TI - Contingent negative variation and its relation to time estimation: a theoretical evaluation. AB - The relation between the contingent negative variation (CNV) and time estimation is evaluated in terms of temporal accumulation and preparation processes. The conclusion is that the CNV as measured from the electroencephalogram (EEG) recorded at fronto-central and parietal-central areas is not a direct reflection of the underlying interval timing mechanism(s), but more likely represents a time based response preparation/decision-making process. PMID- 22207842 TI - Time determines the neural circuit underlying associative fear learning. AB - Ultimately associative learning is a function of the temporal features and relationships between experienced stimuli. Nevertheless how time affects the neural circuit underlying this form of learning remains largely unknown. To address this issue, we used single-trial auditory trace fear conditioning and varied the length of the interval between tone and foot-shock. Through temporary inactivation of the amygdala, medial prefrontal-cortex (mPFC), and dorsal hippocampus in rats, we tested the hypothesis that different temporal intervals between the tone and the shock influence the neuronal structures necessary for learning. With this study we provide the first experimental evidence showing that temporarily inactivating the amygdala before training impairs auditory fear learning when there is a temporal gap between the tone and the shock. Moreover, imposing a short interval (5 s) between the two stimuli also relies on the mPFC, while learning the association across a longer interval (40 s) becomes additionally dependent on a third structure, the dorsal-hippocampus. Thus, our results suggest that increasing the interval length between tone and shock leads to the involvement of an increasing number of brain areas in order for the association between the two stimuli to be acquired normally. These findings demonstrate that the temporal relationship between events is a key factor in determining the neuronal mechanisms underlying associative fear learning. PMID- 22207844 TI - Emergent properties of interacting populations of spiking neurons. AB - Dynamic neuronal networks are a key paradigm of increasing importance in brain research, concerned with the functional analysis of biological neuronal networks and, at the same time, with the synthesis of artificial brain-like systems. In this context, neuronal network models serve as mathematical tools to understand the function of brains, but they might as well develop into future tools for enhancing certain functions of our nervous system. Here, we present and discuss our recent achievements in developing multiplicative point processes into a viable mathematical framework for spiking network modeling. The perspective is that the dynamic behavior of these neuronal networks is faithfully reflected by a set of non-linear rate equations, describing all interactions on the population level. These equations are similar in structure to Lotka-Volterra equations, well known by their use in modeling predator-prey relations in population biology, but abundant applications to economic theory have also been described. We present a number of biologically relevant examples for spiking network function, which can be studied with the help of the aforementioned correspondence between spike trains and specific systems of non-linear coupled ordinary differential equations. We claim that, enabled by the use of multiplicative point processes, we can make essential contributions to a more thorough understanding of the dynamical properties of interacting neuronal populations. PMID- 22207843 TI - An exploratory fNIRS study with immersive virtual reality: a new method for technical implementation. AB - For over two decades Virtual Reality (VR) has been used as a useful tool in several fields, from medical and psychological treatments, to industrial and military applications. Only in recent years researchers have begun to study the neural correlates that subtend VR experiences. Even if the functional Magnetic Resonance Imaging (fMRI) is the most common and used technique, it suffers several limitations and problems. Here we present a methodology that involves the use of a new and growing brain imaging technique, functional Near-infrared Spectroscopy (fNIRS), while participants experience immersive VR. In order to allow a proper fNIRS probe application, a custom-made VR helmet was created. To test the adapted helmet, a virtual version of the line bisection task was used. Participants could bisect the lines in a virtual peripersonal or extrapersonal space, through the manipulation of a Nintendo Wiimote (r) controller in order for the participants to move a virtual laser pointer. Although no neural correlates of the dissociation between peripersonal and extrapersonal space were found, a significant hemodynamic activity with respect to the baseline was present in the right parietal and occipital areas. Both advantages and disadvantages of the presented methodology are discussed. PMID- 22207845 TI - The clinical assessment and remote administration tablet. AB - Electronic data capture of case report forms, demographic, neuropsychiatric, or clinical assessments, can vary from scanning hand-written forms into databases to fully electronic systems. Web-based forms can be extremely useful for self assessment; however, in the case of neuropsychiatric assessments, self-assessment is often not an option. The clinician often must be the person either summarizing or making their best judgment about the subject's response in order to complete an assessment, and having the clinician turn away to type into a web browser may be disruptive to the flow of the interview. The Mind Research Network has developed a prototype for a software tool for the real-time acquisition and validation of clinical assessments in remote environments. We have developed the clinical assessment and remote administration tablet on a Microsoft Windows PC tablet system, which has been adapted to interact with various data models already in use in several large-scale databases of neuroimaging studies in clinical populations. The tablet has been used successfully to collect and administer clinical assessments in several large-scale studies, so that the correct clinical measures are integrated with the correct imaging and other data. It has proven to be incredibly valuable in confirming that data collection across multiple research groups is performed similarly, quickly, and with accountability for incomplete datasets. We present the overall architecture and an evaluation of its use. PMID- 22207846 TI - Passive motion paradigm: an alternative to optimal control. AB - IN THE LAST YEARS, OPTIMAL CONTROL THEORY (OCT) HAS EMERGED AS THE LEADING APPROACH FOR INVESTIGATING NEURAL CONTROL OF MOVEMENT AND MOTOR COGNITION FOR TWO COMPLEMENTARY RESEARCH LINES: behavioral neuroscience and humanoid robotics. In both cases, there are general problems that need to be addressed, such as the "degrees of freedom (DoFs) problem," the common core of production, observation, reasoning, and learning of "actions." OCT, directly derived from engineering design techniques of control systems quantifies task goals as "cost functions" and uses the sophisticated formal tools of optimal control to obtain desired behavior (and predictions). We propose an alternative "softer" approach passive motion paradigm (PMP) that we believe is closer to the biomechanics and cybernetics of action. The basic idea is that actions (overt as well as covert) are the consequences of an internal simulation process that "animates" the body schema with the attractor dynamics of force fields induced by the goal and task specific constraints. This internal simulation offers the brain a way to dynamically link motor redundancy with task-oriented constraints "at runtime," hence solving the "DoFs problem" without explicit kinematic inversion and cost function computation. We argue that the function of such computational machinery is not only restricted to shaping motor output during action execution but also to provide the self with information on the feasibility, consequence, understanding and meaning of "potential actions." In this sense, taking into account recent developments in neuroscience (motor imagery, simulation theory of covert actions, mirror neuron system) and in embodied robotics, PMP offers a novel framework for understanding motor cognition that goes beyond the engineering control paradigm provided by OCT. Therefore, the paper is at the same time a review of the PMP rationale, as a computational theory, and a perspective presentation of how to develop it for designing better cognitive architectures. PMID- 22207847 TI - The evolution of syntax: an exaptationist perspective. AB - The evolution of language required elaboration of a number of independent mechanisms in the hominin lineage, including systems involved in signaling, semantics, and syntax. Two perspectives on the evolution of syntax can be contrasted. The "continuist" perspective seeks the evolutionary roots of complex human syntax in simpler combinatory systems used in animal communication systems, such as iteration and sequencing. The "exaptationist" perspective posits evolutionary change of function, so that systems today used for linguistic communication might previously have served quite different functions in earlier hominids. I argue that abundant biological evidence supports an exaptationist perspective, in general, and that it must be taken seriously when considering language evolution. When applied to syntax, this suggests that core computational components used today in language could have originally served non-linguistic functions such as motor control, non-verbal thought, or spatial reasoning. I outline three specific exaptationist hypotheses for spoken language. These three hypotheses each posit a change of functionality in a precursor circuit, and its transformation into a neural circuit or region specifically involved in language today. Hypothesis 1 suggests that the precursor mechanism for intentional vocal control, specifically direct cortical control over the larynx, was manual motor control subserved by the cortico-spinal tract. The second is that the arcuate fasciculus, which today connects syntactic and lexical regions, had its origin in intracortical connections subserving vocal imitation. The third is that the specialized components of Broca's area, specifically BA 45, had their origins in non-linguistic motor control, and specifically hierarchical planning of action. I conclude by illustrating the importance of both homology (studied via primates) and convergence (typically analyzed in birds) for testing such evolutionary hypotheses. PMID- 22207848 TI - The effect of combined sensory and semantic components on audio-visual speech perception in older adults. AB - Previous studies have found that perception in older people benefits from multisensory over unisensory information. As normal speech recognition is affected by both the auditory input and the visual lip movements of the speaker, we investigated the efficiency of audio and visual integration in an older population by manipulating the relative reliability of the auditory and visual information in speech. We also investigated the role of the semantic context of the sentence to assess whether audio-visual integration is affected by top-down semantic processing. We presented participants with audio-visual sentences in which the visual component was either blurred or not blurred. We found that there was a greater cost in recall performance for semantically meaningless speech in the audio-visual 'blur' compared to audio-visual 'no blur' condition and this effect was specific to the older group. Our findings have implications for understanding how aging affects efficient multisensory integration for the perception of speech and suggests that multisensory inputs may benefit speech perception in older adults when the semantic content of the speech is unpredictable. PMID- 22207850 TI - Regulation of bilirubin clearance by ligand-activated transcription factors of the endo- and xenobiotic metabolism system. PMID- 22207849 TI - Voltage- and Temperature-Dependent Allosteric Modulation of alpha7 Nicotinic Receptors by PNU120596. AB - Alpha7 nicotinic acetylcholine receptors (alpha7 nAChR) are widely distributed throughout the central nervous system and are found at particularly high levels in the hippocampus and cortex. Several lines of evidence indicate that pharmacological enhancement of alpha7 nAChRs function could be a potential therapeutic route to alleviate disease-related cognitive deficits. A recent pharmacological approach adopted to increase alpha7 nAChR activity has been to identify selective positive allosteric modulators (PAMs). alpha7 nAChR PAMs have been divided into two classes: type I PAMs increase agonist potency with only subtle effects on kinetics, whereas type II agents produce additional dramatic effects on desensitization and deactivation kinetics. Here we report novel observations concerning the pharmacology of the canonical type II PAM, PNU120596. Using patch clamp analysis of acetylcholine (ACh)-mediated currents through recombinant rat alpha7 nAChR we show that positive allosteric modulation measured in two different ways is greatly attenuated when the temperature is raised to near physiological levels. Furthermore, PNU120596 largely removes the strong inward rectification usually exhibited by alpha7 nAChR-mediated responses. PMID- 22207851 TI - Sulfur fumigation processing of traditional chinese medicinal herbs: beneficial or detrimental? AB - Majority of traditional Chinese medicine (TCM) herbs need to undergo post harvesting processing to convert raw material into the form readily used for prescription. In general, processing procedures are either according to China Pharmacopeia or based on traditional methods. Recently sulfur fumigation is increasingly used to replace traditional sun-drying for its pesticidal and anti bacterial properties in a cheap and convenient manner. However, to date information on effects of sulfur fumigation on herbal safety and efficacy are limited. This article addresses potential destructive effects of sulfur fumigation on herbal efficacy and safety through reviewing currently available information. Since recently increased numbers of studies have demonstrated that sulfur fumigation-induced dramatic changes in chemical profiles of various sulfur fumigated herbs, consequent alteration of efficacy, and/or potential incidence of toxicity are suspected. Therefore comprehensive investigations on effects of sulfur fumigation on toxicity, chemical profiles, pharmacokinetics, and bioactivities of TCM herbs are timely to provide scientific basis for standardization and regulation of this currently common but potentially harmful processing method. PMID- 22207852 TI - Proteomic Profiling of Fast-To-Slow Muscle Transitions during Aging. AB - Old age is associated with a large spectrum of physical ailments, including muscle wasting. Skeletal muscle degeneration drastically increases the risk of poor balance, frequent falling and impaired mobility in the elderly. In order to identify new therapeutic targets to halt or even reverse age-dependent muscle weakness and improve diagnostic methods to properly evaluate sarcopenia as a common geriatric syndrome, there is an urgent need to establish a reliable biomarker signature of muscle aging. In this respect, mass spectrometry-based proteomics has been successfully applied for studying crude extracts and subcellular fractions from aged animal and human muscle tissues to identify novel aging marker proteins. This review focuses on key physiological and metabolic aspects of sarcopenia, i.e., age-related muscle fiber transitions and metabolic shifts in aging muscle as revealed by proteomics. Over the last decade, proteomic profiling studies have clearly confirmed the idea that sarcopenia is based on a multi-factorial pathophysiology and that a glycolytic-to-oxidative shift occurs in slower-twitching senescent muscles. Both, newly identified protein factors and confirmed alterations in crucial metabolic and contractile elements can now be employed to establish a sarcopenia-specific biomarker signature. PMID- 22207853 TI - Applications of proteomics to osteoarthritis, a musculoskeletal disease characterized by aging. AB - The incidence of age-related musculoskeletal impairment is steadily rising throughout the world. Musculoskeletal conditions are closely linked with aging and inflammation. They are leading causes of morbidity and disability in man and beast. Aging is a major contributor to musculoskeletal degeneration and the development of osteoarthritis (OA). OA is a degenerative disease that involves structural changes to joint tissues including synovial inflammation, catabolic destruction of articular cartilage and alterations in subchondral bone. Cartilage degradation and structural changes in subchondral bone result in the production of fragments of extracellular matrix molecules. Some of these biochemical markers or "biomarkers" can be detected in blood, serum, synovial fluid, and urine and may be useful markers of disease progression. The ability to detect biomarkers of cartilage degradation in body fluids may enable clinicians to diagnose sub clinical OA as well as determining the course of disease progression. New biomarkers that indicate early responses of the joint cartilage to degeneration will be useful in detecting early, pre-radiographic changes. Systems biology is increasingly applied in basic cartilage biology and OA research. Proteomic techniques have the potential to improve our understanding of OA physiopathology and its underlying mechanisms. Proteomics can also facilitate the discovery of disease-specific biomarkers and help identify new therapeutic targets. Proteomic studies of cartilage and other joint tissues may be particularly relevant in diagnostic orthopedics and therapeutic research. This perspective article discusses the relevance and potential of proteomics for studying age-related musculoskeletal diseases such as OA and reviews the contributions of key investigators in the field. PMID- 22207854 TI - The feeling of action tendencies: on the emotional regulation of goal-directed behavior. AB - In this article, we review the nature of the functional and causal relationship between neurophysiologically/psychologically generated states of emotional feeling and action tendencies and extrapolate a novel perspective. Emotion theory, over the past century and beyond, has tended to regard feeling and action tendency as independent phenomena: attempts to outline the functional and causal relationship that exists between them have been framed therein. Classically, such relationships have been viewed as unidirectional, but an argument for bidirectionality rooted in a dynamic systems perspective has gained strength in recent years whereby the feeling-action tendency relationship is viewed as a composite whole. On the basis of our review of somatic-visceral theories of feelings, we argue that feelings are grounded upon neural-dynamic representations (elevated and stable activation patterns) of action tendency. Such representations amount to predictions updated by cognitive and bodily feedback. Specifically, we view emotional feelings as minimalist predictions of the action tendency (what the agent is physiologically and cognitively primed to do) in a given situation. The essence of this point is captured by our exposition of action tendency prediction-feedback loops which we consider, above all, in the context of emotion regulation, and in particular, of emotional regulation of goal directed behavior. The perspective outlined may be of use to emotion theorists, computational modelers, and roboticists. PMID- 22207856 TI - Unimanual SNARC Effect: Hand Matters. AB - A structural representation of the hand embedding information about the identity and relative position of fingers is necessary to counting routines. It may also support associations between numbers and allocentric spatial codes that predictably interact with other known numerical spatial representations, such as the mental number line (MNL). In this study, 48 Western participants whose typical counting routine proceeded from thumb-to-little on both hands performed magnitude and parity binary judgments. Response keys were pressed either with the right index and middle fingers or with the left index and middle fingers in separate blocks. 24 participants responded with either hands in prone posture (i.e., palm down) and 24 participants responded with either hands in supine (i.e., palm up) posture. When hands were in prone posture, the counting direction of the left hand conflicted with the direction of the left-right MNL, whereas the counting direction of the right hand was consistent with it. When hands were in supine posture, the opposite was true. If systematic associations existed between relative number magnitude and an allocentric spatial representation of the finger series within each hand, as predicted on the basis of counting habits, interactions would be expected between hand posture and a unimanual version of the spatial-numerical association of response codes (SNARC) effect. Data revealed that with hands in prone posture a unimanual SNARC effect was present for the right hand, and with hands in supine posture a unimanual SNARC effect was present for the left hand. We propose that a posture-invariant body structural representation of the finger series provides a relevant frame of reference, a within-hand directional vector, that is associated to simple number processing. Such frame of reference can significantly interact with stimulus-response correspondence effects, like the SNARC, that have been typically attributed to the mapping of numbers on a left-to-right mental line. PMID- 22207855 TI - Development of Fetal Movement between 26 and 36-Weeks' Gestation in Response to Vibro-Acoustic Stimulation. AB - BACKGROUND: Ultrasound observation of fetal movement has documented general trends in motor development and fetal age when motor response to stimulation is observed. Evaluation of fetal movement quality, in addition to specific motor activity, may improve documentation of motor development and highlight specific motor responses to stimulation. AIM: The aim of this investigation was to assess fetal movement at 26 and 36-weeks gestation during three conditions (baseline, immediate response to vibro-acoustic stimulation (VAS), and post-response). DESIGN: A prospective, longitudinal design was utilized. SUBJECTS: Twelve normally developing fetuses, eight females and four males, were examined with continuous ultrasound imaging. OUTCOME MEASURES: The fetal neurobehavioral coding system (FENS) was used to evaluate the quality of motor activity during 10-s epochs over the three conditions. RESULTS: Seventy-five percent of the fetuses at the 26-week assessment and 100% of the fetuses at the 36-week assessment responded with movement immediately following stimulation. Significant differences in head, fetal breathing, general, limb, and mouthing movements were detected between the 26 and 36-week assessments. Movement differences between conditions were detected in head, fetal breathing, limb, and mouthing movements. CONCLUSION: Smoother and more complex movement was observed with fetal maturation. Following VAS stimulation, an immediate increase of large, jerky movements suggests instability in fetal capabilities. Fetal movement quality changes over gestation may reflect sensorimotor synaptogenesis in the central nervous system, while observation of immature movement patterns following VAS stimulation may reflect movement pattern instability. PMID- 22207857 TI - Intra-cranial recordings of brain activity during language production. AB - Recent findings in the neurophysiology of language production have provided a detailed description of the brain network underlying this behavior, as well as some indications about the timing of operations. Despite their invaluable utility, these data generally suffer from limitations either in terms of temporal resolution, or in terms of spatial localization. In addition, studying the neural basis of speech is complicated by the presence of articulation artifacts such as electro-myographic activity that interferes with the neural signal. These difficulties are virtually absent in a powerful albeit much less frequent methodology, namely the recording of intra-cranial brain activity (intra-cranial electroencephalography). Such recordings are only possible under very specific clinical circumstances requiring functional mapping before brain surgery, most notably in patients that suffer from pharmaco-resistant epilepsy. Here we review the research conducted with this methodology in the field of language production, with explicit consideration of its advantages and drawbacks. The available evidence is shown to be diverse, both in terms of the tasks and the cognitive processes tested and in terms of the brain localizations being studied. Still, the review provides valuable information for characterizing the dynamics of the neural events occurring in the language production network. Following modality specific activities (in auditory or visual cortices), there is a convergence of activity in superior temporal sulcus, which is a plausible neural correlate of phonological encoding processes. Later, between 500 and 800 ms, inferior frontal gyrus (around Broca's area) is involved. Peri-rolandic areas are recruited in the two modalities relatively early (200-500 ms window), suggesting a very early involvement of (pre-) motor processes. We discuss how some of these findings may be at odds with conclusions drawn from available meta-analysis of language production studies. PMID- 22207858 TI - Preferential Inspection of Recent Real-World Events Over Future Events: Evidence from Eye Tracking during Spoken Sentence Comprehension. AB - Eye-tracking findings suggest people prefer to ground their spoken language comprehension by focusing on recently seen events more than anticipating future events: When the verb in NP1-VERB-ADV-NP2 sentences was referentially ambiguous between a recently depicted and an equally plausible future clipart action, listeners fixated the target of the recent action more often at the verb than the object that hadn't yet been acted upon. We examined whether this inspection preference generalizes to real-world events, and whether it is (vs. isn't) modulated by how often people see recent and future events acted out. In a first eye-tracking study, the experimenter performed an action (e.g., sugaring pancakes), and then a spoken sentence either referred to that action or to an equally plausible future action (e.g., sugaring strawberries). At the verb, people more often inspected the pancakes (the recent target) than the strawberries (the future target), thus replicating the recent-event preference with these real-world actions. Adverb tense, indicating a future versus past event, had no effect on participants' visual attention. In a second study we increased the frequency of future actions such that participants saw 50/50 future and recent actions. During the verb people mostly inspected the recent action target, but subsequently they began to rely on tense, and anticipated the future target more often for future than past tense adverbs. A corpus study showed that the verbs and adverbs indicating past versus future actions were equally frequent, suggesting long-term frequency biases did not cause the recent-event preference. Thus, (a) recent real-world actions can rapidly influence comprehension (as indexed by eye gaze to objects), and (b) people prefer to first inspect a recent action target (vs. an object that will soon be acted upon), even when past and future actions occur with equal frequency. A simple frequency-of experience account cannot accommodate these findings. PMID- 22207859 TI - Orthographic Contamination of Broca's Area. AB - Strong evidence has accumulated over the past years suggesting that orthography plays a role in spoken language processing. It is still unclear, however, whether the influence of orthography on spoken language results from a co-activation of posterior brain areas dedicated to low-level orthographic processing or whether it results from orthographic restructuring of phonological representations located in the anterior perisylvian speech network itself. To test these hypotheses, we ran a fMRI study that tapped orthographic processing in the visual and auditory modalities. As a marker for orthographic processing, we used the orthographic decision task in the visual modality and the orthographic consistency effect in the auditory modality. Results showed no specific orthographic activation neither for the visual nor the auditory modality in left posterior occipito-temporal brain areas that are thought to host the visual word form system. In contrast, specific orthographic activation was found both for the visual and auditory modalities at anterior sites belonging to the perisylvian region: the left dorsal-anterior insula and the left inferior frontal gyrus. These results are in favor of the restructuring hypothesis according to which learning to read acts like a "virus" that permanently contaminates the spoken language system. PMID- 22207860 TI - Multi-sensory and sensorimotor foundation of bodily self-consciousness - an interdisciplinary approach. AB - Scientific investigations on the nature of the self have so far focused on high level mechanisms. Recent evidence, however, suggests that low-level bottom-up mechanisms of multi-sensory integration play a fundamental role in encoding specific components of bodily self-consciousness, such as self-location and first person perspective (Blanke and Metzinger, 2009). Self-location and first-person perspective are abnormal in neurological patients suffering from out-of-body experiences (Blanke et al., 2004), and can be manipulated experimentally in healthy subjects by imposing multi-sensory conflicts (Lenggenhager et al., 2009). Activity of the temporo-parietal junction (TPJ) reflects experimentally induced changes in self-location and first-person perspective (Ionta et al., 2011), and dysfunctions in TPJ are causally associated with out-of-body experiences (Blanke et al., 2002). We argue that TPJ is one of the key areas for multi-sensory integration of bodily self-consciousness, that its levels of activity reflect the experience of the conscious "I" as embodied and localized within bodily space, and that these mechanisms can be systematically investigated using state of the art technologies such as robotics, virtual reality, and non-invasive neuroimaging. PMID- 22207861 TI - Improving perception to make distant connections closer. AB - One of the challenges for perceptually grounded accounts of high-level cognition is to explain how people make connections and draw inferences between situations that superficially have little in common. Evidence suggests that people draw these connections even without having explicit, verbalizable knowledge of their bases. Instead, the connections are based on sub-symbolic representations that are grounded in perception, action, and space. One reason why people are able to spontaneously see relations between situations that initially appear to be unrelated is that their eventual perceptions are not restricted to initial appearances. Training and strategic deployment allow our perceptual processes to deliver outputs that would have otherwise required abstract or formal reasoning. Even without people having any privileged access to the internal operations of perceptual modules, these modules can be systematically altered so as to better serve our high-level reasoning needs. Moreover, perceptually based processes can be altered in a number of ways to closely approximate formally sanctioned computations. To be concrete about mechanisms of perceptual change, we present 21 illustrations of ways in which we alter, adjust, and augment our perceptual systems with the intention of having them better satisfy our needs. PMID- 22207862 TI - Therapeutic hypothermia in stroke and traumatic brain injury. AB - Therapeutic hypothermia (TH) is considered to improve survival with favorable neurological outcome in the case of global cerebral ischemia after cardiac arrest and perinatal asphyxia. The efficacy of hypothermia in acute ischemic stroke (AIS) and traumatic brain injury (TBI), however, is not well studied. Induction of TH typically requires a multimodal approach, including the use of both pharmacological agents and physical techniques. To date, clinical outcomes for patients with either AIS or TBI who received TH have yielded conflicting results; thus, no adequate therapeutic consensus has been reached. Nevertheless, it seems that by determining optimal TH parameters and also appropriate applications, cooling therapy still has the potential to become a valuable neuroprotective intervention. Among the various methods for hypothermia induction, intravascular cooling (IVC) may have the most promise in the awake patient in terms of clinical outcomes. Currently, the IVC method has the capability of more rapid target temperature attainment and more precise control of temperature. However, this technique requires expertise in endovascular surgery that can preclude its application in the field and/or in most emergency settings. It is very likely that combining neuroprotective strategies will yield better outcomes than utilizing a single approach. PMID- 22207863 TI - The role of ATP in sleep regulation. AB - One of the functions of sleep is to maintain energy balance in the brain. There are a variety of hypotheses related to how metabolic pathways interact with sleep/wake regulation. A major finding that demonstrates an interaction between sleep and metabolic homeostasis is the involvement of adenosine in sleep homeostasis. An accumulation of adenosine is supplied from ATP, which can act as an energy currency in the cell. Extracellularly, ATP can act as an activity dependent signaling molecule, especially in regard to communication between neurons and glia, including astrocytes. Furthermore, the intracellular AMP/ATP ratio controls the activity of AMP-activated protein kinase, which is a potent energy regulator and is recently reported to play a role in the regulation of sleep homeostasis. Brain ATP may support multiple functions in the regulation of the sleep/wake cycle and sleep homeostasis. PMID- 22207865 TI - Anaerobic Oxidation of Methane at a Marine Methane Seep in a Forearc Sediment Basin off Sumatra, Indian Ocean. AB - A cold methane seep was discovered in a forearc sediment basin off the island Sumatra, exhibiting a methane-seep adapted microbial community. A defined seep center of activity, like in mud volcanoes, was not discovered. The seep area was rather characterized by a patchy distribution of active spots. The relevance of anaerobic oxidation of methane (AOM) was reflected by (13)C-depleted isotopic signatures of dissolved inorganic carbon. The anaerobic conversion of methane to CO(2) was confirmed in a (13)C-labeling experiment. Methane fueled a vital microbial community with cell numbers of up to 4 * 10(9) cells cm(-3) sediment. The microbial community was analyzed by total cell counting, catalyzed reporter deposition-fluorescence in situ hybridization (CARD-FISH), quantitative real-time PCR (qPCR), and denaturing gradient gel electrophoresis (DGGE). CARD-FISH cell counts and qPCR measurements showed the presence of Bacteria and Archaea, but only small numbers of Eukarya. The archaeal community comprised largely members of ANME-1 and ANME-2. Furthermore, members of the Crenarchaeota were frequently detected in the DGGE analysis. Three major bacterial phylogenetic groups (delta Proteobacteria, candidate division OP9, and Anaerolineaceae) were abundant across the study area. Several of these sequences were closely related to the genus Desulfococcus of the family Desulfobacteraceae, which is in good agreement with previously described AOM sites. In conclusion, the majority of the microbial community at the seep consisted of AOM-related microorganisms, while the relevance of higher hydrocarbons as microbial substrates was negligible. PMID- 22207866 TI - Expression and Partial Characterization of an Ice-Binding Protein from a Bacterium Isolated at a Depth of 3,519 m in the Vostok Ice Core, Antarctica. AB - Cryopreservation of microorganisms in ancient glacial ice is possible if lethal levels of macromolecular damage are not incurred and cellular integrity is not compromised via intracellular ice formation or recrystallization. Previously, a bacterium (isolate 3519-10) recovered from a depth of 3,519 m below the surface in the Vostok ice core was shown to secrete an ice-binding protein (IBP) that inhibits the recrystallization of ice. To explore the advantage that IBPs confer to ice-entrapped cells, experiments were designed to examine the expression of 3519-10's IBP gene and protein at different temperatures, assess the effect of the IBP on bacterial viability in ice, and determine how the IBP influences the physical structure of the ice. Total RNA isolated from cultures grown between 4 and 25 degrees C and analyzed by reverse transcription-PCR indicated constitutive expression of the IBP gene. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis of 3519-10's extracellular proteins revealed a polypeptide of the predicted size of the 54-kDa IBP at all temperatures tested. In the presence of 100 MUg mL(-1) of extracellular protein from 3519-10, the survival of Escherichia coli was increased by greater than 100-fold after 5 freeze-thaw cycles. Microscopic analysis of ice formed in the presence of the IBP indicated that per square millimeter field of view, there were ~5 times as many crystals as in ice formed in the presence of washed 3519-10 cells and non-IBP producing bacteria, and ~10 times as many crystals as in filtered deionized water. Presumably, the effect that the IBP has on bacterial viability and ice crystal structure is due to its activity as an inhibitor of ice recrystallization. A myriad of molecular adaptations are likely to play a role in bacterial persistence under frozen conditions, but the ability of 3519-10's IBP to control ice crystal structure, and thus the liquid vein network within the ice, may provide one explanation for its successful survival deep within the Antarctic ice sheet for thousands of years. PMID- 22207864 TI - Compensation following bilateral vestibular damage. AB - Bilateral loss of vestibular inputs affects far fewer patients than unilateral inner ear damage, and thus has been understudied. In both animal subjects and human patients, bilateral vestibular hypofunction (BVH) produces a variety of clinical problems, including impaired balance control, inability to maintain stable blood pressure during postural changes, difficulty in visual targeting of images, and disturbances in spatial memory and navigational performance. Experiments in animals have shown that non-labyrinthine inputs to the vestibular nuclei are rapidly amplified following the onset of BVH, which may explain the recovery of postural stability and orthostatic tolerance that occurs within 10 days. However, the loss of the vestibulo-ocular reflex and degraded spatial cognition appear to be permanent in animals with BVH. Current concepts of the compensatory mechanisms in humans with BVH are largely inferential, as there is a lack of data from patients early in the disease process. Translation of animal studies of compensation for BVH into therapeutic strategies and subsequent application in the clinic is the most likely route to improve treatment. In addition to physical therapy, two types of prosthetic devices have been proposed to treat individuals with bilateral loss of vestibular inputs: those that provide tactile stimulation to indicate body position in space, and those that deliver electrical stimuli to branches of the vestibular nerve in accordance with head movements. The relative efficacy of these two treatment paradigms, and whether they can be combined to facilitate recovery, is yet to be ascertained. PMID- 22207867 TI - Bromeliad catchments as habitats for methanogenesis in tropical rainforest canopies. AB - Tropical epiphytic plants within the family Bromeliaceae are unusual in that they possess foliage capable of retaining water and impounded material. This creates an acidic (pH 3.5-6.5) and anaerobic (<1 ppm O(2)) environment suspended in the canopy. Results from a Costa Rican rainforest show that most bromeliads (n = 75/86) greater than ~20 cm in plant height or ~4-5 cm tank depth, showed presence of methanogens within the lower anoxic horizon of the tank. Archaea were dominated by methanogens (77-90% of recovered ribotypes) and community structure, although variable, was generally comprised of a single type, closely related to either hydrogenotrophic Methanoregula or Methanocella, a specific clade of aceticlastic Methanosaeta, or Methanosarcina. Juvenile bromeliads, or those species, such as Guzmania, with shallow tanks, generally did not possess methanogens, as assayed by polymerase chain reaction specific for methanogen 16S rRNA genes, nor did artificial catchments (~100 ml volume), in place 6-12 months prior to sample collection. Methanogens were not detected in soil (n = 20), except in one case, in which the dominant ribotype was different from nearby bromeliads. Recovery of methyl coenzyme M reductase genes supported the occurrence of hydrogenotrophic and aceticlastic methanogens within bromeliad tanks, as well as the trend, via QPCR analysis of mcrA, of increased methanogenic capacity with increased plant height. Methane production rates of up to 300 nmol CH(4) ml tank water(-1) day(-1) were measured in microcosm experiments. These results suggest that bromeliad-associated archaeal communities may play an important role in the cycling of carbon in neotropical forests. PMID- 22207868 TI - Fate and Survival of Campylobacter coli in Swine Manure at Various Temperatures. AB - Campylobacter coli is the most common Campylobacter species found in pig (95%), but the ability of this bacterium to survive in swine manure as well as the potential for causing human illness are poorly understood. We present here laboratory-scale experiments to investigate the effect of temperature on the survival of C. coli in spiked swine manure samples at temperatures from 4 to 52 degrees C. The survival of C. coli during storage for 30 days was studied by three different methods: bacterial culture (plate counting), DNA qPCR, and mRNA RT-qPCR. The results indicate that C. coli could survive in swine manure up to 24 days at 4 degrees C. At higher temperatures, this bacterium survived only 7 days (15 degrees C) or 6 days (22 degrees C) of storage. The survival of C. coli was extremely short (few hours) in samples incubated at 42 and 52 degrees C. The results from the RT-qPCR method were consistent with the data from the bacterial culture method, indicating that it detected only viable C. coli cells, thus eliminating false-positive resulting from DNA from dead C. coli cells. PMID- 22207869 TI - Linking microbial heterotrophic activity and sediment lithology in oxic, oligotrophic sub-seafloor sediments of the north atlantic ocean. AB - Microbial heterotrophic activity was investigated in oxic sub-seafloor sediments at North Pond, a sediment pond situated at 23 degrees N on the western flank of the Mid-Atlantic Ridge. The North Pond sediments underlie the oligotrophic North Atlantic Gyre at 4580-m water depth and cover a 7-8 million-year-old basaltic crust aquifer through which seawater flows. Discrete samples for experimentation were obtained from up to ~9 m-long gravity cores taken at 14 stations in the North Pond area. Potential respiration rates were determined in sediment slurries incubated under aerobic conditions with (14)C-acetate. Microbial heterotrophic activity, as defined by oxidation of acetate to CO(2) (with O(2) as electron acceptor), was detected in all 14 stations and all depths sampled. Potential respiration rates were generally low (<0.2 nmol of respired acetate cm(-3) d(-1)) in the sediment, but indicate that microbial heterotrophic activity occurs in deep-sea, oxic, sub-seafloor sediments. Furthermore, discernable differences in activity existed between sites and within given depth profiles. At seven stations, activity was increased by several orders of magnitude at depth (up to ~12 nmol of acetate respired cm(-3) d(-1)). We attempted to correlate the measures of activity with high-resolution color and element stratigraphy. Increased activities at certain depths may be correlated to variations in the sediment geology, i.e., to the presence of dark clay-rich layers, of sandy layers, or within clay-rich horizons presumably overlying basalts. This would suggest that the distribution of microbial heterotrophic activity in deeply buried sediments may be linked to specific lithologies. Nevertheless, high resolution microbial examination at the level currently enjoyed by sedimentologists will be required to fully explore this link. PMID- 22207870 TI - An unusual cause of small bowel obstruction. PMID- 22207871 TI - Don't live in a town where there are no doctors: toxic epidermal necrolysis initially misdiagnosed as oral thrush. AB - Toxic epidermal necrolysis (TEN) is a rare but life threatening skin disease that is most commonly drug induced. The exact pathogenesis of TEN is still unknown and many drugs, including prednisolone, cyclosporin and intravenous immunoglobulin (IVIG), have been used in an attempt to halt the disease process. The use of IVIG in particular is controversial. Recently, the US Food and Drug Administration (FDA) has made a labelling change to the drug information for carbamazepine. Owing to recent data implicating the HLA allele B*1502 as a marker for carbamazepine induced Stevens-Johnson syndrome and TEN in Han Chinese, the FDA recommends genotyping all Asians for the allele. We present an interesting case of carbamazepine induced TEN which was confused with oral thrush, had no skin lesions on presentation, and had an excellent response to a 5 day course of methylprednisolone and high dose IVIG in combination. PMID- 22207872 TI - An unusual cause of cavernous sinus syndrome. PMID- 22207873 TI - Size doesn't matter! AB - An 18-year-old male patient with a known history of Crohn's colitis was admitted for further management of his symptoms. He was treated with anti-tumour necrosis factor (anti-TNF) adalimumab and intravenous steroids in addition to azathioprine. He developed sudden onset pleuritic chest pain. Ventilation/perfusion (V/Q) scanning was reported as normal. A computed tomography pulmonary angiogram (CTPA) showed evidence of a small peripheral wedge shaped area of consolidation in the left lower lobe. He was treated with oral antibiotics but the chest pain persisted for the next 2 weeks. A repeat chest x ray performed 2 weeks later revealed evidence of a large hydro-pneumothorax which was promptly drained. A chest CT later showed evidence of lower lobe consolidation. Sputum cultures grew Staphylococcus aureus. It was felt that a broncho-pleural fistula due to the peripheral cavitating lesion led to the pneumothorax. PMID- 22207874 TI - A case of fulminant diversion pan-colitis presenting 19 years after colonic diversion for neuronal intestinal dysplasia. AB - A 20-year old woman with a long history of abdominal symptoms presented with acute abdominal pain associated with nausea and vomiting. She had had a right iliac fossa end-ileostomy previously fashioned at the age of 11 months for neuronal intestinal dysplasia. A few days after her admission she suffered a hypokalaemic cardiac arrest from which she was resuscitated. Her clinical condition deteriorated as she became increasingly septic. She was diagnosed with a fulminant colitis based on the clinical picture and the finding of fluid filled, thick walled rectum suggestive of proctocolitis on a pelvic magnetic resonance imaging scan. She was taken to the operating theatre where she had a subtotal colectomy. The histopathological diagnosis was that of fulminant diversion colitis. The patient recovered from surgery and was discharged home 5 weeks later. PMID- 22207875 TI - Influence of sagittal balance and physical ability associated with exercise on quality of life in middle-aged and elderly people. AB - We examined 304 persons (135 males and 169 females) who underwent a basic health checkup to evaluate the relationship of quality of life (QOL) with osteoporosis, spinal sagittal balance, spinal mobility, muscle strength, and physical ability, including daily exercise. QOL of middle-aged and elderly subjects was strongly related to sagittal balance and physical ability. INTRODUCTION: Spinal kyphosis with compression fracture and osteoporosis decrease QOL and increase mortality. However, it is unclear if kyphosis, spinal sagittal balance, muscle strength, and physical ability influence QOL. PURPOSE: The goal of the study was to evaluate the relationship of QOL with osteoporosis, spinal sagittal balance, spinal mobility, back muscle strength, and physical ability, including daily exercise, in middle-aged and elderly people. METHODS: The subjects were 304 persons (135 males and 169 females) who underwent a basic health checkup. Lumbar lateral radiograph findings, sagittal balance and spinal mobility determined with SpinalMouse(r), grip, back muscle strength, and 10-m gait time were evaluated. RESULTS: SF-36 physical component summary (PCS) scores showed a significant negative correlation with age (r = -0.375), spinal inclination angle (r = 0.322), and 10-m gait time (r = -0.470), and a significant positive correlation with percent of the young adult mean of bone mineral density (r = 0.223), lumbar lordosis angle (r = 0.184), thoracic spinal range of motion (ROM; r = 0.136), lumbar spinal ROM (r = 0.130), grip strength (r = 0.211), and back muscle strength (r = 0.301). In multiple regression analysis, age (r = -0.372, p < 0.0005), spinal inclination angle (r = -0.336, p < 0.05) and 10-m gait time (r = 2.898, p < 0.0001) were significantly associated with SF-36 PCS (R(2) = 0.288). In the exercise group, SF-36 PCS scores were significantly better (p < 0.05) due to good spinal balance, thoracic spinal ROM, back muscle strength, and gait speed. CONCLUSIONS: QOL of middle-aged and elderly subjects was related to sagittal balance and physical ability. Thus, exercises for spine, muscle, and physical ability may improve QOL in middle-aged and elderly people. PMID- 22207876 TI - Bone mass, bone markers and prevalence of fractures in adults with osteogenesis imperfecta. AB - Still little is known about the manifestations of osteogenesis imperfecta (OI) in adults. We therefore initiated this study of bone mass, bone turnover and prevalence of fractures in a large cohort of adult patients. We found a surprising low prevalence (10%) of osteoporosis. These patients, however, expressed the most severe disease. PURPOSE: To characterize bone mineral density, bone turnover, calcium metabolism and prevalence of fractures in a large cohort of adults with osteogenesis imperfecta. METHODS: One hundred fifty-four patients with adult OI participated and 90 (age range 25-83) provided dual X-ray absorptiometry (DXA) measurements. According to Sillence classification criteria, 68 persons were classified as OI type I, 9 as type III, 11 type IV and 2 were unclassified. Fracture numbers were based on self-reporting. Biochemical markers of bone turnover were measured and bone mineral density (BMD) of the spine, femoral neck and total body were determined by DXA. RESULTS: Only 10% of adults with OI exhibited osteoporotic T scores (T <= -2.5) but compared to patients with normal T scores this subgroup had a threefold higher fracture risk (22 vs. 69). s PTH, s-Ca and 25[OH] vitamin D were all normal. Bone markers did not display major deviations from normal, but patients with OI type III displayed higher resorption marker levels than type I and IV. Multivariate regression analysis showed that only gender and total body BMD were significant determinants of fracture susceptibility, and the differences for total body BMC, BMD and Z scores were significant between the OI subtypes. CONCLUSIONS: In adult OI, DXA measurements only identified few patients as osteoporotic. These patients, however, exhibited a much higher fracture propensity. Due to deformities, low body height and pre-existing fractures, DXA assessment is complicated in this disease, and further studies are needed to work out how to minimize the impact of these confounders. PMID- 22207877 TI - Influence of menopause on mandibular bone quantity and quality in Japanese women receiving dental implants. AB - SUMMARY: The purpose of this study was to evaluate the effect of menopause on bone mineral density and bone width of the mandible. Results indicate that menopause affects the bone quality and quantity of the partially edentulous molar region of the mandible, which should be considered in dental implant treatment for postmenopausal women. INTRODUCTION: The recovery of oral function with dental implant is clinically effective and highly predictable. Bone quantity and quality at the implant installation site affect its prognosis; however, the effects of menopause on jaw bone have not been well documented. The purpose of this study was to evaluate the effect of menopause on bone mineral density (BMD) and bone width of the mandible. METHODS: The subjects were 72 female patients with a partially edentulous molar region of the mandible: 30 premenopausal and 42 postmenopausal women aged 30 to 70 years. Trabecular BMD was measured with quantitative computed tomography. Trabecular region width (TW) and cortical width (CW) were measured with CT. The BMD, TW, and CW of the two groups were compared. RESULTS: The trabecular BMD of postmenopausal women was lower than that of the premenopausal women. The TW of postmenopausal women was greater than that of premenopausal women, whereas the CW of postmenopausal women was significantly smaller than that of premenopausal women. In all these women, BMD correlated negatively with TW and positively with CW. In the premenopausal women, BMD negatively correlated with TW, but it did not correlate with CW. In the postmenopausal women, there was no correlation between BMD and bone width. CONCLUSION: These results indicate that menopause affects the bone quality and quantity of the partially edentulous molar region of the mandible, which should be considered in dental implant treatment for postmenopausal women. PMID- 22207879 TI - Implant removal associated complications in children with limb fractures due to trauma. AB - PURPOSE: The purpose of this study was to analyze the number and type of complications that occurred after fracture implant removal and to investigate whether implant removal should be performed routinely in children. METHODS: In a retrospective study, patient records were used for the analyses of patient characteristics, surgery reports, and complications. Children under the age of 16 years with a limb fracture due to trauma, treated with either Kirschner wires (K wires), elastic stable intramedullary nails (ESIN), or screw fixation between 2000 and 2007, were included. Exclusion criteria were as follows: refracture, pathological fracture, fracture of the hands and feet, or polytrauma patients (Injury Severity Score [ISS] > 15). RESULTS: Three-hundred and nine fractures were analyzed. All K-wires (173) and ESIN (96) were removed as per standard procedure, resulting in 17/173 and 7/96 complications after removal, respectively. In 19/40 patients with screw fixation treatments, it was decided to remove the material after fracture consolidation, resulting in 4/19 complications. The decision in 21 treatments to leave the screw in situ led to four complications. No significant difference in complication rates could be found for the three groups after removal surgery (17/173, 7/96, and 4/19) or between hardware removal (4/19) and retention (4/21) in the case of screw fixation. CONCLUSIONS: The removal of K-wires, ESIN, and screws is considered to be a safe procedure in children and is, by definition, indicated for K-wires and ESIN after fracture healing. PMID- 22207878 TI - Bone pain and extremely low bone mineral density due to severe vitamin D deficiency in celiac disease. AB - CASE REPORT: A 29-year-old wheelchair-bound woman was presented to us by the gastroenterologist with suspected osteomalacia. She had lived in the Netherlands all her life and was born of Moroccan parents. Her medical history revealed iron deficiency, growth retardation, and celiac disease, for which she was put on a gluten-free diet. She had progressive bone pain since 2 years, difficulty with walking, and about 15 kg weight loss. She had a short stature, scoliosis, and pronounced kyphosis of the spine and poor condition of her teeth. Laboratory results showed hypocalcemia, an immeasurable serum 25-hydroxyvitamin D level, and elevated parathyroid hormone and alkaline phosphatase levels. Spinal radiographs showed unsharp, low contrast vertebrae. Bone mineral density measurement at the lumbar spine and hip showed a T-score of -6.0 and -6.5, respectively. A bone scintigraphy showed multiple hotspots in ribs, sternum, mandible, and long bones. A duodenal biopsy revealed villous atrophy (Marsh 3C) and positive antibodies against endomysium, transglutaminase, and gliadin, compatible with active celiac disease. A bone biopsy showed severe osteomalacia but normal bone volume. She was treated with calcium intravenously and later orally. Furthermore, she was treated with high oral doses of vitamin D and a gluten-free diet. After a few weeks of treatment, her bone pain decreased, and her muscle strength improved. DISCUSSION: In this article, the pathophysiology and occurrence of osteomalacia as a complication of celiac disease are discussed. Low bone mineral density can point to osteomalacia as well as osteoporosis. PMID- 22207880 TI - An Oscillatory Contractile Pole-Force Component Dominates the Traction Forces Exerted by Migrating Amoeboid Cells. AB - We used principal component analysis to dissect the mechanics of chemotaxis of amoeboid cells into a reduced set of dominant components of cellular traction forces and shape changes. The dominant traction force component in wild-type cells accounted for ~40% of the mechanical work performed by these cells, and consisted of the cell attaching at front and back contracting the substrate towards its centroid (pole-force). The time evolution of this pole-force component was responsible for the periodic variations of cell length and strain energy that the cells underwent during migration. We identified four additional canonical components, reproducible from cell to cell, overall accounting for an additional ~20% of mechanical work, and associated with events such as lateral protrusion of pseudopodia. We analyzed mutant strains with contractility defects to quantify the role that non-muscle Myosin II (MyoII) plays in amoeboid motility. In MyoII essential light chain null cells the polar-force component remained dominant. On the other hand, MyoII heavy chain null cells exhibited a different dominant traction force component, with a marked increase in lateral contractile forces, suggesting that cortical contractility and/or enhanced lateral adhesions are important for motility in this cell line. By compressing the mechanics of chemotaxing cells into a reduced set of temporally-resolved degrees of freedom, the present study may contribute to refined models of cell migration that incorporate cell-substrate interactions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12195-011-0184-9) contains supplementary material, which is available to authorized users. PMID- 22207881 TI - Modeling the Development of Goal-Specificity in Mirror Neurons. AB - Neurophysiological studies have shown that parietal mirror neurons encode not only actions but also the goal of these actions. Although some mirror neurons will fire whenever a certain action is perceived (goal-independently), most will only fire if the motion is perceived as part of an action with a specific goal. This result is important for the action-understanding hypothesis as it provides a potential neurological basis for such a cognitive ability. It is also relevant for the design of artificial cognitive systems, in particular robotic systems that rely on computational models of the mirror system in their interaction with other agents. Yet, to date, no computational model has explicitly addressed the mechanisms that give rise to both goal-specific and goal-independent parietal mirror neurons. In the present paper, we present a computational model based on a self-organizing map, which receives artificial inputs representing information about both the observed or executed actions and the context in which they were executed. We show that the map develops a biologically plausible organization in which goal-specific mirror neurons emerge. We further show that the fundamental cause for both the appearance and the number of goal-specific neurons can be found in geometric relationships between the different inputs to the map. The results are important to the action-understanding hypothesis as they provide a mechanism for the emergence of goal-specific parietal mirror neurons and lead to a number of predictions: (1) Learning of new goals may mostly reassign existing goal-specific neurons rather than recruit new ones; (2) input differences between executed and observed actions can explain observed corresponding differences in the number of goal-specific neurons; and (3) the percentage of goal-specific neurons may differ between motion primitives. PMID- 22207882 TI - Range of motion implications of proximal humerus fractures: a case study. AB - BACKGROUND: Functional outcome in surgical treatment of Neer three- and four-part proximal humerus fractures (PHF) varies greatly and depends on multiple parameters. Important parameters are the amount and direction of displacement and the necessary reduction of fragments during surgery. These are patient-specific parameters and are difficult to determine using traditional modalities such as radiographs and computed tomography (CT). METHODS: A 58-year-old female patient was reported in the emergency department with a three-part PHF. CT scan images showed that the humeral shaft was medialised and internally rotated, but with a marginally displaced greater tuberosity fragment. Using a bone-determined range of motion (ROM) simulation system, we analysed the CT scan and calculated the required correction needed to prevent post-operative impingement. The fracture was reduced and stabilised by a locking plate, realigning the medialised and internally rotated humeral shaft. The post-operative bone-determined ROM was determined using a post-operative CT scan and the motion simulation system. RESULTS: ROM limitations due to bony impingement visible in the simulations of the pre-operative CT scan had mostly disappeared in the simulations of the post operative CT scan. Twelve weeks post-surgery the patient has regained close to 80% of her ROM. CONCLUSIONS: This case demonstrates the applicability of a new diagnostic tool that can be used to identify bony impingement and helps in making the decision for conservative or surgical treatment of a PHF. The simulation of post-trauma function was indicative of functional outcome. This supports our claim that the system may be used to facilitate the treatment decision regarding PHF. PMID- 22207884 TI - Advances in MRI-Based Detection of Cerebrovascular Changes after Experimental Traumatic Brain Injury. AB - Traumatic brain injury is a heterogeneous and multifaceted neurological disorder that involves diverse pathophysiological pathways and mechanisms. Thorough characterization and monitoring of the brain's status after neurotrauma is therefore highly complicated. Magnetic resonance imaging (MRI) provides a versatile tool for in vivo spatiotemporal assessment of various aspects of central nervous system injury, such as edema formation, perfusion disturbances and structural tissue damage. Moreover, recent advances in MRI methods that make use of contrast agents have opened up additional opportunities for measurement of events at the level of the cerebrovasculature, such as blood-brain barrier permeability, leukocyte infiltration, cell adhesion molecule upregulation and vascular remodeling. It is becoming increasingly clear that these cerebrovascular alterations play a significant role in the progression of post-traumatic brain injury as well as in the process of post-traumatic brain repair. Application of advanced multiparametric MRI strategies in experimental, preclinical studies may significantly aid in the elucidation of pathomechanisms, monitoring of treatment effects, and identification of predictive markers after traumatic brain injury. PMID- 22207885 TI - Elevated peripheral neutrophils and matrix metalloproteinase 9 as biomarkers of functional outcome following subarachnoid hemorrhage. AB - There is growing evidence supporting the role of inflammation in early brain injury and cerebral vasospasm following subarachnoid hemorrhage (SAH). Matrix metalloproteinases (MMPs) are released by inflammatory cells and can mediate early brain injury via disruption of the extracellular matrix and mediate vasospasm by cleaving endothelin-1 into vasoactive fragments. We hypothesize that inflammation marked by neutrophil elevation and MMP-9 release in human SAH is associated with vasospasm and with poor clinical outcome. We enrolled consecutive SAH subjects (N = 55), banked serial blood and cerebrospinal fluid (CSF) samples, and evaluated their 3-month modified Rankin scores (mRS). Vasospasm was defined as >50% vessel caliber reduction on angiography 6-8 days post-SAH. A poor outcome was defined as mRS > 2. We compared blood leukocyte and neutrophil counts during post-SAH days 0-14 with respect to vasospasm and 3-month outcome. In a subset of SAH subjects (N = 35), we compared blood and CSF MMP-9 by enzyme-linked immunosorbent assay (ELISA) on post-SAH days 0-1, 2-3, 4-5, 6-8, and 10-14 with respect to vasospasm and to 3-month outcome. Persistent elevation of blood leukocyte (p = 0.0003) and neutrophil (p = 0.0002) counts during post-SAH days 0 14 are independently associated with vasospasm after adjustment for major confounders. In the same time period, blood neutrophil count (post-SAH days 2-3, p = 0.018), blood MMP-9 (post-SAH days 4-5, p = 0.045), and CSF MMP-9 (post-SAH days 2-3, p = 0.05) are associated with poor 3-month SAH clinical outcome. Neutrophil count correlates with blood MMP-9 (post-SAH days 6-8, R = 0.39; p = 0.055; post-SAH days 10-14, R = 0.79; p < 0.0001), and blood MMP-9 correlates with CSF MMP-9 (post-SAH days 4-5, R = 0.72; p = 0.0002). Elevation of CSF MMP-9 during post-SAH days 0-14 is associated with poor 3-month outcome (p = 0.0078). Neither CSF nor blood MMP-9 correlates with vasospasm. Early rise in blood neutrophil count and blood and CSF MMP-9 are associated with poor 3-month SAH clinical outcome. In blood, neutrophil count correlates with MMP-9 levels, suggesting that neutrophils may be an important source of blood MMP-9 early in SAH. Similarly, CSF and blood MMP-9 correlate positively early in the course of SAH, suggesting that blood may be an important source of CSF MMP-9. Blood and CSF MMP-9 are associated with clinical outcome but not with vasospasm, suggesting that MMP-9 may mediate brain injury independent of vasospasm in SAH. Future in vitro studies are needed to investigate the role of MMP-9 in SAH-related brain injury. Larger clinical studies are needed to validate blood and CSF MMP-9 as potential biomarkers for SAH outcome. PMID- 22207886 TI - Production of free radicals and oxygen consumption by primary equine endothelial cells during anoxia-reoxygenation. AB - The endothelium plays an active role in ischemia/reperfusion injuries. Herein, we report the effect of a single or successive cycles of anoxia/reoxygenation (A/R) on the mitochondrial respiratory function of equine endothelial cells (cultured from carotids) monitored by high resolution oxymetry, and on their production of reactive oxygen species (ROS). ROS were measured by electron paramagnetic resonance (ESR) using POBN and DMPO spin traps, and by gas chromatography (GC) of ethylene released by ROS-induced alpha-keto-gamma-(methylthio)butyric acid (KMB) oxidation. The oxygen consumption significantly decreased with the number of A/R cycles, and POBN-ESR spectra were specific of adducts formed in the cells from superoxide anion. After a one-hour A/R cycle, high intensity DMPO-ESR spectra were observed and assigned to superoxide anion trapping; the GC results confirmed an important production of ROS compared to normoxic cells. These results show that A/R induces mitochondrial alterations in endothelial cells, and strongly stimulates their oxidative activity as demonstrated by ESR and GC methods. PMID- 22207883 TI - Syndromics: a bioinformatics approach for neurotrauma research. AB - Substantial scientific progress has been made in the past 50 years in delineating many of the biological mechanisms involved in the primary and secondary injuries following trauma to the spinal cord and brain. These advances have highlighted numerous potential therapeutic approaches that may help restore function after injury. Despite these advances, bench-to-bedside translation has remained elusive. Translational testing of novel therapies requires standardized measures of function for comparison across different laboratories, paradigms, and species. Although numerous functional assessments have been developed in animal models, it remains unclear how to best integrate this information to describe the complete translational "syndrome" produced by neurotrauma. The present paper describes a multivariate statistical framework for integrating diverse neurotrauma data and reviews the few papers to date that have taken an information-intensive approach for basic neurotrauma research. We argue that these papers can be described as the seminal works of a new field that we call "syndromics", which aim to apply informatics tools to disease models to characterize the full set of mechanistic inter-relationships from multi-scale data. In the future, centralized databases of raw neurotrauma data will enable better syndromic approaches and aid future translational research, leading to more efficient testing regimens and more clinically relevant findings. PMID- 22207887 TI - Clinical features of cardio-renal syndrome in a cohort of consecutive patients admitted to an internal medicine ward. AB - INTRODUCTION: Cardiorenal syndrome (CRS) is a disorder of the heart and kidney whereby interactions between the 2 organs can occur. We recorded the clinical features of CRS in patients consecutively admitted to an Internal Medicine ward. PATIENTS AND METHODS: We retrospectively analyzed the anthropometric, history, clinical, biochemical and treatment characteristics in 438 out of 2,998 subjects (14.6%) admitted to our unit (from June 2007 to December 2009), diagnosed with CRS, according to Acute Dialysis Quality Initiative (ADQI) recommendations. Estimated glomerular filtration (eGFR) was calculated using several equations: MDRD (Modification of Diet in Renal Disease; 2 variations GFR(MDRD186), GFR(MDRD175)), Mayo, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Cockroft-Gault. RESULTS: Mean age was 80+/-8 years, 222 (50.6%) were males, 321 (73.2%) were smokers, 229 (52.2%) were diabetic, 207 (47.2%) had a history of acute myocardial infarction, 167 (38.1%) had angina, 135 (30.8%) were affected by cerebrovascular disease, 339 (77.3%) had peripheral arterial disease. CRS was type 1 in 211 cases (48.2%), type 2 in 96 (21.9%), type 3 in 88 (20.1%), type 4 in 29 (6.6%) and type 5 in 14 (3.2%). eGFR, calculated by different formulae, ranged between 31 and 36 ml/min/1.73 m(2). GFR was lower in CRS type 3 than in the other types, and the values ranged between 24 and 27 ml/min/1.73 m(2). Mean hospital length-of-stay (LOS) was 9.8+/-6.3 days. Diuretics were the most prescribed medication (78.7%); only 5 patients underwent haemodialysis. CONCLUSIONS: CRS is common, especially in the elderly. CRS Type 1 was the prevalent subset and patients had stage 3-4 renal insufficiency. Results obtained from the GFR equations were similar although the Mayo equation tended to overestimate the eGFR. PMID- 22207888 TI - Preventing Cardio-renal Syndrome Rather than Treating It: Could Statins Play A Role? PMID- 22207889 TI - Efficacy of light-activated sealant on enamel demineralization in orthodontic patients: an atomic force microscope evaluation. AB - OBJECTIVE: The purpose of this study was to investigate the efficacy of (Pro Seal) sealant in preventing enamel decalcification in-vivo and compare its effect with fluoride varnish and unfilled sealant using atomic force microscopy. MATERIALS AND METHODS: Eight orthodontic patients who were candidates for extraction of all first premolars for orthodontic treatment were recruited to this study. Thirty two premolars (upper and lower) were randomly divided into four groups (n=8) for each group, 4 maxillary and 4 mandibular); Control (no treatment); Fluoride varnish, Unfilled sealant (Light Bond) and filled sealant (Pro-Seal). After two months the brackets were debonded and the teeth were extracted and prepared for Atomic force microscopic scanning. Each sample was scanned twice at two different scan areas 50 and 10um at the buccal cervical third of the crown. Images were recorded with slow scan rate and resolution and the mean roughness height and total surface area were calculated for each scan area. Comparison between groups was performed using one way analysis of variance test with level of significance was set to be 0.05. RESULTS: Pro Seal treated samples show the lowest roughness height and total surface area. CONCLUSION: Pro Seal was the most effective prophylaxis technique in preventing enamel demineralization during orthodontic treatment. PMID- 22207890 TI - Farnesol, a fungal quorum-sensing molecule triggers Candida albicans morphological changes by downregulating the expression of different secreted aspartyl proteinase genes. AB - The aim of this study was to determine the effect of exogenous farnesol in yeast to-hyphae morphogenesis, and Saps (2, 4, 5 and 6) mRNA expressions by a Candida strain that does not produce endogenous farnesol. C. albicans was cultured in the absence and presence of farnesol at various concentrations (10, 100, and 300 uM), in proteinase induction medium, and then used to determine yeast-to- hyphae changes, Candida ultrastructure and to determine Saps 2, 4, 5 and 6 expressions using q-TR-PCR and ELISA (for Sap2). Data demonstrated that farnesol greatly reduced the yeast-to-hyphae morphogenesis of a Candida strain that does not produce endogenous farnesol. Farnesol induced several ultrastructural alterations, including changes in the cell-wall shape, a visible disconnection between the cell wall and cytoplasm with an electron-lucent zone between them, and the presence of electron-dense vacuoles. Tested on gene expressions, farnesol was able to significantly (p < 0.01) decrease Sap2 secretion and mRNA expression. Farnesol downregulated also Sap4-6 mRNA expression. These results demonstrated for the first time that farnesol modules Candida morphogenesis through a downregulation of Saps 2, 4, 5 and 6 expressions. Overall these data point to the potential use of farnesol as an antifungal molecule. PMID- 22207891 TI - HIV Screening and Awareness Survey for Pregnant Women in a Remote Area in Xinjiang Uyghur Autonomous Region of China. AB - OBJECTIVE: The number of people infected with human immunodeficiency virus (HIV) in China has increased in recent years. HIV screening for pregnant women was performed in a remote area in Xinjiang, as an effort to promote universal HIV screening in pregnant women and to help prevention of mother-to-child transmission. METHODS: Pregnant women in Burqin and Jeminay Counties in Xinjiang were offered free voluntary HIV screening. Local mid-level medical workers were trained to use Determine(r) HIV-1/2 kit for HIV screening. All the tested pregnant women signed a consent form, received HIV education material, and participated in an HIV knowledge survey. RESULTS: All the 890 pregnant women receiving HIV test had negative result. Among these women, 67.6% were Kazakh and 40.9% were farmers. Survey of HIV knowledge showed that these women's awareness about mother-to-child transmission was limited. The levels of HIV knowledge were related with ethnic background, age, education and profession of the pregnant women. CONCLUSION: The results suggested that HIV infection had not become a significant problem among the pregnant women in this remote area of Xinjiang, but continued efforts to improve the awareness of HIV, especially the knowledge about mother-to-child transmission of HIV, in pregnant women were needed. PMID- 22207892 TI - A cell-based protein-protein interaction method using a permuted luciferase reporter. AB - We have developed a novel cell-based protein-protein interaction assay method. The method relies on conversion of an inactive permuted luciferase containing a Tobacco Etch Virus protease (TEV) cleavage sequence fused onto protein (A) to an active luciferase upon interaction and cleavage by another protein (B) fused with the TEV protease. We demonstrate assay applicability for ligand-induced protein protein interactions including G-protein coupled receptors, receptor tyrosine kinases and nuclear hormone receptors. PMID- 22207893 TI - Microfluidic concentration of bacteria by on-chip electrophoresis. AB - In this contribution, we present a system for efficient preconcentration of pathogens without affecting their viability. Development of miniaturized molecular diagnostic kits requires concentration of the sample, molecule extraction, amplification, and detection. In consequence of low analyte concentrations in real-world samples, preconcentration is a critical step within this workflow. Bacteria and viruses exhibit a negative surface charge and thus can be electrophoretically captured from a continuous flow. The concept of phaseguides was applied to define gel membranes, which enable effective and reversible collection of the target species. E. coli of the strains XL1-blue and K12 were used to evaluate the performance of the device. By suppression of the electroosmotic flow both strains were captured with efficiencies of up to 99%. At a continuous flow of 15 MUl/min concentration factors of 50.17 +/- 2.23 and 47.36 +/- 1.72 were achieved in less than 27 min for XL1-blue and K12, respectively. These results indicate that free flow electrophoresis enables efficient concentration of bacteria and the presented device can contribute to rapid analyses of swab-derived samples. PMID- 22207894 TI - Individually Modified Saliva Delivery Changes the Perceived Intensity of Saltiness and Sourness. AB - Individuals vary largely in their salivary flow and composition, and given the importance of saliva on perception of taste, this might influence how the tastant stimuli are perceived. We therefore hypothesise that altering the individual salivary flow rates has an impact on the perceived taste intensity. In this study, we investigated the role of saliva amount on the perceived taste intensity by excluding parotid saliva and adding artificial saliva close to the parotid duct at preset flow rates. Significant decreases in perception with increasing salivary flow rates were observed for citric acid and sodium chloride. This can partially be explained by a dilution effect which is in line with previous studies on detectable concentration differences. However, since the bitterness and sweetness remained unaffected by the salivary flow conditions and the dilution effect was comparable to that of saltiness, further explanation is needed. Furthermore, we investigated whether the suppression of taste intensity in binary mixtures (taste-taste interactions) could possibly be caused by the increased salivary flow rate induced by an additional taste attribute. The results show, however, that suppression of taste intensity in binary mixtures was not affected by the rate of salivation. This was more likely to be explained by psychophysics. PMID- 22207896 TI - Role of sp transcription factors in the regulation of cancer cell metabolism. AB - Cancer cells exhibit altered metabolism characterized by the generation of adenosine triphosphate by glycolysis and generation of fatty acids by de novo synthesis. The majority of genes involved in these pathways have binding sites for specificity protein (Sp) transcription factors in their promoters. Studies showing that Sp transcription factors, particularly Sp1, are involved in the regulation in cancer cells of hexokinase, pyruvate kinase, lactate dehydrogenase, fatty acid synthase, and hypoxia-inducible factor-1alpha are reviewed. Glycolysis and lipogenesis in cancers are also known to be stimulated by the constitutive activation of the PI3K/Akt signaling pathway. Evidence is presented for the notion that Sp transcription factors may act in concert with Akt to regulate the abnormal metabolism of cancer cells. PMID- 22207897 TI - Anti-miR-203 Upregulates SOCS3 Expression in Breast Cancer Cells and Enhances Cisplatin Chemosensitivity. AB - Breast cancer is one of the most common cancers among women in the United States. Although there are effective drugs, such as cisplatin, for treating advanced cancers, many patients eventually develop resistance. MicroRNAs (miRNAs) have emerged to play important roles in tumorigenesis and drug resistance. In this study, the authors observed a significant upregulation of miR-203 expression in human breast cancer tissues as compared to patient-matched nontumor breast tissues. Knockdown of miR-203 following cisplatin treatment enhances p53, p21, and Bax protein expression. Furthermore, knockdown of miR-203 sensitized human breast cancer MCF-7 cells to cisplatin-mediated apoptotic cell death, as evident from caspase-9 and caspase-7 activation, and poly(ADP-ribose) polymerase (PARP) cleavage. Moreover, the authors have demonstrated that suppressor of cytokine signaling 3 (SOCS3) is a novel target of miR-203, and cisplatin treatment in miR 203 knockdown MCF-7 cells enhanced SOCS3 expression. Exogenous expression of SOCS3 in MCF-7 cells increased sensitization to cisplatin-mediated apoptosis. Together, the results suggested a novel role of miR-203 in conferring cisplatin resistance through suppression of SOCS3, implicating an additional therapeutic strategy may be helpful to overcome cisplatin resistance for breast cancer patients. PMID- 22207895 TI - The c-Rel Transcription Factor in Development and Disease. AB - c-Rel is a member of the nuclear factor kappaB (NF-kappaB) transcription factor family. Unlike other NF-kappaB proteins that are expressed in a variety of cell types, high levels of c-Rel expression are found primarily in B and T cells, with many c-Rel target genes involved in lymphoid cell growth and survival. In addition to c-Rel playing a major role in mammalian B and T cell function, the human c-rel gene (REL) is a susceptibility locus for certain autoimmune diseases such as arthritis, psoriasis, and celiac disease. The REL locus is also frequently altered (amplified, mutated, rearranged), and expression of REL is increased in a variety of B and T cell malignancies and, to a lesser extent, in other cancer types. Thus, agents that modulate REL activity may have therapeutic benefits for certain human cancers and chronic inflammatory diseases. PMID- 22207898 TI - Extinction of Tumor Antigen Expression by SF2/ASF in JCV-Transformed Cells. AB - The human neurotropic polyomavirus JC (JCV) induces a broad range of neural origin tumors in experimental animals and has been repeatedly detected in several human cancers, most notably neural crest-origin tumors including medulloblastomas and glioblastomas. The oncogenic activity of JCV is attributed to the viral early gene products, large T and small t antigens, as evident by results from in vitro cell culture and in vivo animal studies. Recently, we have shown that alternative splicing factor, SF2/ASF, has the capacity to exert a negative effect on transcription and splicing of JCV genes in glial cells through direct association with a specific DNA motif within the viral promoter region. Here, we demonstrate that SF2/ASF suppresses large T antigen expression in JCV-transformed tumor cell lines, and the expression of SF2/ASF in such tumor cells thereby inhibits the transforming capacity of the viral tumor antigens. Moreover, down-regulation of SF2/ASF in viral-transformed tumor cell lines induces growth and proliferation of the tumor cells. Mapping analysis of the minimal peptide domain of SF2/ASF responsible for JCV promoter silencing and tumor suppressor activity suggests that amino acid residues 76 to 100 of SF2/ASF are functionally sufficient to suppress the growth of the tumor cells. These observations demonstrate a role for SF2/ASF in JCV-mediated cellular transformation and provide a new avenue of research to pathogenic mechanisms of JCV-induced tumors. PMID- 22207899 TI - Expression of the Adenovirus Early Gene 1A Transcription-Repression Domain Alone Downregulates HER2 and Results in the Death of Human Breast Cancer Cells Upregulated for the HER2 Proto-Oncogene. AB - Adenovirus (Ad) early gene 1A 243 residue protein (E1A 243R) possesses a potent transcription-repression function within the N-terminal 80 amino acids (E1A 1 80). We examined the ability of E1A 243R and E1A 1-80 to repress transcription of both an exogenous and the endogenous HER2 promoter in a human breast cancer cell line upregulated for the HER2 proto-oncogene (SK-BR-3). Both moieties repressed HER2 expression by over 90%. When E1A 1-80 was expressed from a nonreplicative Ad vector, levels of expression were lower than anticipated. Addition of nonspecific sequences to the E1A 1-80 C-terminus (E1A 1-80 C+) enhanced its expression 10- to 20-fold. Because "oncogene addiction" suggests that repression of HER2 could kill HER2 upregulated cells, we examined the ability of full-length E1A 243R and E1A 1 80 C+ delivered by an Ad vector to kill HER2 upregulated SK-BR-3 cells. Expression of both E1A 243R and E1A 1-80 C+ killed SK-BR-3 cells but not normal breast cells. E1A 1-80 C+ is a particularly effective killer of SK-BR-3 cells. At 144 h post infection, over 85% of SK-BR-3 cells were killed by a 100 moi of the Ad vector expressing E1A 1-80 C+. As controls, Ad vectors expressing E1A 243R with deletion of all known functional domains or expressing unrelated beta galactosidase had no effect. Three additional human breast cancer cells lines reported to be upregulated for HER2 or another EGF family member (EGFR) were found to be efficiently killed by expression of E1A 1-80 C+, whereas three additional "normal" cell lines (two derived from breast and one from foreskin) were not. The ability of the E1A transcription-repression domain alone to kill HER2 upregulated breast cancer cells has potential for development of therapies for treatment of aggressive human breast cancers and potentially other human cancers that overexpress HER2. PMID- 22207900 TI - Caspase-2-Based Regulation of the Androgen Receptor and Cell Cycle in the Prostate Cancer Cell Line LNCaP. AB - Caspase-2 can induce apoptosis in response to extrinsic and intrinsic signals. Unlike other caspases, this protein is not expressed solely in nonnuclear compartments; a subpopulation is constitutively localized in the nucleus. As one of the most evolutionarily conserved caspases, caspase-2 may have roles in multiple cellular processes. However, its contribution to nonapoptotic processes remains a mystery. In this study, we show that caspase-2 activity is important for proliferation by cells of the androgen-dependent prostate cancer cell line LNCaP. LNCaP cells expressing either a dominant-negative (dn) form of caspase or an siRNA against caspase-2 had lower androgen receptor (AR)-dependent proliferative responses than control cells, and application of the siRNA resulted in downregulation of the expression of both AR-dependent prostate-specific antigen (PSA) and AR-dependent reporter luciferase. Also, caspase-2 formed complexes with the cell cycle regulatory proteins cyclin D3, CDK4, and p21/Cip1, and caspase-2 regulated AR transactivation by inhibiting the repressive function of cyclin D3. Taken together, these results reveal, for the first time, that caspase-2 is involved in cell cycle promotion and AR activation. Given that prostate cancer cells depend on AR activity in order to survive, the fact that our data indicate that caspase-2 positively regulates AR activity suggests that caspase-2 has potential as a target in the treatment of prostate cancer. PMID- 22207901 TI - Short-Form Ron Promotes Spontaneous Breast Cancer Metastasis through Interaction with Phosphoinositide 3-Kinase. AB - Receptor tyrosine kinases (RTKs) have been the subject of intense investigation due to their widespread deregulation in cancer and the prospect of developing targeted therapeutics against these proteins. The Ron RTK has been implicated in tumor aggressiveness and is a developing target for therapy, but its function in tumor progression and metastasis is not fully understood. We examined Ron activity in human breast cancers and found striking predominance of an activated Ron isoform known as short-form Ron (sfRon), whose function in breast tumors has not been explored. We found that sfRon plays a significant role in aggressiveness of breast cancer in vitro and in vivo. sfRon expression was sufficient to convert slow-growing, nonmetastatic tumors into rapidly growing tumors that spontaneously metastasized to liver and bones. Mechanistic studies revealed that sfRon promotes epithelial-mesenchymal transition, invasion, tumor growth, and metastasis through interaction with p85, the regulatory subunit of phosphoinositide 3-kinase (PI3K). Inhibition of PI3K activity, or introduction of a single mutation in the p85 docking site on sfRon, completely eliminated the ability of sfRon to promote tumor growth, invasion, and metastasis. These findings reveal sfRon as an important new player in breast cancer and validate Ron and PI3K as therapeutic targets in this disease. PMID- 22207902 TI - Erratum. AB - Yoo KH, Baik M, Hennighausen L. Context-specific growth hormone signaling through the transcription factor STAT5: implications for the etiology of hepatosteatosis and hepatocellular carcinoma. Genes Cancer. 2011;2:3-9. (Original doi: 10.1177/1947601911405046)[This corrects the article on p. 3 in vol. 2.]. PMID- 22207903 TI - Pilot trial of Melissa officinalis L. leaf extract in the treatment of volunteers suffering from mild-to-moderate anxiety disorders and sleep disturbances. AB - Botanicals are an alternative option to prescription drugs for the alleviation of symptoms due to anxiety disorders and insomnia. Melissa officinalis L. has been shown as an anti-stress and anxiolytic agent. We previously reported moderate stress improvement in mice in which Cyracos((r)), a standardized Melissa officinalis L. extract, was administrated. Cyracos((r)) contains phytochemicals that inhibit gamma-aminobutyric acid catabolism. This was a prospective, open label, 15-day study to evaluate the efficacy of Cyracos((r)) on stressed volunteers, who have mild-to-moderate anxiety disorders and sleep disturbances. Using clinician rating criteria, primary outcomes showed improvement of symptoms. Cyracos((r)) reduced anxiety manifestations by 18% (p < 0.01), ameliorated anxiety-associated symptoms by 15% (p < 0.01) and lowered insomnia by 42% (p < 0.01). As much as 95% of subjects (19/20) responded to treatment, of which 70% (14/20) achieved full remission for anxiety, 85% (17/20) for insomnia, and 70% (14/20) for both. Our study demonstrates, for the first time that chronic administration of Melissa officinalis L. relieves stress-related effects. It is critical that further studies incorporate a placebo and investigate physiological stress markers. PMID- 22207904 TI - Partial differential equation transform - Variational formulation and Fourier analysis. AB - Nonlinear partial differential equation (PDE) models are established approaches for image/signal processing, data analysis and surface construction. Most previous geometric PDEs are utilized as low-pass filters which give rise to image trend information. In an earlier work, we introduced mode decomposition evolution equations (MoDEEs), which behave like high-pass filters and are able to systematically provide intrinsic mode functions (IMFs) of signals and images. Due to their tunable time-frequency localization and perfect reconstruction, the operation of MoDEEs is called a PDE transform. By appropriate selection of PDE transform parameters, we can tune IMFs into trends, edges, textures, noise etc., which can be further utilized in the secondary processing for various purposes. This work introduces the variational formulation, performs the Fourier analysis, and conducts biomedical and biological applications of the proposed PDE transform. The variational formulation offers an algorithm to incorporate two image functions and two sets of low-pass PDE operators in the total energy functional. Two low-pass PDE operators have different signs, leading to energy disparity, while a coupling term, acting as a relative fidelity of two image functions, is introduced to reduce the disparity of two energy components. We construct variational PDE transforms by using Euler-Lagrange equation and artificial time propagation. Fourier analysis of a simplified PDE transform is presented to shed light on the filter properties of high order PDE transforms. Such an analysis also offers insight on the parameter selection of the PDE transform. The proposed PDE transform algorithm is validated by numerous benchmark tests. In one selected challenging example, we illustrate the ability of PDE transform to separate two adjacent frequencies of sin(x) and sin(1.1x). Such an ability is due to PDE transform's controllable frequency localization obtained by adjusting the order of PDEs. The frequency selection is achieved either by diffusion coefficients or by propagation time. Finally, we explore a large number of practical applications to further demonstrate the utility of proposed PDE transform. PMID- 22207905 TI - Mutation Rate Inferred From Synonymous Substitutions in a Long-Term Evolution Experiment With Escherichia coli. AB - The quantification of spontaneous mutation rates is crucial for a mechanistic understanding of the evolutionary process. In bacteria, traditional estimates using experimental or comparative genetic methods are prone to statistical uncertainty and consequently estimates vary by over one order of magnitude. With the advent of next-generation sequencing, more accurate estimates are now possible. We sequenced 19 Escherichia coli genomes from a 40,000-generation evolution experiment and directly inferred the point-mutation rate based on the accumulation of synonymous substitutions. The resulting estimate was 8.9 * 10( 11) per base-pair per generation, and there was a significant bias toward increased AT-content. We also compared our results with published genome sequence datasets for other bacterial evolution experiments. Given the power of our approach, our estimate represents the most accurate measure of bacterial base substitution rates available to date. PMID- 22207906 TI - The 6th Cachexia Conference: an introduction to clinical and basic research in an exiting area. PMID- 22207908 TI - The ACT-ONE trial, a multicentre, randomised, double-blind, placebo-controlled, dose-finding study of the anabolic/catabolic transforming agent, MT-102 in subjects with cachexia related to stage III and IV non-small cell lung cancer and colorectal cancer: study design. AB - AIMS: Cachexia, the wasting disorder associated with a wide range of serious illnesses including cancer, is a major cause of morbidity and mortality. There is currently no widely approved therapeutic agent for treating or preventing cancer associated cachexia. Colorectal cancer and non-small cell lung cancer have relatively high incidences of cachexia, approximately 28% and 34%, respectively. Neurohormonal overactivity has been implicated in the genesis and progression of cachexia and beta receptor antagonism has been proposed as a potential therapy. MT-102, a novel anabolic/catabolic transforming agent, has a multi-functional effect upon three potential pharmacological targets in cancer cachexia, namely reduced catabolism through non-selective beta-blockade, reduced fatigue, and thermogenesis through central 5-HT1a antagonism and increased anabolism through partial beta-2 receptor agonism. METHODS: At least 132 male and female patients, aged between 25 and 80 years with a confirmed diagnosis of late-stage non-small cell lung cancer or colorectal cancer, with cachexia will be randomised to either one of the two MT-102 doses or placebo in a 3:1:2 ratio (MT-102 10 mg BD(-1)/MT 102 2.5 mg BD/placebo). Patients will continue on study treatment for maximally 16 weeks. The primary endpoint, to be analysed by assigned treatment group, will be body weight change over 16 weeks. For this endpoint, the study has 85% power (0.05% significance level) to detect per 4-week period a mean change of -0.8 kg in the placebo group and 0 kg in the high-dose MT-102 arm. The first patient was randomised in February 2011 and patient recruitment is expected to continue until mid-2012. PERSPECTIVE: The ACT-ONE trial is designed to test whether the anabolic/catabolic transforming agent MT-102 will positively impact on the rate of change of body weight in cancer cachexia, thereby evaluating a novel therapeutic strategy in this hitherto poorly treatable condition. A separate ACT TWO trial will recruit patients who complete the ACT-ONE trial and remain on randomised double-blind medication. Participants in ACT-TWO will be followed for an additional period with a separate primary endpoint. PMID- 22207907 TI - Growth hormone, insulin-like growth factor 1, and insulin signaling-a pharmacological target in body wasting and cachexia. AB - Cachexia is an irreversible process that can develop in the course of chronic disease. It is characterized by the remodeling of the metabolic, inflammatory, and endocrine pathways. Insulin, growth hormone (GH), and insulin-like growth factor 1 (IGF-1) are involved in glucose, protein, and fat metabolism, which regulates body composition. In body wasting and cachexia, their signaling is impaired and causes anabolic/catabolic imbalance. Important mechanisms include inflammatory cytokines and neurohormonal activation. Remodeled post-receptor insulin, GH, and IGF-1 pathways constitute a potential target for pharmacological treatment in the setting of body wasting and cachexia. Peroxisome proliferator activated receptor gamma agonists, drugs inhibiting angiotensin II action (angiotensin II antagonists and inhibitors of angiotensin-converting enzyme), and testosterone, which interfere with post-receptor pathways of insulin, GH, and IGF 1, were investigated as pharmacological intervention targets and various clinically important implications were reported. There are several other potential targets, but their treatment feasibility and applicability is yet to be established. PMID- 22207909 TI - Different imaging modalities in detection of a huge intracardiac mass. PMID- 22207910 TI - Coronary arteriovenous fistula. AB - Congenital coronary arteriovenous fistulas represent abnormal communication between coronary arteries and any cardiac chambers, pulmonary artery, coronary sinus, superior vena cava or pulmonary vein. We reported an interesting case of very long and tortuous coronary arteriovenous fistulas originated from the left circumflex coronary artery, which drained into bronchial arteries in right lower lung field diagnosed by coronary angiography and multidetector computed tomography. PMID- 22207911 TI - Abstracts of the Alzheimer's Imaging Consortium. July 16-21, 2011. Paris, France. PMID- 22207912 TI - Oops! Where problems meet solutions. PMID- 22207913 TI - Exosome characterization from ascitic fluid holds promise for identifying markers of colorectal cancer. PMID- 22207914 TI - Analysis of urinary exosomes to identify new markers of non-small-cell lung cancer. PMID- 22207915 TI - Medical bill problems steady for U.S. families, 2007-2010. AB - More than one in five Americans were in families reporting problems paying medical bills in 2010--about the same proportion as in 2007, according to a new national study by the Center for Studying Health System Change (HSC). Given the severe 2007-09 recession, the sluggish economic recovery and health care costs continuing to increase faster than incomes, it is somewhat surprising that the rate of medical bill problems did not increase between 2007 and 2010. The steady rate of medical bill problems may be a byproduct of decreased use of medical care -both by people who lost jobs and health insurance during the recession and others who cut back on medical care in the face of uncertain economic times. While problems paying medical bills stabilized in recent years, the proportion of Americans in families with medical bill problems remained significantly higher in 2010 compared with 2003--20.9 percent vs. 15.1 percent. And, in 2010, many people in families with problems paying medical bills continued to experience severe financial consequences, with about two-thirds reporting problems paying for other necessities and a quarter considering bankruptcy. PMID- 22207916 TI - Puzzles in Practice. Ebstein's anomaly. PMID- 22207917 TI - Determinants of vaccine supply. PMID- 22207918 TI - Can comparative effectiveness research help reduce health care costs? PMID- 22207919 TI - Merit function to design holographic gratings for moderate-resolution monochromators. AB - A merit function is proposed and applied to design holographic concave gratings for moderate-resolution monochromators. To justify the validity of the merit function, imaging properties of gratings used for the coma-correction Seya Namioka monochromator, designed by the present authors, Noda, and Takahashi, are compared through ray tracing and their aberration-correction mechanisms are also analyzed. The capability of the merit function is well demonstrated in the design of holographic gratings for another two moderate-resolution monochromators with different requirements. All the results obtained show that the merit function is not only straight and effective but also manages to balance various aberrations of the concave holographic grating very well. PMID- 22207920 TI - Factors related to prognosis of refractory glaucoma with diode laser transscleral cyclophotocoagulation treatment. AB - OBJECTIVE: To evaluate the predictive factors of refractory glaucoma treated with diode laser transscleral cyclophotocoagulation (TSCP) in a midterm observation. METHODS: Fifty-four consecutive patients (54 eyes) with refractory glaucoma were enrolled and underwent TSCP (power of 1.5-2.0 W, exposure time of 2 seconds and 20-50 applications). Patients were regularly followed up for 12 months. Intraocular pressure (IOP) was measured before TSCP treatment and at each follow up visit. Patients were divided into the sensitive and insensitive groups according to the effect of a single treatment of TSCP on IOP. The success rate was defined as the percentage of eyes achieving an IOP between 5 and 21 mm Hg following TSCP therapy at their final follow up visit. Difference of age between the sensitive and insensitive groups was evaluated with independent-samples T test and that of gender distribution of two groups was evaluated with Fisher's exact test. The success rate of different types of glaucoma to TSCP was calculated. RESULTS: A total of 32 patients were sensitive to TSCP (sensitive group) and 22 patients were insensitive to TSCP (insensitive group). The success rates of female (77.8%, 14/18) and cases being over 50 years (71.4%, 20/28) were higher than those of male (50.0%, 18/36) and ones being under 50 years (46.2%, 12/26) (all P>0.05). The age of the sensitive and insensitive groups was 56.0+/ 15.5 and 46.4+/-15.4 years, respectively (P=0.029). The age (P=0.029) and gender distribution (P=0.046) of the two groups had significant difference. The success rate of neovascular glaucoma, primary angle-closure glaucoma, primary open angle glaucoma, traumatic glaucoma, uveitic glaucoma, and secondary glaucoma after silicone oil injection to TSCP was 57.1%, 100.0%, 50.0%, 20.0%, 81.8%, and 0%, respectively. CONCLUSION: Age, gender, and type of glaucoma appear to be associated with effect of TSCP on IOP control. PMID- 22207921 TI - Time course of Q value after myopic laser-assisted in situ keratomileusis. AB - OBJECTIVE: To assess the time course of Q value after myopic laser-assisted in situ keratomileusis (LASIK) and preliminarily evaluate the determinants of the difference of Q value between before and after LASIK. METHODS: We performed a retrospective, longitudinal investigation on patients undergoing wavefront optimized LASIK therapy for emmetropization. A total of 418 eyes from 222 cases were examined preoperatively, and partly followed up at one week (172 eyes), one month (134 eyes) and three months (51 eyes) after surgery. The horizontal, vertical and total Q values of cornea were calculated from eccentricity measured at the central 6-mm corneal zones respectively. Potential determinants of the change of Q value were analyzed using multiple linear regressions. RESULTS: The mean Q value was -0.17 +/- 0.13 preoperatively, and 0.99 +/- 0.70, 0.97 +/- 0.66, and 0.86 +/- 0.41 one week, one and three months postoperatively, respectively. One way analysis of variance (ANOVA) demonstrated significant differences between measurements made before surgery and at all postoperative times (at one week, one and three months; all P<0.0001, Bonferroni post hoc), but no significant differences were found among postoperative groups. Significant differences of Q values between horizontal and vertical meridians were found before surgery and at all postoperative times (all P<0.0001). Multiple regression analysis revealed that change of Q value significantly correlated with manifest refraction spherical equivalent (r=0.116, P<0.0001) and axial length (r=0.264, P<0.0001). CONCLUSIONS: Over the study period, the primary changes in Q value occur within 1 week after surgery, and then become slightly decreased and nearly stable. Manifest refraction spherical equivalent and axial length play a significant role in the change of postoperative Q value. PMID- 22207922 TI - Effect of multiple coatings of one-step self-etching adhesive on microtensile bond strength to primary dentin. AB - OBJECTIVE: To investigate the effect of multiple coatings of the one-step self etching adhesive on immediate microtensile bond strength to primary dentin. METHODS: Twelve caries-free human primary molars were randomly divided into 2 groups with 6 teeth each. In group 1, each tooth was hemisected into two halves. One half was assigned to control subgroup 1, which was bonded with a single-step self-etching adhesive according to the manufacturer's instructions; the other half was assigned to experimental subgroup 1 in which the adhesive was applied three times before light curing. In group 2, the teeth were also hemisected into two halves. One half was assigned to control subgroup 2, which was bonded with the single-step self-etching adhesive according to the manufacturer's instructions; the other half was assigned to experimental subgroup 2 in which three layers of adhesive were applied with light curing each successive layer. Microtensile bond strength was immediately tested after specimen preparation. RESULTS: When the adhesive was applied three times before light curing, the bond strength of the experimental subgroup 1 (n=33, 57.49 +/-11.61 MPa) was higher than that of the control subgroup 1 (n=31, 49.71 +/-11.43 MPa, P<0.05). When using the technique of applying multiple layers of adhesive with light curing each successive layer, no difference of immediate bond strength was observed between the control subgroup 2 and the experimental subgroup 2 (P>0.05). CONCLUSION: strength to primary dentin when using the technique of light-curing after applying three layers of adhesive. PMID- 22207923 TI - Induction of endothelial cell apoptosis by anti-alpha-enolase antibody. AB - OBJECTIVE: To assess the prevalence of anti-alpha-enolase antibody in systemic autoimmune diseases in Chinese patients and its role in endothelial cell apoptosis. METHODS: The reactivity of anti-alpha-enolase antibody in a variety of autoimmune disorders in Chinese patients was evaluated by dot blot assay. Endothelial cell apoptosis was investigated by in vitro incubation of endothelial cells with IgG purified from anti-alpha-enolase antibody-positive sera, with or without pre-incubation with recombinant alpha-enolase. RESULTS: Anti-alpha enolase antibody was prevalent in different systemic autoimmune diseases with relatively high reactivity in Chinese patients. In vitro incubation of endothelial cells with IgG containing anti-alpha-enolase antibody induced apoptosis in a time- and dose-dependent manner. Apoptosis was partly inhibited by pre-incubation of the endothelial cells with recombinant alpha-enolase. CONCLUSIONS: Our data suggest that alpha-enolase is a common auto-antigen recognized by anti-endothelial cell antibodies in connective tissue disease. Interaction between alpha-enolase and its autoantibody plays a role in endothelial cell apoptosis. Changes other than cell killing may contribute to the pathogenesis of endothelial damage and microvascular lesions. PMID- 22207924 TI - Serum HIF-1alpha and VEGF levels pre- and post-TACE in patients with primary liver cancer. AB - OBJECTIVE: To investigate the expression levels of serum hypoxia inducible factor 1 alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) pre- and post transcatheter arterial chemoembolization (TACE) in patients with primary liver cancer (PLC), and correlations between prognosis factors and serum HIF-1alpha as well asVEGF levels. METHODS: Forty consecutive patients fulfilling diagnostic criteria for PLC undergoing TACE from March 2008 to May 2009 were enrolled into the study. The serum HIF-1alpha and VEGF levels of PLC patients pre- and 1 day, 1 week, 1 month post-TACE were analyzed using ELISA, and compared with that of 20 healthy volunteers. Patients were divided into complete response (CR) and partial response (PR), stable disease (SD), progressive disease (PD) groups according to the therapeutic efficacy. Pearson correlation was used to analyze the correlation between different clinical variables and serum HIF- 1alpha and VEGF levels before TACE, and correlation between serum HIF-1alpha and VEGF levels was also evaluated. RESULTS: The expression levels of serum HIF-1alpha and VEGF in PLC patients were 154.94 +/- 83.29 and 264.00 +/- 148.10 pg/mL pre-TACE, and both of them were significantly higher than those in control group (23.84 +/- 8.15 and 69.78 +/- 21.42 pg/mL, all P<0.01). One day after TACE, both serum HIF-1alpha (570.64 +/- 230.87 pg/mL) and VEGF levels (362.07 +/- 102.25 pg/mL) reached the peak values (all P<0.01). One week post-TACE, expression levels of them were decreased (198.62 +/- 92.11 and 283.52 +/- 145.46 pg/mL respectively), but still significantly higher than those before TACE (all P<0.01). The levels of both HIF 1alpha (133.96 +/- 57.02 vs. 255.74 +/- 123.44 pg/mL) and VEGF (150.96 +/- 84.89 vs. 368.95 +/- 161.90 pg/mL) in CR group 1 month post-TACE were significantly lower than those in PR+SD+PD group (all P<0.01). The level of serum HIF-1alpha was positively correlated with serum VEGF level (r=0.42, P<0.001). Both serum HIF 1alpha and VEGF levels were observed to be correlated with portal vein tumor thrombi (P<0.05) and metastasis (P<0.05). CONCLUSION: The HIF- 1alpha and VEGF might play an important role in relapse of PLC. They might be considered as predictors of the efficacy ofTACE and metastasis of PLC. PMID- 22207925 TI - Cytogenetic and clinical analysis of 340 Chinese patients with primary amenorrhea. AB - OBJECTIVE: To analyze the relationship between karyotypes and clinic features of patients with primary amenorrhea. METHODS: G banding was done for 340 patients with primary amenorrhea to facilitate individual chromosome identification, and if specific staining for certain portions of the chromosome was necessary, C banding was used. The clinical data were recorded by physical examination and ultrasound scanning. RESULTS: Karyotype analysis of the 340 patients revealed that 180 (52.94%) patients had normal female karyotypes and 160 (47.06%) patients had abnormal karyotypes. The abnormal karyotypes included abnormal X chromosome (150 patients), mosaic X-Y chromosome (4 patients), abnormal autosome (5 patients), and X-autosome translocation (1 patient). The main clinical manifestations in patients with primary amenorrhea were primordial or absent uterus (95.9%), invisible secondary sex features (68.8%), little or absent ovary (62.6%), and short stature (30.0%). The incidence of short stature in patients with X chromosome aberration (46%, 69/150) was significangly higher that in patients with 46, XX (9.44%, 17/180) as well as 46, XY (6.67%, 3/45; Chi square = 146.25, P=0.000). All primary amenorrhea patients with deletion or break-point at Xp1 1.1-11.4 were short statures. CONCLUSIONS: One of the main reasons of primary amenorrhea is choromosome abnormality, especially heterosome abnormality. It implies the need to routinely screen chromosomal anomalies for such patients. There might be relationship between Xp1 1.1-11.4 integrity and height improvement. PMID- 22207926 TI - Clinical characters of gastrointestinal lesions in intestinal Behcet's disease. AB - OBJECTIVE: To investigate the clinical features, diagnosis methods, therapeutic principles of intestinal Behcet's disease. METHODS: king Union Medical College Hospital from August 1998 to April 2010 were retrospectively analyzed. RESULTS: The clinical courses of patients with intestinal Behcet's disease were from 26 days to 33 years, and the average duration was 6.32 +/- 1.01 years. The appearance of extra-gastrointestinal symptoms was significantly earlier than that of gastrointestinal symptoms (7.35 +/- 1.39 years vs. 3.24 +/- 0.82 years, P<0.05). The predominant gastrointestinal manifestations were right lower quadrant pain (95.56%) and hematochezia or melena (40.00%). Misdiagnosis occurred in 17 cases. In patients without systemic medicine therapy before surgery, the incidence of postoperative infection of incision site and abdominal cavity was significantly higher than that in those undergoing systemic medicine therapy (80.00% vs. 0%, P<0.05). CONCLUSIONS: Because of the diversity of gastrointestinal manifestations, intestinal Behcet's disease is easily misdiagnosed. The systemic medical therapy before surgery could decrease the incidence of infection of incision and abdominal cavity. PMID- 22207927 TI - Diagnosis and treatment of primary adult renal sarcoma. AB - OBJECTIVE: To investigate the clinical characteristics of primary adult renal sarcoma. METHODS: A total of 1654 cases with adult renal tumors were treated during 1985 to 2009 in Peking Union Medical College Hospital. Of all, 17 cases were diagnosed as primary renal sarcoma and underwent radical nephrectomy. The clinical features of 17 such patients were retrospectively analyzed. RESULTS: The first symptom of 10 (59%) cases in all renal sarcomas was abdominal mass. The pathological diagnosis was leiomyosarcoma (7 cases), rhabdomyosarcoma (2 cases), malignant fibrous histiocytoma (2 cases), low-differentiated sarcoma (2 cases), chromophobe renal cell carcinoma coexisting with liposarcoma (1 case), fibrosarcoma (1 case), embryonic sarcoma (1 case) and leiomyosarcoma (1 case). One patient died of tumor thrombus of the inferior vena cava during surgery. Finally, 15 cases were regularly followed up for 4 to 60 months. Till now, 1 had tumor-free survival for 9 months, and the other 14 cases died 2-38 months after the operation with a median survival time of 18 (range, 5-60) months. The median survival time of leiomyosarcoma group was 28 (range, 11-60) months, and 2 cases of malignant fibrous histiocytoma died 4 and 8 months after the operation respectively. CONCLUSIONS: The primary renal sarcoma has the clinical symptom similar with advanced renal cell carcinoma and has poor prognosis. Leiomyosarcoma might have relative good prognosis. PMID- 22207928 TI - Influence of deleted in colorectal carcinoma gene on proliferation of ovarian cancer cell line SKOV-3 in vivo and in vitro. AB - OBJECTIVE: To elucidate the effects of the deleted in colorectal carcinoma (DCC) gene on proliferation of ovarian cancer cell line SKOV-3. METHOD: An exogenous recombinant eukaryotic expression vector pcDNA3.1(+)-DCC, containing human DCC cDNA coding sequences, was constructed and transfected into SKOV-3 cells (SKOV 3/DCC). The pcDNA3.1 (+) transfected cells (SKOV-3/Neo) and SKOV-3 cells were used as the positive and negative controls, respectively. Expressions of DCC mRNA and protein were analyzed by RT-PCR and immunocytochemical analysis, respectively. Cell growth was detected by soft agar colony formation assay and MTT assay. Flow cytometry and transmission electron microscopy were used to assess the effects of DCC on cell cycle distribution and ultrastructure, respectively. BALB/c mice were used to evaluate the effects of DCC on tumorigenicity in vivo. RESULTS: RT-PCR and immunocytochemical analysis revealed the exogenous DCC gene was successfully transfected into SKOV-3 cell lines and obtained permanent expression. The half maximal inhibitory concentration (IC50) of SKOV-3/DCC cells was significantly lower than that of SKOV-3 or SKOV-3/Neo cells (all P<0.05). DCC expression caused SKOV-3 cells to be arrested in G1 phase (78.0%), and electron microscopic analysis showed SKOV-3/DCC cells displayed typical morphological changes of apoptosis. Two mice xenografted with SKOV-3/DCC cells showed no tumor tumorigenecity. The tumor volume of BALB/c mice bearing SKOV-3/DCC cells (3.403 mm(3)) was smaller than that of SKOV-3 cells (9.206 mm(3)). CONCLUSION: DCC gene may play an important role in suppressing the growth of SKOV-3 cell line and inducing apoptosis. PMID- 22207929 TI - Sutureless intestinal anastomosis with a novel device of magnetic compression anastomosis. AB - OBJECTIVE: To explore the feasibility and efficiency of a novel magnetic compression anastomats (MCAs) in intestinal anastomosis. METHODS: A total of 36 male mongrel canines underwent intestinal anastomosis using traditional hand-sewn (n=18) or a novel MCAs (n= 18). We compared the anastomosis time, postoperative complications, bursting strength of anastomoses, gross appearance, and pathology between two groups at each timepoint of follow-up. RESULTS: The mean anastomosis time with MCAs was significantly less than that with hand-sewn (8.50 +/- 1.95 vs. 31.1 +/- 4.32 minutes, P<0.001). The blood stools and intussusceptions occurred in both groups during follow-up period. Only 1 mongrel canine receiving intestinal anastomosis by MCAs experienced anastomotic leakage. The average bursting pressure of anastomoses obtained from mongrel canines undergoing intestinal anastomosis by MCAs was significantly higher than that by traditional hand-sewn at 1 week's follow-up time (P<0.05). Gross appearance of the anastomoses constructed by MCAs was relatively smoother and flatter. Pathological evalution of anastomoses revealed that general inflammation was greater in hand sewn anastomoses than magnetic anastomosis. CONCLUSION: The magnetic compression anastomat is a safe and effective device of sutureless intestinal anastomosis in canine models. PMID- 22207930 TI - Sclerosing cholangitis after transcatheter arterial chemoembolization: a case report. PMID- 22207931 TI - Choroidal tuberculoma in an immunocompetent young patient. PMID- 22207932 TI - Amyloidosis of the unilateral renal pelvis, ureter and urinary bladder: a case report. PMID- 22207933 TI - [History and current review of basic research for prostate cancer]. PMID- 22207934 TI - [Application of basic research to the molecular diagnosis of prostate cancer]. PMID- 22207935 TI - [Application of basic research to the treatment of prostate cancer]. PMID- 22207936 TI - [Overview of the prostate cancer pathology]. PMID- 22207937 TI - [General rule for clinical/pathological studies on TNM classification of prostate cancer]. PMID- 22207938 TI - [Updated Gleason grading system and its significance]. PMID- 22207939 TI - [Diagnostic utility of immunohistochemistry for surgical pathology of the prostate]. PMID- 22207940 TI - [Mimickers of adenocarcinoma of the prostate]. PMID- 22207941 TI - [Mechanisms of carcinogenesis and proliferation in prostate cancer]. PMID- 22207942 TI - [Chemoprevention of prostate cancer]. PMID- 22207943 TI - [Role of androgen in prostate carcinogenesis]. PMID- 22207944 TI - [Lifestyle and prostate cancer]. PMID- 22207945 TI - [Genetic diagnosis of prostate cancer: overview]. PMID- 22207946 TI - [Oncogene and abnormality of tumor suppressor gene for prostate cancer]. PMID- 22207947 TI - [Genetic polymorphisms in prostate cancer]. PMID- 22207948 TI - [Promoter hypermethylation of genes in prostate cancer]. PMID- 22207949 TI - [MiRNA profiling in prostate cancer]. PMID- 22207950 TI - [Basic mechanisms of androgen-independent growth in the prostate cancer]. PMID- 22207951 TI - [Androgen receptor mutation]. PMID- 22207952 TI - [Alteration of androgen receptor cofactor in prostate cancer]. PMID- 22207953 TI - [Prostate cancer--the role of adrenal steroids]. PMID- 22207954 TI - [Upregulation of anti-apoptotic gene]. PMID- 22207955 TI - [Signal transduction pathways involved in progression to androgen-independent prostate cancer]. PMID- 22207956 TI - [Biomarker of prostate cancer--present status and future]. PMID- 22207957 TI - [Glycan marker for prostate cancer]. PMID- 22207958 TI - [Inflammatory cytokines]. PMID- 22207959 TI - [New marker proteins for prostate cancer]. PMID- 22207960 TI - [Prostate cancer biomarker search by genome analysis]. PMID- 22207962 TI - [Role of renin-angiotensin system and antitumor effect of ARB in prostate cancer]. PMID- 22207961 TI - [The trend toward development of novel agents based on the mechanism of prostate cancer progression]. PMID- 22207963 TI - [NF-kappaB inhibitor]. PMID- 22207964 TI - [Molecular targeted therapy for castration-resistant prostate cancer]. PMID- 22207965 TI - [Antisense oligonucleotide therapy for patients with castration-resistant prostate cancer]. PMID- 22207966 TI - [Peptide vaccine therapy]. PMID- 22207967 TI - [Epidemiology of prostate cancer in Japan]. PMID- 22207968 TI - [An international comparison of epidemiologic factors of prostate cancer]. PMID- 22207969 TI - [Natural history of prostate cancer]. PMID- 22207971 TI - [Prostate cancer screening in Japan: current status and perspective]. PMID- 22207970 TI - [Characteristics of hereditary and familial prostate cancer in Japan 2011]. PMID- 22207972 TI - [International trends and future perspectives on screening for prostate cancer]. PMID- 22207973 TI - [Mass screening program for prostate cancer in urban area of Kyoto]. PMID- 22207974 TI - [Action assignment of mass screening for prostate cancer]. PMID- 22207975 TI - [How to popularize the PSA screening for prostate cancer nationwide]. PMID- 22207976 TI - [Advancement of diagnosis of prostate cancer: general concept]. PMID- 22207977 TI - [Inquiry and physical examination (including digital rectal examination) for patients with prostate cancer]. PMID- 22207978 TI - [Usefulness of PSA test for diagnosis of prostatic cancer]. PMID- 22207979 TI - [PSA standardization; the past progress and some problems in the future]. PMID- 22207980 TI - [The efficacy of PSA related parameters]. PMID- 22207981 TI - [Usefulness of PSA isoform]. PMID- 22207982 TI - [Problems in PSA screening--distinction from false positives]. PMID- 22207983 TI - [Recent advances in the imaging of the prostate cancer]. PMID- 22207984 TI - [Transrectal ultrasound in the diagnosis of prostate cancer]. PMID- 22207985 TI - [Prostate MR imaging at 3 tesla]. PMID- 22207986 TI - [PET, PET-CT]. PMID- 22207987 TI - [Diagnostic imaging in bone metastasis from prostate cancer]. PMID- 22207988 TI - [Current status and issues of systematic biopsy of the prostate]. PMID- 22207989 TI - [Comparison of diagnostic efficacy among different approach in prostate biopsy]. PMID- 22207990 TI - [How many cores are to be taken at prostate biopsy?]. PMID- 22207991 TI - [Indication and signification of repeat biopsy of the prostate]. PMID- 22207992 TI - [Clinical staging of prostate cancer: the significance and the problem]. PMID- 22207993 TI - [An update of nomogram in predicting of the pathologic stage]. PMID- 22207994 TI - [Preoperative nomogram based on Japanese patients which predicts pathological stage on prostatectomy specimens]. PMID- 22207995 TI - [History and present status of the treatment of prostate cancer]. PMID- 22207996 TI - [Advancement in prostatectomy]. PMID- 22207997 TI - [Radical retropubic prostatectomy]. PMID- 22207998 TI - [Radical perineal prostatectomy]. PMID- 22207999 TI - [Laparoscopic radical prostatectomy]. PMID- 22208000 TI - [Minimum incision endoscopic radical prostatectomy]. PMID- 22208001 TI - [Extended radical prostatectomy]. PMID- 22208002 TI - [Robotic-assisted laparoscopic radical prostatectomy]. PMID- 22208003 TI - [Pelvic lymph node dissection in prostate cancer]. PMID- 22208004 TI - [Perioperative complications and management of radical prostatectomy]. PMID- 22208005 TI - [Assessment for improving continence after radical prostatectomy]. PMID- 22208006 TI - [Preservation of sexual function following radical prostatectomy]. PMID- 22208007 TI - [Recurrence diagnosis of prostate cancer after radical prostatectomy]. PMID- 22208008 TI - [Prognostic factors predicting for postoperative recurrence in prostate cancer]. PMID- 22208009 TI - [Significance of PSA nadir as a tool of predicting biochemical failure after radical prostatectomy for prostate cancer]. PMID- 22208011 TI - [Current situation and perspectives of radiation oncology]. PMID- 22208010 TI - [The optimal salvage therapy for biochemical recurrence after radical prostatectomy]. PMID- 22208012 TI - [Trends and future of external radiotherapy for prostate cancer]. PMID- 22208013 TI - [Intensity-modulated radiation therapy (IMRT)]. PMID- 22208014 TI - [Clinical significance and indication of androgen ablation therapy in radiation therapy for localized prostate cancer]. PMID- 22208015 TI - [Radiation therapy for locally advanced prostate cancer]. PMID- 22208016 TI - [Definition and issue of treatment failure with radiotherapy]. PMID- 22208017 TI - [Treatment option for locally and/or biochemically radiorecurrent prostate cancer]. PMID- 22208018 TI - [Acute and late toxicities and its management]. PMID- 22208019 TI - [Brachytherapy with permanent seed implantation]. PMID- 22208020 TI - [High-dose-rate brachytherapy for prostate cancer]. PMID- 22208021 TI - [PSA kinetics after prostate brachytherapy]. PMID- 22208022 TI - [Heavy charged particle radiotherapy]. PMID- 22208023 TI - [Proton radiotherapy]. PMID- 22208024 TI - [Current status and future prospects of endocrine therapy]. PMID- 22208025 TI - [LH-RH analogue]. PMID- 22208026 TI - [Antiandrogen]. PMID- 22208027 TI - [Maximally androgen blockade therapy]. PMID- 22208028 TI - [Antiandrogen withdrawal syndrome]. PMID- 22208029 TI - [Neoadjuvant hormonal therapy before radical prostatectomy]. PMID- 22208030 TI - [Adverse events of endocrine therapy for prostate cancer]. PMID- 22208031 TI - [Criteria and issues of PSA only relapse in hormonal therapy for prostate cancer]. PMID- 22208032 TI - [Alternative antiandrogen therapy for advanced prostate cancer]. PMID- 22208033 TI - [Recent outcome of intermittent androgen suppression for the prostate cancer]. PMID- 22208034 TI - [Dexamethasone therapy for castration-resistant prostate cancer]. PMID- 22208035 TI - [Androgen synthesis inhibitors and new androgen receptor antagonists]. PMID- 22208036 TI - [A history and current state of chemotherapy against prostate cancer]. PMID- 22208037 TI - [Oral antineoplastic agents for prostate cancer]. PMID- 22208038 TI - [Docetaxel for advanced prostate cancer]. PMID- 22208039 TI - [Docetaxel-based combination chemotherapy for castration-resistant prostate cancer]. PMID- 22208040 TI - [Chemo-hormonal therapy for prostate cancer]. PMID- 22208041 TI - [Gene therapy for prostate cancer: current status and future prospects]. PMID- 22208042 TI - [Gene therapy for the treatment of prostate cancer using osteocalcin promoter]. PMID- 22208043 TI - [Suicide gene and immuno gene therapy for prostate cancer]. PMID- 22208044 TI - [REIC/Dkk-3 gene therapy]. PMID- 22208045 TI - [Oncolytic virus therapy using herpes simplex virus 1(HSV-1)]. PMID- 22208046 TI - [Cryosurgery]. PMID- 22208047 TI - [Bisphosphonate against patients with hormone refractory prostate cancer]. PMID- 22208048 TI - [Palliative pain relief treatment for multiple bone metastases by strontium-89]. PMID- 22208049 TI - [Active surveillance for prostate cancer]. PMID- 22208050 TI - [Palliative medicine]. PMID- 22208051 TI - [QOL as an outcome of prostate cancer treatment]. PMID- 22208052 TI - [Quality of life during hormonal therapy for prostate cancer]. PMID- 22208053 TI - [Quality of life in patients who underwent retropubic radical prostatectomy]. PMID- 22208054 TI - [Essential effect of radical perineal prostatectomy on longitudinal alteration of QOL in patients with localized prostate cancer]. PMID- 22208055 TI - [QOL of laparoscopic radical prostatectomy]. PMID- 22208056 TI - [Health-related quality of life after radiotherapy]. PMID- 22208057 TI - [Isolation and characterization of prostate cancer stem cell]. PMID- 22208058 TI - [Mechanism of the development of osteoblastic bone metastasis of prostate cancer]. PMID- 22208059 TI - [New findings of clinical anatomy for radical prostatectomy]. PMID- 22208060 TI - [Significance of micrometastases in pelvic lymph nodes from patients with localized prostate cancer]. PMID- 22208061 TI - [Changes in the lower urinary tract function after radical prostatectomy]. PMID- 22208062 TI - [Current status of robot assisted radical prostatectomy in Japan]. PMID- 22208063 TI - [Trends of decision making for primary local therapy of prostate cancer: comparative analysis between Japan and foreign countries]. PMID- 22208064 TI - Local technicians in long-term research projects: evaluation of 25 years experience in an active tropical research station. AB - Most field ecology is conceived and financed by scientists from urban areas but is actually carried out in rural areas. Field staff can either be imported from urban areas or recruited from local residents. We evaluated the advantages and disadvantages of involving rural residents as local technicians over a 25- year period at active field research site in Costa Rica. We defined "local technicians" as local residents with no university education who acquired significant experience in field data collection, data management and/or laboratory work. We analyzed the experiences of incorporating these technicians into field research in developing countries from the points of view of scientist and of the local technicians themselves. Primary data were written responses from to a standardized survey of 19 senior scientists and Ph.D. students,and results from standardized personal interviews with 22 local technicians. Researchers highlighted the advantages of highly-skilled technicians with minimal staff turnover, as well as the technicians' knowledge of local ecological conditions. Local technicians considered the primary advantages of their jobs to be opportunities for continuing education training in science as well as cultural enrichment through interactions with people of different cultures. The main challenges identified by researchers were the lack of long-term funding for projects and extended training required for local technicians. Local technicians can be of great benefit to research projects by providing high-quality data collection at reasonable costs with low staff turnover. Over the last 25 years the research model at the field station we studied has evolved to the point that most long-term projects now depend heavily on local technicians. This model of involving local technicians in long-term research has multiple benefits for the researchers, the technicians and the local community, and could be adapted to a variety of settings in rural areas of developing countries. PMID- 22208065 TI - Giant eunicid polychaetes (Annelida) in shallow tropical and temperate seas. AB - Some species of Eunice might reach giant size, often being longer than 2m, and they are known from tropical and temperate seas. Despite their large size and recent internet notoriety, there remain some taxonomic problems in large-sized eunicids, especially since original descriptions were brief and type materials are often missing. As a mean to encourage the solution of this situation, we review the historical progress in the taxonomy of the group, including some comments on generic and specific delineation, and recommend some critical steps to solve the current confusion. These ideally would include collecting in type localities, evaluate ontogenetic morphological changes, and generate some molecular analysis to complement the morphological approach. PMID- 22208066 TI - The Bobbit worm dilemma: a case for DNA. PMID- 22208067 TI - [Molecular characterization and antimicrobial resistance of Clostridium perfringens isolates of different origins from Costa Rica]. AB - Clostridium perfringens, a Gram positive, spore-forming anaerobe, is widely distributed in nature. Based upon their production of four major toxins alpha, beta, epsilon and iota, C. perfringens is classified into five toxinotypes (A-E). Some strains produce an enterotoxin (CPE), encoded by the cpe gene, which causes diarrhea in humans and some animals. C. perfringens strains that had been previously isolated and been kept at -80 degrees C were analyzed for the presence of toxin genes and for antimicrobial resistance: 20 from soils, 20 from animal, 20 from human origin and 21 from food non related to outbreaks. According to PCR results, all strains were classified as C. perfringens type A, since only alpha toxin gene was detected, while cpe was detected in two strains (2.5%) isolated from food, as it has been described in other world regions. Antibiotic resistance to at least one antibiotic was detected in 44% of the strains, 41% was resistant to clindamycin, 25% to chloramphenicol, 22% to penicillin and 20% to metronidazole. Soils strains showed the highest resistance percentages to almost all antibiotics. Multiresistance (to three or more antibiotic groups) was detected in the strains from soil (40%), human origin (30%), food (14%) and animal origin (5%). The high resistance rates found may be explained by the widespread use of antimicrobials as growth promoters in plants and animals; also these resistant strains may act as reservoir of resistance genes that may be transferred between bacteria in different environments. PMID- 22208068 TI - Government conservation policies on Mexican coastal areas: is "top-down" management working? AB - Marine and terrestrial ecosystems are declining globally due to environmental degradation and poorly planned resource use. Traditionally, local government agencies have been responsible of the management of natural reserves to preserve biodiversity. Nonetheless, much of these approaches have failed, suggesting the development of more integrative strategies. In order to discuss the importance of a holistic approach in conservation initiatives, coastal and underwater landscape value and biological/environmental indicators of coral reef degradation were assessed using the study case of Zihuatanejo, Guerrero coastal area. This area shelters representative coral reef structures of the Eastern Pacific coast and its terrestrial biodiversity and archaeology enhance the high value of its coastal area. This study explored the landscape value of both terrestrial and marine ecosystems using the geomorphosite approach in two sites on the Zihuatanejo coastal area: Caleta de Chon and Manzanillo Beach. Sedimentation rate, water transparency, chlorophyll and total suspended solids were recorded underwater in each site for environmental characterization. 50 photo-quadrants on five transects were surveyed between 3-4m depth to record coverage (%) of living corals, dead corals, algae, sand and rocks. The conservation status of coral reefs was assessed by the coral mortality index (MI). Landscape values showed that both terrestrial and marine ecosystems had important scientific and aesthetic values, being Manzanillo Beach the site with the highest potential for conservation initiatives (TtV = 14.2). However, coral reefs face elevated sedimentation rates (up to 1.16 kg/m2d) and low water transparency (less of 5m) generated by coastal land use changes that have increased soil erosion in the adjacent coastal area. High coverage of dead corals (23.6%) and algae (up to 29%) confirm the low values in conservation status of coral reefs (MI = 0.5), reflecting a poorly-planned management. Current conditions are the result of "top down" conservation strategies in Zihuatanejo, as Federal and Municipal authorities do not coordinate, disregard local community in coral reef management, and ignore the intimate relationship between the coastal and marine realms. This work confirms the importance of conservation strategies with a holistic approach, considering both terrestrial and marine ecosystems in coastal areas; and that these initiatives should include local coastal communities in management and decision-taking processes done by government authorities. PMID- 22208069 TI - [Rhodomonas salina (Cryptophyta) pastes as feed for Brachionus plicatilis (Rotifera)]. AB - Rotifers are an important live feed for first feeding larvae of many fish species. The use of concentrated algae cells in the mass culture of the rotifer Brachionus plicatilis (Brachionidae) has opened new horizons for research on this organism. Pastes of Rhodomonas salina (Pyrenomonadaceae) obtained either by centrifugation or flocculation with chitosan were preserved, with or without vitamin C, at -20 degrees C for four weeks and were evaluated biochemically (proteins, lipids, pigments and fatty acids contents) and subsequently, were used to feed the rotifer Brachionus plicatilis at a ratio of 25 mg/L/day. Four different microalgae pastes were prepared: (1) centrifuged and preserved with vitamin C (CV), (2) centrifuged and preserved without vitamin C (C), (3) flocculated and with vitamin C (FV) and (4) flocculated without vitamin C (F). All treatments showed similar contents of proteins and total lipids with respect to control culture (a fresh culture of R. salina), with mean values of 40.0 +/- 2.32% and 12.0 +/- 1.45%, respectively. The pheophytin a/chlorophyll a ratio, a general indicator of the chemical status of microalgal concentrates, was similar (0.09-0.11) between centrifuged pastes and control culture, but was found to be higher in flocculated pastes (1.28-1.48). The fatty acid profile varied with respect to the control culture, mainly in the proportion of the essential polyunsaturated fatty acids (PUFAs): eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Total PUFAs, EPA and DHA contents were statistically similar between centrifuged pastes and control culture (PUFAs: 47%, EPA: 4% and DHA: 4.7%), whereas values obtained for flocculated pastes were significantly lower. The rotifers grew equally well when fed with centrifuged pastes or control culture (maximum density: 320 rotifers/mL; instantaneous growth rate: 0.23 rotifers/day, fecundity: 1.49 eggs/female and productivity: 43 x 10(3) rotifers/L/day. No significant effect of vitamin C was found when used as a paste preservative. We concluded that centrifugation is an effective harvesting method, and that freezing to -20 degrees C for four weeks (no vitamin added), may help maintain the nutritional quality of R. salina paste, similar to fresh microalgae and can be offered to Brachionus plicatilis. PMID- 22208070 TI - [Seasonal variation in proximate composition of mussels Tagelus peruvianus (Bivalvia: Solecurtidae) from the Gulf of Nicoya, Puntarenas, Costa Rica]. AB - Marine bivalves are a very important food source for human consumption, and species that has not been of traditional use as a fishery resource are gaining interest. Seasonal variation in proximate composition, condition index and energy or caloric content of the mussel Tagelus peruvianus were studied in the Gulf of Nicoya, Puntarenas, Costa Rica. From November 2007 to October 2008, a total of 35 to 40 specimens per month were collected. The proximate composition using the AOAC methods was determined. Results showed that the condition index during December, January and May decreased, indicative of two spawning periods and one gonadal resting phase. Soft tissues were respectively characterized by protein (61.9 +/- 4.3%), carbohydrates (15.7 +/- 2.4%), ash (14.0 +/- 1.9%) and lipids (8.5 +/- 1.7%). The average caloric content was 5.0 +/- 0.1 kcal/g. The results showed that the decrease in protein and fat percentage, and calories content, occurred during the spawning seasons. We suggest that T. peruvianus has an optimal nutritional value for human consumption because of the low-fat and moderate protein content. PMID- 22208071 TI - [Dana swimming crab growth Callinectes danae (Decapoda: Portunidae) from Margarita Island, Venezuela]. AB - Callinectes danae is a common species captured with crab traps in nearby areas of coastal lagoons in Margarita Island. Although its considerable economic importance as a fishery resource, few studies have been done on population dynamics and its fishery potential in local coastal environments to support decision making in fishery administration. We present growth pattern details of Callinectes danae to better estimate its population size and exploitation feasibility. For this, we analyzed a total of 3 623 specimens that were monthly captured in crab pots by artisanal fishermen in Las Marites lagoon, from October 2007 to September 2008. The length-weight ratio was determined, and growth parameters estimated from both length and weight curves of the von Bertalanffy model. The general sex ratio showed no significant difference between males and females (chi2 = 0.04, p > 0.05). However, values of slopes b between males and females were significantly different (t(s) = 2.75, p < 0.05), as well as intercepts a (t(s) = 2.44, p < 0.05). Thus, the length-weight ratio was determined separately: W = 7.48e(-5)*L(2.98) for males and W = 1.21e(-4)*L(2.87) for females, indicating a negative allometric growth in both sexes. Growth parameters were established as: L(infinity) =134.80mm, W(infinity) = 166.04g and k = 0.86/yr for males; L(infinity) = 122.35mm, W(infinity) = 118.45g and k = 0.63/yr for females. Lifespan was estimated at 3.05 years for males and 4.24 years for females. We concluded that Callinectes danae is a species with short lifespan and moderately rapid growth. The coefficient of variation values (CV), of the phi-prime growth performance index (O'), showed a different growth pattern compared to those obtained in other regions. We propose that a management strategy will be the periodical review of the minimum capture size for fishing area, after the great variability found in growth parameters. PMID- 22208072 TI - [Functional feeding groups of macroinvertebrates in Gaira river, Colombia]. AB - Tropical rivers are frequently described on their biodiversity but few studies have considered the ecological value of this richness in their food webs. We determined the trophic structure of aquatic macroinvertebrate communities (expressed in the richness and abundance of taxa and biomass proportions of different functional feeding groups) at the level of the river, stretch and microhabitats (functional units - UFs). We evaluated the spatial and temporal variation of these descriptors during wet and dry events, and selected three sites associated with different altitudinal belts. We reported 109 taxa, with 11167 individuals who contributed 107.11g of biomass. Density of macroinvertebrates was favored with increasing height, and biomass showed the opposite pattern (K-W = 10.1, d.f. = 1, p < 0.05), due to the addition of large crustaceans (Macrobrachium), and the taxa diversity was higher in the middle stretch of the river (H'=3.16). The Gaira stream runs through a mid-sized river basin, for this reason we found mainly bedrock (epilithon = 50.5%), gravel and sand (43.7%). The functional unit with more habitat and food resources that contains a higher abundance of leaf litter macroinvertebrates was foliage followed by epilithon, fine sediment and gravel-sand (K-W = 25.3, d.f. = 3, p < 0.05). The biomass values of these organisms were higher in leaves followed by gravel-sands, epilithon and sediment (K-W = 15.3, d.f. = 3, p < 0.05). Autochthonous biomass input by different functional feeding groups can be considered very low, but they define the functionality of the stream, being represented almost exclusively by shredders (Macrobrachium, 73%), present only in the lower reaches, followed by shredder Leptonema with 15%, located mostly in the upper reaches and predatory stoneflies of the genus Anacroneuria to 6.56%, which dominated in the middle stretch of stream. Excluding Macrobrachium from the analysis, there was dominance of Anacroneuria in the lower reaches. Between rainfall and drought events, biomass of functional feeding groups was higher in rain (W = 10.1, d.f. = 1, p < 0.05), favoring the growth of decapods, but the abundance was much higher during drought events. PMID- 22208073 TI - Oligoneuria macabaiba sp. nov. (Insecta: Ephemeroptera) from Brazil. AB - The former monotypic genus Oligoneuria Pictet was known solely by a female subimago of the type-species Oligoneuria anomala Pictet. A new species of the genus Oligoneuria from the Atlantic rainforest of Macae, Rio de Janeiro is described. The description was based in males and females imagos of Oligoneuria macabaiba sp. nov. caught with light traps. This species presents similar wing venation, abdominal posterolateral spines, as well as a membranous extension on anterior portion of the head as seen in the genus. Based on features of the new species, the genus is herein redefined. The species represents the first record of the genus from Southeastern Brazil. PMID- 22208074 TI - Diversity and distribution of Odonata (Insecta) larvae along an altitudinal gradient in Coalcoman mountains, Michoacan, Mexico. AB - Evaluating components of landscape diversity is essential for the implementation of efficient conservation strategies. We evaluated the diversity of Odonata larval assemblages from the Coalcoman mountains (CM), Michoacan, Mexico, and related it to local (site-level) habitat variables. Larvae were collected from shores, riffles and pools in five streams, counted and identified to species, twice per season during 2005. The Shannon Diversity Index (H'), Margalef's Richness Index (R), Simpson's Index as a dominance measure (D) and Pielou's Equitability (J) were used to describe the assemblages, and Renyi's Diversity Profiles were used to order diversity. A Bray-Curtis Similarity Index (BC) was used to evaluate beta diversity. Theoretical richness was estimated using non parametric and parametric methods. A Canonical Correspondence Analysis (CCA) was applied to explore the relationships of species with site-level environmental variables. A total of 12 245 larvae from 75 species, 28 genera and 8 families were recorded. Over all sites, the dominant species were Erpetogomphus elaps, Macrothemis pseudimitans and Argia pulla. The number of species per locality ranged from 18 to 36, and a high number of species (76%) occurred with relative abundances lower than 1%. A differential distribution of species and abundance in streams, time and strata was observed. Renyi's diversity profiles showed diversity was higher in spring and on shores. Most BC similarity values were smaller than 25%, indicating a high turnover rate in the CM. The high turnover rate reflects a differential distribution of the species along the altitudinal gradient, supporting the hypothesis of Mexico as a betadiverse country. According to the slope of Clench's curve, a reliable list of species was gathered. The CM larval assemblage is currently the largest reported for Mexico, and our results support previous proposals of the CM as a species-rich area for conservation. PMID- 22208075 TI - [Postembryonic development, fecundity and food consumption of Dichroplus exilis (Orthoptera: Acrididae) under controlled conditions]. AB - Dichroplus exilis is a widely distributed species in Southern South America. Although there have been reports of D. exilis as an agricultural pest, some recent observations suggest that the damage attributed to D. elongatus may actually have been caused by D. exilis. This study was conducted to determine the postembryonic life cycle stages, fertility and food consumption of this species under controlled conditions (30 degrees C, 14L-10D, 40% RH). Individuals employed belong to the laboratory-hatched first generation (F1), from adults (n = 64, female = 28, male = 36) collected in natural grasslands near Rafaela, Santa Fe province in North-Eastern Argentina. Three cohorts of 16, 17 and 20 individuals were monitored independently in acetate tubes on a daily basis, until death of the last insect. Average fecundity was 381.84, 38.54 eggs per female. Egg-pod incubation time was 14.4, 1.08 days and six nymphal instars were recorded. Nymphal development time was 41.38, 0.71 days (I = 8.73, 0.20; II = 6.38, 0.24; III = 5.64, 0.33; IV = 7.15; 0.43; V=9.76, 0.54; IV = 7.85, 0.95). The recorded food consumption was 9.89, 1.08 (mg/ind/day) for nymphs IV, 18.04, 0.73 (mg/ind/day) for nymphs V-IV, 16.76, 1.06 (mg/ind/day) for pre-reproductive males, 28.09, 1.81 (mg/ind/day) for pre-reproductive females, 7.71,0.91 (mg/ind/day) for reproductive males and 13.06, 0.71 (mg/ind/day) for reproductive females, while the average adult food consumption, regardless of sex and reproductive status, was 16.41, 4.32 mg/day. Average food consumption of adult females was 17.47, 1.15 mg, and was significantly higher than that of males (10.83, 0.91mg). Data obtained in this study showed that D. exilis exhibits at least some of the biological attributes needed to configure an actual or potential agricultural pest, albeit not yet recognized as such. Field monitoring of grasshopper communities in areas where damage by D. exilis is suspected is envisaged in order to determine its possible status as a pest. PMID- 22208076 TI - Diversity of galling insects in Styrax pohlii (Styracaceae): edge effect and use as bioindicators. AB - Impacts of forest fragmentation and edge effect on plant-herbivores interactions are relatively unknown, and the relationships between galling insects and their host plants are very susceptible to environmental variations. The goal of our study was to test the edge effect hypothesis for galling insects associated with Styrax pohlii (Styracaceae) host plant. Samplings were conducted at a fragment of semi-deciduous forest in Goiania, Goias, Brazil. Thirty host plant individuals (15 at fragment edge and 15 in its interior) were sampled in July of 2007; in each plant, 10 apical branches were collected at the top, middle and bottom crown levels. Our results supported the prediction of greater richness of gall morphotypes in the edge habitat compared with remnant interior. In a similar way, gall abundance and frequency of attacked leaves were also greater in the fragment edge. These findings consequently suggest a positive response of galling insect diversity to edge effect; in the Saint-Hilaire forest, this effect probably operates through the changes in microclimatic conditions of edge habitats, which results in an increased hygrothermal stress, a determinant factor to distribution patterns of galling insects. We also concluded that these organisms could be employed as biological indicators (i) because of their host-specificity, (ii) they are sensitive to changes in plant quality, and (iii) present dissimilar and specific responses to local variation in habitat conditions. PMID- 22208077 TI - Size, age and composition: characteristics of plant taxa as diversity predictors of gall-midges (Diptera: Cecidomyiidae). AB - Many hypotheses have been proposed to explain the diversity of gall-midge insects (Diptera: Cecidomyiidae), some of them taking into account plant diversity. This study aims to test the importance of size, age and composition of host plant taxa in the diversity of Cecidomyiidae. For this we used inventories data on the diversity of galling and host plants in Brazil. We found that Asterales, Myrtales and Malpighiales, were the most important orders, with 34, 33 and 25, gall morphotypes, respectively. The most representative host families were Asteraceae (34 morphotypes), Myrtaceae (23) and Fabaceae (22). In general, the order size and the plant family were good predictors of the galling diversity, but not the taxon age. The most diverse host genera for gall-midges were Mikania, Eugenia and Styrax, with 15, 13 and nine galler species, respectively. The size of plant genera showed no significant relationship with the richness of Cecidomyiidae, contrary to the prediction of the plant taxon size hypothesis. The plant genera with the greatest diversity of galling insects are not necessarily those with the greatest number of species. These results indicate that some plant taxa have a high intrinsic richness of galling insects, suggesting that the plant species composition may be equally or more important for the diversity of gall-midges than the size or age of the host taxon. PMID- 22208078 TI - [Abundance and distribution of Aedes aegypti (Diptera: Culicidae), and dengue dispersion in Guasave Sinaloa, Mexico]. AB - Dengue is an important disease that affects humans, and is transmitted by A. aegypti. During 2006, a total of 477 cases of hemorrhagic dengue, and 1 510 of classic dengue were recorded in Sinaloa. Due to this high impact, a study on insect abundance and distribution, as well as their relationship with dengue dispersion, was carried out from April 2008 to March 2009 in Guasave, Sinaloa. The study included a total of six sectors in the city, considering 16 colonies; besides, 96 traps were distributed in these sectors to monitor the vector population density and female number per trap. The adult density index (ADI) and traps positive index (TPI) were calculated, and data were used to obtain the monthly dengue dispersion maps. The highest abundance of female (137 and 139) was found in July and August. In August and September the sectors 2, 4 and 6 showed the highest ADI values 2.44, 3.35 and 2.290, while TPI values were 56.25, 58.82 and 61.54, with the highest epidemiology dengue dispersion. The Pearson correlation (p < 0.05) showed better values with the precipitation (r = 0.80) than mean temperature (r = 0.76) with zero lag months; while the cases of classic dengue and hemorrhagic dengue (CD/HD) is mostly related with the precipitation (r = 0.98), and minimum temperature (r = 0.79), with two lag months. In conclusion, the ADI and TPI index, as well as the maps obtained, allowed us to know the location of epidemiologic dengue risk areas. This information can be used to develop better control measures biological and chemical for the mosquito, in this location. PMID- 22208079 TI - Five new species of the genus Sphelodon (Hymenoptera: Ichneumonidae) from Brazil with a key to the Neotropical species. AB - The parasitoid wasp family Ichneumonidae currently includes approximately 37 subfamilies worldwide. Banchinae subfamily is a cosmopolitan group with three tribes: Atrophini, Banchini and Glyptini, this last characterized with oblique grooves on tergites II-IV, a dorsal subapical notch on the ovipositor, and a median apical impression in the subgenital plate. From the latter tribe, the genus Sphelodon, with eight species reported, can be recognized for the presence of a prominent basolateral tooth in the first abdominal tergite. Significant previous comprehensive studies for that group have been done in Costa Rica by local and international experts, but it is highly probable that many species remain undescribed in the region; before this survey, only one species (S. annulicornis) was registered from Brazil. The material reviewed in this study was obtained from main entomological collections of Southeast and South Brazil, from localities corresponding to 17 of the 27 States of the country, although most of the specimens (70.3%) were collected in Sao Paulo State. Approximately 3 000 specimens of the subfamily have been examined, 29 belonging to Sphelodon. The description format in this work broadly follows previous works; the species were illustrated through SEM in low vacuum mode (without uncoated the specimens). Here five new species of the genus Sphelodon are described and illustrated, one of these (S. brunicornis), differs from the rest of the species by lacking a median band in the flagellum. An identification key to the Neotropical species is provided. PMID- 22208080 TI - Ground-foraging ants (Hymenoptera: Formicidae) and rainfall effect on pitfall trapping in a deciduous thorn woodland (caatinga), Northeastern Brazil. AB - The semi-arid Caatinga is the fourth largest biome of Brazil, which biota still remains one of the most poorly known, especially with regard to invertebrate groups. In this study, a ground-foraging ant assemblage was surveyed during one year and the effect of rainfall on pitfall trapping was assessed. The study was performed in an area located in the municipality of Pentecoste (3 degrees 48' S - 39 degrees 20' W), in the State of Ceara. A 200m transect with 20 equidistant sampling points was established. Transect sampling was performed once a month during 12 months, over the period August 2008-August 2009. At each sampling point, a pitfall trap partially filled with a mixture of ethanol and monoethylene glycol was placed at the beginning of each month and remained in the field for seven days. 39 species belonging to six subfamilies and 19 genera, plus two unidentified species, were collected, with Pheidole (10 spp.) and Camponotus (8 spp.) being the taxa with the most species. 23 species were frequent, being found in more than 50% of the 12 transect samplings. Five species had an intermediate frequency (25 to 50%), while 13 were relatively infrequent (less than 25%). Most of the species (22) showed low occurrence, being found in less than 10% of the 240 samples (20 samples each month, during 12 months). Only five species were collected in more than 50% of the samples, those species being also responsible for most of the total abundance (number of captured individuals of all species) observed each month. The species-accumulation curves (observed and estimated) indicated that sampling sufficiency was attained, and that about 92% of the estimated ground-foraging ant fauna had been collected. 40 and 29 species were collected in the dry and rainy season, respectively, with monthly species richness ranging from 13 to 28. The total ant abundance showed a drastic decrease during the rainy season, and a negative linear correlation was found between rainfall and total ant abundance (R2 = 0.68). A similar negative linear correlation was found for species occurrences against rainfall (R2 = 0.71), and for mean number of species per pitfall trap against rainfall (R2 = 0.71). However, some species showed equal abundance, occurrence and mean number of individuals per pitfall trap in both seasons, while others showed a much higher abundance and occurrence during the rainy season. Pitfall trapping as a method to sample ground-foraging ant assemblage of the Caatinga biome and potential factors responsible for lower pitfall trap performance during rainy season are discussed. PMID- 22208081 TI - [Effect of spiders (Arachnida: Araneae) as predators of insect pest in alfalfa crops (Medicago sativa) (Fabaceae) in Argentina]. AB - Spiders are predators that reduce insect pest populations in agroecosystems. Trials were conducted to measure the selectivity against different insect preys, the daily consumption, effect of predators alone and together with a known number of preys, and the indirect effect of predators on vegetation. For this, experimental units (1 x 1m) were used covered with a fine plastic mesh. Misumenops pallidus, Oxyopes salticus and Araneus sp. were used as generalist predators, and aphids, weevils, locusts, chrysomelids and Lepidoptera larvae as their potential preys. Among the preys offered, the spiders preferred Lepidoptera larvae compared to the other two pests groups (weevils and aphids). The maximum consumption rate was of 93.33% for Lepidoptera larvae, 25.33% for aphids and 11.67% for weevils. The Q Index values for the three species of spiders showed a positive selectivity only for defoliating larvae. O. salticus showed the highest values of consumption rates while Rachiplusia nu was the most consumed. The maximum value of consumption in 24 hours was showed by O. salticus on R. nu (C) = 2.8. The association of several species of predatory spiders increased the total number of insects captured, and also showed that the addition of spiders caused a decrease in the number of leaves damaged by the effect of lepidopterous larvae. PMID- 22208082 TI - A new fish species of Roeboides from Panama (Characiformes: Characidae). AB - A freshwater fish Roeboides loftini n.sp. is described from the Rio Cocle del Norte drainage of the Atlantic versant of Panama. The new species differs from other species of the Roeboides guatemalensis-group by the number of perforated scales on the lateral line (83-100), body depth (31.8-36.1%), predorsal distance (49.1-51.9%) and the shape of the humeral spot. PMID- 22208083 TI - Seasonal diet composition of Fundulus lima (Cyprinodontiformes: Fundulidae) in two oasis systems of Baja California Sur, Mexico. AB - Fundulus lima inhabits river drainage systems and is threatened after the introduction of cichlids in the area. To support conservation programs, the spatial and temporal variation of the diet composition of this endangered killifish, was determined in two oasis systems of Baja California Sur, Mexico (San Ignacio and La Purisima river drainages), during rainy and dry seasons. F. lima was captured by using passive and active capture techniques. A total of 192 stomach contents of F. lima was analyzed. The contribution of each prey item in the diet composition was quantified by means of the indices of occurrence frequency (% OF), numerical (% N) and volume (% V) percentages. The relative importance of each prey item was determined according to the percentage of the Relative Importance Index (% RII). The similarity of the diet was calculated between hydrological basins (populations combined by basin), seasons (rainy versus dry months), sexes and size classes, by using Schoener's resource overlap index. We used two ecological indices to determine the type of feeding strategy exhibited by the fish: (1) niche breadth of Levins and (2) proportional similarity of Feisinger. Sand was the most abundant item in the stomach content of killifishes from both drainages (39% and 47%, respectively). Diet composition was similar for both drainages (74%) as well as among their respective size classes; however, it was different between sexes. In both drainages, F. lima predated mainly on diatom algae, dipterous and trichopteran larvae, and fish scales during the dry season; while it preferred dipterous larvae, filamentous algae and ostracods in the rainy season. A feeding strategy of opportunist type was exhibited by F. lima during the rainy season, changing to specialist type during the dry season. This information will be the basis for future investigations related to the conservation of this endangered species and its habitat. PMID- 22208084 TI - [Larval development of Hypsophrys nicaraguensis (Pisces: Cichlidae) under laboratory conditions]. AB - The cichlid Hypsophrys nicaraguensis is a popular fish known as butterfly, and despite its widespread use as pets, little is known about its reproductive biology. In order to contribute to this knowledge, the study describes the relevant larval development characteristics, from adult and larval cultures in captivity. Every 12h, samples of larvae were collected and observed under the microscope for larval stage development, and every 24h morphometric measurements were taken. Observations showed that at 120h, some larvae had swimming activity and the pectoral fins development was visible; at 144h, the dorsal fin appear and all larvae started food intake; at 168h, the formation of anal fins begins, small rudiments of pelvic fins emerge, the separation of caudal fin from anal and dorsal fins starts, and the yolk sac is reabsorbed almost completely; at 288h, the pelvic fins starts to form; at 432h, the rays and spines of dorsal and anal fins can be distinguished, both the anal and the dorsal fins have the same number of spines and rays as in adults. After 480h larvae have the first scales, ending the larval stages and starting the transformation to fingerlings. Larvae were successfully fed with commercial diet. PMID- 22208085 TI - Changes in the fish community of the Kpong Headpond, lower Volta River, Ghana after 25 years of impoundment. AB - The Kpong Headpond was the second created on the Volta River after Akosombo Dam, primarily as a source of hydroelectric power generation and potable water supply, and additionally, it has supported some fish production in Ghana since impoundment. The changes in fish community of the Kpong Headpond were studied to provide baseline information for strategies formulation to support the socio economic development of the reservoir. The study identified changes in the fish community of the reservoir by comparing occurrence, composition, relative abundance and relative importance estimates of fish species, families and trophic groups, from available previous studies in the reservoir. From the collated information all fishes identified in the reservoir were categorised based on occurrence and importance as disappeared, appeared, permanent, declined or important, to show current status. The results indicated that the fish community has experienced a shift in the composition and relative abundance of important species, families and trophic groups in terms of number and weight, while remaining ecologically balanced. Representatives of the families Osteoglossidae, Centropomidae and Characidae have declined while representatives of the families Claroteidae, Cyprinidae and Cichlidae have increased. The aufwuch-detritus and herbivores declined while semi-pelagic omnivores increased resulting in a shift in dominance to benthic and semi pelagic omnivores. The appearance of five species and the disappearance of 25 others indicated a dynamic restructuring of the fish community in the reservoir, as expected. Enforcement of fishing regulations including the use of appropriate gear and fishing methods, fishery access control, promotion of culture-based fisheries and improvement in fisher education are recommended topics for sustainable fisheries in the reservoir. PMID- 22208086 TI - Prey selection by two benthic fish species in a Mato Grosso stream, Rio de Janeiro, Brazil. AB - Key to understand predator choice is the relationship between predator and prey abundance. There are few studies related to prey selection and availability. Such an approach is still current, because the ability to predict aspects of the diet in response to changes in prey availability is one of the major problems of trophic ecology. The general objective of this study was to evaluate prey selection by two species (Characidium cf. vidali and Pimelodella lateristriga) of the Mato Grosso stream, in Saquarema, Rio de Janeiro, Brazil. Benthos and fishes were collected in June, July and September of 2006 and January and February of 2007. Fish were collected with electric fishing techniques and benthos with a surber net. Densities of benthic organisms were expressed as the number of individuals per/m2. After sampling, the invertebrates were fixed in 90% ethanol, and, in the laboratory, were identified to the lowest taxonomical level. Approximately, seventy individuals from each species were selected randomly in each month. Fishes were fixed in 10% formalin in the field and transferred to 70 degrees GL ethanol in the laboratory. Fishes had their stomachs removed for subsequent analysis. Fish diet was described according to the numeric frequency method. The Manly Electivity Index was applied in order to verify prey selection. The most abundant families in both benthos and diet of both fish species were the same, indicating that these species consume mainly most abundant prey in the environment. We concluded that prey selection occurs even for preys that had small abundance in the environment. However, it is the availability of the macroinvertebrate resources that determines the major composition of items in diet of fish, demonstrating that the abundance is the factor that most influences the choice of prey. PMID- 22208087 TI - Age, growth and mortality of Clarias gariepinus (Siluriformes: Clariidae) in the Mid-Cross River-Floodplain ecosystem, Nigeria. AB - Clarias gariepinus is a threatened highly prized species used for some elite ceremonies by the local communities. Artisanal fishers take advantage of this species annual breeding migration from the lower Cross River to the floodplain lakes in Mid-Cross River during the rainy season, and some migrant stocks are not able to spawn. Since there is a lack of information on this species population dynamics in the Mid-Cross area, this study aimed to evaluate the age, growth and mortality to support the development of effective management plans. For this, monthly overnight gill net catches (from 6 to 72mm mesh sizes) were developed between March 2005 and February 2007. Growth parameters were determined using the FiSAT II length-frequency distribution. A total of 1 421 fish were collected during the survey. The asymptotic growth (L(infinity)) was 80.24cm, growth rate (K) was 0.49/year while the longevity was 6.12 years. The annual instantaneous rate of total mortality (Z) was 2.54/year and the natural mortality (M) was 0.88. Fishing mortality (1.66/year) was higher than the biological reference points (F(opt) = 0.83 and F(limit) = 1.11) and the exploitation rate (0.66) was higher than the predicted value (E(max) = 0.64) indicating that C. gariepinus was over exploited in the Mid-Cross River-Floodplain ecosystem. Some recommended immediate management actions are to strengthen the ban of ichthyocide fishing, closure of the floodplain lakes for most of the year, restricted access to the migratory path of the fish during the flood period and vocational training to the fishers. In order to recover and maintain a sustainable harvest, I suggest that a multi sector stakeholder group should be formed with governmental agents, community leaders, fishers, fisheries scientists and non-governmental organizations. These short and long term measures, if carefully applied, will facilitate recovery of the fishery. PMID- 22208088 TI - [Reproduction of Joturus pichardi and Agonostomus monticola (Mugiliformes: Mugilidae) in rivers of the Sierra Nevada de Santa Marta, Colombia]. AB - The freshwater mugilids Joturus pichardi and Agonostomus monticola, have been documented on ecological and distribution aspects, mainly for Central American populations, nevertheless, little information is available on their reproductive aspects, specifically in Colombian freshwater environments. Reproductive biology of the mugilids J. pichardi and A. monticola from Sierra Nevada de Santa Marta (SNSM) rivers was studied between July 2005 and December 2006. A total of 14 specimens of J. pichardi and 320 of A. monticola were collected. The reproductive biology was analyzed by means of: sexual proportion, gonadosomatic index, and mean size at maturity, fecundity and oocyte diameter. Additionally, a bioassay was carried out to evaluate the effect of salinity on spermatic motility and its possible relationship with the species' spawning area. These mugilids share habitats with similar ecological characteristics, in which strong currents; clear water and stony areas stand out. Gonadal maturity indicators and indirect evidence are presented to support the relationship between reproductive maturity and higher rainfall levels in the area (September, October and November), as well as the catadromous migration of J. pichardi and A. monticola. This last species females outnumbered males with a sex ratio of 2.3:1. Females mean size at maturity was 172mm of their total length (TL) and 108mm TL for males. Fecundity (F) was 23 925 +/- 4 581 eggs per gram of gonad, and was related to size by the equation F = 395.1TL(1.281); besides, the mean oocyte diameter was 362 +/- 40 microm. Considering the salinity effect on sperm motility in both species, results suggested that J. pichardi spawned in estuarine environments but the species did not migrate to fully marine environments; however, A. monticola withstood a broad range of salinity, suggesting a spawning from intermediate to total saline environments. Both species have high culturing potentials, considering that their feeding is based on plant and macroinvertebrates, their meat quality and the size they are able to reach. These species represent an interesting resource to the fisher groups of the region and should be integrally assessed. PMID- 22208089 TI - [Chemical composition of eggs of the Olive Ridley Lepidochelys olivacea (Testudines: Cheloniidae) and it's potential as a food source]. AB - The Olive Ridley is a worldwide distributed species with high nesting production per season, and in La Escobilla Oaxaca, Mexico, there is a 70% of non-hatched eggs that are lost. In order to evaluate their potential use as a source for human and animal food products, their chemical composition was analyzed. Lyophilized egg samples from 25 turtles were obtained and were analyzed following the analytical methods for fatty acids, protein, fat, ash, moisture, amino acids, vitamins, cholesterol and microbiological agents. The analytical composition obtained was (g/100g): moisture (4.7), ash (3.8), protein (53.7), and fat (47.4). The essential amino acid (g aa/100g protein) content was: Ile (4.4), Lys (6.6), Leu (7.4), Met+Cys (8.8), Phe+Tyr (10.8). The vitamin content was: retinol (340 microg/100g), cholecalciferol (5.91 microg/100g) and 8.6 mg/100 tocopherol, 0.3 mg/100g thiamine and 1.1 mg/100g riboflavin. The total lipid content (TL), fatty acids (FA), and cholesterol (Chol) were divided into three groups based on the weight of the turtle: (TL) (44.3-48.7-49.1g/100g) and (Chol) (518.4-522.5 mg/100g 728.7). A total of 17 Saturated FA (SFA), 8 Monounsaturated FA (MUFA) and 11 Polyunsaturated FA (PUFA) were identified. The most abundant SFA (mg/100g) were: C14:0 (445-772), C16:0 (485-1263); MUFA: C16:1 (456-716), C18:1n-9c (904-1754), and PUFA: C20:4n-6 (105-217); two n-3 fatty acids were identified EPA (48-103) and DHA (97-189).There were significant differences (Fisher, p < 0.05) for: (Chol), total FA, SFA, MUFA, PUFAs and n-3 (EPA + DHA) FA. It was not detected any microbiological agent. In conclusion, lyophilized L. olivacea eggs are an option for its inclusion in the development of food products as they can be used as a high quality biological protein and n-3 fatty acid source for fortification and enrichment. PMID- 22208090 TI - Temporal and spatial resource use by female three-toed sloths and their young in an agricultural landscape in Costa Rica. AB - The information on ecological behavior of wild sloths is very scarce. In this study we determined the home ranges and resources used by three adult female three-toed sloths (Bradypus variegatus) and their four young in an agricultural matrix of cacao (Theobroma cacao), pasture, riparian forests and living fencerows in Costa Rica. Births occurred during November-December and the young became independent at five to seven months of age. Initially, mothers remained fixed in one or a few trees, but expanded their use of resources as young sloths became independent from them. Mothers initially guided the young to preferred food and cover resources, but they gradually left their young in small nucleus areas and colonized new areas for themselves. Home range sizes for young sloths (up to seven months of age) varied between 0.04-0.6 hectares, while home range sizes for mothers varied from 0.04-25.0 hectares. During the maternal care period, 22 tree species were used, with the most common being Cecropia obtusifolia (30.9%), Coussapoa villosa (25.6%), Nectandra salicifolia (12.1%), Pterocarpus officinalis (5.8%) and Samanea saman (5.4%). However, young sloths used only 20 tree species, with the most common being C. villosa (18.4%), S. saman (18.5%) and N. salicifolia (16.7%). The cacao agroforest was used only by mother sloths and never by their young following separation. However, in the riparian forest, both mother sloths and young used the tree species. A total of 28 tree species were used by the mother sloth; including the food species: C. obtusifolia, C. villosa, N. salicifolia and P. officinalis. However, the young used 18 trees species in this habitat with N. salicifolia and S. saman most commonly used, although they rested and fed during the day in C. obtusifolia, C. villosa and O. sinnuata. The cacao agroforest with adjacent riparian forests and fencerows provides an important habitat type that links the smaller secondary forests and other patches. PMID- 22208091 TI - [Bats (Chiroptera: Mammalia) from Yurubi National Park, Venezuela: taxonomic list and community study]. AB - Bats represent a key component in the dynamics of many terrestrial ecosystems, and one of the groups of mammals with the highest levels of diversification in the Neotropics. Here we describe the results of a study of the bat fauna from Yurubi National Park (mountain area in Northern Venezuela), that includes a taxonomic list and the characterization of some community attributes in forested areas. Data was collected from zoological collections and diversified sampling methods from February to July of 2009 in an altitudinal gradient (100-1 500m), with three principal ecological units: semideciduous, evergreen and cloud forests. We recorded 64 species grouped in five families (63% of the bats known from La Cordillera de la Costa), of which Phyllostomidae was the dominant taxa (42 species; 66% of total), followed by Vespertilionidae, Molossidae, Emballonuridae and Mormoopidae. The community with the highest taxonomic diversification was found in the lowest elevation range, while the lowest number of species was found at the highest range. Eleven trophic guilds were identified; the insectivorous guild was the richest, whereas the frugivorous was the most abundant. Our results allow us to indicate these forest ecosystems have an appropriate conservation status, taking into account the presence of a relatively high proportion of species from the subfamily Phyllostominae, as well as the presence of other species with conservation priorities. All these aspects, and the fact that this represents a reservoir of the biological diversity of the forest ecosystems of La Cordillera de la Costa, make this protected area of an essential conservation value, in a highly endangered bioregion by neighboring socio-economic growth. PMID- 22208092 TI - [Genetic structure of a group of capybaras, Hydrochoerus hydrochaeris (Rodentia: Hydrocheridae) in the Colombian Eastern Llanos]. AB - The capybaras are the biggest rodents in the world but, however, there are not extensive population genetics studies on them. In the current work, we studied the genetic structure of a troop of 31 capybaras (Hydrochoerus hydrochaeris) sampled in Hato Corozal, Casanare Department at the Colombian Eastern Llanos, by means of five microsatellite markers. The gene diversity was 0.61 and the average allele number was 5.2, which is a medium-low level for markers of this nature. Out five markers employed, three were in Hardy-Weinberg equilibrium meanwhile one showed a significant homozygote excess and other presented a significant heterozygote excess. There were not significant genetic differences between males and females inside this troop. The application of different procedures to determine possible historical demographic changes (population expansions or bottlenecks) clearly showed that the population analyzed crossed over a very narrow recent bottleneck. The illegal hunt is the possibly cause of this strong genetic bottleneck. PMID- 22208093 TI - A new hypothesis for the importance of seed dispersal in time. AB - Most studies on seed dispersal in time have focused on seed dormancy and the physiological triggers for germination. However, seed dispersed by animals with low metabolic and moving rates, and long gut-passage times such as terrestrial turtles, could be considered another type of dispersal in time. This study tests the hypothesis that seeds dispersed in time may lower predation rates. We predicted that seeds deposited below parent trees after fruiting fall has finished is advantageous to minimize seed predators and should show higher survival rates. Four Amazonian plant species, Dicranostyles ampla, Oenocarpus bataua, Guatteria atabapensis and Ocotea floribunda, were tested for seed survival probabilities in two periods: during fruiting and 10-21 days after fruiting. Experiments were carried out in two biological stations located in the Colombian Amazon (Caparu and Zafire Biological Stations). Seed predation was high and mainly caused by non-vertebrates. Out of the four plant species tested, only Guatteria atabapensis supported the time escape hypothesis. For this species, seed predation by vertebrates after the fruiting period increased (from 4.1% to 9.2%) while seed predation by non-vertebrates decreased (from 54.0% to 40.2%). In contrast, seed predation by vertebrates and by non-vertebrates after the fruiting period in D. ampla increased (from 7.9% to 22.8% and from 40.4% to 50.6%, respectively), suggesting predator satiation. Results suggest that for some species dispersal in time could be advantageous to avoid some type of seed predators. Escape in time could be an additional dimension in which seeds may reach adequate sites for recruitment. Thus, future studies should be address to better understand the survival advantages given by an endozoochory time-dispersal process. PMID- 22208094 TI - [The orchid community in the Biosphere Reserve Sierra del Rosario, Cuba]. AB - The Biosphere Reserve Sierra del Rosario is located in Western Cuba and two different areas can be characterized: one for tourism and forestry activities, El Taburete (ET), and the other for conservation and research, El Salon (ES). With the aim to know the effect of visitation activities on the orchid community in the Reserve, a comparative study between the disturbed area and the preserved one was undertaken. The field work, held between 2004-2005, consisted on four transects in each locality (10 x 100m, 0.1ha). For each transect, the existing orchid species (terrestrial and epiphytic), kind of phorophytes, and level of occupation were identified. Different analysis were considered: dominance diversity, Sorensen similarity, the dominance index and the relative abundance of the most abundant species. Our results showed 27 phorophytes species, 20 species in ET (98 phorophytes), and 16 species in ES (76 phorophytes). A total of 22 genus, 26 species and 8 326 individuals of orchids were identified. In ET, 17 genus, 18 species and 5 075 individuals were found, while for ES were 15 genus, 18 species and 3 251 individuals. Both locations have a similarity of species of 57.14%. Oeceoclades maculata, an invasive species, was the most abundant. The most dominant species were Microchilus plantagineus in ES and O. maculata in ET. The dominance in ET was of 81.79%, while in ES of 69.27%. It is important to sketch management plans focused on controlling O. maculata in both areas, and the restoration of the disturbed area. PMID- 22208095 TI - [A growth study of Prioria copaifera (Caesalpinaceae) using dendrochronological techniques]. AB - The Cativo (Prioria copaifera) forms very homogeneous forests called cativales in the flooded plains of some rivers from Costa Rica to Colombia. For over 70 years Cativo has been the main base of the timber industry in the Colombian Darien area. Because of high productivity and high-dominance of Cativo trees, they represent one of the most prone tropical forests for sustainable forest management. The objective of this research is to model diameter and timber volume growth and growth rates (absolute, mean and relative) of Cativo as a function of age, using tree ring data derived from dendrochronologycal techniques. We evaluated the annual nature of the tree rings by radiocarbon analysis and crossdating techniques. Besides, the diameter and volume growth was modeled using von Bertalanffy's model. As of our results, we estimated the life span of Cativo in 614 years as the time required to reach 99% of the asymptotic diameter. By the mean value we have found that the mean rate of diameter growth is 0.31cm/y. The species requires 90 years to reach 40cm in diameter, the regulated cut diameter in Colombia. We find that Cativo reaches maximum current annual increment (ICA) in diameter at 40 years and in volume at 90 years with rates of 0.5cm/y and 0.032m3/y per tree, respectively. The maximum diameter mean annual increments (MAI) are achieved at 80 years and for the volume at 140 year, with growth rates of 0.45cm/y and 0.018m3/y per tree, respectively. The generated information is useful for the sustainable management of Cativo forests. PMID- 22208096 TI - [Spores morphology and synangia in neotropical fern species of Marattia (Marattiaceae)]. AB - The Marattiaceae are represented by a small family of four to six genera that bear esporogenous structures of two types: sorus with free eusporangia in Angiopteris and Archangiopteris, and indurated synangium in Christensenia, Danaea and Marattia. Marattia is a pantropical genus of about eight to ten species in the paleotropic and seven to eight species in the neotropic. In order to describe the spores and sinangia morphology, this study analyzed the shape of the receptacles, and the position of the synangia, and evaluated the spores with SEM, of seven neotropical species of the genus Marattia: M. alata, M. cicutifolia, M. excavata, M. interposita, M. laevis, M. laxa y M. weinmanniifolia from several collections. The receptacles were fully developed in M. cicutifolia and M. laevis, and scarcely overelevated in the rest of the species. The synangium was ellipsoidal and had intramarginal to supramedial position in the laminae. The spores of Marattia were elliptic. Among the taxa, only monolete spores were found, with no trilete, aborted or deformed spores. The laesura was linear and reached about two of the total length of the spore. The perispore appears as a continuous thin layer deposited on the exospore according to its ornamentation in M. cicutifolia and M. laevis. It is smooth in M. alata, rugate in M. excavata and pustulate-rugate in two species: M. interposita and M. laxa. The exospore is echinate in M. cicutifolia and M. laevis and pustulate in the other species. In M. weinmannifolia spores produced by the same sinangium may have different ornamentation types. We concluded that, while the presence of ellipsoidal and superficial synangia and monolete spores aperture were generic traits, the micro and macro-ornamentation types of the perispores and exospores vary at specific level. Besides, macro-ornamentation can be bulliform (pustulate), a combination of bulliform and muriform types (pustulate-rugate), muriform (rugate-retate) and stelliform (echinate); finally, granular micro-ornamentation can be seen frecuently in perispores. PMID- 22208097 TI - [Ontogeny of strobili, sporangia development and sporogenesis in Equisetum giganteum (Equisetaceae) from the Colombian Andes]. AB - Studies on the ontogeny of the strobilus, sporangium and reproductive biology of this group of ferns are scarce. Here we describe the ontogeny of the strobilus and sporangia, and the process of sporogenesis using specimens of E. giganteum from Colombia collected along the Rio Frio, Distrito de Sevilla, Piedecuesta, Santander, at 2200m altitude. The strobili in different stages of development were fixed, dehydrated, embedded in paraffin, sectioned using a rotatory microtome and stained with the safranin O and fast green technique. Observations were made using differential interference contrast microscopy (DIC) or Nomarski microscopy, an optical microscopy illumination technique that enhances the contrast in unstained, transparent. Strobili arise and begin to develop in the apical meristems of the main axis and lateral branches, with no significant differences in the ontogeny of strobili of one or other axis. Successive processes of cell division and differentiation lead to the growth of the strobilus and the formation of sporangiophores. These are formed by the scutellum, the manubrium or pedicel-like, basal part of the sporangiophore, and initial cells of sporangium, which differentiate to form the sporangium wall, the sporocytes and the tapetum. There is not formation of a characteristic arquesporium, as sporocytes quickly undergo meiosis originating tetrads of spores. The tapetum retains its histological integrity, but subsequently the cell walls break down and form a plasmodium that invades the sporangial cavity, partially surrounding the tetrads, and then the spores. Towards the end of the sporogenesis the tapetum disintegrates leaving spores with elaters free within the sporangial cavity. Two layers finally form the sporangium wall: the sporangium wall itself, with thickened, lignified cell walls and an underlying pyknotic layer. The mature spores are chlorofilous, morphologically similar and have exospore, a thin perispore and two elaters. This study of the ontogeny of the spore-producing structures and spores is the first contribution of this type for a tropical species of the genus. Fluorescence microscopy indicates that elaters and the wall of the sporangium are autofluorescent, while other structures induced fluorescence emitted by the fluorescent dye safranin O. The results were also discussed in relation to what is known so far for other species of Equisetum, suggesting that ontogenetic processes and structure of characters sporoderm are relatively constant in Equisetum, which implies important diagnostic value in the taxonomy of the group. PMID- 22208098 TI - [Tradicional use of medicinal plants with diuretic properties at Quemado de Guines Municipality, Cuba]. AB - Medicinal plants are highly rich in Cuba and an amount of 179 species have been reported to be used by the population for diuretic purposes, nevertheless, no experimental validation has supported this effect. This study presents the relative importance of the medicinal plant species most widely used for diuretic purposes in two communities of Quemado de Guines Municipality, Villa Clara province. The information was obtained through the application of an interview to 85 inhabitants, from which 80 were random surveys to people with a great knowledge of plants, and five to herbalists and doctors practicing natural medicine. The etnopharmacological information was registered (gathered) by means of the "Tradicional of the Medicine of the Island" (TRAMIL) methodology and the interesting species were identified by a botanist and deposited in the Herbarium of the Central University "Marta Abreu" from Villa Clara, registered in the Index Herbarium, published periodically by the International Association for Plant Taxonomy. The data was analyzed by means of the indexes of use values and significant use level after TRAMIL. From the total of 19 botanical families, 26 medicinal species were identified, and 10 plants resulted with higher significant use and higher indexes of use values. From the plants reported as diuretics, 53.8% have not been experimentally validated in Cuba, the rest of the identified species have been validated at a preclinical level in some centers in the country, but its use have not been authorized as phytochemicals by the Cuban Regulatory Agency. The documentation related to the use of medicinal plants in the studied areas reveals that the traditional knowledge continues deeply rooted in the communities, and popular wisdom is kept through the representative images of the herbalist and people with considerable knowledge about this topic. PMID- 22208099 TI - Nutrient fluxes in litterfall of a secondary successional alluvial rain forest in Southern Brazil. AB - During forest succession, litterfall nutrient fluxes increase significantly. The higher inputs of organic matter and nutrients through litterfall affects positively soil fertility and the species composition, which are essential components in forest restoration and management programs. In the present study, the input of nutrients to the forest soil via litterfall components was estimated for two sites of different development stages, in an early successional alluvial rain forest in Brazil. Litterfall returned to the soil, in kg/ha, ca. 93 N, 79 Ca, 24 K, 15 Mg, 6 P, 1.7 Mn, 0.94 Fe, 0.18 Zn, 0.09 Cu and 11.2 Al, in the site where trees were more abundant and had higher values of basal area. In the other area, where trees where less abundant and values of basal area were comparatively low, litterfall returned < 50% of those amounts to the forest soil, except for Al. The amount of Al that returned to the soil was similar in both areas due to the high contribution of Tibouchina pulchra (82% of Al returned). Comparatively, high proportion of three dominant native tree species (Myrsine coriacea, T. pulchra and Cecropia pachystachya) explained better litter nutrient use efficiency (mainly N and P) in the site with the least advanced successional stage. Although litterfall of these species show lower nutrient concentrations than the other tree species, their nutrient fluxes were high in both sites, indicating a certain independence from soil essential nutrients. Such feature of the native species is very advantageous and should be considered in forest restoration programs. PMID- 22208100 TI - [Biogeochemical cycles in natural forest and conifer plantations in the high mountains of Colombia]. AB - Plant litter production and decomposition are two important processes in forest ecosystems, since they provide the main organic matter input to soil and regulate nutrient cycling. With the aim to study these processes, litterfall, standing litter and nutrient return were studied for three years in an oak forest (Quercus humboldtii), pine (Pinus patula) and cypress (Cupressus lusitanica) plantations, located in highlands of the Central Cordillera of Colombia. Evaluation methods included: fine litter collection at fortnightly intervals using litter traps; the litter layer samples at the end of each sampling year and chemical analyses of both litterfall and standing litter. Fine litter fall observed was similar in oak forest (7.5 Mg ha/y) and in pine (7.8 Mg ha/y), but very low in cypress (3.5 Mg ha/y). Litter standing was 1.76, 1.73 and 1.3 Mg ha/y in oak, pine and cypress, respectively. The mean residence time of the standing litter was of 3.3 years for cypress, 2.1 years for pine and 1.8 years for oak forests. In contrast, the total amount of retained elements (N, P, S, Ca, Mg, K, Cu, Fe, Mn and Zn) in the standing litter was higher in pine (115 kg/ha), followed by oak (78 kg/ha) and cypress (24 kg/ha). Oak forests showed the lowest mean residence time of nutrients and the highest nutrients return to the soil as a consequence of a faster decomposition. Thus, a higher nutrient supply to soils from oaks than from tree plantations, seems to be an ecological advantage for recovering and maintaining the main ecosystem functioning features, which needs to be taken into account in restoration programs in this highly degraded Andean mountains. PMID- 22208101 TI - Can rice field channels contribute to biodiversity conservation in Southern Brazilian wetlands? AB - Conservation of species in agroecosystems has attracted attention. Irrigation channels can improve habitats and offer conditions for freshwater species conservation. Two questions from biodiversity conservation point of view are: 1) Can the irrigated channels maintain a rich diversity of macrophytes, macroinvertebrates and amphibians over the cultivation cycle? 2) Do richness, abundance and composition of aquatic species change over the rice cultivation cycle? For this, a set of four rice field channels was randomly selected in Southern Brazilian wetlands. In each channel, six sample collection events were carried out over the rice cultivation cycle (June 2005 to June 2006). A total of 160 taxa were identified in irrigated channels, including 59 macrophyte species, 91 taxa of macroinvertebrate and 10 amphibian species. The richness and abundance of macrophytes, macroinvertebrates and amphibians did not change significantly over the rice cultivation cycle. However, the species composition of these groups in the irrigation channels varied between uncultivated and cultivated periods. Our results showed that the species diversity found in the irrigation channels, together with the permanence of water enables these man-made aquatic networks to function as important systems that can contribute to the conservation of biodiversity in regions where the wetlands were converted into rice fields. The conservation of the species in agriculture, such as rice field channels, may be an important alternative for biodiversity conservation in Southern Brazil, where more than 90% of wetland systems have already been lost and the remaining ones are still at high risk due to the expansion of rice production. PMID- 22208102 TI - Seed germination and seedling growth of two Pseudobombax species (Malvaceae) with contrasting habitats from Brazilian Cerrado. AB - Pseudobombax tomentosum and P. longiflorum are common trees in the Cerrado region, but the former species is more common in forest edges while the later is present in open cerrado areas. This work aimed to investigate differences in seed germination and seedling growth in these species, from seed collected from Cerrado areas in Central Brazil. For this, a seed germination experiment was designed and included four replicates with 25 seeds per species; seeds were randomly distributed in the germination chamber. To evaluate initial seedling growth, seedlings height was measured up to 67 days after seedling emergence; besides, some of these seedlings were grown for biomass evaluation during nine months. Results showed that seeds of the two species had the same germinability (near 100%) and mean germination time (ca. 12 days). However, P. longiflorum showed a more spread seed germination through time, with higher values of coefficient of variation in germination time and uncertainty index; and lower values of synchronization than P. tomentosum. The two species showed basically the same growth pattern, but lower values for height of apical meristem, diameter of underground structures (mostly roots), dry mass of shoots, underground structure and total mass of seedlings in P. tomentosum were obtained, compared to P. longiflorum. Both species allocated more dry mass to underground structures in detriment of shoot. This probably allows resprouting behavior which prevents hydric stress and detrimental fire action typical of the open Cerrado areas. PMID- 22208103 TI - Floristic composition and similarity of 15 hectares in Central Amazon, Brazil. AB - The Amazon region is one of the most diverse areas in the world. Research on high tropical forest diversity brings up relevant contributions to understand the mechanisms that result and support such diversity. In the present study we describe the species composition and diversity of 15 one-ha plots in the Amazonian terra firme dense forest in Brazil, and compare the floristic similarity of these plots with other nine one-ha plots. The 15 plots studied were randomly selected from permanent plots at the Embrapa Experimental site, Amazonas State in 2005. The diversity was analysed by using species richness and Shannon's index, and by applying the Sorensen's index for similarity and unweighted pair group average (UPGMA) as clustering method. Mantel test was performed to study whether the differences in species composition between sites could be explained by the geographic distance between them. Overall, we identified 8 771 individuals, 264 species and 51 plant families. Most of the species were concentrated in few families and few had large number of individuals. Families presenting the highest species richness were Fabaceae (Faboideae: 22spp., Mimosoideae: 22spp.), Sapotaceae: 22spp., Lecythidaceae: 15 and Lauraceae: 13. Burseraceae had the largest number of individuals with 11.8% of the total. The ten most abundant species were: Protium hebetatum (1 037 individuals), Eschweilera coriacea (471), Licania oblongifolia (310), Pouteria minima (293), Ocotea cernua (258), Scleronema micranthum (197), Eschweilera collina (176), Licania apelata (172), Naucleopsis caloneura (170) and Psidium araca (152), which represented 36.5% of all individuals. Approximately 49% of species had up to ten individuals and 13% appeared only once in all sampled plots, showing a large occurrence of rare species. Our study area is on a forest presenting a high tree species diversity with Shannon's diversity index of 4.49. The dendrogram showed two groups of plots with low similarity between them (less than 0.25), and the closer the plots were one to another, more similar in species composition (Mantel R = 0.3627, p < 0.01). The 15 plots in our study area share more than 50% of their species composition and represent the group of plots that have the shortest distance between each other. Overall, our results highlight the high local and regional heterogeneity of environments in terra firme forests, and the high occurrence of rare species, which should be considered in management and conservation programs in the Amazon rainforest, in order to maintain its structure on the long run. PMID- 22208104 TI - Reproduction, pollination and seed predation of Senna multijuga (Fabaceae) in two protected areas in the Brazilian Atlantic forest. AB - One important subject is to determine the effectiveness of conservation areas, where different management categories are being applied, to maintain effective sexual reproduction in plants and their interactions with animal groups. To evaluate this issue, we compared the phenology, reproductive success, pollination and pre-dispersal seed predation of the legume tree Senna multijuga in two differently managed protected areas in Southeastern Brazil: the Itatiaia National Park and the Environmental Protection Area of Serrinha do Alambari, from December 2007 to December 2008. Vegetative and reproductive phenodinamycs were registered monthly in 80 individuals; other evaluations included 104 observation hours for pollination (March-May 2008) in 51 inflorescences; besides, fruit counts, fecundity and seed predation. Sexual reproduction of S. multijuga depends on the transfer of pollen by large bees (Bombus, Centris, Epicharis and Xylocopa), as the species is self-incompatible. Bruchidae species of the genus Acanthoscelides and Sennius predate seeds. Vegetative and reproductive phenodynamics differed among sites. Our results indicated that ecological interactions were lower at the protected area, but the reproductive processes in S. multijuga were not ruptured or critically degraded. This reinforces the idea that landscape areas with intermediate levels of protection, such as environmental protection areas, are suitable as buffer zones, and thus, relevant to the conservation of ecological processes when associated with more strictly protected areas. PMID- 22208105 TI - Age-related and situation-related social desirability responding among Chinese teachers. AB - Social desirability responding (SDR) was affected by situation and age. However, most research is only concerned with overall SDR without considering the separation of impression management and self-deception. The purpose of this article is to explore the possible different effects of age and situation on the different components of SDR. A total of 158 teachers completed the BIDR at a 2 (high vs. low SDR situation) x 2 (20-29 vs. 30-39 years old) between-group experiment. The results of multivariate analyses, with gender and tenure controlled, suggested that the effects of age and situation on the four specific components were mixed. Impression management enhancement (IME) and denial (IMD) were significantly affected by situations. The older group had significantly higher self-deception enhancement (SDE) and IME scores than the younger one. Females had significantly higher IME scores than males. More age stages and the main effect of gender should be considered in the future. PMID- 22208106 TI - Similarity and social interaction: when similarity fosters implicit behavior toward a stranger. AB - People interact more readily with someone whom they think they have something in common with. At a pedestrian crossing, confederates asked participants for the time and, in one condition, said she/he had the same watch as the participant. The amount of time that participants lingered near a confederate was used as the dependent variable. Participants in the similarity condition spent significantly more time near the confederate than when no similarity was manipulated. The results showed that similarity fosters implicit behavior, adding to the growing body of data on the positive effects of similarity and its role in social interaction. PMID- 22208107 TI - The influence of social consensus information on intergroup attitudes: the moderating effects of ingroup identification. AB - Two studies examined the role of ingroup identification in the influence of social consensus information (information about others' beliefs) on intergroup attitudes. Research demonstrates that consensus information influences individuals' intergroup attitudes. However, the extent to which individuals identify with the group providing consensus information seems important to understanding consensus effects. In Study 1, 100 high or low ingroup identifiers received information that other ingroup members held favorable or unfavorable attitudes toward African Americans and then provided their own attitudes. In Study 2, 250 participants completed an ingroup identification manipulation (high, low, or control) before receiving favorable or no consensus information. Results of both studies demonstrated that ingroup identification moderated consensus effects, such that high identifiers were more susceptible to others' beliefs than individuals in the low identification and control conditions. In determining critical factors involved in consensus effects, we hope to create a useful method to promote favorable intergroup attitudes and behaviors. PMID- 22208108 TI - Being forgotten: implications for the experience of meaning in life. AB - Two studies investigated the effects of being forgotten on the target of memory. In Study 1, undergraduate women (N = 96) who had completed a lab session two days prior, were randomly assigned to be remembered, forgotten, complimented, or to a control group. In the absence of effects on mood or social self-esteem, being forgotten resulted in lower meaning in life. In Study 2, participants (N = 47) who had completed a group exercise were informed two days later that no one remembered them, that everyone remembered them, or that no one wanted to work with them. Being forgotten led to lower meaning in life than being remembered but did not differ from being excluded. Being forgotten may be considered a type of incipient ostracism that influences meaning in life but not mood or state social self-esteem. PMID- 22208109 TI - Predicting women's and men's reactions to geographic separation: relational interdependence matters. AB - Participant sex and a theorized correlate of biological sex, relational interdependence, were tested as relative predictors of the extent to which daters 1) missed and 2) used emotional support to cope when geographically separated from their dating partners. One hundred twenty-four daters completed multiple measures of missing and coping during their colleges' winter breaks. Results from regression analyses indicated that levels of missing and seeking emotional support differed as a function of biological sex. Further, relational interdependence was reliably associated with missing and seeking emotional support in theoretically consistent ways. Mediation analyses highlighted the importance of considering relational interdependence or other individual differences that covary with biological sex when studying close relationship phenomena. PMID- 22208110 TI - Women and men in love: who really feels it and says it first? AB - A widely held belief exists that women are more romantic and tend to fall in love faster than men. Responses from 172 college students indicated that although both men and women believe that women will fall in love and say "I love you" first in a relationship, men reported falling in love earlier and expressing it earlier than women reported. Analyses also showed no sex differences in attitudinal responses to items about love and romance. These results indicate that women may not be the greater "fools for love" that society assumes and are consistent with the notion that a pragmatic and cautious view of love has adaptive significance for women. PMID- 22208111 TI - Extended contact effects: is exposure to positive outgroup exemplars sufficient or is interaction with ingroup members necessary? AB - Previous research does not inform us if exposure to positive outgroup exemplars is sufficient to explain the observed prejudice reduction effect of extended contact or if interaction with ingroup members is necessary. An experiment (N = 108) in which Romanian students read identical stories about the friendship between a Roma and a Romanian/Bulgarian found that, while information about close outgroup-outgroup relationships is sufficient to improve outgroup attitudes and reduce intergroup anxiety, information about close ingroup-outgroup relationships has stronger and broader positive effects. Mediational analyses revealed that group emotions rather than intergroup anxiety, ingroup norms, or outgroup norms mediated the effect of extended contact on outgroup perception. A core affect perspective of group emotions is used to explain the results. PMID- 22208112 TI - Social comparison orientation moderates the effects of group membership on the similarity-attraction relationship. AB - The present study examined how the similarity-attraction relationship is affected by a combination of the tendency to compare oneself to other people (Social Comparison Orientation, SCO) and group membership. We expected that high-SCO individuals would prefer similar to dissimilar others only when the target belonged to their in-group and was relevant for the evaluation of their self concept. It was also expected that among low-SCO individuals who are more certain about the self and less concerned about "being evaluated," a main effect of attitude similarity would appear, regardless of the group membership of the target. Results partially support these predictions and suggest that further research should be carried out into the combined effects of individual and group variables in the attraction literature. PMID- 22208113 TI - Work stress, Chinese work values, and work well-being in the Greater China. AB - Work values influence our attitudes and behavior at work, but they have rarely been explored in the context of work stress. The aim of this research was thus to test direct and moderating effects of Chinese work values (CWV) on relationships between work stressors and work well-being among employees in the Greater China region. A self-administered survey was conducted to collect data from three major cities in the region, namely Beijing, Hong Kong, and Taipei (N = 380). Work stressors were negatively related to work well-being, whereas CWV were positively related to work well-being. In addition, CWV also demonstrated moderating effects in some of the stressor-job satisfaction relationships. PMID- 22208114 TI - When increased group identification leads to outgroup liking and cooperation: the role of trust. AB - Two studies explored the influence of group identification and the functional relations between groups on outgroup liking. In a laboratory study, Study 1 (N = 112) found that outgroup liking was highest when group identification was high and relations between groups were cooperative, but outgroup liking was lowest when group identification was high and relations were competitive. In a field replication of Study 1, Study 2 (N = 181) similarly found more liking with high group identification and cooperative relations between groups. Additional analyses revealed that the Identification x Relations interactions found in Studies 1 and 2 were mediated by outgroup trust. We discuss how trust is an important factor for predicting outgroup bias for both high and low group identification. PMID- 22208115 TI - Clinical applications of brain-computer interface technology. PMID- 22208116 TI - A comparison among several P300 brain-computer interface speller paradigms. AB - Since the brain-computer interface (BCI) speller was first proposed by Farwell and Donchin, there have been modifications in the visual aspects of P300 paradigms. Most of the changes are based on the original matrix format such as changes in the number of rows and columns, font size, flash/ blank time, and flash order. The improvement in the resulting accuracy and speed of such systems has always been the ultimate goal. In this study, we have compared several different speller paradigms including row-column, single character flashing, and two region-based paradigms which are not based on the matrix format. In the first region-based paradigm, at the first level, characters and symbols are distributed over seven regions alphabetically, while in the second region-based paradigm they are distributed in the most frequently used order. At the second level, each one of the regions is further subdivided into seven subsets. The experimental results showed that the average accuracy and user acceptability for two region-based paradigms were higher than those for traditional paradigms such as row/column and single character. PMID- 22208117 TI - Accuracy of a P300 speller for people with motor impairments: a comparison. AB - A Brain-Computer Interface (BCI) provides a completely new output pathway that can provide an additional option for a person to express himself/herself if he/she suffers a disorder like amyotrophic lateral sclerosis (ALS), brainstem stroke, brain or spinal cord injury or other diseases which impair the function of the common output pathways which are responsible for the control of muscles. For a P300 based BCI a matrix of randomly flashing characters is presented to the participant. To spell a character the person has to attend to it and to count how many times the character flashes. Although most BCIs are designed to help people with disabilities, they are mainly tested on healthy, young subjects who may achieve better results than people with impairments. In this study we compare measurements, performed on people suffering motor impairments, such as stroke or ALS, to measurements performed on healthy people. The overall accuracy of the persons with motor impairments reached 70.1% in comparison to 91% obtained for the group of healthy subjects. When looking at single subjects, one interesting example shows that under certain circumstances, when it is difficult for a patient to concentrate on one character for a longer period of time, the accuracy is higher when fewer flashes (i.e., stimuli) are presented. Furthermore, the influence of several tuning parameters is discussed as it shows that for some participants adaptations for achieving valuable spelling results are required. Finally, exclusion criteria for people who are not able to use the device are defined. PMID- 22208118 TI - Asynchronous P300-based brain-computer interface to control a virtual environment: initial tests on end users. AB - Motor disability and/or ageing can prevent individuals from fully enjoying home facilities, thus worsening their quality of life. Advances in the field of accessible user interfaces for domotic appliances can represent a valuable way to improve the independence of these persons. An asynchronous P300-based Brain Computer Interface (BCI) system was recently validated with the participation of healthy young volunteers for environmental control. In this study, the asynchronous P300-based BCI for the interaction with a virtual home environment was tested with the participation of potential end-users (clients of a Frisian home care organization) with limited autonomy due to ageing and/or motor disabilities. System testing revealed that the minimum number of stimulation sequences needed to achieve correct classification had a higher intra-subject variability in potential end-users with respect to what was previously observed in young controls. Here we show that the asynchronous modality performed significantly better as compared to the synchronous mode in continuously adapting its speed to the users' state. Furthermore, the asynchronous system modality confirmed its reliability in avoiding misclassifications and false positives, as previously shown in young healthy subjects. The asynchronous modality may contribute to filling the usability gap between BCI systems and traditional input devices, representing an important step towards their use in the activities of daily living. PMID- 22208119 TI - A self-paced motor imagery based brain-computer interface for robotic wheelchair control. AB - This paper presents a simple self-paced motor imagery based brain-computer interface (BCI) to control a robotic wheelchair. An innovative control protocol is proposed to enable a 2-class self-paced BCI for wheelchair control, in which the user makes path planning and fully controls the wheelchair except for the automatic obstacle avoidance based on a laser range finder when necessary. In order for the users to train their motor imagery control online safely and easily, simulated robot navigation in a specially designed environment was developed. This allowed the users to practice motor imagery control with the core self-paced BCI system in a simulated scenario before controlling the wheelchair. The self-paced BCI can then be applied to control a real robotic wheelchair using a protocol similar to that controlling the simulated robot. Our emphasis is on allowing more potential users to use the BCI controlled wheelchair with minimal training; a simple 2-class self paced system is adequate with the novel control protocol, resulting in a better transition from offline training to online control. Experimental results have demonstrated the usefulness of the online practice under the simulated scenario, and the effectiveness of the proposed self paced BCI for robotic wheelchair control. PMID- 22208120 TI - A multi-purpose brain-computer interface output device. AB - While brain-computer interfaces (BCIs) are a promising alternative access pathway for individuals with severe motor impairments, many BCI systems are designed as stand-alone communication and control systems, rather than as interfaces to existing systems built for these purposes. An individual communication and control system may be powerful or flexible, but no single system can compete with the variety of options available in the commercial assistive technology (AT) market. BCls could instead be used as an interface to these existing AT devices and products, which are designed for improving access and agency of people with disabilities and are highly configurable to individual user needs. However, interfacing with each AT device and program requires significant time and effort on the part of researchers and clinicians. This work presents the Multi-Purpose BCI Output Device (MBOD), a tool to help researchers and clinicians provide BCI control of many forms of AT in a plug-and-play fashion, i.e., without the installation of drivers or software on the AT device, and a proof-of-concept of the practicality of such an approach. The MBOD was designed to meet the goals of target device compatibility, BCI input device compatibility, convenience, and intuitive command structure. The MBOD was successfully used to interface a BCI with multiple AT devices (including two wheelchair seating systems), as well as computers running Windows (XP and 7), Mac and Ubuntu Linux operating systems. PMID- 22208121 TI - A brain-computer interface as input channel for a standard assistive technology software. AB - Recently brain-computer interface (BCI) control was integrated into the commercial assistive technology product QualiWORLD (QualiLife Inc., Paradiso Lugano, CH). Usability of the first prototype was evaluated in terms of effectiveness (accuracy), efficiency (information transfer rate and subjective workload/NASA Task Load Index) and user satisfaction (Quebec User Evaluation of Satisfaction with assistive Technology, QUEST 2.0) by four end-users with severe disabilities. Three assistive technology experts evaluated the device from a third person perspective. The results revealed high performance levels in communication and internet tasks. Users and assistive technology experts were quite satisfied with the device. However, none could imagine using the device in daily life without improvements. Main obstacles were the EEG-cap and low speed. PMID- 22208122 TI - Brain-computer interface in stroke: a review of progress. AB - Brain-computer interface (BCI) technology has been used for rehabilitation after stroke and there are a number of reports involving stroke patients in BCI feedback training. Most publications have demonstrated the efficacy of BCI technology in post-stroke rehabilitation using output devices such as Functional Electrical Stimulation, robot, and orthosis. The aim of this review is to focus on the progress of BCI-based rehabilitation strategies and to underline future challenges. A brief history of clinical BCI-approaches is presented focusing on stroke motor rehabilitation. A context for three approaches of a BCI-based motor rehabilitation program is outlined: the substitutive strategy, classical conditioning and operant conditioning. Furthermore, we include an overview of a pilot study concerning a new neuro-forcefeedback strategy. This pilot study involved healthy participants. Finally we address some challenges for future BCI based rehabilitation. PMID- 22208123 TI - A large clinical study on the ability of stroke patients to use an EEG-based motor imagery brain-computer interface. AB - Brain-computer interface (BCI) technology has the prospects of helping stroke survivors by enabling the interaction with their environ ment through brain signals rather than through muscles, and restoring motor function by inducing activity-dependent brain plasticity. This paper presents a clinical study on the extent of detectable brain signals from a large population of stroke patients in using EEG-based motor imagery BCI. EEG data were collected from 54 stroke patients whereby finger tapping and motor imagery of the stroke-affected hand were performed by 8 and 46 patients, respectively. EEG data from 11 patients who gave further consent to perform motor imagery were also collected for second calibration and third independent test sessions conducted on separate days. Off line accuracies of classifying the two classes of EEG from finger tapping or motor imagery of the stroke-affected hand versus the EEG from background rest were then assessed and compared to 16 healthy subjects. The mean off-line accuracy of detecting motor imagery by the 46 patients (mu=0.74) was significantly lower than finger tapping by 8 patients (mu=0.87, p=0.008), but not significantly lower than motor imagery by healthy subjects (mu=0.78, p=0.23). Six stroke patients performed motor imagery at chance level, and no correlation was found between the accuracies of detecting motor imagery and their motor impairment in terms of Fugl-Meyer Assessment (p=0.29). The off-line accuracies of the 11 patients in the second session (mu=0.76) were not significantly different from the first session (mu=0.72, p=0.16), or from the on-line accuracies of the third independent test session (mu=0.82, p=0.14). Hence this study showed that the majority of stroke patients could use EEG-based motor imagery BCI. PMID- 22208125 TI - Drawing with divergent perspective, ancient and modern. AB - Before methods for drawing accurately in perspective were developed in the 15th century, many artists drew with divergent perspective. But we found that many university students draw with divergent perspective rather than with the correct convergent perspective. These experiments were designed to reveal why people tend to draw with divergent perspective. University students drew a cube and isolated edges and surfaces of a cube. Their drawings were very inaccurate. About half the students drew with divergent perspective like artists before the 15th century. Students selected a cube from a set of tapered boxes with great accuracy and were reasonably accurate in selecting the correct drawing of a cube from a set of tapered drawings. Each subject's drawing was much worse than the drawing selected as accurate. An analysis of errors in drawings of a cube and of isolated edges and surfaces of a cube revealed several factors that predispose people to draw in divergent perspective. The way these factors intrude depends on the order in which the edges of the cube are drawn. PMID- 22208124 TI - A micro-electrocorticography platform and deployment strategies for chronic BCI applications. AB - Over the past decade, electrocorticography (ECoG) has been used for a wide set of clinical and experimental applications. Recently, there have been efforts in the clinic to adapt traditional ECoG arrays to include smaller recording contacts and spacing. These devices, which may be collectively called "micro-ECoG" arrays, are loosely defined as intercranial devices that record brain electrical activity on the sub-millimeter scale. An extensible 3D-platform of thin film flexible micro scale ECoG arrays appropriate for Brain-Computer Interface (BCI) application, as well as monitoring epileptic activity, is presented. The designs utilize flexible film electrodes to keep the array in place without applying significant pressure to the brain and to enable radial subcranial deployment of multiple electrodes from a single craniotomy. Deployment techniques were tested in non-human primates, and stimulus-evoked activity and spontaneous epileptic activity were recorded. Further tests in BCI and epilepsy applications will make the electrode platform ready for initial human testing. PMID- 22208126 TI - No masking between test and mask components in perceptually different depth planes. AB - 2-D cues to perceived depth organization have been used to segregate test and mask stimulus components in a discrimination task. Observers made either spatial frequency or orientation judgments on a rectangular test component by itself or in the presence of constant rectangular masks. There were two basic masking conditions: same-plane or different-plane. In the same-plane conditions, the test components and masks are perceived as existing in the same depth plane. In the different-plane conditions, the test and mask components are perceived to exist in different depth planes. The perception of different depth planes was achieved by using perceived occlusion, which could place either component closer or further from the observer. The results suggest that when test and mask components are separated into different depth planes they no longer influence one another. This effect could be observed in either depth organization, test components in front of the masks or mask components in front of the test. These results indicate that the figure-ground organization of components is not important. Only the designation as existing in the same or different depth planes affects whether or not a mask is effective. PMID- 22208127 TI - Configural information is processed differently in human action. AB - Recent evidence indicates that observers' sensitivity to configural information in dynamic human action is disrupted when action is inverted, whereas sensitivity to featural action information is not. The current research involved two experiments that expand upon this basic finding. Experiment 1 revealed that featural and configural action information are processed similarly in static representations of action as in dynamic action. Experiment 2 indicated that configural processing is uniquely sensitive to orientation only in human action as compared to a similar control stimulus. These findings further support the idea that the perception of action recruits specialized orientation-specific configural processing, and parallel similar findings in face perception and visual expertise. PMID- 22208128 TI - The role of spatial organization in preference for color pairs. AB - We investigated how spatial organization influences color-pair preference asymmetries: differential preference for one color pair over another when the pairs contain the same colors in opposite spatial configurations. Schloss and Palmer (2011, Attention, Perception, & Psychophysics 73 55-571) found weak figure ground preference asymmetries for small squares centered on large squares in aesthetic ratings. Here, we found robust preference asymmetries using a more sensitive forced-choice task: participants strongly prefer pairs with yellower, lighter figures on bluer, darker grounds (experiment 1). We also investigated which spatial factors influence these preference asymmetries. Relative area of the two component regions is clearly important, and perceived 3-D area of the 2-D displays (ie after the ground is amodally completed behind the figure) is more influential than 2-D area (experiment 2). Surroundedness is not required, because yellowness blueness effects were comparable for pairs in which the figure was surrounded by the ground, and for mosaic arrangements in which the regions were adjacent and separated by a gap (experiment 3). Lightness darkness effects, however, were opposite for figure ground versus mosaic organizations: people prefer figure-ground organizations in which smaller regions are lighter, but prefer mosaic organizations in which smaller regions are darker. Physiological, phenomenological, and ecological explanations of the reported results are discussed. PMID- 22208129 TI - Perceptual weight judgments when viewing one's own and others' movements under minimalist conditions of visual presentation. AB - Across five experiments, we investigated the parameters involved in the observation and in the execution of the action of lifting an object. The observers were shown minimal information on movements, consisting of either the working-point displacement only (ie two points representing the hand and object) or additional configural information on the kinematics of the trunk, shoulder, arm, forearm, and hand, joined by a stick diagram. Furthermore, displays showed either a participant's own movements or those of another person, when different weights were lifted. The participants' task was to estimate the weight of the lifted objects. The results revealed that, although overall performance was not dependent on the visual conditions (working point versus stick diagram) or ownership conditions (self versus other), the kinematic cues used to perform the task differed as a function of these conditions. In addition, the kinematic parameters relevant for action observation did not match those relevant for action execution. This was confirmed in experiments by using artificially altered movement samples, where the variations in critical kinematic variables were manipulated separately or in combination. We discuss the implications of these results for the roles of motor simulation and visual analysis in action observation. PMID- 22208130 TI - Perception in the absence of attention: perceptual processing in the Roelofs effect during inattentional blindness. AB - We present two experiments that examine sensory processing during conditions of inattentional blindness. A large rectangular frame that normally induces a Roelofs effect can go unreported due to inattentional blindness. Even when participants fail to report the frame, they mislocalize an attended target in a way consistent with having processed the frame. A more demanding visuospatial distractor task can increase inattentional blindness during conditions of divided attention, but has no effect on the spatial mislocalization illusion. Our results support theories that postulate a significant amount of perceptual processing in the absence of attention. PMID- 22208131 TI - Seeing with sound? exploring different characteristics of a visual-to-auditory sensory substitution device. AB - Sensory substitution devices convert live visual images into auditory signals, for example with a web camera (to record the images), a computer (to perform the conversion) and headphones (to listen to the sounds). In a series of three experiments, the performance of one such device ('The vOICe') was assessed under various conditions on blindfolded sighted participants. The main task that we used involved identifying and locating objects placed on a table by holding a webcam (like a flashlight) or wearing it on the head (like a miner's light). Identifying objects on a table was easier with a hand-held device, but locating the objects was easier with a head-mounted device. Brightness converted into loudness was less effective than the reverse contrast (dark being loud), suggesting that performance under these conditions (natural indoor lighting, novice users) is related more to the properties of the auditory signal (ie the amount of noise in it) than the cross-modal association between loudness and brightness. Individual differences in musical memory (detecting pitch changes in two sequences of notes) was related to the time taken to identify or recognise objects, but individual differences in self-reported vividness of visual imagery did not reliably predict performance across the experiments. In general, the results suggest that the auditory characteristics of the device may be more important for initial learning than visual associations. PMID- 22208132 TI - Koffka's effect is mediated by figure thickness at the joining region. AB - Three-quarters of a century ago Gestalt psychologist Kurt Koffka described a remarkable effect: when a contiguous gray ring is placed on a background half one shade of gray, half another, the ring appears homogeneous. However, if the ring is divided, the two halves of the ring appear different shades of gray, the half of the ring on the darker background appearing lighter than the half of the ring on the lighter background. The Gestalt principle of continuity is used to explain this effect. But what microscopic principles might be mediating this effect? Recently we found sufficiently thin rings (annuli) appear heterogeneous even when geometrically continuous. Here, using crescent-shaped figures instead of the circular annuli used for the traditional Koffka effect, we show that this effect of thickness of the ring is mediated by the thickness at the boundary of the region where the halves of the figure are joined. PMID- 22208134 TI - Perceived autonomy support, friendship maintenance, and happiness. AB - Decades of empirical research have shown that perceived autonomy support in close relationships is an essential correlate of happiness. However, what might account for the relationship between the 2? For this article, 4 studies (total N=1325) investigated friendship maintenance as a mediator of the association between friendship autonomy support and happiness. The first 3 studies supported the model for the best friendship of the individual when happiness was assessed with 3 different measures. The 4th study extended the findings by showing that the model was generalizable to the other close friendship of the individual. Overall, the results supported the idea that engaging in routine and strategic behaviors to maintain friendships explains how perceived autonomy support in friendships is associated with happiness. The theoretical and applied implications of the findings were discussed and suggestions for future research were made. PMID- 22208133 TI - Negatively biased emotion perception in depression as a contributing factor to psychological aggression perpetration: a preliminary study. AB - Based on research linking depressive symptoms and intimate partner aggression perpetration with negatively biased perception of social stimuli, the present authors examined biased perception of emotional expressions as a mechanism in the frequently observed relationship between depression and psychological aggression perpetration. In all, 30 university students made valence ratings (negative to positive) of emotional facial expressions and completed measures of depressive symptoms and psychological aggression perpetration. As expected, depressive symptoms were positively associated with psychological aggression perpetration in an individual's current relationship, and this relationship was mediated by ratings of negative emotional expressions. These findings suggest that negatively biased perception of emotional expressions within the context of elevated depressive symptoms may represent an early stage of information processing that leads to aggressive relationship behaviors. PMID- 22208135 TI - Examination of a perceived cost model of employees' negative feedback-seeking behavior. AB - The present study extends the feedback-seeking behavior literature by investigating how supervisor-related antecedents (i.e., supervisors' expert power, reflected appraisals of supervisors, and supervisors' emotional intelligence) influence subordinates' negative feedback-seeking behavior (NFSB) through different cost/value perceptions (i.e., expectancy value, self presentation cost, and ego cost). Using data collected from 216 supervisor subordinate dyads from various industries in Taiwan, we employ structural equation modeling analysis to test our hypotheses. The results show that expectancy value mediates the relationship between supervisor expert power and subordinates' NFSB. Moreover, self-presentation cost mediates the relationship between reflected appraisals of supervisors' and subordinates' NFSB. Theoretical and practical implications of this study are also discussed. PMID- 22208136 TI - Breast cancer: an Indian perspective. PMID- 22208137 TI - Protecting young healthcare trainees from tuberculosis: can we overcome apathy? PMID- 22208138 TI - Isoniazid preventive therapy programmes for healthcare workers in India: translating evidence into policy. AB - BACKGROUND: Occupational tuberculosis (TB) among healthcare workers (HCWs) is an important public health issue, especially in India where HCWs are exposed to a high burden of TB and infrastructural infection control procedures are inadequate. We examined the need for implementing isoniazid preventive therapy (IPT) programmes to protect Indian HCWs from occupational TB. METHODS: Bardach's 8-fold path was followed to analyse and formulate the policy for introducing IPT programmes for HCWs in India. The results of surveillance with tuberculin skin testing (TST) and treatment of latent TB infection with isoniazid (INH) for HCWs belonging to two different age groups (< or = 30 years and > 30 years) were compared with each other and with the alternative of maintaining status quo, i.e. no surveillance and no therapy, under various parameters such as the lifetime risks of active TB, deaths due to TB, benefit-risk ratios, cost-savings to the health system and relative risk reductions. RESULTS; The lifetime risk of TB was found to be higher among HCWs in the age group of < or = 30 years. IPT for HCWs reduced the lifetime risks of TB and death due to TB in both age groups, with better results in the age group of < or = 30 years. The relative lifetime risk reduction of active TB was 24.04% for the age group of < or = 30 years and 19.92% for the age group of > 30 years. The relative lifetime risk reduction of death due to TB by administration of IPT was from 13.96% to 19.62% in the two age groups. The benefit-risk ratio of IPT was 11.24 for the age group of < or = 30 years and 2.88 for the age group of > 30 years. IPT was associated with an approximate savings of rupee 4000-8000 for each case prevented. CONCLUSION: TB is a major occupational hazard for Indian HCWs. The inclusion of IPT programmes in the national policy to combat TB, along with infrastructural infection control measures, can contribute to reduction in workplace TB. IPT programmes for HCWs in the younger age group have better results in terms of prevention of active TB, TB related mortality and INH-induced hepatitis as compared to the older age group. There is an urgent need for a mechanism of targeted testing and treatment of latent TB infection to minimize the risk of occupational exposure for TB among HCWs in all age groups. PMID- 22208139 TI - Referral pattern of patients with end-stage renal disease at a public sector hospital and its impact on outcome. AB - BACKGROUND: Late referral of patients with chronic kidney disease (CKD) to a nephrologist has been shown to be associated with greater morbidity and adverse clinical outcomes. METHODS: We did a prospective cross-sectional study of 2490 consecutive, newly diagnosed patients with end-stage renal disease (ESRD) referred to the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh over 2 years. The referral pattern was classified on the basis of the interval between first visit to a nephrologist and initiation of renal replacement therapy (RRT). If the patient reported later to a nephrologist, the disease would have progressed more, and the time interval to initiation of RRT would thus be shorter. A time interval of < 3 months was classified as late referral (LR), 3-12 months as intermediate referral (IR) and > 12 months as early referral (ER). The demographic and clinical characteristics and co-morbid conditions were compared, and factors associated with LR and outcomes were evaluated. RESULTS: About 75% of patients were referred late. Poor socioeconomic status, low level of education and reduced access to reimbursement of treatment costs contributed to LR. The aetiology of ESRD could not be established in a larger number of LR patients as compared to the other groups. LR patients had a higher prevalence of uraemic complications and required emergency dialysis more frequently. A higher proportion of LR patients were lost to follow up because they could not afford to continue dialysis. Early mortality was higher in the ER group than in the other groups. ER patients were older, more likely to have diabetic nephropathy and a higher burden of co-morbid conditions. They were also more likely to choose continuous ambulatory peritoneal dialysis or undergo transplantation. Only 28% of all patients continued RRT beyond 3 months. CONCLUSION: A large majority of patients with ESRD in India seek medical attention late, usually in advanced stages of CKD with uraemic complications. LR is more frequent in younger patients and those with non-diabetic kidney disease, and is associated with poor socioeconomic status, lack of education and poor outcomes. PMID- 22208140 TI - Periodontal infections: a risk factor for various systemic diseases. AB - A healthy periodontium is vital for the general well-being of an individual. However, periodontal diseases are common and periodontal infections are increasingly associated with systemic diseases. We aimed to critically evaluate the literature on the association between periodontal infections and systemic diseases. We searched the PubMed database over a 20-year period for literature on periodontal diseases and their links to various systemic diseases, and examined the strength of association between periodontal disease and each systemic disease, the dose-response relationship, and the biological plausibility. We found that individuals with periodontal disease may be at higher risk for adverse medical outcomes including cardiovascular diseases, respiratory infections, adverse pregnancy outcomes, rheumatoid arthritis and diabetes mellitus. Many cohort, in vitro and animal studies suggest that systemic inflammation due to pathogens associated with periodontal disease may play a role in the initiation and progression of some systemic diseases. Periodontal infections should therefore be considered as a risk factor for various systemic diseases. PMID- 22208141 TI - Can traditional birth attendants be trained to reduce neonatal mortality rate? Lessons from Lufwanyama Neonatal Survival Project. PMID- 22208142 TI - Diabetes mellitus: a risk factor for cancer and non-vascular disease deaths too. PMID- 22208143 TI - Assessment of medical knowledge: the pros and cons of using true/false multiple choice questions. AB - True/false multiple choice items, commonly referred to as true/ false multiple choice questions (MCQs), were previously a widely used selected response examination format. They can be written relatively easily and cover a wide range of content. Educational researchers have however highlighted several adverse features of this format that make it inappropriate for many assessment settings. These include: (i) there is a high chance of guessing the correct answer; (ii) some marks are not awarded for knowing the correct answer, but for knowing that an answer is incorrect; (iii) they are weak in discriminating between high and low performers; (iv) identifying items which are absolutely true or false may lead to assessment of trivial knowledge; (v) there are difficulties with constructing flawless items; (vi) they may not encourage learning around the items; and (vii) they may not assess what they purport to assess. Many assessment agencies abandoned the use of this format decades ago due to these shortcomings. The use of single best answer (SBA) and extended matching item (EMI) formats helps overcome or minimize the above weaknesses. Assessors who plan to change to SBA or EMI formats from true/false MCQs may, however, need to increase the number of questions to include a representative sample of the curriculum (lengthening the question paper). However, they may not need to increase the examination time, as in general students can answer more SBAs or EMIs than true/false MCQs per unit time. It is time that we reflect upon the disadvantages of true/false MCQs and review their place in our assessment toolkit, as their use in summative examinations may not be fair to students, especially 'good' students. PMID- 22208144 TI - Does the insularity of the medical profession threaten its future in national health? PMID- 22208145 TI - Up in the air. PMID- 22208146 TI - Serving our patients. PMID- 22208147 TI - Living donor for an adult-to-adult liver transplantation: need for more regulation? PMID- 22208148 TI - Defensive approach of physicians not inexplicable. PMID- 22208149 TI - ALARA--are we really following it? An ALARM... PMID- 22208150 TI - A patient of multidrug-resistant tuberculosis on category IV treatment regimen presenting with psychosis. PMID- 22208151 TI - Government policies for traditional, complementary and alternative medical services in India: from assimilation to integration? PMID- 22208152 TI - Should doctors learn to teach? PMID- 22208153 TI - Age at initiation of tobacco use in India: a note of caution. PMID- 22208154 TI - Juvenile mitral stenosis in India. 1963. PMID- 22208156 TI - Electrochromic behavior of W(x)Si(y)O(z) thin films prepared by reactive magnetron sputtering at normal and glancing angles. AB - This work reports the synthesis at room temperature of transparent and colored W(x)Si(y)O(z) thin films by magnetron sputtering (MS) from a single cathode. The films were characterized by a large set of techniques including X-ray photoelectron spectroscopy (XPS), Rutherford backscattering spectrometry (RBS), Fourier transform infrared (FT-IR), and Raman spectroscopies. Their optical properties were determined by the analysis of the transmission and reflection spectra. It was found that both the relative amount of tungsten in the W-Si MS target and the ratio O(2)/Ar in the plasma gas were critical parameters to control the blue coloration of the films. The long-term stability of the color, attributed to the formation of a high concentration of W(5+) and W(4+) species, has been related with the formation of W-O-Si bond linkages in an amorphous network. At normal geometry (i.e., substrate surface parallel to the target) the films were rather compact, whereas they were very porous and had less tungsten content when deposited in a glancing angle configuration. In this case, they presented outstanding electrochromic properties characterized by a fast response, a high coloration, a complete reversibility after more than one thousand cycles and a relatively very low refractive index in the bleached state. PMID- 22208157 TI - Implants with internal hexagon and conical implant-abutment connections: an in vitro study of the bacterial contamination. AB - Prevention of microbial leakage at the implant-abutment junction is a major challenge for the construction of 2-stage implants in order to minimize inflammatory reactions and to maximize bone stability at the implant neck. The aim of the present in vitro study was an evaluation of the leakage observed over a period of 28 days in Cone Morse taper internal connections and in screwed abutments connections. In the present study 10 specimens of Cone Morse (Group 1) and 10 of internal hexagon (Group 2) implants were used. The inner parts of 5 implants per group were inoculated with Pseudomonas aeruginosa (PS) suspension and 5 implants per group with Aggregatibacter actinomycetemcomitans (AA). The possible penetration of bacterial suspension into the surrounding solution was determined by the observation of turbidity of the broth. In Group 1, bacterial contamination was found in 3 out of 5 implant-abutment assemblies seeded with the PS and in 2 samples out of 5 in the assemblies seeded with AA, with a total of leaked assemblies in this group of 5 out of 10. In Group 2, bacterial contamination was found in 4 out of 5 implant-abutment assemblies seeded with the PS, and in 4 out of 5 samples seeded with AA, with a total of leaked assemblies of 8 out of 10. The present data confirm the reported high permeability to bacterial leakage of screw-retained abutment connections, and the lower infiltration rates-although not significantly-of Cone Morse taper internal connections. PMID- 22208159 TI - Waterborne versus dietary zinc accumulation and toxicity in Daphnia magna: a synchrotron radiation based X-ray fluorescence imaging approach. AB - Recent studies have suggested that exposure of the freshwater invertebrate Daphnia magna to dietary Zn may selectively affect reproduction without an associated increase of whole body bioaccumulation of Zn. The aim of the current research was therefore to investigate the hypothesis that dietary Zn toxicity is the result of selective accumulation in tissues that are directly involved in reproduction. Since under field conditions simultaneous exposure to both waterborne and dietary Zn is likely to occur, it was also tested if accumulation and toxicity under combined waterborne and dietary Zn exposure is the result of interactive effects. To this purpose, D. magna was exposed during a 16-day reproduction assay to Zn following a 5 * 2 factorial design, comprising five waterborne concentrations (12, 65, 137, 207, and 281 MUg Zn/L) and two dietary Zn levels (49.6 and 495.9 MUg Zn/g dry wt.). Tissue-specific Zn distribution was quantified by synchrotron radiation based confocal X-ray fluorescence (XRF). It was observed that the occurrence of reproductive inhibition due to increasing waterborne Zn exposure (from 65 MUg/L to 281 MUg/L) was accompanied by a relative increase of the Zn burdens which was similar in all tissues considered (i.e., the carapax, eggs, thoracic appendages with gills and the cluster comprising gut epithelium, storage cells and ovaries). In contrast, the impairment of reproduction during dietary Zn exposure was accompanied by a clearly discernible Zn accumulation in the eggs only (at 65 MUg/L of waterborne Zn). During simultaneous exposure, bioaccumulation and toxicity were the result of interaction, which implies that the tissue-specific bioaccumulation and toxicity following dietary Zn exposure are dependent on the Zn concentration in the water. Our findings emphasize that (i) effects of dietary Zn exposure should preferably not be investigated in isolation from waterborne Zn exposure, and that (ii) XRF enabled us to provide possible links between tissue-specific bioaccumulation and reproductive effects of Zn. PMID- 22208160 TI - A possible role to nitric oxide in the anti-inflammatory effects of amitriptyline. AB - Antidepressants are reported to display anti-inflammatory effects. Nitric oxide (NO), in turn, has a key role in inflammation. The objective of the present study was to evaluate the effect of amitriptyline co-administered with L-NAME (a NO synthase inhibitor) on certain parameters of acute inflammatory response in rats, as a form to investigate a possible participation of NO in the anti-inflammatory effects of amitriptyline. For this, two animal models were used: carrageenan induced paw edema and acute peritonitis. In the last one, peritoneal exudate, adhesion molecules expression by peripheral blood leukocytes and serum cytokines levels were evaluated. In a noninflammatory condition, serum levels of nitrates were determined. L-NAME induced a potentiation of the anti-inflammatory effects of amitriptyline (p < 0.05) in the paw edema model; however, these effects were not abrogated when L-NAME was substituted by L-arginine administration. A decrease in both leukocyte concentration and total number of cells in the peritoneal exudate and a reduction in the total serum levels of nitrates were observed with co-administration of L-NAME and amitriptyline (p < 0.05). No significant differences among groups were found concerning the expression of adhesion molecules by peripheral blood leukocytes (p > 0.05). There was a significant decrease on IL-1beta and TNF-alpha serum levels in the experimental groups when compared to the control animals. Together the present results and the literature suggest that the anti-inflammatory effects of amitriptyline may be due to a decrease in NO production. A decrease in IL-1beta/TNF-alpha serum levels may also be implicated in the results observed. PMID- 22208163 TI - Multifocal electroretinogram and Optical Coherence tomography spectral-domain in arc welding macular injury: a case report. AB - BACKGROUND: the purpose of this study was to report a binocular photic retinal injury induced by plasma arc welding and the follow-up after treatment with vitamin supplements for a month. In our study, we used different diagnostic tools such as fluorescein angiography (FA), optical coherence tomography (OCT) and multifocal electroretinogram (mfERG). CASE PRESENTATION: in the first visit after five days from arc welding injury in the left eye (LE) the visual acuity was 0.9 and 1.0 in the right eye (RE). FA was normal in both eyes. OCT in the left eye showed normal profile and normal reflectivity and one month later, a hyperreflectivity appeared in the external limiting membrane (ELM). The mfERG signal in the LE was 102.30 nV/deg2 five days after the injury and 112.62 nV/deg2 after one month and in the RE respectively 142.70 nV/deg2 and 159.46 nV/deg2. CONCLUSIONS: in cases of retinal photo injury it is important for the ophthalmologist to evaluate tests such as OCT and the mfERG in the diagnosis and follow-up of the patient because the recovery of visual acuity cannot exclude the persistence of phototoxic damage charged to the complex inner-outer segment of photoreceptors. PMID- 22208164 TI - "Outer-sphere to inner-sphere" redox cycling for ultrasensitive immunosensors. AB - This paper reports chemical-chemical (CC) and electrochemical-chemical-chemical (ECC) redox cycling, for use in ultrasensitive biosensor applications. A triple chemical amplification approach using an enzymatic reaction, CC redox cycling, and ECC redox cycling is applied toward electrochemical immunosensors of cardiac troponin I. An enzymatic reaction, in which alkaline phosphatase converts 4 aminophenyl phosphate to 4-aminophenol (AP), triggers CC redox cycling in the presence of an oxidant and a reductant, and electrochemical signals are measured with ECC redox cycling after an incubation period of time in an air-saturated solution. To obtain high, selective, and reproducible redox cycling without using redox enzymes, two redox reactions [the reaction between AP and the oxidant and the reaction between the oxidized form of AP (4-quinone imine, QI) and the reductant] should be fast, but an unwanted reaction between the oxidant and reductant should be very slow. Because species that undergo outer-sphere reactions (OSR-philic species) react slowly with species that undergo inner sphere reactions (ISR-philic species), highly OSR-philic Ru(NH(3))(6)(3+) and highly ISR-philic tris(2-carboxyethyl)phosphine (TCEP) are chosen as the oxidant and reductant, respectively. The OSR- and ISR-philic QI/AP couple allows fast redox reactions with both the OSR-philic Ru(NH(3))(6)(3+) and the ISR-philic TCEP. Highly OSR-philic indium-tin oxide (ITO) electrodes minimize unwanted electrochemical reactions with highly ISR-philic species. Although the formal potential of the Ru(NH(3))(6)(3+)/Ru(NH(3))(6)(2+) couple is lower than that of the QI/AP couple, the endergonic reaction between Ru(NH(3))(6)(3+) and AP is driven by the highly exergonic reaction between TCEP and QI (via a coupled reaction mechanism). Overall, the "outer-sphere to inner-sphere" redox cycling in the order of highly OSR-philic ITO, highly OSR-philic Ru(NH(3))(6)(3+)/Ru(NH(3))(6)(2+) couple, OSR- and ISR-philic QI/AP couple, and highly ISR-philic TCEP allows high, selective, and reproducible signal amplification. The electrochemical data obtained by chronocoulometry permit a lower detection limits than those obtained by cyclic voltammetry. The detection limit of an immunosensor for troponin I in serum, calculated from the anodic charges in chronocoulometry, is ca. 10 fg/mL. PMID- 22208165 TI - Overcoming burdens in the regulation of clinical research in children. Proceedings of a consensus conference, in historical context. AB - BACKGROUND: Many investigators are concerned that the modes of implementation and enforcement of the federal regulations designed to protect children are unduly impeding pediatric clinical research. OBJECTIVE: To assess regulatory impediments to clinical research involving children and to develop recommendations to ameliorate them. PARTICIPANTS: The Pediatric Endocrine Society and The Endocrine Society convened a consensus conference involving experts and stakeholders in patient-oriented research involving children and adolescents in 2008. CONSENSUS PROCESS: Following presentations that reviewed problematic issues around key regulations, participants divided into working groups to develop potential solutions that could be adopted at local and federal levels. Presentations to the full assembly were then debated. A writing committee then drafted a summary of the discussions and main conclusions, placing them in historical context, and submitted it to all participants for comment with the aim of developing consensus. CONCLUSIONS: Recommendations designed to facilitate the ethical conduct of research involving children addressed the interpretation of ambiguous regulatory terms such as "minimal risk" and "condition" and called for the development by professional societies of best practice primers for common research procedures that would be informative to both investigators and institutional review boards. A call was issued for improved guidance from the Office for Human Research Protections and Food and Drug Administration as well as for the development by professional societies of a process to monitor progress in improving human subject research regulation. Finally, a need for systematic research to define the nature and extent of institutional obstacles to pediatric research was recognized. PMID- 22208166 TI - Boronate urea activation of nitrocyclopropane carboxylates. AB - Boronate ureas operate as catalysts for the activation of nitrocyclopropane carboxylates in nucleophilic ring-opening reactions. A variety of amines were found to open the urea-activated nitrocyclopropane carboxylates, generating highly useful nitro ester building blocks in good yields. Standard manipulations allow access to a wide range of valuable compounds from the ring-opened products with direct applications in bioactive target synthesis. PMID- 22208171 TI - The Eleventh Wolf Creek Conference on CPR: addressing the scientific basis of reanimation. PMID- 22208168 TI - Ancient Pbx-Hox signatures define hundreds of vertebrate developmental enhancers. AB - BACKGROUND: Gene regulation through cis-regulatory elements plays a crucial role in development and disease. A major aim of the post-genomic era is to be able to read the function of cis-regulatory elements through scrutiny of their DNA sequence. Whilst comparative genomics approaches have identified thousands of putative regulatory elements, our knowledge of their mechanism of action is poor and very little progress has been made in systematically de-coding them. RESULTS: Here, we identify ancient functional signatures within vertebrate conserved non coding elements (CNEs) through a combination of phylogenetic footprinting and functional assay, using genomic sequence from the sea lamprey as a reference. We uncover a striking enrichment within vertebrate CNEs for conserved binding-site motifs of the Pbx-Hox hetero-dimer. We further show that these predict reporter gene expression in a segment specific manner in the hindbrain and pharyngeal arches during zebrafish development. CONCLUSIONS: These findings evoke an evolutionary scenario in which many CNEs evolved early in the vertebrate lineage to co-ordinate Hox-dependent gene-regulatory interactions that pattern the vertebrate head. In a broader context, our evolutionary analyses reveal that CNEs are composed of tightly linked transcription-factor binding-sites (TFBSs), which can be systematically identified through phylogenetic footprinting approaches. By placing a large number of ancient vertebrate CNEs into a developmental context, our findings promise to have a significant impact on efforts toward de-coding gene-regulatory elements that underlie vertebrate development, and will facilitate building general models of regulatory element evolution. PMID- 22208172 TI - Improving microcirculation with therapeutic intrathoracic pressure regulation in a porcine model of hemorrhage. AB - AIM OF STUDY: Intrathoracic pressure regulation (IPR) has been used to treat hypotension and states of hypoperfusion by providing positive pressure ventilation during inspiration followed by augmentation of negative intrathoracic pressure during expiration. This therapy augments cardiac output and lowers intracranial pressure, thereby providing greater circulation to the heart and brain. The effects of IPR on microcirculation remain unknown. METHODS: Using a hemorrhagic model, hemodynamics and sublingual microcirculation were evaluated after a 55% blood loss over a 30 min timeframe in 10 female farm pigs (30 kg) previously anesthetized with isoflurane. RESULTS: After hemorrhage the mean arterial pressure was 27 +/- 4 mm Hg. Blood cell velocity, the key indicator of microcirculation, was significantly reduced after the bleed from 1033 +/- 175 MUm/s pre-bleed to 147 +/- 60 MUm/s (p < 0.0001). Application of an IPR device reduced airway pressure during expiration to -9 mm Hg after each positive pressure breath (10 mL/kg, 10 breaths/min) and resulted in a rapid increase in systemic hemodynamics and microcirculation. During IPR treatment, average mean arterial pressure increased by 59% to 43 +/- 6 mm Hg (p = 0.002) and blood cell velocity increased by 344% to 506 +/- 99 MUm/s (p = 0.001). CONCLUSION: In this animal model, we observed that microcirculation and systemic blood pressures are correlated and may be significantly improved by using IPR therapy. PMID- 22208174 TI - A combination of metabolic strategies plus cardiopulmonary bypass improves short term resuscitation from prolonged lethal cardiac arrest. AB - BACKGROUND: The metabolic or late phase of cardiac arrest is highly lethal. Emergency cardiopulmonary bypass (ECPB) can resuscitate many patients even after prolonged cardiac arrest and provides immediate vascular access for correction of metabolic derangement during the reperfusion process. We developed a rodent model of ECPB resuscitation which showed the superiority of ECPB over conventional CPR, especially when combined with hypothermia. For this study we examined a metabolic strategy against ischemia-reperfusion injury (MS-IR) that included: leukoreduction, low Ca(2+), Mg(2+), buffered pH, red blood cells and a colloid. We tested whether ECPB plus MS-IR and/or hypothermia improves short-term hemodynamic outcomes compared to a standard ECPB reperfusate. METHODS: Using a 2*2 factorial design we tested ECPB with (a) MS-IR versus a standard crystalloid solution; and (b) hypothermia versus normothermia in our rat model. The four reperfusion strategies included: (1) MS-IR plus hypothermia, (2) MS-IR with normothermia, (3) standard plasma-lyte (STD) reperfusate plus hypothermia, or (4) STD plus normothermia. Animals underwent 12 min of untreated asphyxial arrest and were resuscitated with ECPB and one of the four strategies for 30 min. Thereafter, ECPB was discontinued and ventilatory support was provided for 3 hours, while hemodynamic, perfusion and other metrics were serially measured. RESULTS: All rats achieved ROSC with ECPB. Significant differences between the groups emerged after 3 hrs: the best outcomes were in animals with MS-IR plus hypothermia (lactate: 1.1 +/- 0.1 mmol/L; MAP: 83 +/- 4 mm Hg, seizures: 0/10), while the worst outcomes were with STD and normothermia (lactate: 8.9 +/- 1.4 mmol/L, MAP: 36 +/- 4 mm Hg, seizures: 7/10, p < 0.001). The outcomes of the other two groups (MS-IR only; hypothermia only) were intermediate. MS-IR and hypothermia improved outcome in an additive fashion. CONCLUSIONS: While most human ECPB is applied with a normothermic crystalloid priming solution, we observed that in rodents the addition of MS-IR plus hypothermia resulted in considerable short-term benefit after prolonged arrest. Future long-term and translational survival studies are warranted to optimize ECPB resuscitation methods. PMID- 22208173 TI - Prevalence and hemodynamic effects of leaning during CPR. AB - BACKGROUND: Cardiopulmonary resuscitation (CPR) guidelines recommend complete release between chest compressions (CC). OBJECTIVE: Evaluate the hemodynamic effects of leaning (incomplete chest wall release) during CPR and the prevalence of leaning during CPR. RESULTS: In piglet ventricular fibrillation cardiac arrests, 10% and 20% (1.8 kg and 3.6 kg, respectively), leaning during CPR increased right atrial pressures, decreased coronary perfusion pressures, and decreased cardiac index and left ventricular myocardial blood flow by nearly 50%. In contrast, residual leaning of a 260 g accelerometer/force feedback device did not adversely affect cardiac index or myocardial blood flow. Among 108 adult in hospital CPR events, leaning >= 2.5 kg was demonstrable in 91% of the events and 12% of the evaluated CC. For 12 children with in-hospital CPR, 28% of CC had residual leaning >= 2.5 kg and 89% had residual leaning >= 0.5 kg. CONCLUSIONS: Leaning during CPR increases intrathoracic pressure, decreases coronary perfusion pressure, and decreases cardiac output and myocardial blood flow. Leaning is common during CPR. PMID- 22208175 TI - Optimizing the duration of CPR prior to defibrillation improves the outcome of CPR in a rat model of prolonged cardiac arrest. AB - AIMS: This study was to investigate whether optimal duration of CPR prior to defibrillation could be guided by Amplitude Spectrum Analysis (AMSA) in the setting of prolonged VF on outcome of CPR. METHODS: VF was induced in thirty Sprague-Dawley rats and untreated for 8 minutes. Animals were then randomized into 3 groups prior to CPR: The duration of CPR prior to defibrillation was guided by AMSA (CC+AMSA); guidelines-based with delayed defibrillation that simulated the AED algorithm (GL+AED); and guidelines-based with immediate shock (GL+shock ready). RESULTS: Regardless of groups, the majority of the animals (85%) required over 5 min of CPR to achieve restoration of spontaneous circulation (ROSC). Significantly greater rate of ROSC after first defibrillation (70% vs 0%, p < 0.01), lesser CPR interruptions and the number of defibrillations were observed in the CC+AMSA group when compared to both guidelines-based groups (p < 0.001). This was associated with a significantly better post-resuscitation myocardial and neurological function and longer durations of survival. CONCLUSIONS: After prolonged VF, optimal duration of CPR prior to defibrillation guided by AMSA improves the outcome of CPR. PMID- 22208177 TI - Post-cardiac arrest myocardial dysfunction is improved with cyclosporine treatment at onset of resuscitation but not in the reperfusion phase. AB - AIM OF STUDY: Significant myocardial dysfunction and high mortality occur after whole-body ischaemia-eperfusion injuries in the post-cardiac arrest status. The inhibition of mitochondrial permeability transition pore (mPTP) opening during ischaemia-reperfusion can ameliorate injuries in the specific organs. We investigated the effect and therapeutic window of pharmacological inhibition of mPTP opening in cardiac arrest. METHODS: Forty male Wistar rats were resuscitated after cardiac arrest induced by 8.5 min of asphyxia. Cyclosporine (10 mg/kg) was administered intravenously at onset of resuscitation in protocol 1 study and administered 3 min after ROSC in protocol 2 with placebo control in both. RESULTS: Left ventricular systolic (dP/dt 40), diastolic (maximal negative dP/dt) functions and cardiac output were improved in the group with cyclosporine treatment at onset of resuscitation compared to control group (p < 0.01, respectively). Seventy-two hour survival was better in the group with cyclosporine treatment at onset of resuscitation compared to control (p = 0.046). Left ventricular systolic and diastolic function, cardiac output and 72 h survival were not improved in the group with cyclosporine treatment 3 min after ROSC. The severity of mitochondrial damage under electronic microscopy, mPTP opening, mitochondrial respiratory control ratio and ADP:O ratio were ameliorated in the group with cyclosporine treatment at onset of resuscitation (p< 0.05, respectively) but not in the group with cyclosporine treatment at 3 min after ROSC. CONCLUSIONS: Post-cardiac arrest myocardial dysfunction and survival can be improved by cyclosporine treatment at onset of resuscitation, but not by the cyclosporine treatment at 3 min after ROSC. PMID- 22208176 TI - Sodium nitroprusside enhanced cardiopulmonary resuscitation prevents post resuscitation left ventricular dysfunction and improves 24-hour survival and neurological function in a porcine model of prolonged untreated ventricular fibrillation. AB - AIM OF STUDY: Sodium nitroprusside-enhanced CPR, or SNPeCPR, consists of active compression-decompression CPR with an impedance threshold device, abdominal compression, and intravenous sodium nitroprusside (SNP). We hypothesize that SNPeCPR will improve post resuscitation left ventricular function and neurological function compared to standard (S) CPR after 15 min of untreated ventricular fibrillation in a porcine model of cardiac arrest. METHODS: Pigs (n = 22) anesthetized with isoflurane underwent 15 min of untreated ventricular fibrillation, were then randomized to 6 min of S-CPR (n = 11) or SNPeCPR (n = 11) followed by defibrillation. The primary endpoints were neurologic function as measured by cerebral performance category (CPC) score and left ventricular ejection fraction. RESULTS: SNPeCPR increased 24-hour survival rates compared to S-CPR (10/11 versus 5/11, p = 0.03) and improved neurological function (CPC score 2.5 +/- 1, versus 3.8 +/- 0.4, respectively, p = 0.004). Left ventricular ejection fractions at 1, 4 and 24 hours after defibrillation were 72 +/- 11, 57 +/- 11.4 and 64 +/- 11 with SNPeCPR versus 29 +/- 10, 30 +/- 17 and 39 +/- 6 with S-CPR, respectively (p < 0.01 for all). CONCLUSIONS: In this pig model, after 15 min of untreated ventricular fibrillation, SNPeCPR significantly improved 24-hour survival rates, neurologic function and prevented post-resuscitation left ventricular dysfunction compared to S-CPR. PMID- 22208178 TI - Post-cardiac arrest hyperoxia and mitochondrial function. AB - INTRODUCTION: Rapid post-ischemic re-oxygenation is necessary to minimize ischemic injury, but itself can induce further reperfusion injury through the induction of reactive oxygen species. Utilization of oxygen within the cell primarily occurs in the mitochondria. The objective of this study was to determine heart mitochondrial function after 1 h of controlled arterial oxygenation following cardiac arrest and restoration of spontaneous circulation (ROSC). We hypothesized that arterial hyper-oxygenation following ROSC would result in greater impairment of heart mitochondrial function. METHODS: KCl cardiac arrest was induced in anesthetized rats. Following 6.5 min of cardiac arrest, animals were resuscitated with standard thumper CPR, ventilation and epinephrine. Following ROSC, all animals were ventilated for 60 min with either 100% O(2) or 40% O(2) titrated to achieve normoxia utilizing pulse oximetry. At the end of 1 h, heart mitochondria were isolated and mitochondrial respiratory function was measured. RESULTS: Post-ROSC arterial PaO2 was 280 +/- 40 in the 100% O2 group and 105 +/- 10 in the 40% O2 group. One hour after ROSC, heart mitochondrial state 3 respirations and respiration control ratio (state 3/4 respiration) were significantly reduced from baseline in animals ventilated with 100% O(2), but not with 40% O(2). CONCLUSION: Post-ROSC arterial hyperoxia after a short cardiac arrest exacerbates impaired mitochondrial function. The overall clinical significance of these findings is unclear and requires additional work to better understand the role of post-arrest hyperoxia on cardiac and mitochondrial function. PMID- 22208179 TI - Delayed high-quality CPR does not improve outcomes. AB - AIM OF STUDY: The quality of cardiopulmonary resuscitation (CPR) is an important factor in the outcome of cardiac arrest. Our objective was to compare outcomes following either immediate low-quality (LQ) CPR or delayed high-quality (HQ) CPR. We hypothesized that delayed HQ CPR will improve the outcomes of CPR in comparison to immediately performing LQ CPR. METHODS: Eighteen Sprague-Dawley rats were randomized into two groups: (1) Delayed HQ CPR (HQ group, n = 9). (2) Immediate LQ CPR (LQ group, n = 9). Ventricular fibrillation (VF) was induced and untreated for 8 mins. CPR was immediately performed in LQ group for 5 mins. Compression depth was set at 70% of the "optimal compression depth". VF was untreated for an additional 5 mins in HQ group. HQ CPR was started together with ventilation (100% oxygen) and external hypothermia for 8 mins in both groups. The "optimal compression depth" was approximately 30% of the anteroposterior chest diameter. Epinephrine was administrated 3 mins prior to defibrillation attempt. Restoration of spontaneous circulation, postresuscitation myocardial function and survival time were monitored. RESULTS: All animals in the LQ group and 7 of 9 animals in the HQ group were resuscitated. Myocardial function, including ejection fraction and cardiac output was better in the LQ group than in the HQ group (p < 0.05) and survival time was longer in the LQ group (p < 0.05). CONCLUSION: The outcomes after immediate LQ CPR, were better than those after delayed HQ CPR in this rat model of cardiac arrest and resuscitation. PMID- 22208180 TI - Shock advisory system with minimal delay triggering after end of chest compressions: accuracy and gained hands-off time. AB - AIMS: Shortening hands-off intervals can improve benefits from defibrillation. This study presents the performance of a shock advisory system (SAS), which aims to decrease the pre-shock pauses by triggering fast rhythm analysis at minimal delay after end of chest compressions (CC). METHODS: The SAS is evaluated on a database of 1301 samples from 311 out-of-hospital cardiac arrests (OHCA) from automated external defibrillators (AEDs). The following rhythms are identified: 788 asystoles (ASYS), 20 normal sinus rhythms (NSR), 394 other non-shockable rythms (ONS), 81 ventricular fibrillations (VF), 18 rapid ventricular tachycardias (VThi). SAS is launched in two-stages: first stage for accurate detection of actual end of CC (ReEoCC); second stage for early "Shock"/"No-Shock" decision by using all available artifact-free ECG signals after REoCC during 3, 5, 7 s. RESULTS: Performance of the presented SAS versus AEDs is compared. The median hands-off time gained from earlier starting of ECG analysis is 5.8 s and for earlier shock advice is 12.5 s to 8.5 s when SAS rhythm analysis lasts 3 s to 7 s. The SAS accuracy at 3-7 s is: specificity 97.7-98.9% (ASYS), 100-100% (NSR), 98.5-99.2% (ONS); sensitivity 91.4-98.8% (VF), 88.9-96.7% (VThi). CONCLUSION: This study indicates that shortening the pre-shock hands-off pause by more efficient management of the SAS process in AEDs is possible. For analysis duration of 5 s (7 s), the delay between the end of chest compressions and the shock advice can be reduced by 10.5 s (8.5 s) median, while AHA requirements for rhythm detection accuracy are met. The use of this solution in AEDs could provide more reliable rhythm analysis than methods applying filtering techniques during CC. PMID- 22208182 TI - Use of a health information exchange system in the emergency care of children. AB - BACKGROUND: Children may benefit greatly in terms of safety and care coordination from the information sharing promised by health information exchange (HIE). While information exchange capability is a required feature of the certified electronic health record, we known little regarding how this technology is used in general and for pediatric patients specifically. METHODS: Using data from an operational HIE effort in central Texas, we examined the factors associated with actual system usage. The clinical and demographic characteristics of pediatric ED encounters (n = 179,445) were linked to the HIE system user logs. Based on the patterns of HIE system screens accessed by users, we classified each encounter as: no system usage, basic system usage, or novel system usage. Using crossed random effects logistic regression, we modeled the factors associated with basic and novel system usage. RESULTS: Users accessed the system for 8.7% of encounters. Increasing patient comorbidity was associated with a 5% higher odds of basic usage and 15% higher odds for novel usage. The odds of basic system usage were lower in the face of time constraints and for patients who had not been to that location in the previous 12 months. CONCLUSIONS: HIE systems may be a source to fulfill users' information needs about complex patients. However, time constraints may be a barrier to usage. In addition, results suggest HIE is more likely to be useful to pediatric patients visiting ED repeatedly. This study helps fill an existing gap in the study of technological applications in the care of children and improves knowledge about how HIE systems are utilized. PMID- 22208183 TI - Inhibition of tobacco bacterial wilt with sulfone derivatives containing an 1,3,4 oxadiazole moiety. AB - A series of new sulfone compounds containing the 1,3,4-oxadiazole moiety were designed and synthesized. Their structures were identified by (1)H and (13)C nuclear magnetic resonance and elemental analyses. Antibacterial bioassays indicated that most compounds exhibited promising in vitro antibacterial bioactivities against tobacco bacterial wilt at 200 MUg/mL. The relationship between structure and antibacterial activity was also discussed. Among the title compounds, 5'c, 5'h, 5'i, and 5'j could inhibit mycelia growth of Ralstonia solanacearum in vitro by approximately 50% (EC(50)) at 39.8, 60.3, 47.9, and 32.1 MUg/mL, respectively. Among them, compound 5'j was identified as the most promising candidate due to its stronger effect than that of Kocide 3000 [Cu(OH)(2)] within the same concentration range. Field trials demonstrated that the control effect of compound 5'j against tobacco bacterial wilt was better than that of the commercial bactericide Saisentong. For the first time, the present work demonstrated that sulfone derivatives containing 1,3,4-oxadiazole can be used to develop potential bactericides for plants. PMID- 22208184 TI - Fluorescence correlation spectroscopy: past, present, future. AB - In recent years fluorescence correlation spectroscopy (FCS) has become a routine method for determining diffusion coefficients, chemical rate constants, molecular concentrations, fluorescence brightness, triplet state lifetimes, and other molecular parameters. FCS measures the spatial and temporal correlation of individual molecules with themselves and so provides a bridge between classical ensemble and contemporary single-molecule measurements. It also provides information on concentration and molecular number fluctuations for nonlinear reaction systems that complement single-molecule measurements. Typically implemented on a fluorescence microscope, FCS samples femtoliter volumes and so is especially useful for characterizing small dynamic systems such as biological cells. In addition to its practical utility, however, FCS provides a window on mesoscopic systems in which fluctuations from steady states not only provide the basis for the measurement but also can have important consequences for the behavior and evolution of the system. For example, a new and potentially interesting field for FCS studies could be the study of nonequilibrium steady states, especially in living cells. PMID- 22208185 TI - Cardiac bidomain bath-loading effects during arrhythmias: interaction with anatomical heterogeneity. AB - Cardiac tissue is always surrounded by conducting fluid, both in vivo (blood) and in experimental preparations (Tyrode's solution), which acts to increase conduction velocity (CV) close to the tissue-fluid interface, inducing transmural wavefront curvature. Despite its potential importance, computer modeling studies focused on arrhythmia mechanisms have previously not accounted for these bath loading effects. Here, we investigate the increase in CV and concomitant change in transmural wavefront profiles upon both propagation and arrhythmia dynamics within models of differing anatomical complexity. In simplified slab models, in absence of transmural fiber rotation, bath-loading induced transmural wavefront curvature dominates, significantly increasing arrhythmia complexity compared to no bath. In the presence of fiber rotation, bath-loading effects are less striking and depend upon propagation direction: the bath accentuates natural concave curvature caused by transmurally rotating fibers, but attenuates convex curvature, which negates overall impact upon arrhythmia complexity. Finally, we demonstrate that the high degree of anatomical complexity within whole ventricular models modulates bath-loading induced transmural wavefront curvature. However, key is the increased surface CV that dramatically reduces both arrhythmia inducibility and resulting complexity by increasing wavelength and reducing the available excitable gap. Our findings highlight the importance of including bath-loading effects during arrhythmia mechanism investigations, which could have implications for interpreting and comparing simulation results with experimental data where such effects are inherently present. PMID- 22208186 TI - Effects of macromolecular crowding on genetic networks. AB - The intracellular environment is crowded with proteins, DNA, and other macromolecules. Under physiological conditions, macromolecular crowding can alter both molecular diffusion and the equilibria of bimolecular reactions and therefore is likely to have a significant effect on the function of biochemical networks. We propose a simple way to model the effects of macromolecular crowding on biochemical networks via an appropriate scaling of bimolecular association and dissociation rates. We use this approach, in combination with kinetic Monte Carlo simulations, to analyze the effects of crowding on a constitutively expressed gene, a repressed gene, and a model for the bacteriophage lambda genetic switch, in the presence and absence of nonspecific binding of transcription factors to genomic DNA. Our results show that the effects of crowding are mainly caused by the shift of association-dissociation equilibria rather than the slowing down of protein diffusion, and that macromolecular crowding can have relevant and counterintuitive effects on biochemical network performance. PMID- 22208187 TI - A multiscale investigation of repolarization variability and its role in cardiac arrhythmogenesis. AB - Enhanced temporal and spatial variability in cardiac repolarization has been related to increased arrhythmic risk both clinically and experimentally. Causes and modulators of variability in repolarization and their implications in arrhythmogenesis are however not well understood. At the ionic level, the slow component of the delayed rectifier potassium current (I(Ks)) is an important determinant of ventricular repolarization. In this study, a combination of experimental and computational multiscale studies is used to investigate the role of intrinsic and extrinsic noise in I(Ks) in modulating temporal and spatial variability in ventricular repolarization in human and guinea pig. Results show that under physiological conditions: i), stochastic fluctuations in I(Ks) gating properties (i.e., intrinsic noise) cause significant beat-to-beat variability in action potential duration (APD) in isolated cells, whereas cell-to-cell differences in channel numbers (i.e., extrinsic noise) also contribute to cell-to cell APD differences; ii), in tissue, electrotonic interactions mask the effect of I(Ks) noise, resulting in a significant decrease in APD temporal and spatial variability compared to isolated cells. Pathological conditions resulting in gap junctional uncoupling or a decrease in repolarization reserve uncover the manifestation of I(Ks) noise at cellular and tissue level, resulting in enhanced ventricular variability and abnormalities in repolarization such as afterdepolarizations and alternans. PMID- 22208188 TI - Regulation of cell adhesion strength by peripheral focal adhesion distribution. AB - Cell adhesion to extracellular matrices is a tightly regulated process that involves the complex interplay between biochemical and mechanical events at the cell-adhesive interface. Previous work established the spatiotemporal contributions of adhesive components to adhesion strength and identified a nonlinear dependence on cell spreading. This study was designed to investigate the regulation of cell-adhesion strength by the size and position of focal adhesions (FA). The cell-adhesive interface was engineered to direct FA assembly to the periphery of the cell-spreading area to delineate the cell-adhesive area from the cell-spreading area. It was observed that redistributing the same adhesive area over a larger cell-spreading area significantly enhanced cell adhesion strength, but only up to a threshold area. Moreover, the size of the peripheral FAs, which was interpreted as an adhesive patch, did not directly govern the adhesion strength. Interestingly, this is in contrast to the previously reported functional role of FAs in regulating cellular traction where sizes of the peripheral FAs play a critical role. These findings demonstrate, to our knowledge for the first time, that two spatial regimes in cell-spreading area exist that uniquely govern the structure-function role of FAs in regulating cell adhesion strength. PMID- 22208189 TI - Cys-loop receptor channel blockers also block GLIC. AB - The Gloeobacter ligand-gated ion channel (GLIC) is a bacterial homolog of vertebrate Cys-loop ligand-gated ion channels. Its pore-lining region in particular has a high sequence homology to these related proteins. Here we use electrophysiology to examine a range of compounds that block the channels of Cys loop receptors to probe their pharmacological similarity with GLIC. The data reveal that a number of these compounds also block GLIC, although the pharmacological profile is distinct from these other proteins. The most potent compound was lindane, a GABA(A) receptor antagonist, with an IC50 of 0.2 MUM. Docking studies indicated two potential binding sites for this ligand in the pore, at the 9' or between the 0' and 2' residues. Similar experiments with picrotoxinin (IC50 = 2.6 MUM) and rimantadine (IC50 = 2.6 MUM) reveal interactions with 2'Thr residues in the GLIC pore. These locations are strongly supported by mutagenesis data for picrotoxinin and lindane, which are less potent in a T2'S version of GLIC. Overall, our data show that the inhibitory profile of the GLIC pore has considerable overlap with those of Cys-loop receptors, but the GLIC pore has a unique pharmacology. PMID- 22208190 TI - Nucleation and decay initiation are the stiffness-sensitive phases of focal adhesion maturation. AB - A cell plated on a two-dimensional substrate forms adhesions with that surface. These adhesions, which consist of aggregates of various proteins, are thought to be important in mechanosensation, the process by which the cell senses and responds to the mechanical properties of the substrate (e.g., stiffness). On the basis of experimental measurements, we model these proteins as idealized molecules that can bind to the substrate in a strain-dependent manner and can undergo a force-dependent state transition. The model forms molecular aggregates that are similar to adhesions. Substrate stiffness affects whether a simulated adhesion is initially formed and how long it grows, but not how that adhesion grows or shrinks. Our own experimental tests support these predictions, suggesting that the mechanosensitivity of adhesions is an emergent property of a simple molecular-mechanical system. PMID- 22208191 TI - Aqueous viscosity is the primary source of friction in lipidic pore dynamics. AB - A new theory, to our knowledge, is developed that describes the dynamics of a lipidic pore in a liposome. The equations of the theory capture the experimentally observed three-stage functional form of pore radius over time- stage 1, rapid pore enlargement; stage 2, slow pore shrinkage; and stage 3, rapid pore closure. They also show that lipid flow is kinetically limited by the values of both membrane and aqueous viscosity; therefore, pore evolution is affected by both viscosities. The theory predicts that for a giant liposome, tens of microns in radius, water viscosity dominates over the effects of membrane viscosity. The edge tension of a lipidic pore is calculated by using the theory to quantitatively account for pore kinetics in stage 3, rapid pore closing. This value of edge tension agrees with the value as standardly calculated from the stage of slow pore closure, stage 2. For small, submicron liposomes, membrane viscosity affects pore kinetics, but only if the viscosity of the aqueous solution is comparable to that of distilled water. A first-principle fluid mechanics calculation of the friction due to aqueous viscosity is in excellent agreement with the friction obtained by applying the new theory to data of previously published experimental results. PMID- 22208192 TI - On the combined analysis of 2H and 15N/1H solid-state NMR data for determination of transmembrane peptide orientation and dynamics. AB - The dynamics of membrane-spanning peptides have a strong affect on the solid state NMR observables. We present a combined analysis of 2H-alanine quadrupolar splittings together with 15N/(1)H dipolar couplings and 15N chemical shifts, using two models to treat the dynamics, for the systematic evaluation of transmembrane peptides based on the GWALP23 sequence (acetyl-GGALW(LA)6LWLAGA amide). The results indicate that derivatives of GWALP23 incorporating diverse guest residues adopt a range of apparent tilt angles that span 5 degrees -35 degrees in lipid bilayer membranes. By comparing individual and combined analyses of specifically 2H- or 15N-labeled peptides incorporated in magnetically or mechanically aligned lipid bilayers, we examine the influence of data-set size/identity, and of explicitly modeled dynamics, on the deduced average orientations of the peptides. We conclude that peptides with small apparent tilt values (<~10 degrees ) can be fitted by extensive families of solutions, which can be narrowed by incorporating additional 15N as well as 2H restraints. Conversely, peptides exhibiting larger tilt angles display more narrow distributions of tilt and rotation that can be fitted using smaller sets of experimental constraints or even with 2H or 15N data alone. Importantly, for peptides that tilt significantly more than 10 degrees from the bilayer-normal, the contribution from rigid body dynamics can be approximated by a principal order parameter. PMID- 22208193 TI - Effects of sphingosine 2N- and 3O-methylation on palmitoyl ceramide properties in bilayer membranes. AB - To study the role of the interfacial properties of ceramides in their interlipid interactions, we synthesized palmitoylceramide (PCer) analogs in which a methyl group was introduced to the amide-nitrogen or the C3-oxygen of the sphingosine backbone. A differential scanning calorimetry analysis of equimolar mixtures of palmitoylsphingomyelin (PSM) and PCer showed that these sphingolipids formed a complex gel phase that melted between 67 degrees C and 74 degrees C. The PCer analogs also formed gel phases with PSM, but they melted at lower temperatures compared with the system with PCer. In complex bilayers composed of an unsaturated glycerophospholipid, PSM, and cholesterol, the 3O-methylated ceramide formed a cholesterol-poor ordered phase with PSM. However, the 2N-methylated and doubly methylated (2N and 3O) PCer analogs failed to displace sterol from interactions with PSM. Like PCer, the analogs reduced sterol affinity for the complex bilayers, but this effect was most pronounced for the 3O-methylated ceramide. Taken together, our results show that 2N-methylation weakened the ceramide-PSM interactions, whereas the 3O-methylated ceramide behaved more like PCer in interactions with PSM. Our findings are compatible with the view that interlipid interactions between the amide-nitrogen and neighboring lipids are important for the cohesive properties of sphingolipids in membranes, and this also appears to be a valid model for ceramide. PMID- 22208194 TI - KL4 peptide induces reversible collapse structures on multiple length scales in model lung surfactant. AB - We investigated the effects of KL4, a 21-residue amphipathic peptide approximating the overall ratio of positively charged to hydrophobic amino acids in surfactant protein B (SP-B), on the structure and collapse of dipalmitoylphosphatidylcholine and palmitoyl-oleoyl-phosphatidylglycerol monolayers. As reported in prior work on model lung surfactant phospholipid films containing SP-B and SP-B peptides, our experiments show that KL4 improves surfactant film reversibility during repetitive interfacial cycling in association with the formation of reversible collapse structures on multiple length scales. Emphasis is on exploring a general mechanistic connection between peptide-induced nano- and microscale reversible collapse structures (silos and folds). PMID- 22208195 TI - Optimized torsion-angle normal modes reproduce conformational changes more accurately than cartesian modes. AB - We present what to our knowledge is a new method of optimized torsion-angle normal-mode analysis, in which the normal modes move along curved paths in Cartesian space. We show that optimized torsion-angle normal modes reproduce protein conformational changes more accurately than Cartesian normal modes. We also show that orthogonalizing the displacement vectors from torsion-angle normal mode analysis and projecting them as straight lines in Cartesian space does not lead to better performance than Cartesian normal modes. Clearly, protein motion is more naturally described by curved paths in Cartesian space. PMID- 22208196 TI - Modulation of microtubule interprotofilament interactions by modified taxanes. AB - Microtubules assembled with paclitaxel and docetaxel differ in their numbers of protofilaments, reflecting modification of the lateral association between alphabeta-tubulin molecules in the microtubule wall. These modifications of microtubule structure, through a not-yet-characterized mechanism, are most likely related to the changes in tubulin-tubulin interactions responsible for microtubule stabilization by these antitumor compounds. We have used a set of modified taxanes to study the structural mechanism of microtubule stabilization by these ligands. Using small-angle x-ray scattering, we have determined how modifications in the shape and size of the taxane substituents result in changes in the interprotofilament angles and in their number. The observed effects have been explained using NMR-aided docking and molecular dynamic simulations of taxane binding at the microtubule pore and luminal sites. Modeling results indicate that modification of the size of substituents at positions C7 and C10 of the taxane core influence the conformation of three key elements in microtubule lateral interactions (the M-loop, the S3 beta-strand, and the H3 helix) that modulate the contacts between adjacent protofilaments. In addition, modifications of the substituents at position C2 slightly rearrange the ligand in the binding site, modifying the interaction of the C7 substituent with the M-loop. PMID- 22208197 TI - Accurate flexible fitting of high-resolution protein structures to small-angle x ray scattering data using a coarse-grained model with implicit hydration shell. AB - Small-angle x-ray scattering (SAXS) is a powerful technique widely used to explore conformational states and transitions of biomolecular assemblies in solution. For accurate model reconstruction from SAXS data, one promising approach is to flexibly fit a known high-resolution protein structure to low resolution SAXS data by computer simulations. This is a highly challenging task due to low information content in SAXS data. To meet this challenge, we have developed what we believe to be a novel method based on a coarse-grained (one bead-per-residue) protein representation and a modified form of the elastic network model that allows large-scale conformational changes while maintaining pseudobonds and secondary structures. Our method optimizes a pseudoenergy that combines the modified elastic-network model energy with a SAXS-fitting score and a collision energy that penalizes steric collisions. Our method uses what we consider a new implicit hydration shell model that accounts for the contribution of hydration shell to SAXS data accurately without explicitly adding waters to the system. We have rigorously validated our method using five test cases with simulated SAXS data and three test cases with experimental SAXS data. Our method has successfully generated high-quality structural models with root mean-squared deviation of 1 ~ 3 A from the target structures. PMID- 22208198 TI - Visual analysis of concerted cleavage by type IIF restriction enzyme SfiI in subsecond time region. AB - Many DNA regulatory factors require communication between distantly separated DNA sites for their activity. The type IIF restriction enzyme SfiI is often used as a model system of site communication. Here, we used fast-scanning atomic force microscopy to monitor the DNA cleavage process with SfiI and the changes in the single SfiI-DNA complex in the presence of either Mg2+ or Ca2+ at a scan rate of 1-2 fps. The increased time resolution allowed us to visualize the concerted cleavage of the protein at two cognate sites. The four termini generated by the cleavage were released in a multistep manner. The high temporal resolution enabled us to visualize the translocation of a DNA strand on a looped complex and intersegmental transfer of the SfiI protein in which swapping of the site is performed without protein dissociation. On the basis of our results, we propose that the SfiI tetramer can remain bound to one of the sites even after cleavage, allowing the other site on the DNA molecule to fill the empty DNA-binding cleft by combining a one-dimensional diffusion-mediated sliding and a segment transfer mechanism. PMID- 22208201 TI - Comparative studies on IR, Raman, and surface enhanced Raman scattering spectroscopy of dipeptides containing DeltaAla and DeltaPhe. AB - Three dipeptides containing dehydroresidues (DeltaAla, Delta((Z))Phe, and Delta((E))Phe) were examined by IR, Raman, and surface-enhanced Raman techniques for the first time. The effect of the size and isomer type of the beta substituent in the dehydroresidue on the conformational structure of the peptide was evaluated by using the analysis of IR and Raman bands. Additionally, SERS spectroscopy provided insight into the adsorption mechanism of these species on the metal surface. SERS spectra were recorded at alkaline pH on the silver sol using visible light excitation. The dehydroresidues studied here strongly influenced the SERS profile of the peptides. The most pronounced SERS signal for all dipeptides was assigned to the symmetric stretching vibration of the carboxylate ions. This indicates that the dehydropeptides studied here primarily adsorb via the deprotonated carboxylic group. Additionally, the enhanced SERS bands in the range 1550-1650 cm(-1) show differences in contribution of the dehydroresidue to the adsorption mechanism of the studied peptides. PMID- 22208199 TI - Atomistic ensemble modeling and small-angle neutron scattering of intrinsically disordered protein complexes: applied to minichromosome maintenance protein. AB - The minichromosome maintenance (MCM) proteins are thought to function as the replicative helicases in archaea and eukarya. In this work we determined the solution structure of the N-terminal portion of the MCM complex from the archaeon Methanothermobacter thermautotrophicus (N-mtMCM) in the presence and absence of DNA using small-angle neutron scattering (SANS). N-mtMCM is a multimeric protein complex that consists of 12 monomers, each of which contains three distinct domains and two unstructured regions. Using an all-atom approach incorporating modern force field and Monte Carlo methods to allow the unstructured regions of each monomer to be varied independently, we generated an ensemble of biologically relevant structures for the complex. An examination of the subsets of structures that were most consistent with the SANS data revealed that large movements between the three domains of N-mtMCM can occur in solution. Furthermore, changes in the SANS curves upon DNA binding could be correlated to the motion of a particular N-mtMCM domain. These results provide structural support to the previously reported biochemical observations that large domain motions are required for the activation of the MCM helicase in archaea and eukarya. The methods developed here for N-mtMCM solution structure modeling should be suitable for other large protein complexes with unstructured flexible regions. PMID- 22208202 TI - Impact of a six-year integrated thoracic surgery training program at the Medical College of Wisconsin. AB - BACKGROUND: Thoracic residency program enrollment continues to decline. While job market and decreasing reimbursements are often cited as the main reasons, length of and format of training may also be significant. METHODS: The Medical College of Wisconsin established an Accreditation Council for Graduate Medical Education approved 6-year integrated thoracic training program. The number and characteristics of applicants to the 6-year program were then compared with previous applicants applying to the traditional 2-year program. RESULTS: Applicants to the 6-year integrated program scored higher on the United States Medical Licensing Examination part 1 and part 2 than previous applicants to the traditional 2-year program. The 6-year applicants also were more published and a greater percentage of them held other advanced degrees. CONCLUSIONS: Institution of a 6-year integrated thoracic surgery training program at the Medical College of Wisconsin led to a significant increase in number of applications. Additionally, the 6-year applicants appeared to be more academically accomplished than previous applicants to the traditional 2-year program. While early in the experience, it appears that interest in thoracic surgery is high among medical students and institution of a 6-year program has the potential to once again attract the "best and the brightest" to this specialty. PMID- 22208206 TI - A demonstration of the impact of stress abatement programs on reducing employees' accidents and their costs. PMID- 22208205 TI - Management aspects of fitness program development. PMID- 22208203 TI - Congenital dyserythropoietic anemia type II: molecular analysis and expression of the SEC23B gene. AB - BACKGROUND: Congenital dyserythropoietic anemia type II (CDAII), the most common form of CDA, is an autosomal recessive condition. CDAII diagnosis is based on invasive, expensive, and time consuming tests that are available only in specialized laboratories. The recent identification of SEC23B mutations as the cause of CDAII opens new possibilities for the molecular diagnosis of the disease. The aim of this study was to characterize molecular genomic SEC23B defects in 16 unrelated patients affected by CDAII and correlate the identified genetic alterations with SEC23B transcript and protein levels in erythroid precursors. METHODS: SEC23B was sequenced in 16 patients, their relatives and 100 control participants. SEC23B transcript level were studied by quantitative PCR (qPCR) in peripheral erythroid precursors and lymphocytes from the patients and healthy control participants. Sec23B protein content was analyzed by immunoblotting in samples of erythroblast cells from CDAII patients and healthy controls. RESULTS: All of the investigated cases carried SEC23B mutations on both alleles, with the exception of two patients in which a single heterozygous mutation was found. We identified 15 different SEC23B mutations, of which four represent novel mutations: p.Gln214Stop, p.Thr485Ala, p.Val637Gly, and p.Ser727Phe. The CDAII patients exhibited a 40-60% decrease of SEC23B mRNA levels in erythroid precursors when compared with the corresponding cell type from healthy participants. The largest decrease was observed in compound heterozygote patients with missense/nonsense mutations. In three patients, Sec23B protein levels were evaluated in erythroid precursors and found to be strictly correlated with the reduction observed at the transcript level. We also demonstrate that Sec23B mRNA expression levels in lymphocytes and erythroblasts are similar. CONCLUSIONS: In this study, we identified four novel SEC23B mutations associated with CDAII disease. We also demonstrate that the genetic alteration results in a significant decrease of SEC23B transcript in erythroid precursors. Similar down regulation was observed in peripheral lymphocytes, suggesting that the use of these cells might be sufficient in the identification of Sec23B gene alterations. Finally, we demonstrate that decreased Sec23B protein levels in erythroid precursors correlate with down-regulation of the SEC23B mRNA transcript. PMID- 22208208 TI - From short term compliance to long term freedom: culture-based health promotion by health professionals. PMID- 22208207 TI - The social component of health. PMID- 22208209 TI - Health behavior and health promotion. PMID- 22208210 TI - Campbell Soup Company's Turnaround Health and Fitness Program. PMID- 22208211 TI - Research agenda: building a concensus on research questions. PMID- 22208212 TI - Data base: research and evaluation results. PMID- 22208214 TI - Networking. PMID- 22208215 TI - Professional association networking application american journal of health promotion. PMID- 22208216 TI - Profile of an outstanding networking effort: north american networking workshop on health and fitness, 1986. PMID- 22208218 TI - Perspectives on the rest of the world. PMID- 22208217 TI - Resource reviews. PMID- 22208220 TI - Oxidation of phenolic endocrine disrupting chemicals by potassium permanganate in synthetic and real waters. AB - In this study, five selected environmentally relevant phenolic endocrine disrupting chemicals (EDCs), estrone, 17beta-estradiol, estriol, 17alpha ethinylestradiol, and 4-n-nonylphenol, were shown to exhibit similarly appreciable reactivity toward potassium permanganate [Mn(VII)] with a second order rate constant at near neutral pH comparable to those of ferrate(VI) and chlorine but much lower than that of ozone. In comparison with these oxidants, however, Mn(VII) was much more effective for the oxidative removal of these EDCs in real waters, mainly due to the relatively high stability of Mn(VII) therein. Mn(VII) concentrations at low micromolar range were determined by an ABTS [2,2 azino-bis(3-ethylbenzothiazoline)-6-sulfonic acid diammonium] spectrophotometric method based on the stoichiometric reaction of Mn(VII) with ABTS [Mn(VII) + 5ABTS -> Mn(II) + 5ABTS(*+)] forming a stable green radical cation (ABTS(*+)). Identification of oxidation products suggested the initial attack of Mn(VII) at the hydroxyl group in the aromatic ring of EDCs, leading to a series of quinone like and ring-opening products. The background matrices of real waters as well as selected model ligands including phosphate, pyrophosphate, NTA, and humic acid were found to accelerate the oxidation dynamics of these EDCs by Mn(VII). This was explained by the effect of in situ formed dissolved Mn(III), which could readily oxidize these EDCs but would disproportionate spontaneously without stabilizing agents. PMID- 22208223 TI - Immediate placement and provisionalization with buccal plate preservation: a case report of a new technique. PMID- 22208224 TI - Immunotoxicity activity from the essential oils of coriander (Coriandrum sativum) seeds. AB - The seeds of the Coriandrum sativum were extracted and the essential oil composition and immunotoxicity effects were studied. The analysis of the essential oil was conducted by gas chromatography-mass spectroscopy, which revealed 33 components, representing 99.99% of the total oil from the seeds of coriander. The major components are linalool (55.09%), alpha-pinene (7.49%), 2,6 Octadien-1-ol, 3,7-dimethyl-, acetate, (E)- (5.70%), geraniol (4.83%), 3 Cyclohexene-1-methanol, alpha,alpha,4-trimethyl- (4.72%), hexadecanoic acid (2.65%), tetradecanoic acid (2.49%), 2-alpha-pinene (2.39%), citronellyl acetate (1.77%), and undecanal (1.29%). The seed oil had significant toxic effects against the larvae of Aedes aegypti with an LC(50) value of 21.55 ppm and LC(90) value of 38.79 ppm. The above data indicate that the major components in the essential oil of coriander play an important role as immunotoxicity on the A. aegypti. PMID- 22208249 TI - A conversation on definition of life. PMID- 22208250 TI - The complexity of life: can life be simply defined? PMID- 22208251 TI - Attempts to define life do not help to understand the origin of life. PMID- 22208252 TI - Trifonov's meta-definition of life. PMID- 22208253 TI - Defining life: an exercise in semantics or a route to biological insights? PMID- 22208254 TI - Merits and caveats of using a vocabulary approach to define life. PMID- 22208255 TI - Self-generated and reproducible dynamics in "gene years" represent life. PMID- 22208256 TI - A minimal or concise set of definition of life is not useful. PMID- 22208257 TI - On the misgivings of anthropomorphic consensus polling in defining the complexity of life. PMID- 22208258 TI - The role of logic and insight in the search for a definition of life. PMID- 22208259 TI - Life = self-reproduction with variations? PMID- 22208260 TI - Life: self-directing with unlimited variability on self-speeding. PMID- 22208261 TI - Classifying the properties of life. PMID- 22208262 TI - Defining life: products or processes? PMID- 22208263 TI - Life? PMID- 22208264 TI - Is A n+1 definition of life useful? PMID- 22208265 TI - Thermodynamic inversion and self-reproduction with variations: integrated view on the life-nonlife border. PMID- 22208266 TI - Life in its uniqueness remains difficult to define in scientific terms. PMID- 22208267 TI - Definition by means of indefiniteness. PMID- 22208268 TI - The definition of life and the life of a definition. PMID- 22208269 TI - Definition of life: navigation through uncertainties. PMID- 22208270 TI - Computational evidence to inhibition of human acetyl cholinesterase by withanolide a for Alzheimer treatment. AB - Alzheimer's disease (AD), a neurodegenerative disorder, is the most common cause of dementia. So far only five drugs have been approved by US FDA that temporarily slow worsening of symptoms for about six to twelve months. The limited number of therapeutic options for AD drives the exploration of new drugs. Enhancement of the central cholinergic function by the inhibition of acetylcholinesterase is a prominent clinically effective approach for the treatment of AD. Recently withanolide A, a secondary metabolite from the ayurvedic plant Withania somnifera has shown substantial neuro-protective ability. The present study is an attempt to elucidate the cholinesterase inhibition potential of withanolide A along with the associated binding mechanism. Our docking simulation results predict high binding affinity of the ligand to the receptor. Further, long de novo simulations for 10 ns suggest that ligand interaction with the residues Thr78, Trp81, Ser120 and His442 of human acetylcholinesterase, all of which fall under one or other of the active sites/subsites, could be critical for its inhibitory activity. The study provides evidence for consideration of withanolide A as a valuable small ligand molecule in treatment and prevention of AD associated pathology. The present information could be of high value for computational screening of AD drugs with low toxicity to normal cells. Accurate knowledge of the 3D structure of human acetylcholinesterase would further enhance the potential of such analysis in understanding the molecular interaction basis between ligand and receptor. PMID- 22208271 TI - Modelling and bioinformatics analysis of the dimeric structure of house dust mite allergens from families 5 and 21: Der f 5 could dimerize as Der p 5. AB - Allergy represents an increasing thread to public health in both developed and emerging countries and the dust mites Dermatophagoides pteronyssinus (Der p), Blomia tropicalis (Blo t), Dermatophagoides farinae (Der f), Lepidoglyphus destructor (Lep d) and Suidasia medanensis (Sui m) strongly contribute to this problem. Their allergens are classified in several families among which families 5 and 21 which are the subject of this work. Indeed, their biological function as well as the mechanism or epitopes by which they are contributing to the allergic response remain unknown and their tridimensional structures have not been resolved experimentally except for Blo t 5 and Der p 5. Blo t 5 is a monomeric three helical bundle, whereas Der p 5 shows a three helical bundle with a kinked N-terminal helix that assembles in an entangled dimeric structure with a large hydrophobic cavity. This cavity could be involved in the binding of hydrophobic ligands, which in turn could be responsible for the shift of the immune response from tolerance to allergic inflammation. We used molecular modelling approaches to bring out if other house dust mite allergens of families 5 and 21 (Der f 5, Sui m 5, Lep d 5, Der p 21 and Der f 21) could dimerize and form a large cavity in the same way as Der p 5. Monomeric models were first performed with MODELLER using the experimental structures of Der p 5 and Blo t 5 as templates. The ClusPro server processed the selected monomers in order to assess their capacity to form dimeric structures with a positive result for Der p 5 and Der f 5 only. The other allergens (Blo t 5, Sui m 5, Lep d 5, Der p 21 and Der f 21) did not present such a propensity. Moreover, we identified mutations that should destabilize and/or prevent the formation of the Der p 5 dimeric structure. The production of these mutated proteins could help us to understand the role of the dimerization process in the allergic response induced by Der p 5, and if Der p 5 and Der f 5 behave similarly. PMID- 22208272 TI - Molecular dynamics simulation study explaining inhibitor selectivity in different class of histone deacetylases. AB - Histone deacetylases (HDACs) are key regulators of gene expression and thereby compelling targets in the treatment of various cancers. Class- and isoform selective HDAC inhibitors targeting the particular isoform to treat cancers without affecting the normal expression of other isoforms are highly desirable. Molecular dynamics simulations were performed with the set of selective inhibitors and HDAC isoforms of three different classes. The results were compared both within and across the isoforms. The hydrogen bonds between protein and inhibitors are directly correlated with the selective experimental activity. The calculated distances between important amino acids and the metal binding part of inhibitors have disclosed the optimal distance to be maintained by a selective inhibitor. In addition, the calculated non-bonded interaction energies between inhibitor and catalytic residues revealed that the subtle difference in the amino acids at the highly conserved active sites of HDAC isoforms effectively scripts the selectivity story observed experimentally. The results of this study provide valuable information in designing highly selective HDAC inhibitors. PMID- 22208273 TI - Unveiling the unfolding pathway of F5F8D disorder-associated D81H/V100D mutant of MCFD2 via multiple molecular dynamics simulations. AB - Combined factor deficiency (F5F8D) is a rare autosomal recessive disorder caused by mutations in the LMAN1 or MCFD2 genes. It has been proposed that this pathogenic process occurs via a multi-step pathway involving metal loss, EF-hand Ca21 dissociation and assembly of misfolded MCFD2-LMAN1 complex. Here, we have investigated the solution conformations of the MCFD2((D81H,V100D)) protein mutant through extensive molecular dynamics (MD) simulations. The V100D, one of the many MCFD2 mutations known to be associated to F5F8D, is difficult to be reconciled with the pathway model because it is located far from the metal sites and the MCFD2/LMAN1 interface. Consequently, an inspection of all the steps involved in D81H/V100D MCFD2 misfolding is expected to provide hints in the understanding of the molecular basis of the disease. A comparison with parallel studies carried out for the Wild-Type (WT) MCFD2 pointed out that the mutation decreases the affinity of the protein for the Ca21 ion. Multiple explicit solvents MD simulations (50 ns) performed on the two proteins revealed that in the WT protein, stable H-bond network and compact hydrophobic core region are created thus confirming a pivotal role of this region in driving the biophysical properties of the entire protein. In fact it is shown that the V100D mutation, although located far away the EF-hand domain, may induce subtle modification in the structural core of MCFD2 leading to the loosening of metal binding and to the formation of metastable intermediate states along the unfolding pathway. The native-like hydrophobic cluster formed near the V100 residue in the wild-type protein is disrupted by the negatively charged Asparagine residue. Furthermore, the presence of the D81H mutation in the EF-1 hand domain may also increase the protein unfolding rate and consequently prevent the formation of the MCFD2-LMAN1 complex. The detailed structural insights obtained from our large-scale simulations complement the clinical features and offer useful insights into the mechanism behind MCFD2 protein misfolding. PMID- 22208274 TI - Recognition rules for binding of homeodomains to operator DNA. AB - The spatial arrangement of interfaces between homeodomain transcription factors and operator DNA has been considered. We analyzed the binding contacts for a representative set of 22 complexes of homeodomain transcription factors with a double-stranded operator DNA in the region of the major groove. It was shown that the recognition of DNA by the recognizing _-helix of protein is governed by two contact groups. Invariant protein-DNA group of contacts includes six contacts, formed by atomic groups of coding and non-coding DNA chains with the groups of amino acids. The recognizing _-helix forms contacts by polar groups of residues Trp2 (NE1), Asn5, and Lys9 with the canonical sequence T(1)A(2)A(3)T(4) of the coding DNA chain, and contacts by residues Lys0, Arg7 and Lys11 with the sequence A(4)X(5)X(6)X(7) of a non-coding DNA chain, where X is any nucleotide. Variable protein-DNA group of contacts comprises two groups bound with the sequence T(3)A(4)X(5)X(6) of the non- coding DNA-chain. These contacts are mainly with the bases and specify the binding pattern of individual homeodomains. The invariant contact group represents a recognition pattern for transcription factors of the homeodomain family: multiple adenine-asparagine contact and six position-specific phosphate contacts mainly with lysine or arginine. Within this group, we have found three most significant invariant contacts which allow deducing the recognition rules for homeodomains. These rules are inherent for different taxonomic groups of the homeodomain family and can distinguishing members of this family from any other family of transcription factors. PMID- 22208275 TI - Evolutionary patterning of hemagglutinin gene sequence of 2009 H1N1 pandemic. AB - The 2009 H1N1 swine flu is the first pandemic in decades. Infectivity of the influenza virus for human host depends largely on its ability to evade antibodies specific for viral protein called hemagglutinin (HA) that mediates attachment to the host. In the present study we analysed large number of HA gene sequences available in Flu Database maintained at NCBI. Our sequence based analysis clearly demonstrates that the amino acid usage pattern may dramatically change during the course of evolution, and there exists a clear link between a particular pattern of amino acid usage of HA genes and its potential to become infectious. Structural studies revealed how binding efficiency between the HA and sialic acid may alter the pandemic potential of infection. Our work highlights the evolutionary significance and biochemical basis of the selective advantage of certain amino acids of HA in 2009 and provides a link between the characteristics changes in HA protein and their potential to pronounce a global menace to public health. PMID- 22208276 TI - Dynamic and structural changes in the minimally restructuring EcoRI Bound to a minimally mutated DNA chain. AB - The dynamics of a protein plays an important role in protein functionality. Here, we examine the differences in the dynamics of a minimally restructuring protein, EcoRI, when it is bound to its cognate DNA and to a noncognate sequence which differs by just a single basepair. Molecular dynamics simulations of the complexes and essential dynamics analyses reveal that the overall dynamics of the protein subunits change from a coordinated motion in the cognate complex to a scrambled motion in the noncognate complex. This dynamical difference extends to the protein-DNA interface where EcoRI tries to constrict the DNA in the cognate complex. In the noncognate complex, absence of the constricting motion of interfacial residues, overall change in backbone dynamics and structural relaxation of the arms enfolding the DNA leave the DNA less-kinked relative to the situation in the cognate complex, thus indicating that the protein is poised for linear diffusion along the DNA rather than for catalytic action. In a larger context, the results imply that the DNA sequences dictate protein dynamics and that when a protein chances upon the recognition sequence some of the key domains of the protein undergo dynamical changes that prepare the protein for eventual catalytic action. PMID- 22208277 TI - Insights into protein - DNA interactions, stability and allosteric communications: a computational study of mutSalpha-DNA recognition complexes. AB - DNA mismatch repair proteins (MMR) maintain genetic stability by recognizing and repairing mismatched bases and insertion/deletion loops mistakenly incorporated during DNA replication, and initiate cellular response to certain types of DNA damage. Loss of MMR in mammalian cells has been linked to resistance to certain DNA damaging chemotherapeutic agents, as well as to increase risk of cancer. Mismatch repair pathway is considered to involve the concerted action of at least 20 proteins. The most abundant MMR mismatch-binding factor in eukaryotes, MutSalpha, recognizes and initiates the repair of base-base mismatches and small insertion/deletion. We performed molecular dynamics simulations on mismatched and damaged MutSalpha-DNA complexes. A comprehensive DNA binding site analysis of relevant conformations shows that MutSalpha proteins recognize the mismatched and platinum cross-linked DNA substrates in significantly different modes. Distinctive conformational changes associated with MutSalpha binding to mismatched and damaged DNA have been identified and they provide insight into the involvement of MMR proteins in DNA-repair and DNA-damage pathways. Stability and allosteric interactions at the heterodimer interface associated with the mismatch and damage recognition step allow for prediction of key residues in MMR cancer causing mutations. A rigorous hydrogen bonding analysis for ADP molecules at the ATPase binding sites is also presented. Due to extended number of known MMR cancer causing mutations among the residues proved to make specific contacts with ADP molecules, recommendations for further studies on similar mutagenic effects were made. PMID- 22208278 TI - Identification of the structural features that mediate binding specificity in the recognition of STAT proteins by dual-specificity phosphatases. AB - Inactivation of signal transducers and activators of transcription (STAT) proteins is regulated by dual-specificity phosphatases (DSPs) with high substrate specificity. Although experiments have provided useful information about the phosphatase activity and the specificity for STATs, there is up-to-date no data at a molecular level to explain the specific recognition of STAT substrates by this subfamily of phosphatases. Here, a combined approach of molecular modeling, docking and molecular dynamics simulations was used to address the binding between DSPs and their STAT substrates. We identified a binding interface at the protein tyrosine phosphatase (PTP) domain of the DSP VHR that interacts with the SH2-domain of STAT5. This finding is consistent with previous mutational data and supports a "two-step" mechanism for the dephosphorylation event. Application of the same approach suggests the presence of a similar interface between the viral DSP VH1 and STAT1. Furthermore, the interaction network at this interface provides an explanation for the specificity of the DSP-STAT recognition. PMID- 22208279 TI - Fast mapping of biomolecular interfaces by Random Spin Labeling (RSL). AB - Random spin labeling (RSL) is a method for rapid mapping of biomolecular interaction surfaces using an interaction partner with SL and an interaction partner enriched in (13)C or (15)N nuclei for paramagnetic relaxation enhanced NMR-based detection. The SL reaction is conducted in a manner resulting in a heterogeneous reaction product consisting of different populations of the protein carrying a varying number of spin labels at different positions. Preparation of the paramagnetic probe is complete within a few hours and hence much faster than site selective SL. RSL is applicable to tightly interacting systems but shows its particular strength when applied to systems involving weak or transient contacts. PMID- 22208282 TI - Peculiarities of copper binding to alpha-synuclein. AB - Heavy metals have been implicated as the causative agents for the pathogenesis of the most prevalent neurodegenerative disease. Various mechanisms have been proposed to explain the toxic effects of metals ranging from metal-induced oxidation of protein to metal-induced changes in the protein conformation. Aggregation of a-synuclein is implicated in Parkinson's disease (PD), and various metals, including copper, constitute a prominent group of alpha-synuclein aggregation enhancers. In this study, we have systematically characterized the a synuclein-Cu21 binding sites and analyzed the possible role of metal binding in a synuclein fibrillation using a set of biophysical techniques, such as electron paramagnetic resonance (EPR), electron spin-echo envelope modulation (ESEEM), circular dichroism (CD), and size exclusion chromatography (SEC). Our analyses indicated that a-synuclein possesses at least two binding sites for Cu21. We have been able to locate one of the binding sites in the N-terminal region. Furthermore, based on the EPR studies of model peptides and Beta-synuclein, we concluded that the suspected His residue did not appear to participate in strong Cu21 binding. PMID- 22208280 TI - SPINE-D: accurate prediction of short and long disordered regions by a single neural-network based method. AB - Short and long disordered regions of proteins have different preference for different amino acid residues. Different methods often have to be trained to predict them separately. In this study, we developed a single neural-network based technique called SPINE-D that makes a three-state prediction first (ordered residues and disordered residues in short and long disordered regions) and reduces it into a two-state prediction afterwards. SPINE-D was tested on various sets composed of different combinations of Disprot annotated proteins and proteins directly from the PDB annotated for disorder by missing coordinates in X ray determined structures. While disorder annotations are different according to Disprot and X-ray approaches, SPINE-D's prediction accuracy and ability to predict disorder are relatively independent of how the method was trained and what type of annotation was employed but strongly depend on the balance in the relative populations of ordered and disordered residues in short and long disordered regions in the test set. With greater than 85% overall specificity for detecting residues in both short and long disordered regions, the residues in long disordered regions are easier to predict at 81% sensitivity in a balanced test dataset with 56.5% ordered residues but more challenging (at 65% sensitivity) in a test dataset with 90% ordered residues. Compared to eleven other methods, SPINE-D yields the highest area under the curve (AUC), the highest Mathews correlation coefficient for residue-based prediction, and the lowest mean square error in predicting disorder contents of proteins for an independent test set with 329 proteins. In particular, SPINE-D is comparable to a meta predictor in predicting disordered residues in long disordered regions and superior in short disordered regions. SPINE-D participated in CASP 9 blind prediction and is one of the top servers according to the official ranking. In addition, SPINE-D was examined for prediction of functional molecular recognition motifs in several case studies. PMID- 22208283 TI - Capillary monolithic bioreactor of immobilized snake venom phosphodiesterase for mass spectrometry based oligodeoxynucleotide sequencing. AB - A capillary monolithic bioreactor of snake venom phosphodiesterase (SVP) was constructed to generate different single-nucleotide mass ladders of oligodeoxynucleotides for mass spectrometry (MS)-based sequencing by immobilization. The immobilization of SVP in the porous silica monolith significantly enhances its stability for prolonged and repeated applications. The constructed capillary bioreactor has the advantages of handling (sub)microliter DNA samples and having good permeability. Benefiting from its good permeability, DNA solutions can be directly injected into the sequential digestion bioreactor simply by hand pushing or a low-pressure microinjection pump. Moreover, the immobilization of SVP facilitates the elimination or repression of the metal adducts of oligodeoxynucleotides, improving the analytical performance of MS sequencing. By the application of capillary bioreactor of immobilized SVP, the sequence-specific modification of single-stranded oligodeoxynucleotide induced by a ubiquitous pollutant acrolein (Acr) was identified, demonstrating its promising applications in identification of sequence-specific damage, which may further our understanding of DNA damage caused mutagenesis. PMID- 22208285 TI - Optical effects of exposing intact human lenses to ultraviolet radiation and visible light. AB - BACKGROUND: The human lens is continuously exposed to high levels of light. Ultraviolet radiation is believed to play a causative role in the development of cataract. In vivo, however, the lens is mainly exposed to visible light and the ageing lens absorbs a great part of the short wavelength region of incoming visible light. The aim of the present study was to examine the optical effects on human lenses of short wavelength visible light and ultraviolet radiation. METHODS: Naturally aged human donor lenses were irradiated with UVA (355 nm), violet (400 and 405 nm) and green (532 nm) lasers. The effect of irradiation was evaluated qualitatively by photography and quantitatively by measuring the direct transmission before and after irradiation. Furthermore, the effect of pulsed and continuous laser systems was compared as was the effect of short, intermediate and prolonged exposures. RESULTS: Irradiation with high intensity lasers caused scattering lesions in the human lenses. These effects were more likely to be seen when using pulsed lasers because of the high pulse intensity. Prolonged irradiation with UVA led to photodarkening whereas no detrimental effects were observed after irradiation with visible light. CONCLUSIONS: Irradiation with visible light does not seem to be harmful to the human lens except if the lens is exposed to laser irradiances that are high enough to warrant thermal protein denaturation that is more readily seen using pulsed laser systems. PMID- 22208286 TI - Magel2, a Prader-Willi syndrome candidate gene, modulates the activities of circadian rhythm proteins in cultured cells. AB - BACKGROUND: The Magel2 gene is most highly expressed in the suprachiasmatic nucleus of the hypothalamus, where its expression cycles in a circadian pattern comparable to that of clock-controlled genes. Mice lacking the Magel2 gene have hypothalamic dysfunction, including circadian defects that include reduced and fragmented total activity, excessive activity during the subjective day, but they have a normal circadian period. Magel2 is a member of the MAGE family of proteins that have various roles in cellular function, but the specific function of Magel2 is unknown. METHODS: We used a variety of cell-based assays to determine whether Magel2 modifies the properties of core circadian rhythm proteins. RESULTS: Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization. CONCLUSION: Consistent with the blunted circadian rhythm observed in Magel2-null mice, these data suggest that Magel2 normally promotes negative feedback regulation of the cellular circadian cycle, through interactions with key core circadian rhythm proteins. PMID- 22208287 TI - Opposite GC skews at the 5' and 3' ends of genes in unicellular fungi. AB - BACKGROUND: GC-skews have previously been linked to transcription in some eukaryotes. They have been associated with transcription start sites, with the coding strand G-biased in mammals and C-biased in fungi and invertebrates. RESULTS: We show a consistent and highly significant pattern of GC-skew within genes of almost all unicellular fungi. The pattern of GC-skew is asymmetrical: the coding strand of genes is typically C-biased at the 5' ends but G-biased at the 3' ends, with intermediate skews at the middle of genes. Thus, the initiation, elongation, and termination phases of transcription are associated with different skews. This pattern influences the encoded proteins by generating differential usage of amino acids at the 5' and 3' ends of genes. These biases also affect fourfold-degenerate positions and extend into promoters and 3' UTRs, indicating that skews cannot be accounted by selection for protein function or translation. CONCLUSIONS: We propose two explanations, the mutational pressure hypothesis, and the adaptive hypothesis. The mutational pressure hypothesis is that different co-factors bind to RNA pol II at different phases of transcription, producing different mutational regimes. The adaptive hypothesis is that cytidine triphosphate deficiency may lead to C-avoidance at the 3' ends of transcripts to control the flow of RNA pol II molecules and reduce their frequency of collisions. PMID- 22208289 TI - The effectiveness of an intervention in increasing community health clinician provision of preventive care: a study protocol of a non-randomised, multiple baseline trial. AB - BACKGROUND: The primary behavioural risks for the most common causes of mortality and morbidity in developed countries are tobacco smoking, poor nutrition, risky alcohol use, and physical inactivity. Evidence, guidelines and policies support routine clinician delivery of care to prevent these risks within primary care settings. Despite the potential afforded by community health services for the delivery of such preventive care, the limited evidence available suggests it is provided at suboptimal levels. This study aims to assess the effectiveness of a multi-strategic practice change intervention in increasing clinician's routine provision of preventive care across a network of community health services. METHODS/DESIGN: A multiple baseline study will be conducted involving all 56 community health facilities in a single health district in New South Wales, Australia. The facilities will be allocated to one of three administratively defined groups. A 12 month practice change intervention will be implemented in all facilities in each group to facilitate clinician risk assessment of eligible clients, and clinician provision of brief advice and referral to those identified as being 'at risk'. The intervention will be implemented in a non-random sequence across the three facility groups. Repeated, cross-sectional measurement of clinician provision of preventive care for four individual risks (smoking, poor nutrition, risky alcohol use, and physical inactivity) will occur continuously for all three facility groups for 54 months via telephone interviews. The interviews will be conducted with randomly selected clients who have visited a community health facility in the last two weeks. Data collection will commence 12 months prior to the implementation of the intervention in the first group, and continue for six months following the completion of the intervention in the last group. As a secondary source of data, telephone interviews will be undertaken prior to and following the intervention with randomly selected samples of clinicians from each facility group to assess the reported provision of preventive care, and the acceptability of the practice change intervention and implementation. DISCUSSION: The study will provide novel evidence regarding the ability to increase clinician's routine provision of preventive care across a network of community health facilities. TRIAL REGISTRATION: Australian Clinical Trials Registry ACTRN12611001284954 UNIVERSAL TRIAL NUMBER (UTN): U1111-1126 3465. PMID- 22208293 TI - Publisher's Notes. PMID- 22208294 TI - Eating behavior and body weight: physiological influences. PMID- 22208291 TI - Pregnancy in multiple system atrophy: a case report. AB - INTRODUCTION: Multiple system atrophy is a late, adult-onset alpha synucleinopathy with no data on the effect of pregnancy on the disease course. Early stage multiple system atrophy can be difficult to distinguish from Parkinson's disease. CASE PRESENTATION: We describe the case of an Irish woman with parkinsonism starting at age 31, initially diagnosed as having dopa responsive, idiopathic Parkinson's disease, who successfully delivered a full term child at age 35. Her pregnancy was complicated by severe orthostatic hypotension and motor fluctuations. Two years post-partum, she underwent bilateral subthalamic nuclei deep brain stimulation for intractable motor fluctuations and disabling dyskinesia. After this treatment course she experienced deterioration of motor symptoms and death eight years after disease onset. Post-mortem neuropathological examination revealed striatonigral degeneration and alpha-synuclein-positive glial cytoplasmic inclusions in brain stem nuclei, basal ganglia and white matter tracts, consistent with a neuropathological diagnosis of multiple system atrophy. CONCLUSIONS: Multiple system atrophy can affect women of child-bearing age and pregnancy may be associated with marked disease progression. PMID- 22208295 TI - Smoking control programs: premises and promises. PMID- 22208296 TI - Developing A Useful Perspective On Spiritual Health: Well-being, Spiritual Potential and The Search for Meaning. PMID- 22208297 TI - Understanding addictive behaviors: implications for health promotion programming. PMID- 22208299 TI - DataBase: Research and Evaluation Results. PMID- 22208298 TI - Research agenda: building a concensus on research questions. PMID- 22208301 TI - Health promotion: a discipline or a technology? PMID- 22208302 TI - Networking. PMID- 22208303 TI - Professional association networking application american journal of health promotion. PMID- 22208304 TI - Professional association profiles. PMID- 22208306 TI - Resource reviews. PMID- 22208305 TI - Profile of an outstanding networking effort: wellness council of the midlands. PMID- 22208307 TI - Perspectives on the rest of the world. PMID- 22208309 TI - Highly sensitive and selective immuno-capture/electrochemical assay of acetylcholinesterase activity in red blood cells: a biomarker of exposure to organophosphorus pesticides and nerve agents. AB - Acetylcholinesterase (AChE) enzyme activity in red blood cells (RBCs) is a useful biomarker for biomonitoring of exposures to organophosphorus (OP) pesticides and chemical nerve agents. In this paper, we reported a new method for AChE activity assay based on selective immuno-capture of AChE from biological samples followed by enzyme activity assay of captured AChE using a disposable electrochemical sensor. The electrochemical sensor is based on multiwalled carbon nanotubes-gold (MWCNTs-Au) nanocomposites modified screen printed carbon electrode (SPCE), which is used for the immobilization of AChE specific antibody. Upon the completion of immunoreaction, the target AChE (including active and inhibited) is captured onto the electrode surface and followed by an electrochemical detection of enzymatic activity in the presence of acetylthiocholine. A linear response is obtained over standard AChE concentration range from 0.1 to 10 nM. To demonstrate the capability of this new biomonitoring method, AChE solutions dosed with different concentrations of paraoxon were used to validate the new AChE assay method. AChE inhibition in OP dosed solutions was proportional to OP concentration from 0.2 to 50 nM. The new AChE activity assay method for biomonitoring of OP exposure was further validated with in vitro paraoxon-dosed RBC samples. The established electrochemical sensing platform for AChE activity assay not only avoids the problem of overlapping substrate specificity with esterases by using selective antibody, but also eliminates potential interference from other electroactive species in biological samples. It offers a new approach for sensitive, selective, and rapid AChE activity assay for biomonitoring of exposure to OPs. PMID- 22208313 TI - Stereotactic radiosurgery for arteriovenous malformations, part 2: management of pediatric patients. AB - OBJECT: The authors conducted a study to define the long-term outcomes and risks of stereotactic radiosurgery (SRS) for pediatric arteriovenous malformations (AVMs). METHODS: Between 1987 and 2006, the authors performed Gamma Knife surgery in 996 patients with brain AVMs; 135 patients were younger than 18 years of age. The median maximum diameter and target volumes were 2.0 cm (range 0.6-5.2 cm) and 2.5 cm(3) (range 0.1-17.5 cm(3)), respectively. The median margin dose was 20 Gy (range 15-25 Gy). RESULTS: The actuarial rates of total obliteration documented by angiography or MR imaging at 71.3 months (range 6-264 months) were 45%, 64%, 67%, and 72% at 3, 4, 5, and 10 years, respectively. The median time to complete angiographically documented obliteration was 48.9 months. Of 81 patients with 4 or more years of follow-up, 57 patients (70%) had total obliteration documented by angiography. Factors associated with a higher rate of documented AVM obliteration were smaller AVM target volume, smaller maximum diameter, and larger margin dose. In 8 patients (6%) a hemorrhage occurred during the latency interval, and 1 patient died. The rates of AVM hemorrhage after SRS were 0%, 1.6%, 2.4%, 5.5%, and 10.0% at 1, 2, 3, 5, and 10 years, respectively. The overall annual hemorrhage rate was 1.8%. Larger volume AVMs were associated with a significantly higher risk of hemorrhage after SRS. Permanent neurological deficits due to adverse radiation effects developed in 2 patients (1.5%) after SRS, and in 1 patient (0.7%) delayed cyst formation occurred. CONCLUSIONS: Stereotactic radiosurgery is a gradually effective and relatively safe management option for pediatric patients in whom surgery is considered to pose excessive risks. Although hemorrhage after AVM obliteration did not occur in the present series, patients remain at risk during the latency interval until obliteration is complete. The best candidates for SRS are pediatric patients with smaller volume AVMs located in critical brain regions. PMID- 22208312 TI - The chemistry of peptidyltransferase center-targeted antibiotics: enzymatic resistance and approaches to countering resistance. AB - The continued ability to treat bacterial infections requires effective antibiotics. The development of new therapeutics is guided by knowledge of the mechanisms of action of and resistance to these antibiotics. Continued efforts to understand and counteract antibiotic resistance mechanisms at a molecular level have the potential to direct development of new therapeutic strategies in addition to providing insight into the underlying biochemical functions impacted by antibiotics. The interaction of antibiotics with the peptidyltransferase center and adjacent exit tunnel within the bacterial ribosome is the predominant mechanism by which antibiotics impede translation, thus stalling growth. Resistance enzymes catalyze the chemical modification of the RNA that composes these functional regions, leading to diminished binding of antibiotics. This review discusses recent advances in the elucidation of chemical mechanisms underlying resistance and driving the development of new antibiotics. PMID- 22208314 TI - Arteriovenous malformation-associated aneurysms in the pediatric population. AB - OBJECT: Conventional cerebral angiography and treatment for ruptured arteriovenous malformations (AVMs) in children are often performed in a delayed fashion. In adults, current literature suggests that AVM-associated aneurysms may be more likely to hemorrhage than isolated AVMs, which often leads to earlier angiography and endovascular treatment of associated aneurysms. The nature of AVM associated aneurysms in the pediatric population is virtually unknown. In this report, the authors investigate the relationship of associated aneurysms in a large group of children with AVMs. METHODS: Seventy-seven pediatric patients (<= 21 years old) with AVMs were treated at the Columbia University Medical Center between 1991 and 2010. Medical records and imaging studies were retrospectively reviewed, and associated aneurysms were classified as arterial, intranidal, or venous in location. Clinical presentation and outcome variables were compared between children with and without AVM-associated aneurysms. RESULTS: A total of 30 AVM-associated aneurysms were found in 22 children (29% incidence). Eleven were arterial, 9 intranidal, and 10 were venous in location. There was no significant difference in the rate of hemorrhage (p = 0.91) between children with isolated AVMs (35 of 55 [64%]) and children with AVM-associated aneurysms (13 of 22 [59%]). However, of the 11 children with AVM-associated aneurysms in an arterial location, 10 presented with hemorrhage (91%). An association with hemorrhage was significant in univariate analysis (p = 0.045) but not in multivariate analysis (p = 0.37). CONCLUSIONS: Associated aneurysms are present in nearly a third of children with AVMs, and when arterially located, are more likely to present with hemorrhage. These data suggest that early angiography with endovascular treatment of arterial-based aneurysms in children with AVMs may be indicated. PMID- 22208315 TI - Intraventricular twin fetuses in fetu. AB - The authors report a rare case of multiple intracranial fetuses in fetu, fulfilling Willis' traditional criteria, which include an axial and appendicular skeleton with surrounding organized tissue. This case was ascertained from studies of a full-term female neonate who presented with ventriculomegaly. A CT scan showed intracranial calcifications that were suggestive of an axial skeleton. Her birth weight was 3.176 kg (50th-75th percentile), length was 52 cm (90th percentile), head circumference was 35 cm (50th-75th percentile), and Apgar scores were 7 and 8 at 1 and 5 minutes, respectively. Prenatal ultrasonography studies performed at 12 weeks and 5 days, and 19 weeks and 6 days revealed normal findings. A 37-week prenatal ultrasonography study showed ventriculomegaly and obstructive hydrocephalus, with a possible intracranial teratoma. Cranial imaging at birth with ultrasonography, CT and MR imaging, and MR angiography demonstrated 2 complex intraventricular masses with cystic, solid, and bony elements. A craniotomy with resection of the masses was performed at 3 months of age. The infant survived and is now 12 months old with some developmental progress. Two axial skeletons, with accompanying rib cage and extremities, including well formed feet and toes, were noted. Both anencephalic structures had skin with hair, fat, skeletal and smooth muscle, and bony structures with bone marrow and focal areas of calcification. Multiple viscera were present and included thymus, bowel, stomach, salivary gland, kidney, adrenal gland, lung, and presumed adnexal structures. A diagnosis of fetuses in fetu was rendered. Chromosomal studies of the child and tissue from the 2 fetuses in fetu showed normal female karyotypes. A single nucleotide polymorphism array analysis from the proband infant and tissue from the 2 identified fetuses in fetu appeared to be genetically identical. These results are consistent with a monozygotic twin embryonic origin of the fetus in fetu tissue, which is a mechanism that has been suggested in previous reports in which karyotypes, blood types, and limited genetic loci have been studied. This is the first report of a rare example of intracranial intraventricular twin fetuses in fetu for which a genome-wide single nucleotide polymorphism assay has confirmed their genetic identity. PMID- 22208316 TI - Editorial: translaminar screws. PMID- 22208317 TI - A computed tomography-based feasibility study of translaminar screw placement in the pediatric thoracic spine. AB - OBJECT: Translaminar screws (TLSs) were originally described as a safer alternative to pedicle and transarticular screw placement at C-2 in adult patients. More recently, TLSs have been used in both the cervical and thoracic spine of pediatric patients as a primary fixation technique and as a bailout procedure when dysplastic pedicle morphology prohibits safe pedicle screw placement. Although authors have reported the anatomical characteristics of the cervical and thoracic lamina in adults as well as those of the cervical lamina in pediatric patients, no such data exist to guide safe TLS placement in the thoracic spine of the pediatric population. The goal of this study was to report the anatomical feasibility of TLS placement in the thoracic spine of pediatric patients. METHODS: Fifty-two patients (26 males and 26 females), with an average age of 9.5 +/- 4.8 years, were selected by retrospective review of a trauma registry database after institutional review board approval. Study inclusion criteria were an age from 2 to 16 years, standardized axial bone-window CT images of the thoracic spine, and the absence of spinal trauma. For each thoracic lamina the following anatomical features were measured using eFilm Lite software: laminar width (outer cortical and cancellous), laminar height (LH), maximal screw length, and optimal screw trajectory. Patients were stratified by age (an age < 8 versus >= 8 years) and sex. RESULTS: Collected data demonstrate the following general trends as one descends the thoracic spine from T-1 to T-12: 1) increasing laminar width to T-4 followed by a steady decrease to T-12, 2) increasing LH, 3) decreasing maximal screw length, and 4) increasing ideal screw trajectory angle. When stratified by age and sex, male patients older than 8 years of age had significantly larger laminae in terms of both width and height and allowed significantly longer screw placement at all thoracic levels compared with their female counterparts. Importantly, it was found that 78% of individual thoracic laminae, regardless of age or sex, could accept a 4.0-mm screw with 1.0 mm of clearance. As expected, when stratifying by age and sex, it was found that older male patients had the highest acceptance rates. CONCLUSIONS: Data in the present study provide information regarding optimal TLS length, diameter, and trajectory for each thoracic spinal level in pediatric patients. Importantly, the data collected demonstrate no anatomical limitations within the pediatric thoracic spine to TLS instrumentation, although acceptance rates are lower for younger (< 8 years old) and/or female patients. Lastly, given the anatomical variation found in this study, CT scanning can be useful in the preoperative setting when planning TLS use in the thoracic spine of pediatric patients. PMID- 22208318 TI - Open reduction and internal fixation for angulated, unstable odontoid synchondrosis fractures in children: a safe alternative to halo fixation? AB - External orthosis is the accepted and historical management of odontoid synchondrosis fractures; however, this conservative therapy carries a significant complication and fracture nonunion rate among young children. The purpose of this study was to evaluate the authors' own experience in the context of the literature, to explore surgical fixation as a primary treatment for unstable fractures. The authors retrospectively reviewed 2 cases of unstable odontoid synchondrosis fractures treated at their institution; both showed radiographic progression of deformity and subsequently underwent an open surgical reduction and fusion. A literature review was conducted to compare the authors' management strategy with those in published data. External orthosis for treatment of odontoid synchondrosis fractures has a strong history of success. However, in the literature, patients treated with a halo orthosis had a 43.3% rate of complications and an 11.4% risk of nonunion. There are radiographic findings that suggest instability, such as severe angulation and displacement of the odontoid process. Both patients in the present report underwent successful fusion without complication, as documented on CT scans obtained 3 months after surgery. Given the high rate of fusion attained with conservative therapy, it is recommended for most synchondrosis fractures. However, there is a recognized subgroup of synchondrosis fractures with severe angulation (> 30 degrees ) and displacement suggestive of significant ligamentous injury. In these patients, surgical fixation may be a safe and efficacious alternative to halo orthosis as the primary treatment. PMID- 22208319 TI - Orbital hydatid cyst. AB - Hydatid cysts rarely appear in the orbital cavity without the involvement of the other organs. Most of them are situated in the superolateral and superomedial angles of the orbit. Inferiorly located cysts are very uncommon. The authors report a case of a primary hydatid cyst of the orbit with inferolateral localization. The cyst was removed surgically via a frontotemporoorbitozygomatic approach combination with puncture-aspiration-injection-reaspiration technique. This case was considered as a primary infection, because there was no previous history of hydatid disease and no findings of liver and lung cysts on radiological examination. Physicians should include orbital hydatid cyst in the differential diagnosis of unilateral proptosis. To avoid complications that might occur during surgery, the cyst can be easily removed using the combination technique detailed in this report. PMID- 22208320 TI - Primary nerve repair following resection of a neurenteric cyst of the oculomotor nerve. AB - Neurenteric cysts are rare congenital lesions of endodermal origin occurring in the spinal canal and infrequently in the posterior cranial fossa. The authors report the case of a 3-year-old child who presented with a recurrent third cranial nerve palsy. Magnetic resonance imaging showed a large cystic mass lesion in the ambient cistern on the right side, with compression of the anterolateral aspect of the brainstem. The patient underwent a craniotomy, complete excision, and a primary third cranial nerve repair. While there have been 3 reported cases of neurenteric cysts arising from the oculomotor nerve, this is the first documented case with a primary nerve repair. PMID- 22208321 TI - Intracranial endodermal sinus tumors associated with growth hormone replacement therapy in a girl. AB - The primary intracranial endodermal sinus tumor (EST) is regarded as a rare histological subtype that is often associated with components of other germ cell tumors, and there are no reports on the onset of intracranial ESTs after growth hormone (GH) replacement therapy. The authors report an extremely rare case of pure primary EST associated with GH replacement therapy. A 15-year-old girl with GH deficiency experienced headache, nausea, and vomiting after GH replacement therapy for a 17-month period. Magnetic resonance imaging showed 2 tumor masses located in the pineal region and frontal horn of the right lateral ventricle, respectively. Before surgery, the authors administered 1 cycle of neoadjuvant chemotherapy, which shrank the tumor and facilitated surgical intervention. The larger mass located in the pineal region was removed via a right occipital transtentorial approach, and postoperative histopathological analysis revealed a pure EST. While there is a clear association between the initiation of GH replacement therapy and the development of the EST in this case, the causal effect cannot be specified. Nevertheless, this case demonstrates that GH replacement therapy must be used cautiously. PMID- 22208322 TI - Association of intraventricular hemorrhage secondary to prematurity with cerebrospinal fluid shunt surgery in the first year following initial shunt placement. AB - OBJECT: The neurosurgical literature has conflicting findings regarding the association between indications for CSF shunt placement and subsequent shunt surgery. The object of this study was to identify baseline factors at the time of initial CSF shunt placement that are independently associated with subsequent surgery. METHODS: This was a retrospective cohort study of children ages 0-18 years who underwent initial CSF shunt placement between January 1, 1997, and October 12, 2006, at a tertiary care children's hospital. The outcome of interest was CSF shunt surgery (either for revision or infection) within 12 months after initial placement. Associations between subsequent CSF shunt surgery and indication for the initial shunt, adjusting for patient age and surgeon factors at the time of initial placement, were estimated using multivariate logistic regression. Medical and surgical decisions, which varied according to surgeon, were examined separately in a univariate analysis. RESULTS: Of the 554 children in the study cohort, 233 (42%) underwent subsequent CSF shunt surgery, either for revision (167 patients [30%]) or infection (66 patients [12%]). In multivariate logistic regression modeling, significant risk factors for subsequent CSF shunt surgery included (compared with aqueductal stenosis) intraventricular hemorrhage (IVH) secondary to prematurity (adjusted odds ratio [AOR] 2.2, 95% CI 1.1-4.5) and other unusual indications (AOR 3.7, 95% CI 1.0-13.6). The patient's age at initial CSF shunt placement was not significantly associated with increased odds of subsequent surgery after adjusting for other associated factors. CONCLUSIONS: The occurrence of IVH is associated with increased odds of subsequent CSF shunt surgery within 12 months after shunt placement. Families of and care providers for children with IVH should be attuned to their increased risk of shunt failure. PMID- 22208323 TI - Posture-independent piston valve: a novel valve mechanism that actuates based on intracranial pressure alone. AB - OBJECT: Shunt valves are intended to maintain physiological intracranial pressure (ICP). A variety of mechanisms have been designed to accomplish this goal but have had limited success. Siphoning, in particular, has been a problem not effectively solved by proposed or manufactured valves. Poor control of ICP results in headache, neurological disturbances, decreased cognition, shunt malfunction, slit ventricles, subdural hematomas, decreased cranial volume, and maldevelopment. The authors of this study describe a prototype valve that was machined and tested ex vivo and that actuates based on ICP alone regardless of the presence of a siphon. Their object was to determine if a novel shunt mechanism that actuates perpendicular to the flow of fluid would eliminate the effect of siphoning in a valve for the treatment of hydrocephalus. METHODS: A posture-independent piston valve (PIPV) was anchored to a graduated reservoir. Opening pressure was measured by noting the fluid level in the reservoir when the piston moved. Measurements were made using a 90-cm and a 120-cm water-filled siphon tube (1.3-mm standard distal catheter) to simulate an upright posture. A recumbent posture was simulated by the absence of a siphon. RESULTS: Opening pressure of the valve did not change regardless of the presence or absence of a water-filled siphon. CONCLUSIONS: The PIPV was triggered only by the pressure head at the inlet and did not actuate in the presence of a siphon, demonstrating proof of principle of the perpendicular actuating mechanism. The PIPV is a purely mechanical device that has practical application in the treatment of hydrocephalus. PMID- 22208324 TI - Conservative management of ventriculoperitoneal shunts in the setting of abdominal and pelvic infections. AB - OBJECT: The optimal management of a ventriculoperitoneal shunt in the setting of acute, non-shunt related abdominal and pelvic infections is unknown. In the literature, distal shunt catheter reimplantation with or without a variable period of externalization has been recommended to prevent ascending ventriculitis. While this strategy is effective, there is little to almost no published data suggesting that it is necessary in all cases. Furthermore, it is not clear that shunt externalization to an external drainage bag during the treatment of non-shunt related peritonitis is any less likely to lead to ventriculitis than leaving the catheter in place. In the authors' experience, shunt externalization or revision during an episode of acute, non-shunt related peritonitis is unnecessary to prevent ventriculitis or chronic peritonitis. METHODS: In the present case series, the authors report on 7 patients whose shunts were left in the abdomen while they were treated for acute peritonitis. The patients were followed clinically for up to 21 months after the diagnosis to assess for evidence of recurrent abdominal infections, shunt infections, or shunt failure. RESULTS: In a follow-up period ranging from 13 to 22 months, no patient developed ventriculitis, required a shunt revision, or was unable to clear the peritoneal infection. CONCLUSIONS: The results of this small series suggest that leaving the distal end of a shunt catheter in place in a patient with acute peritonitis is a reasonably safe choice in specific patients, provided the source of infection is aggressively treated with systemic antibiotics and local debridement when necessary. PMID- 22208325 TI - Endoscopic third ventriculostomy in hydrocephalus associated with achondroplasia. AB - Hydrocephalus in patients with achondroplasia is thought to be due to increased dural sinus venous pressure resulting from narrowing of the jugular foramen. In this setting, where hydrocephalus is presumed to be "vascular" in origin and therefore communicating, endoscopic third ventriculostomy (ETV) would seem contraindicated. The authors describe 3 patients in whom ETV was successfully performed, resulting in MR imaging-documented decreases in ventricle size. The patients were 11 months, 33 months, and 13 years at the time of surgery. All patients had serial preoperative MR images demonstrating progressive hydrocephalus in a "triventricular" pattern with a small fourth ventricle but an open aqueduct. All patients had undergone suboccipital decompression for foramen magnum stenosis prior to the treatment of hydrocephalus. Preoperative retrograde venography revealed variable pressure gradients across the jugular foramen. It is postulated that the increase in intracranial venous pressure resulting from jugular foramen stenosis may lead to disproportionate venous engorgement of the cerebellum and some degree of obstructive hydrocephalus amenable to ETV. The authors discuss the role of suboccipital decompression in the progression of hydrocephalus in patients with achondroplasia. PMID- 22208326 TI - Giant intradiploic pseudomeningocele of occipital bone. AB - The management of intradiploic CSF collection is controversial. Although it is a benign lesion, even then delay in diagnosis and treatment may lead to significant morbidity. The authors report a very rare case of giant posttraumatic intradiploic pseudomeningocele involving the occipital bone, occipital condyles, and clivus. The pathogenesis and management of intradiploic CSF collection are discussed. This 16-year-old boy presented with a history of enlarging swelling in the suboccipital region associated with headache, lower cranial nerve palsy, and features of high cervical compressive myelopathy. Investigations revealed a giant intradiploic lesion involving the occipital bone, condyles, and clivus associated with secondary basilar invagination, hydrocephalus, and syringomyelia. Intrathecal contrast administration did not reveal communication of intradiploic space with the subarachnoid space. A large occipital craniotomy was performed. A linear fracture and dural defect in the midline was identified, which was closed with fascial graft after removing the inner table of the skull. Cranioplasty was performed using the expanded calvarial bone. Ventriculoperitoneal shunt insertion was performed for hydrocephalus, and the patient improved remarkably. Posttraumatic intradiploic CSF collection, although a benign condition, may present with severe complications if treatment is delayed. Early diagnosis and treatment is essential. The authors suggest that this condition should be treated early, as for growing skull fractures. PMID- 22208327 TI - Gross and microscopic study of the filum terminale: does the filum contain functional neural elements? AB - OBJECT: The filum terminale (FT) is considered a fibrous structure that extends from conus medullaris of the spinal cord to coccyx. Based on previous studies and from their own experience with intraoperative electrophysiological monitoring of the sacral nervous system, the authors postulate that the FT contains functional neural elements in some individuals. METHODS: The FT was dissected from 13 fresh stillborn cadavers (7 male, 6 female; mean gestational age 36 weeks and 1 day). The gross anatomical features were recorded, and connections between the FT and the nerve roots of the cauda equina were noted. These connections, when present, were sectioned for histological studies. The fila (both interna and externa) were also sectioned for histological and immunohistochemical studies. In addition, FT specimens were obtained from 5 patients undergoing sectioning of the FT in an untethering surgical procedure. RESULTS: There were 5 gross connections between the FT and nerve roots demonstrating nerve fibers that were positive for S100. The FT showed islands of cells that were positive for GFAP in 10 cases, synaptophysin in 3 cases, S100 in 11 cases, and nestin in 2 cases. The nerve fibers in the FT were myelinated in 2 cases. The conus ended at the L-1 or L-2 vertebral level in all 13 specimens. The dural sac terminated at the S-2 vertebral level in most of the specimens. The 5 FT specimens that were obtained from patients revealed nerve bundles that were positive for S100 in 4 cases and cells that were positive for GFAP in 3 cases. CONCLUSIONS: There are gross anatomical connections between the FT and nerve roots that contain nerve fibers. Apart from fibrous stroma, the FT may contain nerve bundles and cells that stain positive for GFAP, synaptophysin, S100, and nestin. These microscopic findings and previous intraoperative electrophysiological studies suggest a probable functional role for the FT in some individuals. At birth, the conus ends at a higher vertebral level (lower L-1 or upper L-2) than L-3. PMID- 22208328 TI - Paraspinal subfascial placement of lumbar intrathecal baclofen catheters: short term outcomes of a novel technique. AB - OBJECT: Techniques for the placement of intrathecal baclofen (ITB) systems have been described in detail, with special consideration given to complications from hardware placement. Risks including catheter kinking and migration, hardware erosion through the skin, and lumbar CSF leak are elevated given the often-low body mass index and poor nutritional status of this patient population. The bulk of a spinal catheter and fascial connector within the lumbar wound may increase the potential for the aforementioned risks, leading to potential risks for wound infection and breakdown. The authors' experience has led them to develop a novel method of paraspinal subfascial lumbar catheter placement to address these risks. The authors describe a novel lumbar intrathecal catheter placement technique as part of the ITB system. METHODS: All patients undergoing placement of an ITB system by the senior author at New York University Langone Medical Center between July 2010 and March 2011 underwent paraspinal subfascial lumbar catheter placement. Patients were followed-up by the surgeon 2 weeks after implantation and followed up and managed by their physiatrist thereafter, for an average of 5 months (range 0.5-9 months). Results Of the 20 patients who underwent this method of intrathecal catheter placement, none developed any hardware erosion, catheter migration, or CSF leak. One patient developed an abdominal wound infection 3 weeks after implantation, necessitating pump removal. CONCLUSIONS: In this initial short-term experience, subfascial placement of the lumbar spine intrathecal catheter may be an improvement over the traditional method of catheter placement. There is reduced risk of catheter migration or kinking, hardware erosion, CSF leak, and decreased operative time, all yielding a decreased reoperation rate in this vulnerable population. PMID- 22208329 TI - Deep brain stimulation for medically refractory life-threatening status dystonicus in children. AB - Generalized dystonic syndromes may escalate into persistent episodes of generalized dystonia known as status dystonicus that can be life-threatening due to dystonia-induced rhabdomyolysis and/or respiratory compromise. Treatment of these conditions usually entails parenteral infusion of antispasmodic agents and sedatives and occasionally necessitates a medically induced coma for symptom control. The authors report a series of 3 children who presented with medically intractable, life-threatening status dystonicus and were successfully treated with bilateral pallidal deep brain stimulation. Bilateral globus pallidus internus stimulation appears to be effective in the urgent treatment of medically refractory and life-threatening movement disorders. PMID- 22208330 TI - Juxtapontine abscess around a retained wooden fragment following a penetrating eye injury: surgical management via a transtentorial approach. AB - Penetrating injury through the orbit with a retained intracranial wooden foreign body is rare. The authors report the case of a child with a juxtapontine brain abscess secondary to a retained foreign body. The pitfalls in diagnosis and the surgical management for removal of the wooden fragment and drainage of the abscess are discussed. PMID- 22208331 TI - Letter to the editor. PMID- 22208333 TI - Serum albumin and paraoxonase activity in Iranian veterans 20 years after sulfur mustard exposure. AB - Sulfur mustard, a chemical warfare agent, has short- and long-term effects on various organs including respiratory system. Its late toxic effects on biological macromolecules among exposed veterans have not been well studied. We performed a study to determine paraoxonase-1 (PON1) activity and phenotype distribution as well as its correlation with albumin level in 289 male veterans with severe pulmonary complications who had exposure to sulfur mustard 20 years ago and in 66 age and ethnic matched healthy male subjects as controls. Serum albumin levels were lower in the veterans compared to controls (P < 0.001). Mean basal PON1 activity was 91.61 +/- 44.80 U/mL in the veteran group versus 110.27 +/- 50.23 U/mL in controls (P = 0.005). Arylesterase activity was not significantly different between the two groups. Paraoxonase to arylesterase activity ratio was significantly lower in the veterans as compared to controls (P = 0.005), mainly indicative of decreased PON1 activity rather the enzyme level. Significant reduction was found in serum albumin and PON1 activity with disease severity. Moreover, decreased high active BB (high activity) phenotype and increased intermediate active AB (moderate activity) phenotype were found in the veterans. This condition may lead to long-term accumulation of reactive oxygen metabolites resulting in a pro-oxidation milieu, which in turn can lead to increased peroxide levels and decreased antioxidant PON1 activity. In conclusion, lower serum PON1 activity and albumin might contribute to morbidity and occurrence of other complications such as atherosclerosis and rapid aging in the veterans suffering from late toxic effects of sulfur mustard. PMID- 22208355 TI - Ezetimibe/simvastatin: a guide to its clinical use in hypercholesterolemia. AB - Ezetimibe/simvastatin therapy combines two lipid-lowering compounds with complementary mechanisms of action, thereby blocking the two sources of plasma cholesterol and improving lipid profiles. Ezetimibe/simvastatin is an effective and generally well tolerated adjunct to dietary therapy for markedly reducing low density lipoprotein cholesterol (LDL-C) levels and improving other lipid parameters across diverse patient populations. Dual treatment with ezetimibe/simvastatin is more effective than monotherapy with an HMG-CoA reductase inhibitor (statin), and the addition of ezetimibe to current statin therapy is more effective than doubling the statin dose. PMID- 22208356 TI - Physical workload in neck, shoulders and wrists/hands in dental hygienists during a work-day. AB - Physical workload was recorded by electromyography, inclinometry and goniometry for twelve female dental hygienists during authentic work. Their work was, in relation to other types of work, characterised by pronounced head flexion (90th percentile 46 degrees ), high loads on the forearm extensor muscles (90th percentile 23% and 18% of maximal EMG (MVE), for the right and left sides, respectively), average loads on trapezius muscles (90th percentile 15% and 14% MVE), average arm elevation (99th percentile 83 degrees and 72 degrees ) and average wrist flexion and velocities (50th percentiles 17 degrees of extension and 7.3 degrees /s, for the right side). Manual scaling and machinery (use of ultrasonic scaling and hand-pieces) showed higher loads on the trapezius muscles, regarding muscular rest, as well as the 10th and 50th percentiles, than the other tasks, and for the forearm extensor muscles, an almost complete lack of muscular rest (0.1% time), and much higher loads regarding the 10th and 50th percentiles. Further, more pronounced head flexion and lower head and upper arm velocities were found, indicating more constrained postures for the neck and shoulders for the manual scaling and machinery. Use of ultrasonic scaler reduced the 50th percentile loads on the right forearm extensor muscles, but had no effect on the fraction of muscular rest and on the 10th percentile load. These findings are consistent with the high prevalences of musculoskeletal disorders among dental hygienists. PMID- 22208358 TI - Experience developing national evidence-based clinical guidelines for childhood pneumonia in a low-income setting--making the GRADE? AB - BACKGROUND: The development of evidence-based clinical practice guidelines has gained wide acceptance in high-income countries and reputable international organizations. Whereas this approach may be a desirable standard, challenges remain in low-income settings with limited capacity and resources for evidence synthesis and guideline development. We present our experience using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for the recent revision of the Kenyan pediatric clinical guidelines focusing on antibiotic treatment of pneumonia. METHODS: A team of health professionals, many with minimal prior experience conducting systematic reviews, carried out evidence synthesis for structured clinical questions. Summaries were compiled and distributed to a panel of clinicians, academicians and policy-makers to generate recommendations based on best available research evidence and locally-relevant contextual factors. RESULTS: We reviewed six eligible articles on non-severe and 13 on severe/very severe pneumonia. Moderate quality evidence suggesting similar clinical outcomes comparing amoxicillin and cotrimoxazole for non-severe pneumonia received a strong recommendation against adopting amoxicillin. The panel voted strongly against amoxicillin for severe pneumonia over benzyl penicillin despite moderate quality evidence suggesting clinical equivalence between the two and additional factors favoring amoxicillin. Very low quality evidence suggesting ceftriaxone was as effective as the standard benzyl penicillin plus gentamicin for very severe pneumonia received a strong recommendation supporting the standard treatment. CONCLUSIONS: Although this exercise may have fallen short of the rigorous requirements recommended by the developers of GRADE, it was arguably an improvement on previous attempts at guideline development in low-income countries and offers valuable lessons for future similar exercises where resources and locally-generated evidence are scarce. PMID- 22208360 TI - Refinement of Bos taurus sequence assembly based on BAC-FISH experiments. AB - BACKGROUND: The sequencing of the cow genome was recently published (Btau_4.0 assembly). A second, alternate cow genome assembly (UMD2), based on the same raw sequence data, was also published. The two assemblies have been subsequently updated to Btau_4.2 and UMD3.1, respectively. RESULTS: We compared the Btau_4.2 and UMD3.1 alternate assemblies. Inconsistencies were grouped into three main categories: (i) DNA segments showing almost coincidental chromosomal mapping but discordant orientation (inversions); (ii) DNA segments showing a discordant map position along the same chromosome; and (iii) sequences present in one chromosomal assembly but absent in the corresponding chromosome of the other assembly. The latter category mainly consisted of large amounts of scaffolds that were unassigned in Btau_4.2 but successfully mapped in UMD3.1. We sampled 70 inconsistencies and identified appropriate cow BACs for each of them. These clones were then utilized in FISH experiments on cow metaphase or interphase nuclei in order to disambiguate the discrepancies. In almost all instances the FISH results agreed with the UMD3.1 assembly. Occasionally, however, the mapping data of both assemblies were discordant with the FISH results. CONCLUSIONS: Our work demonstrates how FISH, which is assembly independent, can be efficiently used to solve assembly problems frequently encountered using the shotgun approach. PMID- 22208364 TI - Publisher's Notes. PMID- 22208365 TI - Compliance or Noncompliance: That is the Question! PMID- 22208366 TI - Absenteeism data as a measure of cost effectiveness of stress management programs. PMID- 22208359 TI - Interferon regulatory factor 3 plays an anti-inflammatory role in microglia by activating the PI3K/Akt pathway. AB - BACKGROUND: Microglia are the principal cells involved in the innate immune response in the CNS. Activated microglia produce a number of proinflammatory cytokines implicated in neurotoxicity but they also are a major source of anti inflammatory cytokines, antiviral proteins and growth factors. Therefore, an immune therapy aiming at suppressing the proinflammatory phenotype while enhancing the anti-inflammatory, growth promoting phenotype would be of great benefit. In the current study, we tested the hypothesis that interferon regulatory factor 3 (IRF3), a transcription factor required for the induction of IFNbeta following TLR3 or TLR4 activation, is critical to the microglial phenotype change from proinflammatory to anti-inflammatory, and that this phenotype change can be greatly facilitated by IRF3 gene transfer. METHODS: Cultures of primary human fetal microglia were transduced with IRF3 using recombinant adenovirus (Ad-IRF3) and subjected to microarray analysis, real-time PCR, immunoblotting and ELISA to determine inflammatory gene expression. Two different types of immune stimuli were tested, the TLR ligands, poly IC (PIC) and LPS, and the proinflammatory cytokines, IL-1/IFNgamma. In addition, the role of the PI3K/Akt pathway was examined by use of a pharmacological inhibitor, LY294002. RESULTS: Our results show that Ad-IRF3 suppressed proinflammatory genes (IL-1alpha, IL-1beta, TNFalpha, IL-6, IL-8 and CXCL1) and enhanced anti inflammatory genes (IL-1 receptor antagonist, IL-10 and IFNbeta) in microglia, regardless of the cell stimuli applied. Furthermore, Ad-IRF3 activated Akt, and LY294002 reversed the effects of Ad-IRF3 on microglial inflammatory gene expression. pAkt was critical in LPS- or PIC-induced production of IL-10 and IL 1ra. Significantly, microglial IFNbeta protein production was also dependent on pAkt and required both Ad-IRF3 and immunological stimuli (PIC > IL-1/IFNgamma). pAkt played much less prominent and variable roles in microglial proinflammatory gene expression. This anti-inflammatory promoting role of PI3K/Akt appeared to be specific to microglia, since astrocyte proinflammatory gene expression (as well as IFNbeta expression) required PI3K/Akt. CONCLUSIONS: Our results show a novel anti-inflammatory role for the PI3K/Akt signaling pathway in microglia. They further suggest that IRF3 gene therapy could facilitate the microglial phenotype switch from proinflammatory ("M1-like") to anti-inflammatory and immunomodulatory ("M2-like"), in part, by augmenting the level of pAkt. PMID- 22208362 TI - Early peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass. AB - BACKGROUND: The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARgamma2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARgamma dependent transcriptional responses involved in the process of beta cell mass expansion RESULTS: Here we have investigated PPARgamma dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARgamma2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARgamma in maintenance/activation of mechanisms essential for the continued function of the beta cell. CONCLUSIONS: Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARgamma dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-beta signaling and decreased oxidative phosphorylation. PMID- 22208367 TI - Health promotion efforts in an isolated Hispanic community: the mora substance abuse prevention project. PMID- 22208368 TI - Methodological challenges to program evaluation. PMID- 22208370 TI - DataBase: Research and Evaluation Results. PMID- 22208369 TI - Research agenda: building a concensus on research questions. PMID- 22208372 TI - View point: response to the research agenda evaluation model. PMID- 22208373 TI - Networking. PMID- 22208374 TI - American journal of health promotion: guidelines for professional association networking application. PMID- 22208376 TI - Profile: Ottawa charter for health promotion: an outstanding networking effort. PMID- 22208377 TI - Resource reviews. PMID- 22208378 TI - Perspectives: on the rest of the world. PMID- 22208381 TI - Model of phosphorus precipitation and crystal formation in electric arc furnace steel slag filters. AB - The objective of this study was to develop a phosphorus retention mechanisms model based on precipitation and crystallization in electric arc furnace slag filters. Three slag columns were fed during 30 to 630 days with a reconstituted mining effluent at different void hydraulic retention times. Precipitates formed in columns were characterized by X-ray diffraction and transmission electronic microscopy. The proposed model is expressed in the following steps: (1) the rate limiting dissolution of slag is represented by the dissolution of CaO, (2) a high pH in the slag filter results in phosphorus precipitation and crystal growth, (3) crystal retention takes place by filtration, settling and growth densification, (4) the decrease in available reaction volume is caused by crystal and other particulate matter accumulation (and decrease in available reaction time), and (5) the pH decreases in the filter over time if the reaction time is too low (which results in a reduced removal efficiency). Crystal organization in a slag filter determines its phosphorus retention capacity. Supersaturation and water velocity affect crystal organization. A compact crystal organization enhances the phosphorus retention capacity of the filter. A new approach to define filter performance is proposed: saturation retention capacity is expressed in units of mg P/mL voids. PMID- 22208383 TI - Efficient intracellular delivery of nucleic acid pharmaceuticals using cell penetrating peptides. AB - Over the last 20 years, researchers have designed or discovered peptides that can permeate membranes and deliver exogenous molecules inside a cell. These peptides, known as cell-penetrating peptides (CPPs), typically consist of 6-30 residues, including HIV TAT peptide, penetratin, oligoarginine, transportan, and TP10. Through chemical conjugation or noncovalent complex formation, these structures successfully deliver bioactive and membrane-impermeable molecules into cells. CPPs have also gained attention as an attractive vehicle for the delivery of nucleic acid pharmaceuticals (NAPs), including genes/plasmids, short oligonucleotides, and small interference RNAs and their analogues, due to their high internalization efficacy, low cytotoxicity, and flexible structural design. In this Account, we survey the potential of CPPs for the design and optimization of NAP delivery systems. First, we describe the impact of the N-terminal stearylation of CPPs. Endocytic pathways make a major contribution to the cellular uptake of NAPs. Stearylation at the N-terminus of CPPs with stearyl octaarginine (R8), stearyl-(RxR)(4), and stearyl-TP10 prompts the formation of a self-assembled core-shell nanoparticle with NAPs, a compact structure that promotes cellular uptake. Researchers have designed modifications such as the addition of trifluoromethylquinoline moieties to lysine residues to destabilize endosomes, as exemplified by PepFect 6, and these changes further improve biological responsiveness. Alternatively, stearylation also allows implantation of CPPs onto the surface of liposomes. This feature facilitates "programmed packaging" to establish multifunctional envelope-type nanodevices (MEND). The R8 MEND showed high transfection efficiency comparable to that of adenovirus in non dividing cells. Understanding the cellular uptake mechanisms of CPPs will further improve CPP-mediated NAP delivery. The cellular uptake of CPPs and their NAP complex involves various types of endocytosis. Macropinocytosis, a mechanism which is also activated in response to stimuli such as growth factors or viruses, is a primary pathway for arginine-rich CPPs because high cationic charge density promotes this endocytic pathway. The use of larger endosomes (known as macropinosomes) rather than clathrin- or caveolae-mediated endocytosis has been reported in macropinocytosis which would also facilitate the endocytosis of NAP nanoparticles into cells. PMID- 22208384 TI - Effect of acute and chronic stress on leucocyte count: modulation by chlordiazepoxide. AB - Total and differential leucocyte count (TLC and DLC) in blood circulation influence humoral immune response and stress alters TLC and DLC by leucocyte misdistribution. Chlordiazepoxide, a widely used benzodiazepine anti-stress agent, is reported to reverse suppression of antibody response induced by acute stress but not by chronic stress. The effect of chlordiazepoxide on the changes in leucocyte count by acute and chronic stress has not been clearly defined. We examined the effect of restraint stress (1 h/day) for 6, 10, 14 and 21 days on TLC and DLC and their modulation by chlordiazepoxide pretreatment (10 mg/kg/day) 1 h before exposure to stress in albino rats. Acute stress, i.e. restraint stress (1 h/day) for 6 and 10 days with or with out chlordiazepoxide pretreatment did not alter TLC and DLC. Chronic stress, i.e. restraint stress (1 h/day) for 14 and 21 days significantly decreased TLC and the percentage of lymphocytes in comparison to control. Pretreatment with chlordiazepoxide reversed these changes. We conclude that chlordiazepoxide, a benzodiazepine, reverses changes in TLC and DLC probably by improving chronic stress-induced leucocytes misdistribution. PMID- 22208386 TI - Correlation of activated STAT3 expression with clinicopathologic features in lung adenocarcinoma and squamous cell carcinoma. AB - BACKGROUND AND OBJECTIVE: Signal transducer and activator of transcription (STAT) 3, a member of the STAT family of transcription factors in the Janus kinase (JAK)/STAT signaling pathway, is involved in cell proliferation and apoptosis. STAT3 is activated through phosphorylation (p-STAT3) and is highly expressed in many malignancies. The aims of the present study were to evaluate STAT3 activation (p-STAT3 protein levels) in lung adenocarcinoma and squamous cell carcinoma, and to investigate its correlation with clinicopathologic features of these malignancies. METHODS: Expression of p-STAT3 was detected by immunohistochemistry in tissue from 127 lung carcinomas (100 adenocarcinomas and 27 squamous cell carcinomas) and 56 normal lungs. Genomic DNA was extracted from frozen patient tissue samples, and key epidermal growth factor receptor (EGFR) mutation sites in exons 18 through 21 of the EGFR gene were amplified and sequenced. RESULTS: On the basis of the intensity and percentage of p-STAT3 immunoreactivity, samples were divided into negative and positive p-STAT3 expression groups. 103 of these 183 samples (56.3%) showed immunoreactivity for p STAT3, and this frequency was significantly increased in carcinoma tissue compared with normal tissue (p = 0.001). Positive p-STAT3 expression was detected in 82 of the 127 carcinomas (64.6%) but in only 21 of the 56 normal tissue samples (37.5%). Among the 127 cases of non-small cell lung cancer, p-STAT3 immunoreactivity was significantly correlated with sex (p = 0.004), smoking history (p = 0.006), EGFR mutation status (p = 0.003), clinical stage (p = 0.034), and lymph node metastasis (p = 0.009). CONCLUSION: Our results suggest that p-STAT3 is an important factor during carcinogenesis and metastasis of lung carcinoma, and its relationship to EGFR mutation status may provide potential targeting opportunities in future therapies. PMID- 22208387 TI - Mechanisms behind the generation of protonated ions for polyaromatic hydrocarbons by atmospheric pressure photoionization. AB - In this study, the mechanism behind the generation of protonated polyaromatic hydrocarbon (PAH) ions without heteroatoms by atmospheric pressure photoionization (APPI) is investigated. Comparing data obtained by APPI of anthracene dissolved either in toluene or perdeuterated toluene suggests that toluene acts as a source of protons and that breakage of C-H bonds in the toluene molecule is important for the overall protonation reaction. Our data describing an Arrhenius-type temperature-dependent relationship between the signal intensities of molecular and protonated ions suggest a mechanistic relation between the generated molecular and protonated ions. The APPI protonation mechanism that best explains the observed phenomena is composed of two reactions: electron transfer followed by hydrogen transfer. This two-step mechanism for APPI was originally suggested by Syage (Syage, J. A. J. Am. Soc. Mass Spectrom. 2004, 15 , 1521-1533). Further quantum mechanical study shows that an energetically favorable ion-molecular complex can be generated as a result of electron transfer from toluene to PAH, which subsequently facilitates hydrogen transfer. This suggests that both electron transfer and hydrogen transfer can occur as a "concerted" reaction through the ion-molecular complex precursor state, which is consistent with experimental results. To our best knowledge, this is the first time that the dynamic nature of the APPI process is clearly revealed by combined experimental and quantum mechanical studies. PMID- 22208389 TI - Photodynamic inactivation of Staphylococcus aureus and Escherichia coli biofilms by malachite green and phenothiazine dyes: an in vitro study. AB - OBJECTIVES: The organization of biofilms in the oral cavity gives them added resistance to antimicrobial agents. The action of phenothiazinic photosensitizers on oral biofilms has already been reported. However, the action of the malachite green photosensitizer upon biofilm-organized microorganisms has not been described. The objective of the present work was to compare the action of malachite green with the phenothiazinic photosensitizers (methylene blue and toluidine blue) on Staphylococcus aureus and Escherichia coli biofilms. METHODS: The biofilms were grown on sample pieces of acrylic resin and subjected to photodynamic therapy using a 660-nm diode laser and photosensitizer concentrations ranging from 37.5 to 3000 MUM. After photodynamic therapy, cells from the biofilms were dispersed in a homogenizer and cultured in Brain Heart Infusion broth for quantification of colony-forming units per experimental protocol. For each tested microorganism, two control groups were maintained: one exposed to the laser radiation without the photosensitizer (L+PS-) and other treated with the photosensitizer without exposure to the red laser light (L-PS+). The results were subjected to descriptive statistical analysis. RESULTS: The best results for S. aureus and E. coli biofilms were obtained with photosensitizer concentrations of approximately 300 MUM methylene blue, with microbial reductions of 0.8-1.0 log(10); 150 MUM toluidine blue, with microbial reductions of 0.9-1.0 log(10); and 3000 MUM malachite green, with microbial reductions of 1.6-4.0 log(10). CONCLUSION: Greater microbial reduction was achieved with the malachite green photosensitizer when used at higher concentrations than those employed for the phenothiazinic dyes. PMID- 22208390 TI - Non-stem cancer cell kinetics modulate solid tumor progression. AB - BACKGROUND: Solid tumors are heterogeneous in composition. Cancer stem cells (CSCs) are believed to drive tumor progression, but the relative frequencies of CSCs versus non-stem cancer cells span wide ranges even within tumors arising from the same tissue type. Tumor growth kinetics and composition can be studied through an agent-based cellular automaton model using minimal sets of biological assumptions and parameters. Herein we describe a pivotal role for the generational life span of non-stem cancer cells in modulating solid tumor progression in silico. RESULTS: We demonstrate that although CSCs are necessary for progression, their expansion and consequently tumor growth kinetics are surprisingly modulated by the dynamics of the non-stem cancer cells. Simulations reveal that slight variations in non-stem cancer cell proliferative capacity can result in tumors with distinctly different growth kinetics. Longer generational life spans yield self-inhibited tumors, as the emerging population of non-stem cancer cells spatially impedes expansion of the CSC compartment. Conversely, shorter generational life spans yield persistence-limited tumors, with symmetric division frequency of CSCs determining tumor growth rate. We show that the CSC fraction of a tumor population can vary by multiple orders of magnitude as a function of the generational life span of the non-stem cancer cells. CONCLUSIONS: Our study suggests that variability in the growth rate and CSC content of solid tumors may be, in part, attributable to the proliferative capacity of the non stem cancer cell population that arises during asymmetric division of CSCs. In our model, intermediate proliferative capacities give rise to the fastest-growing tumors, resulting in self-metastatic expansion driven by a balance between symmetric CSC division and expansion of the non-stem cancer population. Our results highlight the importance of non-stem cancer cell dynamics in the CSC hypothesis, and may offer a novel explanation for the large variations in CSC fractions reported in vivo. PMID- 22208391 TI - Discriminant and concurrent validity of a simplified DSM-based structured diagnostic instrument for the assessment of autism spectrum disorders in youth and young adults. AB - BACKGROUND: To evaluate the concurrent and discriminant validity of a brief DSM based structured diagnostic interview for referred individuals with autism spectrum disorders (ASDs). METHODS: To test concurrent validity, we assessed the structured interview's agreement in 123 youth with the expert clinician assessment and the Social Responsiveness Scale (SRS). Discriminant validity was examined using 1563 clinic-referred youth. RESULTS: The structured diagnostic interview and SRS were highly sensitive indicators of the expert clinician assessment. Equally strong was the agreement between the structured interview and SRS. We found evidence for high specificity for the structured interview. CONCLUSIONS: A simplified DSM-based ASD structured diagnostic interview could serve as a useful diagnostic aid in the assessment of subjects with ASDs in clinical and research settings. PMID- 22208392 TI - Nutrient removal in tropical subsurface flow constructed wetlands under batch and continuous flow conditions. AB - The aim of this investigation was to evaluate the influence of batch versus continuous flow on the removal efficiencies of chemical oxygen demand (COD), nitrogen (N) and total phosphorus (TP) in tropical subsurface flow constructed wetlands (SSF CW). The quantitative role of the higher aquatic plants in nutrient removal in these two operational modes was also investigated. Results indicated no significant difference (p > 0.05) in COD removal between batch and continuous flow modes for either the planted or unplanted treatments. Furthermore, the batch loaded planted wetlands showed significantly (p < 0.05) higher ammonium removal efficiencies (95.2%) compared with the continuously fed systems (80.4%), most probably because the drain and fill batch mode presented systematically more oxidized environmental conditions. With respect to TP removal, for both planted and unplanted beds, there was significant enhancement (p < 0.05) in batch flow operation (69.6% for planted beds; 39.1% for unplanted beds) as compared to continuous flow operation (46.8% for planted beds; 25.5% for unplanted beds). In addition, at a 4-day hydraulic retention time (HRT), the presence of plants significantly enhanced both ammonia oxidation and TP removal in both batch and continuous modes of operation as compared to that for unplanted beds. An estimation of the quantitative role of aeration from drain and fill operation at a 4-day HRT, as compared to rhizosphere aeration by the higher aquatic plant, indicated that drain and fill operation might account for only less than half of the higher aquatic plant's quantitative contribution of oxygen (1.55 g O2 per m2 per day for batch flow versus 1.13 g O2 per m2 per day for continuous flow). PMID- 22208394 TI - Why farmers adopt best management practice in the United States: a meta-analysis of the adoption literature. AB - This meta-analysis of both published and unpublished studies assesses factors believed to influence adoption of agricultural Best Management Practices in the United States. Using an established statistical technique to summarize the adoption literature in the United States, we identified the following variables as having the largest impact on adoption: access to and quality of information, financial capacity, and being connected to agency or local networks of farmers or watershed groups. This study shows that various approaches to data collection affect the results and comparability of adoption studies. In particular, environmental awareness and farmer attitudes have been inconsistently used and measured across the literature. This meta-analysis concludes with suggestions regarding the future direction of adoption studies, along with guidelines for how data should be presented to enhance the adoption of conservation practices and guide research. PMID- 22208393 TI - Optimal control of soybean aphid in the presence of natural enemies and the implied value of their ecosystem services. AB - By suppressing pest populations, natural enemies provide an important ecosystem service that maintains the stability of agricultural ecosystems systems and potentially mitigates producers' pest control costs. Integrating natural control services into decisions about pesticide-based control has the potential to significantly improve the economic efficiency of pesticide use, with socially desirable outcomes. Two gaps have hindered the incorporation of natural enemies into pest management decision rules: (1) insufficient knowledge of pest and predator population dynamics and (2) lack of a decision framework for the economic tradeoffs among pest control options. Using a new intra-seasonal, dynamic bioeconomic optimization model, this study assesses how predation by natural enemies contributes to profit-maximizing pest management strategies. The model is applied to the management of the invasive soybean aphid, the most significant serious insect threat to soybean production in North America. The resulting lower bound estimate of the value of natural pest control ecosystem services was estimated at $84 million for the states of Illinois, Indiana, Iowa, Michigan and Minnesota in 2005. PMID- 22208395 TI - Advancing the deliberative turn in natural resource management: an analysis of discourses on the use of local resources. AB - The natural resource management literature stresses the need for public participation and community involvement in resource management and planning. Recently, some of this literature turned to the theory on deliberative democracy and demonstrated that a deliberative perspective on participation can help to challenge established practices and contribute with new ideas about how to conduct participation. The purpose of this paper is to consider the latest developments in deliberative democracy and outline the implications arising from these insights for a "deliberative turn" in resource management. A bottom-up protected area establishment, the Goricko Landscape Park, is examined. The empirical case is discussed from a discursive perspective, which relied on John Dryzek's approach to discourse analysis here used to explore the construction of discourses on the use of local natural resources. Two discourses are identified and the way these interfaced with the participatory park establishment process is considered. Findings indicate that advocates of the two discourses engaged differently with the participatory tools used and this had important implications for the park establishment. The case study suggests that, in contexts where participation has been recently introduced, knowledge of discourses on the use of local natural resources and of mobilization strategies actors may pursue could usefully assist in the design and implementation of participatory processes. PMID- 22208396 TI - Adsorption of Cu(II) ions from aqueous solutions on biochars prepared from agricultural by-products. AB - In this study, the adsorption of Cu(II) from aqueous solutions by agricultural by products, such as rice husks, olive pomace and orange waste, as well as compost, was evaluated. The aim was to obtain sorbent materials (biochars) through hydrothermal treatment (300 degrees C) and pyrolysis (300 degrees C and 600 degrees C). The effect of adsorbent dose, pH, contact time and initial Cu(II) concentration in batch-mode experiments was investigated. The optimum Cu(II) adsorption conditions was found to occur at 5-12 g/L adsorbent dose, initial pH 5 6, and reaction time 2-4 h. Furthermore, the adsorption kinetics were best described by the pseudo-second order model for all the tested materials, while the adsorption equilibrium best fitted by the linear and Freundlich isotherms. Comparing rice husks and olive pomace, the higher adsorption capacity resulted after pyrolysis at 300 degrees C. With respect to the orange waste and compost, the highest adsorption capacity was observed using biochars obtained after hydrothermal treatment and pyrolysis at 300 degrees C. PMID- 22208397 TI - On process optimization considering LCA methodology. AB - The goal of this work is to research the state-of-the-art in process optimization techniques and tools based on LCA, focused in the process engineering field. A collection of methods, approaches, applications, specific software packages, and insights regarding experiences and progress made in applying the LCA methodology coupled to optimization frameworks is provided, and general trends are identified. The "cradle-to-gate" concept to define the system boundaries is the most used approach in practice, instead of the "cradle-to-grave" approach. Normally, the relationship between inventory data and impact category indicators is linearly expressed by the characterization factors; then, synergic effects of the contaminants are neglected. Among the LCIA methods, the eco-indicator 99, which is based on the endpoint category and the panel method, is the most used in practice. A single environmental impact function, resulting from the aggregation of environmental impacts, is formulated as the environmental objective in most analyzed cases. SimaPro is the most used software for LCA applications in literature analyzed. The multi-objective optimization is the most used approach for dealing with this kind of problems, where the epsilon-constraint method for generating the Pareto set is the most applied technique. However, a renewed interest in formulating a single economic objective function in optimization frameworks can be observed, favored by the development of life cycle cost software and progress made in assessing costs of environmental externalities. Finally, a trend to deal with multi-period scenarios into integrated LCA optimization frameworks can be distinguished providing more accurate results upon data availability. PMID- 22208398 TI - Local social capital and the acceptance of Protected Area policies: an empirical study of two Ramsar river delta ecosystems in northern Greece. AB - Managing Protected Areas (PAs) is a challenging task, and globally many instruments have been utilised for this purpose. Existing research demonstrates that the effectiveness of these instruments is highly dependent on their social acceptability among local communities resident within PAs. Consequently, investigating local attitudes and perceptions of Protected Area (PA) policies has been emphasised in recent studies. Drawing on empirical work conducted in two National Parks including river delta ecosystems designated as Ramsar wetlands in northern Greece, this paper examines local residents' perceptions of three hypothesized policy options (regulatory, market-based and participatory) for Park management. The influence of social capital elements (social trust, institutional trust and social networks) on residents' perceptions is explored. The findings reveal a high degree of importance attached by resident communities to Park designation in both PAs, though residents' perceptions of the proposed management options varied. The regulatory option was regarded as the least restrictive, while the most restrictive was perceived to be the market-based option. However, greater benefits were identified by residents from the market-based option, while the fewest benefits were considered to arise from the proposed regulatory option. Furthermore, local residents' perceptions were significantly shaped by the proposed management and decision-making structure offered under each policy option. The influence of different social capital elements on residents' perceptions also varied in the study sample, with social trust and institutional trust positively correlated with the benefits that were perceived to arise from the different policy options. Moreover, when social capital was measured as an aggregate indicator at the level of the individual, it was positively correlated with perceived environmental benefits. PMID- 22208399 TI - Rubber and pulp plantations represent a double threat to Hainan's natural tropical forests. AB - Hainan, the largest tropical island in China, belongs to the Indo-Burma biodiversity hotspot and harbors large areas of tropical forests, particularly in the uplands. The Changhua watershed is the cradle of Hainan's main river and a center of endemism for plants and birds. The watershed contains great habitat diversity and is an important conservation area. We analyzed the impact of rubber and pulp plantations on the distribution and area of tropical forest in the watershed, using remote sensing analysis of Landsat images from 1988, 1995 and 2005. From 1988 to 1995, natural forest increased in area (979-1040 sq km) but decreased rapidly (763 sq km) over the next decade. Rubber plantations increased steadily through the study period while pulp plantations appeared after 1995 but occupied 152 sq km by 2005. Rubber and pulp plantations displace different types of natural forest and do not replace one another. Because pulp is not as profitable as rubber and existing pulp processing capacity greatly exceeds local supply, considerable pressure exists on remaining upland forests. We recommend for future management that these plantation forests be reclassified as 'industrial', making a clear policy distinction between natural and industrial forestry. Additionally, the local government should work to enforce existing laws preventing forest conversion on marginal and protected areas. PMID- 22208400 TI - Designing management options to reduce surface runoff and sediment yield with farmers: an experiment in south-western France. AB - To preserve the quality of surface water, official French regulations require farmers to keep a minimum acreage of grassland, especially bordering rivers. These agro-environmental measures do not account for the circulation of water within the catchment. This paper examines whether it is possible to design with the farmers agri-environmental measures at field and catchment scale to prevent soil erosion and surface water pollution. To support this participatory approach, the hydrology and erosion model STREAM was used for assessing the impact of a spring stormy event on surface runoff and sediment yield with various management scenarios. The study was carried out in collaboration with an agricultural committee in an area of south-western France where erosive runoff has a major impact on the quality of surface water. Two sites (A and B) were chosen with farmers to discuss ways of reducing total surface runoff and sediment yield at each site. The STREAM model was used to assess surface runoff and sediment yield under current cropping pattern at each site and to evaluate management scenarios including grass strips implementation or changes in cropping patterns within the catchment. The results of STREAM simulations were analysed jointly by farmers and researchers. Moreover, the farmers discussed each scenario in terms of its technical and economical feasibility. STREAM simulations showed that a 40 mm spring rainfall with current cropping patterns led to 3116 m3 total water runoff and 335 metric tons of sediment yield at site A, and 3249 m3 and 241 metric tons at site B. Grass strips implementation could reduce runoff for about 40% and sediment yield for about 50% at site A. At site B, grass strips could reduce runoff and sediment yield for more than 50%, but changes in cropping pattern could reduce it almost totally. The simulations led to three main results: (i) grass strips along rivers and ditches prevented soil sediments from entering the surface water but did not reduce soil losses, (ii) crop redistribution within the catchment was as efficient as planting grass strips, and (iii) efficient management of erosive runoff required coordination between all the farmers using the same watershed. This study shown that STREAM model was a useful support for farmers' discussions about how to manage runoff and sediment yield in their fields. PMID- 22208402 TI - Application of a weights-of-evidence method and GIS to regional groundwater productivity potential mapping. AB - The aim of this study is to analyze the relationship among groundwater productivity data including specific capacity (SPC) and transmissivity (T) as well as its related hydrogeological factors in a bedrock aquifer, and subsequently, to produce the regional groundwater productivity potential (GPP) map for the area around Pohang City, Korea using a geographic information system (GIS) and a weights-of-evidence (WOE) model. All of the related factors, including topography, lineament, geology, forest, and soil data were collected and input into a spatial database. In addition, SPC and T data were collected from 83 and 81 well locations, respectively. Four dependent variables including SPC values of >=6.25 m3/d/m (Case 1) and T values of >=3.79 m2/d (Case 3) corresponding to a yield (Y) of >=500 m3/d, and SPC values of >=3.75 m3/d/m (Case 2) and T values of >=2.61 m2/d (Case 4) corresponding to a Y of >=300 m3/d were also input into a spatial database. The SPC and T data were randomly selected in an approximately 70:30 ratio to train and validate the WOE model. Tests of conditional independence were performed for the used factors. To assess the regional GPP for each dependent variable, W+ and W- of each factor's rating were overlaid spatially. The results of the analysis were validated using area under curve (AUC) analysis with the existing SPC and T data that were not used for the training of the model. The AUC of Cases 1, 2, 3 and 4 showed 0.7120, 0.6893, 0.6920, and 0.7098, respectively. In the case of the dependent variables, Case 1 had an accuracy of 71.20% (AUC: 0.7120), which is the best result produced in this analysis. Such information and the maps generated from it could be used for groundwater management, a practice related to groundwater resource exploration. PMID- 22208401 TI - Effects of TiO2 based photocatalytic paint on concentrations and emissions of pollutants and on animal performance in a swine weaning unit. AB - The beneficial effect of a TiO2-based photocatalytic treatment on the indoor air purification of a swine farm has been evaluated in a trial performed in two identical mechanically ventilated traditional weaning units, with 391 animals lodged in each of them. One unit was used as reference, whereas the walls of the second unit (260 m2) were coated with ca. 70 g m(-2) of TiO2 and irradiated with ten UV-A lamps. The environmental parameters (i.e. the ventilation rate, the internal and external temperature and relative humidity), together with NH3, CH4, CO2 and N2O concentrations in the exhaust ducts and PM10 emissions, were monitored in the two units throughout all of the production cycle (75 days). Significant decreases in CH4 concentration (ca. 27%, P < 0.05) and PM10 emission (ca. 17%, P < 0.01) were observed, together with an increase of the piglets' productive performance in the treated unit with respect to the reference one. Indeed, the ADG (Average Daily Gain of piglets) was 424 g vs. 414 g for the piglets lodged in the two units, respectively, with a significantly better feed conversion ratio (FCR, ratio between the food ingested by the animals and their weight gain) of 2.18 vs. 2.44 (P < 0.001). Therefore, the photocatalytic treatment with TiO2 coating had positive effects not only on methane concentration and particulate matter concentration and emission, but also significantly improved the feed conversion ratio of growing piglets, very likely due to the increased quality of indoor air, with positive economic repercussions for the farmer. Internal photocatalytic treatment in swine husbandry could thus be considered as a potential Best Available Technology (BAT). PMID- 22208403 TI - The ecological apparency hypothesis and the importance of useful plants in rural communities from northeastern Brazil: an assessment based on use value. AB - The ecological apparency hypothesis in ethnobotanical studies predicts that the apparent plants (i.e., the most easily found in the vegetation) would be the most commonly collected and used by people. To test this hypothesis, it has been used the concept of use value (VU), which measures the relative importance of useful plants for a group of people. However, the use value has got some limitations, including the fact that it does not distinguish "current use" (plants which are effectively used) from "potential use" (well known plants, however not used). Therefore, this study has tested whether the obtained results through three different use value calculations could be useful in testing the ecological apparency hypothesis. These calculations have included the current use value, the potential use value, and the general use value. It has been carried out a vegetation survey and an interview for residents from the rural communities from Barrocas and Cachoeira (Soledade, Paraiba, Brazil). It has been used Spearman's coefficient to correlate phytosociological and ethnobotanical data. It has been observed that phytosociological parameters in Cachoeira were not correlated with any of the use values calculations, except the relationship between the current use value and the relative dominance (r(s) = 0.57; p < 0.05). In Barrocas, every use value calculation was correlated with the basal area and the relative dominance. When each category of use is analyzed separately, it has been observed that there was no correlation between the use value and the phytosociological parameters, except for the construction category, in which the current use value in Cachoeira was correlated with the relative dominance (r(s) = 0.63; p < 0.05), importance value (r(s) = 0.67; p < 0.01), relative frequency (r(s) = 0.71; p < 0.05), and relative density (r(s) = 0.72; p < 0.01). In Barrocas, the UVc for the construction category was correlated with relative frequency (r(s) = 0.69; p < 0.05) and relative density (r(s) = 0.66; p < 0.01). These results have suggested that, the use value calculation, which takes into consideration just the current use of the species, is the one that best fits in the ecological apparency hypothesis. PMID- 22208404 TI - Bringing diverse knowledge sources together--a meta-model for supporting integrated catchment management. AB - Integrated catchment management (ICM), as promoted by recent legislation such as the European Water Framework Directive, presents difficult challenges to planners and decision-makers. To support decision-making in the face of high complexity and uncertainty, tools are required that can integrate the evidence base required to evaluate alternative management scenarios and promote communication and social learning. In this paper we present a pragmatic approach for developing an integrated decision-support tool, where the available sources of information are very diverse and a tight model coupling is not possible. In the first instance, a loosely coupled model is developed which includes numerical sub-models and knowledge-based sub-models. However, such a model is not easy for decision-makers and stakeholders to operate without modelling skills. Therefore, we derive from it a meta-model based on a Bayesian Network approach which is a decision-support tool tailored to the needs of the decision-makers and is fast and easy to operate. The meta-model can be derived at different levels of detail and complexity according to the requirements of the decision-makers. In our case, the meta-model was designed for high-level decision-makers to explore conflicts and synergies between management actions at the catchment scale. As prediction uncertainties are propagated and explicitly represented in the model outcomes, important knowledge gaps can be identified and an evidence base for robust decision-making is provided. The framework seeks to promote the development of modelling tools that can support ICM both by providing an integrated scientific evidence base and by facilitating communication and learning processes. PMID- 22208405 TI - Selectively enhanced expression of prophenoloxidase activating enzyme 1 (PPAE1) at a bacteria clearance site in the white shrimp, Litopenaeus vannamei. AB - BACKGROUND: The prophenoloxidase-activating (PO activating) system plays an important role in the crustacean innate immunity, particularly in wound healing and pathogen defense. A key member of this system is prophenoloxidase-activating enzyme (PPAE), which is the direct activator of prophenoloxidase (proPO). Despite their importance in crustacean PO activating system, the studies on them remain limited. RESULTS: Here we report on a PPAE of white shrimp, Litopenaeus vannamei (lvPPAE1), which showed 94% similarity to PPAE1 of Penaeus monodon. We found that lvPPAE1 in fluid hemocytes was down regulated after challenge by Vibrio harveyi but was enhanced when shrimps were exposed to a bacteria-rich environment for long-term. In vivo gene silence of lvPPAE1 by RNAi can significantly reduce the phenoloxidase activity (PO) and increase the susceptibility of shrimps to V. harveyi. Although lvPPAE1 was down-regulated in fluid hemocytes by Vibrio challenge, its expression increased significantly in gill after bacteria injection, which is the primary bacteria-clearance tissue. CONCLUSION: Suppressed expression in fluid hemocytes and enhanced expression in gill indicates selectively enhanced expression at the bacterial clearance site. This is a novel feature for PPAE expression. The results will contribute to our understanding of the PO activating system in crustaceans. PMID- 22208406 TI - Occurrence of the invasion associated marker (iam) in Campylobacter jejuni isolated from cattle. AB - BACKGROUND: The invasion associated marker (iam) has been detected in the majority of invasive Campylobacter jejuni retrieved from humans. Furthermore, the detection of iam in C. jejuni isolated from two important hosts, humans and chickens, suggested a role for this marker in C. jejuni's colonization of multiple hosts. However, no data exist regarding the occurrence of this marker in C. jejuni isolated from non-poultry food-animals such as cattle, an increasingly important source for human infections. Since little is known about the genetics associated with C. jejuni's capability for colonizing physiologically disparate hosts, we investigated the occurrence of the iam in C. jejuni isolated from cattle and assessed the potential of iam-containing cattle and human isolates for chicken colonization and human cell invasion. RESULTS: Simultaneous RAPD typing and iam-specific PCR analysis of 129 C. jejuni isolated from 1171 cattle fecal samples showed that 8 (6.2%) of the isolates were iam-positive, while 7 (54%) of human-associated isolates were iam-positive. The iam sequences were mostly heterogeneous and occurred in diverse genetic backgrounds. All iam-positive isolates were motile and possessed important genes (cadF, ciaB, cdtB) associated with adhesion and virulence. Although certain iam-containing isolates invaded and survived in INT-407 cells in high numbers and successfully colonized live chickens, there was no clear association between the occurrence, allelic sequence, and expression levels of the iam and the aforementioned phenotypes. CONCLUSIONS: We show that the prevalence of iam in cattle C. jejuni is relatively lower as compared to isolates occurring in humans and chickens. In addition, iam was polymorphic and certain alleles occur in cattle isolates that were capable of colonizing and invading chickens and human intestinal cells, respectively. However, the iam did not appear to contribute to the cattle-associated C. jejuni's potential for invasion and intracellular survival in human intestinal cells as well as chicken colonization. PMID- 22208409 TI - Cluster-randomized study of intermittent preventive treatment for malaria in infants (IPTi) in southern Tanzania: evaluation of impact on survival. AB - BACKGROUND: Intermittent Preventive Treatment for malaria control in infants (IPTi) consists of the administration of a treatment dose of an anti-malarial drug, usually sulphadoxine-pyrimethamine, at scheduled intervals, regardless of the presence of Plasmodium falciparum infection. A pooled analysis of individually randomized trials reported that IPTi reduced clinical episodes by 30%. This study evaluated the effect of IPTi on child survival in the context of a five-district implementation project in southern Tanzania. [ TRIAL REGISTRATION: clinicaltrials.gov NCT00152204]. METHODS: After baseline household and health facility surveys in 2004, five districts comprising 24 divisions were randomly assigned either to receive IPTi (n = 12) or not (n = 12). Implementation started in March 2005, led by routine health services with support from the research team. In 2007, a large household survey was undertaken to assess the impact of IPTi on survival in infants aged two-11 months through birth history interviews with all women aged 13-49 years. The analysis is based on an "intention-to-treat" ecological design, with survival outcomes analysed according to the cluster in which the mothers lived. RESULTS: Survival in infants aged two 11 months was comparable in IPTi and comparison areas at baseline. In intervention areas in 2007, 48% of children aged 12-23 months had documented evidence of receiving three doses of IPTi, compared to 2% in comparison areas (P < 0.0001). Over the three years of the study there was a marked improvement in survival in both groups. Between 2001-4 and 2005-7, mortality rates in two-11 month olds fell from 34.1 to 23.6 per 1,000 person-years in intervention areas and from 32.3 to 20.7 in comparison areas. In 2007, divisions implementing IPTi had a 14% (95% CI -12%, 49%) higher mortality rate in two-11 month olds in comparison with non-implementing divisions (P = 0.31). CONCLUSION: The lack of evidence of an effect of IPTi on survival could be a false negative result due to a lack of power or imbalance of unmeasured confounders. Alternatively, there could be no mortality impact of IPTi due to low coverage, late administration, drug resistance, decreased malaria transmission or improvements in vector control and case management. This study raises important questions for programme evaluation design. PMID- 22208410 TI - Assessing the social and physical contexts of children's leisure-time physical activity: an ecological momentary assessment study. AB - PURPOSE: To use Ecological Momentary Assessment with mobile phones to describe where and with whom children's leisure-time physical activity occurs. DESIGN: Repeated assessments across 4 days (Friday-Monday) during nonschool time (20 total). SETTING: Chino, California, and surrounding communities. SUBJECTS: Primarily low to middle income children (N =121; aged 9-13 years; x-=11.0 years, SD =1.2 years; 52% male, 38% Hispanic/Latino). MEASURES: Electronic surveys measured current activity (e.g., active play/sports/exercise, watching TV/movies), social company (e.g., family, friends, alone), physical location (e.g., home, outdoors, school), and other perceived contextual features (e.g., safety, traffic, vegetation, distance from home). Analysis . Multilevel linear and multinomial logistic regression. RESULTS: Most of children's physical activity occurred outdoors (away from home) (42%), followed by at home (indoors) (30%), front/backyard (at home) (8%), someone else's house (8%), at a gym/recreation center (3%), and other locations (9%). Children's physical activity took place most often with multiple categories of people together (e.g., friends and family) (39%), followed by family members only (32%), alone (15%), and with friends only (13%). Age, weight status, income, and racial/ethnic differences in physical activity contexts were observed. CONCLUSIONS: The most frequently reported contexts for children's leisure time physical activity were outdoors and with family members and friends together. PMID- 22208411 TI - Formative research conducted in rural Appalachia to inform a community physical activity intervention. AB - PURPOSE: Despite the well-established benefits of physical activity (PA), most Americans, especially those in rural, traditionally underserved areas, engage in considerably less PA than recommended. This study examines perceived barriers to and facilitators of PA and promising organized PA programs among rural Appalachians. DESIGN: Eight focus groups and seven group key informant interviews were conducted. SETTING: This study was conducted in eastern Kentucky, in central Appalachia. SUBJECTS: One hundred and fourteen rural Appalachian residents (74% female, 91% white) participated. MEASURES: Open-ended, semistructured, and structured questions regarding perceptions of, barriers to/facilitators of, and examples of successful/failed PA programs were asked. ANALYSIS: Qualitative data analysis was conducted, including codebook development and steps taken to ensure rigor and transferability. Interrater reliability was over 94%. RESULTS: In addition to barriers that are consistent with those found in other populations, rural Appalachian residents indicated that travel time, family commitments, and inadequate community resources undermine PA. Suggested avenues to increase PA include partnership with churches and the U.S. Department of Agriculture's Cooperative Extension Service; programs that include families, are well advertised, and focus on health rather than appearance; and, underlying all suggestions, culturally relevant yet nonstereotyping activities. CONCLUSIONS: When developing PA interventions in rural Appalachia, it is important to employ community-based participatory approaches that leverage unique assets of the population and show potential in overcoming challenges to PA. PMID- 22208412 TI - Characteristics of step-defined physical activity categories in U.S. adults.. AB - PURPOSE: Descriptive physical activity epidemiology of the U.S. population is critical for program development and resource allocation. The purpose of this project was to describe step-defined categories (as measured by accelerometer) of U.S. adults and to determine predictors of sedentary classification (<5000 steps/d). DESIGN: The National Health and Nutrition Examination Survey (NHANES) is an annual, nationally representative survey used to determine the health status of the U.S. populace. SETTING: In-home interviews and physical examination components of NHANES. PARTICIPANTS: Overall, 4372 eligible adults wore accelerometers in the 2005-2006 NHANES; 628 were excluded, which yielded 3744 adults (of which 46.8% were men). MEASURES: Steps per day; body mass index (BMI); demographic, household and behavioral variables. ANALYSIS: Means and frequencies were calculated. Logistic regression was utilized to determine predictors of sedentary classification. RESULTS: Overall, 36.1% were sedentary (i.e., <5000 steps/d); 47.6% were low to somewhat active (5000-9999 steps/d); 16.3% were active to highly active (>=10,000 steps/d). Advancing age (odds ratio [OR], 1.95; confidence intervals [CIs], 1.78, 2.13), higher BMI (OR, 1.40; CIs, 1.23, 1.59), female sex (OR, 1.86; CIs, 1.46, 2.36), African-American versus European-American ethnicity (OR, 1.36; CIs, 1.13, 1.65), household income versus >=$45,000 (<$25,000: OR, 1.94; CIs, 1.40, 2.69; $25,000-$44,000: OR, 1.51; CIs, 1.23, 1.85), and current versus never smoker (OR, 1.53; CIs, 1.26, 1.86) variables had higher odds of sedentary classification. Usual daily occupational/domestic physical activity categories of standing/walking (OR, .51; CIs, .38, .69); lifting/climbing (OR, .26; CIs, .17, .38); and heavy loads/labor (OR, .16; CIs, .10, .26) had lower odds of sedentary classification than sitting. CONCLUSIONS: Over one-third of the U.S. population was classified as sedentary by accelerometer-determined steps per day, and several characteristics predicted sedentary classification. PMID- 22208414 TI - Making news: the appearance of tobacco control organizations in newspaper coverage of tobacco control issues. AB - PURPOSE: To characterize the presence of advocacy groups in media coverage about tobacco issues. DESIGN: A content analysis of tobacco-related newspaper articles. SETTING: Australia. SAMPLE: All 12 national and state capital daily newspapers published in Australia between 2004 and 2007. MEASURES: We coded each article for explicit mentions of any of 16 major national or state tobacco control advocacy groups; for the article type, prominence, and topic; for the tone of the event; and for the author's opinion. ANALYSIS: A series of 2 * 2 chi(2) analyses assessed the extent to which advocacy groups were more or less likely to be mentioned in articles of each type, prominence, topic, event impact, and opinion orientation. RESULTS: Of the 4387 tobacco-related articles published over this period, 22% mentioned an advocacy group. There was a greater-than-expected proportion of advocacy groups mentioned in news articles with very high prominence (44%; chi(2) [1, N = 3118] = 27.4, p < .001), high prominence (34%; chi(2) [1, N = 3118] = 10.9, p < .001), and medium prominence (30%; chi(2) [1, N = 3118] = 7.3, p = .007), and in articles covering events with mixed (30%; chi(2) [1, N = 4387] = 10.0, p = .002) or positive (24%; chi(2) [1, N = 4387] = 26.1, p < .001) implications for tobacco control. CONCLUSIONS: Australian tobacco control advocacy groups have a reasonable presence within the news discourse on tobacco control issues and so are likely to contribute to generating and shaping this discourse, particularly in relation to evolving and controversial issues. PMID- 22208415 TI - U.S. children's preschool weight status trajectories: patterns from 9-month, 2 year, and 4-year Early Childhood Longitudinal Study-Birth cohort data. AB - PURPOSE: To track changes in U.S. children's early weight status (normal, at risk, or obese) from infancy through preschool. DESIGN: Patterns of change in individual children's weight status are established using three time points from the Early Childhood Longitudinal Study-Birth cohort. SETTING: United States. SUBJECTS: Nationally representative sample of U.S. preschool children surveyed at 9 months (n = 8900), with follow-up at 2 years (n = 7500) and preschool (n = 7000). MEASURES: Individual children's weight status was determined from Centers for Disease Control and Prevention growth charts at multiple time periods. ANALYSIS: Layered, categorical data analysis of changes in weight status patterns at three time periods during infancy through preschool. RESULTS: Young children whose early weight status was normal tend to retain a normal weight status and not to develop an unfavorable status (at-risk, obese). In contrast, children who were obese at an early age were more likely to have an at-risk or obese weight category at a later age. Overall, both favorable and unfavorable early weight statuses were highly associated with subsequent status at preschool. CONCLUSION: Early weight status can provide important information relevant for early entry point prevention and treatment of childhood obesity. PMID- 22208413 TI - A ballroom dance classroom program promotes moderate to vigorous physical activity in elementary school children. AB - PURPOSE: To determine if an existing ballroom dance classroom program meets national recommendations to engage children in moderate to vigorous physical activity (MVPA) for >=50% of class time and to determine class effects on body mass index (BMI). DESIGN: Prospective descriptive study. Setting . Two New York City public schools. PARTICIPANTS: Seventy-nine fourth and fifth grade students. MEASUREMENTS: The System for Observing Fitness Instruction Time (SOFIT) and direct heart rate monitoring were used to determine participants' MVPA levels during class time. Weight and height were measured to calculate BMI. ANALYSIS: Means were calculated for continuous variables; frequency counts and percentages were calculated for categorical variables. Change in BMI percentiles was assessed by using Bhapkar's chi(2) test of overall marginal homogeneity. RESULTS: Data from SOFIT observations showed that a mean of 50.0% and 67.0% of class time in the first and second halves of the program, respectively, were spent in MVPA. Data from the heart rate monitoring revealed that 71.1% of students were at >=25% heart rate reserve, which indicated MVPA for >=50% of class time. Improvement was seen in BMI percentile (p= .051). CONCLUSION: Ballroom dance provides MVPA in elementary school children for >=50% of class time and has a positive impact on BMI percentiles. PMID- 22208416 TI - Social influence and motivation to change health behaviors among Mexican-origin adults: implications for diet and physical activity. AB - PURPOSE: To evaluate whether influence from social network members is associated with motivation to change dietary and physical activity behaviors. DESIGN: Baseline assessment followed by mailing of family health history-based personalized messages (2 weeks) and follow-up assessment (3 months). SETTING: Families from an ongoing population-based cohort in Houston, Texas. SUBJECTS: 475 adults from 161 Mexican-origin families. Out of 347 households contacted, 162 (47%) participated. MEASURES: Family health history, social networks, and motivation to change behaviors. ANALYSIS: Two-level logistic regression modeling. RESULTS: Having at least one network member who encourages one to eat more fruits and vegetables (p = .010) and to engage in regular physical activity (p = .046) was associated with motivation to change the relevant behavior. About 40% of the participants did not have encouragers for these behaviors. CONCLUSIONS: Identification of new encouragers within networks and targeting natural encouragers (e.g., children, spouses) may increase the efficacy of interventions to motivate behavioral changes among Mexican-origin adults. PMID- 22208417 TI - How residential mobility and school choice challenge assumptions of neighborhood place-based interventions. AB - PURPOSE: Explore the importance of residential mobility and use of services outside neighborhoods when interventions targeting low-income families are planned and implemented. DESIGN: Analysis of cross-sectional telephone household survey data on childhood mobility and school enrollment in four large distressed cities. SETTING: Baltimore, Maryland; Detroit, Michigan; Philadelphia, Pennsylvania; and Richmond, Virginia. SUBJECTS: Total of 1723 teens aged 10 to 18 years and their parents. MEASURES: Continuous self-report of the number of years parents lived in the neighborhood of residence and city; self-report of whether the child attends school in their neighborhood; and categorical self report of parents' marital status, mother's education, parent race, family income, child's age, and child's sex. ANALYSIS: Chi-square and multivariate logistic regression. RESULTS: In this sample, 85.2% of teens reported living in the city where they were born. However, only 44.4% of black teens lived in neighborhoods where they were born, compared with 59.2% of white teens. Although 50.3% of black teens attended schools outside of their current neighborhoods, only 31.4% of whites did. Residential mobility was more common among black than white children (odds ratio = 1.82; p < .001), and black teens had 43% lesser odds of attending school in their home communities. CONCLUSIONS: Mobility among low-income and minority families challenges some assumptions of neighborhood interventions premised on years of exposure to enriched services and changes in the built environment. PMID- 22208418 TI - The impact of alternative incentive schemes on completion of health risk assessments. AB - PURPOSE: The biggest challenge for corporate wellness initiatives is low rates of employee participation. We test whether a behavioral economic approach to incentive design (i.e., a lottery) is more effective than a direct economic payment of equivalent monetary value (i.e., a grocery gift certificate) in encouraging employees to complete health risk assessments (HRAs). DESIGN: Employees were assigned to one of three arms. Assignment to a treatment arm versus the nontreatment arm was determined by management. Assignment to an arm among those eligible for treatment was randomized by office. SETTING: A large health care management and information technology consulting company. PATIENTS: A total of 1299 employees across 14 offices participated. INTERVENTION: All employees were eligible to receive $25 for completing the HRA. Those in the lottery condition were assigned to teams of four to eight people and, conditional on HRA completion, were entered into a lottery with a prize of $100 (expected value, $25) and a bonus value of an additional $25 if 80% of team members participated. Those in the grocery gift certificate condition who completed an HRA received a $25 grocery gift certificate. Those in the comparison condition received no additional incentive. MEASURES: HRA completion rates. ANALYSIS: Logistic regression analysis. RESULTS: HRA completion rates were significantly higher among participations in the lottery incentive condition (64%) than in both the grocery gift certificate condition (44%) and the comparison condition (40%). Effects were larger for lower-income employees, as indicated by a significant interaction between income and the lottery incentive. CONCLUSION: Lottery incentives that incorporate regret aversion and social pressure can provide higher impact for the same amount of money as simple economic incentives. PMID- 22208419 TI - Is fear of strangers related to physical activity among youth? AB - PURPOSE: To (1) assess the reliability of the newly developed Fears of Stranger Danger (FSD) scale, (2) examine measurement invariance and identify demographic variation in FSD, and (3) examine associations of FSD with physical activity, screen time, and body mass index (BMI) z score. DESIGN: Cross-sectional survey with test-retest. SETTING: Neighborhoods with various socioeconomic characteristics and walkability in San Diego, Boston, and Cincinnati. PARTICIPANTS: Parent-adolescent pairs (n = 171), and parents of children (n = 116). Response rate was 47% for Survey 1, and 69% were retained for Survey 2. METHODS: Data analyses included test-retest reliability and internal consistency for FSD, tests of differential functioning for measurement invariance, t-test for associations between FSD and demographic variables, and partial correlation for associations of FSD with physical activity, screen time, and BMI z score. RESULTS: The FSD scale had moderate to substantial test-retest reliability (intraclass correlation coefficient = .65-.85) and excellent internal consistency (Cronbach alpha = .88-.94). Measurement invariance was established across gender, race/ethnicity, and income. FSD was higher regarding younger children, females, nonwhites, and lower-income youth. FSD was positively associated with restrictive parental rules for playing outside (partial r = .28-.33), and negatively associated with children's outdoor physical activity in the neighborhood (partial r = -.27), but not associated with other measures of physical activity, screen time, or BMI z score. CONCLUSION: The new measure of FSD had good evidence of reliability and measurement invariance, but there were inconsistent associations of FSD with youth physical activity. PMID- 22208421 TI - Adopting local alcohol policies: a case study of community efforts to regulate malt liquor sales. AB - PURPOSE: To learn how the local context may affect a city's ability to regulate alcohol products such as high-alcohol-content malt liquor, a beverage associated with heavy drinking and a spectrum of nuisance crimes in urban areas. APPROACH: An exploratory, qualitative case study comparing cities that adopted policies to restrict malt liquor sales with cities that considered, but did not adopt policies. SETTING: Nine large U.S. cities in seven states. PARTICIPANTS: City legislators and staff, alcohol enforcement personnel, police, neighborhood groups, business associations, alcohol retailers, and industry representatives. METHOD: Qualitative data were obtained from key informant interviews (n = 56) and media articles (n = 360). The data were coded and categorized. Similarities and differences in major themes among and across Adopted and Considered cities were identified. RESULTS: Cities faced multiple barriers in addressing malt liquor related problems, including a lack of enforcement tools, alcohol industry opposition, and a lack of public and political will for alcohol control. Compared to cities that did not adopt malt liquor sales restrictions, cities that adopted restrictions appeared to have a stronger public mandate for a policy and were less influenced by alcohol industry opposition and lack of legislative authority for alcohol control. Strategies common to successful policymaking efforts are discussed. CONCLUSION: Understanding the local context may be a critical step in winning support for local alcohol control policies. PMID- 22208422 TI - Examining physical activity levels and alcohol consumption: are people who drink more active? AB - OBJECTIVE: Summarize/categorize current scientific literature examining the association between alcohol consumption (AC) and levels of physical activity (PA). DATA SOURCE: Electronic databases spanning education, psychology, sociology, medicine, and interdisciplinary reports. STUDY INCLUSION AND EXCLUSION CRITERIA: Included studies (n =17) must be published in a peer-reviewed, English language journal; measure either AC or PA as an independent/dependent variable; and primarily examine the relationship between AC and PA. DATA EXTRACTION: Search terms/phrases included alcohol, alcohol consumption, drinking, physical activity, exercise, and physically active. DATA SYNTHESIS: The Matrix Method and PRISMA guidelines organized pertinent literature and identified/extracted salient findings. RESULTS: Alcohol consumers of all ages were more physically active than nondrinking peers. Further, several studies suggest a dose-response relationship between AC and PA, indicating that as drinking increases, so does PA level. CONCLUSION: Reviewed studies support a positive association between AC and PA across all ages. Findings were contrary to the hypothesis of the investigators. Future research should place specific emphasis on identifying why alcohol consumers exercise at higher levels than non-alcohol consumers. PMID- 22208424 TI - A billion and change in federal grants for health promotion. AB - The U.S. Department of Health and Human Services announced $1.01 billion in funding opportunities for health promotion in fiscal year 2011 and selected winners for the first phase of these programs. These included $100 million over 5 years for 10 state Medicaid programs to develop incentive-based strategies, $900 million for 61 community-level programs through the Community Transformation Grants, and nearly $10 million to help employers develop comprehensive workplace programs. PMID- 22208425 TI - Enhancing intrinsic motivation in health promotion and wellness. PMID- 22208427 TI - Enantiomeric profiling of chiral drugs in wastewater and receiving waters. AB - The aim of this paper is to discuss the enantiomer-specific fate of chiral drugs during wastewater treatment and in receiving waters. Several chiral drugs were studied: amphetamine-like drugs of abuse (amphetamine, methamphetamine, MDMA, MDA), ephedrines (ephedrine and pseudoephedrine), antidepressant venlafaxine, and beta-blocker atenolol. A monitoring program was undertaken in 7 WWTPs (utilizing mainly activated sludge and trickling filters technologies) and at 6 sampling points in receiving waters over the period of 9 months. The results revealed the enantiomer-specific fate of all studied drugs during both wastewater treatment and in the aqueous environment. The extent of stereoselectivity depended on several parameters including: type of chiral drug (high stereoselectivity was recorded for atenolol and MDMA), treatment technology used (activated sludge showed higher stereoselectivity than trickling filters), and season (higher stereoselectivity was observed in the aqueous environment over the spring/summer time). PMID- 22208429 TI - Delayed onset of paresis in rats with experimental intramedullary spinal cord gliosarcoma following intratumoral administration of the paclitaxel delivery system OncoGel. AB - OBJECT: Treatment options for anaplastic or malignant intramedullary spinal cord tumors (IMSCTs) remain limited. Paclitaxel has potent cytotoxicity against experimental intracranial gliomas and could be beneficial in the treatment of IMSCTs, but poor CNS penetration and significant toxicity limit its use. Such limitations could be overcome with local intratumoral delivery. Paclitaxel has been previously incorporated into a biodegradable gel depot delivery system (OncoGel) and in this study the authors evaluated the safety of intramedullary injections of OncoGel in rats and its efficacy against an intramedullary rat gliosarcoma. METHODS: Safety of intramedullary OncoGel was tested in 12 Fischer 344 rats using OncoGel concentrations of 1.5 and 6.0 mg/ml (5 MUl); median survival and functional motor scores (Basso-Beattie-Bresnahan [BBB] scale) were compared with those obtained with placebo (ReGel) and medium-only injections. Efficacy of OncoGel was tested in 61 Fischer-344 rats implanted with an intramedullary injection of 9L gliosarcoma containing 100,000 cells in 5 MUl of medium, and randomized to receive OncoGel administered on the same day (in 32 rats) or 5 days after tumor implantation (in 29 rats) using either 1.5 mg/ml or 3.0 mg/ml doses of paclitaxel. Median survival and BBB scores were compared with those of ReGel-treated and tumor-only rats. Animals were killed after the onset of deficits for histopathological analysis. RESULTS: OncoGel was safe for intramedullary injection in rats in doses up to 5 MUl of 3.0 mg/ml of paclitaxel; a dose of 5 MUl of 6.0 mg/ml caused rapid deterioration in BBB scores. OncoGel at concentrations of 1.5 mg/ml and 3.0 mg/ml paclitaxel given on both Day 0 and Day 5 prolonged median survival and preserved BBB scores compared with controls. OncoGel 1.5 mg/ml produced 62.5% long-term survivors when delivered on Day 0. A comparison between the 1.5 mg/ml and the 3.0 mg/ml doses showed higher median survival with the 1.5 mg/ml dose on Day 0, and no differences in median survival or BBB scores after treatment on Day 5. CONCLUSIONS: OncoGel is safe for intramedullary injection in rats in doses up to 5 MUl of 3.0 mg/ml, prolongs median survival, and increases functional motor scores in rats challenged with an intramedullary gliosarcoma at the doses tested. This study suggests that locally delivered chemotherapeutic agents could be of temporary benefit in the treatment of malignant IMSCTs under experimental settings. PMID- 22208430 TI - Quantification of the trans influence in hypervalent iodine complexes. AB - The trans influence of various X ligands in hypervalent iodine(III) complexes of the type CF(3)[I(X)Cl] has been quantified using the trans I-Cl bond length (d(X)), the electron density rho(r) at the (3, -1) bond critical point of the trans I-Cl bond, and topological features of the molecular electrostatic potential (MESP). The MESP minimum at the Cl lone pair region (V(min)) is a sensitive measure of the trans influence. The trans influence of X ligands in hypervalent iodine(V) complexes is smaller than that in iodine(III) complexes, while the relative ordering of this influence is the same in both complexes. In CF(3)[I(X)Y] complexes, the mutual trans influence due to the trans disposition of the X and Y ligands is quantified using the energy E(XY) of the isodesmic reaction CF(3)[I(X)Cl] + CF(3)[I(Y)Cl] -> CF(3)[I(Cl)Cl] + CF(3)[I(X)Y]. E(XY) is predicted with good accuracy using the trans-influence parameters of X and Y, measured in terms of d(X), rho(r), or V(min). The bond dissociation energy (E(d)) of X or Y in CF(3)[I(X)Y] is significantly influenced by the trans influence as well as the mutual trans influence. This is confirmed by deriving an empirical equation to predict E(d) using one of the trans-influence parameters (d(X), rho(r), or V(min)) and the mutual trans-influence parameter E(XY) for a large number of complexes. The quantified values of both the trans influence and the mutual trans-influence parameters may find use in assessing the stability of hypervalent iodine compounds as well as in the design of new stable hypervalent complexes. Knowledge about the I-X bond dissociation energies will be useful for explaining the reactivity of hypervalent iodine complexes and the mechanism of their reactions. PMID- 22208431 TI - Detection and management of latent tuberculosis infections before biologic therapy for psoriasis. AB - The biologic agents can be highly efficacious in the treatment of psoriasis and psoriatic arthritis; however, their use is associated with an increased risk of developing active TB. In particular, TNF-alpha plays critical role in preventing TB infection and reactivation of latent TB infection (LTBI). Therefore, it is critical that all patients be screened for LTBI prior to initiating therapy. An expert panel of Italian dermatologists met recently with the goal of producing a consensus paper on screening and chemoprophylaxis for LTBI in Italian psoriasis patients treated with biologics. Current recommendations for the screening algorithm include medical history, chest x-ray, and tests that evaluate immunologic response to the presence of Mycobacterium tuberculosis. Patients with positive screening results and without active disease are to be treated with a full course of chemoprophylaxis; however, if the patient is compliant and tolerating the regimen, biologic therapy for psoriasis may be started after at least 1 month on prophylactic therapy when prompt control of disease is required. PMID- 22208432 TI - Realization of 1 * 10(6) theoretical plates in liquid chromatography using very long pillar array columns. AB - We report on the possibility to achieve ultra high efficiencies (order of 1 million theoretical plates) in liquid chromatography in a relatively short time of 20 min (elution time of unretained marker). This was achieved using a micropillar array column with optimized pillar diameter (5 MUm) and interpillar distance (2.5 MUm) to operate close to the Knox and Saleem limit of micropillar array columns in the region of the 1 million theoretical plate mark under the prevailing pressure restriction (350 bar in the present study). The obtained efficiency was slightly affected (some 15 to 20% around the optimal flow rate) by the turns that were inevitably needed to arrange a 3 m long column on a 4 in. silicon wafer. PMID- 22208434 TI - Growing rate of cesarean section in Iran: dimensions and concerns. PMID- 22208435 TI - Rise in cesarean section rate over a 30-year period in a public hospital in Tehran, Iran. AB - BACKGROUND: Numerous studies show a growing trend in cesarean section rates throughout the world, including Iran. However, existing evidence in our country is scant and previous reports are restricted to short time periods. The aim of the current study is to measure the trend in cesarean sections (CS) rates over the past 30 years in a referral hospital in Tehran. METHODS: We routinely collected data on the demographic characteristics of all women who gave birth in the hospital during the study period. The mode of delivery and the personnel in charge of delivery has likewise been recorded for each birth during the study period. The data were extracted from medical records and entered into a structured checklist. RESULTS: The rate of CS out of all deliveries increased from 14.3% in 1979 to 22.7% in 1989, 52.5% in 1999, and 85.3% in 2009 (P < 0.001). The most common reason for CS was a repeated section. The percentage of vaginal deliveries performed by midwives has not changed significantly and the number of both midwives and obstetricians per 1000 births has increased, from 2.8 to 15.4 midwives per 1000 births and from 5.5 to 23.0 obstetricians per 1000 births. CONCLUSION: Immediate strategies should be adopted to prevent the rising trend and increasing number of unnecessary CS in Iran. PMID- 22208436 TI - Appropriateness of cesarean sections using the RAND Appropriateness Method criteria. AB - BACKGROUND: The aim of this study was to identify the appropriateness of cesarean sections, performed in Tehran hospitals using standardized Rand Appropriateness Method (RAM) criteria. METHODS: In this study we used the RAM criteria. In order to prepare the list of cesarean scenarios, clinical guidelines were selected, and the Appraisal of Guidelines for Research and Evaluation was used to choose the most appropriate. Two panels were held with the participation of related specialists. The scenarios derived through this method were compared with data existing in the medical records of 250 women who underwent cesarean sections in selected hospitals affiliated with Tehran University of Medical Sciences. The appropriateness rate of the cesarean sections was calculated. RESULTS: Out of 250 cases of cesarean sections performed, 91 (36.4%) were inappropriate, 41 (16.4%) were equivocal and 118 (47.2%) were considered to be appropriate. Appropriateness differed between public and private hospitals, which were statistically significant. CONCLUSION: This study shows that as with many other health services, cesarean section has many scenarios that there are different opinions about them and no decision about presenting these scenarios as yet. Moreover the result of study showed the rate of inappropriate cesarean sections in this study is one of the highest reported rates from different communities. PMID- 22208437 TI - Maternal mortality rate in Fars Province: trends and associated factors in a community-based survey. AB - BACKGROUND: The high rate of maternal mortality (MM) remains a challenge, especially in developing countries. In 2000, the World Health Organization (WHO) targeted a 75% reduction by the end of 2015. In this survey, we determine trends in MM rates and associated factors in Fars Province, southwestern Iran. METHODS: All MM in Fars Province from March 2003 to March 2010 were considered in this cross-sectional study. Data were recorded for demographic characteristics, autopsy findings, medical and obstetric histories. The data were then analyzed with a z-test to identify differences in the rate of MM during the study period. RESULTS: The mean MM rate was 22.18 per 100 000 live births (95% CI, 17.55-26.8) during the seven year study period, and was highest (32.3/100 000) in the first year. Most deaths (71.3%) occurred in the postpartum period, and the lowest proportion occurred during delivery (5%). High-risk mothers accounted for 79.2% of maternal deaths. Among the mothers who died, 62% received satisfactory prenatal care, and at least two years elapsed between successive pregnancies in 78%. Hemorrhage was the main cause of death (35.6%) and the least frequent cause was H1N1 virus infection (2%). CONCLUSION: This study provides evidence of serious deficiencies in postpartum care that need urgent action. Priority should be given to vaginal bleeding and high-risk status mothers. PMID- 22208438 TI - Modeling the risk of esophageal squamous cell carcinoma and squamous dysplasia in a high risk area in Iran. AB - BACKGROUND: Identifying people at higher risk of having squamous dysplasia, the precursor lesion for esophageal squamous cell carcinoma (ESCC), would allow targeted endoscopic screening. METHODS: We used multivariate logistic regression models to predict ESCC and dysplasia as outcomes. The ESCC model was based on data from the Golestan Case-Control Study (total n = 871; cases = 300), and the dysplasia model was based on data from a cohort of subjects from a gastroenterology clinic in Northeast Iran (total n = 724; cases = 26). In each of these analyses, we fit a model including all risk factors known in this region to be associated with ESCC. Individual risks were calculated using the linear combination of estimated regression coefficients and individual-specific values for covariates. We used cross-validation to determine the area under the curve (AUC) and to find the optimal cut points for each of the models. RESULTS: The model had an area under the curve of 0.77 (95% CI: 0.74-0.80) to predict ESCC with 74% sensitivity and 70.4% specificity for the optimum cut point. The area under the curve was 0.71 (95% CI: 0.64-0.79) for dysplasia diagnosis, and the classification table optimized at 61.5% sensitivity and 69.5% specificity. In this population, the positive and negative predictive values for diagnosis of dysplasia were 6.8% and 97.8%, respectively. CONCLUSION: Our models were able to discriminate between ESCC cases and controls in about 77%, and between individuals with and without squamous dysplasia in about 70% of the cases. Using risk factors to predict individual risk of ESCC or squamous dysplasia still has limited application in clinical practice, but such models may be suitable for selecting high risk individuals in research studies, or increasing the pretest probability for other screening strategies. PMID- 22208439 TI - Clinical and laboratory diagnosis of the patients with sputum smear-negative pulmonary tuberculosis. AB - BACKGROUND: The objective of this study is to describe the proportion of patients with chronic cough and negative smear microscopy appropriately diagnosed as tuberculosis (TB) and to identify clinical features that could be used in developing a diagnostic scoring system for smear-negative patients. METHODS: Records of patients with chronic cough and >= 3 negative sputum smears for acid fast bacilli who attended a reference University hospital in south-eastern Iran and screened by culture were retrospectively reviewed. We compared confirmed smear-negative pulmonary TB (PTB; culture-positive) and unconfirmed smear negative patients (culture-negative) to describe the appropriateness of treatment and their characteristics. Features independently predictive of smear-negative PTB (SNPTB) were entered into a logistic regression to create a diagnostic rule. RESULTS: This study enrolled 350 patients, of which 52 (14.8%) were culture positive and 298 (85.2%) culture-negative. Of these, 38 out of 52 (sensitivity 73%) confirmed SNPTB were diagnosed as TB and 283 out of 298 (specificity 95%) unconfirmed sputum-negative patients were diagnosed as non-PTB. Variables associated with confirmed SNPTB were the presence of night sweats, family history of TB, typical chest radiography, erythrocyte sedimentation rate > 45 mm and white blood cell count < 11000/mL. The score constructed with these variables had a sensitivity of 94% and specificity of 74% with an area under the curve of 0.90. CONCLUSION: The clinical differences between SNPTB and control patients could be used to develop a clinical scoring system to identify patients with SNPTB. PMID- 22208440 TI - Comparison of the effect of non-antifungal and antifungal agents on Candida isolates from the gastrointestinal tract. AB - BACKGROUND: Non-antifungal drugs appear promising in treatment of opportunistic infections of Candida spp. that are often resistant to current antifungals. METHODS: The broth macrodilution method (NCCLS M27-P document) was used to compare the antifungal activity of trifluoperazine, propranolol, and lansoprazole with that of ketoconazole and amphotericin B, using 50 yeast isolates from the GI tract. The minimum fungicidal concentrations (MFCs), resistance rates and the time required for fungicidal activity of the drugs (2 - 48 hours) were determined. RESULTS: The most effective antifungal activity was exhibited by trifluoperazine. Its MFC was 32 ug/mL for Candida albicans (3.3% resistance) and Candida spp. (0% resistance) yeasts, and 64 ug/mL for Candida tropicalis with 10% resistance. The MFC for C. albicans and Candida spp. was comparable to that of ketoconazole. However, the time required for the inhibitory effect (6 hr) was shorter than that of ketoconazole (48 hr) or amphotericin B (24 hr). The time required for the inhibitory activity on C. tropicalis was 24 hr, which was shorter than that of ketoconazole and amphotericin B (48 hr). A considerable number (40%) of Candida spp. showed resistance to ketoconazole, and 20% of C. tropicalis showed resistance to amphotericin B. Trifluoperazine, an antipsychotic drug, exhibited effective antifungal activity with the MFC, comparable to ketoconazole (32 ug/mL). Among the three yeast groups, C. tropicalis showed resistance to trifluoperazine and amphotericin B, and Candida spp. was considerably resistant to ketoconazole. CONCLUSION: Trifluoperazine could be considered as an alternative antifungal when encountering Candida spp. resistant to current antifungals. PMID- 22208441 TI - Five-year follow-up of the local autologous transplantation of CD133+ enriched bone marrow cells in patients with myocardial infarction. AB - BACKGROUND: The implantation of a CD133+ bone marrow cell population into an ischemic myocardium has emerged as a promising therapeutic modality for myocardial regeneration and restoration of ventricular contractility. While previous studies have documented the short-term safety and efficacy of CD133+ cell transplantation in patients with acute myocardial infarction, there are few reports of long-term follow-up results. Here, we present the results of long-term follow-up of our acute myocardial infarction patients who were treated with intramyocardial injection of CD133+ cells after coronary bypass graft. METHODS: After five years, 13 patients in the cell transplantation group and 5 patients in the control group underwent safety and efficacy investigations by New York Heart Association classification and two-dimensional echocardiography (2D echo). RESULTS: During the five-year study period, no major cardiac adverse events were reported among patients who received CD133+ stem cells. Regarding efficiency, we observed no statistically significant treatment effects for the echocardiographic parameters [left ventricular end-diastolic and end-systolic volumes, and resting ejection fraction] measured during the follow-up period. However, detailed analysis of regional wall motion revealed an improvement in the Wall Motion Score Index from baseline to the six month follow-up, which was maintained during the follow-up period. CONCLUSION: Taken together, the long-term results of the present study indicate that transplantation of CD133+ is a safe and feasible procedure; however, we could not show any major benefits in our patients. Thus, this issue needs to be addressed by conducting other studies with more patients. PMID- 22208442 TI - Primary intestinal NK/T cell lymphoma: a clinicopathologic study of 25 Chinese cases. AB - BACKGROUND: Primary intestinal NK/T cell lymphoma is extremely rare and early diagnosis is frequently difficult. The aim of this study is to investigate the clinicopathological findings, immunophenotype, and T cell receptor (TCR) gamma gene rearrangement of primary intestinal NK/T cell lymphomas in 25 Chinese cases. METHODS: Clinical data of the 25 cases were analyzed. Immunohistochemistry for immunophenotype, in situ hybridization for EBER, and polymerase chain reaction for TCR gamma gene rearrangement were investigated. Survival curves according to clinical characteristics were analyzed. RESULTS: The median age was 33 years and the median survival was 7 months. The common symptoms consisted of abdominal pain, fever, marasmus, diarrhea, and hematochezia. Endoscopically, the tumors were mainly featured by focal, multifocal or diffuse irregular ulcers, which most frequently emerged in the ascending colon. Histologically, the tumors were characterized by the proliferation of pleomorphic atypical lymphoid cells (ALCs), necrosis, lympho-epithelial lesions, and mixed inflammatory infiltration. The positive frequency of CD3epsilon was 88.2%, of CD56 was 84%, granzyme B was 90%, and EBER was 84.2%. A total of 12 out of 14 cases (85.7%) highly expressed Ki67. The negative prognostic factors for survival were Ann Arbor stage IIIE or IVE (P = 0.039) and more than one extranodal site of disease (P = 0.019). CONCLUSION: Primary intestinal NK/T cell lymphomas most frequently favor young people and have a poor prognosis. Due to the nonspecific clinical and endoscopic findings, it is difficult to distinguish intestinal NK/T cell lymphomas from inflammatory and infectious disorders. Histopathology, immunophenotype, and DNA study play key roles in differential diagnosis. PMID- 22208443 TI - Dermatologic manifestations of hepatitis C infection and the effect of interferon therapy: a literature review. AB - The skin could be a main target organ for extrahepatic manifestations in hepatitis C virus- (HCV) infected patients and research data suggest that interferon treatment may be associated with immune-mediated skin lesions. However, case reports propose that the response of dermatologic extrahepatic manifestations to interferon in patients with chronic HCV is greatly different. The objective of this study is to summarize currently available data on dermatologic conditions associated with chronic HCV infection. In addition, we investigate the incidence of the development of immune mediated dermatologic disorders during interferon therapy in these patients. PMID- 22208444 TI - The anticipation and inheritance pattern of c.487A>G mutation in the GJB2 gene. AB - Mutations in the GJB2 gene are the most common causes of hereditary hearing loss. This study reveals some facts about the inheritance pattern of M163V in the GJB2 gene. This study was performed on two different families with non-syndromic hearing loss. We screened the GJB2 coding region with direct sequencing. There was a substitution of A to G in exon 2 at nucleotide 487 (M163V). This mutation was heterozygous in fathers and children while mothers were normal. Fathers of both families showed late onset hearing impairment, but there was early onset hearing loss in the children, which was more severe compared to the fathers. M163V has been reported as an unknown heterozygous mutation that leads to failure of the homotypic junctional channel formation. Another mutation in this codon is M163L, with an autosomal dominant inheritance, which impairs trafficking through the plasma membrane, resulting in cell death. Assessment of the familial pedigree has revealed anticipation in phenotype and autosomal dominant inheritance. These data in addition to the high conservation of methionine residue in mammalian species suggest that M163V is inherited with an autosomal dominant pattern. Therefore, the risk of inheritance will increase. Genetic counselors and otologists should prioritize the evaluation and prevention of this disorder in patients. PMID- 22208445 TI - Clinical trials in Iran; biannual report of Clinical Trial Committee in Food and Drug Organization, Ministry of Health and Medical Education of Iran. PMID- 22208446 TI - H1N1 influenza infection complicated with diabetic ketoacidosis. AB - The 2009 H1N1 Influenza virus was the first infectious pandemic of the 21(st) century which spread rapidly throughout the world. High-risk groups, such as diabetics, suffered more and showed higher hospital admission and death rates due to this virus. Patients with diabetes mellitus (DM) may develop the fulminant picture of their disease after being infected with influenza. From June to December 2009 at Nemazee Hospital, affiliated with Shiraz University of Medical Sciences, two patients with diabetic ketoacidosis (DKA) were admitted. The H1N1 influenza virus triggered DKA and its complications in these patients. Both patients were female, of ages 16 and 40 years. When admitted, they had signs of influenza-like illness (ILI), tachypnea, laboratory confirmation of acidosis, and high blood sugar levels. The 2009 H1N1 influenza viral RNA was detected in their nasopharyngeal specimens by real time polymerase chain reaction (RT-PCR). Both patients received oseltamivir, but eventually both died. This was the first report of an association between DKA and H1N1 influenza in Iran. Conclusively, rapid diagnosis of influenza by RT-PCR and early treatment with oseltamivir should be considered in diabetics and/or DKA patients with flu-like symptoms. PMID- 22208447 TI - Intraosseous fibrosarcoma of maxilla in an HIV patient. AB - Fibrosarcoma is a malignant mesenchymal neoplasm of fibroblasts that rarely affects the oral cavity and can cause local recurrences or metastasis. Fibrosarcomas account for 15% of all soft tissue sarcomas, which represent only 1% of all malignant tumors of the head and neck region. The clinical behavior of the fibrosarcoma is characterized by a high local recurrence rate, and low incidence of loco regional lymph node and/or distant hematogenous metastasis. The etiology for fibrosarcoma has no definite cause but is thought to occur from preexisting lesions or in previously irradiated areas of bone lesions. Immunosuppression associated with HIV infection and acquired immune deficiency syndrome (AIDS) has been consistently linked to various cancers, including Kaposi's sarcoma, non-Hodgkin's lymphoma, and invasive cervical cancer. Rare neoplasms like Hodgkin's disease, anal cancer, leukemia, basal cell carcinoma, and squamous cell carcinoma have also been demonstrated. This paper presents one such a rare incidence of an intraosseous fibrosarcoma occurring in an HIV positive patient. PMID- 22208448 TI - Photoclinic. Coral reef aorta. PMID- 22208449 TI - Clinical training alone is not sufficient for reducing barriers to IUD provision among private providers in Pakistan. AB - BACKGROUND: IUD uptake remains low in Pakistan, in spite of three major efforts to introduce the IUD since the 1960s, the most recent of these being through the private sector. This study examines barriers to IUD recommendation and provision among private providers in Pakistan. METHODS: A facility-based survey was conducted among randomly selected private providers who were members of the Greenstar network and among similar providers located within 2 Kilometers. In total, 566 providers were interviewed in 54 districts of Pakistan.Logistic regression analysis was conducted to determine whether correct knowledge regarding the IUD, self-confidence in being able to insert the IUD, attitudes towards suitability of candidates for the IUD and medical safety concerns were influenced by provider type (physician vs. Lady Health Visitor), whether the provider had received clinical training in IUD insertion in the last three years, membership of the Greenstar network and experience in IUD insertion. OLS regression was used to identify predictors of provider productivity (measured by IUD insertions conducted in the month before the survey). RESULTS: Private providers consider women with children and in their peak reproductive years to be ideal candidates for the IUD. Women below age 19, above age 40 and nulliparous women are not considered suitable IUD candidates. Provider concerns about medical safety, side-effects and client satisfaction associated with the IUD are substantial. Providers' experience in terms of the number of IUDs inserted in their careers, appears to improve knowledge, self-confidence in the ability provide the IUD and to lower age-related attitudinal barriers towards IUD recommendation. Physicians have greater medical safety concerns about the IUD than Lady Health Visitors. Clinical training does not have a consistent positive effect on lowering barriers to IUD recommendation. Membership of the Greenstar network also has little effect on lowering these barriers. Providers' barriers to IUD recommendation significantly lower their monthly IUD insertions. CONCLUSIONS: Technical training interventions do not reduce providers' attitudinal barriers towards IUD provision. Formative research is needed to better understand reasons for the high levels of provider barriers to IUD provision. "Non-training" interventions should be designed to lower these barriers. PMID- 22208450 TI - Effects of methylphenidate on fatigue and depression: a randomized, double-blind, placebo-controlled trial. AB - CONTEXT: Fatigue is highly prevalent in populations with advanced illness and is often associated with depressed mood. The role of psychostimulant therapy in the treatment of these conditions remains ill defined. OBJECTIVES: To evaluate the response of fatigue and depression in patients with advanced illness to titrated doses of methylphenidate (MP) as compared with placebo. METHODS: In a randomized, double-blind, placebo-controlled trial, 30 hospice patients, both inpatients and outpatients, who had fatigue scores of at least four on a scale of zero to 10 (0=no fatigue and 10=worst fatigue), were randomly assigned to receive either 5mg of MP at 8 am and 1 pm or placebo. Doses of MP were titrated every three days according to response and adverse effects. Home care patients were monitored daily by telephone and visited by a research nurse on Study Days 0 (baseline), 3, 7, and 14. Fatigue was assessed using the Piper Fatigue Scale as the primary outcome measure and validated by the Visual Analogue Scale for Fatigue and the Edmonton Symptom Assessment Scale (ESAS) fatigue score. Subjects in inpatient facilities were interviewed or assessed by staff on an identical schedule. Depressive symptoms were assessed by the Beck Depression Inventory-II, Center for Epidemiologic Studies Depression Scale, and the ESAS depression score. Primary statistical analysis was conducted using repeated-measures multivariate analysis of the variance. RESULTS: Both MP- and placebo-treated groups had similar measures of fatigue at baseline. Patients taking MP were found to have significantly lower fatigue scores (Piper Fatigue Scale, Visual Analogue Scale for Fatigue, and ESAS) at Day 14 compared with baseline. The improvement in fatigue with MP treatment was dose-dependent; the mean average effective dose was 10mg on Day 3 and 20mg on Day 14 (dose range of 10-40 mg). Placebo-treated individuals showed no significant improvement in fatigue. For patients with clinically significant depression on Day 0, treatment with MP was associated with a significant reduction in all test indices for depressed mood. For the placebo group, the changes in measures of depression were less than observed in the treatment group but were inconsistent between assessment tools. No significant toxicities were observed. CONCLUSION: MP reduced symptoms of fatigue and depression when compared with placebo. The effect of MP on fatigue was dose dependent and sustained over the duration of the study. PMID- 22208451 TI - Pc-facs. AB - PC-FACS (Fast Article Critical Summaries for Clinicians in Palliative Care), an electronic publication of the American Academy of Hospice and Palliative Medicine, provides palliative care clinicians with concise summaries of the most important findings from more than 50 medical and scientific journals. Each month, structured summaries and insightful commentaries on 6-10 articles help palliative care clinicians stay on top of the research that is critical to contemporary practice. PC-FACS is free to AAHPM members and members can earn up to 3 CME credits quarterly. Following are excerpts from recent issues, and comments from readers are welcomed at resources@aahpm.org. PMID- 22208452 TI - Prevalence and risk factors of major depressive disorder in HIV/AIDS as seen in semi-urban Entebbe district, Uganda. AB - BACKGROUND: Not much is known about the risk factors of major depressive disorder (MDD) in HIV/AIDS in the African socio-cultural context. Therefore a study was undertaken to examine the prevalence and risk factors of MDD in HIV/AIDS in semi urban Uganda. METHODS: A cross-sectional study was undertaken among 618 respondents attending two HIV clinics in Uganda. RESULTS: Prevalence of MDD was 8.1%. Factors associated with MDD at univariate analysis only were female gender, family history of mental illness, negative coping style, alcohol dependency disorder, food insecurity and stress; not associated with MDD were social support, neurocognitive impairment, CD4 counts and BMI. Factors independently associated with MDD were psychosocial impairment, adverse life events, post traumatic stress disorder, generalised anxiety disorder and life-time attempted suicide. CONCLUSION: Psychological and social factors were the main risk factors of MDD among ambulatory HIV positive persons with no evidence for the role of the neurotoxic effects of HIV. Treatment approaches for MDD in this patient group should be modeled on those used among non-HIV groups. PMID- 22208453 TI - B lymphocyte intestinal homing in inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) is thought to be due to an abnormal interaction between the host immune system and commensal microflora. Within the intestinal immune system, B cells produce physiologically natural antibodies but pathologically atypical anti-neutrophil antibodies (xANCAs) are frequently observed in patients with IBD. The objective is to investigate the localisation of immunoglobulin-producing cells (IPCs) in samples of inflamed intestinal tissue taken from patients with IBD, and their possible relationship with clinical features. METHODS: The IPCs in small intestinal, colonic and rectal biopsy specimens of patients with IBD were analysed by means of immunofluorescence using polyclonal rabbit anti-human Ig and goat anti-human IgM. The B cell phenotype of the IPC-positive samples was assessed using monoclonal antibodies specific for CD79, CD20, CD23, CD21, CD5, lambda and kappa chains. Statistical correlations were sought between the histological findings and clinical expression. RESULTS: The study involved 96 patients (64 with ulcerative colitis and 32 with Crohn's disease). Two different patterns of B lymphocyte infiltrates were found in the intestinal tissue: one was characterised by a strong to moderate stromal localisation of small IgM+/CD79+/CD20-/CD21-/CD23-/CD5+/- IPCs (42.7% of cases); in the other (57.3%) no such small IPCs were detected in stromal or epithelial tissues. IPCs were significantly less frequent in the patients with Crohn's disease than in those with ulcerative colitis (p = 0.004). CONCLUSION: Our findings suggest that different immunopathogenetic pathways underlie chronic intestinal inflammation with different clinical expressions. The presence of small B lymphocytes resembling B-1 cells also seemed to be negatively associated with Crohn's disease. It can therefore be inferred that the gut contains an alternative population of B cells that have a regulatory function. PMID- 22208454 TI - Thickness of hydroxyapatite nanocrystal controls mechanical properties of the collagen-hydroxyapatite interface. AB - Collagen-hydroxyapatite interfaces compose an important building block of bone structures. While it is known that the nanoscale structure of this elementary building block can affect the mechanical properties of bone, a systematic understanding of the effect of the geometry on the mechanical properties of this interface between protein and mineral is lacking. Here we study the effect of geometry, different crystal surfaces, and hydration on the mechanical properties of collagen-hydroxyapatite interfaces from an atomistic perspective, and discuss underlying deformation mechanisms. We find that the presence of hydroxyapatite significantly enhances the tensile modulus and strength compared with a tropocollagen molecule alone. The stiffening effect is strongly dependent on the thickness of the mineral crystal until a plateau is reached at 2 nm crystal thickness. We observe no significant differences due to the mineral surface (Ca surface vs OH surface) or due to the presence of water. Our result shows that the hydroxyapatite crystal with its thickness confined to the nanometer size efficiently increases the tensile modulus and strength of the collagen hydroxyapatite composite, agreeing well with experimental observations that consistently show the existence of extremely thin mineral flakes in various types of bones. We also show that the collagen-hydroxyapatite interface can be modeled with an elastic network model which, based on the results of atomistic simulations, provides a good estimate of the surface energy and other mechanical features. PMID- 22208456 TI - PTPN22 polymorphisms may indicate a role for this gene in atopic dermatitis in West Highland white terriers. AB - BACKGROUND: Canine atopic dermatitis is an allergic inflammatory skin disease common in West Highland white terriers. A genome-wide association study for atopic dermatitis in a population of West Highland white terriers identified a 1.3 Mb area of association on CFA17 containing canine protein tyrosine phosphatase non-receptor type 22 (lymphoid) PTPN22. This gene is a potential candidate gene for canine atopic dermatitis as it encodes a lymphoid-specific signalling mediator that regulates T-cell and possibly B-cell activity. FINDINGS: Sequencing of PTPN22 in three atopic and three non-atopic West Highland white terriers identified 18 polymorphisms, including five genetic variants with a bioinformatically predicted functional effect. An intronic polymorphic repeat sequence variant was excluded as the cause of the genome-wide association study peak signal, by large-scale genotyping in 72 West Highland white terriers (gene dropping simulation method, P = 0.01). CONCLUSIONS: This study identified 18 genetic variants in PTPN22 that might be associated with atopic dermatitis in West Highland white terriers. This preliminary data may direct further study on the role of PTPN22 in this disease. Large scale genotyping and complementary genomic and proteomic assays would be required to assess this possibility. PMID- 22208461 TI - Publisher's Notes. PMID- 22208458 TI - Identification of pyrimethamine- and chloroquine-resistant Plasmodium falciparum in Africa between 1984 and 1998: genotyping of archive blood samples. AB - BACKGROUND: Understanding the geographical distribution of drug resistance of Plasmodium falciparum is important for the effective treatment of malaria. Drug resistance has previously been inferred mainly from records of clinical resistance. However, clinical resistance is not always consistent with the parasite's genetic resistance. Thus, molecular identification of the parasite's drug resistance is required. In Africa, clinical resistance to pyrimethamine (Pyr) and chloroquine (CQ) was evident before 1980 but few studies investigating the genetic resistance to these drugs were conducted before the late 1990s. In this study, genotyping of genes involved in resistance to Pyr and CQ was performed using archive blood samples from Africa between 1984 and 1998. METHODS: Parasite DNA was extracted from P. falciparum-infected blood smears collected from travellers returning to Japan from Africa between 1984 and 1998. Genotypes of the dihydrofolate reductase gene (dhfr) and CQ-resistance transporter gene (pfcrt) were determined by polymerase chain reaction amplification and sequencing. RESULTS: Genotyping of dhfr and pfcrt was successful in 59 and 80 samples, respectively. One wild-type and seven mutant dhfr genotypes were identified. Three dhfr genotypes lacking the S108N mutation (NRSI, ICSI, IRSI; amino acids at positions 51, 59, 108, and 164 with mutations underlined) were highly prevalent before 1994 but reduced after 1995, accompanied by an increase in genotypes with the S108N mutation. The dhfr IRNI genotype was first identified in Nigeria in 1991 in the present samples, and its frequency gradually increased. However, two double mutants (ICNI and NRNI), the latter of which was exclusively found in West Africa, were more frequent than the IRNI genotype. Only two pfcrt genotypes were found, the wild-type and a Southeast Asian type (CVIET; amino acids at positions 72-76 with mutations underlined). The CVIET genotype was already present as early as 1984 in Tanzania and Nigeria, and appeared throughout Africa between 1984 and 1998. CONCLUSIONS: This study is the first to report the molecular identification of Pyr- and CQ-resistant genotypes of P. falciparum in Africa before 1990. Genotyping of dhfr and pfcrt using archive samples has revealed new aspects of the evolutionary history of Pyr- and CQ-resistant parasites in Africa. PMID- 22208462 TI - Eating behavior and body weight: psychosocial influences. PMID- 22208464 TI - Organizational stress: implications for health promotion managers. PMID- 22208463 TI - Smokeless tobacco and teenagers: a time to act. PMID- 22208465 TI - Competitions to facilitate health promotion: review and conceptual analysis. PMID- 22208467 TI - Research agenda: building a consensus on research questions. PMID- 22208466 TI - Ethnicity and lifestyle health risk: some possible mechanisms. PMID- 22208468 TI - DataBase: Research and Evaluation Results. PMID- 22208470 TI - Networking. PMID- 22208472 TI - Resource reviews. PMID- 22208473 TI - Perspectives: on the rest of the world. PMID- 22208477 TI - Effect of a traditional Chinese medicine Liu Wei Di Huang Wan on the activities of CYP2C19, CYP2D6 and CYP3A4 in healthy volunteers. AB - Liu Wei Di Huang Wan (LDW), a well-known traditional Chinese medicine, is widely used for the treatment of various diseases in China. This study was designed to investigate the potential herb-drug interactions of LDW in healthy volunteers and attempted to ascertain whether the interaction might be affected by genotypes. We assessed the effect of LDW on the activities of CYP2C19, CYP2D6 and CYP3A4 in 12 Chinese healthy subjects in a single-center, controlled, non-blinded, two-way crossover clinical trial. The subject pool consisted of six extensive metabolizers with CYP2C19*1/*1 and six poor metabolizers with CYP2C19*2/*2. Placebo or 4.8 g LDW (12 pills, 0.2 g/pill, twice daily) was given to each participant for 14 continuous days with a wash-out period of 2 weeks after an oral administration of 30 mg omeprazole, 30 mg dextromethorphan hydrobromide and 7.5 mg midazolam. The activities of CYP2C19, CYP2D6 and CYP3A4 were ascertained by their respective plasma or urinary metabolic ratios on day 14 post-treatment. There is no difference in the activities of the three tested enzymes before or after a 14-day administration of LDW. LDW had no effect on the pharmacokinetic parameters of the substrates and their metabolites. A 14-day administration of LDW did not affect the activities of CYP2C19, CYP2D6 and CYP3A4. LDW is unlikely to cause pharmacokinetic interaction when it is combined with other medications predominantly metabolized by these enzymes. PMID- 22208478 TI - In solution sensitization of Er(III) luminescence by the 4-tetrathiafulvalene-2,6 pyridinedicarboxylic acid dimethyl antenna ligand. AB - In the [Er(hfac)(3)(L)](2) complex (1) (L = 4-tetrathiafulvalene-2,6 pyridinecarboxylic acid dimethyl ester), the Er(III) ion is bonded to the tridentate coordination site. Electrochemical and photophysical measurements in solution reveal that the tetrathiafulvalene moiety is a versatile antenna for erbium luminescence sensitization at 6540 cm(-1) upon excitation in the low energy charge transfer transition (donor to acceptor charge transfer) at 16600 cm(-1) assigned via time-dependent density functional theory calculations. PMID- 22208480 TI - Use of a keratin-based hydrogel in the management of recessive dystrophic epidermolysis bullosa. AB - A new keratin-based hydrogel wound dressing was applied to the neck of a patient who was suffering from recessive dystrophic epidermolysis bullosa. A significant improvement was observed in the robustness of skin in this area: reduced propensity to blister and improved healing of blisters. The improvement allowed the cessation of use of secondary dressings for this area. The factors gave a significant improvement in quality of life for the patient. PMID- 22208481 TI - Test verification and validation for molecular diagnostic assays. AB - With our ever-increasing understanding of the molecular basis of disease, clinical laboratories are implementing a variety of molecular diagnostic tests to aid in the diagnosis of hereditary disorders, detection and monitoring of cancer, determination of prognosis and guidance for cancer therapy, and detection and monitoring of infectious diseases. Before introducing any new test into the clinical laboratory, the performance characteristics of the assay must be "verified," if it is a US Food and Drug Administration (FDA)-approved or FDA cleared test, or "validated," if it is a laboratory-developed test. Although guidelines exist for how validation and verification studies may be addressed for molecular assays, the specific details of the approach used by individual laboratories is rarely published. Many laboratories, especially those introducing new types of molecular assays, would welcome additional guidance, especially in the form of specific examples, on the process of preparing a new molecular assay for clinical use. PMID- 22208482 TI - Verification of performance specifications of a molecular test: cystic fibrosis carrier testing using the Luminex liquid bead array. AB - CONTEXT: The number of clinical laboratories introducing various molecular tests to their existing test menu is continuously increasing. Prior to offering a US Food and Drug Administration-approved test, it is necessary that performance characteristics of the test, as claimed by the company, are verified before the assay is implemented in a clinical laboratory. OBJECTIVE: To provide an example of the verification of a specific qualitative in vitro diagnostic test: cystic fibrosis carrier testing using the Luminex liquid bead array (Luminex Molecular Diagnostics, Inc, Toronto, Ontario). DESIGN: The approach used by an individual laboratory for verification of a US Food and Drug Administration-approved assay is described. RESULTS: Specific verification data are provided to highlight the stepwise verification approach undertaken by a clinical diagnostic laboratory. CONCLUSIONS: Protocols for verification of in vitro diagnostic assays may vary between laboratories. However, all laboratories must verify several specific performance specifications prior to implementation of such assays for clinical use. We provide an example of an approach used for verifying performance of an assay for cystic fibrosis carrier screening. PMID- 22208483 TI - Verification of performance specifications for a US Food and Drug Administration approved molecular microbiology test: Clostridium difficile cytotoxin B using the Becton, Dickinson and Company GeneOhm Cdiff assay. AB - CONTEXT: US Food and Drug Administration (FDA)-approved diagnostic tests based on molecular genetic technologies are becoming available for an increasing number of microbial pathogens. Advances in technology and lower costs have moved molecular diagnostic tests formerly performed for research purposes only into much wider use in clinical microbiology laboratories. OBJECTIVE: To provide an example of laboratory studies performed to verify the performance of an FDA-approved assay for the detection of Clostridium difficile cytotoxin B compared with the manufacturer's performance standards. DESIGN: We describe the process and protocols used by a laboratory for verification of an FDA-approved assay, assess data from the verification studies, and implement the assay after verification. RESULTS: Performance data from the verification studies conducted by the laboratory were consistent with the manufacturer's performance standards and the assay was implemented into the laboratory's test menu. CONCLUSION: Verification studies are required for FDA-approved diagnostic assays prior to use in patient care. Laboratories should develop a standardized approach to verification studies that can be adapted and applied to different types of assays. We describe the verification of an FDA-approved real-time polymerase chain reaction assay for the detection of a toxin gene in a bacterial pathogen. PMID- 22208484 TI - Validation of KRAS testing for anti-EGFR therapeutic decisions for patients with metastatic colorectal carcinoma. AB - CONTEXT: KRAS mutation status is a molecular marker for predicting patient response to treatment with anti-EGFR antibodies (cetuximab and panitumumab) in metastatic colorectal carcinoma. Different approaches may be taken to detect KRAS mutations. There currently are no US Food and Drug Administration-approved assays for the detection of KRAS mutations. For assays that are not approved by the US Food and Drug Administration, the performance characteristics of the assay must be determined and validated by the clinical laboratory before implementation. OBJECTIVE: To provide an example of how a KRAS mutation-analysis assay may be validated in a clinical laboratory. DESIGN: Describing the approach used by an individual laboratory to compare different assays for validation of KRAS mutation analysis in metastatic colon carcinoma. RESULTS: Specific validation data are provided, illustrating how a laboratory established assay performance characteristics for KRAS mutation analysis. CONCLUSIONS: All clinical laboratories must establish several performance specifications mandated by the Clinical Laboratory Improvement Amendments of 1988 before implementation of any laboratory-developed test. Approaches to the validation of such assays may vary among laboratories. We describe an approach used for validation of a KRAS mutation-analysis assay by one laboratory. PMID- 22208485 TI - Design and analytic validation of BCR-ABL1 quantitative reverse transcription polymerase chain reaction assay for monitoring minimal residual disease. AB - CONTEXT: Monitoring minimal residual disease by quantitative reverse transcription polymerase chain reaction has proven clinically useful, but as yet there are no Food and Drug Administration-approved tests. Guidelines have been published that provide important information on validation of such tests; however, no practical examples have previously been published. OBJECTIVE: To provide an example of the design and validation of a quantitative reverse transcription polymerase chain reaction test. DESIGN: To describe the approach used by an individual laboratory for development and validation of a laboratory developed quantitative reverse transcription polymerase chain reaction test for BCR-ABL1 fusion transcripts. RESULTS: Elements of design and analytic validation of a laboratory-developed quantitative molecular test are discussed using quantitative detection of BCR-ABL1 fusion transcripts as an example. CONCLUSIONS: Validation of laboratory-developed quantitative molecular tests requires careful planning and execution to adequately address all required analytic performance parameters. How these are addressed depends on the potential for technical errors and confidence required for a given test result. We demonstrate how one laboratory validated and clinically implemented a quantitative BCR-ABL1 assay that can be used for the management of patients with chronic myelogenous leukemia. PMID- 22208486 TI - Design and analytical validation of clinical DNA sequencing assays. AB - CONTEXT: DNA sequencing is the method of choice for mutation detection in many genes. OBJECTIVES: To demonstrate the analytical accuracy and reliability of DNA sequencing assays developed in clinical laboratories. Only general guidelines exist for the validation of these tests. We provide examples of assay validation strategies for DNA sequencing tests. DESIGN: We discuss important design and validation considerations. RESULTS: The validation examples include an accuracy study to evaluate concordance between results obtained by the newly designed assay and analyzed by another method or laboratory. Precision (reproducibility) studies are performed to determine the robustness of the assay. To assess the quality of sequencing assays, several sequence quality measures are available. In addition, assessing the ability of primers to specifically and robustly amplify target regions before sequencing is important. CONCLUSION: Protocols for validation of laboratory-developed sequencing assays may vary between laboratories. An example summary of a validation is provided. PMID- 22208487 TI - Validation of fluorescence in situ hybridization using an analyte-specific reagent for detection of abnormalities involving the mixed lineage leukemia gene. AB - CONTEXT: Fluorescence in situ hybridization (FISH) is a molecular cytogenetic assay that is commonly used in laboratory medicine. Most FISH assays are not approved by the US Food and Drug Administration but instead are laboratory developed tests that use analyte-specific reagents. Although several guidelines exist for validation of FISH assays, few specific examples of FISH test validations are available in the literature. OBJECTIVE: To provide an example of how a FISH assay, using an analyte-specific reagent probe, may be validated in a clinical laboratory. DESIGN: We describe the approach used by an individual laboratory for validation of a FISH assay for mixed lineage leukemia (MLL) gene. RESULTS: Specific validation data are provided illustrating how initial assay performance characteristics in a FISH assay for MLL may be established. CONCLUSIONS: Protocols for initial validation of FISH assays may vary between laboratories. However, all laboratories must establish several defined performance specifications prior to implementation of FISH assays for clinical use. We describe an approach used for assessing performance specifications and validation of an analyte-specific reagent FISH assay using probes for MLL rearrangement in interphase nuclei. PMID- 22208488 TI - Pathologic diagnostic correlation with breast imaging findings: a College of American Pathologists Q-Probes study of 48 institutions. AB - CONTEXT: Correlation of radiologic and pathologic findings is important for optimal management of patients with image-guided breast biopsies. OBJECTIVES: To (1) evaluate the rates of radiologic and pathologic correlation in breast needle core biopsies, (2) evaluate laboratory and radiology practices associated with greater correlation rates, and (3) determine the rates at which the lack of radiologic-pathologic correlation is documented in pathology reports. DESIGN: The study was offered and conducted as a College of American Pathologists voluntary Q Probes program. Participants in this study retrospectively reviewed 30 consecutive, initial, diagnostic needle core biopsy cases performed for abnormal radiologic findings. If 12 months of accessioned cases were reviewed without identifying 30 qualifying cases, participants stopped the retrospective review and included all cases identified. For each case or specimen, the participants provided detailed information about the radiologic and pathologic findings. RESULTS: In aggregate, a radiologic-pathologic correlation was found in 94.9% (1328 of 1399) of the cases reviewed, based on the participants' judgments. Significant differences in the correlation rates existed when cases were discussed at an interdepartmental, multidisciplinary conference (P < .001). No significant differences were found in the correlation rates of the following: whether surgeons or radiologists performed the biopsy, whether cores with calcifications were identified by any method, and whether the laboratory had one or more designated breast pathologists. CONCLUSIONS: Participation in a multidisciplinary breast conference is useful in radiologic-pathologic correlation. Active involvement by pathologists in correlating pathologic and radiologic findings is important. PMID- 22208489 TI - Mesenchymal chondrosarcoma: clinicopathologic study of 20 cases. AB - CONTEXT: Mesenchymal chondrosarcoma is a rare, high-grade malignancy of bone or soft tissue with a unique, biphasic histology and poor prognosis. Because of its rarity and variable length of disease-free survival, the natural history of the disease remains poorly understood. OBJECTIVE: To present clinical, radiographic, and histopathologic features of mesenchymal chondrosarcoma from one of the largest case series collected by a single, senior-level bone pathologist. DESIGN: Twenty cases were reviewed in consultations spanning 45 years. RESULTS: Eighteen tumors (90%) originated in bone, and 2 tumors (10%) were of extraskeletal origin. Of the skeletal tumors, locations included craniofacial bones (n = 9; 50%), ribs and chest wall (n = 4; 22%), sacrum and spinal elements (n = 3; 17%), and lower extremities (n = 2; 11%), whereas soft tissue tumors were located about the scapula (n = 1; 50%) and lower extremity (n = 1; 50%). Plain radiographs demonstrated calcified, osteolytic lesions with extraosseous extension. Typical histologic features were identified consisting of small, round or spindled cells, interspersed with hyaline cartilage islands. Seventeen patients (85%) were treated surgically, and 8 patients (40%) received adjuvant treatment. Seven patients (35%) were living at last follow-up, 1.8 to 12.5 years after diagnosis, and 8 patients (40%) died between 1.2 and 21.8 years after diagnosis. CONCLUSIONS: Mesenchymal chondrosarcoma presents multiple challenges. Diagnostic pitfalls include inadequate biopsy samples, which may result in sample error. Sox9 has been proposed as a unique marker for mesenchymal chondrosarcoma which may improve diagnostic specificity. Treatment and prognosis vary considerably. Patients who receive surgery and chemotherapy seem to fare better. Multicenter studies with higher sample numbers may improve our understanding of this malignancy. PMID- 22208490 TI - Causes and relevance of unsatisfactory and satisfactory but limited smears of liquid-based compared with conventional cervical cytology. AB - CONTEXT: Recent randomized controlled trials have shown a significant decrease in unsatisfactory rates for liquid-based cytology (LBC) compared with conventional Papanicolaou test (CP). The underlying causes and relevance of unsatisfactory results for LBC and CP have never been compared within the setting of a randomized controlled trial. OBJECTIVE: To examine differences in causes and relevance of unsatisfactory and satisfactory but limited by (SBLB) results for LBC and CP. DESIGN: Data from the Netherlands ThinPrep Versus Conventional Cytology (NETHCON) trial were used, involving 89 784 women. Causes and relevance of unsatisfactory and SBLB results were analyzed. RESULTS: The primary cause for unsatisfactory results for CP and LBC was scant cellularity. Other causes for unsatisfactory CPs were virtually eliminated with LBC. The same was true for SBLB subcategories, with the exception of SBLB absence of transformation zone component and SBLB scant cellularity. The SBLB absence of transformation zone component showed a statistically significant 22% and SBLB scant cellularity a 12% nonsignificant increase with LBC. The detection rates of abnormalities found during 18 months of follow-up of unsatisfactory test results did not differ significantly between the 2 study arms, nor did they differ from the initial test positivity rates from the NETHCON trial. CONCLUSIONS: Liquid-based cytology shows an almost complete elimination of most causes for unsatisfactory CP, with scant cellularity remaining as the sole cause for unsatisfactory LBC. On the other hand, with LBC a significant increase of smears without a transformation zone component was noted. Women with an unsatisfactory test result are not at increased risk for cervical abnormalities either with LBC or with CP. TRIAL REGISTRATION: Nederlands Trial Register, NTR1032, www.trialregister.nl . PMID- 22208492 TI - The practice of pathology in Canada: decreasing pathologist supply and uncertain outcomes. AB - CONTEXT: Pathology organizations in the United States are preparing for a new era of health care reform. Trends in the supply of pathologists in Canada's managed care system may provide some useful insights in any analysis and projection of future pathologist needs in the United States. OBJECTIVE: In this study, population-based Canadian databases were used to devise a parameter for physician supply, cancer cases per physician. The trend in this supply parameter for pathologists was compared to that for radiation oncologists. DESIGN: The number of Canadian pathologists and radiation oncologists and the annual number of new cancer cases in each of 2 years, 1999 and 2009, were extracted from reliable databases. Cancer cases per pathologist and oncologist were calculated, and relative trends in supply of physicians in both specialties were identified. RESULTS: The annual number of new cancer cases increased from 129,300 to 171,000 from 1999 to 2009. The absolute numbers of both pathologists and oncologists also increased in this time period. However, while the increase in the number of radiation oncologists led to an 8.2% decrease in cancer cases per radiation oncologist, the modest increase in the number of pathologists led to an increase of 17.1% in cancer cases per pathologist. CONCLUSIONS: There is a trend toward a decreasing supply of Canadian pathologists relative to that of cancer demands. This finding confirms an earlier population-based study showing a decreased supply relative to population and number of clinical physicians. It is uncertain whether this decreased supply is a result of appropriate application of new, efficient methods or whether health care has been rationed or adversely impacted. Outcome measures to monitor Canadian pathology practice quality are clearly needed. PMID- 22208491 TI - FMS-like tyrosine kinase 3 internal tandem duplication and the patterns of its gene sequence in 207 Chinese patients with de novo acute myeloid leukemia. AB - CONTEXT: Constitutive activation of the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase by internal tandem duplication (ITD) has been researched in patients with de novo acute myeloid leukemia (AML). OBJECTIVE: To study the patterns of FLT3-ITD in Chinese patients with AML. DESIGN: A total of 207 patients with de novo AML were enrolled in the study. Genomic DNA was extracted from peripheral blood and polymerase chain reaction was performed. GeneScan was used to analyze the mutant to wild-type ratio. The sequencing of mutated genes was performed to confirm the mutation types and exclude false positives. RESULTS: A total of 42 cases (20.3%) were associated with mutations. FLT3-ITD was found equally in AML subtypes M1 to M6. The level of the ITD allele was heterogeneous. GeneScan showed that the mutant to wild-type ratio ranged from 0.03 to 3.78 (median, 0.43). Patients with a high ratio had significantly lower cancer remission rates and shorter survival. They also showed distinct clinical features including higher white blood cell counts and higher CD7 and CD56 expression. The length of the duplicated fragment was 26 to 57 bp (median, 43 bp). Twenty-two cases (52%) had simple tandem duplications, while 20 other cases (48%) had an extra interval of 12 to 30 bp before the tandem duplications. A hexanucleotide consisting of GAAAAG was found exclusively in the intervals. Patients with this GAAAAG interval showed better survival. The ITD to wild-type ratio, gene pattern, and CD7 expression status appear to be independent prognostic indices for patients with AML. CONCLUSION: Detection of FLT3 mutation is fast, easy, and inexpensive. The mutant to wild-type ratio is helpful for performing detailed risk stratification. DNA sequence analysis is more precise for confirming and evaluating the mutation pattern. PMID- 22208493 TI - MDM2 amplification in malignant peripheral nerve sheath tumors correlates with p53 protein expression. AB - CONTEXT: MDM2 is known to be abnormally upregulated in a variety of human neoplasms, secondary to gene amplification. Assessment of MDM2 amplification is most useful clinically for separating lipomas (nonamplified) from atypical lipomatous neoplasms or well-differentiated liposarcomas (amplified). MDM2 amplification occurs in approximately 7% of all human neoplasms. In this study, we sought to determine the utility of MDM2 amplification for the separation of benign (schwannomas) and malignant peripheral nerve sheath tumors (MPNSTs). The expression of p53 was correlated with MDM2 amplification because early studies have indicated that MDM2 is rarely amplified in MPNSTs that express p53. OBJECTIVES: To determine the percentage of MPNSTs with MDM2 amplification and the specificity of MDM2 amplification for malignancy in nerve sheath tumors. DESIGN: Fifteen MPNSTs, 14 neurofibromas, and 15 schwannomas were obtained from the files of the Department of Pathology. These cases underwent fluorescent in situ hybridization analysis for the presence of MDM2 amplification. Assessments were also made for cellularity (low or high), percentage of cells staining positively for p53 and MDM2 protein, and percentage of cells staining with MIB-1. RESULTS: Of 15 MPNSTs, 3 (20%) demonstrated amplification of the MDM2 gene. No neurofibromas or schwannomas demonstrated MDM2 amplification. All 3 MDM2 amplified MPNSTs were positive for p53. Correlation of MDM2 amplification status and p53 immunoreactivity was statistically significant (P = .004). CONCLUSIONS: The low frequency (20%) of MDM2 amplification in our series of MPNSTs demonstrates that MDM2 fluorescent in situ hybridization has limited diagnostic value for the separation of benign schwannomas and MPNSTs. Our study demonstrated a positive correlation (P = .004) between MDM2 amplification and p53 expression. PMID- 22208494 TI - Assessing treatment effect in pancreatic cancer. AB - CONTEXT: Pancreatic cancer is one of the most deadly forms of cancer (43,140 new cases per year; 36,800 deaths), and most people with pancreatic cancer do not survive past 5 years. New therapeutic regimens are constantly being evaluated in an attempt to reduce the rapid progression of this disease. Although some patients receive neoadjuvant therapy in an attempt to make a nonresectable or borderline-resectable tumor resectable, more patients with resectable disease are being enrolled in clinical trials that provide neoadjuvant therapy. This means more pancreatic resections must be evaluated for therapy effect. Histologic grading schemes for the assessment of posttherapy response have been described, but difficulties associated with determining the histologic features of treatment effect in pancreatic cancer have not been addressed. OBJECTIVES: To critically review the diagnostic criteria for proposed grading schemes for pancreatic cancer treated with neoadjuvant chemoradiation therapy and to provide guidance to surgical pathologists who encounter treated pancreatic cancer resections. DATA SOURCES: Published peer-reviewed literature and the personal experience of the authors. CONCLUSIONS: Assessment of treatment effect in pancreatic cancer is difficult. Pathologists need to be aware that some histologic features of treatment effect overlap with histologic features seen in untreated pancreatic cancer, such as tumor cell anaplasia, necrosis, and fibrosis. Careful assessment of pancreatic resections, including detailed gross examination and thorough histologic sampling, is important in accurately assessing treatment effect and improving patient outcomes. PMID- 22208495 TI - Primary nodal hemangioma. AB - Benign vascular tumors arising primarily in lymph nodes are rare. The importance of identifying these entities is to avoid misdiagnosing them as malignant vascular tumors, which occur more often in lymph nodes. Hemangioma is a benign nodal vascular tumor, but its occurrence in lymph nodes is extremely rare. Hemangiomas can occur at any age, mostly in females. It is usually asymptomatic, affects only one node, and does not recur. Four histologic types of hemangioma have been identified: capillary/cavernous, lobular capillary, cellular, and epithelioid. This review highlights the key features of previously reported cases and discusses the differential diagnosis. PMID- 22208496 TI - Malignant mesothelioma of the tunica vaginalis testis: diagnostic studies and differential diagnosis. AB - Malignant mesothelioma of the tunica vaginalis testis is an extremely rare tumor representing 0.3% to 5% of all malignant mesotheliomas. Gross examination of testicular mesotheliomas typically reveals tumor nodules studding the thickened tunica vaginalis and, in some cases, infiltrating the testicular parenchyma, leading to diagnostic challenges. Microscopically, the tumor is characterized by epithelioid cells arising from the tunica vaginalis with papillary, tubulopapillary, or solid architectural patterns. The papillae are usually lined by a single layer of cells with relatively bland cytologic features. An epithelial cell phenotype admixed with a sarcomatoid pattern has also been described in a few cases. Immunohistochemically, the tumor is usually positive for calretinin, Wilms tumor-1, epithelial membrane antigen, D2-40, thrombomodulin, cytokeratin 7, and cytokeratin 5/6. Electron microscopic studies reveal epithelial cells joined by tight junctions, forming lumina, and displaying long microvilli with length to width ratios often greater than 10. The most important differential diagnostic considerations include florid mesothelial hyperplasia, adenomatoid tumor, carcinoma of the rete testis, and serous papillary tumors. In addition, the various types of testicular germ cell tumors should be considered, including seminomas, embryonal carcinomas, and intratubular germ cell tumors, particularly in tumors with testicular parenchymal involvement. Pleomorphic sarcomas should also be considered, particularly when dealing with the biphasic variant. The prognosis for this entity is grave, with a median survival of 23 months. Aggressive therapy with radical orchiectomy remains the mainstay of treatment. PMID- 22208497 TI - Antibody response of healthy children to pandemic A/H1N1/2009 influenza virus. AB - BACKGROUND: Little is known about the proportion of pediatric pandemic A/H1N1/2009 influenza cases who showed seroconversion, the magnitude of this seroconversion, or the factors that can affect the antibody level evoked by the pandemic A/H1N1/2009 influenza. Aims of this study were to analyse antibody responses and the factors associated with high antibody titres in a cohort of children with naturally acquired A/H1N1/2009 influenza infection confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR). RESULTS: Demographic, clinical and virologic data were collected from 69 otherwise healthy children with pandemic A/H1N1/2009 influenza (27 females, mean age +/- SD: 5.01 +/- 4.55 years). Their antibody levels against pandemic A/H1N1/2009 and seasonal A/H1N1 influenza viruses were evaluated by measuring hemagglutination-inhibiting antibodies using standard assays. Sixty-four patients (92.8%) with pandemic A/H1N1/2009 influenza had A/H1N1/2009 antibody levels of >= 40, whereas only 28/69 (40.6%) were seroprotected against seasonal A/H1N1 influenza virus. Those who were seroprotected against seasonal A/H1N1 virus were significantly older, significantly more often hospitalised, had a diagnosis of pneumonia significantly more frequently, and were significantly more often treated with oseltamivir than those who were not seroprotected (p < 0.05). The children with the most severe disease (assessed on the basis of a need for hospitalisation and a diagnosis of pneumonia) had the highest antibody response against pandemic A/H1N1/2009 influenza virus. CONCLUSIONS: Otherwise healthy children seem to show seroprotective antibody titres after natural infection with pandemic A/H1N1/2009 influenza virus. The strength of the immune response seems to be related to the severity of the disease, but not to previous seasonal A/H1N1 influenza immunity. PMID- 22208498 TI - The Strathclyde Evaluation of Children's Active Travel (SE-CAT): study rationale and methods. AB - BACKGROUND: The school commute is a prime opportunity to increase children's physical activity levels. However, active commuting has decreased over the past 40 years. Strategies that increase walking to school are therefore needed. Travelling Green (TG) is a school-based active travel resource aimed at increasing children's walking to school. The resource consists of a curriculum based program of lessons and goal setting activities. A previous study found that children who received the TG intervention increased self-reported distance travelled to school by active modes and reduced the distance travelled by inactive modes. This study was limited by self-reported outcome measures, a small sample, and no follow-up measures. A more robust evaluation of TG is required to address these limitations. This paper describes the rationale and methods for such an evaluation of Travelling Green, and describes the piloting of various active commuting measures in primary school children. METHODS/DESIGN: Measures of active commuting were piloted in a sample of 26 children (aged 8-9 years) over one school week. These measures were subsequently used in an 18-month quasi experimental design to evaluate the effect of TG on commuting behaviour. Participants were 166 children (60% male) aged 8-9 years from 5 primary schools. Two schools (n = 79 children) received TG in September/October 2009. Three schools (n = 87 children) acted as a comparison group, and subsequently received TG at a later date. Physical activity was measured using Actigraph GT1M accelerometers. Personal and environmental determinants of active commuting were measured via parent and child questionnaires, as were factors related to the Theory of Planned Behaviour and the construct of habit. Measures were taken pre- and post-intervention and at 5 and 12 months follow-up. DISCUSSION: The piloted protocol was practical and feasible and piloted measures were reliable and valid. All study data, including 5 and 12 month follow-up, have been collected and processed. Data analysis is ongoing. Results will indicate whether TG successfully increases active commuting in a sample of Scottish school children and will inform future efforts in school active travel promotion. PMID- 22208500 TI - Anionic surfactant ionic liquids with 1-butyl-3-methyl-imidazolium cations: characterization and application. AB - For the first time a series of anionic surfactant ionic liquids (SAILs) has been synthesized based on organic surfactant anions and 1-butyl-3-methyl-imidazolium cations. These compounds are more environmentally friendly and chemically tunable as compared to other common ionic liquids. A detailed investigation of physicochemical properties highlights potential applications from battery design to reaction control, and studies into aqueous aggregation behavior, as well as structuring in pure ILs, point to possible uses in electrochemistry. PMID- 22208502 TI - Comparison of RNA extraction methods from biofilm samples of Staphylococcus epidermidis. AB - BACKGROUND: Microbial biofilms are communities of bacteria adhered to a surface and surrounded by an extracellular polymeric matrix. Biofilms have been associated with increased antibiotic resistance and tolerance to the immune system. Staphylococcus epidermidis is the major bacterial species found in biofilm-related infections on indwelling medical devices. Obtaining high quality mRNA from biofilms is crucial to validate the transcriptional measurements associated with the switching to the biofilm mode of growth. Therefore, we selected three commercially available RNA extraction kits with distinct characteristics, including those using silica membrane or organic extraction methods, and enzymatic or mechanical cell lysis, and evaluated the RNA quality obtained from two distinct S. epidermidis bacterial biofilms. RESULTS: RNA extracted using the different kits was evaluated for quantity, purity, integrity, and functionally. All kits were able to extract intact and functional total RNA from the biofilms generated from each S. epidermidis strain. The results demonstrated that the kit based on mechanical lysis and organic extraction (FastRNA(r) Pro Blue) was the only one that was able to isolate pure and large quantities of RNA. Normalized expression of the icaA virulence gene showed that RNA extracted with PureLinkTM had a significant lower concentration of icaA mRNA transcripts than the other kits tested. CONCLUSIONS: When working with complex samples, such as biofilms, that contain a high content extracellular polysaccharide and proteins, special care should be taken when selecting the appropriate RNA extraction system, in order to obtain accurate, reproducible, and biologically significant results. Among the RNA extraction kits tested, FastRNA(r) Pro Blue was the best option for both S. epidermidis biofilms used. PMID- 22208499 TI - Neuroantigen-specific, tolerogenic vaccines: GM-CSF is a fusion partner that facilitates tolerance rather than immunity to dominant self-epitopes of myelin in murine models of experimental autoimmune encephalomyelitis (EAE). AB - BACKGROUND: Vaccination strategies that elicit antigen-specific tolerance are needed as therapies for autoimmune disease. This study focused on whether cytokine-neuroantigen (NAg) fusion proteins could inhibit disease in chronic murine models of experimental autoimmune encephalomyelitis (EAE) and thus serve as potential therapeutic modalities for multiple sclerosis. RESULTS: A fusion protein comprised of murine GM-CSF as the N-terminal domain and the encephalitogenic MOG35-55 peptide as the C-terminal domain was tested as a tolerogenic, therapeutic vaccine (TTV) in the C57BL/6 model of EAE. Administration of GMCSF-MOG before active induction of EAE, or alternatively, at the onset of EAE blocked the development and progression of EAE. Covalent linkage of the GM-CSF and MOG35-55 domains was required for tolerogenic activity. Likewise, a TTV comprised of GM-CSF and PLP139-151 was a tolerogen in the SJL model of EAE. CONCLUSION: These data indicated that fusion proteins containing GM CSF coupled to myelin auto-antigens elicit tolerance rather than immunity. PMID- 22208504 TI - 50 years a biomedical engineer remembering a long and fascinating journey. AB - Looking back at one point of life appears as a nice exercise to round out and summarize. However, the objective should not be simply to tell a story; it must transmit a message to the young. To start with, two concepts are useful: Respect for others begins when you learn to laugh at yourself and, taken from an old saying, I did not want to be poor ... but money wouldn't make me rich. After elementary and high schools, during times of turmoil, I describe my engineering school years at the University of Buenos Aires and a working experience in an international telecommunications company. Significant events taught me a concept, rooted in another motto: Isn't this house nice? It is my house, and I love it very much. In 1960, I began my activities in the USA. A couple of bad decisions resulted in significant events for me teaching me an important truth: "Beware of golden promises; time is the most precious asset". Finally, in 1972, settled down in Tucuman until retirement in 2001, a long period of productive activity came about, not without difficulties and also stained by a dark political interval. Crises seem to characterize our generations in Argentina. Non-the-less, there were some real accomplishments: an undergraduate program in BME and a National BME Society (SABI) plus an archive of specialized published material. After spending time following retirement in Peru and Italy, my current activity came as unexpected dessert at the University of Buenos Aires, with a small research group, so offering the opportunity of transmitting what I still have available. PMID- 22208507 TI - Publisher's Notes. PMID- 22208508 TI - A multivariate analysis of the relationship between cigarette smoking and absence from work. PMID- 22208509 TI - Developing a useful perspective on spiritual health: love, joy, peace and fulfillment. PMID- 22208510 TI - The role of health risk appraisal in the workplace: assessment versus behavior change. PMID- 22208512 TI - Worksite health promotion programs: ethical issues. PMID- 22208511 TI - Roll call voting behavior of the u.s. Senate on selected health legislation 1973 1982: implications for health education. PMID- 22208513 TI - Research agenda: building a consensus on research questions. PMID- 22208516 TI - View point: health promotion program cost effectiveness - a response to murphy et Al. PMID- 22208514 TI - DataBase: Research and Evaluation Results. PMID- 22208519 TI - Profile: national center for health education. PMID- 22208517 TI - Networking. PMID- 22208520 TI - Resource reviews. PMID- 22208521 TI - Perspectives on the rest of the world. PMID- 22208524 TI - The intramolecular rearrangement of phosphinohydrazides [R'2P-NR-NR-M] -> [RN?PR'2-NR-M]: general rules and exceptions. transformations of bulky phosphinohydrazines (R-NH-N(PPh2)2, R = tBu, Ph2P). AB - Reactions of diphosphinohydrazines R-NH-N(PPh(2))(2) (R = tBu (1), Ph(2)P (3)) with some metalation reagents (Co[N(SiMe(3))(2)](2), LiN(SiMe(3))(2), La[N(SiMe(3))(2)](3), nBuLi, MeLi) were performed. Compound 1 was synthesized by the reaction of Ph(2)PCl with tert-butylhydrazine hydrochloride in 83% yield. This compound reveals temperature-dependent (31)P NMR spectra due to hindered rotation about the P-N bonds. Complicated redox reaction of 1 with Co[N(SiMe(3))(2)](2) proceeds with cleavage of the P-N and N-N bonds to form a binuclear cobalt complex [Co{HN(PPh(2))(2)-kappa(2)P,P'}(2)(MU-PPh(2))](2) (2) demonstrating a short Co...Co distance of 2.3857(5) A, which implies a formal double bond between the Co atoms. Strong nucleophiles (nBuLi, MeLi) cause fragmentation of the molecules 1 and 3, while reactions of 3 with lithium and lanthanum silylamides give products of the NNP -> NPN rearrangement [Li{Ph(2)P(NPPh(2))(2)-kappa(2)N,N'}(THF)(2)] (4) and [La{Ph(2)P(NPPh(2))(2) kappa(2)N,N'}{N(SiMe(3))(2)}(2)] (5), respectively. These complexes represent the first examples of a kappa(2)N,N' bonding mode for the triphosphazenide ligand [(Ph(2)PN)(2)PPh(2)](-). DFT calculations showed large energy gain (52.1 kcal/mol) of the [NNP](-) to [NPN](-) anion rearrangement. PMID- 22208527 TI - Cost analysis: treatment of chemotherapy-induced anemia with erythropoiesis stimulating agents in five European countries. AB - OBJECTIVE: Cost-analysis comparing darbepoetin-alfa (DARB), epoetin-alfa (EPO-A), and epoetin-beta (EPO-B) for treatment of chemotherapy-induced anemia in Belgium concluded that costs for DARB-treated patients were significantly lower than costs for EPO-A- or EPO-B-treated patients. The objective of the present study was to extend the Belgian analysis to Austria, France, Italy, Portugal, and Spain, estimating differences in costs between erythropoiesis-stimulating agents (ESAs) in each country. METHODS: Differences in epidemiology and treatment patterns between countries were adjusted using data from Eurostat, national cancer registries, IMS sales data, and reimbursement and treatment guidelines. Belgian unit costs were replaced with country-specific costs. Costs were analyzed using a mixed-effects model stratifying for propensity score quintiles. RESULTS: All populations were comparable to the Belgian population in terms of age, gender, ESA, and blood transfusions use. After adjusting for country-specific chemotherapy use and cancer incidence, total management costs per patient (Euro, 2010) were 19-26% (France, Spain) lower with DARB compared with EPO-A (p < 0.0001) and 20-36% (Portugal, Austria) compared with EPO-B (p < 0.01). Anemia related costs with DARB were between 12% (Portugal; p = 0.0235) and 38% (Italy; p < 0.0001) lower compared with EPO-A (p < 0.01; all remaining countries), and between 13% (Austria; p = 0.064) and 19% (Portugal; p = 0.0028) lower compared with EPO-B (p < 0.05; all remaining countries except Italy; p = 0.0935). LIMITATIONS: Not all differences could be accounted for by a lack of country specific data; however, the potential under- and over-estimation of costs should be similar for all three ESAs. CONCLUSIONS: These findings are in line with the Belgian analysis. In all countries, total and anemia-related costs were lowest in patients receiving DARB vs EPO-A or EPO-B. This study demonstrates the feasibility of adapting real-life country-specific data to other settings, adjusting for differences in patients' characteristics and treatment strategies. These findings should be valuable in healthcare decision-making in oncology patients treated in each of the countries studied. PMID- 22208528 TI - Is there a relationship between the substrate preferences and structural flexibility of cytochromes P450? AB - In the last decades, the structural flexibility of cytochromes P450 has been extensively studied by spectroscopic and in silico methods. Here, both approaches are reviewed and compared. Comparison of both methods indicates that the individual cytochromes P450 differ significantly in the flexibilities of their substrate-binding active sites. This finding probably accounts for the large number of isoforms of these enzymes (there are fifty-seven known cytochrome P450 genes in the human genome) and their functional versatility. On the other hand, most of the known cytochrome P450s have a set of common structural features, with an overall structure consisting of a relatively flexible domain (the distal side), a more rigid domain (the heme-binding core) and a domain on the proximal side of the hemoprotein with intermediate flexibility. Substrate access and product egress channels of CYP enzymes are also important structural elements as the majority of these channels are located in the flexible distal side; the location, flexibility, and function of these channels are discussed. PMID- 22208529 TI - Multiple, ligand-dependent routes from the active site of cytochrome P450 2C9. AB - The active site of liver-specific, drug-metabolizing cytochrome P450 (CYP) monooxygenases is deeply buried in the protein and is connected to the protein surface through multiple tunnels, many of which were found open in different CYP crystal structures. It has been shown that different tunnels could serve as ligand passage routes in different CYPs. However, it is not understood whether one CYP uses multiple routes for substrate access and product release and whether these routes depend on ligand properties. From 300 ns of molecular dynamics simulations of CYP2C9, the second most abundant CYP in the human liver we found four main ligand exit routes, the occurrence of each depending on the ligand type and the conformation of the F-G loop, which is likely to be affected by the CYP membrane interaction. A non-helical F-G loop favored exit towards the putative membrane-embedded region. Important protein features that direct ligand exit include aromatic residues that divide the active site and whose motions control access to two pathways. The ligands interacted with positively charged residues on the protein surface through hydrogen bonds that appear to select for acidic substrates. The observation of multiple, ligand-dependent routes in a CYP aids understanding of how CYP mutations affect drug metabolism and provides new possibilities for CYP inhibition. PMID- 22208530 TI - The role of protein plasticity in computational rationalization studies on regioselectivity in testosterone hydroxylation by cytochrome P450 BM3 mutants. AB - Recently, it was found that mutations in the binding cavity of drug-metabolizing Cytochrome P450 BM3 mutants can result in major changes in regioselectivity in testosterone (TES) hydroxylation. In the current work, we report the intrinsic reactivity of TES' C-H bonds and our attempts to rationalize experimentally observed changes in TES hydroxylation using a protein structure-based in silico approach, by setting up and employing a combined Molecular Dynamics (MD) and ligand docking approach to account for the flexibility and plasticity of BM3 mutants. Using this approach, about 100,000 TES binding poses were obtained per mutant. The predicted regioselectivity in TES hydroxylation by the mutants was found to be in disagreement with experiment. As revealed in a detailed structural analysis of the obtained docking poses, this disagreement is due to limitations in correctly scoring hydrogen-bonding and steric interactions with specific active-site residues, which could explain the experimentally observed trends in regioselectivity in TES hydroxylation. PMID- 22208532 TI - Dynamics and hydration of the active sites of mammalian cytochromes P450 probed by molecular dynamics simulations. AB - The flexibility, active site volume, solvation, and access path dynamics of six metabolically active mammalian cytochromes P450 (human 2A6, 2C9, 2D6, 2E1, 3A4 and rabbit 2B4) are extensively studied using molecular dynamics (MD) simulations. On average, the enzymes' overall structures equilibrate on a 50+ ns timescale. The very open CYP2B4 structure closes slowly over the course of the simulation. The volumes of the active sites fluctuate by more than 50% during the MD runs; these fluctuations are mainly due to movements of the main chains, with only a handful of amino acid residues in CYP2B4, CYP2D6, CYP2A6 and CYP2C9 showing significant independent side chain movement. The volume of the active site of CYP2E1 fluctuates heavily, ranging from 220 to 1310 A(3), due to the opening and closing of gates to two adjacent cavities. CYP2E1 has the least hydrated active site of the studied CYPs; this is consistent with its preference for non-polar substrates. The CYP2A6 and CYP2E1 active sites are deeply buried, with access paths that are narrower than the radius of a water molecule. However, waters are still able to access these active sites due to local adaptations of the channel to accommodate their passage. This finding may imply that the access paths of the CYPs never fully open prior to contact with the substrate; instead, the substrate may induce adaptive conformational changes during its passage to the active site. This may also explain why some substrate recognition sites are localized along individual enzymes' access paths. PMID- 22208531 TI - Plasticity of CYP2B enzymes: structural and solution biophysical methods. AB - In the past three years, major advances in understanding cytochrome P450 2B (CYP2B) structure-function relationships have been made through determination of multiple ligand-bound and one ligand-free X-ray crystal structure of CYP2B4 and one ligand-bound X-ray crystal structure of CYP2B6. These structures have provided insight into the features that provide the high degree of plasticity of the enzymes. A combination of a phenylalanine cluster that allows for concerted movement of helices F through G and a conserved set of electrostatic interactions involving Arg(262) facilitates movement of this region to accommodate binding of ligands of various sizes without perturbing most of the P450 fold. Integrating solution based techniques such as NMR or deuterium exchange mass spectrometry (DXMS) with computational methods including molecular docking has provided further insight into enzyme behavior upon ligand binding. In addition, extended molecular dynamics simulations have provided a link between an open and a closed conformation of ligand-free CYP2B4 found in crystal structures. Other studies revealed the utility of rational engineering in improving stability of P450s to facilitate structural studies. The solution and computational results combined with the X-ray crystal structures yield a comprehensive picture of how these enzymes adopt different conformations to bind various ligands. PMID- 22208533 TI - Malleability and versatility of cytochrome P450 active sites studied by molecular simulations. AB - As the most important phase I drug metabolizing enzymes, the human Cytochromes P450 display an enormous versatility in the molecular structures of possible substrates. Individual isoforms may preferentially bind specific classes of molecules, but also within these classes, some isoforms show remarkable levels of promiscuity. In this work, we try to link this promiscuity to the versatility and malleability of the active site at the hand of examples from our own work. Mainly focusing on the flexibility of protein structures and the presence or absence of water molecules, we establish molecular reasons for observed promiscuity, determine the relevant factors to take into account when predicting binding poses and rationalize the role of individual interactions in the process of ligand binding. A high level of active site flexibility does not only allow for the binding of a large variety of substrates and inhibitors, but also appears to be important to facilitate ligand binding and unbinding. PMID- 22208534 TI - Identification of selectivity determinants in CYP monooxygenases by modelling and systematic analysis of sequence and structure. AB - Cytochrome P450 monooxygenases (CYPs) form a large, ubiquitous enzyme family and are of great interest in red and white biotechnology. To investigate the effect of protein structure on selectivity, the binding of substrate molecules near to the active site was modelled by molecular dynamics simulations. From a comprehensive and systematic comparison of more than 6300 CYP sequences and 31 structures using the Cytochrome P450 Engineering Database (CYPED), residues were identified which are predicted to point close to the heme centre and thus restrict accessibility for substrates. As a result, sequence-structure-function relationships are described that can be used to predict selectivity-determining positions from CYP sequences and structures. Based on this analysis, a minimal library consisting of bacterial CYP102A1 (P450(BM3)) and 24 variants was constructed. All variants were functionally expressed in E. coli, and the library was screened with four terpene substrates. Only 3 variants showed no activity towards all 4 terpenes, while 11 variants demonstrated either a strong shift or improved regio- or stereoselectivity during oxidation of at least one substrate as compared to CYP102A1 wild type. The minimal library also contains variants that show interesting side products which are not generated by the wild type enzyme. By two additional rounds of molecular modelling, diversification, and screening, the selectivity of one of these variants for a new product was optimised with a minimal screening effort. We propose this as a generic approach for other CYP substrates. PMID- 22208535 TI - Chronic hepatitis C infection in the elderly. AB - The prevalence of chronic hepatitis C virus (HCV) tends to be higher in the elderly in many countries. Aging is regarded as an unfavorable factor for liver disease progression and treatment outcome in HCV infection. The efficacy and safety of treating elderly patients remain a source of significant debate. Discrepancies in results may be attributed to dissimilarities in study design and treatment regimens. The long-term benefits of administering interferon-based therapy to elderly patients with HCV infection is a critical issue when taking the patient's remaining life expectancy into consideration. Rapid virological response is the most notable on-treatment response factor that is predictive of treatment success in elderly patients. A shortened treatment course may reduce drug-related side effects and promote treatment adherence, especially in the elderly. A regimen tailored towards super-responders might provide insights for treatment strategies in elderly patients. PMID- 22208536 TI - KMUP-1 inhibits L-type Ca2+ channels involved the protein kinase C in rat basilar artery myocytes. AB - This study investigated whether KMUP-1, a xanthine-based derivative, inhibits L type Ca(2+) currents (I(Ca,L)) in rat basilar artery smooth muscle cells (RBASMCs). We used whole cell patch-clamp recording to monitor Ba(2+) currents (I(Ba)) through L-type Ca(2+) channels (LTCCs). Under voltage-clamp conditions, holding at -40 mV, KMUP-1 (1, 3, 10 MUM) inhibited I(Ba) in a concentration dependent manner and its IC(50) value was 2.27 +/- 0.45 MUM. A high concentration of KMUP-1 (10 MUM) showed without modifying the I(Ba) current-voltage relationship. On the other hand, the protein kinase C (PKC) activator phorbol 12 myristate 13-acetate (PMA, 1 MUM) increase I(Ba) was inhibited by KMUP-1. Pretreatment with the PKC inhibitor chelerythrine (5 MUM) intensified KMUP-1 inhibited I(Ba). However, the Rho kinase inhibitor Y-27632 (30 MUM) failed to affect the I(Ba) inhibition by KMUP-1. In light of these results, we suggest that KMUP-1 inhibition of LTCCs in concentration- and voltage-dependent manners in RBASMCs may be due, at least in part, to its modulation of the PKC pathway. PMID- 22208537 TI - Proteomic analysis of upregulated proteins in Helicobacter pylori under oxidative stress induced by hydrogen peroxide. AB - The development of gastric cancer was suggested to be associated with chronic inflammation as a consequence of Helicobacter pylori infection. Such inflammation related oxidative stress induced by reactive oxygen species (ROS) in vivo may exert bidirectional effects on both hosts and H pylori. In this study, ROS induced oxidative stress was mimicked by coculture of gastric epithelial cells with H pylori treated with hydrogen peroxide (H(2)O(2)). To investigate the effect of H(2)O(2) on the proteome of H pylori, we performed two-dimensional polyacrylamide gel electrophoresis followed by liquid chromatography coupled with nano-electrospray ionization-tandem mass spectrometry (liquid chromatography mass spectrometry) and bioinformatics database analysis. The nine most overexpressed proteins consisted of three virulence factors, including cytotoxin-associated protein A (CagA), vacuolating cytotoxin (VacA), adherence-associated protein (AlpA), and two antioxidant enzymes alkylhydroperoxide reductase (AhpC) and catalase (KatA), plus one serine protease (HtrA), aconitate hydratase, and fumarate reductase. We have also confirmed the upregulation of virulence factors and antioxidant proteins in several H pylori strains isolated from patients of different clinical outcomes. Furthermore, it is noted that H pylori was found to decrease in infection rate and increase in proliferation after being exposed to H(2)O(2). We also found that gastric epithelial cells can be protected from oxidative damage by H(2)O(2) in the presence of H pylori. In conclusion, this study lends support to the supposition that ROS containing H(2)O(2) as one of the major oxidative species can induce upregulation of virulence factors and antioxidant enzymes in H pylori, which may aid in the elucidation of inflammation leading to the development of gastric cancer from H pylori infection. PMID- 22208539 TI - Validation of the Impact of Event Scale-Revised for adolescents experiencing the floods and mudslides. AB - The purpose of this study was to validate the Impact of Event Scale-Revised (IES R) for adolescents who had experienced the floods and mudslides caused by Typhoon Morakot in Taiwan. The internal consistency, construct validity, and criteria validity of the instrument were examined. Principal component analysis followed by an oblique rotation was used to derive a three-factor solution. These factors were labeled intrusion, hyperarousal, and avoidance; all three factors together accounted for 58.1% of the variance. The total Cronbach's alpha of 0.94 reflected the good internal consistency of the instrument. With reference to diagnosis of posttraumatic stress disorder, the IES-R cutoff point for posttraumatic stress disorder was 19 of 20 with a sensitivity of 85.7% and specificity of 84.1%. In conclusion, the IES-R can be used as a reliable and valid instrument when evaluating psychological distress among adolescents who have experienced a natural disaster, such as flooding and mudslides. PMID- 22208538 TI - Potential risk factors for the reactivation of the replication of hepatitis B and C viruses after transcatheter arterial chemoembolization of hepatocellular carcinoma. AB - The purpose of this study was to investigate the potential risk factors for the reactivation of the replication of hepatitis B virus (HBV) and hepatitis C virus (HCV) after transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma. Forty-four hepatocellular carcinoma patients treated by TACE using epirubicin plus mitomycin C were studied. Serum HBV DNA (n=17) and HCV RNA (n=27) levels were measured 1 day before and 3 months after TACE. Plasma concentrations of chemotherapeutic agents were determined at 1 hour and 72 hours after TACE. A total of 29 patients (n=13 for chronic hepatitis Band n=16 for chronic hepatitis C) showed significant changes of the viral loads after TACE. Patients with increased viral loads after TACE were older (p=0.041), had higher incidence of pre-TACE white blood cell counts being less than normal limit (p=0.023), and had higher plasma mitomycin C concentrations (p=0.039) than those in patients with decreased viral loads. Analysis by multiple logistic regressions using age, decreased or normal pre-TACE white blood cell counts, mitomycin C concentrations >3.95 ng/mL adopted by receiver operating characteristic curve (p=0.037), and epirubicin concentrations have shown that decreased pre-TACE white blood cell counts was the only significant factor associated with increased viral loads after TACE (p=0.048). In conclusion, patients with decreased pre-TACE white blood cell counts have a potential risk for the reactivation of the replication of HBV or HCV after TACE. PMID- 22208540 TI - Preliminary results of dancing exercise on postural stability in adolescent females. AB - Twenty-six female student dancers of Chung-hua school of Art (mean age 17.5 +/- 0.5 years) and twenty-five healthy active female collegiate students (mean age 18.1 +/- 1.0 years) participated in this study to investigate the effects of dancing exercise on postural stability of adolescent female through a comparison study of two cohorts. The groups were matched in height and weight. Participants were excluded for left-side dominance, sustained lower extremity injury, any known vestibular system dysfunction, uncorrected visual problems, and other neurological conditions. Static and dynamic standing balances were measured by means of Biodex Stability System in six conditions include bilateral, dominant, and nondominant single leg stances with eye-open and eye-closed conditions. To investigate the difference between static and dynamic stabilities, two protocols were performed: the first protocol consisted of four positions including static position, Level 8, Level 4, and Level 1, respectively. They were instructed to maintain a level platform as stably as possible for a period of 30 seconds for each test and given a 30-second rest between tests. The second protocol was descending stability level that was gradually changed from Level 12 to Level 1 for 60 seconds. Balance indices included overall stability index, anterior posterior stability index (APSI), and medial-lateral stability index. The results of first protocol showed that there were significant differences in overall stability index score between study and control groups at Level 8 with dominant single leg standing in the eye-open condition and the APSI score at Level 8 and at Level 4 with dominant single-leg standing in the eye-closed condition. There was no significant difference in the second protocol. The possible explanation is loss of familiarization adaptation because of level change consequently in both the groups, not step-by-step as in the first protocol study. Furthermore, a positive correlation was found between the dancing experience and the APSI at Level 8 and Level 4 with dominant single-leg standing in the eye-closed condition. In conclusion the findings implied that dancing exercise results in better postural stability and less visual dependence on postural control in adolescent females. PMID- 22208541 TI - Bilateral simultaneous facial palsy following scrub typhus meningitis: a case report and literature review. AB - Scrub typhus is widely distributed across the Asia-Pacific region, Taiwan included. The clinical manifestations and complications of scrub typhus vary and the illness ranges in severity from mild to fatal. The etiology of facial nerve palsy varies and infectious agents have been associated with this condition. Rickettsiae species have, however, rarely been reported as the causative agents. We report the case of a 49-year-old man who had fever, malaise, headache, oligouria and tea-colored urine. Bilateral pneumonitis, acute renal failure, acalculous cholecystitis and aseptic meningitis were diagnosed after a series of examinations. The patient recovered after doxycycline treatment but he developed bilateral facial palsy during the convalescent phase, which improved after the administration of a steroid. The diagnosis of infection with Orientia tsutsugamushi was confirmed by the Taiwan Center of Disease Control and the tests for Leptospira, Rickettsia typhi and Coxiella burnetii were all negative. This case indicates that scrub typhus needs to be included in the differential diagnoses of cases of bilateral and simultaneous facial nerve palsy, particularly in areas where the disease is endemic. PMID- 22208542 TI - Glutaraldehyde-induced colitis: case reports and literature review. AB - Glutaraldehyde-induced colitis is an uncommon colitis in clinical practice. Because the involvement of colonic segment is determined by the endoscopic part where glutaraldehyde remains, a recent history of endoscopy and a demarcated involvement of colonic segment are the most characteristic signs of glutaraldehyde-induced colitis. The typical clinical scenario is acute onset of lower abdominal pain, fever, and bloody stool. Laboratory data usually show leukocytosis and elevated C-reactive protein. The endoscopic pictures of involved segments are compatible with acute colitis, including hyperemic, edematous, with or without multiple erosions. Acute ischemic colitis and infectious colitis should be differentiated at the outset of the disease. Stool pathogen tests are usually negative. Parenteral empiric antibiotic may be considered if severe transmural edema of the involved segment is observed in computed tomography. Conservative treatment, including bowel rest and parenteral hydration, is able to stabilize the condition in a week. Herein, we present two cases of acute proctocolitis caused by glutaraldehyde after uneventful colonoscopy. PMID- 22208543 TI - HIV-negative disseminated Kaposi's sarcoma in a Taiwanese patient. AB - Kaposi's sarcoma is a common malignancy associated with HIV/AIDS. Herein, we describe the case of a 26-year-old man who presented with bilateral neck and inguinal lymphadenopathy, a massive tumor on the gum, and a nodule over the left eye. A series of tests, including tumor biopsies, were performed, and disseminated Kaposi's sarcoma with human herpesvirus 8 infection was diagnosed. To test for HIV, we used enzyme-linked immunosorbent assay and real-time polymerase chain reaction, but the results were negative. The patient was treated by biweekly intravenous infusion of pegylated liposomal doxorubicin (25 mg/m(2)), and this treatment resulted in a partial response. PMID- 22208544 TI - Applying clinical outcome variables to appropriate aerosolized antibiotics for the treatment of patients with cystic fibrosis. AB - Commercial availability of more than one inhaled antibiotic for the management of chronic Pseudomonas aeruginosa lung infections in persons with cystic fibrosis creates a welcome question: Can different inhaled therapies be combined to improve patient outcomes? Although clinicians intuit that antibiotic alternation might extend the duration of benefit, prospective clinical trials will be unable to test this hypothesis. Rather, endpoints acceptable for demonstrating the efficacy of a chronic pulmonary therapy (lung function improvement/stabilization, reduction in exacerbation risk, improvement in quality of life) can test only whether the benefit amplitude is increased during fixed treatment periods. Reduction in pulmonary exacerbation risk appears to be best suited for this task, although lack of consensus on an objective definition of exacerbation independent of the decision to treat is a shortcoming. The broader clinical question of whether a patient has become refractory to a chronic therapy over time would be better addressed with a carefully conducted withdrawal study. PMID- 22208545 TI - Chronic cystic fibrosis respiratory infections: where do we go from here? Introduction. PMID- 22208546 TI - Therapeutic approaches to chronic cystic fibrosis respiratory infections with available, emerging aerosolized antibiotics. AB - Chronic airway infection and inflammation are key events in the clinical course of cystic fibrosis (CF). The most relevant, best investigated strain of bacteria in these circumstances is Pseudomonas aeruginosa. Since pulmonary infection with P. aeruginosa is localized in the lower conducting airways, treatment is accessible with the use of inhaled aerosolized antibiotics. Tobramycin inhalation solution was the first antibiotic to be developed and approved (in 1998) for use as an aerosolized antibiotic in patients with CF. The only other aerosolized antibiotic indicated for this use is aztreonam lysine solution for inhalation, which has been approved by both European and US authorities. In prospective, randomized, controlled trails, both agents exhibited a very acceptable safety profile, along with an increase in forced expiratory volume in 1 second and other clinically relevant endpoints. New developments focus on such components as reducing the treatment burden by using dry power inhalers, decreasing inhalation frequency to once daily, penetrating P. aeruginosa biofilms, and combining two antibiotics in one solution for inhalation. However, the ideal aerosolized antibiotic regimen for the treatment of chronic P. aeruginosa infection has yet not been selected. PMID- 22208547 TI - Technological and behavioral strategies to reduce treatment burden and improve adherence to inhaled antibiotics in cystic fibrosis. AB - Aerosolized antibiotics are a common treatment option for patients with cystic fibrosis and chronic airway infection, as high doses can be delivered topically to the site of the infection while systemic exposure is minimized. Patients also use other aerosolized therapies (e.g. mucus-active agents, airway-wetting agents, and bronchodilators), adding significantly increase timed and complexity to their daily regimen, and often leading to lower adherence rates. A number of novel technological strategies are available that may reduce dose frequency and increase the speed of drug delivery. Psychologically based therapies may also be used to help modify behavior and thus improve adherence to treatment. Clinicians need to explore both technological and psychological strategies that will assist in the successful maintenance of treatment requirements. PMID- 22208548 TI - Aerosolized antibiotic therapy for chronic cystic fibrosis airway infections: continuous or intermittent? AB - The use of inhaled therapies for chronic respiratory infections in cystic fibrosis represents a substantive treatment burden to patients. In this paper, we review the evidence supporting two commonly used inhaled antibiotic regimens for chronic respiratory infections - continuous vs. intermittent (28 days on followed by 28 days off) therapy. We included trials of good methodological quality and excluded those in which the primary intent was eradication. In total, we included 13 trials (5 of intermittent therapy and 8 of continuous therapy) and summarized their main findings, placing particular emphasis on change in FEV(1), emergence of resistance and patient adherence. What is evident from our review is that both continuous and intermittent inhaled therapies work. Although an intermittent regimen would be intuitively "better" in terms of cost savings and patient tolerability, there is currently a lack of head-to-head trials that compare the same drugs (and dosages) using the two different regimens to make such a recommendation based on robust clinical evidence. PMID- 22208549 TI - Assessing the influence of the built environment on physical activity for utility and recreation in suburban metro Vancouver. AB - BACKGROUND: Physical inactivity and associated co-morbidities such as obesity and cardiovascular disease are estimated to have large societal costs. There is increasing interest in examining the role of the built environment in shaping patterns of physical activity. However, few studies have: (1) simultaneously examined physical activity for leisure and utility; (2) selected study areas with a range of built environment characteristics; and (3) assessed the built environment using high-resolution land use data. METHODS: Data on individuals used for this study are from a survey of 1602 adults in selected sites across suburban Metro Vancouver. Four types of physical activity were assessed: walking to work/school, walking for errands, walking for leisure and moderate physical activity for exercise. The built environment was assessed by constructing one kilometre road network buffers around each respondent's postal code. Measures of the built environment include terciles of recreational and park land, residential land, institutional land, commercial land and land use mix. RESULTS: Logistic regression analyses showed that walking to work/school and moderate physical activity were not associated with any built environment measure. Living in areas with lower land use mix, lower commercial and lower recreational land increased the odds of low levels of walking for errands. Individuals living in the lower third of land use mix and institutional land were more likely to report low levels of walking for leisure. CONCLUSIONS: These results suggest that walking for errands and leisure have a greater association with the built environment than other dimensions of physical activity. PMID- 22208551 TI - Genesis of a novel Shigella flexneri serotype by sequential infection of serotype converting bacteriophages SfX and SfI. AB - BACKGROUND: Shigella flexneri is the major pathogen causing bacillary dysentery. Fifteen serotypes have been recognized up to now. The genesis of new S. flexneri serotypes is commonly mediated by serotype-converting bacteriophages. Untypeable or novel serotypes from natural infections had been reported worldwide but have not been generated in laboratory. RESULTS: A new S. flexneri serotype-serotype 1 d was generated when a S. flexneri serotype Y strain (native LPS) was sequentially infected with 2 serotype-converting bacteriophages, SfX first and then SfI. The new serotype 1 d strain agglutinated with both serotype X-specific anti-7;8 grouping serum and serotype 1a-specific anti- I typing serum, and differed from subserotypes 1a, 1b and 1c. Twenty four S. flexneri clinical isolates of serotype X were all converted to serotype 1 d by infection with phage SfI. PCR and sequencing revealed that SfI and SfX were integrated in tandem into the proA-yaiC region of the host chromosome. CONCLUSIONS: These findings suggest a new S. flexneri serotype could be created in nature. Such a conversion may be constrained by susceptibility of a strain to infection by a given serotype converting bacteriophage. This finding has significant implications in the emergence of new S. flexneri serotypes in nature. PMID- 22208550 TI - Shape matters: effects of silver nanospheres and wires on human alveolar epithelial cells. AB - BACKGROUND: In nanotoxicology, the exact role of particle shape, in relation to the composition, on the capacity to induce toxicity is largely unknown. We investigated the toxic and immunotoxic effects of silver wires (length: 1.5 - 25 MUm; diameter 100 - 160 nm), spherical silver nanoparticles (30 nm) and silver microparticles (<45 MUm) on alveolar epithelial cells (A549). METHODS: Wires and nanoparticles were synthesized by wet-chemistry methods and extensively characterized. Cell viability and cytotoxicity were assessed and potential immunotoxic effects were investigated. To compare the effects on an activated and a resting immune system, cells were stimulated with rhTNF-alpha or left untreated. Changes in intracellular free calcium levels were determined using calcium imaging. Finally, ion release from the particles was assessed by ICP-MS and the effects of released ions on cell viability and cytotoxicity were tested. RESULTS: No effects were observed for the spherical particles, whereas the silver wires significantly reduced cell viability and increased LDH release from A549 cells. Cytokine promoter induction and NF-kappaB activation decreased in a concentration dependent manner similar to the decrease seen in cell viability. In addition, a strong increase of intracellular calcium levels within minutes after addition of wires was observed. This toxicity was not due to free silver ions, since the samples with the highest ion release did not induce toxicity and ion release control experiments with cells treated with pre-incubated medium did not show any effects either. CONCLUSIONS: These data showed that silver wires strongly affect the alveolar epithelial cells, whereas spherical silver particles had no effect. This supports the hypothesis that shape is one of the important factors that determine particle toxicity. PMID- 22208552 TI - Erosion resistance of bionic functional surfaces inspired from desert scorpions. AB - In this paper, a bionic method is presented to improve the erosion resistance of machine components. Desert scorpion (Androctonus australis) is a typical animal living in sandy deserts, and may face erosive action of blowing sand at a high speed. Based on the idea of bionics and biologic experimental techniques, the mechanisms of the sand erosion resistance of desert scorpion were investigated. Results showed that the desert scorpions used special microtextures such as bumps and grooves to construct the functional surfaces to achieve the erosion resistance. In order to understand the erosion resistance mechanisms of such functional surfaces, the combination of computational and experimental research were carried out in this paper. The Computational Fluid Dynamics (CFD) method was applied to predict the erosion performance of the bionic functional surfaces. The result demonstrated that the microtextured surfaces exhibited better erosion resistance than the smooth surfaces. The further erosion tests indicated that the groove surfaces exhibited better erosion performance at 30 degrees injection angle. In order to determine the effect of the groove dimensions on the erosion resistance, regression analysis of orthogonal multinomials was also performed under a certain erosion condition, and the regression equation between the erosion rate and groove distance, width, and height was established. PMID- 22208553 TI - Visceral fat and gut inflammation. AB - The etiology of inflammatory bowel disease and, in particular, Crohn's disease involves a deregulated mucosal immune system under the influence of intestinal flora and environmental factors in genetically susceptible individuals. A new hypothesis has focused on mesenteric fat hypertrophy and the presence of ectopic fat surrounding inflamed bowel, the so-called creeping fat, which are hallmarks of Crohn's disease. Mesenteric adipose tissue is currently recognized as an active actor in immunity with a capacity for mediator secretion. These mediators include classic pro- and anti-inflammatory cytokines or chemokines and hormone like adipokines with multiple effects. Mesenteric fat participates in the course of Crohn's disease and may play an active role in the regulation of intestinal inflammation. However, little is known about the origin and role of mesenteric fat in Crohn's disease, essentially because of a lack of experimental models that develop creeping fat. The purpose of this review is to present the recent data describing the immune properties of mesenteric fat and the recent advances in animal models, which have suggested a new hypothesis about the role of creeping fat in Crohn's disease. PMID- 22208554 TI - Saturated fat and cardiovascular disease: the discrepancy between the scientific literature and dietary advice. AB - Given the large social impact of dietary advice, it is important that the advice have a solid scientific basis. Evidence-based dietary advice should be built on results from all studies available, according to a given methodology. Conclusions should be a valid representation of the summarized results. The association between saturated fat intake and cardiovascular disease was examined. Results from three reports of leading U.S. and European advisory committees were compared with results as they were presented in the articles referred to. Findings were put into perspective with results not included in these reports. Different lines of evidence were included in the different reports. No overlap whatsoever was found in the articles included. Most results from the scientific literature were lacking for most different lines of evidence in all reports. All three reports included the effect of saturated fat on low-density lipoprotein cholesterol in the evidence linking saturated fat to cardiovascular disease, but the effect on high-density lipoprotein cholesterol was systematically ignored. Both U.S. reports failed to correctly describe the results from the prospective studies. Results and conclusions about saturated fat intake in relation to cardiovascular disease, from leading advisory committees, do not reflect the available scientific literature. PMID- 22208555 TI - Improved cognitive performance following supplementation with a mixed-grain diet in high school students: a randomized controlled trial. AB - OBJECTIVE: Adolescence is a stage of rapid growth, when rich nutritional supplementation is important. Maintaining optimal cognitive functioning is critical in high school students, who are under considerable academic pressure. The objectives of this study were to identify the effects of a 9-wk randomly assigned diet of mixed grains versus a regular diet on cognitive performance and on levels of plasma brain-derived neurotrophic factor (BDNF) and S100B, a calcium binding protein produced by astroglial cells, in healthy high school students (grades 10 and 11). METHODS: In this 9-wk, single-blind, controlled study, subjects were randomly allocated to either a mixed-grain or a regular diet. Cognitive assessments and measurements of plasma BDNF and S100B levels were performed at baseline and after the 9-wk intake of a mixed-grain or regular diet. Computerized neuropsychological tests and self-rating scales were used for the cognitive assessments. RESULTS: Significant improvements in some neuropsychological tests were found after 9 wk in both the mixed-grain and the regular-diet groups, but the changes from baseline between the two groups were not significantly different. Significant impairments on the AX-continuous performance test were observed at the endpoint in the regular-diet group, and the changes from baseline between the two groups were also significantly different for this test. A significant difference in changes in BDNF levels was observed between the two groups. CONCLUSIONS: These results suggest that intake of mixed grains for 9 wk is beneficial for cognitive performance and plasma BDNF levels in high school students. These beneficial effects seem to be related to the prevention of cognitive deterioration in a mental-fatigue test with the mixed grain diet, rather than cognitive enhancement per se. PMID- 22208556 TI - Identification of microbial metabolites derived from in vitro fecal fermentation of different polyphenolic food sources. AB - OBJECTIVE: The biological effects of dietary polyphenols are linked to their bioavailability and catabolism in humans. The colon, with its symbiotic microbiota, is an active site where complex polyphenolic compounds are possibly modified to smaller and more absorbable molecules. The aim of this study was to identify the major metabolites derived from microbial colonic fermentation of some common polyphenol-rich foods. METHODS: An in vitro fecal fermentation model was applied to 16 polyphenol-rich foods and polyphenolic precursors. Phenolic metabolites were identified by high-performance liquid chromatography coupled with tandem mass spectrometric detection. RESULTS: Twenty-four phenolic fermentation metabolites were characterized. Some metabolites were common to several polyphenol-rich foods, whereas others were characteristic of specific sources. CONCLUSION: The metabolites identified in vitro likely are generated in the human colon after consumption of polyphenol-rich foods. Their occurrence in plasma and/or urine should be considered when evaluating the bioavailability of polyphenols from specific food groups in humans and in the definition of markers of exposure to specific foods or food groups in epidemiologic studies. However, the search for these and other microbial metabolites after a feeding study in vivo should consider their possible further conjugation at the level of the liver. PMID- 22208557 TI - Severe malnutrition due to systemic lupus erythematosus associated protein losing enteropathy. AB - Systemic lupus erythematosus most often targets organs such as joints, serosa, skin, bone marrow, and the kidneys. Gastrointestinal complications are uncommon, and among these, protein losing enteropathy is particularly rare. We present a young woman who suffered from chronic abdominal pain and diarrhea, developed severe malnutrition, and was eventually diagnosed with systemic lupus erythematosus and associated protein losing enteropathy. PMID- 22208559 TI - The burden of moderate-to-heavy soil-transmitted helminth infections among rural malaysian aborigines: an urgent need for an integrated control programme. AB - BACKGROUND: Soil-transmitted helminth (STH) infections, among the most common neglected tropical diseases, continue to be a major threat to the health and socioeconomic wellbeing of infected people especially children in developing countries. METHODS: A cross-sectional study among 254 aboriginal schoolchildren was conducted in order to determine the current prevalence and intensity of infections and to investigate the potential risk factors associated with moderate to-heavy burden of STH infections among these children. RESULTS: Overall, 93.7% of children were found to be infected with one or more STH species. The prevalence of trichuriasis, ascariasis and hookworm infections were 84.6%, 47.6% and 3.9%, respectively. Almost half of the participants had heavy trichuriasis, one-quarter had heavy ascariasis whereas all hookworm infections were light infections. Overall, moderate-to-heavy STH infections accounted for 56.7% of the total infections. Univariate analysis revealed that those using untreated water supply (P = 0.013), living in houses without toilets (P = 0.027) and having domestic animals in the houses (P = 0.044) had significantly higher prevalence of moderate-to-heavy infections than others. Logistic regression analysis confirmed using untreated water for drinking (P = 0.001) and the absence of a toilet in the house (P = 0.003) as significant risk factors of moderate-to-heavy STH infections among these children. CONCLUSION: The high proportion of moderate-to-heavy STH infections further confirms the need for serious attention towards these devastating diseases that has put lives and the future of aboriginal children in jeopardy. Introduction of more poverty alleviation schemes, proper sanitation, provision of clean and safe drinking water, health education, as well as the introduction of periodic school-based deworming programmes are imperative among these communities in order to curtail the transmission and morbidity caused by STH. PMID- 22208561 TI - Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol induced steatohepatitis in mice. AB - BACKGROUND: Peroxisome proliferator activated receptor alpha (PPARalpha) regulates lipids metabolism and inhibits inflammatory response. However, the role of PPARalpha in alcoholic liver disease is largely unknown. We aim to elucidate the effect and the molecular basis of PPARalpha in ethanol induced hepatic injury in mice. RESULTS: C57BL/6J mice fed with 4% ethanol-containing Lieber-DeCarli liquid diet for 12 weeks exhibited hepatocyte steatosis, necrosis and inflammatory infiltration, accompanied with elevated serum alanine aminotransferase (ALT) and aspartic transaminase (AST) levels, decreased hepatic expression of PPARalpha, lipids oxidation promoting genes and anti-inflammatory factors, as well as enhanced hepatic expression of fatty acids synthesis promoting genes and pro-inflammatory cytokines. Induction of PPARalpha by PPARalpha agonist WY14643 treatment for 2 weeks ameliorated the severity of liver injury and restored expression of genes altered by ethanol treatment. However, administration of PPARalpha antagonist GW6471 for 2 weeks promoted the inflammatory response. CONCLUSIONS: The present study provided the evidence for the protective role of PPARalpha in ameliorating ethanol induced liver injury through modulation of the genes related to lipid metabolism and inflammatory response. PMID- 22208565 TI - Employee assistance programs: an historical and literature review. PMID- 22208564 TI - Publisher's Notes. PMID- 22208566 TI - The assessment of family wellness in a university employee wellness program. PMID- 22208567 TI - Analysis of the Effectiveness of a Safety Belt Incentive Program at CIGNA Corporation. PMID- 22208569 TI - Research agenda: building a consensus on research questions. PMID- 22208568 TI - Franklin international: a facility based wellness program adapted to serve a small white and blue collar population. PMID- 22208570 TI - DataBase: Research and Evaluation Results. PMID- 22208572 TI - Networking:. PMID- 22208574 TI - Perspectives on the rest of the world. PMID- 22208575 TI - Unmasking bulk exciton traps and interchain electronic interactions with single conjugated polymer aggregates. AB - For conjugated polymer materials, there is currently a major gap in understanding between the fundamental properties observed in single molecule measurements and the bulk electronic properties extracted from measurements of highly heterogeneous thin films. New materials and methodologies are needed to follow the evolution from single chain to bulk film properties as multiple chains begin to interact. In this work, we used a controlled solvent vapor annealing process to assemble single chains of phenylene-vinylene conjugated polymers into aggregates that can be individually spectroscopically interrogated. This approach allowed us to probe the effects of interchain coupling in isolated conjugated polymer nanodomains of controlled size. By assembling these aggregates from building blocks of both pristine MEH-PPV and MEH-PPV derivatives containing structure-directing ortho- or para-terphenyl inclusions, we were able to control the ordering of these nanodomains as measured by single aggregate polarization anisotropy measurments. Depending on the individual chain constituents, these aggregates varied from highly anisotropic to nearly isotropic, respectively facilitating or inhibiting interchain coupling. From the single chain fluorescence lifetimes, we demonstrated that these structure directing inclusions effectively break the phenylene-vinylene conjugation, allowing us to differentiate interchain electronic effects from those due to hyper-extended conjugation. We observed well-defined bathochromic shifts in the fluorescence spectra of the aggregates containing extensive interchain interactions, indicating that low-energy exciton traps in MEH-PPV are the result of coupling interactions between neighboring chain segments. These results demonstrate the power of the synthetic inclusion approach to control properties at not just the single chain level, but as a comprehensive approach toward ground-up design of bulk electronic properties. PMID- 22208596 TI - Satisfaction with botulinum toxin treatment: a cross-sectional survey of patients with cervical dystonia. AB - OBJECTIVE: Botulinum toxin is widely utilized as a first-line therapy for cervical dystonia (CD). Numerous studies have demonstrated the efficacy and safety of this treatment, but little data exist on patient satisfaction. To address this question, a structured patient survey was conducted in Germany, France, the US, and Canada (n = 136 patients with CD). METHODS: Specific information was collected on the patients' current and prior botulinum toxin treatment cycles and their overall quality-of-life (including completion of the Cervical Dystonia Impact Profile-58 [CDIP-58]). RESULTS: Patients rated the mean onset of action for their previous injection as 3.8 days, with peak effect at 3.6 weeks and a decline in effects at 9.5 weeks. While most patients were satisfied with their current therapy, only 50.7% were very satisfied, 42.6% were somewhat satisfied, and 6.6% not at all satisfied with their current therapy. Patient satisfaction was lowest just prior to injection and highest at the time of peak effect. Approximately 45% of patients reported that they would prefer a treatment cycle of <=10 weeks. The mean patient rating of current state of health was above 50 on a visual analog scale from 0 (low) to 100 (high). CDIP-58 results indicated that patients continued to have symptoms on all domains. CONCLUSIONS: Botulinum toxin is generally very effective for the treatment of CD. However, this survey indicates that patient satisfaction typically declines prior to re-injection, and many patients may prefer an injection interval of less than the standard 12 weeks. While the survey was based on subjective patient recollections, and the degree to which patient satisfaction is attributable to the control of neurological symptoms remains unclear, prospective studies are clearly warranted to confirm the time course of patient satisfaction and to determine the optimal treatment parameters with botulinum toxins. PMID- 22208597 TI - Photodynamic inactivation for controlling Candida albicans infections. AB - Antimicrobial photodynamic therapy (APDT) combines a non-toxic dye, termed photosensitizer, which is activated by visible light of appropriate wavelength which will produce reactive oxygen species (ROS). These ROS will react with cellular components inducing oxidative processes, leading to cell death. A wide range of microorganisms, have already showed susceptibility to APDT. Therefore, this treatment might consist in an alternative for the management of fungal infections that is mainly caused by biofilms, since they respond poorly to conventional antibiotics and may play a role in persistent infections. Biofilms are the leading cause of microbial infections in humans, thus representing a serious problem in health care. Candida albicans is the main type of fungi able to form biofilms, which cause superficial skin and mucous membrane infections as well as deep-seated mycoses, particularly in immunocompromised patients. In these patients, invasive infections are often associated with high morbidity and mortality. Furthermore, the increase in antifungal resistance has decreased the efficacy of conventional therapies. Treatments are time-consuming and thus demanding on health care budgets. Additionally, current antifungal drugs only have a limited spectrum of action and toxicity. The use of APDT as an antimicrobial topical agent against superficial and cutaneous diseases represents an effective method for eliminating microorganisms. PMID- 22208598 TI - Vascular Streak Dieback of cacao in Southeast Asia and Melanesia: in planta detection of the pathogen and a new taxonomy. AB - Vascular Streak Dieback (VSD) disease of cacao (Theobroma cacao) in Southeast Asia and Melanesia is caused by a basidiomycete (Ceratobasidiales) fungus Oncobasidium theobromae (syn. =Thanatephorus theobromae). The most characteristic symptoms of the disease are green-spotted leaf chlorosis or, commonly since about 2004, necrotic blotches, followed by senescence of leaves beginning on the second or third flush behind the shoot apex, and blackening of infected xylem in the vascular traces at the leaf scars resulting from the abscission of infected leaves. Eventually the shoot apex is killed and infected branches die. In susceptible cacao the fungus may grow through the xylem down into the main stem and kill a mature cacao tree. Infections in the stem of young plants prior to the formation of the first 3-4 lateral branches usually kill the plant. Basidiospores released from corticioid basidiomata developed on leaf scars or along cracks in the main vein of infected leaves infect young leaves. The pathogen commonly infects cacao but there are rare reports from avocado. As both crops are introduced to the region, the pathogen is suspected to occur asymptomatically in native vegetation. The pathogen is readily isolated but cultures cannot be maintained. In this study, DNA was extracted from pure cultures of O. theobromae obtained from infected cacao plants sampled from Indonesia. The internal transcribed spacer region (ITS), consisting of ITS1, 5.8S ribosomal RNA and ITS2, and a portion of nuclear large subunit (LSU) were sequenced. Phylogenetic analysis of ITS sequences placed O. theobromae sister to Ceratobasidium anastomosis groups AG-A, AG-Bo, and AG-K with high posterior probability. Therefore the new combination Ceratobasidium theobromae is proposed. A PCR-based protocol was developed to detect and identify C. theobromae in plant tissue of cacao enabling early detection of the pathogen in plants. A second species of Ceratobasidium, Ceratobasidium ramicola, identified through ITS sequence analysis, was isolated from VSD-affected cacao plants in Java, and is widespread in diseased cacao collected from Indonesia. PMID- 22208600 TI - Conspicuous epiphytic growth of an interspecific hybrid Neotyphodium sp. endophyte on distorted host inflorescences. AB - Selected Neotyphodium sp. endophytes are now commonly used to enhance pasture persistence and livestock productivity, with seed of perennial ryegrass and tall fescue cultivars with these selected endophytes being commercially available. In a large population of perennial ryegrass plants infected with a Neotyphodium sp. endophyte that was being grown for seed production a small percentage of inflorescences were distorted and covered with a conspicuous white mycelial growth. Within individual plants only a small number of inflorescences were affected and the amount of distortion differed between affected inflorescences. This Neotyphodium sp. is an interspecific hybrid of Epichloe typhina and Neotyphodium. lolii and like nearly all other Neotyphodium spp is symptomless in host grasses. The fungus isolated from distorted inflorescences had colonies that were identical to those isolated from symptomless inflorescences and these were characteristic of this Neotyphodium sp. This is the first report of distorted inflorescences covered with epiphytic hyphal growth on host grasses infected with an interspecific hybrid Neotyphodium sp. PMID- 22208601 TI - Biotic and abiotic constraints that facilitate host exclusivity of Gondwanamyces and Ophiostoma on Protea. AB - Estimations of global fungal diversity are hampered by a limited understanding of the forces that dictate host exclusivity in saprobic microfungi. To consider this problem for Gondwanamyces and Ophiostoma found in the flower heads of Protea in South Africa, we determined the role of various factors thought to influence their host exclusivity. Results showed that various biotic and abiotic factors influence the growth and survival of these fungi in vitro. Monitoring temperature and relative humidity (RH) fluctuations within infructescences in vivo revealed considerable microclimatic differences between different Protea spp. Fungal growth and survival at different RH levels experienced in the field suggested that this factor does not play a major role in host exclusivity of these fungi. Maximum temperatures within infructescences and host preferences of the vectors of Gondwanamyces and Ophiostoma appear to play a substantial part in determining colonisation of Protea in general. However, these factors did not explain host exclusivity of specific fungal species towards particular Protea hosts. In contrast, differential growth of fungal species on media containing macerated tissue of Protea showed that Gondwanamyces and Ophiostoma grow best on tissue from their natural hosts. Thus, host chemistry plays a role in host exclusivity of these fungi, although some species grew vigorously on tissue of Protea spp. with which they are not naturally associated. A combination of host chemistry and temperature partially explains host exclusivity, but the relationship for these factors on the tested saprobic microfungi and their hosts is clearly complex and most likely includes combinations of various biotic and abiotic factors including those emerging from this study. PMID- 22208602 TI - Multi-gene analysis and morphology reveal novel Ilyonectria species associated with black foot disease of grapevines. AB - Black foot is an important disease of grapevines, which has in recent years been recorded with increased incidence and severity throughout the world, affecting grapevines both in nurseries and young vineyards. In the past the disease has been associated with infections by Ilyonectria macrodidyma, Ilyonectria liriodendri, Campylocarpon fasciculare, and Campylocarpon pseudofasciculare. Based on published data, a high level of genetic diversity was detected among isolates of I. macrodidyma. To resolve this issue, we employed a multigene analysis strategy (based on the beta-tubulin, histone H3, translation elongation factor 1-alpha, and the internal transcribed spacers on both sides of the 5.8S nuclear ribosomal RNA gene) along with morphological characterisation to study a collection of 81 I. macrodidyma-like isolates from grapevine and other hosts. Morphological characters (particularly conidial size) and molecular data (highest resolution achieved with histone H3 nucleotide sequence) enabled the distinction of six monophyletic species within the I. macrodidyma complex, four of which (Ilyonectria alcacerensis, Ilyonectria estremocensis, Ilyonectria novozelandica, and Ilyonectria torresensis) are described here. This work forms part of an effort by the International Council on Grapevine Trunk Diseases to resolve the species associated with black foot disease, which we believe will clarify their taxonomy, and therefore help researchers to devise control strategies to reduce the devastating impact of this disease. PMID- 22208603 TI - Nitrogen sources of Oligoporus placenta and Trametes versicolor evaluated in a 2(3) experimental plan. AB - Four full-factorial 2(3) experimental plans were applied to evaluate the nitrogen (N) sources of Oligoporus placenta and Trametes versicolor and their interaction with the atmospheric N(2)-assimilating bacterium Beijerinckia acida. The effects of N from peptone, of sapwood and of N from gaseous N(2) on fungal, bacterial and fungal-bacterial activity were investigated. The activities were determined by quantification of biomass, formation of CO(2), consumption of O(2) and laccase activity. The significance of each effect was tested according to t-test recommendation. The activity of both fungi was enhanced by peptone rather than sapwood or gaseous N(2). Nevertheless, comparative studies under an N(2)-free gas mixture as well as under air revealed that the presence of N(2) affected bacterial growth and bacterial-fungal cocultivations. Elemental analysis isotope ratio mass spectrometry (IRMS) of the bacterial and fungal biomass enabled estimation of N transfer and underlined gaseous N(2) as requisite for fungal bacterial interactions. Combining full-factorial experimental plans with an analytical set-up comprising gas chromatography, IRMS and enzymatic activity allowed synergistic effects to be revealed, fungal N sources to be traced, and symbiotic fungal-bacterial interactions to be investigated. PMID- 22208599 TI - The oomycete Pythium oligandrum expresses putative effectors during mycoparasitism of Phytophthora infestans and is amenable to transformation. AB - The oomycete Pythium oligandrum is a mycoparasitic biocontrol agent that is able to antagonise several plant pathogens, and can promote plant growth. In order to test the potential usefulness of P. oligandrum as a biocontrol agent against late blight disease caused by the oomycete Phytophthora infestans, we investigated the interaction between P. oligandrum and Ph. infestans using the green fluorescent protein (GFP) as a reporter gene. A CaCl(2) and polyethylene-glycol-based DNA transformation protocol was developed for P. oligandrum and transformants constitutively expressing GFP were produced. Up to 56 % of P. oligandrum transformants showed both antibiotic resistance and fluorescence. Mycoparasitic interactions, including coiling of P. oligandrum hyphae around Ph. infestans hyphae, were observed with fluorescent microscopy. To gain further insights into the nature of P. oligandrum mycoparasitism, we sequenced 2376 clones from cDNA libraries of P. oligandrum mycelium grown in vitro, or on heat-killed Ph. infestans mycelium as the sole nutrient source. 1219 consensus sequences were obtained including transcripts encoding glucanases, proteases, protease inhibitors, putative effectors and elicitors, which may play a role in mycoparasitism. This represents the first published expressed sequence tag (EST) resource for P. oligandrum and provides a platform for further molecular studies and comparative analysis in the Pythiales. PMID- 22208604 TI - Basidiobolus haptosporus is frequently associated with the gamasid mite Leptogamasus obesus. AB - Two species of mites inhabiting a pine forest soil were screened for associated fungi. The fungal community composition was assessed in 49 mite and 19 soil samples by environmental PCR with a focus on fungi of the genus Basidiobolus. PCR products of the fungal ITS rRNA gene were analyzed by sub-cloning, RFLP-analysis, and sequencing. Thereby Basidiobolus haptosporus was found for the first time to be frequently associated with the gamasid mite species Leptogamasus obesus, while being absent from the oribatid mite Oppiella subpectinata, and from the surrounding soil. The fungus was isolated in pure culture for a detailed morphological characterization and experimental approaches concerning the nature of this fungus-mite association. The experiments and a supporting microscopic screening of freshly captured gamasid mites revealed no indications for the fungus being localized in the mites' gut or haemocoel, but a single spore was found attached to an individual of L. obesus. However, an exclusive phoretic association does not satisfactorily explain the frequent detection of B. haptosporus DNA on or in L. obesus, and the absence of the fungus from soil samples seems not to be in line with its assumed ecology as a widespread saprobic soil fungus. Therefore, a second host species in the life cycle of B. haptosporus is discussed as a working hypothesis. PMID- 22208605 TI - Identification of group I introns within the SSU rDNA gene in species of Ceratocystiopsis and related taxa. AB - During a recent phylogenetic study, group I introns were noted that interrupt the nuclear small subunit ribosomal RNA (SSU rDNA) gene in species of Ceratocystiopsis. Group I introns were found to be inserted at the following rDNA positions: S943, S989, and S1199. The introns have been characterized and phylogenetic analysis of the host gene and the corresponding intron data suggest that for S943 vertical transfer and frequent loss appear to be the most parsimonious explanation for the distribution of nuclear SSU rDNA introns among species of Ceratocystiopsis. The SSU rDNA data do suggest that a recent proposal of segregating the genus Ophiostoma sensu lato into Ophiostoma sensu stricto, Grosmannia, and Ceratocystiopsis has some merit but may need further amendments, as the SSU rDNA suggests that Ophiostoma s. str. may now represent a paraphyletic grouping. PMID- 22208606 TI - Diverse sources of infection and cryptic recombination revealed in South African Diplodia pinea populations. AB - This study considers the population diversity and structure of Diplodia pinea in South Africa at different spatial scales from single trees to plantations, as well as comparing infections on healthy and diseased trees. A total of 236 isolates were characterized using 13 microsatellite markers. Analysis of these markers confirmed previous results that D. pinea has a high level of gene and genotypic diversity in South Africa, with the latter values ranging from 6% to 68% for the different plantations. The data also reflect a fungus with randomly associated alleles in populations at local plantation scales and for the population as a whole. These results suggest that recombination is occurring in D. pinea and that it most likely has a cryptic sexual state. The study also reveals the sources of endophytic infection and stress related disease out-breaks as diverse infections that have occurred over a long time period. In contrast, wound-associated die-back appears to be caused by clones of the pathogen occurring in narrow time frames. PMID- 22208607 TI - In vitro effect of pesticides on the germination, vegetative growth, and conidial production of two strains of Metarhizium anisopliae. AB - Entomopathogenic fungi are widely used as biological control agents against a broad range of insect and arachnid pests. However, the control efficacy of entomopathogenic fungi is variable because of unfavourable and fluctuating environmental conditions and intrinsic factors. One strategy to enhance entomopathogenic fungi efficacy is a combined use of entomopathogenic fungi and low dosages of pesticides. These sub-lethal dosages of chemicals can increase the control efficiency of entomopathogenic fungi but only if they do not affect the fungi. Adverse effects could include the inhibition of germination and/or vegetative growth as well as conidiogenesis. The present study investigated the in vitro effects of different concentrations of fipronil, permethrin, imidacloprid, NeemAzal, and amitraz as potential candidates for combined applications on two strains of the entomopathogenic fungus Metarhizium anisopliae (MA). MA was inoculated on a medium amended with five different concentrations (0.32-200 ppm) of the abovementioned pesticides. The germination, vegetative growth, and sporulation were evaluated. The results showed, according to a physiology parameter compatibility classification, that all pesticides were compatible with both tested MA strains. Only fipronil in the higher dose rates of 40 and 200 ppm was close to moderately toxic to MA-7. Furthermore, only higher concentrations of the pesticides caused a slight inhibition (about 15%) of conidial germination and a reduction in colony size. Sporulation was reduced at most by approximately 50% by 40 or 200 ppm of fipronil or amitraz, respectively. Therefore, it is possible to use the tested pesticides in combination with either strain of MA for an integrated pest management approach. Studies on the effect of these combinations on target organisms are in progress. PMID- 22208608 TI - A novel plant-fungal mutualism associated with fire. AB - Bromus tectorum, or cheatgrass, is native to Eurasia and widely invasive in western North America. By late spring, this annual plant has dispersed its seed and died; its aboveground biomass then becomes fine fuel that burns as frequently as once every 3-5 y in its invaded range. Cheatgrass has proven to be better adapted to fire there than many competing plants, but the contribution of its fungal symbionts to this adaptation had not previously been studied. In sampling cheatgrass endophytes, many fire-associated fungi were found, including Morchella in three western states (New Mexico, Idaho, and Washington). In greenhouse experiments, a New Mexico isolate of Morchella increased both the biomass and fecundity of its local cheatgrass population, thus simultaneously increasing both the probability of fire and survival of that event, via more fuel and a greater, belowground seed bank, respectively. Re-isolation efforts proved that Morchella could infect cheatgrass roots in a non-mycorrhizal manner and then grow up into aboveground tissues. The same Morchella isolate also increased survival of seed exposed to heat typical of that which develops in the seed bank during a cheatgrass fire. Phylogenetic analysis of Eurasian and North American Morchella revealed that this fire-associated mutualism was evolutionarily novel, in that cheatgrass isolates belonged to two phylogenetically distinct species, or phylotypes, designated Mel-6 and Mel-12 whose evolutionary origin appears to be within western North America. Mutualisms with fire-associated fungi may be contributing to the cheatgrass invasion of western North America. PMID- 22208609 TI - AreA controls nitrogen source utilisation during both growth programs of the dimorphic fungus Penicillium marneffei. AB - The opportunistic pathogen Penicillium marneffei displays a temperature-dependent dimorphic switching program with saprophytic hyphal growth at 25 degrees C and yeast growth at 37 degrees C. The areA gene of P. marneffei has been isolated and found to be required for the utilisation of nonpreferred nitrogen sources during both growth programs of P. marneffei, albeit to differing degrees. Based on this functional characterisation and high degree of sequence conservation with other fungal GATA factors, P. marneffei areA represents an orthologue of Aspergillus nidulans areA and Neurospora crassa NIT2. Based on this study it is proposed that AreA is likely to contribute to the pathogenicity of P. marneffei by facilitating growth in the host environment and regulating the expression of potential virulence factors such as extracellular proteases. PMID- 22208610 TI - The occurrence and rapid discrimination of Fomes fomentarius genotypes by ITS RFLP analysis. AB - Sequence comparison of available Fomes fomentarius (L.) J. Kickx f. internal transcribed spacer (ITS) of ribosomal DNA sequences demonstrated genetic non homogeneity of the species. Multiple sequence alignment indicated the presence of two genotypes with overall similarity of about 97% and a strong statistics support. Rapid and reliable method for discrimination of F. fomentarius genotypes based on restriction digestion of polymerase chain reaction (PCR)-amplified ITS sequences was developed. BseNI and SchI restriction endonucleases were found to clearly discriminate between two F. fomentarius genotypes. The method was used to study the variability in F. fomentarius isolates collected from natural forest reserves in Vihorlat Mountains (East Slovakia). In most localities both genotypes occur concurrently. The isolates belonging to the genotype A were found to be prevalent on beech (Fagus sylvatica), while genotype B tends to be found mainly on other hosts. The grouping of selected isolates was confirmed by sequence analysis. Our results indicate that F. fomentarius includes at least two sympatric cryptic species. PMID- 22208611 TI - Rapid throughput analysis of filamentous fungal growth using turbidimetric measurements with the Bioscreen C: a tool for screening antifungal compounds. AB - A rapid method for screening antifungal compounds and performing ecophysiological studies with filamentous fungi has been developed by the use of specific semi solid media and spectrophotometric/turbidimetric measurements using the Bioscreen C with 2*100 microtitre well plates. The medium composition and preparation, inoculum size, medium volumes, and incubation parameters for measuring initial germination and growth dynamics have been optimised. These have been applied to assess the effectiveness of 18 concentrations of propyl propane thiosulfinate (PTS) against Aspergillus flavus in YES medium under different environmental regimes. Minimum inhibitory concentrations (MIC), and non-inhibitory concentration (NIC) values, and a newly developed MIC(50), have been calculated for the efficacy of these concentrations of PTS under four different environmental conditions (0.995 and 0.95 water activity (a(w)); 20 and 25 degrees C) over 7d periods with automated measurements every 20 min. Data were modelled using the Lambert-Pearson Model, a mathematical modelling approach previously used for bacterial inhibition. Results have been compared with traditional growth rate data and Lethal Dose(50) (LD(50)) values. This approach could have major implications for rapid screening assays for growth and secondary metabolite production by filamentous organisms and has major advantages in terms of time reduction, culture medium volumes required, measurement and the ability to integrate and model key parameters for comparing efficacy. PMID- 22208612 TI - Preoperative quality of life in patients with degenerative spinal disorders: many are worse than patients with brain tumours and cancer. AB - BACKGROUND: This study compared prospectively the quality of life (QoL), function and mood of patients about to undergo surgery for either an intracranial supratentorial tumour or a spinal degenerative condition. The QoL scores were also compared to that of cohorts with a range of extracranial cancers. MATERIAL AND METHODS: The study took place in a Scottish NHS Neurosurgical Unit. Patients were assessed on the day prior to surgery for their QoL (European Organisation for Research and Treatment of Cancer (EORTC)-QLQ C30), mood status (Hospital Anxiety and Depression Score), Performance status (Karnosky Score, timed 10-m walk) and disability (Barthel Disability Index). All tests were performed by a single trained psychologist. RESULTS: Between 2007 and 2009, 101 patients with intracranial tumours, 75 age- and gender-matched patients with degenerative spinal disorders and 80 healthy adults were evaluated. There was no difference in the mood or disability scores between the two patient cohorts, but mood was significantly worse than a matched healthy cohort. The spinal cohort had significantly worse scores on the Karnovsky Scale, timed 10-m walk and for Global Health than those of the brain tumour cohort. They also had worse mean scores on all five functional scales, as well as six of the nine symptom/single-item scales, of the EORTC QLQ C30. SUMMARY: Patients with degenerative spinal disorders awaiting surgery on the NHS have significantly impaired QoL in multiple domains as well as other functional and mood disorders. Not only are their scores worse than a brain tumour cohort but they are also worse than many cancer cohorts described in the literature using the EORTC QLQ C30. These findings suggest that preoperative care, assessment and management of NHS patients with degenerative spinal disorders could be improved and that the EORTC QLQ C30 may be a useful tool for audit purposes in this cohort. PMID- 22208613 TI - Genomic sequencing of key genes in mouse pancreatic cancer cells. AB - Pancreatic cancer is a multiple genetic disorder with many mutations identified during the progression. Two mouse pancreatic cancer cell lines were established which showed different phenotype in vivo: a non-metastatic cell line, Panc02, and a highly metastatic cell line, Panc02-H7, a derivative of Panc02. In order to investigate whether the genetic mutations of key genes in pancreatic cancer such as KRAS, TP53 (p53), CDKN2A (p16), SMAD4, ZIP4, and PDX-1 contribute to the phenotypic difference of these two mouse pancreatic cancer cells, we sequenced the exonic regions of these key genes in both cell lines and in the normal syngeneic mouse pancreas and compared them with the reference mouse genome sequence. The exons of KRAS, SMAD4, CDKN2A (p16), TP53 (p53), ZIP4, and PDX-1 genes were amplified and the genotype of these genes was determined by Sanger sequencing. The sequences were analyzed with Sequencher software. A mutation in SMAD4 was identified in both cell lines. This homozygote G to T mutation in the first position of codon 174 (GAA) generated a stop codon resulting in the translation of a truncated protein. Further functional analysis indicates that different TGF-beta/SMAD signaling pathways were involved in those two mouse cell lines, which may explain the phonotypic difference between the two cells. A single nucleotide polymorphism (SNP) in KRAS gene (TAT to TAC at codon 32) was also identified in the normal pancreas DNA of the syngenic mouse and in both derived tumoral Panc02 and Panc02-H7 cells. No mutation or SNP was found in CDKN2A (p16), TP53 (p53), ZIP4, and PDX-1 genes in these two cell lines. The absence of mutations in genes such as KRAS, TP53, and CDKN2A, which are considered as key genes in the development of human pancreatic cancer suggests that SMAD4 might play a central and decisive role in mouse pancreatic cancer. These results also suggest that other mechanisms are involved in the substantial phenotypic difference between these two mouse pancreatic cancer cell lines. Further studies are warranted to elucidate the molecular pathways that lead to the aggressive metastatic potential of Panc02-H7. PMID- 22208614 TI - Validation of obesity based on self-reported data in Spanish women participants in breast cancer screening programmes. AB - BACKGROUND: Measurement of obesity using self-reported anthropometric data usually involves underestimation of weight and/or overestimation of height. The dual aim of this study was, first, to ascertain and assess the validity of new cut-off points, for both overweight and obesity, using self-reported Body Mass Index furnished by women participants in breast cancer screening programmes, and second, to estimate and validate a predictive model that allows recalculate individual BMI based on self-reported data. METHODS: The study covered 2927 women enrolled at 7 breast cancer screening centres. At each centre, women were randomly selected in 2 samples, in a ratio of 2:1. The larger sample (n = 1951) was used to compare the values of measured and self-reported weight and height, to ascertain new overweight and obesity cut-off points with self-reported data, using ROC curves, and to estimate a predictive model of real BMI using a regression model. The second sample (n = 976) was used to validate the proposed cut-off points and the predictive model. RESULTS: Whereas reported prevalence of obesity was 19.8%, measured prevalence was 28.2%. The sensitivity and specificity of this classification would be maximised if the new cut-off points were 24.30 kg/m2 for overweight and 28.39 kg/m2 for obesity. The probability of classifying women correctly in their real weight categories on the basis of these points was 82.5% in the validation sample. Sensitivity and specificity for determining obesity using the new cut-off point in the validation sample were 90.0% and 92.3% respectively. The predictive model for real BMI included the self-reported BMI, age and educational level (university studies vs lower levels of education). This model succeeded in correctly classifying 90.5% of women according to BMI categories, but its performance was similar to that obtained with the new cut-off points. CONCLUSIONS: Quantification of self-reported obesity entails a considerable underestimation of this problem, thereby questioning its validity. The new cut-off points established in this study and the predictive equation both allow for more accurate estimation of these prevalences. PMID- 22208615 TI - Fork head transcription factor is required for ovarian mature in the brown planthopper, Nilaparvata lugens (Stal). AB - BACKGROUND: The brown planthopper (BPH), Nilaparvata lugens, is the most devastating rice pest in many areas throughout Asia. The reproductive system of female N. lugens consists of a pair of ovaries with 24-33 ovarioles per ovary in most individuals which determine its fecundity. The fork head (Fox) is a transcriptional regulatory molecule, which regulates and controls many physiological processes in eukaryotes. The Fox family has several subclasses and members, and several Fox factors have been reported to be involved in regulating fecundity. RESULTS: We have cloned a fork head gene in N. lugens. The full-length cDNA of NlFoxA is 1789 bp and has an open reading frame of 1143 bp, encoding a protein of 380 amino acids. Quantitative real-time PCR (RT-qPCR) and Reverse Transcription- PCR (RT-PCR) analysis revealed that NlFoxA mRNA was mainly expressed in the fat body, midgut, cuticle and Malpighian tube, and was expressed continuously with little change during all the developmental stages. NlFoxA belongs to the FoxA subfamily of the Fox transcription factors. Knockdown of NlFoxA expression by RNAi using artificial diet containing double-stranded RNA (dsRNA) significantly decreased the number of offspring and impacted the development of ovaries. ELISA and Western blot analyses showed that feeding-based RNAi of NlFoxA gene also resulted in decreased expression of vitellogenin (Vg) protein. CONCLUSION: NlFoxA plays an important role in regulation of fecundity and development of ovaries in the BPH via regulating vitellogenin expression. PMID- 22208616 TI - The nuclear factor-kappaB inhibitor pyrrolidine dithiocarbamate reduces polyinosinic-polycytidilic acid-induced immune response in pregnant rats and the behavioral defects of their adult offspring. AB - BACKGROUND: Epidemiological studies have indicated that maternal infection during pregnancy may lead to a higher incidence of schizophrenia in the offspring. It is assumed that the maternal infection increases the immune response, leading to neurodevelopmental disorders in the offspring. Maternal polyinosinic polycytidilic acid (PolyI:C) treatment induces a wide range of characteristics in the offspring mimicking some schizophrenia symptoms in humans. These observations are consistent with the neurodevelopmental hypothesis of schizophrenia. METHODS: We examined whether suppression of the maternal immune response could prevent neurodevelopmental disorders in adult offspring. PolyI:C or saline was administered to early pregnant rats to mimic maternal infection, and the maternal immune response represented by tumor necrosis factor alpha (TNF-alpha) and interleukin-10 (IL-10) levels was determined by enzyme-linked immunosorbent assays (ELISA). The NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) was used to suppress the maternal immune response. Neurodevelopmental disorders in adult offspring were examined by prepulse inhibition (PPI), passive avoidance, and active avoidance tests. RESULTS: PolyI:C administration to early pregnant rats led to elevated serum cytokine levels as shown by massive increases in serum TNF-alpha and IL-10 levels. The adult offspring showed defects in prepulse inhibition, and passive avoidance and active avoidance tests. PDTC intervention in early pregnant rats suppressed cytokine increases and reduced the severity of neurodevelopmental defects in adult offspring. CONCLUSIONS: Our findings suggest that PDTC can suppress the maternal immune response induced by PolyI:C and partially prevent neurodevelopmental disorders of adult offspring. PMID- 22208617 TI - Efficient delivery of sticky siRNA and potent gene silencing in a prostate cancer model using a generation 5 triethanolamine-core PAMAM dendrimer. AB - Successful achievement of RNA interference in therapeutic applications requires safe and efficient vectors for siRNA delivery. In the present study, we demonstrate that a triethanolamine (TEA)-core PAMAM dendrimer of generation 5 (G(5)) is able to deliver sticky siRNAs bearing complementary A(n)/T(n) 3' overhangs effectively to a prostate cancer model in vitro and in vivo and produce potent gene silencing of the heat shock protein 27, leading to a notable anticancer effect. The complementary A(n)/T(n) (n = 5 or 7) overhangs characteristic of these sticky siRNA molecules help the siRNA molecules self assemble into "gene-like" longer double-stranded RNAs thus endowing a low generation dendrimer such as G(5) with greater delivery capacity. In addition, the A(n)/T(n) (n = 5 or 7) overhangs act as protruding molecular arms that allow the siRNA molecule to enwrap the dendrimer and promote a better interaction and stronger binding, ultimately contributing toward the improved delivery activity of G(5). Consequently, the low generation dendrimer G(5) in combination with sticky siRNA therapeutics may constitute a promising gene silencing-based approach for combating castration-resistant prostate tumors or other cancers and diseases, for which no effective treatment currently exists. PMID- 22208619 TI - Reactivity of aziridinomitosene derivatives related to FK317 in the presence of protic nucleophiles. AB - The syntheses and reactivity of N-TBDPS and N-trityl protected derivatives of an aziridinomitosene corresponding to FK317 are described. New reactivity patterns were observed for these highly sensitive and functionally dense heterocycles under mild nucleophilic conditions approaching the threshold for degradation. Thus, the silyl or trityl protected aziridinomitosene reacted with Cs(2)CO(3)/CD(3)OD to give isomeric products where substitution occurred at C(10) and C(9a) (mitomycin numbering) providing a CD(3) ether and a CD(3) hemiaminal, respectively. These findings show that heterolysis at C(10) is faster than at aziridine C(1), in contrast to the behavior of typical aziridinomitosenes in the mitomycin series. The labile N-TBDPS hemiaminal and the more stable N-trityl hemiaminal resemble the mitomycin K substitution pattern. A reagent consisting of CsF in CF(3)CH(2)OH/CH(3)CN desilylated a simple N-TBDPS aziridine but caused nucleophilic cleavage at C(1) as well as C(10) without cleavage of the N-TBPDS group in the fully functionalized penultimate aziridinomitosene. The high reactivity of the C(10) carbamate with nucleophiles precludes the use of deprotection methodology that requires N-protonation for fully functionalized aziridinomitosenes in the FK317 series. PMID- 22208625 TI - Publisher's Notes. PMID- 22208620 TI - Effect of an integrated control strategy for schistosomiasis japonica in the lower reaches of the Yangtze River, China: an evaluation from 2005 to 2008. AB - BACKGROUND: Schistosomiasis japonica remains a major public health concern in China. There are many interventions implemented to control the transmission of the disease. The purpose of the present study was to investigate the effects of an integrated control strategy for schistosomiasis control. METHODS: An integrated control strategy for schistosomiasis japonica with emphasis on removing cattle from snail-infested grasslands, providing farmers with mechanized farm equipment, improving sanitation by supplying tap water and building lavatories and latrines and providing boats with fecal-matter containers was implemented in 107 villages of the lower reaches of the Yangtze River, Jiangsu Province, China, during a 32-month period from May 2005 to 2008, and the effectiveness was investigated. RESULTS: Following the effects of the comprehensive control, the snail habitat, infected snail habitat, snail infection rate, and S. japonicum prevalence in both humans and livestock all appeared a declining trend year by year, with reductions of 47.88%, 94.29%, 92.55%, 96.94%, and 100% compared with those before the comprehensive control. In addition, all of the 17 counties achieved the infection control in 2007, and 7 reached the criteria of transmission control in 2008. The confirmed snail habitats reduced from 107 to 20, and the acute infections have also been controlled for 2 successive years since 2007. CONCLUSIONS: The integrated control strategy for schistosomiasis japonica is effective to control the transmission of S. japonicum. PMID- 22208626 TI - Caffeine: is it dangerous to health? AB - Abstract Caffeine is a drug that is a common ingredient of popular foods, beverages, and over-the-counter as well as prescription medications. While at least 30% of Americans consume a moderate amount (200 mg. a day, about two cups of coffee), many others function with a much higher intake, 600 mg. or more (six or more cups of coffee). Researchers are discovering that caffeine may not be as safe as many people believe, since the substance has widespread effects on many body systems. It has also been linked to a variety of ailments, among them anxiety and hypertension, although information linking caffeine to cancer and birth defects is still speculative. In light of the expanding body of knowledge on the deleterious effects of caffeine, individuals should moderate or eliminate their intake of major caffeine-containing foods, beverages, and drugs. Health promotion programs can assist in this goal by providing education and support. PMID- 22208621 TI - Fatty acid distribution of cord and maternal blood in human pregnancy: special focus on individual trans fatty acids and conjugated linoleic acids. AB - BACKGROUND: Maternal nutrition in pregnancy has a crucial impact on the development of the fetus. Dietary trans fatty acids (tFA) are known to have adverse health effects, especially during pregnancy. However, the distribution of tFA produced via partial hydrogenation of vegetable oils (mainly elaidic acid; t9) differs compared to ruminant-derived tFA (mainly vaccenic acid; t11). Recent findings indicate that they may have different impact on human health.Therefore, in this study, plasma and erythrocytes of mother-child pairs (n = 55) were sampled to investigate the distribution of tFA, including individual trans C18:1 fatty acids and conjugated linoleic acids (CLA) in fetal related to maternal lipids; with additional consideration of maternal dairy fat intake. RESULTS: Portion of t9 and t11, but also of c9,t11 CLA was higher in maternal than in fetal blood lipids. The portion of t9 in maternal and fetal lipids differed only slightly. In contrast, the portion of fetal t11 was only half of that in maternal blood. This led to a fetal t9/t11-index in plasma and erythrocytes being twice as high compared to the maternal values. A high dairy fat intake resulted in elevated portions of t11 and its Delta9-desaturation product c9,t11 CLA in maternal blood. In contrast, in the respective fetal blood lipids only c9,t11 CLA, but not t11 was increased. Nevertheless, a positive association between maternal and fetal plasma exists for both t11 and c9,t11 CLA. Furthermore, in contrast to t9, t11 was not negatively associated with n-3 LC-PUFA in fetal blood lipids. CONCLUSIONS: Fetal blood fatty acid composition essentially depends on and is altered by the maternal fatty acid supply. However, in addition to dietary factors, other aspects also contribute to the individual fatty acid distribution (oxidation, conversion, incorporation). The lower portion of fetal t11 compared to maternal t11, possibly results from Delta9-desaturation to c9,t11 CLA and/or oxidation. Based on the fatty acid distribution, it can be concluded that t11 differs from t9 regarding its metabolism and their impact on fetal LC-PUFA. PMID- 22208627 TI - Predicting hazardous lifestyles among adolescents based on health-risk assessment data. AB - Abstract The Rhode Island Department of Health has developed simple and convenient health risk appraisal (HRA) systems for adults, high-school students and college students. Using HRA data collected on 11,652 high-school students, this paper examines the discriminatory power of two mental health questions as predictors of high risk, unhealthy or dangerous behavior. Both questions, when examined separately, show that students who respond that "life is never worth living" and who report that "they never have emotional support available" take proportionally more and greater risks than their fellow students who have happier outlooks and long-term emotional support. By combining responses from both questions, a typology was developed that might identify a more vulnerable, higher risk-taking subgroup; that is, students who felt life was not worth living and who also had no available emotional support. Further refinement of this approach could produce a useful predictive tool to identify students who are at serious risk for premature disability and death and who could benefit from early therapeutic help. PMID- 22208628 TI - Health promotion for persons with disabilities: moving beyond rehabilitation. AB - Abstract Persons with disabilities are at significant risk for additional or secondary disabilities. Because of this increased risk, especially for persons suffering from the "disuse syndrome," it is important that a comprehensive health promotion component is included in the rehabilitation program for disabled individuals. Current concepts of disability are discussed as well as the distinctions between primary and secondary disabilities. Specific types and causes of disabilities are identified and described. Each type of secondary disability is assessed in terms of its "preventability." Examples and characteristics of quality programs for health promotion for disabled persons are presented. Recommendations for further research and study are discussed to include the need for determining effective components of successful programs and ways to encourage the field of rehabilitation to incorporate health promotion into the rehabilitation process for its disabled clients. PMID- 22208629 TI - Health promotion efforts in pennsylvania schools. AB - Abstract The purpose of this study was to investigate and describe health promotion efforts within Pennsylvania public schools. A questionnaire was designed which addressed the following areas: demographics, health issues and concerns, health promotion programming, and variables pertinent to describe districts without programs. The sample consisted of 275 superintendents of public school districts, 41 of which indicated the existence of a health promotion program in their district. Superintendents of districts with health promotion programs indicated the following: the most frequently offered programs were physical fitness activities, stress management and weight reduction; programs were most frequently offered during the after school hours; many programs were not open to family and community; and the administration of the programs was most frequently the responsibility of a school administrator. The remaining 234 school districts did not have health promotion programs. The reasons cited by the superintendents included limited financial resources, an uninterested faculty and staff, and lack of school board support. PMID- 22208630 TI - Recognition of the reviewers of the american journal of health promotion. PMID- 22208632 TI - Business aspects of health promotion. PMID- 22208631 TI - Research and evaluation results. PMID- 22208634 TI - Networking. PMID- 22208633 TI - Let us move beyond the short sighted "blame the victim" rhetoric. PMID- 22208636 TI - Resource reviews. PMID- 22208637 TI - Perspectives beyond health promotion. PMID- 22208638 TI - Determination of the labeling density of fluorophore-biomolecule conjugates with absorption spectroscopy. AB - Dye-biomolecule conjugation is frequently accompanied by considerable spectral changes of the dye's absorption spectrum that limit the use of the common photometrical method for the determination of labeling densities. Here, we describe an improvement of this method using the integral absorbance of the dye instead of its absorbance at the long wavelength maximum to determine the concentration of the biomolecule-coupled dye. This approach is illustrated for three different cyanine dyes conjugated to the antibody IgG. PMID- 22208640 TI - Probing electron transport in proteins at room temperature with single-molecule precision. AB - Studying electron transport through immobilized proteins at the single-molecule level has been of interest for more than two decades, with a view on the fundamentals of charge transport in condensed media and applications in bioelectronics. Scanning tunneling microscopy (STM) is a powerful tool in this context, because, at least in principle, it should be possible to address individual proteins on an electrode surface reproducibly with single-protein precision. As reported in this issue of ACS Nano, MacDonald and colleagues have now achieved this for the first time at room temperature for covalently immobilized cytochrome b562, combining imaging and tunneling spectroscopy in a custom-built, ultralow drift STM, with single-protein precision. Using site directed mutagenesis, cysteines introduced in specific locations in the amino acid sequence of the protein allowed the team to investigate conduction along different directions through the protein, namely along its short and long axes. PMID- 22208644 TI - Plasma thiol status is altered in children with mitochondrial diseases. AB - OBJECTIVE: This study was undertaken to investigate thiol metabolism as a marker of oxidative stress and antioxidative defence capacity in a cohort of children with biochemically and/or genetically confirmed mitochondrial disease. Previous studies suggest that lower glutathione levels, which have been shown to further compromise mitochondrial function, may occur in these diseases. Better understanding of the pathogenesis of mitochondrial diseases is important in order to improve their treatment. METHODS: We studied plasma and erythrocyte glutathione and cysteine levels, the activities of erythrocyte glutathione peroxidase (GPx), glutathione reductase (GR), glucose 6-phosphate dehydrogenase G6PDH) and glutathione S-transferase (GST), as well as the levels of erythrocyte thiobarbituric acid-reactive species (TBA-RS) and protein carbonyls in 10 children with a biochemical and/or genetic diagnosis of mitochondrial disease and six controls. RESULTS: Levels of reduced cysteine (CYSH) as well as reduced to oxidised cysteine ratio were lower in plasma of patients with mitochondrial diseases (p = 0.008 and p = 0.02, respectively). Plasma levels of reduced glutathione (GSH) were low in patients with mitochondrial diseases, mostly below the detection limit. We did not detect significant differences in erythrocyte thiols or glutathione-related enzyme activities. CONCLUSION: Plasma thiols and their redox state are altered in patients with mitochondrial diseases, suggesting an increase in oxidative stress and depletion of antioxidant supplies. If confirmed in further studies, this relative thiol deficiency could be an important factor in the pathophysiology of mitochondrial diseases. PMID- 22208645 TI - Protocol for a national, mixed-methods knowledge, attitudes and practices survey on non-communicable diseases. AB - BACKGROUND: Mongolia is undergoing rapid epidemiological transition with increasing urbanisation and economic development. The lifestyle and health of Mongolians are changing as a result, shown by the 2005 and 2009 STEPS surveys (World Health Organization's STEPwise Approach to Chronic Disease Risk Factor Surveillance) that described a growing burden of Non-Communicable Diseases and injuries (NCDs).This study aimed to assess, describe and explore the knowledge, attitudes and practices of the Mongolian adult population around NCDs in order to better understand the drivers and therefore develop more appropriate solutions to this growing disease burden. In addition, it aimed to provide data for the evaluation of current public health programs and to assist in building effective, evidence-based health policy. METHODS/DESIGN: This national survey consisted of both quantitative and qualitative methods. A quantitative household-based questionnaire was conducted using a nationally representative sample of 3854 rural and urban households. Participants were selected using a multi-stage cluster sampling technique in 42 regions across Mongolia, including rural and urban sites. Permanent residents of sampled households were eligible for recruitment, if aged between 15-64 years. This quantitative arm was then complemented and triangulated with a qualitative component: twelve focus group discussions focusing on diet, exercise and alcohol consumption. Discussions took place in six sites across the country, facilitated by local, trained health workers. These six sites were chosen to reflect major Mongolian cultural and social groups. DISCUSSION: KAP surveys are well represented in the literature, but studies that aim to explore the knowledge, attitudes and practices of a population around NCDs remain scarce. This is despite the growing number of national epidemiological surveys, such as STEPS, which aim to quantify the burden of these diseases but do not explore the level of population-based awareness, understanding, risk-perception and possible motivation for change. Therefore this paper will contribute to building a knowledge base of NCD KAP survey methodology for future use in epidemiology and research worldwide. PMID- 22208646 TI - Overexpression of either lysine-specific demethylase-1 or CLOCK, but not Co-Rest, improves long-term expression from a modified neurofilament promoter, in a helper virus-free HSV-1 vector system. AB - Long-term expression from helper virus-free Herpes Simplex Virus (HSV-1) vectors is required for many specific neural gene therapies and studies on neuronal physiology. We previously developed a promoter that supports long-term, neuron specific expression by fusing the chicken beta-globin insulator (INS), followed by an upstream enhancer from the rat tyrosine hydroxylase (TH) promoter, to a neurofilament heavy gene (NFH) promoter. Here, we examined the capability of specific transcription factors to further improve long-term expression from this promoter. Following a HSV-1 virus infection, the virus genome is localized to promyelocytic leukemia protein (PML) nuclear bodies (NB). At these sites, specific cellular transcription factors interact with HSV-1 encoded transcription factors, and together regulate HSV-1 gene expression. Importantly, lysine specific demethylase-1 (LSD1), CLOCK, and Co-Rest each activate HSV-1 gene expression. However, gene expression from HSV-1 vectors differs in a number of important aspects from the virus, including no HSV-1 genes are expressed. Nonetheless, these observations raise the possibility that specific transcription factors may improve long-term expression from specific promoters in HSV-1 vectors. Here, we show that overexpression of either LSD1 or CLOCK improves long term expression from the INS-TH-NFH promoter, but overexpression of Co-Rest supports levels of long-term expression similar to those supported by a control vector. Further, overexpression of LSD1 is compatible with neuron-specific expression. Thus, overexpressing specific transcription factors can improve long term expression from specific cellular promoters in HSV-1 vectors, and the chromatin structure of the vector has an important role in enabling expression. PMID- 22208648 TI - Proconvulsive effects of oxytocin in the generalized pentylenetetrazol mouse model are mediated by vasopressin 1a receptors. AB - The possible involvement of oxytocin (OT) in the generation of seizures has not received a lot of attention in the past, although generalized epileptic convulsions were observed in humans following intravenous OT infusion. We here aimed to investigate the effect of exogenous OT administration on seizure susceptibility in C57Bl/6 mice subjected to the pentylenetetrazol (PTZ) model. In addition, we studied via which receptor possible effects on seizure thresholds could be mediated since OT binds to both the OT receptor (OTR) and the vasopressin 1a receptor (V1aR). We showed that C57Bl/6 mice treated with 0.5 mg/kg OT had decreased PTZ thresholds for ear twitch, myoclonic twitch, tail twitch, forelimb clonus and falling. This pronconvulsive effect was reversed by the OTR antagonist L-368.899, however, it was not mimicked by the OTR agonist carbetocin (CBT). Nevertheless, CBT had antidepressant-like effects in the forced swim test that could be reversed by L-368.899. These experiments shed some doubt on the involvement of OTR in the observed effect of OT on seizure thresholds. Therefore, we investigated the role of the V1aR as a possible mediator of the proconvulsive effects of OT. We found that the proconvulsive effects of both arginine vasopressin and OT were reversed by the V1aR antagonist SR49059. In summary, OT has proconvulsive effects in our mouse model of generalized seizures that could not be mimicked by CBT. Our results suggest that the binding of OT to V1aRs is the most plausible explanation for the proconvulsive effects of OT. PMID- 22208647 TI - Cocaine facilitates PKC maturation by upregulating its phosphorylation at the activation loop in rat striatal neurons in vivo. AB - Newly synthesized protein kinase C (PKC) undergoes a series of phosphorylation to render a mature form of the enzyme. It is this mature PKC that possesses the catalytic competence to respond to second messengers for activation and downstream signaling. The first and rate-limiting phosphorylation occurs at a threonine residue in the activation loop (AL), which triggers the rest maturation processing of PKC and regulates PKC activity in response to cellular stimulation. Given the fact that PKC is enriched in striatal neurons, we investigated the regulation of PKC phosphorylation at the AL site in the rat striatum by the psychostimulant cocaine in vivo. We found that PKC was phosphorylated at the AL site at a moderate level in the normal rat brain. Acute systemic injection of cocaine increased the PKC-AL phosphorylation in the two striatal structures (caudate putamen and nucleus accumbens). Cocaine also elevated the PKC-AL phosphorylation in the medial prefrontal cortex. The cocaine-stimulated PKC phosphorylation in the striatum is rapid and transient. A reliable increase in PKC phosphorylation was seen 7 min after drug injection, which declined to the normal level by 1h. This kinetics corresponds to that seen for another striatum enriched protein kinase, mitogen-activated protein kinase/extracellular signal regulated kinase, in response to cocaine. This study suggests a new model for exploring the impact of cocaine on protein kinases in striatal neurons. By modifying PKC phosphorylation at the AL site, cocaine is believed to possess the ability to alter the maturation processing of the kinase in striatal neurons in vivo. PMID- 22208649 TI - Calcitonin gene-related peptide and its receptor components in the human sphenopalatine ganglion -- interaction with the sensory system. AB - Clinical studies have suggested a link between the sensory trigeminal system and the parasympathetic ganglia. Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide which plays an important role in vasodilatation and pain transmission in craniocervical structures. The present study was designed to examine if CGRP and CGRP receptor components are present in the human sphenopalatine ganglion (SPG) in order to reveal an interaction between the sensory and parasympathetic systems. Indirect immunofluorescence technique was used for immunohistochemical demonstration of CGRP, the calcitonin receptor-like receptor (CLR) and the receptor activity modifying protein 1 (RAMP1) in human and rat SPG. Cryostat sections were examined and images were obtained using a light- and epifluorescence microscope coupled to a camera to visualize co-labeling by superimposing the digital images. In addition, Western blot technique was used to demonstrate the existence of CGRP receptor components in rat SPG. CGRP immunoreactive fibers were frequently found intraganglionic in the SPG in the vicinity of neurons. CLR immunoreactivity was observed in satellite glial cells (SGCs) as well as in nerve fibers, but not in neurons. RAMP1 immunoreactivity was localized in many neurons and SGCs. Thus, the two CGRP receptor components together were found in the SGCs. In addition, Western blot revealed the presence of RAMP1 and CLR in rat SPG. Our results suggest a possible sensory influence in the parasympathetic cranial ganglia. The sensory CGRP-containing fibers probably originate in the trigeminal ganglion, project to the SPG and act on CGRP receptors on SGCs. PMID- 22208650 TI - Editorial: Primary Sjogren's syndrome research and therapy: has a new dawn arrived? PMID- 22208651 TI - Ectopic lymphoid neogenesis and lymphoid chemokines in Sjogren's syndrome: at the interplay between chronic inflammation, autoimmunity and lymphomagenesis. AB - It has long been demonstrated that a subset of patients with Sjogren's syndrome (SS) develop ectopic lymphoid structures (ELS) in the salivary glands (SG). These structures are characterised by periductal clusters of T and B lymphocytes, development of high endothelial venules and differentiation of follicular dendritic cells (FDC) networks. Evidence in patients with and animal models of SS demonstrated that the formation and maintenance of ELS in the SG is critically dependent on the ectopic expression of lymphotoxins (LT) and lymphoid chemokines CXCL13, CCL19, CCL21 and CXCL12. Several cell types, including resident epithelial, stromal and endothelial cells as well as different subsets of infiltrating immune cells, have been shown to be capable of producing some of these factors during chronic inflammation in SS. In this review we focus on the cellular and molecular mechanisms regulating the formation of ELS in SS SG, with particular emphasis on the role of lymphoid chemokines. In addition, we summarise accumulating data in support of the notion that ELS in SS represent functional niches whereby autoreactive B cells undergo affinity maturation, clonal selection and differentiation into autoantibody producing cells, thus contributing to autoimmunity over and above secondary lymphoid organs. Furthermore, we review the emerging role of ELS and lymphoid chemokines in driving extranodal B cell lymphomagenesis in SS and we focus on recent evidence suggesting that ELS identify subsets of SS patients at increased risk of developing systemic manifestations and lymphoma. PMID- 22208652 TI - Autoantibodies and Sjogren's syndrome: a physiologist's perspective. AB - Sjogren's syndrome is a systemic autoimmune condition centred around salivary gland dysfunction and atrophy. There are a plethora of antibodies that mark the decline of the salivary glands, most of which relate to apoptopic mediated destruction of acinar cells. The best known of these autoantibodies, anti-Ro and anti-La form part of the diagnostic criteria for the condition. An emerging viewpoint in recent years is that glandular dysfunction precedes rather than follows glandular atrophy and attention has shifted to the interface between the immune system and the secretory process. An autoantibody against the muscarinic type 3 acetylcholine receptor occupies precisely this position because it inhibits the acetylcholine receptor which controls salivary and lacrimal fluid secretion. The consequence of identifying an autoantibody that can cause rather than simply reflect the disease process are manifold and could have a huge impact on development of therapeutic treatments. Furthermore, a "functional" autoantibody directed against an important component of the autonomic nervous system could also account for some of the extraglandular features of Sjogren's syndrome. PMID- 22208653 TI - B-lymphocytes govern the pathogenesis of Sjogren's syndrome. AB - T cells have originally occupied central stage of the debate on the type of lymphocytes governing the pathogenesis of Sjogren's syndrome (SS). However, B cells has since been substituted for T cells, and insights into their functions have revealed that they accomplish various tasks. Beyond the paradigm that T lymphocytes maintain strict control over B lymphocytes, these latter cells solicit their own help from the former, release a flurry of cytokines, and act as antigen- presenting cells. In SS, excessive of the B cell-activating factor (BAFF) may cause B-cell quantitative anomalies, such as inflation of mature B (Bm)2/Bm2' cells in the circulation, or accumulation of transitional type 2, marginal zone (MZ) and memory B cells within the exocrine gland infiltrates. These excesses are also associated with B-cell qualitative anomalies, such as the internal synthesis of BAFF, and a default mechanism that promotes the autoantibody production in ectopic germinal centers or MZ equivalents. Thus, SS should rather be conceived as a quintessential model for B cell-induced autoimmunity. Such a view opens novel prospects for treatment, and indeed B cell ablative therapy has already been shown to be beneficial to these patients. PMID- 22208654 TI - Biologic therapies in primary Sjogren's syndrome. AB - Primary Sjogren's Syndrome (PSS) is characterized by dryness of the eyes and mouth due to lymphocytic infiltration of secretory exocrine glands. As well as disabling dryness, patients commonly have fatigue and arthralgia and an associated reduction in quality of life. The condition principally affects adult women and is relatively common--approximately 1:1000 to 1:250 adult women are estimated to have the condition in European/North American studies. Current therapy is principally symptomatic with the use of artificial tears and oral gels, pastilles and sprays. Medications to stimulate residual glandular secretion can be helpful for appropriate individuals. A proportion of patients also develop extraglandular features such as skin vasculitis, or lung, neurological, haematological or other systemic involvement. Conventional general immunosuppressive therapies such as corticosteroids or disease-modifying drugs, have been used in some patients with these clinical features. Biologic therapies specifically directed against molecules involved in disease pathogenesis represent a potentially more effective approach to therapeutic intervention in rheumatic diseases including PSS. The greatest experience in PSS is with rituximab, an anti-B-cell monoclonal antibody already in use for the treatment of B-cell lymphoma and rheumatoid arthritis. A randomised placebo controlled study is currently recruiting in France and a further study is planned in the UK. This review discusses the utility of biologic therapies in PSS, potential challenges for their use, the available data on rituximab and the potential role for other biologic therapies currently in development, or in clinical trials, in other autoimmune conditions. PMID- 22208655 TI - Primary Sjogren's syndrome: time for prospective cohorts. AB - Many important clinical questions concerning primary Sjogren's syndrome (pSS) remain, that can only be adequately addressed by prospective cohorts. Thus, a better knowledge of the clinical outcome, the course of disease activity and the risk factors of lymphoma requires the setting up of cohorts with biobanks. The homogeneous collection of clinical data, disease activity, patient-related outcome, and biological samples, including DNA, RNA and serum, is definitively mandatory to determine new biological prognostic factors and identify disease activity markers. Three large prospective cohorts have already started to enroll patients with pSS. This will be highly invaluable for scientists and clinicians to gain a better insight into the pathogenesis of pSS, as well as to identify prognostic markers and new therapeutic targets. PMID- 22208656 TI - Current and future challenges in primary Sjogren's syndrome. AB - Sjogren's syndrome (SS) is an autoimmune inflammatory disorder of exocrine glands. SS particularly affects the lacrimal and salivary glands. Dry mouth and dry eyes are frequently proffered as presenting symptoms, but nonspecific symptoms such as malaise and fatigue, and extraglandular manifestations like purpura, polyneuropathy and arthritis are also often present. Moreover, lymphomas develop in about 7.5% of SS patients, mostly marginal zone B-cell lymhomas. Futhermore, SS has a very substantial impact on the patients' quality of life and their daily activities. Recently, many breakthroughs have been seen in salivary diagnostics, which not only can be used for diagnosis but also for monitoring of disease activity and disease progression as well as for objectively scoring the effect of intervention treatment with biologicals. In addition, salivary proteomics, genomics and system biology have been shown to be very promising tools in unravelling the pathophysiology of SS, thus providing in depth insight in its underlying mechanisms which could give clues for intervention therapies with biologicals. The latter is of particular interest as B cell depletion therapy has been shown a very promising therapy for a subgroup of SS patients. When applying salivary diagnostics in combination with instruments to rate disease activity and progression in SS, one might be able to select those SS patients who respond to a particular type of biological. These topics are addressed in this review and promises for the near future are described. PMID- 22208657 TI - Primary Sjogren's syndrome and the type I interferon system. AB - Patients with primary Sjogren's syndrome (pSS) have an activated type I interferon (IFN) system that contribute to the etiopathogenesis and clinical manifestations of the disease. The type I IFN system consists of the stimuli for type I IFN production, the receptors, cells and transcription factors involved in the synthesis of type I IFNs, the type I IFN-receptor and the effects on target cells. Increased type I IFN activity has been demonstrated in sera from patients with pSS and IFN-alpha, the main type I IFN, has been detected in the minor salivary glands. Gene expression profiling of peripheral blood mononuclear cells (PBMCs) and minor salivary glands from pSS patients display an up-regulation of type I IFN-induced genes, an "IFN signature". The professional IFN-alpha producing plasmacytoid dendritic cell (pDC) shows a reduced frequency in the peripheral blood, but has been detected in the salivary glands, possibly due to tissue recruitment. Polymorphisms in the interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) genes in the type I IFN system, are associated with increased risk for pSS. A postulated disease model is that an initial viral infection induces type I IFN production in the salivary glands with subsequent activation of the adaptive immune system resulting in the production of autoantibodies against the RNA-binding proteins SSA/SSB/RNP. Interferogenic immune complexes are formed, which trigger the pDCs to an ongoing type I IFN production, which sustain the disease process. Potential therapeutic targets can be identified within the type I IFN system. PMID- 22208658 TI - Local activation and systemic dysregulation of T lymphocytes in Sjogren's syndrome. AB - T cells are implicated in both local and systemic pathophysiology of primary Sjogren's syndrome (PSS). Lymphocytic infiltrates in exocrine glands are dominated by CD4+ T cells, some contributing to ectopic lymphoid tissue, others, unusually, exhibiting cytotoxic potential. Cytokine secretion patterns are complex, with Th1 and Th17 components implicated in pathology. Circulating T cells exhibit phenotypes consistent with hyperactivation, cytokine imbalance, and homeostatic alterations; CD4 lymphopenia is recognized as a risk factor for developing lymphoma. Evidence of oligoclonal expansion is found locally and systemically. Functional alterations (e.g. cytokine secretion profile, migratory potential, target cell interactions) are less clearly defined. Attempts at T cell targeted therapy of PSS have been limited, although therapy targeted at other arms of the immune response may also affect T cells. A better understanding of T cell dysregulation in PSS is required in order to understand its contribution to disease, aid prognosis, and improve therapeutic interventions aimed at this aspect of the disease. PMID- 22208659 TI - Epigenetics and Sjogren's syndrome. AB - There is growing evidence that epigenetics, the study of heritable changes in gene expression that do not involve mutations in the DNA itself, may play an essential role in autoimmune diseases (AID). In Sjogren's syndrome (SS), a chronic AID characterized by an epithelis of the exocrine glands, epigenetic studies have focused on three mechanisms: DNA methylation and its consequences including human endogenous retrovirus (HERV) expression; microRNA expression; and protein post-translational modifications associated with autoantibody production. Although in its infancy, comprehension of the epigenetic (dys)regulation in SS may help us to understand: why SS affects predominantly middle-aged women; why genetically predisposed individuals develop SS but not others; why flare-ups occur; why treatment responses differ between patients; and why some patients develop lymphoma. From these studies will arise a better comprehension of the pathophysiology of SS as well as development of new diagnostic and prognostic biomarkers, and novel therapeutics for prevention and perhaps early intervention. PMID- 22208660 TI - Conservation of ciliary proteins in plants with no cilia. AB - BACKGROUND: Eukaryotic cilia are complex, highly conserved microtubule-based organelles with a broad phylogenetic distribution. Cilia were present in the last eukaryotic common ancestor and many proteins involved in cilia function have been conserved through eukaryotic diversification. However, cilia have also been lost multiple times in different lineages, with at least two losses occurring within the land plants. Whereas all non-seed plants produce cilia for motility of male gametes, some gymnosperms and all angiosperms lack cilia. During these evolutionary losses, proteins with ancestral ciliary functions may be lost or co opted into different functions. RESULTS: Here we identify a core set of proteins with an inferred ciliary function that are conserved in ciliated eukaryotic species. We interrogate this genomic dataset to identify proteins with a predicted ancestral ciliary role that have been maintained in non-ciliated land plants. In support of our prediction, we demonstrate that several of these proteins have a flagellar localisation in protozoan trypanosomes. The phylogenetic distribution of these genes within the land plants indicates evolutionary scenarios of either sub- or neo-functionalisation and expression data analysis shows that these genes are highly expressed in Arabidopsis thaliana pollen cells. CONCLUSIONS: A large number of proteins possess a phylogenetic ciliary profile indicative of ciliary function. Remarkably, many genes with an ancestral ciliary role are maintained in non-ciliated land plants. These proteins have been co-opted to perform novel functions, most likely before the loss of cilia, some of which appear related to the formation of the male gametes. PMID- 22208662 TI - Catalytic asymmetric synthesis of axially chiral o-iodoanilides by phase-transfer catalyzed alkylations. AB - Catalytic asymmetric synthesis of axially chiral o-iodoacrylanilides and N-allyl o-iodoanilides as useful chiral building blocks was achieved via chiral quaternary ammonium salt-catalyzed N-alkylations under phase-transfer conditions. The transition-state structure for the present reaction is discussed on the basis of the X-ray crystal structure of ammonium anilide. PMID- 22208661 TI - A novel SNP in COMT is associated with alcohol dependence but not opiate or nicotine dependence: a case control study. AB - BACKGROUND: It is well established that COMT is a strong candidate gene for substance use disorder and schizophrenia. Recently we identified two SNPs in COMT (rs4680 and rs165774) that are associated with schizophrenia in an Australian cohort. Individuals with schizophrenia were more than twice as likely to carry the GG genotype compared to the AA genotype for both the rs165774 and rs4680 SNPs. Association of both rs4680 and rs165774 with substance dependence, a common comorbidity of schizophrenia has not been investigated. METHODS: To determine whether COMT is important in substance dependence, rs165774 and rs4680 were genotyped and haplotyped in patients with nicotine, alcohol and opiate dependence. RESULTS: The rs165774 SNP was associated with alcohol dependence. However, it was not associated with nicotine or opiate dependence. Individuals with alcohol dependence were more than twice as likely to carry the GG or AG genotypes compared to the AA genotype, indicating a dominant mode of inheritance. The rs4680 SNP showed a weak association with alcohol dependence at the allele level that did not reach significance at the genotype level but it was not associated with nicotine or opiate dependence. Analysis of rs165774/rs4680 haplotypes also revealed association with alcohol dependence with the G/G haplotype being almost 1.5 times more common in alcohol-dependent cases. CONCLUSIONS: Our study provides further support for the importance of the COMT in alcohol dependence in addition to schizophrenia. It is possible that the rs165774 SNP, in combination with rs4680, results in a common molecular variant of COMT that contributes to schizophrenia and alcohol dependence susceptibility. This is potentially important for future studies of comorbidity. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated. PMID- 22208663 TI - Reduced expression of tissue factor pathway inhibitor-2 contributes to apoptosis and angiogenesis in cervical cancer. AB - BACKGROUND: Tissue factor pathway inhibitor-2 (TFPI-2) is an extracellular matrix associated broad-spectrum Kunitz-type serine proteinase inhibitor. Recently, down regulation of TFPI-2 was suggested to be involved in tumor invasion and metastasis in some cancers. METHODS: This study involved 12 normal cervical squamous epithelia, 48 cervical intraepithelial neoplasia (CIN), and 68 cervical cancer. The expression of TFPI-2, Ki-67 and vascular endothelial growth factor (VEGF) were investigated by immunohistochemistry staining. The apoptolic index(AI) was determined with an in situ end-labeling assay(TUNEL). And the marker of CD34 staining was used as an indicator of microvessel density (MVD). RESULTS: TFPI-2 expression has a decreasing trend with the progression of cervical cancer and was significantly correlated with FIGO stage, lymph node metastasis and HPV infection. In addition, there were significant positive correlations between the grading of TFPI-2 expression and AI(P=0.004). In contrast, the expression of TFPI-2 and VEGF or MVD was negatively correlated (both p < 0.001). However, we did not establish any significant correlation between Ki-67 and TFPI-2 expression in cervical cancer. CONCLUSIONS: The results suggested that the expression of TFPI-2 had a decreasing trend with tumor progression of cervical cancer. There was a close association between the expression of TFPI-2 and tumor cell apoptosis and angiogenesis in patients with cervical cancer. TFPI-2 may play an inhibitive role during the development of cervical cancer. PMID- 22208664 TI - Sex-specific association of rs16996148 SNP in the NCAN/CILP2/PBX4 and serum lipid levels in the Mulao and Han populations. AB - BACKGROUND: The association of rs16996148 single nucleotide polymorphism (SNP) in NCAN/CILP2/PBX4 and serum lipid levels is inconsistent. Furthermore, little is known about the association of rs16996148 SNP and serum lipid levels in the Chinese population. We therefore aimed to detect the association of rs16996148 SNP and several environmental factors with serum lipid levels in the Guangxi Mulao and Han populations. METHOD: A total of 712 subjects of Mulao nationality and 736 participants of Han nationality were randomly selected from our stratified randomized cluster samples. Genotyping of the rs16996148 SNP was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. RESULTS: The levels of apolipoprotein (Apo) B were higher in Mulao than in Han (P < 0.001). The frequencies of G and T alleles were 87.2% and 12.8% in Mulao, and 89.9% and 10.1% in Han (P <0.05); respectively. The frequencies of GG, GT and TT genotypes were 76.0%, 22.5% and 1.5% in Mulao, and 81.2%, 17.4% and 1.4% in Han (P <0.05); respectively. There were no significant differences in the genotypic and allelic frequencies between males and females in both ethnic groups. The levels of HDL-C, ApoAI, and the ratio of ApoAI to ApoB in Mulao were different between the GG and GT/TT genotypes in males but not in females (P < 0.01 for all), the subjects with GT/TT genotypes had higher serum levels of HDL C, ApoAI, and the ratio of ApoAI to ApoB than the subjects with GG genotype. The levels of TC, TG, LDL-C, ApoAI, and ApoB in Han were different between the GG and GT/TT genotypes in males but not in females (P < 0.05-0.001), the T allele carriers had higher serum levels of TC, TG, LDL-C, ApoAI, and ApoB than the T allele noncarriers. The levels of HDL-C, ApoAI, and the ratio of ApoAI to ApoB in Mulao were correlated with the genotypes in males (P < 0.05-0.01) but not in females. The levels of TC, TG, HDL-C, LDL-C, ApoAI and ApoB in Han were associated with the genotypes in males (P < 0.05-0.001) but not in females. Serum lipid parameters were also correlated with several enviromental factors in both ethnic groups (P < 0.05-0.001). CONCLUSIONS: The genotypic and allelic frequencies of rs16996148 SNP and the associations of the SNP and serum lipid levels are different in the Mulao and Han populations. Sex (male)-specific association of rs16996148 SNP in the NCAN/CILP2/PBX4 and serum lipid levels is also observed in the both ethnic groups. PMID- 22208668 TI - Speech audiometry in quiet with the Oldenburg Sentence Test for Children. AB - OBJECTIVE: To assess speech perception in children, speech audiometric sentence tests are generally better suited than single word tests because of their steeper discrimination function and thus higher sensitivity. A disadvantage of older German single word speech audiometric tests for children is their inapplicability in quiet and in noise. Moreover, their discrimination functions are shallower than those of optimized sentence tests, particularly in noise. The Oldenburg sentence test for children (Oldenburger Kinder-Satztest; OlKiSa) has already been shown to test reliably the speech perception in noise in normal-hearing children. Testing hearing-impaired children in noise, however, may be difficult. Therefore, quality criteria and norms for testing in quiet are also needed. STUDY SAMPLE: The OlKiSa in quiet was validated with 224 normal-hearing children between ages 4 to 10 years. RESULTS: The discrimination functions are steeper (6.4 to 10.7 %/dB) than those of the commonly used German single word tests. Age-specific standards for 50% speech perception in quiet (speech reception threshold, SRT) are provided. CONCLUSIONS: The OlKiSa is a valid audiometric test to quantify speech perception in quiet in children from age 4. PMID- 22208667 TI - Role of glutamate 64 in the activation of the prodrug 5-fluorocytosine by yeast cytosine deaminase. AB - Yeast cytosine deaminase (yCD) catalyzes the hydrolytic deamination of cytosine to uracil as well as the deamination of the prodrug 5-fluorocytosine (5FC) to the anticancer drug 5-fluorouracil. In this study, the role of Glu64 in the activation of the prodrug 5FC was investigated by site-directed mutagenesis, biochemical, nuclear magnetic resonance (NMR), and computational studies. Steady state kinetics studies showed that the mutation of Glu64 causes a dramatic decrease in k(cat) and a dramatic increase in K(m), indicating Glu64 is important for both binding and catalysis in the activation of 5FC. (19)F NMR experiments showed that binding of the inhibitor 5-fluoro-1H-pyrimidin-2-one (5FPy) to the wild-type yCD causes an upfield shift, indicating that the bound inhibitor is in the hydrated form, mimicking the transition state or the tetrahedral intermediate in the activation of 5FC. However, binding of 5FPy to the E64A mutant enzyme causes a downfield shift, indicating that the bound 5FPy remains in an unhydrated form in the complex with the mutant enzyme. (1)H and (15)N NMR analysis revealed trans-hydrogen bond D/H isotope effects on the hydrogen of the amide of Glu64, indicating that the carboxylate of Glu64 forms two hydrogen bonds with the hydrated 5FPy. ONIOM calculations showed that the wild-type yCD complex with the hydrated form of the inhibitor 1H-pyrimidin-2-one is more stable than the initial binding complex, and in contrast, with the E64A mutant enzyme, the hydrated inhibitor is no longer favored and the conversion has a higher activation energy, as well. The hydrated inhibitor is stabilized in the wild-type yCD by two hydrogen bonds between it and the carboxylate of Glu64 as revealed by (1)H and (15)N NMR analysis. To explore the functional role of Glu64 in catalysis, we investigated the deamination of cytosine catalyzed by the E64A mutant by ONIOM calculations. The results showed that without the assistance of Glu64, both proton transfers before and after the formation of the tetrahedral reaction intermediate become partially rate-limiting steps. The results of the experimental and computational studies together indicate that Glu64 plays a critical role in both the binding and the chemical transformation in the conversion of the prodrug 5FC to the anticancer drug 5-fluorouracil. PMID- 22208673 TI - Comparison of the validity of the Chinese versions of the Hypomania Symptom Checklist-32 (HCL-32) and Mood Disorder Questionnaire (MDQ) for the detection of bipolar disorder in medicated patients with major depressive disorder. AB - OBJECTIVE: The sensitivity and specificity of the Chinese versions of the Hypomania Symptom Checklist-32 (HCL-32) and Mood Disorder Questionnaire (MDQ) for detecting bipolar disorder in Taiwan were explored in this study. METHODS: In total, 59 participants who were initially diagnosed with unipolar depression were recruited from an outpatient clinic and were screened for bipolar disorder using the HCL-32 and MDQ; each participant also underwent a diagnostic interview based on the Structured Clinical Interview for DSM-IV Axis disorder patients (SCID). RESULTS: The results showed that the HCL-32 yielded the best combination of sensitivity (100%) and specificity (46.2%) at a cut-off point of 7/8, and the MDQ yielded the best combination of sensitivity (71.4%) and specificity (76.9%) at a cut-off point of 6/7. CONCLUSION: The results of our study demonstrate that the HCL-32 and MDQ are of reasonable validity to distinguish between bipolar disorder and major depressive disorder. However small sample size may limit generalization of the results. PMID- 22208674 TI - Randomized placebo-controlled cross-over designs in clinical trials: a gold standard to be reassessed. AB - Placebo effects are well-known phenomena in medicine and biology. In fact, placebos are used as control conditions in randomized cross-over clinical trials to validate new treatments. Only recently, however, has it become apparent that the conditioning and/or expectation effects provided by the experience of placebos can influence the results of clinical trials. It seems that combining shams and sequences has prejudiced the conclusions provided by cross-over designs. Frighteningly, this bias is always in the same direction, namely to increase the risk of rejecting potentially valid treatments. New models for clinical trials should be encouraged if we wish to market new and truly valid treatments. PMID- 22208675 TI - Twice daily dosing of dabigatran for stroke prevention in atrial fibrillation: a pharmacokinetic justification. AB - BACKGROUND AND OBJECTIVE: Dabigatran is a new oral anticoagulant recently approved for the prevention of stroke or systemic embolism in patients with atrial fibrillation (AF). Based on its pharmacokinetic profile, dabigatran is dosed twice daily. This analysis provides a quantitative rationale for the selection of the dose regimen in this population. METHODS: The pharmacokinetic profile of dabigatran was simulated for AF patients given a total daily dose of 300 mg, either once or twice daily. Simulations were based on a population pharmacokinetic model supplemented with data collected from 9522 patients enrolled in a pivotal phase III study (RE-LY). RESULTS: The typical RE-LY patient (male, 72 years old, Caucasian, weight 80 kg, creatinine clearance 68.64 mL/min) treated with dabigatran 150 mg twice daily showed less than two-fold difference between peak-trough plasma levels compared with a five-fold difference when the same total dose (300 mg) was administered once daily. For patients who miss or delay taking one scheduled dabigatran dose, twice daily dosing maintained adequate minimum trough concentrations better than once daily dosing. Pharmacokinetic data collected from a phase II study and RE-LY were consistent with the simulation results. The study did not access comparative efficacy and bleeding data for once versus twice daily dosing. CONCLUSION: Pharmacokinetic simulations show that a twice daily regimen in patients with AF minimizes daily fluctuations in plasma concentrations of dabigatran and can maintain trough concentrations sufficient to prevent the development of thrombi while at the same time minimizing the risk of bleeding due to supratherapeutic peak plasma concentrations. The efficacy and safety of this dosing regimen is supported by clinical data from the RE-LY trial. PMID- 22208676 TI - A comparison of the effectiveness of three parenting programmes in improving parenting skills, parent mental-well being and children's behaviour when implemented on a large scale in community settings in 18 English local authorities: the parenting early intervention pathfinder (PEIP). AB - BACKGROUND: There is growing evidence that parenting programmes can improve parenting skills and thereby the behaviour of children exhibiting or at risk of developing antisocial behaviour. Given the high prevalence of childhood behaviour problems the task is to develop large scale application of effective programmes. The aim of this study was to evaluate the UK government funded implementation of the Parenting Early Intervention Pathfinder (PEIP). This involved the large scale rolling out of three programmes to parents of children 8-13 years in 18 local authorities (LAs) over a 2 year period. METHODS: The UK government's Department for Education allocated each programme (Incredible Years, Triple P and Strengthening Families Strengthening Communities) to six LAs which then developed systems to intervene using parenting groups. Implementation fidelity was supported by the training of group facilitators by staff of the appropriate parenting programme supplemented by supervision. Parents completed measures of parenting style, efficacy, satisfaction, and mental well-being, and also child behaviour. RESULTS: A total of 1121 parents completed pre- and post-course measures. There were significant improvements on all measures for each programme; effect sizes (Cohen's d) ranged across the programmes from 0.57 to 0.93 for parenting style; 0.33 to 0.77 for parenting satisfaction and self-efficacy; and from 0.49 to 0.88 for parental mental well-being. Effectiveness varied between programmes: Strengthening Families Strengthening Communities was significantly less effective than both the other two programmes in improving parental efficacy, satisfaction and mental well-being. Improvements in child behaviour were found for all programmes: effect sizes for reduction in conduct problems ranged from 0.44 to -0.71 across programmes, with Strengthening Families Strengthening Communities again having significantly lower reductions than Incredible Years. CONCLUSIONS: Evidence-based parenting programmes can be implemented successfully on a large scale in community settings despite the lack of concentrated and sustained support available during a controlled trial. PMID- 22208677 TI - [Appendix constrictor ring: a rare cause of intestinal obstruction]. PMID- 22208678 TI - Recent patents on oligonucleotide synthesis and gene synthesis. AB - Gene synthesis is an emerging field which has widespread implications in synthetic biology and molecular biology. The field is constantly evolving which has led to key advances in oligonucleotide synthesis and gene synthesis technologies, with simplicity, cost effectiveness and high throughput. The miniaturization, multiplexing, microfluidic processing and the integrated microchip engineering will drive down cost and increase productivity without compromising DNA synthesis fidelity, whereas the gigantic amount of genome information provides infinite source of DNA elements and genes as raw material for synthetic biology. This article describes some of the recent patents on oligonucleotide synthesis and gene synthesis. PMID- 22208679 TI - Gene delivery system: a developing arena of study for the new era of medicine. AB - Gene therapy concept has been being overcome massive challenges from 1972 in ethical, socio-economical and developmental issues. In this review, we have attempted to go through almost all the arenas and described in a methodical way that reflects not only the initial ethical and scientific thoughts but also adorned a solid depiction of gene therapy related physico-chemical barriers, approaches and strategies till to date. PMID- 22208680 TI - Critical steps in tissue processing in histopathology. AB - Histopathological diagnosis using Formalin-Fixed Paraffin Embedded (FFPE) tissues is essential for the prognostic and therapeutic management of cancer patients. Pathologists are being confronted with increasing demands, from both clinicians and patients, to provide immunophenotypic and gene expression data from FFPE tissues to allow the planning of personalized therapeutic regimens. Recent improvements in the protocols for pre-analysis processing of pathological tissues aim to better preserve cellular details and to conserve antigens and nucleic acid sequences. These developments have been recently patented. The international protocol for the transporting of surgical specimens from the surgical theatre to the pathology department is to immerse the specimen in formalin. The alternative method of sealing the specimens into bags under a vacuum and then cooling is a well-accepted and environmentally safe procedure that overcomes the many drawbacks linked to transfer in formalin. Importantly, RNA is notoriously poorly preserved in FFPE tissue. Due to this, successful procedures for the extraction of genetic information from archival tissues have been the object of several studies and patents. Novel molecular approaches for RT-qPCR and gene array analysis on FFPE tissues are presented here. Moreover, a major advance is reported in this study, the observation that tissue fixation in cold conditions allows a much better preservation of nucleic acid sequences. PMID- 22208681 TI - C-reactive protein is an independent predictor for carotid artery intima-media thickness progression in asymptomatic younger adults (from the Bogalusa Heart Study). AB - BACKGROUND: Conflicting information exists regarding the association between hsCRP and the progression of early stages of atherosclerosis. The purpose of the study was to investigate the association of high sensitiviy c-reactive protein (hsCRP) along with major cardiovascular (CV) risk factors on early carotid atherosclerosis progression in a large, population-based cohort study. METHODS: The study cohort included 839 young adults (aged 24 to 43 years, 70% white, 42% men) enrolled in Bogalusa Heart Study, who in 2001-2002 attended baseline examination with measurements of CV risk factors. Progression of carotid artery intima-media thickness (IMT) was assessed during a mean follow-up of 2.4 years. RESULTS: Carotid artery IMT progression rates were as follows: composite carotid artery = 9.2 +/- 52 MUm/y, common carotid artery = 0.0 +/- 51 MUm/y, carotid bulb = 8.8 +/- 103 MUm/y, and internal carotid artery = 18.9 +/- 81 MUm/y. Elevated baseline hsCRP, reflecting an inflammatory state, showed independent association with composite carotid artery IMT progression. Increased age, systolic blood pressure, fasting glucose, LDL cholesterol, and current smoking were other risk associates of carotid artery IMT progression in young adults, indicating an underlying burden on the CV system by multiple risk factors. CONCLUSION: In this population-based study, we observed independent categorical association of increased hsCRP with carotid artery IMT progression in young adults. This study underlines the importance of assesssing hsCRP levels along with smoking and traditional CV risk factor profiles in asymptomatic young adults. PMID- 22208682 TI - Diagnostic Pathology in 2011: reflecting on the development of an open access journal during the last six years. AB - Today, electronic communication is involved in all parts of our lives, either in a directed active, communicative, or passive manner. Whether to live with electronic communication or to ignore it is no longer a question. Instead, the question we have to answer is: How shall we live in our communicative environment? What can we expect? What are we forced to develop in order "to survive"? This Editorial written at the end of a really successful year of our journal Diagnostic Pathology tries to give some answers from different points of view: PMID- 22208684 TI - Blunt adrenal gland trauma in the pediatric population. AB - A retrospective review of the literature was performed to determine the natural history, prevalence, prognosis and management of adrenal injury associated with blunt abdominal trauma in pediatric population. Blunt adrenal injury in children is uncommon, rarely isolated, and typically present as part of a multi organ trauma. Adrenal hemorrhage is being diagnosed more frequently since the emergence of computed tomography in modern emergency rooms. Obstetric birth trauma during vaginal delivery of a macrosomic fetus may result in neonatal adrenal hemorrhage. In children appear to be an incidental finding that resolves on follow-up imaging. Most of these injuries are self-limited and do not require intervention. The differential diagnosis of an adrenal neoplasm, especially in children with an isolated adrenal hemorrhage, must be considered. The presence of adrenal hemorrhage in the absence of a trauma history should alert to the possibility of pediatric inflicted injury. PMID- 22208685 TI - Primary colorectal lymphoma: case series and literature review. AB - Primary colorectal lymphoma is a rare disease that accounts for 0.16% of colorectal malignancies. Treatments include surgical intervention with or without chemotherapy. Outcome of this intervention among the Chinese population are lacking. Perforation resulting from chemotherapy may need further exploration. A retrospective review of patient records was performed among those who were diagnosed with colorectal malignancy in a single center from January 1998 to June 2009. Ten patients met Dawson's diagnostic criteria for primary colorectal lymphoma [0.66% (10/1516) of all colorectal malignancies]. The male-to-female ratio was 9:1, and median age at diagnosis was 76 years. The most common site was the cecum (n = 5). B-cell lymphoma was present in eight patients. Seven patients underwent surgical intervention. The median follow-up of all patients was 16.5 months. Median survival was 17 months and 13 months in the surgical and chemotherapy group, respectively. Primary colonic lymphoma is a rare disease. Surgical intervention appeared to be superior to chemotherapy alone, but the findings were limited by the small number of patients in this study. Whether surgery or chemotherapy should be offered first remains unknown and requires further research. PMID- 22208686 TI - Pelvic exenteration for men with locally advanced rectal cancer: a morbidity analysis of complicated cases. AB - BACKGROUND: The role of pelvic exenteration in locally advanced rectal cancer (LARC) has not been clearly defined. This procedure carries a mortality rate of approximately 10%. The challenges during pelvic surgery are different between men and women. The morbidity in men with LARC who received pelvic exenteration was analyzed. METHODS: Medical records of men with LARC undergoing total pelvic exenteration or supralevator pelvic exenteration from January 1991 to December 2007 were retrospectively reviewed. RESULTS: A total of 23 cases were included in the analysis. Thirteen patients had primary cancer; 10 had recurrent cancer. Microscopically clear surgical margins were obtained in 14 patients (60.9%). Sixteen patients (69.6%) experienced major or minor postoperative complications. The overall in-hospital mortality rate was 8.7%. Ten patients (43.5%) died within 1 year after surgery. All 10 patients with early mortality experienced refractory complications and repeated surgeries. The longest survival of patients with margin involvement was 25 months. The correlation between involved surgical margins and 1-year mortality was statistically significant (p = 0.001). CONCLUSION: Resection margins with tumor involvement after pelvic exenteration is associated with poor prognosis and early mortality in men with locally advanced rectal cancer. PMID- 22208687 TI - Effect of postoperative fractionated radiotherapy on canine ePTFE graft neointima and anastomotic stoma healing: a preliminary experimental study. AB - OBJECTIVE: The present study aimed to determine whether postoperative fractionated radiotherapy, at a total dose of 35 Gy, affected expanded polytetrafluoroethylene (ePTFE) graft anastomotic stoma healing and neointima formation. METHODS: The subrenal abdominal aortas of 20 mongrel dogs were replaced with an ePTFE graft. The dogs were randomly divided into either a radiotherapy or nonradiotherapy control group. Grafts were harvested at 4 or 8 weeks after surgery. Hematoxylin-eosin staining, and immunohistochemistry tests for proliferating cell nuclear antigen (PCNA) and CD34 were undertaken to analyze the anastomotic healing and neointima formation. RESULTS: The patency rate of grafts was 100% in each group. No disunion, rupture, or aneurysm was observed in the anastomotic stoma. Eight weeks after surgery, the graft neointima and anastomotic vessel wall of the radiotherapy group were significantly thinner than those of the control group (p < 0.05). Immunohistochemical examination was carried out in accordance with histomorphology. CONCLUSION: Postoperative fractionated radiotherapy after an ePTFE graft replacement of the abdominal aorta did not affect the healing of the anastomotic stoma. However, it suppressed the development of hyperplasia in the anastomotic stoma neointima and graft neointima formation in the short term. PMID- 22208688 TI - Characterization of hepatocellular carcinoma recurrence after liver transplantation: perioperative prognostic factors, patterns, and outcome. AB - OBJECTIVE: Liver transplantation (LT) is known to be a promising treatment for patients with liver cirrhosis associated with hepatocellular carcinoma (HCC). This study, however, found that HCC recurrence remains to be a concern. METHODS: A total of 126 HCC patients who had undergone LT between January 2000 and December 2009 were retrospectively reviewed. The clinicopathological features of the patients were analyzed by univariate and multivariate analyses to determine prognostic factors. Patients who had HCC recurrence were further analyzed in terms of recurrent pattern, management, and outcome. RESULTS: Seventeen patients (13.5%) exhibited HCC recurrence following LT. Univariate and multivariate analyses identified two prognostic factors: tumor number > three [hazard ratio (HR) = 3.249] and presence of microvascular invasion (HR = 4.336). Among patients with HCC recurrence, 15 out of 17 (88%) patients developed extrahepatic metastasis shortly after recurrence. The survival of patients after HCC recurrence was dismal with 18.3 months of median survival. CONCLUSIONS: Multiple tumors (>three) are an important prognostic factor for HCC recurrence following LT, but an accurate assessment of tumor status by pretransplantation radiological examination is required. The outcome of patients with HCC recurrence after LT remains very poor because of a tendency of HCC to recur as extrahepatic metastasis. PMID- 22208689 TI - Efficacy and safety of photoselective vaporization of the prostate in patients with prostatic obstruction induced by advanced prostate cancer. AB - OBJECTIVE: We evaluated the efficacy and outcome of laser photoselective vaporization of prostate (PVP) in patients with voiding difficulty due to prostatic obstruction induced by advanced prostate cancer (PC). METHODS: We retrospectively studied the records of 13 patients with advanced PC and prostatic obstruction with a mean prostate volume of 65.0 ml. All of the 13 patients received PVP between 2006 and 2010 due to the symptoms of voiding difficulty or acute urinary retention (AUR; N = 10) refractory to medical treatment. Perioperative safety and functional results were evaluated. RESULTS: Lasering time ranged from 24 to 20 minutes (mean 67 +/- 26), during which 66-423 KJ (mean 172 +/- 95) of laser energy was delivered. All patients could resume voiding function with a mean catheterization time of 3.0 days. CONCLUSIONS: Our preliminary results suggest that PVP is a safe and effective procedure for relieving prostatic obstruction without intraoperative blood transfusion, water intoxication, or other complications in patients with advanced prostate cancer. PMID- 22208690 TI - Successful extirpation of thoracic pleural lipoma by single-port thoracoscopic surgery. AB - Video-assisted thorascopic surgery (VATS) is a common technique for thoracic operations. Surgery with access via a single port has gradually become popular. We herein report the unusual case of a 53-year-old Japanese male patient whose chest X-rays revealed an abnormal shadow, which continued to increase in size. The tumor was excised by single-port access surgery. The resected tumor was a pedunculated pleural mass, yellowish in color, and pathological diagnosis confirmed a lipoma. We describe the first known successful treatment by single port VATS. PMID- 22208691 TI - Surgical pitfalls in patients with Ehlers-Danlos type IV: a case of spontaneous sigmoid perforation in a 17-year-old male. AB - Ehlers-Danlos syndrome (EDS) is a group of well described connective tissue disorders in which collagen production is impaired. The surgical management of affected individuals remains challenging, with no general consensus. We report a case of spontaneous sigmoid perforation in a 17-year-old Eurasian male, in whom we subsequently established the diagnosis of EDS type IV (EDS-IV). We review the literature to discuss the clinical features and diagnosis, and the recommended therapeutic management. PMID- 22208692 TI - The impact of frozen sections on final surgical margins in squamous cell carcinoma of the oral cavity and lips: a retrospective analysis over an 11 years period. AB - BACKGROUND: Taking intraoperative frozen sections (FS) is a widely used procedure in oncologic surgery. However so far no evidence of an association of FS analysis and premalignant changes in the surgical margin exists. Therefore, the aim of this study was to evaluate the impact of FS on different categories of the final margins of squamous cell carcinoma (SCC) of the oral cavity and lips. METHODS: FS, pT-stage, grading, and tumor localization of 178 patients with SCC of the oral cavity and lips were compared by uni- and multivariate analysis in patients with positive, dysplastic and negative surgical margin status. RESULTS: Performed on 111 patients (62.4%), intraoperative FS did not have any statistically significant influence on final margin status, independent of whether it was positive (p = 0.40), dysplastic (p = 0.70), or negative (p = 0.70). Positive surgical margins in permanent sections were significantly associated with pT4 tumors (OR 5.61, p = 0.001). The chance for negative margins in permanent sections was significantly higher in tumors located in the tongue (OR 4.70, p = 0.01). CONCLUSIONS: Our data suggests that intraoperative FS in SCC can be useful in selected cases. However it is not advisable as a routine approach. PMID- 22208693 TI - Silica nanoparticles for the layer-by-layer assembly of fully electro-active cytochrome c multilayers. AB - BACKGROUND: For bioanalytical systems sensitivity and biomolecule activity are critical issues. The immobilization of proteins into multilayer systems by the layer-by-layer deposition has become one of the favorite methods with this respect. Moreover, the combination of nanoparticles with biomolecules on electrodes is a matter of particular interest since several examples with high activities and direct electron transfer have been found. Our study describes the investigation on silica nanoparticles and the redox protein cytochrome c for the construction of electro-active multilayer architectures, and the electron transfer within such systems. The novelty of this work is the construction of such artificial architectures with a non-conducting building block. Furthermore a detailed study of the size influence of silica nanoparticles is performed with regard to formation and electrochemical behavior of these systems. RESULTS: We report on interprotein electron transfer (IET) reaction cascades of cytochrome c (cyt c) immobilized by the use of modified silica nanoparticles (SiNPs) to act as an artificial matrix. The layer-by-layer deposition technique has been used for the formation of silica particles/cytochrome c multilayer assemblies on electrodes. The silica particles are characterized by dynamic light scattering (DLS), Fourier transformed infrared spectroscopy (FT-IR), Zeta-potential and transmission electron microscopy (TEM). The modified particles have been studied with respect to act as an artificial network for cytochrome c and to allow efficient interprotein electron transfer reactions. We demonstrate that it is possible to form electro-active assemblies with these non-conducting particles. The electrochemical response is increasing linearly with the number of layers deposited, reaching a cyt c surface concentration of about 80 pmol/cm2 with a 5 layer architecture. The interprotein electron transfer through the layer system and the influence of particle size are discussed. CONCLUSIONS: This study demonstrates the ability to construct fully electro-active cyt c multilayer assemblies by using carboxy-modified silica nanoparticles. Thus it can be shown that functional, artificial systems can be build up following natural examples of protein arrangements. The absence of any conductive properties in the second building block clearly demonstrates that mechanisms for electron transfer through such protein multilayer assemblies is based on interprotein electron exchange, rather than on wiring of the protein to the electrode.The construction strategy of this multilayer system provides a new controllable route to immobilize proteins in multiple layers featuring direct electrochemistry without mediating shuttle molecules and controlling the electro-active amount by the number of deposition steps. PMID- 22208698 TI - External morphology and ultra-structure of eggs and first instar of Prepona laertes laertes (Hubner, [1811]), with notes on host plant use and taxonomy. AB - The external morphology and the tegument ultra-structure of Prepona laertes laertes (Hubner, [1811]) (Lepidoptera: Nymphalidae: Charaxinae) eggs and first instar larvae feeding on Inga spp. (Fabaceae) in a forest fragment in Joinville, Santa Catarina, Brazil, are described. Descriptions of the morphology with illustrations are presented, based upon observations through scanning electron microscopy and stereoscopic and optic microscopes attached to a camera lucida. Descriptions and illustrations of the head capsule, chaetotaxy, tegument, and setae are presented. The taxonomy, morphological characters, and host plant use of Prepona laertes immature stages are discussed. PMID- 22208697 TI - Investigation of the catalytic mechanism of the hotdog-fold enzyme superfamily Pseudomonas sp. strain CBS3 4-hydroxybenzoyl-CoA thioesterase. AB - The 4-hydroxybenzoyl-CoA (4-HB-CoA) thioesterase from Pseudomonas sp. strain CBS3 catalyzes the final step of the 4-chlorobenzoate degradation pathway, which is the hydrolysis of 4-HB-CoA to coenzyme A (CoA) and 4-hydroxybenzoate (4-HB). In previous work, X-ray structural analysis of the substrate-bound thioesterase provided evidence of the role of an active site Asp17 in nucleophilic catalysis [Thoden, J. B., Holden, H. M., Zhuang, Z., and Dunaway-Mariano, D. (2002) X-ray crystallographic analyses of inhibitor and substrate complexes of wild-type and mutant 4-hydroxybenzoyl-CoA thioesterase. J. Biol. Chem. 277, 27468-27476]. In the study presented here, kinetic techniques were used to test the catalytic mechanism that was suggested by the X-ray structural data. The time course for the multiple-turnover reaction of 50 MUM [(14)C]-4-HB-CoA catalyzed by 10 MUM thioesterase supported a two-step pathway in which the second step is rate limiting. Steady-state product inhibition studies revealed that binding of CoA (K(is) = 250 +/- 70 MUM; K(ii) = 900 +/- 300 MUM) and 4-HB (K(is) = 1.2 +/- 0.2 mM) is weak, suggesting that product release is not rate-limiting. A substantial D(2)O solvent kinetic isotope effect (3.8) on the steady-state k(cat) value (18 s(-1)) provided evidence that a chemical step involving proton transfer is the rate-limiting step. Taken together, the kinetic results support a two-chemical pathway. The microscopic rate constants governing the formation and consumption of the putative aspartyl 17-(4-hydroxybenzoyl)anhydride intermediate were determined by simulation-based fitting of a kinetic model to time courses for the substrate binding reaction (5.0 MUM 4-HB-CoA and 0.54 MUM thioesterase), single turnover reaction (5 MUM [(14)C]-4-HB-CoA catalyzed by 50 MUM thioesterase), steady-state reaction (5.2 MUM 4-HB-CoA catalyzed by 0.003 MUM thioesterase), and transient-state multiple-turnover reaction (50 MUM [(14)C]-4-HB-CoA catalyzed by 10 MUM thioesterase). Together with the results obtained from solvent (18)O labeling experiments, the findings are interpreted as evidence of the formation of an aspartyl 17-(4-hydroxybenzoyl)anhydride intermediate that undergoes rate limiting hydrolytic cleavage at the hydroxybenzoyl carbonyl carbon atom. PMID- 22208704 TI - Guest comment: Environmental genomics focus issue. PMID- 22208705 TI - Trigger release liposome systems: local and remote controlled delivery? AB - Target-specific delivery has become an integral area of research in order to increase bioavailability and reduce the toxic effects of drugs. As a drug delivery option, trigger-release liposomes offer sophisticated targeting and greater control-release capabilities. These are broadly divided into two categories; those that utilise the local environment of the target site where there may be an upregulation in certain enzymes or a change in pH and those liposomes that are triggered by an external physical stimulus such as heat, ultrasound or light. These release mechanisms offer a greater degree of control over when and where the drug is released; furthermore, targeting of diseased tissue is enhanced by incorporation of target-specific components such as antibodies. This review aims to show the development of such trigger release liposome systems and the current research in this field. PMID- 22208706 TI - Preparation and in vitro evaluation of salbutamol-loaded lipid microparticles for sustained release pulmonary therapy. AB - The aim of this study was to prepare lipid microparticles (LMs) loaded with the polar bronchodilator agent salbutamol, and designed for sustained release pulmonary delivery. The microparticles were produced by melt emulsification followed by a sonication step, using different biocompatible lipid carriers (tristearin, stearic acid and glyceryl behenate) and phosphatidylcholine as the surfactant. The use of salbutamol free base, rather than salbutamol sulphate, was necessary to obtain the incorporation of the drug in the lipid particle matrix. The prolonged release of salbutamol base was achieved only by the glyceryl behenate microparticles (40.9% of encapsulated drug being released after 8 h). The salbutamol loading was 4.2% +/- 0.1 and the mass median diameter, determined by laser diffraction, ranged from 4.8 to 5.4 um. The sustained release of LMs were formulated as a carrier-free dry powder for inhalation and exhibited a fine particle fraction of 17.3% +/- 2.2, as measured by multi-stage liquid impinger. PMID- 22208708 TI - Technologies applied to diabetes. PMID- 22208709 TI - External insulin pump treatment in the day-to-day management of diabetes: benefits and future prospectives. AB - The aim of diabetes treatment is to achieve tight glucose control to avoid the development of chronic diabetes complications while reducing the frequency of hypoglycaemic episodes. The main clinical indications of pump therapy in type 1 diabetes are persistently elevated HbA(1c) in spite of the best attempts of intensified insulin therapy with multiple daily injections (MDI) and/or frequent, disabling or severe hypoglycaemia. Several trials have demonstrated the superiority of continuous subcutaneous insulin infusion (CSII) over MDI, and highlighted the benefits of using short-acting insulin analogues. However, new MDI regimens with long-acting insulin analogues challenge insulin pump therapy in some indications, thus indicating the need for precise selection of those patients who will benefit the most from CSII. In type 2 diabetes, pump therapy may be an invaluable tool in selected patients characterized by chronic elevation of HbA(1c), obesity and high insulin requirements. In addition, in any case, specific education, training and ongoing evaluation of the benefit/risk ratio of the treatment are mandatory. Furthermore, there is continuing progress in the development of pump and catheter features, and insulin kinetics can still be improved. These technical advances are part of the work in progress towards developing closed-loop systems. PMID- 22208707 TI - The impact of injuries study. multicentre study assessing physical, psychological, social and occupational functioning post injury--a protocol. AB - BACKGROUND: Large numbers of people are killed or severely injured following injuries each year and these injuries place a large burden on health care resources. The majority of the severely injured are not fully recovered 12-18 months later. Psychological disorders are common post injury and are associated with poorer functional and occupational outcomes. Much of this evidence comes from countries other than the UK, with differing health care and compensation systems. Early interventions can be effective in treating psychological morbidity, hence the scale and nature of the problem and its impact of functioning in the UK must be known before services can be designed to identify and manage psychological morbidity post injury. METHODS/DESIGN: A longitudinal multi-centre study of 680 injured patients admitted to hospital in four areas across the UK: Nottingham, Leicester/Loughborough, Bristol and Surrey. A stratified sample of injuries will ensure a range of common and less common injuries will be included. Participants will complete a baseline questionnaire about their injury and pre-injury quality of life, and follow-up questionnaires 1, 2, 4, and 12 months post injury. Measures will include health and social care utilisation, perceptions of recovery, physical, psychological, social and occupational functioning and health-related quality of life. A nested qualitative study will explore the experiences of a sample of participants, their carers and service providers to inform service design. DISCUSSION: This study will quantify physical, psychological, social and occupational functioning and health and social care utilisation following a range of different types of injury and will assess the impact of psychological disorders on function and health service use. The findings will be used to guide the development of interventions to maximise recovery post injury. PMID- 22208710 TI - Improving diabetes management with electronic medical records. AB - Most primary-care physicians have adopted electronic medical records (EMRs) for the management of patients in ambulatory care. Observational trials suggest that the use of EMRs improves the achievement of the recommended standards of diabetes care and intermediate outcomes. A French group of general practitioners has shown, in a randomized controlled trial of diabetes care, the beneficial effects of a follow-up module integrated into an EMR. Electronic reminders, eHealth technology and e-mail messaging to patients integrated into the EMR have also been reported to have a beneficial effect on diabetes care. Some recommendations have been devised for the meaningful use of EMRs to improve the process and, possibly, intermediate outcomes of diabetes care as well. Another potential benefit to consider is the extraction and aggregation of data to create diabetes registers. Large regional and national diabetes registers have been set up in the US and Europe for various purposes, including patient recall, description of care patterns and outcomes, improvement of practices, drug safety, observational research and retrospective trials. In France, the government initiative towards an Internet-based personal health record (PHR) provides an appropriate framework for implementing and sharing the information needed to improve diabetes care, such as electronic summaries of health information, personalized health plans (PHPs), and standardized and structured hospital-discharge forms. All of these materials can be generated from EMRs. The widespread and optimalized use of EMRs for diabetes care with links to the national diabetes register and the capacity to supply PHRs are major considerations. Achieving these goals requires a common initiative comprising primary care and diabetes scientific societies in cooperation with diabetes patients'associations. PMID- 22208711 TI - Improving diabetes management with electronic health records and patients' health records. AB - The lack of patient engagement and clinical inertia both contribute to suboptimal diabetes care. However, both obstacles are amenable to informatics- and Internet based interventions. The use of electronic medical records (EMRs) is now established as being useful for improving diabetes care. Intelligent records that integrate computerized decision-support systems are now able to recommend care protocols tailored to risk levels. Web-based personal health record (PHR) systems, shared with healthcare providers, could also provide added value by promoting self-management of the behaviours related to diabetes. These Web-based programmes include patients' access to EMRs, uploading of glucose monitoring results, a glucose diary, secure e-mail with providers, manual or automated feedback on blood glucose readings and other risk factors, an educational website, and an online diary for entering personal information on exercise, diet and medication. The integration of Web-based patients' systems into the EMR used by physicians is the next frontier. In addition, the input from "smartphones" that are able to provide real-time support to patients could contribute to the reorganization of diabetes care. Convincing data on HbA(1c) improvements with such systems are available for type 2 diabetes, but are still equivocal for type 1 diabetes. Obstacles include patients' compliance with the technology, their ergonomic design and the need to reimburse providers for their care. Designing appropriate electronic tools and tailoring them to the conditions in France merits our attention. PMID- 22208712 TI - How technology has changed diabetes management and what it has failed to achieve. AB - Tremendous improvements have modified diabetes management from pure clinical diagnosis and the discovery of insulin to continuous subcutaneous insulin infusion (CSII) coupled with continuous glucose monitoring (CGM) to allow patients to adapt insulin delivery to glycaemia on a virtually "real-time" basis. Insulin was first discovered in 1923 and, in less than a century, it has been purified, humanized and now synthesized by genetically modified microorganisms. Insulin analogue, kinetics and reproducibility now allow near-normal glycaemia to be targeted without increasing hypoglycaemia, thus allowing greater flexibility in the patient's day-to-day life. In addition, advances have been made over the past few decades in the development of the necessary and complementary technologies for insulin infusion, glucose measurement, glucose insulin interaction and telemedicine. The major remaining limitations are the lack of glycaemic regulation on insulin administration and the burden of parenteral delivery. Thus, the dream of both patients and diabetologists is to close the loop and to build an artificial pancreas. PMID- 22208713 TI - Emergent technologies applied to diabetes: what do we need to integrate continuous glucose monitoring into daily practice? Where the long-term use of continuous glucose monitoring stands in 2011. AB - The earliest continuous glucose monitoring (CGM) devices did not permit real-time readouts of glucose measurements. Instead, they were used to determine the glucose profile of patients in "real life" and as educational tools. In contrast, the latest real-time devices, whether linked or not to an insulin pump, give the patient access to glucose measurements and incorporate alarms that can be set. Thus, they are the newest self-management tools for patients with type 1 diabetes requiring an intensive insulin regimen. Some long-term studies in a selected population of patients with type 1 diabetes have shown improvement of glycaemic control as measured by HbA(1c). Although the characteristics of "responsive" patients have yet to be identified, the ability of the patient to use the system on a near-daily basis (about 80% of the time) is a key point. Initial training of the patient by a professional team with expertise in CGM is also of the utmost importance. To date, CGM is not reimbursed by Social Security in France. PMID- 22208714 TI - Telemedicine: what more is needed for its integration in everyday life? AB - The Health Authorities have huge expectations of telemedicine (TM): improved patient access to healthcare, a solution to the shortage of doctors in the face of an exponentially expanding disease, and reduced healthcare costs with improved quality. There are a host of applications for TM in the area of diabetes. TM has been validated and has been widely used to screen for diabetic retinopathy, and a number of studies are currently underway for the follow-up of diabetic foot ulcers. However, the main indication of TM remains the follow-up and control of blood glucose. In this area, many studies have been conducted to improve glycaemic control. While most of these studies have failed to show any benefits vs. conventional care, a small number have demonstrated great efficacy of this approach with regard to glycaemia. Using these studies, we attempt to define the key qualities of a successful TM system. How can we extend the results of these experiments beyond the framework of clinical studies and integrate them in daily practice so as to improve diabetes management? This is the key challenge for TM, implementation of which will require reorganization of healthcare, given the evolution of medical demographics. This reorganization will involve healthcare providers specialized in diabetes that may intervene in assigning physicians for especially distressed patients. However, such reorganization will require medico economic evaluation before it can be implemented on a larger scale. PMID- 22208715 TI - What do patients with diabetes and diabetologists--especially those in private practice--expect from the new technologies for diabetes care in the future? AB - Thanks to the high volume of patients'consultations delivered, and especially in private practice, diabetologists are able to accurately describe the expectations of diabetic patients with the new and mostly future technologies. In addition, diabetologists are also able to imagine how these technologies will change their medical practices in future. PMID- 22208716 TI - Is continuous glucose monitoring (CGM) for everyone? To whom should CGM be prescribed and how? AB - Are all type 1 diabetes (T1DM) patients potential candidates for continuous glucose monitoring (CGM)? Clearly, some patients improve their metabolic control with this tool, such as adults with poor metabolic control, especially those treated with continuous subcutaneous insulin infusion (CSII), and compliant patients with HbA(1c) levels <7%. There are also less good candidates for CGM, such as patients aged 8-18 years because they are reluctant to wear the sensors or those with new-onset T1DM. Other patient groups have not yet been evaluated, such as patients aged <8 years, women during pregnancy, and those with HbA(1c) >10% and/or severe hypoglycaemia. Beyond the indications, the mode of use of CGM is crucial. An appropriate patient selection, in order to choose those able to run the tool and motivated to use it, is necessary. How to prescribe the sensors is also an important question. Two approaches have been compared: patient-led and physician-driven prescription. Both modes of using CGM provide similar long-term metabolic improvement. However, physician-driven prescription is probably more cost-effective. The last key question is the education of patients by an experienced team. It can help them to translate the large amount of data from the monitor into effective self-management for optimalizing the CGM experience. However, elaboration of a validated algorithm is necessary to take full advantage of this device. PMID- 22208717 TI - Advances in pump technology: insulin patch pumps, combined pumps and glucose sensors, and implanted pumps. AB - This review discusses the most recent developments in insulin pump technology. The benefits of the insulin pump to patients with type 1 diabetes are recognized both for its metabolic effectiveness and its positive effects on quality of life. The current pumps are reliable, small and light, and are becoming more and more sophisticated. Nevertheless, there remain practical and psychological constraints for the patient. However, recent patch-pump advances should simplify the technical aspects of pump treatment and enhance patient comfort. Another advance combines the insulin pump with a glucose sensor. Such a combination is logical for optimizing pump use and, to that end, developing an automated or 'closed loop'system that permits the delivery of subcutaneous insulin adjusted according to measured levels of subcutaneous glucose. Finally, implanted insulin pumps have proven their worth not only because of their simple use, but also for their contribution in the artificial pancreas project. Indeed, the prompt response with intraperitoneal administration of insulin makes it of interest for use in a closed-loop system. PMID- 22208718 TI - Towards an artificial pancreas at home. AB - AIM: To review the recent clinical research related to the development of an artificial pancreas and the current perspectives for its home use. METHODS: All clinical investigations assessing closed-loop insulin delivery systems in diabetic patients in the literature were collected and analyzed to identify any significant advances as well as bottlenecks. RESULTS: The development of an artificial pancreas for ambulatory use offering an optimal substitute for insulin secretion has shown promising evolution over the past decade. The accumulated improvements achieved on the performance of insulin pumps using subcutaneous and intraperitoneal routes, continuous glucose monitoring and algorithms driving insulin infusion according to glucose measurement have led to numerous clinical trials recently, albeit only in a hospital setting so far. The key obstacles to achieving permanent normal glucose control are related to the delay of insulin action when infused subcutaneously or, at a lesser extent, into the peritoneal cavity, and blood glucose estimation made by subcutaneous interstitial measurement. These time lags impair the reactivity of the system, and suggest a need to develop complex algorithms aiming at their compensation. So far, manual interventions are needed at times of food intake to prevent hyper- or hypoglycaemic excursions when insulin changes rapidly. CONCLUSION: The most recent models using subcutaneous insulin infusion and glucose measurements linked by predictive control algorithms offer sufficient effectiveness and safety to consider their forthcoming use at home, during the night as a first step. PMID- 22208719 TI - Dynamics of HBV cccDNA expression and transcription in different cell growth phase. AB - BACKGROUND: The covalently closed-circular DNA (cccDNA) of hepatitis B virus (HBV) is associated with viral persistence in HBV-infected hepatocytes. However, the regulation of cccDNA and its transcription in the host cells at different growth stages is not well understood. METHODS: We took advantages of a stably HBV producing cell line, 1.3ES2, and examine the dynamic changes of HBV cccDNA, viral transcripts, and viral replication intermediates in different cellular growth stages. RESULTS: In this study, we showed that cccDNA increased suddenly in the initial proliferation phase of cell growth, probably attributable to its nuclear replenishment by intracellular nucleocapsids. The amount of cccDNA then decreased dramatically in the cells during their exponential proliferation similar to the loss of extrachromosomal plasmid DNA during cell division, after which it accumulated gradually while the host cells grew to confluency. We found that cccDNA was reduced in dividing cells and could be removed when proliferating cells were subjected to long term of lamivudine (3TC) treatment. The amounts of viral replicative intermediates were rapidly reduced in these proliferating cells and were significantly increased after cells reaching confluency. The expression levels of viral transcripts were increased in parallel with the elevated expression of hepatic transcription factors (HNF4alpha, CEBPalpha, PPARalpha, etc.) during cell growth confluency. The HBV transcripts were transcribed from both integrated viral genome and cccDNA, however the transcriptional abilities of cccDNA was less efficient then that from integrated viral genome in all cell growth stages. We also noted increases in the accumulation of intracellular viral particles and the secretion of mature virions as the cells reached confluency and ceased to grow. CONCLUSIONS: Based on the dynamics of HBV replication, we propose that HBV replication is modulated differently in the different stages of cell growth, and can be divided into three phases (initial proliferation phase, exponential proliferation phase and growth confluency phase) according to the cell growth curve. The regulation of cccDNA in different cell growth phase and its importance regarding HBV replication are discussed. PMID- 22208720 TI - Primary pleural angiosarcoma as a mimicker of mesothelioma: a case report **VS**. AB - Primary pleural angiosarcoma is a rare and clinically aggressive tumor. Patients usually present with chest pain, dyspnea, hemoptysis and/or cough. Radiologic studies reveal diffuse pleural thickening and pleural effusion with or without mass lesion. The clinical and radiological features both resemble those of mesothelioma, and its definite diagnosis requires careful histologic examination. However, frequent epithelioid feature and immunoreactivity to cytokeratin in primary pleural angiosarcoma further complicate the pathologic diagnosis. The use of proper immunohistochemical stains is often needed to support endothelial differentiation in the tumor cells and to exclude metastatic carcinoma and mesothelioma. We report the case of a 49-year-old male patient with primary pleural angiosarcoma, who presented with initial hemothorax, followed by a rapid progress to an inoperable status. PMID- 22208721 TI - Successful strategies for high participation in three regional healthcare surveys: an observational study. AB - BACKGROUND: Regional healthcare facility surveys to quantitatively assess nosocomial infection rates are important for confirming standardized data collection and assessing health outcomes in the era of mandatory reporting. This is particularly important for the assessment of infection control policies and healthcare associated infection rates among hospitals. However, the success of such surveys depends upon high participation and representativeness of respondents. METHODS: This descriptive paper provides methodologies that may have contributed to high participation in a series of administrative, infection control, and microbiology laboratory surveys of all 31 hospitals in a large southern California county. We also report 85% (N = 72) countywide participation in an administrative survey among nursing homes in this same area. RESULTS: Using in-person recruitment, 48% of hospitals and nursing homes were recruited within one quarter, with 75% recruited within three quarters. CONCLUSIONS: Potentially useful strategies for successful recruitment included in-person recruitment, partnership with the local public health department, assurance of anonymity when presenting survey results, and provision of staff labor for the completion of detailed survey tables on the rates of healthcare associated pathogens. Data collection assistance was provided for three-fourths of surveys. High compliance quantitative regional surveys require substantial recruitment time and study staff support for high participation. PMID- 22208722 TI - Crystal face-dependent nanopiezotronics of an obliquely aligned InN nanorod array. AB - This paper proposes an obliquely aligned InN nanorod array to maximize nanorod deformation in the application of nanopiezotronics. The surface-dependent piezotronic I-V characteristics of the InN nanorod array with exposed polar (0002) and semipolar ( 1102) planes were studied by conductive atomic force microscopy. The effects of the piezopotential, created in the InN under straining, and the surface quantum states on the transport behavior of charge carriers in different crystal planes of the InN nanorod were investigated. The crystal plane-dependent electron density in the electron surface accumulation layer and the strain-dependent piezopotential distribution modulate the interfacial contact of the Schottky characteristics for the (0002) plane and the quasi-ohmic behavior for the ( 1102) plane. Regarding the piezotronic properties under applied forces, the Schottky barrier height increases in conjunction with the deflection force with high current density at large biases because of tunneling. The strain-induced piezopotential can thus tune the transport process of the charge carriers inside the InN nanorod over a larger range than in ZnO. The quantized surface electron accumulation layer is demonstrated to modulate the piezopotential-dependent carrier transport at the metal/InN interfaces and become an important factor in the design of InN-based piezotronic devices and nanogenerators. PMID- 22208724 TI - High performance of N-alkoxycarbonyl-imines in triethylborane-mediated tin-free radical addition. AB - Triethylborane-mediated tin-free radical alkylation of N-alkoxycarbonyl-imines, such as N-Boc-, N-Cbz-, and N-Teoc-imines, proceeded smoothly at a low temperature (-78 to -20 degrees C) to give the corresponding adducts in high yield. Although the formation of isocyanate was the major unfavorable reaction at room temperature, a one-pot conversion of N-Boc-imine to N-ethoxycarbonyl-adduct was possible through the corresponding isocyanate generated in situ. The higher performance of N-alkoxycarbonyl-imine than those of N-Ts- and N-PMP-imines is rationalized by a moderate electron-withdrawing character of an alkoxycarbonyl group that makes both addition of alkyl radical and trapping of the resulting aminyl radical by triethylborane efficiently fast. PMID- 22208725 TI - Disturbances of the hypothalamic-pituitary-adrenal axis and plasma electrolytes during experimental sepsis. AB - BACKGROUND: Sepsis continues to be a poorly understood syndrome with a high mortality rate. While we are beginning to decipher the intricate interplay of the inflammatory response during sepsis, the precise regulation of the hypothalamic pituitary-adrenal (HPA) axis and its impact on electrolyte homeostasis during sepsis remains incompletely understood. METHODS: Sepsis was induced in adult male Sprague-Dawley rats by cecal ligation and puncture (CLP). Plasma samples were obtained as a function of time (6-48 hrs) after CLP and compared with healthy animals (neg ctrl). Samples were analyzed for adrenocorticotropin (ACTH), corticosterone, and aldosterone levels, as well as concentrations of sodium (Na+), potassium (K+), chloride (Cl-), and magnesium (Mg2+). RESULTS: ACTH levels were found to be significantly reduced 6-24 hrs after CLP in comparison to baseline levels and displayed gradual recovery during the later course (24-48 hrs) of sepsis. Plasma corticosterone concentrations exhibited a bell-shaped response, peaking between 6 and 12 hrs followed by rapid decline and concentrations below negative control levels 48 hrs after injury. Aldosterone levels in septic animals were continuously elevated between 6 and 48 hrs. Whereas plasma Na+ levels were found to be persistently elevated following CLP, levels of K+, Cl- and Mg2+ were significantly reduced as a function of time and gradually recovered during the later course of sepsis. CONCLUSIONS: CLP-induced sepsis resulted in dynamic changes of ACTH, corticosterone, and aldosterone levels. In addition, electrolyte levels showed significant disturbances after CLP. These electrolyte perturbations might be evoked by a downstream effect or a dysfunctional HPA-axis response during sepsis and contribute to severe complications during sepsis. PMID- 22208726 TI - The Soviet doctor and the treatment of drug addiction: "A difficult and most ungracious task". AB - This paper reviews the development of early Soviet drug treatment approaches by focusing on the struggle for disciplinary power between leading social and mental hygienists and clinical psychiatrists as a defining moment for Soviet drug treatment speciality that became known as "narcology." From this vantage point, I engage in the examination of the rise and fall of various treatment methods and conceptualizations of addiction in Russian metropolitan centres and look at how they were imported (or not) to other Soviet republics. As clinical psychiatrists appeared as undisputed victors from the battle with social and mental hygienists, the entire narcological arsenal was subdued in order to serve the needs of mainstream psychiatry. However, what that 'mainstream' would be, was not entirely clear. When, in 1934, Aleksandr Rapoport insisted on the need for re-working narcological knowledge in line with the Marxist approach, he could only raise questions and recognise that there were almost no "dialectically illuminated scientific data" to address these questions. The maintenance treatment of opiate users, which emerged as the most effective one based on the results of a six-year study published in 1936, was definitely not attuned to the political and ideological environment of the late 1930s. Maintenance was rather considered as a temporary solution, in the absence of radical therapeutic measures to free Soviet society from "narkomania." As the Great Terror swept across the Soviet Union, Stalin's regime achieved its objective of eliminating drug addiction from the surface of public life by driving opiate users deep underground and incarcerating many of them in prisons and the Gulag camps. In the final section, I briefly discuss the changing perceptions of drug use during the World War II and outline subsequent transformations in Soviet responses to the post-war opiate addiction [Additional file 1]. PMID- 22208730 TI - Sampling scarab beetles in tropical forests: the effect of light source and night sampling periods. AB - Light traps have been used widely to sample insect abundance and diversity, but their performance for sampling scarab beetles in tropical forests based on light source type and sampling hours throughout the night has not been evaluated. The efficiency of mercury-vapour lamps, cool white light and ultraviolet light sources in attracting Dynastinae, Melolonthinae and Rutelinae scarab beetles, and the most adequate period of the night to carry out the sampling was tested in different forest areas of Costa Rica. Our results showed that light source wavelengths and hours of sampling influenced scarab beetle catches. No significant differences were observed in trap performance between the ultraviolet light and mercury-vapour traps, whereas these two methods caught significantly more species richness and abundance than cool white light traps. Species composition also varied between methods. Large differences appear between catches in the sampling period, with the first five hours of the night being more effective than the last five hours. Because of their high efficiency and logistic advantages, we recommend ultraviolet light traps deployed during the first hours of the night as the best sampling method for biodiversity studies of those scarab beetles in tropical forests. PMID- 22208729 TI - Active site substitution A82W improves the regioselectivity of steroid hydroxylation by cytochrome P450 BM3 mutants as rationalized by spin relaxation nuclear magnetic resonance studies. AB - Cytochrome P450 BM3 from Bacillus megaterium is a monooxygenase with great potential for biotechnological applications. In this paper, we present engineered drug-metabolizing P450 BM3 mutants as a novel tool for regioselective hydroxylation of steroids at position 16beta. In particular, we show that by replacing alanine at position 82 with a tryptophan in P450 BM3 mutants M01 and M11, the selectivity toward 16beta-hydroxylation for both testosterone and norethisterone was strongly increased. The A82W mutation led to a <=42-fold increase in V(max) for 16beta-hydroxylation of these steroids. Moreover, this mutation improves the coupling efficiency of the enzyme, which might be explained by a more efficient exclusion of water from the active site. The substrate affinity for testosterone increased at least 9-fold in M11 with tryptophan at position 82. A change in the orientation of testosterone in the M11 A82W mutant as compared to the orientation in M11 was observed by T(1) paramagnetic relaxation nuclear magnetic resonance. Testosterone is oriented in M11 with both the A- and D-ring protons closest to the heme iron. Substituting alanine at position 82 with tryptophan results in increased A-ring proton-iron distances, consistent with the relative decrease in the level of A-ring hydroxylation at position 2beta. PMID- 22208736 TI - Measurements of knee rotation-reliability of an external device in vivo. AB - BACKGROUND: Knee rotation plays an important part in knee kinematics during weight-bearing activities. An external device for measuring knee rotation (the Rottometer) has previously been evaluated for validity by simultaneous measurements of skeletal movements with Roentgen Stereometric Analysis (RSA). The aim of this study was to investigate the reliability of the device. METHOD: The within-day and test-retest reliability as well as intertester reliability of the device in vivo was calculated. Torques of 3, 6 and 9 Nm and the examiner's apprehension of end-feel were used at 90 degrees , 60 degrees and 30 degrees of knee flexion. Intraclass Correlation Coefficient 2,1 (ICC 2,1), 95% confidence interval (CI) of ICC and 95% CI between test trials and examiners were used as statistical tests. RESULT: ICC2,1 ranged from 0.50 to 0.94 at all three flexion angles at 6 and 9 Nm as well as end-feel, and from 0.22 to 0.75 at 3 Nm applied torque. CONCLUSION: The Rottometer was a reliable measurement instrument concerning knee rotation at the three different flexion angles (90 degrees , 60 degrees and 30 degrees ) with 6 and 9 Nm applied torques as well as the examiner's apprehension of end-feel. Three Nm was not a reliable torque. The most reliable measurements were made at 9 Nm applied torque. PMID- 22208735 TI - Nandrolone normalizes determinants of muscle mass and fiber type after spinal cord injury. AB - Spinal cord injury (SCI) results in atrophy of skeletal muscle and changes from slow oxidative to fast glycolytic fibers, which may reflect reduced levels of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), increased myostatin signaling, or both. In animals, testosterone reduces loss of muscle fiber cross-sectional area and activity of enzymes of energy metabolism. To identify the molecular mechanisms behind the benefits of androgens on paralyzed muscle, male rats were spinal cord transected and treated for 8 weeks with vehicle, testosterone at a physiological replacement dose, or testosterone plus nandrolone, an anabolic steroid. Treatments were initiated immediately after SCI and continued until the day animals were euthanized. In the SCI animals, gastrocnemius muscle mass was significantly increased by testosterone plus nandrolone, but not by testosterone alone. Both treatments significantly reduced nuclear content of Smad2/3 and mRNA levels of activin receptor IIB and follistatin-like 3. Testosterone alone or with nandrolone reversed SCI-induced declines in cellular and nuclear levels of PGC-1alpha protein and PGC-1alpha mRNA levels. For PGC-1alpha target genes, testosterone plus nandrolone partially reversed SCI-induced decreases in levels of proteins without corresponding increases in their mRNA levels. Thus, the findings demonstrate that following SCI, signaling through activin receptors and Smad2/3 is increased, and that androgens suppress activation of this signaling pathway. The findings also indicate that androgens upregulate PGC-1alpha in paralyzed muscle and promote its nuclear localization, but that these effects are insufficient to fully activate transcription of PGC-1alpha target genes. Furthermore, the transcription of these genes is not tightly coupled with their translation. PMID- 22208738 TI - Measuring combined exposure to environmental pressures in urban areas: an air quality and noise pollution assessment approach. AB - This study presents a methodological scheme developed to provide a combined air and noise pollution exposure assessment based on measurements from personal portable monitors. Provided that air and noise pollution are considered in a co exposure approach, they represent a significant environmental hazard to public health. The methodology is demonstrated for the city of Thessaloniki, Greece. The results of an extensive field campaign are presented and the variations in personal exposure between modes of transport, routes, streets and transport microenvironments are evaluated. Air pollution and noise measurements were performed simultaneously along several commuting routes, during the morning and evening rush hours. Combined exposure to environmental pollutants is highlighted based on the Combined Exposure Factor (CEF) and Combined Dose and Exposure Factor (CDEF). The CDEF takes into account the potential relative uptake of each pollutant by considering the physical activities of each citizen. Rather than viewing environmental pollutants separately for planning and environmental sustainability considerations, the possibility of an easy-to-comprehend co exposure approach based on these two indices is demonstrated. Furthermore, they provide for the first time a combined exposure assessment to these environmental pollutants for Thessaloniki and in this sense they could be of importance for local public authorities and decision makers. A considerable environmental burden for the citizens of Thessaloniki, especially for VOCs and noise pollution levels is observed. The material herein points out the importance of measuring public health stressors and the necessity of considering urban environmental pollution in a holistic way. PMID- 22208737 TI - Environmental and lifestyle factors affect benzene uptake biomonitoring of residents near a petrochemical plant. AB - BACKGROUND: We monitored urinary benzene excretion to examine factors affecting benzene uptake in a sample of the general population living near a petrochemical plant. METHODS: Our study population included 143 subjects: 33 petrochemical plant workers (W) with low level occupational benzene exposure; 30 residents in a small town 2 km from the plant (2kmR); 26 residents in a second small town located 2 to 4 km from the plant (4kmR); and 54 urban residents 25km from the plant (25kmR). Exposure to benzene was evaluated by personal air sampling during one work-shift for the W group, and from 8.00 to 20:00 for general population subgroups, and by urinary benzene (BEN-U). RESULTS: Median airborne benzene exposure was 25, 9, 7 and 6 MUg/m(3) benzene among the W, 2kmR, 4kmR, and 25kmR subgroups, respectively; the highest level was found among the workers, while there was no significant difference among the other groups. Median BEN-U was 2 to 14-fold higher in smokers compared to non-smokers; among non-smokers BEN-U was the highest in W (median 236 ng/L), and lower in the 2kmR (48 ng/L) and 4kmR (63 ng/L) subgroups than in the 25kmR (120 ng/L) subgroup. A multiple linear regression analysis, explaining up to 73% of BEN-U variability, confirmed that active smoking and airborne benzene most strongly affected BEN-U. Among the non smoking, non-occupationally exposed study subjects, a positive association was found between BEN-U and the distance of residence from the plant. This association was explained by increased exposure to urban traffic emissions in the study group residing at a greater distance from the plant. Environmental tobacco smoke had a marginally positive role. CONCLUSION: Among factors affecting benzene uptake in non-occupationally exposed individuals, urban residence contributes to benzene exposure more than residing in close proximity to a petrochemical plant. PMID- 22208739 TI - Highly elevated levels of perfluorooctane sulfonate and other perfluorinated acids found in biota and surface water downstream of an international airport, Hamilton, Ontario, Canada. AB - Per- and poly-fluorinated compounds (PFCs), which include perfluorinated carboxylates (PFCAs) and sulfonates (PFSAs) and various precursors, are used in a wide variety of industrial, commercial and domestic products. This includes aqueous film forming foam (AFFF), which is used by military and commercial airports as fire suppressants. In a preliminary assessment prior to this study, very high concentrations (>1 ppm wet weight) of the PFSA, perfluorooctane sulfonate (PFOS), were discovered in the plasma of snapping turtles (Chelydra serpentina) collected in 2008 from Lake Niapenco in southern Ontario, Canada. We presently report on a suite of C(6) to C(15) PFCAs, C(4), C(6), C(8) and C(10) PFSAs, several PFC precursors (e.g. perfluorooctane sulfonamide, PFOSA), and a cyclic perfluorinated acid used in aircraft hydraulic fluid, perfluoroethylcyclohexane sulfonate (PFECHS) in surface water from the Welland River and Lake Niapenco, downstream of the John C. Munro International Airport, Hamilton, Ontario, Canada. Amphipods, shrimp, and water were sampled from the Welland River and Lake Niapenco, as well as local references. The same suite of PFCs in turtle plasma from Lake Niapenco was compared to those from other southern Ontario sites. PFOS dominated the sum PFCs in all substrates (e.g., >99% in plasma of turtles downstream the Hamilton Airport, and 72.1 to 94.1% at all other sites). PFOS averaged 2223(+/-247.1SE) ng/g in turtle plasma from Lake Niapenco, and ranged from 9.0 to 171.4 elsewhere. Mean PFOS in amphipods and in water were 518.1(+/-83.8)ng/g and 130.3(+/-43.6) ng/L downstream of the airport, and 19.1(+/-2.7) ng/g and 6.8(+/-0.5) ng/L at reference sites, respectively. Concentrations of selected PFCs declined with distance downstream from the airport. Although there was no known spill event or publicly reported use of AFFF associated with a fire event at the Hamilton airport, the airport is a likely major source of PFC contamination in the Welland River. PMID- 22208740 TI - Soil-plant-animal transfer models to improve soil protection guidelines: a case study from Portugal. AB - Food chain models are essential tools to assess risks of soil contamination in view of product quality including fodder crops and animal products. Here we link soil to plant transfer (SPT) models for potentially toxic elements (PTEs) including As, Ba, Cd, Co, Cu, Hg, Ni, Pb, Sb, U and Zn with models describing accumulation in animal organs. Current EU standards for food products and acceptable daily intake levels (ADI) for humans were used as critical limits. The combined model is used to assess the impact of soil contamination on animal health, product quality and human health using data from 100 arable fields. Results indicate that 42 existing arable fields near industrial and mining sites are unsuitable for animal grazing in view of food safety due to elevated intake of Cd, Cu, Hg and Pb by cows and sheep. At 10 sites daily intake levels of As by cows exceeded threshold concentrations regarding the quality of animal products. The food chain model also was used inversely to derive soil threshold concentrations in view of EU fodder standards. Calculated threshold levels in soil for As, Cd, Cu, Pb, Hg and Zn appear to be in line with those proposed or used in other EU countries. As such the approach applied here can form a conceptual basis for a more harmonized risk assessment strategy regarding the protection of animal and human health. PMID- 22208741 TI - Human health effects of residual carbon nanotubes and traditional water treatment chemicals in drinking water. AB - The volume of industrial and domestic wastewater is increasing significantly year by year with the change in the lifestyle based on mass consumption and mass disposal brought about by the dramatic development of economies and industries. Therefore, effective advanced wastewater treatment is required because wastewater contains a variety of constituents such as particles, organic materials, and emulsion depending on the resource. However, residual chemicals that remain during the treatment of wastewaters form a variety of known and unknown by products through reactions between the chemicals and some pollutants. Chronic exposure to these by-products or residual chemicals through the ingestion of drinking water, inhalation and dermal contact during regular indoor activities (e.g., showering, bathing, cooking) may pose cancer and non-cancer risks to human health. For example, residual aluminium salts in treated water may cause Alzheimer's disease (AD). As for carbon nanotubes (CNTs), despite their potential impacts on human health and the environment having been receiving more and more attention in the recent past, existing information on the toxicity of CNTs in drinking water is limited with many open questions. Furthermore, though general topics on the human health impacts of traditional water treatment chemicals have been studied, no comparative analysis has been done. Therefore, a qualitative comparison of the human health effects of both residual CNTs and traditional water treatment chemicals is given in this paper. In addition, it is also important to cover and compare the human health effects of CNTs to those of traditional water treatment chemicals together in one review because they are both used for water treatment and purification. PMID- 22208742 TI - Levels of dechlorane plus and polybrominated diphenylethers in human milk in two Canadian cities. AB - Flame retardant dechlorane plus (DP) and several polybrominated diphenylether (PBDE) congeners have been measured in 87 human milk samples collected in two Canadian cities: Kingston and Sherbrooke. The levels of PBDEs in human milk (mean (median), ng g(-1) lipid weight=10 (5.9), 4.1 (2.8), 3.0 (1.6), 5.12 (1.6), and 15 (ND) for BDE-47, BDE-99, BDE-100, BDE-153, and BDE-209, respectively) were comparable to those reported in Europe, U.S.A. and China. The levels of DP, with a mean value of 0.98 ng g(-1) and a median value of 0.60 ng g(-1) (lipid weight), were two to ten times lower than those of concurrently measured major PBDEs including BDE-209. While there is little difference in the levels of measured contaminants in milk samples collected from the two cities, the contaminants levels in human milk show, indicated by Principal Components Analysis, that DP, deca-BDE, and penta-BDE come from three distinct sources. The mean and median isomer ratio values of DP in milk were 0.67 and 0.69, respectively, very similar to that of DP commercial products. PMID- 22208743 TI - Linking empirical estimates of body burden of environmental chemicals and wellness using NHANES data. AB - Biomonitoring of industrial chemicals in human tissues and fluids has shown that all people carry a "body burden" of synthetic chemicals. Although measurement of an environmental chemical in a person's tissues/fluids is an indication of exposure, it does not necessarily mean the exposure concentration is sufficient to cause an adverse effect. Since humans are exposed to multiple chemicals, there may be a combination effect (e.g., additive, synergistic) associated with low level exposures to multiple classes of contaminants, which may impact a variety of organ systems. The objective of this research is to link measures of body burden of environmental chemicals and a "holistic" measure of wellness. The approach is demonstrated using biomonitoring data from the National Health and Nutrition Examination Surveys (NHANES). Forty-two chemicals were selected for analysis based on their detection levels. Six biological pathway-specific indices were evaluated using groups of chemicals associated with each pathway. Five of the six pathways were negatively associated with wellness. Three non-zero interaction terms were detected which may provide empirical evidence of crosstalk across pathways. The approach identified five of the 42 chemicals from a variety of classes (metals, pesticides, furans, polycyclic aromatic hydrocarbons) as accounting for 71% of the weight linking body burden to wellness. Significant interactions were detected indicating the effect of smoking is exacerbated by body burden of environmental chemicals. Use of a holistic index on both sides of the exposure-health equation is a novel and promising empirical "systems biology" approach to risk evaluation of complex environmental exposures. PMID- 22208744 TI - Degradation of 17alpha-ethinylestradiol by ozonation--identification of the by products and assessment of their estrogenicity and toxicity. AB - The presence of the synthetic estrogen 17alpha-ethinylestradiol (EE2) in waters at low levels is a concern due to its ability to act as an endocrine disruptor. Ozone (O(3)) is commonly used in water treatment and reacts with EE2 to form by products having characteristics that are mostly unknown. The aim of this study was to identify the by-products of E2 and EE2 ozonation and determine their estrogenicity and toxicity relative to the parent compound. Ozonation by-products were identified via LC-MS analysis. The estrogenicity was measured using the YES assay, and toxicity was determined by monitoring effects on histology of fetal rat testes and testosterone secretion by these tissues. Two EE2 by-products were identified with open phenolic ring structures (masses 302 and 344 u). The Yeast Estrogen Screening (YES) assay showed a decreased but incomplete removal of estrogenicity after ozonation of EE2. Histological analysis of fetal testes revealed that neither E2 nor EE2, with or without ozonation, had any effect on seminiferous cord formation; however, a remarkable negative effect on testosterone secretion was observed, with EE2 by-products after ozonation showing the most rapid and extensive inhibition. These results show that the removal of EE2 via reaction with O(3) resulted in the formation of by-products that are less estrogenic (as demonstrated by the YES assay), but have a greater negative impact on testosterone secretion. Thus, the disappearance of the parent compound is not a sufficient endpoint, as the by-products created may be more toxic. Care should be taken when implementing oxidation applications such as ozone during waste water treatment. PMID- 22208745 TI - Anticancer drugs in surface waters: what can we say about the occurrence and environmental significance of cytotoxic, cytostatic and endocrine therapy drugs? AB - This study considers the implications and research needs arising from anticancer (also referred to as antineoplastic) drugs being released into the aquatic environment, for the entire therapeutic classes used: cytotoxic, cytostatic and endocrine therapy drugs. A categorization approach, based on French consumption amounts, allowed to highlight parent molecules and several metabolites on which further occurrence and ecotoxicological studies should be conducted. Investigations of consumption trends at a national and a local scale show an increase in the use of anticancer drugs between 2004 and 2008, thus leading to increased levels released in the environment. It therefore appears necessary to continue surveying their presence in surface waters and in wastewater treatment plant (WWTP) effluents. Furthermore, due to the rise of anticancer home treatments, most of the prescribed molecules are now available in town pharmacies. Consequently, hospital effluents are no longer the main expected entry route of anticancer drugs into the aquatic environment. Concerning ecotoxicological risks, current knowledge remains insufficient to support a definitive conclusion. Risk posed by cytotoxic molecules is still not well documented and it is not possible to conclude on their long-term effects on non target organisms. To date, ecotoxicological effects have been assessed using standardized or in vitro assays. Such tests however may not be suitable for anticancer drugs, and further work should focus on full-life cycle or even multigenerational tests. Environmental significance (i.e. occurrence and effects) of cytostatics (protein kinases inhibitors and monoclonal antibodies), if any, is not documented. Protein kinases inhibitors, in particular, deserve further investigation due to their universal mode of action. Finally, concerning endocrine therapy drugs, molecules such as antiestrogen Tamoxifen and its active metabolites, could be of concern. Overall, to accurately assess the ecotoxicological risk of anticancer drugs, we discuss the need to break away from tests on isolated molecules and to test effects of mixtures at the low ng.l(-1) range. PMID- 22208746 TI - Brominated flame retardants and polychlorinated biphenyls in human breast milk from several locations in India: potential contaminant sources in a municipal dumping site. AB - This study investigated the status of contamination of organohalogen compounds (OCs) such as polychlorinated biphenyls (PCBs) and brominated flame retardant (BFRs), including polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecanes (HBCDs) in human milk samples from several locations in India. The levels of OCs were significantly higher in the milk of mothers living in and near municipal dumping site than other locations indicating that the open dumping sites for municipal wastes act as potential sources of these contaminants in India. The PCB concentrations observed in this study tended to decrease compared to those in the matched locations reported previously, probably due to the restriction of technical PCB usage in India. PBDE levels in human milk were two to three folds lower than those of PCBs in all the sampling locations investigated. Congener profiles of PCBs and PBDEs were different between samples from the dumping site mothers and general populations in other areas suggesting the presence of region-specific sources and pathways. HBCDs were detected in human milk from only two sites, with much lower concentrations and detection frequencies compared to PCBs and PBDEs. When hazard quotients (HQs) of PCBs and PBDEs were estimated for infant health risk, the HQs in some milk samples from the dumping site exceeded the threshold value (HQ>1) of PCBs, indicating the potential risk for infants in the specific site. PMID- 22208747 TI - Ambient nitrogen oxides exposure and early childhood respiratory illnesses. AB - Acute respiratory infections are common in children below 5 years and recent studies suggest a possible link with air pollution. In this study, we investigated the association between ambient nitrogen oxides (NO(x)) and bronchitis or upper airway inflammation. This longitudinal study was conducted in Teplice and Prachatice districts, Czech Republic. Children were followed from birth to 4.5 years of age. Data were compiled from medical records at delivery and at follow up, and from self-administered questionnaires from the same two time points. Air pollution monitoring data were used to estimate exposure over five different averaging periods ranging from three to 45 days prior to an episode. To quantify the association between exposure and outcome, while accounting for repeated measure correlation we conducted logistic regression analysis using generalized estimating equations. During the first 2 years of life, the adjusted rate ratio for bronchitis associated with interquartile increase in the 30-day average NO(x) was 1.31 [95% confidence interval (CI): 1.07, 1.61] and for two to 4.5 year olds, it was 1.23 (95% CI: 1.01, 1.49). The 14-day exposure also had stable association across both age groups: below 2 years it was 1.25 (95% CI: 1.06, 1.47) and for two to 4.5 years it was 1.21 (95% CI: 1.06, 1.39). The association between bronchitis and NO(x) increased with child's age in the under 2 years group, which is a relatively novel finding. The results demonstrate an association between NO(x) and respiratory infections that are sufficiently severe to come to medical attention. The evidence, if causal, can be of public health concern because acute respiratory illnesses are common in preschool children. PMID- 22208748 TI - A methodology for estimating health benefits of electricity generation using renewable technologies. AB - At Copenhagen, the developed countries agreed to provide up to $100 bn per year to finance climate change mitigation and adaptation by developing countries. Projects aimed at cutting greenhouse gas (GHG) emissions will need to be evaluated against dual criteria: from the viewpoint of the developed countries they must cut emissions of GHGs at reasonable cost, while host countries will assess their contribution to development, or simply their overall economic benefits. Co-benefits of some types of project will also be of interest to host countries: for example some projects will contribute to reducing air pollution, thus improving the health of the local population. This paper uses a simple damage function methodology to quantify some of the health co-benefits of replacing coal-fired generation with wind or small hydro in China. We estimate the monetary value of these co-benefits and find that it is probably small compared to the added costs. We have not made a full cost-benefit analysis of renewable energy in China as some likely co-benefits are omitted from our calculations. Our results are subject to considerable uncertainty however, after careful consideration of their likely accuracy and comparisons with other studies, we believe that they provide a good first cut estimate of co-benefits and are sufficiently robust to stand as a guide for policy makers. In addition to these empirical results, a key contribution made by the paper is to demonstrate a simple and reasonably accurate methodology for health benefits estimation that applies the most recent academic research in the field to the solution of an increasingly important problem. PMID- 22208749 TI - Retrospective exposure assessment in a chemical research and development facility. AB - The objective of this exposure assessment was to reconstruct cumulative historical exposures for workers who have been exposed to multiple chemicals and chemical groups to better understand a cluster of brain cancers within a research and development lab. Chemicals of interest, including acrylates, bis-chloromethyl ether (BCME), chloromethyl methyl ether (CMME), isothiazolones and nitrosoamines, were selected on the basis of the plausibility of penetrating the blood-brain barrier and the uniqueness of the chemical's biological activity. In a complicated exposure setting such as a chemical R&D facility, multiple exposure estimation methods were needed. First, similarly exposure groups (SEGs) were created for these materials based on department group, time period of the department's existence and function associated with job titles. A probabilistic framework for assessing exposures was developed using Bayesian analysis of historical monitoring data, mathematical exposure modeling and professional judgments of current and former industrial hygienists at the facility were used to reconstruct the exposure history for acrylates, BCME and CMME for each SEG over the time period of interest. Since sufficient measurement data for isothiazolones and nitrosoamines were not available, the exposure histories for each SEG for these chemicals were estimated. This was done using objective formaldehyde levels and subjective employee interviews. The interviews assessed workplace determinants of exposure as distinct surrogates for estimating inhalation and dermal exposures. The exposure assessments by these methods were compared against each other to estimate the potential for exposure misclassification. A job exposure matrix (JEM) was constructed that contained the exposures obtained from above multiple approaches for each of these chemical groups for each SEG for each year of interest. The combination of methods used in this work is a unique and potentially helpful framework that can be used in analogous workplace settings involving multiple exposures with incomplete objective measurement information. PMID- 22208750 TI - Validation of the ICRP model for caesium intake by lactating mothers with Italian data after the Chernobyl fallout. AB - In the aftermath of the Chernobyl nuclear power plant accident, a research group of the Italian National Institute of Health (Istituto Superiore di Sanita) carried out two research programmes on maternal milk. One concerned the transfer of caesium radionuclides from the diet to breast milk. In the other, the activity concentrations of (137)Cs were also determined in urine and placenta. The first study estimated the mothers' average (137)Cs dietary intake, in the second study the intake was evaluated individually for each subject. In 2004, the International Commission on Radiological Protection published modified systemic biokinetic models which also account for transfer to breast milk. The model for caesium radionuclides was implemented and tested by the authors with the experimental data described above. A good agreement was obtained between measured data and model simulations of (137)Cs activity concentration in human milk. The model, however, tends to systematically overestimate (137)Cs activity concentration in urine, in which case the agreement is to be considered satisfactory in terms of order of magnitude. PMID- 22208751 TI - The influence of neighborhood traffic density on the respiratory health of elementary schoolchildren. AB - BACKGROUND: Several studies have found that living near major roadways is associated with an increase in respiratory illness but few studies have measured the volume and type of traffic. OBJECTIVE: We investigated the relation between traffic volume and respiratory health of 2328 children 9 to 11 years old in the city of Windsor, Canada. METHODS: We identified the roadways within a 200 meter radius of the child's neighborhood using the latitude and longitude of the residential postal code. Traffic exposure was defined as the sum of the annual volume of vehicles on all of these roadways. Volume was calculated using sensors to detect passing vehicles (simple traffic counts), and by counts and direction of traffic at intersections (turning movement counts). Ventilatory lung function was measured by spirometry and airway inflammation by exhaled nitric oxide (eNO). RESULTS: The odds ratio between an interquartile increase in truck turning movement counts and chest congestion was 1.20 (1.06-1.35). The percentage of predicted FVC declined 0.68%, (95% CI 1.32, 0.03) for an interquartile increase in simple traffic counts (33,787 vehicles daily). Among those with self-reported asthma, effect sizes were larger. Percentage predicted FEV(1) declined 1.84% (95% CI 0.07, 3.61) associated with an interquartile range increase in turning movement counts. No statistically significant change was detected between traffic measures and exhaled nitric oxide. CONCLUSIONS: Our findings provide further support for the hypothesis that neighborhood exposure to traffic-related air pollution increases respiratory symptoms and reduces ventilatory function in children, especially those with self-reported asthma. PMID- 22208752 TI - Comment on "Green Space, health inequality, and pregnancy". PMID- 22208753 TI - Estrogenic activity in extracts and exudates of cyanobacteria and green algae. AB - Here is presented some of the first information on interactions of compounds produced by cyanobacteria and green algae with estrogen receptor signaling. Estrogenic potency of aqueous extracts and exudates (culture spent media with extracellular products) of seven species of cyanobacteria (10 different laboratory strains) and two algal species were assessed by use of in vitro trans activation assays. Compounds produced by cyanobacteria and algae, and in particular those excreted from the cells, were estrogenic. Most exudates were estrogenic with potencies expressed at 50% of the maximum response under control of the estrogen receptor ranging from 0.2 to 7.2 ng 17beta-estradiol (E(2)) equivalents (EEQ)/L. The greatest estrogenic potency was observed for exudates of Microcystis aerigunosa, a common species that forms water blooms. Aqueous extracts of both green algae, but only one species of cyanobacteria (Aphanizomenon gracile) elicited significant estrogenicity with EEQ ranging from 15 to 280 ng 17beta-estradiol (E(2))/g dry weight. Scenedesmus quadricauda exudates and extracts of Aphanizomenon flos-aquae were antagonistic to the ER when coexposed to E(2). The EEQ potency was not correlated with concentrations of cyanotoxins, such as microcystin and cylindrospermopsin, which suggests that the EEQ was comprised of other compounds. The study demonstrates some differences between the estrogenic potency of aqueous extracts prepared from the same species, but of different origin, while the effects of exudates were comparable within species. The observed estrogenic potencies are important namely in relation to the possible mass expansion of cyanobacteria and release of the active compounds into surrounding water. PMID- 22208755 TI - Public concern over ecotoxicology risks from nanomaterials: pressing need for research-based information. PMID- 22208754 TI - Tri-decabrominated diphenyl ethers and hexabromocyclododecane in indoor air and dust from Stockholm microenvironments 2: indoor sources and human exposure. AB - Data on polybrominated diphenyl ether (PBDE) and hexabromocyclododecane (HBCD) concentrations from Stockholm, Sweden, indoor microenvironments were combined with information from detailed questionnaires regarding the sampling location characteristics, including furnishing and equipment present. These were used to elucidate relationships between possible flame-retarded sources and the contaminant concentrations found in air and dust. Median concentration ranges of SigmaPenta-, SigmaOcta-, SigmaDecaBDE and HBCD from all microenvironments were 19 570, 1.7-280, 29-3200 and <1.6-2 pg/m(3) in air and 22-240, 6.1-80, 330-1400 and 45-340 ng/g in dust, respectively. Significant correlations were found between concentrations of some PBDEs and HBCD in air and/or dust and the presence of electronic/electrical devices, foam furniture, PUF mattresses and synthetic bed pillows in, as well as floor area and construction year of the microenvironment. Car interiors were a source to indoor air in dealership halls. Using median and maximum concentrations of SigmaPenta-, SigmaOcta-, SigmaDecaBDE and HBCD in air and dust, adult and toddler (12-24 months) intakes from inhalation and dust ingestion were estimated. Toddlers had higher estimated intakes of SigmaPenta-, SigmaDecaBDE and HBCD (7.8, 43, 7.6 ng/d, respectively) from dust ingestion than adults (5.8, 38, 6.0 ng/d, respectively). Air inhalation in offices was also an important exposure pathway for SigmaPenta-, SigmaOcta- and SigmaDecaBDE in adults. For SigmaPentaBDE and HBCD, air inhalation and dust ingestion play minor roles when compared to previously published Swedish dietary intakes (median exposures). However, in worst case scenarios using maximum concentrations, dust ingestion may represent 77 and 95% of toddler intake for SigmaPentaBDE and HBCD, respectively. PMID- 22208756 TI - What is the best biomarker to assess arsenic exposure via drinking water? AB - Arsenic (As) is a ubiquitous element. The current WHO guideline for As in drinking water is 10 MUg/L. Furthermore, about 130 million people have only access to drinking water containing more than 10 g As/L. Although numerous studies have shown the related adverse effects of As, sensitive appropriate biomarkers are still required for studies of environmental epidemiology. A review of the literature has shown that various biomarkers are used for such research. Their limits and advantages are highlighted in this paper: (i) the detection of As or its derivatives in the blood is an indication of the dose ingested but it is not evidence of chronic intoxication. (ii) The detection of As in urine is an indispensible procedure because it is a good marker for internal dose. It has been demonstrated to correlate well for a number of chronic effects related to As levels in drinking water. However confounding factors must be taken into account to avoid misinterpretation and this may require As speciation. (iii) As in the hair and nails reflects the level of long term exposure but it is difficult to relate the level with the dose ingested. (iv) Some studies showed a correlation between urinary As and urinary and blood porphyrins. However, it is difficult to use only porphyrins as a biomarker in a population survey carried out without doing further studies. (v) Genotoxic effects are based on the characterization of these potential effects. Most studies have detected increases in DNA damage, sister chromatid exchange, micronuclei or chromosomal aberrations in populations exposed to As in drinking water. Micronuclei assay is the technique of choice to follow these populations, because it is sensitive and easy to use. To conclude, whatever epidemiological studies are, the urinary and toenail biomarkers are useful to provide indications of internal dose. Moreover, micronuclei assay can be complementary use as biomarker of early effects. PMID- 22208757 TI - Per- and polyfluorinated compounds (PFCs) in house dust and indoor air in Catalonia, Spain: implications for human exposure. AB - A total of 27 per- and polyfluorinated compounds (PFCs) were determined in both house dust (n=10) and indoor air (n=10) from selected homes in Catalonia, Spain. Concentrations were found to be similar or lower than those previously reported for household microenvironments in other countries. Ten PFCs were detected in all house dust samples. The highest mean concentrations corresponded to perfluorodecanoic acid (PFDA) and perfluorononanoic acid (PFNA), 10.7 ng/g (median: 1.5 ng/g) and 10.4 ng/g (median: 5.4 ng/g), respectively, while the 8:2 fluorotelomer alcohol (FTOH) was the dominating neutral PFC at a concentration of 0.41 ng/g (median: 0.35 ng/g). The indoor air was dominated by the FTOHs, especially the 8:2 FTOH at a mean (median) concentration of 51 pg/m(3) (median: 42 pg/m(3)). A limited number of ionic PFCs were also detected in the indoor air samples. Daily intakes of PFCs were estimated for average and worst case scenarios of human exposure from indoor sources. For toddlers, this resulted in average intakes of ?ionic PFCs of 4.9ng/day (0.33 ng/kg(bw)/day for a 15 kg toddlers) and ?neutral PFCs of 0.072 ng/day (0.005 ng/kg(bw)/day) from house dust. For adults, the average daily intakes of dust were 3.6 and 0.053 ng/day (0.05 and 0.001 ng/kg(bw)/day for a 70 kg adult) for ?ionic and ?neutral PFCs, respectively. The average daily inhalation of ?neutral PFCs was estimated to be 0.9 and 1.3 ng/day (0.06 and 0.02 ng/kg(bw)/day) for toddlers and adults, respectively. For PFOS, the main ionic PFC detected in indoor air samples, the median intakes (based on those samples where PFOS was detected), resulted in indoor exposures of 0.06 and 0.11 ng/day (0.004 and 0.002 ng/kg(bw)/day) for toddlers and adults, respectively. Based on previous studies on dietary intake and drinking water consumption, both house dust and indoor air contribute significantly less to PFC exposure within this population. PMID- 22208758 TI - The effect of in utero exposure to dioxins and polychlorinated biphenyls on reproductive development in eight year-old children. AB - We have previously reported on the effects of in utero exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) on thyroid function and growth hormone concentrations at birth and in two and five year-old children. Herein, we present our most recent follow up examination findings for the same cohort of children at eight-years of age. A total of 56 children (23 boys, 33 girls) were examined. Bone age (BA), hormone concentrations, and indicators of reproductive development including Tanner, breast, genital, and armpit stages were assessed. Estradiol concentrations were significantly lower in children exposed to higher levels than median of PCDD/Fs+PCBs TEQ compared to the children exposed to levels lesser than median (P=0.003). Girls exposed to higher levels than median of indicator PCBs had a significantly greater proportion in genital stage 1 and shorter fundi and uteri lengths, as compared to those exposed to low levels (P=0.025 and P<0.05, respectively). There was a significant negative relationship between estradiol concentrations and PCDD/Fs+PCB exposure level (P=0.005). After adjusting for BA, there was a significant association between fundus length and indicator PCB exposure level (P=0.034). Exposure to both high levels of SigmaPCDD/Fs+PCBs TEQ and high levels of total PCBs was associated with decreased fundus length (P=0.016) and uterus length (P=0.016). In utero exposure to high levels of PCDD/Fs and PCBs may result in lower estradiol concentrations in eight year-old children and impaired reproductive development in girls. PMID- 22208760 TI - Chronic risk assessment of exposure to volatile organic compounds in the atmosphere near the largest Mediterranean industrial site. AB - This study focuses on characterising the risk of exposure to volatile organic compounds (VOCs) by means of inhalation in people living in the vicinity of the largest chemical production site in the Mediterranean area. Eighty-six VOCs were initially selected for this study based on their adverse environmental and health effects. The monitoring campaign was conducted for 276 days in three different locations around the chemical site. The analytical method used for the characterisation was based on European standard method EN-14662-2, which consists of the active sampling of air for 24h in charcoal tubes, followed by extraction with carbon disulphide and GC-MS analysis. Forty-four VOCs with toxicological data available concerning their carcinogenic and non-carcinogenic health effects were quantified during the monitoring campaign. None of the quantified VOCs showed average concentrations exceeding their chronic reference concentrations and, therefore, no non-carcinogenic health effects are expected as a result of this exposure. However, the global average cancer risk due to VOC exposure in the area (3.3*10(-4)) was found to be above the values recommended by the WHO and USEPA. The influence of the analytical method was also evaluated by comparing cancer risk estimates using a thermal desorption (TD) method based on method EN 14662-1. The results of the 24-h samples for the solvent extraction method were compared with the average of 12 daily samples of 2-h for the TD method for 24 sampling days. Although the global estimated lifetime cancer risk was statistically comparable for both methods, some differences were found in individual VOC risks. To our knowledge, this is the first study that estimates the carcinogenic and non-carcinogenic risks posed by the inhalation of VOCs in people living near a chemical site of this size, and compares the estimated cancer risk obtained using two different standard analytical methods. PMID- 22208761 TI - The effects of conjugated estrogen, raloxifene and soy extract on collagen in rat bones. AB - OBJECTIVE: To evaluate the action of conjugated equine estrogen, raloxifene and isolated or combined genistein-rich soy extracts on collagen fibers in the bones of oophorectomized rats. MATERIALS AND METHODS: Seventy female rats received testosterone propionate (0.1 ug/g) on the 9th day after birth. At 6 months of age, the rats were administered the vehicle (propylene glycol, 0.5 ml/day), and ten of the rats were randomly chosen to comprise the non-oophorectomized control group (GI). The other 60 rats were ovariectomized and randomized into six groups of ten as follows: GII, vehicle; GIII, conjugated equine estrogen (CEE), 50 ug/kg/day; GIV, raloxifene (RAL), 0.75 mg/kg/day; GV, genistein-rich soy extract (GSE), 300 mg/kg/day; GVI, CEE + GSE, 50 ug/kg/day + 300 mg/kg/day; and GVII, CEE + RAL, 50 ug/kg/day + 0.75 mg/kg/day. Three months after surgery, the drugs were administered for 60 consecutive days. All rats were euthanized, and their left tibiae were removed for histological routine. The histological sections were stained with hematoxylin-eosin, and picrosirius for evaluating bone microarchitecture. Types I and II collagen fibers were analyzed by immunofluorescence. Data analysis was carried out with ANOVA and Tukey's test. RESULTS: Collagen reduction was significant in the GIII animals when compared to the other groups (p < 0.05). There was no significant difference in the thickness of collagen fibers among the groups. There was a greater quantity of type III collagen in GVI than in the other groups. CONCLUSION: Our data indicate that conjugated equine estrogen improves bone quality because it increases the quantity of type I collagen while reducing the quantity of thin collagen fibers. In addition, the combination of CEE and raloxifene or genistein-rich soy extract is not as efficient as CEE itself to improve bone quality. PMID- 22208759 TI - Analysis of the toxicogenomic effects of exposure to persistent organic pollutants (POPs) in Slovakian girls: correlations between gene expression and disease risk. AB - The chemical composition of persistent organic pollutants (POPs) in the environment is not uniform throughout the world, and these contaminants contain many structurally different lipophilic compounds. In a well-defined study cohort in the Slovak Republic, the POP chemicals present in the peripheral blood of exposed children were chemically analyzed. The chemical analysis data revealed that the relative concentration and profile of structurally different organic pollutants, including polychlorinated biphenyls (PCBs), 2,2'-bis(4-chlorophenyl) 1,1-dichloroethylene (p,p'-DDE), 2,2'-bis(4-chlorophenyl)-1,1,1-trichloro-ethane (p,p'-DDT), hexachlorobenzene (HCB) and beta-hexachlorocyclohexane (beta-HCH), may vary from individual to individual, even within the same exposure area. These chemicals can be broadly classified into two groups. The first group, the PCB congeners, primarily originated from industrial compounds and their byproducts. The second group of compounds originated from or was commonly used in the agricultural sector (e.g., DDT, HCB). The objective of this study was to examine the effects of the two POP exposure profiles on gene expression. For the study population, we selected pre-pubertal girls (mean age of 46.2+/-1.4 months) with high POP concentrations in their blood (>75% tile of total POP) and classified them in the high 'PCB' group when the total PCB concentration was significantly higher than the total concentration of other POP components and in the 'Other Than PCB' (OTP) group, when the total PCB concentration was significantly lower than the concentration of the other major POP constituents. A matched control group of girls (<25% tile of total POP) was selected for comparison purpose (n=5 per group). Our aims were to determine whether there were any common effects of high POP exposure at a toxicogenomic level and to investigate how exposure may affect physiological functions of the children in two different exposure scenarios. Global gene expression analysis using a microarray (Affymetrix Gene Chip Human genome U133 Plus 2.0 Array) platform was conducted on the total RNA of peripheral blood mononuclear cells from the girls. The results were analyzed by Partek GS, Louis, MI, which identified twelve genes (ATAD2B, BIVM, CD96, CXorf39, CYTH1 ETNK1, FAM13A, HIRA, INO80B, ODG1, RAD23B, and TSGA14) and two unidentified probe sets, as regulated differentially in both the PCB and OTP groups against the control group. The qRT-PCR method was used to validate the microarray results. The Ingenuity Pathway Analysis (IPA) software package identified the possible molecular impairments and disease risks associated with each gene set. Connective tissue disorders, genetic disorders, skeletal muscular disorders and neurological diseases were associated with the 12 common genes. The data therefore identified the potential molecular effects of POP exposure on a genomic level. This report underscores the importance of further study to validate the results in a random population and to evaluate the use of the identified genes as biomarkers for POP exposure. PMID- 22208762 TI - Image-guided soft-tissue foreign body extraction - success and pitfalls. AB - AIM: To outline the pitfalls for image-guided percutaneous removal of foreign bodies (FBs). MATERIALS AND METHODS: Three hundred and fifty prospective patients were referred for ultrasound imaging for FB diagnosis and percutaneous removal during 2008-2010. Those patients with suitable FBs were offered guided percutaneous removal. The procedural methods and difficulties were recorded and all outcomes were noted, including surgical success and complications. RESULTS: Sixty-three patients had a negative ultrasound for FB and they were discharged with no subsequent attendances. Of the remaining 287 patients, 12 were deemed unsuitable for percutaneous removal, 15 attempted percutaneous removals failed, and eight were not attempted due to lack of symptoms. The remaining 252 patients underwent successful retrieval and there were no procedural complications. The procedural limitations were mainly related to the anatomical site, type of FB, instrumentation, bubbles, ultrasound beam width, and mobility of the FB. CONCLUSION: Ultrasound-guided percutaneous removal of FBs is a safe and viable approach to the management of FBs achieving at least 88% success overall and with attention to the pitfalls, the learning curve should improve the success rate. PMID- 22208763 TI - Inappropriate drug prescription at nursing home admission. AB - BACKGROUND: Inappropriate prescriptions are common in older people admitted to nursing homes. Commonly used instruments to detect potential inappropriate prescriptions have limitations that have precluded wide use, and new instruments are needed. OBJECTIVE: The goal of this study was to determine the value of the Screening Tool of Older Person's potentially inappropriate Prescriptions/Screening Tool to Alert doctors to the Right, ie appropriate, indicated Treatment (STOPP-START) criteria and the Australian criteria to detect potentially inappropriate drug prescriptions in older people on admission to nursing home care. METHODS: Cross-sectional study of 100 consecutive patients (mean age 84.7 +/- 7.5 years, 80% women) admitted to 6 assisted living nursing homes, with systematic review of prescriptions used at the time of nursing home admission using the STOPP-START and the Australian criteria looking for potentially inappropriate drug treatments. RESULTS: Using the STOPP criteria, 79% of the subjects showed at least one potentially inappropriate prescription. Omissions of potentially appropriate drugs were found by the START criteria in 74% of them. The Australian criteria detected at least one potential problem in 95% of the sample. The number of subjects with 2 or more problems detected was highest using the Australian criteria (72%). The most frequent potentially inappropriately used drugs detected were proton-pump inhibitors, benzodiazepines, antipsychotic drugs, and anticholinergic drugs; many cases of duplicate medications and drug interactions were also detected. Underuse of statins and aspirin in patients with high cardiovascular risk, and of calcium and vitamin D in osteoporosis was also frequent. CONCLUSIONS: A high number of potentially inappropriate drug prescriptions can be detected at the time of admission to nursing home care by the use of systematic instruments. Both STOPP-START criteria and the Australian criteria performed well in this setting. The impact of this detection on health outcomes and costs should be assessed before they can be widely recommended. PMID- 22208764 TI - Influenza vaccination coverage among US nursing home nursing assistants: the role of working conditions. AB - OBJECTIVES: To estimate influenza vaccination coverage among nursing assistants (NAs) working in US nursing homes, and to identify demographic and occupational predictors of vaccination status among NAs. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of data on 2873 NAs from the 2004 National Nursing Assistant Survey. Multivariable-adjusted vaccination coverage (prevalence) ratios for demographic and occupational characteristics were calculated using Poisson regression. MEASUREMENTS: Outcome variable was NAs' influenza vaccination status, yes or no, based on the question, "During the past 12 months, did you receive a flu shot?" RESULTS: Coverage for all NAs working in US nursing homes was estimated to be 37.1%. NAs 45 or older were more likely to be vaccinated than younger NAs (prevalence ratio [PR] = 1.23, 95% confidence interval [CI]: 1.07 1.41). Significant negative associations with vaccination status were found for NAs who were non-Hispanic blacks (PR = 0.82, 95% CI: 0.70-0.97), disagreed that they were respected/rewarded for their work (PR = 0.85, 95% CI: 0.71-1.00), worked at for-profit facilities (PR = 0.83, 95% CI: 0.72-0.95), and reported receiving fewer than 7 of 15 nonwage job benefits (PR = 0.77, 95% CI: 0.67-0.90). CONCLUSION: Influenza coverage among nursing home NAs appears to be similar to nationally reported coverage estimates among health care providers in the United States in general. In addition to individual characteristics, occupational characteristics reflective of working conditions are associated with vaccination status among NAs, suggesting that further research into these types of associations may be useful in identifying which institutions may benefit from outreach efforts and types of interventions to increase vaccination coverage. PMID- 22208765 TI - A new strategy for better genome assembly from very short reads. AB - BACKGROUND: With the rapid development of the next generation sequencing (NGS) technology, large quantities of genome sequencing data have been generated. Because of repetitive regions of genomes and some other factors, assembly of very short reads is still a challenging issue. RESULTS: A novel strategy for improving genome assembly from very short reads is proposed. It can increase accuracies of assemblies by integrating de novo contigs, and produce comparative contigs by allowing multiple references without limiting to genomes of closely related strains. Comparative contigs are used to scaffold de novo contigs. Using simulated and real datasets, it is shown that our strategy can effectively improve qualities of assemblies of isolated microbial genomes and metagenomes. CONCLUSIONS: With more and more reference genomes available, our strategy will be useful to improve qualities of genome assemblies from very short reads. Some scripts are provided to make our strategy applicable at http://code.google.com/p/cd-hybrid/. PMID- 22208767 TI - Time-evolution of poly(3-hexylthiophene) as an energy relay dye in dye-sensitized solar cells. AB - Energy relay dyes (ERD) and Forster resonant energy transfer (FRET) are useful techniques for increasing absorption in dye-sensitized solar cells. We use femtosecond transient absorption spectroscopy to monitor charge generation processes in a solid-state DSC containing poly(3-hexylthiophene) (P3HT) as both the hole-transporter and the ERD with a zinc phthalocyanine dye (TT1) as the sensitizer. We observe efficient FRET occurring on picosecond time scales and subsequent hole transfer from TT1 to P3HT occurring onward from 100 ps. PMID- 22208766 TI - Photographic protocol for image acquisition in craniofacial microsomia. AB - Craniofacial microsomia (CFM) is a congenital condition associated with orbital, mandibular, ear, nerve, and soft tissue anomalies. We present a standardized, two dimensional, digital photographic protocol designed to capture the common craniofacial features associated with CFM. PMID- 22208768 TI - The influence of self-owned home blood pressure monitoring (HBPM) on primary care patients with hypertension: a qualitative study. AB - BACKGROUND: Home blood pressure monitoring (HBPM) is gaining popularity among hypertensive patients. This study aimed to explore the influence of self initiated HBPM on primary care patients with hypertension. METHODS: Six in-depth interviews and two focus group discussions were conducted, taking into consideration the experiences of 24 primary care patients with hypertension. These patients had been using HBPM as part of their hypertension management. The overriding influences were grouped under themes which emerged from analyzing the data using the grounded theory approach. RESULTS: There are both positive and negative influences of self-initiated HBPM. Patients used the readings of their HBPM to decide on many aspects of their hypertension management. The HBPM readings both influenced their adherence to diet and exercise and provided certain reassurance when they experienced symptoms. In addition, the act of discussing their HBPM readings with their health care providers resulted in an enhanced doctor-patient therapeutic relationship. Nevertheless, HBPM created confusion at times in some patients, particularly with regard to the target blood pressure level and the need for medication. This led to some patients making their own medical decisions based on their own standards. CONCLUSIONS: HBPM is becoming an integral part of hypertension management. Primary care patients who self-initiated HBPM reported being more self-efficacious, but lack of participation and guidance from their doctors created confusion, and hindered the true benefit of HBPM. PMID- 22208770 TI - Template-directed synthesis of nets based upon octahemioctahedral cages that encapsulate catalytically active metalloporphyrins. AB - meso-Tetra(N-methyl-4-pyridyl)porphine tetratosylate (TMPyP) templates the synthesis of six new metal-organic materials by the reaction of benzene-1,3,5 tricarboxylate with transition metals, five of which exhibit HKUST-1 or tbo topology (M = Fe, Mn, Co, Ni, Mg). The resulting materials, porph@MOMs, selectively encapsulate the corresponding metalloporphyrins in octahemioctahedral cages and can serve as size-selective heterogeneous catalysts for oxidation of olefins. PMID- 22208771 TI - Stereoselective alpha-quaternization of 3-methoxycycloalk-2-enones via 1,4 diastereoinduction of alkoxy dienolates. AB - The alkylation of dienolates generated from 3-methoxycycloalk-2-enones having a 3'-hydroxyl alkenyl chain provides the corresponding quaternized cycloalkenones in a highly diastereoselective manner. The high degree of stereocontrol in the alpha-quaternization possibly implies intervention of a rigid chelating transition state that allows an efficient 1,4-asymmetric induction to take place. PMID- 22208773 TI - Prescribing cannabis for harm reduction. AB - Neuropathic pain affects between 5% and 10% of the US population and can be refractory to treatment. Opioids may be recommended as a second-line pharmacotherapy but have risks including overdose and death. Cannabis has been shown to be effective for treating nerve pain without the risk of fatal poisoning. The author suggests that physicians who treat neuropathic pain with opioids should evaluate their patients for a trial of cannabis and prescribe it when appropriate prior to using opioids. This harm reduction strategy may reduce the morbidity and mortality rates associated with prescription pain medications. PMID- 22208776 TI - Rearing honey bees, Apis mellifera, in vitro 1: effects of sugar concentrations on survival and development. AB - A new method for rearing honey bees, Apis mellifera L. (Hymenoptera: Apidae), in vitro was developed and the effects of sugar concentrations on survival and development were studied. Seven different glucose (G) and fructose (F) compositions (0%G+0%F, 3%G+3%F, 6%G+6%F, 12%G+12%F, 0%G+12%F, 12%G+0%F, and 4%G+8%F) were tested. Larvae were able to grow to the post defecation stage without addition of sugars (Diet 1), but they were not able to metamorphose and pupate. Adults were reared from diets 2-7. The average larval survival, prepupal larval weights, adult weights, and ovariole numbers were affected significantly due to the sugar compositions in the diets. High sugar concentrations (12%G+12%F) increased the number of queens and intercastes. PMID- 22208781 TI - Emission changes resulting from the San Pedro Bay, California Ports Truck Retirement Program. AB - Recent U.S. Environmental Protection Agency emissions regulations have resulted in lower emissions of particulate matter and oxides of nitrogen from heavy-duty diesel trucks. To accelerate fleet turnover the State of California in 2008 along with the Ports of Los Angeles and Long Beach (San Pedro Bay Ports) in 2006 passed regulations establishing timelines forcing the retirement of older diesel trucks. On-road emissions measurements of heavy-duty diesel trucks were collected over a three-year period, beginning in 2008, at a Port of Los Angeles location and an inland weigh station on the Riverside freeway (CA SR91). At the Port location the mean fleet age decreased from 12.7 years in April of 2008 to 2.5 years in May of 2010 with significant reductions in carbon monoxide (30%), oxides of nitrogen (48%) and infrared opacity (a measure of particulate matter, 54%). We also observed a 20-fold increase in ammonia emissions as a result of new, stoichiometrically combusted, liquefied natural gas powered trucks. These results compare with changes at our inland site where the average ages were 7.9 years in April of 2008 and 8.3 years in April of 2010, with only small reductions in oxides of nitrogen (10%) being statistically significant. Both locations have experienced significant increases in nitrogen dioxide emissions from new trucks equipped with diesel particle filters; raising the mean nitrogen dioxide to oxides of nitrogen ratios from less than 10% to more than 30% at the Riverside freeway location. PMID- 22208782 TI - Locally advanced esophageal adenocarcinoma: response to neoadjuvant chemotherapy and survival predicted by ([18F])FDG-PET/CT. AB - BACKGROUND: ([18F])fluorodeoxyglycose-Positron Emission Tomography/Computer Tomography (([18F])FDG-PET/CT) is commonly used in staging of locally advanced esophageal cancer. Its predictive value for response to neoadjuvant therapy and survival after multimodality therapy is controversial. METHODS: Sixty-six consecutive patients with locally advanced adenocarcinoma of the esophagus or esophagogastric junction underwent surgery after neoadjuvant chemotherapy. Staging was done prospectively with ([18F])FDG-PET/CT, before and after completion of neoadjuvant therapy. Pre- and post-therapy maximal standardized uptake values for the primary tumor (SUV1 and SUV2) were determined, and their relative change (SUV?%) calculated. Percentage change in SUV1 was compared with histopathologic response (HPR, complete or subtotal histologic remission), disease-free- (DFS) and overall survival (OS). RESULTS: Resection with negative margins was achieved in 60 patients. HPR rate was 14 of 66 (21.2%). Median follow up was 16 months (range 4-72). For all patients, OS probability at three years was 59% and DFS 50%. In receiver operating characteristics (ROC) analysis, HPR was optimally predicted by a > 67% change in baseline maximal SUV (sensitivity 79% and specificity 75%). In univariate survival analysis (Cox regression proportional hazards), HPR associated with improved DFS (HR 0.208, p = 0.033) but not OS (HR 0.030, p = 0.101), SUV % > 67% associated with improved OS (HR 0.249, p = 0.027) and DFS (HR 0.383, p = 0.040). In a multivariate model (adjusted by age, sex, and ASA score), neither HPR nor SUV?% > 67% was predictive of improved OS and DFS. However, SUV?% as a continuous variable was an independent predictor of OS (HR 0.966, p < 0.0001) or DFS (HR 0.973, p < 0.0001). CONCLUSION: Our results support previous results showing that ([18F])FDG-PET/CT can distinguish a group of patients with worse prognosis after neoadjuvant chemotherapy in adenocarcinoma of the esophagus or esophagogastric junction. This information could offer a new independent preoperative marker of prognosis. PMID- 22208783 TI - Effects on muscle performance of NSAID treatment with piroxicam versus placebo in geriatric patients with acute infection-induced inflammation. A double blind randomized controlled trial. AB - BACKGROUND: Inflammation is the main cause of disease-associated muscle wasting. In a previous single blind study we have demonstrated improved recovery of muscle endurance following celecoxib treatment in hospitalized geriatric patients with acute infection. Here we further evaluate NSAID treatment with piroxicam in a double blind RCT and investigate the role of cytokines and heat shock proteins (Hsp) with respect to muscle performance. We hypothesized that NSAID treatment would preserve muscle performance better than antibiotic treatment alone, by reducing infection-associated inflammation and by increasing expression of cytoprotective Hsp. METHODS: Consecutive admissions to the geriatric ward were screened. 30 Caucasian patients, median age 84.5 years, with acute infection induced inflammation and serum levels of CRP > 10 mg/L were included and randomized to active treatment with 10 mg piroxicam daily or placebo. Assessment comprised general clinical and biochemical parameters, 25 cytokines in serum, intra-and extracellular Hsp27 and Hsp70, Elderly Mobility Scale (EMS) scores, grip strength (GS), fatigue resistance (FR) and lean body mass (LBM). Patients were evaluated until discharge with a maximum of 3 weeks after treatment allocation. RESULTS: EMS scores, FR and grip work (GW), a measure taking into account GS and FR, significantly improved with piroxicam, but not with placebo. Early decreases in IL-6 serum levels with piroxicam correlated with better muscle performance at week 2. Basal expression of Hsp27 in monocytes without heat challenge (WHC) was positively correlated with FR at baseline and significantly increased by treatment with piroxicam compared to placebo. Profound modifications in the relationships between cytokines or Hsp and changes in muscle parameters were observed in the piroxicam group. CONCLUSIONS: Piroxicam improves clinically relevant measures of muscle performance and mobility in geriatric patients hospitalized with acute infection-induced inflammation. Underlying mechanisms may include modifications in the cytokine network and increases in monocytic expression of cytoprotective Hsp27. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN96340690. PMID- 22208784 TI - Hot flushes, vascular reactivity and the role of the alpha-adrenergic system. AB - ABSTRACT Background Seventy percent of postmenopausal women suffer from hot flushes but the pathophysiology is poorly understood. Proposed mechanisms include altered peripheral vascular reactivity and a narrowed thermoneutral zone. A trigger has not yet been identified; however, the alpha-adrenergic system, and specifically noradrenaline, has been implicated. Aim To assess the role of the alpha-adrenergic system by studying the effect of clonidine (alpha-adrenergic agonist) on flushes and cutaneous microvascular perfusion. Methods Thirty-two postmenopausal women with severe flushing and 14 non-flushing postmenopausal women were recruited. Cutaneous microvascular perfusion was measured using laser Doppler imaging and endothelial function was assessed by iontophoresis (administration of vasoactive agents through the skin by an electric current) of acetylcholine (ACh - endothelium-dependent) and sodium nitroprusside (SNP - endothelium-independent). In a double-blind, longitudinal, cross-over study, clonidine (an alpha-adrenergic agonist) was compared to placebo in its ability to modulate this response in the flushing group of women. Results The response of the subcutaneous vessels was greater in women who flushed than those who did not (ACh, p < 0.001 and SNP, p = 0.001). However, even though the intensity and number of flushes were decreased by clonidine, there was no difference compared to placebo (p = 0.21) and this 'placebo effect' was also noted in perfusion responses (ACh, p = 0.98; SNP, p = 0.50). Conclusion There was a significant 'placebo effect' for both clinical response and the reactivity of the subcutaneous vessels, making conclusions regarding the role of the alpha adrenergic nervous system in hot flushing difficult to determine at a peripheral level. The mechanism for the change in vascular reactivity remains unclear. PMID- 22208785 TI - Learning biases predict a word order universal. AB - How recurrent typological patterns, or universals, emerge from the extensive diversity found across the world's languages constitutes a central question for linguistics and cognitive science. Recent challenges to a fundamental assumption of generative linguistics-that universal properties of the human language acquisition faculty constrain the types of grammatical systems which can occur suggest the need for new types of empirical evidence connecting typology to biases of learners. Using an artificial language learning paradigm in which adult subjects are exposed to a mix of grammatical systems (similar to a period of linguistic change), we show that learners' biases mirror a word-order universal, first proposed by Joseph Greenberg, which constrains typological patterns of adjective, numeral, and noun ordering. We briefly summarize the results of a probabilistic model of the hypothesized biases and their effect on learning, and discuss the broader implications of the results for current theories of the origins of cross-linguistic word-order preferences. PMID- 22208786 TI - Pulmonary complications of paediatric systemic disorders. PMID- 22208787 TI - Pulmonary complications of genetic disorders. AB - Many different pulmonary manifestations are seen in conjunction with genetic disorders. Pulmonary findings have been noted with some cytogenetic conditions, many single gene or mendelian disorders, as well as with a number of inborn errors of metabolism. In addition, congenital lung anomalies are relatively common, occurring as isolated anomalies and as part of multiple anomaly syndromes. Recognition of pulmonary problems in patients with genetic disorders may lead to prompt treatment and intervention, which ultimately might translate into improved outcome. This review is focused on the clinical aspects rather than the basic science; comprehensive reviews on specific disease entities are readily available. PMID- 22208788 TI - Pulmonary complications of congenital heart disease. AB - Cardiac and pulmonary pathophysiologies are closely interdependent, which makes the management of patients with congenital heart disease (CHD) all the more complex. Pulmonary complications of CHD can be structural due to compression causing airway malacia or atelectasis of the lung. Surgical repair of CHD can also result in structural trauma to the respiratory system, e.g., chylothorax, subglottic stenosis, or diaphragmatic paralysis. Disruption of the Starling forces in the pulmonary vascular system in certain types of CHD lead to alveolar capillary membrane damage and pulmonary oedema. This in turn results in poorly compliant lungs with a restrictive lung function pattern that can deteriorate to cause hypoxemia. The circulation post single ventricle palliative surgery (the so called "Fontan circulation") poses a unique spectrum of pulmonary pathophysiology with restrictive lung function and a low pulmonary blood flow state that predisposes to thromboembolic complications and plastic bronchitis. As the population of patients surviving post CHD repair increases, the incidence of pulmonary complications has also increased and presents a unique cohort in both the paediatric and adult clinics. PMID- 22208789 TI - Pulmonary complications of gastrointestinal disorders. AB - The pulmonary involvement concurrent with gastrointestinal (GI) diseases is often clinically subtle. Radiological manifestations might lag behind the respiratory compromise, and only such specialized testing as high resolution computed tomography (HRCT), permeability studies with labelled proteins, or comprehensive pulmonary function tests (PFTs) may be sensitive enough to detect the evolving pathophysiology. Increasing recognition of specific entities, such as immune mediated alveolitis, will allow implementation of therapies that can significantly improve a patient's prognosis. PMID- 22208790 TI - Pulmonary complications of endocrine and metabolic disorders. AB - There are many important respiratory manifestations of endocrine and metabolic diseases in children. Acute and chronic pulmonary infections are the most common respiratory abnormalities in patients with diabetes mellitus, although cardiogenic and non-cardiogenic pulmonary oedema are also possible. Pseudohypoaldosteronism type 1 may be indistinguishable from cystic fibrosis (CF) unless serum aldosterone, plasma renin activity, and urinary electrolytes are measured and mutation analysis rules out CF. Hypo- and hyperthyroidism may alter lung function and affect the central respiratory drive. The thyroid hormone plays an essential role in lung development, surfactant synthesis, and lung defence. Complications of hypoparathyroidism are largely due to hypocalcaemia. Laryngospasm can lead to stridor and airway obstruction. Ovarian tumours, benign or malignant, may present with unilateral or bilateral pleural effusions. Metabolic storage disorders, primarily as a consequence of lysosomal dysfunction from enzymatic deficiencies, constitute a diverse group of rare conditions that can have profound effects on the respiratory system. PMID- 22208791 TI - Pulmonary complications of childhood rheumatic disease. AB - The array of paediatric pulmonary complications of the various rheumatologic disorders illustrates both the complexities and challenges of the underlying disorders and the continuing lack of detailed knowledge of the pathophysiology and optimal treatment paradigms in children. While the vertical transfer of information has made much progress from adult studies, such as with the diagnosis and management of pulmonary arterial hypertension, in many instances underlying disorders may differ between children and adults in important and fundamental respects. Recognition of pulmonary complications of rheumatic disorders in children is often more difficult and requires anticipation and a high index of suspicion. Further progress in understanding and treating the various paediatric disorders is hampered by the lack of paediatric-specific information. Crucial to further progress are the expansion of orphan childhood disease databases and research networks. In this way a comprehensive approach to determining basic natural history, risks and outcomes, and defining the next generation of therapies in a disease-specific and age-specific manner can be achieved. PMID- 22208792 TI - Pulmonary complications of systemic vasculitides. AB - The pulmonary vasculitides are a heterogeneous group of diseases that often occur as a component of systemic vasculitic diseases. Most frequently, pulmonary vasculitis is observed in vasculitic syndromes that preferentially affect small vessels. Pulmonary involvement may develop because the lung has an extensive vascular and microvascular network. Sensitising antigens can easily reach the lung, and there are large numbers of vasoactive and activated immune cells in the lung. A diagnosis often can be made on the basis of clinical presentation and serologic studies, but biopsy of skin, nose, kidney, or lung may be necessary to ascertain the precise syndrome. PMID- 22208793 TI - Pulmonary complications of renal disorders. AB - To manage patients with diseases of the lungs and the kidneys, one must first understand the relationship between respiratory and renal function. In treating acute renal failure (ARF), the clinician often must contend with respiratory manifestations of volume overload and metabolic acidosis. Mechanical ventilation in patients with renal failure (RF) can be challenging, particularly with lung protective ventilation and weaning. Patients with chronic renal failure (CRF) experience several respiratory complications. Hypoxaemia during dialysis is now understood to be a predictable effect of the loss of CO(2) into the dialysate. Critical illness of any primary cause predisposes patients not only to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) but also to the development of ARF. Meanwhile, the potential for ventilator-induced renal injury has increasingly become the subject of active investigation. PMID- 22208794 TI - Pulmonary complications of dermatological disorders. PMID- 22208795 TI - Healthcare inequalities in paediatric respiratory diseases. AB - Identifying that health inequalities exist is not enough; nor does the knowledge that a patient has a high-risk genotype or comes from a higher risk socioeconomic background does not, by itself, help the patient. To thoroughly examine the origins of health disparities, a broad view of environmental and molecular influences must be included. As these factors are identified, it is important to focus on interventions that can change outcomes for patients. Tools for education, community involvement, literacy, and environmental safety need to be developed, tested and disseminated. The basic science of health disparities must move forward in a coordinated fashion by structuring research that is an integrated effort between basic sciences, clinical medicine and include all traditionally underserved communities. Only through these collaborations can we hope to eliminate health inequalities in the future. PMID- 22208796 TI - Successful grant writing. AB - Obtaining research funding is central to the research process. However many (clinician-) scientists receive little, or no, training in the process of writing a successful grant application. In an era of reductions in research budgets and application success rates, the ability to construct a well presented, clear, articulate proposal is becoming more important than ever. Obtaining grants is a method to achieve your long term research goals. If you are able to formulate these long term goals, it is relevant to explore the market and investigate all potential grant opportunities. Finally, we will provide an outline of key elements of successful research grants. PMID- 22208797 TI - 2012-2013--the year in preview. AB - A highlight of many journals is a review of pertinent literature in a specific field that has been published in the preceding year. Although such "Year in Review" presentations are important, at PRR we are pleased to present the news that has not yet happened. In this manuscript, which is a combination of science and fiction, I will present the very best research that has not yet been conducted but will be published sometime in 2012 or 2013. This will cover all aspects of paediatric pulmonary disease. Any resemblance to real research that is actually published during this time period is strictly coincidental and the product of a fertile imagination. However, if these ideas inspire you to do these studies and publish the results it would make this science fiction even more interesting. To quote the famous baseball player, Yogi Berra, "It's difficult to make predictions, especially about the future.". PMID- 22208798 TI - Seroprevalence and risk factors of Q fever in goats on commercial dairy goat farms in the Netherlands, 2009-2010. AB - BACKGROUND: The aim of this study was to estimate the seroprevalence of Coxiella burnetii in dairy goat farms in the Netherlands and to identify risk factors for farm and goat seropositivity before mandatory vaccination started. We approached 334 eligible farms with more than 100 goats for serum sampling and a farm questionnaire. Per farm, median 21 goats were sampled. A farm was considered positive when at least one goat tested ELISA positive. RESULTS: In total, 2,828 goat serum samples from 123 farms were available. Farm prevalence was 43.1% (95%CI: 34.3%-51.8%). Overall goat seroprevalence was 21.4% (95%CI: 19.9%-22.9%) and among the 53 positive farms 46.6% (95%CI: 43.8%-49.3%). Multivariable logistic regression analysis included 96 farms and showed that farm location within 8 kilometres proximity from a bulk milk PCR positive farm, location in a municipality with high cattle density (>= 100 cattle per square kilometre), controlling nuisance animals through covering airspaces, presence of cats or dogs in the goat stable, straw imported from abroad or unknown origin and a herd size above 800 goats were independent risk factors associated with Q fever on farm level. At animal level almost identical risk factors were found, with use of windbreak curtain and artificial insemination as additional risk factors. CONCLUSION: In 2009-2010, the seroprevalence in dairy goats in the Netherlands increased on animal and farm level compared to a previous study in 2008. Risk factors suggest spread from relatively closely located bulk milk-infected small ruminant farms, next to introduction and spread from companion animals, imported straw and use of artificial insemination. In-depth studies investigating the role of artificial insemination and bedding material are needed, while simultaneously general biosecurity measures should be updated, such as avoiding companion animals and vermin entering the stables, next to advice on farm stable constructions on how to prevent introduction and minimize airborne transmission from affected dairy goat farms to prevent further spread to the near environment. PMID- 22208800 TI - Effectiveness of an implementation strategy for a breastfeeding guideline in Primary Care: cluster randomised trial. AB - BACKGROUND: The protection and promotion of breastfeeding is considered a priority in Europe where only 22% of infants less than 6 months old are exclusively breastfed. In Spain this percentage reaches 24.8% but in our city it falls to 18.26%. Various studies emphasise that the improvement of these results should be based upon the training of health professionals. Following the recommendations of a breastfeeding guide can modify the practice of health professionals and improve results with respect to exclusively or predominatly breastfed children at 6 months of age. METHOD/DESIGN: This study involves a community based cluster randomized trial in primary healthcare centres in Leganes (Madrid, Spain). The project aims to determine whether the use of an implementation strategy (including training session, information distribution, opinion leader) of a breastfeeding guideline in primary care is more effective than usual diffusion. The number of patients required will be 240 (120 in each arm). It will be included all the mothers of infants born during the study period (6 months) who come to the health centre on the first visit of the child care programme and who give their consent to participate. The main outcome variable is the exclusive o predominant breastfeeding at 6 moths of age..Main effectiveness will be analyzed by comparing the percentage of infants with exclusive or predominant breastfeeding at 6 months between the intervention group and the control group. All statistical tests will be performed with intention to treat. Logistic regression with random effects will be used to adjust for prognostic factors. Confounding factors or factors that might alter the effect recorded will be taken into account in this analysis. DISCUSSION: Strategies need to be found which facilitate the giving of effective advice on breastfeeding by professionals and which provide support to women during the breastfeeding period. By applying the guide's recommendations, clinical variability can be reduced and the care received by patients can be improved. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov, number NCT01474096. PMID- 22208801 TI - Designing and deconstructing the Fano lineshape in plasmonic nanoclusters. AB - By varying the relative dimensions of the central and peripheral disks of a plasmonic nanocluster, the depth of its Fano resonance can be systematically modified; spectral windows where the scattering cross section of the nanocluster is negligible can be obtained. In contrast, electron-beam excitation of the plasmon modes at specific locations within the nanocluster yields cathodoluminescence spectra with no Fano resonance. By examining the selection rules for plasmon excitation in the context of a coupled oscillator picture, we provide an intuitive explanation of this behavior based on the plasmon modes observed for optical and electron-beam excitation in this family of nanostructures. PMID- 22208802 TI - Predictors of change in pain and physical functioning among post-menopausal women with recurrent pain conditions in the women's health initiative observational cohort. AB - Pain complaints are commonly reported symptoms among postmenopausal women and can have significant effects on health-related quality of life. We sought to identify medical and psychosocial factors that predict changes in pain and overall physical functioning over a 3-year period among postmenopausal women with recurrent pain conditions. We examined data from postmenopausal women age 50 to 79 with recurrent pain conditions (low back pain, neck pain, headache or migraines, or joint pain or stiffness) over a 3-year period using the Women's Health Initiative Observational Study Cohort (N = 67,963). Multinomial logistic regression models controlling for demographic and clinical characteristics were used to identify baseline predictors of change in the SF-36 subscales for pain and physical functioning between baseline and 3-year follow-up. Body mass index (BMI) was associated with worsening of pain (OR [95% CI] 1.54 [1.45-1.63] for BMI >=30) and physical functioning (1.83 [1.71-1.95] for BMI >=30). A higher reported number of nonpain symptoms, higher medical comorbidity, and a positive screen for depression (1.13 [1.05-1.22] for worsened pain) were also associated with worsening of pain and physical functioning. Baseline prescription opioid use was also associated with lack of improvement in pain (OR .42, 95% CI .36-.49) and with worsened physical functioning (1.25 [1.04-1.51]). PERSPECTIVE: This study presents prospective data on change in pain and physical functioning in postmenopausal women over a 3-year period. Our results suggest depression, nonpain physical symptoms, obesity, and possibly opioid treatment are associated with worse long-term pain outcomes in this population. PMID- 22208803 TI - Test order of quantitative sensory testing facilitates mechanical hyperalgesia in healthy volunteers. AB - Quantitative sensory testing (QST) has become a widely used method to evaluate different submodalities of the somatic sensory system (predominantly) in patients with neuropathic pain. QST consists of 7 tests measuring 13 parameters in order to assess and quantify the perception of temperature, touch, pain, pressure, and vibration. The German Research Network on Neuropathic Pain implemented a standardized QST protocol including a defined testing order of the measurements. Accordingly, subjects tested with QST undergo thermal before mechanical testing. In the present study, we investigated the effect of testing order on the results of QST. Twenty healthy subjects were tested twice, 1 week apart with 2 different QST testing orders: the standardized testing order according to the German Research Network on Neuropathic Pain and a modified testing order in which mechanical stimuli were applied before thermal stimuli. For the test protocol that began with thermal testing, subjects exhibited signs of an increased mechanical perception: The mechanical pain sensitivity was significantly increased (P = .001, Wilcoxon test) for each pinprick stimulator and the mechanical pain threshold was lowered by a factor of 2 when compared with the modified testing order in which mechanical parameters were tested at the beginning of the session without prior thermal stimulation. Thermal parameters were the same for both test-order paradigms. These data indicate that preceding mild thermal stimulation might lead to a sensitization to mechanical stimuli and thus to mechanical hyperalgesia. Alternative habituation mechanisms in the modified testing order resulting from repeated pinprick stimulation at the beginning should also be debated. QST is a helpful diagnostic tool but interpretation should be done with consideration of interaction between test parameters. Reference data are only valid in the testing order from which they are obtained. PERSPECTIVE: Present data showed that mechanical hyperalgesia followed thermal testing. This article demonstrates that the test order of quantitative sensory testing is relevant in interpreting the results obtained. Reference values are suitable in the test order from which they are obtained. PMID- 22208804 TI - Investigation of central pain processing in shoulder pain: converging results from 2 musculoskeletal pain models. AB - Recent reports suggest deficits in conditioned pain modulation (CPM) and enhanced suprathreshold heat pain response (SHPR) potentially play a role in the development of chronic pain. The purpose of this study was to investigate whether central pain processing was altered in 2 musculoskeletal shoulder pain models. The goals of this study were to determine whether central pain processing: 1) differs between healthy subjects and patients with clinical shoulder pain; 2) changes with induction of exercise-induced muscle pain; and 3) changes 3 months after shoulder surgery. Fifty-eight patients with clinical shoulder pain and 56 age- and sex-matched healthy subjects were included in these analyses. The healthy cohort was examined before inducing EIMP, and 48 and 96 hours later. The clinical cohort was examined before shoulder surgery and 3 months later. CPM did not differ between the cohorts, however; SHPR was elevated for patients with shoulder pain compared to healthy controls. Induction of acute shoulder pain with EIMP resulted in increased shoulder pain intensity but did not change CPM or SHPR. Three months following shoulder surgery, clinical pain intensity decreased but CPM was unchanged from preoperative assessment. In contrast, SHPR was decreased and showed values comparable with healthy controls at 3 months. Therefore, the present study suggests that: 1) clinical shoulder pain is associated with measurable changes in central pain processing; 2) exercise induced shoulder pain did not affect measures of central pain processing; and 3) elevated SHPR was normalized with shoulder surgery. Collectively our findings support neuroplastic changes in pain modulation were associated with decreases in clinical pain intensity only, and could be detected more readily with thermal stimuli. PERSPECTIVE: Longitudinal studies involving quantitative sensory testing are rare. In exploring 2 musculoskeletal shoulder pain models (exercise-induced muscle pain and surgical pain), conditioned pain modulation was unchanged from pre- to post-assessment in both models. Suprathreshold heat pain response decreased after shoulder surgery and was comparable to healthy controls, suggesting this measure may be sensitive to decreases in clinical pain intensity. PMID- 22208805 TI - The effects of ethanol on the bioavailability of oxymorphone extended-release tablets and oxymorphone crush-resistant extended-release tablets. AB - Adverse events may occur with an extended-release (ER) opioid if tampering or coadministration with ethanol causes excessive exposure (dose dumping) to the opioid. The effects of ethanol on the in vitro dissolution and in vivo pharmacokinetics of oxymorphone ER and oxymorphone crush-resistant formulation (CRF) were evaluated. In vitro dissolution rates were measured for oxymorphone ER 40-mg and oxymorphone CRF 40-mg tablets in aqueous solutions of 0 to 40% ethanol. In 2 in vivo, open-label, randomized, crossover studies, fasted healthy volunteers received single oral doses of oxymorphone ER 40 mg or oxymorphone CRF 40 mg with 240 mL of 0 to 40% ethanol. Naltrexone was used to minimize opioid effects. In the in vitro analyses, dissolution rates of oxymorphone ER and CRF were unaffected in aqueous solutions of <=40% ethanol. Coadministration of oxymorphone ER or oxymorphone CRF with ethanol 20 and 40% increased oxymorphone peak plasma concentrations (C(max)) by 14 to 80% and reduced time to C(max). For both formulations, oxymorphone area under the curve and terminal half-life were largely unaffected, but C(max) increased with ethanol dose. Neither oxymorphone formulation exhibited dose dumping in terms of overall exposure when coingested with ethanol. PERSPECTIVE: Administering oxymorphone ER or oxymorphone CRF with 240 mL of <=40% ethanol increased oxymorphone C(max) without dose dumping in terms of area under the curve. These results provide reassurance about the integrity of oxymorphone ER formulations with ethanol. Nonetheless, alcohol and opioids should never be combined because of the risk of respiratory depression. PMID- 22208806 TI - Identifying elemental genomic track types and representing them uniformly. AB - BACKGROUND: With the recent advances and availability of various high-throughput sequencing technologies, data on many molecular aspects, such as gene regulation, chromatin dynamics, and the three-dimensional organization of DNA, are rapidly being generated in an increasing number of laboratories. The variation in biological context, and the increasingly dispersed mode of data generation, imply a need for precise, interoperable and flexible representations of genomic features through formats that are easy to parse. A host of alternative formats are currently available and in use, complicating analysis and tool development. The issue of whether and how the multitude of formats reflects varying underlying characteristics of data has to our knowledge not previously been systematically treated. RESULTS: We here identify intrinsic distinctions between genomic features, and argue that the distinctions imply that a certain variation in the representation of features as genomic tracks is warranted. Four core informational properties of tracks are discussed: gaps, lengths, values and interconnections. From this we delineate fifteen generic track types. Based on the track type distinctions, we characterize major existing representational formats and find that the track types are not adequately supported by any single format. We also find, in contrast to the XML formats, that none of the existing tabular formats are conveniently extendable to support all track types. We thus propose two unified formats for track data, an improved XML format, BioXSD 1.1, and a new tabular format, GTrack 1.0. CONCLUSIONS: The defined track types are shown to capture relevant distinctions between genomic annotation tracks, resulting in varying representational needs and analysis possibilities. The proposed formats, GTrack 1.0 and BioXSD 1.1, cater to the identified track distinctions and emphasize preciseness, flexibility and parsing convenience. PMID- 22208808 TI - Health related quality of life among adolescents with premenstrual disorders: a cross sectional study. AB - BACKGROUND: Premenstrual disorders usually refer to premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). This study was designed to evaluate health-related quality of life (HRQOL) in a sample of Iranian adolescents with premenstrual disorders. METHODS: This was a cross sectional study. A sample of adolescent schoolgirls aged between 14 and 19 years were included in the study. Premenstrual disorders were indicated according to the International Classification of Diseases (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Health-related quality of life was measured using the Short Form Health Survey (SF-36). The data were analyzed in a descriptive fashion and were compared among subgroups of the study sample. RESULTS: In all 602 female students were studied. All students reported at least one premenstrual symptom. Of these, 224 (37.2%) met the diagnostic criteria for premenstrual dysphoric disorder (PMDD). Comparing the SF-36 scores between female students with and without PMDD, it was found that there were significant differences between these two groups in all measures (P < 0.001) except for physical functioning (P = 0.274). These differences were more evident on role emotional, role physical, social functioning and bodily pain. CONCLUSION: The study findings affirm the fact that adolescents with premenstrual disorders suffer from poor health-related quality of life. In order to improve quality of life in female adolescents appropriate support should be provided for this population especially for those who suffer from more severe premenstrual disorders. PMID- 22208812 TI - Moving targets, long-lived infrastructure, and increasing needs for integration and adaptation in water management: an illustration from Switzerland. AB - Switzerland provides an example of successful management of water infrastructure and water resources that was accomplished largely without integration across sectors. Limitations in this approach have become apparent; decisions that were formerly based only on technical and economic feasibility must now incorporate broader objectives such as ecological impact. In addition, current and emerging challenges relate to increasingly complex problems that are likely to demand more integrated approaches. If such integration is to be of benefit, it must be possible to redirect resources across sectors, and the synergies derived from integration must outweigh the additional cost of increased complexity. PMID- 22208813 TI - Pollination of Cambessedesia wurdackii in Brazilian campo rupestre vegetation, with special reference to crepuscular bees. AB - Cambessedesia wurdackii Martins (Myrtales: Melastomataceae) is presumably endemic to the Chapada Diamantina, Bahia State, Brazil. A majority of the species of this family are pollinated by diurnal bees that buzz the floral anthers to collect pollen. The present work examined the interactions between C. wurdackii and visiting bees, focusing on temporal, morphological, and behavioral features, especially in regards to the crepuscular bees Megalopta sodalis (Vachal) (Hymenoptera: Halictidae) and Ptiloglossa off. dubia Moure (Hymenoptera: Colletidae). The study was undertaken in an area of campo rupestre montane savanna vegetation located in the Chapada Diamantina Mountains of Bahia State, Brazil, between August/2007 and July/2008. Flowering in C. wurdackii occurred from April through July, with a peak in May. A total of 592 visits by diurnal and crepuscular bees to the flowers of C. wurdackii were recorded, with a majority of the visits made by M. sodalis and P. dubia (92%) near sunrise and sunset. The anthers of C. wurdackii are arranged in two tiers, which favors cross pollination. The morphological, temporal and behavioral characteristics of M. sodalis and P. dubia indicated that they were potential pollinators of C. wurdackii, in spite of the fact that the colorful and showy flowers of this species are more typical of a diurnal melittophilous pollination syndrome. PMID- 22208815 TI - A case of adaptive self-assembly. AB - We report in this paper direct observation of redox-induced uptake of a charged species in micelles with a complex coacervate core, using a system consisting of negatively charged iron-coordination polymers and positively charged-b-neutral block co-polyelectrolytes. Neutral, charge-balanced micelles are first prepared by stoichiometric mixing of the oppositely charged components. Upon a redox stimulus, the micelles develop excess charges, which (as proposed in our previous work) most likely lead to sequestration of oppositely charged species, as the charge balance has to be restored. In this work we verify this prediction by using a rigid, rod-like iron coordination polymer, namely, the positively charged MEPE, as the species to be taken up. After uptake of this rigid cargo, the morphology of the micelles was found to transform from spheres to banana-shaped bundles and fibers, which clearly indicate the uptake of MEPE in the micellar core. Our result proves that the redox stimulus indeed induces excess charges in the core, which forces the self-assembled particles to change both composition and shape. As an interesting example of "adaptive self-assembly", our findings also pave the way to novel redox-triggered uptake and release systems. PMID- 22208819 TI - Single stage immediate implant placements in the esthetic zone. AB - This case series report documents 5 successful cases of immediate implant placements into fresh extraction sockets in the esthetic zone, subsequently restored with favourable outcomes. The case selection, treatment planning, surgical protocol, restorative outcomes are presented and discussed. PMID- 22208820 TI - Antibody degradation in tobacco plants: a predominantly apoplastic process. AB - BACKGROUND: Interest in using plants for production of recombinant proteins such as monoclonal antibodies is growing, but proteolytic degradation, leading to a loss of functionality and complications in downstream purification, is still a serious problem. RESULTS: In this study, we investigated the dynamics of the assembly and breakdown of a human IgG(1)kappa antibody expressed in plants. Initial studies in a human IgG transgenic plant line suggested that IgG fragments were present prior to extraction. Indeed, when the proteolytic activity of non transgenic Nicotiana tabacum leaf extracts was tested against a human IgG1 substrate, little activity was detectable in extraction buffers with pH > 5. Significant degradation was only observed when the plant extract was buffered below pH 5, but this proteolysis could be abrogated by addition of protease inhibitors. Pulse-chase analysis of IgG MAb transgenic plants also demonstrated that IgG assembly intermediates are present intracellularly and are not secreted, and indicates that the majority of proteolytic degradation occurs following secretion into the apoplastic space. CONCLUSIONS: The results provide evidence that proteolytic fragments derived from antibodies of the IgG subtype expressed in tobacco plants do not accumulate within the cell, and are instead likely to occur in the apoplastic space. Furthermore, any proteolytic activity due to the release of proteases from subcellular compartments during tissue disruption and extraction is not a major consideration under most commonly used extraction conditions. PMID- 22208821 TI - Effects of estrogen and progesterone on cerebrovascular responses to euoxic hypercapnia in women. AB - OBJECTIVES: To determine the cerebral blood flow response to step changes in end tidal Pco(2) in premenopausal women (n = 10; mean age+/-standard deviation 27.0+/ 6.4 years) during the follicular (FP), mid-cycle (MC) and luteal (LP) phases of the menstrual cycle. METHODS: Transcranial Doppler ultrasound was used to measure beat-by-beat averaged peak blood flow velocity (V(p)) in the middle cerebral artery in response to 20 min of euoxic hypercapnia (end-tidal PO(2) = 88 Torr; end-tidal PCO(2) = 7.0 Torr above resting values). The V(p) responses to euoxic hypercapnia were fitted to a simple mathematical model that included gain terms for the on (G(on)) and off (G(off)) responses, time constants for the on (tau(on)) and off (tau(off)) responses, baseline terms and a time delay (T(d)). RESULTS: Serum progesterone levels were significantly greater for LP compared to FP and MC (40.6+/-13.2 vs. 32.6+/-1.4 nmol/l (p < 0.001) and 8.8+/-3.8 nmol/l (p < 0.001), respectively). Serum estrogen concentrations were significantly lower in FP compared to MC and LP (150.9+/-51.2 vs. 506.5+/-220.5 pmol/l (p = 0.002) and 589.1+/-222.8 pmol/l (p < 0.001), respectively). Arterial PCO(2) was significantly greater in MC compared to LP (35.0+/-2.1 and 32.6+/-1.4 Torr, respectively; p = 0.02). There was a significant increase in G(off) during LP compared with FP and MC (3.38+/-0.68 vs. 2.79+/-0.82 cm s(-1) Torr(-1) (p = 0.021) and 2.74+/-0.90 (p = 0.018) cm s(-1) Torr2(1), respectively). Progesterone and the estrogen/progesterone ratio contributed to the observed differences in G(off). CONCLUSION: There is an increase in G(off) during LP that is explained, at least in part, by increases in serum progesterone and estrogen and a decrease in arterial PCO(2). PMID- 22208822 TI - Substituent effects on twisted internal charge transfer excited states of N borylated carbazoles and (diphenylamino)boranes. AB - N-Boryl-substituted carbazoles (carBR(2)) and (diphenylamino)boranes (Ph(2)NBR(2)) with R = Mes (mesityl) and FMes [tris(trifluoromethyl)phenyl] substituents on boron exhibit large UV/vis Stokes shifts. To investigate the substituent effect on the magnitude of the Stokes shifts, we studied the electronic structure and spectroscopic properties of carBR(2) and Ph(2)NBR(2) with R = H, Mes, and FMes using hybrid density functional theory (B3LYP) and time dependent density functional theory (TD-B3LYP) for ground and low-lying excited states. The lowest lying excited state with a nonvanishing oscillator strength is a twisted internal charge transfer (TICT) (1)A state in the C(2) point group, owing to a single-electron excitation from the nitrogen lone pair to the unoccupied boron p(z) AO, Nlp -> Bp(z). Emission from these (1)A excited states are predicted to be much brighter than from the energetically close (1)B excited states that are not directly related to CT excitation from N to B, due to symmetry. An analysis of geometrical relaxations in the excited state and the state energies relative to the ground state energy of the equilibrium geometry reveals that (a) the carbazole skeleton induces a general red shift in UV/vis spectra, (b) bulky boryl substituents reduce the predicted Stokes shifts of TICT states, and (c) the presence of electron-withdrawing functional groups induces a further general red shift in UV/vis spectra but does not significantly alter Stokes shifts. PMID- 22208823 TI - An evaluation of the success of a surgical resident learning portfolio. AB - BACKGROUND: Learning portfolios have gained modest acceptance in graduate medical education because of challenges related to user satisfaction, time and resource commitment, and quality assessment. In 2001, the Department of Surgery implemented the Surgical Learning and Instructional Portfolio (SLIP) to help residents develop a case-based portfolio demonstrating practice-based learning. In 2008, the format was changed to a Web-based platform with open viewing of portfolios for all learners. This study was performed to evaluate the SLIP program using resident and faculty perspectives in the domains of satisfaction, compliance, and educational value. METHODS: Likert scale surveys were distributed to residents to assess satisfaction. Using a semistructured format with subsequent qualitative analysis of the meeting transcript, a focus group discussion was held with the SLIP director, SLIP facilitator, and program coordinator. An analysis of the program compliance was performed by review of SLIP entry dates. Finally, the quality of the SLIP entries (n = 420) was analyzed in a blinded manner using a locally developed standardized SLIP assessment tool. Data analysis was performed using Pearson's correlation and Cronbach's alpha. RESULTS: Residents were satisfied with the program and felt the Web-based format promoted self-reflection. They perceived that time spent was appropriate. Residents also believed they gained medical knowledge of their own specific entry topics but did not learn routinely from others' entries. Faculty asserted that the Web-based platform eased the administrative burden but did not necessarily alter the quality of the SLIP entries. Compliance with the assignment was 100%. SLIP entry analysis demonstrated the reflection and understanding of the topics chosen. However, the overall quality assessment of entries was hindered by suboptimal interrater reliability (inter-rater reliability (IR) = 0.636). CONCLUSIONS: The SLIP program allows residents to demonstrate practice-based learning and improvement of medical knowledge. The Web-based format provides transparency and ease of administration. Quality assessment of individual portfolio entries remains a challenge to the widespread adoption of portfolios. PMID- 22208824 TI - Analysis of the orthopedic in-training examination (OITE) musculoskeletal trauma questions. AB - OBJECTIVES: Residency program directors are responsible for providing assessment and feedback about resident performance and for developing a comprehensive resident curriculum in orthopedic surgery. One measure of resident knowledge is the Orthopedic In-Training Examination (OITE). Scores of the OITE examination have been found to correlate with the American Board of Orthopedic Surgery Part 1 Certifying Examination. The purpose of this study was to identify commonly tested orthopedic trauma topics, the taxonomic distribution of questions, and literature references in the OITE to aid curriculum development and individual test preparation. METHODS: The musculoskeletal trauma-related questions on the OITE during a 5-year period (2004-2008) were reviewed, and the number of questions, topics, taxonomic classification, and educational references associated with each question were analyzed. RESULTS: Nearly 30% of questions each year consist of musculoskeletal trauma-related topics. Femur, tibia, and hip fractures were the most commonly tested topics. The majority (65.6%) of musculoskeletal trauma questions tested recall of specific facts. Examiners referenced primary literature sources (74.9%) more than textbooks (25.1%). The Journal of Bone and Joint Surgery (American) and the Journal of Orthopaedic Trauma were cited most, accounting for 44.3% of all journal references. Forty-seven percent of the primary references were published within 5 years of the test administration. CONCLUSIONS: One method for assessing orthopedic knowledge is the OITE examination. Longitudinal analysis of trauma-related questions shows a consistent pattern of both topics and primary literature citation. This information may be used to help guide structured review for future OITE examinations and develop an orthopedic trauma curriculum for a residency program. PMID- 22208825 TI - Assessment of four tissue models on knot tensile strength. AB - OBJECTIVE: To determine whether the tissue model onto which a knot is tied influences the knot's tensile strength. STUDY DESIGN: Zero-gauge, nonexpired, silk, polyglactin 910, polydioxanone, and polypropylene sutures were tied on 4 different mock tissue models. The tissue models were standard metal hex head screw, uncooked chicken breast, a tube of packaged "string" cheese, and a cylinder of bubble wrap. The knots were tied without a surgeon's knot and with 4 additional square knots (1 = 1 = 1 = 1 = 1). The knots were tied by a single obstetrician/gynecologist investigator (J.M.D.) over the period of 1 week to minimize fatigue. We compared the knots when subjected to a tensiometer until the suture broke or untied. A minimum of 20 knots per group were needed to detect a moderate effect size with a power of 85% and a type I error rate of 5%. RESULTS: A total of 407 knots were tied with 4 types of material (silk, polyglactin 910, polydioxanone, and polypropylene), using 4 different models (chicken, bubble wrap, cheese, and metal). Among the knot failures, 113 of 407 untied rather than broke (28%). No differences in the likelihood of knots coming untied between the different models (p = 0.34) or tension at failure (p = 0.81) were noted. A 4 * 4 factorial analysis of variance (ANOVA) was conducted to determine the effects of the suture material and model type on tension at failure and whether there was any interaction between the 2 factors. No significant difference was observed in the interaction between suture material and model type (p = 0.35), and no effect for model type was found (p = 0.22). CONCLUSIONS: Tissue models that use materials more similar to human tissue do not seem to influence knot strength when compared with standard metal models. We propose that it is possible to have an accurate understanding of how knots withstand force and to simulate an in vivo environment by using low-cost, easily accessible natural and synthetic materials for the mechanism onto which the knot is tied. PMID- 22208826 TI - Can moral reasoning predict general surgery residents' clinical competence? AB - BACKGROUND: When selecting residents for residency programs, there has been little success using standard academic criteria to predict their clinical performance. However, numerous studies in the past have found linkages between the nonstandard variable moral reasoning as measured by the instrument Defining Issues Test (Version 2; DIT-2) and clinical decision making with higher levels of moral reasoning linked to better clinical performance. This study sought to determine whether this important linkage exists in surgery residents. METHODS: The DIT-2 was administered to 20 surgical residents to assess level of moral reasoning, and data were collected on all end-of-rotation evaluations of residents by faculty to measure resident clinical competence. Candidate rank list data were examined from the past 5 years to determine linkages between moral development as measured by the DIT-2 and clinical competence. Correlation analyses, univariate regression, and stepwise multivariate regression were carried out to assess the relationships of moral reasoning as measured by the DIT 2 with other study variables. RESULTS: Analysis of data indicates a low correlation between DIT-2 scores and clinical competence. Rank list order showed a slight correlation with resident DIT-2 scores. Rank position was weakly correlated with individual competencies and aggregated scores for all competencies as measured by faculty evaluations. Rank position coupled with DIT-2 scores were predictive of 4 of the 6 ACGME competencies and predictive of clinical competence as measured by aggregated scores for all competencies. CONCLUSIONS: No linkages emerged between DIT-2 scores and clinical competence. This reasons for this may include the size of the population studied and the assumption that end-of-rotation evaluations measure resident clinical competence. There were significant relationships demonstrated when DIT-2 scores were linked with resident ranking. Future research should be continued in this area but with more rigorous instrumentation to measure clinical performance and a larger sample size. PMID- 22208827 TI - Determining personal talents and behavioral styles of applicants to surgical training: a new look at an old problem, part II. AB - BACKGROUND: The selection of applicants for training in any particular surgical program is an imprecise exercise. Despite the abundance of information on particular candidates, many of the fundamental qualities that are associated with success for the surgical trainee cannot be identified by review of the applicants' grades, scores, letters of recommendation, personal statement, or even from the interview process. We sought a method to determine behavior, motivation, and values possessed by applicants that coincided with traits by our current residents who had demonstrated success in our program. METHODS: The methods have been described in detail in Part I.(1) Briefly, the individual applicants' personal talent report was used to develop a rank-ordered list by the outside consultant and was compared to the traditionally developed rank list developed by the Department in the traditional fashion and the newly developed job benchmark. RESULTS: Five hundred thirty-five applications were received and interviews were offered to 112 (21%) applicants. Seventy-five on-line surveys were completed by the 77 applicants who were interviewed. The consultant was able to identify important personal talents, elements of motivation, and behavioral style that were not gleaned from the application or the interview process, some of which prompted a revision of our final ranking order.(1) This report discusses the results of the motivational analysis and of the Personal Talents Skills Inventory. Applicants with a strong motivation for the theoretical (knowledge) and social commitment (desire to help others) are important characteristics. Clear views of the external world and of self, as well as a sense of satisfaction with the applicants' vision of their future are positively associated with success in our program. CONCLUSIONS: The ability to identify unique behavioral, motivational and personal talents that applicants bring to the program that were not identifiable from the traditional application and interview process has allowed us to determine applicants who were a good match for the structure and culture of our program. PMID- 22208828 TI - Development and evaluation of a novel cadaveric model for performance of image guided percutaneous renal tumor ablation. AB - INTRODUCTION: Thermal ablation is a well established treatment option for the management small renal masses. Increasingly, renal ablation is performed via a percutaneous approach. However, most urologists are not formally trained in image based deployment of ablation needles. To address this need, we created a novel training model to teach urologists to perform precise and accurate percutaneous needle placement. This teaching model was implemented as part of a recent training course on tissue ablation organized by the American Urological Association. METHODS: Two fresh frozen human cadavers (Anatomic Gifts Registry, Hanover, Maryland) were used in the model. Plumber's Putty (Oatey, Cleveland, Ohio) and nonpitted olives soaked in Isovue (Bracco Dianostics, Inc, New York, New York) were used to create ablation targets. Course participants underwent a tutorial on the computed tomography (CT)-guided deployment of a 19-gauge Yueh Needle (Cook Medical, Bloomington, Indiana) or Cool-tip radio-frequency ablation (RFA) probe (Covidien, Inc, Boulder, Colorado). After each needle placement, a CT scan was performed to assess successful deployment. Participants were then queried regarding their experience. RESULTS: A total of 18 urologists performed needle or radio-frequency ablation probe placement on 2 cadavers. A mean of 3.39 (range 2-5) attempts was required to hit targets. Subjectively, participants noted an increase in confidence performing percutaneous needle deployment. The cadaver laboratory exposed participants to pretreatment planning, tactile feel of needle placement, needle readjustment, and 3-D spatial relationships of a percutaneous approach. CONCLUSIONS: The presented cadaveric model is an effective tool for teaching percutaneous needle placement. All urologists evaluated noted increased confidence in this technique after training on the model. PMID- 22208829 TI - Effect of abdominal binders on pulmonary mechanics with implications for the military surgical population. AB - OBJECTIVE: After percutaneous endoscopic gastrostomy (PEG) tube placement, many surgeons will place an abdominal binder to protect the tube. Analysis of the literature shows mixed data as to the safety of abdominal binders with respect to pulmonary function. In this study, pulmonary function tests (PFTs) were used to assess changes in pulmonary status with and without an abdominal binder in volunteer active-duty personnel. DESIGN: Patient's forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), forced expiratory flow (FEF), peak expiratory flow (PEF) maximal inspiratory (P(i) max) and expiratory pressures (P(e) max), total lung capacity (TLC), vital capacity (VC), functional reserve capacity (FRC), expiratory reserve volume (ERV), and residual volume (RV) were measured with and without an elastic abdominal binder in prone, 30 degree and 60 degree positions in 5 male and 5 female active-duty personnel. SETTING: 81st Medical Group Clinical Research Laboratory at Keesler AFB, MS. PARTICIPANTS: Five male and five female active-duty personnel of multiple ethnicities weighing between 125 and 240 lb. RESULTS: There were multiple statistically significant differences in the effect on lung function in the combined data between males and females, including maximum inspiratory pressure (Pi Max) at 60 degree head-of-bed elevation and RV and TLC in the supine position (p < 0.05). There was no statistically significant effect on expiratory pressures at any head-of-bed position. CONCLUSIONS: In otherwise healthy active-duty members, abdominal binder placement has a small but statistically significant effect on some lung function but not on parameters that would impede airway protection. For the purpose of protecting wounds, specifically PEG tubes, we conclude that abdominal binders cause no significant safety risk. PMID- 22208830 TI - Effect of petroleum gauze packing on the mechanical properties of suture materials. AB - OBJECTIVE: To test the tensile properties of knotted suture made of 4 different suture materials and exposed to petroleum gauze. STUDY DESIGN: We tested the tensile strength of United States Pharmacopeia size 0-0 gauge polydioxanone, polyglyconate, glycolide/lactide copolymer, and silk when exposed to petroleum packing or saline. Suture materials were randomized, and knots were tied and then evaluated via tensiometer to the point of knot failure. RESULTS: A total of 285 knots were tied in 8 groups based on material and exposure to saline or petroleum gauze. We found that petroleum exposure knots failed at a mean of 116.7 N (SD = 31.5) and that saline soaked knots failed at 123.8 N (SD = 32.0). We conducted a 4 * 2 factorial analysis of variance, finding knots exposed to petroleum failed at a statistically significantly lower tensile strengths than saline soaked knots (p = 0.002). CONCLUSION: Petroleum-exposed sutures fail at lower tensions than saline-exposed sutures. PMID- 22208831 TI - Monitoring universal protocol compliance through real-time clandestine observation by medical students results in performance improvement. AB - OBJECTIVE: To measure universal protocol compliance through real-time, clandestine observation by medical students compared with chart audit reviews, and to enable medical students the opportunity to become conscious of the importance of medical errors and safety initiatives. DESIGN: With endorsement from Tufts Medical Center's (TMC's) Chief Medical Officer and Surgeon-in-Chief, 8 medical students performed clandestine observation audits of 98 cases from April to August 2009. A compliance checklist was based on TMC's presurgical checklist. Our initial results led to interventions to improve our universal protocol procedures, including modifications to the operating room white board and presurgical checklist, and specific feedback to surgical departments. One year later, 6 medical students performed observations of 100 cases from June to August 2010. SETTING: Tufts Medical Center, Boston, Massachusetts, which is an academic medical center and the principal teaching hospital for Tufts University School of Medicine. PARTICIPANTS: An operating room coordinator placed the medical students into 1 of our 25 operating rooms with students entering under the premise of observing the anesthesiologist for clinical education. The observations were performed Monday to Friday between 7 am and 4 pm. Although observations were not randomized, no single service or type of surgery was targeted for observation. RESULTS: A broad range of departments was observed. In 8.2% of cases, the surgical site was unmarked. A Time Out occurred in 89.7% of cases. The entire surgical team was attentive during the time out in 82% of cases. The presurgical checklist was incomplete before incision in 13 cases. Images were displayed in 82% of cases. The operating room "white board" was filled out completely in 49% of cases. Team introductions occurred in 13 cases. One year later, compliance increased in all Universal Protocol dimensions. CONCLUSIONS: Direct, real-time observation by medical students provides an accurate and granular assessment of compliance with specific components of the universal protocol and engages medical students in the quality improvement process, raises their awareness of the gravity of medical errors, and ensures appreciation of the importance of quality and safety initiatives. PMID- 22208832 TI - Portal venous gas and pneumatosis intestinalis; radiologic signs with wide range of significance in surgery. AB - BACKGROUND: Portal vein gas (PVG) was described as an uncommon ominous radiologic sign usually harboring an intra-abdominal catastrophe. When accompanied by pneumatosis intestinalis (PI), it is more predictive of bowel ischemia. Since the wide use of computed tomography (CT), both signs could also be viewed as incidental findings during routine radiologic investigations. METHODS: We present a series of 12 cases that showed either or both signs, collected in a district general hospital between 1991 and 2011. RESULTS: The diagnoses in these cases varied between fatal bowel ischemia and the mere presence of radiologic signs in the absence of significant pathology. CONCLUSION: PVG and PI are radiologic signs that can represent a wide range of pathology. PMID- 22208833 TI - Spaced education faculty development may not improve faculty teaching performance ratings in a surgery department. AB - OBJECTIVES: To determine the effectiveness of spaced education as a faculty development tool designed to improve teaching skills in a surgery department. DESIGN: Faculty members were randomized to receive either weekly spaced education e-mails with content designed to improve teaching skills (group A) or no e-mails (group B). Using qualitative and quantitative surveys, we assessed both medical students' perception of faculty members' teaching effectiveness and faculty members' perception of the usefulness of the spaced education e-mails. SETTING: Academic medical center. PARTICIPANTS: Twenty-nine surgery faculty members with teaching responsibility for medical students in their Core Surgery Clerkship. RESULTS: All 41 medical students who rotated through the Core Surgery Clerkship rated the quality of teaching for each faculty members; 172 online rating surveys were completed. Overall, faculty members received high ratings on the teaching skills included on the surveys. Additionally, no significant differences were found between the perceived skill level of the faculty members who received the weekly e-mails and those who did not. Specifically, 53.8% and 54% (p = 0.47) of the faculty were felt to deliver feedback more than three times per week; 87.1% and 89.9% (p = 0.15) of faculty were felt to deliver useful feedback; 89.2% and 90.8% (p = 0.71) of faculty were perceived to encourage student autonomy; and 78.1% and 81.9% (p = 0.89) of faculty were felt to set clear learning expectations for students. Postprogram comments from faculty revealed they did not find the e-mails useful as a faculty development tool. CONCLUSIONS: Students perceived high levels of teaching skills among the clinical faculty. Faculty members who received e-mail-based spaced education-based faculty development were not rated to be more effective teachers on the student surveys. Electronically based faculty development does not satisfy faculty expectations. PMID- 22208834 TI - Surgical Morbidity and Mortality Conference using teleconferencing allows for increased faculty participation and moderation from satellite campuses and saves costs. AB - INTRODUCTION: Surgical faculty participation in Morbidity and Mortality Conference (MMC) satisfies criteria for Continuing Medical Education (CME) credit. We hypothesize that using teleconferencing between the main campus to 2 satellite campuses will quantitatively increase faculty attendance and participation as a moderator at surgical MMC. We also want to perform a cost benefit analysis of teleconferencing. METHODS: In this retrospective descriptive study, faculty attendance at MMC at the main campus and 2 satellite campuses was observed from January 1, 2010 through December 31, 2010. Groups were compared with nonparametric statistics, using an alpha = 0.05. We performed an annual cost benefit analysis of teleconferencing with consultation of an economist/financial advisor. The explicit and implicit costs of teleconferencing were compared with the opportunity cost-benefit of travel prevention. RESULTS: In 2010, there were 45 MMC activities. A total of 236 Continuing Medical Education credit hours were reported, with 186 credit hours at the main campus and 68 credit hours at the satellite campuses. A Mann-Whitney U test showed an increase in the median total attendance (5 per conference) with the addition of the satellite campus attendance (2 per conference) (p < 0.001). There were no differences between the number of moderators at the main campus and the satellite campuses (p > 0.99). Cost benefits per faculty member was $96.70 per conference at 1 satellite campus and $193.60 per conference at the second satellite campus. A total of 73.1 hours of travel time was prevented, with a total annual net benefit of $7624. CONCLUSIONS: Teleconferencing allows for increased faculty attendance at MMC and allows for faculty to stay at their respective hospitals for patient care. Teleconferencing also results in significant cost savings. We recommend that institutions with similar resources consider teleconferencing as a way to increase faculty member attendance at surgical MMC and to save hospital costs. PMID- 22208835 TI - Team play in surgical education: a simulation-based study. AB - BACKGROUND: Simulation-based training provides a low-stress learning environment where real-life emergencies can be practiced. Simulation can improve surgical education and patient care in crisis situations through a team approach emphasizing interpersonal and communication skills. OBJECTIVE: This study assessed the effects of simulation-based training in the context of trauma resuscitation in teams of trainees. METHODS: In a New York State-certified level I trauma center, trauma alerts were assessed by a standardized video review process. Simulation training was provided in various trauma situations followed by a debriefing period. The outcomes measured included the number of healthcare workers involved in the resuscitation, the percentage of healthcare workers in role position, time to intubation, time to intubation from paralysis, time to obtain first imaging study, time to leave trauma bay for computed tomography scan or the operating room, presence of team leader, and presence of spinal stabilization. Thirty cases were video analyzed presimulation and postsimulation training. The two data sets were compared via a 1-sided t test for significance (p < 0.05). Nominal data were analyzed using the Fischer exact test. RESULTS: The data were compared presimulation and postsimulation. The number of healthcare workers involved in the resuscitation decreased from 8.5 to 5.7 postsimulation (p < 0.001). The percentage of people in role positions increased from 57.8% to 83.6% (p = 0.46). The time to intubation from paralysis decreased from 3.9 to 2.8 minutes (p < 0.05). The presence of a definitive team leader increased from 64% to 90% (p < 0.05). The rate of spine stabilization increased from 82% to 100% (p < 0.08). After simulation, training adherence to the advanced trauma life support algorithm improved from 56% to 83%. CONCLUSIONS: High-stress situations simulated in a low-stress environment can improve team interaction and educational competencies. Providing simulation training as a tool for surgical education may enhance patient care. PMID- 22208836 TI - Three-phase model for surgical training: a proposal for improved resident training, assessment, and satisfaction. PMID- 22208837 TI - Urogynecology training and practice patterns after residency. AB - OBJECTIVE: The perspective of recent graduates is important in assessing the adequacy of training and for improving clinical and surgical education. The objective of this study was to evaluate the urogynecology experience of recent Obstetrics and Gynecology residency graduates, to examine perceived and actual surgical load during and after residency, and to assess comfort level with diagnosing and treating urinary incontinence and pelvic organ prolapse. DESIGN: Questionnaire assessing satisfaction with urogynecology rotation, perceived surgical load in residency, estimates of surgical procedures in current practice, and comfort level with diagnosing and treating incontinence and prolapse. SETTING: University of Texas Southwestern Medical Center, Dallas, Texas. PARTICIPANTS: Graduates from the University of Texas Southwestern Obstetrics and Gynecology residency program (1997-2006). RESULTS: Fifty-five percent (82/150) responded, with most being Caucasian, female, in private practice, and practicing in the Southern part of the United States. Forty-one of seventy-six (54%) rated their urogynecology experience as either acceptable, above average or superior. The most common procedures performed in residency were cystoscopy (mean, 11.3 +/- 5.2 cases per resident) and anterior (mean, 8.9 +/- 4.3 cases per resident) and posterior repair (mean, 11.1 +/- 5.7 cases per resident). Increasing the surgical volume was reported as the single most important factor that would have enhanced their training. In practice, midurethral slings were the most commonly performed incontinence procedures. Few were performing other urogynecologic cases in practice, except for anterior-posterior colporrhaphy and cystoscopy. Sixty-six of 70 (94%) in practice were comfortable with diagnosing prolapse and incontinence. Seventy percent and 80% estimated that less than 1 quarter of their patient population had prolapse or incontinence, respectively. CONCLUSIONS: Recent graduates from this program are comfortable making the diagnosis of prolapse and incontinence. The most commonly performed surgical procedures in residency and in practice include anterior and posterior colporrhaphy and cystoscopy. PMID- 22208838 TI - Women in academic surgery: the pipeline is busted. AB - PURPOSE: This investigation examined the trends for gender-based advancement in academic surgery by performing a comparative analysis of the rate of change in the percentage of medical students, surgery residents, and full professors of surgery who are women. METHODS: All available Women in Medicine Annual Reports were obtained from the American Association of Medical Colleges (AAMC). The gender compositions of medical graduates, surgery residents, and full professors were plotted. Binomial and linear trendlines were calculated to estimate the year when 50% of surgery full professors would be women. Additionally, the percentage distribution of men and women at each professorial rank was determined from 1995 to 2009 using these reports to demonstrate the rate of academic advancement of each gender. RESULTS: The slope of the line of increase for women full professors is significantly less than for female medical students and for female general surgery residents (0.36, compared with 0.75 and 0.99, respectively). This predicts that the earliest time that females will account for 50% of full professors in surgery is the year 2096. When comparing women and men in academic ranks, we find that women are much less likely than men to be full professors. CONCLUSIONS: The percentage of full professors in surgery who are women is increasing at a rate disproportionately slower than the increases in female medical students and surgery residents. The rates of increase in female medical students and surgery residents are similar. The disproportionately slow rate of increase in the number of female full professors suggests that multiple factors may be responsible for this discrepancy. PMID- 22208839 TI - Teaching evidence based medicine to surgery residents-is journal club the best format? A systematic review of the literature. AB - OBJECTIVE: Systematic reviews were performed to assess methods of teaching the evidence-based medicine (EBM) process and determine which format or what components of journal club appear to be most effective in teaching critical appraisal skills to surgical residents and have the highest user satisfaction. DESIGN: MEDLINE, Embase, Web of Science, AMED, PsychINFO, PubMed, Cochrane Library, and Google scholar were searched to identify relevant articles. To be included, studies had to provide details about the format of their EBM curriculum or journal club and report on the effectiveness or participant satisfaction. Potentially relevant articles were independently reviewed by 2 authors and data were extracted on separate data forms. RESULTS: Seven studies met the inclusion criteria for assessment of teaching EBM and 8 studies (including 3 in the EBM systematic review) met criteria for assessment of journal club format. Overall, study quality was poor. Only 2 studies were randomized controlled trials. Five were before-after studies, which showed significant improvement in critical appraisal skills or statistical knowledge following an EBM course or journal club. The 2 randomized controlled trials (RCTs) compared teaching EBM or critical appraisal skills in lecture format or journal club to online learning. There was no significant difference in mean scores in 1 study whereas the other reported significantly better scores in the journal club format. Four studies reported high participant satisfaction with the EBM course or journal club format. CONCLUSIONS: There is some evidence that courses with or without the addition of journal clubs lead to improved knowledge of the EBM process although the impact on patient care is unknown. Journal clubs seem to be the preferred way of teaching critical appraisal skills but while some components of journal clubs are favored by participants, it remains unclear which elements are most important for resident learning. PMID- 22208840 TI - Colonic volvulus in an adult after childhood Ladd's procedure for malrotation. AB - Malrotation and volvulus are encountered early in infancy and sometimes later in childhood, but rarely in adulthood. This ailment is treated through Ladd's adhesiolysis, detorsion, and possibly bowel resection. Literature is scarce on the long-term outcomes of this procedure, especially into adulthood. We present a case report of an adult female with a history of a laparotomy as a child for a bowel obstruction secondary to malrotation, presenting with an obstruction and colonic volvulus, secondary to an adhesive band, requiring emergent surgery. The patient did well postoperatively without complications. In adult patients presenting with a bowel obstruction and a consistent history in childhood, recurrence of volvulus should be considered as part of the differential diagnosis through a detailed history and assessment. PMID- 22208841 TI - Educational impact of the electronic medical record. AB - INTRODUCTION: The electronic medical record (EMR) is commonly thought to improve the safety and quality of care; however, there is scant information on the impact the EMR has on graduate medical education (GME). METHODS: A review of English language literature was performed using MEDLINE and OVID databases using or combining the terms, EMR, GME, electronic health record, education, medical student, resident, clinical decisions support systems, quality, and safety. RESULTS: The EMR has a negative effect on teacher and learner interactions, clinical reasoning, and has an inconsistent impact on resident workflow. Data on the impact of the EMR on patient safety, quality of care, and medical finances are mixed. DISCUSSION: Based on the literature to date, the EMR has not had as dramatic an effect on patient outcomes is commonly believed. While the overall impact of the EMR on education seems to be negative, there are actions that can be taken to mitigate this impact. PMID- 22208842 TI - Effect of the new standards for case logging on resident operative volume: doing better cases or better numbers? AB - OBJECTIVES: The Accreditation Council for Graduate Medical Education (ACGME) modified the designation of major (index) operative cases to include those previously considered "minor." This study assessed the potential effect of these changes on resident operative experience. METHODS: With Institutional Review Board approval, we analyzed National Surgical Quality Improvement Program participant use files for 2005-2008 for general and vascular surgery cases. Primary CPT case coding was mapped to the ACGME major case category using both the old and new classification schemes. The variables were analyzed using chi(2) analysis in SPSS IBM 19 (IBM, Armonk, New York). RESULTS: A total of 576,019 cases were reviewed. Major cases as defined by the new classification represented an increasing proportion of the cases each year, rising from 88.3% in 2005 to 95% by 2008 (p < 0.001). Major cases as defined by the old scheme decreased from 71% in 2005 to 62% by 2008 (p < 0.001). The cases covered by a resident dropped from 82% in 2005 to 61% in 2008 (p < 0.001). When comparing the new to the old scheme, 364,366 (63.3%) cases were considered major and 30,587 (5.3%) were minor by both standards; 7089 (1.2%) cases previously classified as major were changed to minor, whereas 173,977 (30.2%) (p < 0.001) previously classified as minor were now major. This latter group showed top procedures to include excision of breast lesion (22,175 [12.7%]), laparoscopic gastric bypass (18,825 [10.8%]), ventral hernia repair (14,732 [8.5%]), and appendectomy (10,190 [5.9%]). Of these newly designated major cases, the proportion not covered by residents increased from 22% in 2005 to 44% in 2007 and 2008 (p < 0.001). CONCLUSIONS: Although some operative cases newly classified as major are technically advanced procedures (eg, Roux-en-Y gastric bypass), other cases are not (eg, breast lesion excision), which raises the issue as to whether the major case category has been diluted by less demanding case types. The implications of these findings may suggest preservation of case volumes at the expense of case quality. PMID- 22208843 TI - The certifying examination of the american board of surgery: the effect of improving communication and professional competency: twenty-year results. AB - PURPOSE: In 1985, a small research group identified variables affecting applicant success on the oral Certifying Examination (CE) of the American Board of Surgery (ABS). This led to the design of an oral examination course first taught in 1991. The success of and need for this program led to its continuation. The results from the first 10 years were presented at the 2001 Association of Program Directors in Surgery annual meeting.(1) We now report the outcomes for the course of the second 10 years as measured by success on the CE. METHODS: Thirty-six courses were held over 20 years. There were 57 invited faculty from 27 general surgery programs throughout the United States and Canada. The participant-to faculty ratio ranged from 16:7 to 5:1 in the newer 3-day format (2007). Courses were offered at sites that replicated the actual examination setting. Each course included (1) pretest and posttest examinations, (2) analysis of case presentation skills, (3) measurement of communication apprehension, (4) 1:1 faculty feedback, (5) small-group practice sessions, (6) individual videotaping, (7) didactic review of specific behaviors on examinations, (8) a debrief session with two faculty members, and (9) a written evaluative summary that included an improvement strategy. RESULTS: There were 36 courses with 326 participants (30-54 years). Follow-up data are available for 225 participants. Trends were analyzed between 1991-2001 and 2002-2011. As resident performance on the CE increased in importance, applicant profiles changed from those who had previously failed (1991 2001) to residents identified by program directors as needing assistance (52%). Since 2002, most course participants (69%) who had failed the CE had completed at least 1 other review course. Participants reported more significant stressors (2002-2011) 9%, but communication apprehension remained the same. As a result, individual counseling for anger and family stressors was integrated into the course. The perception of knowledge deficits was associated with those who enrolled in fellowship training and delayed their examination. The recent groups exhibited more professionalism and articulation issues related to performance. Five surgeons (2002-2011) were asked not to return to the course because of severe knowledge deficiencies or ethical/behavioral issues based on faculty evaluations. Although complete follow-up of all participants was not possible (only 225/326), the success rate among those providing follow-up was 97% for those who followed their remediation plan, giving 218/326, a worse-case pass rate of 67%. CONCLUSION: Communication and professionalism deficits are still common in those struggling with the CE, Early identification of those at risk of failing by program directors who are documenting the competencies may promote earlier interventions and thus lead to success. This program continues to be effective at identifying behaviors that interfere with success on the CE of the ABS. PMID- 22208844 TI - Richard B. Cattell: master surgeon, teacher, and innovator. AB - Richard B. Cattell (1900-1964) was a general surgeon widely revered for his masterful technical skills and innovative approaches to complicated surgical cases. In addition to his surgical prowess, he fostered a deep commitment to medical education,but above all emphasized the importance of humanity inpatient care. He has left a remarkable legacy for present and future surgeons to strive to emulate. "To know him was to admire him, to respect him, and to love him. He was a magnificent physician who walked among the greatest, but never lost the common touch. PMID- 22208845 TI - Surgeon-performed ultrasound--a call for consensus and standardization. PMID- 22208846 TI - Nonsuicidal self-injury and diminished pain perception: the role of emotion dysregulation. AB - Nonsuicidal self-injury (NSSI) is the deliberate destruction of one's own body tissue in the absence of suicidal intent (e.g., cutting or burning the skin). Previous studies have found that people with a history of NSSI display diminished pain perception. However, it remains unclear why this effect occurs. In the present study, we used a sample of participants with (n = 25) and without (n = 47) a history of NSSI to test the hypothesis that emotion dysregulation partially explains why NSSI is associated with diminished pain perception. Pain perception was quantified as pain threshold, pain tolerance, and pain intensity ratings assessed during the cold pressor task. Nonsuicidal self-injury was associated with increased emotion dysregulation and diminished pain perception. Results showed that emotion dysregulation was correlated with diminished pain perception within both groups, demonstrating that this association exists regardless of NSSI history. Results also specified that emotion dysregulation partially accounted for the association between NSSI and pain tolerance but not other pain variables. Overall, results were consistent with the hypothesis that emotion dysregulation may increase NSSI risk in part by increasing the willingness to experience the pain involved in self-injury. Studies are needed to more directly investigate this hypothesis. PMID- 22208847 TI - BPEX Pig Health Scheme: a useful monitoring system for respiratory disease control in pig farms? AB - BACKGROUND: Respiratory diseases account for significant economic losses to the UK pig industry. Lesions indicative of respiratory disease in pig lungs at slaughter e.g. pneumonia and pleuritis are frequently recorded to assess herd health or provide data for epidemiological studies. The BPEX Pig Health Scheme (BPHS) is a monitoring system, which informs producers of gross lesions in their pigs' carcasses at slaughter, enabling farm-level decisions to be made. The aim of the study was to assess whether information provided by the BPHS regarding respiratory lesions was associated with respiratory pathogens in the farm, farm management practices and each other. RESULTS: BPHS reports were obtained from a subset of 70 pig farms involved in a cross-sectional study conducted in 2008-09 investigating the epidemiology of post-weaning multi-systemic wasting syndrome. The reports were combined with data regarding the presence/absence of several pathogens in the herd and potential farm-level risk factors for respiratory disease. Principal component analysis (PCA) performed on BPHS reports generated three principal components, explaining 71% of the total variance. Enzootic pneumonia score, severe pleurisy and acute pleuropneumonia had the highest loadings for the principal component which explained the largest percentage of the total variance (35%) (BPHS component 1), it was thought that this component identifies farms with acute disease. Using the factor loadings a score for each farm for BPHS component 1 was obtained. As farms' score for BPHS component 1 increased, average carcass weight at slaughter decreased. In addition, farms positive for H1N2 and porcine reproductive and respiratory disease virus (PRRSV) were more likely to have higher levels of severe and mild pleurisy reported by the BPHS, respectively. CONCLUSIONS: The study found statistical associations between levels of pleurisy recorded by BPHS at slaughter and the presence H1N2 and PRRSV in the herd. There is also some evidence that farms which submit pigs with these lesions may have reduced productivity. However, more research is needed to fully validate the scheme. PMID- 22208848 TI - Down-regulation of HSP70 sensitizes gastric epithelial cells to apoptosis and growth retardation triggered by H. pylori. AB - BACKGROUND: H. pylori infection significantly attenuated the expression of HSP70 in gastric mucosal cells. However, the role of HSP70 cancellation in H. pylori associated cell damages is largely unclear. METHODS: Small interfering RNA (siRNA) was used to down-regulate HSP70 in gastric epithelial cell lines AGS. The transfected cells were then incubated with H. pylori and the functions of HSP70 suppression were observed by viability assay, cell cycle analyses and TUNEL assay. HSP70 target apoptotic proteins were further identified by Western blot. RESULTS: The inhibition of HSP70 has further increased the effect of growth arrest and apoptosis activation triggered by H. pylori in gastric epithelial cells. The anti-proliferation function of HSP70 depletion was at least by up regulating p21 and cell cycle modulation with S-phase accumulation. An increase of apoptosis-inducing factor (AIF) and cytosolic cytochrome C contributes to the activation of apoptosis following down-regulation of intracellular HSP70. Extracellular HSP70 increased cellular resistance to apoptosis by suppression the release of AIF and cytochrome c from mitochondria, as well as inhibition of p21 expression. CONCLUSIONS: The inhibition of HSP70 aggravated gastric cellular damages induced by H. pylori. Induction of HSP70 could be a potential therapeutic target for protection gastric mucosa from H. pylori-associated injury. PMID- 22208851 TI - Three-dimensional Ni/TiO2 nanowire network for high areal capacity lithium ion microbattery applications. AB - The areal capacity of nanowire-based microbatteries can be potentially increased by increasing the length of nanowires. However, agglomeration of high aspect ratio nanowire arrays could greatly degrade the performance of nanowires for lithium ion (Li-ion) battery applications. In this work, a three-dimensional (3 D) Ni/TiO(2) nanowire network was successfully fabricated using a 3-D porous anodic alumina (PAA) template-assisted electrodeposition of Ni followed by TiO(2) coating using atomic layer deposition. Compared to the straight Ni/TiO(2) nanowire arrays fabricated using conventional PAA templates, the 3-D Ni/TiO(2) nanowire network shows higher areal discharging capacity. The areal capacity increases proportionally with the length of nanowires. With a stable Ni/TiO(2) nanowire network structure, 100% capacity is retained after 600 cycles. This work paves the way to build reliable 3-D nanostructured electrodes for high areal capacity microbatteries. PMID- 22208850 TI - MicroRNAs and their isomiRs function cooperatively to target common biological pathways. AB - BACKGROUND: Variants of microRNAs (miRNAs), called isomiRs, are commonly reported in deep-sequencing studies; however, the functional significance of these variants remains controversial. Observational studies show that isomiR patterns are non-random, hinting that these molecules could be regulated and therefore functional, although no conclusive biological role has been demonstrated for these molecules. RESULTS: To assess the biological relevance of isomiRs, we have performed ultra-deep miRNA-seq on ten adult human tissues, and created an analysis pipeline called miRNA-MATE to align, annotate, and analyze miRNAs and their isomiRs. We find that isomiRs share sequence and expression characteristics with canonical miRNAs, and are generally strongly correlated with canonical miRNA expression. A large proportion of isomiRs potentially derive from AGO2 cleavage independent of Dicer. We isolated polyribosome-associated mRNA, captured the mRNA bound miRNAs, and found that isomiRs and canonical miRNAs are equally associated with translational machinery. Finally, we transfected cells with biotinylated RNA duplexes encoding isomiRs or their canonical counterparts and directly assayed their mRNA targets. These studies allow us to experimentally determine genome wide mRNA targets, and these experiments showed substantial overlap in functional mRNA networks suppressed by both canonical miRNAs and their isomiRs. CONCLUSIONS: Together, these results find isomiRs to be biologically relevant and functionally cooperative partners of canonical miRNAs that act coordinately to target pathways of functionally related genes. This work exposes the complexity of the miRNA transcriptome, and helps explain a major miRNA paradox: how specific regulation of biological processes can occur when the specificity of miRNA targeting is mediated by only 6 to 11 nucleotides. PMID- 22208853 TI - Commentary: I want to be sedated. PMID- 22208852 TI - MotifMap: integrative genome-wide maps of regulatory motif sites for model species. AB - BACKGROUND: A central challenge of biology is to map and understand gene regulation on a genome-wide scale. For any given genome, only a small fraction of the regulatory elements embedded in the DNA sequence have been characterized, and there is great interest in developing computational methods to systematically map all these elements and understand their relationships. Such computational efforts, however, are significantly hindered by the overwhelming size of non coding regions and the statistical variability and complex spatial organizations of regulatory elements and interactions. Genome-wide catalogs of regulatory elements for all model species simply do not yet exist. RESULTS: The MotifMap system uses databases of transcription factor binding motifs, refined genome alignments, and a comparative genomic statistical approach to provide comprehensive maps of candidate regulatory elements encoded in the genomes of model species. The system is used to derive new genome-wide maps for yeast, fly, worm, mouse, and human. The human map contains 519,108 sites for 570 matrices with a False Discovery Rate of 0.1 or less. The new maps are assessed in several ways, for instance using high-throughput experimental ChIP-seq data and AUC statistics, providing strong evidence for their accuracy and coverage. The maps can be usefully integrated with many other kinds of omic data and are available at http://motifmap.igb.uci.edu/. CONCLUSIONS: MotifMap and its integration with other data provide a foundation for analyzing gene regulation on a genome-wide scale, and for automatically generating regulatory pathways and hypotheses. The power of this approach is demonstrated and discussed using the P53 apoptotic pathway and the Gli hedgehog pathways as examples. PMID- 22208854 TI - Value of bone SPECT-CT to predict chronic pain relief after percutaneous vertebroplasty in vertebral fractures. AB - BACKGROUND CONTEXT: Longer life span has resulted in increased risk of vertebral osteoporotic fractures. Among minimally invasive procedures, percutaneous vertebroplasty (PV) has shown excellent results in the treatment of chronic vertebral pain. The role of preintervention bone single photon emission computed tomography-computed tomography (SPECT-CT) has not been clearly established for the management of these patients. PURPOSE: To determine the value of bone SPECT CT in patient selection, treatment planning, and prediction of response to PV. A comparison with magnetic resonance imaging (MRI) was also aimed. STUDY DESIGN: Prospective consecutive series. PATIENT SAMPLE: We studied the performance of bone SPECT-CT on 33 consecutive patients with chronic pain because of vertebral fracture intended for PV. OUTCOME MEASURES: Improvement of clinical status was based on comparison of preprocedure and postprocedure outcome measurements of pain, mobility, and analgesic use. METHODS: Bone SPECT was done using a dual detector variable-angle gamma camera coupled with a two-slice CT scanner (Symbia T2 System; Siemens, Munich, Germany). Magnetic resonance imaging was done using a magnet of 1.5 T (Giroscan System ACS NT Intera; Philips, Amsterdam, The Netherlands). RESULTS: Of the 33 patients, 24 finally underwent PV. Positive SPECT-CT images predicted clinical improvement in 91% (21 of 23) of them. Agreement between SPECT-CT and MRI was 80% (20 of 25). Single photon emission computed tomography-computed tomography images showed an alternative cause of pain in some cases, such as new fractures or multiple coexisting fractures, persisting bone remodeling in a previous cemented vertebra, and facet or discal degenerative disease. Single photon emission computed tomography-computed tomography was mandatory in eight patients that could no receive MRI, all of whom improved after PV. CONCLUSIONS: Positive bone SPECT-CT seems a good predictor of postprocedural response. It also adds valuable information as to the cause of back pain and facilitates complete patient evaluation in patients that can not receive MRI. PMID- 22208855 TI - A diagnostic classification for lumbar spine registry development. AB - BACKGROUND CONTEXT: Low back pain (LBP) is a symptom, not a diagnosis. The failure to differentiate underlying diagnoses in patients complaining of LBP is one of the primary reasons that studies examining treatments for LBP have yielded inconsistent results. To design a lumbar spine registry such that the accumulated data provide applicable guidance for clinical treatment, the incorporation of a functional diagnostic matrix is critical. PURPOSE: To propose a clinically relevant diagnostic classification scheme, simple enough for use in clinical practice but granular enough to differentiate characteristics that impact clinical outcome. STUDY DESIGN: Case-based development, feasibility, and reliability testing of a classification scheme. PATIENT SAMPLE: Thirty case histories were compiled. Each case consisted of a brief clinical history with physical examination findings as well as pertinent radiographic images, including computed tomography scan and magnetic resonance image when available. OUTCOME MEASURES: Kappa values for inter- and intrarater reliability. METHODS: Thirty-six physicians were asked to provide a three-digit diagnostic code, specifying Symptoms, Structural Pathology, and Compressive Pathology for each case. The cases were then randomly rearranged and sent back to the physicians 2 weeks later for a second review. Inter- and intraobserver reliability was calculated using Randolph's free-marginal multirater kappa. Symptoms are classified differentiating between patients with back or leg pain dominance and those with equal back and leg pain; symptoms are also divided as acute versus chronic. Additional categories denote neurogenic claudication and cauda equina. Structural Pathology includes an option for age appropriate changes. Additional options include disc pathology with and without disc space collapse; spondylolisthesis or spondylolysis without olisthesis; and regional spinal deformity, either scoliosis or kyphosis. The remaining structural categories are primary facet pathology and nonunion after attempted fusion. Compressive Pathology includes a category indicating the absence of any study on which to judge compressive pathology and a category indicating an available study, but the lack of any clinically relevant compressive pathology. Additional options are for either central compression or lateral recess/foraminal/extraforaminal compressive pathology of any etiology. There is also a category for combined central and lateral compression. The final category is recurrent compression, central, lateral, or combined compression after surgical treatment at the involved level. It is important to emphasize that the intention is only to categorize Structural and Compressive Pathology that is relevant to the patient's symptom complex. When more than one relevant structural or compressive lesion exists, the provider should select the most clinically relevant finding. RESULTS: The interrater agreement was substantial for Symptoms (kappa=0.70) and moderate for Structural Pathology (kappa=0.58) and Compressive Pathology (kappa=0.53). The intrarater agreement was substantial for Symptoms (kappa=0.78), Structural Pathology (kappa=0.70), or Compressive Pathology (kappa=0.67). CONCLUSIONS: This study demonstrates that improved diagnostic stratification of lumbar spine disorders is a feasible goal. The diagnostic coding matrix, based on clinically relevant descriptors, yielded substantial interrater consistency for symptoms, moderate interrater consistency for structural and compressive pathology, and substantial intrarater consistency for all elements. PMID- 22208856 TI - Extraforaminal ligaments of the cervical spinal nerves in humans. AB - BACKGROUND CONTEXT: During the last 120 years, several mechanisms to protect the spinal nerve against traction have been described. All the described structures were located inside the spinal canal proximal to the intervertebral foramen. Ligaments with a comparable function just outside the intervertebral foramen are mentioned ephemerally. No studies are available about ligamentous attachments of cervical spinal nerves to adjacent vertebrae. PURPOSE: To identify and describe ligamentous structures at each cervical level that attaches spinal nerves to structures in the extraforaminal region. STUDY DESIGN/SETTING: An anatomical study of the extraforaminal attachments of the cervical spinal nerves was performed using human spinal columns. METHODS: Five embalmed human cervical spines (C1-C8) were dissected. The extraforaminal region was dissected bilaterally to describe and measure anatomical structures and their relationships with the cervical spinal nerves. Histology was done on the ligamentous connections of nerves to the adjacent vertebral structures. RESULTS: The cervical spinal nerves are attached to the transverse process of the vertebrae. The connecting ligaments consist mainly of collagenous fibers. CONCLUSIONS: At the cervical level, direct ligamentous connections exist between extraforaminal cervical spinal nerves and nearby structures. They may serve as a protective mechanism against traction. In addition, these ligaments play an important role in the positioning of the nerves in the intervertebral foramen. PMID- 22208857 TI - Magnitude of spinal muscle damage is not statistically associated with exercise induced low back pain intensity. AB - BACKGROUND CONTEXT: Findings on imaging of noncontractile anatomic abnormalities and the intensity of low back pain have weak associations because of false positive rates among asymptomatic individuals. This association might be stronger for contractile tissues. PURPOSE: The purpose of this study was to examine the relationship between location and reports of pain intensity in the low back and exercise-induced muscle damage to the lumbar paraspinal muscles. STUDY DESIGN: Nondiagnostic observational study in a laboratory setting. METHODS: Delayed onset muscle soreness was induced in the low back of healthy pain-free volunteers. Measures of pain intensity (100-mm visual analog scale [VAS]) and location (area on the pain diagram) were taken before and 48 hours after exercise. Muscle damage was quantified using mechanical pain thresholds, motor performance deficits, and transverse relaxation time (T2)-weighted magnetic resonance imaging (MRI). Changes pre- to postexercise in signal intensity on T2-weighted imaging within the erector spinae, pain intensity, pain area, mechanical pain threshold, and isometric torque were assessed using paired t tests. Bivariate correlations were conducted to assess associations among muscle damage, pain intensity, and pain drawing area. RESULTS: Twenty participants volunteered (11 women; average age, 22.3 years; average body mass index, 23.5) for study participation. Reports of pain intensity at 48 hours ranged from 0 to 59 mm on the VAS. Muscle damage was confirmed by reductions in mechanical threshold (p=.011) and motor performance (p<.001) and by changes in T2-weighted MRI (p=.007). This study was powered to find an association of at least r=0.5 to be statistically significant. Correlations of continuous variables revealed no significant correlations between pain intensity and measures of muscle damage (ranging between -0.075 and 0.151). There was a significant association between the remaining torque deficit at 48 hours and pain area. CONCLUSIONS: The results of this study indicate that there was no association between the magnitude of muscle damage in the lumbar erector spinae and reported pain intensity in the low back. In future studies, larger cohorts may report statistically significant associations, but our data suggest that there will be low magnitude potentially indicating limited clinical relevance. PMID- 22208858 TI - Neglected esophageal perforation after upper thoracic vertebral fracture. AB - BACKGROUND CONTEXT: Esophageal perforation associated with thoracic fracture is extremely rare. If not diagnosed at an early stage, it can lead to life threatening complications, such as mediastinitis and sepsis. PURPOSE: To report a case of esophageal perforation after T2 compression fracture that was initially missed and subsequently developed into osteomyelitis involving adjacent vertebrae. STUDY DESIGN: A case report and review of the literature. METHODS: A 49-year-old man with severe upper thoracic back pain and intermittent fever was referred to our hospital. Five months before presentation, the patient was diagnosed with compression fracture of T2 vertebra with a teardrop fragment. On initial computed tomography (CT) and magnetic resonance imaging (MRI), there was no appreciable periesophageal-free gas. However, the posterior wall of the esophagus was compressed by a beak-like fracture fragment. Magnetic resonance imaging showed an infectious spondylitis of T1-T2, which mimicked esophageal cancer with local tumor infiltration. No dye leakage from the esophagus was found on contrast esophagography. RESULTS: After empiric antibiotic therapy for 4 months, subsequent radiographs of the spine did not reveal any further collapse or destruction of the vertebral bodies, and inflammatory markers returned to normal limits. There was no recurrence of symptoms at the 2-year follow-up. CONCLUSIONS: Esophageal perforation after upper thoracic vertebral fracture can develop when the fracture fragment pierces the posterior wall of the esophagus. In addition to periesophageal-free air, crushing, distortion, or marked displacement of the esophagus at the cervicothoracic junction on CT or MRI is a clue to potential esophageal injury. If not identified early, patients may present with chronic osteomyelitis extending to adjacent vertebrae. PMID- 22208859 TI - The imaging and management of nonconsecutive pars interarticularis defects: a case report and review of literature. AB - BACKGROUND CONTEXT: Lumbar spondylolysis is a well-recognized condition occurring in adolescents because of repetitive overuse in sports. Multiple-level spondylolysis involving consecutive lower lumbar segments are rare. Several authors have reported failure of conservative treatment in the management of multiple-level pars fractures. STUDY DESIGN: A case report and review of previous literature is presented. OBJECTIVE: The objectives of this case report were to present a rare case of pars fracture involving nonconsecutive segments and discuss image findings and treatment. METHODS: The patent's history, clinical examination, computed tomography (CT), magnetic resonance imaging (MRI) findings, and treatment are reported. We also discuss the pathogenesis, various treatment options, and review the literature. RESULTS: We present the fourth case of bilateral pars fractures involving nonconsecutive lower lumbar spine segments of L3 and L5, in a 16-year-old young adolescent footballer who presented with 4 month history of constant low back pain. After 1 year of conservative management, the more acute fractures at L3 showed complete bony union, symptomatic pain relief, and return to full sporting activity. CONCLUSION: We report a rare case of bilateral pars fractures involving nonconsecutive segments. Multiplane reconstruction of CT images and MRI are very useful in planning treatment and follow-up. Conservative management may be used to treat multilevel nonconsecutive pars fractures. PMID- 22208861 TI - Mapping of the Insomnia Severity Index and other sleep measures to EuroQol EQ-5D health state utilities. AB - BACKGROUND: This study sought to map the Insomnia Severity Index (ISI) and symptom variables onto the EQ-5D. METHODS: A cross-sectional survey was conducted among adult US residents with self-reported sleep problems. Respondents provided demographic, comorbidity, and sleep-related information and had completed the ISI and the EQ-5D profile. Respondents were classified into ISI categories indicating no, threshold, moderate, or severe insomnia. Generalized linear models (GLM) were used to map the ISI's 7 items (Model I), summary scores (Model II), clinical categories (Model III), and insomnia symptoms (Model IV), onto the EQ-5D. We used 50% of the sample for estimation and 50% for prediction. Prediction accuracy was assessed by mean squared errors (MSEs) and mean absolute errors (MAEs). RESULTS: Mean (standard deviation) sleep duration for respondents (N = 2,842) was 7.8 (1.9) hours, and mean ISI score was 14.1 (4.8). Mean predicted EQ-5D utility was 0.765 (0.08) from Models I-III, which overlapped with observed utilities 0.765 (0.18). Predicted utility using insomnia symptoms was higher (0.771(0.07)). Based on Model I, predicted utilities increased linearly with improving ISI (0.493 if ISI = 28 vs. 1.00 if ISI = 0, p < 0.01). From Model II, each unit decrease in ISI summary score was associated with a 0.022 (p < 0.001) increase in utility. Predicted utilities were 0.868, 0.809, 0.722, and 0.579, respectively, for the 4 clinical categories, suggesting that lower utility was related to greater insomnia severity. The symptom model (Model IV) indicated a concave sleep duration function of the EQ-5D; thus, utilities diminished after an optimal amount of sleep. The MSEs/MAEs were substantially lower when predicting EQ-5D > 0.40, and results were comparable in all models. CONCLUSIONS: Findings suggest that mapping relationships between the EQ-5D and insomnia measures could be established. These relationships may be used to estimate insomnia-related treatment effects on health state utilities. PMID- 22208863 TI - Functional binary micropattern of hyperbranched poly(ether amine) (hPEA-AN) network and poly(ether amine) (PEA) brush for recognition of guest molecules. AB - A binary micropattern of anthracene-contained hyperbranched poly(ether amine) (hPEA-AN) network and poly(ether amine) (PEA) brush on gold surface was developed and explored. First, a micropatterned hPEA-AN network array on gold surface was fabricated by photolithography via photodimerization of anthracene moieties, and a PEA brush was subsequently immobilized on the remaining free gold surface areas by chemical adsorption of thiol groups. The patterned hPEA-AN network exhibits selectivity with respect to the adsorption of hydrophilic dyes: Methyl orange is strongly adsorbed, but rhodamine 6G is not, as indicated by the fluorescence response. The PEA brush domain exhibits excellent protein adsorption repellency, whereas the hPEA-AN network layer readily adsorbs protein. These characteristics make the binary hPEA-AN network and PEA brush array sensitive to different kinds of dyes and proteins, which open up pathways to potential applications as microsensors, biochips, and bioassays. PMID- 22208865 TI - Peri-implant biomechanical responses to standard, short-wide, and mini implants supporting single crowns under axial and off-axial loading (an in vitro study). AB - This study compared the biomechanical responses of 3 single crowns supported by 3 different implants under axial and off-axial loading. A standard implant (3.75 mm diameter, 13 mm length), a mini implant (3 mm diameter, 13 mm length), and a short-wide implant (5.7 mm diameter, 8 mm length) were embedded in epoxy resin by the aid of a surveyor to ensure their parallelism. Each implant supported a full metal crown made of Ni-Cr alloy with standardized dimensions. Strain gauges and finite element analysis (FEA) were used to measure the strain induced under axial and off-axial functional loads of 300 N. Results showed that mini implants recorded the highest microstrains, under both axial and off-axial loading. All implants showed a considerable increase in strain values under off-axial loading. Standard and short-wide implants proved to be preferable in supporting crowns, as the standard implant showed the lowest strains under axial and off-axial loading using FEA simulation, while the short-wide implant showed the lowest strains under nonaxial loading using strain gauge analysis. PMID- 22208867 TI - Designing nanoparticle translocation through membranes by computer simulations. AB - Nanoparticle penetration into cells is an important process in drug/gene delivery. Here, we successfully design one type of novel nanoparticles with ligands decorating its surface by dynamic bonds and find that the nanoparticle can spontaneously penetrate through membranes by using dissipative particle dynamics simulations. Moreover, the physical parameters of both ligands (for example, ligand type and density) and nanoparticles (such as size and shape) have significant effects on penetration efficiency and translocation time. Especially for nanoparticles with anisotropic shapes or asymmetric surface decoration, the penetration efficiency may reach about 80%. We also provide insights into the interaction between nanoparticles and asymmetric membranes and find that the membrane asymmetry can even increase the penetration efficiency to above 90%. The present study suggests a potential way to translocate novel nanoparticles through membranes, which may provide new ideas for future experimental nanoparticle design and drug delivery. PMID- 22208869 TI - The diversity and abundance of small arthropods in onion, Allium cepa, seed crops, and their potential role in pollination. AB - Onion, Allium cepa L. (Asparagales: Amaryllidaceae), crop fields grown for seed production require arthropod pollination for adequate seed yield. Although many arthropod species visit A. cepa flowers, for most there is little information on their role as pollinators. Small flower visiting arthropods (body width < 3 mm) in particular are rarely assessed. A survey of eight flowering commercial A. cepa seed fields in the North and South Islands of New Zealand using window traps revealed that small arthropods were highly abundant among all except one field. Insects belonging to the orders Diptera and Thysanoptera were the most abundant and Hymenoptera, Collembola, Psocoptera, Hemiptera, and Coleoptera were also present. To test whether small arthropods might contribute to pollination, seed sets from umbels caged within 3 mm diameter mesh cages were compared with similarly caged, hand-pollinated umbels and uncaged umbels. Caged umbels that were not hand-pollinated set significantly fewer seeds (average eight seeds/umbel, n = 10) than caged hand-pollinated umbels (average 146 seeds/umbel) and uncaged umbels (average 481 seeds/umbel). Moreover, sticky traps placed on umbels within cages captured similar numbers of small arthropods as sticky traps placed on uncaged umbels, suggesting cages did not inhibit the movement of small arthropods to umbels. Therefore, despite the high abundance of small arthropods within fields, evidence to support their role as significant pollinators of commercial A. cepa seed crops was not found. PMID- 22208873 TI - Association of health literacy with complementary and alternative medicine use: a cross-sectional study in adult primary care patients. AB - BACKGROUND: In the United States, it is estimated that 40% of adults utilize complementary and alternative medicine (CAM) therapies. Recently, national surveys report that over 90 million adults have inadequate health literacy. To date, no study has assessed health literacy and its effect on CAM use. The primary objective of this study was to assess the relationship between health literacy and CAM use independent of educational attainment. Second objective was to evaluate the differential effect of health literacy on CAM use by race. METHODS: 351 patients were recruited from an outpatient primary care clinic. Validated surveys assessed CAM use (I-CAM-Q), health literacy (REALM-R), and demographic information. We compared demographics by health literacy (adequate vs. inadequate) and overall and individual CAM categories by health literacy using chi square statistics. We found a race by health literacy interaction and ran sequential logistic regression models stratified by race to test the association between health literacy and overall CAM use (Model 1), Model 1 + education (Model 2), and Model 2 + other demographic characteristics (Model 3). We reported the adjusted effect of health literacy on CAM use for both whites and African Americans separately. RESULTS: 75% of the participants had adequate literacy and 80% used CAM. CAM use differed by CAM category. Among whites, adequate health literacy was significantly associated with increased CAM use in both unadjusted (Model 1, OR 7.68; p = 0.001) and models adjusted for education (Model 2, OR 7.70; p = 0.002) and other sociodemographics (Model 3, OR 9.42; p = 0.01). Among African Americans, adequate health literacy was not associated with CAM use in any of the models. CONCLUSIONS: We found a race by literacy interaction suggesting that the relationship between health literacy and CAM use differed significantly by race. Adequate health literacy among whites is associated with increased CAM use, but not associated with CAM use in African Americans. PMID- 22208874 TI - Adipose stem cell-based soft tissue regeneration. AB - INTRODUCTION: Since their isolation and characterization nearly a decade ago, adipose-derived stem cells (ASCs) have become one of the most popular adult stem cell populations for research in soft tissue engineering and regenerative medicine applications. Compared with other stem cell sources, ASCs offer several advantages including an abundant autologous source, minor invasive harvesting (liposuction), significant proliferative capacity in culture and multi-lineage potential. Numerous preclinical studies have been pursued, with early clinical data appearing in the literature. AREAS COVERED: Autologous fat grafting has gained tremendous momentum in clinical practice over the past several years due to its potential applications in trauma and reconstructive surgery. This review focuses on the published clinical and pre-clinical (i.e., animal) data to date using ASCs for soft tissue reconstruction, with particular attention to experimental models and methodologies. Future directions for rendering soft tissue reconstructive therapies more effective are discussed. EXPERT OPINION: Although standardization of ASC harvesting and processing techniques, as well as long-term results of existing clinical studies, remains to be addressed, the known biological properties of ASCs suggest a potential role in enhancing fat graft retention and facilitating minimally invasive reconstructive treatments. While clinical applications are being reported, well controlled clinical studies are needed to demonstrate safety and efficacy. PMID- 22208875 TI - Halide ion complexes of decaborane (B10H14) and their derivatives: noncovalent charge transfer effect on second-order nonlinear optical properties. AB - Quantum molecular engineering has been performed to determine the second-order nonlinear optical (NLO) properties in different halo complexes of decaborane (B(10)H(14)) and their derivatives using the density functional theory (DFT) method. These decaborane halo complexes of X(-)@B(10)H(14) (X = F, Cl, Br, and I) are found to possess noncovalent charge transfer interactions. The static polarizability (alpha(0)) and first hyperpolarizability (beta(0)) among these complexes increase by moving down the group from F to I, partly due to the increase in size of their anionic radii and the decrease in their electron affinities. A two-level approximation has been employed to investigate the origin of beta(0) values in these halo complexes, which show very consistent results with those by the finite-field method. Furthermore, in the same line, two experimentally existing complexes, I(-)@B(10)H(14) and I(-)@2,4-I(2)B(10)H(12), are found to have considerably large beta(0) values of 2859 and 3092 a.u., respectively, which are about three times larger than a prototypical second-order NLO molecule of p-nitroaniline, as reported by Soscun et al. [Int. J. Quantum Chem.2006, 106, 1130-1137]. Besides this, the special effects of solvent, counterion, and bottom substitutions have also been investigated. Interestingly, 2,4-alkali metal-substituted decaborane iodide complexes show remarkably large second-order NLO response with beta(0) amplitude as large as 62436 a.u. for I( )@2,4-K(2)B(10)H(12) complex, which are explained in terms of their transition energies, frontier molecular orbitals and electron density difference plots. Thus, the present investigation provides several new comparative insights into the second-order NLO properties of halo complexes of decaborane, which possess not only large first hyperpolarizabilities, but also high tunability to get a robustly large second-order NLO response by alkali metal substitution effects. PMID- 22208876 TI - Evaluating gaze control on a multi-target sequencing task: the distribution of fixations is evidence of exploration optimisation. AB - Many high cognitive applications, such as vision processing and representation and understanding of images, often need to analyse in detail how an ongoing visual search was performed in a representative subset of the image, which may be arranged into sequences of loci, called regions of interest (ROIs). We used the Trial Making Test (TMT) in which subjects are asked to fixate a sequence of letters and numbers in a logical alphanumeric order. The main characteristic of TMT is to force the subject to perform a default and well-known path. The comparison of the expected scan-path with the observed scan-path provides a valuable method to investigate how a task force the subject to maintain a top down internal representation of execution and how bottom-up influences the performance. We developed a mechanism that analyses the scan path using different algorithms, and we compared it with other methods: we found that fixations outside the ROI are direct influence of exploration strategy. The paper discusses the method in healthy subjects. PMID- 22208877 TI - Difficulty accessing crack pipes and crack pipe sharing among people who use drugs in Vancouver, Canada. AB - BACKGROUND: Crack pipe sharing can increase health risks among people who use drugs, yet the reasons for sharing these pipes have not been well described. Therefore, we sought to identify the prevalence and correlates of crack pipe sharing among a community-recruited sample of people who use illicit drugs in Vancouver, a setting where crack pipes are provided at low or no cost. FINDINGS: Data for this study were derived from two prospective cohorts of people who use drugs: the Vancouver Injection Drug Users Study (VIDUS) and the AIDS Care Cohort to evaluate Exposure to Survival Services (ACCESS). Multivariate logistic regression was used to identify factors independently associated with crack pipe sharing. Among 503 crack users, 238 (47.3%) participants reported having shared a crack pipe in the previous six months. Having acquired a mouthpiece in the last six months (adjusted odds ratio [AOR] = 1.91; 95% confidence interval [CI]: 1.31 2.79) and difficulty finding new pipes (AOR = 2.19; 95%CI: 1.42 - 3.37) were positively associated with pipe sharing. Binge drug use (AOR = 1.39; 95%CI: 0.96 2.02) was marginally associated with sharing pipes. DISCUSSION: There was a high prevalence of crack pipe sharing in a setting where crack pipes are distributed at low or no cost. Difficulty accessing crack pipes was independently and positively associated with this behavior. These findings suggest that additional efforts are needed to discourage crack pipe sharing as well as increase access to crack pipes. PMID- 22208878 TI - Intracardiac left atrial tuberculoma in an eleven-month-old infant: case report. AB - BACKGROUND: Cardiac tuberculosis is rare and usually manifests as tuberculous pericarditis. Involvement of other part of the heart is unusual and descriptions in the pediatric literature are confined to few case reports regarding mainly myocardial tuberculosis. CASE PRESENTATION: We describe a case of pulmonary miliary tuberculosis associated with intracardiac left atrial tuberculoma in an immunocompetent eleven-month-old infant successfully treated with surgery and antituberculous therapy. CONCLUSION: Although unusual, involvement of endocardium in disseminated tuberculosis should be kept in mind. PMID- 22208881 TI - Application of plasmonic bowtie nanoantenna arrays for optical trapping, stacking, and sorting. AB - We present the use of Au bowtie nanoantenna arrays (BNAs) for highly efficient, multipurpose particle manipulation with unprecedented low input power and low numerical aperture (NA) focusing. Optical trapping efficiencies measured are up to 20* the efficiencies of conventional high-NA optical traps and are among the highest reported to date. Empirically obtained plasmonic optical trapping "phase diagrams" are introduced to detail the trapping response of the BNAs as a function of input power, wavelength, polarization, particle diameter, and BNA array spacing (number density). Using these diagrams, parameters are chosen, employing strictly the degrees-of-freedom of the input light, to engineer specific trapping tasks including (1) dexterous, single-particle trapping and manipulation, (2) trapping and manipulation of two- and three-dimensional particle clusters, and (3) particle sorting. The use of low input power densities (power and NA) suggests that this bowtie nanoantenna trapping system will be particularly attractive for lab-on-a-chip technology or biological applications aimed at reducing specimen photodamage. PMID- 22208880 TI - Interrogation of global mutagenesis data with a genome scale model of Neisseria meningitidis to assess gene fitness in vitro and in sera. AB - BACKGROUND: Neisseria meningitidis is an important human commensal and pathogen that causes several thousand deaths each year, mostly in young children. How the pathogen replicates and causes disease in the host is largely unknown, particularly the role of metabolism in colonization and disease. Completed genome sequences are available for several strains but our understanding of how these data relate to phenotype remains limited. RESULTS: To investigate the metabolism of N. meningitidis we generated and then selected a representative Tn5 library on rich medium, a minimal defined medium and in human serum to identify genes essential for growth under these conditions. To relate these data to a systems wide understanding of the pathogen's biology we constructed a genome-scale metabolic network: Nmb_iTM560. This model was able to distinguish essential and non-essential genes as predicted by the global mutagenesis. These essentiality data, the library and the Nmb_iTM560 model are powerful and widely applicable resources for the study of meningococcal metabolism and physiology. We demonstrate the utility of these resources by predicting and demonstrating metabolic requirements on minimal medium, such as a requirement for phosphoenolpyruvate carboxylase, and by describing the nutritional and biochemical status of N. meningitidis when grown in serum, including a requirement for both the synthesis and transport of amino acids. CONCLUSIONS: This study describes the application of a genome scale transposon library combined with an experimentally validated genome-scale metabolic network of N. meningitidis to identify essential genes and provide novel insight into the pathogen's metabolism both in vitro and during infection. PMID- 22208882 TI - A mixture model with a reference-based automatic selection of components for disease classification from protein and/or gene expression levels. AB - BACKGROUND: Bioinformatics data analysis is often using linear mixture model representing samples as additive mixture of components. Properly constrained blind matrix factorization methods extract those components using mixture samples only. However, automatic selection of extracted components to be retained for classification analysis remains an open issue. RESULTS: The method proposed here is applied to well-studied protein and genomic datasets of ovarian, prostate and colon cancers to extract components for disease prediction. It achieves average sensitivities of: 96.2 (sd = 2.7%), 97.6% (sd = 2.8%) and 90.8% (sd = 5.5%) and average specificities of: 93.6% (sd = 4.1%), 99% (sd = 2.2%) and 79.4% (sd = 9.8%) in 100 independent two-fold cross-validations. CONCLUSIONS: We propose an additive mixture model of a sample for feature extraction using, in principle, sparseness constrained factorization on a sample-by-sample basis. As opposed to that, existing methods factorize complete dataset simultaneously. The sample model is composed of a reference sample representing control and/or case (disease) groups and a test sample. Each sample is decomposed into two or more components that are selected automatically (without using label information) as control specific, case specific and not differentially expressed (neutral). The number of components is determined by cross-validation. Automatic assignment of features (m/z ratios or genes) to particular component is based on thresholds estimated from each sample directly. Due to the locality of decomposition, the strength of the expression of each feature across the samples can vary. Yet, they will still be allocated to the related disease and/or control specific component. Since label information is not used in the selection process, case and control specific components can be used for classification. That is not the case with standard factorization methods. Moreover, the component selected by proposed method as disease specific can be interpreted as a sub-mode and retained for further analysis to identify potential biomarkers. As opposed to standard matrix factorization methods this can be achieved on a sample (experiment)-by-sample basis. Postulating one or more components with indifferent features enables their removal from disease and control specific components on a sample-by-sample basis. This yields selected components with reduced complexity and generally, it increases prediction accuracy. PMID- 22208884 TI - Outcomes of resection for colorectal cancer hepatic metastases stratified by evolving eras of treatment. AB - BACKGROUND AND PURPOSE: The outcomes and management of colorectal cancer (CRC) hepatic metastasis have undergone many evolutionary changes. In this study, we aimed to analyze the outcomes of patients with CRC hepatic metastasis in terms of the era of treatment. METHODS: We conducted a retrospective review of 279 patients who underwent liver resection (LR) for CRC hepatic metastases. The prognoses of patients treated pre-2003 (era 1) and post-2003 (era 2) were examined. RESULTS: Of the patients included in the study, 210 (75.3%) had CRC recurrence after LR. There was a significant difference in the ratio of CRC recurrence between the 2 eras (82.0% in era 1 vs. 69.5% in era 2; p = 0.008). Analysis of recurrence-free and overall survival rates also showed that the patient outcome was significantly better in the post-2003 era than in the pre 2003 era. Further analysis showed that a significantly higher percentage of patients in era 2 had received modern chemotherapeutic regimens including irinotecan and oxaliplatin, while patients in era 1 were mainly administered fluorouracil and leucovorin for adjuvant chemotherapy. Among patients with CRC recurrence, a significant ratio of those in era 2 underwent surgical resection for recurrent lesions, and these patients had a better survival curve than did patients without resection (34.1% vs. 2.2% for 5-year survival; p < 0.0001). CONCLUSION: The incidence of CRC recurrence after LR for hepatic metastasis remains very high. However, the management and outcomes of patients with CRC hepatic metastasis have greatly improved with time, suggesting that the current use of aggressive multimodality treatments including surgical resection combined with modern chemotherapeutic regimens effectively prolongs the life expectancy of these patients. PMID- 22208886 TI - Impression techniques for multiple implants: a photoelastic analysis. Part II: comparison of four acrylic resins. AB - Four commercial brands of chemically activated acrylic resin were compared through photoelastic analysis. Photoelastic resin blocks were made with 2 implants placed parallel to each other and 2 square transfer copings splinted. Both transfers were splinted with chemically activated acrylic resin: Dencrilay, Duralay I, Duralay II, and GC. Data were analyzed by 2-way analysis of variance and Tukey test (P < .05). Statistically significant differences were found among the 3 brands of chemically activated acrylic resin. Dencrilay showed greater dimensional alteration. Duralay I and GC are recommended for the transfer of the position of the multi-implants. PMID- 22208890 TI - Occurrence of pipecolic acid and pipecolic acid betaine (homostachydrine) in Citrus genus plants. AB - The presence of pipecolic acid and pipecolic acid betaine, also known as homostachydrine, is herein reported for the first time in Citrus genus plants. Homostachydrine was found in fruits, seeds, and leaves of orange, lemon, and bergamot (Citrus bergamia Risso et Poit). As homostachydrine was not commercially available, as a comparative source, extracts of alfalfa leaves ( Medicago sativa L.) were used, in which homostachydrine is present at high concentration. Then, the results where confirmed by comparison with an authentic standard synthesized and purified starting from pipecolic acid. The synthesized standard was characterized by a ESI-MS/MS study using a 3D ion-trap mass spectrometer. When subjected to MS/MS fragmentation in positive ion mode, homostachydrine, unlike its lower homologue proline betaine (also known as stachydrine), showed a pattern of numerous ionic fragments that allowed unambiguous identification of the compound. For the quantitation in the plant sources, high sensitivity and specificity were achieved by monitoring the transition (158 -> 72), which is absent in the fragmentation patterns of other major osmolytes commonly used as markers for studies of abiotic stress. As for the metabolic origin of homostachydrine, the occurrence in citrus plants of pipecolic acid leads to the hypothesis that it could act as a homostachydrine precursor through direct methylation. PMID- 22208891 TI - Hybrid Cu(x)O/TiO2 nanocomposites as risk-reduction materials in indoor environments. AB - Photocatalytic TiO(2) powders impart ultraviolet light-induced self-cleaning and antibacterial functions when coated on outdoor building materials. For indoor applications, however, TiO(2) must be modified for visible-light and dark sensitivity. Here we report that the grafting of nanometer-sized Cu(x)O clusters onto TiO(2) generates an excellent risk-reduction material in indoor environments. X-ray absorption near-edge structure using synchrotron radiation and high-resolution transmission electron microscopic analyses revealed that Cu(x)O clusters were composed of Cu(I) and Cu(II) valence states. The Cu(II) species in the Cu(x)O clusters endow TiO(2) with efficient visible-light photooxidation of volatile organic compounds, whereas the Cu(I) species impart antimicrobial properties under dark conditions. By controlling the balance between Cu(I) and Cu(II) in Cu(x)O, efficient decomposition and antipathogenic activity were achieved in the hybrid Cu(x)O/TiO(2) nanocomposites. PMID- 22208892 TI - Ground- and triplet excited-state properties correlation: a computational CASSCF/CASPT2 approach based on the photodissociation of allylsilanes. AB - Excited-state properties, although extremely useful, are hardly accessible. One indirect way would be to derive them from relationships to ground-state properties which are usually more readily available. Herewith, we present quantitative correlations between triplet excited-state (T1) properties (bond dissociation energy, D0(T1), homolytic activation energy, E(a)(T1), and rate constant, k(r)) and the ground-state bond dissociation energy (D0), taking as an example the photodissociation of the C-Si bond of simple substituted allylsilanes CH2=CHC(R1R2)-SiH3 (R1 and R2 = H, Me, and Et). By applying the complete-active space self-consistent field CASSCF(6,6) and CASPT2(6,6) quantum chemical methodologies, we have found that the consecutive introduction of Me/Et groups has little effect on the geometry and energy of the T1 state; however, it reduces the magnitudes of D0, D0(T1) and E(a)(T1). Moreover, these energetic parameters have been plotted giving good linear correlations: D0(T1) = alpha1 + beta1 . D0, E(a)(T1) = alpha2 + beta2 . D0(T1), and E(a)(T1) = alpha3 + beta3 . D0 (alpha and beta being constants), while k(r) correlates very well to E(a)(T1). The key factor behind these useful correlations is the validity of the Evans-Polanyi Semenov relation (second equation) and its extended form (third equation) applied for excited systems. Additionally, the unexpectedly high values obtained for E(a)(T1) demonstrate a new application of the principle of nonperfect synchronization (PNS) in excited-state chemistry issues. PMID- 22208893 TI - Pollen processing behavior of Heliconius butterflies: a derived grooming behavior. AB - Pollen feeding behaviors Heliconius and Laparus (Lepidoptera: Nymphalidae) represent a key innovation that has shaped other life history traits of these neotropical butterflies. Although all flower visiting Lepidoptera regularly come in contact with pollen, only Heliconius and Laparus butterflies actively collect pollen with the proboscis and subsequently take up nutrients from the pollen grains. This study focused on the behavior of pollen processing and compared the movement patterns with proboscis grooming behavior in various nymphalid butterflies using video analysis. The proboscis movements of pollen processing behavior consisted of a lengthy series of repeated coiling and uncoiling movements in a loosely coiled proboscis position combined with up and down movements and the release of saliva. The proboscis-grooming behavior was triggered by contamination of the proboscis in both pollen feeding and non-pollen feeding nymphalid butterflies. Proboscis grooming movements included interrupted series of coiling and uncoiling movements, characteristic sideways movements, proboscis lifting, and occasionally full extension of the proboscis. Discharge of saliva was more pronounced in pollen feeding species than in non-pollen feeding butterfly species. We conclude that the pollen processing behavior of Heliconius and Laparus is a modified proboscis grooming behavior that originally served to clean the proboscis after contamination with particles. PMID- 22208894 TI - Transcranial magnetic resonance imaging-guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain. AB - OBJECT: Recent technological developments open the field of therapeutic application of focused ultrasound to the brain through the intact cranium. The goal of this study was to apply the new transcranial magnetic resonance imaging guided focused ultrasound (tcMRgFUS) technology to perform noninvasive central lateral thalamotomies (CLTs) as a treatment for chronic neuropathic pain. METHODS: In 12 patients suffering from chronic therapy-resistant neuropathic pain, tcMRgFUS CLT was proposed. In 11 patients, precisely localized thermal ablations of 3-4 mm in diameter were produced in the posterior part of the central lateral thalamic nucleus at peak temperatures between 51 degrees C and 64 degrees C with the aid of real-time patient monitoring and MR imaging and MR thermometry guidance. The treated neuropathic pain syndromes had peripheral (5 patients) or central (6 patients) origins and covered all body parts (face, arm, leg, trunk, and hemibody). RESULTS: Patients experienced mean pain relief of 49% at the 3-month follow-up (9 patients) and 57% at the 1-year follow-up (8 patients). Mean improvement according to the visual analog scale amounted to 42% at 3 months and 41% at 1 year. Six patients experienced immediate and persisting somatosensory improvements. Somatosensory and vestibular clinical manifestations were always observed during sonication time because of ultrasound-based neuronal activation and/or initial therapeutic effects. Quantitative electroencephalography (EEG) showed a significant reduction in EEG spectral overactivities. Thermal ablation sites showed sharply delineated ellipsoidal thermolesions surrounded by short-lived vasogenic edema. Lesion reconstructions (18 lesions in 9 patients) demonstrated targeting precision within a millimeter for all 3 coordinates. There was 1 complication, a bleed in the target with ischemia in the motor thalamus, which led to the introduction of 2 safety measures, that is, the detection of a potential cavitation by a cavitation detector and the maintenance of sonication temperatures below 60 degrees C. CONCLUSIONS: The authors assert that tcMRgFUS represents a noninvasive, precise, and radiation-free neurosurgical technique for the treatment of neuropathic pain. The procedure avoids mechanical brain tissue shift and eliminates the risk of infection. The possibility of applying sonication thermal spots free from trajectory restrictions should allow one to optimize target coverage. The real time continuous MR imaging and MR thermometry monitoring of targeting accuracy and thermal effects are major factors in optimizing precision, safety, and efficacy in an outpatient context. PMID- 22208895 TI - Measurement of targeting accuracy in focused ultrasound functional neurosurgery. AB - The object of this study was to describe a method of measuring targeting accuracy in functional neurosurgery using MR imaging and the Stereotactic Atlas of the Human Thalamus and Basal Ganglia. This method should be useful for any functional procedure using these tools or similar ones, and is described here in the specific context of focused ultrasound surgery. The authors describe the atlas coordinate system used, the different relevant targeting and accuracy definitions, the tools used, the intraoperative target determination, the postoperative target reconstructions, and the calculation of the therapeutic lesion volume. The proposed method has been applied to the specific situation of measuring targeting accuracy in focused ultrasound functional neurosurgery. The authors found mean absolute global targeting accuracies between 0.54 and 0.72 mm (SDs between 0.34 and 0.42 mm), with 85% of measured coordinates within 1 mm. The proposed method may be particularly useful in the context of functional neurosurgical procedures implying therapeutic ablations, be they through radiofrequency, focused ultrasound, or any other technique. This method allows an ongoing control of the targeting precision, a basic requirement in any functional neurosurgical procedure. PMID- 22208897 TI - Enhanced therapeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruption for brain tumor treatment: an overview of the current preclinical status. AB - Malignant glioma is a severe primary CNS cancer with a high recurrence and mortality rate. The current strategy of surgical debulking combined with radiation therapy or chemotherapy does not provide good prognosis, tumor progression control, or improved patient survival. The blood-brain barrier (BBB) acts as a major obstacle to chemotherapeutic treatment of brain tumors by severely restricting drug delivery into the brain. Because of their high toxicity, chemotherapeutic drugs cannot be administered at sufficient concentrations by conventional delivery methods to significantly improve long term survival of patients with brain tumors. Temporal disruption of the BBB by microbubble-enhanced focused ultrasound (FUS) exposure can increase CNS-blood permeability, providing a promising new direction to increase the concentration of therapeutic agents in the brain tumor and improve disease control. Under the guidance and monitoring of MR imaging, a brain drug-delivery platform can be developed to control and monitor therapeutic agent distribution and kinetics. The success of FUS BBB disruption in delivering a variety of therapeutic molecules into brain tumors has recently been demonstrated in an animal model. In this paper the authors review a number of critical studies that have demonstrated successful outcomes, including enhancement of the delivery of traditional clinically used chemotherapeutic agents or application of novel nanocarrier designs for actively transporting drugs or extending drug half-lives to significantly improve treatment efficacy in preclinical animal models. PMID- 22208896 TI - Focused ultrasound disruption of the blood-brain barrier: a new frontier for therapeutic delivery in molecular neurooncology. AB - Recent advances in molecular neurooncology provide unique opportunities for targeted molecular-based therapies. However, the blood-brain barrier (BBB) remains a major limitation to the delivery of tumor-specific therapies directed against aberrant signaling pathways in brain tumors. Given the dismal prognosis of patients with malignant brain tumors, novel strategies that overcome the intrinsic limitations of the BBB are therefore highly desirable. Focused ultrasound BBB disruption is emerging as a novel strategy for enhanced delivery of therapeutic agents into the brain via focal, reversible, and safe BBB disruption. This review examines the potential role and implications of focused ultrasound in molecular neurooncology. PMID- 22208898 TI - Sonothrombolysis for acute ischemic stroke: a systematic review of randomized controlled trials. AB - OBJECT: Sonothrombolysis has recently been considered an emerging modality for the treatment of stroke. The purpose of the present paper was to review randomized clinical studies concerning the effects of sonothrombolysis associated with tissue plasminogen activator (tPA) on acute ischemic stroke. METHODS: Systematic searches for literature published between January 1996 and July 2011 were performed for studies regarding sonothrombolysis combined with tPA for acute ischemic stroke. Only randomized controlled trials were included. Data extraction was based on ultrasound variables, patient characteristics, and outcome variables (rate of intracranial hemorrhages and arterial recanalization). RESULTS: Four trials were included in this study; 2 trials evaluated the effect of transcranial Doppler (TCD) ultrasonography on sonothrombolysis, and 2 addressed transcranial color-coded duplex (TCCD) ultrasonography. The frequency of ultrasound waves varied from 1.8 to 2 MHz. The duration of thrombus exposure to ultrasound energy ranged from 60 to 120 minutes. Sample sizes were small, recanalization was evaluated at different time points (60 and 120 minutes), and inclusion criteria were heterogeneous. Sonothrombolysis combined with tPA did not lead to an increase in symptomatic intracranial hemorrhagic complications. Two studies demonstrated that patients treated with ultrasound combined with tPA had statistically significant higher rates of recanalization than patients treated with tPA alone. CONCLUSIONS: Despite the heterogeneity and the limitations of the reviewed studies, there is evidence that sonothrombolysis associated with tPA is a safe procedure and results in an increased rate of recanalization in the setting of acute ischemic stroke when wave frequencies and energy intensities of diagnostic ultrasound systems are used. PMID- 22208899 TI - Utility of intravascular ultrasound in intracranial and extracranial neurointerventions: experience at University at Buffalo Neurosurgery-Millard Fillmore Gates Circle Hospital. AB - Intravascular ultrasound (IVUS) generates high-resolution cross-sectional images and sagittal reconstructions of the vessel wall and lumen. As a result, this imaging modality can provide accurate measurements of the degree of vessel stenosis, allow the detection of intraluminal thrombus, and analyze the plaque composition. The IVUS modality is widely used in interventional cardiology, and its use in neurointerventions has gradually increased. With case examples, the authors illustrate the utility of IVUS as an adjunct to conventional angiography for a wide range of intracranial and extracranial neurointerventions. PMID- 22208900 TI - Focused ultrasound surgery. PMID- 22208901 TI - Etomidate and mortality in cirrhotic patients with septic shock. AB - BACKGROUND: Clinical effects and outcomes of a single dose etomidate prior to intubation in the intensive care setting is controversial. The aim of this study is to evaluate the association of a single dose effect of etomidate prior to intubation on the mortality of septic cirrhotic patients and the impact of the subsequent use of low dose hydrocortisone. METHODS: This is a nested-cohort study within a randomized double blind placebo controlled study evaluating the use of low dose hydrocortisone in cirrhotic septic patients. Cirrhotic septic patients >= 18 years were included in the study. Patients who received etomidate prior to intubation were compared to those who did not receive etomidate for all cause 28 day mortality as a primary outcome. RESULTS: Sixty two intubated patients out of the 75 patients randomized in the initial trial were eligible for this study. Twenty three of the 62 intubated patients received etomidate dose prior to intubation. Etomidate use was not associated with all cause 28-day mortality or hospital mortality but was associated with significantly higher ICU mortality (91% vs. 64% for etomidate and controls groups, respectively; p = 0.02). Etomidate patients who received subsequent doses of hydrocortisone required lower doses of vasopressors and had more vasopressor-free days but no improvement in mortality. CONCLUSIONS: In this group of septic cirrhotic patients with very high mortality, etomidate increased ICU mortality. Subsequent use of hydrocortisone appears to have no benefit beyond decreasing vasopressor requirements. The lowest mortality was observed in patients who did not receive etomidate but received hydrocortisone. PMID- 22208902 TI - Dissociations in mathematical knowledge: case studies in Down's syndrome and Williams syndrome. AB - A study is reported of mathematical vocabulary and factual mathematical knowledge in PQ, a 22 year old with Down's syndrome (DS) who has a verbal mental age (MA) of 9 years 2 months and ST, a 15 year old with Williams syndrome (WS) who has a verbal MA of 9 years 6 months, matched to typically developing controls. The number of mathematical words contained within PQ's lexical stores was significantly reduced as reflected by performance on lexical decision. PQ was also impaired at both naming from descriptions and describing mathematical words. These results contrast with normal lexical decision and item descriptions for concrete words reported recently for PQ (Robinson and Temple, 2010). PQ's recall of mathematical facts was also impaired, whilst his recall of general knowledge facts was normal. This performance in DS indicates a deficit in both lexical representation and semantic knowledge for mathematical words and mathematical facts. In contrast, ST, the teenager with WS had good accuracy on lexical decision, naming and generating definitions for mathematical words. This contrasted with the atypical performance with concrete words recently reported for ST (Robinson and Temple, 2009). Knowledge of addition facts and general knowledge facts was also unimpaired for ST, though knowledge of multiplication facts was weak. Together the cases form a double dissociation and provide support for the distinct representation of mathematical and concrete items within the lexical-semantic system during development. The dissociations between mathematical and general factual knowledge also indicate that different types of factual knowledge may be selectively impaired during development. There is further support for a modular structure within which mathematical vocabulary and mathematical knowledge have distinct representations. This supports the case for the independent representation of factual and language-based knowledge within the semantic system during development. PMID- 22208903 TI - PET/CT aids the staging of and radiotherapy planning for early-stage extranodal natural killer/T-cell lymphoma, nasal type: a case series. AB - Extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, is a rare form of non-Hodgkin lymphoma. Treatment of ENKTL primarily relies on radiation; thus, proper delineation of target volumes is critical. Currently, the ideal modalities for delineation of gross tumor volume for ENKTL are unknown. We describe three consecutive cases of localized ENKTL that presented to the Nova Scotia Cancer Centre in Halifax, Nova Scotia. All patients had a planning CT and MRI as well as a planning FDG-PET/CT in the radiotherapy treatment position, wearing immobilization masks. All patients received radiation alone. In two patients, PET/CT changed not only the stage, but also the target volume requiring treatment. The third patient was unable to tolerate an MRI, but was able to undergo PET/CT, which improved the accuracy of the target volume. PET/CT aided the staging of and radiotherapy planning for our patients and appears to be a promising tool in the treatment of ENKTL. PMID- 22208904 TI - Candidate gene analysis of spontaneous preterm delivery: new insights from re analysis of a case-control study using case-parent triads and control-mother dyads. AB - BACKGROUND: Spontaneous preterm delivery (PTD) has a multifactorial etiology with evidence of a genetic contribution to its pathogenesis. A number of candidate gene case-control studies have been performed on spontaneous PTD, but the results have been inconsistent, and do not fully assess the role of how two genotypes can impact outcome. To elucidate this latter point we re-analyzed data from a previously published case-control candidate gene study, using a case-parent triad design and a hybrid design combining case-parent triads and control-mother dyads. These methods offer a robust approach to genetic association studies for PTD compared to traditional case-control designs. METHODS: The study participants were obtained from the Norwegian Mother and Child Cohort Study (MoBa). A total of 196 case triads and 211 control dyads were selected for the analysis. A case parent triad design as well as a hybrid design was used to analyze 1,326 SNPs from 159 candidate genes. We compared our results to those from a previous case control study on the same samples. Haplotypes were analyzed using a sliding window of three SNPs and a pathway analysis was performed to gain biological insight into the pathophysiology of preterm delivery. RESULTS: The most consistent significant fetal gene across all analyses was COL5A2. The functionally similar COL5A1 was significant when combining fetal and maternal genotypes. PON1 was significant with analytical approaches for single locus association of fetal genes alone, but was possibly confounded by maternal effects. Focal adhesion (hsa04510), Cell Communication (hsa01430) and ECM receptor interaction (hsa04512) were the most constant significant pathways. CONCLUSION: This study suggests a fetal association of COL5A2 and a combined fetal-maternal association of COL5A1 with spontaneous PTD. In addition, the pathway analysis implied interactions of genes affecting cell communication and extracellular matrix. PMID- 22208907 TI - Ruthenium catalyzed synthesis of enaminones. AB - The Grubbs first-generation catalyst has been found to be an effective catalyst for the synthesis of enaminones by coupling thioamides with alpha-diazodicarbonyl compounds. The reaction is successful in converting primary, secondary, and tertiary thioamides into their corresponding enaminones. The reaction is also suitable for the synthesis of chiral enaminones. PMID- 22208906 TI - Partition decoupling for multi-gene analysis of gene expression profiling data. AB - BACKGROUND: Multi-gene interactions likely play an important role in the development of complex phenotypes, and relationships between interacting genes pose a challenging statistical problem in microarray analysis, since the genes involved in these interactions may not exhibit marginal differential expression. As a result, it is necessary to develop tools that can identify sets of interacting genes that discriminate phenotypes without requiring that the classification boundary between phenotypes be convex. RESULTS: We describe an extension and application of a new unsupervised statistical learning technique, known as the Partition Decoupling Method (PDM), to gene expression microarray data. This method may be used to classify samples based on multi-gene expression patterns and to identify pathways associated with phenotype, without relying upon the differential expression of individual genes. The PDM uses iterated spectral clustering and scrubbing steps, revealing at each iteration progressively finer structure in the geometry of the data. Because spectral clustering has the ability to discern clusters that are not linearly separable, it is able to articulate relationships between samples that would be missed by distance- and tree-based classifiers. After projecting the data onto the cluster centroids and computing the residuals ("scrubbing"), one can repeat the spectral clustering, revealing clusters that were not discernible in the first layer. These iterations, each of which provide a partition of the data that is decoupled from the others, are carried forward until the structure in the residuals is indistinguishable from noise, preventing over-fitting. We describe the PDM in detail and apply it to three publicly available cancer gene expression data sets. By applying the PDM on a pathway-by-pathway basis and identifying those pathways that permit unsupervised clustering of samples that match known sample characteristics, we show how the PDM may be used to find sets of mechanistically related genes that may play a role in disease. An R package to carry out the PDM is available for download. CONCLUSIONS: We show that the PDM is a useful tool for the analysis of gene expression data from complex diseases, where phenotypes are not linearly separable and multi-gene effects are likely to play a role. Our results demonstrate that the PDM is able to distinguish cell types and treatments with higher accuracy than is obtained through other approaches, and that the Pathway-PDM application is a valuable technique for identifying disease associated pathways. PMID- 22208909 TI - Photoelastic analysis of stress distribution with different implant systems. AB - The aim of this study was to evaluate stress distribution with different implant systems through photoelasticity. Five models were fabricated with photoelastic resin PL-2. Each model was composed of a block of photoelastic resin (10 * 40 * 45 mm) with an implant and a healing abutment: model 1, internal hexagon implant (4.0 * 10 mm; Conect AR, Conexao, Sao Paulo, Brazil); model 2, Morse taper/internal octagon implant (4.1 * 10 mm; Standard, Straumann ITI, Andover, Mass); model 3, Morse taper implant (4.0 * 10 mm; AR Morse, Conexao); model 4, locking taper implant (4.0 * 11 mm; Bicon, Boston, Mass); model 5, external hexagon implant (4.0 * 10 mm; Master Screw, Conexao). Axial and oblique load (45 degrees ) of 150 N were applied by a universal testing machine (EMIC-DL 3000), and a circular polariscope was used to visualize the stress. The results were photographed and analyzed qualitatively using Adobe Photoshop software. For the axial load, the greatest stress concentration was exhibited in the cervical and apical thirds. However, the highest number of isochromatic fringes was observed in the implant apex and in the cervical adjacent to the load direction in all models for the oblique load. Model 2 (Morse taper, internal octagon, Straumann ITI) presented the lowest stress concentration, while model 5 (external hexagon, Master Screw, Conexao) exhibited the greatest stress. It was concluded that Morse taper implants presented a more favorable stress distribution among the test groups. The external hexagon implant showed the highest stress concentration. Oblique load generated the highest stress in all models analyzed. PMID- 22208914 TI - Fate of 4-nonylphenol and 17beta-estradiol in the Redwood River of Minnesota. AB - The majority of previous research investigating the fate of endocrine-disrupting compounds has focused on single processes generally in controlled laboratory experiments, and limited studies have directly evaluated their fate and transport in rivers. This study evaluated the fate and transport of 4-nonylphenol, 17beta estradiol, and estrone in a 10-km reach of the Redwood River in southwestern Minnesota. The same parcel of water was sampled as it moved downstream, integrating chemical transformation and hydrologic processes. The conservative tracer bromide was used to track the parcel of water being sampled, and the change in mass of the target compounds relative to bromide was determined at two locations downstream from a wastewater treatment plant effluent outfall. In stream attenuation coefficients (k(stream)) were calculated by assuming first order kinetics (negative values correspond to attenuation, whereas positive values indicate production). Attenuation of 17beta-estradiol (k(stream) = -3.2 +/ 1.0 day(-1)) was attributed primarily due to sorption and biodegradation by the stream biofilm and bed sediments. Estrone (k(stream) = 0.6 +/- 0.8 day(-1)) and 4 nonylphenol (k(stream) = 1.4 +/- 1.9 day(-1)) were produced in the evaluated 10 km reach, likely due to biochemical transformation from parent compounds (17beta estradiol, 4-nonylphenolpolyethoxylates, and 4-nonyphenolpolyethoxycarboxylates). Despite attenuation, these compounds were transported kilometers downstream, and thus additive concentrations from multiple sources and transformation of parent compounds into degradates having estrogenic activity can explain their environmental persistence and widespread observations of biological disruption in surface waters. PMID- 22208910 TI - Poly I: C-activated dendritic cells that were generated in CellGro for use in cancer immunotherapy trials. AB - BACKGROUND: For clinical applications, dendritic cells (DCs) need to be generated using GMP-approved reagents. In this study, we tested the characteristics of DCs generated in two clinical grade culture media and activated by three maturation stimuli, Poly I: C, LPS and the mixture of proinflammatory cytokines in order to identify the optimal combination of culture media and activation stimulus for the clinical use. METHOD: We tested DCs generation using two GMP-certified culture media, CellGro and RPMI+5% human AB serum and evaluated DCs morphology, viability and capapability to mature. We tested three maturation stimuli, PolyI:C, LPS and the mixture of proinflammatory cytokines consisting of IL-1, IL-6, TNF and prostaglandin E2. We evaluated the capacity of activated DCs to induce antigen specific T cells and regulatory T lymphocytes. RESULTS: Cell culture in CellGro resulted in a higher yield of immature DCs resulting from increased number of adherent monocytes. DCs that were generated in CellGro and activated using Poly I:C were the most efficient in expanding antigen-specific T cells compared to the DCs that were generated in other media and activated using LPS or the cocktail of proinflammatory cytokines. A comparison of all tested combinations revealed that DCs that were generated in CellGro and activated using Poly I:C induced low numbers of regulatory T cells. CONCLUSION: In this study, we identified monocyte derived DCs that were generated in CellGro and activated using Poly I:C as the most potent clinical-grade DCs for the induction of antigen-specific T cells. PMID- 22208916 TI - AAA ATPases: structure and function. PMID- 22208917 TI - Reusable amperometric biosensor for measuring protein tyrosine kinase activity. AB - This work presents a simple, low-cost and reusable label-free method for detecting protein tyrosine kinase activity using a tyrosinase-based amperometric biosensor (tyrosine kinase biosensor). This method is based on the observation that phosphorylation can block the tyrosinase-catalyzed oxidation of tyrosine or tyrosyl residue in peptides. Therefore, the activity of p60c-src protein tyrosine kinase (Src) on the developed tyrosine kinase biosensor could be quickly determined when its specific peptide substrate, p60c-src substrate I, was used. The tyrosine kinase biosensor was highly sensitive to the activity of Src with a linear dynamic range of 1.9-237.6 U/mL and the lowest detection limit of 0.23 U/mL. Interestingly, the tyrosine kinase activity can be measured using the developed tyrosine kinase biosensor repetitively without regeneration. The inhibitory effect of various kinase inhibitors on the Src activity could be determined on the tyrosine kinase biosensor. Src-specific inhibitors, PP2 and Src inhibitor I, effectively suppressed Src activity, whereas PD153035, an inhibitor of the epidermal growth factor receptor, was ineffective. Staurosporine, a universal kinase inhibitor, inhibited Src activity in an ATP concentration dependent manner. These results suggests that the activities of tyrosine kinases and their behaviors toward various reagents can be effectively measured using the developed tyrosine kinase biosensor. PMID- 22208919 TI - Publisher's Welcome. PMID- 22208920 TI - A review of the impact of nutrition on health and profits and a discussion of successful program elements. PMID- 22208918 TI - Successful management with intravenous immunoglobulins in alemtuzumab-induced acute inflammatory demyelinating neuropathy: clinical report of three patients. AB - Several neurological complications have been associated with the use of monoclonal antibodies (mAbs), and demyelinating disorders have been estimated to affect the 0.02-0.20% of treated patients. Alemtuzumab is a humanized chimeric mAbthat targets the CD52 antigen, it is currently approved for relapsed/refractory and high-risk untreated chronic lymphocytic leukemia (CLL). The major complication of alemtuzumab therapy is the increased risk of opportunistic infections secondary to the profound immunosuppression. Autoimmune diseases as Graves disease, immune thrombocytopenic purpura and Good pasture syndrome, have been reported to be associated to the treatment. In the present report, we present three CLL patients developing acute inflammatory demyelinating neuropathy during treatment with alemtuzumab. Despite the severity of the complication, all the patients showed an univocal good clinical response after treatment with intravenous immunoglobulin (IVIG). As alemtuzumab represents, nowadays, a key therapeutic option for CLL, clinicians should be aware of this rare and disabling toxicity. PMID- 22208921 TI - Stress management: programs and prospects. PMID- 22208922 TI - Spiritual health: a component missing from health promotion. PMID- 22208923 TI - Achieving Health Promotion Objectives through Cultural Change Systems. PMID- 22208924 TI - Northern telecom: a million dollar medically based program in a rapidly changing high tech environment. PMID- 22208927 TI - Evaluation model: a framework for the design of rigorous evaluation of efforts in health promotion. PMID- 22208925 TI - Stevens point: a longstanding program for students at a midwestern university. PMID- 22208929 TI - Resource reviews. PMID- 22208928 TI - Networking. PMID- 22208930 TI - Perspectives on the rest of the world. PMID- 22208931 TI - New editorial areas to appear in future issues. PMID- 22208933 TI - Symptom and joint mobility progression in the joint hypermobility syndrome (Ehlers-Danlos syndrome, hypermobility type). AB - OBJECTIVES: To evaluate progression of symptoms and joint mobility in the joint hypermobility syndrome (JHS) in order to identify specific disease pictures by age at presentation. METHODS: Fifty JHS patients (44 females, 6 males) were evaluated by Beighton score (BS) calculation, and presence/absence and age at onset of 20 key symptoms. Incidence and prevalence rates by age at onset and sex were calculated and compared by chi-square, Fisher's exact test and Mann-Whitney U-test. Relationship between BS and age at examination was evaluated by the Spearman rho correlation. The existence of an age cut-off separating patients with or without a positive BS was analysed by the receiver operating characteristic analysis. Influence of age on the single components of the BS was also investigated. RESULTS: Except for isolated features, the overall clinical presentation was the same between sexes. In the whole sample, statistically significant differences by age at presentation were registered for fatigue, myalgias, muscle cramps, strains/sprains, dislocations, tendon ruptures, tendonitis, gastroesophageal reflux, chronic gastritis, constipation/diarrhoea and abdominal hernias. A clear inverse correlation between age at examination and BS was demonstrated with an age cut-off fixed at 33 years. Among the components of the BS, spine and elbow joints were not significantly influenced by age. CONCLUSIONS: This study confirmed the existence of a protean clinical history of JHS which may be exemplified in different phases with distinguishable presentations. The knowledge of the peculiarities of each of them will help the practitioner in recognising and, hopefully, treating this condition. PMID- 22208935 TI - The indwelling voice prosthesis for speech rehabilitation after total laryngectomy: a safe approach. AB - Primary prosthetic voice restoration by performing tracheoesophageal puncture (TEP) and immediate insertion of a voice prosthesis at the time of total laryngectomy (TLE) is presently the method of choice. This enables the easiest and most comfortable voice rehabilitation with the patient still under general anesthesia when the first prosthesis is inserted. Reconstruction of the pharynx with e.g. free revascularized or pedicled flaps does not preclude surgical prosthetic voice restoration. The TEP can even be done as a primary procedure after total laryngectomy and total pharyngectomy when the full circumference of the neopharynx has to be reconstructed, provided the esophagus is still present at the level of the trachea. Since indwelling devices may have a more robust construction, their device-life generally is longer than that of their non indwelling counterparts. Indwelling devices have the unique advantage in that patient's dexterity plays a lesser role in the daily maintenance of the device. With a few refinements in the surgery of TLE several postlaryngectomy problems can be avoided or diminished such as hypertonicity of the pharyngoesophageal (PE) segment and a poor contour of the stoma. The combination of Heat and Moisture Exchanger (HME) and indwelling voice prosthesis contributes to a significant improvement of both pulmonary function and voice quality. The solution of the majority of prosthesis and TE-fistula related problems by the well trained physician, make prosthetic voice restoration a safe procedure. PMID- 22208934 TI - The association between drospirenone and hyperkalemia: a comparative-safety study. AB - BACKGROUND: Drospirenone/ethinyl-estradiol is an oral contraceptive (OC) that possesses unique antimineralocorticoid activity. It is conjectured that drospirenone, taken alone or concomitantly with spironolactone, may be associated with an increased risk of hyperkalemia. METHODS: A retrospective cohort study was conducted evaluating women between 18-46 years of age in the LifelinkTM Health Plan Claims Database. The study was restricted to new users of OCs between 1997 2009. Cox proportional hazards models were used to estimate the time to first occurrence of hyperkalemia diagnosis. The main analysis compared OCs containing drospirenone with OCs containing levonorgestrel, a second generation OC not known to impact potassium homeostasis. Logistic regression evaluated concomitant prescribing of drospirenone and spironolactone RESULTS: The cohort included 1,148,183 women, averaging 28.8 years of age and 280 days of OC therapy. 2325 cases of hyperkalemia were identified. The adjusted hazard ratio (HR) for hyperkalemia with drospirenone compared to levonorgestrel was 1.10 (95%CI 0.95 1.26). There was an increased risk of hyperkalemia with norethindrone HR 1.15 (95%CI: 1.00-1.33) and norgestimate HR 1.27 (95%CI: 1.11-1.46). Other OCs were unassociated with hyperkalemia. The odds of receiving spironolactone while taking drospirenone were 2.66 (95%CI 2.53-2.80) times higher than the odds of receiving spironolactone and levonorgestrel. Only 6.5% of patients taking drospirenone and spironolactone had a serum potassium assay within 180 days of starting concomitant therapy. CONCLUSIONS: A clinically significant signal for hyperkalemia with drospirenone was not demonstrated in the current study. Despite the bolded warning for hyperkalemia with joint drospirenone and spironolactone administration, physicians are actually using them together preferentially, and are not following the recommended potassium monitoring requirements in the package insert. PMID- 22208936 TI - [Endoscopic treatment of giant skull base osteomas]. AB - INTRODUCTION: Osteomas are relatively common, benign, slow-growing neoplasms. Mainly occurring in frontal and ethmoid sinuses. Endoscopic surgery plays an important role in management of ethmoid, sphenoid and frontal osteomas. AIM: We discuss our experiences in endoscopic treatment of giant osteomas. RESULTS: In giant osteomas Draf III or Lothrop approaches are prefered. Periostium of the orbit was intact in all cases. Discharge of cerebrospinal liquid was not observed. CONCLUSIONS: Size of tumor determines type of surgical aprroach. Endoscopic surgery is more and more popular way in surgical treatment of giant osteomas. PMID- 22208937 TI - [Evaluation of cytochrome concentration in peripheral blood lymphocytes of patients with laryngeal cancer]. AB - The aim of the study was evaluation of cytochrome concentration in the peripheral blood lymphocytes of patients with laryngeal cancer. The study was conducted in a group of 62 patients presenting different clinical advancement of the disease. The study material consisted of the studied population's peripheral blood from which T lymphocytes were isolated and incubated with monoclonal antibodies. To evaluate antigens' expression, a FACS Galibur flow cytometre was used; the evaluated cells were labeled with fluorochrome-conjugated monoclonal antibodies. Next, mononuclear cells were rinsed with cold PBS and suspended in the lysis buffer. In the obtained cell lysate the c cytochrome concentration was determined with the use of an immunoenzymatic test, HumanCytochrome cELISA Kit (BenderMed Systems, Austria). Obtained results were compared with the measurements taken in 20 healthy individuals who constituted the control group. On the basis of conducted study it was found that the level of c cytochrome concentration was significantly increased in the T CD3+ lymphocytes in the peripheral blood of patients with stage IV of laryngeal cancer. A positive correlatio was also found between the cytochrome level in lymphocytes and the advancing stage of the disease. Our own observation give grounds to conjecture that together with the progress of laryngeal cancer the energetic potential of lymphocytes increases and so does the readiness of the lymphatic cells to undergo the redox processes, therefore the amount of c cytochrome in the cells increases. PMID- 22208938 TI - [16 years of experience in laryngeal microsurgery with use laser CO2: cooperation between laryngologist and anesthesiologist - in material of ENT Department of Silesian Medical University]. AB - Laryngeal microsurgery is currently the primary method of treatment of many diseases of the larynx. Breakthrough for the development of laryngeal microsurgery was the introduction of laser technology. The laryngeal microsurgery is used mainly laser CO2. Endoscopic laryngeal microsurgery using the laser poses a unique challenge to the anesthesiologist, ensuring safe conditions of anesthesia, the patient and simultaneously appropriate operating conditions for the surgeon for precisely perform the procedure. MATERIAL AND METHODS: Between 1995 and 2010 carried out in the Department of Otolaryngology SUM 832 microsurgical operations of the larynx using a CO2 laser. CONCLUSION: The perioperative management and close cooperation with the surgeon and anesthesiologist are essential for safe and efficient conduct of the operation the larynx using a microsurgical CO2 laser. PMID- 22208939 TI - [New modification of Reynwald macroglossia reduction]. AB - INTRODUCTION: Macroglossia usually occurs as isolated malformation, however it can coexist with some of the hereditary defect. Enlargement of the tongue can cause cosmetic and functional difficulties. AIM: The aim of this paper was to analyzed patients with macroglossia operated with own modified Reynwald method. It was based on analysis of surgical treatment and rehabilitation of patients with: Down syndrome, oral-facial-digital syndrome and cerebral palsy, treated at the Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Lodz. MATERIAL AND METHODS: 63 patients (32 females and 31 males) with Down syndrome (60), oral-facial-digital syndrome (2) and cerebral palsy (1) were operated at the Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Lodz, because of hypertrophy of the tongue. 42 patients were operated with partial resection of macroglossia, 2 of them with additional correction of the tongue border and 21 patients with own modified Reynwald method. RESULTS: Postoperative treatment was non-complicated in all the patients. Early and long-lasting postoperative results were regard as satisfactory, and lead to improvement of basic physiological functions. CONCLUSIONS: 1. 3-6 years are the optimal age to partial macroglossia reduction. 2. Analyze of surgical macroglossia treatment showed effectiveness of methods based on partial resection of tongue. Surgical treatment with own modified Reynwald method lead to increase of number of satisfied postoperative results. 3. Partial resection of macroglossia influence on patients look, integration and environment acceptance; in children with deep retardation it simplify nursing. PMID- 22208940 TI - [Anatomy and surgical approaches to the parapharyngeal space]. AB - PURPOSE: Analysis of surgical approaches to primary tumors localized in parapharyngeal space used in Head & Neck Cancer Department, Cancer Center Institute in Warsaw. Description of differences in terminology used to describe fascial compartments of the neck. MATERIAL AND METHODS: Retrospective analysis of medical records of 8 selected patients who had an operation for primary parapharyngeal space neoplasm. Analysis has been done of operation protocols, diagnostic images, tumor size and histopathology. RESULTS: Transcervical, transparotid and transmandibular approaches were used with additional rhinotomy and craniotomy in selected cases. Selection of approach should take into account tumor localization, its size and histopathology. CONCLUSIONS: Planning of surgical procedure for parapharyngeal space tumor should be based upon analysis of diagnostic images and selection of the approach depends on tumor localization, size and histopathology. Differences in terminology of superficial and middle cervical fascial compartments can lead to inappropriate clinical decisions. PMID- 22208941 TI - [Quality of voice after implantation of hyaluronic acid to the vocal folds - preliminary report]. AB - INTRODUCTION: Method of vocal folds implantation with allogenic materials has been applied in medical centre all over the world for over 30 years. this voice improving method is usually applied in several indications such as: presbyphonia, vocal folds paralysis, glottis insufficiency, vocal fold scars or sulcus vocalis. all of these illnesses prevent the patients to obtain full glottis closure and produce good quality voice. AIM: TO assess quality of voice after implantation of hyaluronic acid to the vocal folds. MATERIAL: Consisted of 15 patients, who underwent surgical implantation of hyaluronic acid to the vocal folds. 10 patients had the procedure performed on both sides of the larynx, this group included 6 patients with vocal insufficiency of the glottis, 2 with scars and atrophy of the vocal folds and 2 with presbyphonia. In 5 cases the hyaluronic acid was applied on one side of the larynx. The group included 4 patients with vocal folds paralysis and one person with single sided scars and atrophy of the vocal fold. METHOD: Each patient was examined with videostroboscopy and underwent objective and subjective assessment of voice. Hyaluronic acid was injected surgically under Jet Ventilation general anesthesia. In two cases during the procedure scars were removed from the vocal folds. All patients after hyaluronic acid augmentation took part in the rehabilitation program that included series of voice emission exercises before operation and up to 3 months after the procedure. Examination was performed 1, 3 and 6 months after injection. RESULTS: In all cases improvement of quality of voice was obtained which was stated by a physician and the patients subjectively. Improvement of harmonic voice structure was confirmed by spectrographic record. Acoustic examinations revealed that the improvement was obtained within parameters describing frequency, amplitude disturbance and noise existence. CONCLUSIONS: Injection of the hyaluronic acid to the vocal folds improves functional phonation and quality of voice in cases of patients with glottis insufficiency. Injection of the hyaluronic acid to the vocal folds is an efficient method improving quality of voice and can be safe alternative for no surgery method in rehabilitation of voice. This method is a simply, effective and quickly to improve of voice disorders. PMID- 22208942 TI - [Preimplantaion genetic diagnosis of hearing loss with 35delG mutation in GJB2 gene - preliminary report]. AB - INTRODUCTION: 35delG mutation in GJB2 gene is the most frequent mutation in genetic hearing loss. The carrier screening for 35delG mutation to identify affected newborns is at the moment relatively inexpensive method for deafness diagnosis. The casual treatment of DFNB1 is impossible. Preimplantation genetic diagnosis (PGD) is a method allowing transfer mutation free embryos and successful pregnancies. It's an established procedure allowing genetic research of the oocyte before fertilization or embryo before implantation to the uterus. AIM: The aim of the present work was to perform PGD for GJB2 35delG mutation in a couple who had already a child affected with genetic hearing loss. MATERIALS AND METHODS: The patient underwent a standard IVF procedure associated with intracytoplasmic sperm injection. 6-8 cell embryos were biopsied on day 3. Single cell nested PCR-RFLP protocol and sequence analysis for PGD was used for the detection of GJB2 35delG mutation. RESULTS: In the course of IVF-PGD procedures, from 6 analyzed embryos 3 were predicted to be free of GJB2 35delG mutation in both alleles. Two embryos were heterozygous and one was affected for this mutation as homozygous mutation in both alleles. Of these, one healthy embryo was transferred, resulting in an unaffected singleton pregnancy. CONCLUSIONS: Preimplantation genetic diagnosis (PGD) of monogenic disorders is a very efficient method, especially for patients whose previous child is homozygous for genetic disorders. It offers new possibilities for the treatment for genetic disease carriers. PMID- 22208943 TI - [Analysis of histopathological evaluation of pathological lesions removed by endoscopic surgery of the nose and paranasal sinuses in the own material]. AB - INTRODUCTION: The work aimed at evaluating results of histopathological examination of postoperative material in endoscopic paranasal sinus surgery in the own material. MATERIAL AND METHODS: The analysis covered 3,896 results of histopathological examination of routine postoperative material from the Department of Clinical Pathomorphology and Cytopathology Military Medical Academy University Clinical Hospital in Lodz. The study was conducted in hematoxylin and eosin staining according to the principles of this method. The postoperative material included pathological lesions removed by endoscopic surgery of the nose and paranasal sinuses in patients who were treated at Department of Otolaryngology and Laryngological Oncology between 2006 and 2010. The treatment included 1,118 patients, 509 women at the age of 15-79 and 609 men aged 17-77. The material for histopathological examination was sent from merely 1,176 operations because 57 patients were operated twice and one patient was operated three times. RESULTS: Polyps within the nose and paranasal sinuses were confirmed by histopathological examination in 705 patients, including 289 women and 416 men. Hypertrophic changes were diagnosed in 404 patients, including 218 women and 186 men. Inverted papilloma was recognised in histopathological examination in 9 patients, including 2 women and 7 men. Hypertrophies were slightly more common in women than in men. Both in men and women unilateral hypertrophic changes within the ostiomeatal complex were predominant, 42.66% in women and 40.86% in men. CONCLUSION: Histopathological examination of postoperative material in patients under endoscopic treatment due to paranasal sinusitis is considerably important for complex evaluation of inflammation type and confirmation of indications for appropriate anti-inflammatory therapy. PMID- 22208944 TI - [Cervical tuberculosis -- scrofula]. AB - We described a diagnostic procedure of two cases of extrapulmonary tuberculosis in elderly people. The paper presents the diagnostic difficulty caused by the lack of obtaining an adequate amount of material and low sensitivity and specificity of the conventional techniques. The probe Tec ET test was used with conventional microbiology and histology helps in diagnosis of extrapulmonary tuberculosis by improving specificity, sensitivity. Probe Tec ET test takes a few hours. PMID- 22208945 TI - [Neuroendocrine carcinoma of the hypopharynx]. AB - There are a few cases of the neuroendorine carcinoma localized in the hypopharynx. We present two cases of this disease. We also recognize infiltration of the larynx, characteristic clinical findings, metastases in the neck nodes, patomorfological problems in the differential diagnosis which are solved using immunohistochemic testing. PMID- 22208946 TI - Reconstruction of the larynx after a resection of a huge chondrosarcoma. AB - Chondrosarcoma of the larynx is a rare condition of still unknown pathogenesis. This tumor occurs usually between the sixth and seventh decade of life. Forty five years old patient was admitted to the ENT Department in Zabrze for a diagnosis of a slow growing tumor from about 3 years. The great unmovable tumor 2.5 cm/3 cm/3 cm was arising from the cricoid cartilage. The hist-pat result of the biopsy was cartilage. The patient did not agree on the proposed surgical treatment. After one year, in the MRI examination, the tumor sized 46 mm/37 mm/39 mm was found. The patient was again qualified for the operation and agreed for the proposed treatment. In general anesthesia, the tumor together with the part of trachea, cricoids and thyroid cartilages was resected. After excision the reconstruction was performed. During 10 months of the follow-up the patient remains free of the disease. PMID- 22208947 TI - Historic emissions from deforestation and forest degradation in Mato Grosso, Brazil: 1) source data uncertainties. AB - BACKGROUND: Historic carbon emissions are an important foundation for proposed efforts to Reduce Emissions from Deforestation and forest Degradation and enhance forest carbon stocks through conservation and sustainable forest management (REDD+). The level of uncertainty in historic carbon emissions estimates is also critical for REDD+, since high uncertainties could limit climate benefits from credited mitigation actions. Here, we analyzed source data uncertainties based on the range of available deforestation, forest degradation, and forest carbon stock estimates for the Brazilian state of Mato Grosso during 1990-2008. RESULTS: Deforestation estimates showed good agreement for multi-year periods of increasing and decreasing deforestation during the study period. However, annual deforestation rates differed by > 20% in more than half of the years between 1997 2008, even for products based on similar input data. Tier 2 estimates of average forest carbon stocks varied between 99-192 Mg C ha-1, with greatest differences in northwest Mato Grosso. Carbon stocks in deforested areas increased over the study period, yet this increasing trend in deforested biomass was smaller than the difference among carbon stock datasets for these areas. CONCLUSIONS: Estimates of source data uncertainties are essential for REDD+. Patterns of spatial and temporal disagreement among available data products provide a roadmap for future efforts to reduce source data uncertainties for estimates of historic forest carbon emissions. Specifically, regions with large discrepancies in available estimates of both deforestation and forest carbon stocks are priority areas for evaluating and improving existing estimates. Full carbon accounting for REDD+ will also require filling data gaps, including forest degradation and secondary forest, with annual data on all forest transitions. PMID- 22208948 TI - Human cancer cells express Slug-based epithelial-mesenchymal transition gene expression signature obtained in vivo. AB - BACKGROUND: The biological mechanisms underlying cancer cell motility and invasiveness remain unclear, although it has been hypothesized that they involve some type of epithelial-mesenchymal transition (EMT). METHODS: We used xenograft models of human cancer cells in immunocompromised mice, profiling the harvested tumors separately with species-specific probes and computationally analyzing the results. RESULTS: Here we show that human cancer cells express in vivo a precise multi-cancer invasion-associated gene expression signature that prominently includes many EMT markers, among them the transcription factor Slug, fibronectin, and alpha-SMA. We found that human, but not mouse, cells express the signature and Slug is the only upregulated EMT-inducing transcription factor. The signature is also present in samples from many publicly available cancer gene expression datasets, suggesting that it is produced by the cancer cells themselves in multiple cancer types, including nonepithelial cancers such as neuroblastoma. Furthermore, we found that the presence of the signature in human xenografted cells was associated with a downregulation of adipocyte markers in the mouse tissue adjacent to the invasive tumor, suggesting that the signature is triggered by contextual microenvironmental interactions when the cancer cells encounter adipocytes, as previously reported. CONCLUSIONS: The known, precise and consistent gene composition of this cancer mesenchymal transition signature, particularly when combined with simultaneous analysis of the adjacent microenvironment, provides unique opportunities for shedding light on the underlying mechanisms of cancer invasiveness as well as identifying potential diagnostic markers and targets for metastasis-inhibiting therapeutics. PMID- 22208950 TI - Direct, regioselective, and chemoselective preparation of novel boronated tryptophans by Friedel-Crafts alkylation. AB - A facile synthetic approach to the direct preparation of various novel unnatural boronated protected tryptophans using a regio- and chemoselective electrophilic substitution of 4- and 5-boronated indoles with N-protected dehydroalanine is described. The gram-scale synthesis of two free tryptophan boronic acids is also reported. PMID- 22208949 TI - A novel MSMB-related microprotein in the postovulatory egg coats of marsupials. AB - BACKGROUND: Early marsupial conceptuses differ markedly from those of eutherian mammals, especially during cleavage and early blastocyst stages of development. Additionally, in marsupials the zona pellucida is surrounded by two acellular layers, the mucoid coat and shell, which are formed from secretions from the reproductive tract. RESULTS: We report the identification of a novel postovulatory coat component in marsupials, which we call uterinesecreted microprotein (USM). USM belongs to a family of disulfide-rich microproteins of unconfirmed function that is found throughout deuterostomes and in some protostomes, and includes beta-microseminoprotein (MSMB) and prostate-associated microseminoprotein (MSMP). We describe the evolution of this family in detail, including USM-related sequences in other vertebrates. The orthologue of USM in the tammar wallaby, USM1, is expressed by the endometrium with a dynamic temporal profile, possibly under the control of progesterone. CONCLUSIONS: USM appears to have evolved in a mammalian ancestor specifically as a component of the postovulatory coats. By analogy with the known properties of MSMB, it may have roles in regulating sperm motility/survival or in the immune system. However, its C-terminal domain is greatly truncated compared with MSMB, suggesting a divergent function. PMID- 22208951 TI - Blood cadmium concentration and lipid profile in Korean adults. AB - Although animal experiments have shown that cadmium exposure induces alterations in lipid profiles, no epidemiological study of this relationship has been performed. The objective of this study was to evaluate the association between blood cadmium concentration and blood lipid levels in Korean adults. A cross sectional study comprising participants (n=3903) aged 20 years or older from the 2005, 2008, and 2009 Korea National Health and Nutrition Examination Surveys was conducted. Demographic characteristics and dietary intake were obtained from the participants by questionnaire, and cadmium and lipid levels were determined by analysis of blood samples. After adjusting for demographic and dietary factors, blood concentration of cadmium was positively associated with the risk of low high-density lipoprotein cholesterol (HDL-C) in a dose-dependent manner (p for trend <0.001). In addition, the odds ratios (ORs) of a high triglyceride to HDL-C ratio was significantly increased in the high blood cadmium groups [OR=1.36; 95% confidence interval (CI), 1.03-1.79 for fourth quintile and OR=1.41; 95% CI, 1.07 1.86 for fifth quintile] compared with the lowest quintile group. However, high blood cadmium was not associated with a risk of high total cholesterol, high low density lipoprotein cholesterol, or high triglycerides. These data suggest that an increased cadmium body burden increases the risk of dyslipidemia, mainly due to the increased risk of low HDL-C and the high ratio of triglycerides to HDL-C. PMID- 22208955 TI - Prevalence and antimicrobial resistance of Salmonella serotypes isolated from poultry in Spain: comparison between 1993 and 2006. AB - A total of 226 chicken samples (carcasses, legs, wings, necks and breasts) were obtained (73 in 1993 and 153 in 2006) from 10 retail outlets in North-Western Spain and screened for the presence of Salmonella. Isolates were subjected to serotyping, phage typing (Salmonella Enteritidis and Salmonella Typhimurium) and antimicrobial susceptibility testing (15 antimicrobials; disk diffusion method). Salmonella was detected in 40 (55%) samples in 1993 and 19 (12.4%) in 2006 (P<0.001). The serotypes (S. Enteritidis, Salmonella Poona, Salmonella Infantis, Salmonella Newport and S. Typhimurium) and phage types (1, 4, 14b and 35 in the case of S. Enteritidis and 193 for S. Typhimurium) detected are among the main types responsible for human salmonellosis in Spain. All strains were multi resistant (resistant to 3-13 antimicrobials). The average number of resistances per strain increased (P<0.05) from 3.98 in 1993 to 5.00 in 2006. An increase in the incidence of resistance was observed between 1993 and 2006 for cephalothin (P<0.01), enrofloxacin (P<0.001) and tetracycline (P<0.01). The decreases in the prevalence of Salmonella between 1993 and 2006 suggest that the mandatory measures introduced over the last decade in the European Union to reduce the incidence of Salmonella in poultry have apparently been successful. However, the increase in antibiotic resistance rates is of concern and constitutes a threat to public health. Because the data in this study demonstrated that chicken in North Western Spain is a potential source of antibiotic-resistant Salmonella strains, the need of consumer education on good sanitary practices is highlighted. PMID- 22208954 TI - Comprehensive cardiovascular magnetic resonance of myocardial mechanics in mice using three-dimensional cine DENSE. AB - BACKGROUND: Quantitative noninvasive imaging of myocardial mechanics in mice enables studies of the roles of individual genes in cardiac function. We sought to develop comprehensive three-dimensional methods for imaging myocardial mechanics in mice. METHODS: A 3D cine DENSE pulse sequence was implemented on a 7T small-bore scanner. The sequence used three-point phase cycling for artifact suppression and a stack-of-spirals k-space trajectory for efficient data acquisition. A semi-automatic 2D method was adapted for 3D image segmentation, and automated 3D methods to calculate strain, twist, and torsion were employed. A scan protocol that covered the majority of the left ventricle in a scan time of less than 25 minutes was developed, and seven healthy C57Bl/6 mice were studied. RESULTS: Using these methods, multiphase normal and shear strains were measured, as were myocardial twist and torsion. Peak end-systolic values for the normal strains at the mid-ventricular level were 0.29 +/- 0.17, -0.13 +/- 0.03, and 0.18 +/- 0.14 for E(rr), E(cc), and E(ll), respectively. Peak end-systolic values for the shear strains were 0.00 +/- 0.08, 0.04 +/- 0.12, and 0.03 +/- 0.07 for E(rc), E(rl), and E(cl), respectively. The peak end-systolic normalized torsion was 5.6 +/- 0.9 degrees . CONCLUSIONS: Using a 3D cine DENSE sequence tailored for cardiac imaging in mice at 7 T, a comprehensive assessment of 3D myocardial mechanics can be achieved with a scan time of less than 25 minutes and an image analysis time of approximately 1 hour. PMID- 22208956 TI - A miniaturized planar patch-clamp system for transportable use. AB - In the last decade, planar patch-clamp (PPC) has emerged as an innovative technology allowing parallel recordings of cellular electrophysiological activity on planar substrates. If PPC is widely adopted by the pharmaceutical sector, it remains poorly extended to other areas (i.e. environment and safety organizations) probably because of the large, expensive and non-easily transportable format of those commercial equipments. The present work describes for the first time a new compact and transportable planar patch-clamp system (named Toxint'patch or TIP, for Toxin detection with integrated patch-clamp) focusing on environmental matters and meant to be used in coastal laboratories, for direct on-site monitoring of the seawater and shellfish quality. The TIP system incorporates silicon chips tailored to monitor cellular ionic currents from cultured cells stably expressing a phycotoxin molecular target. The functionality of this novel briefcase-sized PPC system is described in terms of fluidic control, electronic performances with amplifying and filtering boards and of user interface for data acquisition and control implemented on a computer. PMID- 22208957 TI - A microfluidic device with passive air-bubble valves for real-time measurement of dose-dependent drug cytotoxicity through impedance sensing. AB - The monitoring and evaluation of cell behaviors under various concentrations of diffusible molecules or drugs are important in drug screening and in many other types of biological studies. In the current study, a novel polydimethylsiloxane (PDMS)-based microfluidic device was established for the real-time monitoring of drug-induced cytotoxicity using electric cell-substrate impedance sensing (ECIS). This device consists of the following three components: a drug gradient generator, planar air-bubble valves, and parallel cell culture cavities that are combined with impedance-sensing electrodes. The gradient generator allows for the simultaneous administration of multiple drug doses to test the functional cytotoxicity, and the incorporated impedance sensing enables the dynamic, automatic and quantitative measurement of in vitro dose-dependent drug responses. The air-bubble valve presented here allows the automatic closure of the valve without the need for any external valve-control instrument. As a proof-of-concept demonstration, this device was applied to dynamically monitor the effects of the anticancer drug cisplatin on apoptosis in four cancer cell lines, which may be useful for drug discovery and other biological studies that require automated analysis combined with concentration gradients. PMID- 22208958 TI - On the optimum contact angle of stability of foams by particles. PMID- 22208959 TI - Synthesis, molecular structure and spectral analysis of ethyl 4-[(3,5 dinitrobenzoyl)-hydrazonomethyl]-3,5-dimethyl-1H-pyrrole-2-carboxylate: a combined experimental and quantum chemical approach. AB - A new hydrazone, ethyl 4-[(3,5-dinitrobenzoyl)-hydrazonomethyl]-3,5-dimethyl-1H pyrrole-2-carboxylate (PDNBAH) has been synthesized and characterized by FT-IR, (1)H NMR, UV-visible spectroscopy. All the quantum chemical calculations have been performed by density functional theory (DFT), using B3LYP functional and 6 31G(d,p) as basis set. The calculated and experimental wavenumber analyses confirm the existence of dimer of PDNBAH. The calculated binding energies of dimer using DFT and Bader's atoms in molecules (AIM) theory are -14.32 and -15.41 kcal/mol respectively. The intermolecular hydrogen bond energy of dimer due to the involvement of intermolecular hetero-nuclear double hydrogen bonds (N H...O=C) through pyrrolic N-H and C=O of ester is also calculated to be equal to 12.29 kcal/mol using AIM calculation. The strength and the nature of hydrogen bonding and weak interactions in dimer have been analyzed by AIM theory in detail. The presence of resonance assisted hydrogen bonds (RAHB) has been confirmed by calculated ellipticity parameters using AIM calculation. The calculated thermodynamic parameters show that the reaction is non spontaneous at room temperature. The local reactivity descriptors show that C(13) is most reactive site for nucleophilic attack. PMID- 22208960 TI - Photoluminescence quenching/recovery kinetics of [Ru(bpy)2(tatp)]2+ and [Ru(bpy)2(dmtatp)]2+ intercalated within DNA by copper(II) ions and EDTA. AB - The quenching and recovery kinetics of photoluminescence of [Ru(bpy)(2)(tatp)](2+) (Ru1) and [Ru(bpy)(2)(dmtatp)](2+) (Ru2) intercalated within DNA (where bpy=2,2'-bipyridine, tatp=1,4,8,9-tetra-aza-triphenylene and dmtatp=2,3-dimethyl-1,4,8,9-tetra-aza-triphenylene) have been investigated by steady-state and time-resolved methods performed at various temperatures (293 333K). Two complexes Ru1 and Ru2 show a single-exponential luminescence decay with tau(Ru1)=246.0 ns and tau(Ru2)=513.5 ns, whose luminescence upon intercalating into DNA exhibits very consistent bi-exponential decay changes. The addition of Cu(2+) ions is found to dynamically quench the luminescence of both DNA-bound Ru(II) complexes, involving a spontaneous exothermic process. The sequential addition of EDTA can partially recover the luminescence quenched by Cu(2+), however depending on methyl substituents of the intercalative ligand. The chemical conversion and luminescence control mechanism of the two DNA-bound Ru(II) complexes is discussed in detail. The present results should be of value for better understanding chemical modulation of DNA-bound Ru(II) complexes as luminescence probes. PMID- 22208961 TI - [Idiopathic and secondary membranous nephropathies]. AB - Antibodies to neutral endopeptidase, a podocyte protein, are responsible for rare alloimmune neonatal membranous nephropathy that develops in children from neutral endopeptidase-deficient mothers. Neutral endopeptidase was the first podocyte antigen described in human membranous nephropathy. PLA2R1, the type-M receptor of soluble phospholipase A2, is a major target antigen in so-called idiopathic membranous nephropathy in adults. Antibodies to PLA2R1 are detected in 60 to 80% of patients before immunosuppressive treatment, and are only occasionally found in secondary membranous nephropathy. To date, they have not been detected in other pathological conditions and in healthy individuals. PLA2R1 and HLA-DQA1 gene variants defined by single nucleotide polymorphisms are strongly associated with idiopathic membranous nephropathy in patients of white ancestry, and can thus be considered as predisposing genes. In addition to their diagnostic value, anti-PLA2R1 antibodies can be used to monitor treatment. Immunization against cationic bovine serum albumin is a cause of early childhood membranous nephropathy. This finding points to a possible role of food and environmental antigens in membranous nephropathy. The newly identified antigen-antibody systems should be considered as molecular signatures challenging the uniform histological definition and having a major impact on patient care in a near future. PMID- 22208962 TI - PET/CT in anal cancer - is it worth doing? AB - AIM: To evaluate the role of 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/ computed tomography (CT) in the current multidisciplinary management of anal cancer, both in initial staging and in follow-up post-treatment. MATERIALS AND METHODS: All patients referred to the region-wide multidisciplinary meeting for anal cancer during the study period received PET/CT imaging in addition to conventional imaging [CT and magnetic resonance imaging (MRI)]. Whether PET/CT altered the stage of the tumour from that suggested by conventional imaging was retrospectively assessed. The effect on management was evaluated. RESULTS: Fifty PET/CT examinations were performed on 44 patients with anal cancer. Thirty were part of initial staging, and 20 were post-chemo/radiotherapy or surgery. Two PET/CTs produced inadequate contemporaneous conventional imaging to allow comparison. Overall PET/CT increased the stage of the anal cancer in 17% of cases (8/48), decreased the stage in 19% (9/48), and did not alter the stage in 65% (31/48). The tumour stage was altered more frequently in initial staging than in follow up imaging. The PET/CT findings altered patient management in 29% (14/48) of cases. The majority (11) of these were cases in which PET/CT was used as part of initial staging. CONCLUSION: PET/CT alters the initial staging sufficiently frequently that it should be used routinely in anal cancer, where it is available. The role of PET/CT in the follow-up of anal cancer is not as clear. Routine follow-up with PET/CT may not be justified, but selected use is of definite benefit in problem solving or if salvage surgery is planned, after multidisciplinary discussion. PMID- 22208963 TI - Salvage treatment with hypofractionated radiotherapy in patients with recurrent small hepatocellular carcinoma. AB - PURPOSE: To investigate the rates of tumor response and local control in patients with recurrent small hepatocellular carcinoma (HCC) treated with hypofractionated radiotherapy (RT) as a salvage treatment and to evaluate treatment-related toxicities. METHODS AND MATERIALS: Between 2006 and 2009, a total of 20 patients with recurrent small HCC were treated with hypofractionated RT after the failure of previous treatment. The eligibility criteria for hypofractionated RT were as follows: 1) HCC less than 5 cm, 2) HCC not adjacent to critical organs, 3) HCC without portal vein tumor thrombosis, and 4) less than 15% of normal liver volume that would be irradiated with 50% of prescribed dose. The RT dose was 50 Gy in 10 fractions. The tumor response was determined by CT scans performed 3 months after the end of RT. RESULTS: The median follow-up period after RT was 22 months. The overall survival rates at 1 and 2 years were 100% and 87.9%, respectively. Complete response (CR) was achieved in seven of 20 lesions (35%) evaluated by CT scans performed 3 months after the end of RT. In-field local control was achieved in 85% of patients. Fourteen patients (70%) developed intra-hepatic metastases. Six patients developed grade 1 nausea or anorexia during RT, and two patients had progression of ascites after RT. There was no grade 3 or greater treatment related toxicities. CONCLUSIONS: The current study showed a favorable outcome with respect to hypofractionated RT for small HCC. Partial liver irradiation with 50 Gy in 10 fractions is considered tolerable without severe complications. PMID- 22208964 TI - Adaptive image-guided radiotherapy (IGRT) eliminates the risk of biochemical failure caused by the bias of rectal distension in prostate cancer treatment planning: clinical evidence. AB - PURPOSE: Rectal distension has been shown to decrease the probability of biochemical control. Adaptive image-guided radiotherapy (IGRT) corrects for target position and volume variations, reducing the risk of biochemical failure while yielding acceptable rates of gastrointestinal (GI)/genitourinary (GU) toxicities. METHODS AND MATERIALS: Between 1998 and 2006, 962 patients were treated with computed tomography (CT)-based offline adaptive IGRT. Patients were stratified into low (n = 400) vs. intermediate/high (n = 562) National Comprehensive Cancer Network (NCCN) risk groups. Target motion was assessed with daily CT during the first week. Electronic portal imaging device (EPID) was used to measure daily setup error. Patient-specific confidence-limited planning target volumes (cl-PTV) were then constructed, reducing the standard PTV and compensating for geometric variation of the target and setup errors. Rectal volume (RV), cross-sectional area (CSA), and rectal volume from the seminal vesicles to the inferior prostate (SVP) were assessed on the planning CT. The impact of these volumetric parameters on 5-year biochemical control (BC) and chronic Grades >=2 and 3 GU and GI toxicity were examined. RESULTS: Median follow up was 5.5 years. Median minimum dose covering cl-PTV was 75.6 Gy. Median values for RV, CSA, and SVP were 82.8 cm(3), 5.6 cm(2), and 53.3 cm(3), respectively. The 5-year BC was 89% for the entire group: 96% for low risk and 83% for intermediate/high risk (p < 0.001). No statistically significant differences in BC were seen with stratification by RV, CSA, and SVP in quartiles. Maximum chronic Grades >=2 and 3 GI toxicities were 21.2% and 2.9%, respectively. Respective values for GU toxicities were 15.5% and 4.3%. No differences in GI or GU toxicities were noted when patients were stratified by RV. CONCLUSIONS: Incorporation of adaptive IGRT reduces the risk of geometric miss and results in excellent biochemical control that is independent of rectal volume/distension while maintaining very low rates of chronic GI toxicity. PMID- 22208965 TI - Local failure in resected N1 lung cancer: implications for adjuvant therapy. AB - PURPOSE: To evaluate actuarial rates of local failure in patients with pathologic N1 non-small-cell lung cancer and to identify clinical and pathologic factors associated with an increased risk of local failure after resection. METHODS AND MATERIALS: All patients who underwent surgery for non-small-cell lung cancer with pathologically confirmed N1 disease at Duke University Medical Center from 1995 2008 were identified. Patients receiving any preoperative therapy or postoperative radiotherapy or with positive surgical margins were excluded. Local failure was defined as disease recurrence within the ipsilateral hilum, mediastinum, or bronchial stump/staple line. Actuarial rates of local failure were calculated with the Kaplan-Meier method. A Cox multivariate analysis was used to identify factors independently associated with a higher risk of local recurrence. RESULTS: Among 1,559 patients who underwent surgery during the time interval, 198 met the inclusion criteria. Of these patients, 50 (25%) received adjuvant chemotherapy. Actuarial (5-year) rates of local failure, distant failure, and overall survival were 40%, 55%, and 33%, respectively. On multivariate analysis, factors associated with an increased risk of local failure included a video-assisted thoracoscopic surgery approach (hazard ratio [HR], 2.5; p = 0.01), visceral pleural invasion (HR, 2.1; p = 0.04), and increasing number of positive N1 lymph nodes (HR, 1.3 per involved lymph node; p = 0.02). Chemotherapy was associated with a trend toward decreased risk of local failure that was not statistically significant (HR, 0.61; p = 0.2). CONCLUSIONS: Actuarial rates of local failure in pN1 disease are high. Further investigation of conformal postoperative radiotherapy may be warranted. PMID- 22208966 TI - Radiation therapy with full-dose gemcitabine and oxaliplatin for unresectable pancreatic cancer. AB - PURPOSE: We completed a Phase I trial of gemcitabine and oxaliplatin with concurrent radiotherapy in patients with previously untreated pancreatic cancer. The results of a subset of patients with unresectable disease who went on to receive planned additional therapy are reported here. METHODS AND MATERIALS: All patients received two 28-day cycles of gemcitabine (1,000 mg/m(2) on Days 1, 8, and 15) and oxaliplatin (40-85 mg/m(2) on Days 1 and 15, per a dose-escalation schema). Radiation therapy was delivered concurrently with Cycle 1 (27 Gy in 1.8 Gy fractions). At 9 weeks, patients were reassessed for resectability. Those deemed to have unresectable disease were offered a second round of treatment consisting of 2 cycles of gemcitabine and oxaliplatin and 27 Gy of radiation therapy (total, 54 Gy). Radiation was delivered to the gross tumor volume plus 1 cm by use of a three-dimensional conformal technique. We used the Common Terminology Criteria for Adverse Events to assess acute toxicity. Late toxicity was scored per the Radiation Therapy Oncology Group scale. Computed tomography scans were reviewed to determine pattern of failure, local response, and disease progression. Kaplan-Meier methodology and Cox regression models were used to evaluate survival and freedom from failure. RESULTS: Thirty-two patients from the Phase I dose-escalation study had unresectable disease, three of whom had low volume metastatic disease. Of this group, 16 patients went on to receive additional therapy to complete a total of 4 cycles of chemotherapy and 54 Gy of concurrent radiation. For this subset, 38% had at least a partial tumor response at a median of 3.2 months. Median survival was 11.8 months (range, 4.4-26.3 months). The 1-year freedom from local progression rate was 93.8% (95% confidence interval, 63.2-99.1). CONCLUSIONS: Radiation therapy to 54 Gy with concurrent full-dose gemcitabine and oxaliplatin is well tolerated and results in favorable rates of local tumor response and 1-year freedom from local progression. PMID- 22208968 TI - FADD expression as a prognosticator in early-stage glottic squamous cell carcinoma of the larynx treated primarily with radiotherapy. AB - PURPOSE: We recently reported on the identification of the Fas-associated death domain (FADD) as a possible driver of the chromosome 11q13 amplicon and the association between increased FADD expression and disease-specific survival in advanced-stage laryngeal carcinoma. The aim of this study was to examine whether expression of FADD and its Ser194-phosphorylated isoform (pFADD) predicts local control in patients with early-stage glottic carcinoma primarily treated with radiotherapy only. METHODS AND MATERIALS: Immunohistochemical staining for FADD and pFADD was performed on pretreatment biopsy specimens of 92 patients with T1 T2 glottic squamous cell carcinoma primarily treated with radiotherapy between 1996 and 2005. Cox regression analysis was used to correlate expression levels with local control. RESULTS: High levels of pFADD were associated with significantly better local control (hazard ratio, 2.40; 95% confidence interval, 1.04-5.55; p = 0.040). FADD overexpression showed a trend toward better local control (hazard ratio, 3.656; 95% confidence interval, 0.853-15.663; p = 0.081). Multivariate Cox regression analysis showed that high pFADD expression was the best predictor of local control after radiotherapy. CONCLUSIONS: This study showed that expression of phosphorylated FADD is a new prognostic biomarker for better local control after radiotherapy in patients with early-stage glottic carcinomas. PMID- 22208967 TI - Characterizing tumor heterogeneity with functional imaging and quantifying high risk tumor volume for early prediction of treatment outcome: cervical cancer as a model. AB - PURPOSE: Treatment response in cancer has been monitored by measuring anatomic tumor volume (ATV) at various times without considering the inherent functional tumor heterogeneity known to critically influence ultimate treatment outcome: primary tumor control and survival. This study applied dynamic contrast-enhanced (DCE) functional MRI to characterize tumors' heterogeneous subregions with low DCE values, at risk for treatment failure, and to quantify the functional risk volume (FRV) for personalized early prediction of treatment outcome. METHODS AND MATERIALS: DCE-MRI was performed in 102 stage IB(2)-IVA cervical cancer patients to assess tumor perfusion heterogeneity before and during radiation/chemotherapy. FRV represents the total volume of tumor voxels with critically low DCE signal intensity (<2.1 compared with precontrast image, determined by previous receiver operator characteristic analysis). FRVs were correlated with treatment outcome (follow-up: 0.2-9.4, mean 6.8 years) and compared with ATVs (Mann-Whitney, Kaplan Meier, and multivariate analyses). RESULTS: Before and during therapy at 2-2.5 and 4-5 weeks of RT, FRVs >20, >13, and >5 cm(3), respectively, significantly predicted unfavorable 6-year primary tumor control (p = 0.003, 7.3 * 10(-8), 2.0 * 10(-8)) and disease-specific survival (p = 1.9 * 10(-4), 2.1 * 10(-6), 2.5 * 10(-7), respectively). The FRVs were superior to the ATVs as early predictors of outcome, and the differentiating power of FRVs increased during treatment. DISCUSSION: Our preliminary results suggest that functional tumor heterogeneity can be characterized by DCE-MRI to quantify FRV for predicting ultimate long-term treatment outcome. FRV is a novel functional imaging heterogeneity parameter, superior to ATV, and can be clinically translated for personalized early outcome prediction before or as early as 2-5 weeks into treatment. PMID- 22208969 TI - Accumulated dose in liver stereotactic body radiotherapy: positioning, breathing, and deformation effects. AB - PURPOSE: To investigate the accumulated dose deviations to tumors and normal tissues in liver stereotactic body radiotherapy (SBRT) and investigate their geometric causes. METHODS AND MATERIALS: Thirty previously treated liver cancer patients were retrospectively evaluated. Stereotactic body radiotherapy was planned on the static exhale CT for 27-60 Gy in 6 fractions, and patients were treated in free-breathing with daily cone-beam CT guidance. Biomechanical model based deformable image registration accumulated dose over both the planning four dimensional (4D) CT (predicted breathing dose) and also over each fraction's respiratory-correlated cone-beam CT (accumulated treatment dose). The contribution of different geometric errors to changes between the accumulated and predicted breathing dose were quantified. RESULTS: Twenty-one patients (70%) had accumulated dose deviations relative to the planned static prescription dose >5%, ranging from -15% to 5% in tumors and -42% to 8% in normal tissues. Sixteen patients (53%) still had deviations relative to the 4D CT-predicted dose, which were similar in magnitude. Thirty-two tissues in these 16 patients had deviations >5% relative to the 4D CT-predicted dose, and residual setup errors (n = 17) were most often the largest cause of the deviations, followed by deformations (n = 8) and breathing variations (n = 7). CONCLUSION: The majority of patients had accumulated dose deviations >5% relative to the static plan. Significant deviations relative to the predicted breathing dose still occurred in more than half the patients, commonly owing to residual setup errors. Accumulated SBRT dose may be warranted to pursue further dose escalation, adaptive SBRT, and aid in correlation with clinical outcomes. PMID- 22208971 TI - Breast conservation therapy: the influence of molecular subtype and margins. AB - PURPOSE: To evaluate treatment results and prognostic factors, especially margin status and molecular subtype, in early-stage breast cancer patients treated with breast conservation therapy (BCT). METHODS AND MATERIALS: The records of 1,058 Stage I or II breast cancer patients treated with BCT (surgical excision plus radiotherapy) at Duke University Medical Center, Durham, North Carolina, from 1985-2005 were retrospectively reviewed. Conventional receptor analyses were used as surrogate markers for molecular subtype classification (luminal A, luminal B, Her2 positive, and basal like). Actuarial estimates of overall survival (OS), cause-specific survival (CSS), failure-free survival, and locoregional control (LRC) were computed by use of Kaplan-Meier plots. We analyzed prognostic variables for significance using Cox proportional hazards univariate and multivariate analysis. The study was approved by the Duke University Medical Center Institutional Review Board. RESULTS: The median age of the patients was 56 years (range, 18-89 years). Of the patients, 80% had T1 disease and 66% N0 disease pathologically. With a median follow-up of 9.8 years, an in-breast recurrence developed in 53 patients and 10 patients had nodal failure. For all patients, the 10-year CSS rate was 94%; LRC rate, 94%; and failure-free survival rate, 88%. Luminal A patients had a CSS rate of 95% and LRC rate of 99%. Basal type patients appeared to do worse, with regard to both CSS rate (74%) and LRC rate (76%), but the numbers were small and the difference was not statistically significant. LRC rates of patients with negative margins (widely negative, close, and extent of margin not known) were virtually identical (93%, 96%, and 94%, respectively). Those with positive margins appeared to fare slightly worse based on LRC rate (88%), but again, the numbers were small and the difference was not statistically significant. CONCLUSIONS: BCT remains the treatment of choice for early-stage breast cancer patients irrespective of molecular subtype. Negative margins of excision are desirable, but the width of the negative margin does not influence outcome. PMID- 22208970 TI - Silencing fibronectin extra domain A enhances radiosensitivity in nasopharyngeal carcinomas involving an FAK/Akt/JNK pathway. AB - PURPOSE: Fibronectin extra domain A (EDA) is known to play important roles in angiogenesis, lymphangiogenesis, and metastasis in malignant tumors. The present study examined the effect of EDA on the radioresistance potential of nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: EDA expression levels in blood samples and tumor tissues of NPC patients were tested by enzyme-linked immunosorbent assay and immunohistochemistry. Radiosensitivity was tested by colony survival assay. Apoptosis was determined by flow cytometry. The expressions of EDA, cleaved caspase 9, cleaved caspase 3, cleaved PARP, Bcl-2, and the levels of phosphorylated FAK, Akt, and JNK were measured by Western blot. Xenografts were used to confirm the effect of EDA on radiosensitivity in vivo. RESULTS: EDA levels in blood samples of advanced NPC patients were much higher than those in early-stage patients. In tumor tissues, the positive expressions of EDA in NPC tumor tissues were shown to be correlated with the differentiation degrees of cancer cells and lymph node metastases. Additionally, the expression of EDA is positively correlated with the expression of antiapoptotic gene (Bcl2), but negatively correlated with the expressions of apoptotic genes (cleaved caspase-3, cleaved caspase-9, cleaved PARP). In vitro, EDA-silenced NPC cells CNE 2 shows substantially enhanced radiosensitivity with lower colony survival and more apoptosis in response to radiation. In vivo, EDA-silenced xenografts were more sensitive to radiation. At the molecular level, FAK/Akt/JNK signaling was demonstrated to be inactivated in EDA-silenced CNE-2 cells. CONCLUSIONS: EDA strongly affected the radiosensitivity of NPC cells. FAK/Akt/JNK signaling was found to be a potential signaling mediating EDA function. PMID- 22208972 TI - Factors predictive of symptomatic radiation injury after linear accelerator-based stereotactic radiosurgery for intracerebral arteriovenous malformations. AB - PURPOSE: To investigate predictive factors in the development of symptomatic radiation injury after treatment with linear accelerator-based stereotactic radiosurgery for intracerebral arteriovenous malformations and relate the findings to the conclusions drawn by Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC). METHODS AND MATERIALS: Archived plans for 73 patients who were treated at the British Columbia Cancer Agency were studied. Actuarial estimates of freedom from radiation injury were calculated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards models were used for analysis of incidence of radiation injury. Log-rank test was used to search for dosimetric parameters associated with freedom from radiation injury. RESULTS: Symptomatic radiation injury was exhibited by 14 of 73 patients (19.2%). Actuarial rate of symptomatic radiation injury was 23.0% at 4 years. Most patients (78.5%) had mild to moderate deficits according to Common Terminology Criteria for Adverse Events, version 4.0. On univariate analysis, lesion volume and diameter, dose to isocenter, and a V(x) for doses >=8 Gy showed statistical significance. Only lesion diameter showed statistical significance (p < 0.05) in a multivariate model. According to the log-rank test, AVM volumes >5 cm(3) and diameters >30 mm were significantly associated with the risk of radiation injury (p < 0.01). The V(12) also showed strong association with the incidence of radiation injury. Actuarial incidence of radiation injury was 16.8% if V(12) was <28 cm(3) and 53.2% if >28 cm(3) (log-rank test, p = 0.001). CONCLUSIONS: This study confirms that the risk of developing symptomatic radiation injury after radiosurgery is related to lesion diameter and volume and irradiated volume. Results suggest a higher tolerance than proposed by QUANTEC. The widely differing findings reported in the literature, however, raise considerable uncertainties. PMID- 22208974 TI - Effect of body mass index on magnitude of setup errors in patients treated with adjuvant radiotherapy for endometrial cancer with daily image guidance. AB - PURPOSE: To determine the impact of body mass index (BMI) on daily setup variations and frequency of imaging necessary for patients with endometrial cancer treated with adjuvant intensity-modulated radiotherapy (IMRT) with daily image guidance. METHODS AND MATERIALS: The daily shifts from a total of 782 orthogonal kilovoltage images from 30 patients who received pelvic IMRT between July 2008 and August 2010 were analyzed. The BMI, mean daily shifts, and random and systematic errors in each translational and rotational direction were calculated for each patient. Margin recipes were generated based on BMI. Linear regression and spearman rank correlation analysis were performed. To simulate a less-than-daily IGRT protocol, the average shift of the first five fractions was applied to subsequent setups without IGRT for assessing the impact on setup error and margin requirements. RESULTS: Median BMI was 32.9 (range, 23-62). Of the 30 patients, 16.7% (n = 5) were normal weight (BMI <25); 23.3% (n = 7) were overweight (BMI >= 25 to <30); 26.7% (n = 8) were mildly obese (BMI >= 30 to <35); and 33.3% (n = 10) were moderately to severely obese (BMI >= 35). On linear regression, mean absolute vertical, longitudinal, and lateral shifts positively correlated with BMI (p = 0.0127, p = 0.0037, and p < 0.0001, respectively). Systematic errors in the longitudinal and vertical direction were found to be positively correlated with BMI category (p < 0.0001 for both). IGRT for the first five fractions, followed by correction of the mean error for all subsequent fractions, led to a substantial reduction in setup error and resultant margin requirement overall compared with no IGRT. CONCLUSIONS: Daily shifts, systematic errors, and margin requirements were greatest in obese patients. For women who are normal or overweight, a planning target margin margin of 7 to 10 mm may be sufficient without IGRT, but for patients who are moderately or severely obese, this is insufficient. PMID- 22208973 TI - Prone whole-breast irradiation using three-dimensional conformal radiotherapy in women undergoing breast conservation for early disease yields high rates of excellent to good cosmetic outcomes in patients with large and/or pendulous breasts. AB - PURPOSE: To report our institution's experience using prone positioning for three dimensional conformal radiotherapy (3D-CRT) to deliver post-lumpectomy whole breast irradiation (WBI) in a cohort of women with large and/or pendulous breasts, to determine the rate of acute and late toxicities and, more specifically, cosmetic outcomes. We hypothesized that using 3D-CRT for WBI in the prone position would reduce or eliminate patient and breast size as negative prognostic indicators for toxicities associated with WBI. METHODS AND MATERIALS: From 1998 to 2006, 110 cases were treated with prone WBI using 3D-CRT. The lumpectomy, breast target volumes, heart, and lung were contoured on all computed tomography scans. A dose of 45-50 Gy was prescribed to the breast volume using standard fractionation schemes. The planning goals were >=95% of prescription to 95% of the breast volume, and 100% of boost dose to 95% of lumpectomy planning target volume. Toxicities and cosmesis were prospectively scored using the Common Terminology Criteria for Adverse Effects Version 3.0 and the Harvard Scale. The median follow-up was 40 months. RESULTS: The median body mass index (BMI) was 33.6 kg/m(2), and median breast volume was 1396 cm(3). The worst toxicity encountered during radiation was Grade 3 dermatitis in 5% of our patient population. Moist desquamation occurred in 16% of patients, with only 2% of patients with moist desquamation outside the inframammary/axillary folds. Eleven percent of patients had Grade >=2 late toxicities, including Grade 3 induration/fibrosis in 2%. Excellent to good cosmesis was achieved in 89%. Higher BMI was associated with moist desquamation and breast pain, but BMI and breast volume did not impact fibrosis or excellent to good cosmesis. CONCLUSION: In patients with higher BMI and/or large-pendulous breasts, delivering prone WBI using 3D-CRT results in favorable toxicity profiles and high excellent to good cosmesis rates. Higher BMI was associated with moist desquamation, but prone positioning removed BMI and breast size as factors for poorer cosmetic outcomes. This series adds to the growing literature demonstrating that prone WBI may be advantageous in select patients. PMID- 22208975 TI - Improved outcomes of breast-conserving therapy for patients with ductal carcinoma in situ. AB - PURPOSE: Patients treated for ductal carcinoma in situ (DCIS) with breast conserving surgery (BCS) and radiation therapy (RT) at our center from 1976 to 1990 had a 15% actuarial 10-year local recurrence (LR) rate. Since then, improved mammographic and pathologic evaluation and greater attention to achieving negative margins may have resulted in a lower risk of LR. In addition, clinical implications of hormone receptor and HER-2 status in DCIS remain unclear. We sought to determine the following: LR rates with this more modern approach; the relation between LR and HER-2 status; and clinical and pathologic factors associated with HER-2(+) DCIS. METHODS AND MATERIALS: We studied 246 consecutive patients who underwent BCS and RT for DCIS from 2001 to 2007. Of the patients, 96 (39%) were Grade III and the median number of involved tissue blocks was 3. Half underwent re-excision and 222 (90%) had negative margins (>2 mm). All received whole-breast RT (40-52 Gy) and 99% (244) received a tumor bed boost (8-18 Gy). Routine estrogen receptor (ER), progesterone receptor (PR), and HER-2 immunohistochemistry was instituted in 2003. RESULTS: With median follow-up of 58 months, there were no LRs. Seven patients (3%) developed contralateral breast cancer (4 invasive and 3 in situ). Among 163 patients with immunohistochemistry, 124 were ER/PR(+)HER-2(-), 27 were ER/PR(+)HER-2(+), 6 were ER(-)/PR(-)HER-2(+), and 6 were ER(-)/PR(-)HER-2(-). On univariable analysis, HER-2(+)was significantly associated with Grade III, ER(-)/PR(-), central necrosis, comedo subtype, more extensive DCIS, and postmenopausal status. On multivariable analysis, Grade III and postmenopausal status remained significantly associated with HER-2(+). CONCLUSIONS: In an era of mammographically identified DCIS, larger excisions, widely negative margins and the use of a tumor bed boost, we observed no LR regardless of ER/PR/HER-2 status. Factors associated with HER-2(+)DCIS included more extensive DCIS, Grade III, ER(-)/PR(-), central necrosis, comedo subtype, and postmenopausal status. Further follow-up and additional studies are required to confirm these results. PMID- 22208976 TI - Phase II study of long-term androgen suppression with bevacizumab and intensity modulated radiation therapy (IMRT) in high-risk prostate cancer. AB - PURPOSE: We report a Phase II trial assessing the acute and late toxicities of intensity-modulated radiation therapy (IMRT), long-term androgen suppression (LTAS), and bevacizumab in patients with high-risk localized prostate cancer. METHODS AND MATERIALS: We treated 18 patients with LTAS with bicalutamide and goserelin in combination with bevacizumab and IMRT. Bevacizumab (10 mg/kg every 2 weeks) was administered for the first 16 weeks, and 15 mg/kg was then given every 3 weeks for 12 additional weeks, with an IMRT dose of 77.9 Gy to the prostate, 64.6 Gy to the seminal vesicles, and 57 Gy to the pelvic lymph nodes. Patients were eligible if they had clinical stage T2b to T4, a Gleason sum score of 8 to 10, or a prostate- specific antigen level of 20ng/mL or greater. The primary endpoint of the study was evaluation of acute and late toxicities. RESULTS: The median age was 69 years, with a median pretreatment prostate-specific antigen level of 12.5 ng/mL and Gleason score of 8. The pretreatment clinical stage was T1c in 4 patients, T2 in 11, and T3 in 3. All patients completed IMRT with median follow-up of 34 months (range, 28-40 months) The most common Grade 2 or higher toxicities were hypertension (61% of patients with Grade 2 and 11% with Grade 3), proteinuria (28% with Grade 2 and 6% with Grade 3), and leucopenia (28% with Grade 2). No Grade 4 or higher acute toxicities were reported. Late toxicities included proctitis (6% of patients with Grade 2 and 11% with Grade 3), rectal bleeding (6% with Grade 2 and 11% with Grade 3), hematuria (6% with Grade 2), proteinuria (17% with Grade 2), hyponatremia (6% with Grade 3), cystitis (6% with Grade 3), and urinary retention (6% with Grade 2 and 11% with Grade 3). Grade 4 prostatitis occurred in 1 patient (6%). CONCLUSIONS: Bevacizumab does not appear to exacerbate the acute effects of IMRT. Late toxicities may have been worsened with this regimen. Further investigations of bevacizumab with LTAS and IMRT should be performed cautiously. PMID- 22208977 TI - Maximizing tumor immunity with fractionated radiation. AB - PURPOSE: Technologic advances have led to increased clinical use of higher-sized fractions of radiation dose and higher total doses. How these modify the pathways involved in tumor cell death, normal tissue response, and signaling to the immune system has been inadequately explored. Here we ask how radiation dose and fraction size affect antitumor immunity, the suppression thereof, and how this might relate to tumor control. METHODS AND MATERIALS: Mice bearing B16-OVA murine melanoma were treated with up to 15 Gy radiation given in various-size fractions, and tumor growth followed. The tumor-specific immune response in the spleen was assessed by interferon-gamma enzyme-linked immunospot (ELISPOT) assay with ovalbumin (OVA) as the surrogate tumor antigen and the contribution of regulatory T cells (Tregs) determined by the proportion of CD4(+)CD25(hi)Foxp3(+) T cells. RESULTS: After single doses, tumor control increased with the size of radiation dose, as did the number of tumor-reactive T cells. This was offset at the highest dose by an increase in Treg representation. Fractionated treatment with medium size radiation doses of 7.5 Gy/fraction gave the best tumor control and tumor immunity while maintaining low Treg numbers. CONCLUSIONS: Radiation can be an immune adjuvant, but the response varies with the size of dose per fraction. The ultimate challenge is to optimally integrate cancer immunotherapy into radiation therapy. PMID- 22208978 TI - Thermoregulation in peripheral nerve injury-induced cold-intolerant rats. AB - PURPOSE: Cold intolerance is defined as pain after exposure to non-painful cold. It is suggested that cold intolerance may be related to dysfunctional thermoregulation in upper extremity nerve injury patients. The purpose of this study was to examine if the re-warming of a rat hind paw is altered in different peripheral nerve injury models and if these patterns are related to severity of cold intolerance. METHODS: In the spared nerve injury (SNI) and complete sciatic lesion (CSL) model, the re-warming patterns after cold stress exposure were investigated preoperatively and at 3, 6 and 9 weeks postoperatively with a device to induce cooling of the hind paws. Thermocouples were attached on the dorsal side of the hind paw to monitor re-warming patterns. RESULTS: The Von Frey test and cold plate test indicated a significantly lower paw-withdrawal threshold and latency in the SNI compared to the Sham model. The CSL group, however, had only significantly lower paw-withdrawal latency on the cold plate test compared to the Sham group. While we found no significantly different re-warming patterns in the SNI and CSL group compared to Sham group, we did find a tendency in temperature increase in the CSL group 3 weeks postoperatively. CONCLUSION: Overall, our findings indicate that re-warming patterns are not altered after peripheral nerve injury in these rat models despite the fact that these animals did develop cold intolerance. This suggests that disturbed thermoregulation may not be the prime mechanism for cold intolerance and that, other, most likely, neurological mechanisms may play a more important role. CLINICAL RELEVANCE: There is no direct correlation between cold intolerance and re-warming patterns in different peripheral nerve injury rat models. This is an important finding for future developing treatments for this common problem, since treatment focussing on vaso regulation may not help diminish symptoms of cold-intolerant patients. PMID- 22208979 TI - Simplified synthetic antibody libraries. AB - Synthetic antibody libraries are constructed from scratch using designed synthetic DNA. Precise control over design enables the use of highly optimized human frameworks and the introduction of defined chemical diversity at positions that are most likely to contribute to antigen recognition. We describe complete methods for the design, construction, and application of simplified synthetic antibody libraries built on a single human framework with diversity restricted to four complementarity-determining regions and two amino acids (tyrosine and serine). Despite the extreme simplicity of design, these libraries are capable of generating specific antibodies against diverse protein antigens. Moreover, the same methods can be used to build more complex libraries that can produce synthetic antibodies with affinities and specificities beyond the scope of natural antibodies. Most importantly, these simplified methods rely on standard supplies, equipment, and methods that are accessible to any molecular biology laboratory. PMID- 22208980 TI - Generation of dual-variable-domain immunoglobulin molecules for dual-specific targeting. AB - Bispecific antibodies may be used to improve clinical efficacy by targeting two disease mechanisms for the treatment of complex human diseases in a single agent. Bispecific antibodies also hold promise for certain therapeutic applications difficult to achieve by single-targeting monospecific antibodies, such as immune (T cell or NK) cell retargeting, site-specific targeting, enabling therapeutics to cross the blood-brain barrier, and unique receptor modulation. Although the history of bispecific antibody research is almost as long as hybridoma technology, it is not until recent that bispecific antibodies have made substantial breakthrough, thanks to promising clinical trial results of a few bispecific antibodies and the development of new formats which largely ease manufacturing and physicochemical property challenges encountered by early bispecific antibody formats. The dual-variable-domain immunoglobulin (DVD-IgTM) format was initially described in 2007. In this format, the target-binding variable domains of two monoclonal antibodies can be combined via naturally occurring linkers to create a tetravalent, dual-targeting single agent. Viable DVD-Ig molecules can be identified through optimization of antibody pair, antibody variable domain orientation, and linkers. An optimized DVD-IgTM molecule has many desirable properties of a mAb, such as good expression in mammalian cells, easy purification to homogeneity using standard approaches, displaying good drug-like biophysical and pharmacokinetic properties, and amenability to large-scale manufacturing. Several DVD-Ig molecules have demonstrated favorable pharmacokinetic properties and efficacy in preclinical animal models. Here, we provide an example of construction and preliminary characterization of a DVD-IgTM molecule and discuss the general approach used in optimization. PMID- 22208982 TI - Optimizing properties of antireceptor antibodies using kinetic computational models and experiments. AB - Monoclonal antibodies are valuable as anticancer therapeutics because of their ability to selectively bind tumor-associated target proteins like receptor tyrosine kinases. Kinetic computational models that capture protein-protein interactions using mass action kinetics are a valuable tool for understanding the binding properties of monoclonal antibodies to their targets. Insights from the models can be used to explore different formats, to set antibody design specifications such as affinity and valence, and to predict potency. Antibody binding to target is driven by both intrinsic monovalent affinity and bivalent avidity. In this chapter, we describe a combined experimental and computational method of assessing the relative importance of these effects on observed drug potency. The method, which we call virtual flow cytometry (VFC), merges experimental measurements of monovalent antibody binding kinetics and affinity curves of antibody-antigen binding into a kinetic computational model of antibody antigen interaction. The VFC method introduces a parameter chi, the avidity factor, which characterizes the ability of an antibody to cross-link its target through bivalent binding. This simple parameterization of antibody cross-linking allows the model to successfully describe and predict antibody binding curves across a wide variety of experimental conditions, including variations in target expression level and incubation time of antibody with target. We further demonstrate how computational models of antibody binding to cells can be used to predict target inhibition potency. Importantly, we demonstrate computationally that antibodies with high ability to cross-link antigen have significant potency advantages. We also present data suggesting that the parameter chi is a physical, epitope-dependent property of an antibody, and as a result propose that determination of antibody cross-linking and avidity should be incorporated into the screening of antibody panels for therapeutic development. Overall, our results suggest that antibody cross-linking, in addition to monovalent binding affinity, is a key design parameter of antibody performance. PMID- 22208981 TI - Discovery of internalizing antibodies to tumor antigens from phage libraries. AB - Phage antibody technology can be used to generate human antibodies to essentially any antigen. Many therapeutic target antigens are cell surface receptors, which can be challenging targets for antibody generation. In addition, for many therapeutic applications, one needs antibodies that not only bind the cell surface receptor but also are internalized into the cell upon binding. This allows use of the antibody to deliver a range of payloads into the cell to achieve a therapeutic effect. In this chapter, we describe how human phage antibody libraries can be selected directly on tumor cell lines to generate antibodies that bind cell surface receptors and which upon binding are rapidly internalized into the cell. Specific protocols show how to (1) directly select cell binding and internalizing antibodies from human phage antibody libraries, (2) screen the phage antibodies in a high-throughput flow cytometry assay for binding to the tumor cell line used for selection, (3) identify the antigen bound by the phage antibody using immunoprecipitation and mass spectrometry, and (4) direct cell binding and internalizing selections to a specific tumor antigen by sequential selection on a tumor cell line followed by selection on yeast displaying the target tumor antigen on the yeast surface. PMID- 22208983 TI - Cell-specific siRNA delivery by peptides and antibodies. AB - Cellular targeting and intracellular delivery of small interfering RNA (siRNA) remain a critical barrier to the clinical application of RNA interference. This chapter provides an overview of various delivery agents employing protein ligands mediating cell-specific delivery of siRNA. Specifically, the chapter details methodologies for the conjugation of antibody or peptide ligands to i) the cationic peptide-oligo-9-arginine (ii) the polymer poly(lactic-co-glycolic acid) (PLGA) and (iii) a lipid-vesicle (liposome). PMID- 22208984 TI - Conjugation of anticancer drugs through endogenous monoclonal antibody cysteine residues. AB - Many methods have been described for the conjugation of drugs to monoclonal antibodies. The presence of a discrete number of readily reducible disulfides in the common IgG subtypes presents a convenient opportunity for conjugation to cysteine residues with thiol-reactive drug-linkers. Such conjugates can be prepared by a straightforward two-step reaction scheme involving the reduction of the antibody disulfides to the desired number of average thiols per antibody, followed by addition of the drug-linker, ideally with a maleimido functionality for rapid, selective reaction. In a discovery setting, this basic method can be scaled down to produce microgram quantities of conjugate for early screening, and in a manufacturing setting can be scaled up to produce grams or kilograms of conjugate for clinical trials and commercialization. The resulting conjugates are readily characterized using common HPLC methods. PMID- 22208985 TI - Building and characterizing antibody-targeted lipidic nanotherapeutics. AB - Immunoliposomes provide a complementary, and in many instances advantageous, drug delivery strategy to antibody-drug conjugates. Their high carrying capacity of 20,000-150,000 drug molecules/liposome, allows for the use of a significantly broader range of moderate-to-high potency small molecule drugs when compared to the comparably few subnanomolar potency maytansinoid- and auristatin-based immunoconjugates. The multivalent display of 5-100 antibody fragments/liposome results in an avidity effect that can make use of even moderate affinity antibodies, as well as a cross-linking of cell surface receptors to induce the internalization required for intracellular drug release and subsequent activity. The underlying liposomal drug must be effectively engineered for long circulating pharmacokinetics and stable in vivo drug retention in order to allow for the drug to be efficiently delivered to the target tissue and take advantage of the site specific bioavailability provided for by the targeting arm. In this chapter, we describe the rationale for engineering stable immunoliposome-based therapeutics, methods required for preparation of immunoliposomes, as well as for their physicochemical and in vivo characterization. PMID- 22208986 TI - Cell-targeting fusion constructs containing recombinant gelonin. AB - Therapeutic agents capable of targeting tumor cells present as established tumors and micrometastases have already demonstrated their potential in clinical trials. Immunotoxins targeting hematological malignancies and solid tumors have additionally demonstrated excellent clinical activity. This review focuses on our design and characterization studies of constructs composed of recombinant gelonin toxin fused to either growth factors or single-chain antibodies targeting solid tumor cells, tumor vasculature or hematological malignancies. These agents demonstrate cytotoxicity at nanomolar or sub-nanomolar levels. All of these constructs display impressive selectivity and specificity for antigen-bearing target cells in vitro and in vivo and are excellent clinical trial candidates. PMID- 22208987 TI - Fusions of elastin-like polypeptides to pharmaceutical proteins. AB - Elastin-like polypeptides (ELPs) are a class of stimulus-responsive biopolymers whose physicochemical properties and biocompatibility are particularly suitable for in vivo applications, such as drug delivery and tissue engineering. The lower critical solution temperature (LCST) behavior of ELPs allows them to be utilized as soluble macromolecules below their LCST, or as self-assembled nanoscale particles such as micelles, micron-scale coacervates, or viscous gels above their LCST, depending on the ELP architecture. As each ELP sequence is specified at its genetic level, functionalization of an ELP with peptides and proteins is simple to accomplish by the fusion of a gene encoding an ELP with that of the peptide or protein of interest. Protein ELP fusions, where the appended protein serves a therapeutic or targeting function, are suitable for applications in which the ELP can improve the systemic pharmacokinetics and biodistribution of the protein, or can be used as an injectable depot for sustained, local protein delivery. Here we describe considerations in the design of therapeutic protein ELP fusions and provide details of their gene design, expression, and purification. PMID- 22208988 TI - Oral enzyme therapy for celiac sprue. AB - Celiac sprue is an inflammatory disease of the small intestine caused by dietary gluten and treated by adherence to a life-long gluten-free diet. The recent identification of immunodominant gluten peptides, the discovery of their cogent properties, and the elucidation of the mechanisms by which they engender immunopathology in genetically susceptible individuals have advanced our understanding of the molecular pathogenesis of this complex disease, enabling the rational design of new therapeutic strategies. The most clinically advanced of these is oral enzyme therapy, in which enzymes capable of proteolyzing gluten (i.e., glutenases) are delivered to the alimentary tract of a celiac sprue patient to detoxify ingested gluten in situ. In this chapter, we discuss the key challenges for discovery and preclinical development of oral enzyme therapies for celiac sprue. Methods for lead identification, assay development, gram-scale production and formulation, and lead optimization for next-generation proteases are described and critically assessed. PMID- 22208990 TI - Engineering reduced-immunogenicity enzymes for amino acid depletion therapy in cancer. AB - Cancer has become the leading cause of death in the developed world and has remained one of the most difficult diseases to treat. One of the difficulties in treating cancer is that conventional chemotherapies often have unacceptable toxicities toward normal cells at the doses required to kill tumor cells. Thus, the demand for new and improved tumor specific therapeutics for the treatment of cancer remains high. Alterations to cellular metabolism constitute a nearly universal feature of many types of cancer cells. In particular, many tumors exhibit deficiencies in one or more amino acid synthesis or salvage pathways forcing a reliance on the extracellular pool of these amino acids to satisfy protein biosynthesis demands. Therefore, one treatment modality that satisfies the objective of developing cancer cell-selective therapeutics is the systemic depletion of that tumor-essential amino acid, which can result in tumor apoptosis with minimal side effects to normal cells. While this strategy was initially suggested over 50 years ago, it has been recently experiencing a renaissance owing to advances in protein engineering technology, and more sophisticated approaches to studying the metabolic differences between tumorigenic and normal cells. Dietary restriction is typically not sufficient to achieve a therapeutically relevant level of amino acid depletion for cancer treatment. Therefore, intravenous administration of enzymes is used to mediate the degradation of such amino acids for therapeutic purposes. Unfortunately, the human genome does not encode enzymes with the requisite catalytic or pharmacological properties necessary for therapeutic purposes. The use of heterologous enzymes has been explored extensively both in animal studies and in clinical trials. However, heterologous enzymes are immunogenic and elicit adverse responses ranging from anaphylactic shock to antibody-mediated enzyme inactivation, and therefore have had limited utility. The one notable exception is Escherichia colil-asparaginase II (EcAII), which has been FDA-approved for the treatment of childhood acute lymphoblastic leukemia. The use of engineered human enzymes, to which natural tolerance is likely to prevent recognition by the adaptive immune system, offers a novel approach for capitalizing on the promising strategy of systemic depletion of tumor-essential amino acids. In this work, we review several strategies that we have developed to: (i) reduce the immunogenicity of a nonhuman enzyme, (ii) engineer human enzymes for novel catalytic specificities, and (iii) improve the pharmacological characteristics of a human enzyme that exhibits the requisite substrate specificity for amino acid degradation but exhibits low activity and stability under physiological conditions. PMID- 22208989 TI - Rational design and evaluation of mammalian ribonuclease cytotoxins. AB - Mammalian pancreatic-type ribonucleases (ptRNases) comprise an enzyme family that is remarkably well suited for therapeutic exploitation. ptRNases are robust and prodigious catalysts of RNA cleavage that can naturally access the cytosol. Instilling cytotoxic activity requires endowing them with the ability to evade a cytosolic inhibitor protein while retaining other key attributes. These efforts have informed our understanding of ptRNase-based cytotoxins, as well as the action of protein-based drugs with cytosolic targets. Here, we address the most pressing problems encountered in the design of cytotoxic ptRNases, along with potential solutions. In addition, we describe assays that can be used to evaluate a successful design in vitro, in cellulo, and in vivo. The emerging information validates the continuing development of ptRNases as chemotherapeutic agents. PMID- 22208991 TI - Protein engineering for therapeutics, Part A. Preface. PMID- 22208992 TI - Thank you for the voyage. PMID- 22208993 TI - IPY Inuit Health Survey speaks to need to address inadequate housing, food insecurity and nutrition transition. PMID- 22208994 TI - The international polar year: continuing the arctic human health legacy. PMID- 22208996 TI - Generation and characterization of a functional Nanobody against the vascular endothelial growth factor receptor-2; angiogenesis cell receptor. AB - Vascular endothelial growth factor receptor-2 (VEGFR2) is an important tumor associated receptor and blockade of the VEGF receptor signaling can lead to the inhibition of neovascularization and tumor metastasis. Nanobodies are the smallest intact antigen binding fragments derived from heavy chain-only antibodies occurring in camelids. Here, we describe the identification of a VEGFR2-specific Nanobody, named 3VGR19, from dromedaries immunized with a cell line expressing high levels of VEGFR2. We demonstrate by FACS, that 3VGR19 Nanobody specifically binds VEGFR2 on the surface of 293KDR and HUVECs cells. Furthermore, the 3VGR19 Nanobody potently inhibits formation of capillary-like structures. These data show the potential of Nanobodies for the blockade of VEGFR2 signaling and provide a basis for the development of novel cancer therapeutics. PMID- 22208997 TI - Parathyroid hormone measurement in chronic kidney disease--an evolving issue for the nephrologist and the clinical laboratorist: minireview. AB - Parathyroid hormone (PTH) is the polypeptide hormone produced by the parathyroid glands, which plays a central role in calcium homeostasis. Circulating PTH must be measured regularly in patients with chronic kidney disease (CKD)--mineral and bone disorders (MBD) to monitor and to adapt treatment with the aim of maintaining PTH levels within a defined narrow range of optimal values for each stage of CKD. Often, for the nephrologists, it is not easy to determine what PTH levels are clinically appropriate. Moreover, the PTH determination also shows many criticisms from the laboratory point of view and there is a clear need to standardize PTH measurements in every phase of the process: pre-analytical, analytical and post-analytical. In this review, all these aspects are summarized with particular reference to the most recent opportunities to improve PTH assays quality on the whole. To this aim, a closer cooperation between nephrologists and clinical laboratories is undoubtedly necessary. PMID- 22208995 TI - What affects pleasure in persons with advanced stage dementia? AB - We examined the impact of environmental, person, and stimulus characteristics on pleasure in persons with dementia. Study participants were 193 residents of 7 Maryland nursing homes who were presented with 25 stimuli from these categories: live human social stimuli, live pet social stimuli, simulated social stimuli, inanimate social stimuli, a reading stimulus, manipulative stimuli, a music stimulus, task and work-related stimuli, and two different self-identity stimuli. Systematic observations of pleasure in the natural environment were conducted using Lawton's Modified Behavior Stream. Analysis showed that pleasure is related to stimulus category, personal attributes and environmental conditions. In the multivariate analyses, all types of social stimuli (live and simulated, human and nonhuman), self-identity stimuli, and music were related to significantly higher levels of pleasure than the control condition. Females and persons with higher ADL and communication functional status exhibited more pleasure. Pleasure was most likely to occur in environments with moderate noise levels. These results demonstrate that these nursing home residents are indeed capable of showing pleasure. Caregivers of nursing home residents with dementia should incorporate social, self-identity, and music stimuli into their residents' care plans so that eliciting pleasure from each resident becomes the norm rather than a random occurrence. PMID- 22208998 TI - Nonapeptides are not just for bonding: a response to van Anders et al. (2011). PMID- 22208999 TI - Salivary cortisol and sleep problems among civil servants. AB - OBJECTIVE: The present study used information from a field study conducted among 4489 civil servants (70% women) in Denmark in 2007. The purpose was to examine the association between sleep problems and salivary cortisol by using a cross sectional design with repeated measures in a subsample three-month later. METHODS: Sleep problems during the past night and the past 4 weeks were assessed by a self-administered questionnaire on overall sleep quality, disturbed sleep, sleep length and awakening problems. Saliva samples were collected in a single day, using cotton tubes, 30 min after awakening and again at 2000 h. A subsample of 387 participants collected saliva samples three-month later at awakening, +20 min and +40 min after awakening and at 2000 h. We adjusted for confounders related to sampling time, life style and personal characteristics, socioeconomic status and work aspects. RESULTS: Sleep problems during the past four weeks were associated with low morning and evening saliva cortisol concentrations: [-3.1% per score of disturbed sleep (p=.009); and -4.7% per score of awakening problems (p<.001)]. Whereas sleep problems were not related with slope (the morning to evening change in cortisol levels). Awakening problems predicted lower cortisol ( 7.51% per score; p=.003) three-month later. Cortisol awakening response (CAR) and slope three-month later were significantly associated with disturbed sleep ( 7.84% and -8.24%) and awakening problems (-6.93). Area under the curve (AUC(morning)) increased with disturbed sleep (3.77%). CONCLUSION: Surprisingly, low morning cortisol was associated with increased sleep problems during a four week period prior to sampling among 4066 Danish civil servants. At follow-up three-month later, those with sleep problems had a flattened cortisol profile. Those with awakening problems also had low salivary cortisol in general. PMID- 22209000 TI - Nitric oxide mediates low magnesium inhibition of osteoblast-like cell proliferation. AB - An adequate intake of magnesium (Mg) is important for bone cell activity and contributes to the prevention of osteoporosis. Because (a) Mg is mitogenic for osteoblasts and (b) reduction of osteoblast proliferation is detected in osteoporosis, we investigated the influence of different concentrations of extracellular Mg on osteoblast-like SaOS-2 cell behavior. We found that low Mg inhibited SaOS-2 cell proliferation by increasing the release of nitric oxide through the up-regulation of inducible nitric oxide synthase (iNOS). Indeed, both pharmacological inhibition with the iNOS inhibitor l-N(6)-(iminoethyl)-lysine-HCl and genetic silencing of iNOS by small interfering RNA restored the normal proliferation rate of the cells. Because a moderate induction of nitric oxide is sufficient to potentiate bone resorption and a relative deficiency in osteoblast proliferation can result in their inadequate activity, we conclude that maintaining Mg homeostasis is relevant to ensure osteoblast function and, therefore, to prevent osteoporosis. PMID- 22209001 TI - Protective effects of chlorogenic acid against ischemia/reperfusion injury in rat liver: molecular evidence of its antioxidant and anti-inflammatory properties. AB - Hepatic ischemia and reperfusion injury (I/R) is accompanied by excessive reactive oxygen species and resultant sterile inflammation. Chlorogenic acid (CGA), one of the most abundant polyphenols in the human diet, has been shown to exert potent anti-inflammatory, antibacterial and antioxidant activities. Thus, the purpose of the present study was to investigate protective effects of CGA and its molecular mechanisms against hepatic I/R injury. Rats were subjected to 60 min of partial hepatic ischemia followed by 5 h of reperfusion. CGA (2.5, 5 and 10 mg/kg, ip) was administered twice: 10 min prior to ischemia and 10 min before reperfusion. CGA treatment resulted in marked improvement of hepatic function and histology, and suppressed oxidative stress, as indicated by hepatic lipid peroxidation and glutathione level. Levels of serum tumor necrosis factor-alpha, inducible nitric oxide synthase and cyclooxygenase-2 protein and mRNA expressions were up-regulated after I/R; these effects were attenuated by CGA. Immunoblot results showed that CGA reduced I/R-induced toll-like receptor 4 overexpression, nuclear translocation of nuclear factor kappa B and interferon regulatory factor 1, high-mobility group box-1 release into extracellular milieu, and enhanced heme oxygenase-1 expression and nuclear translocation of nuclear factor erythroid 2 related factor 2. Our results suggest that CGA alleviates I/R-induced liver injury and that this protection is likely due to inhibition of inflammatory response and enhancement of antioxidant defense systems. Therefore, CGA might have potential as an agent for use in clinical treatment of hepatic I/R injury. PMID- 22209002 TI - Abnormal anandamide metabolism in celiac disease. AB - The endocannabinoid system has been extensively investigated in experimental colitis and inflammatory bowel disease, but not in celiac disease, where only a single study showed increased levels of the major endocannabinoid anandamide in the atrophic mucosa. On this basis, we aimed to investigate anandamide metabolism in celiac disease by analyzing transcript levels (through quantitative real-time reverse transcriptase-polymerase chain reaction), protein concentration (through immunoblotting) and activity (through radioassays) of enzymes responsible for anandamide synthesis (N-acylphosphatidyl-ethanolamine specific phospholipase D, NAPE-PLD) and degradation (fatty acid amide hydrolase, FAAH) in the duodenal mucosa of untreated celiac patients, celiac patients on a gluten-free diet for at least 12 months and control subjects. Also, treated celiac biopsies cultured ex vivo with peptic-tryptic digest of gliadin were investigated. Our in vivo experiments showed that mucosal NAPE-PLD expression and activity are higher in untreated celiac patients than treated celiac patients and controls, with no significant difference between the latter two groups. In keeping with the in vivo data, the ex vivo activity of NAPE-PLD was significantly enhanced by incubation of peptic-tryptic digest of gliadin with treated celiac biopsies. On the contrary, in vivo mucosal FAAH expression and activity did not change in the three groups of patients, and accordingly, mucosal FAAH activity was not influenced by treatment with peptic-tryptic digest of gliadin. In conclusion, our findings provide a possible pathophysiological explanation for the increased anandamide concentration previously shown in active celiac mucosa. PMID- 22209003 TI - Postweaning low-calcium diet promotes later-life obesity induced by a high-fat diet. AB - The aim of this study was to investigate the effects of a postweaning low-calcium diet on later obesity and explore the underlying mechanisms. Ninety-six male rats were weaned at 3 weeks of age, fed standard (STD: 0.50% calcium, n=48) and low calcium (LC: 0.15% calcium, n=48) diets for 3 weeks, and then fed the standard diet for a 3-week washout period successively. Finally, the STD rats were divided into STD control and high-fat diet (HFD) groups, and the LC ones into LC control and LC+HFD (LCHF) groups. The STD and LC rats were fed the standard diet, while the HFD control and LCFD ones were fed a high-fat diet for 6 weeks to induce obesity. During the three feeding periods, adenosine-monophosphate-activated protein kinase (AMPK) and its responsive proteins phospho-acetyl-coA carboxylase, carnitine palmitoyltransferase 1 and uncoupling protein 3 were persistently down regulated in the LC group (decreased by 18%, 24%, 18% and 20%, respectively) versus the STD group, and these effects were significantly more pronounced in the LCHFD group (decreased by 21%, 30%, 23% and 25%, respectively) than the HFD group by a later high-fat stimuli, causing more fat and body weight in adulthood. However, lipolysis enzymes, serum leptin, insulin and lipids were not significantly affected until the body weight and fat content changed at 15 weeks of age. The results suggest that the low-calcium diet after weaning promotes rat adult-onset obesity induced by high-fat diet, which might be achieved by programming expressions of genes involved in AMPK pathway. PMID- 22209004 TI - Trans fatty acids enhance amyloidogenic processing of the Alzheimer amyloid precursor protein (APP). AB - Hydrogenation of oils and diary products of ruminant animals leads to an increasing amount of trans fatty acids in the human diet. Trans fatty acids are incorporated in several lipids and accumulate in the membrane of cells. Here we systematically investigate whether the regulated intramembrane proteolysis of the amyloid precursor protein (APP) is affected by trans fatty acids compared to the cis conformation. Our experiments clearly show that trans fatty acids compared to cis fatty acids increase amyloidogenic and decrease nonamyloidogenic processing of APP, resulting in an increased production of amyloid beta (Abeta) peptides, main components of senile plaques, which are a characteristic neuropathological hallmark for Alzheimer's disease (AD). Moreover, our results show that oligomerization and aggregation of Abeta are increased by trans fatty acids. The mechanisms identified by this in vitro study suggest that the intake of trans fatty acids potentially increases the AD risk or causes an earlier onset of the disease. PMID- 22209005 TI - Unsaturated fatty acids repress expression of ATP binding cassette transporter A1 and G1 in RAW 264.7 macrophages. AB - Reverse cholesterol transport (RCT), a process to deliver excess cholesterol from the periphery to the liver for excretion from body, is a major atheroprotective property of high-density lipoproteins. As major transporters for cholesterol efflux in macrophages, ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) are critical for RCT. We investigated mechanisms for the regulation of ABCA1 and ABCG1 expression by fatty acids (FA) in RAW264.7 macrophages. Cells were incubated with 100 MUmol/L of palmitic, oleic, linoleic, linolenic or eicosapentaenoic acids in the absence or presence of T0901317, a liver X receptor (LXR) agonist. Unsaturated FA, but not saturated FA, significantly reduced ABCA1 and ABCG1 mRNA without the agonist. Trichostatin A (TSA), a histone deacetylase inhibitor, not only increased basal ABC transporter expression but abrogated the transcriptional repression by unsaturated FA. The increased basal ABCA1 and ABCG1 mRNA by TSA paralleled the increased peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgamma coactivator 1alpha expression, whereas LXRalpha and PGC-1beta expression was significantly lowered. Although the repressive effect of ABCA1 and ABCG1 mRNA by unsaturated FA was abolished by T0901317, protein levels remained diminished. Chemical and genetic deficiency of protein kinase C delta did not abolish the repressive effect of linoleic acid on ABCA1 and ABCG1. In conclusion, unsaturated FA repressed ABCA1 and ABCG1 expression by two distinct mechanisms in RAW 264.7 macrophages: LXR-dependent transcriptional repression possibly by modulating histone acetylation state and LXR-independent posttranslational inhibition. PMID- 22209006 TI - Comparison of intracellular zinc signals in nonadherent lymphocytes from young adult and elderly donors: role of zinc transporters (Zip family) and proinflammatory cytokines. AB - Intracellular zinc homeostasis is crucial in regulating the inflammatory/immune response at any age. It is tightly regulated by zinc transporters that control influx, efflux and compartmentalization of zinc within the cells. Specific methods for detecting the age-related differences in intracellular zinc signaling are poorly described. We report a novel assay induced after the in vitro zinc addition in peripheral blood mononuclear cells (PBMCs) and in lymphocytes from young and old donors in the absence/presence of in vitro zinc depletion (using EDTA). The intracellular labile zinc variations are monitored over time by flow cytometry using Fluozin-3 AM probe. The best curve fit of the data is calculated using a nonlinear regression model defined as follows: pr3/[1+Exp(-pr1-pr2*Xt)]. Pr1 depends on the initial free zinc value (time 0); pr2 describes the rate of the speed in reaching the maximum intracellular free zinc concentration; pr3 represents the maximum intracellular zinc increment (plateau curve); Xt is the time course. Age-related intracellular free zinc variations occur in PBMCs and lymphocytes incubated in EDTA-supplemented medium. The higher plateau of the curve (pr3) was observed in younger subjects. An up-regulation of Zip genes (Zip1, Zip2, Zip3), influencing zinc influx, is more pronounced in the young than old donors. Interleukin-6 and tumor necrosis factor-alpha overproduction was enhanced in old individuals, suggesting the presence of more marked zinc deficiency and chronic inflammation. In conclusion, the determination of intracellular zinc signals induced by in vitro zinc addition using logistic parameters may be useful to estimate the rate of intracellular zinc homeostasis and its role in inflammatory/immune response in aging. PMID- 22209008 TI - How nuclei of Giardia pass through cell differentiation: semi-open mitosis followed by nuclear interconnection. AB - Differentiation into infectious cysts (encystation) and multiplication of pathogenic trophozoites after hatching from the cyst (excystation) are fundamental processes in the life cycle of the human intestinal parasite Giardia intestinalis. During encystation, a bi-nucleated trophozoite transforms to a dormant tetra-nucleated cyst enveloped by a protective cyst wall. Nuclear division during encystation is not followed by cytokinesis. In contrast to the well-studied mechanism of cyst wall formation, information on nuclei behavior is incomplete and basic cytological data are lacking. Here we present evidence that (1) the nuclei divide by semi-open mitosis during early encystment; (2) the daughter nuclei coming from different parent nuclei are always arranged in pairs; (3) in both pairs, the nuclei are interconnected via bridges formed by fusion of their nuclear envelopes; (4) each interconnected nuclear pair is associated with one basal body tetrad of the undivided diplomonad mastigont; and (5) the interconnection between nuclei persists through the cyst stage being a characteristic feature of encysted Giardia. Based on the presented results, a model of nuclei behavior during Giardia differentiation is proposed. PMID- 22209007 TI - Diet-induced obesity elevates colonic TNF-alpha in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer. AB - Inflammation associated with obesity may play a role in colorectal carcinogenesis, but the underlying mechanism remains unclear. This study investigated whether the Wnt pathway, an intracellular signaling cascade that plays a critical role in colorectal carcinogenesis, is activated by obesity induced elevation of the inflammatory cytokine tumor necrosis factor-alpha (TNF alpha). Animal studies were conducted on C57BL/6 mice, and obesity was induced by utilizing a high-fat diet (60% kcal). An inflammation-specific microarray was performed, and results were confirmed with real-time polymerase chain reaction. The array revealed that diet-induced obesity increased the expression of TNF alpha in the colon by 72% (P=.004) and that of interleukin-18 by 41% (P=.023). The concentration of colonic TNF-alpha protein, determined by ex vivo culture assay, was nearly doubled in the obese animals (P=.002). The phosphorylation of glycogen synthase kinase 3 beta (GSK3beta), an important intermediary inhibitor of Wnt signaling and a potential target of TNF-alpha, was quantitated by immunohistochemistry. The inactivated (phosphorylated) form of GSK3beta was elevated in the colonic mucosa of obese mice (P<.02). Moreover, beta-catenin, the key effector of canonical Wnt signaling, was elevated in the colons of obese mice (P<.05), as was the expression of a downstream target gene, c-myc (P<.05). These data demonstrate that diet-induced obesity produces an elevation in colonic TNF alpha and instigates a number of alterations of key components within the Wnt signaling pathway that are protransformational in nature. Thus, these observations offer evidence for a biologically plausible avenue, the Wnt pathway, by which obesity increases the risk of colorectal cancer. PMID- 22209009 TI - Ultrastructure of Allapsa vibrans and the body plan of Glissomonadida (Cercozoa). AB - Biciliate, gliding zooflagellate Cercozoa are globally the most abundant and genetically diverse predators in soil (glissomonads and cercomonads). We present the first detailed ultrastructural study of a phylogenetically well-characterized glissomonad, Allapsa vibrans. There are two ventral posterior centriolar roots as in Cercomonadida, but fewer other microtubular roots. Allapsa's centriolar roots and rhizoplast basically resemble those of the less well studied glissomonads Bodomorpha and Neoheteromita. The posterior centriole of Allapsa attaches laterally to the base of the anterior centriole and to the nucleus by striated fibrillar connectors and nests in a shallow cup-like ventrolateral depression; two broad fans of single microtubules line the cup's posterior and inner side. The anterior centriole has a dorsal two-microtubule root and probably also a singlet root. Its medium-length ciliary transition zones have a proximal hub lattice and a prominent dense distal transverse plate/collar complex. Golgi bodies are anterior/paranuclear; isodiametric extrusomes are anterior mid ventral. Tubulicristate mitochondria attach to the nucleus, as do prominent microbodies. We characterize the body plan of glissomonads, comparing it with other Sarcomonadea: their sister group (Pansomonadida) and the phylogenetically more distant Cercomonadida. We discuss glissomonad radiation into families Sandonidae, Proleptomonadidae, Dujardinidae, Bodomorphidae and Allapsidae, establishing Aurigamonadidae fam. n. for the amoeboflagellate pansomonad Aurigamonas. PMID- 22209010 TI - A perfusion confusion? PMID- 22209012 TI - Synthesis of silicalite-poly(furfuryl alcohol) composite membranes for oxygen enrichment from air. AB - Silicalite-poly(furfuryl alcohol) [PFA] composite membranes were prepared by solution casting of silicalite-furfuryl alcohol [FA] suspension on a porous polysulfone substrate and subsequent in situ polymerization of FA. X-ray diffraction, nitrogen sorption, thermogravimetric analysis, scanning electron microscopy, and energy-dispersive X-ray spectroscopy were used to characterize silicalite nanocrystals and silicalite-PFA composite membranes. The silicalite PFA composite membrane with 20 wt.% silicalite loading exhibits good oxygen/nitrogen selectivity (4.15) and high oxygen permeability (1,132.6 Barrers) at 50 degrees C. Silicalite-PFA composite membranes are promising for the production of oxygen-enriched air for various applications. PMID- 22209013 TI - Proliferative diabetic retinopathy is a predictor of coronary artery disease in Japanese patients with type 2 diabetes. AB - A retrospective cohort study was performed to investigate the relationship between diabetic retinopathy and coronary artery disease in 371 Japanese adult patients with type 2 diabetes. We found that proliferative retinopathy was significantly associated with an increased risk of coronary artery disease, even after adjustment for classical coronary risk factors. PMID- 22209014 TI - Personal continuous glucose monitoring (CGM) in diabetes management: review of the literature and implementation for practical use. AB - AIM: Despite recent advances in diabetes therapy including the new long- and rapid-insulin analogs, insulin intensification strategies such as basal/bolus or pump therapy and sophisticated methods for insulin titration derived from the principles of functional insulin therapy, many patients fail to reach or maintain target glycosylated hemoglobin (HbA1c) values, putting them at increased risk for vascular complications. Continuous glucose monitoring (CGM) systems represent an important advance in diabetes technology that can facilitate optimal glucose control in type 1 diabetes. METHOD: This review focuses on the efficacy and safety of CGM systems in diabetes management. The different CGM devices available are also described, as the way to use them and the educational approach to the patient in a step-by-step progression toward optimal glycemic control. RESULTS: In type 1 diabetes, CGM systems are associated with 0.5-1% reduction in HbA1c without increased risk of hypoglycemia. CGM efficacy correlates with compliance to sensor wear, whatever the patient's age range. CONCLUSION: Efficacy of CGM systems is now proven but indications, terms of use and educational issues of this new technology still need to be specified. PMID- 22209011 TI - Alternative origins of stroma in normal organs and disease. AB - Stromal fibroblasts are a new prospective drug target. Mesenchymal stromal cells (MSCs) and monocyte-derived stromal cells, also known as fibrocytes, are distinct fibroblastic populations derived from separate lineages. Mesenchymal and myeloid fibroblast progenitors are multipotent, serve as progenitor cells in animal models, and are implicated in several diseases. In addition, epithelial mesenchymal transition (EMT) has been established as a mechanism for generation of stromal cells. Organ sources, relative contributions, and functions of these populations in normal development and pathology are not well understood. Innovative approaches are needed to identify markers that can distinguish these stromal populations. PMID- 22209015 TI - Progress in the biological synthesis of the plant cell wall: new ideas for improving biomass for bioenergy. AB - Lignocellulosic biomass feedstocks for biofuels are primarily the thickened secondary cells of vascular plants. Recent advances have been made in our basic understanding of how cellulose and the non-cellulosic polysaccharides of the plant cell wall are synthesized, assembled, and integrated with the synthesis of lignin. New complexities have been elucidated in the ways cellulose microfibrils are deposited at the plasma membrane surface and integrated with non-cellulosic polysaccharides are assembled and lignified into functional form. Current strategies focus on the transcriptional events that specify vascularization and fiber formation and how the composition of lignin is modified in expression variants in the natural population. This knowledge base will yield new ideas for how to enhance lignocellulosic composition and cell wall architecture in biomass tailored for its end use. PMID- 22209017 TI - Physical pain associated with depression: results of a survey in Japanese patients and physicians. AB - OBJECTIVES: There is an increasing recognition that pain often coexists with depression. The current survey was undertaken to ascertain patients' and clinicians' perceptions of pain as a physical symptom associated with depression in everyday clinical practices in Japan. METHODS: Web-based surveys were undertaken by a market research company for patients with depression and for physicians treating patients with depression (psychiatrists, psychosomatic physicians, general internists). RESULTS: A total of 848 patients aged 20 to 59 years entered the main survey, of whom 663 returned the completed survey (78.2%). Of the respondents, 424 (64.0%) experienced at least 1 painful symptom, with almost three quarters (72.1%) reporting that the pain affected mental symptoms and 68.6% indicating that it prevented recovery from depression itself. Among 337 patients who discussed their painful symptoms with their physician, 52.5% initiated the discussion. Four hundred fifty-six physicians completed the physician survey. When asked about the influence of pain associated with depression, 61.7% of physicians indicated that they ask their patients about pain during a consultation, 79.9% considered that painful symptoms might disturb the patients' daily life, and 52.8% felt that they would delay recovery from depression. With regard to treatment, 73.2% of physicians considered that they would "like to treat if depressed patients talked about their pain" and 64.7% considered that treatment "would be more effective when patients talked about pain symptoms." CONCLUSIONS: The survey provides further evidence of the association between depression and pain, highlighting the fact that pain is prevalent in this patient population. An increased patient and physician awareness of pain in association with depression and improved physician-patient communication, enabling patients to discuss painful symptoms with their physicians and vice versa, should lead to a better overall management and treatment strategies. PMID- 22209016 TI - Reverse engineering systems models of regulation: discovery, prediction and mechanisms. AB - Biological systems can now be understood in comprehensive and quantitative detail using systems biology approaches. Putative genome-scale models can be built rapidly based upon biological inventories and strategic system-wide molecular measurements. Current models combine statistical associations, causative abstractions, and known molecular mechanisms to explain and predict quantitative and complex phenotypes. This top-down 'reverse engineering' approach generates useful organism-scale models despite noise and incompleteness in data and knowledge. Here we review and discuss the reverse engineering of biological systems using top-down data-driven approaches, in order to improve discovery, hypothesis generation, and the inference of biological properties. PMID- 22209018 TI - First description of group A rotavirus from fecal samples of ostriches (Struthio camelus). AB - This study investigated the occurrence of rotavirus infections in ostriches (Struthio camelus) reared in Northern Parana, Brazil. Fecal (n=66) and serum (n=182) samples from nine farms located in four different cities were analyzed by silver stained-polyacrylamide gel electrophoresis (ss-PAGE), RT-PCR assay, virus isolation, and counterimmunoelectroosmophoresis (CIE). Rotavirus group A seropositivity occurred in 5.49% (10/182) of serum samples of ostriches originated from two farms. Only 9.09% (6/66) of fecal samples from ostriches with diarrhea maintained in one farm were positive by ss-PAGE, RT-PCR, and virus isolation. The G (VP7) and P (VP4) genotypes of rotavirus wild strains isolated in cell culture were determined by multiplex-nested PCR. The genotyping identified two rotavirus strains: G6P[1] and G10P[1]. In three rotavirus strains it was only possible to identify the P type; one strain being P[1] and two strains that presented the combination of P[1]+P[7]. These findings might represent the first characterization of rotavirus in ostriches, and the finding of porcine and bovine-like rotavirus genotypes in ostriches might suggest virus reassortment and possible interspecies transmission. PMID- 22209019 TI - Polycyclic aromatic hydrocarbons (PAHs) in surface sediment and oysters (Crassostrea rhizophorae) from mangrove of Guadeloupe: levels, bioavailability, and effects. AB - Surface sediment and oysters (Crassostrea rhizophorae) from the coastlines of Guadeloupe were analysed for polycyclic aromatic hydrocarbons (PAHs) using GC/MS. Biomarkers of oxidative stress were used to assess the response of these oysters to hydrocarbons exposure. The total concentration of PAHs in the sediment ranged from 49 to 1065 ng/g dw, while concentrations in oyster ranged from 66 to 961 ng/g dw. Molecular indices based on isomeric PAHs ratios characterize the pollution sources and show that most of the contaminations in sediment originate from pyrolytic inputs. Bioaccumulation factors (BAFs) have been related to isomeric ratio calculated for oysters in order to refine PAHs sources. The variations of BAFs observed in the different compounds resulted from different uptake pathways in the mangrove oysters according to the type of inputs. Response of biomarkers showed inhibition of catalase and an increase of lipid peroxidation at the station where PAHs concentrations were the highest. Taken together, data obtained point to the relevance of considering environmental conditions as factors influencing biomarker responses in environmental monitoring programs. These data also indicate the need for regular environmental follow-up studies in Guadeloupe. PMID- 22209020 TI - High YKL-40 levels predict mortality in patients with type 2 diabetes. AB - AIMS: We determined levels of the inflammatory marker YKL-40 in a population of patients with type 2 diabetes (T2D) and investigated the association with mortality. METHODS: In a prospective observational follow-up study, 290 patients with T2D, normoalbuminuria (n=177), microalbuminuria (n=71) and macroalbuminuria (n=42) were followed for a median (range) of 17.2 (0.2-23.0) years. Serum YKL-40 concentration was determined at baseline. RESULTS: Baseline median (IQR) YKL-40 level was 46ng/ml (36-67) in patients with normoalbuminuria, 61ng/ml (43-114) in microalbuminuric patients, and 81.5ng/ml (60-157) in patients with macroalbuminuria, p<0.001. During follow-up 189 patients (65.2%) died, 119 (41.0%) from cardiovascular causes. All-cause mortality was increased in patients with YKL-40 levels in the second and third tertile (hazard ratios (95% CI) compared with the first tertile, (1.50 (1.03-2.19), p=0.034, and 2.88 (2.01 4.12), p<0.001). This association persisted after adjustment for cardiovascular risk factors but was attenuated after additional adjustment for urinary albumin excretion rate and glomerular filtration rate. Cardiovascular mortality was increased with YKL-40 levels in the third tertile compared with the first tertile, (2.70 (1.78-4.08)), p<0.001. This association was diminished after adjustment for covariates. CONCLUSIONS: In patients with T2D and increasing albuminuria high YKL-40 levels predict all-cause mortality. PMID- 22209021 TI - Probing the bioinorganic chemistry of toxic metals in the mammalian bloodstream to advance human health. AB - The etiology of numerous grievous human diseases, including Alzheimer's and Parkinson's Disease is not well understood. Conversely, the concentration toxic metals and metalloids, such as As, Cd, Hg and Pb in human blood of the average population is well established, yet we know strikingly little about the role that they might play in the etiology of disease processes. Establishing functional connections between the chronic exposure of humans to these and other inorganic pollutants and the etiology of certain human diseases is therefore viewed by many as one of the greatest challenges in the post-genomic era. Conceptually, this task requires us to uncover hitherto unknown biomolecular mechanisms which must explain how small doses of a toxic metal/metalloid compound (low MUg per day) - or mixtures thereof - may eventually result in a particular human disease. The biological complexity that is inherently associated with mammals, however, makes the discovery of these mechanisms a truly monumental task. Recent findings suggest that a better understanding of the bioinorganic chemistry of inorganic pollutants in the mammalian bloodstream represents a fruitful strategy to unravel relevant biomolecular mechanisms. The adverse effect(s) that toxic metals/metalloid compounds exert on the transport of essential ultratrace elements to internal organs appear particularly pertinent. A brief overview of the effect that arsenite and Hg(2+) exert on the mammalian metabolism of selenium is presented. PMID- 22209022 TI - The metal binding abilities of Megathura crenulata metallothionein (McMT) in the frame of gastropoda MTs. AB - Metallothioneins (MTs) are proteins that play a major role in metal homeostasis and/or detoxification in all kind of organisms. The MT gene/protein system of gastropod molluscs provides an invaluable model to study the diversification mechanisms that have enabled MTs to achieve metal-binding specificity through evolution. Most pulmonate gastropods, particularly terrestrial snails, harbor three paralogous isogenes encoding three MT isoforms with different metal binding preferences: the highly specific CdMT and CuMT isoforms, for cadmium and copper respectively, and the unspecific Cd/CuMT isoform. Megathura crenulata is a non pulmonate gastropod in which only one MT isogene has so far been reported. In order to elucidate the metal binding character of the corresponding peptide (McMT), it has been recombinantly synthesized in the presence of Cd(2+), Zn(2+) or Cu(2+), and the corresponding metal complexes have been analyzed using electrospray mass spectrometry, and CD and UV-visible spectroscopy. The metal binding traits exhibited by McMT revealed that it is an unspecific MT, similarly to the pulmonate Cd/CuMT isoforms. This is in full concordance with the protein sequence distance analysis in relation to other gastropod MTs. PMID- 22209023 TI - A bioinformatics view of zinc enzymes. AB - Thanks to the contributions of scientists like Bert Vallee, zinc enzymology is an area of research with a rich history and a strong basis of biochemical and biophysical knowledge. In recent years, the dramatic development of the genomic and post-genomic research has provided this as well as all other fields of life sciences with a massive body of new data, including, but not limited to, protein sequence and structural data. By integrating these new data with the wealth of information available in the literature, it is possible to achieve an unprecedented overview of the properties and functions of zinc enzymes in the context of biological systems. To this aim, the role of bioinformatics is essential. In this work, we use bioinformatics tools and databases that we have developed for the study of metalloproteins to gain insights into the functions of zinc in zinc enzymes, its coordination properties, and the usage of zinc enzymes in living organisms. PMID- 22209024 TI - Expression of growth-associated protein 43 in the skin nerve fibers of patients with type 2 diabetes mellitus. AB - The growth-associated protein 43 (GAP-43) is known as a marker of regenerating nerve fibers and their continuous remodeling in the adult human skin. The purpose of this pilot study was to investigate a possible role for GAP-43 in the detection of the early stages of small-fiber neuropathy in patients with type 2 diabetes mellitus (DM2) as compared with a well- established and validated parameter - intra-epidermal nerve fiber density (IENFD) of protein gene product 9.5 (PGP 9.5) immunoreactive intra-epidermal C fibers. In a group of 21 patients with DM2 within three years of diagnosis (13 men, 8 women; mean age 53.9+/-12.8; range 30-74) and a group of 17 healthy volunteers (8 men, 9 women; mean age 55.8+/-8.5; range 45-70 years), skin punch biopsies were taken from a distal calf and double immunostained with both PGP 9.5 and GAP-43. In healthy controls, 96.8% of 629 PGP 9.5 immunoreactive fibers were immunostained with GAP-43; the proportion of PGP 9.5 intra-epidermal nerve fibers immunoreactive for GAP-43 in control subjects ranged from 86.5 to 100%. In DM2 patients, IENFD was significantly lower compared to controls (median, 1.5 vs. 11.2/mm; p<0.001). The proportion of GAP-43 immunoreactive intraepidermal nerve fibers was significantly lower in DM2 patients compared to healthy controls (73.6% of 337 PGP 9.5 positive fibers; p<0.001); ranged from 0 to 98.1%. In conclusion, these results show that impaired regeneration of intra-epidermal C fibers in the early stages of type 2 diabetes mellitus, as indicated by GAP-43, might be a marker of incipient diabetic neuropathy. PMID- 22209025 TI - Positive alcohol expectancies mediate the influence of the behavioral activation system on alcohol use: a prospective path analysis. AB - Gray's (1975, 1987) behavioral activation (BAS) and behavioral inhibition systems (BIS) are thought to underlie sensitivity to reinforcement and punishment, respectively. Consistent with Gray's theory and the Acquired Preparedness model, BAS may facilitate the learning of positive alcohol expectancies (PAEs) over time, leading to increases in drinking. Yet, no prospective tests of this pathway have been reported. The present study investigated whether BAS prospectively predicted PAEs and whether PAEs mediated the association between BAS and subsequent alcohol use. We hypothesized that BAS would influence drinking specifically via enhancement-related PAEs. We also explored the role of BIS in PAEs and drinking. College students (N=557) completed online BAS, PAE, and alcohol use measures in September of their first (T1), second (T2), and third (T3) years of college. We conducted autoregressive path analyses with three BAS subscales and BIS (T1) as predictors, four PAE types (T2) as mediators, and quantity and frequency of drinking (T3) as outcomes. The BAS Fun-Seeking scale was prospectively associated with PAEs, and there was a significant indirect path from Fun-Seeking to alcohol use mediated specifically through activity enhancement PAEs. BIS was positively associated with some PAE types, but did not have indirect effects on drinking. Findings are consistent with both the theory of the BAS and the Acquired Preparedness model, as individuals high on BAS Fun Seeking may find the rewarding properties of alcohol more reinforcing, leading to stronger enhancement PAEs and increased drinking over time. The prospective design helps establish the temporal association between BAS and alcohol-related learning, and points to the need for prevention efforts that target these at-risk students. PMID- 22209026 TI - An examination of smoking outcome expectancies, smoking motives and trait worry in a sample of treatment-seeking smokers. AB - The present study examined the role of trait worry in predicting smoking-based cognitive processes (motives, expectancies, and beliefs about quitting) in a sample of 286 treatment-seeking, daily smokers (43.7% female; M(age)=37.25; SD=12.83). Consistent with prediction, trait worry was significantly and uniquely associated with smoking outcome expectancies and motives pertaining to negative affect reduction after controlling for other relevant variables such as negative affectivity, gender, smoking rate and tobacco-related disease. Trait worry also was significantly independently related to greater perceived barriers to quitting smoking. The significant effects remained consistent when adjusted for axis I psychopathology. These findings provide initial evidence of the theoretical and clinical importance of trait worry with regard to tobacco-related motives, outcome expectancies, and beliefs about quitting smoking. PMID- 22209027 TI - Anaphylaxis in an infant caused by menthol-containing cologne. PMID- 22209028 TI - Oblique sectional planes of block plastinates eased by Sac Plastination. AB - To find an oblique cutting plane of a plastinate, e.g. to cut gamma-nails in the femur, the Block Plastination technique was modified. After CT and MRI examination, the specimens were plastinated with the standard resin mixture E6/E12/E600. Instead of using a box to form a block during the casting and curing stage, we embedded the specimen in a sac made of polyester foil. A polymerized wooden block was attached to the specimen. The sac was wrapped with tape to the embedded specimen with the block. This approach limited the amount of required resin to the inner volume of the plastinate. Then, the plastination sac was put in the incubator for further polymerization and curing. When the foil was removed from the plastinated specimen, the wooden block served as a socket for the grip when sawing. The outer shape of the specimen remained visible. Doing so, the adequate cutting plane could be determined easily. PMID- 22209029 TI - Prediction of groundwater contamination with 137Cs and 131I from the Fukushima nuclear accident in the Kanto district. AB - We measured the concentrations of (131)I, (134)Cs, and (137)Cs released from the Fukushima nuclear accident in soil and rainwater samples collected March 30-31, 2011, in Ibaraki Prefecture, Kanto district, bordering Fukushima Prefecture to the south. Column experiments revealed that all (131)I in rainwater samples was adsorbed onto an anion-exchange resin. However, 30% of (131)I was not retained by the resin after it passed through a soil layer, suggesting that a portion of (131)I became bound to organic matter from the soil. The (137)Cs migration rate was estimated to be approximately 0.6 mm/y in the Kanto area, which indicates that contamination of groundwater by (137)Cs is not likely to occur in rainwater infiltrating into the surface soil after the Fukushima accident. PMID- 22209030 TI - Micronucleated erythrocytes in preterm newborns exposed to phototherapy and/or oxygentherapy. AB - Preterm newborns (PNBs) have an immature antioxidant defense system, and this makes them more susceptible to oxidative stress generated by postnatal treatments. The objective was to determine whether micronucleated erythrocytes increase in PNB by postnatal treatments such as oxygentherapy and phototherapy. We counted micronucleated erythrocytes and micronucleated polychromatic erythrocytes as DNA damage in 72 blood samples of PNB at 26-36 weeks of gestation, taken between 1 and 84 h after birth. We assume that more time passed between sampling and birth would correspond to greater time of exposure to oxygen (37 cases) and phototherapy plus oxygen (35 cases). In the PNB only exposed to oxygen, the differences were not significant, while there was a significant increase in micronucleated polychromatic erythrocytes with increasing exposure time in those treated with phototherapy plus oxygen. In conclusion, our results suggest that the MN increase from phototherapy can be observed in peripheral blood erythrocytes of PNB. PMID- 22209031 TI - Differential diagnosis between experimental endophthalmitis and uveitis in vitreous with Raman spectroscopy and principal components analysis. AB - Raman spectroscopy has been used for the diagnosis of various eye diseases. A diagnostic tool based on Raman spectroscopy has been developed to discriminate endophthalmitis from uveitis in vitreous tissues of rabbits' eyes in vitro. Twenty-two New Zealand rabbits suffering from endophthalmitis induced by Staphylococcus aureus (n=10), non-infectious uveitis induced by lipopolysaccharide from Escherichia coli (LPS) (n=10 animals) and control (n=2) were included in the study. After eye inoculation, vitreous tissues were dissected and a fragment was submitted to dispersive Raman spectroscopy using near-infrared laser excitation (830 nm, 100 mW) and spectrograph/CCD camera for detection of Raman signal with integration time of 50 s. A routine was developed to classify the spectra of endophthalmitis and uveitis using principal components analysis (PCA) and Mahalanobis distance. The mean Raman spectra of tissues with uveitis and endophthalmitis showed several bands in the region of 800-1800 cm( 1), which have been attributed to nucleic acids, amino acids and proteins from inflamed tissue and proliferating bacteria. The bands at 1004, 1258, 1339, 1451 and 1635 cm(-1) showed statistically significant differences between both diseases. It was observed that principal components PC1, PC3 and PC4 showed statistically significant differences for the two tissue types, indicating that these PCs can be used to discriminate between the two groups. The diagnostic model showed 94% sensitivity, 95% specificity and 95% accuracy using PC3*PC4. The Raman spectroscopy technique has been shown to be useful in differentiating uveitis and endophthalmitis in vitreous tissues in vitro, and these results may be clinically relevant for differentiating vitreous tissues to optimise the diagnosis of inflammatory and infectious vitreoretinal diseases. PMID- 22209032 TI - Mobilization of iron and arsenic from soil by construction and demolition debris landfill leachate. AB - Column experiments were performed to examine (a) the potential for leachate from construction and demolition (C&D) debris landfills to mobilize naturally occurring iron and arsenic from soils underlying such facilities and (b) the ability of crushed limestone to remove these aqueous phase pollutants. In duplicate columns, water was added to a 30-cm layer of synthetic C&D debris, with the resulting leachate serially passed through a 30-cm soil layer containing iron and arsenic and a 30-cm crushed limestone layer. This experiment was conducted for two different soil types (one high in iron (10,400mg/kg) and the second high in iron (5400mg/kg) and arsenic (70mg/kg)); also monitored were control columns for both soil types with water infiltration alone. Despite low iron concentrations in the simulated C&D debris leachate, elevated iron concentrations were observed when leachate passed through the soils; reductive dissolution was concluded to be the cause of iron mobilization. In the soil containing elevated arsenic, increased iron mobilization from the soil was accompanied by a similar but delayed arsenic mobilization. Since arsenic sorbs to oxidized iron soil minerals, reductive dissolution of these minerals results in arsenic mobilization. Crushed limestone significantly reduced iron (to values below the detection limit of 0.01mg/L in most cases); however, arsenic was not removed to any significant extent. PMID- 22209033 TI - Cytosolic organelles shape calcium signals and exo-endocytotic responses of chromaffin cells. AB - The concept of stimulus-secretion coupling was born from experiments performed in chromaffin cells 50 years ago. Stimulation of these cells with acetylcholine enhances calcium (Ca(2+)) entry and this generates a transient elevation of the cytosolic Ca(2+) concentration ([Ca(2+)](c)) that triggers the exocytotic release of catecholamines. The control of the [Ca(2+)](c) signal is complex and depends on various classes of plasmalemmal calcium channels, cytosolic calcium buffers, the uptake and release of Ca(2+) from cytoplasmic organelles, such as the endoplasmic reticulum, mitochondria, chromaffin vesicles and the nucleus, and Ca(2+) extrusion mechanisms, such as the plasma membrane Ca(2+)-stimulated ATPase, and the Na(+)/Ca(2+) exchanger. Computation of the rates of Ca(2+) fluxes between the different cell compartments support the proposal that the chromaffin cell has developed functional calcium tetrads formed by calcium channels, cytosolic calcium buffers, the endoplasmic reticulum, and mitochondria nearby the exocytotic plasmalemmal sites. These tetrads shape the Ca(2+) transients occurring during cell activation to regulate early and late steps of exocytosis, and the ensuing endocytotic responses. The different patterns of catecholamine secretion in response to stress may thus depend on such local [Ca(2+)](c) transients occurring at different cell compartments, and generated by redistribution and release of Ca(2+) by cytoplasmic organelles. In this manner, the calcium tetrads serve to couple the variable energy demands due to exo endocytotic activities with energy production and protein synthesis. PMID- 22209034 TI - Ca2+ homeostasis and exocytosis in carotid glomus cells: role of mitochondria. AB - In oxygen sensing carotid glomus (type 1) cells, the hypoxia-triggered depolarization can be mimicked by mitochondrial inhibitors. We examined the possibility that, other than causing glomus cell depolarization, mitochondrial inhibition can regulate transmitter release via changes in Ca(2+) dynamics. Under whole-cell voltage clamp conditions, application of the mitochondrial inhibitors, carbonyl cyanide m-chlorophenylhydrazone (CCCP) or cyanide caused a dramatic slowing in the decay of the depolarization-triggered Ca(2+) signal in glomus cells. In contrast, inhibition of the Na(+)/Ca(2+) exchanger (NCX), plasma membrane Ca(2+)-ATPase (PMCA) pump or sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) pump had much smaller effects. Consistent with the notion that mitochondrial Ca(2+) uptake is the dominant mechanism in cytosolic Ca(2+) removal, inhibition of the mitochondrial uniporter with ruthenium red slowed the decay of the depolarization-triggered Ca(2+) signal. Hypoxia also slowed cytosolic Ca(2+) removal, suggesting a partial impairment of mitochondrial Ca(2+) uptake. Using membrane capacitance measurement, we found that the increase in the duration of the depolarization-triggered Ca(2+) signal after mitochondrial inhibition was associated with an enhancement of the exocytotic response. The role of mitochondria in the regulation of Ca(2+) signal and transmitter release from glomus cells highlights the importance of mitochondria in hypoxic chemotransduction in the carotid bodies. PMID- 22209035 TI - Accuracy of parental report and electronic health record documentation as measures of diet and physical activity counseling. AB - OBJECTIVE: To determine whether parental reports and electronic health record documentation of physician counseling on nutrition and physical activity reflect actual counseling provided. METHODS: Participants were parents of 198 children 2 to 12 years of age seen in a primary care pediatric clinic at an academic medical center for well child care and their 38 physicians. Parents completed a post visit questionnaire to report discussions on weight, nutrition, and physical activity that occurred during the visit. Electronic health records were reviewed to measure documentation of these topics during the visit. Parental reports and records were compared with actual discussions on the basis of coded audiotapes. Counseling was coded as having occurred if specific topics were mentioned during the encounter, however brief this mention was. RESULTS: A total of 48% of the children were female, they were a mean age of 5.4 years, and 28% were overweight or obese. Sensitivity of parental report was high (63%-96%), but specificity was low (43%-77%) because of parents' tendency to overreport counseling. Sensitivity of electronic health record documentation was generally low (40%-53%) except for discussion of screen time (92%) and physical activity (88%); the specificity of these data was also poor (42% and 21%, respectively, for screen time and physical activity). CONCLUSIONS: Electronic health record documentation may not be the most valid method of measuring physician counseling on weight, nutrition, and physical activity in pediatric primary care. Parental report via the use of a questionnaire administered immediately after the visit is a better alternative in quality improvement or research studies when resources do not allow for direct observation, with the caveat that parents may overreport whether counseling was provided. PMID- 22209036 TI - Synthesis of phthalocyanine conjugates with gold nanoparticles and liposomes for photodynamic therapy. AB - The efficiency of [2,9,17,23-tetrakis-(1,6 hexanedithiol)phthalocyaninato]zinc(II) as a photodynamic therapy (PDT) agent was investigated. This compound belongs to the second generation of photosensitizers currently tested for the cellular photo-damage of cancer cells. The production of reactive oxygen species (ROS) and phototoxicity of the photosensitizer were assessed. Healthy fibroblast cells and breast cancer (MCF-7) cells were treated with either free phthalocyanine or phthalocyanine bound to either gold nanoparticles or encapsulated in liposomes. Cell viability studies showed the optimum phototoxic effect on non-malignant cells to be 4.5 J cm(-2). The PDT effect of the liposome bound phthalocyanine showed extensive damage of the breast cancer cells. Gold nanoparticles only showed a modest improvement in PDT activity. PMID- 22209037 TI - Clonality status of multifocal lung adenocarcinomas based on the mutation patterns of EGFR and K-ras. AB - PURPOSE: The purpose of this study is to clarify the clonality status of multifocal lung adenocarcinomas based on the mutation patterns of epidermal growth factor receptor (EGFR) and K-ras. METHODS: We analyzed 82 multifocal lung adenocarcinomas from 36 patients who underwent surgical resection. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue and analyzed for EGFR and K-ras mutations. We determined the clonality status of multifocal lung adenocarcinomas based on the mutation patterns of EGFR and K-ras. The actuarial survival time was estimated and the prognostic factors were evaluated for 31 patients with synchronous multifocal lung adenocarcinomas. RESULTS: EGFR and K ras mutations were detected in 36 (44%) and 19 (23%) of the 82 tumors, respectively. EGFR mutations had occurred randomly in 20 (91%) of the 22 patients with at least one EGFR mutated tumor. K-ras mutations had occurred randomly in 14 (93%) of the 15 patients with at least one K-ras mutated tumor. Combining the results for the EGFR and K-ras mutation patterns, the clonality status of multifocal lung adenocarcinomas could be determined in 30 (83%) of the 36 patients. No statistically significant difference in the actuarial survival of the patient subgroups stratified according to the clonality status, which was based on the presence of EGFR and K-ras mutations, was observed. CONCLUSIONS: Both EGFR and K-ras mutations frequently occur randomly in multifocal lung adenocarcinomas. Combined mutation pattern analyses of EGFR and K-ras may be useful for making decisions regarding treatment strategies for patients with multifocal lung adenocarcinomas. PMID- 22209038 TI - Phytoalexins in defense against pathogens. AB - Plants use an intricate defense system against pests and pathogens, including the production of low molecular mass secondary metabolites with antimicrobial activity, which are synthesized de novo after stress and are collectively known as phytoalexins. In this review, we focus on the biosynthesis and regulation of camalexin, and its role in plant defense. In addition, we detail some of the phytoalexins produced by a range of crop plants from Brassicaceae, Fabaceae, Solanaceae, Vitaceae and Poaceae. This includes the very recently identified kauralexins and zealexins produced by maize, and the biosynthesis and regulation of phytoalexins produced by rice. Molecular approaches are helping to unravel some of the mechanisms and reveal the complexity of these bioactive compounds, including phytoalexin action and metabolism. PMID- 22209039 TI - Tactile sensing in specialized predators - from behavior to the brain. AB - A number of predators depend heavily on tactile cues for pursuing and capturing prey. Here I describe and discuss the whiskers of carnivorous grasshopper mice and shrews, the sensory rays of the star-nosed mole, and the tactile appendages of the tentacled snake. These diverse sensors are accompanied by remarkable corresponding specializations in the central nervous system. But understanding their function and the significance of the central nervous system correlates requires the careful documentation of behavior inherent to a neuroethological approach. PMID- 22209040 TI - The many facets of facial interactions in mammals. AB - Facial interactions are prominent behaviors in primates. Primate facial signaling, which includes the expression of emotions, mimicking of facial movements, and gaze interactions, is visually dominated. Correspondingly, in primate brains an elaborate network of face processing areas exists within visual cortex. But other mammals also communicate through facial interactions using additional sensory modalities. In rodents, multisensory facial interactions are involved in aggressive behaviors and social transmission of food preferences. The eusocial naked mole-rat, whose face is dominated by prominent incisors, uses facial aggression to enforce reproductive suppression. In burrow-living mammals like the naked mole-rat in particular, and in rodents in general, somatosensory face representations in cortex are enlarged. Diversity of sensory domains mediating facial communication might belie underlying common mechanisms. As a case in point, neurogenetics has revealed strongly heritable traits in face processing and identified gene defects that disrupt facial interactions both in humans and rodents. PMID- 22209041 TI - The minimum 10-year results of a second-generation cementless acetabular shell with a polished inner surface. AB - The purpose of this prospective study was to evaluate the minimum 10-year outcomes and survivorship of the Reflection shell with a polished inner surface and an improved locking mechanism. Three hundred sixty-three total hip replacements with a mean follow-up of 11.6 years (range, 10.0-15.1) were evaluated. The mean Harris Hip and WOMAC scores at last follow-up were 87 and 77, respectively. Four cups were revised: 2 for infection and 2 for aseptic loosening. Thirteen cases underwent liner exchange for wear. Radiographic review of remaining cups identified 8.8% with identifiable peri-acetabular osteolysis and no cases of loosening. The overall 10- and 15-year Kaplan-Meier survivorship was 94% and 90% for the total hip arthroplasty system while the survivorship of the shell remained 99.4% at 15 years. PMID- 22209042 TI - Femoral stem fracture and in vivo corrosion of retrieved modular femoral hips. AB - A series of 78 retrieved modular hip devices were assessed for fretting and corrosion. Damage was common at both the head-neck junction (54% showing corrosion; 88% showing fretting) and at the stem-sleeve junction (88% corrosion; 65% fretting). Corrosion correlated to in vivo duration, patient activity, and metal (vs ceramic) femoral heads but did not correlate to head carbon content. Femoral stem fatigue fracture was observed in seven retrievals; all had severe corrosion, were under increased stress, and were in vivo longer than the non fractured cohort. This study emphasizes the potential for stem fracture when small diameter femoral stems with large offsets are used in heavy and active patients. Designs which reduce fretting and corrosion in modular implants is warranted as patients demand longer lasting implants. PMID- 22209043 TI - Functional recovery, complications and CT positioning of total hip replacement performed through a Rottinger anterolateral mini-incision. Review of a continuous series of 103 cases. AB - INTRODUCTION: Minimally invasive approaches entail an increased risk of malpositioning and peri-operative complications. Most studies analyzed these data only on plain X-ray rather than computed tomodensitometry (CT) in assessing implant positioning. HYPOTHESIS: A Rottinger minimally invasive anterolateral (MIS-AL) approach provides rapid complication-free functional recovery with reliable implant positioning on CT-scan. PATIENTS AND METHOD: One hundred and three primary cemented total hip replacements (THR) performed by a single surgeon using a MIS-AL approach underwent clinical assessment at six weeks and three, six and 12 months on X-ray, including CT and postoperative myoglobinemia and creatine phosphokinase (CPK). RESULTS: Pain, on a visual analog scale, was graded less than 1 at 36 hours; canes ceased to be used at a mean three weeks; and mean Postel-Merle-D'Aubigne score at six months was 17.36 (range, 13-18). There were ten approach-related complications (9.7%: one femoral perforation, two dislocations, two femoral neck fissures, two cases of meralgia paresthetica and three of tensor tendinitis). Mean CPK level was 390.9 +/- 252MUg/L (range, 88 1095MUg/L) at 24 hr postoperatively and 319 +/- 256MUg/L (95-1028 MUg/L) at 48 hr. Mean postoperative myoglobinemia was 299 +/- 152.6MUg/L (75-914MUg/L). Mean acetabular inclination and anteversion on CT were respectively 44.7 degrees +/- 4.6 degrees (34 degrees - 56 degrees ) and 9.2 degrees +/-9.2 degrees (-17 degrees -35 degrees ) and mean femoral anteversion 23.5 degrees +/- 9.4 degrees (2 degrees -53 degrees ). DISCUSSION: Functional recovery was quick, but with an 8.7% complications rate (excluding four cases of spontaneously resolved tendon pain). CT showed reliable cup positioning, but a wide scatter in femoral anteversion. Elevated muscle enzyme levels possibly testified to approach-related tissue attrition. The MIS-AL approach involves a learning curve to avoid femoral perforation. It provided rapid functional recovery with reliable positioning, at least for the cup, and a low rate of associated complications. LEVEL OF EVIDENCE: III, prospective continuous study. PMID- 22209044 TI - Endopelvic migration of a sternoclavicular K-wire. Case report and review of literature. AB - We report a unique case, never before published, of sternoclavicular joint fixation K-wire migration to the pelvic region, in a 56 year-old man. Two years previously, sternoclavicular dislocation had been fixed by three wires. A transitory episode of precordial thoracic pain followed by iterative abdominal pain accompanied the migration. Extraction was performed five years later. Scapular K-wire migration is frequent. The proximity of cardiovascular structures may have fatal consequences. This type of internal fixation raises questions, and migration prevention needs to be taken into account. Medical complications and the legal context are major factors leading us to abandon this type of osteosynthesis. Once migration has been diagnosed, the wire should be removed without delay. PMID- 22209045 TI - [Primary choriocarcinoma of the maxillary gingival]. AB - INTRODUCTION: Primary non-gestational extragonadal choriocarcinomas are uncommon and their head and neck localization more exceptional. OBSERVATION: We report on a primary choriocarcinoma case of the mandibular gingivae in a 26-year-old woman who presented with pulmonary and renal metastasis. Complete response (clinical, biological and radiological) was achieved with combined chemotherapy according to APE regimen associating actinomycin, cisplatin and etoposid. The patient was free of disease 4 years after therapy completion. DISCUSSION: Primary gingival mandibular choriocarcinoma is very rare. Clinical presentation is atypical; diagnosis is based on histopathological examination and positivity for HCG. Our case report showed high chemo-sensitivity and comparable outcome to the other localizations. PMID- 22209046 TI - [Diet of neutropenic patients in pediatric oncology service; the experience of the university hospital of Strasbourg (HUS)]. AB - OBJECTIVE: This article clarifies the choices made by the HUS concerning the ways of preparing food reserved to neutropenic children hospitalized in pediatric oncology service. We will describe the results of microbiological analysis of food realized from 2002 to 2007. METHODS: A specific team prepares this food which is canned and treated by "appertisation" (autoclaving). Each dish portion produced is provided to the service only if the microbiological results are conform, that is to say free of organisms. RESULTS: Three thousand and seventy eight dishes were analysed: 82.9% of the analysed packs were conform. The contamination ratio decreased significantly (P<0.001) from 2002 to 2007. The organisms which cause the majority of dishes contamination are Bacillus (44.7%) and environmental mould exhibiting sterile mycelium (8.7%). The food which is the most frequently "nonconform" is the dry food with a contamination rate of 37.9%. The identified concentrations remain mainly lower than 50 colony-forming units per millilitre (CFU/mL): 66.2% for the bacteria and 97.2% for the fungi. CONCLUSION: Considering the lack of consensus on the acceptable microbiological thresholds and on the food protection level, the HUS make it a rule to have a maximal precautionary principle. Currently, this principle appears to us to be a safety option required for the patients hospitalized in pediatric oncology service. PMID- 22209047 TI - Prediction of methylation CpGs and their methylation degrees in human DNA sequences. AB - DNA methylation plays a key role in the regulation of gene expression. The most common type of DNA modification consists of the methylation of cytosine in the CpG dinucleotide. The detections of DNA methylation have been determined mostly by experimental methods, which were time-consuming and expensive, difficult to meet the requirements of modern large-scale sequencing technology. Accordingly, it is necessary to develop automatic, reliable prediction methods for DNA methylation. In this study, the trinucleotide composition, a 64-dimensional feature vector of the occurrence frequency of 64 trinucleotides in the DNA sequence, was utilized to model SVM for the prediction of CpG methylation degrees in humans. The model was evaluated by jackknife validation and the correlation coefficient (R) and root-mean-square error (RMSE) were 0.8223 and 0.2042, respectively. The proposed method was also used to predict methylation sites, the model was evaluated by jackknife validation and the Matthews correlation coefficient (MCC) and accuracy (ACC) were 0.6263 and 0.8133, respectively. The good results indicated that the proposed method was a useful tool for the investigation of DNA methylation prediction research. PMID- 22209049 TI - Circulating tumour cells, their role in metastasis and their clinical utility in lung cancer. AB - Circulating tumour cells (CTCs) have attracted much recent interest in cancer research as a potential biomarker and as a means of studying the process of metastasis. It has long been understood that metastasis is a hallmark of malignancy, and conceptual theories on the basis of metastasis from the nineteenth century foretold the existence of a tumour "seed" which is capable of establishing discrete tumours in the "soil" of distant organs. This prescient "seed and soil" hypothesis accurately predicted the existence of CTCs; microscopic tumour fragments in the blood, at least some of which are capable of forming metastases. However, it is only in recent years that reliable, reproducible methods of CTC detection and analysis have been developed. To date, the majority of studies have employed the CellSearchTM system (Veridex LLC), which is an immunomagnetic purification method. Other promising techniques include microfluidic filters, isolation of tumour cells by size using microporous polycarbonate filters and flow cytometry-based approaches. While many challenges still exist, the detection of CTCs in blood is becoming increasingly feasible, giving rise to some tantalizing questions about the use of CTCs as a potential biomarker. CTC enumeration has been used to guide prognosis in patients with metastatic disease, and to act as a surrogate marker for disease response during therapy. Other possible uses for CTC detection include prognostication in early stage patients, identifying patients requiring adjuvant therapy, or in surveillance, for the detection of relapsing disease. Another exciting possible use for CTC detection assays is the molecular and genetic characterization of CTCs to act as a "liquid biopsy" representative of the primary tumour. Indeed it has already been demonstrated that it is possible to detect HER2, KRAS and EGFR mutation status in breast, colon and lung cancer CTCs respectively. In the course of this review, we shall discuss the biology of CTCs and their role in metastagenesis, the most commonly used techniques for their detection and the evidence to date of their clinical utility, with particular reference to lung cancer. PMID- 22209048 TI - The role of the endotracheal tube cuff in microaspiration. AB - The cuff of the endotracheal tube (ETT) is designed to provide a seal within the airway, allowing airflow through the ETT but preventing passage of air or fluids around the ETT. Deliberate or inadvertent movement of the ETT may affect cuff pressure or shift folds in the cuff, mobilizing pooled secretions. When this seal is compromised, microaspirations contaminated with gastric contents or bacterially colonized oral secretions can occur that leave the patient susceptible to a host of problems, such as hypoxia, pneumonitis, and respiratory infections. These complications are costly in terms of morbidity and mortality, as well as hospital expense. We will discuss the role of the ETT cuff in microaspiration and identify potential directions for future research to improve outcomes in mechanically ventilated patients. PMID- 22209050 TI - Maternal play behaviors, child negativity, and preterm or low birthweight toddlers' visual-spatial outcomes: testing a differential susceptibility hypothesis. AB - OBJECTIVE: We examined the joint roles of child negative emotionality and parenting in the visual-spatial development of toddlers born preterm or with low birthweights (PTLBW). METHOD: Neonatal risk data were collected at hospital discharge, observer- and parent-rated child negative emotionality was assessed at 9-months postterm, and mother-initiated task changes and flexibility during play were observed during a dyadic play interaction at 16-months postterm. Abbreviated IQ scores, and verbal/nonverbal and visual-spatial processing data were collected at 24-months postterm. RESULTS: Hierarchical regression analyses did not support our hypothesis that the visual-spatial processing of PTLBW toddlers with higher negative emotionality would be differentially susceptible to parenting behaviors during play. Instead, observer-rated distress and a negativity composite score were associated with less optimal visual-spatial processing when mothers were more flexible during the 16-month play interaction. Mother-initiated task changes did not interact with any of the negative emotionality variables to predict any of the 24-month neurocognitive outcomes, nor did maternal flexibility interact with mother-rated difficult temperament to predict the visual-spatial processing outcomes. PMID- 22209051 TI - The potential role of microRNA-146 in Alzheimer's disease: biomarker or therapeutic target? AB - Recently, there have been increasing evidences that microRNA-146 (miR-146) is related to up-regulated immune and inflammatory signaling through its target genes, such as IRAK1 and TRAF6. Additionally, abundant data continue to support the hypothesis that progressive up-regulation of inflammatory gene expression and elevated inflammatory signaling facilitate the development and progression of Alzheimer's disease (AD). This review focuses on the recent findings regarding the role of miR-146 in modulating immune response and its subsequent effects in the pathogenesis of AD. PMID- 22209052 TI - iPad-assisted percutaneous access to the kidney using marker-based navigation: initial clinical experience. PMID- 22209053 TI - Temporal national trends of minimally invasive and retropubic radical prostatectomy outcomes from 2003 to 2007: results from the 100% Medicare sample. AB - BACKGROUND: Although the use of minimally invasive radical prostatectomy (MIRP) has increased, there are few comprehensive population-based studies assessing temporal trends and outcomes relative to retropubic radical prostatectomy (RRP). OBJECTIVE: Assess temporal trends in the utilization and outcomes of MIRP and RRP among US Medicare beneficiaries from 2003 to 2007. DESIGN, SETTING, AND PARTICIPANTS: A population-based retrospective study of 19 594 MIRP and 58 638 RRP procedures was performed from 2003 to 2007 from the 100% Medicare sample, composed of almost all US men >= 65 yr of age. INTERVENTION: MIRP and RRP. MEASUREMENTS: We measured 30-d outcomes (cardiac, respiratory, vascular, genitourinary, miscellaneous medical, miscellaneous surgical, wound complications, blood transfusions, and death), cystography utilization within 6 wk of surgery, and late complications (anastomotic stricture, ureteral complications, rectourethral fistulae, lymphocele, and corrective incontinence surgery). RESULTS AND LIMITATIONS: From 2003 to 2007, MIRP increased from 4.9% to 44.5% of radical prostatectomies while RRP decreased from 89.4% to 52.9%. MIRP versus RRP subjects were younger (p<0.001) and had fewer comorbidities (p<0.001). Decreased MIRP genitourinary complications (6.2-4.1%; p = 0.002), miscellaneous surgical complications (4.7-3.7%; p=0.030), transfusions (3.5-2.2%; p=0.005), and postoperative cystography utilization (40.3-34.1%; p<0.001) were observed over time. Conversely, overall RRP perioperative complications increased (27.4-32.0%; p<0.001), including an increase in perioperative mortality (0.5-0.8%, p=0.009). Late RRP complications increased, with the exception of fewer anastomotic strictures (10.2-8.8%; p=0.002). In adjusted analyses, RRP versus MIRP was associated with increased 30-d mortality (odds ratio [OR]: 2.67; 95% confidence interval [CI], 1.55-4.59; p<0.001) and more perioperative (OR: 1.60; 95% CI, 1.45 1.76; p<0.001) and late complications (OR: 2.52; 95% CI, 2.20-2.89; p<0.001). Limitations include the inability to distinguish MIRP with versus without robotic assistance and also the lack of pathologic information. CONCLUSIONS: From 2003 to 2007, there were fewer MIRP transfusions, genitourinary complications, and miscellaneous surgical complications, whereas most RRP perioperative and late complications increased. RRP versus MIRP was associated with more postoperative mortality and complications. PMID- 22209054 TI - Analysis of high-pitched phonation using three-dimensional computed tomography. AB - OBJECTIVES/HYPOTHESIS: Our aim was to use three-dimensional computed tomography (3DCT) to examine arytenoid cartilage movement during a high-pitched tone task. STUDY DESIGN: This was a prospective study. METHODS: This study included 14 patients with male-to-female gender identity disorder who had undergone 3DCT imaging for surgical simulation between January 2007 and May 2008. First, to prove that the phonation condition was indeed one of the high-pitched phonation, we confirmed the rotational movement of the thyroid cartilage, horizontal gliding movement of the inferior horn, and vocal fold elongation on a high-pitched tone task. Next, we detected the arytenoid cartilage positions of the joint during a comparison of comfortable and high-pitched phonations. We measured the movement direction and movement distance of the arytenoid cartilage. RESULTS: In all cases, the cricothyroid space became narrower (rotation movement), and we observed anterior gliding movement of the inferior horn. In all cases, elongation of the vocal folds by the high-pitched phonation was confirmed and the arytenoid cartilages were displaced both anteriorly and caudally from the position during comfortable phonation by the high-pitched tone task. CONCLUSIONS: The arytenoid cartilages did not move posteriorly to elongate the vocal folds during high pitched phonation. The arytenoid cartilages were pulled anteriorly and moved caudally because of tension associated with vocal fold elongation because of the task of high-pitched phonation. These results suggest that there are no movements at the cricoarytenoid joint that directly control the length of the vocal folds in accordance with pitch. PMID- 22209055 TI - A model for treating voice disorders in school-age children within a video gaming environment. AB - OBJECTIVE: Clinicians use a variety of approaches to motivate children with hyperfunctional voice disorders to comply with voice therapy in a therapeutic session and improve the motivation of children to practice home-based exercises. Utilization of current entertainment technology in such approaches may improve participation and motivation in voice therapy. The purpose of this study is to test the feasibility of using an entertainment video game as a therapy device. STUDY DESIGN: Prospective cohort and case-control study. METHODS: Three levels of game testing were conducted to an existing entertainment video game for use as a voice therapy protocol. The game was tested by two computer programmers and five normal participants. The third level of testing was a case study with a child diagnosed with a hyperfunctional voice disorder. Modifications to the game were made after each feasibility test. RESULTS: Errors with the video game performance were modified, including the addition of a time stamp directory and game controller. Resonance voice exercises were modified to accommodate the gaming environment and unique competitive situation, including speech rate, acoustic parameters, game speed, and point allocations. CONCLUSION: The development of video games for voice therapeutic purposes attempt to replicate the high levels of engagement and motivation attained with entertainment video games, stimulating a more productive means of learning while doing. This case study found that a purely entertainment video game can be implemented as a voice therapeutic protocol based on information obtained from the case study. PMID- 22209056 TI - Coprevalence of anxiety and depression with spasmodic dysphonia: a case-control study. AB - INTRODUCTION: There is evidence supporting an association between depression and anxiety in patients with chronic disease. Spasmodic dysphonia (SD) is a chronic, incurable, and disabling voice disorder. Reported rates of depression and anxiety in SD range from 7.1% to 72%, with a maximum number of 18 patients. The goal of this study was to define the coprevalence of depression and anxiety with SD. MATERIALS AND METHODS: A single-institution case-control study was performed from May to July 2010. Consecutive patients with SD and benign voice disorders were enrolled prospectively. On enrollment, patients were asked to fill out a questionnaire that reviewed the duration of the voice disorder and personal history of anxiety and depression, including current and lifetime diagnosis. RESULTS: One hundred forty-six controls with benign voice disorders and 128 patients with SD were enrolled. Patients with SD were no more likely to be diagnosed with depression or anxiety than those of the control group (odds ratio [OR]=0.985, 95% confidence interval [CI]=0.59-1.63; and OR=1.314; 95% CI=0.75 2.3, respectively). Additionally, duration of disease was a risk factor for depression in both the SD group and the control group, and the association was not significantly different between groups. CONCLUSION: Patients with SD were no more likely to have depression or anxiety than those with other voice disorders. It is important for otolaryngologists to be aware of the increased rates of depression in patients diagnosed with chronic diseases, including voice disorders, and to refer to a psychiatrist when appropriate. PMID- 22209057 TI - Sentence intelligibility before and after voice treatment in speakers with idiopathic Parkinson's disease. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to determine whether sentence intelligibility improves in speakers with idiopathic Parkinson's disease (PD) as a result of Lee Silverman Voice Treatment (LSVT). It was hypothesized that all the speakers would improve following treatment, in association with increased vocal loudness, which was the primary target of the treatment. STUDY DESIGN: Prospective study of eight Speakers with PD using a single-blinded, randomized pre-post treatment design, with multiple daily assessments before and after treatment was carried out. Resultant data were corrected for regression to the mean. METHODS: Randomized digital recordings of sentences produced by speakers with idiopathic PD before and after the treatment were presented to normal-hearing listeners with equalized intensity at conversational loudness in the presence of pink noise. Percentage of words understood was calculated before and after the treatment. Changes in overall vocal intensity were also analyzed. RESULTS: There was a statistically significant group effect from pre-to-post voice treatment; however, there was also significant interaction of treatment with speakers. Six of the speakers with PD improved significantly following voice treatment, one exhibited no change, and one exhibited a decline in sentence intelligibility post-treatment. CONCLUSIONS: LSVT yielded significant improvement in sentence intelligibility for most speakers in the study but was not beneficial for two of the speakers despite the fact that they increased their overall vocal loudness. PMID- 22209058 TI - A new voice rating tool for clinical practice. AB - AIMS: Perceptual rating of voice quality is a key component in the comprehensive assessment of voice, but there are practical difficulties in making reliable measurements. We have developed the Newcastle Audio Ranking (NeAR) test, a new referential system for the rating of voice parameters. In this article, we present our first results using NeAR. METHODS: We asked five experts and 11 naive raters to assess 15 male and 15 female voices using the NeAR test. We assessed: validity with respect to the GRBAS scale; interrater reliability; sensitivity to subtle voice differences; and the performance of expert versus naive raters. RESULTS: There was a uniformly excellent agreement with GRBAS (r=0.87) and interrater agreement (intraclass correlation coefficient=0.86). Considering each GRBAS grade of voice separately, there was still good interrater agreement in NeAR, implying it has good sensitivity to subtle changes. All these results were equally true for expert and naive raters. CONCLUSION: The NeAR test is a promising new tool in the assessment of voice disorders. PMID- 22209059 TI - Pre- and posttreatment voice and speech outcomes in patients with advanced head and neck cancer treated with chemoradiotherapy: expert listeners' and patient's perception. AB - OBJECTIVES: Perceptual judgments and patients' perception of voice and speech after concurrent chemoradiotherapy (CCRT) for advanced head and neck cancer. STUDY DESIGN: Prospective clinical trial. METHODS: A standard Dutch text and a diadochokinetic task were recorded. Expert listeners rated voice and speech quality (based on Grade, Roughness, Breathiness, Asthenia, and Strain), articulation (overall, [p], [t], [k]), and comparative mean opinion scores of voice and speech at three assessment points calculated. A structured study specific questionnaire evaluated patients' perception pretreatment (N=55), at 10 week (N=49) and 1-year posttreatment (N=37). RESULTS: At 10 weeks, perceptual voice quality is significantly affected. The parameters overall voice quality (mean, -0.24; P=0.008), strain (mean, -0.12; P=0.012), nasality (mean, -0.08; P=0.009), roughness (mean, -0.22; P=0.001), and pitch (mean, -0.03; P=0.041) improved over time but not beyond baseline levels, except for asthenia at 1-year posttreatment (voice is less asthenic than at baseline; mean, +0.20; P=0.03). Perceptual analyses of articulation showed no significant differences. Patients judge their voice quality as good (score, 18/20) at all assessment points, but at 1-year posttreatment, most of them (70%) judge their "voice not as it used to be." In the 1-year versus 10-week posttreatment comparison, the larynx hypopharynx tumor group was more strained, whereas nonlarynx tumor voices were judged less strained (mean, -0.33 and +0.07, respectively; P=0.031). Patients' perceived changes in voice and speech quality at 10-week post- versus pretreatment correlate weakly with expert judgments. CONCLUSION: Overall, perceptual CCRT effects on voice and speech seem to peak at 10-week posttreatment but level off at 1-year posttreatment. However, at that assessment point, most patients still perceive their voice as different from baseline. PMID- 22209060 TI - The Traditional/Acoustic Music Project: a study of vocal demands and vocal health. AB - OBJECTIVE/HYPOTHESIS: The Traditional/Acoustic Music Project seeks to identify the musical and performance characteristics of traditional/acoustic musicians and determine the vocal demands they face with the goals of (1) providing information and outreach to this important group of singers and (2) providing information to physicians, speech-language pathologists, and singing teachers who will enable them to provide appropriate services. STUDY DESIGN: Descriptive cross-sectional study. METHODS: Data have been collected through administration of a 53-item questionnaire. The questionnaire was administered to artists performing at local venues in Knoxville, Tennessee and also to musicians attending the 2008 Folk Alliance Festival in Memphis, Tennessee. RESULTS: Approximately 41% of the respondents have had no vocal training, whereas approximately 34% of the respondents have had some form of formal vocal training (private lessons or group instruction). About 41% of the participants had experienced a tired voice, whereas about 30% of the participants had experienced either a loss of the top range of the voice or a total loss of voice at least once in their careers. Approximately 31% of the respondents had no health insurance. Approximately 69% of the respondents reported that they get their information about healthy singing practices solely from fellow musicians or that they do not get any information at all. CONCLUSION: Traditional/acoustic musicians are a poorly studied population at risk for the development of voice disorders. Continued research is necessary with the goal of a large sample that can be analyzed for associations, identification of subpopulations, and formulation of specific hypotheses that lend themselves to experimental research. Appropriate models of information and service delivery tailored for the singer-instrumentalist are needed. PMID- 22209061 TI - Surgical removal followed by radiotherapy for refractory vocal process granuloma. AB - OBJECTIVE/HYPOTHESIS: Vocal process granuloma (VPG) is a challenging disease because of its multifactorial etiology, irrespective of treatments. Conservative treatments had shown limited effects, while surgical attempts of removing lesions were only indicated in certain conditions for high recurrent rates. However, a group of patients remained with refractory disease. The objective of this study was to describe the use of surgical removal followed by radiation therapy in the management of patients with refractory VPG. STUDY DESIGN: Retrospective reviews were conducted in patients with refractory VPG to evaluate the effects of surgical removal followed by radiation therapy and compared with that of surgical removal alone. METHODS: Twenty-one patients with refractory disease were enrolled in our study. Fifteen patients accepted surgical removal followed by radiation therapy the day after operation in a total dose of 15 Gy. Six patients who refused radiation therapy accepted surgical removal alone. All patients were followed up for 3-6 years and laryngoscope results were studied in all patients. RESULTS: All of the 15 patients treated with surgical removal followed by radiation therapy in low dose got the disease eliminated completely with mild complications. Recurrences were observed during the 2 weeks to 3 months after operation in five of the six patients who accepted surgical removal alone, whereas no recurrence was observed in the other one in whom the granuloma was believed to be caused by intubation injury. CONCLUSION: This initial study showed that surgical removal followed by radiation therapy in low dose was a safe and an effective approach to manage VPG with a potential for clinical application, but further studies in a larger cohort for a longer term were needed. PMID- 22209062 TI - Objective and subjective assessment of tracheoesophageal prosthesis voice outcome. AB - OBJECTIVE: To investigate the relationships between objective measures and the results of subjective assessment of voice quality and speech intelligibility in patients submitted to total laryngectomy and tracheoesophageal (TE) puncture. STUDY DESIGN: Retrospective. MATERIALS: Twenty patients implanted with voice prosthesis were studied. After surgery, the entire sample performed speech rehabilitation. The assessment protocol included maximum phonation time (MPT), number of syllables per deep breath, acoustic analysis of the sustained vowel /a/ and of a bisyllabic word, perceptual evaluation (pleasantness and intelligibility%), and self-assessment. RESULTS: The correlation between pleasantness and intelligibility% was statistically significant. Both the latter were significantly correlated with the acoustic signal type, the number of formant peaks, and the F2-F1 difference. The intelligibility% and number of formant peaks were significantly correlated with the MPT and number of syllables per deep breath. Moreover, significant correlations were found between the number of formant peaks and both intelligibility% and pleasantness. The higher the number of syllables per deep breath and the longer the MPT, significantly higher was the number of formant peaks and the intelligibility%. The study failed to show significant correlation between patient's self-assessment of voice quality and both pleasantness and communication effectiveness. CONCLUSION: The multidimensional assessment seems to be a reliable tool to evaluate the TE functional outcome. Particularly, the results showed that both pleasantness and intelligibility of TE speech are correlated to the availability of expired air and the function of the vocal tract. PMID- 22209063 TI - A canonical biomechanical vocal fold model. AB - The present article aimed at constructing a canonical geometry of the human vocal fold (VF) from subject-specific image slice data. A computer-aided design approach automated the model construction. A subject-specific geometry available in literature, three abstractions (which successively diminished in geometric detail) derived from it, and a widely used quasi two-dimensional VF model geometry were used to create computational models. The first three natural frequencies of the models were used to characterize their mechanical response. These frequencies were determined for a representative range of tissue biomechanical properties, accounting for underlying VF histology. Compared with the subject-specific geometry model (baseline), a higher degree of abstraction was found to always correspond to a larger deviation in model frequency (up to 50% in the relevant range of tissue biomechanical properties). The model we deemed canonical was optimally abstracted, in that it significantly simplified the VF geometry compared with the baseline geometry but can be recalibrated in a consistent manner to match the baseline response. Models providing only a marginally higher degree of abstraction were found to have significant deviation in predicted frequency response. The quasi two-dimensional model presented an extreme situation: it could not be recalibrated for its frequency response to match the subject-specific model. This deficiency was attributed to complex support conditions at anterior-posterior extremities of the VFs, accentuated by further issues introduced through the tissue biomechanical properties. In creating canonical models by leveraging advances in clinical imaging techniques, the automated design procedure makes VF modeling based on subject-specific geometry more realizable. PMID- 22209064 TI - Radiofrequency assisted liver resection: analysis of 604 consecutive cases. AB - BACKGROUND: Intraoperative blood loss is an important factor contributing to morbidity and mortality in liver surgery. To address this we developed a bipolar radiofrequency (RF) device, the Habib 4X, used specifically for hepatic parenchymal transection. The aim of this study was to prospectively assess the peri-operative data using this technique. METHODS: Between 2001 and 2010, 604 consecutive patients underwent liver resections with the RF assisted technique. Clinico-pathological and outcome data were collected and analysed. RESULTS: There were 206 major and 398 minor hepatectomies. Median intraoperative blood loss was 155 (range 0-4300)ml, with a 12.6% rate of transfusion. There were 142 patients (23.5%) with postoperative complications; none had bleeding from the resection margin. Only one patient developed liver failure and the mortality rate was 1.8%. CONCLUSIONS: RF assisted liver resection allows major and minor hepatectomies to be performed with minimal blood loss, low blood transfusion requirements, and reduced mortality and morbidity rates. PMID- 22209065 TI - Decreased vascular endothelial growth factor response to acute hypoglycemia in type 2 diabetic patients with hypoglycemic coma. AB - INTRODUCTION: Plasma vascular endothelial growth factor (VEGF) was shown to increase during acute hypoglycemia and could mediate rapid adaptation of the brain. In this study we examined the neuroendocrine response in patients with type 2 diabetes mellitus (T2DM) in hypoglycemic coma or with acute neuroglycopenic symptoms. METHODS: We prospectively studied 135 consecutive T2DM patients admitted for severe hypoglycemia during a 2-year period. We collected clinical variables and measured plasma concentrations of VEGF, epinephrine, norepinephrine, cortisol and growth hormone at admission and 30min afterwards. RESULTS: Thirty two patients developed hypoglycemic coma and 103 did not lose consciousness. Median plasma VEGF level of coma patients was 3.1-fold lower at baseline than that of non-coma patients, and even 5.3-fold lower 30min afterwards. Plasma epinephrine concentration was significantly lower just at baseline in coma patients. On the contrary, there were no differences in concentrations of the other hormones. Multivariate logistic regression analysis showed that VEGF concentration (OR 0.68; CI 0.51-0.95) was a protective factor against the development of coma. CONCLUSIONS: VEGF and epinephrine responses to acute hypoglycemia are reduced in T2DM patients who develop hypoglycemic coma. An increased plasma VEGF concentration appeared to be a protective factor against the development of hypoglycemic coma. PMID- 22209066 TI - Are blood investigations, or group and save, required before orthognathic surgery? AB - Most patients who require orthognathic surgery are young patients of American Society of Anesthesiologists' (ASA) grade I, and current publications recommend a policy of group and save, with antibody screening for all such patients. We retrospectively studied 284 patients who had orthognathic procedures over a 5 year period at one hospital. We identified patients with a history of bleeding disorders, and those with abnormal coagulation. No blood transfusions were required for any patient, and abnormal coagulation screens in patients with no history of bleeding disorders made no difference to perioperative medical or surgical management. We therefore recommend that grouping and saving blood with antibody or coagulation screening are not necessary before orthognathic operations in ASA grade I patients who have no history of bleeding disorders or previous blood transfusion. However, a routine full blood count should still be done, in keeping with the current National Institute for Clinical Excellence (NICE) guidelines. PMID- 22209067 TI - Ultrasensitive electrogenerated chemiluminescence biosensor for the determination of mercury ion incorporating G4 PAMAM dendrimer and Hg(II)-specific oligonucleotide. AB - A novel electrogenerated chemiluminescence (ECL) biosensor for highly sensitive and selective detection of mercury ion was developed on the basis of mercury specific oligonucleotide (MSO) served as a molecular recognition element and the ruthenium(II) complex (Ru1) as an ECL emitting species. The biosensor was fabricated on a glassy carbon electrode coated with a thin layer of single wall carbon nanotubes, where the ECL probe, NH(2)-(CH(2))(6)-oligo(ethylene oxide)(6) MSO<->Dend-Ru1, was covalently attached. The Dend-Ru1 pendant was prepared by covalent coupling Ru1 with the 4th generation polyamidoamine dendrimer (Dend), in which each dendrimer contained 35 Ru1 units so that a large amplification of ECL signal was obtained. Upon binding of Hg(2+) to thymine (T) bases of the MSO, the T-Hg-T structure was formed, and the MSO changed from its linear shape to a "hairpin" configuration. Consequently, the Dend-Ru1 approached the electrode surface resulting in the increase of anodic ECL signal in the presence of the ECL coreactant tri-n-propylamine. The reported biosensor showed a high reproducibility and possessed long-term storage stability (92.3% initial ECL recovery over 30 day's storage). An extremely low detection limit of 2.4 pM and a large dynamic range of 7.0 pM to 50 nM Hg(2+) were obtained. An apparent binding constant of 1.6 * 10(9)M(-1) between Hg(2+) and the MSO was estimated using an ECL based extended Langmuir isotherm approach involving multilayer adsorption. Determination of Hg(2+) contents in real water samples was conducted and the data were consistent with the results from cold vapor atomic fluorescence spectroscopy. PMID- 22209068 TI - Layer-by-layer self-assembly of functionalized graphene nanoplates for glucose sensing in vivo integrated with on-line microdialysis system. AB - In this work, a novel amperometric biosensor for hydrogen peroxide was fabricated through the layer-by-layer (LBL) self-assembling of amine-terminated ionic liquid (IL-NH(2)), and sulfonic acid (SO(3)(-)) functionalized graphene by covalent bonding. The modification of the two functionalities introduced positive and negative charge onto the surface of graphene respectively, thus facilitating the formation of a multilayer film denoted with {IL-RGO/S-RGO}(n) through electrostatic interaction and further immobilization of glucose oxidase (GOx). The resulting {IL-RGO/S-RGO}(n)/GOx/Nafion biosensor displayed an excellent response to glucose at a potential of -200 mV. Combined with on-line microdialysis system, the glucose biosensor in the on-line system showed good linear range from 10 MUM to 500 MUM with the detection limit of 3.33 MUM (S/N=3). Consequently, the basal level of glucose in the striatum of anesthetic rats was calculated to be 0.376 +/- 0.028 mM (mean +/- s.d., n=3). The {IL-RGO/S RGO}(n)/GOx/Nafion biosensor was further applied for in vivo sensing of the glucose level in the striatum when rats received intraperitoneal (i.p.) injection of 30 MUL insulin, which resulted in an obvious decrease in the extracellular concentration of glucose within 30 min. The method was proved to be sensitive and reproducible, which enabled its promising application in physiology and pathology. PMID- 22209069 TI - A cost-effective and field-ready potentiostat that poises subsurface electrodes to monitor bacterial respiration. AB - Here, we present the proof-of-concept for a subsurface bioelectrochemical system (BES)-based biosensor capable of monitoring microbial respiration that occurs through exocellular electron transfer. This system includes our open-source design of a three-channel microcontroller-unit (MCU)-based potentiostat that is capable of chronoamperometry, which laboratory tests showed to be accurate within 0.95 +/- 0.58% (95% Confidence Limit) of a commercial potentiostat. The potentiostat design is freely available online: http://angenent.bee.cornell.edu/potentiostat.html. This robust and field-ready potentiostat, which can withstand temperatures of -30 degrees C, can be manufactured at relatively low cost ($600), thus, allowing for en-masse deployment at field sites. The MCU-based potentiostat was integrated with electrodes and a solar panel-based power system, and deployed as a biosensor to monitor microbial respiration in drained thaw lake basins outside Barrow, AK. At three different depths, the working electrode of a microbial three-electrode system (M3C) was maintained at potentials corresponding to the microbial reduction of iron(III) compounds and humic acids. Thereby, the working electrode mimics these compounds and is used by certain microbes as an electron acceptor. The sensors revealed daily cycles in microbial respiration. In the medium- and deep-depth electrodes the onset of these cycles followed a considerable increase in overall activity that corresponded to those soils reaching temperatures conducive to microbial activity as the summer thaw progressed. The BES biosensor is a valuable tool for studying microbial activity in situ in remote environments, and the cost-efficient design of the potentiostat allows for wide scale use in remote areas. PMID- 22209070 TI - Electrochemistry of Escherichia coli JM109: direct electron transfer and antibiotic resistance. AB - In this study, the cyclic voltammetry (CV) and square wave voltammetry (SWV) techniques were used to investigate the extracellular electron transfer from Escherichia coli JM109. It was demonstrated that the formal redox potential of direct electron transfer between electrode and an E. coli JM109 cell in aerobic buffer corresponds to -0.42 V vs. Ag/AgCl. Based on the electroactivity of bacterial cells, the electrochemical system for definition of sensitivity of microbiological material to antibiotics cefepime, ampicillin, amikacin, and erythromycin was proposed. The results obtained indicate that with electrochemical methods it is possible to provide screening of potential drugs for bacterial diseases. The electrochemical method allows estimating the degree of E. coli JM109 cells resistance to antibiotics within 2-5h using disposable screen-printed graphite electrodes. PMID- 22209071 TI - A polycarbonate based surface plasmon resonance sensing cartridge for high sensitivity HBV loop-mediated isothermal amplification. AB - In this study, we report a simple, low-cost surface plasmon resonance (SPR) sensing cartridge based on a loop-mediated isothermal amplification (LAMP) method for the on-site detection of the hepatitis B virus (HBV). For LAMP detection, a SPR based LAMP sensing system (SPRLAMP) was constructed, including a novel SPRLAMP sensing cartridge integrating a polymethyl methacrylate (PMMA) micro reactor with a polycarbonate (PC)-based prism coated with a 50 nm Au film. First, we found that the change of refractive index of the bulk solution was approximately 0.0011 refractive index (RI) units after LAMP reaction. The PC based prism's linearity and thermal responses were compared to those of a traditional glass prism to show that a PC-based prism can be used for SPR measurement. Finally, the HBV template mixed in the 10 MUl LAMP solution could be detected by SPRLAMP system in 17 min even at the detection-limited concentration of 2 fg/ml. We also analyzed the correlation coefficients between the initial concentrations of HBV DNA templates and the system response (DeltaRU) at varying amplification times to establish an optimal amplification time endpoint of 25 min (R(2)=0.98). In conclusion, the LAMP reaction could be detected with the SPRLAMP sensing cartridge based on direct sensing of the bulk refractive index. PMID- 22209072 TI - Evaluation of peripheral blood basophil activation by means of surface plasmon resonance imaging. AB - Basophil activation in response to antigen may represent specificities of type I allergy of individuals and their reactions in the body. We previously demonstrated that surface plasmon resonance (SPR) sensor could detect the activation of human basophils in response to antigens. In this study, we further developed a technique based on SPR imaging (SPRI) system to detect reactions of individual basophils isolated from human blood, and investigated the potential of this sensor as a tool for diagnosis of type I allergy. To detect the change of refractive index (RI) in individual basophils, human basophils were isolated by negative selection with antibodies conjugated with magnetic beads, fixed on a gold film with anti-basophil antibody and stimulated with various antigens under the measurement of SPRI. The sensor could detect the reactions of individual basophils in response to specific antigens as well as non-specific activators. Moreover, the sensor well allocated two spots of basophils on a sensor chip and detected individual reactions to antigen. Thus, the technique developed in this study can visualize the effect of various stimuli or inhibitors on basophils as change of intracellular RI distribution at the single cell level. In combination with a device to rapidly isolate basophils from peripheral blood, this technique may be a useful tool as a high throughput screening system in clinical diagnosis for type I allergy. PMID- 22209073 TI - Selective electrochemical detection of cysteine in complex serum by graphene nanoribbon. AB - Selective detection of cysteine in serum samples was achieved on a graphene nanoribbon (GNR) and Nafion nanocomposite modified electrode with high precision. The superior conductivity and abundant amount of active chemical oxygen groups on the edge of GNR led to extremely highly electrocatalytic activity of GNR towards the electrochemical oxidation of cysteine at +0.025 V. The electrocatalytic behavior was further used for sensitive detection of cysteine by differential pulse voltammetry. Under optimized conditions, the calibration curve was linear in the range from 25 nM to 500 MUM. The electrochemical sensor showed strong antifouling ability, good stability and selectivity. It could effectively exclude the interferences from other kinds of biothiols and the biological relevant species, thus had great perspective for in vivo analysis of biological samples. PMID- 22209074 TI - Ferrocene-functionalized SWCNT for electrochemical detection of T4 polynucleotide kinase activity. AB - A novel electrochemical strategy for monitoring the activity and inhibition of T4 polynucleotide kinase (PNK) is developed by use of titanium ion (Ti(4+)) mediated signal transition coupled with signal amplification of single wall carbon nanotubes (SWCNTs). In this method, a DNA containing 5'-hydroxyl group is self assembled onto the gold electrode and used as substrate for PNK. The biofunctionalized SWCNTs with anchor DNA and ferrocene are chosen as the signal indicator by virtue of the intrinsic 5'-phosphate end of anchor DNA and the high loading of ferrocene for electrochemical signal generation and amplification. The 5'-hydroxyl group of the substrate DNA on the electrode is phosphorylated by T4 PNK in the presence of ATP, and the resulting 5'-phosphoryl end product can be linked with the signal indicator by Ti(4+). The redox ferrocene group on the SWCNTs is grafted to the electrode and generates the electrochemical signal, the intensity of which is proportional to the activity of T4 PNK. This assay can measure activity of T4 PNK down to 0.01 UmL(-1). The developed method is a potentially useful tool in researching the interactions between proteins and nucleic acids and provides a diversified platform for a kinase activity assay. PMID- 22209076 TI - Phase II study on combination therapy with CHOP-Zenapax for HTLV-I associated adult T-cell leukaemia/lymphoma (ATLL). AB - Adult T-cell leukaemia lymphoma (ATLL) is an aggressive T-cell malignancy caused by the human T-lymphotropic virus type-1 (HTLV-1) and is associated with a very poor prognosis. Combination chemotherapy has had little impact on the long term survival of these patients. ATLL cells are characterised by the expression of CD25 (IL-2Ralpha), which is not expressed in normal resting T-cells. Daclizumab (Zenapax((r))) is a humanised murine anti-CD25 monoclonal antibody, which contains 10% murine CDR sequences. In this prospective trial 15 patients with aggressive ATLL were treated with CHOP-Zenapax (CHOP-Z) to determine the tolerability and feasibility of this novel regimen as well as evaluate its efficacy. Eleven patients had acute ATLL and four had the lymphoma subtype. The main presenting features were elevated LDH (100%), lymphocytosis (73%), lymphadenopathy (67%), skin lesions (40%), hypercalcaemia (53%), and hepato splenomegaly (27%). Ten (67%) patients received the six scheduled cycles. Complete response (CR) lasting for two months or more was seen in 5 (33%), partial response in 3 (20%), minor response in 1 (7%), and no response in 6 (40%) patients. The median overall survival was 10 months (95% CI: 0.05-20.88) but this was significantly longer among responders (18 months) compared to non responders (3 months) (P = 0.019). For patients who achieved CR the disease free survival (DFS) was 15 months while the event-free survival (EFS) was 5 months. In conclusion CHOP-Z is safe and in those who achieve a complete response it was associated with prolonged overall survival. PMID- 22209075 TI - Assembly of Drosophila centromeric nucleosomes requires CID dimerization. AB - Centromeres are essential chromosomal regions required for kinetochore assembly and chromosome segregation. The composition and organization of centromeric nucleosomes containing the essential histone H3 variant CENP-A (CID in Drosophila) is a fundamental, unresolved issue. Using immunoprecipitation of CID mononucleosomes and cysteine crosslinking, we demonstrate that centromeric nucleosomes contain CID dimers in vivo. Furthermore, CID dimerization and centromeric targeting require a residue implicated in formation of the four-helix bundle, which mediates intranucleosomal H3 dimerization and nucleosome integrity. Taken together, our findings suggest that CID nucleosomes are octameric in vivo and that CID dimerization is essential for correct centromere assembly. PMID- 22209077 TI - Acquired visual field defects rehabilitation: critical review and perspectives. AB - Visual field deficit (VFD) is one of the most commonly observed symptoms following brain injury. Persistent VFD and defective exploratory oculomotor scanning patterns often cause severe impairment in daily activities, particularly as regards visual exploration and reading. Homonymous hemianopia is consequently a powerful negative predictor of patient outcome. In spite of these quantitative and qualitative factors, there currently exists no consensus on rehabilitative therapy and treatment. Different approaches have nevertheless been developed, all of them having one therapeutic principle in common; repeated practice of a specific visual task, with the hope/expectation that improved performance will extend to a wide range of ecologically useful visual functions. The four main available methods aim at replacing part of the intact visual field with part of the damaged visual field (optical therapy using prisms), at partially restoring the lost visual field region (restorative therapies), at stimulating detection capacities in the blind field (stimulation or blindsight) or at substituting for the lost region by reorganizing the control of visual information processing and eye movements (compensatory therapies). This review explores the key data relative to these different approaches in terms of behavioral or imagery results. It also aims at critically analyzing the advantages and limits of each one. The importance of strict assessment in terms of deficiencies or disabilities is underlined. Finally, upon consideration of these data taken as a whole, it is suggested that efficient treatment would probably have to associate general components and more specific elements, according to what may be done with regard to other aspects of cognitive rehabilitation. PMID- 22209078 TI - Overplaying the role of honey bees as pollinators: a comment on Aebi and Neumann (2011). PMID- 22209079 TI - Targeting TNF superfamily members for therapeutic intervention in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an inflammatory disease is one of the most serious medical problems, affecting ~1% of all people worldwide, irrespective of race. The disease is autoimmune in nature and characterized by chronic inflammation of the synovial tissues in multiple joints that leads to joint destruction. Although T cells are central players in RA development, B cells are required for full penetrance of disease largely via their production of autoantibodies against Fc domain of IgG rheumatoid factor (RF). Treatment options for RA are limited and if any, are inadequate due to associated side effects. Members of the tumor necrosis factor (TNF) superfamily play important roles in a number of autoimmune diseases, including RA. In this review, we briefly summarize key features of the superfamily, we will consider how the well-characterized members concerned with immune regulation are coordinated and their roles in rheumatoid arthritis. PMID- 22209080 TI - Elevated urinary sVCAM-1, IL6, sIL6R and TNFR1 concentrations indicate acute kidney transplant rejection in the first 2 weeks after transplantation. AB - We tested the hypothesis that increased urinary cytokine concentrations may indicate an acute kidney transplant rejection. Eight patients with an early rejection in their protocol biopsy about 14days after transplantation (group A), 9 patients with a biopsy proven rejection 2-3months after transplantation (group B) and 18 patients without acute rejection in their protocol biopsies both at 14days and 3months (group C, represents the control group) were chosen for this study. At the time of biopsy, the mean urinary concentration of interleukin 6 (IL6), soluble IL6 receptor (sIL6R), tumor necrosis factor receptor 1 (TNFR1), and soluble vascular cell adhesion molecule -1 (sVCAM-1) were significantly higher in patients with an early acute transplant rejection, i.e. in group A compared to patients in the control group (p<0.01). Additionally we found already 14days after transplantation significantly higher concentrations of urinary sIL6R and sVCAM-1 in group B patients who suffered of late acute rejection compared to patients with no acute rejection (group C, p<0.05). No significant correlation could be shown for interleukin 1 receptor antagonist (IL1ra), TNF, and TNFR2. In conclusion, elevated urinary concentrations of IL6, sIL6R, TNFR1 and sVCAM-1 clearly indicate an early acute transplant rejection. Especially sVCAM-1 may also serve as an early marker of an upcoming late rejection. However, further studies are warranted to verify the value of individual cytokine profiles to predict acute rejection episodes. PMID- 22209081 TI - Acute phase proteins in healthy and sick cats. AB - Serum acute phase protein concentrations are used as diagnostic, therapeutic and prognostic markers in human and, less frequently, in animal medicine. The aim of this study was to determine how the health status and signalment of the cat are associated with concentrations of acute phase proteins. Generally, medians of the positive acute phase proteins appeared to be higher in sick cats compared to healthy cats. In multivariable regression models, log-transformed serum amyloid A concentration was higher in older cats, in sick and in female cats, while log transformed alpha1-acid glycoprotein and haptoglobin concentrations were higher in older cats and were associated with interactions of health status (sick/healthy) and gender (male/female). The data from healthy cats in this study contribute to the limited knowledge of normal reference ranges for this species. This study highlights the potential of acute phase proteins as diagnostic markers in sick cats, but also emphasises that the signalment of the cat needs to be taken into consideration. PMID- 22209082 TI - Transabdominal ultrasonographic appearance of the gastrointestinal viscera of healthy camels (Camelus dromedaries). AB - The purpose of this study was to describe the ultrasonographic picture of the gastrointestinal tract in healthy camels (Camelus dromedarius). For this purpose, 22 camels were examined. The rumen and its glandular sacs were filling most of the left side of the abdomen. The rumen wall was smooth and echogenic. The ventral part of the reticulum could be best imaged in 17 (77%) camels from the left and right paramedian region just behind to the sternal pad. The reticulum in these animals had a thick wall (1.17+/-0.27 cm) that appeared as a half-moon shaped structure with a biphasic contraction. The omasum was best viewed through the right 8th to 6th intercostal spaces in 18 (82%) camels. In the remaining 4 (18%), it was visualized through four consecutive intercostal spaces (right 9th to 6th). It had a wall thickness of 1.1+/-0.7 cm and a transverse diameter of 8.74+/-3.4 cm. The abomasum could be best visualized from the right 9th and 8th intercostal spaces in 14 (64%) camels, while it was observed in the 9th intercostal space in 3 (14%) animals and in the 8th and 7th intercostal space in 5 (22%) camels. Small intestinal structures were best seen low in the right paralumbar fossa. It was thin-walled (0.43+/-0.14 cm) and had a diameter of 2.62+/-0.47 cm. The cecum was imaged chiefly in the caudal right flank. It was thin-walled (0.37+/-0.05 cm), had a diameter of 13.8+/-1.6 cm. The proximal loop of the large colon appeared as thick, echogenic, continuous and slightly curved lines. It was thin-walled (0.51+/-0.08 cm) and had a diameter of 3.5+/-0.8 cm. The spiral colon was confined in all camels to the caudal ventral half of the abdomen. It appeared as structures with thick echoic lateral walls with a number of echogenic arched lines next to each other. Free peritoneal fluid pockets were imaged in two locations in 19 (86%) camels. Ultrasound-guided abdominocentesis was successful in 15 (68%) of the examined camels. This study provides the ultrasonographic appearance of the normal gastrointestinal tract in healthy camels that could be used as a reference for the interpretation of suspected digestive abnormalities. PMID- 22209083 TI - Ultrastructure of Amoebophrya sp. and its changes during the course of infection. AB - Amoebophrya is a syndinian parasite that kills harmful bloom forming algae. Previously uncharacterized ultrastructural aspects of infection and development were elucidated. The biflagellate dinospore has two mitochondria, electron-dense bodies, striated strips, trichocysts, and a nucleus with peripherally condensed chromatin. After finding an Akashiwo sanguinea host and adhering to its surface, the parasite penetrates the host surface, apparently using a microfilament based motility and electron-dense bodies within a microtubular basket in the process of parasitophorous vacuole membrane formation. After entering the host nucleus, possibly by a similar mechanism used to enter the host cell, the parasite cytosol expanded substantially prior to mitosis. From 12-36 hours mitochondria were inconspicuous but present. Chromatin condensation was variable. By 36 hours post infection, parasites had multiple nuclei, a microtubule-supported cytopharynx, and were beginning to form a fully internal mastigocoel. By 48 hours, the characteristic "beehive" appearance was apparent with flagella projecting into a fully developed mastigocoel. The cytoplasm contained trichocysts, elongated mitochondria, and nuclei with peripherally condensed chromatin. Although Amoebophrya lacks an apical complex, its electron-dense bodies show functional similarities to apicomplexan rhoptries. Its lack of permanently condensed chromosomes, but compact dinospore chromatin, supports the idea that dinoflagellate permanently condensed chromosomes may be a remnant of a parasitic ancestor with a compact dispersal stage. PMID- 22209084 TI - The role of cortisol in PTSD among women exposed to a trauma-related stressor. AB - Research linking post-traumatic stress disorder (PTSD) to hypercortisolism in laboratory experiments was extended to a natural clinical setting. Mothers of children diagnosed with a life-threatening illness (N = 92) completed standardized measures of PTSD and provided a salivary cortisol sample during their child's medical check-up (Time 1) and again 24h later, after the threat of possible negative medical reports was removed (Time 2). Women who met diagnostic criteria for PTSD exhibited significantly higher cortisol levels at Time 1 compared to women who did not meet criteria for a diagnosis. No significant differences were observed for cortisol levels at Time 2 between the women with and without PTSD. These findings extend current laboratory findings linking hypercortisolism and PTSD to a natural, stressful situation. Implications for understanding the etiology of PTSD as well as for possible prevention and intervention options are discussed. PMID- 22209086 TI - Asymptomatic chronic partial obstruction of a normal ureter following dextranomer/hyaluronic acid copolymer (Deflux(r)) injection for grade I vesicoureteral reflux. AB - Endoscopic management of vesicoureteral reflux with dextranomer/hyaluronic copolymer (Deflux((r)), Oceana Therapeutics, Inc., Edison, NJ, USA) has gained widespread acceptance with increasing success rates and minimal morbidity. Formation of a pseudocapsule and calcification are known histologic changes at the injection site. Postoperative ureteral obstruction has been reported in cases of severe voiding dysfunction, neurogenic bladder and abnormal ureteral anatomy. We present a case of chronic asymptomatic obstruction in a normal ureter following injection of 0.7 ml Deflux. PMID- 22209085 TI - The bacterial chemical repertoire mediates metabolic exchange within gut microbiomes. AB - Microbial communities in the gut have been hypothesized to play key roles in the health of the host organism. Exploring the relationship between these populations and disease states has been a focus of the human microbiome project. However, the biological roles of the compounds produced by the gut bacteria are largely unknown. We hypothesize that these compounds act as metabolic exchange factors mediating inter-species and intra-species interactions in the microbiome. This view is supported through this review of known bacterial metabolic exchange factors and evidence for uncharacterized metabolic exchange factors in the gut. The impact of model systems and technological developments in exploring this hypothesis are also discussed. Together, these investigations are revolutionizing our understanding of the gut microbiome-presenting the possibility of identifying new strategies for treating disease in the host. PMID- 22209087 TI - Analysis of genes regulated by the transcription factor LUMAN identifies ApoA4 as a target gene in dendritic cells. AB - Dendritic cells (DCs) are professional antigen presenting cells of the immune system that play a crucial role in initiating immune responses and maintaining self tolerance. Better understanding of the molecular basis of DC immunobiology is required to improve DC-based immunotherapies. We previously described the interaction of transcription factor LUMAN (also known as CREB3 or LZIP) with the DC-specific transmembrane protein DC-STAMP in DCs. Target genes of LUMAN and its role in DCs are currently unknown. In this study we set out to identify genes regulated by LUMAN in DCs using microarray analysis. Expression of a constitutively active form of LUMAN in mouse DC cell line D2SC/1 identified Apolipoprotein A4 (ApoA4) as its target gene. Subsequent validation experiments, bioinformatics-based promoter analysis, and silencing studies confirmed that ApoA4 is a true target gene of LUMAN in bone marrow-derived DCs (BMDCs). PMID- 22209088 TI - Near-field beamforming analysis for acoustic emission source localization. AB - This paper attempts to introduce a near-field acoustic emission (AE) beamforming method to estimate the AE source locations by using a small array of sensors closely placed in a local region. The propagation characteristics of AE signals are investigated based on guided wave theory to discuss the feasibility of using beamforming techniques in AE signal processing. To validate the effectiveness of the AE beamforming method, a series of pencil lead break tests at various regions of a thin steel plate are conducted. The potential of this method for engineering applications are explored through rotor-stator rubbing tests. The experimental results demonstrate that the proposed method can effectively determine the region where rubbing occurs. It is expected that the work of this paper may provide a helpful analysis tool for near-field AE source localization. PMID- 22209089 TI - Ultrasonic backscattering in polycrystals with elongated single phase and duplex microstructures. AB - An analytical solution for a three dimensional integral representation of the backscattering (BS) coefficient in polycrystals with elongated (generally ellipsoidal) grains is obtained; it is a natural generalization of the known explicit result for the BS coefficient in polycrystals with spherical grains. New insights into the dependence of the BS signal on frequency and averaged ellipsoidal grain radii are obtained. In particular it has been shown that the dominant factor for the backscattering is the averaged interaction length of the ellipsoidal grain in the direction of wave propagation, instead of the ellipsoidal cross-section. The theory was applied to a simplified model of Ti alloy duplex microstructure and was compared with experiment. For the experimental data analysis directional backscattering ratios are introduced and shown to be advantageous for characterization of duplex elongated microstructures/microtextures. In addition to the geometrical parameters of the elongated microtextures, the BS directional ratios depend on the newly introduced nondimensional material parameter q. The parameter q exhibits the relative contribution of the second phase (crystallites) to the backscattering signal, the effect of which is measurable and important. Comparison of the model with experiment shows there is a significant advantage in using the directional ratios of backscattering coefficients for data analysis. PMID- 22209090 TI - Evidence for elevated cortical hyperexcitability and its association with out-of body experiences in the non-clinical population: new findings from a pattern glare task. AB - Individuals with no history of neurological or psychiatric illness can report hallucinatory Out-of-Body Experiences (OBEs) and display elevated scores on measures of temporal-lobe dysfunction (Braithwaite et al., 2011). However, all previous investigations of such biases in non-clinical populations are based on indirect questionnaire measures. Here we present the first empirical investigation that a non-clinical OBE group is subject to pattern-glare, possibly as a result of cortical hyperexcitability (Wilkins et al., 1984). Fifty-nine students at the University of Birmingham viewed a series of square-wave gratings with spatial frequencies of approximately .7, 3 and 11 cycles-per-degree, both black/white and of contrasting colours. The illusions and discomfort reported when viewing gratings with mid-range spatial frequency have been hypothesized to reflect cortical hyperexcitability (Wilkins, 1995; Huang et al., 2003). Participants also completed the Cardiff Anomalous Perception Scale (CAPS: Bell et al., 2006) which included experiential measures of disruptions in 'Temporal-lobe Experience'. Participants who reported OBEs also reported significantly more visual illusions/distortions and significantly greater discomfort as a result of viewing the mid-frequency gratings. There were no such differences with respect to gratings with relatively lower or higher spatial frequency. The OBE group also produced significantly elevated scores on the CAPS measures of Temporal-lobe Experience, relative to controls. Collectively, the results are consistent with there being a neural 'vulnerability' in the cortices of individuals pre-disposed to some hallucinations, even in the non-clinical population. PMID- 22209091 TI - A comparison of syringe disposal practices among injection drug users in a city with versus a city without needle and syringe programs. AB - BACKGROUND: The United States (U.S.) approved use of federal funds for needle and syringe programs (NSPs) in December 2009. This study compares syringe disposal practices in a U.S. city with NSPs to a U.S. city without NSPs by examining the prevalence of improperly discarded syringes in public places and the self reported syringe disposal practices of injection drug users (IDUs) in the two cities. METHODS: We conducted visual inspection walkthroughs in a random sample of the top-quartile of drug-affected neighborhoods in San Francisco, California (a city with NSPs) and Miami, Florida (a city without NSPs). We also conducted quantitative interviews with adult IDUs in San Francisco (N=602) and Miami (N=448). RESULTS: In the visual inspections, we found 44 syringes/1000 census blocks in San Francisco, and 371 syringes/1000 census blocks in Miami. Survey results showed that in San Francisco 13% of syringes IDUs reported using in the 30 days preceding the study interviews were disposed of improperly versus 95% of syringes by IDUs in Miami. In multivariable logistic regression analysis, IDUs in Miami had over 34 times the adjusted odds of public syringe disposal relative to IDUs in San Francisco (adjusted odds ratio=34.2, 95% CI=21.92, 53.47). CONCLUSIONS: We found eight-fold more improperly disposed syringes on walkthroughs in the city without NSPs compared to the city with NSPs, which was corroborated by survey data. NSPs may help IDUs dispose of their syringes safely in cities with large numbers of IDUs. PMID- 22209092 TI - Fluorescence lifetime imaging of E-combretastatin uptake and distribution in live mammalian cells. AB - To investigate within live mammalian cells the uptake and disposition of combretastatins, fluorescence lifetime imaging was used with two-photon excitation (2PE). Combretastatin A4 (CA4) and analogues are potential anticancer drugs due to their ability to inhibit angiogenesis. E(trans)-combretastatins are considerably less active than the Z(cis)-combretastatins proposed for clinical use. However the E-combretastatins exhibit stronger intrinsic fluorescence with quantum yields and lifetimes that depend markedly on solvent polarity and viscosity. It is proposed that 2PE in the red and near-infrared tissue window may allow in situ isomerization of E-combretastatins to the more active Z-isomer, offering spatial and temporal control of drug activation and constitute a novel form of photodynamic therapy. In the present work we have characterised 2PE of E CA4 and have used fluorescence lifetime imaging with 2PE to study uptake and intracellular disposition of E-CA4 and an analogue. The results show that these molecules accumulate rapidly in cells and are located mainly in lipidic environments such as lipid droplets. Within the droplets the local concentrations may be up to two orders of magnitude higher than that of the drug in the surrounding medium. PMID- 22209093 TI - Effect of heat treatment on protein oxidation in pig meat. AB - We investigated the oxidative mechanisms and identified the target protein induced by heat treatment. The study was carried out on M. longissimus thoracis from Galia and Redone pigs. Post mortem metabolic parameters and drip loss were determined. Heat treatment was performed at 100 degrees C for 10 and 30 min. Physicochemical state of the protein, TBA-RS and Schiff bases were assessed. Protein aggregates were evaluated and the protein target of oxidation studied. Muscles from Galia had higher residual glycogen and drip loss. Heat treatment increased surface hydrophobicity, carbonyl, protein aggregate and Schiff bases and TBA-RS whatever the treatment time. Immunoblotting revealed oxidized myosin, oxidized actin and high molecular weight proteins after 30 min cooking. Oxidation products were significantly correlated with drip loss, suggesting a possible reduced ability of oxidized proteins to retain water. Moreover, residual glycogen was positively correlated with oxidized myosin, suggesting a possible role of glycogen as a glucose donor. PMID- 22209094 TI - Space, time, form: viewing the Tree of Life. AB - There are numerous ways to display a phylogenetic tree, which is reflected in the diversity of software tools available to phylogenetists. Displaying very large trees continues to be a challenge, made ever harder as increasing computing power enables researchers to construct ever-larger trees. At the same time, computing technology is enabling novel visualisations, ranging from geophylogenies embedded on digital globes to touch-screen interfaces that enable greater interaction with evolutionary trees. In this review, I survey recent developments in phylogenetic visualisation, highlighting successful (and less successful) approaches and sketching some future directions. PMID- 22209095 TI - Characterization of D-3-hydroxybutyrylcarnitine (ketocarnitine): an identified ketosis-induced metabolite. AB - Hydroxybutyrylcarnitine (HB-carnitine) is a metabolite that has been associated with insulin resistance and type 2 diabetes mellitus. It is currently unknown whether HB-carnitine can be produced from D-3-hydroxybutyrate (D-3HB), a ketone body; but its formation from L-3-HB-CoA, a fatty acid beta-oxidation intermediate, is well established. We aimed to assess which stereoisomers of 3-HB carnitine are present in vivo. Ketosis and increased fatty acid oxidation were induced in 12 lean healthy men by a 38-hour fasting period. The D-3HB kinetics (stable isotope technique) and stereoisomers of muscle 3-HB-carnitine (high performance liquid chromatography/ultra-performance liquid chromatography-tandem mass spectrometry) were measured. Muscle D-3HB-carnitine content was much higher compared with L-3HB-carnitine. In addition, muscle D-3HB-carnitine correlated significantly with D-3-HB production. Following the finding that a ketone body can be converted into a carnitine ester in vivo, we show in vitro that D-3-HB can be converted into HB-carnitine (ketocarnitine) via an acyl-CoA synthetase reaction in several tissues including human muscle. During fasting, HB-carnitine in muscle is derived mainly from the ketone body D-3HB. The role of D-3HB carnitine synthesis in metabolism remains to be elucidated. PMID- 22209096 TI - Where do youth in foster care receive information about preventing unplanned pregnancy and sexually transmitted infections? AB - Adolescents in foster care are at risk for unplanned pregnancy and sexually transmitted infections, including HIV infection. A study using a qualitative method was conducted to describe how and where foster youth receive reproductive health and risk reduction information to prevent pregnancy and sexually transmitted infections. Participants also were asked to describe their relationship with their primary health care provider while they were in foster care. Nineteen young adults, recently emancipated from foster care, participated in individual interviews. Using grounded theory as the method of analysis, three thematic categories were generated: discomfort visiting and disclosing, receiving and not receiving the bare essentials, and learning prevention from community others. Recommendations include primary health care providers providing a confidential space for foster youth to disclose sexual activity and more opportunities for foster youth to receive reproductive and risk prevention information in the school setting. PMID- 22209098 TI - Spindle cell lymphoma of the oral cavity: a case report and review of the literature. PMID- 22209097 TI - Sex differences in murine susceptibility to systemic viral infections. AB - Increased susceptibility to autoimmunity in females is often viewed as the consequence of enhanced immunoreactivity providing superior protection against infections. We paradoxically observed greater mortality in female compared to male mice during systemic viral infections with three large double-stranded DNA viruses (herpes simplex virus type I [HSV], murine cytomegalovirus [MCMV], and vaccinia virus [VV]). Indeed, female mice were 27-fold more susceptible to infection with HSV than male mice. Elimination of estrogen by ovariectomy in female mice or addition of estrogen to castrated male mice only partially eliminated the observed sex differences following HSV infection. However, the differences observed in survival between female and male mice were nearly abrogated in the absence of type I interferon receptor signaling and substantially mitigated in absence of DAP12 signaling. Interestingly, the sex specific impact of type I interferon receptor and DAP12 signaling differentially influenced survival during systemic viral infections with type I interferon receptor signaling enhancing male survival and DAP12 signaling increasing the susceptibility of female mice. These results have potential implications for the sex disparities observed in human autoimmune disorders. PMID- 22209099 TI - Myofibromas of the jaws in children. AB - PURPOSE: Controversy exists as to the most appropriate treatment strategy for myofibromas of the jaws: en bloc resection versus enucleation. The purpose of the present study was to evaluate the treatment outcomes in children with these uncommon benign tumors. MATERIALS AND METHODS: We performed a retrospective chart review of pediatric patients with jaw myofibromas. The predictor variables included patient demographics, clinical presentation, imaging characteristics, pathologic features, treatment, and follow-up. The outcome variable was cure or recurrence. The descriptive statistics were computed. RESULTS: A total of 12 patients (mean age 6.7 years) met the inclusion criteria. There were 2 presentations: exophytic soft tissue mass in dentoalveolar segment (n = 5); and intraosseous mass (n = 7). No distinct histopathologic differences were found between the 2 groups. Exophytic myofibromas displayed rapid growth, tooth displacement and/or mobility, bony expansion, and/or cortical thinning/perforation. Most were treated by resection. The intraosseous lesions were asymptomatic and/or incidentally discovered. They were treated by enucleation and curettage. The mean follow-up for the 2 groups was 6.5 and 3.9 years, respectively. There were no recurrences. CONCLUSIONS: The results of the present study indicate that there are 2 clinical presentations of myofibromas of the jaws in children: an aggressive exophytic type and a nonaggressive intraosseous type. They are histopathologically indistinguishable. PMID- 22209100 TI - Is lag screw fixation superior to plate fixation to treat fractures of the mandibular symphysis? AB - PURPOSE: The purpose of this investigation was to evaluate outcomes for patients treated with lag screw or plate and screw fixation for fractures of the mandibular symphysis. PATIENTS AND METHODS: The investigator implemented a retrospective cohort study and enrolled a sample of patients with symphysis fractures. The primary predictor variable was treatment group categorized as lag screw or plate fixation of the fracture. The primary outcome variables were postoperative complications. Other variables collected were grouped into demographic, anatomic, radiographic, and preoperative variables. Appropriate descriptive and bivariate statistics were computed and statistical significance was set at P < .05. RESULTS: Eight hundred eighty-seven patients met the inclusion criteria. Four hundred seventy-six were treated with bone plates and 411 were treated with lag screws. There were no significant differences in demographic data for the 2 groups. There were no statistically significant differences in occlusal or osseous healing outcomes. However, there were significant differences in treatment outcomes for several variables, including wound dehiscence, plate exposure, and the need for hardware removal between the groups. CONCLUSIONS: Plating and lag screw techniques showed very good outcomes. There were more intraoperative difficulties placing lag screws than bone plates, but the application of lag screws was associated with fewer postoperative complications. PMID- 22209101 TI - A study of epidemiologic and recurrence factors of oral cancer. AB - PURPOSE: To analyze the epidemiologic characteristics and recurrence factors of oral squamous cell carcinoma (OSCC) in northwest China. PATIENTS AND METHODS: Patients with OSCC whose first visits to the Stomatology Hospital of the Fourth Military Medical University from January 2007 through December 2008 were investigated. The epidemiologic risk factors and recurrence of OSCC were studied with logistic regression and a Cox regression model. RESULTS: The mean age of all 414 patients with OSCC was 58.16 +/- 9.92 years; 67.15% were men, 43.24% were cigarette smokers, and 26.09% came from rural areas. In addition, 49.03% of these patients were diagnosed at an early stage. One hundred forty-seven patients developed recurrence of the disease, and the median progression-free survival was 7.3 months (range, 1.1 to 32.5 mo). The recurrence rate was approximately 35.5%. CONCLUSION: The study indicated that smoking habit, older age, and living in rural areas were the high-risk epidemiologic factors for OSCC. Smoking habit and late clinical stage were the high-risk factors for the recurrence of OSCC. PMID- 22209102 TI - Clinical and dental computed tomographic evaluation 1 year after coronectomy. AB - PURPOSE: Coronectomy is performed when contact between the mandibular third molar apex and the inferior alveolar nerve is suspected. The efficacy of coronectomy compared with conventional tooth extraction has been recognized in recent years. However, few studies have reported the postoperative prognosis of roots remaining in the bone or surrounding tissue. Therefore, a clinical evaluation was performed with dental computed tomographic imaging of the coronectomy sites 1 year after the procedure. PATIENTS AND METHODS: This study investigated 101 patients (116 teeth) who underwent a coronectomy from March 2006 through December 2009. They were recalled 1 year later for a clinical evaluation and dental computed tomographic imaging of the coronectomy sites. The clinical evaluation was based on palpation and macroscopic findings. RESULTS: In 99.2% (115 teeth) of the studied cases, the soft tissue distal to the mandibular second molar was healthy and the retained roots were covered by bone. In 1 case (0.8%), an eruption of roots into the oral cavity was observed; however, no inflammation was observed in the nearby soft tissue. In all 116 teeth, no transmission images indicative of periapical lesions, which usually result from necrosis of the pulp, were observed in the apical area of the retained roots. CONCLUSIONS: The absence of transmission images indicative of periapical lesions and the presence of bone covering more than 99.2% (115 teeth) of the retained roots showed a safe postoperative course at the 1-year follow-up after coronectomy. PMID- 22209103 TI - Actinomycotic brain abscess and subdural empyema of odontogenic origin: case report and review of the literature. PMID- 22209104 TI - Operative management of temporomandibular joint ankylosis: a systematic review and meta-analysis. AB - PURPOSE: Two common treatments of temporomandibular joint ankylosis are gap arthroplasty and ankylosis resection and reconstruction of the ramus-condyle unit with a costochondral graft. The purpose of the present study was to answer the following clinical question: "Among patients with temporomandibular joint ankylosis, do those patients who undergo gap arthroplasty, compared with those who undergo ankylosis resection and ramus-condyle unit reconstruction with a costochondral graft have better postoperative mandibular range of motion?" METHODS: A systematic search of the published data was performed to identify eligible studies. The primary predictor variable was treatment type (ie, gap arthroplasty or ankylosis resection and ramus-condyle unit reconstruction). The main outcome was the change in maximal incisal opening postoperatively. A random effects model was used to compute the pooled weighted mean difference between the pre- and postoperative maximal incisal opening in both treatment groups. RESULTS: Four studies met the inclusion criteria. Those undergoing gap arthroplasty had a significantly greater maximal incisal opening than the group undergoing ankylosis resection and ramus-condyle unit reconstruction. The weighted mean difference between the 2 groups was 2.4 mm (95% confidence interval 0.9 to 4.0; P = .002). CONCLUSIONS: Subjects with temporomandibular joint ankylosis who underwent gap arthroplasty had significantly better postoperative maximal incisal opening than those undergoing ankylosis resection and ramus-condyle unit reconstruction with a costochondral graft. PMID- 22209105 TI - Long-term donor-site morbidity after microsurgical fibular graft: is there a difference between the medial approach and the lateral approach? AB - PURPOSE: Microvascular fibula harvesting for osseous reconstruction is a valuable aid in maxillofacial surgery. We assessed whether the lateral and the medial harvesting techniques differed with respect to long-term donor-site morbidity. MATERIALS AND METHODS: We conducted a retrospective cohort study of patients who had undergone free fibula harvesting at the University Medical Center Hamburg Eppendorf, Hamburg, Germany, between 1987 and 2008. The primary predictor variable was the surgical approach. The primary and secondary outcome variables were the American Orthopaedic Foot & Ankle Society score and the result of the Short Form 36 Health Survey on quality of life, respectively. Other variables were age, gender, harvest length, operation time, and specific impairments and surgical complications. Statistical analysis was performed with SPSS, version 14.0 (SPSS, Chicago, IL); P < .05 was considered significant. RESULTS: The 42 patients had a mean age of 55.5 years. The mean follow-up period was 81 months (range, 7-174 months). In the medial group, the mean American Orthopaedic Foot & Ankle Society score was 94.4 points and the total number of impairments was 34, as compared with 85.6 points and 46 impairments, respectively, in the lateral group. This tendency for less morbidity with the medial approach was only found in female patients. The Short Form 36 scores were not statistically different between the 2 surgical approaches. CONCLUSIONS: The medial approach led to less functional impairment of the foot and ankle. Our results support the medial approach as a viable alternative, especially in women, but only in cases when a skin paddle is not necessary. PMID- 22209106 TI - Commissural symmetry in unilateral transverse facial cleft patients: an anthropometric study. AB - PURPOSE: To evaluate the commissural symmetry and commissural migration among patients with unilateral transverse facial cleft. PATIENTS AND METHODS: From 2006 to 2009, 31 patients with unilateral transverse facial cleft were repaired with superiorly based vermillion-mucosal flap and orbicularis oris reconstruction. Linear closure and superiorly rotated and inferiorly rotated Z-plasty were randomly chosen for skin closure. An anthropometric method was used immediately after the repair and at the follow-up examination to evaluate the commissural symmetry in both horizontal and vertical directions. RESULTS: A total of 21 patients was followed-up for 19 months on average. Satisfactory horizontal symmetry was obtained right after surgery; however, the new commissure was generally lower than the unaffected commissure. At the follow-up examination, no significant lateral commissural displacement was observed; however, the commissural droop on the cleft side became more noticeable. CONCLUSIONS: The anthropometric method used was convenient and reliable for facial symmetry analysis. Rectangular vermillion-mucosal flap and proper muscle reconstruction could prevent the lateral commissural migration caused by skin scar contracture. Both horizontal and vertical symmetry should be considered for macrostomia repair. PMID- 22209107 TI - Reconstruction of alveolar defects using titanium-reinforced porous polyethylene as a containment device for recombinant human bone morphogenetic protein 2. AB - PURPOSE: The use of recombinant human bone morphogenetic protein 2 (rhBMP-2) in a collagen carrier is a proven alternative to autogenous bone grafting for certain cases. One of the principle limitations of rhBMP-2 at present, however, is the lack of a reliable rigid containment system to prevent soft tissue collapse of the collagen carrier sponge. The present case series describes the use of titanium-reinforced porous polyethylene as a containment device for rhBMP-2 grafted alveolar defects. PATIENTS AND METHODS: A case review was performed of 8 patients who had undergone rhBMP-2 bone grafting using porous polyethylene as the containment device. Eight maxillary and two mandibular alveolar defects were grafted using rhBMP-2 and titanium-reinforced porous polyethylene as a soft tissue barrier. One patient received autologous ramus bone in addition to the rhBMP-2. All patients were followed up by clinical examination and periodic radiographic studies for 6 months to 2 years. Implant-borne prostheses were fabricated on all successful grafts. RESULTS: Of the 10 grafted alveolar defects, 2 (20%) resulted in early exposure of the containment devices, were removed, and resulted in no bone formation. One of the 10 defects (10%) became exposed 3 months postoperatively and resulted in only moderate bone formation. In the 7 nonexposed cases (70%), bone formation was excellent, and implants were successfully placed. CONCLUSIONS: Titanium-reinforced porous polyethylene might be a useful alternative containment device for rhBMP-2-grafted alveolar defects. The exposure rate of 30% in the present case series is comparable to that for titanium alone. Modifications to the shape and thickness of the material might improve its use in alveolar reconstruction and further reduce the incidence of exposure. Further studies are needed; however, titanium-reinforced porous polyethylene could become a new addition to the armamentarium of clinicians grafting alveolar defects. PMID- 22209108 TI - Caldwell-Luc operation without inferior meatal antrostomy: a retrospective study of 50 cases. AB - PURPOSE: In the standard Caldwell-Luc operation, an inferior meatal antrostomy is performed to promote sinus drainage. However, inferior meatal antrostomy has been criticized for its additional operation time and wound, early loss of the opening, and risk of injury to the nasolacrimal duct. This study retrospectively reviewed the results of the Caldwell-Luc operation without inferior meatal antrostomy in the treatment of odontogenic maxillary sinusitis or odontogenic sinus disease. PATIENTS AND METHODS: The records of 50 patients who had an odontogenic sinus disease and underwent the Caldwell-Luc operation without inferior meatal antrostomy were reviewed. The data included the patient's age, gender, surgical indications, surgical condition, and complications. RESULTS: From April 2004 to October 2010, there were 27 male patients and 23 female patients aged 14 to 70 years (mean, 37 years) who underwent the modified Caldwell Luc operation. The surgical indications included intrasinus odontogenic cysts (44%), oroantral fistulae with chronic sinusitis (44%), odontoma (4%), odontogenic sinusitis (4%), and foreign bodies in the maxillary sinus (4%). The patients were successfully treated with minimal complications. CONCLUSIONS: The modified Caldwell-Luc operation provides easier postoperative care and involves fewer complications. It is not necessary to create the inferior meatal antrostomy in the Caldwell-Luc operation when treating odontogenic sinus disease. PMID- 22209109 TI - TAG, you're it! Chlamydomonas as a reference organism for understanding algal triacylglycerol accumulation. AB - Photosynthetic organisms are responsible for converting sunlight into organic matter, and they are therefore seen as a resource for the renewable fuel industry. Ethanol and esterified fatty acids (biodiesel) are the most common fuel products derived from these photosynthetic organisms. The potential of algae as producers of biodiesel precursor (or triacylglycerols (TAGs)) has yet to be realized because of the limited knowledge of the underlying biochemistry, cell biology and genetics. Well-characterized pathways from fungi and land plants have been used to identify algal homologs of key enzymes in TAG synthesis, including diacylglcyerol acyltransferases, phospholipid diacylglycerol acyltransferase and phosphatidate phosphatases. Many laboratories have adopted Chlamydomonas reinhardtii as a reference organism for discovery of algal-specific adaptations of TAG metabolism. Stressed Chlamydomonas cells, grown either photoautotrophically or photoheterotrophically, accumulate TAG in plastid and cytoplasmic lipid bodies, reaching 46-65% of dry weight in starch accumulation (sta) mutants. State of the art genomic technologies including expression profiling and proteomics have identified new proteins, including key components of lipid droplets, candidate regulators and lipid/TAG degrading activities. By analogy with crop plants, it is expected that advances in algal breeding and genome engineering may facilitate realizing the potential in algae. PMID- 22209110 TI - Real-time tumor tracking with an artificial neural networks-based method: a feasibility study. AB - The purpose of this study was to develop and assess the performance of a tumor tracking method designed for application in radiation therapy. This motion compensation strategy is currently applied clinically only in conventional photon radiotherapy but not in particle therapy, as greater accuracy in dose delivery is required. We proposed a tracking method that exploits artificial neural networks to estimate the internal tumor trajectory as a function of external surrogate signals. The developed algorithm was tested by means of a retrospective clinical data analysis in 20 patients, who were treated with state of the art infra-red motion tracking for photon radiotherapy, which is used as a benchmark. Integration into a hardware platform for motion tracking in particle therapy was performed and then tested on a moving phantom, specifically developed for this purpose. Clinical data show that a median tracking error reduction up to 0.7 mm can be achieved with respect to state of the art technologies. The phantom study demonstrates that a real-time tumor position estimation is feasible when the external signals are acquired at 60 Hz. The results of this work show that neural networks can be considered a valuable tool for the implementation of high accuracy real-time tumor tracking methodologies. PMID- 22209111 TI - Exposure to mercury causes formation of male-specific structural deficits by inducing oxidative damage in nematodes. AB - Metal exposure causes reproductive damage in hermaphrodite nematodes, but effects of metals on male development are unclear. We here investigated the effects of mercury chloride exposure on development of males. Hg exposure severely increased the percentage of abnormal males, disrupted the development of male-specific structures, and caused high reactive oxygen species (ROS) production in male tails. Pre-treatment with antioxidant (vitamin E) protected the nematodes against toxicity from Hg exposure on development of male-specific structures. The ROS production in tails was closely correlated with formation of abnormal male specific structures in males induced by Hg exposure. Moreover, mutations of clk 1, encoding ortholog of COQ7/CAT5, and daf-2, encoding an insulin/IGF receptor, functioned in two different pathways to suppress the formation of deficits in development of male-specific structures. Thus, three different lines of evidence support our conclusion that HgCl(2) causes male structure-specific teratogenesis via production of oxidative stress. PMID- 22209112 TI - Effect of IL-10 antisense gene therapy in severely burned mice intradermally infected with MRSA. AB - The effect of IL-10 antisense oligodeoxynucleotides (ODN) on the susceptibility of burned mice to intradermal (i.d.) infection of methicillin-resistant Staphylococcus aureus (MRSA) was studied. Abscesses formed and sepsis did not develop in normal mice infected i.d. with 10(8)CFU/mouse of MRSA. Similarly, sepsis caused by MRSA i.d. infection did not develop and abscesses formed in burned mice treated with IL-10 antisense ODN. However, all of the burned mice treated with scrambled ODN (control group) died by infectious complications stemming from MRSA i.d. infection, and an MRSA-abscess did not form in these mice. Macrophages (Mphi) isolated from the infection site tissue of burned mice that were treated with IL-10 antisense ODN were identified as M1Mphi, while Mphi isolated from burned mice that were treated with scrambled ODN were shown to be M2Mphi. MRSA-abscesses formed in burned mice inoculated with M1Mphi, and these mice resisted a lethal dose of MRSA i.d. infection. However, an abscess did not form, and sepsis caused by MRSA i.d. infection developed in burned mice that were inoculated with M2Mphi. These results indicate that severely burned mice treated with IL-10 antisense ODN are resistant against i.d. infection with MRSA. M1Mphi appeared in the infection site tissues of severely burned mice that were treated with IL-10 antisense ODN may play a role on the abscess formation and inhibiting sepsis caused by MRSA i.d. infection. PMID- 22209113 TI - Anti-C1q autoantibodies specific against the globular domain of the C1qB-chain from patient with lupus nephritis inhibit C1q binding to IgG and CRP. AB - Lupus nephritis is one of the most severe manifestations of systemic lupus erythematosus. Higher titers of serum anti-C1q autoantibodies correlate with disease activity in patients with lupus nephritis. Anti-C1q autoantibodies have been shown to bind neo-epitopes within the collagen region of human C1q. In a preliminary study, we recently reported that the anti-C1q autoantibodies could also recognize epitopes within the globular domain (gC1q) of the C1q molecule. Here, 38 sera from patients with renal biopsy-proven lupus nephritis were screened for the presence of anti-gC1q autoantibodies, using recombinant globular head regions of individual A (ghA), B (ghB) and C (ghC) chains of human C1q. We isolated anti-gC1q autoantibodies from three selected patients. Human C1q was pre incubated with increasing concentrations of the isolated anti-ghA, anti-ghB or anti-ghC autoantibodies and its binding to different C1q target molecules such as IgG and CRP was then evaluated. Anti-ghB, but not anti-ghA and anti-ghC autoantibodies, markedly inhibited C1q interaction with IgG as well as CRP. These results appear to suggest that the anti-ghB autoantibodies may partially induce acquired functional C1q deficiency and thus may interfere with the biological function of C1q. PMID- 22209114 TI - Impact of valproic acid on dendritic cells function. AB - OBJECTIVE: Recent data suggested that histone deacetylase (HDAC) inhibitors possessed potent anti-inflammatory and immunomodulatory properties both in vitro and in vivo. This study assayed the ability of the HDAC inhibitor, valproic acid (VPA), to influence the differentiation and functional properties of dendritic cells (DCs) generated from circulating peripheral blood monocytes. METHODS AND RESULTS: Culture of monocytes in the presence of 0.5mM of VPA did not impair DC differentiation. However, on the phenotypic level, in mature DCs, CD40, CD80 and CD86 were downregulated in the presence of VPA, compared to mature DCs generated in the absence of VPA. VPA led also to a significant down-regulation of CD83 and HLA-DR expression on mature DCs. Moreover, VPA treatment significantly inhibited IL-10 and IL-12p70 production by mature DCs. IL-10 and IL-12p70 altered secretion was observed whether DCs were matured with LPS alone or with LPS and IFN-gamma. In an allogeneic mixed lymphocyte reaction, the proportion of IFN-gamma+CD4+ T cells was decreased (26% vs. 51%, p=0.005) when T cells were stimulated with DCs exposed to VPA. Also, CD8+ T cells stimulated with DCs treated with VPA, exhibited a significant decrease of Granzyme B expression. CONCLUSION: These results suggest that HDAC inhibition by VPA alters essential human DC functions, highlighting the need for monitoring of immune functions in cancer patients receiving HDAC inhibitors, but also making these drugs attractive therapies in inflammatory, and autoimmune diseases. PMID- 22209115 TI - Phase-sensitive spectral estimation by the hybrid filter diagonalization method. AB - A more robust way to obtain a high-resolution multidimensional NMR spectrum from limited data sets is described. The Filter Diagonalization Method (FDM) is used to analyze phase-modulated data and cast the spectrum in terms of phase-sensitive Lorentzian "phase-twist" peaks. These spectra are then used to obtain absorption mode phase-sensitive spectra. In contrast to earlier implementations of multidimensional FDM, the absolute phase of the data need not be known beforehand, and linear phase corrections in each frequency dimension are possible, if they are required. Regularization is employed to improve the conditioning of the linear algebra problems that must be solved to obtain the spectral estimate. While regularization smoothes away noise and small peaks, a hybrid method allows the true noise floor to be correctly represented in the final result. Line shape transformation to a Gaussian-like shape improves the clarity of the spectra, and is achieved by a conventional Lorentzian-to-Gaussian transformation in the time-domain, after inverse Fourier transformation of the FDM spectra. The results obtained highlight the danger of not using proper phase sensitive line shapes in the spectral estimate. The advantages of the new method for the spectral estimate are the following: (i) the spectrum can be phased by conventional means after it is obtained; (ii) there is a true and accurate noise floor; and (iii) there is some indication of the quality of fit in each local region of the spectrum. The method is illustrated with 2D NMR data for the first time, but is applicable to n-dimensional data without any restriction on the number of time/frequency dimensions. PMID- 22209116 TI - Nine months that last a lifetime. Experience from the Danish National Birth Cohort and lessons learned. AB - A growing body of evidence indicates that antenatal care should focus not only on preventing perinatal complications but needs to see the early phase of life as important for a number of adult diseases as well. Most of the research comes from animal studies, since cohorts starting early in life that include biomarkers and have long term follow-up are few, the best known being the National Collaborative Perinatal Project (1959-1974) where only a part of the cohort are being followed (www.birthcohorts.net). Many cohorts are, however, in the planning phase, and the paper provides ten suggestions/recommendations for principal investigators of new or recently established cohorts. PMID- 22209117 TI - The many roles of TOX in the immune system. AB - TOX is a member of an evolutionarily conserved DNA-binding protein family and is expressed in several immune-relevant cell subsets. Here, we review the key role of TOX in regulating development of CD4 T cells, natural killer cells and lymphoid tissue inducer cells, the latter responsible for the generation of lymph nodes. Although the exact molecular mechanism of action of TOX remains to be elucidated, the role of TOX in establishment of gene programs in the thymus and the potential of TOX as a regulator of E protein activity are discussed. PMID- 22209118 TI - Peritoneal tuberculosis in Qatar: a five-year hospital-based study from 2005 to 2009. AB - There is limited information about peritoneal tuberculosis in Qatar. This retrospective study aimed to review our experience with peritoneal tuberculosis in patients admitted to Hamad general hospital over a period of 5 years, from 2005 to 2009, with emphasis on presentation, investigation, diagnosis and therapeutic outcome. Fifty-four patients with peritoneal tuberculosis identified during the study period were included. The mean age of them was 31.85 years and 96.3% (52/54) of them were non-Qataris with male predominance. The main symptoms and signs at the time of presentation were abdominal pain and ascites respectively. Underlying diseases were described in 24% (13/54) and history of contact with tuberculous cases was present in 31.5% (17/54) of patients. Tuberculin test was positive in 66.7% (36/54). The ascitic fluid smear showed acid fast bacilli in 2% (1/53), and culture was positive in 39.6% (21/53) of cases. Laparoscopically obtained peritoneal biopsy showed caseating granulomas in 93% (40/43) and mycobacteria were identified by acid fast staining and culture in 58.5% (24/41) and 98% (40/41) of the tested specimens respectively. Most of the patients (84%; 37/44) who had completed their therapy in Qatar improved with antituberculosis therapy, and only one patient died. In conclusion, the clinical features and the imaging findings of the disease were non-specific. A high index of suspicion is essential for early diagnosis. Culture of ascitic fluid delayed the diagnosis in clinically suspected cases, whereas laparoscopically guided peritoneal biopsy provided rapid and correct diagnosis. A Six-month course with antituberculous therapy was effective and improved the outcome. PMID- 22209119 TI - Beet soil-borne mosaic virus RNA-4 encodes a 32 kDa protein involved in symptom expression and in virus transmission through Polymyxa betae. AB - Beet soil-borne mosaic virus (BSBMV), like Beet necrotic yellow vein virus (BNYVV), is a member of the Benyvirus genus and both are transmitted by Polymyxa betae. Both viruses possess a similar genomic organization: RNA-1 and -2 are essential for infection and replication while RNA-3 and -4 play important roles in disease development and vector-mediated infection in sugar beet roots. We characterized a new species of BSBMV RNA-4 that encodes a 32 kDa protein and a chimeric form of BSBMV RNA-3 and -4. We demonstrated that BSBMV RNA-4 can be amplified by BNYVV RNA-1 and -2 in planta, is involved in symptoms expression on Chenopodium quinoa plants and can also complement BNYVV RNA-4 for virus transmission through its vector P. betae in Beta vulgaris plants. Using replicon mediated expression, we demonstrate for the first time that a correct expression of RNAs-4 encoded proteins is essential for benyvirus transmission. PMID- 22209120 TI - In vitro and in vivo susceptibility of two-drug and three-drug combinations of terbinafine, itraconazole, caspofungin, ibuprofen and fluvastatin against Pythium insidiosum. AB - The present study investigated the in vitro inhibitory activity of terbinafine, itraconazole, caspofungin, fluvastatin and ibuprofen against 15 isolates of Pythium insidiosum in double and triple combinations and determined in vivo correlations using rabbits with experimental pythiosis. The minimal inhibitory concentration (MIC) was determined in accordance with the Clinical and Laboratory Standards Institute M 38-A2 protocol (2008), and the in vitro interactions were evaluated using a checkerboard microdilution method. For the in vivo study, 20 rabbits inoculated with P. insidiosum zoospores were divided into four groups: group 1 was treated with terbinafine and itraconazole; group 2 was treated with terbinafine, itraconazole and fluvastatin; group 3 was treated with terbinafine and caspofungin; and group 4 was the control group. Combinations of terbinafine with caspofungin or ibuprofen were synergistic for 47% of the isolates, and antagonism was not observed in any of the double combinations. The triple combinations were mostly indifferent, but synergism and antagonism were also observed. In the in vivo study, the histological aspect of the lesions was similar among the groups, but group 2 showed the lowest amount of hyphae and differed significantly from the other groups. PMID- 22209121 TI - Bactericidal properties of pradofloxacin against veterinary pathogens. AB - Pradofloxacin is a new veterinary 8-cyano-fluoroquinolone developed for use against bacterial infections in dogs and cats involving both aerobic and anaerobic bacteria. The minimal bactericidal concentrations have been determined against clinical isolates of Staphylococcus pseudintermedius, Staphylococcus aureus, Escherichia coli, Pasteurella multocida, Streptococcus canis, Proteus spp., Fusobacterium spp., Porphyromonas gingivalis and Prevotella species. A subset of these species was selected, and the in vitro rate of kill by pradofloxacin was determined. For 27 of the 30 tested aerobic strains the pradofloxacin MBC was within two doubling dilutions of the MIC. For the remaining strains, the MIC and MBC were within three to four doubling dilutions. Pradofloxacin also demonstrated bactericidal activity against all anaerobic strains, and the MBC was equal to the MIC for four of the strains, within 1 doubling dilution for three strains, within 2 dilutions for a further 3 strains and within 3 dilutions for the remaining five strains. As pradofloxacin concentration was increased, a faster rate of killing was observed; bactericidal effects were seen in all cases at concentrations <= 0.25 MUg/mL. The bactericidal activity against the anaerobic strains was marked, of particular relevance was the complete absence of regrowth even at 48 h at concentrations as low as 0.125 MUg/mL. In conclusion, pradofloxacin exhibits clear bactericidal activity in terms of MBC and kill kinetics against aerobic and anaerobic clinical isolates from dogs and cats at concentrations that are greatly exceeded within the systemic circulation after administration of the recommended therapeutic doses to the target animals. It is expected that such a rapid rate of kill will play a significant role in clinical efficacy. These data demonstrate the complete and rapid killing of anaerobic bacteria by a veterinary 8-cyano-fluoroquinolone. PMID- 22209122 TI - Corticolimbic balance shift of regional glucose metabolism in depressed patients treated with ECT. AB - BACKGROUND: Although the clinical efficacy of electroconvulsive therapy (ECT) has been well established in patients with pharmacotherapy-resistant depression, the physiological mechanism and changes in regional cerebral function after ECT are unclear. METHODS: We recruited 16 depressed patients who underwent ECT, and 11 healthy controls. The change in cerebral glucose metabolism was evaluated before and after a series of ECT using [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET). RESULTS: Before ECT, the patient group showed significant hypometabolism in the superior frontal gyrus, and hypermetabolism in the inferior temporal gyri compared with healthy controls, and these abnormalities remained after ECT. Comparisons between pre- and post-ECT metabolic activity revealed decreased regional metabolism in the frontotemporal neocortical areas after ECT, while increased metabolism was found in the right medial temporal structures including amygdala and pons. In addition, a decrease in glucose metabolism in the fronto-temporo-parietal regions correlated with an increase in glucose metabolism in the right medial temporal regions across subjects. LIMITATIONS: There was considerable variability in the interval between the last ECT and FDG-PET scan. Depressed subjects were maintained on medication. The subjects included both major depressive disorder and bipolar disorder patients, as well as both ECT responders and non-responders. CONCLUSION: Depression refractory to pharmacotherapy might have functional deficits in specific circumscribed frontal and temporal structures. ECT resolves the clinical symptoms without largely affecting these brain metabolic abnormalities. In contrast, ECT shifts the balance of corticolimbic function, which might explain how ECT ameliorates symptoms of depression in patients. PMID- 22209123 TI - Emotional bias in unaffected siblings of patients with bipolar I disorder. AB - BACKGROUND: Bipolar disorder (BPD) research has identified a number of neurocognitive deficits as potential vulnerability markers; however, very few studies have focused on patterns of performance on affective processing tasks (e.g. affective Go/No-Go tasks) which may be more closely tied to the pathophysiology of the illness. We previously reported that stable BPD patients demonstrate a response bias toward negative affective stimuli as compared with healthy controls and schizophrenia patients. The goal of the current study was to expand upon these prior findings to investigate these patterns in the unaffected siblings of BPD patients. METHODS: An affective Go/No-Go test was used to evaluate inhibitory response to negatively-valenced, positively-valenced, and neutral stimuli in 20 unaffected siblings of bipolar I patients versus 20 healthy controls. Accuracy (d') and response bias (beta) served as dependent variables in a series of repeated measures ANCOVAs. RESULTS: We found a non-significant main effect for group when comparing accuracy performance (d') on the affective Go/No Go of unaffected siblings versus healthy controls. However, very similar to the pattern that we previously reported in stable BPD patients, unaffected siblings showed a response bias (beta) toward negatively-valenced stimuli versus healthy controls [F=3.81; p=0.03]. LIMITATIONS: Small sample size. CONCLUSIONS: The current results extend our recent work which suggested that stable bipolar patients attend more readily to negative target stimuli than do schizophrenic or healthy subjects. These data, indicating that unaffected siblings also demonstrate an affective processing bias, implicate this task as a potential endophenotype in BPD. PMID- 22209124 TI - Comorbid anxiety in bipolar spectrum disorders: a neglected research and treatment issue? AB - BACKGROUND: Anxiety disorders are highly prevalent among patients with bipolar disorder and have a substantial impact on the course of illness and response to treatment. Despite the substantial impact that comorbid anxiety disorders have on the prognosis of individuals with bipolar disorder, many aspects of this comorbidity have received little attention from researchers. This study aims to document the current state of the literature on the comorbidity between anxiety and bipolar disorders by analyzing publication trends on the subject. METHOD: This study is a quantitative and qualitative review of articles on the comorbidity between anxiety disorders and bipolar disorder published between 1990 and 2010 in the ISI Web of Science, Medline and PsycINFO databases. The number of articles published each year on this comorbidity was calculated and compared to the literature published on bipolar disorder as a whole. Articles were classified into five categories and 13 subcategories to identify the main focuses of the literature and current gaps in the knowledge on the subject. RESULTS: Interest in the comorbidity between anxiety disorders and bipolar disorder grew continually since 1990, but seems to have reached a plateau. The majority of articles addressing this comorbidity are descriptive in nature, with very few concrete studies examining the mechanisms and treatment approaches that might lead to positive advancements in the field. LIMITATIONS: Articles written in languages other than English or French were not reviewed. CONCLUSIONS: It is time to step up research efforts to better understand and manage this under-studied combination of disorders. PMID- 22209125 TI - The 5-HTTLPR polymorphism modulates the influence on environmental stressors on peripartum depression symptoms. AB - BACKGROUND: Maternal depression during the peripartum period has an incidence of about 13%. Individuals with specific genetic predispositions are more vulnerable to stressful life events suggesting that exploration of gene-environmental pathways might facilitate the identification of risk factors for peripartum depression. The aim of this study was to evaluate the influence of stressful life events in combination with the serotonin transporter gene 5-HTTLPR polymorphism on peripartum depressive symptoms. METHODS: In a non-psychiatric cohort of 419 Caucasians, the severity of depression was assessed prospectively during pregnancy (3rd trimester) and the postpartum period (2-3 days and 6-8 months) using the Edinburgh Postnatal Depression Scale. Satisfaction with the partner and exposure to negative life events were evaluated using self-report questionnaires and the genotype of the 5-HTTLPR was assessed. Repeated measures generalized linear models were used to investigate the gene-environment interaction on depressive symptoms across late pregnancy and the postpartum period. RESULTS: The 5-HTTLPR S-allele carrier status predicted late postpartum depressive symptom severity only in the presence of negative life events. This interaction was not observed for depressive symptoms during the 3rd trimester or the early postpartum. In addition, S-allele carrier status increased the negative effects of dissatisfaction with the current partner on depressive symptoms in the late postpartum period. CONCLUSIONS: In this non-psychiatric cohort, the 5-HTTLPR interacts with both lifetime and current stressors to influence depressive symptoms in the late post partum period. These findings could have clinical implications by allowing identification of women at higher risk for developing postpartum depressive symptoms. PMID- 22209126 TI - Prevalence and correlates of complicated grief in adults who have undergone a coronary artery bypass graft. AB - BACKGROUND: Complicated grief (CG) is a recently described mental health condition that follows bereavement. CG is often comorbid with depression and may also be associated with poor health outcomes. However, CG has not been studied in depressed medically ill populations. This study examined the prevalence, correlates, and impact of CG in depressed post-coronary artery bypass graft surgery (CABG) patients. METHODS: A 5-item CG screen was administered to 302 depressed post-CABG patients participating in a comparative effectiveness intervention trial at 7 Pittsburgh-area hospitals from March 2004 to September 2007. Eligible patients were randomly assigned to either a telephone-delivered collaborative care intervention for depression or their primary care physicians' usual care. Measures examined depression, physical and mental health-related quality of life, and physical functioning over 8 months. RESULTS: Compared to CG screen-negative patients, CG screen-positive patients were younger, more likely to: be female, non-White, have lost a partner or child, and to have used tobacco or antidepressants. At baseline, they had significantly higher depression and lower mental health scores. At 8 months, screen-positives had poorer physical functioning and marginally higher depression scores. LIMITATIONS: The study lacked a definitive measure of CG. Moreover, the CG-positive group was relatively small, reducing the power to detect differences between groups or control for the possible influence of other variables on identified results. CONCLUSIONS: CG in depressed post-CABG patients is associated with negative health and mental health outcomes. These results underscore the importance of identifying and treating CG in depressed medically ill populations. PMID- 22209127 TI - Expressive writing and positive writing for participants with mood disorders: an online randomized controlled trial. AB - INTRODUCTION: Expressive writing--writing about traumatic, stressful or emotional events--often leads to improvements in physical and psychological health in non clinical and clinical populations. Recent studies have shown that positive writing may also be beneficial. Research has not yet investigated whether either expressive writing or positive writing offers benefits for people with mood disorders. METHOD: Participants were recruited online and were randomly allocated to expressive writing, positive writing or control writing. The following questionnaires were completed online: Centre for Epidemiological Studies Depression Scale (CES-D), Depression Anxiety Stress Scales (DASS), Pennebaker Inventory of Limbic Languidness (PILL), overall health questions, Temperament and Personality Questionnaire (TPQ) and COPE Inventory (COPE). Participants then wrote for 20 min on 4 occasions, and then completed follow-up questionnaires. RESULTS: Linear mixed models with custom contrasts were conducted to assess differences between groups and over time. All 3 groups showed significant improvements over time on mental health and some physical health outcomes. There were no significant differences between groups and no significant group by time interactions. These results were not moderated by demographic factors, personality subtypes or coping styles. CONCLUSION: The expressive writing, positive writing and time management control writing groups all reported significantly fewer mental and physical symptoms for at least 4 months post writing. When expressive and positive writing groups were combined, the resulting 'emotional writing group' showed significantly lower scores on the DASS stress subscale than the control writing group at all time-points. Potential reasons are discussed and areas of further study identified. PMID- 22209128 TI - The effect of organic loading rate on bio-hydrogen production from pre-treated rice straw waste via mesophilic up-flow anaerobic reactor. AB - Effect of organic loading rate (OLR) on the continuous biological H(2) production from pretreated rice straw waste using a mesophilic up-flow anaerobic reactor (UAR) was investigated for 140 d. OLR was varied from 7.1 to 26 g COD/ld. H(2) yield was significantly increased from 95.5 to 117 mmol/d, when OLR was largely increased from 7.1 to 21.4 gCOD/ld, respectively. However, further increase in OLR up to 26 g COD/ld, showed a decreasing trend to 107.1 mmol/d. Likewise, H(2) production increased with OLR at the range of 7.1-21.4 g COD/ld, and reached the maximum H(2) production of 2.6l/d. However, the H(2) production started to decrease with the further increase of OLR, and dropped to 2.2l/d at OLR of 26 g COD/ld. The COD and carbohydrate removal efficiency were over 70% and 80% at OLRs of 7.1-21.4 g COD/ld, and decreased thereafter. PMID- 22209129 TI - Energy-efficient treatment of organic wastewater streams using a rotatable bioelectrochemical contactor (RBEC). AB - A membraneless bioelectrochemical system - rotatable bio-electrochemical contactor (RBEC) consists of an array of rotatable electrode disks was developed to convert the chemical energy from wastewater organics (acetate) directly into electricity. Each rotatable electrode disk had an upper-air exposing and a lower water submerging halves. Intermittent rotation (180 degrees ) enabled each halve to alternately serve as anode and cathode. Removal of chemical oxygen demand (COD) was increased by 15% (from 0.79 to 0.91 kg COD m(-3) d(-1)) by allowing electron flow from the lower to the upper disk halves. Coupling with a potentiostat could alleviate cathodic limitation and increased COD removal to 1.32 kg COD m(-3) day(-1) (HRT 5h). About 40% of the COD removed was via current, indicating that the biofilm could use the lower half disk as electron acceptor. The RBEC removed COD more energy-efficiently than conventional activated sludge processes as active aeration is not required (0.47 vs. 0.7-2.0 kW h kg COD(-1)). PMID- 22209130 TI - Effect of light intensity and nitrogen starvation on CO2 fixation and lipid/carbohydrate production of an indigenous microalga Scenedesmus obliquus CNW N. AB - Engineering strategies were applied to improve the CO(2) fixation rate and carbohydrate/lipid production of a Scenedesmus obliquus CNW-N isolate. The light intensity that promotes cell growth, carbohydrate/lipid productivity, and CO(2) fixation efficiency was identified. Nitrogen starvation was also employed to trigger the accumulation of lipid and carbohydrate. The highest productivity of biomass, lipid, and carbohydrate was 840.57 mg L(-1)d(-1), 140.35 mg L(-1)d(-1). The highest lipid and carbohydrate content was 22.4% (5-day N-starvation) and 46.65% (1-day N-starvation), respectively. The optimal CO(2) consumption rate was 1420.6 mg L(-1)d(-1). This performance is better than that reported in most other studies. Under nitrogen starvation, the microalgal lipid was mainly composed of C16/C18 fatty acid (around 90%), which is suitable for biodiesel synthesis. The carbohydrate present in the biomass was mainly glucose, accounting for 77-80% of total carbohydrates. This carbohydrate composition is also suitable for fermentative biofuels production (e.g., bioethanol and biobutanol). PMID- 22209131 TI - One-step, inexpensive high yield strategy for Candida antarctica lipase A isolation using hydroxyapatite. AB - Lipase A from Candida antarctica (CAL A) was purified to apparent homogeneity in a single step using hydroxyapatite (HAP) chromatography. CAL A bound to HAP was eluted with 10mM Na-phosphate buffer, pH 7.0 containing 0.5% Triton X-100. The protocol resulted in a 3.74-fold purification with 94.7% final recovery and 400.83 U/mg specific activity. Silver staining after SDS-PAGE revealed the presence a single band of 45 kDa. The enzyme exhibited a temperature optimum of 60 degrees C, was unaffected by monovalent metal ions, but was destabilized by divalent metal ions (Zn(2+), Ca(2+), Mg(2+), Cu(2+), Mn(2+)) and stimulated by 50mM Fe(2+). Detergents at 0.1% concentrations did not affect lipase activity. Except for Triton X-100, detergent concentrations of 1% had a destabilizing effect. PMID- 22209132 TI - Removal of acid and direct dye by epichlorohydrin-dimethylamine: flocculation performance and floc aggregation properties. AB - A cationic organic flocculant epichlorohydrin-dimethylamine (EPI-DMA) was employed for the treatment of acid and direct dye. The study aims at investigating the flocculation performance of EPI-DMA for the model dye, and corresponding floc aggregation properties, which were determined by jar test and photometric dispersion analysis, respectively. The interactions between cationic flocculant and anionic dye were investigated through spectra analysis. The results showed that EPI-DMA effectively decolorized the tested acid and direct dye. The viscosity and cationicity of EPI-DMA had different influence on the removal of different dye. Chemical interaction was observed between quaternary ammonium of EPI-DMA and sulfonic group of dye. The flocculation dynamic process showed that flocs with better aggregation and sedimentation properties were produced by EPI-DMA with higher viscosity and cationicity for acid dye. Contrarily, flocs with the best aggregation and sedimentation properties were produced by EPI-DMA with the lowest viscosity and cationicity for direct dye. PMID- 22209133 TI - Evaluating operation strategies and process stability of a single stage nitritation-anammox SBR by use of the oxidation-reduction potential (ORP). AB - A single stage nitritation-anammox SBR was operated for 300 days to investigate the impact of cycle operation strategies on process performance and the oxidation reduction potential (ORP) as process monitoring parameter. Different combinations of feeding (interval, continuous, one-time) and aeration (interval, continuous) strategies were tested revealing that interval feeding and interval aeration was the most suitable case in terms of process performance (ammonium removal, nitrate production and pH stability) and use of the ORP value as indicator parameter. Further investigations into the use of the ORP value showed clear correlations of the ORP slope with the air flow rate and the maximum ORP peak with the ammonium loading under varying operation conditions. Depletion of the main substrates (ammonium and oxygen) was also detectable fastest following the ORP value proofing its worth for process control. PMID- 22209134 TI - Improvement in mechanical properties of jute fibres through mild alkali treatment as demonstrated by utilisation of the Weibull distribution model. AB - Chemically modified jute fibres are potentially useful as natural reinforcement in composite materials. Jute fibres were treated with 0.25%-1.0% sodium hydroxide (NaOH) solution for 0.5-48 h. The hydrophilicity, surface morphology, crystallinity index, thermal and mechanical characteristics of untreated and alkali treated fibres were studied.The two-parameter Weibull distribution model was applied to deal with the variation in mechanical properties of the natural fibres. Alkali treatment enhanced the tensile strength and elongation at break by 82% and 45%, respectively but decreased the hydrophilicity by 50.5% and the diameter of the fibres by 37%. PMID- 22209135 TI - Development of biofilm on geotextile in a new multi-zone wastewater treatment system for simultaneous removal of COD, nitrogen and phosphorus. AB - This study investigated the formation and evolution of biofilm on a fixed cylindrical structure wrapped in geotextile, in a multi-zone wastewater treatment system called BioCAST. The organic, nitrogen and phosphorus loading rates of (OLR) 0.95-1.86 g COD/(m(3)d), (NLR) 0.02-0.08 kg N/(m(3)d), and (PLR) 0.014-0.02 kg P/(m(3)d), were applied. The results demonstrated high removal efficiencies of carbon, nitrogen and phosphorus, reaching 98.9%, 98.3% and 94.1%, respectively, after 250 d of operation. The biofilm biomass showed a fast formation (reaching 54.2g/L) and maximum phosphorus content of about 7% (dry basis). Biofilm demonstrated the ability to remove phosphorus, and its characteristics correlated with nitrogen and phosphorus removal rates. The geotextile material with filamentous structure causing rapid attachment and formation of biofilm can solve many problems encountered in conventional attached-growth wastewater treatment systems such as slow start-up, low reactor biomass content and low capacity to handle high organic loading rates. PMID- 22209136 TI - Developing a model for assessing biomass processing technologies within a local biomass processing depot. AB - One solution to the supply chain challenges of cellulosic biofuels is a network of local biomass processing depots (LBPDs) that can produce stable, dense, intermediate commodities and valuable co-products prior to shipping to a refinery. A techno-economic model of an LBPD facility that could incorporate multiple technologies and products was developed in Microsoft Excel to be used to economically and environmentally evaluate potential LBPD systems. In this study, three technologies (ammonia fiber expansion or AFEXTM pretreatment, fast pyrolysis, and leaf protein processing) were assessed for profitability. Pyrolysis was slightly profitable under the base conditions, leaf protein processing was highly unprofitable, and AFEX was profitable if biomass drying was not required. This model can be adapted to multiple feedstocks and end uses, including both economic and environmental modeling. PMID- 22209137 TI - Theoretical and practical aspects of chemical functionalization of carbon nanofibers (CNFs): DFT calculations and adsorption study. AB - The nitric acid-functionalized commercial carbon nanofibers (CNFs) were comprehensively studied by instrumental (XRD, BET, SEM, TGA) and theoretical (DFT calculations) methods. The detailed surface study revealed the variation in the characteristics of functionalized CNFs, such as a decreased (up to 34%) surface area and impacted structural, electronic and chemical properties. The effects of functional groups were studied by comparison with pristine nanofibers. The results showed that the C-C bond lengths of the modified CNFs varied significantly. Chemical functionalization altered the frontier orbitals of the pristine material, and therefore altered the nature of their interactions with other substances. Moreover, the pristine and modified CNFs were tested for the removal of phenol from aqueous solutions. It was observed that surface modification tuned the adsorption capacity of carbon nanofibers (up to 0.35 mmol g(-1)), whereas original fibers did not demonstrate any adsorption capacity of phenol. PMID- 22209138 TI - Carpal tunnel syndrome as an initial manifestation in a case of transthyretin related familial amyloid polyneuropathy with a novel A120T mutation. PMID- 22209139 TI - Peripheral neuropathy and 46XY gonadal dysgenesis: confirmation of a heterogeneous entity. PMID- 22209140 TI - The first case report of neuroacanthocytosis in Thailand: utilization of a proper technique searching for acanthocytes. PMID- 22209141 TI - Novel compound heterozygous mutations of the SACS gene in autosomal recessive spastic ataxia of Charlevoix-Saguenay. PMID- 22209142 TI - Telovelar approach for choroid plexus papilloma in the foramen of Luschka: a safe way using a neuromonitor. AB - BACKGROUND: Tumors located in the 4th ventricle are always challenging to neurosurgeons, especially tumors that extend to the cerebellopontine (CP) angle by the foramen of Luschka. Recent advances in microsurgical technique, including the neuromonitor and brainstem mapping, facilitate the surgical resection of tumors located in the foramen of Luschka. Herein, we present the use of the telovelar approach to access a choroid plexus papilloma within the right foramen of Luschka. CASE PRESENTATION: A 28-year-old female presented with a history of sudden onset pulsatile headache and syncope twice without prodrome. The brain MRI revealed a 4th ventricular tumor deviated to the right foramen of Luschka and extending to the CP angle, 2.2 cm in diameter. There was no secondary hydrocephalus due to the patent foramen of Magendie and left foramen of Luschka. The patient underwent suboccipital craniotomy and C1 laminectomy with a telovelar approach. The right tonsil was elevated and teal chloride was incised from the foramen of Magendie to the telovelar junction. The tumor was centrally decompressed, and the margin was gently dissected from the brainstem and cerebellum peduncles. Functions of the facial, cochlear, glossopharyngeal, vagus, and hypoglossal nerves and nuclei were monitored. Mapping of the facial nucleus, ambiguous nucleus, and hypoglossal nucleus was also done. Total tumor removal was achieved and the histology showed choroid plexus papilloma. No functional neurological disorientation was observed after surgery. CONCLUSION: The report demonstrated a safe and effective surgical approach to the foramen of Luschka. The approach yielded a better view of the foramen of Luschka laterally, and up to the middle cerebellar peduncle superiorly. Also, it minimized neural damage, and preserved the function of the cranial nerves and nucleus. PMID- 22209143 TI - Adjuvant interferon-gamma treatment in two cases of refractory tuberculosis of the brain. AB - Tuberculosis (TB) of the brain is often refractory and has the highest morbidity and mortality among the mycobacterial infections. A recent report suggests that interferon-gamma may be of help since it can modulate the host inflammatory response against mycobacteria in the brain. Here, we report on a 44-year-old woman with multiple tuberculomas in the brainstem and a 40-year-old man with two large TB abscesses in the brain, both of whom had no response to anti-TB medications for 5 and 7 months, respectively, but with near-complete resolution with adjuvant interferon-gamma therapy (50 MUg/m(2), subcutaneously, three times per week). Our cases show that refractory brain TB in immunocompetent patients can be successfully treated with adjuvant interferon-gamma therapy, without any significant side effects. PMID- 22209144 TI - Diffusion tensor tractography indices in patients with frontal lobe injury and its correlation with neuropsychological tests. AB - OBJECTIVES: Diffusion tensor tractography (DTT) was performed to quantify diffuse axonal injury (DAI) in major white matter (WM) fiber bundles (FBs) of patients with frontal lobe injury and to correlate these changes with neuropsychological tests (NPT) at 6 month follow-up. PATIENTS AND METHODS: DTT was performed in 21 patients with moderate traumatic brain injury (TBI) within week and after 6 month follow-up, and in controls. DTI indices were calculated from the entire FBs in patients as well as controls. Bonferroni multiple comparisons Post hoc test was performed for determining the changes in DTI indices. Paired t-test was performed between DTI indices at baseline and follow-up. Pearson's correlation was performed between NPT scores and DTI indices. RESULTS: Significant changes in DTI indices were observed in some of the FBs as compared to controls which incompletely recovered at 6 month follow-up. DTI indices of different WM FBs correlated significantly with some of the NPT. CONCLUSION: We conclude that DTT based quantification helps in assessment of DAI in patients with moderate frontal lobe injury. Some of the FBs recover partially at 6 month follow-up and correlate with NPT scores. PMID- 22209145 TI - Clinical status epilepticus due to anaplastic cortical ependymoma. PMID- 22209146 TI - A case of neuro-Behcet's mimicking herpes encephalitis. PMID- 22209147 TI - Efficacy of mefloquine to progressive multifocal leukoencephalopathy initially presented with parkinsonism. PMID- 22209149 TI - First clinical release of an online, adaptive, aperture-based image-guided radiotherapy strategy in intensity-modulated radiotherapy to correct for inter- and intrafractional rotations of the prostate. AB - PURPOSE: We developed and evaluated a correction strategy for prostate rotations using direct adaptation of segments in intensity-modulated radiotherapy (IMRT). METHOD AND MATERIALS: Implanted fiducials (four gold markers) were used to determine interfractional translations, rotations, and dilations of the prostate. We used hybrid imaging: The markers were automatically detected in two pretreatment planar X-ray projections; their actual position in three-dimensional space was reconstructed from these images at first. The structure set comprising prostate, seminal vesicles, and adjacent rectum wall was transformed accordingly in 6 degrees of freedom. Shapes of IMRT segments were geometrically adapted in a class solution forward-planning approach, derived within seconds on-site and treated immediately. Intrafractional movements were followed in MV electronic portal images captured on the fly. RESULTS: In 31 of 39 patients, for 833 of 1013 fractions (supine, flat couch, knee support, comfortably full bladder, empty rectum, no intraprostatic marker migrations >2 mm of more than one marker), the online aperture adaptation allowed safe reduction of margins clinical target volume-planning target volume (prostate) down to 5 mm when only interfractional corrections were applied: Dominant L-R rotations were found to be 5.3 degrees (mean of means), standard deviation of means +/-4.9 degrees , maximum at 30.7 degrees . Three-dimensional vector translations relative to skin markings were 9.3 +/- 4.4 mm (maximum, 23.6 mm). Intrafractional movements in 7.7 +/- 1.5 min (maximum, 15.1 min) between kV imaging and last beam's electronic portal images showed further L-R rotations of 2.5 degrees +/- 2.3 degrees (maximum, 26.9 degrees ), and three-dimensional vector translations of 3.0 +/-3.7 mm (maximum, 10.2 mm). Addressing intrafractional errors could further reduce margins to 3 mm. CONCLUSION: We demonstrated the clinical feasibility of an online adaptive image guided, intensity-modulated prostate protocol on a standard linear accelerator to correct 6 degrees of freedom of internal organ motion, allowing safe and straightforward implementation of margin reduction and dose escalation. PMID- 22209148 TI - Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. AB - PURPOSE: To prospectively evaluate the association between hippocampal dose and long-term neurocognitive function (NCF) impairment for benign or low-grade adult brain tumors treated with fractionated stereotactic radiotherapy (FSRT). METHODS AND MATERIALS: Adult patients with benign or low-grade adult brain tumors were treated with FSRT per institutional practice. No attempt was made to spare the hippocampus. NCF testing was conducted at baseline and 18 months follow-up, on a prospective clinical trial. Regression-based standardized z scores were calculated by using similar healthy control individuals evaluated at the same test-retest interval. NCF impairment was defined as a z score <=-1.5. After delineation of the bilateral hippocampi according to the Radiation Therapy Oncology Group contouring atlas, dose-volume histograms were generated for the left and right hippocampi and for the composite pair. Biologically equivalent doses in 2-Gy fractions (EQD(2)) assuming an alpha/beta ratio of 2 Gy were computed. Fisher's exact test and binary logistic regression were used for univariate and multivariate analyses, respectively. Dose-response data were fit to a nonlinear model. RESULTS: Of 29 patients enrolled in this trial, 18 completed both baseline and 18-month NCF testing. An EQD(2) to 40% of the bilateral hippocampi >7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall (odds ratio [OR] 19.3; p = 0.043). The association between WMS-WL delayed recall and EQD(2) to 100% of the bilateral hippocampi >0.0 Gy trended to significance (OR 14.8; p = 0.068). CONCLUSION: EQD(2) to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low grade adult brain tumors. Given that modern intensity-modulated radiotherapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold, patients should be enrolled in ongoing prospective trials of hippocampal sparing during cranial irradiation to confirm these preliminary results. PMID- 22209150 TI - Treatment of five or more brain metastases with stereotactic radiosurgery. AB - PURPOSE: To examine the outcomes of patients with five or more brain metastases treated in a single session with stereotactic radiosurgery (SRS). METHODS AND MATERIALS: Sixty-four patients with brain metastases treated with SRS to five or more lesions in a single session were reviewed. Primary disease type, number of lesions, Karnofsky performance score (KPS) at SRS, and status of primary and systemic disease at SRS were included. Patients were treated using dosing as defined by Radiation Therapy Oncology Group Protocol 90-05, with adjustments for critical structures. We defined prior whole-brain radiotherapy (WBRT) as WBRT completed >1 month before SRS and concurrent WBRT as WBRT completed within 1 month before or after SRS. Kaplan-Meier estimates and Cox proportional hazard regression were used to determine which patient and treatment factors predicted overall survival (OS). RESULTS: The median OS after SRS was 7.5 months. The median KPS was 80 (range, 60-100). A KPS of >= 80 significantly influenced OS (median OS, 4.8 months for KPS <= 70 vs. 8.8 months for KPS >= 80, p = 0.0097). The number of lesions treated did not significantly influence OS (median OS, 6.6 months for eight or fewer lesions vs. 9.9 months for more than eight, p = nonsignificant). Primary site histology did not significantly influence median OS. On multivariate Cox modeling, KPS and prior WBRT significantly predicted for OS. Whole-brain radiotherapy before SRS compared with concurrent WBRT significantly influenced survival, with a risk ratio of 0.423 (95% confidence interval 0.191-0.936, p = 0.0338). No significant differences were observed when no WBRT was compared with concurrent WBRT or when the no WBRT group was compared with prior WBRT. A KPS of <= 70 predicted for poorer outcomes, with a risk ratio of 2.164 (95% confidence interval 1.157-4.049, p = 0.0157). CONCLUSIONS: Stereotactic radiosurgery to five or more brain lesions is an effective treatment option for patients with metastatic cancer, especially for patients previously treated with WBRT. A KPS of >= 80 predicts for an improved outcome. PMID- 22209151 TI - The importance of the conformality, heterogeneity, and gradient indices in evaluating Gamma Knife radiosurgery treatment plans for intracranial meningiomas. AB - PURPOSE: To investigate the relationship between the conformality index (CIn), heterogeneity index (HIn), and gradient index (GIn) and the development of toxicity in patients treated with Gamma Knife radiosurgery (GKRS) for intracranial meningiomas. METHODS AND MATERIALS: Treatment records of patients treated from 1997 to 2009 with at least 6 months of follow-up were reviewed. The following parameters were collected: CIn, HIn, GIn (ratio of the volume receiving half the prescription isodose to the volume receiving the full prescription isodose), brainstem (BS) maximum dose (MD), BS volume receiving >= 12 Gy (V12), optic apparatus (OA) MD, OA V8 Gy, OA V10, number of isocenters, number of isocenters outside target volume, and the occurrence of six toxicities. Univariate and multivariate logistic regression modeling were used for analysis. RESULTS: This study included 145 patients (148 meningiomas) with a median follow up time of 27 months (range, 6-113.9 months). The majority of meningiomas were located in the skull base (53%). The median prescription dose was 13 Gy (range, 10-24 Gy) to the 51.50% (range, 50-92%) isodose. A lower HIn was correlated with a higher GIn (p = 0.007). CIn was not associated with any toxicity. Higher HIn was associated with the development of dizziness (odds ratio [OR] 1.9; p = 0.02), whereas a lower GIn was associated with motor deficits (OR 0.38; p = 0.04) and auditory changes (OR 0.59; p = 0.04). The OA MD, V8, and V12 were not associated with visual changes, but visual changes were associated with a higher number of isocenters outside the target volume (OR 1.93; p = 0.07). BS V12 was correlated with the development of auditory changes (OR 1.05; p = 0.05), whereas patients with higher BS MD tended to have increased toxicity. CONCLUSIONS: Close attention must be paid to all three indices (CIn, HIn, GIn) when optimal treatment plans are determined. We recommend that the target CIn should be <= 2.0, the HIn <= 2.0, and the GIn >= 3.0 for intracranial meningiomas. PMID- 22209152 TI - Outcomes of proton radiation therapy for peripapillary choroidal melanoma at the BC Cancer Agency. AB - PURPOSE: To report toxicity, local control, enucleation, and survival rates for patients with peripapillary choroidal melanoma treated with proton therapy in Canada. METHODS AND MATERIALS: We performed a retrospective analysis of patients with peripapillary choroidal melanoma (<= 2 mm from optic disc) treated between 1995 and 2007 at the only Canadian proton therapy facility. A prospective database was updated for follow-up information from a chart review. Descriptive and actuarial data are presented. RESULTS: In total, 59 patients were treated. The median age was 59 years. According to the 2010 American Joint Committee on Cancer TNM classification, there were 20 T1 tumors (34%), 28 T2 tumors (48%), and 11 T3 tumors (19%). The median tumor diameter was 11.4 mm, and the median thickness was 3.5 mm. Median follow-up was 63 months. Nineteen patients received 54 cobalt gray equivalents (CGE) and forty patients received 60 CGE, each in 4 fractions. The 5-year actuarial local control rate was 91% (T1, 100%; T2, 93%; and T3, 59%) (p = 0.038). There was a suggestive relationship between local control and dose. The local control rate was 97% with 60 CGE and 83% with 54 CGE (p = 0.106). The metastasis-free survival rate was 82% and related to T stage (T1, 94%; T2, 84%; and T3, 47%) (p < 0.001). Twelve patients died, including eleven with metastases. The 5-year actuarial rate of neovascular glaucoma was 31% (23% for T1-T2 and 68% for T3, p < 0.001), and that of enucleation was 0% for T1, 14% for T2, and 72% for T3 (p < 0.001). Radiation retinopathy (74%) and optic neuropathy (64%) were common within-field effects. CONCLUSIONS: Proton therapy provides excellent local control with acceptable toxicity while conserving the globe in 80% of cases. These results are consistent with other single-institution series using proton radiotherapy, and toxicity rates were acceptable. T3 tumors carry a higher rate of both local recurrence and metastasis. PMID- 22209153 TI - A multi-institutional study of feasibility, implementation, and early clinical results with noninvasive breast brachytherapy for tumor bed boost. AB - PURPOSE: To evaluate the feasibility, implementation, and early results of noninvasive breast brachytherapy (NIBB) for tumor bed boost with whole breast radiation therapy (WBRT). METHODS AND MATERIALS: NIBB is a commercially available (AccuBoost, Billerica, MA) mammography-based, brachytherapy system in which the treatment applicators are centered on the planning target volume (PTV) to direct (192)Ir emissions along orthogonal axes. A privacy-encrypted online data registry collected information from 8 independent academic and community-based institutions. Data were from 146 consecutive women with early-stage breast cancer after lumpectomy and WBRT receiving boost with NIBB between July 2007 and March 2010. Toxicity and cosmesis were graded according to the Common Toxicity Criteria (v. 3.0) and the Harvard scale. Median follow-up was 6 months (1-39 months). RESULTS: Grade 1-2 skin toxicity was observed in 64%, 48%, and 21% during the acute (1-3 weeks), intermediate (4-26 weeks), and late-intermediate (>26 weeks) periods. There was no Grade 4 toxicity. At 6 months, for the entire cohort, cosmesis was excellent/good in 62%/38%. The subset receiving NIBB before WBRT had cosmetic scores of 32% and 63%, whereas during WBRT, 58% and 37% were rated as excellent and good, respectively. Breast compression was scored as "uncomfortable" in 12%, 29%, and 59% when NIBB was delivered before, during, or after WBRT. For each patient, the fraction-to-fraction variability in PTV was low. Skin flash was associated with a higher proportion of excellent cosmesis (58% vs. 42%) relative to having the applicator all within breast tissue. CONCLUSIONS: These data indicate that NIBB is feasible and can be consistently implemented in a broad array of practice settings. Preliminary evaluation suggests that NIBB is associated with acceptably mild normal tissue toxicity and favorable early cosmesis. The application of NIBB before WBRT may be associated with better patient tolerance at the expense of less favorable cosmetic outcome. PMID- 22209154 TI - Single-fraction radiosurgery for presumed intracranial meningiomas: efficacy and complications from a 22-year experience. AB - PURPOSE: To define the rate of tumor control and factors associated with radiation-related complications after single-fraction radiosurgery (SRS) for patients with imaging defined intracranial meningiomas. MATERIALS AND METHODS: Retrospective review of 251 patients (192 women, 59 men) having SRS for imaging defined intracranial meningiomas between 1990 and 2008. Excluded were patients with radiation-induced tumors, meningiomatosis, or neurofibromatosis. The mean patient age was 58.6 +/- 13.4 years. The majority of tumors involved the skull base/tentorium (n = 210, 83.7%). The mean treatment volume was 7.7 +/- 6.2 cm(3); the mean tumor margin dose was 15.8 +/- 2.0 Gy. Follow-up (mean, 62.9 +/- 43.9 months) was censored at last evaluation (n = 224), death (n = 22), or tumor resection (n = 5). RESULTS: No patient died from tumor progression or radiation related complications. Tumor size decreased in 181 patients (72.1%) and was unchanged in 67 patients (26.7%). Three patients (1.2%) had in-field tumor progression noted at 28, 145, and 150 months, respectively. No patient had a marginal tumor progression. The 3- and 10-year local control rate was 99.4%. One patient had distant tumor progression at 105 months and underwent repeat SRS. Thirty-one patients (12.4%) had either temporary (n = 8, 3.2%) or permanent (n = 23, 9.2%) symptomatic radiation-related complications including cranial nerve deficits (n = 14), headaches (n = 5), hemiparesis (n = 5), new/worsened seizure (n = 4), cyst-formation (n = 1), hemifacial spasm (n = 1), and stroke (n = 1). The 1- and 5-year complication rates were 8.3% and 11.5%, respectively. Radiation related complications were associated with convexity/falx tumors (HR = 2.8, 95% CI 1.3-6.1, p = 0.009) and increasing tumor volume (HR = 1.05, 95% CI 1.0-1.1, p = 0.04) on multivariate analysis. No patient developed a radiation-induced tumor. CONCLUSIONS: Single-fraction SRS at the used dose range provides a high rate of tumor control for patients with imaging defined intracranial meningiomas. However, treatment failures were noted after 10 years emphasizing the need for long-term imaging follow-up after meningioma SRS. PMID- 22209155 TI - Subclassification of recursive partitioning analysis Class II patients with brain metastases treated radiosurgically. AB - PURPOSE: Although the recursive partitioning analysis (RPA) class is generally used for predicting survival periods of patients with brain metastases (METs), the majority of such patients are Class II and clinical factors vary quite widely within this category. This prompted us to divide RPA Class II patients into three subclasses. METHODS AND MATERIALS: This was a two-institution, institutional review board-approved, retrospective cohort study using two databases: the Mito series (2,000 consecutive patients, comprising 787 women and 1,213 men; mean age, 65 years [range, 19-96 years]) and the Chiba series (1,753 patients, comprising 673 female and 1,080 male patients; mean age, 65 years [range, 7-94 years]). Both patient series underwent Gamma Knife radiosurgery alone, without whole-brain radiotherapy, for brain METs during the same 10-year period, July 1998 through June 2008. The Cox proportional hazard model with a step-wise selection procedure was used for multivariate analysis. RESULTS: In the Mito series, four factors were identified as favoring longer survival: Karnofsky Performance Status (90% to 100% vs. 70% to 80%), tumor numbers (solitary vs. multiple), primary tumor status (controlled vs. not controlled), and non-brain METs (no vs. yes). This new index is the sum of scores (0 and 1) of these four factors: RPA Class II-a, score of 0 or 1; RPA Class II-b, score of 2; and RPA Class II-c, score of 3 or 4. Next, using the Chiba series, we tested whether our index is valid for a different patient group. This new system showed highly statistically significant differences among subclasses in both the Mito series and the Chiba series (p < 0.001 for all subclasses). In addition, this new index was confirmed to be applicable to Class II patients with four major primary tumor sites, that is, lung, breast, alimentary tract, and urogenital organs. CONCLUSIONS: Our new grading system should be considered when designing future clinical trials involving brain MET patients. PMID- 22209156 TI - The inflammatory biomarker YKL-40 as a new prognostic marker for all-cause mortality in patients with heart failure. AB - BACKGROUND: Despite progress in management of patients with heart failure (HF) these patients still have a poor prognosis. We tested the hypothesis whether the inflammatory biomarker YKL-40 alone or in combination with high-sensitivity C reactive protein (hs-CRP) and/or N-terminal-pro-B natriuretic peptide (NT-proBNP) could be a new prognostic biomarker for all-cause mortality in patients with HF. METHODS AND RESULTS: A total of 717 of the 1000 patients with severe left ventricular systolic dysfunction included in the EchoCardiography and Heart Outcome Study were included in Denmark and had blood sample available for serum YKL-40 determination. Mean age of patients was 70 years, and 73% were male. During the 7 years follow-up period 458 patients died. Patients were categorised according to serum YKL-40 at entry into four quartiles: quartile I with median serum YKL-40=60 MUg/L (5-95% Confidence interval (CI): 30-82), quartile II: YKL 40=107 MUg/L (CI: 86-132), quartile III: YKL-40=169 MUg/L (CI: 142-221), and quartile IV: YKL-40=286 MUg/L (CI: 230-770). Hazard ratios for all-cause mortality were with quartile I as reference 1.33 (CI: 0.99-1.80), 1.35 (CI: 0.99 1.82), and 1.54 (CI: 1.14-2.08) for serum YKL-40 II to IV quartiles, respectively following multivariable adjustment for cardiovascular risk factors (age, left ventricular ejection fraction, gender, history of heart failure, ischemic heart disease, chronic pulmonary disease, diabetes mellitus, stroke, hypertension, NT proBNP, hs-CRP, and renal function). CONCLUSION: Serum YKL-40 is significantly associated with all-cause mortality in patients with HF and could potentially be a new prognostic biomarker in these patients. PMID- 22209158 TI - Total hip arthroplasty in high dislocated and severely dysplastic septic hip sequelae. AB - The authors analyzed a consecutive series of 20 total hip arthroplasties performed using a cementless conical stem with shortening osteotomy combined with greater trochanter transfer in cases with a highly dislocated hip secondary to sequelae of a septic hip in childhood. Mean patient age was 47.3 years and the mean follow-up period was 3.4 years. An acetabular metal cup was inserted in 5 cases, and only a liner was inserted after cementing in 15 cases. Mean Harris hip score improved from 42.4 preoperatively to 84.2 at final follow-up. Mean leg lengthening was 36.5 mm, and time to greater trochanter union was 3.72 months. No complete radiolucent line of thickness >2 mm was observed in any case. These surgical methods produced satisfactory clinical and radiological results. PMID- 22209159 TI - Costs related to hip disease in patients eligible for total hip arthroplasty. AB - This study was designed to estimate direct and indirect costs incurred by hip disease in patients eligible for total hip arthroplasty (THA). Before THA, 2635 patients completed a questionnaire regarding the use of resources because of their hip disease. Costs were assigned using official statistical sources or market prices. Annual costs amounted to US$ 7666 per patient. In a regression analysis, higher annual costs were associated with working age, female gender, comorbidity, and operation waiting time more than 90 days (P < .005). The burden of disease for THA candidates is extensive, where loss of productivity is the principal cost. Long wait for surgery is associated with increased costs. This study provides baseline cost data, which will be useful for further health economic analyses and could provide guidance for health care decision makers. PMID- 22209160 TI - Internal consistency and validity of the Spanish version of the "Quebec Sleep Questionnaire" quality-of-life questionnaire for obstructive sleep apnea. AB - INTRODUCTION: There is no specific health-related quality of life (HRQL) questionnaire that has been validated in Spanish for its use in patients with sleep apnea-hypopnea syndrome (SAHS). The objective of the present study was to validate the Spanish version of the Quebec Sleep Questionnaire (QSQ). PATIENTS AND METHODS: A multi-center study including a group of patients with SAHS (AHI>=5) referred to the Sleep Unit. All patients completed the following questionnaires: SF-36, FOSQ, QSQ and Epworth scale. Internal consistency, construct validity, concurrent validity, predictive validity, repeatability and responsiveness to change of the QSQ (32 items in five domains: daytime sleepiness, diurnal symptoms, nocturnal symptoms, emotions, and social interactions) were assessed. RESULTS: A hundred twenty one patients were included in the study (mean age: 57 +/- 13; mean Epworth: 9 +/- 4; mean Body Mass Index (BMI): 28 +/- 3 kg.m(-2) and mean AHI: 36 +/- 20 hour(-1)). The factorial analysis showed a construct of five factors with similar distribution to the original questionnaire domains. Internal consistency (Cranach's alpha between 0.78 and 0.93 for the different domains), concurrent validity (compared to SF-36, Epworth scale and FOSQ), predictive validity of SAHS severity and test-retest reliability were appropriate. The test showed good responsiveness to change in diurnal (P=.003) and nocturnal symptoms domains (P=.02). CONCLUSIONS: The Spanish version of the QSQ is a valid HRQL measure with appropriate psychometric properties for use in patients with SAHS and is responsive to change in symptoms domains. PMID- 22209161 TI - In-hospital mortality pattern of severely injured children. AB - BACKGROUND: Although trauma remains a major cause of morbidity and mortality in children, less attention has been directed to this group of patients. Whilst there is considerable literature on trauma in adults, only few studies describe paediatric trauma. The aim of this study was to describe the mortality pattern of severely injured children admitted to a Danish level I trauma centre. METHODS: We included trauma patients aged 15 years or less, who subsequent a trauma team activation were admitted during the 9-year period 1999-2007. Data were collected prospectively for subjects who had a length of stay >= 72 h, were admitted to the intensive care unit (regardless of length of stay), or died in hospital. Logistic regression analysis was performed to assess independent predictors for in hospital mortality. p<0.05 was considered statistically significant. RESULTS: We included 331 patients, 199 (60.1%) boys/132 girls with a median age of 7 years and injury severity score (ISS) of 9. A total of 307/331 (92.7%) survived to discharge, and 16/24 (66.7%) deaths occurred within 24h after admission. Age was significantly lower in patients dying due to trauma (median 5 (0-15) vs. 7 (0-15) years, p=0.04, adjusted odds ratio (OR)=0.89 [95% CI: 0.80-0.99]). ISS was significantly higher in patients who died (median 25 (16-71) vs. 9 (4-29), p<0.0001, adjusted OR=1.15 [95% CI: 1.10-1.20]). CONCLUSIONS: Children who did not survive after severe trauma were significantly younger, more injured, and died early after admission. PMID- 22209162 TI - Case study thoracic radiotherapy in an elderly patient with pacemaker: the issue of pacing leads. AB - To assess clinical outcome of patients with pacemaker treated with thoracic radiation therapy for T8-T9 paravertebral chloroma. A 92-year-old male patient with chloroma presenting as paravertebral painful and compressive (T8-T9) mass was referred for radiotherapy in the Department of Radiation Oncology, Institut Curie. The patient presented with cardiac dysfunction and a permanent pacemaker that had been implanted prior. The decision of Multidisciplinary Meeting was to deliver 30 Gy in 10 fractions for reducing the symptoms and controlling the tumor growth. The patient received a total dose of 30 Gy in 10 fractions using 4-field conformal radiotherapy with 20-MV photons. The dose to pacemaker was 0.1 Gy but a part of the pacing leads was in the irradiation fields. The patient was treated the first time in the presence of his radiation oncologist and an intensive care unit doctor. Moreover, the function of his pacemaker was monitored during the entire radiotherapy course. No change in pacemaker function was observed during any of the radiotherapy fractions. The radiotherapy was very well tolerated without any side effects. The function of the pacemaker was checked before and after the radiotherapy treatment by the cardiologist and no pacemaker dysfunction was observed. Although updated guidelines are needed with acceptable dose criteria for implantable cardiac devices, it is possible to treat patients with these devices and parts encroaching on the radiation field. This case report shows we were able to safely treat our patient through a multidisciplinary approach, monitoring the patient during each step of the treatment. PMID- 22209163 TI - Antibody responses initiated by Clec9A-bearing dendritic cells in normal and Batf3(-/-) mice. AB - Injection of antigens coupled to antibodies against the dendritic cell (DC) surface molecule Clec9A has been shown to produce strongly enhanced antibody responses even without co-administration of adjuvants, via antigen presentation by DC on MHC class II and consequent production of follicular helper T cells. A series of mutant mice were tested to determine the DC subtypes responsible for this MHC II presentation of targeted antigen, compared to presentation of antigen on MHC I. A new clec9A null mouse was developed; these mice did not give enhanced antibody production, confirming the response was dependent on Clec9A-expressing DC. However targeting of antigen to Clec9A in batf3 null mice produced enhanced antibody responses despite the marked reduction in CD8(+) DC, the major Clec9A expressing DC subtype. This was shown to be dependent on efficient MHC II presentation by minor Clec9A-expressing DC subtypes in the environment of the Batf3(-/-) mice, namely early cells of the CD8 DC lineage and the plasmacytoid related CD8(+) DC subset, but not by plasmacytoid cells themselves. However in normal mice most MHC II presentation of the Clec9A-targeted antigen was by the major CD8(+) DC population, the DC also responsible for presentation on MHC I. PMID- 22209164 TI - Adaptation responses in C4 photosynthesis of maize under salinity. AB - The effect of salinity on C(4) photosynthesis was examined in leaves of maize, a NADP-malic enzyme (NADP-ME) type C(4) species. Potted plants with the fourth leaf blade fully developed were treated with 3% NaCl solution for 5d. Under salt treatment, the activities of pyruvate orthophosphate dikinase (PPDK), phosphoenolpyruvate carboxylase (PEPCase), NADP-dependent malate dehydrogenase (NADP-MDH) and NAD-dependent malate dehydrogenase (NAD-MDH), which are derived mainly from mesophyll cells, increased, whereas those of NADP-ME and ribulose-1,5 bisphosphate carboxylase, which are derived mainly from bundle sheath cells (BSCs), decreased. Immunocytochemical studies by electron microscopy revealed that PPDK protein increased, while the content of ribulose-1,5-bisphosphate carboxylase/oxygenase protein decreased under salinity. In salt-treated plants, the photosynthetic metabolites malate, pyruvate and starch decreased by 40, 89 and 81%, respectively. Gas-exchange analysis revealed that the net photosynthetic rate, the transpiration rate, stomatal conductance (g(s)) and the intercellular CO(2) concentration decreased strongly in salt-treated plants. The carbon isotope ratio (delta(13)C) in these plants was significantly lower than that in control. These findings suggest that the decrease in photosynthetic metabolites under salinity was induced by a reduction in gas-exchange. Moreover, in addition to the decrease in g(s), the decrease in enzyme activities in BSCs was responsible for the decline of C(4) photosynthesis. The increase of PPDK, PEPCase, NADP-MDH, and NAD-MDH activities and the decrease of NADP-ME activity are interpreted as adaptation responses to salinity. PMID- 22209165 TI - The effect of strobilurins on leaf gas exchange, water use efficiency and ABA content in grapevine under field conditions. AB - Strobilurins are one of the most important classes of agricultural fungicides. In addition to their anti-fungal effect, strobilurins have been reported to produce simultaneous effects in plant physiology. This study investigated whether the use of strobilurin fungicide improved water use efficiency in leaves of grapevines grown under field conditions in a Mediterranean climate in southern Spain. Fungicide was applied three times in the vineyard and measurements of leaf gas exchange, plant water status, abscisic acid concentration in sap ([ABA]), and carbon isotope composition in leaves were performed before and after applications. No clear effect on stomatal conductance, leaf water potential and intrinsic water use efficiency was found after three fungicide applications. ABA concentration was observed to increase after fungicide application on the first day, vanishing three days later. Despite this transient effect, evolution of [ABA] matched well with the evolution of leaf carbon isotope ratio, which can be used as a surrogate for plant water use efficiency. Morning stomatal conductance was negatively correlated to [ABA]. Yield was enhanced in strobilurin treated plants, whereas fruit quality remained unaltered. PMID- 22209166 TI - Comparative proteomic study reveals dynamic proteome changes between superhybrid rice LYP9 and its parents at different developmental stages. AB - Heterosis is a common phenomenon in which the hybrids exhibit superior agronomic performance than either inbred parental lines. Although hybrid rice is one of the most successful apotheoses in crops utilizing heterosis, the molecular mechanisms underlying rice heterosis remain elusive. To gain a better understanding of the molecular mechanisms of rice heterosis, comparative leaf proteomic analysis between a superhybrid rice LYP9 and its parental cultivars 9311 and PA64s at tillering, flowering and grain-filling stages were carried out. A total of 384 differentially expressed proteins (DP) were detected and 297 DP were identified, corresponding to 222 unique proteins. As DP were divided into those between the parents (DP(PP)) and between the hybrid and its parents (DP(HP)), the comparative results demonstrate that proteins in the categories of photosynthesis, glycolysis, and disease/defense were mainly enriched in DP. Moreover, the number of identified DP(HP) involved in photosynthesis, glycolysis, and disease/defense increased at flowering and grain-filling stages as compared to that at the tillering stage. Most of the up-regulated DP(HP) involved in the three categories showed greater expression in LYP9 at flowering and grain-filling stages than at the tillering stage. In addition, CO(2) assimilation rate and apparent quantum yield of photosynthesis also showed a greater increase in LYP9 at flowering and grain-filling stages than at the tillering stage. These results suggest that the proteins involved in photosynthesis, glycolysis, and disease/defense as well as their dynamic regulation at different developmental stages may be responsible for heterosis in rice. PMID- 22209167 TI - Ggamma1+Ggamma2+Ggamma3=Gbeta: the search for heterotrimeric G-protein gamma subunits in Arabidopsis is over. AB - In Arabidopsis, heterotrimeric G-proteins consist of one Galpha (GPA1), one Gbeta (AGB1) and three Ggamma (AGG1, AGG2 and AGG3) subunits. Gbeta and Ggamma subunits function as obligate heterodimers, therefore any phenotypes observed in Gbeta deficient mutants should be apparent in Ggamma-deficient mutants. Nevertheless, the first two Ggamma subunits discovered failed to explain many of the phenotypes shown by the agb1 mutants in Arabidopsis, prompting the search for additional Ggamma subunits. The recent discovery of an additional, although quite atypical, Ggamma subunit in Arabidopsis (AGG3) has helped to complete the picture and explains almost all of the missing agb1 'orphan' phenotypes. There is nevertheless still one unexplained phenotype, the reduction in rosette size reported for agb1, that has not been observed in any of the individual agg mutants or the double agg1agg2 mutant. We have now created a triple gamma mutant (agg1agg2agg3) in Arabidopsis and show that it recapitulates the remaining 'orphan'agb1 phenotypes. Triple agg1agg2agg3 mutants show the reduction in rosette size previously observed in agb1 mutants. In addition we show that small differences in flower and silique size observed between agb1 and agg3 mutants are also accounted for by the triple agg1agg2agg3 mutant. Our results strongly suggest that there are no additional members of the G-protein family remaining to be discovered in Arabidopsis. PMID- 22209168 TI - A WD40-repeat protein controls proanthocyanidin and phytomelanin pigmentation in the seed coats of the Japanese morning glory. AB - The protein complex composed of the transcriptional regulators containing R2R3 MYB domains, bHLH domains, and WDR in plants controls various epidermal traits, including anthocyanin and proanthocyanidin pigmentation, trichome and root hair formation, and vacuolar pH. In the Japanese morning glory (Ipomoea nil), InMYB1 having R2R3-MYB domains and InWDR1 containing WDR were shown to regulate anthocyanin pigmentation in flowers, and InWDR1 was reported to control dark brown pigmentation and trichome formation on seed coats. Here, we report that the seed pigments of I. nil mainly comprise proanthocyanidins and phytomelanins and that these pigments are drastically reduced in the ivory seed coats of an InWDR1 mutant. In addition, a transgenic plant of the InWDR1 mutant carrying the active InWDR1 gene produced dark-brown seeds, further confirming that InWDR1 regulates seed pigmentation. Early steps in anthocyanin and proanthocyanidin biosynthetic pathways are thought to be common. In the InWDR1 mutant, none of the structural genes for anthocyanin biosynthesis that showed reduced expression in the white flowers were down-regulated in the ivory seeds, which suggests that InWDR1 may activate different sets of the structural genes for anthocyanin biosynthesis in flowers and proanthocyanidin production in seeds. As in the flowers, however, we noticed that the expression of InbHLH2 encoding a bHLH regulator was down regulated in the seeds of the InWDR1 mutant. We discuss the implications of these results with respect to the proanthocyanidin biosynthesis in the seed coats. PMID- 22209169 TI - Recombinant human erythropoietin reduces rhabdomyolysis-induced acute renal failure in rats. AB - BACKGROUND: Rhabdomyolysis is one of the causes of acute renal failure. Erythropoietin (EPO) has been found to interact with its receptor (EPO-R) expressed in a large variety of non-haematopoietic tissues to induce a range of pleiotropic cytoprotective actions. In this study, we used recombinant human erythropoietin (rhEPO) to study the effects on the glycerol-induced rhabdomyolysis with acute renal failure in rats. METHODS: Twenty-four rats were divided into three groups as glycerol group, glycerol+EPO group and normal saline+EPO group. Rhabdomyolysis was induced by intramuscular injection of 10 mlkg(-1) 50% glycerol in rats. Ten minutes later, the rats received an intravenous injection of rhEPO (300 Ukg(-1)). Biochemical substances, including haemoglobin, blood urea nitrogen (BUN), creatinine (Cre), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT) and creatine phosphokinase (CPK), were measured at 0, 1, 3, 6, 9, 12, 18, 24 and 48 h. Rats were sacrificed 48 h later after glycerol administration and the kidneys were removed immediately for pathology and immunohistochemistry (IHC). RESULTS: Intramuscular injection of glycerol significantly increased blood BUN, Cre, GOT, GPT and CPK levels and induced severe histopathologic damage in the kidneys. Nuclear factor-kappaB (NF-kappaB) and inducible nitric oxide synthase (iNOS) were increased and E-cadherin was decreased after glycerol administration, as detected by IHC in the kidneys. Post-treatment with rhEPO decreased blood BUN, Cre, GOT, GPT and CPK levels, decreased markers of kidney injury and suppressed the release of NF-kappaB and iNOS after rhabdomyolysis. CONCLUSION: Treatment with rhEPO suppressed the activities of NF-kappaB and iNOS, decreased BUN, Cre, GOT, GPT and CPK levels, and decreased the markers of kidney injury after rhabdomyolysis. These actions ameliorated rhabdomyolysis-induced acute renal failure in rats. PMID- 22209170 TI - Concomitant laparoscopy: an effective technique for successful retrieval of intra pelvic migrated broken guide pin. PMID- 22209171 TI - Re: Mitchell R, Watson W, Curtis K, Harris I, McDougall P. Difficulties in establishing long-term trauma outcomes data collections. Could trauma outcomes be routinely monitored in New South Wales, Australia: Piloting a 3 month follow-up? doi:10.1016/j.injury.2011.01.006. PMID- 22209172 TI - Propensity-score-matched comparison of perioperative outcomes between open and laparoscopic nephroureterectomy: a national series. AB - BACKGROUND: Nephroureterectomy (NU) represents the primary management for patients with nonmetastatic upper tract urothelial carcinoma (UTUC). Either an open NU (ONU) or a laparoscopic NU (LNU) may be considered. Despite the presence of several reports comparing perioperative and cancer-control outcomes between the two approaches, no reports relied on a population-based cohort. OBJECTIVES: Examine intraoperative and postoperative morbidity of ONU and LNU in a population based cohort. DESIGN, SETTING, AND PARTICIPANTS: We relied on the US Nationwide Inpatient Sample (NIS) to identify patients with nonmetastatic UTUC treated with ONU or LNU between 1998 and 2009. Overall, 7401 (90.8%) and 754 (9.2%) patients underwent ONU and LNU, respectively. To adjust for potential baseline differences between the two groups, propensity-score-based matching was performed. This resulted in 3016 (80%) ONU patients matched to 754 (20%) LNU patients. INTERVENTION: All patients underwent NU. MEASUREMENTS: The rates of intra- and postoperative complications, blood transfusions, prolonged length of stay (pLOS), and in-hospital mortality were assessed for both procedures. Multivariable logistic regression analyses were performed within the cohort after propensity score matching. RESULTS AND LIMITATIONS: For ONU versus LNU respectively, the following rates were recorded: blood transfusions, 15% versus 10% (p<0.001); intraoperative complications, 4.7% versus 2.1% (p=0.002); postoperative complications, 17% versus 15% (p=0.24); pLOS (>=5 d), 47% versus 28% (p<0.001); in-hospital mortality, 1.3% versus 0.7% (p=0.12). In multivariable logistic regression analyses, LNU patients were less likely to receive a blood transfusion (odds ratio [OR]: 0.6; p<0.001), to experience any intraoperative complications (OR: 0.4; p=0.002), and to have a pLOS (OR: 0.4; p<0.001). Overall, postoperative complications were equivalent. However, LNU patients had fewer respiratory complications (OR: 0.4; p=0.007). This study is limited by its retrospective nature. CONCLUSIONS: After adjustment for potential selection biases, LNU is associated with fewer adverse intra- and perioperative outcomes than ONU. PMID- 22209174 TI - The impact of germline genetic variations in hydroxysteroid (17-beta) dehydrogenases on prostate cancer outcomes after prostatectomy. AB - BACKGROUND: The relationship between polymorphisms in the hydroxysteroid (17 beta) dehydrogenase (HSD17B) family of genes, which are involved in steroid hormone biotransformation, and the risk of prostate cancer (PCa) progression remains unexplored. OBJECTIVE: Determine whether inherited variations in HSD17B genes are associated with PCa progression. DESIGN, SETTING, AND PARTICIPANTS: We studied two independent Caucasian cohorts composed of 526 men with organ-confined PCa and 213 men with advanced disease who had a median follow-up of 7.4 yr and 7.8 yr after surgery, respectively. MEASUREMENTS: Patients with localised PCa were genotyped for 88 haplotype-tagging single nucleotide polymorphisms in HSD17B type 1 (HSD17B1), type 2 (HSD17B2), type 3 (HSD17B3), type 4 (HSD17B4), type 5 (HSD17B5), and type 12 (HSD17B12), and their prognostic significance on disease progression was assessed using Kaplan-Meier survival curves and Cox regression models. Positive findings were then investigated in advanced disease. RESULTS AND LIMITATIONS: After adjusting for known risk factors, 12 SNPs distributed across HSD17B2, HSD17B3, and HSD17B12 were significantly associated with risk of biochemical recurrence (BCR) in localised PCa (for variants in HSD17B2: hazard ratio [HR]: 1.92-2.93; p=0.025-0.004). In addition, four variants of HSD17B2 (rs1364287, rs2955162, rs1119933, rs9934209) were significantly associated with progression-free survival (HR: 2.96-4.69; p=0.004-0.00005) and overall survival in advanced disease (HR: 3.98-8.14; p=0.003-0.00002). Four variants of HSD17B3 and HSD17B12 were associated with a reduced risk of BCR (HR: 0.51-0.65; p=0.020 0.036) but not with progression in advanced disease. These results were generated mainly in Caucasians and should be studied in other ethnic groups. CONCLUSIONS: This study suggests a prominent role for common genetic variants in the HSD17B2 pathway in PCa progression. PMID- 22209175 TI - Impact of patients' positions on the incidence of arrhythmias during pulmonary artery catheterization. AB - OBJECTIVE: The complication of cardiac arrhythmias during pulmonary artery catheterization (PAC) may be related to the position of the patient. Therefore, the purpose of this study was to determine the effects of patients' positions on incidence of arrhythmias and the time required to place the pulmonary artery catheter. DESIGN: A prospective, double-blind, randomized, controlled study. SETTING: A tertiary university hospital. PARTICIPANTS: One hundred forty patients undergoing elective coronary artery bypass graft surgery. INTERVENTIONS: Patients were divided into 2 groups. In the study group (n = 70), patients were positioned with their head down at 10 degrees first and then 10 degrees up and tilted right laterally when the PACs were passed from the right atrium to the right ventricle and then the right ventricle to the pulmonary capillary wedge position, respectively. In the control group (n = 70), patients remained in a supine position during pulmonary artery catheterization. MEASUREMENT AND MAIN RESULT: During the catheterization, arrhythmias were recorded and classified into benign (1-3 premature ventricular contractions) and severe (more than 3 premature ventricular contractions or nonsustained ventricular tachycardia). The time for PACs to pass from the right atrium to the right ventricle and the right ventricle to the pulmonary capillary wedge position was measured as T1 and T2, respectively. The incidence of benign arrhythmias between groups was not significantly different (49% for study and 34% for control group, p = 0.196), whereas the incidence of severe arrhythmias was significantly higher in the control group (20% v 5.8%, p = 0.036). The time used for each technique (T1 and T2) in both groups was not significantly different (p = 0.362 and 0.468, respectively). One patient in the study group was excluded because of difficulty in passing the catheter from the right atrium to the right ventricle. CONCLUSIONS: Adjusting patients in the head-up and right lateral position while passing the PAC can reduce the incidence of severe arrhythmias, but not in the time taken to place it. This position may have clinical implications, particularly in high-risk patients. PMID- 22209176 TI - Value of cerebral oxygen saturation monitoring during cardiopulmonary bypass in an adult patient with moyamoya disease. PMID- 22209177 TI - Combined cesarean delivery and repair of acute ascending and aortic arch dissection at 32 weeks of pregnancy. PMID- 22209178 TI - Emerging cellular networks for regulation of T follicular helper cells. AB - The cellular networks that regulate humoral immune responses have been a focus of research over the past three decades. Studies have shown that inhibition of immune responses can be attributed to both suppressor T cells and B cells. More recently, T follicular helper (Tfh) cells have been identified as a target of immune regulation. Tfh cells are a subset of highly activated T helper cells specialized for providing cognate help to B cells during germinal center reactions. In this review, we describe emerging evidence for cellular networks that alter Tfh cell phenotype and function and regulate antibody production during the germinal center reaction. We discuss how these new findings influence our understanding of Tfh cells. PMID- 22209179 TI - A simpler method of improving visibility of the temporomandibular joint space using a polyether block. PMID- 22209180 TI - Comparative study of the effect of dexamethasone injection and consumption in lower third molar surgery. AB - The aim of this study was to compare the effect of intramuscular (IM) injection and consumption of 8 mg dexamethasone in patients after lower third molar (LTM) surgery. 20 healthy Thai patients, average age 20 years, with bilateral LTM removal were recruited for this study, a double blinded, paired sample clinical trial. The washout period was 1 month after the first operation. Clinical assessment of facial swelling, pain and maximum mouth opening were measured before and after operation for 7 days. No significant difference was found in facial swelling between IM injection and consumption of 8 mg dexamethasone after LTM surgery (paired t test P>0.05). The visual analogue scale scores for pain assessment showed no significant difference between IM injection and consumption of dexamethasone (paired t test P>0.05). The results conclude that IM injection or consumption of dexamethasone after LTM surgery can be used to control facial swelling, pain and trismus. PMID- 22209181 TI - Effect of single dose preoperative intramuscular dexamethasone injection on lower impacted third molar surgery. AB - This study aimed to investigate the effects of dexamethasone intramuscular injection 1h preoperatively, in reducing facial swelling, pain and trismus after lower impacted third molar (LITM) surgery. Twenty healthy Thai patients with both LITM surgical extraction were enrolled in the study. The washout period was 1 month after the first operation. Clinical assessment of the facial swelling, pain and trismus were measured before and after operation for 7 days and the patient's total analgesic consumption was recorded. The level of significance used in the statistical decisions was P<0.05. Preoperative intramuscular injection of single dose 8mg dexamethasone reduced postoperative swelling after LITM surgical extraction significantly on the second postoperative day, but immediately after surgery and on day 7 after the surgical extraction, no significant difference was found between the dexamethasone and control groups. Dexamethasone also reduced postoperative pain after LITM surgical extraction significantly on postoperative days 2 and 7. Additionally, the amount of paracetamol decreased significantly. There were no significant differences in trismus in the study and control groups 7 days after LITM operation. Single-dose intramuscular injection of dexamethasone can reduce postoperative facial swelling and pain, without affecting trismus after LITM surgical extraction. PMID- 22209182 TI - Custom-made intraoral mandibular distraction as treatment for neonatal airway obstruction. AB - Hypoplastic mandible related airway obstruction therapy may vary from non surgical to surgical, depending on the severity of the obstruction. Since its introduction in 1992, distraction osteogenesis (DO) has been used to lengthen the mandible. A new intraoral device is presented here. It has no need of screw fixation, whilst placement and activation are intraoral, leading to simple placement and removal. Seven cases with hypoplastic mandible related airway obstruction were treated between 2001 and 2008 with intraoral DO at the authors' institution. Six patients had a tracheostomy and one received continuous positive airway pressure (CPAP). After the distraction phase, five patients could be decanulated and in one case CPAP was no longer required. In one case the desired effect was not achieved. The findings suggest that early mandibular DO leads to damage to the permanent tooth buds resulting in missing teeth. The effectiveness of mandibular DO regarding early discharge of the patient is shown, leading to an overall cost reduction. Knowledge of alternative modalities such as mandibular DO in case of hypoplastic mandible related airway obstruction in neonatal healthcare should lead to early referral to a dedicated maxillofacial surgeon, possibly avoiding long-term airway support or tracheotomy. PMID- 22209183 TI - Epithelial-myoepithelial carcinoma with high grade transformation. AB - Epithelial-myoepithelial carcinoma (EMC) is a rare low-grade salivary gland malignancy of presumed intercalated duct origin comprising 1% of all salivary gland tumours. High grade transformation (HGT) in EMC is a recently recognised entity with only a few cases reported in the literature. The authors report an additional case of EMC with HGT involving the submandibular gland. The patient was a 60-year-old woman who requested examination of the rapid growth of a mass in the left submandibular area, which she had first noticed 20 years previously. Histologically, the tumour had two distinct carcinomatous components. One component had features of a low grade EMC. The second component consisted of polygonal cells, arranged in a solid and nested pattern, with marked nuclear pleomorphism, brisk mitotic activity, and frequent necrosis. The Ki-67 labelling index of the EMC component was 9%, and that of the high grade component was 40%. The patient developed multiple pulmonary metastases 15 months after surgery. The aggressive behaviour of EMC with HGT suggests that it is important to recognise this variant of EMC to avoid misdiagnosis and inappropriate treatment. PMID- 22209184 TI - Bismuth subgallate as a topical haemostatic agent at the palatal wounds: a histologic study in dogs. AB - This study evaluated the early recovery process of the palatal wounds of dogs using bismuth subgallate. Five healthy adult male dogs underwent eight 5-mm partial-thickness punch biopsies in two paired columns on the palatal mastigatory mucosa. For the haemostasis, one side received moistened gauze pressure (test group 1), and the other received bismuth subgallate (test group 2). A description of the epithelium and connective tissue repair was made at 3, 7, 14 and 21 days. During the first days, a mass of disorganized tissue covered the connective tissue, in which there was intense chronic inflammation, and migration of epithelium cells from the edges towards the central region to close to the wound was seen. The final evaluation demonstrated well organized epithelial and connective tissues in all the samples. Epithelium thickness was measured at 0, 14 and 21 days, from images of the digitalized histological sections. In comparisons between the test groups, the bismuth subgallate group was slightly better than the saline group, but no statistically significant difference was found at 21 days. It was possible to conclude that bismuth subgallate did not interfere in the tissue repair of the palatal mastigatory mucosa in dogs. PMID- 22209185 TI - Pneumoparotitis: a diagnostic challenge. AB - Pneumoparotitis is a rare cause of recurrent parotid swelling and its diagnosis can be challenging if the patient does not present with typical symptoms and is not in a risk group for parotitis. Several diagnostic techniques have been described in the literature including plain radiography, sialography and CT scanning. This report suggests that ultrasound is an efficient diagnostic aid and should be routinely used for the diagnosis of this condition. PMID- 22209186 TI - Multifocal cutaneous metastases from squamous cell carcinoma of hard palate. AB - Distant metastases from oral squamous cell carcinoma are unusual, but generally occur in lungs, bone, and liver. Cutaneous metastasis is extremely rare, and it often reflects an advanced stage with sinister prognosis. The authors report an 81-year-old male patient with multifocal cutaneous metastases from a recurrent squamous cell carcinoma of the hard palate 5 months after primary treatment. PMID- 22209187 TI - S100A9 in BALF is a candidate biomarker of idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, and the prognosis remains poor. On the other hand, other fibrotic interstitial pneumonias such as idiopathic nonspecific interstitial pneumonia (I-NSIP) and collagen vascular disease-associated interstitial pneumonia (CVD-IP) resemble IPF, but they respond to therapy and the prognosis is better. We searched for biomarkers to distinguish IPF from other fibrotic interstitial pneumonias and investigated whether S100A9 could be useful for discriminating types of fibrotic interstitial pneumonia based on our preliminary proteomic findings. METHODS: We measured S100A9 levels in serum and bronchoalveolar lavage fluid (BALF) from 28 patients with IPF, 15 with I-NSIP, 20 with cryptogenic organizing pneumonia (COP), 35 with CVD-IP and 23 healthy individuals (controls) using enzyme-linked immunosorbent assays. S100A9 in the lung was also immunohistochemically localized. RESULTS: S100A9 levels in BALF, but not in serum, were significantly elevated in patients with IPF compared with I-NSIP, COP, CVD-IP and healthy individuals. S100A9 immunoreactivity was localized mainly in macrophages and neutrophils in lung specimens from patients with IPF. The results of receiver operating characteristic (ROC) curve analysis showed that BALF S100A9 levels had sufficient specificity and sensitivity to distinguish IPF from I-NSIP and CVD-IP. CONCLUSION: S100A9 in BALF might serve as a candidate biomarker to discriminate between IPF and other fibrotic interstitial pneumonias. PMID- 22209188 TI - Premorbid intelligence and educational level in bipolar and unipolar disorders: a Danish draft board study. AB - BACKGROUND: Registry-based studies have found no or weak associations between premorbid intelligence and the broad entity of affective spectrum disorder, but none of the studies compared bipolar/unipolar subgroups. METHODS: IQ and educational level were assessed at the draft board, and hospital diagnoses were followed up to the ages 43-54 years for 294 individuals hospitalized with bipolar disorder and 1434 with unipolar or depressive disorder. Controls comprised 20,531 individuals without psychiatric registration. RESULTS: Mean IQs of 98.32 and 96.71 were observed for patients with bipolar and depressive disorder respectively. For both patient groups a unimodal, slightly negatively skewed distribution was observed. The difference between the two patient samples was not statistically significant (p=0.10), but both obtained lower mean scores than the controls (p<0.0001 for unipolar and p=0.057 for bipolar patients). The means of the index of educational level were 5.22 and 4.82 for bipolar and unipolar patients (p=0.0006). The mean educational level was similar to the controls in bipolar disorder (p=0.15), while it was significantly lower compared to the controls in the unipolar group (p=0.0005). When possible prodromal patients were excluded, essentially the same results were observed. LIMITATIONS: The study was based on clinical hospital admission diagnoses. CONCLUSIONS: Clinicians should be aware of the relatively high intelligence and educational level in patients with bipolar disorder compared with patients with unipolar disorder. However, we were unable to confirm distinct subgroups of bipolar disorder with high and low premorbid intelligence and educational level. PMID- 22209189 TI - Psychosocial features of depression: a systematic literature review. AB - BACKGROUND: Despite the great burden of depression on sufferers and society, there is a lack of reliable information regarding the full range of psychosocial difficulties associated with depression and their related variables. This systematic review aimed to demonstrate the utility of the International Classification of Functioning, Disability and Health (ICF) in describing the psychosocial difficulties that shape the lived experience of persons with depression. METHODS: An electronic search that included publications from 2005 to 2010 in the MEDLINE and PsycHINFO databases was conducted to collect psychosocial outcomes. Quality of studies was also considered. RESULTS: 103 studies were included. 477 outcomes referring psychosocial difficulties were extracted and grouped into 32 ICF related categories. Emotional functions (19% of studies), followed by energy and drive (17% of studies), were the most frequent psychosocial outcomes. The onset, course, determinants, and related variables of the most important psychosocial difficulties, reported in at least 10% of studies, were described. Medication played a dual role as determinant of onset and change in some psychosocial areas, e.g. in pain, sleep, and energy and drive. LIMITATIONS: The search was limited by year of publication and focused only on minor and major depression diagnoses: other depressive disorders were not included. Some underresearched, but relevant psychosocial areas could have not been analyzed. CONCLUSIONS: The present systematic review provides information on the psychosocial difficulties that depressive patients face in their daily lives. Future studies on depression should include outcome instruments that cover these relevant areas in order to comprehensively describe psychosocial functioning. PMID- 22209190 TI - A 40-week double-blind aripiprazole versus lithium follow-up of a 12-week acute phase study (total 52 weeks) in bipolar I disorder. AB - BACKGROUND: This study followed manic or mixed bipolar I subjects for an additional 40 weeks after initial randomization to 12 weeks of lithium versus aripiprazole monotherapy. This is the only long-term, double-blind study comparing lithium and aripiprazole. METHODS: Patients continued receiving either aripiprazole 15 or 30 mg/day, or lithium 900, 1200 or 1500 mg/day in a double blind fashion for 40 weeks after completing a 12-week double-blind study (52 weeks total treatment). Efficacy endpoints included adjusted mean change from baseline to Week 52 in Young Mania Rating Scale (YMRS) total score and Montgomery Asberg Depression Rating Scale (MADRS) total scores (observed cases). Remission was defined as YMRS total score<=12. Safety and tolerability were also assessed. RESULTS: Of the 66 patients who entered the extension phase, only 20 patients (30.3%) completed the entire phase (aripiprazole n=7; lithium n=13). The significant improvement that occurred over the first 12 weeks was maintained over the 40 weeks of blinded continuation (from Week 12 through Week 52). The most common treatment-emergent adverse events in the extension phase for aripiprazole were akathisia, headache, somnolence, anxiety and nasopharyngitis (all 8%), and for lithium were insomnia (15.8%), headache (13.2%), diarrhea (13.2%) and vomiting (10.5%). Mean weight change was +2.71 kg for lithium and +5.66 kg for aripiprazole (p=0.46). LIMITATIONS: This trial was not powered to statistically compare active treatments, and long-term completion rates were low in both groups. CONCLUSIONS: Aripiprazole monotherapy appears to be equivalently useful to lithium for the extended treatment of mixed or manic bipolar disorder patients. PMID- 22209191 TI - Clinical feasibility trial of a motion detection system for fall prevention in hospitalized older adult patients. AB - The purpose of this pilot study was to test the feasibility of a wireless 5 sensor, motion detection system (5S-MDS) with hospitalized older adults. Interventions to prevent hospital-based falls in older adults are important to reduce morbidity, mortality, and health care costs. Wearable motion sensors, which track and wirelessly transmit body movements, may identify human movement patterns that immediately precede falls, thus allowing early prevention. Descriptive feasibility study in which 5 hospitalized older adults were recruited to wear the 5S-MDS for 4 hours. Measurement included assessment of participant acceptance, skin integrity, and sensor accuracy. All 5 participants (mean age, 90.2 years) agreed that sensors were acceptable and skin integrity was maintained. The sensor data accurately reflected the patient movements. The 5S MDS was feasible for 4 hours' use with hospitalized older adults. It has potential as an early warning system for falls. PMID- 22209192 TI - An internet training to reduce assaults in long-term care. AB - Physical and verbal assaults by residents on care staff are not uncommon in long term residential care facilities (LTCs). This research evaluated an Internet training designed to teach nurse aides (NAs) strategies to work with aggressive resident behaviors. Six LTCs were randomized in an immediate treatment (IT) and delayed treatment (DT) design, and NAs were recruited in each (IT: n = 58; DT; n = 45). The treatment involved 2 weekly visits to the online training. Hard copy assessments collected participant responses at baseline (T1), 8 weeks (T2), and at 16 weeks (T3). The DT group viewed the program after T2. Hierarchical linear models showed significant group differences at T2 in knowledge, and these levels were maintained at T3. The number of aggressive incidents reported per day by the IT group were nonsignificant at T2 but decreased significantly from T1 to T3 with a large effect size. The program was well received by users. These results suggest that the Internet training was an effective tool to reduce assaults in LTCs, and training effects may improve over time as NAs gain experience using the techniques. PMID- 22209193 TI - Analgesic warfare: acetaminophen, really? PMID- 22209195 TI - Outcomes from the implementation of a facility-specific evidence-based falls prevention intervention program in residential aged care. AB - For residents in long-term care facilities, falling is a major concern requiring preventive intervention. A prospective cohort study measured the impact of falls reduction following the implementation of evidence-based fall prevention interventions in 9 Australian residential care facilities. An external project team provided a comprehensive audit of current practice. Facilitated by an action research approach, interventions were individualized to be facility- and patient specific and included the following: environmental modifications such as low beds and height-adjustable chairs, movement alarms, hazard removal, and hip protectors. Participants included 670 residents and 650 staff from 9 facilities across 3 states. A significant reduction of falls were observed per site in the proportion of fallers (P = .044) and single fallers (P = .04). However, overall the number of falls was confounded by multiple falls in residents. Reduction in fallers was sustained in the 6-month follow-up phase. Positive outcomes from interventions varied between facilities. Further research is necessary to target frequent fallers. PMID- 22209196 TI - Inner strength in relation to functional status, disease, living arrangements, and social relationships among people aged 85 years and older. AB - Inner strength is described as an important resource that promotes well-being. We used data from a sample of 185 people in the Umea 85+ cohort study to relate inner strength and its attributes to objective health variables. The Resilience, Sense of Coherence, Purpose in Life, and Self-Transcendence scales were used to assess aspects of inner strength, and strong correlations between the scales were found. Prevalence of heart failure, chronic obstructive pulmonary disorder, osteoporosis, or diagnosed depression was associated with low inner strength. Significant relationships were also found between high inner strength and various measures of social relationships. Participants with a higher degree of inner strength had better physical health and more satisfying social relationships. The promotion of inner strength should be a major aim of geriatric nursing. PMID- 22209197 TI - Effect of air-assisted backwashing on the performance of an anaerobic fixed-bed bioreactor that simultaneously removes nitrate and arsenic from drinking water sources. AB - Contaminant removal from drinking water sources under reducing conditions conducive for the growth of denitrifying, arsenate reducing, and sulfate reducing microbes using a fixed-bed bioreactor may require oxygen-free gas (e.g., N2 gas) during backwashing. However, the use of air-assisted backwashing has practical advantages, including simpler operation, improved safety, and lower cost. A study was conducted to evaluate whether replacing N2 gas with air during backwashing would impact performance in a nitrate and arsenic removing anaerobic bioreactor system that consisted of two biologically active carbon reactors in series. Gas assisted backwashing, comprised of 2 min of gas injection to fluidize the bed and dislodge biomass and solid phase products, was performed in the first reactor (reactor A) every two days. The second reactor (reactor B) was subjected to N2 gas-assisted backwashing every 3-4 months. Complete removal of 50 mg/L NO3- was achieved in reactor A before and after the switch from N2-assisted backwashing (NAB) to air-assisted backwashing (AAB). Substantial sulfate removal was achieved with both backwashing strategies. Prolonged practice of AAB (more than two months), however, diminished sulfate reduction in reactor B somewhat. Arsenic removal in reactor A was impacted slightly by long-term use of AAB, but arsenic removals achieved by the entire system during NAB and AAB periods were not significantly different (p>0.05) and arsenic concentrations were reduced from approximately 200 MUg/L to below 20 MUg/L. These results indicate that AAB can be implemented in anaerobic nitrate and arsenic removal systems. PMID- 22209198 TI - Characterization of intracellular & extracellular algae organic matters (AOM) of Microcystic aeruginosa and formation of AOM-associated disinfection byproducts and odor & taste compounds. AB - Algae organic matters (AOM), including intracellular organic matters (IOM) and extracellular organic matters (EOM), are causing numerous water quality issues, among which formation of disinfection byproducts (DBPs) and odor & taste (O&T) compounds are of particular concern. In this study, physiochemical properties of IOM and EOM of Microcystic aeruginosa under an exponential growth phase (2.01*10(11)/L) were comprehensively characterized. Moreover, the yields of DBPs during AOM disinfection and O&T-causing compounds were quantified. Hydrophilic organic matters accounted for 86% and 63% of DOC in IOM and EOM, respectively. Molecular weight (MW) fractions of IOM in <1 kDa, 40-800 kDa, and >800 kDa were 27%, 42%, and 31% of DOC, respectively, while EOM primarily contained 1-100 kDa molecules. Besides, a low SUVA (0.84 L/mg m) and the specific fluorescence spectra suggested that AOM (especially IOM) was principally comprised of protein like substances, instead of humic-like matters. The formation potentials of chloroform, chloroacetic acid, and nitrosodimethylamine were 21.46, 68.29 and 0.0096 MUg/mg C for IOM, and 32.44, 54.58 and 0.0189 MUg/mg C for EOM, respectively. Furthermore, the dominant O&T compound produced from EOM and IOM were 2-MIB (68.75 ng/mg C) and beta-cyclocitral (367.59 ng/mg C), respectively. Of note, dimethyltrisulfide became the prevailing O & T compound following anaerobic cultivation. PMID- 22209199 TI - Nanomedicine for treatment of diabetes in an aging population: state-of-the-art and future developments. AB - Nowadays diabetes, especially type 2 diabetes (which is strongly related to the Western diet and life-style), has developed worldwide into an epidemic disease. Nanomedicine aims to provide novel tools for diagnosis, therapy and point-of-care management of patients. Several nanotechnological approaches were developed to improve life quality for patients with insulin-dependent diabetes. They facilitate blood glucose management by non-invasive glucose measurement as well as insulin administration mainly by delivering the fragile protein as protected and targeted formulation via nasal or oral route. In the present review the oral or nasal insulin delivery by polymeric nanoparticles is discussed with focus on physiological change either related to the disease, diabetes or age-related metabolic variations influencing insulin release and bioavailability. One critical point is that new generations of targeted nanoparticle based drugs are developed and optimized for certain metabolic conditions. These conditions may change with age or disease. The influence of age-related factors such as immaturity in very young age, metabolic and physiologic changes in old age or insufficient animal models are still under-investigated not only in nanomedicine but also generally in pharmacology. Summarizing it can be noted that the bioavailability of insulin administered via routes others than subcutaneously is comparably low (max. 60%). Moreover factors like changed gut permeability as described for diabetes type 1 or other metabolic peculiarities such as insulin resistance in case of type 2 diabetes also play a role in affecting the development of novel nanoparticulated drug preparations and can be responsible for unsuccessful translation of promising animal results into human therapy. In future insulin nanoparticle development for diabetes must consider not only requirements imposed by the drug but also metabolic changes inflicted by disease or by age. Moreover new approaches are required for prevention of the disease. PMID- 22209200 TI - Protein, lipid, and hematological biomarkers in centenarians: definitions, interpretation and relationships with health. AB - As increasing numbers of individuals reach very advanced age, it is important to understand the influence of modifiable lifestyle factors such as diet and nutrition on both the achievement of exceptional longevity as well as the maintenance of optimal functional capacity. This includes determining the most appropriate biomarkers for monitoring changes in health and nutrition status and response to therapy in oldest old individuals. In an earlier work (Hausman et al., Maturitas 2011;68:203-9), we summarized studies of dietary intake and patterns of long-lived peoples and presented the current knowledge regarding vitamin B12, folate, 25(OH) vitamin D and other specific indicators of nutritional status in centenarians. The present review focuses on less specific biochemical indices of health and nutritional status and summarizes studies comparing protein, lipid and hematological biomarkers in centenarians and older adult controls. Such studies, from many countries worldwide, are often small, convenience samples of 'healthy' and/or community-dwelling centenarians, although a few population-based studies including participants with a broader range of physical and cognitive functioning are also presented. Though heterogeneous in design and demographic region, these studies typically show lower levels of protein and hematological indicators and improved levels of some lipid biomarkers in centenarians as compared with regionally matched older adult controls. As these biomarkers can be influenced by many factors interpretation of results must be approached with caution. Importantly, studies examining potential associations of these biomarkers with cognitive, mental and physical function must carefully control for potential confounders including genetics and chronic disease, an increasing burden at advanced age. PMID- 22209202 TI - Crohn's disease and Mycobacterium avium subsp. paratuberculosis: the need for a study is long overdue. AB - The initial suggestion that Mycobacterium avium subsp. paratuberculosis (Map) might be involved in the pathogenesis of Crohn's disease (CD) was based on the apparent similarity of lesions in the intestine of patients with CD with those present in cattle infected with Map, the etiological agent of Johne's disease (JD). Recent investigations have now revealed the presence of Map or Map DNA in blood or lesions from adults and children with CD. Of special interest, Map has also been found in patients with other diseases as well as healthy subjects. The latter observations indicate all humans are susceptible to infection with Map and that, like with other mycobacterial pathogens such as Mycobacterium tuberculosis, infection does not invariably lead to development of clinical disease but rather development of a persistent latent stage of infection where an immune response controls but does not eliminate the pathogen. Limited information has been obtained on the immune response to Map in healthy subjects and patients with CD. Understanding how Map may be involved in the pathogenesis of CD will require a better understanding of the immune response to Map in one of its common hosts as well as healthy humans and patients with CD. PMID- 22209201 TI - Vitamin D intake and mental health-related quality of life in older women: the Iowa Women's Health Study. AB - OBJECTIVE: Vitamin D deficiency and mood disorders are both prevalent among the elderly. We evaluated the association between vitamin D intake and mental health related quality of life (QOL) among elderly women participating in a large population-based study. STUDY DESIGN: This study was a cross-sectional analysis of the Iowa Women's Health Study, a prospective study of cancer risk factors among post-menopausal women in Iowa that began in 1986. Additional survey data was collected from the cohort members in 1987, 1989, 1992, 1997, and 2004. Data for this analysis came from the 2004 questionnaire. MAIN OUTCOME MEASURE: Mental health-related QOL was assessed using five scales from the Medical Outcomes Study 36-item Short-form Health Survey. QOL scores were analyzed as continuous variables using linear regression, controlling for age, energy intake, BMI, education, smoking, living arrangement, antidepressant usage, comorbidity history, and physical activity. RESULTS: Low vitamin D intake (<400 IU/day) was associated with poorer QOL scores compared to women with higher intake (>=400 IU/day). Differences in QOL scores by vitamin D intake group were attenuated with multivariable adjustment, but a significant overall association between vitamin D and QOL scores persisted. Further adjustment for physical activity attenuated all differences as well as the overall association between vitamin D and QOL scores. CONCLUSIONS: Women who consumed <400 IU/day of vitamin D had significantly lower mental health-related QOL compared to those who consumed >=400 IU/day. Meeting dietary vitamin D recommendations is a potential method for improving QOL among the elderly. PMID- 22209203 TI - Molecular cloning and expression analysis of the canine chemokine receptor CCR9. AB - The chemokine receptor CCR9, which interacts with the thymus-expressed chemokine TECK/CCL25, contributes to the localization of lymphocytes to the small intestine, and is implicated in the development of human inflammatory bowel disease (IBD); however, their role in canine IBD is unknown. The objective of this study was to isolate cDNA encoding CCR9 and to investigate CCR9 expression in normal canine tissues and lymphoid cell lines. The complete open reading frame contained 1104 bp, encoding 367 amino acids, with 85% and 81% identity to human and mouse homologs, respectively. CCR9 mRNA was detected in all tissues investigated with the highest expression level in the small intestine. CCR9 mRNA was also expressed in GL-1, a canine B cell leukemia cell line, but not in CLBL 1, a canine B cell lymphoma cell line. Immunoblot and flow cytometry analyses of these cell lines using an anti-human CCR9 monoclonal antibody revealed that CCR9 protein expression was detected only in GL-1, indicating the cross-reactivity of the antibody. Using the antibody, flow cytometry showed that the proportions of CCR9(+) cells were small (mean, 4.88%; SD, 2.15%) in the normal canine PBMCs. This study will be useful in understanding canine intestinal immunity and the immunopathogenesis of canine IBD. PMID- 22209204 TI - Localization of linear B-cell epitopes on goose parvovirus structural protein. AB - Goose parvovirus (GPV), a small non-enveloped ssDNA virus, can cause Derzsy's disease, a highly contagious and lethal disease in goslings and muscovy ducklings, leading to a huge economic loss. However, little is known about the localization of B-cell epitopes on GPV structural protein. To address the issue, the structural protein of GPV was dissected into sets of partially overlapping fragments and expressed in Escherichia coli. Then Western blot reactivity of these glutathione S-transferase (GST) fusion short peptides to viral infected sera was surveyed. The results showed linear immunodominant epitopes, which were found in seven fragments covering amino acid residues 35-71, 123-198, 423-444, 474-491, 531-566, 616-669, 678-732. Our findings may provide the basis for the development of immunity-based prophylactic, therapeutic, and diagnostic clinical techniques for Derzsy's disease. PMID- 22209205 TI - Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists. AB - Clinical genetic data have shown that the product of the SCN9A gene, voltage gated sodium ion channel Nav1.7, is a key control point for pain perception and a possible target for a next generation of analgesics. Sodium channels, however, historically have been difficult drug targets, and many of the existing structure activity relationships (SAR) have been defined on pharmacologically modified channels with indirect reporter assays. Herein we describe the discovery, optimization, and SAR of potent aminopyrimidinone Nav1.7 antagonists using electrophysiology-based assays that measure the ligand-receptor interaction directly. Within this series, rapid functionalization at the polysubstituted aminopyrimidinone head group enabled exploration of SAR and of pharmacokinetic properties. Lead optimized N-Me-aminopyrimidinone 9 exhibited improved Nav1.7 potency, minimal off-target hERG liability, and improved rat PK properties. PMID- 22209206 TI - Discovery of potent and liver-targeted stearoyl-CoA desaturase (SCD) inhibitors in a bispyrrolidine series. AB - Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model. PMID- 22209207 TI - Preparation and characterization of a novel polymorph of indiplon, Form alpha. AB - A new polymorph alpha of indiplon was discovered, initially prepared by two methods, and further characterized by various means including single-crystal X ray diffraction (SCXRD), powder X-ray diffraction (PXRD), variable temperature powder X-ray diffraction (VT-PXRD), differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), Fourier transform Raman (FT-Raman) spectroscopy and solubility determination. The crystal structure of Form alpha as analyzed by SCXRD differ from the three previously reported polymorphs, Form I, II, and III. In addition, PXRD and solubility measurements could clearly distinguish between Form alpha and Form I. Slight differences between the two forms were also detected by FT-Raman. No differences between Form alpha and I were observed by DSC, which was explained by VT-PXRD results showing a solid-solid phase change from Form alpha to Form I during the heating process. Solubility measurements at various temperatures showed that the two polymorphs were mutually monotropic and that Form I was the relatively thermodynamically stable crystal form. PMID- 22209208 TI - Dissolution and transport of coal tar compounds in fractured clay-rich residuum. AB - We investigated the dissolution and transport of organic contaminants from a crude coal tar mixture in a monolith of fractured clay-rich residuum. An electrolyte solution was eluted through the residuum monolith containing a small emplaced source of coal tar under biologically inhibited and mildly acidic conditions. Concentrations of 10 coal tar compounds, representing mono-, poly-, and heterocyclic aromatic hydrocarbons that constitute crude coal tar were monitored in the effluent over a period of 377 days. Most compounds appeared in the effluent within the first 0.1 pore volume eluted indicating the importance of rapid dissolution and transport through the fracture networks. The concentrations continued to rise but did not reach the corresponding effective solubility limit in most cases. Compounds that were less soluble and those that were more susceptible to sorption or matrix diffusion eluted at a much slower rate. Analysis of contaminant concentrations in microcore residuum samples indicated that all 10 compounds had spread throughout the entire monolith and had diffused into the fine-grained matrix between fractures. These data suggest that the predominantly fine pore structure did not appear to inhibit coal tar dissolution and subsequent transport, even though only a small portion of tar was in direct contact with fractures and macropores that control most flow. PMID- 22209209 TI - Intraosseous pseudotumor of the distal radius in a patient with hemophilia: case report. AB - Hemophilic pseudotumors are rare, particularly when they occur in the distal extremity of an adult patient. We present the case of a 68-year-old man with well controlled factor VIII deficiency who presented with a lytic lesion of the distal radius that was identified as an intraosseous pseudotumor. PMID- 22209210 TI - The use of Integra in hand and upper extremity surgery. PMID- 22209211 TI - Cellular apoptosis and proliferation in the middle and late intrasynovial tendon healing periods. AB - PURPOSE: Cellular apoptosis might be an important molecular event in the middle or late healing periods of intrasynovial tendons, but this has not been studied. We aimed to investigate cellular apoptosis and corresponding cellular proliferation in the middle and late healing stages of intrasynovial tendons. METHODS: The flexor digitorum profundus tendons of 48 long toes (24 chickens) were completely transected within the sheath region and were repaired surgically. At days 28, 42, 56, and 84 after surgery, tendons were harvested and sectioned. In situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to detect apoptotic cells. The sections were stained immunofluorescently with antibodies to proliferating cell nuclear antigen to assess proliferation and to Bcl-2 (an anti-apoptotic protein). Positively stained tenocytes were counted, and their distributional differences were verified in 3 dimensional images. RESULTS: The repaired intrasynovial tendons exhibited generally greater apoptosis in the surface region than in the core. The differences were more remarkable in the extended region than in the junction region of the cut tendon. At the core of the junction site, apoptosis of tenocytes was pronounced at all time points, but it was less severe at the core of the extended region. The proliferating cell nuclear antigen-positive and Bcl-2 positive tenocytes decreased significantly and continually at days 28, 42, and 56, respectively; these tenocytes were at a minimum at days 56 and 84. CONCLUSIONS: Apoptotic changes of tenocytes are most marked in the surface region and in the junction region of the healing tendon in the middle and late healing stages. Apoptosis in the core is less dramatic compared to that in the surface in the extended tendon regions. Cellular proliferation declines drastically and is minimal at days 56 and 84. CLINICAL RELEVANCE: Tenocyte apoptosis in the middle and late stages might be an important event contributing to intrasynovial tendon remodeling, which affects the healing strength and formation of adhesions. PMID- 22209212 TI - Surgical repair of multiple pulley injuries--evaluation of a new combined pulley repair. AB - PURPOSE: We report on a combined repair of multiple annular pulley tears using 1 continuous palmaris longus tendon graft to restore strength and function. METHODS: We treated 6 rock climbers with grade 4 pulley injuries (multiple pulley injuries) using the combined repair technique and re-evaluated them after a mean of 28 months. RESULTS: All patients had excellent Buck-Gramcko scores; the functional outcome was good in 4, satisfactory in 1, and fair in 1. The sport specific outcome was excellent in 5 and satisfactory in 1. Proximal interphalangeal joint flexion deficit slightly increased in 1 patient and remained the same in the other 5. Climbing level after the injury was the same as before in 4 and decreased slightly in 2 climbers. CONCLUSIONS: The technique is effective with good results and has since become our standard treatment. Nevertheless, it is limited in patients with flexion contracture of the proximal interphalangeal joint. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 22209213 TI - Hydrogen decreases athero-susceptibility in apolipoprotein B-containing lipoproteins and aorta of apolipoprotein E knockout mice. AB - OBJECTIVE: It is to characterize the underlying molecular mechanisms of the anti atherosclerotic effects of hydrogen (dihydrogen; H(2)), a novel antioxidant. In particular, to examine the effects of hydrogen on athero-susceptibility in lipoproteins and aorta of apolipoprotein E knockout (apoE-/-) mice. METHODS AND RESULTS: Plasma analysis by enzymatic method and spectrophotometric measurement showed that eight weeks intraperitoneally injection of hydrogen-saturated saline remarkably decreased plasma total and non-high-density lipoprotein (non-HDL) cholesterol, and malondialdehyde in apoE-/- mice fed either chow or high fat diet. Western blot analysis showed hydrogen treatment reduced the contents of apolipoprotein B (apoB), a major protein constituent of non-HDL in either plasma or hepatic tissues. Moreover, ELISA assay revealed that the production of tumor necrosis factor-alpha and interleukin-6 were significantly suppressed by hydrogen in RAW264.7 macrophages, after stimulation with the isolated non-HDL from treated or untreated mice. Immunohistochemistry of aortic valve sections revealed that hydrogen suppressed the expression of several proinflammatory factors and decreased vessel wall infiltration of macrophages. Besides, real-time PCR and Western blot analysis disclosed that hepatic scavenger receptor class B type I (SR-BI), ATP-binding cassette (ABC) transporters ABCG8, ABCB4, ABCB11, and macrophage SR-BI, were all induced by hydrogen treatment. Finally arterial wall lipid disposition displayed by oil red O staining was reduced significantly in aortic root and whole aorta en face in hydrogen administrated mice. In addition, hydrogen significantly improved HDL functionality in C57BL/6J mice assessed in two independent ways, namely (i) stimulation of cholesterol efflux from macrophage foam cells by measuring HDL-induced [(3)H]cholesterol efflux, and (ii) protection against LDL oxidation as a measure of Cu(2+)-induced TBARS formation. CONCLUSION: These results reveal that administration of hydrogen-saturated saline decreases athero-susceptibility in apoB-containing lipoprotein and aortic atherosclerosis in apoE-/- mice and improves HDL functionality in C57BL/6J mice. PMID- 22209214 TI - Angiotensin converting enzyme inhibitors effect on arterial stiffness and wave reflections: a meta-analysis and meta-regression of randomised controlled trials. AB - OBJECTIVE: Several studies have assessed the effect of angiotensin converting enzyme inhibitors (ACEIs) on arterial stiffness and wave reflections as measured by pulse wave velocity (PWV) and augmentation index (AIx), respectively. We conducted a meta-analysis to investigate this effect in comparison to placebo and to other antihypertensive agents. Additionally, we investigated this effect when ACEIs are combined with other antihypertensive agents and in comparison to a combination of antihypertensive agents. METHODS: MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to May 2011 on randomised controlled trials (RCTs) which assessed the effect of ACEIs on arterial stiffness vs. placebo or no treatment and ACEIs vs. angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), beta-blockers and diuretics. RCTs which assessed the effect of ACEIs combined with other antihypertensives or compared ACEIs with a combination of antihypertensives were also sought. Data from included RCTs were pooled with use of fixed and random effects meta-analysis of the weighted mean change differences between the comparator groups. Heterogeneity across studies was assessed with the I(2) statistic. RESULTS: In 5 trials including 469 patients, treatment with ACEIs (n=227) vs. placebo (n=216) significantly reduced PWV (pooled mean change difference -1.69, 95% C.I. -2.05, -1.33, p<0.00001 with insignificant heterogeneity). In 9 trials which included 378 patients, treatment with ACEIs (n=178) insignificantly reduced PWV when compared with other antihypertensives (ARBs, CCBs, beta-blockers, diuretics and a combination of ACEI and ARB) (n=220) (pooled mean change difference -0.19, 95% C.I. -0.59, 0.21, p=0.36, I(2)=0%). ACEI effect on AIx in comparison to placebo was assessed in 7 trials. Treatment with ACEIs significantly reduced AIx (pooled mean change difference -3.79, 95% C.I. -5.96, -1.63, p=0.0006) with significant heterogeneity. In 7 trials, treatment with ACEIs significantly reduced AIx when compared with other antihypertensives (pooled mean change difference -1.84, 95% C.I. -3, -0.68, p=0.002, I(2)=32%, p for heterogeneity=0.11). However, this effect was only significant when compared with beta-blockers (pooled mean change difference -1.6, 95% C.I. -2.84, -0.36, p=0.01). Mean BP differences between baseline and end of treatment did not predict the treatment (ACEI) induced changes in PWV. CONCLUSIONS: ACEIs reduce PWV and AIx which are markers of arterial stiffness and wave reflections in patients with different pathological conditions. However, due to the lack of high quality and properly powered RCTs, it is not clear whether ACEIs are superior to other antihypertensive agents in their effect on arterial stiffness. The ability of ACEIs to reduce arterial stiffness (PWV) seems to be independent of its ability to reduce BP. PMID- 22209215 TI - Effects of motivational interviewing intervention on self-management, psychological and glycemic outcomes in type 2 diabetes: a randomized controlled trial. AB - BACKGROUND: Type 2 diabetes is a serious and growing problem in Taiwan where it is the fifth leading cause of death, and health care costs are 4.3 times higher than for people without diabetes. OBJECTIVES: The purpose of this study was to determine whether participation in a motivational interview for people with type 2 diabetes would improve their self-management, psychological and glycemic outcomes. DESIGN: A randomized controlled trial to assess the effects of the motivational interviewing intervention. SETTINGS: Participants were drawn from the diabetes outpatient clinic of a large teaching hospital in South Taiwan. PARTICIPANTS: A sample of 250 type 2 diabetes people. METHODS: Type 2 diabetes people were randomly allocated into either the motivational interview group or the usual care group from baseline to 3 months follow-up. The intervention was based on motivational interviewing which encompassed a variety of interviewing techniques, and reflected each person's readiness stage to change. The control group was provided with usual care by nursing staff. RESULTS: A total of 250 type 2 diabetic participants were randomized. The retention rate in the intervention group was 83% (n=104). The motivational interview did improve participants significantly in self-management, self-efficacy, quality of life, and HbA1c among diabetes people with appropriate baseline value (<121.24, <174.57, <107.18, and >7.62, respectively) but not in depression, anxiety and stress (F=0.13, p=0.72) compared to the control group at 3 months follow-up. CONCLUSION: The findings provided important evidence concerning the positive effect of motivational interventions in self-management, psychological and glycemic outcomes. This research provided evidence for future clinical practices in diabetes care. PMID- 22209216 TI - Reshaping the optical dimension in optogenetics. AB - Optogenetics has been revolutionizing circuit neuroscience in the last few years. Optical methods combined with genetics and molecular techniques have provided new tools for stimulation of neurons, which hold great promise to provide a solution to the circuit mapping problem and more generally provide us with the ability to artificially control the natural stimulus space. Nevertheless, until very recently almost all applications of optogenetics have been based on relatively simple optical schemes mainly used for inducing population activity in neuronal assembles. In this context, alternative optical schemes that enhance the spatial or temporal resolution of excitation and allow for flexible and arbitrary generation of light patterns have all synergetic impact on the development of new optogenetic actuators. In the following we discuss and compare the main new optical techniques that have become available in the recent years. Their respective strengths and limitations as well as their application to different biological contexts are illustrated. PMID- 22209217 TI - LjABCB1, an ATP-binding cassette protein specifically induced in uninfected cells of Lotus japonicus nodules. AB - Legume plants develop root nodules through symbiosis with rhizobia, and fix atmospheric nitrogen in this symbiotic organ. Development of root nodules is regulated by many metabolites including phytohormones. Previously, we reported that auxin is strongly involved in the development of the nodule vascular bundle and lenticel formation on the nodules of Lotus japonicus. Here we show that an ATP-binding cassette (ABC) protein, LjABCB1, which is a homologue of Arabidopsis auxin transporter AtABCB4, is specifically expressed during nodulation of L. japonicus. A reporter gene analysis indicated that the expression of LjABCB1 was restricted to uninfected cells adjacent to infected cells in the nodule, while no expression was observed in shoot apical meristems or root tips, in which most auxin transporter genes are expressed. The auxin transport activity of LjABCB1 was confirmed using a heterologous expression system. PMID- 22209218 TI - Characterization of L-phenylalanine metabolism to acetophenone and 1 phenylethanol in the flowers of Camellia sinensis using stable isotope labeling. AB - Acetophenone (AP) and 1-phenylethanol (1PE) are the two major endogenous volatile compounds in flowers of Camellia sinensis var. Yabukita. Until now no information has been available on the biosynthesis of AP and 1PE in plants. Here we propose that AP and 1PE are derived from L-phenylalanine (L-Phe), based on feeding experiments using stable isotope-labeled precursors L-[(2)H(8)]Phe and L [(13)C(9)]Phe. The subacid conditions in the flowers result in more hydrogenation than dehydrogenation in the transformation between AP and 1PE. Due to the action of some enzyme(s) responsible for the formation of (R)-1PE from AP in the flowers, (R)-1PE is the dominant endogenous steroisomer of 1PE. The modification of 1PE into nonvolatile glycosidic forms is one of the reasons for why only a little 1PE is released from the flowers. The levels of AP, 1PE, and glycosides of 1PE increase during floral development, whereas the level of L-Phe decreases. These metabolites occur mostly in the anthers. PMID- 22209219 TI - Actin bundler PLIM2s are involved in the regulation of pollen development and tube growth in Arabidopsis. AB - Microspores develop inside the anther, where they are surrounded by nourishing tapetal cells. However, many cellular processes occurring during microspore development in the locule are poorly characterized. The actin cytoskeleton is known to play a crucial role in various aspects of the plant developmental process. During pollen tube tip growth, actin cytoskeleton serves as an efficient molecular transportation track, although how it functions in pollen development is unknown. The plant actin bundler PLIM2s have been shown to regulate actin bundling in different cells. Here, we investigate the biological function of three Arabidopsis pollen-specific LIM proteins, PLIM2a, PLIM2b, and PLIM2c (collectively, PLIM2s), in pollen development and tube growth. Variable degrees of suppressed expression of the PLIM2s by RNA interference resulted in aberrant phenotypes. Complete suppression of the PLIM2s totally disrupted pollen development, producing abortive pollen grains and rendering the transgenic plants sterile. Partial suppression of the PLIM2s arrested pollen tube growth to a lesser extent, resulting in short and swollen pollen tubes. Finally, the PLIM2c promoter initiated expression in pollen during stamen filament elongation, and the PLIM2c protein was located on particle structures in the developing pollen grains in Arabidopsis. These suggest that the actin bundler, PLIM2s, are an important factor for Arabidopsis pollen development and tube growth. PMID- 22209220 TI - Enhanced oxidative stress in the ethylene-insensitive (ein3-1) mutant of Arabidopsis thaliana exposed to salt stress. AB - To better understand the role of ethylene signaling in plant stress tolerance, salt-induced changes in gene expression levels of ethylene biosynthesis, perception and signaling genes were measured in Arabidopsis thaliana plants exposed to 15 days of salinity. Among the genes analyzed, EIN3 showed the highest expression level increase under salt stress, suggesting a key role for this ethylene-signaling component in response to salt stress. Therefore, we analyzed the salt stress response over 15 days (by adding 100 mM NaCl to the nutrient solution) in the ein3-1 mutant compared to the wild-type (Col-0) in terms of growth, oxidative stress markers (lipid peroxidation, foliar pigments and low molecular-weight antioxidants) and levels of growth- and stress-related phytohormones (including cytokinins, auxins, gibberellins, abscisic acid, jasmonic acid and salicylic acid). The ein3-1 mutant grew similarly to wild-type plants both under control and salt stress conditions, which was associated with a differential time course evolution in the levels of the cytokinins zeatin and zeatin riboside, and the auxin indole-3-acetic acid between the ein3-1 mutant and the wild-type. Despite showing no signs of physiological deterioration under salt stress (in terms of rosette biomass, leaf water and pigment contents, and PSII efficiency) the ein3-1 mutant showed enhanced lipid peroxidation under salt stress, as indicated by 2.4-fold increase in both malondialdehyde and jasmonic acid contents compared to the wild-type. We conclude that, at moderate doses of salinity, partial insensitivity to ethylene might be compensated by changes in endogenous levels of other phytohormones and lipid peroxidation-derived signals in the ein3-1 mutant exposed to salt stress, but at the same time, this mutant shows higher oxidative stress under salinity than the wild-type. PMID- 22209221 TI - HBD-1 and hBD-2 expression in HaCaT keratinocytes stimulated with nicotine. AB - OBJECTIVE: The impact of nicotine on the local innate immune response in the oral cavity is unclear. The aim of the present study was to evaluate the possible effects of nicotine on the gene expression of human beta-defensin-1 and -2 in HaCaT keratinocytes. MATERIALS AND METHODS: HaCaTs were cultured in six-well plates in Dulbecco's minimum essential medium (DMEM) supplemented with 10% FBS at a density of *10(6). Cells were pretreated with 10 MUg/ml nicotine (12 h), and then stimulated with 50 ng/ml TNF-alpha (during the following 12 h); or were pretreated with 50 ng/ml TNF-alpha, and then stimulated with 10 MUg/ml nicotine; or were not pretreated but only stimulated with either nicotine or TNF-alpha, or a combination of both. Total RNA was extracted and analysed by real-time RT-PCR for human beta-defensins-1-, -2-, and interleukins IL-1beta- and IL-6-, as well as GAPDH-mRNA. The obtained data were analysed using Tukey's B multiple comparison test for post hoc analysis. RESULTS: Pretreatment with nicotine caused a significant 2.5-fold inhibition of TNF-alpha-stimulated hBD-2 mRNA expression compared to TNF-alpha alone (p = 0.004). Simultaneous treatment with TNF-alpha and nicotine caused a significant 2-fold inhibition of hBD-2 mRNA compared to TNF alpha alone (p = 0.041). CONCLUSION: The present results suggest that the pre exposition to nicotine seems to reduce a stimulating effect of TNF-alpha on the gene expression of hBD-2. PMID- 22209222 TI - Exploring hospice patients' views about participating in research. PMID- 22209223 TI - The pharmacokinetics and pharmacogenetics of the antiemetic cyclizine in palliative care patients. AB - CONTEXT: Cyclizine, an antihistaminic antiemetic, is commonly used in palliative care. Its pharmacokinetics have been poorly studied, and its metabolic pathway is unknown but may involve the genetically controlled cytochrome P450 2D6 (CYP2D6). If this is the case, the metabolic ratio of cyclizine to norcyclizine and efficacy/adverse effects may vary between patients according to their CYP2D6 genotype. OBJECTIVES: To deduce the pharmacokinetics and antiemetic/sedative effects of cyclizine and relate these and its metabolic ratio to the CYP2D6 genotype in palliative care patients. METHODS: Palliative care patients initiated on continuous cyclizine subcutaneous (SC) infusions had blood samples taken and efficacy/toxicity scores measured during the approach to steady state. Another group of patients at steady state receiving oral cyclizine had a single blood sample taken. Samples were analyzed to elucidate pharmacokinetic parameters and CYP2D6 genetics. RESULTS: SC dosing group: The median (interquartile range) cyclizine half-life, volume of distribution, and clearance were 13 (7-48) hours, 23 (12-30)L/kg, and 15 (11-26)mL/min/kg, respectively. Nausea and sedation scores were 3.0 (1.2-5.7) and 5.0 (2.6-8.1), respectively, overall and did not vary with genotype (P=0.76 and 0.11, respectively). The median overall metabolic ratio at steady state was 4.9 (3.8-9.2) and did vary with CYP2D6 genotype (P=0.02). Oral dosing group: The median metabolic ratio was 2.1 (1.5-2.9) and did not vary with CYP2D6 genotype (P=0.37). CONCLUSION: Palliative care patients have similar cyclizine pharmacokinetics to those reported in other patient groups. Cyclizine metabolism to norcyclizine may include CYP2D6 as the metabolic ratio varied with CYP2D6 genotype in the SC group. PMID- 22209224 TI - Improving outcomes for people with progressive cancer: interrupted time series trial of a needs assessment intervention. AB - CONTEXT: Improving the effectiveness of cancer care delivery has become a major focus of research. OBJECTIVES: This study assessed the uptake and impact of the Palliative Care Needs Assessment Guidelines and Needs Assessment Tool: Progressive Disease--Cancer (NAT: PD-C) on the outcomes of people with advanced cancer. METHODS: Given widely varying survival in people with advanced cancer, an interrupted time series design was used, with data on unmet needs, depression, anxiety, and quality of life collected from 195 patients using telephone interviews every two months, for up to 18 months. Patients completed at least two baseline interviews before health professionals were academically detailed in the use of the Palliative Care Needs Assessment Guidelines and NAT: PD-C. Health professionals completed the NAT: PD-C with patients approximately monthly for the remainder of the study. Changes in patients' outcomes were compared prior to and following the introduction of the NAT: PD-C using general estimating equations. RESULTS: Moderate to high needs across all domains were frequently seen in the preintervention phase. The use of the NAT: PD-C was associated with a significant reduction in health system and information and patient care and support needs. CONCLUSION: These resources have the potential as an efficient and acceptable strategy for supporting needs-based cancer care. Further work is required to determine their unique contribution to improvements in patient outcomes. PMID- 22209225 TI - Enzymatic activity and genetic variation in SCD1 modulate the relationship between fatty acids and inflammation. AB - Fatty acids (FA) represent a diverse class of molecules known to regulate inflammatory pathways. Therefore enzymes that regulate FA metabolism are attractive candidates to better understand the relationship between FA and inflammation. Stearoyl-CoA desaturase 1 (SCD1) is rate limiting for the conversion of saturated FA (SFA) to monounsaturated FA (MUFA). Evidence suggests that SCD1 activity may be positively associated with inflammation. Moreover, genetic variation in SCD1 may alter enzyme activity; however, it is unknown whether this affects inflammatory status. The goal of this study was to examine the relationships between plasma FA, SCD1 activity, and SCD1 polymorphisms with C reactive protein (CRP) levels in young adults. SFA, MUFA, and CRP were measured in fasted plasma samples from European (n=279, 198 female and 81 male) and Asian (n=249, 179 female and 70 male) subjects, 20-29 years old. Circulating levels of palmitic (16:0), palmitoleic (16:1), stearic (18:0), and oleic acids (18:1) were measured by gas chromatography and SCD1 activity was estimated by the ratio of product to precursor (16:1/16:0; 18:1/18:0). Positive associations were identified between CRP levels and 16:0 (p<2.0*10(-4)), 16:1 (p<0.05), and the SCD1 index (18:1/18:0; p<6.0*10(-3)) in European and Asian females, while 18:0 was inversely associated with CRP (p<2.0*10(-4)) in both groups. Ten single nucleotide polymorphisms (SNPs) in SCD1 were genotyped in all subjects. One SNP (rs2060792) was associated (p<0.05) with 16:0 and 18:0 levels in females of European descent. This same SNP was also associated with CRP levels in both groups of females (p<0.05). Overall, SCD1 activity and genetic variation have an important role in modulating the relationship between FA and inflammation in young adults. PMID- 22209226 TI - A hyperbaric oxygen chamber for animal experimental purposes. AB - Facilities for hyperbaric oxygen therapy that are suitable for animal experimental research are scarce. In this paper, the authors introduce a hyperbaric oxygen chamber that was developed specifically for animal experimental purposes. The hyperbaric oxygen chamber was designed to meet a number of criteria regarding safety and ease of use. The hyperbaric oxygen chamber conforms to 97/23/EC (Pressure Equipment Directive), Conformity Assessment Module G Product Group 1. It provides easy access, and can be run in manual mode, semi-automatic mode and full-automatic mode. Sensors for pressure level, oxygen level, temperature, humidity and carbon dioxide level allow full control. This state-of the-art hyperbaric oxygen chamber for animal experimental purposes permits the investigation of the biological mechanisms through which hyperbaric oxygen therapy acts at a fundamental level. PMID- 22209227 TI - The influence of a Le Fort I impaction and advancement osteotomy on smile using a modified alar cinch suture and V-Y closure: a prospective study. AB - A previous report from the authors' department showed that a modified alar cinch suture combined with a muco-musculo-periosteal V-Y closure (mACVY) improves nasolabial mobility. To test if the improvements were equal to the range of nasolabial mobility in non-dysgnathic persons, a prospective study was carried out in 56 patients: 31 with mACVY, 25 with simple closing sutures (SCS) and 18 non-operated, angle class I volunteers. Standardized full facial frontal photographs, taken immediately preoperatively and 18 months postoperatively were used. The landmarks, alare, crista philtri and cheilion were analysed. The test has a standard deviation of 0.9 mm. Intra-group changes, paired t-test, and inter group differences, unpaired t-test (p<0.05) were statistically analysed. The results show significant preoperative differences in nasolabial mobility compared with the control group, for both groups. Postoperative mobility improved in both groups, but significantly with mACVY with horizontal movement of cheilion and alare, and the vertical movement of crista philtri and less so for the vertical movement of crista philtri with SCS. Postoperative inter-group differences in mobility were small and significant for SCS vs the control group. It can be concluded that using mACVY improves orofacial movement to the level of normal class I volunteers. PMID- 22209228 TI - Carcinoma ex pleomorphic adenoma of the upper lip. AB - Carcinoma ex pleomorphic adenoma (CXPA) is a rare salivary gland malignancy most often reported within the parotid gland. Of the salivary gland tumours that occur within the minor salivary glands at least 50% are reported to be malignant. This proves to be inaccurate when describing salivary gland tumours within the upper lip which are usually benign. A Medline search of the English language literature yields only one case report of a CXPA located within the upper lip. The authors present a second case report of CXPA within the upper lip and a review of its pathologic features and management. PMID- 22209229 TI - Menopause, and not age, is a critical factor associated with a worse response to antiviral therapy in women affected by chronic hepatitis C. PMID- 22209230 TI - Efficient production of Hantaan and Puumala pseudovirions for viral tropism and neutralization studies. AB - Puumala (PUUV) and Hantaan (HTNV) viruses are hantaviruses within the family Bunyaviridae and associated with Hemorrhagic Fever with Renal Syndrome (HFRS) in humans. Little is known about how these viruses interact with host cells, though pathogenic hantaviruses interact with alpha(v)beta(3) integrin. To study host cell interactions and rapidly test the ability of antibodies to prevent infection, we produced HTNV and PUUV pseudovirions on a vesicular stomatitis virus (VSV) core. Similar to replication-competent hantaviruses, infection was low-pH-dependent. Despite broad cell tropism, several human T cell lines were poorly permissive to hantavirus pseudovirions, compared to VSV, indicating a relative block to infection at the level of entry. Stable expression of alpha(v)beta(3) integrin in SupT1 cells did not restore infectivity. Finally, the pseudovirion system provided a rapid, quantitative, and specific method to screen for neutralizing antibodies in immune sera. PMID- 22209232 TI - CD4- and dynamin-dependent endocytosis of HIV-1 into plasmacytoid dendritic cells. AB - Chronic immune activation, triggered by plasmacytoid dendritic cell (PDC) interferon (IFN)-alpha production, plays an important role in HIV-1 pathogenesis. As the entry of HIV-1 seems to be important for the activation of PDC, we directly characterized the viral entry into these cells using immuno-electron microscopy, cellular fractionation, confocal imaging, and functional experiments. After attachment to PDC, viruses were taken up in an energy-dependent manner. The virions were located in compartments positive for caveolin; early endosomal antigen 1; Rab GTPases 5, 7 and 9; lysosomal-associated membrane protein 1. PDC harbored more virus in endocytic vesicles than CD4+ T cells (p<0.05). Blocking CD4 inhibited the uptake of virions into cytosolic and endosomal compartments. Dynasore, an inhibitor of dynamin-dependent endocytosis, not the fusion inhibitor T-20, reduced the HIV-1 induced IFN-alpha production. Altogether, our morphological and functional data support the role of endocytosis for the entry and IFN-alpha induction of HIV-1 in PDC. PMID- 22209231 TI - The lectins griffithsin, cyanovirin-N and scytovirin inhibit HIV-1 binding to the DC-SIGN receptor and transfer to CD4(+) cells. AB - It is generally believed that during the sexual transmission of HIV-1, the glycan specific DC-SIGN receptor binds the virus and mediates its transfer to CD4(+) cells. The lectins griffithsin (GRFT), cyanovirin-N (CV-N) and scytovirin (SVN) inhibit HIV-1 infection by binding to mannose-rich glycans on gp120. We measured the ability of these lectins to inhibit both the HIV-1 binding to DC-SIGN and the DC-SIGN-mediated HIV-1 infection of CD4(+) cells. While GRFT, CV-N and SVN were moderately inhibitory to DC-SIGN binding, they potently inhibited DC-SIGN transfer of HIV-1. The introduction of the 234 glycosylation site abolished HIV-1 sensitivity to lectin inhibition of binding to DC-SIGN and virus transfer to susceptible cells. However, the addition of the 295 glycosylation site increased the inhibition of transfer. Our data suggest that GRFT, CV-N and SVN can block two important stages of the sexual transmission of HIV-1, DC-SIGN binding and transfer, supporting their further development as microbicides. PMID- 22209233 TI - Casein kinase 2 regulates vaccinia virus actin tail formation. AB - Casein kinase 2 (CK2) is a pleiotropic serine/threonine kinase that regulates numerous cellular processes and is essential to the infectious cycle of several viruses. Here we investigated the potential role of CK2 in vaccinia virus (VACV) infection. We used the CK2 inhibitor TBB and found that CK2 inactivation impaired VACV dissemination and actin tail formation. We used RNAi and confirmed that CK2 depletion impaired VACV actin tail formation. Furthermore, we designed a recombinant virus that allowed us to specifically detect cell-associated enveloped viruses (CEVs) at the plasma membrane and demonstrated that CK2 inactivation does not affect CEV formation. Finally, we showed that CK2 depletion impaired the recruitment of Src to CEVs. We discuss the possibility that CK2 may stimulate the A36-dependent recruitment of Src through A36 phosphorylation. PMID- 22209234 TI - Emergence of novel equine arteritis virus (EAV) variants during persistent infection in the stallion: origin of the 2007 French EAV outbreak was linked to an EAV strain present in the semen of a persistently infected carrier stallion. AB - During the summer of 2007, an outbreak of equine viral arteritis (EVA) occurred in Normandy (France). After investigation, a link was suggested between an EAV carrier stallion (A) and the index premise of the outbreak. The full-length nucleotide sequence analysis of a study reference strain (F27) isolated from the lung of a foal revealed a 12,710 nucleotides EAV genome with unique molecular hallmarks in the 5'UTR leader sequence and the ORF1a sequence encoding the non structural protein 2. The evolution of the viral population in the persistently infected Stallion A was then studied by cloning ORFs 3 and 5 of the EAV genome from four sequential semen samples which were collected between 2000 and 2007. Molecular analysis of the clones confirmed the likely implication of Stallion A in the origin of this outbreak through the yearly emergence of new variants genetically similar to the F27 strain. PMID- 22209235 TI - Clinical experiences of ruptured posteroinferior cerebellar artery aneurysms and anatomical analysis in the cadaver in a single center of China. AB - OBJECTIVE: Posteroinferior cerebellar artery (PICA) aneurysms are uncommon and have not been well investigated previously. We report our series of 29 ruptured PICA aneurysms with surgical treatment along with the description of the surgical anatomy of the PICA to the lower cranial nerves in cadaveric specimen. METHODS: All patients with ruptured PICA aneurysms who were surgically treated at the First Affiliated Hospital of Soochow University during the period from January 1995 to December 2008 were reviewed retrospectively. Data relating to clinical, radiological, and intraoperative findings were analyzed. Forty formalin-fixed cerebellar hemispheres provided the material for the study of describing the detailed surgical anatomic relationship of the PICA to the lower cranial nerves. RESULTS: In our series, ruptured PICA aneurysms reached an incidence of 2.35% of all ruptured intracranial aneurysms. There were 13 aneurysms (44.8%) located in the proximal segment, and 16 (55.2%) located in the distal segment. Of these, 89.7% were saccular, 6.9% fusiform, and 3.4% dissecting aneurysms. Usually, the surgical outcome was influenced by Poor admission grade, the presence of obstructive hydrocephalus and associated distal AVM. In cadaveric specimen, 17.5% of PICAs passed between the glossopharyngeal and vagus nerves, 7.5% between the vagus and accessory nerves, and 62.5% through the rootlets of the accessory nerve. CONCLUSION: This report summarizes the presentation and outcome of a large series of 29 patients with ruptured PICA aneurysms, and we conclude that ruptured PICA with surgical treatment usually gets well recovered. The study does, however, also demonstrate that the anatomic relationship of the PICA and lower cranial nerves is somehow variable and irregular. Recognition of the findings in cadaveric dissection is essential in treating lesions of this region. PMID- 22209236 TI - Reduced striatal activation during reward anticipation due to appetite-provoking cues in chronic schizophrenia: a fMRI study. AB - The occurrence of weight gain in schizophrenia (SZ) has profound clinical impact and interacts with antipsychotic medication, life style and disease severity. The functional neuroanatomy underlying altered nutritional behavior is unraveled, but dysregulated reward anticipation might be one of the involved neuronal mechanisms. The striatum, a core region of the reward network and salience attribution, was previously shown to regulate appetite perception and eating behavior. We studied patients suffering from chronic schizophrenia with a stable medication in comparison to age and gender matched healthy adults. Every subject had to undergo a 6h fasting period before a newly developed, appetite-provoking fMRI task was applied. Subjects saw visual stimuli of appetitive food items in a 3Tesla scanner. In healthy controls food images elicited stronger activation in the striatum compared to SZ patients. When adjusting a ROI-based striatal activation for medication and weight, the group difference remained still significant. This points an effect of illness independent of antipsychotic medication. These data underscore the involvement of the striatum into salience attribution, reward anticipation and the neuronal pathways leading to altered eating behavior and weight gain in schizophrenia. PMID- 22209237 TI - MTCID: a database of genetic polymorphisms in clinical isolates of Mycobacterium tuberculosis. AB - Tuberculosis (TB) is a major cause of morbidity and mortality throughout the world, particularly in developing countries. The response of the patients and treatment outcome depends, in addition to diagnosis, appropriate and timely treatment and host factors, on the virulence of Mycobacterium tuberculosis and genetic polymorphism prevalent in clinical isolates of the bacterium. A number of studies have been carried out to characterize clinical isolates of M. tuberculosis obtained from TB patients. However, the data is scattered in a large number of publications. Though attempts have been made to catalog the observed variations, there is no database that has been developed for cataloging, storing and dissemination of genetic polymorphism information. MTCID (M. tuberculosis clinical isolate genetic polymorphism database) is an attempt to provide a comprehensive repository to store, access and disseminate single nucleotide polymorphism (SNPs) and spoligotyping profiles of M. tuberculosis. It can be used to automatically upload the information available with a user that adds to the existing database at the backend. Besides it may also aid in maintaining clinical profiles of TB and treatment of patients. The database has 'search' features and is available at http://ccbb.jnu.ac.in/Tb. PMID- 22209238 TI - Directed cell invasion and migration during metastasis. AB - Metastasis requires tumor cell dissemination to different organs from the primary tumor. Dissemination is a complex cell motility phenomenon that requires the molecular coordination of the protrusion, chemotaxis, invasion and contractility activities of tumor cells to achieve directed cell migration. Recent studies of the spatial and temporal activities of the small GTPases have begun to elucidate how this coordination is achieved. The direct visualization of the pathways involved in actin polymerization, invasion and directed migration in dissemination competent tumor cells will help identify the molecular basis of dissemination and allow the design and testing of more specific and selective drugs to block metastasis. PMID- 22209241 TI - Five-year trends in spine care: the impact of health care reform. PMID- 22209239 TI - Advances in light-based imaging of three-dimensional cellular ultrastructure. AB - Visualization methods are key to gaining insights into cellular structure and function. Since diffraction has long confined optical microscopes to a resolution no better than hundreds of nanometers, the observation of ultrastructural features has traditionally been the domain of electron microscopes (EM). In the past decade, however, advances in super-resolution fluorescence microscopy have considerably expanded the capability of light-based imaging techniques. Advantages of fluorescent labeling such as high sensitivity, specificity, and multichannel capability, can now be exploited to dissect ultrastructural features of cells. With recent methods capable of imaging specific proteins with a resolution on the order of a few tens of nanometers in 3-dimensions, this has made it possible to elucidate the molecular organization of many complex cellular structures. PMID- 22209240 TI - Quantification of walking ability in subjects with neurogenic claudication from lumbar spinal stenosis--a comparative study. AB - BACKGROUND CONTEXT: Walking limitations caused by neurogenic claudication (NC) are typically assessed with self-reported measures, although objective evaluation of walking using motorized treadmill test (MTT) or self-paced walking test (SPWT) has periodically appeared in the lumbar spinal stenosis (LSS) literature. PURPOSE: This study compared the validity and responsiveness of MTT and SPWT for assessing walking ability before and after common treatments for NC. STUDY DESIGN: Prospective observational cohort study. PATIENT SAMPLE: Fifty adults were recruited from an urban spine center if they had LSS and substantial walking limitations from NC and were scheduled to undergo surgery (20%) or conservative treatment (80%). OUTCOME MEASURES: Walking times, distances, and speeds along with the characteristics of NC symptoms were recorded for MTT and SPWT. Self reported measures included back and leg pain intensity assessed with 0 to 10 numeric pain scales, disability assessed with Oswestry Disability Index, walking ability assessed with estimated walking times and distances, and NC symptoms assessed with the subscales from the Spinal Stenosis Questionnaires. METHODS: Motorized treadmill test used a level track, and SPWT was conducted in a rectangular hallway. Walking speeds were self-selected, and test end points were NC, fatigue, or completion of the 30-minute test protocol. Results from MTT and SPWT were compared with each other and self-reported measures. Internal responsiveness was assessed by comparing changes in the initial results with the posttreatment results and external responsiveness by comparing walking test results that improved with those that did not improve by self-reported criteria. RESULTS: Mean age of the participants was 68 years, and 58% were male. Neurogenic claudication included leg pain (88%) and buttock(s) pain (12%). Five participants could not safely perform MTT. Walking speeds were faster and distances were greater with SPWT, although the results from both tests correlated with each other and self-reported measures. Of the participants, 72% reported improvement after treatment, which was confirmed by significant mean differences in self reported measures. Motorized treadmill test results did not demonstrate internal responsiveness to change in clinical status after treatment but SPWT results did, with increased mean walking times (6 minutes) and distances (387 m). When responsiveness was assessed against external criterion, both SPWT and MTT demonstrated substantial divergence with self-reported changes in clinical status and alternative outcome measures. CONCLUSIONS: Both MTT and SPWT can quantify walking abilities in NC. As outcome tools, SPWT demonstrated better internal responsiveness than MTT, but neither test demonstrated adequate external responsiveness. Neither test should be considered as a meaningful substitution for disease-specific measures of function. PMID- 22209242 TI - A rare case of life-threatening giant plexiform schwannoma. PMID- 22209243 TI - Morbidity and mortality of major adult spinal surgery. A prospective cohort analysis of 942 consecutive patients. AB - BACKGROUND CONTEXT: To date, most reports on the incidence of adverse events (AEs) in spine surgery have been retrospective and dependent on data abstraction from hospital-based administrative databases. To our knowledge, there have been no previous rigorously performed prospective analysis of all AEs occurring in the entire population of patients presenting to an academic quaternary referral center. PURPOSE: To determine the mortality and true incidence and severity of morbidity (major and minor, medical and surgical) in adults undergoing complex spinal surgery, both trauma and elective, in a quaternary referral center. To examine the influence of the introduction of a dedicated weekly multidisciplinary rounds, and a formal abstraction tool, on the recording of this prospective perioperative morbidity data. To examine the validity and inter- and intraobserver reliability of a dedicated Spine AdVerse Events Severity system, version 2 (SAVES V2) AE abstraction tool. STUDY DESIGN: Ours is an academic quaternary referral center serving a population of 4.5 million people. Beginning in April 2008, a spine-specific AE-recording instrument, entitled SAVES V2, was introduced at our center for reporting, categorization, and classification of AEs. The use of this system remains an ongoing prospective study. PATIENT SAMPLE: All adult patients admitted to the spine service of a quaternary referral center for a 12-month period. OUTCOME MEASURES: A validity and an inter- and intraobserver reliability examination of the SAVES V2 system, as used at our institution. Morbidity and inhospital deaths, unplanned second surgeries during index admission, wound infections requiring reoperation, and readmissions during the same calendar year. We also examined in detail all intraoperative and nonsurgical postoperative AEs, as well as hospital length of stay (LOS). METHODS: Data on all patients undergoing surgery over a 12-month period were prospectively collected using a perioperative morbidity abstraction tool at weekly dedicated mortality and morbidity rounds. This tool allows identification of each specific AE and grades the severity. Before the introduction of this system, and using the hospital inpatient database, our documented perioperative morbidity rate (major and minor, medical and surgical) was 23%. Diagnosis, operative data, hospital data, major and minor complications both medical and surgical, and deaths were recorded. RESULTS: One hundred percent of all patients discharged from the unit had complete data available for analysis. Nine hundred forty-two patients with an age range of 16 to 90 years (mean, 54 years; mode, 38 years) were identified. There were 552 males and 390 females. Around 58.5% of patients had undergone elective surgery. Thirty percent of patients were American Spinal Injury Association class D or worse on admission. The average LOS was 13.5 days (range, 1-221 days). Eight hundred twenty-two (87%) patients had at least one documented complication. Thirty-nine percent of these adversely affected hospital LOS. There were 14 mortalities during the study period. The rate of intraoperative surgical complication was 10.5% (4.5% incidental durotomy and 1.9% hardware malposition requiring revision and 2.2% blood loss >2 L). The incidence of postoperative complication was 73.5% (wound complications, 13.5%; delerium, 8%; pneumonia, 7%; neuropathic pain, 5%; dysphagia, 4.5%; and neurological deterioration, 3%). CONCLUSIONS: Major spinal surgery in the adult is associated with a high incidence of intra- and postoperative complications. We identified a very high rate of previously unrecognized postoperative complications, which adversely affect LOS. Without strict adherence to a prospective data collection system, the true complexity of this surgery may be greatly underestimated. PMID- 22209244 TI - The development of a model for translation of the Neck Disability Index to utility scores for cost-utility analysis in cervical disorders. AB - BACKGROUND CONTEXT: The Neck Disability Index (NDI) is a commonly used disease specific instrument for cervical spine disorders with good responsiveness and psychometric properties compared with general health status measures. However, NDI scores are unitless and do not have an intrinsic value that is comparable to other health status measures, and these scores have limited value in cost-utility analysis. The translation of disease-specific measures to Short Form-6 Dimensions (SF-6D) utility scores may be useful in cost-utility analysis. PURPOSE: The purpose of this study is to present a model for translating the NDI to SF-6D utility scores, permitting the use of NDI scores in the cost-utility analysis of cervical disorders. STUDY DESIGN/SETTING: A secondary analysis of a multicenter prospective clinical trial of the Synthes ProDisc-C (Synthes, West Chester, PA, USA) was performed. PATIENT SAMPLE: Patients included were randomized to receive either a total disc arthroplasty or anterior cervical discectomy and fusion for treatment of symptomatic cervical disc disease involving one vertebral level between C3 and C7. All subjects completed NDI and 36-Item Short Form Health Survey (SF-36) self-assessments at preoperative and postoperative follow-ups of 6 weeks, 3, 6, 12, 18, and 24 months. OUTCOME MEASURES: The NDI is a validated and widely used self-reported questionnaire designed to assess patient-determined disability resulting from neck pain, including pain level and effects on activities of daily living. The SF-6D is a preference-based health state classification system derived from six health dimensions of the SF-36 self reported questionnaire, including the domains of physical functioning, role limitation, social functioning, bodily pain, mental health, and vitality. METHODS: The collected data points were divided into two cohorts: one for model formation and one for the assessment of model validity. SF-36 scores were converted to SF-6D utilities via three previously published methods. Correlation analyses and linear regression modeling between SF-6D and NDI created the models for translating scores. For validation, Spearman and Pearson correlations were calculated between the observed and predicted SF-6D utilities, and prediction errors were calculated. RESULTS: Four hundred thirty patients with 2,137 time points were used for creation and validation of the model. Pearson and Spearman correlation coefficients between the NDI and the SF-6D derived from each conversion method were found to be between -0.8255 and -0.8504 (p<.01). R(2) values ranged from 0.68 to 0.71 and root mean squared error (RMSE) from 0.092 to 0.084. Correlations between estimated and observed SF-6D scores ranged from 0.8325 to 0.8372 (p<.01). The mean prediction error was less than 0.006, with standard deviation (SD) between 0.082 and 0.093. DISCUSSION: Correlations between NDI and SF-6D utility scores are strong and statistically significant. The model has a large R(2) and small RMSE. The prediction models produce a small mean prediction error, but the SD of the prediction errors is large. High correlations between NDI and SF-6D permit these models to be used to calculate overall utilities, changes in utilities, and quality-adjusted life-years for large data samples. However, the relatively large observed prediction error SDs may limit the accuracy of translation of individual data points or small sample sizes. PMID- 22209246 TI - De novo and inherited mutations in COL4A2, encoding the type IV collagen alpha2 chain cause porencephaly. AB - Porencephaly is a neurological disorder characterized by fluid-filled cysts or cavities in the brain that often cause hemiplegia. It has been suggested that porencephalic cavities result from focal cerebral degeneration involving hemorrhages. De novo or inherited heterozygous mutations in COL4A1, which encodes the type IV alpha1 collagen chain that is essential for structural integrity for vascular basement membranes, have been reported in individuals with porencephaly. Most mutations occurred at conserved Gly residues in the Gly-Xaa-Yaa repeats of the triple-helical domain, leading to alterations of the alpha1alpha1alpha2 heterotrimers. Here we report on two individuals with porencephaly caused by a heterozygous missense mutation in COL4A2, which encodes the type IV alpha2 collagen chain. Mutations c.3455G>A and c.3110G>A, one in each of the individuals, cause Gly residues in the Gly-Xaa-Yaa repeat to be substituted as p.Gly1152Asp and p.Gly1037Glu, respectively, probably resulting in alterations of the alpha1alpha1alpha2 heterotrimers. The c.3455G>A mutation was found in the proband's mother, who showed very mild monoparesis of the left upper extremity, and the maternal elder uncle, who had congenital hemiplegia. The maternal grandfather harboring the mutation is asymptomatic. The c.3110G>A mutation occurred de novo. Our study confirmed that abnormalities of the alpha1alpha1alpha2 heterotrimers of type IV collagen cause porencephaly and stresses the importance of screening for COL4A2 as well as for COL4A1. PMID- 22209245 TI - Rare deletions at the neurexin 3 locus in autism spectrum disorder. AB - The three members of the human neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3), encode neuronal adhesion proteins that have important roles in synapse development and function. In autism spectrum disorder (ASD), as well as in other neurodevelopmental conditions, rare exonic copy-number variants and/or point mutations have been identified in the NRXN1 and NRXN2 loci. We present clinical characterization of four index cases who have been diagnosed with ASD and who possess rare inherited or de novo microdeletions at 14q24.3 31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3. NRXN3 deletions were found in one father with subclinical autism and in a carrier mother and father without formal ASD diagnoses, indicating issues of penetrance and expressivity at this locus. Notwithstanding these clinical complexities, this report on ASD-affected individuals who harbor NRXN3 exonic deletions advances the understanding of the genetic etiology of autism, further enabling molecular diagnoses. PMID- 22209247 TI - COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke. AB - Collagen, type IV, alpha 1 (COL4A1) and alpha 2 (COL4A2) form heterotrimers and are abundant components of basement membranes, including those of the cerebral vasculature. COL4A1 mutations are an increasingly recognized cause of multisystem disorders, including highly penetrant cerebrovascular disease and intracerebral hemorrhage (ICH). Because COL4A1 and COL4A2 are structurally and functionally associated, we hypothesized that variants in COL4A2 would also cause ICH. We sequence COL4A2 in 96 patients with ICH and identify three rare, nonsynonymous coding variants in four patients that are not present in a cohort of 144 ICH-free individuals. All three variants change evolutionarily conserved amino acids. Using a cellular assay, we show that these putative mutations cause intracellular accumulation of COL4A1 and COL4A2 at the expense of their secretion, which supports their pathogenecity. Furthermore, we show that Col4a2 mutant mice also have completely penetrant ICH and that mutations in mouse and human lead to retention of COL4A1 and COL4A2 within the endoplasmic reticulum (ER). Importantly, two of the three putative mutations found in patients trigger ER stress and activate the unfolded protein response. The identification of putative COL4A2 mutations that might contribute to ICH in human patients provides insight into the pathogenic mechanisms of this disease. Our data suggest that COL4A2 mutations impair COL4A1 and COL4A2 secretion and can also result in cytotoxicity. Finally, our findings suggest that, collectively, mutations in COL4A1 and COL4A2 contribute to sporadic cases of ICH. PMID- 22209249 TI - Simultaneous determination of Cr(III) and Cr(VI) in tannery wastewater using low pressure ion chromatography combined with flow injection spectrophotometry. AB - Trivalent and hexavalent chromium have been successfully separated and determined using low pressure ion chromatography combined with flow injection spectrophotometric analysis (LPIC-FIA). A column packed with crosslinking starch microspheres was used for on-line separation of Cr(III) from Cr(VI) in a flow injection system because of its absorptive effect on Cr(III). To determine the concentration of Cr(III) and Cr(VI) in samples, we used 3.0 mmol/L nitric acid to elute adsorbed Cr(III) from the column and then used ceric sulfate-sulfuric acid as oxidant to convert all Cr(III) into Cr(VI). Then, Cr(VI) directly came from the samples and Cr(VI) came from Cr(III) successively formed a amaranthine complex with diphenycarbazide and the complex shows a maximum absorption at 530 nm. Analytical parameters including the concentration of eluent and oxidant solution, oxidizing temperature, length of oxidizing reaction coil, reaction coil and injection coil, interfering effects, etc., were optimized. The limit of detection was 1.25 MUg/L for Cr(VI) and 3.76 MUg/L for Cr(III). The linear relationship between absorption with the concentration of Cr(VI) and Cr(III) was 0.001-1.000 mg/L and 0.030-1.000 mg/L with correlation coefficients of 0.9995 and 0.9994, respectively. The relative standard deviation of Cr(VI) and Cr(III) was 1.21% and 1.66%, respectively (n=10). Major cations and anions did not show any interference. We validated this method through certified reference materials and through measuring the recovery in tannery wastewater. PMID- 22209250 TI - Energy resource reallocation in Daphnia schodleri (Anomopoda: Daphniidae) reproduction induced by exposure to hexavalent chromium. AB - Cladocerans are able to store energy in the form of macromolecules such as proteins, lipids and carbohydrates. However, their ability to do so depends to a large extent on their physiological and reproductive condition as well as their age. These macromolecules constitute the total caloric reserves of the body and may be modified as a result of environmental stress conditions by either physical or nutritional factors or by exposure to toxic compounds. Neonates of the freshwater cladoceran Daphnia schodleri were exposed to 0.0064, 0.032 and 0.064 mg L(-1) of hexavalent chromium - Cr(VI) - up to age 5, 7, 14, 21 or 28 d. Survival and fecundity of parthenogenetic females was evaluated for 28d (maximum exposure period). Body length and maximum width were determined in specimens of all ages. Caloric content was evaluated in progeny and females within each age group. Female survival was significantly lower with exposure to 0.064 mg L(-1) of Cr(VI) than with other treatments, and negative effects on reproduction were observed from the lowest concentration on. Largest adult size was attained by control specimens towards the end of the observation period, but no significant differences in neonate size occurred between concentrations. Energy content decreased in adults as toxicant concentration increased, but these females allocated a larger amount of energy reserves to their progeny as a possible compensation aimed at ensuring neonate survival in an adverse environment due to toxicant presence. Sublethal concentrations of Cr(VI) modified energy content in D. schodleri, affecting to varying degrees its survival, growth and reproduction. PMID- 22209248 TI - Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. AB - Spontaneous pathologic arterial calcifications in childhood can occur in generalized arterial calcification of infancy (GACI) or in pseudoxanthoma elasticum (PXE). GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. However, the genetic basis in subsets of both disease phenotypes remains elusive. We hypothesized that GACI and PXE are in a closely related spectrum of disease. We used a standardized questionnaire to retrospectively evaluate the phenotype of 92 probands with a clinical history of GACI. We obtained the ENPP1 genotype by conventional sequencing. In those patients with less than two disease-causing ENPP1 mutations, we sequenced ABCC6. We observed that three GACI patients who carried biallelic ENPP1 mutations developed typical signs of PXE between 5 and 8 years of age; these signs included angioid streaks and pseudoxanthomatous skin lesions. In 28 patients, no disease-causing ENPP1 mutation was found. In 14 of these patients, we detected pathogenic ABCC6 mutations (biallelic mutations in eight patients, monoallelic mutations in six patients). Thus, ABCC6 mutations account for a significant subset of GACI patients, and ENPP1 mutations can also be associated with PXE lesions in school-aged children. Based on the considerable overlap of genotype and phenotype of GACI and PXE, both entities appear to reflect two ends of a clinical spectrum of ectopic calcification and other organ pathologies, rather than two distinct disorders. ABCC6 and ENPP1 mutations might lead to alterations of the same physiological pathways in tissues beyond the artery. PMID- 22209251 TI - Biological monitoring of chlorpyrifos exposure to rice farmers in Vietnam. AB - Chlorpyrifos is the most common organophosphate insecticide registered for use in Vietnam and is widely used in agriculture, particularly rice farming. However, chlorpyrifos exposure to and adverse effects on farmers has not been evaluated. In this study, biological monitoring of chlorpyrifos exposure in a group of rice farmers was conducted after a typical application event using back-pack spraying. Urine samples (24 h) were collected from the rice farmers before and post insecticide application. Samples were analysed for 3,5,6-trichloropyridinol (TCP), the major urinary metabolite of chlorpyrifos, using an enzymatic pre treatment before extraction followed by HPLC-MS/MS. Absorbed Daily Dose (ADD) of chlorpyrifos for farmers were then estimated from urinary TCP levels, expressed as MUg g(-1)creatinine. The analytical method for urinary TCP had a low detection limit (0.6 MUg L(-1)), acceptable recovery values (80-114%), and low relative percentage differences in duplicate and repeated samples. Post-application chlorpyrifos ADD of farmers varied from 0.4 to 94.2 MUg kg(-1) (body weight) d( 1) with a mean of 19.4 MUg kg(-1) d(-1) which was approximately 80-fold higher than the mean baseline exposure level (0.24 MUg kg(-1) d(-1)). Hazard Quotients (ratio of the mean ADD for rice farmers to acute oral reference dose) calculated using acute oral reference doses recommended by United States and Australian agencies varied from 2.1 (Australian NRA), 4.2 (US EPA) to 6.9 (ATSDR). Biological monitoring using HPLC-MS/MS analysis of urinary TCP (24 h) was found to be an effective method for measuring chlorpyrifos exposure among farmers. This case study found that Vietnamese rice farmers had relatively high exposures to chlorpyrifos after application, which were likely to have adverse health effects. PMID- 22209252 TI - Benzo[a]pyrene exposure influences the cardiac development and the expression of cardiovascular relative genes in zebrafish (Danio rerio) embryos. AB - It is reported that the most abundant polycyclic aromatic hydrocarbons (PAHs) in weathered crude oils are cardiotoxic. However, the action mechanism of PAHs on vertebrate cardiovascular development and disease is unclear. In the present study, the cardiac morphology and functioning of zebrafish embryos exposed to benzo[a]pyrene [B(a)P], as a high-ring PAHs, for 72 h were observed and determined. The results showed that B(a)P exposure resulted in cardiac developmental defects in zebrafish embryos. Significant changes in expression level of multiple genes potentially critical for regulating the B(a)P-induced cardiovascular developmental defects were also found. A gene network regulating cardiac development perturbed by B(a)P exposure was identified and established by computational analysis and employment of some databases. The information from the network could provide a clue for further mechanistic studies explaining molecular events regulating B(a)P-mediated cardiovascular defects and consequences. PMID- 22209253 TI - Dissipation pathways of organic pollutants during the composting of organic wastes. AB - The organic pollutants (OPs) present in compostable organic residues can be recovered in the final composts leading to environmental impacts related to their use in agriculture. However, the composting process may contribute to their partial dissipation that is classically evaluated through the concentration decrease in extractable OPs, without identification of the responsible mechanisms as mineralization or stabilization of OP as non-extractable residues (NER) or bound residues. The dissipation of four (14)C-labeled OPs (fluoranthene; 4-n nonylphenol, NP; sodium linear dodecylbenzene sulfonate, LAS; glyphosate) was assessed during composting of sewage sludge and green waste. The dissipation of LAS largely resulted from its mineralization (51% of initial LAS), whereas mineralization was intermediate for NP (29%) and glyphosate (24%), and negligible for fluoranthene. The NER pathway mostly concerned NP and glyphosate, with 45% and 37% of the recovered (14)C being found as NER at the end of composting, respectively. In the final composts, the proportions of water soluble residues of OPs considered as readily available were <11% of recovered (14)C-OPs. However, most fluoranthene remained solvent extractable (72%) and potentially available, whereas only 18% of glyphosate and less than 7% of both NP and LAS remained solvent extractable in the final compost. PMID- 22209254 TI - Source characterisation of road dust based on chemical and mineralogical composition. AB - Road dust contain potentially toxic pollutants originating from a range of anthropogenic sources common to urban land uses and soil inputs from surrounding areas. The research study analysed the mineralogy and morphology of dust samples from road surfaces from different land uses and background soil samples to characterise the relative source contributions to road dust. The road dust consist primarily of soil derived minerals (60%) with quartz averaging 40-50% and remainder being clay forming minerals of albite, microcline, chlorite and muscovite originating from surrounding soils. About 2% was organic matter primarily originating from plant matter. Potentially toxic pollutants represented about 30% of the build-up. These pollutants consist of brake and tire wear, combustion emissions and fly ash from asphalt. Heavy metals such as Zn, Cu, Pb, Ni, Cr and Cd primarily originate from vehicular traffic while Fe, Al and Mn primarily originate from surrounding soils. The research study confirmed the significant contribution of vehicular traffic to dust deposited on urban road surfaces. PMID- 22209255 TI - Aberrant heart rate and brainstem brain-derived neurotrophic factor (BDNF) signaling in a mouse model of Huntington's disease. AB - Huntington's disease (HD) is associated with profound autonomic dysfunction including dysregulation of cardiovascular control often preceding cognitive or motor symptoms. Brain-derived neurotrophic factor (BDNF) levels are decreased in the brains of HD patients and HD mouse models, and restoring BDNF levels prevents neuronal loss and extends survival in HD mice. We reasoned that heart rate changes in HD may be associated with altered BDNF signaling in cardiovascular control nuclei in the brainstem. Here we show that heart rate is elevated in HD (N171-82Q) mice at presymptomatic and early disease stages, and heart rate responses to restraint stress are attenuated. BDNF levels were significantly reduced in brainstem regions containing cardiovascular nuclei in HD mice and human HD patients. Central administration of BDNF restored the heart rate to control levels. Our findings establish a link between diminished BDNF expression in brainstem cardiovascular nuclei and abnormal heart rates in HD mice, and suggest a novel therapeutic target for correcting cardiovascular dysfunction in HD. PMID- 22209256 TI - Effect of diesel exhaust particles on human middle ear epithelial cells. AB - OBJECTIVE: In the present study, we investigate whether diesel exhaust particles (DEPs) cause cytotoxicity and induce inflammation or increase the expression of mucin in immortalized human middle ear epithelial cell lines (HMEECs). Several publications have shown an association between traffic-related air pollutants and otitis media. Additionally, DEP have been shown to cause inflammation and an allergic response in the airways. METHODS: Cell viability following DEP treatment was investigated in HMEECs using the MTT assay. We measured the expression of the inflammatory cytokines TNF-alpha and COX-2 and the mucin genes MUC5AC and MUC5B using semiquantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. RESULTS: Cell viability tests showed that exposure to more than 80 MUg/mL of DEP caused a decrease in cell viability. DEP exposure also increased the expression of MUC5AC, but did not induce the expression of MUC5B in HMEECs. CONCLUSION: DEP decreased cell viability, induced an inflammatory response, and increased mucin gene expression in HMEECs. These findings support the hypothesis that environmental diesel exposure is a risk factor for otitis media. PMID- 22209257 TI - The role of rhinomanometry after nasal decongestant test in the assessment of adenoid hypertrophy in children. AB - INTRODUCTION: Nasal respiratory obstruction is a very common otolaryngologic problem, often caused by adenoid hypertrophy (AH). Nasal fiberoptic endoscopy (NFE) represents the gold standard method to diagnose AH. Rhinomanometry represents a valid diagnostic support. OBJECTIVE: The aim of our study was to analyze the diagnostic value of rhinomanometry after nasal decongestant (ND) test for the evaluation of adenoid hypertrophy in children. MATERIALS AND METHODS: Seventy-one of 97 collaborative children, aged 6-12 years, affected by upper airways obstructive symptoms and diagnosed as 'chronic oral breathers' by a standardized questionnaire were included in the study. The first evaluation included a complete physical examination, anterior rhinoscopy and anterior active rhinomanometry. Patients with a positive rhinomanometry underwent a second rhinomanometry after the administration of the nasal decongestant (ND) xylometazoline. All children were evaluated using nasal fiberoptic endoscopy (NFE). RESULTS: At rhinomanometry a normal nasal airflow was found in 19 (26.8%) of children while nasal obstruction was underlined in 52 (73.2%). These patients were tested also with rhinomanometry after ND which confirmed the presence of nasal obstruction in 29 (55.7%) of patients. All patients included in the study underwent a NFE: 34 (47.8%) of them presented severe AH with an occlusion >75% of the choanal opening (grade >= 3) and 37 (52.2%) presented no or a mild form of AH (grade < 3). When compared to NFE, rhinomanometry test after ND had 82.7% sensitivity and 82.6% specificity. Positive predictive value and negative predictive value were 85.7% and 79.2%, respectively. Two receiver operating characteristic (ROC) curves were derived using data related to rhinomanometry vs NFE, and to rhinomanometry after ND vs NFE. CONCLUSIONS: Rhinomanometry after ND, compared to rhinomanometry, is more specific and useful to evaluate nasal obstruction due to AH in children, and it may be helpful to avoid unnecessary surgical procedures in children with temporary nasal obstruction. PMID- 22209258 TI - The effects of biofilm on the transport of stabilized zerovalent iron nanoparticles in saturated porous media. AB - The transport of stabilized zerovalent iron nanoparticles (nZVI) has recently been the topic of extensive research due to its proven potential as an in situ remediation tool. However, these studies have ignored the effects of biofilms complex aggregations of bacterial cells and excreted extracellular polymeric substances present in nearly all aquatic systems-on the transport of these particles. This study examines the effects of Pseudomonas aeruginosa (PAO1) biofilm, at a cell concentration similar to that reported for saturated aquifers, on the transport of commercially available, poly (acrylic acid) stabilized nZVI (pnZVI) in 14 cm long columns packed with saturated glass beads at salt concentrations of 1 and 25 mM NaCl. Compared to retention on uncoated columns, in the presence of biofilm the retention of pnZVI increased at higher ionic strength, while ionic strength played no role in retention of these nanoparticles in the absence of biofilm. The Tufenkji-Elimelech correlation equation predicts lower retention of pnZVI on biofilm coated columns compared to uncoated columns due to a lower Hamaker constant, and DLVO energy considerations predict the most favorable attachment to uncoated porous media at higher ionic strength. A steric (polymer-mediated) model that considers the combined influence of steric effects of polymers and DLVO interactions is shown to adequately describe particle retention in columns. PMID- 22209259 TI - Phosphorus limitation in nitrifying groundwater filters. AB - Phosphorus limitation has been demonstrated for heterotrophic growth in groundwater, in drinking water production and distribution systems, and for nitrification of surface water treatment at low temperatures. In this study, phosphorus limitation was tested, in the Netherlands, for nitrification of anaerobic groundwater rich in iron, ammonium and orthophosphate. The bioassay method developed by Lehtola et al. (1999) was adapted to determine the microbially available phosphorus (MAP) for nitrification. In standardized batch experiments with an enriched mixed culture inoculum, the formation of nitrite and nitrate and ATP and the growth of ammonia-oxidizing bacteria (AOB; as indicated by qPCR targeting the amoA-coding gene) were determined for MAP concentrations between 0 and 100 MUg PO4-P L(-1). The nitrification and microbial growth rates were limited at under 100 MUg PO4-P L(-1) and virtually stopped at under 10 MUg PO4-P L(-1). In the range between 10 and 50 MUg PO4-P L(-1), a linear relationship was found between MAP and the maximum nitrification rate. AOB cell growth and ATP formation were proportional to the total ammonia oxidized. Contrary to Lehtola et al. (1999), biological growth was very slow for MAP concentrations less than 25 MUg PO4-P L(-1). No full conversion nor maximum cell numbers were reached within 19 days. In full-scale groundwater filters, most of the orthophosphate was removed alongside with iron. The remaining orthophosphate appeared to have only limited availability for microbial growth and activity. In some groundwater filters, nitrification was almost totally prevented by limitation of MAP. In batch experiments with filtrate water from these filters, the nitrification process could be effectively stimulated by adding phosphoric acid. PMID- 22209260 TI - The contribution of exopolysaccharides induced struvites accumulation to ammonium adsorption in aerobic granular sludge. AB - Aerobic granular sludge from a lab-scale reactor with simultaneous nitrification/denitrification and enhanced biological phosphorus removal processes exhibited significant amount of ammonium adsorption (1.5 mg NH4+-N/g TSS at an ammonium concentration of 30 mg N/L). Potassium release accompanied ammonium adsorption, indicating an ion exchange process. The existence of potassium magnesium phosphate (K-struvite) as one of potassium sources in the granular sludge was studied by X-ray diffraction analysis (XRD). Artificially prepared K-struvite was indeed shown to adsorb ammonium. Alginate-like exopolysaccharides were isolated and their inducement for struvite formation was investigated as well. Potassium magnesium phosphate proved to be a major factor for ammonium adsorption on the granular sludge. Struvites (potassium/ammonium magnesium phosphate) accumulate in aerobic granular sludge due to inducing of precipitation by alginate-like exopolysaccharides. PMID- 22209261 TI - Effects of disinfectant and biofilm on the corrosion of cast iron pipes in a reclaimed water distribution system. AB - The effects of disinfection and biofilm on the corrosion of cast iron pipe in a model reclaimed water distribution system were studied using annular reactors (ARs). The corrosion scales formed under different conditions were characterized by X-ray diffraction (XRD), energy dispersive spectroscopy (EDS), and scanning electron microscopy (SEM), while the bacterial characteristics of biofilm on the surface were determined using several molecular methods. The corrosion scales from the ARs with chlorine included predominantly alpha-FeOOH and Fe2O3, while CaPO3(OH).2H2O and alpha-FeOOH were the predominant phases after chloramines replaced chlorine. Studies of the consumption of chlorine and iron release indicated that the formation of dense oxide layers and biofilm inhibited iron corrosion, causing stable lower chlorine decay. It was verified that iron oxidizing bacteria (IOB) such as Sediminibacterium sp., and iron-reducing bacteria (IRB) such as Shewanella sp., synergistically interacted with the corrosion product to prevent further corrosion. For the ARs without disinfection, alpha-FeOOH was the predominant phase at the primary stage, while CaCO3 and alpha FeOOH were predominant with increasing time. The mixed corrosion-inducing bacteria, including the IRB Shewanella sp., the IOB Sediminibacterium sp., and the sulfur-oxidizing bacteria (SOB) Limnobacter thioxidans strain, promoted iron corrosion by synergistic interactions in the primary period, while anaerobic IRB became the predominant corrosion bacteria, preventing further corrosion via the formation of protective layers. PMID- 22209262 TI - Distinguishing activity decay and cell death from bacterial decay for two types of methanogens. AB - As bacterial decay consists of cell death and activity decay, and the corresponding information about AOB/NOB, OHO, PAOs and GAOs has been experimentally acquired, another functional type of bacteria in biological wastewater treatment, methanogens, remains to be investigated, to gather the same information, which is extremely important for such bacteria with low growth rates. With successfully selection and enrichment of both aceticlastic and hydrogenotrophic methanogens, and by means of measuring specific methane activity (SMA) and hydrogen consumption rate (HCR), a series of decay experiments and molecular techniques such as FISH verification and LIVE/DEAD staining revealed, identified and calculated the decay and death rates of both aceticlastic and hydrogenotrophic methanogens respectively. The results indicated that the decay rates of aceticlastic and hydrogenotrophic methanogens were 0.070 and 0.034 d(-1) respectively, and the death rates were thus calculated at 0.022 and 0.016 d(-1) respectively. For this reason, cell deaths were only responsible for 31% and 47% of the total bacterial decay of aceticlastic and hydrogenotrophic methanogens, and activity decays actually contributed significantly to the total bacterial decay, respectively at 69% and 53%. PMID- 22209263 TI - Suspended biofilm carrier and activated sludge removal of acidic pharmaceuticals. AB - Removal of seven active pharmaceutical substances (ibuprofen, ketoprofen, naproxen, diclofenac, clofibric acid, mefenamic acid, and gemfibrozil) was assessed by batch experiments, with suspended biofilm carriers and activated sludge from several full-scale wastewater treatment plants. A distinct difference between nitrifying activated sludge and suspended biofilm carrier removal of several pharmaceuticals was demonstrated. Biofilm carriers from full-scale nitrifying wastewater treatment plants, demonstrated considerably higher removal rates per unit biomass (i.e. suspended solids for the sludges and attached solids for the carriers) of diclofenac, ketoprofen, gemfibrozil, clofibric acid and mefenamic acid compared to the sludges. Among the target pharmaceuticals, only ibuprofen and naproxen showed similar removal rates per unit biomass for the sludges and biofilm carriers. In contrast to the pharmaceutical removal, the nitrification capacity per unit biomass was lower for the carriers than the sludges, which suggests that neither the nitrite nor the ammonia oxidizing bacteria are primarily responsible for the observed differences in pharmaceutical removal. The low ability of ammonia oxidizing bacteria to degrade or transform the target pharmaceuticals was further demonstrated by the limited pharmaceutical removal in an experiment with continuous nitritation and biofilm carriers from a partial nitritation/anammox sludge liquor treatment process. PMID- 22209265 TI - Hepatic venous pressure measurements: comparison of end-hole and balloon catheter methods. AB - PURPOSE: To determine the difference in hepatic venous pressures measured with the use of an end-hole diagnostic catheter versus a balloon catheter. MATERIALS AND METHODS: A total of 92 patients underwent transjugular hepatic venous pressure measurements with a 5-F diagnostic end-hole catheter and a balloon catheter, with the catheter type used initially determined randomly. With both catheters, free and wedged systolic, diastolic, and mean pressures were collected. Hepatic venous pressure gradients were calculated from each pressure set. Eighty-five patients (92%) also underwent concurrent transjugular biopsy after pressures were recorded. Demographic, histologic, and specific procedural information were also collected. RESULTS: The study included 47 men and 45 women, with a mean age of 52.7 years (range, 19-84 y). For the entire population, there were statistically significant differences in mean measurements between the two catheters in wedged systolic (P = .004), diastolic (P = .021), and mean (P = .036) pressures. However, the differences between the means were only 0.783, 0.609, and 0.207 mm Hg, respectively. A subanalysis based on histologic stage revealed no difference between catheter types for normal or cirrhotic livers, but a significant (P = .017) difference in systolic wedged pressure (absolute difference of 0.67 mm Hg) in patients with mild to moderate fibrosis (stages 1 3). In all differences, the balloon catheter had the greater pressure reading. CONCLUSIONS: There was a significant difference in wedged pressure measurements between the two catheter systems in the overall population and among patients with a histologic grade indicating fibrosis. However, the absolute value differences between the two systems were comparatively small (< 1 mm Hg). PMID- 22209264 TI - In vivo evaluation of cisplatin-loaded superabsorbent polymer microspheres for use in chemoembolization of VX2 liver tumors. AB - PURPOSE: To investigate the pharmacokinetics and efficacy of chemoembolization with a cisplatin-loaded superabsorbent polymer (SAP) suspension in a rabbit model with transplanted liver VX2 tumors. MATERIALS AND METHODS: VX2 tumors were implanted into the left lobe of the liver in eight rabbits. Embolization of the proper hepatic artery was performed with cisplatin-loaded or unloaded SAP. In the cisplatin-loaded SAP group (n = 4), 5 mg of SAP (106-150 MUm) loading 2.35 mg of cisplatin and 0.5 mL of ionic contrast material (ioxaglic acid 320 mgI/mL) was injected into the proper hepatic artery. In the control group (hepatic arterial infusion [HAI] + SAP; n = 4), 5 mg of SAP loading 0.5 mL of ioxaglic acid alone was injected after a bolus infusion of an equivalent amount of cisplatin. Sequential change of the plasma platinum concentration within the first 24 hours was measured. Blood sampling and histopathologic examination were performed at 1 week follow-up. Magnetic resonance (MR) images were used to calculate the growth rate of the VX2 tumor. RESULTS: All animals underwent successful embolization. Both total and free plasma platinum mean concentrations within the first 24 hours remained lower in the cisplatin-loaded SAP group, although without statistical significance (P > .05). The mean tumor growth rate was significantly lower in the cisplatin-loaded SAP group than the control group (20% vs 116%; P = .049). Histopathologic examination revealed coagulative necrosis to nontumorous liver parenchyma in two rabbits in the cisplatin-loaded SAP group, although no deaths occurred. CONCLUSIONS: These results suggested that chemoembolization with cisplatin-loaded SAP was a safe and tolerable treatment and was more effective in suppressing the tumor growth. PMID- 22209266 TI - [(18)F]FLT: an imaging biomarker of tumour proliferation for assessment of tumour response to treatment. AB - The paradigm of drug development is shifting towards early use of imaging biomarkers as surrogate end-points in clinical trials. Quantitative Imaging in Cancer: Connecting Cellular Processes (QuIC-ConCePT) is an initiative to qualify complementary imaging biomarkers (IB) of proliferation, cell death and tumour heterogeneity as possible tools in early phase clinical trials to help pharmaceutical developers in 'go, no-go' decisions early in the process of drug development. One of the IBs is [(18)F]3'-deoxy-3'-fluorothymidine with Positron Emission Tomography (FLT-PET). We review results of recent clinical trials using FLT-PET for monitoring tumour response to drug treatment and discuss the potential and the possible pitfalls of using this IB as a surrogate end-point in early phase clinical trials for assessing tumour response to drug treatment. From first human trial results it seems that the degree of FLT accumulation in tumours is governed not only by the tumour proliferation rate but also by other factors. Nevertheless FLT-PET could potentially be used as a negative predictor of tumour response to chemotherapy, and hence evaluation of this IB is granted in multi centre clinical trials. PMID- 22209267 TI - A preliminary exploration of predictors of outcome and cognitive mechanisms of change in cognitive behaviour therapy for psychosis in people not taking antipsychotic medication. AB - BACKGROUND: Cognitive behaviour therapy (CBT) has been shown to be effective in an open trial for people with psychotic disorders who have not been taking antipsychotic medication. There is little known about predictors of outcome in CBT for psychosis and even less about hypothesised mechanisms of change. METHOD: 20 participants with schizophrenia spectrum disorders received CBT in an exploratory trial. Our primary outcome was psychiatric symptoms measured using the PANSS. Secondary outcomes were dimensions of hallucinations and delusions, self-rated recovery and social functioning, and hypothesised mechanisms of change included appraisals of psychotic experiences, dysfunctional attitudes and cognitive insight. We also measured patient characteristics that may be associated with outcome. RESULTS: T-tests revealed that several of the hypothesised mechanisms did significantly change over the treatment and follow-up periods. Correlational analyses showed that reductions in negative appraisals of psychotic experiences were related to improvements on outcome measures and that shorter duration of psychosis and younger age were associated with greater changes in symptoms. CONCLUSIONS: CBT based on a specific cognitive model appears to change the hypothesised cognitive mechanisms, and these changes are associated with good outcomes. CBT may be more effective for those who are younger with shorter histories of psychosis. PMID- 22209268 TI - Circumferential evaluation of the neointima by optical coherence tomography after ABSORB bioresorbable vascular scaffold implantation: can the scaffold cap the plaque? AB - OBJECTIVE: To quantify the circumferential healing process at 6 and 12 months following scaffold implantation. BACKGROUND: The healing process following stent implantation consists of tissue growing on the top of and in the space between each strut. With the ABSORB bioresorbable vascular scaffold (BVS), the outer circumference of the scaffold is detectable by optical coherence tomography (OCT), allowing a more accurate and complete evaluation of the intra-scaffold neointima. METHODS: A total of 58 patients (59 lesions), who received an ABSORB BVS 1.1 implantation and a subsequent OCT investigation at 6 (n=28 patients/lesions) or 12 (n=30 patients with 31 lesions) months follow-up were included in the analysis. The thickness of the neointima was calculated circumferentially in the area between the abluminal side of the scaffold and the lumen by means of an automated detection algorithm. The symmetry of the neointima thickness in each cross section was evaluated as the ratio between minimum and maximum thickness. RESULTS: The neointima area was not different between 6 and 12 months follow-up (1.57+/-0.42 mm(2) vs. 1.64+/-0.77 mm(2); p=0.691). No difference was also found in the mean thickness of the neointima (median [IQR]) between the two follow-up time points (210 MUm [180-260]) vs. 220 MUm [150-260]; p=0.904). However, the symmetry of the neointima thickness was higher at 12 than at 6 months follow-up (0.23 [0.13-0.28] vs. 0.16 [0.08-0.21], p=0.019). CONCLUSIONS: A circumferential evaluation of the healing process following ABSORB implantation is feasible, showing the formation of a neointima layer, that resembles a thick fibrous cap, known for its contribution to plaque stability. PMID- 22209269 TI - The prevalence and impact of major depressive disorder among Chinese, Malays and Indians in an Asian multi-racial population. AB - BACKGROUND: Reports of rates of depression among different Asian ethnic groups within the same country using standardized assessments are rare in the extant literature. METHODS: This was a household survey of 6616 adult residents of Singapore which constituted a national representative sample. Face to face interviews were conducted with the English, Chinese and Malay versions of the World Mental Health Composite International Diagnostic Interview. The response rate was 75.9%. RESULTS: The lifetime and 12-month prevalence estimates for MDD were 5.8% and 2.2%, respectively. MDD was significantly higher among the females, Indians, those who were divorced/separated, or widowed. The median age of onset of MDD was 26 years with the highest risk of onset in those aged 18-34 years while the age group of 65 years and above had the lowest risk of onset. Chronic physical conditions were present in approximately half of the respondents with MDD. MDD was also associated with considerable disability in terms of days of role impairment. More than half (59.6%) of those with lifetime MDD had not ever sought professional help. LIMITATIONS: This was a cross-sectional household survey that excluded those who were institutionalized. Responses were self reported and therefore subjected to recall bias. CONCLUSIONS: Our findings add to the body of knowledge on the differential rates of depression among different ethnic groups; the association with disability, comorbid physical conditions and the considerable proportion of untreated cases also have important clinical and policy implications. PMID- 22209270 TI - Assessment of prevalence and determinants of posttraumatic stress disorder in survivors of earthquake in Pakistan using Davidson Trauma Scale. AB - INTRODUCTION: Pakistan's 2005 earthquake claimed almost 87,000 lives and displaced millions. The present study sought to assess PTSD prevalence among earthquake survivors, to evaluate its determinants, and to identify protective factors that suggest future interventions in the aftermath of disasters. METHODS: In a cross-sectional survey, three districts were selected based on their proximity to the epicenter and the presence, accessibility, and security of refugees, 300 earthquake survivors were enrolled. RESULTS: Analysis revealed that after 30months, PTSD prevalence was high. Being female, older, unmarried, head of the family, and currently unemployed and having low income and living in temporary housing confer higher risks of PTSD. Having a high social capital and religious inclination seem to have protective, buffer effect and increase resilience against PTSD. CONCLUSION: This is the first post-quake study in Pakistan that has utilized, adapted and validated Davidson Trauma Scale in the local context. Results imply the significance of continued psychological support, of drawing on resilience factors in PTSD management. Implications and directions for future research are discussed. PMID- 22209271 TI - beta adrenergic blockade prevents cardiac dysfunction following status epilepticus in rats. AB - Status epilepticus (SE) can result in temporary cardiac dysfunction in patients, characterized by reduced ejection fraction, decreased ventricular contractility, and alterations in electrical activity of the heart. Although reversible, the cardiac effects of seizures are acutely life threatening, and may contribute to the delayed mortality following SE. The precise mechanisms mediating acute cardiac dysfunctions are not known. These studies evaluated effects of self sustaining limbic SE in rats on cardiac performance 24h following seizures, and determined if sympathetic nervous system activation during seizures contributed to cardiac dysfunction. Rats subjected to SE received either vehicle (saline) or the B1 adrenergic antagonist atenolol (AT) prior to and during 90 min of seizure activity. Control rats were similarly treated, except they did not undergo seizures. Twenty-four hours after SE, animals were anesthetized and catheterized for measurement of cardiac performance variables. Animals undergoing SE demonstrated significantly reduced cardiac output, decreased ventricular contractility and relaxation, increased blood pressure, and prolonged QT interval. However, heart rate was not altered. Treatment with AT prevented all changes in cardiac performance due to SE, and attenuated the increase in QT interval. These data demonstrate that SE in the rat results in cardiac dysfunction 24h following seizures, mediated by the sympathetic nervous system. PMID- 22209272 TI - Pyrrole alkanoic acid derivatives as nuisance inhibitors of microsomal prostaglandin E2 synthase-1. AB - Microsomal prostaglandin E(2) synthase-1 (mPGES-1) is an enzyme, which is induced during the inflammatory response. Therefore, inhibitors of this enzyme are considered to be potential anti-inflammatory drugs. We have identified 3-(4 dodecanoyl-1,3,5-trimethylpyrrol-2-yl)propionic acid (12) as submicromolar inhibitor of mPGES-1. Surprisingly, structural variations made around this lead only resulted in a relatively small change of enzyme inhibitory potency. Such flat structure-activity relationships are reported to be typical for so called nuisance inhibitors, which exert their action not by directly binding to the enzyme, but by forming colloid-like aggregates at micromolar and sometimes submicromolar concentrations, which somehow sequester and inhibit enzyme targets without specificity. Since aggregate-based inhibition is highly sensitive to non ionic detergents such as Triton X-100, we investigated some of our compounds for inhibition of human recombinant mPGES-1 also in presence of this detergent. The pyrrole derivatives 12, 67 and 81, which exhibited IC(50) values in absence of Triton X-100 in the range of 0.1 and 1MUM, were virtually inactive at the highest test concentration of 10MUM when 0.1% of the detergent was added. In the same way, the published mPGES-1 inhibitor 2-[(4-{[(1,1'-biphenyl)-4-ylmethyl]amino}-6 chloropyrimidin-2-yl)thio]octanoic acid (Cay10589) (6) totally lost its activity under these conditions. Therefore, these compounds have to be judged as nuisance inhibitors of the enzyme. In contrast, the known indole derivative 3-[3-(tert butylthio)-1-(4-chlorobenzyl)-5-isopropylindol-2-yl]-2,2-dimethylpropionic acid (MK-886) (2) showed a considerable activity (75% inhibition at 10MUM) also in the presence of Triton X-100. PMID- 22209273 TI - Proton-pumping-ATPase-targeted antifungal activity of cinnamaldehyde based sulfonyl tetrazoles. AB - Azoles are generally fungistatic, and resistance to fluconazole is emerging in several fungal pathogens. We designed a series of cinnamaldehyde based sulfonyl tetrazole derivatives. To further explore the antifungal activity, in vitro studies were conducted against 60 clinical isolates and 6 standard laboratory strains of Candida. The rapid irreversible action of these compounds on fungal cells suggested a membrane-located target for their action. Results obtained indicate plasma membrane H(+)-ATPase as site of action of the synthesized compounds. Inhibition of H(+)-ATPase leads to intracellular acidification and cell death. Presence of chloro and nitro groups on the sulfonyl pendant has been demonstrated to be a key structural element of antifungal potency. SEM micrographs of treated Candida cells showed severe cell breakage and alterations in morphology. PMID- 22209274 TI - Study of pH effects on the evolution of properties of brown-water natural organic matter as revealed by size-exclusion chromatography during photocatalytic degradation. AB - This study shows the effect of pH on the photocatalytic degradation of natural organic matter (NOM). The experiments were carried out in batch reactor (a solar UV-light simulator) with Degussa P-25 titanium dioxide (TiO2). The NOM degradation was followed by size-exclusion chromatography for dissolved organic carbon (DOC), ultraviolet absorption and fluorescence-detection (SEC-DOC, SEC UV254 and SEC-Fl254/450). Changes in pH values affected the adsorption of NOM onto TiO2, but did not affect the photodegradation sequence of NOM. For high or low pH values, the degradation of the NOM preferentially removed the larger molecular size fraction in comparison to the middle and small molecular size fractions, resulting in the relative increase of these smaller fractions. This sequence of NOM degradation leads to the evolution of the formation potential for disinfection by-products (DBPs). Specifically, the trihalomethanes and halogenated organic compounds formation potential (THMF and AOXFP) decreased steadily. PMID- 22209275 TI - A comparative life cycle assessment of hybrid osmotic dilution desalination and established seawater desalination and wastewater reclamation processes. AB - The purpose of this study was to determine the comparative environmental impacts of coupled seawater desalination and water reclamation using a novel hybrid system that consist of an osmotically driven membrane process and established membrane desalination technologies. A comparative life cycle assessment methodology was used to differentiate between a novel hybrid process consisting of forward osmosis (FO) operated in osmotic dilution (ODN) mode and seawater reverse osmosis (SWRO), and two other processes: a stand alone conventional SWRO desalination system, and a combined SWRO and dual barrier impaired water purification system consisting of nanofiltration followed by reverse osmosis. Each process was evaluated using ten baseline impact categories. It was demonstrated that from a life cycle perspective two hurdles exist to further development of the ODN-SWRO process: module design of FO membranes and cleaning intensity of the FO membranes. System optimization analysis revealed that doubling FO membrane packing density, tripling FO membrane permeability, and optimizing system operation, all of which are technically feasible at the time of this publication, could reduce the environmental impact of the hybrid ODN-SWRO process compared to SWRO by more than 25%; yet, novel hybrid nanofiltration-RO treatment of seawater and wastewater can achieve almost similar levels of environmental impact. PMID- 22209276 TI - Potential nanosilver impact on anaerobic digestion at moderate silver concentrations. AB - Silver nanoparticles (AgNPs, nanosilver) entering the sewers and wastewater treatment plants (WWTPs) are mostly accumulated in the sludge. In this study, we determined the impact of AgNPs on anaerobic glucose degradation, sludge digestion and methanogenic assemblages. At ambient (22 degrees C) and mesophilic temperatures (37 degrees C), there was no significant difference in biogas and methane production between the sludge treated with AgNPs at the concentrations up to 40 mg Ag/L (13.2 g silver/Kg biomass COD) and the control. In these anaerobic digestion samples, acetate and propionic acid were the only detectable volatile fatty acids (VFAs) and they were depleted in 3 days. On the other hand, more than 90% of AgNPs was removed from the liquid phase and associated with the sludge while almost no silver ions were released from AgNPs under anaerobic conditions. Quantitative PCR results indicated that Methanosaeta and Methanomicrobiales were the dominant methanogens, and the methanogenic diversity and population remained largely unchanged after nanosilver exposure and anaerobic digestion. The results suggest that AgNPs at moderate concentrations (e.g., <=40 mg/L) have negligible impact on anaerobic digestion and methanogenic assemblages because of little to no silver ion release. PMID- 22209277 TI - Immediate and long-term impacts of UV-C irradiation on photosynthetic capacity, survival and microcystin-LR release risk of Microcystis aeruginosa. AB - In this study, the immediate and long-term impacts of shortwave ultraviolet (UV C) irradiation on photosynthetic capacity, survival, and recovery of Microcystis aeruginosa were investigated. The risk of microcystin-LR (MC-LR) release during irradiation was also estimated. The cell density was determined by a flow cytometry, and typical chlorophyll fluorescence parameters, including the effective quantum yield, photosynthetic efficiency and maximal electron transport rate, were measured by a pulse amplitude modulated (PAM) fluorometer. Under various UV-C dosages (140-4200 mJ cm(-2)), photosynthetic capacities were reduced, to different degrees, accompanied by slight cytoclasis and complete degradation of extracellular MC-LR immediately after irradiation. In a 6-d cultivation following UV-C irradiation, cell density and extracellular MC-LR in the samples treated by 140 mJ cm(-2) UV-C irradiation increased from 4.0*10(6) cells mL(-1) and 8 MUg L(-1) to 5.1*10(6) cells mL(-1) and 20 MUg L(-1), respectively. Significant M. aeruginosa cytoclasis (cell density from 4.0*10(6) to 1.0*10(6) cells mL(-1)) and MC-LR release (2-25 MUg L(-1)) occurred when the UV-C dosage reached 350 mJ cm(-2). Cell cytoclasis and MC-LR release were enhanced in the cultivated samples under higher UV-C dosages. Results revealed that photosynthetic parameters were useful tools to predict the recovery profiles of M. aeruginosa cells, and the MC-LR release risk should be considered after UV C inactivation. PMID- 22209278 TI - The role of extracellular polymeric substances on the sorption of natural organic matter. AB - In this study, the influence of extracellular polymeric substances (EPS) composition and quantity was explored for biosorption of natural organic matter (NOM), using variants of Pseudomonas aeruginosa and Pseudomonas putida. Model EPS (sodium alginate beads) were tested and sorption capacity for NOM was also elucidated. In the absence of divalent ions, minimal NOM biosorption was observed and differences among strains were negligible. Under presence of divalent ions, biosorption of NOM was proportional to the amount of EPS secreted by P. aeruginosa variants. For sorption tests with model EPS, divalent ions also promoted biosorption of tested NOM, and total biosorption was also proportional to alginate quantity. Carboxyl group content in both alginate EPS and NOM appeared to be linked to increased biosorption via bridging with divalent ions. The alginate overproducing strain possessed more potential NOM biosorption sites, while the wild-type and alginate deficient strains possessed fewer potential binding sites. In comparison, P. putida, secreting protein-based EPS, behaved differently for NOM biosorption, due to its hydrophobicity and the structural characteristics of proteins. Hydrophobic interactions appeared to enhance the biosorption of more hydrophobic Suwannee River humic acid by P. putida, whose biosorption of more hydrophilic NOM variants was similar to the alginate deficient strain. Mechanistically, the presence of a diffuse electrical double layer will present potential energy barriers limiting biosorption; however, divalent ion concentrations in the aquatic environment will promote biosorption processes, permitting functional group interactions between EPS and NOM. Bridging between hydrophilic carboxyl groups on alginate EPS and NOM appeared to be the dominant form of biosorption, while hydrophobic interactions enhanced biosorption for protein-based EPS. PMID- 22209279 TI - Priority pollutants in urban stormwater: part 1 - case of separate storm sewers. AB - Organic and mineral pollutants have become part of today's urban environment. During a rain event, stormwater quality as well as the corresponding contaminant loads is affected by both atmospheric deposition and the various types of impervious surfaces (roads, rooftops, parking lots etc.) on which runoff occurs. This study provides results on stormwater pollution in Paris and its suburbs from three separate storm sewers (n=20 samples). These results show that the stormwater had been contaminated by 55 chemical substances out of the 88 investigated. A particular attention was given to stormwater particle contamination. Concentrations are provided for: metals, PAHs, PCBs, organotins, alkylphenols, phthalates, pesticides, and VOCs. Our findings are among the first available in the literature since the relevant analyses were all conducted on both the particulate (P) and dissolved (D) phases. For most substances, particles from the three storm sewers were more heavily contaminated than dredged sediments and settleable particles from the Seine River. As a consequence of this finding, the release of untreated stormwater discharges may impact the receiving waters and contribute to sediment contamination. PMID- 22209280 TI - Legionellae in engineered systems and use of quantitative microbial risk assessment to predict exposure. AB - While it is well-established that Legionella are able to colonize engineered water systems, the number of interacting factors contributing to their occurrence, proliferation, and persistence are unclear. This review summarizes current methods used to detect and quantify legionellae as well as the current knowledge of engineered water system characteristics that both favour and promote legionellae growth. Furthermore, the use of quantitative microbial risk assessment (QMRA) models to predict potentially critical human exposures to legionellae are also discussed. Understanding the conditions favouring Legionella occurrence in engineered systems and their overall ecology (growth in these systems/biofilms, biotic interactions and release) will aid in developing new treatment technologies and/or systems that minimize or eliminate human exposure to potentially pathogenic legionellae. PMID- 22209281 TI - Estimation of chlorophyll-a concentration in turbid productive waters using airborne hyperspectral data. AB - Algorithms based on red and near infra-red (NIR) reflectances measured using field spectrometers have been previously shown to yield accurate estimates of chlorophyll-a concentration in turbid productive waters, irrespective of variations in the bio-optical characteristics of water. The objective of this study was to investigate the performance of NIR-red models when applied to multi temporal airborne reflectance data acquired by the hyperspectral sensor, Airborne Imaging Spectrometer for Applications (AISA), with non-uniform atmospheric effects across the dates of data acquisition. The results demonstrated the capability of the NIR-red models to capture the spatial distribution of chlorophyll-a in surface waters without the need for atmospheric correction. However, the variable atmospheric effects did affect the accuracy of chlorophyll a retrieval. Two atmospheric correction procedures, namely, Fast Line-of-sight Atmospheric Adjustment of Spectral Hypercubes (FLAASH) and QUick Atmospheric Correction (QUAC), were applied to AISA data and their results were compared. QUAC produced a robust atmospheric correction, which led to NIR-red algorithms that were able to accurately estimate chlorophyll-a concentration, with a root mean square error of 5.54 mg m(-3) for chlorophyll-a concentrations in the range 2.27-81.17 mg m(-3). PMID- 22209283 TI - Benefits and risks of IgA in immunoglobulin preparations. AB - The case of Immunoglobulin A (IgA) in transfusion medicine is unsettled: on one hand IgA is an important component of adaptive immunity and its deficiency may cause disease, on the other its presence in blood products might induce, in rare instances, allergy-like symptoms if not anaphylaxis. The practice with i.v. immunoglobulins currently changes as up to 10% concentrated preparations are given at fast rates hence even trace amounts of IgA contained in these IgG preparations can cause unexpected (side-) effects. Fortunately, the spectrum of sensitive IgA assays, along with anti-IgA screening assays now permits laboratories to narrow down IgA-dependent transfusion reactions to the real cases, in which IgA was the decisive trigger of anaphylaxis, proven or not by the presence of anti-IgA of the IgG or even IgE class. Tolerance to allogenic IgA has recently been reported. The known association of HLA with IgA deficiency (IgAD) has now been completed with an association to the nonsynonymous variant in IFHI1, allowing physicians to more precisely spot recipients at risk for an IgA dependent transfusion reaction. Our review, along with our own experience here in Switzerland, allows us to conclude that IgA is a beneficial antibody rather than an allergen to be placed at the end of the list of non-infectious transfusion complications such as TRALI, febrile non-hemolytic reactions, purpura or volume overload. PMID- 22209282 TI - Lipid ingredients in moisturizers can modulate skin responses to UV in barrier disrupted human skin in vivo. AB - BACKGROUND: Chemicals with a molecular weight <500 and adequate lipid solubility can penetrate the intact human skin. As many lipid ingredients in moisturizers have molecular weights <500, the lipid ingredients may penetrate into the skin and affect skin responses to UV; however, little is known about this phenomenon. OBJECTIVE: To evaluate the effects of major lipid ingredients in moisturizers on skin responses to UV in tape-stripped human skin in vivo. METHODS: We evaluated the effects of three major lipid ingredients in moisturizers (cholesterol, linoleic acid, and a synthetic ceramide, N-oleoyl-phytosphingosine) on skin responses to UV in the tape-stripped skin of healthy volunteers. After 2 days of lipid-application, the areas were irradiated with UV, and skin samples were obtained 24h after irradiation. Histologic features and the expression of the markers of collagen metabolism and inflammatory mediators were evaluated. RESULTS: Compared to vehicle, topical cholesterol significantly decreased the degree of dermal inflammatory infiltrates and exocytosis, and also decreased the expression of MMP-1, IL-6, and IL-1beta mRNA. In contrast, topical linoleic acid increased the induction of apoptotic cells, and the expression of MMP-1 and IL-6 mRNA. N-oleoyl-phytosphingosine increased the expression of MMP-1 and IL-6 mRNA, while decreasing the expression of COX-2 mRNA. CONCLUSIONS: Topical cholesterol can protect the barrier-disrupted skin against UV-induced damage, while linoleic acid or N-oleoyl-phytosphingosine alone has the potential to aggravate the damage. PMID- 22209284 TI - A luciferase reporter assay to investigate the differential selenium-dependent stability of selenoprotein mRNAs. AB - The mechanisms regulating the differential selenium (Se)-dependent stability of selenoprotein mRNAs are partially characterized. To further study the Se dependent regulation of selenoproteins, we developed a novel chemiluminescent reporter to monitor the steady-state mRNA level of an artificial selenoprotein. Our reporter is a fusion of the Renilla luciferase gene and of the beta-globin gene, but contains features required for incorporation of selenocysteine (SEC), namely, a UGA-SEC codon and a 3' untranslated region RNA stem loop called a SEC incorporation sequence (SECIS). At various levels of Se, the activity of reporters containing GPX1 or GPX4 SECIS elements is proportional to the steady state mRNA level of the reporter construct and reflects the level of the corresponding endogenous mRNA. In a reporter containing a UGA codon and a functional GPX1 SECIS, Se-dependent nonsense-mediated decay (NMD) occurred in the cytoplasm, as opposed to the more typical nuclear location. To validate the reporter system, we used genetic and pharmacologic approaches to inhibit or promote NMD. Modulation of UPF1 by siRNA, overexpression, or by inhibition of SMG1 altered NMD in this system. Our reporter is derived from a Renilla luciferase reporter gene fused to an intron containing B-globin gene and is subject to degradation by NMD when a stop codon is inserted before the second intron. PMID- 22209285 TI - The citrus flavonone hesperetin inhibits growth of aromatase-expressing MCF-7 tumor in ovariectomized athymic mice. AB - Aromatase is responsible for the rate-determining reaction in estrogen synthesis and is a prime target for treating estrogen-receptor-positive breast cancer. Previous in vitro study has demonstrated that apigenin (APG), naringenin (NGN) and hesperetin (HSP) are three of the most potent natural aromatase inhibitors. Because the enzyme inhibition could potentially block breast cancer development, we employed an established postmenopausal breast cancer model to examine the chemopreventive effect of these flavonoids in vivo. Athymic mice were ovariectomized and transplanted with aromatase-overexpressing MCF-7 cells. Dietary administration of HSP at 1000 ppm and 5000 ppm significantly deterred the xenograft growth, while a null effect was observed in mice treated with APG or NGN. Further study illustrated that plasma estrogen in HSP-treated mice was reduced. Messenger RNA expression of the estrogen-responsive gene pS2 was also decreased in the tumors of mice treated with 1000 and 5000 ppm HSP. On the other hand, western analysis indicated that cyclin D1, CDK4 and Bcl-x(L) were reduced in the tumors. This study suggested that HSP could be a potential chemopreventive agent against breast carcinogenesis through aromatase inhibition. PMID- 22209286 TI - Diurnal rhythms are altered in a mouse model of multiple sclerosis. AB - Our earlier studies described a disruption of heart rate and blood pressure diurnal rhythms in mice with experimental autoimmune encephalomyelitis (EAE). The present study investigates whether these observations could be extended to additional clock-regulated rhythms in mice with EAE. Analysis of clock gene expression in the liver of EAE mice demonstrated significant variability associated with Per2 rhythmic expression. Corticosterone and leptin hormone rhythms were also altered in EAE mice. The results presented here indicate that disturbances in clock-regulated rhythms are associated with EAE and present a suitable model for investigating the relationship between circadian disruption and autoimmune inflammatory disease. PMID- 22209287 TI - Prevalence of HIV, HBV, HCV, HTLV and Treponema pallidum among patients attending a rural hospital in Southern Ethiopia. PMID- 22209288 TI - Detection of coxsackievirus A10 in multiple tissues of a fatal infant sepsis case. AB - Non-polio enteroviruses are a common cause of childhood infections varying in symptomatology and severity. While infections with many of the enterovirus serotypes can be severe and even fatal, coxsackievirus A10 (CVA10) has most commonly been associated with more mild disease. Here we present the detection of CVA10 in multiple organ tissues in the investigation of an infant death. PMID- 22209289 TI - Performance of an immunofiltration assay detecting IgM antibodies against ZEBRA and viral capsid p18 proteins (Immunoquick((r)) filtration EBV M) for the diagnosis of heterophile antibody-negative primary Epstein-Barr virus infection in children. PMID- 22209290 TI - Epstein-Barr virus load and immune activation in human immunodeficiency virus type 1-infected patients. AB - BACKGROUND: Patients infected with HIV-1 are at high risk of developing Epstein Barr Virus (EBV)-related diseases. Chronic immune activation is a hallmark of HIV 1 pathogenesis and may play a role in B-cell stimulation and expansion of EBV infected cells. OBJECTIVES: The aim of the study was to define the relationship between parameters of immune activation and EBV load in HIV-1-infected subjects. STUDY DESIGN: A total of 156 HIV-1-infected patients were studied. EBV types 1 and 2 were quantified on peripheral blood mononuclear cells by multiplex real time PCR. Plasma levels of cytokines and lipopolysaccharide (LPS) were determined by immunoenzymatic assays. B-cell activation was analyzed by flow cytometry. RESULTS: EBV-DNA was detected in 114 patients, and in all but 3 was EBV type 1. The median [interquartile] EBV-DNA load was 43[1-151] copies/10(5) PBMC. EBV-DNA load was higher in patients with detectable HIV-1 plasma viremia, despite good immunological status (CD4>500 cells/MUl), than in patients with undetectable HIV 1 plasma viremia regardless of immunological status (46[5-136] copies/10(5) cells vs 17[1-56] copies/10(5) cells, p=0.008). Patients with high EBV-DNA load (>median value) had higher levels of LPS and proinflammatory cytokines (IL-6, IL 10 and TNF-alpha) than patients with low EBV load. Furthermore, percentages of activated B-cells correlated with EBV-DNA load (r(s)=0.754; p<0.001). CONCLUSIONS: Overall, these findings indicate a strong association between HIV-1 viremia, markers of immune activation and EBV load and suggest that persistence of HIV-1 viremia and immune activation, regardless of peripheral CD4 cell depletion/repopulation, may favor expansion of EBV-infected cells and onset of EBV-related malignancies. PMID- 22209291 TI - Prevalence of TMC278 (rilpivirine) associated mutations in the Frankfurt Resistance Database. AB - BACKGROUND: Analysis of the 3D structure of the HIV-1 reverse transcriptase led to the development of TMC278 (rilpivirine), a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), which proved to be effective against wild-type HIV-1 strains and NNRTI-resistant mutants emerging after failure of NNRTI-containing therapy regimens. Recently, rilpivirine associated mutations (e.g. at positions 138, 181 or 101) have been described in vitro and in vivo; however, some of these mutations have also been observed in the past. OBJECTIVE: Objective of our investigation was to determine the prevalence of mutations E138K, Y181I/V, and K101E/P before the approval of rilpivirine. STUDY DESIGN: The Frankfurt Resistance Database consists of 7295 samples which have been sent for resistance testing since 1995. RESULTS: The E138K, Y181I/V, and the K101E mutations were found in 0.4%, 0.9%, and 2.4% of the patients, respectively. CONCLUSIONS: Based on these findings we do not expect a broad cross-resistance to rilpivirine due to previous treatment failures of NNRTI-containing regimens. PMID- 22209293 TI - Estimating sex of the human skeleton based on metrics of the sternum. AB - Estimating the sex of skeletal remains is critical in creating the biological profile of an adult individual. Previous research has shown that analyzing the sternum may lead to an accurate estimation of sex based on studies performed on various populations around the globe, such as Indian, European, African, Canadian and North American. The motivation of the current study is to develop classification functions and sectioning points for use in forensic investigations in the United States. The majority of previously published methods are population specific, meaning the data would not prove useful in the United States. For this study, sternal measurements were collected from the William M. Bass Donated Skeletal Collection located at The University of Tennessee, Knoxville following the metric definitions provided by Schwartz and Bass. This collection consists of recent skeletal remains with known age at death, ancestry and sex. Material for the present study consisted of 410 human sterna: 285 male (256 American White/29 American Black) and 125 female (120 American White/5 American Black). Previous studies analyze the applicability of Hyrtl's law in the estimation of sex. This law follows that the mesosternum is greater than twice the length of the manubrium in males and in females the length of the manubrium is greater than half the length of the mesosternum. In this study, comparisons of the proportion of the length of the manubrium to the length of the mesosternum were performed to determine if Hrytl's law is applicable in an American population. Comparisons of these measurements between individuals identified as American Black and American White were analyzed to determine whether this method could be used on both population groups. Further, discriminant function analysis was used to estimate sex and provide a population specific classification function for use in the United States. The discriminate function analysis produced an overall cross validation classification rate of 84.12% for sex estimation. The cross-validation classification rate for males and females was 80.00% and 88.24%, respectively. PMID- 22209292 TI - Evidence of immune memory 8.5 years following administration of a prophylactic human papillomavirus type 16 vaccine. AB - BACKGROUND: The duration of protection conferred by prophylactic human papillomavirus (HPV) L1 virus-like particle vaccines is a critical determinant of their public health impact. A feature of vaccines that confer long-term immunity is their ability to induce immune memory. OBJECTIVES: We evaluated antibody responses against HPV types 6, 11, 16 and 18 following administration of the quadrivalent HPV-6/11/16/18 vaccine to women who had previously received a monovalent HPV-16 vaccine. STUDY DESIGN: As part of an extended follow-up study conducted between 2006 and 2009 in Seattle, Washington, we administered the quadrivalent HPV-6/11/16/18 vaccine to 52 women (19 vaccine and 33 placebo recipients) who had participated in a monovalent HPV-16 vaccine trial 8.5 years earlier. Serum samples were tested for anti-HPV antibodies using competitive Luminex immunoassay. RESULTS: Following administration of the first dose of the quadrivalent HPV-6/11/16/18 vaccine, the anti-HPV-16 geometric mean titer among monovalent HPV-16 vaccine recipients (GMT=5024.0 milli-Merck units per milliliter [mMU/mL]; 95% confidence interval [CI]: 2710.1, 9313.6 mMU/mL) substantially exceeded that among the placebo recipients (GMT=136.1; 95% CI: 78.5, 235.8 mMU/mL; p<0.01) and their own highest anti-HPV-16 response observed during the original trial (GMT at month 7 of the original trial=1552.7 mMU/mL; 95% CI: 1072.6, 2247.7 mMU/mL; p<0.01). CONCLUSIONS: The findings suggest that the administration of the three-dose regimen of the monovalent HPV-16 vaccine had produced memory lymphocytes, characterized by a heightened immune response following administration of the quadrivalent HPV-6/11/16/18 vaccine that effectively served as an antigen challenge. PMID- 22209294 TI - PIK3CA mutations in endometrial carcinomas in Chinese women: phosphatidylinositol 3'-kinase pathway alterations might be associated with favorable prognosis. AB - The aim of this study was to determine the clinicopathological impact of PIK3CA mutations and phosphatidylinositol 3'-kinase pathway alterations in endometrial cancers in Chinese women. The PIK3CA mutation status was analyzed by sequencing in 94 tumors. The status of phosphatase and tensin homolog, p-(Ser/Thr)AKT, human epidermal growth factor receptor 2, p53, and estrogen and progesterone receptor was assessed in 102 tumors using immunohistochemistry. Biomarker status was correlated with clinicopathologic variables and with patient survival. We found that 28 mutations occurred in the helical domain encoded by exon 9 of PIK3CA and 16 occurred in the kinase domain (exon 20). Mutations of both exons were more common in low-grade than in high-grade endometrioid carcinomas, and the correlation between exon 9 mutation and lower grade was statistically significant (P = .045). In univariate analysis, phosphatidylinositol 3'-kinase pathway activation (defined as PIK3CA mutation and/or phosphatase and tensin homolog loss) was associated with a favorable prognosis (P = .034) and showed an increased predictive power when combined with expression of p-AKT, the phosphatidylinositol 3'-kinase pathway downstream effector (P = .022). In multivariate analysis, phosphatidylinositol 3'-kinase pathway activation was not an independent predictor of disease-free survival (P = .091). Interestingly, in the estrogen receptor-negative subgroup, the phosphatidylinositol 3'-kinase pathway alteration was significantly related to prolonged patient survival (P = .048), whereas this association was not present in the estrogen receptor-positive subgroup (P > .05). Our findings suggest that phosphatidylinositol 3'-kinase pathway alteration might have a favorable prognostic impact on endometrial cancers in Chinese women. Furthermore, the function of the phosphatidylinositol 3'-kinase pathway might be affected by estrogen receptor status. PMID- 22209295 TI - [Primary care models in mental health: the Mexico case]. PMID- 22209296 TI - [Medication errors map and patient safety]. PMID- 22209297 TI - [Antidepressant management strategy from the patient perspective: struggling internally and externally]. AB - OBJECTIVE: To identify the consumption pathway and strategies of coping with antidepressants use from the patients perspective. DESIGN: Qualitative research. SETTING: Tenerife. SAMPLING: Theoretical sampling until saturation. METHOD: A total of 17 open interviews with patients who consumed antidepressants whether combined with tranquilisers or not. The age range was between 35-85 years, and there were 13 women. Ten lived in a more urban setting and the rest in rural areas. Interviews were audio-recorded, transcribed verbatim and analysed using a modified Grounded Theory supported by the software program ATLAS.ti. RESULTS: The process identified as coping with antidepressants, was called "struggling internally and externally." It consisted of the individual assessment of the benefits and risks of medication use (internal struggle), addressing stigma and social pressure (external struggle). The outcome of the assessment made by patients may lead to different strategies for adjusting to drug treatment: "unconditional acceptance", "resigned acceptance" or "forced acceptance". CONCLUSIONS: Understanding the evaluation process that the patient needs to go through, given the internal and external struggle in which they are immersed, can be useful to develop interventions that improve medication use. In fact, physicians have an important role, although not always explicitly sought in resolving the dilemma posed by patients using antidepressant drugs and, therefore, reducing the length of patient suffering. PMID- 22209298 TI - Restraining and neck cutting or stunning and neck cutting of veal calves. AB - Brain and heart activities were measured in 31 veal calves during restraining and rotating followed by neck cutting with or without stunning to evaluate welfare. After neck cutting correlation dimension analyses and %power of EEG beta wave fraction decreased gradually to lower values resulting in an induction of unconsciousness lasting on average 80s. Corneal reflex response ceased 135+/-57s after neck cutting. The CD scores and the %power of beta waves fell immediately after post-cut captive bolt and pre-cut electrical stunning to levels indicating unconsciousness. Heart rate in lairage increased upon entrance to the restrainer and again after rotation, heart rate variability decreased. Rotating the restrainer 90 degrees , 120 degrees or 180 degrees compromised veal calf welfare and should be avoided. It is recommended to use post-cut captive bolt stunning or pre-cut electrical stunning inducing immediate unconsciousness. PMID- 22209299 TI - Effects of mussel shell addition on the chemical and biological properties of a Cambisol. AB - The use of a by-product of the fisheries industry (mussel shell) combined with cattle slurry was evaluated as soil amendment, with special attention to the biological component of soil. A wide number of properties related to soil quality were measured: microbial biomass, soil respiration, net N mineralization, dissolved organic carbon, dissolved organic nitrogen, dissolved inorganic nitrogen, dehydrogenase, beta-glucosidase, urease and phosphomonoesterase activities. The amendments showed an enhancement of soil biological activity and a decrease of aluminium held in the cation exchange complex. No adverse effects were observed on soil properties. Given that mussel shells are produced in coastal areas as a by-product and have to be managed as a waste and the fertility constraints in the local soils due to their low pH, our research suggest that there is an opportunity for disposing a residue into the soil and improving soil fertility. PMID- 22209300 TI - The silvering process of European eel (Anguilla anguilla) influences PAH metabolite concentrations in bile fluid: consequences for monitoring. AB - The stock of the catadromous European eel (Anguilla anguilla L.) continues to decline and there is growing evidence that poor health status due to contaminants might be a key element in this decrease. Organic contaminants such as polycyclic aromatic hydrocarbons (PAHs) belong to the major threats to yellow eel in their growth habitat and their metabolites are detectable in the bile. Starting the silvering process eels undergo physiological and morphological changes including cessation of feeding and downstream migration back to their spawning grounds. Reduced feed intake results in a diminishment of bile production and induces accumulation of e.g. PAH-metabolites in bile. Therefore, the aim of the present study was to demonstrate the impact of silvering on biliary PAH metabolite concentrations and to utilize normalization procedures to overcome silvering related accumulation effects of PAH-metabolites in eel bile. We investigated the hydroxyl-metabolites of pyrene (1-OH Pyr) and phenantrene (1-OH Phen) in the bile of different maturation stages of eels (silvering index I-V) from nine German rivers. We detected increasing absolute PAH metabolite levels in bile during the silvering process. The highest rise could be observed at the transition from pre migration stage III to the migrating stage IV, suggesting the onset of cessation of feeding at this stage. A cessation bias in PAH metabolite measurement could be diminished by normalization of absolute values against bile pigments (A(380), biliverdin). In conclusion, we demonstrated the impact of silvering on PAH metabolite concentrations in eel bile and present suitable normalization procedures to overcome silvering related accumulation effects. Thus, for a future eel monitoring we recommend (1) to regularly monitor PAH metabolites in bile, (2) to determine silvering index of eel and (3) to normalize PAH metabolite values in bile based on maturation/silvering stages. The knowledge of the silvering stage is mandatory for an unbiased evaluation of PAH contamination of European eel towards an international harmonized eel monitoring program. PMID- 22209301 TI - Investigation of the reaction of hexabromocyclododecane with polysulfide and bisulfide in methanol/water solutions. AB - Reactions of hexabromocyclododecane (HBCD), a widely used brominated flame retardant, with reduced sulfur species (e.g., polysulfide and bisulfide) were investigated in well-defined solutions under anoxic conditions. It is likely that reactions of HBCD with reduced sulfur species such as polysulfides and bisulfide present in anoxic subregions of coastal water bodies and sediments could have a significant impact on the fate of HBCD. The second-order reaction rate constant of HBCD with polysulfides in 80% methanol/20% water at 40 degrees C is 2.2 (+/ 0.3)*10(-2) M(-1) s(-1). The second-order reaction rate constant of HBCD with bisulfide is 8.9 (+/-2.8)*10(-4) M(-1) s(-1) under the same conditions. The formation of two products was observed with either of the two reduced sulfur species. The experiments also indicate that the gamma-isomer of HBCD is reacting significantly faster with reduced sulfur species than the alpha-isomer. PMID- 22209302 TI - Study of inhibition mechanism of NO3- on photoreduction of Hg(II) in artificial water. AB - Photoreduction is of immense importance to mercury transfer from water to atmosphere. In this investigation, the reduction of HgCl(2) and Hg(NO(3))(2) under dark, natural light and ultraviolet radiation (UV) was estimated using series of laboratory experiments. The result showed that the role of light irradiation in HgCl(2) reduction was entirely different from that in Hg(NO(3))(2). The rate of HgCl(2) reduction was in the order of UV>natural light>dark, compared with dark>natural light>UV of Hg(NO(3))(2). The experiments of mercury reduction treated by KNO(3) and CH(3)OH, which was used as a NO(3)(-) provider and a iOH scavenger respectively, indicated that iOH which was produced via direct photolysis of NO(3)(-) in water should be responsible for the unexpected inhibition of UV to Hg(NO(3))(2) reduction. The reduction of Hg(NO(3))(2) under different radiation intensity each of UVA, UVB and UVC was investigated. The result showed that UVB induced the highest mercury reduction while mercury reduction increased with light intensity. In addition, the kinetic study of mercury reduction under natural light was conducted through both concentration gradient method and trial method. The pseudo first rate constant was estimated to be 7*10(-4) min(-1). PMID- 22209303 TI - Design and evaluation of hydrolytically stable bidentate urea-type stationary phases for hydrophilic interaction chromatography. AB - We have developed conceptually new stationary phases containing two bidentate urea-type functions suitable for the separation of a wide variety of polar compounds by hydrophilic interaction chromatography (HILIC) through a facile one pot two-step procedure with the aim of obtaining high hydrolytic stability in a variety of elution conditions. The preparation of the new phases involves a first reaction of 1,2-ethylendiamine with (3-isocyanatopropyl)triethoxysilane to give an intermediate bis-urea with two pendant triethoxysilane functions, followed by anchoring on the silica surface. Two stationary phases were prepared, namely an urea-type stationary phase (USP-HILIC) and an urea-type phase bearing free amino groups (USP-HILIC-NH(2)), whereas silanization with 1,2-bis(trichlorosilyl)ethane yielded USP-HILIC-sil and USP-HILIC-NH(2)-sil phases, respectively. The silanization step aimed at forming a hydrophilic stable coating through cross linking between adjacent silanols which prevents silica dissolution at alkaline pH. A full chemical characterization of the new materials has been obtained through solid-state NMR (both (29)Si and (13)C CPMAS) spectroscopy. A major application field of the bidentate urea-type stationary phase with free amino groups USP-HILIC-NH(2)-sil was sugars analysis, usually hampered by alpha/beta anomer peak splitting and instability of the stationary phases under conditions normally employed to suppress it. Complex mixtures of mono-, di- and oligosaccharides were successfully resolved under mild chromatographic conditions, which also allowed an easy interface with mass spectrometry. The potential of such materials was shown in the separation of other highly polar compounds, including polyols, hydroxybenzoic acids, nucleobases, and vitamins. PMID- 22209304 TI - Determination of aqueous fullerene aggregates in water by ultrasound-assisted dispersive liquid-liquid microextraction with liquid chromatography-atmospheric pressure photoionization-tandem mass spectrometry. AB - A simple and solvent-minimized method for the determination of three aqueous fullerene aggregates (nC60, nC70, and aqueous [6,6]-phenyl C61 butyric acid methyl ester (nPCBM)) in water samples is described. The method involves the use of ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME) coupled liquid chromatography-tandem mass spectrometry with atmospheric pressure photoionization (LC-APPI-MS/MS). The parameters affecting the extraction efficiency of the analytes from water samples were systematically investigated and the conditions optimized. The best extraction conditions involved the rapid injection of a mixture of 1.0 mL of 2-propanol (as a disperser solvent) and 10 MUL of benzyl bromide (as an extraction solvent) into 10 mL of an aqueous solution (pH 10.0) containing 1% sodium chloride in a conical bottom glass tube. After ultrasonication for 1.0 min and centrifugation at 5000 pm (10 min), the sedimented phase 5.0 MUL was directly injected into the LC-APPI-MS/MS system. The limits of quantification (LOQs) were 150, 60 and 8 ng L-1 for nPCBM, nC60 and nC70, respectively. The precision for these analytes, as indicated by relative standard deviations (RSDs), were less than 12% for both intra- and inter-day analysis. Accuracy, expressed as the mean extraction recovery, was between 70 and 86%. A standard addition method was used to quantitate three aqueous fullerene aggregates, and the concentrations of these aqueous fullerene aggregates were determined to be in the range from n.d. to 130 ng L-1 in various environmental samples including municipal influent and effluent samples, industrial wastewater samples, and surface water samples. PMID- 22209305 TI - Rapid determination of piperazine-type stimulants in human urine by microextraction in packed sorbent after method optimization using a multivariate approach. AB - This paper describes the analysis of piperazine-type stimulants [1 benzylpiperazine (BZP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP), 1-(3 chlorophenyl)piperazine (mCPP) and 1-(4-methoxyphenyl)piperazine (MeOPP)] in low volume urine samples (0.1 mL) by microextraction in packed sorbent and liquid chromatography-diode array detection. Analyte extraction has been comprehensively optimized, and the influencing factors were screened by means of the fractional factorial design approach. Several parameters susceptible of influencing the process were studied, and these included extraction sorbent type (C(8) and C(18)), sample dilution (1:2 and 1:4), number of aspirations through the device (2 and 8) and the amount of methanol on both the washing (0 and 10%) and eluting solvents (10 and 100%). The method was linear from 0.5 (lower limit of quantitation) to 5 MUgmL(-1), with determination coefficients higher than 0.99 for all compounds. Intra- and interday precision ranged from 1 to 9%, trueness was within a +/- 11% interval for all analytes, and analyte recoveries were of about 70% for mCPP and TFMPP, and of about 10% for MeOPP and BZP. The method has shown to be selective, as no interferences from endogenous substances were detected by analysis of blank samples, and the analytes were stable in the samples for short periods at room temperature, after three freeze/thaw cycles and in processed samples. Due to its simplicity and speed, this method can be successfully applied in the screening and quantitation of these compounds in urine samples, and is suitable for application in forensic toxicology routine analysis. PMID- 22209306 TI - Remission from alcohol and other drug problem use in public and private treatment samples over seven years. AB - BACKGROUND: The treatment of alcohol and other drugs is now more commonly framed in terms of a chronic condition which requires ongoing monitoring. A model which includes continuing access to health care may optimize outcomes. Most studies of chronic care models have not included health care and have only examined short term effects. METHODS: The sample (n = 783) included consecutive admissions in ten public and private alcohol and other drug (AOD) treatment programs followed over seven years. The outcome was remission which was defined as alcohol and drug abstinence or non-problem use. RESULTS: In the private sample, receiving health care services predicted remission across the seven years; however this did not occur in the public sample. More patients in the public treatment sample received AOD treatment readmissions each year, while more of those in the private sector received psychiatric and general health visits. Except for drug problem severity, there were no other clinical differences between the samples. There were no differences in the proportions of patients in the two sectors who received the full spectrum of chronic care services. In the final models, 12-step participation was markedly significant for both samples. CONCLUSIONS: Models of chronic care for substance use need to consider differences between private and public treatment and should take into account that individuals may not always have access, or avail themselves of services that may optimize long-term outcomes. PMID- 22209308 TI - A pre-post evaluation of the Adler/Sheiner Programme (ASP): a nursing informational programme to support families and nurses in an intensive care unit (ICU). AB - BACKGROUND: ICU nurses often report that timely informational and supportive resources would ease distress for clients and providers alike. OBJECTIVES: This pilot study was aimed to explore the role of a comprehensive information and support programme in enhancing the work environment, task performance and reducing emotional distress amongst ICU nurses. RESEARCH METHODOLOGY/DESIGN: Through a mixed quantitative and qualitative design, nurses were invited to complete self-report questionnaires (n=25) and to participate in focus groups (n=7) prior to (T1) and 6 weeks after the implementation of the supportive programme (T2). RESULTS: Measures of physical and mental effort were found to be significantly lower (t=2.45, p=0.02) at post test (T2). Statistical trends towards significance were observed for higher performance satisfaction (t=1.70, p=0.10) and lower emotional distress (t=2.00, p=0.06) at T2. Focus group data revealed that nurses felt more supported in their work, had more satisfaction with work tasks accomplished and felt more emotionally supported with the programme being in place. CONCLUSIONS: Preliminary data from this pilot study suggest that a comprehensive information and support programme designed to support nurses in the ICU can enhance well being and workplace related factors. Work is currently underway to document the program's impact on family members in the ICU. Future studies should document further how and when similar programme contribute to enhance the workplace for other ICU staff. PMID- 22209307 TI - Patterns of alternative tobacco use among adolescent cigarette smokers. AB - INTRODUCTION: Alternative tobacco use among adolescents who smoke cigarettes is a growing public health concern, and evidence suggests that patterns of alternative tobacco use varies with respect to cigarette consumption and frequency of cigarette use. This study aimed to examine (a) whether variations in adolescent cigarette smoking and alternative tobacco use can be explained by underlying subtypes and (b) if these subtypes differ in their demographic and psychosocial characteristics. METHODS: Using data from the 2009 National Youth Tobacco Survey, latent class analysis (LCA) was used to identify patterns of cigarette smoking and alternative tobacco use among 2746 current (past 30-day) smokers. After identification, classes were analyzed using multinomial logistic regression to examine differences based on demographics and smoking-related characteristics. RESULTS: Four of the six latent classes identified (non-daily light smokers, chippers, chippers-Indulgent, intermittent smokers) reflected consumption, frequency, and history of cigarette use characteristics commonly attributed to light and intermittent smokers, and the remaining two classes (daily smokers, daily smokers-Indulgent) presented cigarette use behaviors commonly attributed to daily smokers. There were clear class differences in levels of alternative tobacco product use, demographics, and psychosocial characteristics. CONCLUSIONS: Study findings are consistent with previous work demonstrating demographic and psychosocial differences between cigarette smokers based on their alternative tobacco use. The six latent classes identified highlight the importance of including measures of alternative tobacco use when characterizing adolescent cigarette smokers as well as recognizing and tailoring interventions toward these different groups of tobacco users. PMID- 22209309 TI - Churg-Strauss syndrome with concomitant occurrence of ischemic stroke and relapsing purpura. AB - A 77-year-old woman suffering from chronic bronchial asthma and chronic atrial fibrillation who had had a previous ischemic stroke presented to our emergency unit with gait disturbance. She had new-onset truncal ataxia, right hemiparesis, and right sensory disturbance related to the previous stroke. Her lower legs were slightly swollen and had a reddened appearance. Her medical history included mitral valve replacement because of severe mitral valve regurgitation. Her white blood cell count was 8600/MUL, mainly consisting of eosinophils (4480/MUL; 52.1%). Serum nonspecific immunoglobulin E was elevated to 1600 IU/mL (normal range <170 IU/mL). She was taking warfarin for secondary stroke prevention, and on admission her prothrombin time international normalized ratio was 3.06. Diffusion-weighted magnetic resonance imaging revealed a fresh infarct in the right cerebellum. No stenosis or occlusion was shown in the cervicocephalic arteries on magnetic resonance angiography or carotid ultrasound. No emboligenic diseases, except for atrial fibrillation, were identified. On day 3, an extensive itchy, purpuric rash appeared on her lower limbs. The rash remitted and recurred spontaneously for several weeks. A skin biopsy specimen of the purpuric lesions revealed massive eosinophilic infiltration of the dermis and eosinophilic vasculitis involving small vessels. We diagnosed the patient with Churg-Strauss syndrome (CSS). Skin lesions and eosinophilia disappeared after oral corticosteroid therapy. In this case, cerebellar infarction occurred with purpuric rash despite well-controlled anticoagulation. Patients with CSS may suffer from ischemic stroke when the condition of CSS deteriorates. PMID- 22209310 TI - Influence of experimental subarachnoid hemorrhage on nicotine-induced contraction of the rat basilar artery in relation to arachidonic acid metabolites signaling pathway. AB - BACKGROUND: Smoking is one of the most important risk factors for cerebral circulatory disorders. The purpose of this study was to investigate the influence of experimental subarachnoid hemorrhage (SAH) on nicotine-induced contraction (arachidonic acid metabolites) in the basilar arteries of rats. METHODS: Rats were killed at 1 hour and 1 week after blood injection, and the basilar artery was isolated and cut into a spiral strip. RESULTS: Testing of cyclooxygenase-1 (COX-1) and 5-lipoxygenase (5-LOX) inhibitors revealed no significant differences in their effects on normal and SAH (1 hour and 1 week). Phospholipase C (PLC) inhibitor (1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17yl)amino)hexyl)-1H pyrrole-2,5,-dione [U-73122]) slightly inhibited contraction of SAH (1 hour and 1 week) when compared to controls. Phospholipase A2 (PLA2) inhibitor (manoalide) and cytosolic PLA2 (cPLA2) inhibitor (arachidonyltrifluoromenthylketone [AACOCF3]) more strongly attenuated contraction in SAH (1 hour and 1 week) than in controls. Secreted PLA2 (sPLA2) inhibitor (indoxam), PLC inhibitor (2-nitro-4 carboxyphenyl N, N-diphenylcarbamate [NCDC]), and COX-2 inhibitors (nimesulide, (5-methanesulfonamido-6-(2,4-difluorothiophenyl)-1-indanone) [L-745337], and celecoxib) only slightly inhibited contraction of SAH (1 week) when compared to normal and SAH (1 hour). The calcium-independent PLA2 (iPLA2) inhibitor bromoenol lactone (BEL) showed greater inhibition of contraction in SAH (1 hour) when compared to normal and SAH (1 week). CONCLUSIONS: One week after exposure to SAH, PLC, sPLA2, and COX-2 activity were enhanced and cPLA2 activity was inhibited. One hour after exposure to SAH, PLC activity was enhanced and cPLA2 and iPLA2 activity was inhibited. Such changes of inflammatory arachidonic acid metabolites by smoking after SAH may play important roles in fatal cerebral circulatory disorders, suggesting important implications for the etiology and pathogenesis of SAH. PMID- 22209311 TI - A novel method for the generation of multi-block computational structured grids from medical imaging of arterial bifurcations. AB - In this study a description of a new approach, for the generation of multi-block structured computational grids on patient-specific bifurcation geometries is presented. The structured grid generation technique is applied to data obtained by medical imaging examination, resulting in a surface conforming, high quality, multi-block structured grid of the branching geometry. As a case study application a patient specific abdominal aorta bifurcation is selected. For the evaluation of the grid produced by the novel method, a grid convergence study and a comparison between the grid produced by the method and unstructured grids produced by commercial meshing software are carried out. PMID- 22209312 TI - Mechanical changes in the rat right ventricle with decellularization. AB - The stiffness, anisotropy, and heterogeneity of freshly dissected (control) and perfusion-decellularized rat right ventricles were compared using an anisotropic inverse mechanics method. Cruciform tissue samples were speckled and then tested under a series of different biaxial loading configurations with simultaneous force measurement on all four arms and displacement mapping via image correlation. Based on the displacement and force data, the sample was segmented into piecewise homogeneous partitions. Tissue stiffness and anisotropy were characterized for each partition using a large-deformation extension of the general linear elastic model. The perfusion-decellularized tissue had significantly higher stiffness than the control, suggesting that the cellular contribution to stiffness, at least under the conditions used, was relatively small. Neither anisotropy nor heterogeneity (measured by the partition standard deviation of the modulus and anisotropy) varied significantly between control and decellularized samples. We thus conclude that although decellularization produces quantitative differences in modulus, decellularized tissue can provide a useful model of the native tissue extracellular matrix. Further, the large-deformation inverse method presented herein can be used to characterize complex soft tissue behaviors. PMID- 22209313 TI - Dynamic finite element knee simulation for evaluation of knee replacement mechanics. AB - In vitro pre-clinical testing of total knee replacement (TKR) devices is a necessary step in the evaluation of new implant designs. Whole joint knee simulators, like the Kansas knee simulator (KKS), provide a controlled and repeatable loading environment for comparative evaluation of component designs or surgical alignment under dynamic conditions. Experimental testing, however, is time and cost prohibitive for design-phase evaluation of tens or hundreds of design variations. Experimentally-verified computational models provide an efficient platform for analysis of multiple components, sizes, and alignment conditions. The purpose of the current study was to develop and verify a computational model of a dynamic, whole joint knee simulator. Experimental internal-external and valgus-varus laxity tests, followed by dynamic deep knee bend and gait simulations in the KKS were performed on three cadaveric specimens. Specimen-specific finite element (FE) models of posterior-stabilized TKR were created from magnetic resonance images and CAD geometry. The laxity data was used to optimize mechanical properties of tibiofemoral soft-tissue structures on a specimen-specific basis. Each specimen was subsequently analyzed in a computational model of the experimental KKS, simulating both dynamic activities. The computational model represented all joints and actuators in the experimental setup, including a proportional-integral-derivative (PID) controller to drive quadriceps actuation. The computational model was verified against six degree-of freedom patellofemoral (PF) and tibiofemoral (TF) kinematics and actuator loading during both deep knee bend and gait activities, with good agreement in trends and magnitudes between model predictions and experimental kinematics; differences were less than 1.8 mm and 2.2 degrees for PF and TF translations and rotations. The whole joint FE simulator described in this study can be applied to investigate a wide range of clinical and research questions. PMID- 22209314 TI - The distribution of immune cells and macrophages in the endometrium of women with recurrent reproductive failure. II: adenomyosis and macrophages. AB - Adenomyosis, a condition usually associated with multiparity, is not generally seen as a cause of infertility. However, recent studies have reported a reduction in IVF implantation rates and a link with miscarriage, suggesting that adenomyosis may interfere with successful implantation. To investigate this hypothesis, the clinical records and laboratory results, which routinely include immunohistochemical examination of a late luteal phase endometrial biopsy for leukocytes, were retrospectively reviewed for 64 women with implantation failure and who previously had been screened for the presence of adenomyosis by pelvic MRI. The presence of either diffuse or "adenomyoma" type of adenomyosis was associated with a marked increase (p=0.004) in the density of macrophages and natural killer cells in the endometrial stroma, compared to those women with mild focal adenomyosis or no disease. These findings point to an immunological mechanism by which adenomyosis might interfere with successful embryo implantation. PMID- 22209315 TI - AL amyloidosis with temporal artery involvement simulates giant-cell arteritis. AB - Light-chain (AL) amyloidosis may present with features suggesting vasculitis, including giant-cell arteritis (GCA). We describe a case of an 80-year-old man, who initially presented with bilateral jaw claudication, bi-temporal headache and arthralgia, however a temporal-artery biopsy then revealed AL amyloidosis. A diagnosis of AL amyloidosis complicating multiple myelome simulates GCA and polymyalgia rheumatica was established. The patient was successfully treated with melphalan and dexamethasone: the free kappa light chains decreased, the patient's jaw claudication and headache disappeared. Then we discuss similarities between GCA and AL amyloidosis and potential confusion in diagnosis. We suggest that, in patients with clinical features of GCA without any temporal-artery typical findings, specimens are stained with Congo red, which then results in a different diagnosis and treatment. PMID- 22209316 TI - TNFalpha: activator or inhibitor of regulatory T cells? AB - TNFalpha is a cytokine that is central to the pathogenesis of several autoimmune diseases. More specifically, the deleterious effects of TNFalpha in rheumatoid arthritis (RA) are well established. The proinflammatory influence of TNFalpha in RA is related both to direct effects mediated by the induction of other proinflammatory cytokines, metalloproteinases, and free radicals; and to modulation of the regulatory T cells (Tregs). Furthermore, the TNFalpha antagonists used to treat RA can induce the emergence of a distinctive Treg subpopulation. Nevertheless, a recent body of data suggests that TNFalpha may also exert anti-inflammatory effects, which may be mediated in part via Tregs. TNFalpha binds to the TNF receptor 2 expressed preferentially at the Treg surface, thereby activating and promoting the development of Tregs. Data from patients with RA and more recent evidence obtained in the absence of disease are consistent with a paradoxical effect of TNFalpha on Tregs. TNFalpha may have different effects on naturally occurring Tregs and induced Tregs. PMID- 22209317 TI - CYP4F22 is highly expressed at the site and timing of onset of keratinization during skin development. PMID- 22209318 TI - Visualizing radiofrequency-skin interaction using multiphoton microscopy in vivo. AB - BACKGROUND: Redundant skin laxity is a major feature of aging. Recently, radiofrequency has been introduced for nonablative tissue tightening by volumetric heating of the deep dermis. Despite the wide range of application based on this therapy, the effect of this technique on tissue and the subsequent tissue remodeling have not been investigated in detail. OBJECTIVE: Our objective is to evaluate the potential of non-linear optics, including multiphoton autofluorescence and second harmonic generation (SHG) microscopy, as a non invasive imaging modality for the real-time study of radiofrequency-tissue interaction. METHODS: Electro-optical synergy device (ELOS) was used as the radiofrequency source in this study. The back skin of nude mouse was irradiated with radiofrequency at different passes. We evaluated the effect on skin immediately and 1 month after treatment with multiphoton microscopy. RESULTS: Corresponding histology was performed for comparison. We found that SHG is negatively correlated to radiofrequency passes, which means that collagen structural disruption happens immediately after thermal damage. After 1 month of collagen remodeling, SHG signals increased above baseline, indicating that collagen regeneration has occurred. Our findings may explain mechanism of nonablative skin tightening and were supported by histological examinations. CONCLUSIONS: Our work showed that monitoring the dermal heating status of RF and following up the detailed process of tissue reaction can be imaged and quantified with multiphoton microscopy non-invasively in vivo. PMID- 22209319 TI - [Vitamin D and autoimmunity. Second part: Clinical aspects]. AB - Vitamin D is often confined to its role in calcium homeostasis and bone metabolism. An exponential literature discusses its non-skeletal effects, especially its central role in the physiology of the immune system, where it acts at several levels to maintain self-tolerance. Here, the authors review the experimental, epidemiological and clinical studies, illustrating the potential role of vitamin D in the development and perpetuation of autoimmune diseases such as systemic lupus erythematosus, type 1 diabetes mellitus, multiple sclerosis, inflammatory bowel diseases or rheumatoid arthritis. PMID- 22209320 TI - Diagnosis of dissolved organic matter removal by GAC treatment in biologically treated papermill effluents using advanced organic characterisation techniques. AB - Granular activated carbon (GAC) exhaustion rates on pulp and paper effluent from South East Australia were found to be a factor of three higher (3.62cf. 1.47kgm( 3)) on Kraft mills compared to mills using Thermomechanical pulping supplemented by Recycled Fibre (TMP/RCF). Biological waste treatment at both mills resulted in a final effluent COD of 240mgL(-1). The dissolved organic carbon (DOC) was only 1.2 times higher in the Kraft effluent (70 vs. 58mgL(-1)), however, GAC treatment of Kraft and TMP/RCF effluent was largely different on the DOC persisted after biological treatment. The molecular mass (636 vs. 534gmol(-1)) and aromaticity (5.35 vs. 4.67Lmg(-1)m(-1)) of humic substances (HS) were slightly higher in the Kraft effluent. The HS aromaticity was decreased by a factor of 1.0Lmg(-1)m(-1) in both Kraft and TMP/RCF effluent. The molecular mass of the Kraft effluent increased by 50gmol(-1) while the molecular mass of the TMP/RCF effluent was essentially unchanged after GAC treatment; the DOC removal efficiency of the GAC on Kraft effluent was biased towards the low molecular weight humic compounds. The rapid adsorption of this fraction, coupled with the slightly higher aromaticity of the humic components resulted in early breakthrough on the Kraft effluent. Fluorescence excitation-emission matrix analysis of the each GAC treated effluent indicated that the refractory components were higher molecular weight humics on the Kraft effluent and protein-like compounds on the TMP/RCF effluent. Although the GAC exhaustion rates are too high for an effective DOC removal option for biologically treated pulp and paper mill effluents, the study indicates that advanced organic characterisation techniques can be used to diagnose GAC performance on complex effluents with comparable bulk DOC and COD loads. PMID- 22209321 TI - Adsorption equilibrium and kinetics for SO2, NO, CO2 on zeolites FAU and LTA. AB - In order to develop a single-step process for removing SO(2), NO, CO(2) in flue gas simultaneously by co-adsorption method. Pure component adsorption equilibrium and kinetics of SO(2), NO, and CO(2) on zeolite NaY, NaX, CaA were obtained respectively. Equilibrium data were analyzed by equilibrium model and Henry's law constant. The results suggest that Adsorption affinity follows the trend SO(2)>CO(2)>NO for the same adsorbent. Zeolite with stronger polar surface is a more promising adsorbent candidate. Kinetics behavior was investigated using the breakthrough curve method. The overall mass transfer coefficient and diffusivity factor were determined by a linear driving force model. The results are indicative of micropore diffusion controlling mechanism. NaY zeolite has the minimum resistance of mass transfer duo to the wide pore distribution and large pore amount. CaA zeolite exhibits the highest spatial hindered effect. Finally, co-adsorption effect of SO(2), NO, and CO(2) were investigated by multi components breakthrough method. SO(2) and NO may form new adsorbed species, however, CO(2) presents a fast breakthrough. Chemical adsorption causes SO(2) transforms to SO(4)(2-), however, element N and C are not detected in adsorbed zeolites. PMID- 22209322 TI - Effective removal of heavy metal ions Cd2+, Zn2+, Pb2+, Cu2+ from aqueous solution by polymer-modified magnetic nanoparticles. AB - We prepared novel Fe(3)O(4) magnetic nanoparticles (MNPs) modified with 3 aminopropyltriethoxysilane (APS) and copolymers of acrylic acid (AA) and crotonic acid (CA). The MNPs were characterized by transmission electron microscopy, X-ray diffraction, infra-red spectra and thermogravimetric analysis. We explored the ability of the MNPs for removing heavy metal ions (Cd(2+), Zn(2+), Pb(2+) and Cu(2+)) from aqueous solution. We investigated the adsorption capacity of Fe(3)O(4)@APS@AA-co-CA at different pH in solution and metal ion uptake capacity as a function of contact time and metal ion concentration. Moreover, adsorption isotherms, kinetics and thermodynamics were studied to understand the mechanism of the synthesized MNPs adsorbing metal ions. In addition, we evaluated the effect of background electrolytes on the adsorption. Furthermore, we explored desorption and reuse of MNPs. Fe(3)O(4)@APS@AA-co-CA MNPs are excellent for removal of heavy metal ions such as Cd(2+), Zn(2+), Pb(2+) and Cu(2+) from aqueous solution. Furthermore, the MNPs could efficiently remove the metal ions with high maximum adsorption capacity at pH 5.5 and could be used as a reusable adsorbent with convenient conditions. PMID- 22209323 TI - Effects of 2,4-dinitrotoluene exposure on enzyme activity, energy reserves and condition factors in common carp (Cyprinus carpio). AB - In this study relative condition factor (RCF) and hepatosomatic index (HSI) as well as the available energy reserves of common carp (Cyprinus carpio) by 2,4-DNT semi-static bioassay were determined and linked to effects of enzymes in liver tissues. Fish were exposed at sublethal concentrations of 2,4-DNT (0.13 MUg/L, 0.1, 0.5, 1.0mg/L) for 7 and 15 d. Based on the results, there was no significant change in all parameters measured in fish exposed to 2,4-DNT at environmental related concentration, but 2,4-DNT stress in fish exposed to higher concentrations reflected the significant changes of physiological and biochemical responses. 2,4-DNT stress resulted in EROD activity induction in the liver, and the levels of EROD activity ranged from 0.39- to 1.83-fold higher than control. For GK, Na(+)/K(+)-ATPase, and GST, these enzyme activity continued to decline after exposure to 0.1, 0.5 and 1.0mg/L 2,4-DNT, whereas the trend on GK and Na(+)/K(+)-ATPase was more obvious than GST. Through principal component analysis, effects by 2,4-DNT-stress in each test group were distinguished. Additionally, indications of a trade-off between metabolic cost of toxicant exposure and processes vital to the survival of the organism were seen at the enzyme activity level as well as on higher levels of biological organization. PMID- 22209324 TI - One-step preparation of CdS nanocrystals supported on thiolated silica-gel matrix and evaluation of photocatalytic performance. AB - Here we report the use of a thiol-functionalized silica-gel to prepare supported CdS nanocrystals by a facile one-step procedure. Upon changing the relative proportion of the matrix we obtained nanocrystals with different average sizes and size distributions, as evidenced by spectroscopic measurements as well as TEM images. Photoluminescence spectra also indicated that the main effect of the matrix is related to the size control since the spectral profiles were found to be strongly dependent on the excitation wavelength. The performance of the material in the photocatalytic degradation of two commercial dyes (methylene blue and rhodamine 6G) has been tested under sunlight radiation, showing promising results. Almost complete decolorization has been observed after 80 min of exposure, with no adsorption on the silica surface. PMID- 22209325 TI - The use of an agricultural waste material, Jujuba seeds for the removal of anionic dye (Congo red) from aqueous medium. AB - The feasibility of using Indian Jujuba Seeds (IJS) (Zizyphus maruritiana), abundantly available in and around the Nallamalla forest in Andhra Pradesh, for the anionic dye (Congo red, CR) adsorption from aqueous solution, has been investigated as low cost and eco-friendly adsorbent. Adsorption studies were conducted on a batch process, to study the effects of contact time, initial concentration of CR, pH and temperature. Maximum colour removal was observed at pH 2. The equilibrium data was analyzed by the Langmuir, the Freundlich and the General isotherms. The data fitted well with the Langmuir model, with a maximum adsorption capacity of 55.56 mg g(-1). The pseudo-second-order kinetics was the best for the adsorption of CR, by IJS (Z. maruritiana) with good correlation. Thermodynamic parameters, such as standard free energy change (DeltaG degrees ), standard enthalpy change (DeltaH degrees ) and standard entropy change (DeltaS degrees ), were analyzed. The results suggest that IJS (Z. maruritiana) is a potential low-cost adsorbent for the CR dye removal from synthetic dye wastewater. PMID- 22209326 TI - Microbial removal of NOX at high temperature by a novel aerobic strain Chelatococcus daeguensis TAD1 in a biotrickling filter. AB - The removal of NO(X) at high temperature by Chelatococcus daeguensis TAD1 in a biotrickling filter was studied. Media components of the recycling liquid were screened using Plackett-Burman design and then were optimized using response surface methodology, which enhanced the efficiency of nitrate removal by TAD1. The optimal medium was used to perform long-term experiments of NO(X) removal in a biotrickling filter under high concentrations of O(2) and NO in simulated flue gas. Results showed that the biotrickling filter was able to consistently remove 80.2-92.3% NO(X) when the inlet NO concentration was 600ppm under the conditions of oxygen concentration ranging between 2% and 20% and empty bed residence time (EBRT) being 112.5s. Analyses by polymerase chain reaction and denaturing gradient gel electrophoresis (PCR-DGGE) indicated that TAD1 was always predominant in the biofilm under a flue gas environment. Overall, the present study demonstrated that utilizing a biotrickling filter inoculated with the aerobic denitrifier TAD1 to remove NO(X) at high temperature was practically feasible. PMID- 22209327 TI - Neuroimaging of frontal-limbic dysfunction in schizophrenia and epilepsy-related psychosis: toward a convergent neurobiology. AB - Psychosis is a devastating, prevalent condition considered to involve dysfunction of frontal and medial temporal limbic brain regions as key nodes in distributed brain networks involved in emotional regulation. The psychoses of epilepsy represent an important, though understudied, model relevant to understanding the pathophysiology of psychosis in general. In this review, we (1) discuss the classification of epilepsy-related psychoses and relevant neuroimaging and other studies; (2) review structural and functional neuroimaging studies of schizophrenia focusing on evidence of frontal-limbic dysfunction; (3) report our laboratory's PET, fMRI, and electrophysiological findings; (4) describe a theoretical framework in which frontal hypoactivity and intermittent medial temporal hyperactivity play a critical role in the etiopathology of psychosis both associated and unassociated with epilepsy; and (5) suggest avenues for future research. PMID- 22209328 TI - DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. AB - Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression. PMID- 22209329 TI - Angiogenic sprouting requires the fine tuning of endothelial cell cohesion by the Raf-1/Rok-alpha complex. AB - Sprouting angiogenesis, crucial for the development of new blood vessels, is a prime example of collective migration in which endothelial cells migrate as a group joined via cadherin-containing adherens junctions (AJ). The actomyosin apparatus is connected to AJ and generates contractile forces, which, depending on their strength and duration, increase or decrease cell cohesion. Thus, appropriate spatiotemporal control of junctional myosin is critical, but the mechanisms underlying it are incompletely understood. We show that Raf-1 is an essential component of this regulatory network and that its ablation impairs endothelial cell cohesion, sprouting, and tumor-induced angiogenesis. Mechanistically, Raf-1 is recruited to VE-cadherin complexes by a mechanism involving the small G protein Rap1 and is required to bring the Rho effector Rok alpha to nascent AJs. This Raf-1-mediated fine tuning of Rok-alpha signaling allows the activation of junctional myosin and the timely maturation of AJ essential for maintaining cell cohesion during sprouting angiogenesis. PMID- 22209330 TI - A novel aptasensor based on silver nanoparticle enhanced fluorescence. AB - In the present study, we report a novel aptasensor based on silver nanoparticle enhanced fluorescence for the detection of adenosine. First, the distance dependence nature of silver nanoparticle enhanced fluorescence was investigated through fluorescent dyes modified oligonucleotides to control the spacing distance between dyes and AgNP. The results showed that the fluorescence intensity reached the maximum value with the spacing distance of dyes about 8 nm from AgNP surface. The fluorescence intensity decreases when the spacing distance is either above or below this value. Based on this result, a fluorescence switch is constructed. In the "OFF" state, without the target molecules, there is a greater spacing distance between the Cy3 dyes and the AgNP giving comparatively lower fluorescence intensity. While in the "ON" state, in the presence of target molecules, the fluorescence signals increased for the conformation structure change of the aptamer which shorten the spacing distance between the Cy3 dyes and the AgNP to 8 nm. Using adenosine as target, the aptasensor produced a linear range from 200 nM to 200 MUM with a correlation coefficient of 0.9949 and the detection limit was 48 nM estimated using 3sigma. The aptasensor was also found to be specific in targeting adenosine. The presented method shows a new strategy of combining aptamer recognition and silver nanoparticle for fluorescence signal enhancement and increasing sensitivity. PMID- 22209332 TI - Sequential bilateral cochlear implantation in children: parents' perspective and device use. AB - OBJECTIVE: The purpose of this study was (1) to measure parental expectations before surgery of a sequentially placed second cochlear implant and compare these results with parental observations postoperatively and (2) to measure device use of the second cochlear implant and compare to unilateral implant use. METHODS: Thirty prelingually deaf children with a unilateral cochlear implant (mean age at first implant 1.8 years) received a second implant at a mean age of 5.3 years. To measure parental expectations and observations, parents completed the Parents' Perspective before surgery of the second implant and after 12 and 24 months. The questionnaire included 1 additional question on sound localization. Device use of both the first and second implants was assessed retrospectively after 6, 12 and 24 months of implant use. Device use of the study group was also compared to a reference group of 30 unilateral implant users matched for age at second implantation. RESULTS: Parental expectations with regard to sound localization were significantly higher than the observed changes within the first year of bilateral implant use. The observed changes in communication, listening to speech without lipreading, and speech and language skills met or surpassed parental expectations. Irrespective of age at second implantation, the second implant was significantly less worn than the first implant. No significant difference was observed between the use of the second implant of the study group and device use of the reference group. Second implant use was significantly correlated with the difference in speech recognition between the 2 implants alone. CONCLUSIONS: Preoperative parental expectations were too high with regard to the observed localization skills within the first year of bilateral implant use. The study showed that several of these sequentially implanted children had more difficulties in wearing the second implant than in wearing the first implant during the rehabilitation period. The present results suggest that this is caused by the dominant first implant performance. Such data are of high importance in order to provide parents with realistic counseling on what they can expect from sequential bilateral cochlear implantation. PMID- 22209331 TI - Highly sensitive fluorescent detection of trypsin based on BSA-stabilized gold nanoclusters. AB - In this study, fluorescent metal nanoclusters are presented as novel probes for sensitive detection of protease for the first time. The sensing mechanism is based on trypsin digestion of the protein template of BSA-stabilized Au nanoclusters. The decrease in fluorescence intensity of BSA-Au nanoclusters caused by trypsin allows the sensitive detection of trypsin in the range of 0.01 100 MUg/mL. The detection limit for trypsin is 2 ng/mL (86 pM) at a signal-to noise ratio of 3. The present nanosensor for trypsin detection possesses red emission, excellent biocompatibility, high selectivity, and good stability. In addition, we demonstrated the application of the present approach in real urine samples, which suggested its potential for diagnostic purposes. PMID- 22209333 TI - Tracheal reconstruction by mesenchymal stem cells with small intestine submucosa in rabbits. AB - AIM: The increasing number of newborns requiring intubation and artificial ventilation in the sophisticated premature and intensive care units of recent years has been followed by a concomitant increase in the number of children who develop tracheal stenosis as a sequela of prolonged intubation, with a consequent increasing need for tracheal surgical repair. The aim of this study was to evaluate tracheal reconstruction by monolayered autologous mesenchymal stem cells (MSCs) with small intestine submucosa (SIS) in a rabbit model. METHODS: Twelve male rabbits were randomly divided into three groups: rabbits with tracheal defects without reconstruction (untreated group, n=4), rabbits with tracheal defects given porcine small intestine submucosa graft (SIS group, n=4), and rabbits with tracheal defects that underwent transplantation of monolayered mesenchymal stem cells on SIS (SIS+MSC group, n=4). Histological and endoscopic analyses were performed by hematoxylin-eosin staining (H&E), Prussian blue staining and endoscopy. RESULTS: Tracheal stenosis in the SIS+MSC group was minimal, compared to the untreated group and SIS group. Specimens obtained from the untreated and SIS groups showed severe infiltration of inflammatory cells and granulation tissue formation into the trachea. In the SIS+MSC group, however, minimal infiltration of the inflammatory cells and granulation tissue formation were observed. Twelve weeks following the operation, regeneration of pseudostratified columnar epithelium was confirmed by H&E staining with minimal inflammatory cell infiltration in the SIS+MSC group. Moreover, Prussian blue staining clearly demonstrated the presence of labeled MSCs in the regenerated tissue of SIS+MSC group. CONCLUSIONS: These results demonstrate that tracheal reconstruction by MSCs with SIS is effective in rabbits with tracheal defects with minimal mortality and morbidity, which appears to be a promising strategy in the treatment of tracheal defects. PMID- 22209334 TI - Evolution and diversity of dictyostelid social amoebae. AB - Dictyostelid social amoebae are a large and ancient group of soil microbes with an unusual multicellular stage in their life cycle. Taxonomically, they belong to the eukaryotic supergroup Amoebozoa, the sister group to Opisthokonta (animals + fungi). Roughly half of the ~150 known dictyostelid species were discovered during the last five years and probably many more remain to be found. The traditional classification system of Dictyostelia was completely overturned by cladistic analyses and molecular phylogenies of the past six years. As a result, it now appears that, instead of three major divisions there are eight, none of which correspond to traditional higher-level taxa. In addition to the widely studied Dictyostelium discoideum, there are now efforts to develop model organisms and complete genome sequences for each major group. Thus Dictyostelia is becoming an excellent model for both practical, medically related research and for studying basic principles in cell-cell communication and developmental evolution. In this review we summarize the latest information about their life cycle, taxonomy, evolutionary history, genome projects and practical importance. PMID- 22209335 TI - Ring chromosome 21 in the differential diagnosis of waddling gait. AB - Ring chromosome 21 syndrome is a rare clinical condition. Most of the patients have a recognizable phenotype and multisystem involvement is described. Structural neurologic anomalies have also been described, but waddling gait due to lower motor neuron involvement has not been previously reported in association with ring 21. PMID- 22209337 TI - Non-fatal cardiovascular disease, malignancies, and other co-morbidity in adult haemophilia patients. AB - INTRODUCTION: With increasing life expectancy, more haemophilia patients will be confronted with age-related problems. To ensure optimal care, it is important to know the occurrence of both fatal and non-fatal cardiovascular disease, malignancies and other types of co-morbidity in these patients. Our aim was to retrospectively assess the occurrence of co-morbidity and causes of death in a substantial birth-cohort of haemophilia patients. METHODS: Data on all types of co-morbidity were collected from medical records of 408 haemophilia patients (204 severe, 204 non-severe) born before 1971, and compared with the Dutch age-matched general male population. RESULTS: Ten patients had 11 myocardial infarctions, none of which were fatal. The cumulative incidence of non-fatal myocardial infarction was significantly lower in patients with severe haemophilia than in the general population (0.5% versus 4.8%), but was not decreased in patients with non-severe haemophilia (4.4%). Intracranial bleeding occurred significantly more often in haemophilia patients. The occurrence of non-virus related malignancies, and other non-virus related co-morbidities was similar in haemophilia patients and the general population. HIV infection was present in 12% of patients, and hepatitis C infection in 56%. Seventy-eight patients (19%) were deceased. Main causes of death were malignancies, AIDS, hepatitis C, and intracranial bleeding. CONCLUSIONS: Our results showed a decreased occurrence of myocardial infarction in patients with severe haemophilia, suggesting a protective effect of very low clotting factor levels on thrombotic cardiac events. No differences were found between haemophilia patients and the general population in the occurrence of any other type of non-virus related co-morbidity. PMID- 22209338 TI - Prognostic significance of adhesion molecules (sICAM-1, sVCAM-1) and VEGF in colorectal cancer patients. AB - INTRODUCTION: Adhesion molecules take part in the interaction between host cells and cancer cells. In the current study the relationship between the soluble adhesion molecules sICAM-1 and sVCAM-1 and proangiogenic factor VEGF in colorectal cancer progression were measured. MATERIALS AND METHODS: The study group consisted of 46 patients with colorectal carcinoma (classified due to TNM classification) and 40 controls. sICAM-1, sVCAM-1 and VEGF plasma concentration were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: All measured parameters levels were increased significantly in patients with colorectal cancer in comparison to controls (p<0.001). sICAM-1, sVCAM-1 and VEGF increased significantly due to colorectal cancer progression. There was a positive correlation between sICAM-1 and sVCAM-1 in all study groups. CONCLUSIONS: Our results demonstrated in CRC patients significantly increased levels of soluble adhesion molecules (VCAM-1 and sICAM-1) and angiogenic factor (VEGF) as compared to control group. The dynamics of these molecules showed the growing tendency along with tumor size and metastasis formation. PMID- 22209339 TI - ABCB1 C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients: a meta-analysis. AB - INTRODUCTION: The ABCB1 C3435T polymorphism limits oral bioavailability of clopidogrel and may influence prognosis of patients treated with clopidogrel. Several studies have examined the association between the C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients, but the results were inconsistent. To assess the role of the C3435T polymorphism in the impact on clinical outcomes, a meta-analysis was conducted. METHODS: 6 studies with 10,153 subjects were included in this meta-analysis. Fixed- or random-effects model was chosen according to heterogeneity. Publication bias was evaluated by fail-safe numbers. RESULTS: The association of the C3435T polymorphism with risk of overall recurrent ischemic events in clopidogrel treated patients was not statistically significant for all genetic models (OR=1.13, 95%CI: 0.78-1.64, P=0.51; OR=1.15, 95%CI: 0.99-1.33, P=0.07; OR=1.19, 95%CI: 0.81-1.76, P=0.37). Significant association was identified between the C3435T polymorphism and risk of short-term recurrent ischemic events (OR=1.55, 95% CI: 1.09-2.20, P=0.01; OR=1.41, 95% CI: 1.06-1.87, P=0.02; OR=1.77, 95% CI: 1.19-2.63, P=0.005). No statistically significant association between the C3435T polymorphism and stent thrombosis (OR=0.79, 95% CI: 0.47-1.32, P=0.37) or bleeding (OR=0.98, 95% CI: 0.79-1.21, P=0.82) was identified. The results may be affected by publication bias. CONCLUSIONS: This meta-analysis failed to show an association between the ABCB1 C3435T polymorphism and risk of overall recurrent ischemic events, stent thrombosis or bleeding in clopidogrel treated patients. However, the association between TT homozygotes of the C3435T polymorphism and risk of short-term recurrent ischemic events may exist, but needs more studies to confirm. PMID- 22209340 TI - Immunohistochemical expression profile of beta-catenin, E-cadherin, P-cadherin, laminin-5gamma2 chain, and SMAD4 in colorectal serrated adenocarcinoma. AB - The immunohistochemical expression of cell adhesion molecules in colorectal serrated adenocarcinoma is still unknown. The immunostaining patterns of beta catenin, E-cadherin, P-cadherin, laminin 5gamma2, and SMAD4 and their relationship to survival were studied in different tumor areas, namely, tumor center and invasive front, the latter comprising tumor bud and non-tumor bud clusters, as described in a previous study of 66 serrated adenocarcinomas and matched conventional carcinomas. Compared with conventional carcinomas, serrated adenocarcinomas showed significantly reduced nuclear beta-catenin, membranous E cadherin, and nuclear SMAD4 but an increased cytoplasmic expression of laminin 5gamma2 at the invasive front that was particularly pronounced in the tumor buds. E-cadherin loss at the invasive front was identified as an independent prognostic factor for a poorer outcome in serrated adenocarcinoma. Serrated adenocarcinoma shows a distinct immunohistochemical profile at the invasive front compared with conventional carcinoma, which may account for its less favorable outcome. The lower frequency of nuclear beta-catenin in SAC, especially in right-sided tumors, suggests that molecular mechanisms other than the canonical Wnt/beta-catenin pathway may have a role in tumor bud formation. PMID- 22209341 TI - Thyroid paraganglioma. Report of 3 cases and description of an immunohistochemical profile useful in the differential diagnosis with medullary thyroid carcinoma, based on complementary DNA array results. AB - Thyroid paraganglioma is a rare disorder that sometimes poses problems in differential diagnosis with medullary thyroid carcinoma. So far, differential diagnosis is solved with the help of some markers that are frequently expressed in medullary thyroid carcinoma (thyroid transcription factor 1, calcitonin, and carcinoembryonic antigen). However, some of these markers are not absolutely specific of medullary thyroid carcinoma and may be expressed in other tumors. Here we report 3 new cases of thyroid paraganglioma and describe our strategy to design a diagnostic immunohistochemical battery. First, we performed a comparative analysis of the expression profile of head and neck paragangliomas and medullary thyroid carcinoma, obtained after complementary DNA array analysis of 2 series of fresh-frozen samples of paragangliomas and medullary thyroid carcinoma, respectively. Seven biomarkers showing differential expression were selected (nicotinamide adenine dinucleotide dehydrogenase 1 alpha subcomplex, 4 like 2, NDUFA4L2; cytochrome c oxidase subunit IV isoform 2; vesicular monoamine transporter 2; calcitonin gene-related protein/calcitonin; carcinoembryonic antigen; and thyroid transcription factor 1) for immunohistochemical analysis. Two tissue microarrays were constructed from 2 different series of paraffin embedded samples of paragangliomas and medullary thyroid carcinoma. We provide a classifying rule for differential diagnosis that combines negativity or low staining for calcitonin gene-related protein (histologic score, <10) or calcitonin (histologic score, <50) together with positivity of any of NADH dehydrogenase 1 alpha subcomplex, 4-like 2; cytochrome c oxidase subunit IV isoform 2; or vesicular monoamine transporter 2 to predict paragangliomas, showing a prediction error of 0%. Finally, the immunohistochemical battery was checked in paraffin-embedded blocks from 4 examples of thyroid paraganglioma (1 previously reported case and 3 new cases), showing also a prediction error of 0%. Our results suggest that the comparative expression profile, obtained by complementary DNA arrays, seems to be a good tool to design immunohistochemical batteries used in differential diagnosis. PMID- 22209342 TI - "Intrafollicular neoplasia" of nodular lymphocyte predominant Hodgkin lymphoma: description of a hypothetic early step of the disease. AB - The 2008 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues has addressed the problem of intrafollicular neoplasia/"in situ" lesion for follicular lymphoma. The concept of intrafollicular neoplasia has also been proposed for other lymphomas in which the putative normal counterpart of the tumor cell is located in the germinal center or the mantle zone or the marginal zone of the follicle. However, unlike in situ follicular lymphoma, the precise histologic definition of this early lesion for other lymphomas is still lacking. When applied to nodular lymphocyte predominant Hodgkin lymphoma, another germinal center-derived lymphoma, "intrafollicular neoplasia" may be regarded as a neoplasia at an early stage of development, such as in situ follicular lymphoma. Interestingly, this early lesion can be observed in lymph nodes that otherwise show the most common nodular involvement by nodular lymphocyte predominant Hodgkin lymphoma. The recognition of intrafollicular neoplasia is based on the identification of typical, strongly stained BCL6+, lymphocyte predominant tumor cells located within altered follicles with a recognizable germinal center. Lymphocyte predominant tumor cells, surrounded by rosetting PD1+ T cells, reside in an environment reminiscent of a secondary follicle. Intrafollicular neoplasia in nodular lymphocyte predominant Hodgkin lymphoma is correctly identifiable based on immunohistochemical recognition of the CD23+ meshwork of follicular dendritic cells surrounded by an outer zone containing immunoglobulin D+ B cells. This immunoarchitectural pattern, highlighting the intrafollicular involvement by the neoplasia, is of great utility for diagnosis. An appropriate immunohistochemical characterization for diagnosis should include lymphocyte predominant (BCL6 and CD20) and microenvironmental (CD23, immunoglobulin D, and PD1) cell markers. PMID- 22209343 TI - On being a pathologist: a brief chronicle of an academic surgical pathologist. PMID- 22209344 TI - Loss of nuclear expression of Kruppel-like factor 4 is associated with poor prognosis in patients with oral cancer. AB - Kruppel-like factor 4 is not only involved in cell proliferation but also affects cell differentiation and extracellular matrix production via positive and negative regulation of the expression of a wide range of genes. To our knowledge, little information is available regarding the role of Kruppel-like factor 4 in oral squamous cell carcinoma. In this study, we investigated the associations between Kruppel-like factor 4 expression and clinical parameters of oral cancer using immunohistochemical assays in 215 surgical specimens. Compared with positive nuclear Kruppel-like factor 4 expression, we observed that negative nuclear Kruppel-like factor 4 expression was significantly associated with an advanced cancer stage (P = .046), a high tumor recurrence rate (P = .009), and a worse 3-year survival rate in patients with oral cancer (P = .046). Nuclear expression of Kruppel-like factor 4 was shown to have an inverse relationship with Ki67 expression (P = .046). Patients with negative nuclear expression of Kruppel-like factor 4 had significantly worse overall survival rates as defined by the log-rank test (P = .014). Patients with oral cancer with negative nuclear Kruppel-like factor 4 expression in tumor cells had poor prognoses and a 2.5-fold higher death risk. Compared with disease stage (P = .025), negative nuclear Kruppel-like factor 4 expression (P = .006) was an independent prognostic factor. Our results revealed that the loss of nuclear expression of Kruppel-like factor 4 is significantly associated with aggressive clinical manifestations and might be an adverse survival factor. PMID- 22209346 TI - Gastroparesis and Parkinson's disease: a systematic review. AB - Some of the gastrointestinal (GI) symptoms commonly experienced by patients with Parkinson's disease (PD) have been attributed to gastroparesis; however, the precise prevalence and relevance of gastric emptying delay in PD is unclear. The definition of gastroparesis varies; currently the most widely accepted definition (from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium) is the presence of appropriate symptoms (including nausea, retching, vomiting, stomach fullness, and inability to finish a meal) for >= 12 weeks, together with delayed gastric emptying on scintigraphy and the absence of any obstructive lesions on upper GI endoscopy. In PD patients, gastroparesis has the potential to affect nutrition and quality of life, as well as the absorption of PD medications, including L-dopa. This reduced absorption of L-dopa has implications for the control of the PD motor symptoms for which it is administered. We performed a systematic review of the literature on gastroparesis in PD with the aim of developing an evidence-based approach to its management. Based on this review, we conclude that while gastric emptying has been reported to be frequently delayed in PD, the existing data do not permit definitive conclusions concerning its true prevalence, relationship to the underlying disease process, relevance to PD management, or the optimal therapy of related GI symptoms. Further study of these important issues is, therefore, required. PMID- 22209345 TI - Estradiol directly attenuates sodium currents and depolarizing afterpotentials in isolated gonadotropin-releasing hormone neurons. AB - The gonadotropin-releasing hormone (GnRH) neuron is the pivotal control center in a tightly regulated reproductive axis. The release of GnRH controls estradiol production by the ovary, and estradiol acts at the hypothalamus to regulate GnRH release. However, the mechanisms of estradiol feedback are just beginning to be understood. We have previously shown that estradiol administered to the female mouse modulates sodium currents in fluorescently-labeled GnRH neurons. In the current studies, estradiol (1 nM) was applied directly, for 16-24h, to hypothalamic cultures from young or aged female ovariectomized mice. The direct application of estradiol modulated a tetrodotoxin-sensitive sodium current in isolated GnRH neurons from both young and aged animals. Estradiol, and the specific estrogen receptor-beta agonist DPN, decreased current amplitude measured in the morning (AM), but had no effect on afternoon currents. These compounds also decreased the rise and decay slope of the current response, increased the width of the current, and increased action potential width in AM recordings. In addition, estradiol decreased the amplitude of the depolarizing afterpotential (DAP); this effect was not time-of-day dependent. The ER-beta agonist DPN did not mimic the effect of estradiol on DAPs, and the modulation of DAPs by estradiol was no longer present in cells from postreproductive animals. These results indicate that estradiol can affect the physiology of GnRH neurons via multiple pathways that are differentially regulated during the transition to reproductive senescence, suggesting that estradiol regulation of GnRH neuronal output is modulated during the aging process. PMID- 22209347 TI - Amine-functionalised SBA-15 of tailored pore size for heavy metal adsorption. AB - This study examines the synthesis of SBA-15 with tailored pore sizes through controlled thermal treatment for the adsorption of Pb and Cd ions. The aim is to produce a material that can adsorb heavy metals at both high and low concentrations. The materials were characterised by means of N(2) physisorption, powder X-ray diffraction (PXRD), diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), microanalysis and transmission electron microscopy (TEM). The surface areas ranged from 410 to 871 m(2)g(-1), and pore diameter was increased from 5.9 to 10.8 nm. This method allows for maximum adsorption of metal ions at very low concentrations. Metal ion adsorption was determined using an Atomic Absorption Spectrophotometer. The effects of pH were found to play a major role in the precipitation and, therefore, adsorption of metal ions. This method proved to be efficient at adsorbing large quantities of both metals (39 and 41 mg g(-1) for Pb and Cd, respectively). PMID- 22209348 TI - Prediction of normal tissue toxicity as part of the individualized treatment with radiotherapy in oncology patients. AB - Normal tissue toxicity caused by radiotherapy conditions the success of the treatment and the quality of life of patients. Radiotherapy is combined with surgery in both the preoperative or postoperative setting for the treatment of most localized solid tumour types. Furthermore, radical radiotherapy is an alternative to surgery in several tumour locations. The possibility of predicting such radiation-induced toxicity would make possible a better treatment schedule for the individual patient. Radiation-induced toxicity is, at least in part, genetically determined. From decades, several predictive tests have been proposed to know the individual sensitivity of patients to the radiotherapy schedules. Among them, initial DNA damage, radiation-induced apoptosis, gene expression profiles, and gene polymorphisms have been proposed. We report here an overview of the main studies regarding to this field. Radiation-induced apoptosis in peripheral blood lymphocytes seem to be the most promising assay tested in prospective clinical trials, although they have to be validated in large clinical studies. Other promising assays, as those related with single nucleotide polymorphisms, need to be validated as well. PMID- 22209349 TI - A review of smoking cessation interventions for smokers aged 50 and older. AB - OBJECTIVES: Cigarette smoking poses substantial health risks at any age, but is particularly dangerous for older smokers, who are already at heightened risk for various health conditions. Studies suggest that older smokers are motivated to quit and succeed, but few of these have been randomized controlled trials. There is a need to systematically evaluate the research on effective interventions in older smokers. METHODS: We followed PRISMA guidelines in the development of this systematic review, which included randomized controlled trials of cessation interventions with smokers aged 50 or older. RESULTS: We found 740 unique titles matching specified search criteria; 13 met final eligibility criteria. Nearly all the cessation treatments combined counseling with other strategies. Eight studies provided smoking cessation medications. None of the studies used newer forms of technology such as web- or text-based interventions. Nine of the 13 studies reported a significant intervention effect at one or more time points, with three studies reporting sustained treatment effects at 12 mos or longer. In general, more intensive interventions and those with combined approaches including medications and follow-up counseling achieved the best outcomes. CONCLUSION: The quit rates from these studies and the relative effectiveness of different intervention approaches are consistent with the general smoking cessation literature. However, in most studies, treatment effects were of short duration, and absolute quit rates were low, leaving the vast majority of older smokers at high risk for smoking-related health conditions. This systematic review suggests a need for additional research to design and test future interventions specifically tailored for older smokers. PMID- 22209350 TI - Genetics and epigenetics of osteoarthritis. AB - Osteoarthritis (OA) is a common age-related disease that affects the tissues of the synovial joint, leading to loss of function and pain. It impacts on both patient morbidity and mortality. It is a complex, polygenic disease that lacks any large-effect susceptibility loci. Instead, OA susceptibility alleles individually contribute only modestly to the overall disease risk, making their identification challenging. Despite this, breakthroughs have occurred with compelling associations so far reported to polymorphisms within the genes GDF5 and MCF2L and to the genomic region 7q22. The latter two have emerged from genome wide association scans, which are likely to yield more hits in the near future. As for many complex diseases, it is now apparent that epigenetic effects are also important mediators of disease biology, with DNA methylation, histone modifications and non-coding RNAs all having a role. At present, much of the epigenetic focus has been on cartilage, the tissue at the center of the OA disease process. If we are to get close to a qualitative and quantitative understanding of the impact of epigenetics on OA, then in future the other tissues of the joint will also need to be investigated. One of the more exciting insights to have emerged recently is the fact that epigenetic effects can impact on OA genetic effects and this may be a particularly fruitful avenue for integrating both as we move toward a clearer understanding of the pathophysiology of this intriguing disease. PMID- 22209351 TI - News about Black cohosh. PMID- 22209352 TI - Classification criteria for Sjogren's syndrome: a critical review. AB - Over the years, several different criteria sets have been proposed for the classification of Sjogren's syndrome (SS), but none of them has been widely adopted by the scientific community until the publication of the 1993 Preliminary European Classification criteria. These Classification criteria have been largely employed both in clinical practice and in observational and interventional studies for many years. In 2002 the Preliminary European Criteria were re examined by a joint American and European Committee. The result of this revision were the American and European Consensus Group classification criteria (AECG criteria) which introduced more clearly defined rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria. These AECG-criteria set is now considered to be valid to ensure a specific diagnosis of SS by the vast majority of the expert in the field. To date, the AECG-criteria have been cited more than 1.304 in literature and have been used to estimate the point prevalence of the disease in several studies conducted in Greece, UK, Turkey and Norway. However, when employed in epidemiologic studies or in daily practice, the AECG-criteria have demonstrated a higher specificity (75%), but a lesser sensitivity (65.7%) in comparison to the previous Preliminary European criteria, indicating an average prevalence of pSS at ~ 0.2% in the adult population, which is far lower than previously reported. In this paper we will critically analyse the "pro and cons" of the current AECG-criteria and of the potential usefulness of some potential revisions. PMID- 22209353 TI - A novel method of measuring cardiac preservation injury demonstrates University of Wisconsin solution is associated with less ischemic necrosis than Celsior in early cardiac allograft biopsy specimens. AB - BACKGROUND: No consensus exists on the optimal heart preservative solution (HPS) for cardiac allograft preservation. The significance of varying degrees of acute ischemic necrosis (AIN) in early transplant biopsy specimens is unknown. We investigated the effects of HPS on early cardiac histopathology by developing a novel grading system of AIN. METHODS: A retrospective review of our institutional database of orthotopic heart transplants (OHT) identified hearts preserved with University of Wisconsin (UW) or Celsior solutions. AIN severity was graded on early post-transplant biopsy specimens. Primary stratification was by HPS. Multivariable models examined mortality, AIN grade, primary graft dysfunction (PGD), and right heart failure (RHF). RESULTS: From 1996 to 2010, 42 of 174 adult OHTs were preserved with UW and 132 with Celsior, from which 431 biopsy specimens were reviewed. UW and Celsior had similar 30-day (p = 0.79) and 1-year mortality (p = 0.92). Celsior was associated with significantly more AIN on the first (p = 0.02) and second (p = 0.04) specimens and persisted on multivariable analysis for the first (odds ratio, 2.93; 95% confidence interval, 1.26-6.83; p = 0.01) and second biopsy specimen (2.08; 0.99-4.34; p = 0.05). When stratified by AIN score, 30-day and 1-year mortality were similar (p > 0.05). Adjusted analysis showed increasing AIN score on the first biopsy was strongly associated with an increased incidence of PGD (1.59; 1.02-2.47; p = 0.04) and RHF (2.45; 1.14-5.27; p = 0.02). CONCLUSIONS: Our grading system provides a simple, reproducible method for determining AIN. UW is associated with less AIN than Celsior solution. Early biopsy ischemia is associated with PGD and RHF. AIN may have prognostic significance and its routine evaluation should be considered. PMID- 22209354 TI - Endomyocardial biopsy and selective coronary angiography are low-risk procedures in pediatric heart transplant recipients: results of a multicenter experience. AB - BACKGROUND: No prior reports documenting the safety and diagnostic yield of cardiac catheterization and endomyocardial biopsy (EMB) in heart transplant recipients include multicenter data. METHODS: Data on the safety and diagnostic yield of EMB procedures performed in heart transplant recipients were recorded in the Congenital Cardiac Catheterization Outcomes Project database at 8 pediatric centers during a 3-year period. Adverse events (AEs) were classified according to a 5-level severity scale. Generalized estimating equation models identified risk factors for high-severity AEs (HSAEs; Levels 3-5) and non-diagnostic biopsy samples. RESULTS: A total of 2,665 EMB cases were performed in 744 pediatric heart transplant recipients (median age, 12 years [interquartile range, 4.8, 16.7]; 54% male). AEs occurred in 88 cases (3.3%), of which 28 (1.1%) were HSAEs. AEs attributable to EMB included tricuspid valve injury, transient complete heart block, and right bundle branch block. Amongst 822 cases involving coronary angiography, 10 (1.2%) resulted in a coronary-related AE. There were no myocardial perforations or deaths. Multivariable risk factors for HSAEs included fewer prior catheterizations (p = 0.006) and longer case length (p < 0.001). EMB yielded sufficient tissue for diagnosis in 99% of cases. Longer time since heart transplant was the most significant predictor of a non-diagnostic biopsy sample (p < 0.001). CONCLUSIONS: In the current era, cardiac catheterizations involving EMB can be performed in pediatric heart transplant recipients with a low AE rate and high diagnostic yield. Risk of HSAEs is increased in early post-transplant biopsies and with longer case length. Longer time since heart transplant is associated with non-diagnostic EMB samples. PMID- 22209355 TI - Simultaneous enantioselective determination of triazole fungicides in soil and water by chiral liquid chromatography/tandem mass spectrometry. AB - The manuscript concerns the development and validation of a novel and sensitive multi-residue method for simultaneous enantiomeric analysis of 8 triazole fungicides (tetraconazole, fenbuconazole, epoxiconazole, diniconazole, hexaconazole, triadimefon, paclobutrazol, and myclobutanil) in soil and water using chiral liquid chromatography coupled with tandem mass spectrometry. The separation and determination were performed using reversed-phase chromatography on a cellulose chiral stationary phase, a Chiralcel OD-RH (150 mm * 4.6 mm) column, under isocratic conditions using a mixture of ACN-2 mM ammonium acetate in water (55/45, v/v) as the mobile phase at 0.45 mL/min flow rate. The effects of three cellulose-based columns and three amylose-based columns on the separation were also investigated. The QuEChERS (acronym for quick, easy, cheap, effective, rugged and safe) method and solid-phase extraction (SPE) were used for the extraction and clean-up of the soil and water samples, respectively. Parameters including the matrix effect, linearity, precision, accuracy and stability were undertaken. Under optimal conditions, the mean recoveries for all sixteen enantiomers from the soil samples were 76.4-108.1% with 2.6-12.0% intra day relative standard deviations (RSD) and 4.2-14.1% inter-day RSD at 5, 25 and 50 MUg/kg levels; the mean enantiomer recoveries from the water samples were 81.2 106.5% with 2.1-11.5% intra-day RSD and 3.4-13.6% inter-day RSD at 0.25, 0.5 and 2.5 MUg/L levels. Coefficients of determination R2 >= 0.9989 were achieved for all studied analytes in the soil and water matrix calibration curves within the range of 1.0-125 MUg/L. The limits of detection (LOD) (S/N=3) for all enantiomers in the soil and water were less than 1.0 MUg/kg or MUg/L, whereas the limit of quantification (LOQ) (S/N=10) did not exceed 3.0 MUg/kg or MUg/L. The results of the method validation confirm that this proposed method is convenient and reliable for the enantioselective determination of the enantiomers of triazole fungicides in soil and water. PMID- 22209356 TI - Determination of methanol in pulp washing filtrates by desiccated full evaporation headspace gas chromatography. AB - This paper reports on a desiccated full evaporation headspace gas chromatographic (FE HS-GC) technique for determination of the methanol content in dilute mill effluents. Anhydrous K(2)CO(3) was selected as the preferred salt for eliminating the water in the sample in the headspace sample vial. The results showed that the addition of 12 g K(2)CO(3) made it possible to introduce a larger sample size (up to 1 mL) into the FE HS-GC measurement, thereby increasing the sensitivity of the technique. At the given equilibration temperature (105 degrees C), a near complete mass transfer of methanol from the liquid phase to vapor phase (headspace) was achieved within 10 min. Replicate samples showed that the relative standard deviation of the method was less than 1.5%. Further, the limit of quantification (LOQ) was 0.12 MUg and the recovery ranged from 95 to 104%. The present method greatly improves the methanol detection sensitivity in the FE HS GC method and has the added advantage of being simple, rapid and accurate. PMID- 22209357 TI - Stationary phases for packed-column supercritical fluid chromatography. AB - The properties of silica-based, chemically bonded, packed column stationary phases used in supercritical fluid chromatography are described with a focus on column design and retention mechanisms. Supercritical fluid chromatography has benefited substantially from innovations in column design for liquid chromatography even if the separation conditions employed are generally quite different. The mobile phase composition and column operating conditions play an interactive role in modifying selectivity in supercritical fluid chromatography by altering analyte solubility in the mobile phase and through selective solvation of the stationary phase resulting in a wider range and intensity of intermolecular interactions with the analyte. The solvation parameter model is used to identify the main parameters that affect retention in supercritical fluid chromatography using carbon dioxide-methanol as a mobile phase and as a basis for column characterization to facilitate the identification of stationary phases with different separation characteristics for method development. As a caution it is pointed out that these column characterization methods are possibly a product of both the stationary phase chemistry and the column operating conditions and are suitable for use only when columns of similar design and with similar operating conditions are used. PMID- 22209358 TI - Critical evaluation of fiber coatings for organotin determination by using solid phase microextraction in headspace mode. AB - In the present work three different SPME fibers have been investigated for simultaneous determination of methyl-, butyl- and phenyltins by using gas chromatography-pulsed flame photometer detection (GC-PFPD). The optimal experimental conditions for each fiber were determined and the respective figures of merit were evaluated. All fiber evaluated presented similar limit of detection (sub ng L-1) and requires two internal standards to reach an acceptable repeatability. However, the CAR-PDMS fiber offers the best compromise between selectivity and sensibility for determination of organotins selected. The developed method was validated for analysis of certified reference material and spiked samples, obtaining satisfactory results. Finally, some contaminated samples were analyzed demonstrating the applicability of developed method for determination of organotin compounds in the environment and for monitoring their biochemical cycle. PMID- 22209359 TI - Physiological and affective reactivity to a 35% CO2 inhalation challenge in individuals differing in the 5-HTTLPR genotype and trait neuroticism. AB - The inhalation of 35% carbon dioxide (CO2) results in an acute stress response in healthy individuals and may accordingly provide a good paradigm to examine potential vulnerability factors for stress reactivity and stress-related psychopathology. It has been proposed that CO2 reactivity is moderated by genetic (5-HTTLPR) and personality (neuroticism) factors, yet no experimental study has investigated their effects on CO2 reactivity simultaneously. The current study examined the singular and interactive effects of the 5-HTTLPR genotype and neuroticism in predicting the affective and physiological response to a 35% CO2 challenge in a healthy sample of male and female students. From a large group of 771 students, 48 carriers of the low/low expressing allele (S/S, S/Lg, Lg/Lg) and 48 carriers of the high/high expressing allele (La/La) with the lowest and the highest neuroticism scores (77 females, 19 males; mean age +/- SD: 20.6 +/- 2 years) were selected and underwent a 35% CO2 inhalation. Visual analogue scales for anxiety and discomfort and the Panic Symptom List were used to assess affective symptomatology, while salivary samples and heart rate were assessed to establish the physiological response. A typical pattern of responses to CO2 was observed, characterised by increases in anxiogenic symptoms and physical panic symptomatology and a reduction in heart rate; however, no effect on salivary cortisol concentration was observed. Additionally, the CO2 reactivity did not differ between groups divided by the 5-HTTLPR genotype or neuroticism. Findings of the current study do not support a role for singular or interactive effects of the 5-HTTLPR genotype and trait neuroticism on affective and physiological reactivity to a 35% CO2 inhalation procedure. PMID- 22209360 TI - Mapping serotonergic dysfunction in MDMA (ecstasy) users using pharmacological MRI. AB - 3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is a popular recreational drug that has been shown to induce loss of brain serotonin (5-HT) neurons. The purpose of this study was to determine the usefulness of pharmacological magnetic resonance imaging (phMRI) in assessing 5-HT dysfunction by examining the hemodynamic response evoked by infusion with the selective 5-HT reuptake inhibitor citalopram. We studied the effects of MDMA on brain hemodynamics using arterial spin labeling (ASL) based phMRI following a citalopram challenge (7.5mg/kg, i.v.), combined with [123I]beta-CIT SPECT imaging in ten male MDMA users and seven healthy non-users. Single photon emission computed tomography (SPECT) imaging was used to assess the availability of 5-HT transporters (SERT). Imaging results were compared with the results of behavioral measures and mood changes following drug administration, in both groups (using the Beck Depression Inventory, Barratt Impulsiveness Scale and a visual analog scale). Reductions in SERT binding were observed in the occipital cortex of MDMA users. In line with this, citalopram induced decreases in cerebral blood flow (CBF) in the occipital cortex of MDMA users. ASL based phMRI also detected a CBF decrease in the thalamus of MDMA users. In concordance with imaging findings, behavioral measures differed significantly between MDMA users and controls. MDMA users had higher impulsivity scores and felt more uncomfortable after citalopram infusion, compared with control subjects. Our findings indicate that phMRI is very well suited for in-vivo assessment of 5-HT dysfunction. PMID- 22209361 TI - A randomised, double-blind, placebo controlled, duloxetine-referenced, fixed-dose study of three dosages of Lu AA21004 in acute treatment of major depressive disorder (MDD). AB - The efficacy, safety, and tolerability of Lu AA21004 versus placebo, using duloxetine as active reference, in patients with DSM-IV-TR diagnosed major depressive disorder (MDD) were evaluated in this 8-week, multi-site study. Patients (n=766) had a baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score >=26 and were randomly assigned (1:1:1:1:1) to 2.5, 5 or 10 mg Lu AA21004, placebo, or 60 mg duloxetine. The 5mg and 10mg doses of Lu AA21004 were tested separately versus placebo at p<=0.025 in a pre-specified order. In the pre defined primary efficacy analysis [mean change from baseline in MADRS total score at Week 8, full analysis set, ANCOVA, last observation carried forward (LOCF)], the differences to placebo (n=145) of -1.7 (Lu AA21004 5 mg, n=155) and -1.5 points (Lu AA21004 10 mg, n=151) were not statistically significant; nor were those for Lu AA21004 2.5 mg (-1.4 points, n=155) or duloxetine (-2.0 points, n=149). Using mixed model, repeated measures (MMRM) analyses of the primary endpoint and most secondary endpoints were supportive of likely efficacy for Lu AA21004 5 mg and 10 mg and duloxetine. Treatment-emergent adverse events led to the withdrawal of 72 patients: 8% (placebo), 12% (duloxetine), and 6%, 11% and 9% in the Lu AA21004 groups (2.5 mg, 5 mg and 10 mg, respectively). The most common adverse events were nausea, headache, dizziness, and dry mouth. No clinically relevant changes were seen in vital signs, weight, ECG, or laboratory results. In summary, none of the active treatment groups, including duloxetine, separated from placebo in the primary analysis in this 'failed' study. Findings on secondary outcome measures, using MMRM instead of LOCF, were supportive of likely efficacy for Lu AA21004 5mg and 10mg and duloxetine. Lu AA21004 (2.5, 5 and 10 mg) was well tolerated. PMID- 22209362 TI - Predictors of medium and long-term outcome following capsulotomy for obsessive compulsive disorder: one site may not fit all. AB - Patients with treatment-refractory obsessive-compulsive disorder (OCD) are sometimes considered for surgical interventions. The identification of reliable predictors of outcome following such interventions would be of great clinical importance, as it would lead to stricter selection of suitable patients, thus avoiding unnecessary surgery and improving the overall response rate. We analyzed data from 24 severe treatment-resistant patients who underwent capsulotomy for OCD and were carefully followed-up one year after the surgery and at long term (mean 10.8 years after surgery). The Yale-Brown Obsessive Compulsive Scale Symptom Checklist was administered to assess the lifetime presence of the most common symptom types. We applied an algorithm to calculate the patients' scores on 4 well-established symptom dimensions: Contamination/cleaning, forbidden thoughts, symmetry/order and hoarding. Multiple regression models were employed to examine whether scores on certain symptom dimensions were predictive of long term outcome. The presence and number of lifetime symptoms in the symmetry/order domain were associated with greater severity of OCD, depression and anxiety, as well as greater impairment in various functional domains like work, social and family life at both one-year and long-term follow-ups. These results remained consistently significant after controlling for preoperative psychopathology, scores on other OCD symptom dimensions, sex, age, age of onset, duration of follow-up, type of surgical procedure, number of operations and lesion volume. The results could have implications for existing ablative and deep brain stimulation protocols and challenge our current conceptualization of OCD as a unitary diagnostic entity with a single neurobiological substrate. PMID- 22209363 TI - Acutely applied MDMA enhances long-term potentiation in rat hippocampus involving D1/D5 and 5-HT2 receptors through a polysynaptic mechanism. AB - 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a drug of abuse that induces learning and memory deficit. However, there are no experimental data that correlate the behavioral evidence with models of synaptic plasticity such as long term potentiation (LTP) or long-term depression (LTD). Using field potential recordings in rat hippocampal slices of young rats, we found that acute application of MDMA enhances LTP in CA3-CA1 synapses without affecting LTD. Using specific antagonists and paired-pulse facilitation protocols we observed that the MDMA-dependent increase of LTP involves presynaptic 5-HT2 serotonin receptors and postsynaptic D1/D5 dopamine receptors. In addition, the inhibition of PKA suppresses the MDMA-dependent increase in LTP, suggesting that dopamine receptor agonism activates cAMP-dependent intracellular pathways. We propose that MDMA exerts its LTP-altering effect involving a polysynaptic interaction between serotonergic and dopaminergic systems in hippocampal synapses. Our results are compatible with the view that the alterations in hippocampal LTP could be responsible for MDMA-dependent cognitive deficits observed in humans and animals. PMID- 22209364 TI - The melanin-concentrating hormone (MCH) system in an animal model of depression like behavior. AB - Selective breeding for divergence in locomotion in a novel environment (bHR, bred High-Responder; bLR, bred Low-Responder) correlates with stress-reactivity, spontaneous anxiety-like behaviors and predicts vulnerability in a rodent model of depression. Identifying genetic factors that may account for such vulnerability are key determinants not only for the illness outcome but also for the development of better-tailored treatment options. Melanin-concentrating hormone (MCH) is a neuropeptide that exhibits some of the hallmarks of a regulator of affective states. The aim of this study was to ascertain the role of the MCH system in depression-like behaviors in bHR vs. bLR rats. bLR rats showed a 44% increase in hypothalamic pMCH mRNA and a 14% decrease in hippocampal CA1 MCH1R mRNA when compared to bHR rats. Interestingly, the amount of time that rats spent immobile in the FST (depressive-like behavior) correlated positively with the amount of hypothalamic pMCH mRNA and negatively with that of hippocampal CA1 MCH1R. The results indicate that the bLR-bHR is a useful rat model to investigate individual basal genetic differences that participate in the monitoring of emotional responsiveness (i.e., depression- and anxiety-like behaviors). They also point to the MCH system (i.e., chronically higher pMCH expression and consequently receptor down-regulation) as a candidate biomarker for the severity of depressive-like behavior. The data indicate that MCH1R participates in the modulation of depression-like behavior through a process that involves the CA1 region of the hippocampus, supporting the possible use of MCH1R antagonists in the treatment of depression. PMID- 22209365 TI - The acute effects of d-amphetamine and d-methamphetamine on ERP components in humans. AB - While a number of behavioural studies have been conducted to investigate the acute effects of amphetamines on tasks of attention and information processing, there is currently a scarcity of research concerning their electrophysiological effects in healthy adults. It is also unclear as to whether amphetamines exert effects on stimulus evaluation or response selection. In two studies, independent groups of twenty healthy illicit stimulant users aged between 21 and 32 years were administered 0.42 mg/kg d-amphetamine versus placebo, and 0.42 mg/kg d methamphetamine versus placebo respectively, and completed an auditory oddball task on two separate testing days. A 62-channel EEG was recorded during the completion of the task, and the effects of amphetamines on N200 and P300 ERP components were analysed. d-amphetamine significantly decreased reaction time, improved accuracy, and reduced the latency of the P300 component relative to placebo, while having no effect on the N200 component. d-methamphetamine had no effect on reaction time, accuracy or the P300 component, but reduced the amplitude of the N200 component, relative to placebo. It was concluded that there is tentative support to suggest that d-amphetamine at a dose of 0.42 mg/kg may enhance speed of information processing while d-methamphetamine at a dose of 0.42 mg/kg may reflect changes to stimulus evaluation. PMID- 22209366 TI - Quantifying turbulent wall shear stress in a subject specific human aorta using large eddy simulation. AB - In this study, large-eddy simulation (LES) is employed to calculate the disturbed flow field and the wall shear stress (WSS) in a subject specific human aorta. Velocity and geometry measurements using magnetic resonance imaging (MRI) are taken as input to the model to provide accurate boundary conditions and to assure the physiological relevance. In total, 50 consecutive cardiac cycles were simulated from which a phase average was computed to get a statistically reliable result. A decomposition similar to Reynolds decomposition is introduced, where the WSS signal is divided into a pulsating part (due to the mass flow rate) and a fluctuating part (originating from the disturbed flow). Oscillatory shear index (OSI) is plotted against time-averaged WSS in a novel way, and locations on the aortic wall where elevated values existed could easily be found. In general, high and oscillating WSS values were found in the vicinity of the branches in the aortic arch, while low and oscillating WSS were present in the inner curvature of the descending aorta. The decomposition of WSS into a pulsating and a fluctuating part increases the understanding of how WSS affects the aortic wall, which enables both qualitative and quantitative comparisons. PMID- 22209367 TI - Monoclonal antibodies recognizing mucus immunoglobulin and surface immunoglobulin positive cells of flounder (Paralichthys olivaceus). AB - Mucus immunoglobulin (Ig) of flounder (Paralichthys olivaceus) was purified by the combination of salting-out, Sephacryl S-300 gel filtration chromatography and DEAE Sepharose chromatography. According to the SDS-PAGE and native-PAGE, the purified mucus Ig showed apparent molecular weights of 72 kDa (heavy chain) and 26 kDa (light chain), and a total molecular weight of 798 kDa, which indicated mucus IgM was in tetrameric form. Purified mucus Ig was used to immunize the Balb/C mice, nineteen hybridomas secreting monoclonal antibodies (mAbs) against flounder mucus Ig were obtained by indirect enzyme-linked immunosorbent assay, and three of them designated as 1A-M2, 1C-M10 and 3F-M9 were cloned by limiting dilution. In Western blotting, the three mAbs specifically reacted to the heavy (H) chain of mucus Ig, but not reacted with serum Ig of flounder, whereas mAb 2D8 against serum Ig previously produced could react with the H chain of both mucus and serum Ig, indicating the composition of the mucus and serum Ig H chains was different. Meanwhile, surface Ig positive (sIg+) lymphocytes in the peripheral blood, spleen, skin and gills of healthy flounder, were analyzed by flow cytometry using mAb 1A-M2 and mAb 2D8, and the results revealed that both mAbs were reactive with the sIg+ lymphocytes. The positive reactivity rates for mAb 1A M2 were 38.64% in the peripheral blood, 23.6% in the spleen, 16.56% in the skin and 6.26% in the gills, while the positive reactivity rates for mAb 2D8 were 48.89%, 33.7%, 15% and 6.02%, respectively, suggesting mucus Ig was similar, but not identical, to serum Ig. These results generated important mucosal immunological information and gave a valuable insight into understanding the mucosal immunity in flounder. PMID- 22209368 TI - Experimental degradation of polymer shopping bags (standard and degradable plastic, and biodegradable) in the gastrointestinal fluids of sea turtles. AB - The persistence of marine debris such as discarded polymer bags has become globally an increasing hazard to marine life. To date, over 177 marine species have been recorded to ingest man-made polymers that cause life-threatening complications such as gut impaction and perforation. This study set out to test the decay characteristics of three common types of shopping bag polymers in sea turtle gastrointestinal fluids (GIF): standard and degradable plastic, and biodegradable. Fluids were obtained from the stomachs, small intestines and large intestines of a freshly dead Green turtle (Chelonia mydas) and a Loggerhead turtle (Caretta caretta). Controls were carried out with salt and freshwater. The degradation rate was measured over 49 days, based on mass loss. Degradation rates of the standard and the degradable plastic bags after 49 days across all treatments and controls were negligible. The biodegradable bags showed mass losses between 3 and 9%. This was a much slower rate than reported by the manufacturers in an industrial composting situation (100% in 49 days). The GIF of the herbivorous Green turtle showed an increased capacity to break down the biodegradable polymer relative to the carnivorous Loggerhead, but at a much lower rate than digestion of natural vegetative matter. While the breakdown rate of biodegradable polymers in the intestinal fluids of sea turtles is greater than standard and degradable plastics, it is proposed that this is not rapid enough to prevent morbidity. Further study is recommended to investigate the speed at which biodegradable polymers decompose outside of industrial composting situations, and their durability in marine and freshwater systems. PMID- 22209369 TI - Distribution of perfluorinated compounds in Yellow-legged gull eggs (Larus michahellis) from the Iberian Peninsula. AB - This study is aimed to evaluate the presence and distribution of Perfluorinated Compounds (PFCs) in Yellow-legged gull eggs (Larus michahellis) collected from 8 National or Natural Parks from the Iberian Peninsula. In each colony, 12 eggs were randomly collected and pooled from 3 areas of the colony and analyzed using liquid-solid extraction and liquid chromatography coupled to tandem mass spectrometry. Perfluorooctanate sulfonate (PFOS) was the only compound detected in the eggs and its presence was higher in the colonies situated in NE Iberian Peninsula due to the more industrial and mass urbanization in this area compared to the SW Mediterranean or Atlantic colonies. Accordingly, the Medes site, followed by the Ebro Delta and Columbretes, all situated in the NW Mediterranean coast, contained the highest PFOS levels (40.5-54.0ng/g-ww). In all other colonies, PFOS was detected at levels of 10.1-18.6ng/g-ww. Egg shell biometry was studied and it was found that the presence of PFOS did not affect the development of the egg. PMID- 22209370 TI - Associating emergency room visits with first and prolonged extreme temperature event in Taiwan: A population-based cohort study. AB - The present study evaluated emergency room visit (ERV) risks for all causes and cardiopulmonary diseases associated with temperature and long-lasting extreme temperatures from 2000 to 2009 in four major cities in Taiwan. The city-specific daily average temperatures at the high 95th, 97th, and 99th percentiles, and the low 10th, 5th, and 1st percentiles were defined as extreme heat and cold. A distributed lag non-linear model was used to estimate the cumulative relative risk (RR) of ERV for morbidities associated with temperatures (0 to 3-day lags), extreme heat and cold lasting for 2 to 9 days or longer, and with the annual first extreme heat or cold event after controlling for covariates. Low temperatures were associated with slightly higher ERV risks than high temperatures for circulatory diseases. After accounting for 4-day cumulative temperature effect, the ERV risks for all causes and respiratory diseases were found to be associated with extreme cold at the 5th percentile lasting for >8 days and 1st percentile lasting for >3 days. The annual first extreme cold event of 5th percentile or lower temperatures was also significantly associated with ERV, with RRs ranging from 1.09 to 1.12 for all causes and from 1.15 to 1.26 for respiratory diseases. The annual first extreme heat event of 99th percentile temperature was associated with higher ERV for all causes and circulatory diseases. Annual first extreme temperature event and intensified prolonged extreme cold events are associated with increased ERVs in Taiwan. PMID- 22209371 TI - Assessment of Kalman filter bias-adjustment technique to improve the simulation of ground-level ozone over Spain. AB - The CALIOPE air quality modelling system has been used to diagnose ground level O(3) concentration for the year 2004, over the Iberian Peninsula. We investigate the improvement in the simulation of daily O(3) maximum by the use of a post processing such as the Kalman filter bias-adjustment technique. The Kalman filter bias-adjustment technique is a recursive algorithm to optimally estimate bias adjustment terms from previous measurements and model results. The bias adjustment technique improved the simulation of daily O(3) maximum for the entire year and the all the stations considered over the whole domain. The corrected simulation presents improvements in statistical indicators such as correlation, root mean square error, mean bias, and gross error. After the post-processing the exceedances of O(3) concentration limits, as established by the European Directive 2008/50/CE, are better reproduced and the uncertainty of the modelling system, as established by the European Directive 2008/50/CE, is reduced from 20% to 7.5%. Such uncertainty in the model results is under the established EU limit of the 50%. Significant improvements in the O(3) timing and amplitude of the daily cycle are also observed after the post-processing. The systematic improvements in the O(3) maximum simulations suggest that the Kalman filter post processing method is a suitable technique to reproduce accurate estimate of ground-level O(3) concentration. With this study we evince that the adjusted O(3) concentrations obtained after the post-process of the results from the CALIOPE system are a reliable means for real near time O(3) forecasts. PMID- 22209372 TI - Removal of bisphenol A by the freshwater green alga Monoraphidium braunii and the role of natural organic matter. AB - Phytoremediation of waters by aquatic organisms such as algae has been recently explored for the removal of organic pollutants possessing endocrine disrupting capacity. Monoraphidium braunii, a green alga known for rapid growth and good tolerance to different natural organic matter (NOM) qualities, was tested in this study for the ability to tolerate and remove the endocrine disruptor bisphenol A at concentrations of 2, 4 and 10mgL(-1), either in NOM-free or NOM-containing media. NOM at concentrations of 2, 5 and 20mgL(-1) of DOC, was added because it may interfere with xenobiotics and modify their effects, modulate algal growth performances or produce a trade-off of both effects. After 2 and 4 days of algal growth, the cell number and size, the maximum quantum yield of photosystem II in the dark or light adapted state, and the chlorophyll a content were recorded in order to evaluate the algal response to bisphenol A. Moreover, the residual bisphenol A was measured in the algal cultures by chromatographic technique. Results indicated that after 2 and 4 days bisphenol A at the lower concentrations was not toxic for alga, whereas at the highest concentration it reduced algal growth and photosynthetic efficiency. The sole NOM and its combinations with bisphenol A at the lower concentrations increased the cell number and the chlorophyll a content of algae. After 4-day growth, good removal efficiency was exerted by M. braunii at concentrations of 2, 4 and 10mgL(-1) removing, respectively, 39%, 48% and 35% of the initial bisphenol A. Lower removal percentages were found after 2-day growth in the different treatments. NOM at any concentration scarcely influenced the bisphenol A removal. On the basis of data obtained, the use of M. braunii could be reasonably recommended for the phytoremediation of aquatic environments from bisphenol A. PMID- 22209373 TI - Options to reduce greenhouse gas emissions during wastewater treatment for agricultural use. AB - Treatment of primarily-domestic sewage wastewater involves on-site greenhouse gas (GHG) emissions due to energy inputs, organic matter degradation and biological nutrient removal (BNR). BNR causes both direct emissions and loss of fertilizer value, thus eliminating possible reduction of emissions caused by fertilizer manufacture. In this study, we estimated on-site GHG emissions under different treatment scenarios, and present options for emission reduction by changing treatment methods, avoiding BNR and by recovering energy from biogas. Given a typical Israeli wastewater strength (1050mg CODl(-1)), the direct on-site GHG emissions due to energy use were estimated at 1618 and 2102g CO(2)-eq m(-3), respectively, at intermediate and tertiary treatment levels. A potential reduction of approximately 23-55% in GHG emissions could be achieved by fertilizer preservation and VS conversion to biogas. Wastewater fertilizers constituted a GHG abatement potential of 342g CO(2)-eq m(-3). The residual component that remained in the wastewater effluent following intermediate (oxidation ponds) and enhanced (mechanical-biological) treatments was 304-254g CO(2)-eq m(-3) and 65-34g CO(2)-eq m(-3), respectively. Raw sludge constituted approximately 47% of the overall wastewater fertilizers load with an abatement potential of 150g CO(2)-eq m(-3) (385kg CO(2)-eq dry tonne(-1)). Inasmuch as anaerobic digestion reduced it to 63g CO(2)-eq m(-3) (261kg CO(2)-eq dry tonne( 1)), the GHG abatement gained through renewable biogas energy (approx. 428g CO(2) eq m(-3)) favored digestion. However, sludge composting reduced the fertilizer value to 17g CO(2)-eq m(-3) (121kg CO(2)-eq dry tonne(-1)) or less (if emissions, off-site inputs and actual phytoavailability were considered). Taking Israel as an example, fully exploiting the wastewater derived GHG abatement potential could reduce the State overall GHG emissions by almost 1%. This demonstrates the possibility of optional carbon credits which might be exploited in the construction of new wastewater treatment facilities, especially in developing countries. PMID- 22209374 TI - Using group-specific PCR to detect predation of mayflies (Ephemeroptera) by wolf spiders (Lycosidae) at a mercury-contaminated site. AB - Bioaccumulation of contaminants can occur across ecosystem boundaries via transport by emergent aquatic insects. In the South River, Virginia, USA, aquatic mercury has contaminated songbirds nesting in adjacent riparian forests. Spiders contribute the majority of mercury to these songbirds' diets. We tested the hypothesis that massive annual mayfly emergences provide a vector for mercury from river sediments to the Lycosid spiders most frequently eaten by contaminated songbirds. We designed mayfly-specific PCR primers that amplified mtDNA from 76% of adult mayflies collected at this site. By combining this approach with an Agilent 2100 electrophoresis system, we created a highly sensitive test for mayfly predation by Lycosids, commonly known as wolf spiders. In laboratory spider feeding trials, mayfly DNA could be detected up to 192h post-ingestion; however, we detected no mayfly predation in a sample of 110 wolf spiders collected at the site during mayfly emergence. We suggest that mayfly predation is not an important mechanism for dietary transfer of mercury to wolf spiders and their avian predators at the South River. Instead, floodplain soil should be considered as a potential proximate source for mercury in the terrestrial food web. PMID- 22209375 TI - Oncologic efficacy of anatomic segmentectomy in stage IA lung cancer patients with T1a tumors. AB - BACKGROUND: Segmentectomy provides an anatomic, parenchymal-sparing strategy for patients with limited lung function. Recently, interest has been renewed in segmentectomy for the treatment of early stage lung cancer. METHODS: We reviewed the medical records of all patients undergoing segmentectomy from January 1999 through December 2004. Survival curves were estimated using the Kaplan-Meier method. RESULTS: There were 113 consecutive patients (58 men, 55 women); median age was 72.5 years (range, 30 to 94 years). Median forced expiratory volume in 1 second was 1.53 L (range, 0.5 L to 3.27 L). Median diffusion capacity of lung for carbon monoxide was 69% predicted (range, 23% to 129%). Significant comorbidities were present in 62 patients (55%). There was no perioperative mortality. Major morbidity occurred in 28 patients (25%). Mean tumor size was 2.1 cm. Resection margins were negative in all cases. Ninety-two patients (81%) were stage I. Overall 5-year survival was 79% for stage IA patients. Current smoking, diffusion capacity of lung for carbon monoxide less than 69%, tumor size greater than 2 cm, N2 disease, and advanced histology grade were associated with decreased survival by univariate analysis. In a multivariate model, only tumor size greater than 2 cm remained significant. Tumor recurrence was observed in 39 patients (35%): local in 17 patients (15%) and distant only in 22 (20%). For stage IA patients with T1a lesions, local recurrence was 5% and distant recurrence was 13%. Five year recurrence-free survival of these patients was 69%. CONCLUSIONS: Pulmonary segmentectomy can be performed safely in selected patients with preoperative reduced lung function and comorbidities. For stage IA disease, survival approximates that seen after lobectomy, with similar local recurrence rates for patients with T1a tumors. PMID- 22209377 TI - Nodal staging in prostate cancer: still an unresolved issue. PMID- 22209376 TI - Novel molecular targets for the therapy of castration-resistant prostate cancer. AB - CONTEXT: Improved understanding of mechanisms underlying metastatic castration resistant prostate cancer (mCRPC) progression has led to the recognition of multiple molecular targets and advances in the therapeutic landscape. The addition of abiraterone acetate, sipuleucel-T, cabazitaxel, and denosumab to the therapeutic armamentarium and the impending addition of MDV-3100 and radium-223 underscore the importance of androgen pathway inhibition, immunotherapy, tubulin antagonism, and pathophysiology of bone metastasis. OBJECTIVE: Review the next generation of molecular targets in mCRPC. EVIDENCE ACQUISITION: Medline databases were searched for >100 original articles published as of October 18, 2011, with the search terms metastatic castration-resistant prostate cancer, targeted therapy, biologic agents, and immunotherapy. Proceedings from the last 5 yr of conferences of the American Society of Clinical Oncology, American Urological Association, European Society of Medical Oncology, and the European Association of Urology were also searched. We included novel and promising drugs that have reached clinical trial evaluation. EVIDENCE SYNTHESIS: The major findings were addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed. CONCLUSIONS: mCRPC is a disease with multiple molecular drivers. Molecular pathways being targeted in ongoing phase 3 trials are androgen signaling (MDV3100, TAK700), immunoregulatory pathways (ipilimumab, Prostvac-VF-TRICOM), Src (dasatinib), Met (cabozantinib), clusterin (custirsen), and angiogenesis (aflibercept, tasquinimod). The strides made in identifying multiple other novel molecular targets offer potential opportunities for further improving outcomes. PMID- 22209378 TI - Synthesis of the trisaccharide outer core fragment of Burkholderia cepacia pv. vietnamiensis lipooligosaccharide. AB - The synthesis of beta-Gal-(1->3)-alpha-GalNAc-(1->3)-beta-GalNAc allyl trisaccharide as the outer core fragment of Burkholderia cepacia pv. vietnamiensis lipooligosaccharide was accomplished through a concise, optimized, multi-step synthesis, having as key steps three glycosylations, that were in depth studied performing them under several conditions. The target trisaccharide was designed with an allyl aglycone in order to open a future access to the conjugation with an immunogenic protein en route to the development of a synthetic neoglycoconjugate vaccine against this Burkholderia pathogen. PMID- 22209379 TI - Cyclodextrins selectively modified on both rims using an O-3-debenzylative post functionalisation, a consequence of the Sorrento meeting. AB - A de-O-benzylation reaction induced by I(2)-Et(3)SiH and developed by Iadonisi et al. on mono- and disaccharides was applied to per- or polybenzylated alpha cyclodextrins to furnish compounds deprotected at position 3 of all sugar units. This methodology allows the straightforward post-functionalisation of the secondary rim of cyclodextrins already functionalised on their primary rim. PMID- 22209380 TI - [Severe bacterial infections and sudden death in children less than 4-years-old: 3 case reports]. AB - Infectious factors contribute to sudden infant death in about 1 case out of 3. We report 3 children less than 4-years-old who died suddenly of bacterial infection due to Neisseria meningitidis, Streptococcus pneumoniae, and Staphylococcus aureus. The bacteria were isolated from central and peripheral samples. A bacterial origin should be sought in all cases of sudden death in children. When a bacterial origin is confirmed, the question of immunodeficiency should be raised. PMID- 22209381 TI - [Vaccination against hepatitis B in children: survey on knowledge, opinions, and practices of general practitioners in Ile-de-France in 2009]. AB - Vaccination against hepatitis B in infants has been recommended since 1994. However, the WHO target of eradicating the disease in Europe is compromised due to less than 50% coverage in France. A telephone survey conducted in the first quarter of 2009 on 300 general practitioners (GPs) randomly selected in 3 departments in eastern Ile-de-France was used to study the knowledge, reported practices, and opinions on the vaccine in infants and the impact of the hexavalent vaccine's reimbursement. Two hundred and nine GPs agreed to answer. Among those taking care of infants (180), 74.4% reported offering them the vaccine. The GPs who did not practice complementary and alternative medicine (CAM), who knew of the reimbursement of the hexavalent and the recommendations, and who practiced in the suburbs rather than in Paris offered to vaccinate infants more frequently. Among GPs taking care of infants, 40.5% reported they had changed their practice since the reimbursement of the hexavalent vaccine. More than a quarter of GPs (26.2%) were opposed to the vaccination against hepatitis B in infants. They were older, practiced CAM more frequently, and were less familiar with the recommendations. Among the respondents, 79% had encountered the fear of side effects from the parents and among them 17.7% did not insist or postponed the discussion. In conclusion, in 2009, over a quarter of GPs were refractory to the vaccination proposal in infants but the hexavalent vaccine seems to have a significant impact on practices. PMID- 22209382 TI - Penetrating oesophageal injury: a contemporary analysis of the National Trauma Data Bank. AB - BACKGROUND: Oesophageal trauma is uncommon. The aim of this study was to conduct a descriptive analysis of penetrating oesophageal trauma and determine risk factors for oesophageal related complications and mortality in the National Trauma Data Bank (NTDB). METHODS: Patients with penetrating oesophageal trauma from Levels 1 and 2 trauma centres in the NTDB (2007 and 2008) that specified how complication and comorbidity data were recorded were selected. Data collected included age, injury severity score (ISS), abbreviated injury scores (AIS), lengths of stay (LOS) and ventilation days, systolic blood pressure (SBP) in the emergency department (ED), comorbidities, oesophageal related procedures, and oesophageal related complications. Univariate and multivariable analyses were conducted to identify significant predictors of oesophageal-related complications and mortality in patients with LOS>24 h. RESULTS: 227 patients from 107 centres were studied. The mean number of patients per centre was 2 (range 1-15). Overall mortality was found to be 44% with 92% of these deaths in less than 24 h. In patients with LOS>24 h, 62% had primary repair, 13% drainage, 4% resection, 1% diversion, and 20% unspecified. No significant difference in mortality was found in patients with oesophageal related complications. The time to first oesophageal related procedure was not significantly different in those with oesophageal related complications or those who died. Significant predictors of oesophageal related complications were age and AIS of the abdomen or pelvic contents >=3 and the only significant predictor of mortality was ISS. CONCLUSIONS: Most deaths in penetrating oesophageal trauma occur in the first 24 h due to severe associated injuries. Primary repair was the most common intervention, followed by drainage and resection. Oesophageal related complications were not found to significantly increase mortality and time to first oesophageal related procedure did not affect outcomes in this subset of patients from the NTDB. PMID- 22209383 TI - Monoblock hemiarthroplasties for femoral neck fractures--a part of orthopaedic history? Analysis of national registration of hemiarthroplasties 2005-2009. AB - This study from the Swedish Hip Arthroplasty Register (SHAR) compares cemented (Thompson((r)), Exeter Trauma Stem (ETS)((r))) and uncemented (Austin-Moore((r))) monoblock hemiarthroplasties (n=1116 and 616, respectively) with modular ones (n=18,659). Austin-Moore((r)) prostheses lead to more re-operations (6.7%) compared to modular implants (3.5%) and Thompson((r))/ETS((r)) (2.4%). A Cox regression analysis, adjusting for other risk factors, shows twice the risk of re operation for Austin-Moore((r)) implants (CI 1.5-2.8), in particular, due to periprosthetic fracture (5.4; CI 3.2-9.1) and dislocation (1.9; CI 1.3-3.0). The Thompson((r))/ETS((r)) implants do not influence the overall risk of re-operation (0.7; CI 0.5-1.2) compared to modular implants and decrease the risk of re operation due to infection (0.2;CI 0.04-0.7). An increased risk of re-operation is also seen in men, age groups 75-85 years and <75 years and after secondary fracture surgery. Both Swedish and Australian orthopaedic surgeons have decreased their use of Austin-Moore((r)) implants after reports from their national arthroplasty registers identifying inferior outcome for this implant. Due to the increased risk of re-operations, it should not be used in modern orthopaedic care. Cemented Thompson((r)) or ETS((r)) implants could still be suitable for the oldest, low-activity patients. To finally decide if there is a place for them, patient-reported outcome must be analysed as well. PMID- 22209384 TI - Reconstruction of a Bryan and Morrey type I capitellar fracture in a sawbone model with four different fixation devices: an experimental study. AB - BACKGROUND: We evaluated 4 different fixation devices for the reconstruction of a standardised Bryan and Morrey capitellar shear fracture in a sawbone model. Outcome measurements were the quality of reduction, time for reconstruction and stability. METHODS: 80 standardised Bryan and Morrey type I fractures were created for 5 different orthopaedic surgeons in 80 sawbones. Each surgeon reconstructed 16 fractures with 2mm K-wires, 3mm Herbert screws, 2.7 mm AO screws and 2.2mm fine-threaded wires (Fragment Fixation System: FFS). 4 fractures were allocated to each method with a standardised reconstruction procedure. Quality of reduction and time for reconstruction were measured after definitive fixation. Biomechanical testing was performed using a shear loading model with the application of monocyclic or polycyclic stress to the reconstructed capitulum. RESULTS: There was no difference in the quality of reduction with the different fixation devices. Herbert and AO screw fixation was slower than the other implants (p<0.05). No difference in the time for reconstruction was observed with K-wires and FFS. Failure load was less for K-wires compared to FFS, Herbert screws and AO screws (p<0.05). With polycyclic loading, residual deformation was higher with K-wire reconstruction compared to FFS, Herbert screws and AO screws (p<0.05). CONCLUSION: When using four different fixation devices, the fixation of standardised Bryan and Morrey type I fractures in the sawbone model differs when it comes to the time needed for reduction, but not in the quality of reduction. Stability was the same for the implants used, except for the K-wires. There is no argument in favour one of the screw implants over another in clinical use. PMID- 22209385 TI - Prevalence of attention-deficit hyperactivity disorder in substance use disorder patients: a meta-analysis and meta-regression analysis. AB - CONTEXT: Substance use disorders (SUD) are a major public health problem. Attention deficit hyperactivity disorder (ADHD) is a comorbid condition associated with both onset and prognosis of SUD. Prevalence estimates of ADHD in SUD vary significantly. OBJECTIVE: To obtain a best estimate of the prevalence of ADHD in SUD populations. DATA SOURCES: A literature search was conducted using MEDLINE, PsycINFO and EMBASE. Search terms were ADHD, substance-related disorders, addiction, drug abuse, drug dependence, alcohol abuse, alcoholism, comorbidity, and prevalence. Results were limited to the English language. STUDY SELECTION: After assessing the quality of the retrieved studies, 29 studies were selected. Studies in which nicotine was the primary drug of abuse were not included. DATA EXTRACTION: All relevant data were extracted and analysed in a meta-analysis. A series of meta-regression analyses was performed to evaluate the effect of age, primary substance of abuse, setting and assessment procedure on the prevalence of ADHD in a variety of SUD populations. DATA SYNTHESIS: Overall, 23.1% (CI: 19.4-27.2%) of all SUD subjects met DSM-criteria for comorbid ADHD. Cocaine dependence was associated with lower ADHD prevalence than alcohol dependence, opioid dependence and other addictions. Studies using the DICA or the SADS-L for the diagnosis of ADHD showed significantly higher comorbidity rates than studies using the KSADS, DISC, DIS or other assessment instruments. CONCLUSIONS: ADHD is present in almost one out of every four patients with SUD. The prevalence estimate is dependent on substance of abuse and assessment instrument. PMID- 22209386 TI - Effects of cold pressor pain on the abuse liability of intranasal oxycodone in male and female prescription opioid abusers. AB - BACKGROUND: Approximately 1.9 million persons in the U.S. have prescription opioid use disorders often with concomitant bodily pain, but systematic data on the impact of pain on abuse liability of opioids is lacking. The purpose of this study was to determine whether pain alters the intranasal abuse liability of oxycodone, a commonly prescribed and abused analgesic, in males and females. METHODS: Sporadic prescription opioid abusers (10 females, 10 males) participated in this mixed (between and within-subject), randomized inpatient study. Experimental sessions (n=6) tested intranasal placebo, oxycodone 15 or 30 mg/70 kg during cold pressor testing (CPT) and a warm water control. Observer- and subject-rated drug effect measures, analgesia, physiologic and cognitive effects were assessed. RESULTS: The CPT significantly increased blood pressure, heart rate, pain, stress, and "opiate desire" compared to the no-pain control but did not alter opioid liking, high or street value. Intranasal oxycodone produced effects within 10 min, significantly decreasing pain and significantly increasing subjective measures of abuse liability (e.g., high). Females had higher ratings of street value, high, and liking for one or both active doses. CONCLUSIONS: The CPT was a reliably painful and stressful stimulus that did not diminish the abuse liability of intranasal oxycodone. Females were more sensitive to oxycodone on several abuse liability measures that warrant further follow-up. Snorting oxycodone rapidly produced psychoactive effects indicative of substantial abuse liability. PMID- 22209387 TI - Emerging psychoactive substance use among regular ecstasy users in Australia. AB - BACKGROUND: The past decade has seen the development of an array of emerging psychoactive substances (EPS), however, there is minimal information on the extent of their use outside Europe. This study aimed to determine the extent of use of EPS from stimulant (such as mephedrone) and psychedelic classes (such as 5 methoxy-dimethyltryptamine [5-MeO-DMT]) among an Australian sample of regular ecstasy users (REU). Further, to determine if consumers of these drugs represent a distinct subgroup of REU. METHODS: Australian national cross-sectional surveys of 693 regular (at least monthly) ecstasy users conducted during 2010. RESULTS: More than one quarter (28%) of REU had used an EPS in the past six months, most commonly from the stimulant class (20%, typically mephedrone, 17%) rather than the psychedelic class (13%). Demographics and risk behaviours of REU that used stimulant EPS were largely no different from non-EPS consuming REU. Those using psychedelic EPS were distinct, initiating ecstasy use earlier, more frequently using multiple substances (cannabis, inhalants, GHB, ketamine) and more commonly experiencing legal, psychological and social problems. CONCLUSIONS: Psychedelic EPS use appears largely restricted to a distinct subset of REU with high-level non-injecting polydrug use, but use appears generally limited. The demographic similarity of stimulant EPS consumers with 'mainstream' REU, in conjunction with positive responses to the psychoactive effects of these drugs and declining ecstasy purity, suggests strong potential for stimulant EPS to expand further into ecstasy markets. Such drugs may have a greater public health impact than ecstasy, and merit careful monitoring into the future. PMID- 22209388 TI - Improving treatment enrollment and re-enrollment rates of syringe exchangers: 12 month outcomes. AB - BACKGROUND: Developing bridges between community syringe exchange programs (SEPs) and substance abuse treatment could benefit syringe exchangers and the public health. Kidorf et al. (2009) showed that motivational approaches employed at an SEP site improved rates of treatment enrollment and reduced drug use over a 4 month observation window. The present study extends this report by evaluating rates of treatment enrollment and re-enrollment over a 12-month period. METHODS: Opioid dependent individuals (n = 281) newly registered at an SEP were randomly assigned to one of three referral interventions: (1) 8 individual motivational enhancement sessions and 16 treatment readiness group sessions designed to improve treatment interest and readiness (motivated referral condition; MRC only); (2) MRC-only with monetary incentives for attending sessions and enrolling in treatment (MRC+I); or (3) standard referral (SRC). MRC-only and MRC+I participants discharged from treatment could attend a treatment re-engagement group designed to facilitate return to treatment (MRC+I participants received incentives for attending sessions and re-enrolling in treatment). RESULTS: The 4 month outcomes generally extended over 12 months. MRC+I participants were more likely to enroll in methadone maintenance than MRC-only or SRC participants, and to re-enroll in treatment following discharge. MRC+I participants also reported more days of treatment and less heroin and injection use. CONCLUSIONS: The good harm reduction outcomes for many SEP participants can be enhanced through strategies designed to facilitate treatment enrollment and re-enrollment. PMID- 22209389 TI - [Atypical skin lesions of the lower limbs in patients with chronic venous insufficiency: a case of granulomatous fungoid mycosis]. AB - In vascular medicine, venous insufficiency, ocre dermatitis, stasis dermatitis, or lipodermatosclerosis (level C4 in CEAP) may lead to skin lesions involving the lower limbs. Generally, symptoms resolve with etiologic treatment using medical compression, varicosis treatment, or dermocorticoids. However, some skin lesions progress, suggesting another diagnosis, including a specific dermatosis. The diagnosis is based on clinical, biological, radiological and histological criteria. Referral to a dermatologist may be necessary to determine the appropriate etiological treatment. PMID- 22209390 TI - Reirradiation of paraaortic lymph node metastasis by brachytherapy with hyaluronate injection via paravertebral approach: With DVH comparison to IMRT. AB - PURPOSE/INTRODUCTION: To safely irradiate retroperitoneal targets as paraaortic lymph node by separating abdominal at-risk organs from the target during irradiation, we created a percutaneous paravertebral approach of high-dose-rate brachytherapy with hyaluronate gel injection (HGI). We report a case treated with this technique. METHODS AND MATERIALS: We encountered a patient with symptomatic regrowth of paraaortic lymph node metastasis from prostatic cancer. He had previously received 58.4Gy of radiotherapy to the same region 12 months prior. Brachytherapy needles and a HGI needle were deployed via the paravertebral approach under local anesthesia at our outpatient clinic. RESULTS: A single dose of 22.5Gy (equivalent to 60.94Gy in 2Gy per fraction schedule calculated at alpha/beta=10) was delivered to the target, with preservation of the surrounding small intestine by HGI with D(2cc) (minimum dose to the most irradiated volume of 2mL) of 5.05Gy. Therapeutic ratio was 3.64 times higher for this brachytherapy plan compared with an intensity-modulated radiation therapy plan. At followup at 1 year after brachytherapy, the symptoms had disappeared, tumor size had reduced with no fluorodeoxyglucose accumulation, and prostate-specific antigen level had decreased. CONCLUSION: We consider that high-dose-rate brachytherapy with the HGI procedure offers effective treatment even in this type of reirradiation situation. PMID- 22209391 TI - Everolimus in metastatic renal cell carcinoma: Subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study. AB - INTRODUCTION: In the phase III RECORD-1 trial (ClinicalTrials.gov: NCT00410124), patients with metastatic renal cell carcinoma (mRCC) who progressed on previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy were randomised 2:1 to everolimus 10mg once daily (n=277) or placebo (n=139). Median progression-free survival (PFS) was 4.9months with everolimus and 1.9months with placebo (hazard ratio [HR], 0.33; P<.001). This preplanned, prospective sub-analysis evaluated PFS benefit of everolimus versus placebo in patients who had previously received 1 or 2 VEGFr-TKIs. PATIENTS AND METHODS: Median PFS was estimated using the Kaplan-Meier method, and Cox proportional hazards model was used to analyse differences in PFS. RESULTS: All patients (100%) received ?1 previous VEGFr-TKI; 26% of patients received 2 previous VEGFr TKIs. Among patients who received 1 previous VEGFr-TKI, median PFS was 5.4months with everolimus and 1.9months with placebo (HR, 0.32; 95%confidence interval [CI], 0.24-0.43; P<.001). Among patients who received 2 previous VEGFr-TKIs, median PFS was 4.0months with everolimus and 1.8months with placebo (HR, 0.32; 95%CI, 0.19-0.54; P<.001). The everolimus safety profile was similar for both groups. CONCLUSIONS: Everolimus was associated with prolonged PFS relative to placebo in patients who received 1 or 2 previous VEGFr-TKIs. Patients who received only 1 previous VEGFr-TKI had apparently longer PFS with everolimus in reference to those who received 2 previous VEGFr-TKIs. These results support the use of everolimus as the standard of care in patients who fail initial VEGFr-TKI therapy. PMID- 22209392 TI - Manual small incision cataract surgery for subluxated cataract with lens coloboma. AB - INTRODUCTION: The lens coloboma results from a segmental defective or absent development of the zonules. It is usually unilateral and bilateral cases are rare. These eyes are at greater risk of complications during cataract surgery due to ocular malformations. In addition the capsular bag requires stabilization using modified capsule tension ring, capsular tension segment or capsular anchor. METHODS: Lens extraction is indicated for cataract or subluxation if visual function is sufficiently compromised. We report our surgical experience in a patient with bilateral isolated lens coloboma by performing manual small incision cataract surgery (MSICS) in left eye and phacoemulsification in right eye. RESULTS: The nuclear rotation was hampered because of the lack of zonules and presence of lens coloboma. MSICS was converted to the intracapsular technique in left eye, though breaking the nucleus into pieces during phacoemulsification in right eye enabled its mobilization and successful completion with implantation of modified capsule tension ring. CONCLUSIONS: A patient with lens subluxation and lens coloboma is better managed by phacoemulsification as compared to the MSICS. PMID- 22209393 TI - Perceptual and motor inhibitory abilities in normal aging and Alzheimer disease (AD): a preliminary study. AB - Deficits in inhibitory abilities are frequently observed in normal aging and AD. However, few studies have explored the generality of these deficits in a single group of participants. A battery of tasks assessing perceptual and motor inhibitory functioning was administered to young and older healthy participants (Study 1), as well as to mild Alzheimer patients (Study 2). Results did not agree with a selective impairment of motor or perceptual inhibition in either AD or normal aging but rather suggest that a decrease in cognitive resources available in working memory could explain inhibitory performance both in normal aging and AD. PMID- 22209394 TI - Obesity and use of compensatory strategies to perform common daily activities in pre-clinically disabled older adults. AB - OBJECTIVES: To examine the association between the use of compensatory strategies to successfully complete common daily activities-an indicator of pre-clinical disability-and body mass in pre-clinically disabled older adults. DESIGN: Cross sectional observational study. PARTICIPANTS: Two hundred and fifty-nine pre clinically disabled older adults defined as having changed the frequency or manner of performing daily tasks without reporting any difficulty. MEASUREMENTS: The use of compensatory strategies were objectively evaluated using the Modification (MOD) scale-a reliable and valid scale for assessing the manner in which common daily activities were completed. Height and weight were measured to classify participants into the following body mass index (BMI) categories: (1) normal: 18.5-24.9 kg/m(2), (2) overweight: 25.0-29.9 kg/m(2), (3) obese class I: 30.0-34.9 kg/m(2), and (4) obese class II: 35.0-39.9 kg/m(2). RESULTS: Compared to other BMI categories, individuals with class II obesity demonstrated a significantly higher probability of using >=1 compensatory strategies when rising from a chair (30 cm height), kneel to stand, stair ascent, stair descent, and supine to stand tasks. When summarized over all tasks, individuals with class II obesity were 18 times more likely to use extensive compensatory strategies (>=6 on MOD scale) compared to normal weight older adults. Similar trends at a lesser magnitude were found in obese and overweight compared to normal weight older adults. CONCLUSION: Obesity is associated with extensive use of compensatory strategies when performing common daily tasks prior to the onset of perceived difficulty, thus placing them at higher risk of disability compared to their peers with lower body mass. PMID- 22209395 TI - Immunolocalization of lubricin in the rat periodontal ligament during experimental tooth movement. AB - Lubricin is a protein which contributes to the boundary lubrication, facilitating low friction levels at the interfacing surfaces of joints. In tendons and ligaments it facilitates the relative movement of collagen bundles. Its expression is affected by mechanical signals and cytokines. During application of orthodontic forces to teeth, there is a transduction of mechanical forces to the cells of the periodontal ligament (PDL), which triggers several biological reactions causing the synthesis of prostaglandins, cytokines and growth factors. The aim of the present study was to examine the immunolocalization of lubricin and to evaluate if it is time-dependently and differentially detected within the PDL following the application of orthodontic forces to create areas of compression and tension. This was achieved by placing elastic bands between the maxillary first and second molars of 16 male Sprague-Dawley rats (each weighing 120-200g) for 12 and 24h. The molar-bearing segments were dissected and processed for histological and immunohistochemical examination. Binding of a monoclonal antibody was used to evaluate lubricin localization using an indirect streptavidin/biotin immunperoxidase technique. Lubricin, was constitutively expressed in the PDL of rat molars. After the experimental force was applied to the tooth, lubricin was down-regulated, on both sides (compression and tension) of the PDL, in a time-dependent fashion, although to a different extent, being at any time more expressed on the tension side. Furthermore, in every sample, almost all PDL cells in the adjacent tooth cementum and alveolar bone, were more heavily immunolabeled by lubricin antibody, contrary to those located in the central portion of the PDL. Lubricin expression therefore seems related to PDL remodeling and tooth displacement following the application of an orthodontic force, and it appears that lubricin may play an important role during tooth movement. PMID- 22209396 TI - Treatment of pediatric patients with cerebral cavernous malformation. PMID- 22209397 TI - Analysis of the anatomy of the Papez circuit and adjoining limbic system by fiber dissection techniques. AB - Fiber dissection techniques were used to study the limbic system, in particular the Papez circuit. The course, length and anatomical relations of the structures that make up the Papez circuit were delineated. Ten previously frozen and formalin-fixed cadaveric human brains were used, and dissected according to the fiber dissection techniques of Klingler et al. (Schweiz Arch Neurol Psychiatry 1935;36:247-56). The primary dissection tools were thin and curved wooden and metallic spatulas with tips of varying sizes. We found that the Papez circuit (mean length: 350 mm) begins in the hippocampus and continues into the fornix to reach the mamillary body. From there, the mamillothalamic tract continues to the anterior nucleus of the thalamus, which in turn connects to the cingulum by means of anterior thalamic radiations (mean length: 30 mm). The cingulum courses around the corpus callosum to end in the entorhinal cortex, which then projects to the hippocampus, thus completing the circuit. The average length and breadth of the mamillothalamic tract was 18 mm and 1.73 mm respectively. The average length of the cingulum was 19.6 cm and that of the fornix was 71 mm. The entire circuit was anatomically dissected first in situ in the hemisphere and was then reconstructed outside after removing its various components using fine fiber dissection under a surgical microscope. We found that fiber dissection elegantly delineates the anatomical subtleties of the Papez circuit and provides a three-dimensional perspective of the limbic system. Intricate knowledge of the anatomy of this part of the brain aids the neurosurgeon while performing epilepsy surgery and while approaching intrinsic brain parenchymal, ventricular and paraventricular lesions. PMID- 22209398 TI - MRI features in children with desmoplastic medulloblastoma. AB - Desmoplastic medulloblastoma (DMB) is a variant that has a more favorable prognosis compared to classical medulloblastoma, but its MRI features have not been as well described. We retrospectively reviewed the MRI features in children with pathologically proven DMB, including T2-weighted, fluid-attenuated inversion recovery (FLAIR) and contrast enhanced images, with isotropic diffusion-weighted (DW) MRI also performed in some patients. There were 16 tumors in 12 patients; one patient had five discrete lesions. In all patients, the tumor involved the cerebellar vermis, with nine lesions showing multiple peripheral small cysts. In nine of 16 tumors, there were focal areas of isointensity or hypointensity on T2 weighted or FLAIR images; seven of these showed corresponding focal enhancement. There was also one patient with radiating star-shaped enhancement in two lesions, and a multi-nodular enhancing pattern was observed in another patient. Low apparent diffusion coefficient (ADC) values were found in the lesions studied by DW MRI in five patients. DMB may have a typical imaging appearance of peripheral cysts, decreased ADC and focal enhancing areas corresponding to focal isointense or hypointense signal on T2-weighted and FLAIR images. Although these MRI features may distinguish this variant of medulloblastoma, multinodular or star shaped radiating enhancement may also be detected in some patients. PMID- 22209399 TI - Review of risk from potential emerging contaminants in UK groundwater. AB - This paper provides a review of the types of emerging organic groundwater contaminants (EGCs) which are beginning to be found in the UK. EGCs are compounds being found in groundwater that were previously not detectable or known to be significant and can come from agricultural, urban and rural point sources. EGCs include nanomaterials, pesticides, pharmaceuticals, industrial compounds, personal care products, fragrances, water treatment by-products, flame retardants and surfactants, as well as caffeine and nicotine. Many are relatively small polar molecules which may not be effectively removed by drinking water treatment. Data from the UK Environment Agency's groundwater screening programme for organic pollutants found within the 30 most frequently detected compounds a number of EGCs such as pesticide metabolites, caffeine and DEET. Specific determinands frequently detected include pesticides metabolites, pharmaceuticals including carbamazepine and triclosan, nicotine, food additives and alkyl phosphates. This paper discusses the routes by which these compounds enter groundwater, their toxicity and potential risks to drinking water and the environment. It identifies challenges that need to be met to minimise risk to drinking water and ecosystems. PMID- 22209400 TI - First evidences of the occurrence of polycyclic synthetic musk fragrances in surface water systems in Italy: spatial and temporal trends in the Molgora River (Lombardia Region, Northern Italy). AB - The polycyclic synthetic musks (PCMs) such as galaxolide (HHCB), tonalide (AHTN) and celestolide (ABDI) are important ingredients in fragrances for consumer products because of their typical musky scent. In EU, PCMs are classified as HPVC (High Production Volume Chemicals). Furthermore, it has been recognized that these substances are only partially degraded in domestic sewers. For both reasons these chemicals are considered ubiquitous contaminants of aquatic systems. Monitoring data are available for the Northern region of the EU, but it is not known whether they are also representative for the Southern EU countries. The lack of data upon the environmental exposure in Southern EU can be significant, since use patterns and volumes differ from country to country. This is particularly true for Italy that has the largest detergent consumption per capita in EU. Due to this, the objective of the present study was to investigate the occurrence of selected PCMs in the Molgora River (Lombardia region, Italy). To our knowledge it represents the first overview of PCM occurrence in the Italian water bodies. Water samples were collected seasonally in seven sampling stations located before and after the 3 sewage treatment plants present along the river, which serve about 300,000 inhabitants. The spatial and temporal profiles of contamination are described. A comparison of the results with existing monitoring data of other European regions indicated a significant higher level of PCM pollution of the Molgora River and the need to extend the monitoring campaigns to other Italian water bodies, in order to achieve a better knowledge of the levels of PCM contamination in this country. PMID- 22209401 TI - Learning what children know about space from looking at their hands: the added value of gesture in spatial communication. AB - This article examines two issues: the role of gesture in the communication of spatial information and the relation between communication and mental representation. Children (8-10 years) and adults walked through a space to learn the locations of six hidden toy animals and then explained the space to another person. In Study 1, older children and adults typically gestured when describing the space and rarely provided spatial information in speech without also providing the information in gesture. However, few 8-year-olds communicated spatial information in speech or gesture. Studies 2 and 3 showed that 8-year-olds did understand the spatial arrangement of the animals and could communicate spatial information if prompted to use their hands. Taken together, these results indicate that gesture is important for conveying spatial relations at all ages and, as such, provides us with a more complete picture of what children do and do not know about communicating spatial relations. PMID- 22209402 TI - The contribution of short-term memory for serial order to early reading acquisition: evidence from a longitudinal study. AB - Early reading acquisition skills have been linked to verbal short-term memory (STM) capacity. However, the nature of this relationship remains controversial because verbal STM, like reading acquisition, depends on the complexity of underlying phonological processing skills. This longitudinal study addressed the relation between STM and reading decoding acquisition by distinguishing between STM for item information and STM for order information based on recent studies showing that STM for item information, but not STM for order information, recruits underlying phonological representations. If there is a specific link between STM and reading decoding acquisition, STM for order information should be an independent predictor of reading decoding acquisition. Tasks maximizing STM for serial order or item information, measures of phonological abilities, and reading tests were administered to children followed from kindergarten through first grade. We observed that order STM capacity, but not item STM capacity, predicted independent variance in reading decoding abilities 1 year later. These results highlight the specific role of STM for order in reading decoding acquisition and argue for a causal role of order STM capacity in reading acquisition. Mechanisms relating STM for order information and reading acquisition are discussed. PMID- 22209403 TI - An analysis of lignin removal in a fixed bed reactor by reaction of cereal straws with ozone. AB - The chemical pretreatment with ozone of rye and wheat straws was carried out in a fixed bed reactor. The effect of ozone pretreatment time on lignin removal was determined. Glucose and xylose concentrations in the hydrolysates were also measured after the subsequent enzymatic hydrolysis step. Acid insoluble lignin reacts with ozone within the first 90 min reaction. Insoluble lignin reduction was about 50%. The higher hydrolysis yields were obtained after 120 min ozonation: the glucose yield ranged from 40% to 50% for rye straw and from 34% to 39% for wheat straw, whereas xylose yields were about 30%, independently of the cereal straw. The glucose yields corresponding to the untreated raw straws were considerably lower, about 10%. Longer ozonation time sharply reduced the production of monosaccharides, probably due to the formation of side products. The kinetic model, with the reaction parameters estimated, predicted reasonably well the experimental data. PMID- 22209404 TI - Utilization of spent activated carbon to enhance the combustion efficiency of organic sludge derived fuel. AB - This study examines the heating value and combustion efficiency of organic sludge derived fuel, spent activated carbon derived fuel, and derived fuel from a mixture of organic sludge and spent activated carbon. Spent activated carbon was sampled from an air pollution control device of an incinerator and characterized by XRD, XRF, TG/DTA, and SEM. The spent activated carbon was washed with deionized water and solvent (1N sulfuric acid) and then processed by the organic sludge derived fuel manufacturing process. After washing, the salt (chloride) and sulfide content could be reduced to 99% and 97%, respectively; in addition the carbon content and heating value were increased. Different ratios of spent activated carbon have been applied to the organic sludge derived fuel to reduce the NO(x) emission of the combustion. PMID- 22209405 TI - Hydrothermal liquefaction of separated dairy manure for production of bio-oils with simultaneous waste treatment. AB - A bench scale hydrothermal liquefaction (HTL) system was tested using dairy manure to explore biooil production and waste treatment potential. Carbon monoxide was used as the process gas and sodium carbonate (Na(2)CO(3)) as catalyst. At a 350 degrees C process temperature, the HTL unit produced 3.45 g (+/- 0.21) of acetone soluble oil fractions (ASF), with an average Higher Heating Value of 32.16 (+/- 0.23) MJ kg(-1). A maximum ASF yield of 4.8 g was produced at a process temperature of 350 degrees C and 1g of catalyst. The best ASF yield corresponded to 67.6% of energy contained in the raw manure. GC-MS analysis of ASF indicated that the highest quantities of phenolic compounds were formed when 1g catalyst was used. Chemical Oxygen Demand (COD) reduction in the dischargeable slurry was as high as 75%. The results point to an alternative dairy waste treatment technology with a potential to generate transportable biooils. PMID- 22209406 TI - Feasibility of applying forward osmosis to the simultaneous thickening, digestion, and direct dewatering of waste activated sludge. AB - The feasibility of applying forward osmosis (FO) to the simultaneous thickening, digestion, and dewatering of waste activated sludge was investigated. After 19 days of operation, the total reduction efficiencies of the simultaneous sludge thickening and digestion system in terms of mixed liquor suspended solids (MLSS) and mixed liquor volatile suspended solids (MLVSS) were approximately 63.7% and 80%, respectively, and the MLVSS/MLSS ratio continuously decreased from 80.8% to 67.2%. The MLSS concentration reached 39 g/L from an initial amount of 7 g/L, indicating a good thickening efficiency. In using FO for sludge dewatering, two major factors were verified, namely, initial sludge depth and draw solution (DS) concentration. A sludge depth of 3mm, where a dry sludge content of approximately 35% can be achieved in approximately 60 min, is recommended for future applications. In addition, the present study proved the feasibility of using seawater reverse osmosis concentrate as the DS. PMID- 22209407 TI - Thermogravimetric-Fourier transform infrared spectrometric analysis of CO2 gasification of reed (Phragmites australis) kraft black liquor. AB - CO(2) gasification of the reed (Phragmites australis) kraft black liquor (KBL) and its water-soluble lignin (WSL) was analyzed by thermogravimetry coupled with Fourier transform infrared spectrometry (TG-FTIR). In KBL gasification, major mass loss of KBL occurred between 150 and 1000 degrees C, followed by a further slow mass loss until the heating was stopped and the TG curve leveled off. The TG profiles of the WSL and the KBL were similar during gasification; however, the differential thermogravimetry (DTG) curves and mass decrease from 300 degrees C of the TG curves of the WSL and the KBL were different because of their dissimilar ingredients. The CO formation mechanism was the same and independent of structural types of lignins between reed and wood in their KBL CO(2) gasification. PMID- 22209408 TI - Challenges in examining area effects across the life course on physical capability in mid-life: findings from the 1946 British Birth Cohort. AB - A major limitation of past work linking area socioeconomic conditions to health in mid-life has been the reliance on single point in time measurement of area. Using the MRC National Survey of Health and Development, this study for the first time linked place of residence at three major life periods of childhood (1950), young adulthood (1972), and mid-life (1999) to area-socioeconomic data from the nearest census years. Using objective measures of physical capability as the outcome, the purpose of this study was to highlight four methodological challenges of attrition bias, secular changes in socio-economic measures, historical data availability, and changing reporting units over time. In general, standing balance and chair rise time showed clear cross-sectional associations with residing in areas with high deprivation. However, it was the process of overcoming the methodological challenges, which led to the conclusion that in this example percent low social class occupations was the most appropriate measure to use when extending cross-sectional analysis of standing balance and chair rise to life course investigation. PMID- 22209409 TI - Population density, socioeconomic environment and all-cause mortality: a multilevel survival analysis of 2.7 million individuals in Denmark. AB - This study examines the relative effects of population density and area-level SES on all-cause mortality in Denmark. A shared frailty model was fitted with 2.7 million persons aged 30-81 years in 2,121 parishes. Residence in areas with high population density increased all-cause mortality for all age groups. For older age groups, residence in areas with higher proportions of unemployed persons had an additional effect. Area-level factors explained considerably more variation in mortality among the elderly than among younger generations. Overall this study suggests that structural prevention efforts in neighborhoods could help reduce mortality when mediating processes between area-level socioeconomic status, population density and mortality are found. PMID- 22209410 TI - Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice. AB - Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory. Levels of BDNF and its main receptor TrkB (TrkB.TK) have been reported to be decreased while the levels of the truncated TrkB (TrkB.T1) are increased in Alzheimer's disease. We show here that incubation with amyloid-beta increased TrkB.T1 receptor levels and decreased TrkB.TK levels in primary neurons. In vivo, APPswe/PS1dE9 transgenic mice (APdE9) showed an age dependent relative increase in cortical but not hippocampal TrkB.T1 receptor levels compared with TrkB.TK. To investigate the role of TrkB isoforms in Alzheimer's disease, we crossed AP mice with mice overexpressing the truncated TrkB.T1 receptor (T1) or the full-length TrkB.TK isoform. Overexpression of TrkB.T1 in APdE9 mice exacerbated their spatial memory impairment while the overexpression of TrkB.TK alleviated it. These data suggest that amyloid-beta changes the ratio between TrkB isoforms in favor of the dominant-negative TrkB.T1 isoform both in vitro and in vivo and supports the role of BDNF signaling through TrkB in the pathophysiology and cognitive deficits of Alzheimer's disease. PMID- 22209411 TI - The structure of percolating lipid monolayers. AB - The lattice structure and in plane molecular organization of Langmuir monolayer of amphiphilic material is usually determined from grazing incidence X-ray diffraction (GIXD) or neutron reflectivity. Here we present results of a different approach for determination of monolayer lattice structure based on application of fractal analysis and percolation theory in combination with Brewster angle microscopy. The considerations of compressibility modulus and fractal dimension dynamics provide information on percolation threshold and consequently by application of percolation theory on the lattice structure of a monolayer. We have applied this approach to determine the monolayer lattice structures of single chain and double chain lipids. The compressibility moduli were determined from measured pi-A isotherms and fractal dimensions from corresponding BAM images. The monolayer lattice structures of stearic acid, 1 hexadecanol, DPPC and DPPA, obtained in this way conform to the corresponding lattice structures determined previously by other authors using GIXD. PMID- 22209412 TI - Hydrotropic salt promotes anionic surfactant self-assembly into vesicles and ultralong fibers. AB - Molecular self-assembly has become a versatile approach to create complex and functional nanoarchitectures. In this work, the self-assembly behavior of an anionic surfactant (sodium dodecylbenzene sulfonate, SDBS) and a hydrotropic salt (benzylamine hydrochloride, BzCl) in aqueous solution is investigated. Benzylamine hydrochloride is found to facilitate close packing of surfactants in the aggregates, inducing the structural transformation from SDBS micelles into unilamellar vesicles, and multilamellar vesicles. The multilamellar vesicles can transform into macroscale fibers, which are long enough to be visualized by the naked eye. Particularly, these fibers are robust enough to be conveniently separated from the surfactant solution. The combined effect of non-covalent interactions (e.g., hydrophobic effect, electrostatic attractions, and pi-pi interactions) is supposed to be responsible for the robustness of these self assembled aggregates, in which pi-pi interactions provide the directional driving force for one-dimensional fiber formation. PMID- 22209413 TI - Enzymatically synthesized polyaniline film deposition studied by simultaneous open circuit potential and electrochemical quartz crystal microbalance measurements. AB - The chemical and enzymatic deposition of polyaniline (PANI) films by in situ polymerization was studied and the resulting films were characterized. The film formation and polymerization processes were simultaneously monitored by the evolution of the open circuit potential and quartz-crystal microbalance measurements. Different substrates, such as Indium-Tin oxide electrodes and gold coated quartz-crystal electrodes were used as substrates for PANI deposition. Electroactive PANI films were successfully deposited by in situ enzymatic polymerization at low oxidation potential. The electrogravimetric response of the enzymatically deposited PANI film was studied by cyclic voltammetry in monomer free acidic medium. The morphology of the films was observed by scanning electron microscopy, revealing a granular structure in enzymatically deposited PANI. The PANI films were also characterized by thermogravimetric analysis, electrochemical impedance spectroscopy, and X-ray photoelectron and Fourier-transformed infrared spectroscopy. The simultaneous use of quartz crystal microbalance and open circuit potential is presented as a very useful technique to monitor enzymatic reactions involving oxidoreductases. PMID- 22209414 TI - Synthesis, antiproliferative activity and estrogen receptor alpha affinity of novel estradiol-linked platinum(II) complex analogs to carboplatin and oxaliplatin. Potential vector complexes to target estrogen-dependent tissues. AB - In the course of efforts to develop 17beta-estradiol-linked to anticancer agents targeting estrogen-dependent tissue, we identified three estradiol-linked platinum(II) complex analogs to cisplatin (E-CDDP) derivatives namely: VP-128 (1), CD-38 (2) and JMP-39 (3) that exhibit potent in vitro and in vivo (for derivative VP-128) activity along with interaction with the estrogen receptor alpha (ERalpha). In this study, we prepared and biologically evaluated two novel classes of estradiol-linked platinum(II) complex analogs to carboplatin (E CarboP, 1a-3a) and oxaliplatin (E-OxaP, 1b-3b). E-CarboP and E-OxaP were designed and based on the estradiol-linker scaffold of E-CDDP derivatives previously identified. Consequently, we assessed the importance of the nature of platinum(II) salt on the antiproliferative activity on MCF-7 and MDA-MB-231 human mammary carcinoma cell lines together with affinity for the ERalpha by replacing the dichloroplatinum(II) moiety by a cyclobutane-1,1-dicarboxylateplatinum(II) or an oxalateplatinum(II) moiety. Except for compound 3b which is inactive at the concentration tested, the antiproliferative activity of all compounds on both human mammary carcinomas cell lines are in micromolar range and are more active than carboplatin and oxaliplatin alone but less active that their E-CDDP counterparts (1-3). In addition, E-CarboP derivatives 1a-3a show very low affinity for ERalpha whereas E-OxaPs 1b and 2b show higher affinity for ERalpha than their parents E-CDDPs (1-2), suggesting that the nature of the platinum(II) salt involved in the vector complexes is extremely important to both retain significant antiproliferative activity and selectivity for the ERalpha and possibility to target estrogen-dependent tissues. Finally, E-OxaPs 1b and 2b are potentially promising alternatives vector complexes to target estrogen-dependent tissues. PMID- 22209415 TI - Activity of novel quinoxaline-derived chalcones on in vitro glioma cell proliferation. AB - Gliomas are the most common and devastating tumors of the central nervous system (CNS). Many pieces of evidence point out the relevance of natural compounds for cancer therapy and prevention, including chalcones. In the present study, eight synthetic quinoxaline-derived chalcones, structurally based on the selective PI3Kgamma inhibitor AS605240, were evaluated for anti-proliferative activity and viability inhibition using glioma cell lines from human and rat origin (U-138 MG and C6, respectively), at different time-periods of incubation and concentrations. The results revealed that four chalcones (compounds 1, 6, 7 and 8), which present methoxy groups at A-ring, displayed higher efficacies and potencies, being able to inhibit either cell proliferation or viability, in a time- and concentration-dependent manner, with an efficacy that was greater than that seen for the positive control compound AS605240. Flow cytometry analysis demonstrated that incubation of C6 cells with compound 6 led to G1 phase arrest, likely indicating an interference with apoptosis. Furthermore, compound 6 was able to visibly inhibit AKT activation, allied to the stimulation of ERK MAP kinase. The chalcones tested herein, especially those displaying a methoxy substituent, might well represent promising molecules for the adjuvant treatment of glioma progression. PMID- 22209416 TI - Structure-based virtual screening for plant-derived SdiA-selective ligands as potential antivirulent agents against uropathogenic Escherichia coli. AB - The uropathogenic Escherichia coli pathogenecity is affected by quorum sensing transcriptional regulator SdiA. In this study, in vitro characterization of the active principles that could potentially antagonize with SdiA from the Melia dubia bark extracts has been described. After in vitro assays carried out to evaluate the inhibitory activities against the uropathogenic E. coli, the ethanolic extract (30 mg/ml) which showed the strongest suppression of haemolysis, swarming motility, hydrophobicity and biofilm formation, was subjected to GC-MS analysis and an array of 40 unrelated compounds was identified. Docking studies was conducted to screen for plant-based SdiA inhibitors. Five hits were assessed for their binding profiles and 7-(1 bromoethyl)-3, 3-dimethyl-bicyclo [4.1.0]heptan-2-one showed 66.95% binding ability with respect to C(8)HSL. PMID- 22209417 TI - Cytotoxic potential of novel 6,7-dimethoxyquinazolines. AB - Herein, we report the synthesis and cytotoxicity of a series of substituted 6,7 dimethoxyquinazoline derivatives. The cytotoxic activity of all synthesized compounds has been evaluated against HCT116p53(+/+) and HCT116p53(-/-) colon cancer cells and a HEY ovarian cancer cell line naturally resistant to cisplatin. Nine of the tested compounds showed significant cytotoxicity in all cell lines at 10MUM. The most promising derivative (7c) showed IC(50)values of 0.7 and 1.7MUM in the two colon cancer cell lines. PMID- 22209418 TI - A small chemical library of 2-aminoimidazole derivatives as BACE-1 inhibitors: Structure-based design, synthesis, and biological evaluation. AB - In this work, we report a rational structure-based approach aimed at the discovery of new 2-aminoimidazoles as beta-secretase inhibitors. Taking advantage of a microwave-assisted synthetic protocol, a small library of derivatives was obtained and biologically evaluated. Two compounds showed promising activities in both enzymatic and cellular assays. Moreover, one of them exhibited the capability to cross the blood-brain barrier as assessed by the parallel artificial membrane permeability assay. PMID- 22209419 TI - Ultrasound measurements on acromio-humeral distance and supraspinatus tendon thickness: test-retest reliability and correlations with shoulder rotational strengths. AB - OBJECTIVES: To establish the test-retest reliability of ultrasound measurements on acromio-humeral distance (AHD) and supraspinatus tendon thickness; and to explore their relationships with shoulder rotational strengths. DESIGN: Test retest observational study. METHODS: Thirty-seven individuals (age: 21.5+/-1.4 years) participated in this study. Twenty-four were University volleyball players with 15 healthy and 9 players with shoulder impingement syndrome (SIS). Thirteen participants were healthy untrained individuals. Ultrasound measurements of AHD and supraspinatus tendon thickness were taken, and isokinetic testing of concentric shoulder internal rotation (IR) and external rotation (ER) at a speed of 90 degrees /s was performed. RESULTS: The measurement of the AHD and the supraspinatus tendon thickness indicated excellent reliability (ICC=0.922, and ICC=0.933 respectively), and the minimum detectable difference (MDD) were 2.10mm and 0.64 mm respectively. A cut-off AHD distance of 23.9 mm had a sensitivity of 0.67 and specificity of 0.71 (area under curve (AUC): 0.70; p=0.05) in identifying individuals with and without SIS. Hence, individuals with AHD larger than 23.9 mm had greater possibility of having SIS. Positive correlations were found in AHD with supraspinatus tendon thickness (r=0.36, p<0.05) and shoulder external rotational strengths (r=0.47-0.62, all p<0.05) and ER/IR ratios (r=0.56 0.58, all p<0.05). CONCLUSIONS: Ultrasound measurements of AHD and tendon thickness have excellent reliability. The reported cut-off AHD highlighted the potential role of ultrasound measurements in volleyball players for early identification of SIS. The AHD was related to the supraspinatus tendon thickness and shoulder external rotation strengths. Our findings provide a scientific basis for muscle training in overhead athletes such as volleyball players. PMID- 22209420 TI - Symptoms at presentation in children with sleep-related disorders. AB - OBJECTIVE: To assess the link between sleep-disordered breathing and cognitive function in children. To identify correlations among polysomnography, upper respiratory infections, or cephalometric as well as rhinometric measures. METHODS: This study is based on a questionnaire survey of snoring in a population cohort of 2100 children. Altogether, 44 snorers and 51 non-snorers participated in this community based clinical study. All children underwent polysomnography, cephalometry and rhinometric measurements. In addition, a standardized test of intelligence (WPPSI-R), a neuropsychological test battery (NEPSY) and a parental questionnaire on behavioral symptoms (CBCL) were administered. RESULTS: Frequently snoring children scored lower in Language functions (Comprehension of Instructions, P=0.01; Speeded naming, P=0.007) and had more internalizing problems, P=0.04 than did the non-snoring group. However, the polysomnography parameters of these snoring children revealed no major sleep-related breathing disorder. OAHI, mean lowest SpO(2) and respiratory effort correlated with Auditory Attention (P<0.05), Body Part Naming (P<0.05) and Memory (P<0.05). Tonsillar size correlated with OAHI (P<0.01) and respiratory effort (P=0.01) and respiratory airflow (P<0.01). In cephalometry, the minimal distance from velum to posterior wall was shorter showing the shorter length among snorers than non snorers, 5.5mm vs. 6.6mm, respectively (P<0.05). Recurrent upper respirataory infections (URIs) were common among the snoring than non-snoring children (P=0.01). Children suffering recurrent URIs have more somatic complaints than children without recurrent URIs (P<0.01). CONCLUSIONS: Snoring children with apparently normal and/or no obstructive apnea, hypopnea, or marked SpO(2) desaturations appear to suffer impairment in neurocognitive and behavioral functions compared to non-snoring children. These snoring children did not reveal any major abnormalities of polysomnographic parameters, such as sleep-related breathing disorder, including partial upper airway obstruction. Polysomnographic parameters also correlated poorly with neurocognitive test results in these snoring children. The correlations between polysomnography and upper respiratory infections, with cephalometric and rhinometric measures, were also poor. PMID- 22209421 TI - HFE C282Y homozygosity is associated with an increased risk of total hip replacement for osteoarthritis. AB - OBJECTIVE: The evidence for an association between mutations in the HFE (hemochromatosis) gene and the risk of hip or knee osteoarthritis is inconsistent. Total joint replacement is considered a surrogate measure for symptomatic end-stage osteoarthritis. We examined the relationship between HFE gene mutations and risk of total hip and knee replacement using a prospective cohort study. METHODS: The Melbourne Collaborative Cohort Study recruited participants between 1990 and 1994. Participants born in Australia, New Zealand, the United Kingdom, or Ireland (n = 27,848) were genotyped for the HFE C282Y mutation. Total hip and knee replacements for osteoarthritis during 2001 to 2009 were ascertained from the Australian Orthopaedic Association National Joint Replacement Registry. Hazard ratios (HR)/odds ratios (OR) and confidence intervals (CI) were obtained from Cox regression or logistic regression. RESULTS: Compared with those with no C282Y mutation, C282Y homozygotes had an increased risk of single total hip replacement (HR 1.94, 95% CI 1.04-3.62) and bilateral total hip replacement (OR 5.86, 95% CI 2.36-14.57) for osteoarthritis, adjusting for age, sex, body mass index, and educational level. Only 3 C282Y homozygotes had single total knee replacement; the HR was 0.51 (95% CI 0.16-1.57). C282Y/H63D compound heterozygosity was not related to the risk of total hip or knee replacement. CONCLUSIONS: HFE C282Y homozygosity was associated with an increased risk of both single and bilateral total hip replacement for osteoarthritis. PMID- 22209422 TI - Economic outcome of cardiac CT-based evaluation and standard of care for suspected acute coronary syndrome in the emergency department: a decision analytic model. AB - RATIONALE AND OBJECTIVES: Cardiac computed tomography (CCT) in the emergency department may be cost saving for suspected acute coronary syndrome (ACS), but economic outcome data are limited. The objective of this study was to compare the cost of CCT-based evaluation versus standard of care (SOC) using the results of a clinical trial. MATERIALS AND METHODS: We developed a decision analytic cost minimization model to compare CCT-based and SOC evaluation costs to obtain a correct diagnosis. Model inputs, including Medicare-adjusted patient costs, were primarily obtained from a cohort study of 102 patients at low to intermediate risk for ACS who underwent an emergency department SOC clinical evaluation and a 64-channel CCT. SOC costs included stress testing in 77% of patients. Data from published literature completed the model inputs and expanded data ranges for sensitivity analyses. RESULTS: Modeled mean patient costs for CCT-based evaluation were $750 (24%) lower than the SOC ($2384 and $3134, respectively). Sensitivity analyses indicated that CCT was less expensive over a wide range of estimates and was only more expensive with a CCT specificity below 67% or if more than 44% of very low risk patients had CCT. Probabilistic sensitivity analysis suggested that CCT-based evaluation had a 98.9% probability of being less expensive compared to SOC. CONCLUSION: Using a decision analytic model, CCT-based evaluation resulted in overall lower cost than the SOC for possible ACS patients over a wide range of cost and outcome assumptions, including computed tomography related complications and downstream costs. PMID- 22209423 TI - Similar alteration of motor unit recruitment strategies during the anticipation and experience of pain. AB - A motor unit consists of a motoneurone and the multiple muscle fibres that it innervates, and forms the final neural pathway that influences movement. Discharge of motor units is altered (decreased discharge rate and/or cessation of firing; and increased discharge rate and/or recruitment of new units) during matched-force contractions with pain. This is thought to be mediated by nociceptive (pain) input on motoneurones, as demonstrated in animal studies. It is also possible that motoneurone excitability is altered by pain related descending inputs, that these changes persist after noxious stimuli cease, and that direct nociceptive input is not necessary to induce pain related changes in movement. We aimed to determine whether anticipation of pain (descending pain related inputs without nociceptor discharge) alters motor unit discharge, and to observe motor unit discharge recovery after pain has ceased. Motor unit discharge was recorded with fine-wire electrodes in the quadriceps of 9 volunteers. Subjects matched isometric knee-extension force during anticipation of pain (anticipation: electrical shocks randomly applied over the infrapatellar fat pad); pain (hypertonic saline injected into the fat-pad); and 3 intervening control conditions. Discharge rate of motor units decreased during pain (P<.001) and anticipation (P<.01) compared with control contractions. De-recruitment of 1 population of units and new recruitment of another population were observed during both anticipation and pain; some changes in motor unit recruitment persisted after pain ceased. This challenges the fundamental theory that pain related changes in muscle activity result from direct nociceptor discharge, and provides a mechanism that may underlie long-term changes in movement/chronicity in some musculoskeletal conditions. PMID- 22209424 TI - The participation of sialic acids in microglia-neuron interactions. AB - Since it is known that sialic acid participates in neuronal plasticity, it is resonable to investigate its role in microglia-neuron interactions. In this study, we tested the effects of enzymatic removal of sialic acid on neurite and cell body density in microglia-neuron co-cultures. Additionaly, we analyzed the expression of Siglec-F protein, putative receptor for sialic acids, in microglial cells as well as its affinity to neurons. The results showed that removal of sialic acids affects neuronal integrity and changes microglial morphology. In presence of microglial cells, endoneuraminidase and alpha-neuraminidase significantly reduced neurite density (p<0.05). Endoneuraminidase (p<0.05) and alpha-neuraminidase (p>0.05) decreased the number of neuronal cell bodies in comparison to control co-cultures. Neuraminidases-treated neurons showed reduced binding of Siglec-F protein, which we found in microglial cells. Our results suggest that interactions between sialic acids and Siglec receptors may protect neuronal integrity during neurodegenerative processes. PMID- 22209425 TI - A genomic survey shows that the haloarchaeal type tyrosyl tRNA synthetase is not a synapomorphy of opisthokonts. AB - The haloarchaeal-type tyrosyl tRNA synthetase (tyrRS) have previously been proposed to be a molecular synapomorphy of the opisthokonts. To re-evaluate this we have performed a taxon-wide genomic survey of tyrRS in eukaryotes and prokaryotes. Our phylogenetic trees group eukaryotes with archaea, with all opisthokonts sharing the haloarchaeal-type tyrRS. However, this type of tyrRS is not exclusive to opisthokonts, since it also encoded by two amoebozoans. Whether this is a consequence of lateral gene transfer or lineage sorting remains unsolved, but in any case haloarchaeal-type tyrRS is not a synapomorphy of opisthokonts. This demonstrates that molecular markers should be re-evaluated once a better taxon sampling becomes available. PMID- 22209426 TI - Maintaining integrity in the face of death: a grounded theory to explain the perspectives of people affected by lung cancer about the expression of wishes for end of life care. AB - BACKGROUND: An emphasis on patient choice in health and social care underpins a growing interest in advance care planning. Few studies have explored the views and experiences of people with advanced lung cancer about discussing their wishes or preferences for end of life care. Evidence suggests that some people may want nurses and other health professionals to initiate discussions about the future. However, there is a lack of evidence about what priority patients facing death give to their preferences and wishes, and how these shape their views about end of life. OBJECTIVES: To explore the views and experiences of people affected by lung cancer about discussing preferences and wishes for end of life care and treatment. DESIGN: A qualitative study using semi-structured interviews and constant comparative method of analysis to develop a grounded theory. SETTINGS: One multi-cultural city and one post-industrial town in northern England, UK. Data were collected between 2006 and 2008. PARTICIPANTS: Interviews took place with 25 patients with lung cancer and 19 family members. METHOD: Qualitative constructivist grounded theory study. RESULTS: The study found that preferences and wishes for future care and treatment were not the main concern of people with cancer; rather, any concerns for the future were about the social aspects of death. A theory 'maintaining integrity in the face of death' is proposed. This theory purports that patients with advanced lung cancer and their families focus on acting and talking as 'normal' to help them balance living in the present whilst facing death. Participants talked about their experiences of facing death whilst striving to live in the present. Planning for one's own dying and eventual death was not something that people with lung cancer reported having discussed, except when, out of concern for their families, practical arrangements needed to be made following death. CONCLUSION: The study suggests that people facing the end of their life primarily focus on living in the present. The findings suggest that nurses need to develop ways of helping people prepare for the 'social' rather than just the physical or 'medicalised' aspects of death. PMID- 22209427 TI - Children born small for gestational age are not at special risk for preschool emotion and behaviour problems. AB - Despite the wealth of literature examining long term outcomes of preterm low birthweight children, few studies have directly assessed the developmental impact of being born full term but small for gestational age (SGA). We aim to determine whether (i) being SGA increases preschool behavioural problems and (ii) other risk factors operate differently in SGA and appropriate for gestational age (AGA) controls. 550 New Zealand European mothers and their 3.5 year old children participated in this study. All children were born at full term (>37 weeks' gestation) and approximately half were SGA (<=sex specific 10th percentile for gestation) the remainder were AGA controls. Extensive data were collected at the child's birth, 1 year and 3.5 years. Behavioural problems were measured when children were 3.5 years, using the Strengths and Difficulties Questionnaire (SDQ). Multiple regression analyses were used to examine the associations between risk factors and behavioural problems; statistical weighting was used for analyses of the total study group. There was no significant difference in behavioural problems between SGA and AGA groups. In the total sample the significant predictors of behavioural problems included: mothers' school leaving age; smoking during pregnancy; maternal alcohol use during pregnancy; and absence of the father. Predictors of behavioural problems were found to be the same for SGA and AGA groups. These results do not support the view that SGA is a risk for behavioural preschool difficulties or that SGA children are sensitised to risks known to be associated with such difficulties in the preschool years. PMID- 22209428 TI - MRI-findings of nodular lesions in an enlarged spleen, associated with visceral Leishmaniasis. AB - We present a case of a 15-month-old Moroccan girl with fever of unknown origin, hepatosplenomegaly and multiple hypoechoic nodular splenic lesions that appear hypodense on CT. T2-weighted MRI sequences show a markedly inhomogeneous intensity of the parenchyma, seemingly caused by multiple ill-defined and heterogeneous hypointense nodules. Laboratory tests confirmed a recent infection with Leishmania, a parasite endemic to (sub)tropic regions. During and after therapy these lesions gradually resolved. To our knowledge this is the second published case in which different imaging modalities were able to demonstrate organ lesions associated with Leishmania. It is also the first report of MRI findings associated with these lesions. PMID- 22209429 TI - Imaging in bone sarcomas. The chemotherapist's point of view. AB - The role of imaging in planning oncologic treatment and follow-up of patients with bone sarcomas is discussed in the present article. Tumor staging and radiographic assessment of response to chemotherapy in bone sarcomas may be of difficult interpretation. In particular, the use of the criterion of tumor shrinkage to measure response to chemotherapy is not always applicable in bone tumors where higher calcification rather than reduction in size is frequently observed. New techniques such as (18)F-FDG PET/CT, dynamic contrast-enhanced computed tomography or magnetic resonance are now available allowing a more accurate staging of patients and adding information for the evaluation of tumor response. Innovative approaches aiming to evaluate vascular and metabolic response rather than mono- or bi-dimensional changes may be more informative and require further investigations. PMID- 22209430 TI - Imaging of bone tumors for the musculoskeletal oncologic surgeon. AB - The appropriate diagnosis and treatment of bone tumors requires close collaboration between different medical specialists. Imaging plays a key role throughout the process. Radiographic detection of a bone tumor is usually not challenging. Accurate diagnosis is often possible from physical examination, history, and standard radiographs. The location of the lesion in the bone and the skeleton, its size and margins, the presence and type of periosteal reaction, and any mineralization all help determine diagnosis. Other imaging modalities contribute to the formation of a diagnosis but are more critical for staging, evaluation of response to treatment, surgical planning, and follow-up.When necessary, biopsy is often radioguided, and should be performed in consultation with the surgeon performing the definitive operative procedure. CT is optimal for characterization of the bone involvement and for evaluation of pulmonary metastases. MRI is highly accurate in determining the intraosseous extent of tumor and for assessing soft tissue, joint, and vascular involvement. FDG-PET imaging is becoming increasingly useful for the staging of tumors, assessing response to neoadjuvant treatment, and detecting relapses.Refinement of these and other imaging modalities and the development of new technologies such as image fusion for computer-navigated bone tumor surgery will help surgeons produce a detailed and reliable preoperative plan, especially in challenging sites such as the pelvis and spine. PMID- 22209431 TI - Can the localization of primary colonic tumors be improved by staging CT without specific bowel preparation compared to optical colonoscopy? AB - OBJECTIVES: To investigate the ability of staging computed tomography (CT) without bowel preparation to accurately localize colonic tumors compared to optical colonoscopy. METHODS: The local institutional review board approved this retrospective and HIPAA-compliant study. Forty-six patients with colonic adenocarcinoma, preoperative colonoscopy, and staging CT within 60 days of resection were included. Patients underwent contrast enhanced CT imaging without bowel preparation or oral contrast. The colon was divided into four segments with the operative reports used as the standard. Rectal and cecal cancers were excluded. CT scans were reviewed by 5 readers in a segmental binary fashion using a 5-point confidence scale in two sessions blinded and unblinded to the colonoscopy report. RESULTS: At surgery 49 tumors were found in 46 patients. Readers detected 86.1%, 74.3%, and 66.9% of lesions with 92.0%, 94.1%, and 95.4% accuracy for confidence scores of >= 3, >= 4, and 5. CT interobserver agreement was good (kappa=0.82) for the unblinded and moderate (kappa=0.60) for the blinded read. Colonoscopic localization was only 78.7% accurate with 2 tumors undiscovered. Colonoscopic accuracy was low in the descending colon (57.1%) and the transverse colon (55.6%). CONCLUSIONS: Preoperative staging CT is more accurate than colonoscopy in the localization of colonic tumors. PMID- 22209432 TI - "Hot cross bun" sign in multiple system atrophy with predominant cerebellar ataxia: a comparison between proton density-weighted imaging and T2-weighted imaging. AB - OBJECTIVE: To investigate whether proton density-weighted imaging can detect the "hot cross bun" sign in the pons in multiple system atrophy with predominant cerebellar ataxia significantly better than T2-weighted imaging at 3T. METHODS: Sixteen consecutive patients with multiple system atrophy with predominant cerebellar ataxia according to the Consensus Criteria were reviewed. Axial unenhanced proton density-weighted imaging and T2-weighted imaging were obtained using a dual-echo fast spin-echo sequence at 3T. Two neuroradiologists independently evaluated visualisation of the abnormal pontine signal using a 4 point visual grade from Grade 0 (no "hot cross bun" sign) to Grade 3 (prominent "hot cross bun" sign on two or more sequential slices). Differences in grade between proton density-weighted imaging and T2-weighted imaging were statistically analysed using the Wilcoxon signed-rank test. RESULTS: In 11 patients (69%), a higher grade was given for proton density-weighted imaging than T2-weighted imaging. In 1 patient (6%), grades were the same (Grade 3) on both images. In the remaining 4 patients (25%), signal abnormalities were not detected on either image (Grade 0). The "hot cross bun" sign was thus observed significantly better on proton density-weighted imaging than on T2-weighted imaging (P=0.001). CONCLUSIONS: The "hot cross bun" sign considered diagnostic for multiple system atrophy with predominant cerebellar ataxia is significantly better visualised on proton density-weighted imaging than on T2-weighted imaging at 3T. PMID- 22209433 TI - MR imaging versus PET/CT for evaluation of pancreatic lesions. AB - PURPOSE: To retrospectively determine the diagnostic accuracy of magnetic resonance imaging (MRI) and combined positron emission tomography/computed tomography (PET/CT) in the differential diagnosis of benign and malignant pancreatic lesions. MATERIALS AND METHODS: Twenty-seven patients (15 women/12 men, mean age 56.5 years) with MR imaging and PET/CT studies performed to differentiate benign and malignant pancreatic lesions were identified between October 2008 and October 2010. Both MR and PET/CT data sets were retrospectively and blindly evaluated by two independent readers (4 readers total) with different degrees of experience, using a visual five-point score system. The results were correlated with final diagnosis obtained by histopathology. RESULTS: 17 patients had malignant diseases and 10 patients had benign diseases. Depending on the observer, the sensitivity, specificity, positive predictive value and negative predictive value of MRI varied between 88-94%, 50-80%, 75-89% and 71-89% respectively. Sensitivities, specificities, positive predictive values and negative predictive values of PET/CT were 73%, 56%, 73% and 56% respectively. The diagnostic accuracy of MR for the differential diagnosis of pancreatic lesions was 74-89%, compared with 67% for PET/CT. The weighted Cohen's kappa coefficient was 0.47 at MR and 0.53 at PET/CT. CONCLUSION: MRI achieved higher sensitivity and specificity in the differential diagnosis of pancreatic lesions. PMID- 22209434 TI - Perfusion CT in childhood stroke--initial observations and review of the literature. AB - INTRODUCTION: To report the preliminary results of contrast-enhanced perfusion multi-detector CT for diagnoses of perfusion disturbances in children with clinical suspicion of stroke. PATIENTS AND METHODS: Within the last two years emergency perfusion CT was performed in ten children (age: 8-17 years, male:female=3:7) for assessment of suspected childhood stroke. These intracranial perfusion CT, intracranial CT-digital subtraction angiography (CT-DSA) and extracranial CT-angiography (CTA) studies were retrospectively reviewed and compared with MRI, follow-up CT, catheter angiography and final clinical diagnosis. The total dose length product (DLP) for the entire examination was recorded. The image quality of perfusion CT-maps, CT-DSA and CTA were evaluated with a subjective three-point scale ranging from very good to non-diagnostic image quality rating perfusion disturbance, intracranial peripheral vessel depiction, and motion- or streak artifacts. RESULTS: In nine of ten children perfusion CT showed no false positive or false negative results. In one of ten children suffering from migraine focal hypo-perfusion was read as perfusion impairment potentially indicating early stroke, but MRI and MRA follow-up were negative. Overall, perfusion-CT with CT-DSA was rated very good in 80% of cases for the detection of perfusion disturbances and vessel anatomy. CONCLUSIONS: In comparison to standard CT, contrast-enhanced perfusion CT improves CTs' diagnostic capability in the emergency examination of children with a strong suspicion of ischemic cerebral infarction. PMID- 22209435 TI - Succinic acid production and CO2 fixation using a metabolically engineered Escherichia coli in a bioreactor equipped with a self-inducing agitator. AB - A 5-L bioreactor equipped with a self-induction agitator was applied to a two stage culture of Escherichia coli NZN111 for succinic acid production in a mineral salts medium. CO(2) was cycled inside this reactor and a sufficient CO(2) transfer rate was maintained with the elimination of CO(2) wasted by ventilation. In the anaerobic stage, much less supplemental CO(2) was required at pH6.3 compared to that at pH7.0, and the succinate yield increased. The performances of succinate production were little changed when compared to a process with CO(2) sparging indicating that use of the self-inducing agitator reduced CO(2) waste. The succinate production process was further coupled with ethanol fermentation by using the CO(2) produced from ethanol fermentation. This integrated system demonstrated that both succinate and bioethanol can be effectively produced while the emission of the CO(2) formed during ethanol fermentation can be greatly reduced. PMID- 22209436 TI - Optimization and kinetic studies on algal oil extraction from marine macroalgae Ulva lactuca. AB - In this present investigation, kinetic studies on oil extraction were performed in marine macroalgae Ulva lactuca. The algal biomass was characterized by scanning electron microscopy and Fourier Transform-Infra Red Spectroscopy. Six different pre-treatment methods were carried out to evaluate the best method for maximum oil extraction. Optimization of extraction parameters were performed and high oil yield was obtained at 5% moisture content, 0.12 mm particle size, 500 rpm stirrer speed, 55 degrees C temperature, 140 min time and solvent-to-solid ratio as 6:1 with 1% diethyl-ether and 10% methylene chloride in n-hexane solvent mixture. After optimization, 10.88% (g/g) of oil extraction yield was achieved from 30 g of algal biomass. The rate constant was obtained for the first order kinetic study by differential method. The activation energy (Ea) was calculated as 63.031 kJ/mol. From the results obtained in the investigation, U. lactuca biomass was proved to be a suitable source for the biodiesel production. PMID- 22209437 TI - Respirometric evaluation and modelling of acetate utilization in sequencing batch reactor under pulse and continuous feeding. AB - The study investigated the effect of feeding regime and sludge age on acetate utilization. Parallel sequencing batch reactors (SBRs) were operated at steady state with pulse and continuous feeding of acetate at sludge ages of 8 and 2 days. Acetate was always partially converted to poly-beta-hydroxybutyrate (PHB). The adopted model remained equally applicable to oxygen uptake rate and PHB profiles reflecting different feeding regimes and culture history. Sludge age was significant on the rate parameters of storage and direct growth (k(STO), MU(H1)), while the feeding regime affected half saturation coefficients (K(STO), K(S1)). Changing the sludge age from 8 days to 2 days reduced the k(STO) value from 8.0 day(-1) to 6.5 day(-1) and increased the corresponding MU(H1) value from 1.5 day( 1) to 2.5 day(-1), regardless of the feeding regime; conversely, changing from pulse to continuous feeding reduced K(STO) while increasing K(S) for the SBR operation at the same sludge age. PMID- 22209438 TI - Novel anaerobic digestion induced by bacterial components for value-added byproducts from high-loading glycerol. AB - A novel bioprocessing system was developed and tested that involved anaerobic fermentation to degrade high-loading glycerol by a fermentation promoter, and which could be used for the production of important resources. In the absence of a promoter, there was no anaerobic digestion when glycerol (4.0-6.0%, v/v) was added to the reactor. By contrast, glycerol was readily decomposed when sewage sludge, acting as a fermentation promoter, was added to the anaerobic reactor. Fermentation resulted in the generation of hydrogen, 1,3-propanediol (1,3-PDO) and various organic acids. In 7 days, glycerol decomposition reached 88%; hydrogen production was 3.1mg/kg-glycerol (0.0004 g/day/L), and 1,3-PDO yield reached 0.35 kg/kg-glycerol (0.05 g/day/L). Further experiments confirmed that the bacteria Escherichia coli and particularly Schizosaccharomyces pombe (found within sewage sludge) and especially glucose (found within bacterial components (i.e., cell walls)) acted as efficient promoters of fermentation. PMID- 22209439 TI - Biosorptive dehydration of tert-butyl alcohol using a starch-based adsorbent: characterization and thermodynamics. AB - Biosorptive dehydration of tert-butyl alcohol (TBA) using a specially formulated compound starch-based adsorbent was investigated. The net retention time and separation factor of TBA and water were obtained using inverse gas chromatography (IGC), which demonstrated the feasibility of this biosorptive separation process, with low temperature propitious to the process. Through orthogonal experimental design, the optimum adsorption condition was determined from different bed depths, bed temperatures and kettle temperatures. Thermal regeneration experiments showed no change in biosorption capacity after five biosorption/regeneration cycles. Field emission scanning electron microscopy (FESEM) and mercury porosimetry were used to investigate the change in surface morphology and microstructure of the biosorbent before and after adsorption. Finally, the thermodynamic parameters DeltaH(s) and DeltaG(s) were determined, which indicated that the process occurred by physisorption and was spontaneous and exothermic. The results indicated that the biosorbent can be used as an effective low-cost sorbent to dehydrate TBA. PMID- 22209440 TI - Thermogravimetric analyses of combustion of lignocellulosic materials in N2/O2 and CO2/O2 atmospheres. AB - The combustion of paper, fruit waste and plant residue mixtures representing the lignocellulosic materials of municipal solid waste (MSW) in different atmospheres (80N(2)/20O(2), 70N(2)/30O(2), 60N(2)/40O(2), 50N(2)/50O(2), 80CO(2)/20O(2), 70CO(2)/30O(2), 60CO(2)/40O(2), 50CO(2)/50O(2)) was analyzed thermogravimetrically. Replacement of 80% N(2) by 80% CO(2) resulted in a slightly later ignition, a lower maximum weight loss rate and a change in reactions occurring above 600 degrees C; however, as the oxygen concentration increased from 20% to 50% in CO(2)/O(2) atmosphere, the ignition temperature decreased from 318.5 to 310.8 degrees C and the maximum weight loss rate increased from 20.82% to 23.57%/min. An oxygen content of 30% in the CO(2)/O(2) atmosphere achieved a similar combustion performance as a 80N(2)/20O(2). The fruit waste mixture had the least residual weight (about 5%) and the earliest ignition (about 220 degrees C). This work contributes to the comprehensive understanding of lignocellulosic materials combustion and development of MSW oxy fuel combustion. PMID- 22209441 TI - Higher efficiency of CO2 injection into seawater by a venturi than a conventional diffuser system. AB - Mass production of microalgae generally requires the injection of CO(2) into open ponds or photo-bioreactors. The present study compares the CO(2) injection efficiency into seawater of a porous stone air diffuser and a venturi. CO(2) was injected at flow rates of 400, 700 and 1000 standard mL/min and 4, 7 and 10 standard L/min into a small and a large pond, respectively until the pH decreased from 7.8 to 6.8. No significant differences in CO(2) injection efficiency between the three CO(2) flow rates (p>0.05) were observed; however, CO(2) injection efficiency with venturi was about 100% (p<0.05) higher than that of the air diffuser. Therefore, it is possible to both reduce the cost and increase the effectiveness of CO(2) dissolution in seawater by using venturi operated at a lower flow rate, i.e. 400 standard mL/min in a small pond and 4 standard L/min in a large pond. PMID- 22209442 TI - Immobilization of Candida rugosa lipase on hydrophobic/strong cation-exchange functional silica particles for biocatalytic synthesis of phytosterol esters. AB - In this work, mixed-mode silica particles functionalized with octyl and sulfonic acid groups was conveniently prepared by co-bonding a mixture of n octyltriethoxysilane and 3-mercaptopropyltriethoxysilane and then oxidized with hydrogen peroxide. Candida rugosa lipase (CRL) was immobilized on the mixed-mode silica particles via hydrophobic and strong cation-exchange interaction. The resulting immobilized CRL increased remarkably its stability at high temperature in comparison to free CRL. The immobilized CRL was used as biocatalysts for enzymatic esterification of phytosterols with free fatty acids (FFAs) to produce phytosterol esters. The phytosterols linolenate esterification degree of 95.3% was obtained under the optimized condition. Phytosterols esters could also been converted in high yields to the corresponding long-chain acyl esters via transesterification with methyl esters of fatty acids (80.5%) or triacylglycerols (above 95.5%) using mixed-mode silica particles immobilized CRL as biocatalyst. Furthermore, the immobilized CRL by absorption retained 78.6% of their initial activity after 7 recycles. PMID- 22209443 TI - Biomass-based pyrolytic polygeneration system on cotton stalk pyrolysis: influence of temperature. AB - To study the process of biomass-based pyrolytic polygeneration and its mechanism in depth, the pyrolysis of cotton stalk was investigated in a packed bed, with focus on the evolution of the chemical and physical structures of the solid, liquid and gaseous products. The evolution of product characteristics could be good explaining the process mechanism of biomass pyrolysis. A relationship between the pore distribution of solid products and the fused aromatic rings system revealed by Raman analysis might be exist and need to quantify in further study. Regarding the optimum conditions for obtaining high-quality pyrolytic products from the polygeneration system, the optimum temperature is 550-750 degrees C, with a higher calorific value of the obtained charcoal (~ 28 MJ/kg) and a higher surface area (>200 m(2)/g). Meanwhile, the calorific value of the gas reaches 8-9 MJ/m(3) and the liquid oil would be used as a platform product in biorefinery. PMID- 22209444 TI - The complete enzymatic saccharification of agarose and its application to simultaneous saccharification and fermentation of agarose for ethanol production. AB - A sugar platform equipped with acetic acid, multiple agarases and neoagarobiose hydrolase (NABH) converted recalcitrant agar polysaccharide into monosugars, which was evaluated by simultaneous saccharification and fermentation (SSF). The sugar platform was divided into chemical liquefaction and enzymatic saccharification. The chemical liquefaction was carried out in mild conditions (using a dilute acetic acid at 80 degrees C for 1-6h) to avoid the production of fermentation inhibitors and hence the highest degree of liquefaction of 95.6% (w/w) was obtained. We mimicked the natural agarolytic pathway using three microbial agarases (Aga16B, Aga50D and DagA) and NABH, and the enzyme system converted 79.1% of agarose to monosugars. The chemical liquefaction and SSF of 30 g/l agarose resulted in 4.4 g/l ethanol concentration and 49.3% of the theoretical ethanol yield to d-galactose. This is the first report on the complete enzymatic conversion of agarose into its monosugars and the SSF of agarose into ethanol. PMID- 22209445 TI - Fate and cometabolic degradation of benzo[a]pyrene by white-rot fungus Armillaria sp. F022. AB - Armillaria sp. F022, a white-rot fungus isolated from a tropical rain forest in Samarinda, Indonesia, was used to biodegrade benzo[a]pyrene (BaP). Transformation of BaP, a 5-ring polycyclic aromatic hydrocarbon (PAH), by Armillaria sp. F022, which uses BaP as a source of carbon and energy, was investigated. However, biodegradation of BaP has been limited because of its bioavailability and toxicity. Five cosubstrates were selected as cometabolic carbon and energy sources. The results showed that Armillaria sp. F022 used BaP with and without cosubstrates. A 2.5-fold increase in degradation efficiency was achieved after addition of glucose. Meanwhile, the use of glucose as a cosubstrate could significantly stimulate laccase production compared with other cosubstrates and not using any cosubstrate. The metabolic pathway was elucidated by identifying metabolites, conducting biotransformation studies, and monitoring enzyme activities in cell-free extracts. The degradation mechanism was determined through the identification of several metabolites: benzo[a]pyrene-1,6-quinone, 1 hydroxy-2-benzoic acid, and benzoic acid. PMID- 22209446 TI - Treatment outcomes and prognostic features in adenoid cystic carcinoma originated from the head and neck. AB - Surgery is the main treatment modality for adenoid cystic carcinoma (ACC) originated from the head and neck. However, the extensive local infiltrative and perineural spread related to this malignancy often cause difficulty to achieve high tumor control. The aim of this study is to evaluate the efficacy of postoperative radiotherapy (RT) in ACC, and to identify prognostic variables associated with treatment outcomes. A retrospective review of 101 patients diagnosed with ACC in the head and neck region was performed. T stage distribution was T1, 25; T2, 35; T3, 18; and T4, 23 patients. All patients were grouped into two arms: surgery alone or combined with postoperative radiotherapy. The 5-year local-regional control (LRC), overall survival (OS) and disease-free survival (DFS) rates for all the patients were 70.5%, 91.7% and 63.2%, respectively. On univariant analysis, postoperative radiotherapy did improve the 5-year LRC and DFS compared to surgery alone (81.0% vs. 53.4%, p=0.0003 and 71.3% vs. 50.0%, p=0.0052, respectively). And patients with T1-T2 lesions achieved better treatment outcomes, whereas stage T3-T4 was associated with high local failure and poor disease-free survival. Furthermore, multivariate analysis revealed that the addition of radiotherapy and early lesions were both favorite predictors for local control and survival rates. The prognosis for ACC of the head and neck was excellent. Surgery combined with postoperative radiotherapy significantly reduced the local failure, and further improved disease-free survival. Nevertheless, the relatively high distant metastasis was an obstacle of curing the ACC patients. PMID- 22209447 TI - Treatment of alveolar cleft with distraction osteogenesis using anchorage with a tooth-microimplant joint in a dog model. AB - Our aim was to investigate the efficacy of correction of an alveolar cleft with distraction osteogenesis using anchorage with a tooth-microimplant joint in a canine model, which was established in 12 adult mongrel dogs that were subsequently randomised into two groups (n=6 in each). The first group comprised dogs that had osteogenesis using anchorage with a tooth (tooth group), while in the second, anchorage with tooth-microimplant joint (microimplant group) was used. All animals were killed one month after completion of distraction. Samples were collected for gross observation and histological examination. There was a significant difference in the degree of movement of the anchorage teeth in the transport discs between the 2 groups (p<0.01). There was less prominent inclination and shift of the natural teeth in the transport disc and less bony resorption around the root in the microimplant group than in the tooth group. These changes were less remarkable in the microimplant group. Treatment of alveolar cleft by distraction osteogenesis using anchorage with a tooth microimplant joint is practical, and yields better results. PMID- 22209448 TI - Recent advances in reconstructive oral and maxillofacial surgery. AB - Reconstruction within the head and neck is challenging. Defects can be anatomically complex and may already be compromised by scarring, inflammation, and infection. Tissue grafts and vascularised flaps (either pedicled or free) bring healthy tissue to a compromised wound for optimal healing and are the current gold standard for the repair of such defects, but disadvantages are their limited availability, the difficulty of shaping the flap to fit the defect and, most importantly, donor site morbidity. The importance of function and aesthetics has driven advances in the accuracy of surgical techniques. We discuss current advances in reconstruction within oral and maxillofacial surgery. Developments in navigation, three-dimensional imaging, stereolithographic models, and the use of custom-made implants can aid and improve the accuracy of existing reconstructive methods. Robotic surgery, which does not modify existing techniques of reconstruction, allows access, resection of tumours, and reconstruction with conventional free flap techniques in the oropharynx without the need for mandibulotomy. Tissue engineering and distraction osteogenesis avoid the need for autologous tissue transfer and can therefore be seen as more conservative methods of reconstruction. Recently, facial allotransplantation has allowed whole anatomical facial units to be replaced with the possibility of sensory recovery and reanimation being completed in a single procedure. However, patients who have facial allotransplants are subject to life-long immunosuppression so this method of reconstruction should be limited to selected cases. PMID- 22209449 TI - Improved fitness as a measure of success of cardiac rehabilitation: do those who get fitter live longer? PMID- 22209450 TI - Platelet oxidative stress and thrombosis. AB - Experimental and clinical studies support the pivotal role played by reactive oxidant species in the mechanism of platelet activation. This effect is achieved via multiple pathways, including enhanced formation of isoprostanes. Platelet NADPH oxidase seems to be the main source of platelet reactive oxidant species and isoprostanes. Pharmacologic approach that reduces platelet isoprostane formation may represent a future target of antiplatelet drugs. At this regard polyphenols would be of potential interest in virtue of their antioxidant property but interventional trials are necessary to see if they actually inhibit platelet aggregation in vivo and eventually prevent atherosclerotic progression. PMID- 22209452 TI - A new synthesis route for Os-complex modified redox polymers for potential biofuel cell applications. AB - A new synthesis route for Os-complex modified redox polymers was developed. Instead of ligand exchange reactions for coordinative binding of suitable precursor Os-complexes at the polymer, Os-complexes already exhibiting the final ligand shell containing a suitable functional group were bound to the polymer via an epoxide opening reaction. By separation of the polymer synthesis from the ligand exchange reaction at the Os-complex, the modification of the same polymer backbone with different Os-complexes or the binding of the same Os-complex to a number of different polymer backbones becomes feasible. In addition, the Os complex can be purified and characterized prior to its binding to the polymer. In order to further understand and optimize suitable enzyme/redox polymer systems concerning their potential application in biosensors or biofuel cells, a series of redox polymers was synthesized and used as immobilization matrix for Trametes hirsuta laccase. The properties of the obtained biofuel cell cathodes were compared with similar biocatalytic interfaces derived from redox polymers obtained via ligand exchange reaction of the parent Os-complex with a ligand integrated into the polymer backbone during the polymer synthesis. PMID- 22209453 TI - Human sulfite oxidase electrochemistry on gold nanoparticles modified electrode. AB - The present study reports a facile approach for sulfite biosensing, based on enhanced direct electron transfer of a human sulfite oxidase (hSO) immobilized on a gold nanoparticles modified electrode. The spherical core shell AuNPs were prepared via a new method by reduction of HAuCl(4) with branched poly(ethyleneimine) in an ionic liquids resulting particles with a diameter less than 10nm. These nanoparticles were covalently attached to a mercaptoundecanoic acid modified Au-electrode where then hSO was adsorbed and an enhanced interfacial electron transfer and electrocatalysis was achieved. UV/Vis and resonance Raman spectroscopy, in combination with direct protein voltammetry, are employed for the characterization of the system and reveal no perturbation of the structural integrity of the redox protein. The proposed biosensor exhibited a quick steady-state current response, within 2 s, a linear detection range between 0.5 and 5.4 MUM with a high sensitivity (1.85 nA MUM(-1)). The investigated system provides remarkable advantages in the possibility to work at low applied potential and at very high ionic strength. Therefore these properties could make the proposed system useful in the development of bioelectronic devices and its application in real samples. PMID- 22209454 TI - A comparison of physical activity (PA) assessment tools across levels of frailty. AB - PURPOSE: Determine which PA assessment tools are most closely related to frailty and whether PA is different across levels of frailty. METHODS: Fifty community dwelling Greek older women (63-90 years) participated in this study. PA was measured objectively over 10h using an accelerometer, a heart rate (HR) monitor, a portable electromyography (EMG) unit, and a global positioning system (GPS) and subjectively using the short version of the Minnesota Leisure Time Activity Questionnaire (MLTAQ). Participants were divided into three tertiles based on level of frailty as calculated from a Frailty Index (FI): low FI group (<0.17 FI); intermediate FI group (0.17-0.38 FI); and high FI group (>0.38 FI). RESULTS: Accelerometer step counts had the strongest correlation with frailty and were different across levels of frailty. The percentage of time engaged in PA was 31+/ 15% when PA was determined using an accelerometer. Forty-five percent of the variability in the FI was explained by a combination of PA assessment tools including; accelerometer, EMG, GPS, and MLTAQ. The individual contribution of EMG determined activity from the biceps brachii (BB) to the FI prediction was 16%. Accelerometer contributed an additional 10% and time engaged in PA, as assessed with the MLTAQ, added an additional 6% to the prediction of FI score. CONCLUSIONS: PA assessment tools, when used in combination, provide important information about the PA accumulation of older women across levels of frailty. PMID- 22209455 TI - A DNA aptamer sensor for 8-oxo-7,8-dihydroguanine. AB - Abasic site-containing DNA duplex is a versatile structural motif that can be used for the design of purine aptamers and sensors. In this study, several modifications were introduced to the abasic site to explore possible specific binding of free 8-oxoG, a product of DNA base excision repair. The nucleoside opposite the abasic site was replaced by pyrrolo-dC as a reporter group. Binding of 8-oxoG quenched pyrrolo-dC fluorescence by as much as 70%. In contrast, adenine, guanine, thymine, and cytosine showed only minimal fluorescence quenching effect. The best aptamer binds 8-oxoG with a dissociation constant of 5.5+/-0.8MUM. This sensor can be used to accurately measure 8-oxoG concentrations in the presence of guanine. PMID- 22209456 TI - Dithiocarbamates are strong inhibitors of the beta-class fungal carbonic anhydrases from Cryptococcus neoformans, Candida albicans and Candida glabrata. AB - A series of N-mono- and N,N-disubstituted dithiocarbamates have been investigated as inhibitors of three beta-carbonic anhydrases (CAs, EC 4.2.1.1) from the fungal pathogens Cryptococcus neoformans, Candida albicans and Candida glabrata, that is, Can2, CaNce103 and CgNce103, respectively. These enzymes were inhibited with efficacies between the subnanomolar to the micromolar range, depending on the substitution pattern at the nitrogen atom from the dithiocarbamate zinc-binding group. This new class of beta-CA inhibitors may have the potential for developing antifungal agents with a diverse mechanism of action compared to the clinically used drugs for which drug resistance was reported, and may also explain the efficacy of dithiocarbamates as agricultural antifungal agents. PMID- 22209457 TI - SAR studies of C2 ethers of 2H-pyrano[2,3-d]pyrimidine-2,4,7(1H,3H)-triones as nicotinic acid receptor (NAR) agonist. AB - Based on in house screening lead compound 1 for the NAR project, SAR studies have been focused on the modification of the C2 ethers of the pyrimidinedione core structure. In this effort, an unpredictable SAR trend was overcome in the alkyl ether and arylalkyl ether series to identify compound 24 with improved in vitro activity compared to nicotinic acid. More consistent and predictable SAR was achieved in the propargyl ether series. Lead compound 41 was identified with good in vitro and in vivo activity in rat, and much improved rat PK profile. PMID- 22209458 TI - Fatty acid amide hydrolase inhibitors. 3: tetra-substituted azetidine ureas with in vivo activity. AB - We describe here our attempts to optimise the human fatty acid amide hydrolase (FAAH) inhibition and physicochemical properties of our previously reported tetrasubstituted azetidine urea FAAH inhibitor, VER-156084. We describe the SAR of a series of analogues and conclude with the demonstration of in vivo dose dependant FAAH inhibition in an anandamide-loading study in rats. PMID- 22209459 TI - Synthesis of 5-benzyl-2-phenylpyrazolo[1,5-a]pyrazin-4,6(5H,7H)-dione derivatives and discovery of an apoptosis inducer for H322 lung cancer cells. AB - A series of substituted 5-benzyl-2-phenylpyrazolo[1,5-a]pyrazin-4,6(5H,7H)-dione derivatives was synthesized by one-step reaction of ethyl 3-phenyl-1H-pyrazole-5 carboxylate derivatives and N-arylalkyl-2-chloroacetamide. Structures of the compounds were determined by IR, (1)H NMR and mass spectroscopy. In addition, a representative single-crystal structure was characterized by using X-ray diffraction analysis. The compound 5j could selectively inhibit the growth of H322 lung cancer cells which contain a mutated p53 gene in a dose-dependent manner through inducing apoptosis of cells. PMID- 22209460 TI - Antioxidative oligostilbenes from Caragana sinica. AB - Two new oligostilbenes, caragasinins A (5) and B (10), and eight known compounds, kobophenol A (1), (+)-alpha-viniferin (2), (+)-ampelopsin F (3), pallidol (4), (+)-isoampelopsin F (6), miyabenol C (7), carasinaurone (8) and caraphenol B (9) were isolated from the ethylacetate-soluble extract of the roots of Caragana sinica. The structures of the isolates were determined on the basis of extensive spectroscopic analysis including 1D, 2D NMR and HRESI-MS. These compounds were assessed for antioxidant activities. Caragasinin A (5), caraphenol B (9), and caragasinin B (10) showed moderate DPPH scavenging activity and lipid peroxidation inhibitory activities with IC(50) values ranging from 34.7+/-1.0 to 89.1+/-2.3MUM. PMID- 22209461 TI - Synthesis and neurite growth evaluation of new analogues of honokiol, a neolignan with potent neurotrophic activity. AB - A versatile synthetic route is reported towards the preparation of new analogues for potent neurotrophic agent biaryl-type lignan honokiol. A focused 24-membered library of derivatives containing five different groups at 5'-position of honokiol has been prepared in fair to good overall yields. Compared to the natural product, or to analogues with a short alkyl chain in this position, these new derivatives have lost most of the neurotrophic activity. PMID- 22209462 TI - Pyrazolopyridine inhibitors of B-Raf(V600E). Part 3: an increase in aqueous solubility via the disruption of crystal packing. AB - A single crystal was obtained of a lead B-Raf(V600E) inhibitor with low aqueous solubility. The X-ray crystal structure revealed hydrogen-bonded head-to-tail dimers formed by the pyrazolopyridine and sulfonamide groups of a pair of molecules. This observation suggested a medicinal chemistry strategy to disrupt crystal packing and reduce the high crystal lattice energy of alternative inhibitors. Both a bulkier group at the interface of the dimer and an out-of plane substituent were required to decrease the compound's melting point and increase aqueous solubility. These substituents were selected based on previously developed structure-activity relationships so as to concurrently maintain good enzymatic and cellular activity against B-Raf(V600E). PMID- 22209463 TI - Protein restriction inhibits gastric cell proliferation during rat postnatal growth in parallel to ghrelin changes. AB - OBJECTIVE: Gastric development depends directly on the proliferation and differentiation of epithelial cells, and these processes are controlled by multiple elements, such as diet, hormones, and growth factors. Protein restriction affects gastrointestinal functions, but its effects on gastric growth are not fully understood. METHODS: The present study evaluated cell proliferation in the gastric epithelia of rats subjected to protein restriction since gestation. Because ghrelin is increasingly expressed from the fetal to the weaning stages and might be part of growth regulation, its distribution in the stomach of rats was investigated at 14, 30, and 50 d old. RESULTS: Although the protein restriction at 8% increased the intake of food and body weight, the body mass was lower (P < 0.05). The stomach and intestine were also smaller but increased proportionately throughout treatment. Cell proliferation was estimated through DNA synthesis and metaphase indices, and lower rates (P < 0.05) were detected at the different ages. The inhibition was concomitant with a larger number of ghrelin-immunolabeled cells at 30 and 50 d postnatally. CONCLUSION: Protein restriction impairs cell proliferation in the gastric epithelium, and a ghrelin upsurge under this condition is parallel to lower gastric and body growth rates. PMID- 22209464 TI - S-Carboxyethylcysteine (a constituent of Acacia seed) negatively affects casein protein utilization by rats. AB - OBJECTIVE: Two rat bioassay experiments are reported. The first investigated the first limiting amino acid in Acacia colei and the second experiment investigated the effect of S-carboxyethylcysteine (CEC; a compound present in acacia seed) on protein use. METHODS: In the first experiment, Wistar rats were fed A. colei seed supplemented with three levels of methionine, cysteine, and tryptophan (0.1%, 0.2%, and 0.4%). In the second experiment, the Wistar rats were fed CEC incorporated casein diets. RESULTS: Supplementation of A. colei with tryptophan had no significant effect on the protein efficiency ratio, cysteine showed the highest protein efficiency ratio value at the 0.4% level, and the protein efficiency ratio increased significantly with the increase in methionine content, making methionine the first limiting amino acid. The methionine-induced growth rate was suppressed by the incorporation of CEC, which also had a negative effect on the plasma amino acid levels. CONCLUSION: The results indicated that methionine is the first limiting amino acid in A. colei and that CEC could affect the seed's protein use. Acacia colei seed can be used effectively as famine food only if it is complemented with other cereals known to be rich in sulfur amino acids. PMID- 22209465 TI - [Giant cell myocarditis of fulminant evolution]. PMID- 22209467 TI - [A spontaneous bilateral deformity of the wrists]. PMID- 22209466 TI - [Circadian rhythm and time variations in out-hospital sudden cardiac arrest]. AB - OBJECTIVES: To analyze the chronobiological and time variations of out- hospital cardiac arrest (OHCA). DESIGN: A retrospective descriptive study was made. PATIENTS: All cases of OHCA of cardiac origin registered over 18 months in the database of the emergency medical service (EMS) of the Autonomous Community of Castilla y Leon (Spain) were evaluated. VARIABLES ANALYZED: Age, sex, recovery of spontaneous circulation (ROSC), first monitored rhythm (amenable / not amenable to defibrillation), alert site [(home, public place, primary care (PC) center], alerting person (family, witness, law enforcement member, PC center staff), alert time (0-8; 8-16; 16-24), emergency team activation time, care time and day of the week. Univariate analysis (chi-squared), variance, and nonparametric tests comparing the variables in three periods of 8 hours. Chronobiological analysis by fast Fourier transform and Cosinor testing. RESULTS: We studied 1286 cases reported between January 2007 and June 2008. Statistically significant differences were observed in terms of younger age, higher incidence in the victim's home, and greater frequency of family-cohabiting persons as witnesses in the period between 0 and 8 hours. Chronobiological analysis found daily rhythm (circadian) with acrophase at 11.16 h (p<0.001) and weekly rhythm (circaseptan) with acrophase on Wednesday (p<0.05). The median alert time-care time interval and emergency team activation time-care time were 11.7 min and 8.0 min, respectively, without differences between periods. CONCLUSIONS: We have demonstrated the presence of a daily rhythm of emergence of OHCA with a morning peak and a weekly rhythm with a peak on Wednesdays. These results can guide the planning of resources and improvements in response in certain time periods. PMID- 22209468 TI - Antibacterial activities of dendritic amphiphiles against nontuberculous mycobacteria. AB - The anti-mycobacterial activities of nine series of dicarboxyl and tricarboxyl dendritic amphiphiles with one alkyl, two alkyl, and cholestanyl tails against Mycobacterium abscessus, Mycobacterium avium, Mycobacterium chelonae, Mycobacterium marinum and Mycobacterium smegmatis have been measured. The dendritic amphiphiles overcame the limited aqueous solubility of natural long chain fatty acids, alcohols, and amines to enable profiling the susceptibilities of the different mycobacterial species to the physicochemical properties of these amphiphiles. Several dendritic amphiphiles showed strong anti-mycobacterial activity with high critical micelle concentrations and low hemolytic activities thereby offering platforms for the development of antibiotics of higher activity against nontuberculous mycobacteria. PMID- 22209469 TI - Increased Reissner's fiber material in the subcommissural organ and ventricular area in bile duct ligated rats. AB - Hepatic encephalopathy is a common neuropsychiatric complication of acute and chronic liver failure. Whether brain structures with strategic positions in the interface of blood-brain barriers such as the circumventricular organs are involved in hepatic encephalopathy is not yet established. Among the circumventricular organs, the subcommissural organ secretes a glycoprotein known as Reissner's fiber, which condenses and forms an ever-growing thread-like structure into the cerebrospinal fluid. In the present work we describe the Reissner's fiber material within the subcommissural organ and its serotoninergic innervation in an animal model of chronic hepatic encephalopathy following bile duct ligation in experimental rats. The study involved immunohistochemical techniques with antibodies against Reissner's fiber and 5-hydroxytryptamine (5 HT). Four weeks after surgical bile duct ligation, a significant rise of Reissner's fiber immunoreactivity was observed in all subcommissural organ areas compared with controls. Moreover, significant Reissner's fiber immunoreactive materials within the ependyma and inside the parenchyma close to the ventricular borders were also seen in bile duct ligated rats, but not in control rats. Increased Reissner's fiber material in bile duct ligated rats seems to be related to a reduction of 5-HT innervation of the subcommissural organ, the ventricular borders and the nucleus of origin, the dorsal raphe nucleus. Our data describe alterations of the subcommissural organ/Reissner's fiber material and the subcommissural organ 5-HT innervation probably due to a general 5-HT deficit in bile duct ligated rats. PMID- 22209471 TI - Prospects for electron microscopy characterisation of solar cells: opportunities and challenges. AB - Several electron microscopy techniques available for characterising thin-film solar cells are described, including recent advances in instrumentation, such as aberration-correction, monochromators, time-resolved cathodoluminescence and focused ion-beam microscopy. Two generic problems in thin-film solar cell characterisation, namely electrical activity of grain boundaries and 3D morphology of excitionic solar cells, are also discussed from the standpoint of electron microscopy. The opportunities as well as challenges facing application of these techniques to thin-film and excitonic solar cells are highlighted. PMID- 22209470 TI - The role of social support and negative affect in medication adherence for HIV infected men who have sex with men. AB - Combinations of medications that control HIV viral replication are called antiretroviral therapy (ART). Regimens can be complex, so medication adherence is often suboptimal, although high rates of adherence are necessary for ART to be effective. Social support, which has been directly and indirectly associated with better treatment adherence in HIV-infected individuals, influences negative affect, including depression and anxiety. Our study assessed whether current anxious and depressive symptoms mediated the relationship between general social support and recent self-reported medication adherence in HIV-infected men who have sex with men (N= 136; 65% White, 15% Black/African American). Results revealed no direct effect, but an indirect effect of depressive (95% CI [-.011, .0011]) and anxious symptoms (95% CI [-.0097, -.0009]), between social support and medication adherence. Greater levels of social support were associated with lower levels of depression and anxiety, which in turn were associated with lower ART adherence. PMID- 22209472 TI - A Contrast Transfer Function approach for image calculations in standard and aberration-corrected LEEM and PEEM. AB - We introduce an extended Contrast Transfer Function (CTF) approach for the calculation of image formation in low energy electron microscopy (LEEM) and photo electron emission microscopy (PEEM). This approach considers aberrations up to fifth order, appropriate for image formation in state-of-the-art aberration corrected LEEM and PEEM. We derive Scherzer defocus values for both weak and strong phase objects, as well as for pure amplitude objects, in non-aberration corrected and aberration-corrected LEEM. Using the extended CTF formalism, we calculate contrast and resolution of one-dimensional and two-dimensional pure phase, pure amplitude, and mixed phase and amplitude objects. PEEM imaging is treated by adapting this approach to the case of incoherent imaging. Based on these calculations, we show that the ultimate resolution in aberration-corrected LEEM is about 0.5 nm, and in aberration-corrected PEEM about 3.5 nm. The aperture sizes required to achieve these ultimate resolutions are precisely determined with the CTF method. The formalism discussed here is also relevant to imaging with high resolution transmission electron microscopy. PMID- 22209473 TI - Antihyperglycemic, antihyperlipidemic and antioxidant activities of traditional aqueous extract of Zygophyllum album in streptozotocin diabetic mice. AB - OBJECTIVE: The aim of this work was to investigate the antihyperglycemic, antioxidant and antihyperlipidemic effects of the aqueous extract of Zygophyllum album on streptozotocin (STZ)-induced diabetic mice. METHODS: Diabetes was induced in Swiss albino mice by the administration of STZ (45mg/kg b.w.) intraperitoneally. Aqueous extract of Z. album (100 and 300mg/kg b.w.) was administered by oral gavage once a day for a period of 15days. The effect of the extract on blood glucose, lipids, cholesterol levels in plasma, and also on enzymatic and non enzymatic antioxidants of defence systems such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) enzyme activities, and vitamin C, vitamin E and glutathione reductase (GSH) levels in liver and pancreas were studied. RESULTS: Our results showed that Z. album extract reduced the blood glucose, total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels in STZ-diabetic mice. It also significantly abolished the increase in MDA level, and GPx, SOD and CAT activities in both liver and pancreas. The levels of GSH, vitamin C and high density lipoprotein (HDL) were significantly augmented in Z. album treated diabetic mice in comparison with control group. Our findings suggest that Z. album aqueous extract prevented the diabetic induced MDA levels via the enhancement of the tissue GSH and blood vitamin C levels. CONCLUSIONS: These results suggest that Z. album extract exerts the anti-diabetic and antihypercholesterolemic activities through its antioxidant properties. PMID- 22209474 TI - Reliability and validity of scores of a Chinese version of the Frenchay Activities Index. AB - OBJECTIVE: To develop a Chinese version of the Frenchay Activities Index (FAI-C) and evaluate the reliability and validity of its scores. DESIGN: A 2-week test retest study. SETTING: Chinese community in Vancouver, BC, Canada. PARTICIPANTS: Data were collected using a convenience sample of Chinese immigrants living in Vancouver, BC, Canada. Of the 73 participants, data from 66 participants were included in the analysis. The total sample included 2 subsamples: community dwelling (n=32), and assisted-living (n=34). Participants were 65 years or older, lived in Canada for more than 5 years, and were able to read Chinese. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: FAI-C scores. RESULTS: Test retest reliability of the FAI-C scores assessed using an intraclass correlation coefficient was .86 (95% confidence interval [CI], .79-.92) for the total sample, .89 (95% CI, .78-.94) for the community-dwelling subsample, and .71 (95% CI, .50 .85) for the assisted-living subsample. The minimal detectable difference at the 95% CI was 8.64. Correlations between the FAI-C and the Reintegration to Normal Living Index (r=.61, P<.01), Activities-specific Balance Confidence Scale (r=.55, P<.01), and Timed Up & Go test (r=-.68, P<.01) were in the a priori hypothesized direction and magnitude. CONCLUSIONS: The FAI-C scores are reliable and there is support for validity. This tool enables us to measure social participation level in the Chinese-speaking population. PMID- 22209475 TI - Gait training in human spinal cord injury using electromechanical systems: effect of device type and patient characteristics. AB - OBJECTIVE: To report the clinical improvements in spinal cord injury (SCI) patients associated with intensive gait training using electromechanical systems according to patient characteristics. DESIGN: Prospective longitudinal study. SETTING: Inpatient SCI rehabilitation center. PARTICIPANTS: Adults with SCI (n=130). INTERVENTION: Patients received locomotor training with 2 different electromechanical devices, 5 days per week for 8 weeks. MAIN OUTCOME MEASURES: Lower-extremity motor score, Walking Index for Spinal Cord Injury, and 10-meter walking test data were collected at the baseline, midpoint, and end of the program. Patients were stratified according to the American Spinal Injury Association (ASIA) category, time since injury, and injury etiology. A subgroup of traumatic ASIA grade C and D patients were compared with data obtained from the European Multicenter Study about Human Spinal Cord Injury (EM-SCI). RESULTS: One hundred and five patients completed the program. Significant gains in lower limb motor function and gait were observed for both types of electromechanical device systems, to a similar degree. The greatest rate of improvement was shown in the motor incomplete SCI patients, and for patients <6 months postinjury. The positive response associated with training was not affected by injury etiology, age, sex, or lesion level. The trajectory of improvement was significantly enhanced relative to patients receiving the conventional standard of care without electromechanical systems (EM-SCI). CONCLUSIONS: The use of electromechanical systems for intensive gait training in SCI is associated with a marked improvement in lower-limb motor function and gait across a diverse range of patients and is most evident in motor incomplete patients, and for patients who begin the regimen early in the recovery process. PMID- 22209476 TI - Differences in examination characteristics of pigmented skin lesions: results of an eye tracking study. AB - OBJECTIVE: To use computer-based eye tracking technology to record and evaluate examination characteristics of the diagnosis of pigmented skin lesions. METHODOLOGY: 16 study participants with varying levels of diagnostic expertise (little, intermediate, superior) were recorded while diagnosing a series of 28 digital images of pigmented skin lesions, obtained by non-invasive digital dermatoscopy, on a computer screen. Eye tracking hardware recorded the gaze track and fixations of the physicians while they examined the lesion images. Analysis of variance was used to test for differences in examination characteristics between physicians grouped according to expertise. RESULTS: There were no significant differences between physicians with little and intermediate levels of expertise in terms of average time until diagnosis (6.61 vs. 6.19s), gaze track length (6.65 vs. 6.15 kilopixels), number of fixations (23.1 vs. 19.1), and time in fixations (4.91 vs. 4.17s). The experts were significantly different with 3.17s time until diagnosis, 4.53 kilopixels gaze track length, 9.9 fixations, and 1.74s in fixations, respectively. Differentiation between benign and malignant lesions had no effect on examination measurements. CONCLUSION: The results show that experience level has a significant impact on the way in which lesion images are examined. This finding can be used to construct decision support systems that employ important diagnostic features identified by experts, and to optimize teaching for less experienced physicians. PMID- 22209477 TI - Automated interviews on clinical case reports to elicit directed acyclic graphs. AB - OBJECTIVE: Setting up clinical reports within hospital information systems makes it possible to record a variety of clinical presentations. Directed acyclic graphs (Dags) offer a useful way of representing causal relations in clinical problem domains and are at the core of many probabilistic models described in the medical literature, like Bayesian networks. However, medical practitioners are not usually trained to elicit Dag features. Part of the difficulty lies in the application of the concept of direct causality before selecting all the causal variables of interest for a specific patient. We designed an automated interview to tutor medical doctors in the development of Dags to represent their understanding of clinical reports. METHODS: Medical notions were analyzed to find patterns in medical reasoning that can be followed by algorithms supporting the elicitation of causal Dags. Clinical relevance was defined to help formulate only relevant questions by driving an expert's attention towards variables causally related to nodes already inserted in the graph. Key procedural features of the proposed interview are described by four algorithms. RESULTS: The automated interview comprises questions on medical notions, phrased in medical terms. The first elicitation session produces questions concerning the patient's chief complaints and the outcomes related to diseases serving as diagnostic hypotheses, their observable manifestations and risk factors. The second session focuses on questions that refine the initial causal paths by considering syndromes, dysfunctions, pathogenic anomalies, biases and effect modifiers. A case study concerning a gastro-enterological problem and one dealing with an infected patient illustrate the output produced by the algorithms, depending on the answers provided by the doctor. CONCLUSIONS: The proposed elicitation framework is characterized by strong consistency with medical background and by a progressive introduction of relevant medical topics. Revision and testing of the subjectively elicited Dag is performed by matching the collected answers with the evidence included in accepted sources of biomedical knowledge. PMID- 22209478 TI - [Proposal for a new multidisciplinary therapeutic strategy in the breast cancer patient with sentinel lymph node metastasis]. AB - Sentinel lymph node (SLN) biopsy is the standard of practice for assessing axillary spread in clinically node-negative breast cancer patients. On the other hand, axillary lymph node dissection (ALND) is the ideal procedure for patients with SLN metastasis. Different studies over the last few years have suggested that some patients with positive SLN can be treated without ALND. This article presents a literature review carried out by our multidisciplinary group and its strategy for avoiding routine ALND in women with SLN metastases. In this new strategy ALND should not be performed on women with T1 tumours, with 1-2 positive SLN and undergoing breast conservative surgery. On the other hand, ALND would be indicated in those patients with three or more positive SLN, presence of extracapsular invasion, mastectomised women and triple negative subtype or HER2+ tumours that have not received biological treatment with antibodies. PMID- 22209479 TI - Intra-thoracic fat, cardiometabolic risk factors, and subclinical cardiovascular disease in healthy, recently menopausal women screened for the Kronos Early Estrogen Prevention Study (KEEPS). AB - OBJECTIVE: To examine the correlations between intra-hepatic and intra-thoracic (total, epicardial, and pericardial) fat deposition with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis burden in healthy, recently postmenopausal women. METHODS: Women screened for the Kronos Early Estrogen Prevention Study (mean age 52.9 years) who underwent electron beam or multidetector computed tomography (CT) imaging for the quantification of intra hepatic fat and thoracic adipose tissue, and coronary artery calcification (CAC) were included (n=650). RESULTS: Higher levels of intra-hepatic and thoracic fat were each associated with CVD risk markers. After adjustment for BMI, the associations for intra-hepatic fat with hs-CRP and insulin persisted (r=0.21 and 0.19, respectively; P<0.001), while those between thoracic fat indices and lipids persisted (r for total thoracic fat with HDL, LDL, and triglycerides=-0.16, 0.11, and 0.11, respectively, P<0.05). Total thoracic fat was associated with CAC after initial multivariable adjustment (odds ratio [OR] of 2nd, 3rd, and 4th vs. 1st quartile and [95% confidence intervals]: 0.8 [0.4-1.6], 1.5 [0.8-2.9], and 1.8 [1.0-3.4]; p for linear trend=0.017) and was only slightly attenuated after additional adjustment for BMI. Associations between total thoracic fat and CVD risk markers and CAC appeared due slightly more to associations with epicardial than pericardial fat. CONCLUSION: While hepatic fat is related to hs-CRP and insulin, cardiac fat is associated with subclinical atherosclerosis as demonstrated by CAC. Cardiac fat may represent a useful marker for increased CVD risk beyond the standard adiposity measures of BMI and WC. PMID- 22209481 TI - Preparative separation of dryofragin and aspidin BB from Dryopteris fragrans extracts by macroporous resin column chromatography. AB - A simple, efficient and environment-friendly chromatographic separation method was developed for preparative separation and enrichment of dryofragin and aspidin BB from Dryopteris fragrans. The adsorption properties of twelve macroporous adsorption resins were evaluated. The three selected resins were further screened depending on the separation performance of their packed columns, in which AB-8 resin showed better separation efficiency for dryofragin and aspidin BB. In order to maximize column efficiency, the operating parameters (flow rate, ethanol concentration and volume) of the resin column chromatography were optimized and compared with the conventional resin column adsorption. After preparative separation and enrichment on resin column chromatography, the contents of dryofragin and aspidin BB in the product were 8.39- and 5.99-fold increased with recovery yields of 91.22% and 75.64%, respectively. Moreover, the regenerated adsorbent exhibited excellent reusability within at least five cycles of adsorption/desorption. It suggested that multi-targets would be enriched effectively by resin column chromatography. PMID- 22209480 TI - Effect of folic acid supplementation on the progression of carotid intima-media thickness: a meta-analysis of randomized controlled trials. AB - OBJECTIVES: We conducted a meta-analysis of relevant randomized trials to assess whether folic acid supplementation reduces the progression of atherosclerosis as measured by carotid intima-media thickness (CIMT). METHODS: This analysis included 2052 subjects from ten folic acid randomized trials with the change in CIMT reported as one of the end points. Summary estimates of weighted mean differences (WMDs) and 95% CIs were obtained by using random-effect models. Meta regression and subgroup analyses were performed to identify the source of heterogeneity. RESULTS: Our analysis showed that folic acid supplementation significantly reduces the progression of CIMT (WMD: -0.04 mm; 95%CI: -0.07, 0.02; P<0.001), particularly in subjects with chronic kidney disease (CKD) (WMD: 0.16 mm; 95%CI: -0.26, -0.07; P=0.0006) or high cardiovascular disease (CVD) risk (WMD: -0.05 mm; 95%CI: -0.11, 0.00; P=0.06) but not in subjects who were generally healthy with only elevated homocysteine concentrations (WMD:0.00 mm; 95%CI: -0.01, 0.01; P=0.35). Furthermore, meta-regression analysis of the data showed that the baseline CIMT levels (P=0.011) and the percent reduction of homocysteine (P<0.001) were positively related to the effect size. Consistently, a greater beneficial effect was seen in those trials with baseline CIMT levels >=0.8 mm (WMD: -0.14 mm; 95%CI: -0.19, -0.08; P<0.0001), and a reduction in the homocysteine concentration >=30% (WMD: -0.22 mm; 95%CI: -0.38, -0.06; P=0.009). In the corresponding comparison groups, the effect sizes were attenuated and insignificant. CONCLUSIONS: Our findings indicate that folic acid supplementation is effective in reducing the progression of CIMT, particularly in subjects with CKD or high CVD risk and among trials with higher baseline CIMT levels or a larger homocysteine reduction. PMID- 22209482 TI - Method development and validation for optimized separation of quercetin derivatives in selected Potentilla species using high-performance thin-layer chromatography photodensitometry method. AB - A novel HPTLC-densitometry method was developed for separation and quantitative determination of four flavonoids: quercetin 3-O-beta-d-glucuropyranoside (miquelianin; QG), quercetin 3-O-beta-d-glucopyranoside (isoquercitrin; IQ), quercetin 3-O-beta-d-galactopyranoside (hyperoside; HYP) and quercetin 3-O-beta-d (6"-alpha-l-rhamnosylo)-glucopyranoside (rutin; RUT) in ethyl acetate fractions from aerial parts of selected Potentilla species: P. argentea, P. erecta, Dasiphora fruticosa (syn. P. fruticosa), Drymocallis rupestris (syn. P. rupestris), P. nepalensis var. 'Miss Wilmott' and P. thuringiaca. For the first time, separation of this type of flavonoids was achieved on a HPTLC DIOL F(254) plates using a mixture consisting of ethyl acetate/methyl ethyl ketone/diisopropyl ether/formic acid (3:10:4:1, v/v/v/v). QG, IQ, HYP and RUT were determined by densitometry at 363 nm. Sensitivity, accuracy (recovery rates were between 95.0 and 101.4%) and precision (in both cases intra-day precision and inter-day precision were <= 8.0%) of the method were determined. Their amounts were calculated using the regression equations of the calibration curves which were linear in a range of 0.025-0.200 MUg/spot for all investigated compounds. The amounts of marker compounds in ethyl acetate extracts of Potentilla species measured by the method ranged between 16.7 +/- 1.1 and 41.7 +/ 0.6 mg/g for QG, 15.8 +/- 1.3 and 36.7 +/- 1.0mg/g for IQ, 14.5 +/- 0.5mg/g for HYP and 6.7 +/- 0.3 and 27.8 +/- 2.1mg/g for RUT. The method was found to be relatively simple, specific, precise and accurate and may be used for the quality control of simultaneous determination of quercetin derivatives in Potentilla extracts but also in other similar plant materials. PMID- 22209483 TI - Quantitative analysis of mephedrone using liquid chromatography tandem mass spectroscopy: application to human hair. AB - Recent abuse of designer drugs such as mephedrone has presented a requirement for sensitive, reliable and reproducible methods for the detection of these controlled drugs in different matrices. This study focuses on a fully developed validated method for the quantitative analysis of mephedrone and its two metabolites 4-methylephedrine and 4-methylnorephedrine in human hair. The calibration curve was found to be linear in the range 5-100 pg/mg for mephedrone and 10-150 pg/mg for 4-methylephedrine and 4-methylnorephedrine. The method was successfully validated for the intraday precision, interday precision, limit of detection, accuracy and extraction recovery. Five out of 154 hair samples were confirmed to be positive for mephedrone. Due to the structural similarities to other methcathinones and amphetamines, one can propose the metabolism for mephedrone based on a similar pathway that has been previously used for these psychoactive drugs. The outlined method can be valuable for the future detection of mephedrone and its two metabolites in hair. PMID- 22209484 TI - Comparison of shoulder load during power-assisted and purely hand-rim wheelchair propulsion. AB - BACKGROUND: Repetitive forces and moments are among the work requirements of hand rim wheelchair propulsion that are related to shoulder injuries. No previous research has been published about the influence of power-assisted wheelchair propulsion on these work requirements. The purpose of our study was therefore to determine the influence of power-assisted propulsion on shoulder biomechanics and muscle activation patterns. We also explored the theoretical framework for the effectiveness of power-assisted propulsion in preventing shoulder injuries by decreasing the work requirements of hand-rim wheelchair propulsion. METHODS: Nine non-wheelchair users propelled a hand-rim wheelchair on a treadmill at 0.9 m/s. Shoulder biomechanics, and muscle activation patterns, were compared between propulsion with and without power-assist. FINDINGS: Propulsion frequency did not differ significantly between the two conditions (Wilcoxon Signed Rank test/significance level/effect size:4/.314/-.34). During power-assisted propulsion we found significantly decreased maximum shoulder flexion and internal rotation angles (1/.015/-.81 and 0/.008/-.89) and decreased peak force on the rim (0/.008/-.89). This resulted in decreased shoulder flexion, adduction and internal rotation moments (2/.021/-.77; 0/.008/-.89 and 1/.011/-.85) and decreased forces at the shoulder in the posterior, superior and lateral directions (2/.021/-.77; 2/.008/-.89 and 2/.024/-.75). Muscle activation in the pectoralis major, posterior deltoid and triceps brachii was also decreased (2/.038/-.69; 1/.015/-.81 and 1/.021/-.77). INTERPRETATION: Power-assist influenced the work requirements of hand-rim wheelchair propulsion by healthy subjects. It was primarily the kinetics at rim and shoulder which were influenced by power-assisted propulsion. Additional research with actual hand-rim wheelchair users is required before extrapolation to routine clinical practice. PMID- 22209485 TI - Tissue microbiology emerging. PMID- 22209486 TI - Synthesis and evaluation of nitric oxide-releasing DDB derivatives as potential Pgp-mediated MDR reversal agents in MCF-7/Adr cells. AB - Novel furoxan-based nitric oxide (NO)-releasing DDB derivatives (7a-j) were synthesized. Compounds 7i and 7j significantly reversed the resistance of MCF 7/Adr cells to doxorubicin in the combination treatment, and markedly increased the intracellular accumulation of doxorubicin probably via inhibiting Pgp mediated intracellular drug efflux as well as down-regulating doxorubicin-induced Pgp expression. It was demonstrated that NO released by 7i and 7j played an important role in increasing intracellular doxorubicin accumulation and chemo sensitizing MCF-7/Adr cells to doxorubicin, and the synergic effects of DDB and NO-donor moieties in 7i and 7j may contribute to reversing Pgp-mediated MDR in MCF-7/Adr cells to doxorubicin. PMID- 22209487 TI - Design, synthesis, and structure-activity relationship studies of conformationally restricted mutilin 14-carbamates. AB - We report herein the design, synthesis, and structure-activity relationship studies of conformationally restricted mutilin 14-carbamates based on the structure of SB-222734. The antibacterial activities of these newly synthesized compounds were also evaluated and compared with linezolid and retapamulin. Results showed that most of the target compounds exhibit good potency in inhibiting the growth of Gram-positive bacteria including Methicillin-susceptible Staphylococcus aureus MSSA (MIC: 0.0625-2MUg/mL), Methicillin-resistant S. aureus MRSA (MIC: 0.0625-2MUg/mL), Methicillin-susceptible Staphylococcus epidermidis MSSE (MIC: 0.0625-2MUg/mL), Methicillin-resistant S. epidermidis MRSE (MIC: 0.0625-2MUg/mL), and Streptococcus pneumonia (MIC: 0.0625-4MUg/mL). In particular, three remarkable compounds of this series (12l, 12m, and 21l) exhibited comparable in vitro antibacterial profiles to that of retapamulin. PMID- 22209489 TI - Study on binding modes between cellobiose and beta-glucosidases from glycoside hydrolase family 1. AB - The hydrolysis of cellobiose by beta-glucodisases is an important step of cellulose biodegradation. However, the interactive mechanism between cellobiose and beta-glucosidases is still unclear until now. Thus, in this study, we explored the binding modes between cellobiose and three beta-glucosidases from glycoside hydrolase family 1 by means of molecular docking. The three beta glucosidases were named as TmGH1 (from bacterium Thermotoga), SsGH1 (from archaea Sulfolobus solfataricus) and TrGH1 (from fungus Trichoderma reesei) respectively, according to the monophyletic groups they belong to. Molecular dockings were performed between cellobiose and the three beta-glucosidases, resulting in three optimum docking complexes, that is TmGH1-cellobiose, SsGH1-cellobiose and TrGh1 cellobiose complexes. Our docking results indicated that there were non-bonded interactions between cellobiose and the three beta-glucosidases. The binding affinities of the three complexes were -13.6669kJ/mol, -13.2973kJ/mol and 18.6492kJ/mol, respectively. Then the detailed interactions were investigated, which revealed the key amino acid residues interacted with cellobiose by hydrogen bonds (H-bonds) or hydrophobic interactions. It was observed that most of the key residues involved in the non-bonded interactions were equivalent and conserved for the three complexes, and these residues were a glutamine, a histidine, a tyrosine, a phenylalanine, three glutamics, and four tryptophans. This information is of great importance for designing beta-glucosidase with higher cellobiose-hydrolyzing efficiency. PMID- 22209488 TI - Structures of peptide agonists for human protease activated receptor 2. AB - Protease activated receptor 2 (PAR2) is an unusual G-protein coupled receptor in being self-activated, after pruning of the N-terminus by serine proteases like trypsin and tryptase. Short synthetic peptides corresponding to the newly exposed N-terminal hexapeptide sequence also activate PAR2 on immunoinflammatory, cancer and many normal cell types. (1)H nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopy were used here to search for structural clues to activating mechanisms of the hexapeptide agonists SLIGRL (rat), SLIGKV (human) and the peptidomimetic analogue, 2-furoyl-LIGRLO. Either with a free or acetyl capped N-terminus, these agonist peptides display significant propensity in aprotic (DMSO) or lipidic (water-SDS) solvents for turn-like conformations, which are predicted to be receptor-binding conformations in the transmembrane or loops region of PAR2. These motifs may be valuable for the design of small molecule PAR2 agonists and antagonists as prospective new drugs for regulating inflammatory and proliferative diseases. PMID- 22209490 TI - Influence of membrane organization on the interactions between persistent pollutants and model membranes. AB - Langmuir monolayer studies and electrochemical methods were employed to investigate the effect of model membrane organization on the interactions with persistent pollutants such as perfluorinated carboxylic acids (PFCAs). 1,2 dimyristoyl-sn-glycero-3-phosphoethanoloamine (DMPE) was employed to construct the model lipid membrane and perfluorooctanesulphonic acid (PFOS) was chosen as the representative of perfluorinated pollutants. We demonstrate that perfluorinated compounds penetrate a model membrane only when it is less condensed. Such liquid-expanded phase was achieved by compressing the Langmuir monolayer to lower surface pressures. PFOS incorporation into model DMPE membrane during membrane formation was observed in liquid-expanded region, while at higher surface pressures, in the well-organized monolayer the expulsion of perfluorinated compound occurred as the result of a strong attraction between the DMPE molecules. The DMPE monolayers prepared by the Langmuir-Blodgett/Langmuir Schaefer method were transferred onto gold electrode under surface pressure of 3 mN/m and 20 mN/m. The model membrane organization depends on surface pressure during transfer and time of exposure to PFOS solution and is shown to affect the electrode accessibility by three electroactive compounds used as the probes of the blocking properties of the monolayer: menadione, potassium ferricyanide and hexaamineruthenium chloride, differing in the properties and kinetics of electron transfer. PMID- 22209491 TI - Decrease of permittivity of an electrolyte solution near a charged surface due to saturation and excluded volume effects. AB - The dipole moment of a water molecule in liquid water differs from that of an isolated one because each molecule is further polarized by the electric field of its neighbours. In this work a formula for the spatial dependence of the relative permittivity of an electrolyte near a highly charged surface is obtained in which the mutual influence of the water molecules is taken into account by means of the cavity field. The orientational ordering of water dipoles is considered in the saturation regime. It is predicted that the relative permittivity of an electrolyte solution near the highly charged surface (i.e. in saturation regime) may be substantially decreased due to orientational ordering of water (saturation effect) and depletion of water molecules (excluded volume effect) due to accumulation of counterions. PMID- 22209492 TI - Epidemiological description of the sea lice (Caligus rogercresseyi) situation in southern Chile in August 2007. AB - Salmon sea lice represent one of the most important threats to salmon farming throughout the world. Results of private monitoring efforts have shown an increase in the number of positive cages and cage-level abundance of sea lice in southern Chile since 2004. As a consequence, the Chilean Fisheries Service implemented an Official Surveillance Program in the main salmon production area of southern Chile to assess the situation of sea lice in fish farms. Results showed that the prevalence of sea lice in the fish farms was 53.4%, ranging from 3.5% in Puerto Aysen to 100% in the Seno de Reloncavi zone. The average sea lice abundance was 11.8 per fish (Geometrical mean (GM)=8.61, 95% CI (2.1-6.9)). The highest levels were found in Seno de Reloncavi (GM=24.99, 95% CI (15.9-39.2)), Hornopiren (GM=14.7, 95% CI (10.4-20.8)) and Chiloe norte (GM=9.75, 95% CI (1 1.9)), and the lowest loads were observed in Puerto Aysen (GM=1.35, 95%CI (1 1.9)) and Puerto Cisnes (GM=1.67, 95%CI (1.1-2.6)). Salmo salar and Oncorhynchus mykiss had the highest abundance levels (GM=6.93, 95% CI (5.7-8.5), and (GM=5.55, 95% CI (3.6-8.5), respectively). O. kisutch showed lower levels (GM=1.34, 95% CI (1-1.7)), apparently being more resistant to infestation. Sea lice in farmed salmon are widely distributed in different zones of southern Chile, and are becoming a serious threat to this industry. Prevalence and abundance levels were found to be generally high, decreasing in southern zones. PMID- 22209493 TI - RNA dynamics in aging bacterial spores. AB - Upon starvation, the bacterium Bacillus subtilis enters the process of sporulation, lasting several hours and culminating in formation of a spore, the most resilient cell type known. We show that a few days following sporulation, the RNA profile of spores is highly dynamic. In aging spores incubated at high temperatures, RNA content is globally decreased by degradation over several days. This degradation might be a strategy utilized by the spore to facilitate its dormancy. However, spores kept at low temperature exhibit a different RNA profile with evidence supporting transcription. Further, we demonstrate that germination is affected by spore age, incubation temperature, and RNA state, implying that spores can acquire dissimilar characteristics at a time they are considered dormant. We propose that, in contrast to current thinking, entering dormancy lasts a few days, during which spores are affected by the environment and undergo corresponding molecular changes influencing their emergence from quiescence. PMID- 22209494 TI - Endoscopic abdominoplasty providing a perforator fat flap for treatment of hemi facial microsomia. AB - A patient with a history of an extended unilateral hemifacial cleft desired the restoration of the buccal fat on the hollow cheeked side and also wished to reduce an abdominal bulge at the same time. The amount of tissue volume needed exceeded the possibilities of free autologous fat grafting, lipofilling and allogenic implants. Therefore a free fat flap with microvascular anastomoses harvested as part of a minimal invasive abdominoplastic procedure using an incision well hidden within the bikini zone was the most attractive surgical option. This is the first case reported, where the standard free deep inferior epigastric artery (DIEA) perforator flap was utilised. PMID- 22209495 TI - Comparative study of skeletal stability between bicortical resorbable and titanium screw fixation after sagittal split ramus osteotomy for mandibular prognathism. AB - INTRODUCTION: Resorbable screw fixation for orthognathic surgery is widely used in oral and maxillofacial surgery and has several advantages. However, surgeons are concerned about using resorbable screws in orthognathic surgery because of possible postoperative complications such as relapse, screw fracture, and infection. The purpose of this study was to evaluate the skeletal stability of bicortical resorbable screw fixation after sagittal split ramus osteotomies for mandibular prognathism. MATERIALS AND METHODS: This study included 25 patients who underwent mandibular setback surgery fixed with resorbable screws after sagittal split osteotomy at the Department of Oral and Maxillofacial Surgery at Seoul National University Dental Hospital. Five resorbable screws (Inion CPS((r)), Inion Ltd., Finland) were applied bicortically at each osteotomy site via a transbuccal approach. No rigid intermaxillary fixation was applied on the first postoperative day. Passive mouth opening exercises were allowed, using two light, rubber elastics for guidance. The control group was 25 patients fixed with four titanium screws. The follow-up period was 12-22 months (mean 17.8 months). Postoperative skeletal changes on lateral cephalometric radiographs were analyzed and compared between the two groups preoperatively, immediately postoperatively, and 6 months postoperatively. RESULTS: The average setback was 6.9 mm and no major intraoperative complications occurred. One patient experienced infection immediately after surgery that was controlled uneventfully. The data did not demonstrate any significant difference in postoperative skeletal stability between the two groups. Differences between the immediate postoperative state and 6 months after surgery were not significant. In earlier cases, especially for patients with severe mandibular prognathism, immediate postoperative elastic traction was needed for stable occlusal guidance. CONCLUSIONS: The results of this study indicate that bicortical resorbable screws offer a clinically stable outcome for the fixation of mandibular sagittal split osteotomies in mandibular prognathism. However the resorbable screws showed less stable results vertically than the titanium screws. PMID- 22209496 TI - Magnetic resonance disease severity scale (MRDSS) for patients with multiple sclerosis: a longitudinal study. AB - BACKGROUND: We previously described a composite MRI scale combining T1-lesions, T2-lesions and whole brain atrophy in multiple sclerosis (MS): the magnetic resonance disease severity scale (MRDSS). OBJECTIVE: Test strength of the MRDSS vs. individual MRI measures for sensitivity to longitudinal change. METHODS: We studied 84 MS patients over a 3.2+/-0.3 year follow-up. Baseline and follow-up T2 lesion volume (T2LV), T1-hypointense lesion volume (T1LV), and brain parenchymal fraction (BPF) were measured. MRDSS was the combination of standardized T2LV, T1/T2 ratio and BPF. RESULTS: Patients had higher MRDSS at follow-up vs. baseline (p<0.001). BPF decreased (p<0.001), T1/T2 increased (p<0.001), and T2LV was unchanged (p>0.5). Change in MRDSS was larger than the change in MRI subcomponents. While MRDSS showed significant change in relapsing-remitting (RR) (p<0.001) and secondary progressive (SP) phenotypes (p<0.05), BPF and T1/T2 ratio changed only in RRMS (p<0.001). Longitudinal change in MRDSS was significantly different between RRMS and SPMS (p=0.0027); however, change in the individual MRI components did not differ. Evaluation with respect to predicting on-study clinical worsening as measured by EDSS revealed a significant association only for T2LV (p=0.038). CONCLUSION: Results suggest improved sensitivity of MRDSS to longitudinal change vs. individual MRI measures. MRDSS has particularly high sensitivity in RRMS. PMID- 22209497 TI - Frequency domain optical coherence tomography for guidance of coronary stenting. AB - OBJECTIVE: To evaluate the role of Frequency domain optical coherence tomography (FD-OCT) in guiding stent implantation procedures. METHODS: Dragonfly-imaging catheter was used pre-intervention, after pre-dilatation or at various stages of stent deployment/post-dilatation to assess lesion severity, characteristics and guide stent expansion/apposition. RESULTS: We performed 398 OCT pull-backs in 108 consecutive patients. The 371 pull-backs analysable, had an average length of 35 mm and encompassed 193 lesions (1.8 lesions per patient). Seventy-six percent of patient had AHA-ACC-class B-C lesions. In the pre-intervention group deferral of treatment was decided for 13/68 pullbacks (19.1%), whereas strategies different from conventional predilatation (e.g. thrombectomy, rotablator, cutting-balloon) were decided in 23 cases (33.8%). After full lesion dilatation 96 pullbacks (25.9%, pre-stenting group) were performed, 46 (47.9%) of which suggested proceeding directly with stenting while 50 (52.1%) suggesting further treatment. Out of the 207 pullbacks in post-stenting group, 29 (14%) suggested new stent implantation because of dissection or residual stenosis; 64 (30.9%) suggested further optimization with high pressure/larger-sized balloon. Average number of pull-backs per patient was 3.4 requiring 75.8 +/- 19.3 ml of iopamidol. No major complications were observed. Five cases (4.6%) of contrast-induced nephropathy were reported. CONCLUSIONS: Repeated examinations with FD-OCT can be safely used to guide stent selection and improve stent expansion and apposition. PMID- 22209498 TI - Assessment of cardiac function in three mouse dystrophinopathies by magnetic resonance imaging. AB - Lack of dystrophin results in skeletal muscle dystrophy and dilated cardiomyopathy in humans and animal models. To achieve a basic understanding of the natural development of cardiomyopathy in different dystrophinopathy mouse models, left and right ventricular heart function was assessed at different ages in three dystrophinopathy mouse models (mdx, mdx/utrn(+/-) model and mdx/utrn(-/ )) using magnetic resonance imaging. Left ventricular function was significantly decreased, already at 2months in the most severely affected mdx/utrn(-/-) mice. Furthermore, whereas heart function was stable in wild-type mice over time, both mdx and mdx/utrn(+/-) showed a clear decrease at 10months of age, most prominently in the right ventricle. Therefore magnetic resonance imaging is an adequate technique to determine heart function in dystrophinopathy mouse models and can be used to assess the effect of potential therapies. PMID- 22209499 TI - Double-step transport distraction osteogenesis in the reconstruction of unilateral large mandibular defects after tumour resection using internal distraction devices. AB - One-step transport disc distraction osteogenesis (TDDO) is an effective method for the restoration of mandibular defects. This study aimed to investigate the feasibility of double-step TDDO in the reconstruction of unilateral mandibular segmental defects after tumour resection using internal distraction devices. Six patients with unilateral mandibular segmental defects were reconstructed successfully with this technique. In the double-step TDDO procedure, the mandibular body was lengthened first and then the mandibular ramus was restored. The distraction movement was set at a rate of 0.4mm twice per day. Dental rehabilitation followed distractor removal. The maximal amount of lengthening was 55 mm in the mandibular body and 42 mm in the mandibular ramus. The average amount of lengthening was 52 mm in the mandibular body and 34 mm in the mandibular ramus. The aesthetic and functional results were excellent in all patients. The implants were integrated successfully and dental restoration was satisfactory. In this study, double-step TDDO is a reliable method for reconstruction of mandibular defects after tumour resection, especially for large mandibular defects. This technique is an ideal method for dental rehabilitation, despite the long overall treatment time. PMID- 22209500 TI - [Construction and validation of a scale to assess attitudes toward patients with Alzheimer's disease and related disorders]. AB - INTRODUCTION: Patients suffering from dementia are often subjected to discriminatory attitudes, but there are few instruments able to measure these. OBJECTIVE: the construction and validation of a scale to detect negative attitudes toward patients with dementia and determine its psychometric properties, reliability criteria, and convergent and divergent validity. PARTICIPANTS AND METHODS: Fifty subjects were recruited for item selection. The scale was validated using 296 subjects of both genders, and included psychology, medical and nursing students. MATERIAL AND METHODS: A Likert-type attitudes scale of 30 items with 7 answers options was developed. After the pilot analysis of the scale and total item-item correlation a definitive tool of 20 items was developed, with a Cronbach's alpha index of 0.89. After the main component analysis, a 3 factors solution was preferred (rejection, effect and experience), which alone could explain the 65.7% of the total variance. Confirmatory factorial analysis with structural equations showed good fitting indexes (CFI=0.92; GFI=0.94; AGFI=0.90; PGFI=0.91; RMSEA=0.05). Convergent validation showed a positive correlation with scales measuring attitudes toward dementia, handicapped people, aging, and a questionnaire on negative stereotypes toward aging. RESULTS: Higher education and previous contact with the elderly were associated with more positive attitudes (F=29.16 and z=12.45, respectively). CONCLUSIONS: The attitudes toward dementia scale is a valid and reliable instrument to detect these in the general population. PMID- 22209501 TI - Evaluation of the usefulness of a low-calorie diet with or without bread in the treatment of overweight/obesity. AB - BACKGROUND & AIMS: Despite the lack of scientific evidence, bread is one of the most restricted foods in popular hypocaloric diets. The aim of this study was to compare two nutrition strategies (with or without bread) designed to promote weight loss in overweight/obese women. METHODS: A clinical, prospective and randomised study in which 122 women >18 years, BMI >= 25 < 40 kg/m(2) were divided into two groups: intervention group (BREAD, n = 61) and control group (NO BREAD, n = 61). Both groups received a low-calorie diet (with or without bread), nutrition education and physical activity guidelines, and were monitored for 16 weeks. RESULTS: 104 women completed the study (48.4 +/- 9 years, 29.8 +/- 3.5 kg/m(2)). Anthropometric and biochemical markers improved after the intervention without significant differences between groups. BREAD group significantly increased total cereal consumption (3.2 +/- 1.3 to 3.7 +/- 0.5 servings/day, P < 0.05) and the percentage of energy from carbohydrates (41.2 +/- 6.4 vs. 45.9 +/- 5.0% P < 0.001) and reduced fat (39.0 +/- 6.6 vs. 32.7 +/- 5.1% P < 0.001). In contrast, NO BREAD group increased the discrepancy with recommended consumption. NO BREAD group had the most dropouts (21.3% vs. 6.6%, P < 0.05). CONCLUSION: The bread inclusion in a low-calorie diet designed for weight loss favoured a better evolution of dietetic parameters and greater compliance with the diet with fewer dropouts. Registered under ClinicalTrials.gov Identifier no. NCT01223989. PMID- 22209502 TI - Urinary schistosomiasis in children in the United Kingdom. AB - We report on two patients with urinary schistosomiasis, who both presented within a fortnight to our hospital with similar symptoms of persistent painless haematuria. Ultrasound, cystoscopic biopsies and histology were used to confirm diagnosis. Treatment with praziquantel was given. Symptoms of urinary schistosomiasis can easily be missed in non-endemic areas and possibly confused with a more sinister pathology. A thorough history and awareness of disease can avoid interventional investigations. PMID- 22209503 TI - Low local metastatic rate may widen indication of nephron-sparing surgery for renal cell carcinoma. AB - To explore the rationale for renal-sparing surgery as an alternative method to radical nephrectomy in the treatment of renal cell carcinoma (RCC), we analyzed clinical data from 94 patients diagnosed as having RCC. They were divided into 3 groups based on the maximum diameter of their tumor specimens. Group A had tumors size ranging from 0 to 4 cm, group B had tumors size ranging from 4 to 7 cm, and group C had tumors size greater than 7 cm. Tissue samples (5 cm) were taken from the upper pole side, lower pole side, and renal pelvic side of the tumor pseudocapsule; if the tumor was located on 1 pole of the kidney, samples were collected from 2 directions. The specimens were then embedded in paraffin and cut serially at segments 0 to 1, 1 to 3, and 3 to 5 cm. Staining with hematoxylin and eosin, anti-pancytokeratin, and vimentin was performed to determine tumor type and tumor infiltration. From the 94 patients analyzed, 2 patients in group A had RCC metastasis within 1 cm of tissue around the pseudocapsule, and 4 patients in groups B and C had lymph node metastasis without metastasis in the tissue 1 cm outside the pseudocapsule in all 3 directions described. There was no statistical significant difference found between the incidence of local metastasis of the various tumor sizes, suggesting that local metastasis of RCC is not associated with the size of the tumor. Based on the observation that incidences of local metastasis were low in early-stage RCC, we came to the conclusion that pseudocapsule of RCC tumor might have growth-limiting effect on the tumor enclosed. It is theoretically a safer and better surgical option for patients with RCC with a smaller size of tumor and indications for radical nephrectomy to undergo renal-sparing surgery with an excision margin of 1 cm of normal tissue around the pseudocapsule of the tumor. PMID- 22209504 TI - The evaluation of SOX9 expression and its relationship with carcinoembryonic antigen-related cell adhesion molecule 1 in gastric neoplastic and nonneoplastic lesions. AB - The aims of this study were to investigate the expression of SOX9 (sex determining region Y [SRY]-related high-mobility group box 9) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in benign, premalignant, and malignant gastric lesions and to explore the association between SOX9 and CEACAM1 in gastric carcinogenesis. SOX9 and CEACAM1 expression was detected in normal gastric mucosa, hyperplastic polyp, intestinal metaplasia, gastric intraepithelial neoplasia, and adenocarcinoma by immunohistochemistry. There was low expression of SOX9 and no CEACAM1 expression in normal gastric mucosa and hyperplastic polyps. Intestinal metaplasia began to express CEACAM1 and showed more membranous staining of CEACAM1 than normal mucosa and hyperplastic polyps (P = .000), but SOX9 expression had no significant difference, and the coexpression of SOX9 and CEACAM1 ascended; therefore, the difference was significant (P = .000). Gastric intraepithelial neoplasia showed more SOX9 expression, coexpression of SOX9, and CEACAM1 than in intestinal metaplasia (P = .014 and P = .026, respectively). Carcinoma showed more cytoplasmic CEACAM1 (P = .010), more SOX9 expression (P = .001), and more their coexpression (P = .023) than gastric intraepithelial neoplasia. As to the histologic classification, poorly differentiated carcinoma showed more cytoplasmic CEACAM1 than well and moderately differentiated carcinoma (P = .006 and P = .024, respectively). In the Lauren classification, diffuse carcinoma showed more cytoplasmic CEACAM1 than intestinal carcinoma (P = .0035), but the SOX9 expression and their coexpresison showed no difference (P = .065 and P = .074, respectively). With the elevation of SOX9 expression and the changing of CEACAM1 expression patterns, the coexpressions of SOX9 and CEACAM1 were highly elevated from benign proliferative lesions to malignant lesions. Moreover, the SOX9 expression and the coexpression with CEACAM1 were correlated positively (r = 0.310; P = .015). In addition, SOX9 expression was positively correlated with CEACAM1 expression patterns (r = 0.124; P = .032). In addition, CEACAM1 expression patterns and coexpression of SOX9 and CEACAM1 show significant difference between T1 and T2 and T3 and T4 (P = .021 and P = .011, respectively). Accordingly, compared with N0, N2 and N3 showed significant difference in SOX9 expression (P = .018), CEACAM1 expression patterns (P = .010), and their coexpression (P = .010). SOX9 expression significantly increased from nonneoplastic lesions to neoplastic lesions, and CEACAM1 expression patterns markedly changed; their coexpression also showed signally elevated suggesting that SOX9, as a transcriptional regulator, play important roles in the changing of CEACAM1 expression patterns, which might promote the tumor progression. PMID- 22209505 TI - [Factors influencing the start of breastfeeding: Moroccan data]. PMID- 22209507 TI - A subject-specific anisotropic visco-hyperelastic finite element model of female pelvic floor stress and strain during the second stage of labor. AB - OBJECTIVES: To develop an improved model representation of the biomechanics of the levator muscles during the second stage of labor and to use a sensitivity analysis to explore the pathomechanics of levator muscle injury. METHODS: A subject-specific finite element model of human pelvic floor and fetal head was developed based on in vivo MRI data of a fetal head and maternal pelvis. An anisotropic visco-hyperelastic constitutive model employed material parameters estimated from biaxial tests on pelvic floor tissues. Boundary conditions reflected both anatomic constraints and the curve of Carus. A short second stage of labor, scaled to 10 min, was then simulated using a single expulsive push made in the absence of levator co-contraction. RESULTS: Large levator stresses occurred near the levator hiatus reaching 9 MPa at the pubovisceral muscle enthesis. The dominant principal stresses were located at, and aligned with, the edge of the hiatus. Muscle stretch bordering the levator hiatus was inhomogeneous: the average levator stretch was 3.55 with a high of 4.64 at the pubovisceral muscle enthesis. Decreasing perineal body stiffness by 40%, 50%, and 60% led to reductions in the maximum principal stretch ratio at the pubovisceral muscle enthesis of 8%, 13%, and 18%, respectively. CONCLUSIONS: The pubovisceral muscle enthesis and the muscle near the perineal body are the regions of greatest strain thereby placing them at highest risk for stretch-related injury. Decreasing perineal body tissue stiffness significantly reduced tissue stress and strain, and therefore injury risk, in those regions. PMID- 22209508 TI - Endovascular treatment of ruptured intracranial aneurysms during pregnancy: is this the best way forward? Case report and review of the literature. AB - OBJECTIVE AND IMPORTANCE: Subarachnoid haemorrhage in pregnancy has traditionally been treated by surgical clipping however lately cases of successful coiling have been reported. Nevertheless, the long-term outcome of coiling is not well known in pregnant women. Mortality due to rebleeding of an incompletely treated aneurysm remains high. Only 15 cases of successful endovascular coiling during pregnancy have been reported so far. CLINICAL PRESENTATION: We report the case of a pregnant woman who presented with aneurysmal subarachnoid hemorrhage (WFNS Grade III) due to rupture of a right posterior communicating artery aneurysm. INTERVENTION: The patient underwent endovascular coiling successfully followed by an elective caesarian section and delivery of a healthy baby. However, during the course of a 2-year follow up the patient had suffered two relapses of the coiled aneurysm which required additional treatment. These events have affected her choice of extending her family. CONCLUSION: The small risk of recurrence and the potential impact on future pregnancies should be explicitly communicated to patients in cases of endovascular coiling. PMID- 22209509 TI - Emergence and risk factors of beta-lactamase-mediated resistance to oxyimino-beta lactams in Enterobacteriaceae isolates. AB - We studied 193 Enterobacteriaceae isolates presenting diminished susceptibility to oxyimino-cephalosporins recovered in a Portuguese hospital (2004-2008). CTX-M 3 producers, firstly detected in Portugal, were associated with a Klebsiella pneumoniae microepidemic clone. Production of CTX-M-type enzymes (CTX-M-1/-3/-9/ 14/-15/-32), age >=65 years, and nosocomial infection were risk factors for higher nonsusceptibility to oxyimino-beta-lactams. CMY-2 and DHA-1 beta lactamases were only identified in 1% of isolates. PMID- 22209510 TI - Effects of echinocandins on cytokine/chemokine production by human monocytes activated by infection with Candida glabrata or by lipopolysaccharide. AB - Serious Candida glabrata infections, which can be difficult to treat, are often treated with echinocandins. We compared in vitro the effects of high and low concentrations of 3 echinocandins (micafungin [MCF], caspofungin [CAS], and anidulafungin [ANF]), voriconazole (VRC), and amphotericin B (AmB), singly and VRC in combination with MCF, CAS, and ANF, on the production of cytokines/chemokines by human monocyte-derived macrophages (MDM). MDM were activated by infection with C. glabrata or lipopolysaccharide (LPS). Luminex multi-analyte microsphere technology was used for cytokine/chemokine analysis. Concentrations of cytokines/chemokines were significantly elevated following activation by infection or LPS. Treatment with high concentrations of echinocandins, singly or in combination with VRC, was most effective in lowering the elevated cytokine/chemokine levels. This effect occurred only with MDM activated by infection with C. glabrata and not with LPS. Treatment with VRC or AmB alone had little or no effect on cytokine/chemokine levels. In severe C. glabrata infection associated with very high concentrations of dysregulated cytokines/chemokines, echinocandins, singly or in combination with VRC, may decrease cytokine/chemokine concentrations and thus may improve host survival. PMID- 22209511 TI - POM-1 metallo-beta-lactamase-producing Pseudomonas otitidis isolate from a patient with chronic otitis media. PMID- 22209512 TI - Standardization and evaluation of a tetraplex polymerase chain reaction to detect and differentiate Mycobacterium tuberculosis complex and nontuberculous Mycobacteria--a retrospective study on pulmonary TB patients. AB - The clinical presentation of pulmonary tuberculosis by members of Mycobacterium tuberculosis complex (MTC) and nontuberculous mycobacteria (NTM) cannot be differentiated using the available standard diagnostic procedures. A single-tube tetraplex polymerase chain reaction (T-PCR) was designed to simultaneously amplify 4 well-known DNA targets of MTC. Taguchi's protocol was followed for the optimization of the conditions and was then tested on 288 pulmonary TB patient samples. The analytical sensitivity of the T-PCR was 100 fg of purified mycobacterial DNA, and specificity was found to be 100% in being able to distinguish MTC and NTM in all the cases tested. The results correlated well when validated with hsp65 PCR restriction analysis and sequencing of the 16S-23S internal transcribed spacer region, hsp65, and rpoB. The T-PCR described here is a quick, valuable, and cost-effective tool for determining whether the causative organism is MTC or NTM, and thus is useful for disease surveillance. PMID- 22209513 TI - Evaluation of xTAG Respiratory Viral Panel FAST and xTAG Human Parainfluenza Virus Analyte-Specific Reagents for detection of human parainfluenza viruses in respiratory specimens. AB - The multiplex xTAG((r)) Respiratory Viral Panel FAST (RVP FAST) research-use-only assay and xTAG((r)) Human Parainfluenza Virus Analyte-Specific Reagent (HPIV-ASR) assay were evaluated with 99 culture-confirmed human parainfluenza virus (HPIV) positive and -negative specimens and found to have analytical sensitivities of 95.2% and 100% and specificities of 98.3% and 96.6%, respectively. Since the in vitro diagnostic (IVD) version of the RVP FAST assay does not include HPIVs, the HPIV-ASR assay can be tested in parallel with RVP FAST-IVD for optimal detection of HPIVs. PMID- 22209514 TI - Evaluation of the BinaxNOW PBP2a assay for the direct detection of methicillin resistance in Staphylococcus aureus from positive blood culture bottles. PMID- 22209515 TI - Clinical characteristics of infections caused by Roseomonas species and antimicrobial susceptibilities of the isolates. AB - Human infections due to Roseomonas species are uncommon and the vast majority of reported infections are opportunistic and easy to treat. We retrospectively reviewed the computerized database of the Bacteriology Laboratory at the National Taiwan University Hospital to identify patients with infections caused by Roseomonas species during the period January 2000 to December 2010. Isolates of Roseomonas species were confirmed by 16S rRNA gene sequencing analysis. During the study period, 20 patients had cultures positive for Roseomonas species. R. mucosa was the most prevalent isolate (n = 18), followed by 1 each of R. gilardii and Roseomonas genomospecies 5. True infection caused by Roseomonas species was confirmed in 17 (85%) patients. Most (n = 12, 71%) of these infections were health care-associated infection. The majority of the patients (n = 12, 71%) had underlying diseases. Malignancy was the most common underlying disease, and catheter-related bloodstream infection was the most common type of infection. The antimicrobial susceptibility patterns varied among the different Roseomonas species. In conclusion, Roseomonas species can cause infection in children and adults regardless of immune status. Because different Roseomonas species may have different clinical features and susceptibility profiles, molecular studies are necessary to identify Roseomonas isolates to the species level. PMID- 22209516 TI - Occurrence and exposure to polycyclic aromatic hydrocarbons and their derivatives in a rural Chinese home through biomass fuelled cooking. AB - The concentration and composition of PAHs emitted from biomass cooking fuel were characterized in a rural non-smoking household in northern China. Twenty-two parent PAHs (pPAHs), 12 nitro-PAHs (nPAHs), and 4 oxy-PAHs (oPAHs) were measured in the kitchen, bedroom, and outdoors during both summer and winter. The most severe contamination occurred in the kitchen in the winter, where the daily mean concentrations of pPAHs, nPAHs, and oPAHs were 7500 +/- 4100, 38 +/- 29, and 8400 +/- 9200 ng/m(3), respectively. Our results suggest that the nPAHs were largely from secondary formation in ambient air while oPAHs were either from primary emission of biomass burning or secondary formation from pPAHs in the kitchen. The daily mean benzo(a)pyrene equivalent exposure concentration was as high as 200 +/ 160 ng/m(3) in the winter for the housewife who did the cooking compared to 59 +/- 37 ng/m(3) for the control group that did not cook. PMID- 22209518 TI - Synthetic biosystems for the production of high-value plant metabolites. AB - Plants display an immense diversity of specialized metabolites, many of which have been important to humanity as medicines, flavors, fragrances, pigments, insecticides and other fine chemicals. Apparently, much of the variation in plant specialized metabolism evolved through events of gene duplications followed by neo- or sub-functionalization. Most of the catalytic diversity of plant enzymes is unexplored since previous biochemical and genomics efforts have focused on a relatively small number of species. Interdisciplinary research in plant genomics, microbial engineering and synthetic biology provides an opportunity to accelerate the discovery of new enzymes. The massive identification, characterization and cataloguing of plant enzymes coupled with their deployment in metabolically optimized microbes provide a high-throughput functional genomics tool and a novel strain engineering pipeline. PMID- 22209517 TI - Redox regulation of cell migration and adhesion. AB - Reactive oxygen species (ROS), particularly hydrogen peroxide, and the proteins that regulate them play important roles in the migration and adhesion of cells. Stimulation of cell surface receptors with growth factors and chemoattractants generates ROS, which relay signals from the cell surface to key signaling proteins inside the cell. ROS act within cells to promote migration and also in nonmigrating cells to influence the behavior of migrating cells. Hydrogen peroxide has also been suggested to act as a chemoattractant in its own right, drawing immune cells to wounds. We discuss recent progress made towards understanding how organisms use ROS, and to what degree they depend on them, during the related processes of cell migration and adhesion. PMID- 22209519 TI - Intracellular glutathione: a main factor in TEGDMA-induced cytotoxicity? AB - OBJECTIVE: To evaluate whether the reduction/prevention of triethylene glycol dimethacrylate (TEGDMA)-induced decrease of intracellular glutathione (GSH) protects human periodontal ligament fibroblasts (HPLF) against cell death. METHODS: HPLF were preincubated for 30 min with exogenous GSH and then treated with TEGDMA (2.5 mM) with/without GSH (0.5-2.5-5 mM) for the following incubation exposure types: 6h (GI); 6h followed by 18 h recovery time in presence (GII) or absence (GIII) of exogenous GSH; 24 h without recovery time (GIV). TEGDMA cytotoxicity and intracellular glutathione were assessed by Hoechst 33342 and monobromobimane (MBBr) assays. Data were statistically analyzed with Bonferroni ANOVA (p<0.05). RESULTS: Preincubation with exogenous GSH increased the intracellular GSH-concentration. TEGDMA was cytotoxic at all treatment times except at 6h (GI) (94+/-7% of control). In GII the treatment with TEGDMA alone (59+/-7%) showed no different results to cultures exposed to TEGDMA and GSH. Exogenous GSH had no effect on the TEGDMA-induced cytotoxicity also in the GIII and GIV. Thus, a combined incubation with GSH did not prevent the cytotoxicity of TEGDMA, despite of a significant increase of intracellular GSH-concentration in the presence of exogenously supplied GSH. SIGNIFICANCE: The glutathione decreasing effect of TEGDMA is not the major cause of TEGDMA-induced cytotoxicity, indicating more complex mechanisms, which are causative for TEGDMA cytotoxicity in HPLF. PMID- 22209520 TI - Better red than dead? Potential aposematism in a harpacticoid copepod, Metis holothuriae. AB - The conspicuous, red harpacticoid Metis holothuriae grows to a large size (~600 MUm length) and accounts for 29.51% of the numerical meiofaunal abundance within blooms of the toxic, benthic cyanobacterium Lyngbya majuscula. Despite this, the meiobenthic juvenile trumpeter whiting, Sillago maculata, consume M. holothuriae at only 2.16% of numerical meiofaunal biomass within simulated blooms, despite their apparent ease of predation. We compared the predation rates of copepods that had been dyed red (primarily Canuellidae and not known to be toxic) to M. holothuriae by S. maculata, to assess whether avoidance by predators is possibly a response to an aposematic signal conveyed by the colouration of the copepods and reinforced by their potential toxicity from exposure to L. majuscula. M. holothuriae were again strongly avoided, with only 6.25% of M. holothuriae consumed, whereas dyed copepods were consumed with relative alacrity, indicating that predation was not deterred by colouration alone. M. holothuriae copepodites were consumed in preference to adult individuals, supporting the idea that toxin accumulation or other factors relating to maturation might explain avoidance by benthivorous fishes. PMID- 22209521 TI - Activation of AMP-activated protein kinase by MAPO1 and FLCN induces apoptosis triggered by alkylated base mismatch in DNA. AB - O6-methylguanine produced in DNA by the action of simple alkylating agents, such as N-methyl-N-nitrosourea (MNU), causes base-mispairing during DNA replication, thus leading to mutations and cancer. To prevent such outcomes, the cells carrying O6-methylguanine undergo apoptosis in a mismatch repair protein dependent manner. We previously identified MAPO1 as one of the components required for the induction of apoptosis triggered by O6-methylguanine. MAPO1, also known as FNIP2 and FNIPL, forms a complex with AMP-activated protein kinase (AMPK) and folliculin (FLCN), which is encoded by the BHD tumor suppressor gene. We describe here the involvement of the AMPK-MAPO1-FLCN complex in the signaling pathway of apoptosis induced by O6-methylguanine. By the introduction of siRNAs specific for these genes, the transition of cells to a population with sub-G1 DNA content following MNU treatment was significantly suppressed. After MNU exposure, phosphorylation of AMPKalpha occurred in an MLH1-dependent manner, and this activation of AMPK was not observed in cells in which the expression of either the Mapo1 or the Flcn gene was downregulated. When cells were treated with AICA ribose (AICAR), a specific activator of AMPK, activation of AMPK was also observed in a MAPO1- and FLCN-dependent manner, thus leading to cell death which was accompanied by the depolarization of the mitochondrial membrane, a hallmark of the apoptosis induction. It is therefore likely that MAPO1, in its association with FLCN, may regulate the activation of AMPK to control the induction of apoptosis triggered by O6-methylguanine. PMID- 22209522 TI - Accelerating the domestication of forest trees in a changing world. AB - In light of impending water and arable land shortages, population growth and climate change, it is more important than ever to examine how forest tree domestication can be accelerated to sustainably meet future demands for wood, biomass, paper, fuel and biomaterials. Because of long breeding cycles, tree domestication cannot be rapidly achieved through traditional genetic improvement methods alone. Integrating modern genetic and genomic techniques with conventional breeding will expedite tree domestication. Breeders will only embrace these technologies if they are cost-effective and readily accessible, and forest landowners will only adopt end-products that meet with regulatory approval and public acceptance. All parties involved must work together to achieve these objectives for the benefit of society. PMID- 22209523 TI - Thyroid shields for radiation dose reduction during cone beam computed tomography scanning for different oral and maxillofacial regions. AB - AIMS: To evaluate the radiation dose level during cone beam computed tomography (CBCT) scanning for the different oral and maxillofacial regions with and without thyroid collar shielding. MATERIALS AND METHODS: Average tissue-absorbed dose for a DCT PRO CBCT was measured using thermoluminescent dosimeter chips in a phantom with or without applying thyroid collars. Effective organ dose and total effective dose were derived using International Commission on Radiological Protection (ICRP) 2007 recommendations. RESULTS: The total effective doses for large, middle and small field of view (FOV) were 254.3 MUSv, 249.0 MUSv and 180.3 MUSv, respectively, when no thyroid collar was used. Applying one thyroid collar around the front neck can reduce the total effective doses to 208.5 MUSv (18.0% reduction), 149.1 MUSv (40.1% reduction) and 110.5 MUSv (38.7% reduction), respectively. When two thyroid collars were used around the front and back neck, the total effective doses were reduced to 219.1 MUSv (13.8% reduction), 142.0 MUSv (43.0% reduction) and 105.5 MUSv (41.5% reduction), respectively. CONCLUSIONS: Thyroid collar can reduce the radiation dose during CBCT scanning for the oral and maxillofacial regions. The dose reduction becomes more significant when middle or small FOV is chosen. PMID- 22209524 TI - CT head in children. AB - The advances in computerized technology (CT) technique over the last few decades have greatly modified imaging protocols in children. The range of pathologies that can now be demonstrated has broadened with the advent of newer techniques such as CT perfusion and the ability to perform complex reconstructions. Increasing speed of scanning and reduction in scan time have influenced the need for sedation and general anaesthetic as well as impacting on motion artefact. Additionally, concerns about radiation safety and avoidance of unnecessary radiation have further impacted on the inclusion of CT in the imaging armamentarium. Justification and image optimisation are essential. It is important to familiarize oneself with the appearances of normal variants or age related developmental changes. CT does however remain an appropriate investigation in a number of conditions. PMID- 22209525 TI - Computerized tomography in pediatric oncology. AB - Computerized tomography (CT) is an extremely powerful imaging modality, which provides extremely valuable information for the diagnosis, staging, and management of pediatric solid tumors. In recent years, the concern of potential risks associated with ionizing radiation from diagnostic imaging - especially from CT - has greatly increased. In children with cancer the radiation burden from CT studies can easily accumulate because of repeated studies for disease staging, assessment of response to therapy, and follow up. The purpose of this article is to review the role of CT and its imaging key points for diagnosis, staging and planning surgical excision of common extracranial pediatric tumors, according to protocol specific imaging guidelines. The issue of the radiation burden from CT in children with cancer, and criteria of good practice to reduce it, will also be discussed. PMID- 22209526 TI - Association of degree and type of edema in posterior reversible encephalopathy syndrome with serum lactate dehydrogenase level: initial experience. AB - PURPOSE: Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiologic entity characterized by headache, blurred vision and seizures with typical parieto-occipital predominantly vasogenic edema, occasionally with cytotoxic edema. The association between the degree and type of edema in PRES with biochemical parameter, especially serum lactate dehydrogenase, has not been determined. MATERIAL AND METHODS: Thirty-five patients with typical clinical symptoms and characteristic MR imaging findings of PRES were included in this study. The extent of brain edema was graded on the anatomical distribution by 2 observers blinded to patients' clinical record, as well as the type of brain edema determined on DWI and ADC map. The levels of biochemical parameters were correlated with the degree of edema and compared between different types of edema. RESULTS: Serum LDH concentrations between patients with cytotoxic edema and with vasogenic components were not statistically different (NWU test, U=93.0, Z=1.818, P=0.069). Only serum lactate dehydrogenase (LDH) concentration was significantly correlated with the score of brain edema distribution (Spearman's rho correlation, r=0.721, P=0.00). No relationship was found between other biochemical parameters and the degree and type of brain edema. CONCLUSION: Increased serum LDH level, which plays an essential role in endothelial injury, may be a potential risk factor for the development of edema in PRES. PMID- 22209527 TI - PP1-mediated moesin dephosphorylation couples polar relaxation to mitotic exit. AB - Animal cells undergo dramatic actin-dependent changes in shape as they progress through mitosis; they round up upon mitotic entry and elongate during chromosome segregation before dividing into two [1-3]. Moesin, the sole Drosophila ERM family protein [4], plays a critical role in this process, through the construction of a stiff, rounded metaphase cortex [5-7]. At mitotic exit, this rigid cortex must be dismantled to allow for anaphase elongation and cytokinesis through the loss of the active pool of phospho-Thr559moesin from cell poles. Here, in an RNA interference (RNAi) screen for phosphatases involved in the temporal and spatial control of moesin, we identify PP1-87B RNAi as having elevated p-moesin levels and reduced cortical compliance. In mitosis, RNAi induced depletion of PP1-87B or depletion of a conserved noncatalytic PP1 phosphatase subunit Sds22 leads to defects in p-moesin clearance from cell poles at anaphase, a delay in anaphase elongation, together with defects in bipolar anaphase relaxation and cytokinesis. Importantly, similar cortical defects are seen at anaphase following the expression of a constitutively active, phosphomimetic version of moesin. These data reveal a new role for the PP1 87B/Sds22 phosphatase, an important regulator of the metaphase-anaphase transition, in coupling moesin-dependent cell shape changes to mitotic exit. PMID- 22209528 TI - Mad2 and Mad3 cooperate to arrest budding yeast in mitosis. AB - BACKGROUND: The spindle checkpoint ensures accurate chromosome transmission by delaying chromosome segregation until all chromosomes are correctly aligned on the mitotic spindle. The checkpoint is activated by kinetochores that are not attached to microtubules or are attached but not under tension and arrests cells at metaphase by inhibiting the anaphase-promoting complex (APC) and its coactivator Cdc20. Despite numerous studies, we still do not understand how the checkpoint proteins coordinate with each other to inhibit APC(Cdc20) activity. RESULTS: To ask how the checkpoint components induce metaphase arrest, we constructed fusions of checkpoint proteins and expressed them in the budding yeast Saccharomyces cerevisiae to mimic possible protein interactions during checkpoint activation. We found that expression of a Mad2-Mad3 protein fusion or noncovalently linked Mad2 and Mad3, but not the overexpression of the two separate proteins, induces metaphase arrest that is independent of functional kinetochores or other checkpoint proteins. We further showed that artificially tethering Mad2 to Cdc20 also arrests cells in metaphase independently of other checkpoint components. CONCLUSION: Our results suggest that Mad3 is required for the stable binding of Mad2 to Cdc20 in vivo, which is sufficient to inhibit APC activity and is the most downstream event in spindle checkpoint activation. PMID- 22209529 TI - The Papaver self-incompatibility pollen S-determinant, PrpS, functions in Arabidopsis thaliana. AB - Many angiosperms use specific interactions between pollen and pistil proteins as "self" recognition and/or rejection mechanisms to prevent self-fertilization. Self-incompatibility (SI) is encoded by a multiallelic S locus, comprising pollen and pistil S-determinants. In Papaver rhoeas, cognate pistil and pollen S determinants, PrpS, a pollen-expressed transmembrane protein, and PrsS, a pistil expressed secreted protein, interact to trigger a Ca(2+)-dependent signaling network, resulting in inhibition of pollen tube growth, cytoskeletal alterations, and programmed cell death (PCD) in incompatible pollen. We introduced the PrpS gene into Arabidopsis thaliana, a self-compatible model plant. Exposing transgenic A. thaliana pollen to recombinant Papaver PrsS protein triggered remarkably similar responses to those observed in incompatible Papaver pollen: S specific inhibition and hallmark features of Papaver SI. Our findings demonstrate that Papaver PrpS is functional in a species with no SI system that diverged ~140 million years ago. This suggests that the Papaver SI system uses cellular targets that are, perhaps, common to all eudicots and that endogenous signaling components can be recruited to elicit a response that most likely never operated in this species. This will be of interest to biologists interested in the evolution of signaling networks in higher plants. PMID- 22209530 TI - A multivariate approach reveals the behavioral templates underlying visual discrimination in rats. AB - Although rodents are the first-choice animal model in the life sciences, they are rarely used to study higher visual functions. It is unclear to what extent rodents follow complex visual strategies to solve visual object recognition and discrimination tasks [1-5]. We report the performance of rats in a visual discrimination task applying the multivariate "Bubbles" paradigm previously used in highly visual species such as humans, monkeys, and pigeons [6-8]. We demonstrate a relationship between accuracy and local occlusion of stimuli by bubbles, as such revealing the strategies or "templates" that underlie visual discrimination behavior. Performance was guided by relatively simple, screen centered templates as well as more adaptive templates reflecting context dependency and tolerance for changes in stimulus position. These findings demonstrate the complexity of visual strategies followed by rats and reveal interesting similarities (e.g., potential for position tolerance) as well as differences (overall efficiency of visual processing) compared to primates. In conclusion, this study illustrates the feasibility of investigating visual cognition in rats with multivariate behavioral paradigms, with the ultimate aim to use a comparative approach to explore the anatomical and neurophysiological basis of vision, also for those visual abilities that are traditionally studied in humans and monkeys. PMID- 22209531 TI - Wild chimpanzees inform ignorant group members of danger. AB - The ability to recognize other individuals' mental states-their knowledge and beliefs, for example-is a fundamental part of human cognition and may be unique to our species. Tests of a "theory of mind" in animals have yielded conflicting results. Some nonhuman primates can read others' intentions and know what others see, but they may not understand that, in others, perception can lead to knowledge. Using an alarm-call-based field experiment, we show that chimpanzees were more likely to alarm call in response to a snake in the presence of unaware group members than in the presence of aware group members, suggesting that they recognize knowledge and ignorance in others. We monitored the behavior of 33 individuals to a model viper placed on their projected travel path. Alarm calls were significantly more common if the caller was with group members who had either not seen the snake or had not been present when alarm calls were emitted. Other factors, such as own arousal, perceived risk, or risk to receivers, did not significantly explain the likelihood of calling, although they did affect the call rates. Our results suggest that chimpanzees monitor the information available to other chimpanzees and control vocal production to selectively inform them. PMID- 22209532 TI - Functional evidence for a dual route to amygdala. AB - The amygdala plays a central role in evaluating the behavioral importance of sensory information. Anatomical subcortical pathways provide direct input to the amygdala from early sensory systems and may support an adaptively valuable rapid appraisal of salient information. However, the functional significance of these subcortical inputs remains controversial. We recorded magnetoencephalographic activity evoked by tones in the context of emotionally valent faces and tested two competing biologically motivated dynamic causal models against these data: the dual and cortical models. The dual model comprised two parallel (cortical and subcortical) routes to the amygdala, whereas the cortical model excluded the subcortical path. We found that neuronal responses elicited by salient information were better explained when a subcortical pathway was included. In keeping with its putative functional role of rapid stimulus appraisal, the subcortical pathway was most important early in stimulus processing. However, as often assumed, its action was not limited to the context of fear, pointing to a more widespread information processing role. Thus, our data supports the idea that an expedited evaluation of sensory input is best explained by an architecture that involves a subcortical path to the amygdala. PMID- 22209533 TI - [Disseminated cryptococcosis in a patient with a heart transplant]. PMID- 22209534 TI - Hippocampal volume and the AKT signaling system in first-episode schizophrenia. AB - OBJECTIVE: The phosphoinositide 3'-kinase (PI3K)--protein kinase B (AKT1)- glycogen synthase kinase (GSK)-3beta system is modulated by several factors implicated in the pathophysiology of schizophrenia. Evidence suggests that neuregulin 1 (NRG1) induces decreased AKT phosphorylation in schizophrenia relative to healthy controls, which may be related to dysfunctional neurodevelopment and neuroplasticity. The aim of this study was to investigate the relationship between NRG1--induced AKT phosphorylation and hippocampal volume in schizophrenia. METHODS: Participants were 20 first-episode patients with schizophrenia who did not receive psychotropic medications and 20 matched healthy controls. We measured the phosphorylated AKT--total AKT and phosphorylated ERK (extracellular signal-regulated kinase)--total ERK ratios in peripheral lymphoblasts before and after NRG1 administration. Whole-brain, left, and right hippocampal volumes were quantified using FreeSurfer software. RESULTS: Patients with schizophrenia displayed decreased AKT but normal ERK ratio compared with controls. Patients also had a reduction in left hippocampal volume. There was no significant difference between patients and controls in whole-brain and right hippocampal volume. Decreased AKT ratio was associated with reduced hippocampal volume. There was no significant relationship between ERK ratio and brain structure. CONCLUSION: Activation of the AKT system is specifically associated with hippocampal volume in first-episode schizophrenia, which provides further evidence for the pivotal role of this messenger system in the pathophysiology of psychotic disorders. PMID- 22209535 TI - A long-term follow-up of 221 hip fracture patients in southeastern Finland: analysis of survival and prior or subsequent fractures. AB - To analyze the type and effect of prior and subsequent fractures in a hip fracture cohort. MATERIALS AND METHODS: Hip fracture patients (n=221) were followed for a mean of 8 years and all prior and subsequent fractures were studied. Incidence of the first fracture and subsequent fractures according to sex, age group, and time between the first and the index hip fracture were measured. The absolute fracture risk was measured in the study subjects and in the age groups <75 years and >=75 years. Patients' survival was analyzed with the life-table method. RESULTS: One third of the hip fracture patients had sustained previous fractures. In men, these were mostly ankle or hip fractures, and in women, wrist fractures. Of the subjects, 24% suffered a subsequent fracture, which in both sexes was usually a second hip fracture. At the end of the 8-year follow-up, 74% of the patients had died. The observed absolute fracture risk was 7% at one year and 24% at 5 years. In women, excess mortality was lowest during the first 4.8 years after the index hip fracture among patients with one fracture. However, it was highest among women with two fractures. In men, excess mortality was lowest among those with two fractures and highest among those with >=3 fractures. There were no differences between the genders in sustaining subsequent fractures. CONCLUSIONS: The fracture risk subsequent to hip fracture was similar in both genders. Patients with prior hip fractures had the worst survival rate. PMID- 22209536 TI - Dose-dependent effect of rehabilitation in functional recovery of older patients in the post-acute care unit. AB - Post-acute care (PAC) is of great importance to promote functional recovery of older patients, which should be provided by the interdisciplinary team. In PAC services, rehabilitative therapy plays a key role, but the optimal intensity for rehabilitative therapy remained unclear. Between July 2007 and December 2010, all patients with functional decline after acute illness hospitalization admitted to the PAC unit of a community hospital in Taiwan were enrolled. Usual rehabilitation program, 40-min per day and five days a week, was provided to all patients before April 2009. After April 2009, the rehabilitative therapy was increased to 80min per day. Functional improvement was measured by comprehensive geriatric assessment (CGA) at admission and 4 weeks after admissions to the PAC unit. Overall, 458 patients (mean age: 83.4+/-5.5 years, all males) completed PAC services. Compared of all dimensions in CGA, increased dosage of rehabilitative therapy showed significantly better improvement in daily living activities (Barthel index (BI): 28.8+/-18.4 vs. 20.0+/-14.6, p<0.001), depressive mood (geriatric depression score short form (GDS): -0.5+/-1.0 vs. -0.1+/-0.5, p<0.001), and pain reduction (numerical rating scale (NRS): -2.0+/-2.2 vs. -0.9+/ 2.1, p=0.01); but not in cognitive function (mini-mental status examination (MMSE): 2.9+/-3.3 vs. 3.3.+/-5.2, p=0.305), and nutritional status (body mass index (BMI): 0.3+/-0.9 vs. 0.3+/-2.5, p=0.9). In conclusion, intensive rehabilitative therapy significantly promote physical and psychological function with pain reduction, which deserves further investigations to evaluate whether there is a ceiling effect of rehabilitative therapy in PAC services. PMID- 22209537 TI - Pancreatectomy with synchronous vascular resection--an argument in favour. AB - BACKGROUND: The first case-series of pancreatectomy with synchronous en-bloc vascular resection with the aim to improve pancreatic cancer survival was published in 1977. Advances in surgical techniques, intensive care management and teaching centers with high volume cases have dramatically reduced mortality and morbidity of major pancreatic resections. This has led to a progressively wider use of venous and/or arterial resections during pancreatic surgery in selected patients to achieve negative resection margins. METHODS: We review the current literature and discuss our experience in pancreatectomies with en-bloc vascular resections. RESULTS: Survival of patients with pancreatic cancer who undergo an R0 resection with venous reconstruction is comparable to those who have a standard pancreaticoduodenectomy with no added mortality or morbidity. Conversely, arterial resection is associated with a higher morbidity, mortality and overall poorer survival, perhaps reflecting more advanced disease. CONCLUSIONS: Since the need for vascular resection may not be always apparent on pre-operative imaging, surgeons who perform major pancreatic surgery should be familiar with vascular resection and reconstruction techniques in order to offer to these patients the best chance to prolong survival. PMID- 22209538 TI - Intermittent aripiprazole for schizophrenia. PMID- 22209539 TI - Biomarkers in the development of anti-angiogenic therapies for ovarian cancer. AB - The treatment of ovarian cancer remains challenging as the majority of patients will relapse and die from their disease despite successful first-line treatment. New treatment strategies are needed and recently there has been an explosion of new agents being tested in ovarian cancer. Most of these are directed against molecularly defined pathways and a significant proportion target angiogenesis, an important process in the growth of ovarian cancer. We review the role of angiogenesis in the pathophysiology of ovarian cancer and discuss the development of the most promising anti-angiogenic drugs in this disease, including the first large phase III trials with bevacizumab which have demonstrated a disease modifying role in ovarian cancer. Other studies with this drug and other inhibitors of the angiogenic pathways are underway in the first-line and recurrent disease settings. The financial cost of these agents, increased toxicity and requirement for prolonged therapy necessitates the urgent need to identify and validate biomarkers to guide the use of these drugs in the future. There are over 200 candidate biomarkers being studied in ovarian cancer. However, currently there are no validated biomarkers to predict response or progression of disease. In this review we present a selection of biomarkers that are under investigation and discuss their benefits and limitations. PMID- 22209540 TI - Concepts in protistology: species definitions and boundaries. AB - This paper summarises the Symposium 'Concepts in Protistology', during the VI European Congress of Protistology, Berlin, 25-29 July 2011. There is an increasing focus on cataloguing the number of species on earth, species barcoding initiatives, and the increasing need to reconcile molecular with morphological data in protists within a taxonomic framework. We identify several obstructions to defining species in protists, including the high incidence of asexuality, high levels of both morphological conservation and evolutionary convergence, high levels of genetic diversity that cannot so far be correlated with phenotypic characters, conflicting signals between both genetic and phenotypic taxonomic markers, and different requirements and challenges of species definition in different protist groups. We assert that there is no species 'category' for protists, and recommend that a working definition of species is clarified on a case-by-case basis. Thus, a consensus approach may emerge within protist groups, but any one approach is unlikely to encompass a wide phylogenetic range. However, as long as clarity of intent and method is maintained, the utility of the term 'species' in protists will also be maintained as a reproducible and convenient (if artificial) way of referring to particular lineages within a tightly defined context. PMID- 22209541 TI - Evaluation and validation of internal control genes for studying gene expression in the dinoflagellate Prorocentrum minimum using real-time PCR. AB - Housekeeping genes (HKGs) are required for the normalization of expression levels in real-time PCR, and their selection is critical for gene expression studies. However, stable expressions of candidate HKGs vary among organisms and tissues and even according to environmental conditions. Here, we evaluated the gene expressions of 10 frequently used HKGs, including 18S rRNA, P2, ACT, TUA, TUB, CYC, eIF4E, MDH, UBQ, and GAPDH, with a total of 17 RNA samples extracted from the dinoflagellate Prorocentrum minimum. All the RNAs were prepared from various cells cultured under different conditions, including thermal shocks, toxic chemical exposures, and different life stages. Via C(T) analyses of the 10 HKGs using the geNorm software, TUA was selected as the most stable HKG for gene expression studies of the dinoflagellate, followed by MDH. Pair-wise variation (V) analysis showed that at least 2 genes were required for accurate normalization of gene expression studies depending on the experimental conditions. These HKGs are useful internal controls for the normalization of gene expression in P. minimum. PMID- 22209542 TI - Cognitive improvement after long-term electrical stimulation of bilateral anterior thalamic nucleus in refractory epilepsy patients. AB - INTRODUCTION: The cognitive and behavioral effect of deep brain stimulation (DBS) administered to the deep cerebral nuclei for epilepsy treatment is unknown. We investigated the cognitive outcomes at least 12 months after DBS to the bilateral anterior thalamic nucleus (ATN) for controlling intractable epilepsy. METHODS: Nine patients with intractable epilepsy who were not candidates for resective surgery, but who were treated by bilateral ATN DBS underwent cognitive and behavioral assessments before implantation and more than 1 year after DBS surgery. Postoperative cognitive assessments were carried out under a continuous stimulation mode. RESULTS: The mean seizure-reduction rate of these patients after ATN DBS was 57.9% (35.6-90.4%). Cognitive testing showed favorable results for verbal fluency tasks (letter and category, p<0.05), and a significant improvement in delayed verbal memory was observed (p=0.017). However, we did not observe any significant changes in general abilities (IQ, MMSE), information processing (digit forward and backward, Trail A, and Digit Symbol), or executive function (Trail B and WCST). Interestingly, we did not observe any significant cognitive decline approximately 1 year (mean, 15.9 months) after ATN DBS surgery. CONCLUSIONS: We showed that ATN DBS not only resulted in promising clinical effects but was also associated with improvements in both verbal recall and oral information processing, which may be related to the bilateral activation of the fronto-limbic circuit following DBS surgery. Further controlled, long-term studies with larger populations are warranted for elucidating the clinical effects of ATN DBS. PMID- 22209543 TI - Spatial relationships between the morphologies and innervations of the scalene and anterior vertebral muscles. AB - The prevertebral muscles are innervated by the cervical ventral rami. However, little information is available on the spatial relationships between the muscles and the supplying branches. This gross anatomical study investigated the prevertebral muscles and the nerves in 26 cadavers to elucidate their spatial interrelationships and the nerve pathways to each muscle. These muscles were characterized by the variations in the vertebral attachments. The scalenus medius was divisible into the dorsal and ventral parts. The scaleni anterior and medius attached to both the anterior and posterior tubercles of the cervical transverse processes. The oblique fibers arising from the transverse processes joined the vertical part of the longus colli. The rectus capitis anterior, the longus capitis and the scalene anterior and minimus were innervated by the ventromedial branches of the cervical ventral rami, and the branches passed between the origins of the proximal muscles to supply the longus colli. The rectus capitis lateralis and the scalenus medius were innervated by their dorsolateral branches, and the branches pierced the medius to the scalenus posterior. The roots of the brachial plexus passed between the scalenus anterior and the ventral part of the medius. The penetrations by the upper roots and the interconnecting fibers passing between the roots were found in the muscle bundles arising from the fourth or fifth cervical vertebrae. Their anomalies are the possible causes of the cervical-brachial disorders, and the knowledge of the innervation and the variations in this study seems to be useful for surgical and non-surgical treatments. PMID- 22209544 TI - Fatal hypernatraemia after laparoscopic treatment of hydatid liver cyst: medical and legal concerns of a rare complication. AB - A case of fatal hypernatraemia after laparoscopic treatment of hydatid livers cysts is presented in order to highlight the risks associated with the implementation of newer techniques and the use of hypertonic saline as a scolecocidal agent in hydatid disease. Additionally this case raises some concerns on the importance of obtaining a patient's informed consent. PMID- 22209545 TI - Thin-layer chromatography with stationary phase gradient as a method for separation of water-soluble vitamins. AB - The group of hydrophilic vitamins play an important role in human health, and their lack or excess produces specific diseases. Therefore, the analysis of these compounds is indispensable for monitoring their content in pharmaceuticals and food in order to prevent some human diseases. TLC was successfully applied in the analysis of hydrophilic vitamins, but the most difficult problem in the simultaneous analysis of all these compounds is to find an optimum stationary phase-mobile phase system due to different chemical characteristics of analytes. Unfortunately structural analogues are difficult to separate in one chromatographic run, and this is the case in hydrophilic vitamins investigations. TLC gives the possibility to perform two-dimensional separations by using stationary phase gradient achieving the highest resolution by combining two systems with different selectivity. The goal of this work was to develop a method of analysis enabling separation of hydrophilic vitamins using TLC with adsorbent gradient. The developed method was used for identifying the water-soluble vitamins in alcoholic extracts of Hippophae rhamnoides and of Ribes nigrum. PMID- 22209546 TI - Determination of astragalin and astragaloside content in Radix Astragali using high-performance liquid chromatography coupled with pulsed amperometric detection. AB - Astragalin and astragalosides were measured in Radix Astragali using reversed phase chromatography coupled with pulsed amperometric detection. Because the target compounds showed poor stability in aqueous solutions, they were extracted in 100% methanol under reflux. All compounds were detected with high sensitivity under highly alkaline conditions using sodium hydroxide as a post-column eluent. The limits of detection and quantification of target compounds were 0.02-0.36 MUg/mL and 0.06-1.09 MUg/mL, respectively, and the linear regression coefficients were 0.9982-1.0000. The intra- and inter-day precisions were <0.92% in retention time and <4.78% in calculated contents. Average recoveries were >91.33%. Astragalin and astragaloside contents between Radix Astragali at different ages and in different parts were successfully determined without sample purification or concentration. PMID- 22209547 TI - High productivity chromatography refolding process for Hepatitis B Virus X (HBx) protein guided by statistical design of experiment studies. AB - The Hepatitis B Virus X (HBx) protein is a potential therapeutic target for the treatment of hepatocellular carcinoma. However, consistent expression of the protein as insoluble inclusion bodies in bacteria host systems has largely hindered HBx manufacturing via economical biosynthesis routes, thereby impeding the development of anti-HBx therapeutic strategies. To eliminate this roadblock, this work reports the development of the first 'chromatography refolding'-based bioprocess for HBx using immobilised metal affinity chromatography (IMAC). This process enabled production of HBx at quantities and purity that facilitate their direct use in structural and molecular characterization studies. In line with the principles of quality by design (QbD), we used a statistical design of experiments (DoE) methodology to design the optimum process which delivered bioactive HBx at a productivity of 0.21 mg/ml/h at a refolding yield of 54% (at 10 mg/ml refolding concentration), which was 4.4-fold higher than that achieved in dilution refolding. The systematic DoE methodology adopted for this study enabled us to obtain important insights into the effect of different bioprocess parameters like the effect of buffer exchange gradients on HBx productivity and quality. Such a bioprocess design approach can play a pivotal role in developing intensified processes for other novel proteins, and hence helping to resolve validation and speed-to-market challenges faced by the biopharmaceutical industry today. PMID- 22209549 TI - Re: Digital infrared thermal imaging (DITI) of breast lesions: sensitivity and specificity of detection of primary breast cancers. PMID- 22209548 TI - Comparison of reversed-phase/cation-exchange/anion-exchange trimodal stationary phases and their use in active pharmaceutical ingredient and counterion determinations. AB - This study involved three commercial reversed-phase (RP)/anion-exchange (AEX)/cation-exchange (CEX) trimodal columns, namely Acclaim Trinity P1 (Thermo Fisher Scientific), Obelisc R (SIELC Technologies) and Scherzo SM-C18 (Imtakt). Their chromatographic properties were compared in details with respect to hydrophobicity, anion-exchange capacity, cation-exchange capacity, and selectivity, by studying retention behavior dependency on organic solvent, buffer concentration and pH. It was found that their remarkably different column chemistries resulted in distinctive chromatography properties. Trinity P1 exhibited strong anion-exchange and cation-exchange interactions but low RP retention while Scherzo SM-C18 showed strong reversed-phase retention with little cation-exchange and anion-exchange capacities. For Obelisc R, its reversed-phase capacity was weaker than Scherzo SM-C18 but slightly higher than Trinity P1, and its ion-exchange retentions were between Trinity P1 and Scherzo SM-C18. In addition, their difference in selectivity was demonstrated by examples of determining the active pharmaceutical ingredient (API) and counterion of drug products. PMID- 22209550 TI - Emergency department triage: do experienced nurses agree on triage scores? AB - BACKGROUND: The reproducibility of the Canadian Triage & Acuity Scale (CTAS), designed and introduced in the late 1990s in all Canadian emergency departments (EDs), has been studied mostly using measures of interrater agreement. However, each of these studies shares a common limitation: the nurses had received fresh CTAS training, which is likely to have led to an overestimation of the reproducibility of CTAS. OBJECTIVES: This study aims to assess the interrater reliability of the CTAS in current clinical practice, that is, as used by experienced ED nurses without recent certification or recertification. METHODS: A prospective sample of 100 patients arriving by ambulance was identified and yielded a set of 100 written scenarios. Five experienced ED nurses reviewed and blindly assigned a CTAS score to each scenario. The agreement among nurses was measured using the Kappa statistic calculated with quadratic weights. Kappa values were generated for each pair of nurses and a global Kappa coefficient was calculated to measure overall agreement. RESULTS: Overall interrater agreement was moderate, with a global Kappa of 0.44 (95% confidence interval 0.40-0.48). However, pairwise, Kappa values were heterogeneous (0.30 to 0.61, p=0.0013). CONCLUSIONS: The moderate interrater agreement observed in this study is disappointingly low and suggests that CTAS reliability may be lower than expected, and this warrants further research. Intra-observer reliability of CTAS should be ascertained more extensively among experienced nurses, and a future evaluation should involve several institutions. PMID- 22209551 TI - A rare cause of poisoning in childhood: yellow phosphorus. AB - BACKGROUND: Yellow phosphorus poisoning is rare, but when it occurs, it may result in pathological changes in almost all organs of the body, especially the liver, heart, kidney, spleen, and brain, and it has a significant mortality rate. OBJECTIVES: This report presents two cases of poisoning by yellow phosphorus in children. Yellow phosphorus ingestion rarely has been reported among the pediatric population. CASE REPORT: This report presents two cases of yellow phosphorus poisoning in children. The patients were admitted with upper abdominal pain, vomiting, lethargy, and respiratory distress. Laboratory testing revealed hepatotoxicity and coagulation disorder. Yellow phosphorus poisoning was treated with conservative therapy in both patients, and one patient died. CONCLUSION: Yellow phosphorus poisoning is a rare clinical entity and should be considered a dangerous toxic ingestion in children. PMID- 22209552 TI - Complication of acute myocardial infarction by systemic arterial embolism in the era of multimodality imaging. PMID- 22209553 TI - Factors associated with intradialytic systolic blood pressure variability. AB - BACKGROUND: Although blood pressure lability during hemodialysis has long been recognized, little is known about factors that promote nonsystematic intradialytic blood pressure variability. STUDY DESIGN: Prospective observational cohort. SETTING & PARTICIPANTS: Random cluster sample of 218 prevalent hemodialysis patients treated at 5 participating DaVita Dialysis units. PREDICTORS: Clinical variables that may plausibly influence intradialytic systolic blood pressure (SBP) variability. OUTCOMES: SBP variability as described by: (1) the deviation of SBP from its anticipated course (primary metric) and (2) the absolute value of the difference between successive SBP measurements (secondary metric). MEASUREMENTS: SBPs measured and recorded (n = 19,170) per clinical protocol during hemodialysis treatments (n = 2,422; median 11 per patient) occurring in the first 30 days of study. Predictors were assessed through standardized interview, examination, and medical record abstraction. RESULTS: Results were similar when SBP variability was considered in terms of the primary and secondary metrics. Older age and longer dialysis vintage were associated with increased SBP variability, whereas other patient characteristics were not. Greater fluid removal during hemodialysis (whether considered as volume or rate either absolute or relative to total-body water) was associated with greater SBP variability independently of its effects on net pre- to posttreatment SBP reduction. Neither number nor dialyzability of antihypertensive medications nor individual classes of agents showed an association with SBP variability. LIMITATIONS: Over-representation of African Americans and patients with congestive heart failure; observational design; use of clinically measured blood pressures; absence of medication adherence confirmation. CONCLUSIONS: Increased intradialytic SBP variability is associated with greater dialytic fluid removal and rate, as well as demographic characteristics, such as older age and dialysis vintage. Further work is needed to confirm these findings and measure associations between SBP variability and clinical outcomes. PMID- 22209554 TI - The visitor's regard of their need for support, comfort, information proximity and assurance in the intensive care unit. AB - PURPOSE: To describe the relationships between demographic variables and the need for support, comfort, information, proximity and assurance amongst the visitors at the intensive care unit (ICU). METHODS: In a cross-sectional correlational design, data were collected from March 2008 to January 2009 at a university hospital in the city of Oslo, Norway. The Critical Care Family Needs Inventory was used to collect data on the participants' perceived need for support, comfort, information, proximity and assurance. One hundred and forty-six questionnaires were given to the visitors of 74 patients, and 62 (42.5%) responded. RESULTS: The bivariate analyses showed that younger visitors regarded their need for comfort, information, proximity and assurance as more important than older visitors. Women reported a need for more comfort than men. Visitors with a lower level of formal education regarded their need for more support and comfort as more important than those with a higher educational level. After controlling for other socio-demographic variables, linear regression analysis showed that low educational level was directly related to greater need for support, comfort and proximity. CONCLUSIONS: Professionals should pay special attention to the needs of younger visitors to the ICU, females and those with a low level of education. PMID- 22209555 TI - Puerto Rican adolescents' disclosure and lying to parents about peer and risky activities: associations with teens' perceptions of Latino values. AB - Disclosure and lying to mothers and fathers about different activities, as defined within social domain theory, were examined as a function of Latino family values in 109 Puerto Rican lower socioeconomic status middle adolescents (M=15.58 years, SD=1.18) living in the United States. Questionnaires revealed that teens sometimes disclosed to parents about their risky prudential (unhealthy or unsafe) and peer activities. Lying was infrequent, although greater for risky than for peer issues. In general, path analyses demonstrated that teens' greater adherence to Latino family values and trust in parents were associated with more disclosure and less lying to mothers. However, these findings were moderated by the type of issue considered and perceptions of parents' Latino family values. PMID- 22209556 TI - Teens telling tales: how maternal and peer audiences support narrative identity development. AB - Prior research has shown that parents help children to develop the requisite skills to construct an autobiographical self in past event conversations, yet research in adolescence is lacking. Further, friendships increase in importance during adolescence, and these new relationships may play a role in narrative identity development. The current study examined past event conversations between adolescents (n = 22; mean age = 13) and their friends, and adolescents and their mothers. Conversations were reliably coded for degree of personal meaning communicated and listener scaffolding behavior. Results showed that friends showed less frequent explicit scaffolding of narrative identity than mothers, although listener scaffolding behavior was associated with adolescent meaning making for both friends and mothers. Additional qualitative analysis of the conversations suggests that friends may be more engaged in scaffolding the self presentational aspects of narrative identity, as well as providing a safe arena for exploration away from mothers. PMID- 22209557 TI - Directing stem cell fate by controlled RNA interference. AB - Directing stem cell fate remains a major area of interest and also a hurdle to many, particularly in the field of regenerative medicine. Unfortunately, conventional methods of over-expressing inductive factors through the use of biochemical induction cocktails have led to sub-optimal outcomes. A potential alternative may be to adopt the opposite by selectively silencing genes or pathways that are pivotal to stem cell differentiation. Indeed, over recent years, there have been an increasing number of studies on directing stem cell fate through gene knockdown via RNA interference (RNAi). While the effectiveness of RNAi in controlling stem cell differentiation is evident from the myriad of studies, a chaotically vast collection of gene silencing targets have also been identified. Meanwhile, variations in methods of transfecting stem cells have also affected silencing efficiencies and the subsequent extent of stem cell differentiation. This review serves to unite the pioneers who have ventured into the emerging field of RNAi-enhanced stem cell differentiation by summarizing and evaluating the current approaches adopted in utilizing gene silencing to direct stem cell fate and their corresponding outcomes. PMID- 22209558 TI - Metal-free and MRI visible theranostic lyotropic liquid crystal nitroxide-based nanoparticles. AB - The development of improved, low toxicity, clinically viable nanomaterials that provide MRI contrast have tremendous potential to form the basis of translatable theranostic agents. Herein we describe a class of MRI visible materials based on lyotropic liquid crystal nanoparticles loaded with a paramagnetic nitroxide lipid. These readily synthesized nanoparticles achieved enhanced proton relaxivities on the order of clinically used gadolinium complexes such as OmniscanTM without the use of heavy metal coordination complexes. Their low toxicity, high water solubility and colloidal stability in buffer resulted in them being well tolerated in vitro and in vivo. The nanoparticles were initially screened in vitro for cytotoxicity and subsequently a defined concentration range was tested in rats to determine the maximum tolerated dose. Pharmacokinetic profiles of the candidate nanoparticles were established in vivo on IV administration to rats. The lyotropic liquid crystal nanoparticles were proven to be effective liver MRI contrast agents. We have demonstrated the effective in vivo performance of a T1 enhancing, biocompatible, colloidally stable, amphiphilic MRI contrast agent that does not contain a metal. PMID- 22209559 TI - Mussel farming can be used as a mitigation tool--a reply. PMID- 22209560 TI - Spatially variable Rician noise in magnetic resonance imaging. AB - Magnetic resonance images tend to be influenced by various random factors usually referred to as "noise". The principal sources of noise and related artefacts can be divided into two types: arising from hardware (acquisition coil arrays, gradient coils, field inhomogeneity); and arising from the subject (physiological noise including body motion, cardiac pulsation or respiratory motion). These factors negatively affect the resolution and reproducibility of the images. Therefore, a proper noise treatment is important for improving the performance of clinical and research investigations. Noise reduction becomes especially critical for the images with a low signal-to-noise ratio, such as those typically acquired in diffusion tensor imaging at high diffusion weightings. The standard methods of signal correction usually assume a uniform distribution of the standard deviation of the noise across the image and evaluate a single correction parameter for the whole image. We pursue a more advanced approach based on the assumption of an inhomogeneous distribution of noise in space and evaluate correction factors for each voxel individually. The Rician nature of the underlying noise is considered for low and high signal-to-noise ratios. The approach developed here has been examined using numerical simulations and in vivo brain diffusion tensor imaging experiments. The efficacy and usefulness of this approach is demonstrated here and the resultant effective tool is described. PMID- 22209561 TI - Construction of 3D MR image-based computer models of pathologic hearts, augmented with histology and optical fluorescence imaging to characterize action potential propagation. AB - Cardiac computer models can help us understand and predict the propagation of excitation waves (i.e., action potential, AP) in healthy and pathologic hearts. Our broad aim is to develop accurate 3D MR image-based computer models of electrophysiology in large hearts (translatable to clinical applications) and to validate them experimentally. The specific goals of this paper were to match models with maps of the propagation of optical AP on the epicardial surface using large porcine hearts with scars, estimating several parameters relevant to macroscopic reaction-diffusion electrophysiological models. We used voltage sensitive dyes to image AP in large porcine hearts with scars (three specimens had chronic myocardial infarct, and three had radiofrequency RF acute scars). We first analyzed the main AP waves' characteristics: duration (APD) and propagation under controlled pacing locations and frequencies as recorded from 2D optical images. We further built 3D MR image-based computer models that have information derived from the optical measures, as well as morphologic MRI data (i.e., myocardial anatomy, fiber directions and scar definition). The scar morphology from MR images was validated against corresponding whole-mount histology. We also compared the measured 3D isochronal maps of depolarization to simulated isochrones (the latter replicating precisely the experimental conditions), performing model customization and 3D volumetric adjustments of the local conductivity. Our results demonstrated that mean APD in the border zone (BZ) of the infarct scars was reduced by ~13% (compared to ~318 ms measured in normal zone, NZ), but APD did not change significantly in the thin BZ of the ablation scars. A generic value for velocity ratio (1:2.7) in healthy myocardial tissue was derived from measured values of transverse and longitudinal conduction velocities relative to fibers direction (22 cm/s and 60 cm/s, respectively). The model customization and 3D volumetric adjustment reduced the differences between measurements and simulations; for example, from one pacing location, the adjustment reduced the absolute error in local depolarization times by a factor of 5 (i.e., from 58 ms to 11 ms) in the infarcted heart, and by a factor of 6 (i.e., from 60 ms to 9 ms) in the heart with the RF scar. Moreover, the sensitivity of adjusted conductivity maps to different pacing locations was tested, and the errors in activation times were found to be of approximately 10 12 ms independent of pacing location used to adjust model parameters, suggesting that any location can be used for model predictions. PMID- 22209563 TI - Predicting doripenem susceptibility based on meropenem and imipenem interpretation for Pseudomonas aeruginosa. AB - Doripenem is not available on many automated susceptibility testing panels. We evaluated the surrogate predictive value (SPV) of meropenem and imipenem in predicting doripenem susceptibility using the different breakpoint definitions available globally. MIC data for 736 Pseudomonas aeruginosa were extracted, and categorical interpretations were performed using Clinical and Laboratory Standards Institute (CLSI) proposed 2012, European Committee on Antimicrobial Susceptibility Testing (EUCAST), and Food and Drug Administration (FDA) breakpoints. Regardless of the breakpoint applied, very major and major errors were observed in only 0.1-0.8% and 0.1-4.5% of isolates, respectively. Meropenem's SPV was 98.6% for CLSI 2012 breakpoints, 94.0% for EUCAST, and 95.0% for FDA. Imipenem's SPV was 98.6%, 90.9%, and 97.2%, respectively. These data indicate that meropenem and imipenem would be reliable surrogate markers of doripenem susceptibility when using CLSI 2012 and FDA breakpoints. Meropenem would be recommended over imipenem for EUCAST breakpoints. However, meropenem and imipenem nonsusceptible isolates should be directly tested against doripenem since the latter antibiotic may still retain susceptibility against these isolates. PMID- 22209562 TI - Imaging cardiac extracellular matrices: a blueprint for regeneration. AB - Once damaged, cardiac tissue does not readily repair and is therefore a primary target of regenerative therapies. One regenerative approach is the development of scaffolds that functionally mimic the cardiac extracellular matrix (ECM) to deliver stem cells or cardiac precursor populations to the heart. Technological advances in micro/nanotechnology, stem cell biology, biomaterials and tissue decellularization have propelled this promising approach forward. Surprisingly, technological advances in optical imaging methods have not been fully utilized in the field of cardiac regeneration. Here, we describe and provide examples to demonstrate how advanced imaging techniques could revolutionize how ECM-mimicking cardiac tissues are informed and evaluated. PMID- 22209564 TI - Synthesis of uriedo and thiouriedo derivatives of peptide conjugated heterocycles - A new class of promising antimicrobials. AB - Forty five new derivatives of ureas and thioureas were synthesized by the reaction of peptide conjugated heterocycles with isocyanates and isothiocyanates respectively. All the compounds have been characterized by IR, (1)H NMR, mass and elemental analysis. The compounds were evaluated for their ability to inhibit the growth of a panel of microorganisms and all the synthesized compounds displayed an excellent antimicrobial activity. From structure-activity relationship studies, it was apparent that thioureas infact is slightly more active than ureas. Also, substituents on the phenyl ring of the title compounds play a key role in the activity. Further, compound 40 is nearly twenty times more potent than the standard used. These results present a platform for the further studies in this line. PMID- 22209565 TI - Novel and recurrent COL7A1 mutations in Chilean patients with dystrophic epidermolysis bullosa. PMID- 22209566 TI - Evaluation of robot-assisted gait training using integrated biofeedback in neurologic disorders. AB - BACKGROUND: Neurological disorders lead to walking disabilities, which are often treated using robot-assisted gait training (RAGT) devices such as the driven gait orthosis Lokomat. A novel integrated biofeedback system was developed to facilitate therapeutically desirable activities during walking. The aim of this study was to evaluate the feasibility to detect changes during RAGT by using this novel biofeedback approach in a clinical setting for patients with central neurological disorders. METHODS: 84 subjects (50 men and 34 women, mean age of 58 +/- 13 years) were followed over 8 RAGT sessions. Outcome measures were biofeedback values as weighted averages of torques measured in the joint drives and independent parameters such as guidance force, walking speed, patient coefficient, session duration, time between sessions and total treatment time. RESULTS: Joint segmented analysis showed significant trends for decreasing hip flexion activity (p <=.003) and increasing knee extension activity (p <=.001) during RAGT sessions with an intercorrelation of r=-.43 (p <=.001). Further associations among independent variables were not statistically significant. CONCLUSION: This is the first study that evaluates the Lokomat integrated biofeedback system in different neurological disorders in a clinical setting. Results suggest that this novel biofeedback approach used in this study is not able to detect progress during RAGT. These findings should be taken into account when refining existing or developing new biofeedback strategies in RAGT relating to appropriate systems to evaluate progress and support therapist feedback in clinical settings. PMID- 22209567 TI - Measurement of airborne 131I, 134)Cs and 137Cs due to the Fukushima reactor incident in Milan (Italy). AB - After the earthquake and the tsunami occurred in Japan on March 2011, four of the Fukushima reactors had released in air a large amount of radioactive isotopes that diffused all over the world. The presence of airborne (131)I, (134)Cs, and (137)Cs in air particulate due to this accident were detected and measured in the Low Radioactivity Laboratory operating in the Department of Environmental Sciences of the University of Milano-Bicocca. The sensitivity of the detecting apparatus is of 0.2 uBq/m(3) of air. Concentration and time distribution of these radiocontaminations ranging from a few to 400 uBq/m(3) for the (131)I and of a few tens of uBq/m(3) for the (137)Cs and (134)Cs. PMID- 22209568 TI - Severe Whipple's disease with acute myocarditis. PMID- 22209570 TI - Fulminant myocarditis. Can cardiac magnetic resonance predict evolution to heart failure? PMID- 22209571 TI - A pinball game in the left atrium. PMID- 22209572 TI - Effects of heating on the mechanical and chemical properties of human dentin. AB - OBJECTIVES: We had previously discovered that the flexural and tensile strengths of human dentin were 2-2.4 times greater after being heated to 140 degrees C, and deduced that the generation of higher-density structures and therefore dehydration probably promoted the increased strength. Our test hypotheses were that intertubular dentin, which constitutes a major part of organic components, was selectively affected by heating, and such changes could happen without critical damages to the basic structure of dentin type I collagen. METHODS: Micro mechanical changes of human dentin by heating at 140 degrees C were investigated by nano-indentation. Chemical changes in dentin collagen after heating were also investigated by X-ray diffraction study, a microscopic Fourier transform infrared (micro-FTIR) and a laser Raman spectroscopic analyses, and a cross-linking analysis by high-performance liquid chromatography. RESULTS: The results of nano indentation showed that the micro-hardness of intertubular dentin increased after heating at 140 degrees C to 1.8 times more than unheated dentin; on the other hand, peritubular dentin was unchanged. Results of X-ray diffraction showed that the lateral packing of collagen molecules shrank from 13.6+/-0.3 to 10.6+/-0.1A after heating, but the shrinkage reversed to the original after rehydration for seven days. After heating, no substantial chemical changes in the collagen molecules were detected in tests by micro-FTIR or Raman analyses, or by cross linking analysis. SIGNIFICANCE: These results suggest that intertubular dentin, which contains most of the type I collagen, was selectively affected by heating at 140 degrees C without critical damage to its collagen. PMID- 22209573 TI - Three-dimensional finite element analysis of molars with thin-walled prosthetic crowns made of various materials. AB - OBJECTIVES: The aim of the study was to compare the strength of thin-walled molar crowns made of various materials under simulation of mastication. METHODS: Five 3D FE models of the first lower molar with the use of contact elements were created: intact tooth; tooth with a zirconia crown; tooth with a porcelain crown; tooth with a gold alloy crown and tooth with a composite crown. The computer simulations of mastication were conducted. For the models, equivalent stresseswere calculated using the modified von Mises failure criterion (mvM). Contact stresses at the adhesive interface between the cement and tooth structure under the crowns were analyzed. RESULTS: Equivalent stresses in the crowns, did not exceed the tensile strength of their material. The mvM stresses in resin cement under the zirconia crown were 1.3 MPa, and under the composite crown they increased over 6 times. The tensile and shear contact stressesunder the stiff crowns (ceramics and gold alloy), were several times lower than those under the composite one. The maximum mvM stresses in the tooth structure for the zirconia crown were only 2.8 MPa, whereas for the composite crown were 6.4 MPa. The higher elastic modulus the crown was, the lower the equivalent stresses occurred in the composite luting cement and in the tooth structures. Also contact stresses decreased with the increasing stiffness of the crowns. SIGNIFICANCE: Under physiological loads, the thin-walled crowns perfectly luted to molars, made of zirconia ceramic, gold alloys and composite resin are resistant to failure. Prosthetic crowns made of stiff materials are less prone to debonding than those made of composite resin. Prosthetic crowns made of a material with a higher elastic modulus than enamel will strengthen the dental structures of molar teeth. PMID- 22209574 TI - Long-term outcomes and prognostic factors of re-irradiation for locally recurrent nasopharyngeal carcinoma using intensity-modulated radiotherapy. AB - AIMS: To analyse the outcomes and to evaluate the prognostic factors involved in the re-irradiation of locally recurrent nasopharyngeal carcinoma (NPC) using intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: A retrospective analysis of 239 NPC patients with local recurrence who were re-irradiated with IMRT between 2001 and 2008 was conducted. The distribution of disease re-staging was 5.4% for stage I, 18.4% for stage II, 29.7% for stage III and 46.4% for stage IV. Cisplatin-based chemotherapy was administered to 117 patients (49.0%) in addition to the IMRT. RESULTS: The mean D(95) and the V(95) of the gross tumour volume (GTV) were 66.78 Gy and 98.61%, respectively. The mean dose to the GTV was 70.04 Gy (61.73-77.54 Gy). The 5 year overall survival, local recurrence-free survival, distant metastasis-free survival and disease-free survival were 44.9, 85.8, 80.6 and 45.4%, respectively. In a univariate analysis, patient age, recurrent T (rT), recurrent N (rN), recurrent stage, tumour volume, mean dose and mean fractional dose of the GTV were significant prognostic factors for overall survival. In a multivariate analysis, only patient age, rN stage, recurrent stage, mean fractional dose and tumour volume remained significant for overall survival. CONCLUSIONS: Re-irradiation using IMRT is available to improve local tumour control and to prolong patients' survival. A smaller tumour volume, higher fractional dose, younger patient ages, lower rN(0) stage and early recurrent stage are all independent prognostic factors for overall survival of recurrent NPC. It is of clinical importance to select the appropriate recurrent NPC cases for salvage re-irradiation by IMRT. PMID- 22209575 TI - Purification, characterization and gene cloning of the killer toxin produced by the marine-derived yeast Williopsis saturnus WC91-2. AB - As the killer toxin produced by Williopsis saturnus WC91-2 could kill many sensitive yeast strains, including the pathogenic ones, the extracellular killer toxin in the supernatant of cell culture of the marine yeast strain was purified and characterized. The molecular mass of the purified killer toxin was estimated to be 11.0 kDa according to the data from SDS-PAGE. The purified killer toxin had killing activity, but could not hydrolyze laminarin. The optimal conditions for action of the purified killer toxin against the pathogenic yeast Metschnikowia bicuspidate WCY were the assay medium with 10% NaCl, pH 3-3.5 and temperature 16 degrees C. The gene encoding the killer toxin from the marine killer yeast WC91-2 was cloned and the ORF of the gene was 378 bp. The deduced protein from the cloned gene encoding the killer toxin had 125 amino acids with calculated molecular weight of 11.6 kDa. It was also found that the N-terminal amino acid sequence of the purified killer toxin had the same corresponding sequence deduced from the cloned killer toxin gene in this marine yeast, confirming that the purified killer toxin was indeed encoded by the cloned gene. PMID- 22209576 TI - Glycine passivated Fe3O4 nanoparticles for thermal therapy. AB - We demonstrate a single-step facile approach for the synthesis of glycine (amino acid) passivated Fe(3)O(4) magnetic nanoparticles (GMNPs) using soft chemical route. The surface passivation of Fe(3)O(4) nanoparticles with glycine molecules was evident from infrared spectroscopy, thermal and elemental analyses, and light scattering measurements. These nanoparticles show better colloidal stability, good magnetization, excellent self-heating capacity under external AC magnetic field and cytocompatibility with cell lines. Further, the active functional groups (-NH(2)) present on the surface of Fe(3)O(4) nanoparticles can be accessible for routine conjugation of biomolecules/biolabelling through well developed bioconjugation chemistry. Specifically, a new colloidal glycine passivated biocompatible Fe(3)O(4) nanoparticles with excellent specific absorption rate (SAR) have been fabricated, which can be used as an effective heating source for hyperthermia treatment of cancer (thermal therapy). PMID- 22209577 TI - Hybrid polymer/nanoparticle solar cells: preparation, principles and challenges. AB - Hybrid polymer/nanoparticle solar cells have a light harvesting layer composed of semiconducting inorganic nanoparticles and a semiconducting conjugated polymer. They have potential to give high power conversion efficiencies (PCE). However, the PCE values reported for these solar cells are not currently as high as anticipated. This article reviews the main methods currently used for preparing hybrid polymer/nanoparticle solar cells from the colloid perspective. PCE data for the period of 2005-2011 are presented for hybrid polymer/nanoparticle solar cells and compared to those from polymer/fullerene cells. The key reasons for the relatively low PCE values for hybrid polymer/nanoparticle solar cells are uncontrolled aggregation and residual insulating ligands at the nanoparticle surface. Two hybrid polymer/nanoparticle systems studied at Manchester are considered in which the onset of aggregation and its affect on composite film morphology were studied from the colloidal perspective. It is concluded that step change approaches are required to increase the PCEs of hybrid polymer/nanoparticle solar cells and move them toward the 10% value required for widespread commercialisation. A range of nanoparticles that have potential for application in possible longer term terawatt solar energy production are discussed. PMID- 22209578 TI - Mesoporous silica nanoparticles immobilized salicylaldimine cobalt complexes as high efficient catalysts for polymerization of 1,3-butadiene. AB - We have synthesized a series of nanocatalysts with different sizes (50-200 nm) for polymerization of 1,3-butadiene (Bd) by immobilizing salicylaldimine cobalt complexes on the mesoporous silica nanoparticles (MSNs). The prepared catalysts have been characterized by infrared (IR) spectra, thermal gravimetric analyses (TGAs), chemical composition analysis, nitrogen adsorption-desorption, scanning electron microscope (SEM), and transmission electron microscope (TEM). The nanocatalysts in combination with methylaluminoxane (MAO) show excellent catalytic efficiency in polymerization of 1,3-butadiene. The results reveal that these nanocatalysts also show higher activity than the homogeneous analog of cobalt complex and the same catalyst on bulky mesoporous silica supporting materials. The yield and the molecular weight of the poly-butadiene product depend on the particle size of the catalyst support. This catalysis process is also a facile way to directly synthesize the polymer/silica composite materials. PMID- 22209579 TI - A novel method for the templated synthesis of Ag2S hollow nanospheres in aqueous surfactant media. AB - Ag(2)S is an important direct semiconductor material that receives considerable research interest because of its low toxicity and high chemical stability. This work reports an easy and novel route for the synthesis of hollow Ag(2)S particles by a sacrificial core method in surfactant containing aqueous media. Sulfur is used as a sacrificial core in this method and removed by dissolving in carbon disulfide. Core sulfur particles were synthesized in situ by acid catalyzed reaction of sodium thiosulphate in aqueous surfactant media. The particles were characterized by using different instrumental techniques, showing 67% improved light emission capacity in terms of quantum yield compared to solid Ag(2)S particles. The same route is also suggested to prepare other nanoparticles. PMID- 22209580 TI - Hydrophilic/hydrophobic features of TiO2 nanoparticles as a function of crystal phase, surface area and coating, in relation to their potential toxicity in peripheral nervous system. AB - The hydrophilic/hydrophobic properties of a variety of commercial TiO(2) nanoparticles (NP), to be employed as inorganic filters in sunscreen lotions, were investigated both as such (dry powders) and dispersed in aqueous media. Water uptake and the related interaction energy have been determined by means of adsorption microcalorimetry of H(2)O vapor, whereas dispersion features in aqueous solutions were investigated by dynamic light scattering and electrokinetic measurements (zeta potential). The optimized dispersions in cell culture medium were employed to assess the possible in vitro neuro-toxicological effect on dorsal root ganglion (DRG) cells upon exposure to TiO(2)-NP, as a function of crystal phase, surface area and coating. All investigated materials, with the only exception of the uncoated rutile, were found to induce apoptosis on DRG cells; the inorganic/organic surface coating was found not to protect against the TiO(2)-induced apoptosis. The risk profile for DRG cells, which varies for the uncoated samples in the same sequence as the photo-catalytic activity of the different polymorphs: anatase-rutile>anatase>>rutile, was found not to be correlated with the surface hydrophilicity of the uncoated/coated specimens. Aggregates/agglomerates hydrodynamic diameter was comprised in the ~200-400 nm range, compatible with the internalization within DRG cells. PMID- 22209581 TI - Adsorption of non-ionic surfactants to the sapphire/solution interface--effects of temperature and pH. AB - The adsorption of the non-ionic surfactants tetraoxyethylene glycol monododecyl ether (C(12)EO(4)), pentaoxyethylene glycol monododecyl ether (C(12)EO(5)), and hexaoxyethylene glycol monododecyl ether (C(12)EO(6)) to single crystal sapphire substrates has been studied using specular neutron reflection for solutions at the critical micelle concentration. The effects of temperature and pH of the solutions were studied as well as the differences between two different crystal faces, the C and the R planes. At neutral pH, significant adsorption was only observed when the temperature was raised above the cloud temperature. This adsorption was reversible and surfactant was displaced on cooling. Reducing the pH to 3 results in significantly increased adsorption of C(12)EO(5) at 25 degrees C with a central layer consisting mainly of surfactant (about 90%) on the C-plane substrate. A slightly smaller surface excess was observed for the R-plane. This contrasts with the significantly lower density observed even at high temperatures at neutral pH on both substrates. The results suggest that for neutral solutions surfactant association above the cloud point is the primary driving force for adsorption. At low pH, specific interactions with protonated surfaces are important. The structures of the highly hydrated layers are similar to those found for the surfactants at hydrophilic silica surfaces. PMID- 22209582 TI - Anionically cross linked homopolymer colloids applied in formation of platinum nanoparticles. AB - Diprotonic sulfuric and succinic acids react efficiently with the tertiary amine sites in polydimethylaminoethylmethacrylate (PDMAEMA) to produce polymer colloid nano-particles held together by dinegatively charged anions that cross link the partially protonated PDMAEMA homopolymer. This procedure is used to encorporate [PtCl(6)](2-) as a cross linker into the framework of well defined polymer network colloid particles that have dual roles as nanoreactors and a source of protective polymer coating. Reduction of the cross linking [PtCl(6)](2-) groups produces platinum metal nano-particles (1.12(.25)nm) that are relatively small and narrowly dispersed. Formation of colloid particles by reaction of diprotic acids with homopolymers that have proton accepting centers provides a convenient intentional route to incorporate a variety of homopolymers into self assembled polymer network materials for applications as nanoreactors and transport systems. PMID- 22209583 TI - [Severe Bordetella pertussis pneumonia in an immunocompetent adult]. PMID- 22209584 TI - Understanding the abstract role of speech in communication at 12 months. AB - Adult humans recognize that even unfamiliar speech can communicate information between third parties, demonstrating an ability to separate communicative function from linguistic content. We examined whether 12-month-old infants understand that speech can communicate before they understand the meanings of specific words. Specifically, we test the understanding that speech permits the transfer of information about a Communicator's target object to a Recipient. Initially, the Communicator selectively grasped one of two objects. In test, the Communicator could no longer reach the objects. She then turned to the Recipient and produced speech (a nonsense word) or non-speech (coughing). Infants looked longer when the Recipient selected the non-target than the target object when the Communicator had produced speech but not coughing (Experiment 1). Looking time patterns differed from the speech condition when the Recipient rather than the Communicator produced the speech (Experiment 2), and when the Communicator produced a positive emotional vocalization (Experiment 3), but did not differ when the Recipient had previously received information about the target by watching the Communicator's selective grasping (Experiment 4). Thus infants understand the information-transferring properties of speech and recognize some of the conditions under which others' information states can be updated. These results suggest that infants possess an abstract understanding of the communicative function of speech, providing an important potential mechanism for language and knowledge acquisition. PMID- 22209585 TI - Reduction of benzo[a]pyrene with acid-activated magnesium metal in ethanol: a possible application for environmental remediation. AB - Persistent organic pollutants (POPs) are a well-known threat to the environment. Substances such as polycyclic aromatic hydrocarbons (PAHs) in contaminated soils and sediments can have severe and long-term effects on human and environmental health. There is an urgent need for the development of safe technologies for their effective degradation. Here we present a new technique using ball-milled magnesium powder and ethanol solvent as a convenient electron transfer/proton source for the partial reduction of PAHs under ambient conditions. The rates of degradation were determined while evaluating the influences of acetic acid and type of ball-milled magnesium added to the reaction mixture. The results of these triplicate studies indicate that with the use of acetic acid as an activator and ball-milled magnesium carbon (Mg/C), this reducing system (Mg-EtOH) is able to achieve a 94% conversion of 250 MUg/mL of toxic benzo[a]pyrene into a mixture of less toxic and partially hydrogenated polycyclic compounds within 24h. This methodology can be used as a combined process involving ethanol washing followed by reduction reaction and it can also be considered as an easy handling and efficient alternative process to the catalytic hydrogenation of PAHs. PMID- 22209586 TI - Assessment of metal removal, biomass activity and RO concentrate treatment in an MBR-RO system. AB - This work investigated the removal of metals from wastewater using a combined Membrane Bioreactor-Reverse Osmosis (MBR-RO) system. The concentrate produced by the RO system was treated by a fixed bed column packed with zeolite. The average metal removal accomplished by the MBR treating municipal wastewater was Cu(90%), Fe(85%), Mn(82%), Cr(80%), Zn(75%), Pb(73%), Ni(67%), Mg(61%), Ca(57%), Na(30%) and K(21%), with trivalent and divalent metals being more effectively removed than monovalent ones. The metal removal achieved by the MBR system treating wastewater spiked with Cu, Pb, Ni and Zn (4-12 mg L(-1) of each metal) was Pb(96%)>Cu(85%)>Zn(78%)>Ni(48%). The combined MBR-RO system enhanced metal removal from municipal wastewater to the levels of >90.9->99.8%, while for wastewater spiked with heavy metals the removal efficiencies were >98.4%. Fixed bed column packed with zeolite was effective for the removal of Cu, Pb and Zn from the RO concentrate, while Ni removal was satisfactory only at the initial stages of column operation. The presence of heavy metals increased inorganic fouling. PMID- 22209587 TI - Electrochemistry of copper(II) induced complexes in mycorrhizal maize plant tissues. AB - Aim of the present paper was to study the electrochemical behavior of copper(II) induced complexes in extracts obtained from mycorrhizal and non-mycorrhizal maize (Zea mays L.) plants grown at two concentrations of copper(II): physiological (31.7 ng/mL) and toxic (317 MUg/mL). Protein content was determined in the plant extracts and, after dilution to proper concentration, various concentrations of copper(II) ions (0, 100, 200 and 400 MUg/mL) were added and incubated for 1h at 37 degrees C. Further, the extracts were analyzed using flow injection analysis with electrochemical detection. The hydrodynamic voltammogram (HDV), which was obtained for each sample, indicated the complex creation. Steepness of measured dependencies was as follows: control 317 MUg/mL of copper8.5%). The desirable threshold of HbA(1c)<7% was fulfilled by 14% more treated than control patients (43.6 vs. 57.9, P<.05). Reductions of 4.4+/-0.8kg average weight and of 1.7+/-0.3kg/m(2) body mass index were recorded. Although there was not a significant reduction in the overall lipid profile, a decrease of 4.9+/-5.1mg/dl total cholesterol, 3.2+/-4.3mg/dl LDL-C, 8.6+/ 5.6mg/dl noHDL-C and 2.5+/-1, 4mg/dl HDL-C was observed. Patients outside target (LDL>100 and/or triglycerides>150mg/dl) showed significant differences in their concentrations of LDL-C and triglycerides. With respect to blood pressure (BP), significant differences were observed in diastolic BP (-18.9+/-5.7mmHg) but not in systolic BP (P<.05). CONCLUSIONS: Exenatide is an effective drug not only for glycemic control but also for the overall metabolic control of HbA(1c), lipid profile, BP and body weight. PMID- 22209598 TI - Remodeling human cortex through training: comment on May. PMID- 22209600 TI - Cognitive and non-cognitive conceptions of consciousness. PMID- 22209602 TI - Application of the Central Limit Theorem in microbial risk assessment: high number of servings reduces the Coefficient of Variation of food-borne burden-of illness. AB - The Central Limit Theorem (CLT) is proposed as a means of understanding microbial risk in foods from a Public Health perspective. One variant of the CLT states that as the number of random variables, each with a finite mean and variance, increases (->infinity), the distribution of the sum (or mean) of those variables approximates a normal distribution. On the basis of the CLT, the hypothesis introduced by this paper states that the Coefficient of Variation (CV) of the annual number of food-borne illness cases decreases as a result of a larger number of exposures (or servings) (n). Second-order Monte-Carlo analysis and classical statistics were used to support the hypothesis, based on existing risk models on Listeria monocytogenes in deli meat products focused on elderly people in the United States. Likewise, the hypothesis was tested on epidemiological data of annual incidence of salmonellosis and listeriosis in different countries (i.e. different n). Although different sources of error affected the accuracy of the results, both the Monte-Carlo analysis (in silico) and epidemiological data (in vivo), especially for salmonellosis, demonstrated that the CV of the annual number of cases decreased as n increased as stated by the CLT. Furthermore, results from this work showed that classical statistical methods can be helpful to provide reliable risk estimates based on simple and well-established statistical principles. PMID- 22209603 TI - Comparing rapid methods for detecting Listeria in seafood and environmental samples using the most probably number (MPN) technique. AB - The standard Bacteriological Analytical Manual (BAM) protocol for detecting Listeria in food and on environmental surfaces takes about 96 h. Some studies indicate that rapid methods, which produce results within 48 h, may be as sensitive and accurate as the culture protocol. As they only give presence/absence results, it can be difficult to compare the accuracy of results generated. We used the Most Probable Number (MPN) technique to evaluate the performance and detection limits of six rapid kits for detecting Listeria in seafood and on an environmental surface compared with the standard protocol. Three seafood products and an environmental surface were inoculated with similar known cell concentrations of Listeria and analyzed according to the manufacturers' instructions. The MPN was estimated using the MPN-BAM spreadsheet. For the seafood products no differences were observed among the rapid kits and efficiency was similar to the BAM method. On the environmental surface the BAM protocol had a higher recovery rate (sensitivity) than any of the rapid kits tested. ClearviewTM, Reveal(r), TECRA(r) and VIDAS(r) LDUO detected the cells but only at high concentrations (>10(2) CFU/10 cm(2)). Two kits (VIPTM and PetrifilmTM) failed to detect 10(4) CFU/10 cm(2). The MPN method was a useful tool for comparing the results generated by these presence/absence test kits. There remains a need to develop a rapid and sensitive method for detecting Listeria in environmental samples that performs as well as the BAM protocol, since none of the rapid tests used in this study achieved a satisfactory result. PMID- 22209601 TI - Top-down modulation: bridging selective attention and working memory. AB - Selective attention, the ability to focus our cognitive resources on information relevant to our goals, influences working memory (WM) performance. Indeed, attention and working memory are increasingly viewed as overlapping constructs. Here, we review recent evidence from human neurophysiological studies demonstrating that top-down modulation serves as a common neural mechanism underlying these two cognitive operations. The core features include activity modulation in stimulus-selective sensory cortices with concurrent engagement of prefrontal and parietal control regions that function as sources of top-down signals. Notably, top-down modulation is engaged during both stimulus-present and stimulus-absent stages of WM tasks; that is, expectation of an ensuing stimulus to be remembered, selection and encoding of stimuli, maintenance of relevant information in mind and memory retrieval. PMID- 22209604 TI - Combination of culture-dependent and culture-independent molecular methods for the determination of lactic microbiota in sucuk. AB - In this study, the culture-dependent and culture-independent molecular methods were used for the identification of lactic acid bacteria (LAB) in sucuk a Turkish fermented dry sausage. On the one hand, the PCR-DGGE method targetting the V1 and V3 regions of 16S DNA was applied to DNA that was directly extracted from sucuk samples. On the other hand, rep-PCR fingerprinting was performed for the primary differentiation and grouping of the isolates, and the results were confirmed by sequencing of the 16S rDNA and 16S-23S rDNA intergenic spacer region. As a result of the PCR-DGGE analysis of all the samples, total 8 different lactic acid bacteria were identified, and Lactobacillus sakei, Lactobacillus curvatus and Weissella viridescens were the dominant microbiota among these bacteria. The culture-dependent approach indicated that the majority of the strains belonged to the Lactobacillus genera including Lb. sakei, Lactobacillus plantarum, Lb. curvatus, Lactobacillus brevis, Lactobacillus farciminis and Lactobacillus alimentarius. However, Leuconostoc and Weisella were also detected as minor genera. Again, Lactococcus piscium, Weissella halotolerans, Staphylococcus succinus and the comigrated Staphylococcus piscifermentans/Staphylococcus condimenti/Staphylococcus carnosus group were detected only with the culture independent method while Lb. plantarum, Leuconostoc mesenteroides and Leuconostoc citreum were identified only by using the culture-dependent method. In the results, it was concluded that the combination of culture-dependent and culture independent methods was necessary for reliable and detailed investigation of LAB communities in fermented food products. PMID- 22209605 TI - Unusual course of an abdominal aortic aneurysm in a patient treated with chemotherapy for gastric cancer. AB - Most aortic aneurysms have a degenerative genesis and show a slow expansion over years. Only a few patients with a rapid progression of mycotic or inflammatory aneurysm during some weeks or months have been reported. We report a patient with a rapidly growing symptomatic infrarenal aneurysm with a maximal diameter of 53 mm, which developed over a 5-month period from a normal aorta and did not feature typical signs of degenerative, inflammatory, or mycotic aneurysm. The aneurysm was successfully treated by endovascular repair. A complete shrinking of the aneurysm sac was demonstrated during a few weeks postoperatively. Because the patient received chemotherapy with docetaxel, cisplatin, and 5-fluorouracil for metastatic gastric carcinoma 1 year before the aneurysm occurred, we postulate that chemotherapy induced a rapid expansion of the aorta in this patient. PMID- 22209606 TI - A systematic review of symptomatic duodenal perforation by inferior vena cava filters. AB - OBJECTIVE: A systematic review of the literature on symptomatic duodenal perforation caused by inferior vena cava (IVC) filters. METHODS: Three databases, PubMed MEDLINE, Web of Sciences, and Literatura Latino-Americana e do Caribe em Ciencias da Saude (LILACS), reference lists of review articles and conference proceedings were searched. All articles containing data on clinical presentation, diagnostic strategy, and available treatment of symptomatic duodenal perforation caused by an IVC filter were included regardless of design, language, size, or length of follow-up. RESULTS: Seventy-two articles were selected for full-text screening, being 21 case reports were selected. The median age was 46 years old (range, 21-83 years old). Abdominal pain was reported in 11 patients and gastrointestinal bleed in 5 patients. The indications for IVC filter placement in this cohort of patients were contraindication of anticoagulation and recurrent pulmonary embolism (PE) despite therapeutic levels in 8 and 5 patients, respectively. Three different imaging modalities were obtained in 9 patients (43%) before confirming the diagnosis. All but 1 patient underwent open approach through laparotomy with or without removal of the filter. No PEs or deaths were reported and only 1 patient had a severe clinical complication of IVC and bilateral iliac vein thrombosis with massive lower extremities edema. CONCLUSIONS: Duodenal perforation caused by IVC filters is a rare complication that frequently requires extensive workup. Excellent outcomes with low complication rate have been reported in cases where an open procedure was performed with either extraction of the filter or removal of the offending struts. PMID- 22209607 TI - A fresh cadaver laboratory to conceptualize troublesome anatomic relationships in vascular surgery. AB - OBJECTIVE: Opportunities are declining for residents to participate in complex open vascular surgical operations. Open simulation using fresh cadavers potentially can be used to familiarize residents with complex vascular exposures. We evaluated the use of fresh cadavers to assist resident comprehension of complex anatomic relationships in vascular surgery. METHODS: Twenty-two postgraduate year (PGY) 3 (n = 12) and PGY 4 (n = 10) general surgery residents attended five structured 4-hour cadaver skills laboratories. Residents performed five conceptually difficult and infrequently encountered operative vascular exposures: the supraclavicular subclavian and vertebral arteries, supraceliac aorta, superior mesenteric artery, proximal and distal renal arteries, and common iliac artery bifurcations. Residents were tested (oral board examination style with percentage correct of a predetermined checklist) in their knowledge and understanding of the anatomic relationships before and after the cadaver laboratories. Participants' self-reported confidence in performing these complex vascular exposures was also measured before and after the course using the operative confidence score (1 = not confident; 5 = highly confident) for each exposure. RESULTS: Participation in the course resulted in increases in participant comprehension and self-reported operative confidence in the supraclavicular subclavian and vertebral arteries, supraceliac aorta, superior mesenteric artery, renal arteries, and iliac bifurcation exposures. Before vs after the course, the mean oral examination scores were 5% vs 87%, 26% vs 94%, 19% vs 86%, 30% vs 88%, and 29% vs 87%, respectively (all P < .001), and mean operative confidence scores were 1.1 vs 2.9, 1.3 vs 3.5, 1.2 vs 3.2, 1.2 vs 3, and 1.5 vs 3.9, respectively (all P < 0.001). CONCLUSIONS: Fresh cadaver laboratories can provide a learner-centered and safe environment for acquiring procedural understanding and operative confidence of complex vascular exposures. This may allow for the transformational change essential to becoming a competent vascular surgeon. PMID- 22209608 TI - Improved amputation-free survival in unreconstructable critical limb ischemia and its implications for clinical trial design and quality measurement. AB - OBJECTIVE: Amputation-free survival (AFS), a composite endpoint of mortality and amputation, is the preferred outcome measure in critical limb ischemia (CLI). Given the improvements in systemic management of atherosclerosis and interventional management of limb ischemia over the past 2 decades, we examined whether these outcomes have changed in patients with CLI without revascularization options (no option-critical limb ischemia [NO-CLI]). METHODS: We reviewed the literature for published 1-year AFS, mortality, and amputation rates from control groups in NO-CLI trials. Summary proportions of events were estimated by conducting a random effects meta-analysis of proportions. To determine whether there had been any change in event rates over time, we performed a random effects meta-regression and a mixed effects logistic regression, both regressed against the variable "final year of recruitment." RESULTS: Eleven trials consisting of 886 patients satisfied search criteria, 7 of which presented AFS data. Summary proportion of events (95% confidence interval) were 0.551 (0.399 to 0.693) for AFS; 0.198 (0.116 to 0.317) for death; and 0.341 (0.209 to 0.487) for amputation. Regression analyses demonstrated that AFS has risen over time as mortality rates have fallen, and these improvements are statistically significant. The decrease in amputation rates failed to reach statistical significance. The lack of published data precluded a quantitative evaluation of any change in the clinical severity or comorbidities in the NO-CLI population. CONCLUSIONS: AFS and mortality rates in NO-CLI have improved over the past 2 decades. Due to declining event rates, clinical trials may underestimate treatment effects and thus fail to reach statistical significance unless sample sizes are increased or unless a subgroup with a higher event rate can be identified. Alternatively, comparing outcomes to historical values for quality measurement may overestimate treatment effects. Benchmark values of AFS and morality require periodic review and updating. PMID- 22209609 TI - Outcomes of lymphaticovenous side-to-end anastomosis in peripheral lymphedema. AB - OBJECTIVE: Lymphaticovenous anastomosis has been used for patients with peripheral lymphedema. However, the efficacy of this procedure is controversial due to a lack of evidence regarding postoperative patency. We sought to determine midterm postoperative patency of lymphaticovenous side-to-end anastomoses (LVSEAs) using indocyanine green fluorescence lymphography. METHODS: This was a retrospective observational study set in a teaching hospital. Of 107 patients with chronic lymphedema who underwent 472 LVSEAs, 57 (223 anastomoses) consented to fluorescence lymphography and comprised the study cohort. The intervention consisted of a microsurgical LVSEA performed with a suture-stent method. Patients also had preoperative and postoperative complex decongestive physiotherapy. Anastomosis patency was assessed using indocyanine green fluorescence lymphography >=6 months after surgery. Patency rates were calculated using Kaplan Meier analysis. We assessed volume reduction on the operated-on limb and compared this between patients in whom anastomoses were patent and those in whom anastomoses were not obviously patent. RESULTS: Patency could be evaluated only at the dorsum of the foot, ankle, and lower leg because the near-infrared rays emitted by the special camera used could not penetrate the deep subcutaneous layer containing collective lymphatics in areas such as the thigh. Several patterns were observed on fluorescence lymphography: straight, radial, and L shaped. Cumulative patency rates of LVSEAs were 75% at 12 months and 36% at 24 months after surgery. No significant difference in volume change of the affected limb was seen between the 34 patients with patent anastomosis (600 +/- 969 mL) and the 24 patients without obvious evidence of patency (420 +/- 874 mL). CONCLUSIONS: Although further study is required to determine factors leading to anastomotic obstruction and to optimize the results of microlymphatic surgery, the present LVSEA technique appears promising. PMID- 22209610 TI - Prophylactic muscle flaps in vascular surgery. AB - BACKGROUND: Vascular surgery-related groin complications can lead to catastrophic outcomes and pose a significant healthcare burden. We have taken steps to reduce potential complications at the time of initial surgery by performing prophylactic muscle flaps. The purpose of this study is to evaluate the efficacy and benefit of prophylactic flaps in high-risk patients. METHODS: A retrospective cohort study was performed on patients undergoing open vascular surgery involving the femoral vessels through a groin incision between 2005 and 2010. Patients receiving prophylactic muscle flaps at their initial surgery were compared with those patients not receiving a flap (control). RESULTS: Sixty-eight prophylactic flaps in 53 patients were compared with 195 open vascular procedures without flaps in 178 patients. The most frequent indication was reoperative bypass surgery with prosthetic reconstruction (63%). The prophylactic patient group exhibited significantly higher rates of comorbidities, including chronic obstructive pulmonary disease (25.0% vs 12.6%; P = .018) and hyperlipidemia (80.9% vs 59.1%; P = .002). Patients receiving prophylactic flaps had lower rates of overall complications (16.2% vs 50.3%; P < .001), infections (1.5% vs 38.5%; P < .001), seroma (0% vs 7.2%; P = .023), and lymphocele (1.5% vs 15.4%; P = .002). Multivariate regression demonstrated that obesity (odds ratio [OR], 2.1 [1.001 4.49]; P = .05), smoking (OR, 2.7 [1.37-5.16]; P = .004), reoperation (OR, 3.5 [1.41-8.63]; P = .007), and prosthetic graft reconstruction (OR, 2.0 [1.03-3.78]; P = .04) were associated with postoperative complications. Additionally, in analyzing all groin complications in all patients, we found that patients who received a prophylactic flap experienced significantly less groin wound complications (OR, 0.17; P < .001). CONCLUSIONS: Complications following open groin surgery are common, lead to significant morbidity, and are very costly. Performing prophylactic muscle flaps at the initial surgery to cover the femoral vessels and reduce dead space can significantly reduce complications in select high-risk patients. Prophylactic flaps are safe, effective, and should be considered in patients with multiple comorbidities undergoing high-risk groin surgery, such as reoperative prosthetic bypass surgery. PMID- 22209612 TI - A meta-analysis of anticoagulation for calf deep venous thrombosis. AB - OBJECTIVE: This meta-analysis was initiated to assess the efficacy and safety of anticoagulation therapy for adult patients with isolated calf vein deep venous thrombosis (DVT). METHODS: We searched MEDLINE (1950-October 2010), the Cochrane Library (1993-October 2010), trial registries, meeting abstracts, and selected references, using no limits. Included studies compared the results of anticoagulation (vitamin K antagonist or therapeutic heparin) for a minimum of 30 days vs the results of no anticoagulation in adults with calf vein DVT proved by ultrasound imaging or venograph who were monitored for at least 30 days. Two independent reviewers extracted data using a piloted standardized form. Methodologic quality was assessed using the Cochrane Risk of Bias tool for randomized controlled trials (RCTs) and the Newcastle-Ottawa Quality Assessment Scale for cohort and case-control studies. Discrepancies were resolved by consensus or by a third reviewer. Authors were contacted for additional information if necessary. Outcomes were pooled using Peto fixed-effects models. RESULTS: Of 2328 studies identified, two RCTs and six cohorts (126 patients treated with anticoagulation and 328 controls) met selection criteria. The methodologic quality of most studies was poor. Pulmonary embolism (PE; odds ratio, 0.12; 95% confidence interval, 0.02-0.77; P = .03) and thrombus propagation (odds ratio, 0.29; 95% confidence interval, 0.14-0.62; P = .04) were significantly less frequent in those who received anticoagulation. Significant heterogeneity existed in studies reporting mortality rates, but these demonstrated a trend toward fewer deaths with anticoagulation. When limited to randomized trials, the protective effect of anticoagulation for PE was no longer statistically significant, but the benefit for preventing thrombus progression persisted. Adverse events such as bleeding were sparsely reported but favored controls (P = .65). CONCLUSIONS: Our review suggests that anticoagulation therapy for calf vein DVT may decrease the incidence of PE and thrombus propagation. However, due to poor methodologic quality and few events among included studies for PE, this finding is not robust. Thrombus propagation appears reduced with anticoagulation treatment. A rigorous RCT will assist in treatment decisions for calf vein DVT. PMID- 22209613 TI - Predictive factors for mortality after open repair of paravisceral abdominal aortic aneurysm. AB - OBJECTIVE: The use of fenestrated and branched stent graft technology for paravisceral abdominal aortic aneurysms (PAAA) is on the rise; however, its application is limited in the United States to only a few selected centers. Most PAAAs are currently repaired using an open approach. The objective of this study was to determine which patients are at highest risk with open PAAA repair and might benefit most from endovascular repair using fenestrated or branched stent grafts. METHODS: This was a retrospective cohort study using data from American College of Surgeons National Surgical Quality Improvement Program (NSQIP) hospitals. We identified 598 patients (27.5% women) who underwent elective open PAAA repair from the 2007 to 2009 NSQIP, a prospective database maintained at >250 centers. The main outcome measure was 30-day postoperative mortality. RESULTS: The median patient age was 73 years. The 30-day major morbidity rate was 30.1%, and the mortality rate was 4.5%. Major complications included reintubation (10.0%), sepsis (10.7%), return to operating room (9.2%), new dialysis requirement (5.9%), cardiac arrest or myocardial infarction (4.5%), and stroke (1.2%). Multivariate analyses identified four predictors of postoperative mortality after open PAAA repair: peripheral arterial disease (PAD) requiring revascularization or amputation, chronic obstructive pulmonary disease (COPD), anesthesia time, and female sex. PAD and COPD were present in only 5.2% and 20.4% of patients but were associated with a 16.1% and 9.0% mortality rate, respectively. The mortality rate in women was 7.3% vs 3.5% for men (P = .045). CONCLUSIONS: PAD, COPD, and female sex are major risk factors for postoperative mortality after open PAAA repair. Fenestrated or branched stent graft repair may be a more valuable alternative to open repair for patients with one or more of these characteristics who have suitable access vessels. PMID- 22209614 TI - Vein bypasses to branches of pedal arteries. AB - OBJECTIVE: We report a retrospective analysis of our experience in bypass vein graft surgery to lateral tarsal, medial plantar, and lateral plantar arteries for treatment of critical limb ischemia (CLI). METHODS: Between January 1991 and February 2010, we performed 137 inframalleolar bypass graft surgeries; of these, 25 (18%) were conducted using foot branch arteries for distal implant. All patients were treated for CLI and most had extensive infrapopliteal atherosclerotic disease (TransAtlantic Inter-Society Consensus D). Mean follow-up was 46.32 months (range, 0-144 months). Main end points analyzed were cumulative patency, limb salvage, and survival. Statistic analysis of all end points was performed using Kaplan-Meier survival curves. RESULTS: There was a predominance of men (64%), and the group mean age was 66.3 years. Diabetes mellitus was the main associated disease. Eighty percent of ulcers or gangrene were restricted to the midfoot (Rutherford V CLI classification). There was a predominance of short length grafts using the great saphenous vein as the main conduit (72%). The medial plantar artery was the main outflow artery (52%). Early graft occlusion occurred in four patients (primary failure rate, 16%). Secondary patency at 1 and 3 years was 49% and 36.8%, respectively, and limb salvage was 81.7% and 69%, respectively. Nine major amputations occurred, and 10 other minor amputations were necessary. Survival rate at 3 years was 65.4%, and 67% of patients maintained ambulation. Surgical mortality was 8%. No condition was associated with worse results with regard to secondary patency, limb salvage, or survival. CONCLUSIONS: Long-term results for developed foot branch bypass demonstrated good results for limb salvage, and it is an acceptable surgery for patients with extensive atherosclerotic disease. PMID- 22209616 TI - Femoral-femoral stabilizing buddy wire for embolization of the internal iliac artery. AB - Internal iliac artery (IIA) embolization is performed in a variety of clinical scenarios, most commonly in patients undergoing endovascular aneurysm repair (EVAR) with an iliac artery aneurysm or inadequate distal landing zone. In these patients, IIA embolization with iliac limb extension is often performed. While IIA embolization can be routinely performed with either ipsilateral or contralateral femoral arterial access, it can be challenging in some patients with an acutely angulated aortic or iliac bifurcation and in patients with short or ectatic common iliac arteries. In this select group of patients with difficult anatomy, IIA embolization can be challenging and may lead to increased radiation exposure and contrast administration. Having a sheath precisely positioned and stabilized at the internal iliac artery origin will facilitate embolization of the IIA. This report describes a novel technique in which crossover femoral femoral artery buddy wire placement achieves stable positioning of large sheaths for concurrent IIA embolization at the time of EVAR. PMID- 22209615 TI - Endothelium-dependent nitric oxide and hyperpolarization-mediated venous relaxation pathways in rat inferior vena cava. AB - INTRODUCTION: The vascular endothelium plays a major role in the control of arterial tone; however, its role in venous tissues is less clear. The purpose of this study was to determine the role of endothelium in the control of venous function and the relaxation pathways involved. METHODS: Circular segments of inferior vena cava (IVC) from male Sprague-Dawley rats were suspended between two wires and isometric contraction to phenylephrine (Phe; 10(-5)M) and 96 mM KCl was measured. Acetylcholine (Ach; 10(-10) to 10(-5)M) was added and the percentage of venous relaxation was measured. To determine the role of nitric oxide (NO) and prostacyclin (PGI(2)), vein relaxation was measured in the presence of the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 3 * 10( 4) M) and the cyclooxygenase inhibitor indomethacin (10(-5) M). To measure the role of hyperpolarization, vein relaxation was measured in the presence of K(+) channel activator cromakalim (10(-11) to 10(-6) M), and the nonselective K(+) channel blocker tetraethylammonium (TEA; 10(-3) M). To test for the contribution of a specific K(+) channel, the effects of K(+) channel blockers: glibenclamide (adenosine triphosphate [ATP]-sensitive K(ATP), 10(-5) M), 4-aminopyridine (4-AP; voltage-dependent K(v), 10(-3) M), apamin (small conductance Ca(2+)-dependent SK(Ca), 10(-7) M), and iberiotoxin (large conductance Ca(2+)-dependent BK(Ca), 10(-8) M) on Ach-induced relaxation were tested. RESULTS: Ach caused concentration-dependent relaxation of Phe contraction (maximum 49.9 +/- 4.9%). Removal of endothelium abolished Ach-induced relaxation. IVC treatment with L NAME partially reduced Ach relaxation (32.8 +/- 4.9%). In IVC treated with L-NAME plus indomethacin, significant Ach-induced relaxation (33.6 +/- 3.2%) could still be observed, suggesting a role of endothelium-derived hyperpolarizing factor (EDHF). In IVC treated with L-NAME, indomethacin and TEA, Ach relaxation was abolished, supporting a role of EDHF. In veins stimulated with high KCl, Ach caused relaxation (maximum 59.5 +/- 3.5%) that was abolished in the presence of L NAME and indomethacin suggesting that any Ach-induced EDHF is blocked in the presence of high KCl depolarizing solution, which does not favor outward movement of K(+) ion and membrane hyperpolarization. Cromakalim, an activator of K(ATP), caused significant IVC relaxation when applied alone or on top of maximal Ach induced relaxation, suggesting that the Ach response may not involve K(ATP). Ach induced relaxation was not inhibited by glibenclamide, 4-AP, or apamin, suggesting little role of K(ATP), K(v) or SK(Ca), respectively. In contrast, iberiotoxin significantly inhibited Ach-induced relaxation, suggesting a role of BK(Ca). CONCLUSIONS: Thus, endothelium-dependent venous relaxation plays a major role in the control of venous function. In addition to NO, an EDHF pathway involving BK(Ca) may play a role in endothelium-dependent venous relaxation. PMID- 22209617 TI - Sideways displacement of the endograft within the aneurysm sac is associated with late adverse events after endovascular aneurysm repair. AB - OBJECTIVE: Previous studies have shown the importance of proximal and distal endograft fixation. There is little information on the middle, unsupported section of endograft within the aneurysm sac. We quantified sideways movement of the endograft within the aneurysm sac and correlated it to late adverse events. METHODS: Patients who underwent endovascular abdominal aortic aneurysm (AAA) repair with a suprarenal or infrarenal endograft between January 1997 and December 2007 were analyzed for sideways endograft movement. Patients were included if they had a digital preoperative computed tomography angiogram (CTA), a postoperative CTA within 3 months after the index procedure, and at least one follow-up CTA thereafter with a minimal time interval of 6 months. The endograft position within the aneurysm sac was quantitated on cross-sectional images using a fixed vertebral body reference point. Patients with change in endograft position >=5 mm were placed in the sideways displacement (SD) group and compared with patients with no displacement (ND; <5 mm change in position). The relationship between sideways endograft movement and endovascular aneurysm repair (EVAR)-related complications were noted for AAA rupture, AAA-related death, conversion, secondary procedures, AAA growth (>=5 mm), proximal migration (>=10 mm), and new onset of type I or III endoleaks. RESULTS: The study included 144 patients (mean age, 76 +/- 7.6 years). Mean follow-up time was 43 +/- 27 months. Fifty patients (35%) had sideways endograft movement >=5 mm during follow-up. Baseline AAA diameter was larger (SD 60 +/- 9 mm vs ND 57 +/- 9 mm; P < .05) and proximal and iliac endograft fixation lengths were shorter (SD 18 +/- 8 mm vs ND 24 +/- 11 mm; P < .05 and SD 35 +/- 14 vs ND 42 +/- 16 mm; P < .05) in patients with sideways endograft displacement. There was no significant difference between the groups in AAA rupture and AAA-related death (one fatal AAA rupture, ND group). SD patients had a higher surgical conversion rate (10% vs 0%; P = .002), more secondary procedures (44% vs 6%; P < .001), more AAA sac enlargement (42% vs 10%; P < .001), more endograft migration (66% vs 5%; P < .001), and more type I or III endoleaks (36% vs 3%; P < .001). CONCLUSIONS: Positional stability of the endograft within the aneurysm sac is critical for the long-term success of EVAR. Sideways movement of the endograft within the aneurysm sac is associated with an increased risk of late adverse events. PMID- 22209618 TI - [Medicinal prescriptions in geriatrics: overuse, misuse, underuse. Qualitative analysis from the prescriptions of 200 patients admitted in an acute care geriatric unit]. AB - PURPOSE: In the elderly three modalities of suboptimal drug prescriptions are known: overuse, misuse, underuse. PATIENTS AND METHODS: This prospective observational study was conducted between September 2008 and March 2009. The prescriptions of 200 patients aged over 75 years admitted in the acute care geriatric unit at the teaching hospital of Brest (France) have been qualitatively analyzed to assess the prevalence of the three types of suboptimal prescription. RESULTS: A strong prevalence of overuse (77% of the patients), underuse (64.5%) and at minor degree of misuse (47.5%) were evidenced. Overuse and misuse were more frequent in polypathogical and polymedicated patients living in nursing home. Underuse was more prevalent in polypathological patients living at home. No significant relation was found between suboptimal prescriptions, age, gender or cognitive status. CONCLUSION: This study demonstrates the strong prevalence of overuse, misuse and underuse prescriptions in hospitalized elderly patient and analyses the most frequently implicated drugs and the different factors predisposing to these suboptimal prescriptions. This way of analysis of prescriptions could be a pertinent method to improve drug prescription in the elderly. PMID- 22209619 TI - [Concern regarding early exposure to thiomersal and mercury poisoning: comment on the article by Bensefa-Colas et al]. PMID- 22209620 TI - Oculomotor nerve palsy as an initial manifestation of polycythemia vera. AB - In polycythemia vera (PV), even though thrombotic complications are common, ophthalmoplegia rarely occurs, and oculomotor nerve palsy has not been described as an initial manifestation. We present a 53-year-old woman who developed right oculomotor nerve palsy and investigation disclosed PV as the cause of ophthalmoplegia. MRI also revealed an acute silent infarction in the right frontal subcortex. PV may manifest with oculomotor nerve palsy owing to a thrombotic complication and should be considered in the differential diagnosis of acute ophthalmoplegia. PMID- 22209621 TI - Characterization of solid phases and study of transformation kinetics in m chlorofluorobenzene by 35Cl nuclear quadrupole resonance. AB - Polymorphism is of widespread occurrence in the world of molecular crystals. In this work we present experimental results showing the existence of four solid phases in m-chlorofluorobenzene. A glass structure is achieved by quenching the liquid phase at 77 K. This glassy state crystallizes in a disordered phase at T~143 K, which in turn transforms to the high-temperature stable phase (phase I) at T~153 K. Depending on the thermal history of the sample, a different ordered phase (phase III) can be obtained. The disorder is attributed to a molecular orientational disorder. There is no evidence of molecular reorientation in any phase. A study of the disorder-order phase transformation kinetics, using nuclear quadrupole resonance, is presented. The results are analyzed following Cahn's theory. Nucleation seems to take place at grain boundaries. Growth rates for different temperatures have been determined. PMID- 22209622 TI - Effective lubrication of articular cartilage by an amphiphilic hyaluronic acid derivative. AB - BACKGROUND: Intra-articular injection of hyaluronic acid based therapies is gaining popularity as a treatment option for non-operative management of patients with symptomatic osteoarthritis. Although there is an abundance of evidence for both biological and mechanical mechanisms of joint protection by hyaluronic acid, one clear intention of viscosupplementation is to reduce friction and wear by providing an extrinsic lubricant. We tested the in vitro friction response of a novel hyaluronic acid derivative that presents amphiphilic features to promote adhesion to the cartilage surface and thereby improve cartilage lubrication. METHODS: Migrating Contact Area and Static Contact Area friction tests were conducted on bovine articular cartilage to assess the efficacy of two lubricants, a chemically modified amphiphilic hyaluronic acid and synovial fluid from a healthy joint, as well as a phosphate buffered saline negative control. FINDINGS: No differences in lubrication (P=0.34) were evident between the three test articles during the Migrating Contact Area test, which represents articulation of healthy articular cartilage. The modified hyaluronic acid presented an equilibrium friction coefficient 2.8 times less than that of the synovial fluid (P <= 0.0005) and five times less than that of the PBS control (P <= 0.0001) during the Static Contact Area test, representing a mixed lubrication condition. INTERPRETATION: The present study demonstrated that a chemically modified amphiphilic hyaluronic acid can provide equivalent lubrication to synovial fluid during articulation of loaded healthy articular cartilage and can provide superior lubrication as indicated by a lower coefficient of friction than synovial fluid under loading conditions potentially associated with cartilage wear. PMID- 22209623 TI - Unraveling plant-microbe interactions: can multi-species transcriptomics help? AB - Plants in their natural habitats are surrounded by a large number of microorganisms. Some microbes directly interact with plants in a mutually beneficial manner whereas others colonize the plant only for their own benefit. In addition, microbes can indirectly affect plants by drastically altering their environments. Understanding the complex nature of plant-microbe interactions can potentially offer new strategies to enhance plant productivity in an environmentally friendly manner. As briefly reviewed here, the emerging area of multi-species transcriptomics holds the promise to provide knowledge on how this can be achieved. We discuss key aspects of how transcriptome analysis can be used to provide a more comprehensive picture of the complex interactions of plants with their biotic and abiotic environments. PMID- 22209624 TI - Error correction in gene synthesis technology. AB - Accurate, economical and high-throughput gene and genome synthesis is essential to the development of synthetic biology and biotechnology. New large-scale gene synthesis methods harnessing the power of DNA microchips have recently been demonstrated. Yet, the technology is still compromised by a high occurrence of errors in the synthesized products. These errors still require substantial effort to correct. To solve this bottleneck, novel approaches based on new chemistry, enzymology or next generation sequencing have emerged. This review discusses these new trends and promising strategies of error filtration, correction and prevention in de novo gene and genome synthesis. Continued innovation in error correction technologies will enable affordable and large-scale gene and genome synthesis in the near future. PMID- 22209625 TI - Effect of cigarette smoking on cough reflex induced by TRPV1 and TRPA1 stimulations. AB - BACKGROUND: Recent studies have shown that neurogenic inflammation induced by cigarette smoke is inhibited by TRPA1 antagonist, but not by TRPV1 antagonist. Since cough reflex sensitivity is known to be modified by smoking status, we investigated the effects of cigarette smoking on TRPA1- and TRPV1-induced cough and urge-to-cough in healthy males. METHODS: Twenty-six healthy never-smokers and 30 healthy current smokers were recruited via public postings. Cough reflex thresholds and urge-to-cough were evaluated by inhalation of capsaicin, a TRPV1 agonist, and cinnamaldehyde, a TRPA1 agonist. The cough reflex thresholds were defined as the lowest concentrations of capsaicin and cinnamaldehyde that elicited two or more coughs (C(2)) and five or more coughs (C(5)), respectively. The urge-to-cough was evaluated using the modified Borg scale. RESULTS: In capsaicin-induced cough, the cough reflex thresholds, as expressed by C(2) and C(5), in current smokers were significantly higher than those in never-smokers (p<0.01 and p<0.001, respectively). The urge-to-cough log-log slopes in current smokers were significantly lower than those of never-smokers (p<0.001). There were no significant differences in the thresholds of the urge-to-cough between never-smokers and current smokers. In cinnamaldehyde-induced cough, there were no significant differences in cough reflex thresholds in C(2) and C(5) between never smokers and current smokers, nor were there any significant differences in urge to-cough log-log slope between never-smokers and current smokers. There were no significant differences in the thresholds of the urge-to-cough between never smokers and current smokers. CONCLUSION: The study suggests that smoking has a differential effect on cough responses between TRPV1 and TRPA1 stimulations. PMID- 22209626 TI - Development of cylindrical stepwedge phantom for routine quality controls of a helical tomotherapy machine. AB - The aim of this study was to design a cylindrical stepwedge phantom and an appropriate treatment procedure, based on which parameters of tomotherapy machine and generated beam of radiation will be defined. The accuracy of parameter determination, which can be defined with the aid of the measurement system, was also evaluated. The cylindrical phantom that we developed and manufactured (stepwedge phantom) consists of four cylinders with different diameters made of polycaprolactam-PA-6, i.e. material with high mechanical strength, low water absorption (making measurements repeatable) and a density comparable to that of human soft tissues. The appropriate treatment procedure is carried out in a dynamic mode, which is focused on specific properties of the tomotherapy machine. It means that a phantom situated on the couch moves to the inside of the rotating linear accelerator. A total of 18 procedures were implemented in order to calculate the following parameters: couch velocity, dose rate value at a depth, Dose Ratio coefficients, dose variation (so-called Dose Flatness) coefficients, and the time of gantry rotation. Reference intervals for these parameters were determined to be as follows: for the couch velocity: +/-1.2%, the average dose rate measured at depth: +/-1.8%, the calculated values of the coefficients Dose Ratio: +/-0.5% and Dose Flatness: (0.53-0.65)%, the time of gantry rotation: +/ 3%. The final results showed that during a single irradiation procedure, which lasts 5 min, the cylindrical stepwedge phantom allows to precisely determine the values of the above-mentioned parameters. Its use in the daily dosimetric measurements can ensure better control of the work of the tomotherapy machine. PMID- 22209627 TI - Pretreatment serum microRNA-122 is not predictive for treatment response in chronic hepatitis C virus infection. AB - BACKGROUND: MicroRNA-122 is a liver specific microRNA and is elevated in the sera of patients with chronic hepatitis C virus infection. Hepatic microRNA-122 levels have been described to be reduced in patients with non-response to antiviral treatment with pegylated interferon-alpha and ribavirin. AIM: Assessment of differences in serum microRNA-122 levels in patients with sustained virological response and non-response. METHODS: RNA was extracted from pretreatment serum samples and microRNA-122 and microRNA-16 levels were measured by quantitative PCR and compared in patients with sustained virological response and non-response. RESULTS: The levels of microRNA-122 and microRNA-16 in the sera did not differ between patients with sustained virological response and non-response. CONCLUSION: Serum microRNA-122 is not a suitable marker for treatment response prediction to combination therapy with pegylated interferon-alpha and ribavirin in patients with chronic hepatitis C virus infection. PMID- 22209628 TI - Student nurse perceptions of risk in relation to international placements: a phenomenological research study. AB - BACKGROUND: International nursing electives have been identified as a positive learning experience for students. However, whilst there are risks associated with international student placements in general, there is a scarcity of research specifically relating to student nurse's experiences of risk. OBJECTIVE: This study aimed to investigate UK undergraduate student nurse experiences of risk during an international placement. DESIGN AND METHODS: A phenomenological methodology was applied and semi-structured interviews were conducted with student nurses who had recently returned from an international clinical placement abroad. SETTING AND PARTICIPANTS: Ten, second year student nurses, studying on a pre-registration diploma/BSc (Hons) Nursing Studies/Registered Nurse programme from one UK University participated in the study. FINDINGS AND CONCLUSIONS: Findings from the study highlighted that students felt that three types of risk existed; physical risk, clinical-professional risk and socio-cultural risk. Perceptions of risk were influenced by sociological theory relating to the concept of 'the other' and students attempted to reduce risk by employing strategies to reduce 'Otherness'. They also applied psychological theory relating to heuristics such as 'safety in numbers.' It also emerged from the study that exposure to perceived risk enhanced learning as students reported that it encouraged personal and professional development in particular and so assisted students in their move toward self-actualisation. It is suggested, and intended, that findings from this study can be applied to the preparation of students to further enhance their safety and learning experience during international placements abroad. PMID- 22209629 TI - ATP-independent control of autotransporter virulence protein transport via the folding properties of the secreted protein. AB - Autotransporter (AT) proteins are the largest class of extracellular virulence proteins secreted from Gram-negative bacteria. The mechanism by which AT proteins cross the bacterial outer membrane (OM), in the absence of ATP or another external energy source, is unknown. Here we demonstrate a linear correlation between localized regions of stability (DeltaG(folding)) in the mature virulence protein (the AT "passenger") and OM secretion efficiency. Destabilizing the C terminal beta-helical domain of a passenger reduced secretion efficiency. In contrast, destabilizing the globular N-terminal domain of a passenger produced a linearly correlated increase in secretion efficiency. Thus, C-terminal passenger stability facilitates OM secretion, whereas N-terminal stability hinders it. The contributions of regional passenger stability to OM secretion demonstrate a crucial role for the passenger itself in directing its secretion, suggesting a novel type of ATP-independent, folding-driven transporter. PMID- 22209630 TI - Tracking verocytotoxigenic Escherichia coli O157, O26, O111, O103 and O145 in Irish cattle. AB - The purpose of this study was to investigate carriage and transfer of verocytotoxigenic Escherichia coli (VTEC) O157, O26, O111, O103 and O145 from faeces and hide to dressed carcasses of Irish cattle as well as establishing the virulence potential of VTEC carried by these cattle. Individual cattle was tracked and faecal samples, hide and carcass (pre-evisceration and post-wash) swabs were analysed for verotoxin (vt1 and vt2) genes using a duplex real-time PCR assay. Positive samples were screened for the five serogroups of interest by real-time PCR. Isolates were recovered from PCR positive samples using immunomagnetic separation and confirmed by latex agglutination and PCR. Isolates were subject to a virulence screen (vt1, vt2, eaeA and hlyA) by PCR. Isolates carrying vt genes were examined by Pulsed-Field Gel Electrophoresis (PFGE). Of the VTEC isolated, E. coli O157 was the most frequently recovered from hide (17.6%), faeces (2.3%) and pre-evisceration/post-wash carcass (0.7%) samples. VTEC O26 was isolated from 0.2% of hide swabs and 1.5% of faeces samples. VTEC O145 was isolated from 0.7% of faeces samples. VTEC O26 and VTEC O145 were not recovered from carcass swabs. Non-VTEC O103 was recovered from all sample types (27.1% hide, 8.5% faeces, 5.5% pre-evisceration carcass, 2.2% post-wash carcass), with 0.2% of hide swabs and 1.0% of faeces samples found to be positive for VTEC O103 isolates. E. coli O111 was not detected in any samples. For the four serogroups recovered, the direct transfer from hide to carcass was not observed. This study shows that while VTEC O157 are being carried by cattle presented for slaughter in Ireland, a number of other verotoxin producing strains are beginning to emerge. PMID- 22209631 TI - Multidetector computed tomography predictors of late ventricular remodeling and function after acute myocardial infarction. AB - BACKGROUND: Despite advent of rapid arterial revascularization as 1st line treatment for acute myocardial infarction (AMI), incomplete restoral of flow at the microvascular level remains a problem and is associated with adverse prognosis, including pathological ventricular remodeling. We aimed to study the association between multidetector row computed tomography (MDCT) perfusion defects and ventricular remodeling post-AMI. METHODS: In a prospective study, 20 patients with ST-elevation AMI, treated by primary angioplasty, underwent arterial and late phase MDCT as well as radionuclide scans to study presence, size and severity of myocardial perfusion defects. Contrast echocardiography was performed at baseline and at 4 months follow-up to evaluate changes in myocardial function and remodeling. RESULTS: Early defects (ED), late defects (LD) and late enhancement (LE) were detected in 15, 7 and 16 patients, respectively and radionuclide defects in 15 patients. The ED area (r=0.74), and LD area (r=0.72), and to a lesser extent LE area (r=0.62) correlated moderately well with SPECT summed rest score. By univariate analysis, follow-up end-systolic volume index and ejection fraction were both significantly related to ED and LD size and severity, but not to LE size or severity. By multivariate analysis, end-systolic volume index was best predicted by LD area (p<0.05) and ejection fraction by LD enhancement ratio. CONCLUSIONS: LD size and severity on MDCT are most closely associated with pathological ventricular remodeling after AMI and may thus play a role in early identification and treatment of this condition. PMID- 22209632 TI - Investigation of the endovascularly treated and untreated unruptured vertebrobasilar artery aneurysms. AB - BACKGROUND AND PURPOSE: The present study aimed to investigate the endovascular indication with close monitoring of both endovascularly treated and untreated unruptured vertebrobasilar aneurysms. MATERIALS AND METHODS: In the past 2 years, 36 patients [7 women and 29 men with a mean age of 48.5 years (range, 13-75 years)] who had 40 unruptured vertebrobasilar artery aneurysms were reviewed. The decision of the endovascular treatment was not randomized. In both endovascularly untreated and treated patients, overall mortality and morbidity corresponding to Glasgow outcome scale (GOS) score III or worse was counted as unruptured aneurysm related event. The ratio of event free was compared between endovascularly treated and untreated patients using Log-rank test. In a univariate analysis, poor outcome was predicted by endovascularly untreated. RESULTS: Thirty-six patients were followed with a mean period of 10.7 months (range, 0.7 months-21 months). In untreated cases, new neurological deficits caused by the aneurysm were noted in 2 cases. The annual deterioration rate of the untreated cases was 9.1%. In endovascularly treated cases, there was no mortality and morbidity. There was no SAH in all cases during follow-up period. When ratio of event free was compared, significant advantage of endovascular treatment was noted (X(2)=4.429, P=0.035). CONCLUSIONS: The present results indicated that endovascular treatment has a benefit for the unruptured vertebrobasilar artery aneurysms. PMID- 22209633 TI - The role of imaging for the surgeon in primary malignant bone tumors of the chest wall. AB - Primary malignant chest wall tumors are rare. The most frequent primary malignant tumor of the chest wall is chondrosarcoma, less common are primary bone tumors belonging to the Ewing Family Bone Tumors (EFBT), or even rarer are osteosarcomas. They represent a challenging clinical entities for surgeons as the treatment of choice for these neoplasms is surgical resection, excluding EFBT which are normally treated by a multidisciplinary approach. Positive margins after surgical procedure are the principal risk factor of local recurrence, therefore to perform adequate surgery a correct preoperative staging is mandatory. Imaging techniques are used for diagnosis, to determine anatomic site and extension, to perform a guided biopsy, for local and general staging, to evaluate chemotherapy response, to detect the presence of a recurrence. This article will focus on the role of imaging in guiding this often difficult surgery and the different technical possibilities adopted in our department to restore the mechanics of the thoracic cage after wide resections. PMID- 22209634 TI - Depressive symptoms in Parkinson's disease. AB - OBJECTIVE: We aimed to investigate the relationship between the presence and severity of depression and the degree of motor and functional disability in Parkinson's disease (PD). METHODS: One hundred twenty-two outpatients with PD were enrolled in a neurology department: 65 satisfied the Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition criteria for major depression, and 57 did not (PD-C). Depressive symptoms were assessed by means of the Hamilton Rating Scale for Depression (HRSD), and the PD severity was assessed according to the Hoehn and Yahr System. Activities of daily living and motor symptoms were measured by the Unified PD Rating Scale (UPDRS), parts II and III. RESULTS: Twenty-nine patients had a mild depression (HRSD total score ranging between 8 and 17), 30 had a moderate depression (HRSD total score ranging between 18 and 24), and 6 had a severe depression (HRSD total score, >=25). By comparing the 3 groups of patients, it emerged that those with a severe depression showed significantly higher scores at the UPDRS II, UPDRS III, and HY scales than did PD C or patients with a mild depression. Moreover, patients with a moderate depression scored significantly higher on the UPDRS II, UPDRS III, and HY scales than did PD-C or those with a mild depression. CONCLUSIONS: Our findings suggest that depression and motor symptoms/well-being are highly intertwined in patients with PD. PMID- 22209635 TI - Characterization of fecal indicator bacteria in sediments cores from the largest freshwater lake of Western Europe (Lake Geneva, Switzerland). AB - This study characterized the fecal indicator bacteria (FIB), including Escherichia coli (E. coli) and Enteroccocus (ENT), disseminated over time in the Bay of Vidy, which is the most contaminated area of Lake Geneva. Sediments were collected from a site located at ~500 m from the present waste water treatment plant (WWTP) outlet pipe, in front of the former WWTP outlet pipe, which was located at only 300 m from the coastal recreational area (before 2001). E. coli and ENT were enumerated in sediment suspension using the membrane filter method. The FIB characterization was performed for human Enterococcus faecalis (E. faecalis) and Enterococcus faecium (E. faecium) and human specific bacteroides by PCR using specific primers and a matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Bacterial cultures revealed that maximum values of 35.2 * 10(8) and 6.6 * 10(6)CFU g(-1) dry sediment for E. coli and ENT, respectively, were found in the sediments deposited following eutrophication of Lake Geneva in the 1970s, whereas the WWTP started operating in 1964. The same tendency was observed for the presence of human fecal pollution: the percentage of PCR amplification with primers ESP-1/ESP-2 for E. faecalis and E. faecium indicated that more than 90% of these bacteria were from human origin. Interestingly, the PCR assays for specific-human bacteroides HF183/HF134 were positive for DNA extracted from all isolated strains of sediment surrounding WWPT outlet pipe discharge. The MALDI-TOF MS confirmed the presence of general E. coli and predominance E. faecium in isolated strains. Our results demonstrated that human fecal bacteria highly increased in the sediments contaminated with WWTP effluent following the eutrophication of Lake Geneva. Additionally, other FIB cultivable strains from animals or adapted environmental strains were detected in the sediment of the bay. The approaches used in this research are valuable to assess the temporal distribution and the source of the human fecal pollution in aquatic environments. PMID- 22209636 TI - Optogenetics, sex, and violence in the brain: implications for psychiatry. AB - Pathological aggression and the inability to control aggressive impulses takes a tremendous toll on society. Yet aggression is a normal component of the innate behavior repertoire of most vertebrate animal species as well as of many invertebrates. Progress in understanding the etiology of disorders of aggressive behavior, whether genetic or environmental in nature, therefore requires an understanding of the brain circuitry that controls normal aggression. Efforts to understand this circuitry at the level of specific neuronal populations have been constrained by the limited resolution of classical methodologies, such as electrical stimulation and electrolytic lesion. The availability of new, genetically based tools for mapping and manipulating neural circuits at the level of specific, genetically defined neuronal subtypes provides an opportunity to investigate the functional organization of aggression circuitry with cellular resolution. However, these technologies are optimally applied in the mouse, where there has been surprisingly little traditional work on the functional neuroanatomy of aggression. Here we discuss recent, initial efforts to apply optogenetics and other state-of-the-art methods to the dissection of aggression circuitry in the mouse. We find, surprisingly, that neurons necessary and sufficient for inter-male aggression are located within the ventrolateral subdivision of the ventromedial hypothalamic nucleus, a structure traditionally associated with reproductive behavior. These neurons are intermingled with neurons activated during male-female mating, with approximately 20% overlap between the populations. We discuss the significance of these findings with respect to neuroethological and neuroanatomical perspectives on the functional organization of innate behaviors and their potential implications for psychiatry. PMID- 22209637 TI - Cocaine hydrolase encoded in viral vector blocks the reinstatement of cocaine seeking in rats for 6 months. AB - BACKGROUND: Cocaine dependence is a pervasive disorder with high rates of relapse. In a previous study, direct administration of a quadruple mutant albumin fused butyrylcholinesterase that efficiently catalyzes hydrolysis of cocaine to benzoic acid and ecgonine methyl ester acutely blocked cocaine seeking in an animal model of relapse. In the present experiments, these results were extended to achieve a long-duration blockade of cocaine seeking with a gene transfer paradigm using a related butyrylcholinesterase-based cocaine hydrolase (CocH). METHODS: Male and female rats were allowed to self-administer cocaine under a fixed-ratio 1 schedule of reinforcement for approximately 14 days. Following the final self-administration session, rats were injected with CocH vector or a control injection (empty vector or saline), and their cocaine solutions were replaced with saline for 14 days to allow for extinction of lever pressing. Subsequently, they were tested for drug-primed reinstatement by administering intraperitoneal injections of saline (S), cocaine (C) (5, 10, and 15 mg/kg), and d-amphetamine according to the following sequence: S, C, S, C, S, C, S, d amphetamine. Rats then received cocaine-priming injections once weekly for 4 weeks and, subsequently, once monthly for up to 6 months. RESULTS: Administration of CocH vector produced substantial and sustained CocH activity in plasma that corresponded with diminished cocaine-induced (but not amphetamine-induced) reinstatement responding for up to 6 months following treatment (compared with high-responding control animals). CONCLUSIONS: These results demonstrate that viral transfer of CocH may be useful in promoting long-term resistance to relapse to cocaine addiction. PMID- 22209638 TI - Psychostimulants act within the prefrontal cortex to improve cognitive function. AB - BACKGROUND: At low and clinically relevant doses, psychostimulants enhance cognitive and behavioral function dependent on the prefrontal cortex (PFC) and extended frontostriatal circuitry. These actions are observed in individuals with attention-deficit/hyperactivity disorder, as well as in normal human and animal subjects. Despite the widespread use of these drugs, the sites of action involved in their cognition-enhancing and therapeutic effects are poorly understood. Indirect and/or correlative evidence suggests the cognition-enhancing/therapeutic effects of psychostimulants may involve actions directly within the PFC or extended frontostriatal circuitry. The current studies examined the degree to which methylphenidate (MPH) (Ritalin) acts within distinct frontostriatal subfields to improve PFC-dependent cognition as measured in a delayed-response test of spatial working memory. METHODS: Working memory performance was assessed following microinfusion of vehicle or varying doses of MPH (.03-8.0 MUg/500 nL) directly into the dorsomedial PFC (dorsal prelimbic and dorsal anterior cingulate cortex), the ventromedial PFC (infralimbic), and the dorsomedial striatum of rats (n = 69). RESULTS: Methylphenidate infusion into the dorsomedial PFC, but not ventromedial PFC, elicited an inverted U-shaped facilitation of PFC-dependent cognition as measured in this task. The magnitude of this improvement was comparable with that seen with systemic administration. Additional studies demonstrated that although the dorsomedial striatum is necessary for accurate performance in this task, MPH infusion into this region did not affect working memory performance. CONCLUSIONS: These observations provide the first definitive evidence that the PFC is a site of action in the cognition-enhancing and presumably therapeutic actions of low-dose psychostimulants. PMID- 22209639 TI - Cortical thickness and folding deficits in conduct-disordered adolescents. AB - BACKGROUND: Studies of pediatric conduct disorder (CD) have described frontal and temporal lobe structural abnormalities that parallel findings in antisocial adults. The purpose of this study was to examine previously unexplored cortical thickness and folding as markers for brain abnormalities in "pure CD"-diagnosed adolescents. On the basis of current frontotemporal theories, we hypothesized that CD youth would have thinner cortex or less cortical folding in temporal and frontal lobes than control subjects. METHODS: We obtained T1-weighted brain structure images from 24 control and 19 CD participants aged 12 to 18 years, matched by gender and age. We measured group differences in cortical thickness and local gyrification index (regional cortical folding measure) using surface based morphometry with clusterwise correction for multiple comparisons. RESULTS: The CD participants, compared with control subjects, showed both reduced cortical thickness and folding. Thinner cortex was located primarily in posterior brain regions, including left superior temporal and parietal lobes, temporoparietal junction and paracentral lobule, right superior temporal and parietal lobes, temporoparietal junction, and precuneus. Folding deficits were located mainly in anterior brain regions and included left insula, ventro- and dorsomedial prefrontal, anterior cingulate and orbitofrontal cortices, temporal lobe, right superior frontal and parietal lobes, and paracentral lobule. CONCLUSIONS: Our findings generally agree with previous CD volumetric studies but here show the unique contributions of cortical thickness and folding to gray matter reductions in pure CD in different brain regions. PMID- 22209641 TI - Supramolecular assemblies in functional siRNA delivery: where do we stand? AB - The discovery of RNA interference (RNAi) has excited the scientific field due to its potential for wide range of therapeutic applications. The pharmacological mediator of RNAi, short interfering RNA (siRNA), however, has faced significant obstacles in reaching its target site and effectively exerting its silencing activity. Effective pharmacological use of siRNA requires 'carriers' that can deliver the siRNA to its intended site of action. The carriers assemble the siRNA into supramolecular complexes that display functional properties during the delivery process. This review will summarize non-viral approaches to siRNA delivery, emphasizing the current obstacles to delivery and the mechanisms employed to overcome these obstacles. The carriers successfully pursued in pre clinical (animal) models will be presented so as to provide a glimpse of possible candidates for clinical testing. Supramolecular assembly of nucleic acids with carriers will be probed from thermodynamics and computational perspectives to understand supramolecular structures and their dynamics. The delivery and trafficking requirements for siRNA are then dissected and engineering approaches to overcoming these barriers will be articulated. The latter has been attempted both at the cellular levels, focusing on intracellular barriers, as well as systemic level, emphasizing macroscopic challenges affecting siRNA delivery. Clinical experience with non-viral siRNA delivery is summarized, highlighting the nature delivery modes attempted in clinical settings. We conclude with a perspective on the future of siRNA therapeutics, specifically concentrating on the possible impact of non-viral carriers in the field. PMID- 22209640 TI - The effects of stimulant medication on working memory functional connectivity in attention-deficit/hyperactivity disorder. AB - BACKGROUND: Working memory impairments are commonly found in attention deficit/hyperactivity disorder (ADHD) and often improve with psychostimulant treatment. Little is known about how these medications affect the function of frontoparietal brain regions engaged for working memory. This study used functional magnetic resonance imaging (fMRI) to examine medication-related changes in brain activation and functional connectivity in ADHD. METHODS: Eighteen ADHD-combined subtype youths (ages 11-17) twice completed a Sternberg working memory fMRI task in a randomized, double-blind, placebo-controlled design. Medications were individualized as patients' standard, clinically effective psychostimulant (e.g., methylphenidate or dextroamphetamine/amphetamine combination) dose. Brain activity and functional connectivity were characterized using group independent component analysis. SPM5 repeated-measures t tests compared ADHD patients' network engagement and regional functional connectivity on and off medication. RESULTS: Independent component analysis identified six frontoparietal networks/components with hemodynamic responses to encoding/maintenance or retrieval phases of the Sternberg fMRI task. On medication, three of these networks significantly increased activation. Functional connectivity analyses found medication led to recruitment of additional brain regions that were not engaged into the networks when participants were on placebo. Also, medication strengthened connectivity of some frontoparietal regions. Many connectivity changes were directly related to improved working memory reaction time. Overall, there was strong evidence for regional functional connectivity changes following medication in structures previously implicated as abnormal in ADHD, such as anterior cingulate, ventrolateral prefrontal cortex, and precuneus. CONCLUSIONS: Stimulant medication has widespread effects on the functional connectivity of frontoparietal brain networks, which might be a mechanism that underlies their beneficial effects on working memory performance. PMID- 22209642 TI - In vivo detection of glutathione disulfide and oxidative stress monitoring using a biosensor. AB - A highly sensitive in vivo biosensor for glutathione disulfide (GSSG) is developed using covalently immobilized-glutathione reductase (GR) and -beta nicotinamide adenine dinucleotide phosphate (NADPH) on gold nanoparticles deposited on poly[2,2':5',2"-terthiophene-3'-(p-benzoic acid)] (polyTTBA). The fabricated biosensor was characterized with SEM, TEM, XPS, and QCM. Analytical parameters affecting the biosensor performance were optimized in terms of applied potential, NADPH:GR ratio, temperature, and pH. A linear calibration plot is obtained using chronoamperometry in the dynamic range between 0.1 MUM and 2.5 mM of GSSG, with a detection limit of 12.5 +/- 0.5 nM. The developed biosensor is applied to detect GSSG in a real plasma sample. A microbiosensor was applied to detect the in vivo GSSG concentration to monitor the oxidative stress caused by diquat and t-butyl hydroperoxide. The results obtained are reliable, implying a promising approach for a GSSG biosensor in clinical diagnostics and oxidative stress monitoring. PMID- 22209643 TI - Lysosomal membrane destabilization induced by high accumulation of single-walled carbon nanohorns in murine macrophage RAW 264.7. AB - Cellular responses to graphene-based, nanometer-sized materials, such as carbon nanotubes and single-walled carbon nanohorns (SWNHs), have previously been studied at low-uptake levels. Here, by exploiting the availability of large quantities of SWNHs, cytotoxicity and the immunological responses induced by the abundant uptake of these structures were studied in RAW 264.7 murine macrophages. As much as half the cell interior was pigmented black by SWNHs, which were preferentially localized to lysosomes. High-uptake was shown to destabilize lysosomal membranes and generate reactive oxygen species that resulted in apoptotic, as well as necrotic, cell death. Despite these dramatic responses, only low levels of cytokines were released. The results will be interesting for future studies of the nanocarbon toxicity mechanisms and for medical applications of nanocarbons, especially those relying on lysosomes as target organelles for drug delivery or imaging. PMID- 22209644 TI - Clopidogrel responsiveness in stroke patients on a chronic aspirin regimen. AB - This study evaluated the antiplatelet effects of clopidogrel (CPG) in patients sustaining acute ischemic stroke who were already receiving chronic outpatient aspirin therapy (81-325 mg/day). Platelet function was measured using 3 different "point-of-care" platelet function analyzers: the Thrombelastograph hemostasis system, the Accumetrics VerifyNow system, and the Chronolog 570VS impedance aggregometer. Platelet function was assessed before administration of a 300-mg CPG loading dose and again at 26 hours and 64 hours after this loading dose along with a 75-mg daily maintenance dose. All 3 instruments detected marked inhibition of platelet function at 26 hours and 64 hours after CPG administration. There were significant variations among the 3 instruments in monitoring antiplatelet responses to aspirin and CPG; however, these variations were eliminated when the platelet function results were corrected for baseline platelet variability. The percentage of patients who were poor responders to CPG after switching from aspirin depended on the measurement instrument used, but was higher at 26 hours after CPG administration than at 64 hours after CPG administration. Our findings indicate that poor response to antiplatelet agents in general, and to CPG in particular, is a function of the measuring instrument. The correction for baseline platelet variability results in similar levels of platelet inhibition measured by the 3 platelet function analyzers. Future studies are warranted to examine the association between ex vivo CPG-induced platelet inhibition and clinical outcomes in patients with ischemic stroke. PMID- 22209645 TI - Efficacy of endovascular revascularization in elderly patients with acute large vessel occlusion: analysis from the RESCUE-Japan retrospective nationwide survey. AB - BACKGROUND: The purpose of this study was to evaluate the efficacy of endovascular treatment (EVT) in elderly patients (>= 75 years of age) with acute large-vessel occlusion (LVO). METHODS: A total of 229 patients with acute LVO treated by EVT in 2008 were registered from 68 medical centers in Japan. Among the total of 229 patients, 89 were elderly patients. We retrospectively investigated the treatment efficacy of EVT and patient outcome, and compared the parameters between the elderly and the nonelderly group. RESULTS: Recanalization after EVT was equally obtained in both groups (P = .71). There was no significant difference in the favorable outcome (modified Rankin Scale [mRS] 0-2) between the elderly and nonelderly groups (30.3% vs 33.6%; P = .61), whereas poor outcome (mRS 5 and 6) was observed more in the elderly group than in the nonelderly group (48.3% vs 32.1%; P = .01). In patients with any recanalization (Thrombolysis in Myocardial Infarction grading system 1-3), the rates of favorable outcome in both groups were similar (39.7% vs 42.6%; P = .71). In contrast, in patients without recanalization, there was a significant difference in the poor outcome between the elderly and the nonelderly groups (76.2% vs 46.7%; P = .046). Symptomatic intracranial hemorrhage occurred in 6.7% in the elderly group and in 11.4% in the nonelderly group (P = .23). CONCLUSIONS: The elderly population could achieve favorable outcomes comparable to the nonelderly population, especially when they achieve any recanalization by EVT. Elderly patients should not be excluded from recanalization therapy with EVT because of age. PMID- 22209646 TI - Intraprocedural prediction of hemorrhagic cerebral hyperperfusion syndrome after carotid artery stenting. AB - Hyperperfusion syndrome (HPS) is a rare but severe complication after carotid artery stenting (CAS). Reliable methods for predicting HPS remain to be developed. We aimed to establish a predictive value of hemorrhagic HPS after CAS. Our retrospective study included 136 consecutive patients who had undergone CAS. We determined the cerebral circulation time (CCT) by measuring the interval between the point of maximal opacification of the terminal portion of the internal carotid artery and the cortical vein. We calculated intraprocedural CCT changes (DeltaCCT) by subtracting postprocedural CCT values from preprocedural CCT values. The mean DeltaCCT was 0.9 +/- 0.9 seconds; 3 patients (2.2%) with prolonged DeltaCCT (2.7, 5.4, and 5.8 seconds) developed HPS. The cutoff time of 2.7 seconds predicted hemorrhagic HPS retrospectively with 100% sensitivity and 99% specificity. Our findings suggest that post-CAS HPS can be predicted by using the DeltaCCT value obtained by intraprocedural digital subtraction angiography. Patients with a DeltaCCT >2.7 seconds require careful intensive hemodynamic and neurologic monitoring after CAS. PMID- 22209647 TI - Structure-activity relationship of alpha hormones, the mating factors of phytopathogen Phytophthora. AB - The mating hormones alpha1 and alpha2 induce sexual reproduction of the phytopathogenic genus Phytophthora. To demonstrate the structural elements responsible to hormonal activity, 17 derivatives of alpha1 and alpha2 were synthesized and their hormonal activity (oospore-inducing activity) was evaluated. The terminal ester derivatives of alpha1 (diacetate and dibenzoate) retained the hormonal activity, whereas a dicarbamate derivative completely suppressed the activity. Even monocarbamates showed weak activities; among them the 1-O-carbamate was less active than 16-O-carbamate, suggesting that the 1-OH group is a little more important than 16-OH. Dihydro, dehydro, and demethyl derivatives exhibited the minimum level of activity. Surviving activity of 15-epi alpha1 suggested a less importance of this stereochemistry. Contrary to alpha1, not only the terminal diacetate derivative but also monoacetates of alpha2 exhibited no or little activity. Among the monoacetates, 1-O-acetyl-alpha2 exhibited little yet relatively better activity than the others. No activity was observed for mono- and dicarbamoyl derivatives of alpha2. Dihydro alpha2 with the saturated double bond lost most of the activity. These findings suggest that both the mating hormones alpha1 and alpha2 require most of the functional (hydroxyl, keto, and olefinic) groups they possess in their natural form for inducing the sexual reproduction of Phytophthora. PMID- 22209648 TI - Enteral feeding outcomes after chemoradiotherapy for oropharynx cancer: a role for a prophylactic gastrostomy? AB - To determine the outcomes of patients managed with different routes of enteral feeding during chemoradiotherapy for oropharynx cancer. The hospital and dietetic records of consecutive patients with oropharynx squamous cell carcinoma treated between January 2007 and June 2009 with concurrent chemoradiotherapy were reviewed retrospectively. One hundred and four patients were analysed. Seventy one received a prophylactic gastrostomy, 21 were managed with a strategy of NG tube as required and 12 received a therapeutic gastrostomy. Patients with a prophylactic gastrostomy commenced enteral feeding a median of 24 days after commencing radiotherapy, compared with a median of 41 days (p<0.001) for the NG as required group. Comparing prophylactic gastrostomy, NG as required and therapeutic gastrostomy, median number of unplanned inpatient days were 6, 14 and 7, respectively (p<0.01 for prophylactic gastrostomy vs. NG as required). Mean percentage weight loss at the end of treatment (6.1% vs. 7.1% vs. 5.2%, respectively) and at 6 months post-radiotherapy (11.7%, 14.3% and 8.9%) were similar in all groups (p=0.23). There was no significant difference in type of diet post-radiotherapy between prophylactic gastrostomy and NG as required groups (p=0.22). Median duration of enteral feeding was 181, 64 and 644 days, respectively (p<0.01 for prophylactic gastrostomy vs. NG as required). Use of a prophylactic gastrostomy (p<0.01) and higher T stage (p<0.01) were associated with increased duration of enteral feeding on a multivariate analysis. These data reinforce concerns regarding the detrimental impact of prophylactic gastrostomy placement upon long-term enteral feed dependence. PMID- 22209649 TI - Motor learning benefits of self-controlled practice in persons with Parkinson's disease. AB - The present study examined the effectiveness of a training method to enhance balance in people with PD, which could potentially reduce their risk for falls. Specifically, we investigated whether the benefits of the self-controlled use of a physical assistance device for the learning of a balance task, found previously in healthy adults, would generalize to adults with PD. Twenty-eight individuals with PD were randomly assigned to one of two groups, a self-control and a yoked (control) group. The task required participants to stand on a balance platform (stabilometer), trying to keep the platform as close to horizontal as possible during each 30-s trial. In the self-control group, participants had a choice, on each of 10 practice trials, to use or not to use a balance pole. Participants in the yoked group received the same balance pole on the schedule used by their counterparts in the self-control group, but did not have a choice. Learning was assessed one day later by a retention test. The self-control group demonstrated more effective learning of the task than the yoked group. Questionnaire results indicated that self-control participants were more motivated to learn the task, were less nervous, and less concerned about their body movements relative to yoked participants. Possible reasons for the learning benefits of self-controlled practice, including a basic psychological need for autonomy, are discussed. PMID- 22209650 TI - [Rhinophyma and skin carcinoma: a case report and literature review]. AB - Rhinophyma, final stage of rosacea is considered as benign pathology. We present the case of a patient with basal cell carcinoma diagnosed on rhinophyma. The removal of all cutaneous nasal unit and its analysis has diagnosed the presence of three basal cell carcinomas and two in situ squamous cell carcinomas. Reconstruction was performed by full-thickness skin graft. The literature reports a few cases of association between rhinophyma and skin cancers but none ever reported the simultaneous presence of basal cell carcinoma and squamous cell carcinomas. The low number of articles does not reveal statistically significant relationship between rhinophyma and skin cancer, which would consider the rhinophyma as a risk factor. Monitoring of these patients should be as rigorous as possible and surgical care requires histologic analysis not to omit the presence of cancerous lesions. PMID- 22209651 TI - The interfacial interactions of Tb-doped silica nanoparticles with surfactants and phospholipids revealed through the fluorescent response. AB - The quenching effect of dyes (phenol red and bromothymol blue) on Tb(III) centered luminescence enables to sense the aggregation of cationic and anionic surfactants near the silica surface of Tb-doped silica nanoparticles (SN) in aqueous solutions. The Tb-centered luminescence of non-decorated SNs is diminished by the inner filter effect of both dyes. The decoration of the silica surface by cationic surfactants induces the quenching through the energy transfer between silica coated Tb(III) complexes and dye anions inserted into surfactant aggregates. Thus the distribution of surfactants aggregates at the silica/water interface and in the bulk of solution greatly affects dynamic quenching efficiency. The displacement of dye anions from the interfacial surfactant adlayer by anionic surfactants and phospholipids is accompanied by the "off-on" switching of Tb(III)-centered luminescence. PMID- 22209652 TI - Fluorine-containing thermo-sensitive microgels as carrier systems for biomacromolecules. AB - A series of microgels with nanometer diameter were prepared from 2,2,3,4,4,4 hexafluorobutyl methacrylate (HFMA, FA for short) and N-isopropylacrylamide (NIPAAm). The composition and structure of microgels were studied by FTIR and (1)H NMR. The transmission electron microscope (TEM) results showed that the introduction of fluorine was very advantageous in improving the stability and monodisperity of NIPAAm microgel. The differential scanning calorimetry (DSC) and photon correlation spectroscopy (PCS) revealed that fluorinated NIPAAm microgels still displayed obvious temperature-responsiveness, and the lower critical solution temperature (LCST) of microgel particles decreased significantly. PCS tests also displayed the swelling and absorption behavior of microgels. Fluorescence spectrum showed that the microgel particles were able to combine with BSA, which would facilitate further development of fluorinated thermo sensitive microgel in biomacromolecule carrier and delivery system. PMID- 22209653 TI - Comparison of in vitro methods of measuring mucoadhesion: ellipsometry, tensile strength and rheological measurements. AB - In this work three in vitro methods for the measurement of mucoadhesion have been compared: ellipsometry, tensile strength and rheology. The conditions used for the three methods have been as similar as possible. Six different polymers were investigated: sodium carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), chitosan, polyvinyl pyrrolidone (PVP) and two cross-linked polyacrylic acids, Noveon (hydrophobically modified) and Carbopol. The results showed that PVP did not exhibit mucoadhesion according to any of the methods used. Chitosan, Noveon, Carbopol, CMC and HEC showed good mucoadhesion in the tensile strength and the rheological measurements, but not in the ellipsometry investigation. Chitosan was the only polymer showing good mucoadhesion with the ellipsometry method. No two methods gave the same ranking of mucoadhesive strength of the polymers. The conflicting results obtained with the different methods underline the need for further improvements in existing experimental techniques and theoretical concepts for the correct assessment of mucoadhesive properties. PMID- 22209654 TI - Development and validation of the Decisional Balance Scale for problematic Prescription Drug use (DBS-PD)-20. AB - The purpose of this study was to develop a Decisional Balance Scale (DBS) for Prescription Drugs (PD), the DBS-PD-20, to examine its factorial structure and test its reliability and external validity by comparison across Stages of Change. A sample of 126 general hospital inpatients with either regular use of PD (more than 60 days within the last three months) or abuse of or dependence on PD was recruited in a northern German city. Exploratory principal components analysis revealed a two-factor structure, the Pros and Cons of PD intake, as expected. While the DBS-PD-20 showed good reliability (Cronbach's alpha=0.91 for the Pros and=0.89 for the Cons), external validity could be proven for the Cons (significant increase from precontemplation to contemplation/action), whereas the Pros showed an insignificant increase. Although further validation is needed, the DBS-PD-20 may be helpful for interventions and research. PMID- 22209655 TI - Injection behaviors among injection drug users in treatment: the role of hepatitis C awareness. AB - BACKGROUND: Injection drug use (IDU) is a primary vector for blood-borne infections. Awareness of Hepatitis C virus (HCV) infection status may affect risky injection behaviors. This study determines the prevalence of risky injection practices and examines associations between awareness of positive HCV status and risky injection behaviors. METHODS: We surveyed individuals seeking treatment for substance use at 12 community treatment programs as part of a national HIV screening trial conducted within the National Drug Abuse Treatment Clinical Trials Network. Participants reported socio-demographic characteristics, substance use, risk behaviors, and HCV status. We used multivariable logistic regression to test associations between participant characteristics and syringe/needle sharing. RESULTS: The 1281 participants included 244 (19.0%) individuals who reported injecting drugs in the past 6 months and 37.7% of IDUs reported being HCV positive. During the six months preceding baseline assessment, the majority of IDUs reported obtaining sterile syringes from pharmacies (51.6%) or syringe exchange programs (25.0%), but fewer than half of IDUs always used a sterile syringe (46.9%). More than one-third (38.5%) shared syringe/needles with another injector in the past 6 months. Awareness of positive HCV vs. negative/unknown status was associated with increased recent syringe/needle sharing (aOR 2.37, 95% CI 1.15, 4.88) in multivariable analysis. CONCLUSIONS: Risky injection behaviors remain prevalent and awareness of HCV infection was associated with increased risky injection behaviors. New approaches are needed to broadly implement HCV prevention interventions for IDUs seeking addiction treatment. PMID- 22209656 TI - Differences in extrinsic innervation patterns of the small intestine in the cattle and sheep. AB - After oral challenge of the pathological prion protein, the pathogen was first detected in the distal ileum and then deposited in the brain. The present study aims determining the possible neuronal transport pathways from the small intestine to the brain in the cattle and sheep using a tracer protein. After horseradish peroxidase was injected into the wall in the duodenum of the calf and lamb and in the ileum of the lamb, the greater part of labeled neurons was detected in the celiac and cranial mesenteric ganglion complex. In the dorsal root ganglia T3 to L4 of both animals, some sensory neurons were always found to be labeled. Some parasympathetic preganglionic neurons were labeled in the dorsal motor nucleus of the vagus nerve after injections into the duodenum of the cattle and sheep, but extremely a small number of them were labeled after ileal application. The number of labeled sensory neurons in the nodose ganglion after duodenal injections of the sheep was much greater than that after duodenal application of the cattle. After ileal injections in the sheep, practically no labeled sensory neurons were found in the nodose ganglion. These results suggest that the pathological prion protein is mainly transported to the spinal cord and brain via the sympathetic nervous system and partially via the sensory neurons in the dorsal root ganglia. The vagus nerve seems to contribute to the transport of the pathogen not from the ileum, but from the duodenum. PMID- 22209657 TI - The effectiveness of community-based delivery of an evidence-based treatment for adolescent substance use. AB - This study evaluates the effectiveness of motivational enhancement therapy/cognitive behavioral therapy-5 (MET/CBT-5) when delivered in community practice settings relative to standard community-based adolescent treatment. A quasi-experimental strategy was used to adjust for pretreatment differences between the MET/CBT-5 sample (n = 2,293) and those who received standard care (n = 458). Results suggest that youth who received MET/CBT-5 fared better than comparable youth in the control group on five of six 12-month outcomes. A low follow-up rate (54%) in the MET/CBT-5 sample raised concerns about nonresponse bias in the treatment effect estimates. Sensitivity analyses suggest that although modest differences in outcomes between the MET/CBT-5 nonrespondents and respondents would yield no significant differences between the two groups on two of the six outcomes, very large differences in outcomes between responders and nonresponders would be required for youth receiving MET/CBT-5 to have fared better had they received standard outpatient care. PMID- 22209658 TI - Adaptability of contingency management in justice settings: survey findings on attitudes toward using rewards. AB - Contingency management (CM) is widely recognized as an evidence-based practice, but it is not widely used in either treatment settings or justice settings. CM is perceived as adaptable in justice settings given the natural inclination to use contingencies to improve compliance to desired behaviors. In the Justice Steps implementation study, 5 federal district court jurisdictions agreed to consider implementing CM in specialized problem-solving courts or probation settings. A baseline survey (N = 186) examined the acceptance and feasibility of using rewards as a tool to manage offender compliance. The results of the survey revealed that most of the respondents believe that rewards are acceptable, with little difference between social and material rewards. Survey findings also showed that female justice workers and those who were not probation officers were more accepting of material rewards than their counterparts. Findings are consistent with prior research in drug treatment settings where there is little concern about using rewards. PMID- 22209659 TI - Incidence of synchronous liver metastases in patients with colorectal cancer in relationship to clinico-pathologic characteristics. Results of a German prospective multicentre observational study. AB - BACKGROUND: The aim of this prospective observational multicentre study was to evaluate the incidence of synchronous liver metastases in colon and rectal cancer and to determine clinico-pathologic factors of the colorectal cancer that influenced the development of synchronous liver metastases. METHODS: Of 48,894 patients with colorectal cancer and who underwent surgery between January 2000 and December 2004, 7209 developed hepatic metastases and were analyzed. RESULTS: Synchronous liver metastases occurred in 14.7% of the colorectal cancer cases. Colon cancer (15.4%) led significantly more frequently to haematogenous spread to the liver than rectal cancer (13.5%) in a univariate approach. The N, V, and T stage, as well as the number of metastatic-involved local lymph nodes independently influenced the frequency of synchronous liver metastases in colon and rectal cancer in a multivariate analysis. Localization of the cancer in the colon led to a different number of synchronous liver metastases. Localization of the rectal cancer did not influence the rate of synchronous liver metastases. In the case of synchronous liver metastases, patients with colon cancer had significantly more peritoneal metastases (17.9 vs. 9.15%) but less lung (9.7 vs. 14%) and bone (0.7 vs. 1.6%) metastases. Simultaneous curative liver resections were done in 7% of colon cancer cases and in 8.8% of rectal cancer cases. CONCLUSION: In this national study the incidence of synchronous liver metastases in colon and rectal cancer were different. Independent factors leading to synchronous liver metastases could be identified. Venous infiltration seems to be important for the development of distant metastases. PMID- 22209660 TI - Bilateral N20 absence in post-anoxic coma: do you pay attention? PMID- 22209662 TI - Inter-group and intra-group assertiveness: adolescents' social skills following cultural transition. AB - The goals of this study were to examine intra-group and inter-group assertiveness among adolescents, and to compare these two domains of assertiveness between cultural groups in Israel. Measures of intra-group and inter-group assertiveness were developed, and questionnaires were administrated to 441 immigrants from the Former Soviet Union (FSU), 242 immigrants from Ethiopia and 333 non-immigrants. Compared to non-immigrants, FSU and Ethiopian immigrants' inter-group assertiveness was lower. Girls reported higher levels of inter-group assertiveness than boys. Each of the immigrant groups rates itself as equally assertive as the non-immigrant group and more assertive than the other immigrant group. Also, a difference between inter-group and intra-group assertiveness was found among the FSU immigrants. It is argued that adolescents' assertiveness following cultural transition is associated with socio-cultural context, and the implications of this conclusion are discussed. PMID- 22209661 TI - Origin of the low-level EMG during the silent period following transcranial magnetic stimulation. AB - OBJECTIVE: The cortical silent period refers to a period of near silence in the electromyogram (EMG) after transcranial magnetic stimulation (TMS) of the motor cortex during contraction. However, low-level EMG of unknown origin is often present. We hypothesised that it arises through spinal reflexes. Sudden lengthening of the muscle as force drops during the silent period could excite muscle spindles and facilitate motoneurones. METHODS: Subjects (n = 8) performed maximal isometric, shortening and lengthening contractions of the elbow flexors during which TMS (90-100% output) was delivered over the motor cortex. The rate of flexion during shortening contractions reduced muscle lengthening caused by muscle relaxation. Surface EMG was recorded from biceps brachii and brachioradialis, and the low-level EMG during silent periods produced by TMS was measured. RESULTS: Low-level EMG activity was reduced on average by 68% in biceps and 63% in brachioradialis in the shortening contraction compared to all other contraction conditions (p < 0.001). Levels of pre-stimulus EMG were similar between conditions. CONCLUSIONS: Muscle lengthening contributes to low-level EMG activity in the silent period, through spinal reflex facilitation by muscle spindle afferents. SIGNIFICANCE: The silent period depth is not only dependent on cortical output but also reflex effects evoked by muscle lengthening. PMID- 22209663 TI - Antisense reduction of 11beta-hydroxysteroid dehydrogenase type 1 enhances energy expenditure and insulin sensitivity independent of food intake in C57BL/6J mice on a Western-type diet. AB - We recently reported that inhibition of 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) by antisense oligonucleotide (ASO) improved hepatic lipid metabolism independent of food intake. In that study, 11beta-HSD1 ASO-treated mice lost weight compared with food-matched control ASO-treated mice, suggesting treatment-mediated increased energy expenditure. We have now examined the effects of 11beta-HSD1 ASO treatment on adipose tissue metabolism, insulin sensitivity, and whole-body energy expenditure. We used an ASO to knock down 11beta-HSD1 in C57BL/6J mice consuming a Western-type diet (WTD). The 11beta-HSD1 ASO-treated mice consumed less food, so food-matched control ASO-treated mice were also evaluated. We characterized body composition, gene expression of individual adipose depots, and measures of energy metabolism. We also investigated glucose/insulin tolerance as well as acute insulin signaling in several tissues. Knockdown of 11beta-HSD1 protected against WTD-induced obesity by reducing epididymal, mesenteric, and subcutaneous white adipose tissue while activating thermogenesis in brown adipose tissue. The latter was confirmed by demonstrating increased energy expenditure in 11beta-HSD1 ASO-treated mice. The 11beta-HSD1 ASO treatment also protected against WTD-induced glucose intolerance and insulin resistance; this protection was associated with smaller cells and fewer macrophages in epididymal white adipose tissue as well as enhanced in vivo insulin signaling. Our results indicate that ASO-mediated inhibition of 11beta HSD1 can protect against several WTD-induced metabolic abnormalities. These effects are, at least in part, mediated by increases in the oxidative capacity of brown adipose tissue. PMID- 22209665 TI - Early nutritional changes induce sexually dimorphic long-term effects on body weight gain and the response to sucrose intake in adult rats. AB - Long-term metabolic effects induced by early nutritional changes are suspected to differ between males and females, but few studies have analyzed both sexes simultaneously. We analyzed the consequences of neonatal nutritional changes on body weight (BW) and the adult response to a sucrose-enriched diet in both male and female rats. Litter size was manipulated at birth to induce over- and undernutrition (4 pups: L4; 12 pups: L12; 20 pups: L20). From 50 to 65 days of age, half of each group received a 33% sucrose solution instead of water. Serum leptin, insulin, and ghrelin levels were analyzed at day 65. At weaning, rats from L4 weighed more and those from L20 weighed less than controls (L12). Body weight was greater in L4 rats throughout the study and increased further compared with controls in adult life. L20 males ate less and gained less weight throughout the study, but L20 females had a significant catch-up in BW. Sucrose intake increased total energy consumption in all groups, but not BW gain, with L4 males and L4 and L20 females reducing weight gain. Yet, sucrose intake increased serum leptin levels, with this increase being significant in L4 and L20 males. Our results suggest that females are more capable than males of recuperating and maintaining a normal BW after reduced neonatal nutrition. Furthermore, increased sucrose intake does not increase BW, but could alter body composition as reflected by leptin levels, with the percentage of calories consumed in the form of sucrose being affected by sex and neonatal nutrition. PMID- 22209664 TI - Diurnal salivary cortisol and urinary catecholamines are associated with diabetes mellitus: the Multi-Ethnic Study of Atherosclerosis. AB - The objective was to examine the cross-sectional association of diurnal salivary cortisol curve components and urinary catecholamines with diabetes status. Up to 18 salivary cortisol samples over 3 days and overnight urinary catecholamines were collected from 1002 participants in the Multi-Ethnic Study of Atherosclerosis. Diabetes was defined as a fasting blood glucose of at least 126 mg/dL or medication use. Cortisol curve measures included awakening cortisol, cortisol awakening response, early decline, late decline, and cortisol area under the curve (AUC). Urinary catecholamines included epinephrine, norepinephrine, and dopamine. Participants with diabetes had significantly lower cortisol awakening response (beta = -0.19; 95% confidence interval [CI], -0.34 to -0.04) than those without diabetes in multivariable models. Whereas men with diabetes had a nonsignificant trend toward lower total AUC (beta = -1.56; 95% CI, -3.93 to 0.80), women with diabetes had significantly higher total AUC (beta = 2.62; 95% CI, 0.72 to 4.51) (P = .02 for interaction) compared with those without diabetes. Men but not women with diabetes had significantly lower urinary catecholamines compared with those without diabetes (P < .05). Diabetes is associated with neuroendocrine dysregulation, which may differ by sex. Further studies are needed to determine the role of the neuroendocrine system in the pathophysiology of diabetes. PMID- 22209666 TI - The reliability of using the single-biopsy approach to assess basal muscle protein synthesis rates in vivo in humans. AB - It has recently been proposed that basal muscle protein synthesis can be effectively assessed by measuring the background enrichment in total plasma protein, thereby omitting the initial biopsy, and determining the difference in enrichment from a single muscle biopsy obtained during a primed continuous infusion of isotope-labeled amino acids. We determined the reliability of calculating basal mixed muscle protein fractional synthetic rates (FSRs) from mixed plasma proteins and a single muscle biopsy compared against the sequential muscle biopsy approach. Ten men (age, 23 +/- 1 years; body mass index, 22 +/- 1 kg?m(-2)) received muscle biopsies of the vastus lateralis after 2 and 4 hours of a primed continuous infusion of l-[ring-(13)C(6)]phenylalanine. Mixed muscle protein FSR was calculated from baseline plasma enrichments and muscle protein enrichments determined from the biopsy at 2 hours (1BX SHORT) or 4 hours (1BX LONG), or between muscle protein enrichments at 2 and 4 hours (2BX) of the infusion. No differences (P = .50) were observed in mixed muscle protein FSR, using plasma [ring-(13)C(6)]phenylalanine enrichments as the precursor, between the 1BX SHORT (0.031% +/- 0.010%?h(-1)), 1BX LONG (0.032% +/- 0.007%?h(-1)), or 2BX (0.035% +/- 0.011%?h(-1)) approach. A significant correlation was observed between the calculated muscle protein FSR assessed using the 1BX LONG and 2BX approach (r = 0.7, P = .02). Our data demonstrate that the single-biopsy approach, irrespective of whether the biopsy is obtained at 2 or 4 hours, can be used as a surrogate for the sequential-biopsy approach to determine basal muscle protein synthesis in a group. PMID- 22209667 TI - Is perilipin critical in fat utilization during exercise? PMID- 22209668 TI - The ACE insertion/deletion polymorphism and its association with metabolic syndrome. AB - The angiotensin-1-converting enzyme (ACE) gene has been suggested to be involved in the development of metabolic syndrome (MetS). However, results have been inconsistent. In this study, a meta-analysis was performed to investigate the association between ACE insertion/deletion (I/D) polymorphism and MetS. Published literature from PubMed, EMBASE, and ISI Web of Science databases was searched for eligible publications. All studies assessing the association between ACE I/D polymorphism and MetS were included. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated using a fixed- or random-effects model. Ten studies (1939 cases/2845 controls) for ACE I/D polymorphism were included in this meta-analysis. Most of the studies were performed in whites. The ACE I/D polymorphism was associated with an increased OR of MetS under a dominant model (DD + ID vs II: OR = 1.39; 95% CI, 1.22-1.60; P < .001). Using this model, similar results were found among studies using different ethnic populations, studies using different MetS definitions, and studies with more than 100 cases. This meta-analysis indicated that the D allele of the ACE gene, known to be related to higher levels of angiotensinogen, is associated with an increased OR of MetS. However, given the limited sample size, this association warrants further investigation. PMID- 22209669 TI - Fatty acid profile of skeletal muscle phospholipid is altered in mdx mice and is predictive of disease markers. AB - The mdx mouse is a model for Duchenne muscular dystrophy. The fatty acid (FA) composition in dystrophic muscle could potentially impact the disease severity. We tested FA profiles in skeletal muscle phospholipid (PL) and triglyceride in mdx and control (con) mice to assess associations with disease state as well as correlations with grip strength (which is lower in mdx) and serum creatine kinase (CK, which is elevated in mdx). Compared with con, mdx PL contained less docosahexaenoic acid (P < .001) and more linoleic acid (P = .001). Docosahexaenoic acid contents did not correlate with strength or serum CK. Linoleic acid content in PL was positively correlated with CK in mdx (P < .05) but not con. alpha-Linolenic acid content in PL was positively correlated with strength in mdx (P < .05) but not con. The FA profile in triglyceride showed less difference between groups and far less predictive ability for disease markers. We conclude that profiling the FA composition of tissue lipids (particularly PL) can be a useful strategy for generating novel biomarkers and potential therapeutic targets in muscle diseases and likely other pathological conditions as well. Specifically, the present results have indicated potential benefits of raising content of particular n-3 FAs (especially alpha-linolenic acid) and reducing content of particular n-6 FAs (linoleic acid) in PL of dystrophic muscle. PMID- 22209670 TI - Resveratrol improves insulin resistance of catch-up growth by increasing mitochondrial complexes and antioxidant function in skeletal muscle. AB - Caloric restriction followed by refeeding, a phenomenon known as catch-up growth (CUG), affects mitochondrial function and results in systemic insulin resistance (IR). We investigated the potential of resveratrol (RES) in CUG to prevent IR by increasing activity of the mitochondrial respiratory chain and antioxidant enzymes in skeletal muscle. Rats (8 weeks of age) were divided into 3 groups: normal chow, CUG, and CUG with RES intervention. Skeletal muscle and systemic IR were measured in each group after 4 and 8 weeks. Mitochondrial biogenesis and function, oxidative stress levels, and antioxidant enzyme activity in skeletal muscle were assessed. Catch-up growth-induced IR resulted in significant reductions in both average glucose infusion rate(60-120) at euglycemia and skeletal muscle glucose uptake. Mitochondrial citrate synthase activity was lower; and the activity of complexes I to IV in the intermyofibrillar and subsarcolemmal (SS) mitochondria were reduced by 20% to 40%, with the decrease being more pronounced in the SS fraction. Reactive oxygen species levels were significantly higher in intermyofibrillar and SS mitochondria, whereas activities of antioxidant enzymes were decreased. Oral administration of RES, however, increased silent information regulator 1 activity and improved mitochondrial number and insulin sensitivity. Resveratrol treatment decreased levels of reactive oxygen species and restored activities of antioxidant enzymes. This study demonstrates that RES protects insulin sensitivity of skeletal muscle by improving activities of mitochondrial complexes and antioxidant defense status in CUG rats. Thus, RES has therapeutic potential for preventing CUG-related metabolic disorders. PMID- 22209671 TI - The effect of ziprasidone on body weight and energy expenditure in female rats. AB - Ziprasidone, a novel antipsychotic agent with a unique receptor-binding profile, has been reported to have lower propensity for weight gain compared with other atypical antipsychotics. Here, we examined the effects of ziprasidone on resting energy expenditure, physical activity, thermogenesis, food intake, and weight gain in female Sprague-Dawley rats. Ziprasidone (20 mg/kg) or vehicle was administered once daily for 7 weeks; and body weight, food intake, resting energy expenditure, locomotor activity, colonic temperature on cold exposure, and abdominal fat were measured. Compared with control animals, ziprasidone-treated rats gained significantly less weight (P = .031), had a lower level of physical activity (P = .016), showed a higher resting energy expenditure (P < .001), and displayed a greater capacity for thermogenesis when subjected to cold (P < .001). In addition, ziprasidone-treated rats had a lower level of abdominal fat than did controls, although the difference was not significant. Ziprasidone had no effect on food intake. Our results indicate that, in female Sprague-Dawley rats, a 7 week treatment regimen of ziprasidone induces a significant decrease in weight gain by increasing resting energy expenditure without decreasing food intake and even with a lower level of physical activity. Further studies are needed to elucidate the precise mechanism of lower propensity of weight gain of ziprasidone. PMID- 22209672 TI - A fruit and dairy dietary pattern is associated with a reduced risk of metabolic syndrome. AB - This study examines the relationship between adherence to different dietary patterns and the presence of metabolic syndrome and its components among Korean adults. The sample consisted of 406 Korean adults aged 22 to 78 years recruited from hospitals. Metabolic syndrome was defined according to the criteria issued by the Adult Treatment Panel III, with the exception of central obesity, which was defined according to the Asian-Pacific criteria. Dietary information was obtained by means of a 24-hour recall and a 3-day food record, and factor analysis was used to define dietary patterns. Factor analysis identified 4 major dietary patterns, which explained 28.8% of the total variance, based on the percentage of total daily energy intake from each food group: Korean traditional, alcohol and meats, sweets and fast foods, and fruit and dairy. After controlling for all potential confounders, we found that the Korean traditional dietary pattern was not associated with individual components of the metabolic syndrome but was significantly associated with increased odds of having metabolic syndrome. The fruit and dairy pattern was significantly associated with decreased odds of impaired blood glucose, hypertriglyceridemia, and metabolic syndrome. Our findings suggest that the fruit and dairy pattern is associated with reduced risk of having metabolic syndrome. PMID- 22209673 TI - The Swedish perspective--a puzzle. PMID- 22209674 TI - Addressing health inequalities in the US: a life course health development approach. PMID- 22209675 TI - Social strain and cortisol regulation in midlife in the US. AB - Chronic stress has been implicated in a variety of adverse health outcomes, from compromised immunity to cardiovascular disease to cognitive decline. The hypothalamic pituitary adrenal (HPA) axis has been postulated to play the primary biological role in translating chronic stress into ill health. Stressful stimuli activate the HPA-axis and cause an increase in circulating levels of cortisol. Frequent and long-lasting activation of the HPA-axis, as occurs in recurrently stressful environments, can in the long run compromise HPA-axis functioning and ultimately affect health. Negative social interactions with family and friends may be a significant source of stress in daily life, constituting the type of recurrently stressful environment that could lead to compromised HPA functioning and altered diurnal cortisol rhythms. We use data from two waves (1995 and 2004 2005) of the Midlife in the U.S. (MIDUS) study and from the National Study of Daily Experiences (NSDE) and piecewise growth curve models to investigate relationships between histories of social strain and patterns of diurnal cortisol rhythms. We find that reported levels of social strain were significantly associated with their diurnal cortisol rhythm. These effects were more pronounced for individuals with a history of greater reported strain across a ten-year period. PMID- 22209676 TI - alphabeta T cell receptors that do not undergo major histocompatibility complex specific thymic selection possess antibody-like recognition specificities. AB - Major histocompatibility complex (MHC) restriction is the cardinal feature of T cell antigen recognition and is thought to be intrinsic to alphabeta T cell receptor (TCR) structure because of germline-encoded residues that impose MHC specificity. Here, we analyzed alphabetaTCRs from T cells that had not undergone MHC-specific thymic selection. Instead of recognizing peptide-MHC complexes, the two alphabetaTCRs studied here resembled antibodies in recognizing glycosylation dependent conformational epitopes on a native self-protein, CD155, and they did so with high affinity independently of MHC molecules. Ligand recognition was via the alphabetaTCR combining site and involved the identical germline-encoded residues that have been thought to uniquely impose MHC specificity, demonstrating that these residues do not only promote MHC binding. This study demonstrates that, without MHC-specific thymic selection, alphabetaTCRs can resemble antibodies in recognizing conformational epitopes on MHC-independent ligands. PMID- 22209677 TI - Metabolic memory: mechanisms and implications for diabetic retinopathy. AB - Chronic hyperglycemia of diabetes leads to microvascular complications that severely impact quality of life. Diabetic retinopathy (DR) may be the most common of these and is a leading cause of visual impairment and blindness among working age adults in developed nations. Many large-scale type 1 and type 2 diabetes clinical trials have demonstrated that early intensive glycemic control can reduce the incidence and progression of micro and macrovascular complications. On the other hand, epidemiological and prospective data have revealed that the stressors of diabetic vasculature persist beyond the point when glycemic control has been achieved. These kinds of persistent adverse effects of hyperglycemia on the development and progression of complications has been defined as "metabolic memory", and oxidative stress, advanced glycation end products and epigenetic changes have been implicated in the process. Recent studies have indicated that such "hyperglycemic memory" may also influence DR, suggesting that manipulation of hyperglycemic memory may prove a beneficial approach to prevention and treatment. This review summarizes the evidence from DR-related clinical trials and mechanistic studies to investigate the significance of metabolic memory in DR and understand its potential as a target of molecular therapeutics aimed at reversing hyperglycemic memory. PMID- 22209678 TI - Provision of protein and energy in relation to measured requirements in intensive care patients. AB - BACKGROUND & AIMS: Adequacy of nutritional support in intensive care patients is still a matter of investigation. This study aimed to relate mortality to provision, measured requirements and balances for energy and protein in ICU patients. DESIGN: Prospective observational cohort study of 113 ICU patients in a tertiary referral hospital. RESULTS: Death occurred earlier in the tertile of patients with the lowest provision of protein and amino acids. The results were confirmed in Cox regression analyses which showed a significantly decreased hazard ratio of death with increased protein provision, also when adjusted for baseline prognostic variables (APACHE II, SOFA scores and age). Provision of energy, measured resting energy expenditure or energy and nitrogen balance was not related to mortality. The possible cause-effect relationship is discussed after a more detailed analysis of the initial part of the admission. CONCLUSION: In these severely ill ICU patients, a higher provision of protein and amino acids was associated with a lower mortality. This was not the case for provision of energy or measured resting energy expenditure or energy or nitrogen balances. The hypothesis that higher provision of protein improves outcome should be tested in a randomised trial. PMID- 22209679 TI - Increased erythrocytes n-3 and n-6 polyunsaturated fatty acids is significantly associated with a lower prevalence of steatosis in patients with type 2 diabetes. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity, metabolic syndrome and type 2 diabetes. Although dietary fat contributes substantially to the accumulation of liver fat, the role of individual fatty acids in this accumulation is unclear. OBJECTIVE: In this study, we set out to determine whether liver fat content (LFC), was associated with red blood cell fatty acid (RBC-FA) composition in people with type 2 diabetes. DESIGN, SETTINGS, AND PARTICIPANTS: One hundred and sixty-two type 2 diabetic patients were included in this study. LFC was measured using (1)H-MR Spectroscopy. RBC-FA composition was measured by gas chromatography. RESULTS: One hundred and nine (67.2%) patients had steatosis. Patients with steatosis had a higher BMI (p = 0.0005), and higher plasma triglyceride levels (p = 0.009) than did patients without steatosis. We report a significant association between palmitic acid (16:0), palmitoleic acid (16:1n-7) concentrations and ratio of monounsaturated to saturated fatty acid (palmitoleic acid to palmitic acid) and higher liver fat content. Total polyunsaturated fatty acid (PUFA), homo-gamma linolenic acid (20:3n-6), docosahexaenoic acid (22:6n-3), and arachidonic acid (20:4 n-6) were associated with lower LFC. CONCLUSIONS: Our data showed that an increased erythrocytes long-chain n-3 and n-6 fatty acids was associated with a lower prevalence of steatosis in patients with type 2 diabetes. These results suggest that n-3 and n-6 fatty acids supplementation could be a promising treatment for NAFLD in patients with type 2 diabetes. PMID- 22209680 TI - Consensus statement on the care of the hyperglycaemic/diabetic patient during and in the immediate follow-up of acute coronary syndrome. AB - The Diabetes and Cardiovascular Disease study group of the Societe francophone du diabete (SFD, French Society of Diabetes) in collaboration with the Societe francaise de cardiologie (SFC, French Society of Cardiology) have devised a consensus statement on the care of the hyperglycaemic/diabetic patient during and in the immediate follow-up of acute coronary syndrome (ACS); in particular, it includes the different phases of ACS [the intensive care unit (ICU) period, the post-ICU period and the short-term follow-up period after discharge, including cardiac rehabilitation] and also embraces all of the various diagnostic and therapeutic issues with a view to optimalizing the collaboration between cardiologists and diabetologists. As regards diagnosis, subjects with HbA(1c) greater or equal to 6.5% on admission may be considered diabetic while, in those with no known diabetes and HbA(1c) less than 6.5%, it is recommended that an OGTT be performed 7 to 28days after ACS. During hospitalization in the ICU, continuous insulin treatment should be initiated in all patients when admission blood glucose levels are greater or equal to 180mg/dL (10.0mmol/L) and, in those with previously known diabetes, when preprandial glucose levels are greater or equal to 140mg/dL (7.77mmol/L) during follow-up. The recommended blood glucose target is 140-180mg/dL (7.7-10mmol/L) for most patients. Following the ICU period, insulin treatment is not mandatory for every patient, and other antidiabetic treatments may be considered, with the choice of optimal treatment depending on the metabolic profile of the patient. Patients should be referred to a diabetologist before discharge from hospital in cases of unknown diabetes diagnosed during ACS hospitalization, of HbA(1c) greater or equal to 8% at the time of admission, or newly introduced insulin therapy or severe/repeated hypoglycaemia. Referral to a diabetologist after hospital discharge is recommended if diabetes is diagnosed by the OGTT, or during cardiac rehabilitation in cases of uncontrolled diabetes (HbA(1c)>=8%) or severe/repeated hypoglycaemia. PMID- 22209681 TI - Modulation of FoxO1 phosphorylation/acetylation by baicalin during aging. AB - Baicalin is a flavonoid known to modify various redox-related biological activities. Included is its ability to suppress reactive species (RS) producing activity and modulate nuclear factor-kappaB through cellular redox regulation with enhanced thiol ability. FoxO regulates various genes that are known to be involved in cellular metabolism related to cell death and the oxidative stress response. One such case is the prevention of FoxO1 expression by activated insulin-induced phosphatidylinositol 3-kinase (PI3K)/Akt, which leads to increased oxidative stress and aging processes. In the present study, we attempted to elucidate the molecular modulation of antioxidant baicalin on the insulin-induced FoxO1 inactivation. We used HEK293T cultured cells and kidney tissue isolated from 24-month-old rats treated with baicalin at a dose of 10 or 20 mg/kg/day for 10 days. We found that baicalin enhanced catalase and suppressed RS production in cell system and in isolated kidney tissue in contrast to the nontreated aged rats. Results also showed activation of insulin signaling (PI3K/Akt), FoxO1 phosphorylation/acetylation and the down-regulation of catalase and manganese superoxide dismutase, both of which are FoxO1-targeting genes. Furthermore, baicalin-treated rats showed a decreased FoxO1 phosphorylation via PI3K/Akt cascade and FoxO1 acetylation by the cAMP-response element-binding protein binding protein (CBP). These results strongly suggest that treatment with baicalin influenced phosphorylation/acetylation of FoxO1 by up-regulating PI3K/Akt signaling through insulin in aged rats. Our results further reveal that baicalin regulated FoxO1 phosphorylation via PI3K/Akt by insulin and FoxO1 acetylation by the interaction of CBP and SIRT1, leading to changes in catalase gene expression during aging. PMID- 22209682 TI - Oleic acid activates peroxisome proliferator-activated receptor delta to compensate insulin resistance in steatotic cells. AB - Nonalcoholic fatty liver disease is frequently associated with type 2 diabetes; however, this idea is challenged by recent studies because hepatic steatosis is not always associated with insulin resistance (IR). Oleic acid (OA) is known to induce hepatic steatosis with normal insulin sensitivity; however, the mechanism is still unknown. Previous studies depict that activation of peroxisome proliferator-activated receptor delta (PPARdelta?) improves hepatic steatosis and IR, whereas the role of PPARdelta in the improvement of insulin sensitivity by OA is unknown. Here we induced steatosis in HepG2 cells by incubation with OA and OA significantly increased the expression of PPARdelta through a calcium-dependent pathway. OA also induced the expression of G protein-coupled receptor 40 (GPR40), and deletion of GPR40 by small interfering ribonucleic acid transfection partially reversed the effect of OA on PPARdelta?. Inhibition of phospholipase C (PLC) by U73122 also reversed OA-induced PPARdelta expression. Otherwise, deletion of PPARdelta augmented the OA-induced steatosis in HepG2 cells. Furthermore, IR was developed in OA-treated HepG2 cells with PPARdelta deletion, while insulin-related signals and insulin-stimulated glycogen synthesis were reduced through increase of phosphatase and tensin homolog (PTEN) expression. In conclusion, OA activates GPR40-PLC-calcium pathway to increase the expression of PPARdelta and PPARdelta further decreased the expression of PTEN to regulate insulin sensitivity in hepatic steatosis. PMID- 22209683 TI - A simple xylose-based agar medium for the differentiation of Candida dubliniensis and Candida albicans. AB - The utility of xylose-based agar medium for differentiation of Candida dubliniensis from Candida albicans is evaluated. All C. dubliniensis isolates failed to grow on this medium, while C. albicans isolates yielded good growth. This simple in-house medium offers an inexpensive alternative to commercial yeast identification systems for resource poor settings. PMID- 22209684 TI - Profiling clinical cancer research across the Atlantic: a review of research and its characteristics presented at ASCO and ESMO Congresses during the last decade. AB - INTRODUCTION: The comparison of clinical cancer research characteristics across the Atlantic and their evolution over time have not been studied to date. METHODS: We collected oral presentations on breast, lung and colorectal cancer at ASCO (n=506) and ESMO (n=239) Congresses in years 2000-2010. RESULTS: EU originated research constituted 52% of all ASCO presentations while US-research 26.7% of ESMO Congress presentations. Industry sponsorship was reported in 24.8% of ASCO vs. 31.8% of ESMO Congress trials. ASCO-presented trials were larger with longer follow-up periods but were blinded less often. ESMO-presented trials used Event-Free Survival (EFS, 38.1%) and Surrogate (18.4%) primary endpoints and reported positive primary endpoints (65%) more often than ASCO-presented trials. Interim analysis resulted in discontinuation of a trial more often at ASCO Congress (8.3% vs. 3.2%). ASCO Congress-presented research was more often published (69.2% vs. 59.8% at ESMO) at higher impact factor journals. Strong trends over the decade were seen for more frequent industry sponsorship, blinded design, larger sample size, early interim discontinuation, use of EFS endpoints and biomarker evaluation. CONCLUSIONS: Cancer clinical research is a complex scientific activity with common global but also distinct characteristics at the two sides of the Atlantic. PMID- 22209685 TI - Reduction of Salmonella enterica serovar Choleraesuis carrying large virulence plasmids after the foot and mouth disease outbreak in swine in southern Taiwan, and their independent evolution in human and pig. AB - BACKGROUND/PURPOSE: Salmonella enterica serovar Choleraesuis (S. Choleraesuis) is a highly invasive zoonotic pathogen that causes bacteremia in humans and pigs. The prevalence of S. Choleraesuis in man has gradually decreased since the outbreak of foot and mouth disease in pigs in 1997 in southern Taiwan. The goal of this study was to investigate the change in prevalence of S. Choleraesuis carrying the virulence plasmid (pSCV) in human and swine isolates collected in 1995-2005 and characterize these. METHODS: 380 isolates were collected from human and swine blood samples. Large pSCVs were determined by PCR and Southern blot analysis. Antimicrobial susceptibility and resistance genes, and the phylogenetic association of these large pSCV were analyzed. RESULTS: The number of isolates harboring the large pSCV was significantly reduced, and their prevalence differed between human and swine isolates. These large pSCVs were a recombinant of original 50-kb pSCV and R plasmid. In addition, some large pSCVs lacked two pSCV specific deletion regions from pef to repC and from traT to samA. These large pSCVs carried the resistance genes bla(TEM,)aadA2, and sulI, as well as class I integrons of 0.65 and/or 1.9 kb in size, but were inconjugatible. Phylogenetic analysis demonstrated that the large pSCV evolves independently in human and swine isolates. CONCLUSION: S. Choleraesuis with large pSCV was significantly reduced after the foot and mouth disease outbreak and may evolve in human and swine specific isolates. PMID- 22209686 TI - Non-typhoidal Salmonella bacteremia among adults: an adverse prognosis in patients with malignancy. AB - BACKGROUND: Clinical information about non-typhoidal Salmonella (NTS) bacteremia in patients with malignancy has rarely been described. This study investigated clinical characteristics and prognostic variables of patients with malignancy while complicated with NTS bacteremia. METHODS: The study included demographic data, clinical information, and outcome in adults (>=18 years old) with and without malignancy complicated with NTS bacteremia at a medical center from 2000 to 2009. RESULTS: There were 206 patients with NTS bacteremia. The serogroups of NTS isolates included group B (40.2%), group D (30.9%), group C (26.5%), and group E (1.5%). Extraintestinal infections were noted in 66 (32.4%) patients and were mainly endovascular (26/206, 12.7%) or pleuropulmonary (17/206, 8.3%) infections. On multivariate analysis, independent factors for in-hospital mortality included shock (odds ratio [OR] 9.13; 95% confidence interval [CI] 3.81 21.83; p < 0.001), malignancy (OR 8.42; 95% CI 3.12-22.71; p < 0.001), and acute renal failure (OR 2.63; 95% CI 1.11-6.22; p = 0.028). Different clinical presentations and outcome were noted in 74 (36.2%) patients with malignancy and 130 without malignancy. The former had more leucopenia and thrombocytopenia at initial presentation and fewer extraintestinal infections (20.2% vs. 39.2%, p = 0.005), endovascular infections (2.7% vs. 18.5%; p = 0.002), and serovar Choleraesuis (10.8% vs. 27.7%; p = 0.005). An elevated in-hospital mortality rate was noted in patients with malignancy compared to those without malignancy (40.5% vs. 17.7%, p < 0.001). Among patients with malignancy, multivariate analysis revealed that shock was the only independent factor associated with in-hospital mortality (OR 7.52; 95% CI, 2.38-23.80; p = 0.001). CONCLUSION: Malignancy is an adverse prognostic factor in patients with NTS bacteremia. Food safety in patients with malignancy should be emphasized to prevent salmonellosis. PMID- 22209687 TI - Astrovirus gastroenteritis in hospitalized children of less than 5 years of age in Taiwan, 2009. AB - BACKGROUND/PURPOSE: Acute gastroenteritis is a common illness in children under 5 years old. Although rotavirus is a leading cause, other viruses including astrovirus are also important, but have been the subject of limited studies. This is a prospective study to investigate astrovirus gastroenteritis in hospitalized children in Taiwan. MATERIAL/METHOD: From January 2009 to December 2009, children below 5 years of age admitted to three hospitals in Taiwan due to acute gastroenteritis were eligible for this study. Stool specimens were sent for the detection of astrovirus by reverse transcriptase polymerase chain reaction; once positive for astrovirus, the sequencing and phylogenetic analysis of each strain was performed. RESULTS: A total of 989 children were enrolled during the study period. The overall positive rate of astrovirus was 1.6%, ranging from 1.03% to 2.26% in different hospitals, while rotavirus accounted for 20.2% of the patients. Six of the 16 children (37.5%) with astroviral infection had documented coinfection with rotavirus. The median age of infection was 28.2 months. The seasonal distribution of astrovirus peaked from April to June. Diarrhea alone (40% vs. 2.1%, p < 0.0001) was significantly more commonly seen than the triad of fever, vomiting and diarrhea (30% vs. 71%, p = 0.0062) in children with astroviral infection alone than in those with rotaviral infection alone. The mean duration of diarrhea was significantly longer in patients with mixed infection than those with astroviral infection alone (6.8 vs. 4.2 days, p = 0.013). Respiratory symptoms were noted in 10 children (62.5%). Serotype HAstV-1 was the most common (68.8%). CONCLUSION: Astrovirus accounted for 1.6% of infections in children under 5 years hospitalized with acute gastroenteritis in Taiwan. Compared with those caused by rotavirus, the incidence of gastroenteritis in hospitalized children caused by astrovirus was low and the disease severity was mild. PMID- 22209688 TI - Short frontal lobe connections of the human brain. AB - Advances in our understanding of sensory-motor integration suggest a unique role of the frontal lobe circuits in cognition and behaviour. Long-range afferent connections convey higher order sensory information to the frontal cortex, which in turn responds to internal and external stimuli with flexible and adaptive behaviour. Long-range connections from and to frontal lobes have been described in detail in monkeys but little is known about short intralobar frontal connections mediating local connectivity in humans. Here we used spherical deconvolution diffusion tractography and post-mortem dissections to visualize the short frontal lobe connections of the human brain. We identified three intralobar tracts connecting: i) posterior Broca's region with supplementary motor area (SMA) and pre-supplementary motor area (pre-SMA) (i.e., the frontal 'aslant' tract - FAT); ii) posterior orbitofrontal cortex with anterior polar region (i.e., fronto-orbitopolar tract - FOP); iii) posterior pre-central cortex with anterior prefrontal cortex (i.e., the frontal superior longitudinal - FSL faciculus system). In addition more complex systems of short U-shaped fibres were identified in the regions of the central, pre-central, perinsular and fronto marginal sulcus (FMS). The connections between Broca and medial frontal areas (i.e. FAT) and those between the hand-knob motor region and post-central gyrus (PoCG) were found left lateralized in a group of twelve healthy right-handed subjects. The existence of these short frontal connections was confirmed using post-mortem blunt dissections. The functional role of these tracts in motor learning, verbal fluency, prospective behaviour, episodic and working memory is discussed. Our study provides a general model for the local connectivity of the frontal lobes that could be used as an anatomical framework for studies on lateralization and future clinical research in neurological and psychiatric disorders. PMID- 22209689 TI - New challenges for vaccination to prevent chlamydial abortion in sheep. AB - Ovine enzootic abortion (OEA) is caused by the obligate intracellular Gram negative bacterium Chlamydia abortus. OEA remains a common cause of infectious abortion in many sheep-rearing countries despite the existence of commercially available vaccines that protect against the disease. There are a number of confounding factors that influence the uptake and use of these vaccines, which includes an inability to discriminate between infected and vaccinated animals (DIVA) using conventional serological diagnostic techniques. This suggests that the immunity elicited by current vaccines is similar to that observed in convalescent, immune sheep that have experienced OEA. The existence of these vaccines provides an opportunity to understand how protection against OEA is elicited and also to understand why vaccines can occasionally appear to fail, as has been reported recently for OEA. Interferon-gamma (IFN-gamma), the cytokine that classically defines Th1-type adaptive immunity, is a strong correlate of protection against OEA in sheep and has been shown to inhibit the growth of C. abortus in vitro. Humoral immunity to C. abortus is observed in both vaccinated and naturally infected sheep, but antibody responses tend to be used more as diagnostic markers than targets for strategic vaccine design. A future successful DIVA vaccine against OEA should aim to elicit the immunological correlate of protection (IFN-gamma) concomitantly with an antibody profile that is distinct from that of the natural infection. Such an approach requires careful selection of protective components of C. abortus combined with an effective delivery system that elicits IFN-gamma-producing CD4+ve memory T cells. PMID- 22209690 TI - Stiffness of Ca(2+)-pectin gels: combined effects of degree and pattern of methylesterification for various Ca(2+) concentrations. AB - The influence of the degree and pattern of methylesterification (DM and PM, respectively) on the stiffness of Ca(2+)-pectin gels is extensively examined, at various Ca(2+) concentrations. Accordingly, a highly methyl-esterified pectin was selectively de-esterified using NaOH, plant or fungal pectin methylesterase in order to produce series of pectins with varied pattern and broad ranges of methylesterification. The PM was quantified as absolute degree of blockiness (DB(abs)). Ca(2+)-pectin gels were prepared at various Ca(2+) concentrations. Gel stiffness (G' at 1rad/s) was determined and mapped out as a function of DM, DB(abs) and Ca(2+) concentration. At low Ca(2+) concentrations, G' depends on polymer's DM and DB(abs). At high Ca(2+) concentrations, a master curve is obtained over a wide range of DM, irrespective of DB(abs). Depending on methylesterification pattern, increase of G' is related not only to an increase in the number of junction zones per pectin chain, but also to an increase in the size of junction zones and the number of dimerised chains occurring in the gels. These results provide a detailed insight into the occurrence of junction zones in Ca(2+)-pectin gels. PMID- 22209693 TI - The reproductive cycle in the male gonads of Danio rerio (Teleostei, Cyprinidae). Stereological analysis. AB - The studies in Danio rerio testis were performed during the 8 weeks between the first and second spawning. The testes were dissected from the animals and fixed after successive weeks. Semithin epon sections were analysed using stereological methods to assess the relative volumes of cysts containing successive stages of spermatogenesis. During the first three weeks the cysts with spermatogonia B have the highest relative volumes. At the 2nd week the first cysts with spermatocytes appear. At the 4th week the first cysts containing early spermatids are formed. During the 4th, 5th and the 6th weeks of the gonad cycle cysts containing spermatocytes I are the most numerous but one can also see volumes of cysts filled with late spermatids and sperm cells growing. In the 7th week of the cycle the volumes of cysts containing early spermatids as well as those containing late spermatids are very large. Many cysts have released completely formed sperm cells into the tubule lumen. In the 8th week of the gonad cycle the testis tubules are filled with sperm cells. In many places the tubule walls break off and join to make vast chambers filled with sperm. Therefore, the germinal epithelium of the D. rerio testis at this stage turns into a "discontinuous" type. PMID- 22209691 TI - Autoantigenesis: the evolution of protein modifications in autoimmune disease. AB - Protein targets in autoimmune disease vary in location, originating within cells as in system lupus erythematosus (SLE), or found on cell surfaces or in extracellular spaces. The term 'autoantigenesis' is first defined here as the changes that arise in self-proteins as they break self-tolerance and trigger autoimmune B and/or T cell responses. As illustrated in many studies, between 50 and 90% of the proteins in the human body acquire post-translational modification. In some cases, it may be that these modifications are necessary for the biological functions of proteins of the cells in which they reside or as extracellular mediators. Summarized herein, it is clear that some post translational modifications can create new self-antigens by altering immunologic processing and presentation. While many protein modifications exist, we will focus on those created, amplified, or altered in the context of inflammation or other immune system responses. Finally, we will address how post-translational modifications in self-antigens may affect the analyses of B and T cell specificity, current diagnostic techniques, and/or the development of immunotherapies for autoimmune diseases. PMID- 22209694 TI - Fungal osteomyelitis after arthroscopic anterior cruciate ligament reconstruction: a case report with review of the literature. AB - Fungal osteomyelitis is a very rare complication after anterior cruciate ligament (ACL) reconstruction associated with catastrophic consequences. Herein, we present a case of such disastrous complication after ACL reconstruction. A 23 year-old man developed fever, swelling and pain of the affected knee from 18 days after arthroscopic ACL reconstruction. Therefore, he underwent arthroscopic debridement, removal of the graft and internal fixators, irrigation and suction drainage, successively. Negative results for serial bacterial cultures and smear examinations are obtained. However, computer tomography and X-ray examination showed massive bone destruction at 48 days after ACL reconstruction. As the first open debridement was performed at 50 days after ACL reconstruction, fungal infection was diagnosed based on finding Aspergillus hyphae in pathologic examination of the debrided bone sample. After the final debridement, a 12-cm bone loss in the distal femur was treated by Ilizarov's bone transport. The patient got solid arthrodesis of the affected knee without clinical infection at a year after the initial operation. In addition, a review of the literature regarding case reports of fungal osteomyelitis after ACL reconstruction is presented. PMID- 22209695 TI - Phenotypic detection and polymerase chain reaction screening of extended-spectrum beta-lactamases produced by Pseudomonas aeruginosa isolates. AB - BACKGROUND/PURPOSE: A growing number of beta-lactamases have been reported in Pseudomonas aeruginosa isolates. The aims of this study were to survey the types of extended-spectrum beta-lactamases (ESBLs) by polymerase chain reaction (PCR), to evaluate the reliability of phenotypic tests for ESBLs, and to identify the clonal distribution by pulsed-field gel electrophoresis (PFGE) among P. aeruginosa isolates resistant to expanded-spectrum cephalosporins (ceftazidime, aztreonam, or cefepime). METHODS: The antimicrobial susceptibility of 57 P. aeruginosa isolates from blood specimens were examined according to the recommendations of the Clinical Laboratory Standards Institute. ESBL phenotypes were determined by using cloxacillin-containing double disc synergy test (DDST). The existence of 11 beta-lactamase genes was detected by PCR. RESULTS: Of the 57 P. aeruginosa isolates, 35 (61.4%) isolates were PCR-positive for beta-lactamase genes. Twelve of 35 isolates were PCR-positive for combination of ampC and ESBL genes, including TEM, GES, SHV, VEB and OXA-I genes. The sensitivity and specificity of cloxacillin-containing DDST (using the criteria of ceftazidime zone diameter increased ?5 mm) were 84.1% and 54.5%, respectively. Nine clusters were classified among 35 PCR-positive isolates by PFGE. Isolates of clusters B and C were distributed in different wards of this hospital during a period of 3-4 years. CONCLUSION: ESBL genes are not uncommon in P. aeruginosa isolates. Cloxacillin-containing DDST can enhance the sensitivity and has a potential role for phenotypic detection of ESBL-producing P. aeruginosa, and PCR is also helpful for the identification of specific beta-lactamase genes. These P. aeruginosa isolates were classified into several diverse clones which could continue to spread in the hospital over a long period of time. PMID- 22209696 TI - Changing incidence and clinical manifestations of Clostridium difficile associated diarrhea detected by combination of glutamate dehydrogenase and toxin assay in Northern Taiwan. AB - BACKGROUND/PURPOSE: The incidence of Clostridium difficile-associated diarrhea (CDAD) is increasing worldwide. Spread of an epidemic hypervirulent strain in southern Taiwan was associated with poor outcome. This prospective study evaluates the incidence and clinical manifestation of CDAD following a hospital wide hand hygiene promotion program in a 2,200-bed teaching hospital in northern Taiwan. PATIENTS AND METHODS: From June 1, 2010 to October 31, 2010, a predefined protocol was used to actively survey CDAD at 11 high-risk units. Stool samples of patients with antibiotic-associated diarrhea (AAD) were submitted for stool culture and toxin A/B assay using a combined enzyme immunoassay. CDAD was diagnosed by a positive toxin assay. RESULTS: The incidence of CDAD was 0.45/1000 patient-days and was highest in medical intensive care units (7.9/1000 patient days), followed by hemato-oncology wards, and infectious disease wards. Occurrence of CDAD was associated with >=3 stool pus cells per high power field (p = 0.018), prior use of metronidazole (p = 0.029), high usage of beta-lactamase stable penicillins (p = 0.046), and anaerobe-active antibiotics (p = 0.029). No attributable mortality was found. The incidence of CDAD was lower than that previously observed (1.0/1000 patient-days in 2003, p < 0.001). CONCLUSION: This study showed a lower incidence of CDAD and absence of attributable mortality. The impact of hand hygiene promotion and other infection control measures on decreasing incidence of CDAD warrants further elucidation. PMID- 22209697 TI - Calcium dynamics in the secretory granules of neuroendocrine cells. AB - Cellular Ca(2+)signaling results from a complex interplay among a variety of Ca(2+) fluxes going across the plasma membrane and across the membranes of several organelles, together with the buffering effect of large numbers of Ca(2+) binding sites distributed along the cell architecture. Endoplasmic and sarcoplasmic reticulum, mitochondria and even nucleus have all been involved in cellular Ca(2+) signaling, and the mechanisms for Ca(2+) uptake and release from these organelles are well known. In neuroendocrine cells, the secretory granules also constitute a very important Ca(2+)-storing organelle, and the possible role of the stored Ca(2+) as a trigger for secretion has attracted considerable attention. However, this possibility is frequently overlooked, and the main reason for that is that there is still considerable uncertainty on the main questions related with granular Ca(2+) dynamics, e.g., the free granular [Ca(2+)], the physical state of the stored Ca(2+) or the mechanisms for Ca(2+) accumulation and release from the granules. This review will give a critical overview of the present state of knowledge and the main conflicting points on secretory granule Ca(2+) homeostasis in neuroendocrine cells. PMID- 22209698 TI - MU-Calpain-mediated deregulation of cardiac, brain, and kidney NCX1 splice variants. AB - MU-Calpain is a Ca(2+)-activated protease abundant in mammalian tissues. Here, we examined the effects of MU-calpain on three alternatively spliced variants of NCX1 using the giant, excised patch technique. Membrane patches from Xenopus oocytes expressing either heart (NCX1.1), kidney (NCX1.3), or brain (NCX1.4) variants of NCX1 were exposed to MU-calpain and their Na(+)-dependent (I(1)) and Ca(2+)-dependent (I(2)) regulatory phenotypes were assessed. For these exchangers, I(1) inactivation is evident as a Na(+)(i)-dependent decay of peak outward currents whereas I(2) regulation manifests as outward current activation by micromolar Ca(2+)(i) concentrations. Notably, with NCX1.1 and NCX1.4 but not in NCX1.3, higher Ca(2+)(i) levels alleviate I(1) inactivation. Our results show that (i) MU-calpain selectively ablates Ca(2+)-dependent (I(2)) regulation leading to a constitutive activation of exchange current, (ii) MU-calpain has much smaller effects on Na(+)-dependent (I(1)) regulation, produced by a slight destabilization of the I(1) state, and (iii) Ca(2+)-dependent regulation (I(2)) and Ca(2+)-mediated alleviation of I(1) appear to be functionally distinct mechanisms, the latter of which is left largely intact after MU-calpain treatment. The ability of MU-calpain to selectively and constitutively activate Na(+)-Ca(2+) exchange currents may have important pathophysiological implications in tissue where these splice variants are expressed. PMID- 22209700 TI - 3D dose reconstruction for narrow beams using ion chamber array measurements. AB - 3D dose reconstruction is a verification of the delivered absorbed dose. Our aim was to describe and evaluate a 3D dose reconstruction method applied to phantoms in the context of narrow beams. A solid water phantom and a phantom containing a bone-equivalent material were irradiated on a 6 MV linac. The transmitted dose was measured by using one array of a 2D ion chamber detector. The dose reconstruction was obtained by an iterative algorithm. A phantom set-up error and organ interfraction motion were simulated to test the algorithm sensitivity. In all configurations convergence was obtained within three iterations. A local reconstructed dose agreement of at least 3% / 3mm with respect to the planned dose was obtained, except in a few points of the penumbra. The reconstructed primary fluences were consistent with the planned ones, which validates the whole reconstruction process. The results validate our method in a simple geometry and for narrow beams. The method is sensitive to a set-up error of a heterogeneous phantom and interfraction heterogeneous organ motion. PMID- 22209699 TI - PTEN regulates PDGF ligand switch for beta-PDGFR signaling in prostate cancer. AB - Platelet-derived growth factor (PDGF) family members are potent growth factors that regulate cell proliferation, migration, and transformation. Clinical studies have shown that both PDGF receptor beta (beta-PDGFR) and its ligand PDGF D are up regulated in primary prostate cancers and bone metastases, whereas PDGF B, a classic ligand for beta-PDGFR, is not frequently detected in clinical samples. In this study, we examined the role of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in the regulation of PDGF expression levels using both a prostate-specific, conditional PTEN-knockout mouse model and mouse prostate epithelial cell lines established from these mice. We found an increase in PDGF D and beta-PDGFR expression levels in PTEN-null tumor cells, accompanied by a decrease in PDGF B expression. Among Akt isoforms, increased Akt3 expression was most prominent in mouse PTEN-null cells, and phosphatidylinositol 3-kinase/Akt activity was essential for the maintenance of increased PDGF D and beta-PDGFR expression. In vitro deletion of PTEN resulted in a PDGF ligand switch from PDGF B to PDGF D in normal mouse prostate epithelial cells, further demonstrating that PTEN regulates this ligand switch. Similar associations between PTEN status and PDGF isoforms were noted in human prostate cancer cell lines. Taken together, these results suggest a mechanism by which loss of PTEN may promote prostate cancer progression via PDGF D/beta-PDGFR signal transduction. PMID- 22209701 TI - Striking differences in proconvulsant-induced alterations of seizure threshold in two rat models. AB - During drug development, seizure threshold tests are widely used to identify potential proconvulsant activity of investigational drugs. The most commonly used tests in this respect are the timed intravenous pentylenetetrazole (PTZ) infusion seizure test and the maximal electroshock seizure threshold (MEST) test in mice or rats. To our knowledge, no study is available in which proconvulsant drug activities in these models are directly compared, which prompted us to perform such experiments in male Wistar rats. Five drugs with reported proconvulsant activity were tested in the two models: d-amphetamine, chlorpromazine, caffeine, theophylline, and tramadol. Furthermore, the anticonvulsant drug phenobarbital was included in the experiments. While phenobarbital exerted anticonvulsant activity in both models, the five proconvulsant drugs markedly differed in their effects. In the dose range tested, d-amphetamine significantly lowered the PTZ seizure threshold but increased the MEST, caffeine and theophylline did not alter the PTZ seizure threshold but decreased the MEST, and tramadol reduced the PTZ threshold but increased the MEST. These marked differences between seizure threshold tests are most likely a consequence of the mechanisms underlying seizure induction in these tests. Our data indicate that using only one seizure threshold model during preclinical drug development may pose the risk that potential proconvulsant activity of an investigational drug is overseen. However, the label "proconvulsant" may be misleading if such activity only occurs at doses high above the therapeutic range, but the drug is not proconvulsant or even exerts anticonvulsant effects at lower, therapeutically relevant doses. PMID- 22209702 TI - [Wound infiltration with local anesthetics for postoperative analgesia. Results of a national survey about its practice in France]. AB - BACKGROUND AND OBJECTIVE: Local wound infiltration is a component of multimodal postoperative (p.o.) analgesia. Its implementation in current clinical practice remains unknown. Pain and Regional Anesthesia Committee of the French Anaesthesia and Intensive Care Society (Sfar) aimed to appraise its practice. METHOD: Postal sample survey based on representative sample of national activity were sent to heads of anaesthesiology departments. The questionnaires included 36 items on single-shot and continuous wound infiltrations (CWI) with considerations about modality of administration, drugs and development limitations. Results in mean [CI95 %]. RESULTS: Response rate was 32 % (n=120). Sample was in accordance with national representation of health institutions. Local infiltration was included in 85 % [79-91] of the p.o. analgesia protocols. Regardless of the surgery, single-shot wound infiltration and CWI were used in more than 50 % of the patients by respectively 58 % [49-67] and 18 % [11-25] of the responders. However, a significant part of the surgeons remained reluctant to CWI. Lack of information and fear of septic complications were the most reported barriers. Peritoneal instillation after laparoscopy was rarely performed, in contrast with intra-articular infiltration after knee arthroscopy, performed systematically or very frequently by 60 % [50-70] of the responders. CONCLUSION: The practice of local wound infiltration for p.o. analgesia seems presently well established, especially for single-shot injections. CWI is less commonly performed. Several surgical reluctances remain to be overcome. Better information about effectiveness and safety are likely to still improve their practices. PMID- 22209703 TI - [Damage control, haemoglobin and hypothermia]. PMID- 22209704 TI - Influence of an experimental fish farm on the spatio-temporal dynamic of a Mediterranean maerl algae community. AB - This work concerns the monitoring of a Mediterranean maerl bed influenced by an experimental fish cage culture for eighteen months. The maerl bed showed an a priori stratified distribution with depth, which led to the selection of a stratified random sampling design that also took into account the gradient of influence by the fish cages. Maerl coverage and total biomass, macroalgae species richness and community structure as determined from semi-quantitative abundance data were assessed. The content of organic matter sediment was also considered. Sampling campaigns (performed by scuba divers) were carried out six months before the start of the culture, twice during the culture, and two months after the end of the experimental culture. Below the fish cages, the maerl community was almost completely buried and dead blackened calcareous algae were seen beneath a thin layer of sediment prior to the end of the study, and only a few specimens of Lithophyllum racemus, Flabellia petiolata, Gracilaria cylindrica and Meredithia microphylla remained alive. The influence of the experimental culture on the maerl algae community structure bed did not extend beyond the facilities, but a regression of the community was also observed close to the fish cages. Sensitivity to aquaculture activity, and the ecological benefits provided by maerl beds suggest that this community warrants further consideration when planning fish farm site selection and management. PMID- 22209705 TI - Local translation of ATP synthase subunit 9 mRNA alters ATP levels and the production of ROS in the axon. AB - To date, it has been demonstrated that axonal mRNA populations contain a large number of nuclear-encoded mRNAs for mitochondrial proteins. Here, we report that the mRNA encoding ATP synthase subunit 9 (ATP5G1), a key component of Complex V of the oxidative phosphorylation chain, is present in the axons of rat primary sympathetic neurons, as judged by in situ hybridization and qRT-PCR methodology. Results of metabolic labeling studies establish that this nuclear-encoded mRNA is translated in the axon. The siRNA-mediated knock-down of axonal ATP5G1 mRNA resulted in a significant reduction of axonal ATP5G1 protein and ATP levels. Silencing of local ATP5G1 expression enhanced the production of local reactive oxygen species (ROS). Importantly, reduction in the levels of ATP5G1 expression resulted in a marked attenuation in the rate of elongation of the axon. Exposure of the distal axons to nordihydroguaiaretic acid (NDGA), a ROS scavenger, mitigated the reduction in the rate of axon elongation observed after knock-down of ATP5G1. Taken together, these data call attention to the key regulatory role that local translation of nuclear-encoded mitochondrial mRNAs plays in energy metabolism and growth of the axon. PMID- 22209706 TI - Factors associated with knowledge and control of arterial hypertension in the Canary Islands. AB - INTRODUCTION AND OBJECTIVES: To analyze the factors associated with knowledge and control of hypertension in the adult population of the Canary Islands (18-75 years). METHODS: We recruited a random sample of the general population aged >=18 years. Hypertension was defined as systolic/diastolic blood pressure >=140/90 mmHg or known hypertension (self-declared, or controlled hypertension <140/90 mmHg). The bivariate association of known and controlled hypertension with age, sex, anthropometry, serum lipids, medication, and lifestyle was corroborated by adjusting a multivariate logistic model. RESULTS: We included 6675 participants. The prevalence of hypertension was higher in men (40% vs 31%, P<.001), who also had a lower frequency of treated and controlled hypertension. Female sex (P<.001), age >=55 years (P<.001), obesity (P<.001), and diabetes (P<.001) were associated with known hypertension. The modifiable factors that, in spite of treatment, increased the risk of poor control of hypertension were alcohol consumption (>30 g/day, odds ratio [OR]=2.4, P<.001; >15-<=30 g/day, OR=2, P=.009; >5-<=15, g/day, OR=1.83, P=.004), obesity (body mass index >=30, OR=2, P=.003; >24.9-<30, OR=1.7, P=.024), serum cholesterol >250 mg/dL (OR=1.6, P=.006) and elevated heart rate (>80 bpm, OR=1.45, P=.045; >70-<=80 bpm, OR=1.36, P=.038). CONCLUSIONS: The awareness of hypertension increases with frequent use of the health system and with factors associated with known hypertension: female sex, age, underlying health problems. The modifiable factors associated with poor control of known hypertension are alcohol consumption, obesity, elevated heart rate, and hypercholesterolemia. PMID- 22209707 TI - Next-generation biomarkers based on 100-parameter functional super-resolution microscopy TIS. AB - Functional super-resolution (fSR) microscopy is based on the automated toponome imaging system (TIS). fSR-TIS provides insight into the myriad of different cellular functionalities by direct imaging of large subcellular protein networks in morphologically intact cells and tissues, referred to as the toponome. By cyclical fluorescence imaging of at least 100 molecular cell components, fSR-TIS overcomes the spectral limitations of fluorescence microscopy, which is the essential condition for the detection of protein network structures in situ/in vivo. The resulting data sets precisely discriminate between cell types, subcellular structures, cell states and diseases (fSR). With up to 16 bits per protein, the power of combinatorial molecular discrimination (PCMD) is at least 2(100) per subcellular data point. It provides the dimensionality necessary to uncover thousands of distinct protein clusters including their subcellular hierarchies controlling protein network topology and function in the one cell or tissue section. Here we review the technology and findings showing that functional protein networks of the cell surface in different cancers encompass the same hierarchical and spatial coding principle, but express cancer-specific toponome codes within that scheme (referred to as TIS codes). Findings suggest that TIS codes, extracted from large-scale toponome data, have the potential to be next-generation biomarkers because of their cell type and disease specificity. This is functionally substantiated by the observation that blocking toponome specific lead proteins results in disassembly of molecular networks and loss of function. PMID- 22209708 TI - Synthesis of deuterium labeled NMDA receptor inhibitor - 20-Oxo-5beta-[9,12,12 (2)H(3)]pregnan-3alpha-yl-L-glutamyl 1-ester. AB - 20-Oxo-5beta-[9,12,12-(2)H(3)]pregnan-3alpha-yl-l-glutamyl 1-ester 11 was synthesized as an internal standard for quantification of a neuroprotective NMDA receptor ligand, 20-oxo-5beta-pregnan-3alpha-yl-l-glutamyl 1-ester 18 and its metabolites, in plasma and tissue. 11alpha-Hydroxy-progesterone (1) was reduced under basic conditions to yield the corresponding 5beta-steroid. Protection of the 3- and 20-oxo groups and oxidation of the 11alpha-hydroxy group was then followed by a deuterium exchange, conducted under basic conditions using deuterated methanol. Next, the carbonyl moiety at C-11 was reduced and the 11alpha-hydroxyl group removed through utilization of the Barton-McCombie reaction. Subsequent deprotection of the 3- and 20-acetals and stereoselective reduction of the 3-oxo group gave the desired trideuterated pregnanolone (8). This was coupled with protected glutamic acid, which was then deprotected to yield [9,12,12-(2)H(3)]-pregnanolone glutamate (11) with >99% isotopic purity. PMID- 22209710 TI - [Stereotactic body radiation therapy for liver primary and metastases: the Lille experience]. AB - PURPOSE: The CyberKnife((r)) system is a recent radiation therapy technique that allows treatment of liver lesions with real-time tracking. Because of its high precision, the dose administered to the tumor can be increased. We report Oscar Lambret Cancer Centre experience in the treatment of primary and secondary liver lesions. PATIENTS AND METHODS: It is a retrospective study analyzing all the patients who have been treated for their liver lesions since July 2007. A hundred and twenty patients have been treated: 42 for hepatocellular carcinoma, 72 for liver metastases and six for cholangiocarcinoma. Gold seeds need to be implanted before the treatment and are used as markers to follow the movement of the lesion due to respiration. On average, the treatment is administered in three to four sessions over 12 days. A total dose of 40 to 45 Gy at the 80% isodose is delivered. Local control and overall survival analysis with Log-rank is performed for each type of lesion. RESULTS: Treatment tolerance is good. The most common toxicities are of digestive type, pain and asthenia. Six gastro-duodenal ulcers and two radiation-induced liver disease (RILD) were observed. At a median follow up of 15 months, the local control rate is respectively of 80.4% and 72.5% at 1 and 2 years. Overall survival is 84.6 and 58.3% at 1 and 2 years. The local control is significantly better for the hepatocellular carcinoma and overall survival is significantly better for liver metastases (P<0.05). The local control rate and overall survival at 1 year for cholangiocarcinoma is 100%. CONCLUSION: CyberKnife((r)) is a promising technique, well tolerated, with tumoral local control rates comparable to other techniques. Its advantage is that it is very minimally invasive delivered as an outpatient procedure in a frail population of patient (disease, age). PMID- 22209709 TI - Dexamethasone stimulates endothelin-1 gene expression in renal collecting duct cells. AB - Aldosterone stimulates the endothelin-1 gene (Edn1) in renal collecting duct (CD) cells by a mechanism involving the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). The goal of the present study was to determine if the synthetic glucocorticoid dexamethasone affected Edn1 gene expression and to characterize GR binding patterns to an element in the Edn1 promoter. Dexamethasone (1MUM) induced a 4-fold increase in Edn1 mRNA in mIMCD-3 inner medullary CD cells. Similar results were obtained from cortical collecting duct derived mpkCCD(c14) cells. RU486 inhibition of GR completely blocked dexamethasone action on Edn1. Similarly, 24h transfection of siRNA against GR reduced Edn1 expression by approximately 50%. However, blockade of MR with either spironolactone or siRNA had little effect on dexamethasone induction of Edn1. Cotransfection of MR and GR siRNAs together had no additive effect compared to GR siRNA alone. The results indicate that dexamethasone acts on Edn1 exclusively through GR and not MR. DNA affinity purification studies revealed that either dexamethasone or aldosterone resulted in GR binding to the same hormone response element in the Edn1Edn1 promoter. The Edn1 hormone response element contains three important sequence segments. Mutational analysis revealed that one of these segments is particularly important for modulating MR and GR binding to the Edn1 hormone response element. PMID- 22209711 TI - NO-dependent protective effect of VEGF against excitotoxicity on layer VI of the developing cerebral cortex. AB - In industrialized countries, cerebral palsy affects 2.50/00 of preterm and term infants. At a neurochemical level, the massive release of glutamate constitutes a major process leading to excitotoxicity and neonatal brain lesions. Previous studies, conducted in the laboratory, revealed that, in (delta/delta)VEGF(A) transgenic mice, glutamate-induced brain lesions are exacerbated suggesting that VEGF(A) could play a protective action against excitotoxicity. Using a model of cultured cortical brain slices, the aim of the study was to characterize the central effects of VEGF against glutamate-induced excitotoxicity in neonates. Exposure of brain slices to glutamate induced a strong increase of necrotic cell death in the deep cortical layer VI and a decrease of apoptotic death in superficial layers II-IV. When administered alone, a 6-h treatment with VEGF(A) had no effect on both apoptotic and necrotic deaths. In contrast, VEGF(A) abolished the glutamate-induced necrosis observed in layer VI. While MEK and PI3 K inhibitors had no effect on the protective action of VEGF(A), L-NAME, a pan inhibitor of NOS, abrogated the effect of VEGF(A) and exacerbated the excitotoxic action of glutamate. Calcimetry experiments performed on brain slices revealed that VEGF(A) reduced the massive calcium influx induced by glutamate in layer VI and this effect was blocked by L-NAME. Neuroprotective effect of VEGF(A) was also blocked by LNIO and NPLA, two inhibitors of constitutive NOS, while AGH, an iNOS inhibitor, had no effect. Nitrite measurements, electron paramagnetic resonance spectroscopy and immunohistochemistry indicated that glutamate was a potent inducer of NO production via activation of nNOS in the cortical layer VI. In vivo administration of nNOS siRNA promoted excitotoxicity and mimicked the effects of L-NAME, LNIO and NPLA. A short-term glutamate treatment increased nNOS Ser1412 phosphorylation, while a long-term exposure inhibited nNOS/NR2B protein-protein interactions. Altogether, these findings indicate that, in deep cortical layers of mice neonates, glutamate stimulates nNOS activity. Contrasting with mature brain, NO production induced by high concentrations of glutamate is neuroprotective and is required for the anti-necrotic effect of VEGF(A). PMID- 22209712 TI - Orally bioavailable allosteric CCR8 antagonists inhibit dendritic cell, T cell and eosinophil migration. AB - The chemokine receptor CCR8 is associated with asthma. Herein, we describe that both mature and immature dendritic cells (DC) express CCR8, whereas only mature DC migrate towards CCL1. Moreover, transient LPS challenge significantly down regulates CCR8 expression hence attenuating CCL1 chemotaxis. To inhibit CCR8 pathophysiology, we recently developed a novel series of small molecule CCR8 antagonists containing a diazaspiroundecane scaffold, which had micromolar potency. However, these first generation antagonists had high lipophilicity that endowed the compounds with poor physicochemical properties, and were thus not suitable for further development. By introducing polar bicyclic groups on the N benzyl substituent and building in further polar interactions on the amide group we now show second generation diazospiroundecane antagonists with significantly improved overall properties. Potency is substantially improved from micromolar to nanomolar potency in CCR8 binding and inhibition of chemotaxis in human primary T cells, DC and in an eosinophil cell line. In addition to high potency, the most attractive antagonist, AZ084 showed excellent selectivity, high metabolic stability in vitro and an attractive in vivo PK profile with a long half-life in rat. Interestingly, in ligand saturation experiments and in wash-off experiments, CCL1 was shown to have two binding sites to CCR8 with K(d) at 1.2/68pM respectively, and on-off rates of 0.004 and 0.0035/0.02pMmin, respectively. The lead antagonist, AZ084, appears to act as an allosteric inhibitor with a K(i) at 0.9nM. Taken together, we herein report a novel oral allosteric CCR8 antagonist with predicted low once-daily dosing capable of potent inhibition of both human T cell and DC functions. PMID- 22209714 TI - Hydrogen sulfide-releasing aspirin modulates xenobiotic metabolizing enzymes in vitro and in vivo. AB - The balance between phase-I carcinogen-activating and phase-II detoxifying xenobiotic metabolizing enzymes is critical to determining an individual's risk for cancer. We evaluated the effect of Hydrogen sulfide-releasing aspirin (HS ASA) on xenobiotic metabolizing enzymes in HT-29 human colon and Hepa 1c1c7 mouse liver adenocarcinoma cells and in Wistar rats. HS-ASA inhibited the growth of HT 29 and Hepa 1c1c7 cells, with an IC(50) of 3.2 +/- 0.3 MUM and 4.2 +/- 0.4 MUM, respectively. The IC(50) for ASA in both cell lines was greater than 5000 MUM at 24h. In these cell lines, HS-ASA caused a dose-dependent increase in activity and expression of the phase-II enzymes glutathione S-transferase (GST) and NAD(P)H:quinoneoxireductase (NQO1). It also caused an increase in UDP glucuronosyltransferase (UGT) expression. The levels of CYP 1A1 a phase-I enzyme was increased by HS-ASA in both cell lines. Pretreatment of cells with NaF, an esterase inhibitor, abrogated the HS-ASA-mediated increases in NQO1 enzyme activity. HS-ASA increased the protein levels of the transcription factor Nrf2, which is a regulator of the phase-II enzymes. In vivo, HS-ASA at 100mg/kg/day had no effect on rat's weights; it induced a 3.4-fold and 1.4-fold increase in hepatic GST and NQO1 enzyme activities, respectively. GST and NQO1 protein levels were also increased. In contrast to that in cultured cells, CYP 1A1 protein levels were not altered in vivo. Therefore, HS-ASA induces phase-II enzymes, at least in part, through the action of H(2)S and by modulating Nrf2; these effects may be part of its mechanism of action against carcinogenesis. PMID- 22209713 TI - NAD(P)H:quinone oxidoreductase 1 (NQO1) in the sensitivity and resistance to antitumor quinones. AB - Quinones represent a large and diverse class of antitumor drugs and many quinones are approved for clinical use or are currently undergoing evaluation in clinical trials. For many quinones reduction to the hydroquinone has been shown to play a key role in their antitumor activity. The two-electron reduction of quinones by NQO1 has been shown to be an efficient pathway to hydroquinone formation. NQO1 is expressed at high levels in many human solid tumors making this enzyme ideally suited for intracellular drug activation. Cellular levels of NQO1 are influenced by the NQO1*2 polymorphism. Individuals homozygous for the NQO1*2 allele are NQO1 null and homozygous NQO1*2*2 cell lines have been shown to be more resistant to antitumor quinones when compared to isogenic cell lines overexpressing NQO1. In this review we will discuss the role of NQO1 in the sensitivity and resistance of human cancers to the quinone antitumor drugs mitomycin C, beta-lapachone and the benzoquinone ansamycin class of Hsp90 inhibitors including 17-AAG. The role of NQO1 in the bioreductive activation of mitomycin C remains controversial but pre clinical data strongly suggests a role for NQO1 in the activation of beta lapachone and the benzoquinone ansamycin class of Hsp90 inhibitors. Despite a large volume of preclinical data demonstrating that NQO1 is an important determinant of sensitivity to these antitumor quinones there is little information on whether the clinical response to these agents is influenced by the NQO1*2 polymorphism. The availability of simple assays for the determination of the NQO1*2 polymorphism should facilitate clinical testing of this hypothesis. PMID- 22209715 TI - A selective reversible azapeptide inhibitor of human neutrophil proteinase 3 derived from a high affinity FRET substrate. AB - The biological functions of human neutrophil proteinase 3 (PR3) remain unclear because of its close structural resemblance to neutrophil elastase and its apparent functional redundancy with the latter. Thus, all natural inhibitors of PR3 preferentially target neutrophil elastase. We have designed a selective PR3 inhibitor based on the sequence of one of its specific, sensitive FRET substrates. This azapeptide, azapro-3, inhibits free PR3 in solution, PR3 bound to neutrophil membranes, and the PR3 found in crude lung secretions from patients with chronic inflammatory pulmonary diseases. But it does not inhibit significantly neutrophil elastase or cathepsin G. Unlike most of azapeptides, this inhibitor does not form a stable acyl-enzyme complex; it is a reversible competitive inhibitor with a K(i) comparable to the K(m) of the parent substrate. Low concentrations (60 MUM) of azapro-3 totally inhibited the PR3 secreted by triggered human neutrophils (200,000 cells/100 MUL) and the PR3 in neutrophil homogenates and in lung secretions of patients with lung inflammation for hours. Azapro-3 also resisted proteolysis by all proteases contained in these samples for at least 2h. PMID- 22209716 TI - The many faces of Janus kinase. AB - Janus kinases have proved to be essential for many immunological processes but there is growing evidence that they also play a critical role in pathogenesis of many diseases including inflammatory diseases and cancer where they promote multiple steps of tumorigenesis. Several companies are in late stage clinical programs for the development of JAK kinase inhibitors and the first small molecule JAK inhibitor, Jakafi(r) (ruxolitinib) has been just approved for treatment of myeloproliferative neoplasms. Several other molecules are on the rise to treat arthritis, psoriasis and multiple types of cancer. This commentary will provide a review of the JAK kinase field as it pertains to small molecule inhibition for the treatment of cancer and autoimmune diseases with an emphasis on JAK2. The use of experimental and clinical inhibitors of JAK will be discussed for solid tumor and hematological malignancies, lupus, arthritis, colitis, neurological disorders, pain, diabetes and cardiovascular disease. In addition, it will review current paradigms in the field and treatment programs which could be complemented by small molecule inhibitors of Janus kinase. PMID- 22209717 TI - Association of myostatin gene polymorphisms with obesity in Chinese north Han human subjects. AB - CONTEXT: Myostatin (MSTN) is a member of the TGF-beta superfamily of signal transduction proteins, which plays an important role in muscular growth and lipid metabolism. OBJECTIVE: To study the association of myostatin gene polymorphisms with obesity in Chinese north Han human subjects. DESIGN: 297 healthy and 606 over-weight/obesity Chinese north Han subjects were selected as healthy control group and overweight/obesity group, respectively. The methods of DNA Sequencing, Restriction Fragment Length Polymorphism (RFLP) and TaqMan(r) probe were used to screen myostatin gene SNPs and clarify genotype in every individual. RESULTS: Total 11 SNPs in MSTN gene were identified by DNA sequencing and three SNPs including rs35781413 (G/A), rs3791783 (A/G) and rs3791782 (A/G) were selected for further study in total 903 samples. The results showed that the frequency of AA genotype of rs3791783 A/G SNP was significantly higher (56.4% vs. 50.8%) and the frequency GG genotype was significantly lower (3.2% vs. 6.7%) in overweight/obese patients than in normal weight subjects. A logistic regression analysis under a recessive inheritance model (AA+AG vs.GG) demonstrated that the Odd ratio for AA+AG vs.GG were 1.985 (95% CI 1.078-3.643; P=0.029). Among three genotypes of rs3791783, the subjects with AA genotype have much more higher body weight, BMI, waist circumference, TC, TG and LDL-C than those with GG genotype. CONCLUSIONS: Our data firstly suggest that genetic variant rs3791783 A/G in myostatin gene are associated with obesity. The A allele carriers in rs3791783 SNP have an increased susceptibility to obesity compared with the G allele carriers. Participants with AA genotype in rs3791783 SNP site will have higher risk suffered from overweight or obesity than those with GG genotype. PMID- 22209718 TI - A homemade MLPA assay detects known CTNS mutations and identifies a novel deletion in a previously unresolved cystinosis family. AB - Infantile nephropatic cystinosis is a rare, recessive, and genetically homogeneous disorder impairing renal function. It is caused by mutations in CTNS. Several large copy number aberrations have been identified but, for the majority of these, heterozygous patients and carriers can not easily be identified. We therefore developed a multiplex ligation-dependent probe amplification assay targeting eight of the twelve CTNS exons. We show that this assay is valid in detecting known deletions in both the homozygous and heterozygous state. The application to a family previously found mutation-negative by conventional screening revealed a novel large deletion which, as the first of its kind, does not involve the coding region. We conclude that our assay represents a valid tool for further completing the CTNS mutation spectrum and for simplified carrier testing in cystinosis families harboring copy number mutations. More generally, our study exemplifies the use of synthetic, homemade MLPA probesets as cheap, efficient, and rapidly available screening tools for small genes and/or very rare diseases. PMID- 22209719 TI - A high-throughput apple SNP genotyping platform using the GoldenGateTM assay. AB - EST data generated from 14 apple genotypes were downloaded from NCBI and mapped against a reference EST assembly to identify Single Nucleotide Polymorphisms (SNPs). Mapping of these SNPs was undertaken using 90% of sequence similarity and minimum coverage of four reads at each SNP position. In total, 37,807 SNPs were identified with an average of one SNP every 187 bp from a total of 6888 unique EST contigs. Identified SNPs were checked for flanking sequences of >= 60 bp along both sides of SNP alleles for reliable design of a custom high-throughput genotyping assay. A total of 12,299 SNPs, representing 6525 contigs, fit the selected criterion of >= 60 bp sequences flanking a SNP position. Of these, 1411 SNPs were validated using four apple genotypes. Based on genotyping assays, it was estimated that 60% of SNPs were valid SNPs, while 26% of SNPs might be derived from paralogous regions. PMID- 22209720 TI - The complete mitochondrial genome of Gomphocerus tibetanus Uvarov, 1935 (Orthoptera: Acrididae: Gomphocerinae). AB - The complete nucleotide sequence of the mitochondrial genome (mitogenome) of Gomphocerus tibetanus Uvarov, 1935 (Orthoptera: Acrididae: Gomphocerinae) was determined. It is 15,571 bp in length and contains 74.8% A+T. All Gomphocerus tibetanus protein-coding sequences start with a typical ATN codon. The usual termination codons (TAA and TAG) were found from 13 PCGs except COI and COII which took incomplete codon T as termination codons. All tRNA genes could be folded into the typical cloverleaf secondary structure, except tRNA(Ser(AGN)) lacking of dihydrouridine (D) arm. The sizes of the large and small ribosomal RNA genes are 1313 and 822bp, respectively. The A+T content of the A+T-rich region is 82.3%. A preliminary analysis on characteristics of Gomphocerinae mitogenome was made by comparision among three Gomphocerinae mitogenomes and Locusta migratoria. PMID- 22209721 TI - Complete nucleotide sequence of plasmid pST-III from Lactobacillus plantarum ST III. AB - The complete nucleotide sequence of the 53,560-bp plasmid pST-III from Lactobacillus plantarum ST-III has been determined. The plasmid contains 42 predicted protein-coding sequences, and the functions of 34 coding sequences could be assigned. Homology analysis for the replication protein and the typical features of the origin of replication suggested that pST-III replicates via the theta-type mechanism. Among the predicted genes, we identified a kdp gene cluster (a high-affinity K(+)-transport system) for the first time in the Lactobacillus genus and a system for osmolyte transport. Analysis of the plasmid-encoded functions and the plasmid-cured experiment showed that the genes of pST-III could serve for the niche adaptations of L. plantarum ST-III and make significant contributions to its viability under hyperosmotic conditions. Furthermore, the relative copy number of pST-III was determined to be 6.79+/-1.55 copies per cell. PMID- 22209723 TI - Riata implantable cardioverter-defibrillator lead failure: analysis of explanted leads with a unique insulation defect. AB - BACKGROUND: The Riata family of implantable cardioverter-defibrillator leads (St Jude Medical, Sylmar, CA) appears prone to a unique failure mechanism whereby the conductor cables wear through the silicone insulation from inside-out and are seen outside the lead body (externalized conductors). OBJECTIVE: To assess the extent of Riata lead damage associated with inside-out insulation defects and their clinical consequences. METHODS: In September 2011, we searched the U.S. Food and Drug Administration's Manufacturers and User Defined Experience medical device database for reports describing Riata lead failures that had been analyzed by the manufacturer. RESULTS: The Manufacturers and User Defined Experience search identified 105 leads that had inside-out insulation defects. Eight-French single-coil Riata leads accounted for a higher-than-expected proportion (25.7%) of the leads with this defect. A total of 226 insulation defects were found in the 105 leads (2.2 defects per lead), including 143 inside-out defects (1.4 defects per lead). The most common location of insulation defects was distal to the proximal coil (n = 108). Twenty-eight leads (26.7%) had inside-out insulation defects underneath the shocking coils. Of 43 leads whose cables were assessed for the integrity of the ethylene-tetrafluoroethylene cable coating, 22 (51.2%) were found to be abraded, exposing the conductor surfaces. On X-ray radiography or fluoroscopy, 7 leads were found to have externalized cables; 2 of these leads had no electrical abnormalities, while 4 exhibited noise or increased impedance. Inappropriate shocks were experienced by 31 of the 105 patients (29.5%). CONCLUSION: Riata leads that have inside-out insulation defects often have multiple defects, including additional inside-out abrasions along the body of the lead and beneath the shocking coils. Eight-French single-coil Riata models may be more prone to externalized cables than are dual-coil and 7-F designs. Externalized cables are but one manifestation of interior insulation damage. Our findings question the durability of the ethylene-tetrafluoroethylene cable coating on exposed cables. PMID- 22209722 TI - EET agonist prevents adiposity and vascular dysfunction in rats fed a high fat diet via a decrease in Bach 1 and an increase in HO-1 levels. AB - Recent reports have shown interplay between EETs (epoxides) and the heme oxygenase (HO) system in attenuating adipogenesis in cell culture models; prompting an examination of the effectiveness of EET agonist on obesity and associated cardio-metabolic dysfunction. Patho-physiological effects of an EET agonist (NUDSA) were contrasted in the absence and in the presence of stannous mesoporphyrin (an HO inhibitor) in SD rats fed a high fat (58%, HF) for 16 weeks. Animals on HF diet exhibited enhanced oxidative stress, increased levels of inflammatory cytokines and decreased levels of adiponectin along with reduced vascular and adipose tissue levels of EETs, HO-1; as compared to control rats (11% dietary fat). Treatment with NUDSA not only reversed serum adiponectin and vascular and adipose tissue levels of EETs and HO-1, but also, decreased blood pressure, subcutaneous and visceral fat content and serum TNFalpha and IL-6 levels in rats on HF diet. Aortic endothelial function, peNOS expression and adipose tissue markers of energy homeostasis i.e. pAMPK, Sirt1 and FAS, impaired in rats fed a HF diet, were restored in animals treated with this EET agonist. That NUDSA enhanced HO-1 expression, was accompanied by increase in p-GSK-3beta and pAKT levels along with attenuation of adipose tissue levels of Bach 1--the transcriptional suppresser of HO-1 expression. Prevention of these beneficial effects of NUDSA, in animals on HF diet and concurrently exposed to NUDSA and SnMP, supports the role of EET-HO interaction in mediating such effects. Taken together, our findings suggest that the EETs stimulate HO-1 expression via suppression of Bach 1 and interplay of these two systems affords vascular and metabolic protection in diet induced obesity. PMID- 22209724 TI - Effects of aflatoxin B1 on tissue residues of enrofloxacin and its metabolite ciprofloxacin in broiler chickens. AB - The impact of subchronic exposure of aflatoxin B1 on the tissue residues of enrofloxacin and its metabolite ciprofloxacin was examined in broiler chickens. Broiler chickens given either normal or aflatoxin B1 (750 MUg/kg diet) supplemented diets for 6 weeks received enrofloxacin (10 mg/kg/day, p.o.) for 4 days and thereafter, residue levels were determined. Aflatoxin B1 induced alterations in serum marker enzymes. As compared to unexposed broiler chickens, enrofloxacin concentrations in aflatoxin B1-exposed broiler chickens were significantly higher in all tissues (0.62-4.53 MUg/g) analyzed except muscle 24h after termination of enrofloxacin administration. Ciprofloxacin was detectable in tissues of only mycotoxin-exposed broiler chickens. Enrofloxacin residues in liver, kidney and skin plus fat persisted for 10 days in mycotoxin-exposed broiler chickens whereas it was detectable only in liver of unexposed broiler chickens. Our results indicate that subchronic aflatoxin B1 exposure markedly influences the residue levels of enrofloxacin and ciprofloxacin in tissues of broiler chickens. PMID- 22209725 TI - The profile of beta-amyloid precursor protein expression of rats induced by aluminum. AB - The environmental agent aluminum has been extensively investigated for a potential relationship with amyloid precursor protein (APP) expression. Despite many investigations, there is at present no definite proof from which to draw a conclusion. Since APP is an integral membrane protein expressed in different tissues and capable of fluxes across the blood-brain barrier (BBB), which may ultimately affect APP level in brain, it is necessary to assess the expression profile among vital body organs. The present study compared aluminum oxide and aluminum chloride injected rats with control rats (saline treated) to observe if aluminum affected APP expression patterns in different organs by immunohistochemistry (IHC). The expression of APP was observed in the brain of aluminum chloride treated rats and in the liver of aluminum oxide injected group. Results of double IHC staining showed that it is Kupffer cells, which are located in liver sinus and expressed APP after aluminum oxide treatment. Oxidative stress is suggested as the potential pathway that aluminum chloride exert effects in brain. These results suggest that different aluminum compounds may impact the expression of APP in brain and liver tissues. The mechanism that aluminum induced liver APP expression still needs further investigation. PMID- 22209726 TI - Protective effects of catechin and quercetin on antioxidant status, lipid peroxidation and testis-histoarchitecture induced by chlorpyrifos in male rats. AB - Mature male Wistar rats were given chlorpyrifos (5.4 mg/kg, 1/25 of the oral LD(50)), catechin (20 mg/kg),quercetin (20 mg/kg), catechin plus chlorpyrifos, and quercetin plus chlorpyrifos daily via gavage for four weeks. No statistical differences were found in the catechin-only and quercetin-only groups compared with the control group. By the end of the fourth week, chlorpyrifos alone increased the levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), while decreased glutathione peroxidase (GPx) and glutathione-S transferase (GST) activities compared with the control group in rat testis tissues. In the catechin-plus-chlorpyrifos and quercetin-plus-chlorpyrifos groups, there were statistically significantly decreased MDA levels, SOD and CAT activities, while increased GPx and GST activities compared with the chlorpyrifos only group. Light microscopic analyses revealed that chlorpyrifos-only induced numerous histopathological changes in the testis tissues. Milder pathological alterations were observed in rats catechin-plus-chlorpyrifos, and quercetin-plus chlorpyrifos. Thus, it appears that catechin and quercetin ameliorate chlorpyrifos induced toxicity except histopathological changes in rat testis tissues. PMID- 22209727 TI - Combined effects of gamma-irradiation and cadmium exposures on osteoblasts in vitro. AB - The combined effects of gamma-irradiation and cadmium (Cd) exposures on osteoblasts were observed in the present study. Osteoblasts were exposed to gamma irradiation (0.5 Gy) and Cd (0-0.5 MUmol/L). Cell viability, alkaline phosphatase (ALP) activity, mineralization ability, cell apoptosis and genes expression of ALP, osteocalcin (OC) and caspase 3 were observed. Low concentrations of Cd exposure had no obvious influence on cell viability, ALP activity and apoptosis. However, low levels of Cd exposure combined with gamma-irradiation induced more toxic effects on osteoblasts than those treated with Cd or irradiation alone. High concentrations of Cd combined with irradiation exposure induced more significant inhibition in cell viability, ALP activity and mineralization ability than those exposed to Cd or irradiation alone. Meanwhile, OC and ALP mRNA expression of cells treated with Cd combined with irradiation were down-regulated more significantly than those treated with Cd or irradiation alone. Cd combined with gamma-irradiation could obviously enhance osteoblast apoptosis and up regulated caspase 3 mRNA expression compared with those treated with Cd or irradiation alone. This study indicated that ionizing irradiation can enhance Cd toxic effects on osteoblast viability and differentiation and apoptosis may play an important role in this progress. PMID- 22209728 TI - Plant small RNAs as morphogens. AB - RNA interference (RNAi) in plants has long been known to produce a non-cell autonomous signal capable of silencing target genes over great cellular distances. However, only recently have RNAi-derived small RNAs been formally shown to comprise that mobile signal. Interestingly, some of these mobile small RNAs play critical roles in plant development, forming gradients that regulate the activity of their targets in a dosage-dependent manner. These properties resemble features of morphogens in animals, leading us to postulate that such cell-fate-defining small RNAs employ similar principles for the generation, stabilization and interpretation of their expression gradients. Here we review our understanding of small RNA mobility in plants, evaluate their potential as morphogen-like signals, and consider how the graded accumulation patterns that underlie their patterning/biological activity could be created and maintained. PMID- 22209729 TI - Kinetochore dynamics: how protein dynamics affect chromosome segregation. AB - Protein dynamics generate adaptive cellular architecture. This concept is exemplified by kinetochores, organelles that orchestrate chromosome segregation during mitosis. In this review, we will focus on protein dynamics at kinetochores and discuss how these dynamics impact chromosome motility during mitosis. PMID- 22209730 TI - A new class of non-thiazolidinedione, non-carboxylic-acid-based highly selective peroxisome proliferator-activated receptor (PPAR) gamma agonists: design and synthesis of benzylpyrazole acylsulfonamides. AB - Herein, we describe the design, synthesis, and structure-activity relationships of novel benzylpyrazole acylsulfonamides as non-thiazolidinedione (TZD), non carboxylic-acid-based peroxisome proliferator-activated receptor (PPAR) gamma agonists. Docking model analysis of in-house weak agonist 2 bound to the reported PPARgamma ligand binding domain suggested that modification of the carboxylic acid of 2 would help strengthen the interaction of 2 with the TZD pocket and afford non-carboxylic-acid-based agonists. In this study, we used an acylsulfonamide group as the ring-opening analog of TZD as an isosteric replacement of carboxylic acid moiety of 2; further, preliminary modification of the terminal alkyl chain on the sulfonyl group gave the lead compound 3c. Subsequent optimization of the resulting compound gave the potent agonists 25c, 30b, and 30c with high metabolic stability and significant antidiabetic activity. Further, we have described the difference in binding mode of the carboxylic-acid based agonist 1 and acylsulfonamide 3d. PMID- 22209731 TI - Antidiabetogenic oligostilbenoids and 3-ethyl-4-phenyl-3,4-dihydroisocoumarins from the bark of Shorea roxburghii. AB - A methanol extract of the bark of Shorea roxburghii (Dipterocarpaceae) was found to inhibit plasma glucose elevation in sucrose-loaded mice. From the extract, three new 3-ethyl-4-phenyl-3,4-dihydroisocoumarins, 1'S-dihydrophayomphenol A(2) (1) and phayomphenols B(1) (2) and B(2) (3), were isolated together with 24 known compounds including 20 stilbenoids and oligostilbenoids. The structures of 1-3 were determined on the basis of their spectroscopic properties as well as of chemical evidences. Among the isolates, (-)-hopeaphenol (6), hemsleyanol D (8), (+)-alpha-viniferin (15), and (-)-balanocarpol (18) showed inhibitory activity against plasma glucose elevation in sucrose-loaded rats at doses of 100-200mg/kg, p.o. To clarify the mode of action of the antihyperglycemic property, effects of these oligostilbenoids on gastric emptying in mice, those on glucose uptake in isolated intestinal tissues as well as inhibitory activities against rat intestinal alpha-glucosidase and rat lens aldose reductase were examined. PMID- 22209732 TI - Cyclolobatriene, a novel prenylated germacrene diterpene, from the soft coral Lobophytum pauciflorum. AB - A new 10-membered-ring diterpene, cyclolobatriene (1), along with three other known diterpenes, lobatriene (2), eunicol (3), and fuscol (4), were isolated from the Okinawan soft coral Lobophytum pauciflorum. Their structures were established by extensive NMR spectroscopic analyses. Cyclolobatriene (1) is an additional example of rare prenylated germacrenes. Although 1, due to a 10-membered-ring structure, exists as an equilibrium mixture of three conformers, the NMR measurement in CDCl(3) at 7 degrees C enabled us to assign the NMR signals of the three, which is the first example of the complete NMR assignment of all the existing conformers of germacrene-type compounds. Cyclolobatriene (1) was thermally unstable and converted into 2 through Cope rearrangement upon heating at 70 degrees C. Eunicol (3) also possesses the same prenylated germacrene structure as 1, showing similar physico-chemical properties to 1. All four compounds 1-4 showed cytotoxic effect with IC(50)'s of 0.64, 0.41, 0.35 and 0.52 MUM, respectively, against human epidermoid carcinoma A431 cells. PMID- 22209733 TI - Design and synthesis of benzo[c,d]indolone-pyrrolobenzodiazepine conjugates as potential anticancer agents. AB - A series of benzo[c,d]indol-2(1H)one-PBD conjugates (11a-l) have been designed and synthesized as potential anticancer agents. These compounds were prepared by linking the C8-position of DC-81 with a benzo[c,d]indol-2(1H)one moiety through different alkane spacers in good yields and confirmed by (1)H NMR, mass and HRMS data. The DNA binding ability of these conjugates was evaluated by thermal denaturation studies and interestingly, compound 11l showed enhanced DNA binding ability. These compounds were also evaluated for their anticancer activity in selected human cancer cell lines of lung, skin, colon and prostate by using MTT assay method. These new conjugates showed promising anticancer activity with IC(50) values ranging from 1.05 to 36.49 MUM. Moreover, cell cycle arrest in SubG1 phase was observed upon treatment of A549 cells with 1 and 2 MUM (IC(50)) concentrations of compound 11l and it induced apoptosis. This is confirmed by Annexin V-FITC, Hoechst staining, caspase-3 activity as well as DNA fragmentation analysis. PMID- 22209734 TI - Impact of IVS8-(TG)m(T)n on IRT and sweat chloride levels in newborns identified by California CF newborn screening. AB - We examined the relation between the number of (TG) repeats at the (IVS8) (TG)m(T)5 locus of the CFTR gene with neonatal serum immunoreactive trypsinogen (IRT) and sweat chloride (SC) concentrations in hypertrypsinogenemic infants with genotype DeltaF508-9T/5T identified by California cystic fibrosis newborn screening. SC and IRT distributions increased with increasing (TG) repeats. PMID- 22209735 TI - A modified method for the purification of active large enzymes using the glutathione S-transferase expression system. AB - The glutathione S-transferase (GST) fusion protein system is widely used for high level expression and efficient purification of recombinant proteins from bacteria. However many GST-tagged proteins are insoluble, and the existing procedures, which employ a mixture of detergents to solubilize the molecules, frequently compromise their functional activity. A further limitation is that large proteins (>80 kDa) are poorly isolated by the current methods and are contaminated by truncated forms. To overcome these problems, we provide here an improved method for efficient purification of active large GST-tagged enzymes such as the 180-kDa GST-fused mitochondrial RNA polymerase. PMID- 22209736 TI - Method for estimating the single molecular affinity. AB - Affinity constants (k(d), k(a), and K(D)) can be determined by methods that apply immobilized ligands such as immunoassays and label-free biosensor technologies. This article outlines a new surface plasmon resonance (SPR) array imaging method that yields affinity constants that can be considered as the best estimate of the affinity constant for single biomolecular interactions. Calculated rate (k(d) and k(a)) and dissociation equilibrium (K(D)) constants for various ligand densities and analyte concentrations are extrapolated to the K(D) at the zero response level (K(D)(R0)). By applying this method to an LGR5-exo-Fc-RSPO1-FH interaction couple, the K(D)(R0) was determined as 3.1 nM. PMID- 22209737 TI - A high-sensitivity electrochemical immunosensor based on mobile crystalline material-41-polyvinyl alcohol nanocomposite and colloidal gold nanoparticles. AB - A novel competitive immunosensor was developed as a model system using anti-human serum albumin (HSA)-conjugated gold nanoparticles (AuNPs) as an electrochemical label and mobile crystalline material-41 (MCM-41)-polyvinyl alcohol (PVA) mesoporous nanocomposite as an immobilization platform. However, no attempt has yet been made to use the MCM-41 as the supporting electrolyte for the electrosynthesis of nonconducting polymer nanocomposite. This hybrid membrane was evaluated extensively by using field emission scanning electron microscopy (FESEM), cyclic voltammetry (CV), and differential pulse voltammetry (DPV) to determine its physicochemical and electrochemical properties in immunosensor application. FESEM revealed an appropriate and stable attachment between HSA and MCM-41 and also a dense layer deposition of MCM-41-HSA-PVA film onto the electrode surfaces. DPV was developed for quantitative determination of antigen in biological samples. A decrease in DPV responses was observed with increasing concentrations of HSA in standard and real samples. In optimal conditions, this immunosensor based on MCM-41-PVA nanocomposite film could detect HSA in a high linear range (0.5-200 MUg ml-1) with a low detection limit of 1 ng ml-1. The proposed method showed acceptable reproducibility, stability, and reliability and could also be applied to detect the other antigens. PMID- 22209738 TI - Potentiation of Nilotinib-mediated cell death in the context of the bone marrow microenvironment requires a promiscuous JAK inhibitor in CML. AB - In this study, we show that conditioned media (CM) generated from bone marrow (BM)-derived mesenchymal stromal cells lead to BCR-ABL independent STAT3 activation. Activation of STAT3 is important not only for survival of CML cells but also for its protection against Nilotinib (NI), within the BM microenvironment. Reducing the expression of both JAK2 and TYK2 or utilizing a pan-JAK inhibitor blocked CM-mediated STAT3 activation and sensitized CML cells to NI-mediated cell death. Finally, we demonstrate that in patient-derived primitive leukemic cells, co-cultured with BM stromal cells, inhibition of BCR ABL and JAK activity was a successful strategy to potentiate their elimination. PMID- 22209739 TI - Changes of body mass index in celiac children on a gluten-free diet. AB - BACKGROUND AND AIM: Studies of adults and children with celiac disease (CD) performed mostly in tertiary care centers have reported an increased risk of overweight during gluten-free diet (GFD). We measured body mass index (BMI) of CD children followed by family pediatricians in order to estimate prevalence of underweight and overweight at diagnosis and to describe BMI changes during GFD. METHODS AND RESULTS: We compared 150 CD children (age range 2-16 yrs) under GFD from a median (IQR) time of 4.4 (4.2) years with 288 healthy children matched for gender and age. We also evaluated retrospectively BMI changes between CD diagnosis and the current evaluation. The median (IQR) BMI of CD patients was significantly lower than that of controls [-0.38 (1.46) vs. 0.09 (1.18) SDS, p < 0.0001, Italian reference data]. Using the International Obesity Task Force classifications, CD children were less frequently overweight or obese (12% vs. 23.3%, p = 0.014) and more frequently underweight (16% vs. 4.5%, p < 0.001) than controls. During GFD, there was a marked decrease of number of underweight subjects (13 vs. 27) and a minimal increase of number of overweight subjects (9 vs. 6) (p < 0.001). CONCLUSIONS: The frequency of overweight and obesity at diagnosis of CD and during GFD in children followed by family pediatricians is substantially lower than that reported in tertiary care centers. On the other hand, the high frequency of underweight at diagnosis confirms the need of careful personalized nutritional management. PMID- 22209740 TI - Folate, vitamin B12 and homocysteine status in an Italian blood donor population. AB - BACKGROUND AND AIMS: The relevance of folate, other B-vitamins and homocysteine (Hcy) for the occurrence or prevention of several diseases has induced growing interest. Unfortunately, little evidence is available regarding B-vitamin concentrations in Italy. This study evaluated in a region of middle-southern Italy, folate, vitamin B12 and Hcy concentrations and the prevalence of their ideal blood levels. The main determinants of B-vitamins and Hcy were also considered. METHODS AND RESULTS: Male and female blood donors (n=240), aged 18-66 years and living in Molise region (Italy), were enrolled in the study. They completed a brief questionnaire concerning fruit and vegetables intake, physical activity and smoking; serum and red blood cell (RBC) folate and serum vitamin B12 were measured by an immunoassay on an automated analyzer. Total Hcy was measured by high performance liquid chromatography (HPLC). Geometric means of serum folate, RBC folate and serum vitamin B12 were 10.8nmoll(-1), 426.0nmoll(-1) and 245.0pmoll(-1), respectively. Only 22.5%, 24.2% and 16.3% of blood donors showed an adequate level of serum folate, RBC folate or serum vitamin B12 respectively. When a cut-off of RBC folate >=906nmoll(-1) was used no women of childbearing age had adequate levels. A geometric mean of 14.0MUmoll(-1) was found for total Hcy, with an ideal concentration in 12.1% of subjects. Folate concentration was higher in women and non-smokers and in subjects with higher consumption of fruit and vegetable. CONCLUSION: This study shows a low-moderate B-vitamins status in middle-southern Italy, associated with an inadequate fruit and vegetable consumption. A public health strategy should be undertaken to encourage a B vitamin-rich diet with the addition of vitamin supplements or vitamin fortified foods in population subgroups with special needs. PMID- 22209741 TI - Dietary glycemic index/load and peripheral adipokines and inflammatory markers in elderly subjects at high cardiovascular risk. AB - BACKGROUND AND AIMS: Epidemiological and clinical studies suggest that low glycemic index diets could protect against weight gain. However, the relationship between these diets and adipokines or inflammatory markers is unclear. In the present study we examine how the dietary glycemic index (GI) and dietary glycemic load (GL) are associated with several adipokines and related metabolic risk markers of obesity and diabetes in a cross-sectional and longitudinal manner. METHODS AND RESULTS: 511 elderly community-dwelling men and women at high cardiovascular risk were recruited for the PREDIMED trial. Dietary data were collected at baseline and after 1 year of follow-up. The GI and GL were calculated. Plasma leptin, adiponectin and other metabolic risk markers were measured at baseline and after 1 year. At baseline, subjects in the highest quartiles of GI showed significantly higher levels of TNF and IL-6 than those in the lowest quartiles. Dietary GI index was negatively related to plasma leptin and adiponectin levels. After 1 year of follow-up, subjects with a higher increase in dietary GI or GL showed a greater reduction in leptin and adiponectin plasma levels. There was no association between GI or GL and the other metabolic markers measured. CONCLUSION: Our results suggest that the consumption of high-GI or high-GL diets may modulate plasma concentrations of leptin and adiponectin, both adipostatic molecules implicated in energy balance and cardiometabolic risk. PMID- 22209743 TI - Mapping for economic evaluation. AB - INTRODUCTION/BACKGROUND: Mapping provides a statistical algorithm that allows the estimation of utilities and consequently calculation of QALYs in clinical studies where preference-based measures are not implemented. SOURCES OF DATA: Reviews of the mapping literature were utilized. AREAS OF AGREEMENT: Mapping requires similar populations between the estimation and study data sets, with a high degree of overlap between the target and base measures being desirable. The National Institute for Health and Clinical Excellence recognizes mapping as a method to provide utility information. Areas of controversy Issues surrounding mapping include the descriptive system of the measure, the appropriate econometric method and model specification. GROWING POINTS: There is a need for further research into the issue of over-prediction for severe health states and uncertainty around the estimated utility scores. AREAS TIMELY FOR DEVELOPING RESEARCH: Mapping continues to be an important area of research for economic evaluation, in particular validation of mapping functions. PMID- 22209744 TI - Nosocomial bloodstream infections due to Acinetobacter baumannii, Acinetobacter pittii and Acinetobacter nosocomialis in the United States. AB - OBJECTIVES: To compare the clinical features and antimicrobial susceptibilities of the clinically most important Acinetobacter species Acinetobacter baumannii, Acinetobacter pittii (formerly Acinetobacter genomic species 3) and Acinetobacter nosocomialis (formerly Acinetobacter genomic species 13TU). METHODS: 295 Acinetobacter isolates collected prospectively from patients with bloodstream infections (BSI) in 52 US hospitals were identified to species level. Clinical and microbiological features were compared between species. RESULTS: A. baumannii (63%) was the most prevalent species, followed by A. nosocomialis (21%), and A. pittii (8%). Intravascular catheters (15.3%) and the respiratory tract (12.9%) were the most frequent sources of BSI. A higher overall mortality was observed in patients with A. baumannii BSI than in patients with BSI caused by A. nosocomialis and A. pittii (36.9% vs. 16.4% and 13.0%, resp., p < 0.001). The most active antimicrobial agents as determined by broth microdilution were tigecycline (99.6% of isolates susceptible), colistin (99.3%), amikacin (98.5%), and imipenem (95.2%). 27 isolates (10.0%) were multi-drug resistant, all but one of these were A. baumannii. CONCLUSIONS: About one third of Acinetobacter BSI in our study were caused by A. nosocomialis or A. pittii. Patients with A. baumannii BSI had a less favorable outcome. PMID- 22209745 TI - Hypothalamic serotonin-insulin signaling cross-talk and alterations in a type 2 diabetic model. AB - Serotonin and insulin are key regulators of homeostatic mechanisms in the hypothalamus. However, in type 2 diabetes, the hypothalamic responsiveness to serotonin is not clearly established. We used a diabetic model, the Goto Kakizaki (GK) rats, to explore insulin receptor expression, insulin and serotonin efficiency in the hypothalamus and liver by means of Akt phosphorylation. Insulin or dexfenfluramine (stimulator of serotonin) treatment induced Akt phosphorylation in Wistar rats but not in GK rats that exhibit down-regulated insulin receptor. Studies in a neuroblastoma cell line showed that serotonin induced Akt phosphorylation is PI3-kinase dependent. Finally, in response to food intake, hypothalamic serotonin release was reduced in GK rats, indicating impaired responsiveness of this neurotransmitter. In conclusion, hypothalamic serotonin as insulin efficiency is impaired in diabetic GK rats. The insulin serotonin cross-talk and impairment observed is one potential key modification in the brain during the onset of diabetes. PMID- 22209746 TI - Endothelin-1 promotes cytoplasmic accumulation of RIP140 through a ET(A)-PLCbeta PKCepsilon pathway. AB - The physiological signal activating cytoplasmic accumulation of nuclear receptor interacting protein 140 (RIP140) in adipocytes was unclear. We uncover that endothelin-1 (ET-1) promotes cytoplasmic accumulation of RIP140 in 3T3-L1 adipocytes. We determine ET-1's signal transduction pathway in adipocytes, which is by activating ET(A) receptor-PLCbeta-nuclear PKCepsilon. Blocking this pathway in 3T3-L1 adipocyte cultures, by treating cells with an ET(A) antagonist, inhibiting PLCbeta, or silencing PKCepsilon, reduces ET-1-stimulated cytoplasmic accumulation of RIP140. In a HFD-fed obese mouse model, administration of a selective ET(A) antagonist, ambrisentan, effectively dampens cytoplasmic accumulation of RIP140 in the epididymal adipose tissue and reduces HFD-caused adipocyte dysfunctions. Importantly, ambrisentan improves blood glucose control and reduces the severity of hepatic steatosis in HFD-fed mice. This study reports a physiological signal that stimulates nuclear export of RIP140 in adipocytes and provides evidence for a strategy using selective ET(A) antagonist to treat obesity-induced insulin resistance and, possibly, other metabolic disorders. PMID- 22209747 TI - Association of adrenocortical carcinoma with familial cancer susceptibility syndromes. AB - Our knowledge about inherited susceptibility to adrenocortical carcinoma (ACC) almost exclusively stems from experiences with familial cancer susceptibility syndromes, which are caused by single gene mutations (e.g. Li-Fraumeni syndrome (LFS)). Population-based studies are largely unavailable. ACC diagnosed during childhood is known to be commonly part of hereditary cancer syndromes. Childhood ACC is part of the classical tumor spectrum of LFS and Beckwith-Wiedemann syndrome (BWS). In adults ACC has been reported in patients with multiple endocrine neoplasia (MEN1), familial adenomatous polyposis coli (FAP) and neurofibromatosis type 1 (NF1). However, the evidence associating ACC with these syndromes is less well substantiated. Here, we will review the evidence for genetic predisposition in general and the association with known familial cancer susceptibility syndromes in particular. We will also review current recommendations regarding screening and surveillance of these patients as they apply to a specialized ACC or endocrine cancer clinic. PMID- 22209742 TI - The relation of body mass index and abdominal adiposity with dyslipidemia in 27 general populations of the WHO MONICA Project. AB - BACKGROUND AND AIMS: The association between adiposity measures and dyslipidemia has seldom been assessed in a multipopulational setting. METHODS AND RESULTS: 27 populations from Europe, Australia, New Zealand and Canada (WHO MONICA project) using health surveys conducted between 1990 and 1997 in adults aged 35-64 years (n = 40,480). Dyslipidemia was defined as the total/HDL cholesterol ratio >6 (men) and >5 (women). Overall prevalence of dyslipidemia was 25% in men and 23% in women. Logistic regression showed that dyslipidemia was strongly associated with body mass index (BMI) in men and with waist circumference (WC) in women, after adjusting for region, age and smoking. Among normal-weight men and women (BMI<25 kg/m(2)), an increase in the odds for being dyslipidemic was observed between lowest and highest WC quartiles (OR = 3.6, p < 0.001). Among obese men (BMI >= 30), the corresponding increase was smaller (OR = 1.2, p = 0.036). A similar weakening was observed among women. Classification tree analysis was performed to assign subjects into classes of risk for dyslipidemia. BMI thresholds (25.4 and 29.2 kg/m(2)) in men and WC thresholds (81.7 and 92.6 cm) in women came out at first stages. High WC (>84.8 cm) in normal-weight men, menopause in women and regular smoking further defined subgroups at increased risk. CONCLUSION: standard categories of BMI and WC, or their combinations, do not lead to optimal risk stratification for dyslipidemia in middle-age adults. Sex-specific adaptations are necessary, in particular by taking into account abdominal obesity in normal-weight men, post-menopausal age in women and regular smoking in both sexes. PMID- 22209748 TI - Are we there yet? Bevacizumab therapy for retinopathy of prematurity. AB - The publication of the BEAT-ROP study of bevacizumab (Avastin) treatment for Zone I and II retinopathy of prematurity (ROP) has raised hopes that there might now be a simpler, cheaper and more effective treatment than laser therapy, the current standard of care. However, we would urge caution at this point in time. We review the scientific background to the use of intravitreal anti-vascular endothelial growth factor for ROP, highlight a number of design issues in the BEAT-ROP study and problems with interpretation of the results. For example, no visual outcomes were reported and the study was underpowered to assess longer term safety. Intravitreal bevacizumab leaks into the systemic circulation in animals and adult humans and there are real concerns of potential harm to the developing preterm infant because vascular growth factors play a critical role in organogenesis. We conclude that bevacizumab should be reserved for exceptional circumstances and compassionate use pending further studies. Laser remains the proven effective therapy for first line treatment of all forms of ROP with little systemic morbidity. Neonatology and ophthalmology have an impressive record of conducting collaborative multicentre studies and we urgently need further rigorously designed, adequately powered randomised trials of anti-VEGF agents that evaluate visual outcomes as well as short and long term ocular and systemic safety. PMID- 22209749 TI - Combining lectin affinity chromatography and immunodepletion - A novel method for the enrichment of disease-specific glycoproteins in human plasma. AB - Drastic enrichment of potential disease-specific glycoprotein markers in human plasma can be achieved by the combination of affinity- and immuno-depletion. In the affinity-fractionation step all glycoproteins carrying a certain glycostructure are isolated by lectin affinity chromatography, thus depleting other components. Against the respective glycoprotein fraction isolated from the plasma of healthy individuals antibodies are raised in llamas. The llama heavy chain antibodies (which are particularly stable) directed at the isolated plasma glycoprotein fraction are immobilized and the immunoaffinity column thus obtained is used to deplete the respective glycoprotein fraction of patient plasma samples. Depletion of proteins normally found in human plasma by 99.8-99.9% can be achieved, resulting in a 800-1000-fold enrichment of potential disease specific proteins in the flow-through of the immunoaffinity column. PMID- 22209750 TI - Healthcare information technology and medical-surgical nurses: the emergence of a new care partnership. AB - Healthcare information technology in US hospitals and ambulatory care centers continues to expand, and nurses are expected to effectively and efficiently utilize this technology. Researchers suggest that clinical information systems have expanded the realm of nursing to integrate technology as an element as important in nursing practice as the patient or population being served. This study sought to explore how medical surgical nurses make use of healthcare information technology in their current clinical practice and to examine the influence of healthcare information technology on nurses' clinical decision making. A total of eight medical surgical nurses participated in the study, four novice and four experienced. A conventional content analysis was utilized that allowed for a thematic interpretation of participant data. Five themes emerged: (1) healthcare information technology as a care coordination partner, (2) healthcare information technology as a change agent in the care delivery environment, (3) healthcare information technology-unable to meet all the needs, of all the people, all the time, (4) curiosity about healthcare information technology-what other bells and whistles exist, and (5) Big Brother is watching. The results of this study indicate that a new care partnership has emerged as the provision of nursing care is no longer supplied by a single practitioner but rather by a paired team, consisting of nurses and technology, working collaboratively in an interdependent relationship to achieve established goals. PMID- 22209751 TI - MicroRNA regulation of melanoma progression. AB - The aetiology of melanoma, the most lethal form of skin cancer, is complex, involving both genetic and environmental components. Over the past decade, many genetic alterations affecting melanoma development have been identified and more recently a new epigenetic level of regulation has increasingly been explored. MicroRNA (miRNA)-mediated epigenetic regulation of tumour suppressor genes and oncogenes has been shown to play a central role in melanomagenesis. Over the past few years, many studies combining miRNA expression arrays and quantitative reverse transcriptase-PCR assays have identified different miRNAs deregulated during melanoma progression. Several groups have focused their efforts on understanding the functional role of these different miRNAs in melanoma, identifying their direct targets and elucidating their mechanisms of regulation. This review summarizes the present knowledge of miRNA dysregulation in melanoma. On the basis of the current literature, we present a network of miRNA interactions involved in melanoma progression. Some of these key miRNAs may have utility as diagnostic markers or in targeted treatments. PMID- 22209752 TI - Thirty years of heme catalases structural biology. AB - About thirty years ago the crystal structures of the heme catalases from Penicillium vitale (PVC) and, a few months later, from bovine liver (BLC) were published. Both enzymes were compact tetrameric molecules with subunits that, despite their size differences and the large phylogenetic separation between the two organisms, presented a striking structural similarity for about 460 residues. The high conservation, confirmed in all the subsequent structures determined, suggested a strong pressure to preserve a functional catalase fold, which is almost exclusively found in these mono-functional heme catalases. However, even in the absence of the catalase fold an efficient catalase activity is also found in the heme containing catalase-peroxidase proteins. The structure of these broad substrate range enzymes, reported for the first time less than ten years ago from the halophilic archaebacterium Haloarcula marismortui (HmCPx) and from the bacterium Burkholderia pseudomallei (BpKatG), showed a heme pocket closely related to that of plant peroxidases, though with a number of unique modifications that enable the catalase reaction. Despite the wealth of structural information already available, for both monofunctional catalases and catalase peroxidases, a number of unanswered major questions require continuing structural research with truly innovative approaches. PMID- 22209753 TI - Cancer cell detection in tissue sections using AFM. AB - Currently, cancer diagnosis relies mostly on morphological examination of exfoliated, aspirated cells or surgically removed tissue. As long as standard diagnosis is concerned, this classical approach seems to be satisfactory. In the recent years, cancer progression has been shown to be accompanied by alterations in mechanical properties of cells. This offers the detection of otherwise unnoticed cancer cell disregarded by histological analysis due to insignificant manifestations. One of techniques, sensitive to changes in mechanical properties, is the atomic force microscopy, which detects cancer cells through their elastic properties. Such measurements were applied to tissue sections collected from patients suffering from various cancers. Despite of heterogeneity and complexity of cancer cell sections, the use of the Young's modulus as an indicator of cell elasticity allow for detection of cancer cells in tissue slices. PMID- 22209754 TI - Conditioned media from lung cancer cell line A549 and PC9 inactivate pulmonary fibroblasts by regulating protein phosphorylation. AB - Pulmonary fibrosis is a devastating condition resulting from excess extracellular matrix deposition that leads to progressive lung destruction and scarring. In the pathogenesis of fibrotic diseases, activation of myofibroblasts by transforming growth factor-beta (TGF-beta) plays a crucial role. Since no effective therapy for pulmonary fibrosis is currently recognized, finding an effective antifibrotic agent is an important objective. One approach might be through identification of agents that inactivate myofibroblasts. In the current study we examined the potential of conditioned medium obtained from several types of cells to exhibit myofibroblast inactivating activity. Conditioned media from lung cancer cell lines A549 and PC9 were found to have this action, as shown by its ability to decrease alpha-smooth muscle actin expression in MRC-5 cells. Subsequently the inhibitory factor was purified from the medium and identified as 5'-deoxy-5' methylthioadenosine (MTA), and its mechanism of action elucidated. Activation of protein kinase A and cAMP responsive element binding protein (CREB) were detected. MTA inhibited TGF-beta-induced mitogen-activated protein kinase activation. Furthermore, the gain-of-function mutant CREB caused inactivation of myofibroblasts. These results show that A549 and PC9 conditioned media have the ability to inactivate myofibroblasts, and that CREB-phosphorylation plays a central role in this process. PMID- 22209755 TI - Age profile of immunity to influenza: effect of original antigenic sin. AB - When multiple infections are possible during an individual's lifetime, as with influenza, a host's history of infection and immunity will determine the result of future exposures. In turn, the suite of varying individual infection histories will shape the population level dynamics of the disease. Exploring the consequences of precisely how immunity is acquired using mathematical models has proven challenging though: if n strains have circulated previously, there are 2(n) combinations of past infection to consider. However, by using an age structured mathematical model of a disease with multiple strains, we can examine the population immune profile without explicitly keeping track of all possible infection histories. This framework allows previously unknown consequences of assumptions about immune acquisition to be observed. In particular, we see that 'original antigenic sin' can reduce immunity in some age groups: these immune blind spots could be responsible for the unexpectedly high severity of certain past influenza epidemics. PMID- 22209756 TI - A comprehensive three-dimensional dynamic model of the human head and trunk for estimating lumbar and cervical joint torques and forces from upper body kinematics. AB - Linked-segment representations of human body dynamics have been used extensively in biomechanics, ergonomics, and rehabilitation research to systemize thinking, make predictions, and suggest novel experiments. In the scope of upper body biomechanics, these models play an even more essential role as the human spine dynamics are difficult to study in vivo. No study exists to date, however, that specifically disseminates the technical details of a comprehensive three dimensional model of the upper body for the purpose of estimating spinal joint torques and forces for a wide range of scenarios. Consequently, researchers are still bound to develop and implement their own models. Therefore, the objective of this study was to design a dynamic model of the upper body that can comprehensively estimate spinal joint torques and forces from upper body kinematics. The proposed three-dimensional model focuses on the actions of the lumbar and cervical vertebrae and consists of five lumbar segments (L1 to L5), the thorax, six cervical segments (C2 to C7), and the head. Additionally, the model: (1) is flexible regarding the kinematic nature of the spinal joints (free, constrained, or fixed); (2) incorporates all geometric and mass-inertia parameters from a single, high-resolution source; and (3) can be feasibly implemented via different inverse dynamics formulations. To demonstrate its practicality, the model was finally employed to estimate the lumbar and cervical joint torques during perturbed sitting using experimental motion data. Considering the growing importance of mathematical predictions, the developed model should become an important resource for researchers in different fields. PMID- 22209757 TI - Relationship of hyperactivity/inattention with adiposity and lifestyle characteristics in preschool children. AB - We performed a cross-sectional study in 450 nonreferred preschool children aged 4 to 6 years to assess the association between hyperactivity/inattention with adiposity and lifestyle characteristics. Measurements included scores of hyperactivity/inattention, adiposity, objectively measured physical activity, television viewing, and eating habits. Higher scores of hyperactivity/inattention were associated with lower percentage body fat, higher levels of physical activity, and less time spent in sedentary activity (all P <= .01). However, higher scores of hyperactivity/inattention were also associated with more television viewing and less healthy eating habits (all P <= .04). Except for some selected eating habits (P >= .07), those relationships remained significant after adjustment for age, sex, and sociodemographic confounders. To conclude, higher scores of hyperactivity/inattention are linked to different lifestyle characteristics that may in part contribute to a future development of overweight/obesity. Precise mechanisms explaining these associations and possible preventive approaches should be further investigated. PMID- 22209759 TI - Myostatin inhibits proliferation but not differentiation of trout myoblasts. AB - The muscle growth in mammals is regulated by several growth factors including myostatin (MSTN), a member of the transforming growth factor-beta (TGF-beta) superfamily. To date, it is unknown in fish whether MSTN could have any effect on proliferation or differentiation of myogenic cells. Using culture of trout satellite cells, we showed that mstn1a and mstn1b mRNA are expressed in myoblasts and that their expression decreased in differentiating myoblasts. We also demonstrated that a treatment with huMSTN decreased the proliferation of IGF1 stimulated myoblasts in a dose-dependent manner. By contrast, treatment of myoblasts with 100 nM of huMSTN for three days, did not affect the percentage of positive cells for myogenin neither the percentage of nuclei in myosin positive cells. Moreover, our results clearly indicated that huMSTN treatment had no effect on MyoD and myogenin protein levels, which suggests that huMSTN did not strongly affect MyoD activity. In conclusion, we showed that huMSTN inhibited proliferation but not differentiation of trout myoblasts, probably resulting from a lack of huMSTN effect on MyoD activity. Altogether, these results show high interspecies differences in the function of MSTN. PMID- 22209760 TI - Saturday Morning Television Advertisements Aired on English and Spanish Language Networks along the Texas-Mexico Border. AB - OBJECTIVES: The aim of this content analysis study is to characterize the TV advertisements aired to an at-risk child population along the Texas-Mexico border. METHODS: We characterized the early Saturday morning TV advertisements aired by three broadcast network categories (U.S. English language, U.S. Spanish language, and Mexican Spanish language) in Spring 2010. The number, type (food related vs. non-food related), target audience, and persuasion tactics used were recorded. Advertised foods, based on nutrition content, were categorized as meeting or not meeting current dietary guidelines. RESULTS: Most commercials were non-food related (82.7%, 397 of 480). The majority of the prepared foods (e.g., cereals, snacks, and drinks) advertised did not meet the current U.S. Dietary Guidelines. Additionally, nutrition content information was not available for many of the foods advertised on the Mexican Spanish language broadcast network category. CONCLUSIONS: For U.S. children at risk for obesity along the Texas-Mexico border exposure to TV food advertisements may result in the continuation of sedentary behavior as well as an increased consumption of foods of poor nutritional quality. An international regulatory effort to monitor and enforce the reduction of child-oriented food advertising is needed. PMID- 22209758 TI - Transcription of the human EAP1 gene is regulated by upstream components of a puberty-controlling Tumor Suppressor Gene network. AB - Mammalian puberty is initiated by an increased pulsatile release of gonadotropin releasing hormone (GnRH) from specialized neurons located in the hypothalamus. GnRH secretion is controlled by neuronal and glial networks, whose activity appears to be coordinated via transcriptional regulation. One of the transcription factors involved in this process is thought to be the recently described gene Enhanced at Puberty 1 (EAP1), which encodes a protein with dual transcriptional activity. In this study we used gene reporter and chromatin immunoprecipitation (ChIP) assays to examine the hypothesis that EAP1 expression is controlled by transcriptional regulators earlier postulated to serve as central nodes of a gene network involved in the neuroendocrine control of puberty. These regulators include Thyroid Transcription Factor 1 (TTF1), Yin Yang 1 (YY1), and CUX1, in addition to EAP1 itself. While TTF1 has been shown to facilitate the advent of puberty, YY1 (a zinc finger protein component of the Polycomb silencing complex) may play a repressive role. The precise role of CUX1 in this context is not known, but like EAP1, CUX1 can either activate or repress gene transcription. We observed that DNA segments of two different lengths (998 and 2744bp) derived from the 5'-flanking region of the human EAP1 gene display similar transcriptional activity. TTF1 stimulates transcription from both DNA segments with equal potency, whereas YY1, CUX1, and EAP1 itself, behave as transcriptional repressors. All four proteins are recruited in vivo to the EAP1 5'-flanking region. These observations suggest that EAP1 gene expression is under dual transcriptional regulation imposed by a trans-activator (TTF1) and two repressors (YY1 and CUX1) previously postulated to be upstream components of a puberty-controlling gene network. In addition, EAP1 itself appears to control its own expression via a negative auto-feedback loop mechanism. Further studies are needed to determine if the occupancy of the EAP1 promoter by these regulatory factors changes at the time of puberty. PMID- 22209761 TI - Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression. AB - BACKGROUND: Paroxysmal dyskinesias (PDs), a clinically and genetically heterogeneous group of episodic movement disorders, include kinesigenic PD (PKD), exercise-induced PD (PED) and non-kinesigenic PD (PNKD). These disorders are all transmitted as autosomal dominant traits with incomplete penetrance. Several PD related genetic disorders, including PKD and familial infantile convulsions with paroxysmal choreoathetosis (ICCA), mapped to the same region on chromosome 16. Independent genetic studies have recently revealed that PKD can be caused by loss of-function mutations in the proline-rich transmembrane protein 2 gene (PRRT2). We tested the hypothesis that other forms of PDs are also due to PRRT2 mutations. METHODS/RESULTS: The whole genomic region of PRRT2 was sequenced in six Han Chinese families and 15 sporadic cases of PD-related phenotypes. The previously reported mutation, c.649dupC (p.R217Pfs*7), was found in two families with PKD, one family with ICCA, one family with PNKD-like phenotype, and two sporadic cases with PED. In an additional ICCA family, a novel frameshift mutation, c.904dupG (p.D302Gfs*38), was identified. A missense mutation, c.913G->A (p.G305R), and a synonymous substitution, c.1011C->T (p.G337G), were also detected in two sporadic PKD cases. CONCLUSION: This study shows that PKD, ICCA and some other PD-related phenotypes are part of the same phenotypic spectrum, caused by mutations in PRRT2. This underscores the complexity of the phenotypic consequences of PRRT2 mutations. PMID- 22209762 TI - NOTCH2 mutations in Alagille syndrome. AB - BACKGROUND: Alagille syndrome (ALGS) is a dominant, multisystem disorder caused by mutations in the Jagged1 (JAG1) ligand in 94% of patients, and in the NOTCH2 receptor in <1%. There are only two NOTCH2 families reported to date. This study hypothesised that additional NOTCH2 mutations would be present in patients with clinical features of ALGS without a JAG1 mutation. METHODS: The study screened a cohort of JAG1-negative individuals with clinical features suggestive or diagnostic of ALGS for NOTCH2 mutations. RESULTS: Eight individuals with novel NOTCH2 mutations (six missense, one splicing, and one non-sense mutation) were identified. Three of these patients met classic criteria for ALGS and five patients only had a subset of features. The mutations were distributed across the extracellular (N=5) and intracellular domains (N=3) of the protein. Functional analysis of four missense, one nonsense, and one splicing mutation demonstrated decreased Notch signalling of these proteins. Subjects with NOTCH2 mutations demonstrated highly variable expressivity of the affected systems, as with JAG1 individuals. Liver involvement was universal in NOTCH2 probands and they had a similar prevalence of ophthalmologic and renal anomalies to JAG1 patients. There was a trend towards less cardiac involvement in the NOTCH2 group (60% vs 100% in JAG1). NOTCH2 (+) probands exhibited a significantly decreased penetrance of vertebral abnormalities (10%) and facial features (20%) when compared to the JAG1 (+) cohort. CONCLUSIONS: This work confirms the importance of NOTCH2 as a second disease gene in ALGS and expands the repertoire of the NOTCH2 related disease phenotype. PMID- 22209763 TI - The use of warmed water treatment to induce protective immunity against the bacterial cold-water disease pathogen Flavobacterium psychrophilum in ayu (Plecoglossus altivelis). AB - We investigated the induction of protective immunity against bacterial cold-water disease (BCWD) caused by Flavobacterium psychrophilum by warmed water treatment in ayu (Plecoglossus altivelis). Fish were immersed in a live bacterial suspension (107 CFU mL-1) for 30 min and placed in 700 L concrete tanks. The 28 degrees C warmed water treatment lasted 3 days and began 1, 6, and 24 h after immersion in the live bacterial suspension. A naive control fish group was immersed in a sterilized modified Cytophaga (MCY) broth instead of the bacterial suspension. Fourteen days after the immersion, agglutination antibody titers against F. psychrophilum were measured by using micro-titer methods. Fish were then exposed to a bacterial bath to infect them with live F. psychrophilum, and cumulative mortality was monitored. Fish treated with warmed water at 1, 6, and 24 h after immersion in the live bacterial suspension had cumulative mortalities of 36%, 30%, and 18%, respectively, all of which were significantly lower than the cumulative mortality of the naive control fish (90%). Treated fish also showed high antibody titers against F. psychrophilum in agglutination tests. These results demonstrate that warmed water treatment could not only cure BCWD but also immunize the fish against the causative agent F. psychrophilum. PMID- 22209764 TI - MDP25, a novel calcium regulatory protein, mediates hypocotyl cell elongation by destabilizing cortical microtubules in Arabidopsis. AB - The regulation of hypocotyl elongation is important for plant growth. Microtubules play a crucial role during hypocotyl cell elongation. However, the molecular mechanism underlying this process is not well understood. In this study, we describe a novel Arabidopsis thaliana microtubule-destabilizing protein 25 (MDP25) as a negative regulator of hypocotyl cell elongation. We found that MDP25 directly bound to and destabilized microtubules to enhance microtubule depolymerization in vitro. The seedlings of mdp25 mutant Arabidopsis lines had longer etiolated hypocotyls. In addition, MDP25 overexpression resulted in significant overall shortening of hypocotyl cells, which exhibited destabilized cortical microtubules and abnormal cortical microtubule orientation, suggesting that MDP25 plays a crucial role in the negative regulation of hypocotyl cell elongation. Although MDP25 localized to the plasma membrane under normal conditions, increased calcium levels in cells caused MDP25 to partially dissociate from the plasma membrane and move into the cytosol. Cellular MDP25 bound to and destabilized cortical microtubules, resulting in their reorientation, and subsequently inhibited hypocotyl cell elongation. Our results suggest that MDP25 exerts its function on cortical microtubules by responding to cytoplasmic calcium levels to mediate hypocotyl cell elongation. PMID- 22209766 TI - Continuous inhibition of epidermal growth factor receptor phosphorylation by erlotinib enhances antitumor activity of chemotherapy in erlotinib-resistant tumor xenografts. AB - Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been shown to have benefits for non-small cell lung cancer and pancreatic cancer patients; however, almost all patients develop progressive disease during the therapy. On the other hand, it has been reported that a tumor continues to express epidermal growth factor receptor even after developing progressive disease. To demonstrate the clinical relevance of erlotinib treatment after progressive disease, we investigated whether continuous administration of erlotinib in combination with chemotherapy has a useful effect on progressive disease development during erlotinib treatment. For this purpose, we examined the antitumor effect of a combination therapy of a chemotherapeutic agent with erlotinib using two types of erlotinib-resistant tumor xenograft models: a non small cell lung cancer model, in which EBC-1, H1975 and HCC827TR3 tumors were implanted, and an HPAC pancreatic cancer cell xenograft which generates erlotinib resistant tumors in vivo. As a result, the combination therapy showed a significantly higher antitumor activity compared with chemomonotherapy in all xenograft models except the H1975 xenografts. Furthermore, erlotinib alone suppressed the phosphorylation of epidermal growth factor receptor in HPAC tumors and the two non-small cell lung cancer cell lines other than H1975. Therefore, combination therapy which uses erlotinib can be considered effective if epidermal growth factor receptor phosphorylation is inhibited by erlotinib, even in erlotinib-resistant tumor xenograft models. Our results suggest that the continuous inhibition of epidermal growth factor receptor phosphorylation by erlotinib after progressive disease enhances the antitumor activity of chemotherapy. PMID- 22209768 TI - Application of triphasic pulses with adjustable phase amplitude ratio (PAR) for cochlear ECAP recording: I. amplitude growth functions. AB - This study describes the use of triphasic electrical stimulation pulses with an adjustable phase amplitude ratio (PAR) for the reduction of electrical stimulus artifacts. It is hypothesized that the setting of a certain PAR can facilitate a nearly artifact-free recording of electrically evoked compound action potentials (ECAP) in the cochlea. Artifact reduction with triphasic pulses using single epochs is expected to prevent latency or polarity effects, which are seen in standard forward masking or alternating polarity strategies. Although the application of a third phase is already implemented in implants manufactured by MED-EL (Zierhofer, 2003) and Cochlear (Sydney, Nucleus 5 System; van Dijk et al. (2007)) for the reduction of stimulation artifacts generated with these stimulators in ECAP measurements, an elaborate systematic evaluation of PAR for artifact reduction has not yet been conducted (compare evaluation for one subject Schoesser et al. (2001)). In the present paper, the effect of PAR variation on human ECAP recording and the feasibility of amplitude growth function recording with triphasic pulses and an optimized PAR are evaluated. Measurements were accomplished in five subjects, whereby more detailed test series were carried out in one subject. All subjects were implanted with devices from the company MED-EL, Innsbruck. A comparison of PAR optimized triphasic pulses was carried out against two other measurement techniques (biphasic alternating polarity stimulation and biphasic stimulation according to Miller) for apical, middle, and basal electrodes. ECAP thresholds were estimated by means of amplitude growth functions. However, recording of ECAP with triphasic pulses showed drawbacks: additional artifacts depending on stimulation and/or recording parameters are introduced, the ratio between the additional artifact and improved detectability of neural responses is dependent on PAR, and response thresholds obtained with triphasic pulses--although similar in shape--are in most cases substantially higher compared to thresholds measured with the Miller method. Higher thresholds most probably occur because the triphasic pulse patterns seem to less effectively stimulate neural structures compared to biphasic pulses since measured response thresholds are higher. For certain electrode groups threshold profiles obtained with triphasic pulses were found to be similar compared to stimulation with biphasic pulses. PMID- 22209765 TI - Lumen Thiol Oxidoreductase1, a disulfide bond-forming catalyst, is required for the assembly of photosystem II in Arabidopsis. AB - Here, we identify Arabidopsis thaliana Lumen Thiol Oxidoreductase1 (LTO1) as a disulfide bond-forming enzyme in the thylakoid lumen. Using topological reporters in bacteria, we deduced a lumenal location for the redox active domains of the protein. LTO1 can partially substitute for the proteins catalyzing disulfide bond formation in the bacterial periplasm, which is topologically equivalent to the plastid lumen. An insertional mutation within the LTO1 promoter is associated with a severe photoautotrophic growth defect. Measurements of the photosynthetic activity indicate that the lto1 mutant displays a limitation in the electron flow from photosystem II (PSII). In accordance with these measurements, we noted a severe depletion of the structural subunits of PSII but no change in the accumulation of the cytochrome b(6)f complex or photosystem I. In a yeast two hybrid assay, the thioredoxin-like domain of LTO1 interacts with PsbO, a lumenal PSII subunit known to be disulfide bonded, and a recombinant form of the molecule can introduce a disulfide bond in PsbO in vitro. The documentation of a sulfhydryl-oxidizing activity in the thylakoid lumen further underscores the importance of catalyzed thiol-disulfide chemistry for the biogenesis of the thylakoid compartment. PMID- 22209767 TI - Differential sensitivity of plasma carboxylesterase-null mice to parathion, chlorpyrifos and chlorpyrifos oxon, but not to diazinon, dichlorvos, diisopropylfluorophosphate, cresyl saligenin phosphate, cyclosarin thiocholine, tabun thiocholine, and carbofuran. AB - Mouse blood contains four esterases that detoxify organophosphorus compounds: carboxylesterase, butyrylcholinesterase, acetylcholinesterase, and paraoxonase-1. In contrast human blood contains the latter three enzymes but not carboxylesterase. Organophosphorus compound toxicity is due to inhibition of acetylcholinesterase. Symptoms of intoxication appear after approximately 50% of the acetylcholinesterase is inhibited. However, complete inhibition of carboxylesterase and butyrylcholinesterase has no known effect on an animal's well being. Paraoxonase hydrolyzes organophosphorus compounds and is not inhibited by them. Our goal was to determine the effect of plasma carboxylesterase deficiency on response to sublethal doses of 10 organophosphorus toxicants and one carbamate pesticide. Homozygous plasma carboxylesterase deficient ES1(-/-) mice and wild-type littermates were observed for toxic signs and changes in body temperature after treatment with a single sublethal dose of toxicant. Inhibition of plasma acetylcholinesterase, butyrylcholinesterase, and plasma carboxylesterase was measured. It was found that wild-type mice were protected from the toxicity of 12.5mg/kg parathion applied subcutaneously. However, both genotypes responded similarly to paraoxon, cresyl saligenin phosphate, diisopropylfluorophosphate, diazinon, dichlorvos, cyclosarin thiocholine, tabun thiocholine, and carbofuran. An unexpected result was the finding that transdermal application of chlorpyrifos at 100mg/kg and chlorpyrifos oxon at 14mg/kg was lethal to wild-type but not to ES1(-/-) mice, showing that with this organochlorine, the presence of carboxylesterase was harmful rather than protective. It was concluded that carboxylesterase in mouse plasma protects from high toxicity agents, but the amount of carboxylesterase in plasma is too low to protect from low toxicity compounds that require high doses to inhibit acetylcholinesterase. PMID- 22209769 TI - Comparative morphological and immunohistochemical study of human meningioma after intracranial transplantation into nude mice. AB - Although surgical resection of benign human meningiomas is the primary goal, in case of relapse or when they are not fully resectable, other strategies including chemotherapeutical treatment would be appropriate. The initial evaluation of chemotherapeutical agents requires an appropriate tumor model, where the natural characteristics of the original benign tumor is reflected. We here tested, whether primary cell cultures of benign human meningiomas would reliably grow after intracranial transplantation into mice, and whether they would show histomorphological and immunohistochemical characteristics of the original human tumor. Cells of 11 benign human meningiomas were transplanted into the prefrontal cortex of nude mice. After 3 months, the mice were sacrificed and their brains were histologically processed for morphological characterization and measurement of tumor volume. Additionally, the proliferation index (PI), the microvessel density, and epithelial membrane antigen (EMA) were compared between human meningiomas and tumors grown in mice by using immunohistochemical methods. Further, cyclooxygenase-2 (COX-2) expression, a possible target for pharmacological manipulation, was examined. The results showed in almost all mice (93%) a tumor formation with meningothelial histomorphology comparable to the original human tumors. The PI, vascular density and COX-2 expression were similar between human and mice meningiomas, but EMA expression was reduced in mice (P<0.01). In conclusion an implantation of benign human meningioma primary cell cultures in mice reliably results in tumor formation with morphological and immunohistological features comparable to the original human tumor. This model may therefore be suitable to test novel therapeutic agents. PMID- 22209770 TI - Development of BMP7-producing human cells, using a third generation lentiviral gene delivery system. AB - Bone morphogenetic protein 7 (BMP7), a member of the transforming growth factor beta (TGF-beta) superfamily, plays important roles in the development of various tissues and organs in mouse and human. In particular, BMP7 is critical for the formation of the nervous system and it is considered to have therapeutic potential in brain injury and stroke. One approach to make BMP7 more suitable for therapeutic purposes is the development of efficient vectors that allow the consistent, reliable and cost-effective production of the BMP7 protein. In this study, we developed an efficient BMP7 delivery system, using a third generation lentiviral vector to produce functional BMP7 protein. The lentiviral transduction of several human cell types, including human embryonic kidney 293 (HEK293) cells, amniotic fluid cells, NTera2 neurons (NT2-N) and primary neuronal cultures resulted in BMP7 expression. The production of BMP7 protein was achieved for at least 4 weeks post-transduction, as determined by enzyme-linked immunosorbent assay (ELISA). SMAD phosphorylation and neuronal differentiation assays verified the bioactivity and functionality of the lentiviral-based BMP7 protein, respectively. In addition, the intracerebroventricular injection of the lentivirus resulted in exogenous BMP7 expression in both neurons and astrocytes in the mouse brain. Taken together, this gene delivery system provides a reliable source of functional BMP7 protein for future in vitro and in vivo studies. PMID- 22209771 TI - Respiratory consequences of red sludge dust inhalation in rats. AB - The environmental disaster following flooding by red sludge in the Ajka region in Hungary poses a serious public health threat with particular concern regarding the potentially adverse respiratory effects of the inhalation of red sludge dust (RSD). The respiratory consequences of the inhalation of RSD obtained from field samples were investigated in rats. Rats were either exposed to RSD at a high concentration (2 weeks, 8h/day), or kept in room air. After the exposures, the airway resistance (R(aw)) and the respiratory tissues mechanics were measured under baseline condition, and following methacholine (MCh) challenges with the aim of establishing airway hyper-responsiveness (AH). Histopathology was performed to assess lung morphologic alterations. The physical properties and the chemical composition of the RSD were also characterized. The size distribution, chemical composition and topology of the RSD particles applied in our experiments were similar to those observed at the site of the disaster. The inhalation of RSD did not alter the basal respiratory mechanics, whereas it led to greater MCh induced responses in R(aw), demonstrating the progression of mild AH. Histopathological investigations revealed fine, granular particles in the alveolar macrophages, as evidence that RSD had reached the lower respiratory tract and induced mild inflammation around the alveoli and the pulmonary vasculature. The mild respiratory symptoms that developed following short-term exposure of healthy individuals to high concentrations of airborne RSD do not appear to pose a greater respiratory hazard than the inhalation of urban dust at a comparable concentration. PMID- 22209772 TI - NLRC5: a newly discovered MHC class I transactivator (CITA). AB - Major histocompatibility complex (MHC) class I and class II are crucial for the function of the human adaptive immune system. An NLR protein, CIITA (MHC class II transactivator), is a master regulator of MHC class II gene expression as well as of some of the genes involved in MHC class II antigen presentation. It has recently been discovered that another member of the NLR protein family, NLRC5, transcriptionally activates MHC class I genes, and thus acts as "CITA" (MHC class I transactivator), a counterpart to CIITA. In addition to MHC class I genes, NLRC5 can induce the expression of beta2M, TAP1 and LMP2, essential components of MHC class I antigen presentation. These findings indicate that NLRC5 and CIITA are transcriptional regulators that orchestrate the concerted expression of critical components in the MHC class I and MHC class II pathways, respectively. PMID- 22209773 TI - Classical and nerve-sparing radical hysterectomy: an evaluation of the nerve trauma in cardinal ligament. AB - OBJECTIVES: This study evaluated histopathology and clinical outcome of autonomic nerve trauma and vessels removal within the cardinal ligament (CL) during nerve sparing radical hysterectomy (NSRH) compared with radical hysterectomy (RH). METHODS: 25 women with FIGO stage Ib1-IIa cervical cancer underwent RH (n=13) or NSRH (n=12). Removed CLs lengths were measured. Biopsies were collected from the proximal, middle and distal segment of CLs and fixed. Different markers were used for immunohistochemisty analysis: tyrosine hydroxylase for sympathetic nerves; vasoactive intestinal polypeptide for parasympathetic nerves; CD34 for blood vessels; and D2-40 for lymphatic vessels. The volume density (Vv), a parameter of biological stereology, was used to quantitatively measure CL components, while post-operative functions, such as defecation, micturition and two-year disease free survival in RH and NSRH groups were compared. RESULTS: The nerves mainly existed in the middle and distal segments of CLs. The Vv was greater in RH compared with NSRH for both sympathetic and parasympathetic nerve markers (P<0.05), while the Vv of blood and lymphatic vessels were same in the two groups. Average time to achieve residual urine<=50ml and first defecation were shorter in NSRH than in RH (P<0.05). CONCLUSIONS: Less autonomic nerves within CL are transected in NSRH than in RH, while blood/lymphatic vessels are efficiently removed in both treatments. Compared to RH, NSRH decreases iatrogenic injury, which leads to reduced post-operative co-morbidities, with ensure the same radicality. PMID- 22209774 TI - Laterally extended parametrectomy in nodal positive early stage cervical cancer: Right direction, wrong track. PMID- 22209775 TI - Differential in vitro sensitivity to patupilone versus paclitaxel in uterine and ovarian carcinosarcoma cell lines is linked to tubulin-beta-III expression. AB - OBJECTIVE: To compare the in vitro sensitivity/resistance to patupilone versus paclitaxel in uterine and ovarian carcinosarcomas (CS). METHODS: Five primary carcinosarcoma cell lines, two from uterine and three of ovarian origin, were evaluated for growth rate and tested for their in vitro sensitivity/resistance to patupilone versus paclitaxel by MTS assays. To identify potential mechanisms underlying the differential sensitivity/resistance to patupilone, expression levels of beta-tubulin III (TUBB3) were determined with quantitative-real-time polymerase-chain-reaction (q-RT-PCR) in primary uterine and ovarian CS cell lines and in 26 uterine and 9 ovarian CS fresh-frozen-tissues. RESULTS: No appreciable difference in sensitivity to patupilone versus paclitaxel was noted in ovarian CS cell lines, or when uterine and ovarian CS cell lines were compared in their response to paclitaxel. In contrast, uterine CS cell lines were found to be significantly more sensitive to patupilone than to paclitaxel (P<0.002) and demostrated lower IC(50s) to patupilone (range 0.76-0.93nM) when compared to ovarian CS (range 1.9-3.4 nM, p<0.05). Higher levels of TUBB3 were detected in uterine CS cell lines and fresh frozen tissues when compared to ovarian CS (P<0.05). CONCLUSIONS: Uterine CS cell lines are significantly more sensitive than ovarian CS cell lines to patupilone versus paclitaxel. High expression of TUBB3 is associated with sensitivity to patupilone in primary CS cell lines and may act as a genetic marker to predict chemotherapy efficacy. Patupilone may represent a promising drug in the treatment of this subset of rare but highly aggressive gynecological tumors. PMID- 22209776 TI - Monte Carlo modelling of acute and late effects in radiation therapy. AB - Physical models are increasingly used to predict acute and late effects resulting from radiation therapy. These models utilise measured and calculated microdosimetric quantities, and are increasingly used to determine the significant corrections for effective dose used in ion-beam therapy, neutron therapy and boron neutron-capture therapy. The relative biological effect (RBE) of differing radiation sources is predicted using measurable quantities such as lineal energy, which have been also generally been reproduced with calculations using Monte Carlo methods. In addition to the physical data provided by Monte Carlo modelling, in vitro studies and epidemiological data derived from cancer treatments and other exposed populations, are used in the prediction of the risk of late effects such as secondary malignancies. Monte Carlo methods are used in particular to model contaminant components. This work focuses on our understanding of the variation in RBE in photon and electron radiotherapy, how it might affect precision in the treatment of cancer, and how it provides an accurate starting point in extrapolating to prescribed doses with new therapies. In vitro transformation assays and Monte Carlo based calculations of bioeffect used for conventional photon therapy treatments over a range of energies are examined and their utility in the refinement of bioeffect models for both early and late effects are discussed. PMID- 22209777 TI - Study of excitation function of deuteron induced reactions on nat Kr up to 20 MeV. AB - In the frame of a systematic study of the activation cross-sections of deuteron induced reactions on different elements, excitation functions on (nat)Kr were investigated up to 20 MeV. The excitation functions for production of (81 m,81 mg,82 g,83,84 m,84 mg,86 mg)Rb, (79,85 m,87)Kr and (77,82)Br radionuclides were measured for the first time using stacked gas cell irradiation technique and gamma-ray spectrometry. The measured data were compared with the results of the theoretical model codes. PMID- 22209778 TI - Primary charge separation within P870* in wild type and heterodimer mutants in femtosecond time domain. AB - Primary charge separation dynamics in the reaction center (RC) of purple bacterium Rhodobacter sphaeroides and its P870 heterodimer mutants have been studied using femtosecond time-resolved spectroscopy with 20 and 40fs excitation at 870nm at 293K. Absorbance increase in the 1060-1130nm region that is presumably attributed to P(A)(delta+) cation radical molecule as a part of mixed state with a charge transfer character P*(P(A)(delta+)P(B)(delta-)) was found. This state appears at 120-180fs time delay in the wild type RC and even faster in H(L173)L and H(M202)L heterodimer mutants and precedes electron transfer (ET) to B(A) bacteriochlorophyll with absorption band at 1020nm in WT. The formation of the P(A)(delta+)B(A)(delta-) state is a result of the electron transfer from P*(P(A)(delta+)P(B)(delta-)) to the primary electron acceptor B(A) (still mixed with P*) with the apparent time delay of ~1.1ps. Next step of ET is accompanied by the 3-ps appearance of bacteriopheophytin a(-) (H(A)(-)) band at 960nm. The study of the wave packet formation upon 20-fs illumination has shown that the vibration energy of the wave packet promotes reversible overcoming of an energy barrier between two potential energy surfaces P* and P*(P(A)(delta+)B(A)(delta-)) at ~500fs. For longer excitation pulses (40fs) this promotion is absent and tunneling through an energy barrier takes about 3ps. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: from Natural to Artificial. PMID- 22209779 TI - A framework for assessing collaborative capacity in community-based public forest management. AB - Community-based collaborative groups involved in public natural resource management are assuming greater roles in planning, project implementation, and monitoring. This entails the capacity of collaborative groups to develop and sustain new organizational structures, processes, and strategies, yet there is a lack of understanding what constitutes collaborative capacity. In this paper, we present a framework for assessing collaborative capacities associated with community-based public forest management in the US. The framework is inductively derived from case study research and observations of 30 federal forest-related collaborative efforts. Categories were cross-referenced with literature on collaboration across a variety of contexts. The framework focuses on six arenas of collaborative action: (1) organizing, (2) learning, (3) deciding, (4) acting, (5) evaluating, and (6) legitimizing. Within each arena are capacities expressed through three levels of social agency: individuals, the collaborative group itself, and participating or external organizations. The framework provides a language and set of organizing principles for understanding and assessing collaborative capacity in the context of community-based public forest management. The framework allows groups to assess what capacities they already have and what more is needed. It also provides a way for organizations supporting collaboratives to target investments in building and sustaining their collaborative capacities. The framework can be used by researchers as a set of independent variables against which to measure collaborative outcomes across a large population of collaborative efforts. PMID- 22209780 TI - Lack of the DNA glycosylases MYH and OGG1 in the cancer prone double mutant mouse does not increase mitochondrial DNA mutagenesis. AB - Reactive oxygen species (ROS) are formed as natural byproducts during aerobic metabolism and readily induce premutagenic base lesions in the DNA. The 8 oxoguanine DNA glycosylase (OGG1) and MutY homolog 1 (MYH) synergistically prevent mutagenesis and cancer formation in mice. Their localization in the mitochondria as well as in the nucleus suggests that mutations in mitochondrial DNA (mtDNA) contribute to the carcinogenesis in the myh-/-/ogg1-/- double knockout mouse. In order to test this hypothesis, we analyzed mtDNA mutagenesis and mitochondrial function in young (1month) and adult (6months) wt and myh-/ /ogg1-/- mice. To our surprise, the absence of OGG1 and MYH had no impact on mtDNA mutation rates in these mice, even at the onset of cancer. This indicates that mtDNA mutagenesis is not responsible for the carcinogenesis of myh-/-/ogg1-/ mice. In line with these results, mitochondrial function was unaffected in the cancerous tissues liver and lung, whereas a significant reduction in respiration capacity was observed in brain mitochondria from the adult myh-/-/ogg1-/- mouse. The reduced respiration capacity correlated with a specific reduction (-25%) in complex I biochemical activity in brain mitochondria. Our results demonstrate that mtDNA mutations are not associated with cancer development in myh-/-/ogg1-/- mice, and that impairment of mitochondrial function in brain could be linked to nuclear DNA mutations in this strain. OGG1 and MYH appear to be dispensable for antimutator function in mitochondria. PMID- 22209781 TI - Evaluation of susceptibility locus for response to interferon-alpha based therapy in chronic hepatitis B patients in Chinese. AB - In 2009, three independent genome-wide association studies reported that genetic variation in the interleukin 28B gene to be associated with the response to interferon-alpha/ribavirin therapy in hepatitis C virus genotype 1 infected patients. We carried out the present study to assess whether such polymorphisms also affect the therapy effect of another interferon-alpha responsive illness as chronic hepatitis B. Five hundred and twelve interferon-alpha treatment-naive HBeAg seropositive chronic hepatitis B patients were enrolled in the present retrospective nested case-control study. All patients received PEG-IFN-alpha-2a based treatment and were examined for the therapy efficacy. SNP rs8099917 was genotyped using the MassArray system (Sequenom). Interestingly, the frequency of G allele of rs8099917 was significantly higher in response group than in non response group (8.3% vs. 3.9%, p=0.003, OR=0.44, 95%CI=0.25-0.79). The genotype distributions of this SNP also differed significantly between two groups (p=0.003). Our study suggested that the G allele of rs8099917 was associated with higher rate of response in HBeAg seropositive chronic hepatitis B patients treated with interferon alpha. PMID- 22209782 TI - High resolution electrophysiological techniques for the study of calcium activated exocytosis. AB - BACKGROUND: Neurotransmitters, neuropeptides and hormones are released from secretory vesicles of nerve terminals and neuroendocrine cells by calcium activated exocytosis. A key step in this process is the formation of a fusion pore between the vesicle membrane and the plasma membrane. Exocytotic fusion leads to an increase in plasma membrane area that can be measured as a proportional increase in plasma membrane capacitance. SCOPE OF REVIEW: High resolution capacitance measurements in single cells, nerve terminals and small membrane patches have become possible with the development of the patch clamp technique. This review discusses the methods of whole cell patch clamp capacitance measurements and their use in conjunction with voltage clamp pulse stimulation and with stimulation by photorelease of caged calcium. It also discusses patch capacitance measurements for the study of single exocytotic events and fusion pore properties in neuroendocrine cells and nerve terminals. MAJOR CONCLUSIONS: Capacitance measurements provide high resolution information on the extent and time course of fusion for the characterization of vesicle pools and the kinetics of exocytosis. They allow the characterization of the mode of fusion including distinction of single vesicle full fusion, transient kiss-and run fusion or multivesicular compound exocytosis. Furthermore, measurement of fusion pore conductances and their dynamic behavior has enabled the characterization of fusion pore properties in a way that resembles the characterization of ion channel function through single channel recordings. GENERAL SIGNIFICANCE: The combination of patch clamp capacitance measurements with pharmacological and molecular manipulations of exocytosis is emerging as a powerful approach to investigate the molecular mechanisms of calcium-activated exocytotic fusion pore formation. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signalling. PMID- 22209784 TI - Meta-analytical definition and functional connectivity of the human vestibular cortex. AB - Contrary to most other sensory systems, no consensus has been reached within the scientific community about the exact locations and functions of human cortical areas processing vestibular information. Metaanalytical modelling using activation likelihood estimation (ALE) for the integration of neuroimaging results has already been successfully applied to several distinct tasks, thereby revealing the cortical localization of cognitive functions. We used the same algorithm and technique with all available and suitable PET and fMRI studies employing a vestibular stimulus. Most consistently across 28 experiments vestibular stimuli evoked activity in the right hemispheric parietal opercular area OP 2 implicating it as the core region for vestibular processing. Furthermore, we took our primary results as a seeding point and fed them into a functional connectivity analysis based on resting-state oscillations in 100 healthy subjects. This subsequent calculation confirmed direct connections of the area OP 2 with every other region found in the meta-analysis, in particular temporo-parietal regions, premotor cortex, and the midcingulate gyrus. Thus revealing a joint vestibular network in accordance with a concept from animal literature termed the inner vestibular circle. Moreover, there was also a significant vestibular connectivity overlap with frontal but not parietal cortical centres responsible for the generation of saccadic eye movements, likely to be involved in nystagmus fast phase generation. This was shown in an additional ocular motor meta-analysis. We conclude that the cytoarchitectonic area OP 2 in the parietal operculum, embedded in a joint vestibular network, should be the primary candidate for the human vestibular cortex. This area may represent the human homologue to the vestibular area PIVC as proposed by Guldin and Grusser in non-human primates. PMID- 22209783 TI - Using brain imaging to track problem solving in a complex state space. AB - This paper describes how behavioral and imaging data can be combined with a Hidden Markov Model (HMM) to track participants' trajectories through a complex state space. Participants completed a problem-solving variant of a memory game that involved 625 distinct states, 24 operators, and an astronomical number of paths through the state space. Three sources of information were used for classification purposes. First, an Imperfect Memory Model was used to estimate transition probabilities for the HMM. Second, behavioral data provided information about the timing of different events. Third, multivoxel pattern analysis of the imaging data was used to identify features of the operators. By combining the three sources of information, an HMM algorithm was able to efficiently identify the most probable path that participants took through the state space, achieving over 80% accuracy. These results support the approach as a general methodology for tracking mental states that occur during individual problem-solving episodes. PMID- 22209786 TI - Molecular characterization of a porcine kobuvirus strain in China. AB - Porcine kobuvirus was first identified in 2007 in Hungary. The virus has been detected in several Asian countries. In our study, the complete genome of the recently identified porcine kobuvirus strain SH-W-CHN was amplified by RT-PCR and was sequenced. Dendrograms indicated that SH-W-CHN is closely related to other porcine kobuviruses. To identify sites of possible recombination within the genome of the SH-W-CHN strain, the SimPlot program was used to perform recombination analysis. The results showed that no significant recombination event between strain S-1-HUN and Y-1-CHI had occurred. However, certain possible recombination signals were identified, indicating that some early recombination events may have contributed to the genome of SH-W-CHN. This study further confirmed the existence of multiple lineages of porcine kobuvirus and indicated that homologous recombination may be a driving force in its evolution. PMID- 22209785 TI - A survey of geminiviruses and associated satellite DNAs in the cotton-growing areas of northwestern India. AB - Severe symptoms of cotton leaf curl disease (CLCuD) are caused by the association of a single-stranded circular DNA satellite (betasatellite) with a helper begomovirus. In this study, we analyzed 40 leaf samples (primarily cotton with CLCuD symptoms and other plants growing close by) from four sites between New Delhi and the Pakistan/India border, using rolling-circle amplification (RCA) and PCR. In total, the complete sequences of 12 different helper viruses, eight alphasatellites, and one betasatellite from five different plant species were obtained. A recombinant helper virus molecule found in okra and a novel alphasatellite-related DNA from croton are also described. This is the first report of the presence of both DNA components (helper virus and betasatellite) associated with resistance-breaking CLCuD in India, and it highlights the need for further work to combat its damage and spread. PMID- 22209787 TI - Phylogenetic analysis of bovine respiratory syncytial viruses from recent outbreaks in feedlot and dairy cattle herds. AB - Bovine respiratory syncytial virus (BRSV) is one of the major causes of bovine respiratory disease worldwide. In order to study the molecular epidemiology of the virus, samples from 30 BRSV outbreaks in cattle herds located in different parts of Sweden were collected from 2007 to 2011. The samples were analyzed by PCR, and the glycoprotein (G) gene was sequenced. BRSV was detected in outbreaks of respiratory disease in both dairy and feedlot herds most often during the winter period but also during the summer months (May to August). This indicates that circulation of the virus between herds occurs throughout the year. Comparative sequence analysis revealed a high degree (more than 94.5%) of sequence identity among the collected strains. Phylogenetic analysis showed that 29 out of the 30 strains formed a unique clade. Identical sequences found in herds sampled within a few months' time suggested that these herds were part of a common transmission chain. One strain from a single outbreak in a herd in southern Sweden clustered with Danish strains and showed a distant relationship to the rest of the Swedish strains. Further studies are highly warranted to clarify the inter-herd transmission routes of BRSV. Such knowledge is essential for the control of the spread of this virus between herds, regions and even countries. PMID- 22209788 TI - Large conductance Ca2+-activated K+ channels modulate endothelial cell outward currents and nitric oxide release in the intact rat superior mesenteric artery. AB - Endothelial cells (EC) control vascular smooth muscle cell (VSMC) tone by release of paracrine factors. VSMC may also influence the EC layer, and therefore, the present study hypothesized that the opening of large-conductance Ca(2+) activated K(+) (BK(Ca)) channels may indirectly modulate EC hyperpolarization and nitric oxide (NO) release via myoendothelial gap junctions (MEGJ). To address this hypothesis 'in situ' EC ion current recordings, isolated VSMC patch clamp recordings, and simultaneous measurements of NO concentration and relaxation were conducted using segments of the rat superior mesenteric artery. In arteries constricted by alpha(1)-adrenoceptor activation, ACh (1 MUM) evoked EC outward currents, vasorelaxation, and NO release. In contrast to preincubation with iberiotoxin (IbTx, 100nM) application of IbTx after ACh decreased EC outward currents, NO release and vasorelaxation. Furthermore, in phenylephrine (Phe) contracted arteries treated with a gap junction uncoupler, cabenoxolone (CBX), IbTx failed to decrease ACh-evoked EC outward currents. In addition, CBX decreased EC outward currents, time constant of the capacitative transients, input capacitance, and increased input resistance. In isolated VSMC CBX did not affect BK(Ca) currents. Immunohistochemistry revealed only BK(Ca) channel positive staining in the VSMC layer. Therefore, the present results suggest that BK(Ca) channels are expressed in the VSMC, and that Phe by activation of VSMC BK(Ca) channels modulates ACh-evoked EC outward currents, NO release and vasorelaxation via MEGJ in rat superior mesenteric artery. PMID- 22209789 TI - Differential localization of sphingomyelin synthase isoforms in neurons regulates sphingomyelin cluster formation. AB - Sphingomyelin (SM) plays important roles in regulating structure and function of plasma membrane, but how intracellular localization of SM is regulated in neuronal cells is not understood. Here we show that two isoforms of SM synthase (SMS) are differentially expressed in neuronal subtypes and that only SMS2 proteins localize in neurites of hippocampal neurons. Moreover, SMS proteins induce Lysenin-binding SM clusters exclusively in their vicinity although neurons hardly contain such cluster under control condition. These findings indicate three important notions about SM metabolism in neurons. First, the activity of SMS is the rate-limiting step of SM cluster formation. Second, the SM content or clustering can be modulated by SMS activity. Third, SMS1 and SMS2 play distinct roles in regulating local SM clustering. Particularly, SMS2, rather than SMS1, is likely to be the major enzyme that is important for SM synthesis in the long neurites and its tip, the growth cone. PMID- 22209790 TI - Endothelin system in intestinal villi: A possible role of endothelin-2/vasoactive intestinal contractor in the maintenance of intestinal architecture. AB - The endothelin system consists of three ligands (ET-1, ET-2 and ET-3) and at least two receptors (ETA and ETB). In mice ET-2 counterpart is a peptide originally called "vasoactive intestinal contractor" (VIC) for this reason, this peptide is frequently named ET-2/VIC. In intestinal villi, fibroblasts-like cells express endothelin's receptors and response to ET-1 and ET-3 peptides, changing their cellular shape. Several functions have been attributed to these peptides in the "architecture" maintenance of intestinal villi acting over sub-epithelial fibroblasts. Despite this, ET-2/VIC has not been analyzed in depth. In this work we show the intestine gene expression and immunolocalization of ET-1, ET-2 and the ETA and ETB receptors from duodenum to rectus and in the villus-crypt axis in mice, allowing a complete analysis of their functions. While ET-1 is expressed uniformly, ET-2 had a particular distribution, being higher at the bottom of the villi of duodenum, ileum and jejunum and reverting this pattern in the crypts of colon and rectus, where the higher expression was at the top. We postulated that ET-2 would act in a cooperative manner with ET-1, giving to the villus the straight enough to withstand mechanical stress. PMID- 22209791 TI - Specific expression of Olpiwi1 and Olpiwi2 in medaka (Oryzias latipes) germ cells. AB - Piwi is necessary for germ stem cell survival in Drosophila and homologues have been identified in a diverse range of organisms. Here, we identify and characterize two homologous genes of piwi, Olpiwi1 and Olpiwi2, in the model fish medaka (Oryzias latipes). Olpiwi1 is similar to Ziwi in zebrafish or Miwi in the mouse, and Olpiwi2 is similar to Zili in zebrafish or Mili in the mouse. Moreover, Olpiwi2 mRNA is produced from two different chromosomes. RT-PCR showed expression of Olpiwi1 and Olpiwi2 predominantly in the gonads. In situ hybridization revealed germ cell-specific expression of Olpiwi1 and Olpiwi2 throughout the development of oocytes from oogonia to mature oocytes in the ovary, and from spermatogonia to spermatocytes in the testes of adults. RT-PCR and whole mount in situ hybridization showed that both Olpiwi1 and Olpiwi2 were maternally deposited in the embryo. Olpiwi1 and Olpiwi2 were detected in primordial germ cells during embryonic development. These results suggest that both Olpiwi1 and Olpiwi2 are germ cell specific, and may play important roles in germ cell development and gametogenesis in this model species. PMID- 22209792 TI - Epigenetic complexity during the zebrafish mid-blastula transition. AB - The zebrafish developmental transcription program is determined by temporal post translational histone modifications established in a step-wise and combinatorial manner on specific promoters around the time of zygotic genome activation (ZGA). Here, we characterize this increasing epigenetic complexity before, during and after ZGA. H3K4me3/H3K27me3 co-enrichment prevails over H3K4me3/H3K9me3 at the time of ZGA. Whereas most H3K4me3-marked promoters are devoid of transcriptionally repressive H3K9me3 or H3K27me3, the latter marks rarely occur in absence of H3K4me3. On co-enriched genomic regions, H3K4me3 and H3K27me3 can overlap regardless of H3K9me3 enrichment, but H3K4me3 and H3K9me3 are mutually exclusive. H3K4me3 and H3K9me3 may however overlap only when H3K27me3 also marks the overlapping domain, suggesting that H3K27me3 may modulate chromatin states. On metagenes, H3K27me3 enrichment correlates with local alteration in H3K4me3 density, and co-enrichment in H3K9me3 is linked to alterations in both H3K27me3 and H3K4me3 profiles. This suggests physical proximity of these marks and supports a view of existence of bi- or tri-valent chromatin domains. Thus enrichment in trimethylated H3K9 or H3K27 is associated with local remodeling of chromatin manifested by changes in H3K4me3 density. We propose that metagenes can provide information on the multivalency of chromatin sates. PMID- 22209794 TI - Genome-wide identification of cold-responsive and new microRNAs in Populus tomentosa by high-throughput sequencing. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that regulate the expression of target mRNAs in plant growth, development, abiotic stress responses, and pathogen responses. Cold stress is one of the most common abiotic factors affecting plants, and it adversely affects plant growth, development, and spatial distribution. To understand the roles of miRNAs under cold stress in Populus tomentosa, we constructed two small RNA libraries from plantlets treated or not with cold conditions (4 degrees C for 8 h). High-throughput sequencing of the two libraries identified 144 conserved miRNAs belonging to 33 miRNA families and 29 new miRNAs (as well as their corresponding miRNA(*)s) belonging to 23 miRNA families. Differential expression analysis showed that 21 miRNAs were down regulated and nine miRNAs were up-regulated in response to cold stress. Among them, 19 cold-responsive miRNAs, two new miRNAs and their corresponding miRNA(*)s were validated by qRT-PCR. A total of 101 target genes of the new miRNAs were predicted using a bioinformatics approach. These target genes are involved in growth and resistance to various stresses. The results demonstrated that Populus miRNAs play critical roles in the cold stress response. PMID- 22209793 TI - Differential expression of microRNA and predicted targets in pulmonary sarcoidosis. AB - BACKGROUND: Recent studies show that various inflammatory diseases are regulated at the level of RNA translation by small non-coding RNAs, termed microRNAs (miRNAs). We sought to determine whether sarcoidosis tissues harbor a distinct pattern of miRNA expression and then considered their potential molecular targets. METHODS AND RESULTS: Genome-wide microarray analysis of miRNA expression in lung tissue and peripheral blood mononuclear cells (PBMCs) was performed and differentially expressed (DE)-miRNAs were then validated by real-time PCR. A distinct pattern of DE-miRNA expression was identified in both lung tissue and PBMCs of sarcoidosis patients. A subgroup of DE-miRNAs common to lung and lymph node tissues were predicted to target transforming growth factor (TGFbeta) regulated pathways. Likewise, the DE-miRNAs identified in PBMCs of sarcoidosis patients were predicted to target the TGFbeta-regulated "wingless and integrase 1" (WNT) pathway. CONCLUSIONS: This study is the first to profile miRNAs in sarcoidosis tissues and to consider their possible roles in disease pathogenesis. Our results suggest that miRNA regulate TGFbeta and related WNT pathways in sarcoidosis tissues, pathways previously incriminated in the pathogenesis of sarcoidosis. PMID- 22209795 TI - Actions of translocator protein ligands on neutrophil adhesion and motility induced by G-protein coupled receptor signaling. AB - The 18 kDa translocator protein (TSPO) also known as the peripheral benzodiazepine receptor (PBR), mediates the transportation of cholesterol and anions from the outer to the inner mitochondrial membrane in different cells types. Although recent evidences indicate a potential role for TSPO in the development of inflammatory processes, the mechanisms involved have not been elucidated. The present study investigated the ability of the specific TSPO ligands, the isoquinoline carboxamide PK11195 and benzodiazepine Ro5-4864, on neutrophil recruitment promoted by the N-formylmethionyl-leucyl-phenylalanine peptide (fMLP), an agonist of G-protein coupled receptor (GPCR). Pre-treatment with Ro5-4864 abrograted fMLP-induced leukocyte-endothelial interactions in mesenteric postcapillary venules in vivo. Moreover, in vitro Ro5-4864 treatment prevented fMLP-induced: (i) L-selectin shedding and overexpression of PECAM-1 on the neutrophil cell surface; (ii) neutrophil chemotaxis and (iii) enhancement of intracellular calcium cations (iCa(+2)). Intriguingly, the two latter effects were augmented by cell treatment with PK11195. An allosteric agonist/antagonist relation may be suggested, as the effects of Ro5-4864 on fMLP-stimulated neutrophils were reverted by simultaneous treatment with PK11195. Taken together, these data highlight TSPO as a modulator of pathways of neutrophil adhesion and locomotion induced by GPCR, connecting TSPO actions and the onset of an innate inflammatory response. PMID- 22209796 TI - Modification of experimental, lower limb ischemic pain with transcutaneous electrical nerve stimulation. AB - INTRODUCTION: Transcutaneous electrical nerve stimulation (TENS) has been shown to be effective for the reduction of experimentally induced ischemic pain in the upper limb. No studies have been published on the effects of TENS for lower limb ischemic pain. OBJECTIVES: To investigate the pain-modifying effect of TENS on experimentally induced ischemic pain in the lower limb. METHODS: A modified Submaximal Effort Tourniquet Test-induced ischemic pain in the nondominant lower limb of 27 healthy volunteers. Each of the participants completed a baseline modified Submaximal Effort Tourniquet Test (No TENS) and 1 of the experimental conditions: either high-frequency TENS (HF-TENS) or placebo TENS (P-TENS). The outcome measures were the time taken (in seconds) for the participants to report pain threshold and pain tolerance. Pain endurance was calculated as the difference between these points. Pain intensity during ischemia was assessed using a numerical rating scale. The McGill Pain Questionnaire recorded participants' retrospective description of 'intolerable' induced pain. The differences in scores between these measures at the baseline and TENS intervention was calculated and used for the analysis. RESULTS: Paired Student t tests found significant increases in time to pain tolerance and pain endurance in both the TENS groups (P<0.001 HF-TENS and P<0.05 for P-TENS, respectively). When compared with baseline, time to pain threshold increased significantly only with HF-TENS (P<0.01). The independent Student t-tests detected greater increases in pain threshold, tolerance, and endurance in the HF-TENS group compared with the P TENS group (P<0.05, 0.002, and 0.003, respectively). Compared with P-TENS, HF TENS significantly reduced the pain intensity between the fifth and eigth minutes. Both HF-TENS and P-TENS significantly reduced the mean McGill Pain Questionnaire Pain Rating Index scores, but did not show a between-group difference. CONCLUSIONS: HF-TENS had stronger modifying effects on several aspects of laboratory-induced ischemic pain than did P-TENS. HF-TENS delayed the onset of pain, reduced pain levels, and delayed the onset of extreme pain over a period of several minutes. PMID- 22209797 TI - Painful diabetic polyneuropathy: approach to diagnosis and management. AB - OBJECTIVES: To provide a current overview of the diagnostic work-up and management of painful diabetic polyneuropathy (PDPN). METHODS: A review covering the literature from 2004 to 2011, which describes the tools designed to diagnose neuropathic pain and assess its severity, including self-administered questionnaires, validated laboratory tests and simple handheld screening devices, and the evidence-based therapeutic approaches to PDPN. RESULTS: The clinical aspects, pathogenesis, and comorbidities of PDPN, as well as its impact on health related quality of life (HR-QoL), are the main drivers for the management of patients with suspected PDPN. PDPN treatment consists first of all in improving glycemic control and lifestyle intervention. A number of symptomatic pharmacological agents are available for pain control: tricyclic antidepressants and selective serotonin norepinephrine reuptake inhibitors (venlafaxine and duloxetine), alpha2-delta ligands (gabapentin and pregabalin), opioid analgesics (tramadol and oxycodone), and agents for topical use, such as lidocaine patch and capsaicin cream. With the exception of transcutaneous electrical nerve stimulation, physical treatment is not supported by adequate evidence. DISCUSSION: As efficacy and tolerability of current therapy for PDPN are not ideal, the need for a better approach in management further exists. Novel compounds should be developed for the treatment of PDPN. PMID- 22209798 TI - A randomized controlled trial of cognitive-behavioral therapy for the treatment of PTSD in the context of chronic whiplash. AB - OBJECTIVES: Whiplash-associated disorders (WAD) are common and involve both physical and psychological impairments. Research has shown that persistent posttraumatic stress symptoms are associated with poorer functional recovery and physical therapy outcomes. Trauma-focused cognitive-behavioral therapy (TF-CBT) has shown moderate effectiveness in chronic pain samples. However, to date, there have been no clinical trials within WAD. Thus, this study will report on the effectiveness of TF-CBT in individuals meeting the criteria for current chronic WAD and posttraumatic stress disorder (PTSD). METHOD: Twenty-six participants were randomly assigned to either TF-CBT or a waitlist control, and treatment effects were evaluated at posttreatment and 6-month follow-up using a structured clinical interview, self-report questionnaires, and measures of physiological arousal and sensory pain thresholds. RESULTS: Clinically significant reductions in PTSD symptoms were found in the TF-CBT group compared with the waitlist at postassessment, with further gains noted at the follow-up. The treatment of PTSD was also associated with clinically significant improvements in neck disability, physical, emotional, and social functioning and physiological reactivity to trauma cues, whereas limited changes were found in sensory pain thresholds. DISCUSSION: This study provides support for the effectiveness of TF-CBT to target PTSD symptoms within chronic WAD. The finding that treatment of PTSD resulted in improvements in neck disability and quality of life and changes in cold pain thresholds highlights the complex and interrelating mechanisms that underlie both WAD and PTSD. Clinical implications of the findings and future research directions are discussed. PMID- 22209799 TI - Diffuse noxious inhibitory control function in women with provoked vestibulodynia. AB - OBJECTIVES: The objective of the study was to assess diffuse noxious inhibitory control (DNIC) function in women with provoked vestibulodynia (PVD) compared with healthy controls through the use of 2 different methodologies. Furthermore, the study aimed to assess whether pain characteristics correlate with DNIC in women with PVD. METHODS: Twenty-three healthy control women and 23 women diagnosed with PVD by the study gynecologist participated in the study. To assess DNIC, heat pain tolerance, determined through an ascending method of limits and temporal summation of thermal pain were used as test stimuli and a cold water bath was used as the conditioning stimulus. Participants reported on pain characteristics as potential correlates with DNIC function. RESULTS: No significant group differences were found in the number of DNIC responders per group when using heat pain tolerance or temporal summation procedures to examine DNIC. The magnitude of the DNIC response was examined for the overall groups and for positive DNIC responders only. When all participants were included in the analyses with the heat pain tolerance procedure, women with PVD displayed a higher magnitude of DNIC responding. Correlations between pain variables and DNIC responding and magnitude were nonsignificant. DISCUSSION: Results support previous findings of intact DNIC function in women with PVD, using both an ascending method of limits and a temporal summation paradigm. Pain-related variables were not correlated with DNIC function in women with PVD, perhaps this unexpected finding is due to the possibility that central processes other than DNIC, such as descending facilitation, provoke or maintain this chronic pain condition. PMID- 22209800 TI - Predictive factors for postherpetic neuralgia using ordered logistic regression analysis. AB - OBJECTIVES: To identify predictive factors for the occurrence of postherpetic neuralgia (PHN). METHODS: The participants were 73 herpes zoster patients who had been treated at the pain clinic of our hospital between January 2008 and June 2010. Variables present at the initial visit were extracted from the clinical records for regression analysis of factors related to the occurrence of PHN. The following scores for response were used: 0=no PHN after 3 months; 1=PHN present after 3 months but absent after 6 months; and 2=PHN present after 6 months. Multivariate ordered logistic regression analysis was performed to identify the predictive factors for PHN. RESULTS: Advanced age [odds ratio (OR)=2.740, confidence interval (CI)=1.110-6.761; P=0.0288] and deep pain (OR=4.244, CI=1.114 16.163; P=0.0341) at the initial visit to our outpatient pain clinic were found to be significant predictive factors for the occurrence of PHN. Diabetes mellitus (OR=3.075) and pain reduced by bathing (OR=3.389) also had high OR, although they were not significant. DISCUSSION: Our study indicates that advanced age and deep pain at the initial visit are significant predictors for PHN. Our results are considered likely to contribute to the establishment of evidence-based medicine in the optimal treatment of PHN. PMID- 22209801 TI - Natural variation in the MU-opioid gene OPRM1 predicts increased pain on third day after thoracotomy. AB - OBJECTIVES: The mechanism whereby acute postsurgical pain can persist and become chronic remains unknown. Thoracotomy is a common procedure with a high incidence of long-term pain for which acute postsurgical pain is an established risk factor. Therefore, the genetic basis of elevations in acute postsurgical pain after thoracotomy was investigated. METHODS: A cohort of thoracotomy patients participating in an ongoing trial of outcomes after cancer were enrolled. A standard combined general and epidural anesthetic and surgical approach were used. All patients received a standardized postoperative epidural analgesia regimen. Postoperatively, pain scores were determined and blood was collected for genotyping. Our a priori hypothesis was that variability of genes involved in nociception and analgesic therapy would predict pain score >=3 of 10 on the third postoperative day. RESULTS: Ninety patients with pain and genotyping data on postoperative day 3 were examined. We found no association between markers in COMT, COX1, COX2, and TRPV1 and postoperative pain. We demonstrated several statistically significant associations with 4 single nucleotide polymorphism markers in OPRM1 (odds ratio, 95% confidence intervals): rs634479 (0.4, 0.17, 0.97), rs499796 (0.35, 0.13, 0.92), rs548646 (0.47, 0.23, 0.97), and rs679987 (0.1, 0.01, 0.84). From these, we inferred 2 haplotype blocks in OPRM1 where both had a frequency of 9% and P=0.03 and 0.04. Previously published functional single nucleotide polymorphisms in OPRM1 and COMT were not associated with increased pain on the third postoperative day. DISCUSSION: We identified previously unpublished haplotypes of the OPRM1 receptor that predicted increases in self reported pain on the third postoperative day after thoracotomy. These findings require replication and further refinement before their impact on patient care can be determined. PMID- 22209802 TI - Effects of a zinc-deficient diet on hearing in CBA mice. AB - This study investigated the effect of a zinc-deficient diet on the hearing in CBA mice and aimed to verify whether this hearing change is reversible by supplementation of zinc afterwards. We assessed hearing through an auditory brainstem response (ABR) with tone burst stimulation in 4, 8, 16, and 32 kHz and distortion product otoacoustic emissions in 5.6, 8, 11.3, and 16 kHz every week. The ABR threshold started to increase after 4 weeks on a zinc-deficient diet. The difference in the threshold between control and zinc-deficient animals became greater over time and plateaued at about 6 weeks. The ABR threshold differences between control and zinc-deficient mice were greater at higher frequencies. Four weeks of normal diet, following 8 weeks of a zinc-deficient diet, restored the ABR threshold to normal at all measured frequencies. Zinc-deficient mice did not show any distortion product otoacoustic emission threshold change at all frequencies. This finding suggests that a zinc-deficient diet increased the ABR threshold in CBA mice and a zinc-adequate diet restored the ABR threshold to normal. PMID- 22209803 TI - Auditory adaptation to sound intensity in conscious rats: 2-[F-18]-fluoro-2 deoxy-D-glucose PET study. AB - Despite the importance of the adaptive process for discriminating the broad range of sound intensity, there have been few systemic investigations targeting the auditory mechanisms. In this study, the adaptation effect of sound intensity on the change in glucose metabolism in rat brains was examined using a PET technique. In the first experiment, broadband white noise sound (40, 60, 80, or 100 dB sound pressure level) was given for 30 min after an 2-[F-18]-fluoro-2 deoxy-D-glucose injection in an awake condition. In the second experiment, sound stimuli with an intensity modulation of 0, 0.5, and 5.0 Hz in frequency and at three intensity levels were used for examining the metabolism change according to the short time scale variation of the sound intensity. As a result, the metabolic activities in the bilateral cochlear nucleus, superior olivary complexes, and inferior colliculus were proportional to the sound intensity level, whereas the bilateral auditory cortical areas unexpectedly decreased as the sound intensity level increased in the first experiment. In the second experiment, the glucose metabolism in the auditory cortex was higher at 0.5 and 5.0 Hz modulation frequency than the 0.0 Hz modulation frequency, while retaining an inverse relationship with the sound intensity. The metabolism in inferior colliculus was higher at 5.0 Hz modulation frequency than 0.0 and 0.5 Hz modulation frequencies. Taken together, the auditory cortex metabolism seemed to be actively adapted to the average sound intensity, which indicates that it plays an important role in processing the broad range to sound intensity more than the other nucleus of the auditory pathway. Especially, this study demonstrated that the sound intensity dependent glucose metabolism can be seen in a small rodent's brain stem level using 2-[F-18]-fluoro-2-deoxy-D-glucose PET functional neuroimaging. PMID- 22209804 TI - Macrophage receptor with collagenous structure (MARCO) is a dynamic adhesive molecule that enhances uptake of carbon nanotubes by CHO-K1 cells. AB - The toxicity of carbon nanotubes (CNTs), a highly promising nanomaterial, is similar to that of asbestos because both types of particles have a fibrous shape and are biopersistent. Here, we investigated the characteristics of macrophage receptor with collagenous structure (MARCO), a membrane receptor expressed on macrophages that recognizes environmental or unopsonized particles, and we assessed whether and how MARCO was involved in cellular uptake of multi-walled CNTs (MWCNTs). MARCO-transfected Chinese hamster ovary (CHO-K1) cells took up polystyrene beads irrespective of the particle size (20nm-1MUm). In the culture of MARCO-transfected CHO-K1 cells dendritic structures were observed on the bottom of culture dishes, and the edges of these dendritic structures were continually renewed as the cell body migrated along the dendritic structures. MWCNTs were first tethered to the dendritic structures and then taken up by the cell body. MWCNTs appeared to be taken up via membrane ruffling like macropinocytosis, rather than phagocytosis. The cytotoxic EC(50) value of MWCNTs in MARCO-transfected CHO-K1 cells was calculated to be 6.1MUg/mL and transmission electron microscopic observation indicated that the toxicity of MWCNTs may be due to the incomplete inclusion of MWCNTs by the membrane structure. PMID- 22209805 TI - A biogeochemical framework for bioremediation of plutonium(V) in the subsurface environment. AB - Accidental release of plutonium (Pu) from storage facilities in the subsurface environment is a concern for the safety of human beings and the environment. Given the complexity of the subsurface environment and multivalent state of Pu, we developed a quantitative biogeochemical framework for bioremediation of Pu(V)O(2) (+) in the subsurface environment. We implemented the framework in the biogeochemical model CCBATCH by expanding its chemical equilibrium for aqueous complexation of Pu and its biological sub-models for including Pu's toxicity and reduction reactions. The quantified framework reveals that most of the Pu(V) is speciated as free Pu(V)O(2) (+) ((aq)), which is a problem if the concentration of free Pu(V)O(2) (+) is >=28 MUM (the half-maximum toxicity value for bacteria able to reduce Pu(V) to Pu(III)PO(4(am))) or >=250 MUM (the full-toxicity value that takes the bioreduction rate to zero). The framework includes bioreduction of Fe(3+) to Fe(2+), which abiotically reduces Pu(V)O(2) (+) to Pu(IV) and then to Pu(III). Biotic (enzymatic) reduction of Pu(V)O(2) (+) directly to Pu(III) by Shewanella alga (S. alga) is also included in the framework. Modeling results also reveal that for formation of Pu(III)PO(4(am)), the desired immobile product, the concentration of coexisting model strong ligand-nitrilotriacetic acid (NTA) should be less than or equal to the concentration of total Pu(III). PMID- 22209806 TI - Mild traumatic brain injury: the elusive timing of "recovery". PMID- 22209807 TI - Pharmacological modulation of functional connectivity: alpha2-adrenergic receptor agonist alters synchrony but not neural activation. AB - Correlative low frequency fluctuations in functional MRI (fMRI) signals across brain regions at rest have been taken as a measure of functional connectivity to map large-scale neural networks; however, the neural origin is still not clear. Receptor-targeted pharmacological manipulation could elucidate the role of neuroreceptor systems in resting-state functional connectivity to provide another perspective on the mechanism. In this study, the dose-dependent effects of an alpha(2)-adrenergic receptor agonist, medetomidine, on brain activation and functional connectivity were investigated. Forepaw stimulation-induced activation and resting-state fluctuation in the rat somatosensory cortices and caudate putamen were measured using the blood oxygenation level dependent (BOLD) fMRI. The results showed significant dose-dependent suppression of inter-hemispheric correlation but not the amplitude in the somatosensory areas, while the stimulation-induced activation in the same areas remained unchanged. To clarify the potential change in the hemodynamic response caused by the vasoconstrictive effect of medetomidine, the resting perfusion fluctuation was studied by arterial spin labeling and showed similar results as the BOLD. This suggests that the oxygen metabolic rate and hence the neural activity may not be affected by medetomidine but only the synchrony between brain regions was suppressed. Furthermore, no change in functional connectivity with medetomidine dosages was seen in the caudate putamen, a region with much lower alpha(2)-receptor density. These results indicate that resting-state signal correlation may reflect underlying neuroreceptor activity and a potential role of the adrenergic system in the functional connectivity. PMID- 22209808 TI - Performance evaluation of the Champagne source reconstruction algorithm on simulated and real M/EEG data. AB - In this paper, we present an extensive performance evaluation of a novel source localization algorithm, Champagne. It is derived in an empirical Bayesian framework that yields sparse solutions to the inverse problem. It is robust to correlated sources and learns the statistics of non-stimulus-evoked activity to suppress the effect of noise and interfering brain activity. We tested Champagne on both simulated and real M/EEG data. The source locations used for the simulated data were chosen to test the performance on challenging source configurations. In simulations, we found that Champagne outperforms the benchmark algorithms in terms of both the accuracy of the source localizations and the correct estimation of source time courses. We also demonstrate that Champagne is more robust to correlated brain activity present in real MEG data and is able to resolve many distinct and functionally relevant brain areas with real MEG and EEG data. PMID- 22209810 TI - It's only in your head: expectancy of aversive auditory stimulation modulates stimulus-induced auditory cortical alpha desynchronization. AB - Increasing evidence underlines the functional importance of non-phase-locked cortical oscillatory rhythms. Among the different oscillations, alpha (8-12 Hz) has been shown to be modulated by anticipation or attention, suggesting a top down influence. However, most studies to date have been conducted in the visual modality and the extent to which this notion also applies to the auditory cortex is unclear. It is furthermore often difficult to dissociate bottom-up from top down contributions in cases of different stimuli (e.g., standards vs. deviants) or stimuli that are preceded by different cues. This study addresses these issues by investigating neuronal responses associated with intrinsically fluctuating perceptions of an invariant sound. Sixteen participants performed a pseudo frequency-discrimination task in which a "high-pitch" tone was followed by an aversive noise, while the "low-pitch" tone was followed by silence. The participants had to decide which tone was presented even though the stimulus was actually kept constant while pseudo-randomized feedback was given. EEG data show that auditory cortical alpha power decreased by 20% in "high-pitch" trials relative to trials in which a "low pitch" was perceived. This study shows that expectancy of aversive feedback modulates perception of sounds and these fluctuating perceptions become manifest in modulations of sound-related alpha desynchronizations. Our findings extend recent evidence in the visual and somatosensory domain that alpha oscillations represent the excitatory/inhibitory balance of sensory cortical cell assemblies, which can be tuned in a top-down manner. PMID- 22209809 TI - Differentiating BOLD and non-BOLD signals in fMRI time series using multi-echo EPI. AB - A central challenge in the fMRI based study of functional connectivity is distinguishing neuronally related signal fluctuations from the effects of motion, physiology, and other nuisance sources. Conventional techniques for removing nuisance effects include modeling of noise time courses based on external measurements followed by temporal filtering. These techniques have limited effectiveness. Previous studies have shown using multi-echo fMRI that neuronally related fluctuations are Blood Oxygen Level Dependent (BOLD) signals that can be characterized in terms of changes in R(2)* and initial signal intensity (S(0)) based on the analysis of echo-time (TE) dependence. We hypothesized that if TE dependence could be used to differentiate BOLD and non-BOLD signals, non-BOLD signal could be removed to denoise data without conventional noise modeling. To test this hypothesis, whole brain multi-echo data were acquired at 3 TEs and decomposed with Independent Components Analysis (ICA) after spatially concatenating data across space and TE. Components were analyzed for the degree to which their signal changes fit models for R(2)* and S(0) change, and summary scores were developed to characterize each component as BOLD-like or not BOLD like. These scores clearly differentiated BOLD-like "functional network" components from non BOLD-like components related to motion, pulsatility, and other nuisance effects. Using non BOLD-like component time courses as noise regressors dramatically improved seed-based correlation mapping by reducing the effects of high and low frequency non-BOLD fluctuations. A comparison with seed based correlation mapping using conventional noise regressors demonstrated the superiority of the proposed technique for both individual and group level seed based connectivity analysis, especially in mapping subcortical-cortical connectivity. The differentiation of BOLD and non-BOLD components based on TE dependence was highly robust, which allowed for the identification of BOLD-like components and the removal of non BOLD-like components to be implemented as a fully automated procedure. PMID- 22209811 TI - Quantitative measurement of cerebral physiology using respiratory-calibrated MRI. AB - Functional magnetic resonance imaging typically measures signal increases arising from changes in the transverse relaxation rate over small regions of the brain and associates these with local changes in cerebral blood flow, blood volume and oxygen metabolism. Recent developments in pulse sequences and image analysis methods have improved the specificity of the measurements by focussing on changes in blood flow or changes in blood volume alone. However, FMRI is still unable to match the physiological information obtainable from positron emission tomography (PET), which is capable of quantitative measurements of blood flow and volume, and can indirectly measure resting metabolism. The disadvantages of PET are its cost, its availability, its poor spatial resolution and its use of ionising radiation. The MRI techniques introduced here address some of these limitations and provide physiological data comparable with PET measurements. We present an 18 minute MRI protocol that produces multi-slice whole-brain coverage and yields quantitative images of resting cerebral blood flow, cerebral blood volume, oxygen extraction fraction, CMRO(2), arterial arrival time and cerebrovascular reactivity of the human brain in the absence of any specific functional task. The technique uses a combined hyperoxia and hypercapnia paradigm with a modified arterial spin labelling sequence. PMID- 22209812 TI - Reliable optical detection of coherent neuronal activity in fast oscillating networks in vitro. AB - Cognitive and behavioral functions depend on the activation of stable neuronal assemblies, i.e. distributed groups of co-active neurons within neuronal networks. It is therefore crucial to monitor distributed patterns of activity in real time with single-neuron resolution. Microelectrode recordings allow detection of coincidence between discharges of identified units at high temporal resolution, but are not able to reveal the full spatial pattern of activity in multi-cellular assemblies. Therefore, observation of such distributed sets of neurons is a stronghold of optical techniques, but the required resolution, sensitivity, and speed are still challenging current technology. Here, we report a new approach for monitoring neuronal assemblies, using memory-related network oscillations in rodent hippocampal circuits as a model. The cytosolic calcium sensitive fluorescent protein GCaMP3.NES was expressed using recombinant adeno associated viral (rAAV)-mediated gene transfer in CA3 pyramidal neurons of cultured mouse hippocampal slices. After 14-21 days in culture, field potential recordings revealed spontaneous occurrence of sharp wave-ripple network events during which a fraction of local neurons is coherently activated. Using a custom built epi-fluorescence microscope we could monitor a field of view of 410 MUm * 410 MUm with single-neuron optical resolution (20* objective, 0.4 NA). We developed a highly sensitive and specific wavelet-based method of cell identification allowing simultaneous observation of more than 150 neurons at frame rates of up to 60 Hz. Our recording configuration and image analysis provide a tool to investigate cognition-related activity patterns in the hippocampus and other circuits. PMID- 22209814 TI - The evolving landscape of human cortical connectivity: facts and inferences. AB - Human cognitive brain mapping is at a crossroads. On the one hand, it can access a rich data set of synaptic connectivity in the cerebral cortex of the monkey, an animal that lacks many of the complicated behaviors of interest. On the other hand, it is rapidly amassing an even richer data set on the functional map of the human cerebral cortex, but with relatively little hard data on underlying structural connectivity. This second point tends to be blurred in the current literature because of the multiple ways in which the term 'connection' is used in the context of the human brain. In some instances the term is used at a conceptual level, to designate a pathway that should be there if the behavior is to be performed. In other instances, it refers to the computational demonstration of a functional relationship, the structural basis of which is not necessarily known. A third usage is based on connections that are known to exist in the monkey and that are inferred to also exist in the human. The fourth and most direct usage involves connections structurally proven to exist in the human. These four usages have been invoked interchangeably to propose connectivistic mechanisms of human cognitive function. To enlarge the currently limited data set on structural connectivity is of considerable importance for conducting biologically more valid explorations of large-scale neurocognitive networks. This challenging goal will require histological laboratory investigations of the human brain to resume their former prominence and to play an increasingly more substantial role in brain mapping research. PMID- 22209813 TI - Sparse reduced-rank regression detects genetic associations with voxel-wise longitudinal phenotypes in Alzheimer's disease. AB - Scanning the entire genome in search of variants related to imaging phenotypes holds great promise in elucidating the genetic etiology of neurodegenerative disorders. Here we discuss the application of a penalized multivariate model, sparse reduced-rank regression (sRRR), for the genome-wide detection of markers associated with voxel-wise longitudinal changes in the brain caused by Alzheimer's disease (AD). Using a sample from the Alzheimer's Disease Neuroimaging Initiative database, we performed three separate studies that each compared two groups of individuals to identify genes associated with disease development and progression. For each comparison we took a two-step approach: initially, using penalized linear discriminant analysis, we identified voxels that provide an imaging signature of the disease with high classification accuracy; then we used this multivariate biomarker as a phenotype in a genome wide association study, carried out using sRRR. The genetic markers were ranked in order of importance of association to the phenotypes using a data re-sampling approach. Our findings confirmed the key role of the APOE and TOMM40 genes but also highlighted some novel potential associations with AD. PMID- 22209815 TI - The role of the subthalamic nucleus in response inhibition: evidence from local field potential recordings in the human subthalamic nucleus. AB - Response inhibition as measured during a stop-signal task refers to the ability to halt an action that has already been set in motion. Cortical and sub-cortical structures, such as the subthalamic nucleus (STN), that are active during attempts to inhibit action are thought to contribute to a 'stop-process' that must gain dominance over a 'go-process' if inhibition is to be successful. We recorded local field potential activity from the STN of Parkinson's disease patients with implanted deep brain stimulation electrodes during a stop-signal task. In particular we measured activity in the STN that has traditionally been associated with motor action (gamma-band, 60-100 Hz) and inhibition (beta-band, 10-30 Hz). Our data support the idea that beta activity in the STN is related to the inhibition of motor action. Further, we report that gamma oscillatory activity responds robustly to stop-signals as well as go-signals. This unexpected finding might suggest that gamma activity supports a go-process that not only responds to go-signals, but is also sensitive to stimuli that signal stopping. PMID- 22209816 TI - Visual search: a retrospective. AB - Visual search, a vital task for humans and animals, has also become a common and important tool for studying many topics central to active vision and cognition ranging from spatial vision, attention, and oculomotor control to memory, decision making, and rewards. While visual search often seems effortless to humans, trying to recreate human visual search abilities in machines has represented an incredible challenge for computer scientists and engineers. What are the brain computations that ensure successful search? This review article draws on efforts from various subfields and discusses the mechanisms and strategies the brain uses to optimize visual search: the psychophysical evidence, their neural correlates, and if unknown, possible loci of the neural computations. Mechanisms and strategies include use of knowledge about the target, distractor, background statistical properties, location probabilities, contextual cues, scene context, rewards, target prevalence, and also the role of saliency, center-surround organization of search templates, and eye movement plans. I provide overviews of classic and contemporary theories of covert attention and eye movements during search explaining their differences and similarities. To allow the reader to anchor some of the laboratory findings to real-world tasks, the article includes interviews with three expert searchers: a radiologist, a fisherman, and a satellite image analyst. PMID- 22209817 TI - Compliance with bloodborne pathogen standards at eight correctional facilities. AB - This study had three objectives: (a) to examine compliance with the Occupational Safety and Health Administration (OSHA) Bloodborne Pathogens (BBPs) Standard at eight correctional facilities, (b) to identify potential barriers to compliance, and (c) to discuss steps to address these barriers. Eight facilities of different sizes and locations were visited to examine employer adherence to 15 selected BBP risk reduction activities. Facility compliance was less than 50% for four activities: updating exposure control plans, implementing use of appropriate safer medical devices, soliciting employee input on selection of safer devices, and training medical staff when such devices are implemented. Inconsistent compliance may be due to difficulties in applying the standards in the correctional health care work setting. Any BBP training and health communication activities targeted to correctional health care workers should be tailored to the correctional facility setting. PMID- 22209818 TI - Exploring scope of practice issues for correctional facility nurses in Montana. AB - The research aims were to (a) explore how correctional facility nurses in Montana perceived the balance between the autonomy required in their field and their scope of practice rights, and (b) contrast the correctional nursing specialty from the more traditional nurse setting. Twenty percent of Montana correctional nurses surveyed said there are times where they simply have to work beyond their state scope of practice boundaries. Respondents were most likely to report that the greatest differences in nursing process related to assessment and interventions. Nurses emphasized their feelings of safety, noting that in this practice setting safety takes the highest priority. Participants also said that correctional nursing had a stigma compared to other specialties. PMID- 22209819 TI - Gambling addiction. PMID- 22209821 TI - Use of community treatment orders for mental health patients rises 29% in a year. PMID- 22209820 TI - Follow surgical checklists and take time out, especially in a crisis. PMID- 22209822 TI - The feminisation of nature. PMID- 22209823 TI - Cytoskeletal proteins F-actin and beta-dystrobrevin are altered by the cryopreservation process in bull sperm. AB - The cryopreservation process has an important impact on sperm structure and physiology. The negative effects have been mainly observed on the plasma membrane, which is directly stabilized by the cytoskeleton. Since cytoskeleton proteins are osmosensitive and thermosensitive, the aim of this study was to evaluate the damage caused to the bull sperm cytoskeleton by cryopreservation (freezing-thawing). Fresh and frozen-thawed bull semen samples were exposed to a treatment with the neutral detergent Brij 36-T. Electron microscopy evidenced important damages at the sperm perinuclear theca after the protein extraction protocol; the perinuclear theca was partially solubilized, the perinuclear theca substructure disappeared in the cryopreserved samples. Furthermore, the sperm head's shape was significantly altered on the cryopreserved samples. Fluorescence analysis showed a decrease of the intensity of actin and dystrobrevin on the frozen-thawed samples. Western blot assays revealed a stronger signal for actin and beta-dystrobrevin in the frozen-thawed sperm samples than in the fresh ones. Our results suggest that the cryopreservation process highly alters the sperm cytoskeleton stability, causing its proteins to become more fragile and therefore more susceptible to be extracted. PMID- 22209825 TI - Folate-associated lipoplexes mediate efficient gene delivery and potent antitumoral activity in vitro and in vivo. AB - The lack of suitable vectors for efficient nucleic acid delivery into target cells represents a major hurdle for the successful application of gene therapy. Cationic liposomes exhibit attractive features for gene delivery, but their efficacy is still unsatisfactory, particularly for in vivo applications, which justifies the drive to further improve their performance by developing novel and efficient formulations. In the present study, we generated a new formulation of lipoplexes through electrostatic association of folate (FA) to 1-palmitoyl-2 oleoyl-sn-glycero-3-ethylphosphocholine (EPOPC):cholesterol (Chol) liposomes, prepared at different lipid/DNA charge ratios, and explored their potential to mediate gene delivery. The optimal FA-lipoplex formulation was evaluated for its efficacy to mediate antitumoral activity upon application of HSV-tk suicide gene therapy, both in vitro and in an animal model of oral cancer. Our results demonstrate that FA-EPOPC:Chol/DNA lipoplexes were able to promote a great enhancement of transfection and high in vitro antitumoral activity compared to plain lipoplexes in two different cancer cell lines. Most importantly, a considerable reduction of tumor growth was achieved with the developed FA lipoplexes as compared to that observed for control FA-lipoplexes or plain lipoplexes. Overall, our study shows that FA-EPOPC:Chol/DNA lipoplexes constitute a promising system for the successful application of suicide gene therapy aiming at treating solid tumors. PMID- 22209826 TI - Novel hyperbranched polyamidoamine nanoparticle based gene delivery: transfection, cytotoxicity and in vitro evaluation. AB - In this study, hyperbranched polyamidoamine (hPAMAM) was developed as a novel non viral gene vector for the first time. The hPAMAM was synthesized using a modified "one-pot" method. DNA was then bound to hPAMAM at different weight ratios (w(hPAMAM)/w(DNA)). The higher weight ratio could bring larger particle size and higher zeta potential of hPAMAM-DNA complexes. The encapsulated DNA was protected by hPAMAM from degradation for over 3h. Under the optimal condition, high gene transfection efficiency could be achieved in COS7 (47.47 +/- 1.42%) and HEK293 (40.8 +/- 0.98%) cell lines. And hPAMAM showed rather minor cytotoxicity in vitro (cell viability=91.38 +/- 0.46% in COS7 and 92.38 +/- 0.61% in HEK293). The hPAMAM mediated human vascular endothelial growth factor 165 (hVEGF(165)) gene transfected cells could express hVEGF(165) stably for 14 days, with the peak expression at day 2. In conclusion, hPAMAM based gene delivery was economical, effective and biocompatible, and may serve as a promising non-viral vehicle for gene therapy. PMID- 22209824 TI - The bisretinoids of retinal pigment epithelium. AB - The retina exhibits an inherent autofluorescence that is imaged ophthalmoscopically as fundus autofluorescence. In clinical settings, fundus autofluorescence examination aids in the diagnosis and follow-up of many retinal disorders. Fundus autofluorescence originates from the complex mixture of bisretinoid fluorophores that are amassed by retinal pigment epithelial (RPE) cells as lipofuscin. Unlike the lipofuscin found in other cell-types, this material does not form as a result of oxidative stress. Rather, the formation is attributable to non-enzymatic reactions of vitamin A aldehyde in photoreceptor cells; transfer to RPE occurs upon phagocytosis of photoreceptor outer segments. These fluorescent pigments accumulate even in healthy photoreceptor cells and are generated as a consequence of the light capturing function of the cells. Nevertheless, the formation of this material is accelerated in some retinal disorders including recessive Stargardt disease and ELOVL4-related retinal degeneration. As such, these bisretinoid side-products are implicated in the disease processes that threaten vision. In this article, we review our current understanding of the composition of RPE lipofuscin, the structural characteristics of the various bisretinoids, their related spectroscopic features and the biosynthetic pathways by which they form. We will revisit factors known to influence the extent of the accumulation and therapeutic strategies being used to limit bisretinoid formation. Given their origin from vitamin A aldehyde, an isomer of the visual pigment chromophore, it is not surprising that the bisretinoids of retina are light sensitive molecules. Accordingly, we will discuss recent findings that implicate the photodegradation of bisretinoid in the etiology of age-related macular degeneration. PMID- 22209827 TI - Identification of a novel brain derived neurotrophic factor (BDNF)-inhibitory factor: regulation of BDNF by teneurin C-terminal associated peptide (TCAP)-1 in immortalized embryonic mouse hypothalamic cells. AB - The teneurins are a family of four large transmembrane proteins that are highly expressed in the central nervous system (CNS) where they have been implicated in development and CNS function. At the tip of the carboxyl terminus of each teneurin lies a 43-amino acid sequence, that when processed, could liberate an amidated 41-residue peptide. We have called this region the teneurin C-terminal associated peptide (TCAP). Picomolar concentrations of the synthetic version of TCAP-1 inhibit stress-induced cocaine reinstatement in rats. Because cocaine seeking is associated with increased brain derived neurotrophic factor (BDNF) in the brain, we examined whether synthetic mouse TCAP-1 has the potential to regulate BDNF expression in immortalized mouse neurons. Immortalized mouse neurons (N38; mHypoE38) show strong FITC-labeled [K(8)]-TCAP-1 uptake and BDNF labeling in the cytosol. Moreover, FITC-labeled [K(8)]-TCAP-1 bound competitively to membrane fractions. In culture, the labeled TCAP-1 peptide could be detected on cell membranes within 15 min and subsequently became internalized in the cytosol and trafficked toward the nucleus. Administration of 10(-8)M unlabeled TCAP-1 to cultures of the N38 cells resulted in a significant decrease of total cell BDNF immunoreactivity over 4h as determined by western blot and ELISA analyses. Real-time PCR, utilizing primers to the various BDNF transcripts showed a significant decline of promoter IIB- and VI-driven transcripts. Taken together, these studies indicated that in vitro, TCAP-1 induces a significant decline in BDNF transcription and protein labeling in embyronic mouse immortalized hypothalamic neurons. Thus, TCAP-1 may act as a novel BDNF inhibitory factor. PMID- 22209828 TI - Activation of corticotropin releasing factor receptor type 2 in the heart by corticotropin releasing factor offers cytoprotection against ischemic injury via PKA and PKC dependent signaling. AB - Corticotrophin-releasing factor receptor 2beta (CRFR2beta) is expressed in the myocardium. In the present study we explore whether acute treatment with the neuropeptide corticotrophin-releasing factor (CRF) could induce cytoprotection against a lethal ischemic insult in the heart (isolated murine neonatal cardiac myocytes and the isolated Langendorff perfused rat heart) by activating CRFR2. In vitro, CRF offered cytoprotection when added prior to lethal simulated ischemic stress by reducing apoptotic and necrotic cell death. Ex vivo, CRF significantly reduced infarct size from 52.1+/-3.1% in control hearts to 35.3+/-3.1% (P<0.001) when administered prior to a lethal ischemic insult. The CRF peptide did not confer cytoprotection when administered at the point of hypoxic reoxygenation or ischemic reperfusion. The acute effects of CRF treatment are mediated by CRF receptor type 2 (CRFR2) since the cardioprotection ex vivo was inhibited by the CRFR2 antagonist astressin-2B. Inhibition of the mitogen activated protein kinase ERK1/2 by PD98059 failed to inhibit the effect of CRF. However, both protein kinase A and protein kinase C inhibitors abrogated CRF-mediated protection both ex vivo and in vitro. These data suggest that the CRF peptide reduces both apoptotic and necrotic cell death in cardiac myocytes subjected to lethal ischemic induced stress through activation of PKA and PKC dependent signaling pathways downstream of CRFR2. PMID- 22209829 TI - CONSORT-EHEALTH: improving and standardizing evaluation reports of Web-based and mobile health interventions. AB - BACKGROUND: Web-based and mobile health interventions (also called "Internet interventions" or "ehealth/mhealth interventions") are tools or treatments, typically behaviorally based, that are operationalized and transformed for delivery via the Internet or mobile platforms. These include electronic tools for patients, informal caregivers, healthy consumers, and health care providers. The "Consolidated Standards of Reporting Trials" (CONSORT) was developed to improve the suboptimal reporting of randomized controlled trials (RCTs). While broadly the CONSORT statement can be applied to provide guidance on how ehealth and mhealth trials should be reported, RCTs of web-based interventions pose very specific issues and challenges, in particular related to reporting sufficient details of the intervention to allow replication and theory-building. OBJECTIVE: To develop a checklist, dubbed CONSORT-EHEALTH (Consolidated Standards of Reporting Trials of Electronic and Mobile HEalth Applications and onLine TeleHealth), as an extension of the CONSORT statement that provides guidance for authors of ehealth and mhealth interventions. METHODS: A literature review was conducted, followed by a survey among ehealth experts and a workshop. RESULTS: An instrument and checklist was constructed as an extension of the CONSORT statement. The instrument has been adopted by the Journal of Medical Internet Research (JMIR) and authors of ehealth RCTs are required to submit an electronic checklist explaining how they addressed each subitem. CONCLUSIONS: CONSORT EHEALTH has the potential to improve reporting and provides a basis for evaluating the validity and applicability of ehealth trials. Subitems describing how the intervention should be reported can also be used for non-RCT evaluation reports. As part of the development process, an evaluation component is essential, therefore feedback from authors will be solicited, and a before-after study will evaluate whether reporting has been improved. PMID- 22209830 TI - Bmi-1 induces radioresistance in MCF-7 mammary carcinoma cells. AB - Bmi-1, a member of the polycomb family, it is involved in self renewal of stem cells and functions as an oncogene in many malignant human cancer types. Recent studies have demonstrated that Bmi-1 is a predictive factor for poor patient prognosis. However, the underlying mechanisms of radioresistance mediated by Bmi 1 are poorly understood. In this study, the dose-survival relationship was analyzed using a clonogenic survival assay and combined radiation treatment with Bmi-1 overexpression or silencing. DNA double-strand break (DSB) and repair was assessed by immunofluorescence staining of gammaH2AX foci. In addition, mitochondrial membrane potential was detected between Bmi-1 knockdown and control MCF-7 cells after irradiation. Apoptosis and cell cycle were evaluated by flow cytometry. We found that exposure of MCF-7 cells overexpressing Bmi-1 to ionizing radiation resulted in dramatically enhanced survival relative to control cells, whereas cells with silenced Bmi-1 showed markedly reduced survival. Bmi-1 inhibition significantly increased DSBs and decreased DSB repair. Furthermore, Bmi-1 knockdown induced loss of mitochondrial membrane potential and enhanced apoptosis by up-regulating p53, p21, Bax expression and down-regulating p-AKT and Bcl-2 expression. These results indicate that Bmi-1 may play an important role in radiosensitivity, and the suppression of its expression might be a potential therapeutic target for breast cancer. PMID- 22209831 TI - Ultrasound to confirm gastric tube placement in prehospital management. AB - BACKGROUND: In emergency medicine, the gastric tube (GT) has many purposes, however in prehospital settings, the only indication is gastric decompression. To date, there is lack of recommendation on the diagnostic methods to verify correct GT placement in prehospital. The aim of this study is to estimate diagnostic accuracy of ultrasound in confirming gastric tubes placement in a prehospital setting. METHOD: This was a prospective multicentre study conducted in two French towns (Marseille and Grasse) over a one-year period from May 2010 to May 2011. RESULTS: One hundred and thirty patients were included in the study with an M/F sex ratio of 77/53 and a mean age of 55.7+/-19.8 years. The GT position was confirmed by ultrasound, with direct visualization in the gastric area in 116 of the 130 patients. In 14 cases, the ultrasound failed to visualize the tip of the GT; these results were due in 2 cases to gas interposition and in 12 cases the GT was shown by final X-ray to be located in the end of the oesophagus. Direct visualization by ultrasound thus has a sensitivity of 98.3% [94-99.5] and a specificity of 100% [75.7-100], a positive predictive value of 100% and a negative predictive value of 85.7%, Youden's index of 0.98. GT size affects ultrasound visualization; the larger the GT, the easier it is to see. CONCLUSION: Bedside ultrasound thus appears to constitute an effective and reliable diagnostic procedure for confirming correct gastric tube placement in prehospital settings. PMID- 22209832 TI - Novel adhesive glove device (AGD) for active compression-decompression (ACD) CPR results in improved carotid blood flow and coronary perfusion pressure in piglet model of cardiac arrest. AB - OBJECTIVE: ACD-CPR improves coronary and cerebral perfusion. We developed an adhesive glove device (AGD) and hypothesized that ACD-CPR using an AGD provides better chest decompression resulting in improved carotid blood flow as compared to standard (S)-CPR. DESIGN: Prospective, randomized and controlled animal study. METHODS: Sixteen anesthetized and ventilated piglets were randomized after 3 min of untreated VF to receive either S-CPR or AGD-ACD-CPR by a PALS certified single rescuer with compressions of 100 min(-1) and C:V ratio of 30:2. AGD consisted of a modified leather glove exposing the fingers and thumb. A wide Velcro patch was sewn to the palmer aspect of the glove and the counter Velcro patch was adhered to the pig's chest wall. Carotid blood flow was measured using ultrasound. Data (mean+/-SD) was analyzed using one way ANOVA and unpaired t-test; p-value <= 0.05 was considered statistically significant. RESULTS: Right atrial pressure (mmHg) during the decompression phase was lower during AGD-ACD-CPR (-3.32+/-2.0) when compared to S-CPR (0.86+/-1.8, p=0.0007). Mean carotid blood flow was 53.2+/-27.1 (% of baseline blood flow in ml/min) in AGD vs. 19.1+/-12.5% in S-CPR, p=0.006. Coronary perfusion pressure (CPP, mmHg) was 29.9+/-5.8 in AGD vs. 22.7+/-6.9 in S CPR, p=0.04. There was no significant difference in time to ROSC and number of epinephrine doses. CONCLUSION: Active chest decompression during CPR using this simple and inexpensive adhesive glove device resulted in significantly better carotid blood flow during the first 2 min of CPR. PMID- 22209833 TI - Does appropriate treatment of the primary underlying cause of PEA during resuscitation improve patients' survival? AB - AIM OF THE STUDY: We aimed to document how often patients received appropriate treatment of the primary cause underlying pulseless electrical activity (PEA) during cardiopulmonary resuscitation (CPR) and how it affected their outcome. METHODS: Data were collected between 2003 and 2010 in Finland and Sweden. All adult patients who underwent in-hospital cardiac arrest (IHCA) with PEA as the initial rhythm were included, if CPR was attempted. Patients were divided into two groups: those who received appropriate treatment of the primary cause during CPR (treatment of the primary cause group) and those who received conventional CPR (non-specific treatment group). Survival between groups was compared and a multivariable logistic regression analysis was performed to exclude the effect of possible confounders. RESULTS: Of 104 study patients, 19 (18%) received treatment of the primary cause and 85 (82%) received non-specific treatment. 30-Days survival of patients in treatment of primary cause group was superior compared to patients in the non-specific treatment group: 6 (32%) vs. 9 (11%) were alive 30 days after IHCA, p=0.03. Multivariable analysis suggested that treatment of the primary cause improves the odds of survival 2.5-fold, but this was not statistically significant. Age was the only significant independent prognostic factor for 30-days survival. CONCLUSION: During CPR, only a fifth of patients received appropriate treatment of the primary cause underlying PEA. Those patients were more likely to be alive 30 days after IHCA, but age turned out to be the only significant individual factor for better survival. PMID- 22209834 TI - Timing and teamwork--an observational pilot study of patients referred to a Rapid Response Team with the aim of identifying factors amenable to re-design of a Rapid Response System. AB - BACKGROUND: Rapid Response Teams aim to accelerate recognition and treatment of acutely unwell patients. Delays in delivery might undermine efficiency of the intervention. Our understanding of the causes of these delays is, as yet, incomplete. AIM: To identify modifiable causes of delays in the treatment of critically ill patients outside intensive care with a focus on factors amenable to system design. METHODS: Review of care records and direct observation with process mapping of care delivered to 17 acutely unwell patients attended by a Rapid Response Team in a District General Hospital in the United Kingdom. Delays were defined as processes with no added value for patient care. RESULTS: Essential diagnostic and therapeutic procedures accounted for only 31% of time of care processes. Causes for delays could be classified into themes as (1) delays in call-out of the Rapid Response Team, (2) problems with team cohesion including poor communication and team efficiency and (3) lack of resources including lack of first line antibiotics, essential equipment, experienced staff and critical care beds. CONCLUSION: We identified a number of potentially modifiable causes for delays in care of acutely ill patients. Improved process design could include automated call-outs, a dedicated kit for emergency treatment in relevant clinical areas, increased usage of standard operating procedures and staff training using crew resource management techniques. PMID- 22209835 TI - Overexpression of hepatitis B x-interacting protein in HepG2 cells enhances tumor induced angiogenesis. AB - Hepatocellular carcinoma (HCC) is a common malignancy and a leading cause of cancer death worldwide. Hepatitis B x-interacting protein (HBXIP), a cofactor of survivin, was originally identified by binding with the C-terminus of the HBx and negatively regulated the activity of HBx. In this study, the effect of HBXIP on the hepatoma cells-induced angiogenesis was investigated. Proliferation and migration of human umbilical vein endothelial cells (HUVECs) were detected by MTT and transwell assay, respectively. Tube formation and chick chorioallantoic membrane model were used to observe the angiogenesis. Vascular endothelial growth factor activity was assayed using ELISA kits. Western blotting was performed to examine the protein expression. Our results indicated that overexpression of HBXIP increased HepG2 cell-induced endothelial cells migration, proliferation, and angiogenesis, which may be related to increasing phosphorylation of endothelial NO synthase in HUVECs. These results suggest that HBXIP may play an important role in tumorigenesis by enhancing angiogenesis in HCC. PMID- 22209836 TI - Autoepistemic limitation and the brain's neural code: Comment on "Neuroontology, neurobiological naturalism, and consciousness: a challenge to scientific reduction and a solution" by Todd E. Feinberg. PMID- 22209837 TI - Ontology requires epistemological considerations: Comment on "Neuroontology, neurobiological naturalism, and consciousness: a challenge to scientific reduction and a solution" by Todd E. Feinberg. PMID- 22209838 TI - Kick-starting the origin of life: Comment on "Formamide and the origin of life" by R. Saladino, C. Crestini, S. Pino, G. Costanzo and E. Di Mauro. PMID- 22209839 TI - Distinctive microRNA signature is associated with the diagnosis and prognosis of acute leukemia. AB - MicroRNAs (miRNAs) are of great importance in pathogenesis, diagnosis and prognosis of acute leukemia (AL). We studied five AL-related miRNAs to confirm the significance of these miRNAs in AL. Samples tested included acute myeloid leukemia (AML), 107 cases; acute lymphoblastic leukemia (ALL), 40 cases. Five AL related miRNAs: miR-128, let-7b, miR-223, miR-181a and miR-155 expression were detected by qRT-PCR. Analysis showed that miRNA-128 expression was significantly higher in ALL (P<0.001). However, the let-7b and miR-223 expressions in ALL were significantly lower than in AML (P<0.001). Compared with normal controls, miR-128 expression was significantly higher in ALL (P<0.001), but there was no significant difference in AML (P=0.900). The expressions of Let-7b and miR-223 in AL group were higher than in normal controls (P<0.001). MiR-181a was quantitatively detected in 107 AML patients, and we found that the expression of miR181a in M1 or M2 patients was significantly higher compared with it in M4 or M5 (P=0.013). According to karyotype, 84 cases of AML were classified into three groups named favorable, moderate and poor. It was found that the expression of miR-181a in favorable prognosis group was significantly lower than in poor prognosis group (P=0.015). In FLT3-ITD mutation positive patients, the miR-155 expression was significantly higher than in the negative group (P=0.002). These results support that miR-128, let-7b, miR-223 and miR181a have a diagnosis value in AL, while miR-181a and miR-155 are of great prognostic significance in AML. PMID- 22209840 TI - A new dic(7;12)(p12.21;p12.2) and i(12)(q10) during the lymphoid blast crisis of patient with Ph+ chronic myeloid leukemia. AB - Chronic myelogenous leukemia (CML) is a common myeloproliferative disease that is characterized by the clonal expansion of marrow stem cells, and is associated with the Philadelphia chromosome. As the disease progresses, additional chromosome abnormalities may arise. The prognostic impact of secondary chromosomal abnormalities in CML is complex, heterogeneous, and sometimes related to previous treatment. Here, we describe a CML patient in lymphoid blast crisis associated with a new chromosomal abnormality identified, dic(7;12)(p12.21;p12.2) and i(12)(q10) using classical cytogenetics and spectral karyotype analysis. To the best of our knowledge, this is the first report of t(7;12)(p11.1;q11.1) and i(12)(q10) in a CML patient with lymphoid evolution. PMID- 22209841 TI - Prolonged activity of bevacizumab in adenocarcinoma of the lung with multiple brain metastases. AB - Patients with lung cancer having multiple brain metastases have poor outcomes. We present long-term disease treatment in a 60-year-old woman having greater than thirty brain metastases of NSCLC adenocarcinoma with a mutant allele of EGFR treated with differing chemotherapies including erlotinib, but disease response in the brain only with bevacizumab. Although initially restricted in use, increasing clinical reports have demonstrated safety of bevacizumab use in brain involved cancer patients. Our case highlights that disease response to bevacizumab is similar in the brain to systemic disease and likely overcomes anatomical barriers that can limit other therapeutic agents. PMID- 22209842 TI - Bevacizumab in combination with irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) in patients with metastatic colorectal cancer who were previously treated with oxaliplatin-containing regimens: a multicenter observational cohort study (TCTG 2nd-BV study). AB - The efficacy of bevacizumab combined with infusional 5-fluorouracil/leucovorin (5 FU/LV) plus irinotecan (FOLFIRI) as the second-line treatment for metastatic colorectal cancer (mCRC) has not been fully clarified, although bevacizumab combined with infusional 5-FU/LV plus oxaliplatin (FOLFOX) in the second-line setting has demonstrated a survival benefit. We investigated the efficacy of bevacizumab plus FOLFIRI in mCRC patients who failed oxaliplatin-containing regimens without bevacizumab. Patients who received bevacizumab plus FOLFIRI or bevacizumab plus FOLFOX as second-line chemotherapy between July 2007 and March 2008 were registered (trial registration: UMIN000001547). Patient background data and progression-free survival (PFS), overall survival (OS), response, and bevacizumab-related adverse events were prospectively collected every 6 months. A total of 195 patients were enrolled from 26 institutions. Among them, 115 patients received bevacizumab plus FOLFIRI after failure of oxaliplatin and fluoropyrimidine (FOLFIRI+BV after OX/FU group), and 45 patients received bevacizumab plus FOLFOX after failure of irinotecan and fluoropyrimidine (FOLFOX+BV after IRI/FU group). Median PFS was 8.3 months (95% confidence interval [CI], 6.7-9.9) for the FOLFIRI+BV after OX/FU group and 7.8 months (95% CI, 5.8-9.7) for the FOLFOX+BV after IRI/FU group. Median OS was 21.6 months (95% CI, 17.6-25.6) and 16.5 months (95% CI, 11.8-21.2), respectively. Overall response rates were 25 and 29%, respectively. The most common grade>=3 bevacizumab-related adverse events were hypertension (5.0%) and bleeding (3.8%). FOLFIRI+BV after OX/FU showed comparable efficacy to FOLFOX+BV after IRI/FU. PMID- 22209843 TI - Bone morphogenetic protein (BMP)-4 and BMP-7 suppress granulosa cell apoptosis via different pathways: BMP-4 via PI3K/PDK-1/Akt and BMP-7 via PI3K/PDK-1/PKC. AB - BMP-4 and BMP-7 are associated with the suppression of granulosa cell apoptosis. LY294002 (PI3K inhibitor) or UCN-01 (PDK-1 inhibitor) increased the percentage of apoptotic cells in the granulosa cells treated with BMP-4 or BMP-7. The inhibitors of ERK and p38 (SB203580) did not increase the percentage of apoptotic cells in the granulosa cells treated with BMP-4 or BMP-7. Akt inhibitor did not induce apoptosis in the BMP-4-treated granulosa cells, whereas it did induce apoptosis of the BMP-7-treated granulosa cells. In the granulosa cells treated with BMP-4, the PKC inhibitor increased the percentage of apoptotic cells. Our data show that BMP-4 and BMP-7 are associated with granulosa cell survival via several non-Smad specific pathways: BMP-4 via the PI3K/PDK-1/PKC and BMP-7 via the PI3K/PDK-1/Akt. PMID- 22209844 TI - CCL3 induced migration occurs independently of intracellular calcium release. AB - The molecular signalling pathway of cell migration and whether it can occur independently of the release of intracellular calcium is still not completely understood. Therefore we investigated here the molecular mechanisms of CCL3 induced cell migration and the importance of intracellular calcium for chemotaxis in more detail. We show that CCL3 induced cell migration is dependent on activation of PLC. Several PKC inhibitors block the release of intracellular calcium independently of CCL3 activation and do not affect cell migration. This confirms that the release of intracellular calcium is not necessary for chemotaxis towards CCL3 and that PKC inhibitors should be used with caution in calcium release assays. PMID- 22209845 TI - Stepwise renal lineage differentiation of mouse embryonic stem cells tracing in vivo development. AB - The in vitro derivation of renal lineage progenitor cells is essential for renal cell therapy and regeneration. Despite extensive studies in the past, a protocol for renal lineage induction from embryonic stem cells remains unestablished. In this study, we aimed to induce renal lineages from mouse embryonic stem cells (mESC) by following in vivo developmental stages, i.e., the induction of mesoderm (Stage I), intermediate mesoderm (Stage II) and renal lineages (Stage III). For stage I induction, in accordance with known signaling pathways involved in mesoderm development in vivo, i.e., Nodal, bone morphogenic proteins (BMPs) and Wnt, we found that the sequential addition of three factors, i.e., Activin-A (A), a surrogate for Nodal signaling, during days 0-2, A plus BMP-4 (4) during days 2 4, and A4 plus lithium (L), a surrogate for Wnt signaling, during days 4-6, was most effective to induce the mesodermal marker, Brachyury. For stage II induction, the addition of retinoic acid (R) in the continuous presence of A4L during days 6-8 was most effective to induce nephrogenic intermediate mesodermal markers, such as Pax2 and Lim1. Under this condition, more than 30% of cells were stained positive for Pax2, and there was a concomitant decrease in the expression of non-mesodermal markers. For stage III induction, in resemblance to the reciprocal induction between ureteric bud (UB) and metanephric mesenchyme (MM) during kidney development, we found that the exposure to conditioned media derived from UB and MM cells was effective in inducing MM and UB markers, respectively. We also observed the emergence and gradual increase of cell populations expressing progenitor cell marker CD24 from Stage I to Stage III. These CD24(+) cells correlated with higher levels of expression of Brachyury at stage I, Pax2 and Lim1 at stage II and MM markers, such as WT1 and Cadherin 11, after exposure to UB-conditioned media at stage III. In conclusion, our results show that stepwise induction by tracing in vivo developmental stages was effective to generate renal lineage progenitor cells from mESC, and CD24 may serve as a useful surface marker for renal lineage cells at stage II and MM cells at stage III. PMID- 22209846 TI - Capsicum annuum basic transcription factor 3 (CaBtf3) regulates transcription of pathogenesis-related genes during hypersensitive response upon Tobacco mosaic virus infection. AB - Hypersensitive response (HR) cell death upon plant virus infection is an excellent plant strategy for inhibiting viral movement and obtaining systemic acquired resistance (SAR) against further infection. Various host factors are involved in these HR processes, either directly as viral resistance proteins or indirectly. We characterized a gene encoding the CaBtf3 [beta-nascent polypeptide associated complex (NAC) subunit] of NAC from the hot pepper plant. NAC contacts nascent polypeptides to prevent aggregation and degradation of newly synthesized proteins by controlling cotranslational protein folding. CaBtf3 protein fused to green fluorescent protein predominantly localized to the nucleus. Silencing phenotype of CaBtf3 upon the Tobacco mosaic virus (TMV)-P(0) inoculation exhibited reduced HR cell death and decreased expression of some HR-associated genes, but increased TMV coat protein levels compared with TRV2 control plants. Furthermore, silencing of NbBtf3, a highly homologous gene of CaBtf3, also led to the reduced Bax- and Pto-mediated cell death. The results indicate that CaBtf3 might be involved in HR cell death and could function as a transcription factor in the nucleus by transcriptional regulation of HR-related gene expression. PMID- 22209847 TI - Modulation of matrix mineralization by Vwc2-like protein and its novel splicing isoforms. AB - In search of new cysteine knot protein (CKP) family members, we found a novel gene called von Willebrand factor C domain-containing protein 2-like (Vwc2l, also known as Brorin-like) and its transcript variants (Vwc2l-1, Vwc2l-2 and Vwc2l-3). Based on the deduced amino acid sequence, Vwc2l-1 has a signal peptide and 2 cysteine-rich (CR) domains, while Vwc2l-2 lacks a part of 2nd CR domain and Vwc2l 3 both CR domains. Although it has been reported that the expression of Brorin like was predominantly observed in brain, we found that Vwc2l transcript variants were detected in more ubiquitous tissues. In osteoblasts, the induction of Vwc2l expression was observed at matrix mineralization stage. When Vwc2l was stably transfected into osteoblasts, the matrix mineralization was markedly accelerated in Vwc2l-expressing clones compared to that in the control, indicating the modulatory effect of Vwc2l protein on osteoblastic cell function. The mechanistic insight of Vwc2l-modulation was further investigated and we found that the expression of Osterix, one of the key osteogenic markers, was significantly increased by addition of all Vwc2l isoform proteins. Taken together, Vwc2l is a novel secreted protein that promotes matrix mineralization by modulating Osterix expression likely through TGF-beta superfamily growth factor signaling pathway. Our data may provide mechanistic insights into the biological functions of this novel CKP member in bone and further suggest a novel approach to enhance osteoblast function, which enables to accerelate bone formation, regeneration and healing. PMID- 22209848 TI - WRNIP1 accumulates at laser light irradiated sites rapidly via its ubiquitin binding zinc finger domain and independently from its ATPase domain. AB - WRNIP1 (Werner helicase-interacting protein 1) was originally identified as a protein that interacts with the Werner syndrome responsible gene product. WRNIP1 contains a ubiquitin-binding zinc-finger (UBZ) domain in the N-terminal region and two leucine zipper motifs in the C-terminal region. In addition, it possesses an ATPase domain in the middle of the molecule and the lysine residues serving as ubiquitin acceptors in the entire of the molecule. Here, we report that WRNIP1 accumulates in laser light irradiated sites very rapidly via its ubiquitin binding zinc finger domain, which is known to bind polyubiquitin and to be involved in ubiquitination of WRNIP1 itself. The accumulation of WRNIP1 in laser light irradiated sites also required the C-terminal region containing two leucine zippers, which is reportedly involved in the oligomerization of WRNIP1. Mutated WRNIP1 with a deleted ATPase domain or with mutations in lysine residues, which serve as ubiquitin acceptors, accumulated in laser light irradiated sites, suggesting that the ATPase domain of WRNIP1 and ubiquitination of WRNIP1 are dispensable for the accumulation. PMID- 22209849 TI - Diospyrin derivative, an anticancer quinonoid, regulates apoptosis at endoplasmic reticulum as well as mitochondria by modulating cytosolic calcium in human breast carcinoma cells. AB - Diospyrin diethylether (D7), a bisnaphthoquinonoid derivative, exhibited an oxidative stress-dependent apoptosis in several human cancer cells and tumor models. The present study was aimed at evaluation of the increase in cytosolic calcium [Ca(2+)](c) leading to the apoptotic cell death triggered by D7 in MCF7 human breast carcinoma cells. A phosphotidylcholine-specific phospholipase C (PC PLC) inhibitor, viz. U73122, and an antioxidant, viz. N-acetylcysteine, could significantly prevent the D7-induced rise in [Ca(2+)](c) and PC-PLC activity. Using an endoplasmic reticulum (ER)-Ca(2+) mobilizer (thapsigargin) and an ER IP3R antagonist (heparin), results revealed ER as a major source of [Ca(2+)](c) which led to the activation of calpain and caspase12, and cleavage of fodrin. These effects including apoptosis were significantly inhibited by the pretreatment of Bapta-AM (a cell permeable Ca(2+)-specific chelator), or calpeptin (a calpain inhibitor). Furthermore, D7-induced [Ca(2+)](c) was found to alter mitochondrial membrane potential and induce cytochrome c release, which was inhibited by either Bapta-AM or ruthenium red (an inhibitor of mitochondrial Ca(2+) uniporter). Thus, these results provided a deeper insight into the D7 induced redox signaling which eventually integrated the calcium-dependent calpain/caspase12 activation and mitochondrial alterations to accentuate the induction of apoptotic cell death. PMID- 22209850 TI - Critical importance of the de novo pyrimidine biosynthesis pathway for Trypanosoma cruzi growth in the mammalian host cell cytoplasm. AB - The intracellular parasitic protist Trypanosoma cruzi is the causative agent of Chagas disease in Latin America. In general, pyrimidine nucleotides are supplied by both de novo biosynthesis and salvage pathways. While epimastigotes-an insect form-possess both activities, amastigotes-an intracellular replicating form of T. cruzi-are unable to mediate the uptake of pyrimidine. However, the requirement of de novo pyrimidine biosynthesis for parasite growth and survival has not yet been elucidated. Carbamoyl-phosphate synthetase II (CPSII) is the first and rate limiting enzyme of the de novo biosynthetic pathway, and increased CPSII activity is associated with the rapid proliferation of tumor cells. In the present study, we showed that disruption of the T. cruzi cpsII gene significantly reduced parasite growth. In particular, the growth of amastigotes lacking the cpsII gene was severely suppressed. Thus, the de novo pyrimidine pathway is important for proliferation of T. cruzi in the host cell cytoplasm and represents a promising target for chemotherapy against Chagas disease. PMID- 22209851 TI - Lipopolysaccharide affects exploratory behaviors toward novel objects by impairing cognition and/or motivation in mice: Possible role of activation of the central amygdala. AB - Lipopolysaccharide (LPS) produces a series of systemic and psychiatric changes called sickness behavior. In the present study, we characterized the LPS-induced decrease in novel object exploratory behaviors in BALB/c mice. As already reported, LPS (0.3-5 MUg/mouse) induced dose- and time-dependent decreases in locomotor activity, food intake, social interaction, and exploration for novel objects, and an increase in immobility in the forced-swim test. Although the decrease in locomotor activity was ameliorated by 10h postinjection, novel object exploratory behaviors remained decreased at 24h and were observed even with the lowest dose of LPS. In an object exploration test, LPS shortened object exploration time but did not affect moving time or the frequency of object exploration. Although pre-exposure to the same object markedly decreased the duration of exploration and LPS did not change this reduction, LPS significantly impaired the exploration of a novel object that replaced the familiar one. LPS did not affect anxiety-like behaviors in open-field and elevated plus-maze tests. An LPS-induced increase in the number of c-Fos-immunoreactive cells was observed in several brain regions within 6h of LPS administration, but the number of cells quickly returned to control levels, except in the central amygdala where the increase continued for 24h. These results suggest that LPS most prominently affects object exploratory behaviors by impairing cognition and/or motivation including continuous attention and curiosity toward objects, and that this may be associated with activation of brain nuclei such as the central amygdala. PMID- 22209852 TI - Interactive effects of a protein kinase AII inhibitor and testosterone on spatial learning in the Morris water maze. AB - Neurohormones such as testosterone (TE) are important in modulation of learning and memory. In the present study, we investigated the interactive effects of pre training bilateral intra-hippocampal infusions of testosterone and H-89, a selective PKAII inhibitor, on spatial acquisition in the Morris water maze (MWM). Different doses of TE (20, 40 and 80 MUg/side) and H-89 (5 and 10 MUM/side) were administered 30 min before start of the training each day. Control animals received bilateral intra-hippocampal infusions of DMSO as vehicle for TE and H 89. Animals were trained for 4 days and each day included one block of four trials. The results of this study showed that bilateral infusion of TE (40 and 80 MUg/side) or H-89 (10 MUM/side) impaired spatial learning as indicated by significant increases in escape latency and traveled distance compared to the control group. Although pre-training bilateral infusions of a low concentration of either TE (20 MUg/side) or H-89 (5 MUM/side) into the CA1 region of the hippocampus did not affect learning capabilities, but the combination of the low doses of the drugs led to significant deficits in spatial acquisition. Overall, our data suggest that spatial acquisition was affected by PKAII inhibition or TE administration. Moreover, when co-administered, these drugs had a negative synergistic impact on acquisition. PMID- 22209854 TI - Oscillatory power and synchrony in the rat forebrain are altered by a sensitizing regime of D-amphetamine. AB - Repeated injections of psychostimulants, such as D-amphetamine (D-AMPH), provide a well-validated model of progressive cellular and systems-level alterations in brain function and behavior associated with addiction. The present study employed quantitative measures of both power spectral density and synchrony from local field potentials (LFPs) recorded simultaneously from the prefrontal cortex (PFC), parietal cortex (PAR), and hippocampus (HPC) in awake, behaving rats to assess changes in oscillations during different stages of D-AMPH-induced sensitization. The induction and development of sensitization altered the power of multiple frequency bands in a brain region-specific manner, whereas no changes were observed in animals treated with chronic saline. Specifically, the induction of sensitization to D-AMPH was accompanied by alterations in delta (2-5 Hz) and theta (5-11 Hz) oscillations similar to those observed in EEG recordings from addicted individuals describing craving and hedonic experience of the drug. Sensitization was also related to increased theta coherence between the PFC and HPC, along with suppression of cross-frequency correlations between theta and fast-gamma (65-100 Hz) in both the HPC and the PFC. Collectively, the present findings indicated the induction of a state in which the timing and synchronizing effects of oscillations are altered by sensitization to D-AMPH and are especially pronounced in the PFC. Furthermore, numerous LFP-derived measures were characterized that may serve as objective physiological correlates of pathological states observed in addiction. PMID- 22209853 TI - Intra-amygdala inhibition of ERK(1/2) potentiates the discriminative stimulus effects of alcohol. AB - Extracellular signal-regulated kinase (ERK(1/2)) has been implicated in modulating drug seeking behavior and is a target of alcohol and other drugs of abuse. Given that the discriminative stimulus (subjective/interoceptive) effects of drugs are determinants of abuse liability and can influence drug seeking behavior, we examined the role of ERK(1/2) in modulating the discriminative stimulus effects of alcohol. Using drug discrimination procedures, rats were trained to discriminate a moderate intragastric (IG) alcohol dose (1g/kg) versus water (IG). Following an alcohol (1g/kg) discrimination session phosphorylated ERK(1/2) (pERK(1/2)) immunoreactivity (IR) was significantly elevated in the amygdala, but not the nucleus accumbens. Therefore, we hypothesized that intra amygdala inhibition of ERK(1/2) would disrupt expression of the discriminative stimulus effects of alcohol. However, intra-amygdala or accumbens administration of the MEK/ERK(1/2) inhibitor U0126 (1 and 3MUg) had no effect on the discriminative stimulus effects of the training dose of alcohol (1g/kg). Contrary to our hypothesis, intra-amygdala infusion of U0126 (3MUg) potentiated the discriminative stimulus effects of a low alcohol dose (0.5g/kg) and had no effect following nucleus accumbens infusion. Importantly, site-specific inhibition of pERK(1/2) in each brain region was confirmed. Therefore, the increase in pERK(1/2) IR in the amygdala following systemic alcohol administration may be reflective of the widespread effects of alcohol on the brain (activation/inhibition of brain circuits), whereas the site specific microinjection studies confirmed functional involvement of intra-amygdala ERK(1/2). These findings show that activity of the ERK signaling pathway in the amygdala can influence the discriminative stimulus effects of alcohol. PMID- 22209855 TI - Pilocarpine-induced status epilepticus and subsequent spontaneous seizures: lack of effect on the number of gonadotropin-releasing hormone-positive neurons in a mouse model of temporal lobe epilepsy. AB - Women with temporal lobe epilepsy have a higher incidence of reproductive disorders, which have been linked to alterations in the pulsatile release of gonadotropin-releasing hormone (GnRH). These experiments tested the hypothesis that the number of GnRH neurons is reduced in an animal model of temporal lobe epilepsy. The effects of pilocarpine-induced status epilepticus (SE) and the subsequent spontaneous recurrent eizures on the number of GnRH-positive neurons were studied in adult female mice. Systemic injections of pilocarpine were used to induce SE, and diazepam was administered 90 min after the first seizure. Control mice received all drugs except pilocarpine. The mice were euthanized either 1 week or 3 months after SE (i.e. after spontaneous recurrent seizures were observed). Even though the estrous cycle was disrupted after SE, and hippocampal damage was detected in both the CA1 and CA3 regions, pilocarpine treated mice did not show a significant decrease in total or regional numbers of GnRH-immunopositive neurons. Therefore, these data do not support the hypothesis that a reduction in the number of GnRH neurons is responsible for the disruption of the estrous cycle after pilocarpine-induced epilepsy, which suggests that other mechanisms contribute to female reproductive disorders associated with chronic epilepsy. PMID- 22209856 TI - Inhibition of rapamycin-induced autophagy causes necrotic cell death associated with Bax/Bad mitochondrial translocation. AB - Rapamycin, a lipophilic macrolide antibiotic, has been found to reduce injury in different models of neurodegenerative disorders. We have previously shown that in neonatal rats subjected to hypoxia-ischemia (HI) the neuroprotective effect of rapamycin was associated with increased autophagy and decreased caspase-3 activation. We show here that the strong reduction of caspase-3 activation after rapamycin was due, at least in part, to its effect on the intrinsic apoptotic mitochondrial pathway because after rapamycin treatment there was a marked reduction of Bax and Bad translocation to mitochondria, cytochrome c release, and caspase-3 activation. Poly (ADP-ribose) polymerase 1 (PARP-1) cleavage and the number of terminal dUDP nick-end labeling (TUNEL)-positive cells were also reduced. To assess how the antiapoptotic effect of rapamycin was linked to the strong autophagy signal induced by the drug, we blocked the formation of autophagosomes with 3-methyladenine (3MA). 3MA administered 10 min after rapamycin, elicited again Bax and Bad translocation to the mitochondria but did not cause cytochrome c release and caspase-3 activation. After 3MA treatment, cells underwent necrotic cell death. These data indicate that rapamycin administered before HI prevents the apoptotic signaling taking place through the mitochondrial pathway. We hypothesize that rapamycin confers a preconditioning like protection and suggest that caution is necessary before using pharmacological agents targeting autophagy in neuroprotection because they could interfere with endogenous protective mechanisms. PMID- 22209857 TI - Giant taro and its relatives: a phylogeny of the large genus Alocasia (Araceae) sheds light on Miocene floristic exchange in the Malesian region. AB - Alocasia comprises over 113 species of rainforest understorey plants in Southeast Asia, the Malesian region, and Australia. Several species, including giant taro, Alocasia macrorrhizos, and Chinese taro, Alocasia cucullata, are important food plants or ornamentals. We investigated the biogeography of this genus using plastid and nuclear DNA sequences (5200 nucleotides) from 78 accessions representing 71 species, plus 25 species representing 16 genera of the Pistia clade to which Alocasia belongs. Divergence times were inferred under strict and relaxed clock models, and ancestral areas with Bayesian and maximum likelihood approaches. Alocasia is monophyletic and sister to Colocasiagigantea from the SE Asian mainland, whereas the type species of Colocasia groups with Steudnera and Remusatia, requiring taxonomic realignments. Nuclear and plastid trees show topological conflict, with the nuclear tree reflecting morphological similarities, the plastid tree species' geographic proximity, suggesting chloroplast capture. The ancestor of Alocasia diverged from its mainland sister group c. 24 million years ago, and Borneo then played a central role in the expansion of Alocasia: 11-13 of 18-19 inferred dispersal events originated on Borneo. The Philippines were reached from Borneo 4-5 times in the Late Miocene and Early Pliocene, and the Asian mainland 6-7 times in the Pliocene. Domesticated giant taro originated on the Philippines, Chinese taro on the Asian mainland. PMID- 22209858 TI - Body plan convergence in the evolution of skates and rays (Chondrichthyes: Batoidea). AB - Skates, rays and allies (Batoidea) comprise more than half of the species diversity and much of the morphological disparity among chondrichthyan fishes, the sister group to all other jawed vertebrates. While batoids are morphologically well characterized and have an excellent fossil record, there is currently no consensus on the interrelationships of family-level taxa. Here we construct a resolved, robust and time-calibrated batoid phylogeny using mitochondrial genomes, nuclear genes, and fossils, sampling densely across taxa. Data partitioning schemes, biases in the sequence data, and the relative informativeness of each fossil are explored. The molecular phylogeny is largely congruent with morphology crownward in the tree, but the branching orders of major batoid groups are mostly novel. Body plan convergence appears to be widespread in batoids. A depressed, rounded pectoral disk supported to the snout tip by fin radials, common to skates and stingrays, is indicated to have been derived independently by each group, while the long, spiny rostrum of sawfishes similarly appears to be convergent with that of sawsharks, which are not batoids. The major extant batoid lineages are inferred to have arisen relatively rapidly from the Late Triassic into the Jurassic, with long stems followed by subsequent radiations in each group around the Cretaceous/Tertiary boundary. The fossil record indicates that batoids were affected with disproportionate severity by the end-Cretaceous extinction event. PMID- 22209859 TI - Phylogeny of the Tachycineta genus of New World swallows: insights from complete mitochondrial genomes. AB - The Tachycineta genus of swallows is comprised of nine species that range from Alaska to southern Chile. We sequenced the entire mitochondrial genome of each member of Tachycineta and generated a completely resolved phylogenetic hypothesis for the corresponding mitochondrial gene tree. Our analyses confirm the presence of two sub-clades within Tachycineta that are associated with geography: a North American/Caribbean clade and a South/Central American clade. We found considerable variation among regions of the mitochondrial genome in both substitution rates and the level of information that each region supplied for phylogenetic reconstruction. We found no evidence of positive directional selection within mitochondrial coding regions, but we identified numerous sites under purifying selection. This finding suggests that, despite differences in life history traits and distributions, mitochondrial genes in Tachycineta are predominantly under purifying selection for conserved function. PMID- 22209860 TI - Molecular phylogenetics of the arboreal Australian gecko genus Oedura Gray 1842 (Gekkota: Diplodactylidae): another plesiomorphic grade? AB - The family Diplodactylidae is the most ecologically diverse and geographically widespread radiation of geckos within Australasia. Herein we present a first comprehensive phylogenetic analysis of relationships of diplodactylid geckos currently assigned to the genus Oedura, a group of relatively generalised arboreal Australian geckos. Maximum Likelihood, bayesian and Maximum Parsimony analyses of a combination of over two and a half kilobases of nuclear (PDC, Rag 1) and mitochondrial (ND2, ND4, tRNA) sequence data all identified four distinctive lineages within Oedura s.l. Based on their deep divergences and a suite of diagnostic morphological characters we recognise each of these four lineages as genera, two of which are monotypic and newly described herein. Our molecular data also suggest that Oedura s.l. is not monophyletic, but is instead a plesiomorphic grade restricted to islands of rocky or forested habitat around coastal and central Australia. In contrast, combined analysis of all data suggests the Australian arid zone is dominated by a single comparatively derived and relatively species rich clade including most other genera of Australian Diplodactylidae. Additional data are required to properly resolve basal divergence events within the Diplodactylidae, however the emerging pattern of relationships and divergence is consistent with the hypothesis that monsoonal and temperate lineages are ancestral to the arid zone fauna, but also indicate that arid zone lineages and radiations are relatively old, and potentially date back to the mid Miocene or earlier. PMID- 22209861 TI - Drawn to the dark side: a molecular phylogeny of freshwater shrimps (Crustacea: Decapoda: Caridea: Atyidae) reveals frequent cave invasions and challenges current taxonomic hypotheses. AB - Atyid freshwater shrimps are globally distributed and form an important part of freshwater ecosystems, particularly in the tropics and subtropics. Despite their widespread distribution and ecological importance, their phylogenetic relationships are largely unresolved. Here we present the first comprehensive molecular phylogeny of the Atyidae investigating the evolutionary relationships among 32 of the 42 genera using mitochondrial and nuclear markers. Our data indicate that the established classification of the Atyidae is in need of substantial taxonomic revision at all taxonomic levels. We suggest a new suprageneric systematization of atyids and discuss problematic issues at the generic level, particularly in the most speciose genus, Caridina. Molecular clock based divergence time estimates for atyids vary widely, but invariably support the assumption that atyids are an ancient freshwater lineage with an origin in the mid-Cretaceous at the very latest. Atyid distribution patterns are the result of instances of both long-distance dispersal and vicariance, depending largely on the reproductive mode of taxa. From an evolutionary perspective, the high frequency of independent origin of both a complete (landlocked) freshwater life cycle and a cave-dwelling mode of life is remarkable and unparalleled among crustaceans. PMID- 22209862 TI - Short- and long-term effects of selective cyclooxygenase-2 inhibitor paracoxib on ileal and colonic anastomosis in rats. PMID- 22209863 TI - Understanding factors that influence stakeholder trust of natural resource science and institutions. AB - Building trust between resource users and natural resource institutions is essential when creating conservation policies that rely on stakeholders to be effective. Trust can enable the public and agencies to engage in cooperative behaviors toward shared goals and address shared problems. Despite the increasing attention that trust has received recently in the environmental management literature, the influence that individual cognitive and behavioral factors may play in influencing levels of trust in resource management institutions, and their associated scientific assessments, remains unclear. This paper uses the case of fisheries management in the northeast to explore the relationships between an individual's knowledge of the resource, perceptions of resource health, and participatory experience on levels of trust. Using survey data collected from 244 avid recreational anglers in the Northeast U.S., we test these relationships using structural equation modeling. Results indicate that participation in fisheries management is associated with increased trust across all aspects of fisheries management. In addition, higher ratings of resource health by anglers are associated with higher levels of trust of state and regional institutions, but not federal institutions or scientific methods. PMID- 22209864 TI - Synthesis of biologically stable gold nanoparticles using imidazolium-based amino acid ionic liquids. AB - A novel double-step reduction procedure for the synthesis of gold nanoparticles (AuNPs) using amino acid ionic liquids has been employed. 1-Dodecyl-3-methyl imidazolium tryptophan ([C(12)mim]Trp) and 1-ethyl-3-methyl imidazolium tryptophan ([C(2)mim]Trp) were used for this synthesis. The synthesized AuNPs were characterized by UV-vis spectroscopy, transmission electron microscopy and dynamic light scattering. The behavior of these AuNPs were also probed in a biological media. It was proven that AuNPs synthesized at [C(12)mim]Trp have more stability than AuNPs synthesized at [C(2)mim]Trp due to the longer alkyl chain of the imidazolium moiety. The solubility test shows that the resultant AuNPs have a hydrophilic nature. Finally, it was seen that due to the presence of a biomolecule, namely Trp, in the structure of AuNPs protecting shell, higher stability and biocompatibility was achieved in the biological media. PMID- 22209865 TI - N-Succinimidyl 4-[(18)F]-fluoromethylbenzoate-labeled dimeric RGD peptide for imaging tumor integrin expression. AB - RGD peptides, radiolabeled with (18)F, have been used in the clinic for PET imaging of tumor angiogenesis in cancer patients. RGD peptides are typically labeled using a prosthetic group such as N-succinimidyl 4-[(18)F]-fluorobenzoate ([(18)F]SFB) or 4-nitrophenyl 2-[(18)F]-fluoropropionate ([(18)F]NPFP). However, the complex radiosynthetic procedures have impeded their broad application in clinical studies. We previously radiolabeled proteins and peptides with the prosthetic group, N-succinimidyl 4-[(18)F]-fluoromethylbenzoate ([(18)F]SFMB), which was prepared in a simple one-step procedure. In this study, we labeled a PEGylated cyclic RGD peptide dimer, PEG(3)-E[c(RGDyK)](2) (PRGD2), using [(18)F]SFMB and evaluated for imaging tumor alphavbeta3 integrin expression with positron emission tomography (PET). [(18)F]SFMB was prepared in one step using [(18)F]fluoride displacement of a nitrobenzenesulfonate leaving group under mild reaction conditions followed by HPLC purification. The (18)F-labeled peptide, [(18)F]FMBPRGD2 was prepared by coupling PRGD2 with [(18)F]SFMB in pH 8.6 borate buffer and purified with HPLC. The direct labeling on BMBPRGD2 was also attempted. A Siemens Inveon PET was used to image the uptake of the [(18)F]FMBPRGD2 into a U87MG xenograft mouse model. [(18)F]FMBPRGD2, was prepared with a 15% overall radiochemical yield (uncorrected) in a total synthesis time of 90 min, which was considerably shorter than the preparation of [(18)F]SFB- and [(18)F]NPFP-labeled RGD peptides. The direct labeling, however, was not successful. High quality microPET images using [(18)F]FMBPRGD2 clearly visualized tumors by 15 min with good target to background ratio. Early tracer accumulation in the bladder suggests fast renal clearance. No obvious bone uptake can be detected even at 4-h time point indicating that fluorine attachment is stable in mice. In conclusion, N-succinimidyl 4-[(18)F]-fluoromethylbenzoate ([(18)F]SFMB) prosthetic group can be a good alternative for labeling RGD peptides to image alphavbeta3 integrin expression and for labeling other peptides. PMID- 22209866 TI - Pharmacogenomic analysis of ATP-sensitive potassium channels coexpressing the common type 2 diabetes risk variants E23K and S1369A. AB - OBJECTIVES: The common ATP-sensitive potassium (KATP) channel variants E23K and S1369A, found in the KCNJ11 and ABCC8 genes, respectively, form a haplotype that is associated with an increased risk for type 2 diabetes. Our previous studies showed that KATP channel inhibition by the A-site sulfonylurea gliclazide was increased in the K23/A1369 haplotype. Therefore, we studied the pharmacogenomics of seven clinically used sulfonylureas and glinides to determine their structure activity relationships in KATP channels containing either the E23/S1369 nonrisk or K23/A1369 risk haplotypes. RESEARCH DESIGN AND METHODS: The patch-clamp technique was used to determine sulfonylurea and glinide inhibition of recombinant human KATP channels containing either the E23/S1369 or the K23/A1369 haplotype. RESULTS: KATP channels containing the K23/A1369 risk haplotype were significantly less sensitive to inhibition by tolbutamide, chlorpropamide, and glimepiride (IC50 values for K23/A1369 vs. E23/S1369=1.15 vs. 0.71 MUmol/l; 4.19 vs. 3.04 MUmol/l; 4.38 vs. 2.41 nmol/l, respectively). In contrast, KATP channels containing the K23/A1369 haplotype were significantly more sensitive to inhibition by mitiglinide (IC50=9.73 vs. 28.19 nmol/l for K23/A1369 vs. E23/S1369) and gliclazide. Nateglinide, glipizide, and glibenclamide showed similar inhibitory profiles in KATP channels containing either haplotype. CONCLUSION: Our results demonstrate that the ring-fused pyrrole moiety in several A-site drugs likely underlies the observed inhibitory potency of these drugs on KATP channels containing the K23/A1369 risk haplotype. It may therefore be possible to tailor existing therapy or design novel drugs that display an increased efficacy in type 2 diabetes patients homozygous for these common KATP channel haplotypes. PMID- 22209868 TI - Lost in disruption: role of proteases in glioma invasion and progression. AB - A characteristic feature of malignant glial tumors (gliomas) is their tendency to diffusely infiltrate the nervous system preventing their complete surgical resection. Proteases play a decisive role in this malignant process, either by degradation of brain extracellular matrix (ECM) components, adhesion molecules, or by regulating the activity of growth and chemotactic factors. Secreted matrix metalloproteinases (MMPs) and ADAMTS proteases (ADAMs with thrombospondin motifs) cleave different ECM components like the proteoglycans (lecticans) aggrecan, versican, neurocan and brevican with selective preferences; they are further regulated by endogenous inhibitors and activating metallo- and serine proteases. Cell surface proteases of the ADAM family (A Disintegrin And Metalloproteinase), but also serine proteases regulate the activity of growth factors and chemokines that act as autocrine / paracrine stimulators within gliomas. Thus, proteases play a decisive role for the spread and growth of gliomas and are prominent targets for their therapy. PMID- 22209867 TI - Hydrogen sulfide-releasing aspirin suppresses NF-kappaB signaling in estrogen receptor negative breast cancer cells in vitro and in vivo. AB - Hormone-dependent estrogen receptor positive (ER+) breast cancers generally respond well to anti-estrogen therapy. Unfortunately, hormone-independent estrogen receptor negative (ER-) breast cancers are aggressive, respond poorly to current treatments and have a poor prognosis. New approaches and targets are needed for the prevention and treatment of ER- breast cancer. The NF-kappaB signaling pathway is strongly implicated in ER- tumor genesis, constituting a possible target for treatment. Hydrogen sulfide-releasing aspirin (HS-ASA), a novel and safer derivative of aspirin, has shown promise as an anti-cancer agent. We examined the growth inhibitory effect of HS-ASA via alterations in cell proliferation, cell cycle phase transitions, and apoptosis, using MDA-MB-231 cells as a model of triple negative breast cancer. Tumor xenografts in mice, representing human ER- breast cancer, were evaluated for reduction in tumor size, followed by immunohistochemical analysis for proliferation, apoptosis and expression of NF-kappaB. HS-ASA suppressed the growth of MDA-MB-231 cells by induction of G(0)/G(1) arrest and apoptosis, down-regulation of NF-kappaB, reduction of thioredoxin reductase activity, and increased levels reactive oxygen species. Tumor xenografts in mice, were significantly reduced in volume and mass by HS-ASA treatment. The decrease in tumor mass was associated with inhibition of cell proliferation, induction of apoptosis and decrease in NF-kappaB levels in vivo. HS-ASA has anti-cancer potential against ER- breast cancer and merits further study. PMID- 22209869 TI - The impact of computed tomography screening for lung cancer on smoking behaviors: a teachable moment? AB - BACKGROUND: Helical computed tomography (CT) has emerged as a potential screening test for lung cancer. An important component of care surrounding the use of this technology is the impact of screening on decisions surrounding smoking cessation. OBJECTIVE: The aim of this article was to conduct an integrative review of literature on the impact of lung cancer screening with CT on smoking behaviors of current smokers. METHODS: Ganong's [Res Nurs Health. 1987;10(1):1-11] guidelines were used to conduct this integrative review. Computerized databases were used to identify relevant articles. Data were extracted from the studies, and then content analysis was used to synthesize the findings. RESULTS: Nine studies were identified and reviewed. The quit rate among participants ranged from 6.6% to 42% after screening. Among current smokers, smoking abstinence was associated with older age, worse pulmonary function, and having multiple abnormal CT findings. Motivation to quit smoking, within the next 30 days, ranged from 14% to 35% among smokers. Factors associated with increased motivation were older age, lower nicotine addiction, fewer lung cancer symptoms, higher self-efficacy, and acknowledgment of the advantages of quitting smoking. CONCLUSIONS: Participants undergoing lung cancer screening had increased motivation to quit smoking. Computed tomographic screening for lung cancer appears to be a teachable moment to address smoking cessation. IMPLICATIONS FOR PRACTICE: Screening for lung cancer is only one step to fight lung cancer. Incorporating smoking cessation interventions along with the use of technology is necessary to fight this deadly disease. PMID- 22209871 TI - Molecular differentiation between osteophytic and articular cartilage--clues for a transient and permanent chondrocyte phenotype. AB - OBJECTIVE: To identify the molecular differences between the transient and permanent chondrocyte phenotype in osteophytic and articular cartilage. METHODS: Total RNA was isolated from the cartilaginous layer of osteophytes and from intact articular cartilage from knee joints of 15 adult human donors and subjected to cDNA microarray analysis. The differential expression of relevant genes between these two cartilaginous tissues was additionally validated by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and by immunohistochemistry. RESULTS: Among 47,000 screened transcripts, 600 transcripts were differentially expressed between osteophytic and articular chondrocytes. Osteophytic chondrocytes were characterized by increased expression of genes involved in the endochondral ossification process [bone gamma-carboxyglutamate protein/osteocalcin (BGLAP), bone morphogenetic protein-8B (BMP8B), collagen type I, alpha 2 (COL1A2), sclerostin (SOST), growth arrest and DNA damage-induced gene 45beta (GADD45beta), runt-related transcription factor 2 (RUNX2)], and genes encoding tissue remodeling enzymes [matrix metallopeptidase (MMP)9, 13, hyaluronan synthase 1 (HAS1)]. Articular chondrocytes expressed increased transcript levels of antagonists and inhibitors of the BMP- and Wnt-signaling pathways [Gremlin-1 (GREM1), frizzled-related protein (FRZB), WNT1 inducible signaling pathway protein-3 (WISP3)], as well as factors that inhibit terminal chondrocyte differentiation and endochondral bone formation [parathyroid hormone like hormone (PTHLH), sex-determining region Y-box 9 (SOX9), stanniocalcin-2 (STC2), S100 calcium binding protein A1 (S100A1), S100 calcium binding protein B (S100B)]. Immunohistochemistry of tissue sections for GREM1 and BGLAP, the two most prominent differentially expressed genes, confirmed selective detection of GREM1 in articular chondrocytes and that of BGLAP in osteophytic chondrocytes and bone. CONCLUSIONS: Osteophytic and articular chondrocytes significantly differ in their gene expression pattern. In articular cartilage, a prominent expression of antagonists inhibiting the BMP- and Wnt-pathway may serve to lock and stabilize the permanent chondrocyte phenotype and thus prevent their terminal differentiation. In contrast, osteophytic chondrocytes express genes with roles in the endochondral ossification process, which may account for their transient phenotype. PMID- 22209870 TI - Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. AB - Multiple sclerosis (MS) is a disease characterized by inflammation and demyelination. Currently, the cause of MS is unknown. Experimental autoimmune encephalomyelitis (EAE) is the most common mouse model of MS. Treatments with the sex hormones, estrogens and androgens, are capable of offering disease protection during EAE and are currently being used in clinical trials of MS. Beyond endogenous estrogens and androgens, treatments with selective estrogen receptor modulators (SERMs) for estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) are also capable of providing disease protection. This protection includes, but is not limited to, prevention of clinical disease, reduction of CNS inflammation, protection against demyelination, and protection against axonal loss. In EAE, current efforts are focused on using conditional cell specific knockouts of sex hormone receptors to identify the in vivo targets of these estrogens and androgens as well as downstream molecules responsible for disease protection. PMID- 22209872 TI - Descendants of primed Arabidopsis plants exhibit resistance to biotic stress. AB - An attack of plants by pathogens or treatment with certain resistance-inducing compounds can lead to the establishment of a unique primed state of defense. Primed plants show enhanced defense reactions upon further challenge with biotic or abiotic stress. Here, we report that the primed state in Arabidopsis (Arabidopsis thaliana) is still functional in the next generation without additional treatment. We compared the reactions of Arabidopsis plants that had been either primed with beta-amino-butyric acid (BABA) or with an avirulent isolate of the bacteria Pseudomonas syringae pv tomato (PstavrRpt2). The descendants of primed plants showed a faster and higher accumulation of transcripts of defense-related genes in the salicylic acid signaling pathway and enhanced disease resistance upon challenge inoculation with a virulent isolate of P. syringae. In addition, the progeny of primed plants was also more resistant against the oomycete pathogen Hyaloperonospora arabidopsidis. When transgenerationally primed plants were subjected to an additional priming treatment, their descendants displayed an even stronger primed phenotype, suggesting that plants can inherit a sensitization for the priming phenomenon. Interestingly, this primed to be primed phenotype was much reduced in the Arabidopsis beta-amino-butyric acid priming mutant ibs1 (induced BABA sterility1). Our results demonstrate that the primed state of plants is transferred to their progeny and confers improved protection from pathogen attack as compared to the descendants of unprimed plants. PMID- 22209873 TI - Herbivory in the previous generation primes plants for enhanced insect resistance. AB - Inducible defenses, which provide enhanced resistance after initial attack, are nearly universal in plants. This defense signaling cascade is mediated by the synthesis, movement, and perception of jasmonic acid and related plant metabolites. To characterize the long-term persistence of plant immunity, we challenged Arabidopsis (Arabidopsis thaliana) and tomato (Solanum lycopersicum) with caterpillar herbivory, application of methyl jasmonate, or mechanical damage during vegetative growth and assessed plant resistance in subsequent generations. Here, we show that induced resistance was associated with transgenerational priming of jasmonic acid-dependent defense responses in both species, caused caterpillars to grow up to 50% smaller than on control plants, and persisted for two generations in Arabidopsis. Arabidopsis mutants that are deficient in jasmonate perception (coronatine insensitive1) or in the biogenesis of small interfering RNA (dicer-like2 dicer-like3 dicer-like4 and nuclear RNA polymerase d2a nuclear RNA polymerase d2b) do not exhibit inherited resistance. The observation of inherited resistance in both the Brassicaceae and Solanaceae suggests that this trait may be more widely distributed in plants. Epigenetic resistance to herbivory thus represents a phenotypically plastic mechanism for enhanced defense across generations. PMID- 22209874 TI - Short grain1 decreases organ elongation and brassinosteroid response in rice. AB - We identified a short-grain mutant (Short grain1 (Sg1) Dominant) via phenotypic screening of 13,000 rice (Oryza sativa) activation-tagged lines. The causative gene, SG1, encodes a protein with unknown function that is preferentially expressed in roots and developing panicles. Overexpression of SG1 in rice produced a phenotype with short grains and dwarfing reminiscent of brassinosteroid (BR)-deficient mutants, with wide, dark-green, and erect leaves. However, the endogenous BR level in the SG1 overexpressor (SG1:OX) plants was comparable to the wild type. SG1:OX plants were insensitive to brassinolide in the lamina inclination assay. Therefore, SG1 appears to decrease responses to BRs. Despite shorter organs in the SG1:OX plants, their cell size was not decreased in the SG1:OX plants. Therefore, SG1 decreases organ elongation by decreasing cell proliferation. In contrast to the SG1:OX plants, RNA interference knockdown plants that down-regulated SG1 and a related gene, SG1-LIKE PROTEIN1, had longer grains and internodes in rachis branches than in the wild type. Taken together, these results suggest that SG1 decreases responses to BRs and elongation of organs such as seeds and the internodes of rachis branches through decreased cellular proliferation. PMID- 22209876 TI - Effect of celecoxib on proliferation, collagen expression, ERK1/2 and SMAD2/3 phosphorylation in NIH/3T3 fibroblasts. AB - In the present study, the effects of celecoxib on proliferation, collagen expression, ERK1/2 and SMAD2/3 phosphorylation in NIH/3T3 fibroblasts were investigated. NIH/3T3 fibroblasts stimulated with fibroblast growth factor-2 (FGF 2) or transforming growth factor-beta1 (TGF-beta1) were examined in the presence of celecoxib. Proliferation was assessed by MTT assays; ERK1/2 expression and SMAD2/3 expression were assessed by quantitative RT-PCR and western blotting; ERK1/2 phosphorylation and SMAD2/3 phosphorylation were assessed by western blot analysis. The results indicated that celecoxib could suppress cell proliferation stimulated by FGF-2 (IC(50) FGF+group, 75+/-1.9MUmol/l) and TGF-beta1 (IC(50) TGF+group, 48+/-1.4MUmol/l), by inhibiting ERK1/2 phosphorylation but not ERK1/2 expression. Celecoxib also suppressed collagen expression (0.35-fold COL3 and 0.43-fold COL1 at 320MUmol/l celecoxib relative to the untreated control after stimulation with TGF-beta1 for 3h, P<0.01), by inhibiting SMAD2/3 phosphorylation but not SMAD2/3 expression. The suppression of NIH/3T3 fibroblast proliferation and collagen expression upon stimulation by FGF-2 and TGF-beta1 is likely a result of the inhibition of ERK1/2 and SMAD2/3 phosphorylation by celecoxib. PMID- 22209875 TI - Arabidopsis VILLIN2 and VILLIN3 are required for the generation of thick actin filament bundles and for directional organ growth. AB - In plant cells, actin filament bundles serve as tracks for myosin-dependent organelle movement and play a role in the organization of the cytoplasm. Although virtually all plant cells contain actin filament bundles, the role of the different actin-bundling proteins remains largely unknown. In this study, we investigated the role of the actin-bundling protein villin in Arabidopsis (Arabidopsis thaliana). We used Arabidopsis T-DNA insertion lines to generate a double mutant in which VILLIN2 (VLN2) and VLN3 transcripts are truncated. Leaves, stems, siliques, and roots of vln2 vln3 double mutant plants are twisted, which is caused by local differences in cell length. Microscopy analysis of the actin cytoskeleton showed that in these double mutant plants, thin actin filament bundles are more abundant while thick actin filament bundles are virtually absent. In contrast to full-length VLN3, truncated VLN3 lacking the headpiece region does not rescue the phenotype of the vln2 vln3 double mutant. Our results show that villin is involved in the generation of thick actin filament bundles in several cell types and suggest that these bundles are involved in the regulation of coordinated cell expansion. PMID- 22209877 TI - Valosin containing protein (VCP) interacts with macrolide antibiotics without mediating their anti-inflammatory activities. AB - In addition to antibacterial activity, some macrolide antibiotics, such as azithromycin and clarithromycin, also exhibit anti-inflammatory properties in vitro and in vivo, although the targets and mechanism(s) of action remain unknown. The aim of the present study was to identify protein targets of azithromycin and clarithromycin which could potentially explain their anti inflammatory effects. Using chemical proteomics approach, based on compound immobilized affinity chromatography, valosin containing protein (VCP) was identified as a potential target of the macrolides. Validation studies confirmed the interaction of macrolides and VCP and gave some structural characteristics of this interaction. Cell based assays however, including the use of gene silencing and the study of VCP specific cellular functions in J774.A1 (murine macrophage) and IB3-1 (human cystic fibrotic epithelial) cell lines, failed to confirm an association between the binding of the macrolides to VCP and anti-inflammatory effects. These findings suggest the absence of an abundant high affinity protein target and the potential involvement of other biological molecules in the anti inflammatory activity of macrolides. PMID- 22209878 TI - Regulatory role of antigen-induced interleukin-10, produced by CD4(+) T cells, in airway neutrophilia in a murine model for asthma. AB - It has been suggested that interleukin (IL)-10 exerts immunosuppressive effects on allergic inflammation, including asthma, mainly through inhibition of Th2 cell mediated eosinophilic airway inflammation. In a model of experimental asthma utilizing multiple intratracheal antigen challenges in sensitized mice, IL-10 production as well as eosinophilia and neutrophilia in the lung were induced by the multiple challenges. In this study, we set out to reveal the cellular source of endogenously produced IL-10, and the roles of IL-10 in airway leukocyte inflammation using an anti-IL-10 receptor monoclonal antibody. Balb/c mice were sensitized i.p. with ovalbumin+Al(OH)(3), and then challenged by intratracheal administration of ovalbumin 4 times. Flow cytometric analyses revealed that the cellular source of IL-10 was CD4(+) T cells lacking the transcription factor, forkhead box P3. Treatment with anti-IL-10 receptor monoclonal antibody prior to the 4th challenge significantly augmented airway neutrophilia as well as the production of IL-1beta, and CXC chemokines, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2, but not airway eosinophilia, Th2 cytokine (IL-4 and IL-5) production, or a late-phase increase in specific airway resistance. Approximately 40% of IL-10 receptor(+) cells expressed the macrophage marker F4/80, whereas only 3-4% of the IL-10 receptor(+) cells were granulocyte differentiation antigen (Gr)-1(high) cells (neutrophils). In conclusion, multiple airway antigen challenges induced the proliferation of IL-10-expressing CD4(+) T cells in regulating airway neutrophilia. Systemic blockade of IL-10 function coincided with increases in IL-1beta and CXC chemokines. Thus, IL-1beta and CXC chemokines may be targets for development of novel pharmacotherapy for neutrophilic asthma. PMID- 22209879 TI - Anti-inflammatory potential of thienopyridines as possible alternative to NSAIDs. AB - The present study was designed to evaluate the anti-inflammatory and antiarthritic activity of the new synthetic thienopyridine analogs. The anti inflammatory activity of thienopyridines was assayed by using carrageenan; dextran and arachidonic acid induced paw edema models (acute), cotton pellet granuloma model (Sub acute) and Freund's complete adjuvant induced arthritis (chronic) in experimental rats. The compounds BN-4, BN-14 and BN-16 have shown significant inhibition of edema in carrageenan and arachidonic acid induced paw edema model at a dose of 100mg/kg compared to the dextran induced paw edema model and also showed significant inhibition in granuloma tissue formation and Freund's complete adjuvant induced arthritis in experimental rats. These thienopyridine analogs also inhibited the proinflammatory mediators such as Tumor necrosis factor (TNF)-alpha, Interleukin (IL)-1beta and Nitric Oxide (NO) in Lipopolysaccharide (LPS) challenged murine macrophages. Ulcerogenecity study results revealed less ulcerogenic potential of BN-4, BN-14 and BN-16 compared to nonsteroidal anti-inflammatory drug (NSAID) indomethacin in rats. In conclusion, the new thienopyridine analogs were promising for the potential use as anti inflammatory agents for both acute and chronic inflammatory disorders with low toxic effects. PMID- 22209880 TI - The effect of sub-anesthetic and anesthetic ketamine on water maze memory acquisition, consolidation and retrieval. AB - Ketamine, a non-selective inhibitor of NMDA (N-methyl-D-aspartate) channels is used in anesthetic or sub-anesthetic doses to induce analgesia, amnesia, to suppress fear, anxiety and depression. Although the ketamine's effect on memory acquisition is known, its effects on other aspects of memory are controversial. Morris water maze is a task which assesses spatial learning and memory. This study was aimed to assess the ketamine's differential effect on water maze memory acquisition, consolidation and retrieval. Male Sprague-Dawley rats (250-350 g) were trained in water maze single training session. 24h later a probe trial which was consisted of a single trial without platform was done. To assess the effect of ketamine on water maze memory acquisition it was administered before training; to assess its effect on memory consolidation it was administered immediately after training and to assess its effect on memory retrieval it was injected before probe trial. Ketamine both in sub-anesthetic and anesthetic doses impaired water maze memory acquisition, its anesthetic dose but not sub-anesthetic dose impaired memory consolidation and on retrieval stage, both doses deteriorated memory retrieval. It seems that NMDA receptor activity is not just necessary during water maze memory acquisition but also their post-learning reactivation is required to maintain memory consolidation and retrieval. PMID- 22209881 TI - Anti-inflammatory effect of quetiapine on collagen-induced arthritis of mouse. AB - Quetiapine is an atypical antipsychotic and has also been used in the treatment of depression. Since anti-inflammatory effects of antidepressants are well established, we hypothesized that quetiapine may also exert anti-inflammatory effects. Thus this study was designed to examine the anti-inflammatory effect of quetiapine in murine collagen-induced arthritis. Mice were immunized with collagen type II for the induction of arthritis and treated with quetiapine (10mg/kg) daily for 2weeks. Mice were divided into 3 groups: control, CIA, and CIA+quetiapine treatment. Arthritic index and paw thickness were used to compare severity of arthritis. In additions, radiological and histological assessments were employed. Anti-type II collagen-specific antibody, interleukin-6 (IL-6), interleukin-17 (IL-17), and prostaglandin E(2) (PGE(2)) were evaluated at the end of the treatment period. Both arthritic index and paw thickness were markedly improved in CIA+quetiapine treatment group compared with those in CIA groups (arthritic index; P<0.01, paw thickness; P<0.05). Radiologic assessment revealed decreased cartilage damage and bone erosion in CIA+quetiapine treatment group compared with those in CIA groups. Articular cartilage destruction observed in CIA group was not found in CIA+quetiapine group. The concentrations of anti-type II collagen-specific antibody, IL-6, IL-17, and PGE(2) in CIA+quetiapine group were significantly lower than those in CIA groups (P<0.05). Weight gain which is commonly observed with the treatment of antipsychotics was not observed. Taken together, these results suggest that quetiapine shows anti-inflammatory effects in murine collagen-induced arthritis. PMID- 22209882 TI - Roles of Apicomplexan protein kinases at each life cycle stage. AB - Inhibitors of cellular protein kinases have been reported to inhibit the development of Apicomplexan parasites, suggesting that the functions of protozoan protein kinases are critical for their life cycle. However, the specific roles of these protein kinases cannot be determined using only these inhibitors without molecular analysis, including gene disruption. In this report, we describe the functions of Apicomplexan protein kinases in each parasite life stage and the potential of pre-existing protein kinase inhibitors as Apicomplexan drugs against, mainly, Plasmodium and Toxoplasma. PMID- 22209883 TI - Lobby groups call for closure of "revolving door" between drug regulators and industry. PMID- 22209884 TI - Alpinia calcarata Roscoe: a potent antiinflammatory agent. AB - AIM OF THE STUDY: Alpinia calcarata Roscoe (Family: Zingiberaceae) rhizomes are often used in Sri Lankan traditional systems of medicine as a remedy for bronchitis, cough, respiratory ailments, diabetics, asthma and arthritis. Generally drugs that are used for arthritis have antinociceptive and antiinflammatory properties. However, validity of the antiinflammatory activity has not been scientifically investigated so far. Therefore, the aim of this study was to investigate the antiinflammatory potential of Alpinia calcarata rhizomes using hot water extract (AWE) and hot ethanolic extract (AEE). MATERIALS AND METHODS: The antiinflammatory activity of Alpinia calcarata was evaluated by use of the carrageenan-induced paw oedema model in rats. In addition, the mechanism/s by which Alpinia calcarata is mediated the antinflammatory activity was assessed by determining its effects on (a) membrane stabilizing, (b) antihistamine and (c) prostaglandin synthesis inhibition activity. RESULTS: All the tested doses of AWE and AEE (250, 500, 750, and 1000 mg/kg) produced a significant (P<=0.05) inhibition of the inflammation, most pronounced at 4h after the injection of carrageenan. The antiinflammatory effect induced by 500 mg/kg of AEE was superior than the reference drug, indomethacin at 4h. Inhibition of histamine and prostaglandin synthesis production is probable mechanisms by which Alpinia calcarata mediates its antiinflammatory action. CONCLUSION: These findings rationalize the traditional usage of Alpinia calcarata as an antiinflammatory agent for the first time. PMID- 22209885 TI - Cross-cultural comparison of medicinal floras used against snakebites. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Envenomation causes an estimated 1.8-2.5 million incidences per year with a mortality level of 100-125,000 persons annually and more than 100,000 individuals suffer from severe complications, which may end in amputation of the attacked limb. The use of plants is a major part of the traditional practitioners' treatment of snakebites. MATERIALS AND METHODS: A database was created for plants used to treat snakebites worldwide. From this database, we selected five countries with a high number of entries and representing different cultures, geography and floristic zones: Brazil, Nicaragua, Nepal, China and South Africa. The datasets were analysed by regression and binominal analysis to see if any family or genus used against snakebites was overrepresented in the respective traditional medicinal systems relative to the abundance in the local flora. The families from the different geographical areas were compared to ascertain whether the same plant families are preferred by different peoples. RESULTS: Three 'hot' families (Apocynaceae, Lamiaceae and Rubiaceae) were recovered in at least two of the five compared countries in the regression analyses and one 'hot' family (Zingiberaceae) was recovered in two of the compared countries in the binomial analyses. Four out of five floras possess families identified as outliers in both regression and binomial analyses. Eight families were recovered by both the binomial and the regression analysis (40-62% of all highlighted families respectively). At the genus level, only Piper (Piperaceae) was recovered as a 'hot' genus in at least two floras. Seven genera were highlighted by both analyses (25-44% of the highlighted genera). CONCLUSIONS: Cross-cultural comparison of medicinal floras used against snakebites appears to be useful for highlighting candidate families and genera for further studies. PMID- 22209886 TI - Effects of arsenite stress on growth and proteome of Klebsiella pneumoniae. AB - In the present study an arsenite, As(III), tolerating bacterium, MR4, was isolated from Mulla River Pune, India, capable of reducing arsenate to arsenite and identified as Klebsiella pneumoniae (HQ857583). Comparative proteomic analysis using two-dimensional gel electrophoresis (2-DGE) and matrix assisted laser desorption ionization-time of flight-time of flight (MALDI-TOF/TOF) was used to monitor the proteins undergoing changes in expression levels under 2.5 mM As(III) stress. The 2-DGE proteome map has shown that 60 proteins were differentially expressed under As(III) stress, of which 39 proteins were successfully identified with a MASCOT score greater than 70 (p<0.05). Among the identified proteins, membrane transport/binding proteins, porins, and amino acid metabolism enzymes were down-regulated while stress responsive proteins and antioxidant enzymes were up-regulated. Proteins involved in carbohydrate metabolism, particularly those in pentose phosphate pathway were also up regulated while those involved in pyruvate metabolism were down-regulated. However, proteins involved in glycolysis and tricarboxylic acid cycle showed a mixed regulation response. These findings provide new insights into the probable mechanisms by which K. pneumoniae (HQ857583) could be adapting to As(III) stress. PMID- 22209887 TI - Heparin-binding epidermal growth factor-like growth factor is a potent regulator of invasion activity in oral squamous cell carcinoma. AB - Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) has been shown to stimulate the growth of various cell types in an autocrine or paracrine manner. Although HB-EGF is widely expressed in tumors when compared with normal tissue, its contribution to cancer progression remains obscure. The objective of this study was to explore the effects of HB-EGF on proliferation, invasion activity and MMP-9 levels of an oral squamous cell carcinoma cell line, HSC3, in vitro. MTT assays, Matrigel invasion assays and RT-PCR in combination with RNA interference (RNAi) were used in this study. An RNAi-mediated decrease in HB-EGF expression reduced invasion activity and MMP-9 mRNA levels, but not proliferation, in HSC3 cells. The addition of purified HB-EGF to cell culture medium upregulated MMP-9 mRNA levels in HSC3 cells. Furthermore, the TACE inhibitor TAPI-2 or EGFR inhibitor AG1478 decreased MMP-9 mRNA levels in HSC3 cells. These data indicate that HB-EGF released from HSC3 cells by TACE stimulates EGFR in an autocrine manner, which in turn activates invasion activity via MMP-9 upregulation. PMID- 22209888 TI - Role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of pediatric acute lymphoblastic leukemia: update of the 2005 evidence based review. AB - Clinical research published since the first evidence-based review on the role of hematopoietic stem cell transplantation (SCT) in the treatment of pediatric acute lymphoblastic leukemia (ALL) is presented and critically evaluated in this update. Treatment recommendations are provided by an expert panel. Allogeneic SCT is recommended for children who: are in second complete remission (CR2) after experiencing an early marrow relapse for precursor-B ALL; experienced primary induction failure, but subsequently achieved a CR1; have T-lineage ALL in CR2; or have ALL in third or greater remission. Although the 2005 pediatric ALL evidence based review (EBR) recommended allogeneic SCT for children with Philadelphia chromosome positive (Ph+) ALL in CR1, preliminary tyrosine kinase inhibitor (TKI) data demonstrate that early outcomes are comparable for allogeneic SCT and chemotherapy + imatinib. Based on the evidence, autologous SCT is not recommended for ALL in CR1. Allogeneic SCT is not recommended for: T-lineage ALL in CR1; mixed-lineage leukemia (MLL)+ ALL when it is the sole adverse risk factor; isolated central nervous system (CNS) relapse in precursor-B ALL. Based on expert opinion, allogeneic SCT may be considered for hypodiploid ALL and persistent minimal residual disease [corrected] (MRD) positivity in ALL in CR1 or greater, although these are areas that need further study. Treatment recommendations pertaining to various transplantation techniques are also provided, as are areas of needed future research. PMID- 22209889 TI - Stumbling on status: abortion, stem cells, and faulty reasoning. AB - Common arguments from the abortion debate have set the stage for the debate on stem cell research. Unfortunately, those arguments demonstrate flawed reasoning jumping to unfounded conclusions, using value laden language rather than careful argument, and ignoring morally relevant aspects of the situation. The influence of flawed abortion arguments on the stem cell debate results in failures of moral reasoning and in lack of attention to important morally relevant differences between abortion and human embryonic stem cells. Among those differences are whose interests are at stake and the difference between an embryo in and out of the womb. Stem cell research differs from abortion in morally relevant ways and should be freed from the abortion debate and its flawed reasoning. PMID- 22209890 TI - Salsolinol stimulates dopamine neurons in slices of posterior ventral tegmental area indirectly by activating MU-opioid receptors. AB - Previous studies in vivo have shown that salsolinol, the condensation product of acetaldehyde and dopamine, has properties that may contribute to alcohol abuse. Although opioid receptors, especially the MU-opioid receptors (MORs), may be involved, the cellular mechanisms mediating the effects of salsolinol have not been fully explored. In the current study, we used whole-cell patch-clamp recordings to examine the effects of salsolinol on dopamine neurons of the ventral tegmental area (VTA) in acute brain slices from Sprague-Dawley rats. Salsolinol (0.01-1 MUM) dose-dependently and reversibly increased the ongoing firing of dopamine neurons; this effect was blocked by naltrexone, an antagonist of MORs, and gabazine, an antagonist of GABA(A) receptors. We further showed that salsolinol reduced the frequency without altering the amplitude of spontaneous GABA(A) receptor-mediated inhibitory postsynaptic currents in dopamine neurons. The salsolinol-induced reduction was blocked by both naltrexone and [D-Ala2,N-Me Phe4,Gly5-ol]enkephalin, an agonist of MORs. Thus, salsolinol excites VTA dopamine neurons indirectly by activating MORs, which inhibit GABA neurons in the VTA. This form of disinhibition seems to be a novel mechanism underlying the effects of salsolinol. PMID- 22209891 TI - GABAergic actions mediate opposite ethanol effects on dopaminergic neurons in the anterior and posterior ventral tegmental area. AB - It is known that the posterior ventral tegmental area (p-VTA) differs from the anterior VTA (a-VTA) in that rats learn to self-administer ethanol into the p VTA, but not into the a-VTA. Because activation of VTA dopaminergic neurons by ethanol is a cellular mechanism underlying the reinforcement of ethanol consumption, we hypothesized that ethanol may exert different effects on dopaminergic neurons in the p-VTA and a-VTA. In patch-clamp recordings in midbrain slices from young rats (postnatal days 22-32), we detected no significant difference in electrophysiological properties between p-VTA and a-VTA dopaminergic neurons. However, acute exposure to ethanol (21-86 mM) stimulated p VTA dopaminergic neurons but suppressed a-VTA dopaminergic neurons. Conversely, ethanol (>21 mM) dose-dependently reduced the frequency of the GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) generated by inhibitory neuronal firing but not miniature inhibitory postsynaptic currents (mIPSCs) in p VTA dopaminergic neurons. By contrast, ethanol increased the frequency and amplitude of both sIPSCs and mIPSCs in a-VTA dopaminergic neurons. All of these effects of ethanol were abolished by a GABA(A) receptor antagonist. There was a strong negative correlation between ethanol-evoked modulation of sIPSCs and neuronal firing in VTA dopaminergic neurons. These results indicate that GABAergic inputs play an important role in ethanol's actions in the VTA. The differential effects of ethanol on sIPSCs and neuronal firing in the p-VTA and a VTA could be the basis for ethanol reinforcement via the p-VTA. PMID- 22209892 TI - Resveratrol attenuates doxorubicin-induced cardiomyocyte death via inhibition of p70 S6 kinase 1-mediated autophagy. AB - Resveratrol is a plant-derived polyphenol that can attenuate the cardiotoxic effects of doxorubicin (DOX), a powerful antibiotic widely used in cancer chemotherapy. However, the underlying protective mechanisms of resveratrol remain elusive. Here, we show that resveratrol inhibited DOX-induced autophagy and cardiomyocyte death, and autophagy suppression is an important mechanism that mediates the ability of resveratrol to protect against DOX cardiotoxicity. Indeed, resveratrol, 3-methyladenine (3-MA), and a short hairpin RNA directed against autophagy gene beclin 1 (shBCN1) each was able to attenuate DOX-induced autophagy and cardiomyocyte death, but resveratrol did not provide additional protection in the presence of 3-MA or shBCN1. In contrast, up-regulation of autophagy by beclin 1 overexpression not only exacerbated DOX cardiotoxicity but also abolished the protective effects of resveratrol. Intriguingly, p70 S6 kinase 1 (S6K1) was activated by DOX, which was prevented by resveratrol. Knocking down S6K1 with small interfering RNA diminished DOX-induced autophagy and cardiotoxicity, but resveratrol failed to exert an additive effect. In addition, S6K1 overexpression impaired the ability of resveratrol to antagonize DOX-induced autophagy and cardiomyocyte death. Taken together, our data indicate that the protective effect of resveratrol against DOX cardiotoxicity largely depends on its ability to suppress DOX-induced autophagy via the inhibition of S6K1. PMID- 22209897 TI - Isolation of high quality RNA from Phyllanthus emblica and its evaluation by downstream applications. AB - Next generation sequencing is a high-throughput technique widely used for transcriptome profiling. Isolation of high quality RNA is a prerequisite for such large scale transcriptome analysis. Phyllanthus emblica is an important medicinal plant having high amount of metabolites like vitamin C, flavonoids, polyphenolic compounds, tannins, which are responsible for its wondered medicinal properties. High concentration of secondary metabolites like polysaccharides and polyphenols proved to be an obstacle in isolating RNA of good quality. Any compromise with quality of RNA affects the downstream applications and requires extra cleaning steps that further reduce RNA quantity. We have developed a protocol for isolation of high quality RNA from P. embilca. RNA was successfully assessed for downstream applications like reverse transcription polymerase chain reaction, rapid amplification of cDNA ends, mRNA library preparation, and sequencing using HiSeq(TM) 2000 sequencing technology. The protocol is simple and can be completed in 4-5 h. PMID- 22209899 TI - A simple method for finding explicit analytic transition densities of diffusion processes with general diploid selection. AB - The transition density function of the Wright-Fisher diffusion describes the evolution of population-wide allele frequencies over time. This function has important practical applications in population genetics, but finding an explicit formula under a general diploid selection model has remained a difficult open problem. In this article, we develop a new computational method to tackle this classic problem. Specifically, our method explicitly finds the eigenvalues and eigenfunctions of the diffusion generator associated with the Wright-Fisher diffusion with recurrent mutation and arbitrary diploid selection, thus allowing one to obtain an accurate spectral representation of the transition density function. Simplicity is one of the appealing features of our approach. Although our derivation involves somewhat advanced mathematical concepts, the resulting algorithm is quite simple and efficient, only involving standard linear algebra. Furthermore, unlike previous approaches based on perturbation, which is applicable only when the population-scaled selection coefficient is small, our method is nonperturbative and is valid for a broad range of parameter values. As a by-product of our work, we obtain the rate of convergence to the stationary distribution under mutation-selection balance. PMID- 22209900 TI - Notch signaling is antagonized by SAO-1, a novel GYF-domain protein that interacts with the E3 ubiquitin ligase SEL-10 in Caenorhabditis elegans. AB - Notch signaling pathways can be regulated through a variety of cellular mechanisms, and genetically compromised systems provide useful platforms from which to search for the responsible modulators. The Caenorhabditis elegans gene aph-1 encodes a component of gamma-secretase, which is essential for Notch signaling events throughout development. By looking for suppressors of the incompletely penetrant aph-1(zu147) mutation, we identify a new gene, sao-1 (suppressor of aph-one), that negatively regulates aph-1(zu147) activity in the early embryo. The sao-1 gene encodes a novel protein that contains a GYF protein protein interaction domain and interacts specifically with SEL-10, an Fbw7 component of SCF E3 ubiquitin ligases. We demonstrate that the embryonic lethality of aph-1(zu147) mutants can be suppressed by removing sao-1 activity or by mutations that disrupt the SAO-1-SEL-10 protein interaction. Decreased sao-1 activity also influences Notch signaling events when they are compromised at different molecular steps of the pathway, such as at the level of the Notch receptor GLP-1 or the downstream transcription factor LAG-1. Combined analysis of the SAO-1-SEL-10 protein interaction and comparisons of sao-1 and sel-10 genetic interactions suggest a possible role for SAO-1 as an accessory protein that participates with SEL-10 in downregulation of Notch signaling. This work provides the first mutant analysis of a GYF-domain protein in either C. elegans or Drosophila and introduces a new type of Fbw7-interacting protein that acts in a subset of Fbw7 functions. PMID- 22209898 TI - Nuclear export of proteins and drug resistance in cancer. AB - The intracellular location of a protein is crucial to its normal functioning in a cell. Cancer cells utilize the normal processes of nuclear-cytoplasmic transport through the nuclear pore complex of a cell to effectively evade anti-neoplastic mechanisms. CRM1-mediated export is increased in various cancers. Proteins that are exported in cancer include tumor-suppressive proteins such as retinoblastoma, APC, p53, BRAC1, FOXO proteins, INI1/hSNF5, galectin-3, Bok, nucleophosmin, RASSF2, Merlin, p21(CIP), p27(KIP1), N-WASP/FAK, estradiol receptor and Tob, drug targets topoisomerase I and IIalpha and BCR-ABL, and the molecular chaperone protein Hsp90. Here, we review in detail the current processes and known structures involved in the export of a protein through the nuclear pore complex. We also discuss the export receptor molecule CRM1 and its binding to the leucine rich nuclear export signal of the cargo protein and the formation of a nuclear export trimer with RanGTP. The therapeutic potential of various CRM1 inhibitors will be addressed, including leptomycin B, ratjadone, KOS-2464, and specific small molecule inhibitors of CRM1, N-azolylacrylate analogs, FOXO export inhibitors, valtrate, acetoxychavicol acetate, CBS9106, and SINE inhibitors. We will also discuss examples of how drug resistance may be reversed by targeting the exported proteins topoisomerase IIalpha, BCR-ABL, and galectin-3. As effective and less toxic CRM1 export inhibitors become available, they may be used as both single agents and in combination with current chemotherapeutic drugs. We believe that the future development of low-toxicity, small-molecule CRM1 inhibitors may provide a new approach to treating cancer. PMID- 22209901 TI - Estimating the distribution of selection coefficients from phylogenetic data using sitewise mutation-selection models. AB - Estimation of the distribution of selection coefficients of mutations is a long standing issue in molecular evolution. In addition to population-based methods, the distribution can be estimated from DNA sequence data by phylogenetic-based models. Previous models have generally found unimodal distributions where the probability mass is concentrated between mildly deleterious and nearly neutral mutations. Here we use a sitewise mutation-selection phylogenetic model to estimate the distribution of selection coefficients among novel and fixed mutations (substitutions) in a data set of 244 mammalian mitochondrial genomes and a set of 401 PB2 proteins from influenza. We find a bimodal distribution of selection coefficients for novel mutations in both the mitochondrial data set and for the influenza protein evolving in its natural reservoir, birds. Most of the mutations are strongly deleterious with the rest of the probability mass concentrated around mildly deleterious to neutral mutations. The distribution of the coefficients among substitutions is unimodal and symmetrical around nearly neutral substitutions for both data sets at adaptive equilibrium. About 0.5% of the nonsynonymous mutations and 14% of the nonsynonymous substitutions in the mitochondrial proteins are advantageous, with 0.5% and 24% observed for the influenza protein. Following a host shift of influenza from birds to humans, however, we find among novel mutations in PB2 a trimodal distribution with a small mode of advantageous mutations. PMID- 22209902 TI - Among B-type cyclins only CLB5 and CLB6 promote premeiotic S phase in Saccharomyces cerevisiae. AB - The Saccharomyces cerevisiae cyclin Clb5 is required for premeiotic S phase, meiotic recombination, and successful progression through meiosis. Clb5 is not essential for mitotic proliferation because Clb1-Clb4 can support DNA replication in clb5 clb6 mutants. Clb1, Clb3, and Clb4 accumulate in clb5 clb6 cells during meiotic differentiation yet fail to promote premeiotic DNA replication. When expressed under the regulation of the CLB5 promoter, Clb1 and Clb3 accumulate and are active in the early stages of meiotic differentiation but cannot induce premeiotic DNA replication, suggesting that they do not target Cdk1 to the necessary substrates. The Clb5 hydrophobic patch (HP) residues are important for Clb5 function but this motif alone does not provide the specificity required for Clb5 to induce premeiotic S phase. Domain exchange experiments demonstrated that the amino terminus of Clb5 when fused to Clb3 confers upon Clb3 the ability to induce premeiotic S phase. Chimeric cyclins containing smaller regions of the Clb5 amino terminus displayed reduced ability to activate premeiotic DNA replication despite being more abundant and having greater associated histone H1 kinase activity than endogenous Clb5. These observations suggest that Clb5 has a unique ability to trigger premeiotic S phase and that the amino-terminal region of Clb5 contributes to its specificity and regulates the functions performed by the cyclin-Cdk complex. PMID- 22209903 TI - Going in the right direction: mating-type switching of Schizosaccharomyces pombe is controlled by judicious expression of two different swi2 transcripts. AB - Schizosaccharomyces pombe, the fission yeast, cells alternate between P- and M mating type, controlled by the alternate alleles of the mating-type locus (mat1). The mat1 switching occurs by replacing mat1 with a copy derived from a silenced "donor locus," mat2P or mat3M. The mechanism of donor choice ensuring that switching occurs primarily and productively to the opposite type, called directionality, is largely unknown. Here we identified the mat1-Mc gene, a mammalian sex-determination gene (SRY) homolog, as the primary gene that dictates directionality in M cells. A previously unrecognized, shorter swi2 mRNA, a truncated form of the swi2, was identified, and its expression requires the mat1 Mc function. We also found that the abp1 gene (human CENPB homolog) controls directionality through swi2 regulation. In addition, we implicated a cis-acting DNA sequence in mat2 utilization. Overall, we showed that switching directionality is controlled by judicious expression of two swi2 transcripts through a cell-type-regulated dual promoter. In this respect, this regulation mechanism resembles that of the Drosophila sex-determination Slx gene. PMID- 22209904 TI - Extended linkage disequilibrium in noncoding regions in a conifer, Cryptomeria japonica. AB - We measured linkage disequilibrium in mostly noncoding regions of Cryptomeria japonica, a conifer belonging to Cupressaceae. Linkage disequilibrium was extensive and did not decay even at a distance of 100 kb. The average estimate of the population recombination rate per base pair was 1.55 * 10(-5) and was <1/70 of that in the coding regions. We discuss the impact of low recombination rates in a large part of the genome on association studies. PMID- 22209906 TI - The dynamics of HIV-1 adaptation in early infection. AB - Human immunodeficiency virus type 1 (HIV-1) undergoes a severe population bottleneck during sexual transmission and yet adapts extremely rapidly to the earliest immune responses. The bottleneck has been inferred to typically consist of a single genome, and typically eight amino acid mutations in viral proteins spread to fixation by the end of the early chronic phase of infection in response to selection by CD8(+) T cells. Stochastic simulation was used to examine the effects of the transmission bottleneck and of potential interference among spreading immune-escape mutations on the adaptive dynamics of the virus in early infection. If major viral population genetic parameters are assigned realistic values that permit rapid adaptive evolution, then a bottleneck of a single genome is not inconsistent with the observed pattern of adaptive fixations. One requirement is strong selection by CD8(+) T cells that decreases over time. Such selection may reduce effective population sizes at linked loci through genetic hitchhiking. However, this effect is predicted to be minor in early infection because the transmission bottleneck reduces the effective population size to such an extent that the resulting strong selection and weak mutation cause beneficial mutations to fix sequentially and thus avoid interference. PMID- 22209907 TI - Ecological genomics of Anopheles gambiae along a latitudinal cline: a population resequencing approach. AB - The association between fitness-related phenotypic traits and an environmental gradient offers one of the best opportunities to study the interplay between natural selection and migration. In cases in which specific genetic variants also show such clinal patterns, it may be possible to uncover the mutations responsible for local adaptation. The malaria vector, Anopheles gambiae, is associated with a latitudinal cline in aridity in Cameroon; a large inversion on chromosome 2L of this mosquito shows large differences in frequency along this cline, with high frequencies of the inverted karyotype present in northern, more arid populations and an almost complete absence of the inverted arrangement in southern populations. Here we use a genome resequencing approach to investigate patterns of population divergence along the cline. By sequencing pools of individuals from both ends of the cline as well as in the center of the cline- where the inversion is present in intermediate frequency- we demonstrate almost complete panmixia across collinear parts of the genome and high levels of differentiation in inverted parts of the genome. Sequencing of separate pools of each inversion arrangement in the center of the cline reveals large amounts of gene flux (i.e., gene conversion and double crossovers) even within inverted regions, especially away from the inversion breakpoints. The interplay between natural selection, migration, and gene flux allows us to identify several candidate genes responsible for the match between inversion frequency and environmental variables. These results, coupled with similar conclusions from studies of clinal variation in Drosophila, point to a number of important biological functions associated with local environmental adaptation. PMID- 22209908 TI - A novel approach for directing transgene expression in Drosophila: T2A-Gal4 in frame fusion. AB - In Drosophila, the Gal4-UAS system permits a transgene to be expressed in the same pattern as a gene of interest by placing the Gal4 transcription factor under control of the gene's DNA regulatory elements. If these regulatory elements are not known, however, expression of Gal4 in the desired pattern may be difficult or impossible. To solve this problem, we have developed a method for co-expressing Gal4 with the endogenous gene by exploiting the "ribosomal skipping" mechanism of the viral T2A peptide. This method requires explicit knowledge only of the endogenous gene's open reading frame and not its regulatory elements. PMID- 22209910 TI - Disruptive effects of prefeeding and haloperidol administration on multiple measures of food-maintained behavior in rats. AB - Four rats responded under a choice reaction-time procedure. At the beginning of each trial, the rats were required to hold down a center lever for a variable duration, release it following a high- or low-pitched tone, and press either a left or right lever, conditionally on the tone. Correct choices were reinforced with a probability of .95 or .05 under blinking or static houselights, respectively. After performance stabilized, disruptive effects of free access to food pellets prior to sessions (prefeeding) and intraperitoneal injection of haloperidol were examined on multiple behavioral measures (i.e., the number of trials completed, percent of correct responses, and reaction time). Resistance to prefeeding depended on the probability of food delivery for the number of trials completed and reaction time. Resistance to haloperidol, on the other hand, was not systematically affected by the probability of food delivery for all dependent measures. PMID- 22209909 TI - Kinetic analyses and inhibition studies reveal novel features in peptide deformylase 1 from Trypanosoma cruzi. AB - In eubacteria and eukaryotic organelles N-terminal methionine excision requires the sequential action of two activities, a peptide deformylase (PDF), which systematically removes the N-formyl group present on all nascent polypeptides and methionine aminopeptidase (MAP), which exscinds methionine specifically and depends on the previous removal of the N-formyl group. In Trypanosoma cruzi two genes encoding bacterial PDF homologues have been identified and referred to as TcPDF-1 and TcPDF-2. Here we report the biochemical characterization of a truncated soluble version of TcPDF-1 lacking the hydrophobic N-terminal domain that is active with the bacterial PDF substrate formyl-methionyl-alanyl-serine but, in contrast to other PDFs, is not inhibited by actinonin. The enzyme is strongly activated by Cu(2+) and inhibited by Ni(2+). Our results show that T. cruzi PDF exhibits unique features thus providing a new avenue for the design of potential inhibitors for use in the treatment of diseases caused by trypanosomatid parasites. PMID- 22209911 TI - The NK3 receptor agonist senktide ameliorates scopolamine-induced deficits in memory for object, place and temporal order. AB - Senktide, a potent neurokinin-3 receptor (NK3-R) agonist, increases acetylcholine (ACh) release in the striatum, the prefrontal cortex (Schable et al., 2011), the amygdala and hippocampus, presumably via postsynaptic mechanisms. A promnestic action of NK3-R agonists has been described in a variety of learning/memory tasks. The memory-enhancing effects of NK3-R agonists and their activating influence on ACh suggest a possible role of the NK3-R in learning and memory via cholinergic modulation. Deterioration of the cholinergic system in the basal forebrain has been associated with learning and memory deficits and cholinergic agents have promnestic effects in a variety of learning paradigms. The anticholinergic drug, scopolamine, a muscarinic ACh receptor antagonist, incurs deficits in a variety of learning tasks and provides a useful tool to investigate the role of the cholinergic systems in mechanisms underlying learning and memory. The aim of this study was to ascertain the effect of the NK3-R agonist, senktide, in the scopolamine-induced deficit model. We hypothesized that senktide treatment would attenuate scopolamine-induced (subcutaneous--s.c. 0.75 mg/kg) memory impairment in three novelty preference paradigms based on spontaneous object exploration: namely object recognition, object-place recognition and object recognition for temporal order. Administration of senktide reversed the scopolamine-induced memory deficits by re-establishing object recognition (s.c. 0.2 mg/kg), object-place recognition (0.2 and 0.4 mg/kg), as well as object recognition for temporal order (0.4 mg/kg) in adult Wistar rats. These results indicate memory enhancing effects of senktide in animals subjected to scopolamine induced memory impairments and indicate that the promnestic action of NK3-R agonists is mediated by muscarinic cholinergic mechanisms. PMID- 22209912 TI - Human body exhibitions: public opinion of young individuals and contemporary bioethics. AB - PURPOSE: The exhibitions of plastinated cadavers and organs have attracted millions of visitors globally, while raising serious controversy about their content and purpose of implementation. METHODS: We performed a survey based study on 500 randomly chosen individuals, aged 18- to 35-year old, in order to access their opinion regarding the conduction of such shows as well as body donation for scientific purposes. RESULTS: We found that 46.3% of the participants had moral concerns, and 46.1% did not. Religious and philosophical beliefs concerned 21.8% of the sample, while 28% believed that the exhibits may affect visitors' mental health. Human dignity violation was stressed by 21.6%, whereas 26.6% disagreed with body donation to science. CONCLUSIONS: The desire for qualitative-guided anatomy education is evident from the highly popular plastinated body and specimen exhibitions. Hence, additional focused effort could be provided to educate the public about normal and pathological anatomy in order to amend their life-style. This could be effected by certified anatomy demonstrators in graduated steps according to the cohort's age, education, occupation, and health status. PMID- 22209913 TI - Fast analysis of wine for total homocysteine content by high-performance liquid chromatography. AB - Alimentary methionine is believed to be the main source for plasma homocysteine. Recent literature supplies information about homocysteine content in daily food components, but not in wine, an attractive complement of the evening meal in some western countries. In this communication, a simple and fast high-performance liquid chromatography method for determination of total homocysteine in wine is described. The two steps procedure relies on reduction of the disulfide forms of homocysteine with tris-(2-carboxyethyl)phosphine and on-column derivatization with o-phthaldialdehyde followed by separation and fluorescence detection. The entire analysis time, including sample work-up, amounts 14 min. The calibration performed with wine matrix, spiked with homocystine within the practical concentration range, proved linear response of the detector. The proposed method was applied for the analysis of 32 different types of wines for total homocysteine. The average concentration of the analyte was 10.31 (+/-4.25) uM and 6.11 (+/-3.44) uM for red (n = 23) and white (n = 9) wines, respectively. PMID- 22209914 TI - Acute kidney injury in children with visceral leishmaniasis. AB - BACKGROUND: There is no comprehensive study about renal function in children with visceral leishmaniasis (VL). The aim of this study was to investigate the incidence of acute kidney injury (AKI) in children with VL using pRIFLE classification and to determine the risk factors for AKI. METHODS: A retrospective cohort study was conducted with 146 patients younger than 14 years of age with VL diagnosis in one center located at the northeast of Brazil from December 2003 to 2010. AKI was evaluated by pediatric Risk, Injury, Failure, Loss, End-stage kidney disease (pRIFLE) criteria. RESULTS: The mean age was 5 +/- 4.0 years (range, 5 months to 14 years), and 53.4% were males. AKI was observed in 67 patients (45.9%). The distribution according to the pRIFLE criteria was as follows: risk 45 (67.2%), injury 21 (31.3%), and failure 1 (1.5%). Patients in the AKI group were significantly younger (P < 0.001) and had jaundice (P = 0.028) and secondary infections (P = 0.001) more often than non-AKI patients. The AKI group had a significantly lower serum sodium (P = 0.03), potassium (P = 0.009), serum albumin (P = 0.001), and elevated serum globulins (P = 0.04), and a more prolonged prothrombin time (P = 0.001) at admission. Independent risk factors for AKI were: secondary infections (OR: 3.65, 95% CI: 1.426-9.358, P = 0.007), serum albumin decrement (OR: 1.672, 95% CI: 1.065-2.114, P = 0.019 per each 1 mg dL(-1) serum albumin decrement), and high serum globulin (OR: 1.35, 95% CI: 1.031-1.779, P = 0.029 per each 1 mg dL(-1) serum globulin increment). CONCLUSIONS: AKI is a frequent complication in children with VL. The risk factors for AKI were secondary infections, high serum globulin and low serum albumin. PMID- 22209905 TI - The response to heat shock and oxidative stress in Saccharomyces cerevisiae. AB - A common need for microbial cells is the ability to respond to potentially toxic environmental insults. Here we review the progress in understanding the response of the yeast Saccharomyces cerevisiae to two important environmental stresses: heat shock and oxidative stress. Both of these stresses are fundamental challenges that microbes of all types will experience. The study of these environmental stress responses in S. cerevisiae has illuminated many of the features now viewed as central to our understanding of eukaryotic cell biology. Transcriptional activation plays an important role in driving the multifaceted reaction to elevated temperature and levels of reactive oxygen species. Advances provided by the development of whole genome analyses have led to an appreciation of the global reorganization of gene expression and its integration between different stress regimens. While the precise nature of the signal eliciting the heat shock response remains elusive, recent progress in the understanding of induction of the oxidative stress response is summarized here. Although these stress conditions represent ancient challenges to S. cerevisiae and other microbes, much remains to be learned about the mechanisms dedicated to dealing with these environmental parameters. PMID- 22209915 TI - Is 15 days an appropriate cut-off age for considering serious bacterial infection in the management of febrile infants? AB - INTRODUCTION: Febrile infants <3 months of age have a greater risk for serious bacterial infection (SBI). The risk is inversely correlated with age. Most protocols recommend admitting to hospital all febrile infants <28 days of age. However, as the prevalence of SBI is not homogenous in this age group, some authors have considered decreasing this cut-off age, allowing ambulatory management of selected patients meeting low-risk criteria. OBJECTIVE: To determine whether 15 days is a suitable cut-off age for different approaches to the management of infants with fever. PATIENTS AND METHODS: Cross-sectional descriptive study of infants <3 months of age with fever without a source seen between September 1, 2003 and August 30, 2010 in the pediatric emergency department of a tertiary teaching hospital. All infants <3 months of age with fever without a source (<= 38 degrees C) were included. The following data were collected: age, sex, temperature, diagnosis, management in pediatric emergency department, and outcome. RESULTS: Data were collected for 1575 infants; of whom, 311 (19.7%, 95% confidence intervals [CI]: 17.7-21.7) were found to have an SBI. The rate of SBI in the patients who were 15 to 21 days of age was 33.3% (95% CI: 23.7%-42.9%), similar to that among infants who were 7 to 14 days of age (31.9%, 95% CI: 21.1%-42.7%) and higher than among those older than 21 days of age (18.3%, 95% CI: 16.3-20.3%). CONCLUSIONS: Febrile infants 15 to 21 days of age had a rate of SBI similar to younger infants and higher than older age infants. It is not appropriate to establish the approach to management of infants with fever based on a cut-off age of 2 weeks. PMID- 22209916 TI - Rising rates of macrolide-resistant Mycoplasma pneumoniae in the central United States. AB - Macrolide-resistant Mycoplasma pneumoniae is widespread in Asia, and severe cases of pneumonia have been described in children. Little information is available about the resistance pattern in the United States. We collected respiratory samples from 49 patients with Mycoplasma infection in the central United States between 2007 and 2010. We found a macrolide resistance rate of 8.2%. Resistance should be considered when patients with M. pneumoniae infection do not have a satisfactory response to macrolides. Alternative antibiotics include tetracyclines or fluoroquinolones. PMID- 22209917 TI - Safety and pharmacokinetics of oseltamivir for prophylaxis of neonates exposed to influenza H1N1. AB - Oseltamivir was administered at 1.0 mg/kg b.i.d. to 13 neonates exposed to influenza H1N1. No influenza, neurologic, or laboratory adverse effects occurred. The mean Cmax values for oseltamivir and oseltamivir carboxylate were found to be lower than those reported for children 1 to 5 years old, whereas Tmax values were similar to children 1 to 5 years old. Age and gender were found to significantly affect oseltamivir clearance. PMID- 22209918 TI - Q fever as a cause of recurrent soft-tissue nodules and abscesses in a child. AB - A 3-year-old boy from a cattle property in Queensland, Australia developed chronic, multifocal, recurrent subcutaneous nodules and abscesses during a period of 2 years. Serologic and histologic findings and management options are discussed. PMID- 22209919 TI - Anti-hyperalgesic effects of anti-serotonergic compounds on serotonin- and capsaicin-evoked thermal hyperalgesia in the rat. AB - The peripheral serotonergic system has been implicated in the modulation of an array of pain states, from migraine to fibromyalgia; however, the mechanism by which serotonin (5HT) induces pain is unclear. Peripherally released 5HT induces thermal hyperalgesia, possibly via modulation of the transient receptor potential V1 (TRPV1) channel, which is gated by various noxious stimuli, including capsaicin. We previously reported in vitro that 5HT increases calcium accumulation in the capsaicin-sensitive population of sensory neurons with a corresponding increase in proinflammatory neuropeptide release, and both are antagonized by pretreatment with 5HT(2A) and 5HT(3) antagonists, as well as the anti-migraine drug sumatriptan. In the current study, we extended these findings in vivo using the rat hind paw thermal assay to test the hypothesis that peripheral 5HT enhances TRPV1-evoked thermal hyperalgesia that can be attenuated with 5HT(2A) and 5HT(3) receptor antagonists, as well as sumatriptan. Thermal hyperalgesia and edema were established by 5HT injection (0.1-10 nmol/100 MUl) into the rat hind paw, and the latency to paw withdrawal (PWL) from noxious heat was determined. Rats were then pretreated with either 5HT before capsaicin (3 nmol/10 MUl), the 5HT(2A) receptor antagonist ketanserin or the 5HT(3) receptor antagonist granisetron (0.0001-0.1 nmol/100 MUl) before 5HT and/or capsaicin, or the 5HT(1B/1D) receptor agonist sumatriptan (0.01-1 nmol/100 MUl) before capsaicin, and PWL was determined. We report that 5HT pretreatment enhances TRPV1 evoked thermal hyperalgesia, which is attenuated with local pretreatment with ketanserin, granisetron, or sumatriptan. We also report that peripheral 5HT induced a similar magnitude of thermal hyperalgesia in male and female rats. Overall, our results provide in vivo evidence supporting an enhancing role of 5HT on TRPV1-evoked thermal hyperalgesia, which can be attenuated by peripheral serotonergic intervention. PMID- 22209921 TI - Reaction products of [60]fullerene during the autoxidation of methyl linoleate in bulk phase. AB - The antioxidative action of fullerenes has received much attention, but their reaction mechanism toward lipid-derived peroxyl radicals has not been well elucidated. In this study, the reaction products of [60]fullerene (C(60)) during the autoxidation of methyl linoleate (MeL) were isolated and their structures were characterized. MeL containing 0.1mol% C(60) was autoxidized at 60 degrees C in bulk phase and two reaction products of C(60), 1 and 2, were obtained. The structure of 1 was the addition products of C(60) with 9-peroxyl-10-alkyl radicals of methyl (11E)-13-hydroperoxy-11-octadecaenoate (1a and 1b) and with 12 alkyl-13-peroxyl radicals of methyl (10E)-9-hydroperoxy-10-octadecaenoate (1c and 1d). 2 was a mixture of the addition products of C(60) with 9,11-dialkyl radicals of methyl 9,12-octadecadienoate (2a) and with 11,13-dialkyl radicals of methyl 9,12-octadecadienoate (2b). When MeL containing 0.1mol% C(60) was autoxidized at 60 degrees C under air-sufficient and air-insufficient conditions, C(60) could suppress the formation of MeL hydroperoxides in both conditions. The reaction product of C(60) first formed was 2 even under air-sufficient conditions, and then 1 was accumulated. The results indicate that the primary antioxidative action of C(60) would be trapping of chain-initiating carbon-centered radicals of unsaturated lipid to form 2. PMID- 22209922 TI - Aqueous dispersions of DMPG in low salt contain leaky vesicles. AB - Aqueous dispersions of dimyristoyl phosphatidylglycerol (DMPG), at low ionic strength, display uncommon thermal behavior. Models for such behavior need to assign a form to the lipid aggregate. Although most studies accept the presence of lipid vesicles in the lipid gel and fluid phases, this is still controversial. With electron spin resonance (ESR) spectra of spin labels incorporated into DMPG aggregates, quantification of [(14)C]sucrose entrapped by the aggregates, and viscosity measurements, we demonstrate the existence of leaky vesicles in dispersions of DMPG at low ionic strength, in both gel and fluid phases of the lipid. As a control system, the ubiquitous lipid dimyristoyl phosphatidylcholine (DMPC) was used. For DMPG in the gel phase, spin labeling only indicated the presence of lipid bilayers, strongly suggesting that DMPG molecules are organized as vesicles and not micelles or bilayer fragments (bicelles), as the latter has a non-bilayer structure at the edges. Quantification of [(14)C]sucrose entrapping by DMPG aggregates revealed the presence of highly leaky vesicles. Due to the short hydrocarbon chains ((14)C atoms), DMPC vesicles were also found to be partially permeable to sucrose, but not as much as DMPG vesicles. Viscosity measurements, with the calculation of the intrinsic viscosity of the lipid aggregate, showed that DMPG vesicles are rather similar in the gel and fluid phases, and quite different from aggregates observed along the gel-fluid transition. Taken together, our data strongly supports that DMPG forms leaky vesicles at both gel and fluid phases. PMID- 22209920 TI - Frequency selectivity and dopamine-dependence of plasticity at glutamatergic synapses in the subthalamic nucleus. AB - In Parkinson's disease, subthalamic nucleus (STN) neurons burst fire with increased periodicity and synchrony. This may entail abnormal release of glutamate, the major source of which in STN is cortical afferents. Indeed, the cortico-subthalamic pathway is implicated in the emergence of excessive oscillations, which are reduced, as are symptoms, by dopamine-replacement therapy or deep brain stimulation (DBS) targeted to STN. Here we hypothesize that glutamatergic synapses in the STN may be differentially modulated by low frequency stimulation (LFS) and high-frequency stimulation (HFS), the latter mimicking deep brain stimulation. Recordings of evoked and spontaneous excitatory post synaptic currents (EPSCs) were made from STN neurons in brain slices obtained from dopamine-intact and chronically dopamine-depleted adult rats. HFS had no significant effect on evoked (e) EPSC amplitude in dopamine-intact slices (104.4+/-8.0%) but depressed eEPSCs in dopamine-depleted slices (67.8+/-6.2%). Conversely, LFS potentiated eEPSCs in dopamine-intact slices (126.4+/-8.1%) but not in dopamine-depleted slices (106.7+/-10.0%). Analyses of paired-pulse ratio, coefficient of variation, and spontaneous EPSCs suggest that the depression and potentiation have a presynaptic locus of expression. These results indicate that the synaptic efficacy in dopamine-intact tissue is enhanced by LFS. Furthermore, the synaptic efficacy in dopamine-depleted tissue is depressed by HFS. Therefore the therapeutic effects of DBS in Parkinson's disease appear mediated, in part, by glutamatergic cortico-subthalamic synaptic depression and implicate dopamine dependent increases in the weight of glutamate synapses, which would facilitate the transfer of pathological oscillations from the cortex. PMID- 22209923 TI - Effect of head group and curvature on binding of the antimicrobial peptide tritrpticin to lipid membranes. AB - In this work we examine the interaction between the 13-residue cationic antimicrobial peptide (AMP) tritrpticin (VRRFPWWWPFLRR, TRP3) and model membranes of variable lipid composition. The effect on peptide conformational properties was investigated by means of CD (circular dichroism) and fluorescence spectroscopies. Based on the hypothesis that the antibiotic acts through a mechanism involving toroidal pore formation, and taking into account that models of toroidal pores imply the formation of positive curvature, we used large unilamellar vesicles (LUV) to mimic the initial step of peptide-lipid interaction, when the peptide binds to the bilayer membrane, and micelles to mimic the topology of the pore itself, since these aggregates display positive curvature. In order to more faithfully assess the role of curvature, micelles were prepared with lysophospholipids containing (qualitatively and quantitatively) head groups identical to those of bilayer phospholipids. CD and fluorescence spectra showed that, while TRP3 binds to bilayers only when they carry negatively charged phospholipids, binding to micelles occurs irrespective of surface charge, indicating that electrostatic interactions play a less predominant role in the latter case. Moreover, the conformations acquired by the peptide were independent of lipid composition in both bilayers and micelles. However, the conformations were different in bilayers and in micelles, suggesting that curvature has an influence on the secondary structure acquired by the peptide. Fluorescence data pointed to an interfacial location of TRP3 in both types of aggregates. Nevertheless, experiments with a water soluble fluorescence quencher suggested that the tryptophan residues are more accessible to the quencher in micelles than in bilayers. Thus, we propose that bilayers and micelles can be used as models for the two steps of toroidal pore formation. PMID- 22209924 TI - Chronic obstructive pulmonary diseases in the elderly: a paradigm of complexity. PMID- 22209925 TI - Metalloproteases/anti-metalloproteases imbalance in chronic obstructive pulmonary disease: genetic factors and treatment implications. AB - PURPOSE OF REVIEW: The aim is to describe the involvement of matrix metalloprotease (MMP), A Disintegrin And Metalloproteases (ADAM), tissue inhibitors of MMP (TIMP) polymorphisms and the role of alpha-2 Macroglobulin (alpha-2M) in chronic obstructive pulmonary disease (COPD) development and progression, with a focus on interventions with synthetic MMP inhibitors alone or associated with current drugs used in COPD therapy in order to restore MMPs/TIMPs imbalance. RECENT FINDINGS: COPD is one of the major causes of death in the elderly. It is characterized by progressive development of airflow limitation manifested by decreased forced expiratory volume in one second (FEV1) and reduction in the percentage of FEV1/forced vital capacity. The major pathogenic role is played by metalloproteases (MMPs, ADAMs)/anti-metalloproteases (TIMPs, alpha-2M) imbalance, which is responsible for MMP overproduction not sufficiently counteracted by TIMPs or alpha-2M. As a consequence, the lung extracellular matrix is destroyed with obstruction of small airways and appearance of emphysema. SUMMARY: The disease is mainly caused by exposure to cigarette smoke or noxious gases and air pollutants, but also genetic factors are involved. Among them, polymorphisms of MMPs (MMP1, MMP2, MMP9, MMP12), ADAMs (ADAM33) and TIMPs (TIMP1, TIMP2) are relevant, in which the inflammation and the smoking habit play key roles especially in unfavorable allele carriers. The association between these polymorphisms and the current drugs paves the way for personalized therapy with a great impact at clinical level. PMID- 22209926 TI - Comorbidities of chronic obstructive pulmonary disease. AB - PURPOSE OF REVIEW: Defining the nature of the association between chronic obstructive pulmonary disease (COPD) and other chronic conditions is of primary importance to improve the health status of COPD patients through the optimal care of comorbidities. We aimed at providing a reasoned guide to understand, recognize and treat comorbidity of COPD with the perspective of shifting from comorbidity to multimorbidity. RECENT FINDINGS: Select comorbidities, such as atherosclerotic disease, depression, chronic kidney disease, cognitive impairment, obstructive sleep apnea syndrome, lung cancer, osteoporosis, diabetes, heart failure, sarcopenia, aortic aneurysm, arrhythmias and pulmonary embolism are highly prevalent among older COPD patients. Several concerns may affect the management of older COPD patients with comorbidity (e.g. the use of beta-blockers in patients with COPD and cardiovascular diseases or concerns about the cardiovascular safety of inhaled COPD drugs). SUMMARY: Evidence suggests that systemic inflammation may be the link between COPD and comorbidities, but this issue is still debated. Whatever the mechanism underlying comorbidities in COPD may be, it has an important clinical, prognostic and therapeutic impact. Nevertheless, clinical practice guidelines do not take into account comorbidities in their recommendations. Additionally, clinical trials investigating COPD treatment in the context of multimorbidity and considering geriatric outcomes are also distinctly lacking. PMID- 22209927 TI - Common geriatric conditions and disabilities in older persons with chronic obstructive pulmonary disease. AB - PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is one of the most prevalent chronic diseases among older persons worldwide and the rapid increase in commonly associated COPD-disabilities requires urgent awareness among healthcare professionals. The presence of pulmonary and extrapulmonary comorbidities is highly prevalent among COPD patients and complicates treatment management, especially in advanced age. Some of the most common geriatric conditions in COPD patients lead to respiratory function decline, physical function impairment with limited physical performance, cognitive decline, and depression. Unfortunately, the activation of each component may lead to the progression of the other, which, if not corrected, will lead to critical clinical outcomes such as disability (as seen by the worsening of each condition) and death. RECENT FINDINGS: Studies in older persons with COPD have shown that disability is mainly due to the severity of comorbidities that have been shown to significantly impact treatment options and the prognosis for such individuals. In addition to spirometric functional parameters, exercise performance and efficacy of specific therapeutic interventions may be useful indicators for overall health status and outcomes. The scientific literature underlines the necessity to use additional parameters other than spirometry for COPD patient monitoring. SUMMARY: As disability is a growing phenomenon in COPD and substantially impacts patient perception of the disease, we will highlight the recent literature regarding the importance of common geriatric conditions leading to disability in older COPD patients. In particular, we will discuss the impact of the following conditions in older patients with COPD: respiratory function decline, physical function impairment, and mood disorders. Clinical use for measuring such parameters in COPD elderly will aid in identifying those at risk for severe clinical decline. PMID- 22209928 TI - Inflammation, chronic obstructive pulmonary disease and aging. AB - PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal persistent inflammatory response to noxious environmental stimuli, particularly cigarette smoke. The determinants of the dysregulated immune responses, which play a role both in the onset and continuation of COPD, are largely unknown. We examined several molecular mechanisms regulating the inflammatory pathway, such as cytokine polymorphisms, miRNA expression, and DNA methylation in COPD and aging, with the aim to provide evidence supporting the view that aging of the immune system may predispose to COPD. RECENT FINDINGS: The incidence of COPD increases with age. The pathogenesis of the disease is linked to a chronic inflammation and involves the recruitment and regulation of innate and adaptive immune cells. A chronic systemic inflammation characterizes aging and has been correlated with many diseases, most of them age-related. SUMMARY: COPD and aging are associated with significant dysregulation of the immune system that leads to a chronic inflammatory response. The similar molecular mechanisms and the common genetic signature shared by COPD and aging suggest that immunosenescence may contribute to the development of COPD. PMID- 22209929 TI - The economic burden of chronic obstructive pulmonary disease in the elderly: results from a systematic review of the literature. AB - PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a high prevalence condition with a significant clinical and economic burden. In elderly people, COPD is often associated with other chronic comorbidities (i.e. cardiovascular diseases), determining clinical complications and requiring frequent acute healthcare interventions. The aim of this article is to review the economic studies evaluating costs and healthcare resource utilization in elderly (>= 65 years) COPD patients. RECENT FINDINGS: Sixteen of the initial 359 articles retrieved through our research strategy were found to include relevant cost information on elderly COPD patients or to evaluate the effect of older age on healthcare expenditure. Most studies were carried out in the United States and used administrative database claims to determine resource consumption and direct costs (attributable and not). Very few studies focused exclusively on elderly patients. SUMMARY: Results showed a certain variability of cost estimations, mainly due to the different methodologies and adopted cost approach. However, we found a trend of direct cost growth in the elderly population, which can be explained by a more frequent use of acute healthcare services, especially for managing COPD exacerbations. These results cannot be considered definitive and new studies, targeting elderly people, are required in order to confirm these preliminary findings. PMID- 22209930 TI - Practical management problems of stable chronic obstructive pulmonary disease in the elderly. AB - PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is one of the most prevalent and increasing health problems in the elderly on a worldwide scale. The management of COPD in older patients presents practical diagnostic and treatment issues, which are reviewed with reference to the stable stage of the disease. RECENT FINDINGS: In the diagnostic approach of COPD in the elderly the use of spirometry is recommended, but both patient conditions (such as inability to correctly perform it due to fatigue, lack of coordination, and cognitive impairment) and metrics characteristics should be taken into account for the test performance. It has been demonstrated in population studies that the use of the fixed ratio determines a substantial overdiagnosis of COPD in the oldest patients. Other parameters have been suggested [such as the evaluation of Lower Limit of Normality (LLN) for the FEV1/FVC ratio], which may be useful to guide the diagnosis. Several nonpharmacologic - such as smoking cessation, vaccination, physical activity, and pulmonary rehabilitation, nutrition, and eventually invasive ventilation - and pharmacologic interventions have been shown to improve outcomes and have been reviewed. Effective management of COPD in older adults should always consider the ability of patients to properly use inhalers and the involvement of caregivers or family members as a useful support to care, especially when treating cognitively impaired patients. Especially in the older population, timely identification and treatment of comorbidities are also crucial, but evidence in this area is still lacking and clinical practice guidelines do not take comorbidities into account in their recommendations. SUMMARY: The Global Initiative for Obstructive Lung Disease has recommended criteria for diagnosis and management of COPD in the general population. On the contrary, available evidence suggests practical limitations in diagnostic approach and intervention strategies in older patients with stable COPD that need to be further studied for a translation into clinical practice guidelines. PMID- 22209931 TI - Practical management problems of chronic obstructive pulmonary disease in the elderly: acute exacerbations. AB - PURPOSE OF REVIEW: Acute exacerbations of chronic obstructive pulmonary disease (ECOPDs) have numerous causes and are associated with increased mortality and hospitalization, especially in older patients. The urgent need to identify and enable timely treatment of ECOPDs is a necessity for physicians worldwide. This review will highlight the causes and optimal combinations of available treatments for such events in older populations. RECENT FINDINGS: The exact definition of exacerbations is lacking; however, it is agreed that such events are considered episodes of worsening of symptoms, leading to morbidity and death. The aging process is a consistent determinant for ECOPD events and is associated with worsening of COPD stages. The incidence of ECOPD rises across the worsening stages of COPD. Studies have shown that the frequency of exacerbations increases with age and correlated clinical outcomes are poorer than in younger patients. The risk of mortality has also been shown to be significantly higher after a hospital admission following an acute exacerbation. At the moment, the need to rapidly and correctly treat acute exacerbations is crucially important in the rapidly growing elderly population. SUMMARY: ECOPDs are extremely dangerous events for older patients with severe stages of COPD. There is an urgent need to identify risk factors, identify tolerable treatment guidelines and manage acute exacerbations in older patients with COPD. PMID- 22209932 TI - Chronic obstructive pulmonary disease in the elderly: identifying the knowledge gaps to support research and clinical practice guidelines. PMID- 22209933 TI - Pancreatic serine protease extraction by affinity partition using a free triazine dye. AB - Affinity partitioning combines the partitioning behavior of biological macromolecules in aqueous two-phase systems with the principle of biorecognition. Among the numerous substances that have been evaluated as ligands, the reactive dyes constitute a group of low cost textile dyes which have proved to act as biomimetic ligands for many enzymes. The ability of reactive yellow 2 (RY2) to interact with trypsin (TRP) and chymotrypsin (ChTRP) and its behavior in aqueous two-phase systems formed by polyethylene glycol (PEG) and sodium citrate (NaCit) were investigated. Different variables such as PEG molecular weight, tie line length and dye concentration were analyzed. RY2 showed to bind specifically to both TRP and ChTRP with affinity constants near to 10(3)M(-1). Its partition equilibrium is practically displaced to the top phase in systems formed by PEG of different molecular weight. Addition of this dye to PEG 8000/NaCit systems until a final concentration of 0.196% (w/w) induced an increase in TRP and ChTRP partition coefficients of at least 2 times over that in the absence of the ligand. These findings demonstrate that RY2 fulfils all the requirements to be considered as an affinity ligand in aqueous two-phase partitioning of TRP and ChTRP. PMID- 22209934 TI - Toxoplasma gondii Sis1-like J-domain protein is a cytosolic chaperone associated to HSP90/HSP70 complex. AB - Toxoplasma gondii is an obligate intracellular protozoan parasite in which 36 predicted Hsp40 family members were identified by searching the T. gondii genome. The predicted protein sequence from the gene ID TGME49_065310 showed an amino acid sequence and domain structure similar to Saccharomyces cerevisiae Sis1. TgSis1 did not show differences in its expression profile during alkaline stress by microarray analysis. Furthermore, TgSis1 showed to be a cytosolic Hsp40 which co-immunoprecipitated with T. gondii Hsp70 and Hsp90. Structural modeling of the TgSis1 peptide binding fragment revealed structural and electrostatic properties different from the experimental model of human Sis1-like protein (Hdj1). Based on these differences; we propose that TgSis1 may be a potentially attractive drug target for developing a novel anti-T. gondii therapy. PMID- 22209935 TI - Human serum albumin as a new interacting partner of prolactin inducible protein in human seminal plasma. AB - Prolactin inducible protein (PIP) is a 17 kDa glycoprotein. It binds to many proteins including fibrinogen, actin, keratin, myosin, immunoglobulin G, CD4, and human zinc-alpha-2 glycoprotein. Its ability to bind a large array of proteins indicates its multifaceted role in various biological processes, such as fertility, immunoregulation, antimicrobial activity, apoptosis, and tumor progression. Here, we present the first report of native human serum albumin (HSA)-PIP complex formation in seminal plasma. The complex was purified by chromatographic separation techniques, analyzed by gel electrophoresis, identified by MALDI-TOF mass spectrometry and validated by co-immunoprecipitation coupled with western blotting experiments. Moreover, the behavior of complex in solution was analyzed by dynamic light scattering and interacting residues were identified by in silico protein-protein docking. The purified protein complex shows two bands (67 kDa and 17 kDa) on SDS-PAGE gel and a single band (~85 kDa) on native PAGE gel. The predicted complex structure has 13 intermolecular hydrogen bonds, which may contribute to the overall stability of the complex. As HSA has been known to preserve the motility of sperm, native HSA-PIP complex formation may point towards an important role of PIP, which can directly be correlated with male fertility/infertility. PMID- 22209937 TI - Anaerobic bacterial infection of the lung. AB - Anaerobic bacteria are relatively frequent pathogens in pulmonary infections that are associated with aspiration and its associated complications including aspiration pneumonitis, lung abscess, necrotizing pneumonia and empyema. These conditions have been studied since the early 1900's and substantial data with important clinical and microbiologic information are now readily available. However, the reports of these infections in the past 20 years have been sparse in number and much of the previous information relevant to this topic seems much less visible or apparent. The purpose of this report is to summarize the previous data and to celebrate the enormous contributions of Dr. Sydney Finegold to this topic. PMID- 22209938 TI - Interactions between Clostridium perfringens spores and Raw 264.7 macrophages. AB - Clostridium perfringens is the causative agent of a variety of histotoxic infections in humans and animals. Studies on the early events of C. perfringens infections have been largely focused on the interactions between their vegetative cells and macrophages. Consequently, in the current study we have examined the interactions between C. perfringens spores and Raw 264.7 macrophages. Raw 264.7 cells were able to interact and phagocytose Clostridium perfringens spores of a food poisoning isolate, strain SM101, and a non-food borne isolate, strain F4969, albeit to different extents. Phagocytosis and to a lesser extent, association, of C. perfringens spores by Raw 2647 macrophages was completely inhibited in presence of cytochalasin D. Complement increased association and phagocytosis of C. perfringens spores by Raw 264.7 macrophages. Survival of C. perfringens spores during macrophage infection seems to depend on the ability of spore germination during infection as: (i) F4969 spores germinated during infection with Raw 264.7 macrophages and subsequently killed by macrophages; and (ii) SM101 spores remained dormant inside Raw 264.7 macrophages and thus survived up to 24 h of infection. The in vitro spore-resistance factors, alpha/beta-type SASP, SpmA/B proteins and spore's core water content, seems to play no role in mediating SM101 spore-resistance to macrophages. Collectively, these results might well have implications in understanding the initial stages of infections by C. perfringens spores. PMID- 22209940 TI - Hymenolepis diminuta: analysis of the expression of Toll-like receptor genes (TLR2 and TLR4) in the small and large intestines of rats. AB - Toll receptors play a critical role in the rapid activation of innate immune responses to a variety of pathogens. In mammals, Toll-like receptors (TLR) have been found in both immune related cells and other cells. At present little is known about the participation of TLR in host defense mechanisms during parasitic infections. The aim of this study was to determine the expression of TLR2 and TLR4 genes in rat intestines during experimental hymenolepidosis. There is difference in expression of TLR2 and TLR4 genes in the colon and jejunum in uninfected rats: in the colon, mRNA of the examined TLR is present in much higher amounts than the jejunum, while the protein of the TLR also had a segmented specific distribution. In the jejunum isolated rats infected with Hymeolepis diminuta 6 and 8 days post infection (dpi), mRNA for TLR4 and TLR2 were significantly more strongly expressed in comparison with the uninfected controls. In the colon, a statistically significantly increased expression of TLR4 gene was observed only at 6 dpi, and at 8 dpi for the TLR2 gene. Moreover, we observed that during inflammation, the immunopositive cell number and the intensity of immunohistochemical staining (indicating the presence of TLR within intestinal epithelial cells), increased together with the duration of the infection period. PMID- 22209939 TI - Apolipoprotein A-V dependent modulation of plasma triacylglycerol: a puzzlement. AB - The discovery of apolipoprotein A-V (apoA-V) in 2001 has raised a number of intriguing questions about its role in lipid transport and triglyceride (TG) homeostasis. Genome wide association studies (GWAS) have consistently identified APOA5 as a contributor to plasma TG levels. Single nucleotide polymorphisms (SNP) within the APOA5 gene locus have been shown to correlate with elevated plasma TG. Furthermore, transgenic and knockout mouse models support the view that apoA-V plays a critical role in maintenance of plasma TG levels. The present review describes recent concepts pertaining to apoA-V SNP analysis and their association with elevated plasma TG. The interaction of apoA-V with glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) is discussed relative to its postulated role in TG-rich lipoprotein catabolism. The potential role of intracellular apoA-V in regulation of TG homeostasis, as a function of its ability to associate with cytosolic lipid droplets, is reviewed. While some answers are emerging, numerous mysteries remain with regard to this low abundance, yet potent, modulator of TG homeostasis. Given the strong correlation between elevated plasma TG and heart disease, there is great scientific and public interest in deciphering the numerous biological riddles presented by apoA-V. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease. PMID- 22209941 TI - In vitro anthelmintic effect of Melia azedarach L. and Trichilia claussenii C. against sheep gastrointestinal nematodes. AB - The control of parasitic diseases in small ruminants is mainly done with the use of synthetic anthelmintics. However, incorrect and indiscriminate use of these products has caused the emergence of parasite resistance. Plants with anthelmintic activity are used in folk veterinary medicine, but it is necessary to investigate and scientifically validate low-cost phytotherapeutic alternatives for future use to control gastrointestinal nematodes in small ruminants by family farmers. Thus, the aim of this study was to evaluate the in vitro anthelmintic effect of plant extracts from Melia azedarach and Trichilia claussenii by the egg hatch test (EHT) and larval development test (LDT) against sheep gastrointestinal nematodes. The hexane extract of M. azedarach fruits was extracted through cold percolation and the methanol extract of T. claussenii leaves was obtained by extraction at room temperature in solvents in order of increasing polarity. The efficacy results were analyzed using the Probit program of SAS. The M. azedarach extract showed a LC(50) of 572.2 MUg/mL and LC(99) of 1137.8 MUg/mL in the EHT, and LC(50) of 0.7 MUg/mL and LC(99) of 60.8 MUg/mL in the LDT. In turn, the T. claussenii extract presented a LC(50) of 263.8 MUg/mL and LC(99) of 522.5 MUg/mL in the EHT and LC(50) of 1.1 MUg/mL and LC(99) of 26.4 MUg/mL in the LDT. Comparing the extracts of the species from the Meliaceae family, T. claussenii showed greater anti-parasite potential in vitro than M. azedarach. However, studies on the isolated compounds, toxicity and administration forms to animals are also needed to validate low-cost alternative herbal remedies for use to control gastrointestinal nematodes by family farmers. PMID- 22209943 TI - Education of the pediatric patient with asthma: a literature review. PMID- 22209944 TI - Management of vitamin D deficiency in children and adolescents. PMID- 22209942 TI - CDK10 functions as a tumor suppressor gene and regulates survivability of biliary tract cancer cells. AB - Cyclin-dependent kinase 10 (CDK10) is a member of the Cdc2 family of kinases, and has been demonstrated to be an important determinant of resistance to endocrine therapy for breast cancer. To investigate the expression and possible function of CDK10 in biliary tract cancer (BTC), we systematically examined CDK10 in tissues and cell lines. We found that expression of CDK10 was downregulated in both biliary tract tumors and cell lines. Remarkably, the expression of CDK10 correlated with clinical characteristics. Overexpression or knockdown of CDK10, respectively, inhibited or promoted cell proliferation, colony formation and migration. This suggests that CDK10 functions as a tumor suppressor gene in BTC. Overexpression of CDK10 caused malignant cells to become sensitive to chemotherapy and other hostile environments, suggesting that CDK10 functions to regulate survivability of BTC cells. We investigated the expression of six genes to resolve the mechanism. c-RAF was negatively regulated by CDK10 in both cells and specimens. Our results indicate that CDK10 plays a crucial role in the growth and survivability of biliary tract cancer, and offers a potential therapeutic target for this fatal disease. PMID- 22209946 TI - Abrupt bradycardia and grouped beating during treadmill testing: a mimic of upper rate behavior. PMID- 22209945 TI - Concurrent search for unrelated cord and volunteer donor in high-risk acute lymphoblastic leukemia. AB - To assess the effectiveness of the search for an unrelated donor on the outcome of patients with high-risk acute lymphoblastic leukemia, we analyzed prospectively 136 patients who underwent a search for cord blood (CB) and an unrelated volunteer donor (UD) at the same time. The probability of finding a donor was 58.2%, 70.3%, and 75.7% at 3, 6, and 12 months, respectively. The median time to find a donor was 1.8 months for CB and 3.5 months for UD. Of the 99 patients with a donor, 38.4% failed to undergo the transplant because of a relapse observed at a median of 4 months from the start of the search. In univariate analysis, absence of relapse during the search (p < 0.0001) and transplant (p = 0.004) showed a positive impact on long-term survival. In multivariate analysis, relapse during the search remained the key factor affecting survival (p < 0.0001). Since an extension of the search beyond 3 months enables only a slight increase in the probability of finding a donor compared to the increased risk of relapse, the time of the search should not exceed the 3 month time point. The simultaneous search for CB and UD increases the likelihood of performing a timely transplant. PMID- 22209947 TI - Electrocardiographic characteristics of patients with false tendon: possible association of false tendon with J waves. AB - BACKGROUND: The false tendons (FTs) are fibromuscular bands that transverse the left ventricular cavity and often contain conduction tissue, suggesting that FTs may contribute to the occurrence of ventricular arrhythmias. The presence of J waves is associated with vulnerability to ventricular arrhythmias; however, the mechanisms underlying the manifestation of J waves remain to be elucidated. OBJECTIVE: To investigate the electrocardiographic characteristics, including the presence of J waves, in patients with FTs. METHODS: We studied 44 patients with distinct FTs detected by echocardiography (FT group) and 88 age- and sex-matched healthy subjects without FTs (control group). The PQ, QRS, JT, QT, corrected JT, and corrected QT intervals were automatically measured on surface 12-lead electrocardiograms, and the presence or absence of J waves was also determined. J waves were defined as terminal QRS notching or slurring. FTs were classified according to their points of attachment as type 1 (longitudinal, 52%), type 2 (diagonal, 25%), type 3 (transverse, 16%), and type 4 (weblike, 7%). RESULTS: QRS and corrected QT intervals were significantly longer in the FT group than in the control group (P <.005 and P <.05, respectively). The incidence of J waves was significantly higher in the FT group (64%) than in the control group (19%) (P <.0001). J waves were more prevalent in type 1 (78%) and type 2 (73%) than in type 3 (14%) and 4 FTs (33%) (P <0.05) and in patients with thick FTs (>= 2 mm) than with thinner FTs (<2 mm) (71% vs 33%; P <.05). The J-wave location differed according to the FT type. CONCLUSIONS: Our results suggest that FTs may carry a certain role to the genesis of J waves. PMID- 22209948 TI - SCN1Bb, atrial fibrillation, and Brugada syndrome: just another brick in the wall .... PMID- 22209949 TI - Adenovirus-mediated viral interleukin-10 gene transfer prevents concanavalin A induced liver injury. AB - BACKGROUND AND AIM: Liver injury is closely associated with immune inflammation. Lacking immunostimulatory functions, viral interleukin-10 (vIL-10), a cellular IL 10 homologue, has been an attractive molecule for immunomodulatory therapy. We aimed to reveal a protective effect of the gene transfer of an adenoviral vector encoding vIL-10 on liver injury induced by concanavalin A. METHODS: C57BL/6J mice were intravenously injected with adenoviral vector encoding vIL-10 before concanavalin A challenge. Liver injury was assessed. Interferon-gamma and interleukin-4 levels were measured by ELISA. The activation of splenic and hepatic immune cells was analysed using an MTT assay. RESULTS: Adenoviral vector encoding vIL-10 pretreatment significantly decreased concanavalin A-mediated elevations in serum alanine aminotransaminase and aspartate aminotransaminase activity, and necrotic area in liver tissues. The protective effect of adenoviral vector encoding vIL-10 was attributed to its inhibition of T cell activation, and production of interferon-gamma and interleukin-4 by the immune cells. Recombinant mouse IL-10, a high homologous cytokine to vIL-10, effectively downregulated interferon-gamma and interleukin-4 release by hepatic mononuclear cells. CONCLUSION: Adenovirus vector-mediated vIL-10 gene transfer can prevent concanavalin A-induced hepatic injury, minimise pro-inflammatory cytokine release, and inhibit the activation of T lymphocytes. PMID- 22209950 TI - Molecular characterization and expression profile of MAP2K1ip1/MP1 gene from tiger shrimp, Penaeus monodon. AB - MAPK kinase 1 interacting protein 1 (MAP2K1ip1) is an important scaffold proteins of the mitogen-activated protein kinase (MAPK) pathway that form an active signaling module and enhance the specificity and spatiality of MAPK signaling. In the present study, we identified and characterized a MAP2K1ip1 cDNA from tiger shrimp Penaeus monodon (designated as PmMAP2K1ip1). The open reading frame of PmMAP2K1ip1 is 372 bp encoding 123 amino-acid residues with a MAPK interaction domain. The predicted PmMAP2Kip1 protein is 13.6 KDa with the theoretical isoelectric point of 6.3. PmMAP2K1ip1 shared the highest amino acid with Nasonia vitripennis and Strongylocentrotus purpuratus, at 48% and 47.5%, respectively. Phylogenic analysis shows PmMAP2Kip1 is clustering with SpMAP2Kip1, and close to the group of MAP2Kip1s from insect. Furthermore, semiquantitative RT-PCR revealed PmMAP2Kip1 is widely distributed in most examined tissues except nerve, and high expressed in ovary, hemocyte, intestines and hepatopancreas. Meanwhile, PmMAP2k1ip1 is expressed ubiquitously during larval and sex gland development, and keep a high level at the initial development stage. Quantitative real time RT PCR revealed PmMAP2K1ip1 were up-regulated by lipopolysaccharide and peptidoglycan (PGN) in haemocyte. These data reveal MAP2K1ip1 is a multifunction protein that involved development and immune response. It is benefit to characterize other MAPK signal genes and elucidate the molecular regulation mechanism of MAPK signaling in tiger shrimp. PMID- 22209951 TI - Expression of an alfalfa (Medicago sativa L.) ethylene response factor gene MsERF8 in tobacco plants enhances resistance to salinity. AB - Ethylene response factors (ERF) play crucial roles in plant development and response to stresses. Here, a novel cDNA fragment (MsERF8) encoding an ERF protein with an AP2 domain was isolated and characterized from alfalfa. The MsERF8 cDNA has an open reading frame of 603 bp and encodes a nuclear protein of 201 amino acids. Q-RT-PCR analysis revealed that MsERF8 was strongly enriched in roots and leaves compared with stems, flower buds and flowers of mature alfalfa plants. Bioinformatic analysis of the MsERF8 promoter indicated a number of elements associated with stress-related responses, and MsERF8 transcripts in alfalfa seedlings were induced by NaCl, PEG6000, Al(2)(SO(4))(3) and five different hormones. Expression of MsERF8 in transgenic tobacco plants resulted in higher tolerance to salinity than with non-transgenic plants. This data shows that MsERF8 is a gene which prevents or alleviates salinity damage and has strong potential to impart salt tolerance to other crop plants. PMID- 22209952 TI - Vascular endothelial growth factor (VEGF) +405 C/G polymorphism is associated with essential hypertension in a population from Tehran of Iran. AB - Vascular endothelial growth factor (VEGF) has long been recognized as a hypotensive mediator. Little is known regarding the contribution of polymorphisms in VEGF gene to essential hypertension (EH), however. We aimed to investigate the association between +405 VEGF C/G single nucleotide polymorphism (SNP) and occurrence of EH in a sample of patients with diabetes. A study population of 474 subjects with diabetes of which 45.6% (216) had EH was enrolled in this study. Interviews and physical examinations were performed in a clinical setting. Subjects were matched in baseline anthropometric and biochemical characteristics except for total cholesterol. Genotyping of +405 VEGF C/G (rs2010963) SNP was carried out using polymerase chain reaction-restriction fragment length polymorphism. The allelic distribution of the sample did not violate Hardy Weinberg equilibrium. Subjects with EH had a higher frequency of G allele (P = 0.005). Additionally, those with EH had a significantly higher frequency of GG genotype (P = 0.015). In multivariate logistic regression models controlling for possible confounders, having GG against CC genotype was associated with an odds ratio of 2.51 (95% CI: 1.44-4.38; P = 0.001). Moreover, presence of each G allele was linked to a 1.58-fold increase in risk of having EH (95% CI: 1.200-2.086; P = 0.001). In conclusion, +405 VEGF C/G SNP is associated with EH in patients with diabetes, suggesting presence of G allele and GG or CG genotype confer susceptibility towards EH. PMID- 22209954 TI - The evolutionary origins and ecological context of tool use in New Caledonian crows. AB - New Caledonian (NC) crows Corvus moneduloides are the most prolific avian tool users. In the wild, they use at least three distinct tool types to extract invertebrate prey from deadwood and vegetation, with some of their tools requiring complex manufacture, modification and/or deployment. Experiments with captive-bred, hand-raised NC crows have demonstrated that the species has a strong genetic predisposition for basic tool use and manufacture, suggesting that this behaviour is an evolved adaptation. This view is supported by recent stable isotope analyses of the diets of wild crows, which revealed that tool use provides access to highly profitable hidden prey, with preliminary data indicating that parents preferentially feed their offspring with tool-derived food. Building on this work, our review examines the possible evolutionary origins of these birds' remarkable tool-use behaviour. Whilst robust comparative analyses are impossible, given the phylogenetic rarity of animal tool use, our examination of a wide range of circumstantial evidence enables a first attempt at reconstructing a plausible evolutionary scenario. We suggest that a common ancestor of NC crows, originating from a (probably) non-tool-using South-East Asian or Australasian crow population, colonised New Caledonia after its last emersion several million years ago. The presence of profitable but out-of-reach food, in combination with a lack of direct competition for these resources, resulted in a vacant woodpecker-like niche. Crows may have possessed certain behavioural and/or morphological features upon their arrival that predisposed them to express tool-use rather than specialised prey-excavation behaviour, although it is possible that woodpecker-like foraging preceded tool use. Low levels of predation risk may have further facilitated tool-use behaviour, by allowing greater expenditure of time and energy on object interaction and exploration, as well as the evolution of a 'slow' life-history, in which prolonged juvenile development enables acquisition of complex behaviours. Intriguingly, humans may well have influenced the evolution of at least some of the species' tool-oriented behaviours, via their possible introduction of candlenut trees together with the beetle larvae that infest them. Research on NC crows' tool-use behaviour in its full ecological context is still in its infancy, and we expect that, as more evidence accumulates, some of our assumptions and predictions will be proved wrong. However, it is clear from our analysis of existing work, and the development of some original ideas, that the unusual evolutionary trajectory of NC crows is probably the consequence of an intricate constellation of interplaying factors. PMID- 22209956 TI - Analytical method for the accurate determination of tricothecenes in grains using LC-MS/MS: a comparison between MRM transition and MS3 quantitation. AB - The current food crisis demands unambiguous determination of mycotoxin contamination in staple foods to achieve safer food for consumption. This paper describes the first accurate LC-MS/MS method developed to analyze tricothecenes in grains by applying multiple reaction monitoring (MRM) transition and MS(3) quantitation strategies in tandem. The tricothecenes are nivalenol, deoxynivalenol, deoxynivalenol-3-glucoside, fusarenon X, 3-acetyl-deoxynivalenol, 15-acetyldeoxynivalenol, diacetoxyscirpenol, and HT-2 and T-2 toxins. Acetic acid and ammonium acetate were used to convert the analytes into their respective acetate adducts and ammonium adducts under negative and positive MS polarity conditions, respectively. The mycotoxins were separated by reversed-phase LC in a 13.5-min run, ionized using electrospray ionization, and detected by tandem mass spectrometry. Analyte-specific mass-to-charge (m/z) ratios were used to perform quantitation under MRM transition and MS(3) (linear ion trap) modes. Three experiments were made for each quantitation mode and matrix in batches over 6 days for recovery studies. The matrix effect was investigated at concentration levels of 20, 40, 80, 120, 160, and 200 MUg kg(-1) (n = 3) in 5 g corn flour and rice flour. Extraction with acetonitrile provided a good overall recovery range of 90-108% (n = 3) at three levels of spiking concentration of 40, 80, and 120 MUg kg(-1). A quantitation limit of 2-6 MUg kg(-1) was achieved by applying an MRM transition quantitation strategy. Under MS(3) mode, a quantitation limit of 4 10 MUg kg(-1) was achieved. Relative standard deviations of 2-10% and 2-11% were reported for MRM transition and MS(3) quantitation, respectively. The successful utilization of MS(3) enabled accurate analyte fragmentation pattern matching and its quantitation, leading to the development of analytical methods in fields that demand both analyte specificity and fragmentation fingerprint-matching capabilities that are unavailable under MRM transition. PMID- 22209955 TI - Evidence for contagious behaviors in budgerigars (Melopsittacus undulatus): an observational study of yawning and stretching. AB - Yawning is contagious in humans and some non-human primates. If there are social functions to contagious behaviors, such as yawning, they might occur in other highly social vertebrates. To investigate this possibility, we conducted an observational study of yawning and an associated behavior, stretching, in budgerigars (Melopsittacus undulatus), a social, flock-living parrot. Flock housed budgerigars were videotaped for 1.5h at three time-blocks during the day (early morning, afternoon and early evening), and the times of all yawns and stretches for each bird were recorded. Both yawning and stretching were temporally clumped within sessions, but were uniformly distributed across the trials of a particular time-block. This suggests that clumping was not a result of circadian patterning and that both behaviors could be contagious. There was additional evidence of contagion in stretching, which occurred in two forms - a posterior-dorsal extension of either one foot or both feet. Birds that could have observed a conspecific stretch, and that then stretched themselves within 20s, replicated the form of the earlier stretch significantly more often than expected by chance. This study provides the first detailed description of temporal patterns of yawning under social conditions in a flock-living species as well as the first support for contagious yawning and stretching in a non-primate species in a natural context. Experimental evidence will be necessary to confirm the extent of contagion in either behavior. PMID- 22209953 TI - Possible import routes of proteins into the cyanobacterial endosymbionts/plastids of Paulinella chromatophora. AB - The rhizarian amoeba Paulinella chromatophora harbors two photosynthetically active and deeply integrated cyanobacterial endosymbionts acquired ~60 million years ago. Recent genomic analyses of P. chromatophora have revealed the loss of many essential genes from the endosymbiont's genome, and have identified more than 30 genes that have been transferred to the host cell's nucleus through endosymbiotic gene transfer (EGT). This indicates that, similar to classical primary plastids, Paulinella endosymbionts have evolved a transport system to import their nuclear-encoded proteins. To deduce how these proteins are transported, we searched for potential targeting signals in genes for 10 EGT derived proteins. Our analyses indicate that five proteins carry potential signal peptides, implying they are targeted via the host endomembrane system. One sequence encodes a mitochondrial-like transit peptide, which suggests an import pathway involving a channel protein residing in the outer membrane of the endosymbiont. No N-terminal targeting signals were identified in the four other genes, but their encoded proteins could utilize non-classical targeting signals contained internally or in C-terminal regions. Several amino acids more often found in the Paulinella EGT-derived proteins than in their ancestral set (proteins still encoded in the endosymbiont genome) could constitute such signals. Characteristic features of the EGT-derived proteins are low molecular weight and nearly neutral charge, which both could be adaptations to enhance passage through the peptidoglycan wall present in the intermembrane space of the endosymbiont's envelope. Our results suggest that Paulinella endosymbionts/plastids have evolved several different import routes, as has been shown in classical primary plastids. PMID- 22209957 TI - Rapid screening and quantification of sulfonate derivatives in white peony root by UHPLC-MS-MS. AB - A rapid ultra-high-performance liquid chromatographic-tandem mass spectrometric (UHPLC-MS-MS) method has been developed for rapid screening and quantitative analysis of sulfonate derivatives (SDs) in commercial white peony root. Separation was performed on an Agilent Zorbax Eclipse Plus-C18 column by gradient elution with acetonitrile-0.1% (v/v) formic acid as the mobile phase. In-source fragmentation was used to generate the characteristic fragment ion at m/z 259 and to screen for nine SDs. Detection of these SDs was further performed in multiple reaction monitoring (MRM) mode to improve sensitivity and to quantify the two SDs paeoniflorin sulfonate and benzoylpaeoniflorin sulfonate. The method was validated for specificity, linearity, limits of detection and quantification, precision, accuracy, and matrix effects. Nine commercial white peony root samples were examined by use of this method, which revealed great variety in the paeoniflorin sulfonate and benzoylpaeoniflorin sulfonate content. PMID- 22209958 TI - Image-guided robotic radiosurgery (CyberKnife) for pancreatic insulinoma: is laparoscopy becoming old? AB - Insulinomas constitute about 25% of endocrine pancreatic tumors. Laparoscopic surgery is the treatment of choice. However, pancreas-related complications rate is very high, even in experienced hands, ranging up to 37%. Alternative procedures such as embolization with trisacryl have not been accepted by the surgical community. Image-guided robotic radiosurgery or stereotactic radiosurgery (CyberKnife) is a minimally invasive procedure delivering large doses of ionizing radiation to a well-defined target. CyberKnife radiosurgery is successfully used in brain cancer, lung cancer, prostate cancer, liver metastases, kidney cancer, and pancreatic cancer. The authors present the first case to their knowledge of a benign functioning insulinoma successfully treated by a CyberKnife technique with a 3-year follow-up. PMID- 22209959 TI - Tremor and beta(2)-adrenergic agents: is it a real clinical problem? AB - Tremor is one of the most characteristic adverse effects following administration of beta(2)-adrenergic agonists. It is reported by around 2-4% of patients with asthma taking a regular beta(2)-adrenergic agonist and is induced by both short acting and long-acting agents. Tremor associated with beta(2)-adrenergic agonists is dose-related and may occur more commonly with oral dosing. The exact mechanism for tremor induction by beta(2)-adrenergic agonists is still unknown, but there is some evidence that beta(2)-adrenergic agonists act directly on muscle. An early explanation of the tremor was that beta(2)-adrenoceptor stimulation shortens the active state of skeletal muscle, which leads to incomplete fusion and reduced tension of tetanic contractions. More recently, tremor has been correlated closely with hypokalaemia. A possible diverse impact of different modes of administration of beta(2)-adrenergic agonists on tremorogenic responses has been suggested but solid evidence is still lacking. In any case, the desensitization of beta(2)-adrenoceptors that occurs during the first few days of regular use of a beta(2)-adrenergic agonist accounts for the commonly observed resolution of tremor after the first few doses. Therefore, tremor is not a really important adverse effect in patients under regular treatment with a beta(2) adrenergic agonist. PMID- 22209960 TI - Actinobaculum schaalii: review of an emerging uropathogen. AB - Actinobaculum schaalii is a facultative anaerobic, Gram-positive rod-shaped species phylogenetically related to Actinomyces that is likely part of the commensal flora of the human genitourinary tract. Because of its fastidious growth under aerobic conditions and its resemblance to bacteria of the resident flora, A. schaalii is frequently overlooked or considered as a contaminant. It is also difficult to identify phenotypically, still requiring molecular identification. Note that the recent technology of matrix-assisted laser desorption/ionisation time-of-flight-mass spectrometry could be a promising tool for its identification. Recent studies using sensitive PCR assays showed that its clinical significance was largely underestimated. Since its first description in 1997, A. schaalii has been responsible for numerous urinary tract infections (UTIs), mainly in elderly (usually >60 years) and patients with underlying urological conditions. Infected urines usually show many Gram-positive rods with significant leukocyturia and a negative test for nitrites. Numerous cases of severe infections have also been described, such as urosepsis, bacteremia, cellulitis, spondylodiscitis, and endocarditis. In vitro, A. schaalii is highly susceptible to beta-lactams but it is resistant to ciprofloxacin and cotrimoxazole, first-choice antimicrobials for the oral treatment of UTIs. A penicillin (e.g. amoxicillin) or a cephalosporin (e.g. cefuroxime, ceftriaxone) should be the preferred treatment. PMID- 22209961 TI - S. choloroleuca, S. mirzayanii and S. santolinifolia protect PC12 cells from H(2)O (2)-induced apoptosis by blocking the intrinsic pathway. AB - Several studies have shown that neuronal cell death due to apoptosis is the major reason for cognitive decline in Alzheimer's disease. In this study, we report the anti-apoptotic effects of three Salvia species from Iran-S. choloroleuca, S. mirzayanii and S. santolinifolia-against H(2)O(2)-induced cytotoxicity in neuron like PC12 cells. We showed that these antioxidant species could interfere with the intrinsic pathway of apoptosis by attenuating Bax/Bcl-2 ratio, decreasing outer mitochondrial membrane break and decreasing cytochrome c release to cytoplasm. Interestingly, we found that these species were able to replenish reduced glutathione level which affects cellular redox status and cytochrome c activity. Moreover, the decreased level of caspase-3, the executioner caspase, resulted in decrease of PARP-1 cleavage. Anti-apoptotic effects of these species along with their antioxidant effects, may represent a promising approach for treatment of neurodegenerative diseases. PMID- 22209962 TI - WITHDRAWN: Sequence variations and selection analysis of microRNA target genes involved in rice flower development. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22209963 TI - Load-bearing capacity of CAD/CAM milled polymeric three-unit fixed dental prostheses: effect of aging regimens. AB - OBJECTIVE: This study tested the fracture load of milled and conventionally fabricated polymeric and glass-ceramic three-unit fixed dental prostheses (FDPs) after aging. MATERIALS AND METHODS: FDPs were fabricated (N = 1,050) from four computer-aided design and computer-aided manufacturing (CAD/CAM) resins: (1) AT (artBlock Temp); (2) TC (Telio CAD); (3) ZP (ZENO PMMA); (4) CT (CAD-Temp); two conventionally fabricated resins, (5) IES (integral esthetic press), (6) CMK (CronMix K), and a glass-ceramic (control) (7) PG (IMAGINE PressX). Specimens of each group were tested immediately after fabrication (n = 15 per material). Seventy-five FDPs per material type were stored in artificial saliva (37 degrees C) and 15 of them were randomly selected after aging (1, 7, 28, 90, and 180 days) for fracture load measurement. The remaining specimens (n = 60 per material) were subjected to chewing simulation (*120.000-1.200.000, 49 N, 5 degrees C/50 degrees C). The data were analyzed using two-way and one-way ANOVA followed by Scheffe test. RESULTS: The interactions between FDP materials and aging time in both storage media showed a significant impact on the results (p < 0.001). Among saliva storage groups, TC and ZP showed the highest, and PG the lowest fracture load (p < 0.05). AT and CT were not affected from chewing simulation. TC, ZP, and AT presented the highest in ascending order (p < 0.05), PG and CMK showed the lowest fracture load after chewing simulation (p < 0.001). CONCLUSIONS: Aging did not influence the fracture load of FDPs made of CAD/CAM resins. FDPs made of glass-ceramic showed significantly lower fracture load than those of all resin FDPs. CLINICAL RELEVANCE: Considering fracture load measurements, CAD/CAM resins tested could be alternative materials to glass-ceramic for FDP construction. PMID- 22209964 TI - Significant elevation of plasma cathepsin B and cystatin C in patients with community-acquired pneumonia. AB - BACKGROUND: We identified the relationship between plasma level changes of cathepsin B and cystatin C before and after antibiotic treatment in hospitalized adult patients with community-acquired pneumonia (CAP). METHODS: We collected blood specimens from 61 adult patients with CAP before and after antibiotic treatment and from 60 healthy controls and measured the plasma concentrations of cathepsin B and cystatin C expression using the enzyme-linked immunosorbent assay (ELISA). The APACHE II, CURB-65, and Pneumonia Severity Index (PSI) scores were determined to assess CAP severity in patients upon initial hospitalization. RESULTS: The results showed a decline in the number of WBCs and neutrophils, with decreases in the concentrations of CRP, cathepsin B, cystatin C, and the cathepsin B/cystatin C ratio being observed after antibiotic treatment. The plasma concentration of cathepsin B correlated with severity of CAP with the PSI score (r=0.290, p=0.025) and the CURB-65 score (r=0.258, p=0.047), respectively. The plasma concentration of cystatin C correlated with the APACHE II score (r=0.523, p<0.001), severity of CAP in the PSI score (r=0.721, p<0.001) and the CURB-65 score (r=0.609, p<0.001), respectively. CONCLUSIONS: Cathepsin B and cystatin C may play a role in the diagnosis and clinical assessment of the severity of CAP, which could potentially guide the development of treatment strategies. PMID- 22209965 TI - The clinical implications of increased cyclophilin A levels in patients with acute coronary syndromes. AB - BACKGROUND: Cyclophilin A is a secreted molecule that has a physiological and pathological role in cardiovascular diseases. However, limited information is available on the relationship between cyclophilin A concentration and acute coronary syndromes (ACS). We investigated whether cyclophilin A concentration is related to the stability of coronary atherosclerotic plaque in patients with ACS. METHODS: This study included normal controls (n=50), patients with stable angina (SA) (n=60) and patients with ACS, including unstable angina (UA) (n=60) and acute myocardial infarction (AMI) (n=90). Serum soluble cyclophilin A, matrix metalloproteinase 9 (MMP-9), MMP-3 and C-reactive protein concentrations (CRP) were measured. All coronary stenosis were assessed by angiographic coronary stenosis morphology. RESULTS: Serum cyclophilin A concentration in ACS (UA and AMI ) subjects were significantly higher than those in patients with SA and controls (p<0.05). Serum cyclophilin A correlated positively with serum MMP-3 and MMP-9 and CRP in ACS patients(r(1)=0.69, r(2)=0.52, r(3)=0.49 p<0.0001), but not in control. Furthermore, the increased cyclophilin A concentrations was associated with the number of complex coronary stenoses (r(1)=0.63, p<0.0001), but not smooth lesions or stenosis severity, in coronary artery disease patients. Logistic regression analysis also demonstrated that serum cyclophilin A concentration was an independent predictor factor for ACS( OR, 2.721, 95% CI 1.563-4.042, p=0.001). CONCLUSION: Patients with ACS showed that increased concentrations of cyclophilin A may be a valuable marker for predicting the severity of ACS. PMID- 22209966 TI - Plasma homocysteine level and hepatic sulfur amino acid metabolism in mice fed a high-fat diet. AB - PURPOSE: Obesity, a feature of metabolic syndrome, is a risk factor for cardiovascular disease, and elevated plasma homocysteine is associated with increased cardiovascular risk. However, little published information is available concerning the effect of obesity on homocysteine metabolism. METHODS: Hepatic homocysteine metabolism was determined in male C57BL/6 mice fed a high-fat diet for 12 weeks. RESULTS: High-fat diet increased plasma homocysteine but decreased hepatic homocysteine levels. Hepatic S-adenosylhomocysteine hydrolase levels were down-regulated in the obese mice, which was in part responsible for the decrease in hepatic S-adenosylmethionine/S-adenosylhomocysteine, which served as an index of transmethylation potential. Despite the decrease in hepatic cysteine, hepatic taurine synthesis was activated via up-regulation of cysteine dioxygenase. Hepatic levels of methionine adenosyltransferase I/III, methionine synthase, methylene tetrahydrofolate reductase, and gamma-glutamylcysteine ligase catalytic subunit were unchanged. Obese mice showed elevated betaine-homocysteine methyltransferase and decreased cystathionine beta-synthase activities, although the quantities of these enzymes were unchanged. CONCLUSION: This study suggests that plasma homocysteine level is increased in obesity-associated hepatic steatosis, possibly as a result of increased hepatic homocysteine efflux along with an altered sulfur amino acid metabolism. PMID- 22209967 TI - Relationship between the body adiposity index and cardiometabolic risk factors in obese postmenopausal women. AB - OBJECTIVE: The purpose of the present secondary analysis study was to investigate the ability of the body adiposity index (BAI) to detect changes in % body fat levels before and after a weight loss intervention when compared to % body fat levels measured using dual-energy X-ray absorptiometry (DXA) and to examine the relationship between the BAI with cardiometabolic risk factors. METHODS: The study population for this secondary analysis included 132 non-diabetic obese sedentary postmenopausal women (age: 57.2 +/- 4.7 years, BMI: 35.0 +/- 3.7 kg/m(2)) participating in a weight loss intervention that consisted of a calorie restricted diet with or without resistance training. We measured: (1) visceral fat using CT-scan, (2) body composition using DXA, (3) hip circumference and height from which the BAI was calculated, and (4) cardiometabolic risk factors such as insulin sensitivity (using the hyperinsulinemic-euglycemic clamp), blood pressure as well as fasting plasma lipids, hsC-reactive protein (CRP), leptin, and glucose. RESULTS: Percent body fat levels for both methods significantly decreased after the weight loss intervention. In addition, the percent change in % body fat levels after the weight loss intervention was significantly different between % body fat measured using the DXA and the BAI (-4.5 +/- 6.6 vs. -5.8 +/- 5.9%; p = 0.03, respectively). However, we observed a good overall agreement between the two methods, as shown by the Bland-Altman analysis, for percent change in % body fat. Furthermore, similar correlations were observed between both measures of % body fat with cardiometabolic risk factors. However, results from the multiple linear regression analysis showed that % body fat using the BAI appeared to predict cardiometabolic risk factors differently than % body fat using the DXA in our cohort. CONCLUSIONS: Estimating % body fat using the BAI seems to accurately trace variations of % body fat after weight loss. However, this index showed differences in predicting cardiometabolic risk factors when compared to % body fat measured using DXA. PMID- 22209968 TI - The Neurospora crassa mutant NcDeltaEgt-1 identifies an ergothioneine biosynthetic gene and demonstrates that ergothioneine enhances conidial survival and protects against peroxide toxicity during conidial germination. AB - Ergothioneine (EGT) is a histidine derivative with sulfur on the imidazole ring and a trimethylated amine; it is postulated to have an antioxidant function. Although EGT apparently is only produced by fungi and some prokaryotes, it is acquired by animals and plants from the environment, and is concentrated in animal tissues in cells with an EGT transporter. Monobromobimane derivatives of EGT allowed conclusive identification of EGT by LC/MS and the quantification of EGT in Colletotrichum graminicola and Neurospora crassa conidia and mycelia. EGT concentrations were significantly (alpha=0.05) higher in conidia than in mycelia, with approximately 17X and 5X more in C. graminicola and N. crassa, respectively. The first EGT biosynthetic gene in a fungus was identified by quantifying EGT in N. crassa wild type and knockouts in putative homologs of actinomycete EGT biosynthetic genes. NcDeltaEgt-1, a strain with a knockout in gene NCU04343, does not produce EGT, in contrast to the wild type. To determine the effects of EGT in vivo, we compared NcDeltaEgt-1 to the wild type. NcDeltaEgt-1 is not pleiotropically affected in rate of hyphal elongation in Vogel's medium either with or without ammonium nitrate and in the rate of germination of macroconidia on Vogel's medium. The superoxide-producer menadione had indistinguishable effects on conidial germination between the two strains. Cupric sulfate also had indistinguishable effects on conidial germination and on hyphal growth between the two strains. In contrast, germination of NcDeltaEgt-1 conidia was significantly more sensitive to tert-butyl hydroperoxide than the wild type; germination of 50% (GI(50)) of the NcDeltaEgt-1 conidia was prevented at 2.7 mM tert-butyl hydroperoxide whereas the GI(50) for the wild type was 4.7 mM tert butyl hydroperoxide, or at a 1.7X greater concentration. In the presence of tert butyl hydroperoxide and the fluorescent reactive oxygen species indicator 5-(and 6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate, significantly (P=0.0002) more NcDeltaEgt-1 conidia fluoresced than wild type conidia, indicating that EGT quenched peroxides in vivo. While five to 21-day-old conidia of both strains germinated 100%, NcDeltaEgt-1 conidia had significantly (P<0.001) diminished longevity. Linear regression analysis indicates that germination of the wild type declined to 50% in 35 days, in comparison to 25 days for the NcDeltaEgt-1, which is equivalent to a 29% reduction in conidial life span in the NcEgt-1 deletion strain. Consequently, the data indicate that endogenous EGT helps protect conidia during the quiescent period between conidiogenesis and germination, and that EGT helps protect conidia during the germination process from the toxicity of peroxide but not from superoxide or Cu(2+). Based on an in silico analysis, we postulate that NcEgt-1 was acquired early in the mycota lineage as a fusion of two adjacent prokaryotic genes, that was then lost in the Saccharomycotina, and that NcEgt-1 catalyzes the first two steps of EGT biosynthesis from histidine to hercynine to hercynylcysteine sulfoxide. PMID- 22209969 TI - Real-time monitoring of metabolic shift and transcriptional induction of yciG::luxCDABE E. coli reporter strain to a glucose pulse of different concentrations. AB - Ineffective mixing entailing heterogeneity issue within industrial bioreactors has been reported to affect microbial physiology and consequently bioprocess performances. Alteration of these performances results from microorganism ability to modulate their physiology at metabolic and/or transcriptional levels in order to survive in a given environment. Until now, dynamics of both metabolic and transcriptional microbial response to external stimuli have been investigated using mainly ex situ measurements with sampling and/or quenching constraints. This work showed an in situ bioluminescence approach for real-time monitoring of characteristic stress responses of Escherichia coli containing yciG::luxCDABE reporter to glucose pulses in well-controlled steady-state chemostat cultures. Reproducibility of in situ bioluminescence profiles was assessed. A dramatic transient increase in the bioluminescence intensity (sharp peak) was observed for a complete depletion of sugars and for a sudden decrease in the dilution rate. This response was connected to a sudden change of the metabolic activity. On the contrary a bell curve of bioluminescence intensity, dose-dependent, was related to an induction of transcriptional activity. Real-time monitoring of the bioluminescence signal with time-span less than a second gave access to the characteristic times of the metabolic shift and transcriptional induction of the stress response. PMID- 22209970 TI - Molecular microheterogeneity of prostate specific antigen in seminal fluid by mass spectrometry. AB - OBJECTIVES: Prostate specific antigen (PSA) is a widely used and clinically valuable marker for prostate disease. In order to enable the development of new PSA assays and progress the understanding of the biology of PSA we have analyzed PSA in seminal plasma. DESIGN AND METHODS: PSA in seminal plasma from men attending a fertility clinic and healthy controls was analyzed using SDS-PAGE, Western blotting and mass spectrometry. RESULTS: Using mass spectrometry, different forms of PSA could be identified in 1-9 bands seen on SDS-PAGE analysis of the respective sample. However, a majority of these molecular forms of PSA were not observed on Western blots. Enzymatic activity of PSA isoforms was demonstrated by sequencing data in zymogram gels. Multivariate analysis of clinical data revealed well-separated patient groups. CONCLUSIONS: We demonstrated that PSA in seminal plasma occurs in several isoforms, yet not all were detectable using an antibody based clinical routine method. The heterogeneity of PSA expression might be of clinical significance, by an improved patient phenotyping. PMID- 22209971 TI - Identification of ABCG2+ cells in nasopharyngeal carcinoma cells. AB - Tumor stem cells are a small subset of tumor cells with the ability of self renewal and differentiation and are regarded as a cause of tumor growth and recurrence. Previously we have shown that stem-like label-retaining cells (LRCs) can be detected in nasopharynx, tongue, esophagus and xenograft tumors formed by nasopharyngeal carcinoma (NPC) cell lines (5-8F, 6-10B and TMNE). The present study aimed to identify ABCG2+ cells in 5-8F NPC cells and compare their tumorigenic potential with ABCG2- cells, expecting that we can obtain insight into the mechanism of the differential phenotypes of ABCG2+ and ABCG2- cells. By using magnetic cell sorting (MACS) method, we isolated ABCG2+ cells and ABCG2- cells from 5-8F cells. Among these two subpopulations and unsorted 5-8F cells, the rate of ABCG2+ cells at G1 phase was highest, while the rate of ABCG2- cells at S phase was highest, indicating that ABCG2+ cells were mostly quiescent. However, ABCG2+ cells showed lower cloning efficiency and tumorigenicity than ABCG2- cells. We also used Affymetrix U133 plus 2.0 human whole genome expression chip to identify the gene expression profile of ABCG2+ and ABCG2- cells and found that both subpopulations expressed some stem cell associated genes, e.g., PSCA, ABCG2 and ALPI were expressed in ABCG2+ cells, and K19, integrin alpha6, integrin beta4, CD44 and K14 were expressed in ABCG2- cells, suggesting there were stem cells in both ABCG2+ and ABCG2- cells. Our data demonstrated that there exist ABCG2+ cells in NPC cells, but ABCG2 alone is not sufficient for isolating cancer stem cells in 5-8F NPC cells. PMID- 22209972 TI - 1858 C/T polymorphism of the protein tyrosine phosphatase nonreceptor 22 gene and rheumatoid arthritis risk in europeans: a meta-analysis. AB - BACKGROUND AND AIMS: A single nucleotide polymorphism (SNP) of the protein tyrosine phosphatase nonreceptor gene (PTPN22) confers susceptibility to rheumatoid arthritis (RA) and certain other classical autoimmune diseases. The association between PTPN22 1858C/T polymorphism and the risk of RA is still controversial and ambiguous; therefore, we performed this meta-analysis to confirm some relationships. METHODS: We conducted a search in the PubMed database without a language limitation, covering all papers published until June 20, 2011. Overall, 19 case-control studies with 11,727 cases and 12,640 controls were retrieved based on the search criteria for RA susceptibility related to the 1858C/T polymorphism. Odds ratios (OR) and 95% confidence intervals (CI) were used to assess the strength of this association. Publication bias was assessed with Eggers test. RESULTS: We found that PTPN22 1858C/T polymorphism could increase RA risk in overall genetic models in Europeans (T-allele vs. C-allele, OR = 1.54, 95% CI = 1.47-1.62, P(heterogeneity) = 0.143; TT vs. CC, OR = 2.86, 95% CI = 2.29-3.57, P(heterogeneity) = 0.302; TC vs. CC, OR = 1.45, 95% CI = 1.38 1.53, P(heterogeneity) = 0.273; TT + TC vs. CC, OR = 1.49, 95% CI = 1.42-1.56, P(heterogeneity) = 0.208; TT vs. TC + CC, OR = 2.52, 95% CI = 1.95-3.25, P(heterogeneity) = 0.296). Furthermore, significant relationships were detected among PTPN22 1858C/T polymorphism and RF(+) or RF(-) RA risk. No obvious evidence of publication bias was detected in the overall analysis. CONCLUSIONS: Our study indicated that PTPN22 1858T allele was significantly associated with increased RA risk. PMID- 22209973 TI - Is C677T polymorphism in methylenetetrahydrofolate reductase gene a risk factor for diabetic nephropathy or diabetes mellitus in a Chinese population? AB - BACKGROUND AND AIMS: To date, case-control studies on the association between C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) gene and diabetes mellitus (DM) or diabetic nephropathy (DN) in different populations have provided inconclusive results. To clarify the effect of the C677T polymorphism on the risk of both DM and DN in a Chinese population, a meta-analysis was performed. METHODS: A comprehensive literature search was conducted to collect data from all case-control observational studies that investigated association of C677T polymorphism in MTHFR gene with DM or DN in a Chinese population. RESULTS: Overall, 12 studies in a Chinese population published up to 2011 were combined, and the heterogeneity among them varied from none to moderate. The 677T allele showed significant association with DN (OR = 1.97, 95% CI [1.71, 2.28], p <0.00001), but no relationship with DM (OR = 1.03, 95% CI [0.89, 1.18], p = 0.70) compared with the 677C allele in a Chinese population. Similarly, evidence of significant association with DN was detected in the additive model, the recessive model and the dominant model for allele T (additive model: OR = 3.26, 95% CI [2.46, 4.31], p <0.00001; recessive model: OR = 2.32, 95% CI [1.81, 2.97], p <0.00001; dominant model: OR = 2.35, 95% CI [1.89, 2.91], p <0.00001); however, no relationship with DM was found (additive model: OR = 1.01, 95% CI [0.76, 1.35], p = 0.94; recessive model: OR = 0.98, 95% CI [0.76, 1.26], p = 0.87; dominant model: OR = 1.23, 95% CI [0.91, 1.65], p = 0.18). There were no sources of bias in the selected studies, and the sensitivity analysis (exclusion of studies not in Hardy-Weinberg equilibrium) suggested stability of this meta analysis. CONCLUSIONS: C677T polymorphism in MTHFR gene may be a risk factor for DN, but not for DM, in a Chinese population. PMID- 22209974 TI - Expression and prognosis of FOXO3a and HIF-1alpha in nasopharyngeal carcinoma. AB - PURPOSE: The Forkhead Box O3a transcription factor (FOXO3a) and hypoxia-inducible factor-1alpha (HIF-1alpha) have been reported to play important roles in the development and prognosis of human cancers. However, their exact roles are not clear. Therefore, we investigated the expression status and clinical significance of FOXO3a and HIF-1alpha expression in nasopharyngeal carcinoma. METHODS: The expression of FOXO3a and HIF-1alpha proteins was detected in nasopharyngeal carcinoma tissues and normal nasopharyngeal tissues by immunohistochemistry and western blot. Furthermore, we analyzed the association of FOXO3a and HIF-1alpha expression with various clinicopathologic factors including survival status of nasopharyngeal carcinoma patients. RESULTS: FOXO3a was low expressed and HIF 1alpha was high expressed in nasopharyngeal carcinoma tissues, compared with normal nasopharyngeal tissues (both P < 0.05). The low expression of FOXO3a was significantly correlated with clinical stage (P = 0.003), T stage (P = 0.011), lymph node metastasis (P = 0.003), and distant metastasis (P = 0.030), and over expression of HIF-1alpha was significantly correlated with T stage (P = 0.026), lymph node metastasis (P = 0.002), and distant metastasis (P = 0.010). The Spearman analysis indicated that FOXO3a expression was inversely correlated with HIF-1alpha expression(rs = -0.598, P < 0.001). Overall survival curves estimated by Kaplan-Meier showed that tumor patients with low FOXO3a or high HIF-1alpha expression had significantly poorer prognosis compared with patients with high FOXO3a or low HIF-1alpha levels (P < 0.001, and P = 0.012, respectively). In addition, multivariate Cox regression analysis showed that T stage, distant metastasis, and FOXO3a were significant independent prognostic factors for overall survival (P = 0.011, P = 0.008, and P = 0.047, respectively). CONCLUSIONS: Our results suggested that FOXO3a and HIF-1alpha may be considered to be important prognostic markers in nasopharyngeal carcinoma. PMID- 22209975 TI - Tipifarnib and tanespimycin show synergic proapoptotic activity in U937 cells. AB - BACKGROUND: Farnesyltransferase inhibitor tipifarnib (R115777) has been used for treatment of hematological malignancies; however, its observed anticancer effect was limited. This prompted us to search for inhibitors that would show synergic, proapoptotic effect when combined with R115777. We decided to study LY294002, which inhibits PI-3 kinase, and tanespimycin (17AAG), which inhibits Hsp90--a chaperone for a number of proteins, including Akt kinase. METHODS: The effect of drugs, used alone or in combination, was tested in U937 cells (human leukemic monocyte lymphoma), which are often used as a model for liquid tumor. The number of viable cells was evaluated with trypan blue staining, while apoptosis was assessed by presence of active caspase-3 and terminal dUTP nick-end labeling of DNA (TUNEL). RESULTS: At concentrations in which R115777, LY294002 and 17AAG were only slowing down the proliferation rate, when used separately, the combination of R115777 + LY294002 and R115777 + 17AAG significantly reduced the number of cells and induced cellular apoptosis. CONCLUSIONS: Our results suggest that the combination of R115777 + 17AAG could be useful in treating some of the hematological malignancies. PMID- 22209976 TI - Combination of a MDR1-targeted replicative adenovirus and chemotherapy for the therapy of pretreated ovarian cancer. AB - PURPOSE: Targeted oncolytic adenoviruses capable of replication selectively in cancer cells are an appealing approach for the treatment of various cancer types refractory to conventional therapies. The aim of this study was to evaluate the effect of Ad5/3MDR1E1, a multidrug resistance gene 1 (MDR1)-targeted fiber modified replication-competent adenovirus for the therapy of platinum-pretreated ovarian cancer in combination with cytostatic agents. METHODS: MDR1-specific tumor cell killing of Ad5/3MDR1E1 was systematically evaluated in chemotherapy naive and pretreated ovarian cancer cells in vitro. Combinations of Ad5/3MDR1E1 and cytostatic agents were studied in vivo and in vitro. An in vivo hepatotoxicity model was used to evaluate liver toxicity. RESULTS: We demonstrate efficient oncolysis of Ad5/3MDR1E1 in chemotherapy-resistant ovarian cancer cells as well as therapeutic efficacy in an orthotopic mouse model. Further, combining Ad5/3MDR1E1 with paclitaxel resulted in greater therapeutic benefit than either agent alone. CONCLUSION: These preclinical data suggest that a fiber-modified adenovirus vector under the control of the MDR1 promoter represents a promising treatment strategy for platinum-pretreated ovarian cancer as a single agent or in combination with conventional anticancer drugs. PMID- 22209978 TI - Drug eluting stents based on Poly(ethylene carbonate): optimization of the stent coating process. AB - First generation drug eluting stents (DES) show a fivefold higher risk of late stent thrombosis compared to bare metal stents. Therefore, new biodegradable and biocompatible polymers for stent coating are needed to reduce late stent thrombosis. In this study, a reproducible spray-coating process for stents coated with Poly(ethylene carbonate), PEC, and Paclitaxel was investigated. PEC is a biocompatible, thermoelastic polymer of high molecular weight. The surface degradation of PEC is triggered by superoxide anions produced by polymorphonuclear leukocytes and macrophages during inflammatory processes. Stents with different drug loading were reproducibly produced by a spray-coating apparatus. Confocal laser scanning micrographs of fluorescent dye loaded stents were made to investigate the film homogeneity. The abluminal stent site was loaded more than the luminal site, which is superior for DES. The deposition of the layers was confirmed by TOF-SIMS investigations. Referring to the stent surface, the drug loading is 0.32 MUg (+/- 0.05) (once coated), 0.53 MUg (+/- 0.11) (twice coated), or 0.73 MUg (+/- 0.06) (three times coated) Paclitaxel per mm(2) stent surface. The in vitro release mechanism during non-degradation conditions can be explained by diffusion-controlled drug release slightly influenced by swelling of PEC, revealing that 100% of the loaded Paclitaxel will be released via diffusion within 2 months. So, the in vivo release kinetic is a combination of diffusion-controlled drug release and degradation-controlled drug release depending on the presence or absence of superoxide anions and accordingly depending on the presence or absence of macrophages. We conclude that the specific release kinetics of PEC, its biocompatibility, and the favorable mechanical properties will be beneficial for a next generation drug eluting stent meriting further investigations under in vivo conditions. PMID- 22209977 TI - miR-181a sensitizes resistant leukaemia HL-60/Ara-C cells to Ara-C by inducing apoptosis. AB - BACKGROUND: Ara-C is one of the most commonly used drugs in the treatment of AML. However, the development of drug resistance always prevented its further use. It has been shown that miR-181a is associated with the clinical outcome of AML patients. Here, we investigated the possible role of miR-181a in AML Ara-C resistance. METHODS: miR-181a expression was measured by real-time PCR. Cell viability was detected by MTT assay. Protein expressions were measured by western blotting. Caspase activity was examined by fluorescence assay. RESULTS: We found that miR-181a expression was downregulated in the Ara-C-resistant cell line HL 60/Ara-C compared with its parental cell line HL-60. Overexpression of miR-181a in HL-60/Ara-C cells sensitized the cells to Ara-C treatment. Furthermore, Bcl-2 was confirmed as a direct miR-181a target by immunoblot analysis and reporter gene assays. Knockdown of Bcl-2 mimicked the effect of enforced miR-181a expression by reducing cell viability. In addition, the apoptosis pathway was activated by cytochrome C release and caspase 9/caspase 3 activation after miR 181a overexpression. CONCLUSIONS: This study for the first time demonstrated that downregulation of miR-181a and upregulation of Bcl-2 in leukaemia cells confer resistance to Ara-C-based therapy. These results suggest that restoration of miR 181a expression might provide a promising therapeutic in drug resistance of leukaemia. PMID- 22209979 TI - Chinese hamster AP endonuclease operates by a two-metal ion assisted catalytic mechanism. AB - The APE1, an important mammalian AP endonuclease, is an essential enzyme in the base excision DNA repair pathway (BER). The number of metal ions involved directly in the catalysis remains controversial. Here we describe the metal ion titration experiments that demonstrate the requirement for two metal ions for the endonuclease activity of the Chinese hamster APE1. The titration with the non activating metal ion La(3+) showed a biphasic behavior with activating and inhibitory effects of La(3+) in the range of 0-100 MUM in the presence of 5 mM Mg(2+). Modeling of the enzyme-substrate/product complexes provided insight into the endonuclease activity and elucidated the nature of the crystal structures. Accordingly, we proposed a reaction scheme for the two-metal ion assisted catalysis of chAPE1 endonuclease activity. PMID- 22209980 TI - Splice blocking of zygotic sox31 leads to developmental arrest shortly after Mid Blastula Transition and induces apoptosis in zebrafish. AB - Here we report that splice blocking morpholinos (Sb MO) against zebrafish sox31 elicit developmental arrest, likely through creating a series of dominant negative splicing variants. Embryos injected with the Sb MO develop normally before the Mid-Blastula Transition (MBT); however, they do not initiate epiboly. Microarray analysis of mRNAs collected at the dome stage revealed that the Sb MO impairs activation of a large set of zygotic genes and reduces degradation of maternal mRNA during MBT. Furthermore, an apoptotic response occurs in Sb morphants at about 6hpf. SoxB1 family genes including sox31 thus play an essential role for early embryos traversing the transitional stage. PMID- 22209981 TI - Double-stranded RNA induces S100 gene expression by a cycloheximide-sensitive factor. AB - Viral double-stranded RNA (dsRNA) and its synthetic analog polyI:C are recognized via multiple pathways and induce the expression of genes related to inflammation. In the present study, we demonstrated the polyI:C-induced gene expression of the damage associated molecular pattern (DAMP) molecules S100A8 and S100A9, while other S100 genes were not affected. Cycloheximide and Brefeldin A treatment revealed both the expression of S100A8 and S100A9 as secondary response genes and the involvement of polyI:C-induced cytokines herein. Several type I and type III interferons such as IFNbeta, IL-20, IL-24, and IFNlambda/IL-29 were expressed in response to polyI:C, however, they failed to induce S100A8 and S100A9 gene expression. These data indicate the involvement of the danger molecule S100A8/A9 in the resistance against viruses. PMID- 22209983 TI - Role of luteinizing hormone beta-subunit gene variants among South Indian women with polycystic ovary syndrome. AB - Abnormal luteinizing hormone (LH) secretion and action are known to affect ovarian steroidogenesis and thus playing a crucial role in manifestation of polycystic ovary syndrome (PCOS). This study is first of its kind to study association of LH beta-subunit gene variants with PCOS among South-Indian women. 250 PCOS cases and 299 controls were recruited for the study. All the exons of LH beta gene were screened. Allele and genotype frequencies of the SNPs were compared between the cases and controls. We identified seven SNPs in the LH beta gene; one SNP in exon 3 (rs#1056917) exhibited significant difference in the allele frequency between the PCOS cases and controls (p=0.015). Although, the LH beta variants that are found to be more frequent among PCOS cases are silent in nature and not of any functional significance, they might influence other significant functional polymorphisms in the hypothalamic-pituitary-gonadal axis which needs to be explored. PMID- 22209982 TI - Reconstitution of respiratory oxidases in membrane nanodiscs for investigation of proton-coupled electron transfer. AB - The function of membrane-bound transporters is commonly affected by the milieu of the hydrophobic, membrane-spanning part of the transmembrane protein. Consequently, functional studies of these proteins often involve incorporation into a native-like bilayer where the lipid components of the membrane can be controlled. The classical approach is to reconstitute the purified protein into liposomes. Even though the use of such liposomes is essential for studies of transmembrane transport processes in general, functional studies of the transporters themselves in liposomes suffer from several disadvantages. For example, transmembrane proteins can adopt two different orientations when reconstituted into liposomes, and one of these populations may be inaccessible to ligands, to changes in pH or ion concentration in the external solution. Furthermore, optical studies of proteins reconstituted in liposomes suffer from significant light scattering, which diminishes the signal-to-noise value of the measurements. One attractive approach to circumvent these problems is to use nanodiscs, which are phospholipid bilayers encircled by a stabilizing amphipathic helical membrane scaffold protein. These membrane nanodiscs are stable, soluble in aqueous solution without detergent and do not scatter light significantly. In the present study, we have developed a protocol for reconstitution of the aa(3)- and ba(3)-type cytochrome c oxidases into nanodiscs. Furthermore, we studied proton-coupled electron-transfer reactions in these enzymes with microsecond time resolution. The data show that the nanodisc membrane environment accelerates proton uptake in both oxidases. PMID- 22209984 TI - Impaired DNA repair and genomic stability in hereditary tyrosinemia type 1. AB - The autosomal recessive disorder, hereditary tyrosinemia type 1 (HT1), is caused by a defective fumarylacetoacetate hydrolase enzyme. Consequently intermediate metabolites such as fumarylacetoacetate, succinylacetone and p hydroxyphenylpyruvic acid accumulate. Characteristic to HT1 is the development of hepatocellular carcinoma, irrespective of dietary intervention or pharmacological treatment. Carcinogenesis may occur through a chromosomal instability mutator phenotype or a microsatellite instability phenotype, and deficient DNA repair may be a contributing factor thereof. The purpose of this study was to investigate the expression of DNA repair proteins, and the possible occurrence of microsatellite instability in HT1. Gene expression analyses show low expression of hOGG1 and ERCC1 in HT1 patient lymphocytes. Results from microsatellite instability analyses show allelic imbalance on chromosome 7 of the fah(-/-) mouse genome, and instability of the D2S123, D5S346 and (possibly) D17S250 microsatellite markers, in HT1 patient lymphocytes. PMID- 22209985 TI - Q36R polymorphism of KiSS-1 gene in Brazilian head and neck cancer patients. AB - The KiSS-1 metastasis-suppressor gene (KiSS-1) product (metastin, kisspeptin) is reported to act after binding with the natural ligand of a G-protein coupled receptor and this gene product inhibits chemotaxis, invasion, and metastasis of cells. The aim of this study was to evaluate the Q36R polymorphism of KiSS-1 in patients with head and neck cancer and to compare the results with healthy individuals and its association with clinicopathological parameters. Gender, age, smoking and alcohol consumption were analyzed for 744 individual (252 head and neck cancer patients and in 522 control individuals). The molecular analysis of these individuals was made after extraction of genomic DNA using the SSCP-PCR technique. This study did not reveal any significant differences in genotype frequencies between healthy individuals and patients with head and neck cancer or with the clinical parameters. This study showed an increase frequency of the Q36R polymorphism in pharyngeal cancer. PMID- 22209986 TI - Transforming growth factor-beta1 gene +869T/C, but not +915G/C polymorphism is associated with essential hypertension in a Chinese patient cohort. AB - Many studies have suggested that transforming growth factor-beta1 (TGF-beta1) gene might be involved in the development of hypertension. However, results have been inconsistent. In this study, the authors performed a meta-analysis to investigate the associations of +869T/C and +915G/C polymorphisms in TGF-beta1 gene with hypertension risk in Chinese. Published literature from PubMed, EMBASE, CNKI, CBM, and Wanfang Data were searched. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using fixed or random-effects model. Nine studies (1,995 cases/1,840 controls) for +869T/C polymorphism and seven studies (1,547 cases/1,577 controls) for +915G/C polymorphism were included in the meta-analysis. The overall result showed that there was a statistically significant association between +869T/C polymorphism and hypertension risk (CC vs. TT: OR = 1.80, 95% CI 1.34-2.44). Similar results were found among two geographic locations and two subgroups with different sample size. However, no significant association was found for +915G/C polymorphism with the risk of hypertension (CC vs. GG: OR = 1.66, 95% CI 0.74-3.74). The meta-analysis indicated the significant association of +869T/C, but not +915G/C polymorphism with hypertension susceptibility. However, given the limited sample size, the associations warrant further investigation. PMID- 22209987 TI - Antimicrobial susceptibility of Gram-positive cocci isolated from patients with conjunctivitis and keratitis in Crete, Greece. AB - PURPOSE: To assess the in vitro susceptibility of Streptococcus pneumoniae, Staphylococcus aureus and coagulase-negative staphylococci (CoNS) ocular isolates to antibiotics, and identify changing trends in resistance over a 10-year period. METHODS: All isolates from ocular infections collected between 2000 and 2009 were prospectively tested against several antibiotics in vitro. S. pneumoniae isolates (n = 93) were tested against 20 and S. aureus (n = 120) and CoNS (n = 214) against 19 antibiotics. To identify changes in susceptibility patterns, we compared results from 2000-2004 with those from 2005-2009. We also compared the antibiotic susceptibilities against aminoglycosides and quinolones between methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) isolates. RESULTS: All S. pneumoniae isolates were susceptible to quinolones, and 99% were susceptible to chloramphenicol. Regarding S. aureus, we noted a significant increase in resistance against penicillin in recent years (p = 0.016). Over 90% of S. aureus isolates were susceptible to quinolones and aminoglycosides. MRSA isolates were more resistant to ciprofloxacin and ofloxacin than MSSA isolates were (p = 0.016). Concerning CoNS, a significant increase in susceptibility to amikacin was noted in the second study period (p = 0.01). CONCLUSION: Quinolones remain an excellent treatment option for bacterial conjunctivitis and keratitis due to Gram-positive cocci in our region. PMID- 22209988 TI - Mucosal pigmentation caused by imatinib: report of three cases. AB - Imatinib mesylate (STI-571, Gleevec((r))), a tyrosine kinase inhibitor, is a first-line medication for treating chronic myeloid leukemia (CML). Clinical studies revealed very good hematological responses without significant side effects. However, imatinib may lead to mucosal pigmentation. Three patients, two males aged 64 and 53 and one female aged 29 presented with a painless, diffuse, grey-blue pigmentation of the mucosa of the hard palate. Both male patients had a history of CML and had been on imatinib for 4 and 10 years, respectively. The female patient had been on imatinib for 4 years for pelvic fibromatosis. Histopathologically, deposition of fine, dark-brown, spherical granules was noted within the connective tissue. There was no inflammation or hemorrhage, and no melanosis or melanocytic hyperplasia in the epithelium. The granules stained positively for both Fontana-Masson and Prussian blue stains. Imatinib-induced pigmentation is similar to that caused by other medications such as minocycline and anti-malarial medications, namely the deposition of a drug metabolite containing melanin and iron. PMID- 22209989 TI - Selection of tracers for 13C-metabolic flux analysis using elementary metabolite units (EMU) basis vector methodology. AB - Metabolic flux analysis (MFA) is a powerful technique for elucidating in vivo fluxes in microbial and mammalian systems. A key step in (13)C-MFA is the selection of an appropriate isotopic tracer to observe fluxes in a proposed network model. Despite the importance of MFA in metabolic engineering and beyond, current approaches for tracer experiment design are still largely based on trial and-error. The lack of a rational methodology for selecting isotopic tracers prevents MFA from achieving its full potential. Here, we introduce a new technique for tracer experiment design based on the concept of elementary metabolite unit (EMU) basis vectors. We demonstrate that any metabolite in a network model can be expressed as a linear combination of so-called EMU basis vectors, where the corresponding coefficients indicate the fractional contribution of the EMU basis vector to the product metabolite. The strength of this approach is the decoupling of substrate labeling, i.e. the EMU basis vectors, from the dependence on free fluxes, i.e. the coefficients. In this work, we demonstrate that flux observability inherently depends on the number of independent EMU basis vectors and the sensitivities of coefficients with respect to free fluxes. Specifically, the number of independent EMU basis vectors places hard limits on how many free fluxes can be determined in a model. This constraint is used as a guide for selecting feasible substrate labeling. In three example models, we demonstrate that by maximizing the number of independent EMU basis vectors the observability of a system is improved. Inspection of sensitivities of coefficients with respect to free fluxes provides additional constraints for proper selection of tracers. The present contribution provides a fresh perspective on an important topic in metabolic engineering, and gives practical guidelines and design principles for a priori selection of isotopic tracers for (13)C-MFA studies. PMID- 22209990 TI - Macular function evaluated by focal macular electroretinograms after reduced fluence photodynamic therapy in eyes with polypoidal choroidal vasculopathy. AB - The purpose of this study was to evaluate the macular function by measuring the focal macular electroretinograms (ERGs) recorded before and after reduced fluence photodynamic therapy (RFPDT) in patients with polypoidal choroidal vasculopathy (PCV). Eleven eyes of 11 patients with PCV were studied. Their ages ranged from 62 to 85 years with a mean of 74.7 +/- 6.9 years. The exposure time for the RFPDT was reduced to 42 s, so that the total energy of the laser was approximately one half that of the standard PDT. We measured the visual acuity, foveal thickness, and focal macular ERGs before and after the RFPDT. The follow-up period ranged from 13 to 34 months with a mean of 26 months after the treatment. A significant recovery of vision was seen even at 1 week after the RFPDT (P < 0.005), and the visual acuities improved gradually thereafter (P < 0.0005). The foveal thickness was significantly reduced at 1 week after the treatment (P < 0.005) and then continued to become significantly thinner with time (P < 0.0001). A slight recovery of the a- and b-wave amplitudes was seen postoperatively without a transient reduction in the amplitudes. The b-wave amplitude was significantly larger at 3 months after the treatment than at baseline (P < 0.05). Choroidal hypoperfusion did not develop 3 months postoperatively in the indocyanine green angiograms. Exudative changes recurred in 4 (27%) eyes after 1 year and in 9 (82%) eyes during the follow-up period. RFPDT provided short-term benefits in selected patients with PCV with small lesions. The macular function was retained after RFPDT without a transient decrease in visual function. Further study is needed to determine the long-term efficacy of RFPDT for eyes with PCV. PMID- 22209991 TI - Apelin-12 stimulates acid secretion through an increase of histamine release in rat stomachs. AB - BACKGROUND: Apelin is a peptide that was originally isolated from bovine stomach extract and has been demonstrated to be an endogenous ligand for orphan receptor APJ. Both apelin and the APJ receptor are widely distributed in the whole body. Apelin is supposed to have important regulatory roles in the function of many organs such as in the cardiovascular system; however, the mechanism of apelin function has not been elucidated. In this study, we studied the action of apelin in acid secretion and demonstrated its mechanism of action. METHODS: Gastric lumen-perfused rats were prepared and their stomachs were perfused with a saline solution using a peristaltic pump. Apelin-12, 36 or Pyr(1)-apelin-13, were intravenously injected to examine their effects on acid secretion in rats. In some experiments, rats were pretreated with famotidine (0.33 mg/kg) or atropine sulfate (0.1mg/kg) intravenously injected 5 or 15 min before apelin injection. Furthermore, isolated vascularly perfused rat stomachs were prepared to examine the effect of apelin on histamine release, which was assayed in the effluent by radioimmunoassay. Messenger RNA of histidine decarboxylase (HDC) in gastric mucosa of isolated stomach was measured by real-time RT-PCR. RESULTS: Apelin-12 (20-100 MUg/kg) dose-dependently increased gastric acid secretion, with a maximum of 203% at 100 MUg/kg (n=5). Neither Pyr(1)-apelin-13 nor apelin-36 caused a significant increase in acid secretion. Famotidine completely blocked the stimulatory action of apelin on acid secretion. Apelin-12 (100 MUg/20 ml/10 min) markedly increased histamine release from isolated vascularly perfused rat stomachs by 278%, and also increased the mRNA of HDC by 480% of the control. Atropine sulfate did not abolish the effect of apelin on the secretion of gastric acid. Apelin-12 amplified an increase of acid secretion stimulated by gastrin injection. CONCLUSION: These results indicate that apelin-12 stimulates gastric acid secretion through an increase in histamine release and synthesis from gastric mucosa, suggesting that apelin might play a role in the secretion of gastric acid or serve as a regulating factor of the secretion of gastric acid. PMID- 22209992 TI - Altered regulation of nitric oxide and natriuretic peptide system in cisplatin induced nephropathy. AB - Cisplatin is a chemotherapeutic agent used for treating solid tumors. However, nephrotoxicity is the dose-limiting factor in its clinical use. The present study was aimed to determine whether altered regulation of the local nitric oxide (NO) and natriuretic peptide (NP) systems is involved in the pathogenesis of cisplatin induced nephropathy. Cisplatin (6 mg/kg) was injected intraperitoneally into male Sprague-Dawley rats. The control group was not treated with cisplatin. Expression levels of nitric oxide synthase (NOS), nitrotyrosine, soluble guanylyl cyclase and neutral endopeptidase (NEP) in the kidneys were determined 4 days after treatment by semiquantitative immunoblotting. mRNA expression of NPs and natriuretic peptide receptors (NPRs) was determined by real-time polymerase chain reaction. The activities of soluble and particulate guanylyl cyclase were determined by measuring the amount of cyclic 3',5'-guanosine monophosphate (cGMP) generated in responses to sodium nitroprusside and atrial natriuretic peptide (ANP), respectively. In the test rats, creatinine clearance was decreased, while sodium and water excretion were increased. The expression of inducible NOS (iNOS) and nitrotyrosine was increased in the cortex/outer stripe of outer medullar and inner medullar, while that of endothelial and neuronal NOS was decreased in the inner medullar. Excretion of NO metabolites was increased in these rats. The catalytic activity of soluble guanyly cyclase was blunted in the papilla after cisplatin was administered. The mRNA expression of ANP, brain natriuretic peptide, and C-type natriuretic peptide was increased, while that of NPR-A and NPR-C were decreased in the test rats. The catalytic activity of soluble and particulate guanylyl cyclase in the papilla was blunted after cisplatin was administered. In conclusion, increased production of NO by iNOS may contribute to cytotoxic injury, resulting in cisplatin-induced nephropathy, while the up regulation of renal natriuretic peptide synthesis together with the down regulation of NEP and NPR-C may contribute to the natriuresis and diuresis seen in cisplatin-induced nephropathy. PMID- 22209993 TI - Interleukin-23 serum levels in patients affected by peripheral arterial disease. AB - OBJECTIVES: To clarify whether interleukin (IL)-23 is involved in peripheral arterial disease (PAD). DESIGN AND METHODS: We evaluated IL-23 serum levels, in 29 patients suffering from lower extremity PAD and in 30 healthy subjects. RESULTS: IL-23 serum levels were higher during the three times (T0, T1 and T2) compared to the control group, although only statistically significant for T0 and T2: T0 (15.83 +/- 22.08 vs. 8.08 +/- 8.62 pg ml, p=0.026), T1 (16.10 +/- 23.71 vs. 8.08 +/- 8.62 pg/ml, p=0.101), T2 (15.06 +/- 16.72 vs. 8.08 +/- 8.62 pg/ml, p=0.005). CONCLUSION: For the first time, our data gives us reason to believe there is an involvement of IL-23 in PAD. PMID- 22209994 TI - Head-to-head comparison of the prohormone proBNP1-108 with BNP and Nt-proBNP in patients admitted to emergency department. AB - OBJECTIVES: B-type natriuretic peptide (BNP) and amino-terminal proBNP (Nt proBNP) are derived from a common precursor, the proBNP(1-108) (proBNP), synthesized by cardiomyocytes. We determined proBNP concentrations in patients admitted to ED and suspected of CHF. DESIGN AND METHODS: One hundred fifty six consecutive patients admitted to ED were included. ProBNP, BNP and Nt-proBNP levels were determined at admission. RESULTS: In this ED population, assays for proBNP, BNP and Nt-proBNP were positively and significantly correlated. Circulating levels of proBNP were higher in patients admitted to ED for CHF than in patients admitted to ED other reasons. Applying receiver operating characteristic curve (ROC) analysis for the diagnosis of CHF, the area under the curve (AUC) was 0.92 for proBNP. CONCLUSIONS: Our study demonstrated that proBNP testing, the precursor of BNP and Nt-proBNP, appears as a relevant tool to assist the diagnosis of CHF in patients admitted to ED. PMID- 22209995 TI - Controlling lipolysis through steric surfactants: new insights on the controlled degradation of submicron emulsions after oral and intravenous administration. AB - In this work we have investigated how steric surfactants influence the metabolic degradation of emulsions (lipolysis). To do so, we have prepared submicron emulsions stabilized with Pluronic F68, Pluronic F127, Myrj 52 or Myrj 59, four non-ionic surfactants with key differences on their structure. Submicron emulsions have been prepared also with mixtures of these surfactants with different proportions between them. Then, in vitro methods have been applied to analyze the lipolysis of these emulsions, both under duodenal and intravenous conditions, to simulate lipolysis after oral and intravenous administration. Our results show that the properties of the surfactant influence dramatically the lipolysis rates observed both under duodenal and intravenous conditions, e.g., intravenous lipolysis was completely blocked when Pluronic F127 was used, while it was almost complete within 6h when using Myrj 52. The reason for this seems to be the steric hindrance that the surfactant produces around the droplet and at the interface. As a result, we can modify the lipolysis patterns by changing some characteristics of the surfactant, or by varying the proportion between two surfactants in a mixture. These findings may be applied in the development of novel strategies to rationally design submicron emulsions as lipophilic drug carriers. PMID- 22209996 TI - Development of udenafil-loaded microemulsions for intranasal delivery: in vitro and in vivo evaluations. AB - To achieve rapid onset of action and improved bioavailability of udenafil, a microemulsion system was developed for its intranasal delivery. Phase behavior, particle size, transmission electron microscope (TEM) images, and the drug solubilization capacity of the microemulsion were investigated. A single isotropic region was found in pseudo-ternary phase diagrams developed at various ratios with CapMul MCM L8 as an oil, Labrasol as a surfactant, and Transcutol or its mixture with ethanol (1:0.25, v/v) as a cosurfactant. Optimized microemulsion formulations with a mean diameter of 120-154 nm achieved enhanced solubility of udenafil (>10mg/ml) compared with its aqueous solubility (0.02 mg/ml). An in vitro permeation study was performed in human nasal epithelial (HNE) cell monolayers cultured by the air-liquid interface (ALI) method, and the permeated amounts of udenafil increased up to 3.41-fold versus that of pure udenafil. According to the results of an in vivo pharmacokinetic study in rats, intranasal administration of udenafil-loaded microemulsion had a shorter T(max) value (1 min) compared with oral administration and improved bioavailability (85.71%) compared with oral and intranasal (solution) administration. The microemulsion system developed for intranasal administration may be a promising delivery system of udenafil, with a rapid onset of action and improved bioavailability. PMID- 22209997 TI - Quality by design approach for formulation development: a case study of dispersible tablets. AB - The focus of the current investigations was to apply quality by design (QbD) approach to the development of dispersible tablets. Critical material and process parameters are linked to the critical quality attributes of the product. Variability is reduced by product and process understanding which translates into quality improvement, risk reduction and productivity enhancement. The risk management approach further leads to better understanding of the risks, ways to mitigate them and control strategy is proposed commensurate with the level of the risk. Design space in combination with pharmaceutical quality management system provide for flexible regulatory approaches with opportunity for continuous improvement that benefit patient and manufacturer alike. The development of dispersible tablet was proposed in the current study through a QbD paradigm for a better patient compliance and product quality. The quality target product profile of a model biopharmaceutical class II drug was identified. Initial risk analysis led to the identification of the critical quality attributes. Physicochemical characterization and compatibility studies of the drug with commonly used excipients were performed. Experiments were designed with focus on critical material and process attributes. Design space was identified and risk factors for all the possible failure modes were below critical levels after the implementation of control strategy. Compliance to the design space provides an opportunity to release batches in a real time. In conclusion, QbD tools together with risk and quality management tools provided an effective and efficient paradigm to build the quality into dispersible tablet. PMID- 22209998 TI - Self assembling nanocomposites for protein delivery: supramolecular interactions of soluble polymers with protein drugs. AB - Translation of therapeutic proteins to pharmaceutical products is often encumbered by their inadequate physicochemical and biopharmaceutical properties, namely low stability and poor bioavailability. Over the last decades, several academic and industrial research programs have been focused on development of biocompatible polymers to produce appropriate formulations that provide for enhanced therapeutic performance. According to their physicochemical properties, polymers have been exploited to obtain a variety of formulations including biodegradable microparticles, 3-dimensional hydrogels, bioconjugates and soluble nanocomposites. Several soluble polymers bearing charges or hydrophobic moieties along the macromolecular backbone have been found to physically associate with proteins to form soluble nanocomplexes. Physical complexation is deemed a valuable alternative tool to the chemical bioconjugation. Soluble protein/polymer nanocomplexes formed by physical specific or unspecific interactions have been found in fact to possess peculiar physicochemical, and biopharmaceutical properties. Accordingly, soluble polymeric systems have been developed to increase the protein stability, enhance the bioavailability, promote the absorption across the biological barriers, and prolong the protein residence in the bloodstream. Furthermore, a few polymers have been found to favour the protein internalisation into cells or boost their immunogenic potential by acting as immunoadjuvant in vaccination protocols. PMID- 22209999 TI - Use of the skin sandwich technique to probe the role of the hair follicles in sonophoresis. AB - The human skin sandwich technique was used to explore the effect of brief ultrasound exposure on the transfollicular pathway of absorption. Hydrocortisone was used as a model drug. In order to calculate the permeability coefficient of hydrocortisone, its concentration at saturation in the PBS donor solution was determined. Skin samples were prepared by sandwich technique with total hydration of the epidermal and sandwich membranes. The skin was sonicated for 0 s (control), 30 s or 45 s using a pulsed mode (10% duty cycle) with the spatial and temporal average intensity (SATA) of 3.7 W/cm(2). The transducer was then removed and permeation was allowed to proceed for 52 h. Then the percentage follicular contribution was determined. It was determined that without ultrasound, drug entry into follicles accounted for 46% of total penetration. As the duration of sonication increased, the follicular contribution fell to zero even though total transepidermal flux dramatically increased. This is explained by ultrasound exposure causing sloughing off of the uppermost stratum corneum. This permeabilises the continuous surface but at the same time the disturbed cornceocytes will plug hair follicle orifices. PMID- 22210000 TI - Lactose-ornithine bolaamphiphiles for efficient gene delivery in vitro. AB - The development of new nonviral vectors characterized by high transfection efficiency and low cytotoxicity remains an important challenge in the field of gene delivery. Unsymmetrical bolaamphiphiles (bolas) appear as new emerging candidates for this application. In this work, new unsymmetrical bolas, bearing neutral lactonic acid and cationic ornithine residues at the two ends of a hydrophobic spacer, were synthesized and their properties were compared to analogues bearing a gluconic acid residue. The new bolas showed DNA binding and condensation at higher N/P ratios than their gluconic analogues, probably due to their larger neutral head group. Whereas the size of the complexes of the new bolas with DNA (bolaplexes) increased with N/P, as a result of charge neutralization, their formulations with DOPE at high N/P were of small size (ca. 200 nm). These DOPE formulations showed high transfection efficiency in different cell lines (HeLa, COS-7 and HepG2), close to that of jetPEI. Their cytotoxicity was relatively low, which allowed repetitive transfection in vitro. Fluorescence imaging showed that the bolaplexes bind rapidly to cell surface and internalize mainly through endocytosis. This work suggests a new type of efficient nonviral vectors based on bolaamphiphiles. PMID- 22210001 TI - Solid-state nanoparticle coated emulsions for encapsulation and improving the chemical stability of all-trans-retinol. AB - Submicron oil-in-water (o/w) emulsions stabilised with conventional surfactants and silica nanoparticles were prepared and freeze-dried to obtain free-flowing powders with good redispersibility and a three-dimensional porous matrix structure. Solid-state emulsions were characterised for visual appearance, particle size distribution, zeta potential and reconstitution properties after freeze-drying with various sugars and at a range of sugar to oil ratios. Comparative degradation kinetics of all-trans-retinol from freeze-dried and liquid emulsions was investigated as a function of storage temperatures. Optimum stability was observed for silica-coated oleylamine emulsions at 4 degrees C in their wet state. The half-life of all-trans-retinol was 25.66 and 22.08 weeks for silica incorporation from the oil and water phases respectively. This was ~4 times higher compared to the equivalent solid-state emulsions with drug half-life of 6.18 and 6.06 weeks at 4 degrees C. Exceptionally, at a storage temperature of 40 degrees C, the chemical stability of the drug was 3 times higher in the solid-state compared to the wet emulsions which confirmed that freeze-drying is a promising approach to improve the chemical stability of water-labile compounds provided that the storage conditions are optimised. PMID- 22210002 TI - Zinc finger homeobox is required for the differentiation of serotonergic neurons in the sea urchin embryo. AB - Serotonergic neurons differentiate in the neurogenic animal plate ectoderm of the sea urchin embryo. The regulatory mechanisms that control the specification or differentiation of these neurons in the sea urchin embryo are not yet understood, although, after the genome was sequenced, many genes encoding transcription factors expressed in this region were identified. Here, we report that zinc finger homeobox (zfhx1/z81) is expressed in serotonergic neural precursor cells, using double in situ hybridization screening with a serotonergic neural marker, tryptophan 5-hydroxylase (tph) encoding a serotonin synthase that is required for the differentiation of serotonergic neurons. zfhx1/z81 begins to be expressed at gastrula stage in individual cells in the anterior neuroectoderm, some of which also express delta. zfhx1/z81 expression gradually disappears as neural differentiation begins with tph expression. When the translation of Zfhx1/Z81 is blocked by morpholino injection, embryos express neither tph nor the neural marker synaptotagminB in cells of the animal plate, and serotonergic neurons do not differentiate. In contrast, Zfhx1/Z81 morphants do express fez, another neural precursor marker, which appears to function in the initial phase of specification/differentiation of serotonergic neurons. In addition, zfhx1/z81 is one of the targets suppressed in the animal plate by anti-neural signals such as Nodal as well as Delta-Notch. We conclude that Zfhx1/Z81 functions during the specification of individual anterior neural precursors and promotes the expression of tph and synaptotagminB, required for the differentiation of serotonergic neurons. PMID- 22210003 TI - The cytokine macrophage migration inhibitory factor (MIF) acts as a neurotrophin in the developing inner ear of the zebrafish, Danio rerio. AB - Macrophage migration inhibitory factor (MIF) plays versatile roles in the immune system. MIF is also widely expressed during embryonic development, particularly in the nervous system, although its roles in neural development are only beginning to be understood. Evidence from frogs, mice and zebrafish suggests that MIF has a major role as a neurotrophin in the early development of sensory systems, including the auditory system. Here we show that the zebrafish mif pathway is required for both sensory hair cell (HC) and sensory neuronal cell survival in the ear, for HC differentiation, semicircular canal formation, statoacoustic ganglion (SAG) development, and lateral line HC differentiation. This is consistent with our findings that MIF is expressed in the developing mammalian and avian auditory systems and promotes mouse and chick SAG neurite outgrowth and neuronal survival, demonstrating key instructional roles for MIF in vertebrate otic development. PMID- 22210004 TI - Characterization of Chikungunya virus infection in human neuroblastoma SH-SY5Y cells: role of apoptosis in neuronal cell death. AB - Chikungunya infection is characterized by fever, rash and arthritis. The disease pathogenesis is still poorly understood. Hence, unveiling the molecular mechanisms that govern the survival and death of neuronal cells infected by Chikungunya virus (CHIKV) was the particular interest of this study. Human neuroblastoma SH-SY5Y cells infected with CHIKV showed characteristic features of apoptosis with activation of caspase-3, cleavage of PARP and translocation of Cyt c. Cells also showed a loss in the intracellular level of GSH and an increase in the lipid peroxidation of the infected cells with the increasing time of infection, which indicated the involvement of oxidative stress in Chikungunya infection. There was observed a gradual decrease in the fold change of antioxidant enzymes and an increase in the fold change of pro-inflammatory cytokines. This study suggested the implication of virus induced apoptosis in disease pathogenesis which may give a fresh insight for CHIKV induced neuronal cell damage and antiviral therapeutics. PMID- 22210005 TI - Inhaled neutrophil elastase inhibitor reduces oleic acid-induced acute lung injury in rats. AB - RATIONALE: Neutrophil elastases (NE) play an important role in the pathogenesis of acute lung injury (ALI). NE activities are significantly increased in serums and lungs of patients or animals with ALI. Intravenous infusion (IV) of Sivelestat, an NE inhibitor, can reduce ALI. Through inhalation, drugs reach lungs directly and in high concentration. We hypothesized that inhaled Sivelestat would alleviate oleic acid (OA)-induced ALI in rats. METHODS: Rats were anesthetized and mechanically ventilated, and then ALI was induced by OA injection. One hour later, the animals were randomized to receive either Sivelestat (3 mg/kg/h) or saline inhalation. The effect of Sivelestat IV (3 mg/kg/h) was also investigated. All animals were ventilated and observed for 6 h. RESULTS: OA injection increased NE activities in lung tissues and serums. The increase of NE activities in lung tissues and serums markedly reduced by 77%, and 29%, respectively, by the inhalation of Sivelestat; and 53.8%, and 80%, respectively, by Sivelestat IV. Additionally, inhaled Sivelestat resulted in ameliorated lung injury by reducing edema and infiltration of neutrophils in the lung, improved oxygenation and survival. CONCLUSIONS: An over increased NE activity in lungs may play a vital effect in the pathogenesis of OA-induced ALI in rats. Topical application of nebulized Sivelestat, an NE inhibitor, may reduce OA-induced ALI in rats. Sivelestat inhalation can be developed as a novel treatment for ALI. PMID- 22210006 TI - Insulin action on H292 bronchial carcinoma cells as compared to normal bronchial epithelial cells. AB - Inhaled insulin may contribute to bronchial carcinoma due to IGF-I receptor activation by high local concentrations. Therefore, effects of insulin and IGF-I on human bronchial carcinoma cells (H292) and normal bronchial epithelium cells (HBE) were studied. TGF-beta was included since it also influences carcinoma progression. H292 and HBE cells expressed both the insulin receptor and the IGF-I receptor; in H292 cells an additional, shorter, splicing variant (IR-A) of the insulin receptor was present. Insulin receptor expression was around four to five times higher in H292 than in HBE cells at mRNA and protein levels. Insulin and TGF-beta exerted contrary actions on proliferation and gene expression in H292 cells. Genes regulated by insulin, IGF-I, and TGF-beta were linked to inflammation, cell adhesion, muscle contraction and differentiation. Insulin and IGF-I also suppressed DNA repair genes. EC(50) for insulin-induced proliferation was around 5 nM in H292 and around 30 nM HBE cells. The EC(50) values for gene expression ranged from 9 to 90 nM in both cell types, dependent on the gene studied. In H292 cells, the proliferative response was much stronger if TGF-beta was present. In HBE cells this interaction of insulin and TGF-beta was not observed, and changes in gene expression were mostly lower by at least 10-fold as compared to H292. All in all, the insulin effects in H292 were generally much stronger than in HBE cells and - with regard to proliferation - occurred at lower concentrations. Thus, insulin will hardly induce cancer from normal bronchial cells but may favour progression of pre-existing tumours. PMID- 22210007 TI - Bronchopulmonary pharmacokinetic and pharmacodynamic profiles of levofloxacin 750 mg once daily in adults undergoing treatment for acute exacerbation of chronic bronchitis. AB - While previous reports have described the bronchopulmonary profile of the fluoroquinolones in healthy volunteers, limited data are available in infected patients. The purpose of this study was to determine the intrapulmonary profile of high-dose (750 mg) levofloxacin in patients during an acute exacerbation of chronic bronchitis (AECB). Twenty-four patients experiencing clinical signs and symptoms of AECB were enrolled. Once enrolled, patients received levofloxacin 750 mg once daily * 5 days. Bronchoalveolar lavage aspirates and simultaneous plasma samples were obtained at 4 h, 12 h or 24 h after the third dose. Concentrations in biologic matrixes were determined with a validated HPLC method. Epithelial lining fluid (ELF) concentrations were calculated using the urea dilution method. Five patients did not complete the trial, 19 patients underwent bronchoscopy, 18 (52 +/- 13 yrs) had sufficient samples for analysis and confirmed medication compliance. Mean plasma concentrations at 4, 12, and 24 h were 8.0 +/- 2.5, 5.8 +/- 1.2, and 2.2 +/- 1.2 MUg/mL. Mean ELF values at 4, 12, and 24 h were 7.5 +/- 3.0, 8.3 +/- 6.0, and 1.2 +/- 0.9 MUg/mL. Mean alveolar macrophage (AM) concentrations at 4, 12, and 24 h were 38.5 +/- 43.7, 13.4 +/- 14.4, and 9.0 +/- 7.5 MUg/mL. The penetration (ELF/plasma ratio) into the infection site was 113%. In these subjects with AECB, levofloxacin 750 mg once daily reached adequate exposures in the plasma, ELF, and AMs for the most commonly associated pathogens. PMID- 22210008 TI - Gastrin releasing peptide-29 requires vagal and splanchnic neurons to evoke satiation and satiety. AB - We have shown that gastrin-releasing peptide-29 (GRP-29), the large molecular form of GRP in rats, reduces meal size (MS, intake of 10% sucrose solution) and prolongs the intermeal interval (IMI). In these studies, we first investigated possible pathways for these responses in rats undergoing total subdiaphragmatic vagotomy (VGX, removal of vagal afferent and efferent innervation of the gut), celiaco-mesenteric ganglionectomy (CMGX, removal of splanchnic afferent and efferent innervation of the gut) and combined VGX and CMGX. Second, we examined if the duodenum communicates the feeding signals (MS and IMI) of GRP-29 (0, 0.3, 1.0, 2.1, 4.1, 10.3 and 17.2 nmol/kg) with the feeding control areas of the hindbrain by performing duodenal myotomy (MYO), a procedure that severs some layers of the duodenal wall including the vagal, splanchnic and enteric neurons. We found that GRP-29 (2.1, 4.1, 10.3, 17.2 nmol/kg) reduced the size of the first meal (10% sucrose) and (1, 4.1, 10.3 nmol/kg) prolongs the first IMI but did not affect the subsequent meals or IMIs. In addition, CMGX and combined VGX/CMGX attenuated reduction of MS by GRP-29 and all surgeries attenuated the prolongation of the IMI. Therefore, reduction of MS and prolongation of IMI by GRP-29 require vagal and splanchnic nerves, and the duodenum is the major conduit that communicates prolongation of IMI by GRP-29 with the brain. PMID- 22210009 TI - Determination of a molecular shape for netrin-4 from hydrodynamic and small angle X-ray scattering measurements. AB - As part of a continuing investigation of netrins, an emerging class of extracellular matrix proteins that are involved in axon guidance activity, we have used dynamic light scattering (DLS) and small angle X-ray scattering to investigate the solution conformation of a truncated version of netrin-4 (Deltanetrin-4) that lacks the C-terminal portion. The protein is characterized by a hydrodynamic (Stokes) radius (r(H)) of 4.60 (+/-0.20) nm, a radius of gyration (r(G)) of 4.42 (+/-0.20) nm and a maximum particle dimension (D(max)) of 16nm. More detailed ab initio modeling of the SAXS data indicates an extended rod like conformation for Deltanetrin-4 in solution-a concept supported by the excellent agreement observed between experimental parameter estimates and those calculated for the ab initio models for Deltanetrin-4 by the HYDROPRO program. PMID- 22210011 TI - Research synthesis: what is the diagnostic performance of magnetic resonance imaging to discriminate benign from malignant vertebral compression fractures? Systematic review and meta-analysis. AB - STUDY DESIGN: This study is a research synthesis of the published literature evaluating the performance of magnetic resonance imaging (MRI) for differentiation of malignant from benign vertebral compression fractures (VCFs). OBJECTIVE: Perform a systematic review and meta-analysis to summarize and combine the published data on MRI for discriminating malignant from benign VCFs. SUMMARY OF BACKGROUND DATA: The differentiation between benign and malignant VCFs in the spine is a challenging problem confronting spine practitioners. METHODS: MEDLINE, EMBASE, and other databases were searched by 2 independent reviewers to identify studies that reported the performance of MRI for discriminating malignant from benign VCF. Included studies were assessed for described MRI features and study quality. The sensitivity, specificity, and diagnostic odds ratio (OR) of each feature were pooled with a random-effects model weighted by the inverse of the variance of each individual estimate. RESULTS: A total of 31 studies with 1685 subjects met the selection criteria. All the studies focused on describing specific features rather than overall diagnostic performance. Signal intensity ratio on opposed phase (chemical shift) imaging 0.8 or more (OR = 164), apparent diffusion coefficient on echo planar diffusion-weighted images 1.5 * 10(-3) mm2/s or less with b value 500 s/mm2 (OR = 130), presence of other noncharacteristic vertebral lesions (OR = 55), presence of paraspinal mass (OR = 33), involvement of posterior element (OR = 28), involvement of pedicle (OR = 24), complete replacement of normal bone marrow in VCF (OR = 19), presence of epidural mass (OR = 13), and diffuse convexity of posterior vertebral border (OR = 10) were associated with malignant VCFs, whereas coexisting healed benign VCF (OR = 0.006), presence of "fluid sign" (OR = 0.08), presence of focal posterior vertebral border convexity/retropulsion (OR = 0.08), and band-like shape of abnormal signal (OR = 0.07) were associated with benign VCFs. CONCLUSION: Several specific MRI features using signal intensity characteristics, morphological characteristics, quantitative techniques, and findings at other levels can be useful for distinguishing benign from malignant VCFs and can serve as inputs for a prediction model. Observer performance reliability has not been adequately assessed. PMID- 22210010 TI - Effective antitumor immunity against murine gliomas using dendritic cells transduced with hTERTC27 recombinant adenovirus. AB - hTERTC27, a 27-kDa hTERT C-terminal polypeptide has been demonstrated to cause hTERT-positive HeLa cell apoptosis and inhibits the growth of mouse melanoma. hTERTC27 has been associated with telomere dysfunction, regulation of gene regulated apoptosis, the cell cycle and activation of natural killer (NK) cells, but its mechanism of action is not fully understood. Here, we report that dendritic cells (DCs) transduced with hTERTC27 can increase T-cell proliferation, and augment the concentration of interleukin-2 (IL-2) and interferon-gamma (IFN gamma) in the supernatants of T cells. It can also induce antigen-specific cytotoxic T lymphocytes (CTL) against glioma cells in vitro. Moreover, hTERTC27 gene-transduced DCs exhibit a very potent cytotoxicity to glioma cells in vivo. It could prolong the survival time and inhibit the growth of glioma-bearing mice. These data suggest that hTERTC27 gene-transduced DCs can efficiently enhance immunity against gliomas in vitro and in vivo. PMID- 22210012 TI - Surgical site infection in spinal surgery: description of surgical and patient based risk factors for postoperative infection using administrative claims data. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: The objective of this study was to investigate the accuracy of using an automated approach to administrative claims data to assess the rate and risk factors for surgical site infection (SSI) in spinal procedures. SUMMARY OF BACKGROUND DATA: SSI is a major indicator of health care quality. A wide range of SSI rates have been proposed in the literature depending on clinical setting and procedure type. METHODS: All spinal surgeries performed at a university-affiliated tertiary-care center from July 2005 to December 2010 were identified using diagnosis-related group, current procedural terminology, and International Classification of Diseases, Ninth Revision (ICD-9) codes and were validated through chart review. Rates of SSI and associated risk factors were calculated using univariate regression analysis. Odds ratios were calculated through multivariate logistic regression. RESULTS: A total of 6628 hospital visits were identified. The cumulative incidence of SSI was 2.9%. Procedural risk factors associated with a statistically significant increase in rates of infection were the following: sacral involvement (9.6%), fusions greater than 7 levels (7.8%), fusions greater than 12 levels (10.4%), cases with an osteotomy (6.5%), operative time longer than 5 hours (5.1%), transfusions of red blood cells (5.0%), serum (7.4%), and autologous blood (4.1%). Patient-based risk factors included anemia (4.3%), diabetes mellitus (4.2%), coronary artery disease (4.7%), diagnosis of coagulopathy (7.8%), and bone or connective tissue neoplasm (5.0%). CONCLUSION: Used individually, diagnosis-related group, current procedural terminology, and ICD-9 codes cannot completely capture a patient population. Using an algorithm combining all 3 coding systems to generate both inclusion and exclusion criteria, we were able to analyze a specific population of spinal surgery patients within a high-volume medical center. Within that group, risk factors found to increase infection rates were isolated and can serve to focus hospital-wide efforts to decrease surgery related morbidity and improve patient outcomes. PMID- 22210013 TI - The use of a transition rod may prevent proximal junctional kyphosis in the thoracic spine after scoliosis surgery: a finite element analysis. AB - STUDY DESIGN: Finite element analysis. OBJECTIVE: Via finite element analysis: (1) to demonstrate the abnormal forces present at the top of a scoliosis construct, (2) to demonstrate the importance of an intact interspinous and supraspinous ligament (ISL/SSL) complex, and (3) to evaluate a transition rod (a rod that has a short taper to a smaller diameter at one end) as an implant solution to diminish these pathomechanics, regardless of the integrity of the ISL/SSL complex. SUMMARY OF BACKGROUND DATA: The pathophysiology of increased nucleus pressure and increased angular displacement may contribute to proximal junctional kyphosis. Furthermore, high implant stress can be demonstrated at the upper end of the construct, possibly leading to the risk of implant failure. METHODS: A finite element model was constructed to simulate a thoracic spinal fusion. The model was altered to remove the ISL/SSL complex at the level above the construct. Then, the model was altered again by extending the construct one level superior with a transition rod. The angular displacement, the maximum pressure in the nucleus, and stress within the implant were extracted from computational results under 2 conditions: load control and displacement control. The testing was performed with both titanium and stainless steel implants. RESULTS: Pressure in the nucleus and angular displacement are all increased when the ISL/SSL complex is removed immediately above the instrumented levels, whereas the screw pullout force and maximum stress within the screw are decreased. The nucleus pressure increases by more than 50%. The angular displacement increases by 19% to 26%. This absence of the ISL/SSL complex simulates the clinical scenario that occurs when these structures are iatrogenically detached. Abnormal mechanics can be restored to normal level by extending the construct rostral one level with a transition rod. Furthermore, the elevated nucleus pressure and angular displacement noted even when the ISL/SSL complex is intact can be avoided with the use of a transition rod. Under the same bending moment (3 Nm), the nucleus pressure at the level immediately cephalad is up to 23% lower than the pressure in a standard construct. The angular displacement is 18% to 19% less than the standard construct. The maximum implant stress is also decreased by as much as 60%. CONCLUSION: Finite element modeling suggests that the pathomechanics at the proximal end of a scoliosis construct may be diminished by preserving the ISL/SSL complex and possibly completely eliminated with the use of rods with a diameter transition at the most proximal level. PMID- 22210014 TI - How does thoracic kyphosis affect patient outcomes in growing rod surgery? AB - STUDY DESIGN: Retrospective review of a multicenter series. OBJECTIVE: This study was conducted to specifically identify the complication rate of growing rod surgery in patients with normal (10 degrees -40 degrees ) versus abnormal thoracic kyphosis. SUMMARY OF BACKGROUND DATA: Surgical treatment options for progressive early onset scoliosis include spinal fusion versus growth-sparing techniques. The current most commonly employed growing rod technique involves short fusions at the foundation sites using either hooks or screws as anchors and placement of dual growing rods spanning the deformity. Although the coronal deformity in these patients has been studied extensively, the sagittal profile has received less attention as a possible factor in complication rates and patient outcomes. METHODS: Out of 387 patients who underwent surgical placement of growing rods, 90 patients had complete clinical and radiographical data, with 2-year follow-up after initial surgery. Patients were categorized into 3 groups on the basis of preoperative thoracic kyphosis magnitude: less than 10 degrees (K- group), 10 degrees -40 degrees (N group), and more than 40 degrees (K+ group). Patient diagnosis, demographics, surgical information, radiographical measurements, and complication types were tabulated and analyzed. A P value of <0.05 was considered significant for all statistical tests. RESULTS: The K- group experienced 27 total complications including 15 general medical complications, the N group had 20 total and 4 general complications, and the K+ group had 55 total and 22 general complications. Patients in the K+ group were 3.1 times more likely to experience a complication than those in the N group, which was statistically significant (P < 0.05). When considering all types of complications, length of follow-up, T2-T5 proximal kyphosis, postoperative Cobb angle, and rod diameter were identified as confounding variables. When the confounding variables were taken into consideration in the analysis, the odds ratios were no longer significant between the N and K+ groups. Patients in the K+ group and K- group were 2.95 and 2.89 times more likely to experience a general medical complication than those in the N group, respectively (P > 0.05). The rate of implant-related complications between the groups did not reach statistical significance, although the K+ group had the most implant complications (n = 34), including 25 rod breakages in 16 patients. Syndromic patients had 2.9 times the risk of having an overall complication when compared with the entire patient series (P < 0.05). The number of patients who experienced multiple complications was higher in the K- and K+ groups than in the N group. CONCLUSION: Patients with thoracic hyperkyphosis present even more of a challenge with respect to complications, specifically implant-related complications. Our study shows that growing rod surgery in patients with kyphosis more than 40 degrees has significantly more general and implant complications than that in patients with normal thoracic kyphosis. Implant complications were more common in hyperkyphotic (>40 degrees ) patients and increased linearly with increasing kyphosis. The most common implant complication was rod breakage. Patients with hyperkyphotic thoracic spines, particularly syndromic patients, must be monitored closely and parents should be counseled regarding the likelihood of future adverse events. PMID- 22210015 TI - Diffusion tensor imaging in pediatric spinal cord injury: preliminary examination of reliability and clinical correlation. AB - STUDY DESIGN: The design was a nonexperimental, repeated measures design. OBJECTIVE: To examine the reliability of repeated diffusion tensor imaging (DTI) values of the pediatric cord and to compare DTI values with values obtained on the clinical examination and findings from conventional magnetic resonance imaging (MRI). SUMMARY OF BACKGROUND DATA: DTI quantifies the diffusion of water molecules in directions parallel and transverse to the plane of neuronal axons. The unique characteristic architecture of the spinal cord allows DTI to examine the white matter and potentially separate white matter from gray matter and assess structural damage of the cord. METHODS: Ten youths with cervical spinal cord injury (SCI) were evaluated using the International Standards for Neurological Classification of SCI (ISNCSCI) and had 2 scans using a 3.0T Siemens Verio MR scanner. The imaging protocol consisted of conventional sagittal fast spin echo T1- and T2-weighted scans, axial fast spin echo T2-weighted scans, and axial DTI acquisition. Intraclass correlation coefficient (ICC) and 95% confidence interval were calculated for mean, axial, and radial diffusivity (MD, AD, RD, respectively) and fractional anisotropy (FA). Relationships among DTI, MRI, and ISNCSCI were evaluated using Spearman correlation coefficients (rs) and differences were tested using Cohen's method. RESULTS: There was moderate-to strong reliability (ICC = 0.75-0.95) for MD, AD, and RD for all spinal levels. Reliability for FA for mid-C4 and between C5-C6 and C7-T1 was moderate (ICC = 0.75-0.80). Diffusivity values demonstrated moderate-to-good negative relationships (rs = -0.30 to -0.59), with 4 ISNCSCI values. FA values had a moderate-to-good (rs = 0.33-0.53) positive relationship, with 5 ISNCSCI values. Compared with MRI, DTI values had significantly stronger correlations (P <= 0.0001) with the majority of ISNCSCI values. CONCLUSION: DTI values had good-to strong reliability on repeated scans and moderate-to-good concurrent validity with clinical scores. When compared with conventional MRI, DTI values had statistically stronger correlations with the majority of values from the clinical examination. PMID- 22210017 TI - Implant failure of Bryan cervical disc due to broken polyurethane sheath: a case report. AB - STUDY DESIGN: A case report. OBJECTIVE: A rare case of Bryan disc implantation failure due to broken polyurethane sheath was reported. The bone ingrowth at implant-bone interface and wear debris leaking from broken Bryan disc were also observed. SUMMARY OF BACKGROUND DATA: The Bryan disc is one of the most commonly used cervical prostheses and has shown satisfactory results compared with anterior cervical discectomy and fusion in short- and long-term follow-up. The complications, including neurological worsening, heterotopic ossification, kyphosis, and so forth, still occur, although infrequently. The broken polyurethane sheath is an extremely rare complication that has seldom been reported before. METHODS: A 55-year-old female patient experienced progressive neck pain after 8 years of Bryan disc implantation because of cervical spondylotic myelopathy at C5-C6 level. The subsequent magnetic resonance imaging scan demonstrated a cystic mass in front of Bryan disc, with high-signal intensity on T2-weighted images. The Bryan disc was removed and segment (C5-C6) was fused with cage and plate. The bone ingrowth and wear debris of retrieved Bryan disc were studied. RESULTS.: In revision surgery, a cyst with thick pseudocapsule connecting the anterior part of Bryan disc was excised. A transverse crack (5 mm) was identified in the anterior part of polyurethane sheath. The bacteria test of fluid from the cyst showed a negative result. Micro computed tomography and histological study both indicated abundant bone ingrowth at implant-bone interface. The metal wear debris could be observed around titanium alloy shells. CONCLUSION: This case demonstrates the unique incident of broken Bryan disc after 8 years of implantation. Follow-up imaging shortly after the procedure should be mandatory to monitor such potential complication. PMID- 22210018 TI - Exposure-response relationship of AMG 386 in combination with weekly paclitaxel in recurrent ovarian cancer and its implication for dose selection. AB - PURPOSE: To characterize exposure-response relationships of AMG 386 in a phase 2 study in advanced ovarian cancer for the facilitation of dose selection in future studies. METHODS: A population pharmacokinetic model of AMG 386 (N = 141) was developed and applied in an exposure-response analysis using data from patients (N = 160) with recurrent ovarian cancer who received paclitaxel plus AMG 386 (3 or 10 mg/kg once weekly) or placebo. Reduction in the risk of progression or death with increasing exposure (steady-state area under the concentration-versus time curve [AUC(ss)]) was assessed using Cox regression analyses. Confounding factors were tested in multivariate analysis. Alternative AMG 386 doses were explored with Monte Carlo simulations using population pharmacokinetic and parametric survival models. RESULTS: There was a trend toward increased PFS with increased AUC(ss) (hazard ratio [HR] for each one-unit increment in AUC(ss), 0.97; P = 0.097), suggesting that the maximum effect on prolonging PFS was not achieved at the highest dose tested (10 mg/kg). Among patients with AUC(ss) >= 9.6 mg h/mL, PFS was 8.1 months versus 5.7 months for AUC(ss) < 9.6 mg h/mL and 4.6 months for placebo. No relationship between AUC(ss) and grade >= 3 adverse events was observed. Simulations predicted that AMG 386 15 mg/kg once weekly would result in an AUC(ss) >= 9.6 mg h/mL in > 90% of patients with median PFS of 8.2 months versus 5.0 months for placebo (HR [15 mg/kg vs. placebo], 0.56). CONCLUSIONS: Increased exposure to AMG 386 was associated with improved clinical outcomes in recurrent ovarian cancer, supporting the evaluation of a higher dose in future studies. PMID- 22210019 TI - The role of pentraxin-3 as a prognostic biomarker in paraquat poisoning. AB - Paraquat poisoning has been a public health problem in both the developing and developed countries. Pentraxin 3 is a member of the pentraxin family which is expressed as part of the acute-phase response that begins after injury, trauma, and infection. The aim of our study is to determine whether PTX3 levels can be a significant marker of pulmonary fibrosis and outcome of survival in paraquat poisoning. To measure the plasma paraquat level, we collected serum of the patients immediately after admission. EDTA plasma samples for checking the plasma PTX3 concentration were taken before and after the 1st hemoperfusion and after the 2nd hemoperfusion therapy. PTX3 concentrations in EDTA plasma were determined using a commercial solid-phase enzyme-linked immunosorbent assay (ELISA). Plasma paraquat concentration was higher in survivors than in non-survivors (p<0.05). Maximal plasma PTX3 level was significantly higher in the pulmonary fibrosis group, and plasma PTX3 was significantly increased throughout hemoperfusion therapy (p<0.01). Moreover, increase in PTX3 was greater in non-survivors than survivors (p<0.05). Our results show that PTX3 is a useful biomarker of severity and outcome predictor in paraquat poisoning. PMID- 22210020 TI - Amentoflavone stimulates mitochondrial dysfunction and induces apoptotic cell death in Candida albicans. AB - Amentoflavone was isolated from an ethyl acetate extract of the whole plant of Selaginella tamariscina. It is a traditional herb for the therapy of chronic trachitis and exhibits some anti-tumor activity. Previously, we confirmed the antifungal effects of amentoflavone. The objective of this study was to investigate the antifungal mechanism(s) of amentoflavone, such as mitochondria mediated apoptotic cell death. The cells that were treated with amentoflavone exhibited a series of cellular changes that were consistent with apoptosis: externalization of phosphatidylserine, DNA and nuclear fragmentation, accumulation of intracellular reactive oxygen species (ROS) and hydroxyl radicals, and activation of metacaspase. In addition, diagnostic markers of apoptosis, including the reduction of mitochondrial inner-membrane potential and the release of cytochrome c from mitochondria, were observed. These phenomena are important changes in mitochondria-mediated apoptosis. Furthermore, the effect of thiourea as hydroxyl radical scavenger on amentoflavone-induced apoptosis was evaluated. A hydroxyl radical is a more active ROS species. Mitochondrial dysfunction was inhibited, which was indicated by decreased levels of intracellular hydroxyl radicals. Taken together, our results present the first evidence that amentoflavone induces apoptosis in C. albicans cells and is associated with the mitochondrial dysfunction. Besides, amentoflavone-induced hydroxyl radicals may play a significant role in mitochondria-mediated apoptosis. PMID- 22210021 TI - Tuberculous spondylodiskitis with lumbar tumor. PMID- 22210022 TI - Research on Isodon species: still going strong. AB - Isodon species have been much studied for their biologically active ingredients, and Sun and co-workers report the isolation, characterization, and biological activities of twenty three compounds, including three new ones. The new compounds from Isodon coetsa are neolignan, triterpenoid, and diterpenoid types, showing that Isodon species have diverse types of compounds, in addition to the much explored kaurane type diterpenoids. They determined the chemical structures based on extensive spectroscopic analyses and comparison with related compounds. Their report is expected to be yet another stepping stone for more exciting compounds from Isodon species. PMID- 22210023 TI - A new paradigm for stem cell therapy: substance-P as a stem cell-stimulating agent. AB - Bone marrow is a reservoir for hematopoietic stem cells, endothelial precursor cells, and bone marrow stromal cells (also generally called mesenchymal stem cells), whose positive role in tissue repair is highly anticipated. In this report, we introduce a novel function of substance-P (SP), an 11-amino-acid peptide, as an injury-inducible messenger to mobilize bone marrow stem cells to the blood and finally to engage in tissue repair. This new drug may substitute for ex vivo cell culture of therapeutic cells by stimulating cell proliferation in the bone marrow in vivo and mobilizing those therapeutic cells to the patient's own blood stream. Again, the additional role of SP in mitigating inflammation-mediated tissue damage can further rationalize the clinical development of SP-peptide as a stem cell stimulant. PMID- 22210024 TI - Chemical constituents from the aerial parts of Isodon coetsa and their cytotoxicity. AB - Three new compounds (1-3), including a neolignan, a triterpenoid, and a diterpenoid, together with twenty known compounds (4-23), were isolated from the aerial parts of Isodon coetsa. Their structures and relative configurations were elucidated on the basis of spectroscopic data. Compounds 1, 3, 5-9, 11-13, 16-17, and 19-23 were evaluated for their cytotoxicity against HT-29, BEL-7402, and SK OV-3 human tumor cell lines. Compound 7 showed significant inhibitory effects on all three types of cells, with IC50 values of 2.52, 3.06, 2.14 MUM, respectively. PMID- 22210025 TI - New glycosides from Dracocephalum tanguticum maxim. AB - Four new glycosides, luteolin-7-methoxy-3'-O-(3"-O-acetyl)-beta-D-gluco pyranuronic acid-6"-methyl ester (1), benzyl-6-[(2E)-2-butenoate]-beta-D glucopyranoside (2), 2-methoxy-4-(2-propen-1-yl)penyl-6-acetate-beta-D glucopyranoside (3), and 2-methoxy-4-(2-propen-1-yl)penyl-6-[(2E)-2-butenoate] beta-D-glucopyranoside (4), along with benzyl-beta-D-glucopyranoside (5), 2 methoxy-4-(2-propen-1-yl)penyl-beta-D-glucopyranoside (6), and pectolarigenin (7), were isolated from the whole plant of Dracocephalum tanguticum Maxim. The structures of 1-4 were elucidated by detailed spectroscopic analyses, including HR-ESI-MS and 2D NMR spectroscopic data. The inhibitory effects against nitric oxide production in LPS-stimulated RAW264.7 cells of all seven compounds were also evaluated. PMID- 22210026 TI - Chemical constituents of Cynanchum wilfordii and the chemotaxonomy of two species of the family Asclepiadacease, C. wilfordii and C. auriculatum. AB - Definitive identification of original plant species is important for standardizing herbal medicine. Although only the dried roots of Cynanchum wilfordii (Asclepiadaceae) are prescribed as Cynanchi Wilfordii Radix in Korean Pharmacopoeia, the roots of C. wilfordii and C. auriculatum are often misused in the Korean herbal market due to their morphological similarity and similar name. Therefore, it would be very useful to discover an effective chemical marker for the identification of the two species. To this end, we carried out a phytochemical study on the roots of C. wilfordii. As a result, twenty compounds were isolated from the roots of C. wilfordii and their chemical structures were identified as beta-sitosterol (1), wilfoside C1N (2), wilfoside C3N (3), wilfoside K1N (4), methyleugenol (5), wilfoside C1G (6), cynauriculoside A (7), daucosterol (8), 2,4-dihydroxyacetophenone (9), cynandione A (10), 2,5 dihydroxyacetophenone (11), acetovanillone (12), p-hydroxyacetophenone (13), sucrose (14), conduritol F (15), geniposide (16), succinic acid (17), 3-(beta-D ribofuranosyl)-2,3-dihydro-6H-1,3-oxazine-2,6-dione (18), bungeiside A (19), cynanoneside B (20). Among them, compounds 15, 16, 18, 19, and 20 were isolated for the first time from this species. Furthermore, conduritol F (15) was demonstrated to be contained only in C. wilfordii. Therefore, it may be useful as a chemical marker to identify the two species C. wilfordii and C. auriculatum. PMID- 22210027 TI - Lignans from the flowers of Osmanthus fragrans var. aurantiacus and their inhibition effect on NO production. AB - A new lignan, (7R,7'R,8R,8'R)-8-hydroxypinoresinol 8-O-beta-D-glucopyranoside 4' methyl ether (7), was isolated from the flowers of Osmanthus fragrans var. aurantiacus along with six known lignans: (+)-phillygenin (1), phillyrin (2), (-) phillygenin (3), (-)-epipinoresinol-beta-D-glucoside (4), taxiresinol (5), and ( )-olivil (6). The structure of the new compound was elucidated on the basis of 1D and 2D-NMR spectroscopic analysis and specific rotation data. The compounds isolated from the flowers of O. fragrans var. aurantiacus were evaluated for inhibitory activities on nitric oxide production in lipopolysaccharide-stimulated macrophage RAW 264.7 cells. (+)-Phillygenin (1), phillyrin (2), and (-) phillygenin (3) exerted the strongest inhibitory activities on NO production with IC(50) values of 25.5, 18.9, and 25.5 MUM, respectively. These compounds may prove beneficial in the development of natural agents for prevention and treatment of inflammatory diseases. PMID- 22210028 TI - Cytotoxic lasiodiplodin derivatives from the fungus Syncephalastrum racemosum. AB - Chemical investigation of fungal biomass of the fungus Syncephalastrum racemosum led to the isolation of new natural products (3R),(5S)-5-hydroxy-de-O methyllasiodiplodin (1), 6-oxode-O-methyllasiodiplodin (2), in addition to five known compounds, de-O-methyllasiodiplodin (3), lasiodiplodin (4), (3R),(5R)-5 hydroxy-de-O-methyllasiodiplodin (5), ergosterol (6), and ergosterol peroxide (7). Their structures were elucidated by spectroscopic techniques. The absolute configuration of 1 was determined by a modified Mosher's method. Compound 1 showed cytotoxicity against cholangiocarcinoma, KKU-M139, KKU-M156, and KKU-M213 cell lines with IC(50) values in the range of 14-19 MUg/mL, while 3 showed cytotoxicity against KB, BC1, and NCI-H187 cell lines with IC(50) values of 12.67, 9.65, and 11.07 MUg/mL, respectively. PMID- 22210029 TI - A new lignan glycoside from Juniperus rigida. AB - A new lignan glycoside, named juniperigiside (1) was isolated from the CHCl(3) soluble fraction of the MeOH extract of stems and leaves of Juniperus rigida S.et Z. Compound 1 was identified by 1D- and 2D-NMR spectroscopy as well as CD analysis as (2R,3S)-2,3-dihydro-7-methoxy-2-(4'-hydroxy-3'-methoxyphenyl)-3 hydroxymethyl-5-benzofuranpropanol 4'-O-(3-O-methyl)-alpha-L-rhamnopyranoside. Five known lignans, icariside E4 (2), desoxypodophyllotoxin (3), savinin (4), thujastandin (5), and (-)-nortrachelogenin (6) in addition to five known labdane diterpenes including trans-communic acid (7), 13-epi-torulosal (8), 13-epi cupressic acid (9), imbricatoric acid (10), and isocupressic acid (11) were also isolated and their structures were characterized by comparing their spectroscopic data with those in the literature. All compounds were isolated for the first time from this plant, and 5 and 6 were first reported from the genus Juniperus. The isolated compounds were tested for cytotoxicity against four human tumor cell lines in vitro using a Sulforhodamin B bioassay. Compounds 3, 4, 7, and 8 showed considerable cytotoxicity against four human cancer cell lines in vitro. PMID- 22210030 TI - Dose-independent pharmacokinetics of a new peroxisome proliferator-activated receptor-gamma agonist, KR-62980, in Sprague-Dawley rats and ICR mice. AB - The pharmacokinetics of a novel peroxisome proliferator-activated receptor-gamma agonist, KR-62980, were characterized in vitro with respect to liver metabolic stability, cell permeability, and plasma protein binding and in vivo using Sprague-Dawley rats and ICR mice. The metabolic half-life of 0.1-10 MUM KR-62980 was 11.5-15.2 min in rat liver microsomes and 25.8-28.8 min in human liver microsomes. KR-62980 showed high permeability across MDCK cell monolayers, with apparent permeability coefficients of 20.4 * 10(-6) to 30.8 * 10(-6) cm/sec. The plasma protein binding rate of KR-62980 was 89.4%, and most was bound to serum albumin. After intravenous administration of KR-62980 (2 mg/kg), the systemic clearance was 2.50 L/h/kg, and the volume of distribution at steady-state was 9.16 L/kg. The bioavailability after oral administration was approximately 60.9%. The dose-normalized AUC values were 0.50 +/- 0.09, 0.41 +/- 0.20, and 0.62 +/- 0.08 h . MUg/mL after oral administration of 2, 5, and 10 mg/kg KR-62980, respectively, showing no dose-dependency. The in vivo pharmacokinetic parameters in ICR mice were also dose independent. These data suggest that KR-62980 is not significantly dose dependent in rats or mice, although it may disappear rapidly from the systemic circulation via metabolism in the liver. PMID- 22210031 TI - Pharmacokinetics, brain distribution, and plasma protein binding of the antiepileptic drug lacosamide in rats. AB - The study aimed to characterize the pharmacokinetics of lacosamide, a new antiepileptic drug, in rats after intravenous and oral administration at doses of 1, 3, 10, and 30 mg/kg. Moreover, brain distribution and plasma protein binding were estimated. After intravenous injection, terminal half-life, systemic clearance, and steady state volumes of distribution remained unaltered as a function of dose with values in the range 3.01-3.53 h, 221-241 mL/h/kg and 702 732 mL/kg, respectively. Following oral administration, absolute oral bioavailability was not dose dependent and was at 93.3-106%. However, the time to peak concentration and the dose-normalized peak concentration for 30 mg/kg were significantly different with those for other doses. The extent of urinary excretion of lacosamide was 17.1% and 16.5% for intravenous and oral doses, respectively, whereas fecal excretion was negligible. The brain to plasma ratio of lacosamide was consistent regardless of post-dosing time and the brain to plasma partition coefficient was 0.553. Further, the plasma protein binding of lacosamide was concentration independent with free fraction at 95.9%. Lacosamide showed linear pharmacokinetics at an intravenous dose of 1-30 mg/kg and an oral dose of 1-10 mg/kg but non-linear pharmacokinetics at a 30 mg/kg oral dose. PMID- 22210032 TI - Multiple component quantitative analysis for the pattern recognition and quality evaluation of Kalopanacis Cortex using HPLC. AB - A quantitative and pattern recognition analyses were conducted for quality evaluation of Kalopanacis Cortex (KC) using HPLC. For quantitative analysis, four bioactive compounds, liriodendrin, pinoresinol O-beta-D-glucopyranoside, acanthoside B and kalopanaxin B, were determined. The analysis method was optimized and validated using ODS column with mobile phase of methanol and aqueous phosphoric acid. The validation gave acceptable linearities (r > 0.9995), recoveries (98.4% to 101.9%) and precisions (RSD < 2.20). The limit of detection of compounds ranged from 0.4 to 0.9 MUg/mL. Among the four compounds, liriodendrin was recommended as a marker compound for the quality control of KC. The pattern analysis was successfully carried out by analyzing thirty two samples from four species, and the authentic KC samples were completely discriminated from other inauthentic species by linear discriminant analysis. The results indicated that the method was suitable for the quantitative analysis of liriodendrin and the quality evaluation of KC. PMID- 22210033 TI - Simultaneous determination of glimepiride and its metabolites in human plasma by liquid chromatography coupled to a tandem mass spectrometry. AB - Glimepiride, a second-generation sulfonylurea, is a glucose-lowering agent widely used to treat diabetes mellitus. It is converted into metabolite M1 by CYP2C9, and M1 is then transformed into the carboxyl derivative M2 by cytosolic enzymes. In this study, we introduce a sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for determining glimepiride, M1, and M2 in human plasma. After simple protein precipitation with acetonitrile, the analytes were chromatographed on a reversed-phase CN column with a mobile phase of 10 mM ammonium acetate aqueous solution and acetonitrile (1:1, v/v). The accuracy and precision of the assay were in accordance with FDA regulations for the validation of bioanalytical methods. This method was used to measure the concentrations of glimepiride, M1, and M2 in plasma after a single oral 2-mg dose of glimepiride in volunteers. PMID- 22210034 TI - Determination of alendronate in low volumes of plasma by column-switching high performance liquid chromatography method and its application to pharmacokinetic studies in human plasma. AB - A sensitive and simple column-switching high-performance liquid chromatographic (HPLC) method with fluorescence detection was developed for the determination of alendronate in human plasma. Alendronate and pamidronate (internal standard, IS) in plasma including Na(2)EDTA were precipitated with sodium hydroxide and calcium chloride after deproteinization using 10% trichloroacetic acid solution. The precipitated alendronate and IS were reconstituted by sodium citrate and citric acid and then derivatized with 9-fluorenylmethyl chloroformate. The resulting solution was injected onto an HPLC system consisting of a pretreatment column and an analytical column, which were connected with a six-port switching valve. The assay was linear in the concentration range of 2-100 ng/mL in 1 mL of plasma with high precision and accuracy, and the limit of detection was 0.5 ng/mL. It was successfully applied to evaluate the pharmacokinetic parameters of alendronate in human volunteers following single oral administration. The mean value of maximum alendronate plasma concentration (C(max)) was 37.69 ng/mL, and the mean time to reach the C(max) (T(max)) was 1.08 h. The area under the plasma concentration time curve (AUC) and elimination half-life (T(1/2)) were 106.48 ng/mL/h and 1.66 h, respectively. PMID- 22210035 TI - Anti-tumorigenic activity of sophoflavescenol against Lewis lung carcinoma in vitro and in vivo. AB - This study examined the in vitro cytotoxic activity and in vivo antitumor activity as well as intracellular apoptotic capacities of a prenylated flavonol, sophoflavescenol from Sophora flavescens, to evaluate prospective anti tumorigenic drugs, and antitumor potential. In addition, the in vitro antioxidant and anti-inflammatory capacities were evaluated. Despite the small effect on human breast adenocarcinoma (MCF-7), sophoflavescenol showed cytotoxicity against human leukaemia (HL-60), Lewis lung carcinoma (LLC), and human lung adenocarcinoma epithelial (A549) cells. Interestingly, it also exerted potent in vivo antitumor activity by tumor growth inhibition in the LLC tumor model as well as apoptotic activity by caspase-3 activation in HL-60 cells. In addition, it exhibited potent antioxidant activities in 1,1-diphenyl-2-picrylhydrazyl, 2,2' azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt radicals and lipid peroxidation assays. Sophoflavescenol exerted notable anti-inflammatory activity by inhibiting nitric oxide generation and tert-butylhydroperoxide induced ROS generation rather than inhibiting nuclear factor kappa B activation in RAW 264.7 cells. The findings show that the antioxidant, anti-inflammatory, and apoptotic activities of sophoflavescenol might contribute to the antitumor activity without severe side effects, highlighting its potential for chemoprevention and/or anticancer drugs due to multi-effective targets in almost all stages of tumorigenesis, including initiation, promotion, and progression. PMID- 22210036 TI - Inhibitory effect of astragalin on expression of lipopolysaccharide-induced inflammatory mediators through NF-kappaB in macrophages. AB - Astragalin (kaempferol-3-O-glucoside), a newly found flavonoid from leaves of persimmon or Rosa agrestis, is known to have antiatopic dermatitis and antioxidant activity. However, the effect of astragalin on the inflammatory response is not well defined. Nitric oxide (NO) produced from the activated macrophages is well known as a mediator of inflammation. Transcription factor (NF)-kappaB mediates the inducible expression of a variety of genes involved in immune and inflammatory responses including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and cytokines/chemokines. In the present study, we examined the inhibitory effects of astragalin on the lipopolysaccharide (LPS) induced inflammatory mediators. Astragalin significantly reduced LPS-induced expression of iNOS, COX-2 and cytokines/chemokines, and production of NO in J774A.1 mouse macrophages. Astragalin inhibited LPSinduced activation of NF kappaB as indicated by inhibition of degradation of IkappaBalpha, nuclear translocation of NF-kappaB, and NF-kappaB dependent gene reporter assay. The inhibitory effects of astragalin on the inflammatory mediators are comparable with quercetin, a well known flavonoid possessing antioxidant and anti inflammatory activity. Using the mouse peritoneal macrophages, we confirmed the inhibitory effect of astragalin on NO production and NF-kappaB activation. Taken together, our results indicate that astragalin inhibits expression of proinflammatory mediators through the inhibition of NF-kappaB in macrophages. PMID- 22210037 TI - Anti-inflammatory effect of 2-methoxy-4-vinylphenol via the suppression of NF kappaB and MAPK activation, and acetylation of histone H3. AB - Although inflammation acts as host defense mechanism against infection or injury and is primarily a self limiting process, inadequate resolution of inflammatory responses leads to various chronic disorders. This work aimed to elucidate the anti-inflammatory effects of 2-methoxy-4-vinylphenol (2M4VP) isolated from pine needles in LPS-stimulated RAW264.7 cells. Some key pro-inflammatory mediators including nitric oxide (NO), prostaglandins (PGE(2)), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2) were studied by sandwich ELISA and western blot. In addition, suppression of NF-kappaB and MAPK activation, and histone acetylation was studied by western blot analysis and immunostaining. 2M4VP dosedependently inhibited NO and PGE(2) production and also blocked LPS-induced iNOS and COX-2 expression. In addition, 2M4VP potently inhibited the translocation of NF-kappaB p65 into the nucleus by IkappaB degradation following IkappaB-alpha phosphorylation and the phosphorylation of MAPKs such as p38, ERK1/2, and JNK. Also, 2M4VP inhibited hyper-acetylation of histone H3 (Lys9/Lys14) induced by LPS. Taken together, our results suggest that 2M4VP, a naturally occurring phenolic compound, exert potent anti-inflammatory effects by inhibiting LPS-induced NO, PGE(2), iNOS, and COX-2 in RAW264.7 cells. These effects are mediated by suppression of NF-kappaB and MAPK activation and histone acetylation. PMID- 22210038 TI - Inhibitory effect of Lactobacillus plantarum K-1 on passive cutaneous anaphylaxis reaction and scratching behavior in mice. AB - Lactobacillus plantarum K-1 (LP) inhibiting AP-1 (c-Jun) and NF-kappaB activations was isolated from kimchi, and its inhibitory activity against scratching behavior and passive cutaneous anaphylaxis reaction in mice was investigated. Heat-inactivated LP (heated at 60 degrees C for 30 min) potently inhibited the expression of TNF-alpha and IL-4 as well as the activation of their transcription factors, NF-kappaB and c-jun, in phorbol 12'-myristate 13'-acetate stimulated RBL-2H3 cells. LP (1 * 10(10) CFU per mouse) showed a potent inhibition against passive cutaneous anaphylaxis reaction induced by the IgE antigen complex in mice, inhibiting it by 87.5%. LP (1 * 10(10) CFU/mouse) inhibited histamine-induced scratching behavior by 58.9% compared to the control group. LP significantly inhibited vascular permeability induced by histamine. The inhibitory activity of LP against vascular permeability was in proportion to its inhibition against scratching behavior. LP potently inhibited histamine-induced cytokine production: it (1 * 10(10) CFU per mouse) inhibited IL-4, IL-1beta, and TNF-alpha expression by 88.9%, 88.6%, and 98.9%, respectively. LP also inhibited IgE level increased by histamine by 85.3%. It inhibited histamine-induced the activations of their transcription factors, NF-kappaB and c-Jun. Based on these findings, LP may improve allergic diseases, such as anaphylaxis, atopic dermatitis, rhinitis, and pruritus by inhibiting the expression of IgE-switching cytokine IL-4 and proinflammatory cytokines IL-1beta and TNF-alpha via NF-kappaB and AP-1 signaling pathways. PMID- 22210039 TI - Effects of 4',7-dimethoxyflavanone on cell cycle arrest and apoptosis in human breast cancer MCF-7 cells. AB - The present study was designed to investigate the anticancer activity of 4,7 dimethoxyflavanone in vitro. When human breast cancer MCF-7 cells were treated with 4',7-dimethoxyflavanone at various concentrations (1-200 MUM) for 24 h, antiproliferative effects were first observed at 1 MUM and the IC(50) was 115.62 MUM. Conversely, 4',7-dimethoxyflavanone was not cytotoxic (measured as lactate dehydrogenase release in CHO-K1 cells) under the same conditions. MCF-7 cells exposed to the 4',7-dimethoxyflavanone at the IC(50) concentration showed cell cycle arrest and apoptosis. Compared to the respective control level, exposure to 4',7-dimethoxyflavanone resulted in a remarkable increase of small DNA fragments at the sub-G1 phase and an increase in the G2/M phase cell population. Moreover, when 4',7-dimethoxyflavanone treatment caused G2/M phase arrest, an increase in CDK1 together with an increase in cyclin B was observed. Based on these results, 4',7-dimethoxyflavanone may be a useful anticancer agent. PMID- 22210040 TI - Acid-induced COX-2 expression and prostaglandin E2 production via activation of ERK1/2 and p38 MAPK in cultured feline esophageal smooth muscle cells. AB - Cyclooxygenase (COX)-2 is known to play an important role in inflammatory conditions such as reflux esophagitis resulting from acid reflux. In this study, we tested whether an acidic medium (pH 4.0) induces an increase in COX-2 expression or PGE(2) production, and explored the implication of mitogen activated protein kinases (MAPKs) activation in these responses in cultured cat esophageal smooth muscle cells. Acidic cytotoxicity was assessed and expression changes in COXs or phosphorylated MAPKs were analyzed by Western blotting. PGE(2) production was measured by immunoassay. No significant decrease in cell viability was observed for 6 h exposure to acidic medium. COX-2 expression and PGE(2) production significantly increased to maximal levels at 6 h exposure to acidic medium. The cells also exhibited significant activation of ERK1/2 and p38 MAPK, but not JNK within 10 min under acidic medium. The increments of COX-2 expression and PGE(2) production by acidic medium were decreased by pretreatment with PD98059 or SB202190, respectively. These results suggest that acidic environments may enhance the COX-2 expression and PGE(2) production through activation of ERK1/2 and p38 MAPK in the cultured cat esophageal smooth muscle cells. PMID- 22210041 TI - In vitro Na+/K+-ATPase inhibitory activity and antimicrobial activity of sesquiterpenes isolated from Thujopsis dolabrata. AB - A series of sesquiterpenes and hinokitiol-related compounds (1-15) was isolated from the essential oil of Thujopsis dolabrata Sieb. et Zucc. var. hondai Makino, and their structures were determined by combined spectroscopic analyses. The inhibitory effects of these compounds on microbial cell growth and Na(+)/K(+) ATPase were evaluated in vitro. It was found that (-)-elema-1,3,11(13)-trien-12 ol (5), alpha,beta,gamma-costol (8), and chamigrenol (11) inhibit the activities of Na(+)/K(+)-ATPase, with IC(50) values of 11.2 +/- 0.11, 12.2 +/- 0.09, and 15.9 +/- 0.54 MUg/mL, respectively. Thujopsene (1), cedrol (9), gamma-cuparenol (10), and chamigrenol (11) showed potent antibacterial activity, with MIC values in the range of 25-50 MUg/mL, and beta-thujaplicin (12) exhibited a broad spectrum of antibacterial and antifungal activity. These results indicate that these isolated compounds are promising candidates for the development of potent Na(+)/K(+) ATPase inhibitors and antimicrobial agents. PMID- 22210042 TI - Alterations in regulatory regions of erm(B) genes from clinical isolates of enterococci resistant to telithromycin. AB - We determined rates of resistance to the ketolide telithromycin in 56 Enterococcus faecalis isolates and 44 Enterococcus faecium isolates collected from hospitals in Korea between 2005 and 2006. Twenty nine (51.8%) isolates of E. faecalis and 35 (79.5%) isolates of E. faecium were resistant to telithromycin (minimum inhibitory concentrations, >= 4 MUg/mL). All of the telithromycin resistant E. faecalis carried the erm(B) gene only. Of the telithromycin resistant E. faecium, 29 resistant strains carried erm(B) only, the other six carried erm(A) and erm(B) together. The nucleotide sequence of the erm(B) regulatory regions from 29 E. faecalis and 29 E. faecium isolates with erm(B) only was analyzed. Five types of alterations were detected. The first and second types had point mutations that destabilize the secondary structure of erm(B) mRNA sequestering the translation initiation region of the structural gene. The third type was identical to erm(Bv1), a previously reported variant of erm(B) with different induction specificity. The fourth and fifth types had point mutations within the critical sequence for induction and a point mutation destabilizing the stem-loop of erm(B) mRNA sequestering the translation initiation region of the structural gene. PMID- 22210043 TI - Effects of exogenous hydrogen sulfide on apoptosis proteins and oxidative stress in the hippocampus of rats undergoing heroin withdrawal. AB - In this study, the mechanism of H(2)S protection in the hippocampus of heroin treated rats was investigated. Male Sprague-Dawley rats were randomly divided into three groups: a saline group, a heroin and saline group, and a heroin and sodium hydrosulfide group. According to the principle of increasing heroin dosage daily, heroin withdrawal was precipitated on day 9 with an injection of naloxone (5 mg/kg, i.p.), and withdrawal symptoms were scored. The levels of cystathionine beta-synthase, H2S, reduced glutathione and malondialdehyde, as well as the levels of cleaved caspase-3, Bax, and Bcl-2 proteins and the activities of superoxide dismutase, catalase, and glutathione peroxidase were assayed in the hippocampus. The results showed that exogenous H(2)S alleviated heroin withdrawal symptoms. Moreover, exogenous H(2)S not only increased cellular H(2)S and the cystathionine-beta-synthase protein level activity but also significantly improved heroin-induced oxidative stress. Protein expression of cleaved caspase-3 and Bax decreased, whereas Bcl-2 protein levels in hippocampus increased with exogenous H(2)S. Exogenous H(2)S alleviated heroin-induced rat hippocampal damage through antioxidant and antiapoptosis effects. PMID- 22210045 TI - Look who's talking: deregulated signaling in colorectal cancer. AB - BACKGROUND: The phenotypic expression of any given heterogeneous tissue type is the composite of interactions between individual cell types governed principally by inherent, cell-specific molecular mechanisms. MATERIALS AND METHODS: Using a combination of laser-capture microdissection, oligonucleotide microarrays, bioinformatic and statistical tools, we analyzed colorectal cancer tissues in order to spot the significant pathways that were differentially deregulated between the epithelial and stromal compartments and compared these alongside the ones of whole tissue dissection. RESULTS: The stromal pathway profiles were very similar to the ones of whole tissue, in contrast to the epithelial input, with stroma emerging as the major determinant of the cancer phenotype. Differentially expressed genes in the epithelial compartment correlated significantly with the carbohydrate antigen 19-9 tumor marker. CONCLUSION: The accurate interpretation of data arising from the analysis of heterogeneous tissue structures lends itself to inherent biases of its constitutive components with each component presenting explorable analytical advantages. PMID- 22210044 TI - Comparative proteomic analysis of a cytosolic fraction from beta3 integrin deficient cells. AB - Integrins are heterodimeric transmembrane receptors involved in sensing and transmitting informational cues from the extracellular environment to the cell. This study explored sub-proteome changes in response to elimination of the beta3 integrin using a knockout murine model. Cleavable isotope-coded affinity tagging (cICAT) in combination with sub-cellular fractionation, multiple dimensions of separation and tandem mass spectrometry (MS/MS) were used to characterize differentially expressed proteins among beta3 integrin(-/-) (beta3(-/-)) mouse embryonic fibroblasts and isogenic wild-type (WT) controls. From a cytosolic protein fraction, 48 proteins were identified, in which expression differed by > 1.5-fold. Predominant ontological groups included actin-binding/cytoskeletal proteins and protease/protease inhibitors. Interestingly, beta3 integrin expression was inversely correlated with expression of cathepsin B, a lysosomal cysteine protease, as its expression was greater by over 3.5-fold in the beta3(-/ ) cells. This inverse correlation was also observed in stable heterologous cells transfected with beta3 integrin, where the intracellular expression and activity of cathepsin B was lower compared to control cells. Our data suggests that the composition of the cellular proteome is influenced by integrin expression patterns and reveals a strong functional relationship between beta3 integrin and cathepsin B. PMID- 22210047 TI - Dissection of aberrant GPCR signaling in tumorigenesis--a systems biology approach. AB - The superfamily of G-protein-coupled receptors (GPCRs) is one of the largest mammalian protein families. It is involved in signal transduction and participates in the regulation of normal physiological function and pathological progression of a range of diseases. Recent studies have demonstrated that many aberrant GPCRs and their ligands are associated with tumorigenesis, angiogenesis and metastasis, which provides promising opportunities for drug discovery for cancer prevention and treatment. It is necessary to search for drug targets such as ligands of unknown GPCRs and better modulators of known GPCRs using high throughput screening approaches. Here, we review recent research advances in the identification of novel GPCRs and their protein interactions. PMID- 22210046 TI - Plasma biomarkers distinguish non-small cell lung cancer from asthma and differ in men and women. AB - BACKGROUND: Lung cancer (LC) is the leading cause of deaths caused by cancer worldwide. A diagnostic test for LC is needed for monitoring high-risk populations. PATIENTS AND METHODS: Fifty-seven markers were measured using multiplex immunoassays of plasma of patients with non-small cell lung cancer (NSCLC); (245 men, 114 women, 1 unknown), asthma (67 men, 111 women, 2 unknown) and of healthy controls (165 men, 122 women, 1 unknown). Mass spectrometry was used for biomarker discovery. A support vector machine (SVM) was used for data analysis. RESULTS: When all biomarkers and both genders were co-analyzed, SVM classified NSCLC and asthma with an accuracy of 0.94. Restricting to NSCLC versus healthy using best subsets of variables (males: epidermal growth factor (EGF), interleukin-8 (IL-8), soluble Fas (sFas), matrix metalloproteinase-9 (MMP-9), plasminogen activator inhibitor-1 (PAI-1); females: EGF, soluble cluster of differentiation 40 (sCD40) ligand, IL-8) yielded sensitivity and specificity of 1. Expression of eleven mass spectrometric biomarkers differed between pathologies. CONCLUSION: Significant inter-pathology and gender differences between biomarkers may improve diagnosis of LC. PMID- 22210048 TI - KRAS mutation is associated with elevated myeloblastin activity in human lung adenocarcinoma. AB - Lung cancer is the leading cause of all cancer deaths worldwide with suboptimal prognosis and treatment options. Therefore this study aimed to identify molecular characteristics with a predictive clinical utility which at the same time might represent novel therapeutic targets for human lung adenocarcinoma. Within this study mutations of v-Ki-RAS2 Kirsten rat sarcoma viral oncogene homolog (KRAS), a gene frequently mutated in lung adenocarcinoma, and their association with enzymatic activities, as assessed by activity-based proteomics, of members of the serine hydrolase (SH) superfamily, a large class of enzymes that have previously been linked to cancer was investigated. The results revealed that the activity of myeloblastin was significantly altered in the lung adenocarcinoma biopsies harboring a KRAS gene mutation. In conclusion myeloblastin is a potential therapeutic target for human lung adenocarcinoma, indicating that the combination of activity-based proteomics with mutational analysis is a valid approach for the discovery of novel biomarkers. PMID- 22210049 TI - Contribution of cytochrome P450 1B1 to hypertension and associated pathophysiology: a novel target for antihypertensive agents. AB - The aim of this review is to discuss the contribution of cytochrome P450 (CYP) 1B1 in vascular smooth muscle cell growth, hypertension, and associated pathophysiology. CYP1B1 is expressed in cardiovascular and renal tissues, and mediates angiotensin II (Ang II)-induced activation of NADPH oxidase and generation of reactive oxygen species (ROS), and vascular smooth muscle cell migration, proliferation, and hypertrophy. Moreover, CYP1B1 contributes to the development and/or maintenance of hypertension produced by Ang II-, deoxycorticosterone (DOCA)-salt-, and N(omega)-nitro-L-arginine methyl ester induced hypertension and in spontaneously hypertensive rats. The pathophysiological changes, including cardiovascular hypertrophy, increased vascular reactivity, endothelial and renal dysfunction, injury and inflammation associated with Ang II- and/or DOCA-salt induced hypertension in rats, and Ang II induced hypertension in mice are minimized by inhibition of CYP1B1 activity with 2,4,3',5'-tetramethoxystilbene or by Cyp1b1 gene disruption in mice. These pathophysiological changes appear to be mediated by increased production of ROS via CYP1B1-dependent NADPH oxidase activity and extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Src. PMID- 22210050 TI - Localization and functional requirement of yeast Na+/H+ exchanger, Nhx1p, in the endocytic and protein recycling pathway. AB - Acidification of the lumen of intracellular organelles is important for post transcriptional processing, endosomal maturation, receptor recycling, and vesicle trafficking, being regulated by an intricate balance between H+ influx through vacuolar-type H+-ATPase and efflux through ion channels and transporters, such as the Na+/H+ exchanger (NHE). The eukaryotic NHE family comprises two major subgroups, one residing in the plasma membrane and the other in intracellular organelles. While mammalian intracellular NHE isoforms are localized to various organelles, including the mid-trans-Golgi compartments, early and late endosomes, and recycling endosomes, Nhx1p, the sole NHE in yeast, has been reported to be localized predominantly to the late endosomal/prevacuolar compartment. Here, using live cell imaging, we demonstrated that Nhx1p is localized to the trans Golgi network compartments, late endosomes, and recycling endosomes, similar to mammalian intracellular NHE isoforms. Loss of Nhx1p led to accumulation of components of the retromer and endosomal sorting complex required for transport complexes, but not trans-Golgi compartments, in aberrant prevacuolar compartments. Importantly, Nhx1p was also required for recycling of the plasma membrane vesicle SNAP receptor Snc1p. These observations suggest that Nhx1p plays an important role in regulation of the luminal pH of various intracellular organelles, and that this regulation is critical for the protein recycling pathway as well as the endocytic pathway. PMID- 22210051 TI - Bufothionine, a possible effective component in cinobufocini injection for hepatocellular carcinoma. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cinobufacini has been traditionally used in China for the treatment of tumor since hundreds years ago. For recent years, its modern preparation,cinobifucini injection has also obtained satisfactory therapeutic functions for cancer. MATERIALS AND METHODS: High performance liquid chromatography (HPLC) analysis was applied to determine the content of cinobufagin, resibufogenin and bufothionine in cinobufacin extract liquid and injection; MTT assay and flow cytometric analysis were also respectively used to study the effect of cinobufacini extract liquid, injection and three chemical structures on cells and cell cycles. RESULTS: HPLC results demonstrated that in cinobufacini extract liquid three ingredients (cinobufagin, resibufogenin and bufothionine) were all monitored while in cinofacini injection only bufothinone was detected; MTT assays showed bufothionine could obviously inhibit the proliferation of human hepatocellular carcinoma cell lines such as SMMC-7721 and BEL-7402 in a dose- and time-dependent manner as well as cinobufagin and resibufogenin; further flow cytometric analysis indicated obvious increases in G2/M phase and decrease in G0/G1 phase when SMMC-7721 cell line exposure to bufothionine (480 MUg/ml). CONCLUSIONS: These results suggested bufothionine could be involved in treatment of human cancer for cinobufacini injection and the mechanism might be relative to induce G2/M phase cell cycle arrest. PMID- 22210052 TI - Effect and mechanism of fucoidan derivatives from Laminaria japonica in experimental adenine-induced chronic kidney disease. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Laminaria japonica is a popular seafood and medicinal plant in China, Chinese people use them as a traditional medicine for curing edema disease, a symptom of kidney diseases. MATERIALS AND METHODS: The renal protective activity and mechanism of fucoidan derivatives was studied against adenine induced CKD in rats. The fucoidan derivatives were administered at dose of 50 and 150 mg/kg body weight. The serum urea nitrogen (SUN), serum creatinine (SCR) and some enzymic activity were detected. RESULTS: The SUN and SCR level decreased significantly with fucoidan derivatives administration. Histopathological changes of renal tubules and interstitium were markedly alleviated by fucoidan derivatives and the mesangial areas were also greatly reduced. Alterations were observed in the activities/levels of serum enzymic (CAT, GSH-PX) and non-enzymic (GSH) antioxidants, along with high level of malondialdehyde (MDA) in the CKD rats. However, normalized lipid peroxidation and antioxidant defenses occurred with fucoidan derivatives administration. CONCLUSION: This study exhibited a new mechanism of fucoidan derivatives on CKD rats, that was the samples could alleviate renal tubules, interstitium and mesangial areas mediated by replacing the electronegative content of the glomerular cells and inhibition of mesangial cell proliferation. The study also proved the mechanism of fucoidan derivatives on the CKD rats had relationship with their antioxidant activities, the samples which could enhance the activity of antioxidant enzymes and reduce the LPO level could alleviate the symptom of CKD. PMID- 22210053 TI - Effects of GABAB receptor agonists and antagonists on glycemia regulation in mice. AB - gamma-Aminobutyric acid (GABA) inhibits insulin secretion through GABA(B) receptors in pancreatic beta-cells. We investigated whether GABA(B) receptors participated in the regulation of glucose homeostasis in vivo. BALB/c mice acutely pre-injected with the GABA(B) receptor agonist baclofen (7.5mg/kg, i.p.) presented glucose intolerance and diminished insulin secretion during a glucose tolerance test (GTT, 2g/kg body weight, i.p.). The GABA(B) receptor antagonist 2 hydroxysaclofen (15 mg/kg, i.p.) improved the GTT and reversed the baclofen effect. Also a slight increase in insulin secretion was observed with 2 hydroxysaclofen. In incubated islets 1.10(-5)M baclofen inhibited 20mM glucose induced insulin secretion and this effect was reversed by coincubation with 1.10( 5)M 2-hydroxysaclofen. In chronically-treated animals (18 days) both the receptor agonist (5mg/kg/day i.p.) and the receptor antagonist (10mg/kg/day i.p.) induced impaired GTTs; the receptor antagonist, but not the agonist, also induced a decrease in insulin secretion. No alterations in insulin tolerance tests, body weight and food intake were observed with the treatments. In addition glucagon, insulin-like growth factor I, prolactin, corticosterone and growth hormone, other hormones involved in glucose metabolism regulation, were not affected by chronic baclofen or 2-hydroxysaclofen. In islets obtained from chronically injected animals with baclofen, 2-hydroxysaclofen or saline (as above), GABA(B2) mRNA expression was not altered. Results demonstrate that GABA(B) receptors are involved in the regulation of glucose homeostasis in vivo. Treatment with receptor agonists or antagonists, given acutely or chronically, altered glucose homeostasis and insulin secretion alerting to the need to evaluate glucose metabolism during the clinical use of these drugs. PMID- 22210055 TI - How to cool a burn: a heat transfer point of view. AB - The objective of this work is to develop and validate a numerical model that can conduct a transient analysis of heat transfer and the corresponding damage in skin burns. Once this model is developed, an examination of the effect of cooling on reducing damage from skin burns is carried out. A finite element numerical model is used to simulate the conduction of heat and the transient progress of irreversible injury in the skin. The damage function of Henriques and Moritz is used to model the damage that occurs in the skin during the burn and cooling periods. Numerical results are presented that describe the heat transfer during a skin burn. Comparison is made between different burns: a high-temperature, short duration burn (99 degrees C for 1 second) and a medium-temperature, long-duration burn (80 degrees C for 15 seconds). Cooling parameters such as the nature of the cooling fluid, the duration of the cooling period, the temperature of the coolant fluid, and the delay between the termination of the burn and the initiation of the cooling therapy are examined. The authors find that the most influential way to significantly reduce the damage from a burn is to immediately cool the burn. In addition, it was found that cooling a burn for a prolonged period of time or with very cold water cannot be justified from purely a heat transfer point of view. PMID- 22210056 TI - Correlation of American Burn Association sepsis criteria with the presence of bacteremia in burned patients admitted to the intensive care unit. AB - Severe burn injury is accompanied by a systemic inflammatory response, making traditional indicators of sepsis both insensitive and nonspecific. To address this, the American Burn Association (ABA) published diagnostic criteria in 2007 to standardize the definition of sepsis in these patients. These criteria include temperature (>39 degrees C or <36 degrees C), progressive tachycardia (>110 beats per minute), progressive tachypnea (>25 breaths per minute not ventilated or minute ventilation >12 L/minute ventilated), thrombocytopenia (<100,000/MUl; not applied until 3 days after initial resuscitation), hyperglycemia (untreated plasma glucose >200 mg/dl, >7 units of insulin/hr intravenous drip, or >25% increase in insulin requirements over 24 hours), and feed intolerance >24 hours (abdominal distension, residuals two times the feeding rate, or diarrhea >2500 ml/day). Meeting >3 of these criteria should "trigger" concern for infection. In this initial assessment of the ABA sepsis criteria correlation with infection, the authors evaluated the ABA sepsis criteria's correlation with bacteremia because bacteremia is not associated with inherent issues of diagnosis as occurs with pneumonia or soft tissue infections, and blood cultures are typically obtained due to concern for ongoing infections falling within the definition of "septic." A retrospective electronic records review was performed to evaluate episodes of bacteremia in the United States Army Institute of Research from 2006 through 2007. A total of 196 patients were admitted during the study period who met inclusion criteria. The first positive and negative cultures, if present, from each patient were evaluated. This totaled 101 positive and 181 negative cultures. Temperature, heart rate, insulin resistance, and feed intolerance criteria were significant on univariate analysis. Only heart rate and temperature were found to significantly correlate with bacteremia on multivariate analysis. The receiver operating characteristic curve area for meeting >3 ABA sepsis criteria is 0.638 (95% confidence interval 0.573-0.704; P < .001). Among severe burn patients, the ABA trigger for sepsis did not correlate strongly with bacteremia in this retrospective chart review. PMID- 22210054 TI - Mitochondria targeting of non-peroxidizable triphenylphosphonium conjugated oleic acid protects mouse embryonic cells against apoptosis: role of cardiolipin remodeling. AB - Peroxidation of cardiolipin in mitochondria is essential for the execution of apoptosis. We suggested that integration of oleic acid into cardiolipin generates non-oxidizable cardiolipin species hence protects cells against apoptosis. We synthesized mitochondria-targeted triphenylphosphonium oleic acid ester. Using lipidomics analysis we found that pretreatment of mouse embryonic cells with triphenylphosphonium oleic acid ester resulted in decreased contents of polyunsaturated cardiolipins and elevation of its species containing oleic acid residues. This caused suppression of apoptosis induced by actinomycin D. Triacsin C, an inhibitor of acyl-CoA synthase, blocked integration of oleic acid into cardiolipin and restored cell sensitivity to apoptosis. PMID- 22210057 TI - Predictors of patient satisfaction with pain management and improvement 3 months after burn injury. AB - Very little is known about what influences patient satisfaction with burn pain management. The aim of this prospective study was to examine predictors of patient satisfaction with pain management following burn injury. METHODS: Participants were 97 adult burn patients admitted to Royal Perth Hospital, Western Australia between June 2007 and February 2009. Key patient satisfaction domains were: pain treatment in hospital, pain medication provided, and improvement since hospitalisation. Acute pain medication use, pain severity, psychological symptoms, and patient expectations were assessed as potential predictors of patient satisfaction. RESULTS: Patients reported moderate to high levels of satisfaction across all domains. Whether treatment matched patients' expectations was a significant predictor of satisfaction with pain treatment, pain medication and improvement (p < .001, p < .001, p < .05 respectively). Current pain at follow-up was a significant predictor of satisfaction with pain treatment and improvement (p < .01, p < .001 respectively). Acute pain medication use, depressive symptoms and reductions in average pain at three months were not significant independent predictors of patient satisfaction with pain management and improvement in this sample (p > .35). Yet, severity of posttrauma symptoms at three months was a significant predictor of satisfaction with pain medication and was moderately and positively associated with satisfaction with pain treatment (p < .05, p = .07, respectively). DISCUSSION: These findings suggest that acute medication use and reductions in perceived pain symptoms are less closely related to patient satisfaction compared with treatment expectations, current pain and posttrauma symptoms. Collectively, these findings indicate a need to proactively address treatment expectations about pain management, and manage current pain and psychological distress following burn injury in order to improve patient satisfaction with care received. PMID- 22210058 TI - Epidemiology and outcome analysis of severe extensive burns: a 12-year summary of 103 cases in a burn center in China. AB - The purpose of this article is to improve the treatment of severe extensive burns (SEB) patients by summarizing treatment experience in recent 12 years in China and analyzing the follow-up quality of life (QOL) in these patients. Clinical data and rescue measures of 103 SEB patients (>=70% TBSA) admitted in a burn center in Shanghai between 1997 and 2009 were reviewed, and QOL and hand function of those who survived more than 2 years were assessed by Brief Version of Burn Specific Health scale-B and Michigan Hand Outcome Questionnaire. Of these, 76.7% were caused by flames and 15.5% caused by scald. The median burn area was 87.5% (interquartile range, 77.0-95.0%) TBSA, of which third-degree burns accounted for 56.5% (interquartile range, 25.8-80.0%) TBSA; 71.8% were complicated by inhalation injury. The occurrence of in-hospital complications was 75.7%, with the respiratory system complications predominating (49.5%). The fatality rate was 28.2%, mainly due to sepsis and multiple organ dysfunction syndrome. Work, body image, and heat sensitivity got the lowest Brief Version of Burn Specific Health scale-B scores in all nine domains, and Michigan Hand Outcome Questionnaire scores were also relatively poor. Flame burns remain to be the main cause of SEB in China in recent 12 years. Treatment is still challenged because of the depth and extensive burn area and high occurrence of multiple system complications. How to ameliorate QOL of SEB patients, intensify the functional rehabilitation, and improve their physical appearance in particular remain to be a crux. PMID- 22210059 TI - Clinical progression and outcome of dysphagia following thermal burn injury: a prospective cohort study. AB - The objectives of this study were 1) to establish clinical profiles of dysphagic and nondysphagic individuals following thermal burn injury and 2) to provide a clinical profile of the progression and outcome of dysphagia resolution by hospital discharge for a dysphagic cohort. A total of 438 consecutively admitted patients with thermal burns were included. All patients underwent a clinical swallowing examination. Medical parameters regarding burn presentation and its treatment and speech-language pathology specific variables from admission to discharge were collected for each participant. Dysphagia was identified in 49 patients via clinical assessment, and their course of recovery was followed up until the point of dysphagia resolution or discharge. No significant difference was observed between the dysphagic and nondysphagic groups in age, gender, and injury etiology. However, the dysphagic cohort was significantly different from the nondysphagic group in all variables pertaining to injury presentation and medical management. Individuals with dysphagia took significantly longer to start, and maintain, oral intake and required nonoral supplementation for three and a half times longer than those who were nondysphagic. Length of speech language pathology intervention averaged 1 month for the dysphagics and increased with dysphagia severity. Return to normal fluid consistencies occurred in >75% of dysphagic individuals by week 7 after injury, although resumption of normal diet textures was more protracted, with 75% resuming normal oral intake by week 9. Dysphagia had resolved in 50% of the cohort by week 6, and by hospital discharge, 85% of the dysphagic individuals had resumed normal oral intake of thin fluids and a general diet. This is the first large prospective cohort study to establish clinical profiles of dysphagic and nondysphagic cohorts and document the nature of dysphagia and patterns of recovery within the thermal burn population. These current data will assist the allocation and planning of speech-language pathology services and provide baseline data on the course of dysphagia resolution in the adult thermal burn population. PMID- 22210060 TI - Experience with corrective surgery for postburn contractures in Mumbai, India. AB - Postburn contracture is a source of significant morbidity in India, even though its occurrence can be reduced significantly by comprehensive postburn injury care, including surgical intervention. This study investigates whether limited access to initial medical care after burn injury has been associated with increased contracture formation among lower socioeconomic class patients in Mumbai, India. During a surgical mission in Mumbai, India, patients presenting with functionally debilitating burn contractures and minimal income were surveyed for initial care received immediately after burn injury. The survey consisted of questions regarding the history of burn injury and details of any initial treatment. Demographic data were collected by chart review. Thirty-eight patients from the state of Maharashtra participated in the study (mean age 28.1 years). The most common etiology of burn injury was from kerosene stove blasts (74%), and the most common morbidities were contractures of the neck and upper extremity. On average, time elapsed since the original injury was 2.8 years. Nearly all patients sought initial medical care at hospitals (97%) with the majority receiving only dressing changes for their full-thickness or deep-dermal burns (61%). The most common reason for not seeking out delayed burn reconstruction was perceived cost (65%). Ultimately, 60 operations were performed, of which 9 (15%) developed postsurgical complications. These data suggest that a subset of lower socioeconomic class burn patients in Maharashtra received suboptimal initial intervention. Comprehensive initial therapy after burn injury may provide better outcomes and limit the number of patients requiring delayed reconstruction. PMID- 22210061 TI - A pilot study of the use of biocide-impregnated gauze as an adjunct to wound care in a burn population. AB - The aim of this study was to evaluate the use of a polyhexamethylene biguanide biocide-impregnated gauze (KerlixTM AMD gauze dressing, Covidien d/b/a Tyco Healthcare Group LP) as an adjuvant to routine burn care and its impact on the incidence of hospital-associated infections in burn population. One hundred eight burn patients admitted to the Burn Treatment Center were prospectively enrolled from August 2008 to June 2009 and matched 1:2 with historic controls who were admitted from March 2006 to July 2008. Clinical care remained otherwise unchanged; however, several hospital initiatives (the national surgical improvement project, the surgical care improvement project, and a central venous line bundle) were initiated before and during the study. There were significantly less infections in the study population (18.52% of case patients vs 28.70% of control patients had infections, P = .047). Although there was a decrease in each infection subtype analyzed, a statistically significant reduction was only reached for pneumonias (1.85% in cases vs 5.86 in controls, P = .042). Implementation of polyhexamethylene biguanide biocide-impregnated gauze was temporally correlated with a significant decrease in healthcare-associated infections in burn population. As there was no corresponding decrease in wound infections, the impact of the gauze on healthcare-associated infections, if any, cannot be conclusively determined by this study. A larger prospective study powered to detect a decrease in wound-related infections is warranted. PMID- 22210062 TI - Catechol-O-methyltransferase genotype predicts pain severity in hospitalized burn patients. AB - Increasing evidence suggests that stress system activation after burn injury may contribute to burn-related pain. If this is the case, then genetic variations influencing the function of important stress system components, such as the enzyme catechol-O-methyltransferase (COMT), may predict pain severity after thermal burn injury. The authors evaluated the association between COMT genotype and pain intensity in 57 individuals hospitalized after thermal burn injury. Consenting participants at four burn centers were genotyped and completed daily 0 to 10 numeric rating scale pain assessments on 2 consecutive days including evaluation of waking, least, and worst pain. The association between COMT genotype and individual pain outcomes was calculated using a linear mixed model adjusting for sociodemographic and burn injury characteristics. Overall pain (combination of least, worst, and waking pain scores) was significantly higher in patients with a COMT pain vulnerable genotype (6.3 [0.4] vs 5.4 [0.4], P = .037). Individuals with a COMT pain vulnerable genotype also had significantly higher "least pain" scores (3.8 [0.5] vs 2.6 [0.4], P = .017) and significantly higher pain on awakening (6.8 [0.5] vs 5.3 [0.4], P = .004). Differences in worst pain according to genotype group were not significant. COMT pain vulnerable genotype was a stronger predictor of overall pain severity than burn size, burn depth, or time from admission to pain interview assessment. These findings suggest that genetic factors influencing stress system function may have an important influence on pain severity after burn injury. Further studies of genetic predictors of pain after burn injury are needed. PMID- 22210063 TI - Admission chest CT complements fiberoptic bronchoscopy in prediction of adverse outcomes in thermally injured patients. AB - In burned patients, inhalation injury can result in progressive pulmonary dysfunction, infection, and death. Although bronchoscopy is the standard for diagnosis, it only assesses the proximal airway and does not provide a comprehensive analysis of pulmonary insult. Chest radiographs have not been proven helpful in diagnosis of inhalation injury. Our hypothesis is that a CT scan alone or in conjunction with bronchoscopy can be used as a prognostic tool for critically ill burn patients, especially those with inhalation injury. The authors performed a retrospective study of all patients admitted to the U.S. Army Institute of Surgical Research Burn Center between 2002 and 2008 with chest CT within 24 hours of admission. They divided subjects into two groups, those with evidence of inhalation injury on bronchoscopy and those without. They used a radiologist's score to assess the degree of damage to the pulmonary parenchyma. The primary endpoint was a composite of pneumonia, acute lung injury/acute respiratory distress syndrome, and death. The inhalation injury group consisted of 25 patients and the noninhalation injury group of 19 patients. Groups were not different in age, TBSA burned, and percentage full-thickness burn. By multiple logistic regression, detection of inhalation injury on bronchoscopy was associated with an 8.3-fold increase in the composite endpoint. The combination of inhalation injury on bronchoscopy and a high radiologist's score was associated with a 12.7-fold increase in the incidence of the composite endpoint. Admission CT assists in predicting future lung dysfunction in burn patients. PMID- 22210064 TI - Identification of risk factors associated with critical illness related corticosteroid insufficiency in burn patients. AB - The goal of this analysis was to characterize risk factors of patients who develop critical illness-related corticosteroid insufficiency (CIRCI) after acute burn injury. This is a retrospective, single-center case-control descriptive study performed at a regional burn unit at an academic medical center. Patients are adults with acute burn injury who developed CIRCI (cases) and sex-, age-, and burn size-matched controls. Cases were compared with controls based on clinical characteristics. Conditional logistic regression analysis was used to establish potential risk factors for cortisol insufficiency. CIRCI was diagnosed in 23 of 1183 patients during the period reviewed (1.9%); 159 controls were matched. CIRCI patients demonstrated significantly greater length of stay (35.1 vs 65.8 days, P <= .001), ventilator days (20.5 vs 33.2 days, P <= .001), and mortality (2.5% vs 17.4%, P <= .001) than controls. Patients with higher Charlson Comorbidity Index scores were more likely to develop cortisol insufficiency (odds ratio 1.58, 95% confidence interval 1.20-2.08), as were patients with inhalation injury (odds ratio 6.46, 95% confidence interval 2.01-20.72). Antibiotics and sedative/hypnotics analyzed by class were not significant. Multivariate conditional logistic regression analysis including Charlson Comorbidity Index and inhalation injury showed significant association of both dependent variables with CIRCI (pseudo-R2 = .32, P <= .001). Preexisting comorbidities and inhalation injury provide significant risks for development of CIRCI after acute burn injury. Acute burn patients who develop CIRCI have higher mortality, length of stay, and ventilator days than matched controls. PMID- 22210066 TI - Development and evaluation of a DVD for the education of burn patients who were not admitted to hospital. AB - Patient involvement is an important component of burn care and is necessary to produce good outcomes. Patient education using multimedia resources is useful in facilitating self-management and recovery from burn injury. The study aims to provide and evaluate an instructional DVD to assist burn patients with their self management. The project was divided into three phases: 1) research about the needs of patients, 2) production of the DVD based on those needs, and 3) evaluation of the effectiveness of the DVD. In phase III, 49 burn patients (73% male; median age 32 years, median TBSA 3%) completed a survey on confidence in their burn care before development of an educational DVD, the results of which were compared with those of 55 burn patients (58% male; median age 35 years, median TBSA 3%) who completed the same survey questions after viewing a burn care DVD. Patient confidence in all self-management activities showed a statistically significant improvement (P < .01). An instructional burns DVD improves confidence in self-management of patients who have not been admitted to hospital and is a useful adjunct to current burn practice. PMID- 22210065 TI - Assessment of pruritus characteristics and impact on burn survivors. AB - The goal of this cross-sectional study was to characterize and describe persistent postburn pruritus. Cause and treatment of postburn itch is elusive. It has been suggested that burn survivors with persistent pruritus should be divided into acute itch (<=6 months postinjury) and chronic itch (>6 months postinjury) because the cause of itch may be different. Cross-sectional data of itch characteristics reported here are from the baseline data of a prospective, randomized, double-blind, controlled pilot study of 23 subjects with frequent and bothersome postburn pruritus. Subjects self-completed validated scales for variables of itch sensation, affect of itch, and severity. Variables of quality of life, frequency, pain and itch intensity, skin condition, scar, and medication were also recorded. Itch frequency revealed that 87% of subjects experienced itching daily, 96% experienced three or more episodes a day, and 52% had episode durations lasting 5 to 30 minutes per incidence. Itch was reported as unbearable by 94% of subjects with chronic itch and by 86% of subjects with acute itch, whereas bothersome was 88 and 100%, respectively. Itch sensation dimension of stinging was 74% in both acute and chronic itch subjects. Crawling and burning sensations were often severe. Potential itch triggers and relief activities were identified. Differences in sensory and affective itch components were detected between acute and chronic itch subjects. Combinations of itch mechanisms probably contribute to the development of and changes in pruritus. Characterizing the sensation and affective itch dimensions in conjunction with inflammation, burn injury, recovery, scar maturation, medication, and psychological status should better elucidate postburn itch. PMID- 22210067 TI - Free anterolateral thigh flap for coverage of scalp large defects in pediatric burn population. AB - Free anterolateral thigh flap is considered by most surgeons to be the proper choice for restoring scalp defect in the adult population. However, in the pediatric burn population with scalp large defects, the use of this flap has not been well described. From December 2005 to June 2009, 11 free anterolateral thigh flaps were performed to cover scalp defects in eight male children and three female children aged between 3.1 and 5.9 years (mean age: 5.0 years). Causes for the lesions include boiling liquid (5 cases), frictional heat (4 cases), and electricity (2 cases). Defect sites include parietal region (6 cases), occipital region (3 cases), temporal region (1 cases), and forehead (1 case). The size of the flaps ranged from 10 to 25 cm in length and from 8 to 18 cm in width. All the patients were followed up from 5.0 months to 2.1 years after the operation. Satisfactory contour results were shown. The overall flap success rate was 100%. There were no complications such as infections or hematomas after surgery. All the donor sites were covered with no morbidity observed. The free anterolateral thigh flap provides immediate vascularized coverage in scalp large defect that were unable to be treated by other methods, such as local flap or tissue expansion. Despite the smaller diameter of the vessels in pediatric population than that in adults, it is conceivable that this flap should be the reasonable and reliable method of large scalp defect coverage in pediatric population. PMID- 22210069 TI - Adapting to life after burn injury--reflections on care. AB - A burn injury is an unforeseen event that means physical and psychological trauma for the person afflicted. The trauma experienced by different individuals varies greatly, as do perceived problems during care, rehabilitation, and throughout the remainder of life. The purpose of this study was to explore burn patients' experiences of adapting to life after burn injury to acquire a deeper understanding of the most important issues for patients when providing care during and after a burn injury. A qualitative approach was applied, and interviews were conducted with 12 adult burn patients (8 men and 4 women) 6 to 12 months postburn. The interviews were analyzed using Kvales' method for structuring analysis and comprised a close reading and interpretation of the texts. Analysis focused on the personal experiences of burn patients living after burn injury and treatment. Struggling with the consequences of burn injury and how patients perceived life today after treatment are important issues for adapting to life after burn injury. New experiences of a fragile body, coping with daily life, and reflections of burn care were also prominent themes. Patients with burn injuries need adequate repeated information about the plan for their care, about the physiological changes, and more support to handle the trauma event. The patients would also like to be more involved in their care. A program of support and preparatory work to help the patient to cope with the new bodily sensations and new body image is necessary and should begin during hospital care. A multidisciplinary team approach for pain treatment needs to be prioritized. In addition, multidisciplinary follow-up after burns need to include patients with minor burns. PMID- 22210068 TI - Length of stay of elderly patients in an acute burns unit: has the pilot appointment of a geriatrician to the service made a difference? PMID- 22210070 TI - Burned unilateral half-cheek resurfacing techniques. AB - Postburn cheek deformities are a tragedy for patients and pose a great challenge to surgeons due to a limited number of well-matching donor sites. In cases of unilateral half-cheek deformity, the flap's skin should match the contralateral cheek and the residual skin of the deformed cheek. The skin of a distant flap does not match the facial skin and resembles a patch. The most suitable skin type is the neck's skin and residual cheek's skin transposed on the defect with special techniques. Seventy-six patients with unilateral cheek scars covering nearly half of cheek's surface (total cheek deformities are not included in this series) were personally operated. The deformities were divided into four types or forms: lower cheek, lateral, medial, and upper. The flaps and techniques were designed for each type. The cervical skin, residual cheek skin, and periauricular skin (most matching the cheek's skin) was used in form of different flaps, depending on the scar location on the cheek. The basic flap used was the cervical split flap which could include A) a thoracic adipose-cutaneous layer (cervico thoracic flap); B) periauricular fasciocutaneous layer (cervico-periauricular and cervico-thoraco-periauricular flaps); C) residual healthy facial adipocutaneous layer (cervico-facial, cervico-facio-periauricular, and cervico-thoraco facioperiauricular flaps). Cervical flap has axial circulation and is elevated without platysma; it is transposed on the cheek with some tension. The lower and lateral cheek deformities were eliminated most successfully with the cervico thoraco-periauricular flap by one-stage procedure. Medial and upper cheek deformities were eliminated with the cervico-facio-thoraco-periauricular flap. The facial segment can be expanded (usually in cases of upper cheek reconstruction); in such cases, the thoracic region is not included in the flap (cervico-facio-periauricular flap). The cheeks were reconstructed in all patients without serious complications. The flap's skin matched the contralateral cheek and surrounding healthy skin; the donor site's damage was minimal; operation scars' line was maximally shortened. The use of cervical split flap in combination with thoracic, facial, and periauricular adipose-cutaneous layer opens, in author's opinion, a reliable and most successful way for postburn half cheek resurfacing. PMID- 22210071 TI - Incidence of catheter-associated bloodstream infection after introduction of minocycline and rifampin antimicrobial-coated catheters in a pediatric burn population. AB - The Centers for Disease Control and Prevention guidelines for prevention of intravascular catheter-related infections suggest that antimicrobial-coated catheters can decrease the risk of developing catheter-related bloodstream infection in a variety of adult patient populations. There are limited data on their efficacy in the pediatric population, particularly among children with burn injuries. A study was conducted at Shriners Hospitals for Children(r), Boston, to determine whether minocycline/rifampin (MR)-coated catheters could decrease the incidence of catheter-associated bloodstream infection (CABSI) in a pediatric burn population. A historical control group included all patients with double- or triple-lumen catheters inserted in the 18-month period from January 2006 to June 2007. The study group included all patients with MR antimicrobial double- or triple-lumen catheters inserted in the subsequent 18-month period, July 2007 to December 2008. Data collected included name, age, date of burn/injury, date of admission, percent TBSA area burn injury or other diagnosis, catheter site (subclavian, internal jugular, or femoral), method of insertion (new percutaneous stick or guidewire), type of catheter (double or triple lumen), date inserted, duration of catheter placement (days), and positive blood cultures recovered while the central venous catheter was in place. CABSI was defined using the Centers for Disease Control and Prevention definition of laboratory-confirmed bloodstream infection. There were a total of 66 patients with 252 catheters (1780 catheter days) in the control group and 75 patients with 263 catheters (1633 catheter days) in the study group. Age, percent burn injury, catheter site, and method of insertion were not statistically different between the two groups. The percentage of infected catheters and the rate of infection were significantly different for the two groups, with the MR antimicrobial catheters only half as likely to become infected. In a subset of these patients with catheters in place for more than 4 days, the percentage of infected catheters and rate of infection were also significantly different with results similar to those in the entire group. MR antimicrobial-coated catheters significantly reduced the incidence of CABSI in this pediatric burn population compared with noncoated catheters. PMID- 22210072 TI - The relationship between gabapentin and pregabalin and posttraumatic stress disorder in burned servicemembers. AB - Posttraumatic stress disorder (PTSD) affects approximately 30% of burned Servicemembers returning from Operation Iraqi Freedom/Operation Enduring Freedom. Gabapentin and pregabalin are anticonvulsant drugs that limited evidence suggests may also be effective treatments for some psychological disorders. This study examines the relationship between these anticonvulsants and PTSD development in burned Servicemembers. Drugs received, injury severity score, TBSA burned, length of hospital stay, number of intensive care unit days, number of surgeries, and PTSD Checklist-Military scores and administration dates were collected. Subjects were grouped based on receipt of gabapentin or pregabalin, and the groups were compared. The primary outcome was incidence of a positive screen for PTSD. Because injury severity was significantly different between the two groups, propensity score matching based on injury severity score and TBSA was performed. Two hundred ninety burned Servicemembers received the PTSD Checklist-Military at least 30 days after injury. Of these subjects, 104 received gabapentin, pregabalin, or both and 186 did not. Despite significantly greater injuries, the group that received gabapentin or pregabalin did not develop PTSD at a different rate than those patients who did (P = .727). Propensity score matching resulted in 57 patients in each group; there was no difference between these groups in the incidence of PTSD (P = .663). These data suggest that gabapentin or pregabalin administration may not affect PTSD development in burned Servicemembers. Many factors influence the development and progression of PTSD, but few drugs have been identified that are effective at treating or preventing PTSD. PMID- 22210073 TI - Assessment of combined muscarinic antagonist and fibrinolytic therapy for inhalation injury. AB - This study tests the hypothesis that muscarinic receptor antagonist therapy with tiotropium bromide (tiotropium; TIO), alone or in combination with tissue plasminogen activator (TPA), can attenuate pulmonary dysfunction in sheep after smoke inhalation and burn injury. The study consisted of four study groups, sham (uninjured), control (injured and untreated), TIO (injured and treated with nebulized TIO), and TIO + TPA (injured and treated with nebulized TIO and TPA). Cardiopulmonary and ventilatory parameters were monitored for 48 hours. After killing the animal, airway obstruction, submucosal gland neutrophilia, parenchyma histopathology, and lung wet to dry weight ratios were measured. PaO2/FiO2 was significantly improved in the TIO group compared with the control group at 48 hours, 301 +/- 149 vs 99 +/- 33, respectively, P < .05. At 48 hours, peak airway pressures in the control, TIO, and TIO + TPA groups were 35 +/- 6, 24 +/- 7, and 26 +/- 10, respectively, with the mean of the TIO group being significantly different from that of the control group, P < .05. A trend of decreased airway obstruction was seen in the treated animals compared with controls; however, the differences were not statistically significant. The TIO and TIO + TPA groups exhibited significant decreases in gland neutrophilia compared with the control group, P < .05. No differences in parenchyma histopathology and lung edema between injured control and treated groups were observed. Nebulization of TIO was effective in improving pulmonary performance and reducing bronchial submucosal gland neutrophilia in sheep after smoke inhalation and burn injury. There was no additive benefit to the inclusion of nebulized TPA with TIO. PMID- 22210074 TI - Natural expansion of artificial dermal template by successful full-term pregnancy. AB - Extensive postburn scars of the trunk may cause breathing difficulty and, in female patients of reproductive age, render future pregnancy a serious reconstructive goal. Scar excision and skin grafting with or without artificial dermal templates is the current preferred management. A patient who underwent staged extensive grafting of the abdominal wall by dermal regeneration template and completed a full-term successful pregnancy is presented here. Although tissue expanders have been used to expand artificial dermal templates, natural expansion by pregnancy has not been previously documented. A 30-year-old woman with extensive chest and abdominal wall, bilateral gluteal and breast scars after burns sustained at childhood presented with difficulty in deep breathing. Abdominal scar tissue was excised and the abdominal wall was reconstructed by dermal regeneration template and autologous thin split-thickness skin graft in two stages. Six months postoperatively, spirometric values were improved by 15%, while 1 year later the patient completed successfully a full-term pregnancy. Reconstruction of extensive abdominal postburn scars by dermal regeneration template improves breathing by increasing elasticity and compliance of the reconstructed area. In female patients, the template can be extensively and naturally expanded by the gradually growing uterus, allowing for full-term pregnancy. PMID- 22210075 TI - Burn injury caused by unexpected ignition of rifle cartridge gunpowder. PMID- 22210076 TI - Deep dermal fibroblasts refractory to migration and decorin-induced apoptosis contribute to hypertrophic scarring. AB - Hypertrophic scar (HTS) represents the dermal equivalent of fibroproliferative disorders. Fibroblasts from the deep dermis are implicated in the development of HTS after injuries that involve deeper areas of the skin. However, fibroblasts that reside in the superficial layer of the skin show antifibrotic properties, and injuries limited to this area heal with little or no scarring. Previously, cellular and molecular characteristics of superficial fibroblasts and deep dermal fibroblasts that may influence HTS formation were analyzed. In this study, differences in cellular behavior between superficial fibroblasts and deep dermal fibroblasts that may also affect the development of HTS or tissue fibrosis were further characterized. Immunostaining and migration, adhesion, apoptosis, and cell viability assays were performed in fibroblasts from the superficial and deep dermis. Reverse-transcription polymerase chain reaction was used to examine the gene expression of molecules involved in cell death after treatment of fibroblasts with decorin. When compared with superficial fibroblasts, deep dermal fibroblasts showed lower migration rates. Although all the fibroblasts tested showed no difference in adhesion to fibronectin, superficial fibroblasts demonstrated increased apoptotic and dead cells when treated with decorin. Decorin resulted in a significant increase in the expression of apoptosis markers, histone-1, caspase-1, caspase-8, and p53 in superficial fibroblasts when compared with deep dermal fibroblasts. Taken together, the findings suggest that reduced migration, lack of decorin, and resistance of deep dermal fibroblasts to decorin-induced apoptosis may result in hypercellularity in injuries involving the deep dermis, leading to deposition of excess extracellular matrix and HTS formation. PMID- 22210077 TI - Postburn edge shoulder adduction contracture: anatomy and elimination with trapeze-flap plasty--a new approach. AB - Postburn scar shoulder adduction contracture is the most common among big joints' contractures. As the contracture impedes all upper limb function, surgical reconstruction is indicated as early as the contracture is formed. Many flaps and techniques have been suggested, yet the problem is not resolved completely. Three hundred forty-six edge scar shoulder adduction contractures were eliminated personally in 277 patients. Contracture anatomy was studied before and during surgery. Effectiveness of the existing and newly developed techniques was evaluated. Edge shoulder scar adduction contracture is caused by scars located on anterior and/or posterior shoulder joint surface and is characterized by the presence of the fold along the axillary fossa edge. Crest of the fold is the edge of scars. The fold's lateral sheet is scars (causes contracture); medial sheet and axillary fossa skin stay uninjured. Lateral scar sheets have surface deficit in length; the deficit spreads from the fold's crest to the shoulder joint rotation axis and has a trapezoid form. The conclusion was made that the adequate technique should consist of sheet surface deficit compensation with the flap of the same (trapezoid) shape. The medial fold sheet and axillary fossa served as an excellent donor site for the flap. Depending on contracture severity, several variants of the trapeze-flap plasty were developed: trapeze-flaps alone or in combination with skin grafts. In all cases, contractures were eliminated completely with trapeze-flap plasty without serious complications. No flap loss and contracture recurrence took place. The proposed techniques are based on the anatomy of the contracture. They are easy to plan and perform, allow complete restoration of the upper limb's function, and improve shoulder joint region appearance in general. The author believes that the trapeze-flap plasty procedure is a preferred technique for adult and pediatric patients with edge scar shoulder adduction contracture. PMID- 22210078 TI - A modified symblepharon ring for sutureless amniotic membrane patch to treat acute ocular surface burns. AB - The objective of this study is to evaluate a sutureless technique by using a modified symblepharon ring to fix an amniotic membrane (AM) patch on the ocular surface to treat acute ocular burns. Seventy-five patients with acute ocular burns of total 75 eyes graded III to VI were enrolled in this study. They were randomly divided into two groups. Thirty-nine eyes received the sutureless AM patch with a modified symblepharon ring, and the other 36 eyes underwent the conventional sutured AM patch as control. The time and the rate of epithelialization, corneal neovascularization, and complications were recorded. Both the operation time and the time to epithelial closure in the sutureless group were much shorter than that in the suture group (P < .01). The rate of reepithelialization in the sutureless group was higher than in the suture group (P < .05). The rate of the vascularization and symblepharon were lower in the sutureless group than in the suture group (P < .05). The conjunctival sac contraction occurred only in the eyes with grade V and VI in the sutureless group and was later than in the suture group (P < .05). This modified method is simple, minimally invasive, free from trauma, and more effective compared with controls. PMID- 22210080 TI - Burn-injured adolescents report gaining multiple developmental benefits and improved life skills as a result of burn camp attendance. AB - Anecdotally, burn camp has been reported to be a positive developmental and rehabilitative experience for attendees; there is little empirical data to support this belief. This study sought to explore whether burn camp either directly or indirectly elicits positive development outcomes in pediatric burn survivors or increases their psychosocial well-being and achievement. The Youth Experience Survey 2.0, a 66-item self-report inventory designed to measure developmental experiences in an organized youth activity, was administered to children aged 11 to 18 years attending summer burn camp. One hundred and ten burn injured youth, 58 male and 52 female, reported that burn camp had positively impacted their lives through improved identity exploration, goal-setting and problem-solving abilities, increased physical activity, communication, emotional regulation, and time management skills (P < .0001). Participants reported more positive experiences than the norm group and higher mean scores on 90% (48) of the 53 positive items. Attendance at burn camp for more than 5 years resulted in greater improvement. Study results support the burn camp experience as a far reaching and positive developmental activity. Participants credited the camp experience with helping them with identity formation and reflection, improved social interactions, and increased initiative; all positive developmental outcomes for youth. Results suggest that burn camp participation not only helps burn-injured youth to deal with their burns but also assists them in the development of social and basic life skills, which will allow them to navigate the transition from youth to adulthood, more effectively and successfully. PMID- 22210079 TI - Physical and quality of life outcomes of patients with isolated hand burns--a prospective audit. AB - Hand burns can have major implications on function, appearance, and quality of life. Our clinical practice has changed over the last 10 years, with a steady increase in the proportion of hand burns receiving early and aggressive surgical management using Biobrane(r) sheets/gloves and a concomitant fall in the proportion requiring excision and split skin grafting. The aim of this study was to measure a comprehensive range of outcomes for patients admitted with isolated hand burns to review our outcomes and provide us with the "expected" patterns of recovery. A prospective audit was performed over a 14-month period, with outcomes measured during hospital admission and at 2 weeks, 1, 3, 6, and 12 months postinjury (depending on the method of management). Outcomes comprised pain, the Burns Specific Health Scale (abbreviated version B), return to work/leisure, total active range of motion, grip strength, the Michigan Hand Questionnaire, and scar appearance using Matching Assessment with Photographs of Scars. A total of 52 patients (35 male, mean age 39 years) with 57 burned hands participated. Patients whose burn injuries were such that they were able to be managed conservatively or with Biobrane(r) showed rapid recovery in all outcomes, with normal or near-normal values achieved within 2 weeks to 1 month postinjury. The patients whose burn injuries required excision and split skin grafting demonstrated more marked initial deterioration, a slower rate of improvement, but eventual good recovery. In conclusion, for this sample of patients with isolated hand burns, recovery was good and rapid for those whose burn injuries were such that they were managed conservatively or with Biobrane(r). PMID- 22210081 TI - The effectiveness of a computerized IV infusion protocol to treat hyperglycemia in burn patients. AB - Tight glucose control (TGC) in critical care settings is becoming increasingly the standard of care. However, TGC comes with the risk of hypoglycemia, as highlighted by some recent studies. Our aim was to establish TGC in burn patients without increasing rates of hypoglycemia. The authors used a computer-driven glucose control program (CGS) to achieve this goal. The computer program calculates insulin drip rates by using a multiplier that changes according to blood glucose (BG) values as well as trends and keeps a record of BG data and insulin infusion rates for future quality control analysis. CGS is also a useful adjunct in transitioning patients from an IV insulin drip to subcutaneous insulin. A retrospective review of the glucose control program database was performed to obtain information on length of time to goal glucose levels (set at 100-150 mg/dl), glucose level trends, and incidence of hypoglycemia when using the computer program. Over 18 months, we used CGS on 94 critical and noncritical burn patients. Mean time to target BG was 5.1 hours. Glucose levels of 100 to 150 mg/dl were maintained 63.3% of the time, and values within the wider range of 70 to 150 mg/dl were maintained 80.8% of the time. The incidence of hypoglycemia, defined as BG level below 70 mg/dl, was only 1.66% and was treated without any adverse sequelae. Hyperglycemic episodes were directly correlated with surgical interventions during which time the CGS was not utilized in the operating room. CGS offers a safe and effective means of rapidly achieving and maintaining glucose targets in burn patients. Further analysis of the data needs to be conducted to determine whether the BG targets used in our study offer a morbidity benefit to burn patients. PMID- 22210082 TI - Genetic predisposition to peripheral nerve neoplasia: diagnostic criteria and pathogenesis of neurofibromatoses, Carney complex, and related syndromes. AB - Neoplasms of the peripheral nerve sheath represent essential clinical manifestations of the syndromes known as the neurofibromatoses. Although involvement of multiple organ systems, including skin, central nervous system, and skeleton, may also be conspicuous, peripheral nerve neoplasia is often the most important and frequent cause of morbidity in these patients. Clinical characteristics of neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) have been extensively described and studied during the last century, and the identification of mutations in the NF1 and NF2 genes by contemporary molecular techniques have created a separate multidisciplinary field in genetic medicine. In schwannomatosis, the most recent addition to the neurofibromatosis group, peripheral nervous system involvement is the exclusive (or almost exclusive) clinical manifestation. Although the majority of cases of schwannomatosis are sporadic, approximately one-third occur in families and a subset of these has recently been associated with germline mutations in the tumor suppressor gene SMARCB1/INI1. Other curious syndromes that involve the peripheral nervous system are associated with predominant endocrine manifestations, and include Carney complex and MEN2b, secondary to inactivating mutations in the PRKAR1A gene in a subset, and activating mutations in RET, respectively. In this review, we provide a concise update on the diagnostic criteria, pathology and molecular pathogenesis of these enigmatic syndromes in relation to peripheral nerve sheath neoplasia. PMID- 22210083 TI - Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis. AB - While cognitive deficits are increasingly recognized as common symptoms in amyotrophic lateral sclerosis (ALS), the underlying histopathologic basis for this is not known, nor has the relevance of neuroinflammatory mechanisms and microglial activation to cognitive impairment (CI) in ALS been systematically analyzed. Staining for neurodegenerative disease pathology, TDP-43, and microglial activation markers (CD68, Iba1) was performed in 102 autopsy cases of ALS, and neuropathology data were related to clinical and neuropsychological measures. ALS with dementia (ALS-D) and ALS with impaired executive function (ALS Ex) patients showed significant microglial activation in middle frontal and superior or middle temporal (SMT) gyrus regions, as well as significant neuronal loss and TDP-43 pathology in these regions. Microglial activation and TDP-43 pathology in middle frontal and superior or middle temporal regions were highly correlated with measures of executive impairment, but not with the MMSE. In contrast, only one ALS-D patient showed moderate Alzheimer's disease (AD) pathology. Tau and Abeta pathology increased with age. A lower MMSE score correlated with tau pathology in hippocampus and SMT gyrus, and with Abeta pathology in limbic and most cortical regions. Tau and Abeta pathology did not correlate with executive measures. We conclude that microglial activation and TDP 43 pathology in frontotemporal areas are determinants of FTLD spectrum dementia in ALS and correlate with neuropsychological measures of executive dysfunction. In contrast, AD pathology in ALS is primarily related to increasing age and associated with a poorer performance on the MMSE. PMID- 22210084 TI - Elevated interleukin-27 enhances the polarization of Th1/Tc1 cells and the production of proinflammatory cytokines in primary immune thrombocytopenia. AB - Primary immune thrombocytopenia (ITP) is an acquired, organ-specific, autoimmune disease with many immune dysfunctions. Interleukin-27 (IL-27) can regulate T cell differentiation. However, it is unclear whether IL-27 correlates with the dysfunctions of T cell differentiation in ITP patients. Thus, to determine the roles of IL-27 in ITP, we studied the expression of IL-27/IL-27 receptor in ITP patients. The results indicated that the levels of IL-27 in the plasma of untreated active ITP patients were higher than in normal controls. We next evaluated the contribution of IL-27 to T cell differentiation. Our results indicated that IL-27 increased T-bet expression, inhibited GATA-3 and ROR-gammat expression, and promoted the secretion of tumor necrosis factor-alpha, interferon gamma, and granzyme B of peripheral blood mononuclear cells from ITP patients. Also, we confirmed that IL-27 induced the differentiation of T helper (Th)-1 and Tc1 cells. In conclusion, IL-27 might play an important role in the pathogenesis of ITP by inducing the polarization of Th1/Tc1 cells and the production of proinflammatory cytokines. PMID- 22210085 TI - Metabolism of the synthetic progestogen norethynodrel by human ketosteroid reductases of the aldo-keto reductase superfamily. AB - Human ketosteroid reductases of the aldo-keto reductase (AKR) superfamily, i.e. AKR1C1-4, are implicated in the biotransformation of synthetic steroid hormones. Norethynodrel (NOR, 17alpha-ethynyl-17beta-hydroxy-estra-5(10)-en-3-one), the progestin component of the first marketed oral contraceptive, is known to undergo rapid and extensive metabolism to 3alpha- and 3beta-hydroxymetabolites. The ability of the four human AKR1C enzymes to catalyze the metabolism of NOR has now been characterized. AKR1C1 and AKR1C2 almost exclusively converted NOR to 3beta hydroxy NOR, while AKR1C3 gave 3beta-hydroxy NOR as the main product and AKR1C4 predominantly formed 3alpha-hydroxy NOR. Individual AKR1C enzymes also displayed distinct kinetic properties in the reaction of NOR. In contrast, norethindrone (NET), the Delta(4)-isomer of NOR and the most commonly used synthetic progestogen, was not a substrate for the AKR1C enzymes. NOR is also structurally identical to the hormone replacement therapeutic tibolone (TIB), except TIB has a methyl group at the 7alpha-position. Product profiles and kinetic parameters for the reduction of NOR catalyzed by each individual AKR1C isoform were identical to those for the reduction of TIB catalyzed by the respective isoform. These data suggest that the presence of the 7alpha-methyl group has a minimal effect on the stereochemical outcome of the reaction and kinetic behavior of each enzyme. Results indicate a role of AKR1C in the hepatic and peripheral metabolism of NOR to 3alpha- and 3beta-hydroxy NOR and provide insights into the differential pharmacological properties of NOR, NET and TIB. PMID- 22210086 TI - Phase II trial of erlotinib and docetaxel in advanced and refractory hepatocellular and biliary cancers: Hoosier Oncology Group GI06-101. AB - BACKGROUND: Patients with advanced hepatocellular (HCC) and biliary tract carcinomas (BTC) have poor prognosis. While the EGFR pathway is overactive in HCC and BTC, single agent anti-EGFR therapies confer modest activity. Preclinical data showed synergistic antiproliferative and proapoptotic effects between anti EGFR therapies and taxanes. We conducted a phase I study of erlotinib and docetaxel in solid tumors, and noted good tolerability and sustained complete (5 years +) and partial responses in patients with HCC and BTC. This trial evaluated the efficacy of erlotinib with docetaxel in refractory hepatobiliary cancers. METHODS: Eligible patients were allowed to have two prior systemic therapies. Docetaxel 30 mg/m2 i.v. was administered on days 1, 8, 15, and erlotinib 150 mg was dosed orally on days 2-7, 9-14, 16-28 of each 28-day cycle. The primary endpoint was 16 weeks progression-free survival (PFS), and secondary endpoints included response, stable disease, and overall survival. Tumor samples were analyzed for KRAS gene mutations and E-cadherin expression by immunohistochemistry (IHC). Patients with BTC and HCC were accrued and assessed in separate strata for the efficacy endpoints, but for the two-stage initial design of the study, combined PFS was considered. A Simon optimal two-stage design tested the hypothesis that the 16-week PFS is <= 15% (clinically inactive) versus the alternative of >= 30% (warranting further study). RESULTS: Twenty-five patients, 14 with HCC and 11 with BTC, were enrolled. Common toxicities were rash (76%), diarrhea (56%), and fatigue (52%), mostly grade 1 or 2. No objective responses were seen. Seven BTC (64%) and 6 HCC patients (46%) had stable disease as best response, with a median duration of 16.1 weeks (95% CI 3.7-56.3) for BTC, and 17.6 weeks (95% CI 8.1-49.8) for HCC. The 16-week PFS was 64% for BTC (95% CI 29.7-84.5), and 38% for HCC (95% CI 14.1-62.8). Median overall survival was 5.7 and 6.7 months for BTC and HCC patients, respectively. BTC patients with grade >= 2 rash had higher median PFS (6.2 vs 2.2 months) and OS (14.2 vs. 4.2 months). HCC patients with negative/low E-cadherin expression had higher median PFS (6.7 vs. 2.1 months) and OS (14.5 vs. 4 months). CONCLUSION: Erlotinib with docetaxel met the 16-week PFS >= 30% endpoint, but overall survival was comparable to that seen with single-agent erlotinib. With the limitation of small numbers of patients, grade >= 2 rash (in BTC), and negative/low E-cadherin expression (HCC) were associated with higher PFS and OS. Discussion Refractory biliary tract and hepatocellular cancers are difficult to treat, and no chemotherapy or biologically targeted therapies have impacted survival. Based on preclinical synergism and prior phase I data, we conducted a multi-institutional study sequentially combining the EGFR-targeted agent erlotinib with docetaxel. Results from this study show that the primary endpoint, 16-week PFS of >= 30%, was met for the combined group of BTC and HCC patients (as originally planned in the study design), as well as in each disease category: 63.6% for BTC and 38.5% for HCC patients. Nevertheless, no patients attained an objective response and the median survival of 5.7 months for BTC, and 6.7 months for HCC patients (while heavily pretreated), is comparable to that seen with single-agent EGFR-targeted therapies. Safety analysis shows that this regimen was generally well tolerated, and most adverse events were grade 1 or 2. Few patients had reversible grade 3 transaminase elevation (8%), and severe anorexia, fatigue, and rash were uncommon. As expected, patients with grade >= 2 rash experienced higher PFS and OS, but this was noted only among the BTC group, likely because too few HCC patients had grade >= 2 rash. KRAS is an important predictive marker for anti EGFR therapies for lung and colorectal cancers, but for HCC or the heterogeneous group of BTC (with 10-50% KRAS mutations) no significant correlations have been established. We were not able to identify a correlation between KRAS and benefit from erlotinib-based therapy, as all but one HCC patient had KRAS wild type gene status. Preclinical data in multiple tumor types showed that E-cadherin, a signature marker for an "epithelial" tumor phenotype when overexpressed, predicts EGFR pathway activation and determines sensitivity to EGFR-targeted agents. E cadherin is often seen as a poor prognostic marker when downregulated, as noted during cancer progression. Not all studies demonstrate beneficial effects from E cadherin overexpression, possibly due to histological expression variability or tumor type specificity for this biomarker. Six BTC and 8 HCC patients had evaluable tumor samples for E-cadherin analysis. While the numbers were small and conclusions should be viewed with caution, negative/low E-cadherin expression was associated with improved PFS and OS for hepatobiliary cancers (most significant in HCC) in this refractory patient population where we expected lower expression levels. In conclusion, the combination of erlotinib with docetaxel provided a 16 week PFS of >= 30% but showed no appreciable differences in overall survival from historical data with single-agent erlotinib. While EGFR represents an important target in this group of malignancies, it is clear that hepatobiliary cancers are heterogeneous, thus a meaningful improvement in survival most likely will require careful treatment selection based on patient tumor's molecular and genetic profiling. PMID- 22210087 TI - Age-specific nonpersistence of endocrine therapy in postmenopausal patients diagnosed with hormone receptor-positive breast cancer: a TEAM study analysis. AB - BACKGROUND: Early discontinuation of adjuvant endocrine therapy may affect the outcome of treatment in breast cancer patients. The aim of this study was to assess age-specific persistence and age-specific survival outcome based on persistence status. METHODS: Patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational trial were included. Nonpersistence was defined as discontinuing the assigned endocrine treatment within 1 year of follow-up because of adverse events, intercurrent illness, patient refusal, or other reasons. Endpoints were the breast cancer-specific and overall survival times. Analyses were stratified by age at diagnosis (<65 years, 65-74 years, >=75 years). RESULTS: Overall, 3,142 postmenopausal breast cancer patients were included: 1,682 were aged <65 years, 951 were aged 65-74 years, and 509 were aged >=75 years. Older age was associated with a higher proportion of nonpersistence within 1 year of follow-up. In patients aged <65 years, nonpersistent patients had lower breast cancer-specific and overall survival probabilities. In patients aged 65-74 years and patients aged >=75 years, the survival times of persistent and nonpersistent patients were similar. CONCLUSION: Nonpersistence within 1 year of follow-up was associated with lower breast cancer-specific and overall survival probabilities in patients aged <65 years, but it was not associated with survival outcomes in patients aged 65-74 years or in patients aged >=75 years. These results suggest that extrapolation of outcomes from a young to an elderly breast cancer population may be insufficient and urge age-specific breast cancer studies. PMID- 22210088 TI - Is there such a thing as a cancer treatment that isn't worth its cost? PMID- 22210090 TI - Bevacizumab in clinical practice: prescribing appropriateness relative to national indications and safety. AB - The aim of this study was to describe the clinical use of bevacizumab in Lombardy (9.5 million inhabitants), Italy, during 2006-2007 in patients with metastatic colorectal cancer (mCRC) to evaluate compliance with the Italian Medicine Agency (AIFA) indications, the incidence of adverse events, and the survival rate. We performed computerized record linkage among three different Lombardy health care databases: File F registry, Regional discharge database, and Registry Office records. Patients were classified into approved and off-label uses according to the AIFA indications. Treatment with bevacizumab was administered to 780 patients, of whom 81.7% (n = 637) had mCRC. Among these, 37.8% (n = 241) of patients received the drug in observance of AIFA indications. Overall, ~10% of patients had serious treatment-related toxicities (fistula, 3.5%; venous thromboembolism, 2.8%; hemorrhage, 1.9%; intestinal perforation and arterial thromboembolism, <1%). The 1-year survival rate was 74.3% and the 2-year survival rate was 39.2%. The median survival time was 20.5 months, and there were no meaningful differences between gender and age groups. There was a gap between the bevacizumab approved indication and clinical practice pattern: overall, less than one half of the patients received bevacizumab in observance with the regulatory indication. The main reason for nonadherence to the indication was use as a second-line or advanced line of therapy. The incidence of serious adverse events and the survival rates of mCRC patients were similar to those reported in clinical trials. PMID- 22210089 TI - Current status of autologous stem cell transplantation in relapsed and refractory Hodgkin's lymphoma. AB - Despite the relatively high long-term disease-free survival (DFS) rate for patients with Hodgkin lymphoma (HL) with modern combination chemotherapy or combined modality regimens, ~20% of patients die from progressive or relapsed disease. The standard treatment for relapsed and primary refractory HL is salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT), which has shown a 5-year progression-free survival rate of ~50%-60%. Recent developments in a number of diagnostic and therapeutic modalities have begun to improve these results. Functional imaging, refinement of clinical prognostic factors, and development of novel biomarkers have improved the predictive algorithms, allowing better patient selection and timing for ASCT. In addition, these algorithms have begun to identify a group of patients who are candidates for more aggressive treatment beyond standard ASCT. Novel salvage regimens may potentially improve the rate of complete remission prior to ASCT, and the use of maintenance therapy after ASCT has become a subject of current investigation. We present a summary of developments in each of these areas. PMID- 22210091 TI - Panitumumab in patients with KRAS wild-type colorectal cancer after progression on cetuximab. AB - PURPOSE: Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type meta-static colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab. PATIENTS AND METHODS: We used a two-stage study design to treat patients with panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve patients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies. RESULTS: We treated twenty patients for a median of two cycles (range 1-4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months. Panitumumab was well tolerated. Thirteen patients (65%) had grade 1-2 dry skin or rash, and three patients had treatment related grade 3 toxicities (one each with hyperglycemia, hyperbilirubinemia, and hypokalemia). No patients had detectable anti-cetuximab antibodies at any time point; one patient developed anti-panitumumab antibodies. CONCLUSIONS: Panitumumab has minimal benefit in patients with KRAS wild-type metastatic colorectal cancer that has progressed on prior cetuximab. Discussion Both cetuximab and panitumumab competitively inhibit ligand binding to EGFR, thereby promoting receptor internalization and blocking receptor-mediated signaling. Although the two agents have never been compared directly in a randomized clinical trial, they produce similar response rates when used alone as well as in combination with cytotoxic agents. Cetuximab is a chimeric antibody with approximately 30% murine protein, while panitumumab is a fully human monoclonal antibody. Correspondingly, rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). However, the potential efficacy of panitumumab in patients who have developed disease progression on cetuximab has been an open question. Metges et al. (PANERB trial) prospectively treated 32 KRAS wild-type metastatic colorectal cancer patients with cetuximab and irinotecan followed by panitumumab monotherapy after progression. Remarkably, the authors reported an objective response rate of 22% to panitumumab, including a disease control rate (objective response plus stable disease) of 73% in 11 patients who had previously responded to cetuximab and irinotecan. In contrast, we found no responders and a stable disease rate of 45% with a median duration of only 1.7 months in our trial of 20 patients. Moreover, no patients had detectable anti-cetuximab antibodies at baseline. It is not clear to what extent the PANERB trial included patients without objective disease progression on cetuximab or for whom cetuximab-containing regimens may have been ceased due to toxicity in the absence of disease progression. In both circumstances, retreatment with panitumumab may be expected to demonstrate some degree of clinical activity. In our study, disease progression after at least 4 weeks of cetuximab documented radiographically or by increased carcinoembryonic antigen (CEA) levels was required for inclusion in order to ensure that the study population demonstrated unequivocal evidence of progression on cetuximab. While it remains possible that a small subset of patients may benefit from panitumumab after progression on cetuximab, our results suggest that this approach should not be adopted until predictive biomarkers for panitumumab response in this setting have been discovered and validated. Until then, patients who develop progression on cetuximab should be enrolled in trials of novel agents. PMID- 22210093 TI - Suppression of protein phosphatase 2A activity enhances Ad5/F35 adenovirus transduction efficiency in normal human B lymphocytes and in Raji cells. AB - Investigation of the molecular processes which control the development and function of lymphocytes is essential for our understanding of humoral immunity, as well as lymphocyte associated pathogenesis. Adenovirus-mediated gene transfer provided a powerful tool to investigate these processes. We have previously demonstrated that adenoviral vector Ad5/F35 transduces plasma cell lines at a higher efficiency than primary B cells, owing to differences in intracellular trafficking. Given that phosphatases are effectors of intracellular trafficking, here we have analyzed the effects of a panel of phosphatase inhibitors on Ad5/F35 transduction efficiency in B lymphocytes in the present study. FACS analysis was conducted to determine Ad5/F35-EYFP transduction efficiency in lymphoid cells, including human primary B cells, following serine/threonine phosphatase (PSP) inhibitor treatment. We further used confocal microscopy to analyze intracellular trafficking and fate of CY3 labeled Ad5/F35 vectors, in PSP treated lymphoid cell. Finally, we analyzed the MAPK pathway by Western blot in PSP treated cells. Adenoviral transduction efficiency was unresponsive to inhibition of PP1 whereas inhibition of PP2A by cantharidic acid, or PP1 and PP2A by okadaic acid, substantially increased transduction efficiency. Importantly, confocal microscopy analyses revealed that inhibition of PP2A shut down adenovirus recycling. Moreover, inhibition of PP2A resulted in increased phosphorylation of AKT, ERK1/2 and MEK1/2. Taken together, these results suggest that Ad5/F35 is more efficiently transduced in cells following PP2A inhibition. Our results are in agreement with reports indicating that PP2A is involved in the formation of recycling vesicles and might be of interest for gene therapy applications. PMID- 22210092 TI - Candidate targets for Multilocus Sequence Typing of Trypanosoma cruzi: validation using parasite stocks from the Chaco Region and a set of reference strains. AB - A Multilocus Sequence Typing (MLST) scheme was designed and applied to a set of 20 Trypanosoma cruzi stocks belonging to three main discrete typing units (T. cruzi I, V and VI) from a geographically restricted Chagas disease endemic area in Argentina, 12 reference strains comprising two from each of the six main discrete typing units of the parasite (T. cruzi I-VI), and one T. cruzi marinkellei strain. DNA fragments (?400-bp) from 10 housekeeping genes were sequenced. A total of 4178 bp were analyzed for each stock. In all, 154 polymorphic sites were identified. Ninety-five sites were heterozygous in at least one analyzed stock. Seventeen diploid sequence types were identified from 32 studied T. cruzi stocks (including the reference strains). All stocks were correctly assigned to their corresponding discrete typing units. We propose this MLST scheme as provisional, with scope for improvement by studying new gene targets on a more diverse sample of stocks, in order to define an optimized MLST scheme for T. cruzi. This approach is an excellent candidate to become the gold standard for T. cruzi genetic typing. We suggest that MLST will have a strong impact on molecular epidemiological studies of Chagas disease and the phylogenetics of its causative agent. PMID- 22210094 TI - Pitfalls in retrospective analyses of biomarkers: a case study with metastatic melanoma patients. AB - BACKGROUND: Reliable prognostic biomarkers of survival and response to treatment are clearly important in oncology, and many studies have been carried out with the objective of identifying new prognostic biomarkers. Retrospective analysis of blood banked from patients is a frequently used paradigm for these studies. We describe a new study of the association of serum biomarker level with overall survival in melanoma patients, and the problems encountered in carrying it out. METHODS: Blood samples from 56 patients with stage IV metastatic melanoma were drawn prior to initiation of any treatment for their disease. Sera from the samples were stored for up to 94 months at -80 degrees C, and were subsequently thawed at the same time and tested by multiplex Luminex assay for 30 analytes (cytokines, chemokines and growth factors). Cox regression analysis was used to assess the association between these analytes and time-to-death. RESULTS: Of the 30 analytes, 17 were associated with survival, most strongly so, and in all cases, a higher analyte level was associated with increased survival. In addition, the correlations of the levels of all possible pairs of analytes were all positive and in almost all cases highly significant. However, these results are artifacts that arise from the combination of two peculiarities of the data: the apparent decrease in analyte level with storage time, and the uniformly shorter storage times of the samples from censored patients than the storage times of the samples from patients who died. CONCLUSIONS: All retrospective studies can have hidden biases, and thus investigators should not claim new findings before examining the data in detail with the goal of determining whether the findings could be spurious. There were several suspicious findings in our initial analyses: too many analytes found significant, too many very small p values, a uniformly positive association of analyte level with survival, and a uniformly positive correlation between analyte levels. We were convinced that these findings must be artifacts, and further analyses showed that the findings could be explained by an apparent decrease of analyte level storage time. PMID- 22210095 TI - Quantitative method validation for the analysis of 27 antidepressants and metabolites in plasma with ultraperformance liquid chromatography-tandem mass spectrometry. AB - A fast and selective ultraperformance liquid chromatographic-tandem mass spectrometric method was developed and validated for the simultaneous quantification of amitriptyline, citalopram, clomipramine, desipramine, desmethylcitalopram, desmethylclomipramine, desmethyldosulepin, desmethyldoxepin, desmethylfluoxetine, desmethylvenlafaxine, didesmethylcitalopram, dosulepin, doxepin, duloxetine, fluoxetine, fluvoxamine, imipramine, maprotiline, mianserin, mirtazapine, moclobemide, nortriptyline, paroxetine, reboxetine, sertraline, trazodone, and venlafaxine in 100 MUL of plasma. After liquid-liquid extraction with 1-chlorobutane, analytes were separated on a BEH (Ethylene Bridged Hybrid) C18 analytical column with gradient elution. The compounds were ionized and detected over 7-minute analysis time by electrospray ionization tandem mass spectrometry with multiple reaction monitoring. Limits of quantification and limits of detection ranged from 2.5 to 10 ng/mL and 0.2 to 10 ng/mL, respectively. Intra- and interassay imprecision were lower than 15% for all the compounds except for mirtazapine, moclobemide, and desmethylclomipramine [relative standard deviation (RSD) < 20%], and the bias of the assay was lower than 15% for all the compounds except for fluvoxamine (bias < 20.5%), evaluated with 5 commercial quality control and 3 "in-house" quality control. The extraction was found to be reproducible (RSD < 16%) (except for duloxetine RSD 21.9%) and with recoveries varying from 59% to 86%. Furthermore, the stability studies demonstrated that the processed samples were stable in the autosampler for 24 hours for all the compounds. The method was successfully applied to the analysis of authentic samples from forensic toxicology cases and external quality control assays from the Society of Toxicology and Forensic Chemistry (GTFCh). The method was completely validated and can be of interest to clinical and forensic laboratories. PMID- 22210096 TI - Intracellular ATP production in CD4+ T cells as a predictor for infection and allograft rejection in trough-level guided pediatric liver transplant recipients under calcineurin-inhibitor therapy. AB - BACKGROUND: The assessment of cell-mediated immune responses through the measurement of intracellular adenosine-tri-phosphate (iATP) production (Cylex ImmuKnow) as a pharmacodynamic biomarker of immune function represents a potential tool to optimize individual immunosuppressive therapy independent of drug dosage or trough levels. This study aims to investigate the correlations between iATP and adverse events, immunosuppression, calcineurin-inhibitor-trough levels, and age. METHODS: In this prospective trial, 31 nontransplant pediatric subjects and 50 consecutive children were included after they underwent liver transplantation (LTX). During the study period, 4 allograft rejections and 3 acute infections occurred. The patients were treated with cyclosporine, tacrolimus, mycophenolate mofetil, and everolimus either as monotherapy or in combinations. The reactivity of the immune system was measured as iATP concentration in CD4+ T-cells after in vitro stimulation by phytohemagglutinin. RESULTS: The iATP concentrations in patients with intercurrent, clinically significant infections were in the low immune response range (median iATP 181 versus 251 ng/mL, P = 0.308), whereas the patients with incidental allograft rejection had significantly higher iATP concentrations as compared with the event free group (median iATP 444 versus 251 ng/mL, P = 0.017). However, there was a wide range of iATP concentrations in both nontransplant and LTX patient groups, and no clear iATP cut-off values for an increased risk of infection or rejection could be defined. Post LTX, stable-phase patients showed a significantly lower iATP compared with respective controls (median iATP 297 versus 384 ng/mL, P = 0.013). No significant correlation between calcineurin-inhibitor-trough concentrations and iATP was found. iATP was not correlated with age, but was inversely correlated with time after transplantation. CONCLUSIONS: The observed correlation between clinical events and iATP concentrations is similar to the findings previously reported in adult patients who underwent transplantation. The lack of correlation of iATP with trough drug concentrations suggests that the ImmuKnow assay provides independent information that may be useful to guide immunosuppressive therapy in pediatric (liver) transplant patients. However, the wide range of iATP levels in event-free patients suggests that serial iATP measurements will be necessary to assess and guide the individual immunosuppressive therapy. Further investigations are needed to evaluate and extend these findings. PMID- 22210097 TI - Therapeutic drug monitoring of voriconazole in children. AB - Voriconazole is an extended-spectrum triazole antifungal with activity against a wide variety of pathogens, including Aspergillus, Candida, Cryptococcus neoformans, Fusarium, and Scedosporium. It exerts its antifungal activity by blocking the synthesis of fungal cell membranes and is considered the first-line treatment for invasive aspergillosis. Because the pharmacokinetics of voriconazole can demonstrate considerable variability, it has been suggested that monitoring plasma levels of voriconazole may play an important role in optimizing the efficacy and safety of the drug in complex patients like those at risk of or who have invasive aspergillosis. In this article, we review the criteria for therapeutic drug monitoring and assess the evidence for using plasma voriconazole concentrations to individualize doses in children. PMID- 22210098 TI - A rapid HPLC-ESI-MS/MS method for determination of dihydrouracil/uracil ratio in plasma: evaluation of toxicity to 5-flurouracil in patients with gastrointestinal cancer. AB - BACKGROUND: A liquid chromatography-tandem mass spectrometry method for the simultaneous quantitation of endogenous uracil (U) and dihydrouracil (UH2) was developed and tested in a Brazilian population of patients with gastrointestinal cancer previously exposed to 5-fluorouracil (5FU). METHODS: The analytes were extracted by a liquid-liquid method using 5-clorouracil as internal standard. The separation was performed on a reversed-phase XTerra C18 column with a mobile phase composed of methanol and aqueous 0.1% ammonium hydroxide (15:85). Mass spectrometry detection was carried out using negative electrospray ionization and selected reaction monitoring. Bovine serum albumin was employed as an alternative matrix to prepare the calibration standards, aiming to avoid the measurement of physiologic U and UH2. Calibration curves were constructed over the range of 5 200 ng/mL for U and 10-500 ng/mL for UH2. RESULTS: The mean RSD values in the intrarun precision were 6.5% and 10.0% and in the interrun precision were 7.8% and 9.0% for U and UH2, respectively. The mean accuracy values were within the range of 90%-110% for both analytes. The analytes were stable in plasma under different conditions of temperature and time. The validated method was successfully applied to determine the plasma concentrations of U and UH2 in patients with gastrointestinal cancer (n = 32) previously treated with 5FU and for whom clinical toxicity was well documented. U concentrations varied from 21.8 to 56.6 ng/mL, whereas UH2 concentrations varied from 57.7 to 271.5 ng/mL. UH2/U ratio ranged from 1.56 to 6.18. CONCLUSIONS: The method has proved to provide a quick, reliable, and reproducible quantitation of the plasma concentrations of U and its metabolite UH2. The UH2/U ratios did not discriminate patients previously exposed to 5FU with and without severe toxicities, possibly due to the small sample. Further studies in a larger population are desirable. PMID- 22210099 TI - The concentration of cyclosporine metabolites is significantly lower in kidney transplant recipients with diabetes mellitus. AB - BACKGROUND: Diabetes mellitus is prevalent among kidney transplant recipients. The activity of drug metabolizing enzymes or transporters may be altered by diabetes leading to changes in the concentration of parent drug or metabolites. This study was aimed to characterize the effect of diabetes on the concentration of cyclosporine (CsA) and metabolites. METHODS: Concentration-time profiles of CsA and metabolites (AM1, AM9, AM4N, AM1c, AM19, and AM1c9) were characterized over a 12-hour dosing interval in 10 nondiabetic and 7 diabetic stable kidney transplant recipients. All patients were male, had nonfunctional CYP3A5*3 genotype, and were on combination therapy with ketoconazole. RESULTS: The average daily dose (+/-SD) of CsA was 65 +/- 21 and 68 +/- 35 mg in nondiabetic and diabetic subjects, respectively (P = 0.550). Cyclosporine metabolites that involved amino acid 1 (AM1, AM19, AM1c) exhibited significantly lower dose normalized values of area under the concentration-time curve in patients with diabetes. Moreover, during the postabsorption phase (>=3 hours after dose), metabolite-parent concentration ratios for all metabolites, except AM4N, was significantly lower in diabetic patients. The pharmacokinetic parameters of ketoconazole were similar between the 2 groups thus excluding inconsistent ketoconazole exposure as a source of altered CsA metabolism. CONCLUSIONS: This study indicates that diabetes mellitus significantly affects the concentration of CsA metabolites. Because CsA is eliminated as metabolites via the biliary route, the decrease in the blood concentration of CsA metabolites during postabsorption phase would probably reflect lower hepatic cytochrome P450 3A4 enzyme activity. However, other mechanisms including altered expression of transporters may also play a role. Results of cyclosporine therapeutic drug monitoring in diabetic patients must be interpreted with caution when nonspecific assays are used. PMID- 22210100 TI - High-performance liquid chromatography-tandem mass spectrometry method for simultaneous quantification of carbamazepine, oxcarbazepine, and their main metabolites in human serum. AB - BACKGROUND: Antiepileptic drug therapeutic regimens often need to be adjusted individually on the basis of serum assays. We aimed to develop a quantitative, fast, and sensitive liquid chromatography-tandem mass spectrometry method to simultaneously analyze carbamazepine, oxcarbazepine, and the 10-11 epoxide carbamazepine and 10-hydroxy carbazepine (mono-hydroxy derivative, 10,11-Dihydro 10-hydroxycarbamazepine) metabolites, in human serum. METHODS: Serum samples were deproteinized by acetonitrile spiked with dansyl-norvaline as internal standard. Compounds were separated on a reversed-phase high-performance liquid chromatography over a total run time of 10 minutes. Serum concentrations were then measured by means of a triple quadrupole tandem mass spectrometer, set up in positive mode and multiple reaction monitoring. RESULTS: Calibration curves (0.08 50 mcg/mL for carbamazepine and 10,11-dihydro-10-hydroxycarbamazepine; 0.03-20 mcg/mL for oxcarbazepine and epoxide carbamazepine) were linear, with a mean correlation coefficient >0.999. Both the intra- and interassay imprecision and inaccuracy were within 10%. The absolute recovery ranged from 98% to 103% for all analytes. CONCLUSIONS: The method requires minimal sample preparation. Volume of the sample is lower and run time shorter than required by previous published liquid chromatography-tandem mass spectrometry methods. Results are accurate. The method seems, therefore, to be reliable and economically suitable for routine analysis of antiepileptic drugs monitoring in clinical settings. PMID- 22210101 TI - In vivo inferiority of generic product compared with branded vancomycin: a paradigm shift. PMID- 22210102 TI - Metabolomic profiling of the flower bud and rachis of Tussilago farfara with antitussive and expectorant effects on mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Flower bud of Tussilago farfara L. is widely used for the treatment of cough, bronchitis and asthmatic disorders in the Traditional Chinese Medicine. However, due to the increasing demands, adulteration with rachis is frequently encountered in the marketplace. No report demonstrated the chemical and pharmacological differences between flower bud and rachis before. MATERIALS AND METHODS: The water extracts were orally administrated to mice. Ammonia induced mice coughing model was used to evaluate the antitussive activity. The expectorant activity was evaluated by volume of phenol red in mice's tracheas. Metabolites were identified directly from the crude extracts through 1D- and 2D-NMR spectra. A metabolic profiling carried out by (1)H NMR spectroscopy and multivariate data analysis was applied to crude extracts from flower bud and rachis. RESULTS: Flower bud significantly lengthened the latent period of cough, decreased cough frequency caused by ammonia and enhanced tracheal phenol red output in expectorant evaluation. Principal component analysis (PCA) yielded good separation between flower bud and rachis, and corresponding loading plot showed that the phenolic compounds, organic acid, sugar, amino acid, terpene and sterol contributed to the discrimination. CONCLUSIONS: These findings provide pharmacological and chemical evidence that only flower bud can be used as the antitussive and expectorant herbal drug. The high concentration of chlorogenic acid, 3,5-dicaffeoylquinic acid, rutin in flower buds may be related with the antitussive and expectorant effects of Flos Farfara. To guarantee the clinical effect, rachis should be picked out before use. PMID- 22210103 TI - Guidelines for randomised controlled trials investigating Chinese herbal medicine. AB - ETHNOGRAPHIC RELEVANCE: Clinical trials investigating Chinese herbal medicine (CHM) have been frequently criticised for their lack of scientific rigour. As part of the GP-TCM project a team of experienced clinical researchers and CHM practitioners have developed clinical trial guidelines for CHM that combine an appreciation for traditional methods of practice with detailed and practical advice on research methodology. MATERIALS AND METHODS: This paper presents an executive summary of this work. It introduces the practice of CHM and the key considerations that need to be addressed whilst researching this traditional medical system. RESULTS: These guidelines emphasise the importance of identifying best practice, and then developing and applying appropriate and rigorous research methodologies to investigate CHM as a whole system. CONCLUSIONS: It is hoped that this will encourage a thoughtful and meticulous process of investigation that will clarify the contribution that CHM can make to our future healthcare. Innovative new approaches are considered including the application of the new "omic" technologies and systems biology as a way of enhancing our understanding of traditional practice. PMID- 22210104 TI - Inhibitory effects of Scutellaria baicalensis extract on hepatic stellate cells through inducing G2/M cell cycle arrest and activating ERK-dependent apoptosis via Bax and caspase pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The bioactive components extracted from Scutellaria baicalensis Georgi (SB) have been widely used for anti-cancer, anti oxidation, anti-inflammation and modulating the immune response. AIM OF THE STUDY: The purpose of this study is to verify the inhibitory effect and the underlying mechanisms of Scutellaria baicalensis ethanol extract (SBEE) on activated hepatic stellate cells which play a central role in liver fibrogenesis. MATERIALS AND METHODS: Dimethylnitrosamine (DMN)-administrated rat model was applied to evaluate the anti-fibrotic effect of SBEE in vivo. Flow cytometric analysis and immunoblotting were then used to further investigate the molecular mechanisms by which Scutellaria baicalensis extract induces HSC-T6 cell death. RESULTS: Hepatic collagen contents and alpha-smooth muscle actin levels were remarkably reduced by treating with SBEE. 100 MUg/mL SBEE-induced apoptosis of HSC-T6 cell was characterized with elevated levels of activated caspase-3, poly (ADP-ribose) polymerase (PARP) cleavage, and release of cytochrome c into the cytosol in a time-dependent manner. A 24h treatment of SBEE induced G(2)/M cell cycle arrest with increased expression of p21 and downregulation of cdc2 and cyclin B1 protein levels. Again, SBEE induced bax expression with concomitant decrease of bcl-2 and upregulated the p53 and MAPK signaling in HSC-T6 cells. CONCLUSIONS: These findings demonstrated that SBEE could prevent hepatic fibrosis by promoting ERK-p53 pathways which may in turn cause G(2)/M cell cycle arrest and activate caspase system resulting in final apoptosis of HSC-T6 cells. PMID- 22210105 TI - Experimental evidence that changes in mood cause changes in body dissatisfaction among undergraduate women. AB - Previous research has found concurrent and prospective associations between negative mood and body dissatisfaction; however, only experimental research can establish causal relationships. This study utilized an experimental design to examine the influence of negative mood on body dissatisfaction. Undergraduate women were randomly assigned to an experimental or control condition. Participants in the experimental condition (n=21) completed a negative mood induction procedure. Participants in the control condition (n=24) completed a neutral mood procedure. All participants completed visual analog scales regarding their mood and satisfaction with weight and shape before and after each manipulation. Body dissatisfaction increased following the procedure for experimental but not control participants, suggesting that negative mood caused increased body dissatisfaction. In cultures that idealize thinness, body dissatisfaction may arise from funneling general feelings of dysphoria into more concrete and culturally meaningful negative feelings about the body. PMID- 22210106 TI - Perceived value of ward-based pharmacists from the perspective of physicians and nurses. AB - BACKGROUND: Clinical pharmacy in a hospital setting is relatively new in Sweden. Its recent introduction at the University Hospital in Uppsala has provided an opportunity for evaluation by other relevant professionals of the integration of clinical pharmacists into the health-care team. OBJECTIVES: The objectives of this descriptive study were to evaluate the perceived value of wardbased clinical pharmacists from the perspective of hospital based physicians and nurses and to identify potential advantages and disadvantages related to the new inter professional collaboration. Another objective was to evaluate the experiences of general practitioners on receiving medication reports from ward-based clinical pharmacists. SETTING: Two acute internal medicine wards at the University Hospital in Uppsala, where a previously reported randomized controlled trial investigating the effects of ward based clinical pharmacists on re-visits to hospital was undertaken. METHODS: Data were collected by questionnaires containing closed- and open-ended questions. The questionnaires were distributed during the nine-month study period of the randomized controlled trial by an independent researcher to 29 hospital-based physicians and 44 nurses on the study wards and to 21 general practitioners who had received two or more medication reports. Answers were analysed descriptively for the closed-ended questions and by content analysis for the open-ended questions. MAIN OUTCOME MEASURE: The main outcome measure was the physicians' and nurses' level of satisfaction with the new collaboration with clinical pharmacists, from a hospital and primary care perspective. RESULTS: Seventy-six percent of the hospital-based physicians and 81% of the nurses completed the questionnaire. Ninety-five percent of the physicians and 93% of the nurses were very satisfied with the collaboration. Out of the 17 general practitioners (81%) that completed the questionnaire 71% wanted to continue to receive medication reports in a similar way in the future. Increased patient safety and improvements in patients' drug therapy were the main advantages stated by all three groups of respondents. Eighteen percent of the hospital-based physicians and 21% of the nurses thought that the collaboration had been time-consuming to certain or to a high extent. CONCLUSIONS: The majority of the respondents, both GPs and hospital based physicians and nurses, were satisfied with the new collaboration with the ward based pharmacists and perceived that the quality of the patients' drug therapy and drug-related patient safety had increased. PMID- 22210108 TI - CD146, an epithelial-mesenchymal transition inducer, is associated with triple negative breast cancer. AB - The epithelial-mesenchymal transition (EMT) plays an important role in breast cancer metastasis, especially in the most aggressive and lethal subtype, "triple negative breast cancer" (TNBC). Here, we report that CD146 is a unique activator of EMTs and significantly correlates with TNBC. In epithelial breast cancer cells, overexpression of CD146 down-regulated epithelial markers and up-regulated mesenchymal markers, significantly promoted cell migration and invasion, and induced cancer stem cell-like properties. We further found that RhoA pathways positively regulated CD146-induced EMTs via the key EMT transcriptional factor Slug. An orthotopic breast tumor model demonstrated that CD146-overexpressing breast tumors showed a poorly differentiated phenotype and displayed increased tumor invasion and metastasis. We confirmed these findings by conducting an immunohistochemical analysis of 505 human primary breast tumor tissues and found that CD146 expression was significantly associated with high tumor stage, poor prognosis, and TNBC. CD146 was expressed at abnormally high levels (68.9%), and was strongly associated with E-cadherin down-regulation in TNBC samples. Taken together, these findings provide unique evidence that CD146 promotes breast cancer progression by induction of EMTs via the activation of RhoA and up regulation of Slug. Thus, CD146 could be a therapeutic target for breast cancer, especially for TNBC. PMID- 22210110 TI - Micro-chemical synthesis of molecular probes on an electronic microfluidic device. AB - We have developed an all-electronic digital microfluidic device for microscale chemical synthesis in organic solvents, operated by electrowetting-on-dielectric (EWOD). As an example of the principles, we demonstrate the multistep synthesis of [(18)F]FDG, the most common radiotracer for positron emission tomography (PET), with high and reliable radio-fluorination efficiency of [(18)F]FTAG (88 +/ 7%, n = 11) and quantitative hydrolysis to [(18)F]FDG (> 95%, n = 11). We furthermore show that batches of purified [(18)F]FDG can successfully be used for PET imaging in mice and that they pass typical quality control requirements for human use (including radiochemical purity, residual solvents, Kryptofix, chemical purity, and pH). We report statistical repeatability of the radiosynthesis rather than best-case results, demonstrating the robustness of the EWOD microfluidic platform. Exhibiting high compatibility with organic solvents and the ability to carry out sophisticated actuation and sensing of reaction droplets, EWOD is a unique platform for performing diverse microscale chemical syntheses in small volumes, including multistep processes with intermediate solvent-exchange steps. PMID- 22210112 TI - Optimal 3D single-molecule localization for superresolution microscopy with aberrations and engineered point spread functions. AB - Photo-activation localization microscopy is a far-field superresolution imaging technique based on the localization of single molecules with subdiffraction limit precision. Known under acronyms such as PALM (photo-activated localization microscopy) or STORM (stochastic optical reconstruction microscopy), these techniques achieve superresolution by allowing only a sparse, random set of molecules to emit light at any given time and subsequently localizing each molecule with great precision. Recently, such techniques have been extended to three dimensions, opening up unprecedented possibilities to explore the structure and function of cells. Interestingly, proper engineering of the three-dimensional (3D) point spread function (PSF) through additional optics has been demonstrated to theoretically improve 3D position estimation and ultimately resolution. In this paper, an optimal 3D single-molecule localization estimator is presented in a general framework for noisy, aberrated and/or engineered PSF imaging. To find the position of each molecule, a phase-retrieval enabled maximum-likelihood estimator is implemented. This estimator is shown to be efficient, meaning it reaches the fundamental Cramer-Rao lower bound of x, y, and z localization precision. Experimental application of the phase-retrieval enabled maximum likelihood estimator using a particular engineered PSF microscope demonstrates unmatched low-photon-count 3D wide-field single-molecule localization performance. PMID- 22210111 TI - Affinity of talin-1 for the beta3-integrin cytosolic domain is modulated by its phospholipid bilayer environment. AB - Binding of the talin-1 FERM (4.1/ezrin/radixin/moesin) domain to the beta3 cytosolic tail causes activation of the integrin alphaIIbbeta3. The FERM domain also binds to acidic phospholipids. Although much is known about the interaction of talin-1 with integrins and lipids, the relative contribution of each interaction to integrin regulation and possible synergy between them remain to be clarified. Here, we examined the thermodynamic interplay between FERM domain binding to phospholipid bilayers and to its binding sites in the beta3 tail. We found that although both the F0F1 and F2F3 subdomains of the talin-1 FERM domain bind acidic bilayers, the full-length FERM domain binds with an affinity similar to F2F3, indicating that F0F1 contributes little to the overall interaction. When free in solution, the beta3 tail has weak affinity for the FERM domain. However, appending the tail to acidic phospholipids increased its affinity for the FERM domain by three orders of magnitude. Nonetheless, the affinity of the FERM for the appended tail was similar to its affinity for binding to bilayers alone. Thus, talin-1 binding to the beta3 tail is a ternary interaction dominated by a favorable surface interaction with phospholipid bilayers and set by lipid composition. Nonetheless, interactions between the FERM domain, the beta3 tail, and lipid bilayers are not optimized for a high-affinity synergistic interaction, even at the membrane surface. Instead, the interactions appear to be tuned in such a way that the equilibrium between inactive and active integrin conformations can be readily regulated. PMID- 22210114 TI - Human-mouse cystic fibrosis transmembrane conductance regulator (CFTR) chimeras identify regions that partially rescue CFTR-DeltaF508 processing and alter its gating defect. AB - The DeltaF508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is the most common cause of cystic fibrosis. The mutation disrupts biosynthetic processing, reduces channel opening rate, and decreases protein lifetime. In contrast to human CFTR (hCFTR)-DeltaF508, mouse CFTR-DeltaF508 is partially processed to the cell surface, although it exhibits a functional defect similar to hCFTR-DeltaF508. To explore DeltaF508 abnormalities, we generated human-mouse chimeric channels. Substituting mouse nucleotide-binding domain-1 (mNBD1) into hCFTR partially rescued the DeltaF508-induced maturation defect, and substituting mouse membrane-spanning domain-2 or its intracellular loops (ICLs) into hCFTR prevented further DeltaF508-induced gating defects. The protective effect of the mouse ICLs was reverted by inserting mouse NBDs. Our results indicate that the DeltaF508 mutation affects maturation and gating via distinct regions of the protein; maturation of CFTR-DeltaF508 depends on NBD1, and the DeltaF508-induced gating defect depends on the interaction between the membrane spanning domain-2 ICLs and the NBDs. These appear to be distinct processes, because none of the chimeras repaired both defects. This distinction was exemplified by the I539T mutation, which improved CFTR-DeltaF508 processing but worsened the gating defect. Our results, together with previous studies, suggest that many different NBD1 modifications improve CFTR-DeltaF508 maturation and that the effect of modifications can be additive. Thus, it might be possible to enhance processing by targeting several different regions of the domain or by targeting a network of CFTR-associated proteins. Because no one modification corrected both maturation and gating, perhaps more than a single agent will be required to correct all CFTR-DeltaF508 defects. PMID- 22210116 TI - Double-strand break motions shift radiation risk notions? PMID- 22210117 TI - Influence of varying focus of attention conditions on dart throwing performance in experts and novices. AB - Research suggests an external focus of attention positively affects motor learning more than an internal focus; however, little research has considered this relationship in motor control situations. The present study examined the role of varying focus of attention conditions on dart throwing performance. Experts (n = 6) and novices (n = 6) performed 84 throws under two internal and one external conditions and in the presence and absence of knowledge of results (KR). Results indicated clear differences between experts and novices on both performance and motor control outcomes. Further, there was some evidence that movement execution was slowed in experts but not in novices, although results were somewhat inconclusive. Our analyses suggest that varying focus of attention affects temporal parameters of movement execution in experts but not spatial parameters. Interestingly, both experts and novices generally perceived all instruction conditions to be hindrances to performance, with the exception of the external focus with KR condition. Further work is necessary to determine the extent to which these results apply to other open and closed skills. PMID- 22210118 TI - Postural activity and motion sickness during video game play in children and adults. AB - Research has confirmed that console video games give rise to motion sickness in many adults. During exposure to console video games, there are differences in postural activity (movement of the head and torso) between participants who later experience motion sickness and those who do not, confirming a prediction of the postural instability theory of motion sickness. Previous research has not addressed relations between video games, movement and motion sickness in children. We evaluated the nauseogenic properties of a commercially available console video game in both adults and 10-year-old children. Individuals played the game for up to 50 min and were instructed to discontinue immediately if they experienced any symptoms of motion sickness, however mild. During game play, we monitored movement of the head and torso. Motion sickness was reported by 67% of adults and by 56% of children; these rates did not differ. As a group, children moved more than adults. Across age groups, the positional variability of the head and torso increased over time during game play. In addition, we found differences in movement between participants who later reported motion sickness and those who did not. Some of these differences were general across age groups but we also found significant differences between the movement of adults and children who later reported motion sickness. The results confirm that console video games can induce motion sickness in children and demonstrate that changes in postural activity precede the onset of subjective symptoms of motion sickness in children. PMID- 22210119 TI - Applications of saturation transfer difference NMR in biological systems. AB - The method of saturation transfer difference (STD) nuclear magnetic resonance (NMR) is an indispensable NMR tool in drug discovery. It identifies binding epitope(s) at the atomic resolution of small molecule ligands (e.g. organic drugs, peptides and oligosaccharides), while interacting with their receptors, such as proteins and/or nucleic acids. The method is widely used to screen active drug molecules, simultaneously ranking them in a qualitative way. STD NMR is highly successful for a variety of high molecular weight systems, such as whole viruses, platelets, intact cells, lipopolysaccharide micelles, membrane proteins, recombinant proteins and dispersion pigments. Modifications of STD pulse programs using (13)C and (15)N nuclei are now used to overcome the signal overlapping that occurs with more complex structures. PMID- 22210120 TI - The routes to orphan drug designation--our recent experience at the FDA. PMID- 22210121 TI - Compilation of 222 drugs' plasma protein binding data and guidance for study designs. AB - The binding of a drug to plasma protein reduces free drug in the blood circulation that would otherwise be available for penetration into tissues to reach the therapeutic target or the kidney for elimination. Therefore, the binding event affects drug elimination from the body, efficacy, duration of action and toxicity. Co-administration of other drugs, food and pathological conditions of patients can significantly change percentage binding of the drug and result in serious consequences. Here, we present the largest and newest information on plasma protein binding for 222 drugs, of which 50% show 90-100% binding, a range that could be considered as a favorable element for future lead selection. We also provide critical and comprehensive evaluations on the methods and techniques established to determine plasma protein binding, pinpoint advantages and pitfalls of individual approaches, and offer detailed guidance for experimental designs, including ultrafiltration, equilibrium dialysis, ultracentrifugation, charcoal adsorption, high-performance affinity chromatography, high-performance frontal analysis, solid-phase microextraction and in vivo microdialysis. PMID- 22210122 TI - Chemesthesis and the chemical senses as components of a "chemofensor complex". AB - An important function of the chemical senses is to warn against dangerous biological and chemical agents in the environment. The discovery in recent years of "taste" receptor cells outside the oral cavity that appear to have protective functions has raised new questions about the nature and scope of the chemical senses in general and of chemesthesis in particular. The present paper briefly reviews these findings within the context of what is currently known about the body's chemically sensitive protective mechanisms, including nonsensory processes that help to expel or neutralize threatening agents once they have been encountered. It is proposed that this array of defense mechanisms constitutes a "chemofensor complex" in which chemesthesis is the most ubiquitous, functionally diverse, and interactive chemosensory component. PMID- 22210124 TI - Trait anxiety and involuntary processing of facial emotions. AB - There is suggestion that trait anxiety influences the processing of threat related information. To test this hypothesis we recorded ERPs in response to subliminally presented and backward masked fearful and neutral faces, and non face objects, in the preselected low- and high-anxious individuals. The amplitude of N170 was found to be larger when elicited by faces in comparison to non-faces, however it was not found to be emotion-sensitive or modulated by anxiety level. Differences between low- and high-anxious individuals appeared in a time window of the P1 component. At later stages, within the EPN component, stronger negativity specific for fearful faces was recorded exclusively in the low-anxious participants. Our findings indicate that anxiety level modulates early stages of information processing, as reflected in the P1 component. This leads to anxiety related differences in involuntary emotional expression detection at later stages (EPN component). PMID- 22210123 TI - Evaluation of the urban/rural particle-bound PAH and PCB levels in the northern Spain (Cantabria region). AB - The aim of the present study was to evaluate the polycyclic aromatic hydrocarbon (PAH) and polychlorinated biphenyl (PCB) levels in PM(10) and PM(2.5), at one rural and three urban sites in the Cantabria region (northern Spain). From all of these pollutants, benzo(a)pyrene is regulated by the EU air quality directives; its target value (1 ng/m(3)) was not exceeded. The concentration values of the studied organic pollutants at the studied sites are in the range of those obtained at other European sites. A comparison between the rural-urban stations was developed: (a) PAH concentration values were lower in the rural site (except for fluorene). Therefore, the contribution of local sources to the urban levels of PAHs seems relevant. Results from the coefficient of divergence show that the urban PAH levels are influenced by different local emission sources. (b) PCB rural concentration values were higher than those found at urban sites. Because no local sources of PCBs were identified in the rural site, the contribution of more distant emission sources (about 40 km) to the PCB levels is considered to be the most important; the long-range transport of PCBs does not seem to be significant. Additionally, local PAH tracers were identified by a triangular diagram: higher molecular weight PAHs in Reinosa, naphthalene in Santander and anthracene/pyrene in Castro Urdiales. A preliminary PAH source apportionment study in the urban sites was conducted by means of diagnostic ratios. The ratios are similar to those reported in areas affected by traffic emissions; they also suggest an industrial emission source at Reinosa. PMID- 22210125 TI - A single nucleotide polymorphism of the adenosine deaminase, RNA-specific gene is associated with the serum triglyceride level, abdominal circumference, and serum adiponectin concentration. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) of the adenosine deaminase, RNA-specific (ADAR) gene were reported to be associated with human longevity. There are possibilities that ADAR is associated with major risk factors of atherosclerotic cardiovascular diseases (CVD), such as hypertension, diabetes, dyslipidemia, and obesity. OBJECTIVE: To investigate the association between SNPs of the ADAR gene and clinical data associated with major risk factors of atherosclerotic CVD. SUBJECTS: A total of 1504 general population residents (586 males and 918 females) of two towns, Tanno-cho and Sobestu-cho, in Hokkaido, Japan. METHODS: Clinical data associated with risk factors of atherosclerotic CVD were collected from these study subjects. DNA from peripheral blood and written informed consent were obtained. Three single nucleotide polymorphisms of ADARB1 and ADARB2, which were previously reported to be associated with longevity, were genotyped employing the TaqMan PCR method. The associations between SNPs in ADARB1 and ADARB2 and clinical parameters related to risk factors of atherosclerosis were analyzed. RESULTS: On uni- and multivariate analyses, rs2805533 in ADARB2 was significantly associated with the abdominal circumference, body mass index, serum triglyceride level, and serum adiponectin level. The subjects with the AA genotype of rs2805533 had a greater abdominal circumference, higher body mass index, higher triglyceride level, and lower adiponectin level than those with AG and GG genotypes. CONCLUSION: The SNP in ADARB2 related to longevity is associated with metabolic disorders. This finding suggests that genetic factors modulate human longevity via the regulation of metabolic factors such as abdominal obesity and lipid profiles. PMID- 22210126 TI - Protein markers and differentiation in culture for Schlemm's canal endothelial cells. AB - The two cell types that populate the human conventional outflow pathway, Schlemm's canal (SC) and trabecular meshwork (TM) regulate intraocular pressure. In culture, SC and TM cells have been useful tools toward understanding their respective roles in conventional outflow homeostasis. Unfortunately, currently available protein markers that distinguish SC from TM cells are limited, motivating the present study. Antibodies that specifically recognize different vascular endothelial markers were used to probe lysates from mature cell monolayers subjected to SDS-PAGE followed by western blot analyses. Results show that SC and TM cells both expressed many of the endothelial candidate proteins investigated, such as Robo1/4, Tie2/TEK, VEGF-R1/R2, VCAM-1, eNOS and neuropilin 1. In contrast, all SC cell strains tested (n=11) expressed two proteins, fibulin 2 and vascular endothelial (VE) cadherin, not expressed by TM cells. To examine changes in VE-cadherin expression and cell-cell junction formation, indicated by transendothelial electrical resistance (TEER), SC cells were seeded onto filters at confluence and growth factors were withdrawn. Culturing cells in media containing adult bovine serum rather than fetal bovine serum resulted in a 75% mean increase in TEER and 67% corresponding average increase in VE-cadherin expression (p<0.05). While both TM and SC cells form monolayers, are contact inhibited, share some endothelial responsibilities and several endothelial protein markers, SC cells uniquely express at least two proteins which likely reflect a distinction in cellular responsibilities in vivo. One of these responsibilities, maintenance of the blood-aqueous barrier, can be modeled in culture upon withdrawal of growth factors from SC cell monolayers. PMID- 22210128 TI - Avascular necrosis of the femoral head in multiple sclerosis: report of five patients. AB - Osteonecrosis of the femoral head is a severe complication of corticosteroids, which may lead to more disability in multiple sclerosis (MS) patients because of delayed diagnosis. The exact dose and risk period of steroids which cause the necrosis are not clearly known. The aim of the study was to enhance the attention of clinicians to leg pain in MS patients with regard to steroid therapies. We report five MS patients with femoral head necrosis who had relapsing remitting MS and received different doses of methyl prednisolone. Our young cases consist of three females and two males. The duration of disease varied between 1 and 3 years. The least interval between the last pulse of prednisolone and diagnosis of avascular necrosis was 6 months. Two of them received one pulse of 5 g of methyl prednisolone. All five patients had delayed diagnosis because the signs and symptoms were attributed to MS, which indicate the necessity of further focusing attention to early evaluations. PMID- 22210127 TI - Semi-automated, quantitative analysis of retinal ganglion cell morphology in mice selectively expressing yellow fluorescent protein. AB - The development of transgenic mouse lines that selectively label a subset of neurons provides unique opportunities to study detailed neuronal morphology and morphological changes under experimental conditions. In the present study, a mouse line in which a small number of retinal ganglion cells (RGCs) express yellow fluorescent protein (YFP) under control of the Thy-1 promoter was used (Feng et al., 2000). We characterized the number, distribution by retinal region and eccentricity of YFP-labeled RGCs using fluorescence microscopy and Stereo Investigator software (MicroBrightField, VT, USA). Then, we captured images of 4 6 YFP-expressing RGCs from each of 8 retinal regions by confocal microscopy, producing 3-dimensional and flattened data sets. A new semi-automated method to quantify the soma size, dendritic length and dendritic arbor complexity was developed using MetaMorph software (Molecular Devices, PA, USA). Our results show that YFP is expressed in 0.2% of all RGCs. Expression of YFP was not significantly different in central versus peripheral retina, but there were higher number of YFP-expressing RGCs in the temporal quadrant than in the nasal. By confocal-based analysis, 58% of RGCs expressing YFP did so at a high level, with the remainder distributed in decreasing levels of brightness. Variability in detailed morphometric parameters was as great between two fellow retinas as in retinas from different mice. The analytic methods developed for this selective YFP-expressing RGC model permit quantitative comparisons of parameters relevant to neuronal injury. PMID- 22210129 TI - Neuromyelitis optica: atipic clinic presentation. AB - We present a patient with neuromyelitis optica who exhibited longitudinally extensive transverse myelitis and aquaporin-4 IgG positivity. Patient did not have optic neuritis clinically, but we detected it with examination of visual evoked potentials (prolonged P100 wave latans), subclinically. We argue that neuromyelitis optica may also be considered in elderly patients with isolated involvement of the longitudinally extensive transverse myelitis, and visually evoked potential evaluation is important to determine of subclinic optic neuritis and anti-AQP-4 is also important to support to determination. PMID- 22210130 TI - Cardioembolic stroke due to isolated left ventricular non-compaction. PMID- 22210131 TI - Intravenous thrombolysis for ischaemic stroke in Down syndrome. PMID- 22210132 TI - Identification of a point mutation associated with pyrethroid resistance in the para-type sodium channel of Triatoma infestans, a vector of Chagas' disease. AB - The voltage-gated sodium channel is the target site of pyrethroid insecticides. Point mutations in the domain II region of the channel have been implicated in pyrethroid resistance of several insect species. We identified the sequence of domain II from the para sodium channel in Rhodnius prolixus, a vector of Chagas' disease. With this information, we cloned and sequenced the domain II of the sodium channel from the other main Chagas' disease vector: Triatoma infestans. We also identified the presence of a resistance-conferring mutation (L1014F) in a pyrethroid-resistant population of T. infestans from Argentina, and present a PCR based method to detect this mutation in individuals from field populations. These findings have important implications for the implementation of strategies for resistance management, and for the rational design of campaigns for the control of Chagas' disease transmission. PMID- 22210133 TI - Spatial and temporal reconstruction of bovine viral diarrhea virus genotype 1 dispersion in Italy. AB - Bovine viral diarrhea virus (BVDV) is a widespread and economically important pathogen of cattle; genetic typing of BVDV isolates distinguished two species, namely BVDV-1 and BVDV-2. BVDV-1 is the most widespread worldwide and it includes at least 11 subtypes. With the aim of clarifying the routes of circulation of BVDV-1 subtypes in an endemic area and in order to investigate the relationships between the genetic diversity of BVDV and its geographic distribution, a phylogenetic analysis of 5' untranslated region of Italian sequences was performed using a new Bayesian framework allowing the spatial-temporal reconstruction of the evolutionary dynamics of highly variable viruses. Our analyses suggested that different BVDV subtypes entered the North-Eastern part of Italy at different times within a time span between 23 and 7 years ago. The largest virus dispersion occurred between the mid 1990s and the early 2000s. A possible gravity-like dynamic of the infection, originating in larger animal population then following patterns of national commercial-flow, should be hypothesized. PMID- 22210135 TI - Role of CNS efflux drug transporters in antiepileptic drug delivery: overcoming CNS efflux drug transport. AB - Experimental support for the transporter hypothesis of drug resistance in epilepsies has triggered efforts developing and validating approaches to overcome enhanced blood-brain barrier efflux transport. Testing in rodent models has rendered proof-of-concept for an add-on therapy with antiepileptic drugs. However, further development of the approach would require tolerability considerations as efflux transporters serve an important protective function throughout the body limiting distribution of harmful xenobiotics. Relevant progress has been made in the elucidation of mechanisms driving up-regulation of the multidrug transporter P-glycoprotein in response to seizure activity. Based on this knowledge, novel strategies have been evaluated targeting the signaling cascade that regulates P-glycoprotein in the epileptic brain. Further concepts might include by-passing blood-brain barrier transporters by intracerebral administration or by encapsulation of antiepileptic drugs in nano-sized carrier systems. It is important to note that the future perspectives of respective approaches are still questionable based on the limited evidence for a clinical relevance of transporter expression. Thus, techniques are urgently needed for non invasive assessment of blood-brain barrier transporter function. Respective techniques would allow testing for a clinical correlation between pharmacosensitivity and transporter function, validating therapeutic strategies targeting efflux transporters and selecting patients with transporter over expression for respective clinical trials. Provided that further clinical data render support for the transporter hypothesis, the main question remains whether patients exist in which transporter over-expression is the predominant mechanism of drug resistance and in which overcoming drug efflux is equivalent with overcoming drug resistance. Imaging techniques might provide a tool to address these questions in clinical epileptology. However, the complex pharmacological interactions between antiepileptic drugs, radiotracers, and transporter modulators used in these approaches as well as interindividual differences in the brain pathology might hamper clear-cut conclusions and limit the diagnostic significance. PMID- 22210136 TI - Calorimetry and complementary techniques to characterize frozen and freeze-dried systems. AB - Lyophilization is a commonly used drying technique for thermolabile pharmaceuticals. Crystallization of formulation components may occur during various stages of the freeze-drying process. In frozen solutions, while crystallization of bulking agents is desirable, both from processing and product elegance perspectives, buffer salt crystallization can cause a significant pH shift. Lyoprotectants (compounds that protect macromolecules, both during freeze drying and subsequent storage) are effective only when retained amorphous. This review presents numerous applications of differential scanning calorimetry to characterize pharmaceutical systems in frozen state. These studies are aimed at defining the processing parameters and optimizing the freeze-drying cycle. Low temperature pH measurement and sub-ambient X-ray diffractometry served as excellent complementary tools in the characterization of frozen systems. The phase behavior of the systems during annealing (of frozen solutions), primary and secondary drying were monitored by X-ray diffractometry. Finally, the interplay of formulation composition and processing parameters on the development and optimization of freeze-drying cycles are reviewed. PMID- 22210134 TI - Polymeric nanoparticles for drug delivery to the central nervous system. AB - The central nervous system (CNS) poses a unique challenge for drug delivery. The blood-brain barrier significantly hinders the passage of systemically delivered therapeutics and the brain extracellular matrix limits the distribution and longevity of locally delivered agents. Polymeric nanoparticles represent a promising solution to these problems. Over the past 40years, substantial research efforts have demonstrated that polymeric nanoparticles can be engineered for effective systemic and local delivery of therapeutics to the CNS. Moreover, many of the polymers used in nanoparticle fabrication are both biodegradable and biocompatible, thereby increasing the clinical utility of this strategy. Here, we review the major advances in the development of polymeric nanoparticles for drug delivery to the CNS. PMID- 22210137 TI - Homologous whole bacterin vaccination is not able to reduce Streptococcus suis serotype 9 strain 7997 transmission among pigs or colonization. AB - Streptococcus suis (S. suis) is an important porcine pathogen worldwide, and antibiotics are often applied to treat or prevent clinical signs. Vaccination could be an alternative measure to reduce the abundant use of antimicrobials. The aim of this study was to determine the effect of vaccination with homologues whole bacterin vaccine containing S. suis serotype 9 strain 7997 on transmission of this serotype among pigs and on mucosal colonization. Caesarean derived, colostrum deprived pigs (N=50) were housed pair wise. Thirteen pairs were vaccinated intramuscularly with 2-3*10(9) colony forming units (CFU) inactivated S. suis serotype 9 per dose and alpha-tocopherolactetaat as adjuvant at 3 and 5 weeks of age; twelve pairs served as non-vaccinated controls. At 7 weeks of age, one pig of each pair was intranasally inoculated with 1-2*10(9)CFU of the homologues strain, whereas the other pig of each pair was contact-exposed. Tonsil brushings and saliva swabs were collected for 4 weeks, and tested for the presence of S. suis by bacteriological culture. No differences in number of S. suis in the tonsils or saliva samples or in clinical signs were observed between vaccinated and control pigs. In all pairs, transmission between inoculated and contact exposed pigs occurred, and no difference was observed in rate at which this occurred. The estimated transmission rate parameter beta between vaccinated pigs was beta(v)=5.27/day, and for non-vaccinated pigs beta(nv)=2.77/day (P=0.18). It was concluded that vaccination against S. suis serotype 9 did not reduce transmission, nor colonization and that there were no indications that protection against clinical signs was induced. PMID- 22210138 TI - Development of a DNA vaccine targeting Merkel cell polyomavirus. AB - Merkel cell carcinoma (MCC) is a rare but devastating skin disease that is increasing in incidence within the United States. The poor prognosis of MCC patients and limited understanding of MCC pathogenesis warrants innovative treatments to control MCC. Several lines of evidence have pointed to Merkel cell polyomavirus (MCPyV) as the etiological agent of MCC. In particular, the amino terminus of MCPyV large T antigen (LT) (aa1-258) is expressed in all MCPyV positive tumors and plays an important role in MCC oncogenesis, rendering it an ideal therapeutic target for vaccination. In the current study, we developed a DNA vaccine encoding MCPyV LT aa1-258 (pcDNA3-LT). Within our pcDNA3-LT DNA vaccine, we identified that MCPyV LT aa136-160 likely contains an LT-specific CD4+ T helper epitope. We have also created an LT-expressing B16/LT tumor model using B16, a murine melanoma cell line, to characterize the potency of our DNA vaccine. Using this tumorigenic B16/LT tumor model, we found that pcDNA3-LT DNA vaccine generates antitumor effects mainly mediated by CD4+ T cells against B16/LT tumors in vaccinated C57BL/6 mice. Thus, immunotherapy using pcDNA3-LT DNA vaccine may represent a promising approach for the control of MCPyV-associated lesions. The B16/LT tumor model further serves as a useful model for testing various vaccine strategies against MCC. PMID- 22210139 TI - Efficacy of trivalent inactivated influenza vaccines in the cotton rat Sigmodon hispidus model. AB - Annually adjusted inactivated influenza vaccines can prevent infection and limit the spread of seasonal influenza when vaccine strain closely matches circulating strain. For the years when the match is difficult to achieve, a rapid screening of a larger repertoire of vaccines may be required but is difficult to accomplish due to the lack of a convenient small animal model of seasonal influenza vaccines. The goal of this work was to determine whether the cotton rat Sigmodon hispidus, a small laboratory animal susceptible to infection with unadapted influenza viruses, may become such a model. Cotton rats were immunized with a trivalent inactivated vaccine (TIV) FluLaval (2006/2007) and vaccine immunogenicity and antiviral efficacy was evaluated against the homologous H1N1 and a heterologous H3N2 challenge. FluLaval induced a strong virus-specific IgG and neutralizing antibody response against homologous virus, elicited sterilizing immunity in the lungs and significantly reduced viral replication in the nose of infected animals. FluLaval was efficacious in cotton rats as either a single-time or a double immunization, although higher level of protection of the upper respiratory tract was achieved following two doses of vaccine. Antibodies against a heterologous influenza strain were induced in FluLaval-vaccinated animals, but vaccine lacked antiviral efficacy and did not reduce replication of a heterologous virus. Similarity of these findings to human TIV data suggests that the cotton rat may prove to be a reliable small animal model of human influenza vaccines. PMID- 22210140 TI - Prevention of perinatal hepatitis B virus transmission in the Netherlands, 2003 2007: children of Chinese mothers are at increased risk of breakthrough infection. AB - BACKGROUND: In the Netherlands, different hepatitis B vaccination schedules have been used for children born to HBV-infected mothers. All schedules included a birth dose of hepatitis B immunoglobuline (HBIg). We assessed determinants of perinatal HBV transmission and determinants of anti-HBs titers in infants born to HBsAg positive mothers. METHODS: We included infants born to HBV infected mothers between 1.1.2003 and 30.6.2007, using national databases and a separate database for Amsterdam. Risk factors for perinatal transmission and determinants of the anti-HBs titer were studied using logistic and linear regression, respectively. RESULTS: Of 2657 infants registered in the national database, 91% were registered to have received HBIg and at least three hepatitis B vaccinations. In Amsterdam, this coverage among 413 children at risk was higher (96%, p<0.01). Serological test results for 2121 infants (80%) indicated that 13 (0.6%) were HBsAg positive. A mother of Chinese descent was the only risk factor for perinatal HBV infection identified (RR 9.1, 95% CI 3.1-26.8). Receiving a birth dose of hepatitis B vaccine later than in the first week of life was not associated with an increased risk of perinatal HBV infection. A shorter period between last vaccination and testing, and having received more doses of hepatitis B vaccine were independently associated with a higher anti-HBs titer. CONCLUSIONS: Infants born to Chinese mothers were at increased risk of perinatal HBV infection. All HBsAg positive pregnant women of Chinese origin should be assessed to determine whether there is an indication for anti-viral treatment during pregnancy. Among infants who received HBIg at birth, we did not detect an increased risk of perinatal HBV infection when the first dose of hepatitis B vaccine was administered after the first week of life. PMID- 22210141 TI - Immunization with the RrgB321 fusion protein protects mice against both high and low pilus-expressing Streptococcus pneumoniae populations. AB - RrgB321, a fusion protein of the three Streptococcus pneumoniae pilus-1 backbone RrgB variants, is protective in vivo against pilus islet 1 (PI-1) positive pneumococci. In addition, antibodies to RrgB321 mediate a complement-dependent opsonophagocytosis of PI-1 positive strains at levels comparable to those obtained with antisera against glycoconjugate vaccines. In the pneumococcus, pilus-1 displays a biphasic expression pattern, with different proportions of two bacterial phenotypes, one expressing and one not expressing the pilus-1. These two populations can be stably separated in vitro giving rise to the enriched high (H) and low (L) pilus expressing populations. In this work we demonstrate that: (i) the opsonophagocytic killing mediated in vitro by RrgB321 antisera is strictly dependent on the pilus expression ratio of the strain used; (ii) during the opsonophagocytosis assay pilus-expressing pneumococci are selectively killed, and (iii) no switch towards the pilus non-expressing phenotype can be observed. Furthermore, in sepsis and pneumonia models, mice immunized with RrgB321 are significantly protected against challenge with either the H or the L pilus expressing population of strains representative of the three RrgB variants. This suggests that the pilus-1 expression is not down-regulated, and also that the expression of the pilus-1 could be up-regulated in vivo. In conclusion, these data provide evidence that RrgB321 is protective against PI-1 positive strains regardless of their pilus expression level, and support the rationale for the inclusion of this fusion protein into a multi-component protein-based pneumococcal vaccine. PMID- 22210142 TI - Premature atherosclerotic cardiovascular disease in systemic lupus erythematosus: understanding management strategies. AB - Systemic lupus erythematosus (SLE) is associated with increased risk of cardiovascular disease because of the premature development of atherosclerotic plaques. It is a complex autoimmune disorder characterized by the production of autoantibodies against self-antigens. These self-antigens include nucleic acids, blood cells, coagulation proteins, and phospholipids that cause disease manifestations in virtually every organ system. Over the last 3 decades, treatment modalities and preventive therapies for SLE patients have substantially improved, producing decreases in mortality from the disease. However, as life expectancy among SLE patients has increased, the incidence of cardiovascular disease has increased as well. Multiple studies suggest that patients with SLE have between a 9-fold and 50-fold increase in risk of developing cardiovascular disease compared with non-SLE patients. It is thought that these increases result from a combination of traditional risk factors, as well as the dysfunctional immune and inflammatory mechanisms in patients with SLE. At this time, there is limited evidence to support specific treatment guidelines for the prevention of cardiovascular disease in SLE patients. The treatment of these patients currently remains to identify and treat the traditional and SLE-related risk factors. PMID- 22210143 TI - Exercise capacity, physical activity, and obesity in adults with repaired aortic coarctation. AB - BACKGROUND: Patients with aortic coarctation (COA) have a reduced exercise capacity and seem to be more prone to adopt a sedentary lifestyle. During clinical practice, we often observe that patients seem to be overweight. However, data on physical activity and weight status in this population are currently not available. OBJECTIVE: This study aimed to describe weight status, self-reported physical activity levels, and self-perceived health status in adults with repaired COA in comparison with healthy counterparts and to investigate the relationships among exercise capacity, physical activity, weight status, and perceived health status. METHODS: We studied 103 COA patients who underwent cardiopulmonary exercise testing and who completed the Flemish Physical Activity Computerized Questionnaire and the short-form 36 health survey questionnaire. RESULTS: Patients with COA show a significantly lower exercise tolerance than what would be expected in healthy persons (P < .0001). Weight status was similar to the overall Belgian population, but a tendency toward higher body mass index was present. Patients with COA report a lower level of habitual physical activity (P < .05) as well as reductions in perceived vitality, general health, and mental health (P < .05). Parameters of habitual physical activity are related to exercise capacity (total energy expenditure: r = 0.278, P = .0015). The more active COA patients report higher scores of perceived physical functioning, general health, and mental health. Overweight patients did not perform significantly different than patients with a healthy weight did. CONCLUSIONS: Adults with repaired COA have a reduced exercise tolerance, which is related to low physical activity levels. Up to one-third of the COA patients we studied are overweight. As a poor exercise capacity identifies patients at risk for hospitalization and death and obesity might adversely influence the development of cardiovascular disease, it is important to improve the exercise capacity in these patients. Guiding patients toward more physical activity in daily life might therefore be the number 1 preventive measure to be taken in this patient group. PMID- 22210144 TI - Disparities in cardiac care for patients with complex cardiovascular care needs. AB - The United States continues to have a prevailing public health problem related to disparities in healthcare. Factors contributing to disparities include ethnicity, gender, socioeconomic status, educational level, geographic location, and hospital characteristics. In cardiovascular care, gaps in care have been associated with lack of conformity to evidence-based therapies known to improve clinical outcomes, including survival, quality of life, and freedom from rehospitalization. Specifically, there are disparities in use of a number of cardiovascular life-saving procedures including cardiac catheterization, percutaneous coronary intervention, coronary artery bypass surgery, and implantation of defibrillators and cardiac resynchronization devices. The purpose of this article was to illustrate the range of disparities that exist in relation to management of patients with acute coronary syndromes, interventional cardiology procedures, cardiac surgery, heart failure, and device implantation. Because the impact on patient outcomes is high, potential interventions to address disparities will be provided. PMID- 22210145 TI - Complexities of care for patients and families living with advanced cardiovascular diseases: overview. AB - The complexities of care in patients with advanced heart failure, ischemic coronary artery disease, and dysrhythmias span a wide spectrum of physiologic, psychologic, emotional, functional, social, and financial factors. In addition, families may be troubled by care needs associated with the cardiovascular disease itself or its complexities. The purpose of this overview was to gain a better understanding of the complexities associated with advanced heart failure, ischemic heart disease, and dysrhythmias and to highlight a few themes that have received recent attention from healthcare providers. The focus of the overview will include overcoming clinical and financial burdens and improving patient and family quality of life. PMID- 22210146 TI - Patient recovery and transitions after hospitalization for acute cardiac events: an integrative review. AB - Despite increased attention to providing seamless transitions after hospitalization, patients often feel unprepared, lack knowledge, and may be confused by what to expect during recovery at home after a cardiac event. Care transition after hospital discharge could be improved by informing and counseling patients more specifically about expected recovery after a cardiac event. Therefore, an integrative review of research was conducted to evaluate cardiac patients' trajectory of recovery after hospitalization. A total of 61 studies were included in this review. Studies included were those of cardiac patients who had been hospitalized for significant cardiac events and those focused on acute coronary syndrome (n = 18), percutaneous coronary intervention (PCI) (n = 12), cardiac surgery (coronary artery bypass surgery and valve surgery; n = 25), and heart failure (n = 6). Studies included quantitative, mixed-methods, and qualitative designs, with sample sizes ranging from 4 to 2121 participants. Notwithstanding the limitations of this review, findings demonstrated that patients' perceptions of their cardiac event evolved over time from uncertainty, fears, anxiety, and depression, which were often associated with a lack of knowledge of their cardiac condition, to a phase of self-management of their cardiac condition. Furthermore, patterns of commonly occurring symptoms and changes in functioning abilities during recovery after hospitalization were apparent among the different cardiac groups. These findings may be useful to both patients and clinicians to inform them about the recovery trajectory after a cardiac event to improve preparation for the transition from hospital to home. PMID- 22210147 TI - Patient education strategies for hospitalized cardiovascular patients: a systematic review. AB - Although mortality from cardiovascular (CV) disease has fallen in the past decade, the burden of CV disease and related conditions remains high, with rates of hospitalization and disability and cost on the rise. Prevention and treatment of CV conditions often involve a complex regimen of lifestyle modification, medications, and/or symptom monitoring and management. Cardiovascular health professionals spend a great deal of time promoting awareness of and adherence to national guidelines for the prevention and management of CV conditions. In addition, patient education for hospitalized patients is becoming increasingly regulated by national organizations and payors. However, it is unclear which educational intervention elements or strategies are most effective for educating hospitalized CV patients and their families. The purpose of this systematic review of experimental and quasi-experimental studies was to identify and examine the characteristics and outcomes of CV health education interventions for hospitalized CV patients. PMID- 22210148 TI - Upstreaming palliative care for patients with heart failure. AB - Upstreaming palliative care, practicing and advocating for palliative care earlier in the heart failure (HF) trajectory, is an idea whose time has come. In this article, we explore the meaning of palliative care for HF and then discuss its relationships with both chronic care and end-of-life care. A case study is used to envision the practical implementation of palliative care into existing systems of care. We conclude by discussing the clinician's role in implementing palliative care earlier for individuals with HF by practice and advocacy. PMID- 22210149 TI - Dietary restriction in rats and mice: a meta-analysis and review of the evidence for genotype-dependent effects on lifespan. AB - Laboratory survival experiments have shown that dietary restriction (DR) can increase median and maximum lifespan. This paper provides a meta-analysis of laboratory experiments that have evaluated the effects of DR on lifespan in rats and mice (1934-present). In rats, DR increased median lifespan by 14-45% in half of all experiments, but in mice the effects of DR have been much weaker (4-27%). The least favorable effects of DR on lifespan have been observed among inbred rather than non-inbred mouse strains. In fact, some inbred mouse strains do not necessarily live longer with DR, including DBA/2 male mice and several strains from the ILSXISS recombinant inbred panel. Shortening of lifespan with DR has also been observed and confirmed for ILSXISS strain 114. Importantly, all rodent studies may be biased by the effects of laboratory breeding, since one study has shown that median lifespan is not improved by DR in wild-derived mice. These findings suggest that the set of genetic backgrounds studied in rodent DR experiments should be diversified. This will broaden the scope of genotypes studied in aging research, but may also be critical for translation of findings from rodents to historically outbred and genetically heterogeneous primate species. PMID- 22210150 TI - Intestinal aspartate proteases TiCatD and TiCatD2 of the haematophagous bug Triatoma infestans (Reduviidae): sequence characterisation, expression pattern and characterisation of proteolytic activity. AB - Two aspartate protease encoding complementary deoxyribonucleic acids (cDNA) were characterised from the small intestine (posterior midgut) of Triatoma infestans and the corresponding genes were named TiCatD and TiCatD2. The deduced 390 and 393 amino acid sequences of both enzymes contain two regions characteristic for cathepsin D proteases and the conserved catalytic aspartate residues forming the catalytic dyad, but only TiCatD2 possesses an entire C-terminal proline loop. The amino acid sequences of TiCatD and TiCatD2 show 51-58% similarity to other insect cathepsin D-like proteases and, respectively, 88 and 58% similarity to the aspartate protease ASP25 from T. infestans available in the GenBank database. In phylogenetic analysis, TiCatD and ASP25 clearly separate from cathepsin D-like sequences of other insects, TiCatD2 groups with cathepsin D-like proteases with proline loop. The activity of purified TiCatD and TiCatD2 was highest between pH 2 and 4, respectively, and hence, deviate from the pH values of the lumen of the small intestine, which varied in correlation with the time after feeding between pH 5.2 and 6.7 as determined by means of micro pH electrodes. Both cathepsins, TiCatD and TiCatD2, were purified from the lumen of the small intestine using pepstatin affinity chromatography and identified by nanoLC-ESI-MS/MS analysis as those encoded by the cDNAs. The proteolytic activity of the purified enzymes is highest at pH 3 and the respective genes are expressed in the both regions of the midgut, stomach (anterior midgut) and small intestine, not in the rectum, salivary glands, Malpighian tubules or haemocytes. The temporal expression pattern of both genes in the small intestine after feeding revealed a feeding dependent regulation for TiCatD but not for TiCatD2. PMID- 22210151 TI - Two different and functional nuclear rDNA genes in the abalone Haliotis tuberculata: tissue differential expression. AB - Analysis of the 18S rDNA sequences of Haliotis tuberculata tuberculata and H. t. coccinea subtaxa identified two different types of 18S rDNA genes and ITS1 regions. These two different genes were also detected in H. marmorata, H. rugosa and H. diversicolor that are separated from H. tuberculata by 5-65 mya. The mean divergence value between type I and type II sequences ranged from 7.25% for 18S to 80% for ITS1. ITS1 type II is homologous with the ITS1 consensus sequences published for many abalone species, whereas ITS1 type I presented only minor homology with a unique database entry for H. iris ITS1. A phylogenetic analysis makes a clear separation between type I and type II ITS1 sequences and supports grouping H. t. tuberculata, H. t. coccinea and H. marmorata together. The two subtaxa do not show any significant differences between the homologous 18S rDNA sequences. A general structure of the ITS1 transcript was proposed, with four major helices for the two types. The two genes were expressed and, for the first time, a putative differential expression of ITS1 type I was detected in the gills, digestive gland and gonads whereas ITS1 type II was expressed in all tissues. PMID- 22210152 TI - Characterization of macular lesions in punctate inner choroidopathy with spectral domain optical coherence tomography. AB - PURPOSE: Punctate inner choroidopathy (PIC) is an ocular inflammatory disease. Spectral domain optical coherence tomography (SD-OCT) allows detailed visualization of retinal and choroidal structures. We aimed to describe the retinal changes on SD-OCT associated with PIC lesions localized in the macula. METHODS: Retrospective case series: PIC lesions not associated with choroidal neovascularization (CNV) and captured by macular SD-OCT scans were identified and characterized. RESULTS: Twenty-seven PIC lesions from seven patients (eight eyes) were identified and classified into four categories according to disease activity and temporal changes. Among clinically inactive patients, two main patterns were noted on OCT: (1) retinal pigment epithelium (RPE) elevation with sub-RPE hyper reflective signals and (2) localized disruption of outer retinal layers with choroid and Bruch's membrane (BM) generally spared. Clinically active patients demonstrated lesions with intact BM with RPE elevation that fluctuated with disease activity and sub-RPE hyper-reflective signals. Photoreceptor-associated bands on SD-OCT (PRs) were not visible during active disease, but returned to normal visibility when lesions were clinically stable. Seven lesions in patients without clinically detected activity demonstrated alteration of RPE elevation. CONCLUSION: SD-OCT can provide detailed structural characteristics of PIC lesions. RPE elevation is noted in many lesions while BM and choroid are spared. Photoreceptor-associated bands on SD-OCT appear compressed during clinically active stages and are visible during stabilization. OCT may provide information on activity not detected clinically. PMID- 22210154 TI - Characterization of the chitinolytic machinery of Enterococcus faecalis V583 and high-resolution structure of its oxidative CBM33 enzyme. AB - Little information exists for the ability of enterococci to utilize chitin as a carbon source. We show that Enterococcus faecalis V583 can grow on chitin, and we describe two proteins, a family 18 chitinase (ef0361; EfChi18A) and a family 33 CBM (carbohydrate binding module) (ef0362; EfCBM33A) that catalyze chitin conversion in vitro. Various types of enzyme activity assays showed that EfChi18A has functional properties characteristic of an endochitinase. EfCBM33A belongs to a recently discovered family of enzymes that cleave glycosidic bonds via an oxidative mechanism and that act synergistically with classical hydrolytic enzymes (i.e., chitinases). The structure and function of this protein were probed in detail. An ultra-high-resolution crystal structure of EfCBM33A revealed details of a conserved binding surface that is optimized to interact with chitin and contains the catalytic center. Chromatography and mass spectrometry analyses of product formation showed that EfCBM33A cleaves chitin via the oxidative mechanism previously described for CBP21 from Serratia marcescens. Metal depletion studies showed that EfCBM33A is a copper enzyme. In the presence of an external electron donor, EfCBM33A boosted the activity of EfChi18A, and combining the two enzymes led to rapid and complete conversion of beta-chitin to chitobiose. This study provides insight into the structure and function of the CBM33 family of enzymes, which, together with their fungal counterpart called GH61, currently receive considerable attention in the biomass processing field. PMID- 22210153 TI - Amphiphilic adsorption of human islet amyloid polypeptide aggregates to lipid/aqueous interfaces. AB - Many amyloid proteins misfold into beta-sheet aggregates upon interacting with biomembranes at the onset of diseases, such as Parkinson's disease and type II diabetes. The molecular mechanisms triggering aggregation depend on the orientation of beta-sheets at the cell membranes. However, understanding how beta sheets adsorb onto lipid/aqueous interfaces is challenging. Here, we combine chiral sum frequency generation (SFG) spectroscopy and ab initio quantum chemistry calculations based on a divide-and-conquer strategy to characterize the orientation of human islet amyloid polypeptides (hIAPPs) at lipid/aqueous interfaces. We show that the aggregates bind with beta-strands oriented at 48 degrees relative to the interface. This orientation reflects the amphiphilic properties of hIAPP beta-sheet aggregates and suggests the potential disruptive effect on membrane integrity. PMID- 22210156 TI - Toxoplasma gondii infection causes morphological changes in caecal myenteric neurons. AB - The aim of this study was to evaluate the effects of chronic infection of Toxoplasma gondii (with genotype I and genotype III strains) on the population density and morphometry of caecal myenteric neurons in rats. Fifteen, 60-day-old, male Wistar rats (Rattus norvegicus) were used. The animals were assigned into three groups: Control Group (CG), Experimental Group 1 (EG1) and Experimental Group 2 (EG2). EG1 animals received 10(5) tachyzoites of the genotype I (BTU IV) T. gondii strain orally, and the EG2 animals received 10(5) tachyzoites of the genotype III (BTU II) strain orally. Thirty days after inoculation, caecal whole mount preparations were stained by Giemsa technique. The caecal preparations were then analysed by assessing the population density and morphometry of myenteric neurons in specific regions of the caecum: mesenteric apical (MA), antimesenteric apical (AA), antimesenteric basal (AB) and next to caecal ampulla (NA). Myenteric neurons from the AA region were more clustered in EG1 animals (P<0.05). The EG1 animals presented a 16.8% reduction in the area of the nucleus, whereas the EG2 animals showed 18.4% increase (P<0.05). There was a more marked reduction in the cytoplasm of the animals in EG1 (?23.2%) compared to EG2 (?6.2%). There was 35.8% neuronal atrophy in the AB region and 16.8% in the region NA of the EG1 animals (P<0.05). In conclusion, different strains of T. gondii cause morphometric changes in caecal myenteric neurons of rats. Only the genotype I strain was able to cause neuronal density changes. PMID- 22210157 TI - Trypanosoma rangeli expresses a beta-galactofuranosyl transferase. AB - Glycoconjugates play essential roles in cell recognition, infectivity and survival of protozoan parasites within their insect vectors and mammalian hosts. beta-galactofuranose is a component of several glycoconjugates in many organisms, including a variety of trypanosomatids, but is absent in mammalian and African trypanosomes. Herein, we describe the presence of a beta(1-3) galactofuranosyl transferase (GALFT), an important enzyme of the galactofuranose biosynthetic pathway, in Trypanosoma rangeli. The T. rangeli GALFT gene (TrGALFT) has an ORF of 1.2 Kb and is organized in two copies in the T. rangeli genome. Antibodies raised against an internal fragment of the transferase demonstrated a 45 kDa protein coded by TrGALFT was localized in the whole cytoplasm, mainly in the Golgi apparatus and equally expressed in epimastigotes and trypomastigotes from T. rangeli. Despite the high sequence similarity with Trypanosoma cruzi and Leishmania spp. orthologous TrGALFT showed a substitution of the metal-binding DXD motif, conserved amongst glycosyltransferases, for a DXE functionally analogous motif. Moreover, a reduced number of GALFT genes were present in T. rangeli when compared with other pathogenic kinetoplastid species. PMID- 22210155 TI - Nucleocapsid protein annealing of a primer-template enhances (+)-strand DNA synthesis and fidelity by HIV-1 reverse transcriptase. AB - Human immunodeficiency virus type 1 (HIV-1) requires reverse transcriptase (RT) and HIV-1 nucleocapsid protein (NCp7) for proper viral replication. HIV-1 NCp7 has been shown to enhance various steps in reverse transcription including tRNA initiation and strand transfer, which may be mediated through interactions with RT as well as RNA and DNA oligonucleotides. With the use of DNA oligonucleotides, we have examined the interaction of NCp7 with RT and the kinetics of reverse transcription during (+)-strand synthesis with an NCp7-facilitated annealed primer-template. Through the use of a pre-steady-state kinetics approach, the NCp7-annealed primer-template has a substantial increase (3- to 7-fold) in the rate of incorporation (k(pol)) by RT as compared to heat-annealed primer-template with single-nucleotide incorporation. There was also a 2-fold increase in the binding affinity constant (K(d)) of the nucleotide. These differences in k(pol) and K(d) were not through direct interactions between HIV-1 RT and NCp7. When extension by RT was examined, the data suggest that the NCp7-annealed primer template facilitates the formation of a longer product more quickly compared to the heat-annealed primer-template. This enhancement in rate is mediated through interactions with NCp7's zinc fingers and N-terminal domain and nucleic acids. The NCp7-annealed primer-template also enhances the fidelity of RT (3-fold) by slowing the rate of incorporation of an incorrect nucleotide. Taken together, this study elucidates a new role of NCp7 by facilitating DNA-directed DNA synthesis during reverse transcription by HIV-1 RT that may translate into enhanced viral fitness and offers an avenue to exploit for targeted therapeutic intervention against HIV. PMID- 22210158 TI - Cerebellar infarction in a patient with cerebral vein thrombosis and patent foramen ovale: brain-to-brain embolism? AB - Although the association between PFO and cryptogenic stroke is well shown in young adults, the causality is still unclear. The pathogenetic mechanism of ischemic stroke related to PFO is not entirely understood. Indeed, besides the well-known paradoxical embolism, formations of thrombi in situ, especially in the presence of ASA, a higher incidence of atrial fibrillation have been often observed. Cerebral sinus venous thrombosis may be due to local inflammation or to acquired or genetic thrombophilia including hyperhomocysteinemia. We report a case of a young man presenting with a cerebellar infarction probably secondary to a paradoxical brain-to-brain embolism, in which the only detectable embolic source was a cerebral vein thrombosis. PMID- 22210159 TI - Leukocyte telomere length (LTL) is reduced in stable mild cognitive impairment but low LTL is not associated with conversion to Alzheimer's disease: a pilot study. AB - Leukocyte telomere length (LTL) is associated with the aging process and may be related to cognitive aging. Previous studies have shown conflicting results whether LTL is affected in patients with Alzheimer's disease (AD). In this pilot study, we investigated LTL in a well-defined homogeneous mono-center population. Sixty consecutive patients admitted for cognitive impairment to a memory clinic were recruited. The participants included patients with AD or mild cognitive impairment (MCI) diagnosed with AD upon follow-up (n=32), patients with stable MCI (n=13), patients with other dementias diagnosed at primary evaluation or upon follow-up (n=15), and healthy controls (n=20). LTL was determined using a quantitative PCR assay. Patients with AD had similar LTL as healthy controls. Patients with stable MCI had reduced LTL both compared to AD patients (p=0.02) and controls (p=0.008). Subanalyses within the AD group showed that patients with MCI that later converted to AD had similar LTL as patients with clinical diagnosis of AD at primary evaluation and healthy controls whereas the LTL was longer compared to the stable MCI group (p=0.02). There were no correlations between LTL and the core AD biomarkers Abeta(1-42), T-tau and P-tau. In conclusion, in this pilot study, patients with AD or MCI that later converted to AD had similar LTL as healthy controls. Patients with stable MCI that did not progress to dementia had reduced LTL compared to controls, which might suggest a more marked biological aging as a cause of the cognitive symptoms in this group. PMID- 22210161 TI - Hemocompatibility of liposomes loaded with lipophilic prodrugs of methotrexate and melphalan in the lipid bilayer. AB - A panel of in vitro tests intended for evaluation of the nano-sized drug delivery systems' compliance with human blood was applied to liposomal formulations of anticancer lipophilic prodrugs incorporated into the lipid bilayer. Liposomes on the basis of natural phosphatidylcholine (PC) and phosphatidylinositol (PI), 8:1 (mol) were loaded with 10 mol% of either methotrexate or melphalan 1,2 dioleoylglyceride esters (MTX-DOG and Mlph-DOG respectively) and either decorated with 2 mol% of sialyl Lewis X/A (SiaLe(X/A)) tetrasaccharide ligand or not. Hemolysis rate, red blood cells and platelets integrity and size distribution, complement (C) activation, and coagulation cascade functioning were analyzed upon the material incubation with whole blood. Both formulations were negatively charged with the zeta potential value being higher in the case of MTX-DOG liposomes, which also were larger than Mlph-DOG liposomes and more prone to aggregation. Accordingly, in hemocompatibility tests Mlph-DOG liposomes did not provoke any undesirable effects, while MTX-DOG liposomes induced significant C activation and abnormal coagulation times in a concentration-dependent manner. Reactivity of the liposome surface was not affected by the presence of SiaLe(X/A) or PI. Decrease in liposome loading with MTX-DOG from 10 to 2.5% resulted in lower surface charge density, smaller liposome size and considerably reduced impact on C activation and coagulation cascades. PMID- 22210160 TI - A Polymorphism in a gene encoding Perilipin 4 is associated with height but not with bone measures in individuals from the Framingham Osteoporosis Study. AB - There is increasing interest in identifying new pathways and candidate genes that confer susceptibility to osteoporosis. There is evidence that adipogenesis and osteogenesis may be related, including a common bone marrow progenitor cell for both adipocytes and osteoblasts. Perilipin 1 (PLIN1) and Perilipin 4 (PLIN4) are members of the PATS family of genes and are involved in lipolysis of intracellular lipid deposits. A previous study reported gender-specific associations between one polymorphism of PLIN1 and bone mineral density (BMD) in a Japanese population. We hypothesized that polymorphisms in PLIN1 and PLIN4 would be associated with bone measures in adult Caucasian participants of the Framingham Osteoporosis Study (FOS). We genotyped 1,206 male and 1,445 female participants of the FOS for four single-nucleotide polymorphism (SNPs) in PLIN1 and seven SNPs in PLIN4 and tested for associations with measures of BMD, bone ultrasound, hip geometry, and height. We found several gender-specific significant associations with the measured traits. The association of PLIN4 SNP rs8887, G>A with height in females trended toward significance after simulation testing (adjusted P = 0.07) and remained significant after simulation testing in the combined-sex model (adjusted P = 0.033). In a large study sample of men and women, we found a significant association between one SNP in PLIN4 and height but not with bone traits, suggesting that PATS family genes are not important in the regulation of bone. Identification of genes that influence human height may lead to a better understanding of the processes involved in growth and development. PMID- 22210163 TI - Chronobiology of reproduction in garter snakes: neuroendocrine mechanisms and geographic variation. AB - The majority of studies on reproductive neuroendocrinology in snakes have focused on one particular snake population in Manitoba, Canada, the red-sided garter snake (Thamnophis sirtalis parietalis). Although traditionally these studies have emphasized its unusual temporal dissociation between mating behavior and peak gonadal activity, current evidence suggests that reproductive regulation in this population may be more similar to the norm than previously thought. Like other ectotherms, temperature plays a critical role in activating reproductive behavior in red-sided garter snakes. Diel melatonin and corticosterone rhythms appear to be important in transducing temperature cues, and it is clear that both hormones regulate courtship behavior during spring. Current evidence also suggests that sex steroid hormones are in fact central to reproductive regulation in males, although the timing of their action occurs during winter dormancy. Whether this is also true for female T. sirtalis parietalis requires further study, but it should be noted that patterns of sex steroid hormones are sexually dimorphic during winter dormancy, as are melatonin rhythms during spring emergence. While continuing to advance our understanding of reproductive regulation in this extremely well-studied population is prudent, future comparative studies are critical for understanding if and how reproductive regulatory mechanisms differ across environments, populations, and phylogenies. For example, melatonin and corticosterone responses to environmental cues vary significantly among populations of T. sirtalis in a common garden, as do male courtship behavior and androgen concentrations. These data support the hypothesis that neuroendocrine mediated responses to environmental cues underlie phenotypic plasticity in reproductive life history traits. PMID- 22210162 TI - Image-guided drug delivery with magnetic resonance guided high intensity focused ultrasound and temperature sensitive liposomes in a rabbit Vx2 tumor model. AB - Clinical-grade doxorubicin encapsulated low temperature sensitive liposomes (LTSLs) were combined with a clinical magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) platform to investigate in vivo image-guided drug delivery. Plasma pharmacokinetics were determined in 3 rabbits. Fifteen rabbits with Vx2 tumors within superficial thigh muscle were randomly assigned into three treatment groups: 1) free doxorubicin, 2) LTSL and 3) LTSL + MR-HIFU. For the LTSL + MR-HIFU group, mild hyperthermia (40-41 degrees C) was applied to the tumors using an MR-HIFU system. Image-guided non-invasive hyperthermia was applied for a total of 30 min, completed within 1h after LTSL infusion. High pressure liquid chromatography (HPLC) analysis of the harvested tumor and organ/tissue homogenates was performed to determine doxorubicin concentration. Fluorescence microscopy was performed to determine doxorubicin spatial distribution in the tumors. Sonication of Vx2 tumors resulted in accurate (mean = 40.5 +/- 0.1 degrees C) and spatially homogenous (SD = 1.0 degrees C) temperature control in the target region. LTSL + MR-HIFU resulted in significantly higher tumor doxorubicin concentrations (7.6- and 3.4-fold greater compared to free doxorubicin and LTSL respectively, p<0.05, Newman-Keuls). This improved tumor concentration was achieved despite heating <25% of the tumor volume. Free doxorubicin and LTSL treatments appeared to deliver more drug in the tumor periphery as compared to the tumor core. In contrast, LTSL + MR-HIFU treatment suggested an improved distribution with doxorubicin found in both the tumor periphery and core. Doxorubicin bio-distribution in non-tumor organs/tissues was fairly similar between treatment groups. This technique has potential for clinical translation as an image-guided method to deliver drug to a solid tumor. PMID- 22210164 TI - The carboxylesterase/cholinesterase gene family in invertebrate deuterostomes. AB - Carboxylesterase/cholinesterase family members are responsible for controlling the nerve impulse, detoxification and various developmental functions, and are a major target of pesticides and chemical warfare agents. Comparative structural analysis of these enzymes is thus important. The invertebrate deuterostomes (phyla Echinodermata and Hemichordata and subphyla Urochordata and Cephalochordata) lie in the transition zone between invertebrates and vertebrates, and are thus of interest to the study of evolution. Here we have investigated the carboxylesterase/cholinesterase gene family in the sequenced genomes of Strongylocentrotus purpuratus (Echinodermata), Saccoglossus kowalevskii (Hemichordata), Ciona intestinalis (Urochordata) and Branchiostoma floridae (Cephalochordata), using sequence analysis of the catalytic apparatus and oligomerisation domains, and phylogenetic analysis. All four genomes show blurring of structural boundaries between cholinesterases and carboxylesterases, with many intermediate enzymes. Non-enzymatic proteins are well represented. The Saccoglossus and Branchiostoma genomes show evidence of extensive gene duplication and retention. There is also evidence of domain shuffling, resulting in multidomain proteins consisting either of multiple carboxylesterase domains, or of carboxylesterase/cholinesterase domains linked to other domains, including RING finger, chitin-binding, immunoglobulin, fibronectin type 3, CUB, cysteine rich-Frizzled, caspase activation and 7tm-1, amongst others. Such gene duplication and domain shuffling in the carboxylesterase/cholinesterase family appears to be unique to the invertebrate deuterostomes, and we hypothesise that these factors may have contributed to the evolution of the morphological complexity, particularly of the nervous system and neural crest, of the vertebrates. PMID- 22210165 TI - The effect of prolyl oligopeptidase inhibition on extracellular acetylcholine and dopamine levels in the rat striatum. AB - Prolyl oligopeptidase (PREP, EC 3.4.21.26) inhibitors have potential as cognition enhancers, but the mechanism of action behind the cognitive effects remains unclear. Since acetylcholine (ACh) and dopamine (DA) are known to be associated with the regulation of cognitive processes, we investigated the effects of two PREP inhibitors on the extracellular levels of ACh and DA in the rat striatum using in vivo microdialysis. KYP-2047 and JTP-4819 were administered either as a single systemic dose (50 MUmol/kg~17 mg/kg i.p.) or directly into the striatum by retrodialysis via the microdialysis probe (12.5, 37.5 or 125 MUM at 1.5 MUl/min for 60 min). PREP inhibitors had no significant effect on striatal DA levels after systemic administration. JTP-4819 significantly decreased ACh levels both after systemic (by ~25%) and intrastriatal (by ~30-50%) administration. KYP-2047 decreased ACh levels only after intrastriatal administration by retrodialysis (by ~40-50%) when higher drug levels were reached, indicating that higher brain drug levels are needed to modulate ACh levels than to inhibit PREP. This result does not support the earlier hypothesis that the positive cognitive effects of PREP inhibitors in rodents would be mediated through the cholinergic system. In vitro specificity studies did not reveal any obvious off-targets that could explain the observed effect of KYP-2047 and JTP-4819 on ACh levels, instead confirming the concept that these compounds have a high selectivity towards PREP. PMID- 22210166 TI - Effects of different sources of fructans on body weight, blood metabolites and fecal bacteria in normal and obese non-diabetic and diabetic rats. AB - Fructans contribute significantly to dietary fiber with beneficial effects on gastrointestinal physiology in healthy individuals and offer a promising approach to treating some diseases. Two experiments (Experiment 1 = rats with normal weight; Experiment 2 = obese rats) were developed to compare the effects of three fructan sources (Cichorium intybus L. Asteraceae, Helianthus tuberosus L. Asteraceae and Agave angustifolia ssp. tequilana Haw, Agavaceae) on body weight change, blood metabolites and fecal bacteria in non-diabetic (ND) and diabetic (D) rats. In Experiment 1 total body weight gain and daily feed intake in D and ND rats decreased (P < 0.05) with supplements of fructan. Only in D rats, blood glucose concentrations, fecal Clostrodium spp. counts, and liver steatosis decreased, while blood HDL concentrations and fecal Lactobacillus spp. and Bifidobacterium spp. counts increased due to fructans. In Experiment 2, total body weight gain and feed intake in ND and D rats were also decreased by fructans. In ND rats, fructan decreased blood glucose concentrations. In D rats, fructans from A. angustifolia ssp. tequilana decreased blood cholesterol and LDL and liver steatosis. For both ND and D rats, fecal Lactobacillus spp. and Bifidobacterium spp. counts were higher (P < 0.05) with fructan supplements. PMID- 22210167 TI - An approach to improve LOINC mapping through augmentation of local test names. AB - Mapping medical test names into a standardized vocabulary is a prerequisite to sharing test-related data between health care entities. One major barrier in this process is the inability to describe tests in sufficient detail to assign the appropriate name in Logical Observation Identifiers, Names, and Codes (LOINC(r)). Approaches to address mapping of test names with incomplete information have not been well described. We developed a process of "enhancing" local test names by incorporating information required for LOINC mapping into the test names themselves. When using the Regenstrief LOINC Mapping Assistant (RELMA) we found that 73/198 (37%) of "enhanced" test names were successfully mapped to LOINC, compared to 41/191 (21%) of original names (p=0.001). Our approach led to a significantly higher proportion of test names with successful mapping to LOINC, but further efforts are required to achieve more satisfactory results. PMID- 22210168 TI - A new triterpenoid saponin from Abrus precatorius Linn. AB - A new triterpenoid saponin, 3-O-beta-D-glucopyranosyl-(1->2)-beta-D glucopyranosyl subprogenin D (1), together with six known triterpenoids: subprogenin D (2), abrusgenic acid (3), triptotriterpenic acid B (4), abruslactone A (5), abrusogenin (6) and abrusoside C (7) were isolated from the leaves and stems of Abrus precatorius. Their structures were elucidated on the basis of physical and NMR analysis, respectively. Compounds 5 and 6 showed moderate cytotoxicity against MCF-7, SW1990, Hela, and Du-145 cell lines. Compounds 1, 2 and 4 were isolated from this plant for the first time. PMID- 22210169 TI - Enantiomeric separation and determination of the enantiomeric impurity of armodafinil by capillary electrophoresis with sulfobutyl ether-beta-cyclodextrin as chiral selector. AB - A selective capillary electrophoresis method using sulfobutyl ether-beta cyclodextrin as a chiral selector was developed and validated for the determination of the enantiomeric impurity of (R)-modafinil, i.e., armodafinil. Several parameters were optimized for a satisfactory enantioresolution, including the type and concentration of chiral selector and organic modifier, pH of background electrolyte (BGE), capillary temperature. The finally adopted condition was: 20 mmol/L phosphate buffer at pH 7.5, containing 20 mmol/L sulfobutyl ether-beta-cyclodextrin and 20% methanol, at temperature of 25 degrees C. A good resolution of 3.3 for the two enantiomers of modafinil was achieved by applying the optimal conditions. The limit of detection (LOD) and limit of quantification (LOQ) of (S)-modafinil were 1.25 MUg/mL and 2.50 MUg/mL, respectively. The established method was also proven to display good selectivity, repeatability, linearity and accuracy. Finally, the method was used to investigate the enantiomeric purity of armodafinil in bulk samples. PMID- 22210170 TI - Neuroprotective effects of exogenous activin A on oxygen-glucose deprivation in PC12 cells. AB - Ischemic cerebrovascular disease is one of the most common causes of death in the World. Exogenous activin A (ActA) protects neurons against toxicity and plays a central role in regulating the brain's response to injury. In the present study, we investigated the mechanisms involved in the neuroprotective effects of ActA in a model of hypoxic-ischemic brain disease. We found that ActA could effectively increase the survival rate of PC12 cells and relieve oxygen-glucose deprivation (OGD) damage. To clarify the neuroprotective mechanisms of ActA, the effects of ActA on the ActA/Smad pathway and on the up-regulation of inducible nitric oxide synthase (NOS) and superoxide dismutase (SOD) were investigated using OGD in PC12 cells. The results showed that ActA could increase the expression of activin receptor IIA (ActRIIA), Smad3 and Smad4 and that 50 ng/mL and 100 ng/mL of ActA could reduce NO levels and increase SOD activity by 78.9% and 79.9%, respectively. These results suggested that the neuroprotective effects of ActA in ischemia could be related to the activation of the ActA/Smad signaling pathway and to its anti-oxidant activities. PMID- 22210171 TI - Enzyme treatment-free and ligation-independent cloning using caged primers in polymerase chain reactions. AB - A new simple scheme for constructing recombinant vectors that does not require any restriction enzyme, ligase, or any other special enzyme treatment has been developed. By using caged primers in PCR, unnatural sticky-ends of any sequence, which are sufficiently long for ligation-independent cloning (LIC), are directly prepared on the product after a brief UVA irradiation. Target genes and vectors amplified by this light-assisted cohesive-ending (LACE) PCR join together in the desired arrangement in a simple mixture of them, tightly enough to be repaired and ligated in competent cells. PMID- 22210173 TI - Synthesis and 5alpha-reductase inhibitory activity of C21 steroids having 1,4 diene or 4,6-diene 20-ones and 4-azasteroid 20-oximes. AB - The synthesis and evaluation of 5alpha-reductase inhibitory activity of some 4 azasteroid-20-ones and 20-oximes and 3beta-hydroxy-, 3beta-acetoxy-, or epoxy substituted C21 steroidal 20-ones and 20-oximes having double bonds in the A and/or B ring are described. Inhibitory activity of synthesized compounds was assessed using 5alpha-reductase enzyme and [1,2,6,7-3H]testosterone as substrate. All synthesized compounds were less active than finasteride (IC50: 1.2 nM). Three 4-azasteroid-2-oximes (compounds 4, 6 and 8) showed good inhibitory activity (IC50: 26, 10 and 11 nM) and were more active than corresponding 4-azasteroid 20 ones (compounds 3, 5 and 7). 3beta-Hydroxy-, 3beta-acetoxy- and 1alpha,2alpha-, 5alpha,6alpha- or 6alpha,7alpha-epoxysteroid-20-one and -20-oxime derivatives having double bonds in the A and/or B ring showed no inhibition of 5alpha reductase enzyme. PMID- 22210172 TI - Inhibition of sevoflurane postconditioning against cerebral ischemia reperfusion induced oxidative injury in rats. AB - The volatile anesthetic sevoflurane is capable of inducing preconditioning and postconditioning effects in the brain. In this study, we investigated the effects of sevoflurane postconditioning on antioxidant and immunity indexes in cerebral ischemia reperfusion (CIR) rats. Rats were randomly assigned to five separate experimental groups I-V. In the sham group (I), rats were subjected to the same surgery procedures except for occlusion of the middle cerebral artery and exposed to 1.0 MAC sevoflurane 90 min after surgery for 30 min. IR control rats (group II) were subjected to middle cerebral artery occlusion (MCAO) for 90 min and exposed to O2 for 30 min at the beginning of reperfusion. Sevoflurane 0.5, 1.0 and 1.5 groups (III, IV, V) were all subjected to MCAO for 90 min, but at the beginning of reperfusion exposed to 0.5 MAC, 1.0 MAC or 1.5 MAC sevoflurane for 30 min, respectively. Results showed that sevoflurane postconditioning can decrease serum tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL 1beta), nitric oxide (NO), nitric oxide synthase (NOS) and increase serum interleukin-10 (IL-10) levels in cerebral ischemia reperfusion rats. In addition, sevoflurane postconditioning can still decrease blood lipid, malondialdehyde (MDA) levels, infarct volume and increase antioxidant enzymes activities, normal pyramidal neurons density in cerebral ischemia reperfusion rats. It can be concluded that sevoflurane postconditioning may decrease blood and brain oxidative injury and enhance immunity indexes in cerebral ischemia reperfusion rats. PMID- 22210174 TI - Risk assessment of chlorpyrifos on rice and cabbage in China. AB - Chlorpyrifos is a widely used organophosphorus insecticide in agricultural pest control. To understand the residue behavior of chlorpyrifos and to evaluate the dietary risk of chlorpyrifos residue in food in China, a number of residue studies were conducted on rice and cabbage. The supervised trial median residues (STMRs) for rice and cabbage were less than 0.010 and 0.227 mg kg-1, respectively. Only 7.4% and 13.3% of acceptable daily intake (ADI) (0-0.01 mg kg 1 bw) of chlorpyrifos is occupied by dietary daily intake to the Chinese adult and children, respectively, due to the consumption of rice and cabbage. These results on risk assessment were consistent with that of JMPR. Incorporation of market survey residue data gave a 5-fold reduction in the estimated exposures to chlorpyrifos. Concerning the acute exposure, the national estimated short-term intake (NESTI) represents 0.077% and 10.6% for rice and cabbage, respectively, of the acute reference dose (ARfD) (0-0.1 mg kg-1 bw). The application of chlorpyrifos at the recommended dose on rice and cabbage is unlikely to pose any public health issues if it is applied according to the good agricultural practices (GAPs) established by each country. PMID- 22210175 TI - The burden of injuries at the Jigme Dorji Wangchuck National Referral Hospital in Thimphu, Bhutan. AB - A review of the surgical admission, operating room records, and emergency room consultations for the 2006 was undertaken with the objective of assessing the injury burden at the Jigme Dorji Wangchuck National Referral Hospital in Thimphu. The study revealed that trauma accounted for 20% of all surgical admissions in 2006, out of which the Orthopedic department bore the major chunk of trauma admissions at 61%. Trauma was responsible for more than 5000 disability-adjusted life years lost (DALYs) in 2006. On an average, 2 out of 3 orthopedic procedures were performed for trauma-related conditions. It is hoped that this study will stimulate the local practitioners and policy makers to initiate further studies to build up standardized database on injury burden in Bhutan to facilitate evidence-based decisions by the stakeholders. PMID- 22210176 TI - Psoriasis increased the risk of diabetes: a meta-analysis. AB - To evaluate the association between psoriasis and risk of diabetes, pertinent studies were identified by searching electronic databases and by reviewing the reference lists of retrieved articles. We included observational studies that examined the association between psoriasis and risk of diabetes. Two reviewers independently assessed eligibility and used a standardized form to collect data from published studies. The study quality was assessed by the Newcastle-Ottawa Scale. A total of 22 eligible studies that included 3,307,516 participants fulfilled the inclusion criteria. Compared to individuals without psoriasis, subjects with psoriasis had a 1.42-fold increased risk of diabetes (95% CI, 1.40 1.45). Findings from this meta-analysis suggest that individuals with psoriasis may have a modestly increased risk of diabetes. PMID- 22210177 TI - Ab interno management of blocked Ahmed valve in the posterior segment. AB - PURPOSE: To report a case of late failure of a posterior segment placed Ahmed valve in a uveitic eye with a corneal graft and a minimally invasive, ab interno approach in restoring valve function, pressure control, and preservation of vision. DESIGN: Case report. METHODS: A 25 gauge trans-conjunctival 3-port pars plana vitrectomy was performed to inspect and clean the ostium of the Ahmed valve of any vitreous debris. The Ahmed valve was not disturbed externally and conjunctival dissection was not performed. A 27-gauge blunt cannula was introduced through the vitrector site and used to cannulate the tube and flush it with balanced salt solution. A bleb was immediately re-established and all instruments were removed requiring no sutures. RESULTS: Intraocular pressure returned to target levels and a filtration bleb was re-established. Corneal graft clarity was restored with resolution of preoperative microcystic edema. Postoperative inflammation was minimal and vision was restored. CONCLUSIONS: A nonfunctioning tube shunt residing in the vitreous cavity may be revised ab interno without disturbing the shunt placement or the conjunctiva under which it resides to re-establish filtration. PMID- 22210179 TI - Cancer-related inflammation: common themes and therapeutic opportunities. AB - Inflammatory cells and mediators are an essential component of the tumor microenvironment. Inflammatory circuits can differ considerably in different tumors in terms of cellular and cytokine networks and molecular drivers. However, macrophages are a common and fundamental component of cancer promoting inflammation. Drivers of macrophage functional orientation include tumor cells, cancer-associated fibroblasts, T cells and B cells. Dissection of the diversity of cancer-related inflammation is instrumental to the design of therapeutic approaches that target cancer-related inflammation. PMID- 22210178 TI - Combined Baerveldt glaucoma implant and scleral buckling surgery for patients with retinal detachment and coexisting glaucoma. AB - PURPOSE: To report on the usefulness of combined Baerveldt glaucoma implantation (BGI) and scleral buckling surgery for patients with glaucoma requiring a scleral buckle for retinal detachment repair. METHODS: Retrospective, consecutive, noncomparative, and interventional case series of 30 eyes (30 patients) that underwent simultaneous scleral buckle and BGI surgery, using a staged (group 1, n=21 patients) or nonstaged (group 2, n=9 patients) approach to BGI implantation. Successful intraocular pressure (IOP) control was defined as 6 mm Hg<=IOP<=18 mm Hg. RESULTS: Although not statistically significant, mean best corrected visual acuity (LogMAR) improved from 2.0 before surgery to 1.7 after surgery (P=0.13) with a mean follow-up of 27.7 months. Of the 21 patients in group 1, only 13 (62%) required second-stage tube insertion at a mean of 7.0+/-8.0 months (range, 1 to 24 mo) postoperatively. For these eyes combined with group 2 eyes, mean IOP was reduced from 31.1+/-10.8 to 12.7+/-6.0 mm Hg (P<0.0001), and the mean number of glaucoma medications was reduced from 2.9+/-1.4 to 1.2+/-1.3 (P<0.001). Life table rates of successful IOP control were 90% and 80% at 12 and 24 months, respectively. CONCLUSIONS: Combined scleral buckle and BGI is an effective technique for managing coexisting glaucoma and retinal detachment and provides the clinician with a useful surgical option while minimizing surgical risk. PMID- 22210180 TI - Role of EBER and BARF1 in nasopharyngeal carcinoma (NPC) tumorigenesis. AB - Epstein-Barr virus (EBV)-encoded small RNA (EBER) is the most abundant EBV viral transcript and is used as a target molecule to detect EBV-infected cells in tissues by in situ hybridization. EBER is expected to form double-stranded RNA like structures. The results of the present study show that EBER contributes to oncogenesis by modulating innate immunity in patients with NPC and Burkett's lymphoma. BARF1 is a homolog of the human proto-oncogene c-fms and is expressed as a latent gene in NPC. Reconstitution of NPC-type EBV infection using NPC derived cell lines shows that BARF1 contributes to the tumorigenicity of NPC cells. PMID- 22210181 TI - Inflammation and immune surveillance in cancer. AB - Chronic inflammation is a risk factor for tumor development. However, understanding the effect of the immune system on tumor development has only been significantly advanced over the past two decades. We now appreciate that the immune system, in addition to tumor-suppressive function by eliminating nascent transformed tumor cells, can also exert selection pressure on tumor cells and facilitate tumor growth by providing a favorable tumor microenvironment. Yet, the distinctions between tumor-promoting inflammation and tumor-suppressive immunity are still not clear due to the dual role of some cytokines and other molecules in the immune system. The danger signal hypothesis has shaped our view of the role of immunity in cancer development, but still little is known about the exact role of danger signal receptors in cancer progression. In this review, we introduce the processes of cancer immunoediting and inflammation-induced cancer and discuss what is currently known about the role of danger signal receptors in cancer development and progression. PMID- 22210183 TI - Genetically modulating T-cell function to target cancer. AB - The adoptive transfer of tumor-specific T-lymphocytes holds promise for the treatment of metastatic cancer. Genetic modulation of T-lymphocytes using TCR transfer with tumor-specific TCR genes is an attractive strategy to generate anti tumor response, especially against large solid tumors. Recently, several clinical trials have demonstrated the therapeutic potential of this approach which lead to impressive tumor regression in cancer patients. Still, several factors may hinder the clinical benefit of this approach, such as the type of cells to modulate, the vector configuration or the safety of the procedure. In the present review we will aim at giving an overview of the recent developments related to the immune modulation of the anti-tumor adaptive response using genetically engineered lymphocytes and will also elaborate the development of other genetic modifications to enhance their anti-tumor immune response. PMID- 22210182 TI - MicroRNAs and STAT interplay. AB - MicroRNA (miR) are emerging as important gene expression regulators often involved in a variety of pathogenesis such as cancers and autoimmunity. Signal transducers and activators of transcription (STAT) proteins are the principle signaling proteins for many cytokines and growth factors, thereby play a critical role in regulating immune cell homeostasis, differentiation and cellular functions. In this review, we discuss recent advances in the field demonstrating active interactions between STATs and miRs, with our primary focus on the promotion and inhibition of immune cells and cancer. Additionally, we review the reciprocal regulations between STATs and miR, and discuss how we can use this knowledge in the context of diseases. For example, recent findings related to STAT1 and miR-155 support the presence of a positive feedback loop of miR-155 and STAT1 in response to inflammatory signals or infection. STAT3 is known to play critical roles in tumorigenesis and cancer-induced immunosuppression. There is a growing body of evidence demonstrating that STAT3 directly activates miR-21, one of miRs that promote cancer cell survival and proliferation. While some miRs directly regulate STATs, there are findings demonstrating indirect STAT regulation by miRs also mediate important biological mechanisms. Therefore, further research is warranted to elucidate significant contributions made by direct and indirect miR-STAT mechanisms. As we learn more about miR pathways, we gain the opportunity to manipulate them in cancer cells to slow down growth or increase their susceptibility anti-tumor immunity. PMID- 22210184 TI - Preservation of FGF-2 bioactivity using heparin-based nanoparticles, and their delivery from electrospun chitosan fibers. AB - Here we present a novel matrix-mimetic nanoassembly based on polysaccharides. Chitosan electrospun fiber networks are decorated with heparin-containing polyelectrolyte complex nanoparticles (PCNs) that present basic fibroblast growth factor (FGF-2), both stably adsorbed to the surfaces and released into solution. These FGF-2/PCN complexes can be released from the fibers with zero-order kinetics over a period of 30 days. Further modification of fibers with a single bilayer of polyelectrolyte multilayer (PEM) composed of N,N,N-trimethyl chitosan and heparin completely prevent release, and the FGF-2/PCN complexes are retained on the fibers for the duration of the release experiment (30 days). We also compare the mitogenic activity of these FGF-2/PCN complexes delivered in two different states: adsorbed to a surface and dissolved in solution. FGF-2/PCN complexes exhibit mitogenic activity with respect to ovine bone marrow-derived mesenchymal stem cells, even after being preconditioned by incubating for 27 days at 37 degrees C in solution. However, when the FGF-2/PCN complexes are adsorbed to chitosan and coated with PEMs, the mitogenic activity of the FGF-2 steadily decreases with increasing preconditioning time. This work demonstrates a new system for stabilizing and controlling the delivery of heparin-binding growth factors, using polysaccharide-based matrix-mimetic nanomaterials. This work also contributes to our understanding of the preferred mode of growth factor delivery from porous scaffolds. PMID- 22210185 TI - The relationship between species richness and evenness: a meta-analysis of studies across aquatic ecosystems. AB - Biological diversity comprises both species richness, i.e., the number of species in a community, and evenness, measuring how similar species are in their abundances. The relationship between species richness and evenness (RRE) across communities remains, however, a controversial issue in ecology because no consistent pattern has been reported. We conducted a systematic meta-review of RRE in aquatic ecosystems along regional to continental gradients and across trophic groups, differing in body size by 13 orders of magnitude. Hypotheses that RRE responded to latitudinal and scale variability across trophic groups were tested by regression analyses. Significant correlations of species richness and evenness only existed in 71 out of 229 datasets. Among the RRE, 89 were negative and 140 were positive. RRE did not vary with latitude but showed a positive response to scale. In a meta-analysis with ecosystem type as a single explaining variable, RRE did not vary among ecosystem types, i.e. between marine and freshwater. Finally, autotrophs had more positive RRE than heterotrophs. The weak RRE in many aquatic datasets suggests that richness and evenness often reflect independent components of biodiversity, highlighting that richness alone may be an incomplete surrogate for biodiversity. Our results further elucidate that RRE is driven by organismal and environmental properties, both of which must be considered to gain a deeper understanding of large-scale patterns of biodiversity. PMID- 22210186 TI - High-frequency microsatellite instability and BRAF mutation (V600E) in unselected Serbian patients with colorectal cancer. AB - Microsatellite instability (MSI) is a genetic consequence of a MisMatch Repair defect in colorectal cancer (CRC). We compared clinicopathohistological features with MSI status of CRC and evaluated prognostic significance of MSI status and BRAF mutation in the group of MSI-H tumors. 155 primary CRCs were excised surgically, 2006-2008. MSI analysis was carried out using a fluorescence-based pentaplex polymerase chain reaction technique. BRAF mutation (V600E) was analyzed by direct sequencing in MSI-H tumors. For all patients were evaluated: age, gender, localization, tumor cell type, tumor differentiation, mucin production, lymphocytic infiltration (TILs) and TNM stage. Patients' disease-free survival (DFS) was compared according to MSI and BRAF status using Kaplan-Meier test. Of the 155 CRCs, 19 (12.3%) were MSI-H, and 136 (87.7%) were MSS/L. BRAF mutations were found in 4 of the MSI-H tumors. Patients with MSI-H CRC had lower recurrence rate (log rank test; P = 0.04) than MSS/L group. Patients with MSI-H tumor and BRAF mutation had worse DFS than MSI-H tumors without this mutation (log rank test; P = 0.01). Most of the clinicopathologic characteristics of MSI-H CRC in Serbian patients are similar to those reported in previous studies. Patients with MSI tumor phenotype had favourable prognosis, but in those with BRAF mutation higher recurrence rate was observed. PMID- 22210187 TI - Effects of angiotensin II AT1 receptor inhibition and exercise training on insulin action in rats on high-fat diet. AB - AIM: This study was to determine whether combination of the angiotensin II AT1 receptor blocker (ARB), candesartan cilexetil, and exercise training can prevent the development of high-fat diet-induced insulin resistance. MAIN METHODS: F344/NSlc rats were fed normal chow diet or high-fat (HF) diet for 7 weeks. The HF-fed rats were either administered candesartan cilexetil (5 mg.kg(-1).day(-1)), exercise-trained, or received a combination of these 2 treatments. KEY FINDINGS: Oral glucose tolerance tests (OGTT) showed that combined treatment with candesartan cilexetil and exercise increased glucose tolerance as compared with each treatment alone in HF-fed rats. Moreover, euglycemic-hyperinsulinemic clamp analysis showed improvement in glucose infusion rate with exercise training or candesartan cilexetil treatment alone, and further improvement was observed with the combination treatment. Systolic blood pressure improved with candesartan cilexetil but not with exercise alone. Finally, Glut-4 protein expression in soleus muscle was decreased with HF diet, and the expression was increased by exercise and not candesartan cilexetil treatment. SIGNIFICANCE: These results suggest that the combination of candesartan cilexetil and exercise training improves insulin resistance as compared with each treatment alone. PMID- 22210188 TI - Interaction of protein inhibitor of activated STAT 2 (PIAS2) with receptor of activated C kinase 1, RACK1. AB - In this study, the evolutionarily conserved intracellular adaptor protein, receptor of activated C kinase 1 (RACK1) was identified as a novel interaction partner of protein inhibitor of activated STAT 2 (PIAS2) using a yeast two-hybrid screening system. The direct interaction and co-localization of RACK1 with PIAS2 was confirmed by immunoprecipitation and immunofluorescence staining analysis, respectively. The 5th to 7th Trp-Asp 40 (5-7 WD40) repeats of RACK1 were identified as the minimal domain required for interaction with PIAS2 by deletion analysis. Furthermore, multiple PIAS2-domains, particularly the 'PINIT' and RLD domains, bind the RACK1 5-7 WD40 domain. PMID- 22210189 TI - Phosphorylation of Akt/GSK-3beta/eNOS amplifies 5-HT2B receptor blockade mediated anti-hypertrophic effect in rats. AB - Herein, we studied the cross talk between 5-HT(2B) receptor blocker (SB-204741) and GSK-3beta inhibitor (SB-216763) in isoproterenol-induced cardiac hypertrophy for 28 days. SB-204741 treatment significantly ameliorated (P<0.05) myocardial dysfunction, myocyte area, fibrosis and myocardial architecture in isoproterenol insulted myocardium. Moreover, this improvement in functional and morphological changes was associated with suppression of hypertrophic (BNP and CK-MB), inflammatory (IKK-beta/NF-kappaB/TNF-alpha and CRP), and apoptotic markers (TUNEL positivity and Bax expression) along with phosphorylation of Akt/GSK-3beta/beta catenin/eNOS. Intriguingly, co-treatment with GSK-3beta inhibitor (P<0.01) further amplified the anti-hypertrophic effect of SB-204741 (P<0.05) such that the effect was indistinguishable from that of vehicle treated rats. Thus, 5 HT(2B) receptor blockade mediated anti-hypertrophic effect is atleast in part is governed through phosphorylation of Akt/GSK-3beta/beta-catenin/eNOS via attenuating inflammatory and apoptotic pathways. PMID- 22210190 TI - Redox properties of tyrosine and related molecules. AB - Redox reactions of tyrosine play key roles in many biological processes, including water oxidation and DNA synthesis. We first review the redox properties of tyrosine (and other phenols) in small molecules and related polypeptides, then report work on (H20)/(Y48)-modified Pseudomonas aeruginosa azurin. The crystal structure of this protein (1.18A resolution) shows that H20 is strongly hydrogen bonded to Y48 (2.7-2.8A tyrosine-O to histidine-N distance). A firm conclusion is that proper tuning of the tyrosine potential by a proton-accepting base is critical for biological redox functions. PMID- 22210191 TI - Do breast cancer survivors increase their physical activity and enhance their health-related quality of life after attending community-based wellness workshops? AB - Many breast cancer survivors may be at increased risk for physical and psychological complications from cancer treatments. Research has shown that regular exercise can help ameliorate some of the lingering side effects of breast cancer treatments and improve health-related quality of life (HRQOL). Additionally, certain stress management techniques have helped increase HRQOL in breast cancer survivors. Few educational programs exist which address both the promotion of physical activity and use of mindfulness-based strategies to improve the health of breast cancer survivors. Community-based wellness workshops were designed to promote regular exercise and use of mindfulness-based techniques. There was an increase in physical activity and improvements on several HRQOL domains 1 month following the exercise workshops; although the results were not significant, they are encouraging. PMID- 22210192 TI - Genetic transformation of Diaporthe phaseolorum, an endophytic fungus found in mangrove forests, mediated by Agrobacterium tumefaciens. AB - We describe the genetic transformation of the mycelial tissue of Diaporthe phaseolorum, an endophytic fungus isolated from the mangrove species Laguncularia racemosa, using Agrobacterium tumefaciens-mediated transformation (ATMT). ATMT uses both the hygromycin B resistant (hph) gene and green fluorescent protein as the selection agents. The T-DNA integration into the fungal genome was assessed by both PCR and Southern blotting. All transformants examined were mitotically stable. An analysis of the T-DNA flanking sequences by thermal asymmetric interlaced PCR (TAIL-PCR) demonstrated that the disrupted genes in the transformants had similarities with conserved domains in proteins involved in antibiotic biosynthesis pathways. A library of 520 transformants was generated, and 31 of these transformants had no antibiotic activity against Staphylococcus aureus, an important human pathogen. The protocol described here, using ATMT in D. phaseolorum, will be useful for the identification and analysis of fungal genes controlling pathogenicity and antibiotic pathways. Moreover, this protocol may be used as a reference for other species in the Diaporthe genus. This is the first report to describe Agrobacterium-mediated transformation of D. phaseolorum as a tool for insertional mutagenesis. PMID- 22210193 TI - Reconstruction of structural evolution in the trnL intron P6b loop of symbiotic Nostoc (Cyanobacteria). AB - In this study we reconstruct the structural evolution of the hyper-variable P6b region of the group I trnLeu intron in a monophyletic group of lichen-symbiotic Nostoc strains and establish it as a useful marker in the phylogenetic analysis of these organisms. The studied cyanobacteria occur as photosynthetic and/or nitrogen-fixing symbionts in lichen species of the diverse Nephroma guild. Phylogenetic analyses and secondary structure reconstructions are used to improve the understanding of the replication mechanisms in the P6b stem-loop and to explain the observed distribution patterns of indels. The variants of the P6b region in the Nostoc clade studied consist of different combinations of five sequence modules. The distribution of indels together with the ancestral character reconstruction performed enables the interpretation of the evolution of each sequence module. Our results indicate that the indel events are usually associated with single nucleotide changes in the P6b region and have occurred several times independently. In spite of their homoplasy, they provide phylogenetic information for closely related taxa. Thus we recognize that features of the P6b region can be used as molecular markers for species identification and phylogenetic studies involving symbiotic Nostoc cyanobacteria. PMID- 22210194 TI - Infant safe sleep: efforts to improve education and awareness. PMID- 22210195 TI - Gene therapy: a genetic era of technological development to treat pediatric genetic disorders. PMID- 22210196 TI - Stress reactivity in young marmosets (Callithrix geoffroyi): ontogeny, stability, and lack of concordance among co-twins. AB - Variation in response styles in the hypothalamic-pituitary-adrenal (HPA) axis are known to be predictors of short- and long-term health outcomes. The nature of HPA responses to stressors changes with developmental stage, and some components of the stress response exhibit long-term individual consistency (i.e., are trait like) while others are transient or variable (i.e., state-like). Here we evaluated the response of marmoset monkeys (Callithrix geoffroyi) to a standardized social stressor (social separation and exposure to a novel environment) at three different stages of development: juvenile, subadult, and young adult. We monitored levels of urinary cortisol (CORT), and derived multiple measures of HPA activity: Baseline CORT, CORT reactivity, CORT Area Under the Curve (AUC), and CORT regulation. Juvenile marmosets exhibited the most dramatic stress response, had higher AUCs, and tended to show poorer regulation. While baseline CORT and CORT regulation were not consistent within an individual across age, CORT reactivity and measures of AUC were highly correlated across time; i.e., individuals with high stress reactivity and AUC as juveniles also had high measures as subadults and adults, and vice-versa. Marmoset co-twins did not exhibit similar patterns of stress reactivity. These data suggest that regardless of the source of variation in stress response styles in marmosets, individually distinctive patterns are established by six months of age, and persist for at least a year throughout different phases of marmoset life history. PMID- 22210197 TI - The acute glucocorticoid stress response does not differentiate between rewarding and aversive social stimuli in rats. AB - The mere presence of elevated plasma levels of corticosterone is generally regarded as evidence of compromised well-being. However, environmental stimuli do not necessarily need to be of a noxious or adverse nature to elicit activation of the stress response systems. In the present study, the physiological and neuroendocrine responses to repeated social stimuli that can be regarded as emotional opposites, i.e. social defeat and sexual behavior, were compared. Similar corticosterone responses were observed in animals confronted for the first time with either a highly aggressive male intruder or a receptive female, but a decrease was noticed in defeated rats tested during a third interaction. Only if animals are being physically attacked does the corticosterone response remain similar to the one observed during sexual behavior. In addition, the number of activated cells in the parvocellular hypothalamic paraventricular nucleus, as visualized by c-Fos immunocytochemistry, shows no difference between rats 1h after the third exposure to defeat or sex. Finally, biotelemetric recordings of heart rate, body temperature and locomotor activity show a robust response to both social stimuli that is generally, however, higher in animals being confronted with a receptive female. The data clearly indicate that acute plasma corticosterone levels are not reflecting the emotional valence of a salient stimulus. The magnitude of the response seems to be a direct reflection of the behavioral activity and hence of the metabolic requirements of activated tissues. Next to its direct metabolic role, acute increases in plasma corticosterone will have neurobiological and behavioral effects that largely depend on the neural circuitry that is activated by the stimulus that triggered its release. PMID- 22210199 TI - Reproductive rate, not dominance status, affects fecal glucocorticoid levels in breeding female meerkats. AB - Glucocorticoid hormones (GCs) have been studied intensively to understand the associations between physiological stress and reproductive skew in animal societies. However, we have little appreciation of the range of either natural levels within and among individuals, or the associations among dominance status, reproductive rate and GCs levels during breeding. To address these shortcomings, we examined variation in fecal glucocorticoid metabolites (fGC) during breeding periods in free-ranging female meerkats (Suricata suricatta) over 11 years. The vast majority of variation in fGC levels was found within breeding events by the same female (~87%), with the remaining variation arising among breeding events and among females. Concentrations of fGC generally tripled as pregnancy progressed. However, females with a high reproductive rate, defined as those conceiving within a month following parturition (mean = 9 days postpartum), showed significant reductions in fGC in the final 2 weeks before parturition. Despite these reductions, females with a high reproductive rate had higher fGC levels at conception of the following litter than those breeding at a low rate. After controlling for the higher reproductive rate of dominants, we found no association between levels of fGC and either age or dominance status. Our results suggest that one should be cautious about interpreting associations between dominance status, reproductive skew and GCs levels, without knowledge of the natural variation in GCs levels within and among females. PMID- 22210198 TI - Dissociated functional pathways for appetitive and consummatory reproductive behaviors in male Syrian hamsters. AB - In many species, including Syrian hamsters, the generation of male reproductive behavior depends critically on the perception of female odor cues from conspecifics in the environment. The behavioral response to these odors is mediated by a network of steroid-sensitive ventral forebrain nuclei including the medial amygdala (MA), posterior bed nucleus of the stria terminalis (BNST) and medial preoptic area (MPOA). Previous studies have demonstrated that each of these three nuclei is required for appropriate sexual behavior and that MA preferentially sends female odor information directly to BNST and MPOA. It is unknown, however, how the functional connections between MA and BNST and/or MPOA are organized to generate different aspects of reproductive behavior. Therefore, the following experiments used the asymmetrical pathway lesion technique to test the role of the functional connections between MA and BNST and/or MPOA in odor preference and copulatory behaviors. Lesions that functionally disconnected MA from MPOA eliminated copulatory behavior but did not affect odor preference. In contrast, lesions that functionally disconnected MA from BNST eliminated preference for volatile female odors but did not affect preference for directly contacted odors or copulatory behavior. These results therefore demonstrate a double dissociation in the functional connections required for attraction to volatile sexual odors and copulation and, more broadly, suggest that appetitive and consummatory reproductive behaviors are mediated by distinct neural pathways. PMID- 22210200 TI - Titanium dioxide nanoparticles induced cytotoxicity, oxidative stress and DNA damage in human amnion epithelial (WISH) cells. AB - Titanium dioxide nanoparticles (TiO(2)-NPs) induced cytotoxicity and DNA damage have been investigated using human amnion epithelial (WISH) cells, as an in vitro model for nanotoxicity assessment. Crystalline, polyhedral rutile TiO(2)-NPs were synthesized and characterized using X-ray diffraction (XRD), UV-Visible spectroscopy, Fourier transform infra red (FTIR) spectroscopy, and transmission electron microscopic (TEM) analyses. The neutral red uptake (NRU) and [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assays revealed the concentration dependent cytotoxic effects of TiO(2)-NPs (30.6nm) in concentration range of 0.625-10MUg/ml. Cells exposed to TiO(2)-NPs (10MUg/ml) exhibited significant reduction (46.3% and 34.6%; p<0.05) in catalase activity and glutathione (GSH) level, respectively. Treated cells showed 1.87-fold increase in intracellular reactive oxygen species (ROS) generation and 7.3% (p<0.01) increase in G(2)/M cell cycle arrest, as compared to the untreated control. TiO(2)-NPs treated cells also demonstrated the formation of DNA double strand breaks with 14.6-fold (p<0.05) increase in Olive tail moment (OTM) value at 20MUg/ml concentration, vis-a-vis untreated control, under neutral comet assay conditions. Thus, the reduction in cell viability, morphological alterations, compromised antioxidant system, intracellular ROS production, and significant DNA damage in TiO(2)-NPs exposed cells signify the potential of these NPs to induce cyto- and genotoxicity in cultured WISH cells. PMID- 22210201 TI - The use of titanium clips in septal surgery for correction and strengthening. AB - Permanent correction of septal deformities is one of the most difficult and controversial subjects in aesthetic nasal surgery. The main reasons for failure in most of the corrective procedures are either not to weaken the septal cartilage enough to straighten it, or to treat the septum too radically causing iatrogenic deformities or predisposing it to new deformities postoperatively. Our approach to correct septal deformities relies on the principle of strengthening/reinforcing the septal cartilage (with or without some weakening maneuvers to correct the deformities beforehand) with application of titanium hemoclips at some critical locations in septum. Eighty-seven patients operated on between 2007 and 2009 are included in this study. Thirty-six of these patients had combined septo-nasal deformities while the remaining 51 had solely septal deformities. In 30 patients with septo-nasal deformity the technique was proven to be successful. The remaining 6 patients of this group had axial nasal deformity (rather than intrinsic septal problems) and did not respond to our technique successfully. Within four years of follow up, we did not encounter any recurrences, infections, ulcerations or exposure in the mucosa covering the titanium clips. None of the titanium clips were required to be removed for any reasons. PMID- 22210203 TI - Quick Response codes in plastic surgery. PMID- 22210204 TI - Rapid filtration separation-based sample preparation method for Bacillus spores in powdery and environmental matrices. AB - Authorities frequently need to analyze suspicious powders and other samples for biothreat agents in order to assess environmental safety. Numerous nucleic acid detection technologies have been developed to detect and identify biowarfare agents in a timely fashion. The extraction of microbial nucleic acids from a wide variety of powdery and environmental samples to obtain a quality level adequate for these technologies still remains a technical challenge. We aimed to develop a rapid and versatile method of separating bacteria from these samples and then extracting their microbial DNA. Bacillus atrophaeus subsp. globigii was used as a simulant of Bacillus anthracis. We studied the effects of a broad variety of powdery and environmental samples on PCR detection and the steps required to alleviate their interference. With a benchmark DNA extraction procedure, 17 of the 23 samples investigated interfered with bacterial lysis and/or PCR-based detection. Therefore, we developed the dual-filter method for applied recovery of microbial particles from environmental and powdery samples (DARE). The DARE procedure allows the separation of bacteria from contaminating matrices that interfere with PCR detection. This procedure required only 2 min, while the DNA extraction process lasted 7 min, for a total of <10 min. This sample preparation procedure allowed the recovery of cleaned bacterial spores and relieved detection interference caused by a wide variety of samples. Our procedure was easily completed in a laboratory facility and is amenable to field application and automation. PMID- 22210206 TI - Engineering platforms for directed evolution of Laccase from Pycnoporus cinnabarinus. AB - While the Pycnoporus cinnabarinus laccase (PcL) is one of the most promising high redox-potential enzymes for environmental biocatalysis, its practical use has to date remained limited due to the lack of directed evolution platforms with which to improve its features. Here, we describe the construction of a PcL fusion gene and the optimization of conditions to induce its functional expression in Saccharomyces cerevisiae, facilitating its directed evolution and semirational engineering. The native PcL signal peptide was replaced by the alpha-factor preproleader, and this construct was subjected to six rounds of evolution coupled to a multiscreening assay based on the oxidation of natural and synthetic redox mediators at more neutral pHs. The laccase total activity was enhanced 8,000 fold: the evolved alpha-factor preproleader improved secretion levels 40-fold, and several mutations in mature laccase provided a 13.7-fold increase in k(cat). While the pH activity profile was shifted to more neutral values, the thermostability and the broad substrate specificity of PcL were retained. Evolved variants were highly secreted by Aspergillus niger (~23 mg/liter), which addresses the potential use of this combined-expression system for protein engineering. The mapping of mutations onto the PcL crystal structure shed new light on the oxidation of phenolic and nonphenolic substrates. Furthermore, some mutations arising in the evolved preproleader highlighted its potential for heterologous expression of fungal laccases in yeast (S. cerevisiae). PMID- 22210208 TI - Improvement of modified charcoal-cefoperazone-deoxycholate agar by supplementation with a high concentration of polymyxin B for detection of Campylobacter jejuni and C. coli in chicken carcass rinses. AB - Modified charcoal-cefoperazone-deoxycholate agar (mCCDA) was improved by supplementation with a high concentration of polymyxin B. The ability of the supplemented medium to isolate Campylobacter jejuni and C. coli from chicken carcass rinses was compared to that of Campy-Cefex agar and mCCDA. Modification of mCCDA with increased polymyxin B yielded a significantly (P < 0.05) higher isolation rate and greater selectivity than those achieved using Campy-Cefex agar and mCCDA. PMID- 22210207 TI - Dextran sodium sulfate-induced inflammation alters the expression of proteins by intestinal Escherichia coli strains in a gnotobiotic mouse model. AB - To identify Escherichia coli proteins involved in adaptation to intestinal inflammation, mice were monoassociated with the colitogenic E. coli strain UNC or with the probiotic E. coli strain Nissle. Intestinal inflammation was induced by treating the mice with 3.5% dextran sodium sulfate (DSS). Differentially expressed proteins in E. coli strains collected from cecal contents were identified by 2-dimensional difference gel electrophoresis. In both strains, acute inflammation led to the downregulation of pathways involved in carbohydrate breakdown and energy generation. Accordingly, DSS-treated mice had lower concentrations of bacterial fermentation products in their cecal contents than control mice. Differentially expressed proteins also included the Fe-S cluster repair protein NfuA, the tryptophanase TnaA, and the uncharacterized protein YggE. NfuA expression was 3-fold higher in E. coli strains from DSS-treated than from control mice. Reporter experiments confirmed the induction of nfuA in response to iron deprivation, mimicking Fe-S cluster destruction by inflammation. YggE expression, which has been reported to reduce the intracellular level of reactive oxygen species, was 4- to 8-fold higher in E. coli Nissle than in E. coli UNC. This was confirmed by in vitro reporter gene assays indicating that Nissle is better equipped to cope with oxidative stress than UNC. Nissle isolated from DSS-treated and control mice had TnaA levels 4- to 7-fold-higher than those of UNC. Levels of indole resulting from the TnaA reaction were higher in control animals associated with E. coli Nissle. Because of its anti-inflammatory effect, indole is hypothesized to be involved in the extension of the remission phase in ulcerative colitis described for E. coli Nissle. PMID- 22210205 TI - Spatial distribution of viruses associated with planktonic and attached microbial communities in hydrothermal environments. AB - Viruses play important roles in marine surface ecosystems, but little is known about viral ecology and virus-mediated processes in deep-sea hydrothermal microbial communities. In this study, we examined virus-like particle (VLP) abundances in planktonic and attached microbial communities, which occur in physical and chemical gradients in both deep and shallow submarine hydrothermal environments (mixing waters between hydrothermal fluids and ambient seawater and dense microbial communities attached to chimney surface areas or macrofaunal bodies and colonies). We found that viruses were widely distributed in a variety of hydrothermal microbial habitats, with the exception of the interior parts of hydrothermal chimney structures. The VLP abundance and VLP-to-prokaryote ratio (VPR) in the planktonic habitats increased as the ratio of hydrothermal fluid to mixing water increased. On the other hand, the VLP abundance in attached microbial communities was significantly and positively correlated with the whole prokaryotic abundance; however, the VPRs were always much lower than those for the surrounding hydrothermal waters. This is the first report to show VLP abundance in the attached microbial communities of submarine hydrothermal environments, which presented VPR values significantly lower than those in planktonic microbial communities reported before. These results suggested that viral lifestyles (e.g., lysogenic prevalence) and virus interactions with prokaryotes are significantly different among the planktonic and attached microbial communities that are developing in the submarine hydrothermal environments. PMID- 22210209 TI - Genetic characterization of Escherichia coli O104 isolates from different sources in the United States. AB - Escherichia coli O104 isolates collected from different sources in the United States were examined for virulence genes typical of enterohemorrhagic E. coli and those identified in the O104:H4 isolate associated with the 2011 German outbreak. The unexpected presence of virulence markers in these isolates highlights the importance of screening unusual and potentially pathogenic Shiga toxin-producing E. coli serotypes. PMID- 22210210 TI - Enhanced microbial utilization of recalcitrant cellulose by an ex vivo cellulosome-microbe complex. AB - A cellulosome-microbe complex was assembled ex vivo on the surface of Bacillus subtilis displaying a miniscaffoldin that can bind with three dockerin-containing cellulase components: the endoglucanase Cel5, the processive endoglucanase Cel9, and the cellobiohydrolase Cel48. The hydrolysis performances of the synthetic cellulosome bound to living cells, the synthetic cellulosome, a noncomplexed cellulase mixture with the same catalytic components, and a commercial fungal enzyme mixture were investigated on low-accessibility recalcitrant Avicel and high-accessibility regenerated amorphous cellulose (RAC). The cell-bound cellulosome exhibited 4.5- and 2.3-fold-higher hydrolysis ability than cell-free cellulosome on Avicel and RAC, respectively. The cellulosome-microbe synergy was not completely explained by the removal of hydrolysis products from the bulk fermentation broth by free-living cells and appeared to be due to substrate channeling of long-chain hydrolysis products assimilated by the adjacent cells located in the boundary layer. Our results implied that long-chain hydrolysis products in the boundary layer may inhibit cellulosome activity to a greater extent than the short-chain products in bulk phase. The findings that cell-bound cellulosome expedited the microbial cellulose utilization rate by 2.3- to 4.5 fold would help in the development of better consolidated bioprocessing microorganisms (e.g., B. subtilis) that can hydrolyze recalcitrant cellulose rapidly at low secretory cellulase levels. PMID- 22210211 TI - Intraspecies biodiversity of the genetically homologous species Brucella microti. AB - Brucellosis is one of the major bacterial zoonoses worldwide. In the past decade, an increasing number of atypical Brucella strains and species have been described. Brucella microti in particular has attracted attention, because this species not only infects mammalian hosts but also persists in soil. An environmental reservoir may pose a new public health risk, leading to the reemergence of brucellosis. In a polyphasic approach, comprising conventional microbiological techniques and extensive biochemical and molecular techniques, all currently available Brucella microti strains were characterized. While differing in their natural habitats and host preferences, B. microti isolates were found to possess identical 16S rRNA, recA, omp2a, and omp2b gene sequences and identical multilocus sequence analysis (MLSA) profiles at 21 different genomic loci. Only highly variable microsatellite markers of multiple-locus variable-number tandem repeat (VNTR) analysis comprising 16 loci (MLVA-16) showed intraspecies discriminatory power. In contrast, biotyping demonstrated striking differences within the genetically homologous species. The majority of the mammalian isolates agglutinated only with monospecific anti-M serum, whereas soil isolates agglutinated with anti-A, anti-M, and anti-R sera. Bacteria isolated from animal sources were lysed by phages F1, F25, Tb, BK2, Iz, and Wb, whereas soil isolates usually were not. Rough strains of environmental origin were lysed only by phage R/C. B. microti exhibited high metabolic activities similar to those of closely related soil organisms, such as Ochrobactrum spp. Each strain was tested with 93 different substrates and showed an individual metabolic profile. In summary, the adaptation of Brucella microti to a specific habitat or host seems to be a matter of gene regulation rather than a matter of gene configuration. PMID- 22210212 TI - Characteristics of the freshwater cyanobacterium Microcystis aeruginosa grown in iron-limited continuous culture. AB - A continuous culturing system (chemostat) made of metal-free materials was successfully developed and used to maintain Fe-limited cultures of Microcystis aeruginosa PCC7806 at nanomolar iron (Fe) concentrations (20 to 50 nM total Fe). EDTA was used to maintain Fe in solution, with bioavailable Fe controlled by absorption of light by the ferric EDTA complex and resultant reduction of Fe(III) to Fe(II). A kinetic model describing Fe transformations and biological uptake was applied to determine the biologically available form of Fe (i.e., unchelated ferrous iron) that is produced by photoreductive dissociation of the ferric EDTA complex. Prediction by chemostat theory modified to account for the light mediated formation of bioavailable Fe rather than total Fe was in good agreement with growth characteristics of M. aeruginosa under Fe limitation. The cellular Fe quota increased with increasing dilution rates in a manner consistent with the Droop theory. Short-term Fe uptake assays using cells maintained at steady state indicated that M. aeruginosa cells vary their maximum Fe uptake rate (rho(max)) depending on the degree of Fe stress. The rate of Fe uptake was lower for cells grown under conditions of lower Fe availability (i.e., lower dilution rate), suggesting that cells in the continuous cultures adjusted to Fe limitation by decreasing rho(max) while maintaining a constant affinity for Fe. PMID- 22210214 TI - Metabolic engineering of Clostridium acetobutylicum ATCC 824 for isopropanol butanol-ethanol fermentation. AB - Clostridium acetobutylicum naturally produces acetone as well as butanol and ethanol. Since acetone cannot be used as a biofuel, its production needs to be minimized or suppressed by cell or bioreactor engineering. Thus, there have been attempts to disrupt or inactivate the acetone formation pathway. Here we present another approach, namely, converting acetone to isopropanol by metabolic engineering. Since isopropanol can be used as a fuel additive, the mixture of isopropanol, butanol, and ethanol (IBE) produced by engineered C. acetobutylicum can be directly used as a biofuel. IBE production is achieved by the expression of a primary/secondary alcohol dehydrogenase gene from Clostridium beijerinckii NRRL B-593 (i.e., adh(B-593)) in C. acetobutylicum ATCC 824. To increase the total alcohol titer, a synthetic acetone operon (act operon; adc-ctfA-ctfB) was constructed and expressed to increase the flux toward isopropanol formation. When this engineering strategy was applied to the PJC4BK strain lacking in the buk gene (encoding butyrate kinase), a significantly higher titer and yield of IBE could be achieved. The resulting PJC4BK(pIPA3-Cm2) strain produced 20.4 g/liter of total alcohol. Fermentation could be prolonged by in situ removal of solvents by gas stripping, and 35.6 g/liter of the IBE mixture could be produced in 45 h. PMID- 22210215 TI - Detection and differentiation of avian mycoplasmas by surface-enhanced Raman spectroscopy based on a silver nanorod array. AB - Mycoplasma gallisepticum is a bacterial pathogen of poultry that is estimated to cause annual losses exceeding $780 million. The National Poultry Improvement Plan guidelines recommend regular surveillance and intervention strategies to contain M. gallisepticum infections and ensure mycoplasma-free avian stocks, but several factors make detection of M. gallisepticum and diagnosis of M. gallisepticum infection a major challenge. Current techniques are laborious, require special expertise, and are typically plagued by false results. In this study, we describe a novel detection strategy which uses silver nanorod array-surface-enhanced Raman spectroscopy (NA-SERS) for direct detection of avian mycoplasmas. As a proof of concept for use in avian diagnostics, we used NA-SERS to detect and differentiate multiple strains of avian mycoplasma species, including Acholeplasma laidlawii, Mycoplasma gallinarum, Mycoplasma gallinaceum, Mycoplasma synoviae, and M. gallisepticum, including vaccine strains 6/85, F, and ts-11. Chemometric multivariate analysis of spectral data was used to classify these species rapidly and accurately, with >93% sensitivity and specificity. Furthermore, NA-SERS had a lower limit of detection that was 100-fold greater than that of standard PCR and comparable to that of real-time quantitative PCR. Detection of M. gallisepticum in choanal cleft swabs from experimentally infected birds yielded good sensitivity and specificity, suggesting that NA-SERS is applicable for clinical detection. PMID- 22210213 TI - Role for Rhizobium rhizogenes K84 cell envelope polysaccharides in surface interactions. AB - Rhizobium rhizogenes strain K84 is a commercial biocontrol agent used worldwide to control crown gall disease. The organism binds tightly to polypropylene substrate and efficiently colonizes root surfaces as complex, multilayered biofilms. A genetic screen identified two mutants in which these surface interactions were affected. One of these mutants failed to attach and form biofilms on the abiotic surface although, interestingly, it exhibited normal biofilm formation on the biological root tip surface. This mutant is disrupted in a wcbD ortholog gene, which is part of a large locus predicted to encode functions for the biosynthesis and export of a group II capsular polysaccharide (CPS). Expression of a functional copy of wcbD in the mutant background restored the ability of the bacteria to attach and form normal biofilms on the abiotic surface. The second identified mutant attached and formed visibly denser biofilms on both abiotic and root tip surfaces. This mutant is disrupted in the rkpK gene, which is predicted to encode a UDP-glucose 6-dehydrogenase required for O-antigen lipopolysaccharide (LPS) and K-antigen capsular polysaccharide (KPS) biosynthesis in rhizobia. The rkpK mutant from strain K84 was deficient in O-antigen synthesis and exclusively produced rough LPS. We also show that strain K84 does not synthesize the KPS typical of some other rhizobia strains. In addition, we identified a putative type II CPS, distinct from KPS, that mediates cell-surface interactions, and we show that O antigen of strain K84 is necessary for normal cell-cell interactions in the biofilms. PMID- 22210216 TI - Rapid genomic-scale analysis of Escherichia coli O104:H4 by using high-resolution alternative methods to next-generation sequencing. AB - Two technologies, involving DNA microarray and optical mapping, were used to quickly assess gene content and genomic architecture of recent emergent Escherichia coli O104:H4 and related strains. In real-time outbreak investigations, these technologies can provide congruent perspectives on strain, serotype, and pathotype relationships. Our data demonstrated clear discrimination between clinically, temporally, and geographically distinct O104:H4 isolates and rapid characterization of strain differences. PMID- 22210217 TI - Time-dependent profiles of transcripts encoding lignocellulose-modifying enzymes of the white rot fungus Phanerochaete carnosa grown on multiple wood substrates. AB - The abundances of nine transcripts predicted to encode lignocellulose-modifying enzymes were measured over the course of Phanerochaete carnosa cultivation on four wood species. Profiles were consistent with sequential decay; transcripts encoding lignin-degrading peroxidases featured a significant substrate-dependent response. The chitin synthase gene was identified as the optimal internal reference gene for transcript quantification. PMID- 22210218 TI - Production of indole-3-acetic acid via the indole-3-acetamide pathway in the plant-beneficial bacterium Pseudomonas chlororaphis O6 is inhibited by ZnO nanoparticles but enhanced by CuO nanoparticles. AB - The beneficial bacterium Pseudomonas chlororaphis O6 produces indole-3-acetic acid (IAA), a plant growth regulator. However, the pathway involved in IAA production in this bacterium has not been reported. In this paper we describe the involvement of the indole-3-acetamide (IAM) pathway in IAA production in P. chlororaphis O6 and the effects of CuO and ZnO nanoparticles (NPs). Sublethal levels of CuO and ZnO NPs differentially affected the levels of IAA secreted in medium containing tryptophan as the precursor. After 15 h of growth, CuO NP exposed cells had metabolized more tryptophan than the control and ZnO NP challenged cells. The CuO NP-treated cells produced higher IAA levels than control cultures lacking NPs. In contrast, ZnO NPs inhibited IAA production. Mixing of CuO and ZnO NPs resulted in an intermediate level of IAA production relative to the levels in the separate CuO and ZnO NP treatments. The effect of CuO NPs on IAA levels could be duplicated by ions at the concentrations released from the NPs. However, ion release did not account for the inhibition caused by the ZnO NPs. The mechanism underlying changes in IAA levels cannot be accounted for by effects on transcript accumulation from genes encoding a tryptophan permease or the IAM hydrolase in 15-h cultures. These findings raise the issue of whether sublethal doses of NPs would modify the beneficial effects of association between plants and bacteria. PMID- 22210219 TI - Development of a markerless gene replacement system for Acidithiobacillus ferrooxidans and construction of a pfkB mutant. AB - The extremely acidophilic, chemolithoautotrophic Acidithiobacillus ferrooxidans is an important bioleaching bacterium of great value in the metallurgical industry and environmental protection. In this report, a mutagenesis system based on the homing endonuclease I-SceI was developed to produce targeted, unmarked gene deletions in the strain A. ferrooxidans ATCC 23270. A targeted phosphofructokinase (PFK) gene (pfkB) mutant of A. ferrooxidans ATCC 23270 was constructed by homologous recombination and identified by PCR with specific primers as well as Southern blot analysis. This potential pfkB gene (AFE_1807) was also characterized by expression in PFK-deficient Escherichia coli cells, and heteroexpression of the PFKB protein demonstrated that it had functional PFK activity, though it was significantly lower (about 800-fold) than that of phosphofructokinase-2 (PFK-B) expressed by the pfkB gene from E. coli K-12. The function of the potential PFKB protein in A. ferrooxidans was demonstrated by comparing the properties of the pfkB mutant with those of the wild type. The pfkB mutant strain displayed a relatively reduced growth capacity in S(0) medium (0.5% [wt/vol] elemental sulfur in 9K basal salts solution adjusted to pH 3.0 with H(2)SO(4)), but the mutation did not completely prevent A. ferrooxidans from assimilating exogenous glucose. The transcriptional analysis of some related genes in central carbohydrate metabolism in the wild-type and mutant strains with or without supplementation of glucose was carried out by quantitative reverse transcription-PCR. This report suggests that the markerless mutagenesis strategy could serve as a model for functional studies of other genes of interest from A. ferrooxidans and multiple mutations could be made in a single A. ferrooxidans strain. PMID- 22210220 TI - Wolbachia strain wAlbB enhances infection by the rodent malaria parasite Plasmodium berghei in Anopheles gambiae mosquitoes. AB - Wolbachia, a common bacterial endosymbiont of insects, has been shown to protect its hosts against a wide range of pathogens. However, not all strains exert a protective effect on their host. Here we assess the effects of two divergent Wolbachia strains, wAlbB from Aedes albopictus and wMelPop from Drosophila melanogaster, on the vector competence of Anopheles gambiae challenged with Plasmodium berghei. We show that the wAlbB strain significantly increases P. berghei oocyst levels in the mosquito midgut while wMelPop modestly suppresses oocyst levels. The wAlbB strain is avirulent to mosquitoes while wMelPop is moderately virulent to mosquitoes pre-blood meal and highly virulent after mosquitoes have fed on mice. These various effects on P. berghei levels suggest that Wolbachia strains differ in their interactions with the host and/or pathogen, and these differences could be used to dissect the molecular mechanisms that cause interference of pathogen development in mosquitoes. PMID- 22210221 TI - Garvieacin Q, a novel class II bacteriocin from Lactococcus garvieae BCC 43578. AB - Lactococcus garvieae BCC 43578 produces a novel class II bacteriocin, garvieacin Q (GarQ), 70 amino acids in length and containing a 20-amino-acid N-terminal leader peptide. It is cleaved at the Gly-Gly site to generate the mature GarQ (5,339 Da), which is especially inhibitory against Listeria monocytogenes ATCC 19115 and other L. garvieae strains. PMID- 22210222 TI - Construction of a genetic linkage map based on amplified fragment length polymorphism markers and development of sequence-tagged site markers for marker assisted selection of the sporeless trait in the oyster mushroom (Pleurotus eryngii). AB - A large number of spores from fruiting bodies can lead to allergic reactions and other problems during the cultivation of edible mushrooms, including Pleurotus eryngii (DC.) Quel. A cultivar harboring a sporulation-deficient (sporeless) mutation would be useful for preventing these problems, but traditional breeding requires extensive time and labor. In this study, using a sporeless P. eryngii strain, we constructed a genetic linkage map to introduce a molecular breeding program like marker-assisted selection. Based on the segregation of 294 amplified fragment length polymorphism markers, two mating type factors, and the sporeless trait, the linkage map consisted of 11 linkage groups with a total length of 837.2 centimorgans (cM). The gene region responsible for the sporeless trait was located in linkage group IX with 32 amplified fragment length polymorphism markers and the B mating type factor. We also identified eight markers closely linked (within 1.2 cM) to the sporeless locus using bulked-segregant analysis based amplified fragment length polymorphism. One such amplified fragment length polymorphism marker was converted into two sequence-tagged site markers, SD488-I and SD488-II. Using 14 wild isolates, sequence-tagged site analysis indicated the potential usefulness of the combination of two sequence-tagged site markers in cross-breeding of the sporeless strain. It also suggested that a map constructed for P. eryngii has adequate accuracy for marker-assisted selection. PMID- 22210223 TI - Plasmid localization and organization of melamine degradation genes in Rhodococcus sp. strain Mel. AB - Rhodococcus sp. strain Mel was isolated from soil by enrichment and grew in minimal medium with melamine as the sole N source with a doubling time of 3.5 h. Stoichiometry studies showed that all six nitrogen atoms of melamine were assimilated. The genome was sequenced by Roche 454 pyrosequencing to 13* coverage, and a 22.3-kb DNA region was found to contain a homolog to the melamine deaminase gene trzA. Mutagenesis studies showed that the cyanuric acid hydrolase and biuret hydrolase genes were clustered together on a different 17.9-kb contig. Curing and gene transfer studies indicated that 4 of 6 genes required for the complete degradation of melamine were located on an ~265-kb self-transmissible linear plasmid (pMel2), but this plasmid was not required for ammeline deamination. The Rhodococcus sp. strain Mel melamine metabolic pathway genes were located in at least three noncontiguous regions of the genome, and the plasmid borne genes encoding enzymes for melamine metabolism were likely recently acquired. PMID- 22210225 TI - Quantitative and qualitative analysis of antibody response after dose sparing intradermal 2009 H1N1 vaccination. PMID- 22210224 TI - Comparative assessment of a DNA and protein Leishmania donovani gamma glutamyl cysteine synthetase vaccine to cross-protect against murine cutaneous leishmaniasis caused by L. major or L. mexicana infection. AB - Leishmaniasis is a major health problem and it is estimated that 12 million people are currently infected. A vaccine which could cross-protect people against different Leishmania spp. would facilitate control of this disease as more than one species of Leishmania may be present. In this study the ability of a DNA vaccine, using the full gene sequence for L. donovani gamma glutamyl cysteine synthetase (gammaGCS) incorporated in the pVAX vector (pVAXgammaGCS), and a protein vaccine, using the corresponding recombinant L. donovani gammaGCS protein (LdgammaGCS), to protect against L. major or L. mexicana infection was evaluated. DNA vaccination gave transient protection against L. major and no protection against L. mexicana despite significantly enhancing specific antibody titres in vaccinated infected mice compared to infected controls. Vaccination with the LdgammaGCS protected against both species but only if the protein was incorporated into non-ionic surfactant vesicles for L. mexicana. The results of this study indicate that a L. donovani gammaGCS vaccine could be used to vaccinate against more than one Leishmania species but only if the recombinant protein is used. PMID- 22210226 TI - Structural characterisation, stability and antibody recognition of chimeric NHBA GNA1030: an investigational vaccine component against Neisseria meningitidis. AB - A new generation multi-component vaccine, principally directed against serogroup B Neisseria meningitidis (4CMenB), has recently been developed. One of its components, identified through reverse vaccinology, is the neisserial heparin binding antigen (NHBA) which is included in the formulation as a novel NHBA GNA1030 fusion protein (NHBA-FP). We describe here the biophysical characteristics of this vaccine antigen to understand better its structural properties in solution and concurrent immunogenicity prior to formulation. By deliberately stressing the protein to lose its immune responses, we were able to study the protein's structural changes at the molecular level. The unmodified NHBA-FP was found to be mainly monomeric with mass of 67kDa and secondary structure dominated by beta-sheets and turns (57% average). The antigen was very stable in storage buffer. It could be forced to unfold in a low-salt buffer resulting in the exposure of one of its two tryptophan residues at 50 degrees C. Long-term stress studies (10-15 days at 37 degrees C) showed modification in the chromatographic and electrophoretic profiles with progressive degradation and aggregation. Since there was little change in secondary structure (as monitored by circular dichroism and tryptophan fluorescence spectroscopy), the loss of functional immunogenicity of the thermal stressed protein could be mainly attributed to the observed fragmentation and aggregation. We therefore conclude that the maintenance of the intact, non-fragmented state of the NHBA-FP is important to preserve its functional immunogenicity. This may thus be utilised as an assay for the control testing of the protein. PMID- 22210228 TI - The endoplasmic reticulum stress response is involved in apoptosis induced by aloe-emodin in HK-2 cells. AB - Aloe-emodin (AE; 1,8-dihydroxy-3-hydroxymethyl-9,10-anthracenedione) is one of the primary active compounds in total rhubarb anthraquinones (TRAs), which induce nephrotoxicity in rats. However, it is still not known whether AE has a similar effect on human kidney cells. In this study, 3-(4,5,-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assays showed that AE decreases the viability of HK-2 cells (a human proximal tubular epithelial cell line) in a dose- and time dependent manner. AE induced G2/M arrest of cell cycle in HK-2 cells, which was detected with propidium iodide (PI) staining. This apoptosis was further investigated by Hoechst staining, transmission electron microscopy (TEM), DNA fragmentation, and Annexin V/PI staining. Apoptosis of the cells was associated with caspase 3 activation, which was detected by Western blot analysis and a caspase activity assay. In addition, changes in the endoplasmic reticulum (ER) ultrastructure as observed by TEM showed the effects of AE on ER. Treatment with AE also resulted in an increase in eukaryotic initiation factor-2alpha (eIF 2alpha) phosphorylation, X-box binding protein 1 (XBP1) mRNA splicing, c-Jun N terminal kinase (JNK) phosphorylation, glucose-regulated protein (GRP) 78 and CAAT/enhancer-binding protein-homologous protein (CHOP) accumulation. These results suggest that AE induces ER stress in HK-2 cells, which is involved in AE induced apoptosis. In conclusion, AE induces apoptosis in HK-2 cells, and the ER stress is involved in AE-induced apoptosis in vitro. The implications of the toxic effects of AE for clinical use are unclear and these findings should be taken into account in the risk assessment for human exposure. PMID- 22210229 TI - Dietary chlorophyllin inhibits the canonical NF-kappaB signaling pathway and induces intrinsic apoptosis in a hamster model of oral oncogenesis. AB - Chlorophyllin, a water-soluble, semi-synthetic derivative of the ubiquitous green pigment chlorophyll is shown to exert potent anticarcinogenic effects. In the present study, we investigated the chemopreventive effects of chlorophyllin on 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis by analyzing the expression of NF-kappaB family members and markers of intrinsic apoptosis. Dietary administration of chlorophyllin (4 mg/kg bw) suppressed the development of HBP carcinomas by inhibiting the canonical NF kappaB signaling pathway by downregulating IKKbeta, preventing the phosphorylation of IkappaB-alpha, and reducing the expression of nuclear NF kappaB. Inactivation of NF-kappaB signaling by chlorophyllin was associated with the induction of intrinsic apoptosis as evidenced by modulation of Bcl-2 family proteins, enforced nuclear localization of survivin, upregulation of apoptogenic molecules, activation of caspases, and cleavage of PARP. The results of the present study demonstrate that chlorophyllin inhibits the development of DMBA induced HBP carcinogenesis by targeting NF-kappaB and the intrinsic apoptotic pathway. Thus, dietary agents such as chlorophyllin that simultaneously target divergent pathways of cell survival and cell death are novel candidates for cancer chemoprevention. PMID- 22210230 TI - Deletion of the AP1S2 gene in a child with psychomotor delay and hypotonia. AB - We identified a 495 Kb interstitial deletion of chromosome Xp22.2, centered on the AP1S2 gene, by means of oligonucleotide array comparative genomic hybridisation (array-CGH) in a child with marked hypotonia in the first months of life, psychomotor retardation, severely delayed walking and speech development, and unspecific dysmorphic facial features. The deletion was inherited from the healthy mother. Point mutations of the AP1S2 gene have been identified in patients with X-linked mental retardation (XLMR). The clinical features of our patient are quite similar to those reported in male patients carrying point mutations, thus suggesting that point mutations and deletions of the AP1S2 gene lead to a recognisable XLMR phenotype in males. PMID- 22210231 TI - Thiopental-induced burst suppression measured by the bispectral index is extended during propofol administration compared with sevoflurane. AB - BACKGROUND: Thiopental is used to suppress cerebral metabolism during temporary clip ligation of the cerebral arteries. Electroencephalogram (EEG) can measure intraoperative burst suppression as evidence of cerebral metabolic suppression, but EEG is not always available during clip ligation. This study was conducted to compare the effect of propofol-based total intravenous anesthesia (TIVA) with sevoflurane-based inhalational anesthesia on thiopental-induced burst suppression during aneurysm surgery. The effect of thiopental was measured by burst suppression ratio (BSR) using the bispectral index (BIS) monitor. METHODS: Forty six patients who underwent temporary clipping during aneurysm surgery were randomized into 2 groups. The inhalation group (n=21) received sevoflurane-N(2)O anesthesia and the TIVA group (n=25) received propofol-remifenatanil-N(2)O anesthesia. The anesthesia level maintained a BIS value between 40 and 55. Pharmacological burst suppression was induced with bolus administration of thiopental (5 mg/kg) before temporary clipping. The BIS number, BSR values, the onset time and duration of BSR, and hemodynamic variables were recorded every minute in both groups. RESULTS: There were no significant differences between groups in the onset time of burst suppression (P=0.394) and BIS changes (P=0.878). However, statistically significant longer duration (P<0.001) and significantly higher degree of burst suppression (P=0.006) were observed in the TIVA group compared with the inhalation group. CONCLUSIONS: Our results suggest that at equivalent BIS values TIVA with propofol anesthesia provides longer duration and greater cerebral metabolic suppression compared with sevoflurane N(2)O inhalation anesthesia. BIS may be an acceptable alternative to standard EEG monitoring when assessing burst suppression during temporary clipping. PMID- 22210233 TI - Effects of neonatal castration and androgenization on sexual dimorphism in bone, leptin and corticosterone secretion. AB - This study investigated the role of neonatal sex steroids in rats on sexual dimorphism in bone, as well as on leptin and corticosterone concentrations throughout the lifespan. Castration of males and androgenization of females were used as models to investigate the role of sex steroids shortly after birth. Newborn Wistar rats were divided into four groups, two male groups and two female groups. Male pups were cryoanesthetized and submitted to castration or sham operation procedures within 24 h after birth. Female pups received a subcutaneous dose of testosterone propionate (100 MUg) or vehicle. Rats were euthanized at 20, 40, or 120 postnatal days. Body weight was also measured at 20, 40, and 120 days of age, and blood samples and femurs were collected. The length and thickness of the femurs were measured and the areal bone mineral density (areal BMD) was determined by dual-energy X-ray absorptiometry (DEXA). Biomechanical three-point bending testing was used to evaluate bone breaking strength, energy to fracture, and extrinsic stiffness. Blood samples were submitted to a biochemical assay to estimate calcium, phosphorus, alkaline phosphatase, leptin, and corticosterone levels. Weight gain, areal BMD and bone biomechanical properties increased rapidly with respect to age in all groups. In control animals, skeletal sexual dimorphism, leptin concentration, and dimorphic corticosterone concentration patterns were evident after puberty. However, androgen treatment induced changes in growth, areal BMD, and bone mass properties in neonatal animals. In addition, neonatally-castrated males had bone development and mechanical properties similar to those of control females. These results suggest that the exposure to neonatal androgens may represent at least one covariate that mediates dimorphic variation in leptin and corticosterone secretions. The study indicates that manipulation of the androgen environment during the critical period of sexual differentiation of the brain causes long-lasting changes in bone development, as well as serum leptin and corticosterone concentrations. In addition, this study provides useful models for the investigation of bone disorders induced by hypothalamic hypogonadism. PMID- 22210232 TI - The formation of complex acetylcholine receptor clusters requires MuSK kinase activity and structural information from the MuSK extracellular domain. AB - Efficient synaptic transmission at the neuromuscular junction (NMJ) requires the topological maturation of the postsynaptic apparatus from an oval acetylcholine receptor (AChR)-rich plaque into a complex pretzel-shaped array of branches. However, compared to NMJ formation very little is known about the mechanisms that regulate NMJ maturation. Recently the process of in vivo transformation from plaque into pretzel has been reproduced in vitro by culturing myotubes aneurally on laminin-coated substrate. It was proposed that the formation of complex AChR clusters is regulated by a MuSK-dependent muscle intrinsic program. To elucidate the structure-function role of MuSK in the aneural maturation of AChR pretzels, we used muscle cell lines expressing MuSK mutant and chimeric proteins. Here we report, that besides its role during agrin-induced AChR clustering, MuSK kinase activity is also necessary for substrate-dependent cluster formation. Constitutive-active MuSK induces larger AChR clusters, a faster cluster maturation on laminin and increases the anchorage of AChRs to the cytoskeleton compared to MuSK wild-type. In addition, we find that the juxtamembrane region of MuSK, which has previously been shown to regulate agrin-induced AChR clustering, is unable to induce complex AChR clusters on laminin substrate. Most interestingly, MuSK kinase activity is not sufficient for laminin-dependent AChR cluster formation since the MuSK ectodomain is also required suggesting a so far undiscovered instructive role for the extracellular domain of MuSK. PMID- 22210234 TI - Effects of saliva on starch-thickened drinks with acidic and neutral pH. AB - Powdered maize starch thickeners are used to modify drink consistency in the clinical management of dysphagia. Amylase is a digestive enzyme found in saliva which breaks down starch. This action is dependent on pH, which varies in practice depending on the particular drink. This study measured the effects of human saliva on the viscosity of drinks thickened with a widely used starch-based thickener. Experiments simulated a possible clinical scenario whereby saliva enters a cup and contaminates a drink. Citric acid (E330) was added to water to produce a controlled range of pH from 3.0 to 7.0, and several commercially available drinks with naturally low pH were investigated. When saliva was added to thickened water, viscosity was reduced to less than 1% of its original value after 10-15 min. However, lowering pH systematically slowed the reduction in viscosity attributable to saliva. At pH 3.5 and below, saliva was found to have no significant effect on viscosity. The pH of drinks in this study ranged from 2.6 for Coca Cola to 6.2 for black coffee. Again, low pH slowed the effect of saliva. For many popular drinks, having pH of 3.6 or less, viscosity was not significantly affected by the addition of saliva. PMID- 22210235 TI - Takayasu's retinopathy. AB - We report the case of a 63-year-old woman with Takayasu's arteritis who experienced progressive visual loss in her right eye (RE) over several months. Visual acuity was 0.4 in the RE, which showed marked retinal arteriovenous dilation and highly irregular arteriolar calibre. She had no light perception in the left eye, which showed diffuse atrophy of the retinal pigment epithelium and prepapillary fibrovascular proliferation. Fluorescein angiography revealed delayed and slow retinal and choroidal circulation and areas of peripheral ischemia. A diagnosis of Takayasu's retinopathy was made and the non-perfused areas were treated with laser photocoagulation. Takayasu's disease can result in chronic ocular ischemia. Angiographic examination is particularly important in this context and may provide additional findings which affect staging and treatment of the disease. The role of the ophthalmologist includes laser photocoagulation, monitoring for complications and timely referral for vascular surgery. PMID- 22210236 TI - Leptin levels and depressive symptoms in people with type 2 diabetes: the edinburgh type 2 diabetes study. AB - OBJECTIVE: Depression in Type 2 diabetes is associated with obesity, cardiovascular disease, and mortality. Leptin is a plausible mediating factor because it has been related to obesity, depression, and cardiovascular disease in nondiabetic populations. We sought to assess whether leptin is related to depressive symptoms in people with Type 2 diabetes. METHODS: One thousand fifty seven subjects (48.5% women, mean [standard deviation] age = 67.9 [4.2] years) with Type 2 diabetes were assessed for depressive symptoms using the Hospital Anxiety and Depression Scale and other clinical variables by interview and physical examination. Plasma leptin was determined by radioimmunoassay. Multiple linear regression was performed to assess the relationship between depressive symptoms and ln leptin while adjusting for other covariates. A mediation analysis was performed to test whether depressive symptoms mediated the relationship between obesity and leptin. RESULTS: In univariate analyses, symptoms of depression were related to leptin in men (r = 0.214, p < .001) and women (r = 0.146, p = .007). When adjusting for other covariates including body mass index, ischemic heart disease, glycated hemoglobin, duration of diabetes, and treatment with antidepressants, insulin, or glucocorticoids, using a hierarchical multiple linear regression, depressive symptoms (ln Hospital Anxiety and Depression Scale depression score) were significant only in men (B = 0.083, standard error = 0.037, p = .03). In the mediation analysis, depressive symptoms partially mediated the effect of obesity (body mass index) on leptin in men but not in women. CONCLUSIONS: There is a sex difference in the relationship between depressive symptoms and leptin in people with Type 2 diabetes, with a positive association in men but not in women. Adipocyte-derived factors are associated with depressive symptoms in Type 2 diabetes. PMID- 22210237 TI - Fluoxetine effect on aortic nitric oxide-dependent vasorelaxation in the unpredictable chronic mild stress model of depression in mice. AB - OBJECTIVE: Major depression is an independent risk factor for the development of cardiovascular diseases. However, the exact mechanism by which depression may induce cardiovascular events is unclear. Endothelial dysfunction has been reported as a possible link between depression and subsequent cardiovascular events as described in depressed subjects. The purpose of this study was to investigate endothelial dysfunction and atherosclerosis formation in the aorta of mice exposed to the unpredictable chronic mild stress (UCMS) procedure. METHODS: BALB/c mice were exposed to two 7-week UCMS procedures separated by 6 weeks. Treatments (fluoxetine 10 mg/kg; NaCl 0.9%) started at the third week until the end of the seventh week of each procedure. Endothelial function was evaluated by in vitro assessment of acetylcholine-induced vasorelaxation in aortic rings. By using specific inhibitors for nitric oxide (NO)- and prostacyclin-dependent relaxation, we assessed the part played by NO, prostacyclin, and endothelium derived hyperpolarizing factor (EDHF)-like mediators in endothelium-dependent relaxation. Atherosclerosis was evaluated by histological examination. RESULTS: Depression-like behavior was increased in the UCMS versus unstressed group and was reversed by chronic fluoxetine treatment. Vascular reactivity study indicated that UCMS induced a decrease in the NO-dependent relaxation that was partially compensated by an EDHF-like dependent relaxation. Because fluoxetine per se increased the NO-dependent relaxation, fluoxetine was able to reverse UCMS effect on the NO component and abolished the EDHF-like component. Atherosclerotic lesion was found in aorta of UCMS and nonstressed animals. CONCLUSIONS: As an independent risk factor, UCMS reproduced the endothelial alterations observed in depression but was not sufficient to provoke morphological alterations. PMID- 22210238 TI - Selective attention of patients with anorexia nervosa while looking at pictures of their own body and the bodies of others: an exploratory study. AB - OBJECTIVE: Attention and assessment biases are part of body image disturbances shown by patients with anorexia nervosa (AN). The aim of this article was to study these biases by using eye movement analyses. METHODS: As stimuli, the study used 24 standardized pictures showing young women and a standardized picture of the respective study participant. With an eye movement tracer, we were able to determine what body areas that the study participants look at. The study participants were also asked to rate the attractiveness of the stimuli. Data from 35 patients with AN and 32 healthy controls were included. RESULTS: Patients with AN judge their own body areas as being less attractive than the controls on a rating scale from 1 to 5 (e.g., breasts: mean [standard deviation] = 0.9 [1.0] versus 2.2 [0.8], p < .001). They were also more critical in their assessment of the bodies of others (e.g., attractiveness of people with ideal weight: 2.1 [0.9] versus 2.8 [0.5], p < .001). They spent less time looking at their own breasts (1.8 [0.9] versus 2.2 [1.0] seconds, p = .09) but significantly more time at their thighs (1.1 [0.6] versus 0.8 [0.4] seconds, p = .05). CONCLUSIONS: The results confirm the assumption of cognitive biases. The differences, however, are often small and vary greatly. PMID- 22210240 TI - Association of baseline anxiety with depression persistence at 6 months in patients with acute cardiac illness. AB - OBJECTIVE: To assess the association of baseline anxiety with depression persistence and change in depressive symptoms 6 months after cardiac hospitalization. METHODS: Data were analyzed from 137 depressed patients hospitalized on inpatient cardiac units for acute coronary syndrome, decompensated heart failure, or arrhythmia and who were enrolled in a randomized trial of collaborative care depression management. Subjects' demographic, medical, and psychiatric information at baseline was compiled. Measures of health related quality of life, cardiac symptoms, and psychiatric symptoms, including the Hospital Anxiety and Depression Scale-anxiety subscale (HADS-A) for anxiety, were obtained at baseline and serially during a 6-month follow-up period. The association between baseline HADS-A score and depression persistence (<50% reduction in depressive symptoms on the Patient Health Questionnaire-9) at 6 months was assessed by multivariate logistic regression accounting for the effects of multiple relevant medical and psychological covariates. The association between baseline HADS-A score and improvement in depressive symptoms (Patient Health Questionnaire-9) from baseline at 6 months was assessed by linear regression accounting for the same covariates. RESULTS: Baseline HADS-A score was independently associated with depression persistence at 6 months (odds ratio = 1.11, 95% confidence interval = 1.01-1.22, p = .03). Likewise, higher baseline HADS-A score was associated with less improvement in depressive symptoms at 6 months (beta = -0.34, p = .01). CONCLUSIONS: Among a cohort of depressed cardiac patients, higher baseline anxiety score was linked with lesser improvement in depressive symptoms and increased likelihood of depression persistence at 6 months, independent of multiple relevant covariates. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00847132. PMID- 22210239 TI - Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls. AB - OBJECTIVE: Chronic fatigue syndrome (CFS) and multiple sclerosis (MS) are characterized by debilitating fatigue, yet evaluation of this symptom is subjective. We examined metabolite-detecting, adrenergic, and immune gene expression (messenger ribonucleic acid [mRNA]) in patients with CFS (n = 22) versus patients with MS (n = 20) versus healthy controls (n = 23) and determined their relationship to fatigue and pain before and after exercise. METHODS: Blood samples and fatigue and pain ratings were obtained at baseline and 0.5, 8, 24, and 48 hours after sustained moderate exercise. Leukocyte mRNA of four metabolite detecting receptors (acid-sensing ion channel 3, purinergic type 2X4 and 2X5 receptors, and transient receptor potential vanilloid type 1) and four adrenergic (alpha-2a, beta-1, and beta-2 receptors and catechol-O-methyltransferase) and five immune markers (CD14, toll-like receptor 4 [TLR4], interleukin [IL] 6, IL 10, and lymphotoxin alpha) was examined using quantitative polymerase chain reaction. RESULTS: Patients with CFS had greater postexercise increases in fatigue and pain (10-29 points above baseline, p < .001) and greater mRNA increases in purinergic type 2X4 receptor, transient receptor potential vanilloid type 1, CD14, and all adrenergic receptors than controls (mean +/- standard error = 1.3 +/- 0.14- to 3.4 +/- 0.90-fold increase above baseline, p = .04-.005). Patients with CFS with comorbid fibromyalgia (n = 18) also showed greater increases in acid-sensing ion channel 3 and purinergic type 2X5 receptors (p < .05). Patients with MS had greater postexercise increases than controls in beta-1 and beta-2 adrenergic receptor expressions (1.4 +/- 0.27- and 1.3 +/- 0.06-fold increases, respectively, p = .02 and p < .001) and greater decreases in TLR4 (p = .02). In MS, IL-10 and TLR4 decreases correlated with higher fatigue scores. CONCLUSIONS: Postexercise mRNA increases in metabolite-detecting receptors were unique to patients with CFS, whereas both patients with MS and patients with CFS showed abnormal increases in adrenergic receptors. Among patients with MS, greater fatigue was correlated with blunted immune marker expression. PMID- 22210241 TI - Serotonergic and BDNF genes associated with depression 1 week and 1 year after mastectomy for breast cancer. AB - OBJECTIVE: Polymorphisms of serotonin transporter (5-HTT) and brain-derived neurotrophic factor (BDNF) genes have been investigated as candidate genes for depression occurring in medical disorders. The serotonin 2a receptor (5-HTR2a) genes have been investigated as risk factors for depression but rarely in combination with medical conditions. This study aimed to investigate whether polymorphisms of interest in 5-HTT, 5-HTR2a, and BDNF genes are associated with depression after mastectomy for breast cancer. METHODS: A total of 309 patients with breast cancer were evaluated 1 week after mastectomy, and 244 patients (79%) were followed up 1 year later. Depression (major and minor depressive disorders) was diagnosed according to DSM-IV criteria using the Mini-International Neuropsychiatric Interview and was classified into prevalent, persistent, and incident depression. Individual associations with 5-HTT gene-linked promoter region, serotonin transporter intron 2 variable number tandem repeat, 5-HTR2a 1438A/G, 5-HTR2a 102T/C, and BDNF Val66Met polymorphisms were estimated using logistic regression models, and gene-gene interactions were investigated using the generalized multifactor dimensionality reduction method. RESULTS: At baseline, 74 patients (24%) were classified with prevalent depression, and at follow-up, 19 patients (8%) and 25 patients (10%) were classified with persistent and incident depression, respectively. The BDNF Met/Met genotype was independently associated with prevalent (odds ratio = 2.63, 95% confidence interval = 1.12-6.14) and persistent (odds ratio = 8.07, 95% confidence interval = 1.26-51.6) depression. No associations with 5-HTT and 5-HTR2a genes (all p values > .21) were found, and no significant gene-gene interactions were identified (all p values > .36). CONCLUSIONS: Our findings support a role of BDNF, not serotonin, in the etiology of depression occurring in women with breast cancer who received a mastectomy. PMID- 22210242 TI - Disrupted functional connectivity of the pain network in fibromyalgia. AB - OBJECTIVE: To investigate the impact of chronic pain on brain dynamics at rest. METHODS: Functional connectivity was examined in patients with fibromyalgia (FM) (n = 9) and healthy controls (n = 11) by calculating partial correlations between low-frequency blood oxygen level-dependent fluctuations extracted from 15 brain regions. RESULTS: Patients with FM had more positive and negative correlations within the pain network than healthy controls. Patients with FM displayed enhanced functional connectivity of the anterior cingulate cortex (ACC) with the insula (INS) and basal ganglia (p values between .01 and .05), the secondary somatosensory area with the caudate (CAU) (p = .012), the primary motor cortex with the supplementary motor area (p = .007), the globus pallidus with the amygdala and superior temporal sulcus (both p values < .05), and the medial prefrontal cortex with the posterior cingulate cortex (PCC) and CAU (both p values < .05). Functional connectivity of the ACC with the amygdala and periaqueductal gray (PAG) matter (p values between .001 and .05), the thalamus with the INS and PAG (both p values < .01), the INS with the putamen (p = .038), the PAG with the CAU (p = .038), the secondary somatosensory area with the motor cortex and PCC (both p values < .05), and the PCC with the superior temporal sulcus (p = .002) was also reduced in FM. In addition, significant negative correlations were observed between depression and PAG connectivity strength with the thalamus (r = -0.64, p = .003) and ACC (r = -0.60, p = .004). CONCLUSIONS: These findings demonstrate that patients with FM display a substantial imbalance of the connectivity within the pain network during rest, suggesting that chronic pain may also lead to changes in brain activity during internally generated thought processes such as occur at rest. PMID- 22210243 TI - Modeling of intracellular transport and compartmentation. AB - The complexity and internal organization of mammalian cells as well as the regulation of intracellular transport processes has increasingly moved into the focus of investigation during the past two decades. Advanced staining and microscopy techniques help to shed light onto spatial cellular compartmentation and regulation, increasing the demand for improved modeling techniques. In this chapter, we summarize recent developments in the field of quantitative simulation approaches and frameworks for the description of intracellular transport processes. Special focus is therefore laid on compartmented and spatiotemporally resolved simulation approaches. The processes considered include free and facilitated diffusion of molecules, active transport via the microtubule and actin filament network, vesicle distribution, membrane transport, cell cycle dependent cell growth and morphology variation, and protein production. Commercially and freely available simulation packages are summarized as well as model data exchange and harmonization issues. PMID- 22210244 TI - Consistent partnership formation: application to a sexually transmitted disease model. AB - We apply a consistent sexual partnership formation model which hinges on the assumption that one gender's choices drives the process (male or female dominant model). The other gender's behavior is imputed. The model is fitted to UK sexual behavior data and applied to a simple incidence model of HSV-2. With a male dominant model (which assumes accurate male reports on numbers of partners) the modeled incidences of HSV-2 are 77% higher for men and 50% higher for women than with a female dominant model (which assumes accurate female reports). Although highly stylized, our simple incidence model sheds light on the inconsistent results one can obtain with misreported data on sexual activity and age preferences. PMID- 22210245 TI - Evolution of gnathostome prodynorphin and proenkephalin: characterization of a shark proenkephalin and prodynorphin cDNAs. AB - Analyses of prodynorphin and proenkephalin cDNAs cloned from the central nervous system of the shark, Heterodontus portusjacksoni, provided additional evidence that these two opioid precursor-coding genes were most likely directly derived from a common ancestral gene. The two cDNAs could be aligned by inserting only seven gaps. The prodynorphin cDNA encodes five opioid sequences which could be aligned to opioid positions B through F in the proenkephalin cDNA. The sequence identity within the opioid positions was 59% at the amino acid level. Shark alpha neo-endorphin, dynorphin A, and dynorphin B have amino acid motifs in common with shark met-enkephalin-8, and shark proenkephalin opioid positions E and F, respectively, which have not been observed in other gnathostome prodynorphin and proenkephalin precursor sequences. Shark prodynorphin encodes both kappa (alpha neo-endorphin, dynorphin A, and dynorphin B) and delta (met-enkephalin and leu enkephalin) opioid sequences. Mixed function prodynorphin precursors (encoding both enkephalins and dynorphins) are also found in representatives of the teleost fishes, lungfishes, and amphibians. It appears that only mammals evolved a prodynorphin precursor that exclusively encodes kappa opioid agonists (dynorphins). PMID- 22210246 TI - The decline in yolk progesterone concentrations during incubation is dependent on embryonic development in the European starling. AB - Oviparous amniotes, particularly birds, have become model systems in which to study how mothers may utilize steroids to adaptively adjust offspring development. Although there is now ample evidence that maternally derived steroids in the egg at oviposition can influence offspring phenotype, very little is known about how these steroids elicit such effects. Of the major avian steroid hormones found in yolk, progesterone is by far the most abundant at oviposition, but has received little research attention to date. In this study, we examine the metabolism of [(3)H]-progesterone injected into freshly laid European starling eggs throughout the first 5 days of development by characterization of radioactivity within the egg homogenate. We also introduce a technique that utilizes a focal, freeze/thaw cycle to prevent embryonic development and allows us to assess the role of the embryo in metabolizing progesterone during early incubation. Two major findings result. First is that [(3)H]-progesterone is metabolized in eggs possessing a developing embryo, but not in eggs with disrupted embryonic development. Second is that the change in the distribution of radioactivity within eggs possessing an embryo is the result of metabolism of [(3)H]-progesterone to a more polar form that is subsequently conjugated. Together, these data suggest live embryos are necessary for metabolism of progesterone during early incubation, underscoring the potentially important contribution of embryos to functional modulation or mediation of maternal yolk steroid effects. PMID- 22210247 TI - Two novel CYP11B1 mutations in congenital adrenal hyperplasia due to steroid 11beta hydroxylase deficiency in a Tunisian family. AB - Steroid 11beta hydroxylase deficiency (11beta-OHD) (OMIM # 202010) is the second most common form of congenital adrenal hyperplasia (CAH), accounting for 5-8% of all cases. It is an autosomal recessive enzyme defect impairing the biosynthesis of cortisol. The CYP11B1 gene encoding this enzyme is located on chromosome 8q22, approximately 40kb from the highly homologous CYP11B2 gene encoding for the aldosterone synthase. Virilization and hypertension are the main clinical characteristics of this disease. In Tunisia, the incidence of 11beta-OHD appears higher due to a high rate of consanguinity (17.5% of congenital adrenal hyperplasia). The identical presentation of genital ambiguity (females) and pseudo-precocious puberty (males) can lead to misdiagnosis with 21 hydroxylase deficiency. The clinical hallmark of 11beta hydroxylase deficiency is variable, and biochemical identification of elevated precursor metabolites is not usually available. In order to clarify the underlying mechanism causing 11beta-OHD, we performed the molecular genetic analysis of the CYP11B1 gene in a female patient diagnosed as classical 11beta-OHD. The nucleotide sequence of the patient's CYP11B1 revealed two novel mutations in exon 4: a missense mutation that converts codon AGT (serine) to ATT (isoleucine) (c.650G>T; p.S217I) combined with an insertion of a thymine at the c.652-653 position (c.652_653insT). This insertion leads to a reading frame shift, multiple incorrect codons, and a premature stop in codon 258, that drastically affects normal protein function leading to a severe phenotype with ambiguous genitalia of congenital adrenal hyperplasia due to 11beta hydroxylase deficiency. PMID- 22210248 TI - Principles of cancer treatment: impact on reproduction. PMID- 22210249 TI - Fertility preservation options for females. PMID- 22210250 TI - Options for fertility preservation in men and boys with cancer. PMID- 22210251 TI - Contraception and cancer treatment in young persons. PMID- 22210252 TI - Sexual health during cancer treatment. PMID- 22210253 TI - The unique reproductive concerns of young women with breast cancer. PMID- 22210254 TI - Pregnancy and cancer. PMID- 22210255 TI - Preimplantation genetic diagnosis for hereditary cancers. PMID- 22210256 TI - Non-traditional family building planning. PMID- 22210257 TI - Parenting with cancer I: developmental perspective, communication, and coping. PMID- 22210258 TI - Parenting with cancer II: parenting at different stages of illness. PMID- 22210259 TI - Pediatric oncology and reproductive health. PMID- 22210260 TI - Institutional approaches to implementing fertility preservation for cancer patients. PMID- 22210261 TI - Patient provider communication and reproductive health. PMID- 22210262 TI - Fertility preservation in cancer patients: ethical considerations. PMID- 22210263 TI - The legal issue and of assisted reproductive technologies. PMID- 22210264 TI - MRSA-surveillance in Germany: data from the Antibiotic Resistance Surveillance System (ARS) and the mandatory surveillance of MRSA in blood. AB - Data from the German Antibiotic Resistance Surveillance system (ARS) and statutory notification of methicillin-resistant Staphylococcus aureus (MRSA) in blood cultures are presented. ARS is a voluntary laboratory-based surveillance system providing resistance data of all clinical pathogens and sample types from hospitals and ambulatory care. Statutory notification includes MRSA detected in blood and cerebrospinal fluid by microbiological laboratories. Resistance data from 2008 to 2010 and MRSA-bacteraemia incidences from 2010 are presented. From 2008 to 2010, resistance data from 70,935 Staphylococcus aureus isolates were transferred to the national health institution. MRSA proportions in hospitals and outpatient care account for 19.2% and 10.6%, respectively. In hospital care high proportions of MRSA were found in nephrological, geriatric, neurological general wards and surgical ICUs (49.4%, 45.8%, 34.2%, and 27.0%, respectively), while in community outpatient care urological practices (29.2%) account for the highest values. In both healthcare settings urinary tract samples stand out with high proportions of MRSA (hospitals, 32.9%; outpatients, 20.5%). In 2010, 3900 cases of MRSA bacteraemia were reported, accounting for an incidence of MRSA bacteraemia of 4.8/100,000 inhabitants/year. Stratification by federal states shows considerable regional differences (range, 1.0-8.3/100,000 inhabitants/year). Vulnerable areas in hospitals and outpatient care have been pointed out as subjects for further inquiries. PMID- 22210265 TI - Plasmid-mediated fluoroquinolone resistance determinants in Escherichia coli from community uncomplicated urinary tract infection in an area of high prevalence of quinolone resistance. AB - In Italy fluoroquinolones (FQs) are extensively prescribed in empirical therapy of uncomplicated urinary tract infection (UTI) despite recommendations in national guidelines and widespread antibiotic resistance in community. To survey the dissemination of plasmid-mediated quinolone resistance in a peak area of FQs consumption, E. coli strains from 154 community and 41 local hospital patients were collected; low level ciprofloxacin resistance qnrA, qnrB, qnrS, and aac(6)' Ib-cr genes were screened by PCR and patterns of transferable resistances were determined. Clinical ciprofloxacin resistance in hospital doubled community value, while overall rates of FQ resistance genes were similar (31.6% and 27.8%). Prevalence of aac(6')-Ib-cr gene was 11% in outpatients (21%, inpatients) and risk of harbouring this variant was significantly associated with gentamicin resistance; linkage to ceftazidime resistance was significant (P=0.001) and six out of eight strains produced CTX-M-15 and TEM-1 beta lactamases. In transconjugants, the unique pattern ampicillin/kanamycin-gentamicin/ ESBL + was associated with aac(6')-Ib-cr gene presence and with an increase of ciprofloxacin MIC value. Data highlight the need to monitor the resistance risk factors in the local community to provide clinicians with well-grounded guidelines for UTI therapy. PMID- 22210266 TI - Hospital-acquired Clostridium difficile infection: determinants for severe disease. AB - Risk factors of severity (need for surgical intervention, intensive care or fatal outcome) were analysed in hospital-acquired Clostridium difficile infection (CDI) in a 777-bed community hospital. In a prospective analytical cross-sectional study, age (>= 65 years), sex, CDI characteristics, underlying diseases, severity of comorbidity and PCR ribotypes were tested for associations with severe CDI. In total, 133 cases of hospital-acquired CDI (mean age 74.4 years) were identified, resulting in an incidence rate of 5.7/10,000 hospital-days. A recurrent episode of diarrhoea occurred in 25 cases (18.8%) and complications including toxic megacolon, dehydration and septicaemia in 69 cases (51.9%). Four cases (3.0%) required ICU admission, one case (0.8%) surgical intervention and 22 cases (16.5%) died within the 30-day follow-up period. Variables identified to be independently associated with severe CDI were severe diarrhoea (odds ratio [OR] 3.64, 95% confidence interval [CI] 1.19-11.11, p=0.02), chronic pulmonary disease (OR 3.0, 95% CI 1.08-8.40, p=0.04), chronic renal disease (OR 2.9, 95% CI 1.07 7.81, p=0.04) and diabetes mellitus (OR 4.30, 95% CI 1.57-11.76, p=0.004). The case fatality of 16.5% underlines the importance of increased efforts in CDI prevention, in particular for patients with underlying diseases. PMID- 22210267 TI - Cefotaxime for the detection of extended-spectrum beta-lactamase or plasmid mediated AmpC beta-lactamase and clinical characteristics of cefotaxime-non susceptible Escherichia coli and Klebsiella pneumoniae bacteraemia. AB - We investigated the performance of cefotaxime for the detection of extended spectrum beta-lactamase (ESBL) or plasmid-mediated AmpC beta-lactamase (pAmpC) and the clinical characteristics of cefotaxime-non-susceptible Escherichia coli or Klebsiella pneumoniae (CTXNS-EK) bacteraemia. All of the consecutive bloodstream isolates between 2005 and 2010 in a Japanese university hospital were characterised using polymerase chain reaction (PCR). Risk factors and outcomes of CTXNS-EK were analysed by multivariate logistic regression analysis. We identified 58 CTXNS-EK (15.6%) from 249 E. coli and 122 K. pneumoniae. Cefotaxime with a minimum inhibitory concentration (MIC) of >1 MUg/mL had a sensitivity of 98.3% and a specificity of 99.7% for the detection of ESBL or pAmpC. CTXNS-EK had increased from 4.5% in 2005 to 23% in 2009. Risk factors for CTXNS-EK were previous isolation of multidrug-resistant bacteria, use of oxyimino cephalosporins or fluoroquinolones, and high Sequential Organ Failure Assessment (SOFA) score. Patients with CTXNS-EK bacteraemia less frequently received appropriate empirical therapy than patients with cefotaxime-susceptible EK bacteraemia (81% vs. 97%, p<0.001) and died within 30 days (21% vs. 5%, p=0.001). Using the current breakpoints of the Clinical and Laboratory Standards Institute (CLSI) or the European Committee on Antimicrobial Susceptibility Testing (EUCAST), cefotaxime alone can identify ESBL or pAmpC producers. CTXNS-EK is an important and increasingly prevalent bacteraemia pathogen. PMID- 22210268 TI - Epidermal growth factor receptor (EGFR) and neuregulin (Neu) activation in human airway epithelial cells exposed to nickel acetate. AB - Nickel compounds are potential carcinogenic agents that produce a range of biological effects, including inhibition of cell death. Because suppression of apoptosis is thought to contribute to the initiation of carcinogenesis, we investigated the effects of nickel acetate (Ni(2+)) treatment on apoptosis in two different airway epithelial cell lines (A549 and Beas-2B, respectively). Furthermore, since both the epidermal growth factor receptor (EGFR) and neuregulin (Neu) are involved in neoplastic development, mRNAs and expression levels of total and phosphorylated proteins (p-EGFR(Tyr1173) and p-Neu(Tyr1248), respectively) were also measured. We found that exposure of A549 cells to Ni(2+) resulted in significantly reduced cell viability, as well as increased apoptosis and DNA fragmentation at relatively low concentrations (0.1 and 0.5mM) after 24 and 48h. These changes were accompanied by reduced EGFR and Neu mRNAs and proteins, phosphorylated proteins as well as decreased Bcl-2 and increased BAX protein expression. Conversely, Beas-2B cells exposed to equivalent concentrations of Ni(2+) did not show evident signs of apoptosis and DNA damage, hence showing increased expression and phosphorylation of both EGFR and Neu, increased Bcl-2 and reduced BAX expression. Altogether, our finding indicate that Ni(2+) exposure differently affects apoptosis initiation either in non tumorigenic (Beas-2B) and tumorigenic airway epithelial cells (A549), suggesting a potential involvement of EGFR/Neu receptors. PMID- 22210269 TI - Targeting interleukin-33 in rheumatoid arthritis. PMID- 22210271 TI - Four cases of ankylosing spondylitis in medieval skeletal series from Croatia. AB - Osteological changes consistent with ankylosing spondylitis were observed in three males and one female skeleton recovered from four medieval sites-Velim, Koprivno, Buje, and Rijeka-all situated on Croatia's eastern Adriatic coast and its immediate hinterland. The skeletons present changes in the spine, ribs, sacrum, and innominates that are typical of ankylosing spondylitis that is a progressive, inflammatory disease of connective tissue calcification. The disease most commonly affects the sacroiliac joints, the joints of the spine, and the costovertebral joints. In the final stages of the disease, the vertebral bodies remodel and together with the associated syndesmophytes form a continuous, smooth bone surface that is sometimes referred to as "bamboo spine." The prevalence of this disorder in the analyzed Croatian samples is 4/303 or 1.3% and thus corresponds with frequencies recorded in modern European populations. Differential diagnosis rules out the possibility of DISH, rheumatoid arthritis, and melorheostosis. These are the first cases of ankylosing spondylitis identified in Croatian archaeological series. PMID- 22210270 TI - OPG inhibits gene expression of RANK and CAII in mouse osteoclast-like cell. AB - This study was designed to determine the effects of the osteoprotegerin (OPG) on the mRNA expression of carbonic anhydrase II (CAII) and the receptor activator of NF-kappaB (RANK) in mouse osteoclast-like cells. Marrow cells were harvested from femora and tibiae of mouse and cultured in 6-well chamber slides. After 1 day of incubation, the marrow cells were exposed to M-CSF (25 ng/ml), RANKL (50 ng/ml), and different concentrations of OPG (50, 75, and 100 ng/ml, respectively) for 3 days. Osteoclast-like cells were confirmed by both tartrate-resistant acid phosphatase (TRAP) stain and bone resorption assay. The expression of RANK and CAIImRNA was determined with real-time fluorescent quantitative polymerase chain reaction. The numbers of multinucleated, TRAP-positive osteoclast-like cells, and resorption pits formed were observed. Compared with the M-CSF + RANKL group, RANKmRNA expression was statistically decreased in the M-CSF and M-CSF + RANKL + OPG (100 ng/ml) groups (P = 0.004, P = 0.024, respectively); Compared with the M CSF, M-CSF + RANKL, and M-CSF + RANKL + OPG (100 ng/ml) group, CAIImRNA expression in the M-CSF + RANKL + OPG (75 ng/ml) groups was statistically decreased (P = 0.001, P = 0.008, and P = 0.036, respectively). These data suggest that OPG could regulate the expression of RANK and CA II mRNA in the marrow culture system. PMID- 22210273 TI - Treatment for mycetoma with oral itraconazole in ankylosing spondylitis. PMID- 22210272 TI - Brain-derived neurotrophic factor and exercise in fibromyalgia syndrome patients: a mini review. AB - Fibromyalgia syndrome (FMS) is a common chronic pain condition characterized by chronic widespread pain and decreased pain threshold, with hyperalgesia and allodynia. Associated signs include fatigue, morning stiffness, non-restorative sleep, mood disturbance, depression, irritable bowel syndrome, and headache. In addition to the administration of drugs, psychological therapies treatment of FMS mainly consists of physical therapies. Although the precise pathogenesis of FMS remains elucidated, modern understanding conceptualizes FMS as central sensitization as a consequence of altered endogenous pain- and stress-response system and continuous nociceptive input. Altered brain-derived neurotrophic factor (BDNF) levels in FMS suggest that BDNF--well known for its effects on neuronal plasticity--is involved in this sensitization process. Exercise leads to changes in serum BDNF levels, too. This association highlights the importance of exercise in FMS and other chronic pain conditions. PMID- 22210274 TI - A case of uveitis in adult-onset Still's disease with ophthalmologic symptoms. AB - Adult-onset Still's disease (AOSD) is a rare and systemic inflammatory disorder of unknown etiology and pathogenesis. AOSD is characterized by high fever accompanied by a range of systemic symptoms. However, there are rare cases of AOSD with ophthalmologic symptoms as well as with an obvious causation of corticosteroid withdrawal. In this case, a 43-year-old male patient diagnosed with AOSD showed ocular inflammation after withdrawing from corticosteroid treatment. This patient was treated with prednisolone for AOSD and discharged after achieving complete remission of breathlessness, backache, thoracalgia, joint pain, and spiking fever. The patient unauthorizedly stopped taking prednisolone after he was discharged from the hospital and returned to the Department of Ophthalmology with the complaint of decreased visual acuity in both eyes for half a month and sudden vision loss in the left eye for 3 days. After regular ophthalmologic examinations and fluorescence angiography examination, he was diagnosed with acute panuveitis as the manifestation of AOSD. Uveitis was effectively treated with corticosteroid drugs. This case reported a rare manifestation of AOSD in an ophthalmological system that was associated with the withdrawal of corticosteroid treatment. This report highlighted the therapeutic effect of local and systemic corticosteroid use for AOSD manifested with uveitis. This case is interesting for both rheumatologists and ophthalmologists. PMID- 22210275 TI - Relapsing polychondritis in childhood: three case reports, comparison with adulthood disease and literature review. AB - Relapsing polychondritis (RP) is a rare autoimmune systemic disease, especially in childhood. To report three new pediatric RP cases, to provide a literature review and to compare with adulthood disease, retrospective data collection from three childhood RP cases was observed in a Brazilian Pediatric Rheumatology Division. A literature review based on a MEDLINE database search was performed. Arthritis and auricular chondritis were present in our three patients. Two cases presented with early and severe laryngotracheal chondritis, besides initial and symptomatic costochondritis. The other case developed prominent epiphyseal plate involvement. Two patients were refractory to corticosteroids and immunosuppressants and required the use of TNF-alpha inhibitors to improve the symptoms, while corticosteroids plus methotrexate induced remission in the other patient. The literature review showed 44 cases of pediatric-onset disease in English language. Arthritis and ear chondritis are the most common initial and cumulative manifestations of RP in children and adults. Nasal and laryngotracheobronchial chondritis are also common manifestations observed during follow-up in childhood. There is also an early severity of respiratory chondritis in childhood, requiring aggressive treatment with corticosteroids, immunosuppressants and biologic agents. The data presented by those 3 children, considered in conjunction with the data from the 44 published cases, may reflect some distinguishing childhood RP features, such as more severe and frequent respiratory tract involvement, symptomatic costochondritis and the atypical pattern of persistent and destructive arthritis with epiphyseal plate involvement. Response to immunosuppressants and biologic agents is anecdotal, but steroids remain the main drug during the flares. PMID- 22210276 TI - Maximal locomotor depression follows maximal ankle swelling during the progression of arthritis in K/BxN mice. AB - It is well established that arthritis depresses locomotion in humans as well as in animal disease models. The K/BxN mouse model resembles rheumatoid arthritis and is widely used for research. Here, we investigate the behavioral alterations of arthritic K/BxN mice during arthritis development with respect to horizontal locomotion. Locomotor activity measurements and the methodology of ankle thickness measurements are compared to demonstrate the feasibility of motion tracking in the K/BxN mouse model. Arthritic K/BxN mice show significantly decreased locomotion compared to their non-arthritis K/BxN littermates. We found an indirect correlation of ankle thickness and locomotor activity. However, both parameters are only partially interdependent resulting in temporal displacement of maximal ankle swelling and maximal depression of locomotion by 1 week. Assessing the impaired movement as a behavioral test appears to be a valuable multifactorial parameter for the evaluation of arthritis in the K/BxN mouse model and provides additional information on disease progression and severity. PMID- 22210277 TI - Liposomes as a model for the biological membrane: studies on daunorubicin bilayer interaction. AB - In this study the interaction of the antitumoral drug daunorubicin with egg phosphatidylcholine (EPC) liposomes, used as a cell membrane model, was quantified by determination of the partition coefficient (K(p)). The liposome/aqueous-phase K(p) of daunorubicin was determined by derivative spectrophotometry and measurement of the zeta-potential. Mathematical models were used to fit the experimental data, enabling determination of K(p). In the partition of daunorubicin within the membrane both superficial electrostatic and inner hydrophobic interactions seem to be involved. The results are affected by the two types of interaction since spectrophotometry measures mainly hydrophobic interactions, while zeta-potential is affected by both interpenetration of amphiphilic charged molecules in the bilayer and superficial electrostatic interaction. Moreover, the degree of the partition of daunorubicin with the membrane changes with the drug concentration, due mainly to saturation factors. Derivative spectrophotometry and zeta-potential variation results, together with the broad range of concentrations studied, revealed the different types of interactions involved. The mathematical formalism applied also allowed quantification of the number of lipid molecules associated with one drug molecule. PMID- 22210278 TI - Intracellular partitioning of cell organelles and extraneous nanoparticles during mitosis. AB - The nucleocytoplasmic partitioning of nanoparticles as a result of cell division is highly relevant to the field of nonviral gene delivery. We reviewed the literature on the intracellular distribution of cell organelles (the endosomal vesicles, Golgi apparatus, endoplasmic reticulum and nucleus), foreign macromolecules (dextrans and plasmid DNA) and inorganic nanoparticles (gold, quantum dot and iron oxide) during mitosis. For nonviral gene delivery particles (lipid- or polymer-based), indirect proof of nuclear entry during mitosis is provided. We also describe how retroviruses and latent DNA viruses take advantage of mitosis to transfer their viral genome and segregate their episomes into the host daughter nuclei. Based on this knowledge, we propose strategies to improve nonviral gene delivery in dividing cells with the ultimate goal of designing nonviral gene delivery systems that are as efficient as their viral counterparts but non-immunogenic, non-oncogenic and easy and inexpensive to prepare. PMID- 22210279 TI - Chemical properties of antiepileptic drugs (AEDs). AB - Between 1990 and 2011 the following fifteen new antiepileptic drugs (AEDs) were approved: eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. These AEDs (except felbamate) offer appreciable advantages in terms of their favorable pharmacokinetics, improved tolerability and lower potential for drug interactions. All AEDs introduced after 1990 that are not second generation drugs (with the exception of vigabatrin and tiagabine) were developed empirically (sometimes serendipitously) utilizing mechanism-unbiased anticonvulsant animal models. The empirical nature of the discovery of new AEDs in the last three decades coupled with their multiple mechanisms of action explains their diverse chemical structures. The availability of old and new AEDs with various activity spectra and different tolerability profiles enables clinicians to better tailor drug choice to the characteristics of individual patients. With fifteen new AEDs having entered the market in the past 20years the antiepileptic market is crowded. Consequently, epilepsy alone is not attractive in 2011 to the pharmaceutical industry even though the clinical need of refractory epilepsy remains unmet. Due to this situation, future design of new AEDs must also have a potential in non-epileptic CNS disorders such as neuropathic pain, migraine prophylaxis and bipolar disorder or fibromyalgia as demonstrated by the sales revenues of pregabalin, topiramate and valproic acid. This review analyzes the effect that the emerging knowledge on the chemical properties of the old AEDs starting from phenobarbital (1912) has had on the design of subsequent AEDs and new therapeutics as well as the current approach to AED discovery. PMID- 22210280 TI - Coronary collateral growth--back to the future. AB - The coronary collateral circulation is critically important as an adaptation of the heart to prevent the damage from ischemic insults. In their native state, collaterals in the heart would be classified as part of the microcirculation, existing as arterial-arterial anastomotic connections in the range of 30 to 100 MUM in diameter. However, these vessels also show a propensity to remodel into components of the macrocirculation and can become arteries larger than 1000 MUM in diameter. This process of outward remodeling is critically important in the adaptation of the heart to ischemia because the resistance to blood flow is inversely related to the fourth power of the diameter of the vessel. Thus, an expansion of a vessel from 100 to 1000 MUM would reduce resistance (in this part of the circuit) to a negligible amount and enable delivery of flow to the region at risk. Our goal in this review is to highlight the voids in understanding this adaptation to ischemia-the growth of the coronary collateral circulation. In doing so we discuss the controversies and unknown aspects of the causal factors that stimulate growth of the collateral circulation, the role of genetics, and the role of endogenous stem and progenitor cells in the context of the normal, physiological situation and under more pathological conditions of ischemic heart disease or with some of the underlying risk factors, e.g., diabetes. The major conclusion of this review is that there are many gaps in our knowledge of coronary collateral growth and this knowledge is critical before the potential of stimulating collateralization in the hearts of patients can be realized. This article is part of a Special Issue entitled "Coronary Blood Flow". PMID- 22210281 TI - Inter-laboratory assessment of a harmonized zebrafish developmental toxicology assay - progress report on phase I. AB - This report provides a progress update of a consortium effort to develop a harmonized zebrafish developmental toxicity assay. Twenty non-proprietary compounds (10 animal teratogens and 10 animal non-teratogens) were evaluated blinded in 4 laboratories. Zebrafish embryos from pond-derived and cultivated strain wild types were exposed to the test compounds for 5 days and subsequently evaluated for lethality and morphological changes. Each of the testing laboratories achieved similar overall concordance to the animal data (60-70%). Subsequent optimization procedures to improve the overall concordance focused on compound formulation and test concentration adjustments, chorion permeation and number of replicates. These optimized procedures were integrated into a revised protocol and all compounds were retested in one lab using embryos from pond derived zebrafish and achieved 85% total concordance. To further assess assay performance, a study of additional compounds is currently in progress at two laboratories using embryos from pond-derived and cultivated-strain wild type zebrafish. PMID- 22210282 TI - Unequal gains of function are a headache for migraine mechanisms. PMID- 22210283 TI - AC-1 and synaptic development. PMID- 22210284 TI - Understanding the mechanisms of neuromuscular fatigue with paired-pulse stimulation. PMID- 22210285 TI - Mice mechanoreceptors are modulated by Ca(v)3.2 T-type calcium channels. PMID- 22210286 TI - Ligand-gated ion channels: from genes to behaviour. PMID- 22210287 TI - A structured approach to Exposure Based Waiving of human health endpoints under REACH developed in the OSIRIS project. AB - Exposure Based Waiving (EBW) is one of the options in REACH when there is insufficient hazard data on a specific endpoint. Rules for adaptation of test requirements are specified and a general option for EBW is given via Appendix XI of REACH, allowing waiving of repeated dose toxicity studies, reproductive toxicity studies and carcinogenicity studies under a number of conditions if exposure is very low. A decision tree is described that was developed in the European project OSIRIS (Optimised Strategies for Risk Assessment of Industrial Chemicals through Integration of Non-Test and Test Information) to help decide in what cases EBW can be justified. The decision tree uses specific criteria as well as more general questions. For the latter, guidance on interpretation and resulting conclusions is provided. Criteria and guidance are partly based on an expert elicitation process. Among the specific criteria a number of proposed Thresholds of Toxicological Concern are used. The decision tree, expanded with specific parts on absorption, distribution, metabolism and excretion that are not described in this paper, is implemented in the OSIRIS webtool on integrated testing strategies. PMID- 22210288 TI - Seroprevalence of bovine leukemia virus (BLV) infection in dairy cattle in Isfahan Province, Iran. AB - Bovine leukemia virus (BLV), the causative agent of enzootic bovine leukosis (EBL) is an exogenous C-type oncovirus in the Retroviridae family. It causes significant economic losses associated with the costs of control and eradication programs due to carcass condemnation at slaughter and restrictions of export of cattle and semen to importing countries. The main objective of this research was to determine the seroprevalence of BLV infection in cattle herds in central region of Iran (Isfahan province) using a commercial enzyme-linked immunosorbent assay (ELISA) to detect serum antibodies against BLV. Samples of blood serum were collected from 403 female dairy cattle (Holstein-Friesian) from 21 livestock farms and 303 animals (81.9%) were BLV seropositive. A significant association was found between age as a potential risk factor and BVL seroprevalence with animals >= 4 years (86.6%) having a significantly (chi(2) = 35.6, p < 0.001) higher seroprevalence compared to those < 4 years (54.2%). We found no significant statistical association between seroprevalence and pregnancy, lactation status and farming systems as potential risk factors in this study (p > 0.1). It is concluded that BLV infection is a very common problem in the study area. Hence, control measures should be instituted to combat the disease and further studies are required to investigate the impact of this disease on dairy production in the country. PMID- 22210289 TI - Comparison of arterial stiffness in end-stage renal disease patients treated with peritoneal dialysis or hemodialysis. AB - INTRODUCTION: Dialysis patients presents increased arterial stiffness. Results of available studies comparing arterial stiffness in peritoneal dialysis (PD) patients vs hemodialysis (HD) patients are inconsistent. OBJECTIVES: The aim of the study was to compare pulse wave velocity (PWV) in PD and HD patients and to compare value of measured PWV (PWV(M)) with theoretical value of this parameter (PWV(T)) calculated using formula developed by Blacher et al. From the equation it is apparent that PWV increases by 0.8 m/s for each decade of life. PATIENTS AND METHODS: Carotid-femoral PWV(M) was measured in 35 PD and 26 HD patients, using Complior device. In all patients PWV(T) was also calculated. RESULTS: The study groups did not differ significantly with respect to age, gender, and prevalence of diabetes. The value of PWV(M) (PD:12.1 +/- 3.3 vs HD:12.0 +/- 3.0 m/s) and PWV(T) (PD:10.0 +/- 1.4 vs HD:9.9 +/- 1.2 m/s) did not differ significantly between PD and HD. PWV(M) was significantly higher than PWVT in both, PD and HD patients. Diastolic blood pressure and mean arterial pressure was higher in PD patients, but systolic blood pressure and pulse pressure did not differ significantly. In PD patients a higher number of antihypertensive medications was used (3 +/- 1 vs 2 +/- 1;p<0.05). CONCLUSIONS: Arterial stiffness is equally high in peritoneal dialysis patients and in hemodialysis patients. Measured value of PWV in both, PD and HD patients, is significantly higher when compared with theoretical value of PWV. This finding may reflect accelerated arterial aging in patients on dialysis. PMID- 22210290 TI - Comments to the editor concerning the paper entitled "Preclinical renal cancer chemopreventive efficacy of geraniol by modulation of multiple molecular pathways" Shiekh Tanveer Ahmad et al. PMID- 22210291 TI - Social and legal determinants for the marketing of GM products in Poland. AB - The development of biotechnology is influenced by many factors unique for a specific region. In Poland the lack of legislative solutions (to facilitate the promotion of the inventions) and the public resistance against certain sectors of biotechnology are significant factors limiting any further development. Although, science and technology are the front runners in any innovation, the significance of social and legal aspects is difficult to overestimate. In our opinion those factors are interconnected and crucial for marketing of innovative products, therefore, we indicate and explain the most important issues restraining the implementation of innovative biotechnology in the context of national specificity in Poland. PMID- 22210292 TI - Adiponectin, leptin and lipid profiles evaluation in oral contraceptive pill consumers. AB - BACKGROUND: The aim of this study was to evaluate serum lipid profiles, leptin and adiponectin levels in women with a normal menstrual cycle receiving low-dose (LD) combined oral contraceptive pill (COC) (levonorgestrel 0.15 mg, ethinyl estradiol 0.03 mg). STUDY DESIGN: Serum adiponectin and leptin concentrations were measured by enzyme-linked immunosorbent assay (ELISA), and spectrophotometric assay was used for serum lipid and lipoprotein profiles assay in 50 healthy women with normal menstrual cycles who served as the control group and 50 women taking COCs. Unpaired t test and Chi-square test were used for comparison of variables between oral contraceptive users and non-oral contraceptive users. RESULTS: Serum adiponectin and leptin levels were changed in COC consumers. The data obtained for adiponectin in COC consumers (6.6 +/- 4.06 MUg/ml) were significantly lower (-27.4%, P = 0.004) than control group (9.1 +/- 5.09 MUg/ml). The difference between the serum leptin concentration of the control group (11.5 +/- 6.9 ng/ml) and women receiving COCs (14.1 +/- 6.7 ng/ml) was not significant (+18.4%, P = 0.083). There was nonsignificant difference between HDL levels of subjects taking COC (44.02 +/- 10.7 mg/dl) and control group (49.4 +/- 14.3 mg/dl). The LDL levels of COC consumer (131.40 +/- 66.40 mg/dl) was significantly higher (P = 0.002) than controls (102.30 +/- 44.0 mg/dl). The serum cholesterol concentration of women receiving COC (193.2 +/- 70.4 mg/dl) was significantly higher (P = 0.05) than controls (172.8 +/- 49.6 mg/dl). The age of COC consumption and the duration of intake of COCs beyond 36 months had no significant effect on the adiponectin and leptin concentrations. CONCLUSION: LD COC uptake results in a significant decrease in serum adiponectin concentration, nonsignificant increase in leptin levels and a more atherogenic lipid profile by significantly increasing LDL and nonsignificantly decreasing HDL concentrations. These findings suggested that COC may reduce or stimulate the adiponectin and leptin concentrations, respectively. This might be due to an effect of these pills on adipocyte maturation via inhibition or stimulation of the synthesis of new adiponectin and leptin molecules or may be a result of the increased frequency of a particular allele of the adiponectin and leptin. It is suggested that these alterations in adiponectin and leptin concentrations and lipid profiles may be related to their probable effects in response to various pathological and physiological properties of COC or its metabolites. It seems that probably free radicals produced during metabolism of COCs change the amounts of adipokines and atherogenic lipids. PMID- 22210293 TI - Clinical outcomes and patterns of severe late toxicity in the era of chemo radiation for cervical cancer. AB - BACKGROUND: We present a comprehensive analysis of both therapy-induced severe late toxicity and outcome in a cohort of cervical cancer patients following radiation who were treated according to current guidelines and discuss the methodologic problems of systematically reporting these cases. We introduce a revised concept of reporting treatment failure. PATIENTS AND METHODS: The records of 128 cervical cancer patients who received radiation from 2003 to 2008 were reviewed. RESULTS: Thirteen patients (10.2%) developed severe late toxicity. The combination of heavy smoking and cardiovascular diseases was found to be a significant contributing factor (HR 6.55, 95% CI 0.99-43.49, p = 0.048). Thirty patients (23.4%) experienced treatment failure. Of these, 12 (9.4%) were defined to have persistent disease, and 18 (14.0%) developed recurrent disease. Patients with recurrent disease had significantly better survival time (p < 0.001). Compared with the persistence subgroup, they had significantly more often multiple sites of relapse (66.7 vs. 8.3%, p = 0.002) and the sites were more often diagnosed outside the pelvis (70.7 vs. 7.7%, p < 0.001). Early disease stages (OR 4.46, 95% CI 1.87-10.63, p < 0.001) and severe late toxicity (p = 0.037) were found to be significant factors for an improved disease-free survival. CONCLUSIONS: A comprehensive depiction of both late therapy-related toxicity and treatment failure requires precise clinical descriptions and analyses of the clinical courses. Our new concept to differentiate treatment failure following radiotherapy in cervical cancer into persistent and recurrent disease permits a clear differentiation between distinct subgroups of patients with regard to prognosis and clinical presentation and will lead to a more precise description of these cases in the future. PMID- 22210294 TI - The preoperative diagnosis of borderline ovarian tumors: a review of current literature. AB - PURPOSE: To evaluate the available information on the preoperative diagnosis of borderline ovarian tumors (BOTs). METHODS: Articles were identified through electronic databases (Medline and EMBASE, MEDLINE, PubMed), no date or language restrictions were placed; relevant citations were hand searched. RESULTS: Women with BOTs are more likely to have no symptom than women with invasive ovarian cancers; however, the type of symptoms is similar in patients with BOTs and invasive ovarian cancers. Up to 61% of women with BOTs have elevated CA-125; CA 19.9 and endoglin are not useful for diagnosing BOTs. Further studies are required to determine whether the measurements of calprotectin, oviductal glycoprotein 1 and growth differentiation factor-15 are useful for diagnosing BOTs. Ultrasonography and magnetic resonance imaging (MRI) are the mainstay for the diagnosis of BOTs. Combining MRI and positron emission tomography may facilitate the identification of BOTs. CONCLUSION: After completion of this article, the reader should be aware of the symptoms of BOTs, the potential role and pitfalls of tumor marker measurement. In addition, the reader will understand the appearance of BOTs at imaging techniques; the reader will be able to compare and combine ultrasonography, MRI and positron emission tomography in diagnosing BOTs. In clinical practice, the reader should be better able to assess whether an ovarian mass is a benign tumor, a BOT or an invasive cancer. PMID- 22210295 TI - Women's well-being after Manchester procedure for pelvic reconstruction with uterine preservation: a follow-up study. AB - PURPOSE: This study describes the outcomes of a modified Manchester procedure on the quality of life and sexual functioning of women with elongation of the uterine cervix with or without pelvic organ prolapse (POP). METHODS: Data on medical and demographic variables were collected from medical files and then women were invited to for follow-up examination and data collection. RESULTS: Follow-up data were collected from 53 out of 87 women who underwent reconstructive surgery with modified Manchester procedure (60.9% of the women). Prior the surgery, all women in this sample (n = 53) were medically examined and found to have uterine cervix elongation, 40/53 (75.4%) women also had cystocele, 10/53 women (18.8%) had uterine prolapse and 8/53 women (15.1%) had rectocele (all stages II-IV). On follow-up examination, all the cervical stumps were satisfactorily situated, recurrent cystocele was found among 12/53 women (22.6%) women; 13/53 (24.5%) had rectocele; and none of these women had uterine prolapse. Women with POP (cystocele and rectocele) (24/53) had less operative satisfaction (p = 0.004), lower quality of life (p < 0.05 in 3 out of 8 domains), and poorer sexual function (p = 0.03) compared to women without POP (29/53). CONCLUSION: The modified Manchester procedure including reconstructive surgery for women with cervix elongation, with or without POP, prevented recurrent uterine prolapse and was well received in terms of patient's satisfaction, quality of life, and sexual function. PMID- 22210296 TI - Type I collagen and matrix metalloproteinase 1, 3 and 9 gene polymorphisms in the predisposition to pelvic organ prolapse. AB - AIM: To evaluate whether the presence of specific polymorphism in the gene promoter of collagen and some matrix metalloproteinases was associated with the risk of developing pelvic organ prolapse. METHODS: A case-control study was carried on 233 women: 137 were cases with >= stage II pelvic organ prolapse and 96 were matched controls without pelvic pathologies. Allele and genotype frequencies related to polymorphisms at the Sp1 site of type I collagen and some functional polymorphisms in the promoters of metalloproteinases-1, -3 and -9 have been compared between groups. It has been shown that these single insertions/deletions polymorphisms located in the promoter region of the genes have a functional significance in the regulation of their transcriptional level and local expression. Genotypes were determined by polymerase chain reaction (PCR) amplification and sequence analysis. SPSS 14.0 software was used for data analysis. Probability values of <0.05 were considered statistically significant. RESULTS: No difference between groups was found in the genotype distribution polymorphisms for COL1A1, metalloproteinases-9 and -3, while the distribution of the polymorphism of metalloproteinases-1 was significantly increased in the cases when compared with controls (p = 0.04). CONCLUSIONS: Our findings suggest that the polymorphism of metalloproteinases-1 might have a role in mediating susceptibility to pelvic organ prolapse. PMID- 22210297 TI - A modified anterior compartment reconstruction and Prolift-a for the treatment of anterior pelvic organ prolapse: a non-inferiority study. AB - OBJECTIVE: To evaluate, in terms of efficacy and safety, a modified anterior compartment reconstruction procedure for anterior pelvic organ prolapse (POP). METHODS: The patients were assigned to two groups according to their individual willingness and economical condition, of whom 68 were treated with the modified procedure and 37 with the 'Prolift-a' procedure. The objective cure rate was defined by 0 or I according to POP-Q, which was detected by non-inferiority test between the two groups. RESULTS: The cure rates were found to be 94.1% (64/68) in the modified group and 97.3% (36/37) in the Prolift-a group, respectively. No significant difference was found between these two groups in the cure rate by non inferiority test (u = 2.252, P = 0.012). The blood loss and hospitalization costs were significantly lower in the modified group than the Prolift-a group (P < 0.05), while other clinical parameters showed no significant difference between the two groups (P > 0.05). CONCLUSION: Both the modified total pelvic reconstruction and Prolift-a operations are safe, efficacious and minimally invasive surgical treatments, while the modified procedure is relatively inexpensive, which has great perspective of clinical application in developing countries. PMID- 22210298 TI - What can major league baseball teach us about healthcare? PMID- 22210299 TI - Female caregivers of stroke survivors: coping and adapting to a life that once was. AB - Despite the prevalence of women caring for stroke survivors, relatively little research has focused specifically on the experience and needs of informal female caregivers of stroke survivors. Therefore, the purpose of this study was to describe the experience of female caregivers who care for an adult family member who has experienced a stroke within the previous year using a qualitative methodology. A sample of 46 female caregivers of stroke survivors completed a demographic form and responded to open-ended written questions exploring their experiences as caregivers and how they coped with changes in their lives during the first year after the stroke. Four concepts emerged from the data: losing the life that once was, coping with daily burdens, creating a new normal, and interacting with healthcare providers. Findings suggest that female caregivers of stroke survivors grieve the life that they once shared with the stroke survivor and struggle to cope with multiple family and work demands while trying their best to interact with healthcare providers to attain the best possible care for their loved ones. Recognizing the unique challenges of female caregivers of stroke survivors may help nurses provide better support and resources to meet their needs. PMID- 22210300 TI - Moral distress in neuroscience nursing: an evolutionary concept analysis. AB - Moral distress has been explored within a number of nursing contexts, including critical care, neuroscience, and end-of-life decision making. Although the antecedents and consequences of this concept continue to be uncovered, its unique attributes remain ambiguous. This analysis aims to clarify the concept of moral distress, contribute new insights about moral distress to nursing as a whole and to the subspecialty of neuroscience nursing in particular, and enhance advancements in nursing knowledge and practice. Literature published in English between 1987 and 2009 was searched using the Cumulative Index to Nursing and Allied Health Literature and Google Scholar databases. Eleven journal articles were used in the final analysis. Rodgers' evolutionary model of concept analysis was used in this study. Four comprehensive attributes were formulated to describe moral distress in neuroscience nursing: negative feelings, powerlessness, conflicting loyalties, and uncertainty. These attributes are intimately related, holding true meaning only when viewed within the context of one another and with respect to the historical and philosophical underpinnings of nursing praxis. This analysis demonstrates the fluidity, complexity, and multifacetedness of moral distress. Knowledge of the conceptual attributes presented herein will facilitate recognition and validation of personal experiences within the neuroscience nursing community. PMID- 22210302 TI - Impact of treadmill exercise on efficacy expectations, physical activity, and stroke recovery. AB - Stroke survivors are at high risk for cardiovascular mortality which can be in part mitigated by increasing physical activity. Self-efficacy for exercise is known to play a role in adoption of exercise behaviors. This study examines self reported psychological outcomes in a group of 64 stroke survivors randomized to either a 6-month treadmill training program or a stretching program. Results indicated that, regardless of group, all study participants experienced increased self-efficacy (F = 2.95, p = .09) and outcome expectations for exercise (F = 13.23, p < 0.001) and improvements in activities of daily living as reported on the Stroke Impact Scale (F = 10.97, p = .002). No statistically significant between-group differences were noted, possibly because of the fact that specific interventions designed to enhance efficacy beliefs were not part of the study. Theoretically based interventions should be tested to clarify the role of motivation and potential influence on exercise and physical activity in the stroke survivor population. PMID- 22210303 TI - Appreciating life: being the father of a child with severe cerebral palsy. AB - This phenomenological study examined the experience of being the father of a child with severe cerebral palsy (CP). Participants were selected using purposive sampling. Two interviews were conducted with 6 English-speaking, biological fathers whose children with CP (ages 5-27 years) were enrolled in a residential and day school in northeastern United States. Audiotaped interviews were transcribed, and thematic analysis was conducted using van Manen's methodology. Themes identified were as follows: Lost in birth; My beautiful unique child; Illness as a way of life...you can't get used to it and after a while it feels like no one cares; Partners-loyalty and commitment; How the world receives my child; Healthcare providers-I'm here; Torn...when your child can't live at home...finding a place to live and grow; and Faith. Clinicians should encourage, value, and include fathers' input during discussions of medical and social problems and when developing long-term care plans. Further research exploring the experiences of fathers of children with CP should be conducted. PMID- 22210304 TI - An overview of nonpathological geroneuropsychology: implications for nursing practice and research. AB - One aspect of successful aging is maintaining cognitive functioning, which includes both subjective cognitive functioning and objective cognitive functioning even in lieu of subtle cognitive deficits that occur with normal, nonpathological aging. Age-related cognitive deficits emerge across several domains including attention, memory, language, speed of processing, executive, and psychomotor, just to name a few. A primary theory explaining such cognitive deficits is cognitive reserve theory; it posits that biological factors such as demyelination and oxidative stress interfere with neuronal communication, which eventually produces observable deficits in cognitive functioning. Therefore, it is important to maintain or improve cognitive reserve to augment cognitive functioning in later life. This article provides a general overview of the principles of geroneuropsychology along with implications for nursing practice and research. PMID- 22210305 TI - What would you say? Expressing the difficulties of living with multiple sclerosis. AB - This article used a mixed method approach to analyze qualitative and quantitative responses from individuals with multiple sclerosis (MS) to determine differences when patients' perceived stress levels and perceived quality of support are taken into account. Understanding the differences in these responses can help us understand how illness, specifically MS, may influence the relational messages sent by patients to their loved ones. Responses to both quantitative and qualitative questions were obtained from 145 persons who have been diagnosed with MS. Participants responded to scale questions measuring daily stress levels and levels of social support and were divided into four groups on the basis of their scores (low/low, high/low, high/high, and high/low). Thematic analysis was performed on the qualitative responses, and differences were analyzed based on participants' grouping. Additional outcome variables measuring quality of life, anxiety, depression, helplessness, and acceptance were also analyzed to determine the similarities and differences between the groupings. The information presented in this article both informs and supports the idea that patients' levels of stress and perception of support are two major variables that impact their responses to their loved ones and their scores on several outcome variables. PMID- 22210306 TI - The long-term experience of family life after stroke. AB - Stroke is a life-threatening and disabling illness known to have a significant impact on families. The purpose of this study was to illuminate the long-term experience of family life after stroke of stroke survivors and their spouses and children, particularly regarding marital and parent-child relationships. Thirty seven narrative interviews were conducted with stroke survivors and their spouses and adult children who were minors at onset of the illness. A qualitative approach inspired by Gadamer's hermeneutic and van Manen's phenomenological understanding of lived experience was used. The analysis revealed four themes: the family as a lifebuoy, absent presence, broken foundations, and finding a new marital path. Lack of communication and altered roles and relationships endangered marital equilibrium and parent-child relationships after stroke. This study highlighted the need for professional family support as families were unprepared for the life changes that occurred. Nurses and other healthcare workers should examine family relationships and communication patterns and view the family as a unit composed of unique persons with different needs. Further research on the experiences of stroke survivors' children seems urgent. PMID- 22210307 TI - Correlative VIS-fluorescence and soft X-ray cryo-microscopy/tomography of adherent cells. AB - Soft X-ray cryo-microscopy/tomography of vitreous samples is becoming a valuable tool in structural cell biology. Within the 'water-window' wavelength region (2.34-4.37nm), it provides absorption contrast images with high signal to noise ratio and resolution of a few tens of nanometer. Soft X-rays with wavelengths close to the K-absorption edge of oxygen penetrate biological samples with thicknesses in the micrometer range. Here, we report on the application of a recently established extension of the transmission soft X-ray cryo-microscope (HZB TXM) at the beamline U41-XM of the BESSY II electron storage ring by an in column epi-fluorescence and reflected light cryo-microscope. We demonstrate the new capability for correlative fluorescence and soft X-ray cryo microscopy/tomography of this instrument along a typical life science experimental approach - the correlation of a fluorophore-tagged protein (pUL34 GFP of pseudorabies virus, PrV, the nuclear membrane-anchored component of the nuclear egress complex of the Herpesviridae which interacts with viral pUL31) in PrV pUL34-GFP/pUL31 coexpressing mammalian cells, with virus-induced vesicular structures in the nucleus, expanding the nucleoplasmic reticulum. Taken together, our results demonstrate new possibilities to study the role of specific proteins in substructures of adherent cells, especially of the nucleus in toto, accessible to electron microscopy in thinned samples only. PMID- 22210309 TI - Proceedings from the 9th International Conference on Ovarian Cancer. PMID- 22210310 TI - Effect of air-drying on the solvent evaporation, degree of conversion and water sorption/solubility of dental adhesive models. AB - This study evaluated protocols to eliminate acetone from dental adhesives and their effect on the kinetic of water sorption and percent of conversion of these adhesives. Experimental methacrylate-based adhesives with increasing hydrophilicity (R2, R3, R5) were used as reference materials. Primer-like solutions were prepared by addition of 50 wt% acetone. Acetone elimination was measured gravimetrically before and after: a spontaneous evaporation, an application of air-drying at room temperature or application of 40 degrees C air drying. Protocols were performed from 15 to 60 s. Specimens of adhesive/acetone mixtures were photo-activated and tested for degree of conversion, water sorption and solubility. Data were analyzed by ANOVA and Bonferroni's tests (alpha = 0.05). Complete acetone elimination was never achieved, but it was significantly greater after the 40 degrees C air-drying application. Higher acetone elimination was observed for the least hydrophilic adhesive. Longer periods for acetone evaporation and heated air-stream can optimize polymerization and reduce the water sorption/solubility of adhesive system models. PMID- 22210308 TI - Insights from the architecture of the bacterial transcription apparatus. AB - We provide a portrait of the bacterial transcription apparatus in light of the data emerging from structural studies, sequence analysis and comparative genomics to bring out important but underappreciated features. We first describe the key structural highlights and evolutionary implications emerging from comparison of the cellular RNA polymerase subunits with the RNA-dependent RNA polymerase involved in RNAi in eukaryotes and their homologs from newly identified bacterial selfish elements. We describe some previously unnoticed domains and the possible evolutionary stages leading to the RNA polymerases of extant life forms. We then present the case for the ancient orthology of the basal transcription factors, the sigma factor and TFIIB, in the bacterial and the archaeo-eukaryotic lineages. We also present a synopsis of the structural and architectural taxonomy of specific transcription factors and their genome-scale demography. In this context, we present certain notable deviations from the otherwise invariant proteome-wide trends in transcription factor distribution and use it to predict the presence of an unusual lineage-specifically expanded signaling system in certain firmicutes like Paenibacillus. We then discuss the intersection between functional properties of transcription factors and the organization of transcriptional networks. Finally, we present some of the interesting evolutionary conundrums posed by our newly gained understanding of the bacterial transcription apparatus and potential areas for future explorations. PMID- 22210311 TI - Biomechanical characterisation of a degradable magnesium-based (MgCa0.8) screw. AB - Magnesium alloys have been in the focus of research in recent years as degradable biomaterial. The purpose of this study was the biomechanical characterisation of MgCa0.8-screws. The maximum pull out force of screws was determined in a synthetic bone without corrosion and after fixed intervals of corrosion: 24, 48, 72 and 96 h. This in vitro study has been carried out with Hank's solution with a flow rate corresponding to the blood flow in natural bone. A maximum pull out force (F(max)) of 201.5 +/- 9.3 N was measured without corrosion. The biomechanical parameter decreased by 30% after 96 h in corrosive medium compared to the non-corrosion group. A maximum load capacity of 28 +/- 7.6 N/h was determined. Our biomechanical data suggests that this biodegradable screw provides a promising bone-screw-fixation and has great potential for medical application. PMID- 22210312 TI - Global DNA methylation is associated with insulin resistance: a monozygotic twin study. AB - Insulin resistance (IR), the hallmark of type 2 diabetes, may be under epigenetic control. This study examines the association between global DNA methylation and IR using 84 monozygotic twin pairs. IR was estimated using homeostasis model assessment (HOMA). Global DNA methylation of Alu repeats in peripheral blood leukocytes was quantified by bisulfite pyrosequencing. The association between global DNA methylation and IR was examined using generalized estimating equation (GEE) and within-twin pair analyses, adjusting for potential confounders. Results show that methylation levels at all four CpG sites were individually associated with IR by GEE (all false discovery rate-adjusted P values<=0.026). A 10% increase in mean Alu methylation was associated with an increase of 4.55 units (95% CI 2.38-6.73) in HOMA. Intrapair difference in IR was significantly associated with intrapair difference in global methylation level. A 10% increase in the difference in mean Alu methylation was associated with an increase of 4.54 units (0.34-8.71; P=0.036) in the difference in HOMA. Confirmation of the results by intrapair analyses suggests that genetic factors do not confound the association between global DNA methylation and IR. Exclusion of twins taking diabetes medication (n=17) did not change our results. PMID- 22210313 TI - Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity. AB - Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes. PMID- 22210314 TI - Bcl-2-modifying factor induces renal proximal tubular cell apoptosis in diabetic mice. AB - This study investigated the mechanisms underlying tubular apoptosis in diabetes by identifying proapoptotic genes that are differentially upregulated by reactive oxygen species in renal proximal tubular cells (RPTCs) in models of diabetes. Total RNAs isolated from renal proximal tubules (RPTs) of 20-week-old heterozygous db/m+, db/db, and db/db catalase (CAT)-transgenic (Tg) mice were used for DNA chip microarray analysis. Real-time quantitative PCR assays, immunohistochemistry, and mice rendered diabetic with streptozotocin were used to validate the proapoptotic gene expression in RPTs. Cultured rat RPTCs were used to confirm the apoptotic activity and regulation of proapoptotic gene expression. Additionally, studies in kidney tissues from patients with and without diabetes were used to confirm enhanced proapoptotic gene expression in RPTs. Bcl-2 modifying factor (Bmf) was differentially upregulated (P<0.01) in RPTs of db/db mice compared with db/m+ and db/db CAT-Tg mice and in RPTs of streptozotocin induced diabetic mice in which insulin reversed this finding. In vitro, Bmf cDNA overexpression in rat RPTCs coimmunoprecipated with Bcl-2, enhanced caspase-3 activity, and promoted apoptosis. High glucose (25 mmol/L) induced Bmf mRNA expression in RPTCs, whereas rotenone, catalase, diphenylene iodinium, and apocynin decreased it. Knockdown of Bmf with small interfering RNA reduced high glucose-induced apoptosis in RPTCs. More important, enhanced Bmf expression was detected in RPTs of kidneys from patients with diabetes. These data demonstrate differential upregulation of Bmf in diabetic RPTs and suggest a potential role for Bmf in regulating RPTC apoptosis and tubular atrophy in diabetes. PMID- 22210316 TI - Histone deacetylase 6 (HDAC6) is an essential modifier of glucocorticoid-induced hepatic gluconeogenesis. AB - In the current study, we investigated the importance of histone deacetylase (HDAC)6 for glucocorticoid receptor-mediated effects on glucose metabolism and its potential as a therapeutic target for the prevention of glucocorticoid induced diabetes. Dexamethasone-induced hepatic glucose output and glucocorticoid receptor translocation were analyzed in wild-type (wt) and HDAC6-deficient (HDAC6KO) mice. The effect of the specific HDAC6 inhibitor tubacin was analyzed in vitro. wt and HDAC6KO mice were subjected to 3 weeks' dexamethasone treatment before analysis of glucose and insulin tolerance. HDAC6KO mice showed impaired dexamethasone-induced hepatic glucocorticoid receptor translocation. Accordingly, dexamethasone-induced expression of a large number of hepatic genes was significantly attenuated in mice lacking HDAC6 and by tubacin in vitro. Glucose output of primary hepatocytes from HDAC6KO mice was diminished. A significant improvement of dexamethasone-induced whole-body glucose intolerance as well as insulin resistance in HDAC6KO mice compared with wt littermates was observed. This study demonstrates that HDAC6 is an essential regulator of hepatic glucocorticoid-stimulated gluconeogenesis and impairment of whole-body glucose metabolism through modification of glucocorticoid receptor nuclear translocation. Selective pharmacological inhibition of HDAC6 may provide a future therapeutic option against the prodiabetogenic actions of glucocorticoids. PMID- 22210317 TI - Regulated and reversible induction of adult human beta-cell replication. AB - Induction of proliferation in adult human beta-cells is challenging. It can be accomplished by introduction of cell cycle molecules such as cyclin-dependent kinase 6 (cdk6) and cyclin D1, but their continuous overexpression raises oncogenic concerns. We attempted to mimic normal, transient, perinatal human beta cell proliferation by delivering these molecules in a regulated and reversible manner. Adult cadaveric islets were transduced with doxycycline (Dox)-inducible adenoviruses expressing cdk6 or cyclin D1. End points were cdk6/cyclin D1 expression and human beta-cell proliferation, survival, and function. Increasing doses of Dox led to marked dose- and time-related increases in cdk6 and cyclin D1, accompanied by a 20-fold increase in beta-cell proliferation. Notably, Dox withdrawal resulted in a reversal of both cdk6 and cyclin D1 expression as well as beta-cell proliferation. Re-exposure to Dox reinduced both cdk/cyclin expression and proliferation. beta-Cell function and survival were not adversely affected. The adenoviral tetracycline (tet)-on system has not been used previously to drive human beta-cell proliferation. Human beta-cells can be induced to proliferate or arrest in a regulated, reversible manner, temporally and quantitatively mimicking the transient perinatal physiological proliferation that occurs in human beta-cells. PMID- 22210318 TI - Brain glucose sensors play a significant role in the regulation of pancreatic glucose-stimulated insulin secretion. AB - As patients decline from health to type 2 diabetes, glucose-stimulated insulin secretion (GSIS) typically becomes impaired. Although GSIS is driven predominantly by direct sensing of a rise in blood glucose by pancreatic beta cells, there is growing evidence that hypothalamic neurons control other aspects of peripheral glucose metabolism. Here we investigated the role of the brain in the modulation of GSIS. To examine the effects of increasing or decreasing hypothalamic glucose sensing on glucose tolerance and insulin secretion, glucose or inhibitors of glucokinase, respectively, were infused into the third ventricle during intravenous glucose tolerance tests (IVGTTs). Glucose-infused rats displayed improved glucose handling, particularly within the first few minutes of the IVGTT, with a significantly lower area under the excursion curve within the first 10 min (AUC0-10). This was explained by increased insulin secretion. In contrast, infusion of the glucokinase inhibitors glucosamine or mannoheptulose worsened glucose tolerance and decreased GSIS in the first few minutes of IVGTT. Our data suggest a role for brain glucose sensors in the regulation of GSIS, particularly during the early phase. We propose that pharmacological agents targeting hypothalamic glucose-sensing pathways may represent novel therapeutic strategies for enhancing early phase insulin secretion in type 2 diabetes. PMID- 22210315 TI - Low-frequency variants in HMGA1 are not associated with type 2 diabetes risk. AB - It has recently been suggested that the low-frequency c.136-14_136-13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136-14_136-13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136-14_136-13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease. PMID- 22210319 TI - Expression and regulation of chemokines in murine and human type 1 diabetes. AB - More than one-half of the ~50 human chemokines have been associated with or implicated in the pathogenesis of type 1 diabetes, yet their actual expression patterns in the islet environment of type 1 diabetic patients remain, at present, poorly defined. Here, we have integrated a human islet culture system, murine models of virus-induced and spontaneous type 1 diabetes, and the histopathological examination of pancreata from diabetic organ donors with the goal of providing a foundation for the informed selection of potential therapeutic targets within the chemokine/receptor family. Chemokine (C-C motif) ligand (CCL) 5 (CCL5), CCL8, CCL22, chemokine (C-X-C motif) ligand (CXCL) 9 (CXCL9), CXCL10, and chemokine (C-X3-C motif) ligand (CX3CL) 1 (CX3CL1) were the major chemokines transcribed (in an inducible nitric oxide synthase-dependent but not nuclear factor-kappaB-dependent fashion) and translated by human islet cells in response to in vitro inflammatory stimuli. CXCL10 was identified as the dominant chemokine expressed in vivo in the islet environment of prediabetic animals and type 1 diabetic patients, whereas CCL5, CCL8, CXCL9, and CX3CL1 proteins were present at lower levels in the islets of both species. Of importance, additional expression of the same chemokines in human acinar tissues emphasizes an underappreciated involvement of the exocrine pancreas in the natural course of type 1 diabetes that will require consideration for additional type 1 diabetes pathogenesis and immune intervention studies. PMID- 22210320 TI - Potential role of tumor necrosis factor-alpha in downregulating sex hormone binding globulin. AB - Low plasma sex hormone-binding globulin (SHBG) levels are associated with obesity and predict the development of type 2 diabetes. The reason why obese individuals have low circulating SHBG has been attributed to hyperinsulinemia, but no mechanistic evidence has been described. The aim of the current study is to explore whether tumor necrosis factor-alpha (TNF-alpha) rather than insulin could be the main factor accounting for low SHBG levels in obesity. We performed in vitro and in vivo studies using human HepG2 cells and human SHBG transgenic mice. In addition, a cross-sectional study to explore the relationship between TNF alpha and SHBG in obese patients and an interventional study to examine the effect of insulin administration on circulating SHBG in type 2 diabetic patients were performed. We provide evidence that TNF-alpha, but not insulin, is the main factor by which SHBG is reduced in obesity. Plasma SHBG was significantly increased rather than decreased after insulin treatment in diabetic patients. TNF alpha-induced reduction of SHBG expression was mediated by downregulating HNF4A. Finally, a negative and independent correlation was found between plasma TNF alpha receptor 1 and SHBG levels in obese patients. Our results suggest that TNF alpha plays an important role downregulating SHBG in chronic low-grade inflammatory diseases such as obesity and type 2 diabetes. PMID- 22210322 TI - Apelin treatment increases complete Fatty Acid oxidation, mitochondrial oxidative capacity, and biogenesis in muscle of insulin-resistant mice. AB - Both acute and chronic apelin treatment have been shown to improve insulin sensitivity in mice. However, the effects of apelin on fatty acid oxidation (FAO) during obesity-related insulin resistance have not yet been addressed. Thus, the aim of the current study was to determine the impact of chronic treatment on lipid use, especially in skeletal muscles. High-fat diet (HFD)-induced obese and insulin-resistant mice treated by an apelin injection (0.1 MUmol/kg/day i.p.) during 4 weeks had decreased fat mass, glycemia, and plasma levels of triglycerides and were protected from hyperinsulinemia compared with HFD PBS treated mice. Indirect calorimetry experiments showed that apelin-treated mice had a better use of lipids. The complete FAO, the oxidative capacity, and mitochondrial biogenesis were increased in soleus of apelin-treated mice. The action of apelin was AMP-activated protein kinase (AMPK) dependent since all the effects studied were abrogated in HFD apelin-treated mice with muscle-specific inactive AMPK. Finally, the apelin-stimulated improvement of oxidative capacity led to decreased levels of acylcarnitines and enhanced insulin-stimulated glucose uptake in soleus. Thus, by promoting complete lipid use in muscle of insulin resistant mice through mitochondrial biogenesis and tighter matching between FAO and the tricarboxylic acid cycle, apelin treatment could contribute to insulin sensitivity improvement. PMID- 22210321 TI - L-leucine alters pancreatic beta-cell differentiation and function via the mTor signaling pathway. AB - Leucine (Leu) is an essential branched-chain amino acid, which activates the mammalian target of rapamycin (mTOR) signaling pathway. The effect of Leu on cell differentiation during embryonic development is unknown. Here, we show that Leu supplementation during pregnancy significantly increased fetal body weight, caused fetal hyperglycemia and hypoinsulinemia, and decreased the relative islet area. We also used rat embryonic pancreatic explant culture for elucidating the mechanism of Leu action on beta-cell development. We found that in the presence of Leu, differentiation of pancreatic duodenal homeobox-1-positive progenitor cells into neurogenin3-positive endocrine progenitor cells was inefficient and resulted in decreased beta-cell formation. Mechanistically, Leu increases the intracellular levels of hypoxia-inducible factor 1-alpha, a repressor of endocrine fate in the pancreas, by activating the mTOR complex 1 signaling pathway. Collectively, our findings indicate that Leu supplementation during pregnancy could potentially increase the risk of type 2 diabetes mellitus by inhibiting the differentiation of pancreatic endocrine progenitor cells during a susceptible period of fetal life. PMID- 22210323 TI - FGF21 analogs of sustained action enabled by orthogonal biosynthesis demonstrate enhanced antidiabetic pharmacology in rodents. AB - Fibroblast growth factor 21 (FGF21) mitigates many of the pathogenic features of type 2 diabetes, despite a short circulating half-life. PEGylation is a proven approach to prolonging the duration of action while enhancing biophysical solubility and stability. However, in the absence of a specific protein PEGylation site, chemical conjugation is inherently heterogeneous and commonly leads to dramatic loss in bioactivity. This work illustrates a novel means of specific PEGylation, producing FGF21 analogs with high specific activity and salutary biological activities. Using homology modeling and structure-based design, specific sites were chosen in human FGF21 for site-specific PEGylation to ensure that receptor binding regions were preserved. The in vitro activity of the PEGylated FGF21 ana-logs corresponded with the site of PEG placement within the binding model. Site-specific PEGylated analogs demonstrated dramatically increased circulating half-life and enhanced efficacy in db/db mice. Twice-weekly dosing of an optimal FGF21 analog reduced blood glucose, plasma lipids, liver triglycerides, and plasma glucagon and enhanced pancreatic insulin content, islet number, and glucose-dependent insulin secretion. Restoration of insulin sensitivity was demonstrated by the enhanced ability of insulin to induce Akt/protein kinase B phosphorylation in liver, muscle, and adipose tissues. PEGylation of human FGF21 at a specific and preferred site confers superior metabolic pharmacology. PMID- 22210324 TI - Glucocorticoid signaling in the arcuate nucleus modulates hepatic insulin sensitivity. AB - Glucocorticoid receptors are highly expressed in the hypothalamic paraventricular nucleus (PVN) and arcuate nucleus (ARC). As glucocorticoids have pronounced effects on neuropeptide Y (NPY) expression and as NPY neurons projecting from the ARC to the PVN are pivotal for balancing feeding behavior and glucose metabolism, we investigated the effect of glucocorticoid signaling in these areas on endogenous glucose production (EGP) and insulin sensitivity by local retrodialysis of the glucocorticoid receptor agonist dexamethasone into the ARC or the PVN, in combination with isotope dilution and hyperinsulinemic-euglycemic clamp techniques. Retrodialysis of dexamethasone for 90 min into the ARC or the PVN did not have significant effects on basal plasma glucose concentration. During the hyperinsulinemic-euglycemic clamp, retrodialysis of dexamethasone into the ARC largely prevented the suppressive effect of hyperinsulinemia on EGP. Antagonizing the NPY1 receptors by intracerebroventricular infusion of its antagonist largely blocked the hepatic insulin resistance induced by dexamethasone in the ARC. The dexamethasone-ARC-induced inhibition of hepatic insulin sensitivity was also prevented by hepatic sympathetic denervation. These data suggest that glucocorticoid signaling specifically in the ARC neurons modulates hepatic insulin responsiveness via NPY and the sympathetic system, which may add to our understanding of the metabolic impact of clinical conditions associated with hypercortisolism. PMID- 22210325 TI - When splicing turns bad. PMID- 22210326 TI - The other Achilles' heel of BCR-ABL1. PMID- 22210327 TI - The corepressors BCOR and BCORL1: two novel players in acute myeloid leukemia. PMID- 22210328 TI - ATM and chronic lymphocytic leukemia: mutations, and not only deletions, matter. PMID- 22210329 TI - Patient and physician characteristics associated with erythropoiesis-stimulating agent use in patients with myelodysplastic syndromes. AB - Patient and physician characteristics associated with use of erythropoiesis stimulating agents in myelodysplastic syndrome patients have not yet been described. Myelodysplastic syndrome patients diagnosed from 2001 to 2005 were identified from the Surveillance Epidemiology and End Results-Medicare database. Multivariate regressions examined the association between patient and physician characteristics and the probability of receiving any erythropoiesis-stimulating agents, and of receiving therapeutic-length (>= 8 week) treatment episodes. Among the 6,588 myelodysplastic syndrome patients studied, 65% received erythropoiesis stimulating agents. Use of erythropoiesis-stimulating agents was lower for blacks compared to whites (OR 0.78; 95% CI:0.61-0.99), single persons compared to married (OR 0.77; 95% CI:0.62-0.97), Medicaid recipients (OR 0.66; 95% CI:0.55 0.79), and those living in census tracts with lower educational attainment. Patients who did not consult a hematology-oncology specialist were less likely to receive erythropoiesis-stimulating agents. Specialist access, financial resources and mobility are key determinants of receipt of erythropoiesis-stimulating agents among myelodysplastic syndrome patients. PMID- 22210330 TI - Empirical versus pre-emptive antifungal therapy for persistent febrile neutropenia. PMID- 22210331 TI - Predator stress engages corticotropin-releasing factor and opioid systems to alter the operating mode of locus coeruleus norepinephrine neurons. AB - The norepinephrine nucleus, locus coeruleus (LC), has been implicated in cognitive aspects of the stress response, in part through its regulation by the stress-related neuropeptide, corticotropin-releasing factor (CRF). LC neurons discharge in tonic and phasic modes that differentially modulate attention and behavior. Here, the effects of exposure to an ethologically relevant stressor, predator odor, on spontaneous (tonic) and auditory-evoked (phasic) LC discharge were characterized in unanesthetized rats. Similar to the effects of CRF, stressor presentation increased tonic LC discharge and decreased phasic auditory evoked discharge, thereby decreasing the signal-to-noise ratio of the sensory response. This stress-induced shift in LC discharge toward a high tonic mode was prevented by a CRF antagonist. Moreover, CRF antagonism during stress unmasked a large decrease in tonic discharge rate that was opioid mediated because it was prevented by pretreatment with the opiate antagonist, naloxone. Elimination of both CRF and opioid influences with an antagonist combination rendered LC activity unaffected by the stressor. These results demonstrate that both CRF and opioid afferents are engaged during stress to fine-tune LC activity. The predominant CRF influence shifts the operational mode of LC activity toward a high tonic state that is thought to facilitate behavioral flexibility and may be adaptive in coping with the stressor. Simultaneously, stress engages an opposing opioid influence that restrains the CRF influence and may facilitate recovery toward pre-stress levels of activity. Changes in the balance of CRF:opioid regulation of the LC could have consequences for stress vulnerability. PMID- 22210332 TI - Anticonvulsant profile of caprylic acid, a main constituent of the medium-chain triglyceride (MCT) ketogenic diet, in mice. AB - The purpose of the present study was to evaluate the acute anticonvulsant effects of caprylic acid (CA), the main constituent of the medium-chain triglyceride ketogenic diet (MCT KD), in seizure tests typically used in screening for potential antiepileptic drugs in mice. Pharmacodynamic and pharmacokinetic interactions between CA and valproate (VPA) were also investigated. CA (p.o.) and VPA (i.p.) were administered 30 min before testing. Acute effects on motor coordination were assessed in the chimney test. Total plasma and brain concentrations of CA and VPA, when administered alone or in combination, were determined by high performance liquid chromatography. CA (10-30 mmol/kg) increased the threshold for i.v. pentylenetetrazole-induced myoclonic and clonic convulsions, but not tonic convulsions. CA (5-30 mmol/kg) increased the threshold for 6-Hz psychomotor seizures but was ineffective in the maximal electroshock seizure threshold test. CA (10-60 mmol/kg p.o.) impaired motor performance in the chimney test (TD(50) value, 58.4 mmol/kg). Increasing doses of CA (5-30 mmol/kg) produced proportional increases in plasma and brain exposure with constant brain/plasma partitioning. CA increased anticonvulsant potency of VPA in the maximal electroshock seizure and 6-Hz seizure tests. Co-administration of CA and VPA had no effect on brain and plasma concentrations of either compound. In summary, CA exerts acute anticonvulsant effects and potentiates the anticonvulsant effect of VPA at doses that result in plasma exposures comparable to those reported in epileptic patients on the MCT KD. Thus, this acute anticonvulsant property of CA may benefit and add to the overall clinical efficacy of the MCT KD. PMID- 22210334 TI - Characterization of metal ion-nucleic acid interactions in solution. AB - Metal ions are inextricably involved with nucleic acids due to their polyanionic nature. In order to understand the structure and function of RNAs and DNAs, one needs to have detailed pictures on the structural, thermodynamic, and kinetic properties of metal ion interactions with these biomacromolecules. In this review we first compile the physicochemical properties of metal ions found and used in combination with nucleic acids in solution. The main part then describes the various methods developed over the past decades to investigate metal ion binding by nucleic acids in solution. This includes for example hydrolytic and radical cleavage experiments, mutational approaches, as well as kinetic isotope effects. In addition, spectroscopic techniques like EPR, lanthanide(III) luminescence, IR and Raman as well as various NMR methods are summarized. Aside from gaining knowledge about the thermodynamic properties on the metal ion-nucleic acid interactions, especially NMR can be used to extract information on the kinetics of ligand exchange rates of the metal ions applied. The final section deals with the influence of anions, buffers, and the solvent permittivity on the binding equilibria between metal ions and nucleic acids. Little is known on some of these aspects, but it is clear that these three factors have a large influence on the interaction between metal ions and nucleic acids. PMID- 22210333 TI - Suppression of EAE and prevention of blood-brain barrier breakdown after vaccination with novel bifunctional peptide inhibitor. AB - The efficacy of bifunctional peptide inhibitor (BPI) in preventing blood-brain barrier (BBB) breakdown during onset of experimental autoimmune encephalomyelitis (EAE) and suppression of the disease was evaluated in mice. The mechanism that defines how BPI prevents the disease was investigated by measuring the in vitro cytokine production of splenocytes. Peptides were injected 5-11 days prior to induction of EAE, and the severity of the disease was monitored by a standard clinical scoring protocol and change in body weight. The BBB breakdown in diseased and treated mice was compared to that in normal control mice by determining deposition of gadolinium diethylenetriaminepentaacetate (Gd-DTPA) in the brain using magnetic resonance imaging (MRI). Mice treated with PLP-BPI showed no or low indication of EAE as well as normal increase in body weight. In contrast, mice treated with the control peptide or PBS showed a decrease in body weight and a high disease score. The diseased mice had high deposition of Gd-DTPA in the brain, indicating breakdown in the BBB. However, the deposition of Gd-DTPA in PLP-BPI-treated mice was similar to that in normal control mice. Thus, PLP-BPI can suppress EAE when administered as a peptide vaccine and maintain the integrity of the BBB. PMID- 22210335 TI - Nucleic acid-metal ion interactions in the solid state. AB - Metal ions play a key role in nucleic acid structure and activity. Elucidation of the rules that govern the binding of metal ions is therefore an essential step for better understanding of the nucleic acid functions. This review is as an update to a preceding one (Metal Ions Biol. Syst., 1996, 32, 91-134), in which we offered a general view of metal ion interactions with mono-, di-, tri-, and oligonucleotides in the solid state, based on their crystal structures reported before 1994. In this chapter, we survey all the crystal structures of metal ion complexes with nucleotides involving oligonucleotides reported after 1994 and we have tried to uncover new characteristic metal bonding patterns for mononucleotides and oligonucleotides with A-RNA and A/B/Z-DNA fragments that form duplexes. We do not cover quadruplexes, duplexes with metal-mediated base-pairs, tRNAs, rRNAs in ribosome, ribozymes, and nucleic acid-drug and -protein complexes. Factors that affect metal binding to mononucleotides and oligonucleotide duplexes are also dealt with. PMID- 22210336 TI - Metal ion-promoted conformational changes of oligonucleotides. AB - The review will discuss the influence of metal ions on conformational changes of oligonucleotides. First, a short definition of the torsion angles is given, followed by a concise yet critical overview of the commonly applied experimental techniques. Finally, the possible role of metals upon the following conformational changes of oligonucleotides is discussed: (i) the denaturation of double-strands, (ii) the transition from B- to A-DNA, (iii) the transition from right- to left-handed DNA and RNA, (iv) the condensation, (v) and other conformational changes. We conclude with a summary and outlook. PMID- 22210337 TI - G-quadruplexes and metal ions. AB - Metal ions stabilize quadruplex nucleic acids by coordinating the O6 guanine atoms from G-quartets. These quartets form the basic motif of quadruplex structures. This article systematically surveys the available crystallographic data on native quadruplexes, their ligand complexes and (in one instance) a protein complex. Three categories of quadruplex are examined, tetramolecular, bimolecular, and intramolecular: all are formed by telomeric nucleic acid sequences from human or ciliate organisms. PMID- 22210338 TI - Metal ion-mediated DNA-protein interactions. AB - The dramatic changes in the environmental conditions that organisms encountered during evolution and adaptation to life in specific niches, have influenced intracellular and extracellular metal ion contents and, as a consequence, the cellular ability to sense and utilize different metal ions. This metal-driven differentiation is reflected in the specific panels of metal-responsive transcriptional regulators found in different organisms, which finely tune the intracellular metal ion content and all metal-dependent processes. In order to understand the processes underlying this complex metal homeostasis network, the study of the molecular processes that determine the protein-metal ion recognition, as well as how this event is transduced into a transcriptional output, is necessary. This chapter describes how metal ion binding to specific proteins influences protein interaction with DNA and how this event can influence the fate of genetic expression, leading to specific transcriptional outputs. The features of representative metal-responsive transcriptional regulators, as well as the molecular basis of metal-protein and protein-DNA interactions, are discussed on the basis of the structural information available. An overview of the recent advances in the understanding of how these proteins choose specific metal ions among the intracellular metal ion pool, as well as how they allosterically respond to their effector binding, is given. PMID- 22210340 TI - Oxidative DNA damage mediated by transition metal ions and their complexes. AB - DNA damage by redox-active metal complexes depends on the interaction of the metal complex with DNA together with the mechanism of oxygen activation. Weak interaction, tight binding, and direct involvement of DNA in the coordination sphere of the metal are described. Metal complexes acting through the production of diffusing radicals and metal complexes oxidizing DNA by metal-centered active species are compared. Metal complexes able to form high-valent metal-oxo species in close contact with DNA and perform DNA oxidation in a way reminiscent of enzymatic chemistry are the most elegant systems. PMID- 22210339 TI - Spectroscopic investigations of lanthanide ion binding to nucleic acids. AB - Luminescent lanthanide (Ln(III)) ions are valuable spectroscopic probes for metal ion binding sites in nucleic acids. In this chapter, we briefly review Ln(III) luminescence and the information available from these experiments. An emphasis is placed on direct excitation Eu(III) spectroscopy as a tool. Eu(III) excitation spectroscopy is used to show that solutions containing micromolar Eu(III), 100 mM NaCl, and 20 mM MES buffer contain predominantly a mononuclear Eu(III) aqua complex and an Eu(III) hydroxide complexes. The binding of these species to various RNA and DNA sequences are monitored by using Eu(III) excitation spectroscopy. Eu(III) luminescence lifetime data shows that the Eu(III) ion typically loses 1-3 water molecules to form innersphere complexes with RNA and DNA that contain tandem base pair mismatches or hairpin loops. In addition, early studies that used nucleobase-sensitized Eu(III) or Tb(III) luminescence within transfer RNA or in the hammerhead ribozyme are presented. Luminescence resonance energy transfer studies are shown to be useful for determining distances between bound Ln(III) ion and organic fluorophores or between two different Ln(III) ions. To supplement luminescence data, the binding sites of paramagnetic Ln(III) ions are determined by monitoring the chemical shifts of nucleotide protons. Binding sites are identified by following the protons that are influenced by the Ln(III) pseudo-contact shift. PMID- 22210341 TI - Metal ion-dependent DNAzymes and their applications as biosensors. AB - Long considered to serve solely as the genetic information carrier, DNA has been shown in 1994 to be able to act as DNA catalysts capable of catalyzing a trans esterification reaction similar to the action of ribozymes and protein enzymes. Although not yet found in nature, numerous DNAzymes have been isolated through in vitro selection for catalyzing many different types of reactions in the presence of different metal ions and thus become a new class of metalloenzymes. What remains unclear is how DNA can carry out catalysis with simpler building blocks and fewer functional groups than ribozymes and protein enzymes and how DNA can bind metal ions specifically to perform these functions. In the past two decades, many biochemical and biophysical studies have been carried out on DNAzymes, especially RNA-cleaving DNAzymes. Important insights have been gained regarding their metal-dependent activity, global folding, metal binding sites, and catalytic mechanisms for these DNAzymes. Because of their high metal ion selectivity, one of the most important practical applications for DNAzymes is metal ion detection, resulting in highly sensitive and selective fluorescent, colorimetric, and electrochemical sensors for a wide range of metal ions such as Pb(2+), UO2 2 +,[Formula: see text] including paramagnetic metal ions such as Cu(2+). This chapter summarizes recent progresses in in vitro selection of metal ion-selective DNAzymes, their biochemical and biophysical studies and sensing applications. PMID- 22210342 TI - Enantioselective catalysis at the DNA scaffold. AB - The unique chiral structure and the highly specific Watson-Crick base-pairing interactions that characterize natural double-stranded DNA, make this natural biopolymer an attractive ligand for asymmetric catalytic processes. In this chapter the applications of DNA as scaffold and chiral ligand in enantioselective transition metal catalysis are presented. An overview of the state of the art for the different approaches to metal-DNA based catalysts is given, followed by an overview of the mechanistic studies that have been performed to date. PMID- 22210343 TI - Alternative DNA base pairing through metal coordination. AB - Base-pairing in the naturally occurring DNA and RNA oligonucleotide duplexes is based on pi-stacking, hydrogen bonding, and shape complementarity between the nucleobases adenine, thymine, guanine, and cytosine as well as on the hydrophobic hydrophilic balance in aqueous media. This complex system of multiple supramolecular interactions is the product of a long-term evolutionary process and thus highly optimized to serve its biological functions such as information storage and processing. After the successful implementation of automated DNA synthesis, chemists have begun to introduce artificial modifications inside the core of the DNA double helix in order to study various aspects of base pairing, generate new base pairs orthogonal to the natural ones, and equip the biopolymer with entirely new functions. The idea to replace the hydrogen bonding interactions with metal coordination between ligand-like nucleosides and suitable transition metal ions culminated in the development of a plethora of artificial base-pairing systems termed "metal base-pairs" which were shown to strongly enhance the DNA duplex stability. Furthermore, they show great potential for the use of DNA as a molecular wire in nanoscale electronic architectures. Although single electrons have proven to be transmitted by natural DNA over a distance of several base pairs, the high ohmic resistance of unmodified oligonucleotides was identified as a serious obstacle. By exchanging some or all of the Watson-Crick base pairs in DNA with metal complexes, this problem may be solved. In the future, these research efforts are supposed to lead to DNA-like materials with superior conductivity for nano-electronic applications. Other fields of potential application such as DNA-based supramolecular architecture and catalysis may be strongly influenced by these developments as well. This text is meant to illustrate the basic concepts of metal-base pairing and give an outline over recent developments in this field. PMID- 22210344 TI - Metal-mediated base pairs in nucleic acids with purine- and pyrimidine-derived nucleosides. AB - Metal-mediated base pairs are transition metal complexes formed from complementary nucleosides within nucleic acid double helices. Instead of relying on hydrogen bonds, they are stabilized by coordinative bonds. The nucleosides acting as ligands do not necessarily have to be artificial. In fact, several examples are known of naturally occurring nucleobases (e.g., thymine, cytosine) capable of forming stable metal-mediated base pairs that are highly selective towards certain metal ions. This chapter provides a comprehensive overview of metal-mediated base pairs formed from natural nucleosides or from closely related artificial nucleosides that are pyrimidine or purine derivatives. It addresses the different strategies that lead to the development of these base pairs. The article focuses on structural models for metal-mediated base pairs, their experimental characterization within a nucleic acid, and on their possible applications. PMID- 22210345 TI - Metal complex derivatives of peptide nucleic acids (PNA). AB - Peptide nucleic acid (PNA) is a non-cyclic pseudopeptide-nucleic acid structural mimic with promising applications within diagnostics and drug discovery. This review focuses on metal complex derivatives of PNA. Metal ions and their complexes display unique physical and chemical properties and offer the opportunity to introduce new labels and probes for bioanalytical and diagnostic applications of PNA, but also to modulate or to introduce new (for example catalytic) functions and biological activities. PMID- 22210346 TI - The research strategies for probing the function of long noncoding RNAs. AB - Long noncoding RNAs (lncRNAs) represent a new frontier in molecular genetics and molecular biology. They have a tremendous potential for advancing our comprehensive understanding of biological processes in huma n health and disease. The transcripts of lncRNAs are easy to find, but sorting out what they do remains the biggest challenge in lncRNAs' research field. In the paper, we highlight recent progress regarding the methods to explore the roles of lncRNAs. PMID- 22210347 TI - Figuring out food labels. Young adults' understanding of nutritional information presented on food labels is inadequate. AB - Nutritional labelling of packaged foods, mandated by law, includes details of the food content and composition - information that can affect individual and public lifestyle decisions and health status. We studied the comprehension of food labels among 120 young adults (mean age 24.1 years) attending an international travel immunization clinic. Each participant was presented with 10 food packages of common local products and was interviewed regarding the label's content. Most subjects (77.5%) reported that they took note of the food labels; women, the more educated and those engaging regularly in physical exercise were more inclined to do so. Out of a possible 10 points the overall median comprehension score was 6.0 (mean 5.7+/-1.8). The nutritional table section of the food label was understood the best, and the nutritional declaration section the least. The subjects thought they understood the food labels better than they actually did; 43.9% stated that they understood them very well, whereas only 27.2% achieved high scores. This inadequate comprehension of food labels represents a missed opportunity to provide essential information necessary for healthy food choices at the individual level. A combination of strategies is necessary, including improving food labels (simplification and standardization) combined with targeted educational programs. PMID- 22210348 TI - A model of goal directed vegetable parenting practices. AB - The aim of this study was to explore factors underlying parents' motivations to use vegetable parenting practices (VPP) using the Model of Goal Directed Vegetable Parenting Practices (MGDVPP) (an adaptation of the Model of Goal Directed Behavior) as the theoretical basis for qualitative interviews. In-depth interviews with parents of 3-5-year-old children were conducted over the telephone by trained interviewers following a script. MGDVPP constructs provided the theoretical framework guiding script development. Audio-recordings were transcribed and analyzed, with themes coded independently by two interviewers. Fifteen participants completed the study. Interviews elicited information about possible predictors of motivations as they related to VPP, and themes emerged related to each of the MGDVPP constructs (attitudes, positive anticipated emotions, negative anticipated emotions, subjective norms, and perceived behavioral control). Parents believed child vegetable consumption was important and associated with child health and vitality. Parents described motivations to engage in specific VPP in terms of emotional responses, influential relationships, food preferences, resources, and food preparation skills. Parents discussed specific strategies to encourage child vegetable intake. Interview data suggested parents used diverse VPP to encourage child intake and that varied factors predicted their use. Understanding these factors could inform the design of interventions to increase parents' use of parenting practices that promote long-term child consumption of vegetables. PMID- 22210349 TI - Metabolic gray matter changes of adolescents with anorexia nervosa in combined MR proton and phosphorus spectroscopy. AB - INTRODUCTION: There are hints for changes in phospholipid membrane metabolism and structure in the brain of adolescents with anorexia nervosa (AN) using either proton ((1)H) or phosphorus ((31)P) magnetic resonance spectroscopic imaging (MRSI). We aimed to specify these pathological metabolite changes by combining both methods with additional focus on the neuronal metabolites glutamate (Glu) and N-acetyl-l-aspartate (NAA). METHODS: Twenty-one female patients (mean 14.4 +/- 1.9 years) and 29 female controls (mean 16 +/- 1.6 years) underwent (1)H and (31)P MRSI at 3 T applied to the centrum semiovale including the anterior cingulate cortex. We assessed gray matter (GM) and white matter (WM) metabolite concentration changes of the frontal and parietal brain measuring choline(Cho)- and ethanolamine(Eth)-containing compounds, Glutamate (Glu) and glutamine (Gln) and their sum (Glx), myoinositol, NAA, and high-energy phosphates. RESULTS: For (1)H MRSI, a clear discrimination between GM and WM concentrations was possible, showing an increase of Glx (p < 0.001), NAA (frontal p < 0.05), pooled creatine (tCr) (p < 0.001), and choline (tCho) (p < 0.05) in the GM of AN patients. The lipid catabolites glycerophosphocholine (p < 0.07) and glycerophosphoethanolamine (p < 0.03) were increased in the parietal region. CONCLUSIONS: Significant changes in GM metabolite concentrations were observed in AN possibly triggered by elevated excitotoxin Glu. Increased tCho may indicate modifications of membrane phospholipids due to increased catabolism in the parietal region. Since no significant changes in phosphorylated choline compounds were found for the frontal region, the tCho increase in this region may hint to fluidity changes. PMID- 22210350 TI - Local unfolding of Cu, Zn superoxide dismutase monomer determines the morphology of fibrillar aggregates. AB - Aggregation of Cu, Zn superoxide dismutase (SOD1) is often found in amyotrophic lateral sclerosis patients. The fibrillar aggregates formed by wild type and various disease-associated mutants have recently been found to have distinct cores and morphologies. Previous computational and experimental studies of wild type SOD1 suggest that the apo-monomer, highly aggregation prone, displays substantial local unfolding dynamics. The residual folded structure of locally unfolded apoSOD1 corresponds to peptide segments forming the aggregation core as identified by a combination of proteolysis and mass spectroscopy. Therefore, we hypothesize that the destabilization of apoSOD1 caused by various mutations leads to distinct local unfolding dynamics. The partially unfolded structure, exposing the hydrophobic core and backbone hydrogen bond donors and acceptors, is prone to aggregate. The peptide segments in the residual folded structures form the "building block" for aggregation, which in turn determines the morphology of the aggregates. To test this hypothesis, we apply a multiscale simulation approach to study the aggregation of three typical SOD1 variants: wild type, G37R, and I149T. Each of these SOD1 variants has distinct peptide segments forming the core structure and features different aggregate morphologies. We perform atomistic molecular dynamics simulations to study the conformational dynamics of apoSOD1 monomer and coarse-grained molecular dynamics simulations to study the aggregation of partially unfolded SOD1 monomers. Our computational studies of monomer local unfolding and the aggregation of different SOD1 variants are consistent with experiments, supporting the hypothesis of the formation of aggregation "building blocks" via apo-monomer local unfolding as the mechanism of SOD1 fibrillar aggregation. PMID- 22210351 TI - Energy complexes are apparently associated with the switch-motor complex of bacterial flagella. AB - Recently, the switch-motor complex of bacterial flagella was found to be associated with a number of non-flagellar proteins, which, in spite of not being known as belonging to the chemotaxis system, affect the function of the flagella. The observation that one of these proteins, fumarate reductase, is essentially involved in electron transport under anaerobic conditions raised the question of whether other energy-linked enzymes are associated with the switch-motor complex as well. Here, we identified two additional such enzymes in Escherichia coli. Employing fluorescence resonance energy transfer in vivo and pull-down assays invitro, we provided evidence for the interaction of F(0)F(1) ATP synthase via its beta subunit with the flagellar switch protein FliG and for the interaction of NADH-ubiquinone oxidoreductase with FliG, FliM, and possibly FliN. Furthermore, we measured higher rates of ATP synthesis, ATP hydrolysis, and electron transport from NADH to oxygen in membrane areas adjacent to the flagellar motor than in other membrane areas. All these observations suggest the association of energy complexes with the flagellar switch-motor complex. Finding that deletion of the beta subunit in vivo affected the direction of flagellar rotation and switching frequency further implied that the interaction of F(0)F(1) ATP synthase with FliG is important for the function of the switch of bacterial flagella. PMID- 22210352 TI - Ethaselen: a potent mammalian thioredoxin reductase 1 inhibitor and novel organoselenium anticancer agent. AB - Mammalian thioredoxin reductase 1 (TrxR1) is considered to be an important anticancer drug target and to be involved in both carcinogenesis and cancer progression. Here, we report that ethaselen, a novel organoselenium compound with anticancer activity, specifically binds to the unique selenocysteine-cysteine redox pair in the C-terminal active site of mammalian TrxR1. Ethaselen was found to be a potent inhibitor rather than an efficient substrate of mammalian TrxR1. It effectively inhibits wild-type mammalian TrxR1 at submicromolar concentrations with an initial mixed-type inhibition pattern. By using recombinant human TrxR1 variants and human glutathione reductase, we prove that ethaselen specifically targets the C-terminal but not the N-terminal active site of mammalian TrxR1. In A549 human lung cancer cells, ethaselen significantly suppresses cell viability in parallel with direct inhibition of TrxR1 activity. It does not, however, alter either the disulfide-reduction capability of thioredoxin or the activity of glutathione reductase. As a downstream effect of TrxR1 inactivation, ethaselen causes a dose-dependent thioredoxin oxidation and enhances the levels of cellular reactive oxygen species in A549 cells. Thus, we propose ethaselen as the first selenium-containing inhibitor of mammalian TrxR1 and provide evidence that selenium compounds can act as anticancer agents based on mammalian TrxR1 inhibition. PMID- 22210353 TI - Dioscorea nipponica Makino inhibits migration and invasion of human oral cancer HSC-3 cells by transcriptional inhibition of matrix metalloproteinase-2 through modulation of CREB and AP-1 activity. AB - Oral cancer mortality has increased during the last decade due to the difficulties in treating related metastasis. Dioscorea nipponica Makino, a popular folk medicine, exerts anti-obesity and anti-inflammation properties. However, the effect of this folk medicine on metastasis of oral cancer has yet to be fully elucidated. The present study demonstrates that D. nipponica extracts (DNE), at a range of concentrations (0-50 MUg/mL), concentration-dependently inhibited migration/invasion capacities of human oral cancer cells, HSC-3, without cytotoxic effects. The anti-migration effect of DNE was also observed in two other OSCC cell lines, Ca9-22 and Cal-27. Zymography, real time PCR, and Western blotting analyses revealed that DNE inhibited matrix metalloproteinase-2 (MMP-2) enzyme activity, and RNA and protein expression. The inhibitory effects of DNE on MMP-2 proceeded by up-regulating tissue inhibitor of metalloproteinase 2 (TIMP-2), as well as suppressing nuclear translocation and DNA binding activity of cAMP response element-binding (CREB) and activating protein-1 (AP-1) on the MMP-2 promoter in HSC-3 cells. In conclusion, DNE inhibited the invasion of oral cancer cells and may have potential use as a chemopreventive agent against oral cancer metastasis. PMID- 22210354 TI - Restless legs syndrome: relationship between prevalence and latitude. AB - PURPOSE: Restless legs syndrome (RLS) has a broad worldwide prevalence between 0.01% and 18.3%. While differences in RLS definitions and data ascertainment methods account for some variability, other factors likely contribute. The circadian nature of RLS and the fact that RLS symptoms track with endogenous melatonin levels suggest that light or ultraviolet radiation (UVR) may be related to RLS expression. As the amount of UVR decreases with latitude, we considered the potential effect of geography on RLS prevalence with the thought being that RLS prevalence rises with increasing latitude. METHODS: RLS epidemiologic studies were sought via Pubmed search in the period between January 1, 1992 and November 15, 2010. Prevalence was mapped for each country or specific region studied and examined by continent. Pearson's correlational testing was carried out for RLS prevalence and latitude of the region studied. RESULTS: Global RLS prevalence ranges from 0.01% in Africa, 0.7% to 12.5% in Asia, 2.0% to 18.9% in the Americas, and 3.2% to 18.3% in Europe. Mapping RLS prevalence by country or region in both the Americas and in Europe suggests increasing RLS frequency with greater northern latitude. RLS prevalence is positively correlated with northern latitude in both North America and Europe with correlation coefficients of r = 0.77 (0.15, 0.96; p = 0.02) and r = 0.74 (0.44, 0.89; p = 0.0002), respectively. In Europe, lower latitudinal countries like Greece and Turkey had RLS prevalence (per 1,000 persons) of 38 and 34, respectively, middle latitudinal countries like France and England of 108 and 86, respectively, and high latitudinal countries like Norway and Iceland of 143 and 183, respectively. CONCLUSIONS: RLS epidemiology indicates an increase in RLS frequency in northern latitudinal countries as a function of distance from the equator, an effect most evident in Europe. This suggests that factors that track with latitude like UVR may be involved in the expression of RLS. PMID- 22210356 TI - Some new fields in neurology and psychiatry (1917). Reprinted from the J Nerv Ment Dis. 46(2):90-99. PMID- 22210357 TI - Commentary on Thomas W. Salmon's "Some new fields in neurology and psychiatry" (1917). PMID- 22210358 TI - Debates on the narcissism conundrum: trait, domain, dimension, type, or disorder? AB - The clinical implications of the term narcissism are a matter of continuous debate. This article critically examines pertinent literature of the last 12 years using a set of validators and attempting to identify narcissism as a trait, a domain, a dimension, or a personality disorder/type. Narcissistic personality disorder (NPD)-specific literature (particularly in epidemiological, developmental, and laboratory-testing areas) is scarce when compared with other personality disorders. A tendency to ideologically dominated clinical reports is observed with individual cases or small samples of nonclinical populations. Clinical descriptions of the condition vary within a wide range of descriptors, superficial or ambiguous conceptualizations, different subtypes, and inconclusive meta-analytical findings. Comorbidity with many Axes I and II conditions and the presence of narcissistic behavioral and emotional manifestations in other DSM conditions were frequent findings. The reintroduction of NPD in the personality disorders DSM-5 proposal seems to be related to nonclinical or heuristic considerations. It is concluded that NPD as such shows nosological inconsistency and that its consideration as a trait domain with needed further research would be strongly beneficial to the field. PMID- 22210355 TI - Cortical plasticity for visuospatial processing and object recognition in deaf and hearing signers. AB - Experience-dependent plasticity in deaf participants has been shown in a variety of studies focused on either the dorsal or ventral aspects of the visual system, but both systems have never been investigated in concert. Using functional magnetic resonance imaging (fMRI), we investigated functional plasticity for spatial processing (a dorsal visual pathway function) and for object processing (a ventral visual pathway function) concurrently, in the context of differing sensory (auditory deprivation) and language (use of a signed language) experience. During scanning, deaf native users of American Sign Language (ASL), hearing native ASL users, and hearing participants without ASL experience attended to either the spatial arrangement of frames containing objects or the identity of the objects themselves. These two tasks revealed the expected dorsal/ventral dichotomy for spatial versus object processing in all groups. In addition, the object identity matching task contained both face and house stimuli, allowing us to examine category-selectivity in the ventral pathway in all three participant groups. When contrasting the groups we found that deaf signers differed from the two hearing groups in dorsal pathway parietal regions involved in spatial cognition, suggesting sensory experience-driven plasticity. Group differences in the object processing system indicated that responses in the face-selective right lateral fusiform gyrus and anterior superior temporal cortex were sensitive to a combination of altered sensory and language experience, whereas responses in the amygdala were more closely tied to sensory experience. By selectively engaging the dorsal and ventral visual pathways within participants in groups with different sensory and language experiences, we have demonstrated that these experiences affect the function of both of these systems, and that certain changes are more closely tied to sensory experience, while others are driven by the combination of sensory and language experience. PMID- 22210359 TI - Nonverbal behavior during clinical interviews: similarities and dissimilarities among schizophrenia, mania, and depression. AB - Research has shown that patients with schizophrenia and depression differ from nonclinical subjects in nonverbal behavior. In contrast, there is a paucity of studies addressing differences in nonverbal communication between diagnostic groups and as to what extent nonverbal communication feeds into standard ratings of psychopathology. Twenty-six patients with schizophrenia were compared with 24 patients with affective disorders (13 depressed, 11 manic) regarding their nonverbal behavior using the Ethological Coding System for Interviews. Symptom severity was rated using the Brief Psychiatric Rating Scale. Patients with mania displayed more illustrative gestures than did patients with schizophrenia or depression. Subtler behavioral differences between the groups occurred regarding assertive behaviors and displacement activities suggestive of hostility and motivational conflict, respectively. Distinct correlations between nonverbal communication and psychopathology ratings emerged in all three groups. Patients with schizophrenia, depression, and mania differ in nonverbal behavior. Nonverbal communication seems to be a significant contributor to clinicians' intuitive ratings. PMID- 22210360 TI - Do patients with schizophrenia distinguish between attitudes toward antipsychotic medication and pharmacotherapy in general? Validation of the Beliefs About Medication Questionnaire. AB - Attitudes toward medication are important predictors of medication adherence in schizophrenia. However, monitoring their strength and influence in clinical settings is challenged by the absence of assessments separating them from adherence and subjective response and distinguishing between attitudes toward pharmacotherapy in general and antipsychotic medications. This study examined the applicability of the Beliefs about Medication Questionnaire (BMQ) in outpatients with schizophrenia (N = 131). Confirmatory factor analysis (CFA) could not support the original four-factor structure. A subsequent exploratory factor analysis revealed the factors Antipsychotics Necessity, Antipsychotics Concern, and Pharmacotherapy Distrust were supported by an acceptable fit of a completing CFA. These subscales have satisfactory internal reliability, test-retest reliability, and local fit indices. Modest correlations with insight and illness perception indicate construct validity. Criterion validity was supported by a significantly higher medication adherence of accepting patients compared with skeptical patients. The BMQ is a psychometrically sound and valid measure of attitudes toward medication in outpatients with schizophrenia. PMID- 22210361 TI - Cognitive insight and its relationship with symptoms in deficit and nondeficit schizophrenia. AB - Patients with deficit schizophrenia have worse cognition and poorer social functioning compared with those with nondeficit schizophrenia. Insight is another domain in which these two groups might differ. However, there is no literature data specifically on cognitive insight impairment in deficit versus nondeficit schizophrenia. We compared 40 patients with deficit schizophrenia with 81 nondeficit patients and found that schizophrenic patients with deficit syndrome were more self-reflective and have higher self-reflectiveness-self-certainty index scores than did those without deficit syndrome. These differences remained significant when analysis was controlled for sex, age, education, and depression severity. On the other hand, there was no significant difference in self certainty scores between two groups. In addition, we found significant relationships between cognitive insight and specific psychotic symptoms. A better understanding of the cognitive component of insight in schizophrenia with deficit syndrome may help us to understand the true relationship between insight and negative symptoms and contribute to the development of more efficient cognitive strategies, thus improving patients' outcome in a severely disabled psychiatric patient group. PMID- 22210363 TI - The role of self-concept clarity in prolonged grief disorder. AB - Three studies using independent samples of bereaved individuals were conducted to examine the association of self-concept clarity (SCC) with symptoms of prolonged grief disorder (PGD), a debilitating syndrome than can develop after bereavement. Study 1 (N = 67) showed that lower SCC was associated with greater PGD severity, independent from self-concept content change. Using a retrospective design, Study 2 (N = 116) showed that a loss can coincide with a decline in SCC, the magnitude of which was associated with acute PGD severity. Study 2 also showed that the maintenance of PGD symptoms over time was associated with a smaller increase in SCC beyond the first month of bereavement and not with this acute SCC decline. Using a prospective-longitudinal design, Study 3 (N = 121) showed that the impact of lower SCC on concurrent and prospective PGD severity was mediated by lower self-esteem, depressive avoidance, and rumination. Moreover, lower initial SCC predicted PGD severity 6 months later. PMID- 22210362 TI - Improvement in depression scores after 1 hour of light therapy treatment in patients with seasonal affective disorder. AB - The purpose of this study was to investigate possible rapid effects of light therapy on depressed mood in patients with seasonal affective disorder. Participants received 1 hour of bright light therapy and 1 hour of placebo dim red light in a randomized order crossover design. Depressed mood was measured at baseline and after each hour of light treatment using two self-report depression scales (Profile of Mood States-Depression-Dejection [POMS-D] subscale and the Beck Depression Inventory II [BDI-II]). When light effects were grouped for the two sessions, there was significantly greater reduction in self-report depression scores by -1.3 (p = 0.02) on the BDI-II and -1.2 (p = 0.02) on the POMS-D. A significant but modest improvement was detected after a single active light session. This is the first study, to our knowledge, to document an immediate improvement with light treatment using a placebo-controlled design with a clinical sample of depressed individuals. PMID- 22210364 TI - Parental mental health after the accidental death of a son during military service: 23-year follow-up study. AB - We prospectively studied parental mental health after suddenly losing a son in a military training accident. Parents (N = 32) were interviewed at 1, 2 and 23 years after the death of their son. The General Health Questionnaire and Expanded Texas Inventory of Grief were self-reported at 1, 2, 5, and 23 years; the Inventory of Complicated Grief was self-reported at 23 years. We observed a high prevalence of psychiatric disorders at 1- and 2-year follow-ups (57% and 45%, respectively), particularly major depression (43% and 31%, respectively). Only one mental disorder was diagnosed at the 23-year follow-up. Grief and psychological distress were highest at 1- and 2-year follow-ups. Spouses exhibited a high concordance of psychological distress. Mothers reported more intense grief reactions than did fathers. The loss of a son during military service may have a substantial impact on parental mental health particularly during the first 2 years after death. Spouses' grief can be interrelated and may contribute to their psychological distress. PMID- 22210365 TI - Examining the association between stimulant treatment and cognitive outcomes across the life cycle of adults with attention-deficit/hyperactivity disorder: a controlled cross-sectional study. AB - Few studies have evaluated the effects of stimulants on cognition in adults with attention-deficit/hyperactivity disorder (ADHD). We evaluated the impact of stimulant treatment on neurocognition in a cross-sectional sample of adults with ADHD. Comparisons were made between adults with ADHD who received (n = 105) and who had never received pharmacotherapy (n = 116) and 146 controls. The subjects were assessed cross-sectionally using a structured diagnostic interview and a neurocognitive battery. We modeled cognitive measures as a function of age and group status using linear regression. Treated ADHD subjects had statistically significantly better scores on measures of IQ than did untreated ones. The treated group also had better (not statistically significant) scores on neuropsychological measures. The direction of the effects of stimulant on neurocognition suggests that either good cognitive functioning may be a determinant of seeking treatment or that stimulant treatment may improve cognition in adults with ADHD. However, this does not indicate a clear causal relationship. PMID- 22210366 TI - Biases in the evaluation of psychiatric clinical evidence. AB - The evolution of medical research has vaulted randomized clinical trials to the status of current gold standard of clinical evidence. In parallel, the evolution of the science of decision-making has revealed human beings' universal tendency to make biased judgments and systematic errors in their evaluation of information and choices. As a result of numerous psychological biases, randomized clinical trials are more prone to error, misinterpretation, and faulty judgment than is often acknowledged. Interdisciplinary fields of experimental psychology, economics, and social science are drawn upon to examine psychological biases in the interpretation of clinical evidence. A number of these are postulated to be important, both for the investigators generating clinical evidence and for the clinical observers interpreting clinical trials. This study focuses on the field of psychiatry and on the potentially significant implications of evidence biases for psychiatric practice and clinical understanding. PMID- 22210367 TI - Sleep medication in acute psychiatric illness: patient's knowledge and prescription patterns in New Zealand. AB - Adult patients (N = 100) being treated for acute psychiatric illness were interviewed about their sleep problems and attitudes toward available treatments. Most (74%) were using at least one prescribed psychotropic drug with hypnotic or sedative effects. Participants prescribed three or more drugs were less likely to name them correctly compared with those prescribed less. One quarter (24%) did not know that they were on a hypnosedative; more than half of those not prescribed a hypnosedative thought they were. Most participants found their medication effective; however, 54% wished to discontinue it. Two fifths of zopiclone users had been using it for more than 12 months. Although subjective sleep problems are very common in this patient group, they have limited accurate knowledge about their medication treatments. Many want to try alternative nonpharmacological ways to manage their sleep problems. PMID- 22210368 TI - Peritraumatic reactions and posttraumatic stress disorder symptoms after psychiatric admission. AB - The present study aimed to explore exposure to stressful events during a psychiatric admission and the predictive power of peritraumatic distress and dissociation in the development of posttraumatic stress disorder (PTSD) symptoms after exposure to such events. Psychiatric inpatients (N = 239) were asked to report exposure to stressful events during their admission within 48 hours of being admitted. Individuals reporting at least one stressful event during admission (n = 70, 29%) were assessed for peritraumatic dissociation and distress in relation to this event and, 5 weeks later, were reassessed for PTSD symptoms. Eight participants (12.3%) scored above the cutoff for probable PTSD. Multiple regression analyses revealed that peritraumatic distress was a significant predictor of 5-week PTSD symptoms. Our findings suggest that individuals experiencing increased peritraumatic distress in relation to a stressful event experienced during a psychiatric admission might be at risk of PTSD symptoms and might benefit from increased attention. PMID- 22210369 TI - Prevalence of hoarding disorder in individuals at potential risk of eviction in New York City: a pilot study. AB - This study estimated the prevalence of hoarding disorder (HD) in individuals seeking help from Eviction Intervention Services Housing Research Center (EIS), a not-for-profit community organization in New York City (NYC) that aids clients with housing problems including eviction. One hundred fifteen EIS clients were screened for HD. The prevalence of HD among those seeking help from EIS was 22% (clinician-rated) and 23% (self-rated), which is nearly 5 to 10 times greater than the rate of hoarding (2% to 5%) in the general population. Of individuals seeking help from EIS who met the criteria for HD (n = 25), 32% were currently in legal eviction proceedings (i.e., threatened with imminent eviction), 44% had a history of previous legal eviction proceedings, and 20% had been evicted from their home one or more times, yet only 48% were currently seeking mental health treatment. Almost a quarter of individuals seeking help for housing problems from a community eviction prevention organization met the criteria for HD; only about half of these individuals were receiving mental health treatment. Future studies are needed to determine whether HD treatment can reduce the risk of eviction and homelessness in NYC. PMID- 22210370 TI - Traumatic experiences in individuals with body dysmorphic disorder. AB - Individuals with body dysmorphic disorder (BDD) are excessively concerned about perceived defects in their appearance (e.g., blemishes on their skin). BDD is a severe mental disorder often associated with increased suicidality as well as significant social and occupational interference (e.g., J Clin Psychiatry 2005;66:717-725). Recently, investigators have begun to explore variables that might function as risk factors in the development of BDD, such as traumatic experiences (e.g., Child Abuse Negl 2006;30:1105-1115). As such, one of the goals of the current study was to examine the role of early-life sexual, physical, or emotional abuse in BDD. Specifically, the Traumatic Stress Institute Life Event Questionnaire (Treat Abuse Today 1992;2:9-11) was used to examine whether individuals with BDD (n = 18) self-reported having experienced more traumatic events than mentally healthy controls (n = 19). The BDD group reported more retrospective experiences of sexual and physical abuse in childhood or adolescence than did healthy controls. Surprisingly, there was no significant group difference in reports of emotional abuse in early life. This study provides preliminary evidence of the importance of examining abuse as a potential risk factor in the development of BDD. PMID- 22210371 TI - Suicide attempt by self-burning associated with ingestion of S adenosylmethionine: a review of the literature and case report. AB - The treatment of major depressive disorder continues to be challenging in many cases. The high nonresponse rates as well as the poor tolerability of some antidepressants often prompt patients to seek other forms of treatment. S Adenosylmethionine (SAMe) is one of the most popular over-the-counter antidepressants currently sold in the United States. SAMe's antidepressant effect has been clearly demonstrated, but safety and tolerability remain understudied at this time. This report describes the case of a 61-year-old woman with no previous history of suicidal ideations who self-prescribed SAMe for her depressive symptoms and attempted suicide 4 days later by burning herself. Given the rise in the use of over-the-counter antidepressants, further research should be performed regarding the safety of these products, including a need for warnings to the public and adequate labels if necessary. PMID- 22210372 TI - Glucocorticoids enhance airway epithelial barrier integrity. AB - Asthma is a chronic inflammatory disorder of the airways, but its pathogenesis is incompletely understood. While asthma is a complex disease caused by multiple factors, epithelial barrier damage is a cardinal feature. Glucocorticoids (GCs) are the most effective anti-inflammatory drugs in the treatment of asthma. However, the effects of GCs on the airway epithelial barrier have not been evaluated. Epithelial barrier functions were evaluated in cultured human airway epithelial cell monolayers, Calu-3 and 16HBE. Then, the cells were treated with dexamethasone (Dex), fulticasone propionate (FP), or budesonide (BD) for 5 days. Permeability measured by transepithelial electrical resistance was increased by treatment with Dex, FP, and BD in a dose-dependent manner. Permeability to fluorescein isothiocyanate-labeled dextran was markedly reduced by these treatments. Immunocytostaining revealed that Dex treatment potentiated tight junction formation in these polarized epithelial cells. Knockdown of epidermal growth factor receptor (EGFR) by small interference RNA blunted the effects of Dex on barrier integrity. Although EGFR expression was not affected by Dex treatment, EGFR phosphorylation was enhanced in Dex-treated cells. This is suggesting that EGFR are important for this phenomenon. These findings suggest that GC inhalation therapy can improve epithelial barrier integrity and might contribute to the therapeutic effects of GCs for treating asthma. PMID- 22210373 TI - Neem leaf glycoprotein suppresses regulatory T cell mediated suppression of monocyte/macrophage functions. AB - We have shown that neem leaf glycoprotein (NLGP) inhibits the regulatory T cell (Tregs) induced suppression of tumoricidal functions of CD14(+)CD68(+) monocyte/macrophages (MO/Mphi) from human peripheral blood. Cytotoxic efficacy of MO/Mphi toward macrophage sensitive cells, U937, is decreased in presence of Tregs (induced), however, it was increased further by supplementation of NLGP in culture. Associated Treg mediated inhibition of perforin/granzyme B expression and nitric oxide release from MO/Mphi was normalized by NLGP. Altered status of signature cytokines, like, IL-12, IL-10, IL-6, TNFalpha from MO/Mphi under influence of Tregs is also rectified by NLGP. Tregs significantly enhanced the expression of altered marker, mannose receptor (CD206) on CD68(+) cells that was downregulated upon NLGP exposure. In addition to tumoricidal functions, antigen presenting ability of MO/Mphi is hampered by Treg induced downregulation of CD80, CD86 and HLA-ABC. NLGP upregulated these molecules in MO/Mphi even in the presence of Tregs. Treg mediated inhibition of MO/Mphi chemotaxis in contact dependent manner was also normalized partially by NLGP, where participation of CCR5 was documented. Overall results suggest that Treg influenced pro-tumor MO/Mphi functions are rectified in a significant extent by NLGP to create an anti tumor immune environment. PMID- 22210374 TI - Stereocalpin A inhibits the expression of adhesion molecules in activated vascular smooth muscle cells. AB - Up-regulation of cell adhesion molecules on vascular smooth muscle cells (VSMCs) and leukocyte recruitment to the vascular wall contribute to vascular inflammation and atherosclerosis. Stereocalpin A, a chemical compound of the Antarctic lichen Ramalina terebarata, displays tumoricidal activity against several different tumor cell types. However, other biological activities of stereocalpin A and its molecular mechanisms remain unknown. In this study, our work is directed toward studying the in vitro effects of stereocalpin A on the ability to suppress the expression of adhesion molecules induced by TNF-alpha in vascular smooth muscle cells. Pretreatment of VSMCs for 2h with stereocalpin A at nontoxic concentrations of 0.1-10 MUg/ml inhibited TNF-alpha-induced adhesion of THP-1 monocytic cells and expression of vascular cell adhesion molecule-1 (VCAM 1) and intercellular adhesion molecule-1 (ICAM-1). Stereocalpin A reduced TNF alpha-induced production of intracellular reactive oxygen species (ROS) and phosphorylation of p38, ERK, JNK and Akt. Stereocalpin A also inhibited NK-kappaB activation induced by TNF-alpha. Moreover, stereocalpin A inhibited TNF-alpha induced IotakappaBeta kinase activation, subsequent degradation of IotakappaBetaalpha, and nuclear translocation of NF-kappaB. Hence, we describe a new anti-inflammatory activity and mechanism of stereocalpin A, owing to the negative regulation of TNF-alpha-induced adhesion molecule and MCP-1 expression, monocyte adhesion and ROS production in vascular smooth muscle cells. These results suggest that stereocalpin A has the potential to exert a protective effect by modulating inflammation within the atherosclerotic lesion. PMID- 22210376 TI - Which anti-inflammatory drug should we use in asthma? AB - Asthma is a chronic and heterogeneous inflammatory disorder of the airways defined by its clinical, physiological and pathological characteristics. Accordingly to currently available guidelines inhaled glucocorticosteroids (ICS) represent the most effective anti-inflammatory medication for the treatment of persistent asthma, and this class of drugs is recommended as the first-line controller therapy both in children and adults. Leukotriene modifiers (LTRAs) are usually used as a second line of add-on therapy, although they may be regarded as the first-line therapy in exercise induced bronchoconstriction, in patients with comorbid allergic rhinitis and in children with asthma and frequent viral infections. A recently published pragmatic (real-life) study showed that LTRAs provide an alternative treatment for asthma, which, at least for the evaluated endpoints, may be as effective as ICS in our every-day practice. To assess how the recent data may affect our every-day practice and current guidelines for clinical management of asthma, it needs to be clearly understood what pragmatic trials add to our knowledge. In our opinion, it is premature to change current guidelines. However, pragmatic and observational studies are clearly needed as they provide additional information to randomized controlled trials. The main goal of all those efforts is to improve asthma control and decrease the burden of the disease for patients and societies. It may be that the future approach will introduce several new strategies based on system biology studies for the treatment of asthma guided in a personalized medicine approach. PMID- 22210378 TI - Ca2+-activated K+ channels of small and intermediate conductance control eNOS activation through NAD(P)H oxidase. AB - Ca(2+)-activated K(+) channels (K(Ca)) and NO play a central role in the endothelium-dependent control of vasomotor tone. We evaluated the interaction of K(Ca) with NO production in isolated arterial mesenteric beds of the rat. In phenylephrine-contracted mesenteries, acetylcholine (ACh)-induced vasodilation was reduced by NO synthase (NOS) inhibition with N(omega)-nitro-L-arginine (L NA), but in the presence of tetraethylammonium, L-NA did not further affect the response. In KCl-contracted mesenteries, the relaxation elicited by 100 nM ACh or 1 MUM ionomycin was abolished by L-NA, tetraethylammonium, or simultaneous blockade of small-conductance K(Ca) (SK(Ca)) channels with apamin and intermediate-conductance K(Ca) (IK(Ca)) channels with triarylmethane-34 (TRAM 34). Apamin-TRAM-34 treatment also abolished 100 nM ACh-activated NO production, which was associated with an increase in superoxide formation. Endothelial cell Ca(2+) buffering with BAPTA elicited a similar increment in superoxide. Apamin TRAM-34 treatment increased endothelial NOS phosphorylation at threonine 495 (P eNOS(Thr495)). Blockade of NAD(P)H oxidase with apocynin or superoxide dismutation with PEG-SOD prevented the increment in superoxide and changes in P eNOS(Thr495) observed during apamin and TRAM-34 application. Our results indicate that blockade of SK(Ca) and IK(Ca) activates NAD(P)H oxidase-dependent superoxide formation, which leads to inhibition of NO release through P-eNOS(Thr495). These findings disclose a novel mechanism involved in the control of NO production. PMID- 22210379 TI - The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/-/ApoE-/- mice. AB - A number of recent studies suggest that mitochondrial oxidative damage may be associated with atherosclerosis and the metabolic syndrome. However, much of the evidence linking mitochondrial oxidative damage and excess reactive oxygen species (ROS) with these pathologies is circumstantial. Consequently the importance of mitochondrial ROS in the etiology of these disorders is unclear. Furthermore, the potential of decreasing mitochondrial ROS as a therapy for these indications is not known. We assessed the impact of decreasing mitochondrial oxidative damage and ROS with the mitochondria-targeted antioxidant MitoQ in models of atherosclerosis and the metabolic syndrome (fat-fed ApoE(-/-) mice and ATM(+/-)/ApoE(-/-) mice, which are also haploinsufficient for the protein kinase, ataxia telangiectasia mutated (ATM). MitoQ administered orally for 14weeks prevented the increased adiposity, hypercholesterolemia, and hypertriglyceridemia associated with the metabolic syndrome. MitoQ also corrected hyperglycemia and hepatic steatosis, induced changes in multiple metabolically relevant lipid species, and decreased DNA oxidative damage (8-oxo-G) in multiple organs. Although MitoQ did not affect overall atherosclerotic plaque area in fat-fed ATM(+/+)/ApoE(-/-) and ATM(+/-)/ApoE(-/-) mice, MitoQ reduced the macrophage content and cell proliferation within plaques and 8-oxo-G. MitoQ also significantly reduced mtDNA oxidative damage in the liver. Our data suggest that MitoQ inhibits the development of multiple features of the metabolic syndrome in these mice by affecting redox signaling pathways that depend on mitochondrial ROS such as hydrogen peroxide. These findings strengthen the growing view that elevated mitochondrial ROS contributes to the etiology of the metabolic syndrome and suggest a potential therapeutic role for mitochondria-targeted antioxidants. PMID- 22210380 TI - Inhibition of VCAM-1 expression in endothelial cells by CORM-3: the role of the ubiquitin-proteasome system, p38, and mitochondrial respiration. AB - Carbon monoxide (CO) abrogates TNF-alpha-mediated inflammatory responses in endothelial cells, yet the underlying mechanism thereof is still elusive. We have previously shown that the anti-inflammatory effect of CO-releasing molecule-3 (CORM-3) is not completely mediated via deactivation of the NF-kappaB pathway. In this study, we sought to explore other potential mechanisms by which CORM-3 downregulates VCAM-1 expression on TNF-alpha-stimulated HUVECs. By genome-wide gene expression profiling and pathway analysis we studied the relevance of particular pathways for the anti-inflammatory effect of CORM-3. In CORM-3 stimulated HUVECs significant changes in expression were found for genes implicated in the proteasome and porphyrin pathways. Although proteasome activities were increased by CORM-3, proteasome inhibitors did not abolish the effect of CORM-3. Likewise, heme oxygenase-1 inhibitors did not abrogate the ability of CORM-3 to downregulate VCAM-1 expression. Interestingly, CORM-3 inhibited MAPK p38, and the p38 inhibitor SB203580 downregulated VCAM-1 expression. However, downregulation of VCAM-1 by CORM-3 occurred only at concentrations that partly inhibit ATP production and sodium azide and oligomycin paralleled the effect of CORM-3 in this regard. Our results indicate that CORM-3 induced downregulation of VCAM-1 is mediated via p38 inhibition and mitochondrial respiration, whereas the ubiquitin-proteasome system seems not to be involved. PMID- 22210381 TI - Combined treatment of L1CAM antibodies and cytostatic drugs improve the therapeutic response of pancreatic and ovarian carcinoma. AB - The adhesion molecule L1CAM (CD171) accounts for enhanced motility, invasiveness and chemoresistance of tumor cells and represents a novel marker for various tumor entities including pancreatic and ovarian carcinoma. Recently, we showed that L1CAM inhibition increases the apoptotic response of tumor cells towards cytostatic drugs pointing to the potential of L1CAM to serve as a chemosensitizer in anti-cancer therapy. Thus, the present study evaluated the therapeutic potential of combined treatment with L1CAM antibodies and chemotherapeutic drugs in pancreatic and ovarian carcinoma model systems in vivo. Two L1CAM-specific antibodies (L1-14.10 and L1-9.3/2a) exhibiting high binding affinity to the L1CAM expressing pancreatic adenocarcinoma cell line Colo357 and the ovarian carcinoma cell line SKOV3ip were used for treatment. The combined therapy of SCID mice with either L1CAM antibody and gemcitabine and paclitaxel, respectively, reduced the growth of subcutaneously grown Colo357 or SKOV3ip tumors more efficiently than treatment with the cytostatic drug alone or in combination with control IgG. This was accompanied by an increased number of apoptotic tumor cells along with an elevated procaspase-8 expression. Furthermore, a lowered activation of NF-kappaB along with a reduced expression of VEGF and a diminished number of CD31-positive blood vessels were observed in tumors after combined therapy compared to control treatments, while the infiltration of F4/80-positive macrophages increased. Overall, these data provide new insights into the mechanism of the anti-cancer activity of L1CAM-blocking antibodies in vivo and support the suitability of L1CAM as a target for chemosensitization and of L1CAM-interfering antibodies as an appropriate tool to increase the therapeutic response of pancreatic and ovarian carcinoma. PMID- 22210382 TI - Pyrvinium pamoate inhibits proliferation of myeloma/erythroleukemia cells by suppressing mitochondrial respiratory complex I and STAT3. AB - Pyrvinium pamoate (PP), a classical anthelminthic, potently inhibited proliferation and STAT3 Tyr705 phosphorylation of human myeloma (U266B1 and PCM6)/erythroleukemia (HEL 92.1.7) cells. PCM6 cell proliferation was markedly impaired by STAT3 siRNA knockdown. PP inhibited ATP production/O(2) consumption in those three cells and mitochondrial respiratory complex (I+III, but not II+III) activity in mouse kidney mitochondrial fractions. PP inhibition of ATP production, STAT3 Tyr705 phosphorylation, and proliferation was absent in mitochondrial DNA-deficient HEL 92.1.7-rho(0) cells. Moreover, PP acted synergistically with dexamethasone to inhibit PCM6 cell proliferation. In conclusion, we identified PP as a potential anticancer drug directed against mitochondrial respiratory complex I/STAT3. PMID- 22210383 TI - Modeling of cortical bone adaptation in a rat ulna: effect of frequency. AB - We employ a recently developed model for the adaptation of cortical bone in response to mechanical loading to study the effect of loading frequency on the computed response, and we compare our results to previous experimental measurements on rat ulnae. We represent the cortical bone as a poroelastic material with orthotropic permeability. Bone adaptation in the model is related to a mechanical stimulus derived from the dissipation energy of the poroelastic flow induced by deformation. We account for a non-locality in the mechanotransduction of osteocytes present in the lacunae by using a "zone of influence." Calculations are done using the finite element method applied to a rat ulna whose geometry is obtained from micro-computed tomography images. We show that the change in the second moment of inertia of the cross-section increases non-linearly and saturates at higher frequency range. The numerical results are then compared quantitatively to experimental data from the literature. Finally, we examine the role of local narrowing of intramedullary canal in our specific ulna in the development of local irregularities in growth. PMID- 22210384 TI - Thrombotic microangiopathy due to multiple autoantibodies related to antiphospholipid syndrome. AB - BACKGROUND: Antiphospholipid syndrome (APS) is a rare disorder in children. More than half of childhood APS occurs as secondary APS complicated by systemic lupus erythematosus (SLE) and other autoimmune diseases. CASE-DIAGNOSIS/TREATMENT: We encountered a boy with SLE who presented with thrombotic microangiopathy (TMA) due to APS. He was initially diagnosed with SLE and treated with methylprednisolone pulse therapy. However, his renal function rapidly deteriorated. Since poikilocytes were detected, we suspected that his condition was complicated by TMA or APS. Urgent plasma exchange, continuous hemodialysis, and intravenous cyclophosphamide saved the patient and his renal failure ameliorated. A renal biopsy performed at the onset of disease showed multiple microvascular thrombi, diffuse mesangiolysis, and cortical necrosis compatible with TMA. He was positive for anticardiolipin antibody, anti-beta2-glycoprotein I antibody, and lupus anticoagulant as well as anti-phosphatidylserine-prothrombin complex IgG antibody (aPS/PT). Anti-a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) antibody was negative and ADAMTS13 activity was normal. The aPS/PT is thrombogenic and is a newly discovered lupus anticoagulant. CONCLUSIONS: Childhood TMA due to APS has rarely been reported. To the best of our knowledge this is the first report of pediatric TMA due to APS with positive aPS/PT. Physicians need to be aware of aPS/PT in pediatric APS and/or SLE. PMID- 22210385 TI - Weight dosing of steroids in nephrotic syndrome. PMID- 22210386 TI - Caesarean section scar depicted in a ca. 2,500-year-old kylix. PMID- 22210387 TI - Structural and functional specificity of small heat shock protein HspB1 and HspB4, two cellular partners of HspB5: role of the in vitro hetero-complex formation in chaperone activity. AB - The ubiquitous small heat shock proteins are essential elements in cellular protection, through a molecular chaperone activity. Among them, human small heat shock protein HspB1, HspB4 and HspB5 are involved in oncogenesis, anti-apoptotic activity and lens transparency. Therefore, these proteins are potential therapeutic targets in many diseases. Their general chaperone activity is related to their dynamic and multiple oligomeric structures, which are still poorly understood. The tissue selective distribution of HspB1 and HspB4, two cellular partners of HspB5, suggests that these two proteins might have evolved to play distinct physiological functions. Moreover, hetero-complex formation seems to be favoured in vivo, yet the functional specificity of the HspB1-HspB5 and HspB4 HspB5 hetero-complexes compared to the homo-oligomers remains unclear in the stress response pathway. A powerful approach combining biochemistry, biophysics and bioinformatics, allowed us to compare the different assemblies, with a special emphasis on the structural data, subunit exchange properties, activity and sequence evolution. We showed that they all exhibit different properties, from structural organization in physiological versus stress conditions, to chaperone-like activity, whatever the level of sequence conservation. Subunit exchange kinetics leading to HspB1-HspB5 or HspB4-HspB5 hetero-complex formation is also different between these two complexes: HspB5 exchanges more rapidly subunits with HspB1 than with HspB4. The relative sequence conservation in the sHSP superfamily does hide important structural heterogeneity and flexibility, which confer an enlarged range of different surface necessary to efficiently form complexes with various stress-induced cellular targets. Our data suggest that the formation of hetero-complexes could be an original evolutionary strategy to gain new cellular functions. PMID- 22210388 TI - Colicin M hydrolyses branched lipids II from Gram-positive bacteria. AB - Lipids II found in some Gram-positive bacteria were prepared in radioactive form from l-lysine-containing UDP-MurNAc-pentapeptide. The specific lateral chains of Enterococcus faecalis, Enterococcus faecium and Staphylococcus aureus (di-L alanine, D-isoasparagine, and pentaglycine, respectively) were introduced by chemical peptide synthesis using the Fmoc chemistry. The branched nucleotides obtained were converted into the corresponding lipids II by enzymatic synthesis using the MraY and MurG enzymes. All of the lipids were hydrolysed by Escherichia coli colicin M at approximately the same rate as the meso-diaminopimelate containing lipid II found in Gram-negative bacteria, thereby opening the way to the use of this enzyme as a broad spectrum antibacterial agent. PMID- 22210389 TI - Performance evaluation of a whole blood propofol analyser. AB - The authors evaluated an analyser for the determination of propofol concentrations in whole blood. The Pelorus 1000 (Sphere Medical) measures propofol concentrations in around 5 min without the requirement for sample preparation. The performance of the analyser was characterised with respect to linearity, precision in control solutions and whole blood and method comparison to an HPLC based reference method. In addition, the effects of substances considered to potentially affect the assay method were investigated. The analyser was found to be linear up to 12 MUg/ml (R2 = 0.9993), with a lower limit of quantification of 0.75 MUg/ml. Total within device imprecision in control solutions was 0.11 MUg/ml at 5.32 MUg/ml and 0.17 MUg/ml at 10.3 MUg/ml. Within run precision in whole blood was 0.04 MUg/ml at 2.84 MUg/ml and 0.08 MUg/ml at 6.68 MUg/ml and for the reference method was 0.06 MUg/ml and 0.12 MUg/ml respectively. In comparison to the reference method, the overall bias of the Pelorus 1000 system over the range is estimated to be 0.15 MUg/ml (95% confidence interval -0.11-0.41 MUg/ml). The only cross interference of note is to a highly elevated level of conjugated bilirubin, while low haematocrit levels lead to a 0.13 MUg/ml under reading with respect to the HPLC reference. The system fulfils the requirements for measurement of propofol concentrations in whole blood samples with precision and accuracy suitable for elucidating propofol pharmacokinetics at clinically relevant concentrations. With no requirement for sample preparation and a fast time to results, the analyser opens up the possibility of studies to measure and respond to blood propofol concentrations in patients in close to real time. PMID- 22210390 TI - Sequence diversity under the multispecies coalescent with Yule process and constant population size. AB - The study of sequence diversity under phylogenetic models is now classic. Theoretical studies of diversity under the Kingman coalescent appeared shortly after the introduction of the coalescent. In this paper we revisit this topic under the multispecies coalescent, an extension of the single population model to multiple populations. We derive exact formulas for the sequence dissimilarity of two sequences drawn at random under a basic multispecies setup. The multispecies model uses three parameters--the species tree birth rate under the pure birth process (Yule), the species effective population size and the mutation rate. We also discuss the effects of relaxing some of the model assumptions. PMID- 22210391 TI - Equilibrium properties of a multi-locus, haploid-selection, symmetric-viability model. AB - Under haploid selection, a multi-locus, diallelic, two-niche Levene (1953) model is studied. Viability coefficients with symmetrically opposing directional selection in each niche are assumed, and with a further simplification that the most and least favored haplotype in each niche shares no alleles in common, and that the selection coefficients monotonically increase or decrease with the number of alleles shared. This model always admits a fully polymorphic symmetric equilibrium, which may or may not be stable. We show that a stable symmetric equilibrium can become unstable via either a supercritical or subcritical pitchfork bifurcation. In the supercritical bifurcation, the symmetric equilibrium bifurcates to a pair of stable fully polymorphic asymmetric equilibria; in the subcritical bifurcation, the symmetric equilibrium bifurcates to a pair of unstable fully polymorphic asymmetric equilibria, which then connect to either another pair of stable fully polymorphic asymmetric equilibria through saddle-node bifurcations, or to a pair of monomorphic equilibria through transcritical bifurcations. As many as three fully polymorphic stable equilibria can coexist, and jump bifurcations can occur between these equilibria when model parameters are varied. In our Levene model, increasing recombination can act to either increase or decrease the genetic diversity of a population. By generating more hybrid offspring from the mating of purebreds, recombination can act to increase genetic diversity provided the symmetric equilibrium remains stable. But by destabilizing the symmetric equilibrium, recombination can ultimately act to decrease genetic diversity. PMID- 22210392 TI - The effects of repeated handling and corticosterone treatment on behavior in an amphibian (Ocoee salamander: Desmognathus ocoee). AB - Exposure to unpredictable challenges triggers a stress response that helps an animal cope by ensuring energy availability and increasing expression of anti predator behaviors. At the same time, stress responses typically suppress activities non-essential to immediate survival, such as growth and reproduction. Glucocorticoid hormones are key mediators of the stress response. We measured the effects of repeated exposure to a handling stressor and repeated elevation of plasma levels of the glucocorticoid hormone, corticosterone (CORT) in a terrestrial salamander, Desmognathus ocoee. Subjects were handled daily or treated every day with a dermal patch containing CORT. Compared to control treatments, chronic handling and treatment with CORT both resulted in decreased body weight. Repeated handling, but not treatment with CORT, reduced feeding in females and activity in both males and females. Treatments had no effect on white blood cell differentials. Despite a nonsignificant trend for courtship to be delayed in handled animals, most salamanders in all treatment groups courted and mated. Courtship and mating may be relatively resistant to the effects of repeated handling and elevated plasma CORT because courtship and mating are energetically inexpensive in this species. PMID- 22210393 TI - Mismatch or cumulative stress: toward an integrated hypothesis of programming effects. AB - This paper integrates the cumulative stress hypothesis with the mismatch hypothesis, taking into account individual differences in sensitivity to programming. According to the cumulative stress hypothesis, individuals are more likely to suffer from disease as adversity accumulates. According to the mismatch hypothesis, individuals are more likely to suffer from disease if a mismatch occurs between the early programming environment and the later adult environment. These seemingly contradicting hypotheses are integrated into a new model proposing that the cumulative stress hypothesis applies to individuals who were not or only to a small extent programmed by their early environment, while the mismatch hypothesis applies to individuals who experienced strong programming effects. Evidence for the main effects of adversity as well as evidence for the interaction between adversity in early and later life is presented from human observational studies and animal models. Next, convincing evidence for individual differences in sensitivity to programming is presented. We extensively discuss how our integrated model can be tested empirically in animal models and human studies, inviting researchers to test this model. Furthermore, this integrated model should tempt clinicians and other intervenors to interpret symptoms as possible adaptations from an evolutionary biology perspective. PMID- 22210394 TI - Elucidation of thrifty features in adult rats exposed to protein restriction during gestation and lactation. AB - Since the introduction of the thrifty phenotype hypothesis, the potential traits of thrift have been described in increasingly broad terms but biochemical and behavioral evidence of thrift has not been well demonstrated. The objective of our studies was to use a rodent model to identify features of thrift programmed by early life protein restriction. Robust programming of thrifty features requires a thrifty nutritional environment during the entire window of developmental plasticity. Therefore, pregnant rats were exposed to a low protein diet throughout the window of developmental plasticity spanning the period of gestation and lactation and its effects on energy acquisition, storage and expenditure in the adult offspring were examined. Maternal protein restriction reduced birth weight and produced long term reductions in body and organ weights in the offspring. Low protein offspring demonstrated an increased drive to seek food as evidenced by hyperphagia that was mediated by changes in plasma leptin and ghrelin levels. Hyperphagia was accompanied by increased efficiency in converting caloric intake into body mass. The higher feed efficiency was mediated by greater insulin sensitivity. Energy expenditure of low protein offspring in locomotion was not affected either in the light or dark phase. However, low protein offspring exhibited higher resting and basal metabolic rates as evidenced by higher core body temperature in the fed and fasted states. The increased thermogenesis was not mediated by thyroid hormones but by an increased sympathetic nervous system drive as reflected by a lower areal bone mineral density and bone mineral content and lower plasma adiponectin and triglyceride levels. Elevated thermogenesis in the low protein offspring possibly offsets the effects of hyperphagia, minimizes their chances of weight gain, and improves survivability. This constellation of metabolic features in the low protein offspring will maximize survival potential in a post natal environment of nutritional scarcity and constitute a thrifty phenotype. PMID- 22210395 TI - Anti-stress effects of cilnidipine and nimodipine in immobilization subjected mice. AB - The present study was designed to investigate the ameliorative role of cilnidipine and nimodipine in immobilization stress-induced behavioral alterations and memory defects in the mice. Acute stress was induced by immobilizing the mice for 150 min and stress-induced behavioral changes were assessed using actophotometer, hole board, open field and social interaction tests. The learning and memory was evaluated using elevated plus maze tests and biochemically, the corticosterone levels were measured in the blood serum. Acute immobilization stress resulted in decrease in locomotor activity, frequency of head dips and rearings in hole board; line crossing and rearing in the open field; increase in avoidance in social behavior along with development of memory deficits assessed by an increased transfer latency time and elevation of the corticosterone levels. Administration of cilnidipine (10 mg/kg), an L and N-type dual calcium channel blocker, and nimodipine (10 mg/kg), an L-type calcium channel blocker, significantly attenuated the immobilized stress-induced behavioral changes and restored memory deficits along with normalization of the corticosterone levels. Cilnidipine and nimodipine produced comparable beneficial effects in restoring immobilization stress subjected mice. It may be concluded that cilnidipine and nimodipine mediated attenuation of corticosterone release by blockage of calcium channels (both L and N-type) on the HPA-axis is responsible for beneficial effects in restoration of behavioral alterations and memory deficits in immobilization-induced acute stress in mice. PMID- 22210396 TI - Metabolic and cardiovascular adjustments during psychological stress and carotid artery intima-media thickness in youth. AB - OBJECTIVE: Cardiovascular reactivity is associated with carotid artery intima media thickness as early as childhood. Excess cardiovascular responses relative to the metabolic demand during psychological stress have been proposed as a mechanism for this association. However, it is not known whether excess cardiovascular responses in relation to the metabolic demand correlate with carotid artery intima-media thickness as strongly as traditionally measured cardiovascular reactivity. METHODS: Fifty-four adolescents, ages 13-16 years completed a graded exercise test in 1 day and measures of psychological stress reactivity (star tracing, speech) on another day. Heart rate, systolic blood pressure, and oxygen consumption were measured on both days. On a third visit adolescents completed an ultrasound scan to measure carotid artery intima-media thickness. RESULTS: Traditionally measured systolic blood pressure reactivity (beta=0.30, p=0.02, R(2) increase=0.09) and excess systolic blood pressure (beta=0.30, p=0.02, R(2) increase=0.08) while preparing a speech were associated with greater carotid artery intima-media thickness when controlling for demographic characteristics, fitness, and baseline systolic blood pressure. CONCLUSIONS: This study adds to the growing body of literature showing a link between systolic blood pressure reactivity to acute psychological stress and carotid artery intima-media thickness in youth. This was the first study to demonstrate that systolic blood pressure in excess of the metabolic demand during psychological stress was also associated with carotid artery-intima media thickness. PMID- 22210397 TI - The battle against infectious diseases. PMID- 22210398 TI - Ten years after polio eradication from the WPRO region: current status and future problems. PMID- 22210399 TI - Meeting report: 1st Middle East Vaccine Congress, 17-19th November, 2011 at Abu Dhabi, UAE. PMID- 22210400 TI - Peptide vaccination is superior to genetic vaccination using a recombineered bacteriophage lambda subunit vaccine. AB - Genetic immunization holds promise as a vaccination method, but has so far proven ineffective in large primate and human trials. Herein, we examined the relative merits of genetic immunization and peptide immunization using bacteriophage lambda. Bacteriophage lambda has proven effective in immune challenge models using both immunization methods, but there has never been a direct comparison of efficacy and of the quality of immune response. In the current study, this vector was produced using a combination of cis and trans phage display. When antibody titers were measured from immunized animals together with IL-2, IL-4 and IFNgamma production from splenocytes in vitro, we found that proteins displayed on lambda were superior at eliciting an immune response in comparison to genetic immunization with lambda. We also found that the antibodies produced in response to immunization with lambda displayed proteins bound more epitopes than those produced in response to genetic immunization. Finally, the general immune response to lambda inoculation, whether peptide or genetic, was dominated by a Th1 response, as determined by IFNgamma and IL-4 concentration, or by a higher concentration of IgG2a antibodies. PMID- 22210401 TI - Molecular and phenotypic characterization of Acinetobacter strains able to degrade diesel fuel. AB - Characterization of bacterial communities in oil-contaminated soils and evaluation of their degradation capacities may serve as a guide for improving remediation of such environments. Using physiological and molecular methods, the aim of this work was to characterize 17 Acinetobacter strains (13 species) able to use diesel fuel oil as sole carbon and energy source. The strains were first tested for their ability to grow on different alkanes on minimal medium containing high NaCl concentrations. The envelope hydrophobicity of each strain was assessed by microbial adhesion to the hydrocarbon test (MATH) when grown in LB medium or minimal medium containing succinate or diesel fuel. Most strains were hydrophobic both in LB and minimal medium, except for strain Acinetobacter venetianus VE-C3 that was hydrophobic only in minimal medium. Furthermore, two A. venetianus strains, RAG-1(T) and LUH 7437, and strain ATCC 17905 (genomic species 13BJ) displayed biosurfactant activity. The alkM gene encoding alkane hydroxylase was detected in the chromosome of the 15 strains by PCR amplification, sequencing and Southern blot analysis. Phenotype microarray analysis performed on the five A. venetianus strains revealed that they differentially used purines as N-source and confirmed that they are unable to use carbohydrates. PMID- 22210402 TI - Strategies for cancer stem cell elimination: insights from mathematical modeling. AB - The cancer stem cell (CSC) hypothesis states that only a small fraction of a malignant cell population is responsible for tumor growth and relapse. Understanding the relationships between CSC dynamics and cancer progression may contribute to improvements in cancer treatment. Analysis of a simple discrete mathematical model has suggested that homeostasis in developing tissues is governed by a "quorum sensing" control mechanism, in which stem cells differentiate or proliferate according to feedback they receive from neighboring cell populations. Further analysis of the same model has indicated that excessive stem cell proliferation leading to malignant transformation mainly results from altered sensitivity to such micro-environmental signals. Our aim in this work is to expand the analysis to the dynamics of established populations of cancer cells and to examine possible therapeutic avenues for eliminating CSCs. The proposed model considers two populations of cells: CSCs, which can divide indefinitely, and differentiated cancer cells, which do not divide and have a limited lifespan. We assume that total cell density has negative feedback on CSC proliferation and that high CSC density activates CSC differentiation. We show that neither stimulation of CSC differentiation nor inhibition of CSC proliferation alone is sufficient for complete CSC elimination and cancer cure, since each of these two therapies affects a different subpopulation of CSCs. However, a combination of these two strategies can substantially reduce the population sizes and densities of all types of cancer cells. Therefore, we propose that in clinical trials, CSC differentiation therapy should only be examined in combination with chemotherapy. Our conclusions are corroborated by clinical experience with differentiating agents in acute promyelocytic leukemia and neuroblastoma. PMID- 22210403 TI - Evaluation of an asymmetry parameter for curve-fitting in single-chemical and mixture toxicity assessment. AB - In mixture toxicity, concentration-effect data are often used to generate conclusions on combined effect. While models of combined effect are available for such assessments, proper fitting of the data is critical to obtaining accurate conclusions. In this study an asymmetry parameter (s) was evaluated for data fitting and compared with our previous approach. Inhibition of bioluminescence was assessed with Vibrio fischeri at 15, 30 and 45-min of exposure with seven or eight concentrations and a control (each duplicated) for each single-chemical (A or B) and mixture (A:B). Concentration-effect data were fitted to sigmoid curves using the four-parameter logistic function (4PL) and the five-parameter logistic minus one-parameter (5PL-1P) function. For the 4PL, parameters included minimum effect, maximum effect, EC(50) and slope, while for the 5PL-1P the minimum effect parameter was removed and an asymmetry parameter was added. A total of 72 mixture toxicity data sets were evaluated, representing 432 single-chemical and 216 mixture curves. Mean coefficients of determination (r(2)) for all 648 curves showed that the 5PL-1P gave better fitting (0.9982 +/- 0.0018) than the 4PL (0.9973 +/- 0.0030). For both functions, the sum-of-squares of the residuals (SS Res) was determined for each curve. The 5-parameter rational regression best described the relationship between the decrease in sum-of-squares of the residuals (i.e., 4PL: SS-Res - 5PL-1P: SS-Res) and log s, with fitting improved the most at low values of s (s<0.8). This held even when curves with r(2) values <= 0.9970 were removed from the analyses. Subsequent review of the combined effects obtained via the 4PL and the 5PL-1P functions resulted in a change in the interpretation of combined effect in 39/216 (18%) cases. PMID- 22210404 TI - Involvement of IGF-I signaling pathway in the regulation of steroidogenesis in mouse Leydig cells treated with fenvalerate. AB - Exposure to fenvalerate has been shown to be associated with decreased steroid hormone production by mouse Leydig tumor cells (MLTC-1) in our previous study and the interference with cAMP-PKA pathway cannot explain this inhibitory effect completely. In this study, the same cell line was used to investigate the potential involvement of insulin-like growth factor I (IGF-I) signaling pathway in the downregulation of steroidogenesis by fenvalerate. Results showed that fenvalerate treatment decreased IGF-I secretion significantly which was consistent with the reduced expression of IGF-I mRNA. Then inhibitors of the two downstream pathways of IGF-I were added to the medium. The addition of LY294002 (inhibitor of phosphatidylinositol (PI)-3-kinase) did not alter the declining trend of progesterone production with increasing dosages of fenvalerate treatment while the addition of UO126 (inhibitor of extracellular signal-regulated kinases 1/2 (ERK1/2)) markedly attenuated this trend, which strongly indicated the possible involvement of pathway ERK1/2. In addition, phosphorylation of ERK1/2 was also suppressed by fenvalerate. The results suggest that the mechanism by which fenvalerate decreased steroid hormone production might involve the impairment of IGF-I signal pathway by attenuating the IGF-I production and ERK1/2 phosphorylation. PMID- 22210408 TI - Shear wave elastography for breast masses is highly reproducible. AB - OBJECTIVES: To evaluate intra- and interobserver reproducibility of shear wave elastography (SWE) for breast masses. METHODS: For intraobserver reproducibility, each observer obtained three consecutive SWE images of 758 masses that were visible on ultrasound. 144 (19%) were malignant. Weighted kappa was used to assess the agreement of qualitative elastographic features; the reliability of quantitative measurements was assessed by intraclass correlation coefficients (ICC). For the interobserver reproducibility, a blinded observer reviewed images and agreement on features was determined. RESULTS: Mean age was 50 years; mean mass size was 13 mm. Qualitatively, SWE images were at least reasonably similar for 666/758 (87.9%). Intraclass correlation for SWE diameter, area and perimeter was almost perfect (ICC >= 0.94). Intraobserver reliability for maximum and mean elasticity was almost perfect (ICC = 0.84 and 0.87) and was substantial for the ratio of mass-to-fat elasticity (ICC = 0.77). Interobserver agreement was moderate for SWE homogeneity (kappa = 0.57), substantial for qualitative colour assessment of maximum elasticity (kappa = 0.66), fair for SWE shape (kappa = 0.40), fair for B-mode mass margins (kappa = 0.38), and moderate for B-mode mass shape (kappa = 0.58), orientation (kappa = 0.53) and BI-RADS assessment (kappa = 0.59). CONCLUSIONS: SWE is highly reproducible for assessing elastographic features of breast masses within and across observers. SWE interpretation is at least as consistent as that of BI-RADS ultrasound B-mode features. KEY POINTS: * Shear wave ultrasound elastography can measure the stiffness of breast tissue * It provides a qualitatively and quantitatively interpretable colour-coded map of tissue stiffness * Intraobserver reproducibility of SWE is almost perfect while intraobserver reproducibility of SWE proved to be moderate to substantial * The most reproducible SWE features between observers were SWE image homogeneity and maximum elasticity. PMID- 22210410 TI - Variants observed for STR locus SE33: a concordance study. AB - Discordance of STR typing results can be expected between kits that employ different primers for amplification. The complex motif of the SE33 locus and its flanking regions can contribute to the degree of discordant results. Sequence dependent conformational changes can manifest as length differences under certain electrophoretic conditions and/or use of different primers. The AmpFlSTR(r) NGM SElectTM PCR Amplification Kit (Life Technologies, Carlsbad, CA), PowerPlex(r) ESX 17 system (Promega Corporation, Madison, WI), and PowerPlex(r) ESI 17 system (Promega Corporation) were compared for concordance of allele calls for the SE33 marker in selected samples. A total of 16 samples were identified that were discordant at one of the SE33 alleles by an apparent one nucleotide in size. While the ESX 17 and NGM SElectTM kits yielded concordant results for these 16 samples, the ESI 17 kit generated alleles that differed. The discordant alleles were observed in individuals of African and European descent. Sequence analysis revealed that the one-base difference in size is not due to an indel but is instead the result of a single nucleotide polymorphism (SNP) in the flanking region of the SE33 repeat region. Three different SNPs were observed, one of which is novel. Although these migration anomalies were observed only with the ESI 17 kit, one cannot preclude that a similar phenomenon may occur with the other kits as data sets increase. The type and degree of discordance of STR allele calls among STR kits is an important issue when comparing STR profiles among laboratories and when determining search parameters for identifying candidate associations in national databases. PMID- 22210409 TI - Five year colorectal cancer outcomes in a large negative CT colonography screening cohort. AB - OBJECTIVES: To assess the 5-year incidence of clinically presenting colorectal cancers following a negative CT colonography (CTC) screening examination, as few patient outcome data regarding a negative CTC screening result exist. METHODS: Negative CTC screening patients (n = 1,050) in the University of Wisconsin Health system over a 14-month period were included. An electronic medical record (EMR) review was undertaken, encompassing provider, colonoscopy, imaging and histopathology reports. Incident colorectal cancers and other important GI tumours were recorded. RESULTS: Of the 1,050 cohort (mean [+/-SD] age 56.9 +/- 7.4 years), 39 (3.7%) patients were excluded owing to lack of follow-up within our system beyond the initial screening CTC. The remaining 1,011 patients were followed for an average of 4.73 +/- 1.15 years. One incident colorectal adenocarcinoma represented a crude cancer incidence of 0.2 cancers per 1,000 patient years. EMR revealed 14 additional patients with clinically important GI tumours including: advanced adenomas (n = 11), appendiceal goblet cell carcinoid (n = 1), appendiceal mucinous adenoma (n = 1) and metastatic ileocolonic carcinoid (n = 1). All positive patients including the incident carcinoma are alive at the time of review. CONCLUSIONS: Clinically presenting colorectal adenocarcinoma is rare in the 5 years following negative screening CTC, suggesting that current strategies, including non-reporting of diminutive lesions, are appropriate. KEY POINTS: * CT colonography (CTC) screening is increasingly used to identify potential colorectal cancer. * Clinically presenting cancers are rare for 5 years following negative CTC screening. * The practice of setting a 6 mm polyp size threshold seems safe. * An interval of 5 years for routine CTC screening is appropriate. PMID- 22210411 TI - Molecular phylogenetics, historical biogeography, and chromosome number evolution of Portulaca (Portulacaceae). AB - Portulaca is the only genus in Portulacaceae and has ca. 100 species distributed worldwide, mainly in the tropics and subtropics. Molecular data place the genus as one of the closest relatives of Cactaceae, but phylogenetic relationships within Portulaca are barely known. This study samples 59 species of Portulaca, 10 infraspecific taxa, and three cultivars, including multiple samples of widespread species. The sampled taxa represent all subgenera in the classifications of von Poellnitz (1934), Legrand (1958), and Geesink (1969) and come from around the world. Nuclear ITS and chloroplast ndhF, trnT-psbD intergenic spacer, and ndhA intron DNA sequences were analyzed using maximum likelihood and Bayesian methods to produce a hypothesis of relationships within Portulaca. Divergence times were estimated using Hawaiian endemics for calibration, and biogeographical patterns were examined using a Bayes-DIVA approach. In addition, the evolution of chromosome numbers in the genus was investigated using probabilistic models. The analyses strongly support the monophyly of Portulaca, with an age of the most recent common ancestor (MRCA) of 23 Myr. Within Portulaca are two major lineages: the OL clade (comprising opposite-leaved species) distributed in Africa, Asia, and Australia, and the AL clade (comprising alternate to subopposite-leaved species), which is more widespread and originated in the New World. Sedopsis, a genus sometimes recognized as distinct from Portulaca based on a long corolla tube, is nested within the OL clade and does not merit taxonomic recognition. Samples of Portulaca grandiflora, Portulaca halimoides, and Portulaca oleracea were found to be non-monophyletic. It is hypothesized that the ancestral distribution area of Portulaca included southern hemisphere continents and Asia. The OL clade remained restricted to the Old World (except Portulaca quadrifida, a pantropical weed), while the AL clade, with a South American origin, was able to disperse multiple times to other continents. The base chromosome number for Portulaca is inferred to be x=9, although the analysis was primarily based on the available data for the AL clade. A number of chromosome number change events (polyploidization, demi-polyploidization, gain, and loss) were shown to have occurred in the genus, especially within the Oleracea clade. PMID- 22210412 TI - Molecular phylogenetic analysis of mudflat snails (Gastropoda: Euthyneura: Amphiboloidea) supports an Australasian centre of origin. AB - Amphiboloidea is a small but widespread group of snails found exclusively, and often abundantly, in mudflat and associated salt marsh or mangrove habitat. This study uses molecular data from three loci (COI, 16S and 28S) to infer phylogenetic relationships in Amphiboloidea and examine its position in Euthyneura. All but two of the named extant species of Amphiboloidea and additional undescribed taxa from across Southeast Asia and the Arabian Gulf were sampled. In contrast to the current morphology-based classification dividing Amphiboloidea into three families, analysis of molecular data supports revision of the classification to comprise two families. Maningrididae is a monotypic family basal to Amphibolidae, which is revised to comprise three subfamilies: Amphibolinae, Phallomedusinae and Salinatorinae. Sequence divergence between Asian populations of Naranjia is relatively large and possibly indicative of species complexes divergent across the Strait of Malacca. Salinatorrosacea and Salinator burmana do not cluster with other Salinator species, and require generic reassignment. In addition, sequences were obtained from an undescribed species of Lactiforis from the Malay Peninsula. Reconstruction of ancestral distributions indicates a plesiomorphic distribution and centre of origin in Australasia, with two genera subsequently diversifying throughout Asia. Increasing the sampling density of amphiboloid taxa in a phylogenetic analysis of Euthyneura did not resolve the identity of the sister taxon to Amphibolidae, but confirmed its inclusion in Pulmonata/Panpulmonata. PMID- 22210413 TI - Gastrointestinal endoscopy and mucosal biopsy in the first year of life: indications and outcome. AB - OBJECTIVES: Lower threshold and widening indications for paediatric gastrointestinal endoscopy have resulted in a significant increase in the numbers of endoscopic procedures performed in infants. Despite this, knowledge of gastrointestinal mucosal findings in this age group is limited and data on the clinical usefulness of endoscopy are lacking. METHODS: All of the children younger than 1 year referred to a single tertiary paediatric gastroenterology unit during the period June 1987 to August 2007 who underwent gastrointestinal endoscopy were identified and the clinical indications and histological outcomes were reviewed. RESULTS: A total of 933 gastroesophageal duodenoscopies and 439 colonoscopies were performed in 1024 cases in a total of 823 infants. In order of frequency, clinical indications were diarrhoea (51%), failure to thrive (41.2%), symptoms of reflux (27.1%), and rectal bleeding (8.5%). Mucosal biopsies were insufficient for assessment in only 2.4% of cases. Mucosal histology was normal in 33.8%, whereas histological abnormalities were identified in 63.8%. Specific histological diagnoses included microvillous inclusion disease, autoimmune enteropathy, graft-versus-host disease post-bone marrow transplantation, tufting enteropathy, and disaccharidase deficiency. There was only 1 colonic perforation complicating endoscopy in a total of 889 cases for which relevant information was available (0.1%). CONCLUSIONS: In two-thirds of cases, histological abnormalities were detected that influenced management following endoscopic examination and mucosal biopsy in infants. Endoscopy with biopsies is a greatly informative test with low failure and complication rates in the first year of life. PMID- 22210415 TI - Indication of liver transplantation for jaundice-free biliary atresia with portal hypertension. AB - BACKGROUND: At the present time, indications of liver transplantation (LT) for jaundice-free biliary atresia (BA) patients include intractable cholangitis, portal hypertension and pulmonary vascular disorders. However, the timing of LT remains unclear. In the current study, we describe the therapeutic strategies for jaundice-free BA patients. MATERIAL/METHODS: 129 BA patients were undergone LDLT between May, 2001 and April, 2010 in the Department of Transplant Surgery, Jichi Medical University, Japan. RESULTS: The indications of LDLT for jaundice-free BA patients was 30 patients (30/129, 23%), and included portal hypertension (16 patients, 53%). Among the 16 patients with portal hypertension, there were 7 patients (7/16, 23%) in which uncontrollable gastrointestinal bleeding was an indication of LDLT. There were 5 patients (5/7; 71%) in which bleeding sites were not identified, and 3 patients (3/7; 43%) in which supportive treatments against collateral vessels were performed as a previous treatment. CONCLUSIONS: Even in jaundice-free BA patients, after supportive treatments for portal hypertension are performed, it is necessary to assess the esophageal and gastrointestinal varices regularly and to also prepare for LT simultaneously because there is a probability of the complication of uncontrollable gastrointestinal bleeding. PMID- 22210416 TI - Continuous versus interrupted suture for hepatic artery reconstruction using a loupe in living-donor liver transplantation. AB - BACKGROUND: Partial liver transplantation from live donors is now widely performed to compensate for the shortage of deceased donors' organs. Operative microscopy is often used to achieve hepatic artery anastomosis. Here we report our experience of hepatic artery reconstruction using loupe magnification. MATERIAL/METHODS: We used operative microscopy (12-16* magnification) in our early experience. We changed to loupe magnification (3.5*) in 43 cases. Reconstructions were done with continuous, end-to-end anastomoses with 8-0 nylon and a 3.5* loupe was used for the arterial anastomosis. RESULTS: The mean follow up time was 8 months. There were no cases of hepatic artery thrombosis. CONCLUSIONS: Hepatic artery reconstruction in living donor liver transplantation with continuous end-to-end suturing using loupe magnification can yield good results. PMID- 22210414 TI - Of mice and men: the benefits of caloric restriction, exercise, and mimetics. AB - During aging there is an increasing imbalance of energy intake and expenditure resulting in obesity, frailty, and metabolic disorders. For decades, research has shown that caloric restriction (CR) and exercise can postpone detrimental aspects of aging. These two interventions invoke a similar physiological signature involving pathways associated with stress responses and mitochondrial homeostasis. Nonetheless, CR is able to delay aging processes that result in an increase of both mean and maximum lifespan, whereas exercise primarily increases healthspan. Due to the strict dietary regime necessary to achieve the beneficial effects of CR, most studies to date have focused on rodents and non-human primates. As a consequence, there is vast interest in the development of compounds such as resveratrol, metformin and rapamycin that would activate the same metabolic- and stress-response pathways induced by these interventions without actually restricting caloric intake. Therefore the scope of this review is to (i) describe the benefits of CR and exercise in healthy individuals, (ii) discuss the role of these interventions in the diseased state, and (iii) examine some of the promising pharmacological alternatives such as CR- and exercise mimetics. PMID- 22210417 TI - Restrictive pattern in spirometry as a predictor of poor survival in chronic heart failure patients on betaceptor-antagonist, with possible indications for heart transplantation. AB - BACKGROUND: Restrictive spirometry pattern is commonly associated with chronic heart failure (CHF), but its prognostic value is poorly documented. Utility of Lower Limit of Normal (LLN)-based spirometry interpretation has not yet been evaluated in CHF patients. Impact of restrictive pattern defined according to classic or LLN criteria on prognosis in CHF patients was therefore addressed. MATERIAL/METHODS: 171 CHF patients on long-term beta-antagonist treatment with PeakVO2 >12 ml/kg/min (147 men, 49+/-9 years, LVEF 26+/-8%, 51% ischemic) were divided into groups based on their spirometry: Group 1A (N=129) - classic criteria: no restriction, Group 2A (N=12) - classic criteria: restrictive pattern, Group 1B (N=90) - LLN criteria: no restriction, Group 2B (N=26) - LLN criteria: restrictive pattern. PeakVO2 in the study groups equaled 12.1-19.9 ml/kg/min. Control group (N=30) - PeakVO2 >20 ml/kg/min, absence of restriction or obstruction (FEV1%FVC >=70) defined by classic criteria. Classic criteria: VCin% <70 and FEV1%FVC >=70. LLN criteria: VCin% =LLN. LLN is the 5th percentile of spirometry values' normal distribution in the reference population. End-points: time to death, 1- and 2-year mortality, number and duration time of cardiac and all-cause hospitalizations. P<0.05 was considered significant. RESULTS: Significantly worse survival was observed in groups 2A and 2B when compared to the control group. One-year and 2-year mortality were significantly higher in group 2B (19.2 and 40.9%; control group: 0% and 0%, respectively) and 2-year mortality was higher in group 2A (40.0%). CONCLUSIONS: Restrictive spirometry pattern is associated with worse survival in CHF patients with PeakVO2 above the cutoff point for OHT listing. Use of LLN criteria may be useful to predict poor 1-year prognosis. PMID- 22210418 TI - Observations with impact on the indication for kinetic therapy in critically ill liver transplant patients. AB - BACKGROUND: Severe pulmonary complications following orthotopic liver transplantation are a major cause of postoperative deaths. Kinetic therapy (KT) has been reported to prevent and treat respiratory complications in selected critically ill patients, but little has been reported about the value of different criteria for the use of this therapy and its side effects in liver transplant recipients. MATERIAL/METHODS: We performed a prospective observational study of 27 patients treated post-transplantation in our ICU. 12 of 27 patients were treated with KT in case of either high number of blood transfusions (>20) or respiratory insufficiency (PaO2/FiO2 ratio <250 mmHg) or pretransplant pulmonary disease. Over a period of nine days we measured the PaO2/FiO2 ratio to evaluate the beneficial effect of KT. Liver perfusion was quantified by doppler ultrasound. Transplant function was measured by INR (international normalised ratio) and determination of indocyanine green elimination rate. RESULTS: Side effects on graft perfusion and graft function were not seen. 7 of 12 patients decreased in their PaO2/FiO2 ratio significantly 48 hours postoperative to 53% as compared to early postoperative level and recovered under KT during the observed time period nearly to the early postoperative level (95%; p<0.001). The units of perioperative blood transfusions, the MELD-score, the decrease of PaO2/FiO2 ratio 24 h after transplantation and retransplantation for initial non-functioning of the graft all pointed to a likely beneficial effect of KT. CONCLUSIONS: We conclude that these criteria may be helpful to identify patients who are likely to benefit from KT. PMID- 22210419 TI - The impact of donor-specific antibodies on graft outcome in pediatric renal transplantation from deceased donors. AB - BACKGROUND: Despite prospective crossmatching and modern immunosuppression, early acute rejection is still present in cadaveric renal transplantation. The purpose of this study was to evaluate the incidence of preformed anti-donor antibodies, detected by 2 solid-phase techniques, and to analyze their impact on early renal allograft outcome. MATERIAL/METHODS: Flow crossmatch detecting the presence of anti-donor IgG and IgM antibodies was performed in pre-transplant sera of 279 patients with negative cytotoxic crossmatch. Screening for IgG antibodies detected by bead-based multiplex technique was performed in sera of 69 patients from the FCXM group. The incidence of early biopsy-proven rejection and graft failure within 3 months after transplantation was analyzed. RESULTS: Anti-donor IgG antibodies were detected in 33 patients (11.8%) by flow crossmatch and in 10 patients by multiplex (14.5%). IgM antibodies were detected in 23 patients (8.2%). All multiplex-positive sera were also positive for IgG by flow crossmatch, but in 18 cases no antibodies were found by multiplex technique. Biopsy-proven acute rejection within 3 months after transplantation was observed in 16 patients, and 5 allografts were lost due to immunological reasons. Presence of IgG antibodies was found to have no effect on early outcome, while the presence of IgM antibodies was associated with significantly higher rejection rate and immune-related graft failure. CONCLUSIONS: Anti-donor IgG antibodies detected by bead-based and cell-based technique have no impact on biopsy-proven rejection rate or graft failure. Anti-donor IgM detected by flow crossmatch have significant impact on early transplantation outcome. PMID- 22210420 TI - Comparison of the transperitoneal and a semi-open retroperitoneal approach for right-sided laparoscopic donor nephrectomy. AB - BACKGROUND: To investigate whether the retroperitoneal or transperitoneal approach is preferable for right-sided laparoscopic donor nephrectomy (R-LDN). MATERIAL/METHODS: We retrospectively compared the donor and recipient outcomes of R-LDNs performed with a standard transperitoneal approach (n=21) or a semi-open retroperitoneal approach (n=32). RESULTS: Patient demographics were similar between groups. The semi-open retroperitoneal group had shorter operative time (89.5 min vs. 105 min, p<0.001), shorter WIT (102 s vs. 120 s, p<0.001), and longer renal veins (2.5 cm vs. 2.2 cm, p<0.001). No conversions to open procedures occurred. There were no significant differences in the blood loss, length of hospital stay, or donor complication rate between the 2 groups. All grafts functioned adequately, and there were no significant differences in graft function, first-week hemodialysis, and serum creatinine level at discharge between the 2 groups The recipient complication rate was similar between the 2 groups (9.4% vs. 9.5%, p=0.986). CONCLUSIONS: The semi-open retroperitoneal approach is safe and effective for R-LDN. Further study is required to evaluate long-term graft function. PMID- 22210421 TI - Palifermin does not influence the incidence and severity of GvHD nor long-term survival of patients with hematological diseases undergoing HSCT. AB - BACKGROUND: Palifermin is known as the effective growth factor to reduce the incidence, duration and severity of oral mucositis (OM) following hematopoietic stem cell transplantation (HSCT). However, additional data on the long-term safety of palifermin and its potential influence on graft versus host disease (GvHD) are needed. MATERIAL/METHODS: In this multi-center, non-randomized, matched-control study we assessed early overall survival (OS), incidence and severity of acute/chronic GvHD (a/cGvHD) and incidence of secondary malignancies in 36 patients with hematological diseases treated with allogeneic HSCT and palifermin. RESULTS: The incidence of aGvHD was 28.2% and 38.4% (p=0.34) and cGvHD 41% and 53.8% (p=0.70) in the palifermin and control groups, respectively. The incidence of aGvHD grade 0-IV was 69.2%, 5.1%, 17.9%, 2.5%, 2.5% in the palifermin group and 61.5%, 12.8%, 12.8%, 10.2%, 5.2% in the control group, respectively (p>0.4 for each). The incidence of limited and extensive cGvHD was 17.9% and 23% in the palifermin versus 25.6% and 28.2% in the control group (p=0.32 and p=0.50, respectively). The estimated 3-year OS did not differ significantly between studied groups. We did not observe any secondary malignancies in these patients. CONCLUSIONS: Administration of palifermin doesn't seem to influence the incidence and severity of aGvHD/cGvHD, secondary malignancies occurrence and early OS in patients undergoing allogeneic HSCT. PMID- 22210422 TI - Impact of CYP3A5 genotype of recipients as well as donors on the tacrolimus pharmacokinetics and infectious complications after living-donor liver transplantation for Japanese adult recipients. AB - BACKGROUND: The impact of cytochrome P450 3A5 (CYP3A5) genotype of recipients (intestine) as well as donors (graft liver) on the tacrolimus pharmacokinetics and the incidence of infectious complications was assessed in Japanese living donor liver transplant (LDLT) adult recipients. MATERIAL/METHODS: Fifty-six patients were divided into 4 groups based on the CYP3A5 genotype (expression of *1 allele: expressor (EX) and non-expressor (NEX)) in each recipients (R) and donors (D), EX-R/EX-D (n=9), EX-R/NEX-D (n=7), NEX-R/EX-D (n=12) and NEX-R/NEX-D (n=28). Tacrolimus blood concentration and concentration/dosage ratio (C/D) were evaluated every week until 4 weeks and every month until 12 months after LDLT. The incidences of postoperative infectious complication, acute cellular rejection and tacrolimus adverse effect were compared. RESULTS: The tacrolimus blood concentrations among 4 groups did not significantly differ at each follow-up time period. The C/Ds were significantly lower in EX-R/EX-D (median: 122.3 at 2 weeks) than in NEX-R/NEX-D (389.6 at 2 weeks) until 12 months. The C/Ds in EX-R/NEX-D (163.2 at 2 weeks) have been significantly lower than those in NEX-R/NEX-D until 6 months. Over 6 months, however, those in NEX-R/EX-D showed lower levels (84.1 at 8 months) than those in NEX-R/NEX-D (189.3 at 8 months). Additionally, logistic regression analysis showed that EX-R/EX-D had significantly higher risk for the development of infectious complications than NEX-R/NEX-D (odds ratio 8.67, p=0.03). CONCLUSIONS: Preoperative assessment of CYP3A5 genotypes in both recipients and donors would be useful not only for predicting tacrolimus pharmacokinetics but also defining high-risk group of infectious complications after LDLT. PMID- 22210423 TI - Lack of association of the rs2476601 PTPN22 gene polymorphism with transplanted kidney function. AB - BACKGROUND: PTPN22 gene, located on the long arm of chromosome 1, encodes PTPN22 protein, known as lymphoid tyrosine phosphatase (Lyp). The function of Lyp is suggested to be negative regulation of T-cell reaction through dephosphorylation of Src family kinases--Lck and Fyn, negative regulatory kinase Csk and other signaling molecules. Several studies suggested that individuals lacking the C allele of the C1858T PTPN22 gene polymorphism may have reduced capacity to downregulate T-cell response. Therefore, they may present changes in immunological reaction and be more susceptible to autoimmunity. The aim of this study was to examine the association of the rs2476601 (C1858T) PTPN22 gene polymorphism with transplanted kidney function. MATERIAL/METHODS: The study enrolled 269 Caucasian renal transplant recipients (166 males, 103 females, mean age 47.63+/-12.96 years). Genotyping of the rs2476601 (C1858T) PTPN22 gene polymorphism was performed using the PCR-RFLP method. RESULTS: Comparison of the distribution of genotypes and alleles of the rs2476601 PTPN22 gene polymorphism among patients with delayed graft function (DGF) and without DGF revealed no statistically significant differences (OR=0.69, 95%CI=0.37-1.28, p=0.29) for TT+CT vs. CC genotypes. Similarly, there were no statistically significant differences in regard to the studied polymorphism and acute rejection (OR=0.79, 95%CI=0.41-1.52, p=0.52) or chronic allograft nephropathy (CAN) occurrence (OR=1.22, 95%CI=0.64-2.32, p=0.61). CONCLUSIONS: We found no association between rs2476601 (C1858T) PTPN22 gene polymorphism and transplanted kidney function. PMID- 22210424 TI - Association of UDP-glucuronosyltransferase 1A9 (UGT1A9) gene polymorphism with kidney allograft function. AB - BACKGROUND: UDP-glucuronosyltransferases (UGTs) are a group of enzymes involved in the detoxification and excretion of xeno- and endobiotics. Polymorphic variants of the UGT1A9 gene were shown to influence exposition to mycophenolate mophetil (MMF), a common immunosuppressive drug used in kidney allograft recipients. Therefore, the aim of this study was to evaluate an association between key clinical features of kidney post-transplant course in patients receiving MMF therapy and UGT1A9-2152C>T and -275 T>A SNPs, known to induce UGT1A9 gene expression and UGT1A9 98T>C, resulting in reduced enzyme activity. MATERIAL/METHODS: DNA was isolated from peripheral blood of kidney allograft recipients (n=103) and a control group representing the background population of Poland (n=450). Presence of the analyzed SNP was detected using the PCR restriction fragment length polymorphism (RFLP) method. Accuracy of the applied method was confirmed by DNA sequencing. RESULTS: In patients carrying the UGT1A9 2152T and -275A minor alleles we observed a trend of increased risk of acute allograft rejection within 3 months after transplantation, but this difference was at the border of significance. However, the UGT1A9 98C allele was found to be associated with diminished estimated glomerular filtration rate (eGFR) during the first year after engraftment and transient proteinuria in the first and second month post-transplantation. This association was not observed for UGT1A9-2152C>T and -275 T>A. Our data show that transplanted kidney function may be affected in patients carrying UGT1A9 98C allele and receiving MMF. CONCLUSIONS: Genotyping of the functional UGT1A9 SNP may be of practical use in kidney transplant recipients. PMID- 22210425 TI - Immunosuppressive regimens containing generic mycophenolate mofetil (Myfenax) in de novo renal transplant recipients--preliminary results of 6-month observation. AB - BACKGROUND: The aim of the findings presented below is to show the preliminary outcomes of transplantation in patients treated with the generic formulation of mycophenolate mofetil (Myfenax, Teva). MATERIAL/METHODS: Over the past 2 years 34 patients received generic mycophenolate mofetil (Myfenax) after renal transplantation at the Gdansk Transplantology Center. During the same time period another 127 kidney transplantations were performed in our Department and these patients were treated with other formulations of mycophenolate (CellCept, Myfortic or Mycophenolate mofetil Apotex) as a part of the immunosuppressive scheme. Fifteen of the Myfenax patients received a pair of kidneys from the same donor and received original mycophenolate mofetil Cell-Cept. RESULTS: The outcomes of the renal transplants in both groups (Myfenax vs. pair) were good; with satisfactory function of grafts, and no instances of graft loss were reported. There was no difference in the incidence of acute renal graft rejection (AR) in either group. Moderate adverse reactions to immunosupression were observed in both groups. On the other hand, a comparison between the 34 patients with Myfenax and the 127 other patients with other formulations of mycophenolate revealed no differences in the incidence of AR, delayed graft function (DGF), graft loss and death. CONCLUSIONS: There were no differences in the incidence of AR, DGF, graft loss and death in patients with Myfenax vs. original CellCept and other formulations of mycophenolate. In order to confirm its complete biological and pharmacokinetic equivalence with the reference medicine, long-term, randomized observations carried out on larger renal transplant patients groups are needed. PMID- 22210426 TI - Factors impacting short and long-term kidney graft survival: modification by single intra-operative -high-dose induction with ATG-Fresenius. AB - BACKGROUND: A majority of recipients benefited from the intra-operative single high-dose induction (HDI) with ATG-Fresenius (ATG-F) still leaving a group of recipients who did not profit from this kind of induction. Therefore the aim of this retrospective analysis was 1st to identify the risk factors impacting short and long-term graft survival, and 2nd to assess the efficacy of this type of induction in kidney graft recipients with or without these risk factors. MATERIAL/METHODS: A total of 606 recipients receiving two different immunosuppressive treatment regimens (1st: Triple drug therapy [TDT, n=196] consisting mainly of steroids, azathioprine and cyclosporine; 2nd: TDT + 9 mg/kg ATG-F intra-operatively [HDI, n=410]) were included in this analysis and grouped according to their kidney graft survival time (short GST: <=1 yr, n=100 and long GST: >5 yrs, n=506). RESULTS: The main risk factors associated with a shortened graft survival were pre-transplant sensitization, re-transplantation, rejections (in particular vascular or mixed ones) and the necessity of a long-term anti rejection therapy. Adding ATG-F single high dose induction to TDT was more efficient in prolonging kidney graft survival than TDT alone not only in recipients without any risk factors (p<0.005) but also in recipients with at least one risk factor (p<0.021). Only in 4.6% of recipients having two or more risk factors this effect could not be demonstrated. CONCLUSIONS: The intra operative single high-dose induction with ATG-F significantly improves the kidney graft survival in recipients with or without risk factors and can therefore be recommended. PMID- 22210427 TI - Early steroid withdrawal--impact on diabetes mellitus and kidney function in heart transplant recipients. AB - BACKGROUND: The aim of this study was to assess the effect of early steroid withdrawal on renal function, diabetes mellitus (DM) and coronary artery vasculopathy of the transplanted heart (CAV) development and late rejection in orthotopic heart transplant (OHT) recipients. MATERIAL/METHODS: 76 patients undergoing OHT in years 2000-2004 (6 women, 50% ischemic, 49+/-7 years, BMI 24+/ 3.6, glomerular filtration ratio (GFR) - 68-20 ml/kg/min, LVEF 57+/-6%) receiving maintenance immunosuppression (cyclosporine, prednisone and azathioprine or mycophenolate mofetil) were observed for 5 years in groups, depending on steroid withdrawal time: Group 1 (N=48) - withdrawal later than 12 months post-OHT, Group 2 (N=28) - withdrawal up to 12 months post-OHT. Number of serious rejection episodes (SRE >ISHLT grade 2), time to first SRE after steroid withdrawal (TTSRE), need for steroid reinforcement, CAV presence, need for percutaneous coronary intervention (PCI), DM and abnormal GFR were compared between groups. P<0.05 was significant. RESULTS: Steroids were administered for 615+/-188 days in group 1 (G1) and 309+/-96 days in group 2 (G2). There was a difference between group 1 and 2 in the number of SREs before 12 months (2.4+/-1.6 vs. 1.6+/-1.3) and before steroid withdrawal (2.4+/-1.6 vs. 1.5+/-1.3), but not in number (0.15+/-0.62 vs. 0.14+/-0.36) and percent of patients with an SRE (8.3 vs. 14.3%) after steroid withdrawal. There was no difference in TTSRE (314+/-312 vs. 199+/ 122 days), need for steroid reinforcement (6.3 vs. 14.3%), time from steroid withdrawal to reinforcement (377+/-317 vs. 246+/-130 days), CAV (8.3 vs. 3.6%), PCI (4.2 vs. 3.6%), GFR 60-90 ml/kg/min (30.8 vs. 20.0%), and GFR <60 ml/kg/min (64.1 vs. 80.0%) at 5 years. DM was diagnosed in 58.3 and 71.4% of patients at discharge (p=NS) and in 51.3 and 80% at 5 years in group 1 and 2, respectively (p=0.018). CONCLUSIONS: Patients with earlier steroid withdrawal presented DM and tended to present more severe stages of kidney failure more often. Despite lower frequency of CAV, they tended to require PCI equally often. PMID- 22210428 TI - The effect of selective neutrophil elastase inhibitor on pancreatic islet yields and functions in rat with hypercytokinemia. AB - BACKGROUND: It is well known that to achieve insulin independence requires a high number of islets, but at present, isolation techniques can recover 50% or less of the islets present in the pancreas. Brain death is characterized by a cytokine storm that takes place in the body, and this condition reduces the islet yields and functions. In this study, we used selective neutrophil elastase inhibitor, sivelestat sodium to prevent damage to the islets for transplantation. MATERIAL/METHODS: We used three groups of rats, group 1 were transfused with only saline, group 2 received sivelestat sodium (10 mg/kg/h) and group 3 received a higher dose of sivelestat sodium (30 mg/kg/h). Thirty minutes after the treatment, lipopolysaccharide was injected to induce hypercytokinemia. We examined serum cytokine levels, derivatives of reactive oxygen metabolites (d ROMs), islet yields and viability and 24 hours after static incubation, the islet yields, viability, functions (insulin stimulation index and ADP/ATP ratio). RESULTS: The levels of serum cytokines, IL-1beta, IL-6 and IFN-gamma were significantly different between groups 1 and 3. The islet yields and the 24 h recovery rate of islets and insulin stimulation index were significantly higher in group 3 compared with group 1. The d-ROMs and ADP/ATP ratio were decreased by dose dependently in group 2 and 3. CONCLUSIONS: The islet yields and functions in vitro were significantly improved by the treatment with sivelestat sodium. These experiments may lead to marginal donors, pre-treated with sivelestat sodium becoming acceptable for islet transplantation.
PMID- 22210429 TI - Pulmonary embolism and reactivation of tuberculosis during everolimus therapy in a kidney transplant recipient. AB - BACKGROUND: Proliferation signal inhibitors (PSIs) - sirolimus and everolimus - are commonly used in kidney transplant patients with co-existing neoplasms. These drugs may have prothrombotic activity, but aside from use in interventional cardiology, their clinical relevance has not been confirmed. In contrast to pulmonitis, an association of everolimus therapy with pulmonary embolism has never been documented. There have also been no reports on the increased risk of tuberculosis reactivation after an introduction of a PSI, and experience with everolimus dosing during antituberculosis treatment is very limited. CASE REPORT: A 72-year-old man, after kidney transplantation, had been converted to everolimus from tacrolimus after being diagnosed with basal cell carcinoma. One month later he was hospitalized with suspected pneumonia. Because of the lack of clinical improvement after antibiotic therapy, computed tomography (CT) angiography of the chest was performed and showed bilateral pulmonary embolism. Initially the patient responded well to the treatment, but shortly thereafter developed fever with rigors and chest pain. Eventually, after extensive diagnostic work-up, tuberculosis was diagnosed. During 6 months of pyrazinamide (PZA) and rifampicin (RFP) treatment, the repeated reduction of everolimus blood concentration was necessary, despite the substantial increase of the drug dose. CONCLUSIONS: This case shows that kidney transplanted patients treated with everolimus presenting symptoms of pneumonia should also be screened for pulmonary embolism. Patients treated with PSIs may be prone to reactivation of tuberculosis. When tuberculosis treatment is started, much larger doses of everolimus are required. PMID- 22210430 TI - Transplantation in adults with primary hyperoxaluria: single unit experience and treatment algorithm. AB - BACKGROUND: Kidney transplantation alone in Primary Hyperoxaluria is associated with a high rate of recurrence and in many cases early graft loss. Liver transplantation offers the possibility of correcting the metabolic defect. MATERIAL/METHODS: A retrospective review of five cases of Primary Hyperoxaluria managed at a major transplant unit was performed. RESULTS: The 5 patients had a mean age of 32.2 years (range 28-40) at time of first transplantation. 3 patients had kidney only transplants (one live donor, 2 deceased donor) and 2 had segmental liver followed by delayed kidney transplantation. All 3 kidney alone failed and one is now awaiting a live donor transplant, one underwent kidney alone retransplantation (failed 5 years later) and one had a combined deceased donor liver and kidney transplantation (remains well at 4 years). The 2 segmental liver sequential kidney transplant recipients remain well at 1 year and 3 years. CONCLUSIONS: Combined liver-kidney transplantation may be a better choice as the primary transplant procedure. The indication and timing for pre-emptive liver or liver followed by delayed kidney transplantation remains a matter of debate. PMID- 22210431 TI - Donor transmitted left atrial myxoma 13 years after heart transplantation. AB - BACKGROUND: Left atrial cardiac myxomas are among the most common cardiac masses. However, occurrence of left atrial myxomas in post-transplant patients is very rare and often misdiagnosed as left atrial thrombus formation. CASE REPORT: We report the case of a 67-year old female, who was referred due to suspected left atrial thrombus but was found to have a pediculated mass at the suture line of the left atrium on cardiac MRI. After resection, the diagnosis myxoma was confirmed histologically and the donor origin of the myxoma was proven by tissue typing. CONCLUSIONS: Despite a rare entity, atrial myxomas may occur in post cardiac transplant patients and may therefore support the role of advanced imaging techniques in patients with suspected left atrial masses. PMID- 22210432 TI - Management of a ruptured mycotic pseudo-aneurysm following pancreas-kidney transplantation. AB - BACKGROUND: Simultaneous pancreas kidney transplantation (SPK) is accepted as a therapy for patients with type 1 diabetes and coexisting renal failure. Mycotic pseudoaneurysm formation is a life-threatening complication of transplantation, despite this however, little has been published with regards to its occurrence following SPK transplantation. CASE REPORT: We describe the case of a 35 year old patient who 18 days after receiving a SPK transplant developed an iliac-enteric fistula, following mycotic pseudoaneurysm formation. An emergency laparotomy was required to manage a life threatening gastrointestinal hemorrhage, which necessitated graft pancreatectomy. Resection of the diseased segment of recipient iliac artery onto which the allograft was anastomosed was also required. The patient went on to develop a vascular leak, managed initially by endovascular stenting. With the development of subsequent sepsis and a further leak, operative management was required to remove the infected stent and achieve hemostasis. Immunosupression was withdrawn in an attempt to tackle the ensuing life threatening sepsis. The patient showed signs of improvement over the following weeks, but unfortunately, developed signs of recurrent sepsis and increasing, unremitting discomfort over the kidney allograft. On re-exploration the allograft was found to be heavily infected, with the concurrent progressive renal failure, the decision was made to remove the allograft. CONCLUSIONS: This case highlights important considerations when managing mycotic pseudoaneurysms in transplant recipients. Stent placement to manage such complications may not be a long lasting solution and where stent deployment is used close follow-up of patients is mandatory. PMID- 22210433 TI - Radiotherapy is the best treatment method in post transplant lymphoproliferative disorders localizing in brain: a review of the literature. AB - BACKGROUND: Localization of post transplant lymphoproliferative disorders (PTLD) in the central nervous system (CNS) is a rare but life-threatening complication of transplantation. In the current study, we sought to aggregate data of PTLD in the series existing in the literatures on brain localization of PTLD and to concentrate on the management methods of the disease to compare and find the best treatment strategies in these patients. MATERIAL/METHODS: We conducted a thorough search of the literature to find treatment strategies employed to manage CNS involvement by PTLD. Data were pooled and standardized and reanalyzed. RESULTS: Overall 79 patients with CNS PTLD were entered into analysis. Patients undergone radiotherapy represented a significant superior outcome compared to that of patients who had not received radiotherapy (p<0.05). other treatment strategies had no significant impact on the survival (p>0.2 for all). One and five years survival rates for CNS involved PTLD patients who underwent radiotherapy were 71% and 37%, respectively; compared to 41% and 28%, respectively, for the control group. CONCLUSIONS: In the current study, we found that radiotherapy is an effective method of treatment for organ recipients who develop PTLD within central nervous system during their post transplant period. No beneficial effect for chemotherapy, interferon alfa, or a combination of them with radiotherapy was detected. We recommend using radiotherapy in all transplant patients developing CNS PTLD. PMID- 22210434 TI - Microchimerism after pancreas and kidney transplantation--a review. AB - The main cause of a negative response to grafting is immune rejection connected with a reaction to the donor's antigens. The process of rejecting transplanted organs is a whole-body process. The reaction of the organism begins when the donor's antigens reach the recipient's lymphatic organs via blood or lymph. The donor's genetic material (DNA) is detected in the recipient's blood and lymphoid tissues even a few months after transplant rejection. Microchimerism occurs when in an individual patient the cells and genetic material from both the donor and recipient are present and the cell count of one of these is overrepresented. Such situations can occur after blood transfusions, grafts or pregnancies. It is suggested that this phenomenon could have an influence on tolerance, prolonged graft survival or the rejection process. The results of many experiments are thus far equivocal; therefore further research is needed elucidate the process and mechanisms of graft rejection and its molecular aspects. PMID- 22210435 TI - Enhanced activity of linezolid against Staphylococcus aureus in cerebrospinal fluid. AB - Linezolid is considered for treatment of central nervous system (CNS) infections caused by multidrug-resistant Gram-positive bacteria. Therefore, the influence of cerebrospinal fluid (CSF) on the antimicrobial activity of linezolid was evaluated in vitro. Time-kill curves were conducted in CSF and Mueller-Hinton broth (MHB) using Staphylococcus aureus (ATCC 29213) and Staphylococcus epidermidis (ATCC 12228) strains. In CSF lower linezolid concentrations were needed against S. aureus (1* MIC) and S. epidermidis (0.5* MIC) to achieve bacteriostasis than in MHB (4* MIC for both strains). Good activity of linezolid in CSF supports performance of clinical trials evaluating its potential for treatment of CNS infections. PMID- 22210436 TI - Down-modulation of TNFSF15 in ovarian cancer by VEGF and MCP-1 is a pre-requisite for tumor neovascularization. AB - Persistent inflammation and neovascularization are critical to cancer development. In addition to upregulation of positive control mechanisms such as overexpression of angiogenic and inflammatory factors in the cancer microenvironment, loss of otherwise normally functioning negative control mechanisms is likely to be an important attribute. Insights into the down modulation of such negative control mechanisms remain largely unclear, however. We show here that tumor necrosis factor superfamily-15 (TNFSF15), an endogenous inhibitor of neovascularization, is a critical component of the negative control mechanism that operates in normal ovary but is missing in ovarian cancer. We show in clinical settings that TNFSF15 is present prominently in the vasculature of normal ovary but diminishes in ovarian cancer as the disease progresses. Vascular endothelial growth factor (VEGF) produced by cancer cells and monocyte chemotactic protein-1 (MCP-1) produced mainly by tumor-infiltrating macrophages and regulatory T cells effectively inhibits TNFSF15 production by endothelial cells in vitro. Using a mouse syngeneic tumor model, we demonstrate that silencing TNFSF15 by topical shRNA treatments prior to and following mouse ovarian cancer ID8 cell inoculation greatly facilitates angiogenesis and tumor growth, whereas systemic application of recombinant TNFSF15 inhibits angiogenesis and tumor growth. Our findings indicate that downregulation of TNFSF15 by cancer cells and tumor infiltrating macrophages and lymphocytes is a pre-requisite for tumor neovascularization. PMID- 22210437 TI - Safety of cardiac surgery for patients with cirrhosis and Child-Pugh scores less than 8. AB - BACKGROUND & AIMS: Advanced liver disease is a significant risk factor for perioperative complications after cardiac surgery. However, no published studies have adjusted the observed outcomes for other well-known, non-liver-related factors that affect mortality. We evaluated the effects of cirrhosis on operative mortality and morbidity after cardiac surgery, after adjusting for nonrelated risk factors associated with liver disease. METHODS: We analyzed data from patients with cirrhosis who underwent cardiac surgery with cardiopulmonary bypass from 1992 to 2009 (n = 54). Patients who underwent cardiac surgery at the same institution were identified during the same time period and matched 1:4 by using propensity score matching (controls, n = 216). Child-Pugh (CP) class and score were calculated for the patients with cirrhosis. Mortality and morbidity were determined after 30 and 90 days. RESULTS: Within 90 days, 4.6% of patients with CP score <8 and 70% of patients with CP score >= 8 died (P < .017). Mortality of patients with CP score <8 was comparable to that of matched controls. Patients with CP scores <8 had significantly shorter average length of hospital stay (15.6 vs 26 days; P < .017) and were less likely to develop renal failure (P < .017) and require dialysis (P < .017) than patients with CP scores >= 8; these values were similar between patients with CP scores <8 and their matched controls. CONCLUSIONS: After adjusting for non-liver-related risk factors, patients with compensated cirrhosis (defined by CP score <8) can undergo cardiac surgery with cardiopulmonary bypass with no significant increases in postoperative mortality and morbidity. For this group of patients, comorbidities, rather than liver failure, appear to account for the occasional death. PMID- 22210438 TI - The clinical relevance of the increasing incidence of intraductal papillary mucinous neoplasm. AB - BACKGROUND & AIMS: The incidence of intraductal papillary mucinous neoplasm (IPMN) is believed to be increasing; we investigated whether this is the result of increasing burden of disease or more diagnostic scrutiny. METHODS: In a retrospective cohort study, we calculated a trend in reported incidence of IPMN using data collected from Olmsted County, Minnesota, from 1985 to 2005. Total IPMN cases from the Olmsted database were identified through a keyword and International Classification of Diseases, 9th revision, search using a database from the Rochester Epidemiology Project, with all cases verified by subsequent chart review. The subsequent rate of IPMN-related carcinoma was calculated using data from the national Surveillance Epidemiology and End Results-9 database, reflecting trends from 1982 to 2007. Cases of IPMN-related carcinoma were identified in the Surveillance Epidemiology and End Results-9 database by limiting the search to histology codes for noninvasive and invasive IPMN. RESULTS: Between 1985 and 2005, there was a 14-fold increase in the age- and sex adjusted incidence of IPMN, from 0.31 to 4.35 per 100,000 persons. From 2000 to 2001, the rate of reported carcinoma increased from 0.008 to 0.032 per 100,000 persons, but stabilized afterward, with a rate of 0.06 per 100,000 persons in 2007. Mortality from all causes of pancreatic cancer was stable between 1975 and 2007 (approximately 11 deaths per 100,000 individuals). CONCLUSIONS: The incidence of IPMN has increased in the absence of an increase in IPMN-related or overall pancreatic cancer-related mortality, so it likely results from an increase in diagnostic scrutiny, rather than greater numbers of patients with clinically relevant disease. PMID- 22210439 TI - In vitro and in vivo efficacy of tribendimidine and its metabolites alone and in combination against the hookworms Heligmosomoides bakeri and Ancylostoma ceylanicum. AB - Worldwide, 3 billion people are at risk of hookworm infection, particularly in resource-poor countries. While control of soil-transmitted helminthiases relies mostly on chemotherapy, only few drugs are available and concern about potential emergence of drug resistance is rising. In the present study, tribendimidine, a derivative of amidantel, and its metabolites deacylated amidantel (dADT) and acetylated deacylated amidantel (AdADT) were tested in vitro and in vivo against Heligmosomoides bakeri and Ancylostoma ceylanicum, two hookworm rodent models, alone or in combination with standard drugs. Tribendimidine achieved IC(50)s <= 5 MUg/ml against both H. bakeri third-stage larvae and adults in vitro and a single 2 mg/kg oral dose resulted in complete worm elimination in vivo. Comparable results were obtained with dADT, whereas AdADT displayed no effect in vitro and gave a moderate worm burden reduction of 42.9% in H. bakeri-infected mice. Tribendimidine combined with albendazole, levamisole or ivermectin revealed antagonistic interactions against H. bakeri in vitro and no significant killing effect in vivo. Tribendimidine and dADT exerted high efficacies against A. ceylanicum third-stage larvae (IC(50)s < 0.5 MUg/ml) whereas adults were moderately affected in vitro (IC(50)s > 88 MUg/ml). In vivo at single oral doses of 10 mg/kg, dADT showed a slightly higher efficacy than tribendimidine, achieving worm burden reductions of 87.4% and 74.8%, respectively. At the same dose, AdADT reduced the worm burden by 57.9%. Synergistic interactions were observed with tribendimidine-levamisole combinations against A. ceylanicum in vitro (combination index at IC(50)=0.5), and in vivo (combination index at ED(90)=0.19). In conclusion, tribendimidine and dADT show potent anti-hookworm properties. The potential of the promising tribendimidine-levamisole combination should be investigated in greater detail. PMID- 22210440 TI - Dispersion capacity of Triatoma sherlocki, Triatoma juazeirensis and laboratory bred hybrids. AB - Flight dispersion is recognized as one of the most important mechanisms for triatomine house infestation. Triatoma sherlocki and T. juazeirensis are closely related species that occur within the same ecotope and their possible reproductive boundaries are unknown. T. sherlocki has shorter wings than T. juazeirensis; a characteristic that possibly implies in reduced flight dispersion, however, this species has been found to invade and colonize homes in Bahia, Brazil. Here, we tested the flight potential of T. sherlocki, compared to that of T. juazeirensis and laboratory-bred hybrids. Insects were kept in an apparatus designed to distinguish flyers from nonflyers. Fifty-one and 53% of T. juazeirensis and hybrids were flyers respectively, whereas no T. sherlocki were recorded to fly. Morphometric analysis of the main structures associated with the locomotor abilities showed that hybrids exhibited intermediate size for most of characters. The width of pronotum of both hybrids and T. juazeirensis was significantly larger than T. sherlocki. We suggested that lack of flight ability of T. sherlocki is possibly a result of reduced wing size and distinct shape, combined with undeveloped flight muscles in a shorter thoracic box. The mobility of T. sherlocki might be compensated by its significantly longer legs, and may possibly increase its ability to invade human dwellings by active dispersion. What is more, this study showed that hybrids between T. sherloki and T. juazeirensis have intermediate morphological characters that may give them higher fitness than their parents, and thus may advance the process of house infestation by either fight or walking in case of an eventual natural hybridization. PMID- 22210441 TI - Effects of 18beta-Glycyrrhetinic acid in hTNFtg mice - a model of rheumatoid arthritis. AB - INTRODUCTION: Rheumatoid arthritis is a chronic autoimmune disease characterised by inflammation of joints with cartilage and bone destruction leading to progressive disability. While the cause of rheumatoid arthritis is not known and the disease cannot be cured, conventional disease modifying antirheumatic drugs and biologicals are effective treatments for many patients. However, new therapies are needed in order to achieve better relief from rheumatoid arthritis symptoms than currently possible and to fully prevent joint damage. 18beta Glycyrrhetinic acid is not only used frequently in traditional Chinese medicine, but has been reported to target some of the inflammatory mediators involved in the pathogenesis of rheumatoid arthritis. Moreover, it has been reported that liquorice, which contains high levels of 18beta-Glycyrrhetinic acid, reduces inflammation and articular damage in collagen induced arthritis. Therefore, we studied the effects of 18beta-Glycyrrhetinic acid in a Tumor necrosis factor (TNF) dependent mouse model of rheumatoid arthritis. MATERIAL AND METHODS: HTNFtg mice were treated with 18beta-Glycyrrhetinic acid from day 28 after birth every second or third day for 2 weeks, or 3 times a week for six weeks. TNF inhibitor treated animals served as positive control. RESULTS: Clinical scores of arthritis were not altered in animals treated with 18beta-Glycyrrhetinic acid compared to placebo treated animals. Histological data also indicate no effects of 18beta Glycyrrhetinic acid on inflammatory joint destruction. TNF inhibitors, however markedly reduced not only clinical signs of TNF triggered joint inflammation but also histological signs of erosive disease. Therefore, in contrast to previous reports our data indicate that 18beta-Glycyrrhetinic acid does not provide a new therapeutic option for treating patients with rheumatoid arthritis. PMID- 22210442 TI - Ectopic pregnancies with unusual location and an angular pregnancy: Report of eight cases. AB - OBJECTIVE: The increased use of assisted reproduction techniques has been accompanied by an increase in ectopic pregnancies with unusual location being associated with significant maternal morbidity and mortality. This article reports on seven cases of ectopic pregnancies with unusual location and an angular pregnancy. Diagnostic and therapeutic strategies are discussed and a brief review of literature is presented. STUDY DESIGN: Case series of seven cases with ectopic pregnancy in unusual location, following assisted reproductive technique or conceived spontaneously (cesarean scar pregnancy and early abdominal pregnancy in mesoappendix) and an angular pregnancy, having presented at our hospital during the last eight years. Retrospective analyses. RESULTS: Interstitial pregnancy, cornual pregnancy, cesarean scar pregnancy, early abdominal pregnancy in omentum majus, heterotopic (cervical) pregnancy, early abdominal pregnancy in mesoappendix, angular pregnancy. All patients were surgically treated. CONCLUSION: Diagnosis of ectopic pregnancy with unusual location may be difficult, and differentiation of intact intrauterine or extrauterine pregnancy with adequate consideration of the area of uterine ostium of the fallopian tube may be delicate. Moreover, varying treatment strategies and high rates of complications aggravate the situation. PMID- 22210443 TI - Immigration disparities in cardiovascular disease risk factor awareness. AB - The association between immigration status and cardiovascular disease (CVD) risk factor awareness is unknown. Using physical examination-based data and participants' self-report of prior diagnosis, we assessed immigration-based disparities in awareness of diabetes, hypertension, hypercholesterolemia, and overweight among 12,124 participants in the 2003-2008 National Health and Nutrition Examination Survey. Unawareness of CVD risk factors is high among all groups, but tends to be higher among foreign-born English and non-English speaking participants than among US-born participants. After adjusting for demographic factors and access to health care, foreign-born participants appear more likely to be unaware of their hypertension and overweight than US-born participants. Immigrants are more likely than those born in the US to be unaware of their CVD risk factors, and therefore may be less motivated to seek treatment and modify their behavior to prevent negative CVD outcomes. PMID- 22210445 TI - Inhibitory effects and mechanisms of Hydrilla verticillata (Linn.f.) Royle extracts on freshwater algae. AB - To pursue an effective way to control freshwater algae, four extracts from a submerged macrophyte Hydrilla verticillata (Linn.f.) Royle were tested to study its inhibitory effects on Anabaena flos-aquae FACHB-245 and Chlorella pyrenoidosa Chick FACHB-9. Extract with the highest inhibiting ability was further studied in order to reveal the inhibitory mechanism. The results demonstrated that H. verticillata extracts inhibited the growth of A. flos-aquae and C. pyrenoidosa, and methanol extract had the highest inhibiting ability. The mechanism underlying the algal growth inhibition involves the superoxide anion radical generation that induces the damage of cell wall and release of intracellular components. PMID- 22210446 TI - Pesticide residues in tomatoes from greenhouses in Souss Massa Valley, Morocco. AB - Eight pesticide residues in tomato samples collected in the area of Souss Massa Valley (Southern Morocco) were analyzed. The detected residue levels ranged from 0.001 to 0.400 mg kg(-1) for dicofol, from 0.003 to 0.170 mg kg(-1) for procymidone, from 0.001 to 0.250 mg kg(-1) for chlorothalonil, from 0.050 to 0.500 mg kg(-1) for bifenthrin, from 0.001 to 0.010 mg kg(-1) for lambda cyhalothrin, from 0.001 to 0.300 mg kg(-1) for cypermethrin, from 0.010 to 1 mg kg(-1) for deltamethrin and from 0.003 to 1.123 mg kg(-1) for endosulfan. European MRL for endosulfan in tomatoes set in 0.500 mg kg(-1), was exceeded in 8 samples, and MRL for deltamethrin set in 0.300 mg kg(-1) for tomatoes was exceeded in 2 samples. PMID- 22210444 TI - PCB153 reduces telomerase activity and telomere length in immortalized human skin keratinocytes (HaCaT) but not in human foreskin keratinocytes (NFK). AB - Polychlorinated biphenyls (PCBs), ubiquitous environmental pollutants, are characterized by long term-persistence in the environment, bioaccumulation, and biomagnification in the food chain. Exposure to PCBs may cause various diseases, affecting many cellular processes. Deregulation of the telomerase and the telomere complex leads to several biological disorders. We investigated the hypothesis that PCB153 modulates telomerase activity, telomeres and reactive oxygen species resulting in the deregulation of cell growth. Exponentially growing immortal human skin keratinocytes (HaCaT) and normal human foreskin keratinocytes (NFK) were incubated with PCB153 for 48 and 24days, respectively, and telomerase activity, telomere length, superoxide level, cell growth, and cell cycle distribution were determined. In HaCaT cells exposure to PCB153 significantly reduced telomerase activity, telomere length, cell growth and increased intracellular superoxide levels from day 6 to day 48, suggesting that superoxide may be one of the factors regulating telomerase activity, telomere length and cell growth compared to untreated control cells. Results with NFK cells showed no shortening of telomere length but reduced cell growth and increased superoxide levels in PCB153-treated cells compared to untreated controls. As expected, basal levels of telomerase activity were almost undetectable, which made a quantitative comparison of treated and control groups impossible. The significant down regulation of telomerase activity and reduction of telomere length by PCB153 in HaCaT cells suggest that any cell type with significant telomerase activity, like stem cells, may be at risk of premature telomere shortening with potential adverse health effects for the affected organism. PMID- 22210447 TI - Mercury concentrations in commercial fish from freshwater and saltwater. AB - Research was performed to investigate the concentration of mercury in muscle and liver of fish species from freshwater (Barbus xanthopterus, Barbus grypus, Liza abu) and saltwater (Cynoglossus arel, Periophthalmus waltoni, Otolithes ruber) in Khouzestan, Iran. In freshwater fish, muscle was polluted in comparison with liver except for Barbus xanthopterus which high levels of mercury were measured in liver. In saltwater fish liver was contaminated than muscle except for Cynoglossus arel which high level of mercury was found in muscle. Significant variations in metal values were evaluated using student's t test at P < 0.05. Mercury concentrations were well above the permissible limits suggested by WHO and FDA guidelines. PMID- 22210448 TI - Steroids excreted in urine by neonates with 21-hydroxylase deficiency. 2. Characterization, using GC-MS and GC-MS/MS, of pregnanes and pregnenes with an oxo- group on the A- or B-ring. AB - Urine from neonates with 21-hydroxylase deficiency contains a large range of metabolites of 17-hydroxyprogesterone, 21-deoxycortisol and androgens but few have been previously described. We present the second part of a comprehensive project to characterize and identify these in order to enhance diagnosis and to further elucidate neonatal steroid metabolism. Steroids were analyzed, after extraction and enzymatic conjugate hydrolysis, as methyloxime-trimethylsilyl ether derivatives on gas-chromatographs coupled to quadrupole and ion-trap mass spectrometers. GC-MS and GC-MS/MS spectra were used together to determine the structure of the A- and B-rings containing an oxo group. Fragmentations indicating presence of 3-, 6-, and 7-oxo groups and also 1beta-, 2alpha-, 4beta-, and 6beta-hydroxyls are presented and discussed for the first time. Interpretation was aided by comparison with spectra of available relevant standards, of oxidation products of standards and urinary metabolites and of deuterated derivatives. Endogenous 1-enes and 2(3)-ene artifacts of non hydrolyzed 3alpha-sulfates are also reported. D-ring and side chain structure was determined according to our previously published criteria. Likely metabolic relationships were also explored. We conclude that GC-MS combined with GC-MS/MS allows identification of the A- and B-ring structure of pregnane and pregnenes in the presence of an oxo group on one of these rings. Major oxygenations are 1beta, 15beta, 16alpha and 21-hydroxy and 6- and 7-oxo groups. Minor positions of hydroxylation are those at 2alpha, 4beta and 6beta. Three major metabolic streams exist in affected neonates in addition to the classical 3alpha-hydroxy-5beta pregnane pathway, i.e. these of the 3-oxo-4-enes as well as 3alpha- and 3beta hydroxy-5alpha-anes. PMID- 22210449 TI - Subchronic toxicity and genotoxicity of diiodomethyl-p-tolylsulfone (DIMPTS) in laboratory animals. AB - These studies were conducted to determine subchronic toxicity and genotoxicity of the biocide diiodomethyl-p-tolysulfone (DIMPTS) in rats and dogs. Male and female Sprague-Dawley rats and Beagle dogs were administered DIMPTS for 90-days via the diet at 0, 5, 20, and 80 mg/kg/day to rats and via capsules at 0, 2, 10, and 60 mg/kg/day to dogs. In rats, the only treatment-related finding was squamous metaplasia of the salivary gland duct in the 80 mg/kg/day group. In dogs, female body weights in the high-dose group were significantly lower than controls. Altered clinical pathology parameters were considered secondary to inflammatory changes observed in some of the dogs. Treatment-related alterations were found in the thyroid glands, salivary glands, GI-tract in the mid- and/or high-dose groups. DIMPTS was negative in the four in vitro and one in vivo genotoxicity assays. The toxicological effects noted in the two mammalian species are consistent with the principal toxic effects of iodine, and are proposed to arise from release of iodide from the DIMPTS molecule with toxic sequelae. PMID- 22210450 TI - A nonclinical safety and pharmacokinetic evaluation of N6022: a first-in-class S nitrosoglutathione reductase inhibitor for the treatment of asthma. AB - S-nitrosoglutathione reductase is the primary enzyme responsible for the metabolism of S-nitrosoglutathione (GSNO), the body's main source of bioavailable nitric oxide. Through its catabolic activity, GSNO reductase (GSNOR) plays a central role in regulating endogenous S-nitrosothiol levels and protein S nitrosation-based signaling. By inhibiting GSNOR, we aim to increase pulmonary GSNO and induce bronchodilation while reducing inflammation in lung diseases such as asthma. To support the clinical development of N6022, a first-in-class GSNOR inhibitor, a 14-day toxicology study was conducted. Sprague-Dawley rats were given 2, 10 or 50 mg/kg/day N6022 via IV administration. N6022 was well tolerated at all doses and no biologically significant adverse findings were noted in the study up to 10 mg/kg/day. N6022-related study findings were limited to the high dose group. One male rat had mild hepatocellular necrosis with accompanying increases in ALT and AST and several male animals had histological lung assessments with a slight increase in foreign body granulomas. Systemic exposure was greater in males than females and saturation of plasma clearance was observed in both sexes in the high dose group. Liver was identified as the major organ of elimination. Mechanistic studies showed dose-dependent effects on the integrity of a rat hepatoma cell line. PMID- 22210451 TI - Improved bonding of zirconia substructures to resin using a "glaze-on" technique. AB - OBJECTIVE: To investigate the influence of applying thin intermediary coatings of acid-etchable glasses on the shear bond strength between a methacrylate resin based cement and an yttria-stabilized zirconia dental ceramic substrate. METHODS: The upper and lower surfaces of 110 sintered yttria-stabilised tetragonal zirconia polycrystalline disc-shaped specimens were polished using sequential grades of Silicon Carbide, then air-abraded with 25 MUm diameter alumina particles. Specimens were randomly allocated to 11 groups (A-K) (n=10), group A acting as control. The upper surface of Group A specimens was subjected to a tribochemical coating regime (CoJet, 3M ESPE). Five glazing ceramics were applied and fired according to the manufacturer's recommended firing regime. The glaze was etched with 10% HF acid and all specimens coated with a silane primer. Two differing storage regimes were employed (wet storage vs thermocycling). Shear bond strength testing specimens were created by cementing resin-based composite cylinders to the centre of the prepared ceramic surface using Rely-X Unicem (3M ESPE) resin based cement. Shear bond strength testing was performed and load at failure recorded. RESULTS: A factorial analysis of variance at a 95% significance level demonstrated that all glazing techniques resulted in a significant increase in the shear bond strength compared with using the resin based cement alone (P<0.01), with the different glazing ceramics resulting in significant differences in mean shear bond strength (P=0.008). The differences were a function of the storage state (wet storage vs thermocycling (P=0.013)). CONCLUSION: The glazing techniques used in the current investigation resulted in a significantly enhanced shear bond stress to the resin based cement when compared with the current 'gold standard' - tribochemical coating. PMID- 22210452 TI - Telmisartan acts through the modulation of ACE-2/ANG 1-7/mas receptor in rats with dilated cardiomyopathy induced by experimental autoimmune myocarditis. AB - AIM: Recent findings have suggested that a therapeutic approach to amplify or stimulate the angiotensin-converting enzyme-2 [ACE-2]-angiotensin 1-7 [ANG 1-7] mas axis could provide protection against the development of cardiovascular diseases. We investigated the cardioprotective effects of telmisartan in rats with dilated cardiomyopathy [DCM] after experimental autoimmune myocarditis [EAM]. MAIN METHODS: DCM was elicited in Lewis rats by immunization with cardiac myosin, and twenty-eight days after immunization, the surviving Lewis rats were divided into two groups and treated with either telmisartan (10mg/kg/day) or vehicle. KEY FINDINGS: Telmisartan treatment effectively suppressed myocardial protein and mRNA expressions of inflammatory markers [CD68, iNOS, NF-kB, interleukin-1beta, interferon-gamma, monocyte chemotactic protein-1] in comparison to vehicle-treated rats. In contrast, myocardial protein levels of ACE 2 and ANG 1-7 mas receptor were upregulated in the telmisartan-treated group compared with vehicle-treated rats. Telmisartan treatment significantly reduced fibrosis and hypertrophy and their marker molecules [OPN, CTGF, TGF-beta1 and collagens I and III and atrial natriuretic peptide and GATA-4, respectively] compared with those of vehicle-treated rats. In addition, telmisartan treatment significantly lowered the protein expressions of NADPH oxidase subunits p47phox, p67phox, and superoxide production when compared with vehicle-treated rats. Telmisartan treatment significantly decreased the expression levels of mitogen activated protein kinase (MAPK) signaling molecules than with those of vehicle treated rats. Also, telmisartan treatment significantly improved LV systolic and diastolic function. SIGNIFICANCE: These results indicate that telmisartan treatment significantly improved LV function and ameliorated the progression of cardiac remodeling through the modulation of ACE-2/ANG 1-7/Mas receptor axis in rats with DCM after EAM. PMID- 22210453 TI - Metabolism of cholesterol, vitamin D3 and 20-hydroxyvitamin D3 incorporated into phospholipid vesicles by human CYP27A1. AB - CYP27A1 is a mitochondrial cytochrome P450 which can hydroxylate vitamin D3 and cholesterol at carbons 25 and 26, respectively. The product of vitamin D3 metabolism, 25-hydroxyvitamin D3, is the precursor to the biologically active hormone, 1alpha,25-dihydroxyvitamin D3. CYP27A1 is attached to the inner mitochondrial membrane and substrates appear to reach the active site through the membrane phase. We have therefore examined the ability of bacterially expressed and purified CYP27A1 to metabolize substrates incorporated into phospholipid vesicles which resemble the inner mitochondrial membrane. We also examined the ability of CYP27A1 to metabolize 20-hydroxyvitamin D3 (20(OH)D3), a novel non calcemic form of vitamin D derived from CYP11A1 action on vitamin D3 which has anti-proliferative activity on keratinocytes, leukemic and myeloid cells. CYP27A1 displayed high catalytic activity towards cholesterol with a turnover number (k(cat)) of 9.8 min(-1) and K(m) of 0.49 mol/mol phospholipid (510 MUM phospholipid). The K(m) value of vitamin D3 was similar for that of cholesterol, but the k(cat) was 4.5-fold lower. 20(OH)D3 was metabolized by CYP27A1 to two major products with a k(cat)/K(m) that was 2.5-fold higher than that for vitamin D3, suggesting that 20(OH)D3 could effectively compete with vitamin D3 for catalysis. NMR and mass spectrometric analyses revealed that the two major products were 20,25-dihydroxyvitamin D3 and 20,26-dihydroxyvitamin D3, in almost equal proportions. Thus, the presence of the 20-hydroxyl group on the vitamin D3 side chain enables it to be metabolized more efficiently than vitamin D3, with carbon 26 in addition to carbon 25 becoming a major site of hydroxylation. Our study reports the highest k(cat) for the 25-hydroxylation of vitamin D3 by any human cytochrome P450 suggesting that CYP27A1 might be an important contributor to the synthesis of 25-hydroxyvitamin D3, particularly in tissues where it is highly expressed. PMID- 22210457 TI - Recombination detection under evolutionary scenarios relevant to functional divergence. AB - Recombination can negatively impact methods designed to detect divergent gene function that rely on explicit knowledge of a gene tree. However, we know little about how recombination detection methods perform under evolutionary scenarios encountered in studies of functional molecular divergence. We use simulation to evaluate false positive rates for six recombination detection methods (GENECONV, MaxChi, Chimera, RDP, GARD-SBP, GARD-MBP) under evolutionary scenarios that might increase false positives. Broadly, these scenarios address: (i) asymmetric tree topology and sequence divergence, (ii) non-stationary codon bias and selection pressure, and (iii) positive selection. We also evaluate power to detect recombination under truly recombinant history. As with previous studies, we find that power increases with sequence divergence. However, we also find that accuracy to correctly infer the number of breakpoints is extremely low. When recombination is absent, increased sequence divergence leads to increased false positives. Furthermore, one method (GARD-SBP) is sensitive to tree shape, with higher false positive rates under an asymmetric tree topology. Somewhat surprisingly, all methods are robust to the simulated heterogeneity in codon bias, shifts in selection pressure and presence of positive selection. Based on these findings, we recommend that studies of functional divergence in systems where recombination is plausible can, and should, include a pre-test for recombination. Application of all methods to the core genome of Prochlorococcus reveals a substantial lack of concordance among results. Based on analysis of both real and simulated datasets we present some guidelines for the investigation of recombination in genes that may have experienced functional divergence. PMID- 22210459 TI - A "typodont" study of rate of orthodontic space closure: self-ligating systems vs. conventional systems. AB - AIM: The aim of this study was to compare the effectiveness of space closure of two bracket systems, self-ligating and conventional ones, considering two systems with the same design and prescription. The experimental model of this study aims to identify in general if one type of system is more suitable for planning the extractive therapy, without considering the clinical aspect necessary for an adequate orthodontic approach. METHODS: A resin maxilla without the first premolars was used to test the self-ligating and conventional brackets system. Space closure was achieved on 0.016x0.022" in stainless steel wires with nickel titanium coil springs 150 grams in strength and 10 mm in length. Two experiment settings have been prepared. The first setting was made bonding conventional bracket on the right side and self-ligating on the left; the last one was made bonding self-ligating bracket on the right side and conventional on the left. All measurements (runs) have been repeated seven times for both settings. RESULTS: During the closing phase of extraction spaces both systems are equable since there are no significant statistical differences (P=0.70). CONCLUSION: Our typodont model showed no significant difference in the efficiency of space closure between the self-ligating bracket and conventional bracket tied with stainless steel ligatures. PMID- 22210461 TI - An unusual presence of primary retention of permanent teeth in subject with hyperthyroidism. AB - To date neither the eruption mechanism nor the factors controlling eruption have been completely understood. Primary retention of permanent teeth is an isolated condition associated with a localized failure of eruption with no other identifiable local or systemic involvement. Multiple primary retention may be related to lack of eruptive force, rotation of tooth buds, syndromes and metabolic disorders. This article reports an unusual case of primary retention of permanent teeth inclusion in a 21-year-old woman with hyperthyroidism, diagnosed at 14 years of age. PMID- 22210460 TI - Nasolabial cyst: 18.5 year experience in a pathology laboratory. AB - AIM: This paper offers a survey of nasolabial cysts diagnosed at the Pathology Laboratory of the Universidade Federal dos Vales do Jequitinhonha e Mucuri (Brazil) over a period of 18.5 years, and a case report. METHODS: A retrospective study was carried out on biopsies performed at the Pathology Laboratory of the UFVJM School of Dentistry between January 1992 and July 2010. RESULTS: Among a total of 2730 histopathological exams of biopsies performed at the UFVJM Pathology Laboratory, 288 (10.54%) were different types of cysts, The prevalence of NLC was 0.29% (8 cases) in relation to the overall sample and 2.43% among all cysts. NLC only occurred in the female gender in the age group spanning from 25 to 62 years (mean: 40.00 years; standard deviation (SD): 13.48 years). The duration of evolution ranged from six to 18 months (mean: 12 months; SD: 3.79 months). The cysts were asymptomatic in 62.5% of cases. Cyst size ranged from 10 to 30 mm (mean: 16.86; SD: 8.00 mm). In six cases (75%), the radiographic exams were consistent with the final diagnosis, whereas there were no records of radiographic images in two cases (25%). Surgical excision was the treatment of choice for all cases. CONCLUSION: The characteristics of NLC, such as location, elevation of the nasal wing, disappearance of the nasolabial sulcus, nasal obstruction, floatation of the cyst and the presence of cystic liquid in the interior, are enough to suggest the diagnosis of this cyst. However, the confirmation of the diagnosis is performed through biopsy and histopathological analysis. PMID- 22210458 TI - The phylogenomic roots of modern biochemistry: origins of proteins, cofactors and protein biosynthesis. AB - The complexity of modern biochemistry developed gradually on early Earth as new molecules and structures populated the emerging cellular systems. Here, we generate a historical account of the gradual discovery of primordial proteins, cofactors, and molecular functions using phylogenomic information in the sequence of 420 genomes. We focus on structural and functional annotations of the 54 most ancient protein domains. We show how primordial functions are linked to folded structures and how their interaction with cofactors expanded the functional repertoire. We also reveal protocell membranes played a crucial role in early protein evolution and show translation started with RNA and thioester cofactor mediated aminoacylation. Our findings allow elaboration of an evolutionary model of early biochemistry that is firmly grounded in phylogenomic information and biochemical, biophysical, and structural knowledge. The model describes how primordial alpha-helical bundles stabilized membranes, how these were decorated by layered arrangements of beta-sheets and alpha-helices, and how these arrangements became globular. Ancient forms of aminoacyl-tRNA synthetase (aaRS) catalytic domains and ancient non-ribosomal protein synthetase (NRPS) modules gave rise to primordial protein synthesis and the ability to generate a code for specificity in their active sites. These structures diversified producing cofactor-binding molecular switches and barrel structures. Accretion of domains and molecules gave rise to modern aaRSs, NRPS, and ribosomal ensembles, first organized around novel emerging cofactors (tRNA and carrier proteins) and then more complex cofactor structures (rRNA). The model explains how the generation of protein structures acted as scaffold for nucleic acids and resulted in crystallization of modern translation. PMID- 22210462 TI - SET: simplified treatment of edentulous patients. AB - A new technique for making complete denture in a reduced number of clinical sessions maintaining high quality standards is described. This method has been named SET, acronymic for simplified edentulous treatment. SET is a flexible method that can be performed in one, or more sittings, to meet the patient's requirements and/or according to the dentist's preference. All the traditional principles in making complete denture are respected, but new and innovative materials have been designed, built, tested and set up: the multilayer impression tray (MIT) and the bone resorption compensating curve (BRCC). In the first sitting the clinician can obtain, without the need of a dental laboratory, all the clinical information necessary for processing and delivering the denture. PMID- 22210463 TI - Error potential detection during continuous movement of an artificial arm controlled by brain-computer interface. AB - Patients who benefit from Brain-Computer Interfaces (BCIs) may have difficulties to generate more than one distinct brain pattern which can be used to control applications. Other BCI issues are low performance, accuracy, and, depending on the type of BCI, a long preparation and/or training time. This study aims to show possible solutions. First, we used time-coded motor imagery (MI) with only one pattern. Second, we reduced the training time by recording only 20 trials of active MI to set up a BCI classifier. Third, we investigated a way to record error potentials (ErrPs) during continuous feedback. Ten subjects controlled an artificial arm by performing MI over target time periods between 1 and 4 s. The subsequent movement of this arm served as continuous feedback. Discrete events, which are required to elicit ErrPs, were added by mounting blinking LEDs on top of the continuously moving arm to indicate the future movements. Time epochs after these events were used to evaluate ErrPs offline. The achieved error rate for the arm movement was on average 26.9%. Obtained ErrPs looked similar to results from the previous studies dealing with error detection and the detection rate was above chance level which is a positive outcome and encourages further investigation. PMID- 22210464 TI - Bronchodilation induced by muscular contraction in spontaneously breathing rabbits: neural or mechanical? AB - The respective contribution of mechanical and neural mechanisms to the bronchodilation occurring during exercise is not fully identified in spontaneously breathing animals. The airway response to electrically induced muscular contractions (MC) was studied after vagal cold block in 9 spontaneously breathing rabbits. The forced oscillation respiratory system resistance (Rrs) was measured at vagal nerve temperatures 37 degrees C, 8 degrees C and 4 degrees C. Rrs was found to decrease significantly during MC in all conditions. The occasional occurrence of a deep breath was responsible for a sudden decrease in Rrs. However, when the deep breath was absent - after vagal cooling and in some experiments at 37 degrees C - the bronchodilation was frequently dissociated from the change in breathing pattern, most likely illustrating a neural mechanism. Altogether, while some bronchodilation may be ascribed to the mechanical stretching of the airways, Rrs decreasing with little change in breathing pattern is likely related to a reflex effect, possibly a sympathetic-borne mechanism. PMID- 22210465 TI - The impact of obstructive sleep apnea on homocysteine and carotid remodeling in metabolic syndrome. AB - Obstructive sleep apnea (OSA) and metabolic syndrome (MetS) are associated with increased cardiovascular morbidity and mortality. Increased homocysteine is suggested as an independent risk factor for atherosclerosis and cardiovascular disease but remains disputed in OSA. We assessed polysomnography, carotid intima media thickness (CIMT) and biology in 35 MetS patients, according to the presence (OSA+MetS; n=26) or the absence of OSA (MetS; n=9). In OSA+MetS patients, homocysteine levels were increased compared to MetS subjects (12.8 +/- 3.8 vs. 9.5 +/- 2.5 MUmol/L; P=0.026). In the whole population, homocysteine correlated with apnea-hypopnea index (AHI) (r=0.522; P=0.001) and CIMT (r=0.376; P=0.026). Homocysteine was negatively correlated with plasma thiols (r=-0.406; P=0.017) and positively with urinary 15-F2t-isoprostanes (r=0.347; P=0.044). Multivariate regression analysis revealed that AHI (beta=0.559; P<0.001) and urinary 15-F2t isoprostane (beta=0.310; P=0.018) were independently associated with homocysteine level. We conclude that homocysteine level was higher in MetS when associated with OSA and proportional to OSA severity. In this context, vascular remodeling appeared more severe and mediated by oxidative stress. PMID- 22210466 TI - The nucleus retroambiguus as possible site for inspiratory rhythm generation caudal to obex. AB - We investigated whether spinalized animals can produce inspiratory rhythm. We recorded spinal inspiratory phrenic (PNA) and cranial inspiratory hypoglossal (HNA) nerve activity in the perfused brainstem preparation of rat. Complete transverse transections were performed at 1.5 (pyramidal decussation) or 2mm (first cervical spinal segment) caudal to obex. Excitatory drive was enhanced by either extracellular potassium, hypercapnia or by stimulating arterial chemoreceptors. Caudal transections immediately eliminated descending network drive for PNA, while the cranial inspiratory HNA remained unaffected. After transection, PNA bursting remained sporadic even during enhanced excitatory drive. This implies, cervical spinal circuits lack intrinsic rhythmogenic capacity. Rostral transections also abolished PNA immediately. However, HNA also progressively lost its amplitude and rhythm. Chemoreceptor activation only triggered tonic, non-rhythmic HNA. Thus the integrity of ponto-medullary circuitry was maintained. Our results suggest that an area overlapping the caudal nucleus retroambiguus provides critical ascending input to the ponto-medullary respiratory network for inspiratory rhythm generation. PMID- 22210468 TI - p53 is correlated with low BMI negative progesterone receptor status and recurring disease in patients with endometrial cancer. AB - OBJECTIVE: P53 tumor suppressor gene plays a role in endometrial carcinogenesis. Former studies described correlations between p53 protein overexpression in endometrial cancer and prognostic factors, measured by immunohistochemistry. But data is still controversial. The aim of this study was to measure p53 and phospho p53 overexpression by Western blot and evaluate correlations between overexpression and prognostic and clinical factors. Phospho-p53 seems to be the functional p53 protein and was examined for the first time in endometrial cancer. METHODS: 40 patients with endometrial cancer were included in the study. A control group of 20 patients with normal endometrial tissue samples was used. Western blot was performed for detection of p53 and phospho-p53. Clinical and pathological parameters were obtained from medical records. Statistical analysis was performed using the log-rank test, the Mann-Whitney test for two independent groups and the Fisher's exact test for dichotomous groupings. RESULTS: In 17.5% of the patients with endometrial cancer a p53 overexpression could be evaluated. There was a correlation between a p53 overexpression and recurring disease (p: 0.014), a negative progesterone receptor status (p: 0.021) and a low BMI (p: 0.022). Only one of 40 patients had a phospho-p53 expression. CONCLUSION: Western blot is a valid method for the detection of p53 overexpression. As other authors described before, p53 overexpression seems to correlate with negative prognostic factors. The correlation between p53 overexpression and a low BMI may underline the relationship between p53 alterations and biological aggressive endometrial carcinomas. PMID- 22210467 TI - Incidence and factors associated with synchronous ovarian and endometrial cancer: a population-based case-control study. AB - OBJECTIVE: To estimate the incidence of synchronous endometrial cancer (EC) and ovarian cancer (OC) in the female population, among all women with EC, and in women under 50 years of age with EC, and to identify factors associated with synchronous EC/OC. METHODS: All cases of synchronous EC/OC and EC diagnosed in women residing in Olmsted County, Minnesota between 1/1/1945 and 12/31/2008 were identified. Incidence was estimated using the population denominator from decennial census data, corrected for hysterectomy prevalence. A case-control study using 15 identified cases (EC/OC) and 45 controls (EC alone) was performed. RESULTS: The incidence of synchronous EC/OC and EC (age-adjusted to the 2000 US female total and corrected for hysterectomy prevalence) in 1945-2008 was 0.88 and 30.3 per 100,000 person-years, respectively. Among women under 50 years of age, the corrected incidence of EC/OC and EC was 0.51 and 5.1 per 100,000 person years, respectively. Among all women with EC, 3.1% had a synchronous OC compared to 9.4% of women under 50 years of age with EC. Patients with synchronous EC/OC were more likely than those with EC alone to present with a pelvic mass (57.1% vs. 8.9%, p<0.001). Patients with EC alone were more likely to have used oral contraceptive pills (OCPs) than synchronous EC/OC cases (22.7% vs 0%; Odds ratio, 0.10; 95% CI, <0.01-0.87). CONCLUSION: Although the incidence of synchronous EC/OC in the general population is lower than previously reported, nearly 1 in 10 women diagnosed with EC under 50 years of age will have a synchronous OC. PMID- 22210469 TI - Surgical staging and adjuvant chemotherapy in the management of patients with adult granulosa cell tumors of the ovary. AB - OBJECTIVE: To analyze the role of surgical staging and adjuvant chemotherapy in patients with adult type granulosa cell tumor (GCT) of the ovary. METHODS: Patients were divided into those with early-stage (stages I-II, n=93) and advanced-stage (stages III-IV, n=13) GCT and analyzed separately in this retrospective study. RESULTS: Of the 93 patients with early-stage GCT, 30 were completely staged and 25 underwent lymph node dissection. After surgery, 17 patients received adjuvant chemotherapy with bleomycin/etoposide/cisplatin (BEP). None had lymph node metastasis. Completely staged patients had no recurrence or deaths. However, recurrences were observed in 9 of 63 patients (14.3%) who did not undergo complete staging, with four (6.3%) dying due to disease. The 5-year disease-free survival (DFS) rates of groups with and without complete staging were 100% and 84%, respectively (P=0.037). Adjuvant chemotherapy was not significantly associated with DFS (P=0.193). All patients with advanced-stage GCT underwent optimal cytoreduction and received adjuvant chemotherapy with BEP. None of the 6 patients who completed 6 cycles of BEP had recurrence, whereas 5 of the 7 patients (71.4%) who received fewer than 6 cycles of BEP had recurrences and 3 (42.9%) died due to disease. The 5-year DFS rates of these two groups were 100% and 50%, respectively (P=0.022), with cycles of chemotherapy being the only significant factor for DFS in patients with advanced-stage GCT. CONCLUSIONS: Complete surgical staging is recommended, but lymph node removal is not recommended for early-stage GCT. Optimal debulking followed by six cycles of BEP chemotherapy is recommended for advanced-stage GCT. PMID- 22210470 TI - The effect of a novel movement strategy in decreasing ACL risk factors in female adolescent soccer players. AB - There is a need to investigate the effect of specific movement strategies in reducing biomechanical risk factors for anterior cruciate ligament injury in young female athletes. The purpose of this study was (a) to determine the feasibility of implementing a novel movement strategy (Core-PAC) into a team warm up before soccer training based on subject compliance and integration of the Core PAC into the warm-up and (b) to determine whether the Core-PAC would improve peak knee flexion angles and peak abduction moments at the knee during a side cut (SC) and an unanticipated side cut (USC) before kicking a soccer ball, and a side hop (SH) task after immediate instruction and after a 4-week training program. A convenience sample of ten 14- to 16-year-old female soccer players were instructed in the Core-PAC immediately after baseline testing and during a training program consisting of a 20-minute warm-up, 2 times per week. The Core PAC was understood and accepted by the subjects and incorporated into their warm up activities with good compliance. After the immediate instruction, there were significant increases in peak knee flexion angles of a mean 6.4 degrees during the SC (p = 0.001), 3.5 degrees during the USC (p = 0.007), and 5.8 degrees during the SH (p < 0.001) tasks. Peak knee abduction moments decreased by a mean of 0.25 N.m.kg(-1) during the SC (p < 0.03), 0.17 N.m.kg(-1) during the USC (p = 0.05), and 0.27 N.m.kg(-1) during the SH (p = 0.04) tasks. After the 4-week training program, some individuals showed improvement. The results of this study suggest that the Core-PAC may be 1 method of modifying high-risk movements for ACL injury such as side cutting and single-leg landing. PMID- 22210471 TI - Concurrent validation of the OMNI-resistance exercise scale of perceived exertion with Thera-band resistance bands. AB - The concurrent validity of the OMNI-Resistance Exercise Scale (OMNI-RES) of perceived exertion for use with elastic bands was studied during isotonic resistance exercises. Twenty healthy, physically active subjects completed both familiarization and testing sessions. The criterion variables were myoelectric activity, recorded by electromyography, and heart rate, recorded by a heart rate monitor. The subjects performed 2 separate sets of 15 repetitions in each of the 2 testing sessions and for each of the exercises applied (i.e., frontal and lateral raises). One set was carried out with the separation between the hands gripping the elastic band allowing that 15 repetition maximum to be performed in the selected exercise, whereas the other set was carried out with the separation between hands at +50% of the previous grip. The perceived exertion rating for the active muscles and for the overall body, muscular activity, and heart rate were measured during the final repetition of each set. The results showed significant differences (p <= 0.001) in myoelectric activity, heart rate, and OMNI-RES scores between the low- and high-intensity sets and the intraclass correlation coefficient was 0.72-0.76. So it can be concluded that the OMNI-RES can be used for monitoring the intensity of exercises when elastic bands are used. This would allow the training stimulus dosage to be precisely controlled in both the session in progress and between different sessions, and allowing to differentiate between different levels of intensity according to the physical aptitudes and special physiological needs of the subjects. PMID- 22210472 TI - The effect of recovery strategies on contractile properties using tensiomyography and perceived muscle soreness in professional soccer players. AB - The capacity to recover from intense training and matches is considered an important determinant in soccer performance. At present, there is no consensus on the effect of posttraining recovery interventions on subsequent training session. The aim of this study was to determine the effectiveness of active (12 minutes of submaximal running and 8 minutes of static stretching) and passive recovery (20 minutes sit on a bench) interventions performed immediately after a training session on muscle contractile properties using tensiomyography (TMG) and perceived muscle soreness 24 hours after the training. During 2 experimental sessions, 31 professional soccer players participated in a randomized fully controlled trial design. The first session was designed to collect the player's TMG and muscle soreness measurements (pretest). After baseline measurements, the participants performed a standardized soccer training during which the heart rate (HR) and rating of perceived exertion (RPE) were recorded to evaluate the training load. At the end of training unit, all the players were randomly assigned to the active recovery group and the passive recovery group. A second experimental session was organized to obtain the posttest values. The players performed the same test, administered in the same order than in the first trial. The results showed that no differences between groups were observed in the HR and RPE. No significant effect because of recovery strategy was found on TMG parameters and perceived muscle soreness. PMID- 22210473 TI - Graft copolymers of ethyl methacrylate on waxy maize starch derivatives as novel excipients for matrix tablets: drug release and fronts movement kinetics. AB - A previous paper deals with the physicochemical and technological characterization of novel graft copolymers of ethyl methacrylate (EMA) on waxy maize starch (MS) and hydroxypropylstarch (MHS). The results obtained suggested the potential application of these copolymers as excipients for compressed non disintegrating matrix tablets. Therefore, the purpose of the present study was to investigate the mechanism governing drug release from matrix systems prepared with the new copolymers and anhydrous theophylline or diltiazem HCl as model drugs with different solubility. The influence of the carbohydrate nature, drying procedure and initial pore network on drug release kinetics was also evaluated. Drug release experiments were performed from free tablets. Radial drug release and fronts movement kinetics were also analysed, and several mathematical models were employed to ascertain the drug release mechanisms. The drug release markedly depends on the drug solubility and the carbohydrate nature but is practically not affected by the drying process and the initial matrix porosity. A faster drug release is observed for matrices containing diltiazem HCl compared with those containing anhydrous theophylline, in accordance with the higher drug solubility and the higher friability of diltiazem matrices. In fact, although diffusion is the prevailing drug release mechanism for all matrices, the erosion mechanism seems to have some contribution in several formulations containing diltiazem. A reduction in the surface exposed to the dissolution medium (radial release studies) leads to a decrease in the drug release rate, but the release mechanism is not essentially modified. The nearly constant erosion front movement confirms the behaviour of these systems as inert matrices where the drugs are released mainly by diffusion through the porous structure. PMID- 22210474 TI - The management of procedural pain at the Italian Centers of Pediatric Hematology Oncology: state-of-the-art and future directions. AB - PURPOSE: The quality of life of children with cancer can be affected by the experience of cancer-related pain, treatment-related pain, procedural pain, generalized pain, and long-term chronic pain, and the consequences may be permanent. Treatment-related pain and procedural pain are often reportedly the most painful experiences relating to their illness. Procedural pain treatment is therefore now considered essential. This multicenter survey investigated how procedural pain is managed at Italian Pediatric Hematology-Oncology Centers. METHODS: From April to October 2010, questionnaires were collected from the directors and/or referent of the Italian Centers of Pediatric Hematology-Oncology about the management of lumbar punctures, bone marrow aspirates, and biopsies. RESULTS: We received responses from 67% of the centers (which performed a total of 13,271 procedures per year). Fifty percent of the procedures were performed in the operating room. The sedation-analgesia was provided "almost always" for 84% of procedures. Non-pharmacological treatments were used in 55% of the centers. The specialist who practiced analgesia was the anesthetist in 83.3% of the cases. CONCLUSIONS: A nationwide multicentre survey has been conducted for the first time to verify the management of procedural pain in Pediatric Hematology-Oncology patients. The results indicate that many aspects in the management of procedural pain appear consistent with the international guidelines. Some problems still remain, including the inability to ensure adequate sedation-analgesia in all the patients--often due to the lack of adequate staff, the frequent use of the operating room, and an underdeveloped use of non-pharmacological therapies. PMID- 22210475 TI - Tridimensional assessment of adductor spasmodic dysphonia pre- and post-treatment with Botulinum toxin. AB - Spasmodic dysphonia voices form, in the same way as substitution voices, a particular category of dysphonia that seems not suited for a standardized basic multidimensional assessment protocol, like the one proposed by the European Laryngological Society. Thirty-three exhaustive analyses were performed on voices of 19 patients diagnosed with adductor spasmodic dysphonia (SD), before and after treatment with Botulinum toxin. The speech material consisted of 40 short sentences phonetically selected for constant voicing. Seven perceptual parameters (traditional and dedicated) were blindly rated by a panel of experienced clinicians. Nine acoustic measures (mainly based on voicing evidence and periodicity) were achieved by a special analysis program suited for strongly irregular signals and validated with synthesized deviant voices. Patients also filled in a VHI-questionnaire. Significant improvement is shown by all three approaches. The traditional GRB perceptual parameters appear to be adequate for these patients. Conversely, the special acoustic analysis program is successful in objectivating the improved regularity of vocal fold vibration: the basic jitter remains the most valuable parameter, when reliably quantified. The VHI is well suited for the voice-related quality of life. Nevertheless, when considering pre-therapy and post-therapy changes, the current study illustrates a complete lack of correlation between the perceptual, acoustic, and self-assessment dimensions. Assessment of SD-voices needs to be tridimensional. PMID- 22210476 TI - Repair of subtotal tympanic membrane perforation by ultrathin cartilage shield: evaluation of take rate and hearing result. AB - Our aim is to evaluate the function and take rate of 0.2 mm thickness cartilage shield for repair of subtotal tympanic membrane perforation by comparing it with full thickness cartilage and temporalis fascia. Repair of tympanic membrane was done in 85 patients with unilateral chronic otitis media with subtotal perforation. The patients were classified into three groups: group 'A' where 0.2 mm thickness cartilage graft was used, group 'B' repaired with full thickness cartilage graft and group 'C' where temporalis fascia graft was used. Over the follow-up period, we found that the graft take was complete with both partial and complete thickness cartilage grafts while it was not complete in fascia cases. On the other hand, there was marked improvement in hearing in cases repaired by fascia and partial thickness grafts as compared to hearing results of full thickness grafts. We concluded that 0.2 mm partial thickness cartilage graft is optimal in reconstruction of subtotal tympanic membrane perforation because it is excellent to obtain high take rate with good hearing results. PMID- 22210477 TI - The ostrich middle ear for developing an ideal ossicular replacement prosthesis. AB - The aim of the study was to investigate the validity of the avian middle ear model for researching the tympanoplasty mechanics. We studied the morphological details, acoustic transmission and quasi-static behavior of the ostrich tympano ossicular system. The stained specimens of the ostrich middle ear were examined under a light microscope. The sound transfer function and quasi-static performance of the ostrich middle ear were evaluated using laser Doppler vibrometry. The application of pressure to the tip of the extracolumella causes a buckling movement of the ossicle between the cartilaginous and bony parts. Histologically, the intracolumellar connection can be identified as a junction zone between bone and hyaline cartilage. Sound conduction through the human middle ear is less effective than it is through the ostrich middle ear. The greatest difference (35 dB) was observed in the low-frequency region. Because the extracolumella bends, the medial displacements of the eardrum were not fully transmitted to the footplate. The amplitude of the ostrich columella footplate quasi-static medial displacements significantly exceeded that of the human footplate in both intact and reconstructed middle ears. The ostrich middle ear is a suitable model for designing total ossicular replacement implants. The main protective mechanism in the ostrich middle ear under quasi-static stress is a buckling movement of the extracolumella. The total ossicular prostheses of the new generation should contain an elastic element that allows an adaptation to greater quasi-static eardrum movements. PMID- 22210478 TI - Decreased proteasomal activity causes age-related phenotypes and promotes the development of metabolic abnormalities. AB - The proteasome is a multicatalytic enzyme complex responsible for the degradation of both normal and damaged proteins. An age-related decline in proteasomal activity has been implicated in various age-related pathologies. The relevance of decreased proteasomal activity to aging and age-related diseases remains unclear, however, because suitable animal models are not available. In the present study, we established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity. Tg mice exhibited a shortened life span and developed age-related phenotypes. In Tg mice, polyubiquitinated and oxidized proteins accumulated, and the expression levels of cellular proteins such as Bcl-xL and RNase L were altered. When Tg mice were fed a high-fat diet, they developed more pronounced obesity and hepatic steatosis than did wild-type mice. Consistent with its role in lipid droplet formation, the expression of adipose differentiation related protein (ADRP) was elevated in the livers of Tg mice. Of note, obesity and hepatic steatosis induced by a high-fat diet were more pronounced in aged than in young wild-type mice, and aged wild-type mice had elevated levels of ADRP, suggesting that the metabolic abnormalities present in Tg mice mimic those in aged mice. Our results provide the first in vivo evidence that decreased proteasomal chymotrypsin-like activity affects longevity and aggravates age related metabolic disorders, such as obesity and hepatic steatosis. PMID- 22210480 TI - Host-derived TGFB1 deficiency suppresses lesion development in a mouse model of endometriosis. AB - Transforming growth factor-beta1 (TGFB1) is a multifunctional cytokine that is abundant in both endometriotic lesions and the peritoneal fluid in women with endometriosis. However, the role of TGFB1 in the development of endometriosis is as yet undefined. In the present study, we investigated the physiologic function of TGFB1 in endometriotic lesion development, using Tgfb1-null mutant mice on a background of severe combined immunodeficiency. Xenotransplantation of human eutopic endometrial tissue resulted in development of endometriosis-like lesions in 63% of ovariectomized estrogen-supplemented Tgfb1-null mutant mice and in 68% of wild-type control mice. Median lesion weight was reduced by 11-fold in Tgfb1 null mice compared with wild-type control mice, and the fraction of glandular epithelium in lesions from Tgfb1-null mice was reduced by 32% compared with that in control mice. In lesions from Tgfb1-null mice, the relative abundance of both macrophages and alpha-smooth muscle actin-positive myofibroblasts was reduced by 66% and 47%, respectively. Deficiency of TGFB1 neither altered the percentage of proliferating cells in the epithelial or stromal compartments of the lesions nor affected blood vessel density or vessel size. Observation of this study indicates that host-derived TGFB1 deficiency suppresses endometriotic lesion development and provides proof of principle that targeting TGFB1 signaling pathways in cells that support the survival of ectopic endometrium may be an effective therapeutic approach in women with endometriosis. PMID- 22210479 TI - The NF-kappaB subunit c-Rel stimulates cardiac hypertrophy and fibrosis. AB - Cardiac remodeling and hypertrophy are the pathological consequences of cardiovascular disease and are correlated with its associated mortality. Activity of the transcription factor NF-kappaB is increased in the diseased heart; however, our present understanding of how the individual subunits contribute to cardiovascular disease is limited. We assign a new role for the c-Rel subunit as a stimulator of cardiac hypertrophy and fibrosis. We discovered that c-Rel deficient mice have smaller hearts at birth, as well as during adulthood, and are protected from developing cardiac hypertrophy and fibrosis after chronic angiotensin infusion. Results of both gene expression and cross-linked chromatin immunoprecipitation assay analyses identified transcriptional activators of hypertrophy, myocyte enhancer family, Gata4, and Tbx proteins as Rel gene targets. We suggest that the p50 subunit could limit the prohypertrophic actions of c-Rel in the normal heart, because p50 overexpression in H9c2 cells repressed c-Rel levels and the absence of cardiac p50 was associated with increases in both c-Rel levels and cardiac hypertrophy. We report for the first time that c-Rel is highly expressed and confined to the nuclei of diseased adult human hearts but is restricted to the cytoplasm of normal cardiac tissues. We conclude that c-Rel dependent signaling is critical for both cardiac remodeling and hypertrophy. Targeting its activities could offer a novel therapeutic strategy to limit the effects of cardiac disease. PMID- 22210481 TI - Cognitive behavioral HIV risk reduction in those receiving psychiatric treatment: a clinical trial. AB - Among severely mentally ill (SMI) substance abusers, HIV rates are elevated and HIV risk reduction interventions have been shown to be less effective. An enhanced cognitive behavioral HIV risk reduction intervention (E-CB) for SMI was compared to a health promotion condition (HPC) in 222 psychiatric outpatients at 6 months postintervention. Compared to females, males in the E-CB improved on intention to practice safer sex and in condom use skills and in unprotected vaginal sex, but did not differ in HIV knowledge, perceived susceptibility, anxiety, condom attitudes, safer sex self-efficacy, unprotected vaginal sex acts, or sex partners. Across intervention groups, there were improvements in all areas except self-efficacy and number of partners. Risk reduction among SMI may be facilitated by increasing awareness of health related behaviors and HIV-targeted content. However, meaningful changes in critical risk reduction skills and intentions may require a more focused intervention and may vary by gender. PMID- 22210482 TI - Willingness of clinicians to integrate microbicides into HIV prevention practices in southern Africa. AB - The first vaginal microbicide was recently proven effective in clinical trials. We assessed the willingness of clinicians to integrate microbicides into HIV prevention practices in Southern Africa, where women face elevated HIV risks. We conducted in-depth interviews (n = 60) and nationally representative surveys (n = 1,444) in South Africa and Zimbabwe with nurses and physicians. Over half of clinicians (58%) were aware of microbicides, with physicians far more likely than nurses to be familiar. Clinicians, including those in rural areas, were generally willing to discuss microbicides, a female-initiated method less effective than the condom, particularly when condom use was unlikely (70%). Fewer would include microbicides while counseling adolescents (51%). Most clinicians (85%) thought their patients would use microbicides; greater clinician familiarity with microbicides was significant for support. Training for both nurses and physicians prior to introduction is critical, so they have sufficient knowledge and skills to offer a microbicide upon availability. PMID- 22210484 TI - WITHDRAWN: Characterization and antioxidant activities of an acidic polysaccharide from Camellia sinensis. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22210483 TI - Effects of efonidipine on the pharmacokinetics and pharmacodynamics of repaglinide: possible role of CYP3A4 and P-glycoprotein inhibition by efonidipine. AB - The purpose of this study was to investigate the effects of efonidipine on the pharmacokinetics and pharmacodynamics of repaglinide in rats. The pharmacokinetic parameters of repaglinide and blood glucose concentrations were also determined in rats after oral (0.5 mg/kg) and intravenous (0.2 mg/kg) administration of repaglinide to rats in the presence and absence of efonidipine (1 and 3 mg/kg). Efonidipine inhibited CYP3A4 activity with an IC(50) value of 0.08 MUM, and efonidipine significantly inhibited P-gp activity in a concentration-dependent manner. Compared to the oral control group, efonidipine significantly increased the area under the plasma concentration-time curve (AUC(0-infinity)) (P < 0.01 for 3 mg/kg) and the peak plasma concentration (C (max)) (P < 0.05 for 3 mg/kg) of repaglinide by 51.3 and 28.6%, respectively. Efonidipine also significantly (P < 0.01 for 3 mg/kg) increased the absolute bioavailability (AB) of repaglinide by 51.5% compared to the oral control group (33.6%). Moreover, efonidipine significantly increased (P < 0.05 for 3 mg/kg) the AUC(0-infinity) of intravenously administered repaglinide. Consistent with these kinetic alterations, the hypoglycemic effect in the concurrent administration group was more pronounced than that in the control group (i.e., repaglinide alone) when the drug was given orally. A pharmacokinetic/dynamic model involving 2-compartment open model with inhibition in absorption/elimination and an indirect response model was apparently sufficient in estimating the concentration-time and effect time profiles of repaglinide with or without efonidipine. Present study has raised the awareness of potential drug interactions by concomitant use of efonidipine with repaglinide, since efonidipine may alter the absorption and/or elimination of repaglinide by the inhibition of CYP3A4 and P-gp efflux pump. Therefore, the concurrent use of efonidipine with repaglinide may require a close monitoring for potential drug interactions. PMID- 22210485 TI - Biocompatibility and antimicrobial activity of poly(3-hydroxyoctanoate) grafted with vinylimidazole. AB - Vinylimidazole-grafted poly(3-hydroxyoctanoate) (VI-g-PHO) copolymers were prepared by heating homogeneous solutions of PHO, VI monomer, and benzoylperoxide initiator. The Fourier transform infrared spectroscopy attenuated total reflection and electron spectroscopy for chemical analyses showed that VI was successfully grafted onto the PHO chains. The surfaces and the bulk of VI-g-PHO copolymers became more hydrophilic as the VI grafting density in the copolymer increased. Measurements of the growth of Chinese hamster ovary cells and the adsorption of blood proteins and platelets in vitro showed that biocompatibility was also enhanced by grafting of VI groups. Antimicrobial activity of the VI-g PHO copolymers was studied against Escherichia coli, Staphylococcus aureus, and Candida albicans. Treatment of each culture suspension with 2.0% (w/v) copolymers for 12h resulted in >90% reduction in viable cell counts against all test microorganisms. These results indicate that the VI-g-PHO copolymers are promising materials for biomedical applications, as they exhibited both biocompatibility and broad spectrum antimicrobial activity. PMID- 22210486 TI - Evaluation of acetylated moth bean starch as a carrier for controlled drug delivery. AB - The present investigation concerns with the development of controlled release tablets of lamivudine using acetylated moth bean starch. The acetylated starch was synthesized with acetic anhydride in pyridine medium. The acetylated moth bean starch was tested for acute toxicity and drug-excipient compatibility study. The formulations were evaluated for physical characteristics like hardness, friability, % drug content and weight variations. The in vitro release study showed that the optimized formulation exhibited highest correlation (R) value in case of Higuchi kinetic model and the release mechanism study proved that the formulation showed a combination of diffusion and erosion process. There was a significant difference in the pharmacokinetic parameters (T(max), C(max), AUC, V(d), T(1/2) and MDT) of the optimized formulation as compared to the marketed conventional tablet Lamivir((r)), which proved controlled release potential of acetylated moth bean starch. PMID- 22210487 TI - Soy, phytoestrogens and their impact on reproductive health. AB - There is growing interest in the potential health threats posed by endocrine disrupting chemicals (EDCs) to the reproductive system. Soybean is the most important dietary source of isoflavones, an important class of phytoestrogen. While consumption of soy food or phytoestrogen supplements has been frequently associated with beneficial health effects, the potentially adverse effects on development, fertility, and the reproductive and endocrine systems are likely underappreciated. Here we review the available epidemiological, clinical and animal data on the effects of soy and phytoestrogens on the development and function of the male and female reproductive system, and weigh the evidence as to their detrimental impact. PMID- 22210489 TI - The anxiolytic effects of somatostatin following intra-septal and intra-amygdalar microinfusions are reversed by the selective sst2 antagonist PRL2903. AB - Somatostatin (SST) is a polypeptide with two biological isoforms (SST14, and SST28), and five SST receptor subtypes (sst1-5). Together, they mediate a number of neural and hormonal functions. Recently, we found that intracerebroventricular (ICV), intra-amygdalar, and intra-septal microinfusions of SST14, SST28, and a selective sst2 receptor agonist L-779976 all produced anxiolytic-like effects in the elevated plus-maze, a widely used animal model of anxiety. The receptor specificity of these anxiolytic-like effects, however, has not been conclusively established. Accordingly, the anxiolytic effects of SST in the elevated plus-maze were assessed following intra-septal or intra-amygalar microinfusions of 1) SST (1.5MUg per hemisphere), 2) the highly selective sst2 receptor antagonist PRL2903 (1.5MUg per hemisphere), or 3) the combination of SST and PRL2903 (each 1.5MUg per hemisphere). Antagonism of the anxiolytic effects of SST in the plus-maze by PRL2903 should result in open-arm exploration that is equivalent to that of 4) vehicle-injected control rats. Both intra-septal and intra-amygdalar microinfusions of SST produced anxiolytic effects in the elevated plus-maze, consistent with results found previously after ICV microinfusions (see Engin et al., 2008; Engin and Treit, 2009; Yeung et al., 2011). More importantly, infusion of PRL2903 completely reversed the anxiolytic effects of SST in both the amygdala and the septum. These results show that somatostatin's anxiolytic effects are mediated by sst2 receptors contained in the amygdala and septum of the rat brain. PMID- 22210488 TI - Reversal of scopolamine-induced disruption of prepulse inhibition by clozapine in mice. AB - Prepulse inhibition (PPI) of the acoustic startle reflex refers to the reduction of the startle response to an intense acoustic pulse stimulus when it is shortly preceded by a weak non-startling prepulse stimulus and provides a cross-species measure of sensory-motor gating. PPI is typically impaired in schizophrenia patients, and a similar impairment can be induced in rats by systemic scopolamine, a muscarinic cholinergic receptor antagonist that can evoke a range of cognitive and psychotic symptoms in healthy humans that are commonly referred to as the "anti-muscarinic syndrome" resembling some clinical features of schizophrenia. Scopolamine-induced PPI disruption has therefore been proposed as an anti-muscarinic animal model of schizophrenia, but parallel investigations in the mouse remain scant and the outcomes are mixed and often confounded by an elevation of startle reactivity. Here, we distinguished the PPI-disruptive and the confounding startle-enhancing effects of scopolamine (1 and 10mg/kg, i.p.) in C57BL/6 wild-type mice by showing that the latter partly stemmed from a shift in spontaneous baseline reactivity. With appropriate correction for between-group differences in startle reactivity, we went on to confirm that the PPI-disruptive effect of scopolamine could be nullified by clozapine pre-treatment (1.5mg/kg, i.p.) in a dose-dependent manner. This is the first demonstration that scopolamine-induced PPI disruption is sensitive to atypical antipsychotic drugs. In concert with previous data showing its sensitivity to haloperidol the present finding supports the predictive validity of the anti-muscarinic PPI disruption model for both typical and atypical antipsychotic drug action. PMID- 22210490 TI - Evidence for a role of inhibition of orexinergic neurons in the anxiolytic and sedative effects of diazepam: A c-Fos study. AB - The classical benzodiazepine diazepam (DZ) induces anxiolysis at low doses and sedation and hypnosis at higher doses. Different brain areas and neuronal populations most likely mediate these different behavioral effects. We used c-Fos immunohistochemistry as an indirect way to study neuronal activation or inhibition induced by DZ at anxiolytic and sedative doses (0.5 and 5mg/kg, respectively) in various brain areas involved in anxiety, arousal, sedation and addiction in C57BL/6J mice. We also focused on the two neuronal populations, orexinergic and dopaminergic neuronal populations, with the help of double immunohistochemistry using c-Fos and orexin-A antibodies and c-Fos and tyrosine hydroxylase antibodies. We found that different brain areas of unhabituated mice reacted differently to the mild stress induced by vehicle injection. Also the response to anxiolytic or sedative doses of DZ differed between the areas, suggesting that distinct brain areas mediate the behavioral effects of low and high DZ doses. Our findings propose a role for inhibition of orexin neurons in the anxiolytic and sleep-promoting effects of DZ. In addition, the activation of central amygdala neurons by DZ treatment was associated with anxiolytic and sedative effects. On the other hand, the ventral hippocampus, basolateral amygdala, ventral tegmental area and prefrontal cortex were sensitive even to the mild injection stress, but not to the anxiolytic dose of DZ. PMID- 22210491 TI - Functional characterization of a synthetic hydrophilic antifungal peptide derived from the marine snail Cenchritis muricatus. AB - Antimicrobial peptides have been found in mollusks and other sea animals. In this report, a crude extract of the marine snail Cenchritis muricatus was evaluated against human pathogens responsible for multiple deleterious effects and diseases. A peptide of 1485.26 Da was purified by reversed-phase HPLC and functionally characterized. This trypsinized peptide was sequenced by MS/MS technology, and a sequence (SRSELIVHQR), named Cm-p1 was recovered, chemically synthesized and functionally characterized. This peptide demonstrated the capacity to prevent the development of yeasts and filamentous fungi. Otherwise, Cm-p1 displayed no toxic effects against mammalian cells. Molecular modeling analyses showed that this peptide possible forms a single hydrophilic alpha-helix and the probable cationic residue involved in antifungal activity action is proposed. The data reported here demonstrate the importance of sea animals peptide discovery for biotechnological tools development that could be useful in solving human health and agribusiness problems. PMID- 22210492 TI - Unusual subcellular confinement of the fragile X mental retardation protein (FMRP) in circulating human platelets: complete polyribosome dissociation. AB - FMRP, a RNA-binding protein, was shown in association with polyribosomes in every cell types studied so far, suggesting a ubiquitous role as a translational regulator. Platelets are known for their limited protein synthesis potential. However, current investigations put forward that RNA metabolism is more developed than previously thought. Unexpectedly, our results provide evidence that FMRP, in platelets, is not constitutively associated with heavy particles, such as polyribosomes, and possesses a sedimentation coefficient of less than 10S contrasting with values of 150 to 500S as reported in other cell types. In summary, this report brings to light platelets as a simple human biological system to delineate novel FMRP functions as well as strengthening our comprehension of the pathophysiology of the fragile X syndrome which results from the absence of FMRP. PMID- 22210493 TI - Alkyl esters of hydroxycinnamic acids with improved antioxidant activity and lipophilicity protect PC12 cells against oxidative stress. AB - Hydroxycinnamic acids (HCAs) are phenolic compounds present in dietary plants, which possess considerable antioxidant activity. In order to increase the lipophilicity of HCAs, with the aim of improving their cellular absorption and expansion of their use in lipophilic media, methyl, ethyl, propyl and butyl esters of caffeic acid and ferulic acid have been synthesized. All caffeate esters had a slightly lower DPPH IC(50) (13.5-14.5 MUM) and higher ferric reducing antioxidant power (FRAP) values (1490-1588 mM quercetin/mole [mMQ/mole]) compared to caffeic acid (16.6 MUM and 1398 mMQ/mole, respectively) in antioxidant assays. In contrast, ferulate esters were less active in DPPH (56.3 74.7 MUM) and FRAP assays (193-262 mMQ/mole) compared to ferulic acid (44.6 MUM and 324 mMQ/mole, respectively). Redox properties of HCAs were in line with their antioxidant capacities, so that compounds with higher antioxidant activities had lower oxidation potentials. Measurement of partition coefficients disclosed the higher lipophilicity of the esters compared to parent compounds. All esters of caffeic acid significantly inhibited hydrogen peroxide-induced neuronal PC12 cell death assessed by MTT assay at 5 and 25 MUM. However, caffeic acid, ferulic acid and ferulate esters were not able to protect the cells. In conclusion, these findings suggest that alkyl esterification of some HCAs augments their antioxidant properties as well as their lipophilicity and as a consequence, improves their cell protective activity against oxidative stress. These compounds could have useful applications in conditions where oxidative stress plays a pathogenic role. PMID- 22210495 TI - Bystander normal human fibroblasts reduce damage response in radiation targeted cancer cells through intercellular ROS level modulation. AB - The radiation-induced bystander effect is a well-established phenomenon which results in damage in non-irradiated cells in response to signaling from irradiated cells. Since communication between irradiated and bystander cells could be reciprocal, we examined the mutual bystander response between irradiated cells and co-cultured with them non-irradiated recipients. Using a transwell culture system, irradiated human melanoma (Me45) cells were co-cultured with non irradiated Me45 cells or normal human dermal fibroblasts (NHDF) and vice versa. The frequency of micronuclei and of apoptosis, ROS level, and mitochondrial membrane potential were used as the endpoints. Irradiated Me45 and NHDF cells induced conventional bystander effects detected as modest increases of the frequency of micronuclei and apoptosis in both recipient neighbors; the increase of apoptosis was especially high in NHDF cells co-cultured with irradiated Me45 cells. However, the frequencies of micronuclei and apoptosis in irradiated Me45 cells co-cultured with NHDF cells were significantly reduced in comparison with those cultured alone. This protective effect was not observed when irradiated melanomas were co-cultured with non-irradiated cells of the same line, or when irradiated NHDF fibroblasts were co-cultured with bystander melanomas. The increase of micronuclei and apoptosis in irradiated Me45 cells was paralleled by an increase in the level of intracellular reactive oxygen species (ROS), which was reduced significantly when they were co-cultured for 24h with NHDF cells. A small but significant elevation of ROS level in NHDF cells shortly after irradiation was also reduced by co-culture with non-irradiated NHDF cells. We propose that in response to signals from irradiated cells, non-irradiated NHDF cells trigger rescue signals, whose nature remains to be elucidated, which modify the redox status in irradiated cells. This inverse bystander effect may potentially have implications in clinical radiotherapy. PMID- 22210494 TI - Solution structure of the N-terminal dsRBD of Drosophila ADAR and interaction studies with RNA. AB - Adenosine deaminases that act on RNA (ADAR) catalyze adenosine to inosine (A-to I) editing in double-stranded RNA (dsRNA) substrates. Inosine is read as guanosine by the translation machinery; therefore A-to-I editing events in coding sequences may result in recoding genetic information. Whereas vertebrates have two catalytically active enzymes, namely ADAR1 and ADAR2, Drosophila has a single ADAR protein (dADAR) related to ADAR2. The structural determinants controlling substrate recognition and editing of a specific adenosine within dsRNA substrates are only partially understood. Here, we report the solution structure of the N terminal dsRNA binding domain (dsRBD) of dADAR and use NMR chemical shift perturbations to identify the protein surface involved in RNA binding. Additionally, we show that Drosophila ADAR edits the R/G site in the mammalian GluR-2 pre-mRNA which is naturally modified by both ADAR1 and ADAR2. We then constructed a model showing how dADAR dsRBD1 binds to the GluR-2 R/G stem-loop. This model revealed that most side chains interacting with the RNA sugar phosphate backbone need only small displacement to adapt for dsRNA binding and are thus ready to bind to their dsRNA target. It also predicts that dADAR dsRBD1 would bind to dsRNA with less sequence specificity than dsRBDs of ADAR2. Altogether, this study gives new insights into dsRNA substrate recognition by Drosophila ADAR. PMID- 22210496 TI - Prevention of GVHD and graft rejection by a new S1P receptor agonist, W-061, in rat small bowel transplantation. AB - BACKGROUND: In small bowel transplantation (SBTx), inhibition of both graft versus-host disease (GVHD) and allograft rejection is necessary. METHODS: We investigated the potency of a new sphingosine-1-phosphate receptor agonist, W 061, for these two immune responses in SBTx. W-061 has a completely different molecular structure from FTY720. Heterotopic SBTx was performed from Wistar-Furth (WF) into (WF*ACI) F1 rats as a GVHD model or F1 to WF rats as a rejection model. Recipients were orally given 3 mg/kg/day W-061 for 14 days after SBTx. Recipient survival, body weight, histopathology, lymphocyte subpopulations, and the cytokine profile were evaluated. RESULTS: W-061 treatment significantly prolonged graft survival over 100 days in four out of six recipients in the GVHD group and over 60 days in three out of six recipients in the rejection group. W-061 strongly inhibited GVHD and rejection as seen histopathologically in comparison with untreated control rats. W-061 caused a significant reduction in donor derived T cells in target organs and infiltrating T cells in allografts by promoting these cells to home into the secondary lymphoid tissues and sequestrating those cells there. W-061 significantly decreased production of interferon-gamma in target organs and allografts. CONCLUSION: Therefore, these data suggest that W-061 has considerable potential as a new therapeutic immunosuppressant in patients with SBTx. PMID- 22210497 TI - The use of liposomes to differentiate between the effects of nickel accumulation and altered food quality in Daphnia magna exposed to dietary nickel. AB - A potential drawback of traditional dietary metal toxicity studies is that it is difficult to distinguish between the direct toxicity of the metal and indirect effects caused by altered concentrations of essential nutrients in the metal contaminated diet. In previous studies it has become clear that this can hamper the study of the real impact of dietary metal exposure and also complicates the analysis of the mechanisms of dietary metal toxicity in filter-feeding freshwater invertebrates like Daphnia magna. This problem has been partly circumvented by the production of liposomes, since these vectors are invulnerable to metal induced food quality shifts and as such can be applied to study the mechanisms of dietary metal toxicity without the confounding effect of nutritional quality shifts. The aim of current study was to evaluate if there is relevance for dietary Ni toxicity under natural exposures, i.e., when D. magna is exposed to dietary Ni via living algae, and secondly, to quantify how nutritional quality shifts contribute to the toxic effects that are observed when algae are used as contaminated food vectors. For this aim, liposomes were prepared by the hydration of phosphatidylcholine in media containing 0 (control), 10, 50, 100 and 500 mg Ni/L. The liposome particles were then mixed with uncontaminated green algae in a 1/10 ratio (on a dry wt basis) to make up diets with constant nutrient quality and varying Ni contents (i.e., 1.2 MUg Ni/g dry wt in the control and 18.7, 140.3, 165.0 and 501.6 MUg Ni/g dry wt in the Ni-contaminated diet, respectively). A second food type was prepared on the basis of a 1/10 mixture (on a dry weight basis) of control liposomes and Ni-contaminated algae, representing a diet that differed in Ni content (i.e., 1.2, 26.8, 84.7, 262.3 and 742.7 MUg Ni/g dry wt) and concentrations of essential nutrients (in terms of P and omega 3 poly-unsaturated fatty acids like eicosapentaenoic acid and alpha-linolenic acid). Both diets were then simultaneously fed to D. magna during a 21-day chronic bioassay, using reproduction, growth, survival, ingestion rate and Ni bioaccumulation as endpoints. Ni delivered by liposomes caused a significant inhibition of reproduction and growth when the metal accumulated to minimum levels of 11.9 and 20.0 MUg Ni/g dry wt after 7 and 14 days, respectively. Using algae as Ni vector, similar effects of dietary Ni exposure occurred when algae had been pre-exposed to concentrations of at least 133 MUg/L of bioavailable Ni (i.e., Ni2+), which is similar to the reproductive EC50 of waterborne Ni exposure for D. magna (115 MUg Ni2+/L). While this may have some consequences for predicting chronic Ni toxicity in this range of Ni concentrations with the biotic ligand model--which could be further improved by including the dietary toxicity pathway in this model, the occurrence of such high concentrations in the field is very rare. Hence, there seems to be very little environmental relevance for dietary Ni toxicity to D. magna. Finally, besides the direct effects of Ni there was no evidence that nutritional quality shifts could have affected daphnids' growth, but it is very likely that the impairment of reproduction at toxic exposure levels of Ni was also partly the result of reduced fatty acid levels. PMID- 22210498 TI - Enhanced offspring production in Daphnia magna clones exposed to serotonin reuptake inhibitors and 4-nonylphenol. Stage- and food-dependent effects. AB - Risk assessment of emerging pollutants requires the development of bioassays able to detect and understand novel mechanisms of action. This study tested the hypothesis that the increase of offspring production in Daphnia magna induced by certain pollutants may be mediated through different mechanisms, depending on development stages, clones and food rations The study included two selective serotonin reuptake inhibitors (SSRIs), fluoxetine and fluvoxamine, and the detergent metabolite 4-nonylphenol. Organisms were exposed from birth to adulthood or only during adulthood at low and high food ration levels. Results indicated that low exposure levels of the three studied substances increased offspring production and/or juvenile developmental rates similarly for all studied clones, but the responses differed among life-stages and food rations. When individuals were exposed to the studied chemicals from birth, enhanced offspring production per female was observed only at low and intermediate food rations. On the contrary, when exposures started in gravid females most treatments increased offspring production. Results obtained with SSRIs support previous findings, where it was stated that these compounds may amplify serotoninergic signaling in D. magna. Nonylphenol effects may be related to the reported alteration of this compound in Daphnia ecdysteroid metabolism. Further investigations are necessary to resolve the biochemical mechanism of SSRI and nonylphenol enhancing offspring production. PMID- 22210499 TI - Effects of copper on osmoregulation in sheepshead minnow, Cyprinodon variegatus acclimated to different salinities. AB - The sheepshead minnow, Cyprinodon variegatus is a euryhaline fish that inhabits estuaries and coastal marshes where it encounters a wide range of salinities. Many of these areas also have elevated levels of contaminants, creating the potential for toxic ions to interfere with the uptake of ions for osmoregulation. To determine whether the effect of copper on osmoregulatory activity is dependent on the osmotic conditions that individuals have been living at, fish were acclimated for 14 days to 2.5, 10.5 or 18.5 ppt seawater and then exposed to a fixed free cupric ion level (14.6 MUM Cu2+) for 6 h. Plasma Na, plasma Cl, wet/dry weight ratio, transepithelial potential difference (TEPD) and branchial Na(+)/K(+)-ATPase activity were determined before and after copper exposure. We also computed Na and Cl equilibrium potentials. Following the salinity acclimation (in fish not yet exposed to copper), fish from the low salinity group (2.5 ppt) had lower TEPD, lower plasma Na levels and higher branchial Na(+)/K(+) ATPase activity compared to the fish acclimated to higher salinities. No differences in plasma Cl and wet/dry weight ratio were detected. Copper exposure caused a significant decrease in plasma Na levels and Na(+)/K(+)-ATPase activity and an increase in wet/dry weight ratio, but these changes were limited to the 2.5 ppt salinity group. No significant changes in plasma Cl were detected. Copper treatment resulted in a small decrease in TEPD for all except the lowest salinity acclimation group. A comparison of equilibrium potentials with TEPD showed evidence of active transport of both Na and Cl in 2.5 ppt acclimated fish but not for the 10.5 or the 18.5 ppt acclimated fish. Our results show that effects of copper on osmoregulation are dependent on the fish' past salinity regime, and that these effects tend to be more pronounced for euryhaline fish that have been living under hyposmotic conditions. PMID- 22210500 TI - Structural and functional recovery of microbial biofilms after a decrease in copper exposure: influence of the presence of pristine communities. AB - The present study aimed at assessing the recovery of phototrophic and heterotrophic biofilm communities after a decrease in copper exposure. An original experiment was designed to evaluate the possible influence of non exposed (i.e. pristine) communities (e.g. via immigration processes) in recovery dynamics. Laboratory channels were used to study the structural and functional changes in microbial communities after a 4-week Cu exposure period in the presence and absence of pristine biofilms. When pristine biofilms were present, phototrophic communities recovered within 6 weeks, both in terms of biomass, structure and photosynthetic activity. Recovery processes were also detected using the PICT approach. In contrast, in the absence of pristine communities, all of the Cu-induced changes recorded in the phototrophic communities remained throughout the recovery period. Regardless of the presence or absence of pristine biofilms, the decrease in Cu exposure did not abolish Cu-induced changes in bacterial community structure, whereas functional recovery (based on beta glucosidase activity) was complete in both recovery contexts. These results revealed that microbial community response to a decrease in Cu exposure differs between phototrophic and heterotrophic communities. The presence of pristine communities greatly influences the structural and functional recovery of phototrophic communities, suggesting an important role of microbial immigration processes, but have far less influence on the recovery trajectory of heterotrophic communities. PMID- 22210501 TI - Bioconcentration and localization of lead in the freshwater rotifer Brachionus calyciflorus Pallas 1677 (Rotifera: Monogononta). AB - We studied how lead is bioconcentrated and distributed in the rotifer Brachionus calyciflorus using metal histochemistry to locate lead granules, Leadmium Green(r) analysis to establish the route of uptake, atomic absorption to determined the bioconcentration factor (BCF), and detected the presence of microelements in the cuticle by X-ray microanalysis with scanning electron microscopy. Our results indicate: (a) the digestive system is the main route of lead uptake in the rotifer B. calyciflorus, (b) after 24-h lead is deposited in granules in the mastax and vitellarium, (c) our energy-dispersive X-ray microanalysis indicates decalcification taking place in the cuticle of the rotifer after a 24-h lead exposure, and (d) we determined a BCF = 115 for lead after a 24 h exposure. However, the route of mobilization and storage of intracellular lead are still not fully understood in B. calyciflorus. PMID- 22210503 TI - Are alternative airway devices beneficial in out-of-hospital cardiac arrest? PMID- 22210504 TI - Chest compressions: the good, the bad and the ugly. PMID- 22210502 TI - The evolution of gene expression and the transcriptome-phenotype relationship. AB - Changes in gene expression underlie the adaptive evolution in many complex phenotypes, and the recent increase in the availability of multi-species comparative transcriptome data has made it possible to scan whole transcriptomes for loci that have experienced adaptive changes in expression. However, despite the increase in data availability, current models of gene expression evolution often do not account for the complexities and inherent noise associated with transcriptome data. Additionally, in contrast to current models of gene sequence evolution, models of transcriptome evolution often lack the sophistication to effectively determine whether transcriptional differences between species or within a clade are the result of neutral or adaptive processes. In this review, we discuss the tools, methods and models that define our current understanding of the relationship between gene expression and complex phenotype evolution. Our goal is to summarize what we know about the evolution of global gene expression patterns underlying complex traits, as well to identify some of the questions that remain to be answered. PMID- 22210505 TI - Isolated Kaposi sarcoma of the finger pulp in an AIDS patient. AB - A 63-year-old woman with long-standing AIDS and previous Kaposi sarcomas of the lower limb presented to our consultation complaining of a painful left ring finger with pulp enlargement. X-rays revealed an osteolytic lesion of the distal phalanx. We suspected an isolated osseous Kaposi sarcoma and at surgery we found a hemorrhagic lesion with bone extension into the phalanx. Bone involvement is rare in Kaposi sarcoma and even rarer in patients without a cutaneous location. PMID- 22210506 TI - Evaluation of percutaneous surgery in the treatment of thoracolumbar fractures. Preliminary results of a prospective study on 65 patients. AB - INTRODUCTION: We conducted a prospective, single-center, continuous study of patients operated for fractures urelated to osteoporosis at the thoracolumbar junction level using percutaneous techniques. The aim of this study was to investigate the clinical and radiological outcomes of percutaneous techniques for these indications. PATIENTS AND METHODS: This study included patients who underwent standalone balloon kyphoplasty surgery or combined with percutaneous posterior osteosynthesis in cases of associated distraction. The fractures were classified according to the Magerl classification. The patients were evaluated clinically (visual analog scale [VAS], the Oswestry Disability Index, and autonomy) and radiologically (vertebral kyphosis and height variations of the vertebral body) for 12 months. RESULTS: Sixty-five patients were included. The mean age at the time of the surgery was 45.4 years (range, 19-72 years). The main indications were A.1 fractures of L1. We noted 22% cement leakages, none having a clinical impact. In the overall series, the VAS at the lesional level improved from 5.5 (range, 3-8) preoperatively to 0.6 (range, 1-3) at 12 months. In all, 95% of the workers resumed their occupation. Traumatic kyphosis improved from 13.3 degrees (range, 5-23 degrees ) before the surgery to 8.3 degrees (range, 1 20 degrees ). DISCUSSION: The complication rate was low. The radiological results are comparable to those reported in the literature for other series with percutaneous surgery. Only the loss of the correction observed in the group undergoing standalone kyphoplasty with calcium phosphate cement led us to propose another type of treatment for these indications. This study must be continued over the long term to detect the appearance of discopathy related to cement leakage and to answer questions as to how cement evolves. LEVEL OF EVIDENCE: III, prospective study with low statistical power. PMID- 22210507 TI - Spinal cannabinoid CB2 receptors as a target for neuropathic pain: an investigation using chronic constriction injury. AB - Agonists for the cannabinoid CB2 receptor are antinociceptive in several rodent models and several reports have suggested that the target for these drugs is CB2 expressed in the spinal cord pain pathway. After confirming the efficacy of a systemically delivered CB2-selective agonist, GW405833, we tested this hypothesis by administering the CB2 agonists GW405833 and JWH-133, via intrathecal cannulation, to the lumbar spinal cord of rats that had undergone chronic constriction injury to induce mechanical allodynia. We found that although the non-selective CB1/CB2 cannabinoid receptor agonist WIN55,212-2 reversed mechanical allodynia in both ipsilateral and contralateral hind paws, neither GW405833 nor JWH-133 reversed mechanical allodynia. In addition, we investigated the expression of CB2 receptors in the neuropathic spinal cord using immunohistochemistry, Western blot and CB2 agonist stimulated [(35)S]GTPgammaS binding. Although protein-based analysis of CB2 partially matched the results of earlier studies using the same antibody, we found evidence that this antibody may be insufficiently specific for the detection of CB2 in native tissue. Using [(35)S]GTPgammaS binding assays, we found no evidence of functional CB2 in the spinal cord, in sham or surgery-treated tissue. However, WIN55,212-2 stimulated [(35)S]GTPgammaS binding showed clear evidence of functional CB1 receptors consistent with the known distribution of elements of the pain pathway, and we concluded that spinal CB2 receptors are not a likely target for cannabinoid mediated antinociception in this model. PMID- 22210508 TI - Subpopulations of neurokinin 1 receptor-expressing neurons in the rat lateral amygdala display a differential pattern of innervation from distinct glutamatergic afferents. AB - Substance P by acting on its preferred receptor neurokinin 1 (NK1) in the amygdala appears to be critically involved in the modulation of fear and anxiety. The present study was undertaken to identify neurochemically specific subpopulations of neuron expressing NK1 receptors in the lateral amygdaloid nucleus (LA), a key site for regulating these behaviors. We also analyzed the sources of glutamatergic inputs to these neurons. Immunofluorescence analysis of the co-expression of NK1 with calcium binding proteins in LA revealed that ~35% of NK1-containing neurons co-expressed parvalbumin (PV), whereas no co localization was detected in the basal amygdaloid nucleus. We also show that neurons expressing NK1 receptors in LA did not contain detectable levels of calcium/calmodulin kinase IIalpha, thus suggesting that NK1 receptors are expressed by interneurons. By using a dual immunoperoxidase/immunogold-silver procedure at the ultrastructural level, we found that in LA ~75% of glutamatergic synapses onto NK1-expressing neurons were labeled for the vesicular glutamate transporter 1 indicating that they most likely are of cortical, hippocampal, or intrinsic origin. The remaining ~25% were immunoreactive for the vesicular glutamate transporter 2 (VGluT2), and may then originate from subcortical areas. On the other hand, we could not detect VGluT2-containing inputs onto NK1/PV immunopositive neurons. Our data add to previous localization studies by describing an unexpected variation between LA and basal nucleus of the amygdala (BA) in the neurochemical phenotype of NK1-expressing neurons and reveal the relative source of glutamatergic inputs that may activate these neurons, which in turn regulate fear and anxiety responses. PMID- 22210509 TI - Effects of free Ca2+ on kinetic characteristics of holotransketolase. AB - Catalytic activity has been demonstrated for holotransketolase in the absence of free bivalent cations in the medium. The two active centers of the enzyme are equivalent in both the catalytic activity and the affinity for the substrates. In the presence of free Ca2+ (added to the medium from an external source), this equivalence is lost: negative cooperativity is induced on binding of either xylulose 5-phosphate (donor substrate) or ribose 5-phosphate (acceptor substrate), whereupon the catalytic conversion of the bound substrates causes the interaction between the centers to become positively cooperative. Moreover, the enzyme total activity increase is observed. PMID- 22210510 TI - Increased neuronal glutathione and neuroprotection in GTRAP3-18-deficient mice. AB - Glutathione (GSH) is an important neuroprotective molecule in the brain. The strategy to increase neuronal GSH level is a promising approach to the treatment of neurodegenerative diseases. However, the regulatory mechanism by which neuron specific GSH synthesis is facilitated remains elusive. Glutamate transporter associated protein 3-18 (GTRAP3-18) is an endoplasmic reticulum protein interacting with excitatory amino acid carrier 1 (EAAC1), which is a neuronal glutamate/cysteine transporter. To investigate the potential regulatory mechanism to increase neuronal GSH level in vivo, we generated GTRAP3-18-deficient (GTRAP3 18(-/-)) mice using a gene-targeting approach. Disruption of the GTRAP3-18 gene resulted in increased EAAC1 expression in the plasma membrane, increased neuronal GSH content and neuroprotection against oxidative stress. In addition, GTRAP3-18( /-) mice performed better in motor/spatial learning and memory tests than wild type mice. Therefore, the suppression of GTRAP3-18 increases neuronal resistance to oxidative stress by increasing GSH content and also facilitates cognitive function. The present results may provide a molecular basis for the development of treatments for neurodegenerative diseases. PMID- 22210511 TI - Standardized LC-MS/MS based steroid hormone profile-analysis. AB - In order to overcome many limitations of immunoassays, high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) has the potential to find its place in the clinical laboratory medicine for quantification of steroid hormones. A prerequisite for the application of a new analytical procedure in clinical diagnostics is standardization to minimize analytical intra- and interlaboratory variability and inaccuracy. We evaluate a newly standardized HPLC MS/MS assay in kit-format, developed for routine determination of 16 steroid hormones in human serum samples. Fifteen metabolites can be measured quantitatively, which include aldosterone, androstenedione, androsterone, corticosterone, cortisol, cortisone, 11-deoxycortisol, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), 17beta-estradiol (E2), estrone (E1), etiocholanolone, 17alpha-hydroxyprogesterone (17OHP), progesterone, and testosterone. 11-Deoxycorticosterone is the only compound rated as semi quantitative in this kit. The sample preparation is performed by solid phase extraction (SPE) on a 96-well plate. The standardized assay has been validated for human serum in terms of lower and upper limit of quantification (LLOQ 0.01-32 ng/mL, ULOQ 5-8000 ng/mL), linear correlation coefficient of calibration (R(2)>0.9966), intra- and inter-day precision (intra-day 1.1-8.8%, inter-day 5.2 14.8% and 8.2-18.6% for 11-deoxycorticosterone), accuracy (intra-day 88.3-115.5% and 109.3-128.2% for 11-deoxycorticosterone, inter-day 91.4-117.2% and 102.3 137.1% for 11-deoxycorticosterone), analytical total error (3.6-17.8%), proficiency test accuracy (85.4-113.4%), recovery (68-99%), and metabolite stability (freeze/thaw stability 95.5-108.1%, short term stability 86.9-107.2%). Inter-assay comparison with a routine reference HPLC-MS/MS assay and seven immunoassays demonstrates the outstanding high performance of this HPLC-MS/MS based kit by improvements in accuracy for progesterone, androstenedione, and 17OHP. Finally, results of two metyrapone tests demonstrate the potential of the standardized HPLC-MS/MS assay for the analysis of a comprehensive steroid hormone profile in clinical diagnostics. PMID- 22210512 TI - Evaluating the PCPT risk calculator in ten international biopsy cohorts: results from the Prostate Biopsy Collaborative Group. AB - OBJECTIVES: To evaluate the discrimination, calibration, and net benefit performance of the Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) across five European randomized study of screening for prostate cancer (ERSPC), 1 United Kingdom, 1 Austrian, and 3 US biopsy cohorts. METHODS: PCPTRC risks were calculated for 25,733 biopsies using prostate-specific antigen (PSA), digital rectal examination, family history, history of prior biopsy, and imputation for missing covariates. Predictions were evaluated using the areas underneath the receiver operating characteristic curves (AUC), discrimination slopes, chi-square tests of goodness of fit, and net benefit decision curves. RESULTS: AUCs of the PCPTRC ranged from a low of 56% in the ERSPC Goeteborg Rounds 2-6 cohort to a high of 72% in the ERSPC Goeteborg Round 1 cohort and were statistically significantly higher than that of PSA in 6 out of the 10 cohorts. The PCPTRC was well calibrated in the SABOR, Tyrol, and Durham cohorts. There was limited to no net benefit to using the PCPTRC for biopsy referral compared to biopsying all or no men in all five ERSPC cohorts and benefit within a limited range of risk thresholds in all other cohorts. CONCLUSIONS: External validation of the PCPTRC across ten cohorts revealed varying degree of success highly dependent on the cohort, most likely due to different criteria for and work-up before biopsy. Future validation studies of new calculators for prostate cancer should acknowledge the potential impact of the specific cohort studied when reporting successful versus failed validation. PMID- 22210513 TI - A fluorescent method to determine vitamin K-dependent gamma-glutamyl carboxylase activity. AB - The gamma (gamma)-glutamyl carboxylase is a key enzyme in vitamin K-dependent carboxylation of proteins involved in hemostasis and inflammation. It is an endoplasmic enzyme posttranslationally converting glutamic acid residues into gamma-carboxyglutamic acid residues in proteins. The activity of tissue derived gamma-glutamyl carboxylase is commonly assayed by incorporation of H14CO3- into synthetic peptides and subsequent quantification using liquid scintillation counting. We present a nonradioactive assay using a fluorescein isothiocyanate labeled short peptide that can be readily detected in its unmodified and gamma glutamyl carboxylated form by reversed-phase HPLC. This method offers a convenient alternative to the established radioactive labeling techniques. PMID- 22210514 TI - Three-dimensional kinematic lumbar spine motion analyses of trunk motion during axial rotation activities. AB - STUDY DESIGN: An experimental design was conducted to investigate kinematic changes in 3-dimensional trunk motions between subjects with and without chronic low back pain (LBP) while demonstrating axial rotation. OBJECTIVES: The purpose of this study was to compare 3-dimensional kinematic data for the upper and lower thorax and the lumbar spine from the axis of the core spine during axial rotation activities in the standing position while considering anthropometric factors in subjects with and without LBP. SUMMARY OF BACKGROUND DATA: Rotation of the trunk is associated with a large number of LBP cases and surrounding spinal tissue injuries. METHODS: Fifteen subjects with chronic LBP (5 men, 10 women) and 15 subjects without LBP (9 men, 6 women) participated in this study. The outcome measures included kinematic data of actual trunk rotation angles for the upper and lower thorax and the lumbar regions relative to the core spine (spinal root) in sagittal, coronal, and transverse axes. RESULTS: The spinal range of motion was significantly different for each spinal region (F=240.25, P=0.001) and axis (F=213.91, P=0.001). There was a significant interaction between the spinal region and the group (F=4.34, P=0.04). There was also a 3-way interaction with the spinal region, the axis, and the group (F=11.04, P=0.001). These results indicated that spinal region and axes are important to consider because the upper thorax demonstrated a significantly greater rotational displacement in subjects with chronic LBP. Among the anthropometric factors, age (F=6.24, P=0.02) interacted with the spinal region and the axis. CONCLUSIONS: Decreased spinal range of motion in older subjects might result in a stiffened spine in addition to possible poor proprioception from back injuries to passive structures in subjects with chronic LBP. PMID- 22210515 TI - Biomechanical properties of repairs for dislocated AC joints using suture button systems with integrated tendon augmentation. AB - PURPOSE: To evaluate the biomechanical performance of different techniques for CC reconstruction using suture button systems with integrated tendon augmentation. Hypothesis was that (1) reconstructions using a cortical button combined with a biological augmentation (semitendinosus allograft) will demonstrate improved stability than a modified Weaver-Dunn procedure and (2) constructs using two tunnels at the clavicle for fixation will show superior horizontal stability than single-tunnel constructs. METHODS: The acromioclavicular joints of 47 cadaveric shoulders were tested for anterior, posterior, and superior translations (70 N load) and maximal load to failure (superior). Shoulders were assigned to 4 groups: (1) native (n = 18) and after sectioning the AC and CC ligaments; (2) CC reconstruction with 1 clavicular and 1 coracoid tunnel (GR-ST) augmented with semitendinosus graft (n = 15); (3) CC reconstruction augmented with semitendinosus tendon (GR-DT) with 2 clavicular and 1 coracoid tunnel (n = 8); and (4) modified Weaver-Dunn reconstruction (n = 6). RESULTS: The Weaver-Dunn demonstrated statistically more translation than the native joint for posterior direction (P = 0.038). The GR-ST had significantly less translation than the Weaver-Dunn for anterior and posterior translations (P = 0.003, P = 0.004) and compared to the native for superior translation (P = 0.028). The GR-DT differed significantly in anterior and posterior translations compared to the Weaver-Dunn (P = 0.002, P = 0.001). The modified Weaver-Dunn failed at significantly less load to failure compared to all other groups (P = 0.002, P = 0.002, P = 0.005). There was no significant difference between the native and the other reconstructions. CONCLUSION: The evaluated techniques for isolated CC ligament reconstruction (GR-ST) in AC joint dislocation showed biomechanical stability superior to the modified Weaver-Dunn procedure and obtained similar measures compared to the native control. A modified technique (GR-DT), which used two fixation points at the clavicle, did not result in decreased horizontal or vertical translation and therefore no superiority of the GR-DT technique could be shown compared to the GR-ST. LEVEL OF EVIDENCE: Controlled laboratory study. PMID- 22210516 TI - Dynamic knee laxity measurement devices. AB - PURPOSE: Studies have reported that knee kinematics and rotational laxity are not restored to native levels following traditional anterior cruciate ligament (ACL) reconstruction. This has led to the development of anatomic ACL reconstruction, which aims to restore native knee kinematics and long-term knee health by replicating normal anatomy as much as possible. The purpose of this review is to give an overview of current dynamic knee laxity measurement devices with the purpose of investigating the significance of dynamic laxity measurement of the knee. Gait analysis is not included. METHODS: The subject was discussed with experts in the field in order to perform a level V review. MEDLINE was searched according to the discussions for relevant articles using multiple different search terms. All found abstracts were read and scanned for relevance to the subject. The reference lists of the relevant articles were searched for additional articles related to the subject. RESULTS: There are a variety of techniques reported to measure dynamic laxity of the knee. Technical development of methods is one important part toward better understanding of knee kinematics. Validation of devices has shown to be difficult due to the lack of gold standard. Different studies use various methods to examine different components of dynamic laxity, which makes comparisons between studies challenging. CONCLUSION: Several devices can be used to evaluate dynamic laxity of the knee. At the present time, the devices are continuously under development. Future implementation should include primary basic research, including validation and reliability testing, as well as part of individualized surgery and clinical follow-up. LEVEL OF EVIDENCE: Diagnostic study, Level V. PMID- 22210517 TI - Quantitative measurement of the pivot shift, reliability, and clinical applications. AB - Static load-displacement measurement is unrelated to the dynamic knee function of anterior cruciate ligament (ACL) insufficiency. Performing an accurate, dynamic functional evaluation is necessary not only for the primary ACL injury, but also as an outcome measurement in ACL reconstruction. The pivot shift test is commonly used for assessing dynamic rotatory knee laxity in ACL-insufficient knees and is related to subjective knee function. Residual pivot shift after ACL reconstruction is a crucial factor related to poor clinical outcome. However, the pivot shift test is subjectively determined by the examiners' hands. Not only 3 dimensional (3D) position displacement but also its 3D acceleration should be measured for quantitative evaluation of the pivot shift test and is currently feasible by using recent advanced technology, i.e., electromagnetic devices. We summarize the basic knowledge and current concepts of quantitative exploration of the dynamic knee movement during the pivot shift test. PMID- 22210518 TI - Transtibial ACL reconstruction technique fails to position drill tunnels anatomically in vivo 3D CT study. AB - PURPOSE: The purpose of this study was to visualize and quantify the positions of femoral and tibial tunnels in patients who underwent traditional transtibial single-bundle ACL reconstruction, as performed by multiple surgeons, utilizing 3D CT models, and to compare these positions to our previously reported anatomical tunnel positions. METHODS: Fifty-eight knee computed tomography (CT) scans were performed on patients who underwent primary or revision transtibial single-bundle ACL reconstruction, and three-dimensional reconstructions of the CT scans were aligned within an anatomical coordinate system. The position of femoral tunnel aperture centers was measured with (1) the quadrant method and (2) in the anatomic posterior-to-anterior and proximal-to-distal directions. The position of tibia tunnel aperture centers were measured similarly, in the anterior-to posterior and medial-to-lateral dimensions on the tibial plateau. Comparisons were made to previously established anatomical tunnel positions, and data were presented as "mean value +/- standard deviation (range)." RESULTS: The location of tibial tunnels was at 48.0 +/- 5.4% (35.6-59.5%) of the anterior-to-posterior plateau depth and at 47.9 +/- 2.9% (42.2-57.4%) of the medial-to-lateral plateau width. The location of femoral tunnels was at 55.8 +/- 8.0% (41.5-79.5%) in the anatomic posterior-to-anterior direction and at 41.2 +/- 10.4% (15.1-67.4%) in the proximal-to-distal directions. Utilizing a quadrant method, femoral tunnels were positioned at 37.4 +/- 5.1% (24.9-50.6%) from the proximal condylar surface, parallel to Blumensaat line, and at 11.0 +/- 7.3% (-6.0-28.7%) from the notch roof, perpendicular to Blumensaat line. In summary, tibial tunnels were positioned medial to the anatomic PL position (p < 0.001), and femoral tunnels were positioned anterior to both AM and PL anatomic tunnel locations (p < 0.001 and p < 0.001). CONCLUSION: ACL reconstruction via traditional transtibial technique fails to accurately position femoral and tibial tunnels within the native ACL insertion site. To achieve anatomical graft placement, other surgical techniques should be considered. LEVEL OF EVIDENCE: IV. PMID- 22210519 TI - Rotatory laxity evaluation of the knee using modified Slocum's test in open magnetic resonance imaging. AB - PURPOSE: The authors have developed a quantitative method to evaluate rotatory laxity of the anterior cruciate ligament (ACL)-deficient knee using an open MRI. In this study, we evaluated the correlation between the pivot-shift test grading and values measured with this method. Furthermore, the articular contact area in the lateral compartment during the pivot shift was examined. METHODS: Ninety-two subjects were evaluated in this study. Among them, 36 subjects were evaluated before the ACL reconstruction, and 56 subjects were evaluated 1 year after the ACL reconstruction. Subjects were placed in the open MRI scanner in the posture based on the Slocum's ALRI test. Anterior translation of the tibia was measured in the lateral and medial compartments in the sagittal images of the MRI. The correlation between the grading of the pivot-shift test and either anterior translation of the lateral compartment, or the difference between translation of the medial compartment and the lateral compartment, was evaluated by logistic analysis. Furthermore, we examined the contact area of the articular surface in the lateral compartment with variation in the pivot-shift grading. RESULTS: The anterior translation of the lateral compartment had a significant correlation with the pivot-shift grading. A discriminant analysis showed that the lateral translation could predict the grade of the pivot-shift test more accurately than the lateral minus medial translation (84.8% vs. 70.7%, P < 0.001). The summit of the convex lateral tibial articular surface is located anterior to the closest point between the lateral femoral condyle and the tibial plateau in the pivot shift-positive subjects, while it is located posterior to the femoral condyle in the pivot-shift-negative subjects. CONCLUSION: The anterior translation in the lateral compartment measured with this method allows objective and quantitative evaluation of the rotatory laxity that causes the pivot-shift phenomenon. The grade of the pivot-shift test is determined by the magnitude of the movement of the lateral compartment when the femoral condyle surmounts the convex tibial articular surface, rather than by the deviation of the rotational angle of the tibia. LEVEL OF EVIDENCE: II. PMID- 22210520 TI - Prediction of permeability of regular scaffolds for skeletal tissue engineering: a combined computational and experimental study. AB - Scaffold permeability is a key parameter combining geometrical features such as pore shape, size and interconnectivity, porosity and specific surface area. It can influence the success of bone tissue engineering scaffolds, by affecting oxygen and nutrient transport, cell seeding efficiency, in vitro three dimensional (3D) cell culture and, ultimately, the amount of bone formation. An accurate and efficient prediction of scaffold permeability would be highly useful as part of a scaffold design process. The aim of this study was (i) to determine the accuracy of computational fluid dynamics (CFD) models for prediction of the permeability coefficient of three different regular Ti6Al4V scaffolds (each having a different porosity) by comparison with experimentally measured values and (ii) to verify the validity of the semi-empirical Kozeny equation to calculate the permeability analytically. To do so, five CFD geometrical models per scaffold porosity were built, based on different geometrical inputs: either based on the scaffold's computer-aided design (CAD) or derived from 3D microfocus X-ray computed tomography (micro-CT) data of the additive manufactured (AM) scaffolds. For the latter the influence of the spatial image resolution and the image analysis algorithm used to determine the scaffold's architectural features on the predicted permeability was analysed. CFD models based on high-resolution micro-CT images could predict the permeability coefficients of the studied scaffolds: depending on scaffold porosity and image analysis algorithm, relative differences between measured and predicted permeability values were between 2% and 27%. Finally, the analytical Kozeny equation was found to be valid. A linear correlation between the ratio Phi(3)/S(s)(2) and the permeability coefficient k was found for the predicted (by means of CFD) as well as measured values (relative difference of 16.4% between respective Kozeny coefficients), thus resulting in accurate and efficient calculation of the permeability of regular AM scaffolds. PMID- 22210521 TI - Hypoventilation training for asthma: a case illustration. AB - Hyperventilation-induced hypocapnia is common among asthma patients. This case study illustrates both methodology and results from a patient undergoing training in capnometry-assisted respiratory training (CART). CART is a 4-week training aimed at normalizing basal and acute levels of end-tidal carbon dioxide (PCO(2)) using a portable capnometer. In the presented case, basal levels of PCO(2) increased from hypocapnic to normocapnic range over the course of treatment. Improvements were accompanied by improvements in lung function and reductions in diurnal lung function variability. Improvements remained stable throughout follow up. PMID- 22210522 TI - Within-litter variation in maternal care received by individual pups correlates with adolescent social play behavior in male rats. AB - Maternal care represents an essential environmental factor during the first post natal week(s) of rodents and is known to have lasting consequences for neuronal structure, brain function as well as behavioral outcome later in life, including social functions and reward-related processes. Previous experiments have shown that the amount of maternal care received by individual pups varies substantially, even within one litter. During adolescence, mammals display high levels of social play behavior, a rewarding form of social interaction that is of great importance for social and cognitive development. In order to investigate how maternal care influences adaptive social behavior later in life, we here examined whether individual differences in maternal licking and grooming (%LG) received during the first postnatal week affect social play behavior during adolescence. We observed that %LG received by male rats early in life correlates positively with the frequency and duration of pouncing and pinning, the two most characteristic behavioral expressions of social play behavior in rats. The latency to engage in social exploration also correlated with %LG. In female rats we observed no correlation between %LG and any social parameter. The data indicate that subtle variations in maternal care received early in life influence social interactions in male adolescent rats. These changes in social play likely have repercussions for the social development of male rats, suggesting that maternal care can have both direct and indirect effects on the behavioral development of the offspring. PMID- 22210523 TI - The effect of partial reinforcement on instrumental successive negative contrast in inbred Roman High- (RHA-I) and Low- (RLA-I) Avoidance rats. AB - Frustration is an emotional response that can be induced by the sudden devaluation of a reinforcer in the presence of greater reinforcement expectancies (e.g. instrumental successive negative contrast, iSNC). This emotional response seems to be similar to anxiety and can be attenuated by previous experiences of reward loss (e.g. partial reinforcement, PR, as opposed to continuous reinforcement, CR). In this study we used iSNC and PR procedures in order to compare the performance of two strains of rats psychogenetically selected on the basis of their emotional reactivity: the inbred Roman High- (RHA-I, low anxiety) and Low- (RLA-I, high anxiety) Avoidance rats. Animals were exposed to a straight alley, where they were changed from 12 pellets in the preshift phase (presented in 100% of trials-CR vs. 50% of trials-PR) to 2 pellets in the postshift phase, or exposed to 2 pellets throughout the training. The results indicated that the iSNC only appeared in RLA-I rats exposed to CR, as opposed to RLA-I animals exposed to PR and to RHA-I rats exposed to PR or CR. These data seem to support the implication of emotional responses in both iSNC and PR situations, and indicate that the behavioral reactivity to reward loss experiences is modulated by genetic variables. PMID- 22210524 TI - CsCXCe1: A novel Cynoglossus semilaevis CXC chemokine that functions as a chemoattractant and an immunomodulator for peripheral blood leukocytes. AB - Chemokines are small cytokines that, based on their structural differences, are classified into four groups, one of which is called CXC chemokines. In this study, we identified a CXC chemokine, CsCXCe1, from half-smooth tongue sole (Cynoglossus semilaevis) and analyzed its function. The deduced amino acid sequence of CsCXCe1 contains 115 residues and is phylogenetically distinct from known CXC chemokines. CsCXCe1 possesses the conserved RCXC motif in the form of RCWC but lacks the ELR sequence that is found in some CXC chemokines. Expression of CsCXCe1 as determined by quantitative real time RT-PCR occurred abundantly in immune organs and was upregulated by bacterial and viral infection in time dependent manners. Purified recombinant CsCXCe1 (rCsCXCe1) exhibited comparable chemotactic activities against tongue sole and turbot (Scophthalmus maximus) peripheral blood leukocytes (PBL). Microscopic analysis identified lymphocytes as the major cellular population in PBL that responds to rCsCXCe1. Mutational study showed that when the two cysteine residues in the RCWC motif of CsCXCe1 were substituted by serine, the chemoattractive activity of CsCXCe1 was completely lost. Further study showed that treatment of PBL with rCsCXCe1 (i) stimulated cellular proliferation and respiratory burst activity, (ii) upregulated the expression of a wide spectrum of immune relevant genes, and (iii) enhanced cellular resistance against bacterial infection. Taken together, these results indicate that CsCXCe1 is likely a new type of CXC chemokine that exerts chemotactic and immunostimulatory effects on PBL. PMID- 22210525 TI - Silver nanoparticle (AgNPs) doped gum acacia-gelatin-silica nanohybrid: an effective support for diastase immobilization. AB - An effective carrier matrix for diastase alpha amylase immobilization has been fabricated by gum acacia-gelatin dual templated polymerization of tetramethoxysilane. Silver nanoparticle (AgNp) doping to this hybrid could significantly enhance the shelf life of the impregnated enzyme while retaining its full bio-catalytic activity. The doped nanohybrid has been characterized as a thermally stable porous material which also showed multipeak photoluminescence under UV excitation. The immobilized diastase alpha amylase has been used to optimize the conditions for soluble starch hydrolysis in comparison to the free enzyme. The optimum pH for both immobilized and free enzyme hydrolysis was found to be same (pH=5), indicating that the immobilization made no major change in enzyme conformation. The immobilized enzyme showed good performance in wide temperature range (from 303 to 323 K), 323 K being the optimum value. The kinetic parameters for the immobilized, (K(m)=10.30 mg/mL, V(max)=4.36 MUmol mL(-1)min( 1)) and free enzyme (K(m)=8.85 mg/mL, V(max)=2.81 MUmol mL(-1)min(-1)) indicated that the immobilization improved the overall stability and catalytic property of the enzyme. The immobilized enzyme remained usable for repeated cycles and did not lose its activity even after 30 days storage at 40 degrees C, while identically synthesized and stored silver undoped hybrid lost its ~31% activity in 48 h. Present study revealed the hybrids to be potentially useful for biomedical and optical applications. PMID- 22210526 TI - Optimization and characterization of walnut beverage emulsions in relation to their composition and structure. AB - A central composite rotatable design (CCRD) was used to evaluate the effects of walnut oil (WO, 3-6%, w/w) and gum arabic (GA, 5-10%, w/w) on the average droplet size (D(32)), specific surface area (SSA), polydispersity index (span), apparent viscosity, interfacial tension and opacity of walnut-beverage emulsions. The response surface methodology (RSM) showed that the significant second-order polynomial regression equations with high R(2) (>0.95) were successfully fitted for all responses as function of independent variables. The linear effect of WO had a significant term in all reduced models. The overall optimum region was found to be at the combined level of 10% (w/w) GA content and 5.84% (w/w) WO concentration. At this optimum point, D(32), SSA, span, apparent viscosity, interfacial tension and opacity of emulsions were 0.609 MUm, 8.236 m(2)/ml, 0.886, 1.336 Pa s, 51.37 mN/m and 0.810, respectively. No significant (p>0.05) difference was found between the actual values and predicted values. Moreover, principal component analysis (PCA), conducted via PCA variable loadings and cluster dendrogram was able to discriminate the emulsions with different formulations into separate classes. PMID- 22210527 TI - Microwave initiated synthesis of polyacrylamide grafted Psyllium and its application as a flocculant. AB - This paper reports a novel microwave initiated method for synthesis of polyacrylamide grafted Psyllium (Psy-g-PAM). Psyllium was modified through grafting of polyacrylamide (PAM) chains on it using microwave radiations only, in absence of any other free radical initiator. The grafting was confirmed by intrinsic viscosity study and characterization techniques like FTIR spectroscopy, elemental analysis (C, H, N, O and S) and SEM morphology study. Further, the flocculation efficacy of the synthesized graft copolymers was studied in kaolin and coal fine suspension through standard 'Jar test' procedure. PMID- 22210528 TI - Extra-abdominal desmoid tumor with osseous involvement. AB - Deep fibromatoses, or desmoid tumors, arise from connective tissue. Imaging can frequently suggest the diagnosis of these aggressive, benign neoplasms. Cross sectional imaging commonly demonstrates an enhancing solid mass that resembles scar tissue, typically without osseous involvement. We report a case of an extra abdominal desmoid tumor involving the teres minor muscle in a symptomatic 42-year old woman with unusual features of medullary involvement and negative nuclear beta-catenin staining. PMID- 22210529 TI - Xylogenesis in black spruce: does soil temperature matter? AB - In boreal ecosystems, an increase in soil temperature can stimulate plant growth. However, cambium phenology in trees was better explained by air than soil temperature, which suggested that soil temperature is not the main limiting factor affecting xylogenesis. Since soil temperature and snowmelt are correlated to air temperature, the question whether soil temperature directly limits xylogenesis in the stem will remain unresolved without experiments disentangling air and soil temperatures. This study investigated the effects of an increase of 4 degrees C in soil temperature and a consequent 1-week earlier snowmelt on growth of black spruce [Picea mariana (Mill.) BSP] in the boreal forest of Quebec, Canada. The soil of two natural stands at different altitudes was warmed up with heating cables during 2008-2010 and cambial phenology and xylem production were monitored weekly from April to October. The results showed no significant effect of the treatment on the phenological phases of cell enlargement and wall thickening and lignification. The number of cells produced in the xylem also did not differ between control and heated trees. These findings allowed the hypothesis of a direct influence of soil temperature on stem growth to be rejected and supported the evidence that, in the short term, air temperature is the main limiting factor for xylogenesis in trees of these environments. PMID- 22210530 TI - Timing and magnitude of C partitioning through a young loblolly pine (Pinus taeda L.) stand using 13C labeling and shade treatments. AB - The dynamics of rapid changes in carbon (C) partitioning within forest ecosystems are not well understood, which limits improvement of mechanistic models of C cycling. Our objective was to inform model processes by describing relationships between C partitioning and accessible environmental or physiological measurements, with a special emphasis on short-term C flux through a forest ecosystem. We exposed eight 7-year-old loblolly pine (Pinus taeda L.) trees to air enriched with (13)CO(2) and then implemented adjacent light shade (LS) and heavy shade (HS) treatments in order to manipulate C uptake and flux. The impacts of shading on photosynthesis, plant water potential, sap flow, basal area growth, root growth and soil CO(2) efflux rate (CER) were assessed for each tree over a 3 week period. The progression of the (13)C label was concurrently tracked from the atmosphere through foliage, phloem, roots and surface soil CO(2) efflux. The HS treatment significantly reduced C uptake, sap flow, stem growth and fine root standing crop, and resulted in greater residual soil water content to 1 m depth. Soil CER was strongly correlated with sap flow on the previous day, but not the current day, with no apparent treatment effect on the relationship. Although there were apparent reductions in new C flux belowground, the HS treatment did not noticeably reduce the magnitude of belowground autotrophic and heterotrophic respiration based on surface soil CER, which was overwhelmingly driven by soil temperature and moisture. The (13)C label was immediately detected in foliage on label day (half-life = 0.5 day), progressed through phloem by Day 2 (half-life = 4.7 days), roots by Days 2-4, and subsequently was evident as respiratory release from soil which peaked between Days 3 and 6. The delta(13)C of soil CO(2) efflux was strongly correlated with phloem delta(13)C on the previous day, or 2 days earlier. While the (13)C label was readily tracked through the ecosystem, the fate of root C through respiratory, mycorrhizal or exudative release pathways was not assessed. These data detail the timing and relative magnitude of C flux through various components of a young pine stand in relation to environmental conditions. PMID- 22210531 TI - Paget disease of the spine: an evaluation of 101 patients with a histomorphometric analysis of 29 cases. AB - INTRODUCTION: Paget's disease of bone (PDB) is the second most frequent metabolic bone disease with the spine being a common site of manifestation. Still, neither the disease's etiology nor reasons for its manifestation at preferred skeletal sites are understood. The aim of the current study was therefore to perform a histologic and histomorphometric analysis of PBD biopsies of the spine to achieve a more detailed understanding concerning PDB activity and characteristics. MATERIALS AND METHODS: Out of 754 cases with histologically proven PDB, 101 cases were identified to have involvement of the spine. A total of 29 individual vertebral body biopsies were available for histologic and histomorphometric analysis and were compared to age- and sex-matched spinal bone specimens obtained from skeletal-intact individuals at autopsy. Histomorphometric results were correlated with vertebral body height, disease location and iliac crest biopsies. RESULTS: In the majority of patients, PDB was located in the lumbar spine (62.2%). The cervical spine was affected in 8.2% of all cases with involvement of the second vertebral body (C2) in every other case. In comparison to age-matched individuals, histomorphometric analysis of vertebral body biopsies revealed a significant increase both in trabecular bone volume as well as osteoid parameters. In comparison to histomorphometric data obtained for extra-spinal skeletal locations affected by PDB (iliac crest), no differences in bone micro architecture or disease activity were observed. CONCLUSION: Disease activity in terms of osteoblast and osteoclast number does not appear to be significantly associated with disease location when spinal and iliac bone biopsies are compared. However, a positive correlation between vertebral body height and density in skeletal-intact individuals and disease incidence was observed leading to the conclusion that vertebral body height and possibly at least the spine bone volume together with bone density might play an important role in the incidence of PDB. PMID- 22210533 TI - A method for coronary artery calcium scoring using contrast-enhanced computed tomography. AB - BACKGROUND: Limitations to the coronary calcium score include its requirement for noncontrast imaging and radiation exposure that approaches current methods for contrast-enhanced CT angiography. OBJECTIVES: We sought to derive and validate a method of measuring the coronary artery calcium score (CACS) from standard contrast-enhanced CT, obviating the need for a second non-contrast calcium scan. METHODS: The volume of intramural calcium of >320 HU in major coronary vessels was measured in 90 contrast-enhanced and traditional non-contrast calcium scan pairs. An empiric conversion factor was derived to convert the small voxel contrast-enhanced calcium volume to an Agatston calcium score. The accuracy of this technique was then prospectively validated in 120 consecutive patients undergoing clinical calcium scans and contrasted-enhanced coronary CT. Eleven patients were excluded from analysis because of the prespecified criteria of excessive noise in the contrast-enhanced CT or total coronary artery occlusion. RESULTS: The Pearson correlation of the contrast scan-derived calcium score with the measured CACS was r2 = 0.99. With standard CACS risk bands, agreement of the contrast-enhanced calcium score estimate with the measured CAC by quadratic weighted kappa was 0.96. The 95% limits of agreement (Agatston units) were given by +/-(3.2 + 0.14 * CACS + 4.44 mean square root of CACS). Inter-observer and intra-observer reliability with the intraclass correlation was 0.99. CONCLUSION: The calcium score can be accurately measured from contrast-enhanced cardiac CT scans with the use of a Hounsfield unit threshold of 320. PMID- 22210534 TI - Predictors of worsening renal function after computed tomography coronary angiography: assessed by cystatin C. AB - BACKGROUND: An increase in cystatin C (CyC) of >=10% for 24 hours may predict contrast-induced nephropathy and worse outcomes in patients with renal dysfunction undergoing invasive coronary angiography. OBJECTIVE: We investigated the changes in CyC in patients with preserved renal function referred for contrast-enhanced coronary computed tomography angiography (CTA). METHODS: We studied 151 patients undergoing CTA with 70 mL of iopamidol. Serum creatinine and CyC, a sensitive measure of renal dysfunction, shown to be associated with adverse outcomes, were measured 1 day and 1 week after CTA, respectively. The percentage change in CyC (%CyC) was determined and evaluated in comparison to fluid intake. RESULTS: The patients were dichotomized into 2 groups: 47 patients had >=10% increase in CyC 1 day after CTA (group A) and 104 did not (group B). The percentage of diabetic patients, hemoglobin A1c (HbA1c), and the CyC levels at 1 week were significantly greater, and the oral fluid volume was significantly lower in group A than in group B. The %CyC inversely correlated with oral fluid volume (r = -0.80, P < 0.0001) and positively with HbA1c (r = 0.38, P < 0.001). Multiple regression analysis showed that oral fluid intake (beta = -0.796, P < 0.0001) and HbA1c (beta = 0.128, P = 0.007) are independent predictors for %CyC of >=10%. CONCLUSION: Frequency of CyC elevation was strongly related to hydration after the study and also weakly related to HbA1c. Sufficient oral fluid intake (oral fluid volume/kg >= 20 mL/kg) is crucial, particularly for poorly controlled diabetic patients referred for CTA even though they show preserved renal function. PMID- 22210535 TI - Infarct detection with a comprehensive cardiac CT protocol. AB - BACKGROUND: Cardiac CT has the potential to offer comprehensive infarct detection by assessing regional wall motion abnormalities (RWMAs), rest perfusion defects (RPDs), and delayed contrast enhancement (DCE). However, the diagnostic accuracy of these techniques for the detection of myocardial infarction (MI) is unknown. METHODS: Forty-eight patients with intermediate-to-high probability for coronary artery disease after single-photon emitting CT myocardial perfusion imaging were prospectively enrolled for a research comprehensive 64-detector row dual-source cardiac CT protocol that included cine images for RWMA, first-pass images for RPD, and delayed images for DCE. Blinded readers independently assessed each technique. Subsequently, a final combined analysis (cine + rest + DCE) was performed. The universal definition for MI by the 2007 American Heart Association task force was used as the "gold standard." RESULTS: Twenty-four of 48 patients (50%) had infarct by the universal definition. The combined CT analysis was most accurate (90%) with the highest per-patient sensitivity (88%) and specificity (92%) versus individual assessments (RWMA, 79% and 88%; RPD, 67% and 92%; DCE, 79% and 88%). Similar findings were observed on a per-vessel basis analysis. A combination of DCE and cine showed a good accuracy (85%) and high sensitivity (92%). CONCLUSIONS: Infarct detection with CT is feasible with overall good diagnostic accuracy compared with the universal definition. A combined evaluation that included all techniques (cine, RPD, and DCE) had the highest diagnostic accuracy. These findings may have implications when designing future clinical and research CT protocols for optimal infarct detection. PMID- 22210536 TI - Medical care costs and survival associated with hepatocellular carcinoma among the elderly. AB - BACKGROUND & AIMS: We assessed the burden of hepatocellular carcinoma (HCC), in terms of mortality and medical care costs, based on analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare database. METHODS: We analyzed data from the SEER-Medicare database on patients 66 years or older who were diagnosed with primary HCC from 1991 to 2007, entitled for Medicare Parts A and B, and not enrolled in health maintenance organizations (n = 5712). Controls were individuals without HCC, identified from a 5% sample of Medicare beneficiaries residing in SEER areas; they were matched 1:1 with individuals with HCC (cases) for age, sex, race, and geographic region (average age, 75 y; 34.7% female). Kaplan-Meier analysis was used to estimate survival distributions. Costs were reported in 2009 dollars; per-patient-per-month (PPPM) costs were compared between cases and controls using the Wilcoxon rank sum test. RESULTS: The largest proportion of cases had localized disease (38.2%), followed by regional (24.0%), unstaged (20.4%), and distant (17.3%) disease. The median survival times were 5 months for cases and 60 months for controls; they were 3 months for patients with distant disease, 4 months for patients with regional disease, and 9 months for those with localized disease. The mean PPPM costs were $7863 for cases and $1243 for controls (P < .001). These costs were primarily driven by inpatient (mean, $5439 vs $682 without HCC; P < .001) and hospice (mean $554 vs $42 without HCC; P < .001) care. Mean PPPM costs by stage were $7265 for localized disease, $8072 for regional disease, and $9585 for distant disease (P < .001 for trend). CONCLUSIONS: Based on analysis of the SEER-Medicare database, costs for patients with HCC are approximately 6- to 8-fold higher than for those without this cancer. Patients with distant HCC had the greatest costs. These findings highlight that HCC is a substantial medical cost burden for elderly patients. PMID- 22210537 TI - Shallow and deep orthographies in Hebrew: the role of vowelization in reading development for unvowelized scripts. AB - The present study explored the speed, accuracy, and reading comprehension of vowelized versus unvowelized scripts among 126 native Hebrew speaking children in second, fourth, and sixth grades. Findings indicated that second graders read and comprehended vowelized scripts significantly more accurately and more quickly than unvowelized scripts, whereas among fourth and sixth graders reading of unvowelized scripts developed to a greater degree than the reading of vowelized scripts. An analysis of the mediation effect for children's mastery of vowelized reading speed and accuracy on their mastery of unvowelized reading speed and comprehension revealed that in second grade, reading accuracy of vowelized words mediated the reading speed and comprehension of unvowelized scripts. In the fourth grade, accuracy in reading both vowelized and unvowelized words mediated the reading speed and comprehension of unvowelized scripts. By sixth grade, accuracy in reading vowelized words offered no mediating effect, either on reading speed or comprehension of unvowelized scripts. The current outcomes thus suggest that young Hebrew readers undergo a scaffolding process, where vowelization serves as the foundation for building initial reading abilities and is essential for successful and meaningful decoding of unvowelized scripts. PMID- 22210538 TI - Toxicity of raw and processed roots of Polygonum multiflorum. AB - The roots of Polygonum multiflorum (Chinese name: He-Shou-Wu, HSW) are used in traditional Chinese medicine for many diseases in processed form or raw state. There are reports dealing with the toxicity of HSW. However, the toxicity is caused by over dosage or by the herb itself remains unclear. We evaluated the toxicity of raw and processed HSW on Kunming (KM) mice. For raw HSW, the toxicity of water decocta is much higher than that of acetone extract. Meanwhile, the toxicity of acetone extract of raw HSW is considerably higher than that of acetone extract of processed HSW. HPLC analyses revealed that the contents of characteristic compounds in raw HSW were changed after processing: the content of 2,3,4',5-tetrahydroxystilbene 2-O-beta-D-glucoside was decreased by 55.8%, whereas the content of emodin was increased by 34.0%. Thus, processing could reduce the toxicity of HSW. Thus, the toxicity of HSW does not depend on the content of anthranoid derivatives, it may be correlated with the content of tetrahydroxystilbene glucosides. PMID- 22210539 TI - A proteomic study of Hutchinson-Gilford progeria syndrome: Application of 2D chromotography in a premature aging disease. AB - The Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease characterized by segmental premature aging. Applying a two-dimensional chromatographic proteomic approach, the 2D Protein Fractionation System (PF2D), we identified 30 differentially expressed proteins in cultured HGPS fibroblasts. We categorized them into five groups: methylation, calcium ion binding, cytoskeleton, duplication, and regulation of apoptosis. Among these 30 proteins, 23 were down-regulated, while seven were up-regulated in HGPS fibroblasts as compared to normal fibroblasts. Three differentially expressed cytoskeleton proteins, vimentin, actin, and tubulin, were validated via Western blotting and characterized by immunostaining that revealed densely thickened bundles and irregular structures. Furthermore in the HGPS cells, the cell cycle G1 phase was elongated and the concentration of free cytosolic calcium was increased, suggesting intracellular retention of calcium. The results that we obtained have implications for understanding the aging process. PMID- 22210540 TI - Accurately predicting bipolar disorder mood outcomes: implications for the use of electronic databases. AB - BACKGROUND: Monitoring mental health treatment outcomes for populations requires an understanding as to which patient information is needed in electronic format and is feasible to obtain in routine care. OBJECTIVE: To examine whether bipolar disorder outcomes can be accurately predicted and how much clinical detail is needed to do so. RESEARCH DESIGN, DATA SOURCES, AND PARTICIPANTS: Longitudinal study of bipolar disorder patients treated during 2000 to 2004 in the 19-site Systematic Treatment Enhancement Program for Bipolar Disorder observational study arm (N=3168). Clinical data were obtained at baseline and quarterly for over 1 year. We fit a "gold standard" longitudinal random-effects regression model using a detailed clinical information and estimated the area under the receiver operating characteristic curve (AUC) to predict accuracy using a validation sample. The model was then modified to include patient characteristics feasible in routinely collected electronic data (eg, administrative data). We compared the AUCs for the "limited-detail" and gold standard models, testing for differences between the AUCs using the validation sample. MEASURE: Remission, defined as Montgomery-Asberg Depression Rating Scale score <5 and Young Mania Rating Scale score <4. RESULTS: The gold standard models had baseline AUC=0.80 (95% confidence interval=0.74 to 0.86) and 0.75(0.64 to 0.86) at 1-year follow-up. The predicted accuracies of the limited-detail model were lower at baseline [AUC=0.67(0.60 to 0.75)]; correlated test chi=14.25, P=0.002] and not statistically different from the gold standard model at 1 year [AUC=0.67(0.54-0.80); correlated test chi=2.88, P=0.090]. CONCLUSIONS: Future work is needed to develop clinically accurate and feasible models to predict bipolar disorder outcomes. Clinically detailed and limited models performed similarly for shorter-term prediction at 1-year; however, there is room for improvement in prediction accuracy. PMID- 22210541 TI - The pivot shift: a global user guide. AB - PURPOSE: The use of several different maneuvers for the pivot shift test has resulted in inconsistent quantitative measurements. The purpose of this study was to describe, analyze, and group several surgeon-specific techniques for the pivot shift test and to propose a standardized pivot shift test. METHODS: Twelve expert surgeons examined a whole lower cadaveric extremity with their preferred technique and assigned a clinical grade, I-III. Anterior tibial translation and acceleration were measured using an electromagnetic system. The test was repeated after watching an instructional video focused on a standardized pivot shift technique. Measurements were repeated and compared with the preferred technique. RESULTS: The expert surgeons utilized valgus stress unanimously in addition to fixed internal rotation (n = 5), fixed external rotation (n = 1), a motion allowing technique (n = 3), a dislocation-type maneuver (n = 2), and a fixed anterior drawer type of maneuver in extension (n = 1). Anterior tibial translation measured was on average 15.9 +/- 3.7 mm. Average tibial acceleration was 3.3 +/- 2.1 mm/s(2). Average clinical grading was 2.3 +/- 0.5. There were no differences in average clinical grading when using high stress (2.5 +/- 0.6) versus low stress (2.3 +/- 0.5, n.s.), or using fixed rotation (2.2 +/- 0.5) versus a motion-allowing technique (2.3 +/- 0.6; n.s.). CONCLUSIONS: Clinical grading, tibial translation, and acceleration vary between examiners performing the pivot shift test. High forces and extremes of rotation are not necessary to produce a clinical detectable pivot shift. In the future, a standardized pivot shift test-which can be performed universally and utilizes only gentle forces allowing motion to occur-may be beneficial when assessing differences in outcome following ACL reconstruction. PMID- 22210542 TI - Gallbladder perforation: case series and systematic review. AB - BACKGROUND: Gallbladder perforation is a serious complication of acute cholecystitis. Its management has evolved considerably since its classification by Niemeier in 1934. This review summarises the evidence surrounding the natural progression of this condition and potential problems with Niemeier's classification, and proposes a management algorithm for the more complex type II perforation. METHODS: Data from a retrospective case series and a systematic review were combined. The case series included all patients with gallbladder perforations from 2004 to 2008 at a British teaching hospital. The systematic review searched for gallbladder perforation using the MEDLINE, Embase, Web of Science and Cochrane Library (2011 Issue 4) databases, as well as recent conference abstracts. The outcome data were analysed using SPSS version 15. No adjustments were made for multiple testing. RESULTS: 198 patients (including 19 patients from the present series) with a mean age of 62.1+/-9.7 years and male gender proportion of 55.4% (range 33.3-76.7%) were included. The most common gallbladder perforations were type II (median 46.2%, range 7.4-83.3%), followed by type I (median 40.6%, range 16.7-70.0%) and type III (median 10.1%, range 0 48.1%). Perforation was associated with cholelithiasis in 86.6% (range 78.9 90.6%) of patients, and the overall median mortality rate was 10.8% (range 0 12.5%). Male gender was weakly associated with mortality (p = 0.089) but age (p = 0.877) and cholelithiasis (p = 0.425) were not. Mortality did not vary significantly with perforation type. CONCLUSIONS: Gallbladder perforation should be reported according to the original Neimeier's classification to avoid heterogeneity in data (e.g. varying rates of perforation types). The algorithm proposed in this study aims to guide the management of complex type II gallbladder perforations to minimise subsequent morbidity and mortality. PMID- 22210543 TI - Genetic structure within and among populations of Saruma henryi, an endangered plant endemic to China. AB - The endangered perennial plant Saruma henryi Oliv. is endemic to China and has phylogenetic, ecological, and medicinal value. We used 10 microsatellite (SSR) loci to investigate genetic diversity and differentiation in 16 natural populations. Genetic diversity was high at the species level (H(E) = 0.9427, h = 0.9410, I = 3.0213) and low at the population level (H(E) = 0.4441, h = 0.4307, I = 0.6822). Pronounced genetic differentiation was detected among populations (G(ST) = 0.5428, F(ST) = 0.5524), in line with the limited among-population gene flow (Nm = 0.21). The significant isolation-by-distance pattern revealed by a Mantel test (r = 0.311, P = 0.001) suggested a clear geographic tendency in the distribution of genetic variability. Bayesian assignment and principal coordinates analyses supported the clustering of 16 populations into three groups. The present SSR results were also compared with previously published ISSR results. These results have significant implications for conservation of the species. PMID- 22210544 TI - Isolation and gene expression of yellow grouper ferritin heavy chain subunit after lipopolysaccharide treatment. AB - Ferritin is a ubiquitous and conserved iron storage protein that plays a central role in iron metabolism. The ferritin heavy chain subunit (FerH) homolog was isolated from yellow grouper (Epinephelus awoara) spleen using suppression subtractive hybridization and RACE-PCR. The nucleotide sequence of FerH full length cDNA was 1173 bp and contained an open reading frame of 534 bp, encoding a putative protein of 177 amino acids. The encoded protein shows 78-94% identity with homologs. Based on phylogenetic analysis, yellow grouper FerH is highly conserved throughout evolution and is closer to European seabass than to other species. RT-PCR analysis demonstrated that FerH was widely expressed in various healthy tissues and significantly up-regulated in liver, spleen, and anterior kidney by lipopolysaccharide. The results suggest that yellow grouper FerH may play a role in immune response. PMID- 22210545 TI - B lymphopoiesis is characterized by pre-B cell marker gene expression in fetal cattle and declines in adults. AB - Fetal cattle B-cell development proceeds via a pre-B cell stage that is characterized by the expression of surrogate light chain and recombination activation genes. In this paper, we identify a new member of bovine pre-B lymphocyte genes, VPREB2. Using RT-qPCR, we assess the expression of VPREB2 and three other surrogate light chain genes as well as RAG1 and RAG2 in fetal and adult cattle tissues. The absence of VPREB1, IGLL1, RAG1 and RAG2 expression in adult tissues and the lack of B-lymphoid differentiation in adult bone marrow - OP9 stromal cell co-culture, suggest a decline of B lymphopoiesis in adult cattle. The marked differences in the expression profiles of VPREB2 and VPREB3 in comparison to those of VPREB1, IGLL1 and RAGs suggest that the biological roles of VPREB2 and VPREB3 are unrelated to the pre-B cells. PMID- 22210546 TI - Identification of putative cathepsin S in mangrove red snapper Lutjanus argentimaculatus and its role in antigen presentation. AB - Cathepsin S (CTSS) is a key enzyme employed in the histocompatibility complex (MHC) class II-restricted antigens, which are presented by processing class II associated invariant chains and loaded antigen peptides into class II molecules. To date, little is known about the character and function of CTSS in fish. In the present study, we screened and identified a CTSS cDNA sequence from the mangrove red snapper head kidney cDNA library. The full-length CTSS cDNA contained 1339-bp nucleotide acids encoding 337 amino acids. The sequence shared high identity and similarity with other known cathepsins, especially CTSS (about 56-78% and 79-89%, respectively). Like other cathepsins, the deduced peptide consisted of regions with N-terminal signal peptides, propeptides, and mature peptides. A typical ERWNIN motif in L-like cathepsins and three conservative catalytic activity sites forming a catalytic triad active center were respectively identified in the pro peptide and mature peptide regions of CTSS. Phylogenetic analysis revealed that mangrove red snapper CTSS was located in the CTSS clade belonging to the L-like cathepsin group, and evolved from the same ancestry. To further characterize the biological activity of the putative CTSS of mangrove snapper, CTSS was expressed in Escherichia coli M15 strains. Like other mammalian CTSS, the recombinant CTSS (rCTSS) had autocatalytic activation properties, can remove pro-peptides, and can release active mature peptides. Active CTSS had the ability to catalyze Z-Phe-Arg AMC substrates in acidic conditions (pH 5.0) and weak alkaline environments (pH 7.5); this activity could be blocked by the cysteine protease inhibitor E-64. Active CTSS can process recombinant Ii chains (invariant chains) in a stepwise manner in vitro. The results indicate that mangrove red snapper CTSS is a lysosomal cysteine protease family member with a key role in antigen processing in fish. PMID- 22210547 TI - Conserved microRNA miR-8 in fat body regulates innate immune homeostasis in Drosophila. AB - Antimicrobial peptides (AMPs) constitute a major arm of the innate immune system across diverse organisms. In Drosophila, septic injury by microbial pathogens rapidly induces the production of the AMPs in fat body via well elucidated pathways such as Toll and IMD. However, several epithelial tissues were reported to locally express AMPs without septic injury via poorly characterized ways. Here, we report that microRNA miR-8 regulates the levels of AMPs basally expressed in Drosophila. The levels of AMPs such as Drosomycin and Diptericin are significantly increased in miR-8 null animals in non-pathogen stimulated conditions. Analysis of various larval tissues revealed that the increase of Drosomycin is fat body specific. Supporting this observation, re-introduction of miR-8 only in the fat body restored the altered AMP expression in miR-8 null flies. Although loss of miR-8 impedes PI3K in the fat body, inhibition of PI3K does not phenocopy the AMP expression of miR-8 null flies, indicating that miR-8 regulates AMP independently of PI3K. Together, our findings suggest a role of miR 8 in systemic immune homeostasis in generally non-pathogenic conditions in flies. PMID- 22210548 TI - Looking back to 1921 and forward to 2012. PMID- 22210549 TI - Discussion podcast--on "a comparison of health care use for physician-referred and self-referred episodes of outpatient physical therapy ". PMID- 22210550 TI - On "lower limb functional index..." Gabel CP, Melloh M, Burkett B, Michener LA. Phys Ther. 2012;92:98-110. PMID- 22210551 TI - FOXP3+ cell density in lymphoid follicles from histologically normal mucosa is a strong prognostic factor in early stage colon cancer. AB - There are few clearly established prognostic factors available to guide the use of adjuvant chemotherapy in early stage colon cancer patients. Some of the most promising candidates include the invasion of extramural blood vessels by tumour cells and the densities of FOXP3+ T regulatory cells (Tregs) in tumour and adjacent normal colonic mucosal tissue. The aim of our study was to evaluate the prognostic significance of these markers in AJCC stage II colon cancer, with particular reference to lymphoid follicles in the mucosa. Histopathological review for the presence of vascular and serosal invasion was conducted on a series of 165 stage II colon cancers treated by surgery alone. Immunohistochemical staining for FOXP3 was performed on tumour tissue and histologically normal colonic mucosa from the surgical margin. Image analysis software was used to evaluate the density of FOXP3+ cells in the tumour core, invading margin and lymphoid follicles from the colonic mucosa. For survival analysis, cases were classified into high- or low-density of FOXP3+ cells according to the median value. The mean density of FOXP3+ Tregs in lymphoid follicles was twofold and fivefold higher than in the invading margin and tumour core, respectively. Multivariate analysis identified extramural vascular invasion (HR, 2.47; 95% CI: 1.00-6.07; P = 0.05) and high FOXP3+ cell density in lymphoid follicles (HR, 4.22; 95% CI: 1.49-11.91; P = 0.007) as independent factors for worse survival, whereas a high frequency of lymphoid follicles in histologically normal colonic mucosa was associated with better survival (HR, 0.31; 95% CI: 0.12 0.79; P = 0.014). Our data suggest that host factors related to the immune system have major prognostic significance in early stage colon cancer. The density of FOXP3+ cells within lymphoid follicles and the frequency of these structures in normal colonic mucosa represent novel and independent prognostic factors. PMID- 22210553 TI - Early outcomes of HIV exposed children in the first district-wide programme using extended regimens for the prevention of mother-to-child transmission of HIV, in Yaounde, Cameroon. AB - OBJECTIVE: Report on the early outcomes achieved in the prevention of mother-to child transmission (PMTCT) programme in the Djoungolo Health District using more effective antiretroviral PMTCT regimens. METHODS: Observational cohort of HIV exposed infants. MAIN OUTCOME MEASURE: early infant HIV status and 3-month mortality rate. RESULTS: From March 2008 to March 2010, 587 HIV-positive mother baby pairs were enrolled and classified according to the following maternal antiretroviral regimen: Group 1: highly active antiretroviral therapy (HAART), Group 2: dual therapy, Group 3: no treatment. 484/587 (82%) underwent HIV-early infant diagnosis at a median age of 7 weeks; 4.5% (95% CI 2.65-6.34) were HIV infected. HIV transmission rate differed by maternal prophylaxis: 1.7% for HAART, 2.7% for dual therapy and 15.7% for Group 3 (p < 0.001), but not by feeding method (2.74%)-exclusive breastfeeding vs. 5.34% formula (NS). The 3-month mortality rate stands at 1%. CONCLUSIONS: The 4.5% MTCT-rate of HIV-1 reported, confirms the feasibility and effectiveness of a district wide PMTCT programme using HAART in low-income settings. PMID- 22210552 TI - Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer. AB - CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The antitumor mechanism is presumably mediated in part by the expansion of tumor specific T cells. Androgen deprivation, the cornerstone of treatment for patients with metastatic prostate cancer, has been shown to elicit prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a tumor specific immune response elicited by androgen deprivation. We report here the results of a phase I trial evaluating a humanized monoclonal antibody targeting CTLA-4, CP-675,206 (tremelimumab), in combination with androgen deprivation using an antiandrogen. Eligible patients were those with PSA-recurrent prostate cancer after primary surgery and/or radiation therapy, not previously treated with androgen deprivation, and without radiographic evidence of metastatic disease. Subjects were treated in two cycles, 3 months apart, in which they received bicalutamide 150 mg daily days 1-28 and tremelimumab on day 29. The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose. Eleven patients were enrolled and completed at least 1 year of follow-up. Dose-limiting toxicities included grade 3 diarrhea and skin rash. No favorable changes in PSA doubling time were observed in a period shortly after completing treatment; however, three patients experienced a prolongation in PSA doubling time detectable several months after completing treatment. The identification of delayed, prolonged favorable changes in serum PSA suggests that future studies could explore this combination in studies evaluating time to disease progression. PMID- 22210554 TI - Factors affecting tobacco use among middle school students in Saudi Arabia. AB - A rapid rise in the number of tobacco users in Saudi Arabia has occurred in the past decade, particularly among the youth. This study identified socio-cultural determinants of tobacco use and explored possible approaches to prevent adolescents' tobacco use in Saudi Arabia. A cross-sectional survey was administered using a self-administered questionnaire for collecting information on risk and protective factors for tobacco use among middle school students. School selection was stratified by region, gender, and type (public or private). Of 1,186 7-9th grade students, 1,019 questionnaires were analyzed. Risk factors affecting tobacco use included all important others' perceptions; mother, sister, friend, teacher and important person's tobacco use; pressure to use tobacco from brother, sister, friend and important persons; easy access to tobacco and frequent skipping of classes. Protective factors for tobacco use included family's perception; friend, teacher and important person's tobacco use; parents' help; support from family, friends, and teachers; accessibility to tobacco; school performance and family income, father's education, and district of residence. The findings of this study show clear gender differences in social influences and attitudes towards tobacco use. Religious beliefs and access to tobacco products were significantly associated with attitudes towards tobacco use and future intention of use. Developing and implementing effective gender specific school-based tobacco prevention programs, strict reinforcement of tobacco control policies, and a focus on the overall social context of tobacco use are crucial for developing successful long-term tobacco prevention programs for adolescents. PMID- 22210555 TI - Pulmonary artery involvement and associated lung disease in Behcet disease: a series of 47 patients. AB - Pulmonary artery aneurysms (PAAs) are well known causes of mortality and morbidity in Behcet disease (BD). However, pulmonary artery involvement in BD is not limited to PAA; the other main type of pulmonary artery involvement is pulmonary artery thrombus (PAT), with or without associated PAA. In addition, other types of lung disease like nodules and cavities in the lung parenchyma are frequently associated with pulmonary artery involvement, and can be misinterpreted as being due to infection. We surveyed the clinical, radiologic, and laboratory characteristics and outcome of 47 BD patients with pulmonary artery involvement and the associated findings, all seen and followed at a single dedicated tertiary care center.We identified 47 (41 male, 6 female) patients in whom pulmonary artery involvement was diagnosed, who were registered in the multidisciplinary clinic at Cerrahpasa Medical Faculty between January 2000 and December 2007. Mean age at diagnosis was 29 +/- 8 years, and mean disease duration to the onset of pulmonary artery involvement was 3.6 +/- 4.8 years. Hemoptysis was the most common presenting symptom (79%) followed by cough, fever, dyspnea, and pleuritic chest pain. Thirty-four of 47 patients (72%) presented with PAA, including 8 with associated PAT. The remaining 13 patients (28%) had isolated PAT. Patients with isolated PAT in general have clinical features similar to patients with PAA. However, hemoptysis was less frequent and voluminous in patients with isolated PAT. Most (91%) of the patients had active disease outside the lungs when they presented with pulmonary artery involvement.Forty (85%) patients had nodules and 6 (13%) had cavities when first seen. Peripheral venous thrombosis was present in 36 of 47 (77%) patients, and intracardiac thrombi in 12 of the 36 (33%) patients. Nodules, cavities, and intracardiac thrombi were mainly present in the acute stages of pulmonary artery involvement.Pulmonary artery involvement is usually multiple, and involves mostly descending branches of the pulmonary artery. Pulmonary artery involvement may disappear, but arterial stenosis or occlusions usually develop at the same location. After a mean follow-up of 7 years, 12 of 47 (26%) patients were dead; patients with larger aneurysms were more likely to die. Sixteen of 47 (34%) patients were symptom free, and the remaining 40% had mild dyspnea (13/47) and/or small bouts of hemoptysis (8/47).Pulmonary artery pressure may be elevated, and may indicate a poor prognosis. Mediastinal lymphadenopathy and mild pleural and pericardial effusions may also be observed. Corticosteroids and immunosuppressive agents are the mainstays of treatment; however, refractory cases may require embolization, lobectomy, cavitectomy, and decortication. PMID- 22210556 TI - Rituximab for the treatment of IgG4-related disease: lessons from 10 consecutive patients. AB - Patients with IgG4-related disease (IgG4-RD) typically have elevated serum concentrations of IgG4 and share histopathologic features that are similar across affected organ(s). IgG4-RD patients frequently require prolonged treatment with glucocorticoids and are often unable to taper these medications. Traditional disease-modifying antirheumatic drugs (DMARDs) are generally ineffective. We assessed the clinical and serologic responses to B lymphocyte depletion therapy in 10 consecutive patients with steroid- and DMARD-refractory IgG4-RD.Ten patients with IgG4-RD were treated with rituximab (RTX) (2 infusions of 1000 mg, 15 days apart). Clinical improvement was assessed by monitoring the patient's ability to taper prednisone to discontinuation and to stop DMARDs; by serial measurements of total IgG and IgG subclasses; and by follow-up radiologic assessments guided by the patient's particular pattern of organ involvement. We also developed and retrospectively applied the IgG4-RD Disease Activity Index and Flare Tool.Organ involvement included the pancreas, biliary tree, aorta, salivary glands (submandibular and parotid), lacrimal glands, lymph nodes, thyroid gland, and retroperitoneum. Nine of 10 patients demonstrated striking clinical improvement within 1 month of starting RTX. One patient with advanced thyroid fibrosis associated with Riedel thyroiditis and a history of disease in multiple other organ systems did not have improvement in the thyroid gland, but the disease did not progress to involve new organs. All 10 patients were able to discontinue prednisone and DMARDs following RTX therapy. Significant decreases in IgG concentrations were observed for the IgG4 subclass only. Four patients were re-treated with RTX after 6 months because of either symptom recurrence and increasing IgG4 concentration at the time of peripheral B cell reconstitution (n = 2) or because of physician discretion (n = 2). Repeated courses of RTX maintained their effectiveness and resulted in further decreases in IgG4 concentrations. In patients who had an increased IgG4 concentration at the time of presentation, the level of serum IgG4 appeared to be a reliable measure of disease activity.IgG4-RD is an idiopathic, multiorgan inflammatory disease in which diverse organ manifestations are linked by characteristic histopathologic and immunohistochemical features. Treatment with RTX led to prompt clinical and serologic improvement in refractory IgG4-RD in all patients with active inflammation. Serial treatments with RTX may lead to progressive declines in serum IgG4 concentrations and better disease control. Serum IgG4 concentrations may remain low, and clinical disease activity may remain quiescent even after B cell reconstitution in a significant proportion of patients. PMID- 22210557 TI - Cell surface properties of Pseudomonas stutzeri in the process of diesel oil biodegradation. AB - Pseudomonas stutzeri, isolated from crude oil-contaminated soil, was used to degrade diesel oil. Of three surfactants, 120 mg rhamnolipids 1(-1) significantly increased degradation of diesel oil giving 88% loss after 14 days compared to 54% loss without the surfactant. The system with rhamnolipids was characterised by relatively high particle homogeneity. However, the addition of saponins to diesel oil caused the cells to aggregate (the polydispersity index: 0.542) and the biodegradation of diesel oil was only 46%. The cell yield was 0.22 g l(-1). PMID- 22210558 TI - Potential role for therapies targeting DKK1, LRP5, and serotonin in the treatment of osteoporosis. AB - Osteoporosis is a common disorder in which diminished bone mass leads to progressive microarchitectural skeletal deterioration and increased fracture risk. Our understanding of both normal and pathologic bone biology continues to evolve, and with it our grasp of the highly coordinated relationships between primary bone cells (osteoblasts, osteoclasts, and osteocytes) and the complex molecular signals bone cells use to integrate signals derived from other organ systems, including the immune, hematopoietic, gastrointestinal, and central nervous systems. It is now clear that the Wnt signaling pathway is central to regulation of both skeletal modeling and remodeling. Herein, we discuss components of the Wnt signaling pathway (DKK1, an endogenous soluble inhibitor of Wnt signaling) and LRP5 (a plasma membrane-localized Wnt co-receptor) as potential future targets for osteoporosis therapy. Finally, we discuss the current controversial role for serotonin in skeletal metabolism, and the potential role of future therapies targeting serotonin for osteoporosis treatment. PMID- 22210559 TI - Nitric oxide donors for the treatment of osteoporosis. AB - The number of osteoporotic fractures is increasing worldwide as populations age. An inexpensive and widely available treatment is necessary to alleviate this increase in fractures. Current treatments decrease fractures at trabecular bone sites (spine) but have limited effects at cortical sites (hip, legs, forearm, and upper arm)-the most common sites of osteoporotic fracture. Treatments are also limited by costs, side effects, and lack of availability. Nitric oxide is a novel agent that has the potential to influence cortical bone, is inexpensive, is widely available, and has limited side effects. In this review we evaluate the in vitro and in vivo data which support the concept that nitric oxide is important in bone cell function, review the observational and case-control studies reporting on subjects taking organic nitrates that act as nitric oxide donors, and review the effects of nitrates on bone mineral density measurements and fracture risk. PMID- 22210560 TI - Wavelet analysis of lumbar muscle oxygenation signals during whole-body vibration: implications for the development of localized muscle fatigue. AB - The objective of this study was to assess the effects of whole-body vibration (WBV) on lumbar muscle oxygenation oscillations in healthy men based on the wavelet transform of near-infrared spectroscopy signals. Twelve healthy participants were exposed to WBV at frequencies of 3, 4.5 and 6 Hz while muscle oxygenation signal was monitored before, during and recovery from WBV. With spectral analysis based on wavelet transform of NIR signal, six frequency intervals were identified (I, 0.005-0.0095 Hz; II, 0.0095-0.02 Hz; III, 0.02-0.06 Hz; IV, 0.06-0.16 Hz; V, 0.16-0.40 Hz and VI, 0.40-2.0 Hz). It was found that the muscle oxygenation oscillations at 4.5 Hz in the frequency intervals I, II and III was lower during WBV compared with that of at 3 Hz. Present results demonstrated WBV at 4.5 Hz induced lower oscillatory activities than that of at 3 Hz. The lower oscillatory activities might indicate a decrease in the efficiency of oxygen supply to the oxygenated tissue and such mechanism might contribute to the development of local muscle fatigue. PMID- 22210561 TI - Verbal memory capacity after treatment for ruptured intracranial aneurysm--the outcomes of three psychological tests: within a month, 1 year after and 5-7 years after treatment. AB - BACKGROUND: Verbal memory is an essential cognitive ability with scope for adequate treatment of information and for orientation in everyday life. Our study is centered on memory performance in the wake of treatment for ruptured intracranial aneurysm. METHODS: Three psychological tests were performed: (1) within a month of the neurosurgical intervention, (2) 1 year and (3) 5-7 years after the ruptured aneurysm treatment. Under comparison are the overall results of tests for verbal memory capacity in a cohort of patients (N = 59) and in the control group. RESULTS: Three post-treatment measurements revealed a persistent deficit of verbal memory. The cohort's average performance improved from -1.3 SD (standard deviation) below the average of the norm to -0.5 SD below the norm at the second test 1 year after treatment, while at the third test the deficit had worsened to -0.68 SD. Similarly, testing for long-term recovery at 5-7 years postoperatively showed the patients' performances to be 2/3 SD below the average of the general population. CONCLUSIONS: The results of the study imply the need for long-term rehabilitation of memory in this particular group of patients. PMID- 22210562 TI - Association of C-reactive protein with cardiovascular disease mortality according to diabetes status: pooled analyses of 25,979 participants from four U.K. prospective cohort studies. AB - OBJECTIVE: C-reactive protein (CRP) is associated with the risk of cardiovascular disease (CVD); whether the effects are modified by diabetes status still is unclear. This study investigated these issues and assessed the added value of CRP to predictions. RESEARCH DESIGN AND METHODS: Participants were drawn from representative samples of adults living in England and Scotland. Cox proportional hazards regression models were used to relate baseline plasma CRP with all-cause and CVD mortality during follow-up in men and women with and without diabetes. The added value of CRP to the predictions was assessed through c-statistic comparison and relative integrated discrimination improvement. RESULTS: A total of 25,979 participants (4.9% with diabetes) were followed for a median of 93 months, during which period there were 2,767 deaths (957 from CVD). CRP (per SD log(e)) was associated with a 53% (95% CI 43-64) and 43% (38-49) higher risk of cardiovascular and all-cause mortality, respectively. These associations were log linear and did not differ according to diabetes status (both P >= 0.08 for interaction), sex, and other risk factors. Adding CRP to conventional risk factors improved predictions overall and separately by diabetes status but not for CVD mortality, although such improvements only were marginal based on several discrimination statistics. CONCLUSIONS: The association between CRP and CVD was similar across diabetes status, and the effects are broadly similar across levels of other conventional risk factors. PMID- 22210564 TI - Serum 1,5-anhydroglucitol concentrations are a reliable index of glycemic control in type 2 diabetes with mild or moderate renal dysfunction. AB - OBJECTIVE: To assess the relationship between 1,5-anhydroglucitol (AG) levels, which are a marker of glycemic control, and stages of chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS: This was a cross-sectional study with 269 subjects with type 2 diabetes who were divided into four groups based on estimated glomerular filtration rate (eGFR) using Modification of Diet in Renal Disease (eGFR(MDRD)) formula: 57 in control, 111 in CKD stages 1-2, 78 in stage 3, and 23 in stages 4-5. RESULTS: The study groups differed significantly with respect to 1,5-AG and fasting plasma glucose (FPG), age, duration of diabetes, blood pressure, HDL, and percentage of antihypertension or antidyslipidemia medication use. Stepwise multivariate regression analyses showed that 1,5-AG levels in the control group, the CKD stages 1-2 group, and the CKD stage 3 group could be explained by HbA(1c), age, duration of diabetes, FPG, and antihypertension medication. However, eGFR(MDRD) was the only independent determinant of 1,5-AG levels in CKD stages 4-5. Logarithmic transformed 1,5-AG values (ln[1,5-AG]) had significant inverse correlations with HbA(1c) and FPG levels for CKD stages 1-2 and CKD stage 3 (all P < 0.001). However, associations between ln(1,5-AG) and HbA(1c) or FPG were insignificant for CKD stages 4-5 (P = 0.274 and P = 0.080, respectively). CONCLUSIONS: This study demonstrated that 1,5 AG levels do not appear to be influenced by mild or moderate renal dysfunction, suggesting it is a reliable glycemic marker in type 2 diabetes with CKD stages 1 3. PMID- 22210565 TI - A study of patients' perceptions of diabetes care delivery and diabetes: propositional analysis in people with type 1 and 2 diabetes managed by group or usual care. AB - OBJECTIVE: We investigated the perceptions of diabetes care and diabetes in patients followed long-term by group or usual care. RESEARCH DESIGN AND METHODS: Three open questions were administered to 120 patients (43 with T1DM and 77 with T2DM) who had been randomized at least 2 years before to be followed by group care and 121 (41 T1DM and 80 T2DM) who had always been on usual care. The responses were analyzed by propositional analysis, by identifying the focal nuclei, i.e., the terms around which all sentences are organized, and then other predicates, according to their hierarchical relationship to the nuclear proposition. Specific communicative units were arbitrarily classified into three categories: attitudes, empowerment, and locus of control. RESULTS: Patients on group care showed more positive attitudes, higher sense of empowerment, and more internal locus of control than those on usual care. In addition, they expressed a wider and more articulated range of concepts associated with the care received and made less use of medical terminology (P < 0.001, all). Higher HbA(1c) was associated with negative attitudes (P = 0.025) and negative empowerment (P = 0.055). CONCLUSIONS: Group treatment reinforces communication and peer identification and may achieve its clinical results by promoting awareness, self efficacy, positive attitudes toward diabetes and the setting of care, an internal locus of control, and, ultimately, empowerment in the patients. PMID- 22210566 TI - Circulating brain-derived neurotrophic factor concentration is downregulated by intralipid/heparin infusion or high-fat meal in young healthy male subjects. AB - OBJECTIVE: Insulin resistance and type 2 diabetes are associated with an increased risk of neurodegenerative diseases. Brain-derived neurotrophic factor (BDNF) regulates neuronal differentiation and synaptic plasticity, and its decreased levels are supposed to play a role in the pathogenesis of Alzheimer's disease and other disorders. The aim of the current study was to estimate the effects of hyperinsulinemia and serum free fatty acids (FFA) elevation on circulating BDNF concentration in humans. RESEARCH DESIGN AND METHODS: We studied 18 healthy male subjects (mean age 25.6 +/- 3.0 years; mean BMI 26.6 +/- 4.8 kg/m(2)). Serum and plasma BDNF concentration was measured in the baseline state and in the 120 and 360 min of euglycemic hyperinsulinemic clamp with or without intralipid/heparin infusion. Furthermore, plasma BDNF was measured in 20 male subjects (mean age 22.7 +/- 2.3 years; mean BMI 24.9 +/- 1.5 kg/m(2)) 360 min after a high-fat meal. RESULTS: Insulin sensitivity was reduced by ~40% after 6 h of intralipid/heparin infusion (P < 0.001). During both clamps, serum and plasma BDNF followed the same pattern. Hyperinsulinemia had no effect on circulating BDNF. Raising FFA had no effect on circulating BDNF in 120 min; however, it resulted in a significant decrease by 43% in serum and by 35% in plasma BDNF after 360 min (P = 0.005 and 0.006, respectively). High-fat meal also resulted in a decrease by 27.8% in plasma BDNF (P = 0.04). CONCLUSIONS: Our data show that raising FFA decreases circulating BDNF. This might indicate a potential link between FFA-induced insulin resistance and neurodegenerative disorders. PMID- 22210563 TI - Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. AB - OBJECTIVE: To test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally treated (diet and exercise) drug-naive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients were randomized to subcutaneous (SC) EQW 2.0 mg + oral placebo (n = 248), MET 2,000 mg/day + SC placebo (n = 246), PIO 45 mg/day + SC placebo (n = 163), or SITA 100 mg/day + SC placebo (n = 163) for 26 weeks. MET and PIO therapies were increased to maximum-tolerated dosages. Injections with EQW or placebo were administered weekly, while oral medication or placebo was administered daily. RESULTS: Baseline characteristics were as follows: 59% men, 67% Caucasian, mean age 54 years, HbA(1c) 8.5%, fasting serum glucose 9.9 mmol/L, body weight 87.0 kg, and diabetes duration 2.7 years. HbA(1c) reductions (%) at 26 weeks (least-squares means) with EQW versus MET, PIO, and SITA were -1.53 vs. -1.48 (P = 0.620), -1.63 (P = 0.328), and -1.15 (P < 0.001), respectively. Weight changes (kg) were -2.0 vs. -2.0 (P = 0.892), +1.5 (P < 0.001), and -0.8 (P < 0.001), respectively. Common adverse events were as follows: EQW, nausea (11.3%) and diarrhea (10.9%); MET, diarrhea (12.6%) and headache (12.2%); PIO, nasopharyngitis (8.6%) and headache (8.0%); and SIT, nasopharyngitis (9.8%) and headache (9.2%). Minor (confirmed) hypoglycemia was rarely reported. No major hypoglycemia occurred. CONCLUSIONS: EQW was noninferior to MET but not PIO and superior to SITA with regard to HbA(1c) reduction at 26 weeks. Of the agents studied, EQW and MET provided similar improvements in glycemic control along with the benefit of weight reduction and no increased risk of hypoglycemia. PMID- 22210567 TI - Type 1 diabetes increases the expression of proinflammatory cytokines and adhesion molecules in the artery wall of candidate patients for kidney transplantation. AB - OBJECTIVE: Diabetes may accelerate atheromatosis in uremic patients. Our aim was to assess the influence of type 1 diabetes on the atheromatosis-related inflammation in patients with chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS: We analyzed the expression of proinflammatory cytokines and adhesion molecules in the inferior epigastric artery walls of type 1 diabetic patients with CKD (n = 22) and compared it with nondiabetic uremic patients (n = 92) at the time of kidney transplantation. We evaluated the expression of interleukin (IL)-6, monocyte chemotractant protein (MCP)-1, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule-1, and the activation of nuclear factor kappabeta p65 (NFkB-p65). Common carotid intima-media thickness (c-IMT) was determined by conventional echography. RESULTS: IL-6, MCP-1, and VCAM-1 proteins were elevated in type 1 diabetic patients compared with nondiabetic subjects (P < 0.05). The nuclear localization of NFkB-p65 was higher in type 1 diabetic patients (P < 0.01) and correlated with the levels of MCP-1 in this group (r = 0.726, P < 0.001). Arterial fibrosis correlated with IL-6 and MCP-1 levels (r = 0.411, P < 0.001 and r = 0.378, P = 0.001). A significant correlation was observed between VCAM-1 levels and both the degree of arterial narrowing and c IMT. CONCLUSIONS: Type 1 diabetes produces a proinflammatory state in the arteries of end-stage CKD patients, with increased levels of IL-6, MCP-1, and VCAM-1, as well as a greater degree of p65 activation, which are associated with more severe vascular lesions and higher c-IMT. Although causality is not demonstrated, these findings support the major role of inflammation in type 1 diabetic patients with CKD. PMID- 22210568 TI - Nationwide study on trends in hospital admissions for major cardiovascular events and procedures among people with and without diabetes in England, 2004-2009. AB - OBJECTIVE: It is unclear whether people with and without diabetes equally benefitted from reductions in cardiovascular disease (CVD). We aimed to compare recent trends in hospital admission rates for angina, acute myocardial infarction (AMI), stroke, percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG) among people with and without diabetes in England. RESEARCH DESIGN AND METHODS: We identified all patients aged >16 years with cardiovascular events in England between 2004-2005 and 2009-2010 using national hospital activity data. Diabetes- and nondiabetes-specific rates were calculated for each year. To test for time trend, we fitted Poisson regression models. RESULTS: In people with diabetes, admission rates for angina, AMI, and CABG decreased significantly by 5% (rate ratio 0.95 [95% CI 0.94-0.96]), 5% (0.95 [0.93-0.97]), and 3% (0.97 [0.95-0.98]) per year, respectively. Admission rates for stroke did not significantly change (0.99 [0.98-1.004]) but increased for PCI (1.01 [1.005 1.03]) in people with diabetes. People with and without diabetes experienced similar proportional changes for all outcomes, with no significant differences in trends between these groups. However, diabetes was associated with an ~3.5- to 5 fold risk of CVD events. In-hospital mortality rates declined for AMI and stroke, remained unchanged for CABG, and increased for PCI admissions in both groups. CONCLUSIONS: This national study suggests similar changes in admissions for CVD in people with and without diabetes. Aggressive risk reduction is needed to further reduce the high absolute and relative risk of CVD still present in people with diabetes. PMID- 22210569 TI - Strong parent-offspring association of metabolic syndrome in Korean families. AB - OBJECTIVE: To investigate the associations of metabolic syndrome (MetS) and its components between adolescents and their parents in Korea. RESEARCH DESIGN AND METHODS: We analyzed data for 4,657 subjects (1,404 fathers, 1,404 mothers, 957 sons, and 892 daughters) from the Korean National Health and Nutrition Examination Surveys conducted between 1998 and 2008. RESULTS: Compared with adolescents whose parents did not have MetS, the odds ratio (95% CI) for MetS in adolescents with MetS in one parent was 4.2 (2.1-8.5) and 8.7 (3.4-22.3) in those with MetS in both parents. Among obese adolescents, the prevalence of MetS was 18.2% without parental MetS, whereas 29.2% of obese adolescents with MetS in one parent and 53.9% with MetS in both parents also had MetS (P = 0.01 for trend). CONCLUSIONS: The risk of MetS increased significantly in adolescents with parental MetS and was especially high in those with coexisting obesity and parental MetS. PMID- 22210570 TI - Food insecurity and glycemic control among low-income patients with type 2 diabetes. AB - OBJECTIVE: To determine whether food insecurity--the inability to reliably afford safe and nutritious food--is associated with poor glycemic control and whether this association is mediated by difficulty following a healthy diet, diabetes self-efficacy, or emotional distress related to diabetes. RESEARCH DESIGN AND METHODS: We used multivariable regression models to examine the association between food insecurity and poor glycemic control using a cross-sectional survey and chart review of 711 patients with diabetes in safety net health clinics. We then examined whether difficulty following a diabetic diet, self-efficacy, or emotional distress related to diabetes mediated the relationship between food insecurity and glycemic control. RESULTS: The food insecurity prevalence in our sample was 46%. Food-insecure participants were significantly more likely than food-secure participants to have poor glycemic control, as defined by hemoglobin A(1c) >=8.5% (42 vs. 33%; adjusted odds ratio 1.48 [95% CI 1.07-2.04]). Food insecure participants were more likely to report difficulty affording a diabetic diet (64 vs. 49%, P < 0.001). They also reported lower diabetes-specific self efficacy (P < 0.001) and higher emotional distress related to diabetes (P < 0.001). Difficulty following a healthy diet and emotional distress partially mediated the association between food insecurity and glycemic control. CONCLUSIONS: Food insecurity is an independent risk factor for poor glycemic control in the safety net setting. This risk may be partially attributable to increased difficulty following a diabetes-appropriate diet and increased emotional distress regarding capacity for successful diabetes self-management. Screening patients with diabetes for food insecurity may be appropriate, particularly in the safety net setting. PMID- 22210571 TI - A randomized clinical trial to assess the efficacy and safety of real-time continuous glucose monitoring in the management of type 1 diabetes in young children aged 4 to <10 years. AB - OBJECTIVE: Continuous glucose monitoring (CGM) has been demonstrated to improve glycemic control in adults with type 1 diabetes but less so in children. We designed a study to assess CGM benefit in young children aged 4 to 9 years with type 1 diabetes. RESEARCH DESIGN AND METHODS: After a run-in phase, 146 children with type 1 diabetes (mean age 7.5 +/- 1.7 years, 64% on pumps, median diabetes duration 3.5 years) were randomly assigned to CGM or to usual care. The primary outcome was reduction in HbA(1c) at 26 weeks by >=0.5% without the occurrence of severe hypoglycemia. RESULTS: The primary outcome was achieved by 19% in the CGM group and 28% in the control group (P = 0.17). Mean change in HbA(1c) was -0.1% in each group (P = 0.79). Severe hypoglycemia rates were similarly low in both groups. CGM wear decreased over time, with only 41% averaging at least 6 days/week at 26 weeks. There was no correlation between CGM use and change in HbA(1c) (r(s) = -0.09, P = 0.44). CGM wear was well tolerated, and parental satisfaction with CGM was high. However, parental fear of hypoglycemia was not reduced. CONCLUSIONS: CGM in 4- to 9-year-olds did not improve glycemic control despite a high degree of parental satisfaction with CGM. We postulate that this finding may be related in part to limited use of the CGM glucose data in day-to day management and to an unremitting fear of hypoglycemia. Overcoming the barriers that prevent integration of these critical glucose data into day-to-day management remains a challenge. PMID- 22210572 TI - Short sleep duration and poor sleep quality increase the risk of diabetes in Japanese workers with no family history of diabetes. AB - OBJECTIVE: To investigate whether a difference in the risk for diabetes exists in Japanese workers with regard to sleep duration/quality and the presence or absence of a family history of diabetes (FHD). RESEARCH DESIGN AND METHODS: The researchers conducted a prospective, occupational-based study of local government employees in Sapporo, Japan. Between April 2003 and March 2004, 3,570 nondiabetic participants, aged 35-55 years, underwent annual health checkups and completed a self-administered questionnaire that included information on sleep duration/quality and FHD at baseline. Having diabetes was defined as taking medication for diabetes or a fasting plasma glucose level of >=126 mg/dL at follow-up (2007-2008). RESULTS: A total of 121 (3.4%) new cases of diabetes were reported. In multivariate logistic regression models of workers without an FHD, and after adjustment for potential confounding factors, the odds ratio (95% CI) for developing diabetes was 5.37 (1.38-20.91) in those with a sleep duration of <=5 h compared with those with a sleep duration of >7 h. Other risk factors were awakening during the night (5.03 [1.43-17.64]), self-perceived insufficient sleep duration (6.76 [2.09-21.87]), and unsatisfactory overall quality of sleep (3.71 [1.37-10.07]). In subjects with an FHD, these associations were either absent or weaker. CONCLUSIONS: The current study shows that poor sleep is associated with a higher risk of developing diabetes in workers without an FHD. Promoting healthy sleeping habits may be effective for preventing the development of diabetes in people without an FHD. PMID- 22210573 TI - Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. AB - OBJECTIVE: Data on cardiac function in patients with nonalcoholic fatty liver disease (NAFLD) are limited and conflicting. We assessed whether NAFLD is associated with abnormalities in cardiac function in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 50 consecutive type 2 diabetic individuals without a history of ischemic heart disease, hepatic diseases, or excessive alcohol consumption, in whom NAFLD was diagnosed by ultrasonography. A tissue Doppler echocardiography with myocardial strain measurement was performed in all patients. RESULTS: Thirty-two patients (64%) had NAFLD, and when compared with the other 18 patients, age, sex, BMI, waist circumference, hypertension, smoking, diabetes duration, microvascular complication status, and medication use were not significantly different. In addition, the left ventricular (LV) mass and volumes, ejection fraction, systemic vascular resistance, arterial elasticity, and compliance were also not different. NAFLD patients had lower e' (8.2 +/- 1.5 vs. 9.9 +/- 1.9 cm/s, P < 0.005) tissue velocity, higher E-to-e' ratio (7.90 +/- 1.3 vs. 5.59 +/- 1.1, P < 0.0001), a higher time constant of isovolumic relaxation (43.1 +/- 10.1 vs. 33.2 +/- 12.9 ms, P < 0.01), higher LV-end diastolic pressure (EDP) (16.5 +/- 1.1 vs. 15.1 +/- 1.0 mmHg, P < 0.0001), and higher LV EDP/end diastolic volume (0.20 +/- 0.03 vs. 0.18 +/- 0.02 mmHg, P < 0.05) than those without steatosis. Among the measurements of LV global longitudinal strain and strain rate, those with NAFLD also had higher E/global longitudinal diastolic strain rate during the early phase of diastole (E/SR(E)). All of these differences remained significant after adjustment for hypertension and other cardiometabolic risk factors. CONCLUSIONS: Our data show that in patients with type 2 diabetes and NAFLD, even if the LV morphology and systolic function are preserved, early features of LV diastolic dysfunction may be detected. PMID- 22210574 TI - Pioglitazone and bladder cancer: a population-based study of Taiwanese. AB - OBJECTIVE: The association between pioglitazone and bladder cancer has not been investigated in Asians. We aimed to investigate this association. RESEARCH DESIGN AND METHODS: A total of 1,000,000 individuals were randomly sampled from the National Health Insurance database, and incident cases of bladder cancer during the period from 1 January 2006 to 31 December 2009 were analyzed among 54,928 patients with type 2 diabetes and without previous bladder cancer. RESULTS: Among 165 incident case subjects, 10 (0.39%) were ever users and 155 (0.30%) were never users of pioglitazone (adjusted hazard ratio in full model 1.305 [95% CI 0.661 2.576]). All bladder cancer in ever users occurred within a duration of therapy <24 months, suggesting an early effect of pioglitazone on bladder cancer or late use of pioglitazone in high-risk patients. CONCLUSIONS: The association between pioglitazone and bladder cancer was not significant. However, confirmation of this finding is required because of the possible lack of statistical power owing to the small number of events. PMID- 22210575 TI - Clinical and metabolic features of adult-onset diabetes caused by ABCC8 mutations. AB - OBJECTIVE: Gain-of-function ABCC8/sulfonylurea (SU) receptor 1 mutations cause neonatal diabetes mellitus (NDM) or late-onset diabetes in adult relatives. Given the effectiveness of SU treatment in ABCC8-NDM patients, we further characterized late-onset ABCC8-associated diabetes. RESEARCH DESIGN AND METHODS: Seven adult subjects from three NDM families and one family with type 2 diabetes were studied. Insulin secretion and insulin sensitivity were assessed using clamp techniques. We screened 139 type 2 diabetic patients who were well controlled by SU for ABCC8 mutations. RESULTS: ABCC8 mutation carriers exhibited glucose intolerance, frank diabetes, or insulin-requiring diabetes since diagnosis. HbA(1c) improved in five SU-treated patients. Insulin secretion capacity was impaired in three patients compared with adult control subjects but was restored after a 4-week SU trial in two patients. Cohort screening revealed four SU treated patients with ABCC8 mutations, two of which are likely causal. CONCLUSIONS: Although of rare occurrence, recognition of adult-onset ABCC8 associated diabetes may help in targeting patients for SU therapy. PMID- 22210577 TI - High fat intake leads to acute postprandial exposure to circulating endotoxin in type 2 diabetic subjects. AB - OBJECTIVE: To evaluate the changes in circulating endotoxin after a high saturated fat meal to determine whether these effects depend on metabolic disease state. RESEARCH DESIGN AND METHODS: Subjects (n = 54) were given a high-fat meal (75 g fat, 5 g carbohydrate, 6 g protein) after an overnight fast (nonobese control [NOC]: age 39.9 +/- 11.8 years [mean +/- SD], BMI 24.9 +/- 3.2 kg/m(2), n = 9; obese: age 43.8 +/- 9.5 years, BMI 33.3 +/- 2.5 kg/m(2), n = 15; impaired glucose tolerance [IGT]: age 41.7 +/- 11.3 years, BMI 32.0 +/- 4.5 kg/m(2), n = 12; type 2 diabetic: age 45.4 +/- 10.1 years, BMI 30.3 +/- 4.5 kg/m(2), n = 18). Blood was collected before (0 h) and after the meal (1-4 h) for analysis. RESULTS: Baseline endotoxin was significantly higher in the type 2 diabetic and IGT subjects than in NOC subjects, with baseline circulating endotoxin levels 60.6% higher in type 2 diabetic subjects than in NOC subjects (P < 0.05). Ingestion of a high-fat meal led to a significant rise in endotoxin levels in type 2 diabetic, IGT, and obese subjects over the 4-h time period (P < 0.05). These findings also showed that, at 4 h after a meal, type 2 diabetic subjects had higher circulating endotoxin levels (125.4%?) than NOC subjects (P < 0.05). CONCLUSIONS: These studies have highlighted that exposure to a high-fat meal elevates circulating endotoxin irrespective of metabolic state, as early as 1 h after a meal. However, this increase is substantial in IGT and type 2 diabetic subjects, suggesting that metabolic endotoxinemia is exacerbated after high fat intake. In conclusion, our data suggest that, in a compromised metabolic state such as type 2 diabetes, a continual snacking routine will cumulatively promote their condition more rapidly than in other individuals because of the greater exposure to endotoxin. PMID- 22210579 TI - Socioeconomic Status and Health: What is the role of Reserve Capacity? AB - A robust, linear association between socioeconomic status (SES) and health has been identified across many populations and endpoints. This relationship is typically monotonic, so that each step down the SES hierarchy brings increased vulnerability to disease and premature mortality. Despite growing attention to health disparities, scientists and policy makers have made little progress toward confronting their causes and implementing effective solutions. Using the Reserve Capacity Model (Gallo & Matthews, 2003) as an organizing framework, the current article examines the contribution of resilient psychosocial resources to socioeconomic disparities in physical health. Findings suggest that deficient psychosocial resources, such as low perceptions of control and social support, may be one of many factors that connect low SES with poor health. Additional research is needed to test these relationships and their underlying mechanisms, to consider interventions to enhance reserve capacity, and to evaluate the efficacy of such efforts in fostering resilience to socioeconomic hardship. PMID- 22210578 TI - Insulin secretion and its determinants in the progression of impaired glucose tolerance to type 2 diabetes in impaired glucose-tolerant individuals: the Finnish Diabetes Prevention Study. AB - OBJECTIVE: We investigated the effect of early-phase insulin secretion on the incidence of type 2 diabetes in individuals with impaired glucose tolerance (IGT) participating in the Finnish Diabetes Prevention Study (DPS). We examined how a lifestyle intervention affected early-phase insulin secretion (ratio of total insulin area under the curve [AUC] and total glucose AUC [AIGR] from 0 to 30 min) during a 4-year follow-up intervention trial and whether AIGR(0-30) response was modified by insulin sensitivity (IS) and obesity. RESEARCH DESIGN AND METHODS: A total of 443 participants with IGT originally randomized to a lifestyle intervention or control group were studied. IS and AIGR(0-30) were estimated from an oral tolerance glucose test administered annually during the 4-year follow-up trial and were related to the risk of diabetes onset over a 6-year follow-up. RESULTS: Lifestyle intervention resulted in higher IS (P = 0.02) and lower unadjusted AIGR(0-30) (P = 0.08) during the 4-year follow-up. A higher IS and a lower BMI during the follow-up were associated with a lower unadjusted AIGR(0-30) during the follow-up, independently of study group (P < 0.001). A greater increase in IS on the median cutoff point of a 0.69 increase was associated with higher IS-adjusted AIGR(0-30) during the follow-up (P = 0.002). In multivariate models, IS and IS-adjusted AIGR(0-30) were both inversely associated with diabetes incidence (P < 0.001). Participants who progressed to type 2 diabetes were more obese and had lower IS and Matsuda IS index-AIGR(0-30) than nonprogressors. CONCLUSIONS: Our results indicate that the reduction in the risk of developing type 2 diabetes after lifestyle intervention is related to the improvement of IS along with weight loss. Improved IS may also have beneficial effects on preservation of beta-cell function. PMID- 22210580 TI - Embolic protection device use and outcomes in patients receiving saphenous vein graft interventions--a single-center experience. AB - BACKGROUND: Percutaneous treatment of saphenous vein graft disease is hampered by high rates of periprocedural myocardial infarction (MI). The use of embolic protection devices (EPD) during these interventions is a class IB recommendation when technically feasible, yet they are used routinely in less than half of all cases. Our aim was to explore whether or not the under-utilization of EPDs led to any untoward cardiovascular events. METHODS: Consecutive vein graft interventions from 2003-2008 were identified and stratified by EPD use. Information pertaining to demographics, comorbidities, medication use, and procedural details was collected. Primary endpoint was to compare the incidence of periprocedural MI, defined as any creatinine kinase-MB fraction elevation greater than 3 times the upper limit of normal between patients who underwent percutaneous coronary intervention (PCI) for saphenous vein grafts (SVG) with EPD versus patients who underwent PCI for SVG without EPD. Secondary endpoints included comparison of the incidence of recurrent ischemia, MI, revascularization (PCI or coronary artery bypass graft [CABG]), and mortality in the above 2 groups by the end of 1 year. RESULTS: A total of 164 consecutive vein graft interventions were identified. EPDs were used in 71 cases (43.4%). The EPD group was further out since their CABG and had a higher prevalence of hypertension and diabetes. Periprocedural MI occurred in 22 cases; 12 in the non-EPD group and 10 in the EPD group (14.1 vs. 12.9%; P=.82). The composite endpoint of death, MI, or target vessel revascularization at 12 months was significantly lower when EPDs were used (11.3 vs. 25.8%; P=.03). On multivariate analysis, chronic kidney disease increased the risk of periprocedural MI (odds ratio [OR], 5.36; 95% confidence interval [CI], 1.90-15.13; P=.002), whereas the use of beta-blockers was protective (OR, 0.22; 95% CI, 0.07-0.70; P=.011). CONCLUSIONS: EPD use during vein graft interventions did not improve periprocedural MI rates. However, the composite endpoint of adverse cardiovascular outcomes at 1 year was significantly reduced. EPDs are used in a minority of vein graft interventions. Efforts aimed at improving adherence to EPD use may improve long-term outcomes, though this hypothesis should be tested using prospective, randomized studies. PMID- 22210581 TI - Embolic protection devices in saphenous vein graft interventions: is there still a role? PMID- 22210582 TI - Effect of changes in contractility on pressure drop coefficient and fractional flow reserve in a porcine model. AB - OBJECTIVES AND BACKGROUND: Decisions based on invasive functional diagnostic measurements are often made in the setting of fluctuating hemodynamic variables that may alter resting or hyperemic measurements. The purpose of this investigation is to analyze the effect of myocardial contractility (CY) on invasive functional parameters. We hypothesize that the pressure drop coefficient (CDPe; ratio of pressure drop to distal dynamic pressure) and fractional flow reserve (FFR; ratio of average pressures distal and proximal to a stenosis) are not affected by fluctuations in CY and can distinguish between different severities of epicardial stenosis. METHODS: Simultaneous measurements of distal coronary-arterial pressure and velocity were performed in 10 pigs using a dual sensor tipped guidewire for heart rate (HR) <110 bpm and HR >110 bpm, in the presence of coronary lesions of <50% area stenosis (AS) and >50% AS. Variations in myocardial function and vascular resistance were induced by atrial pacing, papaverine and balloon obstruction, respectively. The maximum rate of rise of left ventricular pressure ([dp/dt]max) was the index of contractility. The contractile function of the heart was empirically defined as CY >900 mm Hg/sec (higher) and CY <900 mm Hg/sec (normal). RESULTS: For CY >900 mm Hg/sec, under AS <50% and AS >50%, the mean values of FFR (0.91 +/- 0.02 and 0.78 +/- 0.02), and CDPe (15.6 +/- 5.3 and 70.7 +/- 24.7) were significantly different (P<.05). Similarly, for CY <900 mm Hg/sec, under AS <50% and AS >50%, the mean values of FFR (0.83 +/- 0.04 and 0.63 +/- 0.04), and CDPe (43.8 +/- 14.9 and 191.8 +/- 61.4) were also significantly different (P<.05). CONCLUSIONS: Both FFR and CDPe could effectively distinguish between stenosis severity at normal and higher levels of myocardial contractility. PMID- 22210583 TI - Intravascular ultrasound assessment of postprocedural incomplete stent apposition. AB - BACKGROUND: There has been no detailed intravascular ultrasound (IVUS) analysis to evaluate the degree to which stent underexpansion or reference vessel/stent size mismatch contributes to the occurrence of post-procedural incomplete stent apposition (post-ISA). METHODS: We evaluated 238 lesions treated with everolimus eluting stents (n = 110) or paclitaxel-eluting stents (n = 128). Reference lumen/stent area ratio was defined as the ratio of lumen area adjacent to the stent edge in the reference segment to stent area at the stent edge or at stent body ISA site. RESULTS: Post-ISA was observed in 36 of the 238 cases (15%) at the proximal stent edge, 15 of the 238 cases (6%) at the distal stent edge and 14 of the 238 cases (6%) at stent body. Reference lumen/stent area ratio was significantly greater in the ISA group compared with non-ISA in proximal edge (127 +/- 20 vs. 99 +/- 10%; P<.001), and greater reference lumen/stent area ratio (118 +/- 18 vs. 94 +/- 11%; P<.001) and higher presence of calcification (60 vs. 29%; P<0.001) were observed in distal edge ISA group compared with non-ISA. At the stent body, presence of calcification was more frequently observed in the ISA compared with the non-ISA group (86 vs. 42%; P=.002). CONCLUSIONS: Post-ISA at the stent edge was significantly associated with vessel/stent mismatch rather than stent underexpansion. IVUS-guided appropriate stent or balloon sizing might be useful to prevent post-ISA and optimize initial stent deployment. PMID- 22210584 TI - Incomplete stent apposition...Do we still need to be convinced? PMID- 22210586 TI - Practical considerations of percutaneous ventricular assist devices. AB - Percutaneous ventricular assist devices are increasingly used today, allowing the scope of left ventricular support to move out of the operating room and into the interventional suite and cardiovascular care unit. This has given patients requiring short-term therapy an opportunity to undergo high-risk procedures and provide a failing left ventricular support until native recovery can occur. A growing body of evidence exists that demonstrates device efficacy and safety, as well as its potential clinical importance, a topic that will be reviewed here. Additionally, many providers seek a resource for technical considerations and troubleshooting. We also aim to provide insight into such considerations. PMID- 22210585 TI - Significance of the invasive strategy after acute myocardial infarction on prognosis and secondary preventive medication: a nationwide study of 6364 women and 11,915 men. AB - OBJECTIVE: To describe gender-specific long-term outcome and initiation of secondary preventive medication among patients with acute myocardial infarction (AMI). DESIGN: Observational cohort study. SETTING: Nationwide registries. PATIENTS: We included 18,279 patients: 6364 women (35%) and 11,915 men (65%), admitted with AMI (median age, 67 years; range, 30-90 years) surviving for at least 2 months. INTERVENTIONS: According to sex, patients were stratified by invasive treatment strategy: (1) revascularized; (2) examined with coronary angiography (CAG) but not revascularized; and (3) not examined with CAG. MAIN OUTCOME MEASURES: All-cause mortality and readmission with AMI. Initiation of secondary preventive medication. RESULTS: Of 18,279 patients with a first AMI who survived 2 months, 1857 women (29%) and 1756 men (15%) were not examined with CAG (P<.001), 1295 women (20%) and 1563 men (13%) were examined but not revascularized (P<.001), and 3212 women (51%) and 8596 men (72%) were revascularized (P<.001). Not being examined with CAG after AMI was associated with a three-fold increase in risk of death and, importantly, a 50% increase in the risk of a recurrent AMI compared with patients who were revascularized. Among patients who were revascularized, 85-92% initiated recommended secondary preventive medication compared to 46-71% in patients not examined with CAG (P<.001). Initiation of secondary preventive medication was higher in men (81 84%) than in women (73-79%; P<.001), which could be ascribed to the differences in invasive strategy. CONCLUSIONS: In both sexes, those who were not examined had a highly increased risk of both recurrent AMI and death. Moreover, initiation of secondary preventive medication was closely related to the choice of invasive strategy disfavoring the women. PMID- 22210587 TI - Use of a novel adjunctive kissing-balloon technique with the Trellis device to successfully prevent embolization across juxtaposed kissing aortoiliac stents. AB - The Trellis thrombectomy system (Covidien) has been used successfully to perform isolated pharmacomechanical thrombectomy of both venous and arterial thrombi. The device is designed to provide localized treatment while preventing both systemic spread of the thrombolytic agent and also distal embolization. However, when this device is utilized to remove thrombi at bifurcation lesions, embolization into the contralateral vessel can potentially occur. We describe a novel and simple technique of adjunctive kissing balloon inflation while using the Trellis device for the management of an aortoiliac occlusion that occurred in one of two juxtaposed stents previously placed in the distal aorta into the bilateral iliac arteries. This technique prevented distal embolization into the contralateral iliac artery. PMID- 22210588 TI - Rapid progression of coronary aneurysm to stenosis in a patient with Kawasaki disease. AB - In Kawasaki disease, coronary aneurysms typically regress slowly, although some may develop stenosis 1-2 decades after the acute illness. This is the first case report describing rapid progression of coronary aneurysm to stenosis within 14 weeks. PMID- 22210576 TI - Benefits and safety of long-term fenofibrate therapy in people with type 2 diabetes and renal impairment: the FIELD Study. AB - OBJECTIVE: Diabetic patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-59 mL/min/1.73 m(2)) are at particular cardiovascular risk. Fenofibrate's safety in these patients is an issue because it may elevate plasma creatinine. Furthermore, guidelines regarding fenofibrate dosing in renal impairment vary internationally. We investigated fenofibrate's effects on cardiovascular and end-stage renal disease (ESRD) events, according to eGFR, in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. RESEARCH DESIGN AND METHODS: Type 2 diabetic patients (aged 50-75 years) with eGFR >=30 mL/min/1.73 m(2) were randomly allocated to a fixed dose of fenofibrate (200 mg daily) (n = 4,895) or placebo (n = 4,900) for 5 years. Baseline renal function (Modification of Diet in Renal Disease equation) was grouped by eGFR (30 59, 60-89, and >=90 mL/min/1.73 m(2)). The prespecified outcome was total cardiovascular events (composite of cardiovascular death, myocardial infarction, stroke, and coronary/carotid revascularization). Serious adverse events and instances of ESRD (plasma creatinine >400 MUmol/L, dialysis, renal transplant, or renal death) were recorded. Analysis was by intention to treat. RESULTS: Overall, fenofibrate reduced total cardiovascular events, compared with placebo (hazard ratio 0.89 [95% CI 0.80-0.99]; P = 0.035). This benefit was not statistically different across eGFR groupings (P = 0.2 for interaction) (eGFR 30-59 mL/min/1.73 m(2): 0.68 [0.47-0.97], P = 0.035; eGFR >=90 mL/min/1.73 m(2): 0.85 [0.70-1.02], P = 0.08). ESRD rates were similar between treatment arms, without adverse safety signals of fenofibrate use in renal impairment. CONCLUSIONS: Patients with type 2 diabetes and moderate renal impairment benefit from long-term fenofibrate, without excess drug-related safety concerns compared with those with no or mild renal impairment. Fenofibrate treatment should not be contraindicated in moderate renal impairment, suggesting that current guidelines may be too restrictive. PMID- 22210589 TI - Iatrogenic acute coronary dissection during coronary angioplasty for in-stent restenosis: role of intravascular ultrasound in diagnosis and treatment. AB - We report on a case of coronary dissection resulting from a guidewire passing out of a stent during in-stent restenosis (ISR) treatment and a guidewire successfully negotiated into true lumen and an implanted stent under intravascular ultrasound guidance, resulting in optimal coronary blood flow. PMID- 22210590 TI - Role of hybrid endovascular suite in improving outcomes of surgical ligation of coronary artery fistula. AB - Coronary artery fistulae are rare congenital or acquired coronary artery anomalies that can lead to significant cardiovascular morbidity and mortality. Surgical ligation has long been utilized in the treatment of these abnormalities. However, there is a high rate of recurrence due to incomplete closure of the fistulae, especially when multiple channels are present. Transcatheter techniques have become an acceptable alternative with good outcomes. Nevertheless, not all fistulae are amenable to the transcatheter approach and surgical repair is the treatment of choice. Intraoperative coronary angiography can improve the outcomes of surgery but has only sparingly been used due to the technical difficulties in a standard operating suite. Hybrid suites are becoming quite common these days with the emergence of procedures such as endovascular stent grafting and percutaneous valves. These suites have a complete imaging set up like a traditional catheterization laboratory and are also full operating suites. This case report discusses the use and potential benefits of performing intraoperative coronary angiography in a dedicated hybrid suite to help guide and ensure complete surgical closure of all fistulous connections. PMID- 22210591 TI - Irreversible delayed complete heart block secondary to jailed first septal perforator following PCI of the left anterior descending coronary artery. AB - Permanent complete heart block (CHB) secondary to the loss of first septal perforator after percutaneous coronary intervention (PCI) of the left descending artery (LAD) is an extremely rare complication. We describe a case report where a patient underwent PCI of proximal LAD, complicated by loss of first septal perforator, septal infarction, and bifasicular block, which progressed to symptomatic delayed CHB. One week later, the patient required implantation of a permanent pacemaker following failure to wean off the transvenous temporary pacing maker. PMID- 22210592 TI - Acquired left ventricular to left atrial fistula--not mitral regurgitation! Transcutaneous closure with amplatzer device. AB - Acquired left ventricle (LV) to left atrial (LA) fistula is a very rare complication following aortic valve replacement (AVR). This can usually be surgically repaired but the risk of re-operation is high due to repeat sternotomy and also due to other comorbidities usually seen in this population. We report a case presenting with recurrent episodes of left ventricular failure 10 years following bioprosthetic aortic valve replacement and who was diagnosed to have a communication between the LV and the LA on transesophageal echocardiography (TEE). This was treated percutaneously with an Amplatzer duct occluder (ADO) device (AGA Medical Corp.) as she was considered to be a high surgical risk. PMID- 22210593 TI - Impella-assisted balloon aortic valvuloplasty. AB - The Impella LP 2.5 left ventricular assist device (Abiomed) is safe and effective for assisting high-risk percutaneous interventions. A 77-year-old woman with severe aortic stenosis, severe coronary artery disease, an ejection fraction of 20%, severe peripheral vascular disease, and other comorbidities presented to a private, tertiary referral hospital with shortness of breath that had been worsening over 2 weeks. The patient underwent a successful, Impella-assisted balloon aortic valvuloplasty (BAV) without complications. Impella support may be considered during BAV in high-risk patients with contraindications for a TandemHeart device (CardiacAssist, Inc.). PMID- 22210594 TI - Entrapment of a kinked catheter in the radial artery during transradial coronary angiography. AB - The transradial approach is currently popular for vascular access during percutaneous coronary angiography and intervention. Catheter kinking during catheter manipulation is not uncommon, but mostly the kinked catheter can be unraveled by gentle rotation of catheter in the opposite direction. We describe a case in which the diagnostic catheter was kinked and entrapped in the small radial artery during transradial angiography. Attempts to withdraw or to unravel the catheter with gentle rotation were unsuccessful. We were able to catch the catheter tip with a 6 Fr Amplatz goose-neck snare kit (ev3, Inc.) guided by an 8 Fr guiding catheter via right femoral approach. We pulled the kinked catheter up into the brachial artery with large diameter where successful unraveling was possible, allowing for its successful removal through the radial sheath. PMID- 22210595 TI - CT coronary angiography-guided percutaneous coronary intervention for chronic total occlusion combined with retrograde approach. AB - Percutaneous coronary intervention was performed for chronic total occlusion (CTO) of the right coronary artery (RCA) in a 55-year-old man. CT coronary angiography (CTCA) with a 64-slice scanner showed a large calcified plaque at the entrance to the CTO. A stent that had been implanted at the RCA ostium 10 years earlier was angled toward a side branch, suggesting that the guidewire would not reach the true lumen via the antegrade approach. Therefore, we attempted the retrograde approach via a septal collateral with the kissing wire technique. However, the guidewire failed to cross the CTO because of obstruction by the implanted stent. We next attempted the controlled antegrade and retrograde subintimal tracking technique and 2 stents were successfully deployed. In this patient, CTCA provided useful information for management of a difficult CTO. PMID- 22210596 TI - Physical activity, adiponectin, and cardiovascular structure and function. AB - Physical activity (PA) may modify cardiovascular structure and function as well as insulin sensitivity and level of plasma adipokines in relation to its extent, duration, and intensity. To evaluate the associations of average daily PA and bouts of moderate-to-vigorous-intensity PA with cardiovascular and metabolic measures, 45 healthy volunteers (mean age = 42 +/- 9 years) not involved in regular intensive exercise training and competitive sport activity underwent the following examinations: (1) accelerometer monitoring of ambulatory movements (average monitoring time = 6.1 +/- 1.3 days); (2) complete carotid and cardiac ultrasound; (3) measurement of carotid-femoral pulse-wave velocity; (4) anthropometric measurements; (5) euglycemic hyperinsulinemic clamp; and (6) assessment of plasma levels of leptin, adiponectin, and high-sensitivity C reactive protein (hsCRP). Average PA measured by accelerometer correlated with carotid beta-stiffness index (inversely) and with longitudinal systolic myocardial velocity (directly), independently of age, anthropometric, hemodynamic, and metabolic parameters. Subjects with periods of moderate-to vigorous-intensity PA lasting at least 10 min (n = 28) had higher left ventricular (LV) mass index and lower plasma adiponectin, leptin, and hsCRP (P < 0.05 for all) compared with those who spent the monitoring time only in sedentary and light-intensity PA (n = 17). Minutes per day spent in moderate-to-vigorous PA correlated with LV mass index (directly) and with plasma adiponectin (inversely). Plasma adiponectin was an independent determinant of LV mass, together with body surface area, stroke volume, and systolic blood pressure (cumulative r (2) = 0.80). We conclude that in healthy subjects, average daily PA is independently related to longitudinal systolic myocardial function and to local carotid stiffness. Bouts of moderate-to-vigorous PA seem to induce LV mass increase, which may be partially related to a decrease in plasma adiponectin level. PMID- 22210597 TI - Evolution and functional diversification of the small heat shock protein/alpha crystallin family in higher plants. AB - Small heat shock proteins (sHSPs) are chaperones that play an important role in stress tolerance. They consist of an alpha-crystallin domain (ACD) flanked by N- and C-terminal regions. However, not all proteins that contain an ACD, hereafter referred to as ACD proteins, are sHSPs because certain ACD proteins are known to have different functions. Furthermore, since not all ACD proteins have been identified yet, current classifications are incomplete. A total of 17 complete plant proteomes were screened for the presence of ACD proteins by HMMER profiling and the identified ACD protein sequences were classified by maximum likelihood phylogeny. Differences among and within groups were analysed, and levels of functional constraint were determined. There are 29 different classes of ACD proteins, eight of which contain classical sHSPs and five likely chaperones. The other classes contain proteins with uncharacterised or poorly characterised functions. N- and C-terminal sequences are conserved within the phylogenetic classes. Phylogenetics suggests a single duplication of the CI sHSP ancestor that occurred prior to the speciation of mono- and dicotyledons. This was followed by a number of more recent duplications that resulted in the presence of many paralogues. The results suggest that N- and C-terminal sequences of sHSPs play a role in class-specific functionality and that non-sHSP ACD proteins have conserved but unexplored functions, which are mainly determined by subsequences other than that of the ACD. PMID- 22210599 TI - Disaster victim identification-experiences of the "Autobahn A19" disaster. AB - The chain reaction pile-up on the multilane highway ("Autobahn") A 19 in April 2011 was regarded as the most severe traffic accident within the last 20 years in Germany. The situation worsened when 34 of the 83 involved vehicles caught fire. As a result of this crash, 8 high-grade heat-damaged victims were found. The victim identification algorithm of the IDKO (Identification Commission of the German Federal Office of Criminal Investigation) was applied as the standard tool for forensic mass disaster evaluation. This approach included inspection of the body at the scene, post-mortem CT-scan with 3-D reconstruction, and full autopsy with toxicological examinations and DNA-analyses. As a result of the investigations we were able to identify all 8 victims. Independent of successful victim identification according to IDKO standards, the exact sequence of events and cause of death remained unclear in some of the victims. PMID- 22210598 TI - The pepper extracellular peroxidase CaPO2 is required for salt, drought and oxidative stress tolerance as well as resistance to fungal pathogens. AB - In plants, biotic and abiotic stresses regulate the expression and activity of various peroxidase isoforms. Capsicum annuum EXTRACELLULAR PEROXIDASE 2 (CaPO2) was previously shown to play a role in local and systemic reactive oxygen species bursts and disease resistance during bacterial pathogen infection. Here, we report CaPO2 expression patterns and functions during conditions of biotic and abiotic stress. In pepper plants, CaPO2 expression was strongly induced by abscisic acid, but not by defense-related plant hormones such as salicylic acid, ethylene and jasmonic acid. CaPO2 was also strongly induced by abiotic and biotic stress treatments, including drought, cold, high salinity and infection by the hemibiotrophic fungal pathogen Colletotrichum coccodes. Loss-of-function of CaPO2 in virus-induced gene silenced pepper plants led to increased susceptibility to salt- and osmotic-induced stress. In contrast, CaPO2 overexpression in transgenic Arabidopsis thaliana plants conferred enhanced tolerance to high salt, drought, and oxidative stress, while also enhancing resistance to infection by the necrotrophic fungal pathogen Alternaria brassicicola. Taken together, these results provide evidence for the involvement of pepper extracellular peroxidase CaPO2 in plant defense responses to various abiotic stresses and plant fungal pathogens. PMID- 22210600 TI - The prognostic significance of early and late anaemia in acute coronary syndrome. AB - BACKGROUND AND AIM: Anaemia in acute coronary syndrome (ACS) is a common and strong independent risk factor but it is unknown whether early anaemia is transient or whether it persists over the subsequent weeks. We also sought to evaluate whether late anaemia carries the similar prognostic significance as baseline anaemia. Another unknown is whether haemoglobin improves risk stratification over and above the GRACE score. DESIGN AND METHODS: Haemoglobin levels were prospectively measured in 448 consecutive patients presenting with ACS and at 7-weeks follow-up. Cardiovascular endpoints were defined as death or acute myocardial infarction (AMI) over a median duration of 30 months (range 1 50). RESULTS: The prevalence of anaemia on admission was 20% and this increased to 40% at 7-weeks follow-up. New anaemia occurred in 31% of patients. Baseline anaemia predicted CV endpoints independent of the admission GRACE (Global Registry of Acute Coronary Events) score [adjusted RR 2.54 (95% CI 1.73-3.71)]. Anaemia at 7-weeks follow-up was also a strong predictor of adverse outcomes [adjusted RR 1.67 (95% CI 1.04-2.69)]. Patients with persistent anaemia at 7 weeks were at an increased risk of death or AMI compared to those with persistently normal haemoglobin [unadjusted RR 3.58 (95% CI 2.04-6.29)]. CONCLUSION: In ACS, the prevalence of anaemia doubles from admission to 7-weeks follow-up (40%). Not only did baseline anaemia predict long-term prognosis independent of the admission GRACE score, but haemoglobin at 7-weeks post-ACS was also a simple independent predictor of adverse prognosis. PMID- 22210602 TI - Questionable summaries of questionable evidence. PMID- 22210603 TI - Phylogeny of galactolipid synthase homologs together with their enzymatic analyses revealed a possible origin and divergence time for photosynthetic membrane biogenesis. AB - The photosynthetic membranes of cyanobacteria and chloroplasts of higher plants have remarkably similar lipid compositions. In particular, thylakoid membranes of both cyanobacteria and chloroplasts are composed of galactolipids, of which monogalactosyldiacylglycerol (MGDG) is the most abundant, although MGDG biosynthetic pathways are different in these organisms. Comprehensive phylogenetic analysis revealed that MGDG synthase (MGD) homologs of filamentous anoxygenic phototrophs Chloroflexi have a close relationship with MGDs of Viridiplantae (green algae and land plants). Furthermore, analyses for the sugar specificity and anomeric configuration of the sugar head groups revealed that one of the MGD homologs exhibited a true MGDG synthetic activity. We therefore presumed that higher plant MGDs are derived from this ancestral type of MGD genes, and genes involved in membrane biogenesis and photosystems have been already functionally associated at least at the time of Chloroflexi divergence. As MGD gene duplication is an important event during plastid evolution, we also estimated the divergence time of type A and B MGDs. Our analysis indicated that these genes diverged -323 million years ago, when Spermatophyta (seed plants) were appearing. Galactolipid synthesis is required to produce photosynthetic membranes; based on MGD gene sequences and activities, we have proposed a novel evolutionary model that has increased our understanding of photosynthesis evolution. PMID- 22210604 TI - Discovery and mapping of a new expressed sequence tag-single nucleotide polymorphism and simple sequence repeat panel for large-scale genetic studies and breeding of Theobroma cacao L. AB - Theobroma cacao is an economically important tree of several tropical countries. Its genetic improvement is essential to provide protection against major diseases and improve chocolate quality. We discovered and mapped new expressed sequence tag-single nucleotide polymorphism (EST-SNP) and simple sequence repeat (SSR) markers and constructed a high-density genetic map. By screening 149 650 ESTs, 5246 SNPs were detected in silico, of which 1536 corresponded to genes with a putative function, while 851 had a clear polymorphic pattern across a collection of genetic resources. In addition, 409 new SSR markers were detected on the Criollo genome. Lastly, 681 new EST-SNPs and 163 new SSRs were added to the pre existing 418 co-dominant markers to construct a large consensus genetic map. This high-density map and the set of new genetic markers identified in this study are a milestone in cocoa genomics and for marker-assisted breeding. The data are available at http://tropgenedb.cirad.fr. PMID- 22210605 TI - Characterization of two metagenome-derived esterases that reactivate chloramphenicol by counteracting chloramphenicol acetyltransferase. AB - Function-driven metagenomic analysis is a powerful approach to screening for novel biocatalysts. In this study, we investigated lipolytic enzymes selected from an alluvial soil metagenomic library, and identified two novel esterases, EstDL26 and EstDL136. EstDL26 and EstDL136 reactivated chloramphenicol from its acetyl derivates by counteracting the chloramphenicol acetyltransferase (CAT) activity in Escherichia coli. These two enzymes showed only 27% identity in amino acid sequence to each other; however both preferentially hydrolyzed short-chain p nitrophenyl esters (< or =C5) and showed mesophilic properties. In vitro, EstDL136 catalyzed the deacetylation of 1- and 3- acetyl and 1,3-diacetyl derivates; in contrast, EstDL26 was not capable of the deacetylation at C1, indicating a potential regioselectivity. EstDL26 and EstDL136 were similar to microbial hormone-sensitive lipase (HSL), and since chloramphenicol acetate esterase (CAE) activity was detected from two other soil esterases in the HSL family, this suggests a distribution of CAE among the soil microorganisms. The isolation and characterization of EstDL26 and EstDL136 in this study may be helpful in understanding the diversity of CAE enzymes and their potential role in releasing active chloramphenicol in the producing bacteria. PMID- 22210606 TI - Time-dependent hepatic proteome analysis in lean and diet-induced obese mice. AB - C57BL/6J mice have been widely used as a diet-induced obesity model because they trigger common features of the human metabolic syndrome. In the present study, C57BL/6J male mice were fed either a high-fat diet (HFD) or normal diet (ND) during a 24-week period, and then the age-dependent liver proteome of mice in two groups was analyzed using 2-DE combined with MALDI-TOF-MS. Among identified proteins, up-regulated proteins were subdivided to early (during the first 4 weeks) and late (20~24 weeks) markers that played a role in diet-induced obesity development. Important early markers included ketohexokinase and prohibitin, and late markers included the 75 kDa glucose-regulated protein, citrate synthase, and selenium-binding liver protein. Of these, the 75 kDa glucoseregulated protein has already been linked to obesity; however, prohibitin protein involved in obesity was identified for the first time in this study. In order to validate the proteomic results and gain insight into metabolic changes between the two groups, we further confirmed the expression pattern of some proteins of interest by Western blot analysis. Combined results of proteomic analysis with Western blot analysis revealed that antioxidant enzymes were progressively decreased, whereas cytoskeletal proteins were time-dependently increased in HFD mice. PMID- 22210607 TI - Identification of virulence factors in vibrio vulnificus by comparative transcriptomic analyses between clinical and environmental isolates using cDNA microarray. AB - We compared the gene expression among four clinical and five environmental V. vulnificus isolates, using a cDNA microarray containing 131 genes possibly associated with pathogenicity, transport, signal transduction, and gene regulations in the pathogen. cDNAs from total RNAs of these isolates were hybridized into the cDNA microarray using the cDNA of the wild-type strain MO6/24 O as a reference. We focused on selecting differentially expressed (DE) genes between clinical and environmental isolates using a modified t-statistic. We could detect two statistically significant DE genes between virulent isolates and less-virulent isolates with a marginal statistical significance (pvalue of 0.008). These were genes putatively encoding pilin and adenlyate cylase. Real time-PCR confirmed that these two selected genes transcribed in significantly higher levels in virulent isolates than in less-virulent isolates. Mutants with lesions in the gene encoding pilin showed significantly higher LD50 values than that of wild type. PMID- 22210608 TI - Screening and identification of antimicrobial compounds from Streptomyces bottropensis suppressing rice bacterial blight. AB - Xanthomonas oryzae pv. oryzae (Xoo) is the most devastating pathogen to Oryza sativa and has been shown to cause bacterial blight. Two bioactive compounds showing antimicrobial activities against Xoo strain KACC 10331 were isolated from a Streptomyces bottropensis strain. The ethyl acetate extract was fractionated on a Sephadex LH-20 column, and then purified by preparative HPLC. The purified compounds were identified as bottromycin A2 and dunaimycin D3S by HR/MS and 1H NMR analyses. The MIC value against Xoo and the lowest concentration still capable of suppressing rice bacterial blight were 2 microgram/ml and 16 microgram/ml for bottromycin A2, and 64 microgram/ml and 0.06 microgram/ml for dunaimycin D3S, respectively. These two compounds were shown to exert different bioactivities in vitro and in rice leaf explants. PMID- 22210609 TI - Antimicrobial treatment of grapes using sodium hypochlorite in winemaking and its effects on the chemical and sensory characteristics of wines. AB - This study was performed to examine the use of NaOCl as an alternative antimicrobial compound in winemaking because of the potential health problems that may arise as a result of the use of SO2. For this, the blank (non-treated), control (SO2-added), and sample (NaOCl-treated) wines were made, and microbial and chemical changes including sensory characteristics were analyzed during the fermentation periods. Treatment of grapes with NaOCl decreased the initial contaminating microbial population in grape must, resulting in higher growth of yeast and lactic acid bacteria. After 200 days of fermentation, the chemical analysis of sample wine revealed that it had higher ethanol content, redness (a*), and concentrations of fruity ester compounds and lower total acidity than the control. In the sensory analyses, the sample wine obtained a higher overall acceptability score (5.70) than the control (4.26). This result reveals that NaOCl can be used as an alternative to SO2 in winemaking for inhibiting the growth of contaminating microorganisms. PMID- 22210610 TI - Production of alkaline protease by entrapped Bacillus licheniformis cells in repeated batch process. AB - In this study, Bacillus licheniformis cells were immobilized by entrapment in calcium alginate beads and were used for production of alkaline protease by repeated batch process. In order to increase the stability of the beads, the immobilization procedure was optimized by statistical full factorial method, by which three factors including alginate type, calcium chloride concentration, and agitation speed were studied. Optimization of the enzyme production medium, by the Taguchi method, was also studied. The obtained results showed that optimization of the cell immobilization procedure and medium constituents significantly enhanced the production of alkaline protease. In comparison with the free-cell culture in pre-optimized medium, about 7.3-fold higher productivity was resulted after optimization of the overall procedure. Repeated batch mode of operation, using optimized conditions, resulted in continuous production of the alkaline protease for 13 batches in 19 days. PMID- 22210611 TI - External and internal glucose mass transfers in succinic acid fermentation with stirred bed of immobilized Actinobacillus succinogenes under substrate and product inhibitions. AB - This paper is dedicated to the study on the external and internal mass transfers of glucose for succinic acid fermentation under substrate and product inhibitions using a bioreactor with stirred bed of immobilized Actinobacillus succinogenes cells. By means of the substrate mass balance for a single particle of biocatalysts, considering the kinetic model adapted for both inhibitory effects, specific mathematical models were developed for describing the profiles of the substrate concentration in the outer and inner regions of biocatalysts and for estimating the substrate mass flows in the liquid boundary layer surrounding the particle and inside the particle. The values of the mass flows were significantly influenced by the internal diffusion velocity and rate of the biochemical reaction of substrate consumption. These cumulated influences led to the appearance of a biological inactive region near the particle center, its magnitude varying from 0 to 5.3% of the overall volume of particles. PMID- 22210612 TI - Secretory expression and purification of the recombinant duck interleukin-2 in Pichia pastoris. AB - Interleukin-2 (IL-2) is a vital cytokine secreted by activated T lymphocytes, and plays an important role in the regulation of cellular functions and immunity of animals. In this study, the recombinant duck IL-2 (rduIL-2) was secretory expressed in Pichia pastoris (P. pastoris). The recombinant P. pastoris strain was cultured in shake flasks and then scaled up in a 5.0-l bioreactor. The result showed that the maximal fresh-cell-weight of 594.1 g/l and the maximal OD600 of 408 were achieved in the bioreactor. The rduIL-2 was purified by two steps of purification procedures, and approximately 311 mg of rduIL-2/L fermentation supernatant was obtained. SDS-PAGE showed that the purified rduIL-2 constituted a homogeneous band of ~16 kDa or ~14 kDa corresponding to the glycosylated or non glycosylated duIL-2 protein in size, respectively. The bioactivity of rduIL-2 was determined by lymphocyte proliferation assay. The result indicated that the rduIL 2 greatly promoted the proliferation of ConA-stimulated lymphocytes in vitro. The P. pastoris expression system described here could provide promising, inexpensive, and large-scale production of the rduIL-2, which lays the foundation for development of novel immunoadjuvants to enhance both the immunity of ducks against various infectious pathogens and vaccine efficacy. PMID- 22210613 TI - Molecular and morphological identification of fungal species isolated from bealmijang meju. AB - Bealmijang is a short-term aged paste made from meju, which is a brick of fermented soybeans and other ingredients. Different types of bealmijang are available depending on the geographic region or ingredients used. However, no study has clarified the microbial diversity of these types. We identified 17 and 14 fungal species from black soybean meju (BSM) and buckwheat meju (BWM), respectively, on the basis of morphology, culture characteristics, and internal transcribed spacer and beta-tubulin gene sequencing. In both meju, Aspergillus oryzae, Rhizopus oryzae, Penicillium polonicum, P. steckii, Cladosporium tenuissimum, C. cladosporioides, C. uredinicola, and yeast species Pichia burtonii were commonly found. Moreover, A. flavus, A. niger, P. crustosum, P. citrinum, Eurotium niveoglaucum, Absidia corymbifera, Setomelanomma holmii, Cladosporium spp. and unclassified species were identified from BSM. A. clavatus, Mucor circinelloides, M. racemosus, P. brevicompactum, Davidiella tassiana, and Cladosporium spp. were isolated from BWM. Fast growing Zygomycetous fungi is considered important for the early stage of meju fermentation, and A. oryae and A. niger might play a pivotal role in meju fermentation owing to their excellent enzyme productive activities. It is supposed that Penicillium sp. and Pichia burtonii could contribute to the flavor of the final food products. Identification of this fungal diversity will be useful for understanding the microbiota that participate in meju fermentation, and these fungal isolates can be utilized in the fermented foods and biotechnology industries. PMID- 22210614 TI - Development of a quantitative PCR for detection of Lactobacillus plantarum starters during wine malolactic fermentation. AB - A quantitative, real-time PCR method was developed to enumerate Lactobacillus plantarum IWBT B 188 during the malolactic fermentation (MLF) in Grauburgunder wine. The qRT-PCR was strain-specific, as it was based on primers targeting a plasmid DNA sequence, or it was L. plantarum-specific, as it targeted a chromosomally located plantaricin gene sequence. Two 50 l wine fermentations were prepared. One was inoculated with 15 g/hl Saccharomyces cerevisiae, followed by L. plantarum IWBT B 188 at 3.6 * 10(6) CFU/ml, whereas the other was not inoculated (control). Viable cell counts were performed for up to 25 days on MRS agar, and the same cells were enumerated by qRT-PCR with both the plasmid or chromosomally encoded gene primers. The L. plantarum strain survived under the harsh conditions in the wine fermentation at levels above 10(5)/ml for approx. 10 days, after which cell numbers decreased to levels of 10(3) CFU/ml at day 25, and to below the detection limit after day 25. In the control, no lactic acid bacteria could be detected throughout the fermentation, with the exception of two sampling points where ca. 1 * 10(2) CFU/ml was detected. The minimum detection level for quantitative PCR in this study was 1 * 10(2) to 1 * 10(3) CFU/ml. The qRT-PCR results determined generally overestimated the plate count results by about 1 log unit, probably as a result of the presence of DNA from dead cells. Overall, qRT-PCR appeared to be well suited for specifically enumerating Lactobacillus plantarum starter cultures in the MLF in wine. PMID- 22210615 TI - Biochemical characterization of the exopolysaccharide purified from Laetiporus sulphureus mycelia. AB - The extracellular polysaccharide (EPS) was isolated from mycelial cultures of Laetiporus sulphureus var. miniatus and purified by DEAE cellulose and Sephadex G 50 column chromatography. The purified EPS (EPS-2-1) was composed of only glucose units and its molecular mass was 6.95 kDa. The chemical structure of EPS-2-1 consisted of a main chain containing (1-->4)-Glcp units with branches at the C-6 position of the chain carrying -Glcp-(1-->4)-linked residues. The effect of purified EPS on immunomodulatory genes and proteins of the Bcl-2 family was observed using cultured U937 human leukemia cells. Of note, the levels of Bax and Bad proteins treated with the EPS (4 mg/ml) were approximately 23- and 18-times higher than those in non-treated cells, respectively. These results may suggest that the EPS purified from the mushroom L. sulphureus is associated with the activation of immunomodulatory mediators, Bax and Bad proteins. PMID- 22210616 TI - Cloning of metK from Actinoplanes teichomyceticus ATCC31121 and effect of its high expression on antibiotic production. AB - A metK gene encoding S-adenosyl-L-methionine synthetase was cloned from the non Streptomyces actinomycetes, Actinoplanes teichomyceticus ATCC31121. In order to evaluate the effect of the metK expression on antibiotic production in actinomycetes, an expression vector harboring the metK gene was constructed and introduced into Streptomyces lividans TK24 and A. teichomyceticus, and the antibiotic production of the exconjugants was assessed. As a result, it was determined that the expression of metK induced 17-fold and 2.2-fold increases in actinorhodin production from S. lividans TK24 and teicoplanin production from A. teichomyceticus, respectively, compared with the control strains. PMID- 22210617 TI - Combined TGE-SGE expression of novel PAI-1-resistant t-PA in CHO DG44 cells using orbitally shaking disposable bioreactors. AB - An important modification of thrombolytic agents is resistance to plasminogen activator inhibitor-1 (PAI-1). In previous studies, a new truncated PAI-1 resistant variant was developed based on deletion of the first three domains in t PA and the substitution of KHRR 128-131 amino acids with AAAA in the truncated t PA. The novel variant expressed in a static culture system of Chinese Hamster Ovary (CHO) DG44 cells exhibited a higher resistance to PAI-1 when compared with the full-length commercial drug; Actylase. In the present study, the truncatedmutant protein was expressed in CHO DG44 cells in 50 ml orbital shaking bioreactors. The final yield of the truncatedmutant in the culture was 752 IU/ml, representing a 63% increase compared with the static culture system. Therefore, these results suggest that using the combined features of a transient and stable expression system is feasible for the production of novel recombinant proteins in the quantities needed for preclinical studies. PMID- 22210618 TI - Monitoring of environmental arsenic by cultures of the photosynthetic bacterial sensor illuminated with a near-infrared light emitting diode array. AB - Recombinant Rhodopseudomonas palustris, harboring the carotenoid-metabolizing gene crtI (CrtIBS), and whose color changes from greenish yellow to red in response to inorganic As(III), was cultured in transparent microplate wells illuminated with a light emitting diode (LED) array. The cells were seen to grow better under near-infrared light, when compared with cells illuminated with blue or green LEDs. The absorbance ratio of 525 to 425 nm after cultivation for 24 h, which reflects red carotenoid accumulation, increased with an increase in As(III) concentrations. The detection limit of cultures illuminated with near-infrared LED was 5 microgram/l, which was equivalent to that of cultures in test tubes illuminated with an incandescent lamp. A near-infrared LED array, in combination with a microplate, enabled the simultaneous handling of multiple cultures, including CrtIBS and a control strain, for normalization by the illumination of those with equal photon flux densities. Thus, the introduction of a near-infrared LED array to the assay is advantageous for the monitoring of arsenic in natural water samples that may contain a number of unknown factors and, therefore, need normalization of the reporter event. PMID- 22210619 TI - Chitinolytic and chitosanolytic activities from crude cellulase extract produced by A. niger grown on apple pomace through Koji fermentation. AB - Enzyme extracts of cellulase [filter paper cellulase (FPase) and carboxymethyl cellulase (CMCase)], chitinase, and chitosanase produced by Aspergillus niger NRRL-567 were evaluated. The interactive effects of initial moisture and different inducers for FP cellulase and CMCase production were optimized using response surface methodology. Higher enzyme activities [FPase 79.24+/- 4.22 IU/gram fermented substrate (gfs) and CMCase 124.04+/-7.78 IU/gfs] were achieved after 48 h fermentation in solid-state medium containing apple pomace supplemented with rice husk [1% (w/w)] under optimized conditions [pH 4.5, moisture 55% (v/w), and inducers veratryl alcohol (2 mM/kg), copper sulfate (1.5 mM/kg), and lactose 2% (w/w)] (p<0.05). Koji fermentation in trays was carried out and higher enzyme activities (FPase 96.67+/-4.18 IU/gfs and CMCase 146.50+/ 11.92 IU/gfs) were achieved. The nonspecific chitinase and chitosanase activities of cellulase enzyme extract were analyzed using chitin and chitosan substrates with different physicochemical characteristics, such as degree of deacetylation, molecular weight, and viscosity. Higher chitinase and chitosanase activities of 70.28+/-3.34 IU/gfs and 60.18+/-3.82 to 64.20+/-4.12 IU/gfs, respectively, were achieved. Moreover, the enzyme was stable and retained 92-94% activity even after one month. Cellulase enzyme extract obtained from A. niger with chitinolytic and chitosanolytic activities could be potentially used for making low-molecular weight chitin and chitosan oligomers, having promising applications in biomedicine, pharmaceuticals, food, and agricultural industries, and in biocontrol formulations. PMID- 22210620 TI - Rice straw-decomposing fungi and their cellulolytic and xylanolytic enzymes. AB - Filamentous fungi colonizing rice straw were collected from 11 different sites in Korea and were identified based on characterization of their morphology and molecular properties. The fungi were divided into 25 species belonging to 16 genera, including 14 ascomycetes, one zygomycete, and one basidiomycete. Fungal cellulolytic and xylanolytic enzymes were assessed through a two-step process, wherein highly active cellulase- and/or hemicellulaseproducing fungi were selected in a first screening step followed by a second step to isolate the best enzymeproducer. Twenty-five fungal species were first screened for the production of total cellulase (TC), endo-beta-1,4 glucanase (EG), and endo-beta-1,4 xylanase (XYL) using solid-state fermentation with rice straw as substrate. From this screening, six species, namely, Aspergillus niger KUC5183, A. ochraceus KUC5204, A. versicolor KUC5201, Mucor circinelloides KUC6014, Trichoderma harzianum 1 KUC5182, and an unknown basidiomycete species, KUC8721, were selected. These six species were then incubated in liquid Mandels' media containing cellulose, glucose, rice straw, or xylan as the sole carbon source and the activities of six different enzymes were measured. Enzyme production was highly influenced by media conditions and in some cases significantly increased. Through this screening process, Trichoderma harzianum 1 KUC5182 was selected as the best enzyme producer. Rice straw and xylan were good carbon sources for the screening of cellulolytic and xylanolytic enzymes. PMID- 22210621 TI - Suppressing Erwinia carotovora pathogenicity by projecting N-acyl homoserine lactonase onto the surface of Pseudomonas putida cells. AB - N-Acyl homoserine lactones (AHLs) serve as the vital quorum-sensing signals that regulate the virulence of the pathogenic bacterium Erwinia carotovora. In the present study, an approach to efficiently restrain the pathogenicity of E. carotovora-induced soft rot disease is described. Bacillus thuringiensis-derived N-acyl homoserine lactonase (AiiA) was projected onto the surface of Pseudomonas putida cells, and inoculation with both strains was challenged. The previously identified N-terminal moiety of the ice nucleation protein, InaQ-N, was applied as the anchoring motif. A surface display cassette with inaQ-N/ aiiA was constructed and expressed under the control of a constitutive promoter in P. putida AB92019. Surface localization of the fusion protein was confirmed by Western blot analysis, flow cytometry, and immunofluorescence microscopy. The antagonistic activity of P. putida MB116 expressing InaQ-N/AiiA toward E. carotovora ATCC25270 was evaluated by challenge inoculation in potato slices at different ratios. The results revealed a remarkable suppressing effect on E. carotovora infection. The active component was further analyzed using different cell fractions, and the cell surface-projected fusion protein was found to correspond to the suppressing effect. PMID- 22210622 TI - The new LM-PCR/shifter method for the genotyping of microorganisms based on the use of a class IIS restriction enzyme and ligation mediated PCR. AB - This study details and examines a novel ligation-mediated polymerase chain reaction (LM-PCR) method. Named the LM-PCR/Shifter, it relies on the use of a Class IIS restriction enzyme giving restriction fragments with different 4-base, 5' overhangs, this being the Shifter, and the ligation of appropriate oligonucleotide adapters. A sequence of 4-base, 5' overhangs of the adapter and a 4- base sequence of the 3' end of the primer(s) determine a subset of the genomic restriction fragments, which are amplified by PCR. The method permits the differentiation of bacterial species strains on the basis of the different DNA band patterns obtained after electrophoresis in polyacrylamide gels stained with ethidium bromide and visualized in UV light. The usefulness of the LM-PCR/ Shifter method for genotyping is analyzed by a comparison with the restriction endonuclease analysis of chromosomal DNA by the pulsed-field gel electrophoresis (REA-PFGE) and PCR melting profile (PCR MP) methods for isolates of clinical origin. The clustering of the LM-PCR/Shifter fingerprinting data matched those of the REA-PFGE and PCR MP methods. We found that the LM-PCR/Shifter is rapid, and offers good discriminatory power and excellent reproducibility, making it a method that may be effectively applied in epidemiological studies. PMID- 22210623 TI - pep27 and lytA in Vancomycin-Tolerant Pneumococci. AB - Vancomycin therapy failure due to the emergence of tolerance in pneumococci is increasing. The molecular mechanism of tolerance is not clear, but lytA and pep27 are known to be involved. Our aim was to evaluate the expression of both genes in vancomycin-tolerant Streptococcus pneumoniae (VTSP) strains. Eleven VTSP strains from a total of 309 clinical isolates of S. pneumoniae from 1997 to 2006 were classified according to the criteria of Liu and Tomasz. All VTSP strains were evaluated for susceptibility according to CLSI criteria, serotype by the Quellung test, and clonality by PFGE. The expressions of lytA and pep27 were analyzed in different growth phases by RT-PCR with and without vancomycin. Eighty-two percent of VTSP strains showed resistance to penicillin, and 100% were sensitive to vancomycin and cefotaxime. The most frequent serotypes of VTSP strains were 23F (4/11) and 6B (3/11). Clonal relationship was observed in only two strains. No significant changes were observed in pep27 expression in the three phases of growth in VTSP strains with and without vancomycin. Interestingly, pep27 expression in the stationary phase in the non-tolerant reference strain R6 was significantly higher. However, no significant differences in lytA expression were observed between VTSP and R6 strains during the phases of growth analyzed. The absence of changes in pep27 expression in VTSP strains in the stationary phase may be related to their ability to tolerate high antibiotic concentrations, and thus, they survive and remain in the host under the antibiotic selective pressure reflected in therapeutic failure. PMID- 22210624 TI - Occurrence of virulence determinants in fecal Enterococcus faecalis isolated from pigs and chickens in Korea. AB - Forty-one Enterococcus faecalis (E. faecalis) isolates from feces of pigs and chickens in Korea were screened for the presence of virulence factors. Gelatinase activity (85.4%, 35/41) was the more commonly observed phenotype of virulence in E. faecalis, compared with hemolytic activity (12.2%, 5/41). Thirty-one of 35 (88.6%) gelatinase-positive E. faecalis isolates harbored the gelE and fsrABC genes. A gene encoding for the enterococcal surface protein (Esp) was detected in 24.4% (10/41) of the isolates. All betahemolysin- producing isolates harbored the esp gene. PMID- 22210625 TI - Impaired neural development in a zebrafish model for Lowe syndrome. AB - Lowe syndrome, which is characterized by defects in the central nervous system, eyes and kidneys, is caused by mutation of the phosphoinositide 5-phosphatase OCRL1. The mechanisms by which loss of OCRL1 leads to the phenotypic manifestations of Lowe syndrome are currently unclear, in part, owing to the lack of an animal model that recapitulates the disease phenotype. Here, we describe a zebrafish model for Lowe syndrome using stable and transient suppression of OCRL1 expression. Deficiency of OCRL1, which is enriched in the brain, leads to neurological defects similar to those reported in Lowe syndrome patients, namely increased susceptibility to heat-induced seizures and cystic brain lesions. In OCRL1-deficient embryos, Akt signalling is reduced and there is both increased apoptosis and reduced proliferation, most strikingly in the neural tissue. Rescue experiments indicate that catalytic activity and binding to the vesicle coat protein clathrin are essential for OCRL1 function in these processes. Our results indicate a novel role for OCRL1 in neural development, and support a model whereby dysregulation of phosphoinositide metabolism and clathrin-mediated membrane traffic leads to the neurological symptoms of Lowe syndrome. PMID- 22210627 TI - Silencing of multi-copy HPV16 by viral self-methylation and chromatin occlusion: a model for epigenetic virus-host interaction. AB - In the present study, we used the human papillomavirus type 16 (HPV16)-positive cervical carcinoma cell line CaSki as a paradigmatic model to understand epigenetic silencing of viral multi-copy genomes. We show that most of the hypermethylated HPV16 copies are kept as 'occluded' chromatin that defines a condition where genes were refractory in their response to trans-acting transcription factors and to external reactivation efforts. This provides the first example that viral genomes are silenced by such a host cell mechanism, hitherto only known for endogenous genes to preserve a stable and robust phenotype. Moreover, considering an adaptive cross-talk between viral proteins and the epigenetic modification machinery, we demonstrate that particularly E2 but also ectopically delivered E6/E7-can induce significant de novo methylation within the enhancer and, to a less extent, within the promoter region. These data suggest that under certain physiological conditions, HPV can down-regulate its own gene expression, regardless of the presence of transcriptional activators. We propose that self-methylation of multi-copy HPV could be the first event prior to heterochromatin formation. These processes favour an 'occluded' chromatin conformation, finally being unresponsive to transcriptional activation. The shift from potentially competent heterochromatin towards an occluded state is basically irreversible, possibly using the same mechanism described for lineage differentiation. Along this line, it is tempting to speculate that virus-cell interaction is able to 'sense' viral copy number and down-regulates excess of gene activity in order to guarantee cell viability. PMID- 22210626 TI - Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP. AB - Prion diseases are fatal neurodegenerative diseases of humans and animals caused by the misfolding and aggregation of prion protein (PrP). Mammalian prion diseases are under strong genetic control but few risk factors are known aside from the PrP gene locus (PRNP). No genome-wide association study (GWAS) has been done aside from a small sample of variant Creutzfeldt-Jakob disease (CJD). We conducted GWAS of sporadic CJD (sCJD), variant CJD (vCJD), iatrogenic CJD, inherited prion disease, kuru and resistance to kuru despite attendance at mortuary feasts. After quality control, we analysed 2000 samples and 6015 control individuals (provided by the Wellcome Trust Case Control Consortium and KORA-gen) for 491032-511862 SNPs in the European study. Association studies were done in each geographical and aetiological group followed by several combined analyses. The PRNP locus was highly associated with risk in all geographical and aetiological groups. This association was driven by the known coding variation at rs1799990 (PRNP codon 129). No non-PRNP loci achieved genome-wide significance in the meta-analysis of all human prion disease. SNPs at the ZBTB38-RASA2 locus were associated with CJD in the UK (rs295301, P = 3.13 * 10(-8); OR, 0.70) but these SNPs showed no replication evidence of association in German sCJD or in Papua New Guinea-based tests. A SNP in the CHN2 gene was associated with vCJD [P = 1.5 * 10(-7); odds ratio (OR), 2.36], but not in UK sCJD (P = 0.049; OR, 1.24), in German sCJD or in PNG groups. In the overall meta-analysis of CJD, 14 SNPs were associated (P < 10(-5); two at PRNP, three at ZBTB38-RASA2, nine at nine other independent non-PRNP loci), more than would be expected by chance. None of the loci recently identified as genome-wide significant in studies of other neurodegenerative diseases showed any clear evidence of association in prion diseases. Concerning common genetic variation, it is likely that the PRNP locus contains the only strong risk factors that act universally across human prion diseases. Our data are most consistent with several other risk loci of modest overall effects which will require further genetic association studies to provide definitive evidence. PMID- 22210628 TI - Altered intracellular localization and valosin-containing protein (p97 VCP) interaction underlie ATP7A-related distal motor neuropathy. AB - ATP7A is a P-type ATPase that regulates cellular copper homeostasis by activity at the trans-Golgi network (TGN) and plasma membrane (PM), with the location normally governed by intracellular copper concentration. Defects in ATP7A lead to Menkes disease or its milder variant, occipital horn syndrome or to a newly discovered condition, ATP7A-related distal motor neuropathy (DMN), for which the precise pathophysiology has been obscure. We investigated two ATP7A motor neuropathy mutations (T994I, P1386S) previously associated with abnormal intracellular trafficking. In the patients' fibroblasts, total internal reflection fluorescence microscopy indicated a shift in steady-state equilibrium of ATP7A(T994I) and ATP7A(P1386S), with exaggerated PM localization. Transfection of Hek293T cells and NSC-34 motor neurons with the mutant alleles tagged with the Venus fluorescent protein also revealed excess PM localization. Endocytic retrieval of the mutant alleles from the PM to the TGN was impaired. Immunoprecipitation assays revealed an abnormal interaction between ATP7A(T994I) and p97/VCP, an ubiquitin-selective chaperone which is mutated in two autosomal dominant forms of motor neuron disease: amyotrophic lateral sclerosis and inclusion body myopathy with early-onset Paget disease and fronto-temporal dementia. Small-interfering RNA (SiRNA) knockdown of p97/VCP corrected ATP7A(T994I) mislocalization. Flow cytometry documented that non-permeabilized ATP7A(P1386S) fibroblasts bound a carboxyl-terminal ATP7A antibody, consistent with relocation of the ATP7A di-leucine endocytic retrieval signal to the extracellular surface and partially destabilized insertion of the eighth transmembrane helix. Our findings illuminate the mechanisms underlying ATP7A related DMN and establish a link between p97/VCP and genetically distinct forms of motor neuron degeneration. PMID- 22210630 TI - The association between Mycoplasma genitalium and HIV-1 acquisition in African women. AB - OBJECTIVE: Mycoplasma genitalium is an emerging sexually transmitted infection (STI) and has been associated with reproductive tract infections and HIV in cross sectional studies. In this longitudinal study, we assess whether M. genitalium is associated with risk of acquiring HIV-1 infection. DESIGN: Nested case-control study within a large prospective study in Zimbabwe and Uganda METHODS: A total of 190 women who seroconverted to HIV-1 during follow-up (cases) were matched with up to two HIV-negative controls. Mycoplasma genitalium testing was performed by PCR-ELISA, using archived cervical samples from the HIV-1 detection visit and the last HIV-negative visit for cases, and equivalent visits in follow-up time for controls. Risk factors for HIV-1 acquisition were analyzed using conditional logistic regression, with M. genitalium as the primary exposure. RESULTS: Mycoplasma genitalium was a common infection in these populations (14.8 and 6.5% prevalence among cases and controls, respectively, at the visit prior to HIV-1 detection), and more prevalent than other nonviral STIs. We found a greater than two-fold independent increased risk of HIV-1 acquisition among women infected with M. genitalium at the visit prior to HIV-1 acquisition [adjusted odds ratio (AOR) = 2.42; 95% confidence interval (CI) 1.01-5.80), and at time of HIV-1 acquisition (AOR = 2.18; 95% CI 0.98-4.85). An estimated 8.7% (95% CI 0.1-12.2%) of incident HIV-1 infections were attributable to M. genitalium. CONCLUSION: This is the first longitudinal study to assess the relationship between M. genitalium and HIV-1 acquisition. If findings from this research are confirmed, M. genitalium screening and treatment among women at high risk for HIV-1 infection may be warranted as part of an HIV-1 prevention strategy. PMID- 22210629 TI - Differential regulation of toll-like receptor pathways in acute and chronic HIV-1 infection. AB - OBJECTIVE AND DESIGN: The objective of this study was to determine changes in toll-like receptor (TLR) responses of monocytes, myeloid dendritic cells and plasmacytoid dendritic cells during primary and chronic HIV-1 infection. TLRs serve as important innate receptors to sense pathogens, and have been implicated in mediating immune activation in HIV-1 infection. Studies assessing the consequences of HIV-1 infection on the ability of innate immune cells to respond to TLR stimulation have come to varying conclusions. METHODS: Using intracellular flow cytometry, cytokine production by cryopreserved peripheral blood mononuclear cells from healthy controls and HIV-1-infected individuals were examined after TLR stimulation. RESULTS: We observed that the effect of HIV-1 infection on TLR responses not only depended on the stage of HIV-1 infection, but was also dependent on the individual receptor and cell type examined. Monocyte and myeloid dendritic cell responses to TLR8 stimulation were associated with HIV-1 viral load and CD4 T-cell count, whereas plasmacytoid dendritic cell responses to TLR7 stimulation were not. Responses to TLR2 stimulation were not affected by HIV-1 infection, whereas responses to TLR9 stimulation were universally decreased in all HIV-1-infected individuals examined regardless of treatment or clinical parameters. CONCLUSION: Responsiveness to TLR7/8 stimulation, which have been shown to recognize HIV-1 ssRNA, did not decrease in chronic infection, and may represent a contributing factor to ongoing T-cell immune activation in the setting of chronic viremic HIV-1 infection. PMID- 22210631 TI - Anogenital pseudotumoral herpes and HIV infection: a new challenge for diagnosis and treatment. AB - HIV-infected patients may develop rare anogenital pseudotumoral herpes potentially mimicking epidermoid carcinoma. We assessed treatment in five new cases with a median follow-up of 3.3 years. Recurrence and clinical nucleoside analog resistance were observed in all patients. All drug treatments were only temporarily curative and clinical responses varied between patients and recurrences. Foscavir seemed to be the most appropriate second-line treatment and cidofovir or thalidomide should be considered as alternative treatments. PMID- 22210632 TI - The effectiveness of male circumcision for HIV prevention and effects on risk behaviors in a posttrial follow-up study. AB - BACKGROUND: The efficacy of male circumcision for HIV prevention over 2 years has been demonstrated in three randomized trials, but the longer-term effectiveness of male circumcision is unknown. METHODS: We conducted a randomized trial of male circumcision in 4996 HIV-negative men aged 15-49 in Rakai, Uganda. Following trial closure, we offered male circumcision to control participants and have maintained surveillance for up to 4.79 years. HIV incidence per 100 person-years was assessed in an as-treated analysis, and the effectiveness of male circumcision was estimated using Cox regression models, adjusted for sociodemographic and time-dependent sexual behaviors. For men uncircumcised at trial closure, sexual risk behaviors at the last trial and first posttrial visits were assessed by subsequent circumcision acceptance to detect behavioral risk compensation. RESULTS: By 15 December 2010, 78.4% of uncircumcised trial participants accepted male circumcision following trial closure. During posttrial surveillance, overall HIV incidence was 0.50/100 person-years in circumcised men and 1.93/100 person-years in uncircumcised men {adjusted effectiveness 73% [95% confidence interval (CI) 55-84%]}. In control arm participants, posttrial HIV incidence was 0.54/100 person-years in circumcised and 1.71/100 person-years in uncircumcised men [adjusted effectiveness 67% (95% CI 38-83%)]. There were no significant differences in sociodemographic characteristics and sexual behaviors between controls accepting male circumcision and those remaining uncircumcised. CONCLUSION: High effectiveness of male circumcision for HIV prevention was maintained for almost 5 years following trial closure. There was no self selection or evidence of behavioral risk compensation associated with posttrial male circumcision acceptance. PMID- 22210633 TI - Low prevalence of asymptomatic sexually transmitted infections in HIV-infected heterosexuals visiting an HIV clinic in the Netherlands. AB - Two-hundred and forty-five heterosexual HIV-infected patients (58% women; median age 41 years) were screened for asymptomatic sexually transmitted infections (STIs) during a routine visit at a large HIV outpatient clinic in the Netherlands. High-risk sexual behaviour was rare and STI prevalence was low: three Chlamydia trachomatis infections and one case of syphilis were diagnosed. These results suggest that, in the Netherlands, screening for STI during routine visits is currently not needed for asymptomatic heterosexual HIV-infected patients. PMID- 22210634 TI - Mechanisms involved in CD4 cell gains in HIV-infected patients switched to raltegravir. AB - BACKGROUND: CD4 gains in HIV patients on HAART result from release of T cells recently migrated from the thymus, redistribution from lymphoid tissues, proliferation in the periphery and/or reduced apoptosis. The relative contribution of each mechanism in CD4 restoration in patients with suppressed viremia switching antiretrovirals is unclear. METHODS: HIV patients with undetectable viremia on HAART were identified at our clinic. A subset switched to raltegravir was compared with another group that kept therapy unmodified. Naive and memory CD4 T-cells were measured by flow cytometry using CD45RA and CD27, respectively. Activation was examined using CD38 and recent thymic emigrants using CD31. Apoptosis was analyzed measuring soluble tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL). RESULTS: Thirty seven patients were examined, 19 switched to raltegravir and 18 controls, after a median of 26 months of suppressed viremia. At 6 months, mean CD4 cell counts significantly increased in raltegravir patients from 322 to 448 cells/MUl (P = 0.026) but not in controls (from 312 to 330 cells/MUl; P = 0.813). No significant changes were recognized in activation or CD31 expression in any group. In raltegravir patients, however, the proportion of naive CD4 T cells significantly increased (P = 0.014) as well as CD38 expression in these cells (P = 0.036). A positive correlation was found between CD38 and CD31 expression in naive CD4 T cells (R = 0.51, P < 0.001). TRAIL and FasL did not decline significantly in any group. CONCLUSION: HIV patients with prolonged undetectable viremia on HAART experience more pronounced CD4 gains after raltegravir switching than keeping the same regimen. An increased production of naive CD4 T cells largely explains this effect. PMID- 22210635 TI - A national review of vertical HIV transmission. AB - OBJECTIVES: Prevention of vertical HIV transmission has evolved significantly in Canada over the last two decades. The aim of this analysis is to describe the surveillance programme used, rate of vertical HIV transmission and changing epidemiology of HIV-affected pregnancies in Canada. DESIGN: National perinatal HIV surveillance programme. METHODS: From 1990, annual retrospective data was collected on demographic and clinical characteristics of HIV-infected mothers and their infants referred to 22 participating sites across Canada either before/during pregnancy or within 3 months after delivery. Factors impacting HIV transmission and demographic features were explored. RESULTS: Two thousand, six hundred and ninety-two mother-infant pairs were identified. The overall rate of vertical HIV transmission was 5.2%, declining to 2.9% since 1997. The rate of transmission for mothers who received HAART was 1%, and 0.4% if more than 4 weeks of HAART was given. Forty percent of women delivered by caesarean section, with no difference in transmission rate compared with vaginal delivery for women treated with HAART (1.4 vs. 0.6%, P = 0.129) but significant risk reduction for those who did not receive HAART (3.8 vs. 10.3%, P = 0.016). Black women were the largest group; proportions of black and aboriginal women increased significantly over time (P < 0.001 for both). Heterosexual contact was the most common risk category for maternal infection (65%), followed by injection drug use (IDU) (25%). CONCLUSION: Vertical HIV transmission in Canada has decreased dramatically for women treated with HAART therapy. All pregnant women should be evaluated for HIV infection and programmes expanded to reach vulnerable populations including aboriginal, immigrant and IDU women. PMID- 22210636 TI - Cardiopulmonary function in individuals with HIV infection in the antiretroviral therapy era. AB - OBJECTIVE: To determine relationship of echocardiographic measures of pulmonary hypertension to lung function and inflammatory biomarkers in HIV-infected individuals. DESIGN: Cross-sectional study of 116 HIV-infected outpatients. METHODS: Doppler-echocardiography and pulmonary function testing were performed. Induced sputum and plasma cytokines, sputum cell counts and differentials, markers of peripheral T-cell activation, and serum N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured. Univariate and multivariate analyses determined relationship of echocardiographic variables to pulmonary function, inflammation, and NT-proBNP. RESULTS: Mean estimated pulmonary artery systolic pressure (PASP) was 34.3 mmHg (SD 6.9) and mean tricuspid regurgitant jet velocity (TRV) was 2.5 m/s (SD 0.32). Eighteen participants (15.5%) had PASP of at least 40 mmHg, and nine (7.8%) had TRV of at least 3.0 m/s. Elevated TRV was significantly associated with CD4 cell counts below 200 cells/MUl and higher log HIV-RNA levels. Forced expiratory volume in 1 s (FEV(1)) percentage predicted, FEV(1)/forced vital capacity, and diffusing capacity for carbon monoxide (DLco) percentage predicted were significantly lower in those with elevated PASP or TRV. Sputum interleukin-8, peripheral interleukin-8, peripheral interferon-gamma levels, and CD8(+) T-cell expression of CD69(+) were associated with increasing PASP and TRV. Log NT-proBNP was significantly higher with increasing PASP and TRV. Left ventricular function was not associated with PASP or TRV. CONCLUSION: Echocardiographic manifestations of pulmonary hypertension are common in HIV and are associated with respiratory symptoms, more advanced HIV disease, airway obstruction, abnormal DLco, and systemic and pulmonary inflammation. Pulmonary hypertension and chronic obstructive pulmonary disease coexist in HIV and may arise secondary to common inflammatory mechanisms. PMID- 22210637 TI - Cellular immune responses and susceptibility to HIV-1 superinfection: a case control study. AB - A case-control study was performed to determine the effects of HIV-1-specific cellular immune responses on the odds of acquiring a second HIV-1 infection (superinfection). Changes in the frequency of cytokine-producing or cytolytic CD8+ or CD4+ T cells were not associated with significant alterations in the odds of superinfection, suggesting that HIV-1 specific cellular immune responses at the level induced by chronic infection do not appear to significantly contribute to protection from HIV-1 superinfection. PMID- 22210638 TI - Design challenges facing clinical trials of the effectiveness of new HIV prevention technologies. PMID- 22210640 TI - Data sharing for prevention: a case study in the development of a comprehensive emergency department injury surveillance system and its use in preventing violence and alcohol-related harms. AB - OBJECTIVE: To examine emergency department (ED) data sharing via a local injury surveillance system and assess its contribution to the prevention of violence and alcohol-related harms. METHODS: 6-year (2004-2010) exploratory study analysing injury attendances to one ED in the North West of England using descriptive and trend analyses. RESULTS: Over the 6-year period, there were 242,796 ED injury attendances, including 21,683 for intentional injuries. Compared with unintentional injury patients, intentional injury patients were more likely to be men, aged 18-34 years, live in the most deprived communities, have attended the ED at night/weekends, have been injured in a public place and have consumed alcohol prior to the injury. Detailed data collected on alcohol and violence related ED attendances were shared with local partners to monitor local trends and inform prevention activity including targeted policing and licensing enforcement. Over the 6-year period, intentional ED injury attendances decreased by 35.6% and alcohol-related assault attendances decreased by 30.3%. CONCLUSIONS: The collection of additional ED data on assault details and alcohol use prior to injury, and its integration into multi-agency policy and practice, played an important role in driving local violence prevention activity. Further research is needed to assess the direct contribution ED data sharing makes to reductions in violence. PMID- 22210639 TI - Tenofovir and tenofovir disoproxil fumarate pharmacokinetics from intravaginal rings. AB - OBJECTIVES: To compare the distribution of tenofovir in sheep vaginal lumen, tissue, and plasma following topical delivery of the antiretroviral drug from intravaginal rings, either as tenofovir or the disoproxil fumarate prodrug. DESIGN: Comparative pharmacokinetic study in sheep. METHOD: Intravaginal rings formulated to achieve equivalent release rates of tenofovir and its disoproxil fumarate prodrug were evaluated for 28 days in sheep, with four animals in each group. Drug concentrations were measured by high-performance liquid chromatography-mass spectrometry. RESULTS: Tenofovir levels in cervicovaginal lavage were indistinguishable (P > 0.30) in both groups, but tissue levels in animals receiving the prodrug were 86-fold higher than those receiving tenofovir, and approximately 50 times higher than the level shown to be protective of HIV infection in the CAPRISA 004 trial. CONCLUSION: This is the first study to compare the pharmacokinetics of tenofovir and its disoproxil fumarate prodrug administered topically to the vaginal tract. These in-vivo data show that the prodrug leads to significantly higher drug tissue levels than tenofovir, a finding that may have important implications for the development of preexposure prophylaxis strategies based on topical delivery of antivirals to the female genital tract. PMID- 22210641 TI - Global alliance for care of the injured. PMID- 22210643 TI - Lessons from the past. PMID- 22210644 TI - May 6, 1953: the untold story. AB - A landmark case in the history of cardiac surgery was the first successful use of cardiopulmonary bypass (CPB) in May 1953 by Dr. John H. Gibbon, Jr. The operation was closure of an atrial septal defect, but there were complications in the conduct of CPB that nearly led to a catastrophe. Quick action by personnel on the team saved the patient's life. PMID- 22210645 TI - Mechanical circulatory support of systemic ventricle in adults with transposition of great arteries. AB - We report the successful use of the implantable ventricular assist device HeartWare (HeartWare International Inc., Framingham, MA) to support the systemic circulation in two adult patients with transposition of the great arteries (TGA). One had undergone the Senning procedure as a neonate; the other had congenitally corrected TGA and dextrocardia with palliation in adulthood. It is possible to implant the HeartWare pump into the morphological right ventricle with cannulation of either the diaphragmal surface or the free wall without additional changes in implantation technique and employing off-pump insertion. PMID- 22210646 TI - Discontinuation of HeartWare RVAD support without device removal in chronic BIVAD patients. AB - During biventricular assist device (BVAD) support, right ventricular (RV) assistance may restore sufficient RV function after several weeks to months. Since November 2009, 10 patients (9 men and 1 woman; mean age, 49.7 +/- 14.4 y) suffering from idiopathic dilatative cardiomyopathy received BVAD employing two implantable continuous-flow pumps of the HeartWare type. In three male patients, aged 53, 57, and 60 years, after a right ventricular assist device (RVAD) support time of 15.6, 11.2, and 3.6 months, respectively, the RVAD was stopped, and the percutaneous lead was surgically shortened in two cases. There were no differences in preoperative RV geometry and function or in severity of tricuspid valve regurgitation in patients with and without delayed RV recovery. Follow-up echocardiography revealed no regurgitation through the right pump in any patient. One patient died due to severe sepsis 63 days later; the other two patients are currently on left ventricular assist devices support at home, 120 and 236 days after RVAD deactivation with stable hemodynamic conditions and without any thromboembolic events. RV function may recover even after weeks or months on BVAD support. The HeartWare HVAD used as an RVAD may be stopped and left in place without complications. PMID- 22210647 TI - Effects of gamma radiation on a ventricular assist device and its percutaneous lead components. AB - A patient supported by a left ventricular assist device (LVAD) presented with an abdominal tumor requiring consolidative radiation therapy. To assess the effects of radiation therapy on the operation of the ventricular assist device (VAD) system and assure that the treatment would be safe for the patient with regard to the operation of the VAD system, sample equipment was irradiated and then tested for functionality. Changes in the mechanical properties of components of the percutaneous lead were measured. After testing, it was concluded that radiation therapy would not impede the operation of the pump or produce deleterious alterations of mechanical properties of the various system components. The patient underwent radiation therapy with a total dose of 2,000 cGy without evident complications. There were no observed effects on the LVAD operation nor any indication of alarms or malfunctions. Subsequently, the patient recovered adequate cardiac function for explant of the LVAD and the recovered components were also analyzed confirming the absence of alterations in material properties that would endanger patient safety. PMID- 22210648 TI - In vitro study of the Norwood palliation: a patient-specific mock circulatory system. AB - The aim of this study was to build a mock circulatory system replicating in vitro the hemodynamics following the Norwood procedure and testing patient-specific anatomies focusing on the effect of aortic coarctation. Three anatomies were reconstructed from magnetic resonance images and rapid prototyped with transparent rigid resin. The models presented varying degrees of coarctation (none, moderate, and severe). A Blalock-Taussing (BT) shunt was modeled in all phantoms, which were inserted into a mock circulation. The single ventricle was simulated using a Berlin Heart driven with a PC-controlled piston. Resistive and compliant elements were implemented, creating a lumped parameter network. Pressure was measured at three locations: the transverse aortic arch, just after the aortic isthmus, and further downstream in the thoracic aorta. Volume distribution was derived from the instantaneous flow measurements at three outlets: upper body, lower body, and BT shunt. The combination of three dimensional (3D) detailed anatomy and lumped parameter network effectively renders the circuit a multiscale in vitro model that successfully reproduces physiologic pressure signals. The pressure results highlight the larger pressure drop caused by coarctation and show the effect of pressure recovery. Results also suggest a reduction of flow to the lower body with increasing severity of coarctation, to the advantage of upper body and pulmonary circulation. PMID- 22210649 TI - Effects of fluid viscoelasticity on the performance of an axial blood pump model. AB - An aqueous Xanthan gum solution (XGS) was used as blood analog fluid to explore the influence of fluid viscoelasticity on the performance of an axial blood pump model. For comparison, a 39 wt% Newtonian aqueous glycerin solution (GS), the common fluid in blood pump tests, was also used as a working fluid. The experimental results showed that a higher head curve was obtained using XGS in the pump than using GS. The heads of the XGS that were computed using the viscoelastic turbulence model agreed well with the measured data. In contrast, the standard k-epsilon turbulence model failed to provide satisfactory predictions for the XGS. The computational results revealed that in most parts of the pump model flow fields, the Reynolds shear stress values and turbulent dissipation rates of the XGS were all lower than those of the GS. The hemolysis index of the pump model using the XGS was calculated to be only one-third of that using the GS. PMID- 22210650 TI - Variables associated with circuit life span in critically ill patients undergoing continuous renal replacement therapy: a prospective observational study. AB - One of the greatest problems in performing continuous renal replacement therapy (CRRT) is premature coagulation of the circuit. The aim of the current study was to monitor the circuit function prospectively and analyze patient-related variables that may affect circuit life. Critically ill patients admitted to the intensive care unit of a tertiary hospital between August 2010 and August 2011 receiving continuous veno-venous hemofiltration (CVVH) with systemic heparin anticoagulation were prospectively studied. Variables including body temperature, blood pH value, ionized calcium level, activated partial thromboplastin time (aPTT), prothrombin time (PT), platelet count, and heparin dose were collected and analyzed for their association with circuit life span. Fifty-four patients treated by CVVH were included, with 255 filters. The filter life was 29.7 +/- 13.4 hours (mean +/- standard deviation [SD]). Circuits with longer survival time appeared to have lower body temperature (37.80 +/- 1.14 vs. 36.36 +/- 1.09; p< 0.05), lower levels of serum ionized calcium (0.80 vs. 1.29; p< 0.05), and to be more acidic (7.233 vs. 7.377; p< 0.05). Cox regression showed that pH value and ionized calcium levels were significantly associated with circuit life. Other variables of hematocrit, albumin levels, platelet count, aPTT, PT, or dose of heparin were not significantly associated with circuit life. PMID- 22210651 TI - Molecular adsorbent recirculating system as artificial support therapy for liver failure: a meta-analysis. AB - Molecular Adsorbent Recirculating System (MARS) is an artificial liver support system that has been developed for patients with liver failure until the liver regains function or as a bridge to transplantation. We conducted a meta-analysis to examine the efficacy of this promising therapy. We searched MEDLINE, EMBASE, and the Cochrane Registry of Controlled Trials databases, and abstracts from the proceedings of several scientific meetings. Patients with acute, acute on chronic, and hyperacute liver failure were included and we compared MARS with standard medical therapy. Randomized and nonrandomized controlled trials were included and Molecular Adsorbent Recirculating System was the intervention used. We evaluated net change in total bilirubin levels, improvement in hepatic encephalopathy and mortality. Nine randomized controlled trials and one nonrandomized controlled study met criteria and were included. By meta-analysis, MARS resulted in a significant decrease in total bilirubin levels (net change 7.0 mg/dl; 95% CI -10.4, -3.7; p < 0.001) and in an improvement in the West-Haven grade of hepatic encephalopathy (odds ratio [OR] 3.0; 95% CI 1.9, 5.0; p < 0.001). There was no beneficial effect on mortality (OR 0.91; 95% CI 0.64, 1.31; p = 0.62). The limitations of this study include a small sample size, an inability to blind with significant heterogeneity among studies, and variable definitions of liver failure. The Molecular Adsorbent Recirculating System is associated with a significant improvement in total bilirubin levels and hepatic encephalopathy but has no impact on survival. Large studies are required to assess the merit of this promising therapy on patient-centered outcomes. PMID- 22210652 TI - Challenges in longer-term mechanical support of fontan circulation in sheep. AB - Single ventricle congenital heart defects are usually palliated with the end result of a Fontan circulation. Despite improving results, this circulation is still associated with long-term failure. We previously developed an animal model of mechanical cavopulmonary circulation support that was successful in the acute and mid-term period. In the current study, we evaluated longer support durations in five Western-breed sheep. Through a right thoracotomy we instituted mechanical support from the inferior vena cava to the pulmonary artery, using a Heartmate II axial flow pump (Thoratec Corp., Pleasanton, CA). Postoperatively, the animals were anticoagulated with heparin iv. Hemodynamics, pump flow, anticoagulation, and hepatic and renal function were monitored daily. All animals survived the operation. Signs of moderate liver and kidney injury in general reversed quickly. Two animals had a fatal pump thrombosis. When anticoagulation was effective, hemodynamics and pump flow were maintained to normal values. Effective anticoagulation was difficult to achieve because of the high variability in response to heparin. Survival up to 18 days was accomplished. This study is the longest reported survival of animals with a mechanically assisted cavopulmonary circulation. The performance of the Thoratec Heartmate II has been good, but the issue of effective anticoagulation has not yet been solved. PMID- 22210653 TI - Ovine blood: establishment of a list of reference values relevant for blood coagulation in sheep. AB - Ovine animal models are widely used to conduct preclinical studies, e.g., to evaluate cardiovascular prostheses intended to be applied in man. However, although analyzed in many of those studies, information about ovine blood reference values is scanty. The aim of this study is to establish a reference list of ovine blood parameters relevant for blood coagulation. A cohort of 47 mature ewes was evaluated. Parameters comprised the following: cells and cellular components-platelet, red, and white cell counts (including subsets), hemoglobin (Hb), hematocrit (HCT), mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV), and MCH concentration (MCHC); global tests of coagulation prothrombin time (Quick's time) and activated partial thromboplastin time (aPTT); and parameters relevant for blood coagulation-fibrinogen, antithrombin (AT), and von Willebrand Factor. After explorative data analysis, a list of ovine reference values was established. Interestingly, a comparison with human reference values revealed some interspecies differences between sheep and man, i.e., much higher ovine ranges for some cell counts (neutrophils, lymphocytes, basophils, eosinophils, and platelets) but lower values for some other parameters (Hb, HCT, MCV, MCH, AT, and Quick's test). We established a reference list of ovine blood count and blood coagulation parameters. Because of some peculiarities of the ovine blood, this list may have implications for the interpretation of experimental data. PMID- 22210654 TI - A wireless and battery-less miniature intracardiac pressure sensor: early implantation studies. AB - Permanently implantable hemodynamic monitors show great promise in providing personalized and cost-efficient care to heart failure patients by providing timely intracardiac pressure data under ambulatory conditions. The data may be used to titrate maintenance therapies and to monitor health status so that more intensive interventions can be planned and performed under optimal conditions. In this pilot study, we present the results of the implantation of a novel wireless, battery-less pressure sensor into the apex of the left ventricle of four dogs for a period of 8 weeks. All animals recovered to a normal state and did not show any clinical signs of cardiac insufficiency or any complications suggestive of thromboembolism. All sensors functioned throughout the implantation period and provided detailed waveforms of ventricular pressure. PMID- 22210656 TI - Cryoglobulinaemia related to Sjogren's syndrome or HCV infection: differences based on the pattern of bone marrow involvement, lymphoma evolution and laboratory tests after parotidectomy. AB - OBJECTIVE: The relationship of cryoglobulinaemia with lymphoproliferation of mucosa-associated lymphoid tissue (MALT) as risk factors for lymphoma evolution in SS remains to be clarified. The different biologic background of SS-related cryoglobulinaemia as compared with cryoglobulinaemia linked to HCV infection was clarified by different clinical and biologic approaches. METHODS: B-cell clonal expansion was analysed in the bone marrow of 27 consecutive cases with primary SS and mixed cryoglobulinaemia, HCV unrelated, in comparison with 55 HCV-related patients with cryoglobulinaemic vasculitis (CV) without SS. The results were related to the possible occurrence and localization of B-cell lymphoma in the single case. Secondly, the prevalence of mixed cryoglobulinaemia was investigated in 41 unselected patients with primary SS showing either parotid myoepithelial sialadenitis (MESA) or a frank B-cell non-Hodgkin's lymphoma. Thirdly, the levels of serum cryoglobulins and RF were followed in one patient with primary SS, CV and parotid B-cell lymphoma of MALT after bilateral subtotal parotidectomy. RESULTS: A polyclonal pattern of B expansion in the bone marrow was significantly more frequent in SS-related (19/27 cases) than in HCV-related cryoglobulinaemia (19/55) (P = 0.003). Cryoglobulins were positive in a fraction of patients with SS and malignant lymphoma or with parotid MESA (13/18 and 7/23, respectively), whereas MALT involvement by the lymphoproliferative disorder was the rule. Finally, the levels of serum cryoglobulins and RF markedly decreased in the SS patient undergoing bilateral subtotal parotidectomy. CONCLUSION: Lymphoproliferation of MALT appears as the biologic background of cryoglobulinaemia in SS, differently from HCV-related cryoglobulinaemia. PMID- 22210655 TI - Extracorporeal membrane oxygenation as a bridge to definite surgery in recurrent postinfarction ventricular septal defect. AB - A recurrent shunt after a postinfarction ventricular septal defect (PI-VSD) repair is common. We treated a case of cardiogenic shock caused by a large recurrent shunt after the patch repair of an apical PI-VSD with percutaneous extracorporeal membrane oxygenation (ECMO) for 4 days until a secondary definite repair. This suggests that percutaneous ECMO support is reliable before and after secondary definitive surgery in recurrent PI-VSD and may imply using a delayed surgical strategy with ECMO support to restore hemodynamic stability and avoid primary surgery on freshly fragile infarcted myocardium. PMID- 22210657 TI - Hand workload, computer use and risk of severe median nerve lesions at the wrist. AB - OBJECTIVE: To evaluate the effect of hand workload, especially computer use, on the incidence of severe, idiopathic median nerve lesions at the wrist (MNLW) in patients with idiopathic CTS. METHODS: Data were prospectively collected for 444 patients with classic or probable CTS who were of working age and referred to our electrodiagnostic (EDX) laboratories. Clinical items recorded were age, gender, intensity of hand workload, BMI and bilaterality of the MNLW. EDX data recorded were results of needle examination of the abductor pollicis brevis (APB), distal motor latency (DML) to the APB and orthodromic sensory conduction velocity. MNLW was considered severe if the DML to the APB was >=6.0 ms. Patients were divided into two groups: those exhibiting at least one severe MNLW or not. They were classified into three categories according to occupational activity related to the intensity of hand workload: (i) non-workers (reference category); (ii) white collar workers using computers; and (iii) blue-collar or manual workers. We determined factors associated with severe and non-severe MNLW. RESULTS: We investigated 92 patients with 119 severe MNLW and 352 with 589 non-severe MNLW. The risk of severe MNLW was similar for non-workers and blue-collar workers and was 2.5-fold higher than for workers using computers [adjusted odds ratio = 0.41; (95% CI)] after adjusting for age, gender and BMI. CONCLUSION: Workers who use computers, who represent, in many countries, a large number of compensation claims, have a lower risk of severe MNLW as compared with blue-collar workers and also non-workers. PMID- 22210658 TI - Reduction of direct and indirect costs in patients with AS receiving etanercept: results from an open-label 36-week extension of the ASCEND study in four European countries. AB - OBJECTIVE: To characterize the impact of etanercept (ETN) in AS on cost, work productivity and quality of life (QoL). METHODS: A Phase 4, open-label, multi centre (UK, Scandinavia) extension study in AS. Eligible subjects (n = 84) were treated for 36-52 weeks with ETN 50 mg s.c. once weekly. Analysis included direct costs (transformed out-patient and in-patient care elements), indirect costs (sick leave and lost working days), efficacy and QoL. RESULTS: Annualized direct and indirect costs decreased (55.5%, P <= 0.008) during ETN treatment, as did out patient and in-patient episodes (physiotherapist/physician visits, P = 0.012). Work productivity and QoL increased. CONCLUSION: ETN therapy significantly reduces direct and indirect health-care costs and increases work ability and QoL in AS. Trial Registration. EUDRACT, https://eudract.ema.europa.eu/, 2006-001061 42. PMID- 22210659 TI - Validation of the Dudley Inflammatory Bowel Symptom Questionnaire for the assessment of bowel symptoms in axial SpA: prevalence of clinically relevant bowel symptoms and association with disease activity. AB - OBJECTIVES: To validate the Dudley Inflammatory Bowel Disease Questionnaire (DISQ) for determining the presence and severity of bowel symptoms in axial SpA. METHODS: Seventy-seven SpA patients were assessed for disease activity using the BASDAI. All participants, including 32 healthy controls and 29 patients with Crohn's Disease (CD), completed the DISQ and an assessment of stool form and frequency. Validation of the DISQ was undertaken in accordance with OMERACT criteria. RESULTS: Validity of the DISQ for measuring bowel symptoms in SpA was confirmed (Cronbach's alpha 0.79). Mean DISQ scores (s.d.) were: controls 2.6 (2.6), SpA 8.7 (6.1) and CD 17.1 (10.2). Differences were significant between controls and SpA, and SpA and CD, and correlated with disease activity (rho 0.27, P = 0.02). In SpA, DISQ scores of those taking NSAIDs (n = 59) did not differ from those not taking NSAIDs (n = 18) (P = 0.31). Stool form and frequency differed significantly between SpA patients and healthy controls (P < 0.001). Using the DISQ the prevalence of clinically relevant bowel symptoms in SpA is 31%, and 7.8% experience bowel symptoms equivalent to active CD. CONCLUSION: The DISQ is a valid measure of bowel symptoms in SpA. Bowel symptoms are prevalent in SpA and correlate with disease activity. Symptoms do not relate to treatment with NSAIDs. We conclude that bowel symptoms should be included as a domain in the clinical assessment of patients with SpA and that the DISQ has potential as an outcome measure in clinical trials. PMID- 22210661 TI - The 6-joint ultrasonographic assessment: a valid, sensitive-to-change and feasible method for evaluating joint inflammation in RA. AB - OBJECTIVE: Musculoskeletal US can be useful in monitoring RA. It can be time consuming and there is no consensus in defining the joints to evaluate. We assessed the validity, sensitivity to change and feasibility of a reduced 6-joint US score in patients with RA starting therapy with an anti-TNF agent. METHODS: A group of consecutive RA patients starting etanercept were investigated. The patients underwent clinical evaluation, laboratory tests and US assessment at baseline and 3 months. A semi-quantitative score (0-3) was used to evaluate synovial effusion (SE), synovial proliferation (SP) and power Doppler (PD) signal in 12 joints. A process of data reduction, based on the frequency of synovial site involvement by US-SE, US-SP and US-PD signal, was conducted to investigate the validity of a 6-joint US assessment. RESULTS: Forty-five RA patients were evaluated. A significant decrease in all clinical, serological and 12-joint US parameters was found at follow-up. A significant correlation between changes in the DAS-28 and changes in the US scores in the 12-joint assessment was observed at follow-up (P < 0.001). A reduced 6-joint US score was obtained, including wrist, second MCP and knee joints of both sides, detecting US-SE in 97.78% of patients, US-SP in 100% of patients and positive US-PD in 100% of patients. The 6 joint US score showed a highly significant correlation with changes in DAS-28 (P < 0.001). The 6-joint evaluation was quick and easy to do. CONCLUSION: A 6-joint US assessment may be a valid, sensitive-to-change and feasible method for evaluating joint inflammation in RA. PMID- 22210662 TI - Disappearance of anti-MDA-5 autoantibodies in clinically amyopathic DM/interstitial lung disease during disease remission. AB - OBJECTIVE: Autoantibodies against melanoma differentiation-associated gene 5 (MDA 5) are one of the serological markers for DM. Anti-MDA-5 antibodies are especially associated with rapidly progressive interstitial lung disease (ILD) in amyopathic DM (ADM). It is known that the antibody status of anti-ENAs does not generally change significantly with disease course. For anti-MDA-5 antibodies, however, few longitudinal studies have investigated such changes. This study aimed to establish a quantitative assay for anti-MDA-5 antibodies towards assessing the long-term outcome of ADM patients who had anti-MDA-5 antibodies. METHODS: We established ELISA for measuring anti-MDA-5 antibody levels using in vitro transcription and translation recombinant protein. The antibody levels were measured at different time points in 11 clinically ADM patients who tested positive for the anti-MDA-5 antibody on their first visit (range of follow-up 3 months to 16 years). RESULTS: At the stage of clinical remission, six patients received no medication and the four others received low-dose CS. ELISA showed that anti-MDA-5 antibodies disappeared in nine of the patients and fell to just above the cut-off in one patient; in the patient who died, the antibodies remained. CONCLUSION: Our results suggest that anti-MDA-5 antibodies may be useful as a marker for monitoring disease activity in ILD complicated with ADM. Serial monitoring at short intervals is required to evaluate whether anti-MDA-5 antibody levels correlate with ADM disease activity. PMID- 22210663 TI - Safety and efficacy of US-guided CS injection into temporomandibular joints in children with active JIA. AB - OBJECTIVE: To assess the safety and efficacy of US-guided CS injection done by a paediatric rheumatologist into the TM joints (TMJs) in children with JIA. METHODS: Children with JIA presenting to the rheumatology clinic were assessed for TMJ arthritis. Triamcinolone hexacetonide was injected in children with active arthritis assessed by MRI using US guidance under general anaesthesia by the same paediatric rheumatologist trained in the procedure. Efficacy and safety were assessed post-injection by patient-guided symptoms and physical examination. RESULTS: Thirty-eight children (34 girls) with JIA who had TMJ injection done between January 2009 and January 2011 were included in the analysis. Mean age was 12.25 (+/- 3.55) (range 5-18) years. The mean disease duration was 4.54 (+/- 2.73) (range 1.5-11.1) years. Symptoms pre-injection were pain in 17/38 (44.7%), jaw deviation in 14/38 (36.8%), restricted jaw movement in 13/38 (34.2%) and chewing dysfunction in 7/38 (18.4%). Five (12.5%) children had micrognathia. A total of 63 joints were injected. The injection was efficacious in 58/63 (92.06%) joints. All 17 (100%) children had resolution of pain, and chewing dysfunction improved in 5/7 (71.4%). Jaw deviation improved in 13/14 (92.8%). In the 5/63 (7.9%) injections that were not efficacious, two children with both TMJs injected (four joints) had persisting stiffness with chewing dysfunction and one had persistent jaw deviation. One child developed a scar at the site of injection. CONCLUSION: US-guided CS injection into the TMJ done by a paediatric rheumatologist trained in the procedure is safe with a high rate of success. PMID- 22210660 TI - Genetic association study of NF-kappaB genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopathy. AB - OBJECTIVE: Treatment-resistant muscle wasting is an increasingly recognized problem in idiopathic inflammatory myopathy (IIM). TNF-alpha is thought to induce muscle catabolism via activation of nuclear factor-kappa B (NF-kappaB). Several genes share homology with the NF-kappaB family of proteins. This study investigated the role of NF-kappaB-related genes in disease susceptibility in UK Caucasian IIM. METHODS: Data from 362 IIM cases [274 adults, 49 (+/-14.0) years, 72% female; 88 juveniles, 6 (+/-3.6) years, 73% female) were compared with 307 randomly selected Caucasian controls. DNA was genotyped for 63 single nucleotide polymorphisms (SNPs) from NF-kappaB-related genes. Data were stratified by IIM subgroup/serotype. RESULTS: A significant allele association was observed in the overall IIM group vs controls for the IKBL-62T allele (rs2071592, odds ratio 1.5, 95% CI 1.21, 1.89, corrected P = 0.0086), which strengthened after stratification by anti-Jo-1 or -PM-Scl antibodies. Genotype analysis revealed an increase for the AT genotype in cases under a dominant model. No other SNP was associated in the overall IIM group. Strong pairwise linkage disequilibrium was noted between IKBL-62T, TNF-308A and HLA-B*08 (D' = 1). Using multivariate regression, the IKBL 62T IIM association was lost after adjustment for TNF-308A or HLA-B*08. CONCLUSION: An association was noted between IKBL-62T and IIM, with increased risk noted in anti-Jo-1- and -PM-Scl antibody-positive patients. However, the IKBL-62T association is dependent on TNF-308A and HLA-B*08, due to strong shared linkage disequilibrium between these alleles. After adjustment of the 8.1 HLA haplotype, NF-kappaB genes therefore do not independently confer susceptibility in IIM. PMID- 22210664 TI - Why should rheumatologists be aware of the mucopolysaccharidoses? PMID- 22210665 TI - Pathogenesis of skeletal and connective tissue involvement in the mucopolysaccharidoses: glycosaminoglycan storage is merely the instigator. AB - The mucopolysaccharidoses (MPSs) are a series of rare genetic disorders in which progressive bone and joint disease represents a key source of morbidity for patients. The recent introduction of enzyme replacement therapy for many of the MPSs has led to a need for increased physician awareness of these rare conditions in order to ensure that treatment is initiated at a time that leads to optimal benefit for patients. In addition, the current experiences of the clinical responsiveness of patient's symptoms to enzyme replacement approaches have also fuelled an interest in the development of alternative and adjunctive therapeutic approaches directed particularly to the rheumatological aspects of disease. Understanding the underlying pathogenesis of the MPSs is a key element for advancements in both of these areas. This review highlights the current knowledge underlying the pathophysiology of disease symptoms in the MPSs and underscores the importance and role of pathogenic cascades. PMID- 22210666 TI - Musculoskeletal manifestations of mucopolysaccharidoses. AB - The mucopolysaccharidoses (MPSs) are a heterogeneous group of inherited metabolic disorders caused by enzyme deficiencies that lead to progressive lysosomal storage of glycosaminoglycans. Musculoskeletal manifestations are common across all forms of MPS and are often apparent early in the disease course. Diagnostic delays occur frequently in these patients, especially those with more attenuated forms of disease. Treatments for many types of MPS are now available; however, they are most effective if started early before the development of irreversible damage. Some manifestations such as stiffness and joint contractures may mimic other conditions such as inflammatory arthritis, which may cause further delays. Rheumatologists and other specialists should be aware of the musculoskeletal manifestations of MPS so that diagnostic delays can be avoided and appropriate management initiated. PMID- 22210667 TI - Orthopaedic aspects of mucopolysaccharidoses. AB - Skeletal abnormalities are an early and prominent feature of most mucopolysaccharide (MPS) disorders, with the degree of skeletal involvement varying between and within MPS subtypes. Most patients exhibit a constellation of radiographic abnormalities known as dysostosis multiplex, consisting of abnormally shaped vertebrae and ribs, enlarged skull, spatulate ribs, hypoplastic epiphyses, thickened diaphyses and bullet-shaped metacarpals. Thoracolumbar kyphosis or the gibbus deformity is often a key diagnostic clue. Also common are hip dysplasia, genu valgum and, later in the course of the disease, spinal cord compression, which can be life-threatening. Short stature is ubiquitous. Treatment of skeletal manifestations usually involves surgical intervention. All patients with MPS should be considered at high risk for surgical intervention requiring anaesthesia because of airway and cardiac disease manifestations. Regular imaging of the cervical, thoracic and lumbar spine, the hips and the lower extremities is recommended for patients with MPS. PMID- 22210668 TI - Ocular manifestations as key features for diagnosing mucopolysaccharidoses. AB - Diagnosis of mucopolysaccharidosis (MPS) requires awareness of the multisystem disease manifestations and their diverse presentation in terms of time of onset and severity. Many patients with MPS remain undiagnosed for years and progressively develop irreversible pathologies, which ultimately lead to premature death. To foster timely treatment and ensure a better outcome, it is of utmost importance to recognize and evaluate the typical ocular features that present fairly early in the course of the disease in many children with MPS. These include corneal clouding, ocular hypertension/glaucoma, retinal degeneration, optic disc swelling and optic nerve atrophy. Other associations include pseudo-exophthalmos, amblyopia, strabismus and large refractive errors requiring spectacle correction. While some ocular manifestations require specialized equipment for detecting abnormalities, light sensitivity, pseudo exophthalmos and strabismus are often apparent on a routine physical examination. In addition, patients may be symptomatic from vision impairment, photosensitivity, night blindness and visual field constriction. Combined with the skeletal/joint complications and other manifestations, these ocular features are key in the differential diagnosis of children with joint abnormalities. Rheumatologists should have a high index of suspicion for MPS to facilitate early diagnosis. Referral to a geneticist, a metabolic specialist or physician who specializes in MPS can confirm the diagnosis and provide disease management. Consultation with an ophthalmologist who has expertise in MPS is also needed for thorough examination of the eyes and regular follow-up care. PMID- 22210669 TI - Overview of the mucopolysaccharidoses. AB - The mucopolysaccharidoses (MPSs) are a group of rare, inherited lysosomal storage disorders that are clinically characterized by abnormalities in multiple organ systems and reduced life expectancy. The MPSs are heterogeneous, progressive disorders. Patients typically appear normal at birth, but during early childhood they experience the onset of clinical disease, including skeletal, joint, airway and cardiac involvement, hearing and vision impairment, and mental retardation in the severe forms of MPS I, MPS II and MPS VII and all subtypes of MPS III. There are two treatment options for patients with MPS that are directed at the underlying pathophysiology: haematopoietic stem cell transplantation, which is useful for selected patients, and recombinant i.v. enzyme replacement therapy, which is available for MPS I, II and VI. Early diagnosis and treatment can improve patient outcomes and may reduce the disease burden on patients and caregivers. As skeletal and joint abnormalities are characteristic of many patients with MPS, rheumatologists are positioned to recognize the features of the disease and to facilitate early diagnosis and referral. In this overview, the clinical features of the MPS disorders and a brief review of treatment options will be presented in order to aid the rheumatologist in recognizing the features of these rare genetic disorders. PMID- 22210670 TI - Diagnosis of the mucopolysaccharidoses. AB - The mucopolysaccharidoses (MPSs) often present a diagnostic challenge, particularly for patients who have more slowly progressive disease phenotypes, as early disease manifestations can be subtle or non-specific. However, certain types of bone and joint involvement should always prompt consideration of an MPS diagnosis, such as early joint involvement without classic inflammatory features or erosive bone lesions, claw hand, spinal deformities or dysostosis multiplex. All such patients should be referred to a geneticist or metabolic specialist for diagnostic evaluation. The earlier the diagnosis is made, the better the potential outcome of treatment. Each type of MPS is associated both with deficient activity of a specific lysosomal enzyme that degrades specific glycosaminoglycans (GAGs) and with abnormalities in urinary GAG excretion. MPS patients usually excrete excess GAG in urine and/or have different relative proportions of types of GAG in urine as compared with age-matched normal subjects. Although urinary GAG analyses (both quantitative and qualitative) can suggest the most likely type of MPS, diagnosis must be confirmed by enzyme assay. Multiple assays may be necessary to identify the disease subtype. Correct identification of the MPS type is essential to guide treatment and management decisions. PMID- 22210671 TI - Therapy for the mucopolysaccharidoses. AB - Better understanding of disease pathophysiology, improved supportive care and availability of disease-specific treatments for some of the mucopolysaccharidosis (MPS) disorders have greatly improved the outlook for patients with MPS disorders. Optimal management of these multisystemic disorders involves a multidisciplinary team and regular, comprehensive follow-up. Enzyme replacement therapy (ERT) is now available for MPS I (Hurler, Hurler-Scheie and Scheie syndromes) (laronidase), MPS II (Hunter syndrome) (idursulfase) and MPS VI Maroteaux-Lamy (galsulfase), and is in development for MPS IV (Morquio syndrome) and MPS VII (Sly syndrome). Benefits of ERT can include improved walking ability, improved respiration and enhanced quality of life. Haematopoietic stem cell transplantation (HSCT) can preserve cognition and prolong survival in very young children with the most severe form of MPS I, and is under investigation for several other MPS disorders. Better tissue matching techniques, improved graft-vs host prophylaxis and more targeted conditioning regimens have improved morbidity and mortality associated with HSCT. PMID- 22210672 TI - Putting collagen back in the collagen vascular disorders. PMID- 22210674 TI - Tender points in rheumatoid arthritis--how do they help us? PMID- 22210675 TI - B cell strategy to maintain remission in ANCA-associated vasculitides? PMID- 22210676 TI - Giant intraosseous synovial cyst with intraarticular communication with the ankle joint in longstanding rheumatoid arthritis. PMID- 22210673 TI - Emotion disrupts neural activity during selective attention in psychopathy. AB - Dimensions of psychopathy are theorized to be associated with distinct cognitive and emotional abnormalities that may represent unique neurobiological risk factors for the disorder. This hypothesis was investigated by examining whether the psychopathic personality dimensions of fearless-dominance and impulsive antisociality moderated neural activity and behavioral responses associated with selective attention and emotional processing during an emotion-word Stroop task in 49 adults. As predicted, the dimensions evidenced divergent selective attention deficits and sensitivity to emotional distraction. Fearless-dominance was associated with disrupted attentional control to positive words, and activation in right superior frontal gyrus mediated the relationship between fearless-dominance and errors to positive words. In contrast, impulsive antisociality evidenced increased behavioral interference to both positive and negative words and correlated positively with recruitment of regions associated with motivational salience (amygdala, orbitofrontal cortex, insula), emotion regulation (temporal cortex, superior frontal gyrus) and attentional control (dorsal anterior cingulate cortex). Individuals high on both dimensions had increased recruitment of regions related to attentional control (temporal cortex, rostral anterior cingulate cortex), response preparation (pre-/post-central gyri) and motivational value (orbitofrontal cortex) in response to negative words. These findings provide evidence that the psychopathy dimensions represent dual sets of risk factors characterized by divergent dysfunction in cognitive and affective processes. PMID- 22210677 TI - Thermography detects subclinical inflammation in chronic tophaceous gout. PMID- 22210678 TI - An unusual cause of dysphagia. PMID- 22210679 TI - Psoriatic arthritis: radiographic joint repair following etanercept therapy. PMID- 22210680 TI - Beneficial effect of N-acetylcysteine on antineutrophil cytoplasmic antibody associated vasculitis. PMID- 22210681 TI - Combination biologic treatment of refractory psoriasis and psoriatic arthritis. PMID- 22210682 TI - Anti-tumor necrosis factor inhibitor therapy-induced dermatomyositis and fasciitis. PMID- 22210683 TI - Tophaceous pustule-like rash in a patient with gout. PMID- 22210684 TI - Atypical posterior reversible encephalopathy syndrome: a flare of systemic lupus erythematosus. PMID- 22210685 TI - Pyoderma gangrenosum in a patient with systemic sclerosis. PMID- 22210686 TI - A rare presentation of endocarditis in adult-onset Still's disease in diagnosis of fever of unknown origin. PMID- 22210687 TI - Renal infarction due to spontaneous renal artery dissection in Ehlers-Danlos syndrome type IV. PMID- 22210688 TI - Time will tell-are innovative approaches hastening and improving drug development?. PMID- 22210689 TI - Current management of left main coronary artery disease. AB - Coronary artery bypass surgery is considered as the gold standard treatment of unprotected left main coronary artery (ULMCA) disease. Over the last 20 years, improvement in stent technology and operators experience explained the increased number of reports on the results of percutaneous coronary interventions (PCIs) for the treatment of left main (LM) coronary artery lesion. The recent data comparing efficacy and safety of PCIs using drug-eluting stent and coronary artery bypass surgery showed comparable results in terms of safety and a lower need for repeat revascularization for coronary artery bypass surgery. Patient selection for both techniques is fundamental and directly impacts the clinical outcome. Further randomized trials must be conducted to precise the indications of both techniques of revascularization in the treatment of LM disease. PMID- 22210691 TI - iTRAQ labeling is superior to mTRAQ for quantitative global proteomics and phosphoproteomics. AB - Labeling of primary amines on peptides with reagents containing stable isotopes is a commonly used technique in quantitative mass spectrometry. Isobaric labeling techniques such as iTRAQTM or TMTTM allow for relative quantification of peptides based on ratios of reporter ions in the low m/z region of spectra produced by precursor ion fragmentation. In contrast, nonisobaric labeling with mTRAQTM yields precursors with different masses that can be directly quantified in MS1 spectra. In this study, we compare iTRAQ- and mTRAQ-based quantification of peptides and phosphopeptides derived from EGF-stimulated HeLa cells. Both labels have identical chemical structures, therefore precursor ion- and fragment ion based quantification can be directly compared. Our results indicate that iTRAQ labeling has an additive effect on precursor intensities, whereas mTRAQ labeling leads to more redundant MS2 scanning events caused by triggering on the same peptide with different mTRAQ labels. We found that iTRAQ labeling quantified nearly threefold more phosphopeptides (12,129 versus 4,448) and nearly twofold more proteins (2,699 versus 1,597) than mTRAQ labeling. Although most key proteins in the EGFR signaling network were quantified with both techniques, iTRAQ labeling allowed quantification of twice as many kinases. Accuracy of reporter ion quantification by iTRAQ is adversely affected by peptides that are cofragmented in the same precursor isolation window, dampening observed ratios toward unity. However, because of tighter overall iTRAQ ratio distributions, the percentage of statistically significantly regulated phosphopeptides and proteins detected by iTRAQ and mTRAQ was similar. We observed a linear correlation of logarithmic iTRAQ to mTRAQ ratios over two orders of magnitude, indicating a possibility to correct iTRAQ ratios by an average compression factor. Spike-in experiments using peptides of defined ratios in a background of nonregulated peptides show that iTRAQ quantification is less accurate but not as variable as mTRAQ quantification. PMID- 22210690 TI - On marathons and Sprints: an integrated quantitative proteomics and transcriptomics analysis of differences between slow and fast muscle fibers. AB - Skeletal muscle tissue contains slow as well as fast twitch muscle fibers that possess different metabolic and contractile properties. Although the distribution of individual proteins in fast and slow fibers has been investigated extensively, a comprehensive proteomic analysis, which is key for any systems biology approach to muscle tissues, is missing. Here, we compared the global protein levels and gene expression profiles of the predominantly slow soleus and fast extensor digitorum longus muscles using the principle of in vivo stable isotope labeling with amino acids based on a fully lysine-6 labeled SILAC-mouse. We identified 551 proteins with significant quantitative differences between slow soleus and fast extensor digitorum longus fibers out of >2000 quantified proteins, which greatly extends the repertoire of proteins differentially regulated between both muscle types. Most of the differentially regulated proteins mediate cellular contraction, ion homeostasis, glycolysis, and oxidation, which reflect the major functional differences between both muscle types. Comparison of proteomics and transcriptomics data uncovered the existence of fiber-type specific posttranscriptional regulatory mechanisms resulting in differential accumulation of Myosin-8 and alpha-protein kinase 3 proteins and mRNAs among others. Phosphoproteome analysis of soleus and extensor digitorum longus muscles identified 2573 phosphosites on 973 proteins including 1040 novel phosphosites. The in vivo stable isotope labeling with amino acids-mouse approach used in our study provides a comprehensive view into the protein networks that direct fiber type specific functions and allows a detailed dissection of the molecular composition of slow and fast muscle tissues with unprecedented resolution. PMID- 22210692 TI - Advancing critical care through interdisciplinary research. PMID- 22210696 TI - Bedside nurses' perceptions of intensive care unit telemedicine. AB - BACKGROUND: Intensive care unit telemedicine is an innovative approach to providing critical care services for a broad geographic area, but its success may depend on acceptance by bedside providers. OBJECTIVES: To determine critical care nurses' attitudes toward and perceptions about the use of telemedicine in critical care. METHODS: A total of 179 nurses in 3 critical care units in 2 university-affiliated academic hospitals that use telemedicine intensivists and nurses were surveyed via the Internet about their practice and perceptions of telemedicine. RESULTS: Among the 93 respondents (response rate, 52%), 72 worked at least 1 night shift and therefore had experience with the telemedicine unit. Reported contact with the telemedicine unit was relatively infrequent: 31% reported being called by the unit 3 or more times in the preceding 6 months. A total of 44% reported regularly incorporating interventions suggested by the telemedicine staff. A majority (72%) thought that telemedicine increases patients' survival, but fewer thought that telemedicine prevents medical errors (47%) or improves the satisfaction of patients' families (42%). Some respondents thought that telemedicine interrupted work flow (9%), was intrusive (11%), or resulted in a feeling of being spied upon (13%). Most nurses thought that personally knowing the telemedicine physician was important (79%), and nurses were more likely to contact the telemedicine unit if they knew the physician on call (61%). CONCLUSIONS: Practicing bedside nurses with experience in telemedicine generally support its use, but concerns about privacy issues and the desire to personally know the telemedicine physician may hinder broader application of the technology. PMID- 22210695 TI - Multisociety task force for critical care research: key issues and recommendations. AB - BACKGROUND: Research in critical care extends from the bench to the bedside, involving multiple departments, specialties, and funding organizations. Because of this diversity, it has been difficult for all stakeholders to collectively identify challenges and establish priorities. OBJECTIVE: To define a comprehensive agenda for critical care research using input from a broad range of stakeholders to serve as a blueprint for future initiatives. METHODS: The Critical Care Societies Collaborative (CCSC), consisting of the leadership of the American Association of Critical-Care Nurses (AACN), the American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Society of Critical Care Medicine (SCCM), joined the US Critical Illness and Injury Trials Group (USCIITG) in forming a task force to define a comprehensive critical care research agenda. This group of 25 identified experts was divided into subgroups to address basic, translational, clinical, implementation, and educational research. The subgroups met via conference calls, and the entire task force met in person for a 2-day session. The result was a detailed discussion of the research priorities that served as the basis for this report. RESULTS: The task force identified challenges, specific priority areas, and recommendations for process improvements to support critical care research. Additionally, four overarching themes emerged: 1) the traditional "silo-ed" approach to critical care research is counterproductive and should be modified; 2) an approach that more effectively links areas of research (ie, basic and translational research, or clinical research and implementation) should be embraced; 3) future approaches to human research should account for disease complexity and patient heterogeneity; and 4) an enhanced infrastructure for critical care research is essential for future success. CONCLUSIONS: This document contains the themes/recommendations developed by a large, multiprofessional cross section of critical care scientists, clinicians, and educators. It provides a unique framework for future research in critical care medicine. PMID- 22210697 TI - Intensive care unit telemedicine. PMID- 22210698 TI - Demographic differences in systemic inflammatory response syndrome score after trauma. AB - BACKGROUND: Demographic differences in health outcomes have been reported for chronic diseases, but few data exist on these differences in trauma (defined as acute, life-threatening injuries). OBJECTIVE: To investigate the relationship between the systemic inflammatory response syndrome score after trauma and race/ethnicity and socioeconomic status. METHODS: A retrospective chart review of 600 patients from a level I trauma center (1997-2007) was conducted. Inclusion criteria were age 18 to 44 years, Injury Severity Score 15 or greater, and admission to an intensive care unit. Exclusion criteria were use of transfusions, spinal cord injuries, comorbid conditions affecting the inflammatory response, use of nonsteroidal anti-inflammatory medications, and missing data (final sample, 246 charts/patients). Systemic inflammatory response syndrome was measured by using the systemic inflammatory response syndrome score. Race was self-reported. Socioeconomic status was defined by insurance and employment. Descriptive statistics, Wilcoxon rank sum, Kruskal-Wallis, and chi(2) tests were used for analysis. RESULTS: Compared with whites, African Americans (n = 94) had fewer occurrences of the syndrome (P = .04) and a 14% lower white blood cell count on admission to the intensive care unit (mean, 15,200/MUL; 95% CI, 14,400/MUL to 16,000/MUL vs mean 17,700/MUL; 95% CI, 16,700/MUL to 18,700/MUL; P < .001). CONCLUSIONS: Demographic differences exist in the systemic inflammatory response syndrome score after trauma. Additional studies in larger populations of patients are needed as well as basic science and translational research to determine potential mechanisms that may explain the differences. PMID- 22210699 TI - Family members' informal roles in end-of-life decision making in adult intensive care units. AB - BACKGROUND: To support the process of effective family decision making, it is important to recognize and understand informal roles that various family members may play in the end-of-life decision-making process. OBJECTIVE: To describe some informal roles consistently enacted by family members involved in the process of end-of-life decision making in intensive care units. METHODS: Ethnographic study. Data were collected via participant observation with field notes and semistructured interviews on 4 intensive care units in an academic health center in the mid-Atlantic United States from 2001 to 2004. The units studied were a medical, a surgical, a burn and trauma, and a cardiovascular intensive care unit. PARTICIPANTS: Health care clinicians, patients, and family members. RESULTS: Informal roles for family members consistently observed were primary caregiver, primary decision maker, family spokesperson, out-of-towner, patient's wishes expert, protector, vulnerable member, and health care expert. The identified informal roles were part of families' decision-making processes, and each role was part of a potentially complicated family dynamic for end-of-life decision making within the family system and between the family and health care domains. CONCLUSIONS: These informal roles reflect the diverse responses to demands for family decision making in what is usually a novel and stressful situation. Identification and description of these informal roles of family members can help clinicians recognize and understand the functions of these roles in families' decision making at the end of life and guide development of strategies to support and facilitate increased effectiveness of family discussions and decision-making processes. PMID- 22210701 TI - Hippocrates as hospital employee: balancing beneficence and contractual duty. PMID- 22210700 TI - The relationship of 26 clinical factors to weaning outcome. AB - BACKGROUND: The Burns Wean Assessment Program (BWAP) assessment checklist is designed to assist clinicians in the systematic evaluation of 26 clinical factors important to weaning. The authors recently described the relationship of the BWAP score (derived from the checklist) to weaning trial outcomes (weaning success or failure) in patients receiving mechanical ventilation for 3 days or longer in 5 adult critical care units. A BWAP score of 50 or higher was significantly associated with weaning success regardless of the specific category of patient (surgical, medical, cardiovascular, etc). This secondary analysis extends the evaluation of the BWAP checklist as it focuses on the importance of each individual BWAP factor to weaning outcomes in 5 different populations of patients. OBJECTIVES: To identify the relative importance of the 26 BWAP factors to weaning success in patients undergoing mechanical ventilation for 3 days or longer in 5 adult critical care units. METHODS: BWAP checklists were completed within 24 hours of a weaning attempt in surgical-trauma, medical, neurological, thoracic-cardiovascular, and coronary care units in a 5-year period. Advanced practice nurses using a multidisciplinary pathway, the BWAP checklist, protocols for weaning trials, and sedation guidelines managed the patients similarly. RESULTS: A total of 20 BWAP factors were significantly associated with successful weaning in all units combined (P <= .02). However, some differences in the importance of the BWAP factors to weaning outcome exist between units, with the neuroscience intensive care unit deviating the most from the other units. CONCLUSIONS: Although not all BWAP factors are significantly associated with weaning success, most are predictive. Restructuring the BWAP as a unit-specific weaning checklist and potential predictor may assist clinicians to address factors that may impede weaning more efficiently and effectively. PMID- 22210702 TI - A new puzzler guide. PMID- 22210703 TI - Therapeutic hypothermia for treatment of intractable intracranial hypertension after liver transplantation. AB - A comatose 23-year-old woman with acute liver failure due to an overdose of acetaminophen had indications of intracranial hypertension and underwent liver transplantation. Her level of arousal did not improve, and on postoperative day 1, clinical signs of cerebral herniation became apparent. An intracranial pressure monitor was placed, and intracranial hypertension was documented. Elevations in intracranial pressure persisted despite maximal osmotherapy, and therapeutic hypothermia was started. Normalization of intracranial pressure was rapid. Findings on neurological examination improved and the patient was discharged from the hospital with no neurological impairment. PMID- 22210704 TI - Impact of a delirium screening tool and multifaceted education on nurses' knowledge of delirium and ability to evaluate it correctly. AB - BACKGROUND: The impact of using a validated delirium screening tool and different levels of education on surgical-trauma intensive care unit (STICU) nurses' knowledge about delirium is unclear. OBJECTIVES: To measure the impact of using the Intensive Care Delirium Screening Checklist (ICDSC), with or without a multi faceted education program, on STICU nurses' knowledge and perceptions of delirium and their ability to evaluate it correctly. METHODS: The knowledge and perceptions of subject nurses about delirium, and agreement between the independent assessments of delirium by the subject nurse and by a validated judge (who always used the ICDSC), were compared across 3 phases. Phase 1: No delirium screening tool and no education. Phase 2: ICDSC and minimal education (ie, ICDSC validation study only). Phase 3: ICDSC and multifaceted education (ie, pharmacist led didactic lecture, Web-based module, and nurse-led bedside training). RESULTS: Nurses' knowledge (mean [SD] score out of 10 points) was similar (P = .08) in phase 1 (6.1 [1.4]) and phase 2 (6.5 [1.4]) but was greater (P = .001) in phase 3 (8.2 [1.4]). Agreement between nurses and the validated judge in the assessment of delirium increased from phase 1 (kappa = 0.40) to phase 2 (kappa = 0.62) to phase 3 (kappa = 0.74). Nurses perceived use of the ICDSC as improving their ability to recognize delirium. CONCLUSIONS: Use of a multifaceted education program improves both nurses' knowledge about delirium and their perceptions about its recognition. Implementation of the ICDSC improves the ability of STICU nurses to evaluate delirium correctly. PMID- 22210705 TI - Implications of objective vs subjective delirium assessment in surgical intensive care patients. AB - BACKGROUND: Delirium is an independent predictor of increased length of stay, mortality, and treatment costs in critical care patients. Its incidence may be underestimated or overestimated if delirium is assessed by using subjective clinical impression alone rather than an objective instrument. OBJECTIVES: To determine frequency of discrepancies between subjective and objective delirium monitoring. METHODS: An observational cohort study was performed in a surgical cardiosurgical 31-bed intensive care unit of a university hospital. Patients' delirium status was rated daily by bedside nurses on the basis of subjective individual clinical impressions and by medical students on the basis of scores on the objective Confusion Assessment Method for the Intensive Care Unit. RESULTS: Of 160 patients suitable for analysis, 38.8% (n = 62) had delirium according to objective criteria at some time during their stay in the intensive care unit. A total of 436 paired observations were analyzed. Delirium was diagnosed in 26.1% of observations (n = 114) with the objective method. This percentage included 6.4% (n = 28) in whom delirium was not recognized via subjective criteria. According to subjective criteria, delirium was present in 29.4% of paired observations (n = 128), including 9.6% (n = 42) with no objective indications of delirium. A total of 8 patients with no evidence of delirium according to the objective criteria were prescribed haloperidol and lorazepam because the subjective method indicated they had delirium. CONCLUSIONS: Use of objective criteria helped detect delirium in more patients and also identified patients mistakenly thought to have delirium who actually did not meet objective criteria for diagnosis of the condition. PMID- 22210706 TI - Liposarcoma metastasis of the heart: burst shoots to reveal it. PMID- 22210707 TI - Left ventricular morphology and response to beta-adrenergic stimulation in apical ballooning syndrome. AB - AIMS: The patho-physiology of apical ballooning syndrome (ABS) has not been clearly defined. The aim of this study was to determine whether patients with a history of ABS are more likely to develop left ventricular (LV) mid-cavity or outflow tract obstruction, or have a greater regional LV contractile response to an adrenergic stimulus compared with normal controls. METHODS AND RESULTS: Twenty patients who had recovered from ABS and 15 age-and sex-matched controls had dobutamine stress echocardiography with incremental doses up to 20 ug/kg/min. On average ABS subjects had slightly greater basal LV interventricular septal (1.1 +/- 0.24 cm vs. 0.93 +/- 0.12, P = 0.03) and posterior wall (1.04 +/- 0.16 vs. 0.91 +/- 0.11 cm, P = 0.02) diameters compared with controls but LV end-diastolic and end-systolic volumes and LV ejection fraction were similar both at rest and after dobutamine. Regional and global LV contractility, measured with the strain rate and tissue velocity imaging were also similar during the dobutamine infusion up to 10 ug/kg/min in ABS and controls. Mid-LV or LV outflow tract obstruction was not present at rest in any subjects, but was common during peak dobutamine infusion both in the ABS (45%) and controls (53%, P = 0.62). CONCLUSIONS: Dynamic LV obstruction with dobutamine is common in those with and without prior ABS. However, this study did not identify a greater individual predisposition to LV obstruction, or a different regional or global LV contractile response to dobutamine in patients with a history of ABS compared with control subjects. PMID- 22210708 TI - Accurate measurement of mitral annular area by using single and biplane linear measurements: comparison of conventional methods with the three-dimensional planimetric method. AB - AIMS: The planimetry method using three-dimensional (3D) echocardiography is useful for providing an accurate mitral annulus area (MAA) value. However, this method is relatively unavailable. Therefore, we evaluated the accuracy of conventional methods for MAA measurement compared with that of 3D planimetry. METHODS AND RESULTS: Two-dimensional (2D) and 3D transoesophageal echocardiography (TEE) were performed in 70 patients. The mitral annulus diameter (MAD) was measured using four standard TEE imaging planes: four-chamber (4Ch), two-chamber (2Ch), anterior-posterior (LAX), and commissure-commissure (CC). MAA was calculated using a single diameter based on that of a circle and using two diameters based on that of an ellipse. MAA measurements using the single 4Ch MAD method (r = 0.84, P < 0.001), and two anatomically orthogonal MAD method in 4Ch/2Ch (r = 0.93, P < 0.001) and LAX/CC (r = 0.97, P < 0.001) planes correlated with 3D planimetric MAA measurements. Further analysis with Bland-Altman plots revealed that the LAX/CC MAD measurement exhibited the closest limits of agreement with the 3D planimetric MAA measurement. Notably, in patients showing an elliptical annulus shape, only LAX/CC MAD, but not 4Ch or 4Ch/2Ch MAD, provided results comparable with those of 3D planimetric MAA measurements. However, in patients with a circular annulus shape, reliable MAA measurements can be achieved using either single 4Ch MAD or any biplane MAD. CONCLUSION: Conventional LAX/CC MAD can be recommended for MAA measurements in a diverse patient population. This method is applicable as an alternative to the 3D planimetric method, regardless of the mitral annulus shape. PMID- 22210709 TI - Diffuse tract damage in the hemispheric deep white matter may correlate with global cognitive impairment and callosal atrophy in patients with extensive leukoaraiosis. AB - BACKGROUND AND PURPOSE: Patients with extensive leukoaraiosis are at high risk for vascular dementia. However, these patients exhibit variable severity of global cognitive impairment correlating with callosal atrophy. We hypothesized that callosal atrophy may reflect the severity of HDWM tract damage, which may explain global cognitive impairment. The purpose of this study was to evaluate HDWM tract damage by DTI and to investigate whether HDWM tract damage is associated with callosal atrophy and global cognitive impairment, in patients with extensive leukoaraiosis. MATERIALS AND METHODS: Twenty-four consecutive outpatients with extensive leukoaraiosis were enrolled prospectively. The patients underwent cognitive evaluation and 3T MR imaging. The intercorrelation between cognitive score, DA of the HDWM, callosal DA, and callosal volume was analyzed statistically. The correlation of the cognitive score with DA of the HDWM and the corpus callosum was also evaluated by voxel-based analyses by using TBSS. RESULTS: The patients' MMSE scores varied from 10 to 30 (mean, 25.1 +/- 6.0). Reduced DA of the HDWM, reduced callosal DA, and callosal atrophy intercorrelated significantly. All of these parameters showed a significant correlation with global cognitive impairment. TBSS analyses showed a significant correlation between MMSE score decline and reduced DA in the diffuse HDWM and the corpus callosum. CONCLUSIONS: In patients with extensive leukoaraiosis, atrophy and reduced DA of the corpus callosum may indicate diffuse HDWM tract damage, which may explain global cognitive impairment and development of vascular dementia. PMID- 22210710 TI - 15-Lipoxygenase-1 induces lipid peroxidation and apoptosis, and improves survival in rat malignant glioma. AB - BACKGROUND: Previous studies suggest either an anti- or pro-apoptotic role for 15 lipoxygenase-1 in carcinogenesis. MATERIALS AND METHODS: We used adenovirus gene transfer of human 15-lipoxygenase-1 to characterize its effects in vitro and in vivo. RESULTS: 15-Lipoxygenase-1 expression in mouse macrophages resulted in a significant, 25-fold, induction in the production of the specific 15-lipoxygenase 1 product 13-hydroxyoctadecadienoic acid. Tail vein gene transfers in mice led to highest expression of the transduced 15-lipoxygenase-1 in liver and spleen. In the liver, 15-lipoxygenase-1 significantly increased lipid peroxidation by 3.5 fold and 2-fold, three and seven days after transduction, respectively. A significant 32-fold induction in caspase-3 activity was detected in 15 lipoxygenase-1 expressing livers seven days after transduction. In a syngeneic rat model of malignant glioma, 15-lipoxygenase-1 extended survival significantly (p=0.001). CONCLUSION: Our results support the pro-apoptotic role of 15 lipoxygenase-1 and suggest that 15-lipoxygenase-1 could be a potential new target gene for the therapy of malignant glioma. PMID- 22210711 TI - Repopulation of the irradiation damaged lung with bone marrow-derived cells. AB - AIM: The effect of lung irradiation on reduction of lung stem cells and repopulation with bone marrow-derived cells was measured. MATERIALS AND METHODS: Expression of green fluorescent protein positive cells (GFP(+)) in the lungs of thoracic irradiated FVB/NHsd mice (Harlan Sprague Dawley, Indianapolis, IN, USA) was determined. This was compared to the repopulation of bone marrow-derived cells found in the lungs from naphthalene treated male FVB/NHsd mice and gangciclovir (GCV) treated FeVBN GFP(+) male marrow chimeric HSV-TK-CCSP. The level of mRNA for lung stem cell markers clara cell (CCSP), epithelium 1 (FOXJ1) and surfactant protein C (SP-C), and sorted single cells positive for marrow origin epithelial cells (GFP(+)CD45(-)) was measured. RESULTS: The expression of pulmonary stem cells as determined by PCR was reduced most by GCV, then naphthalene, and least by thoracic irradiation. Irradiation, like GCV, reduced mRNA expression of CCSP, CYP2F2, and FOXJ1, while naphthalene reduced that of CCSP and CYP2F2. Ultrastructural analysis showed GFP(+) pulmonary cells of bone marrow origin, with the highest frequency being found in GCV-treated groups. CONCLUSION: Bone marrow progenitor cells may not participate in the repopulation of the lung following irradiation. PMID- 22210712 TI - Description of a new xenograft model of metastatic neuroblastoma using NOD/SCID/Il2rg null (NSG) mice. AB - In order to develop a relevant xenogenic animal model of neuroblastoma (NB), we compared the tumorigenicity and metastatic potential of SK-N-SH and SK-N-DZ NB cell lines in nude mice and NOD/SCID Il2rg null (NSG) mice. Subcutaneous injection of cell lines induced tumor formation only in NSG mice and was accompanied by metastasis to the liver, adrenal glands, skull and bone marrow. NSG mice injected intravenously showed a profile of distant metastasis that was not observed in nude mice. In addition, tumor growth rates and organ infiltration patterns associated with injected NB cell lines correlated with the in vitro proliferation properties and genetic markers of poor prognosis in NB patients. We also showed that cisplatin chemotherapy was able to inhibit tumor growth. These results clearly demonstrate the higher tumorigenic and metastatic potential of NB cells in NSG mice. Therefore, this xenograft NB model should prove useful in testing the efficacy of new therapeutic approaches for NB. PMID- 22210713 TI - In vivo MRI of intraspinally injected SPIO-labelled human CD34+ cells in a transgenic mouse model of ALS. AB - BACKGROUND/AIM: Administration of stem cells is a promising novel approach for treatment of neurodegenerative diseases. For in vivo monitoring of transplanted cells, non-invasive imaging modalities are needed. In this study we determined the tracking efficiency of a superparamagnetic iron oxide (SPIO)-labelled canine cell line (MTH53A) in vitro as well as the human CD34(+) umbilical cord blood stem cells (hUCBCs) in vitro and in vivo efficiency by magnetic resonance imaging (MRI). MATERIALS AND METHODS: SPIO-labelled MTH53A cells and hUCBCs were scanned in agar gel phantoms at 1.0 T or 7.0 T. For in vivo detection, 100,000 labelled hUCBCs were injected into the spinal cord of a transgenic amyotrophic lateral sclerosis (ALS) mouse and scanned at 7.0 T. RESULTS: In vitro, 100,000 MTH53A cells and 250,000 hUCBCs were visible at 1.0 T. Scanning with 7.0 T revealed 25,000 detectable MTH53A cells. In vivo, 7.0 T MRI showed clear signals of 100,000 implanted cells. CONCLUSION: MRI combined with SPIO nanoparticles provides valuable potential for non-invasive, non-toxic in vivo tracking of cells implanted into the spinal cord. PMID- 22210714 TI - Gene expression changes induced by HIPEC in a murine model of gastric cancer. AB - BACKGROUND: Peritoneal carcinogenesis (PC) is the most frequent pattern of metastasis in patients with locally advanced gastric cancer. Despite this, there is a consensus on the use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of PC from gastric cancer. The molecular mechanisms involved in beneficial effects of HIPEC remain unexplored. MATERIALS AND METHODS: Human gastric cancer MKN45 cells were injected into the peritoneal cavity of immune-deficient NOD-SCID mice. After induction of PC, the animals were randomized into five groups: HIPEC with mitomycin and cisplatin; normothermic intraperitoneal chemotherapy (NIPEC); normothermic intraperitoneal saline; hyperthermic intraperitoneal saline alone; no treatment. After 10 days of treatment, the mice were sacrificed and the extent of PC was assessed. RESULTS: Compared with the other groups of treatment, HIPEC reduced the extent and severity of peritoneal dissemination as measured by assessing the total number of peritoneal and mesenteric nodules (p<0,05) and the HIPEC procedure increased median survival significantly. By gene array analysis, HIPEC was found to effectively modulate the expression of a subset of genes involved in formation of peritoneal metastasis, including adenomatous polyposis coli; beta (3) subunit of the integrin gene; chemokine stromal cell-derived factor-1 receptor; spleen tyrosine kinase; vascular endothelial growth factor receptor 3; collagen, type IV, alpha 2 and Carbossi-terminal binding proteins 1. CONCLUSION: In the present study we have provided evidence that HIPEC protects against peritoneal dissemination in a mouse model of peritoneal gastric carcinogenesis and brings about specific changes in gene expression wich may be related to this protection. PMID- 22210715 TI - Ethanol inhibits B16-BL6 melanoma metastasis and cell phenotypes associated with metastasis. AB - BACKGROUND: Every year, approximately 68,000 new cases of malignant melanoma are diagnosed in the US. Ethanol consumption inhibits metastasis of melanoma in mice, but the mechanism is not well understood. MATERIALS AND METHODS: C57BL/6J ob/+ mice, given either water or 20% ethanol, were injected intravenously with B16-BL6 melanoma cells to determine pulmonary metastasis. The effects of ethanol on cell phenotypes and markers of the epithelial-to-mesenchymal transition were determined in cell culture. RESULTS: In mice, ethanol consumption inhibited experimental pulmonary metastasis. This inhibition was associated with decreased body weight, and levels of systemic leptin, and insulin. In cell culture, ethanol inhibited B16-BL6 cell motility, invasion, and anchorage-independent growth. Additionally, ethanol reduced Snai1 expression and increased E-cadherin expression. Lastly, ethanol increased the expression of Kiss1 metastasis suppressor and the metastasis suppressor Nm23/nucleoside diphosphate kinase. CONCLUSION: In both animal and in cell culture conditions, ethanol inhibited the metastatic ability of B16-BL6 melanoma cells. PMID- 22210716 TI - p53 Codon 72 polymorphism in oral exfoliated cells in a Sudanese population. AB - Earlier studies have investigated the tumor suppressor gene p53 as a co-factor in the development of oral squamous cell carcinoma (OSCC). Our previous studies have indicated that chronic use of Sudanese snuff (toombak) and the presence of human papilloma virus (HPV) may be involved in the high prevalence of OSCC in Sudan. This study investigated the prevalence of p53 codon 72 polymorphism in brush biopsies obtained from a Sudanese population. A total of 174 individuals were included in the study; chronic toombak users (n=152) and non-users (n=22). DNA was extracted from all the samples and genotyped for the codon 72 polymorphism by polymerase chain reaction/restriction fragment length polymorphism. The Arg/Pro genotype was found in 53% of the 174 study participants, compared to 21% found with Arg/Arg and 26% found with Pro/Pro. Stratifying by toombak use, 28 (18%), 45 (29%) and 79 (52%) of the 152 samples from toombak users had Arg/Arg, Pro/Pro and Arg/Pro respectively, compared to 9 (41%), 0 (0%) and 13 (59%) found in the 22 samples from non users. The differences between the samples from toombak users and non users in Arg/Arg and Pro/Pro codon 72 polymorphism and HPV infection were statistically significant (p<0.05). Our study indicated that a high prevalence of the genotype Arg/Pro at the p53 codon 72 may contribute to susceptibility to OSCC, especially in combination with the use of carcinogenic tobacco-specific nitrosamine (TSNA)-rich toombak. Our observations warrant an in-depth study for understanding the role of p53 polymorphism in human oral cancers. PMID- 22210717 TI - Non-invasive monitoring of immunization progress in mice via IgG from feces. AB - A non-invasive method to monitor the humoral immune response in mice after immunization is described. From fecal pellets of an individual mouse, a sufficient amount of active immunoglobulins or their fragments can be extracted to perform a regular examination of the status of the immune response by immunoassay. Hapten-specific antibodies from the feces of mice from three immunization trials showed very similar characteristics to those obtained from serum at a given date. Therefore, it can be suspected that some serum IgG enters the intestinal lumen and ends up in the feces, where they appear to be considerably stable. Hapten-specific IgAs were not found in the feces. Being able to analyze antibody titers in feces could be an interesting animal welfare refinement to standard practice that does not entail repeated blood sampling. PMID- 22210718 TI - A novel der(16)t(3;16)(p25;q24) in a patient with ovarian cancer. AB - BACKGROUND: Non-random simple chromosomal aberrations in various malignancies provide important insights into the molecular pathogenesis of human cancer. Although extensive data exist on recurring chromosomal abnormalities in hematological cancer, data on individual solid tumor types remain limited. Here we present the case of a patient with ovarian cancer with a specific chromosomal abnormality. CASE REPORT: Cytogenetic analysis utilized a G-banding technique, which was performed with direct culture of the surgically removed cancer cells from a 23-year-old woman with grade II ovarian serous cystadenocarcinoma. The patient had no family history of ovarian cancer. RESULTS: We report a novel der(16)t(3;16)(p25;q24) accompanied by terminal deletion of 3p25 as the simple chromosomal aberration in this case. CONCLUSION: To the best of our knowledge, no such translocation has been previously reported. The present study supports the possible role of both del(3)(p25) and the translocation t(3;16)(p25;q24) in ovarian cancer; nevertheless, the significance of these chromosomal changes in the development of ovarian cancer remains unknown. The significance of this finding and its role in the pathogenesis of ovarian cancer requires further clarification. PMID- 22210719 TI - Dexamethasone plus octreotide regimen increases anticancer effects of docetaxel on TRAMP-C1 prostate cancer model. AB - AIM: The aim of this study was to evaluate whether the neoadjuvant use of the dexamethasone (DEX) plus octreotide (OCT) regimen can improve the direct anticancer effects of docetaxel (DOC) in the TRAMP-C1 prostate cancer model. MATERIALS AND METHODS: TRAMP-C1 cells were first characterized for the expression of SSTR1-5 and then were inoculated onto the femur of C57Bl mice. Investigation protocols employed TRAMP-C1 cell proliferation and invasion assays, analysis of radiographic images of the bone lesions and overall survival of the diseased animals. RESULTS: The triple combination treatment scheme showed significant anticancer effects, in both proliferation and invasion assays, compared to any single agent treatment scheme. DOC treatment following the neoadjuvant administration of DEX plus OCT regimen improved significantly the anticancer effects both on the grading of the bone lesions and on the overall survival of the diseased animals. CONCLUSION: Our data suggest that the neoadjuvant administration of DEX plus OCT regimen can improve the anticancer effects of DOC on the TRAMP-C1 model. PMID- 22210720 TI - Retinoid X receptor alpha (RXRalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) expression in breast cancer: an immunohistochemical study. AB - BACKGROUND/AIM: The role of retinoid X receptor alpha (RXRalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) in breast cancer has been well studied in vitro. The aim of the study was to assess the presence of these molecules in human breast cancer specimens and correlate them with major clinicopathological features. PATIENTS AND METHODS: Tissue sections from 82 breast cancer cases clustered according to histological grade, lymph node (LN) and hormone receptor (HR) status were assessed by immunohistochemistry for RXRalpha and PPARgamma. RESULTS: RXRalpha was found to be strongly and moderately expressed in 11 (14.10%) and 33 (42.31%) cases, respectively. PPARgamma was found to be strongly and moderately expressed in 33 (41.25%) and 25 (31.25%) cases, respectively. Only RXRalpha expression was inversely correlated with histological grade. Surprisingly, significantly elevated PPARgamma expression was found in cases with positive LN status. Survival analysis did not yield significant results. CONCLUSION: Our data support the current thesis of RXRalpha being a potential target for feature molecular interventions. PMID- 22210721 TI - Comparative analysis between nasolabial and island pedicle flaps in the ala nose reconstruction. Prospective study. AB - The goals of reconstructing deformities of the face secondary to skin cancer include reconstructing the area with similar tissue. The comparison between different types of local flaps for reconstruction of nasal ala is presented in a prospective, randomized study. The objective of this study was to compare the functional and esthetic outcomes between the nasolabial and island flaps. A total of 60 patients with skin cancer of the nose underwent ala reconstruction: 30 cases by nasolabial flap (group A) and 30 by island flap (group B). The two groups were homogeneous for sex, age, and anatomical area. Complications, scarring according to the scale of Vancouver, cosmetic appearance, and disorders of sensations were analyzed and statistical analysis was performed. In group A, early complications were more common than in group B. The scars of group B patients were more like those of undamaged skin. A total of 10% patients of group A evaluated the cosmetic appearance of their nose as very good, while in group B, 30% patients gave such an evaluation. Local flaps provide better reconstruction and the island flap appears to have more efficacy when compared with nasolabial flap for nasal ala reconstruction. PMID- 22210722 TI - Suppression of Caco-2 and HEK-293 cell proliferation by Kigelia africana, Mimusops zeyheri and Ximenia caffra seed oils. AB - Animal-derived oils and purified fatty acids, but not indigenous fruit-tree derived seed oils, have been used to study cell growth and differentiation. In this study, we determined the effects of the Kigelia africana, the Mimusops zeyheri and the Ximenia caffra seed-oil on cell proliferation in culture. Human colon adenocarcinoma (Caco-2) and human embryonic kidney (HEK-293) cells were maintained and treated with various concentrations (0, 20, 40, 80, 100 and 120 mg/l) of K. africana, M. zehyeri and X. caffra seed oil. The trypan blue dye exclusion method was used to determine cell growth 48-hours after oil treatment. All three tree seed oils suppressed both Caco-2 and HEK-293 cell growth in a dose dependent manner. Importantly, the tree seed oils did not cause increased cell death as the number of dead cells remained unchanged under control and oil treated conditions. K. africana oil significantly suppressed Caco-2 cell growth compared to HEK-293 cell growth at all oil concentrations, whereas M. zeyheri and X. caffra seed oils significantly suppressed HEK-293 and Caco-2 cell growth, only at a concentration of 80 mg/l. The suppression of Caco-2 and HEK-293 cell proliferation by K. africana, M. zeyheri and X. caffra seed oils suggest a potential antiproliferative effect of these tree seed oils on the two cell lines. PMID- 22210723 TI - Dopamine: effect of concentration and pH on the electron emission. Reaction mechanisms. AB - Dopamine (DA) in airfree, aqueous solution (pH 7.4; 37 degrees C) is able to emit e(-)(aq) when electronically excited in its singlet state by monochromatic UV light (lambda=254 nm; 4.85 eV/hnu). The quantum yield Q(e(-)(aq)), was studied in dependence of DA concentration and pH of the media. The DA transients resulting from the electron emission form products, which also have the ability to emit e( )(aq), but with much lower yield. Since DA in the ground state can consume e( )(aq), it is classified as an electron mediator. Some biological consequences based on the e(-)(aq) emission are mentioned. PMID- 22210724 TI - DMBA induces deregulation of miRNA expression of let-7, miR-21 and miR-146a in CBA/CA mice. AB - BACKGROUND: 7,12-Dimethylbenz(alpha)anthracene (DMBA) is a carcinogen capable of inducing various types of tumors. MATERIALS AND METHODS: We investigated the effect of DMBA on micro-RNA expression in CBA/CA H2(k) inbred mice after 24 hours and one week from exposure. RESULTS: Expression levels of miR-21, miR-146a and let-7a were significantly higher in the vital organs of the mice 24 hours after DMBA exposure compared to those of the controls. On the other hand, a significant down-regulation of the miRNAs was observed seven days after DMBA administration. CONCLUSION: Based on our data, DMBA has an impact on the expression of miR-21, let-7a and miR-146a genes. The altered micro-RNA expression can be regarded as an early effect of exposure to chemical carcinogens. To our knowledge, this is the first study of miRNA modulation caused by DMBA in non-malignant tissues. PMID- 22210725 TI - KISS1/KISS1R expression in eutopic and ectopic endometrium of women suffering from endometriosis. AB - BACKGROUND: The KISS1/KISS1R system has been implicated in the physiology of reproduction and many studies have documented the stimulatory effect of kisspeptin on Gonadotropin-releasing Hormone (GnRH) and gonadotropin secretion. In addition, the KISS1/KISS1R system has been implicated in several pathophysiological processes, including cancer. MATERIALS AND METHODS: We examined the pattern of KISS1 and KISS1R expression in eutopic and ectopic endometrium tissues which were obtained from 24 women suffering from endometriosis and 16 control women who underwent laparoscopic excision for other benign gynecological diseases. RESULTS: Significant KISS1R expression was detected in 10 out of the 24 samples of eutopic endometrial biopsies of women suffering from endometriosis, while their matched biopsies of ectopic endometrial lesions did not reveal any KISS1R expression. KISS1R expression was not detected in the endometrial biopsies of control women. In addition, KISS1 expression was not detected in practically any the endometrial tissues of either control women or women with endometriosis. CONCLUSION: The expression of KISS1R in 10/24 samples of human endometrial biopsies of women suffering from endometriosis and the loss of its expression in the samples of matched ectopic endometrial tissues, suggests that the KISS1/KISS1R system may play a role in the pathophysiology of endometriosis only for a particular group of patients. Since KISS1 is not expressed by the endometrium and endometriotic tissue, it is conceivable that the activation of KISS1R in this particular group is mediated by KISS1 expression by non-endometrial tissues (endocrine action). PMID- 22210726 TI - Cytochrome c: electron emission, photodegradation and mutual interaction with vitamin C. AB - Cytochrome c (Cytc) in airfree, aqueous media (pH ~7.4; 37 degrees C) can emit e( )(aq) when exited in single state by monochromatic UV light (lambda=254 nm). The obtained Qi(e(-)(aq)) at lower Cytc concentrations is higher compared to the amount obtained at higher substrate concentrations because at >10(-8) mol l(-1) Cytc 'associates' (unstable complexes) are formed, which consume a part of the ejected e(-)(aq). The primary, as well as secondary, photolytic products of the substrate likewise emit e(-)(aq), but with much lower Qi(e(-)(aq)) values. On the other hand, the photolysis Q(Cytc) values are lower than those of Qi(e(-)(aq)), since Cytc transients can be regenerated by partial consumption of emitted e( )(aq). In addition to this, the produced Cytc(*+) (radical cations) can react with water, thus also regenerating Cytc. PMID- 22210727 TI - Paneth cells and goblet cells express the neuroendocrine peptide synaptophysin. I. Normal duodenal mucosa. AB - Paneth cells are known to produce lysozyme, alpha-defensins, phospholipase, matrilysin and guanylin. This study reports, for the first time, that duodenal Paneth cells may also produce the neuroendocrine peptide synaptophysin. Normal duodenal biopsies from 37 patients were immunostained for synaptophysin and lysozyme. Synaptophysin was expressed in Paneth cells, in goblet cells (in the mucus and cytoplasm) and in the neurons/synapses in the mucosa and submucosa. Mucous glands in the submucosa (Brunner's glands) were synaptophysin negative. Lysozyme was expressed in Paneth cells, goblet cells (in the mucus but not in the cytoplasm) and in the mucous glands in the submucosa. Lysozyme was not expressed in the cytoplasm of goblet cells, nor in the neurons/synapses of the mucosa and submucosa. The differences in expression between synaptophysin and lysozyme seem to validate the immunospecificity of synaptophysin. The finding that synaptophysin is also produced by Paneth cells adds new information which might help to unravel the riddle of the ultimate biological significance of these puzzling cells. PMID- 22210728 TI - A successful combined treatment with dermal substitutes and products of regenerative medicine in a patient affected by extravasation injury from hypertonic solution. AB - In neonatal intensive care units, extravasation is one of the most common injuries occurring in infants as a complication of infusion therapy. These very preterm infants have immature skin which is easily damaged. They often require a longer duration of intravenous therapy, and obtaining intravenous access can be difficult. An invasive treatment should be avoided, whenever possible, particularly for very immature infants. In our Special Operative Unit for ulcers and difficult-to-heal wounds, University of Rome, we successfully treated a premature neonate, who experienced extravasation of hypertonic fluid, using dermal substitutes and products of regenerative medicine. PMID- 22210729 TI - Skin phototype and local trauma in the onset of balanitis xerotica obliterans (BXO) in circumcised patients. AB - The association between balanitis xerotica obliterans (BXO) and skin disorders is long established, however, the role of skin phototype and local trauma in its onset has never been investigated in detail. Medical records of all Caucasian children circumcised over a 6-year period were reviewed. The excised skin underwent histological examination for BXO. Children with histological diagnosis of BXO were classified as group A, whereas children without histological diagnosis of BXO were classified as group B. The Fitzpatrick phototype (FT) was obtained in all children performing a personal or family interview with regards to their sunburn and suntan experience. According to their FT, both group A and B patients were divided into two subgroups: FT 1-2, with a higher tendency to sunburn due to their low skin melanin content; and FT 3-4 with a higher tendency to tan due to their higher skin melanin content. Maneuvers of mechanical reduction of the foreskin (MRF) performed at least 5-10 times per month during the year preceding circumcision was also considered. Statistical analysis was performed using univariate and multivariate analysis. A total of 297 patients met the inclusion criteria of our study: 78 patients were classified as group A and 219 as group B. The risk of developing BXO was significantly greater in FT 1-2 patients (n=76) (odd ratio=0.232, 95% confidence interval=0.124-0.435, p<0.0001). Furthermore, those undergoing MRF (n=131) had a significantly higher risk of developing BXO (odds ratio= 5.344, 95% confidence interval=2.860-9.987, p<0.0001). Although the foreskin is not directly exposed to sunlight, this study emphasizes the role of skin phototype on the onset of BXO in circumcised individuals. Moreover, the data produced suggest should the advantages of repeated MRF be weighed against the increased risk of developing BXO, which in turn may increase complication rate of circumcision surgery. PMID- 22210730 TI - Association of vacuum-assisted closure and platelet gel for the definitive surgical repair of an enterocutaneous fistula: a case report. AB - BACKGROUND: Regenerative surgery deals with damaged tissue via endogenous cell activation or through autologous cell implantation. Several clinical applications employing cell infusions, platelet gel (PG), or both, are currently applied in cases in which no other therapy is application. The vacuum-assisted closure (VAC) system is a non invasive device used in the management of complicated wounds, which creates sub-atmospheric pressure promoting the wound healing process. PATIENTS AND METHODS: We describe the case of a 75-year-old woman who underwent several surgical interventions and presented a non-healing ileo-cutaneous fistula. All standard procedures in order to treat the trauma failed, so a treatment associating VAC and PG was performed. DISCUSSION AND CONCLUSION: VAC and PG represent promising opportunities for the treatment of difficult wounds. In this case, the association of regenerative medicine using homologous PG to the VAC therapy was employed in order to enhance the effect of both techniques on tissue repair. PMID- 22210731 TI - Absence of cytomegalovirus from the gastrointestinal tract of patients with active Crohn's disease. AB - BACKGROUND: Cytomegalovirus (CMV) infection reportedly is detectable in the gastrointestinal mucosa of patients with chronic inflammatory bowel disease. One view is that CMV infection is of clinical significance in patients with Crohn's disease with severe colitis not responding to steroid therapy. In this study, we evaluated the prevalence of CMV infection in our own patients with Crohn's disease treated with colon resection. PATIENTS AND METHODS: The study included 16 consecutive patients with Crohn's disease with colitis who underwent surgery for colonic disease. Histology and immunohistochemistry were used to examine the CMV infection in their surgical specimens by means of enzymatic antigen retrieval, mouse monoclonal antibody, clone CMV01, and a sensitive polymer detection system. RESULTS: All 16 patients underwent colon resection, three of them undergoing emergency surgery. No CMV infection was found in their surgical specimens. CONCLUSION: CMV infection seems not to play a major role in the pathogenesis of Crohn's colitis requiring surgery. However, further prospective studies with larger number of patients are needed to determine the role of CMV in active Crohn's colitis. PMID- 22210732 TI - Feasibility of conservative medical treatment for pyoderma gangrenosum. AB - Pyoderma gangrenosum (PG) is a chronic skin disease with an incidence of 3-10 per million, and it is often associated with underlying systemic disease. A case of PG of the left leg successfully treated with local debridement and advanced and compression dressings, without systemic treatment is reported. Progression and healing of the ulcer was incredibly rapid. The treatment of PG usually consists of systemic administration of corticosteroids. But wherever the administration of systemic immunosuppressive therapy is impractical, a topical treatment can be used. This type of treatment does not represent a mere palliative, but could be significant for healing, as in the case of our patient. PMID- 22210733 TI - Oral angioleiomyoma: a rare pathological entity. AB - Leiomyomas are uncommon in the oral cavity and rare on gingiva. They account only for 0.42% of all soft tissue lesions in the oral cavity. We present an extremely rare case of leiomyoma localized to the attached gingival, simulating an epulis in a healthy 14-year-old boy. The tumour was described at the clinical and instrumental level; moreover, its histopathological phenotype was depicted. The treatment of the choice was the radical excision. The wound was closed by surgical dressing with 2-0 silk suture.The post-operative course was uneventful. The surgical wound healed in one week with normal scarring. Finally, the problems of differential diagnosis with other tumours of the oral cavity and the most appropriate therapeutic procedures are discussed. PMID- 22210734 TI - Potential prevention of thromboembolism by genetic counseling and testing for two common thrombophilia mutations. AB - BACKGROUND/AIM: Thrombophilia is a multifactorial predisposition for thromboembolism affecting about a tenth of any population. We investigated whether genetic counseling combined with molecular testing for two common dominant mutations (coagulation factor V Leiden and prothrombin G20210A) may increase prevention of venous thromboembolic incidents in individuals with a positive family history compared to the general population. PATIENTS AND METHODS: Mutation detection was carried out by Restriction Fragment Length Polymorphism analysis in DNA samples of 96 unrelated healthy Greeks (group A) who asked for genetic counseling for various reasons and had at least two relatives with thromboembolic incidents and 100 unrelated healthy Greeks (group B). RESULTS: In group A, both mutations were detected at five-fold higher frequencies (33.33% for Leiden and 19.79% for G20210A) compared to group B, which had frequencies typically found in the Greek population (6% and 4%, respectively). CONCLUSION: In populations with a high prevalence for these two common mutations, genetic counseling and molecular testing of at-risk individuals may significantly increase prevention of thromboembolic disease. PMID- 22210735 TI - A rare case of postauricular spontaneous keloid in an elderly patient. AB - Keloid represents an exuberant wound healing response, usually secondary to trauma, inflammation, surgery, or burns. Spontaneous keloid formation is rare and it is controversial whether it is really spontaneous. It usually occurs in young people, and it is rare in elderly. Its main features are the infiltration of surrounding normal tissue, the rare regression and the evolution over time. We report the case of an 81 -year -old man with unexpected spontaneous keloid lesion in the right postauricular region. The diagnosis was hard to be performed because of the patient's age, the anatomical site of the lesion and the absence of skin trauma or injury history. Only the histological examination allowed us to perform the right diagnosis. PMID- 22210736 TI - Local versus general anesthesia for carotid endarterectomy: issues beyond stroke, myocardial infarction, and death rates. AB - Like the earlier multicenter General Anesthesia (GA) versus Local Anaesthesia (LA) for carotid surgery (GALA) trial, a recent independent study showed no difference in transient ischemic attack, stroke, myocardial infarction, and death rates between carotid endarterectomy (CEA) performed under LA compared with GA. Besides these outcomes, however, several additional issues may be of interest when comparing the 2 modalities. Examples include the occurrence of post-CEA patient delirium, cognitive dysfunction, and health-related quality of life, as well as the cost-effectiveness, length of hospitalization, and resource utilization. This commentary discusses and compares these outcomes of CEA performed under LA versus GA. PMID- 22210737 TI - Risk factors for myocardial infarction with normal coronary arteries and myocarditis compared with myocardial infarction with coronary artery stenosis. AB - The interest and awareness of myocardial infarction with normal coronary arteries (MINCA) have increased recently due to the frequent use of coronary angiography, the description of Takotsubo stress cardiomyopathy, and new sensitive troponin analyses. The prevalence of MINCA in all patients with myocardial infarction (MI) was registered during a 3-month period in the Stockholm metropolitan area in Sweden. The results showed that MINCA is more common than previously thought (7%) and affecting one third of every woman with MI. Patients with myocarditis were younger and more often presented with signs of inflammation such as elevated C reactive protein and fever. Myocarditis constitutes an important differential diagnosis for coronary artery disease. There is a need for larger studies of MINCA, including investigation with cardiac magnetic resonance imaging, to establish prevalence and pathological process in this important subgroup of MI. PMID- 22210738 TI - Basal cerebral computed tomography as diagnostic tool to improve patient selection in asymptomatic carotid artery stenosis. AB - One-hundred patients were included to evaluate the role of cerebral computed tomography (CT) to improve patient selection in asymptomatic internal carotid stenosis. Symptomatic patients were assigned to group A, asymptomatic patients to group B. A cerebral CT pattern A was observed in groups A and B in 60% and 20%, respectively (P < .0001). Between A and B groups, type 6 plaques were found, respectively, in 26.7% and 7.5% of patients (P = .01); a type 5 in 51.7% and 45% (P = .32) of patients; and a type 4 in 21.7% and 47.5% of patients, respectively (P = .006). Within B group, the association of CT pattern A and histological plaque level 4, 5, and 6 was, respectively, 25% (P = .15), 50% (P = .53), and 25% (P = .16). In group B, a 7-fold risk increase in CT pattern A was found in patients with level 6 plaque. In asymptomatic patients with high-risk plaque, a basal cerebral CT scan can be used as diagnostic tool to improve patient selection for intervention. PMID- 22210739 TI - The prognostic value of serum gamma glutamyl transferase activity on admission in patients with STEMI undergoing primary PCI. AB - We assessed the association between serum gamma glutamyl transferase (GGT) activity with postprimary percutaneous coronary intervention (PCI) coronary flow and in-hospital major advanced cardiac events (MACEs) in patients with ST elevation myocardial infarction (STEMI). Patients with STEMI (n = 425; males 78%; mean age 60 +/- 13 years) were enrolled. Patients were divided into 3 GGT tertiles and 2 groups according to thrombolysis in myocardial infarction (TIMI) flow grade. The TIMI flow percentages were similar in the 3 GGT tertiles (32%, 45%, and 42%, respectively, P = .336). Total MACE increased with GGT tertiles (among tertiles, respectively; P < .001). The total MACE was significantly higher in impaired flow group than in normal flow group (23% vs 7%; P < .001). At multivariate analyses, serum GGT activity was an independent predictor of in hospital MACE (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.01-1.33; P < .001). In conclusion, serum GGT activity is associated with in-hospital MACE in patients with STEMI undergoing primary PCI. PMID- 22210740 TI - Minireview: Endocannabinoids and gonadal hormones: bidirectional interactions in physiology and behavior. AB - Endocannabinoids act as a major neuromodulatory system in a variety of physiological and behavioral functions. Three major lines of evidence suggest that the endocannabinoid system interacts with gonadal hormones. First, the endocannabinoid system is implicated in behaviors and physiological functions that are known to be regulated in part by gonadal hormones. Second, receptors and metabolic enzymes of the endocannabinoid system are localized extensively on structures in the hypothalamic-pituitary-gonadal axis. Third, changes in levels of gonadal hormones alter endocannabinoid signaling. Here we reviewed and summarized the current evidence regarding the interaction between the endocannabinoid system and androgens, estrogens, and progesterone. Overall, it appears that bidirectional interactions characterize the relationship between endocannabinoids and gonadal hormones, with endocannabinoids down-regulating hypothalamic-pituitary-gonadal activity and gonadal hormones modulating protein expression in the endocannabinoid system. An understanding of these interactions will have implications for elucidating the neuroendocrine mechanisms underlying a number of behavioral and physiological functions as well as potential pharmaceutical treatments for disorders of these functions. PMID- 22210741 TI - Perinatal iron deficiency combined with a high-fat diet causes obesity and cardiovascular dysregulation. AB - Consumption of a high-fat Western diet (WD) and the resultant obesity is linked to a number of chronic pathologies, including cardiovascular dysregulation. The purpose of the present study was to determine whether perinatal iron deficiency (PID) added to the consumption of a WD would precipitate an obese phenotype with exacerbated metabolic and cardiovascular outcomes in adult offspring. Female Sprague Dawley rats were fed either a control (225 mg/kg Fe) or an iron restricted diet (3-10 mg/kg Fe) prior to and throughout gestation. At birth, all dams were fed an iron-replete diet. At weaning, offspring were fed a normal diet or WD for up to 21 wk. Hemodynamics and locomotor activity were assessed by radiotelemetry starting at 15 wk of age. Iron restriction during pregnancy caused severe anemia in dams and offspring, resulting in 15% lower birth weights in the offspring. PID offspring fed the WD had greater caloric intake and exhibited reduced locomotor activity compared with their normal diet-fed littermates; no such effects were observed in normal iron control offspring. Despite having a similar effect on serum lipid profiles, consumption of the WD had a greater impact on body weight in the PID group, and this weight gain was due largely to visceral adipose tissue accumulation. A significant correlation between visceral adipose tissue weight and mean arterial pressure was observed in the PID offspring but not in controls. These observations demonstrate that PID predisposes offspring to an enhanced response to WD characterized by increased fat accumulation and cardiovascular dysregulation. PMID- 22210742 TI - Ghrelin interacts with neuropeptide Y Y1 and opioid receptors to increase food reward. AB - Ghrelin, a stomach-derived hormone, is an orexigenic peptide that was recently shown to potently increase food reward behavior. The neurochemical circuitry that links ghrelin to the mesolimbic system and food reward behavior remains unclear. Here we examined the contribution of neuropeptide Y (NPY) and opioids to ghrelin's effects on food motivation and intake. Both systems have well established links to the mesolimbic ventral tegmental area (VTA) and reward/motivation control. NPY mediates the effect of ghrelin on food intake via activation of NPY-Y1 receptor (NPY-Y1R); their connection with respect to motivated behavior is unexplored. The role of opioids in any aspect of ghrelin's action on food-oriented behaviors is unknown. Rats were trained in a progressive ratio sucrose-induced operant schedule to measure food reward/motivation behavior. Chow intake was measured immediately after the operant test. In separate experiments, we explored the suppressive effects of a selective NPY-Y1R antagonist or opioid receptor antagonist naltrexone, injected either intracerebroventricularly or intra-VTA, on ghrelin-induced food reward behavior. The ventricular ghrelin-induced increase in sucrose-motivated behavior and chow intake were completely blocked by intracerebroventricular pretreatment with either an NPY-Y1R antagonist or naltrexone. The intra-VTA ghrelin-induced sucrose motivated behavior was blocked only by intra-VTA naltrexone. In contrast, the intra-VTA ghrelin-stimulated chow intake was attenuated only by intra-VTA NPY-Y1 blockade. Finally, ghrelin infusion was associated with an elevated VTA MU-opioid receptor expression. Thus, we identify central NPY and opioid signaling as the necessary mediators of food intake and reward effects of ghrelin and localize these interactions to the mesolimbic VTA. PMID- 22210743 TI - Differential insulin receptor substrate-1 (IRS1)-related modulation of neuropeptide Y and proopiomelanocortin expression in nondiabetic and diabetic IRS2-/- mice. AB - Insulin resistance and type 2 diabetes correlate with impaired leptin and insulin signaling. Insulin receptor substrate-2 deficient (IRS2(-/-)) mice are an accepted model for the exploration of alterations in these signaling pathways and their relationship with diabetes; however, disturbances in hypothalamic signaling and the effect on neuropeptides controlling food intake remain unclear. Our aim was to analyze how leptin and insulin signaling may differentially affect the expression of hypothalamic neuropeptides regulating food intake and hypothalamic inflammation in diabetic (D) and nondiabetic (ND) IRS2(-/-) mice. We analyzed the activation of leptin and insulin targets by Western blotting and their association by immunoprecipitation, as well as the mRNA levels of neuropeptide Y (NPY), proopiomelanocortin, and inflammatory markers by real-time PCR and colocalization of forkhead box protein O1 (FOXO1) and NPY by double immunohistochemistry in the hypothalamus. Serum leptin and insulin levels and hypothalamic Janus kinase 2 and signal transducer and activator of transcription factor 3 activation were increased in ND IRS2(-/-) mice. IRS1 levels and its association with Janus kinase 2 and p85 and protein kinase B activation were increased in ND IRS2(-/-). Increased FOXO1 positively correlated with NPY mRNA levels in D IRS2(-/-) mice, with FOXO1 showing mainly nuclear localization in D IRS2(-/-) and cytoplasmic in ND IRS2(-/-) mice. D IRS2(-/-) mice exhibited higher hypothalamic inflammation markers than ND IRS2(-/-) mice. In conclusion, differential activation of these pathways and changes in the expression of NPY and inflammation may exert a protective effect against hypothalamic deregulation of appetite, suggesting that manipulation of these targets could be of interest in the treatment of insulin resistance and type 2 diabetes. PMID- 22210745 TI - c-myc and skp2 coordinate p27 degradation, vascular smooth muscle proliferation, and neointima formation induced by the parathyroid hormone-related protein. AB - Parathyroid hormone-related protein (PTHrP) contains a classical bipartite nuclear localization signal. Nuclear PTHrP induces proliferation of arterial vascular smooth muscle cells (VSMC). In the arterial wall, PTHrP is markedly up regulated in response to angioplasty and promotes arterial restenosis. PTHrP overexpression exacerbates arterial restenosis, and knockout of the PTHrP gene results in decreased VSMC proliferation in vivo. In arterial VSMC, expression of the cell cycle inhibitor, p27, rapidly decreases after angioplasty, and replacement of p27 markedly reduces neointima development. We have shown that PTHrP overexpression in VSMC leads to p27 down-regulation, mostly through increased proteosomal degradation. Here, we determined the molecular mechanisms through which PTHrP targets p27 for degradation. S-phase kinase-associated protein 2 (skp2) and c-myc, two critical regulators of p27 expression and stability, and neointima formation were up-regulated in PTHrP overexpression in VSMC. Normalization of skp2 or c-myc using small interfering RNA restores normal cell cycle and p27 expression in PTHrP overexpression in VSMC. These data indicate that skp2 and c-myc mediate p27 loss and proliferation induced by PTHrP. c-myc promoter activity was increased, and c-myc target genes involved in p27 stability were up-regulated in PTHrP overexpression in VSMC. In primary VSMC, PTHrP overexpression led to increased c-myc and decreased p27. Conversely, knockdown of PTHrP in primary VSMC from PTHrP(flox/flox) mice led to cell cycle arrest, p27 up-regulation, with c-myc and skp2 down-regulation. Collectively, these data describe for the first time the role of PTHrP in the regulation of skp2 and c-myc in VSMC. This novel PTHrP-c-myc-skp2 pathway is a potential target for therapeutic manipulation of the arterial response to injury. PMID- 22210744 TI - Positive and negative allosteric modulators promote biased signaling at the calcium-sensing receptor. AB - The calcium-sensing receptor (CaSR) is a G protein-coupled receptor whose function can be allosterically modulated in a positive or negative manner by calcimimetics or calcilytics, respectively. Indeed, the second-generation calcimimetic, cinacalcet, has proven clinically useful in the treatment of chronic kidney disease patients with secondary hyperparathyroidism but is not widely used in earlier stages of renal disease due to the potential to predispose such patients to hypocalcaemia and hyperphosphatemia. The development of a biased CaSR ligand that is more selective for specific signaling pathway(s) leading only to beneficial effects may overcome this limitation. The detection of such stimulus-bias at a G protein-coupled receptor requires investigation across multiple signaling pathways and the development of methods to quantify the effects of allosteric ligands on orthosteric ligand affinity and cooperativity at each pathway. In the current study, we determined the effects of the calcimimetics, NPS-R568 or cinacalcet, and the calcilytic, NPS-2143, on Ca(o)(2+) mediated intracellular Ca(2+) mobilization, ERK1/2 phosphorylation, and plasma membrane ruffling in a stably transfected human embryonic kidney 293-TREx c-myc CaSR cell line and applied a novel analytical model to quantify these modulator effects. We present quantitative evidence for the generation of stimulus bias by both positive and negative allosteric modulators of the CaSR, manifested as greater allosteric modulation of intracellular Ca(2+) mobilization relative to ERK1/2 phosphorylation, and a higher affinity of the modulators for the state of the CaSR mediating plasma membrane ruffling relative to the other two pathways. Our findings provide the first evidence that an allosteric modulator used in clinical practice exhibits stimulus bias. PMID- 22210746 TI - Photoperiod regulates vitamin A and Wnt/beta-catenin signaling in F344 rats. AB - In seasonal mammals, growth, energy balance, and reproductive status are regulated by the neuroendocrine effects of photoperiod. Thyroid hormone (TH) is a key player in this response in a number of species. A neuroendocrine role for the nutritional factor vitamin A has not been considered, although its metabolic product retinoic acid (RA) regulates transcription via the same nuclear receptor family as TH. We hypothesized that vitamin A/RA plays a role in the neuroendocrine hypothalamus alongside TH signaling. Using a reporter assay to measure RA activity, we demonstrate that RA activity levels in the hypothalamus of photoperiod-sensitive F344 rats are reduced in short-day relative to long-day conditions. These lower RA activity levels can be explained by reduced expression of a whole network of RA signaling genes in the ependymal cells around the third ventricle and in the arcuate nucleus of the hypothalamus. These include genes required for uptake (Ttr, Stra6, and Crbp1), synthesis (Raldh1), receptor response (RAR), and ligand clearance (Crapb1 and Cyp26B1). Using melatonin injections into long-day rats, we show that the probable trigger of the fall in RA is melatonin. Surprisingly we also found RPE65 expression in the mammalian hypothalamus for the first time. Similar to RA signaling genes, members of the Wnt/beta-catenin pathway and NMU and its receptor NMUR2 are also under photoperiodic control. Our data provide strong evidence for a novel endocrine axis, involving the nutrient vitamin A regulated by photoperiod and melatonin and suggest a role for several new players in the photoperiodic neuroendocrine response. PMID- 22210747 TI - Sympathetic activation increases basilar arterial blood flow in normotensive but not hypertensive rats. AB - The close apposition between sympathetic and parasympathetic nerve terminals in the adventitia of cerebral arteries provides morphological evidence that sympathetic nerve activation causes parasympathetic nitrergic vasodilation via a sympathetic-parasympathetic interaction mechanism. The decreased parasympathetic nerve terminals in basilar arteries (BA) of spontaneously hypertensive rat (SHR) and renovascular hypertensive rats (RHR) compared with Wistar-Kyoto rats (WKY), therefore, would diminish this axo-axonal interaction-mediated neurogenic vasodilation in hypertension. Increased basilar arterial blood flow (BABF) via axo-axonal interaction during sympathetic activation was, therefore, examined in anesthetized rats by laser-Doppler flowmetry. Electrical stimulation (ES) of sympathetic nerves originating in superior cervical ganglion (SCG) and topical nicotine (10-30 MUM) onto BA of WKY significantly increased BABF. Both increases were inhibited by tetrodotoxin, 7-nitroindazole (neuronal nitric oxide synthase inhibitor), and ICI-118,551 (beta(2)-adrenoceptor antagonist), but not by atenolol (beta(1)-adrenoceptor antagonist). Topical norepinephrine onto BA also increased BABF, which was abolished by atenolol combined with 7-nitroindazole or ICI-118,551. Similar results were found in prehypertensive SHR. However, in adult SHR and RHR, ES of sympathetic nerves or topical nicotine caused minimum or no increase of BABF. It is concluded that excitation of sympathetic nerves to BA in WKY causes parasympathetic nitrergic vasodilation with increased BABF. This finding indicates an endowed functional neurogenic mechanism for increasing the BABF or brain stem blood flow in coping with increased local sympathetic activities in acutely stressful situations such as the "fight-or-flight response." This increased blood flow in defensive mechanism diminishes in genetic and nongenetic hypertensive rats due most likely to decreased parasympathetic nitrergic nerve terminals. PMID- 22210748 TI - Spatio-temporal attributes of left ventricular pressure decay rate during isovolumic relaxation. AB - Global left ventricular (LV) isovolumic relaxation rate has been characterized: 1) via the time constant of isovolumic relaxation tau or 2) via the logistic time constant tau(L). An alternate kinematic method, characterizes isovolumic relaxation (IVR) in accordance with Newton's Second Law. The model's parameters, stiffness E(k), and damping/relaxation MU result from best fit of model-predicted pressure to in vivo data. All three models (exponential, logistic, and kinematic) characterize global relaxation in terms of pressure decay rates. However, IVR is inhomogeneous and anisotropic. Apical and basal LV wall segments untwist at different times and rates, and transmural strain and strain rates differ due to the helically variable pitch of myocytes and sheets. Accordingly, we hypothesized that the exponential model (tau) or kinematic model (MU and E(k)) parameters will elucidate the spatiotemporal variation of IVR rate. Left ventricular pressures in 20 subjects were recorded using a high-fidelity, multipressure transducer (3 cm apart) catheter. Simultaneous, dual-channel pressure data was plotted in the pressure phase-plane (dP/dt vs. P) and tau, MU, and E(k) were computed in 1631 beats (average: 82 beats per subject). Tau differed significantly between the two channels (P < 0.05) in 16 of 20 subjects, whereas MU and E(k) differed significantly (P < 0.05) in all 20 subjects. These results show that quantifying the relaxation rate from data recorded at a single location has limitations. Moreover, kinematic model based analysis allows characterization of restoring (recoil) forces and resistive (crossbridge uncoupling) forces during IVR and their spatio-temporal dependence, thereby elucidating the relative roles of stiffness vs. relaxation as IVR rate determinants. PMID- 22210749 TI - Adiponectin and adipocyte fatty acid binding protein in the pathogenesis of cardiovascular disease. AB - The heart and blood vessels are surrounded by epicardial and perivascular adipose tissues, respectively, which play important roles in maintaining cardiovascular homeostasis by secreting a number of biologically active molecules, termed "adipokines." Many of these adipokines function as an important component of the 'adipo-cardiovascular axis' mediating the cross talk between adipose tissues, the heart, and the vasculature. On the one hand, most adipokines [including tumor necrosis factor-alpha, resistin, adipocyte fatty acid binding protein (A-FABP), and lipocalin-2] are proinflammatory and causally associated with endothelial and cardiac dysfunction by their endocrine/paracrine actions. On the other hand, adiponectin is one of the few adipokines that possesses multiple salutary effects on the prevention of cardiovascular disease, because of its pleiotropic actions on the heart and the blood vessels. The discordant production of adipokines in dysfunctional adipose tissue is a key contributor to obesity-related cardiovascular disease. This review provides an update in understanding the roles of adipokines in the pathogenesis of cardiovascular disorders associated with obesity and diabetes and focuses on the two most abundant adipokines, adiponectin and A-FABP. Indeed, data from both animal studies and clinical investigations imply that these two adipokines are prognostic biomarkers for cardiovascular disease and even promising therapeutic targets for its treatment. PMID- 22210751 TI - Angiotensin II-induced reduction in exercise capacity is associated with increased oxidative stress in skeletal muscle. AB - Angiotensin II (ANG II)-induced oxidative stress has been known to be involved in the pathogenesis of cardiovascular diseases. We have reported that the oxidative stress in skeletal muscle can limit exercise capacity in mice (16). We thus hypothesized that ANG II could impair the skeletal muscle energy metabolism and limit exercise capacity via enhancing oxidative stress. ANG II (50 ng.kg(-1).min( 1)) or vehicle was infused into male C57BL/6J mice for 7 days via subcutaneously implanted osmotic minipumps. ANG II did not alter body weight, skeletal muscle weight, blood pressure, cardiac structure, or function. Mice were treadmill tested, and expired gases were analyzed. The work to exhaustion (vertical distance * body weight) and peak oxygen uptake were significantly decreased in ANG II compared with vehicle. In mitochondria isolated from skeletal muscle, ADP dependent respiration was comparable between ANG II and vehicle, but ADP independent respiration was significantly increased in ANG II. Furthermore, complex I and III activities were decreased in ANG II. NAD(P)H oxidase activity and superoxide production by lucigenin chemiluminescence were significantly increased in skeletal muscle from ANG II mice. Treatment of ANG II mice with apocynin (10 mmol/l in drinking water), an inhibitor of NAD(P)H oxidase activation, completely inhibited NAD(P)H oxidase activity and improved exercise capacity, mitochondrial respiration, and complex activities in skeletal muscle. ANG II-induced oxidative stress can impair mitochondrial respiration in skeletal muscle and limit exercise capacity. PMID- 22210750 TI - Right ventricular regional wall curvedness and area strain in patients with repaired tetralogy of Fallot. AB - A quantitative understanding of right ventricular (RV) remodeling in repaired tetralogy of Fallot (rTOF) is crucial for patient management. The objective of this study is to quantify the regional curvatures and area strain based on three dimensional (3-D) reconstructions of the RV using cardiac magnetic resonance imaging (MRI). Fourteen (14) rTOF patients and nine (9) normal subjects underwent cardiac MRI scan. 3-D RV endocardial surface models were reconstructed from manually delineated contours and correspondence between end-diastole (ED) and end systole (ES) was determined. Regional curvedness (C) and surface area at ED and ES were calculated as well as the area strain. The RV shape and deformation in rTOF patients differed from normal subjects in several respects. Firstly, the curvedness at ED (mean for 13 segments, 0.030 +/- 0.0076 vs. 0.029 +/- 0.0065 mm( 1); P < 0.05) and ES (mean for 13 segments, 0.040 +/- 0.012 vs. 0.034 +/- 0.0072 mm(-1); P < 0.001) was decreased by chronic pulmonary regurgitation. Secondly, the surface area increased significantly at ED (mean for 13 segments, 982 +/- 192 vs. 1,397 +/- 387 mm(2); P < 0.001) and ES (mean for 13 segments, 576 +/- 130 vs. 1,012 +/- 302 mm(2); P < 0.001). In particular, rTOF patients had significantly larger surface area than that in normal subjects in the free wall but not for the septal wall. Thirdly, area strain was significantly decreased (mean for 13 segments, 56 +/- 6 vs. 34 +/- 7%; P < 0.0001) in rTOF patients. Fourthly, there were increases in surface area at ED (5,726 +/- 969 vs. 6,605 +/- 1,122 mm(2); P < 0.05) and ES (4,280 +/- 758 vs. 5,569 +/- 1,112 mm(2); P < 0.01) and decrease in area strain (29 +/- 8 vs. 18 +/- 8%; P < 0.001) for RV outflow tract. These findings suggest significant geometric and strain differences between rTOF and normal subjects that may help guide therapeutic treatment. PMID- 22210752 TI - Non-ST131 Escherichia coli from cattle harbouring human-like bla(CTX-M-15) carrying plasmids. AB - OBJECTIVES: To characterize bla(CTX-M-15)-carrying plasmids and lineages of nine strains of Escherichia coli from cattle. METHODS: Plasmid DNA was analysed using PCR-based replicon typing and plasmid sub-typing schemes, restriction fragment length polymorphism, S1 nuclease-PFGE and Southern hybridization. Strains were characterized by PFGE, multilocus sequence typing, phylogenetic grouping and B2 O25b:H4-ST131 (where ST stands for sequence type) clone screening. Susceptibilities to antimicrobials were determined by agar diffusion and resistance genes were characterized by PCR and sequencing. RESULTS: The bla(CTX-M 15) gene was found on F31:A4:B1/IncFII and F2:A-:B-/IncFII plasmids, which have been reported abundantly in humans. On F31:A4:B1/IncFII plasmids, the bla(CTX-M 15) gene was associated with the bla(TEM-1), bla(OXA-1) and aac(6')-Ib-cr resistance genes. The bla(CTX-M-15) gene was also found on IncI1 plasmids of the CC31 clonal complex, recently identified in the human epidemic and virulent E. coli clone O104:H4. None of the cattle isolates belonged to the human and widespread clone B2-O25b:H4/ST131, but were mostly of new STs and of the phylogenetic groups A (n=4), B1 (n=3) or D (n=2). The E. coli isolates harbouring the bla(CTX-M-15)-carrying plasmids were genetically diverse, and were recovered from different geographical locations and farms and at different times. CONCLUSIONS: This study demonstrates that bla(CTX-M-15)-carrying plasmids from cattle-derived non-ST131 E. coli isolates were highly similar to those found in ST131 E. coli isolates commonly reported in humans. It also exemplifies the key role of plasmids versus clonal dissemination in the spread of the bla(CTX-M-15) gene among cattle, and possibly between E. coli isolates detected in humans and cattle. PMID- 22210753 TI - Characterization of plasmids encoding extended-spectrum beta-lactamases and their addiction systems circulating among Escherichia coli clinical isolates in the UK. AB - OBJECTIVES: To characterize plasmids encoding extended-spectrum beta-lactamases (ESBLs) from a recent UK collection of clinical Escherichia coli isolates. METHODS: The isolates comprised 118 ESBL producers referred from 54 laboratories. Plasmids were transferred by electroporation, and their incompatibility groups, associated addiction systems and resistance genes with the flanking genetic environments were identified by PCR or sequencing. RESULTS: Seventy isolates had plasmids encoding CTX-M-15 (n = 53), CTX-M-14 (n =9), CTX-M-27 (n = 1), CTX-M-3 (n = 2) and SHV-12 (n = 5) ESBLs that were transformable; non-transformable ESBLs were mainly CTX-M enzymes (42/48). Most transformable bla(CTX-M-15) genes (43/53) were harboured on single replicon or multireplicon IncF plasmids, with IncFIA4 FIB1-FII31 (n = 11) and IncFIA1-FII2 (n = 15) being most frequent; the latter included eight pEK499 plasmids, typical of UK epidemic strain A. Plasmids harbouring bla(CTX-M-14) belonged variously to IncF, IncI1 and IncHI2 types, and 16 encoding CTX-M or SHV enzymes were non-typeable. Only IncF plasmid types carried the addiction systems sought and those with bla(CTX-M-15) frequently harboured bla(OXA-1) and aac(6')-Ib-cr, and often transferred trimethoprim and tetracycline resistance; those with bla(CTX-M-14) encoded trimethoprim, sulphonamide, streptomycin and tetracycline resistance. Most ESBL genes were associated with the well-known mobile elements ISEcp1 and IS26, but nearly half (23/55) of the ISEcp1 sequences upstream of bla(CTX-M-15) were interrupted by an IS26 at various positions. CONCLUSIONS: Most ESBLs (70/118) were encoded by transformable plasmids, although a sizable minority could not be transformed. The majority of transformable plasmids (51/70; 72.9%) were diverse multiresistant IncF types possessing multiple addiction systems. The spread of bla(CTX-M-15) can be attributed not just to clonal expansion, but also to the horizontal dissemination of related plasmids. PMID- 22210754 TI - Multiple-dose pharmacokinetics of daptomycin during continuous venovenous haemodiafiltration. AB - OBJECTIVES: Daptomycin is bactericidal against Gram-positive bacteria, with peak dependent effect but trough-dependent toxicity. This study was performed to develop dosing recommendations in continuous venovenous haemodiafiltration (CVVHDF). PATIENTS AND METHODS: Nine critically ill patients in intensive care units of the Medical University Hospital of Vienna, requiring CVVHDF due to acute renal failure and antimicrobial treatment, were included. Blood and effluent samples were collected over 72 h to determine daptomycin concentrations by HPLC. Pharmacokinetic parameters were based on 10 sampling timepoints during the first 24 h, and peak and trough samples thereafter. An open two-compartment model was fitted to each subject's plasma concentration-time data. Simulations of serum concentration-time profiles after different doses and intervals were performed using ADAPT 5. RESULTS: Peak plasma concentrations with 6 mg/kg daptomycin were 62.2 +/- 16.2, 66.1 +/- 17.3 and 78.5 +/- 22.1 mg/L on days 1, 2 and 3, respectively. The total clearance was 6.1 +/- 4.9 mL/min, and the elimination half-life was 17.8 +/- 9.7 h. Daptomycin was filtrated and could therefore be measured in the effluent. Protein binding was lower than that seen in healthy volunteers. The unbound fraction was 16 +/- 4.5%. All subjects maintained trough serum concentrations above 4 mg/L, at which relevant pathogens are considered daptomycin-susceptible. Accumulation resulted when daptomycin was given every 24 h. Simulation of 8 mg/kg daptomycin given every 48 h resulted in adequate levels without accumulation. CONCLUSIONS: We recommend 8 mg/kg daptomycin every 48 h in patients on CVVHDF and therapeutic drug monitoring, if possible. PMID- 22210756 TI - Nosocomial spread of multidrug-resistant group B streptococci with reduced penicillin susceptibility belonging to clonal complex 1. AB - BACKGROUND: Multiple group B Streptococcus (GBS) isolates with reduced penicillin susceptibility (PRGBS) were recovered from several patients, hence a probable nosocomial transmission of PRGBS in a hospital setting was suspected. METHODS: Ten PRGBS recovered from eight patients in a general hospital were characterized. Sequence analysis of genes for penicillin-binding proteins (PBPs) and quinolone resistance-determining regions (QRDRs) of gyrA, gyrB and parC was performed, and the macrolide resistance genes were detected by PCR. Genetic relatedness among the isolates was examined by PFGE and multilocus sequence typing. RESULTS: All the PRGBS had the key amino acid substitution V405A, together with F395L, R433H, H438Y and G648A in PBP 2X and T567I in PBP 2B. A 23S rRNA methylase gene, erm(B), was also found in all 10 PRGBS strains. PFGE analysis revealed considerable genetic relatedness among the isolates. Isolates of pulsotype I were obtained from four patients in ward A and one patient in ward B, while isolates of pulsotypes II and III were obtained from two patients in ward B and one patient in ward C, respectively. Isolates of pulsotype I were resistant to levofloxacin (MIC >8 mg/L) and had the following amino acid substitutions in the QRDRs: S81L in GyrA, E476K in GyrB and S79Y in ParC. However, pulsotype II strains resistant to levofloxacin (MIC 8 mg/L) had no change in GyrA, but changes in GyrB (E476K) and ParC (S79Y). All 10 PRGBS strains belonged to serotype VI and ST458 (where ST stands for sequence type). CONCLUSIONS: This is the first description of the nosocomial spread of multidrug-resistant PRGBS strains belonging to the genetic lineage ST458. PMID- 22210755 TI - Lipid profiles for etravirine versus efavirenz in treatment-naive patients in the randomized, double-blind SENSE trial. AB - BACKGROUND: Etravirine is approved for use in treatment-experienced patients at a dose of 200 mg twice daily. Efavirenz has been associated with greater increases in serum lipids compared with other non-nucleosides in randomized trials of first line treatment. METHODS: In this double-blind, placebo-controlled trial, 157 treatment-naive patients with HIV RNA >5000 copies/mL were randomized 1:1 to either 400 mg of etravirine once daily (n=79) or 600 mg of efavirenz once daily (n=78) plus two nucleoside analogues (either abacavir/lamivudine, zidovudine/lamivudine or tenofovir/emtricitabine) for 48 weeks. Lipids were measured under fasting conditions at baseline and all visits to Week 48. Clinicaltrials.gov identifier: NCT00903682. RESULTS: Overall, the patients had a median baseline CD4 count of 302 cells/mm(3) (range 74-722) and a median HIV RNA of 4.8 log(10) copies/mL (range 3.5-6.6). Both the non-nucleosides and the nucleoside analogues used caused changes in serum lipids. In the efavirenz arm, patients showed significantly larger increases in high-density lipoprotein (HDL) (+0.15 mmol/L, P=0.004), low-density lipoprotein (LDL) (+0.35 mmol/L, P=0.005), total cholesterol (+0.61 mmol/L, P<0.0001) and triglycerides (+0.33 mmol/L, P=0.03) at Week 48 compared with the etravirine arm. Across the two arms, patients taking abacavir/lamivudine showed greater increases in total cholesterol (+0.47 mmol/L, P=0.005) compared with patients taking tenofovir/emtricitabine. There were fewer grade 3/4 elevations in total cholesterol, LDL and triglycerides in the etravirine arm (2 patients, 1 patient and 0 patients, respectively) versus the efavirenz arm (8 patients, 6 patients and 2 patients, respectively). CONCLUSIONS: In the SENSE trial, first-line treatment with 400 mg of etravirine once daily plus two nucleoside analogues led to fewer grade 3 or 4 lipid elevations compared with efavirenz plus two nucleoside analogues. PMID- 22210757 TI - In vivo antibacterial activity of chinfloxacin, a new fluoroquinolone antibiotic. AB - OBJECTIVES: To evaluate the in vivo antibacterial efficacy of chinfloxacin, a novel fluoroquinolone, in murine systemic and local infection models. METHODS: The efficacy of chinfloxacin in systemic infection was evaluated in a mouse peritonitis model using isolates of methicillin-susceptible Staphylococcus aureus (MSSA, n = 3), methicillin-resistant Staphylococcus aureus (MRSA; n = 1), penicillin-intermediate Streptococcus pneumoniae (PISP; n = 1), penicillin resistant S. pneumoniae (PRSP; n = 2), vancomycin-susceptible Enterococcus faecalis (VSE; n = 1), vancomycin-resistant E. faecalis (VRE; n = 2), Escherichia coli (n = 3) and Klebsiella pneumoniae (n = 2). The local infections included mouse pulmonary infections caused by penicillin-susceptible S. pneumoniae (PSSP; n = 1), PRSP (n = 1) and K. pneumoniae (n = 2). RESULTS: In the mouse systemic infection model, chinfloxacin demonstrated potent activity against MSSA [50% effective dose (ED(50)) 2.28-4.15 mg/kg], MRSA (ED(50) 14.75 mg/kg), PISP (ED(50) 6.20 mg/kg), PRSP (ED(50) 3.51-5.03 mg/kg), VSE (ED(50) 25.02 mg/kg), VRE (ED(50) 5.18-15.39 mg/kg), E. coli (ED(50) 1.25-1.90 mg/kg) and K. pneumoniae (ED(50) 2.92-8.28 mg/kg). The therapeutic efficacy of chinfloxacin was generally similar to (P > 0.05) that of moxifloxacin, significantly higher (P < 0.01 or P < 0.05) than that of levofloxacin in Gram-positive isolate infections (MSSA, MRSA, PISP, PRSP, VSE and VRE), and less than that of levofloxacin against E. coli and K. pneumoniae infections (P < 0.01). In the mouse pulmonary infection model, chinfloxacin showed potent activity towards S. pneumoniae (higher than levofloxacin and ciprofloxacin) and K. pneumoniae (lower than levofloxacin and similar to or higher than ciprofloxacin) infections. CONCLUSIONS: The results validated the potent efficacy of chinfloxacin in vivo. The high efficacy of chinfloxacin in murine systemic and local infections warrants investigation of its clinical use. PMID- 22210758 TI - Pan-European monitoring of susceptibility to human-use antimicrobial agents in enteric bacteria isolated from healthy food-producing animals. AB - OBJECTIVES: To determine the antimicrobial susceptibility of Escherichia coli, Salmonella, Campylobacter and Enterococcus from cattle, pigs and chickens across the European Union (EU) using uniform methodology. METHODS: Intestinal samples (1624) were taken at slaughter across five EU countries. Bacteria were isolated in national laboratories, whilst MICs were determined in a central laboratory for key antimicrobials used in human medicine. Clinical resistance was based on CLSI breakpoints and decreased susceptibility based on European Food Safety Authority (EFSA)/EUCAST epidemiological cut-off values. RESULTS: Isolation rates were high for E. coli (n=1540), low for Salmonella (n=201) and intermediate for Campylobacter (n=940) and Enterococcus (n=786). For E. coli and Salmonella, clinical resistance to newer compounds (cefepime, cefotaxime and ciprofloxacin) was absent or low, but decreased susceptibility was apparent, particularly in chicken strains. Resistance to older compounds (except gentamicin) was variable and higher. Colistin resistance was absent for E. coli, but apparent for Salmonella. For Campylobacter jejuni, ciprofloxacin resistance was markedly prevalent for chickens, whereas clinical resistance and decreased susceptibility to erythromycin was absent or very low. For Campylobacter coli, resistance was notably higher. None of the Enterococcus faecium strains was resistant to linezolid, but some were resistant to ampicillin or vancomycin. Resistance to quinupristin/dalfopristin was frequent. CONCLUSIONS: Resistance patterns varied widely depending on bacterial species, antibiotics, hosts and region. Resistance varied among countries, particularly for older antimicrobials, but clinical resistance to newer antibiotics used to treat foodborne disease in humans was generally very low. In the absence of resistance to newer compounds in E. coli and Salmonella, the apparent decreased susceptibility should be monitored. PMID- 22210759 TI - Editorial: molecular endocrinology articles in the spotlight for January 2012. PMID- 22210761 TI - Analysis of the Pseudomonas aeruginosa regulon controlled by the sensor kinase KinB and sigma factor RpoN. AB - Alginate overproduction by Pseudomonas aeruginosa, also known as mucoidy, is associated with chronic endobronchial infections in cystic fibrosis. Alginate biosynthesis is initiated by the extracytoplasmic function sigma factor (sigma(22); AlgU/AlgT). In the wild-type (wt) nonmucoid strains, such as PAO1, AlgU is sequestered to the cytoplasmic membrane by the anti-sigma factor MucA that inhibits alginate production. One mechanism underlying the conversion to mucoidy is mutation of mucA. However, the mucoid conversion can occur in wt mucA strains via the degradation of MucA by activated intramembrane proteases AlgW and/or MucP. Previously, we reported that the deletion of the sensor kinase KinB in PAO1 induces an AlgW-dependent proteolysis of MucA, resulting in alginate overproduction. This type of mucoid induction requires the alternate sigma factor RpoN (sigma(54)). To determine the RpoN-dependent KinB regulon, microarray and proteomic analyses were performed on a mucoid kinB mutant and an isogenic nonmucoid kinB rpoN double mutant. In the kinB mutant of PAO1, RpoN controlled the expression of approximately 20% of the genome. In addition to alginate biosynthetic and regulatory genes, KinB and RpoN also control a large number of genes including those involved in carbohydrate metabolism, quorum sensing, iron regulation, rhamnolipid production, and motility. In an acute pneumonia murine infection model, BALB/c mice exhibited increased survival when challenged with the kinB mutant relative to survival with PAO1 challenge. Together, these data strongly suggest that KinB regulates virulence factors important for the development of acute pneumonia and conversion to mucoidy. PMID- 22210762 TI - Oligomerization of the response regulator ComE from Streptococcus mutans is affected by phosphorylation. AB - We have previously characterized the interactions of the response regulator ComE from Streptococcus mutans and DNA binding sites through DNase I footprinting and electrophoretic mobility shift assay analysis. Since response regulator functions are often affected by their phosphorylation state, we investigated how phosphorylation affects the biochemical function of ComE. Unlike many response regulators, we found that the phosphorylation state of ComE does not likely play a role in DNA binding affinity but rather seems to induce the formation of an oligomeric form of the protein. The role of this oligomerization state for ComE function is discussed. PMID- 22210763 TI - SoxS increases the expression of the zinc uptake system ZnuACB in an Escherichia coli murine pyelonephritis model. AB - Paralogous transcriptional regulators MarA, Rob, and SoxS act individually and together to control expression of more than 80 Escherichia coli genes. Deletion of marA, rob, and soxS from an E. coli clinical isolate prevents persistence beyond 2 days postinfection in a mouse model of pyelonephritis. We used microarray analysis to identify 242 genes differentially expressed between the triple deletion mutant and its parent strain at 2 days postinfection in the kidney. One of these, znuC of the zinc transport system ZnuACB, displayed decreased expression in the triple mutant compared to that in the parental strain, and deletion of znuC from the parental strain reduced persistence. The marA rob soxS triple deletion mutant was less viable in vitro under limited-Zn and Zn-depleted conditions, while disruption of znuC caused a reduction in the growth rates for the parental and triple mutant strains to equally low levels under limited-Zn or Zn-depleted conditions. Complementation of the triple mutant with soxS, but not marA or rob, restored the parental growth rate in Zn-depleted medium, while deletion of only soxS from the parental strain led to low growth in Zn-depleted medium. Both results suggested that SoxS is a major regulator responsible for growth under Zn-depleted conditions. Gel shift experiments failed to show direct binding of SoxS to the znuCB promoter, thus suggesting indirect control of znuCB expression by SoxS. While SoxS expression in the triple mutant fully restored persistence, increased expression of znuACB via a plasmid in this mutant only partially restored wild-type levels of persistence in the kidney. This work implicates SoxS control of znuCB expression as a key factor in persistence of E. coli in murine pyelonephritis. PMID- 22210764 TI - Identification of the bacteriochlorophylls, carotenoids, quinones, lipids, and hopanoids of "Candidatus Chloracidobacterium thermophilum". AB - "Candidatus Chloracidobacterium thermophilum" is a recently discovered chlorophototroph from the bacterial phylum Acidobacteria, which synthesizes bacteriochlorophyll (BChl) c and chlorosomes like members of the green sulfur bacteria (GSB) and the green filamentous anoxygenic phototrophs (FAPs). The pigments (BChl c homologs and carotenoids), quinones, lipids, and hopanoids of cells and chlorosomes of this new chlorophototroph were characterized in this study. "Ca. Chloracidobacterium thermophilum" methylates its antenna BChls at the C-8(2) and C-12(1) positions like GSB, but these BChls were esterified with a variety of isoprenoid and straight-chain alkyl alcohols as in FAPs. Unlike the chlorosomes of other green bacteria, "Ca. Chloracidobacterium thermophilum" chlorosomes contained two major xanthophyll carotenoids, echinenone and canthaxanthin. These carotenoids may confer enhanced protection against reactive oxygen species and could represent a specific adaptation to the highly oxic natural environment in which "Ca. Chloracidobacterium thermophilum" occurs. Dihydrogenated menaquinone-8 [menaquinone-8(H(2))], which probably acts as a quencher of energy transfer under oxic conditions, was an abundant component of both cells and chlorosomes of "Ca. Chloracidobacterium thermophilum." The betaine lipid diacylglycerylhydroxymethyl-N,N,N-trimethyl-beta-alanine, esterified with 13-methyl-tetradecanoic (isopentadecanoic) acid, was a prominent polar lipid in the membranes of both "Ca. Chloracidobacterium thermophilum" cells and chlorosomes. This lipid may represent a specific adaptive response to chronic phosphorus limitation in the mats. Finally, three hopanoids, diploptene, bacteriohopanetetrol, and bacteriohopanetetrol cyclitol ether, which may help to stabilize membranes during diel shifts in pH and other physicochemical conditions in the mats, were detected in the membranes of "Ca. Chloracidobacterium thermophilum." PMID- 22210765 TI - ald of Mycobacterium tuberculosis encodes both the alanine dehydrogenase and the putative glycine dehydrogenase. AB - The putative glycine dehydrogenase of Mycobacterium tuberculosis catalyzes the reductive amination of glyoxylate to glycine but not the reverse reaction. The enzyme was purified and identified as the previously characterized alanine dehydrogenase. The Ald enzyme was expressed in Escherichia coli and had both pyruvate and glyoxylate aminating activities. The gene, ald, was inactivated in M. tuberculosis, which resulted in the loss of all activities. Both enzyme activities were found associated with the cell and were not detected in the extracellular filtrate. By using an anti-Ald antibody, the protein was localized to the cell membrane, with a smaller fraction in the cytosol. None was detected in the extracellular medium. The ald knockout strain grew without alanine or glycine and was able to utilize glycine but not alanine as a nitrogen source. Transcription of ald was induced when alanine was the sole nitrogen source, and higher levels of Ald enzyme were measured. Ald is proposed to have several functions, including ammonium incorporation and alanine breakdown. PMID- 22210766 TI - Altered regulation of Escherichia coli biotin biosynthesis in BirA superrepressor mutant strains. AB - Transcription of the Escherichia coli biotin (bio) operon is directly regulated by the biotin protein ligase BirA, the enzyme that covalently attaches biotin to its cognate acceptor proteins. Binding of BirA to the bio operator requires dimerization of the protein, which is triggered by BirA-catalyzed synthesis of biotinoyl-adenylate (biotinoyl-5'-AMP), the obligatory intermediate of the ligation reaction. Although several aspects of this regulatory system are well understood, no BirA superrepressor mutant strains had been isolated. Such superrepressor BirA proteins would repress the biotin operon transcription in vivo at biotin concentrations well below those needed for repression by wild-type BirA. We isolated mutant strains having this phenotype by a combined selection screening approach and resolved multiple mutations to give several birA superrepressor alleles, each having a single mutation, all of which showed repression dominant over that of the wild-type allele. All of these mutant strains repressed bio operon transcription in vivo at biotin concentrations that gave derepression of the wild-type strain and retained sufficient ligation activity for growth when overexpressed. All of the strains except that encoding G154D BirA showed derepression of bio operon transcription upon overproduction of a biotin-accepting protein. In BirA, G154D was a lethal mutation in single copy, and the purified protein was unable to transfer biotin from enzyme-bound biotinoyl-adenylate either to the natural acceptor protein or to a biotin accepting peptide sequence. Consistent with the transcriptional repression data, each of the purified mutant proteins showed increased affinity for the biotin operator DNA in electrophoretic mobility shift assays. Surprisingly, although most of the mutations were located in the catalytic domain, all of those tested, except G154D BirA, had normal ligase activity. Most of the mutations that gave superrepressor phenotypes altered residues located close to the dimerization interface of BirA. However, two mutations were located at sites well removed from the interface. The properties of the superrepressor mutants strengthen and extend other data indicating that BirA function entails extensive interactions among the three domains of the protein and show that normal ligase activity does not ensure normal DNA binding. PMID- 22210767 TI - Characterization of recombinant UDP- and ADP-glucose pyrophosphorylases and glycogen synthase to elucidate glucose-1-phosphate partitioning into oligo- and polysaccharides in Streptomyces coelicolor. AB - Streptomyces coelicolor exhibits a major secondary metabolism, deriving important amounts of glucose to synthesize pigmented antibiotics. Understanding the pathways occurring in the bacterium with respect to synthesis of oligo- and polysaccharides is of relevance to determine a plausible scenario for the partitioning of glucose-1-phosphate into different metabolic fates. We report the molecular cloning of the genes coding for UDP- and ADP-glucose pyrophosphorylases as well as for glycogen synthase from genomic DNA of S. coelicolor A3(2). Each gene was heterologously expressed in Escherichia coli cells to produce and purify to electrophoretic homogeneity the respective enzymes. UDP-glucose pyrophosphorylase (UDP-Glc PPase) was characterized as a dimer exhibiting a relatively high V(max) in catalyzing UDP-glucose synthesis (270 units/mg) and with respect to dTDP-glucose (94 units/mg). ADP-glucose pyrophosphorylase (ADP Glc PPase) was found to be tetrameric in structure and specific in utilizing ATP as a substrate, reaching similar activities in the directions of ADP-glucose synthesis or pyrophosphorolysis (V(max) of 0.15 and 0.27 units/mg, respectively). Glycogen synthase was arranged as a dimer and exhibited specificity in the use of ADP-glucose to elongate alpha-1,4-glucan chains in the polysaccharide. ADP-Glc PPase was the only of the three enzymes exhibiting sensitivity to allosteric regulation by different metabolites. Mannose-6-phosphate, phosphoenolpyruvate, fructose-6-phosphate, and glucose-6-phosphate behaved as major activators, whereas NADPH was a main inhibitor of ADP-Glc PPase. The results support a metabolic picture where glycogen synthesis occurs via ADP-glucose in S. coelicolor, with the pathway being strictly regulated in connection with other routes involved with oligo- and polysaccharides, as well as with antibiotic synthesis in the bacterium. PMID- 22210768 TI - RelE-mediated dormancy is enhanced at high cell density in Escherichia coli. AB - Bacteria show remarkable adaptability under several stressful conditions by shifting themselves into a dormant state. Less is known, however, about the mechanism underlying the cell transition to dormancy. Here, we report that the transition to dormant states is mediated by one of the major toxin-antitoxin systems, RelEB, in a cell density-dependent manner in Escherichia coli K-12 MG1655. We constructed a strain, IKA121, which expresses the toxin RelE in the presence of rhamnose and lacks chromosomal relBE and rhaBAD. With this strain, we demonstrated that RelE-mediated dormancy is enhanced at high cell densities compared to that at low cell densities. The initiation of expression of the antitoxin RelB from a plasmid, pCA24N, reversed RelE-mediated dormancy in bacterial cultures. The activation of RelE increased the appearance of persister cells against beta-lactams, quinolones, and aminoglycosides, and more persister cells appeared at high cell densities than at low cell densities. Further analysis indicated that amino acid starvation and an uncharacterized extracellular heat-labile substance promote RelE-mediated dormancy. This is a first report on the induction of RelE-mediated dormancy by high cell density. This work establishes a population-based dormancy mechanism to help explain E. coli survival in stressful environments. PMID- 22210770 TI - A 54-kilodalton protein encoded by pBtoxis is required for parasporal body structural integrity in Bacillus thuringiensis subsp. israelensis. AB - Strains of Bacillus thuringiensis such as B. thuringiensis subsp. israelensis (ONR-60A) and B. thuringiensis subsp. morrisoni (PG-14) pathogenic for mosquito larvae produce a complex parasporal body consisting of several protein endotoxins synthesized during sporulation that form an aggregate of crystalline inclusions bound together by a multilamellar fibrous matrix. Most studies of these strains focus on the molecular biology of the endotoxins, and although it is known that parasporal body structural integrity is important to achieving high toxicity, virtually nothing is known about the matrix that binds the toxin inclusions together. In the present study, we undertook a proteomic analysis of this matrix to identify proteins that potentially mediate assembly and stability of the parasporal body. In addition to fragments of their known major toxins, namely, Cry4Aa, Cry4Ba, Cry11Aa, and Cyt1Aa, we identified peptides with 100% identity to regions of Bt152, a protein coded for by pBtoxis of B. thuringiensis subsp. israelensis, the plasmid that encodes all endotoxins of this subspecies. As it is known that the Bt152 gene is expressed in B. thuringiensis subsp. israelensis, we disrupted its function and showed that inactivation destabilized the parasporal body matrix and, concomitantly, inclusion aggregation. Using fluorescence microscopy, we further demonstrate that Bt152 localizes to the parasporal body in both strains, is absent in other structural or soluble components of the cell, including the endospore and cytoplasm, and in ligand blots binds to purified multilamellar fibrous matrix. Together, the data show that Bt152 is essential for stability of the parasporal body of these strains. PMID- 22210769 TI - Integration of sigmaB activity into the decision-making process of sporulation initiation in Bacillus subtilis. AB - Spo0A~P is the master regulator of sporulation in Bacillus subtilis. Activity of Spo0A is regulated by a phosphorelay integrating multiple positive and negative signals by the action of kinases and phosphatases. The phosphatase Spo0E specifically inactivates the response regulator Spo0A~P by dephosphorylation. We identified a sigma(B)-type promoter adjacent to spo0E that is activated by the general stress response sigma factor sigma(B) and is responsible for spo0E induction in vivo. Ectopic expression of sigma(B) and subsequent induction of spo0E cause a sigma(B)-dependent block of sporulation-specific transcription of the spo0A and spoIIE genes and produces a sporulation-deficient phenotype. This effect could be erased by a deletion of the sigma(B) promoter of spo0E and thus solely addresses sigma(B) activity. Here, a molecular mechanism is shown that integrates sigma(B) activity into the decision-making process of sporulation and provides a link to interconnect these two dominant and probably mutually exclusive adaptive responses in the regulatory network of B. subtilis. PMID- 22210771 TI - Transcriptional regulation of central carbon and energy metabolism in bacteria by redox-responsive repressor Rex. AB - Redox-sensing repressor Rex was previously implicated in the control of anaerobic respiration in response to the cellular NADH/NAD(+) levels in gram-positive bacteria. We utilized the comparative genomics approach to infer candidate Rex binding DNA motifs and assess the Rex regulon content in 119 genomes from 11 taxonomic groups. Both DNA-binding and NAD-sensing domains are broadly conserved in Rex orthologs identified in the phyla Firmicutes, Thermotogales, Actinobacteria, Chloroflexi, Deinococcus-Thermus, and Proteobacteria. The identified DNA-binding motifs showed significant conservation in these species, with the only exception detected in Clostridia, where the Rex motif deviates in two positions from the generalized consensus, TTGTGAANNNNTTCACAA. Comparative analysis of candidate Rex sites revealed remarkable variations in functional repertoires of candidate Rex-regulated genes in various microorganisms. Most of the reconstructed regulatory interactions are lineage specific, suggesting frequent events of gain and loss of regulator binding sites in the evolution of Rex regulons. We identified more than 50 novel Rex-regulated operons encoding functions that are essential for resumption of the NADH:NAD(+) balance. The novel functional role of Rex in the control of the central carbon metabolism and hydrogen production genes was validated by in vitro DNA binding assays using the TM0169 protein in the hydrogen-producing bacterium Thermotoga maritima. PMID- 22210772 TI - Dwarfism in mice lacking collagen-binding integrins alpha2beta1 and alpha11beta1 is caused by severely diminished IGF-1 levels. AB - Mice with a combined deficiency in the alpha2beta1 and alpha11beta1 integrins lack the major receptors for collagen I. These mutants are born with inconspicuous differences in size but develop dwarfism within the first 4 weeks of life. Dwarfism correlates with shorter, less mineralized and functionally weaker bones that do not result from growth plate abnormalities or osteoblast dysfunction. Besides skeletal dwarfism, internal organs are correspondingly smaller, indicating proportional dwarfism and suggesting a systemic cause for the overall size reduction. In accordance with a critical role of insulin-like growth factor (IGF)-1 in growth control and bone mineralization, circulating IGF-1 levels in the sera of mice lacking either alpha2beta1 or alpha11beta1 or both integrins were sharply reduced by 39%, 64%, or 81% of normal levels, respectively. Low hepatic IGF-1 production resulted from diminished growth hormone-releasing hormone expression in the hypothalamus and, subsequently, reduced growth hormone expression in the pituitary glands of these mice. These findings point out a novel role of collagen-binding integrin receptors in the control of growth hormone/IGF-1-dependent biological activities. Thus, coupling hormone secretion to extracellular matrix signaling via integrins represents a novel concept in the control of endocrine homeostasis. PMID- 22210773 TI - Structural investigation of the thermostability and product specificity of amylosucrase from the bacterium Deinococcus geothermalis. AB - Amylosucrases are sucrose-utilizing alpha-transglucosidases that naturally catalyze the synthesis of alpha-glucans, linked exclusively through alpha1,4 linkages. Side products and in particular sucrose isomers such as turanose and trehalulose are also produced by these enzymes. Here, we report the first structural and biophysical characterization of the most thermostable amylosucrase identified so far, the amylosucrase from Deinoccocus geothermalis (DgAS). The three-dimensional structure revealed a homodimeric quaternary organization, never reported before for other amylosucrases. A sequence signature of dimerization was identified from the analysis of the dimer interface and sequence alignments. By rigidifying the DgAS structure, the quaternary organization is likely to participate in the enhanced thermal stability of the protein. Amylosucrase specificity with respect to sucrose isomer formation (turanose or trehalulose) was also investigated. We report the first structures of the amylosucrases from Deinococcus geothermalis and Neisseria polysaccharea in complex with turanose. In the amylosucrase from N. polysaccharea (NpAS), key residues were found to force the fructosyl moiety to bind in an open state with the O3' ideally positioned to explain the preferential formation of turanose by NpAS. Such residues are either not present or not similarly placed in DgAS. As a consequence, DgAS binds the furanoid tautomers of fructose through a weak network of interactions to enable turanose formation. Such topology at subsite +1 is likely favoring other possible fructose binding modes in agreement with the higher amount of trehalulose formed by DgAS. Our findings help to understand the inter-relationships between amylosucrase structure, flexibility, function, and stability and provide new insight for amylosucrase design. PMID- 22210774 TI - Structure-guided engineering enhances a phytochrome-based infrared fluorescent protein. AB - Phytochrome is a multidomain dimeric red light photoreceptor that utilizes a chromophore-binding domain (CBD), a PHY domain, and an output module to induce cellular changes in response to light. A promising biotechnology tool emerged when a structure-based substitution at Asp-207 was shown to be an infrared fluorophore that uses a biologically available tetrapyrrole chromophore. We report multiple crystal structures of this D207H variant of the Deinococcus radiodurans CBD, in which His-207 is observed to form a hydrogen bond with either the tetrapyrrole A-ring oxygen or the Tyr-263 hydroxyl. Based on the implications of this duality for fluorescence properties, Y263F was introduced and shown to have stronger fluorescence than the original D207H template. Our structures are consistent with the model that the Y263F change prevents a red light-induced far red light absorbing phytochrome chromophore configuration. With the goal of decreasing size and thereby facilitating use as a fluorescent tag in vivo, we also engineered a monomeric form of the CBD. Unexpectedly, photoconversion was observed in the monomer despite the lack of a PHY domain. This observation underscores an interplay between dimerization and the photochemical properties of phytochrome and suggests that the monomeric CBD could be used for further studies of the photocycle. The D207H substitution on its own in the monomer did not result in fluorescence, whereas Y263F did. Combined, the D207H and Y263F substitutions in the monomeric CBD lead to the brightest of our variants, designated Wisconsin infrared phytofluor (Wi-Phy). PMID- 22210775 TI - Activity of the mycobacterial proteasomal ATPase Mpa is reversibly regulated by pupylation. AB - Pupylation is a bacterial post-translational modification of target proteins on lysine residues with prokaryotic ubiquitin-like protein Pup. Pup-tagged substrates are recognized by a proteasome-interacting ATPase termed Mpa in Mycobacterium tuberculosis. Mpa unfolds pupylated substrates and threads them into the proteasome core particle for degradation. Interestingly, Mpa itself is also a pupylation target. Here, we show that the Pup ligase PafA predominantly produces monopupylated Mpa modified homogeneously on a single lysine residue within its C-terminal region. We demonstrate that this modification renders Mpa functionally inactive. Pupylated Mpa can no longer support Pup-mediated proteasomal degradation due to its inability to associate with the proteasome core. Mpa is further inactivated by rapid Pup- and ATPase-driven deoligomerization of the hexameric Mpa ring. We show that pupylation of Mpa is chemically and functionally reversible. Mpa regains its enzymatic activity upon depupylation by the depupylase Dop, affording a rapid and reversible activity control over Mpa function. PMID- 22210780 TI - Clearing the air. PMID- 22210777 TI - Role of integrin-beta3 protein in macrophage polarization and regeneration of injured muscle. AB - Following injury, skeletal muscle achieves repair by a highly coordinated, dynamic process resulting from interplay among numerous inflammatory, growth factors and myogenic regulators. To identify genes involved in muscle regeneration, we used a microarray analysis; there was a significant increase in the expression of a group of integrin genes. To verify these results, we used RT PCR and Western blotting and found that 12 integrins were up-regulated from 3 h to 15 days following injury. Following muscle injury, integrin-beta3 was initially expressed, mainly in macrophages. In integrin-beta3 global KO mice, the expression of myogenic genes was decreased and muscle regeneration was impaired, whereas fibrosis was enhanced versus events in wild type (WT) mice. The mechanism for these responses in integrin-beta3 KO mice included an infiltration of macrophages that were polarized into the M2 phenotype. These macrophages produced more TGF-beta1 and increased TGF-beta1/Smad signaling. In vitro, we confirmed that M2 macrophages lacking integrin-beta3 produced more TGF-beta1. Furthermore, transplantation of bone marrow cells from integrin-beta3 KO mice into WT mice led to suppression of the infiltration and accumulation of macrophages into injured muscles. There was also impaired muscle regeneration with an increase in muscle fibrosis. Our results demonstrate that integrin-beta3 plays a fundamental role in muscle regeneration through a regulation of macrophage infiltration and polarization leading to suppressed TGF-beta1 production. This promotes efficient muscle regeneration. Thus, an improvement in integrin-beta3 function could stimulate muscle regeneration. PMID- 22210776 TI - Molecular determinants for antibody binding on group 1 house dust mite allergens. AB - House dust mites produce potent allergens, Der p 1 and Der f 1, that cause allergic sensitization and asthma. Der p 1 and Der f 1 are cysteine proteases that elicit IgE responses in 80% of mite-allergic subjects and have proinflammatory properties. Their antigenic structure is unknown. Here, we present crystal structures of natural Der p 1 and Der f 1 in complex with a monoclonal antibody, 4C1, which binds to a unique cross-reactive epitope on both allergens associated with IgE recognition. The 4C1 epitope is formed by almost identical amino acid sequences and contact residues. Mutations of the contact residues abrogate mAb 4C1 binding and reduce IgE antibody binding. These surface exposed residues are molecular targets that can be exploited for development of recombinant allergen vaccines. PMID- 22210781 TI - Rate of decline in FEV1: is emphysema the culprit? PMID- 22210782 TI - Measuring and rewarding quality in the ICU: the yardstick is not as straight as we wish. PMID- 22210783 TI - Inflammation and alphavbeta3 integrin. PMID- 22210784 TI - Risk prediction in idiopathic pulmonary fibrosis. PMID- 22210785 TI - Bronchoalveolar lavage brings mesenchymal stem cells to the light. PMID- 22210786 TI - Computed tomography screening for lung cancer: the challenge of what and how. PMID- 22210787 TI - A drug therapy for muscle dysfunction in respiratory disorders? PMID- 22210788 TI - Multisociety task force for critical care research: key issues and recommendations. AB - BACKGROUND: Research in critical care extends from the bench to the bedside, involving multiple departments, specialties, and funding organizations. Because of this diversity, it has been difficult for all stakeholders to collectively identify challenges and establish priorities. OBJECTIVE: To define a comprehensive agenda for critical care research using input from a broad range of stakeholders to serve as a blueprint for future initiatives. METHODS: The Critical Care Societies Collaborative (CCSC), consisting of the leadership of the American Association of Critical-Care Nurses (AACN), the American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Society of Critical Care Medicine (SCCM), joined the U.S. Critical Illness and Injury Trials Group (USCIITG) in forming a task force to define a comprehensive critical care research agenda. This group of 25 identified experts was divided into subgroups to address basic, translational, clinical, implementation, and educational research. The subgroups met via conference calls, and the entire task force met in person for a 2-day session. The result was a detailed discussion of the research priorities that served as the basis for this report. RESULTS: The task force identified challenges, specific priority areas, and recommendations for process improvements to support critical care research. Additionally, four overarching themes emerged: (1) the traditional "silo-ed" approach to critical care research is counterproductive and should be modified; (2) an approach that more effectively links areas of research (i.e., basic and translational research, or clinical research and implementation) should be embraced; (3) future approaches to human research should account for disease complexity and patient heterogeneity; and (4) an enhanced infrastructure for critical care research is essential for future success. CONCLUSIONS: This document contains the themes/recommendations developed by a large, multiprofessional cross-section of critical care scientists, clinicians, and educators. It provides a unique framework for future research in critical care medicine. PMID- 22210789 TI - Incidental agenesis of the lung presenting as dyspnea. PMID- 22210790 TI - Exposures to diesel motor exhaust and lung cancer: are findings of a large pooled analysis really consistent? PMID- 22210791 TI - The impact of selection bias due to increasing response rates among population controls in occupational case-control studies. PMID- 22210792 TI - The bedside diagnosis of ICU delirium: specificity is high, let's optimize sensitivity. PMID- 22210793 TI - Interleukin-17 and cystic fibrosis lung disease. PMID- 22210794 TI - Immune effects of interferon gamma in persistent staphylococcal sepsis. PMID- 22210795 TI - Obstructive apneas during continuous positive airway pressure: unexpected finding with nasal pillow interface. PMID- 22210796 TI - High-riding pericardial recess mimicking metastatic mediastinal lymph node. PMID- 22210797 TI - Effectiveness of a program using a vehicle tracking system, incentives, and disincentives to reduce the speeding behavior of drivers with ADHD. AB - OBJECTIVE: In this article, the authors investigated the effectiveness of a behavior modification program using global positioning system (GPS) vehicle tracking devices with contingency incentives and disincentives to reduce the speeding behavior of drivers with ADHD. METHOD: Using an AB multiple-baseline design, six participants drove a 5-mile stable driving route weekly while GPS devices recorded speeds. The dependent variable was percentage of feet speeding. Following an initial baseline period, five participants received treatment. One participant remained at baseline. RESULTS: Visual inspection of individual participant graphs, reductions in mean percentages of speeding from baseline to treatment across participants (M = 82%), C-statistic analyses, and visual graphs with applied binomial formula supported a treatment effect. The between participant analysis using R n Test of Ranks was significant, R n = 6, p < .01, and complemented a clean multiple-baseline result. CONCLUSION: Results indicated that this treatment program was effective in reducing speeding by drivers with ADHD and warrants replication. PMID- 22210798 TI - Validation of the AQT color-form additive model for screening and monitoring pharmacological treatment of ADHD. AB - OBJECTIVE: This retrospective study used a quick test of cognitive speed (AQT) processing-speed and efficiency measures for evaluating sensitivity and monitoring effects during pharmacological treatment of adults with ADHD. METHOD: Color (C), form (F), and color-form (CF) combination naming were administered to 69 adults during outpatient evaluation, and pre- and posttreatment results were compared for 64 adults. RESULTS: At intake without medication, naming times (s) were significantly longer and overhead, CF - (C + F), larger than after stabilization of ADHD symptoms. Means for single-dimension naming were in the normal range, and for CF and overhead, means were in the atypical ranges. After treatment, CF and overhead improved to within normal ranges. On average, dual dimension processing speed increased by 31% and efficiency by 73%. Sensitivity at intake was 91%, using fail-criteria for CF and/or overhead. CONCLUSION: Results support previous estimates of sensitivity and ability to monitor pharmacological treatment effects in ADHD. PMID- 22210799 TI - Associations between sleep characteristics, seasonal depressive symptoms, lifestyle, and ADHD symptoms in adults. AB - OBJECTIVE: The authors explored associations between ADHD symptoms, seasonal depressive symptoms, lifestyle, and health. METHOD: Adult ADHD patients (n = 202) and controls (n = 189) completed the ASESA questionnaire involving lifestyle, eating pattern, and physical and psychological health, and validated measures on ADHD and sleep. ASESA is the Dutch acronym for inattention, sleep, eating pattern, mood, and general health questionnaire. RESULTS: Indication for delayed sleep phase syndrome (DSPS) was 26% in patients and 2% in controls (p < .001). Patients reported shorter sleep, longer sleep-onset latency, and later midsleep. Shorter (R (2) = .21) and later (R (2) = .27) sleep were associated with hyperactivity, male gender, younger age, and seasonal depressive symptoms. Seasonal depressive symptoms were related to hyperactivity, female gender, unemployment, and late sleep (pseudo R (2) = .28). Higher body mass index (BMI) was associated with shorter sleep in patients (rho = -.16; p = .04) and controls (rho = -.17; p = .02). Longer sleep showed lower odds for indication of metabolic syndrome (OR = -0.17; p = .053). CONCLUSION: DSPS is more prevalent in ADHD and needs further investigation to establish treatment to prevent chronic health issues. PMID- 22210801 TI - Self-concept of college students with ADHD: discordance between self- and parent reports. AB - OBJECTIVE: To investigate the self-concept of college students with ADHD. METHOD: College students with ADHD and their parents completed self-report and observer report measures of self-concept, respectively. RESULTS: Results indicated that college students with ADHD did not report problems with self-concept but their parents did for them. This difference was statistically significant and large in magnitude (d = .84). CONCLUSION: Perceptions of the self-concept of college students with ADHD appear to vary by informant source. Hypotheses for the discordance between self- and parent-reports are discussed. Multi-informant assessment is recommended as a way to obtain a more complete clinical picture than reliance on self- or parent-report alone. PMID- 22210800 TI - Validation of the Chinese strengths and weaknesses of ADHD-symptoms and normal behaviors questionnaire in Hong Kong. AB - OBJECTIVE: Unlike rating scales that focus on the severity of ADHD symptoms, the Strengths and Weaknesses of ADHD-symptoms and normal-behaviors (SWAN) rating scale is phrased in neutral or positive terms for carers to compare the index child's behaviors with that of their peers. This study explores its psychometric properties when applied to Chinese children in Hong Kong. METHOD: Ratings from the Chinese SWAN scale collected from parents and teachers of a community sample of 3,722 6- to 12-year-old students recruited by stratified random sampling were compared with 247 clinic children with a diagnosis of ADHD. Reliability, validity, factor structure, and cutoff scores were calculated. RESULTS: Favorable psychometrics and a two-factor structure identical to the original were reproduced. Cutoff scores were supported by satisfactory sensitivities and specificities. CONCLUSION: The SWAN scale is a reliable and valid instrument for the assessment of ADHD symptoms in Chinese children in Hong Kong. PMID- 22210802 TI - Differentiating co-occurring behavior problems in children with ADHD: patterns of emotional reactivity and executive functioning. AB - OBJECTIVE: This study examined whether "top-down" and "bottom-up" control processes can differentiate children with ADHD who exhibit co-occurring aggression and/or internalizing symptoms. METHOD: Participants included 74 children (M age = 10.7 years) with a Diagnostic and statistical manual of mental disorders (4th ed.; DSM-IV) diagnosis of ADHD. The authors' top-down measure was executive functioning (EF) indexed via two neuropsychological tasks whereas their bottom-up measure was emotional reactivity. Parents also reported on children's aggression and internalizing symptoms. RESULTS: Emotional reactivity was associated with co-occurring aggressive symptoms, regardless of the presence of internalizing symptoms or ADHD symptom severity, whereas EF deficits were less likely to occur in children with ADHD and co-occurring internalizing symptoms. CONCLUSION: The authors' findings highlight the importance of integrating top down and bottom-up regulatory measures when studying the multipathway conception of ADHD and its co-occurring problems. PMID- 22210803 TI - Special issue: Trichoderma--from basic Biology to Biotechnology. PMID- 22210804 TI - PII signal transduction proteins: pivotal players in post-translational control of nitrogenase activity. AB - The fixation of atmospheric nitrogen by the prokaryotic enzyme nitrogenase is an energy- expensive process and consequently it is tightly regulated at a variety of levels. In many diazotrophs this includes post-translational regulation of the enzyme's activity, which has been reported in both bacteria and archaea. The best understood response is the short-term inactivation of nitrogenase in response to a transient rise in ammonium levels in the environment. A number of proteobacteria species effect this regulation through reversible ADP-ribosylation of the enzyme, but other prokaryotes have evolved different mechanisms. Here we review current knowledge of post-translational control of nitrogenase and show that, for the response to ammonium, the P(II) signal transduction proteins act as key players. PMID- 22210806 TI - Histomorphometrical and clinical study of connective tissue around titanium dental implants with porous surfaces in a canine model. AB - Connective tissue (CT) reactions and collagen fiber orientation were evaluated on titanium implants with porous surfaces made by a laser method. Three groups in which the diameters of pores were 10 +/- 5 um, 40 +/- 5 um, and 70 +/- 5 um were involved in this test, together with a machined group as control. A total of 24 implants were randomly placed in mandibles after 3 months of premolars and the first molar extraction in beagle dogs. All the implants were firmly anchored in the bone after 3-month insertion. Histological sections showed that the gingival tissue was attached tightly to implant surface and there was no significant difference in inflammatory cell invasion and probing depth among all groups (p > 0.05). Histomorphometric analysis demonstrated that no significant difference in total CT length was observed among four groups (p > 0.05), however, the gingival recession in the 40 +/- 5 um and 70 +/- 5 um porous groups was less than in the 10 +/- 5 um porous group and control group (p < 0.05). Collagen fibers at the inner zone of the CT around the 40 +/- 5 um and 70 +/- 5 um porous implants aligned mostly in an oblique orientation, while there was a mainly parallel fiber direction around the 10 +/- 5 um porous and control implants. It was noted that some fibroblasts and fibers in the 70 +/- 5 um porous group was inserted into the pores of implant surface, indicating that pores of a proper size on the implant surface could induce the insertion of CT and prevent gingival recession. PMID- 22210805 TI - Comparing reports from hip-fracture patients and their proxies: implications on evaluating sex differences in disability and depressive symptoms. AB - OBJECTIVE: This study compared sex differences in disability and depressive symptoms using reports from hip fracture patients and their proxies. METHOD: Hip fracture patients (49 men, 183 women) aged >=65 years and proxies were interviewed 1 year postfracture. Outcomes were Center for Epidemiological Studies Depression (CES-D) and number of dependencies in performing activities of daily living and instrumental activities of daily living. RESULTS: Mean ADL sex differences (men minus women) were 0.40 (p = .37) using proxy reports and 0.70 (p = .08) using patient self-reports. Mean CES-D sex differences were -3.60 (p = .02) using proxy reports and -1.26 (p = .38) using patient self-reports. Discrepancies between patients and proxies were smallest for proxies who have lived with the patient >= 1 year. DISCUSSION: Patients and proxies produced conflicting conclusions about sex differences. Results suggest that ideal proxies to recruit are those who have been cohabitating with the patients for an extended length of time. PMID- 22210807 TI - In vitro assessment of blood compatibility: residual and dynamic markers of cellular activation. AB - The blood compatibility of materials and surfaces used for medical device fabrication is a crucial factor in their function and effectiveness. Expansion of device use into more sensitive and longer term applications warrants increasingly detailed evaluations of blood compatibility that reach beyond the customary measures mandated by regulatory requirements. A panel of tests that assess both deposition on the surface and activation of circulating blood in contact with the surface has been developed. Specifically, the ability of a surface to modulate the biological response of blood is assessed by measuring: (1) dynamic thrombin generation; (2) surface-bound thrombin activity after exposure to blood; (3) activation of monocytes, polymorphonuclear leukocytes, lymphocytes, and platelets; (4) activation of complement; and (5) adherent monocytes, polymorphonuclear leukocytes, lymphocytes, and platelets on blood-contacting surfaces. The tests were used to evaluate surfaces modified with immobilized heparin (Ension's proprietary bioactive surface) and demonstrated that the modified surfaces reduced platelet activation, leukocyte activation, and complement activation in flowing human blood. Perfusion of the surfaces with human platelet-rich plasma showed that the immobilized heparin surfaces also reduce both dynamic thrombin levels in the circulating plasma and residual thrombin generated at the material surface. PMID- 22210808 TI - Pulmonary hypertension in patients with sickle cell disease: not so frequent but so different. PMID- 22210809 TI - The fibrocyte in pulmonary hypertension: we seek him here, we seek him there. PMID- 22210810 TI - Improving outcomes from community-acquired pneumonia: we need to be more sophisticated about cause and effect. PMID- 22210811 TI - Circulating fibrocytes and pulmonary arterial hypertension. PMID- 22210812 TI - Artificial lung as an alternative to mechanical ventilation in COPD exacerbation. PMID- 22210813 TI - Intermittent hypoxia enhances cancer progression in a mouse model of sleep apnoea. PMID- 22210814 TI - Malignant mesothelioma in Metsovo, Greece, from domestic use of asbestos: 30 years later. PMID- 22210815 TI - An audit of hypoxaemia, hyperoxaemia, hypercapnia and acidosis in blood gas specimens. PMID- 22210816 TI - Cat litter is a possible trigger for sarcoidosis. PMID- 22210817 TI - Prognostic indices for COPD patient management: how many do we need? PMID- 22210818 TI - Avoiding backward steps in COPD: looking again at roflumilast. PMID- 22210820 TI - Why excessive sleepiness may persist in OSA patients receiving adequate CPAP treatment. PMID- 22210822 TI - Viral wheezing is virus specific and not just host specific. PMID- 22210825 TI - beta2-adrenergic receptor agonists modulate human airway smooth muscle cell migration via vasodilator-stimulated phosphoprotein. AB - Severe asthma manifests as airway remodeling and irreversible airway obstruction, in part because of the proliferation and migration of human airway smooth muscle (HASM) cells. We previously reported that cyclic adenosine monophosphate mobilizing agents, including beta(2)-adrenergic receptor (beta(2)AR) agonists, which are mainstay of asthma therapy, and prostaglandin E2 (PGE2), inhibit the migration of HASM cells, although the mechanism for this migration remains unknown. Vasodilator-stimulated phosphoprotein (VASP), an anticapping protein, modulates the formation of actin stress fibers during cell motility, and is negatively regulated by protein kinase A (PKA)-specific inhibitory phosphorylation at serine 157 (Ser157). Here, we show that treatment with beta(2)AR agonists and PGE2 induces the PKA-dependent phosphorylation of VASP and inhibits the migration of HASM cells. The stable expression of PKA inhibitory peptide and the small interfering (si) RNA-induced depletion of VASP abolish the inhibitory effects of albuterol and PGE2 on the migration of HASM cells. Importantly, prolonged treatment with albuterol prevents the agonist-induced phosphorylation of VASP at Ser157, and reverses the inhibitory effects of albuterol and formoterol, but not PGE2, on the basal and PDGF-induced migration of HASM cells. Collectively, our data demonstrate that beta(2)AR agonists selectively inhibit the migration of HASM cells via a beta(2)AR/PKA/VASP signaling pathway, and that prolonged treatment with albuterol abolishes the inhibitory effect of beta-agonists on the phosphorylation of VASP and migration of HASM cells because of beta(2)AR desensitization. PMID- 22210826 TI - Disruption of iron homeostasis in mesothelial cells after talc pleurodesis. AB - The mechanism for biological effects after exposure to particles is incompletely understood. One postulate proposed to explain biological effects after exposure to particles involves altered iron homeostasis in the host. The fibro inflammatory properties of mineral oxide particles are exploited therapeutically with the instillation of massive quantities of talc into the pleural space, to provide sclerosis. We tested the postulates that (1) in vitro exposure to talc induces a disruption in iron homeostasis, oxidative stress, and a biological effect, and (2) talc pleurodesis in humans alters iron homeostasis. In vitro exposures of both mesothelial and airway epithelial cells to 100 MUg/ml talc significantly increased iron importation and concentrations of the storage protein ferritin. Using dichlorodihydrofluorescein, exposure to talc was associated with a time-dependent and concentration-dependent generation of oxidants in both cell types. The expression of proinflammatory mediators was also increased after in vitro exposures of mesothelial and airway epithelial cells to talc. Relative to control lung tissue, lung tissue from patients treated with sclerodesis demonstrated an accumulation of iron and increased expression of iron related proteins, including ferritin, the importer divalent metal transport-1 and the exporter ferroportin-1. Talc was also observed to translocate to the parenchyma, and changes in iron homeostasis were focally distributed to sites of retention. We conclude that exposure to talc disrupts iron homeostasis, is associated with oxidative stress, and results in a biological effect (i.e., a fibro-inflammatory response). Talc pleurodesis can function as a model of the human response to mineral oxide particle exposure, albeit a massive one. PMID- 22210828 TI - Rapamycin exerts antifungal activity in vitro and in vivo against Mucor circinelloides via FKBP12-dependent inhibition of Tor. AB - The zygomycete Mucor circinelloides is an opportunistic fungal pathogen that commonly infects patients with malignancies, diabetes mellitus, and solid organ transplants. Despite the widespread use of antifungal therapy in the management of zygomycosis, the incidence of infections continues to rise among immunocompromised individuals. In this study, we established that the target and mechanism of antifungal action of the immunosuppressant rapamycin in M. circinelloides are mediated via conserved complexes with FKBP12 and a Tor homolog. We found that spontaneous mutations that disrupted conserved residues in FKBP12 conferred rapamycin and FK506 resistance. Disruption of the FKBP12 encoding gene, fkbA, also conferred rapamycin and FK506 resistance. Expression of M. circinelloides FKBP12 (McFKBP12) complemented a Saccharomyces cerevisiae mutant strain lacking FKBP12 to restore rapamycin sensitivity. Expression of the McTor FKBP12-rapamycin binding (FRB) domain conferred rapamycin resistance in S. cerevisiae, and McFKBP12 interacted in a rapamycin-dependent fashion with the McTor FRB domain in a yeast two-hybrid assay, validating McFKBP12 and McTor as conserved targets of rapamycin. We showed that in vitro, rapamycin exhibited potent growth inhibitory activity against M. circinelloides. In a Galleria mellonella model of systemic mucormycosis, rapamycin improved survival by 50%, suggesting that rapamycin and nonimmunosuppressive analogs have the potential to be developed as novel antifungal therapies for treatment of patients with mucormycosis. PMID- 22210829 TI - Molecular characterization of Toxoplasma gondii formin 3, an actin nucleator dispensable for tachyzoite growth and motility. AB - Toxoplasma gondii belongs to the phylum Apicomplexa, a group of obligate intracellular parasites that rely on gliding motility to enter host cells. Drugs interfering with the actin cytoskeleton block parasite motility, host cell invasion, and egress from infected cells. Myosin A, profilin, formin 1, formin 2, and actin-depolymerizing factor have all been implicated in parasite motility, yet little is known regarding the importance of actin polymerization and other myosins for the remaining steps of the parasite lytic cycle. Here we establish that T. gondii formin 3 (TgFRM3), a newly described formin homology 2 domain (FH2)-containing protein, binds to Toxoplasma actin and nucleates rabbit actin assembly in vitro. TgFRM3 expressed as a transgene exhibits a patchy localization at several distinct structures within the parasite. Disruption of the TgFRM3 gene by double homologous recombination in a ku80-ko strain reveals no vital function for tachyzoite propagation in vitro, which is consistent with its weak level of expression in this life stage. Conditional stabilization of truncated forms of TgFRM3 suggests that different regions of the molecule contribute to distinct localizations. Moreover, expression of TgFRM3 lacking the C-terminal domain severely affects parasite growth and replication. This work provides a first insight into how this specialized formin, restricted to the group of coccidia, completes its actin-nucleating activity. PMID- 22210830 TI - Interplay of a ligand sensor and an enzyme in controlling expression of the Saccharomyces cerevisiae GAL genes. AB - The regulation of the Saccharomyces cerevisiae GAL genes in response to galactose as a source of carbon has served as a paradigm for eukaryotic transcriptional control over the last 50 years. Three proteins--a transcriptional activator (Gal4p), an inhibitor (Gal80p), and a ligand sensor (Gal3p)--control the switch between inert and active gene expression. The molecular mechanism by which the recognition of galactose within the cell is converted into a transcriptional response has been the subject of considerable debate. In this study, using a novel and powerful method of localizing active transcription factors within the nuclei of cells, we show that a short-lived complex between Gal4p, Gal80p, and Gal3p occurs soon after the addition of galactose to cells to activate GAL gene expression. Gal3p is subsequently replaced in this complex by Gal1p, and a Gal4p Gal80p-Gal1p complex is responsible for the continued expression of the GAL genes. The transient role of the ligand sensor indicates that current models for the induction and continued expression of the yeast GAL genes need to be reevaluated. PMID- 22210831 TI - Vacuolar H+-ATPase works in parallel with the HOG pathway to adapt Saccharomyces cerevisiae cells to osmotic stress. AB - Hyperosmotic stress activates an array of cellular detoxification mechanisms, including the high-osmolarity glycerol (HOG) pathway. We report here that vacuolar H(+)-ATPase (V-ATPase) activity helps provide osmotic tolerance in Saccharomyces cerevisiae. V-ATPase subunit genes exhibit complex haploinsufficiency interactions with HOG pathway components. vma mutants lacking V-ATPase function are sensitive to high concentrations of salt and exhibit Hog1p activation even at low salt concentrations, as demonstrated by phosphorylation of Hog1p, a shift in Hog1-green fluorescent protein localization, transcriptional activation of a subset of HOG pathway effectors, and transcriptional inhibition of parallel mitogen-activated protein kinase pathway targets. vma2Delta hog1Delta and vma3Delta pbs2Delta double mutants have a synthetic growth phenotype, poor salt tolerance, and an aberrant, hyper-elongated morphology on solid media, accompanied by activation of a filamentous response element-LacZ construct, indicating cross talk into the filamentous growth pathway. Vacuoles isolated from wild-type cells briefly exposed to salt show higher levels of V-ATPase activity, and Na(+)/H(+) exchange in isolated vacuolar vesicles suggests a biochemical basis for the genetic interactions observed. V-ATPase activity is upregulated during salt stress by increasing assembly of the catalytic V(1) sector with the membrane-bound V(o) sector. Together, these data suggest that the V-ATPase acts in parallel with the HOG pathway in order to mediate salt detoxification. PMID- 22210833 TI - Omecamtiv mecarbil: a promising new drug in systolic heart failure. PMID- 22210834 TI - Salmonella enteritidis Rck-mediated invasion requires activation of Rac1, which is dependent on the class I PI 3-kinases-Akt signaling pathway. AB - The Salmonella outer membrane protein Rck mediates a Zipper-like entry mechanism controlled by Rac, the Arp2/3 complex, and actin polymerization. However, little is known about the early steps leading to Rac activation and Rck-mediated internalization. The use of pharmacological inhibitors or PI 3-kinase dominant negative mutant induced more than 80% less invasion without affecting attachment. Moreover, Rck-mediated internalization caused an increase in the association of p85 with at least one tyrosine-phosphorylated protein, indicating that class I PI 3-kinase activity was stimulated. We also report that this PI 3-kinase activity is essential for Rac1 activation. However, Rac recruitment at the Rck-mediated entry site was independent of its activation. Using a pharmacological approach or Akt-knockout cells, we also demonstrated that Akt was phosphorylated in response to Rck-mediated internalization as demonstrated by immunoblotting analysis and that all three Akt isoforms were required during this process. Overall, our results describe a signaling pathway involving tyrosine phosphorylation, class I PI 3-kinase, Akt activation, and Rac activation, leading to Rck-dependent Zipper entry. The specificity of this signaling pathway with regard to that of the type 3 secretion system, which is the other invasion process of Salmonella, is discussed. PMID- 22210832 TI - Transcriptome and functional analysis of mating in the basidiomycete Schizophyllum commune. AB - In this study, we undertook a functional characterization and transcriptome analysis that enabled a comprehensive study of the mating type loci of the mushroom Schizophyllum commune. Induced expression of both the bar2 receptor and the bap2(2) pheromone gene within 6 to 12 h after mates' contact was demonstrated by quantitative real-time PCR. Similar temporal expression patterns were confirmed for the allelic bbr1 receptor and bbp1 pheromone-encoding genes by Northern hybridization. Interestingly, the fusion of clamp connections to the subterminal cell was delayed in mating interactions in which one of the compatible partners expressed the bar2 receptor with a truncated C terminus. This developmental delay allowed the visualization of a green fluorescent protein (Gfp)-labeled truncated receptor at the cell periphery, consistent with a localization in the plasma membrane of unfused pseudoclamps. This finding does not support hypotheses envisioning a receptor localization to the nuclear membrane facilitating recognition between the two different nuclei present in each dikaryotic cell. Rather, Gfp fluorescence observed in such pseudoclamps indicated a role of receptor-pheromone interaction in clamp fusion. Transcriptome changes associated with mating interactions were analyzed in order to identify a role for pheromone-receptor interactions. We detected a total of 89 genes that were transcriptionally regulated in a mating type locus A-dependent manner, employing a cutoff of 5-fold changes in transcript abundance. Upregulation in cell cycle-related genes and downregulation of genes involved in metabolism were seen with this set of experiments. In contrast, mating type locus B-dependent transcriptome changes were observed in 208 genes, with a specific impact on genes related to cell wall and membrane metabolism, stress response, and the redox status of the cell. PMID- 22210835 TI - Isolation and characterization of EST-SSR markers in Schima mertensiana (Theaceae) using pyrosequencing technology. AB - PREMISE OF THE STUDY: Microsatellite or simple sequence repeat (SSR) markers from expressed sequence tags (ESTs) in Schima mertensiana, an evergreen tree that is endemic to the Bonin Islands, were developed to facilitate evaluation of the species's population genetic structure. METHODS AND RESULTS: Using 149831 ESTs derived by pyrosequencing S. mertensiana complementary DNA (cDNA), 683 EST-SSRs were developed, 48 of which were tested for amplification. Thirty of the 48 showed clear amplification and detected polymorphism in sampled populations, with mean expected heterozygosity at the amplified loci ranging from 0.045 to 0.874 (average 0.545). CONCLUSIONS: The markers developed in this study can be used for future studies of the genetic structure of S. mertensiana and related species. PMID- 22210836 TI - Rapid development of microsatellite markers for Pandanus boninensis (Pandanaceae) by pyrosequencing technology. AB - PREMISE OF THE STUDY: To facilitate rapid development of microsatellite or simple sequence repeat (SSR) markers, an expressed sequence tags (EST) database was constructed for Pandanus boninensis, an evergreen tree endemic to the Bonin Islands, using pyrosequencing technology. METHODS AND RESULTS: We designed primers for 340 EST-SSRs identified from 109620 pyrosequencing reads, 48 of which were tested for PCR amplification. Thirty-four primers provided clear amplification, and 26 of those 34 displayed clear polymorphic patterns in sampled populations, with mean expected heterozygosity at the amplified loci ranging from 0.022 to 0.742 (average 0.262). CONCLUSIONS: The developed markers are promising tools for future genetic studies of P. boninensis and related species. PMID- 22210837 TI - Mechanical properties of wood disproportionately increase with increasing density. AB - PREMISE OF STUDY: Prior work using a large data set has shown that the mechanical properties of wood disproportionately increase with increasing wood density across diverse species, e.g., stems composed of denser wood are stiffer and stronger than stems with equivalent cross-sections composed of less dense wood. However, an alternative approach, introducing the precondition of constant construction cost for the same data set, adduces that for any given construction cost, stems composed of lesser dense woods are stiffer and stronger then stems composed of denser woods. METHODS: We evaluated these two approaches using generic allometric principles and the same large data set. KEY RESULTS: This evaluation shows that construction costs cannot be constant over an entire ensemble of stems composed of different species of wood. For any specified construction cost (denoted by a k-value), only a particular subgroup of stems is addressed. The conclusions derived for this subgroup cannot be generalized to the entire ensemble of stems composed of different species of wood. CONCLUSION: Stems composed of denser wood are, on average as stiff and strong, or stiffer and stronger than stems with equivalent cross-sections composed of less dense wood. Denser wood may have a higher carbon construction cost, but its mechanical benefits likely outweigh the extra cost. PMID- 22210838 TI - Genetic evidence for glacial refugia of the temperate tree Eucryphia cordifolia (Cunoniaceae) in southern South America. AB - PREMISE OF THE STUDY: The temperate forests of southern South America were greatly affected by glaciations. Previous studies have indicated that some cold tolerant tree species were able to survive glacial periods in small, ice-free patches within glaciated areas in the Andes and in southern Patagonia. Here we asked whether populations of the mesothermic species Eucryphia cordifolia also were able to survive glaciations in these areas or only in unglaciated coastal areas. METHODS: The chloroplast intergenic spacer trnV-ndhC was sequenced for 150 individuals from 22 locations. Genetic data were analyzed (standard indexes of genetic diversity, a haplotype network, and genetic differentiation) in a geographical context. KEY RESULTS: Two of the nine haplotypes detected were widespread in high frequency across the entire range of the species. The highest levels of genetic diversity were found around 40 degrees S, decreasing sharply northward and more moderately southward. No differences in genetic diversity were found between Andean and coastal populations. Notably, seven haplotypes were found in a small area of the Coast Range known as the Cordillera Pelada (40 degrees S). The differentiation coefficients G(ST) and N(ST) revealed that most of the genetic variation detected was due to variation within populations. CONCLUSIONS: The low levels of population differentiation and the high genetic diversity found in the Cordillera Pelada suggest that this area was the main refugium for E. cordifolia during glaciations. Nevertheless, given the high levels of genetic diversity found in some Andean populations, we cannot discount that some local populations also survived the glaciation in the Andes. PMID- 22210839 TI - The cuticle on the gametophyte calyptra matures before the sporophyte cuticle in the moss Funaria hygrometrica (Funariaceae). AB - PREMISE OF THE STUDY: In vascular plants, leaf primordia prevent desiccation of the shoot apical meristem. Lacking leaves, the undifferentiated moss sporophyte apex is covered by the calyptra, a cap of maternal gametophyte tissue that is hypothesized to function in desiccation protection. Herein, we compare cuticle development on the calyptra and sporophyte to assess the calyptra's potential to protect the sporophyte from desiccation. As the first comprehensive study of moss sporophyte cuticle development, this research broadens our perspectives on cuticle development and evolution across embryophytes. METHODS: Calyptrae and sporophytes at nine developmental stages were collected from a laboratory-grown population of the moss Funaria hygrometrica. Tissues were embedded, sectioned, then examined using transmission electron microscopy. Epidermal cells were measured for thickness of the cuticle layers, cell wall thickness, and lumen size. KEY RESULTS: The calyptra cuticle develops precociously and reaches maturity before the sporophyte cuticle. Calyptrae are covered by a four-layered cuticle at all stages, whereas sporophyte cuticle maturation is delayed until sporangium formation. The development and thickening of the sporophyte cuticle occurs in an acropetal wave. CONCLUSIONS: A multilayered calyptra cuticle at the earliest developmental stages is consistent with its ability to protect the immature sporophyte from desiccation. Young sporophytes lack a complex cuticle and thus may require protection, whereas in older sporophytes a mature cuticle develops. The moss calyptra is not a vestigial structure, but rather the calyptra's role in preventing desiccation offers a functional explanation for calyptra retention during the 450 Myr of moss evolution. PMID- 22210840 TI - Anatomical, biochemical, and photosynthetic responses to recent allopolyploidy in Glycine dolichocarpa (Fabaceae). AB - PREMISE OF THE STUDY: Previous studies have shown that polyploidy has pronounced effects on photosynthesis. Most of these studies have focused on synthetic or recently formed autopolyploids, and comparatively little is known about the integrated effects of natural allopolyploidy, which involves hybridity and genome doubling and often incorporates multiple genotypes through recurrent origins and lineage recombination. METHODS: Glycine dolichocarpa (designated T2) is a natural allotetraploid with multiple origins. We quantified 21 anatomical, biochemical, and physiological phenotypes relating to photosynthesis in T2 and its diploid progenitors, G. tomentella (D3) and G. syndetika (D4). To assess how direction of cross affects these phenotypes, we included three T2 accessions having D3-like plastids (T2(D3)) and two accessions having D4-like plastids (T2(D4)). KEY RESULTS: T2 accessions were transgressive (more extreme than any diploid accession) for 17 of 21 phenotypes, and species means differed significantly in T2 vs. both progenitors for four of 21 phenotypes (higher for guard cell length, electron transport capacity [J(max)] per palisade cell, and J(max) per mesophyll cell; lower for palisade cells per unit leaf area). Within T2, four of 21 parameters differed significantly between T2(D3) and T2(D4) (palisade cell volume; chloroplast number and volume per unit leaf area; and J(max) per unit leaf area). CONCLUSIONS: T2 is characterized by transgressive photosynthesis related phenotypes (including an ca. 2-fold increase in J(max) per cell), as well as by significant intraspecies variation correlating with plastid type. These data indicate prominent roles for both nucleotypic effects and cytoplasmic factors in photosynthetic responses to allopolyploidy. PMID- 22210841 TI - Variation in amine composition in plant species: how it integrates macroevolutionary and environmental signals. AB - PREMISE OF THE STUDY: While plants show lineage-specific differences in metabolite composition, plant metabolites are also known to vary in response to the environment. The extent to which these different determinants of metabolite composition are mutually independent and recognizable is unknown. Moreover, the extent to which the metabolome can reconcile evolutionary constraint with the needs of the plant for rapid environmental response is unknown. We investigated these questions in plant species representing different phylogenetic lineages and growing in different subantarctic island environments. We studied their amines metabolites involved in plant response to environmental conditions. METHODS: Nine species were sampled under high salinity, water saturation, and altitude on the Kerguelen Islands. Their profiles of free aromatic, aliphatic, and acetyl conjugated amines were determined by HPLC. We related amine composition to species and environment using generalized discriminant analyses. KEY RESULTS: Amine composition differed significantly between species within the same environment, and the differences reflected phylogenetic positions. Moreover, across all species, amine metabolism differed between environments, and different lineages occupied different absolute positions in amine/environment space. Interestingly, all species had the same relative shifts in amine composition between environments. CONCLUSION: Our results indicate a similar response of amine composition to abiotic environments in distantly related angiosperms, suggesting environmental flexibility of species is maintained despite major differences in amine composition among lineages. These results aid understanding of how in nature the plant metabolome integrates ecology and evolution, thus providing primordial information on adaptive mechanisms of plant metabolism to climate change. PMID- 22210843 TI - Still rethinking the value of high wood density. AB - PREMISE OF THE STUDY: In a previous paper, we questioned the traditional interpretation of the advantages and disadvantages of high wood density (Functional Ecology 24: 701-705). Niklas and Spatz (American Journal of Botany 97: 1587-1594) challenged the biomechanical relevance of studying properties of dry wood, including dry wood density, and stated that we erred in our claims regarding scaling. METHODS: We first present the full derivation of our previous claims regarding scaling. We then examine how the fresh modulus of rupture and the elastic modulus scale with dry wood density and compare these scaling relationships with those for dry mechanical properties, using almost exactly the same data set analyzed by Niklas and Spatz. KEY RESULTS: The derivation shows that given our assumptions that the modulus of rupture and elastic modulus are both proportional to wood density, the resistance to bending is inversely proportional to wood density and strength is inversely proportional with the square root of wood density, exactly as we previously claimed. The analyses show that the elastic modulus of fresh wood scales proportionally with wood density (exponent 1.05, 95% CI 0.90-1.11) but that the modulus of rupture of fresh wood does not, scaling instead with the 1.25 power of wood density (CI 1.18-1.31). CONCLUSIONS: The deviation from proportional scaling for modulus of rupture is so small that our central conclusion remains correct: for a given construction cost, trees with lower wood density have higher strength and higher resistance to bending. PMID- 22210842 TI - Molecular phylogeny of Heteroplacidium, Placidium, and related catapyrenioid genera (Verrucariaceae, lichen-forming Ascomycota). AB - PREMISE OF THE STUDY: Verrucariaceae is a fascinating lineage of lichenized fungi for which generic and species delimitation is problematic due to the scarcity of discriminating morphological characters. Members of this family inhabit rocks, but they further colonize soils, barks, mosses, and other lichens. Our aim is to contribute to the DNA-based inference of the Verrucariaceae tree of life and to investigate characters that could be useful for proposing a more natural classification. We focused on catapyrenioid genera, which are often part of biological soil crusts, a cryptogam-dominated ecosystem contributing to soil formation and stabilization in arid environments. Understanding their evolution and taxonomy is essential to assess their roles in these fragile and important ecosystems. METHODS: A multigene phylogeny of Verrucariaceae including catapyrenioid genera is presented. We further examined the phylogenetic relationships among members of Heteroplacidium and Placidium. The evolution of selected characters was inferred using the latter phylogeny. KEY RESULTS: Anthracocarpon and Involucropyrenium were closely related to Endocarpon. Placidium comprised two monophyletic clades sister to Heteroplacidium. Inferred ancestral states of diagnostic characters revealed that the type of medulla and the pycnidia location were homoplasious within the Placidium clade. In contrast, the presence of rhizines was a synapomorphy for Clavascidium. CONCLUSIONS: Our results provide new information on the usefulness of characters for delineating groups in Verrucariaceae. Taxonomic changes are proposed to reflect more natural groupings: Heteroplacidium podolepis is transferred to Placidium, and Clavascidium is recognized as a different genus. Eight new combinations are proposed for Clavascidium. PMID- 22210844 TI - Aeroterrestrial Coleochaete (Streptophyta, Coleochaetales) models early plant adaptation to land. AB - PREMISE OF THE STUDY: The streptophyte water-to-land transition was a pivotal, but poorly understood event in Earth history. While some early-diverging modern streptophyte algae are aeroterrestrial (living in subaerial habitats), aeroterrestrial survival had not been tested for Coleochaete, widely regarded as obligately aquatic and one of the extant green algal genera most closely related to embryophytes. This relationship motivated a comparison of aeroterrestrial Coleochaete to lower Paleozoic microfossils whose relationships have been uncertain. METHODS: We tested the ability of two species of the experimentally tractable, complex streptophyte algal genus Coleochaete Breb. to (1) grow and reproduce when cultivated under conditions that mimic humid subaerial habitats, (2) survive desiccation for some period of time, and (3) produce degradation resistant remains comparable to enigmatic Cambrian microfossils. KEY RESULTS: When grown on mineral agar media or on quartz sand, both species displayed bodies structurally distinct from those expressed in aquatic habitats. Aeroterrestrial Coleochaete occurred as hairless, multistratose, hemispherical bodies having unistratose lobes or irregular clusters of cells with thick, layered, and chemically resistant walls that resemble certain enigmatic lower Paleozoic microfossils. Whether grown under humid conditions or air-dried for a week, then exposed to liquid water, aeroterrestrial Coleochaete produced typical asexual zoospores and germlings. Cells that had been air-dried for periods up to several months maintained their integrity and green pigmentation. CONCLUSIONS: Features of modern aeroterrestrial Coleochaete suggest that ancient complex streptophyte algae could grow and reproduce in moist subaerial habitats, persist through periods of desiccation, and leave behind distinctive microfossil remains. PMID- 22210845 TI - The proliferation rate paradox in antimitotic chemotherapy. AB - Cytotoxic cancer chemotherapy drugs are believed to gain selectivity by targeting cells that proliferate rapidly. However, the proliferation rate is low in many chemosensitive human cancers, and it is not clear how a drug that only kills dividing cells could promote tumor regression. Four potential solutions to this "proliferation rate paradox" are discussed for the microtubule-stabilizing drug paclitaxel: drug retention in tumors, killing of quiescent cells, targeting of noncancer cells in the tumor, and bystander effects. Testing these potential mechanisms of drug action will facilitate rational improvement of antimitotic chemotherapy and perhaps cytotoxic chemotherapy more generally. PMID- 22210846 TI - Polarity sets the stage for cytokinesis. AB - Cell polarity is important for a number of processes, from chemotaxis to embryogenesis. Recent studies suggest a new role for polarity in the orchestration of events during the final cell separation step of cell division called abscission. Abscission shares several features with cell polarization, including rearrangement of phosphatidylinositols, reorganization of microtubules, and trafficking of exocyst-associated membranes. Here we focus on how the canonical pathways for cell polarization and cell migration may play a role in spatiotemporal membrane trafficking events required for the final stages of cytokinesis. PMID- 22210847 TI - The Ca(2+) sensor stromal interaction molecule 1 (STIM1) is necessary and sufficient for the store-operated Ca(2+) entry function of transient receptor potential canonical (TRPC) 1 and 4 channels in endothelial cells. AB - We addressed the requirement for stromal interaction molecule 1 (STIM1), the endoplasmic reticulum (ER) Ca(2+)-sensor, and Orai1, a Ca(2+) selective channel, in regulating Ca(2+) entry through the store-operated channels mouse transient receptor potential canonical (TRPC) 4 or human TRPC1. Studies were made using murine and human lung endothelial cells (ECs) challenged with thrombin known to induce Ca(2+) entry via TRPC1/4. Deletion or knockdown of TRPC4 abolished Ca(2+) entry secondary to depletion of ER Ca(2+) stores, preventing the disruption of the endothelial barrier. Knockdown of STIM1 (but not of Orai1or Orai3) or expression of the dominant-negative STIM1(K684E-K685E) mutant in ECs also suppressed Ca(2+) entry secondary to store depletion. Ectopic expression of WT STIM1 or WT-Orai1 in TRPC4(-/-)-ECs failed to rescue Ca(2+) entry; however, WT TRPC4 expression in TRPC4(-/-)-ECs restored Ca(2+) entry indicating the requirement for TRPC4 in mediating store-operated Ca(2+) entry. Moreover, expression of the dominant-negative Orai1(R91W) mutant or Orai3(E81W) mutant in WT-ECs failed to prevent thrombin-induced Ca(2+) entry. In contrast, expression of the dominant-negative TRPC4(EE647-648KK) mutant in WT-ECs markedly reduced thrombin-induced Ca(2+) entry. In ECs expressing YFP-STIM1, ER-store Ca(2+) depletion induced formation of fluorescent membrane puncta in WT but not in TRPC4(-/-) cells, indicating that mobilization of STIM1 and engagement of its Ca(2+) sensing function required TRPC4 expression. Coimmunoprecipitation studies showed coupling of TRPC1 and TRPC4 with STIM1 on depletion of ER Ca(2+) stores. Thus, TRPC1 and TRPC4 can interact with STIM1 to form functional store-operated Ca(2+)-entry channels, which are essential for mediating Ca(2+) entry-dependent disruption of the endothelial barrier. PMID- 22210848 TI - Annual increments of juniper dwarf shrubs above the tree line on the central Tibetan Plateau: a useful climatic proxy. AB - BACKGROUND AND AIMS: Dendroclimatology is playing an important role in understanding past climatic changes on the Tibetan Plateau. Forests, however, are mainly confined to the eastern Tibetan Plateau. On the central Tibetan Plateau, in contrast, shrubs and dwarf shrubs need to be studied instead of trees as a source of climate information. The objectives of this study were to check the dendrochronological potential of the dwarf shrub Wilson juniper (Juniperus pingii var. wilsonii) growing from 4740 to 4780 m a.s.l. and to identify the climatic factors controlling its radial growth. METHODS: Forty-three discs from 33 stems of Wilson juniper were sampled near the north-eastern shore of the Nam Co (Heavenly Lake). Cross-dating was performed along two directions of each stem, avoiding the compression-wood side as far as possible. A ring-width chronology was developed after a negative exponential function or a straight line of any slope had been fit to the raw measurements. Then, correlations were calculated between the standard ring-width chronology and monthly climate data recorded by a weather station around 100 km away. KEY RESULTS: Our study has shown high dendrochronological potential of Wilson juniper, based on its longevity (one individual was 324 years old), well-defined growth rings, reliable cross-dating between individuals and distinct climatic signals reflected by the ring-width variability. Unlike dwarf shrubs in the circum-arctic tundra ecosystem which positively responded to above-average temperature in the growing season, moisture turned out to be growth limiting for Wilson juniper, particularly the loss of moisture caused by high maximum temperatures in May-June. CONCLUSIONS: Because of the wide distribution of shrub and dwarf shrub species on the central Tibetan Plateau, an exciting prospect was opened up to extend the presently existing tree ring networks far up into one of the largest tundra regions of the world. PMID- 22210849 TI - New perspectives on the evolution of plant mating systems. AB - BACKGROUND: The remarkable diversity of mating patterns and sexual systems in flowering plants has fascinated evolutionary biologists for more than a century. Enduring questions about this topic include why sexual polymorphisms have evolved independently in over 100 plant families, and why proportions of self- and cross fertilization often vary dramatically within and among populations. Important new insights concerning the evolutionary dynamics of plant mating systems have built upon a strong foundation of theoretical models and innovative field and laboratory experiments. However, as the pace of advancement in this field has accelerated, it has become increasingly difficult for researchers to follow developments outside their primary area of research expertise. SCOPE: In this Viewpoint paper we highlight three important themes that span and integrate different subdisciplines: the changes in morphology, phenology, and physiology that accompany the transition to selfing; the evolutionary consequences of pollen pool diversity in flowering plants; and the evolutionary dynamics of sexual polymorphisms. We also highlight recent developments in molecular techniques that will facilitate more efficient and cost-effective study of mating patterns in large natural populations, research on the dynamics of pollen transport, and investigations on the genetic basis of sexual polymorphisms. This Viewpoint also serves as the introduction to a Special Issue on the Evolution of Plant Mating Systems. The 15 papers in this special issue provide inspiring examples of recent discoveries, and glimpses of exciting developments yet to come. PMID- 22210850 TI - Maximum likelihood inference implies a high, not a low, ancestral haploid chromosome number in Araceae, with a critique of the bias introduced by 'x'. AB - BACKGROUND AND AIMS: For 84 years, botanists have relied on calculating the highest common factor for series of haploid chromosome numbers to arrive at a so called basic number, x. This was done without consistent (reproducible) reference to species relationships and frequencies of different numbers in a clade. Likelihood models that treat polyploidy, chromosome fusion and fission as events with particular probabilities now allow reconstruction of ancestral chromosome numbers in an explicit framework. We have used a modelling approach to reconstruct chromosome number change in the large monocot family Araceae and to test earlier hypotheses about basic numbers in the family. METHODS: Using a maximum likelihood approach and chromosome counts for 26 % of the 3300 species of Araceae and representative numbers for each of the other 13 families of Alismatales, polyploidization events and single chromosome changes were inferred on a genus-level phylogenetic tree for 113 of the 117 genera of Araceae. KEY RESULTS: The previously inferred basic numbers x = 14 and x = 7 are rejected. Instead, maximum likelihood optimization revealed an ancestral haploid chromosome number of n = 16, Bayesian inference of n = 18. Chromosome fusion (loss) is the predominant inferred event, whereas polyploidization events occurred less frequently and mainly towards the tips of the tree. CONCLUSIONS: The bias towards low basic numbers (x) introduced by the algebraic approach to inferring chromosome number changes, prevalent among botanists, may have contributed to an unrealistic picture of ancestral chromosome numbers in many plant clades. The availability of robust quantitative methods for reconstructing ancestral chromosome numbers on molecular phylogenetic trees (with or without branch length information), with confidence statistics, makes the calculation of x an obsolete approach, at least when applied to large clades. PMID- 22210851 TI - Seed banks on Attalea phalerata (Arecaceae) stems in the Pantanal wetland, Brazil. AB - BACKGROUND AND AIMS: Seeds can accumulate in the soil or elsewhere, such as on the stems of palms when these are covered by persistent sheaths. These sheaths could act as a safe site for some species. Here, we studied whether persistent sheaths of the palm Attalea phalerata (Arecaceae) are available sites for seed accumulation in the Pantanal wetland of Brazil. We also investigated whether the composition, richness and diversity of species of seeds in the persistent sheaths are determined by habitat (riparian forest and forest patches) and/or season (wet and dry). METHODS: All accumulated material was collected from ten persistent sheaths along the stems of 64 A. phalerata individuals (16 per habitat and 16 per season). The material was then individually inspected under a stereomicroscope to record seed species and number. KEY RESULTS: Of the 640 sheaths sampled, 65 % contained seeds (n = 3468). This seed bank included 75 species belonging to 12 families, and was primarily composed of small, endozoochoric seeds, with a few abundant species (Cecropia pachystachya and Ficus pertusa). Moraceae was the richest family (four species) and Urticaceae the most abundant (1594 seeds). Stems of A. phalerata in the riparian forest had 1.8 times more seeds and 1.3 times more species than those in forest patches. In the wet season we sampled 4.1 times more seeds and 2.2 more species on palm stems than in the dry season. Richness did not differ between habitats, but was higher in the wet season. Abundance was higher in forest patches and in the wet season. CONCLUSIONS: Attalea phalerata stems contain a rich seed bank, comparable to soil seed banks of tropical forests. As most of these seeds are not adapted to grow in flooding conditions, palm stems might be regarded as safe sites for seeds (and seedlings) to escape from the seasonal flooding of the Pantanal. PMID- 22210852 TI - A tight control treatment strategy aiming for remission in early rheumatoid arthritis is more effective than usual care treatment in daily clinical practice: a study of two cohorts in the Dutch Rheumatoid Arthritis Monitoring registry. AB - There is strong evidence from clinical trials that a 'treat to target' strategy is effective in reaching remission in rheumatoid arthritis (RA). However, the question is whether these results can be translated into daily clinical practice and clinical remission is a reachable target indeed. OBJECTIVE: The study aims to investigate whether in early RA a treatment strategy aiming at Disease Activity Score (DAS) 28 <2.6 is more effective than 'usual care' treatment for reaching clinical remission after 1 year. METHODS: Two early RA inception cohorts from two different regions including patients who fulfilled the American College of Rheumatology criteria for RA were compared. Patients in the tight-control cohort (n=126) were treated according to a DAS28-driven step-up treatment strategy starting with methotrexate, addition of sulphasalazine (SSZ) and exchange of SSZ by anti-tumour necrosis factor in case of failure. Patients in the usual-care cohort (n=126) were treated with methotrexate or SSZ, without DAS28-guided treatment decisions. The primary outcome was the percentage remission (DAS28<2.6) at 1 year. Time to first remission and change in DAS28 were secondary outcomes. RESULTS: After 1 year, 55% of tight-control patients had a DAS28<2.6 versus 30% of usual care patients (OR 3.1, 95% CI 1.8 to 5.2). The median time to first remission was 25 weeks for tight control and more than 52 weeks for usual care (p<0.0001). The DAS28 decreased with -2.5 in tight control and -1.5 in usual care (p<0.0001). CONCLUSION: In early RA, a tight control treatment strategy aiming for remission leads to more rapid DAS28 remission and higher percentages of remission after 1 year than does a usual care treatment. PMID- 22210853 TI - Differential expression--the next generation and beyond. AB - RNA-sequencing (RNA-seq) technologies have not only pushed the boundaries of science, but also pushed the computational and analytic capacities of many laboratories. With respect to mapping and quantifying transcriptomes, RNA-seq has certainly established itself as the approach of choice. However, as the complexities of experiments continue to grow, there is still no standard practice that allows for design, processing, normalization, efficient dimension reduction and/or statistical analysis. With this in mind, we provide a brief review of some of the key challenges that are general to all RNA-seq experiments, namely experimental design, statistical analysis and dimensionality reduction. PMID- 22210854 TI - Affymetrix GeneChip microarray preprocessing for multivariate analyses. AB - Affymetrix GeneChip microarrays are the most widely used high-throughput technology to measure gene expression, and a wide variety of preprocessing methods have been developed to transform probe intensities reported by a microarray scanner into gene expression estimates. There have been numerous comparisons of these preprocessing methods, focusing on the most common analyses detection of differential expression and gene or sample clustering. Recently, more complex multivariate analyses, such as gene co-expression, differential co expression, gene set analysis and network modeling, are becoming more common; however, the same preprocessing methods are typically applied. In this article, we examine the effect of preprocessing methods on some of these multivariate analyses and provide guidance to the user as to which methods are most appropriate. PMID- 22210855 TI - Preferred analysis methods for single genomic regions in RNA sequencing revealed by processing the shape of coverage. AB - The informational content of RNA sequencing is currently far from being completely explored. Most of the analyses focus on processing tables of counts or finding isoform deconvolution via exon junctions. This article presents a comparison of several techniques that can be used to estimate differential expression of exons or small genomic regions of expression, based on their coverage function shapes. The problem is defined as finding the differentially expressed exons between two samples using local expression profile normalization and statistical measures to spot the differences between two profile shapes. Initial experiments have been done using synthetic data, and real data modified with synthetically created differential patterns. Then, 160 pipelines (5 types of generator * 4 normalizations * 8 difference measures) are compared. As a result, the best analysis pipelines are selected based on linearity of the differential expression estimation and the area under the ROC curve. These platform independent techniques have been implemented in the Bioconductor package rnaSeqMap. They point out the exons with differential expression or internal splicing, even if the counts of reads may not show this. The areas of application include significant difference searches, splicing identification algorithms and finding suitable regions for QPCR primers. PMID- 22210856 TI - Structural changes of an abasic site in duplex DNA affect noncovalent binding of the spin label c. AB - The influence of structural changes of an abasic site in duplex DNA on noncovalent and site-directed spin labeling (NC-SDSL) of the spin label c were examined with electron paramagnetic resonance (EPR) spectroscopy. The binding affinities of c to sixteen different DNA duplexes containing all possible sequences immediately flanking the abasic site were determined and the results showed that the binding of c is highly flanking-sequence dependent. In general, a 5'-dG nucleotide favors the binding of the spin label. In particular, 5'-d(G__T) was the best binding sequence whereas 5'-d(C__T) showed the lowest affinity. Changing the structure of the abasic site linker from a tetrahydrofuran analog (F) to the anucleosidic C(3)-spacer (C(3)) does not appreciably affect the binding of c to the abasic site. For efficient binding of c, the abasic site needs to be located at least four base pairs away from the duplex end. Introducing a methyl substituent at N3 of c did not change the binding affinity, but a decreased binding was observed for both N3-ethyl and -propyl groups. These results will guide the design of abasic site receptors and spin label ligands for NC-SDSL of nucleic acids. PMID- 22210858 TI - Efficient large-scale protein sequence comparison and gene matching to identify orthologs and co-orthologs. AB - Broadly, computational approaches for ortholog assignment is a three steps process: (i) identify all putative homologs between the genomes, (ii) identify gene anchors and (iii) link anchors to identify best gene matches given their order and context. In this article, we engineer two methods to improve two important aspects of this pipeline [specifically steps (ii) and (iii)]. First, computing sequence similarity data [step (i)] is a computationally intensive task for large sequence sets, creating a bottleneck in the ortholog assignment pipeline. We have designed a fast and highly scalable sort-join method (afree) based on k-mer counts to rapidly compare all pairs of sequences in a large protein sequence set to identify putative homologs. Second, availability of complex genomes containing large gene families with prevalence of complex evolutionary events, such as duplications, has made the task of assigning orthologs and co-orthologs difficult. Here, we have developed an iterative graph matching strategy where at each iteration the best gene assignments are identified resulting in a set of orthologs and co-orthologs. We find that the afree algorithm is faster than existing methods and maintains high accuracy in identifying similar genes. The iterative graph matching strategy also showed high accuracy in identifying complex gene relationships. Standalone afree available from http://vbc.med.monash.edu.au/~kmahmood/afree. EGM2, complete ortholog assignment pipeline (including afree and the iterative graph matching method) available from http://vbc.med.monash.edu.au/~kmahmood/EGM2. PMID- 22210857 TI - Transcription initiation factor DksA has diverse effects on RNA chain elongation. AB - Bacterial transcription factors DksA and GreB belong to a family of coiled-coil proteins that bind within the secondary channel of RNA polymerase (RNAP). These proteins display structural homology but play different regulatory roles. DksA disrupts RNAP interactions with promoter DNA and inhibits formation of initiation complexes, sensitizing rRNA synthesis to changes in concentrations of ppGpp and NTPs. Gre proteins remodel the RNAP active site and facilitate cleavage of the nascent RNA in elongation complexes. However, DksA and GreB were shown to have overlapping effects during initiation, and in vivo studies suggested that DksA may also function at post-initiation steps. Here we show that DksA has many features of an elongation factor: it inhibits both RNA chain extension and RNA shortening by exonucleolytic cleavage or pyrophosphorolysis and increases intrinsic termination in vitro and in vivo. However, DksA has no effect on Rho- or Mfd-mediated RNA release or nascent RNA cleavage in backtracked complexes, the regulatory target of Gre factors. Our results reveal that DksA effects on elongating RNAP are very different from those of GreB, suggesting that these regulators recognize distinct states of the transcription complex. PMID- 22210860 TI - In vitro experimental system for analysis of transcription-translation coupling. AB - Transcription and translation are coupled in bacteria, meaning that translation takes place co-transcriptionally. During transcription-translation, both machineries mutually affect each others' functions, which is important for regulation of gene expression. Analysis of interactions between RNA polymerase (RNAP) and the ribosome, however, are limited due to the lack of an in vitro experimental system. Here, we report the development of an in vitro transcription coupled to translation system assembled from purified components. The system allows controlled stepwise transcription and simultaneous stepwise translation of the nascent RNA, and permits investigation of the interactions of RNAP with the ribosome, as well as the effects of translation on transcription and transcription on translation. As an example of usage of this experimental system, we uncover complex effects of transcription-translation coupling on pausing of transcription. PMID- 22210859 TI - Acute depletion of Tet1-dependent 5-hydroxymethylcytosine levels impairs LIF/Stat3 signaling and results in loss of embryonic stem cell identity. AB - The TET family of FE(II) and 2-oxoglutarate-dependent enzymes (Tet1/2/3) promote DNA demethylation by converting 5-methylcytosine to 5-hydroxymethylcytosine (5hmC), which they further oxidize into 5-formylcytosine and 5-carboxylcytosine. Tet1 is robustly expressed in mouse embryonic stem cells (mESCs) and has been implicated in mESC maintenance. Here we demonstrate that, unlike genetic deletion, RNAi-mediated depletion of Tet1 in mESCs led to a significant reduction in 5hmC and loss of mESC identity. The differentiation phenotype due to Tet1 depletion positively correlated with the extent of 5hmC loss. Meta-analyses of genomic data sets suggested interaction between Tet1 and leukemia inhibitory factor (LIF) signaling. LIF signaling is known to promote self-renewal and pluripotency in mESCs partly by opposing MAPK/ERK-mediated differentiation. Withdrawal of LIF leads to differentiation of mESCs. We discovered that Tet1 depletion impaired LIF-dependent Stat3-mediated gene activation by affecting Stat3's ability to bind to its target sites on chromatin. Nanog overexpression or inhibition of MAPK/ERK signaling, both known to maintain mESCs in the absence of LIF, rescued Tet1 depletion, further supporting the dependence of LIF/Stat3 signaling on Tet1. These data support the conclusion that analysis of mESCs in the hours/days immediately following efficient Tet1 depletion reveals Tet1's normal physiological role in maintaining the pluripotent state that may be subject to homeostatic compensation in genetic models. PMID- 22210861 TI - Recognition of dual symmetry by the controller protein C.Esp1396I based on the structure of the transcriptional activation complex. AB - The controller protein C.Esp1396I regulates the timing of gene expression of the restriction-modification (RM) genes of the RM system Esp1396I. The molecular recognition of promoter sequences by such transcriptional regulators is poorly understood, in part because the DNA sequence motifs do not conform to a well defined symmetry. We report here the crystal structure of the controller protein bound to a DNA operator site. The structure reveals how two different symmetries within the operator are simultaneously recognized by the homo-dimeric protein, underpinned by a conformational change in one of the protein subunits. The recognition of two different DNA symmetries through movement of a flexible loop in one of the protein subunits may represent a general mechanism for the recognition of pseudo-symmetric DNA sequences. PMID- 22210862 TI - Role of polynucleotide kinase/phosphatase in mitochondrial DNA repair. AB - Mutations in mitochondrial DNA (mtDNA) are implicated in a broad range of human diseases and in aging. Compared to nuclear DNA, mtDNA is more highly exposed to oxidative damage due to its proximity to the respiratory chain and the lack of protection afforded by chromatin-associated proteins. While repair of oxidative damage to the bases in mtDNA through the base excision repair pathway has been well studied, the repair of oxidatively induced strand breaks in mtDNA has been less thoroughly examined. Polynucleotide kinase/phosphatase (PNKP) processes strand-break termini to render them chemically compatible for the subsequent action of DNA polymerases and ligases. Here, we demonstrate that functionally active full-length PNKP is present in mitochondria as well as nuclei. Downregulation of PNKP results in an accumulation of strand breaks in mtDNA of hydrogen peroxide-treated cells. Full restoration of repair of the H(2)O(2) induced strand breaks in mitochondria requires both the kinase and phosphatase activities of PNKP. We also demonstrate that PNKP contains a mitochondrial targeting signal close to the C-terminus of the protein. We further show that PNKP associates with the mitochondrial protein mitofilin. Interaction with mitofilin may serve to translocate PNKP into mitochondria. PMID- 22210864 TI - MicroRNA-1 is a candidate tumor suppressor and prognostic marker in human prostate cancer. AB - We previously reported that miR-1 is among the most consistently down-regulated miRs in primary human prostate tumors. In this follow-up study, we further corroborated this finding in an independent data set and made the novel observation that miR-1 expression is further reduced in distant metastasis and is a candidate predictor of disease recurrence. Moreover, we performed in vitro experiments to explore the tumor suppressor function of miR-1. Cell-based assays showed that miR-1 is epigenetically silenced in human prostate cancer. Overexpression of miR-1 in these cells led to growth inhibition and down regulation of genes in pathways regulating cell cycle progression, mitosis, DNA replication/repair and actin dynamics. This observation was further corroborated with protein expression analysis and 3'-UTR-based reporter assays, indicating that genes in these pathways are either direct or indirect targets of miR-1. A gene set enrichment analysis revealed that the miR-1-mediated tumor suppressor effects are globally similar to those of histone deacetylase inhibitors. Lastly, we obtained preliminary evidence that miR-1 alters the cellular organization of F actin and inhibits tumor cell invasion and filipodia formation. In conclusion, our findings indicate that miR-1 acts as a tumor suppressor in prostate cancer by influencing multiple cancer-related processes and by inhibiting cell proliferation and motility. PMID- 22210863 TI - An integer linear programming approach for finding deregulated subgraphs in regulatory networks. AB - Deregulation of cell signaling pathways plays a crucial role in the development of tumors. The identification of such pathways requires effective analysis tools that facilitate the interpretation of expression differences. Here, we present a novel and highly efficient method for identifying deregulated subnetworks in a regulatory network. Given a score for each node that measures the degree of deregulation of the corresponding gene or protein, the algorithm computes the heaviest connected subnetwork of a specified size reachable from a designated root node. This root node can be interpreted as a molecular key player responsible for the observed deregulation. To demonstrate the potential of our approach, we analyzed three gene expression data sets. In one scenario, we compared expression profiles of non-malignant primary mammary epithelial cells derived from BRCA1 mutation carriers and of epithelial cells without BRCA1 mutation. Our results suggest that oxidative stress plays an important role in epithelial cells of BRCA1 mutation carriers and that the activation of stress proteins may result in avoidance of apoptosis leading to an increased overall survival of cells with genetic alterations. In summary, our approach opens new avenues for the elucidation of pathogenic mechanisms and for the detection of molecular key players. PMID- 22210865 TI - Modeling community-wide molecular networks of multicellular systems. AB - MOTIVATION: Multicellular systems, such as tissues, are composed of different cell types that form a heterogeneous community. Behavior of these systems is determined by complex regulatory networks within (intracellular networks) and between (intercellular networks) cells. Increasingly more studies are applying genome-wide experimental approaches to delineate the contributions of individual cell types (e.g. stromal, epithelial, vascular cells) to collective behavior of heterogeneous cell communities (e.g. tumors). Although many computational methods have been developed for analyses of intracellular networks based on genome-scale data, these efforts have not been extended toward analyzing genomic data from heterogeneous cell communities. RESULTS: Here, we propose a network-based approach for analyses of genome-scale data from multiple cell types to extract community-wide molecular networks comprised of intra- and intercellular interactions. Intercellular interactions in this model can be physical interactions between proteins or indirect interactions mediated by secreted metabolites of neighboring cells. Applying this method on data from a recent study on xenograft mouse models of human lung adenocarcinoma, we uncover an extensive network of intra- and intercellular interactions involved in the acquired resistance to angiogenesis inhibitors. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22210866 TI - influx_s: increasing numerical stability and precision for metabolic flux analysis in isotope labelling experiments. AB - MOTIVATION: The problem of stationary metabolic flux analysis based on isotope labelling experiments first appeared in the early 1950s and was basically solved in early 2000s. Several algorithms and software packages are available for this problem. However, the generic stochastic algorithms (simulated annealing or evolution algorithms) currently used in these software require a lot of time to achieve acceptable precision. For deterministic algorithms, a common drawback is the lack of convergence stability for ill-conditioned systems or when started from a random point. RESULTS: In this article, we present a new deterministic algorithm with significantly increased numerical stability and accuracy of flux estimation compared with commonly used algorithms. It requires relatively short CPU time (from several seconds to several minutes with a standard PC architecture) to estimate fluxes in the central carbon metabolism network of Escherichia coli. AVAILABILITY: The software package influx_s implementing this algorithm is distributed under an OpenSource licence at http://metasys.insa toulouse.fr/software/influx/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22210867 TI - CytoSEED: a Cytoscape plugin for viewing, manipulating and analyzing metabolic models created by the Model SEED. AB - CytoSEED is a Cytoscape plugin for viewing, manipulating and analyzing metabolic models created using the Model SEED. The CytoSEED plugin enables users of the Model SEED to create informative visualizations of the reaction networks generated for their organisms of interest. These visualizations are useful for understanding organism-specific biochemistry and for highlighting the results of flux variability analysis experiments. PMID- 22210868 TI - VarSifter: visualizing and analyzing exome-scale sequence variation data on a desktop computer. AB - VarSifter is a graphical software tool for desktop computers that allows investigators of varying computational skills to easily and quickly sort, filter, and sift through sequence variation data. A variety of filters and a custom query framework allow filtering based on any combination of sample and annotation information. By simplifying visualization and analyses of exome-scale sequence variation data, this program will help bring the power and promise of massively parallel DNA sequencing to a broader group of researchers. AVAILABILITY AND IMPLEMENTATION: VarSifter is written in Java, and is freely available in source and binary versions, along with a User Guide, at http://research.nhgri.nih.gov/software/VarSifter/. PMID- 22210870 TI - Approximating the set of local minima in partial RNA folding landscapes. AB - MOTIVATION: We study a stochastic method for approximating the set of local minima in partial RNA folding landscapes associated with a bounded-distance neighbourhood of folding conformations. The conformations are limited to RNA secondary structures without pseudoknots. The method aims at exploring partial energy landscapes pL induced by folding simulations and their underlying neighbourhood relations. It combines an approximation of the number of local optima devised by Garnier and Kallel (2002) with a run-time estimation for identifying sets of local optima established by Reeves and Eremeev (2004). RESULTS: The method is tested on nine sequences of length between 50 nt and 400 nt, which allows us to compare the results with data generated by RNAsubopt and subsequent barrier tree calculations. On the nine sequences, the method captures on average 92% of local minima with settings designed for a target of 95%. The run-time of the heuristic can be estimated by O(n(2)Dnulnnu), where n is the sequence length, nu is the number of local minima in the partial landscape pL under consideration and D is the maximum number of steepest descent steps in attraction basins associated with pL. PMID- 22210869 TI - Small-molecule inhibitor starting points learned from protein-protein interaction inhibitor structure. AB - MOTIVATION: Protein-protein interactions (PPIs) are a promising, but challenging target for pharmaceutical intervention. One approach for addressing these difficult targets is the rational design of small-molecule inhibitors that mimic the chemical and physical properties of small clusters of key residues at the protein-protein interface. The identification of appropriate clusters of interface residues provides starting points for inhibitor design and supports an overall assessment of the susceptibility of PPIs to small-molecule inhibition. RESULTS: We extract Small-Molecule Inhibitor Starting Points (SMISPs) from protein-ligand and protein-protein complexes in the Protein Data Bank (PDB). These SMISPs are used to train two distinct classifiers, a support vector machine and an easy to interpret exhaustive rule classifier. Both classifiers achieve better than 70% leave-one-complex-out cross-validation accuracy and correctly predict SMISPs of known PPI inhibitors not in the training set. A PDB-wide analysis suggests that nearly half of all PPIs may be susceptible to small molecule inhibition. PMID- 22210871 TI - SNPdbe: constructing an nsSNP functional impacts database. AB - Many existing databases annotate experimentally characterized single nucleotide polymorphisms (SNPs). Each non-synonymous SNP (nsSNP) changes one amino acid in the gene product (single amino acid substitution;SAAS). This change can either affect protein function or be neutral in that respect. Most polymorphisms lack experimental annotation of their functional impact. Here, we introduce SNPdbe-SNP database of effects, with predictions of computationally annotated functional impacts of SNPs. Database entries represent nsSNPs in dbSNP and 1000 Genomes collection, as well as variants from UniProt and PMD. SAASs come from >2600 organisms; 'human' being the most prevalent. The impact of each SAAS on protein function is predicted using the SNAP and SIFT algorithms and augmented with experimentally derived function/structure information and disease associations from PMD, OMIM and UniProt. SNPdbe is consistently updated and easily augmented with new sources of information. The database is available as an MySQL dump and via a web front end that allows searches with any combination of organism names, sequences and mutation IDs. AVAILABILITY: http://www.rostlab.org/services/snpdbe. PMID- 22210872 TI - Expression of BMPRIA on human thymic NK cell precursors: role of BMP signaling in intrathymic NK cell development. AB - The bone morphogenetic protein (BMP) signaling pathway regulates survival, proliferation, and differentiation of several cell types in multiple tissues, including the thymus. Previous reports have shown that BMP signaling negatively regulates T-cell development. Here, we study the subpopulation of early human intrathymic progenitors expressing the type IA BMP receptor (BMPRIA) and provide evidence that CD34(+)CD1a(-)BMPRIA(+) precursor cells mostly express surface cell markers and transcription factors typically associated with NK cell lineage. These CD34(+) cells mostly differentiate into functional CD56(+) natural killer (NK) cells when they are cocultured with thymic stromal cells in chimeric human mouse fetal thymic organ cultures and also in the presence of SCF and IL-15. Moreover, autocrine BMP signaling can promote the differentiation of thymic NK cells by regulating the expression of key transcription factors required for NK cell lineage (eg, Id3 and Nfil3) as well as one of the components of IL-15 receptor, CD122. Subsequently, the resulting population of IL-15-responsive NK cell precursors can be expanded by IL-15, whose action is mediated by BMP signaling during the last steps of thymic NK cell differentiation. Our results strongly suggest that BMPRIA expression identifies human thymic NK cell precursors and that BMP signaling is relevant for NK cell differentiation in the human thymus. PMID- 22210873 TI - Killing by neutrophil extracellular traps: fact or folklore? AB - Neutrophil extracellular traps (NETs) are DNA structures released by dying neutrophils and claimed to constitute a new microbicidal mechanism. Killing by NET-forming cells is ascribed to these structures because it is prevented by preincubation with DNase, which has been shown to dismantle NETs, before addition of the target microorganisms. Curiously, the possibility that the microorganisms ensnared in NETs are alive has not been considered. Using Staphylococcus aureus and Candida albicans blastospores, we demonstrate that the microorganisms captured by NETs and thought to be killed are alive because they are released and recovered in cell medium by incubation with DNase. It is concluded that NETs entrap but do not kill microbes. PMID- 22210874 TI - Poor response to second-line kinase inhibitors in chronic myeloid leukemia patients with multiple low-level mutations, irrespective of their resistance profile. AB - Specific imatinib-resistant BCR-ABL1 mutations (Y253H, E255K/V, T315I, F317L, and F359V/C) predict failure of second-line nilotinib or dasatinib therapy in patients with chronic myeloid leukemia; however, such therapy also fails in approximately 40% of patients in the chronic phase of this disease who do not have these resistant mutations. We investigated whether sensitive mutation analysis could identify other poor-risk subgroups. Analysis was performed by direct sequencing and sensitive mass spectrometry on 220 imatinib-resistant patients before they began nilotinib or dasatinib therapy. Patients with resistant mutations by either method (n = 45) were excluded because inferior response was known. Of the remaining 175 patients, 19% had multiple mutations by mass spectrometry versus 9% by sequencing. Compared with 0 or 1 mutation, the presence of multiple mutations was associated with lower rates of complete cytogenetic response (50% vs 21%, P = .003) and major molecular response (31% vs 6%, P = .005) and a higher rate of new resistant mutations (25% vs 56%, P = .0009). Sensitive mutation analysis identified a poor-risk subgroup (15.5% of all patients) with multiple mutations not identified by standard screening. PMID- 22210875 TI - Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation. AB - Recently, the BRAF V600E mutation was reported in all cases of hairy cell leukemia (HCL) but not in other peripheral B-cell neoplasms. We wished to confirm these results and assess BRAF status in well-characterized cases of HCL associated with poor prognosis, including the immunophenotypically defined HCL variant (HCLv) and HCL expressing the IGHV4-34 immunoglobulin rearrangement. Fifty-three classic HCL (HCLc) and 16 HCLv cases were analyzed for BRAF, including 5 HCLc and 8 HCLv expressing IGHV4-34. BRAF was mutated in 42 (79%) HCLc, but wild-type in 11 (21%) HCLc and 16 (100%) HCLv. All 13 IGHV4-34(+) HCLs were wild-type. IGHV gene usage in the 11 HCLc BRAF wild-type cases included 5 IGHV4-34, 5 other, and 1 unknown. Our results suggest that HCLv and IGHV4-34(+) HCLs have a different pathogenesis than HCLc and that a significant minority of other HCLc are also wild-type for BRAF V600. PMID- 22210876 TI - Selection of optimal alternative graft source: mismatched unrelated donor, umbilical cord blood, or haploidentical transplant. AB - Only 30% of patients who require an allogeneic hematopoietic cell transplant will have an HLA-matched sibling donor. A search for an unrelated donor will be undertaken for patients without a matched family donor. However, many patients, particularly patients of diverse racial and ethnic backgrounds, may not be able to rapidly identify a suitably matched unrelated donor. Three alternative graft sources, umbilical cord blood (UCB), haploidentical (haplo)-related donor, and mismatched unrelated donor (MMUD) are available. UCB is associated with decreased GVHD, but hematologic recovery and immune reconstitution are slow. Haplo-HCT is characterized by donor availability for transplantation and after transplantation adoptive cellular immunotherapy but may be complicated by a high risk of graft failure and relapse. A MMUD transplant may also be an option, but GVHD may be of greater concern. Phase 2 studies have documented advances in HLA typing, GVHD prophylaxis, and infection prevention, which have improved survival. The same patient evaluated in different transplant centers may be offered MMUD, UCB, or haplo-HCT depending on center preference. In this review, we discuss the rationale for donor choice and the need of phase 3 studies to help answer this important question. PMID- 22210877 TI - PI3Kdelta inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. AB - GS-1101 (CAL-101) is an oral PI3Kdelta-specific inhibitor that has shown preclinical and clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. To investigate the potential role of PI3Kdelta in Hodgkin lymphoma (HL), we screened 5 HL cell lines and primary samples from patients with HL for PI3Kdelta isoform expression and constitutive PI3K pathway activation. Inhibition of PI3Kdelta by GS-1101 resulted in the inhibition of Akt phosphorylation. Cocultures with stroma cells induced Akt activation in HL cells, and this effect was blocked by GS-1101. Conversely, production of the stroma-stimulating chemokine, CCL5, by HL cells was reduced by GS-1101. GS-1101 also induced dose dependent apoptosis of HL cells at 48 hours. Reductions in cell viability and apoptosis were enhanced when combining GS-1101 with the mTOR inhibitor everolimus. Our findings suggest that excessive PI3Kdelta activity is characteristic in HL and support clinical evaluation of GS-1101, alone and in combination, as targeted therapy for HL. PMID- 22210878 TI - Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. AB - Mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma, is characterized by the hallmark translocation t(11;14)(q13;q32) and the resulting overexpression of cyclin D1 (CCND1). Our current knowledge of this disease encompasses frequent secondary cytogenetic aberrations and the recurrent mutation of a handful of genes, such as TP53, ATM, and CCND1. However, these findings insufficiently explain the biologic underpinnings of MCL. Here, we performed whole transcriptome sequencing on a discovery cohort of 18 primary tissue MCL samples and 2 cell lines. We found recurrent mutations in NOTCH1, a finding that we confirmed in an extension cohort of 108 clinical samples and 8 cell lines. In total, 12% of clinical samples and 20% of cell lines harbored somatic NOTCH1 coding sequence mutations that clustered in the PEST domain and predominantly consisted of truncating mutations or small frame-shifting indels. NOTCH1 mutations were associated with poor overall survival (P = .003). Furthermore, we showed that inhibition of the NOTCH pathway reduced proliferation and induced apoptosis in 2 MCL cell lines. In summary, we have identified recurrent NOTCH1 mutations that provide the preclinical rationale for therapeutic inhibition of the NOTCH pathway in a subset of patients with MCL. PMID- 22210879 TI - Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study. AB - Gene expression profiling was performed on 97 cases of infant ALL from Children's Oncology Group Trial P9407. Statistical modeling of an outcome predictor revealed 3 genes highly predictive of event-free survival (EFS), beyond age and MLL status: FLT3, IRX2, and TACC2. Low FLT3 expression was found in a group of infants with excellent outcome (n = 11; 5-year EFS of 100%), whereas differential expression of IRX2 and TACC2 partitioned the remaining infants into 2 groups with significantly different survivals (5-year EFS of 16% vs 64%; P < .001). When infants with MLL-AFF1 were analyzed separately, a 7-gene classifier was developed that split them into 2 distinct groups with significantly different outcomes (5 year EFS of 20% vs 65%; P < .001). In this classifier, elevated expression of NEGR1 was associated with better EFS, whereas IRX2, EPS8, and TPD52 expression were correlated with worse outcome. This classifier also predicted EFS in an independent infant ALL cohort from the Interfant-99 trial. When evaluating expression profiles as a continuous variable relative to patient age, we further identified striking differences in profiles in infants less than or equal to 90 days of age and those more than 90 days of age. These age-related patterns suggest different mechanisms of leukemogenesis and may underlie the differential outcomes historically seen in these age groups. PMID- 22210880 TI - How I treat childhood CML. AB - Chronic myeloid leukemia (CML) is composed of 3% of pediatric leukemias, making evidence-based recommendations difficult. Imatinib has revolutionized the treatment for adult CML by eliminating allogeneic stem cell transplantation for almost all patients in chronic phase. Shown effective in pediatric CML, imatinib and successive tyrosine kinase inhibitors (TKI) have provided more therapeutic options. Because stem cell transplantation has been better tolerated in children and adolescents, the decision to treat by either TKI or transplantation is controversial. We present a recent case of a 12-month-old boy diagnosed with BCR ABL(+) CML to highlight the controversies in treatment recommendations. We review the pediatric stem cell transplantation outcomes as well as the pediatric experience with imatinib and other TKIs. Finally, we compare the side effects as well as costs associated with allogeneic stem cell transplantation versus TKI therapy. We recommend that frontline therapy for pediatric CML in chronic phase is TKI therapy without transplantation. Patients in accelerated or blast crisis or who fail to reach landmarks on TKIs either because of intolerance or resistance should pursue stem cell transplantation. Although we recommend adopting adult clinical experience to guide therapeutic decision making, the issues of infant CML, drug formulation, pharmacokinetics, and adolescent compliance merit clinical investigation. PMID- 22210881 TI - A newly identified complex of spinophilin and the tyrosine phosphatase, SHP-1, modulates platelet activation by regulating G protein-dependent signaling. AB - Platelets are essential for normal hemostasis, but close regulation is required to avoid the destructive effects of either inappropriate platelet activation or excessive responses to injury. Here, we describe a novel complex comprising the scaffold protein, spinophilin (SPL), and the tyrosine phosphatase, SHP-1, and show that it can modulate platelet activation by sequestering RGS10 and RGS18, 2 members of the regulator of G protein signaling family. We also show that SPL/RGS/SHP1 complexes are present in resting platelets where constitutive phosphorylation of SPL(Y398) creates an atypical binding site for SHP-1. Activation of the SHP-1 occurs on agonist-induced phosphorylation of SHP-1(Y536), triggering dephosphorylation and decay of the SPL/RGS/SHP1 complex. Preventing SHP-1 activation blocks decay of the complex and produces a gain of function. Conversely, deleting spinophilin in mice inhibits platelet activation. It also attenuates the rise in platelet cAMP normally caused by endothelial prostacyclin (PGI(2)). Thus, we propose that the role of the SPL/RGS/SHP1 complex in platelets is time and context dependent. Before injury, the complex helps maintain the quiescence of circulating platelets by maximizing the impact of PGI(2). After injury, the complex gradually releases RGS proteins, limiting platelet activation and providing a mechanism for temporal coordination of pro thrombotic and antithrombotic inputs. PMID- 22210882 TI - MRE11 and RAD50, but not NBS1, are essential for gene targeting in the moss Physcomitrella patens. AB - The moss Physcomitrella patens is unique among plant models for the high frequency with which targeted transgene insertion occurs via homologous recombination. Transgene integration is believed to utilize existing machinery for the detection and repair of DNA double-strand breaks (DSBs). We undertook targeted knockout of the Physcomitrella genes encoding components of the principal sensor of DNA DSBs, the MRN complex. Loss of function of PpMRE11 or PpRAD50 strongly and specifically inhibited gene targeting, whilst rates of untargeted transgene integration were relatively unaffected. In contrast, disruption of the PpNBS1 gene retained the wild-type capacity to integrate transforming DNA efficiently at homologous loci. Analysis of the kinetics of DNA DSB repair in wild-type and mutant plants by single-nucleus agarose gel electrophoresis revealed that bleomycin-induced fragmentation of genomic DNA was repaired at approximately equal rates in each genotype, although both the Ppmre11 and Pprad50 mutants exhibited severely restricted growth and development and enhanced sensitivity to UV-B and bleomycin-induced DNA damage, compared with wild type and Ppnbs1 plants. This implies that while extensive DNA repair can occur in the absence of a functional MRN complex; this is unsupervised in nature and results in the accumulation of deleterious mutations incompatible with normal growth and development. PMID- 22210883 TI - A non-canonical E-box within the MyoD core enhancer is necessary for circadian expression in skeletal muscle. AB - The myogenic differentiation 1 (MyoD) gene is a master regulator of myogenesis. We previously reported that the expression of MyoD mRNA oscillates over 24 h in skeletal muscle and that the circadian clock transcription factors, BMAL1 (brain and muscle ARNT-like 1) and CLOCK (circadian locomotor output cycles kaput), were bound to the core enhancer (CE) of the MyoD gene in vivo. In this study, we provide in vivo and in vitro evidence that the CE is necessary for circadian expression of MyoD in adult muscle. Gel shift assays identified a conserved non canonical E-box within the CE that is bound by CLOCK and BMAL1. Functional analysis revealed that this E-box was required for full activation by BMAL1/CLOCK and for in vitro circadian oscillation. Expression profiling of muscle of CE(loxP/loxP) mice found approximately 1300 genes mis-expressed relative to wild type. Based on the informatics results, we analyzed the respiratory function of mitochondria isolated from wild-type and CE(loxP/loxP) mice. These assays determined that State 5 respiration was significantly reduced in CE(loxP/loxP) muscle. The results of this work identify a novel element in the MyoD enhancer that confers circadian regulation to MyoD in skeletal muscle and suggest that loss of circadian regulation leads to changes in myogenic expression and downstream mitochondrial function. PMID- 22210884 TI - Determinants of mRNA recognition and translation regulation by Lin28. AB - Lin28 is critical for stem cell maintenance and is also associated with advanced human malignancies. Our recent genome-wide studies mark Lin28 as a master post transcriptional regulator of a subset of messenger RNAs important for cell growth and metabolism. However, the molecular basis underpinning the selective mRNA target regulation is unclear. Here, we provide evidence that Lin28 recognizes a unique motif in multiple target mRNAs, characterized by a small but critical 'A' bulge flanked by two G:C base pairs embedded in a complex secondary structure. This motif mediates Lin28-dependent stimulation of translation. As Lin28 is also known to inhibit the biogenesis of a cohort of miRNAs including let-7, we propose that Lin28 binding to different RNA types (precursor miRNAs versus mRNAs) may facilitate recruitment of different co-factors, leading to distinct regulatory outcomes. Our findings uncover a putative yet unexpected motif that may constitute a mechanistic base for the multitude of functions regulated by Lin28 in both stem cells and cancer cells. PMID- 22210885 TI - Involvement of residues of the 29 terminal protein intermediate and priming domains in the formation of a stable and functional heterodimer with the replicative DNA polymerase. AB - Bacteriophage Phi29 genome consists of a linear double-stranded DNA with a terminal protein (TP) covalently linked to each 5' end (TP-DNA) that together with a specific sequence constitutes the replication origins. To initiate replication, the DNA polymerase forms a heterodimer with a free TP that recognizes the origins and initiates replication using as primer the hydroxyl group of TP residue Ser232. The 3D structure of the DNA polymerase/TP heterodimer allowed the identification of TP residues that could be responsible for interaction with the DNA polymerase. Here, we examined the role of TP residues Arg158, Arg169, Glu191, Asp198, Tyr250, Glu252, Gln253 and Arg256 by in vitro analyses of mutant derivatives. The results showed that substitution of these residues had an effect on either the stability of the TP/DNA polymerase complex (R158A) or in the functional interaction of the TP at the polymerization active site (R169A, E191A, Y250A, E252A, Q253A and R256A), affecting the first steps of Phi29 TP-DNA replication. These results allow us to propose a role for these residues in the maintenance of the equilibrium between TP-priming domain stabilization and its gradual exit from the polymerization active site of the DNA polymerase as new DNA is being synthesized. PMID- 22210887 TI - SCOREM: statistical consolidation of redundant expression measures. AB - Many platforms for genome-wide analysis of gene expression contain 'redundant' measures for the same gene. For example, the most highly utilized platforms for gene expression microarrays, Affymetrix GeneChip(r) arrays, have as many as ten or more probe sets for some genes. Occasionally, individual probe sets for the same gene report different trends in expression across experimental conditions, a situation that must be resolved in order to accurately interpret the data. We developed an algorithm, SCOREM, for determining the level of agreement between such probe sets, utilizing a statistical test of concordance, Kendall's W coefficient of concordance, and a graph-searching algorithm for the identification of concordant probe sets. We also present methods for consolidating concordant groups into a single value for its corresponding gene and for post hoc analysis of discordant groups. By combining statistical consolidation with sequence analysis, SCOREM possesses the unique ability to identify biologically meaningful discordant behaviors, including differing behaviors in alternate RNA isoforms and tissue-specific patterns of expression. When consolidating concordant behaviors, SCOREM outperforms other methods in detecting both differential expression and overrepresented functional categories. PMID- 22210886 TI - Expression determinants of mammalian argonaute proteins in mediating gene silencing. AB - RNA interference occurs by two main processes: mRNA site-specific cleavage and non-cleavage-based mRNA degradation or translational repression. Site-specific cleavage is carried out by argonaute-2 (Ago2), while all four mammalian argonaute proteins (Ago1-Ago4) can carry out non-cleavage-mediated inhibition, suggesting that Ago1, Ago3 and Ago4 may have similar but potentially redundant functions. It has been observed that in mammalian tissues, expression of Ago3 and Ago4 is dramatically lower compared with Ago1; however, an optimization of the Ago3 and Ago4 coding sequences to include only the most common codon at each amino acid position was able to augment the expression of Ago3 and Ago4 to levels comparable to that of Ago1 and Ago2. Thus, we examined whether particular sequence features exist in the coding region of Ago3 and Ago4 that may prevent a high level of expression. Swapping specific sub-regions of wild-type and optimized Ago sequence identified the portion of the coding region (nucleotides 1-1163 for Ago-3 and 1 1494 for Ago-4) that is most influential for expression. This finding has implications for the evolutionary conservation of Ago proteins in the mammalian lineage and the biological role that potentially redundant Ago proteins may have. PMID- 22210888 TI - A rapid assay for affinity and kinetics of molecular interactions with nucleic acids. AB - The Differential Radial Capillary Action of Ligand Assay (DRaCALA) allows detection of protein interactions with low-molecular weight ligands based on separation of the protein-ligand complex by differential capillary action. Here, we present an application of DRaCALA to the study of nucleic acid-protein interactions using the Escherichia coli cyclic AMP receptor protein (CRP). CRP bound in DRaCALA specifically to (32)P-labeled oligonucleotides containing the consensus CRP binding site, but not to oligonucleotides with point mutations known to abrogate binding. Affinity and kinetic studies using DRaCALA yielded a dissociation constant and dissociation rate similar to previously reported values. Because DRaCALA is not subject to ligand size restrictions, whole plasmids with a single CRP-binding site were used as probes, yielding similar results. DNA can also function as an easily labeled carrier molecule for a conjugated ligand. Sequestration of biotinylated nucleic acids by streptavidin allowed nucleic acids to take the place of the protein as the immobile binding partner. Therefore, any molecular interactions involving nucleic acids can be tested. We demonstrate this principle utilizing a bacterial riboswitch that binds cyclic-di-guanosine monophosphate. DRaCALA is a flexible and complementary approach to other biochemical methods for rapid and accurate measurements of affinity and kinetics at near-equilibrium conditions. PMID- 22210889 TI - Identification of CTCF as a master regulator of the clustered protocadherin genes. AB - The brain is a large and complex network of neurons. Specific neuronal connectivity is thought to be based on the combinatorial expression of the 52 protocadherins (Pcdh) membrane adhesion proteins, whereby each neuron expresses only a specific subset. Pcdh genes are arranged in tandem, in a cluster of three families: Pcdhalpha, Pcdhbeta and Pcdhgamma. The expression of each Pcdh gene is regulated by a promoter that has a regulatory conserved sequence element (CSE), common to all 52 genes. The mechanism and factors controlling individual Pcdh gene expression are currently unknown. Here we show that the promoter of each Pcdh gene contains a gene-specific conserved control region, termed specific sequence element (SSE), located adjacent and upstream to the CSE and activates transcription together with the CSE. We purified the complex that specifically binds the SSE-CSE region and identified the CCTC binding-factor (CTCF) as a key molecule that binds and activates Pcdh promoters. Our findings point to CTCF as a factor essential for Pcdh expression and probably governing neuronal connectivity. PMID- 22210890 TI - Transcription activation by the siderophore sensor Btr is mediated by ligand dependent stimulation of promoter clearance. AB - Bacterial transcription factors often function as DNA-binding proteins that selectively activate or repress promoters, although the biochemical mechanisms vary. In most well-understood examples, activators function by either increasing the affinity of RNA polymerase (RNAP) for the target promoter, or by increasing the isomerization of the initial closed complex to the open complex. We report that Bacillus subtilis Btr, a member of the AraC family of activators, functions principally as a ligand-dependent activator of promoter clearance. In the presence of its co-activator, the siderophore bacillibactin (BB), the Btr:BB complex enhances productive transcription, while having only modest effects on either RNAP promoter association or the production of abortive transcripts. Btr binds to two direct repeat sequences adjacent to the -35 region; recognition of the downstream motif is most important for establishing a productive interaction between the Btr:BB complex and RNAP. The resulting Btr:BB dependent increase in transcription enables the production of the ferric-BB importer to be activated by the presence of its cognate substrate. PMID- 22210891 TI - Crystal structure of human polynucleotide phosphorylase: insights into its domain function in RNA binding and degradation. AB - Human polynucleotide phosphorylase (hPNPase) is a 3'-to-5' exoribonuclease that degrades specific mRNA and miRNA, and imports RNA into mitochondria, and thus regulates diverse physiological processes, including cellular senescence and homeostasis. However, the RNA-processing mechanism by hPNPase, particularly how RNA is bound via its various domains, remains obscure. Here, we report the crystal structure of an S1 domain-truncated hPNPase at a resolution of 2.1 A. The trimeric hPNPase has a hexameric ring-like structure formed by six RNase PH domains, capped with a trimeric KH pore. Our biochemical and mutagenesis studies suggest that the S1 domain is not critical for RNA binding, and conversely, that the conserved GXXG motif in the KH domain directly participates in RNA binding in hPNPase. Our studies thus provide structural and functional insights into hPNPase, which uses a KH pore to trap a long RNA 3' tail that is further delivered into an RNase PH channel for the degradation process. Structural RNA with short 3' tails are, on the other hand, transported but not digested by hPNPase. PMID- 22210892 TI - Yin Yang 1 extends the Myc-related transcription factors network in embryonic stem cells. AB - The Yin Yang 1 (YY1) transcription factor is a master regulator of development, essential for early embryogenesis and adult tissues formation. YY1 is the mammalian orthologue of Pleiohomeotic, one of the transcription factors that binds Polycomb DNA response elements in Drosophila melanogaster and mediates Polycomb group proteins (PcG) recruitment to DNA. Despite several publications pointing at YY1 having a similar role in mammalians, others showed features of YY1 that are not compatible with PcG functions. Here, we show that, in mouse Embryonic Stem (ES) cells, YY1 has genome-wide PcG-independent activities while it is still stably associated with the INO80 chromatin-remodeling complex, as well as with novel RNA helicase activities. YY1 binds chromatin in close proximity of the transcription start site of highly expressed genes. Loss of YY1 functions preferentially led to a down-regulation of target genes expression, as well as to an up-regulation of several small non-coding RNAs, suggesting a role for YY1 in regulating small RNA biogenesis. Finally, we found that YY1 is a novel player of Myc-related transcription factors and that its coordinated binding at promoters potentiates gene expression, proposing YY1 as an active component of the Myc transcription network that links ES to cancer cells. PMID- 22210893 TI - C6 pyridinium ceramide influences alternative pre-mRNA splicing by inhibiting protein phosphatase-1. AB - Alternative pre-mRNA processing is a central element of eukaryotic gene regulation. The cell frequently alters the use of alternative exons in response to physiological stimuli. Ceramides are lipid-signaling molecules composed of sphingosine and a fatty acid. Previously, water-insoluble ceramides were shown to change alternative splicing and decrease SR-protein phosphorylation by activating protein phosphatase-1 (PP1). To gain further mechanistical insight into ceramide mediated alternative splicing, we analyzed the effect of C6 pyridinium ceramide (PyrCer) on alternative splice site selection. PyrCer is a water-soluble ceramide analog that is under investigation as a cancer drug. We found that PyrCer binds to the PP1 catalytic subunit and inhibits the dephosphorylation of several splicing regulatory proteins containing the evolutionarily conserved RVxF PP1 binding motif (including PSF/SFPQ, Tra2-beta1 and SF2/ASF). In contrast to natural ceramides, PyrCer promotes phosphorylation of splicing factors. Exons that are regulated by PyrCer have in common suboptimal splice sites, are unusually short and share two 4-nt motifs, GAAR and CAAG. They are dependent on PSF/SFPQ, whose phosphorylation is regulated by PyrCer. Our results indicate that lipids can influence pre-mRNA processing by regulating the phosphorylation status of specific regulatory factors, which is mediated by protein phosphatase activity. PMID- 22210894 TI - MUSI: an integrated system for identifying multiple specificity from very large peptide or nucleic acid data sets. AB - Peptide recognition domains and transcription factors play crucial roles in cellular signaling. They bind linear stretches of amino acids or nucleotides, respectively, with high specificity. Experimental techniques that assess the binding specificity of these domains, such as microarrays or phage display, can retrieve thousands of distinct ligands, providing detailed insight into binding specificity. In particular, the advent of next-generation sequencing has recently increased the throughput of such methods by several orders of magnitude. These advances have helped reveal the presence of distinct binding specificity classes that co-exist within a set of ligands interacting with the same target. Here, we introduce a software system called MUSI that can rapidly analyze very large data sets of binding sequences to determine the relevant binding specificity patterns. Our pipeline provides two major advances. First, it can detect previously unrecognized multiple specificity patterns in any data set. Second, it offers integrated processing of very large data sets from next-generation sequencing machines. The results are visualized as multiple sequence logos describing the different binding preferences of the protein under investigation. We demonstrate the performance of MUSI by analyzing recent phage display data for human SH3 domains as well as microarray data for mouse transcription factors. PMID- 22210895 TI - Ectopic over-expression of tristetraprolin in human cancer cells promotes biogenesis of let-7 by down-regulation of Lin28. AB - Tristetraprolin (TTP) is a AU-rich element (ARE) binding protein and exhibits suppressive effects on cell growth through down-regulation of ARE-containing oncogenes. The let-7 microRNA has emerged as a significant factor in tumor suppression. Both TTP and let-7 are often repressed in human cancers, thereby promoting oncogenesis by derepressing their target genes. In this work, an unexpected link between TTP and let-7 has been found in human cancer cells. TTP promotes an increase in expression of mature let-7, which leads to the inhibition of let-7 target gene CDC34 expression and suppresses cell growth. This event is associated with TTP-mediated inhibition of Lin28, which has emerged as a negative modulator of let-7. Lin28 mRNA contains ARE within its 3'-UTR and TTP enhances the decay of Lin28 mRNA through binding to its 3'-UTR. This suggests that the TTP mediated down-regulation of Lin28 plays a key role in let-7 miRNA biogenesis in cancer cells. PMID- 22210896 TI - Base methylations in the double-stranded RNA by a fused methyltransferase bearing unwinding activity. AB - Modifications of rRNAs are clustered in functional regions of the ribosome. In Helix 74 of Escherichia coli 23S rRNA, guanosines at positions 2069 and 2445 are modified to 7-methylguanosine(m(7)G) and N(2)-methylguanosine(m(2)G), respectively. We searched for the gene responsible for m(7)G2069 formation, and identified rlmL, which encodes the methyltransferase for m(2)G2445, as responsible for the biogenesis of m(7)G2069. In vitro methylation of rRNA revealed that rlmL encodes a fused methyltransferase responsible for forming both m(7)G2069 and m(2)G2445. We renamed the gene rlmKL. The N-terminal RlmL activity for m(2)G2445 formation was significantly enhanced by the C-terminal RlmK. Moreover, RlmKL had an unwinding activity of Helix 74, facilitating cooperative methylations of m(7)G2069 and m(2)G2445 during biogenesis of 50S subunit. In fact, we observed that RlmKL was involved in the efficient assembly of 50S subunit in a mutant strain lacking an RNA helicase deaD. PMID- 22210897 TI - MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein. AB - The functional association between intronic miRNAs and their host genes is still largely unknown. We found that three gene loci, which produced miR-26a and miR 26b, were embedded within introns of genes coding for the proteins of carboxy terminal domain RNA polymerase II polypeptide A small phosphatase (CTDSP) family, including CTDSPL, CTDSP2 and CTDSP1. We conducted serum starvation-stimulation assays in primary fibroblasts and two-thirds partial-hepatectomies in mice, which revealed that miR-26a/b and CTDSP1/2/L were expressed concomitantly during the cell cycle process. Specifically, they were increased in quiescent cells and decreased during cell proliferation. Furthermore, both miR-26 and CTDSP family members were frequently downregulated in hepatocellular carcinoma (HCC) tissues. Gain- and loss-of-function studies showed that miR-26a/b and CTDSP1/2/L synergistically decreased the phosphorylated form of pRb (ppRb), and blocked G1/S phase progression. Further investigation disclosed that miR-26a/b directly suppressed the expression of CDK6 and cyclin E1, which resulted in reduced phosphorylation of pRb. Moreover, c-Myc, which is often upregulated in cancer cells, diminished the expression of both miR-26 and CTDSP family members, enhanced the ppRb level and promoted the G1/S-phase transition. Our findings highlight the functional association of miR-26a/b and their host genes and provide new insight into the regulatory network of the G1/S-phase transition. PMID- 22210898 TI - GLABROUS INFLORESCENCE STEMS (GIS) is required for trichome branching through gibberellic acid signaling in Arabidopsis. AB - Cell differentiation generally corresponds to the cell cycle, typically forming a non-dividing cell with a unique differentiated morphology, and Arabidopsis trichome is an excellent model system to study all aspects of cell differentiation. Although gibberellic acid is reported to be involved in trichome branching in Arabidopsis, the mechanism for such signaling is unclear. Here, we demonstrated that GLABROUS INFLORESCENCE STEMS (GIS) is required for the control of trichome branching through gibberellic acid signaling. The phenotypes of a loss-of-function gis mutant and an overexpressor showed that GIS acted as a repressor to control trichome branching. Our results also show that GIS is not required for cell endoreduplication, and our molecular and genetic study results have shown that GIS functions downstream of the key regulator of trichome branching, STICHEL (STI), to control trichome branching through the endoreduplication-independent pathway. Furthermore, our results also suggest that GIS controls trichome branching in Arabidopsis through two different pathways and acts either upstream or downstream of the negative regulator of gibbellic acid signaling SPINDLY (SPY). PMID- 22210900 TI - Post-translational redox modification of ADP-glucose pyrophosphorylase in response to light is not a major determinant of fine regulation of transitory starch accumulation in Arabidopsis leaves. AB - ADP-glucose pyrophosphorylase (AGP) is a heterotetrameric enzyme comprising two small and two large subunits that catalyze the production of ADP-glucose linked to starch biosynthesis. The current paradigm on leaf starch metabolism assumes that post-translational redox modification of AGP in response to light is a major determinant of fine regulation of transitory starch accumulation. According to this view, under oxidizing conditions occurring during the night the two AGP small subunits (APS1) are covalently linked via an intermolecular disulfide bridge that inactivates the protein, whereas under reducing conditions occurring during the day NADP-thioredoxin reductase C (NTRC)-dependent reductive monomerization of APS1 activates the enzyme. In this work we have analyzed changes in the redox status of APS1 during dark-light transition in leaves of plants cultured under different light intensities. Furthermore, we have carried out time-course analyses of starch content in ntrc mutants, and in aps1 mutants expressing the Escherichia coli redox-insensitive AGP (GlgC) in the chloroplast. We also characterized aps1 plants expressing a redox-insensitive, mutated APS1 (APS1mut) form in which the highly conserved Cys81 residue involved in the formation of the intermolecular disulfide bridge has been replaced by serine. We found that a very moderate, NTRC-dependent APS1 monomerization process in response to light occurred only when plants were cultured under photo-oxidative conditions. We also found that starch accumulation rates during the light in leaves of both ntrc mutants and GlgC-expressing aps1 mutants were similar to those of wild-type leaves. Furthermore, the pattern of starch accumulation during illumination in leaves of APS1mut-expressing aps1 mutants was similar to that of APS1-expressing aps1 mutants at any light intensity. The overall data demonstrate that post-translational redox modification of AGP in response to light is not a major determinant of fine regulation of transitory starch accumulation in Arabidopsis. PMID- 22210899 TI - Disruption of the Arabidopsis thaliana inward-rectifier K+ channel AKT1 improves plant responses to water stress. AB - The Arabidopsis thaliana inward-rectifier K(+) channel AKT1 plays an important role in root K(+) uptake. Recent results show that the calcineurin B-like (CBL) interacting protein kinase (CIPK) 23-CBL1/9 complex activates AKT1 in the root to enhance K(+) uptake. In addition, this CIPK-CBL complex has been demonstrated to regulate stomatal movements and plant transpiration. However, a role for AKT1 in plant transpiration has not yet been demonstrated. Here we show that disruption of AKT1 conferred an enhanced response to water stress in plants. Experiments performed in hydroponics showed that, when water potential was diminished by adding polyethylene glycol, akt1 adult plants lost less water than wild-type (WT) plants. Under long-term water stress in soil, adult akt1 plants displayed lower transpiration and less water consumption than WT plants. Finally, akt1 stomata closed more efficiently in response to ABA. Such results were also observed in cipk23 plants. The similar responses shown by cipk23 and akt1 plants to water stress denote that the regulation of AKT1 by CIPK23 may also take place in stomata and has a negative impact on plant performance under water stress conditions. PMID- 22210901 TI - Nitric oxide up-regulates the expression of methionine sulfoxide reductase genes in the intertidal macroalga Ulva fasciata for high light acclimation. AB - Nitric oxide (NO) has emerged as a fundamental signal molecule involved in the responses of plant to stress. A role for NO in the regulation of methionine sulfoxide reductase (MSR) mRNA expression and high light acclimation was studied in a green macroalga Ulva fasciata Delile. Transfer from darkness to high light (>=1,200 MUmol photons m(-2) s(-1)) inhibited photosynthesis and growth but increased NO production and UfMSRA and UfMSRB transcripts. Treatment with an NO scavenger, 2-(4-carboxy- phenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (cPTIO), at 1,200 MUmol photons m(-2) s(-1) caused a further growth inhibition accompanied by an inhibition of the increase of UfMSRA and UfMSRB transcripts by high light, while treatment with an NO generator, sodium nitroprusside (SNP), alleviated the growth inhibition and enhanced UfMSRA and UfMSRB expression. Exposure to moderate light (300 MUmol photons m(-2) s(-1)) conditions also increased UfMSRA and UfMSRB transcripts, which were not affected by cPTIO treatment but were enhanced by SNP treatment. So, NO does not mediate the up regulation of UfMSR genes by transfer to moderate light possibly as a precautionary mechanism in the sense of increasing light intensities in the daytime. In conclusion, NO production can be induced in U. fasciata upon exposure to high light for up-regulation of UfMSRA and UfMSRB expression but the level of NO production is not sufficient for acquisition of full tolerance to high light stress. Enhanced NO production by an exogenously applied NO generator can effectively trigger the high light acclimation process, including UfMSRA and UfMSRB expression. PMID- 22210903 TI - NMR and CD analysis of an intermediate state in the thermal unfolding process of mouse lipocalin-type prostaglandin D synthase. AB - We previously reported that the thermal unfolding of mouse lipocalin-type prostaglandin D synthase (L-PGDS) is a completely reversible process under acidic conditions and follows a three-state pathway, including an intermediate state (I) between native state (N) and unfolded state. In the present study, we investigated the intermediate state of mouse C65A L-PGDS and clarified the local conformational changes in the upper and bottom regions by using NMR and CD spectroscopy. The (1)H-(15)N HSQC measurements revealed that the backbone conformation was disrupted in the upper region of the beta-barrel at 45 degrees C, which is around the T(m) value for the N <-> I transition, but that the signals of the residues located at the bottom region of L-PGDS remained at 54 degrees C, where the maximum accumulation of the intermediate state was found. (1)H-NMR and CD measurements showed that the T(m) values obtained by monitoring Trp54 at the upper region and Trp43 at the bottom region of the beta-barrel were 41.4 and 47.5 degrees C, respectively, suggesting that the conformational change in the upper region occurred at a lower temperature than that in the bottom region. These findings demonstrate that the backbone conformation of the bottom region is still maintained in the intermediate state. PMID- 22210902 TI - Varied effects of Pyrococcus furiosus prefoldin and P. furiosus chaperonin on the refolding reactions of substrate proteins. AB - Prefoldin is a molecular chaperone found in the archaeal and eukaryotic cytosol. Prefoldin can stabilize tentatively nascent polypeptide chains or non-native forms of mainly cytoskeletal proteins, which are subsequently delivered to group II chaperonin to accomplish their precise folding. However, the detailed mechanism is not well known, especially with regard to endogenous substrate proteins. Here, we report the effects of Pyrococcus furiosus prefoldin (PfuPFD) on the refolding reactions of Pyrococcus furiosus citrate synthase (PfuCS) and Aequorea enhanced green fluorescence protein (GFPuv) in the presence or absence of Pyrococcus furiosus chaperonin (PfuCPN). We confirmed that both PfuPFD and PfuCPN interacted with PfuCS and GFPuv refolding intermediates. However, the interactions between chaperone and substrate were different for each case, as was the final effect on the refolding reaction. Effects on the refolding reaction varied from passive effects such as ATP-dependent binding and release (PfuCPN towards GFPuv) and binding which leads to folding arrest (PfuPFD towards GFPuv), to active effects such as net increase in thermal stability (PfuCPN towards PfuCS) to an active improvement in refolding yield (PfuPFD towards PfuCS). We postulate that differences in molecular interactions between substrate and chaperone lead to these differences in chaperoning effects. PMID- 22210904 TI - Important role of methionine 145 in dimerization of bovine beta-lactoglobulin. AB - beta-Lactoglobulin (LG) contains nine beta-strands (strands A-I) and one alpha helix. Strands A-H form a beta-barrel. At neutral pH, bovine LG (BLG) forms a dimer and the dimer interface consists of AB-loops and the I-strands of two subunits. On the other hand, equine LG (ELG) is monomeric. The residues 145-153 of BLG, which compose a dimer interface, are entirely different from those of ELG. The difference in the association states between BLG and ELG can be attributed to the residues 145-153. To confirm this, we constructed a chimeric LG, ImBLG (I-strand mutated BLG), in which the residues 145-153 were replaced with those of ELG. Gel-filtration chromatography and analytical ultracentrifugation revealed that ImBLG existed as a monomer. To identify the residues important for dimerization, we constructed several revertants and investigated their association. This experiment revealed that, in addition to the interface residues (Ile147, Leu149 and Phe151), Met145 is critical for dimerization. Although Met145 does not contact with the other protomer, it seems to be important in determining the backbone conformation of the I-strand. This was supported by the fact that all Met145-containing mutants showed circular dichroism spectra similar to BLG but different from ImBLG. PMID- 22210905 TI - CHOP is a multifunctional transcription factor in the ER stress response. AB - The accumulation of unfolded proteins in the endoplasmic reticulum (ER) induces ER stress. To restore ER homeostasis, cells possess a highly specific ER quality control system called the unfold protein response (UPR). In the case of prolonged ER stress or UPR malfunction, apoptosis signalling is activated. This ER stress induced apoptosis has been implicated in the pathogenesis of several conformational diseases. CCAAT-enhancer-binding protein homologous protein (CHOP) is induced by ER stress and mediates apoptosis. Recent studies by the Gotoh group have shown that the CHOP pathway is also involved in ER stress-induced cytokine production in macrophages. The multifunctional roles of CHOP in the ER stress response are discussed below. PMID- 22210907 TI - Dominant Th2 differentiation of human regulatory T cells upon loss of FOXP3 expression. AB - CD4(+)CD25(+)FOXP3(+) regulatory T cells (Treg) are pivotal for peripheral self tolerance. They prevent immune responses to auto- and alloantigens and are thus under close scrutiny as cellular therapeutics for autoimmune diseases and the prevention or treatment of alloresponses after organ or stem cell transplantation. We previously showed that human Treg with a memory cell phenotype, but not those with a naive phenotype, rapidly downregulate expression of the lineage-defining transcription factor FOXP3 upon in vitro expansion. We now compared the transcriptomes of stable FOXP3(+) Treg and converted FOXP3(-) ex Treg by applying a newly developed intranuclear staining protocol that permits the isolation of intact mRNA from fixed, permeabilized, and FACS-purified cell populations. Whole-genome microarray analysis revealed strong and selective upregulation of Th2 signature genes, including GATA-3, IL-4, IL-5, and IL-13, upon downregulation of FOXP3. Th2 differentiation of converted FOXP3(-) ex-Treg occurred even under nonpolarizing conditions and could not be prevented by IL-4 signaling blockade. Thus, our studies identify Th2 differentiation as the default developmental program of human Treg after downregulation of FOXP3. PMID- 22210906 TI - Functional analysis of the Arabidopsis PLDZ2 promoter reveals an evolutionarily conserved low-Pi-responsive transcriptional enhancer element. AB - Plants have evolved a plethora of responses to cope with phosphate (Pi) deficiency, including the transcriptional activation of a large set of genes. Among Pi-responsive genes, the expression of the Arabidopsis phospholipase DZ2 (PLDZ2) is activated to participate in the degradation of phospholipids in roots in order to release Pi to support other cellular activities. A deletion analysis was performed to identify the regions determining the strength, tissue-specific expression, and Pi responsiveness of this regulatory region. This study also reports the identification and characterization of a transcriptional enhancer element that is present in the PLDZ2 promoter and able to confer Pi responsiveness to a minimal, inactive 35S promoter. This enhancer also shares the cytokinin and sucrose responsive properties observed for the intact PLDZ2 promoter. The EZ2 element contains two P1BS motifs, each of which is the DNA binding site of transcription factor PHR1. Mutation analysis showed that the P1BS motifs present in EZ2 are necessary but not sufficient for the enhancer function, revealing the importance of adjacent sequences. The structural organization of EZ2 is conserved in the orthologous genes of at least eight families of rosids, suggesting that architectural features such as the distance between the two P1BS motifs are also important for the regulatory properties of this enhancer element. PMID- 22210908 TI - IL-2-engineered nano-APC effectively activates viral antigen-mediated T cell responses from chronic hepatitis B virus-infected patients. AB - Impaired function of virus-specific T cells resulting from virus persistence is one of the major mechanisms underlying the development of chronic hepatitis B viral infection. Previously, we found that IL-2 can restore the effector function of T cells rendered tolerant by Ag persistence. However, systemic administration of IL-2 induces organ pathology and expansion of T regulatory cells. In this study, we show that nano-APC with engineered HLA alleles and IL-2 deliver peptide MHC complexes, costimulatory molecules, and IL-2 to Ag-responding T cells, resulting in enhanced expression of CD25 and activation of TCR signaling pathways, while suppressing PD-1 expression on viral-responding CD8 T cells from chronic hepatitis B virus patients. The enhanced activation of CD4 and CD8 T cells induced by IL-2-nano-APC was Ag dependent and IL-2-nano-APC did not affect T regulatory cells. At a size of 500 nm, the nano-APC effectively induce immune synapse formation on Ag-specific T cells and accumulate as free particles in the lymphoid organs. These attributes of IL-2-nano-APC or other bioadjuvant engineered nano-APC have profound implications for their use as a therapeutic strategy in the treatment of chronic hepatitis B virus infection or other chronic viral diseases. PMID- 22210909 TI - Early responding dendritic cells direct the local NK response to control herpes simplex virus 1 infection within the cornea. AB - Dendritic cells (DCs) regulate both innate and adaptive immune responses. In this article, we exploit the unique avascularity of the cornea to examine a role for local or very early infiltrating DCs in regulating the migration of blood-derived innate immune cells toward HSV-1 lesions. A single systemic diphtheria toxin treatment 2 d before HSV-1 corneal infection transiently depleted CD11c(+) DCs from both the cornea and lymphoid organs of CD11c-DTR bone marrow chimeric mice for up to 24 h postinfection. Transient DC depletion significantly delayed HSV-1 clearance from the cornea through 6 d postinfection. No further compromise of viral clearance was observed when DCs were continuously depleted throughout the first week of infection. DC depletion did not influence extravasation of NK cells, inflammatory monocytes, or neutrophils into the peripheral cornea, but it did significantly reduce migration of NK cells and inflammatory monocytes, but not neutrophils, toward the HSV-1 lesion in the central cornea. Depletion of NK cells resulted in similar loss of viral control to transient DC ablation. Our findings demonstrate that resident corneal DCs and/or those that infiltrate the cornea during the first 24 h after HSV-1 infection contribute to the migration of NK cells and inflammatory monocytes into the central cornea, and are consistent with a role for NK cells and possibly inflammatory monocytes, but not polymorphonuclear neutrophils, in clearing HSV-1 from the infected cornea. PMID- 22210910 TI - Epidermal Cadm1 expression promotes autoimmune alopecia via enhanced T cell adhesion and cytotoxicity. AB - Autoimmune alopecia is characterized by an extensive epidermal T cell infiltrate that mediates hair follicle destruction. We have investigated the role of cell adhesion molecule 1 (Cadm1; Necl2) in this disease. Cadm1 is expressed by epidermal cells and mediates heterotypic adhesion to lymphocytes expressing class 1-restricted T cell-associated molecule (CRTAM). Using a murine autoimmune alopecia model, we observed an increase in early-activated cytotoxic (CD8 restricted, CRTAM-expressing) T cells, which preferentially associated with hair follicle keratinocytes expressing Cadm1. Coculture with Cadm1-transduced MHC matched APCs stimulated alopecic lymph node cells to release IL-2 and IFN-gamma. Overexpression of Cadm1 in cultured human keratinocytes did not promote cytokine secretion, but led to increased adhesion of alopecic cytotoxic T cells and enhanced T cell cytotoxicity in an MHC-independent manner. Epidermal overexpression of Cadm1 in transgenic mice led to increased autoimmune alopecia susceptibility relative to nontransgenic littermate controls. Our findings reveal that Cadm1 expression in the hair follicle plays a role in autoimmune alopecia. PMID- 22210911 TI - IL-13 regulates Th17 secretion of IL-17A in an IL-10-dependent manner. AB - IL-13 is a central mediator of airway hyperresponsiveness and mucus expression, both hallmarks of asthma. IL-13 is found in the sputum of patients with asthma; therefore, IL-13 is an attractive drug target for treating asthma. We have shown previously that IL-13 inhibits Th17 cell production of IL-17A and IL-21 in vitro. Th17 cells are associated with autoimmune diseases, host immune responses, and severe asthma. In this study, we extend our in vitro findings and determine that IL-13 increases IL-10 production from Th17-polarized cells and that IL-13-induced IL-10 production negatively regulates the secretion of IL-17A and IL-21. To determine if IL-13 negatively regulates lung IL-17A expression via an IL-10 dependent mechanism in vivo, we used a model of respiratory syncytial virus (RSV) strain A2 infection in STAT1 knockout (KO) mice that increases lung IL-17A and IL 13 expression, cytokines not produced during RSV infection in wild-type mice. To test the hypothesis that IL-13 negatively regulates lung IL-17A expression, we created STAT1/IL-13 double KO (DKO) mice. We found that RSV-infected STAT1/IL-13 DKO mice had significantly greater lung IL-17A expression compared with that of STAT1 KO mice and that increased IL-17A expression was abrogated by anti-IL-10 Ab treatment. RSV-infected STAT1/IL-13 DKO mice also had increased neutrophil infiltration compared with that of RSV-infected STAT1 KO mice. Neutralizing IL-10 increased the infiltration of inflammatory cells into the lungs of STAT1 KO mice but not STAT1/IL-13 DKO mice. These findings are vital to understanding the potential side effects of therapeutics targeting IL-13. Inhibiting IL-13 may decrease IL-10 production and increase IL-17A production, thus potentiating IL 17A-associated diseases. PMID- 22210912 TI - Crucial role of granulocytic myeloid-derived suppressor cells in the regulation of central nervous system autoimmune disease. AB - There is a need in autoimmune diseases to uncover the mechanisms involved in the natural resolution of inflammation. In this article, we demonstrate that granulocytic myeloid-derived suppressor cells (G-MDSCs) abundantly accumulate within the peripheral lymphoid compartments and target organs of mice with experimental autoimmune encephalomyelitis prior to disease remission. In vivo transfer of G-MDSCs ameliorated experimental autoimmune encephalomyelitis, significantly decreased demyelination, and delayed disease onset through inhibition of encephalitogenic Th1 and Th17 immune responses. Exposure of G-MDSCs to the autoimmune milieu led to up-regulation of the programmed death 1 ligand that was required for the G-MDSC-mediated suppressive function both in vitro and in vivo. Importantly, myeloid-derived suppressor cells were enriched in the periphery of subjects with active multiple sclerosis and suppressed the activation and proliferation of autologous CD4(+) T cells ex vivo. Collectively, this study revealed a pivotal role for myeloid-derived suppressor cells in the regulation of multiple sclerosis, which could be exploited for therapeutic purposes. PMID- 22210913 TI - RANKL induces organized lymph node growth by stromal cell proliferation. AB - RANK and its ligand RANKL play important roles in the development and regulation of the immune system. We show that mice transgenic for Rank in hair follicles display massive postnatal growth of skin-draining lymph nodes. The proportions of hematopoietic and nonhematopoietic stromal cells and their organization are maintained, with the exception of an increase in B cell follicles. The hematopoietic cells are not activated and respond to immunization by foreign Ag and adjuvant. We demonstrate that soluble RANKL is overproduced from the transgenic hair follicles and that its neutralization normalizes lymph node size, inclusive area, and numbers of B cell follicles. Reticular fibroblastic and vascular stromal cells, important for secondary lymphoid organ formation and organization, express RANK and undergo hyperproliferation, which is abrogated by RANKL neutralization. In addition, they express higher levels of CXCL13 and CCL19 chemokines, as well as MAdCAM-1 and VCAM-1 cell-adhesion molecules. These findings highlight the importance of tissue-derived cues for secondary lymphoid organ homeostasis and identify RANKL as a key molecule for controlling the plasticity of the immune system. PMID- 22210915 TI - Thy-1 (CD90) is an interacting partner for CD97 on activated endothelial cells. AB - Leukocyte recruitment in response to inflammatory signals is governed, in part, by binding to Thy-1 (CD90) on activated endothelial cells (EC). In this study, we characterized the adhesion G-protein coupled receptor CD97, present on peripheral myeloid cells, as a novel interacting partner for Thy-1. CD97 was upregulated on polymorphonuclear cells (PMNC) of patients with psoriasis. In psoriatic skin lesions, CD97(+) myeloid cells colocalized with Thy-1(+) EC of small vessels in microabscesses, suggesting an interaction between CD97 and Thy-1 that was further examined by adhesion and protein-binding assays. PMNC and cell lines stably overexpressing CD97 adhered specifically to Thy-1(+)-activated human dermal EC, Thy-1(+) CHO cells, and immobilized Thy-1 protein. Binding of the CD97(+) CHO clones correlated with their CD97 expression level. Soluble CD97 bound specifically to immobilized Thy-1 protein, as well as Thy-1(+)-activated EC and CHO cells. In all assays, cellular adhesion or protein binding was blocked partially by CD97 and Thy-1-blocking mAb. Our data suggested that CD97 interacts via its stalk with Thy-1 because mAb directed to the stalk of CD97 showed stronger blocking compared with mAb to its epidermal growth factor-like domains, and binding was calcium independent. Moreover, soluble CD97 without the stalk and soluble EMR2, containing highly homologous epidermal growth factor-like domains but a different stalk, failed to bind. In summary, binding of leukocytes to activated endothelium mediated by the interaction of CD97 with Thy-1 is involved in firm adhesion of PMNC during inflammation and may play a role in the regulation of leukocyte trafficking to inflammatory sites. PMID- 22210914 TI - Treml4, an Ig superfamily member, mediates presentation of several antigens to T cells in vivo, including protective immunity to HER2 protein. AB - Members of the triggering expressed on myeloid cells (Trem) receptor family fine tune inflammatory responses. We previously identified one of these receptors, called Treml4, expressed mainly in the spleen, as well as at high levels by CD8alpha(+) dendritic cells and macrophages. Like other Trem family members, Treml4 has an Ig-like extracellular domain and a short cytoplasmic tail that associates with the adaptor DAP12. To follow up on our initial results that Treml4-Fc fusion proteins bind necrotic cells, we generated a knockout mouse to assess the role of Treml4 in the uptake and presentation of dying cells in vivo. Loss of Treml4 expression did not impair uptake of dying cells by CD8alpha(+) dendritic cells or cross-presentation of cell-associated Ag to CD8(+) T cells, suggesting overlapping function between Treml4 and other receptors in vivo. To further investigate Treml4 function, we took advantage of a newly generated mAb against Treml4 and engineered its H chain to express three different Ags (i.e., OVA, HIV GAGp24, and the extracellular domain of the breast cancer protein HER2). OVA directed to Treml4 was efficiently presented to CD8(+) and CD4(+) T cells in vivo. Anti-Treml4-GAGp24 mAbs, given along with a maturation stimulus, induced Th1 Ag-specific responses that were not observed in Treml4 knockout mice. Also, HER2 targeting using anti-Treml4 mAbs elicited combined CD4(+) and CD8(+) T cell immunity, and both T cells participated in resistance to a transplantable tumor. Therefore, Treml4 participates in Ag presentation in vivo, and targeting Ags with anti-Treml4 Abs enhances immunization of otherwise naive mice. PMID- 22210917 TI - Transient TLR activation restores inflammatory response and ability to control pulmonary bacterial infection in germfree mice. AB - Mammals are colonized by an astronomical number of commensal microorganisms on their environmental exposed surfaces. These symbiotic species build up a complex community that aids their hosts in several physiological activities. We have shown that lack of intestinal microbiota is accompanied by a state of active IL 10-mediated inflammatory hyporesponsiveness. The present study investigated whether the germfree state and its hyporesponsive phenotype alter host resistance to an infectious bacterial insult. Experiments performed in germfree mice infected with Klebsiella pneumoniae showed that these animals are drastically susceptible to bacterial infection in an IL-10-dependent manner. In germfree mice, IL-10 restrains proinflammatory mediator production and neutrophil recruitment and favors pathogen growth and dissemination. Germfree mice were resistant to LPS treatment. However, priming of these animals with several TLR agonists recovered their inflammatory responsiveness to sterile injury. LPS pretreatment also rendered germfree mice resistant to pulmonary K. pneumoniae infection, abrogated IL-10 production, and restored TNF-alpha and CXCL1 production and neutrophil mobilization into lungs of infected germfree mice. This effective inflammatory response mounted by LPS-treated germfree mice resulted in bacterial clearance and enhanced survival upon infection. Therefore, host colonization by indigenous microbiota alters the way the host reacts to environmental infectious stimuli, probably through activation of TLR-dependent pathways. Symbiotic gut colonization enables proper inflammatory response to harmful insults to the host, and increases resilience of the entire mammal microbiota consortium to environmental pressures. PMID- 22210916 TI - Clonotype and repertoire changes drive the functional improvement of HIV-specific CD8 T cell populations under conditions of limited antigenic stimulation. AB - Persistent exposure to cognate Ag leads to the functional impairment and exhaustion of HIV-specific CD8 T cells. Ag withdrawal, attributable either to antiretroviral treatment or the emergence of epitope escape mutations, causes HIV specific CD8 T cell responses to wane over time. However, this process does not continue to extinction, and residual CD8 T cells likely play an important role in the control of HIV replication. In this study, we conducted a longitudinal analysis of clonality, phenotype, and function to define the characteristics of HIV-specific CD8 T cell populations that persist under conditions of limited antigenic stimulation. Ag decay was associated with dynamic changes in the TCR repertoire, increased expression of CD45RA and CD127, decreased expression of programmed death-1, and the emergence of polyfunctional HIV-specific CD8 T cells. High-definition analysis of individual clonotypes revealed that the Ag loss induced gain of function within HIV-specific CD8 T cell populations could be attributed to two nonexclusive mechanisms: 1) functional improvement of persisting clonotypes; and 2) recruitment of particular clonotypes endowed with superior functional capabilities. PMID- 22210918 TI - TLR2 activation enhances HIV nuclear import and infection through T cell activation-independent and -dependent pathways. AB - TLR2 activation plays a crucial role in Neisseria gonorrheae-mediated enhancement of HIV infection of resting CD4(+) T cells. We examined signaling pathways involved in the HIV enhancing effect of TLR2. TLR2 but not IL-2 signals promoted HIV nuclear import; however, both signals were required for the maximal enhancing effect. Although TLR2 signaling could not activate T cells, it increased IL-2 induced T cell activation. Cyclosporin A and IkBalpha inhibitor blocked TLR2 mediated enhancement of HIV infection/nuclear import. PI3K inhibitor blocked HIV infection/nuclear import and T cell activation and exerted a moderate inhibitory effect on cell cycle progression in CD4(+) T cells activated by TLR2/IL-2. Blockade of p38 signaling suppressed TLR2-mediated enhancement of HIV nuclear import/infection. However, the p38 inhibitor did not have a significant effect on T cell activation or TCR/CD3-mediated enhancement of HIV infection/nuclear import. The cell cycle arresting reagent aphidicolin blocked TLR2- and TCR/CD3 induced HIV infection/nuclear import. Finally, cyclosporin A and IkappaBalpha and PI3K inhibitors but not the p38 inhibitor blocked TLR2-mediated IkappaBalpha phosphorylation. Our results suggest that TLR2 activation enhances HIV infection/nuclear import in resting CD4(+) T cells through both T cell activation dependent and -independent mechanisms. PMID- 22210920 TI - A case of estrogen receptor positive secretory carcinoma in a 9-Year-old girl with ETV6-NTRK3 fusion gene. AB - The patient was a 9-year-old premenarcheal pediatric female, whose chief complaint was a well-circumscribed palpable right breast mass without nipple discharge. Although the patient had noticed the lump 2 years prior to hospital admission, its size (1.5 * 1.3 cm) had been stable. There was no family history or previous history of malignancies. Physical examination showed a well delimited, elastic-firm and movable tumor just beneath the nipple and areolar complex. Regional lymph nodes were not palpable. Ultrasonography and breast computed tomography revealed a subareolar oval-shaped tumor exhibiting homogeneous echogenicity with clear margins. Distant metastases could not be detected using whole-body computed tomographic scans. A fine-needle aspiration cytology specimen showed atypical cells with prominent nucleoli and abundant intracellular secretory material, suggesting the possibility of secretory carcinoma. Histopathological analysis of the core needle biopsy specimen revealed that the tumor was a secretory carcinoma. The patient underwent total mastectomy with sentinel lymph node biopsy. Metastases were not observed in the removed lymph nodes. Estrogen receptor was weakly positive and progesterone receptor was negative. Human epidermal growth factor receptor 2 expression was also negative. In addition, the ETV6 (exon 5) and NTRK3 (exon 13) fusion gene was detected using the reverse transcription-polymerase chain reaction method. This gene is considered specific for secretory carcinoma. Immunohistochemistry revealed weak basal differentiation [cytokeratin 5/6(CK5/6)(+), vimentin(+) and epidermal growth factor receptor(+)]. The patient has received no adjuvant therapy and is currently disease free at 12 months after surgery. PMID- 22210919 TI - Regulation of eosinophil trafficking by SWAP-70 and its role in allergic airway inflammation. AB - Eosinophils are the predominant inflammatory cells recruited to allergic airways. In this article, we show that human and murine eosinophils express SWAP-70, an intracellular RAC-binding signaling protein, and examine its role in mediating eosinophil trafficking and pulmonary recruitment in a murine model of allergic airway inflammation. Compared with wild-type eosinophils, SWAP-70-deficient (Swap 70(-/-)) eosinophils revealed altered adhesive interactions within inflamed postcapillary venules under conditions of blood flow by intravital microscopy, exhibiting enhanced slow rolling but decreased firm adhesion. In static adhesion assays, Swap-70(-/-) eosinophils adhered poorly to VCAM-1 and ICAM-1 and exhibited inefficient leading edge and uropod formation. Adherent Swap-70(-/-) eosinophils failed to translocate RAC1 to leading edges and displayed aberrant cell surface localization/distribution of alpha4 and Mac-1. Chemokine-induced migration of Swap-70(-/-) eosinophils was significantly decreased, correlating with reduced intracellular calcium levels, defective actin polymerization/depolymerization, and altered cytoskeletal rearrangement. In vivo, recruitment of eosinophils to the lungs of allergen-challenged Swap-70(-/-) mice, compared with wild-type mice, was significantly reduced, along with considerable attenuation of airway inflammation, indicated by diminished IL-5, IL-13, and TNF alpha levels; reduced mucus secretion; and improved airway function. These findings suggest that regulation of eosinophil trafficking and migration by SWAP 70 is important for the development of eosinophilic inflammation after allergen exposure. PMID- 22210921 TI - Transcatheter arterial chemotherapy using miriplatin-lipiodol suspension with or without embolization for unresectable hepatocellular carcinoma. AB - OBJECTIVE: The purpose of this retrospective study was to compare the anti-tumor and adverse effects of transcatheter arterial chemoembolization and transcatheter arterial infusion chemotherapy using miriplatin-lipiodol suspension in patients with unresectable hepatocellular carcinoma. METHODS: From 2007 to 2010, 162 consecutive patients with unresectable hepatocellular carcinoma were treated using miriplatin. Of these, 122 patients were treated by transcatheter arterial chemoembolization and 40 were treated by transcatheter arterial infusion chemotherapy. There were no significant differences in baseline characteristics between the two groups, except for prothrombin activity. Assessments were performed 1-3 months after treatment. RESULTS: Objective responses were achieved in 13 patients undergoing transcatheter arterial infusion chemotherapy and 70 patients undergoing transcatheter arterial chemoembolization (33 versus 57%, P = 0.003). By multivariate logistic regression analysis, objective response was significantly associated with (i) a Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein <=10% (P = 0.004; risk ratio = 3.09; 95% confidence interval = 1.42-6.70), (ii) no previous transcatheter arterial chemoembolization (P = 0.007; risk ratio = 4.41; 95% confidence interval = 1.49-13.07) and (iii) transcatheter arterial chemoembolization using gelatin sponge 1 mm particles (P = 0.021; risk ratio = 2.97; 95% confidence interval = 1.17-7.49). Fever, anorexia and elevated serum transaminase levels were observed in most patients after miriplatin administration; there were no significant differences in the number of adverse effects between the two groups. CONCLUSIONS: These results suggest that the addition of embolizing agents to a treatment regimen using miriplatin lipiodol suspension can be safely used for patients with unresectable hepatocellular carcinoma. Objective response was achieved in a significantly higher number of transcatheter arterial chemoembolization patients than transcatheter arterial infusion chemotherapy patients. PMID- 22210922 TI - Breastfeeding and breast cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. AB - OBJECTIVE: We reviewed epidemiological studies on breastfeeding and breast cancer among Japanese women. This report is part of a series of articles written by our research group, whose aim was to evaluate the existing evidence concerning the association between health-related lifestyles and cancer. METHODS: Original data were obtained from MEDLINE searches using PubMed or from searches of the Ichushi database, complemented by manual searches. Evaluation of associations was based on the strength of evidence and the magnitude of association, together with biological plausibility. RESULTS: Three cohort studies and five case-control studies were identified. Cohort studies failed to find a significant inverse association between breastfeeding and the risk of breast cancer. Most of the case control studies observed a statistically significant or non-significant risk reduction for women who ever had breastfed or for women with a longer duration of breastfeeding. Experimental studies have supported the biological plausibility of a protective effect of breastfeeding on breast cancer risk. CONCLUSIONS: We conclude that breastfeeding possibly decreases the risk of breast cancer among Japanese women. PMID- 22210923 TI - Differences between squamous cell carcinoma and adenocarcinoma of the lung: are adenocarcinoma and squamous cell carcinoma prognostically equal? AB - OBJECTIVE: We analyzed pulmonary squamous cell carcinoma and adenocarcinoma patient survival in our single institution database, to evaluate the relationship of histologic analysis to survival and tumor aggressiveness. METHODS: We reviewed 1856 consecutive patients with surgically resected pulmonary squamous cell carcinoma or adenocarcinoma regarding their clinicopathologic characteristics, overall survival and recurrence-free proportion. RESULTS: In squamous cell carcinoma patients, there were more elderly male smokers and more patients with T2-4 tumors, moderately/poorly differentiated tumors, lymph node metastasis or vascular invasion than in adenocarcinoma patients. In all patients and in pN0 patients, patients with squamous cell carcinoma showed significantly poorer overall survival than those with adenocarcinoma, but there were no statistically significant differences in the recurrence-free proportion between the two histologic types. There were statistically significantly more lung cancer specific deaths in patients with adenocarcinoma than in patients with squamous cell carcinoma (P= 0.001). CONCLUSIONS: There were no differences in the development of recurrence between squamous cell carcinoma and adenocarcinoma of the lung, but considerable differences in overall survival were observed between the two histologic types. According to the stage grouping strategy of the TNM Classification for Lung and Pleural Tumours, these two histologic types need to be staged differently. This survival difference, however, may reflect the difference in patient background rather than in biologic aggressiveness between the two histologic types. PMID- 22210924 TI - Protein kinase Cbeta deficiency attenuates obesity syndrome of ob/ob mice by promoting white adipose tissue remodeling. AB - To explore the role of leptin in PKCbeta action and to determine the protective potential of PKCbeta deficiency on profound obesity, double knockout (DBKO) mice lacking PKCbeta and ob genes were created, and key parameters of metabolism and body composition were studied. DBKO mice had similar caloric intake as ob/ob mice but showed significantly reduced body fat content, improved glucose metabolism, and elevated body temperature. DBKO mice were resistant to high-fat diet-induced obesity. Moreover, PKCbeta deficiency increased beta-adrenergic signaling by inducing expression of beta1- and beta3-adrenergic receptors (beta-ARs) in white adipose tissue (WAT) of ob/ob mice. Accordingly, p38(MAPK) activation and expression of PGC-1alpha and UCP-1 were increased in WAT of DBKO mice. Consistent with results of in vivo studies, inhibition of PKCbeta in WAT explants from ob/ob mice also increased expression of above beta-ARs. In contrast, induction of PGC 1alpha and UCP-1 expression in brown adipose tissue of DBKO mice was not accompanied by changes in the expression of these beta-ARs. Collectively, these findings suggest that PKCbeta deficiency may prevent genetic obesity, in part, by remodeling the catabolic function of adipose tissues through beta-ARs dependent and independent mechanisms. PMID- 22210925 TI - The fatty acid translocase gene CD36 and lingual lipase influence oral sensitivity to fat in obese subjects. AB - The precise orosensory inputs engaged for dietary lipids detection in humans are unknown. We evaluated whether a common single nucleotide polymorphism (rs1761667) in the CD36 gene that reduces CD36 expression and the addition of orlistat, a lipase inhibitor, to reduce FA release from triacylglycerols (TGs), the main component of dietary fats, would attenuate fat orosensory sensitivity in humans. Twenty-one obese subjects with different rs1761667 genotypes (6 AA, 7 AG, and 8 GG) were studied on two occasions in which oleic acid and triolein orosensory detection thresholds were measured using emulsions prepared with and without orlistat. Subjects homozygous for the G-allele had 8-fold lower oral detection thresholds for oleic acid and triolein than subjects homozygous for the A allele, which associates with lower CD36 expression (P = 0.03). Thresholds for heterozygous subjects were intermediate. The addition of orlistat increased detection thresholds for triolein (log threshold = -0.3 +/- 0.2 vs. 0.3 +/- 0.1; P < 0.001) but not oleic acid (log threshold = -1.0 +/- 0.2 vs. -0.8 +/- 0.2; P > 0.2). In conclusion, this is the first experimental evidence for a role of CD36 in fat gustatory perception in humans. The data also support involvement of lingual lipase and are consistent with the concept that FA and not TG is the sensed stimulus. PMID- 22210928 TI - More than just a friend. PMID- 22210926 TI - Activation of the unfolded protein response pathway causes ceramide accumulation in yeast and INS-1E insulinoma cells. AB - Sphingolipids are not only important components of membranes but also have functions in protein trafficking and intracellular signaling. The LCB1 gene encodes a subunit of the serine palmitoyltransferase, which is responsible for the first step of sphingolipid synthesis. Here, we show that activation of the unfolded protein response (UPR) can restore normal ceramide levels and viability in yeast cells with a conditional defect in LCB1. Dependence on UPR was demonstrated by showing the HAC1-dependence of the suppression. A similar induction of ceramides by UPR seems to take place in mammalian cells. In rat pancreatic INS-1E cells, UPR activation induces the transcription of the CerS6 gene, which encodes a ceramide synthase. This correlates with the specific accumulation of ceramide with a C16 fatty acyl chain upon UPR activation. Therefore, our study reveals a novel connection between UPR induction and ceramide synthesis that seems to be conserved between yeast and mammalian cells. PMID- 22210929 TI - Care of the well newborn. AB - The birth of an infant is one of the most memorable experiences a family shares. Pediatric health care professionals are privileged to participate in this experience and recognize it as a time to promote the health of the newborn and family. Ideally, a well-designed care system would be replete with comprehensive supports during the prenatal period, birth, and transition to home. Opportunities exist to improve the care we deliver with universal screening of all pregnant women; coordinated assessments of family health, including mental health; and access to coordinated supports and services for mother and infant. If 90% of US families could comply with medical recommendations to breastfeed exclusively for 6 months, it is estimated the United States would save billions of dollars per year and prevent more than 900 deaths, nearly all of which would be in infants. All infants, whether breastfed or formula fed, should receive 400 IU supplemental vitamin D. Influenza and TdaP vaccination of postpartum mothers and other caregivers helps cocoon the vulnerable infant from influenza and pertussis until he or she can be fully vaccinated. When children reach the highest weight or length allowed by the manufacturer of their infant-only seat, they should continue to ride rear-facing in a convertible seat. It is best for children to ride rear-facing as long as possible to the highest weight and height allowed by the manufacturer of their convertible seat. PMID- 22210930 TI - Sexual abuse. AB - Child sexual abuse is a common pediatric problem that concerns all pediatric health care providers. Management of child sexual abuse is multifaceted and multidisciplinary. Specialized health providers can provide consultation, but this availability does not minimize the role of the referring physician who often has ongoing contact with the family. Physicians are mandated to report cases of suspected or confirmed sexual abuse. In the majority of cases, a child's statement about sexual abuse is the strongest evidence that abuse has occurred. Physical examination is normal in the majority of sexual abuse victims. Accurate, evidence-based interpretation of physical and laboratory findings is essential. Normal examinations, normal variants, and findings indicative of sexual contact must be differentiated. Forensic evidence collection and prophylactic treatments may be indicated when patients present within 72 hours of an abusive episode, and patients should be triaged accordingly. Potentially negative psychosocial outcomes should be addressed for patients and their families on initial evaluation and follow-up. PMID- 22210931 TI - Ethics for the pediatrician: obstetric conflict: when fetal and maternal interests are at odds. AB - The interests of the fetus generally are aligned with those of the pregnant woman. When they are not, the fetal best interests should be discussed, but respect for the autonomy of the pregnant woman and her bodily integrity should prevail. Gender bias and discrimination toward women should be avoided, and the circumstance of pregnancy should not be used as a reason to infringe upon or limit a competent woman's rights. Evidence indicates that providing prenatal care and treatment in a supportive, rather than coercive way is the most effective way to promote both maternal and child health. Concerns about potential harm to the fetus related to maternal decisions must be evaluated in the context of the best medical evidence, including what is known and what is uncertain. Threats or legal coercion should not be used to force treatment, in particular, to impose cesarean delivery. Hospital guidelines can be developed to support a framework of shared decision-making in the situation of maternal-fetal conflict and provide guidance for compassionate conflict resolution. Pediatricians have an important role in informing the discussion about care and outcomes. At times, an ethics consult maybe helpful to mediate conflict resolution. Intervention by the courts is rarely appropriate or indicated and should be avoided. PMID- 22210932 TI - Index of suspicion. Case 1: Persistent fever and cough following episodes of emesis in a 7-year-old girl. Case 2: Blurry vision and unilateral dilated pupil in a 14-year-old girl. Case 3: Swelling, pain, and erythema of the thumb in a 10 year-old girl with habits of nail biting and thumb sucking. PMID- 22210933 TI - Pleural effusion. PMID- 22210935 TI - Volunteering for your profession?? PMID- 22210934 TI - Scabies: a review of diagnosis and management based on mite biology. AB - Scabies is a contagious parasitic dermatitis that is a significant cause of morbidity, especially outside of the United States. Scabies is diagnosed most often by correlating clinical suspicion with the identification of a burrow. Although scabies should be on the differential for any patient who presents with a pruritic dermatosis, clinicians must consider a wide range of diagnostic possibilities. This approach will help make scabies simultaneously less over- and underdiagnosed by clinicians in the community. Atypical or otherwise complex presentations may necessitate the use of more definitive diagnostic modalities, such as microscopic examination of KOH prepared skin scrapings, high-resolution digital photography, dermoscopy, or biopsy. Scabies therapy involves making the correct diagnosis, recognizing the correct clinical context to guide treatment of contacts and fomites, choosing the most effective medication, understanding how to use the agent properly, and following a rational basis for when to use and reuse that agent. Although the development of new therapeutic agents is always welcome, tried and true treatments are still effective today. Permethrin is the gold standard therapy, with malathion being an excellent topical alternative. Ivermectin is an effective oral alternative that is especially useful in crusted scabies, patients who are bed ridden, and in institutional outbreaks. Despite the availability of effective therapeutics, treatment failures still occur, mostly secondary to application error (ie, failure to treat the face and scalp or close contacts, failure to reapply medication) or failure to decontaminate fomites. Because increasing resistance to scabies treatments may be on the horizon, we propose that standard of care for scabies treatment should involve routine treatment of the scalp and face and re-treating patients at day 4 on the basis of the scabies life cycle to ensure more efficient mite eradication. Practitioners should attempt to treat all close contacts simultaneously with the source patient. To eradicate mites, all fomites should be placed in a dryer for 10 minutes on a high setting, furniture and carpets vacuumed, and nonlaunderables isolated for a minimum of 2 days, or, for those who wish to be rigorous, 3 weeks. PMID- 22210936 TI - An ethicist's commentary on animal intelligence and animal welfare. PMID- 22210938 TI - Surgical treatment and radiation therapy of frontal lobe meningiomas in 7 dogs. AB - The cases of 7 adult dogs with generalized seizures managed by surgical excision and radiation therapy for frontal lobe meningiomas were reviewed. The neurological examination was unremarkable in 6 of the 7 dogs. Five dogs were operated on using a bilateral transfrontal sinus approach and 2 using a unilateral sinotemporal approach to the frontal lobe. One dog was euthanized 14 d after surgery; radiation therapy was initiated 3 wk after surgery in the remaining 6 dogs. Long-term follow-up consisted of neurological examination and magnetic resonance imaging (MRI) and/or computed tomography (CT) scan after radiation therapy. The mean survival time for dogs that had surgery and radiation therapy was 18 mo after surgery. Frontal lobe meningiomas have been associated with poor prognosis. However, the surgical approaches used in these cases, combined with radiation therapy, allow a survival rate for frontal lobe meningiomas similar to that for meningiomas located over the cerebral convexities. PMID- 22210939 TI - Evaluation of methods of rapid mass killing of segregated early weaned piglets. AB - The operational logistics of mass killing of healthy, surplus piglets by manual blunt force trauma, controlled blunt force trauma, intraperitoneal injection of barbiturate, and free bullet were recorded. Objective performance variables evaluated were, speed of application, human resource and input cost, animal restraint required, and failure rate. Subjective evaluation of esthetics and difficulty of application indicated manual blunt force trauma is an unacceptable technique. Under field conditions, physical methods of killing were superior to intraperitoneal injection of concentrated pentobarbital. Considering animal welfare metrics in isolation, controlled blunt force trauma was superior to all other techniques attempted. PMID- 22210940 TI - Ileal impaction in 245 horses: 1995-2007. AB - The objective of this study was to identify parameters that would assist in determining the probability of a successful outcome with medical management versus surgical intervention in horses with ileal impaction. Medical records of 245 horses admitted for ileal impaction were reviewed and placed into 2 groups: medical (med) and surgical (sx) treatment. Persistence of abdominal pain, gastric reflux, frequency of analgesic administration, and 1-year survival were evaluated. There were no differences in signalment, abdominal pain, or heart rate among groups; however, significantly more sx horses had peritoneal fluid abnormalities (51%) and produced gastric reflux (62%) than did med horses (38% and 15%, respectively). Eighty-nine percent of med horses required repeated analgesic administration for successful resolution. One-year survival was 91% for sx horses and 92% for med horses. Horses with ileal impaction responsive to analgesic therapy with minimal gastric reflux are likely to be managed successfully with medical treatment. Horses with persistent abdominal pain and gastric reflux are candidates for surgery. PMID- 22210941 TI - Esophageal laceration and obstruction caused by a foreign body in 2 young foals. AB - This report describes 2 foals with esophageal laceration due to ingestion of foreign bodies. Endoscopic examination of the esophagus revealed full thickness esophageal laceration in 1 colt and partial thickness laceration of the esophagus in the other. The esophageal obstruction was relieved by repetitive esophageal lavages and flush under general anesthesia in both foals. PMID- 22210942 TI - Two cases of vaginal bleeding in pet rats. AB - Two unrelated rats were presented to the Western College of Veterinary Medicine emergency service for vaginal bleeding. Each was taken to surgery due to marked blood loss and suspicion of uterine pathology. Despite similar clinical presentation, gross and histopathologic examination revealed 2 different underlying disease processes, uterine dilatation with mild endometritis and vaginal polyp. PMID- 22210943 TI - Costochondral junction osteomyelitis in 3 septic foals. AB - The costochondral junction constitutes a potential site of infection in septic foals and it could be favored by thoracic trauma. Standard radiographs and ultrasonography are useful tools for diagnosis of this condition and ultrasound guided needle aspiration could permit the definitive confirmation of infection. PMID- 22210944 TI - Central nervous system relapses in 3 dogs with B-cell lymphoma. AB - This report describes cases of central nervous system (CNS) relapse that occurred during chemotherapy in 3 dogs with lymphoma. Diagnosis was made by a combination of clinical signs and cytology of cerebrospinal fluid. The suspected risk factors, clinical features common to the 3 dogs, and treatment options are discussed. PMID- 22210945 TI - Acute respiratory distress syndrome in an alpaca cria. AB - A 7-hour-old alpaca was presented for lethargy and depression. The cria responded favorably to initial treatment but developed acute-onset dyspnea 48 hours later. Acute respiratory distress syndrome was diagnosed by thoracic imaging and blood gas analysis. The cria was successfully treated with corticosteroids and discharged from the hospital. PMID- 22210946 TI - Presumptive bovine neonatal pancytopenia in a Holstein calf in Quebec. AB - An 18-day-old heifer was presented with fever, depression, tachycardia, tachypnea, and prolonged bleeding time. Blood tests revealed severe anemia, thrombocytopenia, and leucopenia. The animal was negative by PCR for bovine virus diarrhea virus antigen. The findings supported a diagnosis of bovine neonatal pancytopenia. Treatments included fresh whole blood transfusion and antibiotics. The animal recovered fully. PMID- 22210947 TI - Hydrops in a heifer as a result of in-vitro fertilization. AB - A 2-year-old Holstein heifer was presented at 7 months gestation with a 2-day history of premature mammary enlargement. It was suspected that the dam was showing clinical symptoms of a pending abortion. Through diagnostic testing and postmortem examination, a final diagnosis of hydrops allantois and amnion was determined. PMID- 22210948 TI - Perpetration-induced traumatic stress - A risk for veterinarians involved in the destruction of healthy animals. PMID- 22210949 TI - Non-DVM wages: Less is not necessarily better. PMID- 22210950 TI - Diagnostic ophthalmology. PMID- 22210951 TI - Investigation of the oxygen exchange mechanism on Pt|yttria stabilized zirconia at intermediate temperatures: Surface path versus bulk path. AB - The oxygen exchange kinetics of platinum on yttria-stabilized zirconia (YSZ) was investigated by means of geometrically well-defined Pt microelectrodes. By variation of electrode size and temperature it was possible to separate two temperature regimes with different geometry dependencies of the polarization resistance. At higher temperatures (550-700 degrees C) an elementary step located close to the three phase boundary (TPB) with an activation energy of ~1.6 eV was identified as rate limiting. At lower temperatures (300-400 degrees C) the rate limiting elementary step is related to the electrode area and exhibited a very low activation energy in the order of 0.2 eV. From these observations two parallel pathways for electrochemical oxygen exchange are concluded.The nature of these two elementary steps is discussed in terms of equivalent circuits. Two combinations of parallel rate limiting reaction steps are found to explain the observed geometry dependencies: (i) Diffusion through an impurity phase at the TPB in parallel to diffusion of oxygen through platinum - most likely along Pt grain boundaries - as area-related process. (ii) Co-limitation of oxygen diffusion along the Pt|YSZ interface and charge transfer at the interface with a short decay length of the corresponding transmission line (as TPB-related process) in parallel to oxygen diffusion through platinum. PMID- 22210958 TI - Information processing, computation, and cognition. AB - Computation and information processing are among the most fundamental notions in cognitive science. They are also among the most imprecisely discussed. Many cognitive scientists take it for granted that cognition involves computation, information processing, or both - although others disagree vehemently. Yet different cognitive scientists use 'computation' and 'information processing' to mean different things, sometimes without realizing that they do. In addition, computation and information processing are surrounded by several myths; first and foremost, that they are the same thing. In this paper, we address this unsatisfactory state of affairs by presenting a general and theory-neutral account of computation and information processing. We also apply our framework by analyzing the relations between computation and information processing on one hand and classicism, connectionism, and computational neuroscience on the other. We defend the relevance to cognitive science of both computation, at least in a generic sense, and information processing, in three important senses of the term. Our account advances several foundational debates in cognitive science by untangling some of their conceptual knots in a theory-neutral way. By leveling the playing field, we pave the way for the future resolution of the debates' empirical aspects. PMID- 22210959 TI - Biological cell-electrical field interaction: stochastic approach. AB - The present work demonstrates how a stochastic model can be implemented to obtain a realistic description of the interaction of a biological cell with an external electric field. In our model formulation, the stochasticity is adopted by introducing various levels of forcing intensities in model parameters. The presence of noise in nuclear membrane capacitance has the most significant effect on the current flow through a biological cell. A plausible explanation based on underlying physics and biological structure of the nuclear membrane is proposed to explain such results. PMID- 22210960 TI - The design of a reflectionless arterial prosthesis. AB - We propose a new technique to characterize a reflectionless arterial prosthesis. The corresponding transmission and reflection coefficients are determined from the geometric and the elastic properties of the arterial wall, and the interaction between the latter and the prosthesis are studied accordingly. PMID- 22210957 TI - A pathway to leadership for adult immunization: recommendations of the National Vaccine Advisory Committee: approved by the National Vaccine Advisory Committee on June 14, 2011. PMID- 22210961 TI - Effects of magnesium ions on two EMCV IRES key activity fragments. AB - Using NMR magnetization transfer from water and ammonia-catalyzed exchange of the imino protons, changes have been monitored in base-pair kinetics induced by Mg(2 + ) in two key activity fragments r(CACCUGGCGACAGGUG) and r(GGCCAAAAGCC) of the encephalomyocarditis virus internal ribosome entry site. For r(CACCUGGCGACAGGUG), the addition of Mg(2 + ) reveals two types of base-pairs: r(U(545).A) and r(G(546).C), in the first category, have lifetimes only slightly higher in the presence of Mg(2 + ), whereas their dissociation constants are substantially reduced. This behavior has been termed proximal. The base-pairs r(G(553).C) and r(G(554).C), in the second category, have lifetimes substantially higher in the presence of Mg(2 + ), whereas their dissociation constants remain almost constant. This behavior has been termed distal. Mg(2 + ) has a specific effect on r(CACCUGGCGACAGGUG), the magnitude of which is progressively modulated from the proximal region of the 16-mer towards its distal region. For r(GGCCAAAAGCC), an intermediate behavior is found for base-pairs r(G(565).C) and r(G(572).C). Their lifetimes are slightly higher in the presence of Mg(2 + ) and their dissociation constants are significantly lower, a behavior resembling that of the 16-mer proximal region. These results indicate that Mg(2 + ) diffusively moves around r(GGCCAAAAGCC). PMID- 22210962 TI - Binding free energy calculation with QM/MM hybrid methods for Abl-Kinase inhibitor. AB - We report a Quantum mechanics/Molecular Mechanics-Poisson-Boltzmann/ Surface Area (QM/MM-PB/SA) method to calculate the binding free energy of c-Abl human tyrosine kinase by combining the QM and MM principles where the ligand is treated quantum mechanically and the rest of the receptor by classical molecular mechanics. To study the role of entropy and the flexibility of the protein ligand complex in a solvated environment, molecular dynamics calculations are performed using a hybrid QM/MM approach. This work shows that the results of the QM/MM approach are strongly correlated with the binding affinity. The QM/MM interaction energy in our reported study confirms the importance of electronic and polarization contributions, which are often neglected in classical MM-PB/SA calculations. Moreover, a comparison of semi-empirical methods like DFTB-SCC, PM3, MNDO, MNDO PDDG, and PDDG-PM3 is also performed. The results of the study show that the implementation of a DFTB-SCC semi-empirical Hamiltonian that is derived from DFT gives better results than other methods. We have performed such studies using the AMBER molecular dynamic package for the first time. The calculated binding free energy is also in agreement with the experimentally determined binding affinity for c-Abl tyrosine kinase complex with Imatinib.Electronic supplementary material The online version of this article (doi:10.1007/s10867-010-9199-z) contains supplementary material, which is available to authorized users. PMID- 22210963 TI - Modulating DNA configuration by interfacial traction: an elastic rod model to characterize DNA folding and unfolding. AB - As a continuum model of DNA, a thin elastic rod subjected to interfacial interactions is used to investigate the equilibrium configuration of DNA in intracellular solution. The interfacial traction between the rod and the solution environment is derived in detail. Kirchhoff's theory of elastic rods is used to analyze the equilibrium configuration of a DNA segment under the action of the interfacial traction. The influences of the interfacial energy factor and bending stiffness on the toroidal spool formation of the DNA segment are discussed. The results show that the equilibrium configuration of DNA is mainly determined by competition between the interfacial energy and elastic strain energy of the DNA itself, and the interfacial traction is one of the forces that drives DNA folding and unfolding. PMID- 22210964 TI - Global stability and persistence in LG-Holling type II diseased predator ecosystems. AB - A Leslie-Gower-Holling type II model is modified to introduce a contagious disease in the predator population, assuming that disease cannot propagate to the prey. All the system's equilibria are determined and the behaviour of the system near them is investigated. The main mathematical issues are global stability and bifurcations for some of the equilibria, together with sufficient conditions for persistence of the ecosystem. Counterintuitive results on the role played by intraspecific competition are highlighted. PMID- 22210965 TI - Optical method for monitoring of photodynamic inactivation of bacteria. AB - Photodynamic inactivation is a new promising approach to treat bacterial infections. Usually, the evaluation of the efficacy of this method is done through time-consuming and labor-intensive microbiological test methods. This paper describes the development and implementation of an optical method to evaluate the photodynamic inactivation of bacteria based on non-invasive diffuse reflectance measurements. Five Staphylococcus aureus cultures and 15 mice have been used in this study. A skin lesion was created on the back of all animals, and it was contaminated with S. aureus (5.16 +/- 0.013 log CFU/ml). Toluidine Blue O (c = 8.67 * 10 (- 3) M) has been used as a photosensitiser agent. The bacterial cultures and animals were exposed to laser radiation (lambda = 635 nm, P = 15 mW, DE = 8.654 J/cm(2)) for 20 min. The photodynamic inactivation of bacteria was monitored by acquiring the wounds' reflection spectra at different time points and by microbiological exams on the bioptical material. The good correlation between the diffuse reflectance and colony-forming units demonstrates the value of this optical method based on diffuse reflectance measurements as a rapid technique to monitor photodynamic bacterial inactivation. PMID- 22210966 TI - DNA condensation by TmHU studied by optical tweezers, AFM and molecular dynamics simulations. AB - The compaction of DNA by the HU protein from Thermotoga maritima (TmHU) is analysed on a single-molecule level by the usage of an optical tweezers-assisted force clamp. The condensation reaction is investigated at forces between 2 and 40 pN applied to the ends of the DNA as well as in dependence on the TmHU concentration. At 2 and 5 pN, the DNA compaction down to 30% of the initial end to-end distance takes place in two regimes. Increasing the force changes the progression of the reaction until almost nothing is observed at 40 pN. Based on the results of steered molecular dynamics simulations, the first regime of the length reduction is assigned to a primary level of DNA compaction by TmHU. The second one is supposed to correspond to the formation of higher levels of structural organisation. These findings are supported by results obtained by atomic force microscopy. PMID- 22210967 TI - Reinfection induced disease in a spatial SIRI model. AB - Spatial models are widely used in epidemiology to investigate persistence and extinction of disease as well as their spatial patterns. One of the most important issues in studying epidemic models is the role of infection on the persistence and extinction of the disease. In this paper, we investigate a spatial susceptible-infected-recovered-infected model using cellular automata. We show that, in the regime where disease disappears in the susceptible-infected recovered-susceptible model, spiral and target waves will emerge in the two dimensional space due to the reinfection. The obtained results may point out that reinfection has great influence on the epidemic spreading, which enriches the findings of spatiotemporal dynamics in epidemic models. PMID- 22210968 TI - Experimental observation of increased fluctuations in an order parameter before epochs of extended brain synchronization. AB - The identification of epileptic seizure precursors has potential clinical relevance. It is conjectured that seizures may be represented by dynamical bifurcations and that an adequate order parameter to characterize brain dynamics is the phase difference in the oscillatory activity of neural systems. In this study, the critical point hypothesis that seizures, or more generally periods of widespread high synchronization, represent bifurcations is empirically tested by monitoring the growth of fluctuations in the putative order parameter of phase differences between magnetoencephalographic and electroencephalographic signals in nearby brain regions in patients with epilepsy and normal subjects during hyperventilation. Implications of the results with regard to epileptic phenomena are discussed. PMID- 22210969 TI - pH effect on cellular uptake of Sn(IV) chlorine e6 dichloride trisodium salt by cancer cells in vitro. AB - The effects of pH value and presence of serum in an incubation medium on photosensitizer drug cellular uptake in MCF7 cancer cells have been investigated. The results showed that the presence of serum in an incubation medium reduced the drug cellular uptake at all pH values. It has been found that decreasing on pH values of the incubation medium increased the cellular uptake of the drug, demonstrating selective uptake of the sensitizer. The HepG2 liver cancer cells exhibited more drug cellular uptake than CCD-18CO normal colon cells, which assessed the selectivity uptake of photosensitizer on cancerous cells. The concentration of photosensitizer measured in 10(6) cells showed a good correlation to the incubation time. Fluorescence and absorption spectroscopy been have used to examine the cells. PMID- 22210970 TI - Market microstructure matters when imposing a Tobin tax-Evidence from the lab. AB - TRADING IN FX MARKETS IS DOMINATED BY TWO MICROSTRUCTURES: exchanges with market makers and OTC-markets without market makers. Using laboratory experiments we test whether the impact of a Tobin tax is different in these two market microstructures. We find that (i) in markets without market makers an unilaterally imposed Tobin tax (i.e. a tax haven exists) increases volatility. (ii) In contrast, in markets with market makers we observe a decrease in volatility in unilaterally taxed markets. (iii) An encompassing Tobin tax has no impact on volatility in either setting. Efficiency does not vary significantly across tax regimes. PMID- 22210971 TI - Semiparametric Bayesian approaches to joinpoint regression for population-based cancer survival data. AB - According to the American Cancer Society report (1999), cancer surpasses heart disease as the leading cause of death in the United States of America (USA) for people of age less than 85. Thus, medical research in cancer is an important public health interest. Understanding how medical improvements are affecting cancer incidence, mortality and survival is critical for effective cancer control. In this paper, we study the cancer survival trend on the population level cancer data. In particular, we develop a parametric Bayesian joinpoint regression model based on a Poisson distribution for the relative survival. To avoid identifying the cause of death, we only conduct analysis based on the relative survival. The method is further extended to the semiparametric Bayesian joinpoint regression models wherein the parametric distributional assumptions of the joinpoint regression models are relaxed by modeling the distribution of regression slopes using Dirichlet process mixtures. We also consider the effect of adding covariates of interest in the joinpoint model. Three model selection criteria, namely, the conditional predictive ordinate (CPO), the expected predictive deviance (EPD), and the deviance information criteria (DIC), are used to select the number of joinpoints. We analyze the grouped survival data for distant testicular cancer from the Surveillance, Epidemiology, and End Results (SEER) Program using these Bayesian models. PMID- 22210972 TI - Population-dynamics focussed rapid rural mapping and characterisation of the peri urban interface of Kampala, Uganda. AB - In developing countries, cities are rapidly expanding and urban and peri-urban agriculture (UPA) has an important role in feeding these growing urban populations; however such agriculture also carries public health risks such as zoonotic disease transmission. It is important to assess the role of UPA in food security and public health risks to make evidence-based decisions on policies. Describing and mapping the peri-urban interface (PUI) are the essential first steps for such an assessment. Kampala, the capital city of Uganda is a rapidly expanding city where the PUI has not previously been mapped or properly described. In this paper we provide a spatial representation of the entire PUI of Kampala economic zone and determine the socio-economic factors related with peri urbanicity using a population-dynamics focussed rapid rural mapping. This fills a technical gap of rapid rural mapping and offers a simple and rapid methodology for describing the PUI which can be applied in any city in developing countries for wide range of studies. PMID- 22210973 TI - Stochastic Stability for Flows with Smooth Invariant Measures. AB - We study the notion of stochastic stability with respect to diffusive perturbations for flows with smooth invariant measures. We investigate the question fully for non-singular flows on the circle. We also show that volume preserving flows are stochastically stable with respect to perturbations that are associated with homogeneous diffusions. PMID- 22210974 TI - The future is physio .... PMID- 22210976 TI - Clinical impact and evidence base for physiotherapy in treating childhood chronic pain. AB - PURPOSE: As part of the special series on pain, our objectives are to describe the key features of chronic pain in children, present the rationale for interdisciplinary treatment, report a case study based on our biopsychosocial approach, and highlight the integral role of physiotherapy in reducing children's pain and improving function. We also evaluate the evidence base supporting physiotherapy for treating chronic neuropathic pain in children. SUMMARY OF KEY POINTS: Chronic pain affects many children and adolescents. Certain challenging pain conditions begin primarily during adolescence and disproportionately affect girls and women. Children with these conditions require an interdisciplinary treatment programme that includes physiotherapy as well as medication and/or psychological intervention. Converging lines of evidence from cohort follow-up studies, retrospective chart reviews, and one randomized controlled trial support the effectiveness of physiotherapy within an interdisciplinary programme for treating children with chronic pain. CONCLUSIONS: Evidence-based practice dictates that health care providers adopt clear guidelines for determining when treatments are effective and for identifying children for whom such treatments are most effective. Thus, additional well-designed trials are required to better identify the specific physiotherapy modalities that are most important in improving children's pain and function. PMID- 22210977 TI - Preliminary development and validation of a paediatric cardiopulmonary physiotherapy discharge tool. AB - PURPOSE: The purpose of this study was to develop a paediatric cardiopulmonary physiotherapy (CPT) discharge tool. We report on the initial stages of its development and the tool's sensibility (face/content validity, feasibility, and ease of usage). METHODS: Using a modified Delphi technique, a panel of paediatric physiotherapy clinicians and academic leaders in the area of CPT (n=25) was recruited. Four rounds of discussion among the members of the Delphi panel focused on (1) generation of discharge items, (2) reduction of items, (3) discussion of contentious items and refinement of criterion definitions, and (4) determination of scoring options for the test instrument. The sensibility of a draft of the tool was assessed using a sample of convenience (n=15). RESULTS: Six items (auscultation, discharge planning, mobility, oxygen saturation, secretion clearance, and signs of respiratory distress) were identified for inclusion in the tool. The global mean of all sensibility domains was 6.4 (median=6.6) of a possible 7.0. CONCLUSION: Using a modified Delphi process, we developed a six item paediatric CPT discharge planning tool with good face and content validity. Future work will determine the scoring method for using this tool, interrater reliability, and predictive validity to facilitate optimal timing of hospital discharge for paediatric CPT patients. PMID- 22210975 TI - Bone health and type 2 diabetes mellitus: a systematic review. AB - PURPOSE: To systematically review the literature related to bone health in older adults with type 2 diabetes mellitus (T2DM). METHODS: We conducted a systematic review of the literature from January 2005 until February 2010, using keywords related to T2DM and bone-health imaging technology in older adults (aged >=60 years) to search PubMed, OVID MEDLINE, Ageline, CINAHL, Embase, and PsycINFO. RESULTS: We found a total of 13 studies that met the inclusion criteria for this review. The majority of the studies used dual X-ray absorptiometry (DXA) and showed either higher or similar areal bone mineral density (aBMD) for older adults with T2DM relative to healthy controls. Studies using more advanced imaging suggested that there may be differences in bone geometry between older adults with and without T2DM. CONCLUSIONS: Older adults with T2DM have similar or higher aBMD at the hip relative to older adults without T2DM, despite previous literature reporting an increased risk of low-trauma fractures. Recent studies with advanced imaging have suggested that there may be differences in bone geometry between older adults with T2DM and those without. Health professionals, especially physiotherapists, should be aware of the increased risk and include assessment of fall risk factors and exercise prescription for fall prevention for older adults with T2DM. PMID- 22210978 TI - Clinician's Commentary. PMID- 22210980 TI - Tests of static balance do not predict mobility performance following traumatic brain injury. AB - PURPOSE: To investigate the extent to which different single-limb support (SLS) parameters predict mobility performance following traumatic brain injury (TBI). METHODS: Seventy-one people with mobility limitations following TBI were assessed for balance and mobility performance in a human movement laboratory. Participants performed a clinical test of static balance that involved balancing in SLS on each leg with eyes open and eyes closed. Mobility performance was measured by self-selected gait speed and performance on the High Level Mobility Scale (HiMAT). Dynamic stability during walking was measured by quantifying lateral centre of mass (COM) displacement, width of base of support, and proportion of double-support stance time. RESULTS: Total static balance scores were strongly correlated with HiMAT scores (r=0.57, p<0.001) and lateral COM displacement (r= 0.51, p<0.001). Despite these strong correlations, however, balance scores explained only 32% of the variance in advanced mobility skills (r(2)=0.32) and 26% of the variance in lateral COM displacement (r(2)=0.26). CONCLUSIONS: Since mobility performance varied widely for people with similar levels of balance, SLS time was not able to predict dynamic stability during gait, self-selected gait speed, or advanced mobility skills in people with TBI. PMID- 22210979 TI - Psychometric Properties of Activity, Self-Efficacy, and Quality-of-Life Measures in Individuals with Parkinson Disease. AB - PURPOSE: To examine the psychometric properties of six outcome measures in people with Parkinson disease (PD). METHOD: Twenty-four participants completed the following twice within 2 weeks: the timed up-and-go test (TUG), Northwestern University Disability Scale (NUDS), Schwab & England ADL Scale (S&E), Activities specific Balance Confidence (ABC) Scale, PD Questionnaire-Short Form (PDQ 8), and Stanford Self-Efficacy for Managing Chronic Disease 6-Item Scale (SSE). Internal consistency, test-retest reliability (ICC[3,1]), and minimal detectable change (MDC) scores were calculated. Convergent and discriminant validity of the ABC were examined. RESULTS: Cronbach's alpha scores for the NUDS, ABC, PDQ-8, and SSE were 0.47, 0.92, 0.72, and 0.91 respectively. The intra-class correlation coefficient (ICC[3,1]) for the TUG was 0.69 and could be improved by averaging two trials. ICCs for the NUDS, S&E, ABC, PDQ-8, and SSE were 0.56, 0.70, 0.79, 0.82, and 0.72 respectively. The ABC correlated with the TUG (r=-0.44, p=0.03) and with PDQ-8 (r(s)=0.51, p=0.01) and NUDS (r(s)=0.48, p=0.02) walking items. The ABC was able to discriminate between stages 1 and 3 of disease progression but not between stages 1 and 2, which suggests that the ABC can distinguish large differences in disease progression but cannot detect more subtle differences. CONCLUSIONS: Homogeneity of the ABC, PDQ-8, and SSE is good to excellent. Test retest reliability scores of all measures except the NUDS are moderate to good. The ABC is a valid measure for use in PD. The MDC statistic may be useful for interpreting group score changes. PMID- 22210981 TI - Inter-professional Education in the Acute-Care Setting: The Clinical Instructor's Point of View. AB - PURPOSE: The purpose of this study was to gain an understanding of the opportunities and challenges involved in providing clinical inter-professional education (IPE) to physical therapy (PT) students in the acute-care setting from the perspective of PT clinical instructors (CIs). METHODS: Focus groups were conducted in four acute-care hospitals in Toronto. Participants were recruited using a purposive and convenience sampling approach in order to enhance our understanding of the perceptions of acute-care PT CIs. Eighteen full-time PT CIs with an average of 11 years in practice participated. A constant comparative process was employed to identify recurrent issues and themes within and between groups. RESULTS: Three main themes emerged from the focus groups: (1) Clinical IPE happens when inter-professional collaboration (IPC) occurs; however, IPC differs according to setting, access to other professions, time, support, and structure. (2) IPE is a lifelong learning process that applies to both CIs and students. (3) Student preparedness is a prerequisite for clinical IPE. CONCLUSIONS: IPC is an integral part of clinical IPE that requires ongoing commitment and reflection by CIs to ensure that they are ready to instruct students who have some preparation in formal IPE. More knowledge about providing clinical IPE in a structured manner, through academic and health institutions, will allow CIs to become role models for future generations of PT students. PMID- 22210982 TI - Clinician's Commentary. PMID- 22210983 TI - The feasibility and acceptability of using a portfolio to assess professional competence. AB - PURPOSE: Little is known about physical therapists' views on the use of portfolios to evaluate professional competence. The purpose of this study was to gather the opinions of physical therapists on the feasibility and acceptability of a portfolio prepared to demonstrate evidence of clinical specialization through reported activities and accomplishments related to professional development, leadership, and research. METHODS: Twenty-nine Canadian physical therapists practising in the neurosciences area were given 8 weeks to prepare a professional portfolio. Participants submitted the portfolio along with a survey addressing the preparation of the portfolio and its role as an assessment tool. Qualitative content analysis was used to interpret the participants' comments. RESULTS: Participants reported that maintaining organized records facilitated the preparation of their portfolio. They experienced pride when reviewing their completed portfolios, which summarized their professional activities and highlighted their achievements. Concerns were noted about the veracity of self reported records and the ability of the documentation to provide a comprehensive view of the full scope of the professional competencies required for clinical specialization (e.g., clinical skills). CONCLUSION: The study's findings support the feasibility and acceptability of a portfolio review to assess professional competence and clinical specialization in physical therapy and have implications for both physical therapists and professional agencies. PMID- 22210984 TI - Clinician's Commentary. PMID- 22210985 TI - Whole-body vibration to treat low back pain: fact or fad? AB - PURPOSE: The purpose of this systematic review was to evaluate the current evidence base for whole-body vibration as a treatment for low back pain (LBP). SUMMARY OF KEY POINTS: Whole-body vibration through occupational exposure has previously been recognized as an aetiological factor in LBP. Previous studies have identified whole-body vibration (WBV) as a cause of LBP in various sitting based occupations that involve machinery and repetitive vibration. In the last decade, however, WBV has been advocated as a safe and effective treatment for LBP. Despite the growing popularity of WBV in clinical practice, this systematic review of the literature identified only two studies that investigated the effectiveness of WBV as a treatment option for LBP, and an assessment of the quality of these studies demonstrated several methodological problems that may have biased their findings. While there is emerging evidence for the effectiveness of WBV in treating some medical conditions, the evidence for WBV as a treatment for LBP remains equivocal. RECOMMENDATIONS: Based on the current body of evidence, routine use of WBV to treat LBP should be undertaken with caution. Further rigorous research designed to investigate the effectiveness of WBV as a safe and high-quality treatment for LBP is required. PMID- 22210986 TI - Development and Early Evaluation of an Inter-professional Post-licensure Education Programme for Extended Practice Roles in Arthritis Care. AB - PURPOSE: The Advanced Clinician Practitioner in Arthritis Care (ACPAC) Program was developed to train experienced physical and occupational therapists within extended practice roles with the aim of facilitating optimal, timely, and appropriate delivery of health care to patients with arthritis. This paper presents (1) the development of the ACPAC Program and (2) performance across the programme, as well as early quantitative and qualitative changes in clinical practice roles for the 2006 through 2008 cohorts of ACPAC Program graduates (n=19). METHODS: Measurement of change in skills and knowledge involved standardized baseline and end-of-programme examinations as well as self evaluation of a number of areas of clinical competence. Practice-focused surveys issued at baseline, mid-programme, and end of programme, as well as at 6 and 12 months after graduation, evaluated the practitioners' integration of advanced knowledge and skills acquired during the ACPAC Program into their extended practice roles. RESULTS: Participants significantly increased their scores on examinations of clinical knowledge (p<0.001) and skills (p<0.001) from baseline through programme completion. There was an increase in frequency of performance of clinical tasks and assumption of responsibilities related to their extended practice roles from the beginning to the end of the programme. The five areas that changed in relation to these new roles were increased clinical responsibilities, efficiencies in practice settings, roles as educational leaders and mentors in the field of arthritis care, inter-professional collaboration, and improved access to care for patients with arthritis, particularly in remote areas. CONCLUSION: Graduates of the ACPAC Program have demonstrated knowledge and skills for practising in extended roles that enhance the available human health resource pool for patients with arthritis. PMID- 22210987 TI - Clinician's Commentary. PMID- 22210988 TI - Comparison of the original and reduced versions of the Berg Balance Scale and the Western Ontario and McMaster Universities Osteoarthritis Index in patients following hip or knee arthroplasty. AB - PURPOSE: To compare the original and reduced versions of the Berg Balance Scale (BBS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), as completed by patients following total hip arthroplasty (THA) or total knee arthroplasty (TKA), with respect to their potential utility in clinical and research settings. METHOD: Patients with THA (n=26) or TKA (n=28) were evaluated before and after 5 to 7 weeks' participation in a home-based exercise programme. They were assessed using the original versions of the BBS and the WOMAC; scores for the reduced versions of the BBS and the WOMAC were extracted from the original versions. RESULTS: Good to excellent correlations (r>=0.80) were observed between the original and the reduced versions of the BBS and the WOMAC. The index of responsiveness, evaluated using standardized response means (SRM), was similar for the original and the reduced versions of the BBS and the WOMAC function sub-scale. CONCLUSIONS: The reduced versions of the BBS and the WOMAC provided similar information to the original versions and were equally responsive. These reduced versions comprise fewer questions and may be completed in considerably less time, which suggests that they may be advantageous for clinical and research use. PMID- 22210989 TI - Rasch Analysis of the Fullerton Advanced Balance (FAB) Scale. AB - PURPOSE: This cross-sectional study explores the psychometric properties and dimensionality of the Fullerton Advanced Balance (FAB) Scale, a multi-item balance test for higher-functioning older adults. METHODS: Participants (n=480) were community-dwelling adults able to ambulate independently. Data gathering consisted of survey and balance performance assessment. Psychometric properties were assessed using Rasch analysis. RESULTS: Mean age of participants was 76.4 (SD=7.1) years. Mean FAB Scale scores were 24.7/40 (SD=7.5). Analyses for scale dimensionality showed that 9 of the 10 items fit a unidimensional measure of balance. Item 10 (Reactive Postural Control) did not fit the model. The reliability of the scale to separate persons was 0.81 out of 1.00; the reliability of the scale to separate items in terms of their difficulty was 0.99 out of 1.00. Cronbach's alpha for a 10-item model was 0.805. Items of differing difficulties formed a useful ordinal hierarchy for scaling patterns of expected balance ability scoring for a normative population. CONCLUSION: The FAB Scale appears to be a reliable and valid tool to assess balance function in higher functioning older adults. The test was found to discriminate among participants of varying balance abilities. Further exploration of concurrent validity of Rasch generated expected item scoring patterns should be undertaken to determine the test's diagnostic and prescriptive utility. PMID- 22210990 TI - What Does the Cochrane Collaboration Say about Physiotherapy Interventions for Spinal Dysfunction? PMID- 22210991 TI - Predictive risk mapping of West Nile virus (WNV) infection in Saskatchewan horses. AB - The objective of this study was to develop a model using equine data from geographically limited surveillance locations to predict risk categories for West Nile virus (WNV) infection in horses in all geographic locations across the province of Saskatchewan. The province was divided geographically into low-, medium-, or high-risk categories for WNV, based on available serology information from 923 horses obtained through 4 studies of WNV infection in horse populations in Saskatchewan. Discriminant analysis was used to build models using the observed risk of WNV in horses and geographic division-specific environmental data as well as to predict the risk category for all areas, including those beyond the surveillance zones. High-risk areas were indicated by relatively lower rainfall, higher temperatures, and a lower percentage of area covered in trees, water, and wetland. These conditions were most often identified in the southwest corner of the province. Environmental conditions can be used to identify those areas that are at highest risk for WNV. Public health managers could use prediction maps, which are based on animal or human information and developed from annual early season meteorological information, to guide ongoing decisions about when and where to focus intervention strategies for WNV. PMID- 22210992 TI - Validation of a disease model in Japanese quail (Coturnix coturnix japonica) with the use of Escherichia coli serogroup O2 isolated from a turkey. AB - This study established a disease model and protocol for bacterial challenge with Escherichia coli serogroup O2 strain EC317 in Japanese quail. Five groups of 10 birds each were injected subcutaneously in the breast with 200 MUL of a brain heart infusion (BHI) culture containing 1 * 10(8), 1 * 10(7), 1 * 10(6), 1 * 10(5), or 1 * 10(4) colony-forming units/mL of the test organism, which had been isolated from a turkey with cellulitis and septicemia. Birds in a 6th group were controls that received sterile BHI alone. Localized lesions of cellulitis developed in all of the birds that received E. coli. The morbidity and mortality rates were highest (100%) in the birds receiving the highest dose of E. coli and decreased linearly with decreasing dose (P < 0.05). Severity of disease, including lesions of pericarditis and perihepatitis, was also directly proportional to the dose of E. coli. These findings indicate that this disease challenge protocol can be used to study disease resistance and immunologic consequences of contaminant exposure or other stressors in birds. PMID- 22210993 TI - Interaction of Bordetella bronchiseptica, Pasteurella multocida, and fumonisin B1 in the porcine respiratory tract as studied by computed tomography. AB - The interaction of Bordetella bronchiseptica, toxigenic Pasteurella multocida serotype D, and the mycotoxin fumonisin B(1) (FB(1)) was studied. On day 0 of the experiment, 28 artificially reared 3-day-old piglets were divided into 4 groups (n = 7 each): a control group (A), a group fed FB(1) toxin (B), a group infected with the 2 pathogens (C), and a group infected with the 2 pathogens and fed FB(1) toxin (D). The B. bronchiseptica infection [with 10(6) colony-forming units (CFU)/mL] was performed on day 4 and the P. multocida infection (with 10(8) CFU/mL) on day 16. From day 16 a Fusarium verticillioides fungal culture (dietary FB(1) toxin content 10 mg/kg) was mixed into the feed of groups B and D. In groups C and D, clinical signs including mild serous nasal discharge, sneezing, panting, and hoarseness appeared from day 4, and then from day 16 some piglets had coughing and dyspnea as well. Computed tomography (CT) performed on day 16 demonstrated lung lesions attributable to colonization by B. bronchiseptica in the infected groups. By day 25 the number of piglets exhibiting lesions had increased, and the lesions appeared as well-circumscribed, focal changes characterized by a strong density increase in the affected areas of the lungs. The gross pathological findings confirmed the results obtained by CT. These results indicate that, when combined with dual infection by B. bronchiseptica and P. multocida, dietary exposure of pigs to FB(1) toxin raises the risk of pneumonia and increases the extent and severity of the pathological changes. PMID- 22210994 TI - Cloning, expression, and characterization of TonB2 from Actinobacillus pleuropneumoniae and potential use as an antigenic vaccine candidate and diagnostic marker. AB - In this study the tonB2 gene was cloned from Actinobacillus pleuropneumoniae JL01 (serovar 1) and expressed as a glutathione-S-transferase (GST) fusion protein in Escherichia coli BL21(DE3). The GST fusion protein was recognized by antibodies in serum positive for A. pleuropneumoniae by Western blot analysis. Purified soluble GST-TonB2 was assessed for its ability to protect BALB/c mice against A. pleuropneumoniae infection. Mice were vaccinated with GST-TonB2 subcutaneously and challenged intraperitoneally with either ~4.0 * 10(5) colony-forming units (CFU) or ~1.0 * 10(6) CFU of A. pleuropneumoniae 4074. They were examined daily for 7 d after challenge. The survival rate of the TonB2-vaccinated mice was significant higher than that of the mice given recombinant GST or adjuvant alone. These results demonstrate that A. pleuropneumoniae TonB2 is immunogenic in mice and should be further assessed as a potential candidate for a vaccine against A. pleuropneumoniae infection. In addition, an indirect enzyme-linked immunosorbent assay (ELISA) based on the GST-TonB2 recombinant protein was developed. Compared with the ApxIVA ELISA, the TonB2 ELISA provided earlier detection of antibodies in pigs at various times after vaccination with A. pleuropneumoniae live attenuated vaccine. When compared with an indirect hemagglutination test, the sensitivity and specificity of the TonB2 ELISA were 95% and 88%, respectively. The TonB2 ELISA provides an alternative method for rapid serologic diagnosis of A. pleuropneumoniae infection through antibody screening, which would be especially useful when the infection status or serovar is unknown. PMID- 22210995 TI - Bovine coronavirus (BCV) infections in transported commingled beef cattle and sole-source ranch calves. AB - This study investigated bovine coronavirus (BCV) in both beef calves direct from the ranch and commingled, mixed-source calves obtained from an auction market. The level of BCV-neutralizing antibodies found in the calves varied among ranches in 2 different studies in a retained-ownership program (ROP), from the ranch to the feedlot. Calves with low levels of BCV-neutralizing antibodies (16 or less) were more likely to be treated for bovine respiratory disease (BRD) than those with higher titers. In 3 studies of commingled, mixed-source calves, BCV was recovered from calves at entry to the feedlot and the infections were cleared by day 8. The BCV was identified in lung samples [bronchoalveolar lavage (BAL) collection] as well as in nasal swabs. Calves with low levels of BCV-neutralizing antibodies at entry were most likely to be shedding BCV. Bovine coronavirus was isolated from both healthy and sick calves, but not from sick calves after 4 d arrival at the feedlot. Bovine coronavirus (BCV) should be considered along with other bovine respiratory viruses in the diagnosis of etiologies in bovine respiratory disease, especially for animals that become sick shortly after arrival. If approved vaccines are developed, it would be best to carry out vaccination programs before calves are weaned, giving them sufficient time to gain active immunity before commingling with other cattle. PMID- 22210996 TI - Host response in rabbits to infection with Pasteurella multocida serogroup F strains originating from fowl cholera. AB - Although Pasteurella multocida serogroup F has been described as an avian-adapted serogroup, it was recently found in rabbit nests in the Czech Republic. Therefore, the ability of 2 avian P. multocida serogroup F strains to induce disease in rabbits was investigated. Two groups of 18 Pasteurella-free rabbits were intranasally challenged with strains isolated from chickens and turkeys. Half of the animals in each challenge group were immunosuppressed using dexamethasone. All of the challenged rabbits exhibited clinical signs of peracute septicemic disease, ending with shock, and died or were euthanized in the terminal stages of the disease 1 to 2 d post-infection. Gross pathological changes included systemic vascular collapse and vascular leak syndrome. Hyperemia, hemorrhage, edema, inflammatory cell infiltrates, focal necrosis, and degenerative changes were observed histologically in parenchymatous organs. This is the first study directly demonstrating that avian P. multocida serogroup F strains are highly virulent in rabbits and that avian hosts cannot be excluded as a possible source of rabbit infection with serogroup F. PMID- 22210997 TI - Breed-specific incidence rates of canine primary bone tumors--a population based survey of dogs in Norway. AB - This is one of few published population-based studies describing breed specific rates of canine primary bone tumors. Incidence rates related to dog breeds could help clarify the impact of etiological factors such as birth weight, growth rate, and adult body weight/height on development of these tumors. The study population consisted of dogs within 4 large/giant breeds; Irish wolfhound (IW), Leonberger (LB), Newfoundland (NF), and Labrador retriever (LR), born between January 1st 1989 and December 31st 1998. Questionnaires distributed to owners of randomly selected dogs--fulfilling the criteria of breed, year of birth, and registration in the Norwegian Kennel Club--constituted the basis for this retrospective, population-based survey. Of the 3748 questionnaires received by owners, 1915 were completed, giving a response rate of 51%. Forty-three dogs had been diagnosed with primary bone tumors, based upon clinical examination and x-rays. The breeds IW and LB, with 126 and 72 cases per 10 000 dog years at risk (DYAR), respectively, had significantly higher incidence rates of primary bone tumors than NF and LR (P < 0.0001). Incidence rates for the latter were 11 and 2 cases per 10 000 DYAR, respectively. Pursuing a search for risk factors other than body size/weight is supported by the significantly different risks of developing primary bone tumors between similarly statured dogs, like NF and LB, observed in this study. Defining these breed-specific incidence rates enables subsequent case control studies, ultimately aiming to identify specific etiological factors for developing primary bone tumors. PMID- 22210998 TI - Effects of adrenocorticotropic hormone challenge and age on hair cortisol concentrations in dairy cattle. AB - Dairy cattle suffer stress from management and production; contemporary farming tries to improve animal welfare and reduce stress. Therefore, the assessment of long-term hypothalamic-pituitary-adrenal function using non-invasive techniques is useful. The aims in this study were: to measure cortisol concentration in cow and calves hair by radioimmunoassay (RIA), to test cortisol accumulation in bovine hair after adrenocorticotropic hormone (ACTH) challenges, and determine the influence of hair color on cortisol concentrations. Fifteen Holstein heifers were allotted to 3 groups (n = 5 each): in control group (C), just the hair was sampled; in the saline solution group (SS), IV saline solution was administered on days 0, 7, and 14; and the ACTH group was challenged 3 times with ACTH (0.15 UI per kg of body weight) on days 0, 7, and 14. Serum samples from the SS and ACTH groups were obtained 0, 60 and 90 min post-injection. Serum cortisol concentration was greater 60 and 90 min after injection with ACTH. Hair was clipped on days 0, 14, 28, and 44. Hair cortisol was methanol extracted and measured by RIA. Hair cortisol was preserved for 11 mo. Hair cortisol concentrations in the ACTH group were greater than in the saline and control groups on days 14 and 28, but not on day 44. Concentrations were greater in calves than in cows and greater in white hair than in black hair. Cortisol accumulated in bovine hair after ACTH challenges, but the concentration was affected by both age and hair color. If hair color effects are taken into account, assessing cortisol concentration in hair is a potentially useful non invasive method for assessing stress in cattle. PMID- 22210999 TI - Characterization of the cDNA and genomic DNA sequence encoding for the platelet integrin alpha IIB and beta III in a horse with Glanzmann thrombasthenia. AB - Glanzmann thrombasthenia (GT) is characterized by a defect of platelet aggregation. This autosomal recessive genetic disorder is caused by an abnormality of the platelet glycoprotein receptors alpha IIb or beta III. Recently, we identified a horse with clinical and pathological features of GT. The aim of this study was to describe this case of GT at the molecular level. A point mutation from G to C in exon 2 of ITGA2B causing a substitution of the expected amino acid arginine 72 (Arg(72)) by a proline (Pro(72)) was encountered. This amino acid change may result in abnormal structural conformations that yield an inactive alpha IIb subunit. The genomic DNA analysis showed that this horse was homozygous for the missense mutation. PMID- 22211000 TI - Failure of nebulized irritant, acidic, or hypotonic solutions or external mechanical stimulation of the trachea to consistently induce coughing in healthy, awake dogs. AB - A useful approach for evaluating antitussive drugs in humans is to determine the sensitivity of the cough reflex to a standard challenge. The purpose of this study was to determine if methods used to induce coughing in humans would be effective when used on awake, untrained, healthy dogs for future application in therapeutic trials involving dogs with spontaneous disease. Methods tested were: mechanically stimulating the trachea by digital compression as well as by vibration from an electric shaver, neck massager, and palm sander (11 dogs), and administering nebulized irritant (3000 MUM capsaicin), acidic (1 M citric acid), and hypotonic (deionized water) solutions using face masks (4 dogs). The threshold for success was defined as induction of at least 2 moderate or strong coughs in at least 75% of the dogs. None of the methods tested was successful. Digital compression induced soft (n = 2) or moderate (n = 1) coughing in 3 of 11 dogs tested. Nebulization of citric acid induced 1 soft cough in 1 of 4 dogs. It was concluded that coughing cannot be successfully induced in awake, healthy dogs using methods that are successful in humans. Other strategies must be developed so that cough sensitivity can be objectively and non-invasively measured in dogs for clinical research purposes. PMID- 22211001 TI - A pilot study to determine the production and health benefits of milking visibly lame cows twice daily compared with three times daily. AB - A randomized clinical trial was conducted on lame cows to study the effect of milking frequency on milk production, lameness prevalence, and body condition score (BCS). At the beginning of the study, the entire herd of lactating Holstein dairy cows was visual locomotion scored (VLS) by 2 trained veterinarians. Lame cows (VLS > 2) were eligible for the study. The initial study population consisted of 270 cows randomly allocated to the three-times-daily milking frequency group (MFG) and 230 cows randomly allocated to the twice-daily MFG. Milking frequencies did not significantly affect average milk production. Cows in the twice-daily MFG had a significant increase in BCS, however, compared with cows in the three-times-daily MFG (P-value < 0.001). In addition, the probability of lameness in cows in the three-times-daily MFG was 36% higher than for cows in the twice-daily milking routine (P-value = 0.006). PMID- 22211002 TI - Changes in luteinizing hormone secretion after estradiol treatment in prepubertal Nelore heifers. AB - Changes in luteinizing hormone (LH) secretion after 17beta-estradiol (E(2)) injection were evaluated during sexual maturation in 10 prepubertal Nelore heifers. Heifers were divided into 2 groups: intact (I) and ovariectomized (OVX). 17beta-estradiol (2 MUg/kg) was administered to both groups at 10, 13, and 17 mo of age. Only at 10 mo of age was there a greater mean LH concentration in OVX heifers (1.33 +/- 0.29 ng/mL) compared with the I group (0.57 +/- 0.15 ng/mL). At 13 and 17 mo of age there was no significant difference between the 2 groups in any of the evaluated variables (number of peaks, total peak area, greatest peak area, and time to greatest peak occurrence). This suggests a decrease in negative E(2) feedback associated with an increase in positive feedback to LH secretion during sexual maturation, and these were likely the key factors that determined the time of first ovulation in Nelore heifers. PMID- 22211003 TI - Great expectations: Past wages and unemployment durations. AB - Decomposing wages into worker and firm wage components, we find that firm-fixed components are sizeable parts of workers' wages. If workers can only imperfectly observe the extent of firm-fixed components in their wages, they might be misled about the overall wage distribution. Such misperceptions may lead to unjustified high reservation wages, resulting in overly long unemployment durations. We examine the influence of previous wages on unemployment durations for workers after exogenous lay-offs and, using Austrian administrative data, we find that younger workers are, in fact, unemployed longer if they profited from high firm fixed components in the past. We interpret our findings as evidence for overconfidence generated by imperfectly observed productivity. PMID- 22211004 TI - Global bioenergy potentials from agricultural land in 2050: Sensitivity to climate change, diets and yields. AB - There is a growing recognition that the interrelations between agriculture, food, bioenergy, and climate change have to be better understood in order to derive more realistic estimates of future bioenergy potentials. This article estimates global bioenergy potentials in the year 2050, following a "food first" approach. It presents integrated food, livestock, agriculture, and bioenergy scenarios for the year 2050 based on a consistent representation of FAO projections of future agricultural development in a global biomass balance model. The model discerns 11 regions, 10 crop aggregates, 2 livestock aggregates, and 10 food aggregates. It incorporates detailed accounts of land use, global net primary production (NPP) and its human appropriation as well as socioeconomic biomass flow balances for the year 2000 that are modified according to a set of scenario assumptions to derive the biomass potential for 2050. We calculate the amount of biomass required to feed humans and livestock, considering losses between biomass supply and provision of final products. Based on this biomass balance as well as on global land-use data, we evaluate the potential to grow bioenergy crops and estimate the residue potentials from cropland (forestry is outside the scope of this study). We assess the sensitivity of the biomass potential to assumptions on diets, agricultural yields, cropland expansion and climate change. We use the dynamic global vegetation model LPJmL to evaluate possible impacts of changes in temperature, precipitation, and elevated CO(2) on agricultural yields. We find that the gross (primary) bioenergy potential ranges from 64 to 161 EJ y(-1), depending on climate impact, yields and diet, while the dependency on cropland expansion is weak. We conclude that food requirements for a growing world population, in particular feed required for livestock, strongly influence bioenergy potentials, and that integrated approaches are needed to optimize food and bioenergy supply. PMID- 22211005 TI - Modelling population-based cancer survival trends using join point models for grouped survival data. AB - In the United States cancer as a whole is the second leading cause of death and a major burden to health care, thus the medical progress against cancer is a major public health goal. There are many individual studies to suggest that cancer treatment breakthroughs and early diagnosis have significantly improved the prognosis of cancer patients. To better understand the relationship between medical improvements and the survival experience for the patient population at large, it is useful to evaluate cancer survival trends on the population level, e.g., to find out when and how much the cancer survival rates changed. In this paper, we analyze the population-based grouped cancer survival data by incorporating joinpoints into the survival models. A joinpoint survival model facilitates the identification of trends with significant change points in cancer survival, when related to cancer treatments or interventions. The Bayesian Information Criterion is used to select the number of joinpoints. The performance of the joinpoint survival models is evaluated with respect to cancer prognosis, joinpoint locations, annual percent changes in death rates by year of diagnosis, and sample sizes through intensive simulation studies. The model is then applied to the grouped relative survival data for several major cancer sites from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute. The change points in the survival trends for several major cancer sites are identified and the potential driving forces behind such change points are discussed. PMID- 22211006 TI - FoxP3: A Key Player in T Regulatory Biology. PMID- 22211008 TI - Design of Allele Specific PCR for Rapid Detection of CYP3A5 (A6986G) and Mdr-1 (C3435T) Polymorphisms. AB - Single nucleotide polymorphisms in CYP3A5 (A6986G) and MDR-1 (C3435T) genes have been shown to be associated with the pharmacokinetics of tacrolimus in case of renal transplant recipients. Knowing these genotypes of the recipients before undergoing transplantation, is therefore essential for physicians to adjust the starting dose of tacrolimus in order to avoid drug induced nephrotoxicity. We have designed an allele specific PCR method for easier and rapid detection of these polymorphisms. 20 Indian renal transplant recipients on tacrolimus who developed nephrotoxicity within 1 month of transplantation and 58 Indian non transplant subjects having the risk factors for kidney disease i.e. hypertension or diabetes or the family history of these, have been studied for these SNPs by allele specific PCR method. The data suggest that the heterozygosity of CYP3A5 and mutant allele frequency of MDR-1 SNP is higher in transplant patients as well as in general population. PMID- 22211007 TI - Biochemistry of nitric oxide. AB - Nitric oxide (NO) a free radical having both cytoprotective as well as tumor promoting agent is formed from l-arginine by converting it to l-citrulline via nitric oxide synthase enzymes. The reaction product of nitric oxide with superoxide generates potent oxidizing agent, peroxynitrite which is the main mediator of tissue and cellular injury. Peroxynitrite is reactive towards many biomolecules which includes amino acids, nucleic acid bases; metal containing compounds, etc. NO metabolites may play a key role in mediating many of the genotoxic/carcinogenic effects as DNA damage, protein or lipid modification, etc. The basic reactions of nitric oxide can be divided as direct effect of the radical where it alone plays a role in either damaging or protecting the cell milieu and an indirect effect in which the byproducts of nitric oxide formed by convergence of two independent radical generating pathways play the role in biological reactions which mainly involve oxidative and nitrosative stress. Nitric oxide is also capable of directly interacting with mitochondria through inhibition of respiration or by permeability transition. Reaction of nitric oxide with metal ions include its direct interaction with the metals or with oxo complexes thereby reducing them to lower valent state. Excessive production of nitric oxide can be studied by inhibiting the synthetic pathway of nitric oxide using both selective or specific nitric oxide synthase inhibitor or non-selective nitric oxide synthase inhibitor with respect to isoforms of nitric oxide. PMID- 22211009 TI - Comparison between serum insulin levels and its resistance with biochemical, clinical and anthropometric parameters in South Indian children and adolescents. AB - There is a rising trend in the prevalence of insulin resistance among obese, overweight children and adolescents. The serum insulin and its correlation with biochemical, clinical and anthropometric parameters were evaluated in 185 children and adolescents (59 control, 52 obese, 49 overweight, 25 congenital heart disease) of age group 10-17 years. The levels of serum insulin were measured by ELISA. Serum insulin levels were found to be significantly increased in children who were obese, overweight and had congenital heart disease, than controls. Serum insulin levels positively correlated with BMI, WHR, and serum C peptide, serum leptin, total cholesterol, triglycerides, LDL-cholesterol, systolic and diastolic blood pressure. Fasting glucose levels were found to be negatively correlated with serum insulin levels. HDL-cholesterol levels were non significant among the study groups. We identified nine obese children (five girls and four boys) with the features of metabolic syndrome and 69% of obese and overweight children were identified with insulin resistance. Insulin resistance was strongly associated with metabolic syndrome and its components, especially with central obesity and hypertriglyceridemia. PMID- 22211010 TI - Myeloperoxidase in chronic kidney disease. AB - Numerous lines of evidence implicate a role of myeloperoxidase (MPO) in the pathogenesis of cardiovascular disease (CVD). It is a well accepted fact that patients with chronic kidney disease (CKD) are at an increased risk for CVD. MPO is a pro-oxidant enzyme which could be involved in the increased susceptibility of these patients to CVD. Hence, the levels of plasma MPO was determined in healthy controls as well as in patients with CKD [stratified with the level of their kidney failure as CKD stages II-V (end stage renal disease)]. Plasma MPO was assayed by a spectrophotometric method. Serum urea and creatinine were estimated on a clinical chemistry analyzer using standard laboratory procedures. The mean plasma MPO levels were significantly lower with advancing stages of renal failure (P < 0.001). There was a positive correlation between MPO and GFR (r = +0.89, P < 0.001) and a negative correlation with urea (r = -0.85, P < 0.001) and creatinine (r = -0.82, P < 0.001). While an inverse association was observed between plasma MPO and urea in CKD patients, such an association was not observed in control subjects (P = 0.43). In conclusion, the decline in plasma MPO levels may be due to the inhibitory effect of uraemic toxins on the enzyme. PMID- 22211011 TI - Anomalous Activity Measurements of Creatine (Phospho) Kinase, CK-MB Isoenzyme in Indian Patients in the Diagnosis of Acute Coronary Syndrome. AB - In the present study, the cause of suspected false-positive (anomalous) values for CK-MB activity, in Indian patients investigated for ACS. Total serum CK and CK-MB activity, serum Troponin I were measured and CK-MB as a percentage of the total CK activity (%CK-MB) calculated. CK-MB was also estimated using densitometry and CK-MB mass assay. Anomalous specimens were tested for the presence of CK isoenzymes. In 22 healthy subjects, 11 male and female, the %CK-MB ranged from 3.6 to 30.2. In 11 male patients, with proven ACS, the %CK-MB was from 4.0 to 17.5. The cut off for anomalous CK-MB activity values was set as >33.0%. In 35 patients with anomalies, total CK values ranged from 39 to 231 U/L, CK-MB from 30 to 161 U/L. Investigation of CK isoenzymes, showed 10 patients had a CK-BB band, 14 an intermediate band between CK-MM and CK-MB (macro-CK type 1), 7 had a cathodal band (macro-CK type 2), and 3 had a band intermediate between CK MB and CK-BB. This later band does not seem to have been previously reported. Against the CK-MB mass assay, the activity assay showed no correlation, in 43 patients (19 M, 24 F), Pearson coefficient (R(2)) was 0.006. The CK-MB immunoinhibition assay is better described as measuring "non-CK-MM activity." A %CK-MB activity >6% as a marker of ACS is not valid in our patient population. Laboratories should not use only CK-MB activity as a biochemical marker of ACS. PMID- 22211012 TI - Potential biochemical markers for preterm labor: a pilot study in north India. AB - Preterm delivery is a major contributor for neonatal mortality. Intensive research is underway to establish a reliable biomarker that can ascertain the risk of preterm delivery in pregnant women. The aim of our study was to evaluate the role of various biochemical parameters as potential biomarker for risk assessment for preterm labor. Forty women presenting with preterm labor and 40 women who delivered at term were included in the study. Parameters that were evaluated include corticotrophin (ACTH), prolactin, thyroid stimulating hormone (TSH), ferritin and Alkaline Phosphatase (ALP). Serum ACTH, ferritin, ALP and Ferritin/Iron ratio were significantly higher in the subjects who delivered prematurely as compared to the controls. Comparison of sensitivity, specificity, likelihood ratio, positive and negative predictive values for different cut offs for ACTH, ferritin, ALP and ferritin/iron ratio was carried out. Ferritin emerged as the best marker with area under curve of 0.96 as compared to 0.88 for ACTH, 0.825 for ALP and 0.735 for ferritin/iron ratio. Our study establishes the superiority of ferritin as a predictive biomarker for preterm labor as compared to the rest of the parameters evaluated. PMID- 22211013 TI - Effect of pre-analytical errors on quality of laboratory medicine at a neuropsychiatry institute in north India. AB - Advances in instrument technology and automation have simplified tasks in laboratory diagnostics reducing errors during analysis thereby improving the quality of test results. However studies show that most laboratory errors occur in the pre-analytical phase. In view of the paucity of studies examining pre analytical errors, we examined a total of 1513 request forms received at our laboratory during a 3 month period. The forms were scrutinized for the presence of specific parameters to assess the pre-analytical errors affecting the laboratory results. No diagnosis was provided on 61.20% of forms. Type of specimen was not mentioned in 61.60% of the forms and 89.25% of all forms were illegible. Critical results were encountered in 17.30% of patients, and of these 76.60% were not communicated due to incomplete forms. Thus, by following standard operating procedures vigorously from patient preparation to sample processing the laboratory results can be significantly improved without any extra cost. PMID- 22211014 TI - Somatic DNA damages in cardiovascular autonomic neuropathy. AB - Cardiovascular autonomic neuropathy (CAN) is one of the most clinically significant complications of diabetes mellitus. Even though many ethological factors have been attributed for the pathogenesis of this disease no attempts were made to correlate DNA damage as a causative factor. Hence the present study was undertaken to asses the extent of somatic DNA damages by cytokinesis-block micronuclei assay (CBMN). An attempt is also being made to correlate the habits and/or risk factors and socioeconomic status with CAN. The CBMN frequency of 46 patients suffering from autonomic neuropathy was compared with that of 25 healthy age and sex matched controls. All the subjects were suffering from type 2 diabetes for at least 8 years and have varying degrees of coronary artery diseases. The mean CBMN frequency of the patients was statistically higher than that of the healthy control subjects (P < 0.05). The CBMN frequency was found to be significantly altered in CAN patients who where physical inactivity and smoking. A significant correlation could also be observed between CAN and smoking, diabetes mellitus, hypertension, dyslipidemia, abdominal obesity, and physical activity. PMID- 22211015 TI - Sex dimorphism in serum lecithin: cholesterol acyltransferase and lipoprotein lipase activities in adult sickle cell anaemia patients with proteinuria. AB - Proteinuria in subjects with sickle cell anaemia (SCA) is an indication of an ongoing renal insufficiency and it's prevalence varies between sexes. We evaluated sex differences in the activities of Lecithin: cholesterol acyltransferase (LCAT), Lipoprotein lipase (LPL) and the levels of lipoproteins in SCA patients with proteinuria. Fifty SCA patients (30 males aged: 26.4 +/- 7.3 years and 20 females, aged 25.4 +/- 2.6 years) and 50 age and sex matched control SCA patients were recruited for the study. Random urine specimens were collected and tested for the presence of albumin by urine dipstick technique. A 24 h urinary protein was quantitated using sulphosalicylic acid technique. Fasting serum total cholesterol, triglyceride, urea and creatinine were determined using enzymes catalyzed colorimetric methods. HDL cholesterol was determined in the supernatant after precipitation with manganese chloride-phosphotungstic acid solution. LCAT was measured using the Anasolv LCAT assay with proteoliposome as substrate. LPL was determined by incubating the serum in glyceryl trioleate substrate, the glycerol liberated was measured in an aliquot of the incubating mixture. In male SCA controls there was 18.2 and 6.9% increase in the activities of LPL and LCAT respectively when compared with females but in SCA patients with proteinuria there was 8.4 and 5.2% decreases in the male SCA patients compared with females. The concentration of 24 h urine protein in the SCA male subjects with proteinuria was significantly higher (0.25 g/day; P < 0.001) compared with the SCA female patients with proteinuria (0.09 g/day). There are sex differences in the activities of LCAT and LPL in SCA patients with proteinuria. Metabolism of these lipolytic enzymes may be modulated differently in SCA patients with proteinuria. PMID- 22211016 TI - Do over 200 million healthy altitude residents really suffer from chronic Acid base disorders? AB - As the oxygen tension of inspired air falls with increasing altitude in normal subjects, hyperventilation ensues. This acute respiratory alkalosis, induces increased renal excretion of bicarbonate, returning the pH back to normal, giving rise to compensated respiratory alkalosis or chronic hypocapnia. It seems a contradiction that so many normal people at high altitude should permanently live as chronic acid-base patients. Blood gas analyses of 1,865 subjects at 3,510 m, reported a P(a)CO(2) (arterial carbon dioxide tension +/- SEM) = 29.4 +/- 0.16 mmHg and pH = 7.40 +/- 0.005. Base excess, calculated with the Van Slyke sea level equation, is -5 mM (milliMolar or mmol/l) as an average, suggesting chronic hypocapnia. THID, a new term replacing "Base Excess" is determined by titration to a pH of 7.40 at a P(a)CO(2) of 5.33 kPa (40 mmHg) at sea level, oxygen saturated and at 37 degrees C blood temperature. Since our new modified Van Slyke equations operate with normal values for P(a)CO(2) at the actual altitude, a calculation of THID will always result in normal values-that is, zero. PMID- 22211017 TI - A Study on the Level of T(3), T(4), TSH and the Association of A/G Polymorphism with CTLA-4 Gene in Graves' Hyperthyroidism among South Indian Population. AB - Graves' disease (GD) is an organ-specific heterogenous autoimmune disorder associated with T-lymphocyte abnormality affecting the thyroid, eyes and skin. GD is a multifactorial disease that develops as a result of complex interaction between genetic susceptibility genes and environmental factors. It has been suggested that the Cytotoxic T lymphocytes associated molecule-4 (CTLA-4) is a genetic susceptibility candidate for GD. The present study was focused on A/G polymorphism at position 49 in exon-1 of the CTLA-4 gene in 80 GD patients (GP) and 80 sex and age matched healthy individuals among South Indian (Madurai) population. Serum concentrations of thyroid hormone (T(4), T(3) and TSH) were determined by using automated analyzer. The genomic DNA was isolated from the patient and control groups and genotyping was performed using the polymerase chain reaction followed by restriction enzyme analysis using Bbv1. Significant difference (P < 0.001) was observed in the level of T(3), T(4) and TSH in GD patients and healthy individuals. The results revealed the CTLA-4 gene G/G genotype to be 32 (40%) in patients and 26 (32.50%) in healthy individuals, A/G genotype to be 37 (46.25%) in patients and 25 (31.25%) in healthy individuals and A/A genotype to be 11 (13.75%) in patients and 29 (36.25%) in healthy individuals. The calculated odds ratio (OR) in individuals with mutant genotype (GG/AG) reveal 3.6 fold risk for GD (95% confidence interval = 1.6-7.8). The mutant "G" allele frequency was observed to be 0.63 in GD patients and 0.48 in healthy individuals. Thus the present study demonstrates an association between the CTLA-4 gene polymorphism and Graves' disease. PMID- 22211018 TI - BMD and Serum Intact Osteocalcin in Postmenopausal Osteoporosis Women. AB - India seems to have the highest prevalence of osteoporosis. With growing awareness of osteoporosis and its impact on life span especially in India, special attention is being paid to early detection, management and treatment of postmenopausal osteoporosis in women. Measurement of BMD and osteocalcin are of value in estimating bone turnover rates. The aim of this study is (1) to measure the specific, sensitive bone formation marker such as osteocalcin and BMD in postmenopausal osteoporosis women and postmenopausal non-osteoporosis women; (2) the follow up study to evaluate the impact of specific antiresorptive therapy (alendronate + calcium + vitamin D) regimen in postmenopausal osteoporosis by assaying osteocalcin and BMD. Sixty clinically diagnosed postmenopausal osteoporosis patients and 60 normal subjects (postmenopausal non-osteoporosis women) were recruited as control. Mean bone mineral density T score and Z score was significantly decreased (P < 0.001) in postmenopausal osteoporosis patients as compared to controls. Highly significant increase in the mean score of BMD-T score and Z score from baseline to post therapy of 3 months was observed in postmenopausal osteoporosis women. Serum osteocalcin levels were significantly increased (P < 0.001) as compared to control group. Serum osteocalcin levels were decreased significantly (P < 0.001) from baseline to post therapy of 3 months in postmenopausal osteoporosis women. BMD is the best quantifiable predictor of osteoporotic fracture and osteocalcin is specific, sensitive, promising, currently used marker for better prognosis of osteoporosis and for monitoring responses to antiresorptive therapy. PMID- 22211019 TI - Evaluation of Oxidative Stress in Type 2 Diabetes Mellitus and Follow-up Along with Vitamin E Supplementation. AB - Increased oxidative stress is a widely accepted participant in the development and progression of diabetes and its complications. The present study has been undertaken to evaluate oxidative stress in type 2 diabetes mellitus and effect of vitamin E supplementation on oxidative stress. In all 120 subjects were enrolled in the present study, 40 subjects are age and sex matched controls. Test group comprised of clinically diagnosed (n = 80) type 2 diabetic patients. Biochemical parameters like serum MDA, nitric oxide, superoxide dismutase, erythrocyte reduced glutathione and platelet aggregation were analyzed in control and diabetic group. Test group is further categorized as Group I (n = 40) diabetics were treated by only hypoglycemic drugs and Group II (n = 40) diabetics were treated by hypoglycemic drugs with vitamin E supplementation. All above biochemical parameters were again reassessed after 3 months follow-up in both group and its values were compared with its respective baseline levels. The study shows, reduction of oxidative stress, improvement in antioxidant enzymes and endothelial dysfunction in group II, those were on treatment of hypoglycemic drugs along with vitamin E supplementation. Hence the present study may conclude that vitamin E supplementation along with hypoglycemic drugs may be beneficial to type 2 DM patients to minimize vascular complications. PMID- 22211020 TI - Study of oxidative stress in vitiligo. AB - Vitiligo is an idiopathic, acquired, circumscribed, hypomelanotic skin disorder, characterized by milky white patches of different sizes and shapes. It is due to the destruction of melanocytes resulting in the absence of pigment production of the skin and mucosal surfaces. Oxidative stress has been implicated in pathophysiology of vitiligo. To study the activity of blood Superoxide dismutase (SOD) and Glutathione peroxidase (GPx) in vitiligo patients. A case-control study was conducted in which 100 patients were enrolled after written consent. 50 cases were of active vitiligo and 50 served as control (25 healthy control and 25 with stable vitiligo). SOD-In our study, among the active vitiligo cases 90% had high level of SOD and 10% had normal level of SOD. Among the stable vitiligo controls, 92% had normal level of SOD and 8% had low levels of SOD.The difference between active vitiligo cases and stable vitiligo control as well as with healthy control was statistically significant (P value < 0.05). GPx-Among the active vitiligo cases 74% had normal GPx levels, 22% had low and only 4% had high levels of GPx. Among the stable vitiligo controls, 64% had normal GPx levels, 16% had low, and 20% had high levels of GPx. The difference between active vitiligo cases and stable vitiligo control as well as with healthy control was statistically not significant (P value > 0.05). Our study shows that oxidative stress is involved in the pathophysiology of vitiligo, as indicated by the high levels of serum superoxide dismutase activity. PMID- 22211021 TI - Electrical conductivity as a tool to detect salt in clinical proteomics samples. AB - Clinical proteomics encompasses the study of the proteins in the human body at different settings to understand the various physiological and pathological pathways. The processing of the samples for electrophoresis based proteomics is a challenge to any researcher. Salt in particular can have an array of effects during the electrophoretic separation of proteins. There is a definite need to determine the concentration of salts in the samples and the effectiveness of salt removing protocols on small volume samples. A simple-cost effective technique to know the salt concentration in the clinical proteomics samples has been highlighted in the report. The application will be of value in a developing country such as India. PMID- 22211022 TI - Effects of long term ethanol consumption on cell death in liver. AB - Apoptosis plays an important role in cellular homeostasis. In this study we have investigated whether apoptosis is a contributory factor to alcohol induced liver damage. Long term ethanol (1.6 g/kg body weight/day) exposure augmented liver apoptosis as reflected by high frequency of positive TUNEL staining nuclei and by an increased activity of caspase-3 and -8. Our study provides evidence that long term ethanol consumption triggers apoptotic process in the liver. PMID- 22211023 TI - Role of vitamin d supplementation in hypertension. AB - Role of Vitamin D supplementation was studied in patients with hypertension. One hundred hypertensive patients (group I) were given conventional antihypertensive drugs while another 100 patients (group II), in addition, were supplemented with Vitamin D(3) (33,000 IU, after every 2 weeks, for 3 months). Besides diastolic and systolic blood pressure, serum calcium, phosphorous, alkaline phosphatase, albumin, albumin-corrected calcium, and 24 h urinary creatinine levels were estimated in both the groups before the start of treatment and after 3 months. Vitamin D supplementation showed a more significant decrease in systolic blood pressure. This group also showed a significant increase in serum calcium as well as albumin-corrected calcium with a decrease in phosphorous. Results of the study confirm that Vitamin D supplementation has a role in reducing blood pressure in hypertensive patients and that it should be supplemented with the antihypertensive drugs. More extensive studies with a larger group, to draw a definite conclusion, are in progress. PMID- 22211024 TI - Diagnostic Dilemma of HbA1c Detection in Presence of a Hemoglobinopathy: A Case Report. AB - We report a case of a diabetic, heterozygote with near normal hematology, marginally low level of hemoglobin A(2)(HbA(2)) having an increased level of hemoglobin F(HbF) that was pancellularly distributed among the red cells. BioRad DiaSTAT measurements gave a high glycated hemoglobin A1c(HbA1c) of 31.5% and the BioRad Variant analyzer recorded an HbA1c value which was very low, in discordance with the detected blood glucose levels. Flow cytometry and polymerization chain reaction (PCR) based studies were carried out which revealed the case to be that of the common hereditary persistence of fetal hemoglobin (HPFH)-3, an Asian Indian mutation. Fructosamine estimation and HbA1c by Boronate affinity chromatography were able to resolve the discordant value detected and was able to confirm the diabetes status. The case would have been a diagnostic dilemma, if reported without correlation. PMID- 22211025 TI - Serum Lipid Profile: Fasting or Non-fasting? AB - Serum lipid profile has now become almost a routine test. It is usually done in fasting state due to certain limitations in non-fasting serum sample. In the recent past efforts have been made to simplify blood sampling by replacing fasting lipid profile with non-fasting lipid profile. However, fasting specimen is preferred if cardiovascular risk assessment is based on total cholesterol, LDL cholesterol or non-HDL cholesterol. A lot has yet to be done in this area. Till then we have to believe in fasting lipid profile for assessment and management of cardiovascular disease. PMID- 22211027 TI - President's Message. PMID- 22211026 TI - Reference intervals of certain liver specific biochemical analytes in Indian population. PMID- 22211028 TI - Who's Afraid of Evidence-Based Surgical Practice? PMID- 22211029 TI - Pharmacovigilance among surgeons and in surgical wards: overlooked or axiomatic? AB - To review the status of pharmacovigilance system among surgeons and in surgical wards with recommendations. Literature search using MEDLINE, cross-reference of published data and review of World Health Organization-Pharmacovigilance transcripts. Pharmacovigilance system is still in its infancy among surgeons and in surgical wards. No major studies have been published addressing this issue, till date. Surgeons are professionals least likely to report adverse drug reactions. Moreover widespread and irrational antibiotic use is contributing towards high incidence of adverse events apart from multidrug resistance. Lack of interest, funding and knowledge pose challenges in effective post marketing drug surveillance in surgery. A three tier proactive pharmacovigilance system in surgical wards is suggested along with specific recommendations. The pros and cons of adverse drug reporting among the surgeons are discussed. With growing awareness of pharmacovigilance in various fields of medicine, surgery can no longer remain an exception. In the transition from medical school to surgery clinic a subtle shift must occur from emphasizing pharmacokinetics to appreciating pharmacodynamics. This change in philosophy will occur at the level of instruction when the surgeons of tomorrow are motivated through regulatory and institutional means at school level to adopt pharmacovigilance in their clinical practices along with the practicing surgeons. PMID- 22211030 TI - Hormone receptor status of breast cancer in the himalayan region of northern India. AB - The role of hormone receptors as a prognostic and therapeutic tool in breast cancer is widely accepted. The frequency of nonreactivity of estrogen and progesterone receptors in breast cancer patients of India is much more common than in the West. This study was conducted with the aim of analysis of steroid receptor status in breast cancer with clinico-pathological characteristics from the northern hilly state of Himachal Pradesh, India located in the region of the Western Himalayas. Fifty five consecutive patients with the diagnosis of breast cancer were included in this study. Detailed clinical and histopathologic data was recorded in all cases. Estrogen receptor and progesterone receptor status was evaluated by immunohistochemistry. Chi-square test was used for statistical analysis. On immunohistochemical staining, 34.5% cases proved to be estrogen receptor positive and 36.4% cases progesterone receptor positive. The results in the present study documented low estrogen receptor and progesterone receptor positivity in breast cancer from this region of India. PMID- 22211031 TI - Review of Inguinal Hernia Repairs by Various Surgical Techniques in a District General Hospital in the UK. AB - Inguinal hernia is the commonest surgical operation. This is a large study from a district general hospital. The study spanned over 2 years with 2 further years of follow up. It is a retrospective analysis of eight hundred and seventy seven (877)inguinal hernia operations performed in a district general hospital. The following factors were looked at: type of repair, grade of surgeon performing the procedure and outcome of various repairs. The results showed that the most common technique was the Lichenstein's repair(58%). Recurrence rates were between 0.4% 30% depending on types of hernia repair. PMID- 22211032 TI - Role of fine-needle aspiration cytology in swellings of the parotid region. AB - To report the role of preoperative fine-needle aspiration cytology (FNAC) in patients with swellings in the parotid region at a tertiary care center. Prospective study of FNAC results compared with final histologic diagnosis as the standard criterion. An academic tertiary care center. A consecutive series of 51 patients who underwent FNAC of swellings in the parotid region between 2007 and 2009, of whom 41 had surgical resection. Predictive value, sensitivity, specificity, and accuracy. FNAC was performed in all the 51 patients who presented with a swelling in the parotid region in the out patient department in our hospital. Sixteen patients (31.4 %) were diagnosed to have malignancy, thirty patients (58.8 %) were diagnosed as benign condition. The FNAC was not satisfactory in 5 patients (9.8%) even after repeated aspiration. The FNAC diagnosis of malignant or suspicious lesion of the parotid region had positive and negative predictive values of 90 % and 96.66%, respectively. The diagnostic accuracy of FNAC is 95 %. We strongly recommend FNAC as a safe and accurate and less expensive method for preoperative diagnosis of the swellings in the parotid region. PMID- 22211033 TI - A comparative study of the burn wound healing properties of saline-soaked dressing and silver sulfadiazine in rats. AB - The purpose of this study was to further investigate that phenomenon and to explore the effect silver sulfadiazine on wound healing. Full-thickness burn wounds were created on the dorsum of Wistar albino rats under anesthesia. The wounds were treated with silver sulfadiazine and saline-soaked dressing for fourteen days, and then observed until healed. Wound surface area was measured each three days. Time to 50% and 90% healing was compared. No clinical infections occurred. Wound half-life and healing times were shortest in the saline-soaked group (P < 0.0001) in full-thickness burns. Wound contraction was delayed by silver sulfadiazine. These data suggest that silver sulfadiazine retard burn wound healing. Infection control without delay of burn wound healing is most appealing and clinical trials are planned. PMID- 22211034 TI - Thyroglossal duct cyst-more than just an embryological remnant. AB - Thyroglossal duct cyst is a congenital malformation that occurs due to incomplete closure of the thyroglossal duct. Apart from being a quiescent embryological remnant, it presents itself clinically at any age and often requires surgical excision. Twenty four patients were encountered at Sri Ramachandra Medical College and Research Institute between June 2004 and June 2009 with thyroglossal duct cyst. The purpose of the study was to analyse their presentation, associated complications including malignancy and the approach to their management. Operative notes, histopathology files and medical records were used for the retrospective analysis of the patients with thyroglossal duct cyst. Thyroid profile and Radioisotope scan were performed on all the patients to document the position of the thyroid gland. Further, these patients were subjected to Ultrasonography and Computerised Tomography neck to conclusively map the location of the cyst. Fine Needle Aspiration of the tissue was done to diagnose malignancy. It was noted that there was maximum clustering of about 62.5% in males. About 45% of them belonged to the paediatric age group. The total number of symptomatic patients was about 59%. Unlike the various studies in literature, most of the thyroglossal duct cyst patients at our hospital were symptomatic. The symptoms were pain, dyspnoea, dysphagia, discharge and recurrence. Malignancy was diagnosed in two patients who were ironically asymptomatic. Other complications were looked into and treated. Thyroglossal duct cyst is a cervical anomaly that is usually found as an asymptomatic painless cystic swelling. However, most of our patients had a symptomatic presentation. Association with malignancy was noted. Surgical intervention was the cure for all the patients. PMID- 22211035 TI - The factors related with postoperative complications in benign nodular thyroid surgery. AB - Thyroid gland is an important endocrine organ because of its functions. Although the morbidity and mortality of thyroid surgery have decreased markedly, serious complications may still occur. The aim of this retrospective study was to identify the factors influencing the complications in benign nodular thyroid surgery. A total of 332 patients who underwent thyroid surgery between April 2004 and May 2008 were evaluated retrospectively to identify the factors influencing the complications. We found that in surgery lasting more than 90 minutes the risk of permanent recurrent laryngeal nerve (RLN) injury was high, daily drainage more than 50 cc increases the risk of seroma formation, retrosternal goiter surgery have higher risk for bleeding. The flap edema rates were high found in the operations made by resident surgeon and patients with size 3-4 thyroid glands. Low complication rates can be achieved after thyroidectomy with better knowledge of the surgical anatomy of the neck, thyroid pathology and required surgical treatment. PMID- 22211036 TI - Standardisation of preoperative marking of incompetent perforators and saphenopopliteal junction on Doppler with evaluation of "t" technique. AB - To standardise the preoperative marking of incompetent perforators and saphenopopliteal junction on Doppler with evaluation of "T" technique. A prospective study including 54 consecutive patients (61 lower limbs) who underwent surgery for varicose veins in 2003 and 2004 were included for preoperative marking. "T" technique is a technique of Doppler marking of an incompetent perforator, long limb of the T representing the course of the superficial vein and the junction of the T representing the site of perforator entering the deep fascia. Surgical correlation was done. The overall surgical detection rate of incompetent perforators was 199 / 220(90.5%); detection of the saphenopopliteal junction was 100%. The "T" technique of Doppler marking was found to be easy to perform and aided intraoperative detection. PMID- 22211037 TI - Buerger's Disease (Thromboangiitis Obliterans)- Management by Ilizarov's Technique of Horizontal Distraction. A Retrospective Study of 60 Cases. AB - In Buerger's disease conservative treatment is questionable. Arterial reconstructive surgery is not feasible and sympathectomy has limited role. Progression of the disease invariably leads to amputation. Ilizarov's method increases the vascularity of the ischaemic limb. Retrospective analysis of Ilizarov's technique in 60 patients was done. Immediate results took into account rest pain, colour of skin, venous return, temperature, pulse oxymeter measured oxygen saturation and ulcer/amputation stump wound healing. Early and late results took into account rest pain, healing of ulcers/amputation stump with or without plastic coverage, claudication distance, resumption of previous occupation and domestic ambulation. The mean follow up of patients was 63 months. Immediate results were promising except two amputations. Early result were excellent to good in 56 and late results were excellent to good in 48 patients. Deterioration had significant correlation with smoking. Ilizarov's method is an excellent and cheap procedure in treatment of Buerger's disease. PMID- 22211038 TI - Evaluation of effect and comparison of superoxidised solution (oxum) v/s povidone iodine (betadine). AB - Wounds expose a patient to serious hazards like wound infection, tissue destruction, disfiguring and disabling scars. Use of superoxidised solution (oxum) in infected wounds, ulcers, diabetic wounds, abcesses, burns reduced morbidity and hospital stay with its early wound healing effect. To evaluate the effect of superoxidised water (Oxum) V/s povidone iodine (Betadine) on similar types of wounds. We retrospectively analysed the records of two hundred patients with different types of wounds who attended Department of Surgery, Guru Nanak Dev Hospital/Govt. Medical College, Amritsar from January 2008 to January 2009. The patients were divided into two groups. Group A where topical management and dressing was done using oxum and group B where topical management and dressing was done using betadine. A standard grading in terms of percentage decrease in wound size, periwound oedema/erythema, pus discharge and percentage increase in granulation, fibrin and epithelisation was noted in various types of wounds in both groups. Oxum treated wounds showed reduction in inflammation and their healing earlier than betadine group. Oxum application was safe having no pain and allergic manifestation. PMID- 22211039 TI - Etiological factors in umbilical pilonidal sinus. AB - The objective of this study is to investigate factors leading to the development of umbilical pilonidal sinus (UPS). 31 patients with UPS treated at Harran University and Kecioren State Training Hospital between January 1997 and November 2007. 100 consecutive volunteer outpatients were administered questionnary. The questionnary included questions on age, sex, profession, body mass index (BMI), skin color, hirsute status, frequency of taking baths, personal history of pilonidal sinus (PS), familyal history of PS, and whether -they wear tight clothes and wheteher they use belt. The results obtained from two groups were compared. UPS is one of the PS group diseases and involves umbilical region. There was statistically significant difference between the patient and control groups in terms of age, profession, hirsute status, familial history of PS, wearing tight clothes and BMI. Improvement in these factors may contribute to the reduction of the prevalance of the disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12262-010-0226-x) contains supplementary material, which is available to authorized users. PMID- 22211040 TI - A case report on parapharyngeal nerve cell tumor (schwannoma). PMID- 22211041 TI - Sigmoid kidney associated with double urethra. AB - An unusual case of crossed renal ectopia (sigmoid kidney) in an adult, compounded with double urethra, is being presented for its rarity and mode of presentation. PMID- 22211042 TI - Idiopathic colonic perforation in adult-a rare case. AB - Idiopathic perforation of normal colon in adults is rare. The cause for idiopathic perforation is not known. We report a case of idiopathic colonic perforation in adult who presented with sign and symptoms of perforative peritonitis. On laparotomy patient was diagnosed to have a colonic perforation. There was no causative factor for perforation in the patient. This case is reported because of rarity of this disease. PMID- 22211043 TI - Gastric gangrene due to necrotizing gastritis. AB - Gangrene of the stomach is a rare, often fatal disease which may be due to vascular, chemical, mechanical or infectious etiologies. We report a case of gastric gangrene due to necrotizing gastritis in a 50 year old female. PMID- 22211044 TI - Spontaneous rupture of incisional hernia-a case report. AB - Spontaneous rupture of an abdominal hernia is very rare and usually occurs in incisional or recurrent groin hernia. The rupture of abdominal hernia demands emergency surgery, to prevent further obstruction, strangulation of bowel and to cover its contents. The hernial contents can be covered primarily by mesh repair if the general condition of the patient and local condition of the operative site allows or can be covered by skin followed by delayed mesh repair. We report a case of spontaneous rupture of incisional hernia in a 60 years old lady who had developed incisional hernia following tubectomy and managed by mesh repair. PMID- 22211045 TI - Buccal mucosa ureteroplasty for the treatment of complex ureteric injury. AB - Bowel interposition and auto-transplantation of kidney, thought to be a major undertaking, remain the traditional option for the treatment of major and complex ureteric lesions. Buccal mucosa, a well known tissue for urethral reconstruction, can be used safely for the repair of ureter. However, this has been reported poorly in the literature. Here we report a 59- year-old female who had a major ureteric injury by Dormia basket during ureteroscopic extraction of a 2.6 cm impacted stone at pelvi- ureteric junction. On exploration, a long anterior slit was found in the upper ureter measuring approximately 8 cm. It was successfully repaired by free buccal mucosal patch graft over a Double J stent. Thus, a major surgery was avoided. Intra venous urography at 6-month follow up demonstrated a patent ureter. Our experience is encouraging and merits wider application in complex ureteric lesion. PMID- 22211046 TI - Abdominal cocoon as a rare cause of small bowel obstruction in an elderly man: report of a case and review of the literature. AB - Abdominal cocoon is a rare cause of intestinal obstruction usually diagnosed incidentally at laparotomy. The cause and pathogenesis of the condition have not been elucidated. It primarily affects adolescent girls living in tropical and subtropical regions. Several earlier cases have been reported in males. We describe an 82-year-old man presenting with small bowel obstruction without history of previous abdominal surgery. He was treated by warfarin following aortic valve replacement. Abdominal cocoon was detected at laparotomy. Excision of membrane and lysis of adhesions led to relief of obstruction. Abdominal cocoon is a rare pathology that may be found in all kinds of populations. It may be a rare form of small bowel obstruction diagnosed during surgery in elderly patients. PMID- 22211047 TI - Computed tomography target sign: a case of mistaken intussusception. AB - A 57-year-old male presented with a complete small bowel obstruction. Computed tomography confirmed an obvious transition point in the distal ileum, as well as an adjacent small bowel target sign. At exploratory laparotomy, the CT target sign had been caused by an obstructing phytobezoar cast ejected from a Meckel's diverticulum. PMID- 22211048 TI - Gangrenous stomach in mesentroaxial volvulus. AB - Volvulus refers to a greater than 180 degrees twisting of a hollow organ about its mesentery and results in luminal obstruction impaired venous return and eventually ischemia though much less common than volvulus of caecum and sigmoid colon ischemia. Gastric volvulus are clinical problems, when not recognized promptly, can lead to necrosis of the involved organ with resultant high morbidity and mortality. PMID- 22211049 TI - Schwannoma of brachial plexus. AB - Brachial plexus tumours are a rare entity. Schwannomas are benign nerve sheath tumours and only about 5% arise from the brachial plexus. Due to its rarity and complex anatomical location they can pose a formidable challenge to surgeons. We present a case of a young patient who presented with an axillary swelling three months after a lymph node biopsy from the same axilla, which turned out to be a Schwannoma arising for the medial cord of the brachial plexus. PMID- 22211050 TI - Sir astley paston cooper: history, english surgeon and anatomist. PMID- 22211051 TI - Amebic liver abscess. PMID- 22211052 TI - Pubertal development of the understanding of social emotions: Implications for education. AB - Recent developmental cognitive neuroscience research has supported the notion that puberty and adolescence are periods of profound socio-emotional development. The current study was designed to investigate whether the onset of puberty marks an increase in the awareness of complex, or "mixed," emotions. Eighty-three female participants (aged 9-16 years) were divided into three groups according to a self-report measure of puberty stage (early-, mid- and post-puberty). Participants were presented with emotional scenarios, and used four linear scales to rate their emotional response to each scenario. Scenarios were designed to evoke social emotions (embarrassment or guilt) or basic emotions (anger or fear), where social emotions are defined as those which require the representation of others' mental states. We measured the relative complexity or "mixedness" of emotional responses, that is, the degree to which participants reported feeling more than one emotion for a given scenario. We found that mixed emotion reporting increased between early- and post-puberty for social emotion scenarios, and showed no relationship with age, whereas there was no change in mixed emotion reporting for basic emotion scenarios across age or puberty groups. This suggests that the awareness of mixed emotions develops during the course of puberty, and that this development is specific to social emotions. Results are discussed in the context of brain development across puberty and adolescence, with speculation regarding the potential implications for education. PMID- 22211053 TI - Exploratory Health Disparities Research: The Need to Provide a Tangible Benefit to Vulnerable Respondents. AB - This article examines the responsibilities of researchers who conduct exploratory research to provide a service to vulnerable respondents. The term "service" is used to denote the provision of a tangible benefit in relation to the research question that is apart from the altruistic research benefits. This article explores what this "service" could look like, who might be responsible for providing it, and the challenges associated with such a service. The article argues that not providing a tangible benefit to vulnerable research participants is inconsistent with the principle of social justice that undergirds much of the rationale for conducting health disparities research. PMID- 22211054 TI - Finding our way. AB - LONG BEFORE I GOT PREGNANT, MY HUSBAND AND I BEGAN TO PREPARE FOR THE KIND OF BIRTH I HAD ALWAYS IMAGINED FOR MYSELF: peaceful, normal, and without medication or unnecessary medical intervention. In the fall of 2008, I got pregnant. At that same time, I started a new career as a labor and delivery nurse in a hospital that specializes in high-risk labor and birth. My daughter's journey into this world turned out to be the beautiful normal experience we had always imagined. This special experience also helped shape the kind of care I offer as a new labor and delivery nurse. PMID- 22211055 TI - Waiting to inhale: how to unhurry the moment of birth. AB - A doula and expectant mother's view of birth is forever changed when she sees a midwife simply place a newly born child below her mother at the moment of birth. The pause that the mother experiences in this moment as she studies, touches, and claims her child prompts the author to reflect in this guest editorial on ways we might be disturbing the natural sequence of birth as we deliver babies directly to their mothers' chests. PMID- 22211056 TI - Japanese Translation and Cultural Adaptation of the Listening to Mothers II Questionnaire. AB - The questionnaire used for the U.S. Listening to Mothers II survey was translated and culturally adapted to measure Japanese women's experience during the period of pregnancy planning through early postpartum. Methods included expert panels and two phases of cognitive interviews with 20 postpartum Japanese adult women. The number of problems with the translated questionnaire effectively decreased in the iterative process. Most problems were found in the question-interpretation stage of cognitive processing, such as wording/tone. Culture-specific concepts and unclear items were adapted to prevent erroneous interpretations in future studies. The future use of this questionnaire to generate data sets will be useful for professionals interested in developing evidence-based practices. The knowledge from this study can be helpful in improving health-care services and education for women with diverse languages and cultural backgrounds. PMID- 22211057 TI - Factors associated with exclusive breastfeeding 2 to 4 weeks following discharge from a large, urban, academic medical center striving for baby-friendly designation. AB - Substantial evidence documents the superiority of breastfeeding for mothers and breastmilk for babies. Although the American Academy of Pediatrics and the U.S. Healthy People 2010 initiative promote breastfeeding, current breastfeeding rates often fall short of recommendations. This study determined factors associated with exclusive breastfeeding 2 to 4 weeks following discharge from a large, urban, academic medical center striving for Baby-Friendly designation. Results indicated that mothers who breastfed within the first hour of birth (61%) were significantly more likely to be exclusively breastfeeding 2 to 4 weeks after discharge. Incorporating care practices that include a number of the "Ten Steps to Successful Breastfeeding," as recommended by the Baby-Friendly Hospital Initiative, may increase the duration of exclusive breastfeeding after discharge. PMID- 22211058 TI - Factors related to breastfeeding discontinuation between hospital discharge and 2 weeks postpartum. AB - Although breastfeeding is known to be beneficial to both mother and infant, many women encounter barriers to breastfeeding, even after successful breastfeeding initiation, which may put them at greater risk for early cessation of breastfeeding. The objectives of this study were to conduct a secondary analysis of data from a longitudinal study of postpartum depression to (a) examine factors related to very early discontinuation of breastfeeding (at 2 weeks postpartum) following hospital discharge and (b) identify women's reasons for very early cessation of breastfeeding. The results of this study support findings from previous research. Having a perceived support system, whether it is personal or professional, may have an effect on both the initiation and duration of breastfeeding. Educating expectant and new mothers, especially women who encounter multiple barriers and are at risk for very early cessation of breastfeeding, of the benefits of breastfeeding and supporting them in developing efficient techniques and problem-solving skills can help increase the duration of breastfeeding. PMID- 22211059 TI - African American Women's Preparation for Childbirth From the Perspective of African American Health-Care Providers. AB - Preparation for birthing has focused primarily on Caucasian women. No studies have explored African American women's birth preparation. From the perceptions of 12 African American maternity health-care providers, this study elicited perceptions of the ways in which pregnant African American women prepare for childbirth. Focus group participants answered seven semistructured questions. Four themes emerged: connecting with nurturers, traversing an unresponsive system, the need to be strong, and childbirth classes not a priority. Recommendations for nurses and childbirth educators include: (a) self-awareness of attitudes toward African Americans, (b) empowering of clients for birthing, (c) recognition of the role that pregnant women's mothers play, (d) tailoring of childbirth classes for African American women, and (e) research on how racism influences pregnant African American women's preparation for birthing. PMID- 22211060 TI - Umbilical cord blood: information for childbirth educators. AB - Umbilical cord blood was once thought of as a waste product. Now, years after the first successful umbilical cord blood transplant, more families seek information about whether or not to save their newborn's cord blood. Childbirth educators may be one of the main sources that an expectant family depends on to gain more knowledge about cord blood banking in order to make an informed decision. Preserving umbilical cord blood in public banks is advisable for any family; however, it is recommended that expectant families only consider private cord blood banking when they have a relative with a known disorder that is treatable by stem cell transplants. The childbirth educator is encouraged to be well versed on the topic of cord blood banking, so that as questions from class participants arise, the topic can be explored and addressed appropriately. PMID- 22211061 TI - Answering questions about herpes in pregnancy. AB - Herpes during pregnancy is a common concern. Because one in every five women is infected with the herpes virus, it is likely that herpes may be a topic that will be raised during a prenatal class, or afterward in private. An expectant mother who has a history of herpes may have concerns about protecting her baby from this virus. She may also have concerns about her own health, relationship issues including the support of her husband and family, or how to communicate with her health-care provider and make the best choices for a safe birth experience. Her childbirth educator can be a source of support and empowerment. PMID- 22211063 TI - Case 1: Immunizations: Are their administration and reactions ever 'routine'? PMID- 22211062 TI - Adapting Mindfulness-Based Cognitive Therapy for Treatment-Resistant Depression: A Clinical Case Study. AB - Major depressive disorder (MDD) is currently ranked the third leading cause of disability in the world. Treatment-Resistant Depression (TRD) causes the majority of MDD's disability. Strikingly, 50% of individuals with MDD will fail to remit with two adequate trials of antidepressant medications, thus qualifying as treatment resistant. Current pharmacological and psychotherapeutic treatment strategies for TRD are limited in effectiveness so new interventions are needed. Mindfulness-Based Cognitive Therapy (MBCT) is a new psychotherapeutic treatment with established efficacy in preventing relapse of depression for individuals in complete remission. MBCT is a group-based, 8-week intervention that uses mindfulness meditation as its core therapeutic technique. It teaches people to have a different relationship to depressive thoughts and feelings. Strategies are focused on decreasing rumination, enhancing self-compassion, increasing acceptance and decreasing avoidance. This modified version of MCBT, which includes the use of metaphor and adaptations of the original intervention will be discussed through the clinical case of a woman with long-standing TRD. A brief review of the current MBCT literature and future directions for the treatment of TRD are discussed. PMID- 22211064 TI - Case 2: Weight loss despite tube feeding. PMID- 22211065 TI - What happens when you mix a transplant with respiratory syncytial virus? PMID- 22211066 TI - Liver fluid collection in neonates and its association with the use of a specific umbilical vein catheter: Report of five cases. AB - In newborns, the presence of liver fluid collection is a rare event. The reported cases are isolated or described over long periods. Within four months, five neonates were diagnosed with liver fluid collection from safety occurrence reports. Clinical, laboratory and radiological data were extracted from medical records. The definite diagnosis was made by ultrasound. Four of the patients were preterm, male and had very low birth weights. The osmolality of the infused solution was within the acceptable range. Investigations revealed that the use of a new brand of umbilical vein catheter introduced in the neonatal intensive care unit, one month before the first case, was associated with this cluster. Low positioning of the umbilical vein catheter tip appeared to be a second contributory factor. Neonatal practitioners may benefit from the present report when facing the occurrence of similar lesions. PMID- 22211067 TI - Improving accountability for children's health: Immunization registries and public reporting of coverage in Canada. PMID- 22211069 TI - Parents may know best! A pilot study suggests that children of parents who do not have contact with health care professionals before attending the emergency department are triaged as more urgent. AB - OBJECTIVE: To assess the influence of prehospital health care contact on triage acuity. METHODS: One hundred fifteen families were assigned Canadian Triage and Acuity Scale scores by a paediatric emergency department (ED) physician. Scores of children who had or had not seen a health care professional before attending the ED were compared. RESULTS: Sixty-two of 72 (86.1%) children without previous health care professional contact, and 30 of 43 (69.8%) children with contact were triaged as 'urgent' (P=0.034). Parents with first aid knowledge (29 of 43 [67.4%]) were more likely to have had contact with a health care professional before visiting the ED compared with those with no such knowledge (27 of 72 [37.5%]; P=0.003). CONCLUSION: Patients without previous health care professional contact were assigned more acute triage categories. Health care professionals may advise families to visit the ED more frequently than necessary, which could contribute to ED congestion. Incorporating a parental estimate of the degree of urgency of their child's complaint into triage procedures represents an intriguing and challenging possibility. PMID- 22211068 TI - Associations between familial affluence and obesity risk behaviours among children. AB - BACKGROUND: Results of studies examining associations between socioeconomic status and obesity among children are mixed. OBJECTIVE: To examine whether physical activity, television viewing, computer use, and fruit, vegetable, soft drink and sweet consumption differed according to familial affluence of children attending schools in disadvantaged communities. METHOD: A total of 218 children (seven to 11 years of age) recruited from three Calgary (Alberta) schools located in two adjacent socioeconomically disadvantaged neighbourhoods completed online surveys during the spring of 2005/2006. The number of days per week participating in vigorous physical activity for more than 20 min, and weekly frequency of fruit, vegetable, sweet and soft drink consumption were collected. Time spent watching television and using a computer during a normal school day was also captured. A family affluence scale was used to assess socioeconomic status (number of family holidays in the past year, ownership of motor vehicles and computers, and bedroom sharing). Associations between familial affluence and obesity risk behaviours were estimated using Pearson's correlation and demographic-adjusted logistic regression ORs. RESULTS: Higher family affluence scale scores were significantly associated with weekly fruit consumption (r=0.14). Children with lower affluence were less likely to participate in vigorous physical activity five days/week or more (OR=0.39), and to use a computer for more than 2 h/day (OR=0.41) than children with higher affluence. Linear trends between familial affluence and the likelihood of participating in physical activity and using a computer were also found. However, no other behaviours were related to affluence. CONCLUSIONS: Increasing opportunities for physical activity and accessibility to healthy food may be important for reducing obesity risk among less affluent children. PMID- 22211070 TI - A harmonized immunization schedule for Canada: A call to action. AB - In Canada, the National Advisory Committee on Immunization systematically reviews the evidence for the effectiveness and safety of new and old vaccines, and sets a 'minimum' recommended schedule. However, in contrast to other industrialized countries where single, harmonized countrywide immunization schedules are de rigeur, Canada has a confusing system, with each province and territory defining its own schedule - and none are the same. The time has come to rectify this decades-old patient equity and safety problem. The Canadian Paediatric Society calls for a harmonized schedule to improve the health and safety of Canadian children and youth. PMID- 22211071 TI - FluMist vaccine: Questions and answers - summary. PMID- 22211072 TI - [Not Available]. PMID- 22211073 TI - [Not Available]. PMID- 22211074 TI - Emergency treatment of anaphylaxis in infants and children. AB - Anaphylaxis is a severe, acute and potentially life-threatening condition, often in response to an allergen. Patients experiencing anaphylaxis can present with cutaneous, respiratory, cardiovascular or gastrointestinal manifestations. Epinephrine given intramuscularly remains the mainstay of treatment for this condition. Other second-line therapies, such as inhaled beta-2 agonists, H1 and H2 receptor antagonists and corticosteroids, may play a role in resolving respiratory and cutaneous signs and symptoms. Biphasic reactions may occur during the resolution phase of symptoms and, thus, all patients should be observed for a minimum of 4 h to 6 h before discharge from hospital. On discharge, all patients should be prescribed epinephrine autoinjectors, and referred to an allergist or immunologist for further evaluation and education. PMID- 22211075 TI - [Not Available]. PMID- 22211076 TI - Infantile colic: Is there a role for dietary interventions? AB - Infantile colic is a behavioural syndrome of early childhood that is associated with irritability and crying. It self-resolves, but may lead to significant parental strife. The etiology is unknown; however, several investigators have examined the effect of nutrition on infantile colic. For the majority of infants, nutritional interventions appear to have no benefit on infantile colic. However, a minority of infants may display symptoms of infantile colic secondary to a cow's milk protein allergy. In these cases, a maternal hypoallergenic diet for breastfed infants and an extensively hydrolyzed formula for bottle-fed infants may result in resolution of colic. There is no proven role for the use of soy based formulas or of lactase therapy in the management of infantile colic, and these interventions are not recommended. Currently, there are insufficient data to make a recommendation on the effect of probiotics for infantile colic. In all cases of infantile colic, it is important to ensure that there is sufficient parental support available. PMID- 22211077 TI - [Not Available]. PMID- 22211078 TI - Re: Haslam RH. Why perform a history and physical examination when we have magnetic resonance imaging? Paediatr Child Health 2010;15(8):495-496. PMID- 22211079 TI - The effectiveness of telephone reminders and home visits to improve measles, mumps and rubella immunization coverage rates in children. AB - INTRODUCTION: In the Saskatoon Health Region (Saskatchewan), only 67.4% of children overall are fully immunized for measles, mumps and rubella (MMR) at 24 months of age, with only 43.7% of low-income children fully immunized. METHODS: Parents of children who were behind in MMR immunizations were contacted to determine knowledge about, beliefs toward and barriers to immunization. The effectiveness of a telephone reminder system in improving immunization rates in a health region compared with a control health region was determined. Finally, the effectiveness of telephone reminders versus telephone reminders combined with home visits in improving child immunization coverage rates in low-income neighbourhoods was compared. RESULTS: The survey was completed by 629 parents (69% response rate). Of those, 81.8% were not aware that their child was behind in immunizations. In the Saskatoon Health Region, the MMR immunization coverage increased from 67.4% to 74.0% in the first year of intervention (rate ratio = 1.10; 95% CI 1.08 to 1.12). All four neighbourhood groupings (three urban by income and one rural) had relative increases ranging from 9% to 11%. The control health region observed an immunization coverage increase from 66.5% to 69.2% in the first year (rate ratio = 1.04; 95% CI 1.01 to 1.07). The three low-income neighbourhoods with only telephone reminders had an immunization coverage rate of 48.7% (95% CI 39.5% to 57.8%). The three low-income neighbourhoods that received a telephone reminder and home visit had an immunization coverage rate of 60.5% (95% CI 52.5% to 68.6%). CONCLUSION: Telephone reminder systems have some benefit in increasing child immunization coverage rates. PMID- 22211080 TI - Evaluation and management of priapism in a newborn: A case report and review of the literature. AB - Idiopathic neonatal priapism is a rare and poorly understood phenomenon. The case of an otherwise healthy premature male newborn who was noted to have a persistent penile erection on the first day of life is presented. A Doppler ultrasound of the penis was performed, along with the first-ever cavernous blood gas analysis reported in a newborn. These investigations indicated that the presentation was consistent with nonischemic (arterial or high-flow) priapism. The patient was managed conservatively and the erection resolved fully on the sixth day of life. A review of the existing literature identified polycythemia as the most common identifiable cause of priapism in newborns, but the majority of cases are idiopathic. In most instances, observation alone is appropriate and spontaneous detumescence occurs. There are no published reports of erectile impairment following neonatal priapism, which suggests that this condition is relatively benign in the absence of other disease states. PMID- 22211081 TI - BIFURCATIONS OF RANDOM DIFFERENTIAL EQUATIONS WITH BOUNDED NOISE ON SURFACES. AB - In random differential equations with bounded noise minimal forward invariant (MFI) sets play a central role since they support stationary measures. We study the stability and possible bifurcations of MFI sets. In dimensions 1 and 2 we classify all minimal forward invariant sets and their codimension one bifurcations in bounded noise random differential equations. PMID- 22211083 TI - Traumatic hemorrhage within a cerebellar dermoid cyst. AB - Intracranial dermoid cysts with hemorrhage are fairly rare. Herein, we reported a 28-year-old female patient with a cerebellar dermoid cyst, which was found accidently on neuro-imaging after head trauma. MR scanning revealed that the lesion was located within the cerebellar vermis and was measured 3.5cm*3.9cm*3.0cm, with hyper-intensity on T1WI and hypo-intensity on T2WI. However, on CT imaging, it showed hyper-dense signals. It was removed completely via midline sub-occipital approach under surgical microscope. Histological examination proved it was a dermoid cyst with internal hemorrhage. In combination with literature review, we discussed the factors that might be responsible for the hemorrhage within dermoid cysts. PMID- 22211082 TI - Improved synthesis strategy for peptide nucleic acids (PNA) appropriate for cell specific fluorescence imaging. AB - Progress in genomics and proteomics attended to the door for better understanding the recent rapid expanding complex research field of metabolomics. This trend in biomedical research increasingly focuses to the development of patient-specific therapeutic approaches with higher efficiency and sustainability. Simultaneously undesired adverse reactions are avoided. In parallel, the development of molecules for molecular imaging is required not only for the imaging of morphological structures but also for the imaging of metabolic processes like the aberrant expression of the cysteine protease cathepsin B (CtsB) gene and the activity of the resulting product associated with metastasis and invasiveness of malign tumors. Finally the objective is to merge imaging and therapy at the same level. The design of molecules which fulfil these responsibilities is pivotal and requires proper chemical methodologies. In this context our modified solid phase peptide chemistry using temperature shifts during synthesis is considered as an appropriate technology. We generated highly variable conjugates which consist of molecules useful as diagnostically and therapeutically active molecules. As an example the modular PNA products with the complementary sequence to the CtsB mRNA and additionally with a cathepsin B cleavage site had been prepared as functional modules for distinction of cell lines with different CtsB gene expression. After ligation to the modular peptide-based BioShuttle carrier, which was utilized to facilitate the delivery of the functional modules into the cells' cytoplasm, the modules were scrutinized. PMID- 22211084 TI - Comparison of laparoscopic and laparotomic surgery for the treatment of peritoneal inclusion cyst. AB - OBJECTIVES: Peritoneal inclusion cyst (PIC) is defined as a fluid-filled mesothelial-lined cysts of the pelvis and it is most frequently encountered in women of reproductive age. The treatment options are observation, hormonal management, imaging-guided aspiration, image-guided sclerotherapy and surgical excision. The objective of this study is to compare between the laparoscopic and laparotomic surgery for the treatment of PIC. METHODS: Thirty-five patients with laparoscopy and forty-eight patients with laparotomy were included in the study. We compared the perioperative and postoperative data, the complications and the recurrence between the two groups. RESULTS: There was a significantly reduced mean length of the hospital stay, estimated blood loss and complication rate in the laparoscopic group as compared to that of the laparotomic group (P=0.037, P=0.047 and P=0.037 respectively). There was also no statistical difference of recurrence rate between thelaparoscopic and laparotomic groups on the Cox proportional hazards model (p=0.209). CONCLUSION: Our study showed that laparoscopy was superior to the laparotomy for the mean estimated blood loss, the mean length of the hospital stay and the complication rate except for the recurrence rate. PMID- 22211085 TI - Cystic lesions of the jaws - a clinicopathological study of 322 cases and review of the literature. AB - Three hundred and twenty-two patients (192 male and 130 female) with cystic lesions of the jaw were successfully diagnosed and treated. One hundred and fifty five (48%) were radicular cysts, 80 (25%) were dentigerous cysts, 23 (7%) were odontogenic keratocyst (=keratocystic odontogenic tumor), 19 (6%) were eruption cysts, 16 (5%) were traumatic bone cysts, and 29 (9%) were non-odontogenic cysts. There were 95 in the pediatric age group (1 month to 16 years) and 227 in the adult age group (17 years and older). Male to female ratio was 1 in the pediatric age group and 1.7 in the adult age group. The treatment modalities were: marsupialization, enucleation, enucleation with bone grafting, or resection. The distribution and characteristics of jaw cysts in children are different from those in adults. In children there is a relatively high rate of developmental cysts, whereas in adults the inflammatory cysts are more common. Following enucleation of a cystic jaw lesion, the entire surgical specimen and not only a biopsy specimen, should be examined histopathologically to prevent any possibility of an intramural squamous cell carcinoma that may be overlooked. The differences in prevalence of each type of jaw cyst during a lifetime may point toward a multifactorial polygenic pattern rather than a monogenic pattern. PMID- 22211086 TI - Efficacy of lamivudine or entecavir on acute exacerbation of chronic hepatitis B. AB - BACKGROUND/AIMS: Spontaneous acute exacerbation of chronic hepatitis B virus (HBV) infection occasionally occurs in its natural history, sometimes leading rapidly to fatal hepatic failure. We compared the effects of lamivudine (LAM) with those of entecavir (ETV) treatments in acute exacerbation of chronic hepatitis B with 500 IU/L or higher alanine aminotransferase (ALT) levels. METHODS: Thirty-four patients with acute exacerbation were consecutively treated with LAM /ETV. Their clinical improvements were compared. RESULTS: Among LAM treated and ETV-treated patients, none showed a reduction of <1 log IU/mL in HBV DNA after 1 or 3 months of treatment. Initial virological response, defined as a reduction of 4 log IU/mL in HBV DNA at 6 months, with LAM and ETV, respectively, was 83.3% and 100%. One LAM patient developed hepatic encephalopathy, but all patients in both groups survived. Twelve months after treatment, 41.6% of 24 LAM group patients switched to another drug or added adefovir to their treatment due to the emergence of LAM-resistant mutants. On the other hand, patients receiving ETV did not need to change drugs. CONCLUSIONS: ETV appears to be as effective as LAM in the treatment of patients with acute exacerbation of chronic hepatitis B. Clinicians should carefully start to treat these patients as soon as possible. PMID- 22211087 TI - Adverse event profiles of 5-fluorouracil and capecitabine: data mining of the public version of the FDA Adverse Event Reporting System, AERS, and reproducibility of clinical observations. AB - OBJECTIVE: The safety profiles of oral fluoropyrimidines were compared with 5 fluorouracil (5-FU) using adverse event reports (AERs) submitted to the Adverse Event Reporting System, AERS, of the US Food and Drug Administration (FDA). METHODS: After a revision of arbitrary drug names and the deletion of duplicated submissions, AERs involving 5-FU and oral fluoropyrimidines were analyzed. Standardized official pharmacovigilance tools were used for the quantitative detection of signals, i.e., drug-associated adverse events, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. RESULTS: Based on 22,017,956 co-occurrences, i.e., drug adverse event pairs, found in 1,644,220 AERs from 2004 to 2009, it was suggested that leukopenia, neutropenia, and thrombocytopenia were more frequently accompanied by the use of 5-FU than capecitabine, whereas diarrhea, nausea, vomiting, and hand-foot syndrome were more frequently associated with capecitabine. The total number of co-occurrences was not large enough to compare tegafur, tegafur-uracil (UFT), tegafur-gimeracil-oteracil potassium (S-1), or doxifluridine to 5-FU. CONCLUSION: The results obtained herein were consistent with clinical observations, suggesting the usefulness of the FDA's AERS database and data mining methods used, but the number of co-occurrences is an important factor in signal detection. PMID- 22211088 TI - The simplified Edinburgh Postnatal Depression Scale (EPDS) for antenatal depression: is it a valid measure for pre-screening? AB - The identification of antenatal depression is critical but poorly conducted. The aim of this study was to construct a simplified depression survey scale and to verify its efficacy as a pre-screening for antenatal depression. A total of 494 pregnant women in the third trimester of gestation who had received antenatal care at Seoul St. Mary's Hospital from July 2009 to June 2010 were included. The Edinburgh Postnatal Depression Scale (EPDS) questionnaire was completed by them. The subjects were randomly divided into two groups: 250 of training set and 244 of validation set. We designed a simplified questionnaire comprising two items of EPDS using the training set. We then validated its efficacy with the training set and reaffirmed the results with the validation set. The sum of item 5 (scare or panic) and item 8 (sadness or misery) explained 75.5% of the total score of the EPDS (AUC = 0.947). Using a score of 3 as a cut-off value of the simplified scale, sensitivity was 92.4% and specificity was 86.3%. The positive and negative predictive values were 56.2% and 98.4%, retrospectively. This study suggests that the simplified EPDS can be an efficient instrument to rule out depression during pregnancy. PMID- 22211089 TI - Oral infection by Staphylococcus aureus in patients affected by White Sponge Nevus: a description of two cases occurred in the same family. AB - INTRODUCTION: White Sponge Nevus (WSN) is a rare pathology with a pathogenesis on genetic basis, a benign course and a localization affecting the mucosal keratin.WSN is usually a symptomless pathology: when pain is present, some authors reported reduction of symptoms by taking penicillin or oral tetracycline rinses, suggesting that a bacterial overinfection could be at the base of possible painful symptoms. CASE REPORT: We describe 2 patients affected by WSN, father and son: they presented two different oral diseases associated with an infection by Staphylococcus aureus. So, we have performed a careful oral hygiene to reduce infection in the oral cavity. In the following days we prescribed 2 rinses a day with a mouthwash containing chlorhexidine digluconate at two different percentages. DISCUSSION: Early diagnosis of this lesion is important, because it allows us to exclude other more serious diseases. In the most part of cases, WSN requires no treatment because of its benign and asymptomatic behaviour: up to now, no protocol of treatment for this condition was standardized. Even if WSN is a painless condition, sometime a correlated painful symptomatology was reported. CONCLUSIONS: In our experience, we have achieved excellent results even with chlorhexidine digluconate rinses, considering that our treated cases were both infected by Staphylococcus aureus. We hypothesize that the corrugated plaques and the altered texture of the mucosa create the right conditions for the colonization and the development of microbial species such as saprophytic bacteria or fungal species. PMID- 22211090 TI - The GHS-R blocker D-[Lys3] GHRP-6 serves as CCR5 chemokine receptor antagonist. AB - [D-Lys3]-Growth Hormone Releasing Peptide-6 (DLS) is widely utilized in vivo and in vitro as a selective ghrelin receptor (GHS-R) antagonist. This antagonist is one of the most common antagonists utilized in vivo to block GHS-R function and activity. Here, we found that DLS also has the ability to modestly block chemokine function and ligand binding to the chemokine receptor CCR5. The DLS effects on RANTES binding and Erk signaling as well as calcium mobilization appears to be much stronger than its effects on MIP-1alpha and MIP-1beta. CCR5 have been shown to act as major co-receptor for HIV-1 entry into the CD4 positive host cells. To this end, we also found that DLS blocks M-tropic HIV-1 propagation in activated human PBMCs. These data demonstrate that DLS may not be a highly selective GHS-R1a inhibitor and may also effects on other G-protein coupled receptor (GPCR) family members. Moreover, DLS may have some potential clinical applications in blocking HIV infectivity and CCR5-mediated migration and function in various inflammatory disease states. PMID- 22211091 TI - A randomized clinical trial comparing the effect of rapidly infused crystalloids on acid-base status in dehydrated patients in the emergency department. AB - STUDY OBJECTIVE: To compare the effect of normal saline (NS), lactated Ringer's, and Plasmalyte on the acid-base status of dehydrated patients in the emergency department (ED). METHOD: We conducted a prospective, double-blind, randomized trial of consecutive adult patients who presented to the emergency department with moderate-severe dehydration. Patients were randomly allocated to blindly receive normal saline (NS), lactated Ringer's or Plasmalyte at 20 ml/kg/h for 2 hours. Outcome measures of the study were pH and changes in electrolytes, including serum potassium, sodium, chloride and bicarbonate levels at 0, 60, and 120 minutes in venous blood gas samples. RESULTS: Ninety patients participated in the study and were randomized to NS (30 patients), lactated Ringer's (30 patients) and Plasmalyte (30 patients) groups. Mean age was 48+/-20 years and 50% (n=45) of the patients were female. All pH values were in the physiological range (7.35-7.45) throughout the study period. In the NS group there was a significant tendency to lower pH values, with pH values of 7.40, 7.37, and 7.36 at 0, 1, and 2 hours respectively. Average bicarbonate levels fell in the NS group (23.1, 22.2, and 21.5 mM/L) and increased in the Plasmalyte group (23.4, 23.9, and 24.4 mM/L) at 0, 1, and 2 hours, respectively. There were no significant changes in potassium, sodium, or chloride levels. CONCLUSIONS: NS, lactated Ringer's, and Plasmalyte have no significant effect on acid-base status and all can be used safely to treat dehydrated patients in the emergency department. However, NS can effect acidosis which might be significant in patients who have underlying metabolic disturbances; thus, its use should be weighed before fluid administration in the ED. PMID- 22211092 TI - Clinicopathological characteristics and prognosis of non-small cell lung cancer patients associated with a family history of lung cancer. AB - INTRODUCTION: Clinicopathological characteristics and prognosis of non-small cell lung cancer (NSCLC) patients with a family history of lung cancer (FHLC) have not been well established. METHODS: Clinical records of patients with NSCLC treated at our institute from 1982 to 2010 were reviewed with special reference to family history of lung cancer and clinicopathological factors including patient's outcome. Univariate analyses of the factors between the groups of FHLC and non FHLC were performed using unpaired two-tailed t tests or the chi-square test. The Cox proportional hazards model was used to evaluate the hazard ratio of death. RESULTS: Of the 1013 NSCLC patients, 124 (12.2%) had a FHLC of whom 119 (96%) were the first-degree relatives. The frequency of early stages of lung cancer was high in both groups of FHLC and non-FHLC patients. Patients with FHLC had a significantly higher frequency of early pathological stages and a prepomderance of adenocarcinoma, and a hazard ratio of death of 0.870 (95% confidence interval: 0.599-1.263, p value: 0.465) compared with the non-FHLC patients. CONCLUSIONS: NSCLC patients with FHLC could be characterized by early pathological stages and preponderance of adenocarcinoma, however they were not at a decreased hazard ratio of death. These findings emphasize the importance of early detection of lung cancer and employment of less invasive therapeutic interventions. PMID- 22211093 TI - Early biventricular molecular responses to an acute myocardial infarction. AB - BACKGROUND: Acute myocardial infarction (AMI) remains as one of the most common lethal diseases in the world and therefore it is necessary to understand its effect on molecular basis. Genome-wide microarray analysis provides us to predict potential biomarkers and signaling pathways for this purpose. OBJECTIVES: The aim of this study is to understand the molecular basis of the immediate right ventricular cellular response to left ventricular AMI. MATERIAL AND METHODS: A rat model of left anterior descending coronary artery ligation was used to assess the effect of left ventricular AMI on both the right ventricle as a remote zone and the left ventricle as an ischemic/infarct zone. Microarray technology was applied to detect the gene expression. Gene Ontology and KEGG pathways analysis were done to identify effected pathways and related genes. RESULTS: We found that immune response, cell chemotaxis, inflammation, cytoskeleton organization are significantly deregulated in ischemic zone as early response within 30 min. Unexpectedly, there were several affected signaling pathways such as cell chemotaxis, regulation of endothelial cell proliferation, and regulation of caveolea regulation of anti-apoptosis, regulation of cytoskeleton organization and cell adhesion on the remote zone in the right ventricle. CONCLUSION: This data demonstrates that there is an immediate molecular response in both ventricles after an AMI. Although the ischemia did not histologically involve the right ventricle; there is a clear molecular response to the infarct in the left ventricle. This provides us new insights to understand molecular mechanisms behind AMI and to find more effective drug targets. PMID- 22211094 TI - Tender papule rising on the digit: Pacinian neuroma should be considered in differential diagnosis. AB - Pacinian corpuscles are sensory nerve-end organs located in the deep dermis and subcutaneous tissue of the palms or soles. Pacinian neuroma is an extremely rare feature, defined as hyperplasia or hypertrophy of Pacinian corpuscles. About half of Pacinian neuromas present with point tenderness. There have been a limited number of cases reported around the world. We observed a 45-year-old woman with an 8-month history of a tender whitish papule on her left thumb tip. Histopathologically, an enlarged hypertrophic Pacinian corpuscle in subcutaneous tissue, surrounded by numerous nerve fibers, was found. Herein, we report a case of Pacinian neuroma presenting as a tender papule on a fingertip that was clearly related to repetitive trauma at that site. This case shows that a meticulous history and histological examination can lead to an exact diagnosis and proper treatment. PMID- 22211095 TI - Effects of female sex hormones on clusterin expression and paclitaxel resistance in endometrial cancer cell lines. AB - OBJECTIVE: We have analyzed the association between clusterin expression in endometrial cancer cells and their resistance to paclitaxel. We also analyzed whether the effects of female sex hormones on clusterin expression by these cell lines affect their resistance to paclitaxel. METHODS: The expression of estrogen receptors alpha and beta, progesterone receptors AB and B, and clusterin mRNA and protein was assayed in the ECC-1 and KLE endometrial cancer cell lines by RT-PCR and Western blotting, respectively. The IC(50) of paclitaxel was measured in each cell line by XTT assay. Using clusterin siRNA, we analyzed the association between clusterin expression and paclitaxel IC(50) in each cell line. We also examined the effects of hormone treatment on cellular resistance to paclitaxel. RESULTS: Paclitaxel IC(50) was significantly higher in KLE cells, which expressed higher levels of clusterin, than in ECC-1 cells, which expressed lower levels of clusterin. Conversely, incubation with clusterin siRNA significantly decreased the viability of KLE cells (P<0.001), but did not alter the viability of ECC-1 cells. Incubation with estrogen tended to increase the level of clusterin expression in these endometrial cancer cell lines, although the level of clusterin expression did not correlate with that of estrogen receptors. Incubation with progesterone did not alter the levels of expression of clusterin and clusterin receptor. Incubation with estrogen and paclitaxel significantly increased the viability of ECC-1 (P<0.001) but not KLE cells. CONCLUSION: Estrogen increases the paclitaxel resistance of endometrial cancer cell lines, by increasing clusterin expression. PMID- 22211096 TI - Electrocardiographic findings in patients with polycythemia vera. AB - BACKGROUND: The 12-lead surface electrocardiogram (ECG) is a useful tool to predict both atrial and ventricular arrhythmias via P-wave and QT measurements and its derivatives. Polycythemia vera (PV) is a chronic myeloproliferative disorder associated with cardiovascular events. The aim of this study was to assess ECG findings of patients with PV. METHOD AND MATERIALS: Sixty patients with PV (34 male, mean age 58+/-11 years) and 60 age and gender-matched healthy volunteers were enrolled into the study. From the 12-lead surface ECG, P-wave and both conventional QT measurements and transmyocardial repolarization parameters (T(peak)-T(end) interval (T(p)-T(e)) and derivatives) were evaluated digitally by two experienced cardiologists. In addition, a novel parameter, Pi was calculated digitally as the standard deviation of the P-wave duration across the 12 ECG leads. RESULTS: QT duration and corrected QT interval were significantly longer in the PV group compared to healthy controls (p<0.01 and p<0.01, respectively). The T(p)-T(e) was longer and the T(p)-T(e)/QT ratio was significantly higher in the PV group compared to the controls. P-wave analyses showed that all P-wave parameters including Pmax, Pmin, P dispersion, and Pi were significantly prolonged in PV patients compared to the controls. The increase of both T(p)-T(e )and P max in the PV group was independent of age, BMI, diabetes and hypertension, gender, systolic blood pressure, hemoglobin, hematocrit, left atrial dimension, left ventricular end-diastolic diameter and early deceleration time in a univariate analysis of co-variance model (F=11.097, p=0.001 and F=31.537, p=0.0001, respectively). CONCLUSION: The present study demonstrated that PV may be associated with electrocardiographic abnormalities of both atrium and ventricle. PMID- 22211097 TI - High-risk human papillomavirus infection in low risk women: incidence, patient characteristics, and clinical meaning for cervical cancer. AB - OBJECTIVE: To investigate the incidence of high-risk human papillomavirus (HPV) infection and its clinical meaning. METHODS: Total 28,339 women attending our hospital for routine gynecologic care underwent Papanicolaou test (PAP test) and high-risk HPV tests. Biopsies were taken from some women and their results were compared. RESULTS: The prevalence of high-risk HPV infection is 24.15%. And the women aged 20-29 years had the highest prevalence (32.3%) compared to 30-70 years (P<0.05). Of the 28,339 women, 1369 (4.83%) had positive PAP test (ASCUS, LSIL, HSIL). Of the 1369 PAP-positive patients, only 16 (1.17%) were negative for HPV test. Of the 1353 patients positive on both tests, 510 (37.7%) had lesions higher than CINII on histology. Of the 1,611 patients who underwent biopsies, 350 underwent the loop electrical excision procedure, with 339 (96%) being positive for HPV test, including 16 with CINI, 48 with CINII/III, 74 with CIS, and 16 with cervical cancer. HPV test had a positive predictive value of 40.7% and a negative predictive value of 100% for higher than CINII. CONCLUSION: Although HPV test has a burden of cost, considering its high negative predictive value, HPV test should be considered for more useful screening test. PMID- 22211098 TI - P-wave dispersion for predicting paroxysmal atrial fibrillation in acute ischemic stroke. AB - BACKGROUND: Detection of paroxysmal atrial fibrillation (PAF) in acute ischemic stroke patients poses diagnostic challenge. The aim of this study was to predict the presence of PAF by means of 12-lead ECG in patients with acute ischemic stroke. Our hypothesis was that P-wave dispersion (P(d)) might be a useful marker in predicting PAF in patients with acute ischemic stroke. METHODS: 12-lead resting ECGs, 24-hour Holter recordings and echocardiograms of 400 patients were analyzed retrospectively. PAF was detected in 40 patients on 24-hour Holter monitoring. Forty out of 360 age and gender matched patients without PAF were randomly chosen and assigned as the control group. Demographics, P-wave characteristics and echocardiographic findings of the patients with and without PAF were compared. RESULTS: Maximum P-wave duration (p=0.002), P(d) (p<0.001) and left atrium diameter (p=0.04) were significantly higher in patients with PAF when compared to patients without PAF. However, in binary logistic regression analysis P(d) was the only independent predictor of PAF. The cut-off value of P(d) for the detection of PAF was 57.5 milliseconds (msc). Area under the curve was 0.80 (p<0.001). On a single 12-lead ECG, a value higher than 57.5 msc predicted the presence of PAF with a sensitivity of 80% and a specificity of 73%. CONCLUSION: P(d) on a single 12-lead ECG obtained within 24 hours of an acute ischemic stroke might help to predict PAF and reduce the risk of recurrent strokes. PMID- 22211099 TI - Relationship of visual cortex function and visual acuity in anisometropic amblyopic children. AB - PURPOSE: To detect the functional deficit of the visual cortex in anisometropic amblyopia children using functional magnetic resonance imaging (fMRI) technique, and investigate the relationship between visual acuity and visual cortex function. METHODS: Blood oxygenation level-dependent fMRI (BOLD-fMRI) was performed in ten monocular anisometropic amblyopia children and ten normal controls. fMRI images were acquired in two runs with visual stimulation delivered separately through the sound and amblyopic eyes. Measurements were performed in cortical activation of striate and extrastriate areas at the occipital lobe. The relationship between cortex function and visual acuity was analyzed by Pearson partial analysis. RESULTS: The activation areas of both the striate and extrastriate cortices in the amblyopic eyes were significantly lower than that of the sound fellow eyes. No relationship was found between the striate and extrastriate cortex activation. No relationship was found between the visual cortical activation of striate, extrastriate areas and visual acuity of anisometropic amblyopes. CONCLUSIONS: BOLD-fMRI revealed the independent striate and extrastriate cortical deficits in anisometropic amblyopes. In addition, the visual acuity lesion and the striate and extrastriate cortical deficits were not parallel, and results of fMRI examination have much potential value in the evaluation of amblyopia. PMID- 22211100 TI - Enhanced antitumor efficacy of gemcitabine by evodiamine on pancreatic cancer via regulating PI3K/Akt pathway. AB - Evodiamine has therapeutic potential against cancers. This study was designed to investigate whether combination therapy with gemcitabine and evodiamine enhanced antitumor efficacy in pancreatic cancer. In vitro application of the combination therapy triggered significantly higher frequency of pancreatic cancer cells apoptosis, inhibited the activities of PI3K, Akt, PKA, mTOR and PTEN, and decreased the activation of NF-kappaB and expression of NF-kappaB-regulated products. In vivo application of the combination therapy induced significant enhancement of tumor cell apoptosis, reductions in tumor volume, and inhibited activation of mTOR and PTEN. In conclusion, evodiamine can augment the therapeutic effect of gemcitabine in pancreatic cancer through direct or indirect negative regulation of the PI3K/Akt pathway. PMID- 22211101 TI - Influence of five potential anticancer drugs on wnt pathway and cell survival in human biliary tract cancer cells. AB - BACKGROUND: The role of Wnt signalling in carcinogenesis suggests compounds targeting this pathway as potential anti-cancer drugs. Several studies report activation of Wnt signalling in biliary tract cancer (BTC) thus rendering Wnt inhibitory drugs as potential candidates for targeted therapy of this highly chemoresistant disease. METHODS: In this study we analysed five compounds with suggested inhibitory effects on Wnt signalling (DMAT, FH535, myricetin, quercetin, and TBB) for their cytotoxic efficiency, mode of cell death, time- and cell line-dependent characteristics as well as their effects on Wnt pathway activity in nine different BTC cell lines. RESULTS: Exposure of cancer cells to different concentrations of the compounds results in a clear dose-dependent reduction of viability for all drugs in the order FH535 > DMAT > TBB > myricetin > quercetin. The first three substances show high cytotoxicity in all tested cell lines, cause a direct cytotoxic effect by induction of apoptosis and inhibit pathway-specific signal transduction in a Wnt transcription factor reporter activity assay. Selected target genes such as growth-promoting cyclin D1 and the cell cycle progression inhibitor p27 are down- and up-regulated after treatment, respectively. CONCLUSIONS: Taken together, these data demonstrate that the small molecular weight inhibitors DMAT, F535 and TBB have a considerable cytotoxic and possibly Wnt-specific effect on BTC cell lines in vitro. Further in vivo investigation of these drugs as well as of new Wnt inhibitors may provide a promising approach for targeted therapy of this difficult-to-treat tumour. PMID- 22211102 TI - Serum bone alkaline phosphatase in assessing illness severity of infected neonates in the neonatal intensive care unit. AB - BACKGROUND: Infections can influence bone metabolism of neonates, which may lead to changes in some bone metabolism biomarkers. The purpose of this study was to determine whether serum bone alkaline phosphatase (BALP), osteocalcin (OC) and beta carboxy-terminal peptide of type I collagen (CTX), as specific biomarkers of bone metabolism, can be used to assess the severity of neonatal infections. METHODS: Sixty-three neonates in the NICU were enrolled in this study. The neonates were divided into infected group (n=33) and non-infected group (n=30). The scores for neonatal acute physiology-perinatal extension II (SNAPPE-II) were calculated and interleukin-6 (IL-6), procalcitonin (PCT), BALP, OC and CTX were measured among the neonates with or without infections, and among the infected neonates before and after treatment. RESULTS: The serum BALP levels were lower in the infected group than that in the non-infected group (p<0.01). The serum BALP levels increased markedly in the infected neonates after treatment (p<0.01). The serum BALP levels were also inversely correlated with SNAPPE-II of infected neonates before and after treatment (r=-0.56, p<0.05; r=-0.37, p<0.05, respectively). In infected neonates, the differences between serum BALP levels before and after treatment were inversely correlated with those of IL-6 levels (p<0.05). There were no significant changes in the OC, CTX and PCT levels in the infected or non-infected group before and after treatment. CONCLUSION: Our data suggest that serum BALP level might be used as a marker for assessing the severity of illness in infected neonates. PMID- 22211103 TI - Two closely related human members of chitinase-like family, CHI3L1 and CHI3L2, activate ERK1/2 in 293 and U373 cells but have the different influence on cell proliferation. AB - The activation of extracellular signal-regulated kinases (ERK1/2) has been associated with specific outcomes. Sustained activation of ERK1/2 by nerve growth factor (NGF) is associated with translocation of ERKs to the nucleus of PC12 cells and precedes their differentiation into sympathetic-like neurons whereas transient activation by epidermal growth factor (EGF) leads to cell proliferation. It was demonstrated that different growth factors initiating the same cellular signaling pathways may lead to the different cell destiny, either to proliferation or to the inhibition of mitogenesis and apoptosis. Thus, further investigation on kinetic differences in activation of certain signal cascades in different cell types by biologically different agents are necessary for understanding the mechanisms as to how cells make a choice between proliferation and differentiation.It was reported that chitinase 3-like 1 (CHI3L1) protein promotes the growth of human synovial cells as well as skin and fetal lung fibroblasts similarly to insulin-like growth factor 1 (IGF1). Both are involved in mediating the mitogenic response through the signal-regulated kinases ERK1/2. In addition, CHI3L1 which is highly expressed in different tumors including glioblastomas possesses oncogenic properties. As we found earlier, chitinase 3 like 2 (CHI3L2) most closely related to human CHI3L1 also showed increased expression in glial tumors at both the RNA and protein levels and stimulated the activation of the MAPK pathway through phosphorylation of ERK1/2 in 293 and U87 MG cells. The work described here demonstrates the influence of CHI3L2 and CHI3L1 on the duration of MAPK cellular signaling and phosphorylated ERK1/2 translocation to the nucleus. In contrast to the activation of ERK1/2 phosphorylation by CHI3L1 that leads to a proliferative signal (similar to the EGF effect in PC12 cells), activation of ERK1/2 phosphorylation by CHI3L2 (similar to NGF) inhibits cell mitogenesis and proliferation. PMID- 22211104 TI - Localization, expression change in PRRSV infection and association analysis of the porcine TAP1 gene. AB - The transporter associated with antigen processing (TAP) translocates antigenic peptides from the cytosol into the lumen of the endoplasmic reticular and plays a critical role in the major histocompatibility complex (MHC) class I molecule mediated antigenic presentation pathway. In this study, the porcine TAP1 gene was mapped to the pig chromosome 7 (SSC7) and was closely linked to the marker SSC2B02 (retention fraction=43%, LOD=15.18). Subcellular localization of TAP1 by transient transfection of PK15 cells indicated that the TAP1 protein might be located in the endoplasmic reticulum (ER) in pig kidney epithelial cells (PK-15). Gene expression analysis by semi-quantitative RT-PCR revealed that TAP1 was selectively expressed in some immune and immune-related tissues. Quantitative real-time PCR (qRT-PCR) analysis revealed that this gene was up-regulated after treatments that mimic viral and bacterial infection (polyriboinosinic polyribocytidylic acid (poly(I:C)) and lipopolysaccharide (LPS), respectively). In addition, elevated TAP1 expression was detected after porcine reproductive and respiratory syndrome virus (PRRSV) infection in porcine white blood cells (WBCs). One single nucleotide polymorphism (SNP) in exon 3 of TAP1 was detected in a Landrace pig population by Bsp143I restriction enzyme digestion. Different genotypes of this SNP had significant associations (P<0.05) with the red blood cell distribution width (RDW) of 1-day-old (1 d) pigs (P=0.0168), the PRRSV antibody level (PRRSV Ab) (P=0.0445) and the absolute lymphocyte count (LYM#) (P=0.024) of 17 d pigs. Our results showed that the TAP1 gene might have important roles in swine immune responses, and these results provide useful information for further functional studies. PMID- 22211105 TI - EZH2 methyltransferase and H3K27 methylation in breast cancer. AB - Histone modifications are thought to control the regulation of genetic programs in normal physiology and cancer. Methylation (mono-, di-, and tri-methylation) on histone H3 lysine (K) 27 induces transcriptional repression, and thereby participates in controlling gene expression patterns. Enhancer of zeste (EZH) 2, a methyltransferase and component of the polycomb repressive complex 2 (PRC2), plays an essential role in the epigenetic maintenance of the H3K27me3 repressive chromatin mark. Abnormal EZH2 expression has been associated with various cancers including breast cancer. Here, we discuss the contribution of EZH2 and the PRC2 complex in controlling the H3K27 methylation status and subsequent consequences on genomic instability and the cell cycle in breast cancer cells. We also discuss distinct molecular mechanisms used by EZH2 to suppress BRCA1 functions. PMID- 22211106 TI - Proteomic analysis on acetate metabolism in Citrobacter sp. BL-4. AB - Mass production of glucosamine (GlcN) using microbial cells is a worthy approach to increase added values and keep safety problems in GlcN production process. Prior to set up a microbial cellular platform, this study was to assess acetate metabolism in Citrobacter sp. BL-4 (BL-4) which has produced a polyglucosamine PGB-2. The LC-MS analysis was conducted after protein separation on the 1D-PAGE to accomplish the purpose of this study. 280 proteins were totally identified and 188 proteins were separated as acetate-related proteins in BL-4. Acetate was converted to acetyl-CoA by acetyl-CoA synthetase up-regulated in the acetate medium. The glyoxylate bypass in the acetate medium was up-regulated with over expression of isocitrate lyases and 2D-PAGE confirmed this differential expression. Using (1)H-NMR analysis, the product of isocitrate lyases, succinate, increased about 15 times in the acetate medium. During acetate metabolism proteins involved in the lipid metabolism and hexosamine biosynthesis were over expressed in the acetate medium, while proteins involved in TCA cycle, pentose phosphate cycle and purine metabolism were down-regulated. Taken together, the results from the proteomic analysis can be applied to improve GlcN production and to develop metabolic engineering in BL-4. PMID- 22211107 TI - The putative metal coordination motif in the endonuclease domain of human Parvovirus B19 NS1 is critical for NS1 induced S phase arrest and DNA damage. AB - The non-structural proteins (NS) of the parvovirus family are highly conserved multi-functional molecules that have been extensively characterized and shown to be integral to viral replication. Along with NTP-dependent helicase activity, these proteins carry within their sequences domains that allow them to bind DNA and act as nucleases in order to resolve the concatameric intermediates developed during viral replication. The parvovirus B19 NS1 protein contains sequence domains highly similar to those previously implicated in the above-described functions of NS proteins from adeno-associated virus (AAV), minute virus of mice (MVM) and other non-human parvoviruses. Previous studies have shown that transient transfection of B19 NS1 into human liver carcinoma (HepG2) cells initiates the intrinsic apoptotic cascade, ultimately resulting in cell death. In an effort to elucidate the mechanism of mammalian cell demise in the presence of B19 NS1, we undertook a mutagenesis analysis of the protein's endonuclease domain. Our studies have shown that, unlike wild-type NS1, which induces an accumulation of DNA damage, S phase arrest and apoptosis in HepG2 cells, disruptions in the metal coordination motif of the B19 NS1 protein reduce its ability to induce DNA damage and to trigger S phase arrest and subsequent apoptosis. These studies support our hypothesis that, in the absence of replicating B19 genomes, NS1-induced host cell DNA damage is responsible for apoptotic cell death observed in parvoviral infection of non-permissive mammalian cells. PMID- 22211108 TI - The complete mitochondrial genome of the damsel bug Alloeorhynchus bakeri (Hemiptera: Nabidae). AB - The complete sequence of the mitochondrial DNA (mtDNA) of the damsel bug, Alloeorhynchus bakeri, has been completed and annotated in this study. It represents the first sequenced mitochondrial genome of heteropteran family Nabidae. The circular genome is 15, 851 bp in length with an A+T content of 73.5%, contains the typical 37 genes that are arranged in the same order as that of the putative ancestor of hexapods. Nucleotide composition and codon usage are similar to other known heteropteran mitochondrial genomes. All protein-coding genes (PCGs) use standard initiation codons (methionine and isoleucine), except COI, which started with TTG. Canonical TAA and TAG termination codons are found in eight protein-coding genes, the remaining five (COI, COII, COIII, ND5, ND1) have incomplete termination codons (T or TA). PCGs of two strands present opposite CG skew which is also reflected by the nucleotide composition and codon usage. All tRNAs have the typical clover-leaf structure, except the dihydrouridine (DHU) arm of tRNA(Ser (AGN))which forms a simple loop as known in many other metazoa. Secondary structure models of the ribosomal RNA genes of A. bakeri are presented, similar to those proposed for other insect orders. There are six domains and 45 helices and three domains and 27 helices in the secondary structures of rrnL and rrnS, respectively. The major non-coding region (also called control region) between the small ribosomal subunit and the tRNA(Ile )gene includes two special regions. The first region includes four 133 bp tandem repeat units plus a partial copy of the repeat (28 bp of the beginning), and the second region at the end of control region contains 4 potential stem-loop structures. Finally, PCGs sequences were used to perform a phylogenetic study. Both maximum likelihood and Bayesian inference analyses highly support Nabidae as the sister group to Anthocoridae and Miridae. PMID- 22211109 TI - Identification of ghrelin receptor blocker, D-[Lys3] GHRP-6 as a CXCR4 receptor antagonist. AB - [D-Lys3]-Growth Hormone Releasing Peptide-6 (DLS) is widely utilized in vivo and in vitro as a selective ghrelin receptor (GHS-R) antagonist. Unexpectedly, we identified that DLS also has the ability to block CXCL12 binding and activity through CXCR4 on T cells and peripheral blood mononuclear cells (PBMCs). Moreover, as CXCR4 has been shown to act as a major co-receptor for HIV-1 entry into CD4 positive host cells, we have also found that DLS partially blocks CXCR4 mediated HIV-1 entry and propagation in activated human PBMCs. These data demonstrate that DLS is not the specific and selective antagonist as thought for GHS-R1a and appears to have additional effects on the CXCR4 chemokine receptor. Our findings also suggest that structural analogues that mimic DLS binding properties may also have properties of blocking HIV infectivity, CXCR4 dependent cancer cell migration and attenuating chemokine-mediated immune cell trafficking in inflammatory disorders. PMID- 22211110 TI - Immune-related microRNAs are abundant in breast milk exosomes. AB - Breast milk is a complex liquid rich in immunological components that affect the development of the infant's immune system. Exosomes are membranous vesicles of endocytic origin that are found in various body fluids and that can mediate intercellular communication. MicroRNAs (miRNAs), a well-defined group of non coding small RNAs, are packaged inside exosomes in human breast milk. Here, we identified 602 unique miRNAs originating from 452 miRNA precursors (pre-miRNAs) in human breast milk exosomes using deep sequencing technology. We found that, out of 87 well-characterized immune-related pre-miRNAs, 59 (67.82%) are presented and enriched in breast milk exosomes (P < 10(-16), chi(2) test). In addition, compared with exogenous synthetic miRNAs, these endogenous immune-related miRNAs are more resistant to relatively harsh conditions. It is, therefore, tempting to speculate that these exosomal miRNAs are transferred from the mother's milk to the infant via the digestive tract, and that they play a critical role in the development of the infant immune system. PMID- 22211112 TI - Altered antioxidant status and increased lipid per-oxidation in seminal plasma of tunisian infertile men. AB - Human seminal plasma is a natural reservoir of antioxidants that protect spermatozoa from oxidative damages. There is evidence in literature supports the fact that impairments in seminal antioxidant and lipid per-oxidation status play important roles in the physiopathology of male infertility. Our present study forms the first one which was carried out in Tunisia. We evaluated the antioxidant status in the seminal plasma of 120 infertile men programmed to In Vitro Fertilization (IVF) for the first tentative. Patients were characterized by an idiopathic infertility. They were divided into three groups: normozoospermics who were considered as controls (n=40), asthenozoospermics (Astheno; n=45) and oligoasthenoteratozoospermics (OAT; n=35). Seminal activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX) and the levels of glutathione (GSH), zinc (Zn) and malondialdehyde (MDA) were measured. With the significant increase of the seminal activities of SOD and GPX in normozoospermics group, there were positive correlations observed between this enzymes and sperm quality. Also, significant elevated rates of seminal zinc and GSH were observed in control group, but there was contradictory associations reflecting the effects of these antioxidants on semen parameters. However, we noted significant increase of MDA levels in groups with abnormal seminogram. We showed negative associations between this per-oxidative marker and sperm parameters. These results obviously suggested that impairment on seminal antioxidants is an important risk factor for low sperm quality associated to idiopathic infertility and as a result can lead to poor IVF outcome. PMID- 22211114 TI - The olfactory co-receptor Orco from the migratory locust (Locusta migratoria) and the desert locust (Schistocerca gregaria): identification and expression pattern. AB - In locusts, olfaction plays a crucial role for initiating and controlling behaviours, including food seeking and aggregation with conspecifics, which underlie the agricultural pest capacity of the animals. In this context, the molecular basis of olfaction in these insects is of particular interest. Here, we have identified genes of two orthopteran species, Locusta migratoria and Schistocera gregaria, which encode the olfactory receptor co-receptor (Orco). It was found that the sequences of LmigOrco and SgreOrco share a high degree of identity to each other and also to Orco proteins from different insect orders. The Orco-expressing cells in the antenna of S. gregaria and L. migratoria were visualized by in situ hybridization. Orco expression could be assigned to clusters of cells in sensilla basiconica and few cells in sensilla trichodea, most likely representing olfactory sensory neurons. No Orco-positive cells were detected in sensilla coeloconica and sensilla chaetica. Orco expression was found already in all nymphal stages and was verified in some other tissues which are equipped with chemosensory hairs (mouthparts, tarsi, wings). Together, the results support the notion for a decisive role of Orco in locust olfaction. PMID- 22211113 TI - Matrine inhibits pacing induced atrial fibrillation by modulating I(KM3) and I(Ca L). AB - AIM: To elucidate the protective effects of Matrine on atrial fibrillation (AF) induced by electric pacing in mice and underlying molecular and ion channel mechanisms. METHODS: AF was introduced by electric pacing in mice and the incidence and duration of AF were evaluated. Functional expression of M(3) receptor (M(3)-R) and Cav1.2 were explored by western and Real-time PCR, action potential (AP) and the density of (I(KM3)) L-type calcium channel (I(Ca-L)) were both recorded using whole-cell patch in isolated atrial cardiomyocytes. RESULTS: In control group, incidence and duration of AF induced by electric pacing were 50 +/- 17% and 3.68 +/- 1.84 s, respectively; after application of carbachol 50 ug/kg both incidence and duration of AF were significantly increased to 86 +/- 24% and 65.2 +/- 29.0 s. Compared with control group, pretreatment of Matrine for 15 days significantly reduced AF incidence and duration in dose-dependent manner. Atrial membrane-protein expression of M(3)-R was decreased and membrane Cav1.2 expression was up-regulated. In single Matrine-treated atrial cardiomyocyte the density of I(KM3) was significantly decreased by 39% as well compared with control group, P < 0.05, whereas, I(Ca-L) density of atrium was increased by 40%. CONCLUSION: These data demonstrated at the first time that the anti-AF effects of Matrine may due, at least in part, to down-regulation of I(KM3) density and M(3) R expression and up-regulation of I(Ca-L )density and alpha1C/Cav1.2 expression. PMID- 22211115 TI - The murine caecal microRNA signature depends on the presence of the endogenous microbiota. AB - The intestinal messenger RNA expression signature is affected by the presence and composition of the endogenous microbiota, with effects on host physiology. The intestine is also characterized by a distinctive micronome. However, it is not known if microbes also impact intestinal gene expression epigenetically. We investigated if the murine caecal microRNA expression signature depends on the presence of the microbiota, and the potential implications of this interaction on intestinal barrier function. Three hundred and thirty four microRNAs were detectable in the caecum of germ-free and conventional male mice and 16 were differentially expressed, with samples from the two groups clustering separately based on their expression patterns. Through a combination of computational and gene expression analyses, including the use of our curated list of 527 genes involved in intestinal barrier regulation, 2,755 putative targets of modulated microRNAs were identified, including 34 intestinal barrier-related genes encoding for junctional and mucus layer proteins and involved in immune regulation. This study shows that the endogenous microbiota influences the caecal microRNA expression signature, suggesting that microRNA modulation is another mechanism through which commensal bacteria impact the regulation of the barrier function and intestinal homeostasis. Through microRNAs, the gut microbiota may impinge a much larger number of genes than expected, particularly in diseases where its composition is altered. In this perspective, abnormally expressed microRNAs could be considered as novel therapeutic targets. PMID- 22211117 TI - Mental Health Stigma: Society, Individuals, and the Profession. AB - Mental health stigma operates in society, is internalized by individuals, and is attributed by health professionals. This ethics-laden issue acts as a barrier to individuals who may seek or engage in treatment services. The dimensions, theory, and epistemology of mental health stigma have several implications for the social work profession. PMID- 22211116 TI - The adhesion modulating properties of tenascin-W. AB - Tenascins are extracellular matrix glycoproteins associated with cell motility, proliferation and differentiation. Tenascin-C inhibits cell spreading by binding to fibronectin; tenascin-R and tenascin-X also have anti-adhesive properties in vitro. Here we have studied the adhesion modulating properties of the most recently characterized tenascin, tenascin-W. C2C12 cells, a murine myoblast cell line, will form broad lamellipodia with stress fibers and focal adhesion complexes after culture on fibronectin. In contrast, C2C12 cells cultured on tenascin-W fail to spread and form stress fibers or focal adhesion complexes, and instead acquire a multipolar shape with short, actin-tipped pseudopodia. The same stellate morphology is observed when C2C12 cells are cultured on a mixture of fibronectin and tenascin-W, or on fibronectin in the presence of soluble tenascin W. Tenascin-W combined with fibronectin also inhibits the spreading of mouse embryo fibroblasts when compared with cells cultured on fibronectin alone. The similarity between the adhesion modulating effects of tenascin-W and tenascin-C in vitro led us to study the possibility of tenascin-W compensating for tenascin C in tenascin-C knockout mice, especially during epidermal wound healing. Dermal fibroblasts harvested from a tenascin-C knockout mouse express tenascin-W, but dermal fibroblasts taken from a wild type mouse do not. However, there is no upregulation of tenascin-W in the dermis of tenascin-C knockout mice, or in the granulation tissue of skin wounds in tenascin-C knockout animals. Similarly, tenascin-X is not upregulated in early wound granulation tissue in the tenascin-C knockout mice. Thus, tenascin-W is able to inhibit cell spreading in vitro and it is upregulated in dermal fibroblasts taken from the tenascin-C knockout mouse, but neither it nor tenascin-X are likely to compensate for missing tenascin-C during wound healing. PMID- 22211118 TI - State of oncology practice. PMID- 22211119 TI - Results of the ASCO Study of Collaborative Practice Arrangements. AB - PURPOSE: ASCO projects a shortfall of oncologists in the next decade. The study was designed to address the workforce shortage by exploring collaborative oncology practice models that include nonphysician practitioners (NPPs). METHODS: ASCO contracted with Oncology Metrics, a division of Altos Solutions, to conduct a national survey of NPP integration and identify collaborative practice models and services provided by NPPs, as the first phase of the ASCO Study of Collaborative Practice Arrangements. Results of the national survey were used to identify practices for the next phase, in which selected practices participated in a more detailed data survey and satisfaction surveys. Focus groups or interviews were conducted with NPPs to collect additional subjective information to inform the project. RESULTS: The incident-to practice model was the predominant model. Satisfaction was universally high for patients and generally high for physicians and NPPs. In virtually all cases (98%), patients recognized they were seeing an NPP rather than a physician. Practices in which the NPP worked with all practice physicians showed significantly higher productivity than those practices in which the NPP worked exclusively with a specific physician or group of physicians. CONCLUSION: The use of NPPs in oncology practices increases productivity for the practice and provides high physician and NPP satisfaction. Patients were aware when care was provided by an NPP and were very satisfied with all aspects of the collaborative care that they received. The integration of nonphysician practitioners into oncology practice offers a reliable means to address increased demand for oncology services without adding physicians. PMID- 22211120 TI - Commentary: Physician Assistant Perspective on the Results of the ASCO Study of Collaborative Practice Arrangements. PMID- 22211121 TI - Commentary: new findings substantiate the successful use of nurse practitioners and physician assistants in collaborative practice models. PMID- 22211122 TI - Oncology Practice Trends From the National Practice Benchmark, 2005 through 2010. AB - Oncology Metrics, a division of Altos Solutions, has been conducting organized surveys of practicing oncologists since 2005. In this article, we present data that represent trends in community oncology practice over a 6-year period, 2005 to 2010, and make projections on the basis of these data. Over the next 3 years, operating margins will continue to decrease, gains in business and clinical operating efficiencies will slow, and labor costs will rise. The cost of drugs provided to patients is also increasing while the amount above cost that is being reimbursed continues a slow decline. The gap between practice costs and practice revenue will continue to narrow, and as this occurs, community oncology practices will find it difficult to maintain their current business models. PMID- 22211123 TI - Commentary: six years of trends in oncology practice data. PMID- 22211124 TI - Commentary: can you replace something with nothing? PMID- 22211125 TI - Economic assessment of the association of northern california oncologists member practices. AB - In late 2009 and early 2010, the Association of Northern California Oncologists conducted an economic assessment on a volunteer sample (n = 14) of northern California state oncology society member practices to measure key economic factors, diagnose economic viability, and prescribe changes to practice management to enhance practice economic viability. Recommendations for individual member practices as well as for the state oncology society were made as a result of the findings of this study. Results from follow-up interviews conducted with study practices approximately 1 year after the original assessments reveal that most recommendations were implemented and seem to have generally strengthened the economic performance of the practices. PMID- 22211126 TI - Benchmarks for value in cancer care: an analysis of a large commercial population. AB - PURPOSE: Cancer costs are increasing at an unprecedented rate. Key cost drivers include chemotherapy, hospital admissions/emergency room visits, and aggressive end-of-life care. We sought to evaluate these costs in a commercial payer population in collaboration with consultants from Milliman. PATIENTS AND METHODS: We used a retrospective analysis of Medstat 2007 to evaluate chemotherapy costs and use. Included patients had a cancer diagnosis; received chemotherapy during the evaluation period; had at least 1 day of coverage between January 1 and December 31, 2007 (medical and prescription coverage); was younger than age 70, and had active employment or was the spouse of an active employee. Costs are allowed amounts and are trended until 2009. Admission rates and emergency room visits are reported. Hospice use and chemotherapy during the last 14 and 30 days of life were also evaluated. RESULTS: In this commercial population of 14 million patients, 0.68% had claims for a cancer diagnosis; approximately 22% of those received chemotherapy during the study time period. Patients with cancer receiving chemotherapy averaged $111,000 per year in total medical and pharmacy costs. The average hospitalization rate for any reason was 1 admission/yr. Approximately 40% (or 0.4 admits/year) were identified as being chemotherapy related. Of the 3.5% of patients who died in the hospital, 51% received chemotherapy within 30 days of death. CONCLUSION: Understanding the costs of cancer care offers opportunities to formulate a strategic plan to control cancer costs and maintain quality care. Comprehensive cancer solutions to address the full spectrum of care will facilitate improved quality and patient outcomes. PMID- 22211127 TI - Medicare reimbursement changes and the practice of oncology: understanding of the past is a key to the future. AB - Previous Medicare payment changes have led to changes in the way oncology practices are structured. Understanding the complexities of oncology care is thus key for the success of newer reimbursement methods. PMID- 22211128 TI - Role of axillary staging in women diagnosed with ductal carcinoma in situ with microinvasion. AB - BACKGROUND: Axillary staging via sentinel node biopsy (SLNB) in patients with ductal carcinoma in situ with microinvasion (DCISM) is routinely performed but remains controversial with regard to the risk-benefit ratio. METHODS: Retrospective single-institution review of patients with diagnosis of DCISM (invasive tumor <= 0.1 cm). Age, clinicopathologic data, and follow-up were recorded. RESULTS: Of 90 patients, 33% were diagnosed by core needle biopsy (CNB), 37% by excisional biopsy, and 29% were upstaged from DCIS on CNB to DCISM at final operation. Three (10%) of 30 patients with DCISM on CNB were upstaged to invasive cancer on final pathology. Median age at diagnosis was 58.9 years (range: 30-89). Lumpectomy was performed in 45% of patients and mastectomy in 55%. Mean number of sentinel nodes was 2.59 (SE 0.17). Six (6.9%) of 87 patients with DCISM as final diagnosis had a positive SLNB (four lumpectomies, two mastectomies). There was no correlation with any clinicopathologic features, including palpable DCIS, DCIS grade/necrosis, or age at diagnosis. All six SLNB positive patients had a complete axillary dissection; two had additional disease. Median follow-up time was 74.2 months (range: 2-169). In-breast recurrence was seen in three patients (5%), regardless of SLN status, DCIS grade, or necrosis. Two patients developed distant metastasis. Overall survival was 94.19% at 5 years for DCISM and 100% for DCISM with nodal disease. CONCLUSION: DCISM comprises 0.6% of breast cancer diagnoses at our institution. There is a low likelihood of nodal spread; however, a lack of identifiable clinicopathologic features associated with a positive SLNB limits selective SLNB use. PMID- 22211129 TI - Do survivorship care plans make a difference? A primary care provider perspective. AB - INTRODUCTION: The growing numbers of cancer survivors will challenge the ability of oncologists to provide ongoing surveillance care. Tools such as survivorship care plans (SCPs) are needed to effectively care for these patients. The UCLA LIVESTRONG Survivorship Center of Excellence has been providing SCPs to cancer survivors and their providers since 2006. We sought to examine views on the value and impact of SCPs from a primary care provider (PCP) perspective. METHODS: As part of a quality improvement project, we invited 32 PCPs who had received at least one SCP to participate in a semistructured interview focused on (1) the perceived value of SCPs for patient management and (2) PCP attitudes toward follow-up care for cancer survivors. Interviews were tape-recorded, transcribed, and analyzed. RESULTS: Fifteen PCPs participated in the interviews and had received a total of 30 SCPs. Ten of them indicated reading the SCPs before being contacted for the interview. All 10 PCPs indicated that the SCP provided additional information about the patient's cancer history and/or recommendations for follow-up care, and eight reported a resulting change in patient care. PCPs identified useful elements of the SCP that assisted them with patient care, and they valued the comprehensive format of the SCP. PCPs indicated that after reading the SCPs they felt more confident and better prepared to care for the cancer survivor. CONCLUSION: SCPs were highly valued by these PCPs, increasing their knowledge about survivors' cancer history and recommended surveillance care and influencing patient care. PMID- 22211130 TI - Patient-oriented cancer information on the internet: a comparison of wikipedia and a professionally maintained database. AB - PURPOSE: A wiki is a collaborative Web site, such as Wikipedia, that can be freely edited. Because of a wiki's lack of formal editorial control, we hypothesized that the content would be less complete and accurate than that of a professional peer-reviewed Web site. In this study, the coverage, accuracy, and readability of cancer information on Wikipedia were compared with those of the patient-orientated National Cancer Institute's Physician Data Query (PDQ) comprehensive cancer database. METHODS: For each of 10 cancer types, medically trained personnel scored PDQ and Wikipedia articles for accuracy and presentation of controversies by using an appraisal form. Reliability was assessed by using interobserver variability and test-retest reproducibility. Readability was calculated from word and sentence length. RESULTS: Evaluators were able to rapidly assess articles (18 minutes/article), with a test-retest reliability of 0.71 and interobserver variability of 0.53. For both Web sites, inaccuracies were rare, less than 2% of information examined. PDQ was significantly more readable than Wikipedia: Flesch-Kincaid grade level 9.6 versus 14.1. There was no difference in depth of coverage between PDQ and Wikipedia (29.9, 34.2, respectively; maximum possible score 72). Controversial aspects of cancer care were relatively poorly discussed in both resources (2.9 and 6.1 for PDQ and Wikipedia, respectively, NS; maximum possible score 18). A planned subanalysis comparing common and uncommon cancers demonstrated no difference. CONCLUSION: Although the wiki resource had similar accuracy and depth as the professionally edited database, it was significantly less readable. Further research is required to assess how this influences patients' understanding and retention. PMID- 22211131 TI - Need for global partnership in cancer care: perceptions of cancer care researchers attending the 2010 australia and Asia pacific clinical oncology research development workshop. AB - PURPOSE: To understand the diversity of issues and the breadth of growing clinical care, professional education, and clinical research needs of developing countries, not typically represented in Western or European surveys of cancer care and research. METHODS: A cross-sectional survey was conducted of the attendees at the 2010 Australia and Asia Pacific Clinical Oncology Research Development workshop (Queensland, Australia) about the most important health care questions facing the participant's home countries, especially concerning cancer. RESULTS: Early-career oncologists and advanced oncology trainees from a region of the world containing significant low- and middle-income countries reported that cancer is an emerging health priority as a result of aging of the population, the impact of diet and lifestyle, and environmental pollution. There was concern about the capacity of health care workers and treatment facilities to provide cancer care and access to the latest cancer therapies and technologies. Although improving health care delivery was seen as a critical local agenda priority, focusing on improved cancer research activities in this select population was seen as the best way that others outside the country could improve outcomes for all. CONCLUSIONS: The burden of cancer will increase dramatically over the next 20 years, particularly in countries with developing and middle-income economies. Cancer research globally faces significant barriers, many of which are magnified in the developing country setting. Overcoming these barriers will require partnerships sensitive and responsive to both local and global needs. PMID- 22211132 TI - Assessment of perceived cost to the patient and other barriers to clinical trial participation. AB - PURPOSE: Less than 5% of patients with cancer participate in trials. Few studies have specifically addressed the role of cost to the patient as an influence on trial participation. Our main purpose was to determine the importance of added cost as a barrier to clinical trial participation in the community setting. Our secondary goal was to determine the most prevalent barriers to trial participation for patients. PATIENTS AND METHODS: Four community practices in New England issued surveys to consecutive cohorts of patients with cancer. Patients were assessed for eligibility for clinical trials at their practice site. Trial eligible patients who declined participation were asked to select reasons that contributed to their decision. RESULTS: Surveys were issued to 1,755 patients. Seventy-one percent of all trial-eligible patients returned surveys. Forty-four percent of nonparticipating trial-eligible patients did not recall hearing about clinical trials from their provider. The most common reasons cited by trial eligible patients for declining trial participation were fear of adverse effects (50%) and discomfort with random assignment (44%). Twenty-eight percent cited concerns about added cost, and 12% noted cost as the most important factor in their decision. CONCLUSION: Concerns about adverse effects and random assignment were the most common reasons cited by patients declining trial participation in four community oncology practices in New England. Cost considerations were important for a significant proportion of these patients. Many patients eligible for trial participation were not informed by their provider about the availability of research trials. PMID- 22211133 TI - Donating tissue for research: patient and provider perspectives. AB - This article illustrates common patient and provider concerns about donating tissue for the purpose of research, discusses best practices, and provides answers to common patient questions. PMID- 22211134 TI - Peek before you treat? Is it a fantasy or reality? AB - Empirical approaches brought about use of the once-promising CSRA. However, oncologists now know that most cancers are highly complex, and that even the same tumor type can harbor differing genetic abnormalities. PMID- 22211135 TI - Potential of the patient protection and affordable care act to reduce cancer care disparities. AB - Although the Patient Protection and Affordable Care act provides some means to reduce disparities in cancer care, it may also have unintended consequences. Oncologists must go beyond its provisions to ensure quality care for all patients. PMID- 22211136 TI - Medicine as it should be: a cultural shift. AB - Increased use of clinical practice guidelines, evidence-based medicine, and electronic health records can help oncologists meet the challenges of workforce shortages, rising costs, and an aging population, creating a culture of care that benefits payers, providers, and patients. PMID- 22211137 TI - Exploring kinase inhibitors as therapies for human arenavirus infections. AB - Arenaviruses are rodent-borne RNA viruses, and some have the capacity to cause hemorrhagic fever and death in infected individuals and thus have been identified as a potential bioterrorism threat. Ribavirin and supportive care are currently the approved therapeutic options for individuals suffering from arenavirus induced hemorrhagic fever. However, new research has suggested that immune plasma treatment or kinase inhibitors may provide a therapeutic option for treating arenavirus infections in humans. This article puts forth a perspective as to the potential use of kinase inhibitors as an antiviral therapeutic for arenavirus infections. PMID- 22211138 TI - Depression in patients with rheumatoid arthritis: description, causes and mechanisms. AB - Two sets of contributory factors to depression among patients with rheumatoid arthritis (RA) are generally examined - the social context of the individual and the biologic disease state of that person's RA. This article will review the evidence for both. RA affects patients both physically and psychologically. Comorbid depression is common with RA and leads to worse health outcomes. Low socioeconomic status, gender, age, race/ethnicity, functional limitation, pain and poor clinical status have all been linked to depression among persons with RA. Systemic inflammation may also be associated with, cause, or contribute to depression in RA. Understanding the socioeconomic factors, individual patient characteristics and biologic causes of depression in RA can lead to a more comprehensive paradigm for targeting interventions to eliminate depression in RA. PMID- 22211139 TI - Preoperative thyroid ultrasound is indicated in patients undergoing parathyroidectomy for primary hyperparathyroidism. AB - BACKGROUND: Primary hyperaparathyroidism (pHPT) is often accompanied by underlying thyroid pathology that can confound preoperative parathyroid localization studies and complicate intra-operative decision making. The aim of this study was to examine the utility of preoperative thyroid ultrasonography (US) in patients prior to undergoing parathyroidectomy for pHPT. METHODS: An Institutional Review Board approved prospective study was undertaken from January 2005 through July 2008. All patients with pHPT meeting inclusion criteria (n=94) underwent preoperative thyroid ultrasound in addition to standard (99m)Tc sestamibi scintigraphy for parathyroid localization. Demographics, operative management and final pathology were examined in all cases. RESULTS: Fifty-four of the 94 patients (57%) were noted to have a thyroid nodule on preoperative US, of which 30 (56%) underwent further examination with fine needle aspiration biopsy. Alteration of the operative plan attributable to underlying thyroid pathology occurred in 16 patients (17%), with patients undergoing either total thyroidectomy (n=9) or thyroid lobectomy (n=7). Thyroid cancer was noted in 33% of patients undergoing thyroid resection, and 6% of all patients with HPT. CONCLUSIONS: The routine utilization of preoperative thyroid ultrasound in patients prior to undergoing parathyroid surgery for pHPT is indicated. The added information from this non-invasive modality facilitates timely management of co incidental, and sometimes malignant, thyroid pathology. PMID- 22211140 TI - Progression-free Survival Decreases with Each Subsequent Therapy in Patients Presenting for Phase I Clinical Trials. AB - BACKGROUND: There is often a finite progression-free interval of time between one systemic therapy and the next when treating patients with advanced cancer. While it appears that progression-free survival (PFS) between systemic therapies tends to get shorter for a number of factors, there has not been a formal evaluation of diverse tumor types in an advanced cancer population treated with commercially available systemic therapies. METHODS: In an attempt to clarify the relationship between PFS between subsequent systemic therapies, we analyzed the records of 165 advanced cancer patients coming to our clinic for consideration for participation in six different phase I clinical trials requiring detailed and extensive past medical treatment history documentation. RESULTS: There were 77 men and 65 women meeting inclusion criteria with a median age at diagnosis of 55.3 years (range 9.4-81.6). The most common cancer types were colorectal (13.9%), other gastrointestinal (11.8%), prostate (11.8%). A median of 3 (range 1-11) systemic therapies were received prior to phase I evaluation. There was a significant decrease in PFS in systemic therapy for advanced disease from treatment 1 to treatment 2 to treatment 3 (p = 0.002), as well as, from treatment 1 through treatment 5 (p < 0.001). CONCLUSIONS: In an advanced cancer population of diverse tumor types, we observe a statistically significant decrease in PFS with each successive standard therapy. Identification of new therapies that reverse this trend of decreasing PFS may lead to improved clinical outcomes. PMID- 22211141 TI - Endometrioid adenocarcinoma with high-grade transformation with serous and choriocarcinomatous differentiation - a case report. AB - A choriocarcinoma component with a malignant tumor is relatively rare. We present a case of an 85-year-old woman with mixed carcinoma, which was endometrioid adenocarcinoma with squamous differentiation, choriocarcinoma and a disseminated peritoneal nodule, which was papillary serous adenocarcinoma. The patient received surgery and conservative treatment. Twenty weeks after surgery, a recurring tumor appeared at the Douglas pouch. Histology showed that the recurring tumor was poorly differentiated carcinoma that was very different from the primary tumor. This case represents an unusual uterine corpus cancer with high-grade transformation with serous and choriocarcinomatous differentiation. This case also demonstrates the capacity of tumor cells to differentiate into divergent elements. PMID- 22211142 TI - Promising Candidate Urinary MicroRNA Biomarkers for the Early Detection of Hepatocellular Carcinoma among High-Risk Hepatitis C Virus Egyptian Patients. AB - MicroRNAs (miRNA) are small endogenously expressed non-coding RNAs that negatively regulate expression of protein-coding genes at the translational level. Accumulating evidence, such as aberrant expression of miRNAs, suggests that they play a role in the development of cancer. They have been identified in various tumor types, demonstrating that different sets of miRNAs are usually deregulated in different cancers. To identify the miRNA signatures specific for Hepatitis C virus (HCV)-associated Hepatocellular carcinoma (HCC), miRNA expression profiling of 32 HCC post-HCV infected, 74 HCV-positive and 12 control individuals was carried out using whole genome expression profiling. Differential expression of two individual miRNAs between control and high risk HCV patients was detected and found to possibly target genes related to HCC development and progression. The sensitivity and specificity of miR-618 for detecting HCC among HCV-positive individuals was found to be 64% and 68%, respectively. Whereas, the sensitivity and specificity of miR-650 were 72% and 58%, respectively. Additionally, the sensitivity and specificity for miR-618/650 in tandem were 58% and 75%, respectively. These predictive values are greatly improved compared to the traditional alpha-feto protein (AFP) level-based detection method. The proposed HCC miRNA signatures may therefore be of great value for the early diagnosis of HCC, before the onset of disease in HCV-positive patients. The significance of this approach is amplified by the use of urine as a sample source as it offers a non-invasive approach for developing screening methods that can reduce mortality rates. PMID- 22211143 TI - Trackable and Targeted Phage as Positron Emission Tomography (PET) Agent for Cancer Imaging. AB - The recent advancement of nanotechnology has provided unprecedented opportunities for the development of nanoparticle enabled technologies for detecting and treating cancer. Here, we reported the construction of a PET trackable organic nanoplatform based on phage particle for targeted tumor imaging. METHOD: The integrin alpha(v)beta(3) targeted phage nanoparticle was constructed by expressing RGD peptides on its surface. The target binding affinity of this engineered phage particle was evaluated in vitro. A bifunctional chelator (BFC) 1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid (DOTA) or 4-((8-amino 3,6,10,13,16,19-hexaazabicyclo [6.6.6] icosane-1-ylamino) methyl) benzoic acid (AmBaSar) was then conjugated to the phage surface for (64)Cu(2+) chelation. After (64)Cu radiolabeling, microPET imaging was performed in U87MG tumor model and the receptor specificity was confirmed by blocking experiments. RESULTS: The phage-RGD demonstrated target specificity based on ELISA experiment. According to the TEM images, the morphology of the phage was unchanged after the modification with BFCs. The labeling yield was 25 +/- 4% for (64)Cu-DOTA-phage-RGD and 46 +/- 5% for (64)Cu-AmBaSar-phage-RGD, respectively. At 1 h time point, (64)Cu-DOTA phage-RGD and (64)Cu-AmBaSar-phage-RGD have comparable tumor uptake (~ 8%ID/g). However, (64)Cu-AmBaSar-phage-RGD showed significantly higher tumor uptake (13.2 +/- 1.5 %ID/g, P<0.05) at late time points compared with (64)Cu-DOTA-phage-RGD (10 +/- 1.2 %ID/g). (64)Cu-AmBaSar-phage-RGD also demonstrated significantly lower liver uptake, which could be attributed to the stability difference between these chelators. There is no significant difference between two tracers regarding the uptake in kidney and muscle at all time points tested. In order to confirm the receptor specificity, blocking experiment was performed. In the RGD blocking experiment, the cold RGD peptide was injected 2 min before the administration of (64)Cu-AmBaSar-phage-RGD. Tumor uptake was partially blocked at 1 h time point. Phage-RGD particle was also used as the competitive ligand. In this case, the tumor uptake was significantly reduced and the value was kept at low level consistently. CONCLUSION: In this report, we constructed a PET trackable nanoplatform based on phage particle and demonstrated the imaging capability of these targeted agents. We also demonstrated that the choice of chelator could have significant impact on imaging results of nano-agents. The method established in this research may be applicable to other receptor/ligand systems for theranostic agent construction, which could have an immediate and profound impact on the field of imaging/therapy and lay the foundation for the construction of next generation cancer specific theranostic agents. PMID- 22211144 TI - Theranostic cRGD-BioShuttle Constructs Containing Temozolomide- and Cy7 For NIR Imaging and Therapy. AB - Innovative and personalized therapeutic approaches result from the identification and control of individual aberrantly expressed genes at the transcriptional and post-transcriptional level. Therefore, it is of high interest to establish diagnostic, therapeutic and theranostic strategies at these levels. In the present study, we used the Diels-Alder Reaction with inverse electron demand (DAR(inv)) click chemistry to prepare a series of cyclic RGD-BioShuttle constructs. These constructs carry the near-infrared (NIR) imaging agent Cy7 and the chemotherapeutic agent temozolomide (TMZ). We evaluated their uptake by and their efficacy against integrin alpha(v)beta(3)-expressing MCF7 human breast carcinoma cells. In addition, using a mouse phantom, we analyzed the suitability of this targeted theranostic agent for NIR optical imaging. We observed that the cyclic RGD-based carriers containing TMZ and/or Cy7 were effectively taken up by alpha(v)beta(3)-expressing cells, that they were more effective than free TMZ in inducing cell death, and that they could be quantitatively visualized using NIR fluorescence imaging. Therefore, these targeted theranostic agents are considered to be highly suitable systems for improving disease diagnosis and therapy. PMID- 22211145 TI - Lasting controversy on ranibizumab and bevacizumab. AB - Vascular endothelial growth factor (VEGF), an important angiogenic factor that is able to stimulate the proliferation and migration of endothelial cells, is the best-studied hallmark of angiogenesis. Neovascularization is a major cause of age related macular degeneration (AMD) which is a leading cause of blindness in the elderly population. Specific molecular inhibitors of VEGF have been proved to be useful in the treatment of AMD. Ranibizumab and Bevacizumab are structurally similar to anti-VEGF drugs in the treatment of AMD. Many studies have indicated that Ranibizumab and Bevacizumab are of roughly equal short-term efficacy and safety, Bevacizumab is an attractive alternative to Ranibizumab due to its lower cost. However, only Ranibizumab has received Food and Drug Administration (FDA) approval for the treatment of macular degeneration. More multicenter clinical trials are required to compare the relative efficacy and safety of these two drugs and some progress has been achieved. This review discusses the clinical effectiveness, safety, cost and other practical implications of Ranibizumab and Bevacizumab. PMID- 22211146 TI - PET Imaging of Integrin Positive Tumors Using F Labeled Knottin Peptides. AB - PURPOSE: Cystine knot (knottin) peptides, engineered to bind with high affinity to integrin receptors, have shown promise as molecular imaging agents in living subjects. The aim of the current study was to evaluate tumor uptake and in vivo biodistribution of (18)F-labeled knottins in a U87MG glioblastoma model. PROCEDURES: Engineered knottin mutants 2.5D and 2.5F were synthesized using solid phase peptide synthesis and were folded in vitro, followed by radiolabeling with 4-nitrophenyl 2-(18)F-fluoropropionate ((18)F-NFP). The resulting probes, (18)F FP-2.5D and (18)F-FP-2.5F, were evaluated in nude mice bearing U87MG tumor xenografts using microPET and biodistribution studies. RESULTS: MicroPET imaging studies with (18)F-FP-2.5D and (18)F-FP-2.5F demonstrated high tumor uptake in U87MG xenograft mouse models. The probes exhibited rapid clearance from the blood and kidneys, thus leading to excellent tumor-to-normal tissue contrast. Specificity studies confirmed that (18)F-FP-2.5D and (18)F-FP-2.5F had reduced tumor uptake when co-injected with a large excess of the peptidomimetic c(RGDyK) as a blocking agent. CONCLUSIONS: (18)F-FP-2.5D and (18)F-FP-2.5F showed reduced gallbladder uptake compared with previously published (18)F-FB-2.5D. (18)F-FP 2.5D and (18)F-FP-2.5F enabled integrin-specific PET imaging of U87MG tumors with good imaging contrasts. (18)F-FP-2.5D demonstrated more desirable pharmacokinetics compared to (18)F-FP-2.5F, and thus has greater potential for clinical translation. PMID- 22211147 TI - Bronchiectasis--diagnosis and treatment. AB - BACKGROUND: Radiologically evident bronchiectasis is seen in 30% to 50% of patients with advanced chronic obstructive pulmonary disease (COPD). As COPD is now becoming more common around the world, bronchiectasis is as well. METHODS: We review pertinent articles published before May 2011 that were retrieved by a selective PubMed search. RESULTS: The principles of treatment of bronchiectasis in patients who do not have cystic fibrosis ("non-CF bronchiectasis") are derived from the treatment of other diseases: secretolytic and anti-infectious treatment are given as in cystic fibrosis, while anti-obstructive treatment is given as in COPD. The few randomized trials of treatment for non-CF bronchiectasis that have been completed to date do not permit the formulation of any evidence-based recommendations. Many potential treatments are now under evaluation. Hypertonic saline is often used because of its demonstrated benefit in CF, even though no benefit has yet been shown for non-CF bronchiectasis. Phase II trials of inhaled mannitol have yielded promising results, leading to phase III trials that are now underway. There may be a future role for inhaled antibiotics, particularly in patients colonized with Gram-negative pathogens. Inhaled tobramycin and colistin are well established in clinical practice, though not approved for non-CF bronchiectasis; clinical trials of aztreonam, ciprofloxacin, and gentamicin are ongoing. Macrolides seem to bring an additional benefit, though the studies that documented this involved only small numbers of patients. Long-term treatment with inhaled antibiotics and/or macrolides is indicated only if a benefit is seen within three months of the start of treatment (less sputum, no exacerbations). CONCLUSION: A national registry of patients with bronchiectasis should be established to help us gain better knowledge of its prognostic factors and treatment options. PMID- 22211149 TI - Persistent hiccups (singultus) as the presenting symptom of medullary cavernoma. AB - BACKGROUND: Singultus (hiccup) is common, usually transient, and only rarely indicative of disease. If it persists, it can be highly bothersome, potentially interfering with sleep and leading to depression and physical exhaustion. It is presumed to be due to a disturbance in a reflex arc that includes the brainstem, the phrenic nerve, the vagus nerve, and the sympathetic chain. It can be induced by mechanical irritation (e.g., gastric distention), metabolic or toxic irritation (e.g., alcohol, cigarette smoke), infectious processes, emotional disturbances, and, rarely, neurological diseases. CASE DESCRIPTION: The patient presented with persistent singultus (by definition, singultus lasting more than 48 hours). Initial diagnostic tests failed to reveal the cause, and the hiccups failed to respond to medications and other attempted treatments. Finally, an imaging study revealed a medullary cavernoma. After neurosurgical resection of this lesion, the patient was asymptomatic and returned to work. CONCLUSION: This case shows that singultus, though it may seem trivial, deserves to be taken seriously, particularly when it persists and does not respond to medications. Its cause can be discovered in timely fashion by means of a thorough clinical history, physical examination, and ancillary testing. PMID- 22211148 TI - Percutaneous and surgical treatment of mitral valve regurgitation. AB - BACKGROUND: Mitral valve regurgitation is the second most common clinically relevant valvular heart disease in adults, with an incidence of about 2% to 3% per year. Surgical mitral valve repair is the treatment of choice. Recent years have seen major advances in minimally invasive mitral valve surgery. Several new catheter-based techniques are now being clinically evaluated, including percutaneous endovascular mitral valve repair with a mitral clip. METHOD: This review is based on a selective review of the literature and on the authors' clinical experience. RESULTS: Minimally invasive and reconstructive techniques for mitral valve surgery have come into more common use in recent years. In Germany, more than 50% of all mitral valve defects are now treated with a valve preserving repair procedure. At the same time, percutaneous techniques have been developed that enable reduction of mitral regurgitation in the cardiac catheterization laboratory, without surgery. The implantation of a mitral clip is the sole currently approved technique of this type. In a recently published, randomized comparative clinical trial (EVEREST II), it was found to be safer, but less effective, than surgery. CONCLUSION: Mitral valve surgery remains the treatment of choice for severe mitral regurgitation. For patients at high risk from surgery, and particularly those with severe heart failure, the implantation of a mitral clip is a safe and feasible treatment option. PMID- 22211150 TI - In Vitro and In Vivo Performance Evaluation of the Second Developmental Version of the PediaFlow Pediatric Ventricular Assist Device. AB - Ventricular assist devices (VADs) have significantly impacted the treatment of adult cardiac failure, but few options exist for pediatric patients. This has motivated our group to develop an implantable magnetically levitated rotodynamic VAD (PediaFlow(r)) for 3-20 kg patients. The second prototype design of the PediaFlow (PF2) is 56% smaller than earlier prototypes, and achieves 0.5-1.5 L/min blood flow rates. In vitro hemodynamic performance and hemolysis testing were performed with analog blood and whole ovine blood, respectively. In vivo evaluation was performed in an ovine model to evaluate hemocompatibility and end organ function. The in vitro normalized index of hemolysis was 0.05-0.14 g/L over the specified operating range. In vivo performance was satisfactory for two of the three implanted animals. A mechanical defect caused early termination at 17 days of the first in vivo study, but two subsequent implants proceeded without complication and electively terminated at 30 and 70 days. Serum chemistries and plasma free hemoglobin were within normal limits. Gross necropsy revealed small, subclinical infarctions in the kidneys of the 30 and 70 day animals (confirmed by histopathology). The results of these experiments, particularly the biocompatibility demonstrated in vivo encourage further development of a miniature magnetically levitated VAD for the pediatric population. Ongoing work including further reduction of size will lead to a design freeze in preparation for of clinical trials. PMID- 22211151 TI - Fascia Research from a Clinician/Scientist's Perspective. AB - The upcoming Third International Fascia Research Congress will have much exciting information for the clinician, as well as for the clinical and basic science researcher. This paper provides a perspective from a clinician/scientist, including the fascial network of body-wide connections between and within individual cells, and sharing of loads between muscle and fascia. Basic studies of fibroblast cell shape show the impact of manual therapy, acupuncture, and yoga like stretching at the cellular level. Advances in scientific equipment have made it possible to study a layer of hyaluronan fluid, which allows sliding between deep fascia and muscle. Collagen fibers within fascia affect both blood flow to muscles and lymphatic fluid flow. PMID- 22211152 TI - Is the Sun Setting on Lecture-based Education? AB - Lecture-based instructional models have been the mainstay of education for centuries. They excel primarily at delivering information from the one to the many. Educators refer to this model as "the sage on the stage". Clearly there are educators who relish this role and are strongly opposed to moving away from it. Yet, educational research and new innovative technologies are suggesting that lecture-based classes may no longer be the most effective teaching method for many situations, especially clinical practice. PMID- 22211153 TI - Vascular fasciatherapy danis bois method: a study on mechanism concerning the supporting point applied on arteries. AB - BACKGROUND: A first study on vascular fasciatherapy enabled us to observe the turning of a turbulent blood flow into a laminar one, and a questioning on the process involved in this transformation emerged. The first question was: What is the nature of artery from the point of view of fascia? And a second question was: Which is the link permitting the observed process working in our first study? So this time, we are investigating a specific aspect of the big question that polarizes the interest of many researchers: "What is fascia?" METHODS: Following Donald Ingber's statement, "It is necessary to understand how tissues and organs are structured across multiple size scales", our research methods have been established in order to collect information on what is artery and what is fascia. Concerning these two organs, we have questioned science across the scales of embryology, anatomy, histology and cytology. Beyond the knowledge on structure, the functional link between artery and fascia is the necessary complement of this study whose starting point is in fact a questioning on process. As an application of this study, vascular fasciatherapy Danis-Bois Method and mechanotransduction have been investigated in theoretical and in research aspects to improve the understanding of how they work. RESULTS: The embryological approach points out a common origin and a histofunctional community of connective tissue and artery. As organs, arteries are sheathed by the adventia-fascia, and are penetrated by connective tissue extensions in media and intima. Furthermore, the functional point of view of this study reports the knowledge on mechanotransduction involving artery, both from the connective side and from the luminal side. Functional anatomy, surgery, histology, and cytology integrating the theory of the extended cytoskeleton, underline continuity from the static and functional points of view, with tensegrity being the architectural principle linking molecules to the entire body. CONCLUSION: By answering these questions, we are attempting a better understanding of the mechanisms occurring in the progress of the arterial supporting point. One could presume that it relaxes adventitia and media, locally and all along the arterial network. Its action could also extend inward to the intima and on blood, as well as outwards to the neighboring connective tissue. By its local and remote action, it may be useful when diseases associate general perturbations and arterial disorders, like in high blood pressure or in aging. PMID- 22211154 TI - Changing the global health care landscape-proceedings of a "glocal" symposium. AB - BACKGROUND: This glocal (global knowledge with local action) symposium was convened by a professional therapeutic massage bodywork professional organization to bring together the fields of economics, politics, and traditional and complementary and alternative medicine (TCAM) to begin development of effective TCAM advocacy worldwide. The symposium addressed the core question, "What information will be needed to address issues that will arise as TCAM practitioners advocate for a respectful and equalfooting access to health care provision, public and private, worldwide?" PARTICIPANTS AND SETTING: The 35 international participants convened in a Victoria, Canada hotel. They were selectively invited to provide expertise in: advocacy, politics, public policy, economics, TCAM practice, integrative practice, sociology and TCAM research, education, media and language framing, psychology, and mediation. METHODS: The two-day symposium used a facilitated dialogue and knowledge-sharing design process geared to achieving group-supported recommendations. Invited panelists discussed each agenda topic, followed by facilitated discussion with the entire group. RESULTS: In general, participants agreed that advocacy from a TCAM perspective is needed. Additionally, more research should use methods with more relevance to everyday health care provision and health care costs such as effectiveness comparative trials and cost effectiveness studies. A number of specific advocacy steps were recommended. Most focused on developing local support for better access and equity regarding TCAM within local health care systems and advocacy work, which needs to both understand and engage the local TCAM practitioners and those using the TCAM services. CONCLUSIONS: The increasing awareness of TCAM and advancement toward integrative medicine-including traditional medicines and perspectives-are themes currently in development worldwide. Now is a good time for TCAM practitioners to open dialogue to develop better partnerships in health care. Such dialogue is facilitated when diverse people at the health care table understand each other's perspectives. More discussions like this, with diverse people across more disciplines, need to occur worldwide. PMID- 22211155 TI - Changing the culture of clinical education in massage therapy. AB - Much within the profession of massage therapy is done according to tradition. From an epistemological viewpoint, tradition is a way of knowing or, by extension, being, that is based upon both tenacity and authority and not always in best practices. As the profession of massage therapy moves in the direction of evidence-based medicine, or evidence-informed practice, the opportunity to re evaluate massage therapy education presents itself. PMID- 22211156 TI - Changes in temporomandibular joint dysfunction symptoms following massage therapy: a case report. AB - PURPOSE: The objective of this case report was to describe the effects that massage therapy had on a woman with temporomandibular joint dysfunction. PARTICIPANT: The 26-year-old woman's primary symptoms were pain, decreased range of motion, clicking, and crepitus. These symptoms were reportedly associated with emotional stress and bruxism. INTERVENTION: Ten 45-minute massage therapy treatments were administered over a five-week period. The client's progress was monitored by an initial, midway, and final assessment, using range of motion testing, personal interview, an orthopedic test, and postural analysis. Progress was also evaluated by the use of a daily journal. The client participated in a home care routine consisting of stretches, self-massage, postural training, a proprioception exercise, and hydrotherapy. RESULTS: Results include an increase in maximal opening from 3.1 cm to 3.8 cm, an overall increase in neck range of motion, a decrease in muscle hypertonicity using the Wendy Nickel's Scale, a decrease in pain from 7/10 to 3/10 on a numerical pain scale, and a decline in stress. CONCLUSION: Although the client in this report experienced positive results, more extensive studies are needed to understand the effects of massage on TMD. PMID- 22211157 TI - A Massage Therapist's Perspective on the Fascia Research Congresses. PMID- 22211159 TI - Effects of Microneedle Design Parameters on Hydraulic Resistance. AB - Microneedles have been an expanding medical technology in recent years due to their ability to penetrate tissue and deliver therapy with minimal invasiveness and patient discomfort. Variations in design have allowed for enhanced fluid delivery, biopsy collection, and the measurement of electric potentials. Our novel microneedle design attempts to combine many of these functions into a single length of silica tubing capable of both light and fluid delivery terminating in a sharp tip of less than 100 microns in diameter. This manuscript focuses on the fluid flow aspects of the design, characterizing the contributions to hydraulic resistance from the geometric parameters of the microneedles. Experiments consisted of measuring the volumetric flow rate of de-ionized water at set pressures (ranging from 69-621 kPa) through a relevant range of tubing lengths, needle lengths, and needle tip diameters. Data analysis showed that the silica tubing (~150 micron bore diameter) adhered to within +/-5% of the theoretical prediction by Poiseuille's Law describing laminar internal pipe flow at Reynolds numbers less than 700. High hydraulic resistance within the microneedles correlated with decreasing tip diameter. The hydraulic resistance offered by the silica tubing preceding the microneedle taper was approximately 1 2 orders of magnitude less per unit length, but remained the dominating resistance in most experiments as the tubing length was >30 mm. These findings will be incorporated into future design permutations to produce a microneedle capable of both efficient fluid transfer and light delivery. PMID- 22211160 TI - Fabrication and Characterization of Planar Plasmonic Substrates with High Fluorescence Enhancement. AB - The use of plasmonic nanostructures for fluorescence signal amplification is currently a very active research field. The detection of submonolayers of proteins labeled with organic dyes is a widely used technique in surface-based immunoassays and DNA hybridization. There is a strong interest in the development of new optical and chemical methods to increase the signal from ultralow concentrations of dyes on the surface of sensor substrates. Herein, we have explored the possibility of using vacuum-deposited silver nanostructures on dielectric layers and silver mirrors as potential plasmonic substrates that effectively amplify fluorescence over a broad spectral range. By optimizing deposition parameters for dielectric layers and silver nanostructures and applying thermal annealing processes, we observed large fluorescence amplifications from three different dye-strept(avidin) conjugates: about 7-fold for a UV/blue dye AF350-Av, 49-fold for a blue-green dye AF488-SA, and up to 208 fold for red-emitting AF647-SA dye. The observed amplification factors for the ensemble of fluorophores are very promising for development of surface-based bioassays. These substrates can be prepared using simple vacuum deposition in which we circumvent using the expensive nanofabrication methods. In addition, unlike most nanofabrication methods, the present approach is appropriate for large scale fabrication of substrates with microscope slide surface area suitable for sensing applications. PMID- 22211161 TI - Evolution of an Early Illness Warning System to Monitor Frail Elders in Independent Living. AB - This paper describes the evolution of an early illness warning system used by an interdisciplinary team composed of clinicians and engineers in an independent living facility. The early illness warning system consists of algorithms which analyze resident activity patterns obtained from sensors embedded in residents' apartments. The engineers designed an automated reasoning system to generate clinically relevant alerts which are sent to clinicians when significant changes occur in the sensor data, for example declining activity levels. During January 2010 through July 2010, clinicians and engineers conducted weekly iterative review cycles of the early illness warning system to discuss concerns about the functionality of the warning system, to recommend solutions for the concerns, and to evaluate the implementation of the solutions. A total of 45 concerns were reviewed during this period. Iterative reviews resulted in greater efficiencies and satisfaction for clinician users who were monitoring elder activity patterns. PMID- 22211162 TI - Congratulations to All are in order, as Allergy, Asthma & Immunology Research (AAIR) is going to Change to a Bimonthly Publication From a Quarterly One. PMID- 22211163 TI - Angiogenic factors play a significant role in nasal airway remodeling in allergic rhinitis. PMID- 22211164 TI - The revised edition of korean calendar for allergenic pollens. AB - The old calendar of pollens did not reflect current pollen distribution and concentrations that can be influenced by changes of weather and environment of each region in South Korea. A new pollen calendar of allergenic pollens was made based on the data on pollen concentrations obtained in eight regions nationwide between 1997 and 2009. The distribution of pollen was assessed every day at 8 areas (Seoul, Guri, Busan, Daegu, Jeonju, Kwangju, Kangneung, and Jeju) for 12 years between July 1, 1997 and June 30, 2009. Pollens were collected by using Burkard 7-day sampler (Burkard Manufacturing Co Ltd, UK). Pollens which were stained with Calberla's fuchsin staining solution were identified and counted. Pine became the highest pollen in May, and the pollen concentrations of oak and birch also became high. Ragweed appeared in the middle of August and showed the highest pollen concentration in the middles of September. Japanese hop showed a high concentration between the middle of August and the end of September, and mugwort appeared in the middles of August and its concentration increased up until early September. In Kangneung, birch appeared earlier, pine showed a higher pollen concentration than in the other areas. In Daegu, Oriental thuja and alder produced a large concentration of pollens. Pine produced a large concentration of pollens between the middle of April and the end of May. Weeds showed higher concentrations in September and mugwort appeared earlier than ragweed. In Busan the time of flowering is relatively early, and alder and Oriental thuja appeared earliest among all areas. In Kwangju, Oriental thuja and hazelnut appeared in early February. Japanese cedar showed the highest pollen concentration in March in Jeju. In conclusion, update information on pollen calendar in South Korea should be provided for allergic patients through the website to manage and prevent the pollinosis. PMID- 22211166 TI - The efficacy of the upright position on gastro-esophageal reflux and reflux related respiratory symptoms in infants with chronic respiratory symptoms. AB - PURPOSE: Gastro-esophageal reflux (GER), particularly non-acid reflux, is common in infants and is a known cause of chronic respiratory symptoms in infancy. Recent guidelines recommended empirical acid suppression therapy and the head-up position in patients with suspected GER. However, the efficacy of the upright position in relieving GER and reflux-related respiratory symptoms in infants is unclear. We conducted this study to investigate the efficacy of the upright position on GER and reflux-related respiratory symptoms in infants with chronic respiratory symptoms. METHODS: Thirty-two infants (21 male; median age, 5 months; range, 0 to 19 months) with unexplained chronic respiratory symptoms underwent multi-channel intraluminal esophageal impedance and pH monitoring. We retrospectively compared the frequencies of GER and reflux-related symptoms according to body position. RESULTS: A mean of 3.30 episodes of reflux per hour was detected. Overall, refluxes were more frequent during the postprandial period than the emptying period (3.77 vs. 2.79 episodes/hour, respectively; P=0.01). Although there was no significant difference in the total refluxes per hour between the upright and recumbent positions (6.12 vs. 3.77 episodes, P=0.10), reflux-related respiratory symptoms per reflux were significantly fewer in infants kept in an upright position than in a recumbent position during the postprandial period (3.07% vs. 14.75%, P=0.016). Non-acid reflux was the predominant type of reflux in infants, regardless of body position or meal time. CONCLUSIONS: The upright position may reduce reflux-related respiratory symptoms, rather than reflux frequency. Thus, it may be a useful non-pharmacological treatment for infantile GER disease resistant to acid suppressants. PMID- 22211165 TI - Epidermal barrier in atopic dermatitis. AB - Atopic dermatitis (AD) is a complex disease that affects up to 20% of children and impacts the quality of patients and families in a significant manner. New insights into the pathophysiology of AD point to an important role of structural abnormalities in the epidermis combined with immune dysregulation. Filaggrin (FLG) is synthesized as a large precursor, profilaggrin, and is expressed in the upper layers of the epidermis. FLG plays a critical role in the epidermal barrier, and FLG mutations cause abnormal epidermal function. FLG mutations are strongly associated with early-onset, and persistent severe AD. In addition, FLG deficiency in the epidermis is related to allergic sensitization and asthma. The basic skin care including repair and protection of the skin barrier with proper hydration and topical anti-inflammatory therapy is important to control the severity of skin disease in patients with AD. PMID- 22211167 TI - Decreased Expression of FOXP3 in Nasal Polyposis. AB - PURPOSE: The pathogenesis of nasal polyposis (NP) is unclear. Eosinophils and mast cells are considered to play important roles in this process. In addition, the levels of Th2-type cells are increased, irrespective of the atopic status of the patient with NP. In this context, we and others have shown high levels of thymus and activation-related chemokine/CCL17, macrophage-derived chemokine, eotaxin, and RANTES in patients with NP. Forkhead box P3 (FOXP3) plays a key role in CD4+CD25+ regulatory T-cell function and represents a specific marker for regulatory T cells (Tregs). Decreased expression of FOXP3 has been reported in allergic diseases. The present study was designed to evaluate the presence and potential roles of Tregs, defined by the expression of FOXP3 protein, in NP. METHODS: Using immunohistochemistry, we estimated the numbers of FOXP3+ cells in the epithelium and lamina propria of the NPs of 17 patients with chronic rhinosinusitis with NP and the nasal mucosa of 15 patients with allergic rhinitis (AR). The number of FOXP3+ cells in NPs was compared with that in the nasal mucosa of patients with AR, and the numbers of FOXP3+ cells in atopic and non atopic NP were also compared. RESULTS: The number of FOXP3+ cells in the lamina propria of patients with NP was significantly lower than that in the nasal mucosa of the AR patients (2.79 vs. 5.99, P=0.008). There was no statistically significant difference noted for the numbers of FOXP3+ cells between the epithelium of the NP and the nasal mucosa (3.60 vs. 2.39, P=0.180). Furthermore, the numbers of CD4+FOXP3+ cells were lower in NPs than in the allergic nasal mucosa. There was no difference in the number of FOXP3+ cells between the atopic and non-atopic NP patients. CONCLUSIONS: Fewer Tregs (i.e., decreased FOXP3 expression) are found in NPs than in the nasal mucosa of AR patients. As the severity of eosinophilic, Th2-type inflammation and the levels of inflammatory mediators are much higher in NPs than in the nasal mucosa of AR patients, an inverse co-relationship may exist between these parameters and the number of Tregs. The deficiency of Tregs in NP may account for the more pronounced Th2-type inflammation seen in these patients. PMID- 22211168 TI - Involvement of human histamine N-methyltransferase gene polymorphisms in susceptibility to atopic dermatitis in korean children. AB - PURPOSE: Histamine N-methyltransferase (HNMT) catalyzes one of two major histamine metabolic pathways. Histamine is a mediator of pruritus in atopic dermatitis (AD). The aim of this study was to evaluate the association between HNMT polymorphisms and AD in children. METHODS: We genotyped 763 Korean children for allelic determinants at four polymorphic sites in the HNMT gene: -465T>C, 413C>T, 314C>T, and 939A>G. Genotyping was performed using a TaqMan fluorogenic 5' nuclease assay. The functional effect of the 939A>G polymorphism was analyzed. RESULTS: Of the 763 children, 520 had eczema and 542 had atopy. Distributions of the genotype and allele frequencies of the HNMT 314C>T polymorphism were significantly associated with non-atopic eczema (P=0.004), and those of HNMT 939A>G were significantly associated with eczema in the atopy groups (P=0.048). Frequency distributions of HNMT -465T>C and -413C>T were not associated with eczema. Subjects who were AA homozygous or AG heterozygous for 939A>G showed significantly higher immunoglobulin E levels than subjects who were GG homozygous (P=0.009). In U937 cells, the variant genotype reporter construct had significantly higher mRNA stability (P<0.001) and HNMT enzyme activity (P<0.001) than the common genotype. CONCLUSIONS: Polymorphisms in HNMT appear to confer susceptibility to AD in Korean children. PMID- 22211169 TI - Role of angiogenic factors in airway remodeling in an allergic rhinitis murine model. AB - PURPOSE: There is growing evidence that nasal airway remodeling occurs in allergic rhinitis (AR). Although angiogenesis is an important component of airway remodeling in asthma, its involvement in AR has been little studied. Furthermore, information regarding the role of potent angiogenic factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), in the nasal airway remodeling process is limited. This study was conducted to investigate the role of VEGF and PDGF in nasal airway remodeling, and to assess the preventive effects of anti-angiogenic drugs on this process in a murine AR model. METHODS: Mice were systemically sensitized and subjected to inhalation of ovalbumin (OVA) twice a week for 3 months. Control mice were challenged with phosphate buffered saline, while the treatment group received SU1498, a VEGF receptor inhibitor, and/or AG1296, a PDGF receptor inhibitor, via intraperitoneal injection 4 hours prior to each OVA inhalation. Staining using hematoxylin and eosin, Masson's trichrome, and periodic acid-Schiff were separately performed to assess eosinophil infiltration, subepithelial fibrosis, and goblet cell hyperplasia, respectively, in the nasal airway. Immunohistochemical staining for matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) was also conducted. RESULTS: Repetitive intranasal inhalation of OVA resulted in significant increases in eosinophil infiltration, subepithelial fibrosis, goblet cell count, and MMP-9/TIMP-1 expression. Administration of SU1498 or AG1296 prevented these abnormal responses. CONCLUSIONS: The results of this study suggest that a causal relationship may exist between angiogenic factors and nasal airway remodeling in AR. Inhibition of VEGF or PDGF receptors may, in turn, suppress the remodeling process through the regulation of MMP 9/TIMP-1 expression. PMID- 22211170 TI - A case of propofol-induced oropharyngeal angioedema and bronchospasm. AB - Propofol (2,6-diisopropylphenol) is an ultrashort-acting sedative agent with sedative and amnestic effects that is used not only for anesthesia but also for sedation during minor outpatient procedures and endoscopic examinations. Rare cases of anaphylaxis following propofol administration have been reported in the medical literature. Documentation of anaphylaxis is often lacking because the cause and effect relationship is often hard to prove. Only a minority of patients get referred for allergy testing to confirm the offending drug. Here we report a 74-year-old woman who had an anaphylactic reaction with severe oropharyngeal edema and bronchospasm for a few minutes after receiving propofol during endoscopic examination. An allergy skin test was positive for both propofol and soybean. Soybean in the intralipid is one component of propofol, and we concluded that this anaphylaxis was caused by soybean. PMID- 22211171 TI - A Case of Occupational Rhinitis Induced by Maize Pollen Exposure in a Farmer: Detection of IgE-Binding Components. AB - Corn is a major staple food, along with rice and wheat, in many parts of the world. There are several reports of hypersensitivity to maize pollen. However, cases of occupational allergic rhinitis induced by inhalation of maize pollen are very rare. We herein report the case of a 67-year-old male with occupational rhinitis caused by occupational exposure to maize pollen in a cornfield. He showed positive responses to maize pollen, as well as grass pollens, in skin prick tests. A high level of serum immunoglobulin E (IgE) specific to maize pollen extracts was detected by an enzyme-linked immunosorbent assay (ELISA). Laboratory tests showed a high serum level of total IgE (724 kU/L) and a high level of IgE specific to maize pollen (8.32 kU/L) using the Immuno-CAP system. Occupational rhinitis was confirmed by a nasal provocation test with maize pollen extracts. IgE ELISA inhibition tests showed antibody cross-reactivity between maize pollen and grass pollen extracts. IgE immunoblotting using maize pollen extracts demonstrated a 27 kDa IgE-binding component. These findings suggest that maize pollen can induce IgE-mediated occupational rhinitis in exposed workers. PMID- 22211172 TI - Meloxicam-induced rhabdomyolysis in the context of an acute ross river viral infection. AB - Acute rhabdomyolysis is a clinical and laboratory syndrome resulting from the breakdown of skeletal muscle, with the release of intracellular contents into the circulatory system, which can cause potentially lethal complications. Here, we present the case of a patient who developed acute rhabdomyolysis after consumption of meloxicam for jaw pain and experienced generalized myalgias in the context of an acute febrile illness with generalized urticaria. Further investigation indicated elevated muscle enzymes and acute renal failure. Serological analysis revealed that the patient was positive for Ross River virus (RRV) IgM. Genetic studies to detect CYP2C9 polymorphisms were negative. Meloxicam was discontinued. He responded to conservative measures within 2 weeks. Oral aspirin challenge was negative, suggesting a drug-specific effect of meloxicam rather than a class effect. Our case indicates a causative role for meloxicam and/or acute RRV in rhabdomyolysis. PMID- 22211173 TI - Fulminant and Fatal Multiple Organ Failure in a 12-Year-Old Boy With Mycoplasma pneumoniae Infection. AB - Mycoplasma pneumoniae (Mp) is a unique pathogen that causes not only pulmonary but also extrapulmonary manifestations that must be rapidly diagnosed. A 12-year old boy, with no relevant medical history, presented with fever, severe epigastric pain, and vomiting. Laboratory findings showed fulminant and cholestatic hepatitis, hemolytic anemia, thrombocytopenia, acute kidney injury, disseminated intravascular coagulopathy, acute myocardial infarction, and rhabdomyolysis. His clinical condition rapidly deteriorated during intubation and continuous renal replacement therapy. Despite intensive treatment, he did not recover. We report a case of fulminant and fatal multiple organ failure in a previously healthy boy with Mp infection, describing the possible pathomechanisms of multiple organ failure involved in the disease. PMID- 22211174 TI - Towards Structuring Unstructured GenBank Metadata for Enhancing Comparative Biological Studies. AB - Within large sequence repositories such as GenBank there is a wealth of metadata providing contextual information that may enhance search and retrieval of relevant sequences for a range of subsequent analyses. One challenge is the use of free-text in these metadata fields where approaches are needed to extract, structure, and encode essential information. The goal of the present study was to explore the feasibility of using a combination of existing resources for annotating unstructured GenBank metadata, initially focusing on the "host" and "isolation_source" fields. This paper summarizes early results for 10 host organisms that include a characterization of associated isolation sources with respect to biomedical ontologies and semantic types. The findings from this preliminary study provide insights to the rich amount of information captured within these unstructured metadata, guidance for addressing the challenges and issues encountered, and highlight the potential value for enriching comparative biological studies towards improving human health. PMID- 22211175 TI - Smooth isotonic regression: a new method to calibrate predictive models. AB - Predictive models are critical for risk adjustment in clinical research. Evaluation of supervised learning models often focuses on predictive model discrimination, sometimes neglecting the assessment of their calibration. Recent research in machine learning has shown the benefits of calibrating predictive models, which becomes especially important when probability estimates are used for clinical decision making. By extending the isotonic regression method for recalibration to obtain a smoother fit in reliability diagrams, we introduce a novel method that combines parametric and non-parametric approaches. The method calibrates probabilistic outputs smoothly and shows better generalization ability than its ancestors in simulated as well as real world biomedical data sets. PMID- 22211176 TI - An informatics framework for testing data integrity and correctness of federated biomedical databases. AB - Clinical research is increasingly relying on information gathered and managed in different database systems and institutions. Distributed data collection and management processes in such settings can be extremely complex and lead to a range of issues involving the integrity and accuracy of the distributed data. To address this challenge, we propose a middleware framework for assessing the data integrity and correctness in federated environments. The framework has two main elements: (1) a test model describing the dependencies between and constraints on data sources and datasets, and (2) a family of testing techniques that create and execute test cases based on the model. PMID- 22211177 TI - Use case and application requirements for a protocol lifecycle tracking tool, with a focus on the trial initiation phase. AB - The time required to initiate clinical trials, from declaration of the investigator's intent to opening of the study for participant accrual, is cited as often being so long that clinical research is seriously impeded. Efforts to improve operational efficiency of trial initiation are confounded by the work flow complexity and the variations encountered with different types of trials and institutional environments. A computer Protocol Lifecycle Tracking (PLT) tool would enable study initiation staff to manage the process, and the various clinical research stakeholders to monitor the progress of a study's initiation, as well as obtain data on the work flow to identify those activities that are in need of operational efficiency improvement. The objective of our work was to develop use cases and system requirements for a PLT tool. The result of our study is a use case document that can serve as the specifications for developing a PLT application. PMID- 22211178 TI - Evaluating Phenotypic Data Elements for Genetics and Epidemiological Research: Experiences from the eMERGE and PhenX Network Projects. AB - Combining genome-wide association studies (GWAS) data with clinical information from the electronic medical record (EMR) provide unprecedented opportunities to identify genetic variants that influence susceptibility to common, complex diseases. While mining the vastness of EMR greatly expands the potential for conducting GWAS, non-standardized representation and wide variability of clinical data and phenotypes pose a major challenge to data integration and analysis. To address this requirement, we present experiences and methods developed to map phenotypic data elements from eMERGE (Electronic Medical Record and Genomics) to PhenX (Consensus Measures for Phenotypes and Exposures) and NCI's Cancer Data Standards Registry and Repository (caDSR). Our results suggest that adopting multiple standards and biomedical terminologies will expose studies to a broader user community and enhance interoperability with a wider range of studies, in turn promoting cross-study pooling of data to detect both more subtle and more complex genotype-phenotype associations. PMID- 22211179 TI - A Temporal Abstraction-based Extract, Transform and Load Process for Creating Registry Databases for Research. AB - In the CTSA era there is great interest in aggregating and comparing populations across institutions. These sites likely represent data differently in their clinical data warehouses and other databases. Clinical data warehouses frequently are structured in a generalized way that supports many constituencies. For research, there is a need to transform these heterogeneous data into a shared representation, and to perform categorization and interpretation to optimize the data representation for investigators. We are addressing this need by extending an existing temporal abstraction-based clinical database query system, PROTEMPA. The extended system allows specifying data types of interest in federated databases, extracting the data into a shared representation, transforming it through categorization and interpretation, and loading it into a registry database that can be refreshed. Such a registry's access control, data representation and query tools can be tailored to the needs of research while keeping local databases as the source of truth. PMID- 22211180 TI - A framework and standardized methodology for developing minimum clinical datasets. AB - The concept of the minimum dataset (MDS) is taking on an increasingly important role in healthcare. In the current environment of health information exchange and universal implementation of electronic health records, work related to the development of one specific type of MDS, the minimum clinical dataset (MCDS), is beginning to permeate the literature. While there is currently no unified definition of either an MDS or an MCDS, an MDS is generally agreed to be a coherent set of explicitly defined data elements. Despite the growing body of literature on MCDSs, very little empirical evidence exists in the literature related to best methods for developing them. The primary objective of the current study is to fill this gap. By presenting a streamlined approach to the development of MCDSs the current study attempts to provide individuals and organizations with a coherent methodology and framework for developing a high quality MCDS. PMID- 22211181 TI - Towards Semantic-Web Based Representation and Harmonization of Standard Meta-data Models for Clinical Studies. AB - In this paper, we introduce our case studies for representing clinical study meta data models such as the HL7 Detailed Clinical Models (DCMs) and the ISO11179 model in a framework that is based on the Semantic-Web technology. We consider such a harmonization would provide computable semantics of the models, thus facilitate the model reuse, model harmonization and data integration.1. PMID- 22211182 TI - CNTRO 2.0: A Harmonized Semantic Web Ontology for Temporal Relation Inferencing in Clinical Narratives. AB - The Clinical Narrative Temporal Relation Ontology (CNTRO) has been developed for the purpose of allowing temporal information of clinical data to be semantically annotated and queried, and using inference to expose new temporal features and relations based on the semantic assertions and definitions of the temporal aspects in the ontology. While CNTRO provides a formal semantic foundation to leverage the semantic-web techniques, it is still necessary to arrive at a shared set of semantics and operational rules with commonly used ontologies for the time domain. This paper introduces CNTRO 2.0, which tries to harmonize CNTRO 1.0 and a list of existing time ontologies or top-level ontologies into a unified model-an OWL based ontology of temporal relations for clinical research. PMID- 22211183 TI - Spatio-temporal Structure of US Critical Care Transfer Network. AB - Most Americans are in Intensive Care Units (ICUs) at some point during their lives. There is wide variation in the outcome quality of ICUs and so, thousands of patients who die each year in ICUs may have survived if they were at the appropriate hospital. In spite of a policy agenda from IOM calling for effective transfer of patients to more capable hospitals to improve outcomes, there appear to be substantial inefficiencies in the existing system. In particular, patients recurrently transfer to secondary hospitals rather than to a most-preferred option. We present data mining schemes and significance tests to discover these inefficient cascades. We analyze critical care transfer data in Medicare across nearly 5,000 hospitals in the United States over 10 years and present evidence that these transfers to secondary hospitals repeatedly cascade across multiple transfers, and that some hospitals seem to be involved in many cascades. PMID- 22211184 TI - Anthocyanins in cardiovascular disease. AB - Anthocyanins are a group of abundant and widely consumed flavonoid constituents that occur ubiquitously in the plant kingdom, providing the bright red-orange to blue-violet colors present in many fruit- and vegetable-based food products. Their intake has been estimated to be up to 9-fold higher than that of other dietary flavonoids. Anthocyanins have become increasingly important to the food industry as their use as natural alternatives to artificial colors has become widespread and knowledge of their health-promoting properties has become more evident. Epidemiological studies suggest that increased consumption of anthocyanins lowers the risk of cardiovascular disease (CVD), the most common cause of mortality among men and women. Anthocyanins frequently interact with other phytochemicals, exhibiting synergistic biological effects but making contributions from individual components difficult to decipher. Over the past 2 decades, many peer-reviewed publications have demonstrated that in addition to their noted in vitro antioxidant activity, anthocyanins may regulate different signaling pathways involved in the development of CVD. This review summarizes the latest developments on the bioavailability/bioactivity and CVD preventative activities of anthocyanins, including results from in vitro cell culture and in vivo animal model systems as related to their multiple proposed mechanisms of action. Limited yet promising data from epidemiological studies and human clinical trials are also presented. Future studies aimed at enhancing the absorption of anthocyanins and characterizing their metabolic and/or breakdown products are necessary to ultimately evaluate their use for protection/prevention against the development of CVD. PMID- 22211185 TI - Which sources of flavonoids: complex diets or dietary supplements? AB - There is increasing interest in the potential health benefits of dietary flavonoids. Fruits and vegetables, tea, and cocoa are rich natural sources of flavonoids. Epidemiological studies have indicated that consumption of these foods is likely to be associated with a reduced risk of cardiovascular disease, but the etiology of this benefit is not yet clearly defined. Furthermore, in some acute interventions, a positive effect of tea and cocoa on vascular function has been reported. An alternative source of flavonoids is dietary supplements, which have become increasingly popular in the recent past. In this context, it needs to be critically evaluated whether vascular health-promoting and other positive properties of flavonoid-rich diets can be replaced by purified flavonoids as dietary supplements. Plant sources of flavonoids contain a complex mixture of secondary plant metabolites and not only flavonoids per se. This complex mixture of secondary plant metabolites cannot be simply exchanged by single purified compounds as dietary supplements. If flavonoids are given as dietary supplements, toxicity issues as well as nutrient drug interactions need to be taken into account. Purified flavonoids given in high doses as dietary supplements may affect trace element, folate, and vitamin C status. Furthermore, they may exhibit antithyroid and goitrogenic activities. In this review article, the available literature on the safety issues surrounding high dose supplemental flavonoid consumption has been summarized. PMID- 22211186 TI - Stearoyl CoA desaturase 1: role in cellular inflammation and stress. AB - Stearoyl CoA desaturase 1 (SCD1) catalyzes the rate-limiting step in the production of MUFA that are major components of tissue lipids. Alteration in SCD1 expression changes the fatty acid profile of these lipids and produces diverse effects on cellular function. High SCD1 expression is correlated with metabolic diseases such as obesity and insulin resistance, whereas low levels are protective against these metabolic disturbances. However, SCD1 is also involved in the regulation of inflammation and stress in distinct cell types, including beta-cells, adipocytes, macrophages, endothelial cells, and myocytes. Furthermore, complete loss of SCD1 expression has been implicated in liver dysfunction and several inflammatory diseases such as dermatitis, atherosclerosis, and intestinal colitis. Thus, normal cellular function requires the expression of SCD1 to be tightly controlled. This review summarizes the current understanding of the role of SCD1 in modulating inflammation and stress. PMID- 22211187 TI - Disparities in pediatric obesity in the United States. AB - This paper describes the disparities in the U.S. childhood obesity epidemic, mainly based on recent nationally representative data. The prevalence of overweight and obesity has increased since the late 1970s; the over time shifts (changes) in distributions of various body fatness measures indicate that U.S. children have become fatter and the obese groups gained more body fat, especially more central obesity, as indicated by waist circumference. However, considerable between-group and regional disparities exist in the prevalence, fatness measures, and over time trends. The disparities and trends are complex, which reflects the complexity and dynamics in obesity etiology. Clearly, some population groups are affected more seriously than others. Native American children have the highest prevalence of obesity, whereas Asians have the lowest rate among all ethnic groups. Preschool age children have a lower obesity prevalence than older children. Young people in some states and cities are twice more likely to be overweight or obese than those living in other regions. Low-socioeconomic status is associated with obesity only among some population groups, e.g. white children and adolescents. Vigorous, effective interventions are needed to promote healthy lifestyles among U.S. young people and to reduce disparities in obesity. PMID- 22211190 TI - Protein. PMID- 22211189 TI - Nutritional aspects of phytoene and phytofluene, carotenoid precursors to lycopene. AB - Epidemiological studies suggest an inverse relationship between tomato consumption and serum and tissue lycopene (LYC) levels with risk of some chronic diseases, including several cancers and cardiovascular disease. LYC, the red carotenoid found in tomatoes, is often considered to be the primary bioactive carotenoid in tomatoes that mediates health benefits, but other colorless precursor carotenoids, phytoene (PE) and phytofluene (PF), are also present in substantial quantities. PE and PF are readily absorbed from tomato foods and tomato extracts by humans. Animal models of carotenoid absorption suggest preferential accumulation of PE and PF in some tissues. The reasonably high concentrations of PE and PF detected in serum and tissues relative to the concentrations in foods suggest that absorption or metabolism of these compounds may be different from that of LYC. Experimental studies, both in vitro and in vivo, suggest that PE and PF exhibit bioactivity but little is known about their impact in humans. Methods for producing isotopically labeled PE, PF, and LYC tracers from tomato plant cell culture offer a unique tool for further understanding the differential bioavailability and metabolism of these 3 prominent tomato carotenoids and how they may affect health. PMID- 22211191 TI - Institute of Medicine. 2009. School meals: building blocks for healthy children. Washington, DC: the National Academies Press. PMID- 22211193 TI - Energy expenditure in the performing arts. PMID- 22211192 TI - CRKL as a lung cancer oncogene and mediator of acquired resistance to EGFR inhibitors: is it all that it is cracked up to be? AB - Cheung and colleagues demonstrate that amplified CRKL can function as a driver oncogene in lung adenocarcinoma, activating both RAS and RAP1 to induce mitogen activated protein kinase signaling. In addition, they show that CRKL amplification may be another mechanism for primary or acquired resistance to epidermal growth factor receptor kinase inhibitors. PMID- 22211188 TI - Herbal extracts and phytochemicals: plant secondary metabolites and the enhancement of human brain function. AB - Humans consume a wide range of foods, drugs, and dietary supplements that are derived from plants and which modify the functioning of the central nervous sytem (CNS). The psychoactive properties of these substances are attributable to the presence of plant secondary metabolites, chemicals that are not required for the immediate survival of the plant but which are synthesized to increase the fitness of the plant to survive by allowing it to interact with its environment, including pathogens and herbivorous and symbiotic insects. In many cases, the effects of these phytochemicals on the human CNS might be linked either to their ecological roles in the life of the plant or to molecular and biochemical similarities in the biology of plants and higher animals. This review assesses the current evidence for the efficacy of a range of readily available plant-based extracts and chemicals that may improve brain function and which have attracted sufficient research in this regard to reach a conclusion as to their potential effectiveness as nootropics. Many of these candidate phytochemicals/extracts can be grouped by the chemical nature of their potentially active secondary metabolite constituents into alkaloids (caffeine, nicotine), terpenes (ginkgo, ginseng, valerian, Melissa officinalis, sage), and phenolic compounds (curcumin, resveratrol, epigallocatechin-3-gallate, Hypericum perforatum, soy isoflavones). They are discussed in terms of how an increased understanding of the relationship between their ecological roles and CNS effects might further the field of natural, phytochemical drug discovery. PMID- 22211194 TI - Development of a portable anchored dynamometer for collection of maximal voluntary isometric contractions in biomechanics research on dancers. AB - Surface electromyography (sEMG) has been used in dance medicine research since the 1970s, but normalization procedures are not consistently employed in the field. The purpose of this project was to develop a portable anchored dynamometer (PAD) specifically for dance-related research. Due to the limited studies in the dance research literature using normalization procedures for sEMG data, a review of the procedures used in the exercise science literature was conducted. A portable anchored dynamometer was then developed and tested with dancers, using methods validated in previous literature. We collected sEMG maximum voluntary isometric contractions (MVIC, mV) from 10 female dancers (mean age 31.0 +/- 15 yrs, mean height 163 +/- 7.6 cm, mean weight 57.6 +/- 6.9 kg, and 17.0 +/- 13.9 yrs of training in ballet and/or modern dance) over three trials (5 sec each) for eight muscles bilaterally (quadriceps, tibialis anterior, abductor hallucis, gastrocnemius, hamstrings, gluteus maximus, erector spinae, and rectus abdominus). Consistency of data and feedback from dancers suggest that this dance specific portable anchored dynamometer is effective for future sEMG studies in dance research. PMID- 22211195 TI - Effect of sprung (suspended) floor on lower extremity stiffness during a force returning ballet jump. AB - Our objective in this study was to compare stiffness of bilateral lower extremities (LEs) in ballet dancers performing saute on a low-stiffness "sprung floor" to that during the same movement on a high-stiffness floor (wood on concrete). LE stiffness was calculated as the ratio of vertical ground reaction force (in kN) to compression of the lower limb (in meters). Seven female dancers were measured for five repetitions each at the point of maximum leg compression while performing saute on both of the surfaces, such that 43 ms of data were represented for each trial. The stiffness of bilateral LEs at the point of maximum compression was higher by a mean difference score of 2.48 +/- 2.20 kN/m on the low-stiffness floor compared to a high-stiffness floor. Paired t-test analysis of the difference scores yielded a one-tailed probability of 0.012. This effect was seen in six out of seven participants (one participant showed no difference between floor conditions). The finding of increased stiffness of the LEs in the sprung floor condition suggests that some of the force of landing the jump was absorbed by the surface, and therefore did not need to be absorbed by the participants' LEs themselves. This in turn implies that a sprung dance floor may help to prevent dance-related injuries. PMID- 22211196 TI - Injury reporting rates and injury concealment patterns differ between high-school cirque performers and basketball players. AB - OBJECTIVE: The performing arts style of cirque has grown in popularity, with high school participants increasingly practicing this style. Still, little research has examined the injury reporting rates and patterns in this population. Our study aimed to compare injury reporting rates and injury concealment patterns between high-school cirque performers and a peer-group of basketball players. METHODS: Fifty participants (30 cirque, 20 basketball) completed a 12-item injury history and concealment instrument with chi-squared analyses and Fisher's exact tests comparing groups (p = 0.05). RESULTS: While no group differences (p = 0.36) existed in injuries reported, basketball players were more likely (p = 0.01) to miss participation due to injury than cirque performers. No significant difference existed between participants regarding which healthcare provider they reported to first (p = 0.27), but basketball players reported their injuries to the athletic trainer at higher rates (50%) than cirque performers (20%). A nonsignificant trend (p = 0.08) was noted in promptness to report injury, with more cirque performers (13%) concealing their injuries than basketball players (5%). Several reasons were noted for concealment of injury, with the most common being the belief that the injury would "go away" on its own. Knee injuries were most common in basketball players (23.7%) and back and knee injuries (10.5% each) in cirque performers. CONCLUSIONS: Despite similar injury rates, cirque participants concealed injuries more than peer-basketball players. Reasons may include losing performance roles, unfamiliarity and low trust with healthcare providers, ignorance about initially minor-looking injuries, and higher pain tolerance thresholds. Education and communication are essential to allow performing artists to seek healthcare support. Research is needed to appropriately understand and meet the needs of this underserved performing artist population. PMID- 22211197 TI - Energy expenditure during competitive Latin American dancing simulation. AB - The aims of this study were to estimate the energy expenditure (EE) and the intensity of physical activity (PA) during a competitive simulation of Latin American dancing and to evaluate the differences in PA and EE values between the sexes, between different dance types, and between the various phases of the competition. METHODS: Ten Italian dancers (five couples, 5 males and 5 females) competing in Latin American dancing at the international level were examined in this study. The EE (kcal) was measured during the semifinal and final phases of the competition using the SenseWear Pro Armband (SWA). Paired-sample t-tests were used to determine differences in the metabolic equivalent (MET) and EE values between the semifinal and final phases and between each dance. One-way analysis of variance was used to analyze the differences in the MET and EE values between the sexes. RESULTS: The intensity of PA during the dance sequence ranged from moderate (3 to 6 METs) to vigorous (6 to 9 METs). The male dancers had higher EE values than the female dancers during all phases of the simulation. Similar MET values were observed in both sexes. The PA intensity during the finals phase was vigorous for 56% of the time of dance. Of all the dance styles, the rumba had the lowest MET and EE values. CONCLUSION: Our results demonstrate that competitive Latin American dancing is a heavy exercise and suggest that monitoring variables during normal training can improve training protocols and the dancers' fitness levels. PMID- 22211198 TI - Trigger point treatment with radial shock waves in musicians with nonspecific shoulder-neck pain: data from a special physio outpatient clinic for musicians. AB - Musicians often suffer from disorders of the musculoskeletal system that are related to their instrument playing. Among the most frequent symptoms are complaints in the shoulder-neck area. Radial shock wave therapy is increasingly used in trigger point treatment, but only few high-level studies have examined of shock wave therapy used together with physical therapy in the treatment of musicians. METHODS: This randomized blinded study in musicians (n = 26) with nonspecific shoulder-neck problems was done to examine the effect of shock wave therapy in addition to current physical therapy on the symptoms and quality of life of the musicians as well as their habits of playing musical instruments (intervention group shock wave vs reference group placebo). The effects were documented by a pain VAS and other instruments. A questionnaire designed specifically for musicians (with initial and final questions) recorded intensity and manifestation of pain and handicaps in daily life, especially when practicing and playing. The Shoulder Pain and Disability Index (SPADI) and the Neck Pain Disability Index Questionnaire (NPDIQ) were also used. RESULTS: Both groups reported subjective improvement in pain, but significance was found only for the intervention group for the SPADI and NPDIQ. CONCLUSIONS: Trigger point treatment with radial shock wave used in combination with physical therapy makes the subjects feel temporarily relieved of neck and shoulder pains. The effects of radial shock wave without physical therapy will need to be examined in further studies. PMID- 22211199 TI - Energy expenditure in brass and woodwind instrumentalists: the effect of body posture. AB - OBJECTIVE: Body posture appears to influence fatigue and musculoskeletal complaints in musicians. Our aim was to determine energy expenditure and to investigate whether energy expenditure is affected by body posture in brass and woodwind instrumentalists. METHODS: Eighteen musicians (10 women, 8 men; 6 brass, 12 woodwinds), with a mean age of 39 +/- 14 years and mean body mass index of 23.8 +/- 4.9 kg/m2, played their instruments for 30 minutes twice: once in nonoptimized body posture (posture A), and once in a posture according to the postural exercise therapy method Mensendieck (posture B). Patients were randomized to the order of postures in a crossover design AB/BA. Playing sessions were preceded and followed by 60 minutes of rest. Energy expenditure was measured in a respiration chamber with indirect calorimetry. Basal metabolic rate was measured with a ventilated hood. RESULTS: Mean metabolic equivalents (MET) for playing a wind instrument in the sitting position in a nonoptimized posture and posture according postural exercise therapy were 1.69 (SD 0.18) and 1.80 (SD 0.22), respectively. Percent change between resting metabolic rate and total energy expenditure while playing was 32% (95% CI 25-39%) in posture B and 23% (95% CI 17-30%) in posture A (p = 0.021). CONCLUSION: Average physical activity while playing a wind instrument approximates 1.8 MET. Our data show an association between energy expenditure and body posture while playing a brass or woodwind instrument: playing a musical instrument in a posture according to postural exercise therapy leads to higher energy expenditure as compared to a nonoptimized body posture. These results suggest that fatigue and the general feeling of lack of energy after playing a musical instrument are not related to actual higher energy expenditure. PMID- 22211200 TI - Why not implement supported employment? PMID- 22211202 TI - State budget cuts, health care reform, and a crisis in rural community mental health agencies. AB - Between 2009 and 2011, states implemented significant budget cuts to community mental health agencies (CMHAs), which are frequently the sole provider of specialized behavioral health services in rural communities. Starting in 2010, federal policy changes created by health care reform and mental health parity are likely to increase the number of individuals who can afford to seek services for a mental illness. CMHAs under financial stress have begun to eliminate services and reduce staff. These trends could result in a growing gap between available behavioral health services and the number of people who can afford to seek treatment for a mental illness. PMID- 22211203 TI - An automated Internet application to help patients with bipolar disorder track social rhythm stabilization. AB - This column describes a pilot study of a fully automated, Internet-based program that provides a key element of interpersonal and social rhythm therapy, a form of psychotherapy shown to be effective in the treatment of bipolar disorder when combined with mood-stabilizing medication. Participants (N=64) recorded the time they completed activities of daily living and their mood at the time of each entry. After 90 days they demonstrated a 31% increase in social rhythm stability and a small, though statistically significant, decrease in symptoms of abnormal mood. Internet-based programs can enhance access to a best practice in the management of bipolar disorder. PMID- 22211204 TI - Opening doors to recovery: a novel community navigation service for people with serious mental illnesses. AB - This column describes Opening Doors to Recovery in Southeast Georgia, a partnership between public agencies, a private corporation, a not-for-profit organization, and an academic institution. Teams of community navigation specialists that include a licensed mental health professional, a family member of an individual with a serious mental illness, and a peer with lived experience in recovery seek to enhance participants' community integration, support them in developing a meaningful day, ensure access to adequate treatment, and facilitate stable housing, improved relationships, and desired vocational, volunteer, or educational activities. PMID- 22211205 TI - Racial-ethnic disparities in substance abuse treatment: the role of criminal history and socioeconomic status. AB - OBJECTIVE: Among persons with substance use disorders, those from racial-ethnic minority groups have been found to receive substance abuse treatment at rates equal to or higher than those of non-Latino whites. Little is known about factors underlying this apparent lack of disparities. This study examines racial-ethnic disparities in treatment receipt and mechanisms that reduce or contribute to disparities. METHODS: Black-white and Latino-white disparities in any and in specialty substance abuse treatment were measured among adult respondents with substance use disorders from the 2005-2009 National Survey on Drug Use and Health (N=25,159). Three staged models were used to measure disparities concordant with the Institute of Medicine definition, assess the extent to which criminal history and socioeconomic indicators contributed to disparities, and identify correlates of treatment receipt. RESULTS: Treatment was rare (about 10%) for all racial ethnic groups. Odds ratios for black-white and Latino-white differences decreased and became significantly less than 1 after adjustment for criminal history and socioeconomic status factors. Higher rates of criminal history and enrollment in Medicaid among blacks and Latinos and lower income were specific mechanisms that influenced changes in estimates of disparities across models. CONCLUSIONS: The greater likelihood of treatment receipt among persons with a criminal history and lower socioeconomic status is a pattern unlike those seen in most other areas of medical treatment and important to the understanding of substance abuse treatment disparities. Treatment programs that are mandated by the criminal justice system may provide access to individuals resistant to care, which raises concerns about perceived coercion. PMID- 22211206 TI - Does minority racial-ethnic status moderate outcomes of collaborative care for depression? AB - OBJECTIVE: The authors examined racial differences in response rates to an intervention involving collaborative care and usual care among 360 veterans treated for depression at Department of Veterans Affairs community-based primary care clinics. METHODS: Individuals who screened positive for depression were assigned randomly to usual care (N=200) or to a collaborative care intervention (N=160) that provided phone contact when necessary with a registered nurse and clinical pharmacist to address issues related to compliance with medication and side effect management as well as supervision by a psychiatrist through video chats with the collaborative care team. Data about patients' characteristics, treatment history, and response to treatment were collected by telephone at baseline and after six months. RESULTS: Seventy-five percent (N=272) of the veterans were Caucasian, and 25% (N=88) belonged to a minority group, including 18% (N=64) who were African American, 3% (N=11) who were Native American, and 3.6% (N=13) who were of other minority groups. There were no significant differences between response rates between the Caucasian and minority group to usual care (18% and 8%, respectively), but the minority group had a higher response rate (42%) than Caucasians (19%) to the intervention (chi2=8.2, df=1, p=.004). Regression analysis indicated that the interaction of minority group status by intervention significantly predicted response (odds ratio [OR]=6.2, 95% confidence interval [CI]=1.6-24.5, p=.009), even after adjustment for other factors associated with minority status (OR=6.0, 95% CI=1.5-24.3, p=.01). CONCLUSIONS: Racial disparities in depression care may be ameliorated through collaborative care programs. PMID- 22211207 TI - Qualitative analysis of barriers to implementation of supported employment in the Department of Veterans Affairs. AB - OBJECTIVE: The aim of this qualitative study was to document perceived barriers to supported employment implementation as described by Department of Veterans Affairs (VA) employees. METHODS: Interviews were conducted over two years at six VA medical centers involved in implementing supported employment, an evidence based practice for helping people with serious mental illness obtain competitive employment. Eighty-four unique semistructured interviews focusing on program development were conducted at the two time points with 110 VA leaders, clinicians, and supported employment staff. A qualitative analysis was performed by using a hybrid of a priori coding categories (focused on organizational transformation) and a data-driven approach to examining perceived barriers to supported employment implementation. RESULTS: Perceived barriers to supported employment implementation were most prominent during the first year of interviews. VA employees across the six sites reported challenges related to employees having paternalistic attitudes about individuals with serious mental illness and being uninformed about the supported employment program. They also reported a lack of organizational structures and leadership to educate providers, facilitate program integration with other teams, and promote the program's value. By the second year, most sites had addressed these challenges. CONCLUSIONS: Paternalistic-uninformed concerns about the ability of persons with serious mental illness to be gainfully employed and a lack of organizational structures and leadership to promote and integrate the supported employment program were common implementation barriers. During implementation, organizations would likely benefit from a formalized educational process of teams involved in the care of supported employment clients and from leadership buy-in to the program and promotion of its significance. PMID- 22211208 TI - A web-based program to empower patients who have schizophrenia to discuss quality of care with mental health providers. AB - OBJECTIVE: This study evaluated a Web-based tool to help patients with schizophrenia communicate with clinicians about evidence-based treatments. METHODS: Fifty patients used an interactive Web-based intervention featuring actors simulating a patient discussing treatment concerns (intervention group; N=24) or were shown an educational video about schizophrenia treatment before an appointment for routine follow-up care (control group; N=26). The visits were recorded and analyzed by using the Roter Interaction Analysis System. RESULTS: Visits by patients in the intervention group were longer (24 versus 19 minutes, p<.05) and had a proportionately greater patient contribution to the dialogue (288 versus 229 statements, p<.05) and a smaller ratio of clinician to patient talk (1.1 versus 1.4, p<.05) compared with visits by the control group. Patients in the intervention group asked more questions about treatment (2 versus .9, p<.05), disclosed more lifestyle information (76 versus 53 statements, p<.005), and more often checked that they understood information (3.6 versus 2.1 checks, p<.05). Clinicians asked more questions about treatment (7.5 versus 5.1, p<.05) and the medical condition (7.8 versus 4.7, p<.05) to control group patients but made more statements of empathy (1.3 versus .4, p<.03) and cues of interest (48 versus 22, p<.05) with the intervention group. The patient-centeredness ratio was greater for visits by patients in the intervention group than by the control group (8.5 versus 3.2, p<.05). Patients' tone was more dominant and respectful (p<.05) and clinicians' tone was more sympathetic (p<.05) during visits by patients in the intervention. CONCLUSIONS: The Web-based tool empowered persons with schizophrenia to engage more fully in a patient-centered dialogue about their treatment. PMID- 22211210 TI - A randomized controlled comparison of seclusion and mechanical restraint in inpatient settings. AB - OBJECTIVE: No evidence is available on the relative restrictiveness of seclusion and mechanical restraint, although guidelines recommend use of the least restrictive intervention. This study compared the restrictiveness of these interventions from patients' point of view. METHODS: Data were collected from three general psychiatric admission units in South Germany. A total of 102 patients with schizophrenia, an affective disorder, or a personality disorder were included in a comprehensive cohort study with optional randomization. Restrictions of human rights as measured by the Coercion Experience Scale (CES) were the primary outcome variable. Possible total scores range from 1 to 5, with higher scores indicating a higher level of restriction. RESULTS: Twenty-six patients were randomly assigned to seclusion (N=12) or mechanical restraint (N=14). A total of 76 were excluded from randomization and included in the cohort arms (48 experienced seclusion, and 28 experienced mechanical restraint). No difference in mean CES total scores was found between the randomly assigned patients after they experienced seclusion or mechanical restraint (seclusion median score=1.88 [range 1.24-4.24]; restraint median score=2.14 [range 1.28 4.00]). When randomly assigned patients and patients in the cohort arms were considered as a group, no significant difference in CES scores was found (seclusion median score=.40, [range 1.1-4.2]; restraint median score=2.59 [range 1.1-4.0]). CONCLUSIONS: The results do not provide evidence for using one intervention rather than the other. Clinical decisions should take into account patients' preferences. Randomized controlled trials of coercive interventions are feasible. Such studies contribute to the development of ethical and evidence based guidelines. PMID- 22211209 TI - An emergency department intervention for linking pediatric suicidal patients to follow-up mental health treatment. AB - OBJECTIVE: Suicide is the third leading cause of death among adolescents. Many suicidal youths treated in emergency departments do not receive follow-up treatment as advocated by the National Strategy for Suicide Prevention. Two strategies for improving rates of follow-up treatment were compared. METHODS: In a randomized controlled trial, suicidal youths at two emergency departments (N=181; ages ten to 18) were individually assigned between April 2003 and August 2005 to one of two conditions: an enhanced mental health intervention involving a family-based cognitive-behavioral therapy session designed to increase motivation for follow-up treatment and safety, supplemented by care linkage telephone contacts after emergency department discharge, or usual emergency department care enhanced by provider education. Assessments were conducted at baseline and approximately two months after discharge from the emergency department or hospital. The primary outcome measure was rates of outpatient mental health treatment after discharge. RESULTS: Intervention patients were significantly more likely than usual care patients to attend outpatient treatment (92% versus 76%; p=.004). The intervention group also had significantly higher rates of psychotherapy (76% versus 49%; p=.001), combined psychotherapy and medication (58% versus 37%; p=.003), and psychotherapy visits (mean 5.3 versus 3.1; p=.003). Neither the emergency department intervention nor community outpatient treatment (in exploratory analyses) was significantly associated with improved clinical or functioning outcomes. CONCLUSIONS: Results support efficacy of the enhanced emergency department intervention for improving linkage to outpatient mental health treatment but underscore the need for improved community outpatient treatment to prevent suicide, suicide attempts, and poor clinical and functioning outcomes for suicidal youths treated in emergency departments. PMID- 22211212 TI - Requiring sobriety at program entry: impact on outcomes in supported transitional housing for homeless veterans. AB - OBJECTIVE: An important distinction in models of housing for the homeless is whether programs that require abstinence prior to program admission produce better outcomes than unrestricted programs. Data from a large transitional housing program were used to compare client characteristics of and outcomes from programs requiring abstinence at admission and programs not requiring abstinence. METHODS: The U.S. Department of Veterans Affairs (VA) Northeast Program Evaluation Center provided records of individuals who were admitted into, and discharged from, the VA Grant and Per Diem program in 2003-2005. Records contained information from intake interviews, program discharge information, and descriptions of provider characteristics. Analyses were based on 3,188 veteran records, 1,250 from programs requiring sobriety at admission and 1,938 from programs without a sobriety requirement. Group differences were examined with t tests and chi square analyses; predictors of program outcome were determined with logistic regression. RESULTS: Individuals using drugs or alcohol at program admission had more problematic histories, as indicated by several general health and mental health variables, and shorter program stays. There were significant differences between groups in the frequency of program completion, recidivism for homelessness, and employment on program discharge, but effect sizes for these analyses were uniformly small and of questionable importance. Regression analyses did not find meaningful support for the importance of sobriety on program entry on any of the outcome measures. CONCLUSIONS: The results add evidence to the small body of literature supporting the position that sobriety on program entry is not a critical variable in determining outcomes for individuals in transitional housing programs. PMID- 22211213 TI - Health monitoring and promotion among youths with psychiatric disorders: program development and initial findings. AB - OBJECTIVE: This study examined initial results of a standardized program of health risk monitoring of a large group of youths with psychiatric disorders treated in outpatient and day-treatment settings. METHODS: The program was implemented at 48 outpatient clinics and day-treatment programs operated by 13 child and general psychiatric centers throughout New York State. At quarterly intervals from June 2009 to April 2010, all youths were screened for body mass index percentile and level of physical activity, and youths aged 13 years and older were also screened for cigarette smoking and alcohol and drug use. RESULTS: As of April 2010, a total of 2,095 youths were enrolled in the treatment programs, and an average of 79% or more had been screened for each health indicator. Rates of overweight (54%) and obesity (35%) were well above national norms and increased from preadolescence to adolescence. Approximately 37% of youths reported low levels of physical activity, which was associated with overweight and obesity (Cramer's v=.23). The rate of cigarette smoking was 19% statewide, in accord with national norms. Alcohol and drug use rates were low (10%) compared with national norms. CONCLUSIONS: This statewide program demonstrated that it is feasible to monitor general medical health among youths with psychiatric disorders on a large scale. Overweight and obesity are major problems among young psychiatric patients, and objective measures of these patients' health status should be employed whenever possible. PMID- 22211211 TI - A randomized trial of a nursing intervention for HIV disease management among persons with serious mental illness. AB - OBJECTIVE: The heightened risk of persons with serious mental illness to contract and transmit HIV is recognized as a public health problem. Persons with HIV and mental illness may be at risk for poor treatment adherence, development of treatment-resistant virus, and worse outcomes. The objective of this study was to test the effectiveness of a community-based advanced practice nurse (APN) intervention (PATH, Preventing AIDS Through Health) to promote adherence to HIV and psychiatric treatment regimens. METHODS: Community-dwelling HIV-positive participants with co-occurring serious mental illnesses (N=238) were recruited from community HIV provider agencies from 2004 to 2008 to participate in the randomized controlled trial. Participants in the intervention group (N=128) were assigned an APN who provided community-based care management at a minimum of one visit per week and coordinated clients' medical and mental health care for one year. Viral load and CD4 cell count were evaluated at baseline and 12 months. RESULTS: Longitudinal models for continuous log viral load showed that compared with the control group, the intervention group exhibited a significantly greater reduction in log viral load at 12 months (d=-.361 log 10 copies per milliliter, p<.001). Differences in CD4 counts from baseline to 12 months were not statistically significant. CONCLUSIONS: This project demonstrated the effectiveness of community-based APNs in delivering a tailored intervention to improve outcomes of individuals with HIV and co-occurring serious mental illnesses. Persons with these co-occurring conditions can be successfully treated; with appropriate supportive services, their viral loads can be reduced. PMID- 22211214 TI - Cardiovascular screening of people with severe mental illness in England: views of service users and providers. AB - OBJECTIVE: In England national clinical guidelines recommend annual screening for cardiovascular risk factors among individuals with schizophrenia and bipolar disorder within primary care supported by efforts to promote healthy behaviors by secondary psychiatric services. This study elicited the views of primary and specialty mental health care staff and service users about such service arrangements and barriers to implementation. METHODS: Surveys were mailed to a representative cross-section of service users, community mental health team (CMHT) staff, and primary care staff in Western England and London. RESULTS: Surveys were completed by 227 service users, 143 primary care staff, and 166 CMHT staff. A majority of staff stated that cardiovascular disease screening and risk reduction work were important, felt that this work was best accomplished in primary care settings, and anticipated good uptake among service users. More than 80% of service users viewed cardiovascular screening favorably, but 30% had not been screened in the past year. The proportion of service users prepared to make healthy changes in their lifestyle varied from 37% to 51%, depending on the change contemplated, but many cited difficulty traveling (35%), time pressures (28%), and a distaste for courses or group work (23%) as barriers to attending courses in healthy living. CONCLUSIONS: The obstacles to service identified by this study reinforce the importance of providing incentives for both providers and users of services to improve implementation of national clinical guidelines on mental illness. PMID- 22211215 TI - Intensity of outpatient monitoring after discharge and psychiatric rehospitalization of veterans with depression. AB - OBJECTIVE: This study assessed whether increased frequency of clinical monitoring during the high-risk period of 12 weeks after discharge from a psychiatric hospitalization reduced subsequent rehospitalization in a national cohort of Veterans Health Administration patients receiving depression treatment between 1999 and 2004. METHODS: A case-control design was used. Patients who had at least two inpatient psychiatric hospitalizations were identified (case group, N=17,852) and then individually matched with up to two patients who also had been discharged from psychiatric inpatient settings but were not rehospitalized for the number of days between the case-group patient's discharge and subsequent rehospitalization (N=35,511). RESULTS: Covariate-adjusted relative risk (RR) did not show an association between increased monitoring and subsequent psychiatric hospitalization, but there was a significant negative interaction between monitoring and a comorbid substance use disorder diagnosis (p<.001). Increased monitoring was positively associated with rehospitalization of patients without a substance use disorder, whereas increased monitoring was not associated with increased risk of rehospitalization of those with a comorbid substance use disorder. The RR of rehospitalization associated with a weekly monitoring visit (12 visits per 84 days) versus no monitoring visit was 1.14 for patients without a substance use disorder, whereas the RR was reduced to .94 for patients with a substance use disorder. CONCLUSIONS: Increased outpatient monitoring during the high-risk period after discharge appears to have a modest protective effect on rehospitalization among depressed patients with a comorbid substance use disorder. PMID- 22211216 TI - Six-month longitudinal patterns of mental health treatment utilization by older adults with depressive symptoms. AB - OBJECTIVE: Aims of the study were to describe behavioral health treatment utilization patterns of community-dwelling older adults with depressive symptoms over a six-month period and to identify factors associated with treatment use, guided by a theoretical model emphasizing the dynamic nature of treatment use patterns over time and social context. METHODS: A total of 144 participants >=65 years old with depressive symptoms completed an in-person baseline interview and six monthly telephone follow-up interviews. Outcomes at each follow-up included the use of antidepressants or counseling. Covariates included personal and social context variables. RESULTS: Approximately half of the participants (N=70, 48%) received no formal treatment (antidepressant prescription or counseling). Treatment use or nonuse did not change for most participants. More participants with severe symptoms received antidepressants (25%-37%) than did those with milder symptoms (10%-14%), although more participants in the latter group started (milder, 62%,versus severe, 49%) and stopped (milder, 77%, versus severe, 26%) antidepressant treatment at least once. Fewer individuals received counseling overall, with no clear patterns by symptom severity. In multivariate longitudinal analyses, treatment use at follow-up was independently associated with younger age, current major depressive episode, baseline use of antidepressant, intention to begin a new treatment at baseline, and receipt of advice to seek treatment. CONCLUSIONS: Over a six-month period, most older adults with depressive symptoms in this study continued their use or nonuse of mental health treatment. Demographic, need, attitudinal, and social variables were related to treatment use over time. Addressing intentions and providing advice may facilitate treatment seeking. PMID- 22211217 TI - Psychiatrist-patient verbal and nonverbal communications during split-treatment appointments. AB - OBJECTIVE: This study characterized psychiatrist and patient communication behaviors and affective voice tones during pharmacotherapy appointments with depressed patients at four community-based mental health clinics where psychiatrists provided medication management and other mental health professionals provided therapy ("split treatment"). METHODS: Audiorecordings of 84 unique pairs of psychiatrists and patients with a depressive disorder were analyzed with the Roter Interaction Analysis System, which identifies 41 discrete speech categories that can be grouped into composites representing broad conceptual communication domains. Cluster analysis identified psychiatrist communication patterns. T test and chi square analyses compared the clusters for verbal dominance, affective voice tone, and characteristics of psychiatrist and patients. RESULTS: On average, 53% of psychiatrist talk was devoted to partnering and relationship building, and 67% of patient talk was about biomedical subjects, such as depression symptoms, and psychosocial information giving. Psychiatrist communication patterns were characterized by two clusters, a biomedical-centered cluster that emphasized biomedical questions (eta2=.22, df=82, p<.001) and education or counseling (eta2=.20, df=82, p<.001) and a patient-centered cluster focused on psychosocial and lifestyle questions (eta2=.24, df=82, p<.001) and information giving (eta2=.17, df=82, p<.001). The patient-centered cluster was associated with patients' expression of distress, anger, or other negative affects (t=3.22, df= 82, p=.002). CONCLUSIONS: Psychiatrists devoted much of their talk to partnering and relationship building while maintaining a focus on symptoms or psychosocial issues. However, patient behaviors did not reflect a similar level of partnering. Future studies should identify psychiatrist communication behaviors that activate collaborative patient communications or improve treatment outcomes. PMID- 22211218 TI - Explaining rare acts of violence: the limits of evidence from population research. AB - After the tragic mass shooting in Tucson, experts struggled to explain why such horrific events occur, in order to prevent them in the future. The author argues that homicides perpetrated with firearms against strangers by individuals with mental disorders occur far too infrequently in the population to allow explanatory statistical modeling and predictability. However, from a public health perspective that seeks to reduce violence in populations, it is likely that efforts to improve treatment access, continuity, and adherence for people with serious mental illnesses will also prevent some violent episodes, even if it remains impossible to reliably predict which specific individuals would otherwise engage in the most serious acts of violence. PMID- 22211219 TI - The problem with optimism. PMID- 22211220 TI - Helping adults who are homeless gain disability benefits: the SSI/SSDI Outreach, Access, and Recovery (SOAR) program. AB - OBJECTIVE: Approval rates for first-time applications for Supplemental Security Income (SSI) and Social Security Disability Insurance (SSDI) among adults who are homeless can be as low as 10%. This study examined approval rates among applicants who were assisted by SSI/SSDI Outreach, Access, and Recovery (SOAR), a federal initiative to increase access to disability benefits among people who are homeless or at risk of homelessness and who have mental illness or other co occurring disorders. METHODS: Data were collected in 37 states that had participated in SOAR for at least one year. RESULTS: Of 8,978 applications assisted by SOAR, 6,558 (73%) were approved. The average number of days between application and decision was 91. SOAR was associated with increased access to housing and cost savings through increased Medicaid reimbursement. CONCLUSIONS: SOAR substantially increased access to SSI and SSDI entitlements for people with disabilities who experience or are at risk for homelessness. PMID- 22211221 TI - Implementing interpersonal and social rhythm therapy for mood disorders across a continuum of care. AB - OBJECTIVE: Interpersonal and social rhythm therapy (IPSRT) is an evidence-based psychotherapy for mood disorders. The goal of this quality improvement initiative was to demonstrate feasibility of implementing IPSRT across the continuum of outpatient and inpatient care within an academic medical center. METHODS: A multidisciplinary work group was convened to implement IPSRT in outpatient (N=48), inpatient (N=602), and intensive outpatient (N=68) programs of an academic medical center. Quality improvement performance markers (including symptoms and group attendance rates) were collected. RESULTS: Institutional preference for group treatments required adaptation of IPSRT from an individual to group psychotherapy format. Iterative problem solving and protocol development resulted in models of group IPSRT appropriate for each level of care. Performance outcome markers were favorable, indicating feasibility of implementation. CONCLUSIONS: At a single, multisite, urban, academic medical center, IPSRT proved a feasible evidence-based psychotherapy for implementation across levels of care in routine practice. PMID- 22211222 TI - Barriers to implementing the clinical guideline on borderline personality disorder in the Netherlands. AB - OBJECTIVE: This study determined the gap between actual care and optimal care (recommended in the clinical guideline) for patients with borderline personality disorder in the Netherlands. Factors that affected guideline implementation were identified. METHODS: Ten specialized mental health organizations participated in this cross-sectional study. The number and proportion of patients who received optimal diagnosis and treatment were calculated. Focus groups explored implementation barriers. RESULTS: Records of 422 patients with a diagnosis of borderline personality disorder were analyzed, and 315 records from six organizations contained the necessary data. Across the six organizations, most of these patients received this as an initial diagnosis (median 85%). However, only a minority received psychotherapy as a first-step treatment (median 23%). Capacity problems and organizational barriers were the main barriers to providing psychotherapy. CONCLUSIONS: Most patients with borderline personality disorder did not receive the recommended first-step treatment (psychotherapy). Care pathways may help improve efficiency and quality of care. PMID- 22211223 TI - A telepsychiatry solution for rural eastern Texas. Burke Center Mental Health Emergency Center, Lufkin, Texas. PMID- 22211224 TI - Culturally sensitive collaborative treatment of depression among Chinese Americans in primary care. Culturally Sensitive Collaborative Treatment program, South Cove Community Health Center, Boston, Massachusetts. PMID- 22211225 TI - Silver and Bronze Achievement Awards. PMID- 22211226 TI - Interpreting risk factors for violence in Australia. PMID- 22211228 TI - Arrest: the "front door" to long-term care? PMID- 22211229 TI - "No suicidal ideation": an inadequate managed care response. PMID- 22211230 TI - A Web-based system for monitoring patient flow in an emergency department. PMID- 22211238 TI - The selective mGluR5 agonist CHPG protects against traumatic brain injury in vitro and in vivo via ERK and Akt pathway. AB - Group I metabotropic glutamate receptors (mGluRs) have been implicated in the pathophysiology of central nervous system injury, but the role of mGluR5 in traumatic brain injury (TBI) remains unclear. In the present study, we investigated the neuroprotective potency of (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG), a selective mGluR5 agonist, for protecting against TBI in both in vitro and in vivo models. Primary cortical neurons were treated with 1 mM CHPG in an in vitro preparation 30 min before TBI, and 250 nM CHPG was injected into the right lateral ventricle of rats 30 min before TBI was induced in in vivo studies. The results showed that CHPG significantly attenuated lactate dehydrogenase (LDH) release and neuronal apoptosis and reduced lesion volume. Compared to the control or vehicle group, the phosphorylation levels of extracellular signal-regulated kinase (ERK) and Akt were increased in the presence of CHPG, even following the induction of TBI. Furthermore, treatment with either the ERK inhibitor PD98059 or Akt inhibitor LY294002 partially reversed the CHPG's neuroprotective effects. These data suggest that CHPG minimizes brain damage after induction of TBI both in vitro and in vivo, and that these protective effects were possibly mediated by activation of the ERK and Akt signaling pathways. Thus, potentiating mGluR5 activity with selective agonists such as CHPG may be useful for the treatment of traumatic brain injury. PMID- 22211239 TI - Nanog and beta-catenin: a new convergence point in EpSC proliferation and differentiation. AB - Skin tissue homeostasis is maintained by the balanced proliferation and differentiation of certain types of proliferating cells such as epidermal stem cells (EpSCs). The proliferation and differentiation of EpSCs are complex processes which are not well understood. This study aimed to find the internal relationship between the Nanog pathway and the Wnt/beta-catenin pathway in the proliferation and differentiation process of EpSCs. In brief, EpSCs were isolated from rat epidermis and cultured. The MTT assay, western blotting, polymerase chain reaction (PCR) and immunocytochemistry were performed during the proliferation and differentiation process of EpSCs. Our results showed that 10-7 M neuropeptide substance P could effectively stimulate proliferation of EpSCs and that a possible link exists between the Nanog pathway and the Wnt/beta-catenin pathway. PMID- 22211240 TI - Alternative splicing of apoptosis-related genes in imatinib-treated K562 cells identified by exon array analysis. AB - Imatinib is the therapeutic standard for newly diagnosed patients with chronic myeloid leukemia (CML). In these patients, imatinib has been shown to induce an apoptotic response specifically in cells expressing the oncogenic fusion protein BCR-ABL. Previous studies in our lab revealed that imatinib-induced apoptosis in K562 cells involves a shift in production of Bcl-x splice isoforms towards the pro-apoptotic Bcl-xs splice variant. Here, we report the findings from our subsequent study to identify other apoptosis-related genes that are differentially spliced in response to imatinib treatment. Gene expression profiling of imatinib-treated K562 cells was performed by the Affymetrix GeneChip Human Exon 1.0 ST array, and differences in exon-level expression and alternative splicing were analyzed using the easyExon software. Detailed analysis by reverse transcription-PCR (RT-PCR) and sequencing of key genes confirmed the experimental results of the exon array. Our results suggest that imatinib treatment of K562 cells causes a transcriptional shift towards alternative splicing in a large number of apoptotic genes. The present study provides insight into the molecular character of apoptotic leukemia cells and may help to improve the mechanism of imatinib therapy in patients with CML. PMID- 22211241 TI - Kanglaite attenuates UVB-induced down-regulation of aquaporin-3 in cultured human skin keratinocytes. AB - Ultraviolet (UV) radiation plays an important role in the pathogenesis of skin photoaging. Depending on the wavelength of UV, the epidermis is affected primarily by UVB. One major characteristic of photoaging is the dehydration of the skin. Membrane-inserted water channels (aquaporins) are involved in this process. In this study we demonstrated that UVB radiation induced aquaporin-3 (AQP3) down-regulation in cultured human skin keratinocytes. Kanglaite is a mixture consisting of extractions of Coix Seed, which is an effective anti neoplastic agent and can inhibit the activities of protein kinase C and NF kappaB. We demonstrated that Kanglaite inhibited UVB-induced AQP3 down-regulation of cultured human skin keratinocytes. Our findings provide a potential new agent for anti-photoaging. The related molecular mechanisms remain to be further elucidated. PMID- 22211242 TI - Females with angina pectoris have altered lipoprotein metabolism with elevated cholesteryl ester transfer protein activity and impaired high-density lipoproteins-associated antioxidant enzymes. AB - In order to investigate non-invasive biomarkers for angina pectoris (AP), we analyzed the lipid and protein composition in individual lipoproteins from females with angina pectoris (n=22) and age- and gender-matched controls (n=20). In the low-density lipoprotein (LDL) fraction, the triglycerides (TG) and protein content increased in the AP group compared to the control group. The AP group had lower total cholesterol (TC) and elevated TG in the high-density lipoprotein (HDL) fraction. In the AP group, cholesteryl ester transfer protein (CETP) activity was enhanced in HDL and LDL, while lecithin:cholesterol acyltransferase (LCAT) activity in HDL3 was almost depleted. Antioxidant activity was significantly decreased in the HDL3 fraction, with a decrease in the HDL2 particle size. In the HDL3 fraction, paraoxonase and platelet activating factor acetylhydrolase (PAF-AH) activity were much lower and the levels of CETP and apoC III were elevated in the AP group. The LDL from the AP group was more sensitive to cupric ion-mediated oxidation with faster mobility. In conclusion, the lipoprotein fractions in the AP group had impaired antioxidant activity and increased TG and apoC-III with structural and functional changes. PMID- 22211243 TI - Microregional antitumor activity of a small-molecule hypoxia-inducible factor 1 inhibitor. AB - Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that play crucial roles in the adaptation of cancer cells to hypoxia. HIF-1alpha overexpression has been associated with poor prognosis in patients with various types of cancer. Here, we describe ER-400583-00 as a novel HIF-1 inhibitor. ER 400583-00 suppressed the production of HIF-1alpha protein in response to hypoxia, with a half-maximal inhibitory concentration value of 3.7 nM in human U251 glioma cells. The oral administration of 100 mg/kg ER-400583-00 to mice bearing U251 tumor xenografts resulted in a rapid suppression of HIF-1alpha that persisted for 24 h. Immunohistochemical analysis revealed that ER-400583-00 suppressed the proliferation of cancer cells most prominently in areas distal to the region of blood perfusion, where HIF-1alpha-expressing hypoxic cancer cells were located. These hypoxic cancer cells were resistant to radiation therapy. ER-400583-00 showed a synergistic interaction with radiation therapy in terms of antitumor activity. These data suggest that HIF-1 blockade by small compounds may have therapeutic value in cancer, especially in combination with radiation therapy. PMID- 22211244 TI - Lipid metabolic pathways as lung cancer therapeutic targets: a computational study. AB - Inhibitors of lipid metabolic pathways, particularly drugs targeting the mevalonate pathway, have been suggested to be valuable in enhancing the effectiveness of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and these compounds may also be effective in patients with inherent or acquired resistance to EGFR-TKIs. The present study examined gene expression profiles in lung adenocarcinoma to characterize the interaction between growth factor signals and lipid metabolic pathways at the transcriptional level. Gene expression correlation analysis showed that genes involved in the mevalonate pathway and unsaturated fatty acid synthesis were negatively correlated with the expression of EGFR, MET and other growth factor receptor genes, as well as with the expression of genes involved in cell migration and adhesion. On the other hand, the expression of genes related to cell cycle progression, DNA repair and DNA replication were positively correlated with the metabolic pathway genes mentioned above, and a significant number of such genes had promoter domains for nuclear factor Y (NFY). Genes whose expression showed a positive correlation with NFY expression and mevalonate pathway genes were found to exhibit protein-protein interactions with several 'hub' genes, including BRCA1, that have been associated with both lung cancer and cell division. These results support the idea that inhibition of lipid metabolic pathways may be valuable as an alternative therapeutic option for the treatment of lung adenocarcinoma, and suggest that NFY is a possible molecular target for such efforts. PMID- 22211245 TI - MicroRNA-200a suppresses the Wnt/beta-catenin signaling pathway by interacting with beta-catenin. AB - The Wnt/beta-catenin signaling pathway is crucial for human organ development and is involved in tumor progression of many cancers. Accumulating evidence suggests that the expression of beta-catenin is, in part, regulated by specific microRNAs (miRNAs). The purpose of this study was to determine the expression of a recently identified epithelial to mesenchymal transition (EMT)-associated tumor suppressor microRNA (miR)-200a, in cancer cells. We also aimed to identify specific miR-200a target genes and to investigate the antitumor effects of miR-200a on the Wnt/beta catenin signaling pathway. We employed TOP/FOP flash luciferase assays to identify the effect of miR-200a on the Wnt/beta-catenin pathway and we confirmed our observations using fluorescence microscopy. To determine target genes of miR 200a, a 3' untranslated region (3' UTR) luciferase assay was performed. Cell viability, invasion and wound healing assays were carried out for functional analysis after miRNA transfection. We further investigated the role of miR-200a in EMT by Western blot analysis. We found fluctuation in the expression of miR 200a that was accompanied by changes in the expression of members of the Wnt/beta catenin signaling pathway. We also determined that miR-200a can directly interact with the 3' UTR of CTNNB1 (the gene that encodes beta-catenin) to suppress Wnt/beta-catenin signaling. MiR-200a could also influence the biological activities of SGC790 and U251 cells. Our results demonstrate that miR-200a is a new tumor suppressor that can regulate the activity of the Wnt/beta-catenin signaling pathway via two mechanisms. MiR-200a is a candidate target for tumor treatment via its regulation of the Wnt/beta-catenin signaling pathway. PMID- 22211246 TI - Involvement of p21waf1/cip1 expression in the cytotoxicity of the potent histone deacetylase inhibitor spiruchostatin B towards susceptible NALM-6 human B cell leukemia cells. AB - Spiruchostatin B (SP-B) is a potent histone deacetylase (HDAC) inhibitor that has potential for the chemotherapy of leukemia. The aim of this study was to study the susceptibility of human leukemia cell lines to SP-B. We found that NALM-6 human B cell leukemia cells are the most susceptible to SP-B. There was a low correlation between the expression of HDAC1 mRNA and HDI susceptibility of leukemia cells. NALM-6 has higher endogenous p21waf1/cip1 mRNA expression than other leukemia cells. SP-B-induced cytotoxicity was mediated by induction of histone acetylation via inhibition of HDACs, and this effect of SP-B was associated with apoptosis, which was mediated by caspase activation in NALM-6 cells. SP-B time-dependently increased the size of the sub-G1 (apoptotic) peak, and this effect correlated with SP-B induction of cellular apoptotic features such as changes in nuclear morphology. SP-B significantly increased p21waf1/cip1 expression prior to induction of apoptosis. In conclusion, NALM-6 cells, which have a higher expression of p21waf1/cip1 mRNA than other leukemia cell lines, were susceptible to SP-B-induced cytotoxicity that resulted in induction of apoptosis. Our findings may be useful when establishing a therapeutic strategy based on SP-B. PMID- 22211247 TI - Effect of hirudin on the levels of acute lung injury rat tumor necrosis factor alpha and matrix metalloproteinase-12. AB - The aim of this study was to observe the effect of hirudin on the expression of lung tissue protease activated receptor-1 (PAR-1) and the correlation between inflammation factors and the expression of PAR-1 after hirudin pre-treatment and to provide the theoretical basis for the treatment of lung injury by hirudin. Wistar rats of the model group were intraperitoneally administered endotoxin by injection (LPS 10 mg/kg) to copy acute lung injury (ALI) animal models, while the rats of the control group were injected with an equal amount of physiological saline. The rats of the hirudin groups were injected with hirudin and endotoxin intraperitoneally at the same time. The lung tissue was stained by HE dye to detect tumor necrosis factor alpha (TNF-alpha) and matrix metallo-proteinase 12 (MMP12) content. RT-PCR was applied to test PAR-1 mRNA expression. The results showed that the expression of PAR-1 mRNA of lung tissue increased significantly, but declined with the increased doses of hirudin when lung injury due to endotoxin occurred. The content of TNF-alpha and MMP12 was significantly lower compared to that of the endotoxin group. The difference was statistically significant (p<0.05). Hirudin reduced the release of TNF-alpha and MMP12 in mice by inhibiting the production of PAR-1 and reduced the content of TNF-alpha and MMP12. Thus, we deduced that hirudin inhibits the inflammation and fibrosis caused by lung injury and plays a role in lung protection as an anti-inflammatory mediator. PMID- 22211249 TI - Combat osteoarthritis with daily physical activity. Regardless of disease severity, exercise should be a vital part of every patient's daily routine. PMID- 22211248 TI - Upregulation of beta2-microglobulin expression in progressive human oral squamous cell carcinoma. AB - The aim of the present study was to investigate beta2-microglobulin (beta2-M) expression in normal oral mucosa and progressive oral squamous cell carcinoma (OSCC) and to assess the clinical significance of beta2-microglobulin expression. The study included 10 cases of normal oral mucosa epithelium specimens, 55 cases of primary OSCC specimens, and 25 cases of OSCC metastasis specimens. Immunohistochemistry was used to determine beta2-M expression, and its correlation with clinicopathological factors in progressive OSCC was evaluated. Immunohistochemistry showed that strong beta2-M expression was significantly asscociated with tumor size (T3, T4 vs. T1, T2; P=0.001), positive node status (N positive vs. N negative; P=0.000) and advanced clinical stage (III, IV vs. I, II, P=0.000) in primary OSCC lesions. Compared to primary OSCC lesions, the frequency of beta2-M expression was significantly increased in metastatic OSCC lesions (P=0.02). In addition, in vitro results from Western blotting showed increased beta2-M expression in the two OSCC lines studied. Therefore, we speculate that the up-regulation of beta2-M expression may contribute to the oncogenesis of human oral mucosa, tumor invasion and metastasis. PMID- 22211250 TI - Keep your heart healthy to help preserve communication skills. Cardiovascular disease, which can cause reduced blood flow, can affect how we understand and respond to spoken language. PMID- 22211252 TI - Practice positive activities to help overcome depression. Acts of kindness and a sense of optimism may help when meds or other treatments don't work, or are financially unavailable. PMID- 22211251 TI - Metabolic syndrome now linked to kidney disease. The five components that make up metabolic syndrome are deadly, but you can take steps to prevent or contain them. PMID- 22211253 TI - Start exercise early in life, to benefit your golden years. Physical activity throughout young and mid-adulthood helps preserve health and independence in later life. PMID- 22211254 TI - I've heard that another form of bad cholesterol has been discovered. What can you tell me about it? PMID- 22211255 TI - What are the health consequences of being under stress? Are there any non pharmacological ways to deal with stress? PMID- 22211256 TI - Why is it so important to get a flu shot every year? PMID- 22211257 TI - [Our approach to the education of Laboratory medicine]. PMID- 22211259 TI - Structural delineation of MDC1-FHA domain binding with CHK2-pThr68. AB - Mammalian MDC1 interacts with CHK2 in the regulation of DNA damage-induced S phase checkpoint and apoptosis, which is directed by the association of MDC1-FHA and CHK2-pThr68. However, different ligand specificities of MDC1-FHA have been reported, and no structure is available. Here we report the crystal structures of MDC1-FHA and its complex with a CHK2 peptide containing pThr68. Unlike other FHA domains, MDC1-FHA exists as an intrinsic dimer in solution and in crystals. Structural and binding analyses support pThr+3 ligand specificity and provide structural insight into MDC1-CHK2 interaction. PMID- 22211260 TI - Coatings capable of germinating and neutralizing Bacillus anthracis endospores. AB - Endospores are formed by various bacterial families, including Bacillus and Clostridium, in response to environmental stresses as a means to survive conditions inhospitable to vegetative growth. Although metabolically inert, the endospore must interact with its environment to determine an optimal time to return to a vegetative state, a process known as germination. Germination has been shown to occur in response to a variety of chemical stimuli from specific nutrient germinants including amino acids, sugars and nucleosides. This process is known to be mediated primarily by the GerA family of spore-specific receptor proteins which initiates a signal transduction cascade that results in a return of oxidative metabolism in response to germinant receptor interactions. Herein, we report the development of a novel coating system capable of germinating B. anthracis endospores, followed by rapid killing of the vegetative bacteria by a novel incorporated amphiphilic biocide. The most effective formulation tested exhibited an ability to germinate and kill B. anthracis endospores and vegetative bacteria, respectively. The formulation reported resulted in a 90% reduction in as little as 5 min, and a 6 log reduction by 45 min. PMID- 22211272 TI - Differential immunotoxic effects of ethanol on murine EL-4 lymphoma and normal lymphocytes is mediated through increased ROS production and activation of p38MAPK. AB - Ethanol has been used to achieve thymic depletion in myasthenia gravis patients. Ethanol (95%) has also been used widely in the therapy of many tumors including hepatocellular carcinoma. In light of these findings, we delineated the differential immunotoxic behavior and mechanism of lower concentration of ethanol towards murine EL-4 lymphoma and its normal counterpart lymphocytes. EL-4 lymphoma and normal lymphocytes were cultured with ethanol (0%-5%) for 6 h and cytotoxicity was measured by various methods. EL-4 cells treated with ethanol showed concentration-dependent loss of viability at 2%-5% ethanol concentration and exhibit proliferative arrest at preG1 stage. Acridine-orange and ethidium bromide staining indicated that ethanol induced death in EL-4 cells, by induction of both apoptosis and necrosis which was further supported by findings of DNA fragmentation and trypan blue dye exclusion test. However, treatment of lymphocytes with similar concentration of ethanol did not show any death associated parameters. Furthermore, ethanol induced significantly higher ROS generation in EL-4 cells as compared to lymphocytes and caused PARP cleavage and activation of apoptotic proteins like p53 and Bax, in EL-4 cells and not in normal lymphocytes. In addition, ethanol exposure to EL-4 cells led to phosphorylation of p38MAPK, and upregulation of death receptor Fas (CD95). Taken together, these results suggest that ethanol upto a concentration of 5% caused no significant immunotoxicity towards normal lymphocytes and induced cell death in EL-4 cells via phosphorylation of p38MAPK and regulation of p53 leading to further activation of both extrinsic (Fas) and intrinsic (Bax) apoptotic markers. PMID- 22211273 TI - Abolition of endocrine dimorphism in hyperthyroid males? An argument for the positive feedback effect of hyperoestrogenaemia on LH secretion. AB - Our aim was (i) to investigate the hypothalamo-hypophyseal-gonadal axis in hyperthyroid Indian males, (ii) to rule out the modulatory role of adrenal steroids on it and (iii) to determine if the simultaneous rise in oestradiol and luteinising hormone (LH) in hyperthyroid males is due to a positive feedback action of oestradiol on pituitary LH release. Age- and BMI-matched men were divided into two groups, I, euthyroid subjects (n = 17) and II, hyperthyroid patients (n = 12) on the basis of their thyroid hormone levels. Serum levels of thyroid-stimulating hormone, triiodothyronine, thyroxine, LH, follicle stimulating hormone (FSH), prolactin, E(2), T, P(4), sex hormone binding globulin and dehydroepiandrosterone sulphate (DHEAS) were assayed. Mean levels of T and E(2) were approximately two times higher in group II in comparison with group I. DHEAS levels were similar in both groups ruling out any adrenal involvement. Mean serum LH level was 2.6 folds higher in group II in comparison with group I. Mean serum levels of FSH were higher in group II, it was marginally nonsignificant. On the basis of these and previous observations, we hypothesise that endocrinological dimorphism in human male and female is not rigid; a sustained rise in serum oestradiol probably induces a positive feedback action on pituitary leading to elevated gonadotrophin levels. PMID- 22211274 TI - What made me feel better? Patients' own explanations for the improvement of their depression. AB - BACKGROUND: Depression is common among primary care patients and the usual treatment often consists of antidepressant medication and supportive counselling/follow-ups. Previous studies have shown that patients and professionals have different beliefs about treatment, which in turn can decrease acceptance of the diagnosis, compliance and treatment outcome. AIMS: The purpose of this study was to investigate previously depressed patients' beliefs about the cause of their improvement. METHODS: Depressed primary care patients (n = 184) who considered themselves improved at follow-up answered an open-ended question about what they believed had made them better. Among these 117 patients had, in addition to treatment as usual, participated in an intervention with patient education and group counselling (the Contactus programme), whereas 67 were controls. The groups were comparable at baseline and 82% were on antidepressants. RESULTS: In total, the patients mentioned 14 separate improving factors, which could be organized to the larger themes external factors, self-management, passing spontaneously and professional help. The most frequently mentioned factors for improvement were the Contactus programme (53.0%), antidepressants (40.2%) and personal development (27.2%). Few gender and age differences were seen. The controls who mentioned professional help were more likely to have a better outcome. CONCLUSIONS: The patients were generally positive to professional help such as antidepressants and the Contactus programme. Patient education and group counselling seems to be a valuable supplement to treatment of depressed patients in primary care. PMID- 22211275 TI - Computational modelling of locomotor muscle moment arms in the basal dinosaur Lesothosaurus diagnosticus: assessing convergence between birds and basal ornithischians. AB - Ornithischia (the 'bird-hipped' dinosaurs) encompasses bipedal, facultative quadrupedal and quadrupedal taxa. Primitive ornithischians were small bipeds, but large body size and obligate quadrupedality evolved independently in all major ornithischian lineages. Numerous pelvic and hind limb features distinguish ornithischians from the majority of other non-avian dinosaurs. However, some of these features, notably a retroverted pubis and elongate iliac preacetabular process, appeared convergently in maniraptoran theropods, and were inherited by their avian descendants. During maniraptoran/avian evolution these pelvic modifications led to significant changes in the functions of associated muscles, involving alterations to the moment arms and the activation patterns of pelvic musculature. However, the functions of these features in ornithischians and their influence on locomotion have not been tested and remain poorly understood. Here, we provide quantitative tests of bipedal ornithischian muscle function using computational modelling to estimate 3D hind limb moment arms for the most complete basal ornithischian, Lesothosaurus diagnosticus. This approach enables sensitivity analyses to be carried out to explore the effects of uncertainties in muscle reconstructions of extinct taxa, and allows direct comparisons to be made with similarly constructed models of other bipedal dinosaurs. This analysis supports some previously proposed qualitative inferences of muscle function in basal ornithischians. However, more importantly, this work highlights ambiguities in the roles of certain muscles, notably those inserting close to the hip joint. Comparative analysis reveals that moment arm polarities and magnitudes in Lesothosaurus, basal tetanuran theropods and the extant ostrich are generally similar. However, several key differences are identified, most significantly in comparisons between the moment arms of muscles associated with convergent osteological features in ornithischians and birds. Craniad migration of the iliofemoralis group muscles in birds correlates with increased leverage and use of medial femoral rotation to counter stance phase adduction moments at the hip. In Lesothosaurus the iliofemoralis group maintains significantly higher moment arms for abduction, consistent with the hip abduction mode of lateral limb support hypothesized for basal dinosaurs. Sensitivity analysis highlights ambiguity in the role of musculature associated with the retroverted pubis (puboischiofemoralis externus group) in ornithischians. However, it seems likely that this musculature may have predominantly functioned similarly to homologous muscles in extant birds, activating during the swing phase to adduct the lower limb through lateral rotation of the femur. Overall the results suggest that locomotor muscle leverage in Lesothosaurus (and by inference basal ornithischians in general) was more similar to that of other non-avian dinosaurs than the ostrich, representing what was probably the basal dinosaur condition. This work thereby contradicts previous hypotheses of ornithischian-bird functional convergence. PMID- 22211276 TI - Response to 'A controversial consensus'; by the International Consensus Panel. PMID- 22211277 TI - Long-term survival, autonomy, and quality of life of elderly patients undergoing aortic valve replacement. AB - AIMS: We reviewed the long-term survival, autonomy, and quality of life (QoL) of elderly patients undergoing aortic valve replacement (AVR). METHODS: Records of patients >=75 years old that underwent AVR from 2002 to 2006 were retrospectively analyzed. Functional status was classified with Barthel Index (BI). QoL was presumed as the self-perception of well-being after AVR. Independent predictors of mortality were identified using the Cox proportional hazards model. RESULTS: We included 114 patients, with a mean age of 78.5 +/- 2.5 years. Seventy (59.8%) patients were females. Mean additive and logistic EuroSCORE were 7 +/- 2 and 9 +/ 7, respectively. Follow-up on vital status was achieved for 113 (99.1%) patients after a mean period of 47.2 +/- 23.4 months. Twenty-seven (23.7%) patients died (including three operative deaths). Survival up to one, three, and five years of follow-up was 94.4%, 86.7%, and 76.1%, respectively. Multivariate analysis showed that pulmonary hypertension and diabetes were independent predictors of all-cause mortality. Information on BI score and QoL was obtained for 77 (89.5%) and patients. Among those, 69 (89.6%) were autonomous according to BI and 72 (93.5%) considered having had an improvement in QoL. CONCLUSION: Patients >=75 years old undergoing AVR presented good medium-term survival. Predictors of an adverse outcome were significant pulmonary hypertension and diabetes. At follow-up, most achieved improvement of QoL and remained autonomous. These results stress that excellent long-term outcomes with AVR can be achieved in appropriately selected elderly patients. PMID- 22211278 TI - Soya-lecithin in extender improves the freezability and fertility of buffalo (Bubalus bubalis) bull spermatozoa. AB - Egg yolk is routinely used as a cryoprotectant in semen extenders. However, it may contain cryoprotective antagonists, and there are hygienic risks associated with its use. Proteins of plant origin, like soya-lecithin, lack these hazards. The aim of this study was to use soya-lecithin as a cryoprotectant in extender and to investigate its effects on in vitro quality and in vivo fertility of buffalo semen. Semen from three buffalo bulls was frozen in tris-citric extender containing 5.0%, 10% or 15% soya-lecithin or 20% egg yolk. Sperm motility, plasma membrane integrity and viability were assessed post-dilution, pre-freezing and post-thaw. In Post-dilution and pre-freezing, the values for motility, plasma membrane integrity and viability remained higher (p <= 0.05) in extenders containing 10% soya-lecithin and control compared with extender containing 5% and 15% soya-lecithin. However, motility, plasma membrane integrity and viability were higher (p < 0.05) in extender containing 10% soya-lecithin compared with control and extenders containing 5% and 15% soya-lecithin. Semen from two buffalo bulls was frozen in tris-citric extender containing either 10% soya-lecithin or 20% egg yolk. Higher (p < 0.05) fertility rate was recorded in buffaloes inseminated with semen containing 10% soya-lecithin (56%) compared with 20% egg yolk (41.5%). The results suggest that 10% soya-lecithin in extender improves the freezability and fertility of buffalo bull spermatozoa and can be used as an alternate to egg yolk in cryopreservation of buffalo semen. PMID- 22211279 TI - Cisplatin- and dietary ascorbic acid-mediated changes in the mitochondria of Dalton's lymphoma-bearing mice. AB - Cisplatin treatment caused a significant increase in the life span of ascites Dalton's lymphoma (DL) Tumor-bearing (TB) mice. However, as compared to cisplatin (CP) alone, combination treatment with ascorbic acid plus CP resulted in better therapeutic efficacy against murine DL. Cisplatin treatment of TB mice resulted in the appearance of thickened and irregular arrangement of mitochondrial cristae in the liver, kidney and DL tumor cells. Combination treatment of the hosts with ascorbic acid and CP lessened deformities in the mitochondria of liver and kidney, while in tumor cells, this increased the formation of vacuoles and disruption in mitochondrial cristae. Cisplatin treatment decreased the succinate dehydrogenase (SDH) activity in the mitochondria of kidney and DL cells and combination treatment caused further decrease in SDH activity in kidney and DL cells during 24-48 h of treatment. After CP treatment, the protein content in the mitochondria of these tissues decreased, and during combination treatment, it showed significant improvement. Mitochondrial lipid peroxidation (LPO) increased in these tissues after CP treatment. However, combination treatment significantly decreased mitochondrial LPO in liver and kidney but increased in DL cells. This increase in mitochondrial LPO in DL cells and decrease in liver and kidney could play an important role in the antitumor activity of combination treatment and at the same time reduce CP-induced toxicity in the host. However, further study may be desirable to explore some aspects of the mechanism(s) involved in these changes in mitochondria. PMID- 22211280 TI - Social cognition in euthymic bipolar disorder: systematic review and meta analytic approach. AB - OBJECTIVE: Deficits in social cognition have been reported in euthymic subjects with bipolar disorder (BD). However, some studies have failed to find differences favoring controls. As most investigations have been conducted with small samples, they have not had sufficient power to detect statistically significant differences. Furthermore, studies communicating positive results have scarcely attempted to estimate effect sizes for patient-control differences. The aim of this study was to summarize the findings of reports on social cognition in patients with euthymic BD and to combine their data to identify possible deficits and quantify their magnitude. METHOD: Systematic literature review and meta analysis. RESULTS: Impairments of moderate magnitude (0.5 < d < 0.8) were noted across mentalizing skills, whereas small but significant effect sizes (d < 0.5) were observed for facial emotion recognition. No patient-control differences were found for decision-making. CONCLUSION: Meta-analytic findings provide evidence for emotion processing and theory of mind deficits in remitted bipolar patients. However, it is not yet clear whether these areas of impairment are related to neurocognitive dysfunctions or to medication effects. The results are discussed with regard to targets for future neuropsychological research on BDs. PMID- 22211281 TI - AIDS knowledge and beliefs related to blood donation in US adults: results from a national telephone survey. AB - BACKGROUND: Misperceptions about the risk of contracting AIDS from donating blood may be preventing people from donating, while incorrect beliefs about AIDS screening tests or the appropriateness of donating with risk factors may place the blood supply at increased risk. STUDY DESIGN AND METHODS: Questions about AIDS transmission and testing and the acceptability of test seeking and donating with risk factors were asked in the National Community Health Survey, a telephone survey of 9859 US adults. Results were weighted to represent the US population. Demographic and donor status (current, lapsed, never) differences in knowledge and attitudes were examined using chi-square and logistic regression. RESULTS: Nearly 25% of respondents thought it was somewhat or very likely that they could get AIDS from donating blood. Almost 80% knew that all blood donations are tested for AIDS, but only 65.5% knew about the test window period. A total of 33.5% felt that it was acceptable to use the blood center for AIDS testing, while 9.1% believed that it was okay for someone to donate even if they had AIDS risk behaviors; all had significant demographic and donor status differences. CONCLUSIONS: While there are many factors that prevent people from giving blood, the incorrect belief that it is possible to contract AIDS from donating is likely a barrier to donation. If blood centers dispelled this myth among those who have never donated, especially among minorities, it could be important for recruitment. In addition, our findings indicate that changes to education or recruitment could be needed to discourage test seeking and donations from risky donors. PMID- 22211282 TI - Changing of the guard. PMID- 22211283 TI - Expression of deleted in malignant brain tumours 1 (DMBT1) relates to the proliferation and malignant transformation of hepatic progenitor cells in hepatitis B virus-related liver diseases. AB - AIMS: The molecular mechanisms underlying proliferation and malignant transformation of hepatic progenitor cells (HPCs) remain largely unknown. The purpose of this study was to evaluate the correlation between the expression of deleted in malignant brain tumours 1 (DMBT1) and the biological behaviour of HPCs in different hepatitis B virus (HBV)-related human liver diseases. METHODS AND RESULTS: Expression of DMBT1 in HPCs was investigated by double immunofluorescence labelling in control-group and HBV-related liver diseases, including hepatitis, hepatocellular carcinoma (HCC), non-tumoral liver tissue away from HCC, non-tumoral cirrhotic tissue adjacent to HCC, and non-HCC cirrhosis. DMBT1-positive HPCs were isolated by laser capture microdissection and subjected to duplex polymerase chain reaction in order to detect homozygous deletion of DMBT1. The number of DMBT1-positive HPCs increased in direct proportion to inflammation severity. Loss of heterozygosity for DMBT1 was more frequent in HCC tumour area and non-tumoral cirrhotic tissue adjacent to HCC, compared with other HBV-related liver diseases (P < 0.05). CONCLUSIONS: DMBT1 may play an important role in the proliferation of HPCs in HBV-related liver diseases. Moreover, down-expression of DMBT1 might enhance the risk of malignant transformation of HPCs. PMID- 22211284 TI - Follicular cholangitis and pancreatitis - clinicopathological features and differential diagnosis of an under-recognized entity. AB - AIMS: Biliary and pancreatic ductal systems can be involved in several lymphoplasmacytic inflammatory conditions, including primary sclerosing cholangitis, immunoglobulin G (IgG) 4-related cholangitis and autoimmune pancreatitis. Here in we describe an unusual pancreatocholangitis whose features suggest a distinct disease entity. METHODS AND RESULTS: The study group consists of five adult patients, three with predominantly hilar bile duct stricture and two with a bulky pancreatic head. Four patients were treated surgically for suspected malignancy and one patient underwent liver transplantation with a clinical diagnosis of primary sclerosing cholangitis. Histological examination revealed extensive lymphoplasmacytic inflammation centred on large biliary or pancreatic ducts. Many lymphoid follicles with germinal centres were noted around the affected ducts. Whipple specimens from two patients with a pancreatic head mass showed similar follicular inflammation histologically around bile ducts. In contrast to autoimmune pancreatitis, diffuse infiltration of IgG4(+) plasma cells, granulocytic epithelial lesions and obliterative phlebitis were not identified. The postoperative course was uneventful, without evidence of recurrence (follow-up period 17-65 months). CONCLUSIONS: This study suggests that a disease entity which can be named follicular cholangitis and pancreatitis exists and may be under-recognized. The disease mainly affects the hilar bile ducts and pancreatic head in adults. PMID- 22211285 TI - Fibrosis distribution in explanted cirrhotic livers. AB - AIMS: Little information is available regarding the distribution of fibrosis within cirrhotic livers. We measured collagen in cirrhotic explants to determine if fibrosis differs (i) between left (L) and right (R) lobes, and (ii) between different aetiologies. METHODS AND RESULTS: Ten cases each of common aetiologies of cirrhosis were studied: alcoholic liver disease (ALD), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), hepatitis C virus (HCV) and hepatitis B virus (HBV). A total of 120 tissue blocks (one block each from L and R lobes) were studied. Collagen was measured as collagen proportionate area (CPA), i.e. the proportion of the tissue sections stained by picro-Sirius red. L and R lobes contained similar amounts of fibrosis (r = 0.788; P < 0.0001) with good agreement between L and R lobes (Bland-Altman analysis, R lobe bias = 1.35%). Median CPA across all aetiologies (R plus L lobes) was 21.5%, (L = 8-40%, R = 10-47%). There was more fibrosis in ALD (30%, 15-47%) than PBC (23.5%, 16-34%) and PSC (22.5%, 8-33%), which in turn showed more than AIH (18.5%, 10-40%), HCV (17%, 13-31%) and HBV (16.5%, 8-30%). CONCLUSIONS: At the time of transplantation cirrhotic livers have different ranges of collagen proportionate area, according to aetiology. R lobe fibrosis corresponds with L lobe fibrosis. The range of fibrosis within each aetiological group could be useful for prognostic subclassification. PMID- 22211286 TI - Insulin-like growth factor II mRNA-binding protein 3 (IMP3) expression in hepatocellular carcinoma. A clinicopathological analysis with emphasis on diagnostic value. AB - AIMS: Patients with hepatocellular carcinoma (HCC) usually present with advanced disease and rarely qualify for curative therapy. Immunohistochemical markers that help to discriminate benign from malignant processes early, and that have prognostic significance, would be useful. Expression of the oncofetal protein insulin-like growth factor II mRNA-binding protein 3 (IMP3) in malignant cells of different tumour types correlates with reduced overall survival. METHODS AND RESULTS: Tissue microarrays (TMAs) containing 55 normal liver samples, 365 HCCs (122 with corresponding non-tumorous liver), 10 hepatocellular adenomas, 13 focal nodular hyperplasias and nine dysplastic nodules from western European patients were stained for IMP3. IMP3 was analysed in 61 core needle biopsies and findings were compared to glypican-3 and CD34. HCCs in TMAs were strongly positive for IMP3 in 18.4% of cases compared to absent expression in normal and non-tumorous liver tissue and benign liver tumours. Patients with IMP3 expression in HCCs showed significantly poorer overall survival in multivariate analysis (P = 0.044). Of the 61 core needle biopsies analysed, 32 (52.5%) of the HCCs were IMP3 positive. CONCLUSIONS: In core needle biopsies, IMP3 expression seems to be of limited use as a single marker for the diagnosis of HCC, given a sensitivity of 52%, but it may be helpful in combination with other markers. PMID- 22211287 TI - Intramucosal variant of nasal natural killer (NK)/T cell lymphoma has a better survival than does invasive variant: implication on loss of E26 transformation specific sequence 1 (ETS-1) and T-box expressed in T cells (T-bet) with invasion. AB - AIMS: Nasal natural killer/T cell lymphoma (NNKTCL) arises from the nasal mucosa, and spreads to adjacent tissues via local invasion or to regional lymph nodes and distant sites via metastasis. The aims of this study were to determine the impact of invasion on the prognosis of NNKTCL, and correlate invasion with the expression of cytotoxic markers of lymphoma cells. METHODS AND RESULTS: Histopathological evaluations of invasion and immunohistochemistry for cytotoxic markers, including E26 transformation-specific sequence 1 (ETS-1), T-box expressed in T cells (T-bet), signal transducer and activator of transcription (STAT-1), CD56 and granzyme B (GB), were performed in 64 NNKTCLs. There were 17 stage I cases without invasion (stage Ia or intramucosal), 21 stage I cases with invasion (stage Ib), 16 stage II cases and 10 stages III/IV cases. Stage Ia NNKTCLs had a better 5-year overall survival rate than that of stages Ib, II or III/IV NNKTCLs (85%, 38%, 33% and 20%, respectively, P < 0.001 by log-rank test). Loss of ETS-1 was found in 24% (four of 17) stage Ia NNKTCLs and in 65% (28 of 43) stages Ib/II/III/IV NNKTCLs (P = 0.04, Fisher's exact test); loss of T-bet was found in 29% (five of 17) stage Ia NNKTCLs and in 67% (30 of 45) stages Ib/II/III/IV NNKTCLs (P = 0.02, Fisher's exact test). CONCLUSIONS: NNKTCL is classically an aggressive lymphoma, but the intramucosal variant is less aggressive. Loss of ETS-1 or T-bet correlated weakly with invasion, a finding that requires further confirmation. PMID- 22211288 TI - Ocular adnexal IgG4-related disease: comparative analysis with mucosa-associated lymphoid tissue lymphoma and other chronic inflammatory conditions. AB - AIMS: Making a differential diagnosis of IgG4-related disease from mucosa associated lymphoid tissue (MALT) lymphoma or any other chronic inflammation is often challenging. Moreover, the association with secondary lymphoma of ocular adnexal IgG4-related disease needs to be elucidated. METHODS AND RESULTS: We investigated 14 cases of IgG4-related disease, nine MALT lymphomas and 12 other chronic inflammations involving the lacrimal gland and orbit. Bilateral involvement was frequent in IgG4-related diseases. The number of IgG4-positive cells and the ratio of IgG4/IgG-positive cells were higher in patients with IgG4 related disease than in those with MALT lymphoma (P = 0.016; P < 0.001) and other types of inflammation (P < 0.001; P < 0.001). Monoclonal B cell proliferation was suspected in two cases (14.3%) of IgG4-related disease. One of these patients also displayed monomorphous features suggesting secondary MALT lymphoma. In the other case, kappa-chain restriction in IgG4-positive cells was observed, raising the possibility of IgG4-producing MALT lymphoma. Trisomy 3, trisomy 18 or MALT1 translocation was observed in none of the IgG4-related cases. Regulatory T-cell infiltration was higher in cases of IgG4-related disease than in MALT lymphomas (P < 0.001) and other types of inflammation (P = 0.006). CONCLUSIONS: Some genetically and morphologically complicated cases of ocular adnexal IgG4-related disease emphasize the need for in-depth studies to differentiate this disease from MALT lymphoma, and to exclude secondary lymphoma. PMID- 22211289 TI - Tumour-associated macrophages in diffuse large B-cell lymphoma: a study of the Osaka Lymphoma Study Group. AB - AIMS: To evaluate the role of tumour-associated macrophages (TAMs) of the M1 and M2 types in the behaviour of diffuse large B-cell lymphoma (DLBCL). METHODS AND RESULTS: Double immunohistochemical staining of HLA-DR/CD68 (M1) or CD163/CD68 (M2) was performed in 101 cases of DLBCL. CD68+ cells represent the total number of TAMs. The average number of double-positive cells was counted, and the cut-off value was set at the mean number of counts, i.e. 30.7 and 27.0 for M1 TAMs and M2 TAMs, respectively. That for total TAMs was set at the 90th percentile number of total counts, i.e. 132.3. Cases were categorized into three pairs: high (34 cases) and low (67 cases) M1 TAM groups, high (39 cases) and low (62 cases) M2 TAM groups, and high (10 cases) and low (91 cases) total TAM groups. The difference in overall survival rates was statistically significant between the high and low M2 TAM groups (P < 0.01) and between the high and low total TAM groups (P < 0.05). Multivariate analysis revealed that the presence of a bulky mass and a higher number of M2 TAMs were significant factors for poor prognosis (P < 0.05). CONCLUSIONS: Estimation of specific type of macrophages, of the M1 and M2 types, is superior to the estimation of TAMs as a whole (CD68+ cells) for prediction of the prognosis of DLBCL patients. PMID- 22211290 TI - Osteopontin predicts the behaviour of atypical meningioma. AB - AIM: Although the World Health Organization (WHO) histological criteria distinguishing benign from atypical and malignant meningioma are clear, discerning benign from atypical meningioma is still somewhat difficult, leading to interobserver diagnostic variability. Osteopontin (OPN) and cortactin play important roles in tumorigenesis, invasion and metastasis of several human cancers. The aim of this study was to evaluate the usefulness of OPN and cortactin immunohistochemistry for distinguishing between benign, atypical and malignant meningioma and predicting their recurrence. METHODS AND RESULTS: Seventy-five specimens (48 benign, 17 atypical and 10 malignant meningiomas) were investigated immunohistochemically. The mean immunohistochemical scoreimmunohistochemical score +/- SE of the mean of both OPN and cortactin were significantly higher in grade II or grade III meningiomas than in grade I meningioma. Discriminant analysis of immunohistochemical OPN expression showed correct classification of 97.7% of WHO grade I meningiomas and 88.2% of WHO grade II meningiomas (95.4% accuracy). However, the same analysis of cortactin expression showed correct classification of 95.8% of WHO grade I meningiomas and only 23.5% of WHO grade II meningiomas (76.9% accuracy). A cut-off for predicting grades I and II meningioma recurrence was determined for OPN (3.0) but not for cortactin. Finally, logistic regression identified both this cut-off (P < 0.05) and WHO grade (P < 0.05) as independent risk factors for recurrence. CONCLUSIONS: OPN expression is a valuable marker for diagnosis of atypical meningioma and prediction of grades I and II meningioma recurrence. PMID- 22211291 TI - Pathology and virology findings in cases of fatal influenza A H1N1 virus infection in 2009-2010. AB - AIMS: To describe the pathological findings, immunohistochemical localization of viral antigen and tissue reverse transcriptase polymerase chain reaction (RT-PCR) findings of different organs in cases of fatal H1N1 influenza virus infection from North India. METHODS AND RESULTS: Nine patients positive for H1N1 virus by a throat swab real-time RT-PCR (rRT-PCR) were included. Underlying risk factors included pregnancy, respiratory diseases, rheumatic heart disease, and chronic kidney disease. Pathological evidence of tracheitis, necrotizing bronchiolitis and diffuse alveolar damage was noted in all of the cases. Influenza viral antigen was observed by immunohistochemistry in the epithelium of the tracheobronchial tree, bronchial glands, gland ducts, and, less frequently, the alveolar epithelial cells. Viral particles were confirmed by electron microscopy in three autopsy cases. Tissue rRT-PCR for H1N1 viral RNA was positive in lung samples, but negative in other organs. Secondary bacterial pneumonia, cytomegalovirus infection and angio-invasive zygomycosis were detected. CONCLUSIONS: The pulmonary findings are similar to those described in past pandemics. Secondary fungal and viral infections, which have not been reported previously, were noted. Although the number of cases in this study is small, the findings reinforce the notion that changes in extrapulmonary organs are attributable to multiorgan dysfunction syndrome rather than a viral cytopathic effect, and that there is no transplacental transmission of virus. PMID- 22211292 TI - Presence of cytogenetic abnormalities in Spitz naevi: a diagnostic challenge for fluorescence in-situ hybridization analysis. AB - AIMS: Spitz naevi are difficult to diagnose, because of significant overlap with melanomas. It has been recently demonstrated that the LSI RREB1(6p25)/LSI MYB(6q23)/LSI CCND1(11q13)/CEP6 fluorescence in-situ hybridization (FISH) assay is a reliable tool with which to distinguish benign naevi and melanomas. Little is known about its diagnostic usefulness in Spitz naevi. METHODS AND RESULTS: We investigated 51 patients with Spitz naevi and long-term median follow-up (8.18 years) with the multicolour FISH probe. Control groups included 11 benign naevi and 14 melanomas. Spitz naevi from 32 (63%) patients did not show cytogenetic abnormalities (FISH-). In contrast, Spitz naevi from 19 (37%) patients showed changes in the investigated loci (FISH+). Spitz naevi with the FISH+ profile showed chromosome X polysomy in 14/18 (78%) patients. All Spitz naevi with the FISH- profile were disomic. All melanomas displayed a FISH+ profile, and 4/11 (36%) showed chromosome X polysomy. No differences in clinicopathological features were detected between Spitz naevi with and without genetic abnormalities. CONCLUSIONS: The presence of gene copy number changes in Spitz naevi as detected by FISH is higher than expected, and Spitz naevi at the genetic level represent a heterogeneous group. The findings of similar cytogenetic alterations in Spitz naevi and melanomas suggest that there should be cautious interpretation of FISH analysis in this setting. PMID- 22211294 TI - Guidelines for the identification of unknown samples for laboratories performing forensic analyses for chemical terrorism. AB - Since the early 1990s, the FBI Laboratory has sponsored Scientific Working Groups to improve discipline practices and build consensus among the forensic community. The Scientific Working Group on the Forensic Analysis of Chemical, Biological, Radiological and Nuclear Terrorism developed guidance, contained in this document, on issues forensic laboratories encounter when accepting and analyzing unknown samples associated with chemical terrorism, including laboratory capabilities and analytical testing plans. In the context of forensic analysis of chemical terrorism, this guidance defines an unknown sample and addresses what constitutes definitive and tentative identification. Laboratory safety, reporting issues, and postreporting considerations are also discussed. Utilization of these guidelines, as part of planning for forensic analysis related to a chemical terrorism incident, may help avoid unfortunate consequences not only to the public but also to the laboratory personnel. PMID- 22211293 TI - Prevalence of the CTNNB1 mutation genotype in surgically resected fibromatosis of the breast. AB - AIMS: To investigate CTNNB1 mutation and beta-catenin expression in resected breast fibromatosis and to identify potential molecular markers of fibromatosis of the breast. METHODS AND RESULTS: We selected 12 patients with fibromatosis of the breast who underwent surgical resection and were confirmed by histological examination. Ultrasonography findings for 10 patients were reviewed and only two cases were suspicious for fibromatosis on imaging. On core needle biopsy for pre operative diagnoses, only three cases were histologically suspicious for fibromatosis. Mutations in exon 3 of CTNNB1 were detected by direct DNA sequencing in nine (75.0%) cases: all were c.121G>A (p.T41A), which was much more frequent in breast fibromatoses than in other soft tissue lesions. Nuclear beta catenin expression was observed in all cases and the level of expression was higher in cases with mutation. In eight of nine cases, the matched biopsy specimen showed the same CTNNB1 mutation status as the pre-operative specimen. CONCLUSIONS: In the majority of cases, clinical presentation and breast imaging are highly suspicious for carcinoma. Definitive pre-operative pathological diagnosis by core needle biopsy is difficult. CTNNB1 mutation and nuclear beta catenin expression are frequently detected in sporadic breast fibromatoses, suggesting their potential as a useful tool to distinguish breast fibromatoses from other neoplasms. PMID- 22211297 TI - Advances in the management of alopecia areata. AB - Spontaneous remission occurs in up to 80% of patients with limited patchy alopecia areata (AA) within 1 year. Therefore, not all patients of AA simplex/multiplex need extensive treatments, and "wait and see" is one of the choices for some patients. However, once the hair loss show progressive course, it is really difficult to manage well and may be recalcitrant to any treatment in some cases. Hair loss symptom is not life-threatening but severely decreases quality of life. There have been two widely known guidelines for AA from the British Association of Dermatologists and the National Alopecia Areata Foundation (USA). These guidelines have been substantial and provide clues for dermatologists but needed to be updated. Recently, the Japanese Dermatological Association also published a guideline for the management of AA. This guideline suggests treatments followed by recommendations and evidence levels. Several new treatments are added such as corticosteroid pulse therapy and antihistamine drugs in addition to Japanese historical therapies. Although the highly recommended therapies are still contact immunotherapy and local injection of corticosteroid, it may result in improvement of AA by use of appropriate treatments decided by age, hair loss type, disease course and desire of the AA patient. PMID- 22211298 TI - Inferring dispersal patterns of the generalist root fungus Armillaria mellea. AB - Investigating the dispersal of the root-pathogenic fungus Armillaria mellea is necessary to understand its population biology. Such an investigation is complicated by both its subterranean habit and the persistence of genotypes over successive host generations. As such, host colonization by resident mycelia is thought to outcompete spore infections. We evaluated the contributions of mycelium and spores to host colonization by examining a site in which hosts pre date A. mellea. Golden Gate Park (San Francisco, CA, USA) was established in 1872 primarily on sand dunes that supported no resident mycelia. Genotypes were identified by microsatellite markers and somatic incompatibility pairings. Spatial autocorrelation analyses of kinship coefficients were used to infer spore dispersal distance. The largest genotypes measured 322 and 343 m in length, and 61 of the 90 total genotypes were recovered from only one tree. The absence of multilocus linkage disequilibrium and the high proportion of unique genotypes suggest that spore dispersal is an important part of the ecology and establishment of A. mellea in this ornamental landscape. Spatial autocorrelations indicated a significant spatial population structure consistent with limited spore dispersal. This isolation-by-distance pattern suggests that most spores disperse over a few meters, which is consistent with recent, direct estimates based on spore trapping data. PMID- 22211299 TI - Lessons learned from Toulouse and Buncefield disasters: from risk analysis failures to the identification of atypical scenarios through a better knowledge management. AB - The recent occurrence of severe major accidents has brought to light flaws and limitations of hazard identification (HAZID) processes performed for safety reports, as in the accidents at Toulouse (France) and Buncefield (UK), where the accident scenarios that occurred were not captured by HAZID techniques. This study focuses on this type of atypical accident scenario deviating from normal expectations. The main purpose is to analyze the examples of atypical accidents mentioned and to attempt to identify them through the application of a well-known methodology such as the bow-tie analysis. To these aims, the concept of atypical event is accurately defined. Early warnings, causes, consequences, and occurrence mechanisms of the specific events are widely studied and general failures of risk assessment, management, and governance isolated. These activities contribute to outline a set of targeted recommendations, addressing transversal common deficiencies and also demonstrating how a better management of knowledge from the study of past events can support future risk assessment processes in the identification of atypical accident scenarios. Thus, a new methodology is not suggested; rather, a specific approach coordinating a more effective use of experience and available information is described, to suggest that lessons to be learned from past accidents can be effectively translated into actions of prevention. PMID- 22211300 TI - Anterior spinal artery syndrome in a patient with vasospasm secondary to a ruptured cervical dural arteriovenous fistula. AB - BACKGROUND: Spinal dural arteriovenous fistulas (DAVF) in the cervical spine are known to cause subarachnoid hemorrhage. Vasospasm after rupture of a DAVF, however, has not previously been reported. CASE PRESENTATION: A 48-year-old woman who presented with the sudden onset of altered mental status. Imaging demonstrated extensive subarachnoid hemorrhage and spinal DAVF at C1 to C2. The patient underwent a suboccipital craniotomy for DAVF ligation. On post-operative day three, she began having acute weakness in all her extremities with proprioception and vibration preserved, whereas pain and temperature sensation was lost. An angiogram demonstrated bilateral vertebral artery vasospasm with no filling of the anterior spinal artery. Bilateral angioplasty of the vertebral arteries was performed successfully and post-angioplasty, the right vertebral artery was filling the anterior spinal artery. The patient clinically improved. She subsequently required treatment with n-butyl cyanoacrylic acid (nBCA) embolization and gamma knife radiosurgery to achieve obliteration of the lesion. CONCLUSIONS: For patients with subarachnoid hemorrhage of unknown origin, differential diagnosis should include DAVF. This patient also presented with vasospasm in the context of ruptured DAVF, a complication previously unreported in the literature. This finding suggests that close monitoring for vasospasm after rupture of DAVF is warranted. PMID- 22211302 TI - The association of functional polymorphisms in the aryl hydrocarbon receptor (AHR) gene with the risk of vitiligo in Han Chinese populations. AB - BACKGROUND: Vitiligo is an acquired depigmentation disorder resulting from selective destruction of melanocytes. The aryl hydrocarbon receptor (AHR) is vital to the regulation of melanogenesis and melanocyte proliferation and differentiation through modulating the expressions of melanogenesis-related genes. AHR mutations may negatively affect AHR proteins and its target genes. Therefore, we hypothesized that AHR polymorphisms might be involved in vitiligo by impacting the transcriptional activities of related genes as mentioned above. OBJECTIVES: To evaluate the potential association between AHR polymorphisms and vitiligo susceptibility. METHODS: We performed a hospital-based, case-control study of 1000 patients with vitiligo and 1000 vitiligo-free but age- and gender matched controls. Two single nucleotide polymorphisms of the AHR gene (rs10249788 and rs2066853) were selected and genotyped using a polymerase chain reaction restriction fragment length polymorphism method. RESULTS: A statistically significantly decreased risk of vitiligo was found to be associated with the TT and CT genotypes of rs10249788 [odds ratio (OR) 0.59, 95% confidence interval (CI) 0.38-0.93; P = 0.028 and OR 0.82, 95% CI 0.68-0.98; P = 0.032, respectively] as well as among subgroups: male, active, nonsegmental vitiligo, and onset age <= 20 years. Moreover, subjects with the combined (CT + TT)/GG genotype or T/G haplotype (rs10249788/rs2066853) showed a decreased risk for vitiligo (OR 0.57, 95% CI 0.37-0.87, P = 0.009 and OR 0.78, 95% CI 0.64-0.96, P = 0.033, respectively). CONCLUSIONS: These results suggest that the T allele of rs10249788 located in the promoter of the AHR gene is associated with a protective effect on vitiligo in Han Chinese populations. PMID- 22211303 TI - A systematic review of post-extractional alveolar hard and soft tissue dimensional changes in humans. AB - BACKGROUND: Removal of teeth results in both horizontal and vertical changes of hard and soft tissue dimensions. The magnitude of these changes is important for decision-making and comprehensive treatment planning, with provisions for possible solutions to expected complications during prosthetic rehabilitation. OBJECTIVES: To review all English dental literature to assess the magnitude of dimensional changes of both the hard and soft tissues of the alveolar ridge up to 12 months following tooth extraction in humans. METHODS: An electronic MEDLINE and CENTRAL search complemented by manual searching was conducted to identify randomized controlled clinical trials and prospective cohort studies on hard and soft tissue dimensional changes after tooth extraction. Only studies reporting on undisturbed post-extraction dimensional changes relative to a fixed reference point over a clearly stated time period were included. Assessment of the identified studies and data extraction was performed independently by two reviewers. Data collected were reported by descriptive methods. Weighted means and percentages of the dimensional changes over time were calculated where appropriate. RESULTS: The search provided 3954 titles and 238 abstracts. Full text analysis was performed for 104 articles resulting in 20 studies that met the inclusion criteria. In human hard tissue, horizontal dimensional reduction (3.79 +/- 0.23 mm) was more than vertical reduction (1.24 +/- 0.11 mm on buccal, 0.84 +/- 0.62 mm on mesial and 0.80 +/- 0.71 mm on distal sites) at 6 months. Percentage vertical dimensional change was 11-22% at 6 months. Percentage horizontal dimensional change was 32% at 3 months, and 29-63% at 6-7 months. Soft tissue changes demonstrated 0.4-0.5 mm gain of thickness at 6 months on the buccal and lingual aspects. Horizontal dimensional changes of hard and soft tissue (loss of 0.1-6.1 mm) was more substantial than vertical change (loss 0.9 mm to gain 0.4 mm) during observation periods of up to 12 months, when study casts were utilized as a means of documenting the changes. CONCLUSIONS: Human re entry studies showed horizontal bone loss of 29-63% and vertical bone loss of 11 22% after 6 months following tooth extraction. These studies demonstrated rapid reductions in the first 3-6 months that was followed by gradual reductions in dimensions thereafter. PMID- 22211304 TI - Surgical protocols for ridge preservation after tooth extraction. A systematic review. AB - OBJECTIVE: This systematic review aims to evaluate the scientific evidence on the efficacy in the surgical protocols designed for preserving the alveolar ridge after tooth extraction and to evaluate how these techniques affect the placement of dental implants and the final implant supported restoration. MATERIAL AND METHODS: A thorough search in MEDLINE-PubMed, Embase and the Cochrane Central Register of controlled trials (CENTRAL) was conducted up to February 2011. Randomized clinical trials and prospective cohort studies with a follow-up of at least 3 months reporting changes on both the hard and soft tissues (height and/or width) of the alveolar process (mm or %) after tooth extraction were considered for inclusion. RESULTS: The screening of titles and abstracts resulted in 14 publications meeting the eligibility criteria. Data from nine of these 14 studies could be grouped in the meta-analyses. Results from the meta-analyses showed a statistically significant greater ridge reduction in bone height for control groups as compared to test groups (weighted mean differences, WMD = -1.47 mm; 95% CI [-1.982, -0.953]; P < 0.001; heterogeneity: I(2) = 13.1%; chi(2) P-value = 0.314) and a significant greater reduction in bone width for control groups compared to the test groups (WMD = -1.830 mm; 95% CI [-2.947, -0.732]; P = 0.001; heterogeneity: I(2) = 0%; chi(2) P-value = 0.837). Subgroup analysis was based on the surgical protocol used for the socket preservation (flapless/flapped, barrier membrane/no membrane, primary intention healing/no primary healing) and on the measurement method utilized to evaluate morphological changes. Meta-regression analyses demonstrated a statistically significant difference favoring the flapped subgroup in terms of bone width (meta-regression; slope = 2.26; 95% IC [1.01; 3.51]; P = 0.003). CONCLUSIONS: The potential benefit of socket preservation therapies was demonstrated resulting in significantly less vertical and horizontal contraction of the alveolar bone crest. The scientific evidence does not provide clear guidelines in regards to the type of biomaterial, or surgical procedure, although a significant positive effect of the flapped surgery was observed. There are no data available to draw conclusions on the consequences of such benefits on the long-term outcomes of implant therapy. PMID- 22211305 TI - A systematic review on survival and success rates of implants placed immediately into fresh extraction sockets after at least 1 year. AB - BACKGROUND: Type I immediate implant placement has gained popularity because it may reduce treatment time, number of surgeries and post-extraction bone loss. However, this is potentially challenged by inadequate keratinized mucosa for flap adaptation and difficulties in achieving primary stability. Moreover, it has been proven that post-extraction bone loss is an inevitable biological process, which affects treatment outcomes. OBJECTIVES: To estimate survival and success rates of implants and the implant-supported prostheses, the prevalence of biological, technical and aesthetic complications, and the magnitude of soft and hard tissue changes following implant placement immediately into fresh extraction sockets. MATERIAL AND METHODS: An electronic search in MEDLINE (PubMed) and the Cochrane Library from 1991 to July 2010 was performed to include prospective studies on immediate implants with a mean follow-up time of at least 1 year. The survival rates were computed using the STATA statistical software. Weighted means of soft and hard tissue changes were obtained by the inverse variance method. RESULTS: A total of 46 prospective studies, with a mean follow-up time of 2.08 years, were included. The annual failure rate of immediate implants was 0.82% (95% CI: 0.48 1.39%), translating into the 2-year survival rate of 98.4% (97.3-99%). Among the five factors analysed (reasons for extraction, antibiotic use, position of implant [anterior vs. posterior, maxilla vs. mandible), type of loading], only the regimen of antibiotic use affected the survival rate significantly. Lower failure rates were found in groups that were provided with a course of post operative antibiotics. The success of implant therapy was difficult to assess due to scarce reporting on biological, technical and aesthetic complications. Soft tissue changes occurred mostly in the first 3 months after the provision of restoration, and then stabilized towards end of the first year. Marginal bone loss predominantly took place in the first year after implant placement, with a magnitude generally less than 1 mm. Controversy on hard tissue preservation with platform-switching technique remained unsolved. CONCLUSIONS: Despite the high survival rate observed, more long-term studies are necessary to determine the success of implant treatment provided immediately after tooth extraction. Special attention has to be given to aesthetic outcomes. PMID- 22211306 TI - Surgical protocols for early implant placement in post-extraction sockets: a systematic review. AB - OBJECTIVES: The aim of this systematic review was to evaluate the best timing for placing implants after tooth extraction, by comparing early vs. delayed implant placement and evaluating the hard and/or soft tissue ridge dimensional changes and the outcomes related with implant survival and prosthesis success. MATERIAL AND METHODS: An online search of the main databases including The National Library of Medicine (MEDLINE via Pubmed), Embase and The Cochrane Central Register of Controlled Trials was conducted up to February 2011. Randomized controlled clinical trials (RCTs), prospective cohort studies and case-control retrospective studies, with a follow-up of at least 1 month after loading of dental implants, comparing: (i) early vs. delayed implant placement, (ii) augmentation vs. no augmentation at implant placement in early placed implants and/or (iii) the comparison of various augmentation procedures at early implant placement, were conducted. A hand search of relevant journals was also performed. Screening of eligible studies, assessment of their methodological quality and data extraction were conducted in duplicate by two independent reviewers. Authors of studies were contacted for clarification or missing information. RESULTS: Eight studies were included, although meta-analysis could only be performed with the data from two studies comparing early vs. delayed implant. The percentage of bone height and bone width reduction favoured the early placement, with pooled mean difference between groups of 13.11% (95% CI: from 3.83 to 22.4; P = 0.057) and 19.85% (95% CI: from 13.85 to 25.81) respectively. Implant survival demonstrated a non-significant higher implant survival rate for the early group (RR = 1.02, 95% CI: 0.96-1.1).With regard to patient satisfaction, statistically significant differences between the groups in favour of the early group for overall satisfaction and appearance with the restoration were demonstrated at 2 years, although these differences were lost at 5 years. CONCLUSIONS: Placement of dental implants at an early timing after tooth extraction may offer advantages in terms of soft and hard tissue preservation, when compared with a delayed protocol. Nevertheless, well-designed, high quality, randomized clinical trials, are needed, because the available evidence is today limited in terms of available studies and quality. PMID- 22211307 TI - Evidence-based knowledge on the biology and treatment of extraction sockets. AB - OBJECTIVES: The fresh extraction socket in the alveolar ridge represents a special challenge in everyday clinical practice. Maintenance of the hard and soft tissue envelope and a stable ridge volume were considered important aims to allow simplifying subsequent treatments and optimizing their outcomes in particular, when implants are planned to be placed. MATERIAL AND METHODS: Prior to the consensus meeting four comprehensive systematic reviews were written on two topics regarding ridge alteration and ridge preservation following tooth extraction and implant placement following tooth extraction. During the conference these manuscripts were discussed and accepted thereafter. Finally, consensus statements and recommendations were formulated. RESULTS: The systematic reviews demonstrated that the alveolar ridge undergoes a mean horizontal reduction in width of 3.8 mm and a mean vertical reduction in height of 1.24 mm within 6 months after tooth extraction. The techniques aimed at ridge preservation encompassed two different approaches: i) maintaining the ridge profile, ii) enlarging the ridge profile. Regarding timing of implant placement the literature showed that immediate implant placement leads to high implant survival rates. This procedure is primarily recommended in premolar sites with low esthetic importance and favorable anatomy. In the esthetic zone, however, a high risk for mucosal recession was reported. Hence, it should only be used in stringently selected situations with lower risks and only by experienced clinicians. In molar sites a high need for soft and hard tissue augmentation was identified. CONCLUSIONS: Future research should clearly identify the clinical and patient benefits resulting from ridge preservation compared with traditional procedures. In addition, future research should also aim at better identifying parameters critical for positive treatment outcomes with immediate implants. The result of this procedure should be compared to early and late implant placement. PMID- 22211308 TI - Linking science with practice in oral tissue regeneration. PMID- 22211310 TI - Extraction sockets: biology and treatment options. Preface. PMID- 22211311 TI - Sex-specific demographic behaviours that shape human genomic variation. AB - In the human species, the two uniparental genetic systems (mitochondrial DNA and Y chromosome) exhibit contrasting diversity patterns. It has been proposed that sex-specific behaviours, and in particular differences in migration rate between men and women, may explain these differences. The availability of high-density genomic data and the comparison of genetic patterns on autosomal and sex chromosomes at global and local scales allow a reassessment of the extent to which sex-specific behaviours shape our genome. In this article, we first review studies comparing the genetic patterns at uniparental and biparental genetic systems and assess the extent to which sex-specific migration processes explain the differences between these genetic systems. We show that differences between male and female migration rates matter, but that they are certainly not the only contributing factor. In particular, differences in effective population size between men and women are also likely to account for these differences. Then, we present and discuss three anthropological processes that may explain sex-specific differences in effective population size and thus human genomic variation: (i) variance in reproductive success arising from, for example, polygyny; (ii) descent rules; and (iii) transmission of reproductive success. PMID- 22211312 TI - The keystone fasciocutaneous flap in the reconstruction of lower extremity wounds. PMID- 22211313 TI - Should rheumatoid factor in rheumatoid arthritis be sent to Davy Jones's Locker? AB - This article reviews the characteristics and weaknesses of the rheumatoid factor (RF) assay compared with anti-citrullinated peptide antibody (ACPA) testing in the work-up of patients with synovitis. This should lead physicians to change their ordering habits and replace RF by ACPA. For RA diagnosis, good clinical judgement based on clinical history, physical examination and routine laboratory work exceeds the value of RF and ACPA assays. In settings of both low and high pretest probability, the added value of each of these assays is low. In cases with intermediate probability, ACPA assays are superior to immunoglobulin (Ig)M RF because of their higher specificity, and they should be the first choice in a RA diagnostic work-up. Dual testing brings few additional advantages and increases costs significantly. ACPA and IgM-RF are both imperfect tests; around 30% of patients with manifest RA will test negative in both assays and therefore caution needs to be exercised when interpreting negative results. Since 2009, the anti-cyclic citrullinated peptide (anti-CCP) antibody assay has been the only assay available at our institution for RA work-up, with IgM-RF available on a case-by-case basis for non-RA diseases. This has led to a 70% reduction in RF assays performed annually. PMID- 22211314 TI - Water-dispersible, uniform nanospheres by heating-enabled micellization of amphiphilic block copolymers in polar solvents. AB - Uniform nanospheres with tunable size down to 30 nm were prepared simply by heating amphiphilic block copolymers in polar solvents. Unlike reverse micelles prepared in nonpolar, oily solvents, these nanospheres have a hydrophilic surface, giving them good dispersibility in water. Furthermore, they are present as individual, separated, rigid particles upon casting from the solution other than continuous thin films of merged micelles cast from micellar solution in nonpolar solvents. These nanospheres were generated by a heating-enabled micellization process in which the affinity between the solvent and the polymer chains as well as the segmental mobility of both hydrophilic and hydrophobic blocks was enhanced, triggering the micellization of the glassy copolymers in polar solvents. This heating-enabled micellization produces purely well-defined nanospheres without interference of other morphologies. The micelle sizes and corona thickness are tunable mainly by changing the lengths of the hydrophobic and hydrophilic blocks, respectively. The heating-enabled micellization route for the preparation of polymeric nanospheres is extremely simple, and is particularly advantageous in producing rigid, micellar nanospheres from block copolymers with long glassy, hydrophobic blocks which are otherwise difficult to prepare with high efficiency and purity. Furthermore, encapsulation of hydrophobic molecules (e.g., dyes) into micelle cores could be integrated into the heating-enabled micellization, leading to a simple and effective process for dye-labeled nanoparticles and drug carriers. PMID- 22211315 TI - Bilateral alterations in somatosensory cortical processing in hemiplegic cerebral palsy. AB - AIM: In individuals with cerebral palsy (CP), cerebral insults during early development may induce profound reorganization of the motor representation. This study determined the extent of alterations in cortical somatosensory functions in adolescents with hemiplegic CP with subcortical brain lesions. METHOD: We recorded somatosensory evoked magnetic fields in response to hand area stimulation from eight adolescents with hemiplegic CP (five females and three males; mean age 14y 6mo, SD 2y 3mo) and eight age- and sex-matched healthy comparison adolescents (mean age 15y 4mo, SD 2y 4mo). All participants in the CP group had purely subcortical brain lesions in magnetic resonance images. RESULTS: The somatosensory representation of the affected limb was contralateral (i.e. ipsilesional), but detailed inspection of the evoked responses showed alterations bilaterally. In the primary somatosensory cortex, the representation areas of digits II and V were in both hemispheres closer to each other in participants with CP than in comparison participants [ANOVA main effect group F(1,14) =5.58; p=0.03]. In addition, the morphology of median nerve evoked fields was altered in the participants with CP. INTERPRETATION: In hemiplegic CP, modification of the somatosensory cortical network extends beyond what would be expected based on the unilateral symptoms and the anatomical lesion. Further understanding of the functional alterations in the sensorimotor networks may aid in developing more precisely designed rehabilitation strategies. PMID- 22211316 TI - Iron replacement therapy in the routine management of blood donors. AB - BACKGROUND: Iron depletion or deficiency in blood donors frequently results in deferrals for low hemoglobin (Hb), yet blood centers remain reluctant to dispense iron replacement therapy to donors. STUDY DESIGN AND METHODS: During a 39-month period, 1236 blood donors deferred for a Hb level of less than 12.5 g/dL and 400 nondeferred control donors underwent health history screening and laboratory testing (complete blood counts, iron studies). Iron depletion and deficiency were defined as a ferritin level of 9 to 19 and less than 9 ug/L in females and 18 to 29 and less than 18 ug/L in males. Deferred donors and iron-deficient control donors were given a 60-pack of 325-mg ferrous sulfate tablets and instructed to take one tablet daily. Another 60-pack was dispensed at all subsequent visits. RESULTS: In the low-Hb group, 30 and 23% of females and 8 and 53% of males had iron depletion or deficiency, respectively, compared with 29 and 10% of females and 18 and 21% of males in the control group. Iron-depleted or -deficient donors taking iron showed normalization of iron-related laboratory parameters, even as they continued to donate. Compliance with oral iron was 68%. Adverse gastrointestinal effects occurred in 21% of donors. The study identified 13 donors with serious medical conditions, including eight with gastrointestinal bleeding. No donors had malignancies or hemochromatosis. CONCLUSION: Iron depletion or deficiency was found in 53% of female and 61% of male low-Hb donors and in 39% of female and male control donors. Routine administration of iron replacement therapy is safe and effective and prevents the development of iron depletion and deficiency in blood donors. PMID- 22211318 TI - Complex samples cyanide detection with immobilized corrinoids. AB - Colorimetric solid phase with spatially separated extraction and detection zones as a rapid, effective and economic method for the optical detection of cyanide in complex samples is described. The system is seven times more sensitive for the optical detection of cyanide than the same class of chemical sensors used under homogeneous conditions. The application of the method in the detection of (i) endogenous cyanide in colored plant samples and of (ii) hydrogen cyanide in tobacco smoke is shown. The optical detection of multiple anions within a single sample has been demonstrated in principle for the detection of both CN(-) and SCN(-). Immobilized aquacyano-corrinoids and immobilized vitamin B12 are applied as chemical sensors, and cyanide is qualitatively identified by the violet color (lambda(max) = 583 nm) of the corresponding dicyano-complex. Quantitative determinations with diffuse reflectance spectroscopy (DRUV-vis) are possible in the linear range up to 0.2 mg/L with a LOD of 1 MUg/L. Alkyl-modified silica particles are employed for immobilization of the indicator on the surface of the solid phase (detection zone), and for removal of colored hydrophobic interferents (extraction zone). PMID- 22211319 TI - Mucosal intestinal alteration in experimental colitis correlates with nitric oxide production by peritoneal macrophages: effect of probiotics and prebiotics. AB - Inflammatory bowel disease (IBD) consists mainly of Ulcerative colitis (UC) and Crohn disease (CD). Although its aetiology is still not clearly established, it is thought to be due to overly aggressive immune response to enteric bacteria in genetically predisposed individuals. Manipulating the microbiota using probiotics or prebiotics is considered as a promising field of new therapeutic strategies used to attenuate immune disorders observed during IBD. The production of nitric oxide (NO) seems to be implicated in IBD pathogenesis. In our study, an acute UC was induced in Swiss mice using 3% Dextran Sulfate Sodium (DSS). The preventive effects of "Ultrabiotique(r)" (a probiotic) and inulin (a prebiotic) on the colitis were investigated. The production of NO was evaluated in the supernatants of peritoneal macrophages (pMphi) cultures. Colonic mucosa histology was subsequently examined. Results showed severe acute UC after administration of DSS. High levels of NO in pMphi cultures were also observed compared to control samples. These findings correlated with a significant destruction of the colonic mucosa. Oral administration of Ultrabiotique(r) or inulin decreased the severity of DSS-induced colitis. These treatments lead to a decrease in NO levels in pMphi cultures. A considerable reduction of colonic lesions was also noticed. Our findings suggest the involvement of NO in experimental UC pathogenesis. Pre- and pro-biotics, as discussed herein, seem to have an anti-inflammatory effect. PMID- 22211322 TI - Brain dysfunction in fibromyalgia and somatization disorder using proton magnetic resonance spectroscopy: a controlled study. AB - OBJECTIVE: To evaluate the brain metabolite patterns in patients with fibromyalgia (FM) and somatization disorder (STD) compared with healthy controls through spectroscopy techniques and correlate these patterns with psychological variables. METHOD: Design. Controlled, cross-sectional study. Sample. Patients were recruited from primary care in Zaragoza, Spain. The control group was recruited from hospital staff. Patients were administered questionnaires on pain catastrophizing, anxiety, depression, pain, quality of life, and cognitive impairment. All patients underwent Magnetic Resonance Imaging and magnetic resonance spectroscopy (MRS). RESULTS: A significant increase was found in the glutamate + glutamine (Glx) levels in the posterior cingulate cortex (PCC): 10.73 (SD: 0.49) for FM and 9.67 (SD: 1.10) for STD 9.54 (SD: 1.46) compared with controls (P = 0.043). In the FM + STD group, a correlation between Glx and pain catastrophizing in PCC (r = 0.397; P = 0.033) and between quality of life and the myo-inositol/creatine ratio in the left hippocampus (r = -0.500; P = 0.025) was found. To conclude Glutamate seems to be relevant in the molecular processes involved in FM and STD. It also opens the door for Proton MRS ((1) H-MRS) in STD and suggests that reducing glutamatergic activity through pharmacological treatment could improve the outcome of patients with FM and STD. CONCLUSION: Glutamate seems to be relevant in the molecular processes involved in FM and STD. It also opens the door for Proton MRS ((1) H-MRS) in STD and suggests that reducing glutamatergic activity through pharmacological treatment could improve the outcome of patients with FM and STD. PMID- 22211323 TI - Reproductive responses to spatial and temporal prey availability in a coastal Arctic fox population. AB - 1. Input of external subsidies in the Arctic may have substantial effects on predator populations that otherwise would have been limited by low local primary productivity. 2. We explore life-history traits, age-specific fecundity, litter sizes and survival, and the population dynamics of an Arctic fox (Vulpes lagopus) population to explore the influence of the spatial distribution and temporal availability of its main prey; including both resident and migrating (external) prey resources. 3. This study reveals that highly predictable cross-boundary subsidies from the marine food web, acting through seasonal access to seabirds, sustain larger local Arctic fox populations. Arctic fox dens located close to the coast in Svalbard were found to have higher occupancy rates, as expected from both high availability and high temporal and spatial predictability of prey resources (temporally stable external subsidies). Whereas the occupancy rate of inland dens varied between years in relation to the abundance of reindeer carcasses (temporally varying resident prey). 4. With regard to demography, juvenile Arctic foxes in Svalbard have lower survival rates and a high age of first reproduction compared with other populations. We suggest this may be caused by a lack of unoccupied dens and a saturated population. PMID- 22211324 TI - Two cases of eruptive pseudoangiomatosis induced by mosquito bites. AB - Eruptive pseudoangiomatosis is a skin eruption characterized by millet-sized erythema with an anemic halo appearing on exposed body areas. Insect bites, particularly mosquito bites, have been reported as one of the causes of eruptive pseudoangiomatosis. We experienced two cases of eruptive pseudoangiomatosis and the eruption was seen on the face and upper extremities of two women aged 48 and 77 years old. The two cases consented to be experimentally bitten by Culex pipiens mosquitoes and Aedes albopictus to determine if eruptive pseudoangiomatosis could be experimentally elicited by these mosquitoes. Our results showed that several minutes after a C. pipiens mosquito bite, an erythematous spot appeared on the bite site, followed by the formation of an anemic halo surrounding the erythema in 30 min; a successful reproduction of eruptive pseudoangiomatosis. The erythema lasted for more than a week and was not accompanied by any pruritus. With A. albopictus, we were able to reproduce a milder eruptive pseudoangiomatosis eruption: in case 1, a smaller erythematous spot with an ill-defined halo which disappeared within 1 week; and in case 2, an immediate response consisting of a wheal and erythema but not eruptive pseudoangiomatosis. We demonstrated that eruptive pseudoangiomatosis was the response manifested in individuals who normally did not demonstrate any immediate or delayed reaction to insect bites; and the typical eruptive pseudoangiomatosis eruption was elicited by C. pipiens mosquito bites. However, the mechanism resulting in the manifestation of eruptive pseudoangiomatosis is still unknown. PMID- 22211325 TI - Lipodystrophia centrifugalis abdominalis infantilis: statistical analysis of 168 cases. AB - Lipodystrophia centrifugalis abdominalis infantilis is a localized lipodystrophic disease affecting young children. A total of 168 cases were collected from dermatology literature. Where possible, details of the data were also obtained from the authors. Most of the patients were Japanese, Korean, or Chinese in origin. The Caucasian patients were from England, Italy, France, Germany, Spain, and the United States. The male-to-female ratio was 1:1.6. The depressed lesions developed during the first 4 years of life in the groin or axilla, surrounded by a slight erythematous change. Histologically, subcutaneous fatty tissue was lost or markedly decreased in the depressed areas, and marked or moderate mononuclear cell infiltration was observed in the fatty tissue of the surrounding erythematous area. The depressed lesions extended centrifugally to involve the abdominal or chest walls. However, in most cases, such enlargement spontaneously ceased by the age of 13 years. No drugs used were effective in preventing the enlargement of depressed lesions, but more than 60% of patients showed spontaneous improvement after the cessation of enlargement. Lipodystrophia centrifugalis abdominalis infantilis is a clinically and histologically distinct lipodystrophic disease affecting young children, mostly in Asian countries, but a few in Western countries. PMID- 22211327 TI - A subcutaneous lattice-like array of thick collagen is a clue to the diagnosis of stiff skin syndrome. PMID- 22211328 TI - I double dare me. PMID- 22211329 TI - Correction and clarification regarding AFX and pleomorphic dermal sarcoma. PMID- 22211330 TI - The 'epidemic' of melanoma between under- and overdiagnosis. AB - In the past decades, the incidence of melanoma has been reported to rise in epidemic proportions. The chief reason for that pseudo-epidemic is improved criteria for diagnosis that allow melanomas to be recognized far more accurately and at earlier stages. The rising number of melanomas diagnosed has resulted in increased diagnostic scrutiny, more pigmented lesions being biopsied and more melanomas recognized, thus enhancing the 'epidemic' in self-perpetuating fashion. Regression of melanomas may, in part, explain why lesions undetected before did not result in a far higher mortality. Another potential reason for the disparity between increasing incidence of melanoma and relatively steady mortality may be overdiagnosis of melanoma. The latter may be curtailed by establishment of well defined diagnostic categories, efforts to establish reliable criteria for recognition of those categories, better clinicopathologic correlation, postponement of biopsy of pigmented lesions in the case of irritation and excisional rather than incisional biopsies. PMID- 22211331 TI - The melanoma 'epidemic': lessons from prostate cancer. AB - The rise in malignant melanoma incidence has been termed "epidemic". Closer scrutiny of epidemiologic data suggests overdiagnosis as the true cause of the dramatic rise in melanoma incidence. In epidemiologic terms, "overdiagnosis" describes lesions that are histologically malignant but biologically benign. Overdiagnosis is not unique to melanoma screening but is prevalent in screening for cancers of other organs, including the thyroid and prostate glands. PMID- 22211332 TI - An atypical melanocytic lesion without genomic abnormalities shows locoregional metastasis. AB - A subset of difficult melanocytic lesions exists with histopathologic features that evade diagnostic consensus from even expert dermatopathologists. Comparative genomic hybridization (CGH) has emerged as a useful diagnostic tool to categorize these lesions, by identifying known chromosomal aberrations in malignant melanoma or the lack thereof in melanocytic nevi. However, determining a lesion's biological behavior primarily on CGH is limited by a relatively small series of corroborative cases without long term follow up. We present a case of a pigmented lesion on the right cheek of a 4 year old boy. The lesion had features of a deep penetrating nevus, but the presence of frequent mitoses, tumor infiltrating lymphocytes, and microscopic foci of tumor necrosis were concerning for an unusual melanoma. We termed this lesion a melanocytic tumor of uncertain potential (MELTUMP) for these reasons. High-resolution array-CGH performed elsewhere on the lesion demonstrated no melanoma-associated genomic abnormalities. A sentinel lymph node biopsy of this patient later revealed multiple small tumor deposits. Although the presence of nodal involvement in similar lesions often do not lead to progressive and fatal disease, this case illustrates that atypical melanocytic lesions with nodal involvement may not demonstrate genomic abnormalities by CGH, and that histopathologic assessment remains paramount in defining these difficult melanocytic lesions. Further comprehensive study of these lesions is needed. PMID- 22211333 TI - An unconventional deep penetrating melanocytic nevus with microscopic involvement of regional lymph nodes. AB - This manuscript represents a reprise of the preceding manuscript (J Cutan Pathol 2012; 39: 21-24). It has different conclusions. The wording of the case report section is very similar in both papers but has been included in both for the convenience of the reader. The illustrations are duplicated in both versions of the manuscript but the captions are not the same. The reader is encouraged to study both versions of the manuscript and consider the issue from both perspectives. PMID- 22211334 TI - CD163 is not a sensitive marker for identification of atypical fibroxanthoma. AB - The histopathological features of atypical fibroxanthoma (AFX) overlap with those of poorly differentiated carcinoma, melanoma and leiomyosarcoma in the skin. As there are no specific stains to identify AFX, the diagnosis is essentially one of exclusion and requires completion of a panel of immunostains. Recently, it has been suggested that the macrophage/monocyte-specific marker CD163 is of value in identifying AFX. To investigate this claim, 57 AFX were stained for CD163. Only 21 of 57 (37%) of AFX stained positively, and intratumoral macrophages confounded interpretation of the stain at times. In four cases, it was not possible to definitively interpret the tumor staining reaction because of this effect. While a lack of stainable CD163 antigenicity may indicate that AFX is not of histiocytic lineage, it is conceivable that expression of the antigen has been lost for some reason in cells that are in fact of macrophage lineage. In summary, CD163 only stains a minority of AFX and staining results can be difficult to interpret. CD163 is therefore of very limited value in the diagnosis of AFX. Beer TW. CD163 is not a sensitive marker for identification of atypical fibroxanthoma. PMID- 22211335 TI - Lymphangiosarcoma arising after 33 years within a background of chronic filariasis: a case report with review of literature. AB - Cutaneous angiosarcoma or lymphangiosarcoma represents an uncommon aggressive tumor known to arise on a background of chronic lymphedema secondary to various etiologies, principally following surgery or irradiation. There have been rarely reported cases of angiosarcoma following infective conditions that eventuate with lymphatic stasis. We report a case of angiosarcoma arising after 33 years within a background of filariasis. Awareness of this association can lead to early diagnosis and appropriate treatment of this potentially fatal malignant tumor. PMID- 22211339 TI - Constrictive pericarditis with ringed calcification along the atrioventricular groove. PMID- 22211340 TI - Chronic illness histories of adults entering treatment for co-occurring substance abuse and other mental health disorders. AB - Little is known about the medical status of individuals entering treatment for co occurring substance abuse and other mental disorders (COD). We analyzed the medical histories of 169 adults entering outpatient treatment for CODs, estimating lifetime prevalence of chronic illness and current smoking, comparing these rates to the general population, and examining psychiatric and substance related correlates of chronic illness. Results revealed significantly higher prevalence of hypertension, asthma, arthritis, and smoking compared to the general US population, and showed an association between chronic illness and psychiatric symptom distress and substance use severity. Findings support integration of chronic illness management into COD treatment. PMID- 22211341 TI - Variation in OPRM1 and risk of suicidal behavior in drug-dependent individuals. AB - Completed suicide and nonfatal suicide-related outcomes (SROs), such as suicidal ideation and attempts, are heritable. A recent genetic association study in a sample of suicide victims reported a protective effect of the G allele of Asn40Asp (rs1799971) on risk for completed suicide. We examined the association of three OPRM1 single nucleotide polymorphisms (SNPs) (rs1799971, rs609148, and rs648893) with SRO in 426 European Americans, using GEE logistic regression analysis to examine the association of a lifetime history of SRO. There was no allelic association with the SRO phenotypes. A larger sample may be needed to identify risk variants that convey SRO risk. OPRM1 may not be important in the risk of SRO. PMID- 22211342 TI - Challenges and strategies in recruiting, interviewing, and retaining recent Latino immigrants in substance abuse and HIV epidemiologic studies. AB - The growth of immigrant populations in the United States over the past 20 years has increased the need to enhance understanding about the risk factors that influence their substance abuse and HIV risk behaviors. Today, Latinos account for the largest majority of immigrants gaining entry into the United States. As the largest and fastest growing minority subgroup in the United States, they bear a disproportionate burden of disease and death compared to non-Latinos. Latinos are confronted with escalating HIV and substance-abuse problems, particularly Latinos between the ages of 18-34. This paper is based on our longitudinal study on the drug using and HIV risk behaviors of 527 recent Latino immigrants between the ages of 18-34 who have lived in the United States less than 1 year. The data collection activities of this study have provided insights in identifying, recruiting, interviewing, and retaining Latinos in community-based studies. Strategies, such as utilizing a combination of translation techniques, ensured the development and implementation of culturally appropriate questionnaires. Respondent-driven sampling facilitated identifying participants. Establishing rapport and trust was critical for interviewing, and maintaining a tracking protocol was most important for retention. The lessons learned from this study can guide substance abuse and HIV researchers when recruiting, interviewing, and retaining recent Latino immigrants in future epidemiologic studies. PMID- 22211343 TI - "Injection first": a unique group of injection drug users in Tijuana, Mexico. AB - Using baseline data from a study of injection drug users (IDUs) in Tijuana, Mexico (N = 1,052), we identified social and behavioral factors associated with injecting at the same age or earlier than other administration routes of illicit drug use (eg, "injection first") and examined whether this IDU subgroup had riskier drug using and sexual behaviors than other IDUs. Twelve-percent "injected first." Characteristics independently associated with a higher odds of "injection first" included being younger at first injection, injecting heroin as their first drug, being alone at the first injection episode, and having a sexual debut at the same age or earlier as when they initiated drug use; family members' illicit drug use was associated with lower odds of injecting first. When adjusting for age at first injection and number of years injecting, "injection first" IDUs had lower odds of ever overdosing, and ever trading sex. On the other hand, they were less likely to have ever been enrolled in drug treatment, and more commonly obtained their syringes from potentially unsafe sources. In conclusion, a sizable proportion of IDUs in Tijuana injected as their first drug using experience, although evidence that this was a riskier subgroup of IDUs was inconclusive. PMID- 22211344 TI - Variability in veterans' alcohol use by place of residence. AB - Rates of risky alcohol use appear to be elevated among active duty and veteran military personnel. Little is known, however, about characteristics associated with alcohol misuse in these groups. Furthermore, although there is evidence to suggest that patterns of alcohol use differ according to place of residence, no prior studies have investigated variability in alcohol use according to level of rurality and geographic region in US military veterans. The present study evaluated variations in alcohol use (ie, past 30-day use, heavy use, and binge drinking) and drinking and driving according to place of residence among 55,452 US military veterans participating in the Behavioral Risk Factor Surveillance System. Veterans residing in rural areas were significantly less likely than those from suburban and urban areas to have consumed alcohol in the past 30 days (p < .001). Conversely, rural-dwelling veterans who did drink alcohol had higher odds of binge drinking (p < .005) and (relative to urban residents) drinking and driving (p = .013). Veterans residing in the South were significantly less likely than those from other geographic regions to report past 30-day alcohol use (p < .001). In addition, veterans living in the Midwest were significantly more likely than those from the South to report drinking and driving (p = .017). No differences in heavy alcohol use were observed based on location of residence. PMID- 22211345 TI - Problem areas reported by substance abusing individuals and their concerned significant others. AB - Substance use disorders (SUDs) have a serious impact on several life areas, including family functioning. This study examined problem areas that patients with SUDs and their family members experience in terms of quality of relations, psychological problems, physical distress, and quality of life. A sample of 32 dyads--persons with SUDs and a family member--were recruited from a substance abuse treatment program, and completed the Maudsley Addiction Profile health symptoms section, EuroQol-5D, Relationship Happiness Scale, Dyadic Adjustment Scale, and the Dedication Scale. Family members reported that four significant others were directly affected by patients' addiction-related problems, while patients reported that less than three family members were affected by their addiction. Consistently, family members indicated that they were less content with their relationship than patients and evaluated the consequences of patients' SUDs as more negative and severe than the patients themselves. Furthermore, patients and their family members reported comparable levels of physical and psychological distress and quality of life scores. These systematically obtained findings support the notion that relationships of patients and family members are disrupted and both need help to improve their physical and psychological well being. PMID- 22211346 TI - The impact of contingency management on quality of life among cocaine abusers with and without alcohol dependence. AB - The use of quality of life (QOL) measures in substance abuse treatment research is important because it may lead to a broader understanding of patients' health status and effects of interventions. Despite the high rates of comorbid cocaine and alcohol use disorders, little is known about the QOL of this population, and even less about the impact of an efficacious behavioral treatment, contingency management (CM), on QOL. In this study, data from three clinical trials were retrospectively analyzed to examine QOL in outpatient cocaine abusers with and without alcohol dependence (AD) and the impact of CM on QOL over time as a function of AD status. Patients were randomized to standard care (n = 115) or standard care plus CM (n = 278) for 12 weeks. QOL was assessed at baseline and Months 1, 3, 6, and 9. At treatment initiation, AD patients had lower QOL total scores and they scored lower on several subscale scores than those without AD. CM treatment was associated with improvement in QOL regardless of AD status. These data suggest that CM produces benefits that go beyond substance abuse outcomes, and they support the use of QOL indexes to capture information related to treatment outcomes. PMID- 22211347 TI - Compliance with buprenorphine medication-assisted treatment and relapse to opioid use. AB - Opioid dependence (OD), often characterized as a chronic relapsing disorder, affects millions of people worldwide. The purpose of this study was to examine the effect of compliance with buprenorphine on reducing relapse among a sample of patients in treatment for OD. Patients new to buprenorphine (N = 703) completed the Addiction Severity Index (ASI) at baseline, and at 1, 2, and 3 months postbaseline. The ASI is a semistructured interview designed to measure problem severity in seven functional areas known to be affected by alcohol and drug dependence. Compliance was defined as taking buprenorphine medication on at least 22 of the past 28 days (80%), while relapse classification was based on resumed use of opioids during the follow-up period (months 2 and 3). Relapse was regressed onto demographic indicators, baseline ASI composite scores, and compliance with buprenorphine. Noncompliant patients were over 10 times more likely to relapse than those who were compliant (exp beta= 10.55; p < .001). Neither demographics nor baseline ASI composite scores were predictive of relapse (p's > .05). Compliance with medication-assisted treatment supports abstinence, essential for patient recovery. Understanding the factors that drive treatment compliance and noncompliance may assist providers in supporting patient compliance and recovery. PMID- 22211348 TI - Adaptation of the patient feedback survey at a community treatment setting. AB - The Patient Feedback Survey is a performance improvement measure designed to assess the quality of outpatient substance abuse treatment. We modified and administered this measure to 500 individuals at a multisite treatment provider. Although the feedback scores were high in general, analyses of variance showed score variability in relation to type and length of treatment. Moreover, respondents who reported any use of marijuana, cravings for substances, or mutual support group attendance (ie, Alcoholics Anonymous or Narcotics Anonymous) had lower feedback scores than respondents without these experiences. We highlight the importance of investigating treatment evaluations in the context of other recovery experiences. PMID- 22211349 TI - Relationship between substance use and body mass index in young males. AB - Recent findings in basic scientific research, such as neurobiological and neuroimaging studies, have suggested common pathways for food and drug intake. It was hypothesized that both compete for the same brain reward sites, and that a higher body mass index (BMI) may be associated with lower substance use. The aim of this study was to investigate the relationship between BMI and substance use in a large sample of young male adults. The sample consisted of 1,902 18-year-old males from a province of Austria in a naturalistic cross-sectional setting. Questionnaires were administered to assess alcohol abuse and dependence (CAGE) and nicotine dependence (Heavy Smoking Index). Urine samples were collected to assess the prevalence of recent illicit drug use. Associations between BMI and substance use were calculated by means of logistic regression analyses. An inverse relationship between BMI and recent illicit drug use was found. This relationship remained significant after adjusting for possible confounding factors such as level of education, nicotine dependence, breath carbon monoxide (CO) levels, and alcohol abuse and dependence. No significant association was found between BMI and nicotine and alcohol dependence. A higher BMI was associated with lower illicit drug use in our sample of young adult males. These results provide further evidence for the hypothesis that food and drugs may compete for the same brain reward sites. PMID- 22211350 TI - Addiction treatment dropout: exploring patients' characteristics. AB - This study explored the characteristics associated with treatment dropout in substance dependence patients. A sample of 122 addicted patients (84 treatment completers and 38 treatment dropouts) who sought outpatient treatment was assessed to collect information on sociodemographic, consumption (assessed by EuropASI), psychopathological (assessed by SCL-90-R), and personality variables (assessed by MCMI-II). Completers and dropouts were compared on all studied variables. According to the results, dropouts scored significantly higher on the EuropASI variables measuring employment/support, alcohol consumption, and family/social problems, as well as on the schizotypal scale of MCMI-II. Because most of the significant differences were found in EuropASI variables, three clusters analyses (2, 3, and 4 groups) based on EuropASI mean scores were carried out to determine clinically relevant information predicting dropout. The most relevant results were obtained when four groups were used. Comparisons between the four groups derived from cluster analysis showed statistically significant differences in the rate of dropout, with one group exhibiting the highest dropout rate. The distinctive characteristics of the group with highest dropout rate included the presence of an increased labor problem combined with high alcohol consumption. Furthermore, this group had the highest scores on three scales of the MCMI-II: phobic, dependent, and schizotypal. The implications of these results for further research and clinical practice are discussed. PMID- 22211351 TI - Frequency of gambling problems among parents of pathological, versus nonpathological, casino gamblers using slot machines. AB - Familial and twin studies suggest the implication of a genetic factor in pathological gambling, but mainly assess probands through treatment settings or advertisements. The question raised here is: are parents of casino pathological gamblers using slot machines more affected with pathological gambling than nonpathological gamblers, all interviewed on site at the same casino? Three hundred and fifty-five casino gamblers on slot machines, which included 96 pathological gamblers, 116 problem gamblers, and 143 nonproblem gamblers, were recruited in situ at the largest casino in the Paris suburbs. We evaluated pathological gambling and two addictive disorders (alcohol dependence and tobacco consumption) in the gamblers and their 690 parents (through the proband). Familial aggregation of pathological gambling was confirmed, with a risk of 3.3 for being a pathological gambler when at least one of the parents has problematic gambling. No familial co-aggregation of pathological gambling with alcohol or tobacco dependence was observed. Pathological gambling is found in excess in the parents of pathological casino gamblers, in accordance with previous aggregation studies devoted to other types of gambling, and with studies recruiting gamblers in different settings. PMID- 22211353 TI - Expression of signal transducer and activator of transcription 3 (STAT3) and its activated forms is negatively altered in trophoblast and decidual stroma cells derived from preeclampsia placentae. PMID- 22211352 TI - A new LC-MS/MS method for the quantification of endogenous and vinyl chloride induced 7-(2-Oxoethyl)guanine in sprague-dawley rats. AB - Vinyl chloride (VC) is an industrial chemical that is known to be carcinogenic to animals and humans. VC primarily induces hepatic angiosarcomas following high exposures (>=50 ppm). VC is also found in Superfund sites at ppb concentrations as a result of microbial metabolism of trichloroethylene and perchloroethylene. Here, we report a new sensitive LC-MS/MS method to analyze the major DNA adduct formed by VC, 7-(2-oxoethylguanine) (7-OEG). We used this method to analyze tissue DNA from both adult and weanling rats exposed to 1100 ppm [(13)C(2)]-VC for 5 days. After neutral thermal hydrolysis, 7-OEG was derivatized with O-t butyl hydroxylamine to an oxime adduct, followed by LC-MS/MS analysis. The limit of detection was 1 fmol, and the limit of quantitation was 1.5 fmol on the column. The use of stable isotope VC allowed us to demonstrate for the first time that endogenous 7-OEG was present in tissue DNA. We hypothesized that endogenous 7-OEG was formed from lipid peroxidation and demonstrated the formation of [(13)C(2)]-7-OEG from the reaction of calf thymus DNA with [(13)C(18)]-ethyl linoleate (EtLa) under peroxidizing conditions. The concentrations of endogenous 7-OEG in liver, lung, kidney, spleen, testis, and brain DNA from adult and weanling rats typically ranged from 1.0 to 10.0 adducts per 10(6) guanine. The exogenous 7-OEG in liver DNA from adult rats exposed to 1100 ppm [(13)C(2)]-VC for 5 days was 104.0 +/- 23.0 adducts per 10(6) guanine (n = 4), while concentrations in other tissues ranged from 1.0 to 39.0 adducts per 10(6) guanine (n = 4). Although endogenous concentrations of 7-OEG in tissues in weanling rats were similar to those of adult rats, exogenous [(13)C(2)]-7-OEG concentrations were higher in weanlings, averaging 300 adducts per 10(6) guanine in liver. Studies on the persistence of [(13)C(2)]-7-OEG in adult rats sacrificed 2, 4, and 8 weeks postexposure to [(13)C(2)]-VC demonstrated a half-life of 7-OEG of 4 days in both liver and lung. PMID- 22211354 TI - A probabilistic transmission and population dynamic model to assess tuberculosis infection risk. AB - The purpose of this study was to examine tuberculosis (TB) population dynamics and to assess potential infection risk in Taiwan. A well-established mathematical model of TB transmission built on previous models was adopted to study the potential impact of TB transmission. A probabilistic risk model was also developed to estimate site-specific risks of developing disease soon after recent primary infection, exogenous reinfection, or through endogenous reactivation (latently infected TB) among Taiwan regions. Here, we showed that the proportion of endogenous reactivation (53-67%) was larger than that of exogenous reinfection (32-47%). Our simulations showed that as epidemic reaches a steady state, age distribution of cases would finally shift toward older age groups dominated by latently infected TB cases as a result of endogenous reactivation. A comparison of age-weighted TB incidence data with our model simulation output with 95% credible intervals revealed that the predictions were in an apparent agreement with observed data. The median value of overall basic reproduction number (R0) in eastern Taiwan ranged from 1.65 to 1.72, whereas northern Taiwan had the lowest R0 estimate of 1.50. We found that total TB incidences in eastern Taiwan had 25 27% probabilities of total proportion of infected population exceeding 90%, whereas there were 36-66% probabilities having exceeded 20% of total proportion of infected population attributed to latently infected TB. We suggested that our Taiwan-based analysis can be extended to the context of developing countries, where TB remains a substantial cause of elderly morbidity and mortality. PMID- 22211355 TI - Core beliefs and psychological distress in patients with psoriasis and atopic eczema attending secondary care: the role of schemas in chronic skin disease. AB - BACKGROUND: The role of ingrained cognitive and emotional patterns (schemas) in patients with psoriasis and eczema has not previously been investigated. High levels of psychiatric morbidity and psychological distress observed in these populations suggest the presence of maladaptive schemas and therefore a possible target for future successful psychological intervention. OBJECTIVES: To investigate the presence of early maladaptive schemas (EMS) in patients with psoriasis and eczema and to explore their links with psychological distress. METHODS: A sample of 185 adults (psoriasis n = 55, atopic eczema n = 54, chronic disease control n = 23, normal control n = 53) completed validated, self administered questionnaires. RESULTS: Differences were found between dermatology patients and control groups. Patients with psoriasis differed on seven EMS from the normal control group: emotional deprivation (P = 0.011), social isolation (P < 0.001), defectiveness (P < 0.001), failure (P < 0.001), vulnerability to harm (P < 0.001), subjugation (P = 0.009) and emotional inhibition (P = 0.002). They differed from the chronic disease group on vulnerability to harm (P = 0.002) only. Patients with eczema differed from the normal control group on eight EMS: emotional deprivation (P < 0.001), social isolation (P < 0.001), defectiveness (P < 0.001), failure (P < 0.001), dependence (P = 0.010), vulnerability to harm (P = 0.002), subjugation (P = 0.006) and insufficient self-control (P = 0.010). EMS were strongly positively related to psychological distress experienced by dermatology patients. Hierarchical regressions demonstrated two schemas, vulnerability to harm (P < 0.001) and defectiveness (P = 0.029), to be predictive of anxiety, and social isolation (P = 0.012) and vulnerability to harm (P = 0.018) to be predictive of depression, irrespective of age and years of coping for dermatology patients. CONCLUSIONS: The findings have important theoretical and clinical implications for psychological management of patients with psoriasis and eczema. Treatment protocols may benefit by targeting schemas. Further studies are needed to investigate the benefits of schema-focused therapy in patients with skin disease. PMID- 22211356 TI - Phylogeography of the catfish Hatcheria macraei reveals a negligible role of drainage divides in structuring populations. AB - Southern South America provides a set of unusual geographic features that make it particularly interesting for studying phylogeography. The Andes Mountains run along a north-to-south axis and act as a barrier to gene flow for much of the biota of this region, with southern portions experiencing extensive historical glaciation. Geological data reveal a series of drainage reversals, shifting from Pacific Ocean outlets to Atlantic Ocean outlets because of glacier formation that dammed and reversed rivers. Once glaciers melted around 13 000 years ago, drainages returned to the Pacific Ocean. This geologic history predicts that aquatic organisms in Pacific rivers should have their closest relationships to their counterparts in Atlantic rivers immediately to their east. We tested this prediction in the trichomycterid catfish Hatcheria macraei from 38 locations using the mitochondrial cytochrome b gene. Our results show that most populations found in Pacific rivers were closely related to fish found in the adjacent Atlantic draining Rio Chubut. Surprisingly, one documented drainage reversal (from Rio Deseado into Rio Baker) did not result in movement of H. macraei. Overall, we found the lowest levels of genetic structure between most Pacific rivers that are adjacent to the Atlantic draining Rio Chubut. We also found low levels of population structuring among three of four contemporary river basins that drain to the Atlantic Ocean. Our findings suggest that drainage basin boundaries have historically not played an important long-term role in structuring between nine of 11 drainages, an unusual finding in freshwater biogeography. PMID- 22211357 TI - Electrodeposition of CuInSe2 (CIS) via electrochemical atomic layer deposition (E ALD). AB - The growth of stoichiometric CuInSe(2) (CIS) on Au substrates using electrochemical atomic layer deposition (E-ALD) is reported here. Parameters for a ternary E-ALD cycle were investigated and included potentials, step sequence, solution compositions and timing. CIS was also grown by combining cycles for two binary compounds, InSe and Cu(2)Se, using a superlattice sequence. The formation, composition, and crystal structure of each are discussed. Stoichiometric CIS samples were formed using the superlattice sequence by performing 25 periods, each consisting of 3 cycles of InSe and 1 cycle of Cu(2)Se. The deposits were grown using 0.14, -0.7, and -0.65 V for Cu, In, and Se precursor solutions, respectively. XRD patterns displayed peaks consistent with the chalcopyrite phase of CIS, for the as-deposited samples, with the (112) reflection as the most prominent. AFM images of deposits suggested conformal deposition, when compared with corresponding image of the Au on glass substrate. PMID- 22211358 TI - Functional folate receptor beta-expressing macrophages in osteoarthritis synovium and their M1/M2 expression profiles. AB - OBJECTIVE: The distribution of folate receptor (FR)-beta+ macrophages and their M1/M2 expression profiles were examined in osteoarthritis (OA) synovial tissues, and compared to those in rheumatoid arthritis (RA) synovial tissues and CD163+ macrophages in both OA and RA synovial tissues. METHOD: The phenotypes and fluorescein isothiocyanate (FITC)-folate uptake of FR-beta+ synovial macrophages were analysed by flow cytometry. The distribution of FR-beta+ macrophages in OA and RA synovial tissues was examined by immunofluorescent microscopy. Tumour necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), interleukin (IL)-10, and transforming growth factor (TGF)-beta expression in FR-beta+ macrophages was detected by double-immunostaining in both OA and RA synovial tissues. RESULTS: FR-beta+ macrophages were predominantly present in the synovial lining layer in OA patients. The proportion of CD163-FR-beta+ cells in synovial mononuclear cells (MNCs) was increased in OA compared to RA synovial tissues. FR beta(high) macrophages from OA synovial tissues represented the majority of folic acid-binding cells. Although FR-beta+ or CD163+ macrophages in the synovial tissues of OA and RA patients expressed a mixed pattern of M1 and M2 macrophage markers, there were more M2 markers expressing synovial macrophages in OA than in RA patients. CONCLUSIONS: The distribution and M1/M2 expression profiles of FR beta+ synovial macrophages were different between OA and RA synovial tissues. Thus, the findings underscore that the M1/M2 paradigm using surface markers FR beta and CD163 is an oversimplification of macrophage subsets. Functional FR-beta present on OA synovial macrophages provides a potential tool for the diagnosis and treatment of OA. PMID- 22211359 TI - Surgical treatment of sinuses by deroofing in hidradenitis suppurativa. PMID- 22211360 TI - A feature-preserving hair removal algorithm for dermoscopy images. AB - BACKGROUND/PURPOSE: Accurate segmentation and repair of hair-occluded information from dermoscopy images are challenging tasks for computer-aided detection (CAD) of melanoma. Currently, many hair-restoration algorithms have been developed, but most of these fail to identify hairs accurately and their removal technique is slow and disturbs the lesion's pattern. METHODS: In this article, a novel hair restoration algorithm is presented, which has a capability to preserve the skin lesion features such as color and texture and able to segment both dark and light hairs. Our algorithm is based on three major steps: the rough hairs are segmented using a matched filtering with first derivative of gaussian (MF-FDOG) with thresholding that generate strong responses for both dark and light hairs, refinement of hairs by morphological edge-based techniques, which are repaired through a fast marching inpainting method. Diagnostic accuracy (DA) and texture quality measure (TQM) metrics are utilized based on dermatologist-drawn manual hair masks that were used as a ground truth to evaluate the performance of the system. RESULTS: The hair-restoration algorithm is tested on 100 dermoscopy images. The comparisons have been done among (i) linear interpolation, inpainting by (ii) non-linear partial differential equation (PDE), and (iii) exemplar-based repairing techniques. Among different hair detection and removal techniques, our proposed algorithm obtained the highest value of DA: 93.3% and TQM: 90%. CONCLUSION: The experimental results indicate that the proposed algorithm is highly accurate, robust and able to restore hair pixels without damaging the lesion texture. This method is fully automatic and can be easily integrated into a CAD system. PMID- 22211361 TI - Trolox mitigates fibrosis in a bile duct ligation model. AB - Several studies suggest that free radicals may play a role in cholestatic liver injury. The aim of this work was to evaluate the role of trolox in chronic bile duct ligation (BDL). Liver injury was induced by 28-day BDL to male Wistar rats. Animals were divided in four groups of six rats. Trolox was administered daily (50 mg/kg, p.o.). Alanine aminotransferase (ALT) was quantified in serum. Fibrosis was assessed measuring liver hydroxyproline content. Reduced (GSH) and oxidized (GSSG) glutathione, lipid peroxidation, catalase (CAT), and glutathione peroxidase (GPx) activities were measured in liver. Transforming growth factor beta (TGF-beta), interleukin-6 (IL-6), and interleukin-10 (IL-10) were determined by western blot and quantified densitometrically. Our results show that trolox treatment in BDL rats prevented the increase in ALT. Collagen was increased by chronic BDL, but trolox administration preserved the normal collagen concentration. BDL produced high levels of the cytokine TGF-beta1, IL-6, and IL 10 levels. Trolox administration was effective to partially prevent the increase of TGF-beta1 and IL-6, and it was able to further augment the levels of IL-10. Oxidative stress (assessed by lipid peroxidation and liver glutathione content) was increased by BDL; this process was normalized by trolox. The activities of CAT and GPx were altered by BDL, and trolox prevented these events. We found that there is a close relationship between cholestatic liver damage and oxidative stress generation, and this was effectively prevented by trolox. Our study shows that the beneficial effects of trolox are because of its important antioxidant and immunomodulatory properties. PMID- 22211362 TI - Ovarian response to oestrous synchronization protocol based on use of reduced doses of cloprostenol in cyclic goats. AB - The objective of this study was to assess the efficacy of two reduced doses vs a high/luteolytic dose of cloprostenol on luteolytic activity and synchronization of oestrus in cyclic goats. Experiment 1, included 24 goats randomly allocated to three groups: control group (group H) received a single high dose of cloprostenol (87.5 MUg; 1.0 ml; i.m.) and M and L groups, which received half (43.75 MUg; 0.5 ml) and a third (26.25 MUg; 0.3 ml) of the highest dose, respectively. Experiment 2, included 24 goats randomly assigned to the same experimental groups. Each group was treated using two injections of cloprostenol administered 10 days apart to synchronize oestrus. Transrectal ultrasonographic scanning (US) was performed to detect the presence, size and development of corpora lutea and ovarian follicles. Furthermore, detection of oestrus was performed every 12 h between 24 and 72 h after the second injection of cloprostenol, and the luteolytic effect was verified by US. In Experiment 1, all goats that had corpora lutea at timing of treatment regressed their corpora lutea. In Experiment 2, the occurrence of oestrus and the interval between treatment to onset of oestrus were: 100%, 49.5 +/- 3.0 h; 100%, 51.0 +/- 3.0 h; and 75%, 56.0 +/- 3.5 h for H, M and L groups, respectively. The development of preovulatory follicles and occurrence of subsequent corpora lutea were similar among groups. In summary, the use of 26.25 MUg of cloprostenol is effective for the synchronization of oestrus in cyclic goats. PMID- 22211363 TI - Cerebellar volume and proton magnetic resonance spectroscopy at term, and neurodevelopment at 2 years of age in preterm infants. AB - AIM: To assess the relation between cerebellar volume and spectroscopy at term equivalent age, and neurodevelopment at 24 months corrected age in preterm infants. METHODS: Magnetic resonance imaging of the brain was performed around term equivalent age in 112 preterm infants (mean gestational age 28wks 3d [SD 1wk 5d]; birthweight 1129g [SD 324g]). Cerebellar volume (60 males, 52 females), and proton magnetic resonance spectroscopy ((1) H-MRS) of the cerebellum in a subgroup of 58 infants were assessed in relation to cognitive, fine motor, and gross motor scores on the Bayley Scales of Infant and Toddler Development-III. Different neonatal variables and maternal education were regarded possible confounders. RESULTS: Cerebellar volume was significantly associated with postmenstrual age at time of magnetic resonance imaging. Cerebellar volume corrected for postmenstrual age was significantly and positively associated with cognition. Cognitive scores related significantly with N-acetylaspartate/choline (NAA/Cho) ratio obtained from cerebellar (1) H-MRS in 53 infants. Correction for neonatal and maternal variables did not change these results. Cerebellar variables were not related to motor performance. INTERPRETATION: In preterm infants, both cerebellar volume and cerebellar NAA/Cho ratio at term equivalent age were positively associated with cognition; however, no relation was found with motor outcome at 2 years of age. These findings support the importance of the cerebellum in cognitive development in preterm infants. PMID- 22211365 TI - Improving the performance of culture-based bacterial screening by increasing the sample volume from 4 mL to 8 mL in aerobic culture bottles. AB - BACKGROUND: In the setting of bacterial detection of apheresis platelets (PLTs), the manufacturer recommended PLT inoculation volume for BacT/ALERT culture bottles (bioMerieux) ranges from 4 to 10 mL. This study compares the rate of capture of true-positive (TP) contaminations between aerobic culture bottles inoculated with either 4 or 8 mL of sample and assesses if a larger sample volume reduces time to detection. STUDY DESIGN AND METHODS: Detection of TP samples and mean time to detection were compared for 4- and 8-mL samples collected between September 1, 2003, and May 2, 2011. RESULTS: A total of 180,263 and 283,114 PLT collections were tested with an 8- and 4-mL sample, respectively. Analysis of TP rates by volume sampled show an increase in the rate of detection of TP with the 8-mL sample relative to the 4-mL sample (139 vs. 106 per million events; odds ratio, 1.31; 95% confidence interval, 0.77-2.23). Comparison of mean time to detection for TP shows a decrease in mean time to detection using 8 mL compared with 4 mL (12.36 +/- 3.7 hr to 15.97 +/- 6.3 hr, p = 0.012). CONCLUSION: Doubling the sample volume to 8 mL showed a trend in improvement for the rate of detection of TP and shortened the mean time of detection for TP by 23% when compared to a sample volume of 4 mL. The decrease in mean time to detection using a larger sample volume suggests that a shorter release time after inoculation could be achieved without significantly increasing patient risk. PMID- 22211366 TI - Evaluation of immunostimulant activity and chemoprotective effect of mangrove Rhizophora apiculata against cyclophosphamide induced toxicity in BALB/c mice. AB - Chemotherapeutic drugs available today are immunosuppressant, cytotoxic and with variety of side effects in cancer chemotherapy. Plant based immunomodulators are often an auxiliary therapy to overcome the repulsive effects of cytotoxic chemotherapeutic agents and to restore immunity with normal health. Mangroves Rhizophora apiculata (R. apiculata) extract was found to protect mice from cyclophosphamide (CTX) induced leukopenia. The leukocyte counts in the R. apiculata extract treated animals was significantly increased (10425 +/- 163 mm3) where the control group shows no significant increase (7855 +/- 282 mm3). The leukocytes count in CTX induced group treated with R. apiculata extract shows significant increase (5235 +/- 303 mm3) when compared with CTX induced group (3416 +/- 172 mm3) on the same day. The hemoglobin level of CTX induced group treated with R. apiculata extract shows increase in the level compared with the CTX induced animals. The bone marrow cellularity and alpha-esterase activity was also significantly higher compared to normal group and CTX induced group. Moreover, R. apiculata extract prevented the loss of organ weight and is increased the organ weight in treated animals. This indicates the efficiency of R. apiculata extract as an effective immunostimulant and better chemoprotectant against CTX induced toxicity in BALB/c mice. PMID- 22211367 TI - Prevalence and mental health outcomes of homicide survivors in a representative US sample of adolescents: data from the 2005 National Survey of Adolescents. AB - BACKGROUND: Each homicide leaves behind several friends and family members, or homicide survivors. However, limited information is available on the impact of homicide on adolescent survivors. The purpose of the current study was to identify the prevalence of homicide survivorship and to determine mental health outcomes within a sample of US adolescent survivors. METHODS: A nationally representative sample of American adolescents (N = 3,614) between the ages of 12 and 17 completed structured telephone interviews assessing homicide survivorship and mental health consequences including posttraumatic stress disorder (PTSD), depression, drug use, and alcohol abuse. RESULTS: Reported prevalence within this sample of losing a loved one to criminal homicide was 9%, losing a loved one to vehicular homicide was 7%, and losing a loved one to both types of homicide was 2%. Logistic regression analyses found that adolescents who reported being homicide survivors were significantly more likely to report depression, drug use, and alcohol abuse after controlling for demographic factors and other violence exposure. CONCLUSIONS: If the results from this study are generalizable to the US population, roughly 1 in 5 American adolescents may be impacted by homicide. Further, adolescents exposed to such a loss are at increased risk for mental health sequelae. Results suggest that greater attention needs to be paid to address the needs of these often underserved victims. PMID- 22211369 TI - Human herpesvirus 8-associated lymphoma mimicking cutaneous anaplastic large T cell lymphoma in a patient with human immunodeficiency virus infection. AB - Primary effusion lymphoma, a human herpesvirus 8 (HHV8)-associated lymphoma, is uncommon, and it is usually seen in human immunodeficiency virus (HIV)-infected patients. It presents as a body cavity-based lymphomatous effusion, but several cases of the so-called solid primary effusion lymphoma presenting as solid tumors without associated lymphomatous effusion have been reported. They have similar clinical, histopathological and immunophenotypical features. Most of them have a B-cell genotype. This suggests the solid variant may represent a clinicopathological spectrum of primary effusion lymphoma. We report a case of HHV8-associated lymphoma histopathologically and immunophenotypically mimicking cutaneous anaplastic large cell lymphoma. The patient was a 31-year-old HIV seropositive man presenting with skin nodules over his right thigh. Biopsy of the nodules showed anaplastic large cells infiltrating the dermis. These malignant cells strongly expressed CD3, CD30 and CD43. Cutaneous anaplastic large T-cell lymphoma was initially diagnosed, but further tests, including immunoreactivity for HHV8 protein and clonal rearrangements of immunoglobulin genes, confirmed the diagnosis of HHV8-associated B-cell lymphoma with aberrant T-cell marker expression. This case provides an example of solid primary effusion lymphoma mimicking cutaneous anaplastic large T-cell lymphoma and highlights the importance of HHV8 immunohistochemistry and molecular tests in the diagnosis of HHV8-associated lymphoma with a cutaneous presentation. PMID- 22211368 TI - Pathophysiology of hypercortisolism in depression: pituitary and adrenal responses to low glucocorticoid feedback. AB - OBJECTIVE: To test three theories of hypercortisolemia in depression-hypothalamic overdrive, impaired glucocorticoid feedback, or autonomous cortisol production. METHOD: We applied an overnight low-cortisol feedback strategy by administering metyrapone to hypercortisolemic depressed in-patients and control subjects. RESULTS: Under metyrapone, the increases of plasma adrenocorticotropic hormone (ACTH) concentrations and of basal and pulsatile ACTH secretion were not exaggerated in hypercortisolemic depressed patients compared with control subjects. ACTH approximate entropy (ApEn) did not differ at baseline or under metyrapone. Thus, neither hypothalamic overdrive nor irregular ACTH secretion was seen. We did not detect impaired cortisol feedback: the ACTH response was not reduced, and ApEn measures that are sensitive to feedback changes were comparable in both groups. Metyrapone disrupted cortisol secretory regularity in depressed and control subjects. On the baseline day, basal cortisol secretion was significantly increased and was highly irregular (high ApEn), and ACTH-cortisol cross-ApEn was markedly elevated in high-cortisol patients. CONCLUSION: Classical feed-forward overdrive and impaired feedback theories of hypercortisolemia in depression were not supported. Depressive hypercortisolemia may result from alternative pathophysiological mechanisms involving irregular basal hypersecretion of cortisol, associated with adrenal enlargement, possibly through splanchnic sympathetic activation of the adrenal cortex. PMID- 22211370 TI - Epidemiology and clinical features of pediatric psoriasis in tertiary referral psoriasis clinic. AB - Few epidemiological studies of pediatric patients with moderate to severe psoriasis have been available despite there being no approved systemic therapy for these patients. The aim of the present study was to elucidate clinical features of pediatric psoriasis in a tertiary referral psoriasis clinic. We analyzed the clinical data of 358 patients under 18 years of age referred to our clinic from other private clinics and medical centers. Our data showed a male :female ratio of 1.06:1 and a peak age of onset of 10-11 years. Of the patients, 32.4% had a positive family history. The most prevalent phenotype was plaque type (67.3%) and the mean Psoriasis Area and Severity Index score was 17.2 +/- 12.7. The most frequently affected body part was the trunk (69.5%), followed by the legs (65.3%). Exposure to sunlight and summer season improved psoriatic lesions, while stress and winter season aggravated the clinical course. Only 26.0% of patients received systemic therapy or phototherapy during the therapeutic course. Oral acitretin (11.2%) was most frequently used followed by ultraviolet B phototherapy (7.3%). The childhood group (<13 years) showed higher prevalence of guttate and generalized pustular phenotypes and more severe clinical course compared with the adolescent group (13-18 years). In conclusion, our patients showed distinctive features in clinical phenotypes, disease severity and affected body parts compared with previous reports. We also found that clinical application of systemic therapies were limited considering the severe disease state of our patients, demanding a need for more research on treatment of pediatric psoriasis. PMID- 22211371 TI - Oligoethylene-glycol-functionalized polyoxythiophenes for cell engineering: syntheses, characterizations, and cell compatibilities. AB - A series of methyl- or benzyl-capped oligoethylene glycol functionalized 2,5 dibromo-3-oxythiophenes are synthesized and successfully polymerized by either Grignard metathesis (GRIM) polymerization or reductive coupling polymerization to yield the corresponding polymers in reasonable yields and molecular weights with narrow molecular weight distribution. These synthesized polyoxythiophenes exhibit high electroactivity and stability in aqueous solution when a potential is applied. Polyoxythiophenes from different polymerization approaches display different colors after purification and spectroelectrochemical studies confirm that the difference of color is from the difference of doping state. Little cytotoxicity is observed for the polymers by in vitro cell compatibility assay. NIH3T3 fibroblast cells are well attached and proliferate on spin-coated films. These results indicate that oligoethylene-glycol-functionalized polyoxythiophenes are promising candidates as conducting biomatierals for biomedical and bioengineering applications. PMID- 22211372 TI - Selection of monoclonal antibodies against 6-oxo-M(1)dG and their use in an LC MS/MS assay for the presence of 6-oxo-M(1)dG in vivo. AB - Oxidative stress triggers DNA and lipid peroxidation, leading to the formation of electrophiles that react with DNA to form adducts. A product of this pathway, (3 (2'-deoxy-beta-d-erythro-pentofuranosyl)-pyrimido[1,2-alpha]purine-10(3H)-one), or M(1)dG, is mutagenic in bacterial and mammalian cells and is repaired by the nucleotide excision repair pathway. In vivo, M(1)dG is oxidized to a primary metabolite, (3-(2-deoxy-beta-d-erythro-pentofuranosyl)-pyrimido[1,2-alpha]purine 6,10(3H,5H)-dione, or 6-oxo-M(1)dG, which is excreted in urine, bile, and feces. We have developed a specific monoclonal antibody against 6-oxo-M(1)dG and have incorporated this antibody into a procedure for the immunoaffinity isolation of 6 oxo-M(1)dG from biological matrices. The purified analyte is quantified by LC MS/MS using a stable isotope-labeled analogue ([(15)N(5)]-6-oxo-M(1)dG) as an internal standard. Healthy male Sprague-Dawley rats excreted 6-oxo-M(1)dG at a rate of 350-1893 fmol/kg.d in feces. This is the first report of the presence of the major metabolite of M(1)dG in rodents without exogenous introduction of M(1)dG. PMID- 22211373 TI - Computed tomographic appearance of equine sinonasal neoplasia. AB - The computed tomography (CT) features of tumors involving the nasal cavity and/or paranasal sinuses of 15 horses were reviewed. The 15 tumors included five neuroendocrine tumors/neuroblastomas, two undifferentiated carcinomas, two myxosarcomas, and one each of nasal adenocarcinoma, hemangiosarcoma, chondroblastic osteosarcoma, anaplastic sarcoma, myxoma, and ossifying fibroma. All tumors except the ossifying fibroma were iso- or hypoattenuating relative to masseter muscle. Thirteen of the fifteen tumors exhibited moderate or marked osteolysis of adjacent cortical bone and 14/15 were characterized by destructive changes of the nasal turbinates, nasal septum, and/or infraorbital canal. Ten horses had moderate or marked involvement of the cribriform plate and six had clear intracranial extension of the mass. CT features were compared to radiographic findings for 10 horses. A mass was observed in 10/10 radiographic studies and mass within the caudal maxillary sinus (7/8) and rostral maxillary sinus (6/7) was identified correctly in most horses. The radiographs were least sensitive for identifying masses within the sphenopalatine sinus (0/5), cranium (0/4), and retrobulbar space (1/7) compared to CT. The radiographs also underestimated potential features of malignancy, such as severity of osteolysis or osseous production. While radiographs are a useful screening tool for identification of sinonasal masses, CT provides greater information regarding mass extent, features of malignancy, and important prognostic indicators. PMID- 22211374 TI - Recognition of nonkeratinizing morphology in oropharyngeal squamous cell carcinoma - a prospective cohort and interobserver variability study. AB - AIMS: Nonkeratinizing morphology in oropharyngeal squamous cell carcinoma (NKSCC) strongly correlates with human papillomavirus and p16 status, but as a unique diagnostic entity is not widely recognized by pathologists. We sought to prospectively examine the performance of a new histological typing system during 1 year of routine clinical practice (Aim 1) and also its reproducibility amongst six head and neck pathologists using a 40 case test set (Aim 2). METHODS AND RESULTS: The three histological types were: Type 1 (keratinizing), Type 2 (nonkeratinizing with maturation) and Type 3 (nonkeratinizing). For Aim 1, there were 85 cases. p16 immunohistochemistry was positive in five of the 18 (27.8%) cases classified as Type 1, 18 of the 19 (94.7%) as Type 2, and 47 of the 48 (97.9%) as Type 3. For Aim 2, agreement among pathologists on the test cases was best for types 1 and 3 (kappa values 0.62 and 0.56; P < 0.0001) and lowest for type 2 (kappa 0.35; P < 0.0001). All 21 cases classified as NK SCC (type 3) by any of the reviewers was p16 positive. CONCLUSIONS: Pathologists can recognize NK SCC with good agreement, and when a pathologist classifies a tumour as NK SCC, this reliably predicts p16 positivity. PMID- 22211377 TI - Why income inequality indexes do not apply to health risks. AB - Several recent papers have sought to apply inequality measures from economics, such as the Atkinson Index (AI) for inequality of income distributions, to compare the risk inequality of different mortality risk distributions in an effort to help promote efficiency and environmental justice in pollution-reducing interventions. Closer analysis suggests that such applications are neither logically coherent nor necessarily ethically desirable. Risk inequality comparisons should be based on axioms that apply to probabilistic risks, and should consider the multidimensional and time-varying nature of individual and community risks in order to increase efficiency and justice over time and generations. In light of the limitations of the AI applied to mortality risk distributions, it has not been demonstrated to have ethical or practical value in helping policymakers to identify air pollution management interventions that reduce (or minimize) risk and risk inequity. PMID- 22211376 TI - Inverse Gottron's papules: an unusual cutaneous manifestation of juvenile dermatomyositis. AB - Dermatomyositis is an autoimmune inflammatory myopathy characterized by unique cutaneous features. Gottron's papules are pathognomonic, lichenoid papules that can be found overlying the joints of the dorsal hand. Papules on the palms of the hand are less commonly seen, especially in the pediatric age group. Recognition of these inverse Gottron's papules as a sign of dermatomyositis is important as they may be the only cutaneous feature and may be a clue of underlying interstitial lung disease. PMID- 22211375 TI - Cryptic lineages and Pleistocene population expansion in a Brazilian Cerrado frog. AB - Diversification of South American species endemic to open habitats has been attributed to both Tertiary events and Pleistocene climatic fluctuations. Nonetheless, phylogeographical studies of taxa in these regions are few, precluding generalizations about the timing and processes leading to differentiation and speciation. We inferred population structure of Hypsiboas albopunctatus, a frog widely distributed in the Brazilian Cerrado. Three geographically distinct lineages were recovered in our phylogeny. The Chapada dos Guimaraes (CG) clade was the first to diverge from other populations and contains multiple haplotypes from a single population in western Cerrado, probably representing a cryptic species. The southeast clade (SE) includes populations along the southeastern limit of the range within the historical distribution of the Brazilian Atlantic forest. Finally, the Central Cerrado (CC) group includes haplotypes from the interior of Brazil that are paraphyletic relative to the SE clade. Analyses of historical demography indicate significant population expansion in the CC and SE populations, likely associated with colonization of newly formed open habitats. The divergence of populations in the CG clade occurred in the late Miocene, concordant with the uplift of the central Brazilian plateau. Divergence of the SE clade from the CC occurred during the mid Pleistocene. Thus, both Tertiary geological events and Pleistocene climatic fluctuations promoted divergences among lineages. Our study reveals a complex history of diversification in the Cerrado, a morphoclimatic domain highly threatened because of anthropogenic habitat alteration. We identified surprisingly deep divergences in a widely distributed frog, indicating that the Cerrado is not a barrier-free habitat and that its diversity is likely underestimated. PMID- 22211378 TI - Removal of sea urchin spines using erbium-doped yttrium aluminum garnet ablation. PMID- 22211380 TI - Cognitive and emotional health risk perceptions among people living in poverty. AB - Many theories of risk perception and health behavior examine cognitive dimensions of risk (i.e., perceived susceptibility or severity) but not emotional dimensions. To address this gap, the authors examined the emotional component of risk perception (as worry) and its relation to cognitive assessments of risk, self-efficacy and response efficacy, and health protective action. Although people in poverty are at high risk for many health conditions, little is known about how concerned they are about these conditions or how their risk perceptions influence health actions. African Americans and Whites with incomes<=$35,000 were surveyed (N=431). Participants reported their worry level for 10 health risks. Among their highest worry risks, they identified the risk they took the most action and the risk they took the least action to prevent. Worry was low or moderate for each health risk and chronic conditions were of the most concern. For high- and low-action risks, response efficacy moderated the relation between cognitive risk perception and health protective action. For low-action risks, decisions to act were affected independently by cognitive and emotional responses. The results support the Risk Perception Attitude Framework and indicate the importance of using cognitive and emotional dimensions of risk in behavior change models. PMID- 22211382 TI - Sebum, acne, skin elasticity, and gender difference - which is the major influencing factor for facial pores? AB - BACKGROUND: Enlarged facial pores have been esthetic problems and have become a matter of cosmetic concern. Several factors are supposed to be related to the enlargement of facial pores, although scientific evaluations were not performed yet. OBJECTIVE: To assess the correlation between facial pores and possible relating factors such as age, gender, sebum secretion, skin elasticity, and the presence of acne, using objective bioengineering instruments. METHODS: Sixty volunteers, 30 males and 30 females, participated in this study. Various parameters of facial pores were assessed using the Robo Skin Analyzer. The facial sebum secretion and skin elasticity were measured using the Sebumeter and the Cutometer, respectively. These data were compared and correlated to examine the possible relationship between facial pores and age, sebum secretion and skin elasticity, according to gender and the presence of acne. RESULTS: Male gender and the existence of acne were correlated with higher number of facial pores. Sebum secretion levels showed positive correlation with facial pores. The R7 parameter of skin elasticity was negatively correlated with facial pores, suggesting increased facial pores with decreased skin elasticity. However, the age and the severity of acne did not show a definite relationship with facial pores. CONCLUSION: Male, increased sebum and decreased skin elasticity were mostly correlated with facial pore development. Further studies on population with various demographic profiles and more severe acne may be helpful to elucidate the potential effect of aging and acne severity on facial pores. PMID- 22211383 TI - Detection of HNA-3a and -3b antibodies using transfected cell lines and recombinant proteins. AB - BACKGROUND: HNA-3 is a diallellic system located on choline transporter-like protein 2 (CTL2), defined by a polymorphism at Amino Acid 154. HNA-3a antibodies are of clinical importance in transfusion-related acute lung injury but antibody detection requires labor-intensive granulocyte isolation from HNA-typed donors and the use of techniques such as the granulocyte agglutination test or granulocyte immunofluorescence test. Also, there is no commercial test for detection of HNA-3 antibodies. STUDY DESIGN AND METHODS: HEK293 cells were transfected to generate stable cell lines expressing CTL2 fragments (Amino Acids 55-230) and full-length membrane bound CTL2 with HNA-3a and -3b epitopes. Soluble fragments were used in enzyme-linked immunosorbent assays to detect HNA-3 antibodies. The cell lines expressing full-length proteins were trypsin treated to remove HLA antigens and frozen at -80 degrees C. Thawed cells were then used to detect HNA-3 antibodies by flow cytometry. RESULTS: Glycosylated and soluble CTL2 fragments were correctly recognized by 15 of 31 anti-HNA-3a sera and by both available anti-HNA-3b sera. Twenty-one anti-HLA sera reacted variably with untreated cell lines expressing full-length CTL2. After trypsin treatment of the cell lines, reactivity with HLA antisera was abrogated and all 31 anti-HNA-3a and two anti-HNA-3b sera bound to the corresponding cell line. CONCLUSION: Whereas soluble, glycosylated CTL2 fragments cannot be used for the detection of HNA-3 antibodies, the HEK293 cells expressing full-length CTL2 proteins were useful in the detection of HNA-3 antibodies even in the presence of HLA antibodies. Moreover, the cell lines can be stored for at least 6 months before use. PMID- 22211384 TI - Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease - treatable motor neuron diseases of childhood. PMID- 22211385 TI - FZD6 encoding the Wnt receptor frizzled 6 is mutated in autosomal-recessive nail dysplasia. AB - BACKGROUND: Isolated nail dysplasia is rare and has been reported in only a small number of families. OBJECTIVES: To describe and characterize two Pakistani families with an autosomal-recessive inherited nail dysplasia. METHODS: Genome wide linkage analysis; mutation screening of candidate genes by Sanger sequencing; cloning of FZD6 and protein analyses; immunohistochemistry. RESULTS: We mapped this genodermatosis to chromosome 8q22.3, and identified a homozygous nonsense mutation c.1750G>T (p.E584X) in the frizzled 6 (FZD6) gene in all affected individuals. Immunohistochemical analyses in nail sections from healthy individuals revealed strong expression of FZD6 in the ventral nail matrix and a less pronounced expression of FZD6 in the nail bed. CONCLUSIONS: FZD6 belongs to a family of proteins that serve as receptors in Wnt signalling pathways, and has been shown to act as a negative regulator of the canonical Wnt/beta-catenin signalling cascade and a positive regulator of the noncanonical Wnt or planar cell polarity pathway. The present results therefore suggest that FZD6 plays a pivotal role in the growth and guidance of the nail plate in humans by acting as a molecular switch between different Wnt pathways. Previous studies have identified mutations in the RSPO4 and LMX1B components of the Wnt pathway in patients with the hypoplastic nail disorders anonychia and nail-patella syndrome, respectively. Only recently, FZD6 mutations were identified in isolated nail dysplasia. The present results emphasize the important role of the Wnt pathways in nail development and increase understanding of Wnt-mediated developmental events in general. PMID- 22211386 TI - Essential oil of Croton zehntneri and its major constituent anethole display gastroprotective effect by increasing the surface mucous layer. AB - Croton zehntneri, a plant native to northeastern Brazil, is widely used in folk medicine to treat gastrointestinal problems and has rich essential oil content. The effects of the essential oil of Croton zehntneri (EOCZ) and its main constituent anethole on several models of gastric lesions were studied in mice and rats. Oral treatment with EOCZ and anethole, both at doses of 30-300 mg/kg, caused similar and dose-dependent gastroprotection against ethanol- and indomethacin-induced gastric damage, but did not change cold-restraint stress induced ulcers in rats. Furthermore, EOCZ and anethole (both at 30 and 300 mg/kg) similarly and significantly increased the mucus production by the gastric mucosa, measured by Alcian blue binding, in ethanol-induced ulcer model. However, at the same doses, neither EOCZ nor anethole promoted significant alteration in gastric production of non-protein sulfhydryl groups. In pylorus-ligated model, neither EOCZ nor anethole (both at 30 and 300 mg/kg) had a significant effect on the volume of gastric juice, pH, or total acidity. The results of this study show for the first time that EOCZ possesses a gastroprotective potential, an effect mostly attributed to the action of anethole. This activity is related predominantly to the ability of EOCZ and anethole to enhance the production of gastric wall mucus, an important gastroprotective factor. Furthermore, they suggest that EOCZ has potential therapeutic application for the treatment of gastric ulcers. PMID- 22211388 TI - Prominent CD56 expression by damaged and regenerating muscle fibers in the skin. AB - BACKGROUND: Antibodies to CD56 label natural killer cells as well as tissues with neural and neuroendocrine differentiation. Despite its apparently limited distribution, other conditions may unexpectedly show strong CD56 expression. METHODS: We report three cases to document another setting with strong expression of CD56 in the skin: damaged and/or regenerating muscle fibers. One case of cutaneous lupus erythematosus, one case of lymphomatoid granulomatosis, and one case of a dermal scar adjacent to cutaneous muscle fibers were evaluated with a panel of antibodies, including CD56. RESULTS: All cases showed histopathologic evidence of muscle fiber damage in the setting of lymphocytic infiltration or trauma. All cases showed prominent expression of CD56 by damaged and/or regenerating muscle fibers. The degree of CD56 expression was directly proportional to the proximity to the injury site and inversely proportional to fiber diameter. CONCLUSIONS: Even though CD56 is a useful marker for certain cytotoxic lymphomas and neural/neuroendocrine neoplasms, its expression is not limited to these conditions. Our cases highlight another unexpected example of strong CD56 expression in the skin: damaged and/or regenerating muscle fibers. The growing list of CD56-positive conditions suggests that this marker may not be as specific as initially assumed. PMID- 22211389 TI - N7-glycidamide-guanine DNA adduct formation by orally ingested acrylamide in rats: a dose-response study encompassing human diet-related exposure levels. AB - Acrylamide (AA) is formed during the heating of food and is classified as a genotoxic carcinogen. The margin of exposure (MOE), representing the distance between the bench mark dose associated with 10% tumor incidence in rats and the estimated average human exposure, is considered to be of concern. After ingestion, AA is converted by P450 into the genotoxic epoxide glycidamide (GA). GA forms DNA adducts, primarily at N7 of guanine (N7-GA-Gua). We performed a dose response study with AA in female Sprague-Dawley (SD) rats. AA was given orally in a single dosage of 0.1-10 000 MUg/kg bw. The formation of urinary mercapturic acids and of N7-GA-Gua DNA adducts in liver, kidney, and lung was measured 16 h after application. A mean of 37.0 +/- 11.5% of a given AA dose was found as mercapturic acids (MAs) in urine. MA excretion in urine of untreated controls indicated some background exposure from endogenous AA. N7-GA-Gua adduct formation was not detectable in any organ tested at 0.1 MUg AA/kg bw. At a dose of 1 MUg/kg bw, adducts were found in kidney (around 1 adduct/10(8) nucleotides) and lung (below 1 adduct/10(8) nucleotides) but not in liver. At 10, respectively, 100 MUg/kg bw, adducts were found in all three organs, at levels close to those found at 1 MUg AA/kg, covering a range of about 1-2 adducts/10(8) nucleotides. As compared to DNA adduct levels from electrophilic genotoxic agents of various origin found in human tissues, N7-GA-Gua adduct levels within the dose range of 0.1-100 MUg AA/kg bw were at the low end of this human background. We propose to take the background level of DNA lesions in humans more into consideration when doing risk assessment of food-borne genotoxic carcinogens. PMID- 22211390 TI - Lifestyle and the risk of dementia in Japanese-american men. AB - OBJECTIVES: To determine whether adhering to a healthy lifestyle in midlife may reduce the risk of dementia. DESIGN: Case-control study nested in a prospective cohort. SETTING: The Honolulu-Asia Aging Study, Oahu, Hawaii. PARTICIPANTS: Three thousand four hundred sixty-eight Japanese-American men (mean age 52 in 1965 1968) examined for dementia 25 years later. MEASUREMENTS: Men at low risk were defined as those with the following midlife characteristics: nonsmoking, body mass index (BMI) less than 25.0 kg/m(2) , physically active, and having a healthy diet (based on alcohol, dairy, meat, fish, fruits, vegetables, cereals, and ratio of monounsaturated to saturated fat). Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for developing overall dementia, Alzheimer's disease (AD), and vascular dementia (VaD), adjusting for potential confounders. RESULTS: Dementia was diagnosed in 6.4% of men (52.5% with AD, 35.0% with VaD). Examining the risk factors individually, BMI was most strongly associated with greater risk of overall dementia (OR = 1.87, 95% CI = 1.26-2.77; BMI > 25.0 vs <22.6 kg/m(2) ). All of the individual risk factors except diet score were significantly associated with VaD, whereas none were significantly associated with AD alone. Men with all four low-risk characteristics (7.2% of the cohort) had the lowest OR for overall dementia (OR = 0.36, 95% CI = 0.15-0.84). There were no significant associations between the combined low-risk characteristics and the risk of AD alone. CONCLUSION: Among Japanese-American men, having a healthy lifestyle in midlife is associated with a lower risk of dementia in late life. PMID- 22211391 TI - Propagation of cutaneous thermal injury: a mathematical model. AB - Cutaneous burn wounds represent a significant public health problem with 500,000 patients per year in the USA seeking medical attention. Immediately after skin burn injury, the volume of the wound burn expands due to a cascade of chemical reactions, including lipid peroxidation chain reactions. Such expansion threatens life and is therefore highly clinically significant. Based on these chemical reactions, the present paper develops for the first time a three-dimensional mathematical model to quantify the propagation of tissue damage within 12 hours post initial burn. We use the model to investigate the effect of supplemental antioxidant vitamin E for intercepting propagation. We show, for example, that if tissue levels of vitamin E tocotrienol are increased, postburn, by five times then this would slow down the lipid peroxide propagation by at least 50%. We chose the alpha-tocotrienol form of vitamin E as it is a potent inhibitor of 12 lipoxygenase, which is known to propagate oxidative lipid damage. Our model is formulated in terms of differential equations, and sensitivity analysis is performed on the parameters to ensure the robustness of the results. PMID- 22211392 TI - Improved knowledge about conception rates influences the decision to stop insemination in dairy cows. AB - The conception rate in dairy cows is dependent on a number of cow factors such as days in milk and insemination number. Unfortunately, some of these factors were not accounted for in optimal insemination and replacement decision models. By using wrong estimates of the conception rate, the calculated optimal insemination and replacement policy might differ from the real optimal insemination and replacement policy. The objective of this study was to evaluate different sets of conception rates with an increasing level of accuracy to determine the insemination policy. An existing dynamic program for optimal insemination and replacement was used to compare three different scenarios in the estimation of conception rates, based on the reproductive performance of Dutch dairy cattle: (i) constant conception rate throughout lactation, (ii) conception rate dependent on parity and months in milk, and (iii) conception rate dependent on parity, months in milk and insemination number. The time step of the model was 30.4 days (1 month). The discounted future cash flow of culling a cow at each time step (replace a heifer immediately) was compared with keeping that cow under optimal future decisions. The difference between immediate culling and optimal decisions is defined as the retention pay-off. The insemination value was calculated as the difference between the future cash flow between immediate insemination of a cow and waiting one time-step. The results show that the difference in the insemination values and the optimal time to stop insemination depend on parity, lactation stage and the relative milk yield. In older cows with equal milk yields and at the same months in milk, the insemination value was lower than in younger cows. Within a parity, the insemination value was higher for cows with a higher milk yield. On individual cow level, using more accurate conception rate as input in the optimal insemination and replacement model might reduce miscalculation of the economic consequences for at least of ?20-?38 per cow per year. Basing insemination decisions on less accurate input of the probabilities of conception, however, did not have an economic consequence at the herd level. In conclusion, using the appropriate conception rate as input in the optimal insemination and replacement model would increase the precise decision for the optimal time to stop insemination and hence improve the reproductive management efficacy. PMID- 22211393 TI - Carrier frequency of the recurrent mutation c.1643_1644delTG in the XPC gene and birth prevalence of the xeroderma pigmentosum in Morocco. AB - Xeroderma pigmentosum (XP) is an autosomal recessive inherited disease which is genetically heterogeneous. The prevalence of this genodermatosis is estimated to be 1/1 000 000 in the USA; it is more common in Japan and probably in other populations with high levels of consanguinity. The molecular diagnosis and identification of mutation in patients requires the knowledge of the causative gene by the determination of XP complementation groups. Soufir et al. have reported that XPC is the major disease-causing gene with a recurrent mutation in the Mediterranean region. The mutation c.1643_1644delTG (p.Val548AlafsX25) represents alone 74% of all the XP probands tested and 87% in XP type C in North African patients with founder effect. We used molecular epidemiological methods in the present study to calculate the frequency of heterozygote for this mutation in Moroccan newborns and estimate the prevalence of XP in the Moroccan population. DNA extracted from umbilical cord blood samples of 250 newborns were tested for the recurrent XPC mutation c.1643_1644delTG using real-time polymerase chain reaction. Heterozygotes profiles were confirmed by direct sequencing. Among 250 newborns tested, one subject was heterozygous for the mutation c.1643_1644delTG. The carrier frequency was estimated to be 1/250 which would imply that the prevalence of XP would be approximately 1/80 504 considering the effect of consanguinity. This is the first report of the prevalence of XP in an Arab country and it shows that the prevalence of xeroderma pigmentosum is higher than that found in Europe and the USA. PMID- 22211394 TI - Risk factors associated with transmission of Mycobacterium avium subsp. paratuberculosis to calves within dairy herd: a systematic review. AB - BACKGROUND: Paratuberculosis has a worldwide distribution and many countries have implemented control programs to prevent transmission among and within herds. For these programs to be efficient, knowledge of the risk factors involved in transmission is essential. OBJECTIVES: Systematically review the scientific literature concerning risk factors associated with Mycobacterium avium subsp. paratuberculosis (MAP) transmission to dairy calves. STUDY DESIGN: Systematic review. METHODS: An electronic search was done in PubMed and CAB to retrieve references relevant to answer at least 1 of the 5 questions concerning neonatal environment, colostrum, milk, housing of calves, and contact of calves with adult cow feces as risk factors in MAP transmission. A 1st screening was done using titles only, then abstracts, and finally full-length articles were reviewed for relevance. From the articles selected, risk factors and presence of a significant association between these risk factors and MAP transmission were recorded. RESULTS: Twenty-three articles from 11 different countries and published in 12 different journals were reviewed. The most common study design was cross sectional (n = 16). The case definition and diagnostic tests used were very variable among studies, but serum ELISA was used in most studies (n = 14). The study unit was the herd in 18 studies. CONCLUSIONS AND CLINICAL IMPORTANCE: The contact of calves with adult cow feces is the most important risk factor in MAP transmission. The 5 categories of risk factors are linked to one another. PMID- 22211396 TI - Coordination of a mitochondrial superoxide burst during the hypersensitive response to bacterial pathogen in Nicotiana tabacum. AB - We characterized responses of Nicotiana tabacum to pathovars of the bacterial pathogen Pseudomonas syringae. These included a compatible response associated with necrotic cell death (pv. tabaci), an incompatible response that included hypersensitive response (HR) cell death (pv. maculicola) and an incompatible response that induced defences but lacked the HR (pv. phaseolicola). Signalling molecules (salicylic acid, nitric oxide, H(2)O(2)) known to induce the stress responsive tobacco Aox1a gene [that encodes the mitochondrial electron transport chain (ETC) component alternative oxidase (AOX)] accumulated preferentially during the HR, but this did not elevate Aox1a transcript or AOX protein, while the transcript and protein were strongly elevated during the defence response to pv. phaseolicola. In addition, matrix manganese superoxide dismutase (MnSOD) activity declined during the HR, unlike its response to the other pathovars, and unlike the response of other superoxide dismutase (SOD) enzymes. Finally, the HR (but not the response to pv. phaseolicola or pv. tabaci) was accompanied by an early and persistent mitochondrial superoxide (O(2)(-)) burst prior to cell death. We propose that a coordinated response of the major ETC mechanism to avoid O(2)(-) generation (AOX) and the sole enzymatic means to scavenge mitochondrial O(2)(-) (MnSOD) is important in the determination of cell fate during responses to pathogen. PMID- 22211397 TI - Health locus of control, acculturation, and health-related Internet use among Latinas. AB - Among individuals residing in the United States, the Internet is the third most used source for obtaining health information. Little is known, however, about its use by Latinas. To understand health-related Internet use among Latinas, the authors examined it within the theoretical frameworks of health locus of control and acculturation. The authors predicted that acculturation would serve as a mediator between health locus of control and health-related Internet use, age and health-related Internet use, income and health-related Internet use, and education and health-related Internet use. Data were collected via a 25-minute self-report questionnaire. The sample consisted of 932 young (M age = 21.27 years), low-income Latinas. Using structural equation modeling, the authors observed that acculturation partially mediated the relation between health locus of control and health-related Internet use and fully mediated the relations among age, income, and Internet use. An internal health locus of control (p < .001), younger age (p < .001), and higher income (p < .001) were associated with higher levels of acculturation. Higher levels of acculturation (p < .001) and an internal health locus of control (p < .004) predicted health-related Internet use. The Internet is a powerful tool that can be used to effectively disseminate information to Latinas with limited access to health care professionals. These findings can inform the design of Internet-based health information dissemination studies targeting Latinas. PMID- 22211395 TI - Annual research review: phenotypic and causal structure of conduct disorder in the broader context of prevalent forms of psychopathology. AB - BACKGROUND: A better understanding of the nature and etiology of conduct disorder (CD) can inform nosology and vice versa. We posit that any prevalent form of psychopathology, including CD, can be best understood if it is studied in the context of other correlated forms of child and adolescent psychopathology using formal models to guide inquiry. METHODS: Review of both cross-sectional and longitudinal studies of the place of CD in the phenotypic and causal structure of prevalent psychopathology, with an emphasis on similarities and differences between CD and oppositional defiant disorder (ODD). Papers were located using Web of Science by topic searches with no restriction on year of publication. RESULTS: Although some important nosologic questions remain unanswered, the dimensional phenotype of CD is well defined. CD differs from other disorders in its correlates, associated impairment, and course. Nonetheless, it is robustly correlated with many other prevalent dimensions of psychopathology both concurrently and predictively, including both other 'externalizing' disorders and some 'internalizing' disorders. Based on emerging evidence, we hypothesize that these concurrent and predictive correlations result primarily from widespread genetic pleiotropy, with some genetic factors nonspecifically influencing risk for multiple correlated dimensions of psychopathology. In contrast, environmental influences mostly act to differentiate dimensions of psychopathology from one another both concurrently and over time. CD and ODD share half of their genetic influences, but their genetic etiologies are distinct in other ways. Unlike most other dimensions of psychopathology, half of the genetic influences on CD appear to be unique to CD. In contrast, ODD broadly shares nearly all of its genetic influences with other disorders and has little unique genetic variance. CONCLUSIONS: Conduct disorder is a relatively distinct syndrome at both phenotypic and etiologic levels, but much is revealed by studying CD in the context of its causal and phenotypic associations with other disorders over time. Advancing and refining formal causal models that specify the common and unique causes and biological mechanisms underlying each correlated dimension of psychopathology should facilitate research on the fundamental nature and nosology of CD. PMID- 22211399 TI - Water pollution risk associated with natural gas extraction from the Marcellus Shale. AB - In recent years, shale gas formations have become economically viable through the use of horizontal drilling and hydraulic fracturing. These techniques carry potential environmental risk due to their high water use and substantial risk for water pollution. Using probability bounds analysis, we assessed the likelihood of water contamination from natural gas extraction in the Marcellus Shale. Probability bounds analysis is well suited when data are sparse and parameters highly uncertain. The study model identified five pathways of water contamination: transportation spills, well casing leaks, leaks through fractured rock, drilling site discharge, and wastewater disposal. Probability boxes were generated for each pathway. The potential contamination risk and epistemic uncertainty associated with hydraulic fracturing wastewater disposal was several orders of magnitude larger than the other pathways. Even in a best-case scenario, it was very likely that an individual well would release at least 200 m3 of contaminated fluids. Because the total number of wells in the Marcellus Shale region could range into the tens of thousands, this substantial potential risk suggested that additional steps be taken to reduce the potential for contaminated fluid leaks. To reduce the considerable epistemic uncertainty, more data should be collected on the ability of industrial and municipal wastewater treatment facilities to remove contaminants from used hydraulic fracturing fluid. PMID- 22211398 TI - The hospital environment for end of life care of older adults and their families: an integrative review. AB - AIM: This article is a report of an integrative review to identify key elements of the physical hospital environment for end of life care of older adults and their families as reported by patients, relatives, staff and policy makers. BACKGROUND: Globally ageing populations and increases in long-term illness mean that more people will need palliative care in the future. Despite policy initiatives to increase end of life care in the community, many older adults prefer, and will require, end of life care in hospital. Providing an appropriate physical environment for older adults requiring end of life care is important given concerns about hospital environments for this group. DATA SOURCES: Thirteen databases from 1966 to 2010 were searched including ASSIA, BNI, Cochrane Library, CINAHL, EMBASE, MEDLINE, PsycINFO, Social Science Citation Index, the Science Citation Index, HMIC and the National Research Register. Reference and citation tracking was performed on included publications. REVIEW METHODS: An integrative review was conducted. Two reviewers independently screened titles and abstracts for inclusion and completed data extraction. Study quality is not reported as this poses methodological difficulties in integrative reviews. Data synthesis involved thematic analysis informed by the findings of included literature. RESULTS: Ten articles were included. Four themes were identified: privacy as needed; proximity (physically and emotionally) to loved ones, home and nature; satisfaction with the physical environment; and deficiencies in physical environment. CONCLUSION: Little evidence exists about physical hospital environments for end of life care of older adults and their families. More research is required in this field. PMID- 22211400 TI - Traffic-related pollutants and wheezing in children. AB - BACKGROUND AND AIMS: Traffic related air pollutants from diesel engine exhaust are found in fine and ultrafine particulates. The Cincinnati Childrens Allergy and Air Pollution Birth Cohort Study was initiated to determine if early exposure to these pollutants increased risk for development of early atopic sensitization and allergic respiratory disease phenotypes in children. MATERIALS AND METHODS: Over 700 infants born to at least one atopic parent were recruited to participate in a birth cohort study. Participants received annual medical evaluations and skin testing to two foods and 15 aeroallergens from ages 1-4 and again at age seven. Indoor home assessments were conducted at age one. Outdoor traffic related air pollutant exposure was estimated using proximity and land use regression (LUR) modeling. Clinical outcomes were based upon case definitions for wheezing at ages one and three and allergic rhinitis at age three. RESULTS: At age 1 exposure to stop and go traffic was associated with wheezing during infancy and recurrent wheezing was twice more likely among African-American infants. Exposure to high levels of elemental carbon attributable to traffic (ECAT) estimated with a LUR model predicted recurrent wheezing at age 1 as well as multiple wheezing phenotypes at age 3. Exposure to high levels of endotoxin combined with multiple dogs during the first year reduced risk for recurrent wheezing during the first year of life. Early sensitization to tree pollen aeroallergens in foods (egg white, milk) in infancy increased likelihood of allergic rhinitis during age 3. CONCLUSION: High exposure to traffic related air pollutants represent independent risk factors for wheezing during infancy and early childhood. Further studies are needed to explore long-term effects of traffic exposure on development of asthma in childhood. Scientific significance. Reduction and mitigation of exposure to traffic related air pollutants could reduce risk of respiratory illnesses during childhood. PMID- 22211401 TI - The plastid redox insensitive 2 mutant of Arabidopsis is impaired in PEP activity and high light-dependent plastid redox signalling to the nucleus. AB - The photosynthetic apparatus is composed of proteins encoded by genes from both the nuclear and the chloroplastic genomes. The activities of the nuclear and chloroplast genomes must therefore be closely coordinated through intracellular signalling. The plastids produce multiple retrograde signals at different times of their development, and in response to changes in the environment. These signals regulate the expression of nuclear-encoded photosynthesis genes to match the current status of the plastids. Using forward genetics we identified PLASTID REDOX INSENSITIVE 2 (PRIN2), a chloroplast component involved in redox-mediated retrograde signalling. The allelic mutants prin2-1 and prin2-2 demonstrated a misregulation of photosynthesis-associated nuclear gene expression in response to excess light, and an inhibition of photosynthetic electron transport. As a consequence of the misregulation of LHCB1.1 and LHCB2.4, the prin2 mutants displayed a high irradiance-sensitive phenotype with significant photoinactivation of photosystem II, indicated by a reduced variable to maximal fluorescence ratio (F(v) /F(m) ). PRIN2 is localized to the nucleoids, and plastid transcriptome analyses demonstrated that PRIN2 is required for full expression of genes transcribed by the plastid-encoded RNA polymerase (PEP). Similarly to the prin2 mutants, the ys1 mutant with impaired PEP activity also demonstrated a misregulation of LHCB1.1 and LHCB2.4 expression in response to excess light, suggesting a direct role for PEP activity in redox-mediated retrograde signalling. Taken together, our results indicate that PRIN2 is part of the PEP machinery, and that the PEP complex responds to photosynthetic electron transport and generates a retrograde signal, enabling the plant to synchronize the expression of photosynthetic genes from both the nuclear and plastidic genomes. PMID- 22211402 TI - Randomized clinical trial comparing two methods for endovenous laser ablation of incompetent perforator veins in thigh and great saphenous vein without evidence of saphenofemoral reflux. AB - BACKGROUND: Percutaneous ablation of incompetent perforators has been introduced as a safe and efficacious alternative. OBJECTIVE: To compare two methods of treating incompetent thigh perforator and great saphenous veins (GSV). MATERIALS AND METHODS: Patients with varicose veins of CEAP C2 and C3 with incompetent perforating veins (IPVs) in the thigh without evidence of saphenofemoral reflux and with obvious venous reflux from IPVs into the GSV distal to IPVs were included. Endovenous laser ablation was done using two methods (IPV ablation (IPVA) versus GSV ablation: GSVA). Their technical success rate, clinical success rate, and complications were compared at 1 week, and 1, 3, 6, and 12 months. RESULTS: Sixty-nine consecutive patients were randomized to IPVA (n = 34) or GSVA (n = 35). Technical success was significantly lower with IPVA than GSVA (p = .002). Clinical success, defined as continued closure of treated veins, was similar with IPVA and GSVA (96.1% vs 100% at 1 week, 100% vs 97.1% at 1 month, and 100% for both at 3, 6, and 12 months, respectively). CONCLUSION: IPVA has clinical results and complications similar to those of GSVA in individuals with C2 and C3 chronic venous disease with IPVs in the thigh combined with incompetent GSV, but its higher technical failure rate makes it difficult to choose it as the primary treatment method. PMID- 22211403 TI - Patterns and processes of dispersal behaviour in arvicoline rodents. AB - A good understanding of mammalian societies requires measuring patterns and comprehending processes of dispersal in each sex. We investigated dispersal behaviour in arvicoline rodents, a subfamily of mammals widespread in northern temperate environments and characterized by a multivoltine life cycle. In arvicoline rodents, variation in life history strategies occurs along a continuum from precocial to delayed maturation that reflects seasonal and ecological fluctuations. We compared dispersal across and within species focusing on the effects of external (condition-dependent) and internal (phenotype-dependent) factors. Our data revealed substantial, unexplained variation between species for dispersal distances and a strong variation within species for both dispersal distance and fraction. Some methodological aspects explained variation across studies, which cautions against comparisons that do not control for them. Overall, the species under consideration display frequent short-distance dispersal events and extremely flexible dispersal strategies, but they also have hitherto unexpected capacity to disperse long distances. Female arvicolines are predominantly philopatric relative to males, but we found no clear association between the mating system and the degree of sex bias in dispersal across species. Dispersal is a response to both various proximate and ultimate factors, including competition, inbreeding avoidance, mate searching and habitat quality. In particular, our review suggests that costs and benefits experienced during transience and settlement are prime determinants of condition dependence. Patterns of phenotype-dependent dispersal are idiosyncratic, except for a widespread association between an exploration/activity syndrome and natal dispersal. Consequences for population dynamics and genetic structures are discussed. PMID- 22211405 TI - Overview of upcoming advances in colonoscopy. AB - Although colonoscopy is a very commonly carried out procedure, it is not without its problems, including a risk of perforation and significant patient discomfort, especially associated with looping formation. Furthermore, looping formation may prevent a complete colonoscopy from being carried out in certain patients. The conventional colonoscope has not changed very much since its original introduction. We review promising technologies that are being promoted as a way to address the problems with current colonoscopy. There are some methods to prevent looping formation, including overtube, variable stiffness, computer guided scopes, Aer-O-Scope, magnetic endoscopic imaging and the capsule endoscope. In recent years, with the progress of microelectromechanical and microelectronic technologies, many biomedical and robotic researchers are developing autonomous endoscopes with miniaturization of size and integration functionality that represent state of the art of the micro-robotic endoscope. The initial results by using aforementioned methods seem promising; however, there are some conflicting reports of clinical trials with the overtube colonoscope, the computer-guided scope and the variable stiffness colonoscope. There are also some limitations in the use of the Aer-o-scope and the capsule endoscope. The autonomous endoscope is based on a self-propelling property that is able to avoid looping completely. This novel technology could potentially become the next generation endoscope; however, there are still critical techniques to be approached in order to develop the effective and efficient novel endoscope. PMID- 22211406 TI - Pneumatic dilation for achalasia cardia: reduction in lower esophageal sphincter pressure in assessing response and factors associated with recurrence during long term follow up. AB - BACKGROUND: Data on utility of post-pneumatic dilation (PD) lower esophageal sphincter (LES) pressure measurement in evaluating short and long-term efficacy of dilation, which tears the non-relaxing LES in achalasia, are scanty. METHODS: Post-PD LES pressure was measured in 72/98 patients with achalasia. The best cut off pressure classifying responders and non-responders was determined by receiver operating characteristic (ROC) curve. Factors associated with non-response and recurrence were evaluated. RESULTS: Of 98 patients (41.1 +/- 13.3 years, 58 male), 75 improved, three had perforation requiring surgery, and 20 did not respond to the first PD session. Of 18/20 patients undergoing a second PD, 11 improved and six non-responders needed myotomy. 37/58 (71%) male and 17/40 (42.5%) female patients had a first PD with a 35-mm balloon (P = 0.03). Age and gender of patients did not influence outcome. LES pressure was lower in responders or in those having recurrence than in non-responders (17 mmHg [6.4 75], 11 mmHg [4.6-31]vs 25 mmHg [13-55]). On the ROC curve, 22.5 mmHg was the best cut-off value differentiating responders and non-responders (area under curve [AUC] 0.73). Of the 86 patients responding to PD, 20 had recurrence. Patients who responded to one session of PD or had LES pressure <10 mmHg after the procedure recurred less often, although there was no relationship with age and gender. CONCLUSION: Post-PD LES pressure measurement is useful to assess treatment response. Patients responding to the first session and those with post PD LES pressure <10 mmHg tended to recur less. Age and gender did not influence outcome, which might be related to preferential use of a 35-mm balloon, particularly for male patients, during the first session. PMID- 22211407 TI - Safety measures for gastrointestinal endoscopy in patients receiving antithrombotic therapy. AB - AIM: Owing to carelessness of endoscopists, invasive procedures, such as biopsy, are sometimes carried out inadvertently in patients receiving antithrombotic therapy. The aim of the present study was to retrospectively evaluate the actual status of such careless mistakes and the efficacy of new safety measures. METHODS: A questionnaire survey was conducted in 34 endoscopists at Toranomon Hospital about experiences of careless mistakes and experiences of anxiety before and after the procedure. 'Anxiety before procedure' was defined as the experience of discontinuing a given procedure because endoscopists remembered that the patient was receiving antithrombotic therapy, and 'anxiety after procedure' was defined as the experience of feeling anxious about the status of medication after the invasive procedure. A new measure was introduced at Health Management Center in August 2009. In this measure, endoscopists directly interview each patient about the status of medication just before examination, and attach forceps valves of one of two colors depending on the status of medication. A blue forceps valve is attached for patients undergoing antithrombotic therapy, and a conventional black forceps valve is attached for patients not undergoing antithrombotic therapy. Six months after introduction, a questionnaire survey was conducted in 10 endoscopists in this center. RESULTS: Approximately half of endoscopists (18/34) experienced such careless mistakes. 'Anxiety' had been experienced by approximately 80%. After introduction, there was no report of careless mistakes and frequency of 'anxiety' evaluated by visual analog scale score decreased significantly. CONCLUSION: This new safety measure is expected to facilitate safer gastrointestinal endoscopy in patients receiving antithrombotic therapy. PMID- 22211408 TI - Beyond the snare: technically accessible large en bloc colonic resection in the West: an animal study. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) and circumferential submucosal incision endoscopic mucosal resection (CSI-EMR) are techniques for en bloc excision of large sessile colonic lesions. Our aims were to compare the efficacy, safety and learning curve of colonic hybrid knife (HK) ESD versus CSI-EMR for en bloc excision of 50 mm diameter hemi-circumferential artificial lesions in a porcine model. PATIENTS AND METHODS: Two separate 50 mm diameter areas of normal recto-sigmoid mucosa were marked out in each of ten pigs. One was excised with HK ESD using succinylated gelatin (SG) submucosal injection. The other was isolated with CSI with the Insulated Tip Knife 2 followed by SG submucosal injection then EMR with a large snare. Euthanasia and colectomy was performed at 72 h followed by blinded histopathology assessment. RESULTS: En bloc excision rates were: HK ESD 100% versus CSI-EMR 20% (P = 0.008). The mean number of resections per lesion was HK-ESD 1 versus CSI-EMR 3 (P = 0.001). The mean dimensions of the largest specimen per technique were HK-ESD 63 * 54 mm versus CSI-EMR 49 * 41 mm (P = 0.005). Procedure duration mean was HK-ESD 54 min versus CSI-EMR 22 min (P < 0.001). When procedure duration was adjusted for the size of the resected en bloc specimen, a statistically significant and accelerated learning effect was noted for HK-ESD (r = -0.83, P = 0.003). There were no perforations and no significant bleeding. CONCLUSIONS: HK-ESD with SG submucosal injection is superior to CSI-EMR for en bloc excision of 50 mm diameter lesions in a porcine model. The technique is rapidly learnt. This novel approach may lower the barrier to colonic ESD for Western endoscopists. PMID- 22211410 TI - Long-term results after endoscopic drainage and necrosectomy of symptomatic pancreatic fluid collections. AB - AIMS: To determine the immediate and long-term results of endoscopic drainage and necrosectomy for symptomatic pancreatic fluid collections. METHODS: The data of 80 patients with symptomatic pancreatic fluid collections (mean diameter: 11.7 cm, range 3-20; pseudocysts: 24/80, abscess: 20/80, infected walled-off necrosis: 36/80) referred for endoscopic management from October 1997 to March 2008 were analyzed retrospectively. RESULTS: Endoscopic drainage techniques included endoscopic ultrasound (EUS)-guided aspiration (2/80), EUS-guided transenteric drainage (70/80) and non-EUS-guided drainage across a spontaneous transenteric fistula (8/80). Endoscopic necrosectomy was carried out in 49/80 (abscesses: 14/20; infected necrosis: 35/36). Procedural complications were bleeding (12/80), perforation (7/80), portal air embolism (1/80) and Ogilvie Syndrome (1/80). Initial technical success was achieved in 78/80 (97.5%) and clinical resolution of the collections was achieved endoscopically in 67/80 (83.8%), with surgery required in 13/80 (perforation: four; endoscopically inaccessible areas: two; inadequate drainage: seven). Within 6 months five patients required surgery due to recurrent fluid collections; over a mean follow up of 31 months, surgery was required in four more patients due to recurrent collections as a consequence of underlying pancreatic duct abnormalities that could not be treated endoscopically. The long-term success of endoscopic treatment was 58/80 (72.5%). CONCLUSIONS: Endoscopic drainage of symptomatic pancreatic fluid collections is safe and effective, with excellent immediate and long-term results. Endoscopic necrosectomy has a risk of serious complications. The underlying pancreatic duct abnormalities must be addressed to prevent recurrence of fluid collections. PMID- 22211409 TI - Impact of technical modification of endoscopic papillectomy for ampullary neoplasm on the occurrence of complications. AB - AIM: To evaluate the usefulness of a modified technique of endoscopic papillectomy (EP) for lessening the occurrence of complications. METHODS: Indications for EP were adenoma or well-differentiated adenocarcinoma confined to the papilla of Vater (T1) without tumor spread into the bile/pancreatic duct. Sixteen patients underwent the modified technique, which consists of resection with the Endocut mode, followed by biliary/pancreatic sphincterotomy and stenting (Group A). Twelve patients who had undergone EP, using a cutting current, followed by pancreatic duct stenting were included as control (Group B). The frequency of complications and clinical outcomes were retrospectively compared between the two groups. RESULTS: Sixteen patients had adenoma, and 12 had adenocarcinoma. Early complications occurred in 36% of all patients (hemorrhage, 7; cholangitis, 3; perforation, 2; cholecystitis, 1). The frequency of early complications in Group A was significantly lower than that in Group B (6% vs 75%, odds ratio [OR] 0.022, 95% confidence interval [CI], 0.0020-0.25). Late complications occurred in 18% of the patients (bile duct stone, 3; hemorrhage, 1; pancreatitis, 1). There was no significant difference in the late complication rate between Group A and Group B (19% vs 17%). Local recurrences were found in 14% of the patients, without a significant difference between Group A and Group B (19% vs 8%) during a mean follow-up period. All recurrent tumors were successfully treated with argon plasma coagulation. CONCLUSIONS: The modified technique of EP for ampullary neoplasm contributed to lessening the occurrence of early complications. However, further refinement of this technique is necessary for improving the clinical outcome. PMID- 22211411 TI - Beneficial use of magnifying endoscopy with narrow-band imaging for diagnosing a patient with squamous cell carcinoma of the anal canal. AB - The patient was a 74-year-old woman. She visited a dermatology clinic with a complaint of discomfort in the anal region. Erosion was observed in the anal region, and biopsies were performed. She was diagnosed with Bowen's disease and was referred to the dermatology department of our hospital for treatment. At our department, an endoscopic examination was performed for assessing the extent of Bowen's disease in the rectum. A retroflexed view of the anal canal revealed a slightly raised lesion with a faded color and an irregular surface. Narrow-band imaging (NBI) revealed a whitish lesion with a relatively clear margin and brown dots on the inside. Magnifying endoscopy with NBI revealed abnormal microvessels with dilatation, tortuosity, caliber change and various shapes, which were quite similar to the intrapapillary capillary loop patterns of superficial esophageal cancer. A complete transanal resection of the anal mucosa was performed thereafter. The patient was diagnosed with a well-differentiated squamous cell carcinoma on the basis of a pathological examination. An early diagnosis is critical for successful treatment of anal canal cancer. In this regard, magnifying endoscopy with NBI may be useful for determining the presence and extent of anal canal cancer. PMID- 22211412 TI - Heterotopic gastric mucosa with focal intestinal metaplasia and squamous epithelium in the rectum. AB - Heterotopic gastric mucosa has been described in all levels of the gastrointestinal tract. However, gastric heterotopia of the rectum is a rare finding. It is usually reported along with polyp located in the rectum between 5 and 8 cm from the anal verge. The most common symptom is painless rectal bleeding, and non-specific gastrointestinal symptoms may also be presented. We report an incidentally found case of a 46-year-old man without any gastrointestinal symptoms. The pathology showed gastric mucosa and squamous epithelium and focal intestinal metaplasia. This finding could be a clue as to the origins of the heterotopic gastric mucosa. Although there are no guidelines for treatment or the follow-up period, regular endoscopic surveillance is necessary for gastric cancer screening. PMID- 22211413 TI - Endoscopic management of recurrent gastrointestinal bleeding due to varices in the terminal ileum. PMID- 22211414 TI - Role of colonoscopy in the diagnosis of acute appendicitis. PMID- 22211415 TI - Splenic rupture following routine colonoscopy. PMID- 22211416 TI - Endoscopic drainage of multiloculated pancreatic abscesses with single endoscopic cystogastrostomy. PMID- 22211417 TI - Snakeskin-like pattern mimicking portal hypertensive gastropathy in patient with eosinophilic gastritis. PMID- 22211418 TI - Endoscopic retrograde cholangiopancreatography with a gastroscope in a case of ectopic opening of common bile duct. PMID- 22211419 TI - Type 1 gastric cancer presenting as protein-losing gastroenteropathy and ball valve syndrome. PMID- 22211422 TI - The management of biliary strictures. PMID- 22211424 TI - Synthesis of nitrogen-doped MnO/graphene nanosheets hybrid material for lithium ion batteries. AB - Nitrogen-doped MnO/graphene nanosheets (N-MnO/GNS) hybrid material was synthesized by a simple hydrothermal method followed by ammonia annealing. The samples were systematically investigated by X-ray diffraction analysis, Raman spectroscopy, X-ray photoelectron spectroscopy, transmission electron microscopy, and atomic force microscopy. N-doped MnO (N-MnO) nanoparticles were homogenously anchored on the thin layers of N-doped GNS (N-GNS) to form an efficient electronic/ionic mixed conducting network. This nanostructured hybrid exhibited a reversible electrochemical lithium storage capacity as high as 772 mAh g(-1) at 100 mA g(-1) after 90 cycles, and an excellent rate capability of 202 mA h g(-1) at a high current density of 5 A g(-1). It is expected that N-MnO/GNS hybrid could be a promising candidate material as a high capacity anode for lithium ion batteries. PMID- 22211426 TI - Ethical implications of new genetic technologies. PMID- 22211425 TI - The first two cases of neonatal alloimmune thrombocytopenia associated with the low-frequency platelet antigen HPA-21bw (Nos) in Japan. AB - BACKGROUND: Neonatal alloimmune thrombocytopenia (NAIT) is a disorder characterized by maternal alloimmunization against paternal fetal platelet antigens. Two healthy, unrelated Japanese women each gave birth to a child with severe NAIT. STUDY DESIGN AND METHODS: To elucidate the maternal causes of NAIT, we conducted serologic and genetic studies in these two NAIT infants. RESULTS: The serologic experiments localized the antigens to the glycoprotein (GP) IIIa subunit of the GPIIb/IIIa complex. Sequence-based typing studies subsequently identified a G>A mutation at Nucleotide 1960 (a glutamic acid > lysine substitution at Position 628) in the 11th exon of the GPIIIa gene. This mutation was recently identified in a report as HPA-21bw. Next, it was determined that the cause of NAIT in both cases was the HPA-21bw antigen, as shown by the mothers' antibodies reacting with the mutated GPIIIa-transfected cells, but not with transfectants expressing wild-type GPIIIa. A molecular genetic screening for the HPA-21bw allele among Japanese donors showed that its genetic frequency in the population was 0.53% (10/1888), indicating that HPA-21bw occurs at a low but appreciable frequency in the population. Furthermore, in a retrospective study of 50 previous NAIT cases of unknown causes, we found one NAIT case associated with the HPA-21bw antibody. The two NAIT cases in this study represent the first ones to be associated with HPA-21bw in Japan. CONCLUSION: We identified the HPA-21bw allele from two unrelated Japanese infants with severe NAIT. We identified 10 individuals (1.06%) positive for the HPA-21bw allele from a genetic screening of 944 Japanese blood donors. PMID- 22211428 TI - Guidelines on the investigation and management of follicular lymphoma. PMID- 22211429 TI - More patients are triaged using the Emergency Severity Index than any other triage acuity system in the United States. AB - OBJECTIVES: Patient acuity triage systems can play an important role in supporting patient safety and emergency department (ED) operations. In 2003, the boards of the American College of Emergency Physicians (ACEP) and the Emergency Nurses Association (ENA) approved a joint statement calling for hospitals to adopt a reliable, valid, five-level triage scale such as the Emergency Severity Index (ESI). Still, there appears to be considerable variation in use of triage acuity systems in the United States, with many hospitals using three- and four level systems that have not been validated. The purpose of this effort was to measure the use of various triage acuity systems in U.S. hospitals. METHODS: The authors conducted a cross-sectional analysis of secondary data. Data were obtained from the 2009 American Hospital Association (AHA) Annual Survey--an intensive questionnaire mailed to all U.S. general medical and surgical hospitals. In 2009, a question was added to the survey about hospitals' use of triage systems in EDs. Descriptive statistics were used to explore various triage acuity systems used by different types of hospitals. RESULTS: Of the 4,897 hospitals surveyed, 82% responded, and 62% (3,024 hospitals) provided information on their ED triage system. The 2009 data revealed that the most commonly used triage system types were the five-level ESI (56.9% of responding hospitals) and three-level triage systems (25.2%). More than 70% of large hospitals and teaching hospitals use the ESI, and the unvalidated three-level systems were more common in small hospitals, public hospitals, nonteaching hospitals, and hospitals in the Midwest. The majority (72.1%) of all ED patient visits to hospitals in our sample were assessed using ESI; only 13.1% of visits were assessed using a three-level system. CONCLUSIONS: Among our sample of more than 3,000 hospitals, the ESI was the most commonly used triage system, and more patients were triaged using the ESI than any other triage acuity system. Still, there is an opportunity to further promote the adoption of validated, reliable triage systems. PMID- 22211430 TI - Longitudinal melanonychia caused by unusual subungual keratosis. PMID- 22211431 TI - Osteochondrolipoma: a subcutaneous lipoma with chondroid and bone differentiation of the chest wall. AB - Lipomas are the most common subtype of benign soft tissue neoplasms and can occur anywhere in the body. Differentiation into a diversity of mesenchymal elements, such as blood vessels, fibrous tissue or muscle, is a frequent event. However, the presence of bone or cartilage in these tumors is extraordinarily rare with very few cases reported in the head and neck area. We report a case of an 'osteochondrolipoma' of the chest wall, in a young individual, providing a rationale in support of this as a possible and distinctive histologic subtype of lipomas, as well as discussion in the differential diagnosis of this lesion. PMID- 22211432 TI - Assessing the reactivity of free chlorine constituents Cl2, Cl2O, and HOCl toward aromatic ethers. AB - Cl(2) and Cl(2)O are highly reactive electrophiles capable of influencing rates of disinfection byproduct (DBP) precursor chlorination in solutions of free available chlorine (FAC). The current work examines how organic compound structure influences susceptibility toward chlorination by Cl(2) and Cl(2)O relative to the more abundant (but less reactive) electrophile HOCl. Chlorination rates and products were determined for three aromatic ethers, whose reactivities with FAC increased in the order: 3-methylanisole <1,3-dimethoxybenzene <1,3,5 trimethoxybenzene. Varying solution conditions (pH, [FAC], [Cl(-)]) permitted quantification of regiospecific second-order rate constants for formation of each product by Cl(2), Cl(2)O, and HOCl. Our results indicate that as the reactivity of methoxybenzenes decreases, the importance of Cl(2) and Cl(2)O (relative to HOCl) increases. Accordingly, Cl(2) and Cl(2)O are likely to play important roles in generating DBPs that originate from natural organic matter (NOM) constituents of somewhat moderate reactivity. As [Cl(2)] is proportional to [Cl(-)] and [Cl(2)O] is proportional to [HOCl](2), ramifications for DBP control measures may differ significantly for these precursors compared to more reactive NOM moieties likely to react predominantly with HOCl. In particular, the role of chloride as a chlorination catalyst challenges its traditional classification as an "inert" electrolyte in water treatment processes. PMID- 22211434 TI - Latent equine herpesvirus-1 in trigeminal ganglia and equine idiopathic headshaking. AB - BACKGROUND: Trigeminal neuralgia or neuropathic pain has been regarded as a putative cause of idiopathic headshaking in horses. Equine herpesvirus-1 (EHV-1) infection and resultant postherpetic pain have been suggested as a possible cause of such neuropathic pain. HYPOTHESIS/OBJECTIVES: To determine the presence of EHV 1 in the trigeminal ganglia of horses with idiopathic headshaking. ANIMALS: Nineteen horses: control (n = 11, 9 geldings, 2 mares, median age 11 years) and headshaking (n = 8, all geldings, median age 11.5 years) horses were sourced from the equine research herd and caseload at the Veterinary Medical Teaching Hospital. METHODS: Prospective study to determine the presence of EHV-1 latency in trigeminal ganglia of horses with idiopathic headshaking by real-time PCR detection of the glycoprotein B (gB) gene and the DNA polymerase (ORF 30) gene of EHV-1 in the absence of detectable late structural protein gene (gB gene) mRNA. Control horses were used for comparison. A house keeping gene (equine GAPDH) and positive and negative samples for EHV-1 were used for quality control. RESULTS: All samples from control horses and 7 of 8 headshaking horses were negative for EHV-1. One headshaking horse tested positive for a single copy of EHV-1 gene. CONCLUSIONS AND CLINICAL IMPORTANCE: This study does not support a role for EHV-1 infection and presumed postherpetic pain in the etiopathogenesis of equine headshaking. PMID- 22211436 TI - Basal cell carcinoma in childhood: a case report. AB - Basal cell carcinoma is the most common tumor of skin. Its incidence increases with age, although it is relatively infrequent under the age of 50 years, and its occurrence in childhood is exceedingly rare. This article describes an otherwise typical basal cell carcinoma arising in young patient, with emphasis on histologic diagnosis. PMID- 22211435 TI - Childhood personality types: vulnerability and adaptation over time. AB - BACKGROUND: Substantial evidence suggests that a Five-Factor Model personality assessment generates a valid description of childhood individual differences and relates to a range of psychological outcomes. Less is known, however, about naturally occurring profiles of personality and their links to psychopathology. The current study explores whether childhood personality characteristics tend to cluster in particular personality profiles that show unique associations with psychopathology and quality of life across time. METHODS: Latent class analysis was conducted on maternal rated general personality of a Flemish childhood community sample (N = 477; mean age 10.6 years). The associations of latent class membership probability with psychopathology and quality of life 2 years later were examined, using a multi-informant perspective. RESULTS: Four distinguishable latent classes were found, representing a Moderate, a Protected, an Undercontrolled and a Vulnerable childhood personality type. Each of these types showed unique associations with childhood outcomes across raters. CONCLUSIONS: Four different personality types can be delineated at young age and have a significant value in understanding vulnerability and adaptation over time. PMID- 22211437 TI - Expression and tissue-specific localization of nitrate-responsive miRNAs in roots of maize seedlings. AB - Nitrogen availability seriously affects crop productivity and environment. The knowledge of post-transcriptional regulation of plant response to nutrients is important to improve nitrogen use efficiency of crop. This research was aimed at understanding the role of miRNAs in the molecular control of plant response to nitrate. The expression profiles of six mature miRNAs were deeply studied by quantitative real time polymerase chain reaction and in situ hybridization (ISH). To this aim, a novel optimized protocol was set up for the use of digoxygenin labelled Zip Nucleic Acid-modified oligonucleotides as probes for ISH. Significant differences in miRNAs' transcripts accumulation were evidenced between nitrate-supplied and nitrate-depleted roots. Real-time PCR analyses and in situ detection of miRNA confirmed the array data and allowed us to evidence distinct miRNAs spatio-temporal expression patterns in maize roots. Our results suggest that a prolonged nitrate depletion may induce post-transcriptionally the expression of target genes by repressing the transcription of specific miRNAs. In particular, the repression of the transcription of miR528a/b, miR528a*/b*, miR169i/j/k, miR169i*/j*/k*, miR166j/k/n and miR408/b upon nitrate shortage could represent a crucial step integrating nitrate signals into developmental changes in maize roots. PMID- 22211438 TI - The integration of science and practice in trauma and dissociation: a clinician's view. PMID- 22211439 TI - Where are we going? An update on assessment, treatment, and neurobiological research in dissociative disorders as we move toward the DSM-5. AB - This article provides an overview of the process of developing the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) of the American Psychiatric Association with a focus on issues related to the trauma-related disorders, particularly the dissociative disorders (DD). We also discuss the highlights of research within the past 5 years in the assessment, treatment, and neurobiological basis of trauma disorders. Recent research shows that DD are associated with severe symptoms as well as a higher rate of utilization of mental health treatment compared with other psychiatric disorders. As a result, DD, like other complex posttraumatic disorders, exact a high economic as well as personal burden for patients and society. The latest research indicates that DD patients show a suboptimal response to standard exposure-based treatments for posttraumatic stress disorder as well as high levels of attrition from treatment. An emerging body of research on DD treatment, primarily of naturalistic and open trials, indicates that patients who receive specialized treatment that addresses their trauma-based, dissociative symptoms show improved functioning and reduced symptoms. Recent studies of the underlying neurobiological basis for dissociation support a model of excessive limbic inhibition in DD that is consistent with the phenomenology and clinical presentation of these patients. We are optimistic that the forthcoming DSM-5 will stimulate research on dissociation and the DD and suggest areas for future studies. PMID- 22211442 TI - Spiritual well-being, dissociation, and alexithymia: examining direct and moderating effects. AB - In the present study we surveyed 131 adults seeking psychotherapy and pastoral care in an intensive outpatient psychotherapy program for full-time religious workers. We sought to determine whether dissociation and alexithymia are associated with spiritual well-being. We utilized the Dissociative Experiences Scale-II (DES-II), the Toronto Alexithymia Scale (TAS-20), the Spiritual Well Being Scale (SWB) as well as the subscales of these instruments in a series of linear multiple regression analyses. DES-II total scores were inversely related to SWB total scores. No association was found between alexithymia and SWB, nor did alexithymia moderate the relationship between dissociation and SWB. Subscale analyses revealed that lower SWB and Existential Well-Being (EWB) were associated with greater nonpathological dissociation (DES-NP), which was unrelated to Religious Well-Being (RWB). By contrast, lower RWB was predicted by higher pathological dissociation (DES-T), which displayed no relationship to SWB or EWB. We conclude with a discussion of some implications of these findings. PMID- 22211441 TI - Pediatric bipolar disorder in an era of "mindless psychiatry". AB - OBJECTIVE: Pediatric bipolar disorder (PBD) reflects shifts in conceptualizing bipolar disorder among children and adolescents since the mid-1990s. Since then, PBD diagnoses, predominantly in the United States, have increased dramatically, and the diagnosis has attracted significant controversy. During the same period, psychiatric theory and practice has become increasingly biological. The aim of this paper is to examine the rise of PBD in terms of wider systemic influences. METHOD: In the context of literature referring to paradigm shifts in psychiatry, we reviewed the psychiatric literature, media cases, and information made available by investigative committees and journalists. RESULTS: Social historians and prominent psychiatrists describe a paradigm shift in psychiatry over recent decades: from an era of "brainless psychiatry," when an emphasis on psychodynamic and family factors predominated to the exclusion of biological factors, to a current era of "mindless psychiatry" that emphasizes neurobiological explanations for emotional and behavioral problems with limited regard for contextual meaning. Associated with this has been a tendency within psychiatry and society to neglect trauma and attachment insecurity as etiological factors; the "atheoretical" (but by default biomedical) premise of the Diagnostic and Statistical Manual of Mental Disorders (3rd and 4th eds.); the influence of the pharmaceutical industry in research, continuing medical education, and direct-to-consumer advertising; and inequality in the U.S. health system that favors "diagnostic upcoding." Harm from overmedicating children is now a cause of public concern. CONCLUSION: It can be argued that PBD as a widespread diagnosis, particularly in the United States, reflects multiple factors associated with a paradigm shift within psychiatry rather than recognition of a previously overlooked common disorder. PMID- 22211440 TI - Prior peritraumatic dissociative experiences affect autonomic reactivity during trauma recall. AB - To better understand the psychophysiological correlates of peritraumatic dissociation (PD), the present study examined the relationship between reports of prior PD and sympathetic and parasympathetic functioning in response to a laboratory stress paradigm in 39 traumatized female undergraduates. Participants were asked to talk about their most distressing traumatizing experience while continuous measures of heart rate, pre-ejection period, and respiratory sinus arrhythmia were taken. Overall, high dissociators had significantly larger increases in heart rate and larger decreases in pre-ejection period and respiratory sinus arrhythmia during trauma recall. In opposition to our hypothesis, these results suggest that female trauma victims reporting high levels of PD during a prior trauma may be more reactive to traumatic reminders than victims who report lower levels of PD. PMID- 22211443 TI - Seeking safety: an intervention for trauma-exposed incarcerated women? AB - Recent guidelines for incarcerated women's programming have called for interventions that address offenders' traumatic experiences, posttraumatic stress disorder (PTSD), and substance use in an integrated manner. Seeking Safety (SS) is an empirically supported cognitive behavioral manualized treatment for individuals with PTSD and substance use disorders. This study examined the effectiveness of SS with 59 incarcerated women who completed the intervention and 55 who were waitlisted. Participants in SS demonstrated greater symptom improvement in PTSD and depression as well as improved interpersonal functioning and coping as compared to waitlisted offenders. These findings provide preliminary support for the use of this intervention with incarcerated women. PMID- 22211444 TI - Relationships among childhood trauma, posttraumatic stress disorder, and dissociation in men living with HIV/AIDS. AB - This study examined the relationships among dissociation, childhood trauma and sexual abuse, and posttraumatic stress disorder (PTSD) symptoms in HIV-positive men. Data were collected from 167 men enrolled in a randomized clinical trial that examined a group therapy intervention to decrease HIV-related risk behavior and trauma-related stress symptoms. Participants completed the Trauma History Questionnaire, the Impact of Events Scale-Revised, and the Stanford Acute Stress Reaction Questionnaire. Overall, 35.3% of the participants reported having experienced childhood sexual abuse. A total of 55.7% of the sample met diagnostic criteria for PTSD. The intensity of dissociative symptoms that participants endorsed was positively associated with experience of childhood sexual abuse (r = .20, p < .01). Dissociative symptoms were also positively associated with specific PTSD symptoms, notably hyperarousal (r = .69, p < .001). Hierarchical regression indicated that hyperarousal symptoms accounted for more of the variance in dissociation than childhood sexual abuse. These results suggest that childhood sexual abuse may be involved in the development of dissociative symptoms in the context of adulthood stress reactions. Furthermore, the pattern of the association between dissociation and PTSD is consistent with the possibility of a dissociative PTSD subtype among HIV-positive men. PMID- 22211445 TI - Dissociation, PTSD, and substance abuse: an empirical study. AB - Few studies have examined the relationship between posttraumatic stress disorder (PTSD), substance use disorder, and dissociation. We studied 77 women with current PTSD and substance dependence, classified into high- versus low dissociation groups per the Dissociative Experiences Scale. They were compared on trauma- and substance-related symptoms, cognitions, coping skills, social adjustment, trauma history, psychiatric symptoms, and self-harm/suicidal behaviors. We found the high-dissociation group consistently more impaired than the low-dissociation group. Also, the sample overall evidenced relatively high levels of dissociation, indicating that even in the presence of recent substance use, dissociation remains a major psychological phenomenon. Indeed, the high dissociation group reported stronger expectation that substances could manage their psychiatric symptoms. The high-dissociation group also had more trauma related symptoms and childhood histories of emotional abuse and physical neglect. The discussion addresses methodology, the "chemical dissociation" hypothesis, and the need for a more nuanced understanding of how substances are experienced in relation to dissociative phenomena. PMID- 22211446 TI - Perspectives on peritoneal dialysis at home: implications for the management of a chronic condition. A study protocol. AB - AIM: This article is a report of a study protocol designed to explore the experience of home peritoneal dialysis from the perspectives of individuals, their families and healthcare professionals in the United Kingdom. BACKGROUND: Peritoneal dialysis is an established life-saving treatment for end-stage renal disease. This daily treatment is undertaken at home, and nurses play a key role in supporting people with their dialysis and monitoring their condition. Although peritoneal dialysis is known to have an impact on peoples' quality of life, few studies have explored peoples' experiences of undertaking this treatment at home, nor investigated their families' and health professionals' perspectives. DESIGN: An ethnographic study is proposed, which will use in-depth interviews and non participant observations with people who are undertaking peritoneal dialysis at home in the United Kingdom. Family members and healthcare professionals closely involved with these individuals will also be interviewed. The local ethics and governance committees approved this study in November 2010. DISCUSSION: It is anticipated that the study's findings will provide a detailed insight into the impact of peritoneal dialysis on individuals and their families. The findings will inform local strategies and/or interventions that could improve peoples' experiences of undertaking this treatment. Furthermore, the appropriateness of ethnographic methodology to examine individuals' and families' experiences of home treatments will be considered. PMID- 22211447 TI - Treatment of actinic cheilitis using a 1,927-nm thulium fractional laser. PMID- 22211448 TI - Effect of dust aerosol in patients with asthma. AB - OBJECTIVE: Sandstorms frequently cause adverse health effects especially in patients with asthma. The aim of our research was to explore the mechanism of sandstorm-induced asthmatic exacerbation by administering dust aerosol through an environmentally controlled exposure chamber. METHODS: Four samples of soil (Ganganagar clay, Bikaner sand, Jaipur sand, and Ganganagar sand) were collected from three sandstorm-prone areas of Rajasthan, the desert state of India. Twenty patients with asthma, who had stable disease with a forced expiratory volume in first second (FEV(1)) more than 70% of predicted, volunteered to participate in this randomized single-blind placebo-controlled crossover study. The four samples of dust and placebo were administered randomly on 5 study days. FEV(1) was measured for the next 60 minutes and the maximal decline in FEV(1) (DeltaFEV(1)) from baseline was measured. The samples of dust were also analyzed for particle size and adhesiveness. RESULTS: The maximal decline in FEV(1) was observed 15 minutes post-exposure with all dust samples. Mean DeltaFEV(1) was 0.69 +/- 0.08 liters for Ganganagar clay, 0.52 +/- 0.06 liters for Bikaner sand, 0.39 +/- 0.07 liters for Jaipur sand, and 0.32 +/- 0.04 liters for Ganganagar sand dust aerosol samples. Decline in FEV(1) correlated with volume of dust particles with size <10 MUm (PM(10)) and adhesiveness of the dust particles. CONCLUSION: Smaller-size sandstorm dust particles with higher adhesive properties have a greater potential of aggravating asthma. PMID- 22211449 TI - Clathrin-independent endocytosis contributes to uptake of glucose into BY-2 protoplasts. AB - In eukaryotic cells, several pathways exist for the internalization of plasma membrane proteins and extracellular cargo molecules. These endocytic pathways can be divided into clathrin-dependent and clathrin-independent pathways. While clathrin-dependent pathways are known to be involved in a variety of cellular processes in plants, clathrin-independent pathways have so far only been identified in animal and yeast cells. Here we show that internalization of fluorescent glucose into BY-2 cells leads to accumulation of the sugar in compartments of the endocytic pathway. This endocytic uptake of glucose was not blocked by ikarugamycin, an inhibitor of clathrin-dependent endocytosis, suggesting a role for clathrin-independent endocytosis in glucose uptake. Investigations of fusion and fission of single vesicles by membrane capacitance measurements revealed stimulation of endocytic activity by extracellular glucose. Glucose-stimulated fission of vesicles was not affected by addition of ikarugamycin or blocking of clathrin coat formation by transient over-expression of HUB1 (the C-terminal part of the clathrin heavy chain). These data demonstrate that clathrin-independent endocytosis does occur in plant cells. This pathway may represent a common mechanism for the uptake of external nutrients. PMID- 22211452 TI - New year's greetings. PMID- 22211450 TI - Estimating population divergence time and phylogeny from single-nucleotide polymorphisms data with outgroup ascertainment bias. AB - The inference of population divergence times and branching patterns is of fundamental importance in many population genetic analyses. Many methods have been developed for estimating population divergence times, and recently, there has been particular attention towards genome-wide single-nucleotide polymorphisms (SNP) data. However, most SNP data have been affected by an ascertainment bias caused by the SNP selection and discovery protocols. Here, we present a modification of an existing maximum likelihood method that will allow approximately unbiased inferences when ascertainment is based on a set of outgroup populations. We also present a method for estimating trees from the asymmetric dissimilarity measures arising from pairwise divergence time estimation in population genetics. We evaluate the methods by simulations and by applying them to a large SNP data set of seven East Asian populations. PMID- 22211454 TI - Editorial comment to a case of large bladder hemangioma successfully treated with endoscopic yttrium aluminium garnet laser irradiation. PMID- 22211455 TI - Luminescent, freestanding composite films of Au15 for specific metal ion sensing. AB - A highly luminescent freestanding film composed of the quantum cluster, Au(15), was prepared. We studied the utility of the material for specific metal ion detection. The sensitivity of the red emission of the cluster in the composite to Cu(2+) has been used to make a freestanding metal ion sensor, similar to pH paper. The luminescence of the film was stable when exposed to several other metal ions such as Hg(2+), As(3+), and As(5+). The composite film exhibited visual sensitivity to Cu(2+) up to 1 ppm, which is below the permissible limit (1.3 ppm) in drinking water set by the U.S. environmental protection agency (EPA). The specificity of the film for Cu(2+) sensing may be due to the reduction of Cu(2+) to Cu(1+)/Cu(0) by the glutathione ligand or the Au(15) core. Extended stability of the luminescence of the film makes it useful for practical applications. PMID- 22211456 TI - Na+-K+-2Cl- cotransporter type 2 trafficking and activity: the role of interacting proteins. AB - The central role of Na+-K+-2Cl- cotransporter type 2 (NKCC2) in vectorial transepithelial salt reabsorption in thick ascending limb cells from Henle's loop in the kidney is evidenced by the effects of loop diuretics, the pharmacological inhibitors of NKCC2, that are amongst the most powerful antihypertensive drugs available to date. Moreover, genetic mutations of the NKCC2 encoding gene resulting in impaired apical targeting and function of NKCC2 transporter give rise to a pathological phenotype known as type I Bartter syndrome, characterised by a severe volume depletion, hypokalaemia and metabolic alkalosis with high prenatal mortality. On the contrary, excessive NKCC2 activity has been linked with inherited hypertension in humans and in rodent models. Interestingly, in animal models of hypertension, NKCC2 upregulation is achieved by post translational mechanisms underlining the need to analyse the molecular mechanisms involved in the regulation of NKCC2 trafficking and activity to gain insights in the pathogenesis of hypertension. PMID- 22211457 TI - A rest period before agitation may improve some in vitro apheresis platelet parameters during storage. AB - BACKGROUND: Whole blood-derived platelets (PLTs) prepared by the PLT-rich plasma method are subjected to a recommended 1-hour rest period after the second centrifugation to avoid excessive PLT activation. Different apheresis PLT preparation methods demonstrate different levels of PLT activation and ability to form macroscopic aggregates immediately after collection. PLT collections are lost on Day 1 of storage if aggregates are not dispersed. It is possible that a rest period may help to disperse PLT aggregates. It is not established whether apheresis PLTs require a rest period before agitation and what the length of this period should be. STUDY DESIGN AND METHODS: Apheresis PLTs (Amicus, Fenwal, Inc.) were divided into five identical aliquots. One aliquot was placed on the flatbed agitator immediately after division. The other aliquots were subjected to agitation after 1, 2, 4, and 6 hours of rest. Samples were taken on Days 1, 5, and 7 for standard PLT assays. RESULTS: No differences during 7-day storage were observed in PLT content, mean PLT volume, pH levels, bicarbonate, glucose, lactate, oxygen and carbon dioxide levels, hypotonic shock response, aggregation, and activation markers in PLT aliquots subjected to different rest periods or without a rest period. In contrast, values of extent of shape change, percentage of discoid PLTs, and expression of GP1b-alpha were greater in aliquots subjected to different periods of rest compared to those of PLTs without a rest period. CONCLUSION: A rest period from 1 to 6 hours may improve some but not all in vitro PLT storage parameters. PMID- 22211458 TI - Evaluation of the pediatric patient with hypotonia: don't forget the hypotonia cystinuria syndrome! PMID- 22211460 TI - Surgical management of axillary necrotizing fasciitis: a case report. AB - Axillary necrotizing fasciitis (NF) is quite rare and requires special management with respect to debridement and delayed surgical reconstruction. A 76-year-old man presented to our emergency department with a 2-day history of high fever, severe left axillary pain and redness. A few hours later, he developed discoloration and hemorrhagic bulla in the axilla, and the redness enlarged on the trunk. Emergency surgical debridement was performed. The blackish necrosis in the axilla was completely excised and the erythematous areas in the chest wall were cut down to the level of the fascia. Split-thickness skin grafts were applied during the second debridement on the 30th day of hospitalization and negative pressure wound therapy was used. Although the grafts took partially, full thickness axillary defects remained. We performed reconstruction with a pedicled latissimus dorsi flap on day 78. This case highlights some of the important surgical considerations in the management of axillary NF. PMID- 22211463 TI - The technical errors of physicians learning to perform focused assessment with sonography in trauma. AB - OBJECTIVES: The objective was to assess the incidence of various technical errors committed by emergency physicians (EPs) learning to perform focused assessment with sonography in trauma (FAST). METHODS: This was a retrospective review of the first 75 consecutive FAST exams for each EP from April 2000 to June 2005. Exams were assessed for noninterpretable views, misinterpretation of images, poor gain, suboptimal depth, an incomplete exam, or backward image orientation. RESULTS: A total of 2,223 FAST exams done by 85 EPs were reviewed. Multiple noninterpretable views or misinterpreted images occurred in 24% of exams for those performing their first 10 exams, 3.6% for those performing their 41st to 50th exams, and 0% for those performing their 71st to 75th exams (Cochran-Armitage trend test = 10.5, p < 0.0001). A single noninterpretable view, poor gain, suboptimal depth, incomplete exam, or backward image orientation occurred in 48% of exams for those performing their first 10 exams, 17% for those performing their 41st to 50th exams, and 5% for those performing their 71st to 75th exams (Cochran-Armitage trend test = 11.6, p < 0.0001). CONCLUSIONS: The incidence of specific technical errors of EPs learning to perform FAST at our institution improved with hands-on experience. Interpretive skills improved more rapidly than image acquisition skills. PMID- 22211461 TI - Overview of special sub-section on money management articles: cross-disciplinary perspectives on money management by addicts. AB - BACKGROUND: How addicts manage their funds can be understood from the studies of impulsive spending, contingency management, self-reported expenditures, behavioral economics, and anthropology. OBJECTIVE: To show how these differing perspectives can provide theoretical explanations for substance abuse, they were applied to the question of when extra "windfall" funds are spent on substances of abuse. Treatment implications of these perspectives were examined. METHODS: Relevant literature was reviewed. RESULTS: Behavioral economics and related approaches provide the basis for money-management-based interventions targeting substance abuse, informed configuration of reinforcers to compete with substances, and therapeutically framing the choice between abstinence and substance use. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: A cross-discipline consideration of how addicts manage their funds has the potential to inform and improve substance abuse treatment. PMID- 22211464 TI - Do occlusal contact detection products alter the occlusion? AB - Clinicians rely on occlusal contact detection products to identify high contacts and to equilibrate occlusions. Concerns about these products have stimulated numerous investigations into marking reproducibility, accuracy and interpretation, but none have looked at their effects on the occlusion itself. The aim of this study was to assess whether these products alter the occlusion that they purport to measure by determining whether there are differences in the forces and moments experienced by occluding teeth with and without their presence. A matched pair of IPN Portrait 33 degrees molar denture teeth was placed into occlusion with the mandibular tooth supported by a load sensor and the maxillary tooth mounted onto a vertically sliding assembly with a total weight of 15.1N. The three-dimensional force and moment components on the mandibular tooth were measured when the teeth were in direct crown-crown contact (control) and with the products in place. All six products, (Accufilm I, Accufilm II, Hanel Articulating Silk, Rudischhauser Thick and Thin, and T-scan) showed significant (P<0.05) differences in forces and moments from control. PMID- 22211465 TI - Going it together: persistence of older adults' accompaniment to physician visits by a family companion. AB - OBJECTIVES: Although older adults are often accompanied to routine physician visits and commonly receive disability-related task assistance, the overlap and persistence of this help is not well understood. This study investigates whether older adults who are accompanied to routine physician visits (1) also receive task assistance and (2) continue to be accompanied at 12-months by the same family companion. DESIGN: Observational study. SETTING: Nationally representative survey. PARTICIPANTS: Community-dwelling adults aged 65 and older who responded to the Medicare Current Beneficiary Survey (MCBS) in 2006 (n = 11,582) and a subset (n = 7,510) who responded in 2005 and 2006. MEASUREMENTS: Accompaniment to physician visits by a family companion and receipt of task assistance with activities of daily living (ADLs) or instrumental activities of daily living (IADLs). Persistent accompaniment and consistent family companion involvement was ascertained from 2005 and 2006 survey responses. RESULTS: Among community dwelling older adults, 18.6% were accompanied to physician visits only, and 12.7% were accompanied to physician visits and received task assistance. Accompanied older adults who received task assistance were older, less educated, and had worse self-rated health than their counterparts who were accompanied only. Family companions who provided task assistance (vs those who did not) were more actively engaged in physician visit processes and more often identified as always present. Three-fourths (74.5%) of accompanied older adults were persistently accompanied to physician visits at 12 months, nearly always (87.9%) by the same family companion. Receipt of task assistance was strongly associated with persistent accompaniment (aOR = 2.52; 95% CI: 1.93-3.29). CONCLUSIONS: Older adults' accompaniment to physician visits typically persists, most often by consistently involved family companions. Findings have implications for the patient-physician partnership and the patient-centered medical home. PMID- 22211466 TI - Direct hydrodynamic radius measurement on dissolved organic matter in natural waters using diffusion NMR. AB - Dissolved organic matter from natural waters is a complex mixture of various chemical components, which play vital roles in many environmental processes such as the global carbon cycle and the fate of many key anthropogenic pollutants. Despite its environmental significance, dissolved organic matter in natural form has never been studied using nuclear magnetic resonance based hydrodynamic radius measurements due to its extremely low concentration (e.g., a few mg/L) in natural waters. In this study, NMR-based hydrodynamic radius measurements were performed directly on unconcentrated pond, river, and sea waters. The key chemical components of the dissolved organic matters from different sources were identified as carbohydrates, carboxyl-rich alicyclic molecules, and aliphatic molecules. By using the Stokes-Einstein-Sutherland equation, the average hydrodynamic radii of the three key components were calculated. PMID- 22211467 TI - Irritant contact dermatitis due to ammonium bifluoride in two infant twins. AB - Ammonium bifluoride is one of the most corrosive acids that may produce severe chemical burns when in contact with skin. This hazardous chemical is widely used in household products. We report two pediatric cases of irritant contact dermatitis after exposure to a rust remover, which contained ammonium bifluoride. PMID- 22211468 TI - The timing of maternal depressive symptoms and child cognitive development: a longitudinal study. AB - BACKGROUND: Maternal depression is known to be associated with impairments in child cognitive development, although the effect of timing of exposure to maternal depression is unclear. METHODS: Data collected for the Avon Longitudinal Study of Parents and Children, a longitudinal study beginning in pregnancy, included self-report measures of maternal depression the Edinburgh Postnatal Depression Scale, completed on 6 occasions up to 3 years of age, and IQ of the index child (WISC) measured at aged 8 years. We used these data to assign women to 8 groups according to whether depression occurred in the antenatal, postnatal, preschool period, any combination of these times, or not at all. We compared a model comprising all patterns of depression (saturated model) with models nested within this to test whether there is a relationship between depression and child cognitive development and, if so, whether there is a sensitive period. We then investigated the relationship with child IQ for each model, following adjustment for confounders. RESULTS: Six thousand seven hundred and thirty-five of 13,615 children from singleton births (49.5%, of eligible core sample) attended a research clinic at 8 years and completed a WISC with a score >= 70. A total of 5,029 mothers of these children had completed mood assessments over the 3 time periods. In unadjusted analyses, all three sensitive period models were as good as the saturated model, as was an accumulation model. Of the sensitive period models, only that for antenatal exposure was a consistently better fit than the accumulation model. After multiple imputation for missing data (to n = 6,735), there was no effect of postnatal depression on child IQ independent of depression at other times [-0.19 IQ points, 95% confidence interval (CI) -1.5 to 1.1 points]. There was an effect of antenatal depression (-3.19 IQ points, 95% CI: -4.33 to -2.06) which attenuated following adjustment (-0.64 IQ points, 95% CI: -1.68 to 0.40). CONCLUSIONS: The postnatal period is not a sensitive one for the effect of maternal depression on child cognitive development. PMID- 22211469 TI - Muscle pain and serum creatine kinase are not associated with low serum 25(OH) vitamin D levels in patients receiving statins. AB - OBJECTIVE: Vitamin D deficiency has been associated in some studies with nonspecific musculoskeletal pain and, more specifically, with statin-induced myalgia, which was ameliorated by high-dose vitamin D supplements. Our objective was to explore the association between vitamin D status and statin-induced myalgia and elevation of serum creatine kinase (CK). DESIGN: Retrospective cohort study, based on the electronic database of a health maintenance organization. PATIENTS: Six thousand eight hundred and eight patients (71.5% women) to whom statins were dispensed during 2008 and who had >=1 CK and 25-hydroxy vitamin D (25OHD) levels measured during statin exposure. Of these, 376 patients (5.5%) had switched from a first-line statin to atorvastatin because of muscle pain (n = 220) or other reasons (n = 156). Measurements; In the entire cohort, we compared serum CK levels among serum 25OHD quartiles. In addition, we compared CK and 25OHD levels among patients with myalgia, other switchers and nonswitchers. RESULTS: The median 25OHD level in the entire cohort was 21.8 ng/ml [interquartile range (IQR), 16.3-27.4]. CK levels were marginally lower in patients in the lowest 25OHD quartile [median CK (IQR) in 25OHD quartiles 1-4, 87 (61-130), 90 (65-131), 91 (65-132) and 91 (67-131) IU/ml, respectively; P = 0.007]. 25OHD levels in statin switchers were similar to those in nonswitchers; moreover, there were no differences in 25OHD among switchers with muscle pain and other switchers. CONCLUSION: Our findings do not support an association between low 25OHD levels and statin-induced myalgia or CK elevation. PMID- 22211470 TI - Genome-wide selection for increased copy number in Acinetobacter baylyi ADP1: locus and context-dependent variation in gene amplification. AB - Renewed interest in gene amplification stems from its importance in evolution and a variety of medical problems ranging from drug resistance to cancer. However, amplified DNA segments (amplicons) are not fully characterized in any organism. Here we report a novel Acinetobacter baylyi system for genome-wide studies. Amplification mutants that consume aromatic compounds were selected under conditions requiring high-level expression from three promoters in a linked set of chromosomal genes. Tools were developed to relocate these catabolic genes to any non-essential chromosomal position, and 49 amplification mutants from five genomic contexts were characterized. Amplicon size (18-271 kb) and copy number (2 105) indicated that 30% of mutants carried more than 1 Mb of amplified DNA. Amplification features depended on genomic position. For example, amplicons from one locus were similarly sized but displayed variable copy number, whereas those from another locus were differently sized but had comparable copy number. Additionally, the importance of sequence context was highlighted in one region where amplicons differed depending on the presence of a promoter mutation in the strain from which they were selected. DNA sequences at amplicon boundaries in 19 mutants reflected illegitimate recombination. Furthermore, steady-state duplication frequencies measured under non-selective conditions (10(-4) to 10( 5) ) confirmed that spontaneous gene duplication is a major source of genetic variation. PMID- 22211471 TI - Occlusion devices and approaches in canine patent ductus arteriosus: comparison of outcomes. AB - BACKGROUND: A comparison of transvascular occlusion methods for closing patent ductus arteriosus (PDA) in dogs has not been done. OBJECTIVES: To determine if clinically important differences exist between the approaches and devices currently used. ANIMALS: A total of 112 client-owned dogs with left-to-right shunting PDA. METHODS: Retrospective study. Records from dogs that underwent attempted transvascular PDA occlusion from January 2006 to December 2009 were examined. Dogs were placed into 4 groups: Group 1: Amplatz Canine Duct Occluder (ACDO) (transarterial) - 36 dogs; Group 2: Gianturco or MReye Flipper Detachable Embolization (Flipper) coil (transarterial) - 38 dogs; Group 3: Amplatzer Vascular Plug (AVP) (transarterial) - 23 dogs; Group 4: Flipper coil (transvenous) - 15 dogs. RESULTS: The overall success rate of the procedures was high (92%) with comparable success rates among groups (87-97%). There were significantly fewer complications (P < .0001) in dogs receiving an ACDO than in the remaining groups (3% for ACDO versus 26-33% for the other groups). Fluoroscopy time for the transvenous method was significantly longer (median, 13 minutes) than for the other groups (median, 6 minutes) (P < .0001). Severity of residual flow 24 hours postprocedure was significantly less in the ACDO group than in the remaining groups (P = .0001-.05). CONCLUSIONS: The ACDO appears superior in ease of use, complication rate, and completeness of occlusion. The remaining limiting factor with this device is patient size. Until a smaller ACDO device is marketed, coils remain the only choice for interventional closure in very small dogs. PMID- 22211472 TI - Nurses' decision-making in cases of physical restraint: a synthesis of qualitative evidence. AB - AIM: This article is a report of a review that aimed to synthesize the available qualitative evidence on nurses' decision-making in cases of physical restraint. BACKGROUND: The use of physical restraint in acute and residential healthcare facilities is a widespread practice in many countries. Decisions about the use of physical restraints are complex and ethically laden. The lack of evidence supporting the use of physical restraints, the negative consequences of restraint for patients, and the low availability of alternatives obviously complicate the decision-making. DATA SOURCES: Research papers published between January 1990 and January 2010 were identified in Cinahl, Embase, Medline, PsycInfo and Web of Science. REVIEW METHODS: A systematic review was carried out to obtain a meta-synthesis of qualitative evidence. The process of meta synthesis was supported by the Joanna Briggs Institute's guidelines. FINDINGS: The decision-making of nurses dealing with the use of physical restraints is a complex trajectory primarily focused on safety. However, thoughtful decision making requires nurses to carefully balance different options and associated ethical values. The decision-making process of nurses is influenced by both nurse and context-related factors. CONCLUSIONS: This review provides a deeper understanding of nurses' decision-making process on the use of physical restraints. Context- and nurse-related factors can hinder nurses from making an ethical decision on the appropriate use of physical restraints. There is an urgent need to stimulate and educate nurses to arrive at an appropriate decision about the use of physical restraints. PMID- 22211473 TI - Maize ZmALMT2 is a root anion transporter that mediates constitutive root malate efflux. AB - Root efflux of organic acid anions underlies a major mechanism of plant aluminium (Al) tolerance on acid soils. This efflux is mediated by transporters of the Al activated malate transporter (ALMT) or the multi-drug and toxin extrusion (MATE) families. ZmALMT2 was previously suggested to be involved in Al tolerance based on joint association-linkage mapping for maize Al tolerance. In the current study, we functionally characterized ZmALMT2 by heterologously expressing it in Xenopus laevis oocytes and transgenic Arabidopsis. In oocytes, ZmALMT2 mediated an Al-independent electrogenic transport product of organic and inorganic anion efflux. Ectopic overexpression of ZmALMT2 in an Al-hypersensitive Arabidopsis KO/KD line lacking the Al tolerance genes, AtALMT1 and AtMATE, resulted in Al independent constitutive root malate efflux which partially restored the Al tolerance phenotype. The lack of correlation between ZmALMT2 expression and Al tolerance (e.g., expression not localized to the root tip, not up-regulated by Al, and higher in sensitive versus tolerance maize lines) also led us to question ZmALMT2's role in Al tolerance. The functional properties of the ZmALMT2 transporter presented here, along with the gene expression data, suggest that ZmALMT2 is not involved in maize Al tolerance but, rather, may play a role in mineral nutrient acquisition and transport. PMID- 22211474 TI - Genetic dissection of methylcrotonyl CoA carboxylase indicates a complex role for mitochondrial leucine catabolism during seed development and germination. AB - 3-methylcrotonyl CoA carboxylase (MCCase) is a nuclear-encoded, mitochondrial localized biotin-containing enzyme. The reaction catalyzed by this enzyme is required for leucine (Leu) catabolism, and it may also play a role in the catabolism of isoprenoids and the mevalonate shunt. In Arabidopsis, two MCCase subunits (the biotinylated MCCA subunit and the non-biotinylated MCCB subunit) are each encoded by single genes (At1g03090 and At4g34030, respectively). A reverse genetic approach was used to assess the physiological role of MCCase in plants. We recovered and characterized T-DNA and transposon-tagged knockout alleles of the MCCA and MCCB genes. Metabolite profiling studies indicate that mutations in either MCCA or MCCB block mitochondrial Leu catabolism, as inferred from the increased accumulation of Leu. Under light deprivation conditions, the hyper-accumulation of Leu, 3-methylcrotonyl CoA and isovaleryl CoA indicates that mitochondrial and peroxisomal Leu catabolism pathways are independently regulated. This biochemical block in mitochondrial Leu catabolism is associated with an impaired reproductive growth phenotype, which includes aberrant flower and silique development and decreased seed germination. The decreased seed germination phenotype is only observed for homozygous mutant seeds collected from a parent plant that is itself homozygous, but not from a parent plant that is heterozygous. These characterizations may shed light on the role of catabolic processes in growth and development, an area of plant biology that is poorly understood. PMID- 22211475 TI - Reactivity of a sigma,sigma,sigma,sigma-tetraradical: the 2,4,6 tridehydropyridine radical cation. AB - The 2,4,6-tridehydropyridine radical cation, an analogue of the elusive 1,2,3,5 tetradehydrobenzene, was generated in the gas phase and its reactivity examined. Surprisingly, the tetraradical was found not to undergo radical reactions. This behavior is rationalized by resonance structures hindering fast radical reactions. This makes the cation highly electrophilic, and it rapidly reacts with many nucleophiles by quenching the N-C ortho-benzyne moiety, thereby generating a relatively unreactive meta-benzyne analogue. PMID- 22211476 TI - Use of fractionated microneedle radiofrequency for the treatment of inflammatory acne vulgaris in 18 Korean patients. AB - BACKGROUND: Nonablative radiofrequency (RF) devices have been shown to be clinically effective for the treatment of moderate to severe acne lesions. OBJECTIVE: To evaluate the efficacy and safety of a fractionated microneedle RF device in the treatment of inflammatory acne vulgaris. METHODS: Eighteen patients (15 male, 3 female; mean age 27, range: 19-33; Fitzpatrick skin type IV) with moderate to severe acne vulgaris who were treated with two sessions of fractionated microneedle RF at 1-month intervals were enrolled in this study. RESULTS: Evaluation of improvement, which took into account number of inflammatory acne lesions, showed that two of the 18 patients had grade 4 clinical improvement, eight had grade 3 improvement, and six had grade 2 improvement. Improvement scores in terms of lesion severity were also evaluated. One of the 18 patients had grade 4 clinical improvement, eight grade 3, and seven grade 2. No patient had worsening of inflammatory acne lesions. CONCLUSION: Fractionated microneedle RF can have a positive therapeutic effect on inflammatory acne vulgaris and related scars. In addition, this technique does not worsen active acne lesions. PMID- 22211477 TI - Synthesis and photovoltaic properties of novel monoadducts and bisadducts based on amide methanofullerene. AB - Four new [6,6]-phenyl-C(61) and C(71) butylsaure n-dibutyl amides (PCBDBA) with mono- and bis-adduction on C(60) and C(70) cages, respectively, have been synthesized as models to study the effect of the mono- and bis-adduction on fullerene cages on device performance when used as electron acceptors with the donor of regioregular P3HT in bulkheterojunction organic photovoltaics (BHJ-OPV). The optoelectronic, electrochemistry, and photovoltaic properties of these mono- and bis-products were fully investigated. The best device performance of these fullerene derivatives were obtained from the two monoadducts with power conversion efficiency (PCE) of 1.77% for C(60) derivative and 1.90% for C(70) derivative, respectively, which are close to PCBM's 2.43%. The results revealed the structure-function relationship among the monoadduct and bisadduct derivatives of C(60) and C(70) with the BHJ-OPV performance. PMID- 22211478 TI - Genome-wide transcriptome analysis of fluoroquinolone resistance in clinical isolates of Escherichia coli. AB - OBJECTIVES: Coincident with their worldwide use, resistance to fluoroquinolones in Escherichia coli has increased. To identify the gene expression profiles underlying fluoroquinolone resistance, we carried out genome-wide transcriptome analysis of fluoroquinolone-sensitive E. coli. METHODS: Four fluoroquinolone sensitive E. coli and five fluoroquinolone-resistant E. coli clinical isolates were subjected to complementary deoxyribonucleic acid microarray analysis. Some upregulated genes' expression was verified by real-time polymerase chain reaction using 104 E. coli clinical isolates, and minimum inhibitory concentration tests were carried out by using their transformants. RESULTS: A total of 40 genes were significantly upregulated in fluoroquinolone-resistant E. coli isolates (P < 0.05). The expression of phage shock protein operons, which are involved in biofilm formation, was markedly upregulated in our profile of fluoroquinolone resistant E. coli. One of the phage shock protein operons, pspC, was significantly upregulated in 50 fluoroquinolone-resistant E. coli isolates (P < 0.0001). The expression of type I fimbriae genes, which are pilus operons involved in biofilm formation, were markedly downregulated in fluoroquinolone resistant E. coli. Deoxyribonucleic acid adenine methyltransferase (dam), which represses type I fimbriae genes, was significantly upregulated in the clinical fluoroquinolone-resistant E. coli isolates (P = 0.007). We established pspC- and dam-expressing E. coli transformants from fluoroquinolone-sensitive E. coli, and the minimum inhibitory concentration tests showed that the transformants acquired fluoroquinolone resistance, suggesting that upregulation of these genes contributes to acquiring fluoroquinolone resistance. CONCLUSIONS: Upregulation of psp operones and dam underlying pilus operons downregulation might be associated with fluoroquinolone resistance in E. coli. PMID- 22211479 TI - Enhancing school-based asthma education efforts using computer-based education for children. AB - BACKGROUND: Schools are an important site for delivery of asthma education programs. Computer-based educational programs are a critical component of asthma education programs and may be a particularly important education method in busy school environments. OBJECTIVE: The objective of this brief report is to review and critique computer-based education efforts in schools. RESULTS: The results of our literature review indicated that school-based computer education efforts are related to improved knowledge about asthma and its management. In some studies, improvements in clinical outcomes also occur. Data collection programs need to be built into games that improve knowledge. Many projects do not appear to last for periods greater than 1 year and little information is available about cultural relevance of these programs. CONCLUSIONS: Educational games and other programs are effective methods of delivering knowledge about asthma management and control. Research about the long-term effects of this increased knowledge, in regard to behavior change, is needed. Additionally, developing sustainable projects, which are culturally relevant, is a goal for future research. PMID- 22211480 TI - Gynodioecy in structured populations: understanding fine-scale sex ratio variation in Beta vulgaris ssp. maritima. AB - Natural selection, random processes and gene flow are known to generate sex ratio variations among sexually polymorphic plant populations. In gynodioecious species, in which hermaphrodites and females coexist, the relative effect of these processes on the maintenance of sex polymorphism is still up for debate. The aim of this study was to document sex ratio and cytonuclear genetic variation at a very local scale in wind-pollinated gynodioecious Beta vulgaris ssp. maritima and attempt to elucidate which processes explained the observed variation. The study sites were characterized by geographically distinct patches of individuals and appeared to be dynamic entities, with recurrent establishment of distinct haplotypes through independent founder events. Along with substantial variation in sex ratio and unexpectedly low gene flow within study sites, our results showed a high genetic differentiation among a mosaic of genetically distinct demes, with isolation by distance or abrupt genetic discontinuities taking place within a few tens of metres. Overall, random founder events with restricted gene flow could be primary determinants of sex structure, by promoting the clumping of sex-determining genes. Such high levels of sex structure provide a landscape for differential selection acting on sex-determining genes, which could modify the conditions of maintenance of gynodioecy in structured populations. PMID- 22211481 TI - Lipoprotein-associated phospholipase A2 and outcome in patients with type 2 diabetes on haemodialysis. AB - BACKGROUND: Lipoprotein-associated phospholipase A2 (LpPLA2) is a lipoprotein bound enzyme involved in inflammation and atherosclerosis. In a post hoc analysis of a controlled trial with atorvastatin in patients with type 2 diabetes (T2D) on haemodialysis, we examined the association between baseline and change by measuring baseline LpPLA2 activity on cardiovascular events (CVE) and mortality. METHODS AND RESULTS: LpPLA2 activity was available of 1202 patients at baseline and 6 months after randomisation from 1255 patients in the German Diabetes Dialysis Study. During the 4-year follow-up, 445 patients (37%) suffered from CVE and 583 patients (49%) died. The highest quartile of LpPLA2 activity (>=615 U/L) was associated with elevated risk for CVE [HR 1.35 (1.02-1.87); P = 0.035]. This association was mainly driven by the placebo group [HR 1.51 (1.01-2.25); P = 0.046]. Receiver-operating characteristics analysis revealed that including LpPLA2 activity in an already adjusted model increased the area under the curve (AUC) for CVE from 0.586 (0.553-0.620) to 0.632 (0.599-0.664; P = 0.020) and for death from 0.704 (0.674-0.733) to 0.708 (0.679-0.737; P = 0.026). In atorvastatin treated patients, the decrease in LpPLA2 was associated with reduced fatal risk [HR per standard deviation 0.74 (0.62-0.90); P = 0.002], an effect not seen in the placebo group. In contrast, those patients in the placebo group presenting a > 25% decrease in LpPLA2 activity (n = 33) had a more than doubled risk of dying [HR 2.48 (1.56-3.95); P < 0.001]. CONCLUSION: LpPLA2 activity is predictive for cardiovascular outcome and total mortality. Reducing LpPLA2 by atorvastatin was associated with reduced mortality in patients with T2D on haemodialysis. PMID- 22211483 TI - Lenalidomide in lower-risk myelodysplastic syndromes with karyotypes other than deletion 5q and refractory to erythropoiesis-stimulating agents. AB - Lenalidomide (LEN) has been shown to yield red blood cell (RBC) transfusion independence in about 25% of lower risk myelodysplastic syndromes (MDS) without del(5q), but its efficacy in patients clearly refractory to erythropoiesis stimulating agents (ESA) is not known. We report on 31 consecutive lower-risk non del(5q) MDS patients with anaemia refractory to ESA and treated with LEN in a compassionate programme, 20 of whom also received an ESA. An erythroid response was obtained in 15 patients (48%), including 10 of the 27 (37%) previously transfusion-dependent (RBC-TD) patients, who became transfusion-independent (RBC TI). Nine of the responders relapsed, whereas 6 (40%) were still responding and transfusion-free after 11(+)-31(+) months. Median response duration was 24 months. The erythroid response rate was lower in refractory cytopenia with multilineage dysplasia (27% vs. 60%) and tended to be higher in patients treated with LEN + ESA (55% vs. 36%). Response duration was significantly longer in responders who obtained RBC-TI and in patients treated with LEN after primary resistance to ESA. The main toxicity of LEN was cytopenias. We confirm that, in a patient population of lower risk MDS without del 5q clearly resistant to ESA, LEN is an interesting second line therapeutic option. Its combination with ESAs in this context warrants prospective studies. PMID- 22211487 TI - Galantamine-based hybrid molecules with acetylcholinesterase, butyrylcholinesterase and gamma-secretase inhibition activities. AB - We previously designed novel peptides-containing galantamine analogues. These compounds we analyzed for their putative inhibitory effect towards acetylcholinesterase, butyrylcholinesterase and gamma-secretase, three activities of which could be central to various neurodegenerative pathologies including Alzheimer's disease. These pharmacological agents were virtually equipotent on acetylcholinesterase activity but display drastically higher inhibitory activities towards butyrylcholinesterase with several compounds displaying an about 100-fold higher activity than that harboured by galantamine. Strikingly, two of the galantamine amides that displayed low activity towards acetylcholinesterase exhibited the highest inhibitory potency towards butyrylcholinesterase (106 to 133 times more active than galantamine). Interestingly, five compounds show a rather good gamma-secretase inhibitory potency while they retain their ability to inhibit AChE and/or BuChE activity. Thus, we have been able to design novel compounds with significant inhibitory activity against several of the enzymes responsible for key dysfunctions taking place in several neurodegenerative diseases. These mixed inhibitors could therefore be envisioned as potential pharmacological tools aimed at circumventing the degenerative processes taking place in these major pathologies. PMID- 22211484 TI - Some observations from behavioral economics for consideration in promoting money management among those with substance use disorders. AB - BACKGROUND: Behavioral economics research has revealed systematic biases in decision making that merit consideration in efforts to promote money management skills among those with substance use disorders (SUDs). OBJECTIVES: The objective of this article was to briefly review the literature on five of those biases (i.e., hyperbolic delay discounting, defaults and preference for the status quo, loss aversion, mental accounting, and failure to account for opportunity cost) that may have particular relevance to the topic of money management. METHODS: Selected studies are reviewed to illustrate these biases and how they may relate to efforts to promote money management skills among those with substance use disorders. Studies were identified by searching PubMed using the terms "behavioral economics" and "substance use disorders", reviewing bibliographies of published articles, and discussions with colleagues. RESULTS: Only one of these biases (i.e., hyperbolic delay discounting) has been investigated extensively among those with SUDs. Indeed, it has been found to be sufficiently prevalent among those with SUDs to be considered as a potential risk factor for those disorders and certainly merits careful consideration in efforts to improve money management skills in that population. There has been relatively little empirical research reported regarding the other biases among those with SUDs, although they appear to be sufficiently fundamental to human behavior and relevant to the topic of money management (e.g., loss aversion) to also merit consideration. There is precedent of effective leveraging of behavioral economics principles in treatment development for SUDs (e.g., contingency management), including at least one intervention that explicitly focuses on money management (i.e., advisor-teller money management therapy). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The consideration of the systematic biases in human decision making that have been revealed in behavioral economics research has the potential to enhance efforts to devise effective strategies for improving money management skills among those with SUDs. PMID- 22211488 TI - Disturbed sleep patterns in elders with mild cognitive impairment: the role of memory decline and ApoE epsilon4 genotype. AB - Sleep disturbances are prevalent in patients with Alzheimer' disease (AD), being one of the most troubling symptoms during the progression of disease. However, little research has been made to determine if impaired sleep patterns appear years before AD diagnosis. This study tries to shed light on this issue by performing polysomnographic recordings in healthy elders and patients with mild cognitive impairment (MCI). We further investigated whether changes in sleep patterns parallel memory decline as well as its relationship with the Apolipoprotein E (ApoE) E4 genotype. Results showed a significant shortening of rapid eye movement (REM) sleep together with increased fragmentations of slow wave sleep in MCI patients relative to healthy elders. Interestingly, we further showed that reduction of REM sleep in MCI patients with ApoE E4 was more noticeable than in E4 non-carriers. Contrary to our initial hypothesis, changes in sleep patterns were not correlated with memory performance in MCI patients. Instead, increased REM sleep accompanied enhanced immediate recall in MCI E4 non carriers. Taken together, these results suggest that sleep disruptions are evident years before diagnosis of AD, which may have implications for early detection of dementia and/or therapeutic management of sleep complaints in MCI patients. PMID- 22211512 TI - Physical training improves motor performance in people with dementia: a randomized controlled trial. AB - OBJECTIVES: To determine whether a specific, standardized training regimen can improve muscle strength and physical functioning in people with dementia. DESIGN: Double-blinded, randomized, controlled trial with 3-month intervention and 3 month follow-up period in 2006 to 2009. SETTING: Outpatient geriatric rehabilitation. PARTICIPANTS: Individuals with confirmed mild to moderate dementia, no severe somatic or psychological disease, and ability to walk 10 m. Most participants were still living independently with or without supportive care. INTERVENTION: Supervised, progressive resistance and functional group training for 3 months specifically developed for people with dementia (intervention, n = 62) compared with a low-intensity motor placebo activity (control, n = 60). MEASUREMENTS: Primary outcome measures were one-repetition maximum in a leg press device for maximal strength and duration of the five-chair stand test for functional performance. Secondary outcome measures were assessed for a number of established parameters for maximal strength, physical function, and physical activity. RESULTS: Training significantly improved both primary outcomes (percentage change from baseline: maximal strength, intervention group (IG): +51.5 +/- 41.5 kg vs control group (CG): -1.0 +/- 28.9 kg, P < .001; functional performance, IG: -25.9 +/- 15.1 seconds vs CG: +11.3 +/- 60.4 seconds, P < .001). Secondary analysis confirmed effects for all strength and functional parameters. Training gains were partly sustained during follow-up. Low baseline performance on motor tasks but not cognitive impairment predicted positive training response. Physical activity increased significantly during the intervention (P < .001). CONCLUSION: The intensive, dementia-adjusted training was feasible and substantially improved motor performance in frail, older people with dementia and may represent a model for structured rehabilitation or outpatient training. PMID- 22211510 TI - Changes in heart valve structure and function in patients treated with dopamine agonists for prolactinomas, a 2-year follow-up study. AB - OBJECTIVE: The use of ergot-derived dopamine agonists (DA) to treat patients with prolactinomas has not been associated with an increased risk of significant heart valve dysfunction. Accordingly, the present study evaluated whether the long-term use of DA for hyperprolactinaemia may be associated with increased risk of significant valvular heart disease. METHODS: A total of 74 patients (mean age 48 +/- 1.4 years, 23% male) with prolactinoma treated with DA for at least 1 year were evaluated with 2-dimensional echocardiography at baseline. After 2 years of follow-up, a repeat echocardiography was performed to evaluate significant changes in valvular heart structure (thickening, calcifications and leaflet motion abnormalities) and function (regurgitation or stenosis). Patients were classified according to treatment: patients treated with cabergoline (group 1: n = 45), and patients not treated with cabergoline (group 2: n = 29). RESULTS: At 2 year follow-up, no significant valvular stenosis was observed in any patient. In addition, the prevalence of any significant valve regurgitation did not change significantly (from 12% to 15%, P = NS). However, there was a significant increase in the prevalence of valvular calcifications (from 48% to 58%, P = 0.004) and, particularly, in the prevalence of aortic valve calcifications (from 39% to 53%, P = 0.002). In a per-treatment-based analysis, the group of patients treated with cabergoline had significantly higher prevalence of aortic valve calcification at 2 years follow-up as compared to the group of patients not treated with cabergoline (63%vs 38%, P = 0.016). CONCLUSIONS: The long-term therapy with DA (cabergoline) of patients with prolactinoma is associated with an increased prevalence of valvular calcification. However, these structural changes were not accompanied by an increased prevalence of valvular dysfunction. PMID- 22211513 TI - Human platelet concentrates: a source of solvent/detergent-treated highly enriched brain-derived neurotrophic factor. AB - BACKGROUND: Human blood platelets (PLTs) contain brain-derived neurotrophic factor (BDNF), a neurotrophin that binds to neurotrophic tropomyosin-related kinase B (TrkB) receptor on central nervous system cells. This binding promotes neural synaptic plasticity and memory and prevents neuronal degeneration. Alterations in BDNF homeostasis are associated with aging and are found in several neurodegenerative conditions such as Alzheimer's, Huntington's, and Parkinson's diseases and multiple sclerosis. We have developed PLT viral inactivation and chromatographic fractionation processes and decided here to identify fractions enriched in BDNF. STUDY DESIGN AND METHODS: PLT concentrates (PCs) were treated by solvent/detergent (S/D), extracted by oil, and subjected to fractionation (C18, sulfopropyl [SP]-Sepharose, diethylaminoethyl [DEAE] Sepharose, or activated charcoal). BDNF and pro-BDNF were evaluated by enzyme linked immunosorbent assay, and Western blot. TrkB was studied by Western blot. Tri-n-butyl phosphate (TnBP) was quantified by high-performance liquid chromatography, and Triton X-45 by gas chromatography. RESULTS: The mean BDNF content of 2.9 +/- 0.7 ng/mL in PC was noted to increase to 56.2 +/- 2.4 ng/mL after S/D treatment and remained stable during oil extraction. Approximately 70% of the BDNF content was recovered after C18 chromatography. BDNF did not bind to DEAE-Sepharose and was almost completely adsorbed by charcoal. Chromatography on SP-Sepharose yielded a highly enriched 13-kDa mature BDNF fraction that was more than 170-fold purified, with a mean of 137 +/- 29.4 ng/mL and 82% chromatographic recovery, devoid of detectable TnBP and Triton X-45. Pro-BDNF and TrkB proteins were not detected in the PLT extracts. CONCLUSION: We obtained a S/D-treated, highly enriched mature PLT-derived BDNF fraction that could help unveil the pharmacokinetics, pharmacodynamic, and potential therapeutic applications of the BDNF neurotrophin. PMID- 22211514 TI - Congenital erosive and vesicular dermatosis: a new case and review of the literature. AB - Congenital erosive and vesicular dermatosis is a rare syndrome first described by Cohen et al in 1985. Most of the 18 cases published have been reported in premature newborns. Affected babies typically present with erosions and vesicles that tend to heal shortly after birth with reticulated scaring. We report an additional case, followed up for 5 years, in which we excluded a pathogenic mutation in the TP63 gene. PMID- 22211516 TI - A role for microtubules in endothelial cell protrusion in three-dimensional matrices. AB - BACKGROUND INFORMATION: Most cells reside in vivo in a three-dimensional (3D) environment surrounded by extracellular matrix and other neighbouring cells, conditions that are different from those found by cells cultured in vitro on two dimensional (2D) substrata. Cell morphology and behaviour are very different under these two different conditions, but the structural basis for these differences is still not understood, especially the role of microtubules (MTs). To address this issue, we studied the early spreading behaviour of bovine aortic endothelial cells (BAECs) cultured in 3D collagen matrices and on 2D substrata, in the presence of MT-disrupting drugs. RESULTS: We found that depolymerisation of MTs greatly reduces the ability of BAECs to form large and stable protrusions inside 3D collagen matrices, an effect that is less pronounced when the cells are cultured on 2D substrata. Colcemid-treated BAECs inside 3D matrices begin assembling protrusions and pull on the matrix, but they fail to extend those protrusions deep into the matrix. It has been previously reported that MT disruption affects Rho signalling which may result in increased cell rigidity and adhesiveness to 2D matrices. Accordingly, we demonstrate that colcemid treatment indeed leads to activation of Rho-kinase (ROCK) targets, which in turn results in activation of regulatory myosin light chains, and that blocking of ROCK mitigates some of the effects of MT disruption in cell spreading in 3D. CONCLUSIONS: Our results show that MT depolymerisation is particularly disruptive when cells interact with pliable 3D matrices, suggesting a role for MTs and the Rho pathway in the fine-tuning of contractile and adhesive forces necessary to sustain cell motility in vivo. PMID- 22211517 TI - Prevalence of psychiatric disorders in preschoolers. AB - BACKGROUND: Many disorders in childhood and adolescence were already present in the preschool years. However, there is little empirical research on the prevalence of psychiatric disorders in young children. A true community study using structured diagnostic tools has yet to be published. METHODS: All children born in 2003 or 2004 in the city of Trondheim, Norway, who attended the regular community health check-up for 4-year-olds (97.2% of eligible children) whose parents consented to take part in the study (N = 2,475, 82.0%) were screened for behavioral and emotional problems with the Strengths and Difficulties Questionnaire (SDQ). A screen-stratified subsample of 1,250 children took part in a furthermore comprehensive study including a structured diagnostic interview (the Preschool Age Psychiatric Assessment, PAPA), which 995 parents (79.6%) completed. RESULTS: The estimated population rate for any psychiatric disorder (excluding encopresis - 6.4%) was 7.1%. The most common disorders were attention deficit hyperactivity disorder (1.9%), oppositional defiant disorder (1.8%), conduct disorder (0.7%), anxiety disorders (1.5%), and depressive disorders (2.0%). Comorbidity among disorders was common. More emotional and behavioral disorders were seen in children whose parents did not live together and in those of low socioeconomic status. Boys more often had attention deficit/hyperactivity disorder (ADHD) and depressive disorders than girls. CONCLUSIONS: The prevalence of disorders among preschoolers was lower than in previous studies from the USA. Comorbidity was frequent and there was a male preponderance in ADHD and depression at this early age. These results underscore the fact that the most common disorders of childhood can already be diagnosed in preschoolers. However, rates of disorder in Norway may be lower than in the USA. PMID- 22211518 TI - Evaluating auxin distribution in tomato (Solanum lycopersicum) through an analysis of the PIN and AUX/LAX gene families. AB - The temporal and spatial control of auxin distribution has a key role in the regulation of plant growth and development, and much has been learnt about the mechanisms that influence auxin pools and gradients in vegetative tissues, particularly in Arabidopsis. For example polar auxin transport, mediated by PIN and AUX/LAX proteins, is central to the control of auxin distribution. In contrast, very little information is known about the dynamics of auxin distribution and the molecular basis of its transport within and between fruit tissues, despite the fact that auxin regulates many aspects of fruit development, which include fruit formation, expansion, ripening and abscission. In addition, functional information regarding the key regulators of auxin fluxes during both vegetative and reproductive development in species other than Arabidopsis is scarce. To address these issues, we have investigated the spatiotemporal distribution of auxin during tomato (Solanum lycopersicum) fruit development and the function of the PIN and AUX/LAX gene families. Differential concentrations of auxin become apparent during early fruit growth, with auxin levels being higher in internal tissues than in the fruit pericarp and the pattern of auxin accumulation depended on polar transport. Ten tomato PIN (SlPIN1 to 10) and five AUX/LAX (SlLAX1 to 5) genes were identified and found to display heterogeneous expression patterns, with tissue and developmental-stage specificity. RNAi mediated co-silencing of SlPIN4 and SlPIN3 did not affect fruit development, which suggested functional redundancy of PIN proteins, but did lead to a vegetative phenotype, and revealed a role for these genes in the regulation of tomato shoot architecture. PMID- 22211519 TI - Palatal rugae pattern in a Portuguese population: a preliminary analysis. AB - Palatal rugae have been related with specific racial groups and are said to be useful in sex discrimination. This work aimed to characterize the palatal rugae patterns in a Portuguese population. Fifty plaster casts were examined for first and third rugae shape evaluation; shape, frequency, and association with sex were studied. In females, the most prevalent first rugae were the straight type on the right and the curve type on the left; in males, the straight type was the most prevalent on both sides. The most frequent third rugae type was sinuous on both sides, in both sexes. No significant sexual dimorphism in rugae shape was found (p > 0.05). When comparing these results with those from other investigations, it was clear that a particular rugae pattern could be established for different ethnic groups. However, the small sample size justifies further work in larger samples to validate these findings. PMID- 22211520 TI - Efficacy of leukotriene receptor antagonist for erosive esophagitis: a preliminary retrospective comparative study. AB - While diagnostic overlap exists between gastroesophageal reflux disease and eosinophilic esophagitis especially on histological findings, therapeutic approaches for the two disease entities are very different. Recently, anti inflammatory treatment, in addition to acid suppressants, has been investigated for gastroesophageal reflux disease. This study investigated whether the incidence of endoscopic erosive esophagitis was lower in recipients of long-term leukotriene receptor antagonist (LTRA) treatment. This retrospective comparative study included 207 recipients of an LTRA and an equal number of controls who underwent screening upper endoscopic examination. Twenty-two (10.6%) and 51 (24.6%) cases of erosive esophagitis were detected in the LTRA and control groups, respectively (P < 0.001). A significantly higher incidence of minimal change esophagitis was also found in the controls compared with the LTRA group (14.5% vs. 2.4%, P < 0.001). On multivariate analysis, LTRA treatment was significantly and inversely associated with erosive esophagitis (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.13 to 0.46). Within the LTRA treatment group, an increased risk of erosive esophagitis was strongly associated with the presence of hiatal hernia (OR, 5.89; 95% CI, 2.20-15.73, P < 0.001) and short duration of LTRA treatment (OR, 0.64; 95% CI, 0.37-0.89, P= 0.022). In conclusion, this preliminary retrospective analysis demonstrated that patients who underwent long-term treatment with a LTRA had low incidence of endoscopic minimal change esophagitis. PMID- 22211521 TI - alpha-Synuclein induces both positive mean curvature and negative Gaussian curvature in membranes. AB - Using a combination of X-ray scattering, fluorescence correlation spectroscopy, coarse-grained molecular dynamics (MD) simulations and potential of mean force calculations, we have explored the membrane remodeling effects of monomeric alpha synuclein (alphaS). Our initial findings from multiple approaches are that alphaS (1) causes a significant thinning of the bilayer and (2) stabilizes positive mean curvature, such that the maximum principle curvature matches that of synaptic vesicles, alphaS-induced tubules, and the synthetic lipid vesicles to which the protein binds most tightly. This suggests that alphaS binding to synaptic vesicles likely stabilizes their intrinsic curvature. We then show that alphaS induces local negative Gaussian curvature, an effect that occurs in regions of alphaS shown previously via NMR and corroborated by MD simulation to have significant conformational flexibility. The induction of negative Gaussian curvature, which has implications for all curvature-sensing and curvature generating amphipathic alpha-helices, supports a hypothesis that connects helix insertion to fusion and fission of vesicles, processes that have recently been linked to alphaS function. Then, in an effort to explain these biophysical properties of alphaS, we promote an intrinsic curvature-field model that recasts long-range protein-protein interactions in terms of the interactions between the local curvature fields generated by lipid-protein complexes. PMID- 22211523 TI - Survival characteristics and prognostic variables of dogs with preclinical chronic degenerative mitral valve disease attributable to myxomatous degeneration. AB - BACKGROUND: Preclinical myxomatous mitral valve degeneration (MMVD) includes a heterogeneous group of dogs. Therefore, identifying risk factors for progression of the disease is of clinical importance. OBJECTIVES: To investigate survival time and risk factors for clinical and echocardiographic variables taken at initial examination for clinical progression in preclinical MMVD dogs. ANIMALS: A total of 256 dogs with stage B1 or B2 MMVD. MATERIALS AND METHODS: Medical records of 256 dogs with preclinical MMVD were reviewed retrospectively. Long term outcome was assessed by telephone interview. Dogs alive at the time of phone interview were asked to return to the hospital for re-evaluation of their cardiac status. RESULTS: Seventy of 256 (27.3%) dogs died during the observation period. The median survival time, regardless of cause of death, was 588 (range 75-1,668) days. The presence of a murmur was associated with an increased risk of death (AHR 2.14; 95% CI 1.12, 4.11; P = 0.022). Thirty (12%) deaths were considered cardiac related. LA/Ao > 1.4 was the only negative predictor (AHR 2.64; 1.13, 6.13; P = 0.024) for cardiac-related deaths. Eighty-three dogs were re-examined, of which 34 progressed to a more advanced stage of MMVD. The presence of Emax > 1.2 (AHR 2.75; 95% CI 1.01, 7.48; P = 0.047) and cough (AHR 7.89; 95% CI 3.18, 20.07; P < 0.001) were significant in the multivariate analysis. CONCLUSIONS AND CLINICAL IMPORTANCE: Preclinical MMVD represents a relatively benign condition in dogs. Clinicians might find stratification of this dog population according to risk factors based on clinical and echocardiographic findings helpful in determining treatment. PMID- 22211522 TI - Analysis of the role of Bacillus subtilis sigma(M) in beta-lactam resistance reveals an essential role for c-di-AMP in peptidoglycan homeostasis. AB - The Bacillus subtilis extracytoplasmic function (ECF) sigma factor sigma(M) is inducible by, and confers resistance to, several cell envelope-acting antibiotics. Here, we demonstrate that sigma(M) is responsible for intrinsic beta-lactam resistance, with sigma(X) playing a secondary role. Activation of sigma(M) upregulates several cell wall biosynthetic enzymes including one, PBP1, shown here to be a target for the beta-lactam cefuroxime. However, sigma(M) still plays a major role in cefuroxime resistance even in cells lacking PBP1. To better define the role of sigma(M) in beta-lactam resistance, we characterized suppressor mutations that restore cefuroxime resistance to a sigM null mutant. The most frequent suppressors inactivated gdpP (yybT) which encodes a cyclic-di AMP phosphodiesterase (PDE). Intriguingly, sigma(M) is a known activator of disA encoding one of three paralogous diadenylate cyclases (DAC). Overproduction of the GdpP PDE greatly sensitized cells to beta-lactam antibiotics. Conversely, genetic studies indicate that at least one DAC is required for growth with depletion leading to cell lysis. These findings support a model in which c-di-AMP is an essential signal molecule required for cell wall homeostasis. Other suppressors highlight the roles of ECF sigma factors in counteracting the deleterious effects of autolysins and reactive oxygen species in beta-lactam treated cells. PMID- 22211525 TI - Auto-antibodies: diagnostic tools in acute myocardial infarction? PMID- 22211524 TI - Photosensitizing mechanism and identification of levofloxacin photoproducts at ambient UV radiation. AB - Levofloxacin (LVFX) is a broad spectrum third generation fluoroquinolone antibiotic, used in the treatment of severe or life-threatening bacterial infections. Photosensitizing mechanism of LVFX was investigated under the ambient environmental intensities of UV-A, UV-B and sunlight exposure. Phototoxic effects of LVFX were assessed on NIH-3T3 and HaCaT cell lines. Results identified first time three photoproducts of LVFX at ambient levels of UV-R by LC-MS/MS. The generation of reactive oxygen species (ROS) was investigated photochemically as well as intracellularly in HaCaT cell line. ROS were significantly quenched by specific quenchers like DABCO, NaN(3), D-mannitol and NAC. Photosensitized LVFX caused lipid peroxidation at different concentrations. Quenching study with superoxide dismutase confirms the LVFX-induced lipid photoperoxidation. Further, photocytotoxicity of LVFX showed significant reduction in cell viability by MTT and neutral red uptake assays. LVFX caused cell arrest in G2/M phases as well as induced apoptosis through ROS-dependent pathway. In addition, photosensitized LVFX also induced upregulation of p21 and Bax/Bcl-2 genes ratio. India is a tropical country and most of the human activities such as agriculture, commerce, sports, etc. take place in bright sunlight; therefore, photosensitive LVFX may lead to skin/ocular disorders and immune suppression. Information is needed regarding the phototoxicity of LVFX for human safety. PMID- 22211526 TI - Maintaining equilibrium in professional role identity: a grounded theory study of health visitors' perceptions of their changing professional practice context. AB - AIMS: This article reports the study of a group of United Kingdom health visitors' interactions with their changing practice context, focusing on role identity and influences on its stability. BACKGROUND: United Kingdom policies have urged health visitors to refocus their role as key public health nurses. Reduced role identity clarity precipitated the emergence of different models of health visiting public health work. An inconsistent role standard can lead to role identity fragmentation and conflict across a group. It may precipitate individual role crisis, affecting optimum role performance. METHODS: Seventeen health visitors in two United Kingdom community healthcare organizations participated in a grounded theory study, incorporating constant comparative analysis. Direct observations and individual interviews were undertaken between 2002 and 2008. RESULTS/FINDINGS: Four interlinked categories emerged: professional role identity (core category); professional role in action; interprofessional working; and local micro-systems for practice; each influencing participants' sense of identity and self-worth. The Role Identity Equilibrium Process explains interactive processes occurring at different levels of participants' practice. CONCLUSION: Re-establishing equilibrium and consistency in health visiting identity is a priority. This study's findings have significance for other nurses and health professionals working in complex systems, affected by role change and challenges to role identity. PMID- 22211527 TI - HLA-A31 strongly associates with carbamazepine-induced adverse drug reactions but not with carbamazepine-induced lymphocyte proliferation in a Japanese population. AB - Carbamazepine (CBZ) is the most frequent culprit drug for severe cutaneous adverse drug reactions (ADR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS). A strong association between human leukocyte antigen (HLA)-B*1502 and CBZ-induced SJS/TEN has been reported in Han Chinese, Thai, Malaysian and Indian populations, but not in Caucasian or Japanese populations. Recent studies showed an association between HLA-A*3101 and CBZ-induced ADR in Caucasian and Japanese populations. We conducted a case-control study to determine HLA genotyping of patients with CBZ-induced ADR in a Japanese population. Fifteen patients with CBZ induced ADR and 33 subjects who had taken CBZ for more than 3 months without evidence of any ADR as a control were enrolled. In addition, the results of a CBZ induced lymphocyte stimulation test were compared between the groups. A strong association was found between HLA-A31 and CBZ-induced ADR (P < 0.001), and a weak association was found between HLA-A11 and HLA-B51 with CBZ-induced ADR. No HLA B*1502 was found in either patients or control subjects. The mean CBZ-induced lymphocyte stimulation index was significantly high in patients with CBZ-induced ADR compared with CBZ-tolerant patients (P < 0.001); however, no significant difference was seen between HLA-A31-positive subjects and HLA-A31-negative subjects in either group. These findings suggest that HLA-A31 is strongly associated with CBZ-induced ADR in the Japanese, but does not determine CBZ induced lymphocyte proliferation. PMID- 22211529 TI - Poorly differentiated neuroendocrine carcinoma of the seminal vesicle. AB - We describe an extremely rare case of poorly differentiated neuroendocrine carcinoma arising from the seminal vesicle. A 67-year-old man presented with a left humeral bone tumor resulting in a pathological fracture. Positron emission tomography scan disclosed a large pelvic tumor mimicking prostatic cancer invading into the seminal vesicle. Laboratory data showed an elevation of neuron specific enolase, despite the normal prostate-specific antigen. Transrectal needle biopsy showed a poorly differentiated carcinoma of the right seminal vesicle and the metastasis of the pelvic lymph node. Immunohistochemical results were compatible with the features of neuroendocrine carcinoma; synaptophysin, chromogranin A and CD 56 were positive. The previously biopsied bone tumor was finally diagnosed as a metastasis. A systemic chemotherapy using etoposide and cisplatin failed. The patient died of cancer one-and-a-half years later. PMID- 22211528 TI - Identification of influenza endonuclease inhibitors using a novel fluorescence polarization assay. AB - Influenza viruses have been responsible for the largest pandemics in the previous century. Although vaccination and prophylactic antiviral therapeutics are the primary defense against influenza virus, there is a pressing need to develop new antiviral agents to circumvent the limitations of current therapies. The endonuclease activity of the influenza virus PA(N) protein is essential for virus replication and is a promising target for novel anti-influenza drugs. To facilitate the discovery of endonuclease inhibitors, we have developed a high throughput fluorescence polarization (FP) assay, utilizing a novel fluorescein labeled compound (K(d) = 0.378 MUM) and a PA(N) construct, to identify small molecules that bind to the PA(N) endonuclease active site. Several known 4 substituted 2,4-dioxobutanoic acid inhibitors with high and low affinities have been evaluated in this FP-based competitive binding assay, and there was a general correlation between binding and the reported inhibition of endonuclease activity. Additionally, we have demonstrated the utility of this assay for identifying endonuclease inhibitors in a small diverse targeted fragment library. These fragment hits were used to build a follow-up library that that led to new active compounds that demonstrate FP binding and anti-influenza activities in plaque inhibition assays. The assay offers significant advantages over previously reported assays and is suitable for high-throughput and fragment-based screening studies. Additionally the demonstration of the applicability of a mechanism-based "targeted fragment" library supports the general potential of this novel approach for other enzyme targets. These results serve as a sound foundation for the development of new therapeutic leads targeting influenza endonuclease. PMID- 22211530 TI - Minimal increase in genetic diversity enhances predation resistance. AB - The importance of species diversity to emergent, ecological properties of communities is increasingly appreciated, but the importance of within-species genetic diversity for analogous emergent properties of populations is only just becoming apparent. Here, the properties and effects of genetic variation on predation resistance in populations were assessed and the molecular mechanism underlying these emergent effects was investigated. Using biofilms of the ubiquitous bacterium Serratia marcescens, we tested the importance of genetic diversity in defending biofilms against protozoan grazing, a main source of mortality for bacteria in all natural ecosystems. S. marcescens biofilms established from wild-type cells produce heritable, stable variants, which when experimentally combined, persist as a diverse assemblage and are significantly more resistant to grazing than either wild type or variant biofilms grown in monoculture. This diversity effect is biofilm-specific, a result of either facilitation or resource partitioning among variants, with equivalent experiments using planktonic cultures and grazers resulting in dominance by a single resistant strain. The variants studied are all the result of single nucleotide polymorphisms in one regulatory gene suggesting that the benefits of genetic diversity in clonal biofilms can occur through remarkably minimal genetic change. The findings presented here provide a new insight on the integration of genetics and population ecology, in which diversity arising through minimal changes in genotype can have major ecological implications for natural populations. PMID- 22211532 TI - The need for new models for delivery of therapy intervention to people with a disability in rural and remote areas of Australia. PMID- 22211562 TI - Subclinical hypothyroidism in in vitro fertilization babies. AB - AIM: Assisted reproduction technology is used widely all over the world. There is a great concern about the morbidity of in vitro fertilization (IVF) babies, but investigations are mostly related to mechanical conditions that are attributed to multiparity. This paper aimed to investigate the effect of IVF on thyroid functions in newborns. METHODS: A total of 98 healthy, term IVF newborns were evaluated between postnatal 2-4 weeks of age by screening of thyroid functions between July 2006 and April 2008. Ten subjects were assessed as a study group whose thyroid-stimulating hormone (TSH) levels were higher than 6.5 mU/L. Control group consisted of randomly selected 10 naturally conceived infants with hyperthyrotropinemia (whose TSH levels were higher than 6.5 mU/L but under 15 mU/L) with the same age. All children were thoroughly examined, and serum fT4, TSH, anti-thyroid peroxidase and anti-thyroglobulin antibodies were measured, and a thyrotropin-releasing hormone (TRH) test was performed in all subjects in both groups. RESULTS: Euthyroid hyperthyrotropinemia was diagnosed in approximately 10% of IVF babies. Exaggerated TSH levels to TRH were obtained in all IVF babies (subclinical hypothyroidism) but in none of the controls. A significant difference was noted in the concentration of TSH at the 20th min between the two groups (p < 0.001). Besides, sustained and delayed TSH responses were observed in IVF babies. Neonatal screening tests were negative in both of the groups. CONCLUSION: In IVF babies, despite normal neonatal screening tests, subclinical hypothyroidism might be observed that suggests the need for screening in this respect. PMID- 22211563 TI - The value of apolipoprotein B/A1 ratio in the diagnosis of metabolic syndrome in a Korean population. AB - OBJECTIVE: The ratio of apolipoprotein B (apoB) to apolipoprotein A1 (apoA1) has been reported to be associated with the metabolic syndrome (MetS). However, the optimal cut-off value of apoB/A1 ratio for detecting subjects with MetS has remained undetermined. In the present study, we aimed to investigate whether apoB/A1 ratio can be an indicator of MetS and to determine the optimal cut-off value of apoB/A1 ratio in detecting subjects with MetS in a Korean population. DESIGN: This cross-sectional study was conducted at the Asan Medical Center, Seoul, Republic of Korea. SUBJECTS AND MEASUREMENTS: We collected the data of 10,940 subjects who participated in a routine health screening examination regarding conventional risk factors and serum levels of apoB and apoA1. RESULTS: The odds for MetS were significantly higher in the highest compared with the lowest apoB/A1 ratio quartiles, after adjustment for confounding variables, in both men [odds ratio (OR) = 4.07, 95% CI = 3.42-4.84] and women (OR = 8.41, 95% CI = 5.85-12.08). The optimal apoB/A1 ratio cut-off value for the detection of MetS was 0.65, which had a sensitivity of 63.5% and a specificity of 61.3% (area under the curve = 0.67, 95% CI = 0.66-0.68, P < 0.001) in men and 0.62, which had a sensitivity of 67.9% and a specificity of 61.9% (area under the curve = 0.70, 95% CI = 0.69-0.71, P < 0.001) in women. CONCLUSIONS: These results suggest that apoB/A1 ratio is independently associated with MetS and that an apoB/A1 ratio >0.65 in men and 0.62 in women is a marker of MetS independent from conventional risk factors. PMID- 22211535 TI - Relations among delay discounting, addictions, and money mismanagement: implications and future directions. AB - BACKGROUND: Delay discounting is a reduction in the subjective value of a delayed outcome. Elevated delay discounting is a type of impulsivity that is associated with harmful behaviors, including substance abuse and financial mismanagement. METHODS: Elevated delay discounting as related to addiction and financial mismanagement was reviewed from psychological, neurobiological, and behavioral economic perspectives. RESULTS: Addiction and financial mismanagement frequently co-occur, and elevated delay discounting may be a common mechanism contributing to both of these problematic behaviors. CONCLUSIONS: Future research on the relationships between delay discounting, substance abuse, and financial mismanagement can provide important insights for developing improved prevention and treatment strategies. PMID- 22211565 TI - The pan-histone deacetylase inhibitor CR2408 disrupts cell cycle progression, diminishes proliferation and causes apoptosis in multiple myeloma cells. AB - In view of the fact that histone deacetylases (HDACs) are promising targets for myeloma therapy, we investigated the effects of the HDAC inhibitor CR2408 on multiple myeloma (MM) cells in vitro. CR2408 is a direct pan-HDAC inhibitor and inhibits all known 11 HDACs with a 50% inhibitory concentration (IC(50) ) of 12 nmol/l (HDAC 6) to 520 nmol/l (HDAC 8). Correspondingly, CR2408 induces hyperacetylation of histone H4, inhibits cell growth and strongly induces apoptosis (IC(50) =0.1-0.5 MUmol/l) in MM cell lines and primary MM cells. CR2408 leads to fragmentation of cells and induces an accumulation in the subG1 phase accompanied with moderately decreased levels of cyclin D1 and cdk4 and strongly decreased levels of cdc25a, pRb and p53. Interruption of the cell cycle is reflected by inhibition of cell proliferation and is accompanied by decreased phosphorylation of 4E-BP1 and p70S6k. Treatment with CR2408 results in increased protein levels of Bim and pJNK and downregulation of Bad and Bcl-xL and activation of Caspases 3, 8 and 9. Furthermore, as HDAC inhibitors have shown synergism with other drugs, these effects were investigated and synergism was observed for combinations of CR2408 with doxorubicin and bortezomib. In conclusion, we have identified potent anti-myeloma activity for this novel HDAC inhibitor that gives further insights into the biological sequelae of HDAC inhibition in MM. PMID- 22211566 TI - Iron deficiency syndromes and iron-restricted erythropoiesis (CME). AB - The relationships between erythropoietin (EPO), iron, and erythropoiesis and the presence of iron-restricted erythropoiesis have important implications in anemia management. Iron-restricted erythropoiesis occurs in the presence of one or more iron deficiency syndromes: absolute iron deficiency, functional iron deficiency, and/or iron sequestration. Absolute iron deficiency is a common nutritional deficiency in women's health, pediatrics, and the elderly and is therefore an important public health problem. Functional iron deficiency occurs in patients with significant EPO-mediated erythropoiesis or therapy with erythropoiesis stimulating agents, even when storage iron is present. Iron sequestration mediated by hepcidin is an underappreciated but common cause of iron-restricted erythropoiesis in patients with chronic inflammatory disease. The challenge for treating and laboratory-based physicians is to understand the contributory role(s) of each of these syndromes, so that the potential value of emerging and innovative pharmacologic strategies can be considered as options in patient blood management. PMID- 22211567 TI - Submucosal mast cells in the gastrointestinal tract are a target of staphylococcal enterotoxin type A. AB - Staphylococcal enterotoxin A (SEA) is a leading causative toxin of staphylococcal food poisoning. However, it remains unclear how this toxin induces emesis in humans, primates, and certain experimental animals. To understand the mechanism of SEA-induced emesis, we investigated the behavior of SEA in the gastrointestinal (GI) tract in vivo using the house musk shrew (Suncus murinus). Immunofluorescence of GI sections showed that perorally administered SEA translocated from the lumen to the interior tissues of the GI tract and rapidly accumulated in certain submucosa cells. These SEA-binding cells in the submucosa were both tryptase- and FcepsilonRIalpha-positive, suggesting these SEA-binding cells were mast cells. These SEA-binding mast cells were 5-hydroxytryptamine (5 HT)-positive, but the intensity of the 5-HT signal decreased over time compared to that of mast cells in the negative control. Furthermore, toluidine blue staining showed the number of metachromatic mast cells was decreased in the duodenal submucosa, suggesting that SEA binding induced degranulation and release of 5-HT from submucosal mast cells. These observations suggest that the target cells of SEA are submucosal mast cells in the GI tract and that 5-HT released from submucosal mast cells plays an important role in SEA-induced emesis. PMID- 22211569 TI - Investigations into the hypothesis of transgenic cannabis. AB - The unusual concentration of cannabinoids recently found in marijuana samples submitted to the forensic laboratory for chemical analysis prompted an investigation into whether genetic modifications have been made to the DNA of Cannabis sativa L. to increase its potency. Traditional methods for the detection of genetically modified organisms (GMO) were used to analyze herbal cannabis preparations. Our analyses support the hypothesis that marijuana samples submitted to forensic laboratories and characterized by an abnormal level of Delta(9)-THC are the product of breeding selection rather than of transgenic modifications. Further, this research has shown a risk of false positive results associated with the poor quality of the seized samples and probably due to the contamination by other transgenic vegetable products. On the other hand, based on these data, a conclusive distinction between the hypothesis of GMO plant contamination and the other of genetic modification of cannabis cannot be made requiring further studies on comparative chemical and genetic analyses to find out an explanation for the recently detected increased potency of cannabis. PMID- 22211568 TI - Long-term determinants of muscle strength decline: prospective evidence from the 22-year mini-Finland follow-up survey. AB - OBJECTIVES: To examine long-term changes in handgrip strength and the factors predicting handgrip strength decline. DESIGN: Longitudinal cohort study with 22 years of follow-up. SETTING: Population-based Mini-Finland Health Examination Survey in Finland. PARTICIPANTS: Nine hundred sixty-three men and women aged 30 to 73 at baseline. MEASUREMENTS: Handgrip strength was measured using a handheld dynamometer at baseline and follow-up. Information on potential risk factors, namely lifestyle and chronic conditions, and their changes throughout the follow up were based on health interviews. RESULTS: Based on linear mixed-effect models, midlife physically strenuous work, excess body weight, smoking, cardiovascular disease, hypertension, diabetes mellitus, and asthma predicted muscle strength decline over 22 years of follow-up (P < .05 for all). In addition, pronounced weight loss, becoming physically sedentary, persistent smoking, incident coronary heart disease, other cardiovascular disease, diabetes mellitus, chronic bronchitis, chronic back syndrome, long-lasting cardiovascular disease, hypertension, and asthma were associated with accelerated handgrip strength decline (P < .05 for all). CONCLUSION: Lifestyle and physical health earlier in life determine rate of muscle strength decline in old age. Efforts should be made to recognize persons at risk in a timely manner and target early interventions to middle-aged persons to slow down muscle strength decline and prevent future functional limitations and disability. PMID- 22211570 TI - Volume 50 and beyond. PMID- 22211571 TI - MIGS: miRNA-induced gene silencing. AB - Gene silencing is an important tool in the study of gene function. Virus-induced gene silencing (VIGS) and hairpin RNA interference (hpRNAi), both of which rely on small interfering RNAs, together with artificial microRNAs (amiRNA), are amongst the most popular methods for reduction of gene activity in plants. However, all three approaches have limitations. Here, we introduce miRNA-induced gene silencing (MIGS). This method exploits a special 22-nucleotide miRNA of Arabidopsis thaliana, miR173, which can trigger production of another class of small RNAs called trans-acting small interfering RNAs (tasiRNAs). We show that fusion of gene fragments to an upstream miR173 target site is sufficient for effective silencing of the corresponding endogenous gene. MIGS can be reliably used for the knockdown of a single gene or of multiple unrelated genes. In addition, we show that MIGS can be applied to other species by co-expression of miR173. PMID- 22211573 TI - Acute morbidity associated with scabies and other ectoparasitoses rapidly improves after treatment with ivermectin. AB - In resource-poor settings, scabies is associated with considerable morbidity. Which factors determine morbidity and how rapidly it recedes after specific treatment is not known. Patients with scabies were recruited in three urban slums in Fortaleza, Northeast Brazil. Diagnosis was established according to dermatoscopy, skin scraping, or adhesive film test. Severity of scabies associated morbidity was assessed semiquantitatively. Patients and close contacts were treated with oral ivermectin (200 MUg/kg, repeated after 7 days) and followed up for 2 weeks. Ninety-five patients were included in the study. Papules were the most common lesion type (98.9%). Excoriations due to scratching were observed in 43.2% and bacterial superinfection in 24.2%. Predilection sites were the arms (82.1%) and the abdomen (81.1%). At baseline, 36.3% of patients complained about intense or severe itching. Intense or severe itch decreased to 6.3% 2 weeks after treatment (p=0.02). Whereas 37.5% of the patients complained about intense or severe itch-related sleep disturbances at baseline, only 8.8% reported the symptom 2 weeks after treatment (p=0.35). At baseline, the degree of itching was correlated with the degree of sleep disturbance (rho=0.64; p<0.001). One week after the first dose of ivermectin, the intensity of itching and of sleep disturbance decreased significantly (p<0.001). In patients living in resource-poor setting, scabies was associated with considerable morbidity. Treatment with ivermectin rapidly reconstituted health in almost all cases. PMID- 22211574 TI - Attention across modalities as a longitudinal predictor of early outcomes: the case of fragile X syndrome. AB - BACKGROUND: Fragile X syndrome (FXS) is an early diagnosed monogenic disorder, associated with a striking pattern of cognitive/attentional difficulties and a high risk of poor behavioural outcomes. FXS therefore represents an ideal model disorder to study prospectively the impact of early attention deficits on behaviour. METHODS: Thirty-seven boys with FXS aged 4-10 years and 74 typically developing (TD) boys took part. Study 1 was designed to assess visual and auditory attention at two time-points, 1 year apart. Study 2 investigated attention to multimodal information. Both tested attention markers as longitudinal predictors of risk for poor behaviour in FXS. RESULTS: Children with FXS attended less well than mental-age matched TD boys and experienced greater difficulties with auditory compared to visual stimuli. In addition, unlike TD children, they did not benefit from multimodal information. Attention markers were significant predictors of later behavioural difficulties in boys with FXS. CONCLUSIONS: Findings demonstrate, for the first time, greater difficulties with auditory attention and atypical processing of multimodal information, in addition to pervasive global attentional difficulties in boys with FXS. Attention predicted outcomes longitudinally, underscoring the need to dissect what drives differing developmental trajectories for individual children within a seemingly homogeneous group. PMID- 22211575 TI - Continuous production of Cu2ZnSnS4 nanocrystals in a flow reactor. AB - A procedure for the continuous production of Cu(2)ZnSnS(4) (CZTS) nanoparticles with controlled composition is presented. CZTS nanoparticles were prepared through the reaction of the metals' amino complexes with elemental sulfur in a continuous-flow reactor at moderate temperatures (300-330 degrees C). High resolution transmission electron microscopy and X-ray diffraction analysis showed the nanocrystals to have a crystallographic structure compatible with that of the kesterite. Chemical characterization of the materials showed the presence of the four elements in each individual nanocrystal. Composition control was achieved by adjusting the solution flow rate through the reactor and the proper choice of the nominal precursor concentration within the flowing solution. Single-particle analysis revealed a composition distribution within each sample, which was optimized at the highest synthesis temperatures used. PMID- 22211576 TI - Intrapericardial hernia presenting with syncope. PMID- 22211577 TI - Graduating nursing students' perceived preparedness for working in critical care areas. AB - AIMS: This article reports a study examining the relationships between undergraduate students' demographics, educational preparation and clinical experience and their self reported preparedness for employment in critical care. BACKGROUND: Increasing demand for critical care services internationally, creates a need to grow the critical care nursing workforce. Limited data are available on factors affecting new graduate nurses' career choices. METHODS: Final year nursing students from a multi-campus Australian University were surveyed during 2009. RESULTS: Over half of the participants were interested in seeking employment in critical care following graduation. Main reasons for choosing critical care nursing were: (i) like varied and challenging work; (ii) opportunities for professional development; and (iii) like working one-on-one with patients. The main barriers identified by participants were related to the lack of knowledge and clinical skills required to work in critical care. Using the 9-item confidence and interest in critical care nursing scale, the study revealed that male participants and those who spent more than 1 week clinical placement in critical care were significantly more likely to report greater confidence and interest in seeking employment in critical care areas. CONCLUSIONS: The value of placing nursing students in critical care areas for more than 1 week during undergraduate clinical placements is affirmed. Whilst most final year students report feeling prepared to work in critical care areas, the next step is to explore the transition of students as new graduates in critical care to identify professional and educational issues that impact on their retention. PMID- 22211578 TI - Structure of the pilus assembly protein TadZ from Eubacterium rectale: implications for polar localization. AB - The tad (tight adherence) locus encodes a protein translocation system that produces a novel variant of type IV pili. The pilus assembly protein TadZ (called CpaE in Caulobacter crescentus) is ubiquitous in tad loci, but is absent in other type IV pilus biogenesis systems. The crystal structure of TadZ from Eubacterium rectale (ErTadZ), in complex with ATP and Mg(2+) , was determined to 2.1 A resolution. ErTadZ contains an atypical ATPase domain with a variant of a deviant Walker-A motif that retains ATP binding capacity while displaying only low intrinsic ATPase activity. The bound ATP plays an important role in dimerization of ErTadZ. The N-terminal atypical receiver domain resembles the canonical receiver domain of response regulators, but has a degenerate, stripped-down 'active site'. Homology modelling of the N-terminal atypical receiver domain of CpaE indicates that it has a conserved protein-protein binding surface similar to that of the polar localization module of the social mobility protein FrzS, suggesting a similar function. Our structural results also suggest that TadZ localizes to the pole through the atypical receiver domain during an early stage of pili biogenesis, and functions as a hub for recruiting other pili components, thus providing insights into the Tad pilus assembly process. PMID- 22211580 TI - The (alpha-4) photoconjugates of 5-methylcytosine, 1,5-dimethylcytosine, 1 methylthymine and thymidine. AB - The pyrimidine nucleobases contained in DNA undergo a variety of photoinduced reactions in which two moieties become joined to form a product (e.g. formation of cyclobutane dimers and [6-4] adducts). Herein, we describe a new type of photoconjugation reaction that has been shown to occur for 5-methylcytosine (5 MeC), 1,5-dimethylcytosine (1,5-diMeC), 1-methylthymine and thymidine; in this reaction the 5-methyl group of one nucleobase (or nucleoside) becomes attached to the 4-position of the second moiety. For example, 5-MeC forms alpha-4'-(5' methylpyrimidin-2'-one)-5-methylcytosine. The various (alpha-4) conjugates are produced upon irradiation of the parent compound in frozen aqueous solution at 78.5 degrees C. The UV spectra of these compounds display a characteristic "double humped" profile, similar to that expected from overlaying the spectrum of parent nucleobase with that of a 2'-pyrimidone moiety. Preliminary results suggest that thymine and 5-methyl-2'-deoxycytidine (5-MedCyd) form analogous photoproducts. A variety of other previously unreported photoproducts are described as well for the 5-MeC, 1,5-diMeC and 5-MedCyd systems. PMID- 22211581 TI - Dramatic impact of a Psoriasis Area and Severity Index 90 response on the quality of life in patients with psoriasis: an analysis of Japanese clinical trials of infliximab. AB - European S3 Guidelines on the systemic treatment of psoriasis in 2009 propose 75% or more improvement in the Psoriasis Area and Severity Index from baseline (PASI 75) and a Dermatology Life Quality Index (DLQI) of 0 or 1 as treatment goals. However, the relationship of these two parameters is yet to be clarified. Herein, we analyzed the data pooled from two Japanese phase III clinical trials on psoriasis with infliximab to clarify the PASI response necessary to achieve a DLQI of 0 or 1. Of the 90 patients, the mean percent improvement in PASI at week 50 or 66 was 74.5%, and the PASI 75 and PASI 90 response rates were 66.7% and 46.7%, respectively; no difference in the improvement was noted among the body areas. Significant improvements in nail psoriasis were also observed. A negative correlation was shown between the improvement in PASI and DLQI. Patients who achieved a PASI 90 response had a significantly higher percentage of achieving a DLQI of 0 or 1 than the patients who achieved a PASI 75 but not a PASI 90 response. The median serum trough level of infliximab was maintained at 2 MUg/mL or more in the PASI 90 responders, whereas it was less than 1 MUg/mL at week 30 and on in the others. The present results demonstrate that a PASI 90 response is necessary to achieve a DLQI of 0 or 1. Infliximab is considered a useful drug in meeting the treatment goal of achieving a DLQI of 0 or 1 through the attainment of a PASI 90 response. PMID- 22211582 TI - Efficacy of protamine zinc recombinant human insulin for controlling hyperglycemia in dogs with diabetes mellitus. AB - BACKGROUND: Alternative insulin preparations are needed when NPH insulin is ineffective in diabetic dogs. This study evaluated the efficacy of recombinant human protamine zinc insulin (rhPZI) for treating diabetic dogs. HYPOTHESIS: rhPZI is effective for treating diabetic dogs. ANIMALS: Six newly diagnosed and 11 insulin-treated diabetic dogs. METHODS: Prospective clinical trial. Dogs were treated with rhPZI for 60 days. Control of glycemia was assessed on days 7, 14, 30, and 60 by evaluation of history, physical examination, body weight, serum fructosamine concentration, and blood glucose concentrations measured before and 2, 4, 6, 8, and 10 hours after rhPZI administration. Adjustments in dosage of rhPZI were made as needed to control glycemia. RESULTS: rhPZI administration resulted in a significant decrease in 10-hour mean blood glucose (MBG(10h) ; 299 +/- 115 versus 457 +/- 38 mg/dL, X +/- SD, P = .0003) and serum fructosamine (478 +/- 83 versus 557 +/- 104 MUmol/L, P = .006) concentration at day 60, compared with day 1, respectively. By day 60, polyuria and polydipsia had improved in 14, body weight was stable or increased in 16, MBG(10h) had decreased in 16, and serum fructosamine concentration had decreased in 11 of 17 dogs, compared with day 1. Hypoglycemia (<80 mg/dL) was the only consistent adverse event. CONCLUSIONS AND CLINICAL RELEVANCE: rhPZI is effective in diabetic dogs and can be considered as an alternative treatment in diabetic dogs that are poorly controlled using other insulin preparations. PMID- 22211583 TI - The calciotropic hormones PTH and vitamin D: from bone to blood vessels. PMID- 22211584 TI - FLCN gene-mutated renal cell neoplasms: mother and daughter cases with a novel germline mutation. AB - Birt-Hogg-Dube syndrome is a familial genodermatosis, of which patients frequently develop renal neoplasms, fibrofolliculomas and pneumatocele. Here, we report a mother and daughter with renal neoplasms surgically resected (69 and 46 years-of-age at surgery, respectively). The mother's tumor was diagnosed as an unclassified type renal cell carcinoma associated with microscopic tumorous nodules, whereas the daughter's tumor was a hybrid oncocytic/chromophobe tumor. The germline mutation analysis of the responsible gene, FCLN (the folliculin gene), showed a deletion of 18 bp in exon 5 (c.332_349del/p.H111_Q116del), predicting an alteration of the amino acid sequence of "HPSHPQ" replaced by a single amino acid, "L". This is a novel germline mutation of the FCLN gene that has not been previously reported. PMID- 22211585 TI - Diffusional motion of a particle translocating through a nanopore. AB - The influence of diffusional motion on the capture and release of individual nanoparticles as they are driven through a conical-shaped glass nanopore membrane (GNM) by pressure-induced flow is reported. In these experiments, one to several hundred particles are driven through the orifice of the nanopore. Following the initial translocation, the pressure is reversed and the particles are driven through the GNM orifice in the reverse direction. The resistive-pulse technique is used to monitor the temporal sequence of particle capture and release translocations. The size of the particles (120-160 nm) and the direction of translocation can be determined from the pulse amplitude and shape. The stochastic influence of diffusion on particle trajectories has been investigated, including instantaneous transfer rate, release probability, and cumulative release success rate. We demonstrate that the sequence of particle translocations in the capture step (a, b, c... where the letters represent different particles) is largely preserved and can be read out by resistive-pulse signature during the release translocations (...c, b, a). The observed stochastic events are in good agreement with a convective diffusion model of particle trajectory within the confined geometry of the nanopore. The pressure-reversal technique opens new avenues for chemical analysis of particles using resistive-pulse methods. PMID- 22211586 TI - A comparison of rural and urban nonmedical prescription opioid users' lifetime and recent drug use. AB - BACKGROUND: Nonmedical prescription opioid use has emerged as a major public health concern. The growing burden of nonmedical prescription opioid use in America may have unique manifestations and consequences in rural areas, which to a large extent have yet to be explored. OBJECTIVES: To describe rural-urban differences among drug users in recent and lifetime use and age of onset of use for alcohol, heroin, OxyContin((r)), oxycodone, hydrocodone, barbiturates, benzodiazepines, cocaine, crack, methamphetamine, amphetamine, marijuana, hallucinogens, and inhalants. METHODS: A purposive sample of 212 prescription drug users was recruited from a rural Appalachian county (n = 101) and a major metropolitan area (n = 111) in Kentucky. Consenting participants were given an interviewer-administered questionnaire examining sociodemographics, psychiatric characteristics, and self-reported drug use. RESULTS: Rural drug users had significantly earlier ages of onset for use of oxycodone, hydrocodone, benzodiazepines, cocaine, and crack. In age-, gender-, and race-adjusted logistic regression analyses, rural drug users had significantly higher odds of lifetime and recent use of methadone, OxyContin((r)), and oxycodone. Rural drug users also had significantly higher odds of lifetime cocaine and crack use. However, urban participants as expected had significantly higher odds of recent crack use. CONCLUSIONS: The findings demonstrate that, in this sample, nonmedical prescription opioid use is dissimilar among rural and urban drug users. Additional research is needed to better understand the individual, social, and structural level factors contributing to the burden of nonmedical opioid use, particularly in rural populations, with the aim of developing tailored substance abuse treatment and prevention. PMID- 22211587 TI - Experiences of supporting people with Down syndrome and Alzheimer's disease in aged care and family environments. AB - BACKGROUND: Research addressing the experiences of families of adults with Down syndrome and Alzheimer's disease in seeking diagnosis and gaining support is limited. The aim of this study was to gain a greater understanding of these processes by exploring the experiences of families and carers in supporting people with Down syndrome and Alzheimer's disease who had lived most or all of their lives with family. METHOD: Three detailed case studies were created from multiple data sources, and then analysed thematically. RESULTS: Families of adults with Down syndrome experienced stress and confusion as they negotiated a service system poorly equipped to meet their needs and professionals more focused on longstanding disability than the recent diagnosis of Alzheimer's disease. Such overshadowing led to mismanagement by services. CONCLUSIONS: This research advances understandings of the support needs of people with Down syndrome and Alzheimer's disease and their families. It exposes gaps in the service system. PMID- 22211589 TI - The microorganisms in chronically infected end-stage and non-end-stage cystic fibrosis patients. AB - Patients suffering from cystic fibrosis (CF) develop chronic lung infections because of highly viscous mucus, where bacteria can form biofilms. In this study, we investigated the microorganisms present in the lungs of end-stage and non-end stage patients using standard culturing techniques and molecular methods. Tissue and sputum samples (n = 34) from explanted lungs of five end-stage patients were examined along with routine expectorates (n = 15) from 13 patients with non-end stage CF, representing earlier stages of chronic lung infections. Previously, using peptide nucleic acid (PNA) fluorescence in situ hybridization (FISH), we have shown that Pseudomonas aeruginosa was the sole pathogen in end-stage CF lungs (Pediatr Pulmonol 2009, 44: 547). In this study, this tendency was supported by the results of real-time PCR, confirming previous results obtained by standard culturing and 16S rRNA gene analysis (J Clin Microbiol 2011, 49: 4352). Conversely, the non-end-stage patients were found to harbor several species by culturing. PNA FISH confirmed heterogeneous microbiota and showed that the bacteria were located in monospecies aggregates with no apparent physical interaction between the different microcolonies. In conclusion, standard culturing identifies the dominating pathogens, which seem to reside in monospecies microcolonies. The possibility of signaling between the distinct microcolonies still has to be verified and elucidated. PMID- 22211625 TI - Congenital multiple clustered dermatofibroma in a 12-year-old girl. AB - Congenital multiple clustered dermatofibroma (MCDF) is a rare, idiopathic, benign tumor presenting at birth as an asymptomatic hyperpigmented patch that is stable until puberty, at which time it enlarges and develops papules. Ultimately, MCDF appears to follow a stable, benign course. We present a case of a 12-year-old girl with congenital MCDF. To our knowledge, this is only the third reported case of congenital presentation of MCDF and the only case featuring atrophoderma-like depression. PMID- 22211626 TI - A comparison of DNA collection and retrieval from two swab types (cotton and nylon flocked swab) when processed using three QIAGEN extraction methods. AB - The Metropolitan Police Service currently uses cotton swabs to retrieve DNA for forensic profiling. Recently, a new nylon flocked swab type has become available from Copan (MicroRheologics, Brescia, Italy) that it is claimed, offers increased sample recovery and release yields. If true, the flocked swab may have important applications in DNA evidence retrieval. This study examines the DNA retrieval capability of cotton and nylon flocked swabs when extracted using three common extraction platforms (QIAcube, BioRobot EZ1 and manually processed QIAamp DNA investigator kit). Results indicate that both swab types are capable of recovering high percentages of DNA (>50%); however, the extraction platform selected was shown to have a significant effect upon DNA retrieval. Across all experiments, the cotton swab combined with the spin-column extractions was shown to be most effective, with the nylon swab and BioRobot EZ1 combination being the least effective. These findings illustrate the importance of extraction method selection. PMID- 22211627 TI - Obstructive sleep apnoea in adults: body postures and weight changes interactions. AB - The aim of this work was to study the relationship between changes of body posture dominance and changes of body weight overtime in adults with obstructive sleep apnoea. The participants were 112 non-treated adults with obstructive sleep apnoea who underwent two polysomnographic evaluations at our Sleep Disorders Unit during an average of 6.2years interval. Positional patients - having most of their breathing abnormalities in the supine posture and who became non-positional patients - had a significant gain in weight and a significant increase in apnoea hypopnoea index, mainly in lateral apnoea-hypopnoea index. On the contrary, non positional patients who became positional patients had a significant decrease in weight (but less than the increase in weight of positional patients who became non-positional patients) and showed a significant improvement in apnoea-hypopnoea index, again mainly in lateral apnoea-hypopnoea index. These non-positional patients who became positional patients initially had a less severe disease, as judged by apnoea-hypopnoea index, lateral apnoea-hypopnoea index and minimum SaO(2) during non-rapid eye movement sleep, and were less obese than non positional patients who remained non-positional patients. The later were the patients who showed initially the worst disease and were more obese than the rest of the patients, and their condition did not change significantly over time. Non positional patients who converted to positional patients showed a decrease in body weight and improvement of obstructive sleep apnoea, while positional patients who converted to non-positional patients showed an increase in body weight and worsening of obstructive sleep apnoea. It appears that weight changes have a modulatory effect on positional dominance, and lateral apnoea-hypopnoea index appears to be a sensitive parameter of these changes. PMID- 22211628 TI - Timing of gonadectomy in adult women with complete androgen insensitivity syndrome (CAIS): patient preferences and clinical evidence. AB - OBJECTIVE: Adult women with complete androgen insensitivity syndrome (CAIS) are increasingly likely to defer or decline gonadectomy despite counselling about malignancy risk. The objectives of this study were to review the evidence on the risk of gonadal malignancy in adult women with CAIS and to explore women's reasons for deferring gonadectomy. STUDY DESIGN: A case series and literature review. PATIENTS: Sixteen women with CAIS over the age of 18 years who have elected to defer gonadectomy. RESULTS: Sixty-two relevant papers were identified. Of these, 14 confirmed that tumours had been reported in 98 adults. Taking into account the limitations of combining historic case series, this review estimates a risk of gonadal malignancy of 14% (range 0% and 22%) in adults with CAIS. The most common reasons women offered for deferring gonadectomy included inconvenience of surgery, concern about surgical risk and reluctance to take hormone replacement therapy. CONCLUSIONS: Perceived benefits for retaining gonads in women with CAIS are prompting more women to keep their gonads in situ. An accurate estimate for adult malignancy risk is unavailable, and the risks currently quoted may be falsely reassuring. PMID- 22211629 TI - Disabilities and health of extremely low-birthweight teenagers: a population based study. AB - AIM: Evaluation of long-term outcome of extremely low-birthweight (ELBW) teenagers born in Iceland in 1991-1995. METHOD: Participants, 30 of 35 ELBW survivors and 30 full term control teenagers (14-19 years), were assessed for disabilities, health problems and learning difficulties. Results of national standardized tests in mathematics and Icelandic language were compared with results of neurodevelopmental assessment at 5 years of age. RESULTS: A quarter of the ELBW teenagers had disabilities. All were initially diagnosed with neurodevelopmental disorders early in life and neurosensory and/or intellectual disabilities were confirmed later in childhood. Chronic lung disorders, neurological problems and psychiatric disorders were most common health problems. Growth parameters were within normal limits for most of the ELBW teenagers. Learning difficulties affected 57% of the ELBW teenagers, 20% attended special education classes and 37% required special teaching. Results of national standardized tests were significantly lower for ELBW survivors and were significantly related to the results of neurodevelopmental assessment at 5 years of age. INTERPRETATION: A quarter of ELBW teenagers have disabilities albeit most of them mild. Chronic health problems and learning difficulties affect many ELBW survivors. Changes with time emphasize need of long-term follow-up. PMID- 22211630 TI - Chlamydia pneumoniae induces a pro-inflammatory phenotype in murine vascular smooth muscle cells independently of elevating reactive oxygen species. AB - NADPH oxidases (Nox) are reactive oxygen species (ROS)-generating enzymes that play important physiological roles in host defence and redox signalling. However, Nox activity is upregulated in the vascular wall during atherosclerosis and contributes to plaque formation by promoting oxidative stress and inflammation. The bacterium Chlamydia pneumoniae has been detected in vascular smooth muscle cells (VSMC) of human atheroma. We hypothesized that C. pneumoniae infection of VSMC causes Nox activation, which initially limits infection but ultimately causes oxidative stress, activation of pro-inflammatory pathways and an atherogenic phenotype. Chlamydia pneumoniae infection of mouse cultured VSMC significantly increased ROS production by twofold but did not upregulate mRNA expression of Nox1 or Nox4. Chlamydia pneumoniae did increase Nox2 mRNA levels significantly by threefold, but this did not translate to elevated Nox2 protein expression. The Nox inhibitor gp91ds-tat had no effect on C. pneumoniae-induced ROS production. In contrast, apocynin significantly reduced ROS levels by 75% in C. pneumoniae-infected VSMC, an effect most likely attributable to its direct anti-oxidant action. Although apocynin had no effect on C. pneumoniae-induced expression of inflammatory markers, bacteria recovered from apocynin-treated VSMC displayed a higher degree of infectivity in HEp-2 cells. In conclusion, C. pneumoniae infection increases ROS production in VSMC independently of Nox activity. Although elevated ROS production appears to serve a protective role by limiting the spread of infection, we speculate that this response will be detrimental over the long term by causing oxidative stress and a smouldering inflammatory response by maintaining C. pneumoniae persistence within the cell. PMID- 22211632 TI - Deletion of the paternal allele of the imprinted MEST/PEG1 region in a patient with Silver-Russell syndrome features. PMID- 22211633 TI - Palaeohexaploid ancestry for Caryophyllales inferred from extensive gene-based physical and genetic mapping of the sugar beet genome (Beta vulgaris). AB - Sugar beet (Beta vulgaris) is an important crop plant that accounts for 30% of the world's sugar production annually. The genus Beta is a distant relative of currently sequenced taxa within the core eudicotyledons; the genomic characterization of sugar beet is essential to make its genome accessible to molecular dissection. Here, we present comprehensive genomic information in genetic and physical maps that cover all nine chromosomes. Based on this information we identified the proposed ancestral linkage groups of rosids and asterids within the sugar beet genome. We generated an extended genetic map that comprises 1127 single nucleotide polymorphism markers prepared from expressed sequence tags and bacterial artificial chromosome (BAC) end sequences. To construct a genome-wide physical map, we hybridized gene-derived oligomer probes against two BAC libraries with 9.5-fold cumulative coverage of the 758 Mbp genome. More than 2500 probes and clones were integrated both in genetic maps and the physical data. The final physical map encompasses 535 chromosomally anchored contigs that contains 8361 probes and 22 815 BAC clones. By using the gene order established with the physical map, we detected regions of synteny between sugar beet (order Caryophyllales) and rosid species that involves 1400-2700 genes in the sequenced genomes of Arabidopsis, poplar, grapevine, and cacao. The data suggest that Caryophyllales share the palaeohexaploid ancestor proposed for rosids and asterids. Taken together, we here provide extensive molecular resources for sugar beet and enable future high-resolution trait mapping, gene identification, and cross-referencing to regions sequenced in other plant species. PMID- 22211634 TI - Cost-effectiveness of using recombinant activated factor VII as an off-label rescue treatment for critical bleeding requiring massive transfusion. AB - BACKGROUND: Recombinant activated factor VII (rFVIIa) is widely used as an off label rescue treatment for patients with nonhemophilic critical bleeding. STUDY DESIGN AND METHODS: Using data from the intensive care unit, transfusion service, and death registry, the long-term survival after using rFVIIa and the associated cost per life-year gained in a consecutive cohort of patients with critical bleeding requiring massive transfusion (>= 10 red blood cell [RBC] units in 24 hr) were assessed. rFVIIa was only used as a lifesaving treatment when conventional measures had failed. RESULTS: Of the 353 patients with critical bleeding requiring massive transfusion, 81 (23%) required rFVIIa as a lifesaving rescue treatment. The patients requiring rFVIIa received a greater number of transfusions (number of units: RBCs, 18 vs. 12; fresh-frozen plasma, 16 vs. 10; platelets, 4 vs. 2; p < 0.001) and had a shorter survival time (24 months vs. 33 months; p = 0.002) than those who did not require rFVIIa. The total cost per life year gained of massive transfusion and incremental cost of rFVIIa as a lifesaving treatment were US$1,148,000 (L711,760; 95% confidence interval [CI], US$825,000 US$1,471,000) and US$736,000 (L456,320; 95% CI, US$527,000-US$945,000), respectively. The incremental costs of rFVIIa increased with severity of illness and transfusion requirement and were greater than the usual acceptable cost effective limit (=60 years, New York Heart Association class II IV, ischaemic systolic HF) in the CORONA population, randomly assigned to 10 mg rosuvastatin or placebo. Results. Multivariate analysis revealed that NGAL added significant information when adjusting for clinical variables, but was no longer significant when further adjusting for apolipoprotein A-1 (ApoA-1), glomerular filtration rate (GFR), C-reactive protein (CRP) and N-terminal pro-brain natriuretic peptide (NT-proBNP). However, belonging to the highest NGAL tertile was associated with more frequent hospitalization, even after adjusting for clinical variables, GFR and ApoA-1, but not after adjusting for CRP and NT proBNP. There was no interaction between rosuvastatin treatment and NGAL. Conclusion. Neutrophil gelatinase-associated lipocalin added no significant information to NT-proBNP and GFR in a multivariate model for primary and secondary end-points. PMID- 22211642 TI - Plasma not serum concentrations. PMID- 22211643 TI - An audit of laryngoscopes applying an ISO standard. PMID- 22211644 TI - Absence of perioperative analgesia in children with cerebral palsy: how justified is it? PMID- 22211645 TI - Cerebral NIRS and superior vena cava ScvO2 should not be compared. PMID- 22211648 TI - The use of milrinone in pediatric intensive care medicine. PMID- 22211649 TI - Ultrasound and regional anesthesia in pediatric patients: new hemodynamic and sonoanatomy acquirements. PMID- 22211651 TI - In response to: Desire for perioperative information and parental ethnicity. PMID- 22211652 TI - Caudals, dimples, and ultrasound--part 2. PMID- 22211653 TI - Simulation: a teaching tool for liver transplantation anesthesiology. AB - Anesthesia for liver transplantation (ALT) requires extensive preparation and rapid recognition of changing clinical conditions. Owing to the proliferation of transplant centers, greater number of anesthesia providers need training in specific skills required to treat these patients. These cases are no longer limited to few transplant centers; therefore, reduction of cases in individual centers has created a need for simulation training to prepare and supplement clinical experience. We have developed an ALT simulation course for senior anesthesia residents which combines didactic sessions with live-patient-based and mannequin-based simulation. Outcomes have been measured using pre- and post simulation course quizzes as well as a survey given at the end of the month-long ALT rotation. Twenty-four senior anesthesiology residents (n = 24) have completed the ALT simulation course. Residents had an average score of 75% +/- 10% on the pre-simulation quiz, which increased to 92% +/- 6.5% on the post-simulation quiz (p < 0.001). Furthermore, survey scores indicated that residents noted that the course provided an improvement in their preparedness, confidence, anticipation, and understanding of the importance of communication skills in the care of this patient population. The ALT simulation course provided a standardized in-depth exposure to clinical issues involved in the perioperative care of liver transplant patients. PMID- 22211654 TI - The influence of AIDS on the morphometric and immune status of the uterine cervix of autopsied patients. AB - INTRODUCTION: Previous studies have shown that HIV infection is related to changes in the immune status of the mucosal surfaces. Such changes may also occur in the genital tract, since patients infected by HIV have the virus in their cervical secretions. METHODS: Fragments of the uterine cervix of 29 autopsied women were collected at a university hospital from 1985 to 2008, and were divided in groups with and without AIDS. Image J software was used to measure the cervical epithelium and to count the epithelial cellular layers. Langerhans cells (LCs) and IgG positive cells were respectively immunostained with anti-S100 and anti-IgG. RESULTS: Women with AIDS, when compared with women without AIDS, had thinner cervical epithelium (103.32 vs 116.71 MUm), lower number of cellular layers (10.41 vs 13.66 MUm), lower mean cell diameter (10.09 vs 11.51 MUm), less number of total LCs (11.19 vs 23.08 LCs/mm(2)), and higher percentage of IgG positive cells (22.64% vs 16.06%). All these results were significant. CONCLUSION: AIDS causes alterations in the structure of the cervical epithelium and in its extracellular matrix, leading to alterations in the local and systemic immunity, and triggering signs and opportunistic infections in the uterine cervix in the course of the disease. PMID- 22211655 TI - HIV drug resistance on HAART despite an undetectable viral load. AB - HIV is known to have the ability to adapt rapidly its genome under drug pressure, resulting in clinical treatment failure. We present the case of an HIV-infected patient who developed mutations of resistance to nevirapine although he always had an undetectable viral load and without context of inobservance. The concepts of undetectability and virological success in HIV infection must be balanced by the possible appearance of resistance under a treatment considered as effective. PMID- 22211656 TI - Position 22 of the V3 loop is associated with co-receptor usage and disease progression in HIV-1 subtype B isolates. AB - Our goal in this study was to analyze position 22 of the V3 loop associated with co-receptor usage and disease progression in human immunodeficiency virus type 1 (HIV-1) subtype B infection. Bioinformatics approaches were used to compare the amino acid sequence and secondary structure of the V3 loop of the CCR5-tropic virus and CXCR4-tropic virus in HIV-1 subtype B. HIV-1 subtype B V3 amino acid sequence files in the FASTA format were collected from the HIV Sequence Database. The amino acid sequences of different tropism were multiple-aligned with CLUSTAL W program, and the frequencies of the amino acids at each position of the V3 loop sequences of two groups were calculated and sorted in descending order. The secondary structure of the consensus V3 amino acid sequences from CCR5-tropic and CXCR4-tropic viruses were predicted with the APSSP2 method. The amino acids at positions 11, 22, and 25 of V3 were different between the CCR5-tropic virus and CXCR4-tropic virus. The consensus amino acid frequencies were found to be 71.9% S, 66.7% A, and 56.0% D for the CCR5-tropic virus and 50.0% R, 57.1% T, and 26.2% Q for the CXCR4- tropic virus at positions 11, 22, and 25, respectively. There was a strong association between the identity of the residues at position 11, 22, and 25 of the V3 loop amino acid sequence and CD4+ T cell counts of different patients. The change of the residue at position 22 in the R5-tropic or X4-tropic viruses is expected to likely change the secondary structure to be similar to the X4-tropic or R5-tropic viruses. Our study indicates that position 22 of the V3 loop amino acid sequence is significantly associated with viral tropism and disease progression in HIV-1 subtype B. PMID- 22211657 TI - Application of outer membrane vesicle of Neisseria meningitidis serogroup B as a new adjuvant to induce strongly Th1-oriented responses against HIV-1. AB - Despite the worldwide efforts made in the field of HIV vaccine development, an efficient AIDS vaccine strategy is still vague. Virus-like particles (VLPs) are one of the introduced aspects for HIV vaccine development since the non replicative nature of HIV VLPs, resulting from the lack of viral genomic RNA, makes them suitable for broad applications. We have previously designed and introduced non-infectious VLPs (mzNL4-3) by introduction of a deletion mutation in the reverse transcriptase and integrase coding regions of HV-1. There are evidences suggesting that an effective cellular immune response against HIV-1 is able to control and suppress viremia during primary and chronic HIV infections. In the present study we have evaluated the potency of mzNL4-3 VLPs mixed with Neisseria meningitidis serogroup B outer-membrane vesicle (OMV), which is among the microbial components with proved adjuvant properties, to induce humoral and cellular responses against HIV-1. Analysis of anti-HIV-1 responses elicited in immunized BALB/c mice following different immunization regimens indicated OMV+VLP as an immunopotent combination which significantly induced anti-HIV-1 IgG with IgG2a dominancy. Results of cytokine and ELISpot assays also showed the capability of VLP+OMV immunogen for effective induction of IFN-gamma; and IL4 secreting cells and further suggested the promotion of Th1-oriented response that was evidenced with the increased IFN-gamma/IL4 secretion ratio. According to our study, HIV-1 VLPs combined with N. meningitidis B OMVs seem to be a promising approach in vaccine development against HIV-1. PMID- 22211658 TI - Induction of strong anti-HIV cellular immunity by a combination of Clostridium perfringens expressing HIV gag and virus like particles. AB - The lower gastrointestinal tract is a major mucosal site of HIV entry and initial infection. Thus, the induction of strong cellular immune responses at this mucosal site will be an important feature of an effective HIV vaccine. We have used a novel prime-boost vaccination approach to induce immune responses at mucosal sites. Orally delivered recombinant Clostridium perfringens expressing HIV-1 gag (Cp-Gag) was evaluated for induction of HIV-1 Gag specific T cell responses in a prime-boost model with intranasal inoculation of HIV-1 virus like particles (VLP). HIV-1 specific cellular immune responses in both the effector (Lamina propria) and inductive sites (Peyer's patches) of the gastrointestinal (GI) tract were significantly higher in mice immunized using Cp-Gag and VLPs in a prime-boost approach compared to mice immunized with either Cp-Gag or VLPs alone. Such cellular immune response was found to be mediated by both CD8(+) and CD4(+) T cells. Such a strong mucosal immune response could be very useful in developing a mucosal vaccine against HIV-1. PMID- 22211659 TI - Does GSS still maintain relevance on HAART outcome after the introduction of newest active antiretroviral drugs? 48 weeks results. AB - BACKGROUND: Since recent observations demonstrated that extended resistance to protease inhibitors, nucleosidic and non - nucleosidic retrotranscriptase inhibitors (PI, NRTI, NNRTI) is a marker of disease progression and death, it is a matter of the greatest importance that experienced human immunodeficiency virus (HIV) - infected patients with limited therapeutic options receive a suppressive therapy pending the availability of at least two new antiretroviral drugs. Aim of the present study is to evaluate if the GSS score, calculated by analyzing the resistance to historical antiretroviral drugs and drug classes, is still relevant since several new potent drugs and drug classes entered the current clinical use. METHODS: Taking into account patients without suppression of HIV replication for >= 6 months from October 2008 and October 2009, we analyzed viroimmunological and resistance data of 38 outpatients starting their last antiretroviral regimen including at least one of the following: maraviroc, enfuvirtide, raltegravir, etravirine, darunavir/ritonavir or tipranavir/ritonavir. Mutations present in all available genotypic resistance tests were recorded for each patient and then correlated to GSS value, assessed using the last genotypic ribonucleic acid (RNA) resistance test. GSS was studied as predictor of virological treatment outcome by univariate and multivariate logistic regression. RESULTS: At 48 weeks, undetectable viral load was obtained in 80% of patients without difference between GSS classes (HIV-RNA median < 50 copies/ml); 95.8% of patients with baseline HIV-RNA < 50,000 copies/ml obtained virological suppression (p=0.003). 48 weeks CD4+ median value was 412 cells/MUl considering GSS1 and 300 cells/MUl for combined GSS2 and GSS3 scores. Data also showed a > 60% recurrence of specific mutations for NRTI: M41L, M184IV, L210W, T215FY, K219EQ and 75% for D67N. K103N and Y181CIV mutations for NNRTI persisted in 35% of cases and their prevalence incresed in parallel with the number of GRTs. About 60% of tests reported L10FIRVC, M36ILV, M46IL, I54VLAMTS, V82AFTSLI, and L90M mutations in the protease region. 63P mutation was found in a total number of GRTs close to 80%. This percentages, when correlated to GSS, revealed a distinct pattern for most mutations, that showed a greater prevalence for GSS = 2. Conversely, only NNRTI 181CIV and NRTI 210W showed larger numbers in GSS1 and GSS3. CONCLUSIONS: Single drugs belonging to new antiretroviral classes did not correlate to viroimmunological success for any GSS. High frequency and recurrence over GRTs for specific mutations confirm their key role following the exposure to ARVs classes. A baseline HIV-RNA < 50,000 cp/ml is a predictor of therapeutic success and a carefully selected HAART based upon the evaluation of GRTs can favorably influence the immunovirologic response. PMID- 22211661 TI - Facts and fiction: cellular models for high throughput screening for HIV-1 reactivating drugs. AB - A curative therapy for HIV-1 infection will have to include measures to eliminate the reservoir of latently HIV- 1 infected cells that allow the virus to persist despite otherwise successful therapy. To date, all efforts to deplete the latent reservoir by triggering viral reactivation have used preexisting drugs that are believed to potentially target molecular mechanisms controlling HIV-1 infection. These therapeutic attempts were not clinically successful. Only in the last few years have cellular models of latent HIV-1 infection suitable for high throughput screening been developed and concerted drug discovery efforts were initiated to discover new HIV-1 reactivating drugs. We here provide a historic overview about the development of cell models with latent HIV-1 infection that lend themselves to drug discovery. We provide an overview from the first reported latently infected cell lines to current in vitro models of latent HIV-1 infection in primary T cells, and compare their potential to be used in future large-scale drug screening efforts. PMID- 22211662 TI - Models of HIV-1 persistence in the CD4+ T cell compartment: past, present and future. AB - The limitations of current anti-retroviral therapies (ART) and the lack of a valid anti-HIV-1 vaccine candidate underscore the need for new therapeutic concepts aiming at the eradication of HIV-1, which represents at the same time an ideal goal and a major challenge for AIDS research. At present, this aim is unattainable due to the existence of cellular and anatomical reservoirs of persistent infection. Memory CD4(+) T cells comprise the largest pool of cells harboring silent, stably integrated HIV-1, which remains undetected by the immune system and refractory to conventional anti-retroviral drugs. The eradication of latent HIV-1 reservoirs will require new, potent and specific therapeutic strategies, which in turn must rely upon a deeper understanding of HIV-1 latency. To facilitate the advancement of our knowledge in this new area of research, several in vitro models of HIV-1 latency in CD4(+) T cells have been established. Here, we dissect and critically compare the rationale behind each experimental approach. Furthermore, we outline new avenues of research that will benefit from these models, including the push toward the development of new classes of viral eradication drugs. PMID- 22211663 TI - Implications of RNA helicases in HIV-1 replication: possible roles in latency. AB - HAART treatment has greatly improved life expectancy of HIV-1-infected individuals. Unfortunately, latency still remains the major barrier towards HIV-1 eradication. Efforts to identify viral and host cell proteins involved in latency remain important research areas to win this war against HIV-1. Here, we review the contributions of several factors in the establishment of latently infected cells. In addition, we also raise the possibility that RNA helicases, while playing important roles at almost every step of the HIV-1 replication cycle, could be implicated in the processes governing the establishment of these latent reservoirs. PMID- 22211660 TI - Control of HIV latency by epigenetic and non-epigenetic mechanisms. AB - Intensive antiretroviral therapy successfully suppresses viral replication but is unable to eradicate the virus. HIV persists in a small number of resting memory T cells where HIV has been transcriptionally silenced. This review will focus on recent insights into the HIV transcriptional control mechanisms that provide the biochemical basis for understanding latency. There are no specific repressors of HIV transcription encoded by the virus, instead latency arises when the regulatory feedback mechanism driven by HIV Tat expression is disrupted. Small changes in transcriptional initiation, induced by epigenetic silencing, lead to profound restrictions in Tat levels and force the entry of proviruses into latency. In resting memory T cells, which carry the bulk of the latent viral pool, additional restrictions, especially the limiting cellular levels of the essential Tat cofactor P-TEFb and the transcription initiation factors NF-kappaB and NFAT ensure that the provirus remains silenced unless the host cell is activated. The detailed understanding of HIV transcription is providing a framework for devising new therapeutic strategies designed to purge the latent viral pool. Importantly, the recognition that there are multiple restrictions imposed on latent proviruses suggest that proviral reactivation will not be achieved when only a single reactivation step is targeted and that any optimal activation strategy will require both removal of epigenetic blocks and the activation of P-TEFb. PMID- 22211664 TI - Humanized mouse models of HIV-1 latency. AB - The existence of long-lasting cellular reservoirs of HIV-1 is one of the major hurdles in developing effective anti-retroviral therapies. These latently infected cells and tissues efficiently evade immune responses and remain dormant until activated, upon which they can generate a productive HIV-1 infection. This classic scenario of viral latency becomes even more difficult to study and model due to the extreme complexity of translating in vivo virus-cell interactions into a controlled in vitro system. The recent developments and constant improvements upon hematopoietic engraftment of human cells and tissues onto recipient immunocompromised murine scaffolds have made it possible to model complex human innate and adaptive immune responses in a small animal model. Specifically, HIV-1 infection has been successfully modeled in these humanized mice to mimic transmission, pathogenesis, host immune responses, and treatment. Here, we review the complexities surrounding modeling HIV-1 latency in vitro and in vivo and highlight the most recent humanized mouse models that support retroviral infection. PMID- 22211665 TI - Daylight photodynamic therapy for actinic keratosis: an international consensus: International Society for Photodynamic Therapy in Dermatology. AB - Photodynamic therapy (PDT) is an attractive therapy for non-melanoma skin cancers including actinic keratoses (AKs) because it allows treatment of large areas; it has a high response rate and results in an excellent cosmesis. However, conventional PDT for AKs is associated with inconveniently long clinic visits and discomfort during therapy. In this article, we critically review daylight mediated PDT, which is a simpler and more tolerable treatment procedure for PDT. We review the effective light dose, efficacy and safety, the need for prior application of sunscreen, and potential clinical scope of daylight-PDT. Three randomized controlled studies have shown that daylight-mediated PDT is an effective treatment of thin AKs. Daylight-mediated PDT is nearly pain-free and more convenient for both the clinics and patients. Daylight-mediated PDT is especially suited for patients with large field-cancerized areas, which can easily be exposed to daylight. Further investigations are necessary to determine at which time of the year and in which weather conditions daylight-mediated PDT will be possible in different geographical locations. PMID- 22211667 TI - Nanoscale noncontact subsurface investigations of mechanical and optical properties of nanoporous low-k material thin film. AB - Revealing defects and inhomogeneities of physical and chemical properties beneath a surface or an interface with in-depth nanometric resolution plays a pivotal role for a high degree of reliability in nanomanufacturing processes and in materials science more generally. (1, 2) Nanoscale noncontact depth profiling of mechanical and optical properties of transparent sub-micrometric low-k material film exhibiting inhomogeneities is here achieved by picosecond acoustics interferometry. On the basis of the optical detection through the time-resolved Brillouin scattering of the propagation of a picosecond acoustic pulse, depth profiles of acoustical velocity and optical refractive index are measured simultaneously with spatial resolution of tens of nanometers. Furthermore, measuring the magnitude of this Brillouin signal provides an original method for depth profiling of photoelastic moduli. This development of a new opto-acoustical nanometrology paves the way for in-depth inspection and for subsurface nanoscale imaging of inorganic- and organic-based materials. PMID- 22211666 TI - Maximum occlusal force and physical performance in the oldest old: the Tokyo oldest old survey on total health. AB - OBJECTIVES: To elucidate the independent relationship between masticatory and physical performance in community-living oldest old people (mean age +/- standard deviation 87.8 +/- 2.2, range 85-102). DESIGN: Cross-sectional analysis. SETTING: University research center or home-based examination. PARTICIPANTS: Four hundred eighty-nine community-living individuals (219 men, 270 women) aged 85 and older. MEASUREMENTS: Maximum occlusal force (MOF) was measured using an occlusal force measuring device. Sociodemographic and functional factors, oral health, comorbidities, blood chemistry, lower extremity performance, and handgrip strength were assessed. Blood chemistry analyses included serum albumin, C reactive protein, interleukin (IL)-6, and total and free testosterone. RESULTS: MOF was significantly associated with age, body mass index, and cognitive impairment in men but not in women. Comorbidities and blood chemistry were not associated with MOF except for a significant association with IL-6 concentration in women. In a multivariate model adjusted for various confounders, lower MOF was associated with greater risk for poor performance on the timed up and go (TUG) test in men and women (men: odds ratio (OR)=2.34, 95% confidence interval (CI)=1.02-5.38; women: OR=2.44, 95% CI=1.12-5.33). MOF was similarly associated with performance in chair standing, one-leg standing, and handgrip strength only in men. These associations remained after adjustment for number of natural teeth. CONCLUSION: MOF was strongly and independently associated with all measures of physical performance in men and with the TUG test in women after adjustment for various confounders, suggesting that age-related declines in masticatory and skeletal muscle functions share common mechanistic pathways in older age, particularly in men. PMID- 22211668 TI - Intractable diffuse alopecia caused by multifactorial side-effects in treatment of acute lymphocytic leukemia: connection to iatrogenic failure of estrogen secretion. AB - Treatment of infantile acute lymphocytic leukemia (ALL) may cause failure to thrive and hypogonadism due to hypopituitarism induced by chemotherapy and whole brain radiotherapy. We report the case of a 22-year-old girl with a genetic predisposition to pattern hair loss who developed inveterate diffuse alopecia. The patient had onset of ALL at 8 years old and underwent bone marrow transplantation (BMT). Diffuse alopecia gradually advanced over her whole body. Her vellus scalp hair gradually came out, and hair loss progressed again at 8 years, after BMT. She later developed iatrogenic failure of secretion of estrogen and was treated with estrogen substitution therapy for 14 months from the age of 20. There was a small increase in the volume of hair during therapy, but alopecia returned to the former level after the therapy was suspended. Histopathologic examinations of the scalp performed during estrogen substitution therapy and 2 years after suspension of the therapy showed a 60% decrease in the number of hair follicles and prominent development of vellus hair. We conclude that estrogen influenced hair growth in the context of a genetic predisposition for pattern hair loss in this case. PMID- 22211669 TI - Effect of electronically delivered prescriptions on compliance and pharmacy wait time among emergency department patients. AB - OBJECTIVES: The primary objectives were to assess whether electronically delivered prescriptions lead to reduced pharmacy wait time, improved patient satisfaction, and improved compliance with prescriptions. Secondary objectives included determining other reasons for noncompliance and if there was an association between prescription noncompliance and subsequent physician and emergency department (ED) visits. METHODS: In this prospective study, patients discharged from the Ronald Reagan UCLA Medical Center ED with prescriptions for nonnarcotic medications were randomized to a control group who were discharged with standard written prescriptions or an intervention group who had their prescriptions electronically delivered to the pharmacy of their choice. All study participants were contacted 7 to 31 days after ED discharge for a structured telephone interview. RESULTS: Of the 454 patients enrolled, follow-up was successful for 224 patients (52.4%). Twenty-eight patients did not fill their prescriptions (12.5% noncompliance rate). The top three reasons patients stated for not picking up their medications were perceiving their prescription as unnecessary (n = 11), medication affordability (n = 5), and lack of time (n = 4). There was no difference in primary prescription noncompliance between the two study groups (p = 0.58). However, electronically delivered prescriptions significantly reduced the median pharmacy wait time, from 15 to 0 minutes (p = 0.001), and improved patient satisfaction at the pharmacy (p = 0.034). Neither subsequent physician nor ED visits were increased by primary prescription noncompliance. CONCLUSIONS: Electronically delivered prescriptions significantly minimized pharmacy wait time and improved patient satisfaction at the pharmacy, but did not improve primary compliance with prescriptions. PMID- 22211670 TI - The rate of dissipation of mouth alcohol in alcohol positive subjects. AB - Seven subjects participated in a two-part study to evaluate mouth alcohol dissipation in alcohol positive subjects. In part one, subjects rinsed their mouths with a vodka solution and were breath tested after 1, 2, 3, 4, and 5 min intervals. On average, breath alcohol concentration (BrAC) decreased 20.4% (range 3.2-47.9%) between 1 and 2 min after rinsing. In part two of the study, multiple breath tests were administered after rinsing once with the vodka solution. The BrAC decreased more than 0.020 g/210 L between the first and second tests for all subjects (average 0.095 g/210 L, range 0.021-0.162 g/210 L). The average time for subjects to reach their unbiased BrAC was 9.35 min (range 4-13 min) after rinsing. This study reaffirms the need for duplicate breath testing and confirms that the minimum of a 15-min observation period is sufficient for mouth alcohol to dissipate in alcohol positive subjects. PMID- 22211671 TI - Short and long sleep duration are associated with prevalent cardiovascular disease in Australian adults. AB - A growing number of studies from a range of different countries have observed an association between sleep duration and cardiovascular disease. The objective of this paper was to examine the associations between sleep duration and prevalent cardiovascular disease in a large sample of Australian adults, and identify the sociodemographic and health-related factors moderating these associations. Participants included 218,155 Australian adults aged 45years and over. The results indicated that 6h versus 7h sleep was associated with increased odds of heart disease [odds ratio (OR)=1.11 (1.06-1.17)], diabetes [OR=1.15 (1.09-1.22)], stroke [OR=1.25 (1.14-1.38)] and high blood pressure [OR=1.08 (1.04-1.11)]. Long sleep (>=9h sleep) was also related to elevated odds of heart disease [OR=1.14 (1.09-1.19)], diabetes [OR=1.25 (1.19-1.31)], stroke [OR=1.50 (1.38-1.62)] and high blood pressure [OR=1.04 (1.01-1.08)] compared to 7h sleep. Some of these relationships varied by age, and were not evident in adults aged 75years and over. The magnitude of some associations varied significantly by body mass index, smoking and physical activity. These findings provide further insight into the nature of the relationship between sleep and cardiovascular health. PMID- 22211672 TI - Characterization of the Acinetobacter baumannii growth phase-dependent and serum responsive transcriptomes. AB - Acinetobacter baumannii has emerged as a bacterial pathogen of considerable healthcare concern. Yet, little is known about the organism's basic biological processes and the regulatory networks that modulate expression of its virulence factors and antibiotic resistance. Using Affymetrix GeneChips , we comprehensively defined and compared the transcriptomes of two A. baumannii strains, ATCC 17978 and 98-37-09, during exponential and stationary phase growth in Luria-Bertani (LB) medium. Results revealed that in addition to expected growth phase-associated metabolic changes, several putative virulence factors were dramatically regulated in a growth phase-dependent manner. Because a common feature between the two most severe types of A. baumannii infection, pneumonia and septicemia, includes the organism's dissemination to visceral organs via the circulatory system, microarray studies were expanded to define the expression properties of A. baumannii during growth in human serum. Growth in serum significantly upregulated iron acquisition systems, genes associated with epithelial cell adherence and DNA uptake, as well as numerous putative drug efflux pumps. Antibiotic susceptibility testing verified that the organism exhibits increased antibiotic tolerance when cultured in human serum, as compared to LB medium. Collectively, these studies provide researchers with a comprehensive database of A. baumannii's expression properties in LB medium and serum and identify biological processes that may contribute to the organism's virulence and antibiotic resistance. PMID- 22211674 TI - Cannabinoid CB1 receptor mediates glucocorticoid effects on hormone secretion induced by volume and osmotic changes. AB - The present study provides the first in vivo evidence that the cannabinoid CB(1) receptor mediates the effects of dexamethasone on hormone release induced by changes in circulating volume and osmolality. Male adult rats were administered with the CB(1) receptor antagonist rimonabant (10 mg/Kg, p.o.), followed or not in 1 hour by dexamethasone (1 mg/Kg, i.p.). Extracellular volume expansion (EVE, 2 mL/100 g of body weight, i.v.) was performed 2 hours after dexamethasone or vehicle treatment using either isotonic (I-EVE, 0.15 mol/L) or hypertonic (H-EVE, 0.30 mol/L) NaCl solution. Five minutes after EVE, animals were decapitated and trunk blood was collected for all plasma measurements. Rimonabant potentiated oxytocin (OT) secretion induced by H-EVE and completely reversed the inhibitory effects of dexamethasone in response to the same stimulus. These data suggest that glucocorticoid modulation of OT release is mediated by the CB(1) receptor. Although dexamethasone did not affect vasopressin (AVP) secretion induced by H EVE, the administration of rimonabant potentiated AVP release in response to the same stimulus, supporting the hypothesis that the CB(1) receptor regulates AVP secretion independently of glucocorticoid-mediated signalling. Dexamethasone alone did not affect atrial natriuretic peptide (ANP) release stimulated by I-EVE or H-EVE. However, pretreatment with rimonabant potentiated ANP secretion induced by H-EVE, suggesting a possible role for the CB(1) receptor in the control of peripheral factors that modulate cardiovascular function. Rimonabant also reversed the inhibitory effects of dexamethasone on H-EVE-induced corticosterone secretion, reinforcing the hypothesis that the CB(1) receptor may be involved in the negative feedback exerted by glucocorticoids on the activity of the hypothalamic-pituitary-adrenal axis. Collectively, the results of the present study indicate that the CB(1) receptor modulates neurohypophyseal hormone secretion and systemic factors, such as corticosterone and ANP, thus participating in homeostatic responses to altered extracellular volume and plasma tonicity. PMID- 22211675 TI - DFNB86, a novel autosomal recessive non-syndromic deafness locus on chromosome 16p13.3. PMID- 22211677 TI - Cord blood interleukin-6 as a predictor of early-onset neonatal sepsis. AB - AIM: To compare diagnostic accuracy in cord blood of interleukin-6 (IL-6) with C reactive protein (CRP) as predictors of early-onset neonatal sepsis (EOS) in newborns with prenatal risk factors for infection. METHODS: During 12 months, cord blood IL-6 and CRP were measured immediately after birth in neonates with prenatal risk factors of infection. The odds of developing sepsis based on IL-6 and CRP values were calculated using likelihood ratios (LR), and their accuracy as predictors was compared by binary logistic regression. Multivariable logistic regression analyses were performed to identify independent risk factors for sepsis. RESULTS: Ten of 128 neonates (7.8%) were diagnosed with EOS confirmed with positive blood culture in five cases (3.9%). Cord blood IL-6 was a greater predictor of sepsis than CRP [ROC for IL-6 (0.88) vs. CRP (0.70)]. IL-6-positive and IL-6-negative LR [7.14 vs. -0.11] were superior to those calculated for CRP [2.86 vs. -0.51]. Chorioamnionitis and Apgar at 1 min were identified as independent risk factors for EOS. CONCLUSIONS: Cord blood IL-6 showed superior LR than CRP; therefore, it is a better predictor to initiate treatment in neonates with prenatal infectious risk factors immediately after birth. PMID- 22211678 TI - A practice-based study on the effect of a short sucrose/xylitol exposure on survival of primary teeth caries free. AB - BACKGROUND: In a randomized double-blinded clinical trial, preschool children used sucrose or xylitol chewing gum regularly for 2 months to study the preventive effect of xylitol on acute otitis media (AOM). Salivary mutans streptococci (sm) levels of the children were measured before the exposure. Those with >=10(5) sm CFU in 1 mL saliva were considered to have high sm levels (sm+); and those with <10(5) CFU low sm levels (sm-). AIM: This practice-based study aims to evaluate long-term dental effects of the sucrose/xylitol exposure on primary teeth. DESIGN: For analyses, individuals were divided into sub groups according to their study group in the original AOM trial and baseline sm levels. Outcome events owing to dental caries of their all primary teeth were followed from dental records up to 12 years. Survival of teeth caries free was determined by Kaplan-Meier method and analysed statistically by Wilcoxon testing. RESULTS: Survival of primary teeth caries free of children with high sm levels in the sucrose group was significantly shorter compared with all other groups when followed until shedding. CONCLUSIONS: Two months' regular exposure to sucrose was sufficient to induce dental caries in primary teeth of children with elevated sm levels at baseline. PMID- 22211681 TI - From small to big molecules: how do we prevent and delay the progression of age related neurodegeneration? AB - Age-related neurodegeneration in the brain and retina is complicated. It comprises a series of events encompassing different modes of degeneration in neurons, as well as inflammation mediated by glial cells. Systemic inflammation and risk factors can contribute to disease progression. Age-related conditions such as Alzheimer's disease (AD), Parkinson's disease (PD) and Age-related Macular Degeneration (AMD) affect patients for 5 to 20 years and are highly associated with risk factors such as hyperhomocysteinaemia, hypercholesterolaemia, hypertension, and symptoms of mood disorder. The long duration of the degeneration and the wide array of systemic factors provide the opportunity for nutraceutical intervention to prevent or delay disease progression. Small molecules such as phenolic compounds are candidates for neuroprotection because they have anti-oxidant activities and can modulate intracellular signaling pathways. Bigger entities such as oligosaccharides and polysaccharides have often been neglected because of their complex structure. However, certain big molecules can provide neuroprotective effects. They may also have a wide spectrum of action against risk factors. In this review we use an integrative approach to the potential uses of nutraceutical products to prevent age-related neurodegeneration. These include direct effects of phenolic compounds and polysaccharides on neurons to antagonize various neurodegenerative mechanisms in AD, PD and AMD, and indirect effects of these compounds on peripheral disease related risk factors. PMID- 22211682 TI - Immunopathogenesis of neurodegenerative diseases: current therapeutic models of neuroprotection with special reference to natural products. AB - Parkinson disease (PD) and Alzheimer disease (AD) are neurodegenerative processes whose frequency is dramatically increasing in the western world. Both diseases share a common pathogenic denominator characterized by an exaggerated activation of the systemic and cerebral immune system, respectively. For instance, lipopolysaccharides in PD and amyloid beta in AD trigger microglia and astrocytes to release reactive oxygen species (ROS) and proinflammatory cytokines. Infiltrating peripheral T cells once activated in the central nervous system also contribute to the neurodegenerative process. Besides innovative biotherapy, nutraceuticals or functional foods are currently investigated for their neuroprotective activities. Especially, vitamin D and polyphenols, seem to be promising therapeutic tools for inhibiting ROS formation and arresting cytokine mediated neuroinflammation in PD and AD. PMID- 22211683 TI - High fat meal increase of IL-17 is prevented by ingestion of fruit juice drink in healthy overweight subjects. AB - An emerging role of IL-17 in the inflammatory response associated with pathogenesis of neurodegeneration has been recently suggested. However, though diet represents a key factor in the modulation of inflammatory processes, evidence is not currently available on the nutritional regulation of IL-17 in humans. In a double blind, randomized, placebo controlled, crossover study, we investigated the effect of High Fat Meal (HFM) on IL-17 circulating levels in presence of a placebo (HFM-P) or with a Fruit Juice Drink (HFM-FJD) composed of pineapple, blackcurrant and plum in fourteen healthy overweight humans. Fasting in the morning subjects ingested a test meal providing 1344 Kcal. Ingestion of HFM-P induced an inflammatory response mediated by TNF-alpha (p < 0.001), IL-6 (p < 0.001) and IL-17 (p < 0.01). Plasma IL-17 concentration significantly increased at 1 h (+2.6 +/- 1.1 pg/ml), remaining high at 4 h (+2.98 +/- 1.2 pg/ml), 6 h (+2.38 +/- 0.6 pg/ml) and 8 h (+2.8 +/- 0.9 pg/ml) (ANOVA for time-course p=0.009). When the HFM was consumed in the presence of the FJD a marked inhibition of IL-17 response to the HFM was observed (ANOVA between treatment p=0.037). We provided, for the first time, evidence on the role of diet in modulating IL-17 production in healthy overweight subjects. PMID- 22211684 TI - Nutraceuticals and prevention of neurodegeneration. PMID- 22211685 TI - Protective effects of chronic green tea consumption on age-related neurodegeneration. AB - Dietary antioxidant compounds, due to their pivotal role in the modulation of cellular redox mechanisms, are gaining attention of researchers in the field of brain aging and related degenerative diseases. In this perspective, green tea (GT) can be an excellent resource, as it contains large amounts of brain accessible polyphenols. Many of these compounds are monomeric catechins, which have been shown to exert antioxidant effects, acting directly as radical scavengers or metal-chelators. In the current article, we review the general properties of GT, the direct antioxidant action of its polyphenols and the fine modulation of signaling systems related to survival and antioxidant defenses in the central nervous system of aging rats. The effects in the glutathione system and the activation of several transcription factors including cyclic AMP response element-binding (CREB) protein, levels of the brain-derived neurotrophic factor (BDNF) and the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) are given in detail. We discuss also the beneficial action of catechins in learning and memory with a particular focus on the hippocampal formation. We conclude that GT polyphenols can have a promising role in the reversal of age-related loss of neuronal plasticity and recovery after neuronal lesions associated with aging. PMID- 22211686 TI - Resveratrol, a neuroprotective supplement for Alzheimer's disease. AB - The polyphenolic compound resveratrol (3,4',5-trihydroxystilbene) is a naturally occurring phytochemical which has been found in more than 70 plant species, including herbs and human food products such as grapes, berries, and peanuts. Resveratrol was first isolated in 1940; however, little attention was paid to it until its benefits in coronary heart disease were studied in 1992. Since then, increasing evidence has indicated that resveratrol may be useful in treating cardiovascular diseases, cancers, pain, inflammation, tissue injury, and in reducing the risk of neurodegenerative disorders, especially Alzheimer's disease (AD). AD is characterized by a progressive dementia, and is one of the most common neurodegenerative disorders in the elderly. It has been reported that resveratrol exhibits neuroprotective benefits in animal models of AD. Resveratrol promotes the non-amyloidogenic cleavage of the amyloid precursor protein, enhances clearance of amyloid beta-peptides, and reduces neuronal damage. Despite the effort spent trying to understand the mechanisms by which resveratrol functions, the research work in this field is still incomplete. Many concerns such as bioavailability, biotransformation, synergism with other dietary factors, and risks inherent to its possible pro-oxidant activities still need to be addressed. This review summarizes and discusses the neuroprotective effects of resveratrol on AD, and their potential mechanisms. PMID- 22211687 TI - Fermented grape marc (FGM): immunomodulating properties and its potential exploitation in the treatment of neurodegenerative diseases. AB - The onset of neurodegenerative diseases has become more frequent than in the past also in relation to inappropriate dietary habits adopted in the western world. Nutraceuticals are currently investigated in order to prevent or retard the outcome of the so-called diet-related diseases, even including neurodegenerative pathologies. Here, we have in vitro studied the ability of fermented grape marc (FGM) from Negroamaro (N) and Koshu (K) Vitis vinifera to modulate the function of human peripheral blood mononuclear cells (PBMCs). Actually, both FGMs were able to increase the release and the intracellular content of inflammatory and anti-inflammatory cytokines, the induction of FoxP3 (a biomarker of T regulatory cells) and reduce the production of Granzyme B from PBMCs. Since these FGM induced effects tend to polarize the immune response toward an anti-inflammatory pathway, the potential use of FGMs may represent a valid therapeutic measure to mitigating neuroinflammation in pathologies such as Parkinson disease and Alzheimer disease. PMID- 22211689 TI - Nutraceuticals and Prevention of Neurodegeneration Herbal Medicines for the Prevention and Treatment of Alzheimer's Disease. AB - Alzheimer's disease (AD) is a chronic neurodegenerative disorder and is the most common cause of progressive dementia in aging. Research on AD therapy has been partly successful in terms of developing symptomatic treatments, but there have been a number of failures with regard to developing disease-modifying therapies. The pathogenesis of AD remains unclear and the present one-drug, one-target paradigm for anti-AD treatment appears to be clinically unsuccessful. In many countries, traditional herbal medicines are used to prevent or treat neurodegenerative disorders, and some have been developed as nutraceuticals or functional foods. This review briefly introduces progress in the development of anti-AD treatments and then focuses on recent advances in the research, characteristics, and development of herbal medicines. Because AD arises via multiple pathological or neurotoxic pathways, herbal medicines have the potential to be developed into optimum pharmaceuticals and nutraceuticals for AD because of their multi-function, multi-target characteristics. PMID- 22211688 TI - Neuroprotective effects of lutein in the retina. AB - Although a large variety of pharmaceutical therapies for treating disease have been developed in recent years, there has been little progress in disease prevention. In particular, the protection of neural tissue is essential, because it is hardly regenerated. The use of nutraceuticals for maintaining the health has been supported by several clinical studies, including cross-sectional and interventional studies for age-related macular disease. However, mechanistic evidence for their effects at the molecular level has been very limited. In this review, we focus on lutein, which is a xanthophyll type of carotenoid. Lutein is not synthesized in mammals, and must be obtained from the diet. It is delivered to the retina, and in humans, it is concentrated in the macula. Here, we describe the neuroprotective effects of lutein and their underlying molecular mechanisms in animal models of vision-threatening diseases, such as innate retinal inflammation, diabetic retinopathy, and light-induced retinal degeneration. In lutein-treated mouse ocular disease models, oxidative stress in the retina is reduced, and its downstream pathological signals are inhibited. Furthermore, degradation of the functional proteins, rhodopsin (a visual substance) and synaptophysin (a synaptic vesicle protein also influenced in other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease), the depletion of brain-derived neurotrophic factor (BDNF), and DNA damage are prevented by lutein, which preserves visual function. We discuss the possibility of using lutein, an antioxidant, as a neuroprotective treatment for humans. PMID- 22211690 TI - Curcumin-glucoside, a novel synthetic derivative of curcumin, inhibits alpha synuclein oligomer formation: relevance to Parkinson's disease. AB - alpha-Synuclein aggregation is centrally implicated in Parkinson's disease (PD). It involves multi-step nucleated polymerization process via the formation of dimers, soluble toxic oligomers and insoluble fibrils. In the present study, we synthesized a novel compound viz., Curcumin-glucoside (Curc-gluc), a modified form of curcumin and studied its anti-aggregating potential with alpha-synuclein. Under aggregating conditions in vitro, Curc-gluc prevents oligomer formation as well as inhibits fibril formation indicating favorable stoichiometry for inhibition. The binding efficacies of Curc-gluc to both alpha-synuclein monomeric and oligomeric forms were characterized by micro-calorimetry. It was observed that titration of Curc-gluc with alpha-synuclein monomer yielded very low heat values with low binding while, in case of oligomers, Curc-gluc showed significant binding. Addition of Curc-gluc inhibited aggregation in a dosedependent manner and enhanced alpha-synuclein solubility, which propose that Curc-gluc solubilizes the oligomeric form by disintegrating preformed fibrils and this is a novel observation. Overall, the data suggest that Curc-gluc binds to alpha-synuclein oligomeric form and prevents further fibrillization of alpha-synuclein; this might aid the development of disease modifying agents in preventing or treating PD. PMID- 22211691 TI - Curcumin: a potential neuroprotective agent in Parkinson's disease. AB - Parkinson's disease (PD) is an age-associated neurodegenerative disease clinically characterized as a movement disorder. The motor symptoms in PD arise due to selective degeneration of dopaminergic neurons in the substantia nigra of the ventral midbrain thereby depleting the dopamine levels in the striatum. Most of the current pharmacotherapeutic approaches in PD are aimed at replenishing the striatal dopamine. Although these drugs provide symptomatic relief during early PD, many patients develop motor complications with long-term treatment. Further, PD medications do not effectively tackle tremor, postural instability and cognitive deficits. Most importantly, most of these drugs do not exhibit neuroprotective effects in patients. Consequently, novel therapies involving natural antioxidants and plant products/molecules with neuroprotective properties are being exploited for adjunctive therapy. Curcumin is a polyphenol and an active component of turmeric (Curcuma longa), a dietary spice used in Indian cuisine and medicine. Curcumin exhibits antioxidant, anti-inflammatory and anti cancer properties, crosses the blood-brain barrier and is neuroprotective in neurological disorders. Several studies in different experimental models of PD strongly support the clinical application of curcumin in PD. The current review explores the therapeutic potential of curcumin in PD. PMID- 22211692 TI - Exploratory in vitro study of red blood cell storage containers formulated with an alternative plasticizer. AB - BACKGROUND: The plasticizer di-2-ethylhexyl phthalate (DEHP) is a common component in medical plastics. There is motivation to replace this component; however, DEHP is necessary to prevent excessive hemolysis in stored red blood cells (RBCs). Our objective is to evaluate a candidate replacement plasticizer (Hexamoll, di-isononyl cyclohexane-1,2-dicarboxylic acid [DINCH], BASF Corp.) compared to DEHP in an in vitro feasibility study. We hypothesize that the candidate will provide at least equivalent protection against hemolysis for RBCs stored for 42 days and periodic mixing of RBCs will add additional protection against hemolysis. STUDY DESIGN AND METHODS: Whole blood was collected into citrate-phosphate-dextrose; combined into pools of 2 ABO identical whole blood units; and divided, leukoreduced, centrifuged, and separated into plasma and RBCs. Additive solution was added, and the RBCs were stored for 42 days at 1 to 6 degrees C. In three parts of this study, split pools were paired as DINCH polyvinyl chloride (PVC) with weekly mixing versus DINCH-PVC with no mixing, DINCH-PVC mixed versus DEHP-PVC no mix, and DINCH-PVC versus DEHP-PVC with neither mixed. A standard panel of in vitro RBC characteristics was determined on Days 0 and 42. RESULTS: Mixing DINCH-PVC weekly improved Day 42 hemolysis (0.36 +/- 0.07% vs.0.56 +/- 0.15%, p = 0.002), and mixed DINCH-PVC bags were noninferior to unmixed DEHP-PVC bags (p <= 0.05). DINCH-PVC bags stored without weekly mixing were inferior to unmixed DEHP-PVC bags for hemolysis on Day 42, although no individual bag exceeded 0.8% hemolysis. CONCLUSION: Periodic mixing of RBCs stored in DINCH-PVC provides additional protection against hemolysis. Unmixed DINCH-PVC bags were inferior to DEHP-PVC bags for prevention of hemolysis, but remain a candidate for replacement DEHP in RBC storage bags. PMID- 22211694 TI - Carbapenem-hydrolyzing gram-negative bacteria: current options for treatment and review of drugs in development. AB - Multidrug resistant gram-negative bacteria are an increasing therapeutic challenge. The beta-lactamases are a group of enzymes that confer resistance to the beta-lactam antibiotics. The carbapenems have been in wide use to treat beta lactamase producing, multidrug resistant gram-negative bacterial infections. However, the emergence of carbapenemases, enzymes capable of hydrolyzing the carbapenems, has limited our therapeutic options. In the recent years, there has been some development in the discovery of new agents such as boronic acid derivatives, ME1071 and Ca-EDTA that may enhance the activity of existing antibiotics, CTC-96 which reverses antibiotic resistance and polymyxin derivatives with decreased renal toxicity. While global efforts towards new drug development should continue, appropriate use of currently available antibiotics is equally important. In this review, we will discuss the general characteristics of carbapenemases, recent patents with drugs under development and current treatment options. PMID- 22211693 TI - The association of serum 25-hydroxyvitamin D3 and D2 with depressive symptoms in childhood--a prospective cohort study. AB - BACKGROUND: Depression in adolescence is common and early onset predicts worse outcome in adulthood. Studies in adults have suggested a link between higher total 25-hydroxyvitamin D [25(OH)D] concentrations and lower risk of depression. OBJECTIVES: To investigate (a) the association between serum 25(OH)D(2) and 25(OH)D(3) concentrations and depressive symptoms in children, and (b) whether the associations of 25(OH)D(2) and 25(OH)D(3) are different from, and independent of, each other. METHODS: Prospective cohort study with serum 25(OH)D(2) and 25(OH)D(3) concentrations measured at mean age of 9.8 years and depressive symptoms assessed with the Mood and Feelings Questionnaire by a trained interviewer at the mean ages of 10.6 years (n = 2,759) and 13.8 years (n = 2,752). RESULTS: Higher concentrations of 25(OH)D(3) assessed at mean age 9.8 years were associated with lower levels of depressive symptoms at age 13.8 years [adjusted risk ratio (RR; 95% confidence interval (CI)): 0.90 (0.86-0.95)], but not at age 10.6 years [adjusted RR (95% CI): 0.98 (0.93-1.03)] and with increased odds of decreasing symptoms between age 10.6 and 13.8 years [adjusted RR (95% CI): 1.08 (1.01-1.16)]. Serum 25(OH)D(2) concentrations were not associated with depressive symptoms. CONCLUSIONS: This is the first study in children to suggest that the association between 25(OH)D(3) concentrations and depression emerges in childhood. The association is independent of a wide range of potential confounding factors, and appears to be stronger with greater time separation between assessment of 25(OH)D(3) and assessment of depressive symptoms. Confirmation of our findings in large prospective studies and trials would be valuable. PMID- 22211695 TI - Water-stable all-biodegradable microparticles in nanofibers by electrospinning of aqueous dispersions for biotechnical plant protection. AB - Pheromone eluting oligolactide (OLA) microcapsules immobilized in electrospun biodegradable polyester nanofibers were obtained by electrospinning of aqueous dispersions of the microcapsules. OLA was prepared by conventional melt polycondensation of lactic acid. Following the protocol of the solvent displacement method, OLA was dissolved in acetone and mixed with Brij S20 and the pheromone of the European grape vine moth, Lobesia Botrana, (E,Z)-7,9-dodecadien l-yl acetate (DA). Up to 32 wt % of this mixture could be dispersed in water with colloidal stability of several weeks without any sedimentation. Without DA as well as OLA, no stable dispersions of OLA in water were obtained. Replacement of DA by classical hydrophobes typically used for miniemulsions did not yield stable dispersions, but the addition of octyl acetate, which shows structural similarity to DA, yielded stable dispersions in water up to 10 wt %. Dispersions of OLA/DA were successfully electrospun in combination with an aqueous dispersion of a biodegradable block copolyester resulting in water-stable nanofibers containing OLA/DA microcapsules. Release of DA from microcapsules and fibers was retarded in comparison with non-encapsulated DA, as shown by model studies. PMID- 22211696 TI - Mutational dissection of the S/T-kinase StkP reveals crucial roles in cell division of Streptococcus pneumoniae. AB - Eukaryotic-like serine/threonine-kinases are involved in the regulation of a variety of physiological processes in bacteria. In Streptococcus pneumoniae, deletion of the single serine/threonine-kinase gene stkP results in an aberrant cell morphology suggesting that StkP participates in pneumococcus cell division. To understand the function of StkP, we have engineered various pneumococcus strains expressing truncated or kinase-dead forms of StkP. We show that StkP kinase activity, but also its extracellular and cytoplasmic domains per se, are required for pneumococcus cell division. Indeed, we observe that mutant cells show round or elongated shapes with non-functional septa and a chain phenotype, delocalized sites of peptidoglycan synthesis and diffused membrane StkP localization. To gain understanding of the underlying StkP-mediated regulatory mechanism, we show that StkP specifically phosphorylates in vivo the cell division protein DivIVA on threonine 201. Pneumococcus cells expressing non phosphorylatable DivIVA-T201A possess an elongated shape with a polar bulge and aberrant spatial organization of nascent peptidoglycan. This brings the first evidence of the importance of StkP in relationship to the phosphorylation of one of its substrates in cell division. It is concluded that StkP is a multifunctional protein that plays crucial functions in pneumococcus cell shape and division. PMID- 22211697 TI - Electrical conductivity as a proxy for groundwater density in coastal aquifers. AB - Groundwater density is an important parameter in the interpretation of flow patterns. This paper investigates the relationship between electrical conductivity (EC) and groundwater density in coastal aquifers and evaluates the suitability of the UNESCO 1980 equation of state, developed for the world's oceans, for determining the density of groundwater based on its EC. To achieve this aim, a dataset of groundwater samples from four different types of coastal aquifers was collected. It is found that the density of a sample can be estimated to a good approximation on the basis of its EC using the UNESCO 1980 equation of state. Deviations from the equation of state were found to be due to the changes in EC and the density caused by geochemical reactions, such as the dissolution of carbonates, degradation of organic carbon, cation exchange, and sulfate loss. Owing to these deviations, the UNESCO 1980 equation of state may underestimate the density by up to 1.5 kg/m(3). The effect of this uncertainty on the correction terms applied to the hydraulic head required for a proper interpretation of groundwater flow patterns and rates is quantified. It was found that the fresh water head may be wrong by centimeters to a few decimeters. From this it is concluded that, unless the purpose of a groundwater investigation requires great accuracy, the equation of state provides an efficient and inexpensive way to estimate density from EC. PMID- 22211698 TI - Interleukin-17- and protease-activated receptor 2-mediated production of CXCL1 and CXCL8 modulated by cyclosporine A, vitamin D3 and glucocorticoids in human keratinocytes. AB - Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor which mediates a variety of functions in the skin including cutaneous inflammation. SLIGKV-NH(2) , an agonist peptide for PAR2, enhanced the interleukin (IL)-17 induced production of two CXC chemokines, CXCL1 (GRO-alpha) and CXCL8 (IL-8), in normal human epidermal keratinocytes (NHEK) in a concentration-dependent manner. The enhanced production of those chemokines was suppressed by a PAR2-specific siRNA. The SLIGKV-NH(2) -induced production of both CXCL1 and CXCL8 was markedly reduced by cyclosporine A. The enhanced production of CXCL1 was suppressed by 1alpha, 24R-dihydroxyvitamin D(3) , an active form of vitamin D(3) , and weakly by glucocorticoids, dexamethasone and clobetasol propionate, whereas production of CXCL8 was not altered by any of those receptor agonists. In psoriatic skin, the thickened upper spinous layer of the epidermis was positive for PAR2 protein and the expression of the IL17A mRNA was increased. These results suggest that the IL-17-induced pro-inflammatory reaction is enhanced by the activation of PAR2 in keratinocytes, and that the effect of PAR2 is differentially modulated by cyclosporine A, the active form of vitamin D(3) and glucocorticoids. PMID- 22211700 TI - Strengthening handover communication in pediatric cardiac intensive care. AB - OBJECTIVE: To evaluate knowledge transfer and perceptions using a structured handover process for the postoperative pediatric cardiac patient being admitted to intensive care. The hypothesis being that knowledge transfer could be optimized by the implementation of this handover structure. AIM: To investigate the effects of the implementation of a structured handover in the intensive care unit, including preadmission cardiac reports and operating room information. BACKGROUND: Patient handover following pediatric cardiac surgery involves a multidisciplinary team and a potentially unstable patient, which may create multiple cognitive demands for the treating team. This may lead to an increased risk of information error with potentially significant sequelae for the patient. METHODS: A prospective interventional study in a tertiary pediatric hospital providing both general and cardiac intensive care in the United Kingdom was undertaken in the postoperative cardiac group. Twenty-one preintervention and 22 postintervention handovers were observed by a trained independent observer. Three phases of the handover, prepatient readiness, prehandover readiness, and information conveyed, were assessed as well as attentiveness, organization of the team, and flow of information during the handover. The duration and number of interruptions were also recorded. Staff perceptions of the handover were also assessed. RESULTS: All three phases of the handover were significantly improved with the handover intervention. The observer scores were also significantly improved as were the perceptions of the staff following the implementation of the handover tool. There was no significant increase in the duration of the handover. CONCLUSIONS: Communication between the operating room and intensive care staff, regarding postoperative pediatric cardiac patients, significantly improved with the implementation of a structured handover. PMID- 22211701 TI - Development of a shared theory in palliative care to enhance nursing competence. AB - AIM: This discussion article focuses on the theoretical development of a shared theory in the field of palliative care nursing through a process of comparison between Bandura's social cognitive theory and Orem's conceptual model. BACKGROUND: In many countries, nurses are little prepared to provide care to patients with life-limiting illness. Bandura's theory provides an appropriate framework for evaluating the impact of training programmes aimed at improving nursing competence in palliative care. However, this borrowed psychological theory is not specific to nursing contexts. Orem's self-care deficit theory seems to be an appropriate nursing model to guide the use of Bandura's theory in palliative care nursing situations. DATA SOURCES: A review of the literature published between 1987 and 2011 was conducted to evaluate how Bandura's social cognitive theory and Orem's conceptual model have been linked at a theoretical level in the past. DISCUSSION: Bandura's theory has been linked with Orem's model essentially at the patient level. A new shared theory that combines Bandura's social cognitive theory and Orem's conceptual model at the nursing level is thus proposed. Palliative care nursing self-competence is hypothesized to influence the quality of nursing interventions in palliative care situations. CONCLUSION: To further demonstrate the relevance of this proposed shared theory in palliative care nursing contexts, empirical studies are recommended. This shared theory has the potential to provide a solid theoretical framework for evaluating nursing training programmes and, eventually, to improve quality of care and quality of life for patients with life-limiting illness. PMID- 22211699 TI - Prostate cancer risk in men with prostate and breast cancer family history: results from the REDUCE study (R1). AB - BACKGROUND: To what degree the associations between PCa risk and family history of prostate cancer (PCa) and/or breast cancer (BCa) are attributable to screening biases is unclear. We examined these questions within the REDUCE study, where biopsies were largely independent of prostate specific antigen (PSA) minimizing screening biases. METHODS: Data were from REDUCE, which tested dutasteride 0.5 mg daily for PCa risk reduction in men with PSA 2.5-10.0 ng mL(-1) and a negative prestudy biopsy. Among men undergoing at least one on-study biopsy with complete data (n = 6415; 78.1%), the association between family history and PCa risk was tested using multivariate logistic regression adjusting for clinicodemographic characteristics. RESULTS: A family history of PCa alone was associated with increased PCa diagnosis (OR: 1.47, 95%CI: 1.22-1.77). In North America, PCa family history was not related to PCa diagnosis (OR: 1.02, 95%CI: 0.73-1.44), whereas outside North America, PCa family history was significantly related to diagnosis (OR: 1.72, 95%CI: 1.38-2.15) (P-interaction = 0.01). A family history of both PCa and BCa (OR: 2.54, 95%CI: 1.72-3.75) but not BCa alone (OR: 1.04, 95%CI: 0.84-1.29) was associated with increased PCa risk versus no family history and irrespective of geographical region. CONCLUSIONS: In REDUCE, PCa family history was significantly related to PCa diagnosis, although only for men outside North America. The presence of both PCa and BCa family history significantly increased risk versus PCa family history alone, irrespective of geographical region. Ultimately, our observations may support the need for changes in how we address family history in terms of both risk of PCa diagnosis and general risk stratification. PMID- 22211702 TI - Guidelines on the safety of light-based home-use hair removal devices from the European Society for Laser Dermatology. AB - In the past 5 years since their US introduction, there has been a rapid proliferation of light-based hair removal devices intended for home-use. In the last 2 years in Europe, sales already run into many tens of thousands of units with well-known multi-national companies entering the market. These guidelines provide a definition of light-based home-use technology, to inform healthcare professionals about home-use light-based technology and encourage manufacturers wishing to sell in Europe to adopt 'best practice'. The review presents the current status on standards and regulation issues and considers home-use safety issues, encompassing human, device and electrical safety, given risks to the eyes and skin from optical radiation both to the consumer and persons in the vicinity. Proposed technical measurement methodology is considered with focus on recognized critical parameters for the safe use of light-based hair removal technology including recording the technical performance and safety claims of a range of home-use hair removal devices. The literature review emphasizes potential adverse incidents and safety aspects of treating cosmetic conditions, such as unwanted hair growth. Although some regulations exist, they differ from region to region and there is a specific need for international common principles and guidelines relating to the manufacture, marketing and use of intense pulsed light and laser devices, including manufacturing standards for home-use products intended, amongst others, for cosmetic hair removal and photo-rejuvenation procedures. In these guidelines, the European Society for Laser Dermatology (ESLD) provides a professional view of what 'best practice' may imply for manufacturers and consumers alike. PMID- 22211704 TI - Novel and conventional assays in determining abundance of Streptococcus mutans in saliva. AB - BACKGROUND: Effective caries control and management requires identification of susceptible children for timely intervention. Streptococcus mutans (S. mutans) is an important biomarker of caries risk. AIM: This study aimed to comparatively evaluate the validities of a novel immunoassay and a conventional culture-based assay in detecting salivary S. mutans in a paediatric cohort. METHODS: 190 children aged 3-4 years were recruited. The abundance of S. mutans in their saliva samples was analysed with three assay systems viz. a conventional culture based assay (Dentocult SM), a novel immunoassay system (Saliva-Check MUTANS) based on monoclonal antibody technology and a Taqman real-time PCR assay taken as a gold standard. RESULTS: The novel immunoassay accurately differentiated saliva samples with high (>=5 * 10(5) CFU/mL) and low (<5 * 10(5) CFU/mL) S. mutans levels. The sensitivity/specificity was 97.6%/90.6%. The conventional culture based assay reached a reasonably high sensitivity/specificity (92.8%/81.3%) in identifying children with moderate (>=10(4) CFU/mL) S. mutans level. Its sensitivity/ specificity in selecting children with high (>=10(5) CFU/mL) and very high (>10(6) CFU/mL) S. mutans levels were not sufficient (78.7%/79.8% and 25.8%/91.8%, respectively). CONCLUSION: The monoclonal antibody-based immunoassay accurately and rapidly determines S. mutans abundance in saliva and could be useful for chairside assessment of children's caries risk. PMID- 22211705 TI - Fluctuations of anti-Xa concentrations during maintenance enoxaparin therapy for neonatal thrombosis. AB - AIM: To evaluate fluctuations in anti-Xa concentrations in infants treated with enoxaparin for thrombosis and describe clinical outcomes. METHODS: A retrospective chart review was performed on infants treated with enoxaparin in the Neonatal Intensive Care Unit, and data on enoxaparin doses, anti-Xa concentrations, clinical characteristics and outcomes were abstracted. RESULTS: Our cohort (n = 26) had a median gestation of 36 (range, 23-41) weeks, birthweight of 2522 (510-3912) grams and 5-min Apgar score of 8(4-9). Fifteen (57.7%) infants were males. Thromboses was diagnosed at a median age of 22 (range, 1-97) days; enoxaparin was initiated at 27.5 (range, 4-98) days at a mean (SD) dose of 1.4 (0.3) mg/kg every 12 h. Therapeutic anti-Xa concentrations (0.5 1 U/mL) were achieved at a mean (SD) dose of 2.1 (0.6) mg/kg at 12.5 (12.2) days of treatment. Of the 143 anti-Xa concentrations, 39 (27%) were within the therapeutic range. During maintenance therapy following initial therapeutic anti Xa concentration, 40% concentrations were therapeutic. Minor bleeding was noted in four infants and intracranial bleed in one infant; four infants died. During treatment, thrombocytopenia, renal and hepatic impairment during treatment were noted in 7, 2 and 4 infants, respectively. Clot resolution was observed in 21 (81%) infants. CONCLUSIONS: Anti-Xa concentrations fluctuate during maintenance enoxaparin therapy, with therapeutic levels being achieved only sporadically in young infants. Despite this, enoxaparin appears efficacious in thrombosis resolution. Further studies on the impact of stringent control of concentrations on outcomes in this population are warranted. PMID- 22211706 TI - An experimental setup for the measurement of nonthermal effects during water filtered infrared A-irradiation of mammalian cell cultures. AB - In many recent publications, supposed athermal effects of water-filtered infrared A (wIRA) irradiation are discussed. Those effects are mainly attributed to wavelengths in the range from 780 to 1440 nm, and should not result from warming of cellular water or any aqueous medium surrounding the irradiated sample caused by wIRA absorption. Athermal effects are considered to be induced directly by absorption of different wavelengths of the wIRA spectrum by cellular molecules or structures except water. To distinguish between thermal and athermal effects, irradiated samples have to be subjected to a very effective and precise temperature homeostasis. Any experimental effects can only be attributed to pure athermal effects, if the temperature of the irradiated samples is verifiably constant and does not result in hyperthermia. Here, data of temperature distribution in Petri dishes of different types filled with aqueous medium are presented which were estimated by model calculation for different setups of cooling. Additionally, the real temperature development was directly measured. Such a cooling unit enables long-term application of high wIRA irradiances and large doses without any detectable warming of the irradiated samples, in single cell layers. Using such a setup, thermal and athermal effects can be compared and in addition to that quantified. PMID- 22211707 TI - Home care in Austria: the interplay of family orientation, cash-for-care and migrant care. AB - This article discusses the development of the home care sector in Austria. It analyses what impacts the interplay of the traditional family orientation to care, a universal cash-for-care scheme (reaching about 5% of the population) and a growing migrant care sector have on formal home care in Austria. The article is based on an analysis of research papers, policy documents and statistical data covering the period from the introduction of the cash-for-care scheme in 1993 up to 2011. Some authors have argued that generous cash benefits with no direct link to service use - as in the case of Austria - limit the development of home care, particularly in countries with a traditionally strong family orientation towards long-term care. Additionally, a tradition of family care and an emphasis on cash benefits may be conducive to the employment of migrant carers in private households, as a potential substitute for both family care and formal care. Despite this context, Austria has seen a substantial increase in formal home care over the past two decades. This has been driven by clients using their increased purchasing power and by policy priorities emphasising the extension of home care. Migrant care work was regularised in 2007, and the analysis suggests that while migrant care has usually worked as a substitute for other care arrangements, migrant care can also become a more integral element of care schemes. The article concludes that family orientation, unconditional cash benefits and the use of migrant carers do not necessarily preclude the development of a strong social service sector. However, there is a risk that budgetary limitations will primarily affect social service development. PMID- 22211708 TI - PRRX1 is mutated in an otocephalic newborn infant conceived by consanguineous parents. PMID- 22211709 TI - Stat3: linking inflammation to (gastrointestinal) tumourigenesis. AB - Tumourigenesis is a multistage process comprising initiation, promotion and progression that is governed by cumulative (epi-)genetic changes. However, tumour initiation, triggered by mutations in proto-oncogenes and/or tumour suppressor genes, is insufficient for the development of cancers. Tumour promotion often depends on the interaction between initiated cells and the microenvironment where an excessive abundance of inflammatory mediators, including those of the interleukin (IL-)6/glycoprotein 130 (gp130) family, promote their expansion. The activity of most soluble mediators ultimately converges on tumour cells through activation of the latent transcription factors nuclear factor (NF)-kappaB and signal transducer and activator of transcription (Stat) 3 to enhance survival of neoplastic cells. In addition, Stat3 promotes tumour cell proliferation, invasion and induction of an angiogenic switch. Persistent activation of STAT3 is a unifying hallmark of a majority of solid malignancies. However, persistent STAT3 activation usually occurs in the absence of activating mutations in, or amplification of, the STAT3 gene. Instead, it is associated with an oversupply of autocrine and/or paracrine activating cytokines secreted by tumour and stromal cells and comprising (among others) cytokines that use the gp130 receptor. Interleukin-6, IL-11 and other members of the gp130 cytokine family have been identified in preclinical mouse models as promising therapeutic targets for gastrointestinal, hepatic and breast cancers. Thus, pharmacological interference with specific cytokines and tyrosine kinases that trigger Stat3 activation affords opportunities to therapeutically target the non-redundant tumour promoting signalling function of Stat3. PMID- 22211710 TI - Comparison of outcomes and the use of multimodality therapy in young and elderly people undergoing surgical resection of pancreatic cancer. AB - OBJECTIVES: To compare outcomes and the use of multimodality therapy in young and elderly people with pancreatic cancer undergoing surgical resection. DESIGN: Retrospective, single-institution study. SETTING: National Cancer Institute/National Comprehensive Cancer Network cancer center. PARTICIPANTS: Two hundred three individuals who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma at Duke University Medical Center comprised the study population. Participants were divided into three groups based on age (<65, n = 97; 65-74, n = 74; >=75, N = 32). MEASUREMENTS: Perioperative outcomes, the use of multimodality therapy, and overall survival of the different age groups were compared. RESULTS: Similar rates of perioperative mortality and morbidity were observed in all age groups, but elderly adults were more likely to be discharged to a rehabilitation or skilled nursing facility. A similar proportion of participants received neoadjuvant therapy, but a smaller proportion of elderly participants received adjuvant therapy. Overall survival was similar between the age groups. Predictors of poorer overall survival included coronary artery disease, positive resection margin, and less-differentiated tumor histology. Treatment with neoadjuvant and adjuvant therapy were predictors of better overall survival. CONCLUSION: Carefully selected elderly individuals experience similar perioperative outcomes and overall survival to those of younger individuals after resection of pancreatic cancer. There appears to be a significant disparity in the use of adjuvant therapy between young and elderly individuals. PMID- 22211712 TI - The immunoregulatory role of CD4+ FoxP3+ CD25- regulatory T cells in lungs of mice infected with Bordetella pertussis. AB - The identification of regulatory T (Treg) cells was originally based on CD25 expression; however, CD25 is also expressed by activated effector T cells. FoxP3 is a more definitive marker of Treg cells, and CD4(+) FoxP3(+) CD25(+) T cells are considered the dominant natural Treg (nTreg) population. It has been suggested that certain CD4(+) FoxP3(+) Treg cells do not express CD25. In this study, we used a murine model of respiratory infection with Bordetella pertussis to examine the role of Treg cells in protective immunity in the lung. We first demonstrated that CD4(+) FoxP3(+) CD25(-) cells are the dominant Treg population in the lung, gut and liver. Pre-activated lung CD4(+) FoxP3(+) CD25(-) cells suppressed CD4(+) effector T cells in vitro, which was partly mediated by IL-10 and not dependent on cell contact. Furthermore, CD4(+) FoxP3(+) CD25(-) IL-10(+) T cells were found in the lungs of mice at the peak of infection with B. pertussis. The rate of bacterial clearance was not affected by depletion of CD25(+) cells or in IL-10-deficient (IL-10(-/-) ) mice, but was compromised in CD25-depleted IL-10(-/-) mice. Our findings suggest that IL-10-producing CD4(+) FoxP3(+) CD25(-) T cells represent an important regulatory cell in the lung. PMID- 22211713 TI - Use of intravital microscopy to study the microvascular behavior of microbubble based ultrasound contrast agents. AB - PURPOSE: The study describes the use of intravital microscopy (IVM) to assess the behavior of ultrasound contrast agents (UCAs), including targeted UCAs, in the microcirculation of rodents. MATERIALS AND METHODS: IVM was performed on various exteriorized organs: hamster cheek pouch, rat mesentery, liver, spinotrapezius muscle, and mouse cremaster muscle. A dorsal skin-fold chamber with MatBIII tumor cells was also implanted in rats. Nontargeted UCAs (SonoVue((r)) and BR14) and targeted UCAs (BR55 and P-selectin targeted microbubbles) were tested. IVM was used to measure microbubble size, determine their persistence, and observe their behavior in the blood circulation. RESULTS: Intravenous and intra-arterial injections of high doses of UCAs did not modify the local microvascular hemodynamics. No microbubble coalescence and no increased size were observed. Adhesion of some microbubbles to leukocytes was observed in various microcirculation models. Microbubbles are captured by Kupffer cells in the liver. Targeted microbubbles were shown to adhere specifically to endothelial receptors without compromising local blood flow. CONCLUSION: These results support the safety of both targeted and nontargeted UCAs as no microvascular flow alteration or plugging of microvessels were observed. They confirm that binding observed with targeted microbubbles are due to the binding of these microbubbles to specific endothelial receptors. PMID- 22211714 TI - The development and in vivo evaluation of a colon drug delivery system using human volunteers. AB - The aim of this study was to develop a multiple-unit dosage system that released model drug into the colon, and also to evaluate the efficiency of the dosage form in human volunteers. The developed system combines pH-, time- and biodegradable polymer-based mechanisms for drug targeting to the colon. Pellet cores containing caffeine as model drug and chitosan and microcrystalline cellulose as excipients were prepared by the extrusion/spheronization method. The prepared pellets were film coated with a pH-dependent polymer, Eudragit FS 30 D. The coating total weight gain was 28.83% (w/w). Thanks to the application of an outer enteric film and the multiple unit design of the dosage form, the variability in gastric emptying was overcome, and a colon-specific targeting relied on the reproducibility of a small intestinal transit time, which was reported to be 3 +/ 1 hours. A biodegradable polymer in the pellet core, chitosan, ensured the site specific release of the model drug due to its solubility at the lower pH of the colonic region and by its biodegradability from the bacteria present. The efficiency of the system was confirmed by the in vivo testing of human saliva. The time of the first appearance of caffeine into the saliva, T(lag), was used as a parameter to estimate the disintegration time of the pellets into the gastrointestinal tract. The caffeine appeared in the saliva within 6.95 +/- 1.12 hours (T(lag)) in 9 volunteers. A comparison of the reported colon arrival times indicates that the developed system is applicable to colonic drug delivery. PMID- 22211715 TI - Cost analysis of renal replacement therapy by transplant in a system of bundled payment of dialysis. AB - Renal replacement therapies (RRT) for patients with end-stage renal failure represent a high burden on European countries' healthcare budget. Our purpose was to report and compare the costs of RRT by hemodialysis (HD) or peritoneal dialysis (PD) and renal transplantation (RT) after introduction of a bundled payment system of dialysis. We analyzed average annual cost of RT in a public national health system hospital - surgical/anesthesiologist team and material, induction and maintenance immunosuppression therapy, hospital stay, diagnostic examinations (DE), and post-transplant office visits (including DE). Incentives paid to hospitals performing RT were included. Annual cost of HD or PD was estimated by bundled payment established in a recently revised law - 537.25 ?/wk. Total first year cost or RT is 61 658.14 ? and from the second year forth 543.86 ?/month. Dialysis costs 28 033.71 ?/yr. Break-even point for cost is at 32 months, and from there on, RT is less expensive. Strategies aimed at increasing RT are needed as it confers better survival than RRT by dialysis with lower costs to Portuguese health system. PMID- 22211717 TI - The effect of electrical lighting power and irradiance on indoor-grown cannabis potency and yield. AB - The floral development and potencies [Delta(9) -tetrahydrocannabinol (THC) contents] of cannabis plants were compared when grown indoors under high-pressure sodium lamps consuming electrical power at three densities (270, 400, and 600 W/m(2)). After a 3-week vegetative phase, plants were grown for 8 weeks, with lamps maintaining an artificial day length of 12 h. Foliar and floral yields were measured. Gas chromatography was used to measure the content of the psychoactive cannabinoid THC. Mean yields per unit of electrical power in each lighting regime ranged from 0.9 to 1.6 g/W, the highest being achieved in the lowest irradiance regime. The individual potencies of the separated leaf and flower materials were not affected by increasing irradiance. However, there was a corresponding increase in the overall potency of the aerial plant tissue. This was because of the plants in brighter conditions producing a higher proportion of floral material. PMID- 22211716 TI - Outcomes in pediatric atypical spitz tumors treated without sentinel lymph node biopsy. AB - The diagnosis of atypical Spitz tumor (AST) in a pediatric patient conveys an uncertain potential for malignancy. Although pediatric melanoma is rare, AST may be treated aggressively with sentinel lymph node biopsy (SLNB) and subsequent completion lymphadenectomy. These procedures have unclear therapeutic benefit and potential morbidity. We aimed to collect outcomes on children with AST treated with excision alone to assist in the management of these lesions. We queried our institution's pathology database for AST specimens submitted between 1994 and 2009. A dermatopathologist reviewed pathology slides to confirm AST diagnosis. Clinical information was obtained from medical records, and outcomes surveys were administered to children with AST. Twenty-nine patients met AST diagnostic criteria and were included in this study. Mean age at first excision was 9.0 +/- 4.2 (range 2.3-17.5), and 19 patients underwent more than one excision procedure to achieve clear margins. No patient had SLNB. Fourteen patients (48%) with mean follow-up time of 8.4 years (range 3.5-15.8) completed clinical outcomes surveys. Outcomes with mean follow-up time of 2.8 years (range 0.02-8.1 years) were obtained for 10 additional patients from medical records. There were no reports of recurrence, additional lesions, or metastases in these 24 patients. We report one of the largest series of children with AST treated using excision alone and who remain disease free after a significant follow-up period. Our data suggest that SLNB is not warranted in the routine management of pediatric AST. We recommend complete excision with clear margins and careful clinical follow-up. PMID- 22211718 TI - The mutual prospective influence of child and parental post-traumatic stress symptoms in pediatric patients. AB - BACKGROUND: Previous studies found notable rates of post-traumatic stress symptoms (PTSS) and post-traumatic stress disorder (PTSD) in pediatric patients and their parents and suggest a significant association between child and parent PTSS. However, little is known about mutual influences between child and parental PTSS over time. This study prospectively examined the presence of PTSS and PTSD and the mutual influence of child and parental PTSS in a large sample of pediatric patients with different medical conditions. METHODS: A total of 287 children (aged 6.5-16 years) and their mothers (n = 239) and fathers (n = 221) were assessed at 5-6 weeks and 1 year after an accident or a new diagnosis of cancer or diabetes mellitus type 1 in the child. RESULTS: At the first assessment 11.1% and at the second assessment 10.2% of the children had moderate to severe PTSS. At 5-6 weeks 29.3% of mothers and 18.6% of fathers met criteria for PTSD. At 1 year the rates were 14.6% for mothers and 7.9% for fathers. There were considerable differences of PTSS among different medical diagnostic groups in children and parents. Mothers were more vulnerable than fathers. Structural equation analysis revealed that initially high PTSS in mothers and fathers were longitudinally related to poorer recovery from PTSS in the child. Cross-lagged effects from the child to the parents and from one parent to the other were not significant. CONCLUSIONS: This study highlights the long-term influence of parental PTSS on the child's recovery after trauma and calls for a family systems approach and for early interventions in the treatment of traumatized pediatric patients. PMID- 22211719 TI - Factors affecting microbial contamination rate of cord blood collected for transplantation. AB - BACKGROUND: Collection and processing of cord blood (CB) is associated with significant risk of microbial contamination and hence relevant standards mandate microbial screening of the final product. This study aimed to determine the contamination rate and associated risk factors during 14 years of banking at the Sydney Cord Blood Bank. STUDY DESIGN AND METHODS: CB was collected and processed using a closed system and tested for contamination using blood culture bottles (BacT/ALERT, bioMerieux) incubated for a minimum of 5 days. Four microbial screening methods were used with different combinations of inoculated bottles (adult or pediatric) and associated sample volumes (10 or 1 mL). RESULTS: Of 13,344 CB units screened, 537 (4.0%) tested positive for contamination, with Bacteroides spp. (20.9%), Staphylococcus spp. (18.6%), and Propionibacterium spp. (13.7%) being the most common isolates. The contamination rate reduced from 10% in 1997 to 1.1% in 2009. Multivariate analysis demonstrated the following variables were independently associated with higher contamination rates: vaginal delivery, collection by obstetric staff, and use of an anaerobic bottle in addition to an aerobic bottle (which facilitated a larger sample inoculation volume than pediatric bottles). CONCLUSIONS: This study demonstrates that contamination rates of CB collected for transplantation can be substantially reduced by collection after cesarean delivery and utilizing trained CB collection staff. These data also indicate that the common practice of testing using a pediatric (aerobic) bottle with its attendant small volume of the final CB product may be suboptimal for sensitive detection of contaminating anaerobic microbes. PMID- 22211720 TI - Imbalance between endothelial injury and repair in patients with polymyalgia rheumatica: improvement with corticosteroid treatment. AB - OBJECTIVES: Polymyalgia rheumatica (PMR) is a rheumatic disease that is characterized by intense activation of systemic inflammation. Systemic inflammation has been associated with an imbalance between endothelial injury and repair, defined by an increased number of circulating endothelial microparticles (EMPs) and a reduced number of endothelial progenitor cells (EPCs). We investigated the association between inflammation and endothelial injury and repair in patients with PMR and evaluated the effects of corticosteroid therapy on EMP and EPC levels. DESIGN, SETTING AND SUBJECTS: We conducted a case-control study in 34 patients with never-treated active PMR and 34 healthy age- and sex matched controls. Patients with PMR participated in a 1-month intervention open label study with corticosteroid therapy. Circulating EMPs (CD31+/CD42-) and EPCs (CD34+/KDR+) were quantified by fluorescence-activated cell sorting analysis. RESULTS: Patients with PMR had an increased EMP/EPC ratio compared with controls [median (IQR): 6.5 (3.0-11.5) vs. 1.1 (0.7-1.5), P < 0.001], because of both increased EMP and reduced EPC levels. Levels of C-reactive protein (CRP) were associated with an increased EMP/EPC ratio (beta = 0.48, P = 0.001), irrespective of traditional cardiovascular risk factors. Corticosteroid therapy led to a significant CRP reduction [from 3.9 (1.5-6.7) to 0.6 (0.2-1.2) mg dL(-1) , P < 0.05], paralleled by a consistent 81% decline in the EMP/EPC ratio. CRP and EMP/EPC ratio reductions were significantly correlated (rho = 0.37, P = 0.04). CONCLUSIONS: Polymyalgia rheumatica is associated with a significant imbalance between endothelial injury and repair, which is dependent on the degree of systemic inflammation. Attenuation of inflammation by short-term corticosteroid therapy might have a role in limiting endothelial fragmentation and promote endothelial repair. PMID- 22211722 TI - Association of TLR polymorphisms with development of tuberculosis in Indonesian females. AB - Tuberculosis (TB) is caused by Mycobacterium tuberculosis and is a major cause of morbidity and mortality worldwide. Many candidate genes have been investigated for a possible association with TB. Toll-like receptors (TLRs) are known to play important roles in human innate immune systems. Polymorphisms in and functions of TLRs have been investigated to identify associations with specific infectious diseases, including TB. Here, we examined whether single-nucleotide polymorphisms (SNPs) in TLRs and genes in TLR signaling were associated with TB susceptibility in Indonesian and Vietnamese populations. A statistically significant association was observed between TB susceptibility in a classified Indonesian female group and rs352139, an SNP located in the intron of TLR9, using the genotype (P = 2.76E 04) and recessive (AA vs AG+GG, P = 2.48E-04, odds ratio = 1.827, 95% confidence interval = 1.321-2.526) models. Meta-analysis of the Indonesian and Vietnamese populations showed that rs352139 was significantly associated with TB in the recessive model. This finding indicated that a TLR9 polymorphism might have an important role in the susceptibility to M. tuberculosis in Asian populations. PMID- 22211725 TI - Frequency of non-histologically diagnosed basal cell carcinomas in daily Dutch practice. AB - BACKGROUND: Population-based basal cell carcinoma (BCC) incidences are based on cancer registry data; however, these only include histologically diagnosed tumours. OBJECTIVES: First, to investigate the number of subsequent non histologically diagnosed BCC(s) in patients with a first histologically diagnosed BCC in 2004. Secondly, to observe differences in tumour characteristics between subsequent histologically and subsequent non-histologically diagnosed BCC(s). METHODS: All patients, from four hospitals located in the serving area of the Eindhoven Cancer Registry, with a first histologically diagnosed BCC in 2004 (n = 1290) were selected. A linkage was made with PALGA, the nationwide network and registry of histo- and cytopathology, to obtain pathology reports of subsequent histologically diagnosed BCC(s) up to 1 November 2010. Patient records were extracted from the participating dermatology departments and reviewed up to 1 November 2010 to identify non-histologically diagnosed BCC(s). RESULTS: Overall, 33.2% of the 1089 followed up patients developed subsequent histologically and/or non-histologically diagnosed BCCs. In total, 1974 BCCs were observed of which 1833 were histologically and 141 were non-histologically diagnosed BCCs. The distribution of tumour site and subtype differed significantly between subsequent histologically and subsequent non-histologically diagnosed BCCs. CONCLUSIONS: The total burden of BCC is underestimated by the absence of data on the occurrence of non-histologically diagnosed BCCs in daily dermatological practice. It is pivotal for Dutch healthcare policy makers to acknowledge this to make accurate BCC related cost estimates. PMID- 22211723 TI - The GtaR protein negatively regulates transcription of the gtaRI operon and modulates gene transfer agent (RcGTA) expression in Rhodobacter capsulatus. AB - The gtaI gene of Rhodobacter capsulatus encodes an N-acyl-homoserine lactone (acyl-HSL) synthase. Immediately 5' of the gtaI gene is ORF rcc00328 that encodes a potential acyl-HSL receptor protein. A combination of genetic and biochemical approaches showed that rcc00328 (renamed gtaR) modulates the production of a genetic exchange element called the gene transfer agent (RcGTA), and regulates the transcription of gtaI. Although gtaI mutants exhibited decreased levels of RcGTA production, mutagenesis of gtaR did not, whereas a gtaR/gtaI double mutant produced wild-type levels of RcGTA. Because mutagenesis of gtaR suppressed the effect of the gtaI mutation, we suggest that the GtaR protein is a negative transcriptional regulator of RcGTA gene expression. We discovered that the gtaR and gtaI genes are co-transcribed, and also negatively regulated by the GtaR protein in the absence of acyl-HSL. A His-tagged GtaR protein was purified, and DNA-binding experiments revealed a binding site in the promoter region of the gtaRI operon. This GtaR protein did not bind to the RcGTA promoter region, and therefore modulation of RcGTA production appears to require at least one additional factor. We found that RcGTA production was stimulated by spent media from other species, and identified exogenous acyl-HSLs that induce RcGTA. PMID- 22211726 TI - Functional imaging of the cerebellum and basal ganglia during predictive motor timing in early Parkinson's disease. AB - BACKGROUND AND PURPOSE: The basal ganglia and the cerebellum have both emerged as important structures involved in the processing of temporal information. METHODS: We examined the roles of the cerebellum and striatum in predictive motor timing during a target interception task in healthy individuals (HC group; n = 21) and in patients with early Parkinson's disease (early stage PD group; n = 20) using functional magnetic resonance imaging. RESULTS: Despite having similar hit ratios, the PD failed more often than the HC to postpone their actions until the right moment and to adapt their behavior from one trial to the next. We found more activation in the right cerebellar lobule VI in HC than in early stage PD during successful trials. Successful trial-by-trial adjustments were associated with higher activity in the right putamen and lobule VI of the cerebellum in HC. CONCLUSIONS: We conclude that both the cerebellum and striatum are involved in predictive motor timing tasks. The cerebellar activity is associated exclusively with the postponement of action until the right moment, whereas both the cerebellum and striatum are needed for successful adaptation of motor actions from one trial to the next. We found a general ''hypoactivation'' of basal ganglia and cerebellum in early stage PD relative to HC, indicating that even in early stages of the PD there could be functional perturbations in the motor system beyond striatum. PMID- 22211727 TI - Interaction of an antituberculosis drug with nano-sized cationic micelle: Forster resonance energy transfer from dansyl to rifampicin in the microenvironment. AB - In this contribution, we report studies on the interaction of an antituberculosis drug rifampicin (RF) in a macromolecular assembly of CTAB with an extrinsic fluorescent probe, dansyl chloride (DC). The absorption spectrum of the drug RF has been employed to study Forster resonance energy transfer (FRET) from DC, bound to the CTAB micelle using picosecond resolved fluorescence spectroscopy. We have applied a kinetic model developed by Tachiya to understand the kinetics of energy transfer and the distribution of acceptor (RF) molecules around the donor (DC) molecules in the micellar surface with increasing quencher concentration. The mean number of RF molecules associated with the micelle increases from 0.24 at 20 MUm RF concentration to 1.5 at 190 MUm RF concentration and consequently the quenching rate constant (k(q)) due to the acceptor (RF) molecules increases from 0.23 to 0.75 ns(-1) at 20 and 190 MUm RF concentration, respectively. However, the mean number of the quencher molecule and the quenching rate constant does not change significantly beyond a certain RF concentration (150 MUm), which is consistent with the results obtained from time resolved FRET analysis. Moreover, we have explored the diffusion controlled FRET between DC and RF, using microfluidics setup, which reveals that the reaction pathway follows one-step process. PMID- 22211728 TI - Case presentation: abdominal compartment syndrome complicating posterior spinal fusion. AB - Abdominal compartment syndrome (ACS) is a life-threatening entity that requires rapid recognition and treatment. This case report represents the first case report of ACS associated with the correction of a marked scoliosis. Of the many possible causes for respiratory compromise and cardiovascular collapse associated with major spine surgery, ACS should be considered, particularly in instances of profound spinal curvature correction. We present the case of an 8-year-old child with Duchenne muscular dystrophy (DMD) undergoing correction of a severe scoliotic curvature. Near the end of an otherwise unremarkable surgery, he developed severe respiratory compromise associated with respiratory acidosis, hypoxia, and hypotension in the face of a catastrophic decrease in lung compliance. After supine positioning and examination, he was discovered to have ACS, which was treated with laparotomy. Complete recovery occurred after 5 days. This case report should raise awareness of a rare, life threatening, but imminently treatable entity that can accompany scoliosis surgery. The description of this case should be particularly important for pediatric anesthesiologists and orthopedic surgeons who care for patients undergoing correction of marked scoliosis. We suggest possible mechanisms for the development of ACS in this setting that offer insights into the pathology of this entity, which could be useful in many other clinical situations where visceral venous drainage or bowel perfusion may be compromised. PMID- 22211729 TI - Initiating end-of-life care pathways: a discussion paper. AB - AIMS: To discuss the intricacies of the decision-making process about initiating end-of-life care pathways. BACKGROUND: Internationally, enhancing the quality of end-of-life care has become a central concern in governments' health policies. Despite limited empirical evaluation, end-of- life care pathways have been championed and widely adopted as complex interventions to enhance end-of-life care worldwide. DATA SOURCES: A literature search of established electronic databases was conducted for published articles in English addressing decision making and end-of-life care pathways between 1997-2010. Manual searches of relevant journals and internet sites were also undertaken. DISCUSSION: The initiation of an end-of-life care pathway marks the transition to the terminal phase of care. Although guidance for commencing these pathways exists, this may not overcome the complexities of the decision-making process, which must be viewed in context, namely: marking the transition to terminal care, dealing with ambiguity, reaching professional consensus and engaging patients and families. Implications for nursing. Nurses in all care settings have an important role in easing the transition to end-of- life care. Accordingly, nurses need not only an appreciation of end-of-life care pathways, but the complexities surrounding the decision to commence a pathway and their role within. CONCLUSION: The initiation of an end-of-life care pathway is contingent on the outcome of a complex decision making process which is rarely explored and poorly understood. PMID- 22211732 TI - "Synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome": comment on the article by Zhao et al. PMID- 22211733 TI - Effect of excess levels of lysine and leucine in wheat-based, amino acid fortified diets on the mRNA expression of two selected cationic amino acid transporters in pigs. AB - An experiment was conducted to evaluate the effect of excess levels of Leu and Lys on the expression of b(0,+) and CAT-1 mRNA in jejunum, liver and the muscles Longissimus dorsi (LDM) and Semitendinosus (STM). Twenty pigs with an average initial BW of 16.4 +/- 1.7 kg were used in a Randomized Complete Block. Dietary treatments (T) were as follows: T1, basal diet; T2, basal plus 3.5 g l-Lys/kg diet; T3, basal plus 1.5 g l-Leu/kg diet; T4, basal plus 3.5 g l-Lys plus 1.5 g l Leu/kg diet. Diets in T1 and T3 met 100% the requirement of Lys for pigs within the 10 to 20 kg body weight range; diets in T2 and T4 contained 35% excess of Lys. Also, diets in T1 and T2 supplied 104%, whereas diets in T3 and T4 supplied 116% the requirement of Leu. The expression of b(0,+) in jejunum was reduced (p = 0.002) because of the supplementation of l-Leu, but l-Lys supplementation had no effect (p = 0.738). In contrast, the expression of b(0,+) in STM (p = 0.012) and liver (p = 0.095) was reduced by the high level of Lys, but Leu had no effect (p > 0.100). CAT-1 expression in STM increased by high Lys (p = 0.023) and Leu (p = 0.007) levels. In liver, the expression of CAT-1 substantially increased (p = 0.001) because of Lys. In conclusion, excess levels of dietary Lys and Leu affect the expression of cationic amino acid transporters, and this effect varies depending on the studied tissue. PMID- 22211734 TI - Description and validation of an Italian ICHD-II-based questionnaire for use in epidemiological research. AB - BACKGROUND: In the absence of biological markers, the diagnosis of primary headache in epidemiological studies rests on clinical findings, as reported through ad-hoc interviews. OBJECTIVES: The aim of this study was to validate a specially designed headache questionnaire to be administered by a physician for the diagnosis of primary headaches or of probable medication overuse headache in the general population according to the 2004 International Classification of Headache Disorders, 2nd edition (ICHD-II). METHODS: The questionnaire comprises 76 questions based on the ICHD-II diagnostic criteria for migraine (codes 1.1, 1.2.1, 1.2.2, 1.2.3, 1.5.1, and 1.6), tension-type headache (codes 2.1, 2.2, 2.3, and 2.4), primary stabbing headache (code 4.1), and probable medication-overuse headache (code 8.2.7), as well as on other clinical features (eg, age at onset, relation between headache and pregnancy, etc). The answers to each question could be of the following types: (1) numbers (ie, age at onset); (2) "Yes" or "No" (eg, as in reply to "Do you have nausea during headache?"); and (3) predefined answers (eg, quality of pain). We assessed the validity and reliability of the questionnaire and its sensitivity and specificity for migraine and tension-type headache. RESULTS: The study population consisted of 50 patients (37 women and 13 men) aged 18-76 years (mean, 40.7) seen for the first time on a consecutive basis at the University of Parma Headache Centre. The questionnaire was administered independently by 2 trained physicians (E1 and E2) prior to the visit performed by a headache specialist taken as the gold standard (GS). GS, E1, and E2 were blind to the diagnosis made by each others. If appropriate, more than 1 headache type were considered. When present, we defined the 2 different headache types in the same subject as Diagnosis 1 and Diagnosis 2. Questionnaire-based diagnosis was compared with the diagnosis established by GS. For Diagnosis 1 (n = 50), we found an agreement rate of 98% (K-value: 0.96; 95% confidence interval [CI]: 0.88-1.00) between E1 and GS and between E2 and GS, and of 96% (K-value: 0.91; 95% CI: 0.80 1.00) between E1 and E2. For Diagnosis 2 (n = 24), we found an agreement rate of 83.3% (K-value: 0.80; 95% CI: 0.63-0.98) between E1 and GS, of 62.5% (K-value: 0.62; 95% CI: 0.41-0.82) between E2 and GS, and of 70.8% (K-value: 0.66; 95% CI: 0.45-0.87) between E1 and E2. Sensitivity and specificity were 100% and 93.3%, respectively, for migraine without aura (code 1.1) and 100% for frequent episodic tension-type headache (code 2.2). CONCLUSION: Our findings support the use of this questionnaire as a valid and reliable tool for diagnosis of headaches in epidemiological studies. PMID- 22211735 TI - Health outcomes among Swedish children: the role of social capital in the family, school and neighbourhood. AB - AIM: The aim of the study was to explore the extent to which Swedish children's perceptions of social capital in the family, school and neighbourhood predicted health complaints and well-being. METHODS: The study used data from the Swedish Health Behaviour in School-aged Children survey. The sample consisted of 3926 children aged 11-15 years. Correlations and hierarchical multiple linear regression were performed. RESULTS: Higher degrees of family, school and neighbourhood social capital corresponded to lower levels of health complaints and higher levels of well-being. Social capital in these three spheres had a cumulative effect on children's health and well-being. CONCLUSIONS: Social capital in the family, school and neighbourhood matters for children's health and well-being and the contributions from each context seem to be additive. Besides the family context, investments for improving child health should primarily be in the school, focusing on social relations and on creating safe and cohesive school environments. Neighbourhood social capital is also of importance and so must be taken into consideration when planning child health promotion interventions. PMID- 22211737 TI - Calcium hydroxide partial pulpotomy is an alternative to formocresol pulpotomy based on a 3-year randomized trial. AB - BACKGROUND: Considering formocresol's toxicity, Ca(OH)(2) partial pulpotomy (PP) was studied as a treatment alternative. AIM: To compare success rates of Ca(OH)(2) PP versus formocresol pulpotomy (FP) treatment of pulpally exposed lower primary molars. DESIGN: A total of 84 lower primary molars, which met study criteria, from 56 child patients were randomly assigned for each treatment. After treatment, blinded clinical and radiographic evaluation with 96.9% and 90% reliability was performed at 6-month intervals to determine treatment success/failure. Chi-squared test was used to compare success rates between the two treatments. RESULTS: The success rates from 6 to 36 months for PP ranged from 95.03% to 75%, whereas for FP, it was 92.7-74.2%. The success rates for the two treatments at each 6-month interval were not different (P >= 0.05). The most frequent failure was internal resorption, affecting five FP teeth and three PP teeth. The resorption was arrested in five of the teeth and was replaced by a radiopaque calcified tissue in one case. CONCLUSION: Considering the favourable clinical and radiographic success rate of PP and the potentially toxic effects of formocresol leads us to recommend the use of PP instead of FP in primary teeth with deep carious lesions. PMID- 22211739 TI - Association of genomic deletions in the STXBP1 gene with Ohtahara syndrome. PMID- 22211742 TI - Parallel development of orientation maps and spatial frequency selectivity in cat visual cortex. AB - In an early stage of the postnatal development of cats, orientation maps mature and spatial frequency selectivity is consolidated. To investigate the time course of orientation map maturation associated with the consolidation of spatial frequency selectivity, we performed optical imaging of intrinsic signals in areas 17 and 18 of cats under the stimulation of drifting square-wave gratings with different orientations and spatial frequencies. First, orientation maps for lower spatial frequencies emerged in the entire part of the lateral gyrus, which includes areas 17 and 18, and then these orientation maps in the posterior part of the lateral gyrus disappeared as orientation maps for higher spatial frequencies matured. Independent of age, an anteroposterior gradient of response strengths from lower to higher spatial frequencies was observed. This indicates that the regional distribution of spatial frequencies is innately determined. The size of iso-orientation domains tended to decrease as the stimulus spatial frequency increased at every age examined. In contrast, orientation representation bias changed with age. In cats younger than 3 months, the cardinal (vertical and horizontal) orientations were represented predominantly over the oblique orientations. However, in young adult cats from 3 to 9 months old, the representation bias switched to predominantly oblique orientations. These age dependent changes in the orientation representation bias imply that orientation maps continue to elaborate within postnatal 1 year with the consolidation of spatial frequency selectivity. We conclude that both intrinsic and mutual factors lead to the development of orientation maps and spatial frequency selectivity. PMID- 22211740 TI - Fluoxetine rescues impaired hippocampal neurogenesis in a transgenic A53T synuclein mouse model. AB - The accumulation of alpha-synuclein in Lewy bodies and Lewy neurites of different neuronal populations is one of the neuropathological hallmarks in Parkinson disease (PD). Overexpression of human wildtype or mutant alpha-synuclein affects the generation of new neurons in the adult dentate gyrus (DG) of the hippocampus in models of PD. Hippocampal dysfunction with reduced neurogenesis plays an important role in the pathogenesis of depression, an important non-motor symptom in PD. Moreover, effective antidepressant treatment is still an unmet need in PD. The present study explored if impaired hippocampal neurogenesis in the A53T transgenic animal model of PD may be restored by chronic oral application of the selective serotonin reuptake inhibitor (SSRI) fluoxetine. First, we determined the expression pattern of transgenic mutant A53T synuclein in developing DG neurons and showed early expression of the transgene linked to a severely impaired neurogenesis. After chronic fluoxetine treatment we observed an increased adult neurogenesis in the hippocampus of more than threefold in treated A53T mice compared with controls. The pro-neurogenic effect of chronic fluoxetine application is predominantly related to an increased proliferation of neural precursor cells in the DG, and to a lesser extent by induction of differentiation into mature neurons. Analysis of the underlying mechanisms revealed an induction of brain-derived and glial cell-derived neurotrophic factor levels as a result of fluoxetine treatment. This study underlines the large potential of SSRI-dependent mechanisms to stimulate adult hippocampal neurogenesis in alpha-synuclein models and may lead to novel means to improve neuropsychiatric symptoms in PD. PMID- 22211741 TI - Profound defects in pupillary responses to light in TRPM-channel null mice: a role for TRPM channels in non-image-forming photoreception. AB - TRPM1 is a spontaneously active non-selective cation channel that has recently been shown to play an important role in the depolarizing light responses of ON bipolar cells. Consistent with this role, mutations in the TRPM1 gene have been identified as a principal cause of congenital stationary night blindness. However, previous microarray studies have shown that Trpm1 and Trpm3 are acutely regulated by light in the eyes of mice lacking rods and cones (rd/rd cl), a finding consistent with a role in non-image-forming photoreception. In this study we show that pupillary light responses are significantly attenuated in both Trpm1(-/-) and Trpm3(-/-) animals. Trpm1(-/-) mice exhibit a profound deficit in the pupillary response that is far in excess of that observed in mice lacking rods and cones (rd/rd cl) or melanopsin, and cannot be explained by defects in bipolar cell function alone. Immunolocalization studies suggest that TRPM1 is expressed in ON bipolar cells and also a subset of cells in the ganglion cell layer, including melanopsin-expressing photosensitive retinal ganglion cells (pRGCs). We conclude that, in addition to its role in bipolar cell signalling, TRPM1 is involved in non-image-forming responses to light and may perform a functional role within pRGCs. By contrast, TRPM3(-/-) mice display a more subtle pupillary phenotype with attenuated responses under bright light and dim light conditions. Expression of TRPM3 is detected in Muller cells and the ciliary body but is absent from pRGCs, and thus our data support an indirect role for TRPM3 in pupillary light responses. PMID- 22211743 TI - Dissecting the projections of different groups of raphe serotonergic neurons (commentary on Bang et al.). PMID- 22211744 TI - Transcranial direct current stimulation preconditioning modulates the effect of high-frequency repetitive transcranial magnetic stimulation in the human motor cortex. AB - Experimental studies emphasize the importance of homeostatic plasticity as a mean of stabilizing the properties of neural circuits. In the present work we combined two techniques able to produce short-term (5-Hz repetitive transcranial magnetic stimulation, rTMS) and long-term (transcranial direct current stimulation, tDCS) effects on corticospinal excitability to evaluate whether and how the effects of 5-Hz rTMS can be tuned by tDCS preconditioning. Twelve healthy subjects participated in the study. Brief trains of 5-Hz rTMS were applied to the primary motor cortex at an intensity of 120% of the resting motor threshold, with recording of the electromyograph traces evoked by each stimulus of the train from the contralateral abductor pollicis brevis muscle. This interventional protocol was preconditioned by 15 min of anodal or cathodal tDCS delivered at 1.5 mA intensity. Our results showed that motor-evoked potentials (MEPs) increased significantly in size during trains of 5-Hz rTMS in the absence of tDCS preconditioning. After facilitatory preconditioning with anodal tDCS, 5-Hz rTMS failed to produce progressive MEP facilitation. Conversely, when 5-Hz rTMS was preceded by inhibitory cathodal tDCS, MEP facilitation was not abolished. These findings may give insight into the mechanisms of homeostatic plasticity in the human cerebral cortex, suggesting also more suitable applications of tDCS in a clinical setting. PMID- 22211745 TI - Essentials for publishing program evaluations. PMID- 22211746 TI - Are lead risk questionnaires adequate predictors of blood lead levels in children? AB - OBJECTIVE: To evaluate the accuracy of the verbal lead risk assessment tool in identifying the presence of measurable blood lead levels (BLL) in children. DESIGN AND SAMPLE: A retrospective analysis comparing results of a verbal lead risk assessment tool intended to identify elevated BLL in children with actual capillary fingerstick lead screening laboratory data. Three hundred and forty nine children aged 5 years and younger enrolled in Head Start during the 2008 2009 school year were evaluated. Sixty-nine children had complete data and were included for final analysis. MEASURES: Results of the verbal lead risk assessment and laboratory capillary fingerstick BLL. RESULTS: All 69 children had measurable BLL. The Pass group, 84.3% of the sample, had BLL scores of 2.2+/-1.5 MUg/dl, while the Fail group, 15.7% of the sample, had BLL scores of 1.5+/-0.65 MUg/dl. There was no significant difference in BLL between children that passed the verbal risk assessment and those that failed ( p>.05). CONCLUSIONS: The verbal lead risk assessment did not accurately predict measurable BLL in children. Universal BLL screening for children is necessary to identify low levels of lead so that parents and caretakers of children can be notified and assisted in identifying and eliminating sources of lead exposure. PMID- 22211747 TI - Benchmark attainment by maternal and child health clients across public health nursing agencies. AB - OBJECTIVES: Benchmark client outcomes across public health nursing (PHN) agencies using Omaha System knowledge, behavior, and status ratings as benchmarking metrics. DESIGN AND SAMPLE: A descriptive, comparative study of benchmark attainment for a retrospective cohort of PHN clients (low-income, high-risk parents, primarily mothers) from 6 counties. MEASURES: Omaha System Problem Rating Scale for Outcomes data for selected problems. Benchmark measures were defined as a rating of 4 on a scale from 1 (lowest) to 5 (highest). INTERVENTION: Family home visiting services to low-income, high-risk parents. RESULTS: The highest percentage of benchmark attainment was for the Postpartum problem (knowledge, 76.2%; behavior, 94.0%; status, 96.6%), and the lowest was for the Interpersonal relationship problem (knowledge, 21.7%; behavior, 69.0%; status, 40.7%). All counties showed significant increases in client knowledge benchmark attainment, and 4 of 6 counties showed significant increases from baseline in behavior and status benchmark attainment. Significant differences were found between counties in client characteristics and benchmark attainment for knowledge, behavior, and status outcomes. CONCLUSIONS: There were consistent patterns in benchmark attainment and outcome improvement across counties and family home visiting studies. Benchmarking appears to be useful for comparison of population health status and home visiting program outcomes. PMID- 22211748 TI - Perceptions of self-esteem in a welfare-to-wellness-to-work program. AB - OBJECTIVE: The study investigates welfare recipients' perceptions of personal self-esteem in relationship with their participation in a welfare-to-wellness-to work program. DESIGN AND SAMPLE: The cross-sectional, mixed-methods design examined a convenience sample of 33 participants who attended a welfare-to wellness-to-work program called Work Wellness: The Basics that is based in an agency called Wellness Works!. MEASURES: A demographic survey, Rosenberg's Self Esteem scale, and qualitative interviews were used. RESULTS: Even with normal self-esteem scores, the participants credited the program with decreasing negative thoughts and improving self-esteem. The themes identified include program, self-esteem, mental health, and domestic violence. CONCLUSION: Information about the benefits of a holistic wellness program and its relationship with self-reported enhanced self-esteem can be used to assist with health promotion, policy, and the development of innovative programs that assist with transition from public assistance. PMID- 22211749 TI - Mobile outreach strategies for screening hepatitis and HIV in high-risk populations. AB - OBJECTIVES: To screen, counsel and offer hepatitis A and B vaccination for subjects at high risk for hepatitis C virus (HCV) and HIV, and determine any relationship between risk factors and HCV positivity. DESIGN AND SAMPLE: A descriptive correlational design. We correlated risk factors and HCV positivity and measured vaccination completion rates. Two hundred and two unduplicated subjects in 4 locations in Western Massachusetts: a walk in substance abuse clinic, a homeless shelter, a county jail, and a community corrections facility. MEASURES: Demographic data and a standard HCV risk- screening survey were used. RESULTS: Significantly higher rates of HCV were found in subjects who were currently using injection drugs (83.3% HCV positive, chi2(1) = 20.85, p<.001), who had a history of sharing needles for drug use (75% HCV positive chi(2) (1)=83.20, p<.001), or a history of receiving treatment for drug abuse/alcoholism (38.4% HCV positive chi2(1) = 12.14, p<.001). Vaccination completion ranged by setting between 18% and 38%. CONCLUSIONS: Targeted outreach to hard to reach groups is effective in providing access for those at high risk for HIV and HCV infection. A mobile outreach strategy can focus needed resources for a variety of groups in a community. PMID- 22211750 TI - Does similarity in educational level between health promotion volunteers and local residents affect activity involvement of the volunteers? AB - OBJECTIVES: This study examined whether similarity in educational level, as a socioeconomic background factor, between health promotion volunteers (HPVs) and residents in the district where HPVs work encourages the volunteers' involvement in providing activities. DESIGN AND SAMPLE: Cross-sectional questionnaire survey. A total of 512 HPVs in a Japanese city with 5 districts. MEASURES: We focused on the number of activities related to working as an HPV as an aspect of involvement in the HPV role. HPV individual educational level was collected from a questionnaire. District educational level was obtained from the Japanese census database. RESULTS: Of 512 questionnaires, 363 were returned and used for the analysis. Multiple regression analysis stratified by district educational level indicated that a higher educational level in HPVs was significantly associated with a greater number of self-motivated activities in the districts with a higher educational level, although the association between a lower HPV educational level and more activity involvement was not found in districts with a lower educational level. CONCLUSIONS: It is important to consider similarity in educational level, as a socioeconomic status factor, between HPVs and the districts in which they will work when recruiting new members and when allocating HPVs to work areas. PMID- 22211751 TI - Use of an emergency preparedness disaster simulation with undergraduate nursing students. AB - This is a report of an educational strategy to prepare nursing students to respond to disasters. The strategy includes an emergency preparedness disaster simulation (EPDS) implemented in a school of nursing simulation lab using patient simulators, task trainer mannequins, and live actors. The EPDS immerses student groups into a "tornado ravaged assisted-living facility" where the principles of emergency preparedness can be employed. A total of 90 B.S.N. students participated in the EPDS in the final semester of their senior year. Student post simulation survey responses were overwhelmingly positive, with mean scores of 4.65 (on a 5-point Likert scale) reported for the EPDS "increasing understanding of emergency preparedness" and "well organized." Mean scores were over 4.40 for "scenario believability, increasing knowledge base, increasing confidence in working in teams, ability to handle emergency preparedness situations and to work more effectively in hospital or clinic." The lowest mean score of 4.04 was for "prompting realistic expectations." Owing to the effectiveness of this educational strategy, the EPDS has been incorporated into the undergraduate curriculum. PMID- 22211752 TI - Evaluation of a statewide public health nursing training in Utah. AB - Public health nurses continue to struggle to provide culturally relevant services that focus on the multiple needs of an ethnically diverse population while at the same time providing services to the population at large. This article describes the formative research, implementation, and results of a statewide effort to broaden UtahAEs public health nurses perception about their role and responsibility in addressing and serving the emerging needs of underserved and atrisk populations in Utah. A total of 51% of Utah state and local health department public health nurses participated in the training. There was a statistically significant increase in the mean level of perceived understanding of topic material from pretest to posttest, and 80% of participants reported applying what they learned in the training to their practice. Our experience demonstrates that even with limited resources, it is possible to deliver high quality training to a large proportion of public health nurses practicing in urban, rural, and frontier populations; observe significant results in their comprehension of training material and, most importantly; see application of what they learned in the training to their health care practice. PMID- 22211753 TI - Education-service partnership to promote best practices in a latent tuberculosis infection program. AB - The education-service partnership described addresses the challenges presented to local health departments and public health nurses in completing required latent tuberculosis (LTBI) follow-up in population groups. A service learning partnership between the local health department and a Midwestern university school of nursing resulted in the development of an LTBI follow-up program that completed contacts with 193 subjects. Populations served by the program included immigrants to the community and workers from several occupational settings. Outcome data from the project included recommendations for the management of the information database for local health department LTBI follow-up. Nursing students gained an appreciation for the complexities involved in TB surveillance, and improved their cultural competence in the interface with Latino, African, and East European immigrant populations. Students gained first-hand experience with the current health care system, which resulted in communication challenges between health care providers and economic barriers in compliance with the CDC protocol for LTBI follow-up. The program demonstrated a successful partnership between service and education with positive results for the LTBI clients and the local health department nurses. PMID- 22211754 TI - Ill-informed consent? A content analysis of physical risk disclosure in school based HPV vaccine programs. AB - OBJECTIVES: This study examines the accuracy, completeness, and consistency of human papilloma virus (HPV) vaccine related physical risks disclosed in documents available to parents, legal guardians, and girls in Canadian jurisdictions with school-based HPV vaccine programs. DESIGN AND SAMPLE: We conducted an online search for program related HPV vaccine risk/benefit documents for all 13 Canadian jurisdictions between July 2008 and May 2009 including follow-up by e-mail and telephone requests for relevant documents from the respective Ministries or Departments of Health. The physical risks listed in the documents were compared across jurisdictions and against documents prepared by the vaccine manufacturer (Merck Frosst Canada), the National Advisory Committee on Immunization (NACI), the Society of Obstetricians and Gynecologists of Canada (SOGC), and a 2007 article in Maclean's Magazine. RESULTS: No jurisdiction provided the same list of vaccine related physical risks as any other jurisdiction. Major discrepancies were identified. CONCLUSIONS: Inaccurate, incomplete, and inconsistent information can threaten the validity of consent/authorization and potentially undermine trust in the vaccine program and the vaccine itself. Efforts are needed to improve the quality, clarity, and standardization of the content of written documents used in school-based HPV vaccine programs across Canada. PMID- 22211755 TI - Pillars for the care of older persons in the Caribbean. AB - Pillars for the Care of Older Persons in the Caribbean: A Comprehensive Community Based Framework (Pillars) is a hybrid of multiple public health frameworks developed through community-based participatory research processes. Health and social service professionals, governmental organizations, elderly persons, and others from across the English-speaking Caribbean countries developed the Pillars framework to address the growing elderly population and with an aim to increase the number of healthy and active years of life. The Pillars framework consists of four interrelated pillars organized across multiple sectors of society: primary care with care management; integrated services coordination; population-based health promotion and disease prevention; and planning and accountability. Pillars is enabled by an envisioned integrated system of information technology that will increase community-based services delivery, interprofessional communication and coordination, and will aggregate data with all identifiers removed for surveillance, planning, forecasting, policy making, evaluation, and research. PMID- 22211756 TI - Questions and answers: Some questions discussed at one of the round tables held at Chicago Institute with public health nurses. AB - There were a number of issues confronting public health nurses in 1919, including the differentiation of practice between visiting nurses and public health nurses, use of community partnerships when developing a new nursing service in a community, and standards of nursing work. Other issues included the focus of nursing work at the community/population versus individual level, how to balance the work load where there was only one nurse in a community, and educating the public about the value of public health nursing to the community. In this excerpt from the original publication, Ella Phillips Crandall responded to questions raised at a round table session held in Chicago in 1919 as a part of a Public Health Nursing Forum, and then published in the October 1919 issue of The Public Health Nurse. While the social context in which PHNs worked in 1919 were significantly different from those nurses face today, these insights are prescient to the issues faced by PHNs today as the profession continues to address issues related to standards of practice, role development, and educational preparation for both entry level and advanced practice. PMID- 22211757 TI - Biodegradable three-dimension micro-device delivering 5-fluorouracil in tumor bearing mice. AB - A novel three-dimension micro-device was formulated to control delivery of 5 fluorouracil (5-FU) for the treatment of solid tumors. The poly-(lactic-co glycolic) acid (PLGA), which is both biocompatible and biodegradable, was used as carrier material. The characteristics of drug release in vitro and in vivo and the performance of the micro-device after implantation in tumor bearing mice were evaluated. A constant release profile from in vitro test was obtained for a period of 7 days, and it correlated well with the in vivo release profile. In the distribution experiment of 5-FU micro-device, it was demonstrated that 5-FU remained in the tumor tissues for more than 7 days after implantation. Likewise, we found that the 5-FU concentration in tumor correlated well with the in vivo release. Tumors treated with 5-FU loaded micro-device of three different dosages showed significant tumor reduction (P < 0.05) compared with empty control micro device 7 days after administration. Moreover, the implantation treatment showed enhanced efficacy compared with the intraperitoneal administration with the same dosage. These results suggested that the three-dimensional micro-device may provide a promising local and controlled release drug delivery system, which may enable delivery of multiple drugs for post-surgical chemotherapy against solid tumor. PMID- 22211758 TI - The use and importance of liposomes in positron emission tomography. AB - Among different imaging modalities, Positron Emission Tomography (PET) gained importance in routine hospital practice depending on ability to diagnose diseases in early stages and tracing of therapy by obtaining metabolic information. The combination of PET with Computed Tomography (CT) forms hybrid imaging modality that gives chance to obtain better images having higher resolution by fusing both functional and anatomical images in the same imaging modality at the same time. Therefore, better contrast agents are essentially needed. The advance in research about developing drug delivery systems as specific nanosized targeted systems gained an additional importance for obtaining better diagnosis and therapy of different diseases. Liposomes appear to be more attractive drug delivery systems in delivering either drugs or imaging ligands to target tissue or organ of diseases with higher accumulation by producing in nano-scale, long circulating by stealth effect and specific targeting by modifying with specific ligands or markers. The combination of positron emitting radionuclides with liposomes are commonly in research level nowadays and there is no commercially available liposome formulation for PET imaging. However by conjugating positron emitter radionuclide with liposomes can form promising diagnostic agents for improved diagnosis and following up treatments by increasing image signal/contrast in the target tissue in lower concentrations by specific targeting as the most important advantage of liposomes. More accurate and earlier diagnosis of several diseases can be obtained even in molecular level with the use of stable and effectively radiolabeled molecular target specific nano sized liposomes with longer half lived positron emitting radionuclides. PMID- 22211760 TI - Resveratrol induces gastric cancer cell apoptosis via reactive oxygen species, but independent of sirtuin1. AB - The currently available chemotherapeutic regimens against gastric cancer are not very effective, leading to high recurrence and poor survival. Resveratrol is a naturally occurring polyphenol with potent apoptosis-inducing activity. However, the mechanism underlying its actions remains unknown. In the present study, human gastric adenocarcinoma SGC7901 cells were treated with resveratrol (0, 25, 50, 100 and 200 MUmol/L) for 48 h, and cellular apoptosis DNA damage were determined. In certain experiments, cells were incubated with superoxide dismutase (100 U/mL), catalase (300 U/mL) or sirtinol (10 MUmol/L) to determine the role of reactive oxygen species (ROS) and sirtuin1 in resveratrol-induced cellular apoptosis. Treatment with resveratrol (50-200 MUmol/L) for 48 h significantly induced apoptosis and DNA damage in human gastric cancer SGC7901 cells. This was due to the increased generation of ROS following resveratrol treatment because incubation of cells with superoxide dismutase (100 U/mL) or catalase (300 U/mL) attenuated resveratrol-induced cellular apoptosis. Interestingly, treatment with resveratrol (25-200 MUmol/L) did not affect the level and activity of sirtuin1, whereas the sirtuin1 inhibitor sirtinol (10 MUmol/L) significantly reduced sirtuin1 activity. Furthermore, treatment with sirtinol (10 MUmol/L) did not have any effect on apoptosis induced by resveratrol. These data provide evidence that resveratrol induces apoptosis via ROS, but independent of sirtuin1, in the human gastric cancer cell line SGC7901. PMID- 22211761 TI - Drug-facilitated sexual assault using tetrahydrozoline. AB - Drug-facilitated sexual assault (DFSA) has been defined as the use of a chemical agent to facilitate a sexual assault. We report two cases of the use of tetrahydrozoline for DFSA. We believe this is the first report with urinary quantification of tetrahydrozoline levels postassault. Blood and urine were obtained c. 20 h postexposure in two cases of reported DFSA. Tetrahydrozoline was not detected in blood but was identified in urine in both victims. After initial identification in the urine using the 2010 update to the AAFS mass spectrometry database library, tetrahydrozoline was quantified at 114 and 150 ng/mL, respectively, using GC/MS. Two unique clinical features reported in these cases were intermittent periods of consciousness and postexposure vomiting. Use of GC/MS was successful in identifying tetrahydrozoline in the 100 ng/mL range up to 20 h postexposure. For victims with late presentation, urine may be a better sample for evaluation for tetrahydrozoline. PMID- 22211763 TI - Is the use of fluoride toothpaste optimal? Knowledge, attitudes and behaviour concerning fluoride toothpaste and toothbrushing in different age groups in Sweden. AB - OBJECTIVES: The most effective method to prevent caries is the regular use of fluoride toothpaste. The aim of this study was to evaluate self-care routines in a population by identifying knowledge, attitudes and behaviour relating to fluoride toothpaste and toothbrushing habits. METHODS: A questionnaire was sent to 3200 individuals in two municipalities in Sweden. Four age groups representing different life stages were chosen: 15-16, 31-35, 61-65 and 76-80 years of age. The participants were selected from the population register by random selection of birth dates. RESULTS: Totally 2023 (63%) individuals answered the questionnaire. The majority (84-94%) in all age groups brushed their teeth twice a day or more often. Good toothpaste behaviour identified as brushing at least twice a day, using at least 1 cm toothpaste, brushing 2 minutes or longer and using a small amount of water when rinsing was reported by only 10% of the respondents. The factors that increased the odds for having good caries preventive behaviour were: (i) being female, (ii) being younger than 35 years, (iii) having knowledge about fluoride, (iv) finding use of fluoride toothpaste important and (v) rating own oral health as good. CONCLUSIONS: The population seems to have embraced regular toothbrushing with fluoride toothpaste to a large extent. However, regarding techniques for using fluoride toothpaste effectively, there was great potential for improvement, especially among the older respondents. PMID- 22211764 TI - HLA-DMA and DMB genes in rheumatoid arthritis. PMID- 22211762 TI - miRNA in wound inflammation and angiogenesis. AB - Chronic wounds represent a rising health and economic burden to our society. Emerging studies indicate that miRNAs play a key role in regulating several hubs that orchestrate the wound inflammation and angiogenesis processes. Of interest to wound inflammation are the regulatory loops where inflammatory mediators elicited following injury are regulated by miRNAs, as well as regulate miRNA expression. Adequate angiogenesis is a key determinant of success in ischemic wound repair. Hypoxia and cellular redox state are among the key factors that drive wound angiogenesis. We provided first evidence demonstrating that miRNAs regulate cellular redox environment via a NADPH oxidase-dependent mechanism in human microvascular endothelial cells (HMECs). We further demonstrated that hypoxia-sensitive miR-200b is involved in induction of angiogenesis by directly targeting Ets-1 in HMECs. These studies point toward a potential role of miRNA in wound angiogenesis. miRNA-based therapeutics represent one of the major commercial hot spots in today's biotechnology market space. Understanding the significance of miRs in wound inflammation and angiogenesis may help design therapeutic strategies for management of chronic nonhealing wounds. PMID- 22211765 TI - Combinational sensitization of Leishmania with uroporphyrin and aluminum phthalocyanine synergistically enhances their photodynamic inactivation in vitro and in vivo. AB - Leishmania were previously shown to undergo photolysis when their transgenic mutants were induced endogenously to accumulate cytoplasmic uroporphyrin or when loaded exogenously with aluminum phthalocyanine chloride. A combinational use of both is reported here, which renders Leishmania far more susceptible to photolysis. Fluorescence microscopy of cells loaded with the two photosensitizers localized them to different subcellular sites. Pre-exposure of Leishmania to both synergistically sensitized them for photolysis as extracellular promastigotes and intracellular amastigotes in infected macrophages in vitro when illuminated at specific wavelengths to excite the respective photosensitizers for production of reactive oxygen species. Both Leishmania stages lost their viability completely when doubly photosensitized optimally and illuminated at low intensity, the host cells being left unscathed. Inoculation of mice with photoinactivated Leishmania produced no lesions, which invariably developed in the control groups during a period of observations for 8 weeks. Pretreatment of Leishmania with both photosensitizers rendered these cells susceptible to clearance from the ear dermis by white light illumination. The results suggest that double photosensitization for synergistic activity enhances the efficacy and safety of photodynamic therapy in general and for Leishmania in particular. PMID- 22211766 TI - Clinical significance of serum retinol binding protein-4 levels in patients with systemic sclerosis. AB - BACKGROUND: Retinol binding protein-4 (RBP-4) is a member of adipocytokines, which is potentially associated with fibrosis, vasodilation, and angiogenesis in addition to insulin resistance. OBJECTIVE: To investigate the clinical significance of serum RBP4 levels in patients with systemic sclerosis (SSc), which is a systemic autoimmune disease characterized by fibrosis and vasculopathy. METHODS: Serum RBP4 levels were determined by enzyme-linked immunosorbent assay in 62 SSc patients and 19 healthy controls. RESULTS: Similar to patients with chronic kidney disease, serum RBP4 levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction. Therefore, analyses were carried out by excluding SSc patients with estimated glomerular filtration rate <60 mL/min/1.73 m(2) . Serum RBP4 levels were significantly lower in diffuse cutaneous SSc (dcSSc) than in control subjects [median (25-75 percentile); 25.8 MUg/mL (19.6-47.0) vs. 43.1 MUg/mL (31.7-53.4), P < 0.05], while there was no significant difference between limited cutaneous SSc (lcSSc) [28.0 MUg/mL (25.4-43.3)] and control subjects. In both of dcSSc and lcSSc, patients with Raynaud's phenomenon had RBP4 levels significantly lower than those without. Furthermore, serum RBP4 levels inversely correlated with pulmonary function test results in dcSSc and with right ventricular systolic pressure in lcSSc. CONCLUSION Decreased RBP4 levels are associated with the prevalence of Raynaud's phenomenon in dcSSc and lcSSc, with the severity of interstitial lung disease in dcSSc, and with the degree of pulmonary vascular involvement in lcSSc, suggesting the possible contribution of RBP4 to the pathological events in this disorder. PMID- 22211767 TI - Editorial: identifying the cognitive and physiological underpinning of child psychiatric conditions. PMID- 22211770 TI - Orthotopic liver transplantation for adults with Alagille syndrome. AB - INTRODUCTION: Alagille syndrome (AGS) is an inherited multisystem disorder, and liver transplantation (LT) may be required in pediatric patients with AGS (P AGS). There are limited data regarding the outcomes of LT in adults with AGS (A AGS). AIM: To determine and compare the outcomes of LT in A-AGS vs. P-AGS as well as A-AGS vs. adults with biliary atresia (A-BA). METHODS: Adults (>18 yr), with AGS and BA, and children (<=18 yr), with AGS who underwent isolated first LT between 10/1987 and 5/2008, were identified from the UNOS database. RESULTS: Forty-four of 79,400 adults transplanted for AGS were compared with 407 P-AGS and 56 A-BA, respectively. A-AGS patients had a significantly higher rate of encephalopathy, lower serum albumin, and higher serum creatinine in comparison with P-AGS. One- and five-yr patient and graft survival in A-AGS who underwent LT were not significantly different in comparison with either P-AGS or A-BA (A-AGS patient survival: 95.5%, 90.9%, P-AGS: 88. 7%, 86.2%, A-BA: 89.3%, 87.5%; A-AGS graft survival: 84.1%, 79. 5%, P-AGS: 80.3%, 76%. 1%, A-BA: 82.1%, 78.6%, respectively). CONCLUSION: The outcome of first LT in A-AGS is excellent compared with the overall reported adult patient and graft survival. Although A-AGS were sicker than P-AGS at transplant, their outcomes were comparable with that of P AGS. PMID- 22211768 TI - Geritalk: communication skills training for geriatric and palliative medicine fellows. AB - Expert communication is essential to high-quality care for older patients with serious illness. Although the importance of communication skills is widely recognized, formal curricula for teaching communication skills to geriatric and palliative medicine fellows is often inadequate or unavailable. The current study drew upon the educational principles and format of an evidence-based, interactive teaching method to develop an intensive communication skills training course designed specifically to address the common communication challenges that geriatric and palliative medicine fellows face. The 2-day retreat, held away from the hospital environment, included large-group overview presentations, small group communication skills practice, and development of future skills practice commitment. Faculty received in-depth training in small-group facilitation techniques before the course. Geriatric and palliative medicine fellows were recruited to participate in the course and 100% (n = 18) enrolled. Overall satisfaction with the course was very high (mean 4.8 on a 5-point scale). After the course, fellows reported an increase in self-assessed preparedness for specific communication challenges (mean increase 1.4 on 5-point scale, P < .001). Two months after the course, fellows reported a high level of sustained skills practice (mean 4.3 on 5-point scale). In sum, the intensive communication skills program, customized for the specific needs of geriatric and palliative medicine fellows, improved fellows' self-assessed preparedness for challenging communication tasks and provided a model for ongoing deliberate practice of communication skills. PMID- 22211771 TI - Ultrastructure of the spermatozoa of the domestic duck (Anas platyrhynchos sp.). AB - The ultrastructure of the spermatozoa of the domestic duck (Anas platyrhynchos sp.) was analysed by transmission and scanning electron microscopies and compared with the results obtained in preliminary studies involving other non-passerine birds. The spermatozoa were characterised by the presence of a short head, short midpiece and long principal piece. The head consisted of a reduced acrosome that contained moderately electron-dense homogenous material. The implantation fossa was observed between the base of the nucleus and the proximal centriole. The midpiece contained electron-dense material associated with the proximal centriole and nuclear membrane, and a long distal centriole surrounded throughout its length by 11-12 elliptical mitochondria. A dense annulus separating the midpiece from the principal piece was visible. Posterior to the annulus, the axoneme was formed surrounded by a dense fibrous sheath, representing the principal piece or flagellum, which was a long segment with a smooth surface and a smaller diameter than the midpiece. The spermatozoon of the domestic duck resembles that of other non-passerine birds, corresponding to a basic type of spermatozoon similar to that of reptiles, called sauropsid type. PMID- 22211772 TI - Severe psychotic exacerbation during combined treatment with aripiprazole/haloperidol after prior treatment with risperidone. AB - OBJECTIVE: Aripiprazole is a new generation antipsychotic drug that shows a partial agonistic activity at D(2) and 5-HT(1A) receptors. This might lead in some cases to an exacerbation of psychotic symptoms due to dopamine agonism. METHODS: We report the case of a 39-year-old woman with an ICD-10 defined schizoaffective disorder. RESULTS: Risperidone was started to treat psychotic symptoms. Psychotic symptoms disappeared but because of galactorrhoea risperidone needed to be discontinued. Subsequently, an antipsychotic treatment regimen with aripiprazole and haloperidol was prescribed. After initiating aripiprazole and haloperidol the patient's psychotic symptoms increased drastically. Therefore aripiprazole and haloperidol were discontinued. Olanzapine was prescribed and psychotic symptoms declined again. CONCLUSION: Concurrent causes for this serious adverse event may be the partial agonistic activity of aripiprazole at D(2) receptors as well as an up-regulation of dopamine receptors during prior treatment with risperidone. Both aspects may have contributed to the severe psychotic exacerbation. Clinicians should be aware of this possible, serious adverse event while switching to aripiprazole or prescribing aripiprazole with other antipsychotics. Because of their lower D(2) receptor affinity quetiapine and clozapine might be a better choice for combined treatment with aripiprazole. PMID- 22211774 TI - The many facets of the HbA(1c) test. PMID- 22211775 TI - Spinal anesthesia in pediatric patients. AB - Spinal anesthesia (SA) in pediatrics began to be used in the late nineteenth century in multiple procedures, with priority for high-risk and former preterm infants, for its suggested protective role compared to the development of postoperative apnea with general anesthesia (GA). In children, higher doses of local anesthetics are required with a shorter duration of action and a greater hemodynamic stability compared to adults. The puncture must be performed in the L4-L5 or L5-S1 spaces to prevent spinal injuries. The practice of SA in pediatric patients requires skill and experience; failure rates of up to 28% have been reported. The drugs most commonly used for SA are tetracaine and bupivacaine alone or with adjuvants. SA complications are rare and often without consequences, except for postdural puncture headaches and backaches. Although SA is today considered safe and effective for pediatric patients, it remains relatively underutilized compared to GA. PMID- 22211776 TI - Multicenter study of safety in stenting for symptomatic vertebral artery origin stenosis: results from the Society of Vascular and Interventional Neurology Research Consortium. AB - PURPOSE: To assess the safety and efficacy of vertebral artery origin angioplasty and stenting for stroke prevention in a multicenter clinical experience. METHODS: Patients with symptomatic vertebral artery origin stenosis (VAOS) were gathered from the Society of Vascular and Interventional Neurology Research Consortium. Demographic, clinical, and procedural data were collected. The main outcome measure was procedural and peri-procedural risks of stroke, transient ischemic attack (TIA), or death at 1 and 3 months. Logistic regression analysis was used to assess covariates associated with future restenosis. RESULTS: A total of 148 patients were included with mean age of 66.2 +/- 11.5; 74% men and 77% Caucasian. One patient (.8%) had a stroke at 1 month and 5 of 96 (5.2%) patients had TIA at 3 months. There were no immediate procedural events or deaths. The mean angiographic pre-treatment stenosis was 80.5 +/- 12.7%, which was reduced to 5.3 +/- 9.1% after stent deployment. Follow-up angiography showed 15.5% of patients had significant restenosis (>=50%). Predictors of restenosis included age (OR 3.08; 95% CI 1.01, 9.41) and smoking (OR 3.10; 95% CI 1.12, 8.64). CONCLUSIONS: Endovascular intervention of VAOS is associated with low peri-procedural complication rates. Restenosis remains a concern; age and smoking predicted future restenosis. PMID- 22211778 TI - Role of pH in the pathogenesis of dermatophytoses. AB - The secretion of proteolytic enzymes by dermatophytes is a key factor in their invasion and subsequent dissemination through the stratum corneum of the host. During the first stages of infection, dermatophytes respond to the skin by de repressing a number of genes coding for proteins and enzymes such as adhesins, lipases, phosphatases, DNAses, non-specific proteases, and keratinases. These proteins have their optimal activity at acidic pH values, which matches the acidic pH of human skin, allowing the pathogen to adhere and penetrate the host tissue, scavenge nutrients and overcome host defence mechanisms. The conserved PacC/Rim101p signal transduction pathway mediates diverse metabolic events involved in ambient pH sensing and in the virulence of pathogenic microorganisms. The seven dermatophyte genomes analysed here revealed the presence of the PacC/Rim101p pH-responsive signal transduction pathway, which consists of the six pal genes (palA, B, C, F, H and I) and the transcription factor PacC. The PacC binding site was present in the promoter regions of pacC, palB, palI and palH genes of all dermatophytes, suggesting functional equivalency with the signalling cascade of other fungi. Moreover, the promoter region of pacC gene of the seven dermatophytes had multiple PacC DNA-binding sites, suggesting that these genes, like their homologues in model fungi, are auto-regulated. PMID- 22211777 TI - Rippled-pattern basal cell carcinoma. AB - Basal cell carcinoma (BCC) is the most common malignant cutaneous neoplasm, however, there have been few studies on BCC with a "rippled pattern" so far. We reviewed the 650 BCC specimens from the archives of our institution, and only one example of BCC with a rippled pattern was found. We herein report the histopathological characteristics of this case. Within the lesion, which showed the typical histopathological features of nodular BCC, there was a noticeable area composed of 10-15 basaloid aggregations, which showed the rippled pattern. The rippled pattern was characterized by alternating bands of epithelial cords of spindle-shaped basaloid cells and mucinous spaces. Characteristically, around the rippled-pattern area, neoplastic aggregations with a mucinous reticulated or cystic pattern (pseudo-tubular structures), and many cord-like structures were seen. A review of the published work and the present case suggested that the histopathological characteristics of rippled-pattern BCC are: (i) a nodular type of BCC; (ii) considerably rare; (iii) have frequent intervention by mucinous spaces between the epithelial cords; and (iv) no apparent divergent differentiation with folliculosebaceous-apocrine lineage. The last three characteristics contrasted with those of the rippled-pattern sebaceoma/trichoblastoma. However, neoplastic germinative cells in rippled pattern BCC may naturally form cord-like structures in a manner similar to rippled-pattern sebaceoma/trichoblastoma. PMID- 22211779 TI - Headache following intracranial neuroendovascular procedures. AB - AIMS: Predicting who will develop post-procedure headache (PPH) following intracranial endovascular procedures (IEPs) would be clinically useful and potentially could assist in reducing the excessive diagnostic testing so often obtained in these patients. Although limited safety data exist, the use of triptans or dihydroergotamine (DHE) often raise concern when used with pre/post coiled aneurysms. We sought to determine risk factors for PPH following IEP, to evaluate the utility of diagnostic testing in patients with post-coil acute headache (HA), and to record whether triptans and DHE have been used safely in this clinical setting. METHODS: We conducted a retrospective chart review of adult patients undergoing IEPs. Bivariate analyses were conducted to compare patients who did and did not develop PPH. RESULTS: We reviewed records pertaining to 372 patients, of whom 263 underwent intracranial coil embolizations, 21 acrylic glue embolizations, and 88 stent placements. PPH occurred in 72% of coil patients, 33% of glue patients, and 14% of stent patients. Significant risk factors for post-coil HA were female gender, any pre-coil HA history, smoking, and anxiety/depression. A pre-stent history of HA exceeding 1 year's duration, and smoking were risk factors for post-stent HA. A pre-glue history of HA exceeding 1 year was the only risk factor for post-glue HA. In the small subgroup available for study, treatment with triptans or DHE was not associated with adverse events in pre/post-coiled aneurysms. Diagnostic testing was low yield. CONCLUSIONS: Occurrence of PPH was common after IEPs and especially so with coiling and in women, smokers, and those with anxiety/depression, and was often of longer duration than allowed by current International Classification of Headache Disorders-II criteria. The yield of diagnostic testing was low, and in a small subgroup treatment with triptans or DHE did not cause adverse events in pre/post-coiled aneurysms. Prospective studies are needed to confirm these findings. PMID- 22211780 TI - Estimation of body surface area in various childhood ages--validation of the Mosteller formula. AB - AIM: The aim of the present study was to validate the Mosteller formula for the estimation of body surface area (BSA) in various childhood ages. Many physiological processes including drug metabolism correlate with values for BSA. In addition, dosing of many drugs, especially drugs with low therapeutic index, for example, anti-neoplastics, are based on estimated values of BSA. METHODS: Published data from measured BSA in 268 children and infants (median age: 8 month; range: 0-18 years) were compared with BSA values estimated by the Mosteller formula. Correlation between estimated and measured BSA values was performed by the Spearman rank correlation. Bias and precision were evaluated as outlined by Sheiner and Beal. Measured and estimated BSA values were compared by the Eksborg's plot. RESULTS: Measured values of BSA and BSA values estimated by the Mosteller formula were closely correlated (r(s) = 0.973; p < 0.0001). The formula of Mosteller had with a precision of 9.38% and underestimated BSA by 4.06%. The quotients Estimated/Measured BSA were within the range 0.9-1.1 in 71.3% of the observations, but deviation up to 35% occurred. CONCLUSION: The Mosteller formula underestimates BSA in the paediatric population and must be used with precautions because of low precision, most pronounced in neonates and infants. PMID- 22211782 TI - Essential but toxic: controlling the flux of iron in the body. AB - Iron is an essential nutrient, but, because it is toxic when present in excess, its levels in the body are tightly controlled. This regulation is affected by controlling the release of iron into the plasma. Most iron enters the plasma from macrophages, which recycle iron from senescent erythrocytes, but dietary iron absorption and the release of hepatocyte storage iron are other major sources. Cellular iron export is mediated by the membrane iron transporter ferroportin 1, in conjunction with an iron oxidase. Hephaestin provides this oxidase activity in the intestine, whereas ceruloplasmin is the oxidase used by most other tissues. The liver-derived peptide hepcidin binds to ferroportin 1 and removes it from the cell surface, thus reducing iron donation to the plasma. The levels of hepcidin, in turn, reflect body iron requirements. At the cellular level, ferroportin 1 can also be regulated independently of hepcidin by hypoxia-inducible factors and the iron regulatory proteins. The hepcidin-ferroportin axis plays a critical role in regulating body iron homeostasis. PMID- 22211783 TI - Impaired wake-promoting mechanisms in ghrelin receptor-deficient mice. AB - Ghrelin receptors are expressed by key components of the arousal system. Exogenous ghrelin induces behavioral activation, promotes wakefulness and stimulates eating. We hypothesized that ghrelin-sensitive mechanisms play a role in the arousal system. To test this, we investigated the responsiveness of ghrelin receptor knockout (KO) mice to two natural wake-promoting stimuli. Additionally, we assessed the integrity of their homeostatic sleep-promoting system using sleep deprivation. There was no significant difference in the spontaneous sleep-wake activity between ghrelin receptor KO and wild-type (WT) mice. WT mice mounted robust arousal responses to a novel environment and food deprivation. Wakefulness increased for 6 h after cage change accompanied by increases in body temperature and locomotor activity. Ghrelin receptor KO mice completely lacked the wake and body temperature responses to new environment. When subjected to 48 h food deprivation, WT mice showed marked increases in their waking time during the dark periods of both days. Ghrelin receptor KO mice failed to mount an arousal response on the first night and wake increases were attenuated on the second day. The responsiveness to sleep deprivation did not differ between the two genotypes. These results indicate that the ghrelin receptive mechanisms play an essential role in the function of the arousal system but not in homeostatic sleep-promoting mechanisms. PMID- 22211786 TI - Cytokines produced by microwave-radiated Sertoli cells interfere with spermatogenesis in rat testis. AB - Microwave radiation resulted in degeneration, apoptosis or necrosis in germ cells at different stages. The molecular mechanisms by which microwaves induce spermatogenesis disorder have not been completely understood. Sertoli cells play crucial roles in mammalian spermatogenesis. Cytokines produced by Sertoli cells play pleiotropic roles in different conditions. At physiologically low concentration, TNFalpha, IL-1beta and IL-6 behave as survival factors; while under pathological condition, these cytokines can induce apoptosis in testis. The effects of cytokines produced by microwave-radiated Sertoli cells on spermatogenesis are poorly understood. The purpose of this study was to determine the effect of cytokines produced by microwave-radiated Sertoli cells on the germ cells. We focused the effect of TNFalpha, IL-1beta and IL-6 on the germ cells. The results showed that TNFalpha, IL-1beta and IL-6 were increased in Sertoli cells after exposure to microwave radiation. These up-regulated cytokines can induce apoptosis and lipid peroxidation in the membrane of germ cells. In addition, germ cell apoptosis was associated with the up-regulation of Bax/Bcl-2 and caspase-3. These results suggest that cytokines produced by microwave radiated Sertoli cells may disrupt spermatogenesis. Our data provided novel insight into the injury mechanism of germ cells induced by microwave radiation. PMID- 22211788 TI - Response to Monesi et al. Prevalence, incidence and mortality of diagnosed diabetes: evidence from an Italian population-based study. PMID- 22211787 TI - Inhibition or enhancement by 4 Pacific Island food plants against cancers induced by 2 amino-3-methylimidazo[4,5-f]quinoline in male Fischer 344 rats. AB - A 1-yr carcinogenicity bioassay was conducted in rats fed 2-amino-3 methylimidazo[4,5-f]quinoline (IQ), simultaneously with AIN-76/ high-fat (HF) diet alone, or with 10% starch replaced with kumara, pineapple, coconut, or taro, prepared as for a human diet. All of the non-IQ treated control, kumara, pineapple, or taro but not coconut-fed rats survived to 1 yr. None of the IQ-fed animals survived to 1 yr and although there were minor survival time differences among the groups, none was statistically significant. At sacrifice, IQ/HF controls had tumors in the skin, Zymbal's gland, ear canal, oral cavity, liver, and small intestine, totaling 32 among 20 animals. Kumara-fed rats had a similar tumor distribution but no tumors in the ear or oral cavity, and a total of 27 tumors among 20 animals, whereas pineapple-fed rats showed a somewhat lower tumor incidence (23/20 animals), including no small intestine lesions. Unexpectedly, a higher tumor incidence, especially of skin tumors, was seen in coconut and taro fed animals (35/20 and 41/20 animals, respectively). In particular, the incidence of malignant liver tumors and gastrointestinal tumors were significantly increased in the taro-fed group in comparison with the kumara group. PMID- 22211789 TI - The relationship of body fatness and body fat distribution with microvascular recruitment: The Amsterdam Growth and Health Longitudinal Study. AB - INTRODUCTION: Microvascular function has been proposed to link body fatness to CVD and DM2. Current knowledge of these relationships is mainly based on studies in selected populations of extreme phenotypes. Whether these findings can be translated to the general population remains to be investigated. AIM: To assess the relationship of body fatness and body fat distribution with microvascular function in a healthy population-based cohort. METHODS: Body fatness parameters were obtained by anthropometry and whole-body dual-X-ray absorptiometry (DEXA) in 2000 and 2006. Microvascular recruitment (i.e., absolute increase in perfused capillaries after arterial occlusion, using nailfold capillaroscopy) was measured in 2006. Linear regression analysis was used to examine the relationship of (changes in) body fatness and body fat distribution with microvascular recruitment. RESULTS Data were available for 259 participants (116 men). Capillary density was higher in women than in men (difference 7.3/ mm(2); p < 0.05). In the total population, the relationship between total body fatness and microvascular recruitment was positive (beta = 0.43; p = 0.002), whereas a central pattern of fat distribution (trunk-over-total fatness) showed a negative relationship (beta = -26.2; p = 0.032) with microvascular recruitment. However, no association remained apparent after adjustment for gender. In addition, there was no relationship between 6-year changes in body fatness or fat distribution and microvascular recruitment. CONCLUSION: Women show higher capillary recruitment values than men. This study does not support a linear relationship between microvascular function and body fatness or body fat distribution within a population-based normal range. PMID- 22211792 TI - Mice vaccinated with enteropathogenic Escherichia coli ghosts show significant protection against lethal challenges. AB - AIM: To prepare enteropathogenic Escherichia coli (EPEC) E2348/69 ghosts and investigate whether immunization with EPEC bacterial ghosts can elicit protective immune responses. METHODS AND RESULTS: A recombinant plasmid with double lambdaPL/PR-cI857 temperature-sensitive regulatory cassettes was constructed. The lysis gene E and/or the staphylococcal nuclease A (SNA) gene were separately inserted downstream of the two regulatory cassettes to construct the lysis plasmids pBV220::E and pBV220::E::CI-P-SNA. An EPEC reference strain E2348/69 (serotype O127:H6) was transformed with the lysis plasmids to produce EPEC ghosts. Mice injected with bacterial ghosts EGE (EPEC ghosts produced using lysis protein E) or EGES (EPEC ghosts produced using a combination of lysis protein E and SNA) gained weight normally and showed no clinical signs of disease. Vaccination trials showed that mice immunized with EGE or EGES were significantly protected against subsequent challenge with the wild-type virulent parent strain, EPEC E2348/69 (42/50 and 45/50 survival, respectively); in contrast, none of the 30 control mice survived. CONCLUSIONS: Immunization with EPEC ghosts can elicit protective immune responses in BALB/c mice. SIGNIFICANCE AND IMPACT OF THE STUDY: EPEC ghosts may represent a promising new approach for vaccination against EPEC infection. PMID- 22211791 TI - Geographical variation in residence and risk of multiple nonmelanoma skin cancers in US women and men. AB - Residence in high ultraviolet (UV) locations is associated with increased risk for incident nonmelanoma skin cancer (NMSC). However, the effect of geographic location on multiple NMSC development has not been well studied. We evaluated the association between state of residence at birth, age 15 and 30 and risk of multiple NMSCs among 80275 women and men. After adjusting for age, gender, hair color, number of sunburns, tanning ability, family history of melanoma and nevus count, the cumulative relative risks (RRs) of developing >=1 NMSC for those consistently residing in medium- and high-UV index states were 1.20 (95% CI 1.14 1.27) and 1.42 (95% CI 1.32-1.53) respectively. We found that compared to individuals with one lifetime NMSC, the multivariate cumulative RRs of developing >=2 NMSCs for those who stayed in medium- and high-UV index states at all three timepoints were 1.09 (95% CI 1.00-1.19) and 1.15 (95% CI 1.02-1.30) respectively. These results cannot account for migration during the interval period and seasonal changes in residence; further, as BCC is the predominant NMSC, the results may be BCC-driven. In conclusion, we found that consistent residence in medium- or high-UVR locations was significantly associated an incremental risk of >=2 NMSCs later in life. PMID- 22211793 TI - Polymorphic variants of the IL2RA gene and susceptibility to type 1 diabetes in the Polish population. AB - Polymorphic variants of the IL2RA gene, which encodes high-affinity alpha subunit (CD25) of the interleukin-2 receptor, were recently found to affect the risk of several autoimmune disorders. This study was aimed to investigate the association of selected IL2RA polymorphisms (rs11594656, rs3118470, rs2104286 and rs7093069) with type 1 diabetes (T1D) in a Polish cohort comprising 445 patients and 671 healthy control subjects. The minor A allele at rs11594656 was found significantly less frequently among T1D subjects, compared with the control group [P = 0.011; odds ratio (OR) = 0.77; 95% confidence interval (CI) = 0.629-0.942]. In contrast, the minor C allele at rs3118470 appeared to be significantly associated with the occurrence of T1D (P = 0.003; OR = 1.30; 95% CI = 1.094 1.550). Two other IL2RA single nucleotide polymorphisms (SNPs) did not show significant differences among investigated groups. In conclusion, the study confirms the association of the IL2RA locus with T1D in the Polish population. PMID- 22211794 TI - High frequency of p.Thr93Met in Smith-Lemli-Opitz syndrome patients in Turkey. PMID- 22211795 TI - Not all elderly people benefit from vitamin D supplementation with respect to physical function: results from the Osteoporotic Fractures in Men Study, Hong Kong. AB - OBJECTIVES: To examine vitamin D status and its association with physical performance and muscle mass in older Chinese men. DESIGN: Cross-sectional and prospective cohort study design. SETTING: Hong Kong, People's of Republic of China. PARTICIPANTS: Nine hundred thirty-nine community-dwelling men aged 65 and older for cross-sectional analysis and 714 for longitudinal analysis. MEASUREMENTS: Baseline serum 25-hydroxyvitamin D (25OHD) was measured using a competitive radioimmunoassay kit. Baseline and 4-year physical performance measures (grip strength, 6-m walking speed, step length in a 6-m walk, time to complete five chair stands) were measured, and appendicular skeletal muscle mass (ASM) was assessed using dual-energy X-ray absorptiometry. Data were collected for confounding factors: demographic, number of diseases, smoking, alcohol use, body mass index, physical activity, diet, season of blood sampling, and serum parathyroid hormone (PTH) level. Multivariate regression analyses were performed with adjustments for confounding factors. RESULTS: Mean +/- standard deviation serum 25OHD level of this sample of Chinese community-dwelling older men who had a high level of baseline physical function was 77.9 +/- 20.5 nmol/L; 94.1% of participants had serum 25OHD levels of 50 nmol/L or greater. Median (interquartile range) serum PTH level was 4.1 pmol/L (3.1-5.5 pmol/L). After adjustment for potential confounding factors, serum 25OHD levels were not associated with baseline or 4-year change in physical performance measures and ASM. CONCLUSION: In Chinese older men who are vitamin D replete and have a high level of baseline physical function, vitamin D may not have an important role in physical function and muscle mass. PMID- 22211796 TI - Developmental validation of RSIDTM-Semen: a lateral flow immunochromatographic strip test for the forensic detection of human semen. AB - Tests for the identification of semen commonly involve the microscopic visualization of spermatozoa or assays for the presence of seminal markers such as acid phosphatase (AP) or prostate-specific antigen (PSA). Here, we describe the rapid stain identification kit for the identification of semen (RSIDTM Semen), a lateral flow immunochromatographic strip test that uses two antihuman semenogelin monoclonal antibodies to detect the presence of semenogelin. The RSIDTM-Semen strip is specific for human semen, detecting <2.5 nL of semen, and does not cross-react with other human or nonhuman tissues tested. RSIDTM-Semen is more sensitive with certain forensic evidence samples containing mixtures of vaginal secretions and semen than either of the commercially available PSA-based forensic semen detection tests or tests that measure AP activity that were tested in parallel. The RSIDTM-Semen kit also allows sampling a fraction of a questioned stain while retaining the majority of the sample for further processing through short tandem repeat analysis. PMID- 22211798 TI - Different immunoprofiles in patients with chronic myeloid leukemia treated with imatinib, nilotinib or dasatinib. AB - Immunomodulation induced by dasatinib is reportedly related to better prognosis in chronic myeloid leukemia (CML). However, the underlying mechanism has not yet been fully elucidated. The immunoprofiles of 63 patients in the chronic phase of CML were evaluated during treatment with a tyrosine kinase inhibitor (imatinib, n = 36; nilotinib, n = 9; dasatinib, n = 18). The numbers of CD56 + CD57 + and CD3 + CD57 + cells increased significantly in the dasatinib group. The numbers of regulatory T-cells were comparable among the three groups. Dasatinib markedly enhanced natural killer (NK)-cell reactivity. Only one patient treated with dasatinib showed a slight cytomegalovirus (CMV) reactivation. In contrast, nilotinib suppressed NK-cell reactivity. Plasma levels of interleukin-8 (IL-8), interferon-gamma inducible protein-10 (IP-10) and monocyte chemoattractant protein-1 (MCP-1) were significantly elevated in all three groups, and plasma levels of granulocyte macrophage-colony stimulating factor (GM-CSF) were significantly elevated in the imatinib and dasatinib groups. Our results suggest the presence of a mechanism for dasatinib-associated immunomodulatory effects that is distinct from CMV reactivation and a decreased number of regulatory T cells. PMID- 22211799 TI - Blood donors on teratogenic drugs and donor deferral periods in a clinical situation. AB - Deferral of blood donors taking teratogenic drugs is critical. From March 2008 to January 2009, we analysed stored blood specimens from donors who had taken teratogenic drugs and whose blood was transfused to women of childbearing age to determine the plasma concentration at the time of donation using high-performance liquid chromatography. In total, 167 specimens were examined. The numbers of specimens exceeding the quantification limit were 7, 39, 4, 2 and 1 for finasteride, isotretinoin, acitretin, etretinate and dutasteride, respectively. Finasteride was beyond the recommended drug deferral period in one specimen. These results may help create practical deferral policies. PMID- 22211800 TI - Spread and habitat selection of Chrysomya albiceps (Wiedemann) (Diptera Calliphoridae) in Northern Italy: forensic implications. AB - Habitat selection exploited by Chrysomya albiceps during its initial spread in Northern Italy was analyzed in relation to landscape structure. The results of two short studies and a case report are here discussed. C. albiceps was not found on experimental pig carcasses in the urban area of Pavia. It was missing in the woody mountains surrounding Lecco, but it was found in the same area, at a lower altitude, within the typical "urban sprawl" landscape. It was then recorded in a natural reserve, among a rich carrion-fly population. Indications coming from habitat selection suggest that C. albiceps has not yet saturated its potential ecological niche in newly colonized areas of Northern Italy. Factors like temperature, altitude, and interspecific competition can act as limiting factors, affecting habitat selection and distribution in newly colonized areas; the influence of those factors has to be taken into account for forensic purposes. PMID- 22211801 TI - Cytokines, chemokines and growth factors in wound healing. AB - In wound healing, a variety of mediators have been identified throughout the years. The mediators discussed here comprise growth factors, cytokines and chemokines. These mediators act via multiple (specific) receptors to facilitate wound closure. As research in the last years has led to many new findings, there is a need to give an overview on what is known, and on what might possibly play a role as a molecular target for future wound therapy. This review aims to keep the reader up to date with selected important and novel findings regarding growth factors, cytokines and chemokines in wound healing. PMID- 22211802 TI - Inverse association of serum long-acting natriuretic peptide and bone mineral density in renal transplant recipients. AB - OBJECTIVE: Our aim was to evaluate the relationship between bone mineral density (BMD) and fasting serum long-acting natriuretic peptide (LANP) concentration in renal transplant recipients. PATIENTS AND METHODS: Fasting blood samples were obtained from 65 renal transplant recipients. BMD was measured using dual energy X-ray absorptiometry in lumbar vertebrae (L2-L4). Serum LANP levels were measured using a commercial enzyme immunoassay kit. RESULTS: Six patients (9.2%) had osteoporosis and 28 patients (43.1%) had osteopenia in renal transplant recipients. Increased serum LANP (p<0.001) was significantly correlated with low lumbar T-score cut-off points between groups (normal, osteopenia, and osteoporosis) in renal transplant recipients. Female patients had lower lumbar BMD than male renal transplant recipients (p=0.027). Univariate linear regression analysis indicated that lumbar BMD were positively correlated with height (p=0.038), body weight (p=0.003), and body mass index (BMI; p=0.019), whereas negatively correlated with LANP (p=0.004) among the renal transplant recipients. Multivariate forward stepwise linear regression analysis of the significant variables revealed that body weight (R(2) change=0.132; p=0.006) and LANP (R(2) change=0.093; p=0.008) were the independent predictors of lumbar BMD values in the renal transplant recipients. CONCLUSION: Serum LANP concentration correlates negatively with lumbar BMD values in renal transplant recipients. PMID- 22211803 TI - Fish gills alterations as potential biomarkers of environmental quality in a eutrophized tropical river in south-eastern Brazil. AB - Gill anomalies in three common fish species of different taxonomic order, habitat dwelling and feeding habits (one Characiformes, Oligosarcus hepsetus; one Siluriformes, Hypostomus auroguttatus; and one Perciformes, Geophagus brasiliensis) from a eutrophized tropical river in south-eastern in Brazil were compared. The aim of this study was to search for sentinel species that could be used as potential biomarkers of environmental quality. Most fish had gills with histological changes, namely epithelial lifting, interstitial oedema, leucocyte infiltration, hyperplasia of the epithelial cells, lamellar fusion, vasodilatation and necrosis. On the other hand, lamellar blood congestion and lamellar aneurysm, which are more serious and often irreversible changes, were recorded for the water column carnivorous O. hepsetus and, to a lesser extent, for the bottom-dwelling detritivorous H. auroguttatus. A histopathological alteration index (HAI) based on the occurrence and severity of gills anomalies indicated that O. hepsetus (mean score = 11.4) had significantly higher values (Kruskall-Wallis H(2,41) = 15.95, P = 0.0003) compared with G. brasiliensis (mean score = 7.0). Overall, the omnivorous G. brasiliensis had comparatively lesser occurrence of most gill anomalies compared with other two species, being less suitable as biomarker of environmental quality. In contrast, the water column dweller O. hepsetus (water column) and the bottom-dweller H. auroguttatus had gills most susceptible to changes, making them more suitable for using as histological biomarkers of the environmental quality in entrophized tropical rivers. PMID- 22211805 TI - Consent for pediatric anesthesia: an observational study. AB - BACKGROUND: Informed consent prior to anesthesia is an important part of the pediatric pre-anesthetic consultation. This study aimed to observe and identify the number and nature of the anesthesia risks considered and communicated to parents/guardians and children during the pediatric informed consent process on the day of elective surgery. METHODS: A convenience sample of anesthetists had their pre-anesthesia consultations voice recorded, prior to elective surgery, during a 4-month period at the largest tertiary referral centre for pediatric care in South Australia. A data collection form was used to note baseline demographic data, and voice recording transcripts were independently documented by two researchers and subsequently compared for accuracy regarding the number and nature of risks discussed. RESULTS: Of the 96 voice recordings, 91 (92%) were suitable for the analysis. The five most commonly discussed risks were as follows: nausea and vomiting (36%); sore throat (35%); allergy (29%); hypoxia (25%); and emergence delirium (19%). Twenty-seven pre-anesthetic consultations (30%) were found to have had no discussion of anesthetic risk at all while a further 23 consultations (26%) incorporated general statements inferring that anesthesia carried risks, but with no elaboration about their nature, ramifications or incidence. The median number of risks (IQR) specifically mentioned per consultation was higher, 3 (1) vs 1 (1), P < 0.05, when the consultation was performed by a trainee rather than a consultant anesthetist and when the patient had previous anesthesia experience odds ratio 0.34, 95% CI [0.13, 0.87], P = 0.025. CONCLUSIONS: The pediatric anesthesia risk discussion is very variable. Trainees tend to discuss more specific risks than consultants and a patient's previous experience of anesthesia was associated with a more limited discussion of anesthesia risk. PMID- 22211808 TI - The effector and scaffolding proteins AF6 and MUPP1 interact with connexin36 and localize at gap junctions that form electrical synapses in rodent brain. AB - Electrical synapses formed by neuronal gap junctions composed of connexin36 (Cx36) occur in most major structures in the mammalian central nervous system. These synapses link ensembles of neurons and influence their network properties. Little is known about the macromolecular constituents of neuronal gap junctions or how transmission through electrical synapses is regulated at the level of channel conductance or gap junction assembly/disassembly. Such knowledge is a prerequisite to understanding the roles of gap junctions in neuronal circuitry. Gap junctions share similarities with tight and adhesion junctions in that all three reside at close plasma membrane appositions, and therefore may associate with similar structural and regulatory proteins. Previously, we reported that the tight junction-associated protein zonula occludens-1 (ZO-1) interacts with Cx36 and is localized at gap junctions. Here, we demonstrate that two proteins known to be associated with tight and adherens junctions, namely AF6 and MUPP1, are components of neuronal gap junctions in rodent brain. By immunofluorescence, AF6 and MUPP1 were co-localized with Cx36 in many brain areas. Co-immunoprecipitation and pull-down approaches revealed an association of Cx36 with AF6 and MUPP1, which required the C-terminus PDZ domain interaction motif of Cx36 for interaction with the single PDZ domain of AF6 and with the 10th PDZ domain of MUPP1. As AF6 is a target of the cAMP/Epac/Rap1 signalling pathway and MUPP1 is a scaffolding protein that interacts with CaMKII, the present results suggest that AF6 may be a target for cAMP/Epac/Rap1 signalling at electrical synapses, and that MUPP1 may contribute to anchoring CaMKII at these synapses. PMID- 22211809 TI - Trevo System: single-center experience with a novel mechanical thrombectomy device. AB - BACKGROUND AND PURPOSE: Recent reports have indicated that mechanical thrombectomy may have the potential to treat acute ischemic stroke. This study aims to describe the safety and effectiveness of Trevo Retriever, using Stentriever technology, in revascularization of patients with acute ischemic stroke. METHODS: Prospective study evaluating the clinical, radiological, and functional outcome of 13 patients with an angiographically verified occlusion of the anterior cerebral circulation. All patients underwent thrombectomy with TR as monotherapy or in combination with intra-arterial thrombolysis, within the first 8 hours from the onset of symptoms. Successful revascularization was defined as thrombolysis in cerebral ischemia grade 2a to 3. Good outcome was defined as modified Rankin Scale score <= 2. RESULTS: Median baseline National Institutes of Health Stroke Scale score was 19(16-22). The occlusion site was middle cerebral artery in 8 patients and internal carotid artery in 5 patients. Revascularization was achieved in 10 of 13 patients (77%). The mean time from groin puncture to recanalization was 95 +/- 31 minutes. No significant intra-procedural complications occurred. Four patients (30%) died during the 90-day follow-up period and 4 patients (30%) achieved functional independence. CONCLUSION: Early clinical experience suggests that the TR can allow safe and effective revascularization in certain subjects with acute ischemic stroke. PMID- 22211810 TI - Newcastle disease virus: a promising agent for tumour immunotherapy. AB - Malignant tumours are a major cause of mortality in humans. Currently used therapeutic regimens have not improved survival rates of patients suffering from malignant tumours much because of their limited efficacy and side-effects. A therapeutic approach that uses Newcastle disease virus (NDV) represents an attractive new tool for tumour immunotherapy. The present review highlights the mechanisms and advances that are likely to have considerable impact on NDV virotherapy. Significant evidence exists regarding the oncolytic effects of NDV, suggesting its potential use in the treatment of various tumours. Furthermore, clinical trials have suggested that several NDV strains have the potential for cancer virotherapy with few side-effects compared with traditional treatments. Many studies have been performed to investigate the oncolytic mechanisms of NDV. Apoptosis following NDV infection may contribute to the observed oncolytic effects; however, NDV could also stimulate both innate and adaptive antitumour immune responses. For many years, different approaches have been investigated (or are in the process of being developed) regarding the use of NDV for the treatment of malignancies. Recent advances using reverse genetics have provided a means of generating recombinant NDV strains with improved oncolytic and immune regulatory properties. PMID- 22211811 TI - The reliability of the disabled children's quality-of-life questionnaire in Swedish children with diabetes. AB - AIM: To determine the reliability of the disabled children's quality-of-life measure (DISABKIDS) chronic generic questionnaire and diabetes module in children. The questionnaire is being evaluated for repeated routine health related quality-of-life (HrQoL) assessment and in association with the Swedish national paediatric diabetes registry (Swediabkids), which is a tool for regular clinical use. METHODS: Children and parents completed the questionnaire during a routine visit to the diabetes clinic. In total, 120 families completed the test and retest. Split-half reliability correlation and intraclass correlation (ICC) coefficients were calculated. Bland & Altman plots were calculated on the generic HRQoL domain. RESULTS: Both child and parent versions showed good internal consistency. Test-retest ICC coefficients for the generic HrQoL module were 0.913 for the children and 0.820 for the parent version. All generic domains independently showed good reliability. The diabetes module had a score of 0.855 for children and 0.823 for parents. Split-half correlation for generic and diabetes modules was 0.930 and 0.848 for children, 0.953 and 0.903 for parents. Bland and Altman plots showed substantial agreement between the two administrations for both children and parents. CONCLUSION: The DISABKIDS questionnaire is a reliable instrument for the repeated measurements of HrQoL in children with diabetes. PMID- 22211812 TI - Male accessory gland infections: anatomical extension of inflammation and severity of symptoms evaluated by an original questionnaire. AB - The study was aimed at evaluating a new diagnostic interview, arbitrarily named Structured Interview about male accessory gland infections (SI-MAGI), administered to three different groups of patients with MAGI according to ultrasound evaluation [prostatitis (P) or prostato-vesciculitis (PV) or prostato vesciculo-epididymitis (PVE)]. We evaluated 110 consecutively selected infertile patients, with diagnosis of MAGI and underwent to transrectal and scrotal ultrasound (US) examination. After ultrasound evaluation, they were divided into three well-characterised, aged-matched groups: prostatitis (P; n = 45), prostato vesciculitis (PV; n = 30) and prostato-vesciculo-epididymitis (PVE; n = 35). Then, all patients were submitted to active clinical history oriented by SI-MAGI questionnaire elucidated by the operator. The SI-MAGI was structured in four domains (urinary symptoms, ejaculatory pain or discomfort, sexual dysfunction and quality-of-life impact) for a total of 30 questions with four possible answers. Infertile patients of PVE and PV groups showed scores significantly higher than P group in all domains (anovaP < 0.005). PVE showed scores significantly higher than PV group in domain 2 and 3. Our study demonstrates the MAGI's symptoms worsen with major extension of inflammation and ultrasound can evaluate the true extent of MAGI and symptoms can help to suggest the severity of MAGI. PMID- 22211813 TI - Differential influence of dietary soy intake on the risk of breast cancer recurrence related to HER2 status. AB - The effects of soy products and isoflavone on breast cancer recurrence were compared according to receptor status including epidermal growth factor receptor 2 (HER2) with 339 Korean women. Dietary intake of soy foods was assessed using a validated food frequency questionnaire with 103 food items. Twenty-five patients experienced breast cancer recurrence, 17 patients were HER2 negative, and 8 patients were HER2 positive. Legume intake (mostly from black soybeans) was inversely associated with the risk of breast cancer recurrence in HER2 negative cancer patients (HR: 0.27, 95% CI: 0.13-0.57, P for trend < 0.01), whereas legume intake was positively associated in HER2 positive cancer patients (P for trend = 0.02). In HER2 negative cancer patients, isoflavone was inversely associated with breast cancer recurrence (HR: 0.23, 95% CI: 0.06-0.89; P for trend = 0.01). Total soy intake was not associated with an increased risk of cancer recurrence. In conclusion, overall soy food intake might not affect the risk of cancer recurrence, but high intake of soy isoflavones increased the risk of cancer recurrence in HER2-positive breast cancer patients. However, further research is needed to confirm these results due to the small number of cancer recurrence events. PMID- 22211815 TI - Multiple, diffuse schwannomas in a RASopathy phenotype patient with germline KRAS mutation: a causal relationship? PMID- 22211816 TI - Preoperative breast MRI in the surgical treatment of ductal carcinoma in situ. AB - Accurate determination of the size or extent of ductal carcinoma in situ (DCIS) by imaging is uncertain, and incomplete resection of tumor results in involved margins in up to 81% of cases. This study examined the accuracy of magnetic resonance imaging (MRI) for assessment of DCIS size, and evaluated the effect of preoperative breast MRI on achievement of tumor-free surgical margins after breast-conserving surgery (BCS). One-hundred and fifty-eight female patients with DCIS were identified from a prospective database: 60 patients (62 cases) had preoperative breast MRI, and 98 patients did not have MRI. The accuracy of tumor size assessed by MRI was determined by comparison with histopathologic size. All patients underwent BCS initially. The rate of involved margins after resection was compared in MRI and no-MRI groups. The overall correlation between MRI size and histopathologic size was high (p < 0.0001). MRI assessment of size was significantly more accurate when DCIS was high grade (p < 0.0001) or intermediate grade (p = 0.005) versus low grade (p = 0.187). The rate of tumor-involved margins was not significantly different in MRI and no-MRI groups (30.7% and 24.7%, respectively; p = 0.414). The rate of mastectomy was significantly higher in the MRI group than the no-MRI group (17.7% versus 4.1%; p = 0.004). These findings indicate that MRI can detect DCIS, especially when lesions are high or intermediate grade, but that MRI does not accurately predict the size of DCIS. In this study, MRI did not improve the surgeon's ability to achieve clear margins following BCS. PMID- 22211817 TI - Association between dental status and incident disability in an older Japanese population. AB - OBJECTIVES: To determine the association between dental health status and onset of functional disability in older Japanese people. DESIGN: Prospective cohort study. SETTING: Six Japanese municipalities. PARTICIPANTS: Four thousand four hundred twenty-five community-dwelling individuals aged 65 and over. MEASUREMENTS: The outcome measure was the onset of functional disability based on public records of people receiving long-term care insurance benefits, determined through a standardized multistep assessment of functional and cognitive impairment including a personal interview and an examination by a physician. Disability data were analyzed for 4,425 respondents during 2003 to 2007. Self reported number of remaining teeth and eating ability were used as measures of dental health status. Age, sex, body mass index, self-rated health, present illness, smoking, alcohol, exercise, and equivalent income were used as covariates. RESULTS: In the age- and sex-adjusted Cox proportional hazard models, there were significant associations between number of remaining teeth, eating ability, and onset of disability. After adjusting for sociodemographic, behavioral, and health status variables, respondents with 19 or fewer teeth had a significant 1.21 (95% confidence interval = 1.06-1.40) times higher hazard ratio for the onset of functional disability. In contrast, eating ability was not significantly associated with the onset of disability. CONCLUSION: Poor dental status was associated with a higher risk of onset of functional disability in older Japanese people. Sociodemographic, behavioral, and health status covariates explained the association between eating ability and onset of disability. PMID- 22211818 TI - C-reactive protein concentration predicts mortality in type 2 diabetes: the Diabetes Heart Study. AB - AIMS: Although current American Heart Association guidelines address C-reactive protein concentration and cardiovascular disease risk, it remains unclear whether this paradigm is consistent across populations with differing disease burdens. Individuals with Type 2 diabetes mellitus represent one group at increased risk of cardiovascular disease and subsequent mortality. This study aimed to examine the relationship between C-reactive protein concentrations and risk for all-cause mortality in European Americans with Type 2 diabetes from the Diabetes Heart Study. METHODS: A total of 846 European Americans with Type 2 diabetes and baseline measures of C-reactive protein were evaluated. Vital status was determined after a follow-up period of 7.3 +/- 2.1 years (mean +/- SD). C reactive protein concentrations were compared between living and deceased subgroups along with other known risk factors for cardiovascular disease, including blood lipids. Logistic regression was performed to determine risk for mortality associated with increasing C-reactive protein concentrations. RESULTS: At follow-up 160 individuals (18.7%) were deceased. No significant differences in baseline serum glucose or lipid measures were observed between living and deceased subgroups. Baseline C-reactive protein concentrations were significantly higher in the deceased subgroup (9.37 +/- 15.94) compared with the living subgroup (5.36 +/- 7.91 mg/l; P < 0.0001). Participants with C-reactive protein concentrations of 3-10 mg/l were approximately two times more likely to be deceased at follow-up (OR 2.06; 95% CI 1.17-3.62); those with C-reactive protein >10 mg/l were more than five times more likely to be deceased (OR 5.24; CI 2.80 9.38). CONCLUSIONS: This study documents the utility of C-reactive protein in predicting risk for all-cause mortality in European Americans with Type 2 diabetes and supports its use as a screening tool in risk prediction models. PMID- 22211822 TI - Sexual dimorphism in the tarsal bones: implications for sex determination. AB - An accurate determination of sex is essential in the identification of human remains in a forensic context. Measurements of some of the tarsals have been shown to be sexually dimorphic by previous researchers. The purpose of the present study is to determine which dimensions of the seven tarsals demonstrate the greatest sexual dimorphism and therefore have the most potential for accurate sex determination. Eighteen measurements of length, width, and height were obtained from the tarsals of 160 European-American males and females from the William M. Bass Donated Skeletal Collection. These measurements were made using a mini-osteometric board. Logistic regression analyses were performed to create equations for sex discrimination. All measurements showed significant sexual dimorphism, with the talus, cuboid, and cuneiform I producing allocation accuracies of between 88 and 92%. Combinations of measurements provided better accuracy (88.1-93.6%) than individual measurements (80.0-88.0%). PMID- 22211823 TI - Photochemically generated elemental selenium forms conjugates with serum proteins that are preferentially cytotoxic to leukemia and selected solid tumor cells. AB - The objective of this study was to determine if and how photoproducts contribute to the antitumor effect of merocyanine-mediated PDT. A panel of barbituric, thiobarbituric and selenobarbituric acid analogues of Merocyanine 540 was photobleached, and the resulting photoproducts were characterized by absorption, fluorescence emission, mass, energy dispersive X-ray, and X-ray photoelectron spectroscopy and tested for cytotoxic activity against tumor cell lines and freshly explanted bone marrow cells. While all dyes were readily photobleached, only photoproducts of selone dyes showed cytotoxic activity. One-hour incubations with micromolar concentrations of selone-derived photoproducts were sufficient to reduce leukemia/lymphoma cells >=10 000 fold, whereas preserving virtually all normal CD34-positive bone marrow cells. Of six multidrug-resistant tumor cell lines tested, five were as sensitive or more sensitive to photoproducts than the corresponding wild-type lines. Physicochemical characterizations of the cytotoxic activity indicated that it consisted of conjugates of subnano particles of elemental selenium and (lipo)proteins. The discovery of cytotoxic Se-protein conjugates provides a rare example of photoproducts contributing substantially to the antitumor effect of PDT and challenges the long-held view that Se in oxidation state zero is biologically inert. Agents modeled after our Se-protein conjugates may prove useful for the treatment of leukemia. PMID- 22211824 TI - Randomised clinical trial: pregabalin attenuates the development of acid-induced oesophageal hypersensitivity in healthy volunteers - a placebo-controlled study. AB - BACKGROUND: Acid infusion in humans induces primary and secondary oesophageal hypersensitivity. The effects of pregabalin, a centrally-acting modulator of voltage-sensitive calcium channels, on development of acid-induced oesophageal hypersensitivity remain unknown. AIM: To study the effects of pregabalin on development of secondary oesophageal hypersensitivity in healthy humans. METHODS: Placebo-controlled, double-blind, randomised, cross-over study of 15 healthy volunteers (six women, age 21-56 years). After oesophageal manometry, baseline pain thresholds (PTs) to proximal oesophageal electrical stimulation were determined using bipolar ring electrodes. A 30-min infusion of HCl was performed in the distal oesophagus followed by PT measurements at 30 and 90 min. This protocol was repeated after administration of pregabalin (dosing schedule: 75 mg twice daily for 3 days then 150 mg twice daily for 1 day and then 150 mg on the morning of study) or placebo. RESULTS: T0 PTs were similar in patients after receiving placebo or pregabalin [mean (s.d.) 32.9 mA (20.5) vs. 34.1 (15.7), P = 0.42]. Pregabalin reduced development of acid-induced hypersensitivity in the proximal oesophagus at 30 min [mean change in PT (C.I.) placebo -6.2 mA (-11.3 to +1.3) vs. pregabalin +0.20 mA (-2.7 to +3.3)] and 90 min [placebo -3.7 mA (-10.0 to +2.0) vs. pregabalin +0.7 mA (-4.7 to 7.3)] overall P = 0.001. Pregabalin reduced median visual analogue scale score for acid-induced pain (1/10 vs. placebo 3/10, P = 0.027). CONCLUSIONS: Pregabalin attenuates development of secondary hypersensitivity in the proximal oesophagus after distal oesophageal acidification; it may thus have a role in treatment of patients with proven oesophageal pain hypersensitivity. PMID- 22211825 TI - Pharmacokinetic profiles of epidural bupivacaine and ropivacaine following single shot and continuous epidural use in young infants. AB - AIMS: The primary aim of this study was to describe the pharmacokinetics of total and unbound bupivacaine and ropivacaine following epidural bolus and infusion in neonates and young infants. Secondary aims were to investigate the influence of alpha-1-acid glycoprotein (AAG) on the concentration-time profiles and to determine the efficacy and adverse event profile of the epidural regimen. METHODS/MATERIALS: Thirty-one infants aged 40-63 weeks of postmenstrual age (PMA) undergoing hernia repair or abdominal surgery received an epidural injection of 1.5 mg . kg(-1) bupivacaine (0.25%) or ropivacaine (0.2%) followed 2 h later by an infusion of 0.2 mg . kg(-1) . h(-1) in those undergoing abdominal surgery. Total and unbound concentrations of bupivacaine and ropivacaine were analyzed using nonmem. Hourly pain scores and adverse effects were recorded. RESULTS: Bupivacaine data were available from 11 infants (five had infusions) and ropivacaine from 13 infants (four had infusions). Alpha-1-acid glycoprotein and total bupivacaine and ropivacaine concentrations accumulated during infusions, but unbound concentrations did not. Maximum unbound concentrations for bupivacaine and ropivacaine were 0.12 mg . l(-1) (bupivacaine) and 0.13 mg . l( 1) (ropivacaine). Typical clearance/bioavailability estimates of total (unbound) bupivacaine were 0.215 (4.65) l . h(-1) . kg(-1) and of total (unbound) ropivacaine were 0.288 (3.31) l . h(-1) . kg(-1). Pain scores requiring pain team referral occurred once with bupivacaine and four times with ropivacaine. No toxicity was observed. CONCLUSIONS: Epidural infusions of 0.2 mg(-1) . kg(-1) . h(-1) bupivacaine or ropivacaine appeared to be well tolerated and efficacious in this population. No accumulation of unbound drug concentrations occurred. PMID- 22211826 TI - Successful switch-over administration of intravenous-to-oral tacrolimus after isolated living-donor liver transplantation in a child with ultra short gut syndrome. PMID- 22211827 TI - Growth and shape modelling of the rabbit tibia: study of the dynamics of developing skeleton. AB - The proliferative impulse of the growth plate cartilage and related structures and its effect on the dimensions of long bones are well documented. The modulation of shape, however, is less known, and in general, it is referred to the coupled resorption/apposition process of bone modelling. A morphometric study was carried out on rabbit tibiae comparing size increments and shape changes in relation to age. Utilizing measurements made using dried bones, radiography and computerized tomography, it was possible to perform a three-dimensional analysis of shape modulation occurring during a period of growth extending from 3 months to 1 year of age. The dynamics of the shape changes related to growth were studied with a fluorescent tetracycline labelling. This enabled correlation of shape modulation with the 3-D distribution of apposition and resorption. The current thinking behind the influences and mechanical forces affecting bone architecture was discussed in the light of these findings. Several factors play a role in the structural organization of the human and upper vertebrates' skeleton, whose shape is genetically determined in the complex process usually referred as 'modelling'. This does not conflict with the existing evidence of remodelling being influenced by mechanical stimuli, but the unsolved question remains how physical forces (strains) act on the biological substrate of cartilage and bone cells. PMID- 22211828 TI - Divergent clinical and neuropathological phenotype in a Gerstmann-Straussler Scheinker P102L family. AB - OBJECTIVES: Gerstmann-Straussler-Scheinker syndrome belongs to the genetic prion diseases being associated with mutations in the prion protein gene (PRNP). The most common is the point mutation at codon 102, leading to the substitution of proline to leucine (P102L). Previous reports have indicated a phenotypic heterogeneity among individuals with this mutation. Here, we describe the clinical and pathological phenotype in members of the first Finnish kindred with the P102L mutation in the PNRP gene. MATERIALS AND METHODS: Genetic and clinical information was available in five members of a family, while a systematic histologic and immunohistochemical assessment of the post-mortem brain was carried out in three. RESULTS: Clinical presentation, disease duration and the clinical phenotype (ataxia vs dementia) varied between patients. There was a significant correlation between clinical symptoms and the neuroanatomical distribution of prion protein-immunoreactive aggregates, i.e. subtentorial predominance in ataxia vs cortical predominance in dementia. A significant concomitant Alzheimer is disease-related pathology was observed in the brain of one patient with dementia as onset symptom. CONCLUSIONS: This is the first Scandinavian family carrying the P102L mutation in the PRNP gene. Gerstmann Straussler-Scheinker syndrome should be considered in the differential diagnosis when handling with patients with ataxia and/or dementia of unclear aetiology. PMID- 22211829 TI - Effectiveness of three instrumentation systems to remove Enterococcus faecalis from root canals. AB - AIM: To assess the effectiveness of three systems of mechanical preparation to reduce Enterococcus faecalis within root canals. METHODOLOGY: Twenty-four human single-rooted canine teeth were standardized to a length of 17 mm and the canal contents removed using a size 20 K-file, as the last apical file. After irrigation and sterilization, the canals were contaminated with E. faecalis and incubated for 21 days at 37 degrees C with 5% CO(2). Then, the teeth were divided into three groups for mechanical preparation with: ProTaper rotary system, ProTaper manual system and manual K-files. Samples of the root canal contents, before and after the debridement, were collected with sterile paper points for 1 min. Then, the samples were diluted and plated in Brain Heart Infusion (BHI) agar. The colony-forming units were counted and the percentage reduction calculated. The reduction and log CFU mL(-1) were compared between groups using Wilcoxon nonparametric test and two-way analysis of variance, respectively. RESULTS: There was a significant reduction in the number of CFU/mL (P = 0.000) before and after debridement for all the systems used. However, there was no significant difference between the systems. CONCLUSION: All the three instrumentation systems reduced E. faecalis counts to a similar degree. PMID- 22211830 TI - A patch testing and cross-sensitivity study of carbamazepine-induced severe cutaneous adverse drug reactions. AB - BACKGROUND: The usefulness of the drug patch testing for Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is still controversial. Recent studies have shown that HLA-B*1502 is strongly associated with CBZ-SJS/TEN in Chinese and Southeast Asian populations. OBJECTIVE: To evaluate the usefulness of patch tests for patients with carbamazepine (CBZ)-induced SJS, TEN and drug reaction with eosinophilia and systemic symptoms (DRESS) and the cross-reactivity in patch tests among the aromatic antiepileptic drugs. METHODS: We measure the frequency of positive patch test reactions and cross-sensitivity to structure-related aromatic anti-epileptic drugs (AEDs) for patients after SJS/TEN or DRESS episodes caused by CBZ. CBZ and other structure-related AEDs used for patch testing were prepared in 10% and 30% petrolatum. Secondary measures included the association of HLA-B*1502 genotype and frequency of possible side effects from the patch tests. RESULTS: Positive patch test reactions to 30% CBZ in the CBZ-SJS/TEN were 62.5% (10/16), and 70% (7/10) in the CBZ-DRESS. None of the 10 healthy controls displayed a positive reaction to tested agents. Cross-sensitivity to other aromatic AEDs was observed in both the CBZ-SJS/TEN and the CBZ-DRESS. Only the HLA-B*1502 genotype was present and strongly associated with the CBZ-SJS/TEN, but not with the CBZ-DRESS. CONCLUSION: Drug patch testing is a safe and useful method for the identification of CBZ as the culprit drug of SJS/TEN as well as DRESS. Testing of chemically or pharmacologically related AEDs may provide information on cross-reactivity for these patients. PMID- 22211831 TI - Rural residency and the risk of mortality while waiting for liver transplantation. AB - Our liver transplant program services a region that has a prominent rural demographic. The influence of rural residency on liver transplant wait-list mortality has not been previously studied. We hypothesized that residence in a rural setting, by imposing challenges to medical care access, might be associated with inferior survival while waiting for liver transplantation. To test this hypothesis, multivariable time-to-event analysis was performed using Cox proportional hazards and competing risks regression on data from a consecutive five-yr cohort of 159 primary liver transplant candidates, to derive covariate adjusted effect measures for the association between residence in a rural area and wait-list mortality. For the primary analysis, a standardized, census-based, definition was used to assign rural residency status. The Kaplan-Meier estimated 90-d and one-yr wait-list mortality for the cohort was 7.6% (95% CI: 4.2-13.8) and 15.6% (95% CI: 9.4-25.2). The covariate adjusted hazard ratio for the relationship between Rural and Small Town residency status and wait-list mortality was 0.497 (95% CI: 0.171-1.438, p = 0.197) for the Cox regression model and 0.628 (95% CI: 0.224-1.757, p = 0.376) for the competing risk regression model. As defined in this study, candidate residence in a rural setting was not found to be associated with inferior survival while awaiting liver transplantation. PMID- 22211832 TI - Objective and self-reported cognitive dysfunction in breast cancer women treated with chemotherapy: a prospective study. AB - The objective of this study is to investigate if changes in cognitive functions can be recognised in patients undergoing chemotherapy for breast cancer. Forty women with breast cancer and without depression underwent cognitive evaluation before and after 6 months of chemotherapy; emotional evaluation was performed before and after 1, 3 and 6 months of chemotherapy. Self-reported cognitive deficit evaluation was included. Global cognitive functioning before starting chemotherapy was good. After 6 months of treatment there was a significant decline in some cognitive functions, particularly involving the attention subdomain. Objective cognitive deficit resulted independent from the emotional status. On the contrary, self-perceived mental dysfunction was unrelated to the objective cognitive decline, but it was associated with depression and anxiety. Breast cancer chemotherapy can induce domain-specific cognitive dysfunction. Patients' self-perception of mental decline is unrelated to objective cognitive deficit. Breast cancer patients negatively judge their cognitive performances if they have a negative emotional functioning. PMID- 22211833 TI - Perioperative dilutional coagulopathy treated with fresh frozen plasma and fibrinogen concentrate: a prospective randomized intervention trial. AB - BACKGROUND AND OBJECTIVES: Treatment of dilutional coagulopathy by transfusing fresh frozen plasma (FFP) remains sub-optimal. We hypothesized that partial replacement of transfused FFP by fibrinogen concentrate results in improved coagulant activity and haemostasis. This was tested in a controlled clinical intervention trial with patients experiencing massive bleeding during major surgery. METHODS: Patients undergoing major elective surgery were treated according to current protocols. When transfusion with FFP was required, patients were randomized as follows: group A received 4 units FFP and group B received 2 units FFP plus 2 g fibrinogen concentrate. Blood samples were taken before and after the intervention. Analysts were blinded to the treatment type. RESULTS: Group A (B) consisted of 21 (22) patients, in 16 (17) of whom bleeding stopped after intervention. Plasma fibrinogen increased significantly more in group B (0.57 g/l) than in group A (0.05 g/l). However, levels of prothrombin and factors VIII, IX and X increased more in group A than in group B. Rotational thromboelastometry (ROTEM) of whole blood and plasma revealed improved fibrin clot formation in group B but not in group A. Thrombin generation [calibrated automated thrombogram (CAT)] in plasma increased more in group A. Principal parameters determining whole-blood thromboelastometry were the fibrinogen level and platelet count. In vitro addition of fibrinogen and prothrombin complex concentrate to pre-intervention samples restored both ROTEM and CAT parameters. CONCLUSIONS: Partial replacement of transfused FFP by fibrinogen increases fibrin clot formation at the expense of less improved thrombin generation. Coagulation factors other than fibrinogen alone are required for full restoration of haemostasis. PMID- 22211836 TI - Efficacy of lenalidomide plus dexamethasone in patients older than 75 years with relapsed multiple myeloma. AB - Few data are available on the efficacy of the combination of lenalidomide plus dexamethasone (Len/Dex) in very elderly patients above 75 years of age with relapsed multiple myeloma (MM). We report here a single-center series of 45 consecutive patients aged 75 years or older with relapsed MM treated with this combination. The overall response rate was 62% and the median progression-free survival was 14 months, which compares favorably to that described in the two pivotal prospective studies that formed the basis for the approval of Len/Dex in the relapse setting. Our study confirms that Len/Dex is an effective combination in very elderly patients with relapsed MM. PMID- 22211838 TI - Arterial blood gas analysis of samples directly obtained beyond cerebral arterial occlusion during endovascular procedures predicts clinical outcome. AB - Real-time intra-procedure information about ischemic brain damage degree may help physicians in taking decisions about pursuing or not recanalization efforts. METHODS: We studied gasometric parameters of blood samples drawn through microcatheter in 16 stroke patients who received endovascular reperfusion procedures. After crossing the clot with microcatheter, blood sample was obtained from the middle cerebral artery (MCA) segment distal to occlusion (PostOcc); another sample was obtained from carotid artery (PreOcc). An arterial blood gas (ABG) study was immediately performed. We defined clinical improvement as National Institutes of Health Stroke Scale (NIHSS) decrease of >=4. RESULTS: The ABG analysis showed differences between PreOcc and PostOcc blood samples in mean oxygen partial pressure (Pre-PaO2: 78.9 +/- 16 .3 vs. 73.9 +/- 14 .9 mmHg; P < .001). Patients who presented clinical improvement had higher Post-PaO2 (81 +/- 11 .4 vs. 64.8 +/- 14 .4 mmHg; P = .025). A receiver-operator characteristic (ROC) curve determined Post-PaO2 > 70 mmHg that better predicted further clinical improvement. Patients with Post-PaO2 > 70 mmHg had higher chances of clinical improvement (81.8% vs. 0%; P = .002) and lower disability (median mRS:3 vs. 6; P= .024). In the logistic regression the only independent predictor of clinical improvement was Post-PaO2 > 70 (OR: 5.21 95% CI: 1.38-67.24; P = .013). CONCLUSION: Direct local blood sampling from ischemic brain is feasible during endovascular procedures in acute stroke patients. A gradient in oxygenation parameters was demonstrated between pre- and post-occlusion blood samples. ABG information may be used to predict clinical outcome and help in decision making in the angio-suite. PMID- 22211839 TI - Experimental adipocere formation: implications for adipocere formation on buried bone. AB - Adipocere, or grave wax (adipo = fat, cere = wax), is a distinctive decomposition product composed primarily of fatty acids (FA) and their alkali salts. FA result from the bacterial enzymatic hydrolysis of body fats. Reactions with ammonia and alkali metals originating from body fluids and pore waters of the depositional environment produce alkali salts of FA (soap). Adipocere formation is generally associated with burial of corpses with ample adipose tissue available. No indications that adipocere can form on defleshed remains have been presented in the literature. At the termination of a long-term bone diagenesis experiment, several samples were found to possess growths of an unknown compound. Gas chromatography-mass spectrometry confirmed that the growths are adipocere. The results herein reveal that adipocere can indeed form on defleshed bones under the right conditions and that even residual adipose and lipids in defleshed bones are sufficient to produce adipocere growth on the surfaces of bone. PMID- 22211840 TI - AMPA receptor modulation by cornichon-2 dictated by transmembrane AMPA receptor regulatory protein isoform. AB - Transmembrane AMPA receptor regulatory proteins (TARPs) are auxiliary subunits that modulate AMPA receptor trafficking, gating and pharmacology throughout the brain. Why cornichon-2 (CNIH-2), another AMPA receptor-associated protein, modulates AMPA receptor gating and pharmacology in hippocampal neurons but not cerebellar granule neurons remains unresolved. Here, we report that CNIH-2 differentially impacts Type-Ia (gamma-2 or gamma-3) vs. Type-Ib (gamma-4 or gamma 8) TARP-containing AMPA receptors. Specifically, with AMPA receptors comprising gamma-2, the cerebellar-enriched TARP isoform, CNIH-2 decreases I(KA) /I(Glu) ratio and decreases cyclothiazide efficacy while having minimal impact on recovery from desensitization and deactivation kinetics. By contrast, with AMPA receptors comprising gamma-8, the hippocampal-enriched TARP isoform, we find that CNIH-2 slows deactivation kinetics, increases cyclothiazide potency and occludes a novel AMPA receptor kinetic phenomenon, namely resensitization. Additionally, we find that CNIH-2 differentially modulates the glutamate off-kinetics of gamma 8-containing, but not gamma-2-containing, AMPA receptors in a manner dependent upon the duration of agonist application. Together, these data demonstrate that the modulation of AMPA receptors by CNIH-2 depends upon the TARP isoform composition within the receptor complex. PMID- 22211842 TI - Transforming growth factor-beta/Smad signalling in diabetic nephropathy. AB - Diabetic nephropathy (DN) is a major diabetic complication that is mediated by transforming growth factor (TGF)-beta1 via Smad-dependent and -independent signalling pathways. Under diabetic conditions, many profibrotic factors, such as advanced glycation end-products and angiotensin II, can also activate the Smad signalling pathway via the extracellular signal-regulated kinase/p38 mitogen activated protein kinase-Smad signalling cross-talk pathway. Thus, Smads act as signal integrators and interact with other signalling pathways to mediate DN. In the context of renal fibrosis, Smad3 is pathogenic, but Smad2 is protective. Deletion of Smad3 inhibits, whereas disruption of Smad2 upregulates, connective tissue growth factor and vascular endothelial growth factor expression and promotes both epithelial-myofibroblast and endothelial-myofibroblast transition. Smad7 plays a protective role in DN because deletion of Smad7 enhances, whereas overexpression of Smad7 inhibits, Smad3-mediated renal fibrosis and nuclear factor-kappaB-driven renal inflammation. Transforming growth factor-beta1 activates Smad3 to regulate microRNAs that mediate renal fibrosis. Of these, miR 21 and miR-192 are upregulated, whereas the miR-29 and miR-200 families are downregulated. Targeting downstream TGF-beta/Smad signalling by overexpressing Smad7- or Smad3-dependent microRNA related to fibrosis may represent a novel and effective strategy for the treatment of DN. PMID- 22211843 TI - Single nucleotide polymorphism and FMR1 CGG repeat instability in two Basque valleys. AB - Fragile X Syndrome (FXS, MIM 309550) is mainly due to the expansion of a CGG trinucleotide repeat sequence, found in the 5' untranslated region of the FMR1 gene. Some studies suggest that stable markers, such as single nucleotide polymorphisms (SNPs) and the study of populations with genetic identity, could provide a distinct advance to investigate the origin of CGG repeat instability. In this study, seven SNPs (WEX28 rs17312728:G>T, WEX70 rs45631657:C>T, WEX1 rs10521868:A>C, ATL1 rs4949:A>G, FMRb rs25707:A>G, WEX17 rs12010481:C>T and WEX10 ss71651741:C>T) have been analyzed in two Basque valleys (Markina and Arratia). We examined the association between these SNPs and the CGG repeat size, the AGG interruption pattern and two microsatellite markers (FRAXAC1 and DXS548). The results suggest that in both valleys WEX28-T, WEX70-C, WEX1-C, ATL1-G, and WEX10 C are preferably associated with cis-acting sequences directly influencing instability. But comparison of the two valleys reveals also important differences with respect to: (1) frequency and structure of "susceptible" alleles and (2) association between "susceptible" alleles and STR and SNP haplotypes. These results may indicate that, in Arratia, SNP status does not identify a pool of susceptible alleles, as it does in Markina. In Arratia valley, the SNP haplotype association reveals also a potential new "protective" factor. PMID- 22211844 TI - Markers of systemic inflammation in children with hyperuricemia. AB - AIM: The purpose of the study was to investigate serum concentrations of the monocyte chemoattractant protein-1 (MCP-1) and high-sensitivity CRP (hs-CRP) in children with hyperuricemia and to evaluate its association with obesity. PATIENTS AND METHODS: The study involved 52 hyperuricemic patients with mean age of 15.53 +/- 1.7 years. Twenty-seven healthy individuals with normal serum uric acid (SUA) level were selected as the control group (C). Serum MCP-1 and hs-CRP were measured by enzyme-linked immunosorbent assay (ELISA) and immunonephelometry, respectively. RESULTS: Hyperuricemic patients showed increased sMCP-1 (median: 69.58 pg/mL) and hs-CRP (median: 0.53 mg/L) vs. controls (48.39 pg/mL, 0.24 mg/L; respectively) (p < 0.01). The obese children also presented significantly higher levels of sMCP-1 and hs-CRP (median, 81.69 and 1.18 mg/L, respectively) in comparison with nonobese (median, 59.62 and 0.41 mg/L, respectively; p < 0.01). Only hs-CRP correlated positively with body mass index Z-score (r = 0.33, p < 0.05). Receiver operator characteristic analyses checking the sensitivity and specificity of examined markers for hyperuricemia revealed the higher area under the curve (AUC) for sMCP-1; however, the difference between AUC for sMCP-1 and for hs-CRP was not significant (p > 0.05). CONCLUSION: Serum MCP-1 and hs-CRP are elevated in hyperuricemic patients, but the role of obesity in inflammation markers needs further investigation. PMID- 22211845 TI - Meta-analysis: the diagnostic accuracy of lactose breath hydrogen or lactose tolerance tests for predicting the North European lactase polymorphism C/T-13910. AB - BACKGROUND: The diagnostic accuracy of two indirect tests of lactose digestion, lactose breath hydrogen and lactose tolerance tests, have not been systematically reviewed for comparison with available publications on genotype. AIM: To perform a meta-analysis of available studies that compares the north-European genetic polymorphism C/T-13910 with the lactose breath hydrogen and the lactose tolerance tests, to determine their ability to predict geno/phenotype relationships. We examine the effects of lactose loading dose, inclusion of children and latitudes of study centre on comparative outcome. METHODS: An electronic database of the literature as well as individual references in articles were searched with the theme of genetics of lactase and comparisons with breath or lactose tolerance tests were carried out. Random effect and fixed effect models were used for breath and lactose tolerance tests respectively, to report summary accuracy measures with 95% confidence intervals (CI). RESULTS: The search revealed 19 studies: 17 evaluated breath hydrogen, five lactose tolerance test (3/17 overlapped). Overall sensitivity was 0.88 (CI, 0.85-0.90), specificity was 0.85 (CI, 0.82-0.87) for breath test. Heterogeneity was explored by adjusting for studies including children, high or low dose lactose and to some extent by site of study. The lactose tolerance test showed sensitivity of 0.94 (0.9-0.97) and specificity of 0.90 (0.84-0.95) with a nonsignificant heterogeneity. CONCLUSION: The diagnostic accuracy of both tests individually reflects expected geno/phenotypes when the populations are well defined. PMID- 22211847 TI - Aarskog-Scott syndrome: first report of a duplication in the FGD1 gene. PMID- 22211848 TI - Prevalence of late-onset hypogonadism in men with type 2 diabetes mellitus. AB - Late-onset hypogonadism (LOH) or age-associated testosterone deficiency syndrome is defined as a clinical and biochemical syndrome associated with advancing age and characterised by symptoms and a deficiency in serum testosterone levels. This condition may result in significant detriment in the quality of life and adversely affect the function of multiple organ systems. It has been suggested that sex steroid hormones may play a causal role in the development of insulin resistance and type II diabetes. This comparative study was aimed at determining the prevalence of LOH in diabetic men with erectile dysfunction and investigating the effect of testosterone replacement therapy on erectile function and on glycaemic control. PMID- 22211846 TI - Keratinocyte stem cells and the targets for nonmelanoma skin cancer. AB - The mammalian skin is a complex dynamic organ composed of thin multilayered epidermis and a thick underlying connective tissue layer dermis. The epidermis undergoes continuous renewal throughout life. The stems cells uniquely express particular surface markers utilized for their identification, isolation and localization in specific niches in epidermis as well as hair follicles (HFs). The two stage skin carcinogenesis model involves stepwise accumulation of genetic alterations and ultimately leading to malignancy. Whereas early research on skin carcinogenesis focused on the molecular nature of carcinogens and tumor promoters, more recent studies have focused on the identification of the target cells and tumor promoting cells for both chemical and physical carcinogens and promoters. Recent studies support the hypothesis that keratinocyte stem cells are the targets in skin carcinogenesis. In this review, we discuss briefly the localization of stem cells in the epidermis and HFs, and review the possibility that skin papillomas and carcinomas are derived from stem cells, as well as from other cells in the cutaneous epithelium whose stem cell properties are not well known. PMID- 22211849 TI - An essay on sexual frustration as the cause of breast cancer in women: how correlations and cultural blind spots conceal causal effects. AB - The main premise of this hypothesis is that breast cancer is caused by sexual frustration. Sexual frustration is triggered by multiple forms of dissonance between the absence or lack of sexual reward and the (un)conscious motivation to obtain these sexual rewards. I assume that neural and hormonal processes are capable of adjusting or distorting biologically active forms of specific sex hormones depending on experienced sexual stimuli. I hypothesize that prolonged sexual frustration will ultimately lead via aberrantly metabolized sex hormones to the development of breast cancer. Human female sexual behavior research links sexual frustration with breast cancer risk. The distinction between human female sexual behavior and reproduction is crucial to understand breast cancer risk. Current explanations are focused on reproduction. However, human female sexual behavior is causal in breast cancer development and androgens rather than estrogens are crucial for sexual behaviors in women. Social learning is the main determinant of human sexual behaviors that is why cultural and social processes are very important to understand breast cancer risk. Epidemiologists should evaluate breast cancer risk based on cultural female attitudes towards sexually related issues. Female mate choices should be examined for (un)conscious cultural, ethnic, religious, and socio-economic pressure to make a thorough assessment of breast cancer risk. Closer examination of (un)conscious female copulation strategies reveal that they are potential sources of sexual frustration in specific groups of women. Postmenopausal women seem vulnerable for self-fulfilling prophecies about post reproductive sexuality, body image, and negative perceptions of menopause which may cause sexual frustrations. PMID- 22211851 TI - Apparent homozygosity for p.E1841K mutation in a patient with MYH9-related disorder: a misdiagnosis for an autosomal dominant disorder? PMID- 22211850 TI - Development of an updated phytoestrogen database for use with the SWAN food frequency questionnaire: intakes and food sources in a community-based, multiethnic cohort study. AB - Phytoestrogens, heterocyclic phenols found in plants, may benefit several health outcomes. However, epidemiologic studies of the health effects of dietary phytoestrogens have yielded mixed results, in part due to challenges inherent in estimating dietary intakes. The goal of this study was to improve the estimates of dietary phytoestrogen consumption using a modified Block Food Frequency Questionnaire (FFQ), a 137-item FFQ created for the Study of Women's Health Across the Nation (SWAN) in 1994. To expand the database of sources from which phytonutrient intakes were computed, we conducted a comprehensive PubMed/Medline search covering January 1994 through September 2008. The expanded database included 4 isoflavones, coumestrol, and 4 lignans. The new database estimated isoflavone content of 105 food items (76.6%) vs. 14 (10.2%) in the 1994 version and computed coumestrol content of 52 food items (38.0%), compared to 1 (0.7%) in the original version. Newly added were lignans; values for 104 FFQ food items (75.9%) were calculated. In addition, we report here the phytonutrient intakes for each racial and language group in the SWAN sample and present major food sources from which the phytonutrients came. This enhanced ascertainment of phytoestrogens will permit improved studies of their health effects. PMID- 22211853 TI - Imaging of subacute blood-brain barrier disruption after methadone overdose. AB - BACKGROUND: Methadone intoxication can cause respiratory depression, leading to hypoxia with subsequent coma and death. Delayed postanoxic leukoencephalopathy (DAL) has been reported with intoxication by carbon monoxide, narcotics, and other toxins. OBJECTIVE: To investigate the metabolic derangement of the white matter (WM) and blood-brain barrier (BBB) after DAL caused by methadone overdose. DESIGN, SETTING, AND PATIENTS: Case report of 2 patients with DAL after a single dose of "diverted" methadone used for pain control. RESULTS: In both cases brain magnetic resonance imaging (MRI) revealed initial extensive bilateral restricted diffusion lesions within the WM. Follow-up MRI using proton magnetic resonance spectroscopic imaging ((1) H-MRSI) showed markedly lower N-acetylaspartate and higher choline within the WM. BBB permeability, calculated by Patlak graphical analysis of MRI T1 data obtained after contrast agent injection, showed disruption of the BBB within the WM lesions, which persisted longer than a year in 1 patient. Neuropsychological evaluation showed executive dysfunction in both patients. After 1 year, one patient recovered whereas the second remained impaired. CONCLUSIONS: Methadone overdose can cause DAL with profound disturbances of neural metabolism and the BBB. The time course of these disturbances can be monitored with MR methods. PMID- 22211854 TI - Key factors in paediatric organ and tissue donation: an overview of literature in a chronological working model. AB - There is a growing shortage of size-matched organs and tissues for children. Although examples of substandard care are reported in the literature, there is no overview of the paediatric donation process. The aim of the study is to gain insight into the chain of events, practices and procedures in paediatric donation. Method; a survey of the 1990-2010 literature on paediatric organ and tissue donation and categorization into a coherent chronological working model of key events and procedures. Studies on paediatric donation are rare. Twelve empirical studies were found, without any level I or level II-1 evidence. Seventy five per cent of the studies describe the situation in the United States. Literature suggests that the identification of potential donors and the way in which parental consent is requested may be substandard. We found no literature discussing best practices. Notwithstanding the importance of looking at donation care as an integrated process, most studies discuss only a few isolated topics or sub-processes. To improve paediatric donation, more research is required on substandard factors and their interactions. A chronological working model, as presented here, starting with the identification of potential donors and ending with aftercare, could serve as a practical tool to optimize paediatric donation. PMID- 22211855 TI - Patients with diabetes are not more likely to have atypical symptoms when seeking care of a first myocardial infarction. An analysis of 4028 patients in the Northern Sweden MONICA Study. AB - AIM: To describe symptoms of a first myocardial infarction in men and women with and without diabetes. METHODS: We conducted a population-based study of 4028 people aged 25-74 years, with first myocardial infarction registered in the Northern Sweden Multinational MONItoring of trends and determinants in CArdiovascular disease (MONICA) myocardial infarction registry between 2000 and 2006. Symptoms were classified as typical or atypical according to the World Health Organization MONICA manual. RESULTS: Among patients with diabetes, 90.1% reported typical symptoms of myocardial infarction; the corresponding proportion among patients without diabetes was 91.5%. In the diabetes group, 88.8% of women and 90.8% of men had typical symptoms of myocardial infarction. No differences were found in symptoms of myocardial infarction between women with and without diabetes or between men with and without diabetes. Atypical symptoms were more prevalent in the older age groups (> 65 years) than in the younger age groups (< 65 years). The increases were approximately equal among men and women, with and without diabetes. Diabetes was not an independent predictor for having atypical symptoms of myocardial infarction. CONCLUSIONS: Typical symptoms of myocardial infarction were equally prevalent in patients with and without diabetes and there were no sex differences in symptoms among persons with diabetes. Diabetes was not a predictor of atypical symptoms. PMID- 22211856 TI - Bone age assessment: the applicability of the Greulich-Pyle method in eastern Turkish children. AB - The aim of this study was to investigate whether or not the Greulich-Pyle (GP) method is adequate for Turkish children. A group of 767 individuals (425 girls and 342 boys) between 7 and 17 years were studied. Bone age (BA) from plain radiographs of left hands and wrists by GP standards was estimated. The total mean differences between BA and chronological age (CA) for girls and boys were found to be 0.20 and -0.13 years, respectively. There were significant differences between BA and CA in age groups 7-, 8-, 10-, 11-, 12-, 13-, 15-, and 16-year-olds for girls and 7-, 10-, and 12-year-olds for boys. The results of this study suggest that the mean differences between BA and CA are low enough to be of no practical significance, and thus, for the time being unless any other methods will be proved more useful, this method could be used in all age groups. PMID- 22211858 TI - Chromobacterium violaceum infections in 13 non-human primates. AB - BACKGROUND: Recently, an Indian-origin macaque was found dead and Chromobacterium violaceum was isolated from the skin wound, and hepatic and pulmonary abscesses. METHODS: By searching the database, a total of thirteen cases of C. violaceum infection in pigtail macaques (n = 8), rhesus macaques (n = 4), and one baboon were identified from 2001 to 2010 at Tulane National Primate Research Center. Medical records were reviewed for breed, sex, age, clinical findings, treatment, outcome, bacteriology, and gross and histological findings. RESULTS: Seven pigtail macaques and one Indian-origin rhesus macaque died of chromobacterial septicemia. All chromobacterial septicemic pigtail macaques were adult with higher incidence in female. Hepatic abscess and thrombosis were typical findings along with pulmonary abscess and thrombosis, renal venous thromboembolism, and necrosuppurative pleuritis, peritonitis, splenitis, myocarditis, pericarditis, and meningoencephalitis. Skin wound, uterine infection, and oral and respiratory exposure were considered the points of entry for these animals. CONCLUSIONS: This represents the first report of chromobacteriosis in pigtail, rhesus macaque, and baboon. Our experience suggests that chromobacterial infections may be more common in non-human primates than previously recognized. PMID- 22211860 TI - Survey on the management of skin toxicity associated with EGFR inhibitors amongst French physicians. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are part of the therapeutic arsenal available for advanced cancer. However, they are frequently associated with cutaneous side-effects, which can hamper compliance, lead to treatment refusal and impair quality of life. OBJECTIVE: To know the attitudes of French oncologists who deal with this skin toxicity. This work is one of the steps to build a therapeutic algorithm of side-effects induced by EGFR inhibitors taking both evidence-based medicine and standard practices into account. METHODS: Physicians completed a questionnaire as part of regional meetings, before any discussion. Questions concerned the management of 11 clinical situations in the context of EGFR inhibitor prescription. RESULTS: Sixty-seven questionnaires were analysed. The collaboration with dermatologists was especially planned for persisting or worsening lesions beyond 2 weeks, but never considered at the time of the introduction of targeted therapy. The results demonstrated the difficulties encountered in diagnosing and grading skin lesions. Attitudes of oncologists were uniform for preventive care and management of mild lesions for which moisturizing and cyclines were widely prescribed. Significant differences appeared in the treatment of less typical cases such as the involvement of skin appendages, secondary infections of folliculitis or cases associated with radiodermatitis. Discrepancies existed also for what to do in relation with maintenance or interruption of EGFR inhibitor mainly if they were responsible for severe lesions. CONCLUSION: This original survey emphasizes the interest of greater multidisciplinary collaboration and the necessity to harmonize practice. PMID- 22211861 TI - Nano-indentation testing of new and fractured nickel-titanium endodontic instruments. AB - AIM: To investigate the effect of cyclic fatigue on nickel-titanium (NiTi) endodontic instruments using a nano-indentation test. METHODOLOGY: Eight ProFile NiTi rotary instruments (size 30, taper 0.06; Dentsply Maillefer, Ballaigues, Switzerland) were tested using a cyclic fatigue set-up until fracture. The fractured instruments and eight new NiTi instruments of the same size and taper were used for a nano-indentation test on the internal surfaces of a NiTi instruments in the region just adjacent to their fractured edge (group I) and in the same region of the new group (group II), and the cutting part beside the shaft for both instruments [group III (fractured) and group IV (new)]. Data were statistically analyzed using one-way analysis of variance and Games-Howell post hoc test. The alpha-type error was set at 0.05. RESULTS: Significant differences in terms of hardness and elastic modulus for each group (P < 0.05) were found, with group I having the lowest mean values followed by group III. Additionally, standard deviations increased remarkably after failure, as represented by groups I and III. CONCLUSION: The nano-indentation technique can be applied to determine the performance and the failure mechanism of NiTi instruments. The fatigue process revealed a significant decrease in the hardness and elastic modulus of the NiTi instrument. As indicated by the low hardness, the fatigue process did not result in work hardening but rather work softening. PMID- 22211862 TI - The nurses' role in the prevention of Solanum infection: dealing with a zombie epidemic. AB - AIMS: To outline the background and nursing interventions for Solanum infection in the event of a zombie epidemic. BACKGROUND: Literature and feature film evidence supports the theoretical probability for an outbreak of a Solanum infection which could result in a zombie epidemic. This paper discusses the causative agent, history of zombiism, signs and symptoms, diagnosis and nursing interventions. DESIGN: Review. METHODS: Academic and general literature and web sites were searched up to February 2011 for the key words, 'zombie', 'zombie nurses', 'zombie epidemic' and 'zombie nursing interventions'. Limited academic literature was sourced pointing to a serious knowledge deficit in this area. RESULTS: If nurses are to respond successfully to a potential Solanum epidemic they need to be prepared and able to recognise Solanum infection, prevent its spread and care appropriately for sufferers and victims of a zombie attack. Advice is offered on prevention, initial nursing management and secondary nursing interventions including dealing with reanimation, palliative care and psychological support. CONCLUSION: History offers numerous examples of the sudden appearance of a serious disease that has impacted on man kind's survival. While difficult to conceive, a zombie epidemic is theoretically possible and nurses have a responsibility to be as prepared as possible to support and care for victims. RELEVANCE TO CLINICAL PRACTICE: Nurses are likely to be the front line staff faced with initiating most primary and secondary care interventions, including isolation and infection control, wound care, pain relief, documentation observations, support for activities of daily living, nutrition and fluid support, medication administration and other interventions. PMID- 22211863 TI - Isolated leptomeningeal infiltration of a primary CNS B-cell lymphoma diagnosed by flow cytometry and confirmed by necropsy. AB - BACKGROUND: The diagnosis of the isolated leptomeningeal involvement of a primary central nervous system B-cell lymphoma without parenchyma lesions may be difficult. Patients with leptomeningeal meningeosis lymphomatosa can present with various neurologic deficits. AIMS OF THE STUDY: To demonstrate the impact of cerebrospinal fluid (CSF) flow cytometry in the diagnosis of an isolated leptomeningeal manifestation of B-cell lymphoma by presenting an interesting case report. METHODS: Flow cytometric analysis of B-cell monoclonality of the CSF was performed as complementary diagnostic procedure in addition to CSF cytology. Final diagnosis was confirmed by necropsy. RESULTS: We suspected isolated leptomeningeal manifestation of B-cell lymphoma with palsy of the VI and VII cranial nerves in a 79-year-old male, because of mononuclear pleocytosis in CSF. Interestingly, the decisive diagnostic hint was given by implementation of flow cytometry of the CSF. Diagnosis was confirmed by postmortem autopsy. CONCLUSION: Our case shows that flow cytometry of the CSF in addition to conventional CSF cytology has the potential to accelerate diagnosis of lymphomeningeal infiltration of B-cell lymphoma. PMID- 22211864 TI - A rapid wire-based sampling method for DNA profiling. AB - This paper reports the results of a commission to develop a field deployable rapid short tandem repeat (STR)-based DNA profiling system to enable discrimination between tissues derived from a small number of individuals. Speed was achieved by truncation of sample preparation and field deployability by use of an Agilent 2100 Bioanalyser(TM). Human blood and tissues were stabbed with heated stainless steel wire and the resulting sample dehydrated with isopropanol prior to direct addition to a PCR. Choice of a polymerase tolerant of tissue residues and cycles of amplification appropriate for the amount of template expected yielded useful profiles with a custom-designed quintuplex primer set suitable for use with the Bioanalyser(TM). Samples stored on wires remained amplifiable for months, allowing their transportation unrefrigerated from remote locations to a laboratory for analysis using AmpFlSTR((r)) Profiler Plus((r)) without further processing. The field system meets the requirements for discrimination of samples from small sets and retains access to full STR profiling when required. PMID- 22211865 TI - Striatal NTS1 , dopamine D2 and NMDA receptor regulation of pallidal GABA and glutamate release--a dual-probe microdialysis study in the intranigral 6 hydroxydopamine unilaterally lesioned rat. AB - The current microdialysis study elucidates a functional interaction between the striatal neurotensin NTS(1) receptor and the striatal dopamine D(2) and N-methyl d-aspartic acid (NMDA) receptors in the regulation of striatopallidal gamma aminobutyric acid (GABA) and glutamate levels after an ipsilateral intranigral 6 hydroxydopamine-induced lesion of the ascending dopamine pathways to the striatum. Lateral globus pallidus GABA levels were higher in the lesioned group while no change was observed in striatal GABA and glutamate levels. The 6 hydroxydopamine-induced lesion did not alter the ability of intrastriatal NT (10 nm) to counteract the decrease in pallidal GABA and glutamate levels induced by the dopamine D(2) -like receptor agonist quinpirole (10 MUm). A more pronounced increase in the intrastriatal NMDA- (10 MUm) induced increase in pallidal GABA levels was observed in the lesioned group while it attenuated the increase in striatal glutamate levels and amplified the increase in pallidal glutamate levels compared with that observed in the controls. NT enhanced the NMDA-induced increase in pallidal GABA and glutamate and striatal glutamate levels; these effects were counteracted by the NTS(1) antagonist SR48692 (100 nm) in both groups. These findings demonstrate an inhibitory striatal dopamine D(2) and an excitatory striatal NMDA receptor regulation of striatopallidal GABA transmission in both groups. These actions are modulated by NT via antagonistic NTS(1) /D(2) and facilitatory NTS(1) /NMDA receptor-receptor interactions, leading to enhanced glutamate drive of the striatopallidal GABA neurons associated with motor inhibition, effects which all are counteracted by SR48692. Thus, NTS(1) antagonists in combination with conventional treatments may provide a novel therapeutic strategy in Parkinson's disease. PMID- 22211867 TI - Does topical lidocaine before tracheal intubation attenuate airway responses in children? An observational audit. AB - BACKGROUND: The use of topical lidocaine, applied to the airways with various administration techniques, is common practice in pediatric anesthesia in many institutions. However, it remains unclear whether these practices achieve their intended goal of reducing the risk of perioperative respiratory adverse events (PRAE) in children undergoing elective endotracheal intubation without neuromuscular blockade (NMB). The relative frequency of PRAE (laryngospasm, coughing, desaturation <95%) associated with no use of topical airway lidocaine (TAL), with TAL sprayed directly onto the vocal cords, and TAL administered blindly into the pharynx was assessed. METHODS: This prospective audit involved 1000 patients undergoing general anesthesia with elective endotracheal intubation without NMB. Patients with suspected difficult airways or undergoing airway surgery were excluded. The use of TAL and the mode of administration were recorded. Respiratory adverse events were recorded in the perioperative period. RESULTS: Two hundred and fifty-four patients had the vocal cords sprayed under direct vision, 236 had lidocaine blindly dripped into the pharynx, and 510 received no TAL. The mean age and known risk factors for PRAE (asthma, recent upper respiratory tract infection (<=2 weeks), passive smoking, hayfever, past or present eczema, nocturnal dry cough) were similar among the groups. The proportion of patients with desaturation (<95%) between induction of anesthesia and discharge from the recovery room was higher in the two groups who received TAL (data combined for all patients receiving lidocaine regardless of administration method, P = 0.01) compared to those who received no TAL. No difference in the rates of laryngospasm (P = 0.13) or cough (P = 0.07) was observed among the groups. There was no difference in the rates of PRAE between the groups given TAL directly onto the vocal cords and in those whom received TAL blindly. CONCLUSIONS: The incidence of desaturation was higher in patients receiving TAL compared with children who did not. This association should perhaps be considered when contemplating the use of this technique. PMID- 22211869 TI - Functional polymorphisms in FAS, FASL and CASP8 genes and risk of childhood acute lymphoblastic leukemia: a case-control study. AB - Genetic polymorphisms in the promoter regions of FAS, FASL and CASP8 involved in the apoptotic signaling pathway are thought to be associated with susceptibility to cancer. We hypothesized that these functional genetic variants might be associated with the risk of childhood acute lymphoblastic leukemia (ALL). A case control study in a Chinese population with 361 cases of ALL and 519 controls was performed to evaluate the association between FAS, FASL and CASP8 variants and risk of childhood ALL. Individuals with FAS - 1377AG had an odds ratio (OR) of 0.72 for the risk of ALL compared to - 1377GG and the variant FASL - 844CC was associated with a statistically significantly decreased risk of childhood ALL (OR = 0.38). Furthermore, combined genotypes with 5-8 protective alleles were associated with a significantly decreased risk of childhood ALL compared with those with 0-4 variants, and this decreased risk was more pronounced among the subgroups of age < 6 years, female, parental never-drinking status and never house-painting. Our results provide evidence that FAS-FASL-CASP8 polymorphisms contributed to a reduced risk of childhood ALL in our population. Larger studies are warranted to validate our findings. PMID- 22211870 TI - Rescue therapy for acute migraine, part 1: triptans, dihydroergotamine, and magnesium. AB - OBJECTIVE: To review and analyze published reports on the acute treatment of migraine headache with triptans, dihydroergotamine (DHE), and magnesium in emergency department, urgent care, and headache clinic settings. METHODS: MEDLINE was searched using the terms "migraine" and "emergency," and "therapy" or "treatment." Reports from emergency department and urgent care settings that involved all routes of medication delivery were included. Reports from headache clinic settings were included only if medications were delivered by a parenteral route. RESULTS: Acute rescue treatment studies involving the triptans were available for injectable and nasal sumatriptan, as well as rizatriptan. Effectiveness varied widely, even when the pain-free and pain-relief statistics were evaluated separately. As these medications are known to work best early in the migraine, part of this variability may be attributed to the timing of triptan administration. Multiple studies compared triptans with anti-emetics, dopamine antagonists, and non-steroidal anti-inflammatory drugs. The overall percentage of patients with pain relief after taking sumatriptan was roughly equivalent to that recorded with droperidol and prochlorperazine. Sumatriptan was equivalent to DHE when only paired comparisons were performed. While the data extracted suggest that magnesium may be effective in treating all symptoms in patients experiencing migraine with aura across all migraine patients, its effectiveness seems to be limited to treating only photophobia and phonophobia. CONCLUSIONS: Although there are relatively few studies involving health-care provider-administered triptans or DHE for acute rescue, they appear to be equivalent to the dopamine antagonists for migraine pain relief. The relatively rare inclusion of a placebo arm and the frequent use of combination medications in active treatment arms complicate the comparison of single agents with each other. PMID- 22211872 TI - Low-dose celecoxib improves coronary function after acute myocardial ischaemia in rabbits. AB - The role of celecoxib in cardiovascular events remains contentious. The aim of the present study was to investigate the effects of celecoxib in acute myocardial ischaemia (AMI) in rabbits in comparison with those of another non-steroidal anti inflammatory drug, namely aspirin. Male New Zealand white rabbits were divided into four groups: (i) a sham-operated group; (ii) an AMI group, in which the left anterior descending coronary arteries were occluded for 60 min; (iii) the celecoxib + AMI group, pretreated with 3 mg/kg celecoxib, twice a day, for 3 days before AMI induction; and (iv) the aspirin + AMI group, pretreated with 12.5 mg/kg aspirin, twice a day, for 3 days before AMI induction. Haemodynamic parameters were monitored using a multichannel physiological recorder. Serum levels of creatine kinase (CK), malondialdehyde (MDA), cyclo-oxygenase-2 (COX-2), tumour necrosis factor (TNF)-alpha, total nitrate/nitrite (NO(x) ), nitric oxide synthase (NOS) and myocardial infarct size were determined. Changes in isometric tension of isolated coronary rings were recorded by a myograph system. Compared with the sham group, the AMI group had lower blood pressure, higher left ventricular (LV) end-diastolic pressure, depressed maximum dP/dt of LV pressure, a larger infarct size and higher CK and MDA levels. Celecoxib, but not aspirin, pretreatment significantly ameliorated these effects of AMI. Celecoxib reversed AMI-induced increases in COX-2 levels to a similar extent as aspirin. Pretreatment with celecoxib resulted in a significant reduction in TNF-alpha levels and an increase in NO(x) and NOS levels compared with the AMI group. The dysfunctional vasoconstriction and vasodilation of coronary arteries were ameliorated by celecoxib administration. 4. In conclusion, the experimental evidence suggests that celecoxib exerts its protective effects in a COX independent manner. PMID- 22211873 TI - Skin and rectal temperature in newborns. PMID- 22211874 TI - Morphofunctional evaluation of the testicle and the spermatogenic process of adult white-eyed parakeets (Aratinga leucophthalma MULLER, 1776) during the different seasons of the year. AB - In this experiment, testicle fragments of 14 adult White-eyed Parakeets (Aratinga leucophthalma) were evaluated as for their seasonal reproductive activities using the following quantitative parameters: average thickness of the testicular tunica albuginea, volumetric proportion of tubular and extratubular compartments, average diameter of the seminiferous tubules and corporal weight. Parameters were created for qualitative evaluations of the degree of spermatogenic development. In this experiment, all the animals were distributed into four groups, and their testicular fragments were collected during the middle of summer, fall, winter and spring. The animals were submitted to volatile general anaesthesia, and a biopsy was made by celioscopy. The fragments collected were processed histologically. The slides were prepared and later evaluated by using an optical microscope. The average seasonal values of the corporal weight increased, starting in the winter and reaching the peak during the spring. A seasonal testicle cycle was observed, because, in the spring, the testicles showed values for the quantitative and qualitative parameters of spermatic production compatible with the period of greater activity, while the opposite thing happened during the fall. Our data indicate that the parameters of sperm production may be correlated with daily light rather than with air humidity. PMID- 22211875 TI - Effect of aracnotoxin from Latrodectus mactans on bovine sperm function: modulatory action of bovine oviduct cells and their secretions. AB - Latrodectus mactans' aracnotoxin (Atx) induces changes in sperm function that could be used as a co-adjuvant in male contraceptive barrier methods. This effect includes the suppression of intracellular reactive oxygen species (ROS), an event necessary for capacitation, chemotaxis and acrosome reaction (AR). The sperm that are not trapped by the barrier method can reach the oviduct before fertilisation and be exposed to the secretions of the oviducts. This study evaluated the effect of bovine tubal explants (TU) and conditioned media (CM) from the ampullar and isthmal regions on spermatozoa exposed to Atx. Thawed bovine sperm were incubated with Atx, TU and CM from the ampullar and isthmal regions for 4 h and then DNA integrity, intracellular ROS and lysophosphatidylcholine-induced AR were determined. Spermatozoa exposed to Atx and co-incubated with TU and CM for 4 h produced an increase in sperm DNA damage, a decrease in ROS production and a decrease in %AR, compared with the control. A similar result was obtained from the co-incubation of spermatozoa with Atx. In conclusion, the effect of Atx is not modified by tubal cells or their secretions and this opens the door to future studies to evaluate the application of synthetic peptides obtained from Atx as a co-adjuvant of contraceptive barrier methods. PMID- 22211876 TI - Intracranial abscess as a complication of allergic fungal sinusitis. AB - BACKGROUND AND PURPOSE: This case involves a common disease, allergic fungal sinusitis (AFS), with the uncommon complication of intracranial abscess. Although AFS is known to result in bone erosion, invasive complications are rare. METHODS: The clinical and pathologic information were reviewed. A literature review was performed to clarify the clinical, radiologic, and pathologic features of AFS. RESULTS: The clinical and radiographic presentations were typical for AFS, including the relatively common complication of sinus wall erosion. Follow-up imaging demonstrated spread of fungal disease into the adjacent masticator space and intracranial spread by foramen ovale. CONCLUSION: This case illustrates the importance of identifying AFS and describing findings such as sinus erosion that may alter management. In this example, knowledge of the altered anatomy and potential for mucosal injury may facilitate surgical planning and decrease the likelihood of future complications. PMID- 22211877 TI - Antimetastatic effects and mechanisms of apo-8'-lycopenal, an enzymatic metabolite of lycopene, against human hepatocarcinoma SK-Hep-1 cells. AB - Lycopene is primarily metabolized by carotenoid monoxygenase II into apo-8'- and apo-12'-lycopenal in the rat liver. Although lycopene possesses antimetastatic activity in a highly invasive hepatoma SK-Hep-1 cell line, little is known whether its metabolites have a similar effect. In this study, we investigated the antimetastatic effects of apo-8'-lycopenal (1-10 MUM) in comparison with lycopene (10 MUM) in SK-Hep-1 cells. We found that both apo-8'-lycopenal and lycopene inhibited the invasion and migration of SK-Hep-1 cells, and the effect of apo-8' lycopenal was stronger than that of lycopene at the same concentration (10 MUM). Mechanistically, apo-8'-lycopenal: 1) decreased the activities and protein expression of metalloproteinase-2 (MMP-2) and -9; 2) increased the protein expression of nm23-H1 and the tissue inhibitor of MMP (TIMP)-1 and -2; 3) suppressed protein expression of Rho small GTPases; and 4) inhibited focal adhesion kinase-mediated signaling pathway, such as ERK/p38 and PI3K-Akt axis. Overall, these results demonstrate that apo-8'-lycopenal possesses antimetastatic activity in SK-Hep-1 cells and that this effect is stronger than that of lycopene, suggesting that the antimetastatic effect may be attributed, at least in part, to its metabolites such as apo-8'-lycopenal. PMID- 22211878 TI - Is duct excision still necessary for all cases of suspicious nipple discharge? AB - Despite the low likelihood of malignancy, it is recommended that all women with pathologic nipple discharge undergo duct excision based on the inadequate sensitivity of diagnostic modalities. However, these data originates prior to recent improvements in breast imaging. We performed a retrospective review of patients evaluated in the setting of modern diagnostic breast imaging. Of 175 women referred to our breast clinic with a primary complaint of nipple discharge, 142 (81%) had suspicious discharge. Of the 23 patients who opted for observation over duct excision, with a mean follow-up of 3.3 years, none have been diagnosed with cancer. Among patients who proceeded with surgery, cancer was diagnosed in seven patients (5%). Six of the seven patients had either an abnormal mammogram or ultrasound. Among 46 patients with suspicious nipple discharge, a normal physical exam and normal diagnostic mammogram/ultrasound, only one malignancy (2%) was identified in a 79-year-old patient with a personal history of breast cancer. In selected patients with suspicious nipple discharge, but normal physical exam and diagnostic imaging, short-term observation with repeat evaluation seems reasonable for patients who do not desire duct excision. PMID- 22211879 TI - Characterization of interactions between naturally mutated forms of the TIN2 protein and its known protein partners of the shelterin complex. PMID- 22211880 TI - Xanthene dyes induce membrane permeabilization of bacteria and erythrocytes by photoinactivation. AB - We analyzed the photoinactivation of the membrane functions of bacteria and erythrocytes induced by xanthene dyes. The dyes tested were rose bengal, phloxine B, erythrosine B and eosin B. These dyes induced the leakage of K(+) from Staphylococcus aureus cells within minutes of photoirradiation, in the order of rose bengal > phloxine B > erythrosine B > eosin B. The ability of dyes to inhibit respiration was weak, except for rose bengal, and the dyes dissipated the membrane potential in similar time traces with changes in K(+) permeability. The xanthene dyes also induced the leakage of K(+) from bovine erythrocytes upon photoirradiation in the same order as that observed with bacteria. Furthermore, we found that the ability to cause the leakage of K(+) from erythrocytes was associated with dye-induced morphological changes, forming a crenated form from the normal discoid. These results are discussed in connection with the ability of xanthene dyes to generate singlet oxygen and bind to bacterial cells, and further compared with the actions of cationic porphyrins, which induced photoinactivation of bacteria through respiratory inhibition. PMID- 22211881 TI - Non-invasive measures of tissue autofluorescence are increased in Type 1 diabetes complications and correlate with a non-invasive measure of vascular dysfunction. AB - OBJECTIVE: To determine if ocular and skin autofluorescence, reflecting advanced glycation end-products, and vascular stiffness correlate in non-diabetic and Type 1 diabetic subjects and if levels differ by diabetes status. RESEARCH DESIGN AND METHODS: Patients with Type 1 diabetes (n = 69, 19 with and 50 without vascular complications) and 60 subjects without diabetes (control) had ocular and skin autofluorescence and pulse-wave analysis performed in the fasted state. Correlations between measures within groups used the Pearson or Spearman correlation-coefficient and measures between groups were compared by ANOVA. RESULTS: Lens and skin autofluorescence correlated in control (r = 0.58, P = 0.0001) and in Type 1 diabetes (r = 0.53, P = 0.001). Corneal autofluorescence correlated with lens (r = 0.53, r = 0.52, P = 0.0001) and skin autofluorescence (r = 0.34, P = 0.01 and r = 0.49, P = 0.00001) in control and Type 1 diabetes respectively. In Type 1 diabetes, small and large artery elasticity correlated inversely and systemic vascular resistance correlated positively with skin autofluorescence (all P = 0.001), and with lens and corneal autofluorescence (all P < 0.03). In Type 1 diabetes tissue advanced glycation end-products correlated with C-reactive protein and inversely with the estimated glucose disposal rate and with circulating advanced glycation end-product levels. Relative to non diabetic subjects, lens, corneal and skin fluorescence were increased (all P < 0.001) and small artery elasticity was decreased in diabetes (P = 0.04). Lens, corneal and skin autofluorescence were greater (all P = 0.0001) in patients with Type 1 diabetes with complications compared to those without complications, but small artery elasticity did not differ significantly. CONCLUSIONS: Ocular and skin autofluorescence and vascular stiffness correlate in non-diabetic and Type 1 diabetes subjects and are increased in Type 1 diabetes. Tissue advanced glycation end-products correlate with vascular risk factors, including circulating advanced glycation end-products. PMID- 22211884 TI - Evaluation of long-distance dispersal of Culicoides midges into northern Australia using a migration model. AB - The introduction of novel bluetongue serotypes and genotypes into northern Australia is considered possible via the long-distance windborne dispersal of Culicoides (Diptera: Ceratopogonidae) vectors from Southeast Asia. Initial findings from simulation modelling of potential dispersal over a 15-year period revealed that the greatest risk for incursion of windborne Culicoides from the island of Timor into northern Australia occurs during December-March. The regions at greatest risk for incursion include the top end of the Northern Territory and the Kimberley region in Western Australia, but there is potential for more widespread dispersal into northern Australia based on Timor as the putative source. The establishment of a more pathogenic strain of the virus, or of a novel Culicoides vector introduced by such inter-continental dispersal events, could dramatically alter Australia's current bluetongue disease status. PMID- 22211885 TI - Transplant glomerulopathy and rapid allograft loss in the presence of HLA-Cw7 antibodies. PMID- 22211886 TI - Whole body postmortem magnetic resonance angiography. AB - Computed tomography (CT) and magnetic resonance (MR) imaging have become important elements of forensic radiology. Whereas the feasibility and potential of CT angiography have long been explored, postmortem MR angiography (PMMRA) has so far been neglected. We tested the feasibility of PMMRA on four adult human cadavers. Technical quality of PMMRA was assessed relative to postmortem CT angiography (PMCTA), separately for each body region. Intra-aortic contrast volumes were calculated on PMCTA and PMMRA with segmentation software. The results showed that technical quality of PMMRA images was equal to PMCTA in 4/4 cases for the head, the heart, and the chest, and in 3/4 cases for the abdomen, and the pelvis. There was a mean decrease in intra-aortic contrast volume from PMCTA to PMMRA of 46%. PMMRA is technically feasible and allows combining the soft tissue detail provided by MR and the information afforded by angiography. PMID- 22211887 TI - Impact of biocides on biofilm formation by methicillin-resistant Staphylococcus aureus (ST239-SCCmecIII) isolates. AB - Procedures of sterilization and disinfection are essential to ensure that medical and surgical instruments will not transmit infectious pathogens to patients. In the present paper, we tested the residual effect of these compounds on biofilm formation and its efficiency in disrupting preformed biofilms using methicillin resistant Staphylococcus aureus (MRSA) isolates of the lineage ST239-SCCmecIII. All compounds examined, except 70% alcohol, caused a significant impairment in biofilm formation with concomitant inhibition of cell growth. Among the compounds examined, 10% povidone-iodine (PVP-I) was the only antiseptic that exhibited more than 90% reduction of both biofilm formation and dispersion. In the group of sterilants and disinfectants, a formulation containing 7% hydrogen peroxide and 0.2% peracetic acid (HP-PA), and sodium hypochlorite with 1% active chlorine (NaOCl) were equally effective. PMID- 22211888 TI - Polymorphism in interleukin 1A but not in interleukin 8 gene predisposes to acne vulgaris in Polish population. PMID- 22211891 TI - Interactions between metabolism and circadian clocks: reciprocal disturbances. AB - Obesity is a medical condition of excess body fat, recognized as a global epidemic. Besides genetic factors, overconsumption of high-energy food and a sedentary lifestyle are major obesogenic causes. A newly identified determinant is altered circadian rhythmicity. To anticipate and adapt to daily changes in the environment, organisms have developed an endogenous circadian timing system, comprising a main circadian clock, located in the suprachiasmatic nucleus (SCN) of the hypothalamus, principally synchronized to the light-dark cycle. Secondary peripheral clocks are found in various tissues, such as the liver, pancreas, and adipose tissue. These clocks control the rhythmic patterns of myriad metabolic processes. We will review the evidence that metabolic dysfunction is associated with circadian disturbances at both central and peripheral levels and, conversely, that disruption of circadian clock functioning can lead to obesity. The roots of these reciprocal interactions will be illustrated by transcriptional crosstalk between metabolic and circadian systems. Chronotherapeutic approaches of dieting to maintain or restore a proper circadian alignment could be useful to limit the magnitude of metabolic risks. PMID- 22211892 TI - The role of stearoyl-CoA desaturase in obesity, insulin resistance, and inflammation. AB - Stearoyl-CoA desaturase 1 (SCD1) is an essential lipogenic enzyme that has been shown to play an intrinsic role in the development of obesity and related conditions, such as insulin resistance. Through the generation of various mouse models of SCD1 deficiency, we have come to understand that SCD1 plays a role, directly or indirectly, in diverse metabolic processes, including lipogenesis, fatty acid oxidation, insulin signaling, thermogenesis, and inflammation. This review will address recent advances in our understanding of this key regulator of cellular metabolic processes, including the role of SCD1 in maintaining skin barrier integrity and the role of skin SCD1 in the metabolic phenotype elicited by global SCD1 deficiency. PMID- 22211889 TI - Central nervous control of energy and glucose balance: focus on the central melanocortin system. AB - Studies have suggested that manipulations of the central melanocortin circuitry by pharmacological agents produce robust effects on the regulation of body weight and glucose homeostasis. In this review, we discuss recent findings from genetic mouse models that have further established the physiological relevance of this circuitry in the context of glucose and energy balance. In addition, we will discuss distinct neuronal populations that respond to central melanocortins to regulate food intake, energy expenditure, insulin sensitivity, and insulin secretion, respectively. Finally, multiple hormonal and neural cues (e.g., leptin, estrogen, and serotonin) that use the melanocortin systems to regulate energy and glucose homeostasis will be reviewed. These findings suggest that targeting the specific branches of melanocortin circuits may be potential avenues to combat the current obesity and diabetes epidemics. PMID- 22211890 TI - Obesity, leptin, and Alzheimer's disease. AB - Obesity has various deleterious effects on health largely associated with metabolic abnormalities including abnormal glucose and lipid homeostasis that are associated with vascular injury and known cardiac, renal, and cerebrovascular complications. Advanced age is also associated with increased adiposity, decreased lean mass, and increased risk for obesity-related diseases. Although many of these obesity- and age-related disease processes have long been subsumed to be secondary to metabolic or vascular dysfunction, increasing evidence indicates that obesity also modulates nonvascular diseases such as Alzheimer's disease (AD) dementia. The link between peripheral obesity and neurodegeneration will be explored, using adipokines and AD as a template. After an introduction to the neuropathology of AD, the relationship between body weight, obesity, and dementia will be reviewed. Then, population-based and experimental studies that address whether leptin modulates brain health and mitigates AD pathways will be explored. These studies will serve as a framework for understanding the role of adipokines in brain health. PMID- 22211893 TI - Diabetes, cancer, and metformin: connections of metabolism and cell proliferation. AB - Diabetes is associated with an increased risk of developing and dying from cancer. This increased risk may be due to hyperglycemia, hyperinsulinemia, and insulin resistance or other factors. Metformin has recently gained much attention as it appears to reduce cancer incidence and improve prognosis of patients with diabetes. In vitro data and animal studies support these findings from human epidemiological studies. Metformin has multiple potential mechanisms by which it inhibits cancer development and growth. For example, metaformin inhibits hepatic gluconeogenesis, thus decreasing circulating glucose levels, and it increases insulin sensitivity, thus reducing circulating insulin levels. Intracellularly, metformin activates AMPK, which decreases protein synthesis and cell proliferation. Metaformin also reduces aromatase activity in the stromal cells of the mammary gland. Finally, metformin may diminish the recurrence and aggressiveness of tumors by reducing the stem cell population and inhibiting epithelial to mesenchymal transition. Here, we discuss the metabolic abnormalities that occur in tumor development and some of the mechanisms through which metformin may alter these pathways and reduce tumor growth. PMID- 22211894 TI - Prioritization of care in adults with diabetes and comorbidity. AB - Approximately half of adults with diabetes have at least one comorbid condition. However, diabetes care guidelines focus on diabetes-specific care, and their recommendations may not be appropriate for many patients with diabetes and comorbidity. We describe Piette and Kerr's typology of comorbid conditions, which categorizes conditions based on if they are clinically dominant (eclipse diabetes management), symptomatic versus asymptomatic, and concordant (similar pathophysiologic processes as diabetes) versus discordant. We integrate this typology with clinical evidence and shared decision-making methods to create an algorithmic approach to prioritizing care in patients with diabetes and comorbidity. Initial steps are determining the patient's goals of care and preferences for treatment, whether there is a clinically dominant condition or inadequately treated symptomatic condition, and the risk of cardiovascular disease. With these data in hand, the clinician and patient prioritize diabetes treatments during a shared decision-making process. These steps should be repeated, especially when the patient's clinical status changes. This patient centered process emphasizes overall quality of life and functioning rather than a narrow focus on diabetes. PMID- 22211896 TI - Type 1 diabetes: role of intestinal microbiome in humans and mice. AB - Type 1 diabetes is a disease involving autoimmune destruction of pancreatic beta cells in genetically predisposed individuals. Identifying factors that trigger initiation and progression of autoimmunity may provide opportunities for directed prophylactic and therapeutic measures to prevent and/or treat type 1 diabetes. The human intestinal microbiome is a complex, symbiotic ecological community that influences human health and development, including the development and maintenance of the human immune system. The role of the intestinal microbiome in autoimmunity has garnered significant attention, and evidence suggests a particular role for intestinal microbiome alterations in autoimmune disease development, including type 1 diabetes. This review will examine the role of the intestinal microbiome in the development and function of the immune system and how this relates to the development of autoimmunity. Data from animal and human studies linking alterations in the intestinal microbiome and intestinal integrity with type 1 diabetes will be closely examined. Finally, we will examine the interactions between the intestinal microbiome and dietary exposures and how these interactions may further influence autoimmunity and type 1 diabetes development. PMID- 22211897 TI - Making progress: preserving beta cells in type 1 diabetes. AB - The clinical care of patients with type 1 diabetes (T1D) has greatly improved over the past few decades; however, it remains impossible to completely normalize blood sugar utilizing currently available tools. Research is underway with a goal to improve the care and, ultimately, to cure T1D by preserving beta cells. This review will outline the progress that has been made in trials aimed at preserving insulin secretion in T1D by modifying the immune assault on the pancreatic beta cell. Although not yet ready for clinical use, successful trials have been conducted in new-onset T1D that demonstrated utility of three experimental agents with disparate modes of action (anti-T cell, anti-B cell, and costimulation blockade) to preserve insulin secretion. In contrast, prevention studies have so far failed to produce positive results but have shown that such studies are feasible and have identified new promising agents for study. PMID- 22211895 TI - Receptor for AGE (RAGE): signaling mechanisms in the pathogenesis of diabetes and its complications. AB - The receptor for advanced glycation endproducts (RAGE) was first described as a signal transduction receptor for advanced glycation endproducts (AGEs), the products of nonenzymatic glycation and oxidation of proteins and lipids that accumulate in diabetes and in inflammatory foci. The discovery that RAGE was a receptor for inflammatory S100/calgranulins and high mobility group box 1 (HMGB1) set the stage for linking RAGE to both the consequences and causes of types 1 and 2 diabetes. Recent discoveries regarding the structure of RAGE as well as novel intracellular binding partner interactions advance our understanding of the mechanisms by which RAGE evokes pathological consequences and underscore strategies by which antagonism of RAGE in the clinic may be realized. Finally, recent data tracking RAGE in the clinic suggest that levels of soluble RAGEs and polymorphisms in the gene encoding RAGE may hold promise for the identification of patients who are vulnerable to the complications of diabetes and/or are receptive to therapeutic interventions designed to prevent and reverse the damage inflicted by chronic hyperglycemia, irrespective of its etiology. PMID- 22211900 TI - Anal sphincter electromyography in patients with newly diagnosed idiopathic parkinsonism. AB - OBJECTIVES: The differential diagnosis of patients with idiopathic parkinsonism is difficult, especially early in the course of the disease. External anal sphincter electromyography (EAS-EMG) has been reported to be of value in the differential diagnosis between Parkinson's disease (PD) and multiple system atrophy (MSA). Patients with MSA are reported to have pathological EAS-EMG and patients with PD are reported to have significantly less pathological EAS-EMG results. Comparisons between patients with parkinsonian disorders have usually been made many years into the disease, and thus it is largely unknown if the results of EAS-EMG can be used to distinguish the different diagnoses in the early phase of the disease. MATERIALS AND METHODS: We investigated 148 newly diagnosed patients with idiopathic parkinsonism from a population-based incidence cohort (100 definite PD, 21 probable PD, 16 MSA, 11 progressive supranuclear palsy, and 40 controls) with EAS-EMG within 3 months of their first visit and, in the majority of patients, before start of treatment with dopaminergic drugs. The clinical diagnoses were made using established clinical diagnostic criteria after a median follow-up of 3 years. RESULTS: All patient groups had more pathological EAS-EMG results than controls. No EAS-EMG differences were found between the patient groups, especially not between PD and MSA. CONCLUSIONS: External anal sphincter electromyography examination cannot separate the different parkinsonian subgroups from each other in early course of the diseases. PMID- 22211905 TI - Allergen-free immunotherapy using DNA vaccines in treatment of established allergic disease. PMID- 22211901 TI - Differential effects of brain-derived neurotrophic factor and neurotrophin-3 on hindlimb function in paraplegic rats. AB - We compared the effect of viral administration of brain-derived neurotrophic factor (BDNF) or neurotrophin 3 (NT-3) on locomotor recovery in adult rats with complete thoracic (T10) spinal cord transection injuries, in order to determine the effect of chronic neurotrophin expression on spinal plasticity. At the time of injury, BDNF, NT-3 or green fluorescent protein (GFP) (control) was delivered to the lesion via adeno-associated virus (AAV) constructs. AAV-BDNF was significantly more effective than AAV-NT-3 in eliciting locomotion. In fact, AAV BDNF-treated rats displayed plantar, weight-supported hindlimb stepping on a stationary platform, that is, without the assistance of a moving treadmill and without step training. Rats receiving AAV-NT-3 or AAV-GFP were incapable of hindlimb stepping during this task, despite provision of balance support. AAV-NT 3 treatment did promote the recovery of treadmill-assisted stepping, but this required continuous perineal stimulation. In addition, AAV-BDNF-treated rats were sensitized to noxious heat, whereas AAV-NT-3-treated and AAV-GFP-treated rats were not. Notably, AAV-BDNF-treated rats also developed hindlimb spasticity, detracting from its potential clinical applicability via the current viral delivery method. Intracellular recording from triceps surae motoneurons revealed that AAV-BDNF significantly reduced motoneuron rheobase, suggesting that AAV-BDNF promoted the recovery of over-ground stepping by enhancing neuronal excitability. Elevated nuclear c-Fos expression in interneurons located in the L2 intermediate zone after AAV-BDNF treatment indicated increased activation of interneurons in the vicinity of the locomotor central pattern generator. AAV-NT-3 treatment reduced motoneuron excitability, with little change in c-Fos expression. These results support the potential for BDNF delivery at the lesion site to reorganize locomotor circuits. PMID- 22211906 TI - On childhood asthma, obesity and inflammation. PMID- 22211907 TI - Re: Influenza immunization in egg allergy: an update for the 2011-2012 season - a comparison with 'GREEN Book', Department of Health UK guideline. PMID- 22211911 TI - A plea for a more physiological ICSI. AB - Intracytoplasmic sperm injection (ICSI) can be considered the most 'revolutionary' in vitro insemination technique because it has efficiently allowed the treatment of male factor infertility. Although ICSI has been successfully and safely applied worldwide for almost 20 years, currently, we have no real knowledge regarding the hypothetical long-term side effects on ICSI adults, given the increased likelihood of spermatozoa with defective nuclear content fertilising the oocytes. The aim of this review article is to investigate the most recent advances of performing ICSI in the safest possible manner, thus, minimising the theoretical hazards of this procedure. To allow for substantiated recommendation which male gametes to choose for physiological ICSI an updated search was performed in Medline and Embase, from 1996 to June 2011. Recent technical advances allow operators to more or less simulate physiological conditions in the laboratory, reducing potential damage to the gametes. It seems possible to prevent fertilisation by DNA-damaged and chromosomal-unbalanced spermatozoa by selecting ICSI sperm by motility and/or maturation markers such as hyaluronic acid or other zona pellucida receptors. Furthermore, novel non invasive imaging techniques can be valid tools for helping in the morphological selection of ICSI spermatozoa. PMID- 22211910 TI - CT-guided percutaneous lung biopsy under general anesthesia: a pediatric case series and literature review. AB - We describe 14 consecutive children who received computed tomography-guided percutaneous lung biopsy (CT-PLB) under general anesthesia over an 18-month period at our institution. Pulmonary hemorrhage (occurring in 36%) and pneumothorax (29%) were the two most common complications; the overall complication rate was 64%. When complications did occur, immediate airway management was facilitated by the presence of an endotracheal tube (ETT). We conclude as follows: (i) CT-PLB in our series is associated with a high risk of both overall and severe complications; (ii) risk of complications is increased by both patient and procedure-related factors; (iii) airway management with ETT may be preferable should a complication arise; (iv) severe complications may necessitate ICU admission, which should be available before proceeding. PMID- 22211912 TI - Isolation and characterization of Stemphylium sedicola SBU-16 as a new endophytic taxol-producing fungus from Taxus baccata grown in Iran. AB - In this study, a total of 25 endophytic fungi were successfully isolated from the inner bark of Taxus baccata grown in Iran by the aseptic technique. Genomic DNA was extracted from isolated endophytic fungi and subjected to polymerase chain reaction (PCR) analysis for the presence of the Taxus taxadiene synthase (ts) gene, which encodes the enzyme catalyzing the first committed step of taxol biosynthesis. Four of 25 isolated endophytic fungi isolates showed PCR positive for the ts gene. Subsequently, taxol and 10-deacetylbaccatin III (10-DAB III) were extracted from culture filtrates and mycelia of the PCR positive isolates and analyzed by high-performance liquid chromatography and mass spectrometry. The analysis showed that one isolate (SBU-16) produced taxol (6.9 +/- 0.2 MUg L(-1) ) and its intermediate compound, 10-DAB III (2.2 +/- 0.1 MUg L(-1) ). The isolate SBU-16 was identified as Stemphylium sedicola SBU-16, according to its morphological characteristics as well as the internal transcribed spacer nuclear rDNA gene sequence analysis. Interestingly, this is the first report of the genus Stemphylium as a taxol-producing taxon. PMID- 22211914 TI - Minilaparoscopy and laparoendoscopic single-site surgery: mini- and single-scar in urology. AB - PURPOSE: To review the development of laparoscopic single-site surgery (LESS) and minilaparoscopy (ML), with particular attention to the urological field, focusing on nomenclature, history and outcomes. METHODS: A literature search was conducted on laparoendoscopic single-site surgery, minilaparoscopy, needlescopy and microlaparoscopy. The most relevant papers were selected over the last 30 years. RESULTS: 830 manuscripts were found about LESS, 251 in urology, two CRTs and nine match-case controls. 258 papers were about ML and 55 in urology. ML is the main topic (169 papers), followed by needlescopy (58) and microlaparoscopy (32). The most significant articles are four non-randomized match-case control studies. CONCLUSIONS: Over the last few years, many urological laparoscopic operations have been successfully performed by LESS. However, the actual role of LESS remains to be determined with controversial data about postoperative pain control and almost no results on cosmesis. We are facing second-generation ML with superior performance granted by new endoscopes and most effective instruments. ML has demonstrated in almost all urologic indications to be feasible, safe and able to improve cosmetic and postoperative pain control. Anyway, CRTs are still lacking and only studies from other discipline can corroborate this trend. PMID- 22211915 TI - Laparo-endoscopic single-site sleeve gastrectomy: results from a preliminary series of selected patients. AB - Laparoscopic sleeve gastrectomy (LSG) has received recognition in the treatment of patients with morbid obesity and BMI <40 kg/m2 and high-risk patients with BMI >50 kg/m2. Conventional LSG usually requires the placement of four or more trocars. Recently, newly designed access devices have allowed a single-incision laparoscopic approach; however, the clinical application of this method is still limited. We describe the operative steps of laparo-endoscopic single-site (LESS) sleeve gastrectomy and report the preliminary results: in 12 selected patients. The functional results did not differ significantly from those of standard LSG, with a median excess weight loss of 79% twelve months after surgery. Furthermore, cosmetic results seemed to be improved and postoperative pain reduced compared to standard LSG. PMID- 22211916 TI - Minimally invasive management of huge ovarian cysts by laparoscopic extracorporeal approach. AB - Laparoscopy has been widely performed in adnexal surgery for benign masses. For large adnexal masses, laparoscopy has not been commonly used and laparotomy remains the gold standard due to several technical difficulties in the former, including a limited surgical field, risk of unintended cyst rupture during the insertion of the Veress needle or trocar, and the possibility of malignancy. Recent advances in laparoscopic techniques have offered acceptable options for performing laparoscopy in patients with very large adnexal cysts. We performed ovarian cystectomy of huge ovarian cysts via a laparoscopic extracorporeal approach through an umbilical single-site incision, successfully minimizing the possibility of cyst contents leaking into the peritoneal cavity. Use of a single site incision at the umbilicus for huge adnexal cystic masses appears safe and spares the additional costs of using conventional surgical instruments. It is also cosmetically effective and highly appreciated by patients because it results in minimal abdominal scarring. PMID- 22211917 TI - Transumbilical multiple-port laparoscopic cholecystectomy using standard laparoscopic instruments. AB - INTRODUCTION: As a complement to standard laparoscopy, single incision laparoscopic cholecystectomy (SILS) is gaining popularity. We report our technique and our initial experience with transumbilical multi-port laparoscopic cholecystectomy (TUMP-LC) without an access device, with standard laparoscopic instruments, and report the clinical outcomes. MATERIAL AND METHODS: Twenty-five (23 F: 2 M) consecutive patients with symptomatic cholelithiasis were included. The surgical outcomes such as length of stay, complications and perioperative morbidity were analyzed. For evaluation of surgical stress preoperative and postoperative C-reactive protein (CRP) values at 6 h and 24 h were measured. Postoperative pain was evaluated using a standard 10-point visual analogue scale (VAS). RESULTS: The mean duration of the surgery was 44.56 minutes (range, 18 110). Additional trocars were needed in two (8%) cases. Mean pain scores post operatively at 4 h, 12 h and 24 h were 4 +/- 1.19, 3.64 +/- 1.03 and 2.24 +/- 0.96, respectively (p < 0.0001). Plasma CRP values increased at 6 h and started to decrease at 24 h (p < 0.0001). None of the cases were converted to open surgery and no major complications occurred. DISCUSSION: TUMP-LC using standard laparoscopic instrumentation without an access device is an effective alternative to standard four-incision laparoscopic cholecystectomy. Our technique maintains the principles of the conventional procedure and the instrumentation, but also improves the access. PMID- 22211919 TI - Actinobaculum schaalii, a cause of urinary tract infections in children? AB - AIM: To inform that Actinobaculum schaalii can colonize the urine and cause urinary tract infection in children. METHODS: Urine samples were examined by wet smear microscopy, incubated in 5% CO(2) for 1-2 days, and species-specific real time polymerase chain reaction (PCR) for A. schaalii was performed. RESULTS: In 5 of the 29 screened urines, A. schaalii was found only by real-time PCR in quantities equivalent to >= 10(4) -10(5) CFU/mL. In addition, A. schaalii was found in quantities equivalent to >= 10(6) CFU/mL by both culture and PCR in two children with a urinary tract infection and large numbers of leucocytes in the urine. CONCLUSION: Actinobaculum schaalii is CO(2)-dependent. Therefore, if there are clinical symptoms and/or a negative culture despite the presence of leucocytes in the urine, Gram staining and incubation in 5% CO(2) or species specific real-time PCR should be performed to identify A. schaalii. PMID- 22211918 TI - Integrin signalling and function in immune cells. AB - Integrins not only mediate cell-cell and cell-extracellular matrix adhesion, but also affect the multitude of signal transduction cascades in control of cell survival, proliferation, differentiation and organ development. Mutations in integrins or the major effectors of integrin signalling pathways cause defective organ development, immunodeficiency, cancer or autoimmune disease. Understanding of the signalling events that drive integrin activation and signalling is therefore crucial to uncover the molecular mechanisms of these diseases. This review discusses the key signalling complexes regulating integrin activation and function in both 'inside-out' and 'outside-in' pathways in T lymphocytes, including kinases, SLP-76, VAV1, ADAP, SKAP-55, RapL, RIAM, Rap1, Talin and Kindlin. PMID- 22211920 TI - SPECT study of the nigrostriatal dopaminergic system in Huntington's disease. AB - BACKGROUND AND PURPOSE: The pathological process of Huntington's disease (HD) preferentially targets spiny neurons in the striatum, with later involvement of the substantia nigra and other structures. The purpose of this study is to investigate the nigrostriatal dopaminergic system in a genetically confirmed HD family. METHODS: We used single photon emission computed tomography (SPECT) with the radiotracers [(99m) Tc]TRODAT-1 and [123I]IBZM to study the binding potentials of dopamine transporter (DAT) and dopamine D2 receptors in the striatum of 3 symptomatic HD patients, 1 mutation-negative member of the HD family, and 7 healthy controls. Specific binding potentials were calculated as (striatum-occipital lobe)/occipital lobe. RESULTS: Reduced binding potential of striatal dopamine D2 receptors was found in the 3 symptomatic HD patients. The DAT binding potential was reduced in 1 symptomatic HD patient. We also found that the more severe the clinical status, the lower the DAT and D2 receptor binding potentials, and the larger the bicaudate ratio. CONCLUSIONS: We showed that the postsynaptic part of the nigrostriatal pathway was involved. The presynaptic part is usually not affected but could occur in very advanced cases. Our findings suggest that SPECT imaging of D2 receptors is useful for diagnosing and monitoring HD. PMID- 22211921 TI - Adipocytokine zinc alpha2 glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathy. AB - OBJECTIVE: A substantial proportion of diabetic nephropathy individuals are non albuminuric. Using a proteomic approach, we searched for novel urinary biomarkers. METHODS: We studied three groups (n = 6 per group) of males with Type 2 diabetes: (1) normal renal function; (2) classical diabetic nephropathy (urinary albumin-creatinine ratio > 1000 mg/g and glomerular filtration rate < 60 ml/min.1.73 m(2) ) and (3) non-albuminuric diabetic nephropathy (glomerular filtration rate < 60 ml/min.1.73 m(2) and urinary albumin-creatinine ratio < 30 mg/g). We used two-dimensional fluorescence differential gel electrophoresis, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry peptide identification and western blot validation in the study. RESULTS: Sixty protein spots were differentially abundant between the non-albuminuric and macro albuminuric subjects (> 2.5-fold, P < 0.05). In the non-albuminuric subjects, in addition to previously reported alpha(1) -microglobulin, the next most interesting spot (upregulated 3.44-fold, P = 0.0026) was human zinc-alpha(2) glycoprotein, a novel adipose-cytokine associated with glomerular injury. This was confirmed by western blot and replicated in female diabetic nephropathy subjects. CONCLUSIONS: From our preliminary results, human zinc-alpha(2) glycoprotein may be a novel urinary biomarker for non-albuminuric diabetic nephropathy. PMID- 22211922 TI - Risk of recurrence of non-metastatic breast cancer in women under 40 years: a population-registry cancer study in a European country. AB - Breast cancer in young patients is relatively uncommon. There is no consensus about the impact of young age on prognosis. The aim of this study was to analyze the effect of young age over the risk of recurrence of breast cancer using a population-registry cancer database in Spain. A retrospective study case-control type was designed. A total of 1,210 patients fulfilled the inclusion criteria. A cutoff at 40 years was used to define two groups of patients: group A, <=40 years (n = 111); and group B, >40 years (n = 1,099). Younger women showed a higher rate of undifferentiated tumors; a higher percentage of positive lymph nodes; lower rate of positivity of estrogen receptor, higher rate of nonconservative surgery and higher proportion of adjuvant therapies. The risk of recurrence was higher for women <=40 years: HR =2.59 (95% CI: 1.60-4.18). CONCLUSION: Breast cancer diagnosed at a young age (<=40 years) is correlated with higher recurrence rates. PMID- 22211923 TI - The incidence of basal cell carcinoma in the under-30s in the UK. AB - BACKGROUND: Basal cell carcinoma (BCC) is the commonest cancer in many countries, but the current incidence in young people from the UK is unknown. AIM: To ascertain a recent incidence of BCC in the under-30 population in the UK. Methods. Cancer registry data from part of the Eastern Region of the UK was analysed for two periods: 1981-1989 and 1998-2006. Case notes were examined for a cohort of the patients from 1998 to 2006. RESULTS: The incidence of BCC increased from 0.73 to 1.79 per 100 000 in those aged < 30 years over the study period. More than half (55%) of BCCs were on the head and neck, and the most common histological subtype was superficial BCC (38%). CONCLUSIONS: The reported incidence of BCC in those aged < 30 years has increased by 145% during this period, corresponding to an average annual increase of 8.53%. This may be partially due to earlier presentation and to increased use of surgical treatments. PMID- 22211924 TI - Contribution of neutrophil-derived myeloperoxidase in the early phase of fulminant acute respiratory distress syndrome induced by influenza virus infection. AB - Because the pathogenesis of acute respiratory distress syndrome (ARDS) induced by influenza virus infection remains unknown, we can only improve on existing therapeutic interventions. To approach the subject, we investigated immunological etiology focused on cytokines and an acute lung damage factor in influenza induced ARDS by using a PR-8 (A/H1N1)-infected mouse model. The infected mouse showed fulminant severe pneumonia with leukocyte infiltration, claudin alteration on tight junctions, and formation of hyaline membranes. In addition to interferon (IFN)-alpha, plenty of keratinocyte-derived chemokines (KC), macrophage inflammatory protein 2 (MIP-2), regulated on activation normal T-cell expressed and secreted (RANTES), and monocyte chemotactic protein 1 (MCP-1) were significantly released into bronchoalveolar lavage fluid (BALF) of the model. We focused on neutrophil myeloperoxidase (MPO) as a potent tissue damage factor and examined its contribution in influenza pneumonia by using mice genetically lacking in MPO. The absence of MPO reduced inflammatory damage with suppression of leakage of total BALF proteins associated with alteration of claudins in the lung. MPO(-/-) mice also suppressed viral load in the lung. The present study suggests that MPO-mediated OCl(-) generation affects claudin molecules and leads to protein leakage and viral spread as a damage factor in influenza-induced ARDS. PMID- 22211925 TI - Growth and nitrogen use in Xanthium canadense grown in an open or in a dense stand. AB - Plants develop branches profusely when grown solitarily, while less so when grown in a dense stand. Such changes in architecture are associated with changes in dry mass allocation and nitrogen use. Here, we studied what traits in plant growth and nitrogen use were influenced by different light climates in the stand. Annual plants (Xanthium canadense) were grown solitarily or in a dense stand. Dry mass growth was analyzed as the product of the net assimilation rate (NAR) and leaf area (LA). Nitrogen use efficiency (NUE) was analyzed as the product of nitrogen productivity (NP) and the mean residence time (MRT) of nitrogen. These growth variables were further factorized into their components. Solitary plants maintained a high NAR, whereas plants in the dense stand decreased the NAR due to mutual shading. Plants in the dense stand developed a larger LA with a higher specific leaf area than solitary plants. Solitary plants had higher NUE due to higher NP. A temporal increase in NUE was attributed to the increase in MRT of nitrogen. Light climate was different between solitary and dense-stand plants, but they took up a comparable amount of nitrogen and used it differently in response to the given light climate. NUE was thus demonstrated to be a useful tool for analyzing the mechanism leading to different N use in plant growth. PMID- 22211927 TI - Foci report on indigenous Dermacentor reticulatus populations in Belgium and a preliminary study of associated babesiosis pathogens. AB - The occurrence of autochthonous clinical cases of canine and equine babesiosis in Belgium during the last two decades suggests that the vector of the pathogens responsible for these diseases, Dermacentor reticulatus (Ixodida: Ixodidae), may be present in this country. Consequently, evidence for the presence of this tick species in different locations within Belgium was investigated. Four different locations were monitored by flagging in 2010; these included the locations at which D. reticulatus was previously found on a dog in 2009 and on two red deer in 2007. Two different species of tick were identified, Ixodes ricinus (Ixodida: Ixodidae) and D. reticulatus. A total of 282 D. reticulatus adult ticks (98 males, 184 females) were collected from the four sites. Ticks were found mainly from early March until the end of May and a peak in activity was apparent in March. A Babesia spp. (Piroplasmida: Babesiidae) genus-specific polymerase chain reaction test based on the amplification of a fragment of the 18S rRNA gene was used to investigate the potential presence of Babesia spp. All DNA extracts isolated from the total tick samples yielded negative results. Additional studies to accurately determine the distribution and vectorial capacity of this important tick species in Belgium are warranted. PMID- 22211928 TI - Conversion to tacrolimus once-daily from ciclosporin in stable kidney transplant recipients: a multicenter study. AB - This 24-week, open, single-arm, prospective, multicenter study evaluated the effects of conversion from ciclosporin to Tacrolimus QD in adult kidney transplant patients. Stable patients receiving ciclosporin were converted to Tacrolimus QD at 0.1mg/kg/day. Relative change in renal function (primary endpoint) was assessed using estimated creatinine clearance (eCrCl) with a noninferiority margin set at -10%. A total of 346 patients were enrolled; and 301 patients were treated per protocol (PPS) in the hyperlipidemia (n=42), hypertrichosis (n=106), hypertension (n=77) and gingival hyperplasia (n=76) groups. Relative change in eCrCl was -0.6% in all PPS patients (95% CI, -2.2; 0.9) and -5.3% in the hyperlipidemia (CI, -9.59; -0.97), 0.9% in the hypertrichosis (CI, -2.59; 4.45), -0.1% in the hypertension (CI, -3.8; 3.68), and -1% in the gingival hyperplasia groups (CI, -4.63; 2.65) (PPS), meeting noninferiority criteria. There was no acute rejection. Decreases in serum lipids and blood pressure were moderate but without meaningful change in the number of treatment medications. Substantial decreases in severity of ciclosporin-related cosmetic side effects were evident from investigator and patient self-report of symptoms. Renal function remained stable after conversion to Tacrolimus QD. The effect of conversion on cardiovascular parameters was not clinically meaningful, however, marked improvement in ciclosporin-related cosmetic side effects was observed. (ClinicalTrials.gov number: NCT00481481). PMID- 22211929 TI - Interaction of 3,4-methylenedioxymethamphetamine and methamphetamine during metabolism by in vitro human metabolic enzymes and in rats. AB - Illicit amphetamine-type stimulant (ATS) tablets commonly contain one or more active ingredients, which have hallucinogenic and/or stimulant effects. Because components such as 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (MA) in ATS tablets have similar chemical structures, they could be metabolized by common metabolic enzymes. To investigate potential metabolic interactions of ATS tablet components, we studied the in vitro metabolism of MDMA and MA using human metabolic enzymes. MDMA and MA were mainly metabolized by cytochrome P450 2D6 (CYP2D6) and mutually inhibited the production of their main metabolites. In vivo experiments were also performed using intravenous administration of MDMA, MA, or their mixture to rats. The plasma concentrations of MDMA and MA after co administration were higher than those after administration of MDMA or MA alone. The results in this study imply that multiple components in ATS tablets can interact to mutually inhibit their metabolism and potentially enhance the toxicity of each component. PMID- 22211931 TI - Hydroxyethyl starch 130/0.42/6:1 for perioperative plasma volume replacement in 1130 children: results of an European prospective multicenter observational postauthorization safety study (PASS). AB - INTRODUCTION: Third-generation hydroxyethyl starch (HES) is now approved also for the use in children, but safety studies including large numbers of pediatric patients are still missing. Therefore, we performed an European multicentric prospective observational postauthorization safety study (PASS) to evaluate the use of HES 130/0.42/6:1 in normal saline (ns-HES) or a balanced electrolyte solution (bal-HES) in children undergoing surgery. METHODS: Children aged up to 12 years with ASA risk scores of I-III receiving ns-HES (Venofundin 6%; Braun) or bal-HES (Tetraspan 6%; Braun) were followed perioperatively. Demographic data, surgical procedures performed, anesthesia, hemodynamic and laboratory data, adverse events (AE), and adverse drug reactions (ADR) were documented using a standardized case report form. RESULTS: Of 1130 children studied at 11 European pediatric centers from 2006 to 2009 (ns-HES, 629 children; bal-HES, 475 children; mean age, 3.6 +/- 3.8 [range, day of birth-12 years]; and body weight, 15.4 +/- 13 [0.9-90 kg]), 1104 were included for analysis. The mean infused HES volume was 10.6 +/- 5.8 (0.83-50) ml.kg(-1). In the 399 (36.1%) cases with blood gas analysis before and after HES infusion, hemoglobin and strong ion difference decreased significantly in both groups, whereas bicarbonate and base excess (BE before infusion: ns-HES -1.8 +/- 3.1, bal-HES -1.2 +/- 3.3 mm; after infusion: ns HES -2.5 +/- 2.8; bal-HES -1.1 +/- 3.2 mm, P < 0.05) decreased only with ns-HES but remained stable with bal-HES. Chloride concentrations increased in both groups and were significantly higher with ns-HES (Cl before infusion: ns-HES 105.5 +/- 3.6, bal-HES 104.9 +/- 2.9 mm; Cl after infusion: ns-HES 107.6 +/- 3.4, bal-HES 106.3 +/- 2.9 mm, P < 0.05). For the AE/ADR rates, dose-response but no age relationships could be demonstrated. No serious and no severe ADR directly related to HES (i.e. anaphylactoid reaction, clotting disorders, renal failure) were observed. CONCLUSION: Moderate doses of HES 130/0.42/6:1 for perioperative plasma volume replacement seem to be safe even in neonates and small infants. The probability of serious ADR is lower than 0.3%. Changes in acid-base balance may be decreased when HES is used in an acetate-containing balanced electrolyte solution instead of normal saline. Caution should be exercised in patients with renal function disturbances and those with an increased bleeding risk. PMID- 22211932 TI - Long microsatellites and unusually high levels of genetic diversity in the Orthoptera. AB - Much remains to be learned about the mutational processes governing the evolution of microsatellite repeat regions and the associated levels of genetic diversity observed at microsatellite markers across populations or species. An extensive survey of microsatellite variation in 210 insect species from six major orders revealed that within Orthopterans, which are characterized by giant genomes, levels of genetic diversity were ~20% higher and microsatellite repeat arrays were longer than in any other group. Because of the mutation dependence on repeat length, this result suggests a higher microsatellite loci mutation rate in the Orthoptera. We deem it plausible that differences among insect orders, either in mismatch repair systems or in abundance of transposable element-derived microsatellites, can shape the size distribution of both genomes and microsatellite repeat regions. Our findings emphasise that observed levels of genetic diversity can greatly vary across species (orders at least) because of molecular differences in the mechanisms that determine microsatellite size, and are therefore critical to conservation and population genetics studies, where microsatellite repeat variability is primarily interpreted in terms of population demography and history. PMID- 22211934 TI - Responding to climate change in New York State: the ClimAID integrated assessment for effective climate change adaptation in New York State. Final report. AB - Climate change is already beginning to affect New York State, and these impacts are projected to grow. At the same time, the state has the ability to develop adaptation strategies to prepare for and respond to climate risks now and in the future. The ClimAID assessment provides information on climate change impacts and adaptation for eight sectors in New York State: water resources, coastal zones, ecosystems, agriculture, energy, transportation,telecommunications, and public health. Observed climate trends and future climate projections were developed for seven regions across the state. Within each of the sectors, climate risks, vulnerabilities, and adaptation strategies are identified. Integrating themes across all of the sectors are equity and environmental justice and economics.Case studies are used to examine specific vulnerabilities and potential adaptation strategies in each of the eight sectors. These case studies also illustrate the linkages among climate vulnerabilities, risks, and adaptation, and demonstrate specific monitoring needs. Stakeholder participation was critical to the ClimAID assessment process to ensure relevance to decision makers across the state. PMID- 22211935 TI - Risk factor analysis of hepatitis C virus infection among Chinese blood donors in Hong Kong. AB - BACKGROUND: Hepatitis C virus (HCV) infection can result in serious hepatic complications and hence potentially significant burden to the society. Despite advances in technology, transfusion-transmitted HCV infection still exists. To further minimise the risk, a review on the epidemiology of HCV infection among Chinese blood donors in Hong Kong was conducted. METHODS: All donations associated with HCV infection confirmed by positive serologic diagnosis with or without molecular confirmation during the period from 2003 to 2010 were studied. Demographic data were retrieved and risk factors were identified. RESULTS: HCV infection was more commonly seen in first time donors and donors with blood transfusion history before the availability of HCV testing, whereas its association with intravenous drug use was noted to be decreasing. Interestingly, half of the HCV positive donors in 2008-2010 were young donors aged below 21, which was also the group with the highest rate of no known source of infection. CONCLUSION: A subgroup of younger age donors was found to have no known risk factor. To develop better screening strategy, it is recommended that a more detailed analysis of this group of donors is required. PMID- 22211937 TI - Intake of antioxidant nutrients and risk of non-Hodgkin's Lymphoma in the Women's Health Initiative. AB - Incidence rates of non-Hodgkin's lymphoma (NHL) increased substantially in the United States and worldwide during the latter part of the 20(th) century, but little is known about the etiology of this condition. Antioxidant nutrients may reduce the risk of NHL by quenching free radicals, which may contribute to carcinogenesis by damaging DNA and lipid membranes. We examined the association of intake of vitamin A and antioxidant nutrients with risk of NHL and its major subtypes in 1,104 cases of NHL identified among 154,363 postmenopausal women followed for an average of 11 yr in the Women's Health Initiative. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Of all nutrients examined, only total vitamin A intake (from diet and supplements combined) was inversely associated with risk of NHL overall (multivariate adjusted HR for highest vs. lowest quartile 0.83, 95% CI 0.69-0.99), whereas total vitamin C intake was inversely associated with risk of diffuse large B-cell lymphoma (HR for highest vs. lowest quartile 0.69, 95% CI 0.49-0.98). Overall, this study provides some evidence of inverse associations of intake of total vitamin A and total vitamin C with the risk of NHL and diffuse lymphoma, respectively. PMID- 22211938 TI - Reflectance confocal microscopy for diagnosis of mammary and extramammary Paget's disease. AB - BACKGROUND: Paget's disease is an intraepidermal adenocarcinoma that is difficult to diagnose clinically as it mimics inflammatory or infectious diseases. As a consequence, it may be clinically misdiagnosed resulting in a delay in appropriate management. Reflectance confocal microscopy allows the visualization of the upper layers of the skin and mucosa at cellular resolution. Paget's disease is characterized histologically by the presence of neoplastic cells scattered throughout all layers of the epidermis in a pattern similar to that also observed in melanoma (and termed Pagetoid spread). OBJECTIVE: In vivo confocal microscopy is an excellent diagnostic tool for detecting Pagetoid spread and for diagnosing melanoma. We therefore hypothesized that it may also assist in the diagnosis of Paget's disease. METHODS: In this study, we describe the confocal features of nine cases of extramammary Paget's disease and one case of mammary one. RESULTS: Large atypical Pagetoid cells were present singly and in clusters in all 10 cases and were readily visualized on ex vivo and in vivo confocal microscopy. The presence of Pagetoid spread and other confocal features, in the appropriate clinical context, is suggestive Paget's disease and should allow distinction from other inflammatory diseases that may appear similar clinically. CONCLUSION: The use of confocal microscopy is likely to facilitate earlier diagnosis of Paget's disease and the instigation of appropriate management with concomitant improvement in clinical outcomes. PMID- 22211939 TI - Identification of Chromera velia by fluorescence in situ hybridization. AB - Chromera velia is evolutionarily the closest free-living and photosynthetic organism to the medically important obligatory parasitic apicomplexans that cause diseases including malaria and toxoplasmosis. In this study, a novel oligonucleotide probe targeting C. velia's small subunit ribosomal RNA was designed. To enable usage of this probe as a detection tool, a fluorescence in situ hybridization (FISH) protocol was optimized. The results obtained showed that when used in combination, the C. velia CV1 probe and optimized FISH protocol enabled efficient detection of C. velia in culture. This new technique will allow a better understanding of the ecological role of C. velia within the coral microhabitat. PMID- 22211941 TI - Physical activity and multiple sclerosis: new insights regarding inactivity. AB - OBJECTIVES: There is increasing recognition that physical activity has beneficial consequences among persons with multiple sclerosis (MS), but there is concern regarding the current degree of physical inactivity in this population because of limitations with previous research and increased recognition of health behaviors in MS. This study compared physical activity levels between large samples of persons with mild MS and matched controls using validated measures of physical activity. MATERIALS AND METHODS: The sample included 77 cases of MS and 77 controls matched on age, height, weight, and gender. Physical activity was assessed using five measures, namely the Godin Leisure-Time Exercise Questionnaire (GLTEQ), International Physical Activity Questionnaire (IPAQ), and activity counts per day, step counts per day, and time spent in moderate-to vigorous physical activity (MVPA) per day by accelerometry. RESULTS: There were statistically significant differences between groups in accelerometer activity counts (t = -3.87, P = 0.0001), accelerometer step counts (t = -4.29, P = 0.0001), time spent in MVPA (t = -2.39, P = 0.01), GLTEQ scores (t = -3.83, P = 0.0001), and IPAQ scores (t = -3.42, P = 0.0001). The average effect size across all five measures was d = -0.59 and indicated that persons with MS overall were moderately less physically active than the matched controls. CONCLUSIONS: The primary finding was a moderate reduction in physical activity among those with MS, but the magnitude was substantially smaller than reported in a published meta analysis. Importantly, the degree of physical inactivity can likely be overcome through the delivery of behavioral interventions for increasing physical activity and this should translate into meaningful consequences for persons with MS. PMID- 22211942 TI - Voxel-based statistical analysis of fractional anisotropy and mean diffusivity in patients with unilateral temporal lobe epilepsy of unknown cause. AB - PURPOSE: To determine regional alterations of fractional anisotropy (FA) and mean diffusivity (MD) in patients with magnetic resonance imaging (MRI)-negative temporal lobe epilepsy with unknown cause (TLEu) using diffusion tensor imaging (DTI) and voxel-based statistics (VBS). METHODS: Ten patients with left TLEu and no abnormality on conventional MRI and 81 age-matched neurological healthy controls were studied. VBS analyses were used to compare FA and MD differences between patients and controls. All results were reported using stringent statistical thresholds corrected for multiple comparisons. RESULTS: Patients with TLEu had widespread and bilateral reduction of white matter FA, encompassing the temporal lobes, entire corpus callosum, thalamus, and other regions relative to controls. Increased MD was more spatially limited in patients, but was also observed in the thalamus. FA of the putamen was significantly increased bilaterally in patients relative to controls, which correlated with increasing macroscopic atrophy of the putamen. DISCUSSION: Water diffusion abnormalities are widespread and bilaterally distributed in patients with unilateral TLEu, which are beyond the resolution of conventional MRI. FA alterations are more widespread relative to MD alterations. This is the first study to show evidence of interrelated microscopic (ie, FA increase) and macroscopic (ie, atrophy) alterations of the putamen in patients with TLEu. PMID- 22211943 TI - Comparison of cryopreserved human sperm from solid surface vitrification and standard vapor freezing method: on motility, morphology, vitality and DNA integrity. AB - Solid surface vitrificaition (SSV) is a cryoperservative method that has been used in the cryopreservation of oocytes, and embryos. Here, we report an application of the SSV in the cryopreservation of human spermatozoa. We compared the SSV with a standard freezing method in terms of sperm motility, morphology, vitality and DNA integrity. Sperm motility was determined by computer assisted semen analysis, morphology and vitality were determined by eosin-methylene blue staining, and DNA integrity was determined by a TUNEL assay. We found that while both cryopreservative methods produced spermatozoa with comparable vitality and motility, the SSV gave slightly, but significantly fewer sperm with DNA damage, and loose tail. We concluded that, a cryopreservation of human spermatozoa by SSV is feasible and provides a quick and practical way to preserve human spermatozoa with a comparable, if not better, quality of the preserved spermatozoa to the standard freezing method. PMID- 22211944 TI - Human coxal bone sexual dimorphism and multislice computed tomography: geometric morphometric analysis of 65 adults. AB - The authors studied sexually dimorphic differences in coxal shape using geometric morphometric analysis of 15 osteometric landmarks recorded by multislice computed tomography (MSCT), based on three-dimensional reconstructions of 65 Caucasian adults. Geometric morphometric analysis, principal component analysis, canonical variates analysis, and other discriminant analysis (Goodall's F-test and Mahalanobis distance) were performed for the three separate bones of the left innominate (pubis, ilium, and ischium), the modified pubis (pubis and ischiopubic ramus), the modified ilium (ilium and ischial spine), three bone complexes (ischiopubic, iliopubic, and ilio-ischial), and the complete innominate. A cross validation test was also performed. All areas studied were dimorphic, but results for sexual dimorphism in decreasing order were as follows: the modified pubis, followed by the ischiopubic complex, the iliopubic complex and the complete innominate, the pubis, the modified ilium, the ilio-ischial complex, the ilium, and finally the ischium. These results show the potential of this approach for future anthropological research. PMID- 22211945 TI - Right-left asymmetry in the cortical processing of sounds for social communication vs. navigation in mustached bats. AB - In the Doppler-shifted constant frequency processing area in the primary auditory cortex of mustached bats, Pteronotus parnellii, neurons respond to both social calls and to echolocation signals. This multifunctional nature of cortical neurons creates a paradox for simultaneous processing of two behaviorally distinct categories of sound. To test the possibility of a stimulus-specific hemispheric bias, single-unit responses were obtained to both types of sounds, calls and pulse-echo tone pairs, from the right and left auditory cortex. Neurons on the left exhibited only slightly higher peak response magnitudes for their respective best calls, but they showed a significantly higher sensitivity (lower response thresholds) to calls than neurons on the right. On average, call-to-tone response ratios were significantly higher for neurons on the left than for those on the right. Neurons on the right responded significantly more strongly to pulse echo tone pairs than those on the left. Overall, neurons in males responded to pulse-echo tone pairs with a much higher spike count compared to females, but this difference was less pronounced for calls. Multidimensional scaling of call responses yielded a segregated representation of call types only on the left. These data establish for the first time, a behaviorally directed right-left asymmetry at the level of single cortical neurons. It is proposed that a lateralized cortex emerges from multiparametric integration (e.g. combination sensitivity) within a neuron and inhibitory interactions between neurons that come into play during the processing of complex sounds. PMID- 22211946 TI - Decreased peripheral blood mitochondrial DNA content is related to HbA1c, fasting plasma glucose level and age of onset in type 2 diabetes mellitus. AB - AIMS: Mitochondrial DNA (mtDNA) content is essential for maintaining normal mitochondrial function, and the mitochondrial function is critical for the production and the release of insulin in Type 2 diabetes mellitus. We investigated whether peripheral blood mtDNA content was reduced in Type 2 diabetes, and what were the major factors? METHODS: The mtDNA content of peripheral blood in a sample of 147 Type 2 diabetes and 170 normal Chinese subjects was determined by amplification of the mitochondrial gene CYT-B and normalized by a nuclear DNA beta-globin gene. Fasting plasma glucose, HbA(1c) , fasting plasma insulin and lipid profile (HDL-cholesterol, LDL-cholesterol, total cholesterol, triglyceride) were analysed with commercial kits on an automatic analyser. RESULTS: In Type 2 diabetes group, the mean HbA(1c) was 62 mmol/mol (7.8%). Moreover, BMI, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, LDL-cholesterol, triglyceride, fasting plasma insulin and homeostasis model assessment for insulin resistance were significantly higher in Type 2 diabetes group than that in control group. Peripheral blood mtDNA content was 24% lower than that in the controls (1.4 +/- 0.5 vs. 1.8 +/- 0.7, P < 0.001). The mtDNA content was negatively correlated with BMI, fasting plasma glucose, fasting plasma insulin, homeostasis model assessment for insulin resistance (P < 0.01), and age, triglyceride and LDL-cholesterol levels (P < 0.05); while positively correlated with HDL-cholesterol level (P < 0.05) in both groups. Stepwise regression analysis indicated that HbA(1c), fasting plasma glucose and age of onset were the major factors affecting the mtDNA content in the Type 2 diabetes group; however, BMI was the only variable associated with lower mtDNA content in control group. CONCLUSION: Our results demonstrate that lower peripheral blood mtDNA content is associated with Type 2 diabetes in Chinese individuals, and HbA(1c), fasting plasma glucose and age of onset are the major factors affecting the mtDNA content. PMID- 22211947 TI - Predictors and protective factors for adolescent Internet victimization: results from a 2008 nationwide Danish youth survey. AB - AIM: To examine the rate of Internet victimization in a nationally representative sample of adolescents aged 14-17 and to analyze predictors and protective factors for victimization. METHODS: Data were collected for 3707 pupils in Danish schools in 2008, using a multimedia computer-based self-interviewing programme. Family characteristics, alcohol and drug abuse, exposure to physical/sexual abuse, emotional problems, social conduct and own risky Internet behaviour were included in the analyses. RESULTS: Any online victimization was reported by 27% of the adolescents, most frequently a rumour spread online (9% of boys and 15% of girls) and sexual solicitation (5% of boys and 16% of girls). Parental surveillance of adolescents' Internet use significantly reduced their risk of online victimization. Roughly half of the adolescents had met Internet acquaintances face to face, with few instances resulting in forced sex (five boys and nine girls). Female gender, parental physical violence, previous exposure to sexual abuse, alcohol abuse in the family, self-reported emotional problems and antisocial behaviour and high Internet use were all weakly and risky online behaviour strongly associated with online victimization. CONCLUSIONS: Danish adolescents are generally aware of the principles of 'safe chatting'; however, online harassment is relatively frequent, but offline victimization based on Internet acquaintances is rare. PMID- 22211949 TI - Space-time data fusion under error in computer model output: an application to modeling air quality. AB - We provide methods that can be used to obtain more accurate environmental exposure assessment. In particular, we propose two modeling approaches to combine monitoring data at point level with numerical model output at grid cell level, yielding improved prediction of ambient exposure at point level. Extending our earlier downscaler model (Berrocal, V. J., Gelfand, A. E., and Holland, D. M. (2010b). A spatio-temporal downscaler for outputs from numerical models. Journal of Agricultural, Biological and Environmental Statistics 15, 176-197), these new models are intended to address two potential concerns with the model output. One recognizes that there may be useful information in the outputs for grid cells that are neighbors of the one in which the location lies. The second acknowledges potential spatial misalignment between a station and its putatively associated grid cell. The first model is a Gaussian Markov random field smoothed downscaler that relates monitoring station data and computer model output via the introduction of a latent Gaussian Markov random field linked to both sources of data. The second model is a smoothed downscaler with spatially varying random weights defined through a latent Gaussian process and an exponential kernel function, that yields, at each site, a new variable on which the monitoring station data is regressed with a spatial linear model. We applied both methods to daily ozone concentration data for the Eastern US during the summer months of June, July and August 2001, obtaining, respectively, a 5% and a 15% predictive gain in overall predictive mean square error over our earlier downscaler model (Berrocal et al., 2010b). Perhaps more importantly, the predictive gain is greater at hold-out sites that are far from monitoring sites. PMID- 22211948 TI - Reversal of functional defects in highly differentiated young and old CD8 T cells by PDL blockade. AB - Highly differentiated CD8(+) CD28(-) CD27(-) T cells have short telomeres, defective telomerase activity and reduced capacity for proliferation. In addition, these cells express increased levels of inhibitory receptors and display defective Akt(ser(473)) phosphorylation following activation. It is not known whether signalling via programmed death 1 (PD-1) contributes to any of the attenuated differentiation-related functional changes in CD8(+) T cells. To address this we blocked PD-1 signalling during T-cell receptor (TCR) activation using antibodies against PD-1 ligand 1 (PDL1) and PDL2. This resulted in a significant enhancement of Akt(ser(473)) phosphorylation and TCR-induced proliferative activity of highly differentiated CD8(+) CD28(-) CD27(-) T cells. In contrast, the reduced telomerase activity in these cells was not altered by blockade of PDL1/2. We also demonstrate that PD-1 signalling can inhibit the proliferative response in primary human CD8(+) T cells from both young and older humans. These data collectively highlight that some, but not all, functional changes that arise during progressive T-cell differentiation and during ageing are maintained actively by inhibitory receptor signalling. PMID- 22211950 TI - Pseudoaneurysm after ultrasound-guided vacuum-assisted core breast biopsy. PMID- 22211951 TI - Validation of a method for recording pharmaceutical interventions. AB - WHAT IS KNOWN AND OBJECTIVE: The validation of a method for recording pharmaceutical interventions measures the instrument's ability to provide consistent values when the same analysis is performed several times. Our aim was to validate the inter-rater reliability of the method used to record pharmaceutical interventions in our hospital. METHODS: We recorded interventions in a database, entering variables related to the patient, treatment and impact of the recommendation. We also recorded the type, cause and clinical significance of the negative outcome associated with use of the medicinal product (NOM). Twenty interventions performed during a 3-year study period (2007-2009) were randomly tested for consistency to analyse the kappa (kappa) coefficient statistic of the recommendations as coded by nine senior and junior clinical pharmacists. RESULTS AND DISCUSSION: There were 87.8% global consistency for NOM cause, 66.1% for intervention impact and 95.0% for NOM type. Agreement was substantial for 'intervention reasons', with a kappa value of 0.74 (95%CI 0.61-0.87), fair for 'intervention impact', with a kappa value of 0.24 (95%CI 0.15-0.32) and excellent for 'NOM type', with a kappa value of 0.87 (95%CI 0.71-1.00), respectively. Our results are globally good, especially with regard to the analysis of intervention reasons and NOM type, which matches other authors' findings. Furthermore, our validation method is suitable for recording and considering the impact of pharmaceutical interventions. WHAT IS NEW AND CONCLUSION: We describe a systematic method for clinical pharmacists to record their activities and assess their value. This methodology should help in the development of clinical pharmacy in Spain and should be translatable to other settings. PMID- 22211952 TI - The protective effects of Ginkgo biloba extract (EGb-761) on radiation-induced dermatitis: an experimental study. AB - BACKGROUND: Irradiation of the skin induces production of free radicals, resulting in oxidative stress. EGb-761, an extract from the leaves of the Ginkgo biloba tree, has been reported to be an effective exogenous antioxidant based on its free-radical scavenger properties. AIM: To investigate the protective effect of G. biloba extract (EGb-761) on radiation-induced dermatitis in rats. METHODS: Forty male Wistar rats were divided equally into four groups: group 1 received sham radiotherapy (RT) without EGb-761, group 2 received sham RT with EGb-761, group 3 received RT without EGb-761, and group 4 received RT with EGb-761. Levels of malondialdehyde (MDA), nitric oxide (NOx) and glutathione (GSH) were measured. Dermatitis was assessed with a semiquantitative dermatitis item score. The intensity of staining and diffusion of expression for proliferating cellular nuclear antigen (PCNA) and transforming growth factor (TGF)-beta3 were also evaluated. RESULTS: The enhanced oxidative stress seen after RT was markedly diminished when EGb-761 was administered with RT; significantly lower mean MDA (P < 0.005) and higher mean GSH (P < 0.001) levels were seen in group 4 compared with group 3. Although there was a decrease in NOx levels, this was not significant. All (100%) of the animals in group 3 developed dermatitis, whereas only 13% of the animals in group 4 did so (P < 0.0001). There was a significant difference between group 1 and group 3 in PCNA and TGF-beta3 staining (P < 0.05), whereas no difference was seen between groups 3 and 4; however, the intensity of staining and diffusion of expression were lower in group 4 than in group 3. CONCLUSIONS: Prophylactic administration of EGb-761 seems to have a protective effect against radiation-induced dermatitis. PMID- 22211953 TI - Virulence genotypes and drug resistance of Helicobacter pylori from Vladivostok, Russia: another feature in the Far East. AB - Helicobacter pylori in Vladivostok, Far Eastern Russia, was investigated during 2004 to 2009. The genotype cagA(+) vacA(+) (s1/m1 or m2) accounted for 74.7%, with cagA(-) vacA(+) (s2/m2) at 11.2%. The CagA EPIYA type was mainly Western ABC, with minor types (ABCCC and novel AAABC) or non-Western/non-East Asia type (AB). Regarding drug resistance, metronidazole resistance was the highest, with a marked decrease in 6 years (from 71.4% to 30.8%); in contrast, levofloxacin and clarithromycin resistance increased. The data indicate that in Vladivostok, H. pylori was mainly the Western (not East Asian) type and dynamic changes in drug resistance occurred during 6 years. PMID- 22211955 TI - Long-term structural canopy changes sustain net photosynthesis per ground area in high arctic Vaccinium uliginosum exposed to changes in near-ambient UV-B levels. AB - Full recovery of the ozone layer is not expected for several decades and consequently, the incoming level of solar ultraviolet-B (UV-B) will only slowly be reduced. Therefore to investigate the structural and photosynthetic responses to changes in solar UV-B we conducted a 5-year UV-B exclusion study in high arctic Greenland. During the growing season, the gas exchange (H2O and CO2) and chlorophyll-a fluorescence were measured in Vaccinium uliginosum. The leaf dry weight, carbon, nitrogen, stable carbon isotope ratio, chlorophyll and carotenoid content were determined from a late season harvest. The net photosynthesis per leaf area was on average 22% higher in 61% reduced UV-B treatment across the season, but per ground area photosynthesis was unchanged. The leaf level increase in photosynthesis was accompanied by increased leaf nitrogen, higher stomatal conductance and F(v)/F(m). There was no change in total leaf biomass, but reduction in total leaf area caused a pronounced reduction of specific leaf area and leaf area index in reduced UV-B. This demonstrates the structural changes to counterbalance the reduced plant carbon uptake seen per leaf area in ambient UV-B as the resulting plant carbon uptake per ground area was not affected. Thus, our understanding of long-term responses to UV-B reduction must take into account both leaf level processes as well as structural changes to understand the apparent robustness of plant carbon uptake per ground area. In this perspective, V. uliginosum seems able to adjust plant carbon uptake to the present amount of solar UV-B radiation in the High Arctic. PMID- 22211956 TI - Efficacy of alfuzosin and sildenafil combination in male patients with lower urinary tract symptoms. AB - Lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) are frequently encountered in ageing males. We compared the efficacy of alfuzosin 10 mg alone or in combination with sildenafil 50 mg in the treatment of LUTS due to benign prostatic hyperplasia. One hundred male patients older than 45 years were randomized to two groups containing 50 patients each; one group receiving alfuzosin 10 mg and the other group alfuzosin 10 mg combined with sildenafil 50 mg. International Prostate Symptom Score (IPSS), quality of life (QoL), maximum flow rate (Q(max)), prostate volume and post-void residual urine were evaluated. The mean age was 60.2 +/- 17.8. Mean data of evaluated parameters in both groups at the end of 3rd month compared with baseline values are given respective order as; 5.1 (26.8%) and 5.8 (28.2%) points decreases in IPSS; 1.6 (41.1%) and 1.8 (45%) points decreases in QoL; and 3.4 (29.6%) and 3.4 (33%) points increases in Q(max) . The outcomes of our study cannot be interpreted in such a way to report that alpha blocker-PDE5 inhibitor combination has a better efficacy than alpha blocker treatment alone in patients with LUTS. PMID- 22211957 TI - Morphologic analysis of third-molar mineralization for eastern Turkish children and youth. AB - To date, there has been no chronological age estimation according to third-molar mineralization in eastern Turkish children and adolescents. The aim of this study was to analyze the development of the mandibular third molar and its relationship to chronological age in subjects aged 7-22 years according to Demirjian's stages. The final sample consisted of 1348 [622 males (mean age, 12.72 +/- 3.14) and 726 females (mean age, 12.92 +/- 2.89)] conventional orthopantomograms from eastern Turkish youths. An independent t-test was performed to evaluate the difference between sexes. Regression analysis was performed to obtain regression formulae for dental age calculation with chronological age. In males, there was a difference between males and females only at stage C (p = 0.03); females were advanced 0.37 years compared with males at the stage C. Third-molar development among eastern Turkish children and youths occurs at a more advanced age than other populations for almost all stages. PMID- 22211959 TI - Giant basal cell carcinoma of the skin: literature review and personal experience. AB - As the most common form of skin cancer, basal cell carcinoma (BCC) is typified by locally infiltrative growth and a very low risk of metastasis. On occasion, however, this otherwise indolent neoplasm may behave aggressively, demonstrating deep tissue invasion and a high rate of postsurgical recurrence. The pathogenesis and determinants of such tenacious growth are not completely understood. Only 1% of all BCC's achieve the status of 'giant', as defined in 1988 by the American Joint Committee on Cancer. In this article, the authors provide a comprehensive review of the scientific literature on giant basal cell carcinoma (GBCC) of the skin and report their experience with this rare tumour subtype. PMID- 22211960 TI - Factors influencing the fulfillment of women's preferences for birthing positions during second stage of labor. AB - Having choices and being involved in decision making contributes to women's positive childbirth experiences. During a physiological birth, women's preferences can play a leading role in the choice of birthing positions. In this study, we explored women's preferences with regard to birthing positions during second stage of labor, with a special focus on women who preferred positions other than common supine positions. A questionnaire survey was conducted among women in 54 Dutch midwifery practices. Of the 1154 women in the study, 58.9% preferred supine positions, 19.6% preferred other positions (e.g. sitting or standing), and 21.5% had no distinct preference. Women who preferred supine positions gave birth in these positions more often than women with preferences for other positions. Among the women having a preference for other positions, the actual fulfillment of their preference was related to longer duration of second stage of labor, higher levels of education, the strength of the preference, and giving birth at home. These results demonstrate differences in women's use of preferred positions during childbirth. Midwives can contribute to women-centered care by proactively exploring women's preferences for birthing positions throughout pregnancy and birth, supporting women in developing well-informed choices and facilitating these choices where possible. PMID- 22211961 TI - A D-octapeptide drug efflux pump inhibitor acts synergistically with azoles in a murine oral candidiasis infection model. AB - Clinical management of patients undergoing treatment of oropharyngeal candidiasis with azole antifungals can be impaired by azole resistance. High-level azole resistance is often caused by the overexpression of Candida albicans efflux pump Cdr1p. Inhibition of this pump therefore represents a target for combination therapies that reverse azole resistance. We assessed the therapeutic potential of the D-octapeptide derivative RC21v3, a Cdr1p inhibitor, in the treatment of murine oral candidiasis caused by either the azole-resistant C. albicans clinical isolate MML611 or its azole-susceptible parental strain MML610. RC21v3, fluconazole (FLC), or a combination of both drugs were administered orally to immunosuppressed ICR mice at 3, 24, and 27 h after oral inoculation with C. albicans. FLC protected the mice inoculated with MML610 from oral candidiasis, but was only partially effective in MML611-infected mice. The co-application of RC21v3 (0.02 MUmol per dose) potentiated the therapeutic performance of FLC for mice infected with either strain. It caused a statistically significant decrease in C. albicans cfu isolated from the oral cavity of the infected mice and reduced oral lesions. RC21v3 also enhanced the therapeutic activity of itraconazole against MML611 infection. These results indicate that RC21v3 in combination with azoles has potential as a therapy against azole-resistant oral candidiasis. PMID- 22211963 TI - Have animal models of disease helped or hindered the drug discovery process? AB - Animal models have played an important role in target validation, screening of compounds for efficacy and optimization of pharmacokinetic properties and toxicological testing. However, new paradigms for drug discovery and development will require a greater emphasis on animal models of mechanism. PMID- 22211962 TI - The butanol fraction of guava (Psidium cattleianum Sabine) leaf extract suppresses MMP-2 and MMP-9 expression and activity through the suppression of the ERK1/2 MAPK signaling pathway. AB - The leaf extract of guava (Psidium cattleianum Sabine) has traditionally been used for the treatment of diarrhea and diabetes in East Asia and other countries. Recently, the leaf extract has been employed in the therapy of cancer, bacterial infections, and inflammation in experimental models. However, the exact mechanisms of how guava leaf extract inhibits tumor metastasis and invasion are still unknown. In the present study, we investigated in detail the molecular mechanism(s) responsible for the potential antimetastatic and antiinvasive effects of the butanol fraction of guava leaf extract (GBF). Interestingly, we observed for the first time that GBF suppressed both matrix metalloproteinases (MMP)-9 and MMP-2 expression and activity in part through the downregulation of the ERK1/2 activation in lung cancer cells. Also, importantly, the major components of the GBF were identified as d-glucuronic acid, quercetin 3 glucuronide, loganin, and xanthyletin by LC-ESI-MS/MS. Collectively, our data indicate that the guava leaf could reduce the metastasis of lung cancer cells and therefore suggest that it could be advantageously used to control the metastatic process. PMID- 22211964 TI - Current models and strategies in the development of antiobesity drugs. AB - Animal models have enabled investigation of the complex mechanisms underlying energy homeostasis and, therefore, the development of antiobesity drugs. PMID- 22211965 TI - Relevance of angiotensin II-induced aortic pathologies in mice to human aortic aneurysms. AB - Angiotensin II infusion in mice promotes abdominal and thoracic aortic aneurysms, which provides a feasible approach to study the mechanisms of these two distinct diseases. PMID- 22211967 TI - Animal welfare and the 3Rs in European biomedical research. AB - The new Directive 2010/63/EU to ensure harmonization of animal experimentation rules has potential to increase implementation of the 3Rs (reduce, refine, replace) and improve animal welfare across Europe. PMID- 22211966 TI - Novel, nonreflex tests detect analgesic action in rodents at clinically relevant concentrations. AB - We propose that predictive validity of tests for analgesia may be improved by looking to reinstate specific, innate behaviors suppressed by pain, e.g., burrowing, because effective plasma concentrations in the rat are closer to effective clinical plasma concentrations than those generally used in rodent reflex withdrawal assays. PMID- 22211968 TI - Best practices for the use of animals in toxicological research and testing. AB - Animal models serve an important role in assessing preclinical safety and efficacy of new medicines and vaccines; however, such assessments can involve significant pain and distress and large numbers of animals. Best practice approaches seek to enhance animal well-being, minimize or avoid pain and distress, and use fewer animals. Advances in science and technology are providing opportunities for improved mechanism-based models and integrated safety assessments that will support improved animal welfare and reduce animal use. PMID- 22211969 TI - Progress toward generating informative porcine biomedical models using induced pluripotent stem cells. AB - Porcine induced pluripotent stem cells hold significant promise in modeling human biomedical regenerative medicine and as translational large animal disease models. PMID- 22211970 TI - A knockout mouse resource for the biomedical research community. AB - The Knockout Mouse Project (KOMP) Repository archives and distributes vectors, embryonic stem cell clones, frozen germplasm, and live mutant mice for 8,500 knockout genes. Here, we describe the creation and functions of the KOMP Repository. PMID- 22211971 TI - Minimizing strain influences in a genetically modified mouse phenotyping platform. AB - Our approach has been to power studies to allow for detection of at least modest changes from a wild-type littermate control, include assays with overlapping physiological systems to provide cross-functional interpretive value, and to employ challenge assays. PMID- 22211972 TI - The blessings and curses of C57BL/6 substrains in mouse genetic studies. AB - Phenotypic and genetic differences among C57BL/6 substrains are accumulating. Investigators must address these differences to improve the quality of their studies. PMID- 22211973 TI - Modeling inflammation and microvascular dysfunction. AB - We are using confocal intravital microscopy to understand the mechanisms behind leukocyte trafficking in the brain, thus providing potential therapeutic targets for neurovascular diseases, for example, stroke and multiple sclerosis. PMID- 22211974 TI - TRPV1 and TRPA1 channels in inflammatory pain: elucidating mechanisms. AB - Transient receptor potential (TRP) receptors are ion channels that mediate pain and inflammation. We provide evidence for the distinct roles of TRPV1 and TRPA1 in arthritis. PMID- 22211975 TI - Imaging of endocrine gene expression in a humanized transgenic rat. AB - Reporter gene imaging has revealed cyclical patterns of gene expression in living cells. Transgenic animal studies show that these patterns are modified by tissue architecture. PMID- 22211976 TI - Systems biology of the heart: hype or hope? AB - Systems biology, the approach that combines reduction and integration to explore dynamic structure-function interrelations across biomedically relevant spatio temporal scales, is applied to heart research. PMID- 22211977 TI - Is it time for in silico simulation of drug cardiac side effects? AB - Cardiac simulation is used to integrate information on drug action to predict side effects on the whole heart. Could simulation begin to replace animal models? PMID- 22211978 TI - Human stem cell-derived cardiomyocytes for pharmacological and toxicological modeling. AB - Cardiomyocytes derived from human pluripotent stem cells have advantages for modeling in terms of phenotype, longevity in culture, ease of transfection, and high-throughput capability. PMID- 22211979 TI - Humanized mice as a preclinical tool for infectious disease and biomedical research. AB - Immunodeficient mice bearing an IL2rgamma(null) mutation permit engraftment of a functional human immune system and study of human-specific infectious agents that was not previously possible. PMID- 22211980 TI - Humanized mice for the study of type 1 and type 2 diabetes. AB - The availability of immunodeficient mice engrafted with functional human immune systems and islets permits in vivo study of human diabetes without putting patients at risk. PMID- 22211981 TI - Deconstructing hepatitis C virus infection in humanized mice. AB - Hepatitis C virus is a major medical problem. Novel small-animal models are likely to accelerate the development of more effective therapeutics and a vaccine. PMID- 22211982 TI - Animal models got you puzzled?: think pig. AB - Swine are an excellent large animal model for human health and disease because their size and physiology are similar to humans, in particular, with respect to the skin, heart, gastrointestinal tract, and kidneys. In addition, the pig has many emerging technologies that will only enhance the development of the pig as the nonrodent biomedical model of choice. PMID- 22211983 TI - Neuroradiology investigations before scanning. AB - Coaxial tomography (CT) and magnetic resonance imaging (MRI) scans are so much part of neurological investigation these days and provide such detailed information that even thorough neurological clinical examination may be neglected. The investigations in common use forty years ago were pneumoencephalography, ventriculography in babies with hydrocephalus, and carotid angiography with the injection of X-ray contrast to outline the arteries. PMID- 22211984 TI - RHD alleles in Brazilian blood donors with weak D or D-negative phenotypes. AB - The RHD gene is highly polymorphic and the existence of a large number of alleles results in RhD variant phenotypes. RHD genotyping has been used to distinguish normal D antigen from D variants due to limitations of serologic methods. The purpose of this study was to determine the phenotypic frequency of RhD and RhCE antigens and to investigate the RHD alleles present in samples with the weak D or D- phenotypes from Brazilian blood donors. A total of 2007 donors were phenotyped for D, C, c, E and e antigens. Samples phenotyped as D- were genotyped by polymerase chain reaction-sequence specific primers, and exon 10 and intron 4 of the RHD gene were analysed. D- samples containing the RHD gene or samples considered weak D were further characterised using genotyping platform or nucleotide sequencing. Using serologic methods we found that 87.3% of the donors were D+, 11.9% D- and 0.8% weak D. The frequency of RHD gene in D- individuals was 9.2%. Five RHD alleles from phenotypically D- donors were characterised in six molecular backgrounds: RHDPsi, RHD-CE-D(s), RHD-CE-(2-9)-D, RHD/RHDPsi, RHDPsi/RHD-CE-D(s) and RHD-CE(2)-D. The most common weak D antigens types found were 1, 3, 4.0/4.1 and 4.2, whereas the most prevalent weak D type was 4.2 (or DAR). The RHD genotyping proved to be a necessary tool to characterise RHD alleles in donors phenotyped as D- or weak D to increase the transfusion safety in highly racial mixed population. PMID- 22211986 TI - Successful intra-arterial thrombolytic therapy for a right middle cerebral artery stroke in a 2-year-old supported by a ventricular assist device. AB - Embolic stroke is a common complication in patients on ventricular assist devices in both adults and children. The reported incidence of strokes in children supported by VAD's varies from 7 to 38%. The rapid increase in recent years in the availability of both adult and pediatric VADs will likely add to the overall prevalence of strokes in patients being bridged to heart transplant. Strokes in this population can be lethal as they frequently necessitate withdrawal of the extracorporeal device support and withdrawal from the organ transplant waiting list. We present a case of a fully anti-coagulated 29-month-old supported on a Berlin EXCOR LVAD (Berlin, Germany) with embolic stroke which was treated successfully with direct thrombolysis with recombinant tissue plasminogen activator. This is the first report which uses intra-arterial thrombolytics while on a ventricular assist device in a pediatric patient. PMID- 22211988 TI - Matrix metalloproteinase-9 and non-amyloidogenic pathway of amyloid precursor protein processing. PMID- 22211989 TI - Expression pattern of a 'Plus-C' class odorant binding protein in the antenna of the malaria vector Anopheles gambiae. AB - In the malaria mosquito Anopheles gambiae (Ag), olfaction plays a crucial role in various behaviours, most strikingly in the seeking of females after a blood meal. The first step of odorant recognition in antennal sensilla involves soluble odorant binding proteins (OBPs), which transfer odorous compounds to olfactory receptors (ORs) in the dendritic membrane of sensory neurons. A particular OBP subtype of the 'Plus-C' class, called AgOBP48, is abundantly transcribed in female antennae and partially down-regulated after a blood meal, suggesting a possible role in host detection. In the present study, we have identified the AgOBP48-expressing cells, explored their antennal topography and determined their position relative to cells that express the 'classic' AgOBP1, the AgOR co receptor (AgOrco) and the receptor AgOR1. By means of two-colour whole-mount fluorescence in situ hybridization it was found that AgOBP48 was expressed in cells, which are closely associated with AgOrco-expressing sensory neurons. Furthermore, AgOBP48 was not expressed in the same cells as AgOBP1, but subpopulations of AgOBP48- and of AgOBP1-expressing cells were found closely associated and adjacent to sensory neurons expressing AgOR1. Together, the results indicate that cells that express either AgOBP48, AgOBP1 or AgOR1 are housed together in distinct olfactory sensilla and that an interplay of the proteins may contribute to the specific responsiveness of the sensillum to distinct odorants. PMID- 22211987 TI - Quantitative T2' imaging in patients with clinically isolated syndrome. AB - OBJECTIVE: The T2' imaging has been shown to be sensitive to oxygen saturation changes in normal appearing white and grey matter (NAWM, NAGM) in patients with relapsing-remitting multiple sclerosis (RRMS). We aimed to explore the presence and extent of T2' changes in patients with a clinically isolated syndrome (CIS) and a possible association of T2' with conventional magnetic resonance imaging and clinical outcomes. MATERIAL AND METHODS: Quantitative T2- and T2*-weighted images were acquired in 32 treatment-naive patients with a CIS within 3 months of presentation and 15 age-matched healthy controls (HC). Quantitative T2' values were determined in six regions of interest (ROIs). RESULTS: The T2' values in CIS did not differ significantly from those in HC. Among patients, T2' values correlated positively with the T2 lesion volume (T2LV, r = 0.34, P < 0.05). T2' values of the frontal NAWM correlated with the T2LV (r = 0.35, P < 0.05) and T2 lesion count (r = 0.4, P = 0.02). CONCLUSION: As opposed to RRMS, patients with CIS did not show T2' alterations compared to HC. However, the association between the T2LV and higher T2' values suggests that T2' reflects disease evolution. In CIS metabolic changes might be masked by compensatory mechanisms and become overt when disease progresses as has been shown for RRMS patients. PMID- 22211992 TI - A correlation between fractional anisotropy variations and clinical recovery in spinal cord infarctions. AB - PURPOSE: To describe diffusion-weighted imaging and diffusion tensor imaging variations in spinal cord infarctions. METHODS: We studied the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) local variations in 2 patients with spinal cord infarcts in the conus region at days 3-4, 9-10, and 15-22 after clinical onset, and correlated them with the clinical outcome. RESULTS: Both patients (19 and 53 years-old) presented spinal cord infarction unraveled by paraparesis and bladder dysfunction. Although initial clinical and radiological presentations were similar, the first patient early and fully recovered whereas the second kept severe bladder dysfunctions. Early absolute values of FA and ADC did not seem to correlate with outcome. At day 9-10, the second patient, who presented definitive sequel, had decreasing values of FA in the ischemic region whereas they had increased in the first patient, who fully recovered. CONCLUSION: FA values could be an interesting prognosis marker in spinal cord ischemia, which needs to be confirmed by a larger study. PMID- 22211993 TI - A comparison of echo-enhanced voiding urosonography with X-ray voiding cystourethrography in the first year of life. AB - BACKGROUND: Second-generation echo-enhanced voiding urosonography (VUS) with improved contrast-specific ultrasound (US) techniques is increasingly being used for vesicoureteric reflux (VUR) detection. AIM: To compare VUS with X-ray voiding cystourethrography (VCUG) and to evaluate the predictive value of pelvicalyceal dilatation for detecting VUR in the first year of life. MATERIALS AND METHODS: Sixty-six children younger than one were investigated by US, VUS and VCUG. VCUG represented the reference method for VUR detection. RESULTS: According to VCUG, VUR was present in 16/132 (12%) renal units. VUS confirmed all these and additionally revealed VUR in 26 renal units (all together 42/132 (32%) renal units with VUR). It should be noted that all VUR detected only with VUS and missed by VCUG were of grades II and III. In 27/92 (29%) US normal and in 15/40 (37%) renal units with pelvicalyceal dilatation, VUR was detected by VUS. CONCLUSION: We believe that VUS could safely replace VCUG in VUR detection in infants, with no regard to the degree of abnormality of the upper urinary tract seen on US. VCUG should be limited only to cases where bladder and/or urethra pathology are suspected. PMID- 22211996 TI - Photoinduced dermatitis and oral lichenoid reaction in a chronic myeloid leukemia patient treated with imatinib mesylate. AB - BACKGROUND: Imatinib mesylate (IM) is a phenylaminopyrimidine that represents the first-line treatment for chronic myeloid leukemia (CML), Philadelphia chromosome positive. It acts as a potent and selective inhibitor of the bcr-abl fusion protein by a competitive inhibition at the adenosine triphosphate-binding site of the enzyme, which leads to the inhibition of tyrosine phosphorylation of the proteins involved in bcr-abl signal transduction. IM is generally well tolerated and usually provokes only mild side effects consisting of nausea, myalgia, edema and muscle cramps. OBSERVATION: This is a report of a patient affected by CML, who developed a photoinduced dermatitis and an oral lichenoid reaction associated with IM treatment. The lesions were resolved, thanks to the withdrawal of the therapy, and they relapsed after the reintroduction of IM, confirming the drug induced pathogenesis. CONCLUSION: Skin changes are the most common non hematologic side effects to IM treatment and are usually dose dependent. In particular, patients with IM therapy reported a lightening and depigmentation of the skin, that may alter the skin protection against ultraviolet exposure, with a possible subsequent intolerance to sun exposure, as reported in our patient, and higher risk of skin cancer. They are frequently self-limited or easily managed; nevertheless, in some cases, the therapy needs to be discontinued or may only be continued with concomitant oral steroid. PMID- 22211994 TI - Foxp3(+) regulatory T cells, immune stimulation and host defence against infection. AB - The immune system is intricately regulated allowing potent effectors to expand and become rapidly mobilized after infection, while simultaneously silencing potentially detrimental responses that averts immune-mediated damage to host tissues. This relies in large part on the delicate interplay between immune suppressive regulatory CD4(+) T (Treg) cells and immune effectors that without active suppression by Treg cells cause systemic and organ-specific autoimmunity. Although these beneficial roles have been classically described as counterbalanced by impaired host defence against infection, newfound protective roles for Treg cells against specific viral pathogens (e.g. herpes simplex virus 2, lymphocytic choriomeningitis virus, West Nile virus) have been uncovered using transgenic mice that allow in vivo Treg-cell ablation based on Foxp3 expression. In turn, Foxp3(+) Treg cells also provide protection against some parasitic (Plasmodium sp., Toxoplasma gondii) and fungal (Candida albicans) pathogens. By contrast, for bacterial and mycobacterial infections (e.g. Listeria monocytogenes, Salmonella enterica, Mycobacterium tuberculosis), experimental manipulation of Foxp3(+) cells continues to indicate detrimental roles for Treg cells in host defence. This variance is probably related to functional plasticity in Treg cell suppression that shifts discordantly following infection with different types of pathogens. Furthermore, the efficiency whereby Treg cells silence immune activation coupled with the plasticity in Foxp3(+) cell activity suggest that overriding Treg-mediated suppression represents a prerequisite 'signal zero' that together with other stimulation signals [T-cell receptor (signal 1), co-stimulation (signal 2), inflammatory cytokines (signal 3)] are essential for T-cell activation in vivo. Herein, the importance of Foxp3(+) Treg cells in host defence against infection, and the significance of infection induced shifts in Treg-cell suppression are summarized. PMID- 22211997 TI - Excimer light photototherapy of segmental and non-segmental vitiligo: experience in Taiwan. AB - PURPOSE: To determine the efficacy of excimer light in the treatment vitiligo and to assess parameters affecting therapeutic results. METHODS: This retrospective study analyzed 227 patches of vitiligo in 142 patients. Treatment was performed twice weekly and treatment efficacy was assessed by two independent dermatologists. Patients who received less than 24 treatment sessions were excluded from the analysis of predictive factors for response. RESULTS: Sixty eight (30.0%) patches achieved more than 50% repigmentation, and 42 (18.5%) achieved more than 75% repigmentation. The mean treatment numbers to achieve any repigmentation and more than 50% repigmentation were 19.41 and 34.93, respectively. Fewer treatment sessions number, segmental lesions and absence of melasma were significant predictors for poor treatment response in multivariate analysis. Lesions on the hands/feet needed the highest dose and scalp lesions needed the highest number of treatment sessions to produce initial repigmentation. CONCLUSIONS: Excimer light is a valuable treatment modality for both segmental and non-segmental vitiligo even in patients who have failed previous treatments. The number of treatment sessions needed to produce initial pigmentation may be higher than 30 for scalp lesions. There is a need to find other combination methods, both medical and surgical, to enhance its therapeutic efficacy. PMID- 22211998 TI - Protective effects of beta-carotene and melanin against protoporphyrine IX induced phototoxicity in the photo hen's egg test. AB - PURPOSE: The aim of our study was to evaluate the photoprotective potential of melanin and beta-carotene against protoporphyrine IX-induced phototoxicity via photo hen's egg test. METHODS: In three independent test groups, the yolk sac blood vessel system of hen's eggs was exposed to protoporphyrine IX and irradiated with ultraviolet A (UVA). One of the test groups also received melanin to investigate its photoprotective capacity; another test group received beta carotene for the same purpose. Morphological changes and embryo lethality were recorded in these three test groups for a period of 24 h. The same parameters were obtained in five different control groups. RESULTS: The control groups exhibited only minimal morphological changes and no fatalities. In contrast, severe phototoxic damage and a high lethality rate (75%) were observed in the test group exposed to protoporphyrine IX and UVA. Lethality was somewhat lower in the beta-carotene test group (58%) and was considerably lower in the melanin test group (17%). CONCLUSIONS: The photoprotective potential against protoporphyrine IX-induced phototoxic damage was moderate for beta-carotene and was remarkable for melanin. Given that synthetic melanocyte stimulating hormone (MSH) analogues induce a de novo synthesis of melanin without any previous ultraviolet irradiation in human skin, the application of MSH analogues might be conceived of as 'light hardening' without light. Synthetic MSH analogues thus may represent a new promising therapeutic option for photodermatoses especially for erythropoietic protoporphyria. PMID- 22211999 TI - Effect of PUVA therapy on melanocytes and keratinocytes in non-segmental vitiligo: histopathological, immuno-histochemical and ultrastructural study. AB - BACKGROUND AND AIMS: Psoralen ultraviolet A (PUVA) is an important modality in treating vitiligo. Its effect on melanocytes and keratinocytes is not sufficiently studied. In this work, we investigated 30 cases of non-segmental vitiligo regarding the changes of melanocytes and keratinocytes in both vitiliginous and nearby areas before and after PUVA therapy. METHODS: Three skin biopsies were obtained from each patient from the vitiliginous, marginal and perilesional areas before and after 12 months of PUVA. Biopsies were examined histologically using haematoxylin and eosin, Masson-Fontana stains and 3,4 dihydroxyphenylalanine (DOPA) reaction and histochemically using human melanoma black-45 (HMB-45) antibody while ultrastructural examination was performed on six patients. Control biopsies were taken from five healthy volunteers. RESULTS: In 10% of pretreated biopsies from the centre of vitiligo lesions, scanty melanocytes were detected histologically and ultrastructurally, while they did not stain with DOPA or HMB-45 antibody suggesting that these melanocytes were inactive. Moreover, degenerative changes were detected by electron microscopy in both melanocytes and keratinocytes in all areas. After PUVA therapy, obvious improvement of the histopathological changes occurred with significant increase in active melanocytes. The degeneration of melanocytes and keratinocytes was also reduced at the ultrastructural level. CONCLUSION: Vitiligo affects both melanocytes and keratinocytes causing degenerative changes. These changes were present in both the leucodermic and the apparently normal perilesional skin. PUVA increases the number of active epidermal melanocytes in the three tested areas and recovers the melanocyte and keratinocyte degeneration. PMID- 22212000 TI - Neonatal mice do not have increased sensitivity to induction of squamous cell carcinomas. AB - BACKGROUND: Squamous cell carcinoma (SCC) is linked with the lifelong cumulative effect of ultraviolet radiation (UVR). In contrast, epidemiological data have shown that sunburn in childhood is a stronger risk factor for cutaneous malignant melanoma than continuous UVR, indicating a higher carcinogenic sensitivity early in life. METHODS: We investigated how a high neonatal dose of UVR affects the development of SCC in mice irradiated later in life. We used simulated solar radiation (sun) and solarium radiation (solarium). Ninety-nine C3.Cg/TifBomTac immunocompetent hairless mice received 0, 25 or 35 standard erythema doses (SED) UVR when they were 4 days old followed by 4 SED sun or 4 SED solarium three times/weekly from 9 weeks of age. RESULTS: Tumours developed faster in mice treated with 35 SED UVR + 4 SED sun compared with 4 SED sun, but no change was observed in the cumulative dose required to achieve tumours. Tumours also developed faster in mice treated with 35 SED UVR + 4 SED solarium compared with 4 SED solarium, and a difference was also observed in the cumulative dose required to achieve tumours. If the Skin Cancer Utrecht-Philadelphia-murine spectrum was used to weigh the delivered irradiance instead of the International Commission on Illumination erythema action spectrum, tumours developed after the same accumulated dose. CONCLUSION: In conclusion, this study does not indicate increased sensitivity to induction of SCC early in life. PMID- 22212001 TI - Miniature swine model of phototoxicity testing. AB - BACKGROUND/PURPOSE: This study determined the threshold doses for 'solar erythema' and for phototoxic responses to 8-methoxypsoralen (8-MOP) in white skin Hanford and grey skin Yucatan miniature swine. METHODS: For threshold erythema determinations, the UVR exposures included both UVA (315-400 nm) and UVB (290-315 nm) radiation by positioning one fluorescent 'sunlamp' among 10 'PUVA' lamps. With this configuration the UVR exposures ranged from 0.5-2.8 times the 'instrumental MED' (MEDi) for Hanford and from 1.0-5.6 times the MEDi for Yucatan. For phototoxicity determinations (i.e., with and without topically applied graduated concentrations of 8-MOP), the UVB component was minimized by extinguishing the sunlamp, thus permitting higher UVA exposures. RESULTS: The Hanford had the lower UV erythema dose threshold (1.0-1.4 times the MEDi) and the erythema that developed was readily observable. The exposure doses for the phototoxicity test were 5 J/cm(2) of UVA in 35 minutes or 10 J/cm(2) in 70 minutes. The phototoxic (vascular) response to 8-MOP was observed in the two highest concentrations (0.01% and 0.1%) in Hanford pigs, in a dose-related manner. Microscopic evidence of a dose-related response was also observed as the concentration of 8-MOP increased. CONCLUSION: This verified that the Hanford miniature swine is the preferable strain for phototoxic effects. In contrast, UVR exposure of the Yucatan pig skin produced tanning rather than erythema, confirming that the Yucatan is the more appropriate strain for studying the melanization response. Thus, Hanford and Yucatan miniature swine have cutaneous photobiological responses that reflect their respective strain differences. PMID- 22212002 TI - A new morphometric technique for assessment of melanization in skin of guinea pigs. AB - BACKGROUND: The degree of melanization is an important finding in many skin disorders. An objective measurement of melanin density is needed to achieve an accurate evaluation. OBJECTIVES: The present work aims at translating the subjective increase of melanin particles after narrow band ultraviolet-B (NB-UVB) irradiation into objective numerical values ready for statistical analysis. MATERIALS AND METHODS: This study had involved 18 guinea pigs that were exposed to biweekly sessions of NB-UVB radiation for 4 weeks to induce skin pigmentation. Two skin biopsies were obtained from each animal; the first before treatment and the second at the end of the study, using 5 mm punch and stained with hematoxylin and eosin and Masson-Fontana (MF) stains. Surface area of both the epidermis (ESA) and the melanin particles (MPSA) were measured in MUm(2) using a software supplied with Olympus light microscope. The MPSA/ESA percentage was calculated for each biopsy. The results before and after NB-UVB exposure were compared and statistically analyzed. RESULTS: In the MF-stained sections, the mean +/- SD of the MPSA/ESA percentage were 0.24 MUm(2) +/- 0.09 and 6.21 MUm(2) +/- 2.45 at the start of the study and at its end, respectively, with a highly significant difference (P < 0.001). CONCLUSION: This technique offers a new methodology for an accurate numerical evaluation of epidermal melanization. PMID- 22212003 TI - Granuloma annulare photoinduced by paroxetine. AB - Granuloma annulare (GA) is a benign granulomatous skin disease with several clinical manifestations and characteristic histological findings. GA located in photoexposed areas is a rare finding and its association to a drug-induced systemic photosensitivity is even less common. To the best of our knowledge, only one case of systemic drug photosensitivity manifesting as a GA has been reported. We describe a patient with systemic photosensitivity to paroxetine with clinical and histological manifestations of GA, which was confirmed by the photobiological study. The phototest revealed a reduction of the minimal erythematous dose for UVB while taking the paroxetine and its normalization after its withdrawal, which was accompanied by the clinical resolution of the skin eruption. The manifestation of systemic drug photosensitivity as a GA like in our case is exceptional. PMID- 22212004 TI - Acquired perforating dermatosis successfully treated with photodynamic therapy. AB - Acquired perforating dermatosis is a rare perforating skin disorder characterized by intensely pruritic papules or nodules with central adherent plugs mainly observed on the lower extremities and transepidermal elimination of collagen bundles. Treatment of acquired perforating dermatosis is a matter of debate and conventional treatment options including topical and systemic retinoids, topical corticosteroids and keratolytics, ultraviolet B phototherapy, psoralen plus ultraviolet A (PUVA), allopurinol and cryosurgery show mixed results. Herein, we describe a 60-year-old woman with a diagnosis of acquired perforating dermatosis secondary to diabetes mellitus in whom we achieved excellent results with photodynamic treatment. As far as we are aware, this is the first case report of photodynamic treatment for acquired perforating dermatosis. PMID- 22212005 TI - Incomplete efficacy of 5-aminolevulinic acid (5 ALA) photodynamic therapy in the treatment of widespread extramammary Paget's disease. AB - Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) is an effective treatment for several conditions such as Bowen's disease, subsets of basal cell carcinomas and actinic keratosis. Surgical resection is the first-choice therapy for extramammary Paget's disease (EMPD), but extensive resection is highly invasive and recurrences are frequent. We report two cases of genital EMPD treated by PDT with partial efficacy. The first patient, a 78-year-old male, suffered from pubic and scrotal Paget's disease for 6 years despite numerous treatments. The second patient, a 78-year-old female, had vulvar involvement for 2 years that was resistant to multiple treatments. The disease was recurrent and chronic with important pruritus and significant impact on the quality of life. Methyl 5-aminolevulinate was applied for 3 h, and irradiation was applied with red light (630 nm) using a total light dose of 37 J/cm(2) for a period of 10 min. The patients were treated every 2 to 4 weeks for a total of at least three treatments. Both patients experienced a partial transient reduction in their symptoms. One patient had a partial transient remission (< 50% reduction of the involved surface), whereas in the other patient, PDT failed to reduce the surface area of the lesions. PMID- 22212006 TI - Using the Johns Hopkins' Aggregated Diagnosis Groups (ADGs) to predict 1-year mortality in population-based cohorts of patients with diabetes in Ontario, Canada. AB - AIMS: There are limited validated methods to ascertain comorbidities for risk adjustment in ambulatory populations of patients with diabetes using administrative health-care databases. The objective was to examine the ability of the Johns Hopkins' Aggregated Diagnosis Groups to predict mortality in population based ambulatory samples of both incident and prevalent subjects with diabetes. METHODS: Retrospective cohorts constructed using population-based administrative data. The incident cohort consisted of all 346,297 subjects diagnosed with diabetes between 1 April 2004 and 31 March 2008. The prevalent cohort consisted of all 879,849 subjects with pre-existing diabetes on 1 January, 2007. The outcome was death within 1 year of the subject's index date. RESULTS: A logistic regression model consisting of age, sex and indicator variables for 22 of the 32 Johns Hopkins' Aggregated Diagnosis Group categories had excellent discrimination for predicting mortality in incident diabetes patients: the c-statistic was 0.87 in an independent validation sample. A similar model had excellent discrimination for predicting mortality in prevalent diabetes patients: the c-statistic was 0.84 in an independent validation sample. Both models demonstrated very good calibration, denoting good agreement between observed and predicted mortality across the range of predicted mortality in which the large majority of subjects lay. For comparative purposes, regression models incorporating the Charlson comorbidity index, age and sex, age and sex, and age alone had poorer discrimination than the model that incorporated the Johns Hopkins' Aggregated Diagnosis Groups. CONCLUSIONS: Logistical regression models using age, sex and the John Hopkins' Aggregated Diagnosis Groups were able to accurately predict 1 year mortality in population-based samples of patients with diabetes. PMID- 22212007 TI - Two-dimensional informative array testing. AB - Array-based group-testing algorithms for case identification are widely used in infectious disease testing, drug discovery, and genetics. In this article, we generalize previous statistical work in array testing to account for heterogeneity among individuals being tested. We first derive closed-form expressions for the expected number of tests (efficiency) and misclassification probabilities (sensitivity, specificity, predictive values) for two-dimensional array testing in a heterogeneous population. We then propose two "informative" array construction techniques which exploit population heterogeneity in ways that can substantially improve testing efficiency when compared to classical approaches that regard the population as homogeneous. Furthermore, a useful byproduct of our methodology is that misclassification probabilities can be estimated on a per-individual basis. We illustrate our new procedures using chlamydia and gonorrhea testing data collected in Nebraska as part of the Infertility Prevention Project. PMID- 22212008 TI - Salivary gland choristoma of breast. PMID- 22212010 TI - Comparison of two methods for isolating DNA from human skeletal remains for STR analysis. AB - The quality and efficiency of a standard organic DNA isolation method and a silica-based method using the QIAGEN Blood Maxi Kit were compared to obtain human DNA and short tandem repeats (STRs) profiles from 39 exhumed bone samples for paternity testing. DNA samples were quantified by real-time PCR, and STR profiles were obtained using the AmpFlSTR((r)) Identifiler((r)) PCR amplification kit. Overall, the silica-based method recovered less DNA ranging from 0 to 147.7 ng/g (average 7.57 ng/g, median = 1.3 ng/g) than did the organic method ranging from 0 to 605 ng/g (average 44.27 ng/g, median = 5.8 ng/g). Complete profiles (16/16 loci tested) were obtained from 37/39 samples (95%) using the organic method and from 9/39 samples (23%) with the silica-based method. Compared with a standard organic DNA isolation method, our results indicate that the published silica based method does not improve neither the quality nor the quantity of DNA for STR profiling. PMID- 22212012 TI - Shortcuts in complex engineering systems: a principal-agent approach to risk management. AB - In this article, we examine the effects of shortcuts in the development of engineered systems through a principal-agent model. We find that occurrences of illicit shortcuts are closely related to the incentive structure and to the level of effort that the agent is willing to expend from the beginning of the project to remain on schedule. Using a probabilistic risk analysis to determine the risks of system failure from these shortcuts, we show how a principal can choose optimal settings (payments, penalties, and inspections) that can deter an agent from cutting corners and maximize the principal's value through increased agent effort. We analyze the problem for an agent with limited liability. We consider first the case where he is risk neutral; we then include the case where he is risk averse. PMID- 22212011 TI - Compliance of deferoxamine injection in beta-thalassaemia major patients in Iran. AB - AIM/OBJECTIVE: Iran is located on the Mediterranean belt and has high prevalence of thalassaemia. Deferoxamine therapy requires burdensome hours of daily infusion several times a week. METHODS: We studied 510 thalassaemia major patients referring to thalassaemia tertiary care centre for compliance of deferoxamine and also assessed various reasons for non-compliance. A questionnaire was developed. RESULTS: Our study showed that 418 (82%) subjects were adherent to deferoxamine therapy. Females were more adherent to the chelation therapy. Among patients whose age was <= 12 years, 90.4% showed drug compliance compared with 80.3% in patients aged >12 years (P = 0.03). The most frequently reported reason for poor compliance was pain (38%). CONCLUSION: High percentage of patients had adherence to iron chelation, which is in contrast to previous studies. This may be attributed to the vigorous efforts of governmental and non-governmental organisations in educating patients and provision of free drug and equipment in the past few years. The results were satisfying but still more is to be done to increase drug adherence and to minimise reasons causing poor compliance. PMID- 22212013 TI - Theoretical studies of chromophore maturation in the wild-type green fluorescent protein: ONIOM(DFT:MM) investigation of the mechanism of cyclization. AB - The availability of a gene encoding green fluorescence immediately stimulates interest in the puzzle of autocatalytic formation of the green fluorescent protein (GFP) chromophore. Numerous experimental and theoretical studies have indicated that cyclization is the first and most important step in the maturation process of the GFP. In our previous paper based on cluster models [J. Phys. Chem. B2010, 114, 9698-9705], two possible mechanisms have been investigated with the conclusion that the backbone condensation initiated by deprotonation of the Gly67 amide nitrogen is easier than deprotonation of the Tyr66 alpha-carbon. However, the impact of the protein environment on the reaction mechanism remains to be explored. In this paper, we investigated the two possible mechanisms with inclusion of protein environmental effects by using molecular dynamics (MD) and combined quantum mechanics/molecular mechanics (QM/MM) calculations. Our calculations reveal no hydrogen bonding network that would facilitate deprotonation of the amide nitrogen of Gly67, although it is the lower energy pathway in the cluster model system. Contrastingly, there is a hydrogen bonding network between Tyr66 alpha-carbon and Glu222, which is in good agreement with X ray data. The ONIOM studies show that proton transfer from Tyr66 alpha-carbon to Glu222 is a long-distance charge transfer process. The charge distribution of the MM region has a significant perturbation to the wave function for the QM region, with the QM energy for the proton transfer product being increased under the influence of the electrostatic protein environment. The barrier for the rate limiting step in cyclization is quite high, about 40.0 kcal/mol in the case of ONIOM-EE. PMID- 22212014 TI - Melatonin attenuates doxorubicin-induced testicular toxicity in rats. AB - This study investigated the protective effects of melatonin (MLT) against doxorubicin (DXR)-induced testicular toxicity and oxidative stress in rats. DXR was given as a single intraperitoneal dose of 10 mg kg(-1) body weight to male rats at 1 h after MLT treatment on day 6 of the study. MLT at 15 mg kg(-1) body weight was administered daily by gavage for 5 days before DXR treatment followed by an additional dose for 5 days. Sperm analysis, histopathological examination and biochemical methods were used for this investigation. DXR caused a decrease in the weight of seminal vesicles, epididymal sperm count and motility and an increase in the incidence of histopathological changes of the testis. In addition, an increased malondialdehyde (MDA) concentration and decreased glutathione content, glutathione reductase (GR), glutathione-S-transferase (GST), superoxide dismutase (SOD) and catalase activities were observed. On the contrary, MLT treatment significantly ameliorated DXR-induced testicular toxicity in rats. Moreover, MDA concentration and GR, GST and SOD activities were not affected when MLT was administered in conjunction with DXR. These results indicate that MLT had a protective effect against DXR-induced testicular toxicity and that the protective effects of MLT may be due to both the inhibition of lipid peroxidation and increased antioxidant activity. PMID- 22212015 TI - Mucocutaneous manifestations of HIV-infected patients in the era of HAART in Guangxi Zhuang Autonomous Region, China. AB - BACKGROUND: Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) are frequently associated with diverse mucocutaneous manifestations. However, few studies of HIV/AIDS-related mucocutaneous manifestations have been reported in China. OBJECTIVE: To investigate the occurrence of mucocutaneous disorders and their relationship with the degree of immunosuppression in 348 HIV-infected Chinese patients. The influence of highly active antiretroviral therapy (HAART) on the spectrum of mucocutaneous manifestations was also evaluated. METHODS: A cross-sectional study was performed on 348 HIV-infected Chinese patients seen at the Guangxi Longtan Hospital from August 2010 to November 2010. Collected information included demographic data, HIV-associated mucocutaneous disorders, CD4 cell count, AIDS defining illness and antiretroviral therapy. RESULTS: In this study, 62.9% of all patients had mucocutaneous disorders. The prevalence of mucocutaneous disorders in the patients who had received HAART was lower than in those without HAART (54.05% vs. 88.76%, P < 0.001). The prevalence of mucocutaneous disorders was higher in the patients with CD4 < 200 cells/mm(3) in comparison to those with CD4 >= 200 cells/mm(3) (P < 0.05). The most common mucocutaneous disorders were oral candidiasis (28.47%), Penicillium marneffei infection (11.49%), drug eruptions (10.06%) and pruritic papular eruption (PPE 5.75%). Oral candidiasis, P. marneffei infection and PPE were significantly more prevalent in patients with a CD4 cell count below 200 cells/mm(3) , but frequency of drug eruptions was not related to the level of CD4 cell counts. Patients treated with HAART had decreased rates of herpes simplex, oral candidiasis and P. marneffei infection, but increased rates of drug eruptions. CONCLUSIONS: A wide range of mucocutaneous disorders were observed in HIV-infected Chinese patients. Oral candidiasis, P. marneffei infection and PPE may be the signs of advanced HIV infection. HAART had an impact on the spectrum of HIV-associated mucocutaneous disorders. PMID- 22212016 TI - CTBT (7-chlorotetrazolo[5,1-c]benzo[1,2,4]triazine) producing ROS affects growth and viability of filamentous fungi. AB - CTBT (7-chlorotetrazolo[5,1-c]benzo[1,2,4]triazine) causes intracellular superoxide production and oxidative stress and enhances the susceptibility of Saccharomyces cerevisiae, Candida albicans, and C. glabrata cells to cycloheximide, 5-fluorocytosine, and azole antimycotic drugs. Here, we demonstrate the antifungal activity of CTBT against 14 tested filamentous fungi. CTBT prevented spore germination and mycelial proliferation of Aspergillus niger and the pathogenic Aspergillus fumigatus. The action of CTBT is fungicidal. CTBT increased the formation of reactive oxygen species in fungal mycelium as detected by 2',7'-dichlorodihydrofluorescein diacetate and reduced the radial growth of colonies in a dose-dependent manner. Co-application of CTBT and itraconazole led to complete inhibition of fungal growth at dosages lower than the chemicals alone. Antifungal and chemosensitizing activities of CTBT in filamentous fungi may be useful in combination treatments of infections caused by drug-resistant fungal pathogens. PMID- 22212017 TI - Scintigraphic evaluation of intra-arterial and intravenous regional limb perfusion of allogeneic bone marrow-derived mesenchymal stem cells in the normal equine distal limb using (99m) Tc-HMPAO. AB - REASONS FOR PERFORMING STUDY: Mesenchymal stem cells (MSCs) are commonly injected intralesionally for treatment of soft tissue injuries in the horse. Alternative routes of administration would be beneficial for treatment of lesions that cannot be accessed directly or to limit needle-induced iatrogenic damage to the surrounding tissue. OBJECTIVES: The purpose of our study was to evaluate MSC distribution after intra-arterial (IA) and intravenous (IV) regional limb perfusions (RLP) using scintigraphy. We hypothesised that MSCs would persist in the distal limb after tourniquet removal and that both techniques would lead to diffuse MSC distribution. METHODS: Six horses were used in the study. MSCs were labelled with hexamethyl propylene amine oxime (HMPAO) and technetium-99m. RLP was performed through the median artery of one forelimb and the cephalic vein of the opposite limb under general anaesthesia. The tourniquet was left in place for 45 min. Scintigraphic images were obtained at 0, 45, 75 min, 6 h and 24 h post injection. RESULTS: Distribution of labelled MSCs through the entire distal limb was achieved with all 6 IA RLP, but 3 out of 6 IV RLP showed poor or absent uptake distal to the metacarpus. Mesenchymal stem cell persistence was 39% (30 60%) and 28% (14-50%) (median [minimum-maximum]) at 6 h for IA and IV RLP, respectively. Severe arterial thrombosis occurred in one horse after IA RLP. CONCLUSIONS: Both IA and IV RLP of the distal limb result in MSC persistence in perfused tissues. The IA perfusion resulted in more reliable cell distribution to the pastern and foot area. POTENTIAL RELEVANCE: Regional limb perfusion of MSCs might be used in cases where intralesional injection is not possible or in order to avoid iatrogenic needle damage. Further work is needed to assess the safety of IA RLP before its clinical use. PMID- 22212020 TI - Criminal recidivism and mortality among patients discharged from a forensic medium secure hospital. AB - BACKGROUND: One of the goals in forensic psychiatric care is to reduce the risk of recidivism, but current knowledge about the general outcome of forensic psychiatric treatment is limited. AIMS: To analyse the rate of criminal recidivism and mortality after discharge in a sample of patients sentenced to forensic psychiatric treatment in a Swedish county. METHODS: All offenders in Orebro County, Sweden, sentenced to forensic psychiatric treatment and discharged during 1992-2007 were included: 80 males and eight females. Follow-up data was retrieved from the Swedish National Council for Crime Prevention, the National Cause-of-Death register and clinical files. Mean follow-up time was 9.4 years. RESULTS: The mean age at discharge was 40 years. Schizophrenia, other psychoses and personality disorders were the most prevalent diagnoses. Thirty-eight percent of those still alive and still living in the country re-offended and were sentenced to a new period of forensic psychiatric treatment or incarceration during follow-up. Four male re-offenders committed serious violent crimes. Substance-related diagnosis was significantly associated with risk of recidivism and after adjustment for diagnoses, age and history of serious violent crime, the Hazard Ratio was 4.04 (95% CI 1.51-10.86, P = 0.006). Of all included patients, 23% had died at the end of follow-up (standardized mortality rate 10.4). CONCLUSIONS: Since repetition of serious violent crimes was unusual, results indicate a positive development subsequent to treatment for those alive at follow up. CLINICAL IMPLICATIONS: The high mortality rate suggests that more attention should be paid in evaluation of the patients' somatic and psychiatric health during and after care in order to prevent premature death. PMID- 22212022 TI - Cortical activation changes in patients suffering from post-stroke arm spasticity and treated with botulinum toxin a. AB - BACKGROUND AND PURPOSE: Botulinum toxin (BoNT) treatment relieves focal arm spasticity after stroke, likely acting at several hierarchical levels of the motor system. The central correlate of BoNT-induced spasticity relief may be detected using repeated functional MRI (fMRI) during motor task. METHODS: Five patients (4 males, 1 female, mean age 67 years) with hemiparesis and distal arm spasticity after chronic ischemic stroke were studied. FMRI was performed while moving the paretic hand in three sessions: before and 4 and 11 weeks after BoNT treatment. RESULTS: Arm spasticity significantly decreased following BoNT treatment across the group (mean modified Ashworth scale change .6). FMRI prior to BoNT treatment showed extensive bilateral active networks, whereas post-BoNT activation was limited to midline and contralateral sensorimotor cortices, and the third examination, when the toxin effect has worn off, again showed extensive activation similar to pre-BoNT examination. Post-BoNT session 2 compared to sessions 1 and 3 demonstrated a significantly less activation in contralateral frontoparietal areas including inferior frontal, postcentral, and middle frontal gyri as well as transient crossed cerebellar activation. CONCLUSION: Relief of post-stroke arm spasticity may be associated with changes at several hierarchical levels of the cortical sensorimotor system, including the prefrontal cortex. PMID- 22212024 TI - Investigation of a significant increase in referrals during neonatal hearing screening: a comparison of Natus ALGO Portable and ALGO 3i. AB - OBJECTIVE: Neonatal hearing screening programs in Flanders and the Netherlands use Natus ALGO screening devices. Since 2006 in Flanders and 2009 in the Netherlands, both programs have replaced the older ALGO Portable devices with the newer ALGO 3i devices. However, in both countries, ALGO 3i devices have a significantly higher rate of referrals than ALGO Portable devices. In Flanders, the refer rate has more than doubled with the switch to ALGO 3i devices. In the Netherlands, screening centers which used ALGO 3i devices also showed a significant increase in referrals. In both countries, the percentage of children diagnosed with permanent hearing loss remained approximately the same. DESIGN: A technical comparison of both device types was carried out to identify possible causes for the increase in referrals. The stimulus output of two ALGO Portable and three ALGO 3i devices was recorded and analysed for stimulus level, spectral properties, and stimulus irregularities. RESULTS: ALGO 3i devices stimulate at a peak level 4.6 dB lower than ALGO Portable devices, have a different stimulus spectrum and show unexplained stimulus irregularities during 4% of the stimulation time. CONCLUSIONS: A number of technical differences were found between both device types which could explain the increase in referrals. PMID- 22212025 TI - Botryomycosis presenting as nasal cutaneous fistulas caused by Prevotella melaninogenica. AB - Botryomycosis is an uncommon chronic suppurative granulomatous bacterial infection that can affect the skin and viscera. Clinically, lesions typically consist of small tender nodules from which draining sinuses may develop to expel a purulent discharge. Histopathological features include characteristic aggregation of microorganisms (grain) within the inflammatory infiltrate. The commonest causative organisms are Staphylococcus aureus and Pseudomonas aeruginosa, of others. Botryomycosis resulting from Prevotella melaninogenica has not been reported previously. We report the case of a middle-aged patient with botryomycosis presenting as nasal cutaneous fistulas caused by P. melaninogenica, which was successfully treated with surgical intervention combined with systemic antibiotic treatment. PMID- 22212027 TI - Musculoskeletal disorders and ergonomics in dermatologic surgery: a survey of Mohs surgeons in 2010. AB - BACKGROUND: Dermatologic surgeons perform numerous procedures that put them at risk of developing work-related musculoskeletal disorders. OBJECTIVE: To study the prevalence of work-related musculoskeletal disorders and role of ergonomics in dermatologic surgery. METHODS AND MATERIALS: A survey study was sent to members of the American College of Mohs Surgery in 2010. The main outcome measures were survey responses relating to surgeon demographics, musculoskeletal symptoms, workstyle habits and attitudes, and ergonomic practices. RESULTS: Ninety percent of respondents reported some type of musculoskeletal symptoms or injuries. The most common complaints were neck, lower back, shoulder, and upper back pain. Most respondents were not using ergonomic modifications in their practice. CONCLUSION: Mohs surgeons have a high prevalence of musculoskeletal disorders. Symptoms present early and persist throughout the careers of Mohs surgeons. The nature of the occupation leaves the surgeon vulnerable to injury. Ergonomic modifications in behavior and workplace are recommended to reduce pain and injury to surgeons. PMID- 22212019 TI - Microbial antigenic variation mediated by homologous DNA recombination. AB - Pathogenic microorganisms employ numerous molecular strategies in order to delay or circumvent recognition by the immune system of their host. One of the most widely used strategies of immune evasion is antigenic variation, in which immunogenic molecules expressed on the surface of a microorganism are continuously modified. As a consequence, the host is forced to constantly adapt its humoral immune response against this pathogen. An antigenic change thus provides the microorganism with an opportunity to persist and/or replicate within the host (population) for an extended period of time or to effectively infect a previously infected host. In most cases, antigenic variation is caused by genetic processes that lead to the modification of the amino acid sequence of a particular antigen or to alterations in the expression of biosynthesis genes that induce changes in the expression of a variant antigen. Here, we will review antigenic variation systems that rely on homologous DNA recombination and that are found in a wide range of cellular, human pathogens, including bacteria (such as Neisseria spp., Borrelia spp., Treponema pallidum, and Mycoplasma spp.), fungi (such as Pneumocystis carinii) and parasites (such as the African trypanosome Trypanosoma brucei). Specifically, the various DNA recombination-based antigenic variation systems will be discussed with a focus on the employed mechanisms of recombination, the DNA substrates, and the enzymatic machinery involved. PMID- 22212028 TI - Combined enhancements of temperature and UVB influence growth and phenolics in clones of the sexually dimorphic Salix myrsinifolia. AB - Although several climatic factors are expected to change simultaneously in the future, the effect of such combined changes on plants have seldom been tested under field conditions. We report on a field experiment with dark-leaved willow, Salix myrsinifolia, subjected to enhancements in ultraviolet-A (UVA), UVB radiation and temperature, setup in Joensuu, Eastern Finland. S. myrsinifolia is a dioecious species, known as an important food plant for many herbivores. Cuttings of eight clones, four of each sex, of dark-leaved willow were planted in the field in spring 2009. In both 2009 and 2010, the total biomass increased significantly with temperature, and in 2010 there was an additive effect of UVB radiation. Both height and diameter increased with temperature in 2009, while the effect on height growth ceased in 2010. Males had greater diameter growth than females in 2010. Most phenolic compounds in the leaves decreased under enhanced temperature in both growing seasons. In 2010, four of six salicylates increased in response to enhanced temperature. Some quercetin derivatives increased under enhanced UVB radiation. Females had higher concentrations of chlorogenic acids than males, and while enhanced temperature reduced chlorogenic acid in females only, luteolins were reduced only in males. In summary, the combined enhancements gave no effects in addition to those that appeared under the single-factor treatments, except for the additive effect of UVB on temperature-increased biomass. The few gender-related differences found in response to climate change do not allow any marked expectations of future climate-induced changes in sex ratios. PMID- 22212030 TI - Sabina. PMID- 22212031 TI - Clinical work with emptiness and sexuality: a commentary on Maurizio Balsamo's paper 'Sabina'. PMID- 22212032 TI - A commentary on Maurizio Balsamo's paper 'Sabina'. PMID- 22212033 TI - Inside and outside the window: some fundamental elements in the theory of psychoanalytic technique. AB - The underlying concern of this paper is that psychoanalysis as practised today is in danger of losing its specificity and so losing its way. The author suggests this is possible for three reasons: the problem analysts face in responding to the strong emotional demands the great majority of patients necessarily place on them, the unintended consequences of the apparent success of 'here and now technique' and the absence of good clinical theory. The paper mainly discusses the author's ideas about some core elements of the clinical theory that all psychoanalysts must use when they are working and proposes (at the risk of being facile) some relatively simple heuristics related to them which are meant to be helpful. Recalling Kurt Lewin's maxim that 'there is nothing so practical as a good theory', he will suggest that continuous reflection on how one is using theory in daily practice is highly practical, if the theory is good enough. Theory in fact is a necessary 'third' in psychoanalytic practice which, if kept in sufficient working order close enough to clinical experience, provides an ongoing and very necessary check on our sense of reality. But, of course, as a third it can, like reality itself, be the focus of both love and hate with equally problematic consequences. The paper starts with a clinical example of a difficult but apparently successful analysis reaching its end, which will be used throughout the paper to illustrate and elaborate the theoretical ideas set out. PMID- 22212034 TI - On authenticity: the question of truth in construction and autobiography. AB - Freud was occupied with the question of truth and its verification throughout his work. He looked to archaeology for an evidence model to support his ideas on reconstruction. He also referred to literature regarding truth in reconstruction, where he saw shifts between historical fact and invention, and detected such swings in his own case histories. In his late work Freud pondered over the impossibility of truth in reconstruction by juxtaposing truth with 'probability'. Developments on the role of fantasy and myth in reconstruction and contemporary debates over objectivity have increasingly highlighted the question of 'truth' in psychoanalysis. I will argue that 'authenticity' is a helpful concept in furthering the discussion over truth in reconstruction. Authenticity denotes that which is genuine, trustworthy and emotionally accurate in a reconstruction, as observed within the immediacy of the analyst/patient interaction. As authenticity signifies genuineness in a contemporary context its origins are verifiable through the analyst's own observations of the analytic process itself. Therefore, authenticity is about the likelihood and approximation of historical truth rather than its certainty. In that respect it links with Freud's musings over 'probability'. Developments on writing 'truths' in autobiography mirror those in reconstruction, and lend corroborative support from another source. PMID- 22212035 TI - The analytic state of consciousness as a form of play and a foundational transference. AB - The analytic state of consciousness is a particular regressive altered state in the patient characterized by an increased sensitivity and reactivity to impressions arising from both the inner world and the analyst, a heightened sense of dependence and vulnerability, a permeability of boundaries in regard to the analyst, and a shift toward functioning on the basis of omnipotent fantasy in the analytic relationship. These changes are accompanied by a feeling of realness of one's psychic reality, but without any true loss of reality testing. Based on an analysis of the structure of play, this state can itself be understood as a kind of play; it serves as a foundational transference underlying more specific transference manifestations; and it is central to the analytic process. Over time, in response to physical aspects of the analytic setting, its safety, the analyst's emotional accompaniment, and a generally restrained analytic stance (an issue I discuss in some detail), it emerges in a more developed form that promotes symbolization and ownership of aspects of self, greater emotional presence, and a deeper sense of meaning in one's experience. Additionally, the concept of the analytic state of consciousness provides a new look at the role of abstinence and frustration in analytic process. PMID- 22212036 TI - 'A serious venture': John Rodker (1894-1955) and the Imago Publishing Company (1939-60). AB - John Rodker (1894-1955) was the founder of the British publishing house--the Imago Publishing Company--which undertook the republication of the complete works of Sigmund Freud in German just before World War II. Rodker, himself a writer as well as a publisher, was initially tempted by a psychoanalytic career; numerous obstacles, however, lay in his path. War, along with the complicated management of the royalties from Freud's writings, compromised the progress of what seemed to him to be 'a serious venture'. Besides Rodker, we meet numerous actors of the psychoanalytic movement: Anna Freud, Marie Bonaparte, Ernest Jones, James Strachey, all of whom had worked for the dissemination of Freud's writings. This paper shows how the English language gradually became the 'official norm' for psychoanalysts. According to the editors of the Standard Edition, at that time 'nothing new [was] being written' in German or in French. The failure of the Gesammelte Werke project signalled the end of an era in which psychoanalysis was mainly written about in German. PMID- 22212037 TI - Vicissitudes of ideas of cure in analysands and their analysts: a longitudinal interview study. AB - This longitudinal prospective study focuses on analysands' and analysts' implicit ideas of how psychoanalysis might help analysands' psychological problems. Seven analysands and their analysts were periodically interviewed. Single ideas of cure from 75 interviews were inductively categorized. Nine distinct types of cures emerged, representing the wished-for goals of psychoanalysis, as well as the actions to achieve the wished-for changes. Each category might comprise more or less utopian ideas of wished-for cure as well as ideas of an attainable, more limited cure, or combinations of these. The utopian ideas of wished-for cures persisted throughout the psychoanalytic process for more than half the analysands and analysts. The abandonment of these ideas was related to the experienced outcome of psychoanalysis. The relation between the theories of one analysand and her analyst is explored in depth in a case study with special emphasis on the analytic process. The study suggests that the psychoanalytic process might profit from the analyst's observance of such incongruities and an openness to work through them. PMID- 22212038 TI - A 'quantum' of truth in a field of lies: the investigation of emotional truth in a child analysis. AB - Following Bion's ideas of analytical research the author intends to consider the need to pursue emotional truth between patient and psychotherapist in order to produce a psychological development. It is shown through the analysis of a child how emotional falsification can distort first of all the definition of the child identity. Successively the attention is focused on how lies, as an unconscious element that twist the research of the truth, obstruct the development of thoughts able to transform emotions.Using a quantisation physical model of space, the author hypothesises that the transformation of beta elements in alpha elements is always in an unstable equilibrium. The distortion of emotional truth co-produced by lies affects the oscillation beta<->alpha at a primitive level of transformation, changing the "physical" state of the analytical field from conductor to insulator. The most important consequence of the particular point of view suggested by the quantistic model is that in the third analytical space the same definition of alpha elements or beta elements depends on the analyst's point of view. This change of perspective can vitalise the analytical thinking of patient and analyst during an impasse. PMID- 22212039 TI - Limitations to the capacity to love. AB - This paper is a meditation on the potential and problems of establishing and maintaining loving and passionate relationships, drawn from a lifetime of struggling with these issues in the course of doing analysis. It describes interferences with the capacity for mature sexual love as reflecting various psychopathological conditions. These limitations include a variety of psychological restrictions determined most frequently by masochistic, narcissistic and paranoid personality features. Clinical case material illustrates both mature and disturbed capability for love relations. PMID- 22212040 TI - Metamorphosis and the aesthetics of loss: II. Lady of the woods--the transformative lens of Francesca Woodman. AB - As interpreted by the celebrated American photographer, Francesca Woodman, the myth of Apollo and Daphne forms an allegorical locus for the transitions and tensions of adolescence and young adulthood. Woodman's employment of this myth and related themes is also expressive of a preoccupying topos of regressive longings. Seamlessly extending Ovid's transformation of the metamorphic myths into poetic epic, her work delves deeply into their driving purpose: to make sense of change, of loss, and of life itself. Over the millennia, classical myth is infused and enriched with personal meaning by the reanimating, clarifying and transformative lens of art. PMID- 22212041 TI - Thoughts on Rigoletto. AB - The author discusses the traditional interpretations of the principal dramatis personae in Verdi's Rigoletto, suggesting that the opera expresses the composer's unconscious but highly perceptive and intuitive exploration of: (i) paranoid and perverse father-daughter oedipal dynamics as enacted between Rigoletto and Gilda; (ii) a folie-a-deux sado-masochistic relationship between Rigoletto and the Duke; (iii) the avoidance of conscious guilt and responsibility for Rigoletto's part in the tragedy through the rejection of insight achieved via massive projection, an addiction to mania, and perversion. In this respect Rigoletto is compared with King Lear. Some technical aspects of Verdi's compositional style employed to portray the contrasting characters of the protagonists are analysed. The paper also touches on Verdi's own possible unconscious (as well as conscious) investment in this particular opera, noting similarities between Verdi's portrait of the tragic, hunchback jester and his own self-depiction. The author notes similarities and contrasts between his analysis of the opera and recent papers by Hudson (1992),Tarnopolsky (1995)and Bergstein (2003)on the same subject. PMID- 22212042 TI - Separation and individuation in Picasso's Guernica. AB - A systematic, psychoanalytically oriented analysis of Picasso's preparatory studies for his master-painting Guernica as well as of his many alterations in the course of his work on the painting itself revealed a prominent concern with issues of attachment and of separation, differentiation and maturation, in association with loss, death and destruction. Background information on the circumstances of Picasso's work on the painting, his personality and his biography, as well as information gleaned from other of his works from various periods of his life were also taken into account. Integration of the direct findings from the analysis of Guernica's evolution and from this comprehensive background information suggests that the process of creating Guernica represents a symbolic attempt at individuation and establishment of separateness from the mother, by means of aggressive acts expressed towards representations of the mother figure in the painting. The preparatory studies and the painting itself are perceived as transitional objects. PMID- 22212043 TI - On neuropsychoanalytic metaphysics. AB - Neuropsychoanalysis focuses on the neural counterparts of psychoanalytically interesting phenomena and has left the difference in the metaphysical presuppositions between neuroscience and psychoanalysis unexamined. The authors analyse the logical possibilities concerning the relation between the brain and the mental unconscious in terms of the serial, parallel, epiphenomenalist and Kantian conceptions, and conclude that none of them provides a satisfactory ground for neuropsychoanalysis. As far as psychoanalytic explanations refer to the mental unconscious, they cannot be verified with the help of neuroscience. Neither is it possible to form a picture of how a neuro-viewpoint might be of help for psychoanalytic theorizing. Neuropsychoanalysis has occasionally been seen as a reductionist affair, but the authors suggest that neuropsychoanalysts themselves lean on the hybrid conception, which combines neuroscientific and psychoanalytic viewpoints. The authors state arguments in favour of the interfield conception of neuropsychoanalysis that takes seriously the metaphysical tensions between neuroscience and psychoanalysis. PMID- 22212044 TI - Some thoughts on the diffusion of psychoanalysis: the group dimension, ethics and the sense of identity. AB - In this paper the author questions some of the ways in which psychoanalysis is passed on to the wider public, one of which is sometimes evocative of the sales promotion of a consumer product in contemporary society. This methodology does not give sufficiently deep prior thought to the eventual consequences of side effects. The detailed exposition of clinical cases, for example, raises sensitive ethical issues, even when anonymity is preserved. Although it is true that making information about Freud's theories more widely available may indeed encourage people to think about training as psychoanalysts, it is noticeable that this process is sometimes considered to be a form of training in itself. Some participants feel that acquiring a psychoanalytical vocabulary and reading clinical reports form a sufficient basis for practising thereafter as psychotherapists, both in institutional contexts and in private practice. The absence of group work on the part of the organizers might explain why closer study is not made of the methodologies of transmission and the different levels that it involves. This is sometimes due to the absence of a common object, formed within and by the group, and to the emergence of manic defences in the group. PMID- 22212045 TI - Transcending the caesura: the reading effects of Borges's fiction. AB - This essay explores the assumption that the sense of perplexity and surprise that characterizes the reading of many of Borges's works of fiction is related to these stories' direct and explicit exposition of transitive thoughts transcending caesurae (Bion, 1977). Borges presents a world in which diverse and even contradictory points of view or interpretations coexist. These texts allow for paradox to be acknowledged and to remain unresolved. The author suggests that Borges's writing style, the form of his stories and essays, allows for the containment of the anxiety that the possibility of evolutionary change may create. Borges's works of fiction symbolize the paradoxical nature of the caesura: inner continuity where there appears to be a break After reviewing Bion's concepts of caesura and transcendence of caesura, the stylistic devices that Borges uses in relation to the coexistence of different perspectives or interpretations will be discussed. A psychoanalytical reading of Borges's Theme of the Traitor and the Hero and The South enriches the understanding of processes of failure and success in transcending caesurae. The relevance of the transcendence of the caesura for analytic listening is underscored. PMID- 22212046 TI - The Sweet Hereafter by Atom Egoyan: extreme loss and psychic survival. AB - In a small mountain community of British Columbia a school bus swerves off the road, causing the death of 14 children. Mitchell Stephens, a New York lawyer, immediately enters the fray with the idea of instigating a large-scale lawsuit to obtain compensation for the victims, making contact with each of the parents who had lost children in the accident. Many are persuaded to join his cause. The lawyer, bombarded by phone calls from his daughter, a drug addict, even turns to Dolores Driscoll, the bus driver, who survived the accident. The latter, however, with the support of her paraplegic husband, refuses to become involved in the lawsuit. Another character who is vigorously opposed to the collective cause is Billy Ansel, a garage owner who had already lost his beloved wife and witnesses the death of his two children from the pick-up truck in which he is following the school bus. Among the survivors there is, finally, the 14 year-old Nicole Burnell, who had dreamt of becoming a folk singer and now finds herself paralysed from the waist down. Nicole is initially persuaded by the lawyer and by her parents--in particular by her father Sam, with whom she has had an incestuous relationship--to testify in favour the party seeking compensation, but when she steps into the witness box, realizing that such legal action was misguided, she offers a 'false' account of the accident, invalidating the case. Two years after the tragedy of the school bus, Mitchell Stephens bumps into Allison, a friend of his daughter's, on an airplane and ends up revealing to her some of his painful experiences. PMID- 22212047 TI - Pharmacokinetics of lidocaine and its active metabolite monoethylglycinexylidide after a single intravenous administration in chickens (Gallus domesticus) anesthetized with isoflurane. PMID- 22212048 TI - Should children dive with self-contained underwater breathing apparatus (SCUBA)? AB - Diving with self-contained underwater breathing apparatus (SCUBA) has become a popular recreational activity in children and adolescents. This article provides an extensive review of the current literature. CONCLUSIONS: Medical contraindications to SCUBA diving for adults apply to children and adolescents, too, but must be adapted. Additional restrictions to the fitness to dive must apply to both, children and adolescents. Children should always be accompanied by a trained adult when diving. PMID- 22212049 TI - Postoperative analgesia via transversus abdominis plane (TAP) catheter for small weight children-our initial experience. AB - Pain management in small infants and children is challenging. We report the use of unilateral transversus abdominis plane (TAP) catheters for analgesia following single-sided open lower abdominal surgery when epidural analgesia was undesirable in a series of six low-weight children. Data collection was done via a retrospective chart review. All catheters attempted were successfully placed with resultant low pain scores and the minimal use of rescue analgesic medications. No complications were reported related to these catheters. TAP catheters, although technically challenging, are feasible for the provision of analgesia for surgeries involving the lower abdominal wall in very small patients. PMID- 22212050 TI - Migrating thoracic epidural catheter in an infant. AB - Infants have a shorter neuraxial length and shorter skin to epidural space than adults. Even small amounts of migration may produce significant and unintended effects. Optimal fixation to prevent migration, bacterial colonization, and leakage is not clear from the literature. We report the case of a thoracic epidural that migrated inward for six centimeters, associated with loss of analgesic effect. PMID- 22212051 TI - Melatonin attenuates kainic acid-induced neurotoxicity in mouse hippocampus via inhibition of autophagy and alpha-synuclein aggregation. AB - In this study, the protective effect of melatonin on kainic acid (KA)-induced neurotoxicity involving autophagy and alpha-synuclein aggregation was investigated in the hippocampus of C57/BL6 mice. Our data showed that intraperitoneal injection of KA (20 mg/kg) increased LC3-II levels (a hallmark protein of autophagy) and reduced mitochondrial DNA content and cytochrome c oxidase levels (a protein marker of mitochondria). Atg7 siRNA transfection prevented KA-induced LC3-II elevations and mitochondria loss. Furthermore, Atg7 siRNA attenuated KA-induced activation of caspases 3/12 (biomarkers of apoptosis) and hippocampal neuronal loss, suggesting a pro-apoptotic role of autophagy in the KA-induced neurotoxicity. Nevertheless, KA-induced alpha-synuclein aggregation was not affected in the Atg7 siRNA-transfected hippocampus. The neuroprotective effect of melatonin (50 mg/kg) orally administered 1 hr prior to KA injection was studied. Melatonin was found to inhibit KA-induced autophagy lysosomal activation by reducing KA-induced increases in LC3-II, lysosomal associated membrane protein 2 (a biomarker of lysosomes) and cathepsin B (a lysosomal cysteine protease). Subsequently, KA-induced mitochondria loss was prevented in the melatonin-treated mice. At the same time, melatonin reduced KA increased HO-1 levels and alpha-synuclein aggregation. Our immunoprecipitation study showed that melatonin enhanced ubiquitination of alpha-synuclein monomers and aggregates. The anti-apoptotic effect of melatonin was demonstrated by attenuating KA-induced DNA fragmentation, activation of caspases 3/12, and neuronal loss. Taken together, our study suggests that KA-induced neurotoxicity may be mediated by autophagy and alpha-synuclein aggregation. Moreover, melatonin may exert its neuroprotection via inhibiting KA-induced autophagy and a subsequent mitochondrial loss as well as reducing alpha-synuclein aggregation by enhancing alpha-synuclein ubiquitination in the CNS. PMID- 22212052 TI - Treating childhood allergy with gut microbes: facts or fiction? PMID- 22212053 TI - Photodynamic therapy for actinic keratoses: procedure matters? PMID- 22212054 TI - Beyond atopic eczema: filaggrin loss-of-function mutations in dry, fissured hand eczema. PMID- 22212055 TI - Narrowband ultraviolet B and biologics in psoriasis. PMID- 22212056 TI - Prophylactic antibiotics for the prevention of cellulitis (erysipelas) of the leg. A commentary. PMID- 22212057 TI - Pharmacogenetic screening to prevent carbamazepine-induced toxic epidermal necrolysis and Stevens-Johnson syndrome: a critical appraisal. PMID- 22212060 TI - Commentary: pharmacogenetic screening to prevent carbamazepine-induced toxic epidermal necrolysis and Stevens-Johnson syndrome. PMID- 22212061 TI - Clear duct tape is not duct tape: reply from authors. PMID- 22212063 TI - Effect of sexual recombination on population diversity in aflatoxin production by Aspergillus flavus and evidence for cryptic heterokaryosis. AB - Aspergillus flavus is the major producer of carcinogenic aflatoxins (AFs) in crops worldwide. Natural populations of A. flavus show tremendous variation in AF production, some of which can be attributed to environmental conditions, differential regulation of the AF biosynthetic pathway and deletions or loss-of function mutations in the AF gene cluster. Understanding the evolutionary processes that generate genetic diversity in A. flavus may also explain quantitative differences in aflatoxigenicity. Several population studies using multilocus genealogical approaches provide indirect evidence of recombination in the genome and specifically in the AF gene cluster. More recently, A. flavus has been shown to be functionally heterothallic and capable of sexual reproduction in laboratory crosses. In the present study, we characterize the progeny from nine A. flavus crosses using toxin phenotype assays, DNA sequence-based markers and array comparative genome hybridization. We show high AF heritability linked to genetic variation in the AF gene cluster, as well as recombination through the independent assortment of chromosomes and through crossing over within the AF cluster that coincides with inferred recombination blocks and hotspots in natural populations. Moreover, the vertical transmission of cryptic alleles indicates that while an A. flavus deletion strain is predominantly homokaryotic, it may harbour AF cluster genes at a low copy number. Results from experimental matings indicate that sexual recombination is driving genetic and functional hyperdiversity in A. flavus. The results of this study have significant implications for managing AF contamination of crops and for improving biocontrol strategies using nonaflatoxigenic strains of A. flavus. PMID- 22212064 TI - Are three patients better than one? PMID- 22212065 TI - Obovatol improves cognitive functions in animal models for Alzheimer's disease. AB - Etiology of Alzheimer's disease (AD) is obscure, but neuroinflammation and accumulation of beta-amyloid (Abeta) are implicated in pathogenesis of AD. We have shown anti-inflammatory and neurotrophic properties of obovatol, a biphenolic compound isolated from Magnolia obovata. In this study, we examined the effect of obovatol on cognitive deficits in two separate AD models: (i) mice that received intracerebroventricular (i.c.v.) infusion of Abeta(1-42) (2.0 MUg/mouse) and (ii) Tg2576 mice-expressing mutant human amyloid precursor protein (K670N, M671L). Injection of Abeta(1-42) into lateral ventricle caused memory impairments in the Morris water maze and passive avoidance tasks, being associated with neuroinflammation. Abeta(1-42) -induced abnormality was significantly attenuated by administration of obovatol. When we analyzed with Tg2576 mice, long-term treatment of obovatol (1 mg/kg/day for 3 months) significantly improved cognitive function. In parallel with the improvement, treatment suppressed astroglial activation, BACE1 expression and NF-kappaB activity in the transgenic mice. Furthermore, obovatol potently inhibited fibrillation of Abetain vitro in a dose-dependent manner, as determined by Thioflavin T fluorescence and electron microscopic analysis. In conclusion, our data demonstrated that obovatol prevented memory impairments in experimental AD models, which could be attributable to amelioration of neuroinflammation and amyloidogenesis by inhibition of NF-kappaB signaling pathway and anti fibrillogenic activity of obovatol. PMID- 22212067 TI - The impact of human-technology cooperation and distributed cognition in forensic science: biasing effects of AFIS contextual information on human experts. AB - Experts play a critical role in forensic decision making, even when cognition is offloaded and distributed between human and machine. In this paper, we investigated the impact of using Automated Fingerprint Identification Systems (AFIS) on human decision makers. We provided 3680 AFIS lists (a total of 55,200 comparisons) to 23 latent fingerprint examiners as part of their normal casework. We manipulated the position of the matching print in the AFIS list. The data showed that latent fingerprint examiners were affected by the position of the matching print in terms of false exclusions and false inconclusives. Furthermore, the data showed that false identification errors were more likely at the top of the list and that such errors occurred even when the correct match was present further down the list. These effects need to be studied and considered carefully, so as to optimize human decision making when using technologies such as AFIS. PMID- 22212069 TI - Why the alcohol and other drug community should support gay marriage. PMID- 22212070 TI - A resounding success or a disastrous failure: re-examining the interpretation of evidence on the Portuguese decriminalisation of illicit drugs. AB - In this Harm Reduction Digest two observers and scholars of the 2001 Portuguese drug policy reform consider divergent accounts of the reform which viewed it as a 'resounding success' or a 'disastrous failure'. Acknowledging from their own experience the inherent difficulties in studying drug law reform, Caitlin Hughes and Alex Stevens take the central competing claims of the protagonists and consider them against the available data. They remind us of the way all sides of the drug policy debates call upon and alternatively use or misuse 'evidence' to feed into discussions of the worth, efficacy and desirability of different illicit drug policies. In doing so they provide pause for thought for those of us who operate as drug policy researchers and drug policy advocates. PMID- 22212071 TI - Computing free energy of a large-scale allosteric transition in adenylate kinase using all atom explicit solvent simulations. AB - During allosteric motions proteins navigate rugged energy landscapes. Hence, mapping of these multidimensional landscapes into lower dimensional manifolds is important for gaining deeper insights into allosteric dynamics. Using a recently developed computational technique, we calculated the free energy difference between the open and closed states of adenylate kinase, an allosteric protein which was extensively studied previously using both experimental and theoretical approaches. Two independent simulations indicate reasonable convergence of the computed free energy profiles. The numerical value of the open/closed free energy difference is only 1-2 k(B)T, much smaller than some of the prior estimates. We also found that the conformations structurally close to the open form still retain many LID-NMP contacts, suggesting that the conformational basin of the closed form is larger than expected. The latter suggestion may explain the discrepancy in relative populations of open and closed forms of unligated adenylate kinase, observed in NMR and FRET experiments. PMID- 22212073 TI - Clinical patterns and epidemiological characteristics of facial melasma in Brazilian women. AB - BACKGROUND; Melasma is a common acquired chronic hypermelanosis of sun-exposed areas which significantly impacts quality of life. There are few epidemiological studies in medical literature concerning these patients. OBJECTIVE: Characterize clinical and epidemiological data on Brazilian female patients with melasma. METHODS: A semi-structured questionnaire was administered to melasma patients treated at a dermatology clinic between 2005 and 2010. Association between variables was performed by multivariate regression models. RESULTS: We assessed 302 patients; intermediate skin phototypes III (34.4%) and IV (38.4%) were prevalent. Mean disease onset age was 27.5 +/- 7.8 years and familiar occurrence of melasma was identified in 56.3%. The most commonly reported trigger factors were pregnancy (36.4%), contraceptive pills (16.2%) and intense sun exposure (27.2%). Preferred facial topographies were zygomatic (83.8%), labial superior (51.3%) and frontal (49.7%). Pregnancy induced melasma has been associated to early disease (OR = 0.86) and number of pregnancies (OR = 1.39). Childbearing was correlated to melasma extension. Older disease onset age was associated to darker skin phototypes. Co-occurrence of facial topographies supported clinical classification as centrofacial and peripheral melasma. CONCLUSION: This population was characterized by: a high prevalence in adult females, intermediate skin phototypes, disease precipitation by hormonal stimulus and familiar genetic influence. PMID- 22212074 TI - Prostate cancer: towards the standardization and synthesis of morphology, genetics, and prognosis. AB - Prostate cancer research and diagnosis is undergoing a revolution in our understanding of the disease process and standardization of diagnostic criteria. Although great progress has been made, there remain many areas of uncertainty and debate. The revolution towards a synthesis of pathology with genetic changes and prognostic models is only just beginning. This supplement presents the opinions and findings of leading international experts in histopathology and prostate research dealing with subjects ranging from aetiology, basic anatomy and morphology to prognostic models, genetic changes and new drug treatments. We hope that this exciting and rapidly changing field will capture the imagination of both experienced and trainee pathologists to advance the field in both research and diagnosis. PMID- 22212075 TI - Precursors of prostate cancer. AB - High-grade prostatic intraepithelial neoplasia (PIN) is the only accepted precursor of prostatic adenocarcinoma, according to numerous studies of animal models and man; other proposed precursors include atrophy and malignancy associated changes (with no morphologic changes). PIN is characterized by progressive abnormalities of phenotype and genotype that are intermediate between benign prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. The only method of detection of PIN is biopsy because it does not significantly elevate serum prostate-specific antigen concentration and cannot be detected by ultrasonography. The mean incidence of PIN in biopsies is 9% (range, 4%-16%), representing about 115,000 new cases of isolated PIN diagnosed each year in the United States. The clinical importance of PIN is its high predictive value as a marker for adenocarcinoma, and its identification warrants repeat biopsy for concurrent or subsequent carcinoma, especially when multifocal or observed in association with atypical small acinar proliferation (ASAP). Carcinoma develops in most patients with PIN within 10 years. Androgen deprivation therapy and radiation therapy decrease the prevalence and extent of PIN, suggesting that these forms of treatment may play a role in prevention of subsequent cancer. Multiple clinical trials to date of men with PIN have had modest success in delaying or preventing subsequent cancer. PMID- 22212076 TI - Diagnosis of limited adenocarcinoma of the prostate. AB - This article provides an overview of the diagnosis of limited prostate cancer on needle biopsy. A few of the more common mimickers of prostate cancer, such as adenosis, partial atrophy, and high-grade prostatic intraepithelial neoplasia, are also covered. A systematic approach to diagnosing prostate cancer by evaluating architectural, nuclear, intraluminal and ancillary features is presented. The use of immunohistochemistry, including its pitfalls and limitations, is described and illustrated. By the use of a systematic diagnostic approach as outlined in this article, the threshold for diagnosing limited carcinoma of the prostate can be decreased. If a pathologist is not comfortable in diagnosing carcinoma in a particular small focus, this review will help them to recognize these foci as atypical and suspicious for carcinoma, so that further workup might lead to a more definitive diagnosis. Some of the more common situations leading to an atypical diagnosis have also been presented to help prevent the overdiagnosis of prostatic malignancy. PMID- 22212072 TI - Pseudomonas biofilm matrix composition and niche biology. AB - Biofilms are a predominant form of growth for bacteria in the environment and in the clinic. Critical for biofilm development are adherence, proliferation, and dispersion phases. Each of these stages includes reinforcement by, or modulation of, the extracellular matrix. Pseudomonas aeruginosa has been a model organism for the study of biofilm formation. Additionally, other Pseudomonas species utilize biofilm formation during plant colonization and environmental persistence. Pseudomonads produce several biofilm matrix molecules, including polysaccharides, nucleic acids, and proteins. Accessory matrix components shown to aid biofilm formation and adaptability under varying conditions are also produced by pseudomonads. Adaptation facilitated by biofilm formation allows for selection of genetic variants with unique and distinguishable colony morphology. Examples include rugose small-colony variants and wrinkly spreaders (WS), which over produce Psl/Pel or cellulose, respectively, and mucoid bacteria that over produce alginate. The well-documented emergence of these variants suggests that pseudomonads take advantage of matrix-building subpopulations conferring specific benefits for the entire population. This review will focus on various polysaccharides as well as additional Pseudomonas biofilm matrix components. Discussions will center on structure-function relationships, regulation, and the role of individual matrix molecules in niche biology. PMID- 22212077 TI - The spectrum of morphology in non-neoplastic prostate including cancer mimics. AB - The spectrum of morphology in non-neoplastic prostate includes lesions of prostatic epithelial origin, the most common being atrophy, including partial atrophy, adenosis (atypical adenomatous hyperplasia), basal cell hyperplasia and crowded benign glands, as well as those of non-prostatic origin, such as seminal vesicle epithelium. These lesions often mimic lower-grade prostatic adenocarcinoma whereas others, such as granulomatous prostatitis, for example, are in the differential diagnosis of adenocarcinoma, Gleason grades 4 or 5. Diagnostic awareness of the salient histomorphological and relevant immunohistochemical features of these prostatic pseudoneoplasms is critical to avoid rendering false positive diagnoses of malignancy. PMID- 22212078 TI - Histological variants of prostatic carcinoma and their significance. AB - The vast majority of prostatic cancers are acinar adenocarcinomas. Histological variants of prostatic carcinoma have been variably defined. One approach is to consider two groups of variants. The first group comprises histological variants of acinar adenocarcinoma and the second group non-acinar carcinoma variants or types. Variants of usual acinar adenocarcinoma defined in 2004 by the World Health Organization (WHO) include atrophic, pseudohyperplastic, foamy, colloid, signet ring, oncocytic and lymphoepithelioma-like carcinomas. The second group of non-acinar carcinoma histological variants or types of prostatic carcinoma accounts for about 5-10% of carcinomas that originate in the prostate. These include sarcomatoid carcinoma, ductal adenocarcinoma, urothelial carcinoma, squamous and adenosquamous carcinoma, basal cell carcinoma, and neuroendocrine tumours, specifically small-cell carcinoma. Recently characterized variants not present in the 2004 WHO classification, including microcystic adenocarcinoma, prostatic intraepithelial neoplasia-like adenocarcinoma, large-cell neuroendocrine carcinoma, and pleomorphic giant cell carcinoma, are also described. The aims of this review are to present the essential histomorphological diagnostic attributes of these variants, and to emphasize the clinical signficance of the variants, when different from usual acinar adenocarcinoma, including clinical presentation and outcome. PMID- 22212079 TI - Gleason grading: past, present and future. AB - In 1966 Donald Gleason developed his grading and scoring system for prostatic adenocarcinoma. This classification was refined in 1974 and gained almost universal acceptance, being classified as a category 1 prognostic parameter by the College of American Pathologists. Modifications to the classification were recommended at a conference convened by the International Society of Urological Pathology (ISUP) in 2005. This modified classification has resulted in a significant upgrading of tumours, although some studies have shown a greater concordance between needle biopsy and radical prostatectomy scores when compared to classical Gleason (CG) grading. The ISUP consensus conference recommended that for needle biopsies higher tertiary patterns should be incorporated into the final Gleason score, and this has been correlated with biochemical failure, tumour volume and mortality. Recently the validity of including cribriform glands as a component of Gleason pattern 3 has been questioned and it has been recommended that all tumours showing cribriform architecture should be classified as Gleason pattern 4. The recommendations arising from the 2005 Consensus Conference were largely unsupported by validating data, yet this new grading system has achieved widespread usage. It is unfortunate that recent suggestions for further modification are similarly lacking in supporting evidence. In view of this it is recommended that the Modified Gleason Scoring Classification should continue to be utilized in its original (2005) format and that any future alterations should be implemented only when mandated by tumour-related outcome studies. PMID- 22212080 TI - Staging of prostate cancer. AB - Prostatic carcinoma (PCa) is a significant cause of cancer morbidity and mortality worldwide. Accurate staging is critical for prognosis assessment and treatment planning for PCa. Despite the large volume of clinical activity and research, the challenge to define the most appropriate and clinically relevant staging system remains. The pathologically complex and uncertain clinical course of prostate cancer further complicates the design of staging classification and a substaging system suitable for individualized care. This review will focus on recent progress and controversial issues related to prostate cancer staging. The 2010 revision of the American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) tumour, node and metastasis (TNM) system is the most widely used staging system at this time. Despite general acceptance of the system as a whole, there is controversy and uncertainty about its application, particularly for T2 subclassification. The three-tiered T2 classification system for organ-confined prostate cancer is superfluous, considering the biology and anatomy of PCa. A tumour size-based substaging system may be considered in the future TNM subclassification of pT2 cancer. Lymph node status is one of the most important prognostic factors for prostate cancer. Nevertheless, clinical outcomes in patients with positive lymph nodes are variable. Identification of patients at the greatest risk of systemic progression helps in the selection of appropriate therapy. The data suggest that the inherent aggressiveness of metastatic prostate cancer is closely linked to the tumour volume of lymph node metastasis. We recommend that a future TNM staging system should consider subclassification of node-positive cancer on the basis of nodal cancer volume, using the diameter of the largest nodal metastasis and/or the number of positive nodes. PMID- 22212081 TI - Handling of radical prostatectomy specimens. AB - Accurate reporting of radical prostatectomy specimens is becoming more important as we gain insights into how cancer therapy should be tailored according to risk categories. Adjuvant therapy after radical prostatectomy is now given more commonly to patients with pathological findings indicating a high risk of disease recurrence. The handling of these specimens must therefore be standardized, enabling the correct identification of histopathological risk factors for poor outcome. Several efforts have been made in recent years to reach consensus on the handling of radical prostatectomy specimens. Some of the recommendations are summarized in this review, including guidelines for gross description, biobanking of fresh tissue, fixation and cutting. PMID- 22212082 TI - Diagnostic and prognostic molecular biomarkers for prostate cancer. AB - Prostate cancer is the most common malignant tumour in men and is a major research focus of pathologists, urologists and uro-oncologists alike. The pathologist is confronted with an increasing number of biospsies, necessitating ancillary tests in morphologically challenging cases. Next to basal cell markers, additional positive markers that aid in the differential diagnosis are presented here. The clinical decision of urologists, whom and how to treat these men, is dependent predominantly on pathological parameters, but still the grid spanned by these is too wide to allow a sufficient prognostication of the individual case. Here, a brief and critical overview is given of recent developments of prognostic biomarkers in prostate cancer. PMID- 22212083 TI - Anatomy of the prostate revisited: implications for prostate biopsy and zonal origins of prostate cancer. AB - Over the past 25 years, our understanding of prostatic disease has evolved secondary to the increased detection, treatment and study of both benign and neoplastic prostatic lesions. The advent of aggressive prostate-specific antigen screening and standardization of extended transrectal needle biopsy protocols has resulted in significant stage migration and earlier detection of prostate cancers, a growing proportion of which are lower-volume posterior peripheral zone tumours. Consequently, an increased incidence of anterior-predominant prostate cancers has been observed. Given the histomorphological complexity of the prostate, these developments have necessitated a reconsideration of prostatic anatomy, biopsy strategies in the detection of anterior tumours and the determination and relevance of zonal origin in prostate cancer. This review will provide a contemporary update of these topics, while highlighting specific areas in which a keen understanding of prostatic histoanatomy may influence biopsy interpretation. PMID- 22212084 TI - Therapy-associated effects in the prostate gland. AB - Diverse therapies are used to treat both benign prostatic hyperplasia and adenocarcinoma. Transurethral resection, a common surgical procedure, may give rise to characteristic necrobiotic granulomas that manifest in subsequent pathology samples. Radiation and hormone therapy have traditionally been used in prostatic adenocarcinoma. Morphological effects are often identified in needle biopsy specimens, transurethral resectates, and radical prostatectomy specimens. A range of histological changes are noted in the non-neoplastic prostate tissue, as well as in the pre-neoplastic and carcinomatous areas. Other ablative therapies, such as cryotherapy, and emerging focal therapies, including high intensity focused ultrasound, photodynamic therapy, and interstitial laser thermotherapy, may have morphological effects on prostate tissue. It is important for the pathologist to be aware of the spectrum of histological changes affecting the prostate gland post-therapy. The treatment effects may obscure residual carcinoma, and make measurements of tumour extent and stage difficult. Furthermore, some therapies can profoundly alter the neoplastic glands to such an extent that Gleason scoring is no longer valid. As new therapies are developed for prostate cancer, it is important to document their effects on benign and malignant prostate tissue and to understand possible implications for traditional prognostic factors, especially Gleason grade. PMID- 22212085 TI - Non-epithelial neoplasms of the prostate. AB - Non-epithelial prostatic neoplasms are infrequent and cover a broad array of entities that include both benign and highly aggressive tumours. Because they are very infrequent, there is often limited understanding of them, and the recognition of these entities, when encountered, may pose a diagnostic challenge, owing to histological overlap between them or their rarity. Most lesions in this category are mesenchymal in origin, such as prostatic stromal tumours arising from specialized prostatic stroma, smooth muscle tumours, both benign and malignant, and solitary fibrous tumours. Less commonly occurring tumours include neural, germ cell and melanocytic tumours that may be derived from cells not normally present in the prostate. Some tumours have well-established extraprostatic counterparts and, when encountered, are more commonly extraprostatic/secondary in origin; these include gastrointestinal stromal tumours and most haematopoietic tumours. The majority of tumours are characterized by a spindle cell pattern with significant overlap in morphological features. In this setting, appropriate use of immunohistochemistry and molecular studies are often necessary for accurate diagnosis, prognosis, or prediction for therapy. This review addresses and updates the clinicopathological features of the entire spectrum of non-epithelial tumours with an approach to the histological diagnosis. PMID- 22212086 TI - Molecular genetics of prostate cancer: emerging appreciation of genetic complexity. AB - The emergence of Next Generation Sequencing is providing novel insights into cancer genomes as part of large-scale efforts by the International Cancer Genome Consortium (ICGC), as well as individual Genome Centers. Studies performing whole genome or whole exome DNA sequencing are remarkable both for the alterations discovered and equally important for the infrequent nature of recurrent mutations. Current understanding of the prostate cancer (PCa) genome is based on extensive RNA-sequencing for novel gene fusions and the first whole genome sequencing effort. The emerging data suggest that there are few recurrent genetic mutations. Surprisingly, the PCa genome undergoes frequent large-scale genomic rearrangements that could not have been predicted using previous DNA sequencing approaches, or even whole exome sequencing approaches. These large-scale rearrangements appear not to occur randomly, but demonstrate patterns leading to the 'chained' juxtaposition of known oncogenes. Future efforts in DNA sequencing will help to determine the recurrent nature of these genomic rearrangements, their association with other alterations and their effect on PCa disease progression. These discoveries raise the possibility that PCa might soon transition from a poorly understood, clinically heterogeneous disease to a collection of homogeneous subtypes identifiable by molecular criteria, and perhaps vulnerable to targeted therapies. PMID- 22212088 TI - Targeted therapy in prostate cancer. AB - The therapeutic approach to advanced prostate cancer has seen greater changes in the last 7 years than it did in the preceding 70. Although only one of the newly approved agents that improve overall survival is a targeted agent, it is a validation of the method of pathway analysis and drug design in delivering novel, clinically usable agents. As our knowledge of the molecular circuitry of tumour invasion, metastases and treatment resistance has become more refined, the number of new, potentially useful, targets has grown exponentially. This is reflected in the vast array of diverse targeted agents that are currently being evaluated in human trials. In this review, we briefly describe some of the key pathways that are involved in the evolution of the prostate cancer 'lethal phenotype', and review the clinical activity of some of the newly approved targeted therapies or those in advanced phases of clinical development. PMID- 22212089 TI - Multiple resource limitation theory applied to herbivorous consumers: Liebig's minimum rule vs. interactive co-limitation. AB - There is growing consensus that the growth of herbivorous consumers is frequently limited by more than one nutrient simultaneously. This understanding, however, is based primarily on theoretical considerations and the applicability of existing concepts of co-limitation has rarely been tested experimentally. Here, we assessed the suitability of two contrasting concepts of resource limitation, i.e. Liebig's minimum rule and the multiple limitation hypothesis, to describe nutrient-dependent growth responses of a freshwater herbivore (Daphnia magna) in a system with two potentially limiting nutrients (cholesterol and eicosapentaenoic acid). The results indicated that these essential nutrients interact, and do not strictly follow Liebig's minimum rule, which consistently overestimates growth at co-limiting conditions and thus is not applicable to describe multiple nutrient limitation of herbivorous consumers. We infer that the outcome of resource-based modelling approaches assessing herbivore population dynamics strongly depends on the applied concept of co-limitation. PMID- 22212087 TI - Prostate cancer and inflammation: the evidence. AB - Chronic inflammation is now known to contribute to several forms of human cancer, with an estimated 20% of adult cancers attributable to chronic inflammatory conditions caused by infectious agents, chronic non-infectious inflammatory diseases and/or other environmental factors. Indeed, chronic inflammation is now regarded as an 'enabling characteristic' of human cancer. The aim of this review is to summarize the current literature on the evidence for a role for chronic inflammation in prostate cancer aetiology, with a specific focus on recent advances regarding the following: (i) potential stimuli for prostatic inflammation; (ii) prostate cancer immunobiology; (iii) inflammatory pathways and cytokines in prostate cancer risk and development; (iv) proliferative inflammatory atrophy (PIA) as a risk factor lesion to prostate cancer development; and (v) the role of nutritional or other anti-inflammatory compounds in reducing prostate cancer risk. PMID- 22212090 TI - Stochastic processes in the aetiopathogenesis of scleroderma. AB - We review the aetiology of scleroderma from an epidemiological perspective examining genetic, environmental and stochastic risk factors. The presence of familial clustering (but with low twin concordance) suggests a genetic contribution, and this has been confirmed with recent candidate gene and genome wide association screening demonstrating both major histocompatibility complex and non-major histocompatibility complex genetic linkage. In contrast, environmental associations are weak or inconsistent. An examination of the age adjusted incidence curve of scleroderma is consistent with a stochastic process involving five to eight random events. In pathogenesis, scleroderma is best considered as an autoimmune disorder where genetic and environmental factors are both important variables, but random events are also likely to play a pivotal role. We suggest that these random events might result in acquired somatic mutations or epigenetic alterations involving genes coding for immune receptors, tolerogenic gates or proteins involved in immune regulation, inflammation and/or repair that, over time, might summate to form a requisite cassette (of genetic changes), which allows the initiation and progression of the autoimmune process. PMID- 22212091 TI - Hindlimb laminar inflammatory response is similar to that present in forelimbs after carbohydrate overload in horses. AB - REASONS FOR PERFORMING STUDY: A significant proinflammatory response is known to occur in the forelimb lamina after carbohydrate administration. As the hindlimbs are often less affected by laminitis compared with the forelimbs, we assessed hindlimb inflammatory response in the early stages of carbohydrate-induced laminitis to determine whether differences in the response existed. OBJECTIVE: To determine whether a similar proinflammatory response occurs in the hindlimb laminae to that previously reported for the forelimb. METHODS: Archived laminar samples from 12 horses administered 17.6 g of starch (85% corn starch, 15% wood flour)/kg bwt via nasogastric tube that were anaesthetised either after developing a temperature >38.9 degrees C (DEV; n = 6) or at the onset of Obel grade 1 lameness (OG1; n = 6) were used in addition to 6 control horses (CON) that were anaesthetised 24 h after administration of water. Real-time quantitative polymerase chain reaction for selected proinflammatory mediators and MAC387 immunohistochemistry were performed. The data were analysed nonparametrically to compare groups. RESULTS: Increases in laminar MAC387 positive leucocytes and laminar messenger ribonucleic acid (mRNA) concentrations (P<0.05) for interleukin-1beta, interleukin-6, cyclo-oxygenase-2, chemokine (C-X C motif)ligand (CXCL)1 and CXCL8 were present in both fore- and hindlimb laminae from horses with OG1 lameness. Both CXCL1 and CXCL8 were also increased in forelimb and hindlimb laminae in the DEV horses. CONCLUSIONS: Administration of carbohydrate resulted in a similar inflammatory response in the hindlimb laminae to that previously reported for the forelimb laminae. These findings suggest that other factors, such as weightbearing, may play an important role in the development of laminitis after a systemic inflammatory condition develops. POTENTIAL RELEVANCE: Evidence of inflammation in the hindlimb laminae suggests that the hindfeet should be addressed in the septic horse at risk for laminitis; however, laminitis is often less severe in the hindlimbs due to other factors, such as weightbearing and hoof angle. PMID- 22212092 TI - Prohibitins are involved in protease-activated receptor 1-mediated platelet aggregation. AB - BACKGROUND: Prohibitins (PHBs), comprising the two homologous members PHB1 and PHB2, are ubiquitously expressed and highly conserved. The membrane PHBs have been reported to be involved in typhoid fever, obesity, and cancer metastasis. Proteomic studies have revealed the presence of PHBs in human platelets, but the roles of PHBs during platelet aggregation are unknown. OBJECTIVES: To investigate the role of PHBs in platelet aggregation. METHODS AND RESULTS: PHB1 and PHB2 were detected on the surfaces of human platelets by flow cytometry and confocal microscopy. The PHBs were distributed in lipid rafts, as determined by sucrose density centrifugation. In addition, the PHBs were associated with protease activated receptor 1 (PAR1), as determined by Bm-TFF2 (a PAR1 agonist)-affinity chromatography, coimmunoprecipitation, and confocal microscopy. The platelet aggregation, alpha(IIb) beta(3) activation, granular secretion and calcium mobilization stimulated by low concentrations of thrombin (0.05 U mL(-1)) or PAR1 activating peptide (PAR1-AP) (20 MUm) were reduced or abolished as a result of the blockade of PHBs by anti-PHB antibodies or their Fab fragments; however, the same results were not obtained with induction by high concentrations of thrombin (0.6 U mL(-1)) or protease-activated receptor 4-activating peptide (300 MUm). The calcium mobilization in MEG-01 megakaryocytes stimulated by PAR1-AP was significantly suppressed by PHB depletion with RNA interference against PHB1 and PHB2. CONCLUSIONS: PHBs are localized on the human platelet membrane and are involved in PAR1-mediated platelet aggregation. Until recently, PHBs were unknown as regulators of PAR1 signaling, and they may be effective targets for antiplatelet therapy. PMID- 22212093 TI - On solving the cornea. PMID- 22212094 TI - Corneal biomechanical properties and their correlates with refractive error. AB - PURPOSE: The aim was to study the link between refractive error and corneal biomechanical properties. METHODS: Corneal hysteresis and corneal resistance factor were measured using the Ocular Response Analyser in 117 participants. The spherical equivalent refractive error of the participants ranged between -9.00 and +3.00 D. RESULTS: Corneal hysteresis and corneal resistance factor showed a considerable degree of variability between individuals. Corneal hysteresis was not found to correlate significantly with refractive error (p = 0.82). Corneal resistance factor showed a weak but significant correlation with spherical equivalent refractive error (r(2) = 0.04; p = 0.03), with myopic participants exhibiting a higher corneal resistance factor compared with non-myopes. CONCLUSIONS: Refractive error accounted for four per cent of the variance in corneal resistance factor measurements, indicating that patients with mild to moderate myopia have higher corneal resistance compared with non-myopes. PMID- 22212096 TI - TcyR regulates L-cystine uptake via the TcyABC transporter in Streptococcus mutans. AB - Streptococcus mutans, a primary dental pathogen, has a remarkable capacity to scavenge nutrients from the oral biofilm for its survival. Cystine is an amino acid dimer formed by the oxidation of two cysteine residues that is required for optimal growth of S. mutans, which modulates l-cystine uptake via two recently identified transporters designated TcyABC and TcyDEFGH, which have not been fully characterized. Using a nonpolar tcyABC-deficient mutant (SmTcyABC), here, we report that l-cystine uptake is drastically diminished in the mutant, whereas its ability to grow is severely impaired under l-cystine starvation conditions, relative to wild type. A substrate competition assay showed that l-cystine uptake by the TcyABC transporter was strongly inhibited by dl-cystathionine and l djenkolic acid and moderately inhibited by S-methyl-l-cysteine and l-cysteine. Using gene expression analysis, we observed that the tcyABC operon was upregulated under cystine starvation. TcyABC has been shown to be positively regulated by the LysR-type transcriptional regulator CysR. We identified another LysR-type transcriptional regulator that negatively regulates TcyABC with homology to the Bacillus subtilis YtlI regulator, which we termed TcyR. Our study enhances the understanding of l-cystine uptake in S. mutans, which allows survival and persistence of this pathogen in the oral biofilm. PMID- 22212097 TI - Zinc finger E-box binding homeobox 1 promotes vasculogenic mimicry in colorectal cancer through induction of epithelial-to-mesenchymal transition. AB - Our previous studies have shown that epithelial-mesenchymal transition (EMT) may be involved in the vasculogenic mimicry (VM) formation in hepatocellular carcinoma. Here, we hypothesize that zinc finger E-box binding homeobox 1 (ZEB1) promotes VM formation in colorectal carcinoma (CRC) by inducing EMT. We identified VM in 39 (19.2%) out of 203 CRC patients. The presence of VM was associated with aggressive biological behavior and was an unfavorable prognostic indicator. By immunohistochemical analysis, we found that the VM-positive CRC samples showed increased ZEB1 expression compared with the VM-negative samples and the ZEB1 expression occurred concomitantly with features of EMT. In vitro, knockdown of ZEB1 in poorly differentiated HCT116 CRC cells destroyed the vessel like structures in the 3-D culture, a property associated with VM formation. Knockdown of ZEB1 resulted in restoration of epithelial phenotypes and significantly inhibited the ability to migrate and invade. In addition, ZEB1 underexpression decreased the expression of vascular endothelial (VE)-cadherin and Flk-1, which are characteristics of endothelial cells. Taken together, our results suggest that ZEB1 can promote VM formation by inducing EMT in CRC and might represent an important target in CRC. PMID- 22212098 TI - Operation profile of zebrafish guanylate cyclase-activating protein 3. AB - The expression pattern and property profile of the neuronal Ca(2+) sensor guanylate cyclase-activating protein 3 (zGCAP3) was studied by immunochemical approaches, biophysical methods and enzymatic assays. Using affinity purified antibodies immunoreactivity towards zGCAP3 was weakly detected in the outer and strongly in the inner segments of cone cells as well as in the outer plexiform layer, to a lesser degree also in the inner plexiform and ganglion cell layer of the zebrafish retina. This cellular distribution was independent of a dark/light cycle. Some neuronal Ca(2+) sensors are acylated (mainly myristoylated) at the amino-terminus. Probing larval and adult stages of the developing zebrafish retina indicated that zGCAP3 was first expressed in a non-myristoylated form, but was finally present in the adult retina as a myristoylated protein. While zGCAP3 did not undergo a classical Ca(2+) -myristoyl switch as investigated by surface plasmon resonance spectroscopy, myristoylation had two main other consequences: it enhanced the Ca(2+) -sensitivity of the Ca(2+) -induced conformational change and it stabilized the protein conformation. Differences between myristoylated and non-myristoylated zGCAP3 were also observed in modulating the kinetic and catalytic parameters of the GCAP-target, a membrane bound guanylate cyclase. Thus, the stabilizing effect of the myristoyl group is apparently less important in the larval than in the adult fish. PMID- 22212099 TI - Structure of the apo form of Bacillus stearothermophilus phosphofructokinase. AB - The crystal structure of the unliganded form of Bacillus stearothermophilus phosphofructokinase (BsPFK) was determined using molecular replacement to 2.8 A resolution (Protein Data Bank entry 3U39 ). The apo BsPFK structure serves as the basis for the interpretation of any structural changes seen in the binary or ternary complexes. When the apo BsPFK structure is compared with the previously published liganded structures of BsPFK, the structural impact that the binding of the ligands produces is revealed. This comparison shows that the apo form of BsPFK resembles the substrate-bound form of BsPFK, a finding that differs from previous predictions. PMID- 22212100 TI - Pharmacokinetics of diminazene diaceturate in healthy cats. PMID- 22212101 TI - Examining the relationship between early axon growth and transcription factor expression in the developing cerebral cortex. AB - The transcription factors Satb2 (special AT-rich sequence binding protein 2) and Ctip2 (COUP-TF interacting protein 2) have been shown to be required for callosal and corticospinal axon growth respectively from subtypes of cerebral cortex projection neurons. In this study we investigated early stages of directed axon growth in the embryonic mouse cerebral cortex, and studied the possible correlation with the expression of Satb2 and Ctip2. Electroporation of an EYFP expressing plasmid at embryonic day 13.5 to label developing projection neurons revealed that directed axon growth is first seen in radially migrating neurons in the intermediate zone (IZ), prior to migration into the cortical plate, as has been suggested previously. Onset of expression of SATB2 and CTIP2 was also observed in the IZ, correlating well with this stage of migration and initiation of axon growth. Immunohistochemical staining through embryonic and early postnatal development revealed a significant population of Satb2/Ctip2 co expressing cells, while retrograde axon tracing from the corpus callosum at embryonic day 18.5 back-labelled many neurons with bi-directional axon processes. However, through retrograde tracing and simultaneous immunohistochemical staining we show that these bi-directional processes do not correlate with Satb2/Ctip2 co expression. Our work shows that although expression of these transcription factors correlates well with the appearance of directed axon growth during cortical development, the transcriptional code underlying the bi-directional axonal projections of early neocortical neurons is not likely to be the result of Satb2/Ctip2 co-expression. PMID- 22212102 TI - Benzo[alpha]pyrene-induced anti-depressive-like behaviour in adult female mice: role of monoaminergic systems. AB - Benzo[alpha]pyrene (B[alpha]P) is a ubiquitous environmental pollutant exhibiting adverse effects on cognitive function and behaviour. In this study, depressive or antidepressive effects of B[alpha]P were investigated. Here, we report that a subacute B[alpha]P oral exposure (0.02-0.2 mg/kg) increases mobility behaviour in female adult mice in the tail suspension test, but not in the forced swimming test, without altering locomotion, suggesting that the tail suspension test was a more sensitive indicator of B[alpha]P-induced neurobehavioural disturbance. This might be because of differences in neurochemical substrates and pathways, mediating the performance in these behavioural models of depression. The effect of B[alpha]P on female adult mice in the tail suspension test was similar to that obtained with subacute treatment of the antidepressant reference drug imipramine (10 mg/kg). Therefore, B[alpha]P at 0.02 mg/kg and 0.2 mg/kg induces an antidepressant-like effect in mice, suggesting a neurobehavioural disturbance after oral exposure to this environmental compound. Furthermore, oral exposure to B[alpha]P at 0.02 mg/kg significantly increased gene expression levels of the brain receptors 5-hydroxytryptamine (serotonin) 1A (5HT(1A)) and alpha-1D adrenergic (ADRA(1D)). In summary, the presented findings suggest that subacute oral exposure to B[alpha]P results in behavioural changes in female adult mice, possibly caused by alterations in the serotoninergic and adrenergic systems. PMID- 22212103 TI - Psychotropic drug and polypharmacy use among adolescents and young adults: findings from the Finnish 1981 Nationwide Birth Cohort Study. AB - BACKGROUND: Little is known about the timing of the start of psychotropic drug use and psychotropic polypharmacy use. AIMS: This study describes these patterns in a Finnish representative cohort aged between 12 and 25. METHODS: 5525 subjects born in 1981 were followed up between 1994 and 2005 using the Finnish National Prescription Register. RESULTS: Survival analysis revealed that the cumulative incidence of any psychotropic drug use was 1.3% by age 15, 6.1% by age 20 and 15.2% by age 25. Antidepressants and benzodiazepines were the most used drug groups, with cumulative incidences of 12.2% and 5.2%, respectively, by age 25. The cumulative incidence of polypharmacy was 0.02% by age 15, 0.9% by age 20 and 4.1% by age 25, i.e. having purchased at least two psychotropic drugs from different classes during the same day. Polypharmacy occurred among the majority of antipsychotic and benzodiazepine users, but among a minority of antidepressant users. More females than males had used any psychotropic drug, antidepressants, the antidepressant-benzodiazepine combination and the antidepressant-mood stabilizer combination. CONCLUSIONS: Both general psychotropic drug use and psychotropic polypharmacy use was often started in late adolescence. PMID- 22212104 TI - Arabinogalactan proteins contribute to the immunostimulatory properties of New Zealand honeys. AB - CONTEXT: Factors in honey that improve wound healing are poorly understood, but are thought to include lipopolysaccharide (LPS), apalbumin-1 and -2, and a 5.8 kDa component that stimulate cytokine release from macrophages. OBJECTIVE: To characterize the ability of New Zealand honeys to elicit the release of tumor necrosis factor-alpha (TNF-alpha) from monocytic cell lines as a model for early events within a wound site. MATERIALS AND METHODS: The ability of kanuka (Kunzea ericoides), manuka (Leptospermum scoparium), and clover (Trifolium spp.) honeys to stimulate the release of TNF-alpha from monocytic cell lines THP-1 and U937 was assayed by ELISA. RESULTS: All three honeys stimulated TNF-alpha release from THP-1 cells, with kanuka honey being the most active. The activity of kanuka honey was associated with a high molecular weight (>30 kDa) component that was partially heat labile and inhibitable with polymyxin B. LPS concentrations in the honeys were too low to adequately explain the level of immunostimulation. The contribution of type II arabinogalactan proteins (AGPs) we recently identified in kanuka honey was tested, as AGPs are known immunostimulators. AGPs purified from kanuka honey stimulated the release of TNF-alpha from THP-1 and U937 cells. DISCUSSION: Here we demonstrated that AGPs we recently identified in kanuka honey have immunostimulatory activity. We propose that the immunostimulatory properties of individual honeys relate to their particular content of LPS, apalbumins, the 5.8 kDa component and AGPs. CONCLUSION: The immunostimulatory activity of kanuka honey may be particularly dependent on AGPs derived from the nectar of kanuka flowers. PMID- 22212106 TI - Sociogenetic structure, kin associations and bonding in delphinids. AB - Social systems are the outcomes of natural and sexual selection on individuals' efforts to maximize reproductive success. Ecological conditions, life history, demography traits and social aspects have been recognized as important factors shaping social systems. Delphinids show a wide range of social structures and large variation in life history traits and inhabit several aquatic environments. They are therefore an excellent group in which to investigate the interplay of ecological and intrinsic factors on the evolution of mammalian social systems in these environments. Here I synthetize results from genetic studies on dispersal patterns, genetic relatedness, kin associations and mating patterns and combine with ecological, life history and phylogenetic data to predict the formation of kin associations and bonding in these animals. I show that environment type impacts upon dispersal tendencies, with small delphinids generally exhibiting female-biased philopatry in inshore waters and bisexual dispersal in coastal and pelagic waters. When female philopatry occurs, they develop moderate social bonds with related females. Male bonding occurs in species with small male-biased sexual size dimorphism and male-biased operational sex ratio, and it is independent of dispersal tendencies. By contrast, large delphinids, which live in coastal and pelagic waters, show bisexual philopatry and live in matrilineal societies. I propose that sexual conflict favoured the formation of these stable societies and in turn facilitated the development of kin-biased behaviours. Studies on populations of the same species inhabiting disparate environments, and of less related species living in similar habitats, would contribute towards a comprehensive framework for the evolution of delphinid social systems. PMID- 22212105 TI - No evidence of cross-species transmission of mouse retroviruses to animal workers exposed to mice. AB - BACKGROUND: Although recent data have brought into question the association between xenotropic murine leukemia virus-related virus (XMRV) and chronic fatigue syndrome, one group has reported evidence of human infection with distinct polytropic murine leukemia viruses (MLVs). Occult retroviral infection among humans poses a significant public health risk should it be introduced into the blood supply. To explore the possibility of cross-species transmission of MLVs to humans, we sought molecular and serologic evidence of XRMV/MLV infection among a cohort of animal workers highly exposed to mice. STUDY DESIGN AND METHODS: Before the commencement of the study, the laboratory and equipment were demonstrated to be free of XMRV/MLV DNA sequences. DNA extracted from 43 animal workers was tested using nested polymerase chain reaction (PCR) with published primer sets, targeting regions of XMRV and MLV gag. Negative controls were assayed in a 1:1 ratio with specimens. Serum specimens were tested using a validated immunoblot assay containing cross-reactive XMRV antigens. RESULTS: Initial molecular assays demonstrated that the physical space and laboratory equipment were free of MLV and XMRV DNA sequences. Nested PCR assays using multiple primer sets successfully amplified XMRV and MLV sequences from positive controls with high sensitivity. A single, nonreproducible, false-positive result from one specimen was shown to be the result of subsequent contamination. Immunoblotting of all subjects' sera failed to demonstrate any evidence of seroreactivity to XMRV proteins. CONCLUSIONS: There was no evidence of human infection with XMRV/MLV among a cohort of individuals highly exposed to mice. These data suggest that the likelihood of cross-species transmission events of MLV from mice to humans is low. PMID- 22212107 TI - Organ transplants do not escape paradoxical embolisms. AB - Acute renal allograft dysfunction in the first weeks after transplantation primarily requires examination for acute rejection, drug-associated injury, pre renal failure due to exsiccosis/dehydration, and post-renal problems such as urinary tract obstruction. In rare instances, main renal artery or vein thrombosis may be found, e.g. due to acute rejection of the vessels. Herein, we describe the clinical course of a patient with a recent renal transplantation who presented with an acute enigmatic renal allograft failure which, after intensive diagnostic efforts, emerged as paradoxical embolism with extensive allograft ischemia in consequence of a venous thrombosis and a patent foramen ovale - a so far unreported case. PMID- 22212108 TI - Prediction of morphine dose in humans. AB - BACKGROUND: Morphine is widely used throughout the human life span. Several pharmacokinetic models have been proposed to predict how morphine clearance changes with weight and age. This study uses a large external data set to evaluate the ability of pharmacokinetic models to predict morphine doses. METHODS: A data set of morphine clearance estimates was created from published reports in premature neonates, full-term neonates, infants, children, and adults. This external data set was used to evaluate published models for morphine clearance as well as other models proposed for use in neonates and infants. Morphine clearance predictions were used to predict morphine dose rates to achieve similar target concentrations in all age groups. RESULTS: An allometric 3/4 power model using weight combined with a sigmoid maturation model using postmenstrual age successfully predicted the morphine dose rate (within 25% of target) in all age groups except infants [predicted dose 30% under target (95% CI, 7-46%)]. Other published models based on empirical allometric scaling all made unacceptable predictions (>100% of target) in at least one age group. CONCLUSIONS: Clearance based on empirical allometric scaling predicted unacceptable doses. Theory-based allometric scaling combined with a maturation function has been confirmed by external evaluation to provide a sound basis for describing clearance and predicting morphine doses in humans of all ages. PMID- 22212109 TI - From meadows to milk to mucosa - adaptation of Streptococcus and Lactococcus species to their nutritional environments. AB - Lactic acid bacteria (LAB) are indigenous to food-related habitats as well as associated with the mucosal surfaces of animals. The LAB family Streptococcaceae consists of the genera Lactococcus and Streptococcus. Members of the family include the industrially important species Lactococcus lactis, which has a long history safe use in the fermentative food industry, and the disease-causing streptococci Streptococcus pneumoniae and Streptococcus pyogenes. The central metabolic pathways of the Streptococcaceae family have been extensively studied because of their relevance in the industrial use of some species, as well as their influence on virulence of others. Recent developments in high-throughput proteomic and DNA-microarray techniques, in in vivo NMR studies, and importantly in whole-genome sequencing have resulted in new insights into the metabolism of the Streptococcaceae family. The development of cost-effective high-throughput sequencing has resulted in the publication of numerous whole-genome sequences of lactococcal and streptococcal species. Comparative genomic analysis of these closely related but environmentally diverse species provides insight into the evolution of this family of LAB and shows that the relatively small genomes of members of the Streptococcaceae family have been largely shaped by the nutritionally rich environments they inhabit. PMID- 22212110 TI - Prospective randomised trial of endobronchial ultrasound-guide sheath versus computed tomography-guided percutaneous core biopsies for peripheral lung lesions. AB - AIM: To determine diagnostic rate, complications and patient tolerability of endobronchial ultrasound-guide sheath (EBUS-GS) and computed tomography (CT) guided percutaneous core biopsy for peripheral lung lesions. METHODS: Lesions >1 cm diameter on CT were randomised to either EBUS-GS or CT-guided biopsy. Excluded were patients with severe chronic obstructive airway disease, lesions touching visceral pleura or hilum, and patients with symptoms needing bronchoscopic evaluation. Patients completed preprocedure and postprocedure questionnaires on tolerability. RESULTS: Of 64 participants (mean lesion size 29 +/- 16 mm), 57 completed the study. Diagnostic sensitivity was 67% for EBUS-GS and 78% for CT guided biopsy (P = not significant). In those with negative results, in the EBUS group, nine had a CT-guided biopsy as a cross-over, seven of which were positive. In the CT group, four had cross-over EBUS-GS of which three were diagnostic. Sensitivity for malignancy was 17/23 for EBUS-GS (74%) and 23/26 (88%, P = not significant). For lesions <2 cm, CT-guided biopsy had a significantly better diagnostic yield (80% vs 50%, P = 0.05). In EBUS-GS cases, for lesions with an air bronchogram, sensitivity was 89%. Pneumothorax and intercostal catheter insertion occurred in three and two cases, respectively, for EBUS, and 10 and 3 cases for CT-guided biopsy (P = 0.02 for pneumothorax). Nine unexpected admissions occurred after CT-guided biopsy compared with three after EBUS-GS. Overall, tolerability was high for both groups; however three patients had moderate-to-severe pain after CT-guided biopsy. CONCLUSIONS: In lesions <2 cm, CT guided biopsy had higher yields; however, EBUS-GS had better tolerability and fewer complications. PMID- 22212111 TI - Differentiating conflicts in beliefs versus value tradeoffs in the domestic intelligence policy debate. AB - Since the 9/11 terrorist attacks, there has been an increase in public discussion regarding U.S. domestic intelligence activities. Domestic intelligence activities focus on gathering information about potential threats from individuals within the United States, and completely rational members of the public can have different opinions about the acceptability of various alternatives depending on one's values toward privacy, civil liberty, and security. Past studies have demonstrated that construction of a multiobjective value model can help clarify public values in controversial risk debates. This research explores a range of domestic intelligence alternatives that vary on multiple objectives, and applies value-focused thinking to develop a multiattribute utility model to evaluate and compare the alternatives. The process demonstrates the feasibility of eliciting model parameters from individuals and provides a method for identifying the locus of possible disagreements among individuals. The development of the model is described first, followed by insights found from participants who provided both value tradeoffs and performance scores for six different domestic intelligence alternatives. The participants were two student groups and a group of police officers. The analysis showed differences among weights for an additive model for different stakeholder groups and differences among the performance scores. In particular, there is a "halo" effect for alternatives, such that its supporters ranked the alternative higher on all attributes compared to respondents who find the alternative unacceptable. This modeling approach and results offer organizations such as the Department of Homeland Security insights into the debate surrounding new policy initiatives, particularly those requiring sensitive value tradeoffs. PMID- 22212112 TI - Successful treatment of systemic cold contact urticaria with etanercept in a patient with psoriasis. PMID- 22212113 TI - Clinical evaluation of chlorhexidine and essential oils for adjunctive effects in ultrasonic instrumentation of furcation involvements: a randomized controlled clinical trial. AB - BACKGROUND: The aim of this clinical study was to evaluate and compare the clinical efficacy of subgingival ultrasonic mechanical instrumentation (UMI) irrigated with essential oils (EOs) and chlorhexidine (CHX) at the furcation involvements (FI). METHODS: Forty-five patients (244 FI) who presented with Class II FI were recruited to the study. Patients were randomly assigned to CHX (UMI irrigated with 0.2% CHX), EO (UMI irrigated with EOs) or control (UMI irrigated with distilled water) groups. All treatments were performed in one session. For all groups, plaque index (PI), gingival index (GI), position of gingival margin (PGM), pocket depth (PD), bleeding on probing (BOP), clinical attachment level (CAL) and horizontal attachment level (HAL) scores were recorded at baseline and 1 and 3 months after therapy. RESULTS: In all groups, there were significant reductions in PI, GI, PD and BOP, increase in PGM scores and gain in CAL and HAL scores, at 1 and 3 months compared to baseline. Except in BOP scores, there were no significance differences among the groups at any time point. At 1 and 3 months, there were significant reductions in the BOP scores of the EO group compared with the CHX and control groups. CONCLUSION: Within the limits of this study, the use of EOs as a cooling liquid of UMI may promote slight adjunctive effects at FI compared to CHX and water. PMID- 22212114 TI - Oral microcirculation in post-menopause: a possible correlation with periodontitis. AB - OBJECTIVES: The reduction in the level of oestrogen, typical in menopause, has some effect on the health of the oral cavity. In fact, post-menopausal women present more severe periodontal disease than pre-menopausal women. Numerous factors can be held to be responsible for this increase, among which are the effects of oestrogens on the oral epithelium, on the salivary glands, on bone tissue and on the endothelium. Our double blind study aims to evaluate the possible variations in oral microcirculation in post-menopausal women. METHODS: Twenty-seven women in post-menopause (age: Mean +/- SD: 57.3 +/- 8.73) and 27 women in pre-menopause (age: Mean +/- SD: 27.77 +/- 3.56) were examined. Oral microcirculation was investigated using oral videocapillaroscopy. RESULTS: The study showed significant differences between cases and controls for the following parameters: decrease in diameter of loops (mean +/- SD: 0.038 +/- 0.008; 0.045 +/ 0.005), increase in tortuosity (mean +/- SD: 3.83 +/- 1.13; 1.83 +/- 1.06) in labial mucosa and decrease in density in periodontal mucosa (Mean +/- SD: 28.86 +/- 10.92; 89.62 +/- 17.83). CONCLUSION: The decrease in periodontal density may compromise the epithelium tropism, making it prone to inflammation. The tortuosity may indicate a greater permanence of inflammatory factors, increased in post-menopausal women. PMID- 22212115 TI - Re: How often do patients return to the operating room after colorectal surgery? PMID- 22212116 TI - Profiling of humoral immune responses to influenza viruses by using protein microarray. AB - The emergence of pandemic A(H1N1) 2009 influenza showed the importance of rapid assessment of the degree of immunity in the population, the rate of asymptomatic infection, the spread of infection in households, effects of control measures, and ability of candidate vaccines to produce a response in different age groups. A limitation lies in the available assay repertoire: reference standard methods for measuring antibodies to influenza virus are haemagglutination inhibition (HI) assays and virus neutralization tests. Both assays are difficult to standardize and may be too specific to assess possible partial humoral immunity from previous exposures. Here, we describe the use of antigen-microarrays to measure antibodies to HA1 antigens from seven recent and historical seasonal H1, H2 and H3 influenza viruses, the A(H1N1) 2009 pandemic influenza virus, and three avian influenza viruses. We assessed antibody profiles in 18 adult patients infected with A(H1N1) 2009 influenza virus during the recent pandemic, and 21 children sampled before and after the pandemic, against background reactivity observed in 122 persons sampled in 2008, a season dominated by seasonal A(H1N1) influenza virus. We show that subtype-specific and variant-specific antibody responses can be measured, confirming serological responses measured by HI. Comparison of profiles from persons with similar HI response showed that the magnitude and broadness of response to individual influenza subtype antigens differs greatly between individuals. Clinical and vaccination studies, but also exposure studies, should take these findings into consideration, as they may indicate some level of humoral immunity not measured by HI assays. PMID- 22212118 TI - Monitoring of the West Nile virus epidemic in Spain between 2010 and 2011. AB - West Nile virus (WNV) is a mosquito-transmitted flavivirus recognized as an emerging and re-emerging pathogen in different countries. This study describes the monitoring of the first WNV epidemic in Spain between 2010 and 2011. Between September and December 2010, 36 outbreaks of WNV in horses were reported in three different provinces of Andalusia (southern Spain), with no apparent spread outside this area. The temporal distribution and the clinical signs observed during the WNV epidemic in Spain were, in general, similar to those reported in Europe and in the Mediterranean Basin. Morbidity, mortality and fatality rate in the affected herds were 4.6, 1.4 and 35.3%, respectively. Thirty-six of 75 (47.4%) suspected herds investigated presented at least one IgM seropositive animal. The individual seroprevalence in unvaccinated animals from the infected holdings was 51.7%. RNA WNV lineage 1 virus was confirmed from blood and cerebrospinal fluid samples in a lethally infected horse. The entomological survey showed that the most abundant mosquito species detected in the affected area was Culex pipiens. A cross-sectional study was carried out in non-suspected herds between April 2010 and February 2011 in the affected area. The individual seroprevalence was 11.0%, and six of the 38 herds sampled (15.8%) presented at least one seropositive animal. The results showed active WNV circulation several months before the first outbreak was reported in horses. The seropositivity found in municipalities where clinical cases were not reported indicates a higher geographical dissemination of the virus. Significantly higher seroprevalences were detected in areas close to Morocco. Furthermore, 90 wild ruminants were tested for the presence of antibodies against WNV, but the results were all negative. PMID- 22212119 TI - Molecular and genetic features of myelodysplastic syndromes. AB - Multifactorial pathogenetic features underlying myelodysplastic syndromes (MDS) relate to inherent abnormalities within the hematopoietic precursor cell population. The predominant final common pathogenetic pathway causing ineffective hematopoiesis in MDS has been the varying degrees of apoptosis of the hematopoietic precursors and their progeny. A variety of molecular abnormalities have been demonstrated in MDS. These lesions are attributable to nonrandom cytogenetic and oncogenic mutations, indicative of chromosomal and genetic instability, transcriptional RNA splicing abnormalities, and epigenetic changes. Evolutionary cytogenetic changes may occur during the course of the disorder, which are associated with disease progression. These genetic derangements reflect a multistep process believed to underlie the transformation of MDS to acute myeloid leukemia. Recent findings provide molecular insights into specific gene mutations playing major roles for the development and clinical outcome of MDS and their propensity to progress to a more aggressive stage. Use of more comprehensive and sensitive methods for molecular profiling using 'next generation' sequencing techniques for MDS marrow cells will likely further define critical biologic lesions underlying this spectrum of diseases. PMID- 22212120 TI - Transcriptome analysis of ein3 eil1 mutants in response to iron deficiency. AB - Multiple transcriptome and proteome studies indicated that the micronutrient deficiency stress caused by lack of iron results in increased molecular responses for the mobilization and uptake of iron and also in altered metabolic adaptation and stress responses. Recently, we identified the ethylene-regulated transcription factors ETHYLENE INSENSITIVE3 (EIN3) and EIN3-LIKE1 (EIL1) as protein interaction partners of the Fe deficiency response regulator and transcription factor FER-LIKE FE DEFINCY-INDUCED TRANSCRPTION FACTOR1 (FIT). EIN3/EIL1 contribute to high level gene expression of FIT downstream genes and also promote FIT protein abundance. Transcriptome analyses showed that more genes were differentially regulated in ein3 eil1 mutants versus wild type upon iron deficiency than upon sufficient iron supply. Moreover, several of the differentially expressed genes are implicated in photo-oxidative stress responses in leaves. We therefore speculated that by enhancing Fe uptake through interaction with FIT and by re-organizing the photo-oxidative stress responses, EIN3/EIL1 might contribute to decreasing photo-oxidative stress that may occur under light conditions in response to Fe deficiency. Here, we present an additional analysis of our previously published transcriptome data of ein3 eil1 and wild type between sufficient iron supply and iron deficiency, respectively. PMID- 22212121 TI - A model for leaf initiation: determination of phyllotaxis by waves in the generative circle. AB - A biophysical model is proposed for how leaf primordia are positioned on the shoot apical: meristem in both spiral and whorl phyllotaxes. Primordia are initiated by signals that propagate: in the epidermis in both azimuthal directions away from the cotyledons or the most recently: specified primordia. The signals are linear waves as inferred from the spatial periodicity of the: divergence angle and a temporal periodicity. The periods of the waves, which represent actively: transported auxin, are much smaller than the plastochron interval. Where oppositely directed: waves meet at one or more angular positions on the periphery of the generative circle, auxin: concentration builds and as in most models this stimulates local movement of auxin to: underlying cells, where it promotes polarized cell division and expansion. For higher order: spirals the wave model requires asymmetric function of auxin transport; that is, opposite wave: speeds differ. An algorithm for determination of the angular positions of leaves in common leaf: phyllotaxic configurations is proposed. The number of turns in a pattern repeat, number of leaves: per level and per pattern repeat, and divergence angle are related to speed of auxin transport and: radius of the generative circle. The rule for composition of Fibonacci or Lucas numbers: associated with some phyllotaxes is discussed. A subcellular model suggests how the shoot: meristem might specify either symmetric or asymmetric transport of auxin away from the: forming primordia that produce it. Biological tests that could make or break the mathematical: and molecular hypotheses are proposed. PMID- 22212123 TI - The monoterpene limonene in orange peels attracts pests and microorganisms. AB - Plant volatiles include terpenoids, which are generally involved in plant defense, repelling pests and pathogens and attracting insects for herbivore control, pollination and seed dispersal. Orange fruits accumulate the monoterpene limonene at high levels in the oil glands of their fruit peels. When limonene production was downregulated in orange fruits by the transgenic expression of a limonene synthase (CitMTSE1) in the antisense configuration, these fruits were resistant to the fungus Penicillium digitatum (Pers.) Sacc. and the bacterium Xanthomonas citri subsp. citri and were less attractive to the medfly pest Ceratitis capitata. These responses were reversed when the antisense transgenic orange fruits were treated with limonene. To gain more insight into the role of the limonene concentration in fruit responses to pests and pathogens, we attempted to overexpress CitMTSE1 in the sense configuration in transgenic orange fruits. Only slight increases in the amount of limonene were found in sense transgenic fruits, maybe due to the detrimental effect that excessive limonene accumulation would have on plant development. Collectively, these results suggest that when limonene reaches peak levels as the fruit develops, it becomes a signal for pest and pathogen attraction, which facilitate access to the fruit for pulp consumers and seed dispersers. PMID- 22212122 TI - Arabidopsis peroxidase AtPRX53 influences cell elongation and susceptibility to Heterodera schachtii. AB - Cyst nematodes establish and maintain feeding sites (syncytia) in the roots of host plants by altering expression of host genes. Among these genes are members of the large gene family of class III peroxidases, which have reported functions in a variety of biological processes. In this study, we used Arabidopsis Heterodera schachtii as a model system to functionally characterize peroxidase 53 (AtPRX53). Promoter assays showed that under non-infected conditions AtPRX53 is expressed mainly in the root, the hypocotyl and the base of the pistil. Under infected conditions, the AtPRX53 promoter showed upregulation at the nematode penetration sites and in their migration paths. Interestingly, strong GUS activity was observed in H. schachtii-induced syncytia during the early stage of infection and remained strong in the syncytia of third-stage juveniles. Also, AtPRX53 showed upregulation in response to wounding and jasmonic acid treatments. Manipulation of AtPRX53 expression through overexpression and knockout mutation affected both plant morphology and nematode susceptibility. While AtPRX53 overexpression lines exhibited short hypocotyls, aberrant flower development and reduced nematode susceptibility to H. schachtii, the atprx53 mutant showed long hypocotyls and a 3-carpel silique phenotype as well as a non significant increase of nematode susceptibility. Taken together these data, therefore, indicate diverse roles of AtPRX53 in the wound response, flower development and syncytium formation. PMID- 22212124 TI - Cytokinin-induced root growth involves actin filament reorganization. AB - Root architecture is developmentally plastic and affected by many intrinsic factors (e.g. plant hormones) and extrinsic factors (e.g. touch, gravity) in order to maximize nutrient and water acquisition. We have recently shown that asymmetrical exposure of cytokinin (CK) at the root tip causes root growth directional changes that is dependent on ethylene signaling and is potentiated by glucose signaling. Auxin homeostasis as maintained by auxin signaling and transport is also involved in CK-induced root cell elongation and differential growth. The signaling pathways eventually converge at actin filament organization since actin filament organization inhibitor latrunculin B (Lat B) can also induce similar growth. We, show that CK can actually alter actin filament organization as seen in actin binding protein 35S::GFP-ABD2-GFP transgenic lines as is also altered by auxin polar transport inhibitor 1-N-naphthylphthalamic acid (NPA) and Lat B in different manners. PMID- 22212125 TI - Comparisons of polybrominated diphenyl ether and hexabromocyclododecane concentrations in dust collected with two sampling methods and matched breast milk samples. AB - Household dust from 19 Swedish homes was collected using two different sampling methods: from the occupant's own home vacuum cleaner after insertion of a new bag and using a researcher-collected method where settled house dust was collected from surfaces above floor level. The samples were analyzed for 16 polybrominated diphenyl ether (PBDE) congeners and total hexabromocyclododecane (HBCD). Significant correlations (r = 0.60-0.65, Spearman r = 0.47-0.54, P < 0.05) were found between matched dust samples collected with the two sampling methods for ?OctaBDE and ?DecaBDE but not for ?PentaBDE or HBCD. Statistically significantly higher concentrations of all PBDE congeners were found in the researcher collected dust than in the home vacuum cleaner bag dust (VCBD). For HBCD, however, the concentrations were significantly higher in the home VCBD samples. Analysis of the bags themselves indicated no or very low levels of PBDEs and HBCD. This indicates that there may be specific HBCD sources to the floor and/or that it may be present in the vacuum cleaners themselves. The BDE-47 concentrations in matched pairs of VCBD and breast milk samples were significantly correlated (r = 0.514, P = 0.029), indicating that one possible exposure route for this congener may be via dust ingestion. PRACTICAL IMPLICATIONS: The statistically significant correlations found for several individual polybrominated diphenyl ether (PBDE) congeners, ?OctaBDE and ?DecaBDE between the two dust sampling methods in this study indicate that the same indoor sources contaminate both types of dust or that common processes govern the distribution of these compounds in the indoor environment. Therefore, either method is adequate for screening ?OctaBDE and ?DecaBDE in dust. The high variability seen between dust samples confirms results seen in other studies. For hexabromocyclododecane (HBCD), divergent results in the two dust types indicate differences in contamination sources to the floor than to above-floor surfaces. Thus, it is still unclear which dust sampling method is most relevant for HBCD as well as for ?PentaBDE in dust and, further, which is most relevant for determining human exposure to PBDEs and HBCD. PMID- 22212126 TI - Host species and strain combination determine growth reduction of spruce and birch seedlings colonized by root-associated dark septate endophytes. AB - Interactions of Betula pendula and Picea abies with dark septate endophytes of the Phialocephala fortinii-Acephala applanata species complex (PAC) were studied. PAC are ubiquitous fungal root symbionts of many woody plant species but their ecological role is largely unknown. Sterile birch and spruce seedlings in monoculture and mixed culture were exposed to four PAC strains, added either singularly or paired in all possible combinations at 18 degrees C and 23 degrees C. Plant and fungal biomass was determined after 4 months. The most significant factors were strain and host combination. One of the strains significantly reduced biomass gain of spruce but not of birch. Plant biomass was negatively correlated with total endophytic fungal biomass in half of the strain - plant combinations. Endophytic PAC biomass was four times higher in spruce (~ 40 mg g( 1) drw) than in birch (~ 10 mg g(-1) drw). Competition between strains was strain dependent with some strains significantly reducing colonization density of other strains, and, thus, attenuating adverse effects of 'pathogenic' strains on plant growth in some strain - plant combinations. Biomass gain of spruce but not of birch was significantly reduced at higher temperature. In conclusion, host, fungal genotype, colonization density and presence of a competing PAC strain were the main determining factors for plant growth. PMID- 22212128 TI - Burden of rotavirus gastroenteritis and distribution of rotavirus strains in Asia: a systematic review. AB - BACKGROUND: Rotavirus is the leading cause of severe diarrhea in children worldwide. We systematically reviewed the burden of rotavirus gastroenteritis (RVGE) and distribution of rotavirus strains in Asia. METHODS: We searched MEDLINE, EMBASE and the World Health Organization (WHO) website for the term "rotavirus" and the name of each country. We included studies that were conducted in children between 2000 and 2011 and that examined the epidemiology, health and/or economic burden of RVGE, and G and P-type distribution in Eastern, South East, Southern and Central Asia. Random effects models were used to pool the proportions of RVGE. We also estimated child mortality due to RVGE using the updated WHO and United Nations Children's Fund's mortality estimates in 2008. RESULTS: The search identified 113 eligible articles. The incidence rates of rotavirus-related hospitalizations in children under 5 years of age ranged from 2.1 to 20.0 cases per 1000 children per year with the highest rates reported in Bangladesh, South Korea, Taiwan, Thailand, and Vietnam. Rotavirus accounted for 37.5% of year-round hospitalized gastroenteritis cases, with higher proportions reported in South East Asia. Rotavirus was associated with approximately 145,000 deaths every year in Asia, with the greatest numbers occurring in India, Pakistan, and Indonesia. The highest annual societal costs of treating RVGE were reported in China (US$365 million), followed by Japan (US$254 million) and India (US$41-72 million). A diversity of rotavirus G and P-types was observed across Asia and the distribution of strains differed by country and year. The most common strains were G1P[8] (23.6%), G2P[4] (11.8%), G3P[8] (18.9%), and G9P[8] (7.4%). CONCLUSIONS: Rotavirus is associated with substantial hospitalizations and deaths among children and causes large healthcare expenditures throughout Asia. Safe and effective rotavirus vaccines could substantially reduce the burden of disease. PMID- 22212127 TI - Vaccination of adults 65 years of age and older with tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Boostrix((r))): results of two randomized trials. AB - BACKGROUND: Pertussis can cause significant morbidity in elderly patients, who can also transmit this disease to infants and young children. There is little data available on the use of acellular pertussis vaccines in recipients >=65 years of age. METHODS: Two studies examined the safety and immunogenicity of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine (Boostrix((r))) in healthy >=65 year olds. In Study A subjects received single doses of Tdap and seasonal influenza vaccine either co-administered or given one month apart. In Study B subjects received either Tdap or tetanus-diphtheria (Td) vaccine. Antibodies were measured before and one month after vaccination. Reactogenicity and safety were actively assessed using diary cards. RESULTS: A total of 1104 subjects 65 years of age and older received a Tdap vaccination in the two studies. In study A, no differences in immune responses to Tdap or influenza vaccine were observed between co-administered or sequentially administered vaccines. In study B, Tdap was non-inferior to Td with respect to diphtheria and tetanus seroprotection, and anti-pertussis GMCs were non-inferior to those observed in infants following a 3-dose diphtheria, tetanus and acellular pertussis (DTaP) primary vaccination series, in whom efficacy against pertussis was demonstrated. Reports of adverse events were similar between Tdap and Td groups. CONCLUSIONS: Tdap was found to be immunogenic in subjects >=65 years, with a safety profile comparable to US-licensed Td vaccine. Tdap and influenza vaccine may be co-administered without compromise of either the reactogenicity or immunogenicity profiles of the two vaccines. PMID- 22212129 TI - A pestivirus DNA vaccine based on a non-antibiotic resistance Escherichia coli essential gene marker. AB - Antibiotic resistance genes are widely used to produce plasmid DNA vaccines, but risk unwanted exposure to antibiotic residues and the spread of resistance genes. To overcome the limitations of existing selection technologies, we developed an alternative system applying the widely used household biocide triclosan as the selective agent and an endogenous growth essential target gene, fabI, as the plasmid-borne marker in Escherichia coli. The fabI/triclosan system enables efficient, non-antibiotic selection of transformed bacteria, with improved safety and plasmid production features. Here we aimed to evaluate the performance of this non-antibiotic selection system using a plasmid DNA vaccine against bovine viral diarrhoea virus as an example. The new system displayed high-yield plasmid DNA production in a standard E. coli host strain and growth media. Notably, the purified pDNA provided efficient in vitro protein expression and a strong in vivo neutralising antibody response in a mouse model, with measures comparable to that of the parental plasmid DNA based on ampicillin resistance. The fabI/triclosan system requires only low levels of triclosan for selection (1 MUM) and residual triclosan in isolated DNA was below the limit of detection (< 20 parts per trillion). The fabI/triclosan selection system provides a simple, non-antibiotic resistance marker for plasmid selection, applicable to DNA vaccines and possibly other recombinant vaccine applications. PMID- 22212130 TI - The successful treatment of acute refractory pseudo-obstruction with prucalopride. PMID- 22212131 TI - Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. AB - BACKGROUND: Intellectual disability ('developmental delay' at age<5 years) affects 2.5% of population worldwide. Recommendations to investigate genetic causes of intellectual disability are based on frequencies of single conditions and on the yield of diagnostic methods, rather than availability of causal therapy. Inborn errors of metabolism constitute a subgroup of rare genetic conditions for which an increasing number of treatments has become available. To identify all currently treatable inborn errors of metabolism presenting with predominantly intellectual disability, we performed a systematic literature review. METHODS: We applied Cochrane Collaboration guidelines in formulation of PICO and definitions, and searched in Pubmed (1960-2011) and relevant (online) textbooks to identify 'all inborn errors of metabolism presenting with intellectual disability as major feature'. We assessed levels of evidence of treatments and characterised the effect of treatments on IQ/development and related outcomes. RESULTS: We identified a total of 81 'treatable inborn errors of metabolism' presenting with intellectual disability as a major feature, including disorders of amino acids (n=12), cholesterol and bile acid (n=2), creatine (n=3), fatty aldehydes (n=1); glucose homeostasis and transport (n=2); hyperhomocysteinemia (n=7); lysosomes (n=12), metals (n=3), mitochondria (n=2), neurotransmission (n=7); organic acids (n=19), peroxisomes (n=1), pyrimidines (n=2), urea cycle (n=7), and vitamins/co-factors (n=8). 62% (n=50) of all disorders are identified by metabolic screening tests in blood (plasma amino acids, homocysteine) and urine (creatine metabolites, glycosaminoglycans, oligosaccharides, organic acids, pyrimidines). For the remaining disorders (n=31) a 'single test per single disease' approach including primary molecular analysis is required. Therapeutic modalities include: sick-day management, diet, co factor/vitamin supplements, substrate inhibition, stemcell transplant, gene therapy. Therapeutic effects include improvement and/or stabilisation of psychomotor/cognitive development, behaviour/psychiatric disturbances, seizures, neurologic and systemic manifestations. The levels of available evidence for the various treatments range from Level 1b,c (n=5); Level 2a,b,c (n=14); Level 4 (n=45), Level 4-5 (n=27). In clinical practice more than 60% of treatments with evidence level 4-5 is internationally accepted as 'standard of care'. CONCLUSION: This literature review generated the evidence to prioritise treatability in the diagnostic evaluation of intellectual disability. Our results were translated into digital information tools for the clinician (www.treatable-id.org), which are part of a diagnostic protocol, currently implemented for evaluation of effectiveness in our institution. Treatments for these disorders are relatively accessible, affordable and with acceptable side-effects. Evidence for the majority of the therapies is limited however; international collaborations, patient registries, and novel trial methodologies are key in turning the tide for rare diseases such as these. PMID- 22212132 TI - Is atrial fibrillation associated with pulmonary embolism? AB - BACKGROUND: A pulmonary embolism (PE) is thought to be associated with atrial fibrillation (AF). Nevertheless, this association is based on weak data. OBJECTIVES: To assess whether the presence of AF influences the clinical probability of PE in a cohort of patients with suspected PE and to confirm the association between PE and AF. PATIENTS/METHODS: We retrospectively analyzed the data from two trials that included 2449 consecutive patients admitted for a clinically suspected PE. An electrocardiography (ECG) was systematically performed and a PE was diagnosed by computer tomography (CT). The prevalence of AF among patients with or without a PE was compared in a multivariate logistic regression model. RESULTS: The prevalence of PE was 22.8% (519/2272) in patients without AF and 18.8% (25/133) in patients with AF (P = 0.28). After adjustment for confounding factors, AF did not significantly modify the probability of PE (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.42-1.11). However, when PE suspicion was based on new-onset dyspnea, AF significantly decreased the probability of PE (OR 0.47, 95% CI 0.26-0.84). If isolated chest pain without dyspnea was the presenting complaint, AF tended to increase the probability of PE (OR 2.42, 95% CI 0.97-6.07). CONCLUSIONS: Overall, the presence of AF does not increase the probability of PE when this diagnosis is suspected. Nevertheless, when PE suspicion is based on new-onset dyspnea, AF significantly decreases the probability of PE, as AF may mimic its clinical presentation. However, in patients with chest pain alone, AF tends to increase PE probability. PMID- 22212133 TI - The nephroprotective effect of tauroursodeoxycholic acid on ischaemia/reperfusion induced acute kidney injury by inhibiting endoplasmic reticulum stress. AB - The incidence of acute kidney injury (AKI) is very high, and multiple physiopathological processes are involved, including endoplasmic reticulum stress (ERS). Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid derivative that has been reported to inhibit ERS. To determine whether TUDCA had a nephroprotective effect on AKI and to explore the exact mechanism, an ischaemia/reperfusion (I/R)-induced AKI mouse model and a tunicamycin-pre-treated TCMK-1 cell model were established. It was found that the renal tubular necrosis score and cell apoptosis index reached their peak 24 hr after I/R. GRP78 and C/EBP homologous protein (CHOP) expression and Caspase 12 activation were enhanced, reaching their peaks at 4 and 12 hr, respectively. TUDCA intervention not only decreased the renal tubular necrosis score and the cell apoptosis index but also down-regulated GRP78 and CHOP expression and Caspase 12 activation. The survival rate of TCMK-1 cells pre-treated with TUDCA was significantly higher than that of TCMK-1 cells without TUDCA pre-treatment. In conclusion, TUDCA had a nephroprotective effect on IR-induced AKI by inhibiting ERS and by blocking GRP78 and CHOP expression, reducing Caspase 12 activation and inhibiting cell apoptosis. PMID- 22212134 TI - An evidence-based response to 'Genes and schizophrenia: a pseudoscientific disenfranchisement of the individual'. PMID- 22212135 TI - Comparison of preserved vascular allografts using glycerol and University of Wisconsin solution in a goat carotid artery transplantation model. AB - BACKGROUND: Prosthetic grafts have poor patency rates in peripheral arterial reconstructions. Glycerol (GL)-preserved grafts are an alternative. The aim of this study was to examine patency, graft morphology and function of GL-preserved allografts in a goat carotid artery animal model. METHODS: The first group (n = 7) underwent bilateral replacement of the carotid artery by a carotid allograft that was preserved in GL for 1 week. In the second group (n = 5), a carotid artery allograft that was preserved in University of Wisconsin solution (UW) for 48 h was used. In the third group (n = 5), the jugular vein (autologous vein, AU) was used. The follow-up was 3 months. RESULTS: One UW graft and 1 GL graft occluded in the first 24 h postoperatively. Three-month primary patency rates for GL, UW and AU grafts were 93, 100 and 80%, respectively (p = 0.39). Graft diameter was increased in UW allografts (p < 0.005), whereas GL allografts remained unchanged. After explantation, GL allografts demonstrated contraction and relaxation capacity and lower intimal thickness (p < 0.001). CONCLUSION: GL preservation has proven to be a feasible method for arterial allograft transplantation in a large animal model with decreased intimal hyperplasia and renewed functional capability. PMID- 22212136 TI - Transcriptome-wide analysis of protein-RNA interactions using high-throughput sequencing. AB - Protein-RNA interactions are emerging as an important functional element in the regulation of gene expression. Cross-linking of proteins to RNA by UV irradiation followed by immunoprecipitation (CLIP) has provided a crucial tool for research in this field. Initially, the bottleneck of the method was the relatively low number of identified RNA binding sites. It was only the arrival of next generation sequencing that allowed a comprehensive and unbiased description of the cross-linked protein-RNA fragments. Here, we summarize recent progress in the study of protein-RNA interactions, as well as some of the important findings obtained using different CLIP approaches in cultured cells and organisms. These efforts allowed the identification of functional RNA-binding sites for a wide range of RNA-interacting proteins. Experimental and bioinformatic progress will further advance this dynamic area of research. The combination of high-resolution protein-RNA interaction maps with transcriptome-wide data describing the stability, modifications and structures of RNAs, in addition to protein expression profiling, will provide deeper insight into post-transcriptional and translational regulatory events and mechanisms. PMID- 22212137 TI - Control of BACE1 degradation and APP processing by ubiquitin carboxyl-terminal hydrolase L1. AB - Deposition of amyloid beta protein (Abeta) in the brain is the hallmark of Alzheimer's disease (AD) pathogenesis. Beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the beta-secretase in vivo essential for generation of Abeta. Previously we demonstrated that BACE1 is ubiquitinated and the degradation of BACE1 is mediated by the ubiquitin-proteasome pathway (UPP). However the mechanism underlying regulation of BACE1 degradation by UPP remains elusive. Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme highly specific to neuron, catalyzing the hydrolysis of ubiquitin conjugates from ubiquitinated substrates. UCHL1 regulates ubiquitin-dependent protein degradation. However, whether UCHL1 is particularly involved in the proteasomal degradation of BACE1 and what is the role of UCHL1 in AD pathogenesis remain elusive. To investigate the effect of UCHL1 on BACE1 degradation, HUCH cells, a UCHL1 stably over-expressed HEK293 cell line, was established. We found that inhibition of UCHL1 significantly increased BACE1 protein level in a time dependent manner. Half life of BACE1 was reduced in HUCH cells compared with HEK. Over-expression of UCHL1 decreased APP C-terminal fragment C99 and Abeta levels in HUCH cells. Moreover, disruption of Uchl1 gene significantly elevated levels of endogenous BACE1, C99 and Abeta in the Uchl1-null gad mice. These results demonstrated that UCHL1 accelerates BACE1 degradation and affects APP processing and Abeta production. This study suggests that potentiation of UCHL1 might be able to reduce the level of BACE1 and Abeta in brain, which makes it a novel target for AD drug development. PMID- 22212138 TI - Modified CD4(+) T-cell response in recipients of old cardiac allografts. AB - With an increasing demand, organs from elderly donors are more frequently utilized for transplantation. Herein, we analyzed the impact of donor age on CD4(+) T-cell responses with regard to regulatory and effector mechanisms. Young (3months) BM12 recipients were engrafted with young or old (18months) B6 cardiac allografts. Systemic CD4(+) T-cell responses and intragraft changes were monitored and compared to age-matched syngenic transplant controls. While elderly, nonmanipulated hearts contained significantly elevated frequencies of donor-derived leukocytes prior to transplantation, allograft survival was age independent. T-cell activation, however, was delayed and associated with a compromised immune response in mixed lymphocyte cultures (MLR; P=0.0002) early after transplantation (day 14). During the time course after transplantation, recipients of old grafts demonstrated an augmented immune response as shown by significantly higher frequencies of activated CD4(+) T-cells and a stronger in vitro alloreactivity (MLR; ELISPOT; P<0.01). In parallel, frequencies of regulatory T-cells had increased systemically and overall fewer CD4(+) T-cells were detected intragraft. Interestingly, changes in the CD4(+) T-cell response were not reflected by graft morphology. Of note, transplantation of young and old syngenic hearts did not show age-related differences of the CD4(+) T-cells response suggesting that old grafts can recover from a period of short cold ischemia time. Our data suggest that donor age is associated with an augmented CD4(+) T-cells response which did not affect graft survival in our model. These findings contribute to a better understanding of the immune response following the engraftment of older donor organs. PMID- 22212142 TI - Primary cutaneous B-cell lymphomas. AB - Cutaneous B-cell lymphomas (CBCL) are the second most common form of primary cutaneous lymphomas. The cutaneous follicle center lymphoma and the cutaneous marginal zone lymphoma (extranodal MALT type lymphoma) account for the vast majority of CBCL and manifest with nodules. These two lymphoma entities have an indolent, slowly progressive course and an excellent prognosis despite a high rate of recurrences. In contrast, cutaneous diffuse large B-cell lymphoma, leg type, and other rare forms of CBCL display an impaired prognosis and therefore require to be treated with multiagent chemotherapy and anti-CD20 monoclonal antibodies in most cases. Clinico-pathologic correlation, histology with immunohistochemical profile and genotyping as well as staging examinations are crucial diagnostic elements in the work-up of CBCL. PMID- 22212147 TI - [Multiple mucous and conjunctival nodules in a 16-year old patient]. PMID- 22212150 TI - Association between genetic variant on chromosome 12p13 and stroke survival and recurrence: a one year prospective study in Taiwan. AB - BACKGROUND: The association between ischemic stroke and 2 single nucleotide polymorphisms (SNPs) on chromosome 12p13, rs12425791 and rs11833579 appears inconsistent across different samples. These SNPs are close to the ninjurin2 gene which may alter the risk of stroke by affecting brain response to ischemic injury. The purpose of this study was to investigate the association between these two SNPs and ischemic stroke risk, as well as prognostic outcomes in a Taiwanese sample. METHODS: We examined the relations of these two SNPs to the odds of new-onset ischemic stroke, ischemic stroke subtypes, and to the one year risk of stroke-related death or recurrent stroke following initial stroke in a case-control study. A total of 765 consecutive patients who had first-ever ischemic stroke were compared to 977 stroke-free, age-matched controls. SNPs were genotyped by Taqman fluorescent allelic discrimination assay. The association between ischemic stroke and SNPs were analyzed by multivariate logistic regression. Cox proportional hazard model was used to assess the effect of individual SNPs on stroke-related mortality or recurrent stroke. RESULTS: There was no significant association between SNP rs12425791 and rs11833579 and ischemic stroke after multiple testing corrections. However, the marginal significant association was observed between SNP rs12425791 and large artery atherosclerosis under recessive model (OR, 2.30; 95%CI, 1.22-4.34; q-value = 0.062). Among the 765 ischemic stroke patients, 59 died or developed a recurrent stroke. After adjustment for age, sex, vascular risk factors and baseline stroke severity, Cox proportional hazard analysis indicated that the hazard ratios were 2.76 (95%CI, 1.34-5.68; q-value, 0.02) and 2.15 (95%CI, 1.15-4.02; q-value, 0.03) for individuals with homozygous variant allele of rs12425791 and rs11833579, respectively. CONCLUSIONS: This is a precedent study that found genetic variants of rs12425791 and rs11833579 on chromosome 12p13 are independent predictors of stroke-related mortality or stroke recurrence in patients with incident ischemic stroke in Taiwan. Further study is needed to explore the details of the physiological function and the molecular mechanisms underlying the association of this genetic locus with ischemic stroke. PMID- 22212151 TI - Intravitreal ranibizumab for macular edema secondary to retinal vein occlusion. AB - BACKGROUND/AIMS: To investigate the effects of intravitreal ranibizumab treatment for macular edema (ME) secondary to retinal vein occlusion (RVO) and the relationship between spectral-domain optical coherence tomography (SD-OCT) findings and visual outcome after successful resolution of ME. METHODS: Forty consecutive eyes with ME secondary to branch RVO (BRVO; 29 eyes of 29 patients) or central RVO (CRVO; 11 eyes of 11 patients) were included in a prospective study and treated with 3 initial intravitreal injections of 0.5 mg ranibizumab at monthly intervals. Retreatment was based on visual acuity changes and OCT findings. Patients with complete resolution of ME were classified into two groups according to final best-corrected visual acuity (BCVA) of better than 0.30 logMAR (group 1) or poorer than 0.30 logMAR (group 2), and SD-OCT findings were analyzed at baseline and at 12 months. RESULTS: In patients with BRVO, mean BCVA at 12 months (0.19 +/- 0.18) was significantly better than that at baseline (0.76 +/- 0.37; p = 0.000). The mean number of injections was 4.4 +/- 1.2. In patients with CRVO, the mean BCVA at 12 months (0.39 +/- 0.23) was slightly improved from that at baseline (0.84 +/- 0.68), but the difference was not significant (p = 0.063). Patients with CRVO received a mean number of 6.1 +/- 1.4 injections of ranibizumab. Baseline SD-OCT more frequently detected the foveal inner/outer segment (IS/OS) line and external limiting membrane (ELM) in group 1 (p = 0.003) than in group 2 (p = 0.012). Preservation of the foveal IS/OS line (odds ratio = 5.400; p = 0.036) and ELM (odds ratio = 7.312; p = 0.016) at baseline correlated with good final visual outcome. CONCLUSION: Intravitreal ranibizumab injections effectively treat ME secondary to RVO. Good visual outcome was associated with preservation of the foveal IS/OS line and ELM at baseline. PMID- 22212152 TI - Modelling the effect of temperature on the range expansion of species by reaction diffusion equations. AB - The spatial dynamics of range expansion is studied in dependence of temperature. The main elements population dynamics, competition and dispersal are combined in a coherent approach based on a system of coupled partial differential equations of the reaction-diffusion type. The nonlinear reaction terms comprise population dynamic models with temperature dependent reproduction rates subject to an Allee effect and mutual competition. The effect of temperature on travelling wave solutions is investigated for a one dimensional model version. One main result is the importance of the Allee effect for the crossing of regions with unsuitable habitats. The nonlinearities of the interaction terms give rise to a richness of spatio-temporal dynamic patterns. In two dimensions, the resulting non-linear initial boundary value problems are solved over geometries of heterogeneous landscapes. Geo referenced model parameters such as mean temperature and elevation are imported into the finite element tool COMSOL Multiphysics from a geographical information system. The model is applied to the range expansion of species at the scale of middle Europe. PMID- 22212153 TI - Congenital heart disease-associated pulmonary arterial hypertension: preliminary results from a novel registry. AB - BACKGROUND/AIMS: Pulmonary arterial hypertension (PAH) frequently accompanies childhood congenital heart disease (CHD) and may persist into adult life. The advent of specific PAH therapies for PAH prompted formation of a national Australian and New Zealand registry in 2010 to document the incidence, demographics, presentation and outcomes for these patients. METHODS: This multicentre, prospective, web-based registry enrols patients with CHD-associated PAH being followed in a tertiary centre. The inclusion criteria stipulated patient age >=16 years, a measured mean pulmonary arterial pressure >25 mmHg at rest or echocardiographical evidence of PAH or a diagnosis of Eisenmenger syndrome, and followed since 1 January 2000. A single observer collected standardised data during a series of site visits. RESULTS: Of the first 50 patients enrolled, 30 (60%) were female. The mean age (standard deviation (SD)) at the time of PAH diagnosis or confirmation in an adult centre was 27.23 (10.07) years, and 32 (64%) patients are currently aged >30 years. Fourteen (28%) patients were in World Health Organization Functional Class II and 36 (72%) in Class III at the time of diagnosis. Forty-seven of 50 (94%) had congenital systemic-pulmonary shunts, and 36 (72%) never underwent intervention. Thirteen (26%) had Down syndrome. Confirmation of PAH by recent cardiac catheterisation was available in 30 (60%) subjects. During follow up, a total of 32 (64%) patients received a PAH-specific therapy. CONCLUSIONS: CHD associated with PAH in adult life has resulted in a new population with unique needs. This registry will allow documentation of clinical course and long-term outcomes for these patients. PMID- 22212154 TI - Mixed phenotype acute leukemia of T/myeloid type with a prominent cellular heterogeneity and unique karyotypic aberration 45,XY, dic(11;17). AB - INTRODUCTION: A 26-yr-old male patient with mixed phenotype acute leukemia of T/myeloid type with prominent leukemic cell heterogeneity, and the presence of a so far unreported karyotype aberration in this type of acute leukemia 45,XY, dic(11;17)(11qter->11p11.2::17p11.2->17qter) is presented. METHODS: Flow immunocytometry was performed by direct multicolor immunofluorescent technique on bone marrow aspirates. Cytogenetic analyses were performed using G-banding method by direct preparation of unstimulated bone marrow cells and following 24 hours of culture in RPMI 1540 culture medium with 25% fetal calf serum at 37 degrees C RESULTS: The flow immunocytometry of bone marrow nucleated cells revealed the existance of three distinct blast cell populations with overlapping immunophenotypes. Predominant blast cell population had an early myeloid phenotype and aberrant expression of CD7 antigen (HLA-DR(+), CD34(+), anti MPO(+), CD117(+), CD33(+), CD13(+), CD7(+low), cyCD3(-), TdT(-)). The other two blast cell populations, smaller in cell diameter and less sizable in cell proportion, both shared the T-lymphoid features. The patient was treated with ADE protocol (etoposide, cytarabine and doxorubicine). A complete remission was achieved and lasted 5 months. CONCLUSION: A case of MPAL with complex biological features, 45,XY, dic(11;17)(11qter->11p11.2::17p11.2->17qter) karyotype and an aggressive, therapy-resistant clinical course, is presented. PMID- 22212155 TI - The eyes have it. PMID- 22212156 TI - Focused force fistuloplasty as an adjunct to conventional balloon fistuloplasty in resistant stenosis. PMID- 22212157 TI - [HIV infection]. AB - The skin can be an indicator of decreased immunocompetence. Dermatological markers include new and extensive seborrheic eczema, psoriasis without a family history, widespread herpes zoster in young adults, oral hairy leucoplakia and mollusca in adults. In these cases an HIV test should be offered. During the last 15 years the clinical picture of HIV has changed dramatically. Almost every year new drugs with better efficacy, lower pill burden and less side effects have been approved. Life expectancy is close to normal in western countries. In spite of better treatment options, prevention is the key to stop the worldwide epidemic. Awareness campaigns have to account for the synergies between HIV and other sexually transmitted diseases. This poses a great challenge for dermatovenereology. PMID- 22212158 TI - [Psoriasis or atopic eczema: skin-infiltrating effector memory T cells make the difference]. PMID- 22212159 TI - Seclusion reduction in a forensic mental health setting. AB - Seclusion has become a contentious practice and initiatives have commenced to reduce or eliminate its use. This paper presents the initiatives that were introduced during a seclusion reduction project that was undertaken at an Australian forensic hospital. These initiatives are based on the six core strategies that have been successfully used in North America to reduce seclusion. However, there are challenges (patient characteristics, prisoner culture and ensuring safety) and opportunities (longer admissions, higher staff-patient ratio, staff confidence, sound risk assessment and management) that can influence projects to reduce seclusion in a forensic hospital. During this project, the frequency (mainly multiple seclusions of patients) and duration of seclusion events were reduced but there was less reduction in the number of patients that were secluded. It is possible that the strategies were successfully supported by the identified opportunities to reduce the frequency and duration of seclusion but the challenges were significantly powerful in the early period of admission to prompt the need for seclusion. Reducing seclusion in a forensic hospital is a complex undertaking as nurses must provide a safe environment while dealing with volatile patients and may have little alternative at present but to use seclusion after exhausting other interventions. PMID- 22212160 TI - [Management of infections from cardiac implantable electronic devices: recommendations from a study panel]. AB - Cardiac Implantable Electronic Device (CIED) infections are an emerging clinical issue. There are no national recommendations on the management of these infections, also due to the limited number of dedicated and high quality clinical studies. Therefore, researchers from southern Italian centres have decided to share the clinical experience gathered so far in this field and report practical recommendations for the diagnosis and treatment of adult patients with CIED infection or endocarditis. Here we review the risk factors, diagnostic issues (microbiological and echocardiographic) and aetiology, and describe extensively the best therapeutic approach. We also address the management of complications, follow-up after discharge and the prevention of CIED infections. In this regard, a multidisciplinary approach is fundamental to appropriately manage the initial diagnostic process and the comorbidities, to plan proper antimicrobial treatment and complete percutaneous hardware removal, with the key support of microbiology and echocardiography. PMID- 22212161 TI - [NDM-1: the superbug?]. AB - A novel type of carbapenemase, New Delhi metallo beta-lactamase 1 (NDM 1), was first identified in 2008 in two Enterobacteriacea isolates, both recovered from a Swedish patient transferred from India. The emergence of NDM 1 is now reported from all continents, often in patients with a history of travel or hospitalization in the Indian subcontinent. The NDM 1 producing Gram-negative bacteria are mainly Enterobacteriaceae, which can cause colonization or fatal infections, with worrying antimicrobial susceptibility profiles: some isolates have developed resistance to practically all available antibiotics. Is the NDM-1 the super-bug? Are we in the post-antibiotic era? This review is a summary of currently available knowledge of NDM-1 that draws attention to future antimicrobial resistance scenarios. PMID- 22212162 TI - Utility of brain natriuretic peptide as prognostic marker in community-acquired pneumonia and chronic obstructive pulmonary disease exacerbation patients presenting to the emergency department. AB - Brain natriuretic peptide (BNP) is a strong prognostic predictor in congestive heart failure patients. Community-acquired pneumonia (CAP) is frequently associated with systemic inflammatory response syndrome (SIRS), evolving into septic shock, with high mortality. The aim of this study was to compare BNP mean values in CAP, chronic obstructive pulmonary disease (COPD) exacerbation, and acute bronchitis patients, and to evaluate the correlation of BNP values with length of hospital stay. In all, we analysed 56 patients (28 males and 28 females) admitted to our Emergency Department from May 2010 to April 2011 because of dyspnea. The CAP patients had significantly higher mean BNP values in comparison to acute bronchitis patients (127.2 Vs 45.9 pg/mL; p=0.003), and a significantly positive correlation was found between their BNP values and length of hospital stay (r=0.404; p=0.05). A stepwise multivariate linear regression analysis model showed white blood cell count as the only independent predictor of length of hospital stay (p=0.05). The results suggest that CAP patients with SIRS have increased mean BNP levels compared to acute bronchitis patients, but this parameter failed to predict the length of hospital stay. PMID- 22212163 TI - [Risk factors for toxoplasmosis in pregnant women in central Italy]. AB - Between 2005 and 2007 we examined 2356 pregnant women. We interviewed the patients concerning their dietary behaviour and lifestyles during pregnancy in correlation with the possibility of contracting toxoplasmosis. Our purpose was to ascertain the importance of different risk factors in a group of Italian patients and assess the level of knowledge on this matter. The survey questions were related to: 1) eating rare/raw meat; 2) eating commercial or homemade ham or other pork derivatives such as dry sausage and salami; 3) owning a garden or a plot for fruit and vegetables; 4) owning pets, especially cats; 5) living in town or in the country; 6) eating fresh uncooked vegetables. On the basis of serological tests (Toxo IgG, IgM, IgA, avidity test) we identified three groups of women: those with primary infection, seronegative women (control), and those with inactive infections. Comparison of the first two groups showed that each risk factor significantly increases the likelihood of acquiring toxoplasmosis. Higher odds ratios were observed for those living in the country and for those consuming homemade cured meat. PMID- 22212164 TI - [Mediterranean spotted fever in paediatric and adult patients: two clinical aspects of the same disease]. AB - Mediterranean Spotted Fever is an acute febrile disease caused by Rickettsia conorii and transmitted to humans by the brown dog tick Rhipicephalus sanguineus. Nearly 400 cases are reported every year in Sicily, mainly from June to September. The aim of this study is to compare the clinical and laboratory features of two different groups of patients , one of adults and one of children. The analysis included all adult patients with MSF diagnosed at the Institute of Infectious Diseases, Paolo Giaccone University Polyclinic in Palermo, during the period January 2007- August 2010 and all the children diagnosed with MSF at the G. Di Cristina Children Hospital in Palermo during the period January 1997- December 2004. On admission, a complete physical and laboratory examination was carried out on every patient. An indirect immunofluorescence assay for Rickettsia conorii was performed in every case, a PCR assay was performed with blood samples from some adult patients. Analysis of the results confirms that MSF is a benign, and self-limiting disease in children, while severe complications can often arise in adults. PMID- 22212165 TI - [Renal abscess in childhood: a case report]. AB - We describe the case of a previously healthy six-year-old boy with a right renal abscess due to a methicillin-resistant Staphylococcus aureus, which necessitated a radical nephrectomy. Although renal ultrasonography is often the initial tool to identify fluid collection, in our case the diagnosis was obtained only after performing an abdominal CT with intravenous contrast. It is therefore necessary to combine these different imaging techniques in all children with fever and abdominal/lumbar pain without any apparent cause in order to obtain an early diagnosis and minimise organ damage. PMID- 22212166 TI - [Chronic osteomyelitis due to Pseudomonas aeruginosa: treatment with elastomeric infusor in an outpatient setting]. AB - Chronic bacterial osteomyelitis requires long-term antibiotic treatment (at least 6-8 weeks). After in-hospital management, patients are usually discharged and treated in outpatient settings. However, when the aetiology is represented by Gram-negative microorganisms, outpatient treatment could be difficult. Beta lactam administration by means of an elastomeric infusor may represent an attractive approach. We report two cases of osteomyelitis due to Pseudomonas aeruginosa successfully treated with continuous ceftazidime administration via an elastomeric infusor in outpatient settings. In both cases the patients were free from clinical and laboratory signs of osteomyelitis at the end of treatment and after 12 months follow-up. PMID- 22212167 TI - Streptococcus bovis meningitis associated with colonic diverticulosis and hearing impairment: a case report. AB - A 75-year-old woman presented to the Tropical Diseases Hospital, Goiania, Brazil, with a two-day history of fever and chills followed by headache and vomiting over the last 24 hours. The cerebrospinal fluid (CSF) showed 270 leukocytes/mmc (30 percent neutrophils); 20 red cells/mmc; undetectable levels of glucose and 232 mg/dL of protein. The Gram stain revealed several Gram-positive cocci, and CSF culture yielded Streptococcus bovis. A colonoscopy showed diverticula in descendent and transverse colon. After a 14-day course of penicillin G, the patient was discharged in a good state of health, with only mild hearing impairment. PMID- 22212168 TI - [Epidemiological, social and public health aspects of tuberculosis in Ferrara in the 19th century]. AB - Our first study of tuberculosis in Ferrara during the nineteenth century, whose results have been recently published, focused on disease treatment. Here we present the descriptive analysis of mortality, with the following results being attained: two behavioural patterns are detected with regard to the onset of disease, before and after 1850; TB is a specific disease that affects all parts of the body in all age groups: childhood, and active and passive populations; there are no significant differences with regard to gender; as regards the occupations performed by the deceased, those related to industry and agriculture and to various other activities and services are those with the highest mortality; tuberculosis has a seasonal pattern; summer and autumn are the periods of greatest prevalence (hot weather and humidity are factors that affect the respiratory system); among the forms of tuberculosis it can be observed that up to the year 1850 people died in Ferrara either of pulmonary tuberculosis or TB localised in other areas; from 1851 onward there appears to have been a dramatic change, with a decrease in unspecific diagnosis but the appearance of disease manifestations in its various clinical forms. PMID- 22212169 TI - Ocular lesions following suspected lightning injury in a horse. AB - PURPOSE: To describe the gross and histopathological ocular findings in a horse following suspected lightning injury. METHODS: The eyes of a 2-year-old thoroughbred gelding were clinically and histopathologically evaluated following a severe lightning storm following euthanasia because of visual impairment. RESULTS: Severe corneal edema and hydrops were noted clinically oculus dexter. Indirect ophthalmoscopy revealed bilateral symmetrical raised hyporeflective peripapillary geographic lesions. Histopathologic evaluation revealed corneal edema in the right eye with normal corneal endothelium. Posterior segment evaluation revealed localized, pericentral choroidal lesions characterized by the presence of hemorrhage, early fibrosis, and minimal lymphoplasmacytic, neutrophilic, and histiocytic inflammation with spindle cell proliferation. The retinas overlying the choroidal lesions were necrotic and mostly absent. Peripheral to the focal lesion, the retina abruptly returned to normal architecture peripheral to a zone of apoptotic photoreceptors. Centrally, swollen axons extended into the optic disc. CONCLUSIONS: There have been few descriptions of ocular lesions in animals following suspected lightning injury. We believe these findings to be unique because of the type of thermal injury that may be characteristic of lightening injury. We do not know whether these lesions would have progressed over time. PMID- 22212170 TI - Using ESTs database to predict and validate single polymorphisms at the HLA system. AB - We propose a bioinformatics pipeline in which we use an ESTs database to predict and validate single-nucleotide polymorphisms (SNPs) directly linked to gene coding regions at the HLA class I genes (HLA-A, HLA-B and HLA-C). Annotation originated from our analysis revealed various classes of possible new variations that may indicate possible new alleles. Thus, bioinformatics pipelines seem to be useful approaches to help screening for novel genetic variations at the HLA panel, and further analysis will foster this aim to provide celerity at the massive analysis of data currently generated in large-scale high-throughput experiments. PMID- 22212171 TI - The influence of enamel matrix derivative on the angiogenic activity of primary endothelial cells. AB - BACKGROUND AND OBJECTIVE: Angiogenesis plays a crucial role in early wound healing and tissue regeneration. Although enamel matrix derivative (EMD) has demonstrated the potential to stimulate periodontal regeneration, the biological effects of EMD on angiogenesis and underlying mechanisms have not been fully elucidated. The aim of the present study was to examine the angiogenic effects of EMD in vitro. MATERIAL AND METHODS: Human umbilical vein endothelial cells (HUVECs) were used to assess the effect of EMD on proliferation, survival, adhesion and migration. The effect of EMD on HUVEC angiogenesis was assessed by a three-dimensional sprouting assay. In order to understand the signalling mechanism of altered cell proliferation of HUVECs caused by EMD, the phosphorylation status of ERK1/2 and of the serine/threonine protein kinase Akt was analysed by western blot using phospho-specific antibodies. RESULTS: The proliferation of HUVECs was stimulated by 50 MUg/mL EMD, whereas higher concentrations (>=100 MUg/mL) resulted in an increased apoptotic rate. The mitogenic response to EMD was associated with the activation of ERK1/2. Enamel matrix derivative did not affect cell adhesion, but all concentrations of EMD tested (0.1-250 MUg/mL) promoted migration of HUVECs. Furthermore, EMD induced capillary-like sprout formation from HUVEC spheroids in a dose-dependent manner. CONCLUSION: Our data indicate that EMD acts as a proangiogenic factor in vitro and, as such, might contribute to periodontal tissue regeneration by stimulation of vessel formation during wound healing. PMID- 22212172 TI - MRSA eradication in dermatologic outpatients - theory and practice. AB - BACKGROUND: The dissemination of methicillin resistant staphylococcus aureus (MRSA) is an increasing challenge in medical care. Apart from hospital acquired MRSA, there has also been an increase in community acquired and livestock associated MRSA. While the risks of MRSA (e. g. wound infections) and consequences (e. g. rejection of patients) are well known, there are little data on the effectiveness of eradication procedures. PATIENTS AND METHODS: 32 patients with proven MRSA colonization were monitored during eradication for the following aspects: (1) localization of MRSA (swabs from hairline, anterior nares, throat, axillae, groins, perineum, and wounds, if present), (2) presence of eradication impairing factors, (3) length of time needed for eradication, (4) cost of eradication, (5) molecular fingerprint and risk assessment (spa-types). RESULTS: We describe the successful eradication of MRSA in all 32 patients. Most positive nasal swabs were obtained from the anterior nares and the throat and only rarely from the hairline or axillae. The greater the number of positive swabs, the more time was needed for eradication. In most patients (37.5%), eradication with topical antiseptics was successful. The average time for eradication was 12.97 (+/- 7.6) days. Twelve patients required systemic antibiotic therapy. Treatment costs associated with the use of systemic antibiotics were significantly higher. The most frequent spa types were t032 and t003. CONCLUSIONS: We report successful MRSA eradication in outpatients. Systemic antibiotics are unnecessary in the majority of patients. A combined anti-MRSA strategy for inpatients and outpatients is recommended. PMID- 22212174 TI - A multi-biomarker approach to assess effects of Triclosan in the clam Ruditapes philippinarum. AB - The effects of 7 days' exposure to differing Triclosan (TCS) concentrations (300, 600, and 900 ng/L) were investigated in the clam Ruditapes philippinarum. Vitellogenin (Vg)-like protein levels in haemolymph and digestive gland from males and females, gill acetylcholinesterase (AChE) activity, superoxide dismutase (SOD) and catalase (CAT) activities in gills and digestive gland, and gill lipid peroxidation (LPO) were measured. The highest TCS concentrations decreased significantly Vg levels in male haemolymph and digestive gland, whereas no significant variations were found in females. The highest TCS concentrations increased significantly SOD activity in gills, but decreased it in digestive gland. No changes in CAT activity were observed. In gills, TCS reduced significantly AChE activity, but it did not induce significant variations in LPO. Our study demonstrates that TCS alters biochemical parameters in R. philippinarum, even at environmentally realistic concentrations, and suggests differing modes of action of the contaminant, in clams at least. PMID- 22212173 TI - Systemic illness moderates the impact of N-acetyl cysteine in bipolar disorder. AB - OBJECTIVES: Bipolar disorder (BD) is intricately associated with chronic clinical conditions. Medical comorbidity is not only more prevalent in mood disorders, but is associated with increased costs, cognitive impairment and, ultimately, premature mortality. Oxidative stress and inflammation may mediate part of this association. To further investigate the association between medical comorbidity status and clinical improvement with adjuvant N acetyl cysteine (NAC) in the context of a placebo-controlled trial. METHODS: Placebo-controlled randomized clinical trial assessing the effect of NAC over 24 weeks. Symptomatic and functional outcomes were collected over the study period. Medical comorbidities were self-reported, and we took special interest in cardiovascular and endocrine conditions. We evaluated change from baseline to endpoint and the interaction between change and reported medical comorbidities. RESULTS: Fifty-one percent of patients reported have a cardiovascular or endocrine comorbidity. Although not found for depressive symptoms or quality of life, a significant interaction between medical comorbidity and change scores was consistently found for all functional outcomes. This indicated an advantage of NAC over placebo in those with a clinical comorbidity. CONCLUSION: Systemic illness moderated only the effect of NAC on functioning, not on depression. Demonstrating an improvement in functional outcomes with an agent that modulates redox and inflammatory pathways, this study lends empirical support to the idea that medical and psychiatric comorbidity are additive in contributing to allostatic states. One intriguing possibility is that comorbid clinical illness could be a marker for more severe oxidative stress states--and thus guide antioxidant use--in BD. PMID- 22212175 TI - Measuring tongue shapes and positions with ultrasound imaging: a validation experiment using an articulatory model. AB - OBJECTIVE: The goal of this paper is to assess the validity of various metrics developed to characterize tongue shapes and positions collected through ultrasound imaging in experimental setups where the probe is not constrained relative to the subject's head. PATIENTS AND METHODS: Midsagittal contours were generated using an articulatory-acoustic model of the vocal tract. Sections of the tongue were extracted to simulate ultrasound imaging. Various transformations were applied to the tongue contours in order to simulate ultrasound probe displacements: vertical displacement, horizontal displacement, and rotation. The proposed data analysis method reshapes tongue contours into triangles and then extracts measures of angles, x and y coordinates of the highest point of the tongue, curvature degree, and curvature position. RESULTS: Parameters related to the absolute tongue position (tongue height and front/back position) are more sensitive to horizontal and vertical displacements of the probe, whereas parameters related to tongue curvature are less sensitive to such displacements. CONCLUSION: Because of their robustness to probe displacements, parameters related to tongue shape (especially curvature) are particularly well suited to cases where the transducer is not constrained relative to the head (studies with clinical populations or children). PMID- 22212176 TI - Intracellular trafficking of P-glycoprotein. AB - Overexpression of P-glycoprotein (P-gp) is a major cause of multidrug resistance in cancer. P-gp is mainly localized in the plasma membrane and can efflux structurally and chemically unrelated substrates, including anticancer drugs. P gp is also localized in intracellular compartments, such as endoplasmic reticulum (ER), Golgi, endosomes and lysosomes, and cycles between endosomal compartments and the plasma membrane in a microtubular-actin dependent manner. Intracellular trafficking pathways for P-gp and participation of different Rab proteins depend on cellular polarization and choice of primary culture, cell line or neoplasm. Interruption of P-gp trafficking to the plasma membrane increases intracellular P gp accumulation and anticancer drug levels, suggesting a potential approach to overcome P-gp-mediated multidrug resistance in cancer. PMID- 22212178 TI - Long-term results of endoscopic treatment of vesicoureteral reflux in children: comparison of different bulking agents. AB - OBJECTIVE: To determine the long-term effect in children of endoscopic treatment of vesicoureteral reflux (VUR) using different bulking agents. VUR status, recurrence of urinary tract infection (UTI), and recurrence of febrile UTI were evaluated as endpoints. METHODS: From 1993 to 2005, we injected 229 refluxive ureters (VUR grade II-IV) in 135 children. Mean age of the children was 55.7 months. We used collagen in 98 (years 1993-2000), polydimethylsiloxane in 32 (years 1999-2000), and dextranomer/hyaluronic acid copolymer (Dx/HA) in 99 ureters (years 2000-2005). Of the 135 children, 127 underwent a voiding cystourethrogram (VCUG) (radiologic or nuclid) 3 months after the first injection, and 88 children a second VCUG (nuclid) after 37 months (mean) postoperatively. Clinically, patients were monitored for non-febrile or febrile UTI. Data were collected and analyzed retrospectively by chart review. RESULTS: After first injection with collagen, polydimethysiloxane and Dx/HA, 52%, 55% and 81.5% of the children were without VUR, respectively. Repeated injections were successful in only 21% (collagen) to 42% (Dx/HA). Of the 88 with a second VCUG, 48.5% of the initially reflux-free children developed relapse VUR after collagen, 45.5% after polydimethylsiloxane and 21.5% after Dx/HA injection. Clinically, there was a significant difference in postoperative UTI occurrence in favor of the Dx/HA group. CONCLUSIONS: Clinically and radiologically, Dx/HA exhibited the best results, giving better protection against UTIs and a better VUR cure rate. There was still a risk of VUR recurrence in successfully treated children after 3 years of follow up. PMID- 22212179 TI - Corticosteroid minimization after renal transplantation*. PMID- 22212180 TI - Does a 'code stroke' rapid access protocol decrease door-to-needle time for thrombolysis? AB - BACKGROUND: Timely administration of intravenous tissue plasminogen activator (IVtPA) for acute ischaemic stroke is associated with better clinical outcomes. Therefore, a coordinated hospital system of acute clinical assessment and neuroimaging will likely avoid delays in IV-tPA administration. AIM: In July 2007, we implemented a 'code stroke' rapid access protocol at the Royal Melbourne Hospital with the aim of achieving rapid stroke assessment and treatment. This study investigates the quality of our 'code stroke' protocol and its impact on door-to-needle time and IV-tPA usage. METHODS: We included patients thrombolysed with IV-tPA from January 2003 to June 2007 (pre-code stroke era) and patients thrombolysed from July 2007 to December 2010 (code stroke era). Data collected were demographics, time points (stroke symptom onset, presentation to emergency department, neuroimaging and thrombolysis) and clinical outcomes (modified Rankin Scale) at discharge, symptomatic, intracerebral haemorrhage and death during admission). We compared the door-to-needle time and usage of IV-tPA between the two eras. RESULTS: Patient data on 98 'pre-code stroke' thrombolysed patients and 189 'code stroke' thrombolysed patients were collected. The median age was 71 (60 79), 56% were males, and the median baseline National Institute of Health Stroke Scale score was 13 +/- 6.3. There was an 18-min reduction in the median door-to needle time (90 min in 'pre-code stroke era' vs 72 min in 'code stroke era', P < 0.001). The rate of IV-tPA usage increased from 3.9% in 2004 to 17.3% in 2010. CONCLUSION: Our study showed that 'code stroke' rapid access protocol decreased door-to-needle time and possibly contributed to the increased IV-tPA usage. PMID- 22212181 TI - An effective dietary method for chronic tryptophan depletion in two mouse strains illuminates a role for 5-HT in nesting behaviour. AB - Physiological depletion of tryptophan, the precursor to serotonin has been shown to alter mood and cognition in both humans and rodents. Few studies have investigated the neurochemical and behavioural effects associated with tryptophan depletion in mice. Given that BALB/c and C57BL/6J mice differ in tryptophan hydroxylase (TPH) functionality, serotonin levels and behavioural phenotype, we hypothesised that a differential strain response to chronic dietary tryptophan manipulations would be observed. Therefore, the effects of four chronic dietary tryptophan manipulations were investigated, the diets include a depleted diet (0% tryptophan, TRP(-)), a deficient diet (0.25% tryptophan, TRP(-/+)), an enhanced diet (1.25% tryptophan, TRP(+)) and a control diet (0.7%). Diet-induced alterations in peripheral and central tryptophan levels and brain serotonin turnover were determined by high performance liquid chromatography. In addition, dietary-induced alterations in behaviour were assessed in several commonly used tasks. Peripheral and central tryptophan levels and consequently central serotonergic turnover were significantly decreased by the TRP(-) diet in both strains, however, no effect of tryptophan supplementation was observed on tryptophan or serotonin levels. Dietary tryptophan manipulation induced pronounced behavioural effects, particularly in nesting behaviour where a reduction in nesting was observed following depletion and an increase in nesting behaviour was observed with enhanced tryptophan in both strains. Additionally, depletion produces an anxiolytic-like effect and did not impede locomotion. This study demonstrates significant alterations in the levels of tryptophan, serotonin turnover and behaviour following chronic dietary tryptophan depletion. PMID- 22212182 TI - Response to 'Improved automated screening of diabetic retinopathy' by Carlos M. Oliveira et al. PMID- 22212184 TI - Effect of all-trans retinoic acid on unilateral ureteral obstruction model. PMID- 22212183 TI - Study of the TmoS/TmoT two-component system: towards the functional characterization of the family of TodS/TodT like systems. AB - The two-component system TmoS/TmoT controls the expression of the toluene-4 monooxygenase pathway in Pseudomonas mendocina RK1 via modulation of P(tmoX) activity. The TmoS/TmoT system belongs to the family of TodS/TodT like proteins. The sensor kinase TmoS is a 108 kDa protein composed of seven different domains. Using isothermal titration calorimetry we show that purified TmoS binds a wide range of aromatic compounds with high affinities. Tightest ligand binding was observed for toluene (K(D) = 150 nM), which corresponds to the highest affinity measured between an effector and a sensor kinase. Other compounds with affinities in the nanomolar range include benzene, the 3 xylene isomers, styrene, nitrobenzene or p-chlorotoluene. We demonstrate that only part of the ligands that bind to TmoS increase protein autophosphorylation in vitro and consequently pathway expression in vivo. These compounds are referred to as agonists. Other TmoS ligands, termed antagonists, failed to increase TmoS autophosphorylation, which resulted in their incapacity to stimulate gene expression in vivo. We also show that TmoS saturated with different agonists differs in their autokinase activities. The effector screening of gene expression showed that promoter activity of P(tmoX) and P(todX) (controlled by the TodS/TodT system) is mediated by the same set of 22 compounds. The common structural feature of these compounds is the presence of a single aromatic ring. Among these ligands, toluene was the most potent inducer of both promoter activities. Information on the TmoS/TmoT and TodS/TodT system combined with a sequence analysis of family members permits to identify distinct features that define this protein family. PMID- 22212185 TI - Plant original Massilia isolates producing polyhydroxybutyrate, including one exhibiting high yields from glycerol. AB - AIMS: The purpose of this study was to isolate new and potentially better polyhydroxyalkanoate (PHA)-producing bacteria, with a view to obtaining high yields from inexpensive substrates like glycerol, a major by-product of the biodiesel process. METHODS AND RESULTS: Eleven new plant original isolates of the genus Massilia, a poorly studied lineage within the Betaproteobacteria, were isolated and characterized. Two isolates, 2C4 and 4D3c, could not be assigned to a validated Massilia species and probably represent new species. Six isolates were found to produce poly-3-hydroxybutyrate (P3HB) when cultured with glucose or glycerol as carbon source. Isolate 4D6 accumulated up to 50 wt% of cell mass as polyhydroxybutyrate (PHB) when grown on glycerol. CONCLUSIONS: The phyllosphere may be a good source of bacteria unrelated or weakly related to human/animal pathogens for screening for new PHA producers for industrial application. Isolate 4D6 was capable of accumulating particularly high levels of PHB from glycerol. SIGNIFICANCE AND IMPACT OF THE STUDY: With the increase in biodiesel production, which generates increasing amounts of glycerol as a by-product, there is a major interest in exploiting this compound as feedstock for the synthesis of interesting products, like biopolymers, such as PHA. The new Massilia sp. 4D6 isolate described in this study may be a useful candidate as a cell factory for the industrial production of PHA from glycerol. PMID- 22212186 TI - Silaphenolates and silaphenylthiolates: two unexplored unsaturated silicon compound classes influenced by aromaticity. AB - Monosilicon analogs of phenolates and phenylthiolates are studied by quantum chemical calculations. Three different silaphenolates and three different silaphenylthiolates are possible; the ortho-, meta-, and para-isomers. For the silaphenolates, the meta-isomer is the thermodynamically most stable, regardless if the substituent R at Si is H, t-Bu or SiMe(3). However, with R = H and SiMe(3) the energy differences between the three isomers are small, whereas with R = t-Bu the meta-isomer is ~5 kcal/mol more stable than the ortho-isomer. For the silaphenylthiolates the ortho-isomer is of lowest energy, although with R = H the ortho- and meta-isomers are isoenergetic. The calculated nucleus independent chemical shifts (NICS) indicate that the silaphenolates and silaphenylthiolates are influenced by aromaticity, but they are less aromatic than the parent silabenzene. The geometries and charge distributions suggest that all silaphenolates and silaphenylthiolates to substantial degrees are described by resonance structures with an exocyclic C=O double bond and a silapentadienyl anionic segment. Indeed, they resemble the all-carbon phenolate and phenylthiolate. Silaphenylthiolates are less bond alternate and have slightly more negative NICS values than analogous silaphenolates, suggesting that this compound class is a bit more aromatic. Dimerization of the silaphenolates and silaphenylthiolates is hampered due to intramolecular Coulomb repulsion in the dimers, and silaphenolates with a moderately bulky SiMe(3) group as substituent at Si should prefer the monomeric form. PMID- 22212187 TI - Efficacy and safety of suberoylanilide hydroxamic acid (Vorinostat) in the treatment of canine corneal fibrosis. AB - OBJECTIVE: Study aims were to evaluate the safety and efficacy of the Food and Drug Administration-approved drug Vorinostat [suberoylanilide hydroxamic acid (SAHA)] in the treatment of canine corneal fibrosis using an in vitro model. METHODS: Healthy donor canine corneas were collected and used to generate primary canine corneal fibroblasts (CCFs) by growing cultures in minimal essential medium supplemented with 10% fetal bovine serum. Canine corneal myofibroblasts, used as a model for corneal fibrosis, were produced by growing CCF cultures in serum-free medium containing transforming growth factor beta1 (1 ng/mL). Trypan blue exclusion assays were used to determine the optimal SAHA dose for this in vitro model. Four hour after culturing with TGFbeta1, CCF cultures were treated with 0.06% SAHA for 5 min (group 1) and for 24 h (group 2), representing single and multiple dose treatment regimes, respectively. Cultures were then further incubated in the presence of TGFbeta1 (1 ng/MUL) under serum-free conditions until they reached 70% confluence. Trypan blue exclusion, immunocytochemistry, and TUNEL assays were used to evaluate the cytotoxicity of SAHA. Real-time PCR, western blot analysis, and immunocytochemistry were used to determine the efficacy of SAHA to inhibit canine corneal myofibroblast formation. RESULTS: Topical SAHA application in both treatment groups successfully decreased alpha smooth muscle actin expression when compared to the TGFbeta1 only treatment group (P < 0.05). Tested SAHA did not affect CCF phenotype or cellular viability and did not cause significant cell death. CONCLUSIONS: Suberoylanilide hydroxamic acid safely and effectively inhibits TGFbeta1-induced CCFs transformation to myofibroblast in vitro. PMID- 22212188 TI - Commissioned reviews. PMID- 22212189 TI - Statistics: more than pictures. AB - This, the third of our series of articles on statistics in veterinary medicine, moves onto the more complex concepts of hypothesis testing and confidence intervals. As these two areas are widely discussed in many clinical research publications, an awareness of the underlying methodology behind their use is essential to appreciate the information they convey. PMID- 22212190 TI - The use of haemostatic gelatin sponges in veterinary surgery. AB - OBJECTIVES: To describe the use of absorbable gelatin sponges as haemostatic implants in clinical veterinary surgical cases and to document any related postoperative complications. METHODS: Practice databases were searched for the product names "Gelfoam" and "Spongostan". Patient records were retrieved and data regarding patient signalment, surgical procedure, National Resource Council (NRC) wound classification, source of haemorrhage, pre- and postoperative body temperature, postoperative complications, time to discharge and details of any postoperative imaging were recorded and reviewed. Follow-up information was obtained by repeat clinical examination or telephone interview with either the owner or referring veterinary surgeon. Cases with incomplete surgical records or those which were not recovered from anaesthesia were excluded from the analysis. RESULTS: Fifty cases (44 dogs and 6 cats) satisfied the inclusion criteria. Satisfactory haemostasis was achieved in 49 cases with one case requiring reoperation during which a second gelatin sponge was used. There were no detected hypersensitivity responses or confirmed postoperative complications relating to the use of gelatin sponges during the follow-up period (median 13 months). CLINICAL SIGNIFICANCE: This is the first review of the use of gelatin sponges in clinical veterinary surgery and suggests that gelatin sponges are safe to use in cats and dogs. PMID- 22212192 TI - Polymorphisms of NOD2 and the risk of tuberculosis: a validation study in the Chinese population. AB - A genome-wide association study (GWAS) of leprosy reported four specific genetic polymorphisms of NOD2 that were associated with susceptibility to Mycobacterium leprae in China. Considering the role of NOD2 in innate immune defence, we performed a study in a Chinese population to determine whether the same SNPs of NOD2 that were associated with disease caused by M. leprae were also associated with disease caused by Mycobacterium tuberculosis. We performed a frequency matched case-control study in 1043 patients with pulmonary tuberculosis and 808 unaffected controls. All subjects were >15 years old and were Han Chinese from Jiangsu Province. We extracted DNA from a blood sample from each study participant. SNPs of rs3135499, rs7194886, rs8057341 and rs9302752 in the NOD2 gene were genotyped using a TaqMan-based allelic discrimination system. Using all possible patients with tuberculosis as cases, no significant association was found between the four specific SNPs and the risk of tuberculosis. In a subgroup analysis restricted to cases with bacteriologically confirmed tuberculosis (sputum culture positive), the variant genotype of rs7194886 was significantly associated with an altered risk of tuberculosis. Compared with the CC genotype, individuals carrying the CT/TT genotype of rs7194886 had an increased risk [odds ratio (OR) 1.35, 95% confidence interval (CI) (1.05-1.72)]. The association was stronger among tobacco smokers and males. By haplotype analysis, rs9302752C rs7194886T was associated with an increased risk of bacteriologically confirmed tuberculosis (sputum culture positive) (P = 0.039), but it was not significant after correcting for multiple comparisons. In summary, genetic polymorphisms of the SNP rs7194886 in the NOD2 gene, which were discovered in the GWAS of leprosy, might also be associated with the pulmonary tuberculosis in the Chinese population. PMID- 22212193 TI - Participatory action research and photovoice in a psychiatric nursing/clubhouse collaboration exploring recovery narrative. AB - The Clubhouse of Winnipeg (a community psychosocial rehabilitation centre) collaborated with a psychiatric nursing assistant professor on a participatory action research (PAR) project exploring the concept of recovery using a using a research method called photovoice. The collaborative project -Our Photos Our Voices- demonstrates how PAR and photovoice are well suited for collaborative research in mental health which honours principles underlying consumer empowerment and recovery. The foundation of empowerment is the power to act on one's behalf; PAR and photovoice support the full participation of concerned individuals in all aspects of research with the ultimate goal of action to solve problems or to meet goals identified by those individuals. Empowerment is also the ability to lay claim to one's own truth. At the core of the recovery model is the principle that recovery is defined by the individual and based on individual determinations of meaningful goals and a meaningful life. The Our Photos Our Voices project uses PAR and photovoice to effectively access, explore, document and share personal, local knowledge about recovery grounded in the personal experience of the Clubhouse researchers. PMID- 22212194 TI - Cell behavior on a CCN1 functionalized elastin-mimetic protein polymer. AB - We report the design of an elastin-mimetic triblock copolymer with the ability to guide endothelial cell adhesion, spreading, and migration while maintaining the elastomeric properties of the protein polymer. The V2 ligand sequence from matricellular protein CCN1 (cysteine-rich 61, CYR61) was multimerized and cloned into elastin polymer LysB10, creating LysB10.V2. Cell adhesion studies demonstrated that a LysB10.V2 surface density of at least 40 pmol/cm(2) was required to elicit cell attachment. Peptide blocking studies confirmed V2 specific engagement with integrin receptor alpha(v)beta(3) (P < 0.05) and we observed the formation of actin stress fiber networks and vinculin clustering, characteristic of focal adhesion assembly. Haptotatic migration assays demonstrated the ability of LysB10.V2 surfaces to stimulate migration of endothelial cells (P < 0.05). Significantly, we illustrated the ability of LysB10.V2 to support a quiescent endothelium. The CCN1 molecule functions to support many key biological processes necessary for tissue repair and thus presents a promising target for bioengineering applications. Collectively, our results demonstrate the potential to harness CCN1 specific function in the design of new scaffold materials for applications in regenerative medicine. PMID- 22212195 TI - A generalized sequential Bonferroni procedure using smoothed weights for genome wide association studies incorporating information on Hardy-Weinberg disequilibrium among cases. AB - BACKGROUND/OBJECTIVES: For genome-wide association studies (GWAS) with case control designs, one of the most widely used association tests is the Cochran Armitage (CA) trend test assuming an additive mode of inheritance. The CA trend test often has higher power than other association tests under additive and multiplicative disease models. However, it can have very low power under a recessive disease model in GWAS. Although tests (such as MAX3) robust to different genetic models have been developed, they often have relatively lower power than the CA trend test under additive and multiplicative models. The goal of this study is to propose an efficient method that not only has higher power than the CA trend test under dominant and recessive models but also maintains the power of the CA trend test under additive and multiplicative models. METHODS: We employed the generalized sequential Bonferroni (GSB) procedure of Holm to incorporate information from a Hardy-Weinberg disequilibrium (HWD) test into the CA trend test based on estimating weights from the p values of the HWD test. We proposed to smooth the weights to reduce possible noise. RESULTS AND CONCLUSIONS: Results from extensive simulation studies showed that the proposed GSB procedure can achieve the goal described above. PMID- 22212197 TI - Cytarabine induced cerebellar neuronal damage in juvenile rat: correlating neurobehavioral performance with cellular and genetic alterations. AB - Cytosine arabinoside (Ara-C), a pyrimidine analogue induces cerebellar dysfunction and behavioral abnormalities. Although many in vitro experiments have been conducted in the past demonstrating the lethal potential of Ara-C to cerebellar neurons, there is a paucity of literature available regarding the effects of Ara-C on the cellular and genetic material of cerebellum and its subsequent influence on the neurobehavioral performance in vivo. Rats were treated with Ara-C at the dose levels 50, 100 and 200mg/kg/day for 5 and 14 days by intraperitoneal (i.p.) route. Endpoints of the evaluation included food and water intake, body and organ weight, behavioral parameters, histopathology, oxidative stress, DNA damage, apoptosis, expression of p53, caspase-3 and calbindin D-28K (calbindin) as well as histone acetylation and methylation. Ara-C treatment for 14 days significantly decreased the food and water intake, body weight gain and brain weight in rat as compared to the control. Alterations in various behavioral parameters were observed, indicating the impaired cerebellar function. Further, cellular abnormalities in the cerebellum such as Purkinje cell misalignment and granule cell cytotoxicity were observed. Positive correlation was observed between Ara-C induced disturbance in the motor performance and the Purkinje cell loss in rat cerebellum. Moreover, Ara-C treatment significantly increased the oxidative stress, DNA damage, TUNEL positive cells, p53 and caspase 3 positive cells in the rat cerebellum. Unlike short-term treatment, long-term Ara-C treatment significantly reduced calbindin expression in the cerebellum. Apart from this, 14 days Ara-C treatment led to significant alterations in the histone acetylation and methylation in the cerebellum, while in 5 days treatment no such alterations were observed. Present results indicated that Ara-C, by inducing oxidative stress mediated DNA damage, executes neuronal apoptosis which is accompanied by an increase in the p53 and caspase-3, but decrease in the calbindin expression. PMID- 22212198 TI - Impact of pre-analytical parameters on the measurement of circulating microparticles: towards standardization of protocol. AB - BACKGROUND: Microparticles (MP) are small vesicles of 0.1-1 MUm, released in response to activation or apoptosis. Over the past decade, they received an increasing interest both as biomarkers and biovectors in coagulation, inflammation and cancer. Clinical studies were conducted to assess their contribution to the identification of patients at cardiovascular risk. However, among the limitation of such studies, pre-analytical steps remains an important source of variability and artifacts in MP analysis. OBJECTIVES: Because data from the literature are insufficient to establish recommendations, the objective of the present study was to assess the impact of various pre-analytical parameters on MP measurement. These parameters included the type of collection tube, phlebotomy conditions, transportation practices, centrifugation steps and freezing. METHODS: MP were assessed by three methods: flow cytometry using a standardized approach, a thrombin generation test (Calibrated Automated Thrombogram((r))) and a procoagulant phospholipid-dependent clotting time assay (STA((r)) -Procoag-PPL). RESULTS: The main results show that the three major pre analytical parameters which impact on MP-related data are the delay before the first centrifugation, agitation of the tubes during transportation and the centrifugation protocol. CONCLUSIONS: Based on both this work and literature data, we propose a new protocol that needs to be validated on a larger scale before being applied for multicenter studies. PMID- 22212199 TI - Rubella contact tracing associated with air travel. AB - This report reviews U.S. guidelines for the identification of persons exposed to rubella during air travel. In response to an individual with rubella who traveled on multiple flights, CDC conducted an airline contact investigation that was expanded beyond customary protocol to assess if current operating procedures are adequate. Of 250 potentially exposed airline passengers, 215 (86%) were contacted and none developed a rubella-like rash, arguing against the need to notify passengers beyond the standard protocol in most cases. PMID- 22212200 TI - Photo catalogue for the classification of cell colonies in the Syrian hamster embryo (SHE) cell transformation assay at pH 6.7. AB - This catalogue is a display of Syrian hamster embryo (SHE) cell colony photos representative of the cell transformation assay (CTA) carried out at pH 6.7. It is intended as a visual aid for the identification and the scoring of cell colonies in the conduct of the assay. A proper training from experienced personnel together with the protocol reported in this issue and the present photo catalogue will support method transfer and consistency in the assay results. PMID- 22212201 TI - Recommended protocol for the BALB/c 3T3 cell transformation assay. AB - The present protocol has been developed for the BALB/c 3T3 cell transformation assay (CTA), following the prevalidation study coordinated by the European Centre for the Validation of Alternative Methods (ECVAM) and reported in this issue (Tanaka et al. [16]). Based upon the experience gained from this effort and as suggested by the Validation Management Team (VMT), some acceptance and assessment criteria have been refined compared to those used during the prevalidation study. The present protocol thus describes cell culture maintenance, the dose-range finding (DRF) experiment and the transformation assay, including cytotoxicity and morphological transformation evaluation. Use of this protocol and of the associated photo catalogue included in this issue (Sasaki et al. [17]) is recommended for the future conduct of the BALB/c 3T3 CTA. PMID- 22212202 TI - Strengthening research capabilities in reproductive diagnostics, cryobanking and conservation biology of indigenous livestock in Indonesia. Editorial. PMID- 22212203 TI - Banteng and Bali cattle in Indonesia: status and forecasts. AB - Bali cattle still represents 27% of the total cattle population in Indonesia, and it is considered the pillar breed for small farmers. Moreover, it is a breed of evolutionary importance regarding its direct ancestry from Banteng. However, there is a need for the establishment of a rational system for the evaluation of breeding soundness for indigenous Bali bulls to be used as sires for artificial insemination breeding programmes. Moreover, there is a need for cryobanking of well-identified genetic resources pertaining their use in evolutionary research and application as essential germplasm in breeding programmes. PMID- 22212204 TI - A global strategy of using molecular genetic information to improve genetics in livestock. AB - Traditional breeding programmes have largely contributed to disseminate the benefits of several quantitative traits in livestock. In developing countries such as Indonesia where animal population scattered throughout the country, it is difficult to invest for molecular research. On the other side, yet, it is worthy asset for breeding purposes. Based on theory and evidence, it has been proved that those scattered population evolved different genetic adaptations in response to a given natural pressure selection. A global strategy can be applied to the use of molecular genetic information for identification of economically important value. The use of genetic markers or more effective of marker-assisted selection (MAS) for desired important traits would be more valuable and useful and even more efficient in important trait selection of superior livestock. DNA marker technology would be very useful when applied for quantitative trait identification. Marker-assisted selection can be used for enhancing conventional breeding and works best for the traits with low heritability such as in reproductive traits and disease resistance. Application of conventional breeding for lower heredity traits would not be efficient because of waiting longer for generation interval, expensive in measurements, more population and more employees needed. Study of quantitative trait loci mapping is early investment to improve genetic merit. It can be performed once but can be used for exploring many genetic traits with economically important values. An effective option is biotechnology application in livestock for the development of genetic varieties such as stress tolerance, growth and carcass traits. Application of biotechnology approaches will enable improvement in productivity, reduction in costs, enrichment of milk compositions and extension of shelf life products. PMID- 22212205 TI - Indigenous Bali cattle is most suitable for sustainable small farming in Indonesia. AB - Livestock husbandry is essential for Indonesia. This study reviews cattle characteristics and husbandry methods in the country with special interest in describing the importance of indigenous breeds of cattle. As a conclusion, the Bali cattle ought to be considered the most suitable indigenous cattle breed for the low-input, high stress production system still practised by millions of families in Indonesia. PMID- 22212206 TI - Genetic characterization of the Aceh cattle using phenotypic, mitochondrial DNA of D-loop region and microsatellite DNA analyses. AB - The present study reports the phenotypic variation of body weight and body size, the genetic variation of D-loop of mtDNA and microsatellite DNA allele in Aceh cattle in Indonesia within the frame of the design of a conservation programme for this indigenous species. Aceh cattle differ from Bali, Madura, Java-Ongole and Pesisir cattle, but its ancestry relates it closest to Pesisir, thus adding more information to its entry from the Indian sub-continent. PMID- 22212207 TI - The origin of Indonesian cattle and conservation genetics of the Bali cattle breed. AB - Both Bos indicus (zebu) and Bos javanicus (banteng) contribute to the Indonesian indigenous livestock, which is supposedly of a mixed species origin, not by direct breeding but by secondary cross-breeding. Here, the analysis of mitochondrial, Y-chromosomal and microsatellite DNA showed banteng introgression of 10-16% in Indonesian zebu breeds with East-Javanese Madura and Galekan cattle having higher levels of autosomal banteng introgression (20-30%) and combine a zebu paternal lineage with a predominant (Madura) or even complete (Galekan) maternal banteng origin. Two Madura bulls carried taurine Y-chromosomal haplotypes, presumably of French Limousin origin. There was no evidence for zebu introgression in five populations of the Bali cattle, a domestic form of the banteng. PMID- 22212208 TI - Assisted reproductive techniques for cattle breeding in developing countries: a critical appraisal of their value and limitations. AB - Commercialization of animal biotechnologies, including those related to reproduction [also known as assisted reproductive techniques (ARTS)], is an increasing reality in developing countries, following the enormous flow of information around us and the increasing global commercial interests in areas where cattle production has its major assets. The present review discusses the achievements of various biotechnological tools for reproduction in cattle including semen handling for artificial insemination (AI), superovulation and embryo transfer (MOET), in vitro handling of oocytes and production of embryos, reproductive cloning and emerging technologies (sex selection, gene targeting and nuclear transfer for livestock transgenesis, genomics for marker-assisted selection, etc.). The application of these technologies for cattle breeding is critically discussed in relation to their impact in the improvement of the efficiency of dairy and beef production in developed and - particularly - in developing countries, which ultimately rule the possibilities of a competitive and sound production of food for human consumption. Despite the remarkable progress made and the punctual importance of some of the above-mentioned technologies, AI remains the most important assisted reproductive technology (ART) in developing countries. Any attempt to gain widespread of any other ART under the predominant economical conditions in developing countries ought to match the simplicity and the success of AI as a breeding tool. PMID- 22212209 TI - MHC class II is an important genetic risk factor for canine systemic lupus erythematosus (SLE)-related disease: implications for reproductive success. AB - Major histocompatibility complex (MHC) class II genes are important genetic risk factors for development of immune-mediated diseases in mammals. Recently, the dog (Canis lupus familiaris) has emerged as a useful model organism to identify critical MHC class II genotypes that contribute to development of these diseases. Therefore, a study aimed to evaluate a potential genetic association between the dog leukocyte antigen (DLA) class II region and an immune-mediated disease complex in dogs of the Nova Scotia duck tolling retriever breed was performed. We show that DLA is one of several genetic risk factors for this disease complex and that homozygosity of the risk haplotype is disadvantageous. Importantly, the disease is complex and has many genetic risk factors and therefore we cannot provide recommendations for breeders exclusively on the basis of genetic testing for DLA class II genotype. PMID- 22212210 TI - Onset of sexual maturity in female chickens is genetically linked to loci associated with fecundity and a sexual ornament. AB - Onset of sexual maturation is a trait of extreme importance both evolutionarily and economically. Unsurprisingly therefore, domestication has acted to reduce the time to sexual maturation in a variety of animals, including the chicken. In comparison with wild progenitor chickens [the Red Junglefowl (RJF)], domestic layer hens attain maturity approximately 20% earlier. In addition, domestic layers also possess larger combs (a sexual ornament), produce more eggs and have denser bones. A large quantitative trait loci (QTL) analysis (n=377) was performed using an F(2) intercross between a White Leghorn layer breed and a RJF population, with onset of sexual maturity measured and mapped to three separate loci. This cross has already been analysed for comb mass, egg production and bone allocation. Onset of sexual maturity significantly correlated with comb mass, whilst the genetic architecture for sexual maturity and comb mass overlapped at all three loci. For two of these loci, the QTL for sexual maturity and comb mass were statistically indistinguishable from pleiotropy, suggesting that the alleles that increase comb mass also decrease onset of sexual maturity. PMID- 22212211 TI - A randomised controlled trial of a theory-based intervention to improve sun protective behaviour in adolescents ('you can still be HOT in the shade'): study protocol. AB - BACKGROUND: Most skin cancers are preventable by encouraging consistent use of sun protective behaviour. In Australia, adolescents have high levels of knowledge and awareness of the risks of skin cancer but exhibit significantly lower sun protection behaviours than adults. There is limited research aimed at understanding why people do or do not engage in sun protective behaviour, and an associated absence of theory-based interventions to improve sun safe behaviour. This paper presents the study protocol for a school-based intervention which aims to improve the sun safe behaviour of adolescents. METHODS/DESIGN: Approximately 400 adolescents (aged 12-17 years) will be recruited through Queensland, Australia public and private schools and randomized to the intervention (n = 200) or 'wait-list' control group (n = 200). The intervention focuses on encouraging supportive sun protective attitudes and beliefs, fostering perceptions of normative support for sun protection behaviour, and increasing perceptions of control/self-efficacy over using sun protection. It will be delivered during three * one hour sessions over a three week period from a trained facilitator during class time. Data will be collected one week pre-intervention (Time 1), and at one week (Time 2) and four weeks (Time 3) post-intervention. Primary outcomes are intentions to sun protect and sun protection behaviour. Secondary outcomes include attitudes toward performing sun protective behaviours (i.e., attitudes), perceptions of normative support to sun protect (i.e., subjective norms, group norms, and image norms), and perceived control over performing sun protective behaviours (i.e., perceived behavioural control). DISCUSSION: The study will provide valuable information about the effectiveness of the intervention in improving the sun protective behaviour of adolescents. PMID- 22212212 TI - The estimation of glomerular filtration rate in an Australian and New Zealand cohort. AB - BACKGROUND: Accurate estimation of glomerular filtration rate (GFR) allows early detection of renal disease and maximizes opportunity for intervention. AIM: To assess the accuracy of estimated GFR (eGFR) in an Australian and New Zealand cohort with chronic kidney disease using the 4-variable Modification of Diet in Renal Disease equation (MDRD(4V)), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, and the Cockcroft and Gault equation with actual and ideal body weight. METHODS: Retrospective review of patients who had measured GFR (mGFR) by 51Cr-EDTA clearance and simultaneous measurements of serum biochemistry and anthropometrics. eGFR was compared with mGFR using the concordance correlation coefficient (CCC) and Bland-Altman measures of agreement. RESULTS: 178 patients had 441 radioisotope measurements of GFR. Mean mGFR of was 22.6 mL/min per 1.73 m(2) . The MDRD(4V) equation using the 'black' correction factor was most accurate with a mean eGFR of 19.74 (CCC 0.733, bias -2.86). The CKD-EPI equations also using the 'black' correction factors were almost as good at 19.11 (CCC 0.719, bias -3.49). The Cockcroft-Gault creatinine clearance values had the poorest agreement with mGFR. In the 18 nonwhite non-Asian patients, the MDRD(4V) and CKD-EPI equations were generally less accurate although the use of the 'black' correction factor resulted in greater accuracy for both equations. CONCLUSION: The MDRD(4V) equation was the most accurate. However, its accuracy might be less for nonwhite non-Asian patients if the 'black' correction factor is omitted. Further study of the estimation of GFR in Australian and New Zealand ethnic subgroups would be helpful. PMID- 22212213 TI - Implantable cardioverter-defibrillators: a long-term view. AB - BACKGROUND: No long-term data on implantable cardioverter-defibrillators (ICDs) exist in Australasia. AIMS: We examined all patients receiving a new ICD implant at Wellington Hospital between January 2001 and December 2005 to determine long term outcomes in this patient population. METHODS: Follow-up data were collected and Kaplan-Meier curves were constructed for survival and long-term outcomes, and Cox proportional hazard model was used for calculation of hazard ratio. RESULTS: In the study period, 138 new ICDs were implanted, and the mean follow-up time was 84 +/- 16 months. Patients were predominantly male (76%), 75% were European, 20% were Maori. Median age was 59 years (range 16-80 years). In 47% of patients, there was an ischaemic substrate. A secondary-prevention indication was present in 77%. The 7-year survival rate was 72%. No difference in mortality was observed between primary- and secondary-prevention groups. The 7-year appropriate therapy rate was 55%. The appropriate shock rate was greater in secondary prevention than in primary-prevention patients was observed (hazard ratio = 2.11, 95% confidence interval 1.16-3.85, P= 0.01). Over the study period, inappropriate therapy rate was 25%. This was more common in patients with prior atrial fibrillation (hazard ratio = 3.57, 95% confidence interval 1.80-7.09, P < 0.001). The median device longevity was 6.8 years. CONCLUSIONS: This is the first long-term follow-up study of ICD patients in New Zealand. We observed a low mortality rate when compared with other published registries, but a similar rate of both appropriate and inappropriate shock therapy. PMID- 22212214 TI - Year round patchiness of Vibrio vulnificus within a temperate Texas bay. AB - AIMS: To investigate with high geographical resolution the small-scale spatial and temporal distribution of the pathogen Vibrio vulnificus throughout the water column in a temperate Texas bay where numerous V. vulnificus infections had been reported by the regional media the previous summer. METHODS AND RESULTS: Surface and bottom water samples were collected from 19 sites between April 2005 and October 2006 from Matagorda Bay, TX. Physicochemical parameters were measured and V. vulnificus were analysed using quantitative polymerase chain reaction (Q-PCR) as a means of overcoming constraints of traditional culturing techniques. V. vulnificus was detected through out the year, although its temporal and spatial distribution was patchy. V. vulnificus abundances at individual sites ranged from <10 to >1.1*10(3)cellsml(-1) . No statistically reliable predictive model related to the physicochemical parameters could be developed for this pathogen. CONCLUSIONS: This study demonstrates that year round detection of V. vulnificus while likely in the viable but nonculturable (VBNC) state during the winter months and emphasizes why physicochemical factors are insufficient metrics for robust regression modelling of this pathogen. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides an effective new tool, Q-PCR, to study environmental distribution of V. vulnificus and that in the light of the patchy distribution observed, new reliable approaches and a mechanistic understanding of pathogen ecology need to be considered to effectively model the aquatic distribution of V. vulnificus. PMID- 22212216 TI - [Psychiatric aspects of epileptic disorders]. AB - Psychiatric complications are common in people with epilepsy and contribute significantly to the impaired quality of life of patients and relatives. This paper discusses psychosis, depression and psychiatric adverse events of anticonvulsants with a focus on practical issues of diagnosis and treatment. PMID- 22212217 TI - Federal politics and the clinical and translational sciences. PMID- 22212219 TI - Update: APOR. PMID- 22212220 TI - University of Florida Clinical and Translational Science Institute: transformation and translation in personalized medicine. PMID- 22212221 TI - Assessing research participants' perceptions of their clinical research experiences. AB - INTRODUCTION: Participants' perceptions of their research experiences provide valuable measures of ethical treatment, yet no validated instruments exist to measure these experiences. We conducted focus groups of research participants and professionals as the initial step in developing a validated instrument. METHODS: Research participants enrolled in 12 focus groups, consisting of: (1) individuals with disorders undergoing interventions; (2) in natural history studies; or (3) healthy volunteers. Research professionals participated in six separate groups of: (1) institutional review board members, ethicists, and Research Subject Advocates; (2) research nurses/coordinators; or (3) investigators. Focus groups used standard methodologies. RESULTS: Eighty-five participants and 29 professionals enrolled at eight academic centers. Altruism and personal relevance of the research were commonly identified motivators; financial compensation was less commonly mentioned. Participants were satisfied with informed consent processes but disappointed if not provided test results, or study outcomes. Positive relationships with research teams were valued highly. Research professionals were concerned about risks, undue influence, and informed consent. CONCLUSIONS: Participants join studies for varied, complex reasons, notably altruism and personal relevance. They value staff relationships, health gains, new knowledge, and compensation, and expect professionalism and good organization. On the basis of these insights, we propose specific actions to enhance participant recruitment, retention, and satisfaction. PMID- 22212222 TI - CETP inhibitor torcetrapib promotes reverse cholesterol transport in obese insulin-resistant CETP-ApoB100 transgenic mice. AB - Insulin resistance and type 2 diabetes are associated with low HDL-cholesterol (HDL-c) levels, which would impair reverse cholesterol transport (RCT). A promising therapeutic strategy is to raise HDL with cholesteryl ester transfer protein (CETP) inhibitors, but their effects on RCT remains to be demonstrated in vivo. We therefore evaluated the effects of CETP inhibitor torcetrapib in CETP apolipoprotein (apo)B100 mice made obese and insulin resistant with a 60% high fat diet. High-fat diet over 3 months increased body weight and homeostasis model of insulin resistance index by 30% and 846%, respectively (p < 0.01 for both vs. chow-fed mice). Total cholesterol (TC) increased by 46% and HDL-c/TC ratio decreased by 28% (both p < 0.05). Compared to vehicle, high-fat-fed mice treated with torcetrapib (30 mg/kg/day, 3 weeks) showed increased HDL-c levels and HDL c/TC ratio by 41% and 37% (both p < 0.05). Torcetrapib increased in vitro macrophage cholesterol efflux by 22% and in vivo RCT through a 118% increase in (3) H-bile acids fecal excretion after (3) H-cholesterol labeled macrophage injection (p < 0.01 for both). Fecal total bile acids mass was also increased by 158% (p < 0.001). In conclusion, CETP inhibition by torcetrapib improves RCT in CETP-apoB100 mice. These results emphasize the potential of CETP inhibition to prevent cardiovascular diseases. PMID- 22212223 TI - Defining clinical research nursing practice: results of a role delineation study. AB - Clinical research nursing is a specialty nursing practice focused on the care of research subjects and implementation of clinical research. A five-dimensional model (Clinical Practice [CP], Study Management, Care Coordination and Continuity, Contributing to the Science [CS], Human Subjects Protection) has been validated nationally to represent the domain of clinical research nursing practice. The purpose of this study was to describe the frequency and importance of activities within each dimension as performed by nurses in clinical research and to describe differences between roles. One thousand and four nurses from the NIH Intramural Campus in Bethesda, Maryland, were invited to participate in an anonymous web-based survey. Participants (N = 412) were predominantly female (90%) with >=11 years research experience (70%). Two hundred eighty-eight respondents (70%) identified themselves as clinical research nurses (CRNs) and 74 (18%) as research nurse coordinators (RNCs). CP activities were reported most frequent and important whereas CS activities were least frequent and important. CRN and RNC activity frequency differed across all dimensions (p < 0.001) with CRNs reporting significantly higher levels of CP activities and significantly lower levels in other dimensions. Delineating specialty activities and practice across roles enhances the understanding of nurses' role in clinical research and provides groundwork for role-based training. PMID- 22212224 TI - A capacity building program to promote CBPR partnerships between academic researchers and community members. AB - INTRODUCTION: Community-based participatory research (CBPR) adds community perspectives to research and aids translational research aims. There is a need for increased capacity in CBPR but few models exist for how to support the development of community/university partnerships. OBJECTIVE: Evaluate an approach to promote nascent CBPR partnerships. METHODS: Design was a mixed-methods evaluation using interviews, process notes, and open- and close-ended survey questions. We trained 10 community scholars, matched them with prepared researchers to form seven partnerships, and supported their developing partnerships. Sequential mixed-methods analysis assessed research and partnership processes and identified integrated themes. RESULTS: Four of seven partnerships were funded within 15 months; all self-reported their partnerships as successful. Themes were: (1) motivators contributed to partnership development and resiliency; (2) partners took on responsibilities that used individuals' strengths; (3) partners grappled with communication, decision making, and power dynamics; and (4) community-university infrastructure was essential to partnership development. CONCLUSIONS: This program for developing nascent partnerships between academicians and community members may guide others in increasing capacity for CBPR. PMID- 22212225 TI - A multiinstitutional, multidisciplinary model for developing and teaching translational research in health disparities. AB - Health disparities may affect any person in any community in the world, resulting from a multitude of factors including socioeconomic status, race, ethnicity, environment, and genetics. The impact of health disparities is felt by affected individuals, their families, communities, and the greater health care system. There is a critical need to increase health disparities research activities. This may be achieved by expanding and strengthening the training, education and career development of motivated clinicians, physicians and basic scientists, engaging them in clinical and translational research. Translational research relies on collaboration across disciplines, facilitating the dissemination and transfer of knowledge to populations for the overall improvement of health while decreasing the economic burden of health care. The University of Puerto Rico Medical Sciences Campus (UPR-MSC), Schools of Health Professions and Medicine joint initiatives, Clinical Research Education and Career Development (CRECD) and Hispanics in Research Capability (HiREC) programs, convened health disparities experts, faculty and scholars from multiple disciplines, cultural backgrounds and institutions. Together, they created a model for teaching translational research in health disparities that spans disciplines without boundaries. PMID- 22212226 TI - Identifying and aligning expectations in a mentoring relationship. AB - The mentoring relationship between a scholar and their primary mentor is a core feature of research training. Anecdotal evidence suggests this relationship is adversely affected when scholar and mentor expectations are not aligned. We examined three questions: (1) What is the value in assuring that the expectations of scholars and mentors are mutually identified and aligned? (2) What types of programmatic interventions facilitate this process? (3) What types of expectations are important to identify and align? We addressed these questions through a systematic literature review, focus group interviews of mentors and scholars, a survey of Clinical and Translational Science Award (CTSA) KL2 program directors, and review of formal programmatic mechanisms used by KL2 programs. We found broad support for the importance of identifying and aligning the expectations of scholars and mentors and evidence that mentoring contracts, agreements, and training programs facilitate this process. These tools focus on aligning expectations with respect to the scholar's research, education, professional development and career advancement as well as support, communication, and personal conduct and interpersonal relations. Research is needed to assess test the efficacy of formal alignment activities. PMID- 22212227 TI - Evaluating mastery of biostatistics for medical researchers: need for a new assessment tool. AB - Research training has enabled academic clinicians to contribute significantly to the body of medical research literature. Biostatistics represents a critical methodological skill for such researchers, as statistical methods are increasingly a necessary part of medical research. However, there is no validated knowledge and skills assessment for graduate level biostatistics for academic medical researchers. In this paper, I review graduate level statistical competencies and existing instruments intended to assess physicians' ability to read the medical literature and for undergraduate statistics for their alignment with core competencies necessary for successful use of statistics. This analysis shows a need for a new instrument to assess biostatistical competencies for medical researchers. PMID- 22212228 TI - Finding translational science publications in MEDLINE/PubMed with translational science filters. AB - Translational Science Search (TSS; http://tscience.nlm.nih.gov) is a web application for finding MEDLINE/PubMed journal articles that are regarded by their authors as novel, promising, or may have potential clinical application. A set of "translational" filters and related terms was created by reviewing journal articles published in clinical and translational science (TS) journals. Through E Utilities, a user's query and TS filters are submitted to PubMed, and then, the retrieved PubMed citations are matched with a database of MeSH terms (for disease conditions) and RxNorm (for interventions) to locate the search term, translational filters found, and associated interventions in the title and abstract. An algorithm ranks the interventions and conditions, and then highlights them in the results page for quick reading and evaluation. Using previously searched terms and standard formulas, the precision and recall of TSS were 0.99 and 0.47, compared to 0.58 and 1.0 for PubMed Entrez, respectively. PMID- 22212229 TI - Congenital hepatic fibrosis in autosomal recessive polycystic kidney disease. AB - Autosomal recessive polycystic kidney disease (ARPKD) is a developmental disorder that mainly affects the kidneys and the biliary tract. Affected patients often have massively enlarged cystic kidneys as well as congenital hepatic fibrosis (CHF) characterized by dilated bile ducts and associated peribiliary fibrosis. This review will examine what is known about ARPKD-associated liver disease and will highlight areas of ongoing research into its pathogenesis and potential treatment. PMID- 22212231 TI - Erythropoietin and myocardial infarction. PMID- 22212230 TI - Statistical considerations for analysis of microarray experiments. AB - Microarray technologies enable the simultaneous interrogation of expressions from thousands of genes from a biospecimen sample taken from a patient. This large set of expressions generates a genetic profile of the patient that may be used to identify potential prognostic or predictive genes or genetic models for clinical outcomes. The aim of this article is to provide a broad overview of some of the major statistical considerations for the design and analysis of microarrays experiments conducted as correlative science studies to clinical trials. An emphasis will be placed on how the lack of understanding and improper use of statistical concepts and methods will lead to noise discovery and misinterpretation of experimental results. PMID- 22212232 TI - Angiosarcoma related to immunosuppressive therapy 8 years after renal transplantation. PMID- 22212235 TI - Understanding biological timing using mechanistic and black-box models. AB - The use of mathematical modelling in understanding and dissecting physiological mechanisms in plants has seen many successes. Notably, studies of the component interactions of the Arabidopsis circadian clock have yielded multiple insights into the roles of specific regulators at the transcriptional and post transcriptional level. In this article, I review the use of mathematical techniques in dissecting the Arabidopsis clock mechanism, covering first the well established use of mechanistic models implemented as systems of nonlinear ordinary differential equations. In situations where mechanistic models are not appropriate, I describe how linear time-invariant (LTI) systems, a type of black box model, can offer quantitative descriptions of biological systems that provide a systems-level understanding without detailed descriptions of the underlying mechanism. A comparison of the two approaches is provided to exemplify when LTI systems modelling might offer advantages for interpreting biological measurements. In particular, formal analysis of large datasets with LTI systems can offer genome-scale inferences, which is of timely relevance as novel experimental techniques are generating increasingly large quantities of data. PMID- 22212234 TI - Subversion of NPC1 pathway of cholesterol transport by Anaplasma phagocytophilum. AB - Intracellular cholesterol amounts, distribution and traffic are tightly regulated to maintain the healthy eukaryotic cell function. However, how intracellular pathogens that require cholesterol, interact with the host cholesterol homeostasis and traffic is not well understood. Anaplasma phagocytophilum is an obligatory intracellular and cholesterol-robbing bacterium, which causes human granulocytic anaplasmosis. Here we found that a subset of cholesterol-binding membrane protein, Niemann-Pick type C1 (NPC1)-bearing vesicles devoid of lysosomal markers were upregulated in HL-60 cells infected with A. phagocytophilum, and trafficked to live bacterial inclusions. The NPC1 localization to A. phagocytophilum inclusions was abolished by low-density lipoprotein (LDL)-derived cholesterol traffic inhibitor U18666A. Studies using NPC1 siRNA and the cell line with cholesterol traffic defect demonstrated that the NPC1 function is required for bacterial cholesterol acquisition and infection. Furthermore, trans-Golgi network-specific soluble N-ethylmaleimide sensitive factor attachment protein receptors, vesicle-associated membrane protein (VAMP4) and syntaxin 16, which are associated with NPC1 and LDL-derived cholesterol vesicular transport were recruited to A. phagocytophilum inclusions, and VAMP4 was required for bacteria infection. Taken together, A. phagocytophilum is the first example of a pathogen that subverts the NPC1 pathway of intracellular cholesterol transport and homeostasis for bacterial inclusion membrane biogenesis and cholesterol capture. PMID- 22212233 TI - PDCD4 expression inversely correlated with miR-21 levels in gastric cancers. AB - PURPOSE: The specific aim of this study was to investigate whether the PDCD4 gene is involved in the development and progression of gastric cancer. METHODS: We examined the genetic and epigenetic alterations of the PDCD4 gene as well as the expression of PDCD4 protein in gastric cancers. The mRNA expression of PDCD4 and miRNA-21 expression were also analyzed using quantitative real-time RT-PCR. RESULTS: Loss or reduced PDCD4 expression was observed in 79 (36.7%) of 215 gastric cancer specimens. Statistically, altered PDCD4 expression was not associated with the clinicopathological parameters, including tumor differentiation, location, lymph node metastasis and overall survival (P > 0.05). miRNA-21 overexpression was frequently detected in gastric cancers (31 of 46, 67.4%), and there was a significant inverse correlation between miRNA-21 and PDCD4 protein expression (P = 0.029), but not between miRNA-21 and PDCD4 mRNA expression. In genetic analysis, no mutation was detected in the coding region of the PDCD4 gene, and promoter hypermethylation was found in 24 (36.4%) of the 66 gastric cancer samples. CONCLUSIONS: Our data suggest that overexpression of miRNA-21 and reduced or loss of PDCD4 expression may play a role in the development and progression of gastric cancers. PMID- 22212236 TI - Chitosan microparticles for the controlled delivery of fluoride. AB - OBJECTIVES: To manufacture and characterise chitosan/fluoride microparticles prepared by spray drying and assess their utility as controlled release vehicles for fluoride. METHODS: Microparticles were manufactured from dispersions containing 1.0% and 2.0% (w/v) chitosan and 0.20% or 0.40% (w/v) NaF in the absence/presence of glutaraldehyde. Particle size distributions were determined using laser diffraction; fluoride loading and release were determined by ion selective electrode. Release profiles were studied in isotonic media (pH 5.5) over 360 min; microparticles exhibiting greatest cumulative fluoride release were further evaluated at pH 4.0 and 7.0. Particle morphology was investigated using environmental scanning electron microscopy. Bioadhesion parameters were determined with a texture-probe analyser. RESULTS: Microparticles exhibited low polydispersity and volume mean diameters (VMDs) <6 MUm. VMDs increased on doubling the chitosan/fluoride concentrations but were largely independent of glutaraldehyde concentration. Recovered yields were inversely proportional to dispersion viscosity due to compromised fluid atomisation; adding NaF reduced viscosity and improved yields. Best-case entrapment efficiency and NaF loading were 84.1% and 14%, respectively. Release profiles were biphasic, releasing 40 60% of the total fluoride during the first 600 s, followed by a prolonged release phase extending out to 6h. Incorporation of 0.40% NaF to the 2.0% chitosan dispersion yielded microparticles with reduced bioadhesive parameters (F(max) and WOA) versus the chitosan-only control whilst retaining significant bioadhesive potential. CONCLUSIONS: Bioadhesive chitosan/fluoride microparticles manufactured using a spray-drying protocol have been extensively characterised and further opportunity for optimisation identified. These microparticles may provide a means of increasing fluoride uptake from oral care products to provide increased protection against caries, however further work is required to demonstrate this principle in vivo. CLINICAL SIGNIFICANCE: Spray-drying is a low-cost route for the manufacture of bioadhesive chitosan/fluoride microparticles which can be exploited as controlled fluoride release agents to aid fluoride retention in the oral cavity. The potential exists to optimise release profiles to suit the delivery format thereby maximising the cariostatic benefits. PMID- 22212237 TI - Congenital keratoconjunctivitis sicca and ichthyosiform dermatosis in 25 Cavalier King Charles spaniel dogs. Part I: clinical signs, histopathology, and inheritance. AB - The clinical presentation and progression (over 9 months to 13 years) of congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID) in the Cavalier King Charles spaniel dog are described for six new cases and six previously described cases. Cases presented with a congenitally abnormal (rough/curly) coat and signs of KCS from eyelid opening. Persistent scale along the dorsal spine and flanks with a harsh frizzy and alopecic coat was evident in the first few months of life. Ventral abdominal skin was hyperpigmented and hyperkeratinized in adulthood. Footpads were hyperkeratinized from young adulthood with nail growth abnormalities and intermittent sloughing. Long-term follow-up of cases (13/25) is described. Immunomodulatory/lacrimostimulant treatment had no statistically significant effect on Schirmer tear test results, although subjectively, this treatment reduced progression of the keratitis. Histopathological analysis of samples (skin/footpads/lacrimal glands/salivary glands) for three new cases was consistent with an ichthyosiform dermatosis, with no pathology of the salivary or lacrimal glands identified histologically. Pedigree analysis suggests the syndrome is inherited by an autosomal recessive mode. PMID- 22212238 TI - Societal participation: examining the impact of a rehabilitation approach for young people with schizophrenia. AB - This paper is based on research that focuses on the impact of a rehabilitation approach with respect to 99 young people diagnosed with schizophrenia in a Dutch mental health facility. The approach focused on societal participation goals. Nurses and social workers play a key role in such treatment. The research focused on developmental trajectories and showed significant improvement with respect to societal participation levels. Impairment scores remained stable. The results indicate that rehabilitation counselling by nurses and social workers, in addition to medication and psychosocial treatment and integrated in a multidisciplinary team, can make a difference in a patient's societal participation. PMID- 22212239 TI - Impulsivity and aggressive behavior in Roman high and low avoidance rats: baseline differences and adolescent social stress induced changes. AB - Adverse and stressful experiences during adolescence are often of a social nature. The social defeat model in rats is used as an animal model for bullying in humans. Usually large individual differences in response to social defeat are found. The personality type that is mostly affected and the underlying mechanisms are unknown. We used male rats of the Roman selection lines to test whether social defeat (between postnatal days 45 and 57) followed by social isolation has a different impact in animals with divergent levels of emotional reactivity and coping style. The level of offensive aggression, impulsivity and performance during frustrating non-reward (extinction) were used as measures for the adult coping style of animals. Impulsivity was measured by performance on an unpredictable operant conditioning schedule (variable interval-15, VI-15) for food reinforcement. This study demonstrates that the adult, baseline level of impulsivity is higher in Roman high avoidance (RHA) rats. RHA rats showed a higher number of lever presses compared to Roman low avoidance (RLA) rats on a VI 15 schedule. The level of offensive aggression did not differ between the two lines. Surprisingly, a tendency towards more offensive aggression in RLA rats was found. Social stress during adolescence disturbed the normal development of adult personality, mostly in RHA rats. RHA rats that were defeated during adolescence reduced the number of lever presses on the VI-15 schedule of reinforcement and were more persistent during a session of frustrating non-reward. However, we did not find an effect of social defeat on performance during extinction. A tendency towards increased attack latencies after social defeat in adolescence was found. The time spent on offensive aggression was unaffected by social defeat. PMID- 22212240 TI - Melatonin administrated immediately before an intense exercise reverses oxidative stress, improves immunological defenses and lipid metabolism in football players. AB - Acute sport exercise leads to a strong stimulation of muscle tissue and a change in the organism energy demands. This study was designed to investigate the effect of oral melatonin supplementation on human physiological functions associated with acute exercise. Immune, endocrine and metabolic parameters were measured in 16 young male football players, who were divided into two groups, an experimental group (supplementation with 6 mg of melatonin administered 30 min prior to exercise) and a control group (placebo without melatonin). They performed a continuous exercise of high intensity (135 beats/min). Samples were collected 30 min before the exercise and 3, 15 and 60 min during the exercise. The results indicated that the acute sport training presented: a) increased lipid peroxidation products (MDA) in both groups, control and experimental, with levels significantly decreased in the group treated with melatonin after 15 and 60 min of high-intensity exercise, b) the total antioxidant activity (TAS) was lower in the control group than in the experimental, the latter showing significant differences at 60 min of high-intensity exercise c) the lipid profile of subjects in the experimental group showed lower triglyceride levels than the control group after 15 and 60 min of high-intensity exercise, d) immunological studies only showed, in the experimental group, an increase in IgA levels at 60 min after the exercise, and finally there were no significant differences between the groups for any of the other variables. In conclusion these results indicated that treatment with melatonin in acute sports exercise reversed oxidative stress, improved defenses and lipid metabolism, which would result in an improvement in fitness. PMID- 22212241 TI - The effects of haloperidol on cocaine-induced conditioned taste aversions. AB - Although the mechanism underlying the rewarding effects of cocaine has been well characterized, little is known about the mechanism underlying its aversive effects. Several reports have indicated a possible role of dopamine (DA) in the aversive effects; however, several procedural issues limit any conclusions regarding its specific role. In order to investigate a possible dopaminergic role in cocaine-induced CTAs using procedures that circumvented these possible issues, the present series of investigations assessed the aversive effects of the DA antagonist haloperidol alone (Experiment 1) and in combination with cocaine (Experiment 2). Haloperidol, at doses that were determined to be non-aversive, yet behaviorally active in a locomotor assessment, attenuated cocaine-induced taste aversions, suggesting that cocaine's aversive effects are mediated in part by dopaminergic activity. These findings were discussed in consideration with other evidence implicating DA and other neurotransmitter systems in cocaine induced CTAs. PMID- 22212242 TI - Stable allele frequency distribution of the polymorphic region of SURFIN(4.2) in Plasmodium falciparum isolates from Thailand. AB - Plasmodium falciparum SURFIN4.2 (PFD1160w) is a polymorphic protein expressed on the surface of parasite-infected erythrocytes. Such molecules are expected to be under strong host immune pressure, thus we analyzed the nucleotide diversity of the N-terminal extracellular region of SURFIN4.2 using P. falciparum isolates obtained from a malaria hypoendemic area of Thailand. The extracellular region of SURFIN4.2 was divided into four regions based on the amino acid sequence conservation among SURFIN members and the level of polymorphism among SURFIN4.2 sequences; N-terminal segment (Nter), a cysteine-rich domain (CRD), a variable region 1 (Var1), and a variable region 2 (Var2). Comparison between synonymous and non-synonymous substitutions, Tajima's D test, and Fu and Li's D* and F* tests detected signatures of positive selection on Var2 and to a lesser extent Var1, suggesting that these regions were likely under host immune pressure. Strong linkage disequilibrium was detected for nucleotide pairs separated by a distance of more than 1.5 kb, and 7 alleles among 19 alleles detected in 1988 1989 still circulated 14 years later, suggesting low recombination of the analyzed surf4.2 sequence region in Thailand. The allele frequency distribution of polymorphic areas in Var2 did not differ between two groups collected in different time points, suggesting the allele frequency distribution of this region was stable for 14 years. The observed allele frequency distribution of SURFIN4.2 Var2 may be fixed in Thai P. falciparum population as similar to the observation for P. falciparum merozoite surface protein 1, for which a stable allele frequency distribution was reported. PMID- 22212243 TI - Regulation of growth hormone secretion in nursing ewes: an involvement of MU receptor subtype. AB - Suckling by newborns induces a surge of lactogenic hormones, that is prolactin and growth hormone (GH), in mother's body, with endogenous opioid peptide (EOP) participating in generation of this surge. The aim of the current study was to investigate which types of opioid receptors are involved in generation of the GH surge in ewes during suckling. A series of intracerebroventricular infusions of opioid receptors antagonists: naloxone (for all types of receptors), naloxonazine (specific for MU receptor) and 5'-guanidinonaltrindole (GNTI--specific for kappa receptor) and the vehicle (control) were performed in nursing sheep during the fifth week of lactation. All infusions were carried out in a serial manner: five 30-min infusions (60 MUg/60 MUl) from 10:00 to 15:00, at 30-min intervals. The period of the experiment consisted of the non-suckling (10:00-12:30) and suckling (12:30-15:00) periods. Simultaneously, blood samples were collected at 10-min intervals to determine plasma GH concentration by radioimmunoassay. Suckling evoked a rapid increase in GH concentration in control ewes. Naloxone and naloxonazine significantly decreased both the basal GH release in the non suckling period and the suckling-induced GH surge. Specifically, the suppressive effect concerned either the duration or the amplitude of the GH surge. In contrast, GNTI did not significantly affect the GH release. In conclusion, the EOPs may affect the regulatory process of GH secretion in lactating sheep, especially through MU opioid receptor. PMID- 22212245 TI - Cochran-Armitage test versus logistic regression in the analysis of genetic association studies. AB - OBJECTIVE: The Cochran-Armitage trend test based on the linear regression model has become a standard procedure for association testing in case-control studies. In contrast, the logistic regression model is generally used for estimating effect sizes. The aim of this paper is to propose an approach that allows for association testing and parameter estimation by means of the same statistic. METHODS/RESULTS: The trend test is recommendable as a test of no association between genotype and risk of disease. It is a two-sample test for differences between cases and controls with respect to the average number of risk alleles occurring in the genotype of an individual. We argue that this difference is not of primary interest in genetic association studies. It should be replaced with the disease odds ratio, which can be assessed under both cohort sampling and case control sampling. CONCLUSION: The Cochran-Armitage trend test should be replaced by the Wald statistic from a logistic regression model for hypothesis testing and estimation in genetic association studies. PMID- 22212246 TI - Costs analysis of the treatment of imported malaria. AB - BACKGROUND: To document the status of imported malaria infections and estimate the costs of treating of patients hospitalized with the diagnosis of imported malaria in the Slovak Republic during 2003 to 2008. CASE STUDY: Calculating and comparing the direct and indirect costs of treatment of patients diagnosed with imported malaria (ICD-10: B50 - B54) who used and not used chemoprophylaxis. The target sample included 19 patients diagnosed with imported malaria from 2003 to 2008, with 11 whose treatment did not include chemoprophylaxis and eight whose treatment did. RESULTS: The mean direct cost of malaria treatment for patients without chemoprophylaxis was 1,776.0 EUR, and the mean indirect cost 524.2 EUR. In patients with chemoprophylaxis the mean direct cost was 405.6 EUR, and the mean indirect cost 257.4 EUR. CONCLUSIONS: The analysis confirmed statistically significant differences between the direct and indirect costs of treatment with and without chemoprophylaxis for patients with imported malaria. PMID- 22212247 TI - Synthesis of novel nalidixic acid-based 1,3,4-thiadiazole and 1,3,4-oxadiazole derivatives as potent antibacterial agents. AB - Novel nalidixic acid-based 1,3,4-thia(oxa)diazoles, their thio ethers, sulfones, bis mercapto, and Mannich bases were synthesized and characterized by Infrared spectra, (1) H NMR, (13) C NMR, and elemental analysis. These compounds were evaluated for their antibacterial activity against two Gram-positive and three Gram-negative bacteria. The preliminary bioassay showed that most of the compounds had better antibacterial activity than the parent compounds, 1,3,4 thia(oxa)diazoles, at the dosage 50MUg/mL toward five test bacteria. Four Mannich bases of nalidixic acid-based 1,3,4-thiadiazole exhibited maximum antibacterial activity against Bacillus subtilis, Klebsiella pneumoniae, and Pseudomonas aeruginosa with minimum inhibitory concentration in the range of 6.25-125MUg/mL. PMID- 22212248 TI - A randomized comparison of two prophylaxis regimens and a paired comparison of on demand and prophylaxis treatments in hemophilia A management. AB - BACKGROUND: Prophylaxis with factor (F)VIII is considered the optimal treatment for managing hemophilia A patients without inhibitors. OBJECTIVES: To compare the efficacy of two prophylaxis regimens (primary outcome) and of on-demand and prophylaxis treatments (secondary outcome), and to continue the evaluation of immunogenicity and overall safety of the ADVATE Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method (rAHF-PFM). PATIENTS/METHODS: Previously on-demand-treated patients aged 7-59 years (n = 66) with FVIII levels <= 2% received 6 months of on-demand treatment and then were randomized to 12 months of either standard (20-40 IU kg(-1) every other day) or pharmacokinetic (PK)-tailored (20-80 IU kg(-1) every third day) prophylaxis, both regimens intended to maintain FVIII trough levels at or above 1%. Efficacy was evaluated in terms of annualized bleeding rates (ABRs). As subjects were first treated on demand and then on prophylaxis, statistical comparisons between these treatments were paired. RESULTS: Twenty-two (33.3%) subjects on prophylaxis experienced no bleeding episodes, whereas none treated on-demand were free from an episode of bleeding. ABRs for the two prophylaxis regimens were comparable, whereas differences between on-demand and either prophylaxis were statistically significant (P < 0.0001): median (interquartile range [IQR]) ABRs were 43.9 (21.9), 1.0 (3.5), 2.0 (6.9) and 1.1 (4.9) during on-demand treatment, standard, PK-tailored and any prophylaxis, respectively. There were no differences in FVIII consumption or adverse event rates between prophylaxis regimens. No subject developed FVIII inhibitors. CONCLUSIONS: The present study demonstrates comparable safety and effectiveness for two prophylaxis regimens and that prophylaxis significantly reduces bleeding compared with on-demand treatment. PK tailored prophylaxis offers an alternative to standard prophylaxis for the prevention of bleeding. PMID- 22212250 TI - TMED2/p24beta1 is expressed in all gestational stages of human placentas and in choriocarcinoma cell lines. AB - Members of the transmembrane emp24 domain (Tmed)/p24 family of proteins are required for transport of proteins between the endoplasmic reticulum and the Golgi. One member of this family, Tmed2/p24beta1, is expressed during placental development in mice and its expression is required for normal development of the labyrinth layer. Although TMED2 is conserved in humans, little is known about its expression and function in human placenta. We examined TMED2 expression in human placenta between 5.5 and 40 weeks of gestation and showed that TMED2 is expressed in syncytiotrophoblast, cytotrophoblast, and stromal cells. We also found high levels of TMED2 expression in BeWo but not in JEG-3 choriocarcinoma cell line. We used the BeWo cell line to determine TMED2 subcellular localization in placental cells and show its co-localization with the endoplasmic reticulum Golgi intermediate compartment. Our findings show conservation of TMED2 expression in human placenta and suggest that this protein may also play a role during placental development in humans. PMID- 22212249 TI - Pro-inflammatory cytokine-stimulated first trimester decidual cells enhance macrophage-induced apoptosis of extravillous trophoblasts. AB - OBJECTIVE: As human blastocyst-derived extravillous trophoblasts (EVTs) invade the early decidua, they are positioned to interact with immune cells and resident decidual cells, and remodel spiral arteries into high capacity vessels that increase blood flow to the developing fetal-placental unit. Shallow EVT invasion elicits incomplete vascular transformation and reduces uteroplacental blood flow that presages adverse pregnancy outcomes. Excess macrophages in the decidua induce EVT apoptosis via tumor necrosis factor-alpha (TNF-alpha) secretion. Our previous observation that pro-inflammatory cytokines enhance neutrophil and macrophage activator granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in first trimester decidual cells is now extended to include: (1) the specific macrophage activator M-CSF; (2) macrophage activation and subsequent enhancement of EVT apoptosis by both GM-CSF and M-CSF. STUDY DESIGN: Quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay assessed M-CSF expression in first trimester decidual cells incubated with interleukin-1 beta (IL-1beta) or TNF-alpha. Peripheral monocyte-derived macrophages pre-incubated with conditioned media from decidual cell cultures were co-cultured with a first trimester EVT cell line, HTR-8/SVneo cells. Macrophage activation was examined and EVT apoptosis evaluated by DNA fragmentation, caspase activation and cell membrane asymmetry. RESULTS: IL-1beta or TNF-alpha significantly enhanced M-CSF expression in first trimester decidual cells. The conditioned media from these cultures activates macrophages, which promote caspase 3/7-dependent EVT apoptosis with antibodies against GM-CSF or M-CSF blocking this effect. CONCLUSIONS: Pro-inflammatory cytokines increases synthesis of M-CSF in first trimester decidual cells. Both GM-CSF and M-CSF activate macrophages, which initiate caspase-dependent EVT apoptosis. PMID- 22212251 TI - KHA-CARI guideline: KHA-CARI adaptation of the KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. PMID- 22212252 TI - 17-beta-hydroxysteroid dehydrogenase type 3 deficiency in three adult Iranian siblings. AB - 17-beta-hydroxysteroid dehydrogenase type 3 (17-beta-HSD 3) deficiency is an autosomal recessive form of 46,XY disorder of sex development (DSD). To date, a total of 27 HSD17B3 gene mutations have been described in 46,XY patients exhibiting different phenotypes at birth and virilization at puberty, sometimes in association with gynecomastia. Herein, we investigate the 46,XY DSD in an Iranian family consisting of 7 siblings, 3 of which are affected and virilized at puberty. We clinically characterized these patients and performed direct DNA sequencing of the steroid 5-alpha-reductase type 2 (SRD5A2) and the HSD17B3 gene, respectively. We identified a homozygous mutation in the HSD17B3 gene (R80W; c.238C>G) in all affected siblings. No mutation was detected in the SRD5A2 gene. The detected mutation in the HSD17B3 gene was previously described in a newborn child, who died from other congenital malformations, and in a 12-year-old girl. Hence, our report adds novel value to the phenotype classification of 17-beta-HSD 3 deficiency. PMID- 22212253 TI - Analysis of the slow germination of multiple individual superdormant Bacillus subtilis spores using multifocus Raman microspectroscopy and differential interference contrast microscopy. AB - AIM: To analyse the dynamic germination of hundreds of individual superdormant (SD) Bacillus subtilis spores. METHODS AND RESULTS: Germination of hundreds of individual SD B. subtilis spores with various germinants and under different conditions was followed by multifocus Raman microspectroscopy and differential interference contrast microscopy for 12h and with temporal resolutions of <=30s. SD spores germinated poorly with the nutrient germinant used to isolate them and with alternate germinants targeting the germinant receptor (GR) used originally. The mean times following mixing of spores and nutrient germinants to initiate and complete fast release of Ca-dipicolinic acid (CaDPA) (T(lag) and T(release) times, respectively) of SD spores were much longer than those of dormant spores. However, the DeltaT(release) times (T(release) -T(lag) ) of SD spores were essentially identical to those of dormant spores. SD spores germinated almost as well as dormant spores with nutrient germinants targeting GRs different from the one used to isolate the SD spores and with CaDPA that does not trigger spore germination via GRs. CONCLUSIONS: Since (i) DeltaT(release) times were essentially identical in GR-dependent germination of SD and dormant spores; (ii) rates of GR-independent germination of SD and dormant spores were identical; (iii) large increases in T(lag) times were the major difference in the GR dependent germination of SD as compared with spores; and (iv) higher GR levels are correlated with shorter T(lag) times, these results are consistent with the hypothesis that low levels of a GR are the major reason that some spores in a population are SD with germinants targeting this same GR. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides information on the dynamic germination of individual SD spores and improves the understanding of spore superdormancy. PMID- 22212254 TI - Throwing velocity and kinematics in elite male water polo players. AB - AIM: Fifty-three members of the Italian Men Water Polo Team were filmed using two synchronized cameras, while they were shooting a goal. Considering the differences in body mass, height, training strategies and the technical-tactical features of the players, the aims of this study were to employ video-analysis techniques in order to investigate selected kinematic parameters in water polo throwing, and to provide comprehensive quantitative information on the throwing movement in relation to the different team player positions. METHODS: Video analysis was used to estimate the elbow angle at release, the shoulder angle at follow through, the back and head height at ball release, trunk rotation angle and ball velocity at release. RESULTS: Ball release velocities ranged from 21.0 to 29.8 m/s (average value 25.3+/-1.4 m/s), for field players. Goal keepers show the lowest team values (average 21.7+/-0.3 m/s). Similar to previous study results, ball release was typically reached just prior to the elbow approaching full extension (151.6+/-3.6 degrees ), and the follow through shoulder angle was 143+/-5.9 degrees . CONCLUSION: No significant statistical difference was recorded between injured and non-injured athletes. No positive association was demonstrated between physical characteristics (body mass and height) and ball velocity. PMID- 22212255 TI - The use of session RPE for interval training in master endurance athletes: should rest be included? AB - AIM: The aim of this study was to evaluate the effectiveness of the session rate of perceived exertion (RPE) method as a tool to quantify internal training load during interval training in master athletes. In addition, we investigated whether it is appropriate to take into account rest periods when calculating the session RPE. METHODS: Eight male master endurance athletes (age: 45.3+/-7.3 years; stature: 1.74+/-0.06 m; body mass: 64.9+/-9.1 kg) were monitored during an interval training session consisting of 5 x 1000 m performed at 95% of vVO2max with 5 min rest between bouts. Edwards' summated heart rate zone method was used as a reference measure and the session RPE rating was obtained using the CR10 Borg's scale modified by Foster. RESULTS: High (r: 0.82; R2: 0.67) and significant (P=0.013) correlation was observed between the Edwards' heart rate (HR) and the session-RPE method when rest periods are taken into account; meanwhile a higher significant correlation (r: 0.86; R2: 0.74; P=0.003) was found between Edwards' HR and the session-RPE methods when rest periods were eliminated for the session-RPE computation. CONCLUSION: Despite the rest period exclusion from the computation of session RPE seems more appropriate, the statistical analysis indicates that there is no significant difference between the two correlation coefficients. These findings suggest that the session-RPE can be a useful tool to monitor internal training load during interval training and that the inclusion/exclusion of rest periods in its computation needs further investigation. PMID- 22212256 TI - Physiological effects of a new racing suit for elite cross country skiers. AB - AIM: The aim of this paper was to investigate the influence of the new cross country racing suit, designed for the Olympic Winter Games in Vancouver 2010, on cardio-respiratory, thermoregulatory and perceptual responses. METHODS: Six elite cross country skiers (29+/-6 years, peak oxygen uptake 73.2+/-6.9 mL.min-1.kg-1) performed two exercise bouts wearing either the 2009 or the 2010 racing suit. Bouts consisted of incremental testing on roller skis (12 km.h-1 at 5 degrees inclination; 11 km.h-1 at 6 degrees inclination and 12 km.h-1at 8 degrees inclination for six minutes). RESULTS: During increasing intensities, significantly lower values were found for oxygen uptake, minute ventilation, RER and heart rate when wearing the new suit compared to the old one (P<0.05; effect sizes: 0.21-4.00). Core temperature was lower with the new suit during steps 2 and 3 (P<0.05, effect size: 1.22-1.27). Also, mean skin temperature was lower during the last increment (P<0.05, effect size: 0.87). CONCLUSION: The new 2010 racing suit, developed specifically for the Olympic Winter Games in Vancouver 2010, demonstrated lower values for oxygen uptake, minute ventilation, heart rate, skin and core temperature, ratings of thermal and sweat sensation when compared to the 2009 racing suit. PMID- 22212257 TI - Muscle strength, resting muscle tone and EMG activation in untrained men: interaction effect of time of day and test order-related confounding factors. AB - AIM: This article was designed to study an interaction effect of time of day and test order-related confounding factors on daily variation in maximum muscle strength and power. METHODS: Seventeen untrained men were randomized into four groups and measured at four time points (08:00 a.m., 12:00 a.m., 04:00 p.m. and 08:00 p.m.) throughout one or two days. Each groups started at different time of day in a counter-balanced order. Peak force and myoelectrical activity (EMG) of vastus medialis, vastus lateralis and biceps femoris muscles during bilateral isometric leg extension and power output during explosive dynamic leg extension was measured. Computerized muscle tonometer was used to assess resting muscle tone. RESULTS: Resting muscle tone did not change significantly regardless of time of day or test order. In contrast, time-of-day effect was found in force and EMG during isometric leg extension and in power output; all variables were significantly lower in the morning compared to the individual best performance/highest value achieved at any time point. In addition, the above variables were also affected by test order. Regardless of time of day, isometric force and EMG were typically highest during the first test session, while the dynamic power output gradually improved with test order. CONCLUSION: Daily variation in maximum voluntary strength and power performance could be detected despite the test order-related confounding factors. PMID- 22212258 TI - Effects of relative age on physical and physiological performance characteristics in youth soccer. AB - AIM: In youth sport, birth-date positioning of performers has significant implications for future success. This phenomenon is particularly evident in soccer and is identified as the "Relative Age Effect" (RAE). To date, limited work has been conducted into the RAE from a laboratory setting. METHODS: Subjects completed a modified cycling intermittent sprint protocol (mCISP) of 15, 6 s sprints against a resistance of 7.5%.body mass, interspersed with 120 s active recovery. Nineteen (male) athletes (mean+/-SD) age 14.2+/-0.7 y; height 164+/-7.9 cm and body mass 54+/-8.7 kg participated and were separated into six-month groups, Early-Born (EB) or Late-Born (LB) based on birth-month. Ethical approval was granted by the University Ethics Committee. RESULTS: Statistically significant differences (P<0.05) were found between EB and LB peak power outputs (PPO) and mean power outputs (MPO) (absolute and relative to body mass). EB subjects had significantly higher inter-sprint MPOs and PPOs for 15 and 13 sprints respectively. Borderline significance was observed for height and fat free mass (P=0.11). CONCLUSION: The present study suggests EB individuals are often more physically and physiologically mature than LB counterparts. PMID- 22212259 TI - Anaerobic capacity of physically active eumenorrheic females at mid-luteal and mid-follicular phases of ovarian cycle. AB - AIM: The present study was undertaken to evaluate the anaerobic capacity in repeated sprint cycling bouts during mid-luteal (ML) and mid-follicular (MF) phases of ovarian cycle. METHODS: Twelve physically active females aged 22.41+/ 1.68 years, with normal regular menstrual cycle and VO2max of 34.92+/-4.85 mL.kg 1.min-1 volunteered as subjects in this study. The menstrual phases were verified through daily basal body temperature recording and serum progesterone analysis. Anaerobic capacity was quantified by measuring maximal accumulated oxygen deficit (MAOD). In this study, MAOD was measured following well established method. Initially, the VO2max of the subjects was measured following a graded exercise protocol on a cycle ergometer. On separate days, the subjects performed sub maximal cycling exercise at 50%, 60%, 70% and 80% of VO2max for 10 minutes. The linear regression determined from the sub-maximal VO2-power relationship was used to estimate the supra-maximal power output at 120% VO2max. The subjects performed repeated sprint cycling for 3 times at 120% of VO2max with 20 minutes rest between consecutive sprints during MF and ML phases. RESULTS: Results indicated there was no significant difference in maximal accumulated oxygen deficit (MAOD) and sprint performance between MF and ML phases in repeated sprint cycling. Serum progesterone was significantly lower in luteal phase after repeated sprints. CONCLUSION: Hence, it is concluded that the anaerobic capacity is unaffected by ovarian phases in women with regular menstrual cycle. Lower serum progesterone after repeated sprints might be due to the repeated anaerobic activity. PMID- 22212260 TI - The impact of physical, nutritional, and mental preparation on triathlon performance. AB - AIM: There are numerous variables that can impact a triathletes' performance. Research with this population has primarily focused on physical training habits to determine performance predictors, thus the purpose of this study was to explore the impact of nutritional and mental preparation strategies in addition to physical training on race times of Olympic-distance triathletes. METHODS: Triathletes were asked to complete an online survey that focused on physical conditioning, nutritional habits, mental training, and educational experience related to triathlon training. Participants included 272 age-group triathletes (146 males, 126 females). ANOVAs and MANOVAs were conducted to identify variables that significantly related to race time, while a logistic regression was used to determine variables that predicted performance. RESULTS: Race time was predicted by competitive motivation to participate, participation in strength training, and use of intervals during run and swim training. Mental strategies that predicted faster race times included pre-competition routines, use of energizing strategies before a race, and setting outcome goals for races. Nutritional habits did not have an impact on race time. CONCLUSION: The results support the need to go beyond investigating physical training preparation. PMID- 22212261 TI - Specificity of test selection for the appropriate assessment of different measures of stretch-shortening cycle function in children. AB - AIM: The purpose of this study was to determine from a range of vertical jump and rebound tests, which were the most suitable to measure different forms of stretch shortening cycle function, and whether such tests could be used interchangeably. METHODS: Two hundred and fifty male youths (age, 12.26 +/- 2.94 years; body mass, 47.11 +/- 16.91 kg; standing height, 152.98 +/- 17.40 cm; and sitting height, 76.89 +/- 9.32 cm) were tested for squat and countermovement jump height, reactive strength index (during a maximal hopping test), and leg stiffness (during a sub-maximal hopping test). Stepwise multiple regressions were used to examine the relationships between different measures of SSC function in youths. RESULTS: Absolute leg stiffness was best predicted by body mass (r2=62%), however the explained variance was significantly reduced when normalized to leg length and body mass (r2=15.3%). Squat jump height best explained the total variance for reactive strength index (r2=53.9%), whilst countermovement and squat jump height were the best predictors of each other (r2=86%). CONCLUSION: Results would suggest that the test protocols used in this study were representative of different forms of SSC performance. Coaches and athletes should take these findings into account when attempting to select the appropriate testing protocols to measure the correct SSC action. PMID- 22212262 TI - Heat stress and dehydration in kendo. AB - AIM: This study aimed to analyze sweat rate, water percentage alteration, and temperature variation during kendo practice in order to relate the thermal stress induced by such sports and draw recommendations for its secure practice. METHODS: Participants were 12 male individuals. The studied variables were: age, weight, stature, body mass index, fat percentage, water loss percentage, tympanic temperature, and sweat rate. Measures were obtained in one day of 120 min practice (T: 24.1 +/- 2.5 degrees C; RH: 73 +/- 8.5%) using obligatory training equipment. RESULTS: The age of participants was on average 26 +/- 6.2 years, stature 1.8 +/- 0.03 m, weight 78 +/- 13.7 kg, BMI 24.12 +/- 4.03 kg/m2 and fat percentage 15.7 +/- 5.1%. Weight and temperature final values were significantly different from the initial ones (P<0.01). Estimated sweat rate was 0.35 L.h-1 (95% CI = [0.299; 0.400]) and estimated percentage of water loss was 0.946% (95% CI = [0.694; 1.174]). CONCLUSION: Kendo practice using obligatory equipment significantly increases temperature, even when sweat rate and water loss percentage are low. The almost complete obstruction of the evaporative surface leads to heat accumulation, which may result in risks comparable to those of American football players. Thus, preventive measures must be established to minimize the risks of the combination among environment (tropical climate), equipment (bogu) and the high physiological demand of this sport in order to prevent greater damages to the health of practitioners. PMID- 22212263 TI - Effects of cold-water immersion and contrast-water therapy after training in young soccer players. AB - AIM: Recent studies have investigated the importance of recovery strategies after training session, including hydrotherapy and cryotherapy. However, only a few studies have focused on cold-water immersion (CWI) treatments in team sport disciplines. The present study investigates the effects of CWI and contrast-water therapy (CWT) on the performance of young male soccer players during a week of training. METHODS: Eighteen young soccer players participated in the present study (age 15.5+/-1.0 years, weight 61.8+/-3.0 Kg, height 175.5+/-4.0 cm and training experience 8.1+/-1.0 years). They were involved in a four-day study with recovery using CWI or with CWT after each training session by using performance tests and small-sided games. We measured uric acid concentration, leukocytes, haemoglobin, reticulocytes and creatine kinase changes in the blood, axillary temperature, rating of perceived exertion after a training session, heart rate during exercise, performance tests (counter movement jump, repeated sprint ability and 5' shuttle run). RESULTS: No significant difference were reported between groups when different physiological tests were used; CWI and CWT did not negatively influence the performances of the athletes. The principal effect of CWI was a reduced perception of fatigue after the training session. The use of active recovery protocols based on cold water or cold/thermoneutral water did not induce modifications of inflammatory and haematological markers in young soccer players. CONCLUSION: The beneficial effect of a reduced perception of fatigue can improve training and competitions in young soccer players. PMID- 22212264 TI - Efficacy of a multimodal therapeutic exercise program in shellfish gatherers for the prevention of musculoskeletal disorders: a quasi-experimental study. AB - AIM: Aim of the present study was to determine the efficacy of a therapeutic exercise program to modify the muscular endurance of the trunk, the localization and intensity of musculoskeletal pain, fear-avoidance beliefs, perceived change after the treatment and satisfaction. METHODS: The present study has a quasi experimental design (N.=19) with measurements taken before and after 16 sessions. The measures included: trunk extensors and flexors endurance, localization and intensity of pain and fear avoidance behavior. At the end of the program the perception of changes at musculoskeletal level and satisfaction were also obtained. Statistical analysis was carried out using Student's T-test for paired data, Wilcoxon's test and McNemar's test. The study was approved by the Ethics Committee and the patients gave their informed consent. RESULTS: The 94% were women with a mean age of 58 years. The 42.1% had musculoskeletal pain, with the most frequent locations being the lower back, neck and shoulder regions. A significant increase in the muscular endurance of the trunk extensors and flexors (in seconds) was detected; (67.1+/-42 vs. 96.1+/-55.2) (P=0.005) and (28.2+/-18.3 vs. 67.8+/-41.1) (P=0.000), respectively. A decrease that was close to statistical significance (P=0.19) was observed in the score on the FABQ (53.9+/ 18.8 vs. 48+/-19.7). The prevalence of lower back pain (84.2% vs. 47.4%; P=0.016) and upper back pain (42.1% vs. 10.5%; P=0.031) decreased significantly after the treatment. The 78.4% had improved and 89.5% were very satisfied with the treatment. CONCLUSION: The treatment increased the muscular endurance of both the trunk extensors and flexors. A decrease in the prevalence of lower back, upper back and neck pain was observed. The perceived change and satisfaction were high. PMID- 22212265 TI - Effect of snowboard-related concussion safety education for recognizing possible concussions. AB - AIM: The aim of this study was to examine the understanding of snowboard-related concussion and to measure the recognition of possible concussion occurrence after an intervention of snowboard-related concussion safety education in snowboarding. METHODS: Incidence cohort design. SETTING: 2008-2009 season Gangwon-do Ski resorts, South Korea. A total of 208 university students (female-72; male-136; age-18 to 32) who registered for a snowboarding class and received credit participated in this project. Snowboard-related concussion safety education class was administered for 30 minutes before the snowboard class began. The knowledge of snowboard-related concussion before and after the safety education was evaluated. Concussion data were collected via a self-report case form at the last day of snowboarding class. The incidence of possible concussion and factors associated with concussions were analyzed by chi2 test. RESULTS: The mean score of snowboard-related concussion knowledge improved from fifteen points to eighteen points out of 20 total points possible. Overall the incidence of concussion was 10 per 100 snowboarder-exposures. chi2 tests showed concussion rates to be significantly different in female snowboarders (P=0.00) and in helmet users (P=0.02). CONCLUSION: The incidence of possible concussion is high among snowboarding class participants. Emphasis should be given for instituting pre participation balance training, especially for females to reduce falling in snowboarding. To verify the effects of pre-participation balance training and falling results in a concussion, more research is needed in the future. PMID- 22212266 TI - Echocardiographic study of structure and functional cardiac profile of football referees. AB - AIM: The aim of this study was to analyze, through echocardiography, the structure and functional cardiac profile of national category Spanish soccer referees. METHODS: The sample consisted of 54 licensed referees, who belonged to the Football Inter-Insular Federation of Las Palmas. The sample presented a mean age of 28.52 +/- 6.39 years, a height of 1.76 +/- 0.07 m, a body mass of 77.26 +/ 10.74 kg and a Body Mass Index of 24.90 +/- 2-73 kg/m2. The diastolic and systolic dimensions of the left ventricle were 50.03 +/- 4.79 mm and 33.74 +/- 5.23 mm, respectively. The thicknesses of the interventricular septum and the posterior wall of the left ventricle were 9.77 +/- 1.53 mm and 9.47 +/- 1.54 mm, respectively. The left ventricular mass was 112.80 +/- 26.53 g/m2, the diastolic volume of the left ventricle 135.09 +/- 39.63 mL and the ejected volume 47.34 +/- 12.44 mL/m2. RESULTS: This study shows that the echocardiographic profile of football referees is characterized by presenting an increase in the left ventricular mass caused by an increase of the cardiac chambers and a normal systolic and diastolic function. The values obtained by football referees were higher than those found in sedentary people and lower than in professional football players. CONCLUSION: These differences may be due to the different physical training workloads employed by football players and referees. PMID- 22212267 TI - Physical activity of predialysis patients with chronic kidney disease measured using SenseWear Armban. AB - AIM: The aim of the study was to analyze the correlations between age, BMI, fat mass, muscle mass, GFR and factors related to physical activity (PA) of predialysis individuals with chronic kidney disease (CKD). METHODS: Into the study were enrolled 24 predialysis CKD patients: 6 male, 18 female (mean age 60.3 +/- 10.2 years, BMI 27.5 +/- 4.5 kg/m2, GFR 17.67 +/- 6.52 mL/min/1.73 m2). PA was assessed during 24-hours using the multisensor system Armband SenseWear Pro 3. Body composition (BC) was measured using bioimpedance. RESULTS: Total energy expenditure was 32.4+/-5.8 kcal/kg of body mass. Number of steps was 10423 +/- 3680/day. Average lying down duration was 527 +/- 107 min, median of physical activity duration was 74 min. All analyzed factors, except sleep duration, were dependent on the age. Fat mass and muscle mass were correlated with total energy expenditure (respectively r=-0.59, P=0.003; r=0.56, P=0.005), lying down duration (r=0.43, P=0.030; r=-0.52, P=0.009), physical activity duration (r=-0.53, P=0.008; r=0.56, P=0.004). GFR was correlated with lying down duration (r=-0.42, P=0.046). CONCLUSION: PA of CKD patients was satisfactory - all patients demonstrated PA duration higher than 40 min. No influence of gender on the level of PA was observed, but PA decreased with the age progress. Higher level of PA was connected with favourable BC. The GFR level in the observed patients did not influence PA, except lying down duration, which was longer in patients with lower GFR. PMID- 22212268 TI - Physical activity patterns in normal-weight adolescents on week-days and week ends. AB - AIM: This study aimed to assess the day-to-day variability of children's physical activity by accelerometer on week-days and week-end days, and to determine the proportion of children that comply with the established physical activity (PA) guidelines. METHODS: Physical activity was recorded every minute by uniaxial accelerometer in 104 normal-weight adolescent students (64 boys and 40 girls) for up to two different weeks (in winter and spring) and over seven consecutive days each week. We examined the difference in minutes for each gender and for the intensity of physical activity over the days of the week. The study took place in the north-east of Spain in 2009. RESULTS: Gender was found to produce the most significant results. Boys engaged in more moderate, vigorous and moderate to vigorous physical activity (MVPA) than girls. Children accumulated more physical activity on week-days than on week-end days. Adolescents' PA is mainly derived from their engagement in light activities. The majority of the adolescents did not reach the recommended >=60 minutes of MVPA. CONCLUSION: This study suggests that Spanish adolescents engage in limited amounts of MVPA on week-days and week ends, with activity levels differing according to sex and day of the week. Given that less activity is accumulated at the week-end, especially amongst girls, the out-of-school environment should be the focus for more activity. PMID- 22212269 TI - Effects of exercise program on appetite-regulating hormones, inflammatory mediators, lipid profiles, and body composition in healthy men. AB - AIM: Exercise can improve appetite, inflammatory mediators, lipid profiles, and body composition in overweight or obese patients. However, it has not yet been clearly elucidated how exercise affects healthy people in relation to these variables. Thus, we investigated the effects of an exercise program on appetite regulating hormones, inflammatory mediators, lipid profiles, and body composition in healthy men. METHODS: Thirty sedentary men were recruited and randomly assigned to two groups (exercise group, EG, N.=15 and control group, CG, N.=15). Total plasma ghrelin, leptin, C-reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) were determined by radioimmunoassay and immunoassay. Total cholesterol (TC), triglyceride (TG), high- and low-density lipoprotein cholesterol (HDL-C and LDL-C) were determined by enzymatic assay. Body composition was determined by bioelectrical impedance analysis. RESULTS: After 8 weeks, the ghrelin and leptin levels of CG showed a tendency to increase, whereas those of EG were significantly decreased. Although TNF-alpha and CRP, except for IL-6, showed a tendency to increase in CG, all three tended to decrease in EG after 8 weeks. TG and LDL-C were significantly increased in CG. The TC, TG, and LDL-C levels of EG were remarkably decreased, whereas HDL-C was significantly increased. In EG, body weight, fat mass, percent fat, and waist/hip ratio were significantly decreased, whereas muscle mass was significantly increased after 8 weeks. CONCLUSION: The present study results have demonstrated the beneficial effects of an exercise program by altering appetite-regulating hormones, decreasing inflammatory factors, and improving lipid profiles and body composition in healthy young men. PMID- 22212270 TI - Exercise training improves body composition, blood lipid profile and serum insulin levels in obese children. AB - AIM: Increasing prevalence of obesity and related diseases especially in children and adolescent has gained more scientific attention. The present study was conducted to determine the effects of regular exercise on childhood obesity often associated with clinical conditions such as hypertension, dyslipidemia and diabetes already at a young age. METHODS: The subjects were 40 obese children at 11 +/- 1 years and with Body Mass Index (BMI) of at least 30 kg/m2 who volunteered to the study and randomly classified into exercising and non exercising control group. Physical load of the exercising group was first determined by the Karvonen protocol after which to the subjects underwent a 12 week aerobic exercise training program primary consisting of walking and jogging exercise. Blood pressure, biochemical cardiovascular risk factors and body composition were assessed before and after the exercise-training period and compared to the non-exercising control group. RESULTS: In the exercising group, statistically significant changes were observed in the circumference of forearm, elbow, calf, knee, waist, chest and hip, as well as skin fold thickness of chest, subscapulae, calf, abdomen, suprailiac and leg. Similarly, total cholesterol, triglyceride, LDL, VLDL and insulin levels were found to be lower and HDL levels higher than in the non-exercising control group. CONCLUSION: While treating obesity in children, a major emphasis should be directed towards increasing regular physical activity and supported with dietary interventions. By this approach the risk of other chronic diseases often associated with obesity could be minimized thereby improving the quality of life. PMID- 22212271 TI - Changes in obesity, cardiorespiratory fitness and habitual physical activity following a one-year intervention program in obese youth: a pilot study. AB - AIM: The aim To assess the effects of a unique twelve month program of physical activity and health education on body mass index, cardiorespiratory fitness and physical activity habits in obese youth. METHODS: Thirty-seven physician referred subjects, nineteen girls (12.7 +/- 3.1 years) and eighteen boys (12.2 +/- 2.8 years) participated in the study. Treatment consisted of a unique program of physical activity that emphasized playing games. Activity sessions were offered one time per week, two hours each session, for twelve months. A two hour health education class was provided every 3 months. Weight, height, Body Mass Index, cardiorespiratory fitness and habitual physical activity were measured. RESULTS: Findings of the study demonstrated a significant improvement in body mass index, cardiorespiratory fitness (P<0.001), and habitual physical activity (P<0.05). CONCLUSION: Results of the pilot study were favorable in addressing serious health issues in young obese boys and girls. PMID- 22212272 TI - Effects of resistance training periodization on performance and salivary immune endocrine responses of elite female basketball players. AB - AIM: The aim of this paper was to examine the effects of resistance training periodization on the performance and salivary hormone-immune responses of elite female basketball players. METHODS: Twelve female athletes were monitored across a 50 day period of resistance training that emphasized strength, endurance and power. One repetition maximum (1RM) strength, maximal repetitions at 50% 1RM and vertical jump performance was assessed pre- and post-training. Saliva samples were also collected at 0700, 0930, 1100 and 1730 hours and analyzed for testosterone (T), cortisol (C) and immunoglobulin A (IgA). RESULTS: Improvements in 1RM strength, maximal repetitions and vertical jump performance were identified post-training (P<0.05). Training had no effect on salivary T and C concentrations, but the T:C ratio increased at 0730 hours (P<0.05) and IgA concentrations were lowered at 0930 and 1100 hours (P<0.05). The changes (? Pre Post training) in strength and T concentrations were positively correlated at 0730 hours (P<0.05). CONCLUSION: A periodized approach to resistance training increased muscle performance in elite female basketball players, but only minor changes in the salivary T:C ratio and IgA were noted. Correlational analysis identified a possible role for early morning changes in T as a regulator of individual strength changes. PMID- 22212274 TI - Interobserver and intraobserver reliability in lower-limb flexibility measurements. AB - AIM: To describe the inter- and intraobserver reliability of lower extremity flexibility tests, and to explore the effect of sports activity on the results. METHODS: A total of 66 subjects consisting of 20 professional athletes, 26 active subjects performing any sporting activity and 20 control subjects were included. Various flexibility tests were performed to determine hamstring, quadriceps and hip adductor muscle flexibility by two examiners blinded to each other for interobserver reliability. Intraobserver reliability of tests were evaluated by one the examiners 1 week later. Inter- and intraobserver reliability was analyzed with intraclass correlation coefficient (ICC), coefficient of variation (CV) and critical difference (CD). RESULTS: ICC analysis showed that inter- and intra observer reliability results were satisfactory for all measurements. Athletes performed the best results of inter- and intraobserver reliability for flexibility tests in means of CV and CD compared with active and control groups (P<0.05). Popliteal angle measurement was the most reliable one among hamstring flexibility tests where as the least reliable test was chair sit and reach test in all groups. CONCLUSION: This is the first study evaluating extensively the reliability of flexibility tests in different intensities of sports activity. Flexibility measurements of quadriceps and hip adductor muscles can be used reliably in clinical practice as hamstring flexibility tests. The intensity of performed activity may have an effect on the reliability of flexibility tests. PMID- 22212273 TI - Peroxisomal proliferator-activated receptor gamma co-activator-1 alpha gene expression increases above the lactate threshold in human skeletal muscle. AB - AIM: Peroxisomal proliferator-activated receptor gamma co-activator-1 alpha (PGC 1alpha) plays a role not only as an activator of mitochondrial biogenesis, but also as a suppressor of inflammatory cytokines, which induce chronic diseases. Therefore, increasing PGC-1alpha expression can be one of the important factors for preventing chronic diseases. PGC-1alpha expression is activated by adenosine monophosphate-activated protein kinase (AMPK) and cAMP dependent kinase. The activity of these enzymes depends on the exercise intensity. Therefore, this study compared the effects of two different exercise intensities (above lactate threshold (LT) and below LT) with an equal amount of energy expenditure on PGC 1alpha gene expression in human skeletal muscle. METHODS: Six young men participated in this study. They performed exercise at 120% and 80% LT intensity. The duration of the 120% LT exercise was 60 minutes and the duration of the session performed at 80% LT was calculated to yield equal energy expenditure as the 120% LT intensity exercise. Skeletal muscle was obtained after 1 hour of exercise. RESULTS: The working rate, % peak VO2 and HR during exercise were significantly higher in at 120% LT than at 80% LT. PGC-1alpha gene expression was not significantly different between control (0.087; 0.026-0.284 (the median; inter quartile range)) and 80% LT (0.171; 0.030-0.484). However, PGC-1alpha gene expression after 120% LT (0.441; 0.121-4.643) was significantly higher than in the control. CONCLUSION: The findings of this study suggest that PGC-1alpha gene expression depends on exercise intensity. PMID- 22212275 TI - Changes in cardiovascular risk factors and inflammatory markers of young, healthy, men after six weeks of moderate or high intensity resistance training. AB - AIM: The present study was done to see the Influence of moderate and severe intensity resistance exercises on some cardiovascular risk factors. METHODS: Thirty young healthy male were randomly divided in to two types of intervention [MI: moderate intensity (45-55% 1RM), HI: high intensity (80-90% 1RM)] and one Control (no intervention) groups. Subjects in MI and HI intervention groups underwent 3 supervised resistance-training sessions per week for six weeks. IL-1, IL-6, HS-CRP, fibrinogen, ApoB, ApoA, LDL, HDL, ApoB/ApoA ratio, Lipoprotein Lipase (LPL), TG, cholesterol, cholesterol/HDL ratio, body mass index (BMI), systolic pressure (Ps), diastolic pressure (Pd) and waist/hip ratio (WHR) before and after resistance training period were assessed. RESULTS: IL-1, IL-6, ApoB, ApoA, LPL, TG levels, ApoB/ApoA ratio, Ps, Pd, WHR, BMI and CPR did not change significantly in trained groups. In post test HS-CRP was significantly lower in trained groups in comparison to control group (P<=0.05). LDL, Cholesterol and cholesterol/HDL ratio decreased significantly in trained groups (P<=0.05). In the HI group plasma level of fibrinogen were decreased while HDL level were increased (P<=0.05). CONCLUSION: Resistance training for 6 weeks in young healthy males evoked beneficial effects regarding some inflammatory and cardiovascular risk markers. Higher-intensity resistance training was more effective in reducing plasma fibrinogen and increasing plasma HDL levels than moderate resistance training. PMID- 22212276 TI - The effect of preseason training on mucosal immunity in male basketball players. AB - AIM: This study examined the effects of pre season training on restring level and acute response of mucosal immunity in male basketball players. METHODS: Twenty male basketball players performed 8 weeks progressive exercise training, consisting of interval and continuous parts. Five mL un-stimulated saliva was collected from each subject before, immediately and one hour after the end of one bout of exercise to exhaustion on treadmill at the beginning of the first week and end of 8 weeks to determine the acute responses. At the beginning of each 2 weeks (resting state) induced changes in basal mucosal immunity was evaluated. The concentration of sIgA and total protein was measured by the ELISA and Bradford methods respectively. RESULTS: One bout exercise training at beginning of first week decreased significantly sIgA level but not at the end of 8th week. Total protein did not change significantly at 1st week after exercise, but at eight week significantly increased and remained at high level until one hour after exercise. sIgA to total protein ratio at first week significantly decreased and remained constant one hour after exercise. At the eight week sIgA decreased significantly immediately after exercise and remained low until one hour after exercise. The comparison of sIgA and total protein levels indicates significant decrease after eight weeks training. CONCLUSION: These results suggest that repetition of single bout of exercise training have a cumulative effect on the mucosal immune system. PMID- 22212277 TI - Endurance markers are related with local neuromuscular response for the intact but not for the ACL reconstructed leg during high intensity running. AB - AIM: It has been demonstrated that the local neuromuscular response during high intensity exercise has a strong relationship with endurance markers. However, a diminished neuromuscular response has been reported for the operated leg in athletes having undergone anterior cruciate ligament reconstruction (ACLR). The purpose of the present study was to examine the relationships between endurance markers and the EMG response during high intensity running in ACLR athletes. METHODS: Fourteen ACLR soccer players underwent a GXT test to volitional exhaustion and a 10-min bout of high intensity running. During the 10-min bout, EMG data were recorded at the 3rd and 10th minute from the vastus lateralis bilaterally using a telemetric system. The final EMG levels were expressed as a percentage of the initial values. Pearson moment product correlations were used to assess the relationship between the endurance markers of VO2max, velocity at lactate threshold (vLT), velocity at 4mM (V4) and the final EMG levels. RESULTS: Final EMG levels for the intact leg had a very strong relationship with vLT (r=0.77, P=0.001) and a strong relationship with V4 (r=0.68, P=0.008). Final EMG levels for the reconstructed leg had moderate relationship with vLT (r=0.47, P=0.09) and V4 (r=0.52, P=0.06). CONCLUSION: The neuromuscular response of the intact leg during high intensity running shows strong to very strong relationships with endurance markers. Failure of the ACLR leg to present relationships of similar strength may indicate that chronic perturbations modify the ability of the local muscular environment to tolerate sustained high intensity efforts. PMID- 22212278 TI - Tracing the origin and evolutionary history of plant nucleotide-binding site leucine-rich repeat (NBS-LRR) genes. AB - Plant disease resistance genes (R genes) encode proteins that function to monitor signals indicating pathogenic infection, thus playing a critical role in the plant's defense system. Although many studies have been performed to explore the functional details of these important genes, their origin and evolutionary history remain unclear. In this study, focusing on the largest group of R genes, the nucleotide-binding site-leucine-rich repeat (NBS-LRR) genes, we conducted an extensive genome-wide survey of 38 representative model organisms and obtained insights into the evolutionary stage and timing of NBS-LRR genes. Our data show that the two major domains, NBS and LRR, existed before the split of prokaryotes and eukaryotes but their fusion was observed only in land plant lineages. The Toll/interleukin-1 receptor (TIR) class of NBS-LRR genes probably had an earlier origin than its nonTIR counterpart. The similarities of the innate immune systems of plants and animals are likely to have been shaped by convergent evolution after their independent origins. Our findings start to unravel the evolutionary history of these important genes from the perspective of comparative genomics and also highlight the important role of reorganizing pre-existing building blocks in generating evolutionary novelties. PMID- 22212280 TI - Family environment is associated with HPA-axis activity in adolescents. The TRAILS study. AB - The purpose of the present study was to investigate the developmental programming part of the theory of biological sensitivity to context using family environmental factors and hypothalamus-pituitary-adrenal (HPA) axis functioning. Specifically, we investigated whether perceived parenting (Rejection and Emotional Warmth) and socio-economic status (SES) predicted basal cortisol levels and the cortisol awakening response (CAR). In a population-based cohort of 1594 adolescents (mean age=11.08, SD=0.54) we assessed salivary cortisol, SES and perceived parenting. Perceived parental Emotional Warmth showed an inverse, linear association with basal cortisol levels. In addition, there was a curvilinear relationship between SES and both basal cortisol levels and the CAR. Our findings with regard to basal cortisol levels confirmed our hypothesis: lower basal HPA-axis activity in both high and low SES families compared to intermediate SES families. PMID- 22212281 TI - Phase re-setting of gamma neural oscillations during novelty processing in an appetitive context. AB - Based on the previous study where phase-synchronization (PS) of gamma-band responses (GBRs) proved a reliable cerebral correlate of involuntary attention and its enhancement under threat, we measured gamma-PS elicited by novel sounds from human electroencephalogram (EEG) scalp-recordings when participants responded to visual stimuli displaying either highly motivational or neutral sceneries. We then tested the modulatory effect of the emotional conditions on auditory responses. Novel distractor sounds did not affect behavioural accuracy on subjects' visual task performance in neutral context but markedly decreased hit rate in the appetitive one. Similarly, gamma-PS to novel sounds remained intact in neutral context, whereas it showed an increase, within the 35-Hz sub range, in the appetitive context. These results suggest that a context of processing positive emotional stimuli results into an enhanced processing of task irrelevant novel auditory events, and, furthermore, that gamma-PS is tuned under conditions that could promote long-term survival. PMID- 22212279 TI - Transcriptome analysis of rin mutant fruit and in silico analysis of promoters of differentially regulated genes provides insight into LeMADS-RIN-regulated ethylene-dependent as well as ethylene-independent aspects of ripening in tomato. AB - A thorough understanding of molecular mechanisms underlying ripening is the prerequisite for genetic manipulation of fruits for better shelf-life and nutritional quality. Mutation in LeMADS-RIN, a MADS-box gene, leads to non ripening phenotype of rin fruits in tomato. Characterization of ripening inhibitor (rin) mutant has elucidated important role of ethylene in the regulation of climacteric fruit ripening. A complete understanding of this mutation will unravel novel genetic regulatory mechanisms involved in fruit ripening. In this study, fruit transcriptomes of two genotypes, including a cultivated Indian cultivar Solanum lycopersicum cv. Pusa Ruby and a homozygous line harboring the rin mutation (LA1795) were compared to get better insight into RIN-regulated ethylene-dependent and ethylene-independent events during ripening. Cluster analysis of ripening-related genes indicated a major shift in their expression profiles in rin mutant fruit. A total of 112 genes, exhibiting expression patterns similar to that of LeMADS-RIN in wild-type fruits, showed down regulation of expression in the rin mutant. In silico analysis of putative promoters of these genes for the presence of CArG box along with ERE and ethylene inducibility of these genes revealed that genes lacking CArG box in their regulatory regions could be indirectly regulated by LeMADS-RIN. New regulators of ethylene-dependent aspect of ripening were also identified. In this study, we have made an attempt to distinguish between ethylene-dependent and ethylene independent aspects of ripening, which will be useful for developing strategies to improve fruit-related agronomic traits in tomato and other crops. PMID- 22212283 TI - Centralisation of major trauma: an opportunity for acute urology services in the UK. PMID- 22212282 TI - Porphyromonas gingivalis SerB-mediated dephosphorylation of host cell cofilin modulates invasion efficiency. AB - Porphyromonas gingivalis, a host-adapted opportunistic pathogen, produces a serine phosphatase, SerB, known to affect virulence, invasion and persistence within the host cell. SerB induces actin filament rearrangement in epithelial cells, but the mechanistic basis of this is not fully understood. Here we investigated the effects of SerB on the actin depolymerizing host protein cofilin. P. gingivalis infection resulted in the dephosphorylation of cofilin in gingival epithelial cells. In contrast, a SerB-deficient mutant of P. gingivalis was unable to cause cofilin dephosphorylation. The involvement of cofilin in P. gingivalis invasion was determined by quantitative image analysis of epithelial cells in which cofilin had been knocked down or knocked in with various cofilin constructs. siRNA-silencing of cofilin led to a significant decrease in numbers of intracellular P. gingivalis marked by an absence of actin colocalization. Transfection with wild-type cofilin or constitutively active cofilin both increased numbers of intracellular bacteria, while constitutively inactive cofilin abrogated invasion. Expression of LIM kinase resulted in reduced P. gingivalis invasion, an effect that was reversed by expression of constitutively active cofilin. These results show that P. gingivalis SerB activity induces dephosphorylation of cofilin, and that active cofilin is required for optimal invasion into gingival epithelial cells. PMID- 22212285 TI - A technique for safe and smooth re-catheterisation of a vesico-urethral anastomosis after radical prostatectomy. PMID- 22212284 TI - Phase II escalation study of sorafenib in patients with metastatic renal cell carcinoma who have been previously treated with anti-angiogenic treatment. AB - OBJECTIVE: To assess both clinical and biological efficacy and toxicity of sorafenib in patients with metastatic renal cell carcinoma (mRCC) previously treated with an anti-angiogenic vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. METHODS: Sorafenib is an orally active multikinase inhibitor approved for the treatment of mRCC. Drug-focused translational research on tissues (i.e. B-RAF) and plasma (VEGFR-alpha, circulating endothelial cells, endothelial progenitor cells) was performed to define biological predictive and prognostic markers and their related kinetics. Patients with mRCC pretreated with an anti-angiogenic treatment, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2 and adequate organ function were eligible. Patients received sorafenib 400 mg twice a day continuously in 4-week cycles. Patients with no progressive disease at 12 weeks continued to receive sorafenib at the standard dose, whereas progressing patients received an increased dose (600 mg twice a day) with early disease restaging after 4 weeks. Patients who progressed at 600 mg twice a day went off study. Efficacy (overall tumour control) was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS: In all, 19 patients were entered. The baseline characteristics were as follows: ECOG PS 0-1 94.8%; median (range) age 62 (41-81) years; nephrectomy 100%; surgery for metastatic disease 26.4%; clear cell 79.1%; papillary cell 15.7%; sarcomatoid/high grade 5.2%; two or more metastatic sites 84%. Overall, 11 patients (58%) had disease control at 6 months without significant correlation between response to prior therapy and hypertension. Progression-free survival (PFS) of 8.3 months was observed. Of six patients for whom the dose was escalated due to early progression, three benefitted with PFS of >3 months. Three (15.7%) of 19 patients had a V600E mutation and one had a K601E mutation; PFS appeared to be substantially shorter in these patients compared with 15 patients with wild-type B-RAF (2.5 vs 9.1 month, P < 0.05). The most common toxicity (National Cancer Institute Common Toxicity Criteria, NCIC 3.0, all patients) was grade >=1 diarrhoea and grade 2-3 hand-foot syndrome in 11 patients. Grade 3 mucositis was observed in one patient. CONCLUSIONS: Sorafenib at doses of 400-600 mg twice a day continuously results in acceptable and well tolerated salvage treatment after VEGFR tyrosine kinase inhibitor failure. In progressive patients, treatment with a higher dose could be a valid option and B RAF mutations may be an interesting predictive marker to be studied in a larger randomized trial. PMID- 22212286 TI - Smartphone applications for the urology trainee. PMID- 22212287 TI - Comparison of percutaneous nephrolithotomy and retrograde flexible nephrolithotripsy for the management of 2-4 cm stones: a matched-pair analysis. PMID- 22212291 TI - How can we predict lymphorrhoea and clinically significant lymphoceles after radical prostatectomy and pelvic lymphadenectomy? Clinical implications. PMID- 22212292 TI - East meets west in urology. PMID- 22212293 TI - Acupuncture: gaining acceptance in urology: proves effective for a number of chronic conditions. PMID- 22212294 TI - Hepatitis B status in migrants and refugees: increasing health burden in Western Australia. AB - BACKGROUND: In light of increasing migration from endemic countries with chronic hepatitis B (CHB), this study describes the changing epidemiology of CHB patients born outside Australia referred to a tertiary hospital in Western Australia. It aims to stratify risk and progression to cirrhosis and hepatocellular carcinoma according to viral factors and to provide an indication of the growing burden of disease and current and future treatment costs. METHODS: Demographic, serological and biochemical data were obtained from patients with CHB between July 2002 and December 2008. Hepatitis B virus DNA quantification was performed to assess baseline viral loads in the patients. Total cost estimates for surveillance and treatment are based on probabilities of the population anticipated to be at a given stage of the disease in a given year. RESULTS: There is a progressive increase in referrals (n=478) with the majority coming from Asia (57%) and Africa (35%). The mean age of Africans is 11 years less than that of Asians, with a lower proportion of Africans having hepatitis B virus DNA>2000 IU/mL compared with Asians (36.7% vs 54.3%). Approximately 50% of CHB patients referred are at risk of cirrhosis and hepatocellular carcinoma unless treated. Without treatment, a substantial increase in cost over 10 years (from $401,460 to $2,027,078) is estimated at 400%. CONCLUSION: This study highlights the increasing burden of CHB in Western Australia, from people born in endemic countries, in particular, the direct costs of treatment. It will help to develop strategies that can be tailored to Western Australia with appropriate allocation of resources. PMID- 22212295 TI - Botulinum toxin A modulates afferent fibers in neurogenic detrusor overactivity. AB - BACKGROUND: Although botulinum toxin (BoNT/A) injected into the detrusor muscle improves overactive bladder symptoms in patients with neurogenic detrusor overactivity, how it does so remains unclear. In this study, we investigated whether BoNT/A improves detrusor overactivity by modulating bladder afferent activity. METHODS: To do so, during urodynamic assessment, we tested the soleus muscle Hoffmann (H) reflex during bladder filling before and after intradetrusor BoNT/A in patients with Parkinson's disease (PD) and in patients with complete chronic spinal cord lesion (SCI) and detrusor overactivity refractory to conventional therapy. Healthy subjects underwent H reflex studies during urodynamic assessment and acted as controls. RESULTS: Our findings show that BoNT/A injected into the detrusor muscle effectively reduces clinical overactive bladder symptoms in patients with PD and SCI. In healthy subjects and patients with PD, bladder filling [at maximum cystometric capacity, (MCC)] significantly decreased the H reflex size, whereas in patients with SCI, it slightly facilitated the H reflex size. At MCC, in patients with PD, BoNT/A significantly reduced the expected H reflex inhibition, whereas in those with SCI, BoNT/A turned the H reflex facilitation at maximum bladder filling into a slight inhibition. CONCLUSIONS: These findings show that BoNT/A injected into the detrusor muscle in patients with PD and SCI modulates bladder afferent activity. Modulation of bladder afferents possibly explains why BoNT/A improves detrusor overactivity. PMID- 22212296 TI - Performance of genotype imputations using data from the 1000 Genomes Project. AB - Genotype imputations based on 1000 Genomes (1KG) Project data have the advantage of imputing many more SNPs than imputations based on HapMap data. It also provides an opportunity to discover associations with relatively rare variants. Recent investigations are increasingly using 1KG data for genotype imputations, but only limited evaluations of the performance of this approach are available. In this paper, we empirically evaluated imputation performance using 1KG data by comparing imputation results to those using the HapMap Phase II data that have been widely used. We used three reference panels: the CEU panel consisting of 120 haplotypes from HapMap II and 1KG data (June 2010 release) and the EUR panel consisting of 566 haplotypes also from 1KG data (August 2010 release). We used Illumina 324,607 autosomal SNPs genotyped in 501 individuals of European ancestry. Our most important finding was that both 1KG reference panels provided much higher imputation yield than the HapMap II panel. There were more than twice as many successfully imputed SNPs as there were using the HapMap II panel (6.7 million vs. 2.5 million). Our second most important finding was that accuracy using both 1KG panels was high and almost identical to accuracy using the HapMap II panel. Furthermore, after removing SNPs with MACH Rsq <0.3, accuracy for both rare and low frequency SNPs was very high and almost identical to accuracy for common SNPs. We found that imputation using the 1KG-EUR panel had advantages in successfully imputing rare, low frequency and common variants. Our findings suggest that 1KG-based imputation can increase the opportunity to discover significant associations for SNPs across the allele frequency spectrum. Because the 1KG Project is still underway, we expect that later versions will provide even better imputation performance. PMID- 22212297 TI - Investigation on association and expression of ESR2 as a candidate gene for boar sperm quality and fertility. AB - ESR2 is involved in oestrogen-related apoptosis in cell cycle spermatogenesis but their effects have not yet confirmed in pig. Therefore, this study was aimed to investigate the association of ESR2 polymorphism with sperm quality and boar fertility traits and to analyse the ESR2 mRNA and protein expressions in boar reproductive tissues. DNA samples from 203 Pietrain (PI) and 100 Pietrain * Hampshire (PIHA) pigs with records of sperm quality [sperm concentration (SCON), motility (MOT), semen volume (VOL), plasma droplet rate (PDR) and abnormal spermatozoa rate (ASR)] and fertility [non-return rate (NRR) and number of piglet born alive (NBA)] traits were available. A SNP in coding region of ESR2 g.35547A>G in exon 5 was associated with MOT and PDR in the PI and with SCON, VOL, MOT and PDR in PIHA population. For mRNA and protein expression study, a total of six boars were divided into two groups with group I (G-I) and group II (G-II) where G-I characterized for relatively a better sperm quality according to the mean of two groups. mRNA expression was higher in brain and testis than that in all parts of epididymis. Both qRT-PCR and western blot analysis revealed that the ESR2 gene expression and protein expression were significantly higher in testis collected from G-II compared with that of G-I boars. Moreover, ESR2 protein localization in germ cell, Leydig and Sertoli cells, epithelial cells and spermatozoa was remarkable, which indicated the important role of ESR2 in spermatogenesis process. These results might shed new light on the roles of ESR2 in spermatogenesis as candidate for boar fertility, but still the lack of association across populations should be considered. PMID- 22212298 TI - Population pharmacokinetics of cytarabine, etoposide, and daunorubicin in the treatment for acute myeloid leukemia. AB - PURPOSE: Interpatient variability in the pharmacokinetics (PK) of cytarabine, etoposide, and daunorubicin following body surface area-adjusted doses calls for studies that point to other covariates to explain this variability. The purpose of this study was to investigate such relationships and give insights into the PK of this combination treatment. METHODS: A prospective population PK study of twenty-three patients with acute myeloid leukemia was undertaken. Plasma concentrations of patients were determined by high-pressure liquid chromatography. PK models were developed with NONMEM; for daunorubicin, PK information from a prior study was utilized. RESULTS: Baseline white blood cell count (bWBC) influenced the PK for all drugs. A small, statistically insignificant improvement in model fit was achieved when a relationship between bWBC and daunorubicin central volume of distribution was included. The volume increased 1.9% for each increase in bWBC by 1 * 10(6) cells/mL. The clearances of etoposide and cytarabine were significantly increased and decreased, respectively, by increased bWBC. Tenfold changes in bWBC were needed for these relationships to have potential clinical relevance. A decrease in creatinine clearance of 60 mL/min resulted in a decrease in etoposide clearance of 32%. CONCLUSIONS: Population-based models characterized the PK for all three drugs. bWBC was a significant covariate for etoposide and cytarabine and showed a trend for daunorubicin. Linking the significant bWBC relationships and the relationship between kidney function and etoposide clearance to clinical end points would support dose individualization. Patients with above-normal creatinine clearances and high bWBC may receive sub-optimal treatment due to elevated etoposide clearances. PMID- 22212299 TI - Mass balance, excretion and metabolism of [14C] ASA404 in cancer patients in a phase I trial. AB - PURPOSE: To determine the mass balance, excretion and metabolism of the small molecule flavonoid tumour vascular disrupting agent ASA404 in patients with advanced cancer. METHODS: Seven cancer patients were given a single dose of 3,000 mg [(14)C] ASA404 by intravenous infusion over 20 min prior to collection of samples of plasma, urine and faeces. Pharmacokinetic samples were analysed by HPLC, liquid scintillation counting, mass spectrometry, glusulase treatment and comparison to authentic standards. Descriptive pharmacokinetic parameters were generated by noncompartmental analysis. RESULTS: Mass balance was achieved (mean recovery of radioactivity in excreta = 86.9% of the dose) with balanced excretion between urine (mean recovery of radioactivity in urine = 53.9% of dose) and faeces (mean recovery of radioactivity in faeces = 33.3% of dose). ASA404 was eliminated as parent drug, three known metabolites (6-methylhydroxy-ASA404, ASA404 acyl glucuronide and 6-methylhydroxy-ASA404 acyl glucuronide) and two novel metabolites (an ASA404 dimer and an ASA404 dimer glucuronide conjugate). Unchanged ASA404 was the major radioactivity component detected in plasma within the first 24 h after dosing. At later time points, irreversibly protein bound ASA404 and all of the metabolites that had been detected in excreta contributed to total plasma radioactivity. CONCLUSION: This study defined the substantial excretion of ASA404, mainly as metabolites, in both urine (over half of the dose) and faeces (about one-third of the dose) after intravenous administration. Two novel metabolites were identified that were not reported by previous studies using nonradioactive techniques. PMID- 22212300 TI - Difference in interpretation of computed tomography pulmonary angiography diagnosis of subsegmental thrombosis in patients with suspected pulmonary embolism. PMID- 22212301 TI - Incidence of severe congenital heart disease at the province of Al-Qassim, Saudi Arabia. AB - Worldwide, congenital heart defects (CHD) are the leading cause of infant deaths owing to congenital anomalies. Knowing the actual incidence of severe CHD is important for defining the requirement for resources and the burden of disease within the total population. OBJECTIVES: The aim of the study is to estimate the incidence of severe CHD at the province of Al-Qassim as a reflection of that in the Kingdom of Saudi Arabia. STUDY DESIGN: A retrospective database review of all cases diagnosed to have severe CHD at Prince Sultan Cardiac Center-Qassim during a 3-year period from January 2008 to December 2010. RESULTS: During the study period, 316 patients were diagnosed to have severe CHD. During the 3-year study period, the total live birth at the province of Al-Qassim was 58,908. The incidence of severe CHD is 5.4/1000 live birth/year. Sixty-five percent of cases were diagnosed at less than 2 months of age, with a median age at diagnosis of 45 days (range of 1 day to 1 year). Ventricular septal defect was the most common lesion diagnosed (22.5%). Collectively, prostaglandin-dependent lesions constitute 38% of cases. Fifteen percent of patients were proved to have a syndrome. The most common syndrome was Down syndrome. CONCLUSION: . Severe CHD is a major health problem at the Kingdom of Saudi Arabia and worldwide. The incidence of severe CHD likely to require intervention in infancy, in the province of Al-Qassim, Saudi Arabia, is 5.4 per 1000 live births. PMID- 22212302 TI - Cytotoxic cardenolides from the stems of Periploca forrestii. AB - Six new cardenolides, periforosides D-E (1-2), periforgenin C (3) and periforosides F-H (4-6), as well as 10 previously identified cardenolides (7-16) were isolated from the ethanol extract of the stems of Periploca forrestii. The structures of the new compounds were determined using extensive spectroscopic analyses including HRESI-MS, 1D and 2D NMR data. Evaluation of the cytotoxic activity of all the isolated compounds in five different human cancer cell lines indicated that compounds 2-6, 8, 9 and 12-16 have potent activity. PMID- 22212303 TI - Addition of rituximab to high-dose methotrexate-based chemotherapy improves survival of adults with Burkitt lymphoma/leukemia. PMID- 22212304 TI - A limited sampling strategy for the simultaneous estimation of tacrolimus, mycophenolic acid and unbound prednisolone exposure in adult kidney transplant recipients. AB - AIM: The aim of this study was to develop a limited sampling strategy (LSS) for the simultaneous estimation of exposure to tacrolimus, mycophenolic acid and unbound prednisolone in adult kidney transplant recipients. METHODS: Tacrolimus, mycophenolic acid and unbound prednisolone area under the concentration-time curve profiles from 0 to 12 h post dose (AUC(0-12)) were collected from 20 subjects. Multiple linear regression analyses were performed to develop a LSS enabling the simultaneous estimation of exposure to all three drugs. Median percentage prediction error and median absolute percentage prediction error were calculated via jackknife analysis to evaluate bias and imprecision. RESULTS: LSS showed superior ability to predict exposure compared with single concentration time points. A LSS incorporating concentration measurements at 0.5 h (C(0.5)), 2 h (C(2)) and 4 h (C(4)) post dose displayed acceptable predictive ability for all three drugs. CONCLUSION: This LSS may serve as a useful research tool for further investigation of the utility of concentration monitoring of these medications. PMID- 22212305 TI - The usefulness of casein-specific IgE and IgG4 antibodies in cow's milk allergic children. AB - BACKGROUND: Cow's milk allergy is one of the most common food allergies among younger children. We investigated IgE antibodies to milk, and IgE and IgG4 antibodies to casein, alpha-lactalbumin and beta-lactoglobulin in cow's milk allergic (CMA) and non-allergic (non-CMA) children in order to study their clinical usefulness. METHODS: Eighty-three children with suspected milk allergy (median age: 3.5 years, range: 0.8-15.8 years) were diagnosed as CMA (n = 61) or non-CMA (n = 22) based on an open milk challenge or convincing clinical history. Their serum concentrations of allergen-specific (s) IgE and IgG4 antibodies were measured using ImmunoCAP(r). For the sIgG4 analysis, 28 atopic and 31 non-atopic control children were additionally included (all non-milk sensitized). RESULTS: The CMA group had significantly higher levels of milk-, casein- and beta lactoglobulin-sIgE antibodies as compared to the non-CMA group. The casein test showed the best discriminating performance with a clinical decision point of 6.6 kUA/L corresponding to 100% specificity. All but one of the CMA children aged > 5 years had casein-sIgE levels > 6.6 kUA/L. The non-CMA group had significantly higher sIgG4 levels against all three milk allergens compared to the CMA group. This was most pronounced for casein-sIgG4 in non-CMA children without history of previous milk allergy. These children had significantly higher casein-sIgG4 levels compared to any other group, including the non-milk sensitized control children. CONCLUSIONS: High levels of casein-sIgE antibodies are strongly associated with milk allergy in children and might be associated with prolonged allergy. Elevated casein-sIgG4 levels in milk-sensitized individuals on normal diet indicate a modified Th2 response. However, the protective role of IgG4 antibodies in milk allergy is unclear. PMID- 22212306 TI - Empowerment, patient centred care and self-management. AB - BACKGROUND: Patient or person centred care is widely accepted as the philosophy and practice that underpins quality care. An examination of the Australian National Chronic Disease Strategy and literature in the field highlights assumptions about the self-manager as patient and a focus on clinical settings. OBJECTIVE AND CONCLUSION: This paper considers patient or person centred care in the light of empowerment as it is understood in the health promotion charters first established in Alma Ata in 1977. We argue that patient or person centred care can be reconfigured within a social justice and rights framework and that doing so supports the creation of conditions for well-being in the broader context, one that impacts strongly on individuals. These arguments have broader implications for the practice of patient centred care as it occurs between patient and health professional and for creating shared responsibility for management of the self. It also has implications for those who manage their health outside of the health sector. PMID- 22212307 TI - Epidemiology, complications and management of diabetes in Ethiopia: a systematic review. AB - Non-communicable diseases are becoming major problems of public health importance in most developing countries as a result of the effects of globalization and epidemiologic transition; however, there is little evidence regarding diabetes and other non-communicable diseases in these countries. The aim of this study was to conduct a systematic review of the literature on the magnitude of diabetes, the relationship between malnutrition and diabetes, diabetic complications, and the management of diabetes in Ethiopia. Relevant studies and other evidence were identified by searches in the Embase from 1970 to December 2011 and by reviewing the reference lists from retrieved articles. Relevant articles from non-indexed local journals were also included. Data were extracted and summarized using the major themes of the systematic review. Although the prevalence of diabetes in Ethiopia is estimated to be 2% nationally, evidence suggests that it prevalence could be >5% in those older than 40 years of age in some settings. Studies in the 1980s and 1990s have reported conflicting evidence regarding malnutrition-related diabetes; however, more recent studies are reconfirming a strong association between malnutrition and diabetes. There is remarkable prevalence of both acute and chronic complications in diabetic cases in Ethiopia. In addition to this, more than one-third, but only less than half, of diabetic patients in Ethiopia receive standard diabetes care. The results of this study indicate that, in response to the emergence of diabetes and other non-communicable diseases, effective and efficient prevention and control strategies should be designed and implemented in Ethiopia. PMID- 22212308 TI - Interview with Alexander Blake. PMID- 22212309 TI - Ovarian torsion during pregnancy. PMID- 22212310 TI - Laparoscopic hysterectomies for large uteri. AB - Laparoscopic hysterectomies increase recently due to several advantages of minimally invasive surgery. Controversy exists for laparoscopic hysterectomies for large uteri weighing >500g because some reports show increased complications and morbidities and high laparoconversion rate in the past. With familiarity of laparoscopic procedures and progress in surgical techniques, the issue should be discussed and reviewed by evidence again. Hence, we conducted a systematic review of laparoscopic hysterectomies for large uteri. PMID- 22212311 TI - Management of moderate to severe Alzheimer's disease: focus on memantine. AB - Alzheimer's disease (AD) is the most common form of dementia, and one of the principal causes leading to death around the world. It is a progressive neurodegenerative disorder that still remains without definite cure. Memantine, a licensed AD drug, is an open-channel and partial trapping blocker that functions as a potent NMDA receptor antagonist, even at low concentrations. Aside from being uncompetitive, it also allows near-normal physiological NMDA receptor activity throughout the brain even with high glutamate concentrations, making it more reliable and tolerable than other AD-targeted drugs. It has also been found to be effective, safe, and well-tolerated in animal models as well as patients with moderate-to-severe AD. Aside from NMDA receptor antagonism, numerous studies have reported that memantine can also affect dopamine receptors, block excessive calcium influx and production of reactive oxygen species (ROS) induced by Abeta oligomers, and inhibit the internal ribosome entry site (IRES), thus preventing the expression of the amyloid precursor and tau proteins which are considered as early indicators of Alzheimer's. PMID- 22212312 TI - Conjoined twins detected in the first trimester: a review. AB - Conjoined twinning occurs in 1 in 100 sets of monozygotic twins, 1 in 50,000 gestations or 1 in 250,000 live births. With the advent of ultrasound technology, prenatal diagnosis of conjoined twins is possible. This article provides a comprehensive review of conjoined twins detected in the first trimester including fetal gender, maternal age, parity, types of fusion, related ultrasound abnormalities, perinatal outcome and association with assisted reproduction. PMID- 22212313 TI - Low-dose GnRH antagonist protocol is as effective as the long GnRH agonist protocol in unselected patients undergoing in vitro fertilization and embryo transfer. AB - OBJECTIVE: The present retrospective and controlled comparative study was designed to evaluate the pregnancy rate achieved using a modified, fixed, multiple-dose 0.125mg gonadotropin-releasing hormone (GnRH) antagonist protocol with the long GnRH agonist protocol as the control group. MATERIALS AND METHODS: One hundred and twenty unselected women between 30 and 40 years of age, in their first cycle of IVF/ICSI, with a baseline follicle-stimulating hormone (FSH) <10 IU and an antral follicle count >3 were assigned into two groups: (1) the study group received 0.125mg of cetrorelix daily starting on Day 6 of stimulation; and (2) the control group received leuprolide daily starting in the mid-luteal phase of the preceding cycle. Both groups were given a flexible dose of recombinant FSH for stimulation. An ongoing pregnancy rate of more than 12 weeks was the primary outcome measure of the study. RESULTS: Primary and secondary outcomes were comparable in both groups. A shorter duration of stimulation, a lower dosage of recombinant FSH consumption and a thinner endometrium on the day of human chorionic gonadotropin administration were all observed in the GnRH antagonist group. CONCLUSION: A dosage of 0.125mg GnRH antagonist protocol was effective for these unselected patients during IVF/ET. PMID- 22212314 TI - Single-port access laparoscopic surgery using a novel laparoscopic port (Octo Port). AB - OBJECTIVE: We present our initial experience with single-port access (SPA) surgery using a novel laparoscopic port (Octo-Port). MATERIALS, METHODS, AND RESULTS: In a prospective study, SPA surgery was carried out on 11 patients with the Octo-Port from July 2009 to December 2009 by a single surgeon (T.-J. K.). The procedures carried out were hysterectomy (seven patients), ovarian cystectomy (two patients) and salpingo-oophorectomy (two patients). In 10 cases the procedure was successfully performed without the use of additional ports. In one case the SPA procedure failed and ancillary ports were required; this patient had anatomical variations that made use of the SPA technique difficult. All procedures were performed without complications. There were no perioperative port related or surgical problems. The Octo-Port had certain advantages such as reducing the need for long laparoscopic instruments, reducing extracorporeal instrumental crowding, and providing better deflection of smoke compared to other SPA devices that used a wound retractor and a glove. CONCLUSION: Our study demonstrated that the Octo-Port allows laparoscopic surgery to be performed safely and easily with a reduced number of ports. PMID- 22212315 TI - Patient -controlled epidural ropivacaine as a post-Cesarean analgesia: a comparison with epidural morphine. AB - OBJECTIVE: Conventional, intermittent, epidural morphine is widely applied as a post-Cesarean delivery analgesia. We compared the analgesic efficacy, motor weakness, and side effects of administering a patient-controlled epidural analgesia (PCEA) of pure ropivacaine versus the intermittent administration of epidural morphine after Cesarean delivery. MATERIALS AND METHODS: This randomized, double-blind study included 120 full-term parturients who underwent elective Cesarean delivery and received either PCEA with pure ropivacaine or an intermittent bolus epidural of 2 mg/10 mL morphine in normal saline twice per day. The efficacy of pain relief, post-Cesarean side effects, motor blockades, time to first ambulation, and global satisfaction scores were evaluated. RESULTS: Pain scores were recorded at the four evaluation times (2, 12, 24, and 48 hours post-Cesarean delivery), and the time to first ambulation did not statistically differ between the two groups. Patients in the ropivacaine group experienced more motor weakness at 2 and 12 hours, fewer side effects, and higher global satisfaction scores than those in the morphine group (p < 0.05). CONCLUSION: The analgesic efficacy after cesarean delivery was almost equivalent between two groups. PCEA with pure ropivacaine induced significant motor blockade during the first 12 hours, but without delaying the time to first ambulation. Patients in the ropivacaine group reported higher patient satisfaction scores due to the significant reduction of annoying side effects, such as pruritus, nausea, vomiting, and urinary retention. PMID- 22212316 TI - Comparative transcriptome analysis reveals a fetal origin for mesenchymal stem cells and novel fetal surface antigens for noninvasive prenatal diagnosis. AB - OBJECTIVE: Mesenchymal stem cells (MSCs) are an attractive source for providing the cells necessary for regenerating damaged tissues. Fetal MSCs (fMSCs) are known to proliferate fast and have an excellent osteogenic capacity, yet the underlying mechanisms need to be explored. A better understanding of MSCs from different anatomic origins and ages will eventually benefit cell-based therapies, as well as subsequent mechanistic studies in the field of stem cell biology. MATERIALS AND METHODS: We identified the molecular signatures of fetal and adult MSCs via a meta-analytic strategy and compared the enriched canonical pathways and genetic networks within each signature. RESULTS: Fetal MSCs were found to express more cell cycle genes, which is consistent with the results of wetlab functional assays. In addition, the genes involved in vasculogenesis, neurogenesis, Wnt, MAPKKK pathways, and RNA splicing were found to be enriched in fMSCs. Correlating with the overexpression of multilineage differentiation genes, fMSCs share more genes with embryonic stem cells (ESCs) and are, therefore, more primitive. Further exploration into the transcriptome similarities revealed that MSCs from umbilical cord blood (UCB) express dominant fMSC genes, but not adult genes, suggesting a fetal origin for UCB MSCs. Novel surface proteins that were dominantly expressed in fetal and UCB MSCs, but not in adult MSCs or maternal PBMCs, were also identified. CONCLUSION: Our results systematically revealed the underlying genes and regulatory networks of two MSCs from unique origins, the resulting phenotypes, as well as the origin of UCB MSCs. The novel membrane proteins on the fetal MSC surface are promising candidate biomarkers for positively isolating fetal MSCs from maternal blood for noninvasive prenatal diagnosis. PMID- 22212317 TI - Surgical intervention for maternal ovarian torsion in pregnancy. AB - OBJECTIVE: Maternal ovarian torsion in pregnancy is a rare complication. This study was conducted to review the clinical manifestations, and to compare the outcome between laparoscopy and laparotomy in women undergoing surgery for ovarian torsion (OT) during pregnancy. MATERIALS AND METHODS: Using the International Classification of Disease, Ninth Revision, and Clinical Modification, we reviewed the clinical records of patients with OT during pregnancy between 1997 and 2008 at a university hospital. RESULTS: Twenty pregnant women were identified with surgically proven OT, 10 in the first trimester, eight in the second, and two in the third. Thirteen (65%) cases were suspected before operation to be adnexal torsion. The most common symptom and sign were pelvic pain (95%) and an adnexal or pelvic mass (95%), followed by nausea and vomiting (65%), elevated white blood cell count >12*10(9)/L (45%), and fever (10%). Most patients in the first trimester (75%) and a minority in the second and third trimesters (37.5%) received management via laparoscopy. Patients undergoing laparoscopy treatment had smaller ovarian masses and a shorter postoperative hospital stay than those receiving laparotomy. None of these patients had significant complications during or after surgery. However, the outcomes of pregnancy varied: 12 (60%) term deliveries, three (15%) preterm deliveries at over 31 gestational weeks, one missed abortion and four elective abortions in the first trimester. CONCLUSION: The diagnosis of OT during pregnancy is often missed due to nonspecific clinical features and uncommon objective findings. Detorsion only or detorsion plus ancillary procedures via laparoscopy is recommended to treat pregnant women suffering from OT, owing to the advantages of a shorter hospital stay and favorable surgical and pregnancy outcomes. PMID- 22212318 TI - An analysis of risk factors for postoperative pelvic cellulitis after laparoscopic-assisted vaginal hysterectomy. AB - OBJECTIVE: To assess risk factors for postoperative pelvic cellulitis in women undergoing laparoscopic-assisted vaginal hysterectomy (LAVH). MATERIALS AND METHODS: A total of 195 patients who underwent LAVH for benign gynecological diseases during the period 2007-2008 were enrolled. Among them, 11 patients developed pelvic cellulitis (group 1, cases) and 184 did not (group 2, controls). RESULTS: The proportion of patients in American Society of Anesthesiologists physical status scale (ASA) class II was significantly higher in group 1 (p=0.017). The grade of pelvic adhesion was significantly more severe in group 1 (p=0.044). The mean length of hospital stay in group 1 was significantly longer than in group 2. Logistic regression analysis revealed that patients in ASA class II were six times more likely to develop postoperative pelvic cellulitis than patients in ASA class I. In addition, the analysis showed that there was a twofold increase in risk for pelvic cellulitis with each single-grade increase in the degree of pelvic adhesion. Women with postoperative pelvic cellulitis also had a significantly increased length of hospital stay. CONCLUSION: Understanding the risk factors for postoperative pelvic infection, such as systemic disease, pelvic adhesion, and prolonged hospital stay, comprehensive care of patients, and correction of modifiable risk factors will help reduce the rate of postoperative pelvic cellulitis in women undergoing LAVH. PMID- 22212319 TI - Preimplantation and prenatal genetic diagnosis of aromatic L-amino acid decarboxylase deficiency with an amplification refractory mutation system quantitative polymerase chain reaction. AB - OBJECTIVES: To develop a diagnostic platform for preimplantation genetic diagnosis (PGD) and prenatal genetic diagnosis (PND) to prevent births of aromatic L-amino acid decarboxylase deficiency (AADC) patients. MATERIALS AND METHODS: Five Taiwanese families carrying AADC were enrolled. A novel technique, amplification refractory mutation system-quantitative polymerase chain reaction (ARMS-qPCR), was developed for both of PGD and PND. For PGD, blastomere biopsies of day-3 cleavage-stage embryos were subjected to ARMS-qPCR. Villi, cultured amniocytes, or both were used to confirm the PGD result; this approach could also be used as the sole method for PND after in vivo conception). RESULTS: Unaffected live births were achieved in four of the five families, except one with ongoing PGD. The ARMS-qPCR correctly classified blastomeres (from day-3 cleavage-stage embryos) as affected (homozygous mutant), carrier (heterozygous for mutant and wild-type alleles), or normal (homozygous wild-type) within 1 working day. CONCLUSIONS: To our knowledge, this is the first report of successful PGD of AADC. The molecular technique we devised (ARMS-qPCR) was applicable for PGD as well as PND of AADC. Furthermore, it has great potential for similar applications in other monogenic disorders. PMID- 22212320 TI - Non-classical estrogen receptors action on human dermal fibroblasts. AB - OBJECTIVE: To study the possible non-genomic effect of selective estrogen receptor modulators on human dermal fibroblasts (HDF). MATERIALS AND METHODS: WS1 cells were used to test the effect of raloxifene. The mRNA expressions of estrogen receptor (ER) alpha and beta and G protein-coupled ER 1(GRP30) were examined by reverse transcription polymerase chain reaction. Apoptosis was identified by TUNEL assay and FACS analysis. MAPK and PI3 K/Akt pathways were determined by immunoblotting analysis. RESULTS: Neither ERalpha nor ERbeta, but GPR30 was detected in WS1 cells. Raloxifene increased apoptosis, which was blocked by pertussis toxin, an inhibitor of G protein, or by LY294002. Phosphorylated p38 MAPK and Akt were also increased after raloxifene treatment. CONCLUSION: SERMs could induce apoptosis of HDF through G protein and PI3 K/Akt signaling, which may help understand the role of SERMs on the skin. PMID- 22212322 TI - Mosaic deletion-duplication syndrome of chromosome 3: prenatal molecular cytogenetic diagnosis using cultured and uncultured amniocytes and association with fetoplacental discrepancy. AB - OBJECTIVE: To present prenatal molecular cytogenetic diagnosis of mosaicism for terminal 3p deletion and distal 3q duplication using cultured and uncultured amniocytes, and the association with fetoplacental discrepancy. MATERIALS, METHODS, AND RESULTS: A 35-year-old primigravid woman was referred for genetic counseling at 21 weeks of gestation because of 20% (5/25 colonies) mosaicism for add(3)(p26) detected by amniocentesis. Repeated amniocenteses were performed. Array comparative genomic hybridization (aCGH) and interphase fluorescence in situ hybridization (FISH) were applied in the uncultured amniocytes. aCGH analysis detected 0.15-Mb microdeletion of 3p26.3 with CHL1 haploinsufficiency and a 49.42-Mb duplication of 3q24-q29 in the uncultured amniocytes. Interphase FISH analysis revealed 27.3% mosaicism (12/44 cells) in the uncultured amniocytes. Metaphase FISH analysis revealed 23.3% mosaicism (7/30 cells) in the cultured amniocytes. Conventional cytogenetic analysis showed a karyotype of 46,XX,der(3)(qter -> q24::p26.3 -> qter)[10]/46,XX[20] (33% mosaicism). Subsequent fetal blood sampling showed a karyotype of 46,XX,der(3) (qter >q24::p26.3->qter)[5]/46,XX[35] (12.5% mosaicism). The parents elected to terminate the pregnancy, and a malformed fetus was delivered at 24 weeks of gestation with characteristic facial dysmorphism and clinodactyly of the hands. Cytogenetic analysis of the extraembryonic tissues revealed the results of 46,XX (40 cells) in placenta, 25% mosaicism (10/40 cells) in amniotic membrane and 50% mosaicism (20/40 cells) in umbilical cord. CONCLUSION: Our presentation highlights the utility of molecular cytogenetic technologies in prenatal diagnosis of rare mosaic chromosome rearrangements and provides evidence for fetoplacental discrepancy under such circumstances. PMID- 22212321 TI - Double aneuploidy with Edwards-Klinefelter syndromes (48,XXY,+18) of maternal origin: prenatal diagnosis and molecular cytogenetic characterization in a fetus with arthrogryposis of the left wrist and aplasia of the left thumb. AB - OBJECTIVE: To present the prenatal diagnosis and molecular investigation of the parental origin and mechanism of nondisjunction underlying an 48,XXY,+18 karyotype in a fetus with congenital abnormalities, and to review the literature. MATERIALS, METHODS, AND RESULTS: A 42-year-old woman was referred for amniocentesis at 18 weeks of gestation because of advanced maternal age. Prenatal ultrasound revealed bilateral choroid plexus cysts. Amniocentesis revealed a karyotype of 48,XXY,+18. The parental karyotypes were normal. Level II ultrasound revealed a flexion contracture deformity of the left wrist with absence of the thumb. The pregnancy was terminated at 22 weeks of gestation. A 332 g male fetus was delivered with clenched hands, arthrogryposis of the left wrist, aplasia of the left thumb, micrognathia, low-set ears, hypertelorism, rocker-bottom feet, and a normal penis. Quantitative fluorescent polymerase chain reaction assays using polymorphic DNA markers showed a triallelic pattern with a dosage ratio of 1:1:1 (paternal:maternal:maternal) for chromosome 18-specific markers, and a monoallelic pattern of a single maternal allele for chromosome X-specific markers. The fetus inherited two copies of two different maternal alleles on chromosome 18, and two copies of a single maternal allele on chromosome X. The molecular result, along with the karyotype of 48,XXY,+18, was consistent with the occurrence of nondisjunction of chromosome 18 in a maternal meiosis I error and nondisjunction of chromosome X in a maternal meiosis II error or less likely a postzygotic mitotic error. CONCLUSION: The present case provides evidence that abnormal separation of chromosomes 18 and X resulting in double aneuploidy may occur in different cell divisions, and such an occurrence is related to advanced maternal age. PMID- 22212323 TI - A de novo duplication of chromosome 21q22.11->qter associated with Down syndrome: prenatal diagnosis, molecular cytogenetic characterization and fetal ultrasound findings. AB - OBJECTIVES: To present prenatal diagnosis and molecular cytogenetic characterization of de novo partial partial trisomy 21q (21q22.11->qter) associated with clinodactyly and hypoplastic midphalanx of the fifth fingers, midface hypoplasia, and an intracardiac echogenic focus on prenatal ultrasound. MATERIALS, METHODS, AND RESULTS: A 34-year-old gravida 2, para 1 woman underwent amniocentesis at 20 weeks of gestation because of fetal structural abnormalities on prenatal ultrasound. A level II ultrasound at 20 weeks of gestation showed polyhydramnios, clinodactyly and hypoplastic midphalanx of the fifth fingers, midface hypoplasia, and an intracardiac echogenic focus. Amniocentesis revealed an aberrant derivative chromosome 9, or der(9). Parental karyotypes were normal. Spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) analyses revealed that the der(9) contained a segment of chromosome 21 distal to chromosome 9q, and FISH analysis additionally showed that the distal subtelomeric region of 9q was not deleted. Array comparative genomic hybridization (aCGH) demonstrated a 14.8-Mb duplication of distal 21q encompassing the Down syndrome critical region (DSCR) but no genomic imbalance in the distal euchromatic region of chromosome 9. The karyotype was 46,XX,der(9)t(9;21) (q34.3;q22.11)dn. Polymorphic DNA marker analysis revealed the maternal origin of the aberrant chromosome. The pregnancy was subsequently terminated. A malformed female fetus was delivered with a characteristic phenotype of Down syndrome. CONCLUSION: SKY, FISH and aCGH are useful in prenatal investigation of the nature of a de novo aberrant derivative chromosome. Partial trisomy 21q encompassing the DSCR may present characteristic Down syndrome features on prenatal ultrasound. PMID- 22212324 TI - Universal insertion/deletion-enrich PCR. AB - OBJECTIVE: Insertions and deletions (indels) are sometimes critical genetic events and can lead to various diseases. Identifying indel types by DNA sequencing is difficult and labor intensive. The sensitivity of DNA sequencing techniques such as Sanger's direct sequencing, which broadly screens all types of microindels in predefined areas, is somewhat limited. Other techniques such as indel variant-specific primer sets are sensitive and specific, but are expensive, labor intensive, less efficient and only cover known indel variants. MATERIALS AND METHODS: We report on the universal insertion/deletion-enrich PCR (Unindel PCR) which has ultra-high sensitivity and can be used to screen for known and unknown indels in a predefined area. In brief, the Unindel-PCR consists of one forward, one reverse and one blocking primer. At very condition, blocking primer is superior to forward primer in recognizing the wild-type template and prevent nucleotide extension and wild-type amplification during PCR cycles. Conversely, forward primer is superior to blocking primer in recognizing the indel template and promote indel-type amplification during PCR cycles. RESULTS: Unindel-PCR performs well in detecting any indels in a wild-type background. The sensitivity is 1% in Unindel-PCR and 0.01% in nested Unindel-PCR. The wild-type inhibition capacity of Unindel-PCR is 10(7). One thousand copies of deletion type plasmids are sufficient for detection by Unindel-PCR, whereas nested Unindel-PCR requires only 10 copies. CONCLUSION: Unidel-PCR will remold the capability of PCR-based genetic testing, especially in the field of cancer molecular diagnosis, infectious disease and identification of minor populations of alternative splicing variants of RNA transcribed. PMID- 22212325 TI - Vulvar yolk sac tumor mixed with embryonal carcinoma in a peri-pubertal girl: a case report. AB - OBJECTIVE: Vulvar cancer is rare in Eastern females, especially in pre- and peripubertal girls. The prognosis of vulvar cancer is poor and treatment is variable. CASE REPORT: A 14-year-old girl suffered from a left vulvar tenderness mass and underwent excision of the mass. The diagnosis of the pathology was vulvar yolk tumor with an embryonal carcinoma. After the vulvectomy, inguinal area lymph node dissection, chemotherapy (bleomycin, etoposide and cisplatin) treatment and radiotherapy, metastasis to lung was also noted after eight months. Resection of lung tumor was performed. She received chemotherapy with a combination of paclitaxel, ifosphamide and cisplatin (TIP) and received peripheral blood stem cell transplantation (PBSCT) twice and chemotherapy treatment of gemitabine and oxaliplatin (GEMOX). Up until now, the patient has been free of disease. CONCLUSION: High-dose TIP and GEMOX chemotherapy plus PBSCT for bone marrow rescues could be considered to treat patients with metastatic malignant vulvar germ cell tumor after failed first-line chemotherapy and radiation. PMID- 22212326 TI - Wolf-Hirschhorn (4p-) syndrome: prenatal diagnosis, molecular cytogenetic characterization and association with a 1.2-Mb microduplication at 8p22-p21.3 and a 1.1-Mb microduplication at 10p15.3 in a fetus with an apparently pure 4p deletion. AB - OBJECTIVE: To present prenatal diagnosis and molecular cytogenetic characterization of Wolf-Hirschhorn syndrome (WHS) associated with microduplications at 8p and 10p in a fetus with an apparently pure 4p deletion. CASE REPORT: A 35-year-old gravida 2, para 1 woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Her husband was 38 years of age. There was no family history of congenital malformations. Amniocentesis revealed a karyotype of 46,XY,del(4p16.1). The parental karyotypes were normal. Array comparative genomic hybridization (aCGH) analysis revealed a 6.5-Mb deletion at 4p16.3-p16.1, a 1.2-Mb microduplication at 8p22-p21.3, and a 1.1-Mb microduplication at 10p15.3, or arr cgh 4p16.3p16.1 (0-6,531,998 bp)*1, 8p22p21.3 (18,705,388-19,940,445 bp)*3, 10p15.3 (0-1,105,065 bp)*3. Polymorphic DNA marker analysis confirmed a paternal origin of 4p deletion. Prenatal ultrasound revealed facial dysmorphism and hypospadias. The aCGH analysis of the parents revealed no genomic imbalance. Fluorescence in situ hybridization study showed an unbalanced reciprocal translocation between chromosomes 4 and 10 at bands 4p16.1 and 10p15.3. The cytogenetic result, thus, was 46,XY,der(4)t(4;10)(p16.1;p15.3),dup(8)(p21.3p22). The parents elected to terminate the pregnancy, and a 470-g malformed fetus was delivered. CONCLUSION: The present case provides evidence that an apparently pure 4p deletion can be associated with subtle chromosome imbalances in other chromosomes. PMID- 22212327 TI - Presacral teratoma in a Curarrino syndrome woman with an unreported insertion in MNX1 gene. AB - OBJECTIVE: Currarino syndrome (CS) comprises a presacral mass, anorectal malformation, and a sacral bony defect. It is rarely reported in the gynecological field. CASE REPORT: We describe here the case of a 26-year-old married woman with Currarino syndrome who presented with a presacral teratoma and a previously unreported insertion in MNX1 gene. She had had a pelvic teratoma diagnosed by laparoscopy 8 years previously. She was referred to our clinic because of the increasing size of the teratoma and associated compression symptoms. Computed tomography demonstrated a heterogeneous 12 cm mass in the presacral region. Spina bifida at S2eS5 was also noted. Laparotomy confirmed the diagnosis of presacral teratoma. Genetic analysis disclosed a triple CGC repeat insertion in exon 1 of MNX1, resulting in three in-frame shifts encoding for the amino acid alanine. No siblings had known similar symptoms. CONCLUSION: Currarino syndrome is known to be an autosomal dominant disorder. The presence of constipation can lead to a diagnosis of the syndrome early in childhood. In sporadic cases diagnosis is late because of atypical symptoms. Delayed treatment of a presacral tumor may cause serious complications such as central nervous system infection or subsequent neurological dysfunction. In clinical practice, a presacral tumor with a sacral bony defect may indicate Currarino syndrome. Genetic analysis of the family may provide information on the hereditary traits of specific MNX1 mutation. PMID- 22212328 TI - Impact of anesthetic methods on neonatal outcome in women receiving temporary balloon occlusion of the common iliac artery during cesarean section for placenta accreta. AB - OBJECTIVE: Placenta accreta is associated with significant maternal morbidity and is the leading indication for peripartum hysterectomy. In our institution, occlusion balloon catheters are commonly placed in bilateral common iliac arteries in order to reduce blood loss and facilitate surgery in patients with this obstetric complication. Few studies, however, have evaluated the effect of different anesthetic methods for cesarean hysterectomy on neonatal outcome. In this study, we compared Apgar scores among neonates born to mothers under general anesthesia with those who received regional anesthesia. CASE REPORTS: A retrospective analysis of 19 women with placenta accreta/percreta who underwent cesarean hysterectomy in our hospital, revealed that the 1-minute Apgar score was <7 in 4/12 neonates born to women who underwent general anesthesia and in 1/7 neonates born to mothers who received regional anesthesia. The 5-minute Apgar score was >7 after immediate resuscitation in all neonates. There were no significant differences in demographic data, induction-to-delivery period, or Apgar scores between the general and the regional anesthesia groups. CONCLUSION: We acknowledge that the retrospective nature of this study makes it difficult to conclude whether the different anesthesia management strategies had an impact on Apgar score; however, according to our clinical observation, regional anesthesia may be a better alternative in the induction-to-delivery period, especially for women with accreta/percreta and in situations in which poor neonatal outcome is expected. PMID- 22212329 TI - Uterine adenosarcoma with ovarian sex cord-like differentiation: a case report and review of the literature. AB - OBJECTIVES: To determine the prognosis of uterine adenosarcoma with ovarian sex cord like-differentiation after treatment and to review the literature. CASE REPORT: A 47-year-old premenopausal unmarried woman presented with irregular menstrual bleeding and uterine mass. Sonographic examination, suggested two uterine fibroids located in the uterine fundus and cervix measuring 4 * 3 cm and 3 * 3 cm, respectively. Total abdominal hysterectomy with bilateral salpingo oopherectomy was performed and the histopathology report confirmed the diagnosis of uterine adenosarcoma with ovarian sex cord like-differentiation. The patient received neither chemotherapy nor other adjuvant therapy because the tumor had low malignant potential, and the extent of myometrial invasion was less than half of the whole myometrium. The patient had an uneventful recovery, and no recurrence was detected for 2 years in the follow-up period. CONCLUSION: Uterine adenosarcomas mostly have relatively low malignant potential. Surgery is the optimal standard treatment for patients. Although there is not enough data in the present literature, benign epithelial differentiations, such as sex cord-like elements may reflect the behaviour of the tumour and shows the tendency to have a benign course in most of cases. PMID- 22212330 TI - Rapidly growing ovarian endometrioid adenocarcinoma involving the vagina: a case report. AB - OBJECTIVE: We present a rare case of a very rapidly growing stage IV ovarian endometrioid adenocarcinoma involving the uterine cervix and vagina without lymph node involvement. CASE REPORT: A 43-year-old woman visited the hospital with complaints of lower abdominal discomfort and vaginal bleeding over the previous 3 months. Serum levels of tumor marker CA 125 and SCC antigen (TA-4) were normal. On magnetic resonance imaging, a 7.9*9.7cm heterogeneous mass with intermediate signal intensity was observed in the posterior low body of the uterus. Two months ago, a computed tomography scan revealed an approximate 4.5*3.0cm heterogeneously enhanced subserosal mass with internal ill-defined hypodensities. A laparotomy, including a total abdominal hysterectomy with resection of the upper vagina, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, appendectomy, total omentectomy, and biopsy of rectal serosa was performed. A histological examination revealed poorly differentiated endometrioid ovarian adenocarcinoma with vaginal involvement. The patient had an uncomplicated post operative course. After discharge, she completed six cycles of adjuvant chemotherapy with paclitaxel (175mg/m(2)) and carboplatin (300mg/m(2)) and has remained clinically disease-free until June 2010. CONCLUSION: Epithelial ovarian cancer may grow very rapidly. The frequent measurement of tumor size by ultrasonography may provide important information on detection in a subset of ovarian carcinomas that develop from preexisting, detectable lesions. PMID- 22212331 TI - Prenatal diagnosis of a de novo interstitial deletion of chromosome 20q12 in a fetus with complex congenital heart defects, corpus callosum agenesis and intrauterine growth restriction. PMID- 22212332 TI - Complete bilateral ureteral obstruction following retrograde catheterization and radical hysterectomy. PMID- 22212333 TI - Mesentery band-like adhesion which caused entrapment of duodenum at 32 gestational weeks. PMID- 22212334 TI - Urinary ascites with elevated blood creatinine following cesarean section indicating bladder injury. PMID- 22212335 TI - Laparoscopic diagnosis of tuberculous peritonitis mimicking ovarian malignancy. PMID- 22212336 TI - Squamous cell carcinoma arising from an ovarian teratoma related to human papillomavirus infection: using a PCR-based reverse-blot assay. PMID- 22212337 TI - Synchronous primary ovarian granulosa cell tumor and endometrial cancer. PMID- 22212338 TI - Prenatal diagnosis of mosaic trisomy 9. PMID- 22212339 TI - Prenatal diagnosis of a de novo 17p13.1 microduplication in a fetus with ventriculomegaly and lissencephaly. PMID- 22212340 TI - First-trimester two-dimensional and three-dimensional ultrasound demonstration of craniofacial defects, abdominal wall defects and upper limb deficiency associated with limb-body wall complex. PMID- 22212341 TI - Magnetic resonance imaging demonstration of sirenomelia in one fetus of a dizygotic twin pregnancy conceived by intracytoplasmic sperm injection, in vitro fertilization and embryo transfer. PMID- 22212342 TI - Limiting assumptions in structure-based design: binding entropy. AB - In order to deal with the complexity of biological systems at the atomic level, limiting assumptions are often made which do not reflect the reality of the system under study. One example is the assumption that the entropy of binding of the macromolecule is not influenced significantly by the different ligands. Recent experimental data on ligands binding to HIV-1 protease challenge this assumption. PMID- 22212343 TI - Fermentation of crude glycerol from biodiesel production by Clostridium pasteurianum. AB - Clostridium pasteurianum can utilize glycerol as the sole carbon source for the production of butanol and 1,3-propanediol. Crude glycerol derived from biodiesel production has been shown to be toxic to the organism even in low concentrations. By examination of different pretreatments we found that storage combined with activated stone carbon addition facilitated the utilization of crude glycerol. A pH-controlled reactor with in situ removal of butanol by gas stripping was used to evaluate the performance. The fermentation pattern on pretreated crude glycerol was quite similar to that on technical grade glycerol. C. pasteurianum was able to utilize 111 g/l crude glycerol. The average consumption rate was 2.49 g/l/h and maximum consumption rate was 4.08 g/l/h. At the maximal glycerol consumption rate butanol was produced at 1.3 g/l/h. These rates are higher than those previously reported for fermentations on technical grade glycerol by the same strain. A process including pretreatment and subsequent fermentation of the crude glycerol could be usable for industrial production of butanol by C. pasteurianum. PMID- 22212344 TI - Localization of high level of sequence conservation and divergence regions in cotton. AB - In a previous study, we observed that the variations in chromosome size are due to uneven expansion and contraction by comparing the structures and sizes of a pair of homoeologous high-resolution cytogenetic maps of chromosomes 12A and 12D in tetraploid cotton. To reveal the variation at the sequence level, in the present paper, we sequenced two pairs of homoeologous bacterial artificial chromosomes derived from high- to low-variable genomic regions. Comparisons of their sequence variations confirmed that the highly conserved and divergent sequences existed in the distal and pericentric regions, e.g., high- and low variable genome size regions in these two pairs of cotton homoeologous chromosomes. Sequence analysis also confirmed that the differential accumulation of Gossypium retrotransposable gypsy-like element (Gorge3) accounted for the main contributions for the size difference between the pericentric regions. By fluorescence in situ hybridization analysis, we found that Gorge3 has a bias distribution in the A(T)/A proximal regions and is associated with the heterochromatin along the chromosomes in the entire Gossypium genome. These results indicate that, between A(T)/A and D(T)/D genomes, the distal and pericentric regions usually possess high level of sequence conservation and divergence, respectively, in cotton. PMID- 22212345 TI - Trace elements present in airborne particulate matter--stressors of plant metabolism. AB - Changes of amino acid concentrations (glutamic acid, glutamine, asparagine, aspartate, proline, tryptophan, alanine, glycine, valine and serine), gas exchange parameters (net photosynthetic rate, transpiration rate, stomatal conductance and intercellular CO(2) concentration) and nitrate levels in Lactuca serriola L. under airborne particulate matter (PM) contamination reported here reveal their role in plant chronic stress adaptation. Results of the pot experiment confirmed the toxic effect of trace elements present in PM for lettuce. PM applied to soil or on the lettuce leaves were associated with the strong inhibition of above-ground biomass and with the enhancement of plant trace element contents. The significant changes of amino acid levels and leaf gas exchange parameters of the plants showed strong linear dependences on PM contamination (R(2)=0.60-0.99). PM application on leaves intensified toxic effect of trace elements (As, Pb, Cr and Cd) originating from PM by shading of the leaf surface. The plant accumulation of nitrate nitrogen after PM contamination confirmed to block nitrate assimilation. PMID- 22212346 TI - Pharmacokinetics and safety of Intragam 10 NF, the next generation 10% liquid intravenous immunoglobulin, in patients with primary antibody deficiencies. AB - BACKGROUND AND AIMS: Intragam(r) 10 NF is the next generation 10% intravenous immunoglobulin with three pathogen reduction steps and a noncarbohydrate stabiliser. This open label, cross-over study in patients with primary immunodeficiency was designed to evaluate whether Intragam 10 NF differed in its pharmacokinetics (PK) compared with Intragam P and to assess Intragam 10 NF safety and tolerability. METHODS: Nineteen primary immunodeficiency patients were administered one cycle of their existing Intragam P dose (0.2-0.8 g/kg 3-4 weekly), followed by seven cycles of Intragam 10 NF administered at the same dosing schedule as Intragam P. The primary objective was to compare serum immunoglobulin G (IgG) trough levels. Secondary endpoints were PK variables, safety and tolerability. RESULTS: There was no significant within-patient difference in the average trough immunoglobulin G concentration between Intragam P and Intragam 10 NF (8.76 g/L, 8.55 g/L respectively) (geometrical mean ratio 1.034; 95% confidence interval 0.996-1.073; P = 0.079). Mean PK parameters for both products were similar, with all 95% confidence interval encompassing 1.0 except for time to maximum concentration. Time to maximum concentration occurred earlier with Intragam 10 NF compared with Intragam P, with a shorter infusion time (mean 1.75 h vs 2.52 h respectively; P < 0.05). Headache was the most frequent treatment-related event following both products. There were no study withdrawals, deaths, or notable changes in laboratory values or vital signs. CONCLUSION: Intragam 10 NF was well tolerated and exhibited similar PK to Intragam P, with the advantage of a 45 min shorter infusion time. PMID- 22212347 TI - Phoma medicaginis stimulates the induction of the octadecanoid and phenylpropanoid pathways in Medicago truncatula. AB - Gene expression changes and metabolite abundances were measured during the interaction of Medicago truncatula with the fungal necrotrophic pathogen Phoma medicaginis in leaf tissue of susceptible and resistant accessions. Over 330 genes were differentially expressed in plants infected with P. medicaginis relative to mock-inoculated plants at 12 h post-inoculation. Of these, 191 were induced in either the resistant or the susceptible accession, with 143 genes repressed. Expression changes were observed in genes involved in the oxidative burst, cell wall strengthening and lipid metabolism, as well as several transcription factors. Genes related to salicylic acid, jasmonate and ethylene responses were up-regulated, as well as genes leading to the production of jasmonic acid. Significant induction of genes in the phenylpropanoid pathway leading to lignin and isoflavonoid biosynthesis occurred. High-pressure liquid chromatography with UV detection (HPLC-UV) identified several phenolic compounds induced by P. medicaginis, as well as constitutively higher levels of phenolic compounds, in the resistant M. truncatula accession. Differentially regulated genes induced in both the resistant and susceptible accessions, but with different kinetics, and constitutively more highly expressed and induced phenolic compounds provide candidates for functional analysis. Taken together, these results highlight the importance of the octadecanoid and phenylpropanoid pathways in defence against this necrotrophic pathogen. PMID- 22212348 TI - Escherichia coli-induced epithelial hyporesponsiveness to secretagogues is associated with altered CFTR localization. AB - Both pathogenic and commensal strains of Escherichia coli colonize the human intestinal tract. Pathogenic strains differ only in the expression of virulence factors, many of which comprise a type III secretion system (TTSS). Little is known regarding the effect of E. coli on the intestinal epithelial response to the secretagogues that drive ion secretion, despite its importance in causing clinically significant diarrhoea. Using Ussing chambers to measure electrogenic ion transport of T84 intestinal epithelial cell monolayers, we found that all strains of E. coli tested (pathogenic, commensal, probiotic and lab strain) significantly reduced cAMP-dependent ion secretion after 4-8 h exposure. Enteropathogenic E. coli mutants lacking a functional TTSS caused similar hyposecretion while not causing significant apoptosis (as shown by caspase-3 cleavage) or necrosis (lactate dehydrogenase release), as did the commensal strain F18, indicating that epithelial cell death was not the cause of hyposecretion. Enteropathogenic E. coli and the TTSS mutant significantly reduced cell surface expression of the apical anion channel, cystic fibrosis transmembrane conductance regulator, which is likely the mechanism behind the pathogen-induced hyposecretion. However, F18 did not cause cystic fibrosis transmembrane conductance regulator mislocalization and the commensal-induced mechanism remains unclear. PMID- 22212349 TI - Customized design of electronic noses placed on top of air-lift bioreactors for in situ monitoring the off-gas patterns. AB - A specially designed electronic nose was coupled to an air-lift bioreactor in order to perform on-line monitoring of released vapors. The sensor array was placed at the top of the bioreactor sensing the headspace in equilibrium with the evolving liquor at any time without the need of aspiration and pumping of gases into a separated sensor chamber. The device was applied to follow the off-gas of a bioreactor with Acidithiobacillus thiooxidans grown on beds of elemental sulfur under aerobic conditions. Evolution was monitored by acid titration, pH and optical density measurements. The electronic nose was capable to differentiate each day of reactor evolution since inoculation within periods marked off culture medium replacements using multivariate data analysis. Excellent discrimination was obtained indicating the potentiality for on-line monitoring in non-perturbed bioreactors. The prospects for electronic nose/bioreactor merging are valuable for whatever the bacterial strain or consortium used in terms of scent markers to monitor biochemical processes. PMID- 22212350 TI - Peripheral painful traumatic trigeminal neuropathies. AB - The aim of this article is to review the clinical, pathophysiological, and therapeutic aspects of traumatically induced trigeminal nerve pain. We introduce a new and, in our view, more accurate terminology: peripheral painful traumatic trigeminal neuropathy (PPTTN) to define this patient group. The proposed pathophysiology of PPTTN is largely based on studies in spinal nerve injury models. However, trigeminal nerve injury studies have shown some subtle differences in response to physical and inflammatory insults, and these are discussed. The treatment of painful neuropathies is difficult and carries a poor prognosis. Based on the available literature on efficacy and side effects, we propose a treatment algorithm for traumatic trigeminal neuropathies. PMID- 22212351 TI - Mean-field Boolean network model of a signal transduction network. AB - In this paper we provide a mean-field Boolean network model for a signal transduction network of a generic fibroblast cell. The network consists of several main signaling pathways, including the receptor tyrosine kinase, the G protein coupled receptor, and the Integrin signaling pathway. The network consists of 130 nodes, each representing a signaling molecule (mainly proteins). Nodes are governed by Boolean dynamics including canalizing functions as well as totalistic Boolean functions that depend only on the overall fraction of active nodes. We categorize the Boolean functions into several different classes. Using a mean-field approach we generate a mathematical formula for the probability of a node becoming active at any time step. The model is shown to be a good match for the actual network. This is done by iterating both the actual network and the model and comparing the results numerically. Using the Boolean model it is shown that the system is stable under a variety of parameter combinations. It is also shown that this model is suitable for assessing the dynamics of the network under protein mutations. Analytical results support the numerical observations that in the long-run at most half of the nodes of the network are active. PMID- 22212352 TI - ConvAn: a convergence analyzing tool for optimization of biochemical networks. AB - Dynamic models of biochemical networks usually are described as a system of nonlinear differential equations. In case of optimization of models for purpose of parameter estimation or design of new properties mainly numerical methods are used. That causes problems of optimization predictability as most of numerical optimization methods have stochastic properties and the convergence of the objective function to the global optimum is hardly predictable. Determination of suitable optimization method and necessary duration of optimization becomes critical in case of evaluation of high number of combinations of adjustable parameters or in case of large dynamic models. This task is complex due to variety of optimization methods, software tools and nonlinearity features of models in different parameter spaces. A software tool ConvAn is developed to analyze statistical properties of convergence dynamics for optimization runs with particular optimization method, model, software tool, set of optimization method parameters and number of adjustable parameters of the model. The convergence curves can be normalized automatically to enable comparison of different methods and models in the same scale. By the help of the biochemistry adapted graphical user interface of ConvAn it is possible to compare different optimization methods in terms of ability to find the global optima or values close to that as well as the necessary computational time to reach them. It is possible to estimate the optimization performance for different number of adjustable parameters. The functionality of ConvAn enables statistical assessment of necessary optimization time depending on the necessary optimization accuracy. Optimization methods, which are not suitable for a particular optimization task, can be rejected if they have poor repeatability or convergence properties. The software ConvAn is freely available on www.biosystems.lv/convan. PMID- 22212353 TI - Potential role of store-operated Ca2+ entry in Th2 response induced by histamine in human monocyte-derived dendritic cells. AB - Store-operated calcium entry (SOCE) is the main Ca(2+) influx pathway of dendritic cells (DCs). DCs primed with histamine facilitate Th2 immune response via different types of histamine receptors. Histamine induces DCs to release Ca(2+) from internal store. Therefore, we wonder that whether histamine could activate SOCE in DCs through its receptors, and what's the functional relevance of the Ca(2+) influx through SOCE induced by histamine in Th(2) response. We certificate that histamine induced a transient Ca(2+) release followed by pronounced Ca(2+) influx after re-addition of external Ca(2+) which could be inhibited by SOCE blockers SKF-96365 and BTP-2. Moreover, the percentages of DCs that showed an obvious Ca(2+) release response to histamine were decreased in the presence of histamine 1 (H1) receptor antagonist pyridylethylamine (Pyr) or histamine 4 (H4) receptor antagonist JNJ7777120 (JNJ). Histamine up-regulated the mRNA expression of STIM1 in DCs, one of the two major proteins of SOCE channel. SOCE blocker BTP-2 and histamine receptor antagonists JNJ and Pyr inhibited the increase of CD86 induced by histamine on DCs. Histamine increased the level of IL 10 and decreased the level of IL-12p70 secreted by DCs. SOC blockers SKF and BTP 2 inhibited the level of both IL-10 and IL-12p70 secreted by DCs. Pretreatment of SOC blockers and H1, H4 receptor antagonists with DCs inhibited the Th2 polarization of T helper cells induced by histamine in mixed lymphocyte responses (MLR). We demonstrated that SOCE was involved in histamine-induced maturation and Th(2) response of DCs which was through histamine 1 and 4 receptor. PMID- 22212355 TI - Teaching science and ethics to undergraduates: a multidisciplinary approach. AB - The teaching of the ethical implications of scientific advances in science courses for undergraduates has significant advantages for both science and non science majors. The article describes three courses taught by the author as examples of the concept, and examines the disadvantages as well as the advantages. A significant advantage of this approach is that many students take the courses primarily because of the ethical component who would not otherwise take science. A disadvantage is less time in the course for the science; arguably, this is outweighed by the greater retention of the science when it is put into context. PMID- 22212354 TI - Calcium influx blocked by SK&F 96365 modulates the LPS plus IFN-gamma-induced inflammatory response in murine peritoneal macrophages. AB - A rise in intracellular Ca(2+) ([Ca(2+)](i)) is crucial for the activation of macrophages, however, the mechanisms and consequences of this [Ca(2+)](i) increase remain unclear. This study investigated the role of calcium in mouse peritoneal macrophages stimulated with LPS plus IFN-gamma by using the store operated Ca(2+) channel (SOCC) blocker SK&F 96365. Our results showed that SK&F 96365 pretreatment significantly inhibited the elevation of [Ca(2+)](i) induced by ionomycin, thapsigargin, and LPS plus IFN-gamma, respectively. Phagocytosis analyzing results showed that SK&F 96365 efficiently diminished the uptake of nonopsonized 1 MUM yellow-green beads or pHrodoTM-labeled Escherichia coli bacteria both on the resting and LPS plus IFN-gamma-stimulated macrophages. In addition, SK&F 96365 significantly inhibited the LPS plus IFN-gamma-induced brisk uptake of NO and ROS. The CBA analyzing results showed that SK&F 96365 pretreatment efficiently inhibited the production of LPS plus IFN-gamma-induced inflammatory cytokines of IL-6, MCP-1, TNF, INF-gamma, and IL-10. However, SK&F 96365 pretreatment did not inhibit but augment the production of LPS plus IFN gamma-induced IL-1beta secretion. Furthermore, SK&F 96365 pretreatment inhibited the LPS plus IFN-gamma-induced translocation of NF-kappaB to the nucleus, and induced a decrease in mitochondrial membrane potential (DeltaPsim) in LPS plus IFN-gamma-activated macrophages. This study provides insight into the role of calcium in the activation of peritoneal macrophages induced by LPS plus IFN gamma, and blocking the calcium influx by SK&F 96365 exhibited a domain inhibitory effect on the LPS plus IFN-gamma-induced inflammatory response in macrophages. PMID- 22212356 TI - Text-based plagiarism in scientific writing: what Chinese supervisors think about copying and how to reduce it in students' writing. AB - Text-based plagiarism, or textual copying, typically in the form of replicating or patchwriting sentences in a row from sources, seems to be an issue of growing concern among scientific journal editors. Editors have emphasized that senior authors (typically supervisors of science students) should take the responsibility for educating novices against text-based plagiarism. To address a research gap in the literature as to how scientist supervisors perceive the issue of textual copying and what they do in educating their students, this paper reports an interview study with 14 supervisors at a research-oriented Chinese university. The study throws light on the potentiality of senior authors mentoring novices in English as an Additional Language (EAL) contexts and has implications for the efforts that can be made in the wider scientific community to support scientists in writing against text-based plagiarism. PMID- 22212357 TI - Designing robots for care: care centered value-sensitive design. AB - The prospective robots in healthcare intended to be included within the conclave of the nurse-patient relationship--what I refer to as care robots--require rigorous ethical reflection to ensure their design and introduction do not impede the promotion of values and the dignity of patients at such a vulnerable and sensitive time in their lives. The ethical evaluation of care robots requires insight into the values at stake in the healthcare tradition. What's more, given the stage of their development and lack of standards provided by the International Organization for Standardization to guide their development, ethics ought to be included into the design process of such robots. The manner in which this may be accomplished, as presented here, uses the blueprint of the Value sensitive design approach as a means for creating a framework tailored to care contexts. Using care values as the foundational values to be integrated into a technology and using the elements in care, from the care ethics perspective, as the normative criteria, the resulting approach may be referred to as care centered value-sensitive design. The framework proposed here allows for the ethical evaluation of care robots both retrospectively and prospectively. By evaluating care robots in this way, we may ultimately ask what kind of care we, as a society, want to provide in the future. PMID- 22212359 TI - Comparison of engagement with ethics between an engineering and a business program. AB - Increasing university students' engagement with ethics is becoming a prominent call to action for higher education institutions, particularly professional schools like business and engineering. This paper provides an examination of student attitudes regarding ethics and their perceptions of ethics coverage in the curriculum at one institution. A particular focus is the comparison between results in the business college, which has incorporated ethics in the curriculum and has been involved in ethics education for a longer period, with the engineering college, which is in the nascent stages of developing ethics education in its courses. Results show that student attitudes and perceptions are related to the curriculum. In addition, results indicate that it might be useful for engineering faculty to use business faculty as resources in the development of their ethics curricula. PMID- 22212358 TI - Patenting and the gender gap: should women be encouraged to patent more? AB - The commercialization of academic science has come to be understood as economically desirable for institutions, individual researchers, and the public. Not surprisingly, commercial activity, particularly that which results from patenting, appears to be producing changes in the standards used to evaluate scientists' performance and contributions. In this context, concerns about a gender gap in patenting activity have arisen and some have argued for the need to encourage women to seek more patents. They believe that because academic advancement is mainly dependent on productivity (Stuart and Ding in American Journal of Sociology 112:97-144, 2006; Azoulay et al. in Journal of Economic Behavior & Organization 63:599-623, 2007), differences in research output have the power to negatively impact women's careers. Moreover, in the case of patenting activity, they claim that the gender gap also has the potential to negatively affect society. This is so because scientific and technological advancement and innovation play a crucial role in contemporary societies. Thus, women's more limited involvement in the commercialization of science and technology can also be detrimental to innovation itself. Nevertheless, calls to encourage women to patent on grounds that such activity is likely to play a significant role in the betterment of both women's careers and society seem to be based on two problematic assumptions: (1) that the methods to determine women's productivity in patenting activities are an appropriate way to measure their research efforts and the impact of their work, and (2) that patenting, particularly in academia, benefits society. The purpose of this paper is to call into question these two assumptions. PMID- 22212360 TI - The effectiveness of ethics education: a quasi-experimental field study. AB - Ethical conduct is the hallmark of excellence in engineering and scientific research, design, and practice. While undergraduate and graduate programs in these areas routinely emphasize ethical conduct, few receive formal ethics training as part of their curricula. The first purpose of this research study was to assess the relative effectiveness of ethics education in enhancing individuals' general knowledge of the responsible conduct of research practices and their level of moral reasoning. Secondly, we examined the effects of ethics education on the positive psychological outcomes of perspective-taking, moral efficacy, moral courage, and moral meaningfulness. To examine our research hypotheses, we utilized a pretest-posttest quasi-experimental design consisting of three ethics education groups (control, embedded modules, and stand-alone courses). Findings revealed that both embedded and stand alone courses were effective in enhancing participants' perspective-taking, moral efficacy, and moral courage. Moral meaningfulness was marginally enhanced for the embedded module condition. Moral judgment and knowledge of responsible conduct of research practices were not influenced by either ethics education condition. Contrary to expectations, stand alone courses were not superior to embedded modules in influencing the positive psychological outcomes investigated. Implications of these findings for future research and practice are discussed. PMID- 22212361 TI - Reverse-mode NCX current in mouse airway smooth muscle: Na(+) and voltage dependence, contributions to Ca(2+) influx and contraction, and altered expression in a model of allergen-induced hyperresponsiveness. AB - AIM: We examined the electrophysiological properties of reverse-mode Na(+) /Ca(2+) exchange (NCX) in mouse airway smooth muscle (ASM), assessing its contributions to regulation of [Ca(2+) ], and its expression in acute and chronic airway hyperresponsiveness (AHR). METHODS: Membrane currents were studied in single murine ASM cells under voltage clamp at -60 mV using ramp depolarizing commands to +80 mV. Confocal fluorimetric and RT-PCR techniques were used to monitor changes in cytosolic [Ca(2+) ] and NCX expression, respectively. RESULTS: With standard KCl-containing electrode, 30 MUm KB-R7943 (an inhibitor of reverse mode NCX activity) exhibited variable effects on membrane current, indicating modulation of more than one conductance. KB-R7943 activated outwardly rectifying current that was inhibited by 100 MUm iberiotoxin (blocker of large-conductance Ca(2+) -dependent K(+) channels), indicating a direct enhancing effect of KB R7943 on those K(+) channels. After obviating K(+) currents, we found that a current sensitive to 4-4'-diisothiocyanostilbene-2,2'-disulfonic acid (blocker of Ca(2+) -dependent Cl- channels) was markedly increased by elevating [Na(+) ] in the electrode solution to 13, 15.5 and 18 mm and suppressed by KB-R7943, indicating Ca(2+) influx via reverse-mode NCX activity. With conditions preventing Ca(2+) influx through voltage-dependent Ca(2+) channels but promoting that through NCX, we found that introduction of Ca(2+) led to marked but transient KB-R7943-sensitive elevation of [Ca(2+) ]. Additionally, KB-R7943 suppressed cholinergically evoked Ca(2+) waves. Finally, NCX1 expression was not significantly changed in allergen-induced AHR acute model but increased approx. 2.5-fold in a chronic model. CONCLUSION: Reverse-mode NCX activity leads to a physiologically relevant increase in [Ca(2+) ] even under control conditions, and this may be exaggerated in allergen-induced AHR and asthma. PMID- 22212363 TI - A robust method for testing association in genome-wide association studies. AB - In genetic association studies, due to the varying underlying genetic models, no single statistical test can be the most powerful test under all situations. Current studies show that if the underlying genetic models are known, trend-based tests, which outperform the classical Pearson chi2 test, can be constructed. However, when the underlying genetic models are unknown, the chi2 test is usually more robust than trend-based tests. In this paper, we propose a new association test based on a generalized genetic model, namely the generalized order restricted relative risks model. Through a Monte Carlo simulation study, we show that the proposed association test is generally more powerful than the chi2 test, and more robust than those trend-based tests. The proposed methodologies are also illustrated by some real SNP datasets. PMID- 22212362 TI - Podoplanin-expressing inflammatory macrophages activate murine platelets via CLEC 2. PMID- 22212364 TI - Rosuvastatin preserves renal structure following unilateral ureteric obstruction in the neonatal rat. AB - BACKGROUND/AIMS: Unilateral ureteric obstruction (UUO) in neonatal rodents can be used as a paradigm for in utero obstruction in humans and a platform for studying the potential of novel therapies for congenital obstructive nephropathy. The present study examined the effect of rosuvastatin (Ros) on key morphometric measures of renal injury and corresponding gene expression correlates following neonatal UUO in the rat. METHODS: Neonatal rats subjected to UUO and controls were treated daily with vehicle or Ros for 14 days. Quantification of tubular dilatation, glomerular size and number and tubulointerstitial fibrotic area was performed and changes validated by reference to appropriate renal gene expression correlates. RESULTS: UUO increased tubular diameter and interstitial fibrosis by 2.7- and 7-fold, respectively, in parallel with increases in renal transforming growth factor-beta(1) (TGF-beta(1)) and tumor necrosis factor-alpha (TNF-alpha) mRNA levels. Glomerular number and size were reduced by 52 and 33%, respectively. Reductions in WT-1 mRNA and protein expression were noted following obstruction occurring in tandem with reduced mRNA levels for BMP-7 and E-cadherin. Ros attenuated tubular dilatation (33%) and interstitial fibrosis (72%) in association with the normalization of renal TGF-beta(1) and TNF-alpha mRNA levels. Ros improved glomerular number and size (30 and 50%), and preserved mRNA and protein expression levels of WT-1 and normalized mRNA levels for BMP-7 and E cadherin. CONCLUSIONS: Ros treatment attenuated all changes, most notably the increase in interstitial fibrosis. Notably, Ros treatment was unable to completely salvage glomerular development. Together these data highlight the therapeutic potential and limitations of Ros in neonatal obstruction. PMID- 22212365 TI - Realist thoughts on Cinderella, Alice in Wonderland and health care interventions. PMID- 22212366 TI - A critical realist approach to knowledge: implications for evidence-based practice in and beyond nursing. AB - This paper will identify some of the key conceptual tools of a critical realist approach to knowledge. I will then apply these principles to some of the competing epistemologies that are prevalent within nursing. There are broadly two approaches which are sometimes distinct from each other and sometimes inter related. On one side, there is the view that all healthcare interventions should be judged on the principles of randomised controlled trials and the other is a preoccupation with language in which healthcare interventions are subjected to a discursive interrogation. These debates are configured through the idea of a hierarchy of knowledge that is accorded uncritical acceptance by some and virulent distaste by others. I will argue that the notion of hierarchy is problematic and is largely argued for in unproductive epistemological terms. What is required is a shift towards a theory that emphasises the contextual nature of the ways that knowledge is produced and disseminated. In other words, there is no single hierarchy of knowledge, but there are multiple hierarchies of knowledge. PMID- 22212367 TI - The use and limitation of realistic evaluation as a tool for evidence-based practice: a critical realist perspective. AB - The use and limitation of realistic evaluation as a tool for evidence-based practice: a critical realist perspective In this paper, we assess realistic evaluation's articulation with evidence-based practice (EBP) from the perspective of critical realism. We argue that the adoption by realistic evaluation of a realist causal ontology means that it is better placed to explain complex healthcare interventions than the traditional method used by EBP, the randomized controlled trial (RCT). However, we do not conclude from this that the use of RCTs is without merit, arguing that it is possible to use both methods in combination under the rubric of realist theory. More negatively, we contend that the rejection of critical theory and utopianism by realistic evaluation in favour of the pragmatism of piecemeal social engineering means that it is vulnerable to accusations that it promotes technocratic interpretations of human problems. We conclude that, insofar as realistic evaluation adheres to the ontology of critical realism, it provides a sound contribution to EBP, but insofar as it rejects the critical turn of Bhaskar's realism, it replicates the technocratic tendencies inherent in EBP. PMID- 22212368 TI - Understanding health decisions using critical realism: home-dialysis decision making during chronic kidney disease. AB - Understanding health decisions using critical realism: home-dialysis decision making during chronic kidney disease This paper examines home-dialysis decision making in people with Chronic Kidney Disease (CKD) from the perspective of critical realism. CKD programmes focus on patient education for self-management to delay the progression of kidney disease and the preparation and support for renal replacement therapy e.g.) dialysis and transplantation. Home-dialysis has clear health, societal and economic benefits yet service usage is low despite efforts to realign resources and educate individuals. Current research on the determinants of modality selection is superficial and insufficient to capture the complexities embedded in the process of dialysis modality selection. Predictors of home-dialysis selection and the effect of chronic kidney disease educational programmes provide a limited explanation of this experience. A re conceptualization of the problem is required in order to fully understand this process. The epistemology and ontology of critical realism guides our knowledge and methodology particularly suited for examination of these complexities. This approach examines the deeper mechanisms and wider determinants associated with modality decision making, specifically who chooses home dialysis and under what circumstances. Until more is known regarding dialysis modality decision making service usage of home dialysis will remain low as interventions will be based on inadequate epistemology. PMID- 22212369 TI - Understanding the recruitment and retention of overseas nurses: realist case study research in National Health Service Hospitals in the UK. AB - This paper illustrates one of the possible applications of critical realist ideas to the analysis of health services, in the use of comparative case study research design, to elucidate the causal social processes underlying events. In the research reported here, a comparative research design was used as a basis for improving our understanding of the processes involved in the assimilation of overseas nurses (OSN) into the salient long-term workforce of the National Health Service (NHS) hospitals in the UK. The work brought to light the salient experiences of overseas nurses during their initial work in the NHS hospitals, and these were used as a basis for developing an account of the general mechanisms typically underlying the recruitment and assimilation at work. The authors conclude that successful assimilation is often hindered by the presence of occupational closure mechanisms, by which home nurses effectively excluded recruits from participation and promotion; these mechanisms, which articulate with everyday racism, threaten successful assimilation for obvious reasons. If the treatment recruits receive does not lead to withdrawal, it is because they typically have very strong economic motives to continue despite unfavourable and sometimes inhumane treatment. Thus, the research offered substantial reasons why recruitment policies should be reviewed by policy-makers. PMID- 22212370 TI - The complexity of postpartum mental health and illness: a critical realist study. AB - The complexity of postpartum mental health and illness: a critical realist study Postpartum depression (PPD) is a major public health issue that profoundly impacts the woman, her infant and family. Although it may be linked to hormone changes, no direct hormonal aetiology has been established. A large body of evidence implicates numerous psychosocial predictors of PPD. While a history of depression predicts about 50% of cases of PPD, it remains unclear why some women with a history do not develop depression following childbirth, even taking psychosocial factors into account. The aim of this study was to identify the main mechanisms and factors associated with the presence or absence of PPD in women with a history of depression, and the presence of PPD in women without a history, using a critical realist approach. The findings indicate a number of personal and contextual factors that influence postpartum mental health and illness. In addition, and perhaps most importantly, women who did not develop depression identified goal-oriented actions that were protective. These factors and processes did not exist in isolation and the interplay among them in influencing health was apparent. More research is needed to explore the effects of these mechanisms in different contexts. PMID- 22212371 TI - Positioning positivism, critical realism and social constructionism in the health sciences: a philosophical orientation. AB - Positioning positivism, critical realism and social constructionism in the health sciences: a philosophical orientation This article starts by considering the differences within the positivist tradition and then it moves on to compare two of the most prominent schools of postpositivism, namely critical realism and social constructionism. Critical realists hold, with positivism, that knowledge should be positively applied, but reject the positivist method for doing this, arguing that causal explanations have to be based not on empirical regularities but on references to unobservable structures. Social constructionists take a different approach to postpositivism and endorse a relativist rejection of truth and hold that the task of research is to foster a scepticism that undermines any positive truth claim made. It is argued that social constructionism is a contradictory position. PMID- 22212372 TI - Back- and fore-grounding ontology: exploring the linkages between critical realism, pragmatism, and methodologies in health & rehabilitation sciences. AB - Back- and fore-grounding ontology: exploring the linkages between critical realism, pragmatism, and methodologies in health & rehabilitation sciences As two doctoral candidates in a health and rehabilitation sciences program, we describe in this paper our respective paradigmatic locations along a quite nonlinear ontological-epistemological-axiological-methodological chain. In a turn-taking fashion, we unpack the tenets of critical realism and pragmatism, and then trace the linkages from these paradigmatic locations through to the methodological choices that address a community-based research problem. Beyond serving as an answer to calls for academics in training to demonstrate philosophical theoretical-methodological integrity and coherence in their scholarship, this paper represents critical realism and its fore-grounding of a deeply stratified ontology in reflexive relation to pragmatism and its back-grounding of ontology. We conclude by considering the merits and challenges of conducting research from within singular versus proliferate paradigmatic perspectives. PMID- 22212374 TI - Predator-prey coevolution driven by size selective predation can cause anti synchronized and cryptic population dynamics. AB - Population dynamics and evolutionary dynamics can occur on similar time scales, and a coupling of these two processes can lead to novel population dynamics. Recent theoretical studies of coevolving predator-prey systems have concentrated more on the stability of such systems than on the characteristics of cycles when they are unstable. Here I explore the characteristics of the cycles that arise due to coevolution in a system in which prey can increase their ability to escape from predators by becoming either significantly larger or significantly smaller in trait value (i.e., a bidirectional trait axis). This is a reasonable model of body size evolution in some systems. The results show that antiphase population cycles and cryptic cycles (large population fluctuation in one species but almost no change in another species) can occur in the coevolutionary system but not systems where only a single species evolves. Previously, those dynamical patterns have only been theoretically shown to occur in single species evolutionary models and the coevolutionary model which do not involve a bi-directional axis of adaptation. These unusual dynamics may be observed in predator-prey interactions when the density dependence in the prey species is strong. PMID- 22212375 TI - Development of a 44K SNP assay focussing on the analysis of a varroa-specific defence behaviour in honey bees (Apis mellifera carnica). AB - Honey bees are exposed to a number of damaging pathogens and parasites. The most destructive among them, affecting mainly the brood, is Varroa destructor. A promising approach to prevent its spread is to breed for Varroa-tolerant honey bees. A trait that has been shown to provide significant resistance against the Varroa mite is hygienic behaviour, a behavioural response of honey bee workers to brood diseases in general. This study reports the development of a 44K SNP assay, specifically designed for the analysis of hygienic behaviour of individual worker bees (Apis mellifera carnica) directed against V. destructor. Initially, 70,000 SNPs chosen from a large set of SNPs published by the Honey Bee Genome Project were validated for their suitability in the analysis of the Varroa resistance trait 'uncapping of Varroa-infested brood'. This was achieved by genotyping of pooled DNA samples of trait bearers and two trait-negative controls using next generation sequencing. Approximately 36,000 of these validated SNPs and another 8000 SNPs not validated in this study were selected for the construction of a SNP assay. This assay will be employed in following experiments to analyse individualized DNA samples in order to identify quantitative trait loci (QTL) involved in the control of the investigated trait and to evaluate and possibly confirm QTL found in other studies. However, this assay is not just suitable to study Varroa tolerance, it is as well applicable to analyse any other trait in honey bees. In addition, because of its high density, this assay provides access into genomic selection with respect to several traits considered in honey bee breeding. It will become publicly available via AROS Applied Biotechnology AS, Aarhus, Denmark, before the end of the year 2011. PMID- 22212376 TI - Elder mistreatment in a rural area in Egypt. AB - AIM: Mistreatment of the elderly is a hidden problem frequently cloaked under the shroud of family secrecy. The aim of the present study was to determine the extent of mistreatment of older people living at their homes in the rural area of Mansoura city, Dakahlia governorate, Egypt. METHODS: The present cross-sectional study was carried out on 1106 respondents, 518 men (mean age 67.6 +/- 6.3 years) and 588 women (mean age 68.5 +/- 8.4 years), who answered face-to-face survey questionnaires. The questionnaires used were; Questionnaire to elicit elder abuse, Actual abuse tool, Elder Assessment Instrument, Risk of abuse tool, Katz index and Geriatric depression scale 15 items. RESULTS: Of the respondents, 43.7% reported mistreatment by family members. The predominant type of reported mistreatment was neglect (42.4%) followed by physical abuse (5.7%), psychological abuse (5.1%) and financial abuse (3.8%). CONCLUSIONS: The independent risk factors for overall mistreatment of the elderly were older age, insufficient pension and caregiver other than spouse. Although being dependent, the number of children being three or less and caregiver other than spouse were significant independent attributes for "neglect" as a form of elder mistreatment. PMID- 22212377 TI - The effect of a 12-week course of omega-3 polyunsaturated fatty acids on lipid parameters in hypertriglyceridemic adult HIV-infected patients undergoing HAART: a randomized, placebo-controlled pilot trial. AB - BACKGROUND: Hypertriglyceridemia is common in patients with HIV treated with highly active antiretroviral therapy (HAART). OBJECTIVE: The goal of this study was to investigate the effect of the polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA) 460 mg/eicosapentaenoic acid (EPA) 380 mg on hypertriglyceridemia in HIV-treated patients. METHODS: A double-blind, placebo controlled, randomized, multicenter pilot study was undertaken in 48 evaluable HIV-infected patients undergoing HAART, with fasting triglyceride levels of 3.39 to 11.3 mmol/L. Patients were allowed fibrate or niacin but not statins and were randomized to PUFA 4 g daily versus placebo for 12 weeks. The primary end point was mean fasting triglyceride levels. RESULTS: The study included 48 patients; 23 in the PUFA group (mean age, 46.1 years) and 25 in the placebo group (mean age, 43.6 years). All except one were male. All patients in the PUFA group were white; in the placebo group, 20 were white, 4 Asian, and 1 black. The PUFA group had a mean body mass index of 24.7 kg/m(2); the placebo group, 24.1 kg/m(2). All patients were receiving concomitant fibrate therapy. Median baseline triglyceride levels were 5.58 (1.76-10.6) mmol/L for the PUFA group and 4.29 (1.81-6.14) mmol/L for the placebo group. PUFA reduced triglycerides by a median of 1.75 mmol/L versus a 0.41 mmol/L increase for the placebo group (baseline-corrected percentage change relative to placebo [95% CI, -69.48% to -6.53%; P = 0.019). No effect was seen on biochemical or virologic safety parameters. No severe treatment-emergent adverse events (TEAEs) occurred. Mild and moderate TEAEs occurred in 20 PUFA-treated patients versus 19 patients receiving placebo. Five were adjudged treatment related, and one was due to cholelithiasis, which led to early discontinuation. Most TEAEs affected the gastrointestinal tract (DHA/EPA, n = 7; placebo, n = 4) and comprised diarrhea, nausea, and flatulence (DHA/EPA vs placebo: 3, 2, and 2 vs 2, 0, and 0, respectively). CONCLUSIONS: PUFA therapy with DHA/EPA reduced triglyceride levels significantly compared with placebo in HIV-infected patients with HAART-associated hypertriglyceridemia. PMID- 22212379 TI - Evaluation of the behaviour of fluorine-containing bioactive glasses: reactivity in a simulated body fluid solution assisted by multivariate data analysis. AB - Potentially bioactive fluorine-containing glasses of formula 46.2SiO(2).24.3Na(2)O.(26.9-x)CaO.2.6P(2)O(5).xCaF(2) [x = (0), 5, 10, 15] have been studied: the study was carried out as a function of fluorine percentage, dimensions and time of soaking in SBF. The results are compared to those obtained in the same conditions for Bioglass((r)) 45S5. Due to the high number and different kind of variables/conditions explored by this set of data, the results are rationalized for the first time by means of multivariate data analysis (MDA); in this way it is possible to classify the behaviour of bioglasses toward bioactivity. The presence of fluorine does not inhibit the formation of HA; in particular, for a fast bioactivity (in term of HA crystallization) it will be better to have large particle size or slabs, while for a fast dissolution fine particle sizes should be preferred. PMID- 22212380 TI - Humour in health-care interactions: a risk worth taking. AB - BACKGROUND: Humour is a complex, dynamic phenomenon that mainly occurs in social situations between two or more people. Most humour research reviews rehearsed as opposed to spontaneous humour and rarely review the patients' perspective. AIM: We explore patients' perspectives on the use of humour in health care. We discuss the asymmetrical and divergent humour use between patients and clinical nurse specialists and posit nurses' approaches to risk as a contributing factor. DESIGN: A constructivist grounded theory collated researcher-provoked (interviews, observation, field notes, pre-and post-interaction audio diaries) and non-researcher-provoked data (naturally occurring interactions) over 18 months. This paper is based upon four patient focus groups. A constant comparison approach to data collection and analyses was applied using interpretative and illustrative frameworks that balanced what was 'known' and 'unknown' about humour. SETTING AND PARTICIPANTS: Patients were recruited from four patient-peer groups. Three audio-taped (n = 20) and one observed focus group interactions (n = 12) were undertaken at the groups' regular meeting places. RESULTS: Patients hold a broad appreciation of humour and recognize it as being evident in subtle and nuanced forms. Patients wish health-care staff to initiate and reciprocate humour. CONCLUSION: A chasm exists between what patients apparently want with regard to humour use in health-care interactions and what actually transpires. Initiating humour involves risk, and risk-taking requires a degree of self-esteem and confidence. Nurses are, arguably, risk-averse and have low self-esteem. Future research could review confidence and self-esteem markers with observed humour use in nurses and their interactions across a range of specialities. PMID- 22212382 TI - Inferior-based pharyngeal flap for correction of stress velopharyngeal incompetence in musicians: case reports and review of the literature. AB - Stress velopharyngeal incompetence (SVPI) is a special form of velopharyngeal incompetence observed in musicians who play wind and brass instruments. Due to high intraoral pressures generated while playing, the velopharyngeal structures fail to seal off the nasopharynx properly, resulting in unwanted nasal air leakage or noises. We present two young female professional clarinetists who experience symptoms of SVPI that preclude the development of their professional career. Both musicians underwent an inferior based pharyngeal flap, a well-known flap frequently used in cleft palate surgery. Both musicians were symptom-free after surgery and remain free of nasal noises while playing the clarinet after 2 and 4 years of follow-up. We present a review of literature of management of SVPI and show that the inferior-based pharyngeal flap is a feasible option for management of these potentially career ending symptoms. PMID- 22212381 TI - Innate immunity in multiple sclerosis white matter lesions: expression of natural cytotoxicity triggering receptor 1 (NCR1). AB - BACKGROUND: Pathogenic or regulatory effects of natural killer (NK) cells are implicated in many autoimmune diseases, but evidence in multiple sclerosis (MS) and its murine models remains equivocal. In an effort to illuminate this, we have here analysed expression of the prototypic NK cell marker, NCR1 (natural cytotoxicity triggering receptor; NKp46; CD335), an activating receptor expressed by virtually all NK cells and therefore considered a pan-marker for NK cells. The only definitive ligand of NCR1 is influenza haemagglutinin, though there are believed to be others. In this study, we investigated whether there were differences in NCR1+ cells in the peripheral blood of MS patients and whether NCR1+ cells are present in white matter lesions. RESULTS: We first investigated the expression of NCR1 on peripheral blood mononuclear cells and found no significant difference between healthy controls and MS patients. We then investigated mRNA levels in central nervous system (CNS) tissue from MS patients: NCR1 transcripts were increased more than 5 times in active disease lesions. However when we performed immunohistochemical staining of this tissue, few NCR1+ NK cells were identified. Rather, the major part of NCR1 expression was localised to astrocytes, and was considerably more pronounced in MS patients than controls. In order to further validate de novo expression of NCR1 in astrocytes, we used an in vitro staining of the human astrocytoma U251 cell line grown to model whether cell stress could be associated with expression of NCR1. We found up-regulation of NCR1 expression in U251 cells at both the mRNA and protein levels. CONCLUSIONS: The data presented here show very limited expression of NCR1+ NK cells in MS lesions, the majority of NCR1 expression being accounted for by expression on astrocytes. This is compatible with a role of this cell-type and NCR1 ligand/receptor interactions in the innate immune response in the CNS in MS patients. This is the first report of NCR1 expression on astrocytes in MS tissue: it will now be important to unravel the nature of cellular interactions and signalling mediated through innate receptor expression on astrocytes. PMID- 22212383 TI - Single-stage salvage hypospadias repair. PMID- 22212385 TI - Diabetes reduces statherin in human parotid: immunogold study and comparison with submandibular gland. AB - BACKGROUND AND OBJECTIVE: Alteration of salivary gland secretion is one of the consequences of diabetes. In a recent study on the submandibular gland of diabetic subjects, we found changed expression of statherin, a salivary protein of fundamental importance in preserving tooth integrity, whose reduction was related with the high incidence of oral diseases in patients with diabetes. The goal of this report is to extend the study to human parotid gland and to compare the effects of diabetes on statherin expression with those previously described in submandibular gland. MATERIALS AND METHODS: Fragments of parotid glands obtained from diabetic and non-diabetic patients were fixed, dehydrated, embedded in Epon Resin and processed for the immunogold histochemistry. The staining density was expressed as number of gold particles per MUm(2) and statistically evaluated. RESULTS AND CONCLUSIONS: In all samples, statherin reactivity was specifically localized in secretory granules of acinar cells. The statistical analysis showed that labelling density was significantly lower in diabetic than in non-diabetic parotid glands and that diabetes affects protein expression at identical extent in parotid and submandibular glands. The results strengthen the hypothesis that a reduced statherin secretion may be responsible for the higher incidence of oral disorders in diabetic subjects. PMID- 22212386 TI - Autophagy is a cell death mechanism in Toxoplasma gondii. AB - Nutrient sensing and the capacity to respond to starvation is tightly regulated as a means of cell survival. Among the features of the starvation response are induction of both translational repression and autophagy. Despite the fact that intracellular parasite like Toxoplasma gondii within a host cell predicted to be nutrient rich, they encode genes involved in both translational repression and autophagy. We therefore examined the consequence of starvation, a classic trigger of autophagy, on intracellular parasites. As expected, starvation results in the activation of the translational repression system as evidenced by elevation of phosphorylated TgIF2alpha (TgIF2alpha-P). Surprisingly, we also observe a rapid and selective fragmentation of the single parasite mitochondrion that leads irreversibly to parasite death. This profound effect was dependent primarily on the limitation of amino acids and involved signalling by the parasite TOR homologue. Notably, the effective blockade of mitochondrial fragmentation by the autophagy inhibitor 3-methyl adenine (3-MA) suggests an autophagic mechanism. In the absence of a documented apoptotic cascade in T. gondii, the data suggest that autophagy is the primary mechanism of programmed cell death in T. gondii and potentially other related parasites. PMID- 22212387 TI - Adenine phosphoribosyltransferase deficiency in children. AB - Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder characterized by 2,8-dihydroxyadenine (2,8-DHA) crystalluria that can cause nephrolithiasis and chronic kidney disease. The aim of our study was to assess the clinical presentation, diagnosis, and outcome of APRT deficiency in a large pediatric cohort. All pediatric cases of APRT deficiency confirmed at the same French reference laboratories between 1978 and 2010 were retrospectively reviewed. Twenty-one patients from 18 families were identified. The median age at diagnosis was 3 years. Diagnosis was made after one or more episodes of nephrolithiasis (17 patients), after urinary tract infection (1 patient), and by family screening (3 patients). The diagnosis was based on stone analysis and microscopic examination of urine and/or enzymatic determination of APRT on red blood cells. All children had null APRT enzyme activity in erythrocytes. APRT gene sequencing was performed on 18 patients, revealing six homozygous and 12 compound heterozygous mutations. At diagnosis, half of the patients had decreased kidney function, and two children presented with acute renal failure. Allopurinol treatment was given to all patients at a median dose of 9 mg/kg/day. After a median follow-up of 5 years, all patients showed stabilization or improvement of kidney function, normal growth and development, and six patients had recurrence of nephrolithiasis. Based on these results, we conclude that an excellent outcome can be achieved in children with APRT deficiency who receive the proper treatment. PMID- 22212388 TI - Systematic review and meta-analysis of the effects of high protein oral nutritional supplements. AB - Disease-related malnutrition is common, detrimentally affecting the patient and healthcare economy. Although use of high protein oral nutritional supplements (ONS) has been recommended to counteract the catabolic effects of disease and to facilitate recovery from illness, there is a lack of systematically obtained evidence to support these recommendations. This systematic review involving 36 randomised controlled trials (RCT) (n=3790) (mean age 74 years; 83% of trials in patients >65 years) and a series of meta-analyses of high protein ONS (>20% energy from protein) demonstrated a range of effects across settings and patient groups in favour of the high protein ONS group. These included reduced complications (odds ratio (OR) 0.68 (95%CI 0.55-0.83), p<0.001, 10 RCT, n=1830); reduced readmissions to hospital (OR 0.59 (95%CI 0.41-0.84), p=0.004, 2 RCT, n=546); improved grip strength (1.76 kg (95%CI 0.36-3.17), p<0.014, 4 RCT, n=219); increased intake of protein (p<0.001) and energy (p<0.001) with little reduction in normal food intake and improvements in weight (p<0.001). There was inadequate information to compare standard ONS (<20% energy from protein) with high protein ONS (>20% energy from protein). The systematic review and meta analysis provides evidence that high protein supplements produce clinical benefits, with economic implications. PMID- 22212389 TI - PKCalpha regulates vasopressin-induced aquaporin-2 trafficking in mouse kidney collecting duct cells in vitro via altering microtubule assembly. AB - AIM: Aquaporin-2 (AQP2) is a vasopressin-regulated water channel located in the collecting tubule and collecting duct cells of mammalian kidney. The aim of this study is to investigate whether PKCalpha plays a role in vasopressin-induced AQP2 trafficking in mouse inner medullary collecting duct 3 (mIMCD3) cells. METHODS: AQP2-mIMCD3 stable cell line was constructed by transfection of mouse inner medullary collecting duct 3 (mIMCD3) cells with AQP2-GFP construct. Then the cells were transfected with PKCalpha shRNA, PKCalpha A/25E, or PKCalpha scrambled shRNA. The expression levels of PKCalpha, AQP2, and phospho-S256-AQP2 were analyzed using Western blot. The interaction between AQP2 and PKCalpha was examined using immunoprecipitation. The distribution of AQP2 and microtubules was studied using immunocytochemistry. The AQP2 trafficking was examined using the biotinylation of surface membranes. RESULTS: Treatment of AQP2-mIMCD3 cells with 100 MUmol/L of 1-desamino-8-D-arginine vasopressin (DdAVP) for 30 min stimulated the translocation of AQP2 from the cytoplasm to plasma membrane through influencing the microtubule assembly. Upregulation of active PKCalpha by transfection with PKCalpha A/25E plasmids resulted in de-polymerization of alpha tubulin and redistributed AQP2 in the cytoplasm. Down-regulation of PKCalpha by PKCalpha shRNA partially inhibited DdAVP-stimulated AQP2 trafficking without altering alpha-tubulin distribution. Although 100 MUmol/L of DdAVP increased AQP2 phosphorylation at serine 256, down-regulation of PKCalpha by PKCalpha shRNA did not influence DdAVP-induced AQP2 phosphorylation, suggesting that AQP2 phosphorylation at serine 256 was independent of PKCalpha. Moreover, PKCalpha did not physically interact with AQP2 in the presence or absence of DdAVP. CONCLUSION: Our results suggested that PKCalpha regulates AQP2 trafficking induced by DdAVP via microtubule assembly. PMID- 22212393 TI - Effect of substrate concentration on dark fermentation hydrogen production using an anaerobic fluidized bed reactor. AB - The effect of substrate (glucose) concentration on the stability and yield of a continuous fermentative process that produces hydrogen was studied. Four anaerobic fluidized bed reactors (AFBRs) were operated with a hydraulic retention time (HRT) from 1 to 8 h and an influent glucose concentration from 2 to 25 g L( 1). The reactors were inoculated with thermally pre-treated anaerobic sludge and operated at a temperature of 30 degrees C with an influent pH around 5.5 and an effluent pH of about 3.5. The AFBRs with a HRT of 2 h and a feed strength of 2, 4, and 10 g L(-1) showed satisfactory H(2) production performance, but the reactor fed with 25 g L(-1) of glucose did not. The highest hydrogen yield value was obtained in the reactor with a glucose concentration of 2 g L(-1) when it was operated at a HRT of 2 h. The maximum hydrogen production rate value was achieved in the reactor with a HRT of 1 h and a feed strength of 10 g L(-1). The AFBRs operated with glucose concentrations of 2 and 4 g L(-1) produced greater amounts of acetic and butyric acids, while AFBRs with higher glucose concentrations produced a greater amount of solvents. PMID- 22212390 TI - Iron sucrose promotes endothelial injury and dysfunction and monocyte adhesion/infiltration. AB - BACKGROUND/AIMS: Intravenous (IV) iron preparations are widely used in the management of anemia in ESRD populations. Recent changes in reimbursement policy have dramatically increased the use of IV iron to lower the use of costly erythropoiesis-stimulating agents. These preparations are frequently administered with insufficient attention to the total body iron stores or presence of inflammation which is aggravated by excess iron. Endothelial injury and dysfunction are critical steps in atherosclerosis, thrombosis and cardiovascular disease. IV iron preparations raise plasma non-transferrin-bound iron which can promote oxidative stress, endothelial damage and dysfunction. We explored the effect of an IV iron preparation on endothelial cells, monocytes and isolated arteries. METHODS: Primary cultures of human aortic endothelial cells (HAEC) were treated with pharmacologically relevant concentrations of iron sucrose (10-100 MUg/ml) for 4-24 h. Endothelial cell morphology, viability, and monocyte adhesion were tested. Endothelial function was assessed by measuring the vasorelaxation response to acetylcholine in normal rat thoracic aorta rings preincubated with iron sucrose (200 MUg/ml). RESULTS: In contrast to the control HAEC which showed normal cobblestone appearance, cells treated with iron sucrose (50-100 MUg/ml) for 4 h showed loss of normal morphological characteristics, cellular fragmentation, shrinkage, detachment, monolayer disruption and nuclear condensation/fragmentation features signifying apoptosis. HAEC exposure to iron sucrose (10-100 MUg/ml) increased monocyte adhesion 5- to 25-fold. Incubation in media containing 200 MUg/ml iron sucrose for 3 h caused marked reduction in the acetylcholine-mediated relaxation in phenylephrine-precontracted rat aorta. CONCLUSION: Pharmacologically relevant concentration of iron sucrose results in endothelial injury and dysfunction and marked increase in monocyte adhesion. PMID- 22212391 TI - Bioactive electroconductive hydrogels: the effects of electropolymerization charge density on the storage stability of an enzyme-based biosensor. AB - Electrode-supported hydrogels were conferred with the biospecificity of enzymes during the process of electropolymerization to give rise to a class of bioactive, stimuli-responsive co-joined interpenetrating networks of inherently conductive polymers and highly hydrated hydrogels. Glucose responsive biotransducers were prepared by potentiostatic electropolymerization [750 mV vs. Ag/AgCl (3 M KCl)] of pyrrole at Poly(hydoxyethyl methacrylate)-based hydrogel-coated Pt micro electrodes (Phi = 100 MUm) from aqueous solutions of pyrrole and glucose oxidase (GOx; 0.4 M pyrrole, 1.0 mg/ml GOx) to 1.0 and 10.0 mC/cm2. Polypyrrole was them over-oxidized by cyclic voltammetry (0-1.2 V vs. Ag/AgCl, 40 cycles in PBKCl, pH = 7.0). Biotransducers were stored at 4 degrees C in PBKCl for up to 18 days. Amperometric dose-response at 0.4 V vs. Ag/AgCl followed by Lineweaver-Burk analysis produced enzyme kinetic parameters as a function of electropolymerization charge density and storage time. Apparent Michaelis constant (K (Mapp)) increased from 18.6-152.0 mM (1.0 mC/cm2) and from 2.7-6.1 mM (10.0 mC/cm2). Biotransducer sensitivity increased to 21.2 nA/mM after 18 days and to 12.8 pA/mM after 10 days for the 1.0 and 10.0 mC/cm2 membranes, respectively. Maximum current, I (max), also increased over time to 2.7 nA (1.0 mC/cm2) and to 170 pA (10.0 mC/cm2). Electropolymerization of polypyrrole is shown to be an effective means for imparting bioactivity to a hydrogel-coated microelectrode. GOx was shown to be stabilized and to increase activity over time within the electroconductive hydrogel. PMID- 22212394 TI - High pH solubilization and chromatography-based renaturation and purification of recombinant human granulocyte colony-stimulating factor from inclusion bodies. AB - Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is a very efficient therapeutic protein drug which has been widely used in human clinics to treat cancer patients suffering from chemotherapy-induced neutropenia. In this study, rhG-CSF was solubilized from inclusion bodies by using a high-pH solution containing low concentration of urea. It was found that solubilization of the rhG CSF inclusion bodies greatly depended on the buffer pH employed; alkalic pH significantly favored the solubilization. In addition, when small amount of urea was added to the solution at high pH, the solubilization was further enhanced. After solubilization, the rhG-CSF was renatured with simultaneous purification by using weak anion exchange, strong anion exchange, and hydrophobic interaction chromatography, separately. The results indicated that the rhG-CSF solubilized by the high-pH solution containing low concentration of urea had much higher mass recovery than the one solubilized by 8 M urea when using anyone of the three refolding methods employed in this work. In the case of weak anion exchange chromatography, the high pH solubilized rhG-CSF could get a mass recovery of 73%. The strategy of combining solubilization of inclusion bodies at high pH with refolding of protein using liquid chromatography may become a routine method for protein production from inclusion bodies. PMID- 22212395 TI - Two SET domain containing genes link epigenetic changes and aging in Caenorhabditis elegans. AB - Changes in epigenetic status and chromatin structure have been shown to associate with aging in many organisms. Here, we report an RNAi screen of putative histone methyltransferases and demethylases in wild-type Caenorhabditis elegans using reproduction inhibitor. We identified six genes that when inactivated by RNAi, consistently extend lifespan. Five of these genes do not require germline proliferation to affect lifespan. We further characterized two of these genes, the highly homologous SET domain containing genes, set-9 and set-26. They share redundant functions in maintaining normal lifespan, while exhibiting differential tissue expression patterns. Furthermore, we found that set-9 and set-26 partially act through the Forkhead box O (FOXO) transcription factor, DAF-16, to modulate lifespan. Interestingly, inactivation of somatic SET-26 alone results in a robust lifespan extension and alters the levels of histone H3 protein and the repressive histone marks, H3K9me3 and H3K27me3, in an age-dependent manner. We hypothesize that inactivation of SET-26 triggers compensation mechanisms to restore repressive chromatin structure and hence affects chromatin stability to promote longevity. PMID- 22212396 TI - Identification of differentially expressed genes in matched formalin-fixed paraffin-embedded primary and metastatic melanoma tumor pairs. PMID- 22212397 TI - Albuterol isomers modulate platelet-activating factor synthesis and receptor signaling in human bronchial smooth muscle cells. AB - BACKGROUND: Racemic albuterol is a 50:50 mixture of the (R)- and (S)-enantiomers of albuterol. Its clinical efficacy resides in the (R)-enantiomer (levalbuterol). Studies have shown that (S)-albuterol induces human bronchial smooth muscle cell (HBSMC) proliferation via a pathway linked to platelet-activating factor (PAF), but the underlying mechanism by which (S)-albuterol augments PAF effects is not clear. In this study, we compared effect of levalbuterol and (S)-albuterol on PAF receptor (PAFr)-mediated signaling and PAF metabolism by HBSMCs after incubation with the albuterol isomers. METHODS: PAF binding and inositol phosphate (IP(3)) release were studied on adherent cultured cells. PAFr protein expression was measured by Western blotting, PAF synthesis and catabolism were measured in membrane and cytosolic proteins of cells incubated with albuterol isomers. RESULTS: Compared to control conditions, (S)-albuterol increased PAF binding by 70% after 30 min of preincubation and by 150% after 24 h of preincubation. Levalbuterol had no effect on PAF binding under both conditions. (S)-albuterol also augmented PAF stimulation of IP(3) release, while levalbuterol and the racemic mixture had no effect. WEB 2170, a PAFr antagonist, inhibited the ability of (S)-albuterol to increase PAF binding or stimulate IP(3) release. (S) albuterol stimulated PAFr protein expression. With PAF metabolism, (S)-albuterol treatment augmented PAF synthesis, but significantly inhibited PAF catabolism. CONCLUSIONS: Our data suggest that one mechanism by which (S)-albuterol stimulates HBSMC proliferation involves upregulation of PAFr-mediated effects including increased PAF synthesis and decreased PAF catabolism. PMID- 22212399 TI - Pulmonary function vascular index predicts prognosis in idiopathic interstitial pneumonia. AB - BACKGROUND AND OBJECTIVE: Pulmonary hypertension (PH) is associated with increased mortality in fibrotic idiopathic interstitial pneumonia (IIP). We hypothesize that baseline K(CO) (diffusing capacity of carbon monoxide/alveolar volume) and 6-month decline in K(CO) reflect PH, thus predicting mortality in IIP. METHODS: All IIP referrals (2004-2007) were identified (n = 269). 192 had pulmonary function at 6 months. Fifty-two (27%) died during follow-up (median 22.5 months). Outcome was evaluated for early (1 year from 6-month pulmonary function) and overall mortality. A vascular index best predicting mortality was identified (using baseline and 6-month decline in K(CO) ) and evaluated against PH at echocardiography. RESULTS: Baseline and 6-month decline in K(CO) were associated with early and overall mortality. A positive vascular index (baseline K(CO) % <= 50% and/or >=15% decline in K(CO) at 6 months; n = 40) was strongly predictive of early and overall mortality. Neither a diagnosis of idiopathic pulmonary fibrosis nor PH predicted early death when incorporated into this model. In patients without baseline PH, with follow-up echocardiography (n = 60), a positive vascular index was associated with PH at follow-up. CONCLUSIONS: A vascular index comprised of baseline and 6-month decline in K(CO) strongly predicted increased mortality and development of PH on echocardiography. In, K(CO) may be an important marker for pulmonary vascular disease and its associated mortality. PMID- 22212400 TI - Safety of ESWL in elderly: evaluation of independent predictors and comorbidity on stone-free rate and complications. AB - AIM: Urinary stone disease affects people of all ages. With its satisfactory efficacy ranges in all age groups and lack of side-effects, extracorporeal shock wave lithotripsy (ESWL) has become the preferred treatment modality for uncomplicated renal and proximal calculi <= 20 mm. In the present study, we aimed to assess the safety and efficacy of the ESWL treatment in elderly patients. METHODS: A retrospective study was carried out on patients aged over 65 years who underwent shock wave lithotripsy at our Department from 2009 to 2011, with a Siemens Lithostar electromagnetic shockwave lithotripter. A total of 231 patients (157 males, 74 females) out of 1694 (13.6%) were studied. The patients were divided into two groups (group 1 = 65-70; group 2 >70). The effect of age and other possible predicting factors (sex, stone localization and stone size) were investigated. Concomitant diseases and related complications were also evaluated. RESULTS: An overall stone-free rate (SFR) of 82.2% was found. The influence of sex on SFR was non-significant. There was no significant difference when comparing SFR between the age groups. When patients were divided into those with renal and ureteral stones, the SFR were 94.4% and 67.6% (P < 0.01), respectively. The SFR of the stone size groups, <= 10 mm and > 10 mm were 80% and 84.4%, respectively. Comorbidity was present in 148 patients. Complications were noted in 56 of 231 patients. Of 56 patients, 43 had minor complications and 13 major complications. CONCLUSION: ESWL seems to be an effective first-line treatment choice for urinary stones in elderly patients with careful patient selection and personalized preparation. PMID- 22212401 TI - Expression changes of the neuregulin 1 isoforms in neuropathic pain model rats. AB - The neuregulin1 (Nrg1) gene that is expressed in the dorsal root ganglion (DRG) contains an EGF-like domain, which is known to be a direct ligand for ErbB3 and ErbB4. Multiple splice variants of the Nrg1 gene are broadly classified into 3 groups by structural features (type I, type II and type III) and their functions differ in various tissues. The Nrg1 gene has emerged as a key mediator of axon Schwann cell interactions and as a regulator of Schwann cell development. The Nrg1 gene is indicated as a promising growth factor for neuronal development. However, the function of the Nrg1 in pain has not been clarified. We therefore, examined the expression profiles of each type of the Nrg1 transcript in the bilateral L4/L5 DRGs using L5 spinal nerve ligation (SNL) model rats and complete Freund's adjuvant (CFA) model rats. Behavior tests have shown typical mechanical hyperalgesia in both the L5SNL model and the CFA model. In the L5SNL model, expression of the Nrg1 type I and type II were significantly increased in the L5 DRG. On the other hand, the expression of the Nrg1 type III was decreased in the L5 DRG. We demonstrated that the expression changes of the Nrg1 isoforms in the ipsilateral DRGs were preferentially related to the response to nerve injury. Our findings suggest that the aberrant expression may play an important role in nerve injury, regeneration and subsequent neuropathic pain on the L5SNL. PMID- 22212402 TI - The beta-lactam antibiotic, ceftriaxone, inhibits the development of opioid induced hyperalgesia in mice. AB - The glutamate transporter GLT-1 is primarily responsible for glutamate clearance in the spinal cord. beta-Lactam antibiotics have been shown to attenuate neuropathic pain behaviors by promoting GLT-1 expression and function in the CNS. The present study tested the hypothesis that ceftriaxone, a prototype beta-lactam antibiotic, can prevent the development of opioid-induced hyperalgesia (OIH) in mice. Repeated morphine administration produced mechanical allodynia and thermal hyperalgesia, signs of OIH, and reduced spinal GLT-1 expression in mice. Ceftriaxone (200mg/kg/d, i.p., for 7 d) inhibited OIH. Correlating with the behavioral effects, ceftriaxone reversed downregulation of GLT-1 expression that was induced by OIH. These results suggest that ceftriaxone inhibited the development of OIH by up-regulating spinal GLT-1 expression. PMID- 22212403 TI - In vivo monitoring of venous thrombosis in mice. AB - BACKGROUND: Venous thrombosis (VT) is an important cause of morbidity and mortality in clinical medicine. Animal models studying venous thrombosis are scarce and, in most cases, very crude and rely on sacrificing the animals to excise formed thrombi. Developing an in vivo murine model of venous thrombosis can be a powerful tool for studying venous thrombosis. OBJECTIVES: We sought to use a high-frequency ultrasound system (HFUS) to dynamically and non-invasively monitor thrombus formation in the inferior vena cava (IVC) of mice. METHODS: We developed a murine model of venous thrombosis using, for detection, the Vevo 770((r)), a micro-imaging HFUS. Two different thrombosis models were used to generate thrombi in the IVC of C57Bl/6NCr mice: (i) ligation and (ii) application of ferric chloride (FeCl(3)). We then assessed venous thrombosis by HFUS. RESULTS: In both models, measurements of the clot pathologically correlated favorably with measurements acquired with HFUS. Thrombus develops less than an hour after ligation or FeCl(3) -induced injury of the IVC and the size of the clot increases over time for up to 24 h. Importantly, we demonstrate that HFUS can be used to monitor the effect of an anticoagulant such as dalteparin until complete resolution of the thrombus. CONCLUSIONS: These data show that HFUS assesses venous thrombosis in mice reliably and non-invasively. Developing a murine model of thrombosis using more accurate, and clinically more relevant, techniques such as ultrasonography, is a step towards a better understanding of the pathophysiology of venous thromboembolism. PMID- 22212404 TI - The arbuscular mycorrhizal symbiosis promotes the systemic induction of regulatory defence-related genes in rice leaves and confers resistance to pathogen infection. AB - Arbuscular mycorrhizal (AM) symbioses are mutualistic associations between soil fungi and most vascular plants. Their association benefits the host plant by improving nutrition, mainly phosphorus nutrition, and by providing increased capability to cope with adverse conditions. In this study, we investigated the transcriptional changes triggered in rice leaves as a result of AM symbiosis, focusing on the relevance of the plant defence response. We showed that root colonization by the AM fungus Glomus intraradices is accompanied by the systemic induction of genes that play a regulatory role in the host defence response, such as OsNPR1, OsAP2, OsEREBP and OsJAmyb. Genes involved in signal transduction processes (OsDUF26 and OsMPK6) and genes that function in calcium-mediated signalling processes (OsCBP, OsCaM and OsCML4) are also up-regulated in leaves of mycorrhizal rice plants in the absence of pathogen infection. In addition, the mycorrhizal rice plants exhibit a stronger induction of defence marker genes [i.e. pathogenesis-related (PR) genes] in their leaves in response to infection by the blast fungus Magnaporthe oryzae. Evidence indicates that mycorrhizal rice plants show enhanced resistance to the rice blast fungus. Overall, these results suggest that the protective effect of the AM symbiosis in rice plants relies on both the systemic activation of defence regulatory genes in the absence of pathogen challenge and the priming for stronger expression of defence effector genes during pathogen infection. The possible mechanisms involved in the mycorrhiza-induced resistance to M. oryzae infection are discussed. PMID- 22212405 TI - The early events of Alzheimer's disease pathology: from mitochondrial dysfunction to BDNF axonal transport deficits. AB - Although there are numerous studies regarding Alzheimer's disease (AD), the cause and progression of AD are still not well understood. The researches in the past decade implicated amyloid-beta (Abeta) overproduction as a causative event in disease pathogenesis, but still failed to clarify the mechanism of pathology from Abeta production to central neural system defects in AD. The present review raises the hypothesis that the onset of AD pathology is closely related with mitochondrial dysfunction induced by Abeta and brain-derived neurotrophic factor (BDNF) axonal transport deficits. It is well-known that axonal transport defect and attenuation of BDNF-neurotrophic tyrosine receptor kinase 2 (TrkB) signal are fatal to neuronal function and survival. We hypothesized that abnormal amyloid precursor protein (APP) processing and Abeta production in mitochondria disturb the axonal transport by impairing mitochondrial function and attenuate BDNF neurotrophic tyrosine receptor kinase 2 signal subsequently. For this hypothesis, the factors related with the initiation of AD pathology are not only limited to the neurons per se but also expanded to the microenvironment around neurons, such as the secretion of BDNF from astrocytes. The modification of the origin in this pathway may contribute to slow down the disease progression of AD. PMID- 22212406 TI - A phase II study of neoadjuvant bevacizumab plus capecitabine and concomitant radiotherapy in patients with locally advanced rectal cancer. AB - PURPOSE: To assess safety and activity of neoadjuvant bevacizumab, capecitabine and standard radiotherapy in locally advanced rectal cancer as well as potential predictive biomarkers. PATIENTS AND METHODS: The multicentric phase II study enrolled 43 patients who received bevacizumab infusion (5 mg/kg) every 2 weeks for 4 cycles; oral capecitabine at 825 mg/m(2) twice a day for 5.5 weeks with external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks). We determined certain biomarkers before and after therapy for correlation with response. RESULTS: Post-operative histologic examination revealed no residual cancer cells in 6 of the 43 patients (14%; 95% confidence limits 3.60-24.31%). In another 22 patients (51.2%) a varying percentage of cancer cells in residual areas of fibrosis/ necrosis was found, corresponding to Mandard TRG 2 or 3 classification. Tumor resection with negative circumferential margin was achieved in 38/40 (95%) operated patients. Sphincter-sparing surgery was obtained in 31 (72.1%) patients. Primary tumor and lymph nodes downstaging was observed in 15 (34.9%) and 16 (37.2%) cases, respectively. Neoadjuvant therapy was safe and well tolerated. The most frequent side effects were G1-2 diarrhea, proctitis, rectal bleeding and hypertension. No biomarker tested was significantly predictive of both pathological complete response and disease-free survival. Pre-treatment CD-34 vessel density, post-treatment Ki-67 labeling index and VEGFR-2 cancer cells expression significantly correlated with residual tumor area. CONCLUSIONS: The schedule of neoadjuvant therapy tested was safe and active. Pre-treatment vessel density by the panendothelial marker anti CD-34 antibody, post-treatment Ki-67 labeling index and VEGFR-2 expression were significantly associated to residual tumor area. The biomarkers correlations warrant further evaluation in prospective clinical trials. PMID- 22212408 TI - Effects of SLC2A9 variants on uric acid levels in a Korean population. AB - Elevated uric acid levels are associated with a variety of adverse health risks. Genome-wide association studies have identified several candidate genes associated with serum uric acid levels, including SLC2A9. We carried out a replication study of SLC2A9 variants in two Korean cohorts. A total of 961 participants in Seoul City were genotyped using a genome-wide marker panel, and 1,859 participants in the Bundang-Gu area were used for a replication study with a selected marker. Multivariate linear regression models were employed to test for genotypic effects on uric acid levels while adjusting for age, sex, and smoking status using an additive model. The top single nucleotide polymorphism associated with uric acid levels was rs4529048 in the SLC2A9 gene on chromosome 4 (P = 2.12 * 10(-6) in the Seoul City sample; P = 1.55 * 10(-9) in the Bundang-Gu sample). The meta-analysis P value for rs4529048 in the combined 2,820 individuals was 1.17 * 10(-14). This study demonstrates that genetic variants in SLC2A9 influence uric acid levels in Korean adults. PMID- 22212410 TI - Hypokalemic periodic paralysis in Sjogren's syndrome secondary to distal renal tubular acidosis. AB - We report a 53-year-old Turkish female presented with progressive weakness and mild dyspnea. Laboratory results demonstrated severe hypokalemia with hyperchloremic metabolic acidosis. The urinary anion gap was positive in the presence of acidemia, thus she was diagnosed with hypokalemic paralysis from a severe distal renal tubular acidosis (RTA). Immunologic work-up showed a strongly positive ANA of 1:3,200 and positive antibodies to SSA and SSB. Schirmer's test was abnormal. Autoimmune and other tests revealed Sjogren syndrome as the underlying cause of the distal renal tubular acidosis. Renal involvement in Sjogren's syndrome (SS) is not uncommon and may precede sicca complaints. The pathology in most cases is a tubulointerstitial nephritis causing among other things, distal RTA, and, rarely, hypokalemic paralysis. Treatment consists of potassium repletion, alkali therapy, and corticosteroids. Primary SS could be a differential in women with acute weakness and hypokalemia. PMID- 22212409 TI - The role of first-pass perfusion deficit in the detection of cardiac subendocardial manifestation in patients with autoimmune vasculitis. AB - This report describes the potential of cardiac magnetic resonance imaging (cMRI) based on myocardial first-pass perfusion imaging in the visualization of cardiac manifestations in autoimmune vasculitis, which in the heart are typically localized at the level of small subendocardial vessels. Two patients with primary or secondary autoimmune vasculitis were investigated in this study. Myocardial first-pass perfusion imaging was performed using an ECG-gated T1-weighted MRI sequence after the injection of intravenous bolus of gadolinium chelate. In both cases, the cMRI showed findings of subendocardial first-pass perfusion deficit (FPPD), a phenomenon so far described as microvascular obstruction (MVO) only in patients with acute cardiac infarction due to thromboembolic obstruction of small myocardial vessels. The two patients showed local subendocardial and myocardial hypoenhancement (characterized by a darker appearance than normal myocardial tissue), which is the typical morphological stigma of FPPD initially after injection of contrast media. The perfusion deficit, although morphologically very similar to the well-known phenomenon of MVO in acute cardiac infarction, was conceivably caused by different vasculitis-specific mechanisms such as occlusion of the microvasculature with erythrocytes, neutrophils and cellular debris. This study indicates that FPPD is useful for the non-invasive assessment of the microvasculature in patients with acute cardiac involvement in primary and secondary vasculitis. PMID- 22212411 TI - Immunohistological analysis of synovium treated with abatacept in rheumatoid arthritis. AB - The aim of this study was to investigate the histological changes following the treatment with abatacept compared with methotrexate (MTX) by an immunohistological examination of synovial tissue for eleven different molecules to detect the expression patterns of cytokines. We histologically assessed the synovial tissues from 10 methotrexate (MTX)-treated RA patients as controls and 5 abatacept plus MTX-treated RA patients. The synovium samples from both group were assessed by hematoxylin and eosin (HE) staining and analyzed for their expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), CD20, CD68, vascular endothelial growth factor (VEGF), CD4, CD8, CD28, CD80, and CD86 by an immunohistological examination. HE staining showed that there was a decrease in cell proliferation in the synovium of the RA patients who received abatacept compared with the controls. TNF-alpha, IL-6, and VEGF were not significantly different in either of the groups. On the other hand, MMP-3, CD68, CD4, CD8, CD20, CD80, and CD86 were significantly decreased in the abatacept group compared with the control (P < 0.05). Based on the histological analysis of the synovium, it appears that the efficacy of the treatment with abatacept may involve the inhibition of cell proliferation, with decreases in the expression of MMP-3, CD68, CD4, CD8, CD20, CD80, and CD86 in the synovium. These findings indicate inhibition of not only T cells but also B cells and macrophages, which likely plays a role in the efficacy of abatacept in RA patients. PMID- 22212412 TI - Value of diffusion-weighted magnetic resonance imaging in early diagnosis of ankylosing spondylitis. AB - The objective of this study is to estimate the value of diffusion-weighted MRI (DWI) in the detection of abnormalities in sacroiliac joints in the patients with early ankylosing spondylitis (AS) and investigate the feasibility of whole-body DWI (WB-DWI) in systemic evaluation of AS. Sixteen patients with early AS, 18 patients with simple low back pain (LBP), and 18 healthy volunteers were involved in this study. All subjects underwent conventional MRI and DWI. Apparent diffusion coefficient (ADC) in subchondral bone marrows of sacroiliac joints was measured. Independent-sample t test was used to statistically analyze the difference of ADC values between groups. WB-DWI was performed in additional 12 patients with clinically confirmed AS. The image results were analyzed by multiple post-processing techniques, as compared to conventional MRI. In AS patients, mean ADC values were (0.494 +/- 0.170) * 10(-3) mm(2)/s in sacrum and (0.513 +/- 0.129) * 10(-3) mm(2)/s in ilium, which were significantly higher than those of LBP ((0.306 +/- 0.057) * 10(-3) mm(2)/s in sacrum and (0.323 +/- 0.083) * 10(-3) mm(2)/s in ilium) and healthy volunteers ((0.315 +/- 0.009) * 10(-3) mm(2)/s in sacrum and (0.319 +/- 0.012) * 10(-3) mm(2)/s in ilium). No statistical differences were found between simple LBP and healthy volunteers. Mean ADC value of multiple lesions in AS was (0.932 +/- 0.299) * 10(-3) mm(2)/s. By WB-DWI, abnormal signals of sacroiliac joints and extra-sacroiliac joint lesions were demonstrated in the locations corresponding with clinical findings. Mean ADC values of multiple lesions were (1.298 +/- 0.323) * 10(-3) mm(2)/s in sacrum and (1.216 +/- 0.311) * 10(-3) mm(2)/s in ilium. DWI and WB-DWI were shown to be effective in differentiation and systemic evaluation of early AS. Both techniques are likely to play an importance role in the early diagnosis of AS and assessment of treatment response. PMID- 22212413 TI - Retrospective analysis on the impact of tuberculosis on patients with systemic lupus erythematosus (SLE). AB - Up to now, there have been few reports concerning changes in lupus activity and immune indices of tuberculosis in patients with systemic lupus erythematosis (SLE). A retrospective investigation was given to survey the case data of SLE patients companied with tuberculosis that were treated in our hospital from 2001 to 2010 and compared with that of sex- and age-matched patients with single SLE. Changes in autoantibodies, lupus activity, inflammatory indices, positive rates of tuberculin (PPD) test and tuberculosis antibody (TB-Ab) of both groups were observed. It was indicated by results that ANA antibody level and positive rates of anti-Sm, anti-SSA and anti-SSB antibodies were significantly lower in the TB group than those in the control group (P < 0.05); C3 and C4 levels were significantly higher in the TB group than those in the control group; damage of hematological system (predominantly platelet) was less severe in the TB group than that in the control group (P < 0.05); no significant differences in IgG, IgM and IgA were noted between two groups (P > 0.05); ESR, C-reactive protein and LDH levels were significantly higher in the TB group than those in the control group (P < 0.05); PPD-IgG were significantly higher in the TB group than those in the control group (P < 0.05). These results suggested that after SLE patients were infected with tuberculosis, immune function was altered and lupus activity was inhibited as well. PMID- 22212414 TI - Endotracheal tube cuff--small important part of a big issue. AB - Many of the complications related to prolonged ventilation are related to inappropriate handling of endotracheal tube (ETT) cuff. This article reviews the possible complications associated with the ETT cuff, and the landmark development made in that field. The article challenges the present paradigm of cuff use and reviews the current clinical practice in that area. PMID- 22212415 TI - Dietary restriction increases skeletal muscle mitochondrial respiration but not mitochondrial content in C57BL/6 mice. AB - Dietary restriction (DR) is suggested to induce mitochondrial biogenesis, although recently this has been challenged. Here we determined the impact of 1, 9 and 18 months of 30% DR in male C57BL/6 mice on key mitochondrial factors and on mitochondrial function in skeletal muscle, relative to age-matched ad libitum (AL) controls. We examined proteins and mRNAs associated with mitochondrial biogenesis and measured mitochondrial respiration in permeabilised myofibres using high resolution respirometry. 30% DR, irrespective of duration, had no effect on citrate synthase activity. In contrast, total and nuclear protein levels of PGC-1alpha, mRNA levels of several mitochondrial associated proteins (Pgc-1alpha, Nrf1, Core 1, Cox IV, Atps) and cytochrome c oxidase content were increased in skeletal muscle of DR mice. Furthermore, a range of mitochondrial respiration rates were increased significantly by DR, with DR partially attenuating the age-related decline in respiration observed in AL controls. Therefore, DR did not increase mitochondrial content, as determined by citrate synthase, in mouse skeletal muscle. However, it did induce a PGC-1alpha adaptive response and increased mitochondrial respiration. Thus, we suggest that a functionally 'efficient' mitochondrial electron transport chain may be a critical mechanism underlying DR, rather than any net increase in mitochondrial content per se. PMID- 22212416 TI - Removal of methylmercury and tributyltin (TBT) using marine microorganisms. AB - Two marine species of bacteria were isolated that are capable of degrading organometallic contaminants: Pseudomonas balearica, which decomposes methylmercury; and Shewanella putrefaciens, which decomposes tributyltin. P. balearica decomposed 97% of methylmercury (20.0 MUg/L) into inorganic mercury after 3 h, while S. putrefaciens decomposed 88% of tributyltin (55.3 MUg Sn/L) in real wastewater after 36 h. These data indicate that the two bacteria efficiently decomposed the targeted substances and may be applied to real wastewater. PMID- 22212417 TI - GLUT1 deficiency syndrome as a cause of encephalopathy that includes cognitive disability, treatment-resistant infantile epilepsy and a complex movement disorder. AB - Glucose transporter-1 (GLUT1) deficiency syndrome is caused by heterozygous mutations in the SLC2A1 gene, resulting in impaired glucose transport into the brain. It is characterized by a low glucose concentration in the cerebrospinal fluid (hypoglycorrhachia) in the absence of hypoglycemia, in combination with low to normal lactate in the cerebrospinal fluid (CSF). It often results in treatment resistant infantile epilepsy with progressive developmental disabilities and a complex movement disorder. Recognizing GLUT1 deficiency syndrome is important, since initiation of a ketogenic diet can reduce the frequency of seizures and the severity of the movement disorder. There can be a considerable delay in diagnosing GLUT1 deficiency syndrome, and this point is illustrated by the natural history of this disorder in a 21-year-old woman with severe, progressive neurological disabilities. Her encephalopathy consisted of treatment-resistant seizures, a complex movement disorder, progressive intellectual disability, and deceleration of her head growth after late infancy. Focused evaluation at age 21 revealed GLUT1 deficiency caused by a novel heterozygous missence mutation in exon 7 (c.938C > A; p.Ser313Try) in SLC2A1 as the cause for her disabilities. PMID- 22212418 TI - Structural social support predicts functional social support in an online weight loss programme. AB - BACKGROUND: Online weight loss programmes allow members to use social media tools to give and receive social support for weight loss. However, little is known about the relationship between the use of social media tools and the perception of specific types of support. OBJECTIVE: To test the hypothesis that the frequency of using social media tools (structural support) is directly related to perceptions of Encouragement, Information and Shared Experiences support (functional support). DESIGN: Online survey. PARTICIPANTS: Members of an online weight loss programme. METHODS: The outcome was the perception of Encouragement (motivation, congratulations), Information (advice, tips) and Shared Experiences (belonging to a group) social support. The predictor was a social media scale based on the frequency of using forums and blogs within the online weight loss programme (alpha = 0.91). The relationship between predictor and outcomes was evaluated with structural equation modelling (SEM) and logistic regression, adjusted for sociodemographic characteristics, BMI and duration of website membership. RESULTS: The 187 participants were mostly female (95%) and white (91%), with mean (SD) age 37 (12) years and mean (SD) BMI 31 (8). SEM produced a model in which social media use predicted Encouragement support, but not Information or Shared Experiences support. Participants who used the social media tools at least weekly were almost five times as likely to experience Encouragement support compared to those who used the features less frequently [adjusted OR 4.8 (95% CI 1.8-12.8)]. CONCLUSIONS: Using the social media tools of an online weight loss programme at least once per week is strongly associated with receiving Encouragement for weight loss behaviours. PMID- 22212419 TI - Recognition of Streptococcus pneumoniae by the innate immune system. AB - Streptococcus pneumoniae is both a frequent colonizer of the upper respiratory tract and a leading cause of life-threatening infections such as pneumonia, meningitis and sepsis. The innate immune system is critical for the control of colonization and for defence during invasive disease. Initially, pneumococci are recognized by different sensors of the innate immune system called pattern recognition receptors (PRRs), which control most subsequent host defence pathways. These PRRs include the transmembrane Toll-like receptors (TLRs) as well as the cytosolic NOD-like receptors (NLRs) and DNA sensors. Recognition of S. pneumoniae by members of these PRR families regulates the production of inflammatory mediators that orchestrate the following immune response of infected as well as neighbouring non-infected cells, stimulates the recruitment of immune cells such as neutrophils and macrophages, and shapes the adaptive immunity. This review summarizes the current knowledge of the function of different PRRs in S. pneumoniae infection. PMID- 22212420 TI - Comparison between acetazolamide challenge and 10% carbon dioxide challenge perfusion CT in rat C6 glioma. AB - RATIONALE AND OBJECTIVES: The aim of this study was to investigate the effect of perfusion computed tomography (PCT) with acetazolamide (ACZ) challenge and compare it to 10% carbon dioxide (CO(2)) challenge in rat C6 glioma. MATERIALS AND METHODS: PCT was performed on 32 rats, including 20 with orthotopically implanted C6 gliomas and 12 serving as controls. Ten rats with gliomas and six normal rats underwent PCT with ACZ challenge. The other 10 rats with gliomas and six normal rats underwent PCT with 10% CO(2) challenge. The raw data were processed using Philips computed tomographic brain perfusion software. Perfusion parameters before and after the challenge were recorded. Percentage changes due to ACZ administration and 10% CO(2) challenge were calculated. Pearson's correlation coefficients were used to investigate relationships between percentage changes in perfusion parameters and vascular endothelial growth factor and microvessel density. RESULTS: In C6 gliomas, percentage change in cerebral blood flow was significantly different between ACZ (72.73%) and 10% CO(2) (28.47%) challenge (P < .01). Percentage change in cerebral blood volume was 37.85% with ACZ and 24.69% with 10% CO(2) challenge (P = .02). In controls, percentage change in cerebral blood flow was significantly different between ACZ (117.42%) and 10% CO(2) (65.86%) challenge (P < .01). For percentage change in cerebral blood volume, there was no significant difference between ACZ (107.51%) and 10% CO(2) (92.95%) challenge. Significant correlations were observed among percentage changes in vascular endothelial growth factor, microvessel density, and cerebral blood volume (P < .01). Percentage change in cerebral blood flow correlated well with vascular endothelial growth factor. CONCLUSIONS: The results of this study indicate that PCT with ACZ challenge is a more reliable technique compared to 10% CO(2) challenge for the quantitative evaluation of microcirculation in gliomas. PMID- 22212421 TI - Out of hours multidetector computed tomography pulmonary angiography: are specialist resident reports reliable? AB - RATIONALE AND OBJECTIVES: The purposes of this study were to assess the accuracy of trainee radiologists' reports for computed tomographic pulmonary angiographic (CTPA) imaging and to determine agreement or discrepancy with final verified consultant reports. MATERIALS AND METHODS: A total of 100 consecutive out-of hours CTPA examinations were prospectively analyzed. Fifty-one male and 49 female subjects were included in the study. The mean age of patients scanned was 63.7 years (range, 17-98 years). RESULTS: Eighteen of the 100 subjects (18%) had findings positive for pulmonary embolism. The interobserver agreement for pulmonary embolism between on-call radiology residents and consultant radiologists was almost perfect (kappa = 0.932; 95% confidence interval, 0.84 1.0; P < .0001). There was one false-negative CTPA report. Eighty-two CTPA scans (82%) were reported as negative for pulmonary embolism by consultant radiologists. In this group, there was a single false-positive interpretation by the on-call specialist resident. The interobserver agreement for all findings between resident and consultant reports was almost perfect (weighted kappa = 0.87; 95% confidence interval, 0.79-0.96; P < .0001). The overall discrepancy rate, including both false-positive and false-negative findings, between the on call radiology resident and consultant radiologist was 8% (eight of 100). CONCLUSIONS: CTPA reports by radiology residents can be relied and acted upon without any major discrepancies. There is a relatively much higher proportion of patients with alternative diagnoses, mainly infective consolidation and heart failure presenting with similar symptoms and signs as pulmonary emboli. It is imperative for trainees to be systematic and review all images if observational omissions are to be reduced. PMID- 22212422 TI - Accuracy of a remote eye tracker for radiologic observer studies: effects of calibration and recording environment. AB - RATIONALE AND OBJECTIVES: To determine the accuracy and reproducibility of a remote eye-tracking system for studies of observer gaze while displaying volumetric chest computed tomography (CT) images. MATERIALS AND METHODS: Four participants performed calibrations using three different gray-scale backgrounds (black, gray, and white). Each participant then observed a three-dimensional 10 point test pattern embedded in five Digital Imaging and Communications in Medicine (DICOM) datasets (test backgrounds): a full 190-section chest CT scan, 190 copies of a single chest CT section, and three 190-section datasets of homogeneous intensity (black, gray, and white). RESULTS: Significant variances between participants, calibration backgrounds, and test backgrounds were observed. The least mean systematic error (deviation of recorded gaze position from target) was obtained when the calibration background and test background were black (27 pixels). Systematic error increased when displaying a test background that deviated from the calibration background intensity. Hence, the largest mean systematic error occurred when calibrating to a black background and displaying a white background (67 pixels). For complex chest CT volumes the white calibration background performed best (38 pixels). An angular analysis of the systematic error was performed and demonstrated that the systemic error primarily affects the vertical position of the estimated gaze position. CONCLUSION: Our findings indicate a potential source of systematic error during gaze recording in a dynamic environment and highlight the importance of configuring the calibration procedure according to the brightness of the display. We recommend that investigators develop routines for postcalibration accuracy measurement and report the effective accuracy for the display environment in which the data are collected. PMID- 22212423 TI - Enterprise imaging: planning and business justification. AB - To evaluate financial performance, academic radiology departments most often measure examination volume and general technical and professional expenses. Although these metrics are not standardized, their frequency of use reflects that productivity and financial health are high priorities for academic radiology departments across the United States. In this article, we discuss both of these topics, in the context of projects to expand services, particularly those with an information technology (IT) component. First, we discuss several informatics innovations that increase productivity or expand service. Second, we explain core financial analysis concepts applicable to radiology departments. Third, we discuss the unique challenge of evaluating a potential IT project for an academic radiology department, when intangible benefits are difficult to quantify. Financial models are only one of several components used for guidance in strategic decisions, but are crucial to building a business case that justifies the initial or capital investment as well as startup and ongoing operational expenses. PMID- 22212424 TI - Meaningful use a call to arms. AB - The benefits of an interactive online world have affected the way we purchase products and plan our vacations. It is only a matter of time before consumers start demanding health care with the same convenience that comes with booking an airline flight or managing a bank account. The health care industry itself requires periodic and mandatory data analysis for outcome analysis, clinical benchmarking, quality improvement, forming guidelines, and making decisions. The federal government and health care community have been working together to come up with more robust and cost-effective health care informatics solutions. Meaningful use (MU) intends to establish a new standard for health care informatics in the United States. The term "meaningful use" implies that health care information and technology systems not just exist, but also serve as an integral part of physician and hospital workflow; leading to cost savings as well as improved outcomes. Under this concept, the federal government is offering maximum incentive payments of up to $44,000 per physician (including radiologists) if they can meet all the requirements as laid down in the MU measures. Unfortunately, penalties will kick in if physicians are not compliant with MU by 2015. This will be done in at least three stages, with Stage 1 already in effect (as of January 3, 2011). This will be the first in a series of articles outlining MU and what is in store for radiology. We will go in depth about who is eligible, and how the payment schedule is set up. We will break down the core and menu set measures to suggest what can be excluded by most radiologists. We will also go through some case studies and examine what lies in store for radiology. PMID- 22212425 TI - Picture Archiving and Communication System (PACS) implementation, integration & benefits in an integrated health system. AB - The availability of the Picture Archiving and Communication System (PACS) has revolutionized the practice of radiology in the past two decades and has shown to eventually increase productivity in radiology and medicine. PACS implementation and integration may bring along numerous unexpected issues, particularly in a large-scale enterprise. To achieve a successful PACS implementation, identifying the critical success and failure factors is essential. This article provides an overview of the process of implementing and integrating PACS in a comprehensive health system comprising an academic core hospital and numerous community hospitals. Important issues are addressed, touching all stages from planning to operation and training. The impact of an enterprise-wide radiology information system and PACS at the academic medical center (four specialty hospitals), in six additional community hospitals, and in all associated outpatient clinics as well as the implications on the productivity and efficiency of the entire enterprise are presented. PMID- 22212426 TI - X-rays can harm you and others. PMID- 22212427 TI - A hearty solution for acute myeloid leukemia. PMID- 22212428 TI - A novel tumor suppressor miRNA miR-520e contributes to suppression of hepatoma. PMID- 22212429 TI - Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor. AB - Obstructive sleep apnea (OSA) is well known for its metabolic as well as neurobehavioral consequences. Chronic intermittent hypoxia (IH) is a major component of OSA. In recent years, substantial advances have been made in elucidating the cellular and molecular mechanisms underlying the effect of chronic IH on neurocognitive functions, many of which are based on studies in animal models. A number of hypotheses have been put forward to explain chronic IH induced neurological dysfunctions. Among these, the roles of oxidative stress and apoptosis-related neural injury are widely accepted. Here, focusing on results derived from animal studies, we highlight a possible role of reduced expression of brain-derived neurotrophic factor (BDNF) in causing impairment in long-term synaptic plasticity and neurocognitive functions during chronic IH. The possible relationship between BDNF and previous findings on this subject will be elucidated. PMID- 22212430 TI - Thrombin induced connective tissue growth factor expression in rat vascular smooth muscle cells via the PAR-1/JNK/AP-1 pathway. AB - AIM: To investigate the signaling pathways involved in thrombin-induced connective tissue growth factor (CTGF) expression in rat vascular smooth muscle cells (VSMCs). METHODS: Experiments were preformed on primary rat aortic smooth muscle cells (RASMCs) and a rat VSMC line (A10). CTGF protein levels were measured using Western blotting. Luciferase reporter genes and dominant negative mutants (DNs) were used to investigate the signaling pathways mediating the induction of CTGF expression by thrombin. RESULTS: Thrombin (0.3-3.0 U/mL) caused a concentration- and time-dependent increase in CTGF expression in both RASMCs and A10 cells. Pretreating A10 cells with the protease-activated receptor 1 (PAR 1) antagonist SCH79797 (0.1 MUmol/L) significantly blocked thrombin-induced CTGF expression, while the PAR-4 antagonist tcY-NH(2) (30 MUmol/L) had no effect. The PAR-1 agonist SFLLRN-NH(2) (300 MUmol/L) induced CTGF expression, while the PAR-4 agonist GYPGQV-NH(2) (300 MUmol/L) had no effect. Thrombin (1 U/mL) caused time dependent phosphorylation of c-Jun N-terminal kinase (JNK). Pretreating with the JNK inhibitor SP600125 (3-30 MUmol/L) or transfection with DNs of JNK1/2 significantly attenuated thrombin-induced CTGF expression. Thrombin (0.3-3.0 U/mL) increased activator protein-1 (AP-1)-luciferase activity, which was inhibited by the JNK inhibitor SP600125. The AP-1 inhibitor curcumin (1-10 MUmol/L) concentration-dependently attenuated thrombin-induced CTGF expression. CONCLUSION: Thrombin acts on PAR-1 to activate the JNK signaling pathway, which in turn initiates AP-1 activation and ultimately induces CTGF expression in VSMCs. PMID- 22212431 TI - AVE8134, a novel potent PPARalpha agonist, improves lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats. AB - AIM: AVE8134 is a structurally novel potent PPARalpha agonist. The aim of this study is to investigate the efficacy of AVE8134 on lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats. METHODS: A cell based PPAR Gal4 transactivation assay was constructed for testing the activities of AVE8134 at 3 different PPAR isoforms in vitro. Transgenic human Apo A1 (hApo A1) mice and insulin-resistant ZDF rats were used to evaluate the effects of AVE8134 in vivo. RESULTS: AVE8134 was a full PPARalpha dominated PPAR agonist (the values of EC(50) for human and rodent PPARalpha receptor were 0.01 and 0.3 MUmol/L, respectively). AVE8134 was not active at PPARdelta receptor. In female hApo A1 mice, AVE8134 (1-30 mg.kg(-1).d(-1), po for 12 d) dose-dependently lowered the plasma triglycerides, and increased the serum HDL-cholesterol, hApo A1 and mouse Apo E levels. In female ZDF rats, AVE8134 (3-30 mg.kg(-1).d(-1) for 2 weeks) improved insulin-sensitivity index. In pre-diabetic male ZDF rats (at the age of 7 weeks), AVE8134 (10 mg.kg(-1).d(-1) for 8 weeks) produced an anti-diabetic action comparable to rosiglitazone, without the PPARgamma mediated adverse effects on body weight and heart weight. In male ZDF rats (at the age of 6 weeks), AVE8134 (20 mg.kg(-1).d(-1) for 12 weeks) increased mRNA levels of the target genes LPL and PDK4 about 20 fold in the liver, and there was no relevant effect with rosiglitazone. CONCLUSION: AVE8134 improves lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats. PMID- 22212432 TI - Inhibition of the STAT3 signaling pathway is involved in the antitumor activity of cepharanthine in SaOS2 cells. AB - AIM: To investigate the molecular mechanisms underlying the antitumor activity of cepharanthine (CEP), an alkaloid extracted from Stephania cepharantha Hayata. METHODS: Human osteosarcoma cell line SaOS2 was used. MTT assay, Hoechst 33342 nuclear staining, flow cytometry, Western blotting and nude mouse xenografts of SaOS2 cells were applied to examine the antitumor activity of CEP in vitro and in vivo. The expression levels of STAT3 and its downstream signaling molecules were measured with Western blotting and immunochemistry analysis. The activity of STAT3 was detected based on the phosphorylation level of STAT3, luciferase gene reporter assay and translocation of STAT3 to the nucleus. RESULTS: Treatment of SaOS2 cells with CEP (2.5-20 MUmol/L) inhibited the cell growth in a concentration- and time-dependent manner. CEP (10 MUmol/L) caused cell cycle arrest at G(1) phase and induced apoptosis of SaOS2 cells. CEP (10 and 15 MUmol/L) significantly decreased the expression of STAT3 in SaOS2 cells. Furthermore, CEP (5 and 10 MUmol/L) significantly inhibited the expression of target genes of STAT3, including the anti-apoptotic gene Bcl-xL and the cell cycle regulators c-Myc and cyclin D1. In nude mouse xenografts of SaOS2 cells, CEP (20 mg.kg(-1).d(-1), ip for 19 d) significantly reduced the volume and weight of the tumor. CONCLUSION: Our findings suggest that inhibition of STAT3 signaling pathway is involved in the anti-tumor activity of CEP. PMID- 22212433 TI - A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats. AB - AIM: To develop a pharmacokinetic/pharmacodynamic (PK/PD) model describing the receptor/gene-mediated induction of CYP3A1/2 by dexamethasone (DEX) in rats. METHODS: A group of male Sprague-Dawley rats receiving DEX (100 mg/kg, ip) were sacrificed at various time points up to 60 h post-treatment. Their blood sample and liver were collected. The plasma concentration of DEX was determined with a reverse phase HPLC method. CYP3A1/2 mRNA, protein levels and enzyme activity were measured using RT-PCR, ELISA and the testosterone substrate assay, respectively. Data analyses were performed using a first-order conditional estimate (FOCE) with INTERACTION method in NONMEM version 7.1.2. RESULTS: A two-compartment model with zero-order absorption was applied to describe the pharmacokinetic characteristics of DEX. Systemic clearance, the apparent volume of distribution and the duration of zero-order absorption were calculated to be 172.7 mL.kg(-1).h(-1), 657.4 mL/kg and 10.47 h, respectively. An indirect response model with a series of transit compartments was developed to describe the induction of CYP3A1/2 via PXR transactivation by DEX. The maximum induction of CYP3A1 and CYP3A2 mRNA levels was achieved, showing nearly 21.29- and 8.67-fold increases relative to the basal levels, respectively. The CYP3A1 and CYP3A2 protein levels were increased by 8.02 fold and 2.49-fold, respectively. The total enzyme activities of CYP3A1/2 were shown to increase by up to 2.79-fold, with a lag time of 40 h from the Tmax of the DEX plasma concentration. The final PK/PD model was able to recapitulate the delayed induction of CYP3A1/2 mRNA, protein and enzyme activity by DEX. CONCLUSION: A mechanism-based PK/PD model was developed to characterize the complex concentration-induction response relationship between DEX and CYP3A1/2 and to resolve the drug- and system-specific PK/PD parameters for the course of induction. PMID- 22212434 TI - TACI-Fc gene therapy improves autoimmune sialadenitis but not salivary gland function in non-obese diabetic mice. AB - OBJECTIVE: Patients with Sjogren's syndrome (SS) show aberrant expression of the B cell-related mediators, B cell-activating factor (BAFF), and a proliferation inducing ligand (APRIL) in serum and salivary glands (SGs). We studied the biological effect of neutralizing these cytokines by local gene transfer of the common receptor transmembrane activator and CAML interactor (TACI) in an animal model of SS. MATERIAL AND METHODS: A recombinant serotype 2 adeno-associated virus (rAAV2) encoding TACI-Fc was constructed, and its efficacy was tested in the SGs of non-obese diabetic mice. Ten weeks later, SG inflammation was evaluated and serum and SG tissue were analyzed for inflammatory markers including immunoglobulins (Ig) and cytokines. RESULTS: AAV2-TACI-Fc gene therapy significantly reduced the number of inflammatory foci in the SG, owing to a decrease in IgD(+) cells and CD138(+) cells. Moreover, IgG and IgM levels, but not IgA levels, were reduced in the SG. Overall expression of mainly proinflammatory cytokines tended to be lower in AAV2-TACI-Fc-treated mice. Salivary flow was unaffected. CONCLUSION: Although local expression of soluble TACI-Fc reduced inflammation and immunoglobulin levels in the SG, further research will have to prove whether dual blockade of APRIL and BAFF by TACI-Fc can provide a satisfying treatment for the clinical symptoms of patients. PMID- 22212435 TI - A versatile toolkit for high throughput functional genomics with Trichoderma reesei. AB - BACKGROUND: The ascomycete fungus, Trichoderma reesei (anamorph of Hypocrea jecorina), represents a biotechnological workhorse and is currently one of the most proficient cellulase producers. While strain improvement was traditionally accomplished by random mutagenesis, a detailed understanding of cellulase regulation can only be gained using recombinant technologies. RESULTS: Aiming at high efficiency and high throughput methods, we present here a construction kit for gene knock out in T. reesei. We provide a primer database for gene deletion using the pyr4, amdS and hph selection markers. For high throughput generation of gene knock outs, we constructed vectors using yeast mediated recombination and then transformed a T. reesei strain deficient in non-homologous end joining (NHEJ) by spore electroporation. This NHEJ-defect was subsequently removed by crossing of mutants with a sexually competent strain derived from the parental strain, QM9414. CONCLUSIONS: Using this strategy and the materials provided, high throughput gene deletion in T. reesei becomes feasible. Moreover, with the application of sexual development, the NHEJ-defect can be removed efficiently and without the need for additional selection markers. The same advantages apply for the construction of multiple mutants by crossing of strains with different gene deletions, which is now possible with considerably less hands-on time and minimal screening effort compared to a transformation approach. Consequently this toolkit can considerably boost research towards efficient exploitation of the resources of T. reesei for cellulase expression and hence second generation biofuel production. PMID- 22212436 TI - The missing left atrial appendage. AB - A 34 year old man underwent a transesophageal echocardiogram (TEE) prior to implantation of a biventricular ICD and DC cardioversion, to exclude left atrium and left atrial appendage thrombus. He had a history of repaired tetralogy of Fallot as a child, Stickler syndrome, atrial flutter and was status post recent mitral valve replacement, pulmonary valve replacement and tricuspid valve repair. The left atrial appendage was not visualized on TEE. A cardiac CT clarified that there was a left atrial appendage and provided an explanation as to why it was not visualized on TEE, highlighting the importance of multimodality imaging in patients with complex congenital heart disease. PMID- 22212437 TI - Increased presence of cognitive impairment in hemodialysis patients in the absence of neurological events. AB - BACKGROUND/AIMS: Cognitive impairment (CI) is highly prevalent among hemodialysis (HD) patients and is associated with increased morbidity and mortality. The aim was to compare cognitive function in HD patients with no history of stroke or dementia and well-matched controls. Studies are required to determine the impact of HD and chronic kidney disease-specific risks on CI. METHODS: 76 outpatients (50 receiving outpatient HD and 26 with normal kidney function matched for age and comorbidity) underwent a cross-sectional observational study. HD patients were well dialyzed and had optimal hemoglobin levels. A battery of eight neuropsychological tests was used. Outcomes included assessment scores of neurocognitive testing and prevalence and subtype of CI. RESULTS: Compared to controls, HD subjects had significantly lower composite scores for each tested cognitive domain. In each domain except memory, the percentage of subjects with impairment was significantly higher in HD subjects than controls. Differences between the groups were independent of vascular and dementia risk factors. 82% of HD subjects met criteria for CI versus 50% of controls. Non-amnestic subtype of CI was more prevalent in both groups. CONCLUSION: Well-dialyzed HD patients with optimized hemoglobin levels and with no history of stroke or dementia performed significantly worse on multiple measures of cognition compared to controls. A higher prevalence of non-memory impairment may suggest an underlying vascular versus neurodegenerative mechanism. HD and chronic kidney disease-specific risk factors may contribute to early CI not readily detected by routine screening methods. PMID- 22212438 TI - Airway effects of repeated exposures to ozone-initiated limonene oxidation products as model of indoor air mixtures. AB - Repeated low-level indoor air exposure to volatile organic compounds (VOCs) may influence the reporting of sensory irritation in the eyes and airways. The ozone initiated reaction products of limonene, an abundant VOC, were used as a model of indoor air mixtures to study upper airway (sensory) irritation, bronchoconstrictive and alveolar level effects after repeated exposures. Mice were exposed 1h/day for 10 consecutive days to: air, limonene (52 ppm/289 mg/m(3)); ozone (0.1 ppm/0.2mg/m(3)); a reaction mixture of limonene (52+/-8 ppm) and ozone (0.5, 2.5 and 3.9 ppm) resulting in ~0.05 ppm residual ozone. Neither the limonene nor the ozone exposures alone showed consistent effects on the respiratory parameters. In the limonene/ozone groups, the respiratory rate decreased concentration-dependently with an extrapolated no-effect-level of ~0.3 ppm admixed ozone. Both sensory irritation and airflow limitation were conspicuous effects of the mixtures; sensory irritation appeared rapidly and airflow limitation developed slowly during each exposure. The effects of these parameters did not change with increasing number of exposures. No firm conclusion could be drawn about alveolar level effects. Cells in bronchoalveolar lavage were unchanged irrespective of exposure to air, ozone, and limonene with and without ozone. In conclusion, the study indicated that repeated exposures to ozone initiated limonene mixtures did not cause sensitization of sensory irritation and airflow limitation. Bronchoalveolar lavage after exposures to ozone, and limonene with and without ozone, respectively, did not show airway inflammation. PMID- 22212439 TI - Analysis of various etiologies of hypertension in patients hospitalized in the endocrinology division. AB - This research aimed to analyze the clinical data of various etiologies of hypertension in patients hospitalized in the Endocrinology Division. The differences between essential and secondary hypertension were examined to provide a basis for clinical differential diagnosis. The data from all the inpatients with hypertension of unknown origin admitted in the Endocrinology Division of the First Affiliated Hospital of the Zhejiang University School of Medicine from January 2001 to May 2011 were reviewed. The patients were classified into either essential or secondary hypertensive groups. The differentiating parameters of these forms of hypertension were analyzed using the one-factor and multi-factor logistic regression analysis. A total of 1,001 cases were selected in which 346 cases (34.6%) were essential hypertensive and 655 cases (65.4%) were secondary hypertensive. Adrenal hypertension was the primary cause of secondary hypertension, followed by renal artery, central, psychogenic, and renal hypertension as well as others that have not been classified systematically. Using one-factor analysis, significant differences were found among duration of hypertension, age, the onset age, family history of hypertension, diastolic pressure on admission, Cushing syndrome, body mass index (BMI), urine protein, serum creatinine, orthostatic aldosterone, ratio of orthostatic aldosterone to renin activity, incidence of fatty liver displayed by type-B ultrasound, and computed tomography adrenal masses incidence (P < 0.05). Multi-factor regression analysis showed that family history of hypertension (OR = 7.196) and BMI above the normal range (OR = 15.124) were the independent factors that predicted essential hypertension, but failed to determine any other valid predictors of secondary causes except adrenal masses (OR = 10.114), orthostatic aldosterone value >200 pg/ml (OR = 9.742), and a ratio of orthostatic aldosterone and renin activity >40 (OR = 4.723). PMID- 22212440 TI - Phytosterol additive boosts adrenal response to ACTH in male Japanese quail (Coturnix coturnix japonica). AB - To investigate the adrenal effect of a phytosterol (PS) additive, 80 male Japanese quail were divided into four sub-groups and fed 0, 40, 400, and 4,000 ppm of PS, respectively, for 21 days. Subsequently, 50% of the birds from each dosage group were subjected to a 6-day adrenal function test, whereby they were injected with long-lasting adrenocorticotropin (ACTH). The remaining quail in each PS dosage group were raised under normal conditions. The groups receiving 400 and 4000 ppm PS exhibited decreased serum levels of LDL-cholesterol with and without ACTH stimulation (P < 0.01). No amount of dose of PS changed serum corticosterone (CORT) under normal conditions (P > 0.05). Enhancement of CORT was observed on the 2nd and the 6th days of the ACTH challenge in birds receiving 400 ppm (P < 0.05). Average ACTH-induced CORT levels in the 400 ppm group were higher than in the 0 ppm group (P < 0.01). Our results demonstrated that PS can boost ACTH-induced CORT levels in male Japanese quail. PMID- 22212441 TI - Work of breathing and respiratory drive in obesity. AB - Obesity, particularly severe central obesity, affects respiratory physiology both at rest and during exercise. Reductions in expiratory reserve volume, functional residual capacity, respiratory system compliance and impaired respiratory system mechanics produce a restrictive ventilatory defect. Low functional residual capacity and reductions in expiratory reserve volume increase the risk of expiratory flow limitation and airway closure during quiet breathing. Consequently, obesity may cause expiratory flow limitation and the development of intrinsic positive end expiratory pressure, especially in the supine position. This increases the work of breathing by imposing a threshold load on the respiratory muscles leading to dyspnoea. Marked reductions in expiratory reserve volume may lead to ventilation distribution abnormalities, with closure of airways in the dependent zones of the lungs, inducing ventilation perfusion mismatch and gas exchange abnormalities. Obesity may also impair upper airway mechanical function and neuromuscular strength, and increase oxygen consumption, which in turn, increase the work of breathing and impair ventilatory drive. The combination of ventilatory impairment, excess CO(2) production and reduced ventilatory drive predisposes obese individuals to obesity hypoventilation syndrome. PMID- 22212443 TI - Health disparities in mid-to-late life: the role of earlier life family and neighborhood socioeconomic conditions. AB - The relationship between neighborhoods of residence in young adulthood and health in mid-to-late life in the United States are examined using the 1968-2005 waves of the Panel Study of Income Dynamics (PSID). The sample consists of persons who were aged 20-30 in 1968 and are followed for a period of 38 years (N=2730). Four level hierarchical random effects models of self-assessed general health status as a function of individual, family, and neighborhood factors are estimated. Using the original sampling design of the PSID, we analyze adult health trajectories of married couples and neighbors followed from young adulthood through elderly ages to assess the magnitudes of the possible causal effects of family and neighborhood characteristics in young adulthood on health in mid-to late life. Estimates suggest disparities in neighborhood conditions in young adulthood account for one-quarter of the variation in mid-to-late life health. Living in poor neighborhoods during young adulthood is strongly associated with negative health outcomes in later-life. This result is robust even in the presence of a reasonably large amount of potential unobservable individual and family factors that may significantly affect both neighborhood of residence and subsequent health status. Racial differences in health status in mid-to-late life are also associated with family and neighborhood socioeconomic conditions earlier in life. Three quarters of the black-white gap in health status at ages over 55 can be accounted for by differences in childhood socioeconomic status and neighborhood and family factors in young adulthood. PMID- 22212444 TI - Examining the differential association between self-rated health and area deprivation among white British and ethnic minority people in England. AB - Recent discourses in the area of neighbourhood effects on health have advocated for a relational perspective of space and place, focussing on the mutually reinforcing and reciprocal relationship between the environment and the individual. An example of such relationship is that of the interaction between area deprivation and individual ethnicity on reports of self-rated health, which we explored using cross-sectional data from the 2007 Citizenship Survey linked to the 2001 UK census. We aimed to examine whether the association between area deprivation and poor self-rated health differs for ethnic minority groups, as compared to white British people. Following from this, we also examined whether possible differential associations were mediated by ethnic density effects and perceptions of and satisfaction with neighbourhood characteristics. Results of random effects multilevel logistic regression models showed the detrimental association between area deprivation and self-rated health to be of greater magnitude and stronger for white British people than for ethnic minority people. This differential association was not mediated by ethnic density effects or perceptions of and satisfaction with neighbourhood characteristics. PMID- 22212445 TI - Early computed tomography signs as early predictors of hemorrhagic transformation under heparinization in patients with cardiogenic embolism. AB - AIM: Early computed tomography (CT) signs are crucial to predict the onset of hemorrhagic transformation (HT) and are preventive to avoid a fatal hematoma after thrombolysis. In the present study, we retrospectively reviewed the clinical records of patients receiving heparinization to investigate the correlation between early CT signs and the frequency of HT. METHODS: We reviewed 96 patients with cardiogenic cerebral embolism. These patients were admitted within 24 h of the onset and were subsequently given 5000-15,000 units of heparin per day for 3 days. Owing to CT on admission, early CT changes were evaluated. Patient characteristics were also estimated, including evidence of hypertension, diabetes mellitus, hyperlipidemia, coronary heart disease and history of smoking. The probability of hemorrhagic transformation, or good outcome and independence was assessed by backward stepwise logistic regression analysis based on the maximum likelihood ratio. RESULTS: Higher baseline National Institutes of Health Stroke Scale (NIHSS) score, early CT signs and absence of hyperlipidemia diversely correlated with the occurrence of HT. Also, the presence or absence of early CT signs was significantly related to HT classification (chi(2)-test; P < 0.05). It was statistically significant that a higher baseline NIHSS score (OR 8.51; 95% CI 3.11-27.75) affected the outcome without showing a significant relationship to early CT signs. CONCLUSIONS: Presence of early CT signs correlated more strongly with HT than with the interval from symptom onset to hospital arrival. We might extend the therapeutic time for thrombolytic therapy, only if the early CT sign does not appear. PMID- 22212446 TI - A meta-analysis of impact of proton pump inhibitors on antiplatelet effect of clopidogrel. PMID- 22212448 TI - Pravastatin normalizes endothelium-derived contracting factor-mediated response via suppression of Rho-kinase signalling in mesenteric artery from aged type 2 diabetic rat. AB - AIM: Although pravastatin has known pleiotropic effects against adverse cardiovascular conditions, little is known about its effects on endothelium derived contracting factor (EDCF)-mediated signalling. We aimed to determine the effects of pravastatin on the production of and responses to EDCF in superior mesenteric arteries isolated from rats at the chronic stage of type 2 diabetes. METHODS: Contractions to acetylcholine (ACh) were examined in superior mesenteric artery rings from aged type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats (56-60 weeks old), from control age-matched non-diabetic Long-Evans Tokushima Otsuka (LETO) rats and from pravastatin-treated (10 mg kg(-1) , p.o., daily for 4 weeks) OLETF rats. Mesenteric artery expressions of cyclo-oxygenases (COXs), microsomal-PGE synthases (mPGESs), RhoA and Rho-kinase proteins, and also the level of phosphorylated ezrin, radixin and moesin (PERM), a substrate for Rho kinase, were detected by Western blotting. RESULTS: Arteries from OLETF rats exhibited (vs. LETO rats) (1) enhanced ACh-induced EDCF-mediated contractions, which were inhibited by the Rho-kinase inhibitor Y27632, (2) reductions in the ACh-stimulated release of both PGE(2) and superoxide and (3) increased COX-1 and PERM protein expressions. Mesenteric arteries from OLETF rats treated with pravastatin exhibited (vs. untreated OLETF) (1) reduced ACh-induced contraction, (2) suppressed ACh-induced PGE(2) production and superoxide generation and (3) reduced ACh-induced PERM protein expression. CONCLUSIONS: These results suggest that pravastatin exerts beneficial effects against abnormal EDCF signalling by suppressing Rho-kinase and promoting antioxidant activity in the mesenteric arteries of rats at the chronic stage of type 2 diabetes. PMID- 22212449 TI - LhnR and upstream operon LhnABC in Agrobacterium vitis regulate the induction of tobacco hypersensitive responses, grape necrosis and swarming motility. AB - The characterization of Tn5 transposon insertional mutants of Agrobacterium vitis strain F2/5 revealed a gene encoding a predicted LysR-type transcriptional regulator, lhnR (for 'LysR-type regulator associated with HR and necrosis'), and an immediate upstream operon consisting of three open reading frames (lhnABC) required for swarming motility, surfactant production and the induction of a hypersensitive response (HR) on tobacco and necrosis on grape. The operon lhnABC is unique to A. vitis among the sequenced members in Rhizobiaceae. Mutagenesis of lhnR and lhnABC by gene disruption and complementation of DeltalhnR and DeltalhnABC confirmed their roles in the expression of these phenotypes. Mutation of lhnR resulted in complete loss of HR, swarming motility, surfactant production and reduced necrosis, whereas mutation of lhnABC resulted in loss of swarming motility, delayed and reduced HR development and reduced surfactant production and necrosis. The data from promoter-green fluorescent protein (gfp) fusions showed that lhnR suppresses the expression of lhnABC and negatively autoregulates its own expression. It was also shown that lhnABC negatively affects its own expression and positively affects the transcription of lhnR. lhnR and lhnABC constitute a regulatory circuit that coordinates the transcription level of lhnR, resulting in the expression of swarming, surfactant, HR and necrosis phenotypes. PMID- 22212450 TI - Carbohydrate functionalized iron(III) complexes as biomimetic siderophores. AB - Catechol functionalized iron(III) glycodendrimers have been prepared using a self assembly process for targeting a specific strain of E. coli bacteria and have been shown to exhibit carbohydrate-lectin mediated iron delivery in growth promotion assay. PMID- 22212451 TI - Age-dependent reduction of the PI3K regulatory subunit p85alpha suppresses pancreatic acinar cell proliferation. AB - The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is important for tissue proliferation. Previously, we found that tissue regeneration after partial pancreatic resection was markedly attenuated in aged mice as compared to young mice and that this attenuation was because of an age-dependent reduction of PI3K/Akt signaling in the pancreatic acini; however, the mechanisms for the age associated decline of pancreatic PI3K/Akt signaling remained unknown. To better delineate the mechanisms for the decreased PI3K/Akt activation with aging, age associated changes in cell proliferation and PI3K/Akt signaling were investigated in the present study using in vitro primary pancreatic acinar cell cultures derived from young and aged mice. In response to treatment with insulin-like growth factor 1 (IGF-1), acinar cells from young but not aged mice showed increased activation of PI3K/Akt signaling and cell proliferation, indicating that intrinsic cellular mechanisms cause the age-associated changes in pancreatic acinar cells. We also found that the expression of PI3K p85alpha subunit, but not IGF-1 receptor or other PI3K subunits, was significantly reduced in pancreatic acinar cells from aged mice; this age-associated reduction of p85alpha was confirmed in both mouse and human pancreatic tissues. Finally, small interfering RNA (siRNA)-mediated knockdown of p85alpha expression in acinar cells from young mice resulted in markedly attenuated activation of PI3K/Akt downstream signaling in response to IGF-1. From these results, we conclude that exocrine pancreatic expression of PI3K p85alpha subunit is attenuated by aging, which is likely responsible for the age-associated decrease in activation of pancreatic PI3K signaling and acinar cell proliferation in response to growth-promoting stimuli. PMID- 22212452 TI - Withdrawal from repeated treatment with ethanol induces a protracted decrease in novelty-seeking behavior and enhancement of environmental habituation in mice. AB - Ethanol withdrawal syndrome is characterized by somatic and behavioral symptoms, including increased anxiety and anhedonia. In animal models, however, there are many studies on the anxiogenic effects occurring during the first 24h after ethanol withdrawal, while anhedonia has been overlooked. Recently, we have found that amphetamine withdrawal reduced novelty seeking and enhanced environmental habituation in mice, two motivation-related behaviors. We now investigate the effects of withdrawal from ethanol, a drug of abuse with a different pharmacological profile, on these two motivation-related behaviors. Swiss male mice (3months old) were treated with 1.8g/kg ethanol for 21 consecutive days in their home cages. Seven days after ethanol withdrawal, mice were tested in a free choice novelty apparatus containing one familiar and one novel compartment. Novelty-seeking behavior was assessed by comparing time spent in the novel compartment versus the familiar compartment, whereas environmental habituation was concomitantly evaluated by the time-response curve of total locomotion (novel+familiar). Novelty seeking was decreased and environmental habituation was enhanced during ethanol withdrawal. These anhedonic responses were not associated with concurrent changes in the anxiety-like behavior of mice (as confirmed in the elevated plus-maze test). We propose that the concomitant evaluation of novelty seeking behavior and environmental habituation can be useful to study the behavioral consequences not only of amphetamine withdrawal but also of ethanol withdrawal. Furthermore, the present data support recent clinical findings that suggest the occurrence of protracted anhedonia well beyond the limited period immediately following the abrupt cessation of ethanol intake. PMID- 22212453 TI - Barriers and facilitators to routine distribution of patient decision support interventions: a preliminary study in community-based primary care settings. AB - BACKGROUND: A growing body of literature documents the value of decision support interventions (DESIs) in facilitating patient participation in preference sensitive decision making, but little is known about their implementation in routine care. OBJECTIVE: This study explored barriers and facilitators to prescribing DESIs in primary care. SETTING AND PARTICIPANTS: Four community-based primary care practices across Los Angeles County serving diverse low and middle income populations participated. DESIGN: The first phase focused on implementing DESI prescribing into routine care. Weekly academic detailing visits served to identify barriers to DESI prescribing, generate ethnographic field notes and record DESI prescriptions. The second phase explored the impact of a financial incentive on DESI prescribing. At the project's conclusion, each physician completed an in-depth interview. RESULTS: The four practices prescribed an average of 6.5 DESIs a month (range 3.6-9.2) during Phase I. The financial incentive increased DESI prescribing by 71% to 11.1 per month (range 3.5-21.4). The estimated percentages of patients who viewed the DESI were 37.9 and 43.9% during Phases I and II, respectively. Qualitative data suggest that physician buy in with the project goal was crucial to DESI distribution success. Competing demands and time pressures were persistent barriers. The effects of the financial incentive were mixed. CONCLUSIONS: This study confirmed the importance of physician engagement when implementing DESIs and found mixed effects for providing financial incentives. The relatively low rate of DESI viewing suggests further research on increasing patient uptake of these interventions in routine practice is necessary. PMID- 22212454 TI - Have we enough glutamine and how does it work? A clinician's view. AB - There is a gap between the scientific basis of the claim that in several disease states glutamine is lacking and the widespread belief that supplementation of glutamine to the nutritional regimen is beneficial in severely ill patients. Glutamine shortage exists when consuming tissues, playing a crucial role in the response to trauma and disease, receive insufficient amounts of glutamine. In these tissues (immune system, wound), glutamine is only partly oxidized but has more specific roles as nontoxic nitrogen carrier, precursor of several crucial metabolites required for cell proliferation and for maintenance of the redox potential, and as osmolyte. In inflammatory states, glutamine concentrations in plasma and tissues are decreased due to many disease-related factors, precluding its use as a reliable indicator of shortage. Isotope studies have yielded equivocal results, precluding their use as a reliable indicator of glutamine shortage or adequacy. The increase in the net release of glutamine from peripheral tissues to central tissues (immune system, liver, spleen, wound) in inflammatory states provides a better basis for the necessity to supplement the organism with extra glutamine in these conditions. Glutamine supplementation was beneficial in a few studies in burn or trauma patients. The clinical benefit of parenteral glutamine supplementation in patients with severe inflammation has been demonstrated more convincingly. The amounts of glutamine supplemented approximate the amounts released by peripheral tissues and utilized by central organs operative in host defense and are therefore in the physiological range. PMID- 22212455 TI - Prescription and transcription errors in multidose-dispensed medications on discharge from hospital: an observational and interventional study. AB - BACKGROUND: Medication errors frequently occur when patients are transferred between health care settings. The main objective of this study was to investigate the frequency, type and severity of prescribing and transcribing errors for drugs dispensed in multidose plastic packs when patients are discharged from the hospital. The secondary objective was to correct identified errors and suggest measures to promote safe prescribing. METHODS: The drugs on the patients' multidose drug dispensing (MDD) order sheets and the medication administration records were reconciled prior to the MDD orders being sent to the pharmacy for dispensing. Discrepancies were recorded and the prescribing physician was notified and given the opportunity to change the order. Discrepancies categorized as unintentional and related to the discharge process were subject to further analysis. RESULTS: Seventy-two (25%) of the 290 reviewed MDD orders had at least one discharge error. In total, 120 discharge errors were identified, of which 49 (41%) were assessed as being of moderate and three (3%) of major severity. Orders with a higher number of medications and orders from the orthopaedic wards had a significantly higher error rate. CONCLUSION: The main purpose of the MDD system is to increase patient safety by reducing medication errors. However, this study shows that prescribing and transcribing errors frequently occur when patients are hospitalized. Because the population enrolled in the MDD system is an elderly, physically vulnerable group with a high number of prescribed drugs, preventive measures to ensure safe prescribing of MDD drugs are warranted. PMID- 22212456 TI - Snake venomics of the pit vipers Porthidium nasutum, Porthidium ophryomegas, and Cerrophidion godmani from Costa Rica: toxicological and taxonomical insights. AB - Within the Neotropical pit vipers, a lineage of primarily Middle American snake species referred to as the "Porthidium group" includes the genera Atropoides, Cerrophidion, and Porthidium. In this study, the venom proteomes of Porthidium nasutum, P. ophryomegas, and Cerrophidion godmani from Costa Rica were analyzed, and correlated to their toxic and enzymatic activities. Their HPLC profiles revealed a higher similarity between the two Porthidium species than between these and C. godmani. Proteins belonging to nine (P. nasutum), eight (P. ophryomegas), and nine (C. godmani) families were identified by mass spectrometry or N-terminal sequencing. Final cataloging of proteins and their relative abundances confirmed the close relationship between venoms of P. nasutum and P. ophryomegas, departing from that of C. godmani. Since the latter species had been taxonomically classified as Porthidium godmani previously, our venomic analyses agree with its current generic status. Venoms of P. nasutum and P. ophryomegas, despite containing abundant metalloproteinases and serine proteinases, lack procoagulant activity on human plasma, in contrast to venom of C. godmani. The latter induced strong myotoxicity in mice, which correlates with its high proportion of phospholipases A(2), whereas venoms from the two Porthidium species, containing lower amounts of these enzymes, induced only mild muscle damage. PMID- 22212457 TI - Psychometric properties of the German version of the Short-Form Supportive Care Needs Survey Questionnaire (SCNS-SF34-G). AB - PURPOSE: The recommendation to screen for distress and supportive care needs among cancer patients focuses on improving the quality, effectiveness, and efficiency of comprehensive cancer care. The purpose of this study was to test the psychometric properties of the German version of the Short-Form Supportive Care Needs Survey (SCNS-SF34-G). METHODS: One thousand forty-seven participants with heterogeneous tumor entities were recruited in inpatient and outpatient cancer care facilities (female, 51%; median age, 57 years; breast cancer, 26%; prostate cancer, 22%). Concurrent and divergent validity of the SCNS-SF34-G was analyzed through associations with measures of distress, depression, anxiety, and social support. RESULTS: Principal component analyses revealed five dimensions replicating the factorial structure of the original SCNS-SF34 (health system and information, psychological, physical and daily living, patient care and support, sexuality needs) explaining 68% of variance. Cronbach's alpha values ranged from 0.82 to 0.94. Convergent validity was supported by significant correlations between all SCNS-SF34-G subscales and psychosocial burden. Divergent validity was indicated by marginal correlations with social support. The SCNS-SF34-G was able to discriminate patient groups with respect to sex and age but not regarding tumor stage. CONCLUSIONS: The SCNS-SF34-G is an instrument with excellent psychometric properties for assessing supportive care needs among patients with various cancer entities. It seems to be useful to integrate the questionnaire into diagnostic assessment to tailor interventions according to patient needs. Further research is needed to gain knowledge of the development of unmet needs during the illness trajectory as well as of associations with offer and utilization of healthcare services. PMID- 22212458 TI - Images in endocrine pathology: a starry-sky in the thyroid. PMID- 22212459 TI - On a Cercopithifilaria sp. transmitted by Rhipicephalus sanguineus: a neglected, but widespread filarioid of dogs. AB - BACKGROUND: This study was aimed at investigating the distribution of a Cercopithifilaria sp. sensu Otranto et al., 2011 with dermal microfilariae recently identified in a dog from Sicily (Italy). A large epidemiological survey was conducted by examining skin samples (n = 917) and ticks (n = 890) collected from dogs at different time points in Italy, central Spain and eastern Greece. RESULTS: The overall prevalence of Cercopithifilaria sp. in the sampled animal populations was 13.9% and 10.5% by microscopy of skin sediments and by PCR on skin samples, respectively. Up to 21.6% and 45.5% of dogs in Spain were positive by microscopical examination and by PCR. Cumulative incidence rates ranging from 7.7% to 13.9% were estimated in dogs from two sites in Italy. A low level of agreement between the two diagnostic tests (microscopical examination and PCR) was recorded in sites where samples were processed in parallel. Infestation rate as determined by tick dissection (from 5.2% to 16.7%) was higher than that detected by PCR (from 0% to 3.9%); tick infestation was significantly associated with Cercopithifilaria sp. infestation in dogs from two out of four sites. Developing larvae found in ticks were morphometrically studied and as many as 1469 larvae were found in a single tick. CONCLUSIONS: Our data suggest that, in addition to the most common species of filarioids known to infest dogs (i.e., Dirofilaria immitis, Dirofilaria repens and Acanthocheilonema reconditum), Cercopithifilaria sp. with dermal microfilariae should be considered due to its widespread distribution in southern Europe and high frequency in tick-exposed dogs. PMID- 22212460 TI - Analysis of p15INK4b and p16INK4a gene methylation in patients with oral squamous cell carcinoma. PMID- 22212461 TI - Sugarcane genes differentially expressed in response to Puccinia melanocephala infection: identification and transcript profiling. AB - Brown rust caused by the fungus Puccinia melanocephala is a major disease of sugarcane (Saccharum spp.). A sugarcane mutant, obtained by chemical mutagenesis of the susceptible variety B4362, showed a post-haustorial hypersensitive response (HR)-mediated resistance to the pathogen and was used to identify genes differentially expressed in response to P. melanocephala via suppression subtractive hybridization (SSH). Tester cDNA was derived from the brown rust resistant mutant after inoculation with P. melanocephala, while driver cDNAs were obtained from the non-inoculated resistant mutant and the inoculated susceptible donor variety B4362. Database comparisons of the sequences of the SSH recombinant clones revealed that, of a subset of 89 non-redundant sequences, 88% had similarity to known functional genes, while 12% were of unknown function. Thirteen genes were selected for transcript profiling in the resistant mutant and the susceptible donor variety. Genes involved in glycolysis and C4 carbon fixation were up-regulated in both interactions probably due to disturbance of sugarcane carbon metabolism by the pathogen. Genes related with the nascent polypeptide associated complex, post-translational proteome modulation and autophagy were transcribed at higher levels in the compatible interaction. Up regulation of a putative L-isoaspartyl O-methyltransferase S-adenosylmethionine gene in the compatible interaction may point to fungal manipulation of the cytoplasmatic methionine cycle. Genes coding for a putative no apical meristem protein, S-adenosylmethionine decarboxylase, non-specific lipid transfer protein, and GDP-L-galactose phosphorylase involved in ascorbic acid biosynthesis were up regulated in the incompatible interaction at the onset of haustorium formation, and may contribute to the HR-mediated defense response in the rust-resistant mutant. PMID- 22212462 TI - Transgenic sweet potato expressing thionin from barley gives resistance to black rot disease caused by Ceratocystis fimbriata in leaves and storage roots. AB - Black rot of sweet potato caused by pathogenic fungus Ceratocystis fimbriata severely deteriorates both growth of plants and post-harvest storage. Antimicrobial peptides from various organisms have broad range activities of killing bacteria, mycobacteria, and fungi. Plant thionin peptide exhibited anti fungal activity against C. fimbriata. A gene for barley alpha-hordothionin (alphaHT) was placed downstream of a strong constitutive promoter of E12Omega or the promoter of a sweet potato gene for beta-amylase of storage roots, and introduced into sweet potato commercial cultivar Kokei No. 14. Transgenic E12Omega:alphaHT plants showed high-level expression of alphaHT mRNA in both leaves and storage roots. Transgenic beta-Amy:alphaHT plants showed sucrose inducible expression of alphaHT mRNA in leaves, in addition to expression in storage roots. Leaves of E12Omega:alphaHT plants exhibited reduced yellowing upon infection by C. fimbriata compared to leaves of non-transgenic Kokei No. 14, although the level of resistance was weaker than resistance cultivar Tamayutaka. Storage roots of both E12Omega:alphaHT and beta-Amy:alphaHT plants exhibited reduced lesion areas around the site inoculated with C. fimbriata spores compared to Kokei No. 14, and some of the transgenic lines showed resistance level similar to Tamayutaka. Growth of plants and production of storage roots of these transgenic plants were not significantly different from non-transgenic plants. These results highlight the usefulness of transgenic sweet potato expressing antimicrobial peptide to reduce damages of sweet potato from the black rot disease and to reduce the use of agricultural chemicals. PMID- 22212463 TI - Tocol modified glycol chitosan for the oral delivery of poorly soluble drugs. AB - The aim of this study was to develop tocol derivatives of chitosan able (i) to self-assemble in the gastrointestinal tract and (ii) to enhance the solubility of poorly soluble drugs. Among the derivatives synthesized, tocopherol succinate glycol chitosan (GC-TOS) conjugates spontaneously formed micelles in aqueous solution with a critical micelle concentration of 2 MUg mL(-1). AFM and TEM analysis showed that spherical micelles were formed. The GC-TOS increased water solubility of 2 model class II drugs. GC-TOS loading efficiency was 2.4% (w/w) for ketoconazole and 0.14% (w/w) for itraconazole, respectively. GC-TOS was non cytotoxic at concentrations up to 10 mg mL(-1). A 3.4-fold increase of the apparent permeation coefficient of ketoconazole across a Caco-2 cell monolayer was demonstrated. Tocol polymer conjugates may be promising vehicles for the oral delivery of poorly soluble drugs. PMID- 22212464 TI - Follow up of aerobic capacity in children affected by severe acute respiratory syndrome. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to investigate the aerobic capacity of children 3 years after they were diagnosed with severe acute respiratory syndrome (SARS). METHODS: Twenty-seven patients who completed both pulmonary function and maximal aerobic capacity tests at 6 and 15 months after the acute illness were invited to return for reassessment. RESULTS: Twenty-one patients (median age 18.2 years, interquartile range (IQR) 16.5-19.7) completed all investigations at 36 months. Pulmonary function was normal in all patients. Maximal aerobic capacity, peak oxygen pulse (peak VO(2) ) and ventilatory anaerobic threshold showed significant improvements compared with values measured at 6 months in both boys and girls. In girls, ventilatory efficiency (ventilatory equivalents for oxygen and carbon dioxide) and perfusion of the lungs (end-tidal partial carbon dioxide pressure) had not increased further compared with the values measured at 15 months. Although peak VO(2) improved further at 36 months in patients with or without persistent radiological abnormalities, the values were 68% (IQR 50-84) and 74% (IQR 60-99), respectively, of those for normal control subjects. CONCLUSIONS: There were improvements in aerobic capacity at 36 months in children affected by SARS; however, the measured values remained suboptimal. PMID- 22212465 TI - In vitro and in vivo trypanocidal activity of some benzimidazole derivatives against two strains of Trypanosoma cruzi. AB - The trypanocidal effect of five benzimidazole derivatives (1-5) was determined in vitro and in vivo assays against two strains of Trypanosoma cruzi (NINOA and INC5). The in vitro trypanocidal activity was evaluated by measuring the percentage of lysis of bloodstream trypomastigotes of T. cruzi. Results point to 5-chloro-1H-benzimidazole-2-thiol (1) as the best activity profile compound with a 50% lytic concentration (LC(50)) of 0.014 mM (NINOA strain) and 0.32 mM (INC5 strain). Reference drugs were nifurtimox (Nfx) and benznidazole (Bnz), which on NINOA strain displayed a LC(50)=0.60 mM and LC(50)=0.78 mM, respectively; while on INC5 strain they exhibited LC(50) values of 0.31 mM and 0.69 mM, respectively. The in vivo trypanocidal activity of 1-5 on parasitemia in a murine model acute Chagas' disease indicated that 1 and Nfx showed similar activity on INC5 strain, while 5-chloro-1-methyl-1H-benzimidazole-2-thiol (2) and its regioisomer, 6 chloro-1-methyl-1H-benzimidazole-2-thiol (3), displayed better activity than Nfx and Bnz on NINOA strain. All compounds showed low cytotoxicity against Vero cells, with selective index 38-3000 times higher to the parasite. PMID- 22212467 TI - Polypharmacy as a risk for fall occurrence in geriatric outpatients. AB - OBJECTIVE: To investigate the predictors of falls, such as comorbidity and medication, in geriatric outpatients in a longitudinal observational study. METHODS: A total of 172 outpatients (45 men and 126 women, mean age 76.9 +/- 7.0 years) were evaluated. Physical examination, clinical history and medication profile were obtained from each patient at baseline. These patients were followed for up to 2 years and falls were self-reported to their physicians. The factors associated with falls were analyzed statistically. RESULTS: A total of 32 patients experienced falls within 2 years. On univariate analysis, older age, osteoporosis, number of comorbid conditions and number of drugs were significantly associated with falls within 2 years. On multiple logistic regression analysis, the number of drugs was associated with falls, independent of age, sex, number of comorbid conditions and other factors that were significantly associated in univariate analysis. A receiver-operator curve evaluating the optimal cut-off value for the number of drugs showed that taking five or more drugs was a significant risk. CONCLUSION: In geriatric outpatients, polypharmacy is associated with falls. Intervention studies are needed to clarify the causal relationship between polypharmacy, comorbidity and falls. PMID- 22212466 TI - Bivalirudin inhibits periprocedural platelet function and tissue factor expression of human smooth muscle cells. AB - AIM: A major concern of stent implantation after percutaneous coronary intervention (PCI) is acute stent thrombosis. Effective inhibition of periprocedural platelet function in patients with coronary artery disease (CAD) leads to an improved outcome. In this study, we examined the periprocedural platelet reactivity after administrating bivalirudin during PCI compared to unfractionated heparin (UFH) administration. Further, the effect of bivalirudin on induced tissue factor (TF) expression in smooth muscle cells (SMC) was determined. METHODS: Patients with CAD (n = 58) and double antithrombotic medication were treated intraprocedural with UFH (n = 30) or bivalirudin (n = 28). Platelet activation markers were flow cytometrically measured before and after stenting. The expression of TF in SMC was determined by real-time PCR and Western blotting. The thrombogenicity of platelet-derived microparticles and SMC was assessed via a TF activity assay. RESULTS: Bivalirudin significantly diminished the agonist-induced platelet reactivity post-PCI. Compared to UFH treatment, the adenosine diphosphate (ADP) and thrombin receptor-activating peptide (TRAP)-induced thrombospondin expression post-PCI was reduced when bivalirudin was administrated during intervention. In contrast to UFH, bivalirudin reduced the P-selectin expression of unstimulated and ADP-induced platelets post-PCI. Moreover, bivalirudin inhibited the thrombin-, but not FVIIa- or FVIIa/FX-induced TF expression and pro-coagulant TF activity of SMC. Moreover, bivalirudin reduced the TF activity of platelet-derived microparticles postinduction with TRAP or ADP. CONCLUSIONS: Bivalirudin is better than UFH in reducing periprocedural platelet activation. Moreover, thrombin-induced TF expression is inhibited by bivalirudin. Thus, bivalirudin seems to be a better anticoagulant during PCI than UFH. PMID- 22212470 TI - Effects of Se-enriched polysaccharides produced by Enterobacter cloacae Z0206 on alloxan-induced diabetic mice. AB - In this study, the water-soluble selenium-enriched exopolysaccharides (Se-ECZ EPS) were isolated from submerged culture broth of Enterobacter cloacae Z0206 through fermentation, ethanol precipitation and deproteinization. The protective effects of Se-ECZ-EPS on alloxan-induced diabetic mice were investigated. Diabetes was induced in ICR (Institute of Cancer Research) mice by administration of single doses of alloxan intraperitoneally (190 mg/kg body weight). Se-ECZ-EPS at a dose of 200 mg/kg body weight were administered per os (p.o.) as single dose per day to diabetes-induced mice for a period of 42 days. The decrease in body weight, serum insulin level, and the increase in blood glucose level, glycosylated serum protein (GSP), total cholesterol (TC) and triglycerides (TG) in liver were observed in diabetic mice. On the other hand, oral administration of Se-ECZ-EPS resulted in a significant reduction in fasting blood glucose levels, GSP, TC and TG contents in liver coupled with improvement of body weight and serum insulin level in comparison with diabetic control group. These results suggest that Se-ECZ-EPS possess significant protective and anti-diabetic effects in alloxan-induced diabetic mice. PMID- 22212471 TI - Functional and conformational changes in the aspartic protease cardosin A induced by TFE. AB - Conformational and functional changes of cardosin A, an aspartic protease of vegetal origin, in the presence of 2,2,2-trifluoroethanol (TFE), were assessed. TFE induced alterations of cardosin activity and conformation that differed with the solvent concentration. MD simulations showed that there are significant local alterations in protein flexibility and TFE molecules were found to replace several hydration molecules in the active site of the enzyme. This may explain some of the activity loss observed in the presence of TFE, especially at low TFE concentrations, as well as the recovery of enzyme activity upon aqueous dilution, indicating the release of the TFE molecules from the active site. PMID- 22212472 TI - Identification of age-specific Nrf2 binding to a novel antioxidant response element locus in the Gclc promoter: a compensatory means for the loss of glutathione synthetic capacity in the aging rat liver? AB - NFE2-related factor 2 (Nrf2) transcriptionally governs the cellular response to harmful electrophiles, xenobiotics, and reactive oxygen species. Its nuclear levels decline with age (Suh et al., 2004a), which in part explains the age related loss of phase II detoxification. However, little work has yet characterized how age affects Nrf2 DNA binding or the role that alterations to the Nrf2 transcriptional apparatus plays in modulating Nrf2-mediated gene expression. In this study, we used immunoprecipitation assays to show that Nrf2 bound to the active antioxidant response element (ARE) of the catalytic subunit of glutamate cysteine ligase (GCLC) is significantly lower in hepatic chromatin from aged vs. young rats. Moreover, the activity at this ARE locus is diminished during aging because of the presence of Bach1 and the absence of CREB-binding protein (CBP), a transcriptional repressor and co-activator, respectively. Further analysis reveals that Nrf2 occupies an alternate ARE site located -2.2 kb downstream from the normally active ARE binding site in livers of old rats, indicating an age-specific adaptation to maintain gene expression. Our results, thus, show that the conversion of Nrf2 binding from an active ARE to an alternative ARE element is not adequate to maintain basal expression of hepatic Gclc in old rats, which provides a potential mechanism for the age-related loss of glutathione synthetic and other phase II enzymes. PMID- 22212473 TI - Proteinuria in AMPD2-deficient mice. AB - The AMPD2 gene, a member of the AMPD gene family encoding AMP deaminase, is widely expressed in nonmuscle tissues including kidney, although its functions have not been fully elucidated. In this study, we studied the function of the AMPD2 gene by establishing AMPD2-deficient model animal. We established AMPD2 knockout mice by using gene transfer and homologous recombination in murine ES cells and studied phenotypes and functions in the kidneys of these animals. AMPD activity was decreased from 22.9 mIU/mg protein to 2.5 mIU/mg protein in the kidneys of AMPD knockout mice. In addition to changes in nucleotide metabolism in the kidneys, proteinuria was found in 3-week-old AMPD2 knockout mice, followed by a further increment up to a peak level at 6 weeks old (up to 0.6 g/dL). The major protein component in the urine of AMPD2 knockout mice was found to be albumin, indicating that AMPD2 may have a key role in glomerular filtration. Indeed, an ultrastructure study of glomerulus specimens from these mice showed effacement of the podocyte foot processes, resembling minimal-change nephropathy in humans. Based on our results, we concluded that AMPD2 deficiency induces imbalanced nucleotide metabolism and proteinuria, probably due to podocyte dysfunction. PMID- 22212474 TI - Localized expression of human BMP-7 by BM-MSCs enhances renal repair in an in vivo model of ischemia-reperfusion injury. AB - Ischemia and subsequent reperfusion (I/R) damage kidney tubular cells and consequently impair renal function. Rabbit bone marrow mesenchymal stem cells (BM MSCs) expressing human bone morphogenic protein-7 (hBMP-7) regenerated tubular cells and improved renal function in a kidney I/R model. Rabbits were injected immediately after I/R with one of the following: (i) hBMP-7-transduced BM-MSCs (BM-MSCshBMP-7); (ii) enhanced green fluorescent protein-transduced BM-MSCs (BM MSCsEGFP); or (iii) PBS. The activity of superoxide dismutase (SOD) was higher, and the amount of malondialdehyde (MDA) was lower in the BM-MSCshBMP-7 group than in the BM-MSCsEGFP group. Both the BM-MSCshBMP-7 group and the BM-MSCsEGFP group had higher SOD activity and lower amounts of MDA than the PBS group. Bcl-2- and Bcl-2-associated X protein levels, and other variables, indicated the regeneration of the kidney in both experimental groups. However, the BM-MSCs (hBMP-7) group showed higher activity than the BM-MSCsEGFP group, indicating that the combined strategy of BM-MSC transplantation with hBMP-7 gene therapy could be a useful approach for the treatment of renal IRI. PMID- 22212475 TI - Nucleosome surface containing nucleosomal DNA entry/exit site regulates H3-K36me3 via association with RNA polymerase II and Set2. AB - A nucleosome is composed of intrinsically disordered histone tails and a structured nucleosome core surrounded by DNA. A variety of modifiable residues on the intrinsically disordered histone tails have been identified in the last decade. Mapping of the functional residues on the structured nucleosome core surface was recently initiated by global analysis of a comprehensive histone point mutant library (histone-GLibrary). It stands to reason that a functional relationship exists between modifiable residues on the intrinsically disordered histone tails and functional residues on the structured nucleosome core; however, this matter has been poorly explored. During transcription elongation, trimethylation of histone H3 at lysine 36 (H3-K36me3) is mediated by histone methyltransferase Set2, which binds to RNA polymerase II. Here, we used a histone GLibrary that encompasses the nucleosomal DNA entry/exit site to show that six residues (H2A-G107, H2A-I112, H2A-L117, H3-T45, H3-R49 and H3-R52) form a surface on the structured nucleosome core and regulate H3-K36me3. Trimethylation at H3-K4 introduced by histone methyltransferase Set1 was not affected by the mutation of any of the six residues. Chromatin immunoprecipitation analysis showed that most of these residues are critical for the chromatin association of RNA polymerase II and Set2, suggesting that these components regulate H3-K36me3 through functional interactions with the structured nucleosome core surface. PMID- 22212476 TI - Glycemic responses of patients with type 2 diabetes to individual carbohydrate rich foods and mixed meals. AB - AIMS: Our purpose was to determine whether the glycemic index (GI) of individual foods applies to mixed meals. METHODS: The glycemic responses elicited by portions of 4 individual foods with 25 g of available carbohydrate when served alone (rice, lacy pancake, flatbread and noodles) and when made into typical Malaysian mixed meals (coconut milk rice, lacy pancake with chicken curry, flatbread with dhal curry and fried noodles) were measured in 10 subjects with type 2 diabetes. To allow calculation of the GI of the foods and the relative glycemic responses of the mixed meals, each subject also tested 25 g of glucose 3 times. Capillary blood glucose was measured at 30-min intervals for 180 min after consuming each test meal. RESULTS: The mean +/- SEM incremental area under the curve (AUC) after flatbread (345 +/- 26 mmol * min/l) was significantly greater than after rice (238 +/- 35) and lacy pancake (235 +/- 31, p < 0.05), with noodles being intermediate (294 +/- 35). The AUC after the flatbread with dhal curry (341 +/- 49), coconut milk rice (238 +/- 39) and fried noodle (272 +/- 42) mixed meals were similar to those after the individual foods, but the AUC after the lacy pancake with chicken curry mixed meal (388 +/- 52) was significantly greater than after the individual food item (p < 0.01). CONCLUSIONS: The results support the utility of the GI of individual foods such as rice, flatbread and noodles when applied to mixed meals. The reason for the higher response after the lacy pancake mixed meal compared to the individual food is not clear and may warrant further research. PMID- 22212477 TI - Telomere length and iPSC re-programming: survival of the longest. PMID- 22212478 TI - Breathless cancer cells get fat on glutamine. PMID- 22212479 TI - A human ESC model for MLL-AF4 leukemic fusion gene reveals an impaired early hematopoietic-endothelial specification. AB - The MLL-AF4 fusion gene is a hallmark genomic aberration in high-risk acute lymphoblastic leukemia in infants. Although it is well established that MLL-AF4 arises prenatally during human development, its effects on hematopoietic development in utero remain unexplored. We have created a human-specific cellular system to study early hemato-endothelial development in MLL-AF4-expressing human embryonic stem cells (hESCs). Functional studies, clonal analysis and gene expression profiling reveal that expression of MLL-AF4 in hESCs has a phenotypic, functional and gene expression impact. MLL-AF4 acts as a global transcriptional activator and a positive regulator of homeobox gene expression in hESCs. Functionally, MLL-AF4 enhances the specification of hemogenic precursors from hESCs but strongly impairs further hematopoietic commitment in favor of an endothelial cell fate. MLL-AF4 hESCs are transcriptionally primed to differentiate towards hemogenic precursors prone to endothelial maturation, as reflected by the marked upregulation of master genes associated to vascular endothelial functions and early hematopoiesis. Furthermore, we report that MLL AF4 expression is not sufficient to transform hESC-derived hematopoietic cells. This work illustrates how hESCs may provide unique insights into human development and further our understanding of how leukemic fusion genes, known to arise prenatally, regulate human embryonic hematopoietic specification. PMID- 22212480 TI - MRG-1 is required for genomic integrity in Caenorhabditis elegans germ cells. AB - During meiotic cell division, proper chromosome synapsis and accurate repair of DNA double strand breaks (DSBs) are required to maintain genomic integrity, loss of which leads to apoptosis or meiotic defects. The mechanisms underlying meiotic chromosome synapsis, DSB repair and apoptosis are not fully understood. Here, we report that the chromodomain-containing protein MRG-1 is an important factor for genomic integrity in meiosis in Caenorhabditis elegans. Loss of mrg-1 function resulted in a significant increase in germ cell apoptosis that was partially inhibited by mutations affecting DNA damage checkpoint genes. Consistently, mrg-1 mutant germ lines exhibited SPO-11-generated DSBs and elevated exogenous DNA damage-induced chromosome fragmentation at diakinesis. In addition, the excessive apoptosis in mrg-1 mutants was partially suppressed by loss of the synapsis checkpoint gene pch-2, and a significant number of meiotic nuclei accumulated at the leptotene/zygotene stages with an elevated level of H3K9me2 on the chromatin, which was similarly observed in mutants deficient in the synaptonemal complex, suggesting that the proper progression of chromosome synapsis is likely impaired in the absence of mrg-1. Altogether, these findings suggest that MRG-1 is critical for genomic integrity by promoting meiotic DSB repair and synapsis progression in meiosis. PMID- 22212481 TI - Determinants of public T cell responses. AB - Historically, sharing T cell receptors (TCRs) between individuals has been speculated to be impossible, considering the dramatic discrepancy between the potential enormity of the TCR repertoire and the limited number of T cells generated in each individual. However, public T cell response, in which multiple individuals share identical TCRs in responding to a same antigenic epitope, has been extensively observed in a variety of immune responses across many species. Public T cell responses enable individuals within a population to generate similar antigen-specific TCRs against certain ubiquitous pathogens, leading to favorable biological outcomes. However, the relatively concentrated feature of TCR repertoire may limit T cell response in a population to some other pathogens. It could be a great benefit for human health if public T cell responses can be manipulated. Therefore, the mechanistic insight of public TCR generation is important to know. Recently, high-throughput DNA sequencing has revolutionized the study of immune receptor repertoires, which allows a much better understanding of the factors that determine the overlap of TCR repertoire among individuals. Here, we summarize the current knowledge on public T-cell response and discuss future challenges in this field. PMID- 22212482 TI - A distinct response to endogenous DNA damage in the development of Nbs1-deficient cortical neurons. AB - Microcephaly is a clinical characteristic for human nijmegen breakage syndrome (NBS, mutated in NBS1 gene), a chromosomal instability syndrome. However, the underlying molecular pathogenesis remains elusive. In the present study, we demonstrate that neuronal disruption of NBS (Nbn in mice) causes microcephaly characterized by the reduction of cerebral cortex and corpus callosum, recapitulating neuronal anomalies in human NBS. Nbs1-deficient neocortex shows accumulative endogenous DNA damage and defective activation of Ataxia telangiectasia and Rad3-related (ATR)-Chk1 pathway upon DNA damage. Notably, in contrast to massive apoptotic cell death in Nbs1-deficient cerebella, activation of p53 leads to a defective neuroprogenitor proliferation in neocortex, likely via specific persistent induction of hematopoietic zinc finger (Hzf) that preferentially promotes p53-mediated cell cycle arrest whilst inhibiting apoptosis. Moreover, Trp53 mutations substantially rescue the microcephaly in Nbs1-deficient mice. Thus, the present results reveal the first clue that developing neurons at different regions of brain selectively respond to endogenous DNA damage, and underscore an important role for Nbs1 in neurogenesis. PMID- 22212483 TI - Haemodynamic management strategies are not explicitly defined in the majority of therapeutic hypothermia implementation studies. AB - BACKGROUND: Therapeutic hypothermia (TH) has revolutionized the management of comatose post-cardiac arrest syndrome (PCAS) patients. The 2008 ILCOR/AHA Consensus Statement for the treatment of PCAS suggests that goal-directed therapy, targeting mean arterial pressure (MAP), central venous pressure (CVP), and central venous oxygen saturation (ScvO(2)), should be employed to normalize oxygen delivery. However, the optimal PCAS haemodynamic management strategy has not been defined and few objective data exist to guide clinicians. OBJECTIVE: To describe the haemodynamic strategies used in TH implementation studies. METHODS: A Medline search (time period, 3/2002 to 3/2010) was performed using the terms cardiac arrest and hypothermia, induced, then limited post-search to implementation studies of TH in comatose adults. The identified studies were examined for explicit definitions of the following terms: MAP; systolic blood pressure (SBP), CVP, ScvO(2), pulmonary artery catheter (PAC), echocardiogram (ECHO), lactate, and volume status. RESULTS: Forty-four implementation studies were identified and 43% (19/44) of them mentioned haemodynamics in any fashion. At least one haemodynamic goal was specifically defined in 16/44 (36%). The median number defined was 4 (range 1-6); individual goals as follows: MAP, 13/44 (30%); SBP, 3/44 (7%); CVP, 5/44 (11%); ScvO(2), 4/44 (9%); PAC, 7/44 (16%); ECHO, 7/44 (16%); lactate, 5/44 (11%); and volume status, 8/44 (18%). CONCLUSIONS: Specific haemodynamic goals are defined in a minority of published TH implementation studies. Given the volatile haemodynamics of the PCAS and lack of consensus on an optimal resuscitation strategy, explicit description of haemodynamic goals should be provided in future studies. PMID- 22212486 TI - Predicting responses to sunitinib using single nucleotide polymorphisms: Progress and recommendations for future trials. AB - Targeted therapy with tyrosine kinase inhibitors has led to a substantial improvement in the standard of care for patients with advanced or metastatic clear cell renal cell carcinoma. Because the mechanism of action, metabolism and transport of tyrosine kinase inhibitors can affect outcome and toxicity, several investigators have pursued the identification of single nucleotide polymorphisms (SNPs) in genes associated with these actions. We discuss SNPs associated with outcome and toxicity following sunitinib therapy and provide recommendations for future trials to facilitate the use of SNPs in personalized therapy for this disease. PMID- 22212485 TI - (-)-Epigallocatechin-3-gallate increases the number of neural stem cells around the damaged area after rat traumatic brain injury. AB - A major component of green tea is (-)-epigallocatechin gallate (EGCG), which has strong antioxidant properties. Here, we investigated the effect of EGCG on neural stem cell (NSC) proliferation around the damaged area following traumatic brain injury (TBI). In this study, male Wistar rats that had access to normal drinking water, or water containing 0.1% (w/v) EGCG, ad libitum received TBI at 10 weeks of age. Immunohistochemistry revealed that the number of nestin-positive cells around the damaged area after TBI in the EGCG treatment group increased significantly compared with the normal water group (P < 0.05). However, the number of 8-hydroxy-2'-deoxyguanosine-, 4-hydroxy-2-nonenal-, single-stranded DNA (ssDNA)-positive cells and the level of peroxidation around the damaged area after TBI significantly decreased in the EGCG treatment group when compared with the water group (P < 0.05). Furthermore, in contrast to the EGCG group, almost all ssDNA-positive cells in the water group co-localized with NeuN and nestin staining. Ex vivo studies revealed that spheres could only be isolated from injured brain tissue in the water group at 3 days following TBI. However, in the EGCG group, spheres could be isolated at both 3 and 7 days following TBI. A greater number of spheres could be isolated from the EGCG group, which differentiated into neurons and glia in culture without basic fibroblast growth factor. These results indicate that consumption of water containing EGCG pre- and post-TBI inhibits free radical-induced degradation of NSCs, which have the potential to differentiate into neurons and glia around the area of damage following TBI. PMID- 22212484 TI - Reactive oxygen/nitrogen species and their functional correlations in neurodegenerative diseases. AB - The continuous production and efflux of reactive oxygen/nitrogen species from endogenous and exogenous sources can damage biological molecules and initiate a cascade of events. Mitochondria are pivotal in controlling cell survival and death. Cumulative oxidative stress, disrupted mitochondrial respiration, and mitochondrial damage are related with various neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and others. Biochemical cascades of apoptosis are mediated in signaling molecules, including protein kinases and transcription factors. The expressions in the pro-apoptotic signal transduction networks may indeed promote cell death and degeneration in brain cells. The regulation of that protein phosphorylation by kinases and phosphatases is emerging as a prerequisite mechanism in the control of the apoptotic cell death program. In this review, we attempt to put forth the evidence for possible mechanistic explanations for involvement of free radicals in the pathogenesis of neurodegenerative diseases. PMID- 22212487 TI - PINK1 overexpression protects against C2-ceramide-induced CAD cell death through the PI3K/AKT pathway. AB - The etiology of Parkinson's disease (PD) remains unknown. Mutations in several genes, including PINK1, have provided an understanding of the molecular mechanisms of this pathology. We analyzed the role of PINK1 overexpression (wild type PINK1 or PINK1 with G309D or L347P mutations) on neurotoxicity associated with C2-ceramide exposure in CAD cells. CAD cells were transiently transfected with either PINK1 (wild type or mutated) or with empty vector and then treated with 25-MUM C2-ceramide for 6 h. Cell viability and mitochondrial membrane potential were analyzed by flow cytometry, expression of Bax and Bcl-2 was determined by real-time PCR, and AKT phosphorylation was analyzed by western blot. CAD cells overexpressing wild-type PINK1 and treated with C2-ceramide showed lower percentages of depolarized mitochondria, lower expressions of Bax and higher expressions of Bcl-2 than non-transfected cells. In addition, wild type PINK1 rescued C2-ceramide-induced inhibition of AKT phosphorylation. Overexpression of PINK1 G309D mutation caused an increase of depolarized mitochondria, a decrease of Bax and an increase in Bcl-2 expression levels. PINK1 L4347P mutation was associated with a higher drop in mitochondrial membrane potential and increased expression of Bax, with minimal variation in the expression of Bcl-2. PINK1 mutations did not result in variations of AKT phosphorylation. We suggest that by preventing mitochondrial dysfunction and reinforcing anti-apoptotic and neuronal survival pathways such as Bcl-2 and PI3K/AKT, PINK1 confers a neuroprotective effect against the neurotoxin C2 ceramide. These effects were abrogated by PINK1 mutations. PMID- 22212488 TI - Tetrahydrocurcumin ameliorates homocysteinylated cytochrome-c mediated autophagy in hyperhomocysteinemia mice after cerebral ischemia. AB - High levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy), contribute to autophagy and ischemia/reperfusion injury (I/R). Previous studies have shown that I/R injury and HHcy cause increased cerebrovascular permeability; however, the associated mechanism remains obscure. Interestingly, during HHcy, cytochome-c becomes homocysteinylated (Hcy-cyto-c). Cytochrome-c (cyto-c) transports electrons and facilitates bioenergetics in the system. However, its role in autophagy during ischemia/reperfusion injury is unclear. Tetrahydrocurcumin (THC) is a major herbal antioxidant and anti-inflammatory agent. Therefore, the objective of this study was to determine whether THC ameliorates autophagy during ischemia/reperfusion injury by reducing homocysteinylation of cyto-c in hyperhomocysteinemia pathological condition. To test this hypothesis, we employed 8-10-week-old male cystathionine-beta-synthase heterozygote knockout (CBS+/-) mice (genetically hyperhomocystemic mice). Experimental group was: CBS+/-, CBS+/- + THC (25 mg/kg in 0.1% DMSO dose); CBS +/ /I/R, and CBS+/-/I/R + THC (25 mg/kg in 0.1% DMSO dose). Ischemia was performed for 30 min and reperfusion for 72 h. THC was injected intra-peritoneally (I.P.) once daily for a period of 3 days after 30 min of ischemia. The infarct area was measured using 2,3,5-triphenyltetrazolium chloride staining. Permeability was determined by brain edema and Evans Blue extravasation. The brain tissues were analyzed for oxidative stress, matrix metalloproteinase-9 (MMP-9), damage regulated autophagy modulator (DRAM), and microtubule-associated protein 1 light chain 3 (LC3) by Western blot. The mRNA levels of S-adenosyl-L-homocysteine hydrolases (SAHH) and methylenetetrahydrofolate reductase (MTHFR) genes were measured by quantitative real-time polymerase chain reaction. Co immunoprecipitation was used to determine the homocysteinylation of cyto-c. We found that brain edema and Evans Blue leakage were reduced in I/R + THC-treated groups as compared to sham-operated groups along with reduced brain infarct size. THC also decreased oxidative damage and ameliorated the homocysteinylation of cyto-c in-part by MMP-9 activation which leads to autophagy in I/R groups as compared to sham-operated groups. This study suggests a potential therapeutic role of dietary THC in cerebral ischemia. PMID- 22212489 TI - Proximal giant neurofilamentous axonopathy in mice genetically engineered to resist calpain and caspase cleavage of alpha-II spectrin. AB - We use 1,2-diacetylbenzene (1,2-DAB) to probe molecular mechanisms of proximal giant neurofilamentous axonopathy (PGNA), a pathological hallmark of amyotrophic lateral sclerosis. The spinal cord proteome of rodents displaying 1,2-DAB PGNA suggests a reduction in the abundance of alpha-II spectrin (Spna2), a key protein in the maintenance of axonal integrity. Protein immunoblotting indicates that this reduction is due to Spna2 degradation. We investigated the importance of such degradation in 1,2-DAB PGNA. Spna2 mutant mice lacking a calpain- and/or caspase-sensitive domain (CSD), thus hypothetically resistant to 1,2-DAB, and wild-type littermates, were treated with 1,2-DAB, 35 mg/kg/day, or saline control, for 3 weeks. 1,2-DAB induced motor weakness and PGNA, irrespective of the genotype. Spna2-calpain breakdown products were not detected in mutant mice, which displayed a normal structure of the nervous system under saline treatment. Intriguingly, treatment with 1,2-DAB reduced the abundance of the caspase specific 120-kDa Spna2 breakdown products. Our findings indicate that degradation of Spna2 by calpain- and/or caspase is not central to the pathogenesis of 1,2-DAB axonopathy. In addition, the Spna2-CSD seems to be not required for the maintenance of the cytoskeleton integrity. Our conceptual framework offers opportunities to study the role of calpain-caspase cross talk, including that of the protease degradomics, in models of axonal degeneration. PMID- 22212490 TI - Sequencing and de novo analysis of the Chinese Sika deer antler-tip transcriptome during the ossification stage using Illumina RNA-Seq technology. AB - Deer antlers are the only mammalian appendages capable of repeated rounds of regeneration. Every year, deer antlers are shed and regrown from blastema into large branched structures of cartilage and bone. Little is known about the genes involved in antler development particularly during the later stages of ossification. We have produced more than 39 million sequencing reads in a single run using the Illumina sequencing platform. These were assembled into 138,642 unique sequences (mean size: 405 bp) representing 50 times the number of Sika deer sequences previously available in the NCBI database (as of Nov 2, 2011). Based on a similarity search of a database of known proteins, we identified 43,937 sequences with a cut-off E-value of 10(-5). Assembled sequences were annotated using Gene Ontology terms, Clusters of Orthologous Groups classifications and Kyoto Encyclopedia of Genes and Genomes pathways. A number of highly expressed genes involved in the regulation of Sika deer antler ossification, including growth factors, transcription factors and extracellular matrix components were found. This is the most comprehensive sequence resource available for the deer antler and provides a basis for the molecular genetics and functional genomics of deer antler. PMID- 22212491 TI - Effective therapeutic exercise prescription: the right exercise at the right dose. AB - The prescription of an effective therapeutic exercise program requires the right dosage of the right exercise, at the right time for that patient. The therapist must understand and apply training principles effectively in the presence of pathology, injury, or otherwise unhealthy tissue. The intervention goal is to close the gap between current performance and the desired goal or capacity. Although there may be a preferred linear path from current performance to optimal outcome, complexities of the human body, internal factors, and external variables may create barriers to this direct path. Successful programs include key program design considerations such as ensuring a stable baseline before progression, treating the right impairments and activity limitations, understanding contextual factors, considering the principles of specificity and optimal loading, and applying dosing principles. Program progression can be achieved through increases in total exercise volume and/or through manipulation of exercise challenges at the same exercise volume. Effective application of these principles will guide patients toward their goals as quickly and efficiently as possible. PMID- 22212492 TI - Edema: a silent but important factor. AB - Edema is a normal response to injury. Even the smallest injury is associated with some inflammation, and initial edema is part of the normal inflammatory process. However, edema becomes a concern when it persists beyond the inflammatory phase. Once we have progressed into the rebuilding, or fibroplastic phase of healing, edema will delay healing and contribute to complications such as pain and stiffness. Early prevention and management to prevent this progression are therefore critical. This article discusses edema in relation to stages of healing and presents the research behind techniques available to the clinician to manage localized extracellular upper extremity edema in the patient with an intact lymphatic system. PMID- 22212493 TI - Colonic venous malformation and portal hypertension: association, management, and review of the literature. AB - We present a case of an adolescent with lower gastrointestinal bleeding caused by a colorectal venous malformation (VM) with concomitant portal hypertension. After an episode of massive gastrointestinal bleeding, we performed an extended right hemicolectomy and resection of the VM and selective portosystemic shunt. Here, we present the case and review the literature regarding portal hypertension and gastrointestinal vascular malformations. Additionally, we discuss the physiologic and hemodynamic effects of gastrointestinal vascular malformations on the portal system. PMID- 22212494 TI - A prospective, randomized, double-blind study comparing the efficacy of diltiazem, glyceryl trinitrate, and lidocaine for the treatment of anal fissure in children. AB - PURPOSE: Anal fissure (AF) is a common perianal condition in children. Although adult patients with AF have been treated successfully using diltiazem, it has not been studied in children. The present randomized, prospective, double-blind study assessed the response, side effects, and recurrence of diltiazem. METHODS: Ninety three children with AF were randomly divided into three groups. Each group received topical ointment. Group GTN received 0.2% glyceryl trinitrate, group L received 10% lidocaine, and group D received 2% diltiazem ointment. RESULTS: Eighty-two patients completed the 12-month study. At the end of the first 8-week course, the healing rate in group D was significantly higher than that of the other groups (p < 0.0001, chi (2) = 19.82). Nonresponders received a second course of the same treatment. Group D showed significantly higher healing rates than the other groups (p < 0.05, chi (2) = 7.227) at the end of the second 8-week course. The group D recurrence rate was significantly different than that of the other groups (p < 0. 002, chi (2) = 12.79). CONCLUSION: Diltiazem application is effective and safe for the treatment of AF in children, and has a low recurrence rate. The smooth dose-concentration curve causes minimal side effects. PMID- 22212495 TI - Incidence, risk factors, and outcomes associated with cytomegalovirus disease in small bowel transplant recipients. AB - Despite improved prophylaxis, monitoring, and more efficient immunosuppression, CMV infection remains a common opportunistic infection in transplant recipients. We assessed the incidence of CMV disease in pediatric SBT recipients, the timing of CMV disease after transplantation, and its impact on patient outcome. The medical records of 98 SBT recipients were reviewed. We performed descriptive analysis, regression analysis, and Kaplan-Meier curves to determine the time-to event after transplantation. Fifty-three percent patients were male and 47% female, with a mean age of 38.3 months. Thirty-five percent of patients received prophylactic VGC, 55% GCV, 10% a combination of GCV/VGC, and 99% CMV immunoglobulins. A total of 24.5% recipients were CMV D+/R- (CMV serostatus donor positive/recipient negative). Seven (c. 7%) patients developed CMV disease. CMV disease was associated with 2.5 times (0.52-12.1; p = 0.25) higher rate of CMV mismatch and 11.1 times (1.3-95.9; p = 0.03) higher risk of death. CMV prophylaxis increased time-to-death (p = 0.074). Time-to-CMV disease was shorter in patients with enteritis (p < 0.0001), and CMV disease was associated with shorter time-to-death after transplantation (p = 0.001). CMV disease in SBT recipients was associated with an 11-fold mortality increase and a fourfold faster time-to-death. Time-to-death was significantly shorter with CMV enteritis. PMID- 22212496 TI - Maturation is associated with changes in rat cerebral artery structure, biomechanical properties and tone. AB - AIM: This study evaluated the hypothesis that physiological maturation affects cerebral artery smooth muscle-endothelial interactions involved in pressure induced tone and alters the dimensional and biomechanical properties of small posterior cerebral arteries (PCA). METHODS: Secondary branches of PCA from young (4-5 weeks old, n=11), adult (14-16 weeks old, n=11) and mature (44-47 weeks old, n=11) male Sprague-Dawley rats were isolated, cannulated, pressurized and subjected to a range of intraluminal pressures (10-110 mmHg) to determine tone with and without pharmacologic nitric oxide synthase (NOS) inhibition. Measurements of passive lumen diameter and wall thickness as a function of pressure were used to determine changes in structure, distensibility and wall stress; histological analysis was performed on vessel cross-sections to assess collagen and elastin contents. RESULTS: Although pressure-dependent tone decreased significantly during ageing, differences between groups were abolished by NOS inhibition. Vessel diameters increased in adult vs. young rats (at 90 mmHg, 233 +/- 6.0 MUm vs. 192 +/- 4.5 MUm; P<0.05), possibly secondary to somatic growth. Further ageing was associated with reductions in lumen diameter (207 +/- 6.5 MUm; P<0.05), increased wall and media thickness (and wall/lumen ratio) and cross-sectional area. Distensibility and wall collagen were unchanged, although elastin content was significantly reduced. CONCLUSIONS: Maturation is associated with differences in PCA dimensional properties that indicate a pattern of initial outward eutrophic, followed by inward hypertrophic remodelling. Functionally, the contribution of basal NO increases with age in a way that reduces pressure dependent tone and diminishes vasodilator reserve. PMID- 22212497 TI - Gender-specific patterns in age-related decline in general health among Danish and Chinese: a cross-national comparative study. AB - AIM: Studies carried out in Western populations have shown age-related changes in multiple health domains together with gender-specific patterns. By focusing on five health domains, self-rated health, hand grip strength, sit-to-stand test, cognitive performance and depression, we examined the age trajectories in general health in a cross-sectional Chinese sample representing the world's largest ethnic population and compare with Danish data that represent Western populations in developed countries. METHODS: Multiple regression models were fitted to compare patterns across genders and populations together with gender- and population-specific patterns in age-related decline. RESULTS: Better self-rated health for males than for females was observed in both countries, and Danes reported better health than the Chinese for both genders. For hand grip strength, significant gender differences were shown across countries and significant population differences observed in Danish and Chinese males. There was no population difference in sit-to-stand time across genders. Female Danes outperformed males in cognitive performance. No significant gender differences in depression were observed in both populations. CONCLUSION: Our cross population analysis identified significant gender and population differences suggesting endogenous biological, physical and social environmental determinants in age related decline in general health. PMID- 22212498 TI - One-pot characterization of cancer cells by the analysis of mucin-type glycans and glycosaminoglycans. AB - We developed an automated apparatus for rapid releasing of O-glycans from mucin type glycoproteins [Anal. Biochem. 371 (2007) 52-61; Anal. Chem. 82 (2010) 7436 7443] and applied the device to analyze them in some cancer cell lines [J. Proteome Res. 8 (2009) 521-537]. We also found that the device is useful to release glycosaminoglycans from proteoglycans [Anal. Biochem. 362 (2007) 245 251]. Based on these studies, we developed a method for one-pot analysis of mucin type glycans and glycosaminoglycans after releasing them from total protein pool obtained from some cancer cell lines. Mucin-type glycans were analyzed by a combination of high-performance liquid chromatography and mass spectrometry techniques, and glycosaminoglycans were analyzed by capillary electrophoresis as fluorescent-labeled unsaturated disaccharides after digestion with specific eliminases followed by fluorescent labeling. Ten cancer cell lines, including blood cancer cells as well as epithelial cancer cells, were used to assess the method. The results clearly revealed that both mucin-type glycans and glycosaminoglycans showed quite interesting profiles. Thus, the current technique will be a powerful tool for discovery of glycan markers of diseases. PMID- 22212499 TI - Effect of tight blood glucose control versus conventional control in patients with type 2 diabetes mellitus: a systematic review with meta-analysis of randomized controlled trials. AB - Tight control of blood glucose reduces cardiovascular events and total mortality is conflicting. To summarize clinical effects of tight versus conventional glucose control in patients with type 2 diabetes. We systematically searched MEDLINE, EMBASE, Cochrane Library, and ISI Web of Knowledge with no limits of language and time. Further trials were searched from the reference lists of identified studies. We included randomized controlled comparing different levels of blood glucose control intensity in type 2 diabetic patients. Two independent reviewers extracted data of eligible studies using standard case report forms. We investigated total mortality, cardiovascular and microvascular events, and hypoglycemia in patients with type 2 diabetes. We used random-effects models to obtain relative risks (RR) with 95% confidence intervals (CI). We included 6 trials involving 27,654 patients. There was no significant effect of tight blood glucose control on all-cause mortality (RR 1.03; 95% CI 0.90-1.17) or cardiovascular mortality (RR 1.04; 95% CI 0.83-1.29). Tight glucose control reduced the risk for nonfatal MI (RR 0.85; 95% CI 0.76-0.95), although had no effect on the incidence of nonfatal stroke (RR 1.02; 95% CI 0.88-1.17). For microvascular events, tight glucose control reduced the risk progression of retinopathy (RR 0.80; 95% CI 0.71-0.91), incidence of peripheral neuropathy (RR 0.94; 95% CI 0.89-0.99), and progression of nephropathy (RR 0.55; 95% CI 0.37 0.80), but had not significant effect on the incidence of nephropathy (RR 0.69; 95% CI 0.42-1.14). The risk of severe hypoglycemia increased with tight glucose control (RR 2.39; 95% CI 1.79-3.18). Tight blood glucose control reduces the risk for some macrovascular and microvascular events, without effect on all-cause mortality and cardiovascular mortality. Tight glucose control increases the risk of severe hypoglycemia. PMID- 22212500 TI - (2S)-naringenin from Typha angustata inhibits vascular smooth muscle cell proliferation via a G0/G1 arrest. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Typha angustata is used in traditional Chinese medicine for a variety of clinical disorders. Its pharmacological actions include beneficial effects on hyperlipidemia and myocardial infarction, as well as labor inducing and antibacterial effects. AIM OF THE STUDY: We investigated the mechanism underlying the ability of (2S)-naringenin, an active compound from Typha angustata, to inhibit the proliferation of vascular smooth muscle cells (VSMCs). MATERIALS AND METHODS: After measuring the antiproliferative effect of (2S)-naringenin on VSMC proliferation using cell proliferation and viability assays, the possible involvement of a signaling pathway associated with platelet derived growth factor receptor beta (PDGF-Rbeta), extracellular signal regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3K)-linked protein kinase B (Akt/PKB), or phospholipase C-gamma1 (PLCgamma1) was investigated by immunoblotting. Moreover, the effect of (2S)-naringenin on DNA synthesis and the cell cycle was examined using a [(3)H]-thymidine incorporation assay and flow cytometry. RESULTS: (2S)-Naringenin significantly inhibited PDGF-BB-induced VSMC proliferation in a concentration-dependent manner, but did not affect signaling pathways associated with PDGF-Rbeta, Akt/PKB, ERK1/2, or PLCgamma1. However, (2S) naringenin suppressed DNA synthesis via a G(0)/G(1) cell cycle arrest. Accordingly, the expression of cyclins D1 and E and cyclin-dependent kinases 2 and 4 was inhibited in a concentration-dependent manner; moreover, the phosphorylation of retinoblastoma protein was suppressed. CONCLUSIONS: Our results show that (2S)-naringenin inhibited the PDGF-BB-induced proliferation of VSMCs via a G(0)/G(1) arrest; thus, (2S)-naringenin may be valuable as a therapeutic agent for managing atherosclerosis and/or vascular restenosis. PMID- 22212501 TI - Anti-Parkinsonian drug discovery from herbal medicines: what have we got from neurotoxic models? AB - ETHNOPHARMACOLOGICAL RELEVANCE: Herbal medicines are used to treat Parkinson's disease (PD) in ancient medical systems in Asian countries such as India, China, Japan and Korea based on their own anecdotal or experience-based theories. AIM OF THE REVIEW: To systematically summarize and analyze the anti-Parkinsonian activities of herbal preparations (including active compounds, herbal extracts and formulations) investigated in the neurotoxic models of PD and provide future references for basic and clinical investigations. MATERIALS AND METHODS: All the herbal materials tested on in vitro and in vivo neurotoxic models of PD were retrieved from PubMed database by using pre-set searching strings. The relevant compounds and herbal extracts with anti-Parkinsonian activities were included and analyzed according to their chemical classifications or biological activities. RESULTS: A total of 51 herbal medicines were analyzed. A diversity of compounds isolated from herbal materials were reported to be effective on neurotoxic models of PD by modulating multiple key events or signaling pathways implicated in the pathogenesis of PD. The main structure types of these compounds belong to catechols, stilbenoids, flavonoids, phenylpropanoids and lignans, phenylethanoid glycosides and terpenes. Although some herbal extracts and formulations have shown positive results on PD animal models, the relative compounds accounting for the effects and the underlying mechanisms remain to be further investigated. CONCLUSIONS: Herbal medicines can be an alternative and valuable source for anti Parkinsonian drug discovery. Compounds classified into stilbenoids, flavonoids, catechols and terpenes may be the most promising candidates for further investigation. Some well-studies compounds such as baicalein, puerarin, resveratrol, curcumin and ginsenosides deserve further consideration in clinical trials. In-depth experimental studies are still needed to evaluate the efficacy of herbal extracts and formulations in PD models. PMID- 22212502 TI - Bioactive polyphenols in Ximenia americana and the traditional use among Malian healers. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ximenia americana is a medicinal bushy, spiny shrub or small tree used in Mali in West Africa for treatment of various diseases, most common are infectious and inflammatory ailments. AIMS OF THE STUDY: (1) To perform an ethnopharmacological survey on the traditional use of Ximenia americana among healers in Mali. (2) To isolate and identify chemical constituents from the ethanol extract of Ximenia americana leaves and to study their radical scavenging and enzyme inhibitory effects. MATERIALS AND METHODS: In five different districts in Mali, 38 healers were interviewed about their medicinal use of Ximenia americana. An aqueous ethanol extract of the leaves of this tree was prepared and further fractionated with liquid-liquid extraction, VersaFlash and Sephadex LH-20 column chromatography, and preparative HPLC. Isolated compounds were identified by 1D and 2D NMR spectroscopy. Extracts, subfractions and isolated compounds were investigated as DPPH radical scavengers and as inhibitors of xanthine oxidase and 15-lipoxygenase. RESULTS: Major areas of use by Malian healers were against throat infection, amenorrhea and as tonic. Fractionation of the ethanol extract led to the isolation and identification of the cyanogenic glycoside sambunigrin (1), which is previously known from the plant. Additionally, gallic acid (2) and the gallotannins beta-glucogalline (3) and 1,6-digalloyl-beta-glucopyranose (4) were found. The following flavonoids were isolated: quercetin (5), quercitrin (quercetin-3-O-alpha-rhamnopyranoside) (6), avicularin (quercetin-3-O-alpha-arabinofuranoside) (7), quercetin-3-O-beta xylopyranoside (8), quercetin-3-O-(6"-galloyl)-beta-glucopyranoside (9) and kaempferol-3-O-(6"-galloyl)-beta-glucopyranoside (10). The flavonoids were active both as enzyme inhibitors and DPPH radical scavengers. CONCLUSION: Sambunigrin (1) was the main compound in the EtOAc soluble fraction of the alcoholic extract of Ximenia americana leaves. Gallic acid (2), gallotannins (3-4) and flavonoids (5-10) were identified for the first time in the genus Ximenia. The identified compounds may give a rationale for the traditional use of Ximenia americana in Mali. Healers interviewed reported the use against throat infections, amenorrhea, as tonic, for wound healing and against pain. PMID- 22212503 TI - Immuno-enhancement effects of Shenqi Fuzheng Injection on cyclophosphamide induced immunosuppression in Balb/c mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Radix Codonopsis and Radix Astragali, of which Shenqi Fuzheng Injection (SFI) is composed, are commonly used in traditional Chinese medicine to improve immune function against chronic diseases. AIM OF THE STUDY: The present study was thus designed to systematically elucidate the in vivo immuno-enhancement effects of SFI in immunosuppressed mice induced by cyclophosphamide (Cy) treatment. MATERIALS AND METHODS: Balb/c mice were injected intraperitoneally (i.p.) once daily with low-dose (2.5 g raw materials/kg), intermediate-dose (5 g raw materials/kg), high-dose (10 g raw materials/kg) of SFI for 10 consecutive days, respectively, accompanied by i.p. injection of Cy (80 mg/kg) on Days 4-6. RESULTS: Compared with vehicle group, low-, intermediate- and high-dose SFI treatment accelerated recovery dose-dependently of spleen index, peripheral white blood cell and bone marrow cell counts, enhanced T cell and B cell proliferation responses, as well as splenic nature killer cell activity and peritoneal macrophage phagocytosis, and restored the level of interleukin-2 in the serum. Furthermore, SFI treatment promoted recovery of the amount of peripheral white blood cells on Day 6, rather than recombinant human Granulocyte Colony-Stimulating Factor (rhG-CSF) did. CONCLUSIONS: These results demonstrate, for the first time, that chronic treatment with SFI results in accelerating recovery of immunosuppression in Cy-treated mice, which is competent in taking into consideration for both precautions and remedy. Our findings provide experimental evidences for further researches and clinical application in cancer patients undergoing chemotherapy. PMID- 22212504 TI - Antidiabetic activity of Passiflora incarnata Linn. in streptozotocin-induced diabetes in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The present study was designed to investigate the hypoglycemic and hypolipidemic properties of Passiflora incarnata Linn. leaves which are widely used as traditional treatment for diabetes mellitus. MATERIALS AND METHODS: The methanolic extracts of leaves of Passiflora incarnata were administered orally (100 and 200 mg/kg, for 15 days) to streptozotocin-induced diabetic mice. Hypoglycemic effects, oral glucose tolerance test, change in body weight and lipid profile of diabetic mice treated with methanolic extracts were assessed and compared with normal, diabetic control and standard drug treated mice. Histological examination during 15 days of treatment was also carried out. RESULTS: Methanolic extract (200 mg/kg) produced a significant reduction in fasting blood glucose level in streptozotocin-induced diabetic mice. Significant differences were also observed in urine glucose level, oral glucose tolerance test, serum lipid profile and body weight of methanolic extract treated diabetic mice, when compared with diabetic, normal and standard drug treated mice. Histopathological studies of the pancreas showed comparable regeneration of the cells by extract which were earlier necrosed by streptozotocin. CONCLUSION: Methanolic extract of Passiflora incarnata exhibit significant anti-hyperglycemic and hypolipidemic activities in streptozotocin-induced diabetes in mice. PMID- 22212505 TI - Antidiabetic effect of total saponins from Entada phaseoloides (L.) Merr. in type 2 diabetic rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The seed of Entada phaseoloides (L.) Merr. (Entada phaseoloides) has been long used as an effective herb for the treatment of Diabetes mellitus by Dai people, one of the Chinese ethnic minorities. Saponin is an abundant type of secondary metabolic products in the seed of this plant. The aim of this study is to evaluate the potential therapeutic effects of total saponins from Entada phaseoloides (TSEP) in experimental type 2 Diabetes mellitus (T2DM) rats. MATERIALS AND METHODS: T2DM rats were induced by high-fat diet and low-dose streptozotocin (STZ). Then different oral doses of TSEP (25, 50 and 100 mg/kg) were administrated to T2DM rats for 21 days. For comparison, a standard antidiabetic drug, metformin (200 mg/kg), was used as a positive control drug. Then the relative biochemical analysis and histopathological examination were made to evaluate the antidiabetic effect of TSEP. RESULTS: TSEP dramatically reduced fasted blood glucose and serum insulin levels and alleviates hyperglycemia associated oxidative stress in T2DM rats. Moreover, a significantly hypolipidemic effect and an improvement in tissue steatosis could be observed after TSEP administration. Further investigations revealed a possible anti inflammation effect of TSEP by examining serum levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein (CRP). The effects of TSEP exhibited a dose-dependent manner and were comparable to metformin. CONCLUSION: Our present study demonstrates both hypoglycemic and hypolipidemic activities of TSEP in T2DM rats, which support its antidiabetic property. This work also implies a possibility that TSEP exerts its therapeutic effect through repressing chronic inflammation responses. PMID- 22212506 TI - Protective effect of indigo naturalis extract against oxidative stress in cultured human keratinocytes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Indigo naturalis is used in traditional Chinese medicine to treat various skin disorders. AIM OF THE STUDY: The aims were to explore the effect of indigo naturalis on suppressing oxidative stress and protein modifications by hydrogen peroxide (H(2)O(2)) and 4-hydroxy-2-nonenal (HNE), a lipid peroxidation product, in cultured primary human keratinocytes. MATERIALS AND METHODS: Indigo naturalis extract at a dose that did not cause cytotoxicity was added to cultured keratinocytes in the absence or the presence of H(2)O(2) or HNE. The degree of cytotoxicity, levels of reactive oxygen species (ROS), and amount of protein carbonyl groups were evaluated. RESULTS: Indigo naturalis extract at the concentration of 10MUg/ml had no protective effect against H(2)O(2) or HNE-induced cytotoxicity, but decreased intracellular levels of ROS after H(2)O(2) treatment and suppressed the increase of protein carbonyl groups induced by HNE. CONCLUSION: Indigo naturalis possesses an inhibitory effect on formation of intracellular ROS induced by exogenous ROS and protein modification induced by HNE in human keratinocytes, which is relevant to the alleviation of inflammatory skin diseases. PMID- 22212508 TI - Interaction of HRP-2 isoforms with HDGF: chromatin binding of a specific heteromer. AB - Hepatoma-derived growth-factor-related protein 2 (HRP-2) belongs to a family with five additional members: hepatoma-derived growth factor (HDGF); lens epithelium derived growth factor; and the HDGF-related proteins -1, -3 and -4. Very little is known regarding the function of HRP-2 in particular. This study shows for the first time heteromer formation of different members of the HRP family; HDGF and HRP-2. In addition, we discovered a previously unknown splice variant of HRP-2 mRNA encoding for a protein with a 53-amino acid deletion in its hath region. This HRP-2 isoform c interacts preferentially with a processed form of HDGF probably because of the loss of an alpha helix of HRP-2. Furthermore, in contrast to other isoforms of HRP-2, isoform c binds to chromatin similar to its most closely related family member lens epithelium-derived growth factor with potential consequences regarding its function in HIV integration. Interestingly, only the new HRP-2 isoform c and a processed form of HDGF are displaced from condensed mitotic metaphase chromatin. In conclusion, these observations provide a new perspective for understanding the biological functions of HDGF and related proteins. PMID- 22212509 TI - Gene expression analysis of common carp (Cyprinus carpio L.) lines during Cyprinid herpesvirus 3 infection yields insights into differential immune responses. AB - Cyprinid herpesvirus 3 (CyHV-3), also known as koi herpesvirus (KHV), is the etiological agent of a virulent and lethal disease in common and koi carp. This study aimed to determine the genetic basis underlying the common carp immune response to the CyHV-3 virus. Two common carp lines (R3 and K) were infected with CyHV-3 by immersion. The R3 line presented a 20% higher survival rate compared to the K line and significantly lower viral loads as measured at day 3 post infection (p.i.). Microarray analysis using a common carp slides containing a number of 10,822 60-mer probes, revealed that 581 genes in line K (330 up regulated, 251 down-regulated) and 107 genes in line R3 (77 up-regulated, 30 down regulated), showed at least a 2-fold difference in expression at day 3 p.i. compared to day 0. Genes which showed at least a 4-fold difference in expression in both lines were selected as potential markers of a CyHV-3 infection in common carp. Additionally, 76 genes showed at least 2-fold differentially expression between K and R3 lines at day 3 p.i. Significantly higher expression of several immune-related genes including number of those which are involve in pathogen recognition, complement activation, MHC class I-restricted antigen presentation and development of adaptive mucosal immunity was noted in more resistant R3 line. Further real-time PCR based analysis provided evidence for higher activation of CD8(+) T cells in R3 line. This study uncovered wide array of immune-related genes involved into antiviral response of common carp toward CyHV-3. It is also demonstrated that the outcome of this severe disease in large extent could be controlled by genetic factors of the host. PMID- 22212511 TI - Dependence of Saccharomyces cerevisiae Golgi functions on V-ATPase activity. AB - The V-ATPase of Saccharomyces cerevisiae is an ATP-dependent proton pump responsible for acidification of the vacuole and other internal compartments including the whole secretory pathway. We have studied the behavior of several glycoprotein processing reactions occurring in different Golgi compartments of representative vmaDelta mutants. We found that outer chain initiation is not altered in the mutants while mannosylphosphate transfer, alpha(1,3)-linked mannoses addition, and alpha factor maturation seem to be affected. The results suggest a gradation in the dependence of Golgi functions on V-ATPase activity, from early Golgi (unaffected) to late Golgi (significantly reduced). These findings are in agreement with the internal pH of Golgi cisternae measured in mammalian cells, which is more acidic in the late region. The mutant defects can be partially restored by buffering the external medium to pH 6.0, which supports the existence of a mechanism that, in the absence of a functional V-ATPase, could contribute to pH regulation at least in the late Golgi. PMID- 22212512 TI - MBSJ MCC Young Scientist Award 2010. Recent progress in research on small post translationally modified peptide signals in plants. AB - Peptide signaling plays a major role in various aspects of plant growth and development, as has been shown in recent biochemical, genetic and bioinformatic studies. There are over a dozen secreted peptides recognized in plants known to regulate cellular functions. To become functional, these secreted peptide signals often undergo post-translational modifications, such as tyrosine sulfation, proline hydroxylation, and hydroxyproline arabinosylation, and successive proteolytic processing. These types of 'small post-translationally modified peptide signals' are one of the major groups of peptide signals found in plants. In parallel with the discovery of peptide signals, specific receptors for such peptide signals were identified as being membrane-localized leucine-rich repeat receptor kinases. This short review highlights the recent progress in research on small post-translationally modified peptide signals, including our own research. PMID- 22212513 TI - Early human herpesvirus type 6 reactivation after allogeneic stem cell transplantation: a large-scale clinical study. AB - This study investigated the impact of human herpesvirus type 6 (HHV6) reactivation within 100 days of allogeneic stem cell transplantation (allo-SCT) on patient outcomes. HHV6 plasma loads were monitored weekly by quantitative PCR. Of 235 consecutive patients, 112 (48%) had an early positive HHV6 PCR test (group A) and 123 (52%) did not (group B). HHV6 reactivation was less frequent in patients who received reduced-intensity conditioning (P = .028). In group A, only 6 patients (5%) were asymptomatic; the most common clinical manifestations were fever (n = 60), skin rash (n = 57), diarrhea (n = 51), pulmonary complications (n = 19), and neurologic disorders (n = 12). Compared with the patients in group B, those in group A experienced delayed platelet engraftment (P = .003) and more frequent grade II-IV acute graft-versus-host disease (GVHD) (47% versus 30% in group B; P = .009). In multivariate analysis, the most important factors influencing the development of grade II-IV acute GVHD development were early HHV6 reactivation (P = .03) and unrelated donor status (P < .001). HHV6 reactivation adversely influenced 6-month survival (P = .04). Of the 38 evaluable patients receiving antiviral treatment, 34 had a significantly decreased HHV6 load. Our findings indicate that HHV6 reactivation after allo-SCT is associated with delayed platelet engraftment, early posttransplantation mortality, and the development of acute GVHD. Careful monitoring of HHV6 by PCR is warranted during the early posttransplantation period. PMID- 22212514 TI - High-MUFA diets reduce fasting glucose in patients with type 2 diabetes. PMID- 22212515 TI - Value of cardiovascular magnetic resonance imaging in myocardial hypertrophy. PMID- 22212516 TI - Interleukin-6, -7, -8 and -10 predict outcome in acute myocardial infarction complicated by cardiogenic shock. AB - BACKGROUND: The IABP-SHOCK-trial was a morbidity-based randomized controlled trial in patients with infarction-related cardiogenic shock (CS), which used the change of the quantified degree of multiorgan failure as determined by APACHE II score over a 4-day period as primary outcome measure. The prospective hypothesis was that adding IABP therapy to "standard care" would improve CS-triggered multi organ dysfunction syndrome (MODS). The primary endpoint showed no difference between conventionally managed cardiogenic shock patients and those with IABP support. In an inflammatory marker substudy, we analysed the prognostic value of interleukin (IL)-1beta, -6, -7, -8, and -10 in patients with acute myocardial infarction complicated by cardiogenic shock. DESIGN: Inflammatory marker substudy of the prospective, randomized, controlled, open label IABP-SHOCK-trial (ClinicalTrials.gov ID-NCT00469248). SETTING AND METHODS: A single-center study was performed in a 12-bed Intensive-Care-Unit in an university hospital in which 40 consecutive patients were enrolled with an observational period of 96 h. RESULTS: The pro- and anti-inflammatory markers IL-6, -7, -8 and -10 showed a predictive power for mortality of infarct-related CS patients, while IL-1beta did not discriminate. The maximal values during the observational period, in case of IL-7 the minimal value, showed the best power to predict mortality. Both, ROC and multivariate analyses confirmed these suggestions (area under the curve: IL-8, 0.80 +/- 0.08; IL-6, 0.79 +/- 0.08; IL-10, 0.76 +/- 0.08; IL-7, 0.69 +/- 0.08). Inflammatory markers were not affected by the presence of IABP support. CONCLUSION: The inflammatory response in patients with myocardial infarction complicated by cardiogenic shock, as reflected by the inflammatory markers IL-6, IL-7, IL-8 and IL-10, demonstrates a clinically relevant prognostic contribution to clinical outcome. PMID- 22212517 TI - Coronary artery fistula with myocardial infarction due to steal syndrome. PMID- 22212518 TI - N-acetylcysteine in preventing contrast-induced nephropathy assessed by cystatin C. AB - AIMS: Prophylactic oral N-acetylcysteine (NAC) has been widely used for prevention of contrast-induced nephropathy (CIN). However, clinical studies have not been demonstrating this effect consistently because of evidence that NAC can alter serum creatinine levels without affecting glomerular filtration rate (GFR). We investigated NAC for the prevention of CIN by monitoring creatinine and cystatin C. METHODS: We enrolled 113 patients (49 patients in NAC group and 64 patients in control group) with normal to subnormal GFR who were scheduled for cardiovascular procedures. Patients in NAC group receive acetylcysteine 600 mg twice a day, on the day before and on the day of cardiovascular procedure. All patients received a periprocedural intravenous infusion ("volume expansion") of 1 ml/kg/h with 0.45% saline for 24 h (12 h before and 12 h after exposure to contrast medium). Serum cystatin C and creatinine levels were measured before and at 12, 24, and 48 h after procedure. RESULTS: The incidence of cystatin C-based CIN was 28.5% (n = 14) in NAC and 23.4% (n = 15) in control group (p = 0.663) and serum creatinine-based CIN was 12.2% (n = 6) in NAC and 17.2% (n = 11) in control group (P= 0.468). In this study, oral NAC had no effect on the prevention of CIN in patients undergoing cardiovascular procedures. CONCLUSION: In this study, oral NAC administration does not reduce neither the incidence of cystatin C-based CIN nor serum creatinine-based CIN in patients undergoing cardiovascular procedures. PMID- 22212519 TI - The influence of age and aerobic fitness: effects on mitochondrial respiration in skeletal muscle. AB - AIM: Mitochondrial function has previously been studied in ageing, but never in humans matched for maximal oxygen uptake ((V).O2max). Furthermore, the influence of ageing on mitochondrial substrate sensitivity is not known. METHODS: Skeletal muscle mitochondrial respiratory capacity and mitochondrial substrate sensitivity were measured by respirometry in young (23 +/- 3 years) and middle-aged (53 +/- 3 years) male subjects with similar (V).O2max. Protocols for respirometry included titration of substrates for complex I (glutamate), complex II (succinate) and both (octanoyl carnitine) for calculation of substrate sensitivity (C(50) ). Myosin heavy chain (MHC) isoforms, citrate synthase (CS) and beta-hydroxy-acyl CoA-dehydrogenase (HAD) activity, mitochondrial DNA (mtDNA) content, protein levels of complexes I-V and antioxidant defence system [manganese superoxide dismutase (MnSOD)] were measured. RESULTS: No differences were found in maximal mitochondrial respiration or C(50) with glutamate (2.0 +/- 0.3 and 1.8 +/- 0.3 mm), succinate (3.7 +/- 0.2 and 3.8 +/- 0.4 mm) or octanoyl carnitine (47 +/- 8 and 56 +/- 7 MUm) in young and middle-aged subjects respectively. Normalizing mitochondrial respiration to mtDNA young subjects had a higher (P < 0.05) respiratory capacity per mitochondrion compared to middle-aged subjects. HAD activity and mtDNA per mg tissue were higher in middle-aged compared to young subjects. Middle-aged had a higher MHC I isoform and a lower MHC IIX isoform content compared to young subjects. CONCLUSION: Mitochondrial substrate sensitivity is not affected by ageing. When young and middle-aged men are carefully matched for (V).O2max, mitochondrial respiratory capacity is also similar. However, per mitochondrion respiratory capacity was lower in middle-aged compared to young subjects. Thus, when matched for (V).O2max, middle-aged seem to require a higher mitochondrial content than young subjects. PMID- 22212520 TI - Social anxiety score is high in adolescents with chronic migraine. AB - BACKGROUND: Social anxiety disorder, also known as social phobia, is a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. It usually begins in mid-adolescence and has a chronic course and interferes in academic, social, family and personal functioning. Recent studies have shown that social anxiety disorder is more prevalent in adults with migraine. Little evidence on this subject is available for the adolescent population. METHODS: This study was performed between August 2009 and August 2010; all patients were recruited in schools, pediatric or neuropediatric facilities, and were submitted to a detailed headache questionnaire, which consisted of demographic and clinical data. To evaluate social anxiety, the Social Phobia Inventory was used. RESULTS: A total of 151 subjects were evaluated: 50 had chronic migraine, 50 had episodic migraine and 51 were control subjects. In the chronic migraine group, the mean score in the Social Phobia Inventory was 18.5 +/- 12.4, which was significantly higher than in the episodic migraine group (12.1 +/- 8.1) and in the control group (13.8 +/- 10.8; F(2131) = 4.8, P= 0.010). The mean score, however, was not significantly different between the control and episodic migraine groups. CONCLUSIONS: Chronic migraine is strongly associated with high social anxiety score, regardless of demographic data and pain intensity. The total burden of migraine may be increased with social anxiety disorder comorbidity. PMID- 22212521 TI - Interactions of household composition and required care level with functional and cognitive status among disabled Japanese elderly living in a suburban apartment complex. AB - AIM: In the forthcoming super-aging society, the appropriate assessment of functional and cognitive conditions of disabled elderly people will become increasingly significant in providing care services. Care level and household composition would be key factors to assess function. There might also be an interaction between the two factors with the function. The present study examined the associations of household composition and care level with functional and cognitive status among the disabled elderly living in a suburban apartment complex with a high rate of aged residents (39% in 2009). METHODS: Participants were 190 disabled elderly persons aged 65 years and over who lived in the apartment complex. Cross-sectional data were collected between May 2009 and August 2010, including care level, household composition, basic activities of daily living (BADL), instrumental activities of daily living (IADL) and the independence level in relation to cognitive status. Lower scores meant less independence in BADL and IADL, and as determined by the cognitive/independence scale. RESULTS: Approximately half of the participants lived alone. Generalized linear model procedure showed significant interactions with the BADL score and cognitive/independence scale between household composition and care level. Scores for BADL and the cognitive/independence scale in groups receiving a higher care level were lower; however, the slope of the trend for the elderly living alone was more gradual than for the elderly living with others. CONCLUSION: It is important for health-care providers to assess in detail the status of the disabled elderly considering both their household composition and care level in planning and providing assistance for them. PMID- 22212522 TI - Creation of an artificial metalloprotein with a Hoveyda-Grubbs catalyst moiety through the intrinsic inhibition mechanism of alpha-chymotrypsin. AB - An L-phenylalanyl chloromethylketone-based inhibitor equipped with a Hoveyda Grubbs catalyst moiety was regioselectively incorporated into the cleft of alpha chymotrypsin through the intrinsic inhibition mechanism of the protein to construct an artificial organometallic protein. PMID- 22212523 TI - Involvement of molecular chaperones and the transcription factor Nrf2 in neuroprotection mediated by para-substituted-4,5-diaryl-3-thiomethyl-1,2,4 triazines. AB - Much evidence supports that oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease. Herein, we studied the compensatory/adaptive mechanisms involved in 3-thiomethyl-5,6 (diphenyl)-1,2,4-triazine and 3-thiomethyl-5,6-(dichlorophenyl)-1,2,4-triazine neuroprotection. We found that these compounds could counteract H(2)O(2)-induced rupture of neurite outgrowth in differentiated PC12 cells. In addition, we found that pretreatment of cells with triazine derivatives could modulate the expression of heat shock proteins Hsp70, Hsp90, and Hsp32 in H(2)O(2)-treated PC12 cells. These compounds could also increase nuclear level of stress sensing transcription factor, NF-E2 related factor 2, which contributes to redox homeostasis and cell survival following stress. As a result, the elevated levels of glutamylcysteine synthetase, glutathione peroxidase-1, and glutathione, as well as superoxide dismutase and catalase, increased cellular antioxidant capacity. Studying the relation between structure and activity of these compounds will pave the way for exploiting preventive and/or therapeutic strategies for the management of oxidative stress-mediated disorders. PMID- 22212524 TI - Dengue virus infection in renal allograft recipients: a case series during 2010 outbreak. AB - Dengue virus infection is an emerging global threat caused by Arbovirus, a virus from Flaviridiae family, which is transmitted by mosquitoes, Aedes aegypti and Aedes albopictus. Renal transplant recipients who live in the endemic zones of dengue infection or who travel to an endemic zone could be at risk of this infection. Despite multiple epidemics and a high case fatality rate in the Southeast Asian region, only a few cases of dengue infection in renal transplant recipients have been reported. Here, we report a case series of 8 dengue viral infection in renal transplant recipients. Of the 8 patients, 3 developed dengue hemorrhagic shock syndrome and died. PMID- 22212525 TI - Chronological lifespan extension by Ecl1 family proteins depends on Prr1 response regulator in fission yeast. AB - ecl1+, ecl2+ and ecl3+ genes encode highly homologous small proteins, and their over-expressions confer both H2O2 stress resistance and chronological lifespan extension on Schizosaccharomyces pombe. However, the mechanisms of how these Ecl1 family proteins function have not been elucidated. In this study, we conducted microarray analysis and identified that the expression of genes involved in sexual development and stress responses was affected by the over-expression of Ecl1 family proteins. In agreement with the mRNA expression profile, the cells over-expressing Ecl1 family proteins showed high mating efficiency and resistant phenotype to H2O2. We showed that the H2O2-resistant phenotype depends on catalase Ctt1, and over-expression of ctt1+ does not affect chronological lifespan. Furthermore, we showed that six genes, ste11+, spk1+, hsr1+, rsv2+, hsp9+ and lsd90+, whose expressions are increased in cells over-expressing Ecl1 family proteins are involved in chronological lifespan in fission yeast. Among these genes, the induction of ste11+ and hsr1+ was dependent on a transcription factor Prr1, and we showed that the extensions of chronological lifespan by Ecl1 family proteins are remarkably diminished in prr1 deletion mutant. From these results, we propose that Ecl1-family proteins conduct H2O2 stress resistance and chronological lifespan extension in ctt1+- and prr1+-dependent manner, respectively. PMID- 22212527 TI - Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1beta and enhancing NMDA signaling. AB - Understanding the factors that contribute to age-related cognitive decline is imperative, particularly as age is the major risk factor for several neurodegenerative disorders. Levels of several cytokines increase in the brain during aging, including IL-1beta, whose levels positively correlate with cognitive deficits. Previous reports show that reducing the activity of the mammalian target of rapamycin (mTOR) extends lifespan in yeast, nematodes, Drosophila, and mice. It remains to be established, however, whether extending lifespan with rapamycin is accompanied by an improvement in cognitive function. In this study, we show that 18-month-old mice treated with rapamycin starting at 2 months of age perform significantly better on a task measuring spatial learning and memory compared to age-matched mice on the control diet. In contrast, rapamycin does not improve cognition when given to 15-month-old mice with pre existing, age-dependent learning and memory deficits. We further show that the rapamycin-mediated improvement in learning and memory is associated with a decrease in IL-1beta levels and an increase in NMDA signaling. This is the first evidence to show that a small molecule known to increase lifespan also ameliorates age-dependent learning and memory deficits. PMID- 22212528 TI - Lethal misconceptions: interpretation and bias in studies of traffic deaths. AB - Clinical epidemiology studies are vulnerable to subtle confounding, leading skeptics to claim that an odds ratio below three rarely indicates a clinically important finding. We argue that such a high threshold is inappropriate when interpreting traffic death studies in clinical epidemiology research. We review 10 concepts that emphasize the value of modest effect sizes by taking into account the baseline frequency, nonfatal disability, numbers needed to treat, shared responsibility, event diversity, behavioral offsets, measurement error, indirect reinforcement, delayed progression, and economic affordability. An awareness of these concepts may help when interpreting effect sizes in studies of traffic deaths. PMID- 22212529 TI - Effectiveness of male-only weight loss and weight loss maintenance interventions: a systematic review with meta-analysis. AB - The objectives of this systematic review were to investigate the effectiveness of male-only weight loss and weight loss maintenance interventions and to identify intervention characteristics associated with effectiveness. In May 2011, a systematic literature search with no date restrictions was conducted across eight databases. Twenty-four articles describing 23 studies met the eligibility criteria. All studies included a weight loss intervention and four studies included an additional weight loss maintenance intervention. Study quality was mostly poor for weight loss studies (median = 3/10, range = 1-9) and weight loss maintenance studies (median = 3.5/10, range = 1-6). Twenty-three of 31 individual weight loss interventions (74%) from the eligible studies were considered effective. Meta-analysis revealed a significant difference in weight change favouring weight loss interventions over no-intervention controls at the last reported assessment (weighted mean difference -5.66 kg [-6.35, -4.97], Z = 16.04 [P < 0.00001]). Characteristics common to effectiveness were younger sample (mean age <= 42.8 years), increased frequency of contact (> 2.7 contacts/month), group face-to-face contact and inclusion of a prescribed energy restriction. Preliminary evidence suggests men-only weight loss programmes may effectively engage and assist men with weight loss. However, more high-quality studies are urgently needed to improve the evidence base, particularly for maintenance studies. PMID- 22212530 TI - 10th anniversary: Focus on Germany. Editorial. PMID- 22212531 TI - Correlation between leukocyte membrane lipid peroxidation and expression of Cu/Zn superoxide dismutase mRNA in hemodialysis patients. AB - BACKGROUND: Previously, we reported an increase in expressions of mRNA of Cu/Zn superoxide dismutase (SOD) in leukocytes of hemodialysis (HD) patients, and speculated that the increase is associated with oxidative stress on the leukocyte membrane due to the HD process. METHODS: Expressions of Cu/Zn-SOD mRNA in leukocytes, contents of plasma SOD, and malondialdehyde (MDA) in leukocyte and erythrocyte membranes, respectively, were examined in 25 HD patients and 14 healthy volunteers. These were also determined after using a vitamin E-coated dialyzer (VE dialyzer) for 4 weeks. RESULTS: All values were significantly higher in HD patients. A significant correlation was found between leukocyte Cu/Zn-SOD mRNA expression and membrane MDA. After using the VE dialyzer, all values were significantly lowered, showing a significant correlation between changing rate of leukocyte Cu/Zn-SOD mRNA expression and membrane MDA. CONCLUSION: In HD patients, oxidative stress is generated on the leukocyte membrane, and the level of Cu/Zn SOD mRNA in leukocytes can be a useful oxidative stress marker. PMID- 22212532 TI - Age related changes in selenium and glutathione levels in different lobes of the rat prostate. AB - Aging represents a major risk factor for prostate cancer; however, mechanisms responsible for this relationship remain unclear. Preclinical and some clinical investigations support the protective role of selenium against prostate cancer possibly through the reduction of oxidative stress. While increased levels of oxidative stress together with decreases in selenium and the major cellular antioxidant glutathione (GSH) are common in tissues of old animals, there is little data available on these parameters in the prostate. In the present study we have compared the levels of selenium, GSH and protein-bound GSH (GSSP) in blood and prostate tissues in young (4-month), mature (12-month), old (18 month), and very old (24 month) male F344 rats. Each prostate lobe (dorsolateral, DL; anterior, AL; ventral, VL) was analyzed separately based upon their differing potential for prostate cancer development. At all ages, selenium levels were lowest in DL=400 copies/ml) were compared between the two groups using the Mann-Whitney rank sum test and logistic regression respectively. RESULTS: Of 88 women aged 20-40 years receiving ART, 23 became pregnant. At ART initiation, there were no significant differences between those who became pregnant and those who did not in clinical, immunological and virological parameters. Among women who became pregnant, CD4 cell count increased before pregnancy (average 75.9 cells/mm(3) per year), declined during pregnancy (average 106.0) but rose again in the first year after delivery (average 88.6). Among women who did not become pregnant, the average CD4 cell count rise per year for the first 3 years was 88.5. There was no significant difference in the proportions of women with detectable viral load at last clinic visit among those who became pregnant (8.7%) and those who did not (16.1%), P = 0.499. CONCLUSION: Pregnancy had no lasting effect on the immunological and virological outcomes of HIV-infected women on ART. PMID- 22212562 TI - Clinical outcome of twice-weekly hemodialysis patients in shanghai. AB - BACKGROUND: Twice-weekly hemodialysis (HD) is prevalent in the developing countries and the clinical outcome of this population remains to be elucidated. METHODS: Data were collected from Shanghai Renal Registry. 2,572 patients undergoing regular HD in Shanghai on January 2007 were enrolled into the cohort study with 2 years' follow-up. Clinical and HD parameters obtained from the network were utilized to compare twice-weekly with thrice-weekly HD. RESULTS: Compared with patients on thrice-weekly HD, the twice-weekly HD patients were significantly younger and had significantly longer HD session time, higher single pool Kt/V (spKt/V) but shorter HD vintage (p < 0.001). Kaplan-Meier survival analysis indicated that the two groups had similar survival. Multivariate Cox regression analysis showed that age, body mass index, serum albumin and weekly Kt/V were predictors of patient mortality. CONCLUSIONS: The similar survival between twice-weekly HD and thrice-weekly HD is likely relating to patient selection; dialysis adequacy of twice-weekly HD remains to be elucidated. PMID- 22212563 TI - Apatinib (YN968D1) enhances the efficacy of conventional chemotherapeutical drugs in side population cells and ABCB1-overexpressing leukemia cells. AB - P-glycoprotein (P-gp, ABCB1) overexpression and enrichment of stem-like cells are linked to poor prognosis in tumor patients. In this study, we investigated the effect of apatinib, an oral multi-targeted tyrosine kinase inhibitor (TKI) on enhancing the efficacy of conventional anticancer drugs in side population (SP) cells and ABCB1-overexpressing leukemia cells in vitro, in vivo and ex vivo. Our results showed that apatinib significantly enhanced the cytotoxicity and cell apoptosis induced by doxorubicin in SP cells sorted from K562 cells. Furthermore, apatinib also strongly reversed multidrug resistance (MDR) in K562/ADR cells, and the primary leukemia blasts overexpressing ABCB1 while showed no synergistic interactions with chemotherapeutic agents in MRP1-, MRP4-, MRP7- and LRP overexpressing cells. Apatinib treatment markedly increased the intracellular accumulation of doxorubicin and rhodamine 123 in K562/ADR cells and the accumulation of rhodamine 123 in the primary leukemia blasts with ABCB1 overexpression. Apatinib stimulated the ATPase activity of P-gp in a dose dependent manner but did not alter the expression of ABCB1 at both mRNA and protein levels. The phosphorylation level of AKT and ERK1/2 remained unchanged after apatinib treatment in both sensitive and MDR cells. Importantly, apatinib significantly enhanced the antitumor activity of doxorubicin in nude mice bearing K562/ADR xenografts. Taken together, our results suggest that apatinib could target to SP cells and ABCB1-overexpressing leukemia cells to enhance the efficacy of chemotherapeutic drugs. These findings should be useful for the combination of apatinib and chemotherapeutic agents in the clinic. PMID- 22212564 TI - Editorial: Towards the eradication of hepatitis C virus. PMID- 22212565 TI - 2011 European Association of the Study of the Liver hepatitis C virus clinical practice guidelines. AB - Hepatitis C virus (HCV) is the leading cause of liver transplantation in Europe and is associated with an increased risk of hepatocellular carcinoma (HCC). Because of the chronic nature of the disease, estimates suggest that the burden on healthcare will increase dramatically for this entity. Clinical care of patients with HCV-related liver disease has advanced considerably in the last two decades, thanks to increasing knowledge about the mechanisms of the disease, development of diagnostic procedures, and advances in therapeutic and preventive approaches. HCV RNA testing, HCV genotyping and staging of liver disease are essential for the diagnosis and the management of HCV therapy. Furthermore, the important role of host polymorphisms of the IL28B gene on virological response to treatment with pegylated interferon (PEG-IFN) alpha and ribavirin (RBV) has recently been clearly demonstrated. In relation to treatment, although numerous drugs for HCV are in various stages of preclinical and clinical development, the current standard of care (SoC) is the combination of PEG-IFN-alpha and RBV for chronic hepatitis C. With SoC, a sustained viral response (SVR) is achieved in approximately 45% of patients infected with HCV genotype 1 and in approximately 80% of patients infected with HCV genotypes 2 and 3. The EASL HCV guidelines recommend treating all naive patients with compensated disease from HCV without contraindications to treatment and strongly suggest initiating SoC promptly in patients with advanced fibrosis. Further recommendations on monitoring treatment efficacy, treatment duration, dose reduction indications and the role of co factors are provided. PMID- 22212566 TI - New targets for antiviral therapy of chronic hepatitis C. AB - Until recently, chronic hepatitis C caused by persistent infection with the hepatitis C virus (HCV) has been treated with a combination of pegylated interferon-alpha (PEG-IFNalpha) and ribavirin (RBV). This situation has changed with the development of two drugs targeting the NS3/4A protease, approved for combination therapy with PEG-IFNalpha/RBV for patients infected with genotype 1 viruses. Moreover, two additional viral proteins, the RNA-dependent RNA polymerase (residing in NS5B) and the NS5A protein have emerged as promising drug targets and a large number of antivirals targeting these proteins are at different stages of clinical development. Although this progress is very promising, it is not clear whether these new compounds will suffice to eradicate the virus in an infected individual, ideally by using a PEG-IFNalpha/RBV-free regimen, or whether additional compounds targeting other factors that promote HCV replication are required. In this respect, host cell factors have emerged as a promising alternative. They reduce the risk of development of antiviral resistance and they increase the chance for broad-spectrum activity, ideally covering all HCV genotypes. Work in the last few years has identified several host cell factors used by HCV for productive replication. These include, amongst others, cyclophilins, especially cyclophilinA (cypA), microRNA-122 (miR-122) or phosphatidylinositol-4-kinase III alpha. For instance, cypA inhibitors have shown to be effective in combination therapy with PEG-IFN/RBV in increasing the sustained viral response (SVR) rate significantly compared to PEG-IFN/RBV. This review briefly summarizes recent advances in the development of novel antivirals against HCV. PMID- 22212567 TI - Telaprevir user's guide. AB - Telaprevir is a potent HCV NS3/4A protease inhibitor. A completed development program has demonstrated the superior efficacy of a regimen of telaprevir combined with pegylated interferon alfa and ribavirin (PR) over PR alone in patients with HCV genotype 1. In the ADVANCE trial in treatment-naive patients, 12 weeks of telaprevir, peginterferon alfa-2a and ribavirin followed by either 12 or 36 weeks of PR alone (depending upon extended rapid virologic response, or eRVR, i.e. HCV RNA undetectability at weeks 4 and 12), was associated with sustained virological response (SVR) in 75% of patients compared with 46% receiving PR for 48 weeks. The ILLUMINATE trial established the foundation for response-guided therapy in patients with eRVR. The REALIZE trial in treatment experienced patients showed a gradient of SVR from prior relapsers (86%) to partial responders (57%) to null responders (31%), with rates of virologic failure and emergent resistance highest in the latter group. Incremental adverse effects of telaprevir include rash, anemia, pruritus, diarrhea, and nausea. Treatment naive patients and relapsers are eligible for response-guided therapy. Stopping rules of telaprevir-based treatment include HCV RNA > 1000 IU/ml at weeks 4 and 12. PMID- 22212568 TI - Phase III results of Boceprevir in treatment naive patients with chronic hepatitis C genotype 1. AB - INTRODUCTION: Chronic hepatitis C virus infection affects approximately 2% of the world population and can result in cirrhosis and hepatocellular carcinoma. Until 2011, the standard of care (SOC) has been therapy with pegylated interferon alfa and ribavirin (PEG-IFN/RBV). Sustained virologic response rates (SVR) after SOC in patients infected with genotype 1 have been 40-50%. The development of new direct antiviral agents (DAA) is vital. The first drugs that specifically target the HCV protease have been approved in 2011. This review summarizes the results of SPRINT-2, a phase III double blind, placebo controlled study in which the efficacy and safety of Boceprevir, a new HCV protease inhibitor, was compared to SOC. DESIGN: A total of 1097 treatment-naive, genotype 1, chronic hepatitis C patients were randomized into three different groups. All patients received a 4 week lead in phase with peginterferon alfa-2b and ribavirin. A total of 363 patients were randomized to the control group and received 44 additional weeks of PEG-IFN/RBV; of the 368 patients randomized to group 2, the response-guided treatment regimen (RGT), patients with undetectable HCV RNA through week 8 and 24 received 24 weeks of triple therapy (PEG-IFN/RBV/Boceprevir); patients whose HCV RNA was detectable between weeks 8 and 24 but undetectable at week 24 received subsequently 20 weeks of (PEG-IFN/RBV); 366 patients in group 3 were treated with lead-in followed by triple therapy through week 48. RESULTS: Treatment with Boceprevir triple therapy increased SVR to 63-66% compared to 38% receiving PEG IFN/RBV therapy. Non-Black patients achieved higher SVR rates compared to Black patients. Responsiveness to interferon in the lead-in phase was predictive for SVR. SVR rates did not differ between patients randomized to RGT with Boceprevir and those treated with a fixed duration. Anaemia was the most important adverse event leading to dose reduction of RBV in 13% of controls and 21% of Boceprevir recipients. CONCLUSION: Triple therapy of Boceprevir in combination with PEG-IFN 2b/RBV is more effective than SOC alone. RGT is possible without reducing the SVR rates. Management of anaemia has to be considered. PMID- 22212569 TI - Boceprevir and telaprevir for the treatment of chronic hepatitis C: safety management in clinical practice. AB - Effective management of adverse events (AEs) is important to prevent treatment discontinuation and optimize hepatitis C virus infection eradication rates. The addition of direct-acting antiviral agents, telaprevir (TVR) or boceprevir to pegylated interferon (PEG-IFN) and ribavirin (RBV) represents a new era of therapy associated with an improvement in treatment response rates and an impairment of the safety profile compared to PEG-IFN/RBV. An increase in the frequency and severity of anaemia was reported in clinical trials for both drugs, and skin disorders including rash and pruritus occurred more frequently with the TVR-based regimen. These AEs are generally manageable and do not lead to early discontinuation. The management of anaemia has not been clearly established, and the impact of RBV dose reductions and erythropoietin alpha use on treatment efficacy and safety must be clarified. The management of rashes, which were mild and moderate in more than 90% of the cases, is well planned, does not require TVR discontinuation and can be treated using emollients and topical corticosteroids. However, approximately 5% of rashes were severe, and a few cases were classified as severe cutaneous adverse reactions leading to treatment discontinuation. PMID- 22212570 TI - Phase III results in Genotype 1 naive patients: predictors of response with boceprevir and telaprevir combined with pegylated interferon and ribavirin. AB - The addition of telaprevir or boceprevir to pegylated interferon (PEG-INF) and ribavirin (RBV) has improved sustained viral response (SVR) rates in genotype-1 infected individuals. The recent publication of Phase III trials has made it possible to examine pretreatment and on-treatment predictors of response in genotype 1 naive patients. Both telaprevir- and boceprevir-based therapy improve SVR rates in most treatment groups including individuals who are difficult-to treat such as those with a high viral load, Black patients and those with advanced fibrosis. Although data sets were not complete, patients with IL28B CT and TT genotype appear to significantly improve when these agents are combined with PEG-INF and RBV. The presence of the IL-28B CC genotype appears to be predictive for a short duration of therapy. On-treatment viral response is also predictive of the SVR: approximately half of the patients are successfully treated with short duration and response-guided therapy. PMID- 22212571 TI - Triple therapy with telaprevir: results in hepatitis C virus-genotype 1 infected relapsers and non-responders. AB - Treatment for chronic hepatitis C virus (HCV) infection has evolved considerably in the last few years. Combination therapy with pegylated interferon (PEG-IFN) alpha plus ribavirin (RBV) has been the standard of care (SoC) treatment in the past few years. Several viral and host factors have been associated with treatment failure, including age, male gender, ethnicity, genotype, IL28B genotype, steatosis, obesity and insulin resistance. Several studies have also shown that in patients who fail treatment, several interferon-stimulated genes are upregulated before treatment. Recently, the NS3/4A protease inhibitors telaprevir and boceprevir have been approved and are considered the new SoC therapy in combination with PEG-IFN-alpha/RBV in HCV genotype 1 treatment-naive patients, as well as in previously treated patients, with significant improvements in SVR rates. The REALIZE phase III trial with telaprevir in previously treated patients showed SVR rates of 83-88% in prior relapsers, 54-58% in prior partial responders and, 29-33% in prior non-responders. PMID- 22212572 TI - Triple therapy with boceprevir for HCV genotype 1 infection: phase III results in relapsers and nonresponders. AB - This is an excellent time for patients with hepatitis C virus infection who have failed past treatment with standard of care (SOC) peginterferon (PEG-IFN) and ribavirin (RBV). New treatments have been shown to increase sustained virological response (SVR) rates. Previous relapsers and those with some responsiveness to interferon will clearly benefit from protease inhibitor-based therapy. Patients with little interferon response may not be suited for these regimens, but can be treated by careful selection on a case-by-case basis. Resistance needs to be carefully monitored as these newer and more potent drugs are added to IFN and RBV backbone drugs. Adverse events will be more frequent and will require special attention. PMID- 22212573 TI - Triple therapy for HCV genotype 1 infection: telaprevir or boceprevir? AB - Boceprevir and telaprevir are the first two protease inhibitors available for the treatment of patients infected with hepatitis C virus (HCV) genotype 1. A sustained virological response (SVR) of 70-80% is observed when either of these protease inhibitors is utilized with pegylated interferon (PEG-IFN) and ribavirin (RBV) in treatment naive patients. Both agents are also highly effective in patients who failed to achieve a SVR during previous treatment with PEG-IFN/RBV. A rapid virological response (RVR) is observed in 56-60% of treatment naive patients. Patients who achieve a RVR can be treated with a shorter course of therapy (24-28 weeks) and still achieve a SVR rate of 90% or higher. Patients who do not achieve a RVR, those with cirrhosis and certain prior non-responders should be treated for 48 weeks. Although the SVR rates observed with boceprevir and telaprevir are quite similar both globally and within sub-populations, the treatment algorithms for the two agents are unique. The decision of which protease inhibitor to use should assess several factors including the treatment scheme, duration of therapy, adverse event profile, cost and the likelihood of achieving a RVR. The latter is highly dependent upon IFN sensitivity and the IL28B genotype. PMID- 22212574 TI - Triple combination treatment for chronic hepatitis C with protease inhibitors, pegylated interferon and ribavirin: 'lead-in or no lead-in'? AB - Direct acting antiviral agents for the management of chronic hepatitis C infection have recently been licensed. These new protease inhibitors are combined with pegylated interferon and ribavirin and markedly increase the proportion of patients who respond to antiviral therapy. The protease inhibitors may be used with a 'lead-in' phase of pegylated interferon and ribavirin and the value of this approach has been much debated with those supporting 'lead in' citing the advantages of assessing the early response to therapy before commencing the direct acting antiviral agent. Those opposed to the 'lead-in' phase cite the complexity of the regime and the lack of robust evidence showing an improvement in clinical outcome in those treated in this fashion. PMID- 22212575 TI - Response-guided and -unguided treatment of chronic hepatitis C. AB - Over time, HCV therapy with pegylated interferon and ribavirin has evolved from a fixed duration strategy to one of response guided therapy and this has enabled us to optimize treatment duration. With the evolution of protease inhibitor based therapy, the paradigm of response guided therapy has further helped in decreasing treatment duration in greater number of patients and which then translates into shorter duration of adverse events. However, several population groups have done better with extended duration therapy as opposed to response guided therapy despite early viral clearance. These include the Black population, and those with cirrhosis, decreased interferon sensitivity, and unfavorable IL28B genotypes. The proper identification of those who might benefit from extended duration HCV therapy will undoubtedly lead to optimal care and outcomes. PMID- 22212576 TI - IL28B genetic polymorphism testing in the era of direct acting antivirals therapy for chronic hepatitis C: ten years too late? AB - An association between variations at the IL28B gene locus and HCV clearance (spontaneous recovery or sustained virological response under pegylated interferon (PEG-IFN) and ribavirin (RBV) has been extensively described. In genotype 1-infected patients, the new direct antiviral agents (DAA) including the two approved protease inhibitors boceprevir and telaprevir, in association with the PEG-IFN/RBV combination is the new standard of care making it necessary to redefine the interest of the IL28B genotype in the decision to treat and how to treat genotype 1-infected patients. In treatment-naive patients, IL28B status can certainly identify those with a high probability of achieving SVR with response guided therapy and probably in whom the duration of treatment can be markedly reduced. In experienced patients, the impact of IL28B genotypes is limited and cancelled by early viral kinetics. However, the decision to initiate or withhold therapy remains a clinical one. In summary, although it was a major milestone in the treatment of patients with PEG-IFN/RBV, IL28B polymorphism testing entered the clinical arena almost 10 years too late. PMID- 22212577 TI - Future treatment of chronic hepatitis C with direct acting antivirals: is resistance important? AB - Recent advances in molecular biology have led to the development of novel small molecules that target specific viral proteins of the hepatitis C virus (HCV) life cycle. These drugs, collectively termed directly acting antivirals (DAA), include a range of non-structural (NS) 3/NS4A protease, NS5B polymerase and NS5A inhibitors at various stages of clinical development. Some others drugs called 'non DAA'or indirect inhibitors are not focused on one site of the life cycle target and are still in early pre-clinical and clinical phase I, II and III trials. The rapid replication rate of HCV, along with the low fidelity of its polymerase, results in a generation of mutations throughout the viral genome and sequence variation in the HCV population known as a quasispecies. The efficacy of DAA is limited by the presence of these mutations, resulting in amino acid substitutions within the targeted proteins which affect viral sensitivity to these compounds. Thus, attributable to the high genetic variability of HCV, variants with reduced susceptibility to DAA can occur naturally even before treatment begins, but usually at low levels. Thus it is not surprising that these changes are selected in patients that either breakthrough or do not respond to potent DAA treatment. Six major position mutations in the NS3 HCV Protease (36, 54, 155, 156, 168 and 170), fifteen in the NS5B polymerase (96, 282, 316, 365, 414, 419, 423, 448, 482, 494, 495, 496, 499, 554, 559) and five in the NS5 A region (28, 30, 31, 58 and 93) have now been reported in vitro or in vivo associated with different levels of resistance. The amino acid composition at several of the drug resistance sites can vary between the HCV genotypes/subtypes, resulting in different consensus amino acids leading to a reduction in replicative fitness as well as reduced DAA and non- DAA sensitivity. Information on patterns of resistance to and cross resistance between antiviral agents is increasingly available and may be important for decisions on how to combine drugs to achieve an optimum antiviral effect. This review debates the clinical relevance of resistance to direct and indirect inhibitors taking into account the future potential therapeutic strategies to help patients who do develop resistance to HCV inhibitors. Finally, this chapter treats two points of view: 'for' and 'against' the question of the importance of resistance. PMID- 22212578 TI - Direct acting antivirals for the treatment of chronic hepatitis C: one pill a day for tomorrow. AB - Chronic hepatitis C is one of the leading causes of chronic liver disease with approximately 170 million people infected worldwide. Sustained virological response (SVR) is equivalent to viral eradication and associated with a reduction in the risk of cirrhosis. Nowadays the treatment for hepatitis C virus (HCV) genotype 1 chronic infection is the addition of direct acting antivirals (DAA) with a protease inhibitor (telaprevir or boceprevir) to the pegylated interferon (PEG-IFN) plus ribavirin (RBV) regimen. The future management of patients with these new molecules will require good clinical practice, knowledge of indications, management of side effects and monitoring for antiviral resistance. Certain major medical needs are still unmet and require studies in special populations (HIV-HCV coinfected patients, transplanted patients, etc....) and also in HCV non-1 genotype patients and in non-responders. Second generation DAA are in development. Combinations of antivirals with additive potency that lack cross resistance and with a good safety profile may provide new regimens in the future to make HCV the first chronic viral infection eradicated worldwide with a finite duration of combination DAA therapy without IFN. The aim of this review is to summarize mechanisms of action and results obtained with DAAs. PMID- 22212579 TI - The role of ribavirin in direct acting antiviral drug regimens for chronic hepatitis C. AB - Despite years of clinical use and extensive research efforts, the mechanism of action of ribavirin (RBV) is not well understood. Although it has only a mild, transient antiviral effect on HCV replication when administered as monotherapy, when combined with interferon, RBV improves sustained virological response (SVR) rates by approximately 25-30%. Proposed mechanisms of action for RBV against HCV include (1) a direct effect against the HCV RNA dependent RNA polymerase; (2) induction of misincorporation of nucleotides leading to lethal mutagenesis; (3) depletion of intracellular pools via inhibition of inosine monophosphate dehydrogenase; (4) alteration in the cytokine balance between a Th2 profile (anti inflammatory) to a Th1 profile (pro-inflammatory); and (5) potentiating the effect of interferon via up-regulation of genes involved in interferon signalling. Given the lack of a clear understanding of RBV mechanism of action, it has been challenging to confidently position this drug with new direct antiviral agents (DAA). However, early clinical studies provide strong evidence for a benefit of RBV in combination with DAAs for both IFN containing and sparing regimens. The addition of RBV reduces viral breakthroughs and/or relapses, at least when drugs with low to moderate genetic barriers to resistance are paired together. This is particularly true in patients harbouring HCV subtype 1a. Ongoing studies are now addressing the utility of RBV in nucleoside containing DAA regimens, which offer both potent antiviral activity as well as a high genetic barrier to resistance. It is remarkable that the age-old question of the role of RBV in the future of HCV therapy remains as real today as it was two decades ago. PMID- 22212580 TI - Treatment of chronic hepatitis C--are interferons really necessary? AB - Due to the side effect profile of pegylated interferons interferon treatment has become the holy grail of drug development for chronic hepatitis C. The precise role of interferon in treatment of hepatitis C is not fully understood, besides its antiviral effects interferon is an immune modulator. Nevertheless, recent proof of concept studies indicated, that cure of chronic hepatitis C can be achieved without interferon. Various compounds achieved this goal, like the polymerase inhibitor PSI 7977, the combination of NS5a inhibitor (daclatasvir) and a protease inhibitor (asunaprevir) and the cyclophillin antagonist alisporivir. Various other combinations are investigated currently. Providing that phase 3 studies will confirm these exciting data, direct acting antivirals or host targets will replace peginterferon/ribavirin combination therapy. PMID- 22212581 TI - Future treatment of patients with HCV cirrhosis. AB - Of all hepatitis C virus (HCV) patients, those with cirrhosis are most in need of treatment because of increased morbidity and mortality. Treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV) (PR) has definitely shown the benefits of successful treatment by improving fibrosis, causing the regression of cirrhosis and reducing and preventing cirrhosis-related complications. However, the sustained virological response (SVR) is lower in patients with cirrhosis. First generation protease inhibitors (boceprevir and telaprevir) in combination with PR are a major advancement in the treatment of both naive and treatment experienced genotype 1 patients. In naive patients, the SVR rate with the triple regimen with boceprevir was increased by 14% in patients with severe fibrosis or cirrhosis compared with PR. This benefit was lower than that observed in patients with mild or moderate fibrosis (30%). The SVR rate of the triple regimen with telaprevir was increased by 10-30% compared with PR in patients with severe fibrosis or cirrhosis compared with nearly 30% in patients with mild or moderate fibrosis. In treatment-experienced patients, previous relapsers have the highest increase in SVR with the triple regimen compared with PR, whatever the status of fibrosis. Previous partial or non-responder patients with cirrhosis had lower SVR rates than those without cirrhosis. However, the benefits of telaprevir and boceprevir vs PR was maintained. Previous non-responder patients with cirrhosis benefited the least from treatment. The relapse rate was always higher and side effects were more frequent in patients with cirrhosis compared with those without. First generation protease inhibitors plus PR appear to be a new step forward in the management of HCV genotype 1 patients with cirrhosis. PMID- 22212582 TI - Hepatitis C virus treatment pre- and post-liver transplantation. AB - Liver disease caused by the hepatitis C virus is the main indication for liver transplantation in Western countries. However, HCV re-infection post transplantation is constant and recent data confirm that it significantly impairs patient and graft survival. Chronic HCV infection develops in 75-90% of patients, and 5-30% ultimately progress to cirrhosis within 5 years. Because of the impact of HCV recurrence on graft and patient survival, several treatment strategies have been evaluated. Antiviral therapy could be administered before transplantation to suppress viral replication and reduce the risk of recurrence. However, this approach is applicable in around 50% of patients and tolerance is poor, particularly in patients with decompensated cirrhosis. Pre-emptive therapy in the early post-transplant period is limited by the high rate of side effects. Frequently, antiviral therapy is initiated when HCV recurs to obtain viral eradication and/or reduce disease progression. Treatment of established graft lesions with Pegylated Interferon (PEG-IFN) and Ribavirin (RBV) combination therapy results in a sustained virological response (SVR) in around 30% of patients. The new classes of potent and direct antiviral agents (DAA) will certainly improve the results of pre- and post-transplant antiviral therapy. However, at the present time, no data are available on the use of these drugs in patients with decompensated cirrhosis or post-transplant hepatitis. PMID- 22212583 TI - Hepatitis C virus-human immunodeficiency virus coinfection. AB - As a result of shared modes of transmission, chronic hepatitis C infection is common in HIV-infected patients, particularly among those who have used injection drugs as well as men who have sex with men (MSMs). In the era of effective antiretroviral therapy, HCV infection has emerged as a major cause of morbidity and mortality worldwide. Over the last decade, treatment with peginterferon (PEG IFN) plus ribavirin (RBV) has been recommended for coinfected patients who are at the greatest risk for liver disease; however, the effectiveness of HCV treatment in this population has been disappointing. Challenges to the use of HCV NS3/4A protease inhibitors, telaprevir and boceprevir, patients with HIV/HCV coinfection include the potential for interactions between different drugs, addition of drug toxicities, and the need for therapy with PEG-IFN. Despite these challenges, limited data indicate that telaprevir and boceprevir given in combination with PEG-IFN/RBV increase the rate of viral suppression in coinfected patients with manageable toxicity and drug-drug interaction profile. Accordingly, these agents may be recommended for HCV treatment in carefully selected HIV-infected persons. PMID- 22212584 TI - What's new in HCV genotype 2 treatment. AB - Genotype 2 (HCV-2) accounts for 8% of the patients with chronic hepatitis C virus in Europe. Because of the favourable response to interferon (IFN)-based treatment, this group is considered an 'easy-to-treat' genotype along with HCV-3. However, experimental and clinical data suggest possible differences between HCV 2 and -3. Recently, subtle differences in treatment efficacy have also been shown in response-guided treatment studies. In these studies, the duration of pegylated interferon (PEG-IFN) and ribavirin (RBV) treatment was tailored according to treatment response. Although SVR rates were similar between HCV-2 and HCV-3 patients after a rapid virological response (RVR), in the absence of RVR, the rates were lower in HCV-3 than in HCV-2. The triple combination treatment, including direct-acting antivirals (DAA) that will be commercialized in the coming months might increase SVR rates in this particular subgroup of patients. According to existing results, telaprevir might be beneficial in HCV-2 but not in HCV-3 patients. A nucleotide analogue polymerase inhibitor, PSI-7977 by Pharmasett has been shown to be active against both. The role of the IL28B polymorphism as a predictor of response to the current standard of care (SoC), PEG-IFN and RBV treatment is the subject of debate, but this mainly seems to be because of the small size of the samples in the studies performed so far. Existing results suggest that the genetic evaluation of IL28B may be useful in patients with HCV-2 for predicting response in patients without RVR. PMID- 22212585 TI - Treatment of patients with genotype 3 chronic hepatitis C--current and future therapies. AB - Genotype 3 is a common type of HCV infection, and standard therapy using pegylated interferon (PEG-IFN) and ribavirin (RBV) is quite effective in these patients. While a short course of 16 weeks may result in comparable end of therapy responses, relapse rates are often high. A 24-week course is therefore preferable, and is expected to result in sustained virological response (SVR) rates of more than 70%. The 24-week course is especially recommended in the presence of steatosis (often associated with Genotype 3 infection), fibrosis stage two or more, high BMI and high viral load. In patients who do not achieve a rapid viral response (RVR) with combination therapy, an extended course up to 48 weeks should be considered. While not as definite as for genotype 1 patients, the presence of the CC variant of IL28b could help in the initial prognosis and the need for additional treatment, if an RVR is not achieved. The role of directly acting antiviral agents (DAA) has not been fully evaluated in treatment naive, non-responders and relapsers in genotype 3 patients. Initial results with the cyclophilin inhibitor Debio-025 are quite encouraging. There is an urgent need for large clinical trials using DAA and host modulators in patients with G3 infection. PMID- 22212586 TI - The future for the treatment of genotype 4 chronic hepatitis C. AB - Hepatitis C virus genotype 4 (HCV-4) is the most common type of hepatitis C virus (HCV) in the Middle East and Africa, in particular Egypt. Since the development of new protease inhibitors, the response of HCV-4 to the standard regimen of treatment (pegylated interferon/ribavirin) lags behind other genotypes and has become the most resistant type to treat. The development of therapeutic strategies for all patients with HCV-4 whether they are naive, have experienced a virological breakthrough, are relapsers or non-responders is still a considerable challenge. New types of interferon (Consensus Interferon, Y-shaped, Albinterferon...) and new direct action antiviral drugs (Nitazoxanide, Vit.D, other) may improve the treatment of patients with HCV-4. The IL28B CC polymorphism may be associated with sustained virological response. PMID- 22212588 TI - Face identity recognition in autism spectrum disorders: a review of behavioral studies. AB - Face recognition--the ability to recognize a person from their facial appearance- is essential for normal social interaction. Face recognition deficits have been implicated in the most common disorder of social interaction: autism. Here we ask: is face identity recognition in fact impaired in people with autism? Reviewing behavioral studies we find no strong evidence for a qualitative difference in how facial identity is processed between those with and without autism: markers of typical face identity recognition, such as the face inversion effect, seem to be present in people with autism. However, quantitatively--i.e., how well facial identity is remembered or discriminated--people with autism perform worse than typical individuals. This impairment is particularly clear in face memory and in face perception tasks in which a delay intervenes between sample and test, and less so in tasks with no memory demand. Although some evidence suggests that this deficit may be specific to faces, further evidence on this question is necessary. PMID- 22212587 TI - Barriers to hepatitis C treatment. AB - Despite the availability of highly effective therapy for hepatitis C virus (HCV) infection, few patients receive treatment. Barriers arising at multiple levels, from diagnosis to specialist referral, may impede the delivery of hepatitis C care. At the patient level, lack of awareness, fear of side effects, poor adherence and comorbid conditions may prevent treatment. For providers, limited knowledge, lack of availability and communication difficulties may be problematic. At the government and payer level, a lack of promotion, surveillance and funding may interfere. Each of these barriers needs to be addressed if wider implementation of antiviral therapy is to be achieved. PMID- 22212589 TI - Fostering interdisciplinary biology. PMID- 22212590 TI - Economic impact of childhood obesity on health systems: a systematic review. AB - The primary purpose of this study is to analyse the costs related to childhood obesity (CO) with reference to different models of healthcare systems. A systematic review of the economic impact of CO on healthcare systems was conducted by searching the main electronic scientific databases. Cost-of-illness (COI) analyses of children aged under 18 years who had been diagnosed as overweight or obese published up to July 2010 were considered. Short- and long term consequences of CO were taken into account. In order to appraise the quality of the included studies, the British Medical Journal referees' checklist was used. About 3,844 COI analyses were initially found and 10 were finally considered in the current review: two studies referred to Beveridge and eight referred to Voluntary health insurance models. No studies have been conducted within a Bismarck model. Six studies considered in-patient costs, four studies estimated outpatient and primary care costs and seven studies considered pharmaceutical costs. The average quality of the included analyses was medium. The analysis confirmed the significance of CO related costs and the heterogeneity among available studies, which made it impossible to compare the different healthcare models. PMID- 22212591 TI - Cystamine attenuates lupus-associated apoptosis of ventricular tissue by suppressing both intrinsic and extrinsic pathways. AB - Cystamine, a disulphide metabolite, has been demonstrated to ameliorate various lupus-associated tissue damages by animal models. However, effects of cystamine on apoptosis of cardiac tissue, a main cardiac damage attributing to lupus, are less obvious. Therefore, we aimed to investigate whether or not cystamine possesses anti-apoptotic effects with emphasis on LV tissue of lupus-prone mice NZB/W-F1. Cystamine treatment was performed by daily intraperitoneal administration. Morphology and apoptotic status of ventricular tissues in the treated mice were assessed by microscopy and TUNEL assay, respectively. Levels of apoptotic biomarkers were determined using immunoblot. Our results revealed that cystamine significantly attenuated the apoptosis of LV tissues in NZB/W-F1 mice, whereas the morphology of the tissues was slightly altered. In addition, cystamine reduced level of Fas and inhibited activation of caspase-8. Cystamine also increased level of Bcl-2 and phosphorylation of Bad, and decreased level of Bad and truncated Bid (tBid). Moreover, level of cytosolic cytochrome c and Apaf 1, and activation of caspase-9 and caspase-3 were suppressed in response to cystamine treatment. In Balb/c mice, as normal control mice, changes in cell morphology and levels of the tested apoptotic components were found insignificant in the LV tissues. These findings indicate that cystamine treatment attenuates apoptosis of LV tissues of NZB/W-F1 mice through suppressing both intrinsic and extrinsic apoptotic pathways. Therefore, cystamine is considered beneficial to alleviating lupus-associated cardiac damages. PMID- 22212592 TI - Comparative syntheses of peptides and peptide thioesters derived from mouse and human prion proteins. AB - Prions are suspected as causative agents of several neuropathogenic diseases, even though the mode of their action is still not clear. A combination of chemical and recombinant syntheses can provide suitable probes for explanation of prions role in pathogenesis of neurodegenerative diseases. However, the prions contain several difficult sequences for synthesis by Fmoc/tBu approach. For that reason, the peptide thioesters as the key building blocks for chemical syntheses of proteins by native chemical ligation were employed. A scan of the mouse prion domain 93-231 was carried out in order to discover availability of derived thioesters as the suitable building blocks for a total chemical synthesis of the prion protein based probes. The synthesis on 2-chlorotritylchloride resin was utilized and after a deprotection of the samples for analysis, the peptide segments were purified and characterized. If the problems were detected during the synthesis, the segment was re-synthesized either using the special pseudoproline dipeptides or by splitting its molecule to two or three smaller segments, which were prepared easier. The protected segments, prepared correctly without any deletion and in sufficient amounts, were coupled either with EtSH after DIC/DMAP activation or with p-Ac-NH-Ph-SH using PyBOP activation to yield corresponding thioesters. In some special cases, the other techniques of thioester formation, like sulfonamide-safety catch and/or trimethylaluminium approach were utilized. PMID- 22212593 TI - Determinants for substrate specificity of the bacterial PP2C protein phosphatase tPphA from Thermosynechococcus elongatus. AB - Members of the Mg(2+)- or Mn(2+)-dependent protein phosphatases/PP2C-like serine/threonine phosphatases (PPM/PP2C) are abundant and widely distributed in prokaryotes and eukaryotes, where they regulate diverse signal transduction pathways. Despite low sequence conservation, the structure of their catalytic core is highly conserved except for a flexible loop termed the flap subdomain. Bacterial PPM/PP2C members without C- or N-terminal regulatory domains still recognize their substrates. Based on the crystal structure of tPphA (a PPM/PP2C member from the cyanobacterium Thermosynechococcus elongatus), variants of tPphA were generated by site-directed mutagenesis to identify substrate specificity determinants. Furthermore, a PPM/PP2C chimera containing the tPphA catalytic core and the flap subdomain of human PP2Calpha was also generated. tPphA variants and the chimera were tested towards different artificial substrates and native phosphorylated P(II). A binding assay combining chemical crosslinking and pull down was designed to analyze the binding of the various phosphatase variants to phosphoprotein P(II) . Together, these data showed that the metal 1-metal 2 cluster in the catalytic center, but not the catalytically active metal 3, is required for the binding of phosphorylated substrate. Residues outside the catalytic center are pivotal for the recognition and turnover of phosphorylated protein substrate. In particular, a histidine residue (His39) of tPphA was identified to play a specific role in protein substrate dephosphorylation. Furthermore, mutations in the variable flap subdomain can affect enzyme activity as well as substrate specificity. PMID- 22212594 TI - Genome-wide expression profiling of schizophrenia using a large combined cohort. AB - Numerous studies have examined gene expression profiles in post-mortem human brain samples from individuals with schizophrenia compared with healthy controls, to gain insight into the molecular mechanisms of the disease. Although some findings have been replicated across studies, there is a general lack of consensus on which genes or pathways are affected. It has been unclear if these differences are due to the underlying cohorts or methodological considerations. Here, we present the most comprehensive analysis to date of expression patterns in the prefrontal cortex of schizophrenic, compared with unaffected controls. Using data from seven independent studies, we assembled a data set of 153 affected and 153 control individuals. Remarkably, we identified expression differences in the brains of schizophrenics that are validated by up to seven laboratories using independent cohorts. Our combined analysis revealed a signature of 39 probes that are upregulated in schizophrenia and 86 that are downregulated. Some of these genes were previously identified in studies that were not included in our analysis, while others are novel to our analysis. In particular, we observe gene expression changes associated with various aspects of neuronal communication and alterations of processes affected as a consequence of changes in synaptic functioning. A gene network analysis predicted previously unidentified functional relationships among the signature genes. Our results provide evidence for a common underlying expression signature in this heterogeneous disorder. PMID- 22212595 TI - Amine oxidase activity of beta-amyloid precursor protein modulates systemic and local catecholamine levels. AB - The catecholamines dopamine (DA), norepinephrine (NE) and epinephrine (E) are neurotransmitters and hormones that mediate stress responses in tissues and plasma. The expression of beta-amyloid precursor protein (APP) is responsive to stress and is high in tissues rich in catecholamines. We recently reported that APP is a ferroxidase, subsuming, in neurons and other cells, the iron-export activity that ceruloplasmin mediates in glia. Here we report that, like ceruloplasmin, APP also oxidizes synthetic amines and catecholamines catalytically (K(m) NE=0.27 mM), through a site encompassing its ferroxidase motif and selectively inhibited by zinc. Accordingly, APP knockout mice have significantly higher levels of DA, NE and E in brain, plasma and select tissues. Consistent with this, these animals have increased resting heart rate and systolic blood pressure as well as suppressed prolactin and lymphocyte levels. These findings support a role for APP in extracellular catecholaminergic clearance. PMID- 22212596 TI - Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants. AB - We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder. PMID- 22212598 TI - Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology. PMID- 22212597 TI - Resting functional connectivity of language networks: characterization and reproducibility. AB - The neural basis of language comprehension and production has been associated with superior temporal (Wernicke's) and inferior frontal (Broca's) cortical areas, respectively. However, recent resting-state functional connectivity (RSFC) and lesion studies have implicated a more extended network in language processing. Using a large RSFC data set from 970 healthy subjects and seed regions in Broca's and Wernicke's, we recapitulate this extended network that includes not only adjoining prefrontal, temporal and parietal regions but also bilateral caudate and left putamen/globus pallidus and subthalamic nucleus. We also show that the language network has predominance of short-range functional connectivity (except posterior Wernicke's area that exhibited predominant long range connectivity), which is consistent with reliance on local processing. Predominantly, long-range connectivity was left lateralized (except anterior Wernicke's area that exhibited rightward lateralization). The language network also exhibited anti-correlated activity with auditory (only for Wernicke's area) and visual cortices that suggests integrated sequential activity with regions involved with listening or reading words. Assessment of the intra-subject's reproducibility of this network and its characterization in individuals with language dysfunction is required to determine its potential as a biomarker for language disorders. PMID- 22212599 TI - Oxytocin receptor (OXTR) is not associated with optimism in the Nurses' Health Study. PMID- 22212600 TI - What is common becomes normal: the effect of obesity prevalence on maternal perception. AB - BACKGROUND AND AIMS: This analysis investigates the poorly-known effect of local prevalence of childhood obesity on mothers' perception of their children's weight status. METHODS AND RESULTS: In 2008, a national nutritional survey of children attending the third grade of elementary school was conducted in Italy. Children were measured and classified as underweight, normal weight, overweight and obese, using the International Obesity Task Force cut-offs for body mass index (BMI). A parental questionnaire included parental perception of their child's weight status (underweight, normal, a little overweight and a lot overweight). Regions were classified by childhood obesity prevalence (<8%, 8-12%, >=13%). The association between incorrect maternal perception and regional obesity prevalence, and maternal and child characteristics were examined using bivariate and logistic regression analyses. Complete data were available for 37 590 children, of whom 24% were overweight and 12% obese. Mothers correctly identified the status of 84% of normal weight, 52% of overweight and 14% of obese children. Among overweight children, factors associated with underestimation of the child's weight included lower maternal education (adjusted odds ratio, aOR, 1.9; 95% confidence interval (CI) 1.6-2.4), residence in a high-obesity region (aOR 2.2; 95% CI 1.9-2.6), male gender (aOR 1.4; 95% CI 1.2-1.6) and child's BMI. CONCLUSION: Higher regional obesity prevalence is associated with lower maternal perception, suggesting that what is common has a greater likelihood of being perceived as normal. As perception is a first step to change, it may be harder to intervene in areas with high-obesity prevalence where intervention is most urgent. PMID- 22212601 TI - Soluble receptor for advanced glycation end-product levels are related to albuminuria and arterial stiffness in essential hypertension. AB - BACKGROUND AND AIMS: Emerging evidence suggests that the soluble receptor for advanced glycation end-products (sRAGE) is implicated in the development of vascular disease. We investigated the interrelationships of sRAGE with albumin to creatinine ratio (ACR) and arterial stiffness in essential hypertension. METHODS AND RESULTS: In 309 untreated non-diabetic hypertensives, ACR values were determined as the mean of three non-consecutive morning spot urine samples and aortic stiffness was evaluated on the basis of carotid to femoral pulse wave velocity (c-f PWV). In all subjects, venous blood sampling was performed for the estimation of sRAGE levels. Patients with low (n = 155) compared to those with high sRAGE values (n = 154) had greater 24-h systolic BP (140 +/- 8 vs. 134 +/- 7 mmHg, p < 0.0001), exhibited higher ACR (36.3 +/- 51.6 vs. 17.2 +/- 1.2 mg g(-1), p < 0.0001) and c-f PWV (8.3 +/- 1.5 vs. 7.8 +/- 1.1 m s(-1), p = 0.003), independently of confounding factors. Multiple regression analyses revealed that age, male sex, 24-h systolic BP and sRAGE were the 'independent correlates' of ACR (R(2) = 0.493, p < 0.0001), while age, 24-h systolic BP and sRAGE were the 'independent correlates' of c-f PWV (R(2) = 0.428, p < 0.0001). CONCLUSION: In hypertensives, decreased sRAGE levels are accompanied by pronounced albuminuria and arterial stiffening. The association of sRAGE with ACR and c-f PWV suggests involvement of sRAGE in the progression of hypertensive vascular damage. PMID- 22212602 TI - Homocysteinylation of low-density lipoproteins (LDL) from subjects with type 1 diabetes and human aortic endothelial cells: an in vitro study. PMID- 22212603 TI - Traumatic brain injury in the neonate, child and adolescent human: an overview of pathology. AB - In the middle of the last century it had been thought that a good recovery of function and behavior would occur after traumatic brain injury (TBI) in very young human beings. A recent major change in thinking states that early childhood TBI may result in a severe compromise of normal brain growth and development such that TBI, rather, may compromise later normal development resulting in a need for very long term patient care and management. The mechanisms of injury and pathology within the injured brain are reviewed and compared between when injury occurs at or close to the time of birth, in an infant, in a young child, in a child between ages 5 and 10, in young and older adolescents and in young adulthood. Our understanding of pathophysiological responses by cells of the human central nervous system has recently greatly increased but has really only served to illustrate the great complexity of interactions between different types of cell within the growing and developing CNS. The hypothesis is developed that the outcome for a very young patient differs with the relative state of development of injured cells at the locus of injury. And that the potential for either repair, re-instatement of normal cellular and organ function or for continued normal development is much reduced after an early brain insult (EBI) compared with TBI in a slightly older child or young adult patient. The advent of increasingly sophisticated non-invasive imaging technology has allowed assessment of the influence and time course of brain pathology both early and late after TBI. This has generated greater confidence on the part of clinicians in forecasting outcomes for an injured patient. But our increased understanding has still not allowed development of therapeutic strategies that might ameliorate the effect of an injury. It is suggested that an improved integration of major clinical and scientific effort needs to be made to appreciate the import of multiple interactions between cells forming the neurovascular unit in order to improve any potential for post-traumatic recovery after TBI in neonates and young children. PMID- 22212604 TI - SCG postnatal remodelling--hypertrophy and neuron number stability--in Spix's yellow-toothed cavies (Galea spixii). AB - Whilst a fall in neuron numbers seems a common pattern during postnatal development, several authors have nonetheless reported an increase in neuron number, which may be associated with any one of a number of possible processes encapsulating either neurogenesis or late maturation and incomplete differentiation. Recent publications have thus added further fuel to the notion that a postnatal neurogenesis may indeed exist in sympathetic ganglia. In the light of these uncertainties surrounding the effects exerted by postnatal development on the number of superior cervical ganglion (SCG) neurons, we have used state-of-the-art design-based stereology to investigate the quantitative structure of SCG at four distinct timepoints after birth, viz., 1-3 days, 1 month, 12 months and 36 months. The main effects exerted by ageing on the SCG structure were: (i) a 77% increase in ganglion volume; (ii) stability in the total number of the whole population of SCG nerve cells (no change--either increase or decrease) during post-natal development; (iii) a higher proportion of uninucleate neurons to binucleate neurons only in newborn animals; (iv) a 130% increase in the volume of uninucleate cell bodies; and (v) the presence of BrdU positive neurons in animals at all ages. At the time of writing our results support the idea that neurogenesis takes place in the SCG of preas, albeit it warrants confirmation by further markers. We also hypothesise that a portfolio of other mechanisms: cell repair, maturation, differentiation and death may be equally intertwined and implicated in the numerical stability of SCG neurons during postnatal development. PMID- 22212605 TI - The impact of obesity in systemic lupus erythematosus on disease parameters, quality of life, functional capacity and the risk of atherosclerosis. AB - OBJECTIVE: To study the effect of obesity on the quality of life (QoL), functional capacity and the risk of carotid atherosclerotic plaque formation in systemic lupus erythematosus (SLE) patients and to correlate the findings with disease parameters, activity and damage. PATIENTS AND METHODS: Sixty SLE patients were clinically examined, investigated and their carotid intima media thickness (IMT) measured by ultrasonography. Assessment of the QoL, Health Assessment Questionnaire(HAQ-II), fatigue severity scale (FSS), the disease activity using Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the damage by Systemic Lupus International Collaboration Clinics (SLICC)/American College of Rheumatology (ACR) damage index were performed on all patients. Patients were grouped according to their body mass index (BMI). RESULTS: The mean age of the patients was 28.55 8.08 years, disease duration 6.49 5.18 years with a female : male ratio of 5.67 : 1. There was a significant association of increased BMI with lupus nephritis and hypertension. In obese SLE patients, there was a significant decrease in QoL and functional capacity and obvious dyslipidemia. The IMT was increased and significantly correlated with waist circumference. CONCLUSION: In SLE patients, there is an association of BMI with dyslipidemia and decreased QoL. Its role in disease activity is not clear and obesity was associated with SLE damage accrual, especially lupus nephritis among other risk factors, including age, disease duration and increased steroid use. Increased waist circumference increases the risk of atherosclerosis. PMID- 22212606 TI - Type I interferon signaling regulates the composition of inflammatory infiltrates upon infection with Listeria monocytogenes. AB - Type I IFN is key to the immune response to viral pathogens, however its role in bacterial infections is less well understood. Mice lacking the type I IFN receptor (IFNAR-/-) demonstrate enhanced resistance to infection with Listeriamonocytogenes. We have now determined that following infection with Listeria, the composition of innate cells recruited to the peritoneal cavity of IFNAR-/- mice reflects an increase in the frequency of neutrophils and a decrease in monocyte frequency compared to WT controls. These differences in inflammatory infiltrates could not be attributed to distinct bone marrow composition prior to infection or to level of apoptosis. We also observed no differences in neutrophil oxidative burst. However, blocking CXCR2 prevented enhanced neutrophil influx and hampered bacterial clearance. Taken together, these studies highlight a novel mechanism by which type I interferon signaling regulates the immune response to Listeria, through negative regulation of chemokines driving neutrophil recruitment. PMID- 22212607 TI - Self-efficacy mediates the associations of social support and depression with treatment adherence in heart failure patients. AB - BACKGROUND: Nonadherence to treatment recommendations is a leading preventable cause of rehospitalization and premature mortality in chronic heart failure (HF) patients. PURPOSE: This study examined whether self-efficacy mediates the contributions of social support and depression to treatment adherence. METHODS: A sample of 252 HF outpatients with a mean age of 54 years completed self-report questionnaires assessing depression, perceived social support, self-efficacy, and treatment adherence. RESULTS: Self-efficacy mediated the associations of social support and depression with treatment adherence after adjusting for demographic (age, gender, marital status, education, and ethnicity) and medical (New York Heart Association Classification and comorbidity) covariates. CONCLUSION: Self efficacy explains the influence of social support and depression on treatment adherence and may be a key target for interventions to improve disease management and self-care behaviors in HF patients. PMID- 22212608 TI - Analysis of biennial outbreak pattern of respiratory syncytial virus according to subtype (A and B) in the Zagreb region. AB - BACKGROUND: The epidemic pattern of respiratory syncytial virus (RSV) in Croatia is biennial. In order to determine if the circulation of different RSV subtypes affects the outbreak cycle, the aim of the present study was to analyze the epidemic pattern of RSV in children in Croatia (Zagreb region) over a period of 3 consecutive years. METHODS: The study group consisted of 696 inpatients, aged 0-5 years, who were hospitalized with acute respiratory tract infections caused by RSV, in Zagreb, in the period 1 January 2006-31 December 2008. The virus was identified in nasopharyngeal secretions using direct immunofluorescence. The virus subtype was determined on real-time polymerase chain reaction. RESULTS: Of 696 RSV infections identified in children, subtype A virus caused 374 infections, and subtype B, 318. Four patients had a dual RSV infection (subtypes A and B). The period of study was characterized by four epidemic waves of RSV infections: the first, smaller, in the spring of 2006; the second, larger, in December 2006/January 2007; the third in spring 2008, followed by a fourth outbreak beginning in November of 2008. The biennial virus cycles were persistent although the predominant RSV subtype in the first two epidemic waves was subtype B, and in the second two it was subtype A. CONCLUSION: Over a 3 year period of observation, the biennial RSV cycle in Croatia cannot be explained by a difference in the predominant circulating subtype of RSV. Other unknown factors account for the biennial cycle of RSV epidemics in Croatia. PMID- 22212609 TI - Health-related quality of life before and after management in adults referred to otolaryngology: a prospective national study. AB - OBJECTIVE: An assessment of the effect of otolaryngological management on the health-related quality of life of patients. DESIGN: Application of the Health Utilities Index mark 3 (HUI-3) before and after treatment; application of the Glasgow Benefit Inventory (GBI) after treatment. SETTING: Six otolaryngological departments around Scotland. PARTICIPANTS: A 9005 adult patients referred to outpatient clinics. MAIN OUTCOME MEASURES: Complete HUI-3 data was collected from 4422 patients; complete GBI data from 4235; complete HUI-3 and GBI data from 3884. RESULTS: The overall change in health related quality of life from before to after management was just +0.02. In the majority of subgroups of data (classified by type of management) there was essentially no change in HUI-3 score. The major exceptions were those patients provided with a hearing aid (mean change 0.08) and those whose problem was managed surgically (mean change 0.04). The mean GBI score was 5.3 which is low. Those managed surgically reported a higher GBI score of 13.0. CONCLUSION: We found that patients treated surgically or given a hearing aid reported a significant improvement in their health related quality of life after treatment in otolaryngology departments. In general, patients treated in other ways reported no significant improvement. We argue that future research should look carefully at patient groups where there is unexpectedly little benefit from current treatment methods and consider more effective methods of management. PMID- 22212610 TI - Measured body mass index in adolescence and the incidence of pancreatic cancer in a cohort of 720,000 Jewish men. AB - PURPOSE: The increasing prevalence of adolescent obesity affects adult health. We investigated the association of adolescent overweight with pancreatic cancer incidence in a cohort of 720,927 Jewish Israeli men. METHODS: Body mass index (BMI) was measured during a general health examination at ages 16-19 between the years 1967 and 1995. Overweight was defined as BMI >= 85th percentile of the reference US-CDC distribution in adolescence. Pancreatic cancer was identified by linkage with the Israel National Cancer Registry up to 2006. RESULTS: The mean follow-up period was 23.3 +/- 8.0 years. During 16.8 million person-years, 98 cases of pancreatic cancer were detected. Using Cox proportional hazards modeling, overweight in adolescence predicted an increased risk of pancreatic cancer [hazard ratio (HR) = 2.09; 95% confidence interval (CI): 1.26-3.50, p = 0.005]. Compared with adolescents with 'normal' range BMI Z-scores (-1 to +1), adolescents with Z-scores > 1 showed significantly increased risk [HR, 2.28 (95% CI: 1.43-3.64), p = 0.001]. Lower education level (10 or less years of schooling vs. 11-12 years) was also associated with increased risk of pancreatic cancer [HR 1.90 (95% CI: 1.27-2.86, p = 0.002)], whereas height, country of origin and immigration status were not. CONCLUSIONS: Adolescent overweight is substantially associated with pancreatic cancer incidence in young to middle-aged adults. Applying our point estimates to the 16.8% prevalence of excess weight in Israeli adolescents in the past decade suggests a population fraction of 15.5% (95% CI: 4.2-29.6%) for pancreatic cancer attributable to adolescent overweight in Israel. PMID- 22212611 TI - Anthropometric factors and physical activity and risk of thyroid cancer in postmenopausal women. AB - PURPOSE: To investigate the associations of anthropometric factors and physical activity with risk of thyroid cancer in a large prospective study. METHODS: We examined these associations with risk of incident thyroid cancer in a cohort of 144,319 postmenopausal women enrolled in the Women's Health Initiative. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) for factors of interest with risk of all thyroid cancer (n = 294) and of the two major subtypes: papillary (n = 245) and follicular thyroid cancer (n = 32). RESULTS: After adjustment for covariates, measured height at baseline was positively associated with thyroid cancer overall (HR for highest vs. lowest quartile 1.48, 95% CI 1.04-2.13, p for trend 0.02) and with papillary carcinoma (HR 1.49, 95% CI 1.01-2.21, p for trend 0.03, respectively). For each 5 cm-increase in height, the HR for all thyroid cancer was 1.15, 95% CI 1.04-1.27 and for papillary thyroid cancer was 1.14, 95% CI 1.03 1.27. In addition, self-reported weight at age 18 was positively associated with risk of papillary thyroid cancer. In contrast, baseline weight, body mass index, waist circumference, hip circumference, waist-hip ratio, weight change from age 18 to baseline, and level of self-reported recreational physical activity were not associated with risk. CONCLUSIONS: Our results suggest that attained stature is a risk factor for thyroid cancer in postmenopausal women. This association may reflect the influence of either genetic or environmental factors in early life on risk of thyroid cancer. PMID- 22212613 TI - [Radiation therapy versus chemoradiation as adjuvant treatment in high-risk endometrial cancer]. AB - Endometrial cancer is a common malignancy. Management of these tumors depends on several risk factors such as FIGO staging, myometrial invasion, histology or pelvic lymph node involvement. According to those factors, low risk, intermediate and high risk groups were defined. A high risk endometrial cancer has a poorer prognostic and more risks of recurrence. Treatment of such disease should be more aggressive. However modalities of these treatments have not yet been clearly defined. PMID- 22212612 TI - Non-steroidal anti-inflammatory drugs and cancer incidence by sex in the VITamins And Lifestyle (VITAL) cohort. AB - PURPOSE: Use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the incidence of several cancers. A recent meta-analysis of randomized trials of aspirin reported a reduction in cancer mortality; however, few studies have investigated whether aspirin or other NSAIDs reduce overall cancer risk. METHODS: 64,847 residents of western Washington State, aged 50-76, completed a baseline questionnaire in 2000-2002 and reported on their use of individual NSAIDs over the past 10 years. Behavior was categorized as non-use, low (<4 days/week or <4 years), and high (>=4 days/week and >=4 years). Over 7 years of follow-up, 5,946 incident invasive cancer cases were identified. Multivariable proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Relative to non-use, high 10-year use of regular strength NSAIDs was inversely associated with total cancer risk in men (HR 0.88, 95% CI: 0.79-0.97) and not associated with risk in women (HR 1.10, 95% CI: 0.96 1.25; p interaction <0.01). Use of regular-strength NSAIDs was strongly and inversely associated with colorectal cancer risk in men and women, but differentially associated with sex-specific risk of shared cancer sites other than colorectal cancer (men: HR 0.83, 95% CI: 0.71-0.97; women: HR 1.18, 95% CI: 0.97-1.44; p interaction < 0.01). CONCLUSIONS: Long-term use of NSAIDs was associated with a reduced risk of total cancer among men and colorectal cancer among both sexes. Our findings do not support NSAID use for overall cancer prevention among women. Additional high-quality studies with long-term follow-up for cancer among women are needed before a public health recommendation can be made. PMID- 22212614 TI - Transglutaminase 2: biology, relevance to neurodegenerative diseases and therapeutic implications. AB - Neurodegenerative disorders are characterized by progressive neuronal loss and the aggregation of disease-specific pathogenic proteins in hallmark neuropathologic lesions. Many of these proteins, including amyloid Alphabeta, tau, alpha-synuclein and huntingtin, are cross-linked by the enzymatic activity of transglutaminase 2 (TG2). Additionally, the expression and activity of TG2 is increased in affected brain regions in these disorders. These observations along with experimental evidence in cellular and mouse models suggest that TG2 can contribute to the abnormal aggregation of disease causing proteins and consequently to neuronal damage. This accumulating evidence has provided the impetus to develop inhibitors of TG2 as possible neuroprotective agents. However, TG2 has other enzymatic activities in addition to its cross-linking function and can modulate multiple cellular processes including apoptosis, autophagy, energy production, synaptic function, signal transduction and transcription regulation. These diverse properties must be taken into consideration in designing TG2 inhibitors. In this review, we discuss the biochemistry of TG2, its various physiologic functions and our current understanding about its role in degenerative diseases of the brain. We also describe the different approaches to designing TG2 inhibitors that could be developed as potential disease-modifying therapies. PMID- 22212616 TI - Maps and legends: the quest for dissociated ligands of the glucocorticoid receptor. AB - Glucocorticoids are steroid hormones that have pleiotropic effects on development, metabolism, cognitive function and other aspects of physiology. Since the demonstration more than sixty years ago of their capacity to suppress inflammation, synthetic glucocorticoids have been extremely widely used in the treatment of inflammatory diseases. However, their clinical use is limited by numerous, unpredictable and potentially serious side effects. Glucocorticoids regulate gene expression both positively and negatively. Both of these effects are mediated by the glucocorticoid receptor, a ligand-dependent transcription factor. It has become widely accepted that anti-inflammatory effects of glucocorticoids are mostly due to inhibition of transcription, whereas the activation of transcription by the glucocorticoid receptor accounts for the majority of side effects. This dogma (which we refer to as the "transrepression hypothesis") predicts the possibility of uncoupling therapeutic, anti inflammatory effects from side effects by identifying novel, selective ligands of the glucocorticoid receptor, which preferentially mediate inhibition rather than activation of transcription. It is argued that such "dissociated" glucocorticoid receptor ligands should retain anti-inflammatory potency but cause fewer side effects. Here we critically re-examine the history and foundations of the transrepression hypothesis. We argue that it is incompatible with the complexity of gene regulation by glucocorticoids and poorly supported by experimental evidence; that it no longer aids clear thinking about the actions of the glucocorticoid receptor; and that it will not prove a fruitful basis for continued refinement and improvement of anti-inflammatory drugs that target the glucocorticoid receptor. PMID- 22212617 TI - Agmatine (decarboxylated L-arginine): physiological role and therapeutic potential. AB - Agmatine, a cationic amine formed by decarboxylation of l-arginine by the mitochondrial enzyme arginine decarboxylase (ADC), is widely but unevenly distributed in mammalian tissues. Agmatine in the tissues originates from cellular enzymatic de novo synthesis and from agmatine absorbed from the lumen of the gut. Absorption from the gut and accumulation in the tissues and cells must occur via a specific carrier mechanism because the compound is charged at physiologic pH and, hence, biological membranes are almost completely impermeable to the organic cation in the absence of an uptake system. Agmatine initially attracted attention as an endogenous ligand at imidazoline receptors and alpha(2) adrenoceptors. However, independent of binding to those receptors, agmatine induces a variety of physiological and pharmacological effects exhibiting a great therapeutic potential of the compound. Although the precise function of endogenous agmatine is presently still unclear, this review summarizes the current knowledge concerning the physiological and pathophysiological function of agmatine. PMID- 22212618 TI - Drug-eluting stent restenosis: effect of drug type, release kinetics, hemodynamics and coating strategy. AB - Restenosis following stent implantation diminishes the procedure's efficacy influencing long-term clinical outcomes. Stent-based drug delivery emerged a decade ago as an effective means of reducing neointimal hyperplasia by providing localized pharmacotherapy during the acute phase of the stent-induced injury and the ensuing pathobiological mechanisms. However, drug-eluting stent (DES) restenosis may still occur especially when stents are used in complex anatomical and clinical scenarios. A DES consists of an intravascular metallic frame and carriers which allow controlled release of active pharmaceutical agents; all these components are critical in determining drug distribution locally and thus anti-restenotic efficacy. Furthermore, dynamic flow phenomena characterizing the vascular environment, and shear stress distribution, are greatly influenced by stent implantation and play a significant role in drug deposition and bioavailability within local vascular tissue. In this review, we discuss the performance of DES and the interaction of the different DES components with the hemodynamic milieu emphasizing on the inhibition of clinical restenosis. PMID- 22212620 TI - Unraveling the molecular recognition of "three methylene spacer" bis(benzimidazolium) moiety by dibenzo-24-crown-8: pseudorotaxanes under study. AB - "Three methylene spacer" bis(benzimidazolium) derivatives act as a new template for threading dibenzo-24-crown-8 into [2]pseudorotaxanes. In this Article we sought to unveil the difference in the extent of threading of various "three methylene spacer" bis-benzimidazolium moieties based on differences in aromatic methyl substituent positions and anions through the macrocycle dibenzo-24-crown 8. The temperature of the systems were also varied (low temperatures of 240 K and 253 K), when such interwinding of the thread and crown were not detected at room temperature of 308 K. The presence of such threaded complexes was determined based on (1)H-NMR initially and finally corroborated by high resolution mass spectrometry and DFT calculations. 2D-NMR experiments ((1)H-(1)H-NOESY) proved to be a very important tool in elucidating the interaction present between the components of the pseudorotaxanes. The dethreading/rethreading process was studied. DFT optimized structures suggest lower energy H-bonding orientations and compare the effect of methyl substituents on the axle. PMID- 22212619 TI - The traditional ayurvedic medicine, Eugenia jambolana (Jamun fruit), decreases liver inflammation, injury and fibrosis during cholestasis. AB - BACKGROUND: Cholestasis is a common disease of the liver. Chronic cholestasis eventually leads to hepatic cirrhosis and fibrosis, and rodent chronic cholestasis models are used to study aspects of fibrosis and cirrhosis. Cholestasis-induced liver injury and fibrosis are associated with increased oxidative stress and inflammation. Few pharmacological therapies exist for treatment of cholestasis or cirrhosis, but it is known that humans with better nutritional intake are less likely to develop certain types of cirrhosis. Eugenia jambolana (Jamun) is a tropical berry fruit rich in antioxidant anthocyanin compounds. AIM: As anthocyanins decrease cellular lipid peroxidation and oxidative stress, it was hypothesized that Jamun fruit extract (JFE) administration could protect against cholestatic liver injury and inflammation in mice. METHOD: Starting 24 h after sham or bile-duct ligation (BDL) surgery, male C57Bl/6 mice were administered vehicle or JFE (100 mg/kg, po) for 10 days. RESULTS: Mice that underwent BDL had elevated serum ALT levels, which were reduced to 60% by JFE treatment. Likewise, BDL caused hepatic inflammation, macrophage infiltration, fibrosis and necrosis, all of which were largely improved by JFE. Interestingly, hepatoprotection was observed in JFE-treated BDL mice, despite suppressed transporter expression and increased hepatic bile acid concentrations. CONCLUSION: Jamun fruit phytochemicals decreased hepatic inflammation and oxidative stress, and protected against hepatocellular injury in mice. Jamun warrants further investigation as a potential antioxidant/anti inflammatory therapy not only to treat cholestasis but also other liver diseases with an inflammatory component. PMID- 22212621 TI - Clinical performance targets and quality of life in hemodialysis patients. AB - BACKGROUND/AIMS: Patients value health-related quality of life (HRQOL) over survival. It was our aim to study the relation between attainment of widely accepted performance targets and HRQOL in hemodialysis patients. METHODS: This study included baseline data from 715 hemodialysis patients from 29 dialysis centers. Six clinical performance targets, as recommended by the Kidney Disease Outcomes Quality Initiative (KDOQI), were evaluated: single-pool Kt/V (>=1.2), hemoglobin (11-13 g/dl), vascular access (fistula), phosphorus (2.3-4.5 mg/dl), parathyroid hormone (150-300 pg/ml), and blood pressure (predialysis <140/90 and postdialysis <130/ 80 mm Hg). RESULTS: After correction for case-mix and multiple comparisons, no association was found between the 6 KDOQI clinical performance targets and the 14 HRQOL domains, or between the number of performance targets reached and HRQOL. CONCLUSION: Attainment with widely accepted clinical performance targets was not related to the HRQOL of hemodialysis patients. Hence, in clinical guidelines, HRQOL should be adopted as an explicit treatment goal for these individuals. PMID- 22212622 TI - Hearing loss and depressive symptoms in elderly patients. AB - AIMS: Hearing loss is a common disability that has a profound impact on communication and daily functioning in the elderly. The present study assesses the effects of hearing aids on mood, quality of life and caregiver burden when hearing loss, comorbidity and depressive symptoms coexist in the elderly. METHODS: A total of 15 patients aged older than 70 years suffering from hearing loss and depressive mood were recruited. Comorbidity was evaluated by the Cumulative Illness Rating Scale, functional ability by the Activities of Daily Living scale and the Lawton Instrumental Activities of Daily Living scale, cognitive capacity by the Mini-mental State Examination and the Clock Drawing Test, psychological status by the Center for Epidemiological Studies-Depression scale, and quality of life by the Short Form (36) Health Survey. Caregiver burden was appraised by the Caregiver Burden Inventory. Testing was carried out at baseline and at 1-, 3- and 6-month intervals, assessing the use of binaural digital and programmable hearing aids. RESULTS: Reduction in depressive symptoms and improved quality of life at statistically significant levels were observed early on with the use of hearing aids. In particular, general health (P < 0.02), vitality (P < 0.03), social functioning (P < 0.05), emotional stability (P < 0.05) and mental health (P < 0.03) all changed for the better, and were maintained for the study duration. The degree of caregiver burden also declined, remaining low throughout the study. CONCLUSIONS: The benefits of digital hearing aids in relation to depressive symptoms, general health and social interactivity, but also in the caregiver - patient relationship, were clearly shown in the study. The elderly without cognitive decline and no substantial functional deficits should be encouraged to use hearing aids to improve their quality of life. PMID- 22212615 TI - Stable isotope-resolved metabolomics and applications for drug development. AB - Advances in analytical methodologies, principally nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS), during the last decade have made large-scale analysis of the human metabolome a reality. This is leading to the reawakening of the importance of metabolism in human diseases, particularly cancer. The metabolome is the functional readout of the genome, functional genome, and proteome; it is also an integral partner in molecular regulations for homeostasis. The interrogation of the metabolome, or metabolomics, is now being applied to numerous diseases, largely by metabolite profiling for biomarker discovery, but also in pharmacology and therapeutics. Recent advances in stable isotope tracer-based metabolomic approaches enable unambiguous tracking of individual atoms through compartmentalized metabolic networks directly in human subjects, which promises to decipher the complexity of the human metabolome at an unprecedented pace. This knowledge will revolutionize our understanding of complex human diseases, clinical diagnostics, as well as individualized therapeutics and drug response. In this review, we focus on the use of stable isotope tracers with metabolomics technologies for understanding metabolic network dynamics in both model systems and in clinical applications. Atom resolved isotope tracing via the two major analytical platforms, NMR and MS, has the power to determine novel metabolic reprogramming in diseases, discover new drug targets, and facilitates ADME studies. We also illustrate new metabolic tracer-based imaging technologies, which enable direct visualization of metabolic processes in vivo. We further outline current practices and future requirements for biochemoinformatics development, which is an integral part of translating stable isotope-resolved metabolomics into clinical reality. PMID- 22212623 TI - Serum ferritin level is associated with the prevalence of metabolic syndrome in Korean adults: the 2007-2008 Korean National Health and Nutrition Examination Survey. AB - BACKGROUND: Increased ferritin concentrations, which reflect body iron stores, contribute to insulin dysfunction and metabolic syndrome (MetS). METHODS: This cross-sectional study included 7346 subjects (3229 men and 4117 women) who participated in the 2007-2008 Korean National Health and Nutrition Examination Survey (KNHANES). We adopted the modified Asian criteria for MetS from the American Heart Association/National Heart, Lung, and Blood Institute. RESULTS: In comparison with participants in the first serum ferritin quartile, the odds ratio (95% confidence interval) for MetS for participants in the fourth serum ferritin quartile was 1.67 (1.24-2.23) in men and 1.41 (1.06-1.88) in women after adjusting for multiple covariates (including menopausal status in women) except insulin resistance. This association was attenuated, however, after additionally adjusting for insulin resistance [1.46 (1.08-1.98) in men and 1.22 (0.91-1.65) in women]. In particular, higher serum ferritin concentrations were associated with increased triglyceride concentrations in men and glucose intolerance in women. CONCLUSIONS: Increased serum ferritin level was positively associated with the prevalence of MetS and with some diagnostic components of MetS, i.e., we found that increased serum ferritin concentrations were associated with high triglyceride and glucose concentrations in men and women, respectively. PMID- 22212624 TI - Evaluation of the performance of urine albumin, creatinine and albumin-creatinine ratio assay on two POCT analyzers relative to a central laboratory method. AB - BACKGROUND: The evaluation of microalbumin, creatinine and albumin-creatinine ratio is very important in patients with diabetes for the early detection of kidney disease and the identification of patients at risk for complications from diabetes or hypertension. METHODS: A total of 88 spot urine samples previously analyzed using the Vitros 5,1 FS (creatinine) and Beckman Coulter Immage (microalbumin) located in the central laboratory and having microalbumin and creatinine values within the Afinion and DCA Vantage reportable ranges were run on 2 point of care (POC) instruments (Siemens DCA Vantage and Axis-Shield Afinion). RESULTS: The mean values for the DCA Vantage were: 42.6 mg/l for albumin, 10.3 mol/l for creatinine, and 5.4 mg/mol for ACR. For the Afinion AS100, the mean values were: 48.5mg/l for albumin, 9.5 mol/l for creatinine, and 6.7 mg/mol for ACR. The mean values obtained for CL were: 40.8 mg/l for albumin, 10.0 mol/l for creatinine, and 5.4 mg/mol for ACR. All POC analyzers showed good correlation to the central laboratory tests for microalbumin, creatinine and albumin creatinine ratio (ACR) for Afinion (R(2)=0.954, 0.974, and 0.964, respectively) and DCA Vantage (R(2)=0.989, 0.987, and 0.991, respectively). With the exception of the DCA Vantage ACR (p=0.53), the levels of microalbumin, creatinine and ACR obtained for the Afinion and DCA Vantage instruments as compared to the CL were statistically different (p<0.05). The inter and intraday imprecision for both POC instruments was <2.9% and total imprecision <8.7%. CONCLUSIONS: The 2 instruments evaluated in this study were in good agreement with the quantitative laboratory results and thus can be used for microalbumin, creatinine and ACR assays at the POC. However, facilities using Afinion will have to use different normal range for ACR. PMID- 22212625 TI - Reticulocyte hemoglobin content allows early and reliable detection of functional iron deficiency in blood donors. AB - BACKGROUND: Frequent blood donations may lead to a depletion of body iron stores resulting in manifest anemia. Reticulocyte hemoglobin content (CHr) - a marker for impaired hemoglobinisation (IH) caused by functional iron deficiency (FID) - was investigated regarding its value as a routine screening parameter in frequent whole blood donors. METHODS: In a prospective study, 917 frequent blood donors and 688 first time or reactivated donors were tested for iron status and red blood cell count, including CHr. The ferritin index as a marker to indicate absent iron stores (AIS) was calculated. RESULTS: Depending on the number of donations during the preceding 12 months, AIS were detected in up to 21.4% of male and 27.8% of female donors, respectively. IH was present in up to 6.4% male and 16.7% female donors with 2 and 4 preceding donations, respectively. The defined CHr cut-off value was 28.0 pg to detect IH in frequent whole blood donors with AIS, leading to a test specificity of 98.2% (positive predictive value, PPV: 57.7%) in male and of 97.8% (PPV: 82.9%) in female donors. CONCLUSION: Determination of CHr is feasible to detect FID resulting in IH in frequent blood donors. It may help to prevent the development of anemia in frequent blood donors and also can help to decide whether donor deferral or even iron substitution need to be recommended. PMID- 22212626 TI - Small molecule regulators of postnatal Nkx2.5 cardiomyoblast proliferation and differentiation. AB - While recent data have supported the capacity for a neonatal heart to undergo cardiomyogenesis, it is unclear whether these new cardiomyocytes arise from an immature cardiomyoblast population or from the division of mature cardiomyocytes. By following the expression of enhanced Green Fluorescent Protein (eGFP) in an Nkx2.5 enhancer-eGFP transgenic mice, we have identified a population of immature cells that can undergo cardiomyogenic as well as smooth muscle cell differentiation in the neonatal heart. Here, we examined growth factors and small molecule regulators that potentially regulate the proliferation and cardiomyogenic versus smooth muscle cell differentiation of neonatal Nkx2.5-GFP (+) cells in vitro. We found that A83-01 (A83), an inhibitor of TGF-betaRI, was able to induce an expansion of neonatal Nkx2.5-eGFP (+) cells. In addition, the ability of A83 to expand eGFP (+) cells in culture was dependent on signalling from the mitogen-activated protein kinase kinase (MEK) as treatment with a MEK inhibitor, PD0325901, abolished this effect. On the other hand, activation of neonatal Nkx2.5-eGFP (+) cells with TGF-beta1, but not activin A nor BMP2, led to smooth muscle cell differentiation, an effect that can be reversed by treatment with A83. In summary, small molecule inhibition of TGF-beta signalling may be a promising strategy to induce the expansion of a rare population of postnatal cardiomyoblasts. PMID- 22212628 TI - Sulfadoxine-pyrimethamine resistance and intermittent preventive treatment during pregnancy: a retrospective analysis of birth weight data in the Democratic Republic of Congo (DRC). AB - OBJECTIVE: To assess the effect of intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) on birth weight in sites with varying degrees of drug resistance. METHODS: Birth weight data from three regions in Democratic Republic of Congo with varying degrees of sulfadoxine-pyrimethamine (SP) resistance (1.6% in Mikalayi, 21.7% in Kisangani and 60.6% in Rutshuru) were analysed retrospectively by means of a logistic model that included the number of SP doses taken by the mother and other potentials confounding factors. RESULTS: The IPTp-SP reduced the risk of low birth weight (LBW) in Kisangani (adjusted OR, 0.15; IC95%, 0.05-0.46) and in Mikalayi (adjusted OR, 0.12; IC95%, 0.01-0.89). In both sites, the average birth weight was higher for mothers having received two rather than one or no SP doses (P < 0.001). In Rutshuru, IPTp-SP had an effect in primigravidae but not in multigravidae. However, after adjustment for other LBW risk factors, there was no difference in the proportion of LBW (adjusted OR 0.92; IC95%, 0.37-2.25) between women having taken at least 2 SP doses and those with only one dose or none. CONCLUSION: IPT-SP remains an effective strategy in Kisangani and Mikalayi where the therapeutic failure to SP in children with clinical malaria was 21.7% and 1.6%, respectively, while IPTp-SP effect seems lower in Rutshuru where the therapeutic failure to SP was 60.6%. The threshold value of SP resistance at which IPTp-SP fails to have a significant impact on birth weight and LBW is unknown. Considering that no alternative is currently available, additional studies on the efficacy of IPTp-SP in the areas of high SP resistance such as Rutshuru are needed so that the threshold at which this intervention fails to provide any benefit is determined with some precision. PMID- 22212629 TI - Increasing body weight and risk of limitations in activities of daily living: a systematic review and meta-analysis. AB - This study examined the relationship between normal weight, overweight and obesity class I and II+, and the risk of disability, which is defined as impairment in activities of daily living (ADL). Systematic searching of the literature identified eight cross-sectional studies and four longitudinal studies that were comparable for meta-analysis. An additional four cross-sectional studies and one longitudinal study were included for qualitative review. Results from the meta-analysis of cross-sectional studies revealed a graded increase in the risk of ADL limitations from overweight (1.04, 95% confidence interval [CI] 1.00-1.08), class I obesity (1.16, 95% CI 1.11-1.21) and class II+ obesity (1.76, 95% CI 1.28-2.41), relative to normal weight. Meta-analyses of longitudinal studies revealed a similar graded relationship; however, the magnitude of this relationship was slightly greater for all body mass index categories. Qualitative analysis of studies that met the inclusion criteria but were not compatible for meta-analysis supported the pooled results. No studies identified met all of the pre-defined quality criteria, and subgroup analysis was inhibited due to insufficient comparable studies. We conclude that increasing body weight increases the risk of disability in a graded manner, but also emphasize the need for additional studies using contemporary longitudinal cohorts with large numbers of obese class III individuals, a range of ages and with measured height and weight, and incident ADL questions. PMID- 22212630 TI - Brain metastases: pathobiology and emerging targeted therapies. AB - Brain metastases (BM) are common in cancer patients and are associated with high morbidity and poor prognosis, even after intensive multimodal therapy including resection, radiotherapy (stereotactic radiosurgery or whole brain radiotherapy) and chemotherapy. However, advances in the understanding of the pathobiology of BM and the development of molecular targeted agents hold promise for improved prophylaxis and therapy of BM. Here we provide a comprehensive review of the current concepts on mechanisms of the brain-metastatic cascade involving hematogenous dissemination of tumor cells, attachment to microvessel endothelial cells, extravasation into the brain, interaction with the local microenvironment, angiogenesis and intraparenchymal proliferation. Transendothelial migration depends on adhesion molecules such as integrins, selectins and chemokines. Tumor cells invade the brain by degrading extracellular matrix components using heparanase and matrix metalloproteinases. Astrocytes and microglial cells exert not only anti-, but also pro-neoplastic effects on brain-invading tumor cells. Some tumor types (e.g. melanoma) show prominent cooption of preexisting vasculature, while other tumor types (e.g. lung cancer) tend to show early angiogenesis after brain invasion. In this article we also critically summarize the data on currently studied targeted therapeutics in BM especially in the context of recent preclinical data. The most promising agents for BM patients include anti-angiogenic drugs, inhibitors of v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) for BRAF V600E mutated melanoma and inhibitors of epithelial growth factor receptor for non-small cell lung cancer. Molecular analysis of the BRAF V600E status of melanoma BM using DNA-based methods or immunohistochemistry may soon enter the routine neuropathological practice. PMID- 22212631 TI - Conservation of structure and mechanism within the transaldolase enzyme family. AB - Transaldolase (Tal) is involved in the central carbon metabolism, i.e. the non oxidative pentose phosphate pathway, and is therefore a ubiquitous enzyme. However, Tals show a low degree in sequence identity and vary in length within the enzyme family which previously led to the definition of five subfamilies. We wondered how this variation is conserved in structure and function. To answer this question we characterised and compared the Tals from Bacillus subtilis, Corynebacterium glutamicum and Escherichia coli, each belonging to a different subfamily, with respect to their biochemical properties and structures. The overall structure of the Tal domain, a (beta/alpha)(8) -barrel fold, is well conserved between the different subfamilies but the enzymes show different degrees of oligomerisation (monomer, dimer and decamer). The substrate specificity of the three enzymes investigated is quite similar which is reflected in the conservation of the active site, the phosphate binding site as well as the position of a catalytically important water molecule. All decameric enzymes characterised so far appear to be heat stable no matter whether they originate from a mesophilic or thermophilic organism. Hence, the thermostability might be due to the structural properties, i.e. tight packing, of these enzymes. Database The crystal structures have been deposited in the Protein Data Bank with accession code 3R8R for BsTal and 3R5E for CgTal. PMID- 22212632 TI - Study of the cost-benefit analysis of electronic medical record systems in general hospital in China. AB - Electronic medical record (EMR) systems have been proposed as technology to improve the quality of patient care, decrease medical errors, control and reduce medical expenditure, however the financial effects have not yet been as well documented in China. We presented a net financial cost-benefit analysis of implementing electronic medical record systems in general hospital in China. The data, which were obtained from studies of the general hospital and the published literature, collected from 15 consecutive fiscal months from May 1, 2009 to August 30, 2010. We performed a perspective cost-benefit study to analyze the financial effects of EMR system implementing. The reference strategy for comparisons was the traditional paper-based medical record. The net financial benefits or costs for a 6-year period were calculated. All data were adjusted for inflation. The totally assessed net benefit from implementing an EMR system for a 6-year period was $559,025 in the general hospital. Benefits accrue primarily from savings in new medical record creation, decreased full-time-equivalent (FTE) employees, saving of adverse drug events (ADEs) and dose errors, improved charge capture and decreased billing errors. In this model, the time of return on investment is 3.00 years. In one-way sensitivity analysis, the model was most sensitive in new medical record creation; the net benefit varied from $398,057 to $719,992. The five-way sensitivity analysis with the most pessimistic and optimistic assumptions showed results ranging from a $76,970 net cost to a $1,062,122 net benefit; the pessimistic time of return on investment is 5.38 years. An EMR system cost-benefit analysis can rapidly demonstrate a positive return on investment when implemented in hospitals. The magnitude of the return is sensitive to several key factors. PMID- 22212633 TI - Bordetella bronchiseptica in a paediatric cystic fibrosis patient: possible transmission from a household cat. AB - Bordetella bronchiseptica is a zoonotic respiratory pathogen commonly found in domesticated farm and companion animals, including dogs and cats. Here, we report isolation of B. bronchiseptica from a sputum sample of a cystic fibrosis patient recently exposed to a kitten with an acute respiratory illness. Genetic characterization of the isolate and comparison with other isolates of human or feline origin strongly suggest that the kitten was the source of infection. PMID- 22212634 TI - Long-term bortezomib treatment reduces allergen-specific IgE but fails to ameliorate chronic asthma in mice. AB - BACKGROUND: Allergen-specific immunoglobulin (Ig) E initiates the effector cascade of allergic asthma and has been identified as a valuable target for therapeutic treatment of this disease. The proteasome inhibitor bortezomib was previously shown to deplete Ig-secreting plasma cells and to efficiently suppress Ig serum titers. The present study aimed at evaluating the therapeutic potential of the proteasome inhibitor bortezomib in allergic bronchial asthma. METHODS: To address this question, a chronic experimental asthma mouse model was used in a therapeutic setting. Mice were sensitized to ovalbumin (OVA) and challenged with OVA aerosol for 12 weeks. After 6 weeks of challenge, bortezomib treatment was started and continued for 1 week (short-term) or 6 weeks (long-term) with a dosage of 0.75 mg/kg body weight twice a week. Lung function, lung histology, Ig serum titers and plasma cell numbers were assessed. RESULTS: Whereas short-term treatment lowered bronchoalveolar lavage eosinophils, long-term treatment considerably reduced serum titers of anti-OVA IgE in mice with chronic experimental asthma. However, neither short-term nor long-term treatment significantly reduced plasma cell numbers, anti-OVA IgG1 serum titers or allergic airway inflammation or ablated airway hyperresponsiveness. CONCLUSION: Our results suggest that bortezomib treatment has only limited value as plasma cell depleting therapy against allergic bronchial asthma. PMID- 22212635 TI - Diagnostic accuracy of small intestine ultrasonography using an oral contrast agent in Crohn's disease: comparative study from the UK. AB - AIM: To evaluate the usefulness of small intestine contrast-enhanced ultrasonography (SICUS) using an oral contrast agent in routine clinical practice by assessing the level of agreement with the established techniques, small bowel follow-through (SBFT) and computed tomography (CT), and diagnostic accuracy compared with the final diagnosis in the detection of small bowel Crohn's disease (CD) and luminal complications in a regional centre. MATERIALS AND METHODS: All symptomatic known or suspected cases of CD who underwent SICUS were retrospectively reviewed. The level of agreement between SICUS and SBFT, CT, histological findings, and C-reactive protein (CRP) level was assessed using kappa (kappa) coefficient. Sensitivity was demonstrated using the final diagnosis as the reference standard defined by the outcome of clinical assessment, follow up, and results of investigations other than SICUS. RESULTS: One hundred and forty-three patients underwent SICUS of these 79 (55%) were female. Eighty-six (60%) were known to have CD and 57 (40%) had symptoms suggestive of intestinal disease with no previous diagnosis. Forty-six (55%) of the known CD patients had had at least one previous surgical resection. The sensitivity of SICUS in detecting active small bowel CD in known CD and undiagnosed cases was 93%. The kappa coefficient was 0.88 and 0.91 with SBFT and CT, respectively. SICUS detected nine patients who had one or more small bowel strictures and six patients with a fistula all detected by SBFT or CT. CONCLUSION: SICUS is not only comparable to SBFT and CT but avoids radiation exposure and should be more widely adopted in the UK as a primary diagnostic procedure and to monitor disease complications in patients with CD. PMID- 22212636 TI - Radiographic features of primary cavitary sarcoidosis with "lotus seed-like" manifestations. PMID- 22212637 TI - CT appearances of abdominal tuberculosis. AB - The purpose of this article is to review and illustrate the spectrum of computed tomography (CT) appearances of abdominal tuberculosis. Tuberculosis can affect any organ or tissue in the abdomen, and can be mistaken for other inflammatory or neoplastic conditions. The most common sites of tuberculosis in the abdomen include lymph nodes, genitourinary tract, peritoneal cavity and gastrointestinal tract. The liver, spleen, biliary tract, pancreas and adrenals are rarely affected, but are more likely in HIV-seropositive patients and in miliary tuberculosis. This article should alert the radiologist to consider abdominal tuberculosis in the correct clinical setting to ensure timely diagnosis and enable appropriate treatment. PMID- 22212638 TI - Influenza-like illness surveillance on the California-Mexico border, 2004-2009. AB - BACKGROUND: Since 2004, the Naval Health Research Center, with San Diego and Imperial counties, has collaborated with the US Centers for Disease Control and Prevention to conduct respiratory disease surveillance in the US-Mexico border region. In 2007, the Secretariat of Health, Mexico and the Institute of Public Health of Baja California joined the collaboration. OBJECTIVES: The identification of circulating respiratory pathogens in respiratory specimens from patients with influenza-like illness (ILI). METHODS: Demographic, symptom information and respiratory swabs were collected from enrollees who met the case definition for ILI. Specimens underwent PCR testing and culture in virology and bacteriology. RESULTS: From 2004 through 2009, 1855 persons were sampled. Overall, 36% of the participants had a pathogen identified. The most frequent pathogen was influenza (25%), with those aged 6-15 years the most frequently affected. In April 2009, a young female participant from Imperial County, California, was among the first documented cases of 2009 H1N1. Additional pathogens included influenza B, adenovirus, parainfluenza virus, respiratory syncytial virus, enterovirus, herpes simplex virus, Streptococcus pneumoniae, and Streptococcus pyogenes. CONCLUSIONS: The US-Mexico border is one of the busiest in the world, with a large number of daily crossings. Due to its traffic, this area is an ideal location for surveillance sites. We identified a pathogen in 36% of the specimens tested, with influenza A the most common pathogen. A number of other viral and bacterial respiratory pathogens were identified. An understanding of the incidence of respiratory pathogens in border populations is useful for development of regional vaccination and disease prevention responses. PMID- 22212640 TI - Mitochondrial connexin 43 impacts on respiratory complex I activity and mitochondrial oxygen consumption. AB - Connexin 43 (Cx43) is present at the sarcolemma and the inner membrane of cardiomyocyte subsarcolemmal mitochondria (SSM). Lack or inhibition of mitochondrial Cx43 is associated with reduced mitochondrial potassium influx, which might affect mitochondrial respiration. Therefore, we analysed the importance of mitochondrial Cx43 for oxygen consumption. Acute inhibition of Cx43 in rat left ventricular (LV) SSM by 18alpha glycyrrhetinic acid (GA) or Cx43 mimetic peptides (Cx43-MP) reduced ADP-stimulated complex I respiration and ATP generation. Chronic reduction of Cx43 in conditional knockout mice (Cx43(Cre ER(T)/fl) + 4-OHT, 5-10% of Cx43 protein compared with control Cx43(fl/fl) mitochondria) reduced ADP-stimulated complex I respiration of LV SSM to 47.8 +/- 2.4 nmol O(2)/min.*mg protein (n = 8) from 61.9 +/- 7.4 nmol O(2)/min.*mg protein in Cx43(fl/fl) mitochondria (n = 10, P < 0.05), while complex II respiration remained unchanged. The LV complex I activities (% of citrate synthase activity) of Cx43(Cre-ER(T)/fl) +4-OHT mice (16.1 +/- 0.9%, n = 9) were lower than in Cx43(fl/fl) mice (19.8 +/- 1.3%, n = 8, P < 0.05); complex II activities were similar between genotypes. Supporting the importance of Cx43 for respiration, in Cx43-overexpressing HL-1 cardiomyocytes complex I respiration was increased, whereas complex II respiration remained unaffected. Taken together, mitochondrial Cx43 is required for optimal complex I activity and respiration and thus mitochondrial ATP-production. PMID- 22212641 TI - Different NF-kappaB activation characteristics of human respiratory syncytial virus subgroups A and B. AB - Human respiratory syncytial virus (HRSV) is a member of the family Paramyxoviridae, and is responsible for serious respiratory illness in infants, the elderly and the immunocompromised. HRSV exists as two distinct lineages known as subgroups A and B, which represent two lines of divergent evolution with extensive genetic and serologic differences. While both subgroup A and B viruses contribute to overall HRSV disease, subgroup A isolates are associated with both increased frequency and morbidity of infections, and reasons for this are unclear. HRSV disease is characterized by virus-mediated cell destruction in combination with extensive inflammatory and immune modulatory responses, and for HRSV subgroup A isolates, several of these signaling pathways are regulated through activation of the transcription factor NF-kappaB. In contrast, the NF kappaB activation characteristics of HRSV subgroup B infection remain untested. Here, we performed a quantitative and comparative analysis of NF-kappaB activation in response to infection of both continuous and primary cell cultures with HRSV subgroup A and B isolates. Our results showed the model HRSV subgroup A isolate consistently induced increased NF-kappaB activation compared to its HRSV subgroup B counterpart. The differential NF-kappaB activation characteristics of HRSV subgroup A and B viruses may contribute to differences in their pathogenesis. PMID- 22212639 TI - Characterisation of asthma that develops during adolescence; findings from the Isle of Wight Birth Cohort. AB - BACKGROUND: Understanding of adolescent-onset asthma remains limited. We sought to characterise this state and identify associated factors within a longitudinal birth cohort study. METHODS: The Isle of Wight Whole Population Birth Cohort was recruited in 1989 (N=1456) and characterised at 1, 2, 4, 10 and 18-years. "Adolescent-onset asthma" was defined as asthma at age 18 without prior history of asthma, "persistent-adolescent asthma" as asthma at both 10 and 18 and "never asthma" as those without asthma at any assessment. RESULTS: Adolescent-onset asthma accounted for 28.3% of asthma at 18-years and was of similar severity to persistent-adolescent asthma. Adolescent-onset asthmatics showed elevated bronchial hyper-responsiveness (BHR) and atopy at 10 and 18 years. BHR in this group at 10 was intermediate to that of never-asthmatics and persistent adolescent asthma. By 18 their BHR, bronchodilator reversibility and sputum eosinophilia was greater than never-asthmatics and comparable to persistent adolescent asthma. At 10, males who later developed adolescent-onset asthma had reduced FEV(1) and FEF(25-75), while females had normal lung function but then developed impaired FEV(1) and FEF(25-75) in parallel with adolescent asthma. Factors independently associated with adolescent-onset asthma included atopy at 10 (OR=2.35; 95% CI=1.08-5.09), BHR at 10 (3.42; 1.55-7.59), rhinitis at 10 (2.35; 1.11-5.01) and paracetamol use at 18-years (1.10; 1.01-1.19). CONCLUSIONS: Adolescent-onset asthma is associated with significant morbidity. Predisposing factors are atopy, rhinitis and BHR at age 10 while adolescent paracetamol use is also associated with this state. Awareness of potentially modifiable influences may offer avenues for mitigating this disease state. PMID- 22212642 TI - Translation initiation factor eIF-5A, the hypusine-containing protein, is phosphorylated on serine and tyrosine and O-glycosylated in Trichomonas vaginalis. AB - The eukaryotic translation factor eIF-5A is highly conserved throughout eukaryotes and undergoes an unusual polyamine-dependent post-translational modification called hypusination. Trichomonas vaginalis has two tveif-5a genes (tveif-5a1 and tveif-5a2), each encoding a 19-kDa protein. In this report, we describe the detection of two forms with different isoelectric points (5.2 and 5.5) that correspond to the precursor and mature TveIF-5A, respectively. In addition, we demonstrated that only the mature form of TveIF-5A is phosphorylated and glycosylated via two-dimensional gel electrophoresis-western blot (2DE-WB) assays using anti-phosphoserine and anti-phosphotyrosine antibodies and the SNA, ConA and MAA lectins. Interestingly, when the protozoa were grown in 1,4-diamino 2-butanone (DAB), an inhibitor of putrescine biosynthesis, and transferred to medium containing exogenous putrescine, a new spot with an isoelectric point of 5.3 was observed, presumably corresponding to a phosphorylated intermediate or deoxyhypusine form. Our data indicate that, in T. vaginalis, phosphorylations and glycosylations are necessary to obtain the mature TveIF-5A, and we confirm the identity of the precursor, intermediate and mature forms of TveIF-5A by mass spectrometry analysis. PMID- 22212643 TI - Quantification of systemic delivery of substrates for intermediate metabolism during citrate anticoagulation of continuous renal replacement therapy. AB - BACKGROUND: There are limited data on systemic delivery of metabolic substrates during citrate anticoagulation. The direct citrate measurements are usually not available. METHODS: Patients on 2.2% acid-citrate-dextrose (ACD, n = 41) were compared to a control group on unfractionated heparin (n = 17). All were treated on 1.9-m(2) polysulfone filters. Samples were taken from the central venous catheter, ports pre- and post-filter and from effluent. RESULTS: The gain of citrate in CVVH (n = 18) was not different from CVVHDF (n = 23, p = 0.8). Mean gain of citrate was 25.4 +/- 6.4 mmol/h. The systemic loads of lactate (p = 0.12) and glucose (p = 0.23) in CVVH were similar to CVVHDF. Mean inputs of lactate and glucose were 62.9 +/- 21.1 and 26.6 +/- 10.4 mmol/h, respectively. The mean difference between post- and prefilter unmeasured anions (d-UA) correlated with mean difference of citrate concentrations (p < 0.0001, r(2) = 0.66). The estimated caloric load of the citrate modalities was 5,536 +/- 1,385 kJ/ 24 h. CONCLUSIONS: ACD might represent a significant load of metabolic substrates, particularly if used with lactate buffer. Systemic delivery of citrate can be predicted using d-UA in the extracorporeal circuit. PMID- 22212644 TI - Possible evolution of alliarinoside biosynthesis from the glucosinolate pathway in Alliaria petiolata. AB - Nitrile formation in plants involves the activity of cytochrome P450s. Hydroxynitrile glucosides are widespread among plants but generally do not occur in glucosinolate producing species. Alliaria petiolata (garlic mustard, Brassicaceae) is the only species known to produce glucosinolates as well as a gamma-hydroxynitrile glucoside. Furthermore, A. petiolata has been described to release diffusible cyanide, which indicates the presence of unidentified cyanogenic glucoside(s). Our research on A. petiolata addresses the molecular evolution of P450s. By integrating current knowledge about glucosinolate and hydroxynitrile glucoside biosynthesis in other species and new visions on recurrent evolution of hydroxynitrile glucoside biosynthesis, we propose a pathway for biosynthesis of the gamma-hydroxynitrile glucoside, alliarinoside. Homomethionine and the corresponding oxime are suggested as shared intermediates in the biosynthesis of alliarinoside and 2-propenyl glucosinolate. The first committed step in the alliarinoside pathway is envisioned to be catalysed by a P450, which has been recruited to metabolize the oxime. Furthermore, alliarinoside biosynthesis is suggested to involve enzyme activities common to secondary modification of glucosinolates. Thus, we argue that biosynthesis of alliarinoside may be the first known case of a hydroxynitrile glucoside pathway having evolved from the glucosinolate pathway. An intriguing question is whether the proposed hydroxynitrile intermediate may also be converted to novel homomethionine-derived cyanogenic glucoside(s), which could release cyanide. Elucidation of the pathway for biosynthesis of alliarinoside and other putative hydroxynitrile glucosides in A. petiolata is envisioned to offer significant new knowledge on the emerging picture of P450 functional dynamics as a basis for recurrent evolution of pathways for bioactive natural product biosynthesis. PMID- 22212645 TI - [Fertility sparing management of endometrial adenocarcinoma and atypical hyperplasia: a literature review]. AB - In endometrial carcinoma (EC) and atypical hyperplasia (AH) diagnosed in childbearing years, the principle of uterine sparing consists in prescription of antigonadotropic treatment to obtain the remission of the endometrial lesion and allow pregnancy, always with a close follow-up looking for progression or persistence of the tumour. Studies evaluating this strategy have suggested the safety of such an approach, but numerous questions remain unanswered, like those concerning the type and the duration of treatment, and the systematic use of Assisted Reproductive Technologies... We performed a critical literature review in order to analyse patients and tumoral characteristics, treatment management and the results of fertility sparing strategy. This review shows that fertility sparing management of AH and intramucous EC permits to obtain pregnancy in one third of candidates. Few disease-related deaths have been reported after this management. One-third of patients experienced progression lesion beyond the endometrium, but generally limited to the myometrium. Progestins have been widely evaluated in this indication and provide an overall remission rate of 80% with a recurrence risk of 25%. PMID- 22212646 TI - Effect of vitamin D supplementation during pregnancy on neonatal mineral homeostasis and anthropometry of the newborn and infant. AB - Hypovitaminosis D is common in India. In the present prospective partially randomised study of vitamin D (D3) supplementation during pregnancy, subjects were randomised in the second trimester to receive either one oral dose of 1500 MUg vitamin D3 (group 1, n 48) or two doses of 3000 MUg vitamin D3 each in the second and third trimesters (group 2, n 49). Maternal 25-hydroxyvitamin D (25(OH)D) at term, cord blood (CB) alkaline phosphatase (ALP), neonatal serum Ca and anthropometry were measured in these subjects and in forty-three non supplemented mother-infant pairs (usual care). Median maternal 25(OH)D at term was higher in group 2 (58.7, interquartile range (IQR) 38.4-89.4 nmol/l) v. group 1 (26.2, IQR 17.7-57.7 nmol/l) and usual-care group (39.2, IQR 21.2-73.4 nmol/l) (P = 0.000). CB ALP was increased (>8.02 MUkat/l or >480 IU/l) in 66.7 % of the usual-care group v. 41.9 % of group 1 and 38.9 % of group 2 (P = 0.03). Neonatal Ca and CB 25(OH)D did not differ significantly in the three groups. Birth weight, length and head circumference were greater and the anterior fontanelle was smaller in groups 1 and 2 (3.08 and 3.03 kg, 50.3 and 50.1 cm, 34.5 and 34.4 cm, 2.6 and 2.5 cm, respectively) v. usual care (2.77 kg, 49.4, 33.6, 3.3 cm; P = 0.000 for length, head circumference and fontanelle and P = 0.003 for weight). These differences were still evident at 9 months. We conclude that both 1500 MUg and two doses of 3000 MUg vitamin D3 had a beneficial effect on infant anthropometry, the larger dose also improving CB ALP and maternal 25(OH)D. PMID- 22212647 TI - Serological profiles and evaluation of parasitaemia by PCR and blood culture in individuals chronically infected by Trypanosoma cruzi treated with benzonidazole. AB - OBJECTIVE: To evaluate the serological and parasitological status of patients with chronic Chagas disease (CD) after chemotherapy with benzonidazole. METHODS: Retrospective study of patients treated with benzonidazole (5 mg/kg/day for 60 days) between 1980 and 2010. Twenty-nine patients who had CD confirmed by two reagent immunological tests and/or one positive xenodiagnosis before treatment were included. Conventional serology (ELISA and IIF) and parasitological tests (haemoculture and N-PCR) were performed. RESULTS: At the time of treatment, the mean age of patients was 36 +/- 7.24 years (20-39 years) and the time post treatment varied from 1 to 29 years. After chemotherapy, all individuals had reagent ELISA and 93.1% had positive results for the IIF test. T. cruzi DNA was detected by N-PCR in 48.3%. Negative results were observed in 41.4% and inconclusive ones in 10.3%. Haemoculture was negative for all individuals. CONCLUSIONS: Our results suggest that N-PCR may be useful in the early identification of therapeutic failure of CD. Although it is difficult to determine parasitological cure in negative N-PCR cases, we can infer that this condition represents a declination of parasitaemia as a favourable consequence of aetiological treatment. PMID- 22212648 TI - Contribution of ribavirin transporter gene polymorphism to treatment response in peginterferon plus ribavirin therapy for HCV genotype 1b patients. AB - BACKGROUND: Standard-dose ribavirin is crucial for the standard-of-care treatment of chronic hepatitis C virus (HCV) infection. Equilibrative nucleoside transporter 1 (ENT1), encoded by SLC29A1 gene, is the main transporter that imports ribavirin into human hepatocytes. AIMS: To determine whether single nucleotide polymorphisms (SNPs) at the SLC29A1 gene could influence the probability of treatment response compared with other baseline and host genetic factors. METHODS: A total of 526 East Asian patients monoinfected with HCV genotype 1b who had received pegylated interferon alpha plus ribavirin therapy were enrolled in this study. They were assigned randomly to the derivation and confirmatory groups. SNPs related to the IL28B, ITPA and SLC29A1 genes were genotyped using real-time detection polymerase chain reaction. Factors associated with sustained virological response (SVR) were analysed using multiple logistic regression analysis. RESULTS: Multivariate analysis for the derivation group identified six baseline variables significantly and independently associated with SVR: age [P = 0.023, odds ratio (OR) = 0.97], gender (P = 0.0047, OR = 2.25), platelet count (P = 0.00017, OR = 1.11), viral load (P = 0.00026, OR = 0.54), IL28B SNP rs12979860 (P = 1.09 * 10(-7) , OR = 8.68) and SLC29A1 SNP rs6932345 (P = 0.030, OR = 1.85). Using the model constructed by these independent variables, positive and negative predictive values and predictive accuracy were 73.3, 70.1 and 71.9% respectively. For the confirmatory group, they were 71.4, 84.6 and 75.3% respectively. The SLC29A1 and IL28B SNPs were also significantly associated with rapid virological response. CONCLUSIONS: The SNP at the major ribavirin transporter ENT1 gene SLC29A1 was one of significantly independent factors influencing treatment response, although the impact on the prediction was small. PMID- 22212649 TI - Vaginal estrogen therapy in postmenopausal breast cancer patients treated with aromatase inhibitors. AB - INTRODUCTION: Breast cancer is the most frequent cancer among women with about 1.38 million new cases worldwide every year. Most of these patients are postmenopausal and suffer from hormone receptor positive breast tumors. About 50% of postmenopausal women between 50 and 60 years and 72% of women over 70 years suffer from vulvovaginal athrophy (VVA). Adjuvant treatment with aromatase inhibitors (AIs) improves outcomes in postmenopausal women with hormone receptor positive early stage breast cancer compared with tamoxifen. A frequent side effect of AI use is VVA with symptoms like vaginal dryness, vaginitis, pruritus, dyspareunia and cystitis. MATERIALS AND METHODS: We searched major databases (i.e. pubmed) with the following selection criteria: breast cancer, hormone therapy, vaginal estrogen, aromatase inhibitor, vaginal atrophy, serum estrogen levels. CONCLUSIONS: Vaginal administration of estradiol is a well known and safe alternative to systemic estrogen therapy, but studies demonstrated significant increases in plasma concentrations of estradiol. Such observations have also been reported in postmenopausal breast cancer patients treated with AIs. Further studies are needed to explore risk of breast cancer recurrence after vaginal estrogen application for patients on adjuvant endocrine therapy with AIs. PMID- 22212651 TI - Measures for peripartum hysterectomy for placenta previa accreta: avoiding uterotonic agents and "double distal edge pickup" mass ligation. PMID- 22212650 TI - Effect of liquid-based gel application during speculum examination on satisfactory level of smear examination. AB - PURPOSE: The aim was to evaluate the use of liquid-based gel during cytologic follow-up and the effect of liquid-based gel application during speculum examination on satisfactory level of smear. METHODS: A total of 1,999 patients were taken into the study. Patients were divided into two groups as gel-applied group and control group. Age and menopausal status of patients, and the physicians taking the smear (resident or specialist) were recorded. In control group, dry speculum was used for the collection of smear sample. All specimens were evaluated for correlation of the cytopathology, the number of "unsatisfactory" samples, and any secondary diagnoses. RESULTS: Assessment of smear satisfactoriness revealed that 2.2% (43) of them were unsatisfactory. Unsatisfactory smear ratio was significantly high in gel-applied group. Screening done by residents increased unsatisfactory result risk for about 5.5 times. Evaluation of effect of menopausal status on smear adequency revealed no difference between premenopausal and postmenopausal women. CONCLUSION: Cervical smear seems to be more accurate without gel application. Experience of the physician is also important. Water-based gel can be used in some women who experience overt pain during speculum examination, but these patients must be warned about unsatisfactory results and the need of repeat test. PMID- 22212652 TI - High-pressure tolerance in Halobacterium salinarum NRC-1 and other non piezophilic prokaryotes. AB - In this study, we examined the high-pressure survival of a range of prokaryotes not found in high-pressure environments to determine the effects of adaptations to osmotic and oxidative stresses on piezo-resistance. The pressure survivals of Halobacterium salinarum NRC-1, Deinococcus radiodurans R1, and Chromohalobacter salexigens were compared to that of Escherichia coli MG1655. C. salexigens, which uses the compatible solute ectoine as an osmolyte, was as piezo-sensitive as E. coli MG1655, suggesting that ectoine is not a piezolyte. D. radiodurans R1 and H. salinarum NRC-1, both resistant to oxidative stress, were found to be highly piezo-resistant. H. salinarum NRC-1 showed nearly full survival after pressurization up to 400 MPa; a survival 3.5 log units higher than E. coli MG1655. This piezo-resistance was maintained in H. salinarum NRC-1 for pressurizations up to 1 h. We hypothesize that the high-pressure resistance of H. salinarum NRC-1 is due to a combination of factors including cell envelope structure and the presence of intracellular salts. PMID- 22212653 TI - Cloning and expression analysis of two different LhcSR genes involved in stress adaptation in an Antarctic microalga, Chlamydomonas sp. ICE-L. AB - Light-harvesting complexes (LHCs) play essential roles in light capture and photoprotection. Although the functional diversity of individual LHCs in many plants has been well described, knowledge regarding the extent of this family in the majority of green algal groups is still limited. In this study, two different LhcSR genes, LhcSR1 and LhcSR2 from Chlamydomonas sp. ICE-L, were cloned from the total cDNA and characterized in response to high light (HL), low light (LL), UV-B radiation and high salinity. The lower F (v)/F (m) as well as the associated induction of non-photochemical quenching (NPQ), observed under those conditions, indicated that Chlamydomonas sp. ICE-L was under stress. Under HL stress, the expression of LhcSR1 and LhcSR2 increased rapidly from 0.5 h HL and reached a maximum after 3 h. In LL, LhcSR2 expression was up-regulated during the first 0.5 h after which it decreased, while the expression of LhcSR1 decreased gradually from the beginning of the experiment. In addition, the transcript levels of LhcSR1 and LhcSR2 increased under UV-B radiation and high salinity. These results showed that both genes were inducible and up-regulated under stress conditions. A higher NPQ was accompanied by the up-regulated LhcSR genes, suggesting that LhcSR plays a role in thermal energy dissipation. Overall, the results presented here suggest that LhcSR1 and LhcSR2 play a primary role in photoprotection in Chlamydomonas sp. ICE-L under stress conditions and provide an important basis for investigation of the adaptation mechanism of LhcSR in Antarctic green algae. PMID- 22212654 TI - Identification of cold-inducible inner membrane proteins of the psychrotrophic bacterium, Shewanella livingstonensis Ac10, by proteomic analysis. AB - Shewanella livingstonensis Ac10 is a psychrotrophic Gram-negative bacterium that grows at temperatures close to 0 degrees C. Previous proteomic studies of this bacterium identified cold-inducible soluble proteins and outer membrane proteins that could possibly be involved in its cold adaptation (Kawamoto et al. in Extremophiles 11:819-826, 2007). In this study, we established a method for separating the inner and outer membranes by sucrose density gradient ultracentrifugation and performed proteomic studies of the inner membrane fraction. The cells were grown at temperatures of 4 and 18 degrees C, and phospholipid-enriched inner membrane fractions were obtained. Two-dimensional polyacrylamide gel electrophoresis and peptide mass fingerprinting analysis of the proteins identified 14 cold-inducible proteins (more than a 2-fold increase at 4 degrees C). Six of these proteins were predicted to be inner membrane proteins. Two predicted periplasmic proteins, 5 predicted cytoplasmic proteins, and 1 predicted outer membrane protein were also found in the inner membrane fraction, suggesting their association with the inner membrane proteins and/or lipids. These cold-inducible proteins included proteins that are presumed to be involved in chemotaxis (AtoS and PspA), membrane protein biogenesis (DegP, SurA, and FtsY), and morphogenesis (MreB). These findings provide a basis for further studies on the cold-adaptation mechanism of this bacterium. PMID- 22212655 TI - Bacterial gene expression at low temperatures. AB - Under suboptimal environmental conditions such as low temperatures, many bacteria have an extended lag phase, altered cell structures, and composition such as a less fluid (more rigid) and leaky cytoplasmic membrane. As a result, cells may die, enter into a starvation mode of metabolism or a physiologically viable but non-culturable (VBNC) state. In the latter state, the amount of gene expression per cell is virtually undetectable. In this article, gene expression under (suboptimal) low temperature conditions in non-psychrophilic environmental bacteria is examined. The pros and cons of some of the molecular methodologies for gene expression analysis are also discussed. PMID- 22212656 TI - The third plasmid pVV8 from Thermus thermophilus HB8: isolation, characterization, and sequence determination. AB - The extremely thermophilic bacterium Thermus thermophilus is a model organism for structural biology and systems biology, and the so-called "Structural and Functional Whole-Cell Project for T. thermophilus HB8" is in progress. The released genomic sequence of the strain HB8 is composed of chromosome, pTT27 megaplasmid, and pTT8 plasmid. In this paper, however, a third plasmid was demonstrated and its sequence was determined. Although this plasmid pVV8 had been reported before, limited information and an unfortunate dropout in the substrain, whose genomic sequence was determined, would have prevented the plasmid from coming to public attention. The intrinsic circular plasmid, which was estimated to be six to ten copies in a cell, is 81151 bp and its G + C content is 68%. Among the identified 91 ORFs, a single gene has been experimentally analyzed before and is known as xylose isomerase. The phnCDEGHIJKLMX operon related to phosphonate metabolism, alkaline phosphatase, putative transcriptional regulators, several sets of toxin-antitoxin system, and transposase-like ORFs are also encoded on the pVV8 plasmid. Although association with cell aggregation was the one phenotypic characteristic of the plasmid that had been reported, it was never confirmed. Comparison of T. thermophilus HB8 strains suggests that the pVV8 is nonessential for growth. PMID- 22212657 TI - Thermotomaculum hydrothermale gen. nov., sp. nov., a novel heterotrophic thermophile within the phylum Acidobacteria from a deep-sea hydrothermal vent chimney in the Southern Okinawa Trough. AB - A novel heterotrophic, thermophilic bacterium, designated strain AC55(T), was isolated from a deep-sea hydrothermal vent chimney at the Hatoma Knoll in the Okinawa Trough, Japan. Cells of strain AC55(T) were non-motile, long rods (2.0- to 6.8-MUm long and 0.3- to 0.6-MUm wide). The strain was an obligatory anaerobic heterotroph capable of fermentative growth on complex proteinaceous substances. Elemental sulfur was reduced to hydrogen sulfide but did not stimulate growth. Growth was observed between 37 and 60 degrees C (optimum 55 degrees C), pH 5.5 and 8.5 (optimum pH 6.6), and in the presence of 1.5-4.5% (w/v) NaCl (optimum 2.5%, w/v). Menaquinone-7 and -8 were the major respiratory quinones. The G + C content of the genomic DNA from strain AC55(T) was 51.6 mol%. The 16S rRNA gene sequence analysis revealed that strain AC55(T) was the first cultivated representative of Acidobacteria subdivision 10. Based on the physiological and phylogenetic features of the novel isolate, the genus name Thermotomaculum gen. nov. is proposed, with Thermotomaculum hydrothermale sp. nov. as the type species. The type strain is AC55(T) (=JCM 17643(T) = DSM 24660(T) = NBRC 107904(T)). PMID- 22212658 TI - Localized synthesis of the outer envelope from Thermus thermophilus. AB - In agreement with its distinct phylogenetic origin, the envelope of Thermus thermophilus consists of a complex pattern of layers with properties intermediate between those of Gram positives and Proteobacteria. Its cell wall of Gram positive composition is surrounded by an outer envelope that includes a crystalline layer scaffold built up by the SlpA protein, lipids and polysaccharides. The synthesis of this outer envelope has been studied by confocal microscopy. Available amino groups from the cell surface, mainly belonging to the SlpA protein, were covalently labelled in vivo with fluorescent dyes. Stained cells were able to grow without any apparent loss of viability, allowing the localization of the regions of new synthesis as dark nonfluorescent spots. Our results demonstrate that the outer envelope of T. thermophilus is synthesized from a central point in the cells, likely following a helical pattern. Cell poles and subpolar regions are basically inert and retain their label for generations. PMID- 22212660 TI - Understanding of the roles of phospholipase D and phosphatidic acid through their binding partners. AB - Phospholipase D (PLD) is a phosphatidyl choline (PC)-hydrolyzing enzyme that generates phosphatidic acid (PA), a lipid second messenger that modulates diverse intracellular signaling. Through interactions with signaling molecules, both PLD and PA can mediate a variety of cellular functions, such as, growth/proliferation, vesicle trafficking, cytoskeleton modulation, development, and morphogenesis. Therefore, systemic approaches for investigating PLD networks including interrelationship between PLD and PA and theirs binding partners, such as proteins and lipids, can enhance fundamental knowledge of roles of PLD and PA in diverse biological processes. In this review, we summarize previously reported protein-protein and protein-lipid interactions of PLD and PA and their binding partners. In addition, we describe the functional roles played by PLD and PA in these interactions, and provide PLD network that summarizes these interactions. The PLD network suggests that PLD and PA could act as a decision maker and/or as a coordinator of signal dynamics. This viewpoint provides a turning point for understanding the roles of PLD-PA as a dynamic signaling hub. PMID- 22212659 TI - Distribution and phylogenetic diversity of cbbM genes encoding RubisCO form II in a deep-sea hydrothermal field revealed by newly designed PCR primers. AB - To investigate the phylogenetic diversity of putative chemolithoautotrophs possessing the RubisCO form II gene (cbbM) in various environments, we designed a new PCR primer set targeting this gene. The primer set was designed to cover more diverse and longer sequences of cbbM genes than those reported previously. We analyzed various samples (i.e., benthic sands, basement rocks, sulfide chimneys, vent fluids and overlying bottom seawater) collected in a deep-sea hydrothermal field of the Suiyo Seamount, Izu-Bonin Arc, Western Pacific, by PCR-based analysis using the designed primer set. Most of the cbbM phylotypes recovered from the liquid samples were related to those of the SUP05 group that belongs to the Gammaproteobacteria and includes putative sulfide-oxidizing chemolithoautotrophs. In contrast, the cbbM phylotypes recovered from the solid samples were related to environmental clones with low similarity (74-90%) and not closely related to the SUP05 group (69-74%). The cbbM phylotypes recovered from the liquid samples were different from those of the solid samples. Furthermore, the cbbM phylotypes recovered from the solid samples were different from each other. Our results expand knowledge of the phylogenetic diversity and distribution of putative chemolithoautotrophs possessing RubisCO form II cbbM genes in deep-sea hydrothermal fields. PMID- 22212662 TI - Hydrogelators of cyclotriveratrylene derivatives. AB - Developing cavity-based supramolecular hydrogels is in its infancy because not many such hydrogelators are available. Reported herein is our creation of rigid cavitand cyclotriveratrylene (CTV) based hydrogelators from the molecular backbones of CTVs that were in limited cases shown to form organogels. For doing so deprotonable -COOH or protonable -NH(2) was introduced as terminal group into the rigid and hydrophobic CTV backbones. We thus successfully obtained optically anisotropic supramolecular hydrogels from these new CTVs hydrogelators with excellent thermostability and high tolerance towards strong electrolytes. The obtained CTV-1 and CTV-2 hydrogels are luminescent and exhibit reversible gel-to sol and sol-to-gel transitions upon pH variations. The success in creating CTV-1 and CTV-2 hydrogelators on the basis of the skeleton of a CTV-organogelator suggests that balancing the hydrophilic and hydrophobic characters of the ionic and hydrophobic moieties well in the gelator molecule is important for designing a promising hydrogelator. PMID- 22212661 TI - Diagnostic value of coronary CT angiography with prospective ECG-gating in the diagnosis of coronary artery disease: a systematic review and meta-analysis. AB - To perform a systematic review and meta-analysis of the diagnostic value of prospective ECG-gating coronary CT angiography in the diagnosis of coronary artery disease. A search of biomedical databases for English literature was performed to identify studies investigating the diagnostic value of 64- or more slice CT angiography with use of prospective ECG-gating in the diagnosis of coronary artery disease. Sensitivity, specificity, positive and negative predictive value estimates pooled across studies were tested using a fixed effects model. Fourteen studies met selection criteria for inclusion in the analysis. Pooled estimates and 95% confidence interval (CI) of sensitivity, specificity, positive and negative predictive value of prospective ECG-gating coronary CT angiography for diagnosis of significant coronary stenosis were 99% (95% CI: 98, 100%), 91% (95% CI: 88, 94%), 94% (95% CI: 91, 96%) and 99% (95% CI: 97, 100%), according to the patient-based assessment. The mean values of sensitivity, specificity, positive and negative predictive value of prospective ECG-gating coronary CT angiography were 95% (95% CI: 93, 96%), 95% (95% CI: 93, 95%), 88% (95% CI: 86, 90%), and 98% (95% CI: 97, 98%), according to vessel-based assessment; 92% (95% CI: 90, 93%), 97% (95% CI: 97, 98%), 84% (95% CI: 82, 86%), 99% (95% CI: 99, 99%), according to segment-based assessment, respectively. The mean effective dose was 3.3 mSv (95% CI: 2.3, 4.1 mSv) for the prospective ECG gating coronary CT angiography. This analysis shows that for a predominantly male population with a high disease prevalence the use of coronary CT angiography with prospective ECG gating allows for a reduced radiation exposure without a sacrifice in diagnostic efficacy. PMID- 22212663 TI - New neglected disease research scheme pools IP and expertise. PMID- 22212664 TI - 2011 in reflection. PMID- 22212666 TI - Market watch: upcoming market catalysts in Q1 2012. PMID- 22212667 TI - Deal watch: high hopes for oral SYK inhibitor in rheumatoid arthritis. PMID- 22212668 TI - Trial watch: PCSK9 antibody reduces LDL cholesterol. PMID- 22212669 TI - Patent watch. PMID- 22212670 TI - Mark Fishman. Interview by Asher Mullard. PMID- 22212671 TI - A decade of change. PMID- 22212672 TI - Brentuximab vedotin. PMID- 22212676 TI - G protein-coupled receptors: Case builds for TGR5 as metabolic syndrome target. PMID- 22212677 TI - Cancer: Opening the door to a new class of proteasome inhibitors. PMID- 22212678 TI - Antiparasitic drugs: Two-pronged tactics for malaria control. PMID- 22212681 TI - Variations on variability: effects of display composition on same-different discrimination in pigeons. AB - Discriminating same from different multiitem arrays can be represented as a discrimination between arrays involving low variability and arrays involving high variability. In the present investigation, we first trained pigeons with the extreme values along the variability continuum (arrays containing 16 identical items vs. 16 nonidentical items), and we later tested the birds with arrays involving intermediate levels of variability; we created these testing arrays either by manipulating the combination of same and different items (mixture testing) or by changing the number of items in the same and different arrays (number testing). According to an entropy account (Young & Wasserman, Journal of Experimental Psychology: Animal Behavior Processes 23:157-170, 1997), the particular means of changing variability should have no effect on same-different discrimination performance: Equivalent variability should yield equivalent performance. In this critical test of an entropy account, we found that entropy could explain a large portion of our data, but not the entire collection of results. PMID- 22212679 TI - The pharmacological landscape and therapeutic potential of serine hydrolases. AB - Serine hydrolases perform crucial roles in many biological processes, and several of these enzymes are targets of approved drugs for indications such as type 2 diabetes, Alzheimer's disease and infectious diseases. Despite this, most of the human serine hydrolases (of which there are more than 200) remain poorly characterized with respect to their physiological substrates and functions, and the vast majority lack selective, in vivo-active inhibitors. Here, we review the current state of pharmacology for mammalian serine hydrolases, including marketed drugs, compounds that are under clinical investigation and selective inhibitors emerging from academic probe development efforts. We also highlight recent methodological advances that have accelerated the rate of inhibitor discovery and optimization for serine hydrolases, which we anticipate will aid in their biological characterization and, in some cases, therapeutic validation. PMID- 22212682 TI - The impact of extended care on the long-term maintenance of weight loss: a systematic review and meta-analysis. AB - Behavioural weight management interventions consistently produce 8-10% reductions in body weight, yet most participants regain weight after treatment ends. One strategy for extending the effects of behavioural interventions has been the provision of extended care. The current study is a systematic review and meta analysis of the literature on the effect of extended care on maintenance of weight loss. Through database searches (using PubMED, PsychInfo and Cochrane Reviews) and manual searches through reference lists of related publications, 463 studies were identified. Of these, 11 were included in the meta-analysis and an additional two were retained for qualitative analysis. The average effect of extended care on weight loss maintenance was g=0.385 (95% confidence interval: 0.281, 0.489; P<0.0001). This effect would lead to the maintenance of an additional 3.2 kg weight loss over 17.6 months post-intervention in participants provided extended care compared with control. There was no significant heterogeneity between studies, Q=5.63, P=0.845, and there was minimal evidence for publication bias. These findings suggest that extended care is a viable and efficacious solution to addressing long-term maintenance of lost weight. Given the chronic disease nature of obesity, extended care may be necessary for long term health benefits. PMID- 22212680 TI - Targeting proteinase-activated receptors: therapeutic potential and challenges. AB - Proteinase-activated receptors (PARs), a family of four seven-transmembrane G protein-coupled receptors, act as targets for signalling by various proteolytic enzymes. PARs are characterized by a unique activation mechanism involving the proteolytic unmasking of a tethered ligand that stimulates the receptor. Given the emerging roles of these receptors in cancer as well as in disorders of the cardiovascular, musculoskeletal, gastrointestinal, respiratory and central nervous system, PARs have become attractive targets for the development of novel therapeutics. In this Review we summarize the mechanisms by which PARs modulate cell function and the roles they can have in physiology and diseases. Furthermore, we provide an overview of possible strategies for developing PAR antagonists. PMID- 22212683 TI - Retrospective clinical and laboratory evaluation of children with brucellosis. AB - BACKGROUND: Acute brucellosis is a zoonotic disease seen in childhood, with non specific complaints and clinical findings that can affect the locomotor, gastrointestinal, genitourinary, hematologic, cardiovascular, respiratory, and central nervous systems. Particularly in endemic regions, it occurs as a result of consumption of unpasteurized milk and dairy products. In this study, clinical and laboratory findings of children with acute brucellosis are presented. METHODS: Data for 147 patients, aged 2-16 years, were evaluated retrospectively. RESULTS: The most frequent complaints and clinical findings were abdominal pain and fever. Other complaints and clinical findings included arthralgia, myalgia, loss of appetite, weakness, sweating, fatigue, headache, arthritis, hepatomegaly, and splenomegaly. Anemia was the most frequent hematological abnormality detected; other abnormalities included leukopenia, thrombocytopenia, and pancytopenia. CONCLUSION: Childhood brucellosis can cause non-specific complaints and particularly anemia and leukopenia as hematological abnormalities. It is easily treated, however, with appropriate antibiotics. PMID- 22212684 TI - Susceptibility of different populations of ticks to entomopathogenic fungi. AB - This study aimed to evaluate the in vitro effect of the entomopathogenic fungi Metarhizium anisopliae sensu lato (s.l.) and Beauveria bassiana sensu lato (s.l.) on two distinct populations of Rhipicephalus microplus, from two different experimental farms. Bioassays were performed with engorged females, eggs and larvae. Fungal infection was evaluated based on biological parameters of treated engorged females, percentage of hatch from treated eggs, and percentage of mortality and mean lethal time (LT90) of treated larvae. When the treatments were compared between the two populations, there were significant differences in the following parameters: pre-oviposition period, hatching period and egg production index. Moreover, the results showed that B. bassiana s.l., isolate Bb 986, was more virulent than M. anisopliae s.l., isolate 959, for engorged females, showing a control percentage of 49%. In the bioassay with eggs, the hatching percentage ranged from 3.1% to 49.5% in one population and from 3.4% to 42.7% in the other, with no significant difference between the two populations. In the bioassay with unfed larvae, the mortality percentage ranged from 91.8% to 98.7% in one population and from 71.0% to 94.0% in the other. The LT(90) varied from 19.52 to 27.51 days in one of the populations and 22.89 to 37.31 days in the other. These results suggest that populations of R. microplus show distinct variation in their susceptibility to B. bassiana s.l. and M. anisopliae s.l. PMID- 22212685 TI - Lifespan based indirect response models. AB - In the field of hematology, several mechanism-based pharmacokinetic pharmacodynamic models have been developed to understand the dynamics of several blood cell populations under different clinical conditions while accounting for the essential underlying principles of pharmacology, physiology and pathology. In general, a population of blood cells is basically controlled by two processes: the cell production and cell loss. The assumption that each cell exits the population when its lifespan expires implies that the cell loss rate is equal to the cell production rate delayed by the lifespan and justifies the use of delayed differential equations for compartmental modeling. This review is focused on lifespan models based on delayed differential equations and presents the structure and properties of the basic lifespan indirect response (LIDR) models for drugs affecting cell production or cell lifespan distribution. The LIDR models for drugs affecting the precursor cell production or decreasing the precursor cell population are also presented and their properties are discussed. The interpretation of transit compartment models as LIDR models is reviewed as the basis for introducing a new LIDR for drugs affecting the cell lifespan distribution. Finally, the applications and limitations of the LIDR models are discussed. PMID- 22212687 TI - On the role of left ventricular diastolic function in the critically ill patient. PMID- 22212686 TI - Toxin pores endocytosed during plasma membrane repair traffic into the lumen of MVBs for degradation. AB - Cells permeabilized by the bacterial pore-forming toxin streptolysin O (SLO) reseal their plasma membrane in a Ca(2+) -dependent manner. Resealing involves Ca(2+) -dependent exocytosis of lysosomes, release of acid sphingomyelinase and rapid formation of endosomes that carry the transmembrane pores into the cell. The intracellular fate of the toxin-carrying endocytic vesicles, however, is still unknown. Here, we show that SLO pores removed from the plasma membrane by endocytosis are sorted into the lumen of lysosomes, where they are degraded. SLO permeabilized cells contain elevated numbers of total endosomes, which increase gradually in size while transitioning from endosomes with flat clathrin coats to large multivesicular bodies (MVBs). Under conditions that allow endocytosis and plasma membrane repair, SLO is rapidly ubiquitinated and gradually degraded, in a process sensitive to inhibitors of lysosomal hydrolysis but not of proteasomes. The endosomes induced by SLO permeabilization become increasingly acidified and promote SLO degradation under normal conditions, but not in cells silenced for expression of Vps24, an ESCRT-III complex component required for the release of intraluminal vesicles into MVBs. Thus, cells dispose of SLO transmembrane pores by ubiquitination/ESCRT-dependent sorting into the lumen of late endosomes/lysosomes. PMID- 22212688 TI - Effect of ribavirin on junin virus infection in guinea pigs. AB - Junin virus (JUNV) is the aetiological agent of Argentine haemorrhagic fever. The pathogenesis of the infection is not well understood, no licensed vaccines exist and no specific antiviral therapy is available. Previous studies have demonstrated the ability of ribavirin to delay and reduce JUNV disease and virus burden in guinea pigs without preventing death. Based on available data, we performed three different studies to determine the efficacy of ribavirin against JUNV in the guinea pig model with a focus on survival. Different doses and treatment schedules of ribavirin were tested in a lethal model of JUNV infection. Our results show that prolonged treatment with high doses of ribavirin significantly reduces the mortality in guinea pigs infected with JUNV. These results may be useful in future experimental studies or clinical testing. PMID- 22212689 TI - Assessing degree of flowering implicates multiple Chenopodiaceae/Amaranthaceae species in allergy. AB - BACKGROUND: IgE-mediated sensitization to the Chenopodiaceae/Amaranthaceae families is a cause of allergic symptoms in arid areas. Salsola kali and Chenopodium album are considered the main species responsible; however, there is a discrepancy between the pollination period of these two plants and clinical symptoms. The objectives of this study were to identify new Chenopodiaceae/Amaranthaceae members with sensitization capacity and to correlate symptoms, pollen counts and degree of flowering of different species. METHODS: A total of 37 individuals monosensitized to S. kali and C. album were included in the study. All patients recorded daily symptom scores between May and October 2007. Extracts from Chenopodium (album, vulvaria and murale), Salsola (kali, vermiculata, and oppositifolia), Bassia scoparia, Atriplex (patula and halimus) and Amaranthus (deflexus and muricatus) were manufactured and used in skin prick tests (SPTs). Protein content and IgE binding were assessed for each extract. Pollen counts and degree of flowering (based on the Orshan specific semiquantitative method) were assessed weekly. RESULTS: Symptom scores demonstrated a positive correlation with pollen counts even outside the pollination period of S. kali. Positive SPTs were obtained with all 11 species tested, which showed common proteins with IgE-binding capacity. Different species flowered at different times during the pollen season. CONCLUSION: Different taxonomically related species of Chenopodiaceae/Amaranthaceae can induce allergic sensitization and should be considered for use in diagnosis and treatment. Degree of flowering is a complementary method for assessing pollination that could be used for botanical families with indistinguishable pollen grains. PMID- 22212690 TI - An outbreak of the 2009 influenza a (H1N1) virus in a children's hospital. AB - CONTEXT: Preventing nosocomial transmission of influenza is essential to reduce the morbidity and mortality associated with this infection. In October 2009, an outbreak of the 2009 influenza A (H1N1) virus occurred in a hematology ward of a children's hospital over a 21-day period and involved two patients and four healthcare workers. OBJECTIVE: To investigate nosocomial transmission of the 2009 influenza A (H1N1) virus in patients and healthcare workers. DESIGN, SETTING, AND PARTICIPANTS: An outbreak investigation was initiated in response to suspected nosocomial transmission of the 2009 influenza A (H1N1) virus during the peak of the 2009 pandemic. Cases were confirmed using a polymerase chain reaction (PCR) test specific for the 2009 H1N1 influenza A virus. Viruses isolated from nasopharyngeal swabs were genetically characterized using Sanger sequencing of uncloned "bulk" PCR products. MAIN OUTCOME MEASURES: Virus sequencing to investigate nosocomial transmission. RESULTS: Two immunocompromised patients and four healthcare workers were found to be part of a nosocomial outbreak of the 2009 influenza A (H1N1) virus. One immunocompromised patient had a second episode of clinical influenza infection after isolation precautions had been discontinued, resulting in additional exposures. Strain-specific PCR showed that all cases were caused by infection of the 2009 H1N1 virus. Sequencing of viral genes encoding hemagglutinin and polymerase basic subunit 2 (PB2) revealed that all viruses isolated were genetically identical at these loci, including the two episodes occurring in the same immunocompromised patient. CONCLUSIONS: Prompt institution of isolation precautions is essential in preventing nosocomial outbreaks of the 2009 novel influenza A (H1N1) virus. Our data suggest that isolation precautions may need to be continued for a prolonged period of time in immunocompromised patients with influenza infection. PMID- 22212691 TI - Serum Mg and Zn levels in postmenopausal women. AB - Approximately 30% of a woman's life is spent in the postmenopausal period. This is when steroid hormone deficiency is often accompanied by mineral homeostasis perturbations and deficiencies that could be related to the intensity of any clinical symptoms. The aim of this study was to assess how serum Mg and Zn levels in postmenopausal women correlate with climacteric symptoms, body mass index (BMI), and the time interval since the final menstruation. The study involved 171 healthy, postmenopausal women, who had had their final menstruation at least one year prior to the study and who did not use menopausal hormone therapy. Both hypomagnesaemia and hypozincaemia were detected in the postmenopausal women involved in this study. The analysis revealed statistically significant differences between serum Mg levels, depending on the time interval since the final menstruation (p<0.05). No statistically significant differences were found in serum Mg and Zn levels between women as regards the severity of the climacteric symptoms or BMI (p>0.05). In conclusion, serum Mg and Zn concentrations in postmenopausal women, not using MHT, were low. The average serum Mg levels decreased considerably with the time since the final menstruation. No correlation between BMI and worsening of climacteric symptoms and serum Mg and Zn concentrations in postmenopausal women, not using MHT was found. PMID- 22212692 TI - Phosphate recovery as struvite within a single chamber microbial electrolysis cell. AB - An energy efficient method of concurrent hydrogen gas and struvite (MgNH(4)PO(4).6H(2)O) production was investigated based on bioelectrochemically driven struvite crystallization at the cathode of a single chamber microbial electrolysis struvite-precipitation cell (MESC). The MESC cathodes were either stainless steel 304 mesh or flat plates. Phosphate removal ranged from 20% to 40%, with higher removals obtained using mesh cathodes than with flat plates. Cathode accumulated crystals were verified as struvite using a scanning electron microscope capable of energy dispersive spectroscopy (SEM-EDS). Crystal accumulation did not affect the rate of hydrogen production in struvite reactors. The rate of struvite crystallization (g/m(2)-h) and hydrogen production (m(3)/m(3)-d) were shown to be dependent on applied voltage and cathode material. Overall energy efficiencies (substrate and electricity) were high (73 +/- 4%) and not dependent on applied voltage. These results show that MESCs may be useful both as a method for hydrogen gas and struvite production. PMID- 22212693 TI - Materials flow modeling of nutrient recycling in biodiesel production from microalgae. AB - Biodiesel production based on microalgae as feedstock is associated with a high demand of nutrients, respectively nitrogen and phosphorus. The production of 1l biodiesel requires between 0.23 and 1.55 kg nitrogen and 29-145 g of phosphorus depending of the cultivation conditions for microalgae. The supply of nutrients can be expected to severely limit the extent to which the production of biofuels from microalgae can be sustainably expanded. The nutrient demand can be reduced if the nutrients in the residual algae biomass after oil extraction are reused for algae cultivation. This modeling work illustrates that for the investigated process chains and scenarios the nutrient recycling rates are in the range from 30% to 90% for nitrogen and from 48% to 93% for phosphorus. The highest recycling values can be achieved by hydrothermal gasification of the oil-free residues. PMID- 22212694 TI - Cloning, expression and applicability of thermo-alkali-stable xylanase of Geobacillus thermoleovorans in generating xylooligosaccharides from agro residues. AB - A xylanase gene (xyl-gt) of 1.224 kbp was cloned from the extremely thermophilic bacterium Geobacillus thermoleovorans that encodes a protein containing 408 amino acid residues. Eight conserved regions (signature sequences) of GH family 10 xylanases have been found in the xylanase. When the xylanase gene was cloned and expressed in Escherichia coli BL21 (DE3), the recombinant strain produced xylanase titer of 270 U mg(-1) which is 27-fold higher than the wild strain. It is optimally active at 80 degrees C and pH 8.5 with a high thermostability over broad range of pH (6-12) and temperature (40-100 degrees C). The end products of the hydrolysis of birch wood xylan and agro-residues included xylobiose, xylotriose, xylotetraose and xylopentaose. The xylanase of G. thermoleovorans is one of the rare xylanases that exhibits thermo-alkali-stability, and thus, it is a suitable candidate for pre-bleaching of paper pulps and generating xylooligosaccharides from agro-residues for use as prebiotics. PMID- 22212695 TI - Microbial characterization and removal of anionic surfactant in an expanded granular sludge bed reactor. AB - This study evaluated linear alkylbenzene sulfonate removal in an expanded granular sludge bed reactor with hydraulic retention times of 26 h and 32 h. Sludge bed and separator phase biomass were phylogenetically characterized (sequencing 16S rRNA) and quantified (most probable number) to determine the total anaerobic bacteria and methanogenic Archaea. The reactor was fed with a mineral medium supplemented with 14 mg l(-1)LAS, ethanol and methanol. The stage I-32 h consisted of biomass adaptation (without LAS influent) until reactor stability was achieved (COD removal >97%). In stage II-32 h, LAS removal was 74% due to factors such as dilution, degradation and adsorption. Higher HRT values increased the LAS removal (stage III: 26 h - 48% and stage IV: 32 h - 64%), probably due to increased contact time between the biomass and LAS. The clone libraries were different between samples from the sludge bed (Synergitetes and Proteobacteria) and the separator phase (Firmicutes and Proteobacteria) biomass. PMID- 22212696 TI - Combination therapy in pulmonary arterial hypertension: a meta-analysis. AB - OBJECTIVES: It is unclear whether combination therapy is efficient and well tolerated in patients with pulmonary arterial hypertension (PAH). The objective was to analyze completed trials assessing the efficacy and safety of treating PAH with combination therapy. METHODS: We performed a meta-analysis of all randomized controlled combination therapy trials that evaluated efficacy and safety in PAH patients. Trials were identified in the Cochrane Library, EMBASE and PubMed databases, reviews and reference lists of relevant papers. RESULTS: Six trials with a total of 858 patients were included in the meta-analysis. Compared with the control group, combination therapy reduced clinical worsening [relative risk (RR) 0.48, 95% confidence interval (CI) 0.26-0.91, p = 0.023], increased the 6 min-walk distance significantly by 22.22 m, and reduced mean pulmonary arterial pressure, right atrial pressure and pulmonary vascular resistance. The incidence of serious adverse events was similar in the 2 groups (RR 1.17, 95% CI 0.40-3.42, p = 0.77). However, combination therapy did not influence mortality. CONCLUSIONS: Treatment of PAH with combination therapy improves multiple clinical and hemodynamic outcomes, but it has no effect on mortality. The long-term efficacy and safety of combination therapy in PAH requires further study based on large and rational-designed controlled clinical trials. PMID- 22212697 TI - Is HINARI appropriate for medical students in the developing world? AB - The Health InterNetwork Access to Research Initiative (HINARI), which arose in response to medical literature needs in developing countries, gives online access to scientific information to a variety of institutions throughout the world. This is a great resource; however, little research has been performed on the effectiveness and usefulness of HINARI, specifically to medical schools. Our study sought to find out whether the textbooks (e-books) available on HINARI could form a virtual library that would cover the curriculum of a medical school. After categorising and reviewing the medically relevant e-books on HINARI, we found that they were insufficient in providing adequate subject material relevant to medical school curricula from Rwanda, the United Kingdom and the United States. This literature gap could be closed by additional medical textbooks being made available from contributing publishers. An increase of only 14% in HINARI e book resources would provide material for the entire medical school curriculum. PMID- 22212698 TI - Auditory middle latency responses in children with specific language impairment. AB - Auditory-evoked potentials represent the response of the auditory pathway to an auditory stimulus. Specific language impairment (SLI) children have delayed language development with difficulties in both understanding and producing spoken language. Hence, the purpose of this study was to determine whether a group of children with SLI had abnormal changes in the auditory middle latency response (AMLR). AMLR was obtained for 19 SLI children and they were studied and compared to normal. Audiological assessment and speech language tests were done for the study group. The results revealed no significant statistical differences between SLI children and the normal with regard to AMLR (P > 0.05). Our results suggest that children with SLI do not have abnormal auditory system response at the level measured by AMLR casting doubt on affection of the hypnotized origin of AMLR, mainly primary auditory cortex, as a cause for delayed language development in those children. PMID- 22212699 TI - The effects of CPAP treatment on nasal mucosa in patients with obstructive sleep apnea. AB - The aim of the study was to demonstrate the effects of nasal CPAP treatment on the morphology and function of nasal mucosa in patients with obstructive sleep apnea (OSA). Patients with complaints relevant to OSA underwent respiratory function tests, arterial blood gas analyses and polysomnography. Saccharine test and nasal biopsies were performed to assess the mucociliary transport time and to observe the histopathological changes in patients with apnea-hypopnea index >=15 in whole night polysomnography. Tissue samples were obtained from middle and inferior turbinates and septal mucosa to observe the degree of inflammation and fibrosis by semiquantitative means. Biopsies and mucociliary transport test were performed before and 3 months after the initiation of CPAP treatment. A total of 25 patients with a mean age of 52 were enrolled in the study. While the pretreatment mucociliary transport time before and 3 months after the treatment were 10.50 and 11.50 min respectively. The difference between these values was statistically insignificant. Mean apnea-hypopnea index was 63.19, while mean partial oxygen pressure was 75.46 mmHg. Nasal CPAP treatment was introduced with a mean pressure of 9.54 cmH2O. The degree of inflammation and fibrosis was found to be significantly increased after CPAP treatment. Nasal CPAP leads to alterations in mucosa. Efforts should be directed to make CPAP treatment a safer method via protecting the morphologic and functional properties of the nasal mucosa. PMID- 22212701 TI - Public health nutrition and the environment. PMID- 22212700 TI - Large animal induced pluripotent stem cells as pre-clinical models for studying human disease. AB - The path to induced pluripotency Discovery of a pan-species pluripotency network Animal iPSCs and disease modelling Issues with large animal iPSCs Conclusions The derivation of human embryonic stem cells and subsequently human induced pluripotent stem cells (iPSCs) has energized regenerative medicine research and enabled seemingly limitless applications. Although small animal models, such as mouse models, have played an important role in the progression of the field, typically, they are poor representations of the human disease phenotype. As an alternative, large animal models should be explored as a potentially better approach for clinical translation of cellular therapies. However, only fragmented information regarding the derivation, characterization and clinical usefulness of pluripotent large animal cells is currently available. Here, we briefly review the latest advances regarding the derivation and use of large animal iPSCs. PMID- 22212702 TI - Ice-free cryopreservation of heart valve allografts: better extracellular matrix preservation in vivo and preclinical results. AB - The purpose of this study was evaluation of an ice-free cryopreservation method for heart valves in an allogeneic juvenile pulmonary sheep implant model and comparison with traditionally frozen cryopreserved valves. Hearts of 15 crossbred Whiteface sheep were procured in Minnesota. The valves were processed in South Carolina and the pulmonary valves implanted orthotopically in 12 black faced Heidschnucke sheep in Germany. The ice-free cryopreserved valves were cryopreserved in 12.6 mol/l cryoprotectant (4.65, 4.65, and 3.31 mol/l of dimethylsulfoxide, formamide and 1,2-propanediol) and stored at -80 degrees C. Frozen valves were cryopreserved by controlled slow rate freezing in 1.4 mol/l dimethylsulfoxide and stored in vapor-phase nitrogen. Aortic valve tissues were used to evaluate the impact of preservation without implantation. Multiphoton microscopy revealed reduced but not significantly damaged extracellular matrix before implantation in frozen valves compared with ice-free tissues. Viability assessment revealed significantly less metabolic activity in the ice-free valve leaflets and artery samples compared with frozen tissues (P < 0.05). After 3 and 6 months in vivo valve function was determined by two-dimensional echo-Doppler and at 7 months the valves were explanted. Severe valvular stenosis with right heart failure was observed in recipients of frozen valves, the echo data revealed increased velocity and pressure gradients compared to ice-free valve recipients (P = 0.0403, P = 0.0591). Histo-pathology showed significantly thickened leaflets in the frozen valves (P < 0.05) and infiltrating CD3+ T-cells (P < 0.05) compared with ice-free valve leaflets. Multiphoton microscopy at explant revealed reduced inducible autofluorescence and extracellular matrix damage in the frozen explants and well preserved structures in the ice-free explant leaflets. In conclusion, ice-free cryopreservation of heart valve transplants at -80 degrees C avoids ice formation, tissue-glass cracking and preserves extracellular matrix integrity resulting in minimal inflammation and improved hemodynamics in allogeneic juvenile sheep. PMID- 22212703 TI - PRP-fibrinogen gel-like chondrocyte carrier stabilized by TXA-preliminary study. AB - Three dimensional scaffolds are becoming increasingly popular in the treatment of cartilage defects. Platelet-rich plasma (PRP) and fibrinogen can be used potentially as a three dimensional cell delivery vehicle. PRP is a fraction of plasma containing high levels of growth factors such as PDGF, IGF-I and TGF-I, which stimulate chondrocyte to synthesize extracellular matrix. The aim of this study was to prepare grafts based on fibrinogen, and PRP with fibrinogen as a chondrocyte carrier. Another goal was to estimate tranexamic acid as an antifibrynolytic agent in chondrocyte grafts and in monolayer culture for about 3 weeks. 450 ml blood was collected to produce fibrinogen and PRP from a Regional Blood Center voluntary donor. To prepare gel grafts, chondrocytes were mixed with PRP and, fibrinogen and then with thrombin in calcium chloride. Different doses of tranexamic acid or aprotinin were used to stabilize the constructs. Grafts were cultivated for 4 weeks in vitro to evaluate and compare their disintegration. Grafts were stable for the entire observation period and revealed no shrinkage. During graft storage, cells appeared to be viable, and cell migration from the graft to the culture plate was observed. Chondrocyte graft preparation based on PRP and fibrinogen is a promising method. PRP-fibrinogen carrier in combination with cells constitutes highly plastic and adhesive grafts. Tranexamic acid can be used as an anti-fibrinolytic agent in chondrocyte graft preparation instead of aprotinin. PMID- 22212704 TI - Analysis of predisposing factors for contamination of bone and tendon allografts. AB - Bone and tissue allografts are widely used in transplantation. The increasing demand for safe allografts must be met, while minimizing disease transmission. We analysed the incidence and potential risk factors of allograft contamination and the effectiveness of disinfection, by reviewing 22 years of tissue bank activity and 474 donor procurements. We also compared different disinfection procedures used over the 22 years. The overall contamination rate was 10.1%. Risk factors were related to the donor or procurement method. Immediate culture at the tissue recovery site diminished the rate of false positives by reducing later sample manipulation. High-virulence allograft contamination was mainly related to donor factors, while low-virulence contamination was related to procurement methods. Analysis of donor-related risk factors showed no statistical differences for age, sex, or cause of death. An intensive care unit stay was associated with less contamination with high-virulence microbes. Procurement in a setting other than an operating theatre was associated with higher contamination rate. Team experience reduced contamination. Pelvic and tendon allografts were most frequently contaminated. Proper disinfection considerably reduced the contamination rate to 3.6%. We conclude that procurement must be performed under aseptic conditions, with short delays, and by trained personnel. Grafts should be disinfected and packed as soon as possible. PMID- 22212705 TI - Pitfalls in assessing platelet activation status in patients with liver disease. PMID- 22212706 TI - Psychological aspects of prostate cancer: a clinical review. AB - Prostate cancer is the most common non-skin cancer in men. It is fraught with both physical and psychological symptomatology. Depression, anxiety, stress, fatigue, pain and psychosocial factors all affect the patient with prostate cancer. Impotence, erectile dysfunction, sexual issues and incontinence in these patients complicate matters further. Anxiety may exist both before testing and while awaiting test results. Confusion over choosing from various interventions often adds to anxiety and depression in these patients. Various demographic factors and the developmental stage of the couple affect these psychological symptoms. The caregiver may undergo significant psychological turmoil while caring for a patient diagnosed with prostate cancer, which is addressed. The role of nurses in the management of prostate cancer is discussed. The present review looks at psychological issues in patients with prostate cancer from a clinical perspective, with the aim of highlighting these issues for the clinical urologist dealing with these patients. It also explores the consultation-liaison relationship between psychiatrists, psychologists and urologists as a team for the multimodal management of prostate cancer. PMID- 22212707 TI - Spectroscopic characterization of Venus at the single molecule level. AB - Venus is a recently developed, fast maturating, yellow fluorescent protein that has been used as a probe for in vivo applications. In the present work the photophysical characteristics of Venus were analyzed spectroscopically at the bulk and single molecule level. Through time-resolved single molecule measurements we found that single molecules of Venus display pronounced fluctuations in fluorescence emission, with clear fluorescence on- and off-times. These fluorescence intermittencies were found to occupy a broad range of time scales, ranging from milliseconds to several seconds. Such long off-times can complicate the analysis of single molecule counting experiments or single molecule FRET experiments. PMID- 22212708 TI - Cloning and overexpression of an important functional gene ATP6V1F encoding a component of vacuolar ATPase from the Giant Panda (Ailuropoda melanoleuca). AB - ATP6V1F encodes a component of vacuolar ATPase mediating acidification. The cDNA and the genomic sequences of ATP6V1F were cloned successfully for the first time from the Giant Panda (Ailuropoda melanoleuca) using reverse transcription polymerase chain reaction and touchdown-polymerase chain reaction, respectively. The cDNA fragment cloned is 364 bp in size, containing an open reading frame of 360 bp encoding 119 amino acids. Alignment analysis indicated that both ORF and the deduced amino acid sequence are highly conserved. The length of the genomic sequence of the Giant Panda is 2225 bp, including two exons and one intron. Topology prediction showed that there is one protein kinase C phosphorylation site, two Casein kinase II phosphorylation sites, and one N-myristoylation site in the ATP6V1F protein. The ATP6V1F gene was overexpressed in Escherichia coli indicating that ATP6V1F fusion with the N-terminally His-tagged form gave rise to the accumulation of an expected 17 kDa polypeptide, which was according with the predicted protein and also could be used to purify the protein and study its function. PMID- 22212709 TI - Molecular characterization and tissue expression profile of three novel ovine genes: ATP5O, NDUFA12 and UQCRH from muscle full-length cDNA library of black boned sheep. AB - Three novel ovine genes were obtained from muscle full-length cDNA library of black-boned sheep. Sequence analysis revealed that nucleotide sequences of these genes were not homologous to any of the known sheep or goat genes, but these genes have high similarity to ATP synthase subunit O (ATP5O), NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 12 (NDUFA12) and ubiquinol-cytochrome c reductase hinge protein (UQCRH) genes of other mammal animals (accession number: FJ546085, FJ546078 and FJ546083). The alignment analysis showed that the ovine ATP5O, NDUFA12 and UQCRH genes and proteins have closer genetic relationships with the ATP5O, NDUFA12 and UQCRH genes and proteins from cattle. Conserved domain prediction showed that these three genes included OSCP, NDUFA12 superfamily and UCR-hinge superfamily domains respectively. The deduced sequence of ATP5O, NDUFA12 and UQCRH protein had 213, 145 and 91 amino acid residues, with a molecular weight of approximately 23419.66, 17089.50 and 10657.75 Da and a theoretical isoelectric point of 9.90, 9.68 and 4.45. The secondary structure prediction revealed that 60% helix structure in ATP5O, 60% coils in NDUFA12 and no strand in UQCRH. One potential signal peptide structure in ATP5O protein were found. NDUFA12 and UQCRH have the extremely low possibility of signal peptides. Meanwhile, RasMol was used for visualizing the PDB files generated by Swiss-Model in cartoon or three-dimensional format. ATP5O and UQCRH protein were modeled by Swiss-Model. Tissue expression profile indicated that the ovine ATP5O, NDUFA12 and UQCRH genes could be expressed in all detected tissues including muscles, heart, liver, spleen, lung, kidney and adipose tissues, but the expression abundance of these genes were various in the different tissues. Our experiment supplied the primary foundation for further researches on these three ovine genes. PMID- 22212711 TI - Reliability of sensory predictions determines the experience of self-agency. AB - This study examines the neurocognitive mechanisms underlying the sense of agency, that is, the experience of causing and controlling events in our environment. Specifically, we tested the hypothesis that the sense of agency depends on an optimal integration of different anticipatory signals, generated by motor and nonmotor systems. An established marker of pre-reflective agency experience is the suppression of cortical responses to actively generated feedback as compared to passively observed feedback, which was measured here by event-related potentials (ERPs). Sensory expectations based on motor-related and unrelated signals were induced by varying the probabilistic contingency between action and feedback, and by priming the feedback prior to the action. Moreover, simultaneous conscious agency judgments were assessed. A reduction of visual N1 response was found to self- as compared to externally generated feedback. In addition, the N1 was modulated by accurate anticipations based on prime stimuli, independent of the precision of motor predictions. Conscious agency judgments, in contrast, were enhanced by prime stimuli only in situations where no precise motor predictions of the action feedback were available. These results indicate that anticipatory signals arising from motor and nonmotor systems are integrated differently depending on the level of agency processing. Our findings suggest that, at a pre reflective level, the brain's agency system relies on both embodied signals and nonmotor sensory expectations. At higher cognitive levels, motor and nonmotor cues are weighted differently depending on their relative reliability in a given context, thereby providing a basis for robust agentive self-awareness. PMID- 22212710 TI - PDGF-induced airway smooth muscle proliferation is associated with Human antigen R activation and could be weakened by AMPK activation. AB - CyclinD1 over-expression is the key pathogenetic event underlying airway smooth muscle (ASM) proliferation. Human antigen R (HuR) is a ubiquitously expressed RNA binding protein, and is known to regulate the expression of multiple cell cycle regulators. The aim of the study is to investigate whether HuR might also be involved in ASM proliferation. In cultured ASM cells, PDGF treatment induced a significant elevation of HuR expression at both mRNA and protein levels. Immunofluorescence analysis demonstrated PDGF might promote HuR translocation from nucleus to cytoplasma as well. RNA-interference of HuR effectively decreased PDGF-induced cyclinD1 over-expression in ASM cells. Furthermore, AMPK activation by AICAR could effectively decrease PDGF-induced HuR cytoplasmatic translocation, cyclinD1 expression and ASM cells proliferation. In conclusion, altered expression and activity of HuR might participate in PDGF-induced ASM cells cyclinD1 expression and proliferation. The effectiveness of AMPK activation indicated a novel intervention method for airway remodeling. PMID- 22212712 TI - Effects of physical exercise prescribed by a medical support team on elderly lower extremity osteoarthritis combined with metabolic syndrome and/or type 2 diabetes. AB - AIM: The aims of the present study were to investigate the effectiveness of exercise intervention provided by a medical support team specializing in lifestyle-related diseases in the treatment of elderly lower extremity osteoarthritis and to examine the influence of bodyweight decrease on changes in the evaluation indexes. METHODS: Participants were 61 patients (57 women and 4 men, aged 68.3 +/- 9.6 years) with lower extremity osteoarthritis (109 total diseased joints) and either one or more of the following diseases: obesity, metabolic syndrome and type 2 diabetes. Indexes relating to metabolic diseases, orthopedic disorders, lifestyle activity level and health-related quality of life (HRQOL) were obtained before and after exercise intervention. RESULTS: The numbers of patients with obesity, metabolic syndrome, type 2 diabetes, gonarthrosis and coxarthrosis were 56, 49, 32, 56 and 9, respectively. The mean intervention period was 4.7 +/- 1.6 months (2-10.8 months). Indexes relating to metabolic diseases and orthopedic disorders, activity level and HRQOL were all significantly improved after intervention (P < 0.05). Bodyweight decreased by 10.3% and showed a correlation with other evaluated items. Five explanatory variables were extracted through multiple regression analysis that bodyweight reduction rate was set as the criterion variable: changes of bodyweight, body mass index, percent body fat, glycated hemoglobin and total energy expenditure per bodyweight. CONCLUSION: The exercise intervention provided by our medical support team clearly improved indexes relating to metabolic diseases and orthopedic disorders. In addition, decreased bodyweight was related to improvements in metabolic factors, motor function and HRQOL. PMID- 22212713 TI - Photomixotrophic growth of Rhodobacter capsulatus SB1003 on ferrous iron. AB - This study investigates the role iron oxidation plays in the purple non-sulfur bacterium Rhodobacter capsulatus SB1003. This organism is unable to grow photoautotrophically on unchelated ferrous iron [Fe(II)] despite its ability to oxidize chelated Fe(II). This apparent paradox was partly resolved by the discovery that SB1003 can grow photoheterotrophically on the photochemical breakdown products of certain ferric iron-ligand complexes, yet whether it could concomitantly benefit from the oxidation of Fe(II) to fix CO(2) was unknown. Here, we examine carbon fixation by stable isotope labeling of the inorganic carbon pool in cultures growing phototrophically on acetate with and without Fe(II). We show that R. capsulatus SB1003, an organism formally thought incapable of phototrophic growth on Fe(II), can actually harness the reducing power of this substrate and grow photomixotrophically, deriving carbon both from organic sources and from fixation of inorganic carbon. This suggests the possibility of a wider occurrence of photoferrotrophy than previously assumed. PMID- 22212714 TI - Local reaction to the different meshes at the vesicovaginal space in rabbit model. AB - INTRODUCTION AND HYPOTHESIS: This paper aims to study the vesicovaginal space local tissue reaction to type I and II polypropylene mesh in a rabbit model. METHODS: Different types of meshes were implanted into the rabbit vesicovaginal space. The animals were killed at days 7 and 60, and the initial implant and the neighboring host tissue were removed, including the bladder and vaginal wall. Histopathology and immunohistochemistry (Ki-67 and proliferating cell nuclear antigen) were performed to evaluate the cell proliferation, and the indirect local inflammatory response was described. RESULTS: One rabbit had erosion at the urinary bladder mucous membrane, which resulted in vesical stone formation in the type I mesh group at day 60. Obvious local tissue reaction was found after the different types of meshes were implanted, and the reaction tapered and disappeared over time. At day 7, the reaction in the type I mesh group was stronger than that in the type II group, while at day 60, the reaction shows no difference. CONCLUSION: The two types of meshes could induce local tissue reaction, but this was stronger in type I mesh group at day 7 and shows no obvious difference between the two groups at day 60. PMID- 22212715 TI - A preliminary anatomical basis for dual (uterosacral and sacrospinous ligaments) vaginal vault support at colporrhaphy. Dual-balanced vaginal vault support at colporrhaphy. AB - INTRODUCTION AND HYPOTHESIS: This study aims to assess anatomically the likely effects of dual vaginal vault support using the uterosacral (USL) and sacrospinous ligaments (SSL) at colporrhaphy. METHODS: Observations were made from 13 formalinized cadaver hemipelves to determine the vaginal vault support likely to be provided by traction on the (a) USLs and (b) the posterior vaginal vault towards the SSL. RESULTS: Traction on the USLs and SSLs both appeared to create a posterior and superior vector of vaginal vault tension, though that on the USLs appeared to be mainly on the anterior vaginal vault (and wall) with that on the SSL seemingly mostly on the posterior vaginal vault (and wall). CONCLUSIONS: Concomitant USL and SSL traction on the vaginal vault, now technically possible, appears, from these preliminary findings, to give complementary support to the anterior and posterior aspects of the vaginal vault and walls in a similar posterior and superior vector. PMID- 22212716 TI - Peroxisome formation requires the endoplasmic reticulum channel protein Sec61. AB - In peroxisome formation, models of near-autonomous peroxisome biogenesis with membrane protein integration directly from the cytosol into the peroxisomal membrane are in direct conflict with models whereby peroxisomes bud from the endoplasmic reticulum and receive their membrane proteins through a branch of the secretory pathway. We therefore reinvestigated the role of the Sec61 complex, the protein-conducting channel of the endoplasmic reticulum (ER) in peroxisome formation. We found that depletion or partial inactivation of Sec61 in yeast disables peroxisome formation. The ER entry of the early peroxisomal membrane protein Pex3 engineered with a glycosylation tag is reduced in sec61 mutant cells. Moreover, we were able to reconstitute Pex3 import into ER membranes in vitro, and we identified a variant of a signal anchor sequence for ER translocation at the Pex3 N-terminus. Our findings are consistent with a Sec61 requirement for peroxisome formation and a fundamental role of the ER in peroxisome biogenesis. PMID- 22212717 TI - The impact of pandemic influenza A (H1N1) 2009 on the circulation of respiratory viruses 2009-2011. AB - Surveillance of respiratory viruses has been conducted for many years at the public health laboratory in Hong Kong. With the occurrence of pandemic influenza A (H1N1) 2009, we observed a change in the seasonality of influenza activity with a seemingly corresponding change in the activity of respiratory syncytial virus, parainfluenza virus, and adenovirus during 2009-2011. This phenomenon could most likely be explained by virus interference. PMID- 22212718 TI - Functional characterisation of human SGLT-5 as a novel kidney-specific sodium dependent sugar transporter. AB - Sodium glucose cotransporters (SGLT) actively catalyse carbohydrate transport across cellular membranes. Six of the 12 known SGLT family members have the capacity to bind and/or transport monosaccharides (SGLT-1 to 6); of these, all but SGLT-5 have been characterised. Here we demonstrate that human SGLT-5 is exclusively expressed in the kidney. Four splice variants were detected and the most abundant SGLT-5-mRNA was functionally characterised. SGLT-5 mediates sodium dependent [(14)C]-alpha-methyl-D-glucose (AMG) transport that can be inhibited by mannose, fructose, glucose, and galactose. Uptake studies using demonstrated high capacity transport for mannose and fructose and, to a lesser extent, glucose, AMG, and galactose. SGLT-5 mediated mannose, fructose and AMG transport was weakly (MUM potency) inhibited by SGLT-2 inhibitors. In summary, we have characterised SGLT-5 as a kidney mannose transporter. Further studies are warranted to explore the physiological role of SGLT-5. PMID- 22212719 TI - FLU, a negative feedback regulator of tetrapyrrole biosynthesis, is physically linked to the final steps of the Mg(++)-branch of this pathway. AB - Regulation of tetrapyrrole biosynthesis in higher plants has been attributed to negative feedback control. Two effectors of feedback inhibition have been identified, heme and the FLU protein. Inhibition by heme implicates the Fe-branch via regulation of the initial step of tetrapyrrole synthesis. In the present work a FLU-containing chloroplast membrane complex was identified, that besides FLU comprises the four enzymes catalyzing the final steps of chlorophyll synthesis. The results support the notion that FLU links chlorophyll synthesis and the target of feedback control, glutamyl-tRNA reductase, thereby allowing also the Mg branch to control the initial step of tetrapyrrole synthesis. PMID- 22212720 TI - Immunotherapy is allergen-specific: a double-blind trial of mite or timothy extract in mite and grass dual-allergic patients. AB - BACKGROUND: One hundred years ago, Noon [Lancet 1911;1:1572-1573], using conjunctival provocation testing (CPT), was the first to demonstrate the effectiveness of subcutaneous immunotherapy (SCIT) in grass-allergic subjects with hay fever. In this centenary year, we present data that, by use of CPT and allergen-specific IgG, replicate this observation and additionally confirm the allergen specificity of SCIT by using a double-blind design employing either grass or mite SCIT in dual grass- and mite-allergic individuals. METHODS: Twenty adults (11 females) with perennial rhinoconjunctivitis and exacerbation of symptoms during the grass pollen season and in the autumn had immediate skin and conjunctival sensitivity and raised specific IgE to both Dermatophagoides farinae and Phleum pratense. Participants were randomly assigned to either timothy or D. farinae immunotherapy for 3 years. CPT and specific IgG tests to both allergens were performed annually. After 3 years, subjects gave their blinded overall evaluation. RESULTS: Six mild-to-moderate general reactions occurred in 2 timothy and 4 mite-treated patients. Four of these patients and 2 other patients withdrew from the study. Seven patients in each group completed the study. After 3 years of immunotherapy, the timothy CPT threshold concentration had increased 16- fold in timothy-treated patients (p < 0.05; between-group change, p < 0.05). The increase in the mite CPT threshold in mite- compared to grass-treated patients was 31-fold (p < 0.05). The overall assessment of conjunctival sensitivity was highly significant in favour of treatment (p < 0.015), as was that of allergen-specific IgG (p < 0.0001). CONCLUSIONS: Allergen immunotherapy is allergen species-specific, as judged by decreased conjunctival sensitivity and changes in allergen-specific IgG concentrations. PMID- 22212721 TI - Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases. AB - The alpha isoform of the phosphatidylinositol-3-kinases (PI3Kalpha) is often mutated, amplified and overexpressed in human tumors. In an effort to develop new inhibitors targeting this enzyme, we carried out a pharmacophore model study based on six PI3Kalpha-selective compounds. The pharmacophore searching identified three structurally novel inhibitors of PI3Kalpha and its H1047R mutant. Our biological studies show that two of our hit molecules suppressed the formation of pAKT, a downstream effector of PI3Kalpha, and induced apoptosis in the HCT116 colon cancer cell line. QPLD-based docking showed that residues Asp933, Glu849, Val851, and Gln859 appeared to be key binding residues for active inhibitors. PMID- 22212722 TI - Constituents of Dalbergia sissoo Roxb. leaves with osteogenic activity. AB - One new isoflavone glucoside, caviunin 7-O-[beta-d-apiofuranosyl-(1->6)-beta-d glucopyranoside] (10) and a new itaconic derivative, (E)-4-methoxy-2-(3,4 dihydroxybenzylidene)-4-oxobutanoic acid (15) along with series of isoflavones and flavonols with their glucosides (1-9 and 11-14) and a lignan glucoside (16) were isolated from the ethanolic extract of Dalbergia sissoo leaves. The structures of these compounds were established on the basis of IR, UV, (1)H and (13)C NMR, DEPT, COSY, HSQC, HMBC and MS data. All compounds (1-16) were assessed for osteogenic activity in primary calvarial osteoblast cultures. Compounds 1-4 and 10 increased alkaline phosphatase activity and mineralization thus resulting in significant osteogenic activity. PMID- 22212723 TI - Coronary artery disease: evidence of interaction between PTPN22 and p53 genetic polymorphisms. AB - OBJECTIVES: We recently reported an association between the PTPN22 genetic polymorphism and coronary artery disease (CAD) in nondiabetic subjects. Since recent studies suggest that p53 may be involved in coronary atherosclerosis, we have investigated a possible interaction between PTPN22 and p53 codon 72 genetic polymorphisms regarding their effects on susceptibility to CAD in nondiabetic subjects. METHODS: The genotypes of p53 codon 72 and PTPN22 were determined by DNA analysis in 128 nondiabetic subjects with CAD, 122 healthy blood donors and 117 nondiabetic subjects with cardiovascular diseases without CAD. RESULTS: In subjects with the *Arg/*Arg genotype of p53 codon 72, no association was observed between CAD and PTPN22. However, this association was very strong in subjects carrying the *Pro allele of p53 codon 72. Subjects carrying both the *T allele of PTPN22 and the *Pro allele of p53 were overrepresented in CAD nondiabetic cases relative to the other two groups (p = 0.001). CONCLUSIONS: Since both p53 and PTPN22 are involved in autoimmune inflammation, an interaction between the two systems appears biologically plausible. In the analysis of multifactorial disorders, the simultaneous analysis of multiple genes functionally related to diseases will provide a more productive approach than studies of single genetic factors performed from a Mendelian perspective. PMID- 22212724 TI - Ethics of clinical research with mentally ill persons. AB - This article describes ethical, legal and professional components of the two core requirements of clinical research: informed consent and risk-benefit relationships. It deals particularly with the ethically relevant reasons, criteria, procedures and validity of (1) the informed consent process, (2) the relationship between benefits and risks, and as a requirement of its assessment: (3) standards and (quasi quantitative) criteria of benefits and risks and/or burdens of a research intervention. These requirements will be discussed with specific reference to research interventions in mentally ill patients, and particularly in those who are incompetent to consent. (4) The analysis concludes by demanding a strong adherence to the ethical rules of clinical research in order to protect participants and preserve the trust of both the patients and the public and (5) yields in a set of recommendations. PMID- 22212725 TI - A new rating scale for adult ADHD based on the Symptom Checklist 90 (SCL-90-R). AB - Attention deficit hyperactivity disorder (ADHD) in adults is increasingly recognized as a clinically important syndrome. The aim of this study was to evaluate the psychometric performance of a new scale for adult ADHD based on the widely used Symptom Checklist 90 Revised (SCL-90-R). Scale performance was assessed in a clinical study including 100 ADHD patients and 65 opiate-dependent patient controls, and in the Zurich study, an epidemiological age cohort followed over 30 years of adult life. Assessments included a ROC analysis of sensitivity and specificity, internal consistency, test-retest reliability, external validity and measurement invariance over nine testing occasions. The new scale showed a sensitivity and specificity of 75 and 54%, respectively, internal consistency over 0.8 (McDonald's omega, Cronbach's alpha), one-year test-retest reliabilities over 0.7, statistically significant and substantial correlations with two other validated self-rating scales of adult ADHD (R = 0.5 and 0.66, respectively), and an acceptable degree of longitudinal stability (i.e., measurement invariance). The proposed scale must be further evaluated, but these preliminary results indicate it could be a useful rating instrument for adult ADHD in situations where SCL-90-R data, but no specific ADHD assessment, are available, such as in retrospective data analysis or in prospective studies with limited methodical resources. PMID- 22212726 TI - A cell-contact-regulated operon is involved in genetic variability in Neisseria meningitidis. AB - The ability of Neisseria meningitidis to establish efficient interaction with host cells is crucial for its survival. We recently demonstrated that an entire operon containing genes NMA1802 to NMA1806 was overexpressed during the early stage of the colonization process. In this work, we investigated whether upregulation of the expression of this operon facilitated the ability of N. meningitidis to adapt to growth on host cells. Using a strain displaying an inducible operon, we demonstrated that the NMA1802-NMA1806 cell-contact-regulated operon could potentially improve the adaptability of meningococcus during growth on the cell surface through enhanced generation of variants. PMID- 22212727 TI - West Nile transmission in resident birds in Italy. AB - Migratory birds are considered one of the main sources for West Nile virus (WNV) introduction into European countries. Following the WNV epidemic in the late summer of 1998 in a marshy area of Tuscany (Padule of Fucecchio), an extensive ornithological surveillance programme was carried out in the infected areas from 2006 to 2008. Several species of migratory and resident birds were trapped, sampled and serologically tested. The results of this surveillance programme gave a useful indication of potential sources of WNV re-introduction and spread into Italy. The area under study was also investigated and classified into ecological areas through satellite image processing. In August 2008, the WNV infection re emerged in Italy in the area surrounding the Po river delta, involving three regions: Lombardy, Emilia Romagna and Veneto. Several surveillance activities were immediately put in place, including the extensive monitoring of wild birds found dead or trapped in the framework of other surveillance programmes. These activities were also prolonged in the 2009, when the virus circulation re occurred at the border of the area already infected in 2008. The possible epidemiological role of the different species of migratory and resident birds is discussed, in relation to the different ecological patterns identified in the area and their potential ability to introduce, spread and support the endemization of WNV infection. PMID- 22212729 TI - Hybrid treatment of celiac artery compression (median arcuate ligament) syndrome. PMID- 22212728 TI - alpha-lipoic acid prevents the induction of iNOS gene expression through destabilization of its mRNA in proinflammatory cytokine-stimulated hepatocytes. AB - BACKGROUND/AIMS: alpha-Lipoic acid (alpha-LA) has been reported to reduce ischemia-reperfusion injury (IRI). Proinflammatory cytokines stimulate the induction of inducible nitric oxide synthase (iNOS) gene expression, leading to excess production of NO and resulting in liver injury including IRI. We hypothesized that inhibition of iNOS induction underlies the protective effects of alpha-LA on the liver. The objective was to investigate whether alpha-LA directly influences iNOS induction in cultured hepatocytes, which is used as a simple in vitro injury model, and the mechanism involved. METHODS: Primary cultured rat hepatocytes were treated with interleukin (IL)-1beta in the presence or absence of alpha-LA. The induction of iNOS and NO production and its signal were analyzed. RESULTS: alpha-LA inhibited the expression of iNOS mRNA and protein dose- and time-dependently, resulting in decreases in NO production. alpha-LA had no effects on the degradation of IkappaB proteins and activation of NF-kappaB. In contrast, alpha-LA inhibited the upregulation of type I IL-1 receptor stimulated by IL-1beta, although alpha-LA had no effect on Akt activation. Transfection experiments with iNOS promoter-luciferase constructs revealed that alpha-LA had no effect on the transactivation of the iNOS promoter, but decreased the stabilization of iNOS mRNA. Further, alpha-LA inhibited the expression of an iNOS gene antisense-transcript, which is involved in iNOS mRNA stability. CONCLUSIONS: Results indicate that alpha-LA inhibits the induction of iNOS gene expression at a posttranscriptional step via iNOS mRNA stabilization, rather than promoter activation. It may provide useful therapeutic effects through the suppression of iNOS induction involved in liver injury. PMID- 22212730 TI - The impact of the Great Tohoku Earthquake on the dialysis practice in the disaster-stricken area. PMID- 22212731 TI - A polymorphism in the thyroid hormone receptor gene is associated with bronchodilator response in asthmatics. AB - A pro-asthmatic culture milieu and beta2-agonist (isoproterenol) were previously shown to regulate the expression of select transcription factors (TFs) within human airway epithelial and smooth muscle cells. This study tests 1116 single nucleotide polymorphisms (SNPs) across 98 of these TF genes for association with bronchodilator response (BDR) in asthma patients. Genotyping was conducted using the Illumina HumanHap550v3 Beadchip in 403 non-Hispanic White asthmatic children and their parents. SNPs were evaluated for association with BDR using family and population-based analyses. Forty-two SNPs providing P-values <0.1 in both analyses were then genotyped in three adult asthma trials. One SNP 5' of the thyroid hormone receptor-beta gene was associated with BDR in the childhood population and two adult populations (P-value=0.0012). This investigation identified a novel locus for inter-individual variability in BDR and represents a translation of a cellular drug-response study to potential personalization of clinical asthma management. PMID- 22212733 TI - Hydrogen-bonding interactions in adrenaline-water complexes: DFT and QTAIM studies of structures, properties, and topologies. AB - omegaB97XD/6-311++G(d,p) calculations were carried out to investigate the hydrogen-bonding interactions between adrenaline (Ad) and water. Six Ad-H(2)O complexes possessing various types of hydrogen bonds (H-bonds) were characterized in terms of their geometries, energies, vibrational frequencies, and electron density topology. Natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) analyses were performed to elucidate the nature of the hydrogen bonding interactions in these complexes. The intramolecular H-bond between the amino and carboxyl oxygen atom of Ad was retained in most of the complexes, and cooperativity between the intra- and intermolecular H-bonds was present in some of the complexes. H-bonds in which hydroxyls of Ad/water acted as proton donors were stronger than other H-bonds. Both hydrogen-bonding interactions and structural deformation play important roles in the relative stabilities of the complexes. The intramolecular H-bond was broken during the formation of the most stable complex, which indicates that Ad tends to break the intramolecular H-bond and form two new intermolecular H-bonds with the first water molecule. PMID- 22212732 TI - Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population. AB - Risperidone non-compliance is often high due to undesirable side effects, whose development is in part genetically determined. Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results. Thus, the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment: sleepiness, weight gain, extrapyramidal symptoms and sexual adverse events. A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response. Presence of adverse events was the main variable and potential confounding factors were considered. Allele 16Gly of ADRB2 was significantly associated with a higher risk of sexual adverse events. There were other non-significant trends for DRD3 9Gly and SLC6A4 S alleles. Our results, although preliminary, provide new candidate variants of potential use in risperidone safety prediction. PMID- 22212734 TI - Design and selection of nitrogen-rich bridged di-1,3,5-triazine derivatives with high energy and reduced sensitivity. AB - The heats of formation (HOFs), electronic structures, energetic properties, and thermal stabilities of a series of energetic bridged di-1,3,5-triazine derivatives with different substituents and linkages were studied using density functional theory. It was found that the groups -N(3) and -N=N- are effective structural units for improving the HOF values of the di-1,3,5-triazine derivatives. The effects of the substituents on the HOMO-LUMO gap combine with those of the bridge groups. The calculated detonation velocities and detonation pressures indicate that substituting the -ONO(2), -NF(2), or -N=N- group is very useful for enhancing the detonation performance of these derivatives. Analysis of the bond dissociation energies for several relatively weak bonds suggests that most of the derivatives have good thermal stability. On the whole, the -NH(2), N(3), -NH-, and -CH=CH- groups are effective structural units for increasing the thermal stabilities of the derivatives. Based on detonation performance and thermal stability, nine of the compounds can be considered potential candidates for high energy density materials with reduced sensitivity. PMID- 22212735 TI - Mechanism of electron transfer processes photoinduced by lumazine. AB - UV-A (320-400 nm) and UV-B (280-320 nm) radiation causes damage to DNA and other biomolecules through reactions induced by different endogenous or exogenous photosensitizers. Lumazines are heterocyclic compounds present in biological systems as biosynthetic precursors and/or products of metabolic degradation. The parent and unsubstituted compound called lumazine (pteridine-2,4(1,3H)-dione; Lum) is able to act as photosensitizer through electron transfer-initiated oxidations. To get further insight into the mechanisms involved, we have studied in detail the oxidation of 2'-deoxyadenosine 5'-monophosphate (dAMP) photosensitized by Lum in aqueous solution. After UV-A or UV-B excitation of Lum and formation of its triplet excited state ((3)Lum*), three reaction pathways compete for the deactivation of the latter: intersystem crossing to singlet ground state, energy transfer to O(2), and electron transfer between dAMP and (3)Lum* yielding the corresponding pair of radical ions (Lum(-) and dAMP(+)). In the following step, the electron transfer from Lum(-) to O(2) regenerates Lum and forms the superoxide anion (O(2)(-)), which undergoes disproportionation into H(2)O(2) and O(2). Finally dAMP(+) participates in subsequent reactions to yield products. PMID- 22212736 TI - The post-fracture care gap among Canadian First Nations peoples: a retrospective cohort study. AB - Despite targeted attempts to reduce post-fracture care gaps, we hypothesized that a larger care gap would be experienced by First Nations compared to non-First Nations people. First Nations peoples were eight times less likely to receive post-fracture care compared to non-First Nations peoples, representing a clinically significant ethnic difference in post-fracture care. INTRODUCTION: First Nations peoples are the largest group of aboriginal (indigenous or native) peoples in Canada. Canadian First Nations peoples have a greater risk of fracture compared to non-First Nations peoples. We hypothesized that ethnicity might be associated with a larger gap in post-fracture care. METHODS: Non-traumatic major osteoporotic fractures for First Nations and non-First Nations peoples aged >= 50 years were identified from a population-based data repository for Manitoba, Canada between April 1996 and March 2002. Logistic regression analysis was used to examine the probability of receiving a BMD test, a diagnosis of osteoporosis, or beginning an osteoporosis-related drug in the 6 months post-fracture. RESULTS: A total of 11,234 major osteoporotic fractures were identified; 502 occurred in First Nations peoples. After adjustment for confounding covariates, First Nations peoples were less likely to receive a BMD test [odds ratio (OR) 0.1, 95% confidence interval (CI), 0.0-0.5], osteoporosis-related drug treatment (OR, 0.5; 95% CI, 0.3-0.7), or a diagnosis of osteoporosis (OR, 0.5; 95% CI, 0.3-0.7) following a fracture compared to non-First Nations peoples. Females were more likely to have a BMD test (OR, 5.0; 95% CI, 2.6-9.3), to be diagnosed with osteoporosis (OR, 1.7; 95% CI, 1.5-2.0), and to begin drug treatment (OR, 4.1; 95% CI, 2.7-6.4) compared to males. CONCLUSIONS: An ethnicity difference in post fracture care was observed. Further work is needed to elucidate underlying mechanisms for this difference and to determine whether failure to initiate treatment originates with the medical practitioner, the patient, or a combination of both. It is imperative that all residents of Manitoba receive efficacious and equal care post-fracture, regardless of ethnicity. PMID- 22212737 TI - Transmission of pandemic influenza H1N1 (2009) in Vietnamese swine in 2009-2010. AB - BACKGROUND: The pandemic of 2009 was caused by an H1N1 (H1N1pdm) virus of swine origin. This pandemic virus has repeatedly infected swine through reverse zoonosis, although the extent of such infection in swine remains unclear. OBJECTIVE: This study targets small and commercial pig producers in North Vietnam, in order to estimate the extent of H1N1pdm infection in swine and to identify the risk factors of infection. METHODS: Virologic and serologic surveillance of swine was carried out in 2009-2010 in pig farms (38 swabs and 1732 sera) and at a pig slaughterhouse (710 swabs and 459 sera) in North Vietnam. The sera were screened using a influenza type A-reactive ELISA assay, and positive sera were tested using hemagglutination inhibition tests for antibody to a panel of H1-subtype viruses representing pandemic (H1N1) 2009 (H1N1pdm), triple reassortant (TRIG), classical swine (CS), and Eurasian avian-like (EA) swine lineages. Farm-level risk factors were identified using a zero-inflated negative binomial model. RESULTS: We found a maximal seroprevalence of H1N1pdm of 55.6% [95% CI: 38.1-72.1] in the slaughterhouse at the end of December 2009, 2 weeks after the peak of reported human fatalities with H1N1pdm. Farm-level seroprevalence was 29% [95% CI: 23.2-35.7]. In seropositive farms, within-herd seroprevalence ranged from 10 to 100%. We identified an increased risk of infection for farms that specialized in fattening and a decreased risk of infection in farms hiring external swine workers. CONCLUSIONS: Our findings suggest extensive reverse-zoonotic transmission from humans to pigs with subsequent onward transmission within pig herds. PMID- 22212738 TI - Endobronchial ultrasound plus fluoroscopy versus fluoroscopy-guided bronchoscopy: a comparison of diagnostic yields in peripheral pulmonary lesions. AB - BACKGROUND: Even though fluoroscopy-guided bronchoscopy has been well developed, the diagnostic yield of peripheral pulmonary lesions (PPLs) remains unsatisfying. Therefore, endobronchial ultrasound (EBUS) has been implemented recently to enhance the possibility of attaining true diagnosis. However, there are few studies that directly compare the success rate of fiber-optic bronchoscopy with fluoroscopic guidance to that of EBUS guidance in the diagnosis of PPLs in the same institute and in the same study period. The aim of this study was to compare the performance of EBUS plus fluoroscopy guidance with that of fluoroscopy-guided bronchoscopy in the diagnosis of PPLs. METHODS: A retrospective study was conducted on 114 patients who were diagnosed with PPLs and underwent either EBUS plus fluoroscopy or fluoroscopy-guided bronchoscopy. The diagnostic yields of both modalities were calculated. RESULTS: The mean diameter of the PPLs measured by computed tomography of the chest was 23.7 mm. EBUS plus fluoroscopy obtained higher diagnostic yield than fluoroscopy-guided bronchoscopy (82.5 vs. 57.9%; P = 0.004). Subgroup analysis demonstrated that for PPLs larger than 20 mm, the accuracy of EBUS plus fluoroscopy was not different from that of the fluoroscopy guided technique (85.7 vs. 72.2%, respectively; P = 0.19). In contrast, for lesions smaller than 20 mm, EBUS plus fluoroscopy guidance provided significantly greater diagnostic performance than fluoroscopy-guided bronchoscopy (79.3 vs. 33.3%; P = 0.001). CONCLUSIONS: Bronchoscopy under EBUS and fluoroscopy guidance improved the diagnostic yield of PPLs, especially of those smaller than 20 mm in diameter. PMID- 22212739 TI - Solubility limits and phase diagrams for fatty acids in anionic (SLES) and zwitterionic (CAPB) micellar surfactant solutions. AB - The limiting solubility of fatty acids in micellar solutions of the anionic surfactant sodium laurylethersulfate (SLES) and the zwitterionic surfactant cocamidopropyl betaine (CAPB) is experimentally determined. Saturated straight chain fatty acids with n=10, 12, 14, 16, and 18 carbon atoms were investigated at working temperatures of 25, 30, 35, and 40 degrees C. The rise of the fatty acid molar fraction in the micelles is accompanied by an increase in the equilibrium concentration of acid monomers in the aqueous phase. Theoretically, the solubility limit is explained with the precipitation of fatty acid crystallites when the monomer concentration reaches the solubility limit of the acid in pure water. In agreement with theory, the experiment shows that the solubility limit is proportional to the surfactant concentration. For ideal mixtures, the plot of the log of solubility limit vs. the chainlength, n, must be a straight line, which is fulfilled for n=14, 16, and 18. For the fatty acids of shorter chains, n=10 and 12, a deviation from linearity is observed, which is interpreted as non ideal mixing due to a mismatch between the chainlengths of the surfactant and acid. The data analysis yields the solubilization energy and the interaction parameter for the fatty acid molecules in surfactant micelles. By using the determined parameter values, phase diagrams of the investigated mixed solutions are constructed. The four inter-domain boundary lines intersect in a quadruple point, whose coordinates have been determined. The results can be applied for the interpretation and prediction of the solubility, and phase behavior of medium- and long-chain fatty acids and other amphiphiles that are solubilizable in micellar surfactant solutions, as well as for determining the critical micellization concentration (CMC) of the respective mixed solution. PMID- 22212740 TI - Using the neurotransmitter serotonin to target imaging agents to glioblastoma cells. AB - The neurotransmitter serotonin is involved in numerous bodily functions via seven different serotonin receptor subfamilies. Serotonin plays a role in gastrointestinal functions like intestinal secretion or peristalsis and neuropsychiatric events like depression or migraine. One of these subtypes has been found on glioblastoma cells, inducing growth promotion. In our study we attempted to target imaging agents to glioblastoma cells via the serotonin receptor. For this we coupled serotonin to the fluorescent dye rhodamine and the magnetic resonance imaging contrast agent gadolinium (Gd)-1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The cellular uptake, cytotoxicity and detection sensitivity of the conjugates were evaluated by confocal laser scanning microscopy (CLSM), cell growth analysis, flow cytometry and magnetic resonance relaxometry on U373 human glioblastoma cells. Receptor dependency of the uptake was confirmed by competition experiments with excess of unmarked serotonin. Cellular uptake of the conjugates was found in CLSM, magnetic resonance relaxometry and flow cytometry experiments.CLSM revealed the cytoplasmic character of the uptake. In cell growth analysis experiments no adverse effect of either conjugate on the cells was observed. Competition experiments performed with the conjugates and unmarked serotonin showed decreased conjugate uptake compared to the experiments without competition. In conclusion the neurotransmitter serotonin could be successfully used to target imaging agents into human glioblastoma cells. This makes it of interest for future glioblastoma imaging methods. PMID- 22212742 TI - Flexible sigmoidoscopy does not significantly increase polyp and cancer detection yield when used to supplement CT colonography. AB - BACKGROUND AND AIMS: Flexible sigmoidoscopy (FS) increases polyp and carcinoma detection in addition to double contrast barium enema (DCBE). However, CT colonography (CTC) is now the preferred technique. Our aim was to explore whether FS increases polyp and carcinoma detection rates when used in addition to CTC. METHODS: Patients who underwent FS and CTC between 2007 and 2009 were included and data were collected from patient records. Yields of polyp, adenoma and carcinoma detection were calculated for FS and CTC. RESULTS: In a cohort of 294 patients, CTC detected 36 patients with carcinomas while FS detected 28. One rectal cancer not seen on CTC was diagnosed by FS. Polyps were seen by CTC in 66 and FS in 45 patients. In 5 patients FS found polyps that were not detected by CTC; 3 of which were small adenomas. FS detected extra adenomas or carcinomas in 1.36% (4/294). Adding FS to CTC neither increased the cancer nor the polyp detection yield significantly. CONCLUSIONS: This first study investigating the use of FS in addition to CTC detected little additional pathology. The routine use of FS as a supplement to CTC for adenoma and carcinoma detection is of questionable utility. PMID- 22212743 TI - The translocation selectivity of the kinesins that mediate neuronal organelle transport. AB - Polarized kinesin-driven transport is crucial for development and maintenance of neuronal polarity. Kinesins are thought to recognize biochemical differences between axonal and dendritic microtubules in order to deliver their cargoes to the appropriate domain. To identify kinesins that mediate polarized transport, we prepared constitutively active versions of all the kinesins implicated in vesicle transport and expressed them in cultured hippocampal neurons. Seven kinesins translocated preferentially to axons and five translocated into both axons and dendrites. None translocated selectively to dendrites. Highly homologous members of the same subfamily displayed distinctly different translocation preferences and were differentially regulated during development. By expressing chimeric kinesins, we identified two microtubule-binding elements within the motor domain that are important for selective translocation. We also discovered elements in the dimerization domain of kinesin-2 motors that contribute to their selective translocation. These observations indicate that selective interactions between kinesin motor domains and microtubules can account for polarized transport to the axon, but not for selective dendritic transport. PMID- 22212744 TI - Clinical utility of IgE antibodies to omega-5 gliadin in the diagnosis of wheat allergy: a pediatric multicenter challenge study. AB - BACKGROUND: There are contradictory results regarding the clinical usefulness of the determination of IgE antibodies to omega-5 gliadin in children with a suspicion of wheat allergy (WA). METHODS: The study comprised 311 children and young adults with suspected wheat intolerance treated at three separate pediatric clinics and, with the exception of 25, were found to be positive in specific IgE antibody determinations to wheat. Their ages ranged from 6 months to 20.4 years (median age, 2.3 years). Possible relationships between IgE antibodies to omega-5 gliadin and a physician's diagnosis of WA and challenge symptoms were studied. RESULTS: The mean concentration of IgE antibodies to omega-5 gliadin was 1.2 kU(A)/l in WA patients and <0.35 kU(A)/l in patients without WA (p < 0.0001). Seventy-two percent of the WA patients had positive omega-5 gliadin levels and 75% of the patients without WA had negative levels. Logistic regression showed a significant relationship between the probability of WA and the concentration of IgE antibodies to omega-5-gliadin with a 2.6-fold (95% CI: 2.0-3.3) increased risk. Age was an important factor to consider as the risk of WA increased 5.4 fold (95% CI: 1.4-21) for children <=1 year of age and 2.5-fold (95% CI: 2.0-3.2) for children >1 year of age with increasing levels of IgE. CONCLUSION: Detection of IgE to omega-5 gliadin seems to be associated with responsiveness to the challenge test and is particularly useful in infants with a suspicion of WA. PMID- 22212745 TI - Effect of vitamin D on insulin sensitivity in elderly patients with impaired fasting glucose. AB - AIM: Recent data has shown that vitamin D increases insulin sensitivity; however, there is little evidence about the effects of this treatment on elderly people with impaired fasting glucose. The aim of the present study was to investigate the effect of vitamin D treatment on insulin sensitivity and metabolic parameters in elderly people with impaired fasting glucose. METHODS: A total of 28 elderly patients were enrolled into the vitamin D treatment group. The control group included 23 age-, sex- and body mass index-matched elderly participants. The vitamin D treatment group was treated with vitamin D(3) according to serum concentrations of 25(OH)D. RESULTS: With supplementation, 96.0% of patients achieved a mean serum 25(OH)D concentration of 123.2 +/- 59.9 nmol/L. After 4.7 +/- 2.5 months of treatment, there was a significant decrease in homeostasis model assessment of insulin resistance, insulin and glucose concentrations in the vitamin D treatment group (P = 0.007, P = 0.007, P = 0.037, respectively). Vitamin D treatment significantly increased high-density lipoprotein cholesterol (P = 0.037), but did not cause statistically significant differences in other lipid parameters. CONCLUSION: We found that vitamin D treatment might modify insulin sensitivity in the elderly with impaired fasting glucose. PMID- 22212747 TI - DNA damage induced by mammography in high family risk patients: only one single view in screening. AB - Women with high risk of breast or ovarian cancers might be more susceptible to radiation-induced cancer because most of tumor suppressor genes are also implicated in the radio-induced DNA damage repair and signaling. Recent radiobiological advances may help to re-consider the potential cellular and molecular consequences of the standard two-view mammographic screening. A major radiobiological effect exacerbated in high family risk women caused by mammographic repeated doses was pointed out on relevant cellular model (untransformed and non tumoral human breast epithelial cells): the Low and Repeated Dose (LORD) effect. In parallel, while magnetic resonance imaging (MRI) is reported to be less sensitive than mammography for detection of ductal carcinoma in situ, a recent study highlighted the increased ability of MRI to detect them related to the experience both of radiologists and MRI centers. Hence, along with studies confirming improvement of the sensitivity of MRI to detect ductal carcinoma in situ, the supra-additivity effect induced by the two view mammographic screening in high family risk patients suggests that mammographic exposures can be limited seriously. Consequently, a single view (oblique) per breast in association with annual MRI, with the sole aim to detect calcifications reflecting carcinoma in situ non detectable by MRI, might represent currently a compromise. PMID- 22212748 TI - [Comparison of the image quality of a storage phospor system and a flat-panel detector in feline thoracic radiography]. AB - OBJECTIVE: The aim of the study was to compare the image quality of radiographs obtained with a storage phosphor (SP) system and a flat-panel detector (FD). Furthermore, the influence of different exposure settings was investigated. MATERIAL AND METHODS: In a prospective study a series of lateral thoracic radiographs of 45 normal cats were acquired by use of a standard SP-system and an opto-direct FD. From each animal four radiographs were taken with exposure settings adjusted to achieve sensitivity (S)-values of the system-specific dose indicator of S180 and S360. In a blind study, five observers rated the presentation of anatomical structures (trachea, cranial lung field, sternum, cardiac silhouette, caudal thoracic field) by use of a four-point scale (1 - excellent; 4 - insufficient). RESULTS: Independent of the detector-type and the exposure level applied the mean values of the ratings of the respective image criteria ranged from 1.14 to 1.67. In both systems higher doses related to better rating results. While comparing the detectors on the basis of identical exposure settings the FD demonstrated superior performance. CONCLUSION AND CLINICAL RELEVANCE: At the dose levels investigated both detectors reveal an image quality sufficient for the depiction of subtle, low-contrast thoracic structures in cats. Therefore, the detectors can be recommended for practical use in small animal radiology. In both systems a dose reduction of 50% in comparison to the original level (S180) is possible without a substantial loss of information. Because of the superior quantum efficiency the dose saving potential of the FD might be even higher. Alternatively, the higher dose efficiency can be utilised to improve image quality in comparison to the SP-system with identical exposure settings. PMID- 22212746 TI - Biopsy of liver metastasis for women with breast cancer: impact on survival. AB - BACKGROUND: Biopsy of metastatic site of disease can influence treatment decisions, but its impact on survival remains uncertain. PATIENTS AND METHODS: One-hundred patients with first metachronous liver metastases (LM) from breast cancer (BC) who underwent liver biopsy between 1999 and 2009 were identified. One hundred matched control patients with LM from BC and no biopsy were selected. RESULTS: Liver biopsy had no statistically significant impact on survival when comparing biopsied patients to controls [HR 0.82 (95% CI 0.58-1.16)]. Patients with early metastasis (within 3 years) undergoing liver biopsy had a better survival [HR 0.60 (95% CI 0.38-0.97)] compared to those who did not. Liver biopsy had no statistically significant impact on survival in patients with late LM (after 3 years) [HR 1.09 (95% CI 0.69-1.74)]. We observed that 18 out of 100 biopsied patients (18.0%) had a conversion of predictive factors which allowed adjusting for therapy, specifically new expression of ER (n=5), overexpression of HER2 (n=12) or both (n=1). Fourteen out of 18 (77.8%) received anti-HER2 treatment for the first time at the time of metastasis and 3 others (16.7%) received hormone therapy. Those 18 patients showed a better survival compared to the other 82 biopsied patients [HR 0.55 (95% CI 0.28-1.10)] and compared to the 13 biopsied patients with disappearance of features which predicted responsiveness to a given treatment [HR 0.19 (95% CI 0.06-0.62)]. CONCLUSIONS: Liver biopsy can impact survival of patients with early metastases from BC. Discordance between primary and distant lesions can offer the patients new treatment options. PMID- 22212749 TI - [Tonsillar squamous cell carcinoma in the dog. A retrospective study of 33 cases]. AB - OBJECTIVE: Retrospective evaluation of clinical findings in 33 dogs with tonsillar squamous cell carcinomas. MATERIAL AND METHODS: At the owners' request 9 patients were euthanized after diagnosis. 24 treated patients were grouped into six categories depending on the type of therapy: 1. tonsillectomy and NSAID (Piroxicam or Metacam) (n=10); 2. tonsillectomy, NSAID, and palliative radiation (24-30Gy in 3-5 fractions) (n=4); 3. tonsillectomy, NSAID, palliative radiation, and chemotherapy (5' Carboplatin 280-300mg/m2 BSA) (n=3); 4. NSAID, palliative radiation, and chemotherapy (n=1); 5. NSAID alone (n=5), 6. tonsillectomy alone (n=1). RESULTS: There were no breed predispositions but medium sized (10-20kg; 43%) and large dogs (>20kg; 20%), and males (n=22; 71%) were overrepresented. The average age was 10.7years (range, 6.5-14.5years). At the first presentation, 22 of the 33 dogs (67%) had lymph node metastasis. None of the dogs had lung metastasis at the time of diagnosis, as determined by three view chest X-rays. The best survival times (ST) were achieved in groups 2 and 3 with three of seven patients living longer than 1year. Patients without lymph node metastasis had a trend for longer survival times, independent of the type of therapy. Treated patients with lymph node metastasis (n=17) had a mean and median ST of 9.5 and 4months, respectively. Only two dogs survived longer than 1year. Dogs without lymph node metastasis had a mean and median ST of 17.7 and 12 months, respectively; the ST for four of the eight dogs exceeded 1year, two survived longer than 2years. CONCLUSION: It could be confirmed that tonsillar squamous cell carcinomas are aggressive tumours with a high rate of cervical lymph node metastasis. In most cases with metastasis the survival times were relatively short, irrespective of treatment. In early stages of the disease however, good survival times could be achieved using surgical debulking followed by multimodality treatment. CLINICAL RELEVANCE: In squamous cell carcinoma of the tonsils thorough staging is mandatory due to the high metastatic potential of the tumour. Verification of metastasis carries a poor prognosis. Further studies are required to find the best treatment (combination) for these patients. PMID- 22212750 TI - [Selenium level in the sera of dogs and cats in West Pomerania and WestUkraine]. AB - OBJECTIVE: Main function of the trace element selenium is the protection of the body against free radicals by means of the selenium-containing enzyme glutathione peroxidase acting as an intracytoplasmatic antioxydant. This study determined serum selenium concentration in dogs and cats from West Pomerania, Poland, and West Ukraine (Lviv region). MATERIAL AND METHODS: Serum samples were obtained from 74 dogs and 42 cats. 49 dogs and 20 cats were from West Pomerania, and 25 dogs and 22 cats from West Ukraine. Selenium concentrations were determined with a spectrofluorometric method according to Watkinson (1966), modified by Grzebula et al. (1977). RESULTS: The mean selenium concentrations in dog and cat serum in animals from West Pomerania were 2.927 and 6.169MUmol/l, respectively and exceeded the serum selenium concentration in dogs and cats from West Ukraine by 0.687 and 2.053MUmol/l, respectively. Statistically significant differences in selenium concentration were observed between healthy animals (3.842MUmol/l) and those with symptoms of allergy (3.240MUmol/l) or dogs with neoplasias (1.749MUmol/l). No statistical differences in serum selenium concentration were related to age and to sex. CONCLUSION: This research shows that in dogs with neoplasias, serum selenium concentration was about 45% lower than in healthy dogs. CLINICAL RELEVANCE: In patients with selenium deficiency supplementation of selenium might have a positive impact on the course of diseases like neoplasia, heart insufficiency, liver necrosis, myopathy, and pancreatitis. PMID- 22212751 TI - [Acceptance of case-based, interactive e-learning in veterinary medicine on the example of the CASUS system]. AB - OBJECTIVE: New teaching methods such as e-learning, are increasingly used to support common methods such as lectures, seminars and practical training in universities providing education in veterinary medicine. In the current study, the acceptance of e-learning in the example of the CASUS system by veterinarians as well as students of veterinary medicine of all German-speaking universities was analyzed. Material und methods: For this purpose an online evaluation questionnaire was developed. Members of the target groups were informed by e-mail and references in professional journals, as well as through veterinarian exchange platforms on the internet. Additionally, 224 students' final anatomy marks were compared and correlated to the utilization of CASUS to gain an important insight for the development of new teaching practices in the teaching of veterinary medicine. RESULTS: In total 1581 questionnaires were evaluated. A good acceptance regarding new teaching practices was found, although the classical textbook is still the most important instrument for imparting knowledge. The degree of utilization of e-learning strongly depends on its integration into the teaching content. CASUS is regarded as an efficient teaching method, with over 90% of the respondents indicating a strong desire to expand the number of case studies. Due to the present low degree of integration into the teaching content, no significant correlation could be found between the utilization of anatomy case studies and the final anatomy mark. However, based on their subjective perception, the students reported a high level of success in their study results with the likely effect of supporting increasing self-assurance in the situation of examinations. CONCLUSION: With the help of e-learning, educational objectives can be achieved that are not attainable by traditional teaching methods, e.g. the review of individual improvements by using the integrated feedback-function of e learning programs. However, e-learning is not able to completely replace current teaching practices and hence should be considered as an additional element in future teaching models. PMID- 22212752 TI - [Luteal insufficicency in the bitch - symptoms, diagnosis, consequences and therapy. A review of the literature]. AB - Insufficient progesterone synthesis, so called hypoluteoidism or luteal insufficiency, is one of the possible reasons for infertility in the bitch. Confirming this diagnosis may be difficult if the dynamic changes of progesterone during the reproductive cycle are not taken into account. The bitch ovulates at progesterone concentrations of about 5-10ng/ml (15.7-31.4 nmol/L). The concentrations increase to >25ng/mL (78.5 nmol/L) within 3-4 weeks and then subsequently decrease after a plateau of 7-14 days. In the pregnant bitch, progesterone rapidly drops to <2ng/ml (6.3 nmol/L) approximately 24-48 hours before parturition induced by PGF2alpha secretion. Luteal insufficiency, characterized as an early decrease of progesterone secretion, is most commonly observed between days 20 and 35 of pregnancy. Progesterone concentrations of approximately 2ng/ml (6.3nmol/L) are thought to be necessary for maintaining pregnancy. Lower concentrations result in resorption and abortion, respectively. In bitches suspected to have luteal insufficiency, weekly progesterone determinations using quantitative tests should be performed from 5-7 days after mating or at least from the date of early pregnancy diagnosis. The frequency has to be increased in the case of progesterone concentrations below 10ng/ml (31.4 nmol/L). Progesterone administration is indicated in the case of viable foetuses and progesterone concentrations <5 ng/ml (15.7 nmol/L) before day 58/60 of pregnancy or after the detection of a rapid progesterone decline of about 10 15ng/ml (31.4-47.1 nmol/L) between days 20 and 35 with viable foetuses in the sonographic examination. Either natural or synthetic progestins can be used. However, synthetic progestins have a greater risk potential for side effects (masculinisation of female puppies and cryptorchidism in male puppies), especially when administered between days 20 and 35 of pregnancy. Administration of natural progesterone should be stopped 2-3 days before expected parturition otherwise it would result in a prolonged duration of pregnancy with dystocia and stillbirth. PMID- 22212753 TI - Sertoli Leydig cell tumour in a bitch, 10 years after spaying. A case report. PMID- 22212754 TI - Ileocolic intestinal intussusception in a dog with leptospirosis. PMID- 22212755 TI - [Diagnosis of permethrin intoxication in the cat by use of a toxicological screening]. PMID- 22212756 TI - [Chronic regurgitation in the budgerigar - a diagnostic and therapeutic challenge]. PMID- 22212757 TI - Capture antibody targeted fluorescence in situ hybridization (CAT-FISH): dual labeling allows for increased specificity in complex samples. AB - Pathogen detection using biosensors is commonly limited due to the need for sensitivity and specificity in detecting targets within mixed populations. These issues were addressed through development of a dual labeling method that allows for both liquid-phase fluorescence in situ hybridization (FISH) and capture antibody targeted detection (CAT-FISH). CAT-FISH was developed using Escherichia coli O157:H7 and Staphylococcus aureus as representative bacteria, and processing techniques were evaluated with regard to FISH intensities and antibody recognition. The alternative fixative solution, methacarn, proved to be superior to standard solid-phase paraformaldehyde fixation procedures, allowing both FISH labeling and antibody recognition. CAT-FISH treated cells were successfully labeled with FISH probes, captured by immunomagnetic separation using fluorescent cytometric array beads, and detected using a cytometric array biosensor. CAT-FISH treated cells were detectable with LODs comparable to the standard antibody-based technique, (~10(3)cells/ml in PBS), and the technique was also successfully applied to two complex matrices. Although immunomagnetic capture and detection using cytometric arrays were demonstrated, CAT-FISH is readily applicable to any antibody-based fluorescence detection platform, and further optimization for sensitivity is possible via inclusion of fluorescently tagged antibodies. Since the confidence level needed for positive identification of a detected target is often paramount, CAT-FISH was developed to allow two separate levels of specificity, namely nucleic acid and protein signatures. With proper selection of FISH probes and capture antibodies, CAT-FISH may be used to provide rapid detection of target pathogens from within complex matrices with high levels of confidence. PMID- 22212758 TI - A specific statistical model and algorithm related to the detection of Mollicutes in contaminated biological samples by Real-Time Transcription Mediated Amplification. AB - Among all nucleic acid amplification technologies, Real-Time Transcription Mediated Amplification (Real-Time TMA) is an isothermal method that can amplify RNA targets a billion-fold in less than one hour's time. By using this method, a new assay was developed for detecting the presence of Mollicutes in mammalian cell cultures and biologics. Production of amplicons is monitored in real time by measuring continuously a fluorescence signal during the reaction. The shape of this signal curve is a sigmoid, where an initial baseline phase precedes an exponential phase ending with a maximum followed by a linear decreasing phase. The aim of this study was to develop a curve-analysis tool to unambiguously assign a Mollicutes positive or negative status to a biological sample. In this context, a statistical analysis of the data combined with the selection of the best predictors allowed the development of an algorithm which removes erroneous data and applies the best predictors to generate the Mollicutes status prediction. Our results demonstrate that this algorithm assigns positive/negative/invalid status coming from Real-Time TMA fluorescence signal analysis with a confidence (true predictions) in the results close to 100%. PMID- 22212759 TI - Standardizing methylation method during phospholipid fatty acid analysis to profile soil microbial communities. AB - Phospholipid fatty acid (PLFA) as biomarkers, is widely used to profile microbial communities in environmental samples. However, PLFA extraction and derivatization protocols are not standardized and have widely varied among published studies. Specifically investigators have used either HCl/MeOH or KOH/MeOH or both for the methylation step of PLFA analysis, without justification or research to support either one. It seems likely that each method could have very different outcomes and conclusions for PLFA based studies. Therefore, the objective of this study was to determine the effect of catalyst type for methylation on detecting PLFAs and implications for interpreting microbial profiling in soil. Fatty acid samples extracted from soils obtained from a wetland, an intermittently flooded site, and an adjacent upland site were subjected to HCl/MeOH or KOH/MeOH catalyzed methylation procedures during PLFA analyses. The methylation method using HCl/MeOH resulted in significantly higher concentrations of most PLFAs than the KOH/MeOH method. Another important outcome was that fatty acids with a methyl group (18:1omega,7c 11Me, TBSA 10Me 18:0, 10Me 18:0, 17:0 10Me and 16:0 10Me being an actinomycetes biomarker) could not be detected by HCl/MeOH catalyzed methylation but were found in appreciable concentrations with KOH/MeOH method. From our results, because the HCl/MeOH method did not detect the fatty acids containing methyl groups that could strongly influence the microbial community profile, we recommend that the KOH/MeOH catalyzed transesterification method should become the standard procedure for PLFA profiling of soil microbial communities. PMID- 22212760 TI - Evaluation of propidium monoazide (PMA) treatment directly on membrane filter for the enumeration of viable but non cultivable Legionella by qPCR. AB - A PMA (propidium monoazide) pretreatment protocol, in which PMA is applied directly to membrane filters, was developed for the PCR-based quantification (PMA qPCR) of viable Legionella pneumophila. Using this method, the amplification of DNA from membrane-damaged L. pneumophila was strongly inhibited for samples containing a small number of dead bacteria. PMID- 22212761 TI - Identification of F-box only protein 7 as a negative regulator of NF-kappaB signalling. AB - The nuclear factor kappaB (NF-kappaB) signalling pathway controls important cellular events such as cell proliferation, differentiation, apoptosis and immune responses. Pathway activation occurs rapidly upon TNFalpha stimulation and is highly dependent on ubiquitination events. Using cytoplasmic to nuclear translocation of the NF-kappaB transcription factor family member p65 as a read out, we screened a synthetic siRNA library targeting enzymes involved in ubiquitin conjugation and de-conjugation for modifiers of regulatory ubiquitination events in NF-kappaB signalling. We identified F-box protein only 7 (FBXO7), a component of Skp, Cullin, F-box (SCF)-ubiquitin ligase complexes, as a negative regulator of NF-kappaB signalling. F-box protein only 7 binds to, and mediates ubiquitin conjugation to cIAP1 and TRAF2, resulting in decreased RIP1 ubiquitination and lowered NF-kappaB signalling activity. PMID- 22212763 TI - Postlingually deaf adults of all ages derive equal benefits from unilateral multichannel cochlear implant. AB - BACKGROUND: Controversy still exists regarding the impact of age on speech recognition following cochlear implant in postlingually deaf adults. In some studies elderly recipients did not perform as well as younger patients on standard speech recognition tests. Furthermore, previous studies have shown that cochlear implantation improves quality of life, as measured by self-administered questionnaires, but the sample sizes of these studies have been relatively small, thus making age stratification a challenge. PURPOSE: The primary objective was to assess whether the age at which a patient receives a unilateral cochlear implant affects improvements in speech recognition scores and perceived quality of life. A secondary objective was to determine whether preoperative use of hearing aids correlates with improvement in speech recognition and perceived quality of life after cochlear implantation. RESEARCH DESIGN: A retrospective study in a tertiary referral center. PATIENTS: A total of 161 postlingually deaf adults, who were divided based on age (<50, 50-65, >65) and on prior hearing aid(s) use. INTERVENTION: All patients received a unilateral multichannel cochlear implant. DATA COLLECTION AND ANALYSIS: Speech recognition was quantified by percent correct scores on the Hearing in Noise Test sentences delivered in a quiet setting only (HINT%), and quality of life was quantified by the Hearing Handicap Inventory (HHI) before and 1 yr after cochlear implantation. RESULTS: Speech recognition, as measured by HINT%, improved significantly and to similar extents in all three age groups following cochlear implantation. Similarly, quality of life as quantified by HHI improved markedly and to similar extents in all age groups. Whether hearing aids were used pre-implant, or whether the cochlear implant (CI) was implanted on the same side or contralateral to the hearing aid side, had no substantial effect on the patients' performances on either speech recognition or quality of life. Moreover, there were no statistically significant correlations between pre-implant speech recognition scores and pre-implant quality of life scores or between postimplant speech recognition scores and postimplant quality of life scores. CONCLUSION: The findings of the present study demonstrate that cochlear implantation improves HINT% and HHI scores to similar extents across all age groups. This finding suggests that elderly patients may derive speech recognition and quality of life benefits similar to those of younger patients and that age should not be an essential factor in the determination of CI candidacy. Furthermore, prior use of a hearing aid, and its location in relation to the cochlear implant, does not influence the extent of improvement in speech recognition or quality of life measurements following cochlear implantation. PMID- 22212765 TI - A randomized, controlled trial of the short-term effects of complementing an educational program for hearing aid users with telephone consultations. AB - BACKGROUND: Audiologic rehabilitation aims to improve communication for people with hearing impairment. Education is widely regarded as an integral part of rehabilitation, but the effect of the delivery method of an educational program on the experience of hearing problems has rarely been investigated in controlled trials. PURPOSE: The purpose of this study was to examine the short-term effects of complementing an educational program for hearing aid users with telephone consultations, delivered through weekly discussions with the subjects about information obtained from a book on hearing and hearing aids. RESEARCH DESIGN: This study used a randomized, controlled design. STUDY SAMPLE: In total, 69 hearing aid users were randomly assigned to an intervention group (n = 33) or a control group (n = 36). INTERVENTION: The intervention group had access to a book and received weekly topic-based reading instructions related to the different chapters of the book. Five telephone calls were made to the members of the intervention group. During the calls, an audiologist discussed new information with the participant as needed. The control participants also read the book, but they did not discuss the contents of the book with a professional. DATA COLLECTION AND ANALYSIS: The Hearing Handicap Inventory for the Elderly (HHIE), the Hospital Anxiety and Depression Scale (HADS), and the International Outcome Inventory for Hearing Aids (IOI-HA) were used to measure the outcomes of this study. RESULTS: Participants in the intervention group had a reduction in self reported hearing handicap, while there were no significant changes in the control group. In the intervention group, 45% of the participants showed an improvement of >=36% on the HHIE, while only 17% of the control group showed an improvement of >=36%. There were also improvements on the HADS total and the depression subscale for the intervention group. No changes occurred on the IOI-HA. CONCLUSIONS: Reading about hearing and hearing aids can reduce the hearing handicap and reported anxiety in hearing aid users. In this study, discussing the content of the book that was provided with a professional during weekly telephone consultations and having weekly home assignments further improved emotional well being, as demonstrated by the HHIE (emotional scale) and HADS (depression scale), but these activities had no effect on hearing aid outcomes as measured by the IOI HA. PMID- 22212764 TI - The HEAR-QL: quality of life questionnaire for children with hearing loss. AB - BACKGROUND: Few quality of life (QOL) assessment tools are available for children with specific chronic conditions, and none have been designed specifically for children with hearing loss (HL). A validated hearing-related QOL questionnaire could help clinicians determine whether an intervention is beneficial and whether one intervention is better than another. PURPOSE: To examine QOL in children with HL and assess the validity, reliability, and factor structure of a new measure, the Hearing Environments and Reflection on Quality of Life (HEAR-QL) questionnaire. RESEARCH DESIGN: A descriptive and correlational study of a convenience sample of children. STUDY SAMPLE: Participants included 35 children with unilateral HL, 45 with bilateral HL, and 35 siblings with normal hearing. DATA COLLECTION AND ANALYSIS: Children 7-12 yr old were recruited by mail from a tertiary-care pediatric otolaryngology practice and the local county's Special School District. With parent consent, children completed the validated Pediatric Quality of Life InventoryTM (PedsQL) 4.0 and a 35-item HEAR-QL questionnaire. The factor structure of the HEAR-QL was determined through principal components analysis (PCA), and mean scores were computed for each subscale and the total HEAR-QL. Three weeks following the return of the initial questionnaires, a second HEAR-QL questionnaire was sent to participants to assess test-retest reliability. Both PedsQL and HEAR-QL scores were compared between children with and without HL, between children with unilateral and bilateral HL, and between children who used and did not use a hearing device using analysis of variance. Sensitivity and specificity were calculated for both the HEAR-QL and the PedsQL. A multivariable, hierarchical linear regression analysis was conducted with independent variables associated with the HEAR-QL in unadjusted tests. RESULTS: Using exploratory PCA, the 35-item HEAR-QL was reduced to 26 items (Cronbach's alpha = 0.97, sensitivity of 91% and specificity of 92% at a cutoff score of 93.5) loading on three factors: difficulty hearing in certain environments/situations (Environments alpha = 0.97), impact of HL on social/sports activities (Activities alpha = 0.92), and impact of HL on child's feelings (Feelings alpha = 0.88). Sensitivity of 78.8% and specificity of 30.9% at a cutoff score of 69.6 on the PedsQL (at risk for impaired QOL) were lower than for the HEAR-QL. Participants with HL reported significantly lower mean total HEAR-QL scores (71 [SD 18] vs. 98 [SD 5], p < .001), but not mean total PedsQL scores (77 [SD 14] vs. 83 [SD 15], p = .47), than participants with normal hearing. Among children with bilateral HL, children who used a hearing device reported lower mean total HEAR-QL scores (p = .01), but not mean total PedsQL scores (p = .55), than children who did not use a hearing device. The intraclass correlation coefficient for test-retest reliability for the 26-item HEAR-QL total score was 0.83. Hearing status and use of a device were independently associated with the HEAR-QL, and the variables in the model accounted for 46% of the HEAR-QL total score variance. CONCLUSIONS: The HEAR-QL appears to be a valid, reliable, and sensitive questionnaire for children with HL. The HEAR-QL was better able than the PedsQL to distinguish between children with and without HL and can help evaluate interventions for children with HL. PMID- 22212766 TI - Teenage use of portable listening devices: a hazard to hearing? AB - BACKGROUND: Recently, a number of popular media articles have raised some concern that portable listening devices (PLDs) may be increasing the risk for music induced hearing loss (MIHL). However, literature regarding adolescents' listening behavior and how their attitudes and beliefs relate to behavior is currently limited. PURPOSE: The purposes of this study were (1) to investigate the relationship between volume control settings and output levels of PLDs, (2) to examine how adolescents' listening behavior changes as a function of background noise and noise isolation, (3) to investigate the relationship between self reported listening levels and laboratory-measured listening levels, and (4) to evaluate the validity of the Listening Habits Questionnaire as a research tool for evaluating how attitudes and beliefs relate to PLD use behavior. RESEARCH DESIGN: A descriptive study. Experiment 1 evaluated the output levels of a set of PLDs, and Experiment 2 characterized the listening behavior and attitudes toward PLD use of a group of adolescents. STUDY SAMPLE: Twenty-nine adolescents aged 13 17 yr, with normal hearing, participated in Experiment 2. DATA COLLECTION AND ANALYSIS: Experiment 1 evaluated the output levels of a set of PLDs with stock and accessory earphones using an acoustic manikin. Experiment 2 included survey measures of listening behavior and attitudes as well as output levels measured using a probe microphone. CONCLUSIONS: The output levels of PLDs are capable of reaching levels that could increase the risk for MIHL, and 14% of teenagers in this study reported behavior that puts them at increased risk for hearing loss. However, measured listening levels in the laboratory settings did not correlate well with self-reported typical listening levels. Further, the Listening Habits Questionnaire described in this study may provide a useful research tool for examining the relationship between attitudes and beliefs and listening behavior. PMID- 22212767 TI - Development and evaluation of the LiSN & learn auditory training software for deficit-specific remediation of binaural processing deficits in children: preliminary findings. AB - BACKGROUND: The LiSN & Learn auditory training software was developed specifically to improve binaural processing skills in children with suspected central auditory processing disorder who were diagnosed as having a spatial processing disorder (SPD). SPD is defined here as a condition whereby individuals are deficient in their ability to use binaural cues to selectively attend to sounds arriving from one direction while simultaneously suppressing sounds arriving from another. As a result, children with SPD have difficulty understanding speech in noisy environments, such as in the classroom. PURPOSE: To develop and evaluate the LiSN & Learn auditory training software for children diagnosed with the Listening in Spatialized Noise-Sentences Test (LiSN-S) as having an SPD. The LiSN-S is an adaptive speech-in-noise test designed to differentially diagnose spatial and pitch-processing deficits in children with suspected central auditory processing disorder. STUDY SAMPLE: Participants were nine children (aged between 6 yr, 9 mo, and 11 yr, 4 mo) who performed outside normal limits on the LiSN-S. RESEARCH DESIGN: In a pre-post study of treatment outcomes, participants trained on the LiSN & Learn for 15 min per day for 12 weeks. Participants acted as their own control. Participants were assessed on the LiSN-S, as well as tests of attention and memory and a self-report questionnaire of listening ability. Performance on all tasks was reassessed after 3 mo where no further training occurred. INTERVENTION: The LiSN & Learn produces a three dimensional auditory environment under headphones on the user's home computer. The child's task was to identify a word from a target sentence presented in background noise. A weighted up-down adaptive procedure was used to adjust the signal level of the target based on the participant's response. RESULTS: On average, speech reception thresholds on the LiSN & Learn improved by 10 dB over the course of training. As hypothesized, there were significant improvements in posttraining performance on the LiSN-S conditions where the target and distracter stimuli are spatially separated and which specifically evaluate binaural processing ability (p ranging from <.003 to .0001, eta2 ranging from 0.694 to 0.873). In contrast, there was no improvement on the LiSN-S control conditions where the target and distracter stimuli emanate from the same direction (p ranging from .07 to .86, eta2 ranging from 0.362 to 0.004). Significant improvements were found posttraining on measures of memory, on one measure of attention, and on self-reported ratings of listening ability. There were no significant differences between post- and 3 mo posttraining scores on any of the assessment tools. CONCLUSIONS: The initial LiSN & Learn study has shown that children as young as 6 yr of age are able to complete the training (although some coaxing was needed in a minority of cases). Both parents and children have reported benefits from the training, and feedback from the trial has resulted in extra features being added to the software. In order to further evaluate the efficacy of LiSN & Learn to remediate binaural processing deficits in children a clinical trial is currently under way utilizing a randomized blinded control group design. PMID- 22212768 TI - Listening in Spatialized Noise-Sentences Test (LiSN-S): normative and retest reliability data for adolescents and adults up to 60 years of age. AB - BACKGROUND: The Australian version of the Listening in Spatialized Noise Sentences Test (LiSN-S) was originally developed to assess auditory stream segregation skills in children aged 6 to 11 yr with suspected central auditory processing disorder. The LiSN-S creates a three-dimensional auditory environment under headphones. A simple repetition-response protocol is used to assess a listener's speech reception threshold (SRT) for target sentences presented in competing speech maskers. Performance is measured as the improvement in SRT in decibels gained when either pitch, spatial, or both pitch and spatial cues are incorporated in the maskers. PURPOSE: To collect additional normative data on the Australian LiSN-S for adolescents and adults up to 60 yr of age, to analyze the effects of age on LiSN-S performance, to examine retest reliability in the older population, and to extrapolate findings from the Australian data so that the North American version of the test can also be used clinically with older adults. RESEARCH DESIGN: In a descriptive design, normative and test-retest reliability data were collected from adolescents and adults and combined with previously published data from Australian children aged 6 to 11 yr. STUDY SAMPLE: One hundred thirty-two participants with normal hearing aged 12 yr, 0 mo, to 60 yr, 7 mo, took part in the normative data study. Fifty-five participants returned between 2 and 4 mo after the initial assessment for retesting. RESULTS: Analysis of variance revealed a significant effect of age on LiSN-S performance (p < .01 for all LiSN-S measures, etap2 ranging from 0.16 to 0.54). On the low and high cue SRT measures, planned contrasts revealed significant differences between adults and children aged 13 yr and younger, as well as between 50- to 60-yr-olds and younger adults aged 18-29 yr. Whereas there were significant differences between adults and children on the talker, spatial, and total advantage measures, there were no significant differences in performance in adults aged 18-60 yr. There was a small but significant improvement on retest ranging from 0.5 to 1.2 dB across the four LiSN-S test conditions (p ranging from .01 to <.001). However, there was no significant difference between test and retest on the advantage measures (p ranging from .143 to .768). Test-retest differences across all LiSN-S measures were significantly correlated (r ranging from 0.2 to 0.7, p ranging from .023 to <.00000001) and did not differ as a function of age (p ranging from .178 to .980). CONCLUSIONS: As there was no significant difference among adults aged 18-60 yr on the LiSN-S talker, spatial, and total advantage measures, it appears that the decline in ability to understand speech in noise experienced by 50- to 60-yr-olds is not related to their ability to use either spatial or pitch cues. This result suggests that some other factor/s contributes to the decline in speech perception in noise experienced by older adults that is reported in the literature and was demonstrated in this study on the LiSN-S low and high cue SRT measures. PMID- 22212769 TI - Aldosterone inhibits endothelial morphogenesis and angiogenesis through the downregulation of vascular endothelial growth factor receptor-2 expression subsequent to peroxisome proliferator-activated receptor gamma. AB - Angiogenesis plays a pivotal role in cardiovascular diseases such as ischemic heart disease, limb ischemia and heart failure, and has recently been shown to mediate various biological activities related to the pathogenesis of these diseases. In the present study, we evaluated the role of aldosterone in angiogenesis. Tube formation assay on Matrigel using human umbilical vein endothelial cells (HUVEC) revealed that aldosterone inhibited endothelial morphogenesis in a manner sensitive to eplerenone, a selective mineralocorticoid receptor antagonist. The anti-angiogenic effect of aldosterone was further confirmed by an in vivo angiogenesis assay using a Matrigel plug model in mice. Reverse transcription-mediated polymerase chain reaction and immunoblotting demonstrated that aldosterone downregulated the expression levels of vascular endothelial growth factor receptor-2 (VEGFR-2) and peroxisome proliferators activated receptor gamma (PPAR gamma). VEGFR-2 expression was found to be enhanced in response to PPAR gamma activation by troglitazone, and attenuated by GW9662, a specific antagonist of PPAR gamma. In the tube formation assay, endothelial morphogenesis was stimulated by troglitazone, and inhibited by GW9662, indicating that PPAR gamma activation mediates positive regulation of angiogenesis through enhancement of VEGFR-2 expression. These data suggest that aldosterone inhibits angiogenesis through VEGFR-2 downregulation, subsequent to, at least in part, attenuation of PPAR gamma expression. The present findings provide a new insight into the possible therapeutic application of mineralocorticoid receptor blockade to various cardiovascular diseases. PMID- 22212771 TI - Tunable fiber ring laser with an intracavity high resolution filter employing two dimensional dispersion and LCoS modulator. AB - We demonstrate a tunable fiber ring laser employing a two-dimensional dispersion arrangement filter, with the lasing determined by a liquid crystal on silicon (LCoS) spatial light modulator. Lasing wavelengths can be tuned discontinuously across the communication C-band at an addressable resolution of less than 200 MHz. We introduce full characterization of the laser output including phase and amplitude stability and short and long-term bandwidth measurements. PMID- 22212770 TI - Life history of impulsive behavior: development and validation of a new questionnaire. AB - A self-report version of the Lifetime History of Impulsive Behaviors (LHIB) interview was developed and its psychometric properties examined. Initially, forty-two personality disordered and 20 control subjects completed both the interview (I) and self-report (Q53) versions of the LHIB along with other self report measures of impulsivity and an assessment of venturesomeness and empathy.The LHIB-Q53 demonstrated good to excellent internal consistency, test retest reliability, and evidence of convergent and divergent validity. The LHIB Q53 was then simplified to 20 items and administered to a large population-based sample of adults from the community. Following this, it was administered to nearly 400 subjects with or without histories of Axis I and/or II disorders. The latter two studies demonstrated good to excellent psychometric properties as well as evidence of convergent and divergent validity. Since the LHIB quantifies the occurrence of impulsive behaviors, rather than a self-assessment of a personality trait of impulsivity, we propose that the LHIB-Q20 represents a needed additional assessment of impulsivity for behavioral science research. PMID- 22212772 TI - Design and analysis of multilayered structures with metal-dielectric gratings for reflection resonance and color generation. AB - A multilayered structure incorporating a metal-dielectric subwavelength grating, with the characteristic of polarization separation for visible light and the capability of creating reflection resonance and distinctive polarization dependent color effects, is proposed. Its reflection resonance and color for TE and TM polarizations are discussed, as well as the influence of its structural parameters on them. Moreover, a reflection filter with characteristics of red for TE-polarized light, green for TM-polarized light, and yellow for daylight is designed and fabricated by replacing its grating region with a sinusoidal grating, and its related characteristics also are verified. The structure and its properties can achieve practical applications in various fields, such as color security, image reproduction, color filtering, and polarization-based information hiding. PMID- 22212773 TI - Photonic approach to the simultaneous measurement of the frequency, amplitude, pulse width, and time of arrival of a microwave signal. AB - A photonic approach to the simultaneous measurement of the frequency, pulse amplitude (PA), pulse width (PW), and time of arrival (TOA) of an unknown pulsed microwave signal is proposed and demonstrated. The measurement is performed based on optical carrier-suppressed modulation, complementary optical filtering, low speed photodetection, and electrical signal processing. A proof-of-concept experiment is carried out. A frequency measurement range of 2-11 GHz with a measurement error for frequency, PA, PW, and TOA within +/-0.1 GHz, +/-0.05 V, +/ 1 ns, and +/-0.16 ns is achieved. PMID- 22212774 TI - Robust visual correspondence computation using monogenic curvature phase based mutual information. AB - Visual correspondence has been a major research topic in the fields of image registration, 3D reconstruction, and object tracking for some decades. However, due to the radiometric variations of images, conventional approaches fail to produce robust matching results. The traditional method of intensity-based mutual information performs very good for global variations between images, however, its performance degrades in the case of local radiometric variations. Monogenic curvature phase information, as an important local feature of the image, has the advantage of being robust against brightness variation. Hence, in this Letter, we propose an approach to compute the visual correspondence by coupling the advantages of mutual information and monogenic curvature phase. Experimental results demonstrate that the proposed approach can work robustly under radiometric variations. PMID- 22212775 TI - Reduction of scattering loss of silicon slot waveguides by RCA smoothing. AB - Because of stronger optical confinement density, silicon slot waveguides tend to have higher scattering loss than normal ridge waveguides with same sidewall roughness. A wet chemical process is found to be highly effective in reducing the surface roughness and scattering loss. A reduction in scattering loss by 10.2 dB/cm for TE and 8.5 dB/cm for TM polarizations has been achieved. PMID- 22212776 TI - Energy transfer between laser filaments in liquid methanol. AB - We demonstrate energy exchange between two filament-forming femtosecond laser beams in liquid methanol. Our results are consistent with those of previous works documenting coupling between filaments in air; in addition, we identify an unreported phenomenon in which the direction of energy exchange oscillates at increments in the relative pulse delay equal to an optical period (2.6 fs). Energy transfer from one filament to another may be used in remote sensing and spectroscopic applications utilizing femtosecond laser filaments in water and air. PMID- 22212777 TI - Generalization of three-dimensional N-ocular imaging systems under fixed resource constraints. AB - The performance of multiview three-dimensional imaging systems depends on several factors, including the number of sensors, sensor pixel size, relative sensor configuration, imaging optics, and computational reconstruction algorithm. Therefore, it is important to compare the performance of such systems under equally constrained resources. In this Letter, we develop a unifying framework to evaluate the lateral and axial resolution of N-ocular imaging systems ranging from stereo (two cameras) to multiple sensors (integral imaging) under fixed resource constraints. The proposed framework enables one to evaluate the system performance as a function of sensing parameters such as the number of cameras, the number of pixels, parallax, pixel size, lens aperture, and focal length. We carry out Monte Carlo simulations based on this framework to evaluate system performance as a function of sensing parameters. To the best of our knowledge, this is the first report on quantitative analysis of N-ocular imaging systems under common resource constraints. PMID- 22212778 TI - Fabrication of optical mosaics mimicking human corneal endothelium for the training and assessment of eye bank technicians. AB - The determination of endothelial cell density (ECD) is a crucial activity in eye banks for the assessment of corneal tissue quality. These cells are responsible for corneal transparency, and ECD correlates with graft survival. ECD is mainly assessed with a manual "naked-eye" procedure under a transmitted light microscope in Europe and using a specular microscope in the United States. Interbank and intrabank variability has been previously demonstrated. In order to facilitate training and continuing education of technicians and reliability assessment of eye banks' ECD determination, we use micro-optics technologies to fabricate test mosaics that exactly reproduce the image of human corneal endothelium. The description of the fabrication process is detailed, and comparisons are made between amplitude and phase mosaics. PMID- 22212779 TI - Grating-based wavelength control of single- and two-color vertical-external cavity-surface-emitting lasers. AB - Wide wavelength tunability of single- and two-color operating vertical-external cavity-surface-emitting lasers (VECSELs) is demonstrated. Employing an external feedback based on a diffractive grating outside the cavity of a narrow-line single-color VECSEL allows for a continuous tuning of the emission wavelength over 10 nm. Employing a dual-feedback-configuration for tunable two-color emission, a tunability of the difference frequency between the two lasing wavelengths from 300 gigahertz to up to 3.5 terahertz is demonstrated. PMID- 22212780 TI - Optical fiber refractometers based on indium tin oxide coatings fabricated by sputtering. AB - This Letter presents the fabrication of optical fiber refractometers based on indium tin oxide (ITO) coatings deposited by sputtering with response in the visible region. ITO thin films have been sputtered by means of a rotating mechanism that enables the fabrication of smooth and homogeneous coatings onto the optical fiber core. The ITO coating acts as a resonance supporting layer. This permits us to couple light from the waveguide to the ITO-coating/external medium region at specific wavelength ranges. The device is sensitive to external medium refractive index, which allows its utilization as a refractometer. The sensitivity is dependent on the coating thickness, ranging from 523.21 to 1221 nm/refractive index unit in the explored sensors. The sensor development process is time effective compared to other techniques such as dip coating or layer-by layer self-assembly, which is interesting in terms of mass production. PMID- 22212781 TI - Efficient and accurate local model for colorimetric characterization of liquid crystal displays. AB - Taking the chromaticity inconstancy of LCDs and the inverse efficiency into account, a novel local colorimetric characterization model was developed in this Letter. Rather than dividing the device color space into many subspaces to refine the chromaticity description as existent local models, the proposed model tailored the transformation relationship uniquely for each characterized color with look-up tables and a local chromaticity matrix. Based on this model, the characterization task could be efficiently accomplished within a few steps for either the forward or the inverse transformation. Test experiments on several commercial LCDs indicated that the average color difference between the estimated and measured tristimulus values could be achieved in a low level of about 0.4 CIEDE2000 units, effectively demonstrating the proposed model. PMID- 22212782 TI - Photostability of lasing process from water solution of Rhodamine 6G with gold nanoparticles. AB - We report the lasing performance and photobleaching of gain material containing a water solution of Rhodamine 6G dye and gold nanoparticles (NPs). In comparison to a pure dye solution, the investigated material demonstrated both enhancement and quenching of the lasing output, depending on the relative concentration of the gold NPs. Although the presence of NPs with an optimized concentration looks preferable in terms of the lasing output enhancement, such additives deteriorate the operational resource of the gain material; i.e., the photobleaching rate speeds up. PMID- 22212783 TI - Continuous-wave Yb-doped Sc2SiO5 thin-disk laser. AB - We present in this Letter experimental results of a Yb:Sc(2)SiO(5) (Yb:SSO) thin disk laser. To our knowledge, this is the first lasing demonstration of this crystal in thin-disk configuration reported on to date. Preliminary tests regarding the characterization and the laser operation are presented. Two different resonator configurations, a simple linear multimode cavity, and a fundamental-mode folded resonator providing a double pass in the laser crystal were set up. The gain and the small signal gain of the available Yb:SSO sample were calculated using the experimental results of the multimode resonator. The operation in a fundamental-mode resonator with the double pass in the laser crystal led to 9.4 W of output power with an optical efficiency of 25.4%. PMID- 22212784 TI - Compact all-optical switch for WDM networks based on Raman effect in silicon nanowavegide. AB - We propose an all-optical switching scheme based on Raman gain in a silicon nanowaveguide suitable for multichannel optical communication. Raman gain is used for amplification of a control pulse with a higher wavelength, which depletes the tuned channel signal. Separation between control and signal pulses should be equal to the Raman shift in silicon. By employing a 3 mm channel nanowaveguide, we demonstrate a channel attenuation of about 12 dB, while the suppression ratios for the first and second neighboring channels are about 1.6 dB and 1 dB, respectively. This scheme can be used as an all-optical switch in dense wavelength division multiplexing networks. Moreover, we demonstrate that the depleted channel can be retrieved by a control pulse with lower wavelength in which the pulse amplifies the channel in contrast to the prior situation. PMID- 22212785 TI - Normal group-velocity dispersion Kerr frequency comb. AB - We show via numerical simulation that Kerr frequency combs can be generated in a nonlinear resonator characterized with normal group-velocity dispersion. We find the spectral shape of the comb and temporal envelope of the corresponding optical pulses formed in the resonator. PMID- 22212786 TI - Spinning disk for compressive imaging. AB - We report the first, to the best of our knowledge, experimental implementation of a spinning-disk configuration for high-speed compressive image acquisition. A single rotating mask (i.e., the spinning disk) with random binary patterns was utilized to spatially modulate a collimated terahertz (THz) or IR beam. After propagating through the sample, the THz or IR beam was measured using a single detector, and THz and IR images were subsequently reconstructed using compressive sensing. We demonstrate that a 32-by-32 pixel image could be obtained from 160 to 240 measurements in both the IR and THz ranges. This spinning-disk configuration allows the use of an electric motor to rotate the spinning disk, thus enabling the experiment to be performed automatically and continuously. This, together with its compact design and computational efficiency, makes it promising for real time imaging applications. PMID- 22212787 TI - Wavelength tunable laser beam shaping. AB - Laser beam shaping by phase-only transformations, often referred to as field mapping, has for a long time been considered wavelength dependent. In this Letter we outline a simple mathematical argument that shows how the problem may be formulated in a wavelength tunable manner, requiring only a minor adjustment in the observation plane. We verify the theoretical prediction by experiment using the example of a Gaussian-to-flattop-beam transformation, and we show that the shaping is valid across a wide range of wavelengths for a single diffractive optical element. PMID- 22212788 TI - Enhancement of the broadband modulation diffraction efficiency of liquid-crystal displays. AB - We report a method to maximize the broadband modulation diffraction efficiency of liquid-crystal spatial light modulators for polychromatic applications requiring a wide range of wavelengths. An optimized encoding pattern based on the minimum Euclidean projection principle is applied in order to increase the diffraction efficiency at large wavelengths that exhibit phase modulation depth lower than 2pi. We demonstrate modulation efficiencies over 80% on a wavelength range from 454 to 633 nm, which can reach up to 98% when the range is reduced to 60 nm. Experimental results are shown to confirm the calculations. PMID- 22212789 TI - Compact and silicon-on-insulator-compatible hybrid plasmonic TE-pass polarizer. AB - Hybrid plasmonic waveguides consisting of a metal plane separated from a high index medium by a low-index spacer have recently attracted much interest. Here we show that, by suitably choosing the dimensions and material properties of the hybrid waveguide, a very compact and broadband TE-pass polarizer can be implemented. Finite-difference time-domain simulation indicates that the proposed device can provide large extinction ratio with low insertion loss for the TE mode. PMID- 22212790 TI - Slow-light dispersion in periodically patterned silicon microring resonators. AB - We demonstrate a novel periodically patterned ring resonator evanescently coupled with a coupler waveguide (CWG) on a silicon-on-insulator platform. In order to optimize the coupling, we phase match the ring resonator and the CWG by tuning the width of the CWG. In the transmission spectra, we measure a high extinction ratio of more than 20 dB and achieve a group index of ~20 in the slow-light regime. Beating patterns in the calculated mode profiles suggest strong interference between degenerate modes. This device opens up the possibility of new applications in compact device integration in wavelength-division multiplexing system while reducing the in-band four-wave mixing cross talk. PMID- 22212791 TI - Solar energy harvesting scheme using syringe-like ZnO nanorod arrays for InGaN/GaN multiple quantum well solar cells. AB - Syringe-like ZnO nanorod arrays (NRAs) synthesized by a hydrothermal method were applied as the light-harvesting layer on InGaN-based multiple quantum well (MQW) solar cells. Theoretical calculations show that the NRAs with an abrupt shrinkage of tip diameter can further suppress surface reflectance in comparison with the flat NRAs. InGaN-based MQW solar cells with the syringe-like NRAs exhibit greatly improved conversion efficiencies by 36%. These results are attributed to the improved flatness of the refractive index profile at the air/device interface, which results in enhanced light trapping effect on the device surface. PMID- 22212792 TI - High average power 2 MUm generation using an intracavity PPMgLN optical parametric oscillator. AB - An intracavity quasi-phase-matched optical parametric oscillator (OPO) has been developed for the purpose of generating radiation with high average power and high repetition rate in the 2 MUm regime. The device is a degenerate OPO based on a 3 mm thick MgO-doped periodically poled LiNbO(3) (PPMgLN) crystal, which is pumped in turn within the cavity by a diode side-pumped, Q-switched 1 MUm Nd:YAG laser operating at 10 kHz. Up to 20 W broadband 2 MUm radiation can be generated with a compact configuration under the crystal temperature of 115 degrees C. The beam profile is close to circularly symmetric with M(2) ~ 10. PMID- 22212793 TI - Refractive index sensor using microfiber-based Mach-Zehnder interferometer. AB - A simple and robust refractive index (RI) sensor based on a Mach-Zehnder interferometer has been demonstrated. A section of optical microfiber drawn from silica fiber is employed as the sensing arm. Because of the evanescent field, a slight change of the ambient RI will lead to the variation of the microfiber propagation constant, which will further change the optical length. In order to compensate the variation of the optical length difference, a tunable optical delay line (ODL) is inserted into the other arm. By measuring the delay of the ODL, the ambient RI can be simply demodulated. A high RI sensitivity of about 7159 MUm/refractive index unit is achieved at microfiber diameter of 2.0 MUm. PMID- 22212794 TI - Photoreprogrammable dual-function grating based on photochromism and selective metal deposition. AB - We introduce photoreprogrammable dual-function gratings, which show different diffraction in transmission and reflection. Parallel metal lines on the photochromic diarylethene (DAE) surface were prepared by selective metal deposition, enabling one-dimensional diffraction in transmission and reflection. Then, another isomerization pattern was programmed on the DAE layer by light irradiation. This grating generated unique diffraction: one-dimensional diffraction in the reflection but two-dimensional diffraction in the transmission, and a dual-function grating was achieved. This programmed state on the DAE layer could be erased by UV irradiation and could be reprogrammed to generate different diffraction by visible laser scanning. This result shows the great potential of the photoreprogrammable dual-function grating as a key element in various future optical devices and systems. PMID- 22212795 TI - Feasibility of infrared Earth tracking for deep-space optical communications. AB - Infrared (IR) Earth thermal tracking is a viable option for optical communications to distant planet and outer-planetary missions. However, blurring due to finite receiver aperture size distorts IR Earth images in the presence of Earth's nonuniform thermal emission and limits its applicability. We demonstrate a deconvolution algorithm that can overcome this limitation and reduce the error from blurring to a negligible level. The algorithm is applied successfully to Earth thermal images taken by the Mars Odyssey spacecraft. With the solution to this critical issue, IR Earth tracking is established as a viable means for distant planet and outer-planetary optical communications. PMID- 22212796 TI - Instance-based attention: where could humans look first when searching for an object instance. AB - We present an instance-based attention model to predict where humans could look first when searching for an object instance, and we show its application in image synthesis. The proposed model learns configurational rules from vast scene images described by global scene representations. The rules are then used to predict the focus of attention for the purpose of searching for a given object instance with special scale and pose. Finally, the image synthesis results are obtained by putting the object instance into the scene at the position that attracts most attention. Promising experimental results demonstrate the effectiveness of the proposed model. PMID- 22212797 TI - Plasmon-enhanced light emission based on lattice resonances of silver nanocylinder arrays. AB - Diffractive arrays of silver nanocylinders are used to increase the radiative efficiency of InGaN/GaN quantum wells emitting at near-green wavelengths. Large enhancements in luminescence intensity (up to a factor of nearly 5) are measured when the array period exceeds the emission wavelength in the semiconductor material. The experimental results and related numerical simulations indicate that the underlying mechanism is a strong resonant coupling between the light emitting excitons in the quantum wells and the plasmonic lattice resonances of the arrays. These excitations are particularly well suited to light-emission efficiency enhancement, compared to localized surface plasmon resonances at similar wavelengths, due to their larger scattering efficiency and larger spatial extension across the sample area. PMID- 22212798 TI - Wavelength conversion of nanosecond pulses to the mid-IR in photonic crystal fibers. AB - We investigate degenerate four wave mixing with nanosecond pulses in fused silica photonic crystal fibers. Phase-matching curves are calculated taking into account the material and waveguide dispersion. Experiments with a nanosecond pulsed Nd:YAG pump laser and relatively short fiber lengths show more than an octave spanning conversion to idler and signal wavelengths at 3.105 MUm and 0.642 MUm, respectively. Conversion efficiency depends on the fiber length and pump intensity and is limited in our experiments by damage of the fiber input facet. Our results represent a new stretch towards the limit of the silica transmission window in the mid-infrared (IR). PMID- 22212799 TI - Two-photon fluorescence isotropic-single-objective microscopy. AB - Two-photon excitation provides efficient optical sectioning in three-dimensional fluorescence microscopy, independently of a confocal detection. In two-photon laser-scanning microscopy, the image resolution is governed by the volume of the excitation light spot, which is obtained by focusing the incident laser beam through the objective lens of the microscope. The light spot being strongly elongated along the optical axis, the axial resolution is much lower than the transverse one. In this Letter we show that it is possible to strongly reduce the axial size of the excitation spot by shaping the incident beam and using a mirror in place of a standard glass slide to support the sample. Provided that the contribution of sidelobes can be removed through deconvolution procedures, this approach should allow us to achieve similar axial and lateral resolution. PMID- 22212800 TI - Improving the optical performance of InGaN light-emitting diodes by altering light reflection and refraction with triangular air prism arrays. AB - The effect of triangular air prism (TAP) arrays with different distance-to-width (d/w) ratios on the enhancement of light extraction efficiency (LEE) of InGaN light-emitting diodes (LEDs) is investigated. The TAP arrays embedded at the sapphire/GaN interface act as light reflectors and refractors, and thereby improve the light output power due to the redirection of light into escape cones on both the front and back sides of the LED. Enhancement in radiometric power as high as 117% and far-field angle as low as 129 degrees are realized with a compact arrangement of TAP arrays compared with that of a conventional LED made without TAP arrays under an injection current of 20 mA. PMID- 22212801 TI - Metrology of laser-guided particles in air-filled hollow-core photonic crystal fiber. AB - Micrometer-sized particles are trapped in front of an air-filled hollow-core photonic crystal fiber using a novel dual-beam trap. A backward guided mode produces a divergent beam that diffracts out of the core, and simultaneously a focused laser beam launches a forward-propagating mode into the core. By changing the backward/forward power balance, a trapped particle can be selectively launched into the hollow core. Once inside, particles can be optically propelled along several meters of fiber with mobilities as high as 19 cm.s(-1) W(-1) (precisely measured using in-fiber Doppler velocimetry). The results are in excellent agreement with theory. The system allows determination of fiber loss as well as the mass density and refractive index of single particles. PMID- 22212802 TI - Optical microresonator based on hollow sphere with porous wall for chemical sensing. AB - A porous-wall hollow glass microsphere (PW-HGM) was investigated as an optical resonator for chemical vapor sensing. A single mode optical fiber taper was used to interrogate the microresonator. Adsorption of chemical molecules into the nanosized pores induced a refractive index change of the thin wall and thus a shift in its resonance spectrum. The PW-HGM resonator had shown higher vapor detection sensitivity in comparison with a solid microsphere under similar test conditions. PMID- 22212803 TI - Generation of soft x-ray and water window harmonics using a few-cycle, phase locked, optical parametric chirped-pulse amplifier. AB - Multimillijoule, few-cycle, carrier-envelope-phase (CEP)-locked, near-IR pulses at 750 nm from an optical parametric chirped-pulse amplifier are applied to the generation of CEP-dependent, soft x-ray high harmonics around the boron K-edge at 188 eV. The dependence on the CEP manifests the phase coherence of high harmonics preserved in the highest-photon energy ever reported. Multimillijoule optical pulses also allow the extension of the cutoff energy up to 325 eV, exceeding the carbon K-edge of the water window. However, in this spectral range, the CEP dependence of harmonic spectra is not observed, suggesting the degradation of temporal coherence due to the heavy ionization of helium atoms. PMID- 22212804 TI - Diffraction from carbon nanofiber arrays. AB - A square planar photonic crystal composed of carbon nanofibers was fabricated using e-beam lithography and chemical vapor deposition. The diffraction properties of the system were characterized experimentally and compared with theory and numerical simulations. The intensities of the (-1,0) and (-1,-1) diffraction beams were measured as functions of the angles of incidence for both s and p-polarization. The obtained radiation patterns can be explained using a simple ray interference model, but finite-difference time-domain (FDTD) calculations are necessary to reproduce the observed dependence of the scattered radiation intensity on incident laser polarization. We explain this in terms of the aspect ratio of the nanofibers and the excitation of surface plasmon polaritons at the substrate interface. PMID- 22212805 TI - Fundamental structure of Fresnel diffraction: longitudinal uniformity with respect to fractional Fourier order. AB - Fresnel integrals corresponding to different distances can be interpreted as scaled fractional Fourier transformations observed on spherical reference surfaces. Transverse samples can be taken on these surfaces with separation that increases with propagation distance. Here, we are concerned with the separation of the spherical reference surfaces along the longitudinal direction. We show that these surfaces should be equally spaced with respect to the fractional Fourier transform order, rather than being equally spaced with respect to the distance of propagation along the optical axis. The spacing should be of the order of the reciprocal of the space-bandwidth product of the signals. The space dependent longitudinal and transverse spacings define a grid that reflects the structure of Fresnel diffraction. PMID- 22212806 TI - Double-pumped multiwavelength fiber optical parametric oscillator based on a Sagnac loop filter. AB - We propose a double-pumped ring cavity multiwavelength fiber optical parametric oscillator (MW-FOPO) using a highly nonlinear dispersion-shifted fiber (HNL-DSF) as the gain medium and a polarization maintained fiber based Sagnac loop filter as the comblike filter. 22-wavelength lasing of the double-pumped MW-FOPO with a ripple less than +/-2.5 dB and a wavelength spacing of about 0.8 nm in a wavelength range from 1541 nm to 1558 nm is experimentally demonstrated. We discussed the power stability of the multiwavelength lasing of the double-pumped MW-FOPO. A comparison of the output spectra between the double-pumped MW-FOPO and single-pumped MW-FOPO is also presented. PMID- 22212807 TI - Room-temperature diode-pumped Yb, Na: PbF2 laser. AB - Growth, spectroscopic properties, and laser performance of Yb, Na:PbF(2) crystals have been investigated. With a 2 mol.% Yb(3+)-doped sample we obtained 2.65 W output power at 1045 nm for 7.5 W of incident power at 976 nm. The laser wavelength could be tuned from 1017 to 1078 nm, showing the great potential of Yb, Na:PbF(2) as an amplifier medium for femtosecond pulses. PMID- 22212808 TI - Effective optical response of silicon to sunlight in the finite-difference time domain method. AB - The frequency dependent dielectric permittivity of dispersive materials is commonly modeled as a rational polynomial based on multiple Debye, Drude, or Lorentz terms in the finite-difference time-domain (FDTD) method. We identify a simple effective model in which dielectric polarization depends both on the electric field and its first time derivative. This enables nearly exact FDTD simulation of light propagation and absorption in silicon in the spectral range of 300-1000 nm. Numerical precision of our model is demonstrated for Mie scattering from a silicon sphere and solar absorption in a silicon nanowire photonic crystal. PMID- 22212809 TI - Frequency-modulation-mode-locked optical parametric oscillator. AB - We demonstrate a novel technique for the generation of mode-locked pulses from a continuous-wave (cw) optical parametric oscillator (OPO). The technique is based on the deployment of a phase modulator in combination with an antiresonant ring interferometer internal to a cw OPO, simultaneously providing spectral broadening and phase-to-amplitude feedback modulation. The scheme is implemented in a doubly resonant cw OPO based on MgO:sPPLT, configured in a standing-wave cavity and pumped at 532 nm. With the phase modulator activated and the cavity length synchronized, a stable train of 800 ps pulses is generated at a repetition rate of 160 MHz. Using single-pass second harmonic generation (SHG) of the OPO output, we observe a four times enhancement in SHG compared with cw operation, confirming the real achievement of energy concentration as a result of mode-locked operation. PMID- 22212810 TI - Polarization spectroscopy of an excited state transition. AB - We demonstrate polarization spectroscopy of an excited state transition in room temperature cesium vapor. An anisotropy induced by a circularly polarized pump beam on the D2 transition is observed using a weak probe on the 6P(3/2)->7S(1/2) transition. At high pump power, a subfeature due to Autler-Townes splitting is observed that theoretical modeling shows is enhanced by Doppler averaging. Polarization spectroscopy provides a simple modulation-free signal suitable for laser frequency stabilization to excited state transitions. PMID- 22212811 TI - How does the neck flexion affect the cervical MRI features of Hirayama disease? AB - Although flexion cervical MRI has been recommended for the diagnosis of Hirayama disease (HD), no study focused on the MR features at different neck flexion angles. Moreover, no uniform flexion angle has been confirmed in clinical practice. The purpose of this study is to quantitatively investigate the MRI typical signs of HD patients in different neck flexion degree and gives a suggestion to the MR scanning. Cervical MRI in neutral and different flexion positions (cervical flexion angle 20 degrees , 25 degrees , 30 degrees , 35 degrees , and 40 degrees ) were performed in 45 HD patients. Three MRI features including anterior shifting of the posterior wall of the cervical dural canal (ASD), widening of cervical epidural space, and epidural flow voids (EFV) at each flexed position were summarized. To evaluate ASD quantitatively, the widest cervical epidural space with the maximum sagittal diameters (d) and cervical canal sagittal diameter (D) at the same level were measured. The d/D values at different angles were calculated and compared. ASD was demonstrated in 34 out of 45 cases (75.6%) at 20 degrees and in all cases (100%) at other 4 angles (chi (2) = 25.728, P < 0.05). Significant difference was demonstrated for the appearance rate of EFV (mean 72.8%) among different angles (chi (2) = 11.373, P = 0.021). The peak mean d/D value was found at 35 degrees . Neck flexion angles have effects on ASD, widening of cervical epidural space and EFV. 25 degrees is recommended as the least effective diagnostic flexion angle for MRI diagnosis of HD, and 35 degrees may be the best one. PMID- 22212812 TI - ADAMTS13 gene deletion enhances plasma high-mobility group box1 elevation and neuroinflammation in brain ischemia-reperfusion injury. AB - Highly adhesive glycoprotein von Willebrand factor (VWF) multimer induces platelet aggregation and leukocyte tethering or extravasation on the injured vascular wall, contributing to microvascular plugging and inflammation in brain ischemia-reperfusion. A disintegrin and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) cleaves the VWF multimer strand and reduces its prothrombotic and proinflammatory functions. Although ADAMTS13 deficiency is known to amplify post-ischemic cerebral hypoperfusion, there is no report available on the effect of ADAMTS13 on inflammation after brain ischemia. We investigated if ADAMTS13 deficiency intensifies the increase of extracellular HMGB1, a hallmark of post-stroke inflammation, and exacerbates brain injury after ischemia-reperfusion. ADAMTS13 gene knockout (KO) and wild-type (WT) mice were subjected to 30-min middle cerebral artery occlusion (MCAO) and 23.5-h reperfusion under continuous monitoring of regional cerebral blood flow (rCBF). The infarct volume, plasma high-mobility group box1 (HMGB1) level, and immunoreactivity of the ischemic cerebral cortical tissue (double immunofluorescent labeling) against HMGB1/NeuN (neuron-specific nuclear protein) or HMGB1/MPO (myeloperoxidase) were estimated 24 h after MCAO. ADAMTS13KO mice had larger brain infarcts compared with WT 24 h after MCAO (p < 0.05). The rCBF during reperfusion decreased more in ADAMTS13KO mice. The plasma HMGB1 increased more in ADAMTS13KO mice than in WT after ischemia-reperfusion (p < 0.05). Brain ischemia induced more prominent activation of inflammatory cells co-expressing HMGB1 and MPO and more marked neuronal death in the cortical ischemic penumbra of ADAMTS13KO mice. ADAMTS13 deficiency may enhance systemic and brain inflammation associated with HMGB1 neurotoxicity, and aggravate brain damage in mice after brief focal ischemia. We hypothesize that ADAMTS13 protects brain from ischemia reperfusion injury by regulating VWF-dependent inflammation as well as microvascular plugging. PMID- 22212813 TI - The CD14++CD16+ monocyte subset and monocyte-platelet interactions in patients with ST-elevation myocardial infarction. AB - AIM: Monocytes contribute to both myocardial damage and repair by virtue of subset heterogeneity. The dynamics and functional characteristics of the three human monocyte subsets, including the unique CD14++CD16+ subset, and their contributions to monocyte platelet aggregates (MPAs) following ST-elevation myocardial infarction (STEMI) are unknown. We aimed to examine dynamic changes and relation to left ventricular ejection fraction (LVEF) of the three human monocyte subsets and their aggregates with platelets following STEMI. METHODS: Three monocyte subsets, CD14++CD16-CCR2+ ('classical', Mon1), CD14++CD16+CCR2+ ('intermediate', Mon2) and CD14+CD16++CCR2- ('non-classical', Mon3), and their contribution to MPAs were analyzed by flow cytometry in 50 patients with STEMI, 40 patients with stable coronary artery disease (CAD) and 40 healthy volunteers. Study parameters were measured within 24 h of primary percutaneous coronary intervention (PCI) (day1) and on days 3, 7 and 30. Monocyte activation was assessed by measuring the nuclear factor kappaB (NFkappaB) pathway. LVEF was assessed 6 weeks after STEMI. Correlations between monocyte subsets/MPAs and plasma cytokines and troponin were assessed. RESULTS: We observed marked differences in subset dynamics, with a prominent increase in Mon2 (P < 0.0001) but no changes in Mon3. Significant increases in Mon2 CD14 (P = 0.002) and CCR2 (P < 0.0001) expression, and reduction in CD16 expression (P = 0.001) were seen. NFkappaB pathway activity increased most prominently in Mon2 (P = 0.007). Mon2 count correlated with peak troponin (r = 0.31, P = 0.04) and plasma interleukin (IL)-6 (r = 0.65, P < 0.0001) and IL-10 (r = 0.34, P = 0.017). Mon1 correlated with IL-6 (r = 0.55, P < 0.0001). Reduced Mon2 expression of CD16 on day 1 was independently predictive of higher LVEF (beta = -0.37, P = 0.013). The increase in MPA count following STEMI persisted at 1 month. CONCLUSION: The Mon2 'intermediate' subset has unique dynamic and functional characteristics following STEMI and significant correlations with troponin, plasma cytokines and convalescent left ventricular function. The persistent increase in MPA count 30 days after STEMI may affect monocyte subset functional activity. PMID- 22212815 TI - Zwitterionic biphenyl quinone methides in photodehydration reactions of 3 hydroxybiphenyl derivatives: laser flash photolysis and antiproliferation study. AB - In aqueous media, photochemical excitation to S(1) of 3-phenylphenols 4-8 leads to deprotonation of the phenol OH, coupled with protonation of the benzyl alcohol and overall dehydration that delivers zwitterions 17-21. The zwitterions react with nucleophiles (CH(3)OH, CF(3)CH(2)OH and ethanolamine) converting them in high quantum yields to the corresponding adducts and photosolvolysis products (for photomethanolysis Phi~0.1-0.5). Zwitterions 20 and 21 were characterized by laser flash photolysis in CH(3)CN-H(2)O (tau~7.5 and 25 MUs, respectively) and the associated quenching rate constants with nucleophiles azide and ethanolamine determined. In vitro studies of antiproliferative activity of the photochemicaly generated QMs and zwitterions formed from 2-, 3- and 4-phenylphenols were carried out on three human cancer cell lines HCT 116 (colon), MCF-7 (breast), and H 460 (lung). Irradiation of cells incubated with 3, 6, and 26 showed enhanced antiproliferative activity compared to the cells that were not irradiated. PMID- 22212814 TI - Sna3 is an Rsp5 adaptor protein that relies on ubiquitination for its MVB sorting. AB - The process in which ubiquitin (Ub) conjugation is required for trafficking of integral membrane proteins into multivesicular bodies (MVBs) and eventual degradation in the lumen of lysosomes/vacuoles is well defined. However, Ub independent pathways into MVBs are less understood. To better understand this process, we have further characterized the membrane protein Sna3, the prototypical Ub-independent cargo protein sorted through the MVB pathway in yeast. We show that Sna3 trafficking to the vacuole is critically dependent on Rsp5 ligase activity and ubiquitination. We find Sna3 undergoes Ub-dependent MVB sorting by either becoming ubiquitinated itself or associating with other ubiquitinated membrane protein substrates. In addition, our functional studies support a role for Sna3 as an adaptor protein that recruits Rsp5 to cargo such as the methionine transporter Mup1, resulting in efficient Mup1 delivery to the vacuole. PMID- 22212816 TI - Early closure of ileostomy is associated with less postoperative nausea and vomiting. AB - BACKGROUND/AIMS: Temporary loop ileostomy is increasingly used in colorectal surgery but necessitates secondary closure. We evaluated postoperative complications, particularly nausea and vomiting, in patients with early, intermediate, or late elective ileostomy closure. METHODS: We included all patients undergoing ileostomy closure from 2001 to 2008. Time from ileostomy construction to closure was classified as early (EC, <12 weeks), intermediate (IC, 12-18 weeks), and late (LC, >18 weeks). Using multivariable logistic regression, we compared the frequency of postoperative complications between the groups. RESULTS: We included 134 patients (87 males; median age 71 years, range 29-91). Carcinoma of the rectum (n = 67, 50%) was the main reason for ileostomy construction. The median time to ileostomy closure was 103 days (range 8-461). Among patients with EC, IC, and LC, postoperative nausea occurred in 50.0, 73.1, and 78.6%, respectively (p = 0.006), and postoperative vomiting in 22.5, 57.7, and 59.5%, respectively (p = 0.001). Adjusting for important covariates, the odds ratio for postoperative nausea was 2.0 (95% CI 0.76-5.1) for IC and 4.1 (95% CI 1.2-14.3) for LC compared to EC (p = 0.069). For postoperative vomiting, adjusted odds ratios were 3.8 (95% CI 1.4-10.4) for IC and 4.6 (95% CI 1.4-15.5) for LC (p = 0.012). Other complications did not differ between the groups. CONCLUSIONS: These findings suggest that early ileostomy closure might reduce postoperative nausea and vomiting. PMID- 22212817 TI - Enrichment and solubility of trace metals associated with magnetic extracts in industrially derived contaminated soils. AB - Magnetic fractions (MFs) in industrially derived contaminated soils were extracted with a magnetic separation procedure. Total, soluble, and bioaccessible Cr, Cu, Pb and Zn in the MFs and non-magnetic fractions (NMFs) were analyzed using aqua regia and extraction tests, such as deionized water, toxicity characteristic leaching procedure (TCLP), and gastric juice simulation (GJST) test. Compared with the non-magnetic fractions, soil MFs were enriched with Fe, Mn, Pb, Cd, Cr, Cu, and Ni. Extraction tests indicated that soil MFs contained higher water, TCLP, and GJST-extractable Cr, Cu, Pb, and Zn concentrations than the soil NMFs. The TCLP-extractable Pb concentration in the MFs exceeded the USEPA hazardous waste criteria, suggesting that soil MFs have a potentially environmental pollution risk. Solubility of trace metals was variable in the different extraction tests, which has the order of GJST > TCLP > water. TCLP test showed Cu and Zn were more mobile than Cr and Pb while bioaccessibility of trace metal defined by GJST test showed the order of Cu ~ Cr ~ Zn > Pb. These findings suggested that the MFs in the industrially derived contaminated soils had higher possibility of polluting water bodies, and careful environmental impact assessment was necessary. PMID- 22212818 TI - Surveillance of feral cats for influenza A virus in north central Florida. AB - BACKGROUND: Transmission of highly pathogenic avian influenza and the recent pandemic H1N1 viruses to domestic cats and other felids creates concern because of the morbidity and mortality associated with human infections as well as disease in the infected animals. Experimental infections have demonstrated transmission of influenza viruses in cats. OBJECTIVES: An epidemiologic survey of feral cats was conducted to determine their exposure to influenza A virus. METHODS: Feral cat sera and oropharyngeal and rectal swabs were collected from November 2008 through July 2010 in Alachua County, FL and were tested for evidence of influenza A virus infection by virus isolation, PCR, and serological assay. RESULTS AND CONCLUSIONS: No virus was isolated from any of 927 cats examined using MDCK cell or embryonated chicken egg culture methods, nor was viral RNA detected by RT-PCR in 200 samples tested. However, 0.43% of cats tested antibody positive for influenza A by commercial ELISA. These results suggest feral cats in this region are at minimal risk for influenza A virus infection. PMID- 22212819 TI - Hairpin RNA derived from the gene for Pns9, a viroplasm matrix protein of Rice gall dwarf virus, confers strong resistance to virus infection in transgenic rice plants. AB - The nonstructural Pns9 protein of Rice gall dwarf virus (RGDV) accumulates in viroplasm inclusions, which are structures that appear to play an important role in viral morphogenesis and are commonly found in host cells infected by viruses in the family Reoviridae. An RNA interference construct was designed to target the gene for Pns9 of RGDV, namely Trigger_G9. The resultant transgenic plants accumulated short interfering RNAs specific for the construct. All progenies from self-fertilized transgenic plants had strong and heritable resistance to RGDV infection and did not allow the propagation of RGDV. By contrast, our transgenic plants remained susceptible to Rice dwarf virus, another phytoreovirus. There were no significant changes in the morphology of our transgenic plants compared with non-inoculated wild-type rice plants, suggesting that genes critical for the growth of rice plants were unaffected. Our results demonstrate that the resistance to RGDV of our transgenic rice plants is not due to resistance to the vector insects but to specific inhibition of RGDV replication and that the designed trigger sequence is functioning normally. Thus, our strategy to target a gene for viroplasm matrix protein should be applicable to plant viruses that belong to the family Reoviridae. PMID- 22212820 TI - N-linked glycosylation influences on the catalytic and biochemical properties of Penicillium purpurogenum beta-d-glucuronidase. AB - To study the influence of N-linked carbohydrate moiety on the catalytic and biochemical properties of glycosylated enzyme, a recombinant beta-d-glucuronidase (PGUS-P) from Penicillium purpurogenum as a model glycoprotein, was deglycosylated with peptide-N-glycosidase F (PNGase-F) under native conditions. The enzymatic deglycosylation procedure resulted in the complete removal of carbohydrate moiety. Compared with the glycosylated PGUS-P, the deglycosylated PGUS-P exhibited 20-70% higher activity (p<0.05) within pH 6-9, but 15-45% lower activity (p<0.05) at 45-70 degrees C. The apparent decrease in the thermal stability of the deglycosylated enzyme was reflected by a decrease in the denaturation temperature (T(d)) values determined by differential scanning calorimetry (DSC). The removal of N-linked glycans also reduced enzyme's sensitivity to certain metal ions. The deglycosylated PGUS-P displayed lower K(m) vaules, but higher k(cat)/K(m) ratios than the glycosylated isoform towards glycyrrhizin. The consequent conformational changes were also determined by circular dichroism (CD) and fluorescence spectroscopy which revealed no significant difference in the secondary but a slight dissimilarity between the tertiary structures of both isoforms of PGUS-P. PMID- 22212821 TI - The use of highly expressed FTH1 as carrier protein for cytosolic targeting in Hansenula polymorpha. AB - The iron storage protein ferritin is a member of the non-heme iron protein family. It can store and release iron, therefore it prevents the cell from damage caused by iron-dioxygen reactions as well as it provides iron for biological processing. To study whether the human ferritin heavy chain (FTH1) can be expressed in Hansenula polymorpha, we integrated an expression cassette for FTH1 and analyzed the protein expression. We found very efficient expression of FTH1 and obtained yields up to 1.9 g/L under non-optimized conditions. Based on this result we designed a FTH1-PTH fusion protein to successfully express the parathyroid hormone fragment 1-34 (PTH) for the first time intracellular in H. polymorpha. PMID- 22212822 TI - Assessment of lifestyle effect on oxidative stress biomarkers in free-living elderly in rural Japan. AB - BACKGROUND: Oxidative stress is believed to play a crucial role in aging and age related diseases, and is widely thought to increase morbidity and mortality in the elderly. Assessment of biomarkers of oxidative stress, such as 8-isoprostane and 8-hydroxy-2-deoxyguanosine, are considered to be useful in predicting disease risks at the population level. OBJECTIVE: The aim of the present study was to assess the health status of the elderly by comparing their lifestyles and levels of oxidative stress biomarkers. METHODS: We carried out a cross-sectional study where urine samples from a total of 100 elderly men and women were assayed for 8 isoprostane, 8-hydroxy-2-deoxyguanosine, selenium, cadmium and creatinine. They were asked to answer a questionnaire that included questions about their lifestyle. RESULTS: Most of the participants were prehypertensive, non-alcohol users and on a rich plant-based diet. There were no differences in any biomarkers of oxidative stress between men and women. 8-Isoprostane was found to correlate positively with systolic blood pressure in women, but not in men. There was a slight increase of 8-isoprostane in participants with a poor intake of vegetables, and a decrease of 8-hydroxy-2-deoxyguanosine in participants who consumed fish. Multiple regression analysis showed that oxidative stress biomarkers were positively associated with cadmium, and negatively associated with selenium and fish intake in all participants, 89% of which were non-smokers. CONCLUSION: Results from the present study show that fish intake has the potential of decreasing oxidative stress among elderly persons. PMID- 22212823 TI - The pattern of the maxillofacial fractures - A multicentre retrospective study. AB - Aim of the present study was to report on the survey of fractures, frequency of presentation, sex and age distributions, aetiology, site distributions, associated injuries & modalities of treatment rendered at muticentres treated by the division of oral and maxillofacial surgery between 2000 and 2005 in Karnataka state of India. Study revealed that the common cause for the facial fractures was found to be traffic accidents (72.7%) with a male preponderance and peak incidence during 20-30 years of age. Isolated mandibular fractures were most frequent [1035 patients (41.7%)] followed by isolated mid face fractures [526 patients (21.2%)]. Among mid face fractures, zygomatic bone and arch were most frequently involved. Open reduction and internal fixation and closed method were used in almost the same frequency. Traffic accidents are the leading cause of the maxillofacial fractures from the observation made from the study. Legislations preventive measures to be enforced and abided by every citizen. PMID- 22212824 TI - Parental eczema increases the risk of double-blind, placebo-controlled reactions to milk but not to egg, peanut or hazelnut. AB - BACKGROUND: While genetic factors are known to be important in the development of sensitization to foods, it is not known whether they also play a role in clinical allergic reactivity to foods. OBJECTIVE: We aimed to determine whether parental atopic diseases are associated with a higher risk of a reaction to common allergenic foods when tested in a double-blind, placebo-controlled food challenge (DBPCFC). METHODS: Parents of children suspected of being food allergic were interviewed about their own and their child's atopic history. Specific IgE and skin prick tests to food allergens and the outcome of food challenges in the child were recorded. RESULTS: Data from 553 double-blind food challenges performed in 396 children were analyzed. The foods tested were milk (n = 185), egg (n = 110), peanut (n = 198) and hazelnut (n = 60). Only parental eczema was significantly associated with positive outcomes for food challenges with milk after correction for age, sex, atopic comorbidity in the child and milk-specific IgE test results (odds ratio 3.1, 95% confidence interval 1.5-6.3). CONCLUSIONS: Children with a positive DBPCFC to milk more frequently have parents with eczema than children with a negative test. This effect of parental eczema was not seen in children challenged with egg, peanut or hazelnut. Clinical reactivity to milk may be caused by genetic factors which are shared with parental eczema to a greater extent than clinical reactivity to other foods. PMID- 22212825 TI - Natural variation in gestational cortisol is associated with patterns of growth in marmoset monkeys (Callithrix geoffroyi). AB - High levels of prenatal cortisol have been previously reported to retard fetal growth. Although cortisol plays a pivotal role in prenatal maturation, heightened exposure to cortisol can result in lower body weights at birth, which have been shown to be associated with adult diseases like hypertension and cardiovascular disease. This study examines the relationship between natural variation in gestational cortisol and fetal and postnatal growth in marmoset monkeys. Urinary samples obtained during the mother's gestation were analyzed for cortisol. Marmoset body mass index (BMI) was measured from birth through 540 days in 30- or 60-day intervals. Multi-level modeling was used to test if marmoset growth over time was predicted by changes in gestational cortisol controlling for time, sex, litter, and litter size. The results show that offspring exposed to intra-uterine environments with elevated levels of cortisol had lower linear BMI rates of change shortly after birth than did offspring exposed to lower levels of cortisol, but exhibited a higher curvilinear growth rate during adolescence. Average daily change in gestational cortisol during the first trimester had a stronger relationship with postnatal growth than change during the third trimester. Higher exposure to cortisol during gestation does alter developmental trajectories, however there appears to be a catch-up period during later post natal growth. These observations contribute to a larger discussion about the relationship of maternal glucocorticoids on offspring development and the possibility of an earlier vulnerable developmental window. PMID- 22212826 TI - Insights into the transcriptomics of polyphagy: Bemisia tabaci adaptability to phenylpropanoids involves coordinated expression of defense and metabolic genes. AB - The whitefly Bemisia tabaci is a major generalist agricultural pest of field and horticultural crops world-wide. Despite its importance, the molecular bases of defense mechanisms in B. tabaci against major plant secondary defense compounds, such as the phenylpropanoids, remain unknown. Our experimental system utilized transgenic Nicotiana tabacum plants constitutively expressing the PAP1/AtMYB75 transcription factor which activates relatively specifically the phenylpropanoid/flavonoids biosynthetic pathway. Our study used suppression subtractive hybridization (SSH) and cDNA microarray approaches to compare gene expression between B. tabaci adults subjected to wild-type or transgenic plants for 6 h. A total of 2880 clones from the SSH libraries were sequenced. Both the SSH and cDNA microarray analyses indicated a complex interaction between B. tabaci and secondary defense metabolites produced by the phenylpropanoids/flavonoids pathway, involving enhanced expression of detoxification, immunity, oxidative stress and general stress related genes as well as general metabolism and ribosomal genes. Quantitative real-time PCR revealed significant changes in the expression of several of these genes in response to feeding on artificial diet containing the flavonoids quercetin. The elevated transcriptional activity was not accompanied by reduced reproductive performance, indicating high adaptability of B. tabaci to this large group of plant secondary defense metabolites. PMID- 22212827 TI - Genomic and proteomic studies on the effects of the insect growth regulator diflubenzuron in the model beetle species Tribolium castaneum. AB - Several benzoylphenyl urea-derived insecticides such as diflubenzuron (DFB, Dimilin) are in wide use to control various insect pests. Although this class of compounds is known to disrupt molting and to affect chitin content, their precise mode of action is still not understood. To gain a broader insight into the mechanism underlying the insecticidal effects of benzoylphenyl urea compounds, we conducted a comprehensive study with the model beetle species and stored product pest Tribolium castaneum (red flour beetle) utilizing genomic and proteomic approaches. DFB was added to a wheat flour-based diet at various concentrations and fed to larvae and adults. We observed abortive molting, hatching defects and reduced chitin amounts in the larval cuticle, the peritrophic matrix and eggs. Electron microscopic examination of the larval cuticle revealed major structural changes and a loss of lamellate structure of the procuticle. We used a genomic tiling array for determining relative expression levels of about 11,000 genes predicted by the GLEAN algorithm. About 6% of all predicted genes were more than 2-fold up- or down-regulated in response to DFB treatment. Genes encoding enzymes involved in chitin metabolism were unexpectedly unaffected, but many genes encoding cuticle proteins were affected. In addition, several genes presumably involved in detoxification pathways were up-regulated. Comparative 2D gel electrophoresis of proteins extracted from the midgut revealed 388 protein spots, of which 7% were significantly affected in their levels by DFB treatment as determined by laser densitometry. Mass spectrometric identification revealed that UDP-N-acetylglucosamine pyrophosphorylase and glutathione synthetase were up regulated. In summary, the red flour beetle turned out to be a good model organism for investigating the global effects of bioactive materials such as insect growth regulators and other insecticides. The results of this study recapitulate all of the different DFB-induced symptoms in a single model insect, which have been previously found in several different insect species, and further illustrate that DFB treatment causes a wide range of effects at the molecular level. PMID- 22212828 TI - Rapid detection of CWD PrP: comparison of tests designed for the detection of BSE or scrapie. AB - Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) mainly affecting cervids in North America. The accumulation of an abnormal form of host-encoded prion protein (PrP(CWD) ) in the CNS and lymphoid tissues is characteristic of the disease and known to be caused by pathogenic prion proteins (PrP(res) ), which are thought to be transmitted mainly by contact with body fluids, such like saliva. Species known to be naturally infected by CWD include Rocky Mountain elk (Cervus elaphus nelsoni), white-tailed deer (Odocoileus virginianus) and mule deer (Odocoileus hemionus). Recently, large-scale disease eradication or control programs have been attempted to curtail the spread of disease. But reports of diseased free-ranging and farmed cervids in many locations in the USA and Canada are still continuing. The goal of this study was to find sensitive rapid test systems that are reliably able to detect CWD associated PrP(CWD) in cervids, thereby reviewing an important control tool in case the disease spreads further and reaches Europe. Seven tests, originally developed for the detection of other TSE diseases such as Scrapie and bovine spongiform encephalopathy, including two Western blots, four enzyme-linked immunosorbent assays (ELISAs), and one lateral flow device, were included in this study. All seven tests evaluated were able to detect pathogenic prion proteins (PrP(CWD) ) in Northern American infected animals and distinguish physiologic prion protein (PrP(c) ) in brainstem (obex region) and lymph node samples from North American and European cervids, respectively. However, the specificity and sensitivity of the tests differed significantly. Highly sensitive tests for the detection of prion proteins are an important tool both for the design of effective disease surveillance and control strategies and the safety of the food chain. Thus, this study contributes to the emergency preparedness against CWD. PMID- 22212829 TI - [25 years after the health reform of Ernest Lluch]. PMID- 22212830 TI - [Psychiatric reform 25 years after the General Law of Health]. AB - The paper analyzes the situation of the psychiatric reform 25 years of the General Health Law. The author wonders what has been done and what has been left undone, on the degree of implementation of the Community model that adopts the law and its future sustainability. It highlights, among the strengths, the loss of hegemony of the psychiatric hospital and the great development of alternative resources, and seeks to explain the reason for the inadequacies of care, policy and training, as well as threats: the changes in the management of social and health services, increased privatization of services, the theoretical impoverishment and changing demands of the population. PMID- 22212831 TI - [Contemporary relevance of the Spanish General Health Act after twenty five years]. AB - Since its enactment in 1986, the General Health Law (Law 14/1986) has undergone several changes that have consolidated a model of National Health System. The law was embodied in 113 articles, ten Additional Provisions, five transitional arrangements, two Repeal and fifteen Final Provisions, has altogether 143 articles. After reviewing all legislation that appeared from 1986 to until today we can see that there are 106 articles (74.2%) that have lost regulatory effectiveness and merit analysis or reflection. All these items can be classified into four groups, the repealed and amended 26 articles (18.2%), 33 items of obsolete group (23.1%); the group of ill-developed are 6 articles (4.2%) and the critical (controversial and under ambiguous wording) group that has 41 articles (28.6%). After a quarter century of enforcement of the Act, two thirds of it to be reviewed. This legal weakness suggest the need of a new General Health Act for the Spanish National health System, being it a central objective of a political wide agreement. PMID- 22212833 TI - [Without reciprocal recognition there is not quality of care]. AB - Understanding the classic doctor-patient relationship has entered a crisis in medicine today. Communication difficulties, underestimation of empathy, or bringing economic criteria are leading to care styles that facilitate the objectification of patients, contempt for doctors, and indifference of both to collective measures of health. Basic principles of this relationship such as quality, justice, patient autonomy and beneficence may appear weak content. We intend to apply the concept of "reciprocal recognition" from philosophy to "recharge" content different aspects of the clinical relationship: a look "inside", dealing with the identity of the protagonists seek to promote it by using reciprocal recognition of both patient and the professional. In one aspect "external", focusing on the quality of care, a key objective of the clinical relationship. With reciprocal recognition, issues of justice and equity are reinforced through public health, building an identity of citizens with rights. PMID- 22212832 TI - [Twenty five years of health reports in Barcelona: a commitment to transparency and a tool for action]. AB - After a quarter century of annual health reports in the city of Barcelona, this study documents the experience and draws some elements that may be useful in other contexts, specifying the analysis on the Health Report of 2008. We show the conceptual framework, the process of preparing the report, sources of information used and the contents. We evaluate the dissemination of the health report, both at the political level, as well as the media, professionals and the public. Furthermore, we examine the impact of the report as a tool for social change and planning. PMID- 22212834 TI - [Impact of morbidity on the health of the Basque Country population 2002-2007: a comprehensive approach through health expectancies]. AB - BACKGROUND: The estimation of the impact of morbidity on health is essential to health planning. The objective was to estimate this impact using disability free life expectancy, and to analyze whether the hypothetical elimination of various diseases would have led to a compression or expansion of morbidity. METHODS: Cross-sectional study on the population of the Basque Country. Data on mortality (2002-2006), health survey data (2007) and population based data were used. The impact of different groups of diseases on mortality rates, years of life and potential years of life lost (PYLL) and disability (absolute number and rates) were calculated. An integrated analysis was also done, using disability free life expectancy (DFLE), using the Sullivan method. RESULTS: The diseases causing the greatest impact on mortality were tumours among men (35,2% and 39,3% of deaths and PYLL respectively), and circulatory diseases (34,5% of deaths) and tumours (43,6% of PYLL) among women. Osteomuscular diseases had a major impact on disability, causing the 26,6% and the 45,2% of the total cases in men and women). Circulatory diseases had the highest impact as a whole (4.2 years of DFLE in men and 3.8 in women). However, osteomuscular diseases had the highest influence on years of life with disability. CONCLUSIONS: The diseases which caused the overall greatest impact on mortality and disability were circulatory system related ones, tumors, and osteomuscular diseases. The elimination of this last group of diseases would have led to a morbidity compression, meaning the greatest reduction in life years with disability among all the causes. PMID- 22212835 TI - Relationship between daily physical activity, recess physical activity, age and sex in scholar of primary school, Spain. AB - BACKGROUND: Sedentary behavior has negative effects on health. School recess playgrounds provide important settings and opportunities for children to engage in physical activity. The aim of this study was to describe the daily physical activity (PA) and physical activity during recess of Primary School children and the relationship with sex and age. METHOD: 783 children (379 boys and 359 girls; age=8.5+/-1.7 years; range 6 to 11) participated in the study. Daily PA of each child was measured using a validated questionnaire that was completed by the parents of each child, whilst playground recess PA was measured using accelerometry. An ANOVA was used to determine differences by sex in each age group with confidence intervals and effect sizes. Also MANOVA was used to analyse the main and interaction effects of age and sex on variables. The Scheffe post hoc test was used for comparisons. RESULTS: Boys reported higher daily PA levels than girls across all age groups. The differences was bigger in seven (47,6+/-6,5 vs 42,6+/-6,4 MET/day; p<0,001), eight (48,5+/-8,6 vs 41,9+/-4,6MET/day; p<0,001) and nine years old (49,8+/-8,3 vs 44,1+/-5,9 MET/day; p<0,001). Measured recess PA was higher for boys compared to girls at age nine (28,4+/-12,0 vs 23.7+/-11,8 motion counts; p<0,039), ten (28,5+/-10,8 vs 23,7+/-10,0 motion counts; p<0,014) and eleven years old (24,6+/-12,2 vs 20,7+/-9,3 motion counts; p<0,047). CONCLUSION: Daily PA is higher in boys compared to girls across all age groups (six to eleven years old). On the other hand, recess PA was higher only in boys between nine and eleven years. PMID- 22212836 TI - [Prevalence of risk factors for fragility fracture in men aged 40 to 90 years of a Spanish basic Rural Health Area]. AB - BACKGROUND: Osteoporosis and as a consequence fragility fractures have emerged in recent years as a major public health issue in developed countries. Although its epidemiology and risk factors in postmenopausal women are well known, few studies exist focused on analyzing this pathology in men. Our objective is to determine the prevalence of fragility fracture risk factors in men belonging to our population and to calculate the absolute risk of major osteoporotic fracture and hip fracture. METHODS: Cross-sectional study conducted in a Rural Health Basic Area. The target population was composed by males between 40 and 90 years old. Causes of exception were not considered. Personal interviews were carried out collecting the following data: age, weight, height, body mass index (BMI), previous fractures, background on parent hip fracture, smoking habits, use of corticosteroids, background on rheumatoid arthritis, secondary osteoporosis, alcohol and bone mineral density (BMD). With this data, later in our Health Center, the Absolute Fracture Risk and the Hip Fracture Risk were calculated using the FRAX (r) tool. RESULTS: 431 cases were studied. Mean age 65,8 +/- 13,9 years old and BMI 28,4 +/- 4,3 kg/m2. BMD had not been determined for any of the patients. Prevalence of risk factors: previous fracture 3,7%; parents with hip fractures 10,4%; smokers 21,1%; glucocorticoids 2,8%; rheumatoid arthritis 0,9%; secondary osteoporosis 2,3%; alcohol 30,9%. Absolute fracture risk, 3,7 +/- 3,1 95% CI (3,43-4,02); hip fracture risk 1,7 +/- 2,5 95% CI (1,51-1,98). CONCLUSION: Particularly important for males, the elimination of alcohol and tobacco. PMID- 22212837 TI - [Prevalence and relationship between physical activity and abnormal eating attitudes in Spanish women university students in Health and Education Sciences]. AB - BACKGROUND: Future education and health professionals will be responsible for promoting physical activity and correct eating habits among the general population. This work aims to describe the prevalence and the degree of correlation between physical level and eating disorders in a sample made of nursing, physiotherapy and education female students. METHODS: A total of 258 female students doing university courses during the academic year 2009-2010 at the University of Vigo (Pontevedra's Campus) and who were registered in nursing (87), physiotherapy (73) and education (98) took part in this transversal descriptive study. The International Physical Activity Questionnaire and the Eating Attitude Test were used to assess the prevalence of physical activity and eating disturbed attitudes respectively. RESULTS: The data showed that 63 (64,7%) of nursing students and 63 (72,1%) of education students reported the higher physical inactivity values, while 19 (19.4%) and 13 (15,3%) of them were likely to suffer from eating disorders respectively. Significant differences were found between the academic degree and the physical activity level of the sample (chi2=10,265; Sig.<0,05). The degree of association observed between physical activity energy expenditure and the existence of eating disturbed attitudes was only significant among education students (OR= 3,58; IC 95%= 1,29-9,93; Sig.<0.05). CONCLUSION: An important prevalence of physical inactivity and eating disturbed attitudes seems to exist attitudes among education and nursing students. There is a chance that the performance of intense physical activity could be related to inadequate eating habits. PMID- 22212838 TI - [Interpersonal sensorimotor coordination dynamics in schizophrenic patients: introducing a new experimental paradigm]. AB - Compared to healthy individuals, schizophrenic patients suffer from sensorimotor disorders including problems when tracking moving targets and perceiving biological motion. Recent advances in embodied cognition and social coordination dynamics have emphasized the important role played by bodily information exchange (e.g. facial expressions, posture, and movements) in the way people interact with and mutually influence each other. These experimental studies on healthy participants provide data on sensorimotor performances of a patient that are recorded at high temporal and spatial resolutions. They should therefore be considered in studies on schizophrenic patients. These functional, quantitive and dynamic aspects of sensorimotor coordination abilities, may offer promising perspectives and could lead to a better understanding of sensorimotor disorders in schizophrenia. The purpose of this article is to introduce a new experimental paradigm in schizophrenia inspired by the field of coordination dynamics, a theoretical and experimental approach born more than 30 years ago that has recently expanded to interpersonal interactions, the so-called social coordination dynamics. In our study, we hypothesize that the sensorimotor deficits associated with schizophrenia in social interaction may be, at least partially, due to a failure to properly pick up information about the movements of other people. We therefore designed a study where healthy individuals and schizophrenic patients were asked to intentionally track the oscillations of visual targets of various social relevance using hand movements. Four different rhythmic visual stimuli varying in degree of biological relevance (form and motion) are used: [1] an oscillating dot; [2] a computer generated hand moving up and down continuously driven by a sine function; [3] pre-recorded oscillatory movements of a real hand; and [4] the hand of a real individual (behind a curtain that occluded vision of the rest of the body). Two distinct dependent variables are computed to quantify the coordination between the movements of the participants and the visual stimuli: the relative phase and the power spectrum overlap between their own movements. In this preliminary study, analyses of kinematic data revealed that schizophrenic patients had trouble synchronizing to (the more) "biological" target unlike control healthy individuals. These results suggest that patients with schizophrenia may suffer from sensorimotor coordination disabilities with socially relevant visual stimuli. The novel paradigm we introduce in research on schizophrenia should allow for a better understanding of the troubles these patients encounter when interacting with other people thanks to an approach rooted and building on social coordination dynamics as well as motor and social cognition. PMID- 22212839 TI - [Decision-making and schizophrenia]. AB - Abnormalities involving the prefrontal cortex (PFC) have long been postulated to underpin the pathophysiology of schizophrenia. Investigations of PFC integrity have focused mainly on the dorsolateral PFC (DLPFC) and abnormalities in this region have been extensively documented. However, defects in schizophrenia may extend to other prefrontal regions, including the ventromedial PFC (VMPFC), and evidence of VMPFC abnormalities comes from neuropathological, structural and functional studies. Patients with acquired brain injury to the VMPFC display profound disruption of social behaviour and poor judgment in their personal lives. The Iowa Gambling Task (IGT) was developed to assess decision-making in these neurological cases : it presents a series of 100 choices from four card decks that differ in the distribution of rewarding and punishing outcomes. Whilst healthy volunteers gradually develop a preference for the two "safe" decks over the course of the task, patients with VMPFC lesions maintain a preference for the two "risky" decks which are associated with high reinforcement in the short term, but significant long-term debt. Interestingly, damage to VMPFC may cause both poor performance on the IGT and lack of insight concerning the acquired personality modification. Recently, our group reported a trait-related decisionmaking impairment in the three phases of bipolar disorder. In a PET study, VMPFC dysfunction was shown in bipolar manic patients impaired on a decision-making task and an association between decision-making cognition and lack of insight was described in mania. A quantitative association between grey matter volume of VMPFC and memory impairment was previously reported in schizophrenia. Research suggests that lack of insight is a prevalent feature in schizophrenia patients, like auditory hallucinations, paranoid or bizarre delusions, and disorganized speech and thinking. Because schizophrenia is associated with significant social or occupational dysfunction, previous research assessed decision-making function but indicates conflicting results. Thirteen studies have reported impaired IGT performance in patients with schizophrenia and, in seven reports, no significant differences in IGT performance between patient and healthy control groups were found. Those discrepancies may relate to multiple factors. First, most of the studies included small sample size and negative findings may be due to the large variance of net scores. Second, as suggested by Rodriguez-Sanchez et al., there is a wide disparity in performance by control subjects across studies. Third, intelligence quotient (IQ) score and level of education may be correlated with IGT performance, which may explain IGT performance differences in studies that did not control for educational or IQ score. Fourth, only two studies have systematically controlled for substance use disorder, a potential confounder. Fifth, only two studies assessed the impact of antipsychotic (AP) class on performance. Sixth, to our knowledge, no study assessed the impact of AP dosage on decision-making ability, while AP dose reduction and dopamine increase, might lead to improvements, in cognitive functions in schizophrenia and in IGT performance in bipolar disorder, respectively. Finally, discrepancies between studies may be related to the heterogeneity of diagnostic groups. Two of the negative studies included schizophrenia and schizoaffective disorder while positive studies have generally included only patients with schizophrenia. Nevertheless, some studies that included only patients with schizophrenia failed to find differences between groups. Thus, further research should assess decision-making in schizophrenia by testing a large group of patients with homogeneity of diagnostic, in comparison with a large group of control subjects. Authors should control for IQ or level of education, substance use disorder and smoking status. While it is now accepted that DLPFC defects in schizophrenia may extend to VMPFC, future investigations should test for an association between memory, insight ability and IGT performance and assess the impact of antipsychotic dosage upon performance. PMID- 22212840 TI - [Theory of mind and schizophrenia]. AB - In social cognition, the notion of Theory of Mind (ToM) is widely studied among people with schizophrenia to give an account for intersubjective disturbances. ToM is classically defined as the ability to make inferences about other persons'mental states, as beliefs, thoughts or intentions. However, ToM is not understood or explored as a homogeneous notion. First, this review briefly describes main theoretical models, as well as experimental tasks of ToM. Second, clinical results strongly suggest that patients with schizophrenia present impaired ToM performances. However, the presence of a robust relationship between ToM and schizophrenic symptomatology, or clinical course, is still controversial. Third, we highlight main findings from functional brain imaging studies based on ToM. Finally and in a more critical perspective, we suggest a few theoretical and experimental limitations regarding impaired ToM as a core feature of schizophrenic disturbances in social interactions. PMID- 22212841 TI - [Schizophrenia, cognition and neuroimaging]. AB - Schizophrenia is a complex illness whose mechanisms are still largely unknown. Functional brain imaging, by making the link between psyche and brain, has recently become an indispensable tool to study in vivo the neural bases underlying cognitive dysfunction in this disease. But despite the proliferation of data coming from this approach, the exact impact of functional imaging on our understanding of the disease remains blurry. In general, studies of the brain functioning of patients with schizophrenia found activation abnormalities which vary in nature and localization depending of the cognitive paradigm used. However, it appears that neurofunctional abnormalities observed in patients cannot be reduced to a simple well-localized deficit. It would be rather an alteration of the dynamics of the interactions between different brain regions that underlie the cognitive disturbances encountered in the disease. Functional brain imaging now offers new perspectives to clarify the dynamics of the brain networks, and particularly those involved in high-level cognitive functions, such as cognitive control or social cognition which seem to play a crucial role in the disease. The characterization of these features is an important issue not only to develop new hypotheses on the pathophysiology of the disorder, but also more pragmatically to identify potential therapeutic targets. PMID- 22212842 TI - [Schizophrenia, genetics and cognition]. AB - Schizophrenia is a complex and heritable disorder. Nevertheless, molecular genetics of schizophrenia remains inconclusive. By developing the concept of endophenotype for the disorder, it is easier to define an association between a phenotype and genetic variants or physiopathological processes. Cognitive disorders could be useful endophenotypes for schizophrenia. For example, the val(158)/met COMT polymorphism has been associated with executive function or working memory. Therefore, several cognitive dysfunctions were proposed as endophenotypes and were investigated in the context of different genetic polymorphisms. Genome-wide association studies and epistatic studies demonstrated the complexity of the mechanisms underlying cognitive disturbance. However, meta analysis remains inconclusive. Altogether, the study of endophenotypes is an attractive approach to solve the complex mechanisms causing schizophrenia vulnerability. Nevertheless, several limitations exist and include the lack of reproducibility, the discordant results between healthy subjects and patients, the exclusion of the many rare variants. PMID- 22212843 TI - [Schizophrenia and cognition: a neurodevelopmental approach]. AB - Accumulating evidence supports the hypothesis of abnormal neurodevelopment in schizophrenia. According to this hypothesis, schizophrenia is the consequence of prenatal abnormalities resulting from the interaction of genetic and environmental factors. In line with this hypothesis, several studies indicate that pregnancy and birth complications are risk factors for developing schizophrenia. At the clinical level, multiple cognitive deficits can be found in schizophrenic patients before illness onset. The neurodevelopmental hypothesis considers these cognitive deficits as the expression of early abnormalities on the central nervous system development. Consistently, brain imaging data show early structural abnormalities and abnormal progressive brain changes in schizophrenia. Finally, genetic and histological data indicate that genes associated with schizophrenia are involved in brain development. PMID- 22212844 TI - [Schizophrenia, psychotropic drugs and cognition]. AB - The robust and specific associations between cognitive abilities and the functional prognosis of patients suffering from schizophrenia lead to a major concern for cognitive impairment in this disorder. Among the strategies considered to correct or enhance cognition in schizophrenia, drugs hold a pivotal place. Evidently, antipsychotic drugs, which are inextricable from patients' management, have generated considerable scrutiny in this topic. This paper first aims to outline the current views on the impact of antipsychotic drugs in schizophrenia. The distinction between conventional and atypical drugs is reminded in order to more precisely review existing data comparing the impact of these two types of molecules on cognitive impairment. More specifically, an elementary framework is proposed to facilitate the recognition of methodological flaws and offer a critical examination of previous findings. It emerges subsequently that differences between atypical and conventional drugs appear far less contrasted than initially suggested. Also, atypical antipsychotics compose a disparate pharmacological class and much clarification could be obtained by differentiating the individual effects of these molecules rather than considering them as a group. Finally, the relevance of these cognitive measures is also considered. In particular, we address alternative measures closer to real life situations as well as the growing interest in the broad field of social cognition. A last part of this article deals with strategies relying on adjunctive therapies. The fairly modest results obtained with these approaches is evoked and briefly reviewed. PMID- 22212845 TI - [Perception of atypical antipsychotics' side effects through speech analysis of schizophrenic patients. TALK Study]. AB - OBJECTIVE: Patients with schizophrenia often become non-adherent following negative treatment experiences as antipsychotics'side-effects. The objective of this study was to propose an alternative measure of patients'perception of atypical antipsychotics'side-effects on weight, as weight is a major concern reported by patients. METHOD: We used a computer-assisted method called Alceste, which is a pragmatic analysis of speech. We selected three groups of ten patients respectively treated by three different atypical antipsychotics: aripiprazole, olanzapine and risperidone. Participants were administered an interview. All speeches were retranscribed and structured in a set of texts, called a corpus. Regarding antipsychotic treatment, we constituted three corpuses of ten speeches. We analyzed separately the three corpuses with the software Alceste. RESULTS: Our findings revealed the presence of a specific class dealing with treatment and illness in the speech of patients, regardless of their treatment. We found weight related words in all three-treatment groups. The examination of the context of use showed this notion was differently employed in each treatment group: if weight was statistically associated with the notion of loss in the aripiprazole group, the reverse was found (notion of gain) in the two other treatment groups. CONCLUSION: Our findings are valuable because they contribute to validate this speech analysis method. Actually our results, which are mathematically obtained through speech analysis, are convergent with those objectively observed by clinicians. Thus we hypothesize the Alceste-software is a relevant tool to evaluate the perceptions of antipsychotic side-effects. PMID- 22212846 TI - [Schizophrenia, cognition and psychoeducation]. AB - Cognitive impairment among patients suffering from schizophrenia is closely linked to psychoeducation and therapeutic education. First, this cognitive impairment requires specific communication strategy and special cognitive and behavioral techniques, which make possible for the patients to improve their trainability. Some of these tools are detailed, such as solving problems, communication skills, role plays, repetition, rewarding, and motivational support. Second, functional and social impairment, and outcome, are partly consequences of these cognitive problems. Cognitive remediation targets elementary cognitive impairment, mostly with repetitive cognitive tasks, and studies show an improvement in these specific tasks, but without positive effect on functional and social aspects of the illness. Overall approaches, such as psychoeducation or therapeutic education, obtain real gains in quality of life for the patients, autonomy and clinical improvement. It's not yet possible to know if these positive results underlie improvement in elementary cognitive impairment. The combination between remediation and psychoeducation seems to be promising. PMID- 22212847 TI - [What perspectives for cognitive remediation in schizophrenia?]. AB - Cognitive deficits are routinely evident in schizophrenia, and are of sufficient magnitude to influence functional outcomes in work, social functioning and illness management. Cognitive remediation is an evidenced-based non pharmacological treatment for the neurocognitive deficits seen in schizophrenia. Narrowly defined, cognitive remediation is a set of cognitive drills or compensatory interventions designed to enhance cognitive functioning, but from the vantage of the psychiatric rehabilitation field, cognitive remediation is a therapy which engages the patient in learning activities that enhance the neurocognitive skills relevant to their chosen recovery goals. Cognitive remediation programs vary in the extent to which they reflect these narrow or broader perspectives but a metaanalytic study reports moderate range effect sizes on cognitive test performance, and daily functioning. Reciprocal interactions between baseline ability level, the type of instructional techniques used, and motivation provide some explanatory power for the heterogeneity in patient response to cognitive remediation. Recent studies indicate that intrinsic motivation mediates the relationship between neurocognition and functional outcomes. Results of these studies suggest that intrinsic motivation should be a viable treatment target in cognitive remediation intervention. In this perspective, NEAR (Neuropsychological Educational Approach to Remediation) program was created to enhance intrinsic motivation by employing more engaging and interesting software packages for cognitive practice, involving consumers in choosing the focus of training and having the NEAR leader serve as a coach to engage the consumers in active guidance of their own treatment program. PMID- 22212848 TI - [Schizophrenia and cognition: long-standing and current issues]. PMID- 22212849 TI - [Schizophrenia, executive control and memory]. AB - Schizophrenia affects 1% of the general population. In addition to disabling clinical symptoms, cognitive deficits have also been updated. It has further been proposed that the well-known diversity of schizophrenia in terms of functional outcome and recovery from acute episode is best characterized by cognitive deficits, but not by its classical symptoms. DSM-V acknowledges the importance of cognition in schizophrenia, and could recommend a formal neuropsychological assessment in individuals with psychosis. Schizophrenic patient's cognitive functioning has been studied extensively in the domain of memory and executive control. To date, the studies highlight important deficits in both of these domains. However, within the memory systems, some of them remain unaffected. Altogether, the data invalidate the hypothesis of a global damage and are in favor of specific cognitive deficits. The observed deficits would depend on the dominant symptoms and pre-morbid functioning. The interest of these results was to give impulse to the development of comprehensive assessment battery designed to evaluate the cognitive profiles of each patient and develop a personalized program of cognitive remediation. PMID- 22212850 TI - Outcomes after discontinuation of antiepileptic drugs after surgery in patients with low grade brain tumors and meningiomas. AB - Low grade tumors are associated with a high risk of seizures. Prolonged use of antiepileptic drugs (AEDs) is associated with morbidity. Determining which patients can safely discontinue AEDs perioperatively is difficult. We examined patients with low grade supratentorial brain tumors to determine characteristics of patients who underwent AED withdrawal. A retrospective chart review was performed in patients who underwent resection between 1/1/2004 and 12/31/2005 at a single center. Data were collected regarding the use of postoperative AEDs, occurrence of postoperative seizures, and patient/tumor characteristics. We examined 169 patients with a median follow-up of 3.1 years. AEDs were withdrawn or never started in 111 patients; post-withdrawal seizures occurred in 11 (9.9%). The rate was similar between meningiomas and primary brain tumors. No independent risk factors for post-withdrawal seizures were found. Of 58 patients whose AEDs were not withdrawn, postoperative seizures occurred in 28 (48%). Predictors of AED continuation included existence of preoperative seizures, temporal tumor location, tumor recurrence, incomplete resection, and male sex. The decision to continue AEDs was predictive for postoperative seizures even after controlling for known risk factors. Although clinicians are able to identify patients at high risk for postoperative seizures, treatment with AEDs is ineffective in many patients. PMID- 22212851 TI - Identification of Brassica napus lysophosphatidylcholine acyltransferase genes through yeast functional screening. AB - Acyl-CoA:lysophosphatidylcholine acyltransferase (LPCAT), which acylates lysophosphatidylcholine (LPC) to produce phosphatidylcholine (PC), is a key enzyme in the Lands cycle. There is evidence that acyl exchange involving LPCAT is a prevailing metabolic process during triacylglycerol (TAG) synthesis in seeds. In this study, by complementing the yeast lca1Delta mutant deficient in LPCAT activity with an Arabidopsis seedling cDNA library, it was found that the previously reported lysophospholipid acyltransferases (LPLATs), At1g12640 and At1g63050, were the only two acyltransferase genes that restored hyposensitivity of the lca1Delta mutant to lyso-platelet-activating factor (lyso-PAF). A developing seed cDNA library from Brassica napus L. cv Hero was constructed to further explore the heterologous yeast complementation approach. Three B. napusLPCAT homologs were identified, of which BnLPCAT1-1 and BnLPCAT1-2 are orthologous to ArabidopsisAtLPLAT1 (At1g12640) while BnLPCAT2 is an ortholog of AtLPLAT2 (At1g63050). The proteins encoded by BnLPCAT1-1 and BnLPCAT2 were chosen for further study. Enzymatic assays demonstrated that both proteins exhibited a substrate preference for LPCs and unsaturated fatty acyl-CoAs. In addition to the enzymatic properties of plant lysophosphatidylcholine acyltransferases uncovered in this study, this report describes a useful technique that facilitates subsequent analyses into the role of LPCATs in PC turnover and seed oil biosynthesis. PMID- 22212852 TI - Evaluation of the effects of circular Descemet's membrane incision on the biomechanical, topographic and optical properties of rabbit corneas. AB - BACKGROUND: Prospective interventional animal case series to investigate quantitatively changes in corneal light-scattering, corneal hysteresis, keratometry and pachymetry induced by circular Descemet's membrane incision. METHODS: Thirty mature New Zealand White rabbits were divided into three study groups: (i) surgical intervention with circular Descemet's incision; (ii) surgical control; and (iii) medical control. Group 1 eyes had two paracenteses placed 120 degrees apart and an 8.5-mm-diameter Descemetorhexis was created with a reverse Sinskey hook. Group 2 eyes had two paracenteses placed 120 degrees apart. The main outcome measures were scatterometry, corneal hysteresis, pachymetry and keratometry measurements, which were performed prior to and 2 weeks following the interventions. Histology and transmission electron microscopy were performed post-mortem in representative eyes. RESULTS: Eyes that had undergone circular Descemet's incision had significantly decreased mean keratometry (43.9 +/- 0.7 dioptres [mean +/- standard deviation] preoperatively vs. 43.5 +/- 0.9 dioptres postoperatively, P = 0.007). Circular Descemet's membrane incision did not significantly change corneal hysteresis (4.4 +/- 1.1 mmHg preoperatively vs. 4.6 +/- 0.9 mmHg postoperatively, P = 0.664). Corneal light scattering decreased after Descemet's scoring (0.00254 +/- 0.00059 preoperatively vs. 0.00206 +/- 0.00031 postoperatively, P = 0.0025). Pachymetry measurements remained relatively stable (341.3 +/- 18.6 um preoperatively vs. 330.6 +/- 20.0 um postoperatively) without postoperative oedema. CONCLUSIONS: Circular Descemet's scoring flattened the corneal curvature by a mean of 0.4 dioptres without affecting corneal hysteresis in rabbit corneas. These findings may have important implications for ongoing developments in endothelial keratoplasty. PMID- 22212853 TI - Induction of immediate early genes in the mouse auditory cortex after auditory cued fear conditioning to complex sounds. AB - Immediate early genes (IEGs) are widely used as markers to delineate neuronal circuits because they show fast and transient expression induced by various behavioral paradigms. In this study, we investigated the expression of the IEGs c fos and Arc in the auditory cortex of the mouse after auditory cued fear conditioning using quantitative polymerase chain reaction and microarray analysis. To test for the specificity of the IEG induction, we included several control groups that allowed us to test for factors other than associative learning to sounds that could lead to an induction of IEGs. We found that both c fos and Arc showed strong and robust induction after auditory fear conditioning. However, we also observed increased expression of both genes in any control paradigm that involved shocks, even when no sounds were presented. Using mRNA microarrays and comparing the effect of the various behavioral paradigms on mRNA expression levels, we did not find genes being selectively upregulated in the auditory fear conditioned group. In summary, our results indicate that the use of IEGs to identify neuronal circuits involved specifically in processing of sound cues in the fear conditioning paradigm can be limited by the effects of the aversive unconditional stimulus and that activity levels in a particular primary sensory cortical area can be strongly influenced by stimuli mediated by other modalities. PMID- 22212854 TI - The efficacy and tolerability of two novel H(1)/H(3) receptor antagonists in seasonal allergic rhinitis. AB - BACKGROUND: A therapeutic role for histamine H(3) receptor antagonism in allergic rhinitis has been proposed and may be complimentary to the well-known benefits of H(1) receptor antagonism. Combined H(1)/H(3) blockade has therefore been investigated as a novel therapeutic approach that may enhance symptom relief, particularly nasal blockage. METHODS: Two novel H(1)/H(3) dual receptor antagonists were investigated in phase I and II safety and efficacy studies. One molecule (GSK1004723) was designed for intranasal administration as a suspension or solution and the other molecule (GSK835726) for oral administration. In phase I and II studies, both molecules were compared with an active control and/or placebo in randomised studies. In phase II studies, efficacy was assessed in an environmental allergen challenge chamber (ECC). Subjects with seasonal allergic rhinitis were exposed to allergen to induce symptoms. Efficacy and safety was measured over 4, 7 and 20-24 h post-dose. The endpoints included total nasal symptom score and nasal blockage. RESULTS: Intranasal suspension of GSK1004723 and oral GSK835726 were well tolerated. Single-dose intranasal suspensions of GSK1004723 (220, 1,100 MUg) failed to demonstrate clinically significant attenuation of symptoms of allergic rhinitis induced in the ECC. Single (10, 50, 100 mg) and 3-day repeat (10 mg) dose oral GSK835726 demonstrated clinically significant attenuation of symptoms in the ECC comparable to cetirizine 10 mg. Three-day repeat dosing of the intranasal solution GSK1004723 1,000 MUg also demonstrated a statistically significant attenuation of nasal symptoms, but was less than seen with cetirizine and GSK835726 and caused initial nasal discomfort. CONCLUSIONS: Combined H(1)/H(3) antagonism did not show differentiation from H(1) antagonism in reducing total nasal symptom score or nasal blockage. PMID- 22212855 TI - Detection and genetic characterization of foot-and-mouth disease viruses in samples from clinically healthy animals in endemic settings. AB - A total of 1501 oral swab samples from Pakistan, Afghanistan and Tajikistan were collected from clinically healthy animals between July 2008 and August 2009 and assayed for the presence of foot-and-mouth disease virus (FMDV) RNA. The oral swab samples from two (of four) live animal markets in Pakistan (n = 245), one (of three) live animal market in Afghanistan (n=61) and both the live animal markets in Tajikistan (n=120) all tested negative. However, 2 of 129 (~2%) samples from Gondal and 11 of 123 (9%) from Chichawatni markets in Pakistan were positive for FMDV RNA. Similarly, 12 of 81 (15%) samples from Kabul and 10 of 20 (50%) from Badakhshan in Afghanistan were found to be positive. Serotypes A and O of FMDV were identified within these samples. Oral swab samples were also collected from dairy colonies in Harbanspura, Lahore (n=232) and Nagori, Karachi (n=136), but all tested negative for FMDV. In the Landhi dairy colony, Pakistan, a cohort of 179 apparently healthy animals was studied. On their arrival within the colony, thirty-nine (22%) of these animals were found positive for FMDV RNA (serotype A was identified), while 130 (72.6%) had antibodies to FMDV non structural proteins. Thus, newly introduced animals may be a significant source of the disease in the colony. Only two animals from the cohort were detected as becoming positive for FMDV RNA during a follow-up period of 4months; however, only 10 animals remained negative for anti-NSP antibodies during this period. PMID- 22212856 TI - Behavior of seeds and soil in the mechanism of metastasis: a deeper understanding. AB - The so-called "seed and soil" hypothesis proposed by Stephen Paget in 1889 to explain the metastatic behavior of cancer cells and the homing of certain cancers to "selected" sites has been a well-recognized phenomenon for over a century. What advances have been made to increase our understanding of this phenomenon and what does it really implicate in terms of targets for therapy? PMID- 22212857 TI - High on-treatment platelet reactivity assessed by various platelet function tests: is the consensus-defined cut-off of VASP-P platelet reactivity index too low? PMID- 22212859 TI - Excessive vomiting. PMID- 22212858 TI - Seroprevalence of pandemic (H1N1) 2009 influenza and effectiveness of 2010/2011 influenza vaccine during 2010/2011 season in Beijing, China. AB - BACKGROUND: In the post-pandemic period, pandemic (H1N1) 2009 virus was expected to circulate seasonally and was introduced into trivalent influenza vaccine during 2010/2011 season in the Northern Hemisphere. OBJECTIVES: The aim of this study was to examine the evolution of herd immunity against pandemic (H1N1) 2009 virus in Beijing, China, during 2010/2011 season and effectiveness of the 2010/2011 trivalent vaccine. METHODS: Two serological surveys were conducted before and after 2010/2011 season in Beijing. A case-control study was used to investigate vaccine effectiveness against influenza-like illness (ILI) and lower respiratory tract infection (LRI). RESULTS: A total of 4509 and 4543 subjects participated in the pre- and post-season surveys, respectively. The standardized seroprevalence of pandemic (H1N1) 2009 influenza increased from 22.1% pre-season to 24.3% post-season (P<0.001). Significant elevation in seroprevalence appeared in the >= 60 years age-group (P<0.001), but not in others. The 2010/2011 trivalent vaccine contributed to the higher post-seasonal seroprevalence in unvaccinated individuals (P=0.024), but not in those vaccinated with monovalent pandemic vaccine (P=0.205), as well as in those without prior immunity versus those with immunity. The adjusted effectiveness of the 2010/2011 trivalent vaccine was 79% protection against ILI (95% CI, 61-89%) and 95% against LRI (95% CI: 59-99%). CONCLUSIONS: A slight increase in herd immunity against pandemic (H1N1) 2009 influenza was observed in Beijing, China, during the 2010/2011 season. Prior vaccination and immunity had a suppressive impact on immune response toward this novel influenza virus, elicited by 2010/2011 trivalent vaccine. This trivalent vaccine conferred good protection against ILI and LRI. PMID- 22212860 TI - Direct effect of acaricides on pathogen loads and gene expression levels in honey bees Apis mellifera. AB - The effect of using acaricides to control varroa mites has long been a concern to the beekeeping industry due to unintended negative impacts on honey bee health. Irregular ontogenesis, suppression of immune defenses, and impairment of normal behavior have been linked to pesticide use. External stressors, including parasites and the pathogens they vector, can confound studies on the effects of pesticides on the metabolism of honey bees. This is the case of Varroa destructor, a mite that negatively affects honey bee health on many levels, from direct parasitism, which diminishes honey bee productivity, to vectoring and/or activating other pathogens, including many viruses. Here we present a gene expression profile comprising genes acting on diverse metabolic levels (detoxification, immunity, and development) in a honey bee population that lacks the influence of varroa mites. We present data for hives treated with five different acaricides; Apiguard (thymol), Apistan (tau-fluvalinate), Checkmite (coumaphos), Miteaway (formic acid) and ApiVar (amitraz). The results indicate that thymol, coumaphos and formic acid are able to alter some metabolic responses. These include detoxification gene expression pathways, components of the immune system responsible for cellular response and the c-Jun amino-terminal kinase (JNK) pathway, and developmental genes. These could potentially interfere with the health of individual honey bees and entire colonies. PMID- 22212861 TI - Warm-up effects on muscle oxygenation, metabolism and sprint cycling performance. AB - To investigate the effects of warm-up intensity on all-out sprint cycling performance, muscle oxygenation and metabolism, 8 trained male cyclists/triathletes undertook a 30-s sprint cycling test preceded by moderate, heavy or severe warm up and 10-min recovery. Muscle oxygenation was measured by near-infrared spectroscopy, with deoxyhaemoglobin ([HHb]) during the sprint analysed with monoexponential models with time delay. Aerobic, anaerobic glycolytic and phosphocreatine energy provision to the sprint were estimated from oxygen uptake and lactate production. Immediately prior to the sprint, blood [lactate] was different for each warm up and higher than resting for the heavy and severe warm ups (mod. 0.94 +/- 0.36, heavy 1.92 +/- 0.64, severe 4.37 +/- 0.93 mmol l(-1) P < 0.05), although muscle oxygenation was equally raised above rest. Mean power during the sprint was lower following severe compared to moderate warm up (mod. 672 +/- 54, heavy 666 +/- 56, severe 655 +/- 59 W, P < 0.05). The [HHb] kinetics during the sprint were not different among conditions, although the time delay before [HHb] increased was shorter for severe versus moderate warm up (mod. 5.8 +/- 0.6, heavy 5.6 +/- 0.9, severe 5.2 +/- 0.7 s, P < 0.05). The severe warm up was without effect on estimated aerobic metabolism, but increased estimated phosphocreatine hydrolysis, the latter unable to compensate for the reduction in estimated anaerobic-glycolytic metabolism. It appears that despite all warm ups equally increasing muscle oxygenation, and indicators of marginally faster oxygen utilisation at the start of exercise following a severe intensity warm up, other energy sources may not be able to fully compensate for a reduced glycolytic rate in sprint exercise with potential detrimental effects on performance. PMID- 22212862 TI - Phlebodium decumanum is a natural supplement that ameliorates the oxidative stress and inflammatory signalling induced by strenuous exercise in adult humans. AB - Strenuous exercise induces muscle damage due to a highly increased generation of free radicals and inflammatory response and therefore, in this type of exercise, it is important to reduce both oxidative stress and inflammation, at least their negative aspects. The purpose of this study was investigate, for the first time, whether a purified, standard water-soluble fraction obtained from Phlebodium decamanum could reduce the over-expression of inflammation and oxidative stress induced by strenuous exercise. The physical test consisted of a constant run that combined several degrees of high effort (mountain run and ultra-endurance), in permanent climbing. Biochemical parameters, oxidative stress and inflammatory mediators were assessed. The results showed that oral supplementation of P. decumanum during high-intensity exercise effectively reduces the degree of oxidative stress (decreased 8-hydroxy-2'-deoxyguanosine and isoprostanes generation, increased antioxidant enzyme activities in erythrocyte and total antioxidant status in plasma). The data obtained also indicate that this supplementation is efficient in reducing the inflammatory response through the decrease of TNF-alpha and increase of sTNF-RII, but kept the levels of IL-6 and IL-1ra. In conclusion, oral supplementation of P. decamanum extract during high intensity exercise effectively reduces the degree of oxidative stress and has anti-inflammatory protective effects, preventing the over-expression of TNF-alpha but keeping the levels and effects of IL-6. These findings provide a basis for similar Phlebodium supplementation for both professional and amateur athletes performing strenuous exercise in order to reduce the undesirable effects of the oxidative stress and inflammation signalling elicited during high-intensity exercise. PMID- 22212864 TI - Peptide nucleic acid molecular beacons for the detection of PCR amplicons in droplet-based microfluidic devices. AB - The use of droplet-based microfluidics and peptide nucleic acid molecular beacons for the detection of polymerase chain reaction (PCR)-amplified DNA sequences within nanoliter-sized droplets is described in this work. The nanomolar attomolar detection capabilities of the method were preliminarily tested by targeting two different single-stranded DNA sequences from the genetically modified Roundup Ready soybean and the Olea europaea genomes and detecting the fluorescence generated by peptide nucleic acid molecular beacons with fluorescence microscopy. Furthermore, the detection of 10 nM solutions of PCR amplicon of DNA extracted from leaves of O. europaea L. encapsulated in nanoliter sized droplets was performed to demonstrate that peptide nucleic acid molecular beacons can discriminate O. europaea L. cultivar species carrying different single-nucleotide polymorphisms. PMID- 22212863 TI - Targeting stroma to treat cancers. AB - All cancers depend on stroma for support of growth. Leukemias, solid tumors, cancer cells causing effusions, metastases as well as micro-disseminated cancer cells release factors that stimulate stromal cells, which in turn produce ligands that stimulate cancer cells. Therefore, elimination of stromal support by destroying the stromal cells or by inhibiting feedback stimulation of cancer growth is in the focus of many evolving therapies. A stringent evaluation of the efficacy of stromal targeting requires testing in animal models. Most current studies emphasize the successes of stromal targeting rather than deciphering its limitations. Here we show that many of the stromal targeting approaches, while often reducing tumor growth rates, are rarely curative. Therefore, we will also discuss conditions where stromal targeting can eradicate large established tumors. Finally, we will examine still unanswered questions of this promising and exciting area of cancer research. PMID- 22212866 TI - Chronic vitamin C deficiency does not accelerate oxidative stress in ageing brains of guinea pigs. AB - Increased oxidative stress in the brain has consistently been implied in ageing and in several degenerative brain disorders. Acting as a pivotal antioxidant in the brain, vitamin C is preferentially retained during deficiency and may play an essential role in neuroprotection during ageing. Thus, a lack of vitamin C could be associated with an increase in redox imbalance in the ageing brain. The present study compared oxidative stress of ageing to that of a long-term non scorbutic vitamin C deficiency in guinea pigs. Adults (3-9 months old) were compared to old (36-42 months old) animals during a 6-month dietary intervention by assessing vitamin C transport and redox homoeostasis in the brain. In contrast to our hypothesis, chronic vitamin C deficiency did not affect the measured markers of oxidative stress in the brains of adult and aged animals. However, aged animals generally showed increased lipid oxidation (p < 0.001), decreased glutathione (p < 0.05), increased p53 mRNA expression (p < 0.01) and somewhat elevated DNA oxidation (p = 0.08) compared to adult counterparts irrespective of dietary vitamin C intake. Increased mRNA expression of sod1 (p < 0.05) and svct2 (p = 0.05) was observed in aged animals together with increased superoxide dismutase activity (p < 0.01) and cerebrospinal fluid vitamin C status (p < 0.001) suggesting a compensatory effort that did not counterbalance the effects of ageing. Essentially, no effects of age were observed in the liver demonstrating the brain's unique susceptibility to redox imbalance. Consistent with previous findings, we show that ageing per se constitutes a considerable oxidative insult in the brain. However, our data also suggest that a long-term poor vitamin C status does not accelerate this process. PMID- 22212865 TI - Enigmatic sex disparities in cancer incidence. AB - In this study we aimed to identify cancers where there is a consistent sex disparity, with the goal of identifying unexplained sex disparities that may offer promising opportunities for etiologic research. Age- and sex-specific cancer incidence data from Cancer Incidence in Five Continents, provided by the International Agency for Research on Cancer, were used to calculate incidence rate ratios for 35 cancer sites, comparing men to women, adjusting for attained age, gross domestic product (GDP), and geographical region. Genital cancers and breast cancer were excluded. The consistency of relative risks was examined by GDP and geographical region and, in a subset of longstanding cancer registers, by calendar year. For each cancer site, the sex disparity was broadly classified as plausibly explained by established environmental risk factors, partly explained, or unexplained. Cancer incidence was statistically significantly higher in men than women at 32 of 35 sites, with disparities >2-fold for 15 sites and >4-fold for 5 sites. For nearly all sites, the sex disparity was consistent across GDP groups and geographical regions. However, the incidence rate ratios varied considerably by age at diagnosis. The sex disparity for 13 cancer sites was considered to be entirely unexplained by known risk factors; these sites showed strikingly little variation in the incidence rate ratios over decades. Thus, the basis of many of the largest sex disparities in cancer incidence seems mostly unknown, highlighting the need for intensified research into its origins. PMID- 22212867 TI - [Bipolar depression]. PMID- 22212868 TI - [Major depression: features indicative of bipolarity?]. AB - Several recent studies have shown that bipolar disorder is underdiagnosed in patients with major depression. Missing the diagnosis of a bipolar disorder may have serious and even occasionally fatal consequences for a patient with the disease. Moreover misdiagnosis may lead to inappropriate treatment and therefore contribute to worsening medical and functional prognosis. Although there are no pathognomonic characteristics of bipolar depression compared to unipolar depression, evidence-based findings suggest that some features may be indicative of bipolarity, in patients with depression. These features are related to clinical picture of depressive state, course of episode and illness, response to treatment, family history, comorbid conditions, as well as demographic and temperamental characteristics. Based on such features, some authors have proposed operationalized criteria or a diagnostic specific for bipolarity, to identify bipolar depression. Screening instruments may also be used, to facilitate early recognition. Validation studies of these diagnostic features and instruments are underway. PMID- 22212869 TI - [Bipolar depression and suicidal behavior]. AB - Suicide is a frequent and tragic consequence of bipolar depression. The prevention of suicidal behavior (SB) need an assessment of vulnerability traits related related to SB (personal suicide history, impulsive traits...), characteristics of depression (mixed depression, subtype of bipolar disorder...), psychiatric comorbidities and stressors psycho-social. Meanwhile, the characteristics of suicidal behavior (ie: severe or multiple attempts) suggest a diagnosis of bipolar disorder rather than major depressive disorder. In addition to a correct screening of bipolar disorders and assessment of suicidal behavior, the removal of lethal means, networking and treatment of depression reduces the risk of suicidal behavior. Finally, lithium may have a particular interest in subjects at high risk of suicide. PMID- 22212870 TI - Consequences of delayed diagnosis of bipolar disorders. AB - Over 60% of individuals with bipolar disorders report that they received between 1-4 prior diagnoses, with delay in diagnosis being a particular problem in females with bipolar II disorders. Clinical recognition of bipolarity may take up to 10 years, during which time individuals may have received a number of inadequate or inappropriate treatments. This paper describes the adverse clinical, functional and economic consequences of the failure to identify cases of bipolar disorder at the earliest possible time. PMID- 22212871 TI - [What is the burden associated with bipolar depression?]. AB - Intensity and frequency of the thymic symptoms are specific of the clinical picture of bipolar disorder patients. International classifications, don't take into account polarity as an operational criteria. Despite the lack of a consensual definition of polarity, close to 2/3 of the patients can be considered as having a predominant depressive form. Polarity can be considered as idiosyncratic of a patient and could be the preferential mode of evolution. Identification of the polarity of the disorder has interests in terms of prognosis and choice of treatment. PMID- 22212872 TI - [Emotional reactivity: a tool for diagnosis?]. AB - Emotional reactivity can be defined regarding the threshold needed to induce emotion and the amplitude of emotional response. In bipolar disorder, emotional dysregulations can be observed, sometimes related to mood. Description of emotional reactivity can contribute to the characterization of the different phases of bipolar disorder. During manic or mixed episodes, emotional reactivity is increased. Bipolar depression is a heterogeneous entity and emotional reactivity can help to characterize it and to define the most adequate therapeutic. Exploration of emotional reactivity can be helpful to understand pathophysiology of the different Thymic states observed in Bipolar disorder. PMID- 22212873 TI - [Can we identify biomarkers in bipolar depression? From imaging to biology]. AB - Biomarkers can be used to describe and quantify a biological process related to pathology or to the effect of a treatment. In bipolar depression, progresses in the fields of structural and functional imaging, but also in biological research help to identify such biomarkers. Results in structural imaging are heterogeneous. Using functional imaging, in bipolar depression we can identify an hyperactivity of limbic and striatal regions with a specific implication of the lateral part of the orbito-frontal cortex. Bipolar depression is also associated with a modification of neurotrophic factors and of factors involved in the inflammatory process. Modifications in circadian rhythms have also be described but their level of specificity have to be demonstrated. The identification of biomarkers for bipolar depression seems to be an interesting field, but it still remains in the domain of research. PMID- 22212874 TI - [Cognitive disturbances and bipolar depression]. AB - The existence of cognitive deficits during the acute phases of bipolar disorder (manic, depressive, hypomanic or mixed episodes) has long been demonstrated and by numerous studies. The existence of cognitive deficits during euthymic periods has been much less studied. In addition, these studies are hampered by several methodological difficulties (small sample sizes, confounding factors influencing cognitive performance such as residual symptoms, comorbidities, age.. not considered). More recently, several studies have clearly documented the existence of memory deficits (especially, verbal), attention and executive function during euthymic periods in bipolar patients. In addition, several prospective studies and meta-analyses suggest that these deficits independent predictors of the functional. Thus the development of specific cognitive remediation programs is a major stake. These deficits may be markers of vulnerability to bipolar disorder, but may also reflect the cognitive " toxicity " of major mood episodes. PMID- 22212875 TI - [Antidepressants in bipolar disorder]. AB - Whereas mania defines the bipolar disorder, depression is the major challenge of treatment. In general, depressions are more frequent, longer, with a major prognostic impact in terms of disability and suicide. How should we treat a patient with bipolar depression? Antidepressants are the treatment of choice for depression, but not in the bipolar disorder. In this context, we have traditionally accepted that antidepressants are effective but they were inducing a significant risk of destabilization of the bipolar disorder, because of the transitions to mania and rapid cycling. Current data reconsider both the two aspects of this risk-benefit ratio. The effectiveness of antidepressants finally seems very limited, especially after the more recent studies with a robust methodology. Manic switches and rapid cycling may not be increased, particularly with new antidepressants and mood stabilizer combinations. The current literature reminds us that these course's modalities are inherent to the disease, with numerous risk factors, and among them, exposure to antidepressants. Who are the bipolar patients who only get the benefits of antidepressant treatment? Research will tell. They are in any case limited. How to navigate in our treatment strategies ? By choosing first drugs that demonstrated efficacy in bipolar depression. When the situation is more complex, "primum non nocere" should lead to support the prescription of the antidepressant in association with mood stabilizer. PMID- 22212876 TI - [Lithium and anticonvulsants in bipolar depression]. AB - For decades, lithium and anticonvulsants have been widely used in the treatment of bipolar disorder. Their efficacy in the treatment of mania is recognized. These drugs have been initially evaluated in old and methodologically heterogeneous studies. Their efficacy in bipolar depression has not always been confirmed in more recent and methodologically more reliable studies. Thus, lithium's efficacy as monotherapy was challenged by the study of Young (2008) that showed a lack of efficacy compared with placebo in the treatment of bipolar depression. In two recent meta-analyses, valproate has shown a modest efficacy in the treatment of bipolar depression. As for lithium, valproate appeared to have a larger antimanic effect for acute phase and prophylaxis of bipolar disorder. In contrast, lamotrigine is more effective on the depressive pole of bipolar disorder with better evidence for the prevention of depressive recurrences. The guidelines include these recent studies and recommend lamotrigine as a first-line treatment of bipolar depression and for maintenance treatment. Because of more discordant data concerning lithium and valproate, these two drugs are placed either as first or as second line treatment of bipolar depression. The different safety/efficacy ratios of mood stabilizers underlie the complementarity and the importance of combination between them, or with some second-generation antipsychotics, in the treatment of patients with bipolar disorder. PMID- 22212877 TI - [Second generation antipsychotics in bipolar depression: a new therapeutic option?]. AB - Bipolar depression, the most common phase of bipolar disorder, causes significant morbidity and mortality. Lithium, anticonvulsants or antidepressants offer some clinical efficacy. However, efficacy can be limited and side effects are sometimes problematic. There is still a major unmet need for effective, well tolerated agents for the treatment of bipolar depression. The second-generation antipsychotics, with their proven efficacy against manic symptoms, are emerging as candidates for use against the depressive phase of bipolar disorder. Several studies have shown that some second-generation antipsychotics may improve depressive symptoms in mixed episodes in patients with bipolar disorder. More recently, specific studies have been performed in patients with bipolar depressive episodes. Quetiapine or olanzapine, as monotherapy or associated with other compounds, demonstrate an interesting efficacy. The international guidelines for the treatment of bipolar depression have identified quetiapine as a first line treatment in monotherapy. Second generation antipsychotics may prove to be important future treatments for patients with bipolar depression. PMID- 22212878 TI - Which psychosocial interventions in bipolar depression? AB - This review of psychosocial interventions in bipolar disorders demonstrates that some therapies, when combined with medication, are more efficacious at preventing or delaying depressive relapse, and can be more effective than medication alone in reducing time to recovery from an acute bipolar depressive episode. However, apparent benefits diminish over time, suggesting that maintenance or " booster " therapy sessions may be needed. Given the scarcity of trained therapists, further studies are needed to determine which bipolar depressed patients should be targeted and to establish more clearly the potential cost and benefits of such interventions. PMID- 22212879 TI - [Guidelines for the biological treatment of bipolar depression]. AB - Numerous guidelines for the treatment of bipolar disorder have been published in the recent years. A review focusing on recent international and French guidelines the last 5 years on the management of bipolar depression was conducted. The comparison of guidelines showed differences in the choice of initial treatment: monotherapy (in first line: quetiapine and lamotrigine) or polypharmacotherapy (in first line: combination olanzapine/fluoxetine). All guidelines recommend in patients with inadequate response a therapeutic strategy in two steps. An initial clinical stage seeking the causes of poor therapeutic response and a second therapeutic stage trying to optimize the current treatment, to change treatment or to consider a co-therapy. In first line, the prophylactic drugs recommended are: lithium, valproate, quetiapine; olanzapine, risperidone (and long-acting formulation) and aripiprazole mainly for the prevention of manic episodes; lamotrigine limited to prevention of depressive episodes. The duration of treatment before patient reassessment and that of maintenance therapy are not consensual. The development of second-generation antipsychotics in bipolar depression is an interesting development for our therapeutic armamentarium and has been incorporated in recent guidelines. PMID- 22212880 TI - Induction of tyrosine hydroxylase gene expression by glucocorticoids in the perinatal rat brain is age-dependent. AB - Brain noradrenergic system has been implicated in early-life stress effects on adult physiology and behavior; however, the mechanisms for this relationship are not clear. Here we tested the hypothesis that stress hormones, glucocorticoids, may affect noradrenergic system activity by modulating gene expression and function of tyrosine hydroxylase (TH), the key enzyme for catecholamine synthesis, in the rat brain during perinatal life. We have shown that TH mRNA levels and enzyme activity increase in the fetal rat brainstem during the last days of pregnancy. Administration of hydrocortisone or dexamethasone to female rats on day 20 of pregnancy significantly increased TH mRNA levels (real-time PCR) and enzyme activity (DOPA accumulation after inhibition of aromatic L: amino acid decarboxylase with NSD-1015) as well as noradrenaline concentrations in the brainstem of fetuses 6 h after the treatment. Similar glucocorticoid effects on fetal TH and noradrenaline were observed 72 h after the treatment with hydrocortisone on days 16 and 18 of pregnancy. In contrast to fetuses, no effects on the TH were revealed in the brainstem of neonatal pups after single or repeated injections of hydrocortisone or dexamethasone. TH gene expression remains at a relatively constant level in the early neonatal rat brain. The results suggest that glucocorticoids are capable of inducing TH at both transcriptional and enzyme activity levels in the brainstem of near-term fetuses. PMID- 22212881 TI - Effect of chronic administration of the vinyl chalcogenide 3-methyl-1-phenyl-2 (phenylseleno)oct-2-en-1-one on oxidative stress in different brain areas of rats. AB - Selenium (Se) is an essential mineral for mammals. It is a nutrient related to the complex metabolic and enzymatic functions. Although Se has important physiological functions in the cells, organic compounds of Se can be extremely toxic, and may affect the central nervous system. This study aims to investigate the effect of the chronic treatment with the vinyl chalcogenide 3-methyl-1-phenyl 2-(phenylseleno)oct-2-en-1-one on some parameters of oxidative stress in the brain of rats. Animals received the vinyl chalcogenide (125, 250 or 500 MUg/kg body weight) intraperitoneally once a day during 30 days. The cerebral cortex, the hippocampus, and the cerebellum were dissected and homogenized in KCl. Afterward, thiobarbituric acid reactive substances (TBARS), carbonyl, sulfhydryl, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured in the brain. Results showed that the organoselenium enhanced TBARS in the cerebral cortex of rats but the compound was not able to change carbonyl levels. Furthermore, the organoselenium reduced thiol groups measured by the sulfhydryl assay in all tissues studied. The activity of the antioxidant enzyme CAT was increased by the organochalcogen in the cerebral cortex and in the cerebellum, and the activity of SOD was increased in the hippocampus. On the other hand, the activity of the antioxidant enzyme GPx was reduced in all brain structures. Our findings indicate that this organoselenium compound induces oxidative stress in different brain regions of rats, corroborating to the fact that this tissue is a potential target for organochalcogen action. PMID- 22212882 TI - Spatial and seasonal toxicity in a stormwater management facility: evidence obtained by adapting an integrated sediment quality assessment approach. AB - Stormwater ponds have been widely used to control increased surface runoff resulting from urbanization, and to enhance runoff quality. As receiving waters, they are impacted by intermittent stormwater pollution while also serving as newly created aquatic habitats, which partly offset changes of aquatic ecosystems and their biodiversity by urbanization. Thus, determining ecological risks in stormwater ponds is important for the preservation and rehabilitation of biodiversity in urban areas. Limitations of the conventional toxicity assessment techniques in stormwater ponds have led us to use the sediment quality triad approach with the specific analyses of oligochaetes. The latter analyses build on the earlier work by the Cemagref (Lyon, France) and use the oligochaetes as bioindicators of the sediment quality. This integrative approach was tested at eight sites in the Terraview-Willowfield stormwater facility in Toronto, Ontario, in all four seasons (summer 2008-spring 2009). The facility receives direct runoff from the MacDonald-Cartier freeway with a traffic intensity of 340,000 vehicles/d. Sediment chemistry results indicate that several heavy metals and PAH compounds exceeded the Ontario sediment quality guidelines in the facility. Regardless of the season, laboratory bioassays revealed a strong spatial variation in sediment toxicity along the flow path from the inlet to the outlet, agreeing with decreasing concentrations of contaminants in sediment, especially of heavy metals. However, in situ assessments of the benthic macroinvertebrate community structure and in particular of the oligochaete community revealed an overriding influence of seasonally varying toxicity. This seasonal pattern was described as high toxicity in spring and recovery in fall and corresponded to the influx and flushing-out of road salts and of several heavy metals within the facility. PMID- 22212883 TI - An integrated multi-level watershed-reservoir modeling system for examining hydrological and biogeochemical processes in small prairie watersheds. AB - Eutrophication of small prairie reservoirs presents a major challenge in water quality management and has led to a need for predictive water quality modeling. Studies are lacking in effectively integrating watershed models and reservoir models to explore nutrient dynamics and eutrophication pattern. A water quality model specific to small prairie water bodies is also desired in order to highlight key biogeochemical processes with an acceptable degree of parameterization. This study presents a Multi-level Watershed-Reservoir Modeling System (MWRMS) to simulate hydrological and biogeochemical processes in small prairie watersheds. It integrated a watershed model, a hydrodynamic model and an eutrophication model into a flexible modeling framework. It can comprehensively describe hydrological and biogeochemical processes across different spatial scales and effectively deal with the special drainage structure of small prairie watersheds. As a key component of MWRMS, a three-dimensional Willows Reservoir Eutrophication Model (WREM) is developed to addresses essential biogeochemical processes in prairie reservoirs and to generate 3D distributions of various water quality constituents; with a modest degree of parameterization, WREM is able to meet the limit of data availability that often confronts the modeling practices in small watersheds. MWRMS was applied to the Assiniboia Watershed in southern Saskatchewan, Canada. Extensive efforts of field work and lab analysis were undertaken to support model calibration and validation. MWRMS demonstrated its ability to reproduce the observed watershed water yield, reservoir water levels and temperatures, and concentrations of several water constituents. Results showed that the aquatic systems in the Assiniboia Watershed were nitrogen-limited and sediment flux played a crucial role in reservoir nutrient budget and dynamics. MWRMS can provide a broad context of decision support for water resources management and water quality protection in the prairie region. PMID- 22212884 TI - The heterogeneous coagulation and flocculation of brewery wastewater using carbon nanotubes. AB - Coagulation and flocculation treatment processes play a central role in the way wastewater effluents are managed. Their primary function is particle removal that can impart colour to a water source, create turbidity, and/or retain bacterial and viral organisms. This study was carried out to investigate whether carbon nanotubes (CNTs) can be used as heterogeneous coagulants and/or flocculants in the pretreatment of brewery wastewater. A series of experiments were conducted in which the efficiencies of pristine and functionalised CNTs were compared with the efficiency of traditional ferric chloride in a coagulation/flocculation process. Turbidity and chemical oxygen demand (COD), including the zeta potential were used to monitor the progress of the coagulation/flocculation process. Both pristine and functionalised CNTs demonstrated the ability to successfully coagulate colloidal particles in the brewery wastewater. Overall, ferric chloride was found to be a more effective coagulant than both the pristine and functionalised CNTs. PMID- 22212885 TI - Complex obstacle negotiation exercise can prevent falls in community-dwelling elderly Japanese aged 75 years and older. AB - OBJECTIVES: The aim of the present study was to evaluate whether a complex course obstacle negotiation exercise (CC), a 24-week exercise program, can reduce falls and fractures in older adults, as compared with a simple course obstacle negotiation exercise (SC). METHODS: This trial was carried out on older adults, aged 75 years and above in Japan. In total, 157 participants were randomized into the CC group (n = 78) and the SC group (n = 79). Participants were enrolled in the exercise class using the CC program or the SC program for 24 weeks. The outcome measure was the number of falls and fracture rates in CC and SC groups for 12 months after the completion of the 24-week exercise class. RESULTS: Two participants (2.8%) in the CC group and 19 (26.0%) in the SC group experienced falls during 12 months. During the 12-month follow-up period after the intervention, the incidence rate ratio (IRR) of falls in the SC group against the CC group was 9.37 (95% CI = 2.26-38.77). One participant (1.4%) in the CC group and eight (10.9%) in the SC group had experienced fractures during 12 months after the exercise class. The IRR of fractures in the SC group compared with the CC group was 7.89 (95% CI = 1.01-61.49). CONCLUSIONS: The results of the present trial show that the participants who received individualized obstacle avoidance training under complex tasks combined with a traditional intervention had a lower incidence rate of falls and fractures during the 12 months after the intervention. PMID- 22212887 TI - Plato's elements challenge. PMID- 22212886 TI - High-grade osteosarcoma treated with hemicortical resection and biological reconstruction. AB - BACKGROUND AND OBJECTIVES: Wide excision with a 2-3 cm safe margin is widely accepted in treating high-grade osteosarcoma. However, a wider margin sacrifices more healthy bone and may jeopardize joint function. We hypothesize that our innovative hemicortical resection for such tumors leads to better joint function without higher recurrence rate. METHODS: Between August 2002 and April 2007, six patients of high-grade osteosarcoma were treated with hemicortical resection and biological reconstruction. RESULTS: Five tumors were located around the knee and one was located in the distal tibia. The mean tumor size was 20.5 cm(3). The bone defects were reconstructed using recycled autograft in four cases (one by extracorporeal irradiation; three by liquid nitrogen) and structural allograft in two. In an average follow-up of 52 months (24-96), all patients survived without local recurrence or metastasis. All bone grafts incorporated well without mechanical failure or infection. The average Musculoskeletal Tumor Society score was 97.7%. CONCLUSIONS: Hemicortical resection for high-grade osteosarcomas located eccentrically in the long bones may be a reliable technique leading to good joint function by preserving surrounding healthy tissues. The functional outcome was encouraging, although long-term follow-up is mandatory to validate. With the advancement of chemotherapy and radiographic three-dimensional imaging, the safe margin in wide excision of high-grade osteosarcoma may be narrowed down in light of joint surface preservation. PMID- 22212888 TI - Solution to the molality-molarity challenge. PMID- 22212889 TI - Safety and efficacy of long-term etanercept in the treatment of methotrexate refractory polyarticular-course juvenile idiopathic arthritis in Japan. AB - OBJECTIVES: Previous short-term trials found etanercept (0.2 or 0.4 mg/kg) to be effective and well tolerated in Japanese children with juvenile idiopathic arthritis (JIA) who were intolerant/resistant to methotrexate. The aim of this study was to evaluate the long-term safety and efficacy of etanercept in Japanese children with JIA. METHODS: Patients (4-19 years) who received etanercept in one of three short-term studies continued onto this long-term open-label study. RESULTS: Of the 32 patients enrolled, 18 (56.3%) completed 192 weeks of the study and 14 (43.8%) were discontinued; 7 (21.9%) for patient refusal, 2 (6.3%) for adverse events (AEs), and 5 (15.6%) for lack of efficacy. All patients reported AEs; 31 (96.9%) reported infections and 6 (18.8%) reported serious AEs. Main efficacy assessments included change from baseline in the American College of Rheumatology Pediatric core components, including mean improvements from baseline in the physician global assessment (90.7%), patient/guardian global assessments (54.1%), Childhood Health Assessment Questionnaire (84.6%), and median improvements in C-reactive protein levels (92.7%). No unexpected safety results were reported, and early efficacy responses were sustained in the long term. CONCLUSIONS: This study provides further evidence that etanercept is an effective therapeutic option for Japanese children with polyarticular-course JIA. PMID- 22212890 TI - Correlation of factor IXa subsite modulations with effects on substrate discrimination. AB - BACKGROUND: A key feature of factor IXa is its allosteric transformation from an enzymatically latent form into a potent procoagulant. Although several small molecules have been found to be capable of partially affecting FIXa function (i.e. ethylene glycol, Ca(2+), and low molecular weight heparin [LMWH]), the resulting modest changes in peptidolytic activity have made the study of their mechanisms of action challenging. As these effects provide hints about potential regulatory forces that may be operational in the full expression of FIXa coagulant activity, their description remains of great interest. Studies of crystal structures have yielded insights into the structural changes induced by these effectors, but there remains a paucity of information to correlate any given structural change with specific consequences for FIXa function. OBJECTIVES: To correlate structural changes induced by these modulators with defined consequences for FIXa substrate discrimination and function. METHODS: A peptidomics-based mass spectrometry (MS) approach was used to examine the patterns of hydrolysis of four combinatorial chemistry-derived pentapeptide libraries by FIXa under various conditions in a soluble, active enzyme system. RESULTS: Ethylene glycol specifically altered the S3 subsite of FIXa to render it more tolerant to side chains at the P3 substrate position, whereas Ca(2+) enhanced tolerance at the S2 subsite. In contrast, LMWH altered both the S2 and S1' subsites. CONCLUSIONS: These results demonstrate the role of plasticity in regulating FIXa function with respect to discrimination of extended substrate sequences, as well as providing crucial insights into active site modulations that may be capitalized on by various physiologic cofactors of FIXa and in future drug design. PMID- 22212891 TI - Ecogeographical associations between climate and human body composition: analyses based on anthropometry and skinfolds. AB - In the 19th century, two "ecogeographical rules" were proposed hypothesizing associations of climate with mammalian body size and proportions. Data on human body weight and relative leg length support these rules; however, it is unknown whether such associations are attributable to lean tissue (the heat-producing component) or fat (energy stores). Data on weight, height, and two skinfold thickness were obtained from the literature for 137 nonindustrialized populations, providing 145 male and 115 female individual samples. A variety of indices of adiposity and lean mass were analyzed. Preliminary analyses indicated secular increases in skinfolds in men but not women, and associations of age and height with lean mass in both sexes. Decreasing annual temperature was associated with increasing body mass index (BMI), and increasing triceps but not subscapular skinfold. After adjusting for skinfolds, decreasing temperature remained associated with increasing BMI. These results indicate that colder environments favor both greater peripheral energy stores, and greater lean mass. Contrasting results for triceps and subscapular skinfolds might be due to adaptive strategies either constraining central adiposity in cold environments to reduce cardiovascular risk, or favoring central adiposity in warmer environments to maintain energetic support of the immune system. Polynesian populations were analyzed separately and contradicted all of the climate trends, indicating support for the hypothesis that they are cold-adapted despite occupying a tropical region. It is unclear whether such associations emerge through natural selection or through trans-generational and life-course plasticity. These findings nevertheless aid understanding of the wide variability in human physique and adiposity. PMID- 22212892 TI - Methodology of the global and regional burden of stroke study. AB - BACKGROUND: Setting priorities for the prevention of stroke requires an empirical understanding of the pattern of disease burden and exposure to major risk factors. In this manuscript we aim to report the methodology of a systematic review of the epidemiological literature on stroke and how this information will be synthesized to produce updated estimates of the global burden of stroke. METHODS: We will use multi-state models implemented in the software program DisMod III to estimate age-specific prevalence, incidence, and early case fatality (defined as either 28-day, 30-day or 1-month case fatality) for stroke by the 21 global burden of disease (GBD) regions as well as by gender and pathological stroke type based on information obtained from a systematic review. We conducted a two-stage search strategy in order to identify studies published between 1980 and 2011 for the GBD stroke review. Eligible studies: (a) distinguished between stroke and transient ischaemic attack (TIA); (b) distinguished between 1st ever and recurrent stroke; (c) reported on age-specific rates; (d) if reported, provided survival status within 28 days, 30 days or 1 month of onset for fatal and nonfatal events; (e) specified methods for ascertaining stroke cases, and (f) described imaging modalities to determine stroke subtypes. Details of included studies were recorded on a detailed data extraction form by trained reviewers. We will gather information on demographics, natural history and clinical outcomes (e.g. Rankin scale, Glasgow Coma Scale), after stroke which will be used to facilitate the estimation of epidemiological parameters. Reporting and methodological quality was rated. Populations were coded as urban, rural, or combined and studies classified as national, subnational, healthcare system-based, or community level. Studies published in non-English languages were translated and coded centrally. DISCUSSION: In international health research, there is a crucial need for accurate assessment of global health patterns. A thorough GBD reassessment of stroke will ensure that global health policy decisions are based on the most up-to-date, valid and reliable epidemiological information available. PMID- 22212893 TI - Respiratory sinus arrhythmia: a marker for positive social functioning and receptive language skills in children with autism spectrum disorders. AB - The current study builds on the emerging autism spectrum disorder (ASD) literature that associates autonomic nervous system activity with social function, and examines the link between respiratory sinus arrhythmia (RSA) and both social behavior and cognitive function. The RSA response pattern was assessed in 23 4- to 7-year-old children diagnosed with an ASD. Higher baseline RSA amplitudes were associated with better social behavior (i.e., more conventional gestures, more instances of joint attention) and receptive language abilities. Similar to reports of typically developing children, ASD children with higher RSA amplitude at baseline showed greater RSA and HP reactivity during an attention-demanding task. These results highlight the importance of studying RSA as a marker of positive function in children with ASD. PMID- 22212894 TI - William L. Ogren was honored with a Lifetime Achievement Award by the Rebeiz Foundation for Basic Research. AB - This News Report is a brief description of the 2010 Lifetime Achievement Award received by William (Bill) L. Ogren from the Rebeiz Foundation for Basic Research, at Champaign, Illinois, on Sep 10, 2011. It focuses mainly on the presentations by two of us (ARP and Gov), Christoph Benning (on behalf of Chris Somerville), David Krogmann and Jack Widholm, at this ceremony. It is enriched by the testimonial received from George Bowes at the time of the preparation of this report. PMID- 22212895 TI - Organosulfur derivatives of the HDAC inhibitor valproic acid sensitize human lung cancer cell lines to apoptosis and to cisplatin cytotoxicity. AB - Lung cancer is the leading cause of cancer mortality worldwide and despite efforts made to improve clinical results, continuing poor survival rates indicate that novel therapeutic approaches are needed. Valproic acid (VPA), a short-chain branched fatty acid used mainly for the treatment of epilepsy and bipolar disorder, has been shown to inhibit class I histone deacetylases (HDAC-I), a group of enzymes involved in chromatin remodeling and which are thought to play a role in tumor development. Although evidence of VPA's therapeutic efficacy has also been observed in patients with solid tumors, the very high concentration required to induce antitumor activity limits its clinical usefulness. We used a panel of NSCLC cell lines to evaluate the activity and mechanisms of action of organosulfur valproic acid derivatives, a promising new class of compounds designed to improve the safety and efficacy of the valproic acid molecule and created by coupling it with a hydrogen sulfide (H(2) S)-releasing moiety. Our results highlighted the increased cytotoxic activity of the novel organosulfur derivatives, ACS33 and ACS2, with respect to VPA, starting from low concentrations. In particular, ACS2 exhibited important pro-apoptotic activity triggered by the mitochondrial pathway and also showed anti-invasion potential. Furthermore, our in vitro results identified a highly effective combination schedule of ACS2 and cisplatin capable of inducing a synergistic interaction even when the two drugs were used at low concentrations, which could prove a valid alternative to traditional chemotherapeutic regimens used for advanced lung cancer. Further studies are needed to confirm these preliminary findings. PMID- 22212897 TI - Copper kinetics and internal distribution in the marbled crayfish (Procambarus sp.). AB - Metal pollution e.g. copper, in water bodies occurs worldwide. Although copper is an essential trace metal, at certain levels it is still considered as pollutant. The aim of this study was to investigate the effect of exposure concentration on copper bioaccumulation in marbled crayfish (Procambarus sp.) by determining uptake and elimination kinetics. Crayfish were exposed to sub-lethal copper concentrations (average measured concentrations of 0.031 and 0.38 mg Cu L(-1)) for 14 d and transferred to copper-free water for another 14 d. At different time points during the uptake and elimination phases copper concentrations were measured in five organs (exoskeleton, gills, muscle, ovaries and hepatopancreas). At 0.031 mg Cu L(-1), copper levels in the crayfish organs were not significantly increased compared to the control animals, suggesting effective regulation. Exposure to 0.38 mg Cu L(-1) did lead to not significantly increased copper levels in muscles and ovaries, while the gills and exoskeleton, which are in direct contact with the water, showed significantly higher copper concentrations. In these four organs, copper showed fast uptake kinetics with equilibrium reached within 10 d of exposure. Copper accumulation was highest in the hepatopancreas; uptake in this storage organ steadily increased with time and did not reach equilibrium within the 14-d exposure period. Copper accumulation levels in the marbled crayfish found in this study were hepatopancreas>gills>exoskeleton>muscle. PMID- 22212896 TI - Metal concentrations and metallothionein levels in Mytilus galloprovincialis from Elefsis bay (Saronikos gulf, Greece). AB - Spatial and temporal variability of Cd, Cu, Cr, Ni, Zn, Fe and Mn and metallothionein (MT) concentrations were determined in mussels Mytilus galloprovincialis from Elefsis bay (Saronikos gulf, Greece). Higher concentrations of both metal concentrations and MTs were recorded in mussels inhabiting industrial locations (steelworks and shipyard), indicating a markedly higher metal bioavailability. However at these sites, located at the eastern part of the bay, mussel metal concentrations were not always correlated with both seawater metal concentrations and MTs possibly due to different time scales of integration of the metal sources into mussels and/or the participation of other metal regulatory mechanisms except MT induction. The pattern of the temporal variation of mussel metal concentrations and the MT levels was similar among stations with higher values during the winter-spring season and lower during the summer-autumn period. The inverse relationship of flesh condition index with mussel metal concentrations was attributed to the influence of mussel annual reproductive cycle. PMID- 22212898 TI - Expression, purification and characterization of recombinant human serine proteinase inhibitor Kazal-type 6 (SPINK6) in Pichia pastoris. AB - Human serine proteinase inhibitor Kazal-type 6 (SPINK6) belongs to the medically important SPINK family. Malfunctions of SPINK members are linked to many diseases, including pancreatitis, skin barrier defects, and cancer. SPINK6 has been shown to selectively inhibit Kallikrein-related peptidases (KLKs) in human skin. As a SPINK protein, it contains a typical Kazal domain, which requires three intramolecular disulfide bonds for correct folding and activity. Preparation of functional protein is a prerequisite for studying this important human factor. Here, we report the successful generation of tagless SPINK6 using a yeast expression system. The recombinant protein was secreted and purified by cation exchange and size-exclusion chromatography. The protein identity was confirmed by MALDI-TOF MS and N-terminal sequencing. Pichia pastoris-derived recombinant human SPINK6 (rhSPINK6) showed higher inhibitory activity against Kallikrein-related peptidase 14 (KLK14) (K(i)=0.16 nM) than previously reported Escherichia coli-derived rhSPINK6 (K(i)=0.5 nM). This protein also exhibited moderate inhibition of bovine trypsin (K(i)=33 nM), while previous E. coli derived rhSPINK6 did not. The results indicate that P. pastoris is a better system to generate active rhSPINK6, warranting further studies on this medically important SPINK family candidate. PMID- 22212899 TI - B-cells and IL-4 promote methylcholanthrene-induced carcinogenesis but there is no evidence for a role of T/NKT-cells and their effector molecules (Fas-ligand, TNF-alpha, perforin). AB - Mice deficient either in subtypes of immune cells, cytokines or lytic pathways have been subjected to chemical carcinogenesis by methylcholanthrene to evaluate whether these components of the immune system affect tumor development. Inbred mice of the same genotype but from different sources differed in tumor development in magnitude comparable to that previously attributed to differences in immunocompetence. This suggested that genetic drift between separate inbred colonies of mice and/or environmental factors (e.g., transport of the animals) influenced carcinogenesis. Therefore, littermates were used as control in subsequent experiments. Although deficiency of T-cells, NKT-cells, perforin, Fas ligand, TNF-alpha-receptor failed to reveal significant differences in tumor development, the presence of B-cells and IL-4 enhanced tumor development under similar experimental conditions. PMID- 22212901 TI - Evolution of oncolytic adenovirus for cancer treatment. AB - Oncolytic adenovirus (Ad) has been used in cancer gene therapy largely due to its ability to selectively infect and replicate in tumor cells. However, because the oncolytic antitumor activity is insufficient to effectively eliminate tumors, various strategies have been devised to improve the therapeutic efficacy. Single vector Ads "armed" with short hairpin RNA, cytokines, or matrix-modulating proteins have been developed. Two clear advantages are viral amplification of the therapeutic gene, and the additive effects of oncolytic and therapeutic gene mediated antitumor activities. To develop systemically injectable Ad carriers, strategies to modify the Ad surface with polymers, liposomes, or nanoparticles have been shown to extend circulation time, reduce immunogenicity, and result in increased antitumor effect as well as lower accumulation and toxicity in liver. Specific targeting platforms for tumor-selective oncolytic therapies against both primary and metastatic cancers have been developed. This review will focus on updated strategies to develop potent oncolytic Ads for use in cancer treatment. PMID- 22212902 TI - Cancer stromal targeting (CAST) therapy. AB - Despite great advances in cell and molecular biology, pharmacology and medicine, there is to date no antitumor drug available which can specifically kill tumor cells in the human body without damaging normal tissue, because it has not been possible to find a truly cancer specific molecule to target. Low molecular weight (MW) anticancer drugs extravasate easily from normal vessels in the body causing drug adverse effects. Conversely, high MW anti-tumor agents including antibodies against cancer cell antigens, accumulate selectively in tumors because of their leaky vasculature. However, most human solid tumors possess abundant intercellular connective tissue, hindering diffusion of such macromolecules. That is why immunoconjugate therapy for stroma rich common solid cancer has not yet proved successful in clinics. In this review, I describe a successful new strategy that overcomes the above contradictory drawbacks by conjugating a small MW cyototoxic drug with an antibody against particular components of tumor stroma. Stroma-targeting immunconjugates bound to the stroma to create a scaffold, from which sustained release of cytotoxic agent occurred and subsequently diffused throughout the tumor tissue to damage both tumor cells and tumor vessels. Cancer-stroma targeting (CAST) therapy was thus validated as a new modality of oncological therapy, especially for refractory, stromal-rich cancers. PMID- 22212900 TI - Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers. AB - Oral delivery is the most common method for drug administration. However, poor solubility, stability, and bioavailability of many drugs make achieving therapeutic levels via the gastrointestinal (GI) tract challenging. Drug delivery must overcome numerous hurdles, including the acidic gastric environment and the continuous secretion of mucus that protects the GI tract. Nanoparticle drug carriers that can shield drugs from degradation and deliver them to intended sites within the GI tract may enable more efficient and sustained drug delivery. However, the rapid secretion and shedding of GI tract mucus can significantly limit the effectiveness of nanoparticle drug delivery systems. Many types of nanoparticles are efficiently trapped in and rapidly removed by mucus, making controlled release in the GI tract difficult. This review addresses the protective barrier properties of mucus secretions, how mucus affects the fate of orally administered nanoparticles, and recent developments in nanoparticles engineered to penetrate the mucus barrier. PMID- 22212903 TI - Anti-neutrophil cytoplasmic antibody-associated systemic vasculitis: nature or nurture? AB - This review examines the environmental and genetic contributions to the anti neutrophil cytoplasmic antibody-associated systemic vasculitides. The dominant environmental risk factors appear to be silica exposure for all three syndromes, and vitamin D deficiency is strongly suggested by the latitude and ultraviolet radiation gradient observed for Wegener's granulomatosis and Churg-Strauss syndrome. Genetic factors are generally not very strong, consistent with the rarity of these conditions in children. However, multiple genetic factors, each with a relatively small effect, may combine to create a state of susceptibility towards autoimmunity. With infection as a triggering agent, it is possible to synthesise a pathogenetic hypothesis that accounts for both environmental and genetic effects in regard to both necrotising vasculitis and granuloma formation. PMID- 22212904 TI - New introduction of clade 2.3.2.1 avian influenza virus (H5N1) into Bangladesh. AB - Since the first outbreak of highly pathogenic H5N1 avian inafluenza (HPAI) in Bangladesh in February 2007, a total of 519 disease events have been reported till 22 October 2011. Partial HA gene sequences of 11 selected H5N1 HPAI isolates of 2007 to 2011 were determined and subjected to phylogenetic analysis. The study revealed a recent introduction of clade 2.3.2 and 2.3.4 viruses into Bangladesh in 2011 in addition to clade 2.2 viruses that had been in circulation since 2007. Clade 2.3.2 virus isolates from Bangladesh are phylogenetically related to the newly designated clade 2.3.2.1 viruses, reported recently from Asia and Eastern Europe. PMID- 22212905 TI - Synthesis of (-)-Astrogorgiadiol. AB - Astrogorgiadiol is a naturally occurring Vitamin D analogue that, in cell culture, downregulates the production of the cytokine osteopontin (OPN). OPN has been implicated in virulent asthma, and OPN knockout mice do not develop osteoporosis. As we have pursued whole animal studies with astrogorgiadiol, we have increased the scale of the synthesis. We report an improved preparation of the A-ring synthon and the scale-up of the diasteromerically pure D ring/sidechain chiron. PMID- 22212906 TI - Analysis of the APX, PGD1 and R1G1B constitutive gene promoters in various organs over three homozygous generations of transgenic rice plants. AB - We have previously characterized the constitutively active promoters of the APX, PGD1 and R1G1B genes in rice (Park et al. 2010 in J Exp Bot 61:2459-2467). To have potential crop biotechnology applications, gene promoters must be stably active over many generations. In our current study, we report our further detailed analysis of the APX, PGD1 and R1G1B gene promoters in various organs and tissues of transgenic rice plants for three (T3-5) homozygous generations. The copy numbers in 37 transgenic lines that harbor promoter:gfp constructs were determined and promoter activities were measured by real-time qPCR. Analysis of the 37 lines revealed that 15 contained a single copy of one of the three promoter:gfp chimeric constructs. The promoter activity levels were generally higher in multi-copy lines, whereas variations in these levels over the T3-5 generations studied were observed to be smaller in single-copy than in multi-copy lines. The three promoters were further found to be highly active in the whole plant body at both the vegetative and reproductive stages of plant growth, with the exception of the APX in the ovary and R1G1B in the pistil and filaments where zero or very low levels of activity were detected. Of note, the spatial activities of the PGD1 promoter were found to be strikingly similar to those of the ZmUbi1, a widely used constitutive promoter. Our comparison of promoter activities between T3, T4 and T5 plants revealed that the APX, PGD1 and R1G1B promoters maintained their activities at comparable levels in leaves and roots over three homozygous generations and are therefore potentially viable alternative promoters for crop biotechnology applications. PMID- 22212907 TI - Natural variation for Fe-efficiency is associated with upregulation of Strategy I mechanisms and enhanced citrate and ethylene synthesis in Pisum sativum L. AB - Iron (Fe)-deficiency is a common abiotic stress in Pisum sativum L. grown in many parts of the world. The aim of the study was to investigate variation in tolerance to Fe deficiency in two pea genotypes, Santi (Fe-efficient) and Parafield (Fe-inefficient). Fe deficiency caused greater declines in chlorophyll score, leaf Fe concentration and root-shoot development in Parafield compared to Santi, suggesting greater Fe-efficiency in Santi. Fe chelate reductase activity and ethylene production were increased in the roots of Santi and to a lesser extent in Parafield under Fe deficiency, while proton extrusion was only occurred in Santi. Moreover, expression of the Fe chelate reductase gene, FRO1, and Fe transporter, RIT1 were upregulated in Fe-deficient roots of Santi. Expression of HA1 (proton extrusion) was also significantly higher in Santi when compared to Parafield grown in Fe-deficient conditions. Furthermore, the application of the ethylene biosynthesis inhibitor, 1-aminoisobutyric acid reduced the Fe chelate reductase activity, supporting a direct role for ethylene in its induction. A significant increase in root citrate was only observed in Santi under Fe deficiency indicating a role for citrate in the Fe-efficiency mechanism. Taken together, our physiological and molecular data indicate that genotypic variation in tolerance to Fe deficiency in Santi and Parafield plants is a result of variation in a number of Strategy I mechanisms and also suggest a direct role for ethylene in Fe reductase activity. The pea cultivar, Santi provides a new source of Fe-efficiency that can be exploited to breed more Fe-efficient peas. PMID- 22212908 TI - Effect of interleukin-28B on treatment outcome in hepatitis C virus G1/4 patients receiving response-guided therapy with pegylated interferon alpha-2a/ribavirin. PMID- 22212910 TI - Role of streaming potential on pulsating mass flow rate control in combined electroosmotic and pressure-driven microfluidic devices. AB - In the present study, we investigate the implications of streaming potential on the mass flow rate control in a microfluidic device actuated by the combined application of a pulsating pressure gradient and a pulsating, externally applied, electric field. We demonstrate that the temporal dynamics due to streaming potential effects may lead to interesting non-trivial aspects of the resultant transport characteristics. Our results highlight the importance of an adequate accounting of the streaming potential effects for temporally tunable mass flow rate control strategies, which may act as a useful design artifice to augment mass flow rates in practical scenarios. PMID- 22212909 TI - Deficiency of DNA repair nuclease ERCC1-XPF promotes prostate cancer progression in a tissue recombination model. AB - BACKGROUND: The excision repair cross complementing (ERCC1) gene product plays a vital role in the nucleotide excision repair (NER) and DNA interstrand crosslink repair pathways, which protect the genome from mutations and chromosomal aberrations, respectively. Genetic deletion of Ercc1 in the mouse causes dramatically accelerated aging. We examined the effect of Ercc1 deletion in the development of prostate cancer in a prostate recapitulation model as Ercc1 deficient mice die within four weeks of birth. METHODS: Prostate tissues from Ercc1(-/-) mice or wild-type littermates were combined with embryonic rat urogenital mesenchyme and grown as renal grafts for a total of 8, 16, and 24 weeks before histological, expression and proliferative evaluation. RESULTS: Invasive adenocarcinoma was observed in Ercc1(-/-) tissue recombinants but not wild-type as early as 8 weeks post-grafting. PIN-like lesions in Ercc1(-/-) tissue recombinants had more cytologic and architectural atypia than wild-type (P = 0.02, P = 0.0065, and P = 0.0003 at the 8, 16, and 24 weeks, respectively), as well as more proliferative cells (P = 0.022 and P = 0.033 at 8 and 16 weeks, respectively). With serial grafting, Ercc1(-/-) tissue recombinants progressed to a more severe histopathological phenotype more rapidly than wild-type (P = 0.011). CONCLUSIONS: Results show that ERCC1 and by implication the NER and/or interstrand crosslink repair mechanisms protect against prostate carcinogenesis and mutations or polymorphisms affecting these DNA repair pathways may predispose prostate epithelial cells to transformation. PMID- 22212911 TI - Prognostic significance of lymph node station 7 for patients with gastric cancers underwent radical surgery. AB - BACKGROUND: To investigate the validity of gastric cancers with nodes metastasis at Level II stations limited to No. 7 being classified as level-based n1 stage disease and the impact of this revision on lymph node staging. METHODS: Clinicopathologic features and prognosis of 1,606 node positive gastric cancers were retrospectively reviewed. Four patient groups were classified according to the status of node involvement: Group A, 734 patients with node metastasis at Level I stations; Group B, 317 patients with nodes metastasis at Level II stations limited to No. 7; Group C, 501 patients with nodes metastasis at Level II stations besides No. 7; and Group D, 54 patients with nodes metastasis at Level III stations. RESULTS: Although the extent of node metastasis for patients in Group B was more severe than that for patients in Group A, clinicopathologic features (especially pT stage) were not significantly different. Although overall survival for patients in Group B was significantly worse than that for patients in Group A, no significant differences in prognosis could be observed when stratified by pN or rN category. A revised level-based n category was established by considering cancers in Group B as level-based n1 stage disease. Multivariate analysis confirmed rN category and the revised level-based n category independently predicted patients' survival. A novel N category was established by combining rN category and the revised level-based n category. Further analysis revealed the novel N category had better homogeneity, discriminatory ability, and monotonicity of gradients than the other node categories, indicating the novel N system might be the most valuable node staging system for prognostic assessment. CONCLUSION: It might be more suitable for cancers in Group B being classified as level-based n1 stage disease. And we recommend the anatomical location of metastatic lymph nodes also being considered in the categorization of lymph node metastasis. PMID- 22212912 TI - Mathematical modeling of invadopodia formation. AB - In invasive cancer cells, specialized sub-cellular membrane structures which carry out a pivotal process in cancer invasion, termed invadopodia, are observed. Invadopodia appear irregularly within the cytoplasm and their general shape is small punctuated finger-like protrusions with dimension up to several MUm long. They may exist and persist on a timescale between several tens of minutes to one hour. The formation of invadopodia requires the integration of several processes that include actin reorganization, extracellular matrix (ECM) degradation, signaling processes through receptors such as the epidermal growth factor receptor (EGFR) and matrix metalloproteinase (MMP) synthesis and delivery to the location of the invading front. In this paper, we consider a mathematical model investigating the coupling of these fundamental processes, and we investigate how invadopodia appear in this model. We investigate the spatio-temporal dynamics of the model in two spatial dimensions by using numerical computational simulations. We show that in a special parameter region of the model, random fluctuations of ECM degradation and a positive feedback loop regarding the up-regulation of MMPs allow us to reproduce finger-like protrusions which have similar size and lifetime as invadopodia. This study provides a new insight into how invadopodia appear in cancer cells and why space and time scales exist for invadopodia. PMID- 22212913 TI - Lie Markov models. AB - Recent work has discussed the importance of multiplicative closure for the Markov models used in phylogenetics. For continuous-time Markov chains, a sufficient condition for multiplicative closure of a model class is ensured by demanding that the set of rate-matrices belonging to the model class form a Lie algebra. It is the case that some well-known Markov models do form Lie algebras and we refer to such models as "Lie Markov models". However it is also the case that some other well-known Markov models unequivocally do not form Lie algebras (GTR being the most conspicuous example). In this paper, we will discuss how to generate Lie Markov models by demanding that the models have certain symmetries under nucleotide permutations. We show that the Lie Markov models include, and hence provide a unifying concept for, "group-based" and "equivariant" models. For each of two and four character states, the full list of Lie Markov models with maximal symmetry is presented and shown to include interesting examples that are neither group-based nor equivariant. We also argue that our scheme is pleasing in the context of applied phylogenetics, as, for a given symmetry of nucleotide substitution, it provides a natural hierarchy of models with increasing number of parameters. We also note that our methods are applicable to any application of continuous-time Markov chains beyond the initial motivations we take from phylogenetics. PMID- 22212914 TI - Factors contributing to the development of an HIV ministry within an African American church. AB - Having an HIV ministry within a church depends on the religious culture of that church. However, little is known about how a church's religious culture influences an HIV ministry. This study's purpose was to examine how an African American church's religious culture supported the development, implementation, and maintenance of an HIV ministry within the church. An ethnographic case study research design was used. Data were collected through interviews, nonparticipant and participant observations, review of pertinent documents, and survey of congregants. Results revealed the following as important for an HIV ministry: (a) a belief in helping others and treating everyone with respect and dignity, (b) feelings of compassion toward individuals infected with HIV, and (c) HIV education. This information can assist in developing interventions to enhance the African American church movement toward HIV ministries. PMID- 22212915 TI - Favourable prognosis in medulloblastoma with extensive nodularity is associated with mitogen-activated protein kinase upregulation. AB - Medulloblastoma with extensive nodularity (MBEN) is the only type of medulloblastoma (MB), an aggressive CNS tumour of childhood, that is connected with favourable prognosis. In patients with MBEN tumour resection and chemotherapy are sometimes sufficient. While development of other types of MB is usually connected with activation of the wingless pathway, sonic hedgehog pathway or mammalian target of rapamycin (mTor) pathway, little is known about the molecular basis of MBEN pathophysiology. In the present paper we evaluated activation of the mTor pathway and kinases upstream of mTor, mitogen-activated protein kinase (MAPK/Erk) and protein kinase B (PKB/Akt) in an MBEN sample. Using western blot technique with antibodies directed against active, phosphorylated forms of proteins, we found upregulation of mTor, Akt and Erk. Thus we postulate that the mTor pathway, often implicated in the development of CNS tumours, is also responsible for MBEN progression. Especially interesting seems implication of Erk and other kinases belonging to the same pathway: mitogen-activated protein kinase kinase (MEK-1) or phospho-ribosomal S6 kinase-1 (p90 RSK1), whose activity we usually demonstrate in more benign neoplasms. However, it remains to be clarified whether Erk pathway activation is actually prognostic for benign tumour development. PMID- 22212916 TI - Fibre integrity and diffusivity of the pyramidal tract and motor cortex within and adjacent to brain tumour in patients with or without neurological deficits. AB - BACKGROUND: Assessment of the relationship between preoperative neurological deficits and diffusion tensor imaging (DTI) parameters in patients with brain tumour within/adjacent to pyramidal tract and motor cortex. Evaluation of the difference in fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values in patients with low and high grade gliomas. MATERIAL AND METHODS: 20 patients with supratentorial brain tumours were divided into two groups: I with preoperative neurological deficits and II without preoperative neurological deficits. 8/20 tumours were classified as low grade gliomas, 10/20 as high grade gliomas and 2/10 as metastases. All MR examinations were performed on a 3T scanner. FA and ADC values were calculated for a precentral gyrus (PCG), a posterior limb of the internal capsule (PLIC) and a pyramidal tract (PT) ipsilateral and contralateral to the tumour side. These values were compared between patients with and without preoperative neurological deficits, with low and high grade gliomas. RESULTS: A statistical analysis revealed significant differences between patients with and without preoperative neurological deficits in PCGs and PTs ipsilateral to the tumour side. Separate analysis conducted in the group with preoperative neurological deficits showed significant statistical differences only in terms of FA values comparing ipsilateral and contralateral tumour side. No statistically significant difference was observed comparing FA and ADC values ipsilateral and contralateral to the tumour side in the group without preoperative neurological deficits and between patients with low and high grade gliomas. CONCLUSIONS: There is a relation between FA and ADC values and preoperative deficits in patients with brain tumour adjacent/within the main white matter tracts. Tumour relation to the white matter tracts is more important than the glioma WHO grade. PMID- 22212917 TI - Brain metastases in paediatric patients: characteristics of a patient series and review of the literature. AB - In contrast to the occurrence of brain metastases advanced malignant tumours in adult cancer patients, the dissemination of solid tumours to the brains of paediatric cancer patients is very uncommon. We present a neuro-pathological and clinical study of a group of children and adolescents with brain metastases (BM) from extracranial solid malignancies. The analysed patients were diagnosed with soft tissue sarcomas (three), germ cell tumours (three), or osteosarcoma, neuroblastoma, clear cell sarcoma of the kidney, or pleuropulmonary blastoma (one each). In our series, BM frequently coexisted with pulmonary metastases. Three different metastatic patterns were discernible: a solitary tumour, multiple lesions and diffuse parenchymal dissemination. Two cases showed haemorrhagic presentation. Most of the children died due to BM progression, while children with germ cell tumours showed the best prognosis. The histopathological pictures of BM can be different from the primary tumour, showing dedifferentiation or a diverse neoplastic component. The autopsy examination can still be helpful in the final diagnosis of certain cases with atypical clinical presentations. PMID- 22212918 TI - Cerebellar cortical neurons misplaced in the white matter due to disturbed migration during development of human brain. AB - The normal laminar organisation of the cerebellar cortex is the result of the precisely controlled migration, differentiation and maturation of the neurons. Occasionally the migrating neurons lose their proper way of migration and form nests of grey matter in the improper place. The aim of this study was to investigate the morphological features of the lost neurons in the cerebellar white matter during development, with particular emphasis on their localisation, arrangement and differentiation. We analyzed 31 fetal and infantile brains, aged from 28 gestational weeks to 18 postnatal months. We observed different morphological patterns of cerebellar heterotopias. Clusters of grey matter reflecting the cerebellar cortical pattern with well-defined molecular layer and altered granular and Purkinje cells were most frequently observed. The compact heterotopias were composed of bands or whirls of spindle and round granule cells situated closely together, while Purkinje neurons were completely disorganised. The ectopic cortex in the white matter with a normal layered structure containing all the components of the cerebellar cortex was localised by the large vessels. Aggregations of Purkinje cells scattered in the white matter without accompanying granule cells were observed. The evaluation of the biological features of the misplaced cerebellar cortical components showed high activity of neurons. PMID- 22212919 TI - Immunodistribution of amyloid beta protein (Abeta) and advanced glycation end product receptors (RAGE) in choroid plexus and ependyma of resuscitated patients. AB - RAGE (receptor for advanced glycation end-products) participates in the influx transport of glycated Abeta (amyloid beta) from the blood to the brain. Because little is known of the RAGE operating in brain barriers such as those in the choroid plexus and ependyma, the aim of the present study was to examine the immunodistributions of RAGE and Abeta peptides in the choroid plexus where the blood-cerebrospinal fluid barrier (B-CSF) is located, and in ependyma of the brain ventricles associated with functions of the cerebrospinal fluid-brain barrier (CSF-B). The study was performed on patients over 65 years successfully resuscitated after cardiac arrest with survival a few weeks. The control group consisted of age-matched individuals who were not resuscitated and died immediately after cardiac arrest. In resuscitated patients, but not in controls, RAGE receptors were localized in choroid plexus (CP) epithelial cells and in ependymal cells bordering the brain ventricles. These cells form the B-CSF and CSF-B barriers. The presence of Abeta was detected within the CP blood vessels and in the basement membrane of the CP epithelium. In numerous cytoplasmic vacuoles of CP epithelial and ependymal cells Abeta protein was found and our observations suggest that the contents of those vacuoles were undergoing progressive digestion. The results demonstrated that CP epithelium and ependymal cells, equipped with RAGE receptors, not only play an important role in the creation of amyloid deposits in the brain but are also places where Abeta may be utilized. The RAGE transportation system should be a main target in the therapy of brain amyloidosis, a well-known risk factor of Alzheimer disease. PMID- 22212920 TI - Survival motor neuron: motor neuron insurance for a whole lifespan? AB - The SMN (survival motor neuron) gene plays an important role in ontogenesis and its dysfunction leads to immatu-rity of skeletal muscles and motor neurons in the spinal cord. As a result of SMN mutations the affected cells die and clinical symptoms of spinal muscular atrophy (SMA) develop. Physiologically, SMN together with gemins is part of a multiprotein complex of particular importance to motor neuron development. Since the SMN gene is necessary for normal motor neuron maturity, a question arises whether its expression is preserved in postnatal life or finishes with the end of ontogenesis. To answer this question we examined expression of SMN and gemins 2, 3 and 4 in spinal cords of Wistar rats at age 1 350 days using immunofluorescence and immunohistochemical methods. In the examined animals expression of SMN appeared in neurons in 20-day old rats and increased with animal age. In rats aged 30-350 days SMN immunoreactivity was similar in all the examined animals. The same phenomenon was observed in assessment of gemin expression. Our study revealed that in rat spinal cord expression of SMN and gemins 2, 3 and 4 is present through a whole animal lifespan and not only in motor but also in sensory and autonomic neurons. PMID- 22212921 TI - Blood-brain barrier permeability differentiates Sadowski mouse lines of high and low stress-induced analgesia: electron microscopy analysis. AB - The blood-brain barrier (BBB) forms a filtering system between peripheral circulating blood and the central nervous system. Pathological leakage of the BBB is probably responsible for various dysfunctions and diseases. Over twenty years ago, Sadowski et al. separated two lines of mouse, one with high sensitivity (HA) and the other with low sensitivity (LA) to stress-induced analgesia (SIA). We propose that leakage of the BBB is responsible for the difference in SIA of the "Sadowski mouse" model. The presented BBB electron microscopy structural analysis of both lines provided evidence for this hypothesis. Up to now, a good natural animal model of differences of BBB permeability is not known. The "Sadowski mouse" may fulfil this deficiency. PMID- 22212922 TI - Alteration of GSK-3beta in the hippocampus and other brain structures after chronic paraquat administration in rats. AB - Systemic exposure of rodents to the herbicide paraquat (PQ) was suggested to reproduce pathological features of Parkinson's disease. Our recent data showed that long-term PQ administration influenced levels of glycogen synthase kinase 3beta (GSK-3beta) and its active form phosphorylated on tyrosine 216 in the nigrostriatal system, which may be related to its vulnerability to PQ toxicity. The aim of this study was to analyse selectivity of the toxic effect of PQ after its systemic administration in rats. PQ was administered for 37 weeks and the protein level of total GSK-3beta and its active GSK-3beta (pY216) form in subcellular fractions of hippocampus, brain cortex and cerebellum was examined. Our data indicated that the long-term administration of PQ significantly decreased the level of both GSK-3beta forms in nuclear and cytosolic fractions of hippocampus in rats. In the brain cortex and cerebellum PQ decreased the level of both forms of GSK-3beta in the nuclear fraction but increased their levels in mitochondria and in some cases also in the cytosol. The results of the present study indicate that PQ influenced levels and activation of GSK-3beta in different brain structures, which may contribute to its toxicity, but on the other hand may suggest development of adaptive, protective mechanisms. PMID- 22212923 TI - Effect of intrauterine morphine sulfate exposure on cerebellar histomorphological changes in neonatal mice. AB - Neurotoxic effects of morphine sulfate in adult cerebellar cortex and neonatal cerebral cortex have been studied in animal models. This study was done to determine the neurotoxic effects of prenatal morphine exposure on the histo morphological changes of cerebellar cortical layer and Purkinje cells in mice neonates. In this experimental study 30 female mice were randomly allocated into cases and controls. In the case group, animals received morphine sulfate 10 mg/kg/body weight intraperitoneally for 7 days. After mating, dams received morphine sulfate 10 mg/kg/body weight intraperitoneally for 20 days of gestation. Animals in the control group received normal saline. On the day of delivery (P0), the cerebella of six neonates for each group were removed and stained with cresyl violet. Quantitative computer-assisted morphometric study was done on the cortical layer of the cerebellum. Morphine exposure caused a non-significant increase in fetal weight in the case group. Purkinje cells in cases were decreased in comparison with controls (p < 0.05). Histomorphometric examination revealed that the thickness of Purkinje and internal granular layers of the cerebellar cortex decreased in the morphine-exposed group (p < 0.05). This study revealed that morphine administration before and during pregnancy can cause Purkinje cell loss and reduction of thickness of the Purkinje and internal granular layer of the cerebellar cortex and size of Purkinje cells in neonatal mice. PMID- 22212924 TI - Inflammatory cerebral amyloid angiopathy: the overlap of perivascular (PAN-like) with vasculitic (Abeta-related angiitis) form: an autopsy case. AB - Beside advanced age, cerebral amyloid angiopathy (CAA) and hypertension (HTA) are the two most important risk factors for haemorrhagic stroke. Inflammatory changes of amyloid-laden vessels have been reported only in rare sporadic CAA cases. We present the case of a 78-year-old woman with a history of hypertension, dementia and haemorrhagic stroke of the right frontal lobe 2 years before admission. She was admitted with recurrence of symptoms of transient aphasia and central, right side facial paresis that occurred an hour before her arrival at the hospital. In the admission unit, she was only slightly confused, with no other neurological deficits. An urgent CT scan revealed a recent haemorrhagic stroke in the left frontal lobe. In an hour her condition suddenly deteriorated. After a generalized seizure she presented with right-side hemiparesis with signs of uncal herniation and remained unconscious. A control CT scan showed a large haemorrhagic expansion that comprised the whole left brain hemisphere with 2 cm midline shift. She died about 10 hours after the onset of symptoms. At autopsy chronic inflammation of the thyroid gland, bronchopneumonia, fibrous and fatty heart degeneration and kidney haemorrhagic infarcts were documented. Amyloid deposition and systemic immune disorders in the inner organs were not demonstrated. In neuropathological examination we diagnosed inflammatory form of CAA with coexistence (the overlap) of two, perivascular and vascular, subtypes of CAA-related inflammation. PMID- 22212925 TI - Initial mini-mental state and cerebral perfusion in Alzheimer's disease. AB - PURPOSE: The relationship between the initial mini-mental state examination (MMSE) score and cerebral perfusion was evaluated in patients with Alzheimer's disease (AD). METHODS: In the study single photon emission computed tomography (SPECT) images of the brains of 40 AD patients were compared with the brain scans of 10 healthy controls. Each patient underwent MMSE analysis at initial evaluation as well as Tc-99 m hexamethylpropyleneamine oxine (HMPAO) brain SPECT. The patients were followed up for at least 42 months. RESULTS: The regional cerebral blood flow (rCBF) values for patients were found to be significantly decreased for all cerebral lobes compared to the control subjects and p-values were calculated to be less than 0.001 except for occipital lobes. The most statistically significant correlation between the MMSE scores and rCBF values was determined for the left temporal lobe (p < 0.0001). A significant correlation was also found for the right temporal lobe (p < 0.005). A minimal statistically significant correlation was found for the frontal lobes and the left parietal lobe (p < 0.05). CONCLUSIONS: The overall cerebral perfusion was decreased except in the occipital lobes in AD cases with low initial MMSE scores and there was a significant relationship between the decrease in perfusion of the temporal/frontal lobes and the left parietal lobe with the decrease in the initial MMSE scores. The most significant relationship between the decrease in the initial MMSE scores and the rCBF values was determined for the temporal lobes (especially for the left temporal lobe). It was also found that the left frontal lobe was affected from the beginning of the disease. PMID- 22212926 TI - Comparison of Mandibular Phenotypic and Genetic Integration between Baboon and Mouse. AB - In this study we compare patterns of mandibular integration between mice and baboons using both phenotypic and quantitative genetic data. Specifically, we test how well each species fits with the mosaic model of mandibular integration suggested by Atchley and Hall (Biol Rev Camb Philos Soc 66:101-157, 1991) based on developmental modules. We hypothesize that patterns of integration will be similar for mice and baboons and that both species will show strong integration within developmental modules and weaker integration between modules. Corresponding landmark data were collected from the hemi-mandibles of an advanced intercross mouse sample (N = 1239) and mandibles from a baboon sample of known pedigree from the Southwest Foundation for Biomedical Research (N = 430). We used four methods of analysis to quantify and compare the degree of mandibular integration between species including two methods based on a priori assumptions, and two a posteriori analyses. We found that patterns of integration are broadly similar for baboon and mouse mandibles, with both species displaying a modular pattern of integration. While there is a general trend of similarity in integration patterns between species, there were some marked differences. Mice are strongly correlated among distances within the coronoid process and the incisive alveolar region, whereas baboons are strongly integrated within the condylar process. We discuss the potential evolutionary implications of the similar patterns of integration between these species with an emphasis on the role of modularity. PMID- 22212927 TI - Osteological and molecular identification of Brucellosis in ancient Butrint, Albania. AB - Ancient skeletal remains can harbor unique information about past civilizations at both the morphological and molecular levels. For instance, a number of diseases manifest in bone, some of which have been confirmed through DNA analysis, verifying their presence in ancient populations. In this study, anthropological analysis of skeletal remains from the ancient Albanian city of Butrint identified individuals with severe circular lytic lesions on their thoracic and lumbar vertebrae. Differential diagnosis suggested that the lesions resulted from pathologies known to affect these skeletal regions, such as tuberculosis (TB) or brucellosis. Relevant bones of two adolescent males from the 10th to 13th century AD that displayed the lesions, along with unaffected individuals, were collected in the field. Genetic screening of the skeletal samples for TB was repeatedly negative, thus additional testing for Brucella spp. bacteria of livestock and the causative agent of brucellosis in humans-was conducted. Two Brucella DNA markers, the IS6501 insertion element and Bcsp31 gene, amplified from the affected vertebrae and/or ribs, whereas all unaffected individuals and control samples were negative. Subsequent DNA sequencing confirmed the presence of the brucellar IS6501 insertion element. On the basis of the skeletal lesions, negative tests for TB, and positive Brucella findings, we report a confirmed occurrence of brucellosis in archaeologically recovered human bone. These findings suggest that brucellosis has been endemic to the area since at least the Middle Ages. PMID- 22212928 TI - ATP-gated P2X1 ion channels protect against endotoxemia by dampening neutrophil activation. AB - BACKGROUND: In sepsis, extracellular ATP, secreted by activated platelets and leukocytes, may contribute to the crosstalk between hemostasis and inflammation. Previously, we showed that, in addition to their role in platelet activation, ATP gated P2X(1) ion channels are involved in promoting neutrophil chemotaxis. OBJECTIVES: To elucidate the contribution of P2X(1) ion channels to sepsis and the associated disturbance of hemostasis. METHODS: We used P2X(1) (-/-) mice in a model of lipopolysaccharide (LPS)-induced sepsis. Hemostasis and inflammation parameters were analyzed together with outcome. Mechanisms were further studied ex vivo with mouse and human blood or isolated neutrophils and monocytes. RESULTS: P2X(1) (-/-) mice were more susceptible to LPS-induced shock than wild type mice, despite normal cytokine production. Plasma levels of thrombin antithrombin complexes were higher, thrombocytopenia was worsened, and whole blood coagulation time was markedly reduced, pointing to aggravated hemostasis disturbance in the absence of P2X(1). However, whole blood platelet aggregation occurred normally, and P2X(1) (-/-) macrophages displayed normal levels of total tissue factor activity. We found that P2X(1) (-/-) neutrophils produced higher amounts of reactive oxygen species. Increased amounts of myeloperoxidase were released in the blood of LPS-treated P2X(1) (-/-) mice, and circulating neutrophils and monocytes expressed higher levels of CD11b. Neutrophil accumulation in the lungs was also significantly augmented, as was lipid peroxidation in the liver. Desensitization of P2X(1) ion channels led to increased activation of human neutrophils and enhanced formation of platelet leukocyte aggregates. CONCLUSIONS: P2X(1) ion channels play a protective role in endotoxemia by negatively regulating systemic neutrophil activation, thereby limiting the oxidative response, coagulation, and organ damage. PMID- 22212929 TI - Hepatocellular carcinoma in 2011 and beyond: from the pathogenesis to molecular targeted therapy. AB - Hepatocellular carcinoma is a malignant tumor responsible for approximately 600,000-700,000 deaths worldwide, and it is becoming more prevalent not only in Southeast Asia and Africa but also in Western countries; therefore, interest in hepatocellular carcinoma has mounted in recent years in the West, where little or no interest was evident 10-20 years ago. PMID- 22212930 TI - Hepatocarcinogenesis in hepatitis C: HCV shrewdly exacerbates oxidative stress by modulating both production and scavenging of reactive oxygen species. AB - Persistent infection with hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC). One of the characteristics of HCV infection is the unusual augmentation of oxidative stress, which is exacerbated by iron accumulation in the liver, as observed frequently in hepatitis C patients. Using a transgenic mouse model, in which HCC develops late in life after the preneoplastic steatosis stage, the core protein of HCV was shown to induce the overproduction of reactive oxygen species (ROS) in the liver. In excessive generation of ROS, HCV affects the steady-state levels of a mitochondrial protein chaperone, i.e. prohibitin, leading to an impaired function of the mitochondrial respiratory chain with the overproduction of ROS. Insulin resistance and hepatic steatosis, which frequently accompany HCV infection, exacerbate ROS production. On the other hand, HCV compromises some of the antioxidant systems, including heme oxygenase-1 and NADH dehydrogenase quinone 1, resulting in the provocation of oxidative stress, together with ROS overproduction, in the liver with HCV infection. Thus, HCV infection not only induces ROS but also hampers the antioxidant system in the liver, thereby exacerbating oxidative stress that would facilitate hepatocarcinogenesis. Combination with the other activated pathway, including an alteration in the intracellular signaling cascade of MAP kinase, along with HCV-associated disturbances in lipid and glucose metabolism would lead to the unusual mode of hepatocarcinogenesis, i.e. very frequent and multicentric development of HCC, in persistent HCV infection. PMID- 22212931 TI - Signaling pathways in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the sixth most common cancer, and its mortality rate is the third highest after lung and colon cancer. Its incidence has significantly increased in the last two decades in close relation with the ubiquitous spread of viral hepatitis. HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Molecular therapies such as sorafenib, a BRAF/ VEGFR/PDGFR tyrosine kinase inhibitor, have shown to improve survival in patients with advanced HCC. This recent success has spurred intensive research aimed at identifying aberrant activation of signaling pathways. This approach will probably aid to define previously unrecognized oncogenic addiction loops in HCC and in developing more effective targeted therapies. PMID- 22212932 TI - Signaling pathways governing tumor angiogenesis. AB - Angiogenesis is regulated by the highly coordinated function of various proteins with pro- and antiangiogenic functions. Proangiogenic factors include vascular endothelial growth factor (VEGF), fibroblast growth factor, platelet-derived growth factor, insulin-like growth factor, transforming growth factor, angiopoietins, and several chemokines; antiangiogenic factors include thrombospondin-1, angiostatin, and endostatin. Matrix metalloproteinases display a dual role in vascular development. Notch signaling affects remodeling of the primary vascular network of uniformly sized vessels into functionally and morphologically distinct arteries, veins, and capillaries. Tumors, described as 'wounds that never heal', lose the appropriate balance among these factors. Although VEGF-targeted therapies are showing promise, new angiogenesis targets are needed to make additional gains. Here, we highlight recent advances in our understanding of the regulation of tumor angiogenesis and discuss the potential of molecular targeting as a new therapeutic approach. PMID- 22212933 TI - Adriamycin enhances proteasome-mediated generation of the proapoptotic processed form of MAGE-A4 in hepatoma cells. AB - BACKGROUND: Melanoma antigen (MAGE)-A4 is processed to generate a C-terminal fragment with proapoptotic activity. Here we demonstrate that Adriamycin promotes generation of the processed MAGE-A4 by activating the proteasome. The proteasome is known to prevent accumulation of toxic proteins to maintain cellular homeostasis. METHODS AND RESULTS: Treatment of hepatoma cells expressing MAGE-A4 with a sublethal dose of Adriamycin increased the MAGE-A4 processing and sensitized the cells to Adriamycin-induced apoptosis. The processing of MAGE-A4 was inhibited by the proteasome inhibitors MG115, MG132, lactacystin and epoxamicin. MAGE-A4 was coimmunoprecipitated with the S6 proteasomal ATPase, and present in the fractions containing the proteasome during glycerol gradient centrifugation. Consistent with the notion that the proteasome cleaves MAGE-A4, the 26S proteasome, ubiquitin, and cell lysates were necessary for efficient in vitrocleavage of MAGE-A4. CONCLUSIONS: The present study suggests that a low dose of Adriamycin increases the proteasome activity, which either maintains cellular homeostasis or leads to apoptosis depending, at least under the present conditions, on the expression of MAGE-A4. PMID- 22212934 TI - Hospital- and community-based screenings for hepatocellular carcinoma in Taiwan. AB - In Taiwan, hepatocellular carcinoma (HCC) has been the leading cause of cancer incidence and mortality in recent decades. The majority of patients have hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. The HBV carrier rate and incidence of HCC in children have declined with the implementation of a hepatitis B vaccination program for newborns since 1984. A combination of alpha fetoprotein and ultrasonography (US) has been used for surveillance in patients with chronic HBV and HCV infection in intervals of 3-6 and 6-12 months for cirrhosis and chronic liver disease, respectively. A secular survival improvement in HCC patients has been demonstrated. A reasonable screening protocol should include two stages. The first stage is identification of high-risk subjects and the second stage is US screening of high-risk subjects. Community-based HCC screening programs have been conducted for more than two decades in Taiwan. The commonly used first-stage markers are HBsAg and anti-HCV, while the platelet count should be a useful marker in HCV-endemic communities. The benefit of HCC screening was shown by a prolonged overall survival. However, this was limited to the early curable stage in elderly subjects. Prevention and control of HCC have multiple modalities. Identification of a high-risk group for active surveillance, effective antiviral treatment for chronic HBV and HCV infection, and early detection and prompt treatment of HCC should decrease the sequelae of HCC in Taiwan. PMID- 22212935 TI - Prevention of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. AB - Chronic hepatitis B (CHB) accounts for approximately 50% of the underlying etiologies for the development of hepatocellular carcinoma (HCC) worldwide. We reviewed the primary, secondary, and tertiary measures for the prevention of HCC in CHB patients. First, the most effective method is preventing the acquisition of CHB through global vaccination of infants. However, in patients already chronically infected, antiviral treatment using interferon or nucleoside analogs can prevent disease progression to cirrhosis or HCC. Studies have found viral replications indicated by a HBV DNA level to be a strong predictor for cirrhosis and HCC, irrespective of other viral and biochemical factors. Additionally, periodic surveillance using ultrasonography and serum alpha-fetoprotein every 3-6 months for earlier detection of HCC is also important so that curative treatments can be used. Once HCC occurs, hepatic resection is the mainstay of curative treatments. To prevent tumor recurrence after resection, adjuvant interferon treatments have been tried with promising results based on the assumption that they not only suppress viral activity but also have tumoricidal, antiangiogenetic, and antiproliferative effects. Using nucleoside analogs also has its rationale for preventing de novo tumor development in remnant liver, considering that viral replications are a strong risk factor for HCC. Optimal preventive plans should be further investigated in future studies. PMID- 22212936 TI - Adjuvant therapy after curative treatment for hepatocellular carcinoma. AB - It is widely accepted that hepatocellular carcinoma (HCC) has an annual recurrence rate of approximately 15-20% even after potentially curative treatment, with the 5-year recurrence rate reaching 80-90%. This recurrence rate is also known to be similar after various curative treatments including resection, percutaneous ethanol injection therapy, and radiofrequency ablation. Generally, in treating patients with HCC associated with hepatitis C or liver cirrhosis, aggressive efforts to prevent secondary carcinogenesis are necessary rather than simply observing the clinical course after treatment. Presently, a combination of peg-interferon and ribavirin is known to be highly effective in patients with difficult-to-treat hepatitis C with a high viral load and genotype I virus. Therefore, indications of these treatments must be considered to prevent secondary carcinogenesis in patients with hepatitis C. Recently, long-term follow up of low-dose, long-term maintenance therapy using pegylated interferon-alpha2a for cirrhotic patients clearly showed a preventive effect on HCC occurrence and recurrence. Preventing secondary carcinogenesis by suppressing inflammation employing the same treatment as that against primary carcinogenesis is also important. The molecular targeted agent sorafenib markedly suppresses the serine/threonine kinases of Raf in the MAP kinase cascade and inhibits the tyrosine kinases of angiogenesis factor receptors such as vascular endothelial growth factor and platelet-derived growth factor receptors. It thus simultaneously prevents the proliferation of tumors and inhibits angiogenesis. A clinical trial to examine the recurrence-preventing effect of sorafenib by administration of it after curative treatment such as resection or ablation is in progress (STORM trial: http://clinicaltrials.gov.com, NCT00692770). Treatments to prevent recurrence (including intrahepatic metastasis and multicentric carcinogenesis) as well as early detection and early curative treatment are extremely important to improve the prognosis of patients with HCC. Thus, further research on this issue should be carried out, especially in relation to molecular targeted therapy. PMID- 22212937 TI - Controversies in surveillance and early diagnosis of hepatocellular carcinoma. AB - The surveillance of hepatocellular carcinoma (HCC) is an established approach to detect early cancers in patients with defined risks. However, there are still varied controversies and issues to be addressed regarding the optimal surveillance methods and interval. Moreover, there are discrepancies in the opinion or practice of HCC surveillance between Eastern and Western countries. The Western strategy of ultrasound without a biomarker such as alpha-fetoprotein reflects the cost-effective utilization of limited resources. On the contrary, combined measurements of biomarkers in Eastern countries are based on the assumption that increased detection of early cancers could result in an overall survival benefit. To address this complicated issue, a prospective study comparing different surveillance tests might be required. More importantly, discovery of a novel biomarker with higher performance would be an alternative. PMID- 22212938 TI - Highly sensitive Lens culinaris agglutinin-reactive alpha-fetoprotein: a new tool for the management of hepatocellular carcinoma. AB - OBJECTIVES: The highly sensitive Lens culinaris agglutinin-reactive alpha fetoprotein (hs-AFP-L3), measured using a newly developed method involving microfluidics-based separation technology, was evaluated as a new tool for the management of hepatocellular carcinoma (HCC) in clinical practice. METHODS: The sensitivity and specificity of hs-AFP-L3 for the diagnosis of HCC and its ability to predict the outcome of patients with HCC were analyzed based on reported studies. RESULTS: Compared to AFP-L3 measured using conventional methods, the sensitivity of hs-AFP-L3 was markedly higher and the specificity was comparable. In all studies, multivariate analysis found that elevation of hs-AFP-L3 was an independent factor that affected patient survival. CONCLUSIONS: The use of hs-AFP L3 improves the true positive rate of patients with HCC at diagnosis, maintaining the high specificity of AFP-L3 and its indicative value for poor prognosis. The utility of this tumor marker for prediction of the development of HCC in high risk patients under surveillance needs to be investigated. PMID- 22212939 TI - Usefulness of combination of imaging modalities in the diagnosis of hepatocellular carcinoma using Sonazoid(r)-enhanced ultrasound, gadolinium diethylene-triamine-pentaacetic acid-enhanced magnetic resonance imaging, and contrast-enhanced computed tomography. AB - OBJECTIVE: To clarify the diagnostic ability of combining imaging methods to diagnose hepatocellular carcinoma (HCC) using Sonazoid(r)-enhanced ultrasound (US), gadolinium diethylene-triamine-pentaacetic acid-enhanced (Gd-EOB-DTPA) magnetic resonance imaging (MRI), and contrast-enhanced computed tomography (CECT). METHODS: A total of 32 patients who underwent surgical resection for HCC were studied. Sonazoid-enhanced US, Gd-EOB-DTPA MRI, CECT, and intraoperative contrast-enhanced ultrasonography were done for all patients. The definitive diagnosis of HCC in those patients was based on histopathological confirmation. RESULTS: A total of 50 histologically proven HCCs were obtained from 32 patients; their mean (+/- SD) age was 68.3 years +/- 8.1. The mean (+/- SD) nodule size was 2.6 cm +/- 1.9. Twenty percent were well-differentiated HCC, 64% were moderately differentiated HCC, 10% were poorly differentiated HCC, 4% were combined HCC and CCC, and 2% were HCC with severe necrosis. The overall diagnostic sensitivity of CEUS, CECT, and Gd-EOB-DTPA MRI was 72, 74, and 86%, respectively; however, there was no significant difference between the three imaging modalities in diagnosing typical HCC (p = 0.092). When combining the diagnostic ability of the different imaging modalities, the diagnostic sensitivity of Sonazoid-enhanced US and Gd-EOB DTPA MRI was 90%, while addition of Sonazoid-enhanced US to CECT and CECT to Gd EOB-DTPA MRI had a sensitivity of 82 and 88%, respectively. There was no significant difference between the three imaging combinations (p = 0.970). CONCLUSION: Sonazoid-enhanced US and Gd-EOB-DTPA MRI can be confidently used in daily clinical practice for the management of HCC. PMID- 22212940 TI - Diagnostic imaging of hepatocellular carcinoma: recent progress. AB - The diagnostic imaging of hepatocellular carcinoma (HCC) has recently undergone marked progress. The advent of the ultrasound (US) contrast agent Sonazoid, approved in January 2007, and magnetic resonance imaging (MRI) with the liver specific MRI contrast agent gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA-MRI), approved in January 2008, are of particular significance. Sonazoid contrast-enhanced US (Sonazoid-CEUS) is useful not only for the diagnosis of HCC, but also for guiding treatment and assessing treatment response. Sonazoid-CEUS has proven to be particularly effective for screening and staging, which used to be considered impossible with CEUS, through the introduction of the newly developed diagnostic technique of defect reperfusion imaging. It is still not possible if other vascular agents such as SonoVue and Definity are used. In particular, Gd-EOB-DTPA-MRI has been suggested to be much more reliable in the differentiation of early HCC from precancerous dysplastic nodules than any other modalities such as multidetector raw computed tomography, dynamic MRI, and superparamagnetic iron oxide-MRI. A decrease in contrast uptake in the hepatocyte phase observed on EOB-MRI is strongly suggestive of cancer, and the absence of early staining in the arterial phase suggests early HCC. The differential diagnostic capacity of Gd-EOB-DTPA-MRI is considered to far exceed that of what were previously the most useful imaging techniques, computed tomography (CT) during hepatic arteriography or CT during arterial portography, and to be comparable to that of the pathological diagnosis by pathologists specialized in liver. PMID- 22212941 TI - Ultrasonography, computed tomography and magnetic resonance imaging of hepatocellular carcinoma: toward improved treatment decisions. AB - Detection, characterization, staging, and treatment monitoring are major roles in imaging diagnosis in liver cancers. Contrast-enhanced ultrasonography (CEUS) using microbubble contrast agents has expanded the role of US in the detection and diagnosis of liver nodules in patients at high risk of hepatocellular carcinoma (HCC). CEUS provides an accurate differentiation between benign and malignant liver nodules, which is critical for adequate management of HCC and is also useful for guidance of percutaneous local therapy of HCC and postprocedure monitoring of the therapeutic response. The technology of multidetector-row computed tomography (MDCT) has increased spatial and temporal resolutions of computed tomography (CT). It has made possible a more precise evaluation of the hemodynamics of liver tumor, and the diagnostic accuracy of dynamic MDCT has improved. Perfusion CT can measure tissue perfusion parameters quantitatively and can assess segmental hepatic function. Dynamic MDCT with high spatial and temporal resolution enables us to reconstruct 3- and 4-dimensional imaging, which is very useful for pretreatment evaluation. Dual-energy CT makes possible the differentiation of materials and tissues in images obtained based on the differences in iodine and water densities. Monochromatic images, which can be reconstructed by dual-energy CT data, provide some improvement in contrast and show a higher contrast-to-noise ratio for hypervascular HCCs. Dynamic magnetic resonance imaging with fast imaging sequence of 3-dimensional Fourier transformation T(1)-weighted gradient echo and nonspecific contrast medium can show high detection sensitivity of hypervascular HCC. However, the hepatic tissue specific contrast medium, gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid, has become an essential contrast medium for liver imaging because of its higher diagnostic ability. It may replace CT during hepatic arteriography and during arterioportography. PMID- 22212942 TI - Role of radiofrequency ablation in the treatment of hepatocellular carcinoma: experience of a cancer center in China. AB - Radiofrequency ablation (RFA) has become an important treatment for hepatocellular carcinoma (HCC). The good candidates for RFA are patients with HCC at an early stage (solitary tumor <= 5 cm in diameter or <= 3 nodules <= 3 cm in diameter). Several clinical trials have shown that RFA is effective in resection for the treatment of small HCC. Until now, RFA has been widely used as a radical treatment for small HCC. RFA also plays an important role in the multidisciplinary treatment of HCC and is usually combined with other therapies such as resection, vascular intervention, intratumor ethanol injection, radiotherapy, chemotherapy, targeted drug therapy, and biological immune therapy. In this study, we will introduce our experience of RFA in the treatment of HCC in a cancer center in China. PMID- 22212943 TI - Superselective transarterial chemoembolization for hepatocellular carcinoma: recent progression and perspective. AB - Transcatheter arterial chemoembolization (TACE) is widely performed in 32% of the patients with unresectable hepatocellular carcinoma (HCC) at initial diagnosis and in 58% of those with recurrent HCC in Japan. However, the patient population which undergoes TACE is heterogeneous, and thus the 3-year survival rate varies from 26 to 47%. The selection criteria for TACE is 2-3 tumors >3 cm or 4 or more tumors in patients with liver damage A/B (corresponding well to Child-Pugh class A/B) and absence of vascular invasion and extrahepatic spread, as proposed by Japanese guidelines. The 3-year survival rate of TACE for patients with 2-3 tumors >3 cm or 4 or more tumors was 55 and 46%, respectively, in Child-Pugh A and 30 and 22%, respectively, in class B. These outcomes could help to understand the various results of TACE in different backgrounds in the East and West. Recently, TACE with calibrated drug-eluting beads loaded with doxorubicin showed a similar tumor response and radioembolization with yttrium-90 microspheres demonstrated a similar median survival compared with conventional TACE. Based on these results, the combination of TACE and novel molecular targeted agents can be used to elucidate the synergic effect on survival. PMID- 22212944 TI - Living donor liver transplantation for hepatocellular carcinoma: the Japanese experience. AB - Treatment strategies against hepatocellular carcinoma have progressed remarkably over the past decade. In Asia, evidence-based guidelines for the management of hepatocellular carcinoma have evolved, including the option of liver transplantation. Due to severe organ shortage, however, living donor liver transplantation has become mainstream in Japan. Unlike deceased donor transplantation, living donor transplantation is not limited by the restrictions imposed by the nationwide allocation system. The decision for transplantation often depends on institutional or case-by-case considerations, balancing the will of the donor, the operative risk, and the overall survival benefit for the recipient. Cumulative data from the national multicenter registry analysis as well as individual center experience suggest that expansion of the Milan criteria is warranted. PMID- 22212945 TI - Prognostic indicators for tumor recurrence after liver transplantation in hepatocellular carcinoma and related molecular targeted therapy. AB - Liver transplantation (LT) is a viable therapeutic option for hepatocellular carcinoma (HCC). Many criteria, such as the Milan criteria and the University of California at San Francisco (UCSF) criteria, have been established to select a subset of HCC patients who stand to benefit from LT. However, they are still insufficient for predicting HCC patients at high risk for recurrence and selecting those at low risk. Many molecules which are probable candidates for recognizing HCC patients at high or low risk for recurrence give a wider perspective to consider for LT indication. Besides working as biomarkers, most of them are also functionally involved in some important pathways which contribute to HCC metastasis. The complex network constituted by them shows a multichannel, multistep HCC metastatic process which indicates difficulty in tumor therapy. Given the efficacy of some molecular targeted drugs in the treatment of HCC or prevention of tumor recurrence after LT, the emerging molecular targeted therapy is also discussed in this review. PMID- 22212946 TI - Radiotherapeutic strategies in the management of hepatocellular carcinoma. AB - Although potentially curative therapies for hepatocellular carcinoma (HCC) are well established, they are offered only to a limited number of patients. For advanced HCC, sorafenib is now the treatment of choice. Radiotherapy technology has evolved remarkably during the past decade and can be precisely delivered, thereby permitting higher doses to the tumor and reduced doses to surrounding normal tissues. According to the Korean Liver Cancer Study Group (KLCSG) practice guidelines, radiation therapy is considered appropriate for unresectable, locally advanced HCC without extrahepatic metastasis, Child-Pugh class A or B, and tumors occupying less than two thirds of the liver with level II evidence. In this review, we discuss the radiotherapeutic strategies for each clinical setting in patients with HCC. PMID- 22212948 TI - Treatment algorithm for intermediate and advanced stage hepatocellular carcinoma: Korea. AB - The practice guideline for hepatocellular carcinoma (HCC) in Korea was revised in 2009. It was based on clinical evidence. The treatment algorithm was divided into curative and noncurative treatments. According to Barcelona Clinic Liver Cancer (BCLC) staging, the curative treatment group included early stage HCC (BCLC-A), and the noncurative treatment group consisted of intermediate and advanced stages of HCC (BCLC-B, C). The intermediate stage of HCC stands for noncurative disease, and therefore surgical resection and radiofrequency ablation are not considered as primary treatment modalities. Transarterial chemoembolization (TACE) forms the backbone of the treatment for intermediate stage HCC with Child-Pugh A cirrhosis. Patients in whom complete necrosis is not achieved or early recurrence after TACE develops should receive individualized treatments such as systemic treatment or combined radiation therapy (RT). Liver transplantation (LT) can be carried out for intermediate stage HCCs. However, the long-term survival rate after LT for intermediate stage HCCs is inferior to that of early stage HCCs because intermediate stage HCCs exceed the Milan criteria. In patients with Child-Pugh C liver function, LT would be better than TACE in terms of survival gain if the tumor burden is acceptable by expert opinion standards. The treatment algorithm becomes very complicated when it comes to advanced stage HCC. Sorafenib, a multikinase inhibitor with antiangiogenic and antiproliferative properties, has been shown to prolong the median overall survival and the median time to radiological progression compared to placebo in randomized controlled trials (RCTs) and has become the current standard of care for patients with advanced stage tumors not suitable for surgical or locoregional therapies. RT is in the process of becoming a modality with a high efficacy and minimum side effects for HCC treatment, with recent improvements in equipment as well as radiation methods. However, to discover whether RT is really beneficial in the treatment of large-sized intermediate and advanced stage HCC, prospective RCTs should be carried out. PMID- 22212947 TI - Multidisciplinary management of nonresectable hepatocellular carcinoma. AB - This article summarizes the consensus of an early morning workshop on the multidisciplinary management of nonresectable hepatocellular carcinoma (HCC) held on July 4, 2010, under the auspices of the 1st Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE) Scientific Advisory Committee. Important points are as follows: (1) nonresectable HCC consists of locally advanced HCC and HCC with extrahepatic spread. The grouping system for locally advanced HCC comprises the following categories: nodular, massive with intrahepatic metastases, diffuse, and disease with vascular invasion. (2) In actual clinical practice, the orchestration of multimodality treatment options is keenly needed for successful treatment of individual patients with nonresectable HCC. Physicians in charge tend to prefer maximal cytoreductive measures as long as the condition of the individual patient allows. (3) There are a few studies on the combined use of radiation therapy and transcatheter arterial chemoembolization or hepatic arterial infusion chemotherapy in the form of phase I and II trials. (4) At this stage, scientific evidence on multidisciplinary management of nonresectable HCC is lacking. Further studies on multidisciplinary management should focus on the subcategory of locally advanced HCC. (5) Further discussion is needed in the upcoming APPLE meeting to clarify the guidelines as well as to determine a practical multidisciplinary approach for nonresectable HCC patients. PMID- 22212949 TI - Current situation of hepatocellular carcinoma in Mongolia. AB - Mongolia is one of the nations with the highest incidence of hepatocellular carcinoma (HCC) worldwide; it occurs in 54.1 cases per 100,000 people each year and is attributable to a high prevalence of chronic viral hepatitis. Although universal vaccination for hepatitis B virus has been implemented and sterilization of medical devices is being improved, the prevalence of chronic hepatitis B and C is still over 10%. Primary prevention of HCC is currently hard to achieve because of a limited availability of antiviral therapy. A significant proportion of HCC patients in Mongolia is diagnosed in the advanced stage, and this is due to the lack of a surveillance system using ultrasound and serum alpha fetoprotein for early detection. Moreover, the resources for high resolution imaging such as computed tomography are absolutely insufficient in number, and the treatment modalities physicians can choose are largely restricted. Considering that HCC is the most prevalent malignancy in Mongolia, a systematic approach to prevention, early detection, and effective treatment is urgently required. PMID- 22212950 TI - Complete response of advanced hepatocellular carcinoma with multiple lung metastases treated with sorafenib: a case report. AB - Sorafenib, an oral multikinase inhibitor, has demonstrated clinical efficacy in patients with advanced hepatocellular carcinoma (HCC). However, in the SHARP trial (Sorafenib HCC Assessment Randomized Protocol trial) and the Asia-Pacific trial (conducted in the Asia-Pacific region), no cases of complete response (CR) were reported. Thereafter, only a relatively small number of CR cases were reported worldwide for sorafenib therapy. We herein report a case of CR in a patient treated with sorafenib for 4 months. The patient had advanced HCC with multiple lung metastases, and there has been no recurrence after 8 months following cessation of administration. To our knowledge, this is the first time a female treated with sorafenib alone for HCC has had a CR. PMID- 22212951 TI - Asian consensus workshop report: expert consensus guideline for the management of intermediate and advanced hepatocellular carcinoma in Asia. AB - Hepatocellular carcinoma (HCC) is a highly prevalent disease in many Asian countries, accounting for 80% of victims worldwide. Screening programs improve the detection of early HCC and have a positive impact on survival, but the majority of HCC patients in Asia still present with advanced stage disease. The treatment outcomes of HCC are affected by multiple variables, including liver function, performance status of the patient, and tumor stage. Therefore, it is not easy to apply a multidisciplinary therapeutic approach for optimal management. At present, limited numbers of HCC patients are eligible for curative therapies such as surgery or ablation in Asia. Therefore, most patients are eligible for only palliative treatments. For optimal management, the treatment choice is guided by staging systems and treatment guidelines. Numerous staging systems have been proposed and treatment guidelines vary by region. According to the Barcelona Clinic Liver Cancer (BCLC) guideline based on evidence from randomized clinical trials, only transarterial chemoembolization (TACE) is recommended for intermediate stage HCC and sorafenib for advanced stage HCC. However, treatment guidelines from Asian countries have adopted several other therapeutic modalities such as a surgical approach, hepatic arterial infusion chemotherapy, external radiation, and their combinations based on clinical experiences for intermediate and advanced stage HCC. Although TACE is the main therapeutic modality in the intermediate stage, overall therapeutic outcomes depend on the tumor size. In the advanced stage, the prognosis depends on the tumor status, e.g. major vessel invasion or extrahepatic spread. Thus, a new staging system representing prognoses suitable for Asian HCC patients and a corresponding optimal treatment algorithm should be further investigated using evidence-based data, which will finally bring about an Asian consensus for the management of intermediate and advanced stage HCC. PMID- 22212953 TI - Orientation of newborn mice to lactating females: identifying biological substrates of semiochemical interest. AB - Among mammals, odor-based communication between females and infants is decisive for neonatal survival. So far, the nature of odor substrates involved in the localization of the mother and their nipples is unknown in mice. The present study aims: (1) to evaluate the specific attractive value of lactating females to newborn mice, (2) to localize the abdominal region that is most attractive to pups, and (3) to identify odor substrates that support such attraction. Results showed that 5-6-day-old mice roam preferentially over the abdomen of lactating females than the abdomen of non-lactating females. In lactating females, pups are more attracted to abdominal areas comprising nipples. The blend of odor substrates from nipples, as well as separate sources presumed to compose it, viz. milk, maternal saliva and pup saliva, were detectable and equivalently attractive to pups. The equivalent attraction of these different odor substrates may derive either from overlap in chemical constituents, or from associative learning during nursing. PMID- 22212952 TI - Apoptosis in Anthracycline Cardiomyopathy. AB - Apoptosis is a tightly regulated physiologic process of programmed cell death that occurs in both normal and pathologic tissues. Numerous in vitro or in vivo studies have indicated that cardiomyocyte death through apoptosis and necrosis is a primary contributor to the progression of anthracycline-induced cardiomyopathy. There are now several pieces of evidence to suggest that activation of intrinsic and extrinsic apoptotic pathways contribute to anthracycline-induced apoptosis in the heart. Novel strategies were developed to address a wide variety of cardiotoxic mechanisms and apoptotic pathways by which anthracycline influences cardiac structure and function. Anthracycline-induced apoptosis provides a very valid representation of cardiotoxicity in the heart, an argument which has implications for the most appropriate animal models of damaged heart plus diverse pharmacological effects. In this review we describe various aspects of the current understanding of apoptotic cell death triggered by anthracycline. Differences in the sensitivity to anthracycline-induced apoptosis between young and adult hearts are also discussed. PMID- 22212954 TI - Radical-scavenging activity, protective effect against lipid peroxidation and mineral contents of monofloral Cuban honeys. AB - Several monofloral Cuban honeys were analyzed to determine their free radical scavenging activity and from this the total antioxidant content was estimated. The protective effect against lipid peroxidation in an in vitro model of rat liver homogenates was evaluated and, lastly, the mineral content of the honeys, which can be related to the maintenance of intracellular oxidative balance, was determined. The scavenging capacities against hydroxyl and superoxide radicals were determined using the spin-trapping technique and the hypoxanthine/xanthine oxidase assay, respectively. Lipid peroxidation was evaluated through the production of TBARS and hydroperoxides. All honeys tested showed potential antioxidant activity with Linen vine displaying the highest scavenging capacity towards the DPPH, hydroxyl and superoxide radicals, while the least efficient was Christmas vine honey. Honeys also inhibited, in a concentration-dependent mode, lipid peroxidation in rat liver homogenates, with Linen vine resulting the best while the least effective was Christmas vine honey. The ability to scavenge free radicals and protect against lipid peroxidation may contribute to the ability of certain Cuban honeys to help in preventing/reducing some inflammatory diseases in which oxidative stress is involved. A total of eight minerals were identified and quantified as follows: cadmium, chromium, copper, nickel, iron, manganese, lead, and zinc. Minerals found in higher concentrations were iron, zinc and manganese. PMID- 22212955 TI - Association of serum bilirubin and promoter variations in HMOX1 and UGT1A1 genes with sporadic colorectal cancer. AB - Heme oxygenase-1 (HMOX1) and bilirubin UDP-glucuronosyltransferase (UGT1A1) enzymes, both involved in bilirubin homeostasis, play an important role in the oxidative stress defense. The objective of our study was to assess the effect of promoter variations of HMOX1 and UGT1A1 genes and of serum bilirubin on the risk of sporadic colorectal cancer (CRC). This exploratory case-control study was based on 777 CRC patients and 986 controls from the Czech Republic. The (GT)(n) and (TA)(n) dinucleotide variations in HMOX1 and UGT1A1 gene promoters, respectively, were determined by fragment analysis. In addition, the A(-413)T variant in HMOX1 promoter was also analyzed using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Serum bilirubin levels were compared in a subset of 174 cases and 247 controls, for whom biochemical data were available. After adjustment for age, a significant association between CRC risk and UGT1A1*28 allele carrier status was detected [odds ratio (95% confidence intervals) = 0.80 (0.60-0.97), p = 0.022]. No association between CRC risk and individual HMOX1 gene variants was observed, although a diplotype analysis revealed an increased risk for a specific HMOX1 genotype combination. These effects were more pronounced in males. Substantially lower serum bilirubin levels were detected in CRC patients compared to the controls (p < 0.001); each 1 MUmol/L decrease in serum bilirubin was associated with a 7% increase of CRC risk (p < 0.001). In conclusion, UGT1A1*28 allele carrier status might be a protective factor against the development of CRC in the male population, whereas low serum bilirubin levels are associated with an increased risk of CRC in both genders. PMID- 22212956 TI - Theory of mind in bulimia nervosa. AB - OBJECTIVE: This study aimed to investigate theory of mind (ToM) in individuals with bulimia nervosa (BN), an area neglected by empirical research despite social functioning difficulties in this disorder and evidence of ToM deficits in people with anorexia nervosa (AN). METHOD: ToM was assessed in 48 BN and 34 Eating Disorder Not Otherwise Specified BN-type (EDNOS-BN) outpatients and 57 healthy controls (HCs) using the Reading the Mind in the Eyes and the Reading the Mind in the Films (RMF), an ecologically valid task novel to BN research. RESULTS: Overall performance in BN and EDNOS-BN groups was equivalent to HCs on both tasks. Individuals with BN had enhanced negative emotion recognition on the RMF. DISCUSSION: Individuals with AN and BN have distinct socio-cognitive profiles. Further research into social cognition is required to establish the link between interpersonal difficulties and psychopathology in people with BN. PMID- 22212958 TI - Prioritizing treatment experienced patients with hepatitis C infection for treatment with telaprevir: a number needed to treat approach. PMID- 22212957 TI - Phosphorylation of serine 21 modulates the proliferation inhibitory more than the differentiation inducing effects of C/EBPalpha in K562 cells. AB - The CCAAT/enhancer binding protein alpha (C/EBPalpha) is a transcription factor required for differentiation of myeloid progenitors. In acute myeloid leukemia (AML) cells expressing the constitutively active FLT3-ITD receptor tyrosine kinase, MAP kinase-dependent phosphorylation of serine 21 (S21) inhibits the ability of C/EBPalpha to induce granulocytic differentiation. To assess whether this post-translational modification also modulates the activity of C/EBPalpha in BCR/ABL-expressing cells, we tested the biological effects of wild-type and mutant C/EBPalpha mimicking phosphorylated or non-phosphorylatable serine 21 (S21D and S21A, respectively) in K562 cells ectopically expressing tamoxifen regulated C/EBPalpha-ER chimeric proteins. We show here that S21D C/EBPalpha-ER induced terminal granulocytic differentiation of K562 cells almost as well as wild-type C/EBPalpha-ER, while S21A C/EBPalpha-ER was less efficient. Furthermore, wild-type C/EBPalpha suppressed the proliferation and colony formation of K562 cells vigorously, while S21D and S21A C/EBPalpha mutants had more modest anti-proliferative effects. Both mutants were less effective than wild-type C/EBPalpha in suppressing endogenous E2F-dependent transactivation and bound less E2F-2 and/or E2F-3 proteins in anti-C/EBPalpha immunoprecipitates. Together, these findings suggest that mutation of S21 more than its phosphorylation inhibits the anti-proliferative effects of C/EBPalpha due to reduced interaction with or impaired regulation of the activity of E2F proteins. By contrast, phosphorylation of serine 21 appears to have a modest role in modulating the differentiation-inducing effects of C/EBPalpha in K562 cells. PMID- 22212959 TI - MALDI based identification of soybean protein markers--possible analytical targets for allergen detection in processed foods. AB - Soybean (Glycine max) is extensively used all over the world due to its nutritional qualities. However, soybean is included in the "big eight" list of food allergens. According to the EU directive 2007/68/EC, food products containing soybeans have to be labeled in order to protect the allergic consumers. Nevertheless, soybeans can still inadvertently be present in food products. The development of analytical methods for the detection of traces of allergens is important for the protection of allergic consumers. Mass spectrometry of marker proteolytical fragments of protein allergens is growingly recognized as a detection method in food control. However, quantification of soybean at the peptide level is hindered due to limited information regarding specific stable markers derived after proteolytic digestion. The aim of this study was to use MALDI-TOF/MS and MS/MS as a fast screening tool for the identification of stable soybean derived tryptic markers which were still identifiable even if the proteins were subjected to various changes at the molecular level through a number of reactions typically occurring during food processing (denaturation, the Maillard reaction and oxidation). The peptides (401)Val-Arg(410) from the G1 glycinin (Gly m 6) and the (518)Gln-Arg(528) from the alpha' chain of the beta-conglycinin (Gly m 5) proved to be the most stable. These peptides hold potential to be used as targets for the development of new analytical methods for the detection of soybean protein traces in processed foods. PMID- 22212960 TI - Mechanisms of cytosolic targeting of matrix metalloproteinase-2. AB - Matrix metalloproteinase-2 (MMP-2) is best understood for its biological actions outside the cell. However, MMP-2 also localizes to intracellular compartments and the cytosol where it has several substrates, including troponin I (TnI). Despite a growing list of cytosolic substrates, we currently do not know the mechanism(s) that give rise to the equilibrium between intracellular and secreted MMP-2 moieties. Therefore, we explored how cells achieve the unique distribution of this protease. Our data show that endogenous MMP-2 targets inefficiently to the endoplasmic reticulum (ER) and shows significant amounts in the cytosol. Transfection of canonical MMP-2 essentially reproduces this targeting pattern, suggesting it is the quality of the MMP-2 signal sequence that predominantly determines MMP-2 targeting. However, we also found that human cardiomyocytes express an MMP-2 splice variant which entirely lacks the signal sequence. Like the fraction of ER-excluded, full-length MMP-2, this variant MMP-2 is restricted to the cytosol and specifically enhances TnI cleavage upon hypoxia-reoxygenation injury in cardiomyocytes. Together, our findings describe for the first time a set of mechanisms that cells utilize to equilibrate MMP-2 both in the extracellular milieu and intracellular, cytosolic locations. Our results also suggest approaches to specifically investigate the overlooked intracellular biology of MMP-2. PMID- 22212961 TI - Mayo clinic proceedings 2012: "a new era in journal stewardship". PMID- 22212962 TI - Hepatitis C virus infection and the rising incidence of hepatocellular carcinoma. PMID- 22212963 TI - Hepatocellular carcinoma in olmsted county, Minnesota, 1976-2008. AB - OBJECTIVE: To analyze longitudinal trends in the incidence, etiology, and treatment of hepatocellular carcinoma (HCC) in community residents in Olmsted County, Minnesota, and their survival. PATIENTS AND METHODS: Olmsted County residents 20 years or older with HCC newly diagnosed from January 1, 1976, through December 31, 2008, were identified using a community-wide medical record linkage system (Rochester Epidemiology Project). The incidence rate of HCC was calculated by age and sex according to the 2000 US Census population. Temporal trends of HCC etiology, treatment, and patient survival were assessed. RESULTS: The age- and sex-adjusted incidence rate for HCC in Olmsted County was 3.5 per 100,000 person-years for the first era (1976-1990), 3.8 per 100,000 for the second era (1991-2000), and 6.9 per 100,000 for the third era (2001-2008). Alcohol use was the most common risk factor in the first and second eras and chronic hepatitis C virus in the third. The proportion attributed to nonalcoholic fatty liver disease was small (5/47 [10.6%] in the third era). Because the proportion of patients receiving curative treatment increased over time, survival also improved, with a median survival time of 3, 6, and 9 months in the first, second, and third eras, respectively (P=.01). CONCLUSION: In this midwestern US community, the incidence of HCC has increased, primarily due to hepatitis C virus. Although there was a demonstrable improvement in the outcome of HCC in community residents over time, the overall prognosis remains poor. PMID- 22212964 TI - Viral hepatitis among Somali immigrants in Minnesota: association of hepatitis C with hepatocellular carcinoma. AB - OBJECTIVE: To study the frequencies of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, and their associations with hepatocellular carcinoma (HCC) in immigrant Somalis seen at Mayo Clinic in Rochester, Minnesota. PATIENTS AND METHODS: We determined the frequencies of HBV and HCV infection and HCC in immigrant Somalis seen at Mayo Clinic from July 1, 1996, through October 31, 2009. Non-Somali Olmsted County residents served as controls. RESULTS: For Somali males and females, age-adjusted proportions (per 1000 population) were 209 and 123 for hepatitis B surface antigen (HBsAg), 644 and 541 for hepatitis B core antibody (HBcAb), and 99 and 66 for anti-HCV. The comparative proportions in non Somalis were 20 and 9 for HBsAg, 126 and 97 for HBcAb, and 32 and 17 for anti HCV. Hepatitis C virus RNA confirmed that 68 of 73 Somalis (93.2%) and 261 of 282 non-Somalis (92.6%) with positive anti-HCV test results had active HCV infection. Of 30 Somali patients with HCC, 22 (73.3%) tested anti-HCV positive (odds ratio [OR], 31.3; 95% confidence interval [CI], 13.0-75.5; P<.001; compared with anti HCV-negative Somalis), 5 (16.7%) were HBsAg positive (OR, 1.4; 95% CI, 0.5-3.7; P=.53), and 18 (60.0%) were HBcAb positive (OR, 1.8; 95% CI, 0.8-4.2; P=.16). Viral hepatitis was diagnosed coincident with HCC in 9 of 20 patients (45.0%) with HCV-associated HCCs. Only 4 of 24 cases of HCC (16.7%) were detected during surveillance. CONCLUSION: Both HBV and HCV occurred frequently in this sample of Somali immigrants. However, HCV was the major risk factor for HCC. Screening Somali immigrants for HCV infection may enhance the prevention, early detection, and optimal treatment of HCC. PMID- 22212965 TI - One thousand patients with primary myelofibrosis: the mayo clinic experience. AB - OBJECTIVE: To share our decades of experience with primary myelofibrosis and underscore the importance of outcomes research studies in designing clinical trials and interpreting their results. PATIENTS AND METHODS: One thousand consecutive patients with primary myelofibrosis seen at Mayo Clinic between November 4, 1977, and September 1, 2011, were considered. The International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus were applied for risk stratification. Separate analyses were included for patients seen at time of referral (N=1000), at initial diagnosis (N=340), and within or after 1 year of diagnosis (N=660). RESULTS: To date, 592 deaths and 68 leukemic transformations have been documented. Parameters at initial diagnosis vs time of referral included median age (66 vs 65 years), male sex (61% vs 62%), red cell transfusion need (24% vs 38%), hemoglobin level less than 10 g/dL (38% vs 54%), platelet count less than 100 * 10(9)/L (18% vs 26%), leukocyte count more than 25 * 10(9)/L (13% vs 16%), marked splenomegaly (21% vs 31%), constitutional symptoms (29% vs 34%), and abnormal karyotype (31% vs 41%). Mutational frequencies were 61% for JAK2V617F, 8% for MPLW515, and 4% for IDH1/2. DIPSS-plus risk distributions at time of referral were 10% low, 15% intermediate-1, 37% intermediate-2, and 37% high. The corresponding median survivals were 17.5, 7.8, 3.6, and 1.8 years vs 20.0, 14.3, 5.3, and 1.7 years for patients younger than 60 years of age. Compared with both DIPSS and IPSS, DIPSS-plus showed better discrimination among risk groups. Five-year leukemic transformation rates were 6% and 21% in low- and high-risk patients, respectively. CONCLUSION: The current document should serve as a valuable resource for patients and physicians and provides context for the design and interpretation of clinical trials. PMID- 22212966 TI - Sixteen-year longitudinal changes in serum prostate-specific antigen levels: the olmsted county study. AB - OBJECTIVE: To determine the distribution of longitudinal changes in serum prostate-specific antigen (PSA) levels from a population-based sample of men. PATIENTS AND METHODS: In this prospective cohort study, a random sample of Olmsted County, Minnesota, men aged 40 to 79 years in 1990 were followed up biennially from January 1, 1990, through August 29, 2007. Serum PSA levels were determined at each examination, and men were censored for follow-up with a diagnosis of prostate cancer or treatment for benign prostatic hyperplasia. The empirical distributions of annual percent change and annual absolute change in serum PSA level were calculated and tabulated, including the median and 75th and 95th percentiles. RESULTS: For men with PSA measurements 2 years apart, the median annual percent change in serum PSA level was 4.83% and the 95th percentile was about 49.76%. The variability in estimated annual change decreased with increasing time between assessments, with a 95th percentile of 21.82% after 8 or more years between assessments. Although the median absolute change per year increased with increasing age, the median percent change per year was fairly consistent across age groups. CONCLUSION: These data demonstrate that, with shorter intervals between assessments, greater variability should be expected. These distributions should prove helpful to patients and clinicians in interpreting changes in serum PSA levels observed in typical clinical practices. PMID- 22212967 TI - Postoperative emergency response team activation at a large tertiary medical center. AB - OBJECTIVE: To study characteristics and outcomes associated with emergency response team (ERT) activation in postsurgical patients discharged to regular wards after anesthesia. PATIENTS AND METHODS: We identified all ERT activations that occurred within 48 hours after surgery from June 1, 2008, through December 31, 2009, in patients discharged from the postanesthesia care unit to regular wards. For each ERT case, up to 2 controls matched for age (+/-10 years), sex, and type of procedure were identified. A chart review was performed to identify factors that may be associated with ERT activation. RESULTS: We identified 181 postoperative ERT calls, 113 (62%) of which occurred within 12 hours of discharge from the postanesthesia care unit, for an incidence of 2 per 1000 anesthetic administrations (0.2%). Multiple logistic regression analysis revealed the following factors to be associated with increased odds for postoperative ERT activation: preoperative central nervous system comorbidity (odds ratio [OR], 2.53; 95% confidence interval [CI], 1.20-5.32; P=.01), preoperative opioid use (OR, 2.00; 95% CI, 1.30-3.10; P=.002), intraoperative use of phenylephrine infusion (OR, 3.05; 95% CI, 1.08-8.66; P=.04), and increased intraoperative fluid administration (per 500-mL increase, OR, 1.06; 95% CI, 1.01-1.12; P=.03). ERT patients had longer hospital stays, higher complication rates, and increased 30 day mortality compared with controls. CONCLUSION: Preoperative opioid use, history of central neurologic disease, and intraoperative hemodynamic instability are associated with postoperative decompensation requiring ERT intervention. Patients with these clinical characteristics may benefit from discharge to progressive or intensive care units in the early postoperative period. PMID- 22212968 TI - Prediction of cardiovascular events by inflammatory markers in patients undergoing carotid stenting. AB - OBJECTIVE: To assess whether inflammatory markers predict atherosclerotic disease activity after carotid treatment in patients with severe carotid stenosis and nonsignificant coronary artery disease undergoing carotid stenting. PATIENTS AND METHODS: From March 1, 2004, to September 30, 2005, a total of 55 consecutive patients (mean +/- SD age, 69+/-8.3 years; 26 men) with severe carotid stenosis and nonsignificant coronary artery disease were treated with carotid stent implantation. Patients were followed up for a period of 5 years for the occurrence of cardiovascular events. RESULTS: A significant correlation between quantitative analysis of debris entrapped in the filters and inflammatory markers was found. Moreover, the number of particles per filter, the total particles area, and the mean particle axis per filter were significantly higher in patients with clinical events at the follow-up compared with patients without events (87 vs 32, P=.006; 50,118.7 vs 17,782, P=.002; 33.9 vs 30.2, P=.03). At 5-year follow up we recorded cardiovascular or neurologic events in 11 of the 55 patients (20%). Higher preprocedural levels of high-sensitivity C-reactive protein, interleukin 6 soluble receptor, and interleukin 6 were significantly associated with clinical events at follow-up (P<.001, P=.05, and P=.02, respectively). In particular high-sensitivity C-reactive protein measured at 24 and 48 hours after carotid stenting showed a significant correlation with clinical events (P=.001). Also preprocedural intracellular adhesion molecule 1 and circulating vascular cell adhesion molecule 1 blood concentrations were significantly correlated with a worse prognosis at follow-up (P=.04 and P=.03, respectively). CONCLUSION: In patients with severe carotid stenosis and nonsignificant coronary artery disease, inflammation is associated with atherosclerotic disease activity and a worse prognosis. Interleukin 6, interleukin 6 soluble receptor, intracellular adhesion molecule 1, vascular cell adhesion molecule 1, and high-sensitivity C-reactive protein levels at baseline and 24 and 48 hours after carotid stenting are predictive of neurologic and cardiovascular events at follow-up. PMID- 22212969 TI - Deep brain stimulation in tourette syndrome: a description of 3 patients with excellent outcome. AB - Tourette syndrome (TS) is a complex neuropsychiatric disorder often starting in childhood and characterized by the presence of multiple motor and vocal tics and psychiatric comorbidities. Patients with TS usually respond to medical treatment, and the condition often improves during adolescence; however, surgery has been considered a possible approach for the subset of patients with ongoing medically refractory disease. Ablative procedures have been associated with unsatisfactory results and major adverse effects, prompting trials of deep brain stimulation (DBS) as an alternative therapy. It remains unclear which of the various nuclear targets is most effective in TS. We describe 3 patients with TS who underwent DBS targeting the bilateral thalamic centromedian/parafascicular complex (CM/Pf) with an excellent clinical outcome. At 1-year follow-up, the mean reduction in the total Yale Global Tic Severity Scale score in the 3 patients was 70% (range, 60% 80%).Our study further supports the role of the CM/Pf DBS target in medically intractable TS. PMID- 22212970 TI - Fighting the good fight: responsibility and rationale in the confrontation of patients. PMID- 22212971 TI - My treatment approach to hairy cell leukemia. AB - Hairy cell leukemia (HCL) is a rare chronic lymphoproliferative disorder characterized by circulating B cells with cytoplasmic projections, pancytopenia, splenomegaly, and a typical flow cytometry pattern. Recently, the BRAF V600E mutation was uniformly identified in one HCL series, which may provide insights into the pathogenic mechanisms. The disease course is usually indolent but inexorably progressive. Patients require treatment when they have significant cytopenia or occasionally recurrent infections from immunocompromise. In the mid 1980s, interferon replaced splenectomy as the initial treatment. A few years later, 2 purine nucleoside analogs, cladribine and pentostatin, showed promising activity in HCL. Complete response rates approached 95% with cladribine given as a single 7-day intravenous infusion. Newer methods of cladribine administration and modified dosing schedules have since been studied. Pentostatin response rates are comparable. We generally prefer cladribine because of its ease of administration, single infusion schema, and favorable toxicity profile. Since the introduction of these drugs, which have never been randomly compared, long-term follow-up studies have confirmed impressive and durable response durations. However, roughly 40% of patients with HCL eventually relapse. In this setting, patients can be re-treated with purine analogs. Rituximab also has a reasonable response rate in relapsed HCL; it can be given as a single agent sequentially after purine nucleosides or concurrently. Immunotoxins have robust responses but remain in development. Targeting the BRAF pathway will be an exciting future area of research. Many patients have minimal residual disease after initial treatment, but the clinical significance of this remains unknown. PMID- 22212972 TI - The expanding role of vascular endothelial growth factor inhibitors in ophthalmology. AB - Vascular endothelial growth factor (VEGF) plays an important role in both physiologic and pathologic angiogenesis and contributes to increased permeability across both the blood-retinal and blood-brain barriers. After 2 decades of extensive research into the VEGF families and receptors, specific molecules have been targeted for drug development, and several medications have received US Food and Drug Administration approval. Bevacizumab, a full-length antibody against VEGF approved for the intravenous treatment of advanced carcinomas, has been used extensively in ophthalmology for exudative age-related macular degeneration, diabetic retinopathy, retinal vein occlusions, retinopathy of prematurity, and other chorioretinal vascular disorders. Pegaptanib and ranibizumab have been developed specifically for intraocular use, whereas the soon-to-be-introduced aflibercept (VEGF Trap-Eye) is moving through clinical trials for both intraocular and systemic use. Although these drugs exhibit excellent safety profiles, ocular and systemic complications, particularly thromboembolic events, remain a concern in patients receiving therapy. Patients experiencing adverse events that may be related to VEGF suppression should be carefully evaluated by both the ophthalmologist and the medical physician to reassess the need for intraocular therapy and explore the feasibility of changing medications. For this review a search of PubMed from January 1, 1985 through April 15, 2011, was performed using the following terms (or combination of terms): vascular endothelial growth factors, VEGF, age-related macular degeneration, diabetic retinopathy, retina vein occlusions, retinopathy of prematurity, intravitreal injections, bevacizumab, ranibizumab, and VEGF Trap. Studies were limited to those published in English. Other articles were identified from bibliographies of retrieved articles and archives of the author. PMID- 22212973 TI - Clinical pearls in women's health. PMID- 22212974 TI - 52-year-old man with liver enzyme abnormalities and elevated ferritin level. PMID- 22212975 TI - Practical considerations in the use of outpatient antimicrobial therapy for musculoskeletal infections. AB - Successful treatment of many musculoskeletal infections often requires an extended course of outpatient antimicrobial therapy, much of which is administered parenterally outside the hospital under the guidance of an infectious disease specialist. Delivery of outpatient parenteral antimicrobial therapy (OPAT) may occur in physicians' offices, ambulatory infusion centers, or hospital clinics but most frequently is done in patients' homes, often by the patients themselves. In this article, we outline the essential elements of outpatient antimicrobial therapy for musculoskeletal infections with particular emphasis on OPAT, including patient selection and evaluation; antimicrobial administration, including the route, duration, and complications of central venous access; and clinical and laboratory monitoring of antimicrobial therapy. We believe that primary care physicians, orthopedists, and infectious disease specialists caring for patients with musculoskeletal infections should become familiar with the use of, indications for, and complications of OPAT. PMID- 22212976 TI - Nonpulsatile chest wall swelling. PMID- 22212977 TI - Nikolay Basov--nobel prize for lasers and masers. PMID- 22212979 TI - Androgen receptor overexpression alters binding dynamics of the receptor to chromatin and chromatin structure. AB - BACKGROUND: Castration-resistant prostate cancers (CRPCs) overexpress often androgen receptor (AR). Here, we investigated the effect of AR overexpression on the dynamics of AR loading and RNA polymerase II (RNA Pol II) recruitment to chromatin. Acetylation of histone 3 (AcH3) on lysines 9 and 14 (K9 and K14) was also studied. METHODS: We used an LNCaP-based AR overexpression cell line model that includes a control line and two sublines, LNCaP-ARmo and LNCaP-ARhi, which overexpress AR twofold to threefold and fourfold to fivefold, respectively. Cells were exposed to 1 or 100 nM of dihydrotestosterone (DHT). Chromatin immunoprecipitation (ChIP) on the promoters and enhancers of prostate specific antigen (PSA) and transmembrane protease, serine 2 (TMPRSS2) genes was performed. qRT-PCR was used to measure the levels of PSA and TMPRSS2 transcripts. RESULTS: Upon stimulation with 1 nM DHT, AR and RNA Pol II were recruited onto PSA and TMPRSS2 enhancer regions to a greater extent (P < 0.05) in AR-overexpressing cells compared to control cells. The difference in AR loading between the control and AR-overexpressing cells was abolished by a higher DHT concentration. The ratio of AcH3/H3 was increased in AR-overexpressing cells. The induction of transcription of PSA and TMPRSS2 occurred earlier in the AR-overexpressing cells. CONCLUSIONS: Our findings suggest that the levels of AR potentiate the recruitment of the AR, as well as components of the basic transcription machinery, to chromatin and affect the acetylation of histones in the presence of low levels of androgens. These changes result in enhanced gene transcription of AR target genes. PMID- 22212980 TI - Overtraining and the use of feature and geometric cues for reorientation. AB - Using a dynamic three-dimensional virtual environment task, we investigated the influence of overtraining of feature and geometric cues on preferential spatial cue use. We trained two groups of human participants to respond to feature and geometric cues in separate enclosures before placing these cues in conflict on a critical test trial. All participants learned to respond to rewarded features located along the principal axis of a rectangular search space and to rewarded geometric cues of a rectangular search space in separate training phases followed by a single test trial. During the test trial, we situated the rewarded features in the unrewarded geometric corners and the unrewarded features in rewarded geometric corners. For one group, participants were overtrained with feature cues compared to geometric cues before experiencing the conflict test; whereas, for another group, participants were overtrained with geometric cues compared to feature cues before experiencing the conflict test. Although both groups learned to respond to both feature and geometric cues at an equivalent rate and to an equivalent level of terminal accuracy, testing results revealed no difference between the groups with respect to their preference for feature or geometric cues. Despite a lack of influence of overtraining on spatial cue preference, participants showed an overall preference for feature cues. We discuss the results with respect to implications for theoretical accounts of spatial learning. PMID- 22212982 TI - [Expert opinion on use of intravenous immunoglobulins in the management of neurological disorders]. PMID- 22212981 TI - Dietary nitrogen and fish welfare. AB - Little research has been done in optimizing the nitrogenous fraction of the fish diets in order to minimize welfare problems. The purpose of this review is to give an overview on how amino acid (AA) metabolism may be affected when fish are under stress and the possible effects on fish welfare when sub-optimal dietary nitrogen formulations are used to feed fish. In addition, it intends to evaluate the current possibilities, and future prospects, of using improved dietary nitrogen formulations to help fish coping with predictable stressful periods. Both metabolomic and genomic evidence show that stressful husbandry conditions affect AA metabolism in fish and may bring an increase in the requirement of indispensable AA. Supplementation in arginine and leucine, but also eventually in lysine, methionine, threonine and glutamine, may have an important role in enhancing the innate immune system. Tryptophan, as precursor for serotonin, modulates aggressive behaviour and feed intake in fish. Bioactive peptides may bring important advances in immunocompetence, disease control and other aspects of welfare of cultured fish. Fishmeal replacement may reduce immune competence, and the full nutritional potential of plant-protein ingredients is attained only after the removal or inactivation of some antinutritional factors. This review shows that AA metabolism is affected when fish are under stress, and this together with sub-optimal dietary nitrogen formulations may affect fish welfare. Furthermore, improved dietary nitrogen formulations may help fish coping with predictable stressful events. PMID- 22212983 TI - Sex hormone patterns in women with multiple sclerosis as related to disease activity--a pilot study. AB - BACKGROUND AND PURPOSE: The influence of sex hormones on immune system activity in multiple sclerosis (MS) has been suggested by clinical evidence. The aim of the study was to ana-lyse the pattern of sex hormones in MS women and to correlate the hormone pattern abnormalities to the disease course as well as to the magnetic resonance imaging (MRI) results. MATERIAL AND METHODS: We studied the serum level of the progesterone, beta-oestradiol and prolactin in 46 women with clinical definite MS aged from 19 to 65; mean disease duration was 11.80 +/- 9.86 years. The evaluation of the intensity of hormonal changes was done using a scoring system (0-3). On the brain MRI, the presence of brain atrophy, of hypothalamic demyelination as well as demyelination intensity (or degree) were analysed. The evaluation of the degree of demyelination and brain atrophy was done using a scoring system (0-4). RESULTS: The main hormonal abnormalities consisted of decreased progesterone level, increased oestradiol level or both. The sex hormone pattern was abnormal in 56% of patients. Hypothalamic lesions were found on MRI in 53% of cases. The abnormal hormonal pattern correlated with intensity of MR changes (p < 0.05, Fisher's exact test), but neither with presence of hypothalamic changes nor with disease parameters (Expanded Disability Status Scale, relapse rate, disease duration). CONCLUSIONS: It is important to check the hormonal pattern in MS women because according to our results it may be related to the disease activity and probably affects the type of therapeutic intervention. This pilot study will be extended in a larger population. PMID- 22212984 TI - Predictors of postoperative mortality in ruptured aneurysms of internal carotid artery. AB - BACKGROUND AND PURPOSE: An analysis of predictors of mortality in patients with ruptured intracranial aneurysm is an important aspect in the assessment of outcome. The aim of the study was to analyse factors determining mortality risk after the surgical treatment of ruptured internal carotid artery (ICA) aneurysm. MATERIAL AND METHODS: This study comprised 242 patients operated on between 1997 and 2006 in the Neurosurgery Department of the Medical University Hospital in Gdansk, Poland. Multivariate logistic regression, ROC curves (for model assessment as a mortality classifier) and population attributable risk for contribution of individual factor mortality explanation were used to assess factors related to in-hospital mortality. RESULTS: 14.9% of patients died postoperatively. In univariate analysis, increased risk of death was related to the Glasgow Coma Scale score, WFNS score, Hunt-Hess and Fisher grade, preoperative neurological deficit, delayed cerebral ischaemia (DCI), trapping and bypass operative method. Multivariate analysis revealed two independent predictors of in-hospital mortality: DCI and Hunt-Hess grade. 91% of mortality risk was attributed to grade 4 or 5 in Hunt-Hess scale and DCI. The dominant predictor of survival was the Hunt-Hess scale. Increase by one grade in the Hunt Hess scale resulted in two-fold increase of in-hospital mortality risk. CONCLUSIONS: Postoperative mortality after ICA aneurysm rupture is determined by clinical status at admission and the occurrence of DCI. PMID- 22212985 TI - Sonographic diagnosis of carpal tunnel syndrome--diagnostic value of the triangular cross-section sign. AB - BACKGROUND AND PURPOSE: Carpal tunnel syndrome (CTS) is a common neuropathy resulting from compression of the median nerve at the carpal tunnel. Sonographic diagnosis of this condition relies on enlargement, flattening and/or demonstration of impaired mobility of the median nerve, as well as bowing or thickening of the flexor retinaculum. In most patients the cross-section of the median nerve at the level of the carpal tunnel has an oval or elliptical shape. We have noticed, however, that in a number of cases the cross-section of the median nerve at the inlet of the carpal canal was deformed, assuming a triangular shape. The purpose of this study was to assess the diagnostic value of the triangular median nerve cross-section sign. MATERIAL AND METHODS: One hundred and thirty-nine sonographic examinations in 76 patients with clinical signs of CTS, and 25 examinations in 14 healthy volunteers were performed. Standard electrodiagnostic studies were performed in all symptomatic patients. RESULTS: Triangular shape of the median nerve cross-section in the carpal canal was observed in 13/118 (11.0%) median nerves with abnormal result of the electrodiagnostic study, and in 2/21 (9.5%) cases with a normal electrodiagnostic examination result. No such deformation was seen in the control group. CONCLUSIONS: The triangular cross-section sign has high specificity (0.90) and positive predictive value (0.87) in dia-gnosis of CTS. PMID- 22212986 TI - Seizure frequency and bioelectric brain activity in epileptic patients in stable and unstable atmospheric pressure and temperature in different seasons of the year--a preliminary report. AB - BACKGROUND AND PURPOSE: An epileptic seizure is a sum of exogenous and endogenous factors affecting an epileptic focus. The aim of the study was to examine the influence of changes in atmospheric pressure and temperature on the increase in the frequency of seizures and changes in EEG in epileptic patients. MATERIAL AND METHODS: The study included 30 epileptic patients (aged 19-54) reporting the influence of changes in weather conditions on the increase in the frequency of seizures for at least 2 years. EEG was performed twice each season at the time of stable and unstable weather conditions. RESULTS: In stable and unstable weather conditions, epileptic changes in EEG were most often found in winter (in 43.3% and 63.3% of patients, respectively). Unstable weather conditions increased the proportion of patients with epileptic changes in EEG also in the other seasons. Unstable weather conditions caused an increase in the frequency of seizures in 40% of patients in spring, 43.3% in autumn, 40% in winter and in approximately 7% in summer. CONCLUSIONS: In spring, autumn and winter, unstable weather conditions cause an increase in the frequency of seizures in almost half of the epileptic patients but only in 7% in summer. The increase in frequency of seizures in unstable weather conditions did not correspond in all patients with increase of changes in EEG. The higher proportion of epileptic patients with changes in EEG in unstable weather conditions in all seasons suggests an impact of these conditions on subclinical seizure discharges in this period. PMID- 22212987 TI - Neuropsychological assessment of language functions during functional magnetic resonance imaging: development of new tasks. Preliminary report. AB - BACKGROUND AND PURPOSE: Due to the complex and extended cerebral organization of language functions, the brain regions crucial for speech and language, i.e. eloquent areas, have to be affected by neurooncological surgery. One of the techniques that may be helpful in pre-operative planning of the extent of tumour removal and estimating possible complications seems to be functional magnetic resonance imaging (fMRI). The aim of the study was to develop valid procedures for neuropsychological assessment of various language functions visualisable by fMRI in healthy individuals. MATERIAL AND METHODS: In this fMRI study, 10 healthy (with no CNS pathology), right-handed volunteers aged 25-35 were examined using four tasks designed to measure different language functions, and one for short term memory assessment. A 1.5-T MRI scanner performing ultrafast functional (EPI) sequences with 4-mm slice thickness and 1-mm interslice gap was used to detect the BOLD response to stimuli present-ed in a block design (30-second alternating blocks of activity and rest). The analyses used the SPM software running in a MATLAB environment, and the obtained data were interpreted by means of colour coded maps superimposed on structural brain scans. RESULTS: For each of the tasks developed for particular language functions, a different area of increased neuronal activity was found. CONCLUSIONS: The differential localization of function-related neuronal activity seems interesting and the research worth continuing, since verbal communication failure may result from impairment of any of various language functions, and studies reported in the literature seem to focus on verbal expression only. PMID- 22212988 TI - Surgical treatment of symptomatic vertebral haemangiomas. AB - BACKGROUND AND PURPOSE: Vertebral haemangiomas are relatively common, benign vascular lesions; symptomatic ones that cause spinal cord compression are rare, however. Only 0.9-1.2% of all vertebral haemangiomas are symptomatic. The aim of the paper is to present indications, operative techniques and stabilization methods in patients with symptomatic vertebral haemangiomas. MATERIAL AND METHODS: Clinical analysis included 7 patients treated between 1995 and 2007. There were 4 females and 3 males, aged 24 to 63 yrs (average age 44 yrs). Symptomatic vertebral haemangiomas were diagnosed on the basis of neuroradiological studies. Surgery was applied in all cases. Implantation of internal stabilization followed vertebral haemangioma resection. RESULTS: Localization of vertebral haemangiomas included 1 case in the cervical, 5 cases in the thoracic and 1 case in the lumbar segment of the vertebral column. Symptoms of medulla compression were observed in 7 patients. Neurological symptoms were caused usually by hypertrophy or ballooning of the posterior cortex of the vertebral body into the vertebral canal. The anterior surgical approach was carried out in 2 cases, posterolateral in 3 cases and posterior in 2 cases. Spinal stability was secured by various implant systems and autogenic bone grafts. Bone defects in the vertebral body were filled with acrylic cement in 4 patients. In histological examinations, cavernous types were found in all patients. Neurological condition improved after the treatment in 5 patients. CONCLUSIONS: No standard therapy exists for symptomatic thoracic vertebral haemangiomas. However, immediate surgical intervention is necessary in cases with acute compressive myelopathy before the symptoms become irreversible. PMID- 22212989 TI - Spinal cheiro-oral syndrome: a common neurological entity in an unusual site. AB - BACKGROUND AND PURPOSE: Cheiro-oral syndrome (COS) is an established neurological entity characterized by a sensory impairment confined to the mouth angle and ipsilateral finger(s)/ hand. The current understanding of localization is a concomitant involvement of the spinothalamic and trigeminothalamic tract between the cortex and pons. The cervical spinal cord has not been mentioned in this situation yet, and this unusual location may heretofore increase the risk of misdiagnosis. MATERIAL AND METHODS: Six patients who presented with unilateral COS due to cervical cord disorder are reported. RESULTS: All patients were women and their age ranged between 42 and 70 years. Their neurological deficits included unilateral paraesthesiae restricted to cheirooral distribution, positive radicular sign, and mild change of tendon reflex. Cervical spinal stenosis at middle/lower cervical spine with variable magnitude of cord compression and intrinsic cord damage was found. A diagnostic dilemma obviously arises from the lack of tangible neurological signs or typical pattern of myelopathy, in addition to the previous concept of cerebral involvement. A benign course ensued in all reported patients. CONCLUSIONS: Cheiro-oral syndrome can be an early neurological sign for cervical cord disorder; it further suggests that it is a strong neurological but weak localizing sign. A reciprocal influence of multiple factors is considered to generate COS at the cervical cord. Therefore, an absence of brain pathology should lead to a thorough examination of the cervical cord in case of COS. PMID- 22212990 TI - [Deep brain stimulation in the treatment of torticollis and Meige syndrome]. AB - Deep brain stimulation (DBS) is an established and accepted treatment modality of generalized dystonia. The stereotactic target to be approached with DBS leads is the internal segment of the globus pallidus (GPi). Bilateral GPi stimulation in patients suffering from primary generalized dystonia reduced dystonic movement not only in the trunk and limbs but also in the neck and face. These observations have led to the use of GPi stimulation in patients with severe torticollis and Meige syndrome refractory to pharmacological agents as well to botulinum toxin injections. An increasing number of reports indicate the effectiveness of GPi stimulation in the treatment of intractable focal and segmental dystonia. Moreover, DBS can be performed simultaneously on both sides during one operative session. This treatment modality is reversible and safer when compared to stereotactic ablative techniques. In future, DBS can become an alternative treatment for intractable focal and segmental dystonia. PMID- 22212991 TI - Cerebrotendinous xanthomatosis: a rare cause of spinocerebellar syndrome. AB - A 34-year-old patient demonstrating pyramidal and cerebellar signs, accompanied by epilepsy, peripheral neuropathy, mental retardation and bilateral cataract was diagnosed with cerebrotendinous xanthomatosis based on the clinical picture, magnetic resonance imaging of the brain and serum sterol analysis. Tendon xanthomas were not observed in this case. After establishing the diagnosis, treatment with chenodeoxycholic acid and statin was introduced. During the next two years of the follow-up, serum cholestanol and 7alpha-hydroxycholesterol levels decreased in response to the therapy, but this was not reflected in the patient's neurological condition, which was slowly progressing. Treatment effectiveness in cerebrotendinous xanthomatosis is variable, notably better in patients who had started therapy before the injury to the nervous system took place. The present case report points to cerebrotendinous xanthomatosis as a rare cause of spinocerebellar syndrome, which might be treatable if diagnosed in early life. PMID- 22212992 TI - Pineal cyst apoplexy: report of an unusual case managed conservatively. AB - Pineal cyst apoplexy is a very rare entity with previously reported symptoms of severe frontal or occipital headache, gaze paresis and visual field defects, nausea or vomiting, syncope, ataxia, hearing loss and sudden death. The treatment options for symptomatic pineal cysts are observation, shunting, aspiration via stereotactic guidance or endoscopy, third ventriculostomy, ventriculocysternostomy, and/or surgical resection by craniotomy and microsurgery. Here, the authors report an unusual case of a 28-year-old male patient with pineal cyst apoplexy, presenting with headache, insomnia, and sexual dysfunction symptoms who is being managed conservatively and observed for two years by an academic tertiary care unit. PMID- 22212993 TI - Professor Anatol Dowzenko--clinical neurologist, scientist and educator. PMID- 22212994 TI - Drastic difference in the photo-driven hydrogenation reactions of ruthenium complexes containing NAD model ligands. AB - Successful control of photo-driven NAD(+)/NADH type hydrogenation reactions in ruthenium complexes has been accomplished by using a new NAD(+) model ligand with modulated distortion of the ligand taking advantage of the substituent effect. PMID- 22212995 TI - Hypermethylation of CpG islands is more prevalent than hypomethylation across the entire genome in breast carcinogenesis. AB - This study aimed to establish a high-throughput, genome-wide and non-gene specific approach to assess the methylation status of multiple CpG islands in parallel and employ it to detect the CpG island methylation profiling alterations in breast carcinogenesis. We used methylation-sensitive restriction fingerprint (MSRF) to screen the permutations of primers that could detect varied and specific methylation profiling in genomic DNA isolated from four different cell lines. Five permutations of nine arbitrary primers were determined for the following experiments based on the above test. We then examined the methylation profiling alterations of CpG islands in 31 breast cancer tissue samples relative to their adjacent non-neoplastic tissues with modified MSRF that replaced silver staining with denatured high-performance liquid chromatography for size fraction. We found that two pairs of primers could reveal specific alterations of CpG methylation in the examined tissues, and 83.9% (26/31) of breast cancer tissues exhibited specific CpG island methylation profiling relative to their adjacent non-neoplastic tissues. Size fraction analysis revealed that hypermethylation of CpG islands was responsible for the aberrant methylation profiling in breast cancer tissues. Our work not only established a relative high-throughput, genome wide and economic method to detect methylation alterations of CpG island profiling, but also revealed that hypermethylation of CpG islands was more prevalent than hypomethylation across the entire genome in our examined cancer tissues. The methylation profiling alterations revealed by two primer pairs used in the present study might be a novel marker for breast cancer. PMID- 22212996 TI - Simultaneous determination of deoxycytidine diphosphate and deoxycytidine triphosphate by capillary electrophoresis with transient isotachophoretic stacking: a sensitive monitoring method for ribonucleotide reductase activity. AB - A simple and rapid capillary electrophoretic method was developed for simultaneous determination of sub-micromolar 2'-deoxycytidine 5'-diphosphate (dCDP) and 2'-deoxycytidine 5'-triphosphate (dCTP) levels in enzyme assays without using radioactively labeled substrates. The separation was performed at 25 degrees C using MES in the BGE as the terminating ion, the chloride ions in the sample buffer as the leading ion, and PEG 4000 in the BGE as the EOF suppressor for sample stacking by transient isotachophoresis (tITP). Several parameters affecting the separation were investigated, including the pH of the BGE, the concentration of sodium chloride in the sample buffer, and the concentrations of MES and PEG 4000 in the running buffer. Good separation with high separation efficiency was achieved within 6 min under optimal conditions. In comparison with the simple CZE method, the present tITP-CZE method enabled a 150 fold increase in the injection time without any decrease in resolution and the sensitivity was enhanced up to two orders of magnitude with the new method. The linear range of the method was 0.1-10 MUM for dCDP and dCTP. The limits of detection of dCDP and dCTP were 85 and 73 nM, respectively. The proposed method was successfully applied for the activity assay of ribonucleotide reductase from Hep G2 and Sf9 cells. PMID- 22212997 TI - A model of genetic search for beneficial mutations: estimating the constructive capacities of mutagenesis. AB - We attempted to answer the following question: What evolutionary conditions are required to generate novel genetic modules? Our broad formulation of the problem allows us to simultaneously consider such issues as the relationship between the stage of "genetic search" and the rate of adaptive evolution; the theoretical limits to the generative capacities of spontaneous mutagenesis; and the correlation between genome organization and evolvability. We show that adaptive evolution is feasible only when the mutation rate is fine-tuned to a specific range of values and the structures of the genome and genes are optimized in a certain way. Our quantitative analysis has demonstrated that the rate of evolution of novelty depends on several parameters, such as genome size, the length of a module, the size of the adjacent nonfunctional DNA spacers, and the mutation rate at various genomic scales. We evaluated the efficiency of some mechanisms that increase evolvability: bias in the spectrum of mutation rates towards small mutations, and the availability and size of nonfunctional DNA spacers. We show that the probability of successful duplication and insertion of a copy of a functional module increases by several orders of magnitude depending on the length of the spacers flanking the module. We infer that the adaptive evolution of multicellular organisms has become feasible because of the abundance of nonfunctional DNA spacers, particularly introns, in the genome. We also discuss possible reasons underlying evolutionary retention of the mechanisms that increase evolvability. PMID- 22212998 TI - Chemical species separation with simultaneous estimation of field map and T2* using a k-space formulation. AB - Chemical species separation techniques in image space are prone to incorporate several distortions. Some of these are signal accentuation in borders and geometrical warping from field inhomogeneity. These errors come from neglecting intraecho time variations. In this work, we present a new approach for chemical species separation in MRI with simultaneous estimation of field map and T2* decay, formulated entirely in k-space. In this approach, the time map is used to model the phase accrual from off-resonance precession and also the amplitude decay due to T2*. Our technique fits the signal model directly in k-space with the acquired data minimizing the l(2)-norm with an interior-point algorithm. Standard two dimensional gradient echo sequences in the thighs and head were used for demonstrating the technique. With this approach, we were able to obtain excellent estimation for the species, the field inhomogeneity, and T2* decay images. The results do not suffer from geometric distortions derived from the chemical shift or the field inhomogeneity. Importantly, as the T2* map is well positioned, the species signal in borders is correctly estimated. Considering intraecho time variations in a complete signal model in k-space for separating species yields superior estimation of the variables of interest when compared to existing methods. PMID- 22212999 TI - Red meat consumption and cancer: reasons to suspect involvement of bovine infectious factors in colorectal cancer. AB - An increased risk for colorectal cancer has been consistently reported for long time consumption of cooked and processed red meat. This has frequently been attributed to chemical carcinogens arising during the cooking process of meat. Long-time fish or poultry consumption apparently does not increase the risk, although similar or higher concentrations of chemical carcinogens were recorded in their preparation for consumption. The geographic epidemiology of colorectal cancer seems to correspond to regions with a high rate of beef consumption. Countries with a virtual absence of beef in the diet (India) or where preferably lamb or goat meat is consumed (several Arabic countries) reveal low rates of colorectal cancer. In China, pork consumption has a long tradition, with an intermediate colorectal cancer rate. In Japan and Korea, large scale beef and pork imports started after World War II or after the Korean War. A steep rise in colorectal cancer incidence was noted after 1970 in Japan and 1990 in Korea. The consumption of undercooked beef (e.g., shabu-shabu, Korean yukhoe and Japanese yukke) became very popular in both countries. The available data are compatible with the interpretation that a specific beef factor, suspected to be one or more thermoresistant potentially oncogenic bovine viruses (e.g., polyoma-, papilloma- or possibly single-stranded DNA viruses) may contaminate beef preparations and lead to latent infections in the colorectal tract. Preceding, concomitant or subsequent exposure to chemical carcinogens arising during cooking procedures should result in increased risk for colorectal cancer synergistic with these infections. PMID- 22213000 TI - Cognitive dysfunction in cirrhosis is associated with falls: a prospective study. AB - Falls are frequent among patients with debilitating disorders and can have a serious effect on health status. Mild cognitive disturbances associated with cirrhosis may increase the risk for falls. Identifying subjects at risk may allow the implementation of preventive measures. Our aim was to assess the predictive value of the Psychometric Hepatic Encephalopathy Score (PHES) in identifying patients likely to sustain falls. One hundred and twenty-two outpatients with cirrhosis were assessed using the PHES and were followed at specified intervals. One third of them exhibited cognitive dysfunction (CD) according to the PHES (< 4). Seventeen of the forty-two patients (40.4%) with CD had at least one fall during follow-up. In comparison, only 5 of 80 (6.2%) without CD had falls (P < 0.001). Fractures occurred in 4 patients (9.5%) with CD, but in no patients without CD (P = 0.01). Patients with CD needed more healthcare (23.8% versus 2.5%; P < 0.001), more emergency room care (14.2% versus 2.5%; P = 0.02), and more hospitalization (9.5% versus 0%; P = 0.01) as a result of falls than patients without CD. Patients taking psychoactive treatment (n = 21) had a higher frequency of falls, and this was related to an abnormal PHES. In patients without psychoactive treatment (n = 101), the incidence of falls was 32.4% in patients with CD versus 7.5% in those without CD (P = 0.003). In the multivariate analysis, CD was the only independent predictive factor of falls (odds ratio, 10.2; 95% confidence interval, 3.4-30.4; P < 0.001). The 1-year probability of falling was 52.3% in patients with CD and 6.5% in those without (P < 0.001). CONCLUSION: An abnormal PHES identifies patients with cirrhosis who are at risk for falls. This psychometric test may be useful to promote awareness of falls and identify patients who may benefit from preventive strategies. PMID- 22213001 TI - Comparative toxicity of four chemically dispersed and undispersed crude oils to rainbow trout embryos. AB - The chronic toxicity of crude oil to fish embryos depends on the chemical constituents of the test oil and on factors that control the exposure of embryos to those constituents. The partitioning of chemicals from oil to water depends on the surface area of oil exposed to water and thus on the susceptibility of oil to be dispersed into droplets. The chronic toxicity of four different crude oils to embryos of rainbow trout (Oncorhynchus mykiss) was measured by exposure to the water-accommodated fraction (WAF; no droplet formation) and to the chemically enhanced WAF (CEWAF) of each oil. When effects were compared with the amount of WAF or CEWAF added to test solutions, chemical dispersion increased toxicity dramatically, by >35 to >300-fold, with the smallest difference measured for the lightest and least viscous oil. When effects were compared with measured concentrations of oil in test solutions, there were no differences in toxicity between WAF and CEWAF treatments, indicating that chemical dispersion promoted droplet formation and the partitioning of hydrocarbons from oil to water. On a dilution basis, the differences in toxicity among the four oils were correlated with the concentrations in oil of polynuclear aromatic hydrocarbons (PAH), particularly those with three to five rings, and with their viscosity, an index of dispersibility. However, when PAH concentrations were measured in solution, toxicity did not vary substantially among the four oils, suggesting that the PAH of each oil had equivalent toxicities and that differences in toxicity represented differences in dispersability. PMID- 22213002 TI - Comments on 'Adaptive increase in sample size when interim results are promising: a practical guide with examples' by C. R. Mehta and S. J. Pocock. PMID- 22213004 TI - Overexpression of ZEB1 relates to metastasis and invasion in osteosarcoma. AB - BACKGROUND: This study aimed to investigate the expression of ZEB1 in osteosarcoma tissues and to discuss the relationship between ZEB1 expression and osteosarcoma metastasis. METHODS: Using RT-PCR and Western blotting, the mRNA and protein expressions of ZEB1 in the osteosarcoma and normal bone tissues were detected. Using the RNA interference technique, the expression of ZEB1 in the human osteosarcoma MG-63 cell line was downregulated, and the changes in the invasion of MG-63 cells were examined. RESULTS: The positive mRNA expression rate of ZEB1 in the osteosarcoma tissues was significantly higher than that in normal bone tissue (P < 0.05). The protein expression level of ZEB1 in the sarcoma tissues from patients with positive lung metastasis was significantly higher than that from patients without lung metastasis (P < 0.05). After the transfection of ZEB1 siRNA into the MG-63 cells, the protein expression of ZEB1 was significantly reduced (P < 0.05), and the number of cells that passed through the Transwell chamber was significantly lower than that in the non-transfected control group as well as the transfected control group (P < 0.05). CONCLUSIONS: The overexpression of ZEB1 in osteosarcoma may be related to the carcinogenesis and development as well as metastasis and invasion of osteosarcoma. PMID- 22213005 TI - Multivariate carbon and nitrogen stable isotope model for the reconstruction of prehistoric human diet. AB - Using a sample of published archaeological data, we expand on an earlier bivariate carbon model for diet reconstruction by adding bone collagen nitrogen stable isotope values (delta(15) N), which provide information on trophic level and consumption of terrestrial vs. marine protein. The bivariate carbon model (delta(13) C(apatite) vs. delta(13) C(collagen) ) provides detailed information on the isotopic signatures of whole diet and dietary protein, but is limited in its ability to distinguish between C(4) and marine protein. Here, using cluster analysis and discriminant function analysis, we generate a multivariate diet reconstruction model that incorporates delta(13) C(apatite) , delta(13) C(collagen) , and delta(15) N holistically. Inclusion of the delta(15) N data proves useful in resolving protein-related limitations of the bivariate carbon model, and splits the sample into five distinct dietary clusters. Two significant discriminant functions account for 98.8% of the sample variance, providing a multivariate model for diet reconstruction. Both carbon variables dominate the first function, while delta(15) N most strongly influences the second. Independent support for the functions' ability to accurately classify individuals according to diet comes from a small sample of experimental rats, which cluster as expected from their diets. The new model also provides a statistical basis for distinguishing between food sources with similar isotopic signatures, as in a previously analyzed archaeological population from Saipan (see Ambrose et al.: AJPA 104(1997) 343-361). Our model suggests that the Saipan islanders' (13) C enriched signal derives mainly from sugarcane, not seaweed. Further development and application of this model can similarly improve dietary reconstructions in archaeological, paleontological, and primatological contexts. PMID- 22213006 TI - The zebra in the room. PMID- 22213007 TI - Epistatic interactions between Fc (GM) and FcgammaR genes and the host control of human immunodeficiency virus replication. AB - Host genetic factors are thought to contribute to the interindividual differences in the control of human immunodeficiency virus (HIV) replication. The aim of the present investigation was to determine whether genes encoding GM and KM allotypes genetic markers of immunoglobulin gamma and kappa chains, respectively-and those encoding Fcgamma receptor (FcgammaR) IIa and IIIa are associated with the host control of HIV replication. A case-control design was employed among HIV-infected subjects, with a group that spontaneously controlled HIV replication ("controllers") as cases (n = 73) and those who did not control replication as controls (n = 100). Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism, direct DNA sequencing, and TaqMan genotyping assays. In Caucasian Americans, certain combinations of FcgammaR and GM genotypes were differentially distributed between controllers and noncontrollers. Among the noncarriers of the FcgammaRIIa arginine allele, GM21 noncarriers had over 7-fold greater odds of being controllers than the carriers of this allele (odds ratio [OR] = 7.47). These GM determinants also interacted with FcgammaRIIIa alleles. Among the carriers of the FcgammaRIIIa valine allele, GM21 noncarriers had over 3-fold greater odds of being controllers than the carriers of this allele (OR = 3.26). These results demonstrate epistatic interactions of genes on chromosomes 14 (GM) and 1 (FcgammaR) in influencing the control of HIV replication. PMID- 22213008 TI - Trypsin-like proteolytic contamination of commercially available psa purified from human seminal fluid. AB - BACKGROUND: Prostate-Specific Antigen (PSA) is a serine protease whose expression is maintained in all stages of prostate cancer. A role for PSA in the pathobiology for prostate cancer has not been firmly established. Experimental studies to date support a role for PSA through mechanisms such as release or processing of growth factors and degradation of the extracellular matrix. Exposure of prostate cancer cells to exogenous PSA also results in gene expression changes. These in vitro and biochemical assays rely on the use of commercially available PSA. Contamination of these commercial preparations can significantly impact the results of these in vitro studies. METHODS: We characterized PSA and trypsin-like activity of PSA preparations obtained from three commercial sources: Calbiochem, Fitzgerald, and AbD Serotec. Silver stained gels were used to compare the purity of each preparation and mass spectrometry was performed to characterize contaminating proteases. RESULTS: PSA activity varied between PSA preparations with AbD Serotec PSA having highest degree of activity. Significant trypsin-like activity, which was inhibited by aprotinin, was observed in PSA preparations from Calbiochem and Fitzgerald, but not AbD Serotec. These former two PSA preparations also contained the greatest degree of non-PSA contaminants by silver stain and mass spectrometry. CONCLUSIONS: Commercially available preparations of PSA contain contaminating proteins, including trypsin-like protease activity, that could potentially complicate the interpretation of results obtained from in vitro studies assessing PSA proteolysis of potential protein substrates and effects of PSA on gene expression. PMID- 22213009 TI - To have and to hold: episodic memory in 3- and 4-year-old children. AB - Episodic memory endows us with the ability to reflect on our past and plan for our future. Most theorists argue that episodic memory emerges during the preschool period and that its emergence might herald the end of childhood amnesia. Here, we show that both 3- and 4-year-old children form episodic memories, but that 3-year-old children fail to retain those memories following a delay (Experiments 1 and 2). In contrast, 4-year-old children retained episodic memories over delays of 24 hr (Experiment 1) and 1 week (Experiment 3). This marked change in the retention of episodic memories between 3 and 4 years of age suggests that it is our ability to retain, rather than to form, an episodic memory that limits our ability to recall episodes from early childhood. PMID- 22213010 TI - Chemical transfection of dye-conjugated microRNA precursors for microRNA functional analysis of M2 macrophages. AB - MicroRNAs (miRNAs) are short noncoding ribonucleic acids known to affect gene expression at the translational level and there is mounting evidence that miRNAs play a role in the function of tumor-associated macrophages (TAMs). To aid the functional analyses of miRNAs in an in-vitro model of TAMs known as M2 macrophages, a transfection method to introduce artificial miRNA constructs or miRNA molecules into primary human monocytes is needed. Unlike differentiated macrophages or dendritic cells, undifferentiated primary human monocytes have been known to show resistance to lentiviral transduction. To circumvent this challenge, other techniques such as electroporation and chemical transfection have been used in other applications to deliver small gene constructs into human monocytes. To date, no studies have compared these two methods objectively to evaluate their suitability in the miRNA functional analysis of M2 macrophages. Of the methods tested, the electroporation of miRNA-construct containing plasmids and the chemical transfection of miRNA precursor molecules are the most efficient approaches. The use of a silencer siRNA labeling kit (Ambion) to conjugate Cy 3 fluorescence dyes to the precursor molecules allowed the isolation of successfully transfected cells with fluorescence-activated cell sorting. The chemical transfection of these dye-conjugated miRNA precursors yield an efficiency of 37.5 +/- 0.6% and a cell viability of 74 +/- 1%. RNA purified from the isolated cells demonstrated good quality, and was fit for subsequent mRNA expression qPCR analysis. While electroporation of plasmids containing miRNA constructs yield transfection efficiencies comparable to chemical transfection of miRNA precursors, these electroporated primary monocytes seemed to have lost their potential for differentiation. Among the most common methods of transfection, the chemical transfection of dye-conjugated miRNA precursors was determined to be the best-suited approach for the functional analysis of M2 macrophages. PMID- 22213011 TI - Towards ultrathick battery electrodes: aligned carbon nanotube-enabled architecture. AB - Vapor deposition techniques were utilized to synthesize very thick (~1 mm) Li-ion battery anodes consisting of vertically aligned carbon nanotubes coated with silicon and carbon. The produced anode demonstrated ultrahigh thermal (>400 W.m( 1) .K(-1)) and high electrical (>20 S.m(-1)) conductivities, high cycle stability, and high average capacity (>3000 mAh.g(Si) (-1)). The processes utilized allow for the conformal deposition of other materials, thus making it a promising architecture for the development of Li-ion anodes and cathodes with greatly enhanced electrical and thermal conductivities. PMID- 22213012 TI - Multitissue assessment of in vivo postprandial intracellular lipid partitioning in rats using localized 1H-[13C] magnetic resonance spectroscopy. AB - Excess accumulation of lipids in nonadipose tissues such as skeletal muscle and liver has been implicated in the development of obesity-related disorders, but the cause of this ectopic lipid overload remains unknown. The aim of this study was to determine in vivo postprandial lipid partitioning in rat skeletal muscle and liver, using localized 1H-[13C] magnetic resonance spectroscopy in combination with the oral administration of 13C-labeled lipids. Six rats were measured at baseline and 5 and 24 h after administration of 400 mg [U-13C] labeled algal lipids. Five hours after administration, fractional 13C enrichments of the lipid pools in muscle and liver were increased 3.9-fold and 4.6-fold (P<0.05), respectively, indicating that part of the ingested lipids had been taken up by muscle and liver tissue. At 24 h, fractional 13C enrichments of muscle and liver lipids were decreased 1.6-fold and 2.2-fold (P<0.05), respectively, compared with the 5 h values. This can be interpreted as a depletion of 13C-labeled lipids from the intracellular lipid pools as a consequence of lipid turnover. In conclusion, the novel application of 1H-[13C] magnetic resonance spectroscopy in combination with the oral administration of 13C-labeled lipids is applicable for the longitudinal assessment of in vivo lipid partitioning between multiple tissues. PMID- 22213013 TI - Evolution and taxonomic split of the model grass Brachypodium distachyon. AB - BACKGROUND AND AIMS: Brachypodium distachyon is being widely investigated across the world as a model plant for temperate cereals. This annual plant has three cytotypes (2n = 10, 20, 30) that are still regarded as part of a single species. Here, a multidisciplinary study has been conducted on a representative sampling of the three cytotypes to investigate their evolutionary relationships and origins, and to elucidate if they represent separate species. METHODS: Statistical analyses of 15 selected phenotypic traits were conducted in individuals from 36 lines or populations. Cytogenetic analyses were performed through flow cytometry, fluorescence in situ hybridization (FISH) with genomic (GISH) and multiple DNA sequences as probes, and comparative chromosome painting (CCP). Phylogenetic analyses were based on two plastid (ndhF, trnLF) and five nuclear (ITS, ETS, CAL, DGAT, GI) genes from different Brachypodium lineages, whose divergence times and evolutionary rates were estimated. KEY RESULTS: The phenotypic analyses detected significant differences between the three cytotypes and demonstrated stability of characters in natural populations. Genome size estimations, GISH, FISH and CCP confirmed that the 2n = 10 and 2n = 20 cytotypes represent two different diploid taxa, whereas the 2n = 30 cytotype represents the allotetraploid derived from them. Phylogenetic analysis demonstrated that the 2n = 20 and 2n = 10 cytotypes emerged from two independent lineages that were, respectively, the maternal and paternal genome donors of the 2n = 30 cytotype. The 2n = 20 lineage was older and mutated significantly faster than the 2n = 10 lineage and all the core perennial Brachypodium species. CONCLUSIONS: The substantial phenotypic, cytogenetic and molecular differences detected among the three B. distachyon sensu lato cytotypes are indicative of major speciation processes within this complex that allow their taxonomic separation into three distinct species. We have kept the name B. distachyon for the 2n = 10 cytotype and have described two novel species as B. stacei and B. hybridum for, respectively, the 2n = 20 and 2n = 30 cytotypes. PMID- 22213014 TI - Ace inhibitor therapy for heart failure in patients with impaired renal function: a review of the literature. AB - Heart failure syndromes are often associated with multi-organ dysfunction, and concomitant liver, renal, and neurologic involvement is very common. Neuro hormonal antagonism plays a key role in the management of this syndrome, and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are one of the cornerstones of therapy. Cardiorenal physiology is becoming more recognized in these patients with advanced heart failure, and the role of neuro hormonal blockade in this setting is vaguely defined in the literature. Often, angiotensin-converting enzyme inhibitors are decreased or even withheld in these circumstances. The purpose of this article is to review the role and pathophysiology of ace inhibition and angiotensin receptor blockade in patients with acute and chronic heart failure syndromes and concomitant cardiorenal physiology. PMID- 22213016 TI - Decreased expression of WWOX in the development of esophageal squamous cell carcinoma. AB - The WW domain-containing oxidoreductase (WWOX) gene, located on chromosome 16q23.3-24.1 in the region recognized as the common fragile site FRA16D is considered to be a tumor suppressor gene involved in various carcinomas. The present study was to investigate the alterations of WWOX expression and its correlation with polymorphism, the level of WWOX loss of heterozygosity (LOH), and methylation status in esophageal squamous cell carcinoma (ESCC). Immunohistochemistry and RT-PCR methods were used, respectively, to examine the protein and mRNA expression of WWOX in ESCC tissues. PCR-RFLP, PCR-SSLP, and MSP approach were used, respectively, to detect polymorphisms of rs3764340, rs2548861, and rs1079635 site, the level of LOH, and WWOX methylation status. Family history of upper gastrointestinal cancer (UGIC) significantly increased the risk of developing ESCC. Protein and mRNA expression of WWOX was reduced in ESCC tumor tissues and was associated with LOH and hypermethylation of the gene. The G allele of rs3764340 significantly elevated the risk of developing ESCC and was associated with TNM stage. LOH at the WWOX loci was observed in 41.4% tumors. The hypermethylation of promoter and exon1 of WWOX was found to be occurred in dysplastic tissues and the methylation frequency of WWOX in ESCC tumor tissues was significantly higher than that in corresponding normal tissues and was associated with UGIC family history. In all, these results indicate that the WWOX gene may play an important role in the development of ESCC especially in individuals with UGIC family history. PMID- 22213017 TI - An extension of the grid empowered molecular simulator to quantum reactive scattering. AB - Within the activities of the D37 COST Action, we have further developed the quantum dynamics framework of the grid empowered molecular simulator (GEMS) implemented on the segment of the European grid available to the COMPCHEM (computational chemistry) virtual organization. GEMS does now include in a full ab initio approach, the evaluation of the detailed quantum (both time dependent and time independent) dynamics of small systems starting from the calculation of the electronic structure properties as well as the direct calculation of thermalized properties. Illustrative, full dimensional applications of the extended simulator to the H + H(2) , N + N(2) , and O + O(2) systems are presented. PMID- 22213015 TI - VE-cadherin trans-interactions modulate Rac activation and enhancement of lung endothelial barrier by iloprost. AB - Small GTPase Rac is important regulator of endothelial cell (EC) barrier enhancement by prostacyclin characterized by increased peripheral actin cytoskeleton and increased interactions between VE-cadherin and other adherens junction (AJ) proteins. This study utilized complementary approaches including siRNA knockdown, culturing in Ca(2+) -free medium, and VE-cadherin blocking antibody to alter VE-cadherin extracellular interactions to investigate the role of VE-cadherin outside-in signaling in modulation of Rac activation and EC barrier regulation by prostacyclin analog iloprost. Spatial analysis of Rac activation in pulmonary EC by FRET revealed additional spike in iloprost-induced Rac activity at the sites of newly formed cell-cell junctions. In contrast, disruption of VE-cadherin extracellular trans-interactions suppressed iloprost activated Rac signaling and attenuated EC barrier enhancement and cytoskeletal remodeling. These inhibitory effects were associated with decreased membrane accumulation and activation of Rac-specific guanine nucleotide exchange factors (GEFs) Tiam1 and Vav2. Conversely, plating of pulmonary EC on surfaces coated with extracellular VE-cadherin domain further promoted iloprost-induced Rac signaling. In the model of thrombin-induced EC barrier recovery, blocking of VE cadherin trans-interactions attenuated activation of Rac pathway during recovery phase and delayed suppression of Rho signaling and restoration of EC barrier properties. These results suggest that VE-cadherin outside-in signaling controls locally Rac activity stimulated by barrier protective agonists. This control is essential for maximal EC barrier enhancement and accelerated barrier recovery. PMID- 22213018 TI - Stretchable coil arrays: application to knee imaging under varying flexion angles. AB - To fit high-density receiver arrays for MRI closely around individual target anatomies, there is a need to provide a high degree of geometric adjustability with ease of handling and patient comfort. In this work, this is accomplished by the construction of a coil array that is stretchable such that it automatically conforms to a given anatomy's shape and size. Stretchability is implemented by creating the coil conductors from braided wire mounted on an elastic textile substrate. The signal-to-noise ratio yield of such coils is measured by MRI experiments at 3 T, and the signal-to-noise ratio effect of coil stretching is investigated with and without adjustment of the matching between each coil and the respective preamplifier. Four-channel and eight-channel arrays of stretchable receiver coils are evaluated in phantoms as well as for in vivo imaging of the human knee. Exploiting stretchability, it is demonstrated that the knee can be imaged under varying flexion angles up to 60 degrees while maintaining closely coupled array detection, high signal-to-noise ratio, and uniform coverage of the entire joint. PMID- 22213020 TI - One step treatment of forgotten ureteral stents. PMID- 22213021 TI - Particle stabilization of oil-in-water-in-air materials: powdered emulsions. PMID- 22213022 TI - Lanthanide(III) complexes that contain a self-immolative arm: potential enzyme responsive contrast agents for magnetic resonance imaging. AB - Enzyme-responsive MRI-contrast agents containing a "self-immolative" benzylcarbamate moiety that links the MRI-reporter lanthanide complex to a specific enzyme substrate have been developed. The enzymatic cleavage initiates an electronic cascade reaction that leads to a structural change in the Ln(III) complex, with a concomitant response in its MRI-contrast-enhancing properties. We synthesized and investigated a series of Gd(3+) and Yb(3+) complexes, including those bearing a self-immolative arm and a sugar unit as selective substrates for beta-galactosidase; we synthesized complex LnL(1), its NH(2) amine derivatives formed after enzymatic cleavage, LnL(2), and two model compounds, LnL(3) and LnL(4). All of the Gd(3+) complexes synthesized have a single inner-sphere water molecule. The relaxivity change upon enzymatic cleavage is limited (3.68 vs. 3.15 mM(-1) s(-1) for complexes GdL(1) and GdL(2), respectively; 37 degrees C, 60 MHz), which prevents application of this system as an enzyme-responsive T(1) relaxation agent. Variable-temperature (17)O NMR spectroscopy and (1)H NMRD (nuclear magnetic relaxation dispersion) analysis were used to assess the parameters that determine proton relaxivity for the Gd(3+) complexes, including the water-exchange rate (k(ex)(298), varies in the range 1.5-3.9*10(6) s(-1)). Following the enzymatic reaction, the chelates contain an exocyclic amine that is not protonated at physiological pH, as deduced from pH-potentiometric measurements (log K(H)=5.12(+/-0.01) and 5.99(+/-0.01) for GdL(2) and GdL(3), respectively). The Yb(3+) analogues show a PARACEST effect after enzymatic cleavage that can be exploited for the specific detection of enzymatic activity. The proton-exchange rates were determined at various pH values for the amine derivatives by using the dependency of the CEST effect on concentration, saturation time, and saturation power. A concentration-independent analysis of the saturation-power-dependency data was also applied. All these different methods showed that the exchange rate of the amine protons of the Yb(III) complexes decreases with increasing pH value (for YbL(3), k(ex)=1300 s(-1) at pH 8.4 vs. 6000 s(-1) at pH 6.4), thereby resulting in a diminution of the observed CEST effect. PMID- 22213019 TI - Is oxidative stress, a link between nephrolithiasis and obesity, hypertension, diabetes, chronic kidney disease, metabolic syndrome? AB - Epidemiological studies have provided the evidence for association between nephrolithiasis and a number of cardiovascular diseases including hypertension, diabetes, chronic kidney disease, metabolic syndrome. Many of the co-morbidities may not only lead to stone disease but also be triggered by it. Nephrolithiasis is a risk factor for development of hypertension and have higher prevalence of diabetes mellitus and some hypertensive and diabetic patients are at greater risk for stone formation. An analysis of the association between stone disease and other simultaneously appearing disorders, as well as factors involved in their pathogenesis, may provide an insight into stone formation and improved therapies for stone recurrence and prevention. It is our hypothesis that association between stone formation and development of co-morbidities is a result of certain common pathological features. Review of the recent literature indicates that production of reactive oxygen species (ROS) and development of oxidative stress (OS) may be such a common pathway. OS is a common feature of all cardiovascular diseases (CVD) including hypertension, diabetes mellitus, atherosclerosis and myocardial infarct. There is increasing evidence that ROS are also produced during idiopathic calcium oxalate (CaOx) nephrolithiasis. Both tissue culture and animal model studies demonstrate that ROS are produced during interaction between CaOx/calcium phosphate (CaP) crystals and renal epithelial cells. Clinical studies have also provided evidence for the development of oxidative stress in the kidneys of stone forming patients. Renal disorders which lead to OS appear to be a continuum. Stress produced by one disorder may trigger the other under the right circumstances. PMID- 22213023 TI - Effects of neuroimaging evidence on mock juror decision making. AB - During the penalty phase of capital trials, defendants may introduce mitigating evidence that argues for a punishment "less than death." In the past few years, a novel form of mitigating evidence-brain scans made possible by technological advances in neuroscience-has been proffered by defendants to support claims that brain abnormalities reduce their culpability. This exploratory study assessed the impact of neuroscience evidence on mock jurors' sentencing recommendations and impressions of a capital defendant. Using actual case facts, we manipulated diagnostic evidence presented by the defense (psychosis diagnosis; diagnosis and neuropsychological test results; or diagnosis, test results, and neuroimages) and future dangerousness evidence presented by the prosecution (low or high risk). Recommendations for death sentences were affected by the neuropsychological and neuroimaging evidence: defendants deemed at high risk for future dangerousness were less likely to be sentenced to death when jurors had this evidence than when they did not. Neuropsychological and neuroimaging evidence also had mitigating effects on impressions of the defendant. We describe study limitations and pose questions for further research. PMID- 22213024 TI - Weight change and prostate cancer incidence and mortality. AB - The relationship between obesity and prostate cancer risk has been studied extensively but with inconsistent findings, particularly for tumor aggressiveness. Few studies have investigated weight change and prostate cancer incidence or mortality. Using the Melbourne Collaborative Cohort Study, which recruited 17,045 men aged between 40 and 69 years at study entry, we investigated associations between reported weight and body mass index (BMI) at age 18 and measured at study entry, height, weight change between age 18 and study entry and prostate cancer incidence and mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression. During follow-up (mean = 15 years) of 16,514 men, we ascertained 1,374 incident prostate cancers of which 410 were classified as aggressive, and 139 deaths from prostate cancer. The incidence of all prostate cancer was not associated with body size or weight change. Weight and BMI at study entry were positively associated with aggressive prostate cancer risk (HR = 1.06, 95% CI: 1.00-1.13 per 5 kg; HR = 1.27, 95% CI: 1.08-1.49 per 5 kg/m(2)) and prostate cancer mortality (HR = 1.12, 95% CI: 1.01-1.23 per 5 kg; HR = 1.49, 95% CI: 1.11-2.00 per 5 kg/m(2)). Weight gain was positively associated with prostate cancer mortality (HR = 1.13, 95% CI: 1.02-1.26 per 5 kg increment); the HR for >= kg weight gain between age 18 and study entry compared to <5 kg gain over this period was 1.84, 95% CI: 1.09-3.09. Higher adult weight and BMI increases the risk of aggressive prostate cancer and mortality from prostate cancer. Weight gain during adult life is associated with increased prostate cancer mortality. PMID- 22213025 TI - Awareness of infection, knowledge of hepatitis C, and medical follow-up among individuals testing positive for hepatitis C: National Health and Nutrition Examination Survey 2001-2008. AB - Many persons infected with hepatitis C virus (HCV) are unknown to the healthcare system because they may be asymptomatic for years, have not been tested for HCV infection, and only seek medical care when they develop liver-related complications. We analyzed data from persons who tested positive for past or current HCV infection during participation in the National Health and Nutrition Examination Survey (NHANES) from 2001 through 2008. A follow-up survey was conducted 6 months after examination to determine (1) how many participants testing positive for HCV infection were aware of their HCV status before being notified by NHANES, (2) what actions participants took after becoming aware of their first positive test, and (3) participants' knowledge about hepatitis C. Of 30,140 participants tested, 393 (1.3%) had evidence of past or current HCV infection and 170 (43%) could be contacted during the follow-up survey and interviewed. Only 49.7% were aware of their positive HCV infection status before being notified by NHANES, and only 3.7% of these respondents reported that they had first been tested for HCV because they or their doctor thought they were at risk for infection. Overall, 85.4% had heard of hepatitis C; correct responses to questions about hepatitis C were higher among persons 40-59 years of age, white non-Hispanics, and respondents who saw a physician after their first positive HCV test. Eighty percent of respondents indicated they had seen a doctor about their first positive HCV test result. CONCLUSION: These data indicate that fewer than half of those infected with HCV may be aware of their infection. The findings suggest that more intensive efforts are needed to identify and test persons at risk for HCV infection. PMID- 22213026 TI - Thrombin generation in vitro and in vivo, and disturbed tissue factor regulation in patients with acute pancreatitis. AB - BACKGROUND: Being a central link between inflammation and coagulation, tissue factor (TF) and its inhibitor (TFPI) might be associated with the severity of acute pancreatitis (AP) and the development of organ failure (OF). METHODS: The study comprises 9 severe AP patients with OF and 24 reference patients (11 mild AP and 13 severe AP without OF). Plasma samples were collected on admission. TF induced thrombin generation in plasma samples was studied using the thrombogram method. In vivo thrombin generation was estimated by prothrombin fragment F1+2. Free and total TFPI levels were measured. To evaluate coagulation status the activated partial thromboplastin time, prothrombin time, platelet count, D-dimer, fibrinogen, antithrombin (AT) 3 and protein C (PC) were determined. RESULTS: There was no significant difference in F1+2 levels between the patient groups. Patients with severe AP tended to show low platelet counts, PC and AT3 levels, and high D-dimer levels. In 11 patients the standard TF stimulation did not trigger thrombin generation in the thrombogram. All deaths occurred in these patients. Free TFPI levels and free/total TFPI ratios were significantly higher in these patients and in non-survivors. CONCLUSION: Failure of TF-initiated thrombin generation in the thrombogram assay explained by high levels of circulating free TFPI may be associated with OF and mortality in AP. and IAP. PMID- 22213028 TI - Light-harvesting in multichromophoric rotaxanes. AB - Two rotaxanes with benzyl ether axles and tetralactam wheels were synthesized through an anion template effect. They carry naphthalene chromophores attached to the stopper groups and a pyrene chromophore attached to the wheel. The difference between the two rotaxanes is represented by the connecting unit of the naphthyl chromophore to the rotaxane axle: a triazole or an alkynyl group. Both rotaxanes exhibit excellent light-harvesting properties: excitation of the naphthalene chromophores is followed by energy transfer to the pyrene unit with efficiency higher than 90% in both cases. This represents an example of light-harvesting function among chromophores belonging to mechanically interlocked components, that is, the axle and the wheel of the rotaxanes. PMID- 22213027 TI - Mutual mate choice in a female-dominant and sexually monomorphic primate. AB - Sexual dimorphism is common in polygynous species, where intrasexual competition is often thought to drive the evolution of large male body size, and in turn, male behavioral dominance over females. In Madagascar, the entire lemur radiation, which embraces diverse mating systems, lacks sexual dimorphism and exhibits frequent female dominance over males. The evolution of such morphological and behavioral peculiarities, often referred to as "the lemur syndrome," has proven difficult to understand. Among other hypotheses, a potential role of intersexual selection has been repeatedly proposed but hardly ever tested. Here, we investigate whether female choice favors small and compliant males, and whether male choice favors large females in captive gray mouse lemurs (Microcebus murinus). Detailed analysis of a combination of behavioral observations and hormonal data available for both sexes shows that (1) females accept more matings from males with higher fighting abilities, (2) males adjust their investment in intrasexual competition to female fertility, and (3) both male and female strategies are weakly influenced by the body mass of potential partners, in directions contradicting our predictions. These results do not suggest a prominent role of intersexual selection in the evolution and maintenance of the lemur syndrome but rather point to alternative mechanisms relating to male-male competition, specifically highlighting an absence of relationship between male body mass and fighting ability. Finally, our findings add to the growing body of evidence suggesting flexible sex roles, by showing the expression of mutual mate choice in a female-dominant, sexually monomorphic and promiscuous primate. PMID- 22213029 TI - Streptococcus mutans GS-5 antigen I/II stimulates cell survival in serum deprived cultures through PI3K/Akt pathways. AB - The antigen I/II (AgI/II) protein is a major surface protein that mediates the attachment of Streptococcus mutans (S. mutans) to the saliva-coated pellicle. Numerous studies have investigated not only the mechanisms by which AgI/II signaling is transduced within cells, but have also attempted to use AgI/II specific antibodies to treat dental caries and host immune responses. However, little information is available about the effects of AgI/II on basic cellular events in bone cells. In this study, we examined the effects of the His-tagged recombinant N-terminal half of the AgI/II protein (rAgI/II-N) generated from S. mutans GS-5 on the viability, proliferation, and cell cycle progression of primary calvarial osteoblasts. We also investigated the mechanisms involved in the rAgI/II-N-mediated survival of serum-starved osteoblasts. We found that rAgI/II treatment attenuated the serum deprivation-induced decrease in cell viability and proliferation of osteoblasts. rAgI/II-N also prevented the loss of mitochondrial membrane potential (MMP), alterations in levels of two key mitochondrial Bcl-2 family proteins, and the accumulation of numerous cells into the sub-G(1) phase that were observed in serum-starved osteoblasts. Pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), but not of extracellular signal-regulated kinase or Ras, blocked the rAgI/II-N-mediated protection against serum deprivation-induced cell death. Additional experiments revealed that the integrin alpha5beta1-mediated PI3K pathway is required for rAgI/II-N-mediated Akt phosphorylation in osteoblasts. Collectively, these results suggest that rAgI/II-N induces survival signals in serum-starved osteoblasts through integrin-induced PI3K/Akt signaling pathways. PMID- 22213030 TI - T cells localized to the androgen-deprived prostate are TH1 and TH17 biased. AB - BACKGROUND: T cells infiltrate the prostates of prostate cancer patients undergoing neoadjuvant androgen deprivation. These prostate-infiltrating T cells have an oligoclonal phenotype, suggesting the development of an antigen-specific T-cell response. We hypothesized that androgen deprivation might elicit a prostate tissue-specific T-cell response that could potentially be combined with other immune-active therapies, and consequently sought to investigate the nature and timing of this T-cell response following castration. METHODS: We investigated the phenotype and cytokine expression of T cells at various time points in the prostates of Lewis rats following surgical castration, and used adoptive transfer of prostate-infiltrating lymphocytes (PILs) to determine whether the infiltration by T cells was mediated by effects of castration on the prostate or lymphocytes. RESULTS: Prostate T-cell infiltration shortly after castration was T(H) 1 biased up to approximately 30 days, followed by a predominance of T(H) 17-type cells, which persisted until at least 90 days post castration. PILs from sham-treated or castrate rats localized to the prostates of castrate animals. CONCLUSIONS: These observations suggest castration elicits a time-dependent prostate-specific T-cell infiltration, and this infiltration is likely mediated by effects of castration on prostate tissue rather than T-cells. These findings have implications for the timing of immunotherapies combined with androgen deprivation as treatments for prostate cancer. PMID- 22213031 TI - KIT protein expression and mutational status of KIT gene in pituitary adenomas. AB - KIT protein expression and mutational status of KIT gene in different types of tumours have been intensively studied since Imatinib Mesylate, KIT/PDGFRA tyrosine kinase inhibitor became available. However, only one immunohistochemical study on KIT expression in pituitary adenomas has been published. There are currently no reports on mutational status of KIT gene in pituitary adenomas. We have immunohistochemically investigated KIT expression in 252 pituitary adenomas and found cytoplasmic reactivity in 52.4% and membranous reactivity in 8.3% of all adenomas. There was statistically significant difference in KIT expression between clinically non-functioning, growth hormone- and adrenocorticotroph hormone-producing adenomas. The group with membranous expression was dominated by somatotropinomas and clinically non-functioning adenomas. KIT expression in a subset of adenomas was also confirmed by western blot analysis of 48 adenomas. Immunohistochemical KIT expression was correlated with basic clinical data and in a cohort of acromegalic patients with additional data (somatostatin receptor type 2A expression, response to somatostatin analogue treatment and mutational status of gsp oncogene). Exons 9, 11, 13 and 17 of KIT gene were searched for mutations in the tumours with membranous KIT expression and in a minority of tumours with cytoplasmic KIT expression using denaturing high-performance liquid chromatography and in suspected cases sequencing of one or more exons. No mutations in the examined exons were found. Our results may suggest a role of KIT in the pathogenesis of a subset of pituitary adenomas and point out the need for further research to find out if KIT-reactive adenomas could be sensitive to Imatinib Mesylate. PMID- 22213033 TI - Drastic change of molecular orientation in a thiazolothiazole copolymer by molecular-weight control and blending with PC61BM leads to high efficiencies in solar cells. AB - A thiazolothiazole-thiophene copolymer is examined as the active material in bulk heterojunction (BHJ) solar cells. By optimizing the molecular weight, the polymer based cells exhibit power conversion efficiencies as high as 5.7%. The increase in molecular weight improves the orientational order, and blending with phenyl C61-butyric acid methyl ester (PC61BM) changes the orientational motif from edge on to face-on, which accounts for the trend in photovoltaic performances. These results might give new insight into the structure-property relationships in BHJ solar cells. PMID- 22213032 TI - Mechanism and function of decreased FOXO1 in renal cell carcinoma. AB - BACKGROUND AND OBJECTIVES: Forkhead box O-class 1 (FOXO1), a putative tumor suppressor, is dysregulated in many cancers. Our study aims to reveal the underlying functions and regulation mechanisms of FOXO1 in renal cell carcinoma (RCC). METHODS: The clinical significance of FOXO1 expression in surgically resected specimens was assessed by immunohistochemistry. The siRNAs targeted FOXO1 and miR-27a inhibitor were transfected into RCC cells. QRT-PCR, Western blot, and cell proliferation assay were used to assess the expression and function of FOXO1 and miR-27a. RESULTS: The positive immunostaining for FOXO1 was low in 51 RCC samples compared with 15 normal kidney tissues. And the expression of FOXO1 was related with RCC subtypes and the grade and stage in clear cell RCC (cRCC) (P < 0.05). Inhibition of FOXO1 promoted proliferation of 769-P cells. However, upregulation of FOXO1 by miR-27a inhibitor was accompanied by the anti proliferative effect in cells of 786-O and Caki-1. Furthermore, the expression of FOXO1 mRNA and miR-27a had inverse relation in eight cRCC samples. CONCLUSION: Reduced expression of FOXO1 is common in RCC and a potentially suitable marker of different histological subtypes and prognosis of cRCC. Increasing expression of FOXO1 by the miR-27a inhibitor could prevent cell growth. PMID- 22213035 TI - Scriptaid effects on breast cancer cell lines. AB - In breast cancer tumor expression of estrogen receptors (ERs) is important as a marker of prognosis and mostly as a predictor of response to endocrine therapy. In fact, the loss of alpha-ER expression leads to unresponsiveness to anti hormone treatment. In a significant fraction of breast cancers, this loss of expression is a result of epigenetic mechanisms, such as DNA methylation and histone deacetylation, within the alpha-ER promoter. Previous studies have shown that pharmacologic inhibition of these mechanisms using the DNA methyltransferase inhibitor, 5-aza-2-deoxycytidine (AZA), and the histone deacetylase (HDAC) inhibitor, Trichostatin A (TSA), results in expression of functional alpha-ER mRNA and protein. Moreover, the activity of a novel HDAC inhibitor, Scriptaid, has been shown to induce inhibition of tumor growth in breast cancer and to cause re-expression of functional alpha-ER in alpha-ER negative breast cancer cells. We sought to better characterize the effects of Scriptaid on cell growth, apoptosis, and alpha-ER expression in alpha-ER-positive (MCF-7), alpha-ER-negative (MDA-MB 231), and alpha-ER-negative/Her-2 over-expressing (SKBr-3) human breast cancer cell lines. In all of these cell lines Scriptaid treatment resulted in significant growth inhibition and apoptosis, and RT-PCR confirmed an increase of alpha-ER mRNA transcript in MDA-MB-231 after 48 h of Scriptaid treatment. Furthermore, following treatment with Scriptaid, the formerly unresponsive MDA-MB 231 and SKBr-3 breast cancer cells became responsive to tamoxifen. These results show that the HDAC inhibitor Scriptaid is able to sensitize tamoxifen hormone resistant breast cancer cells, and that Scriptaid or related HDAC inhibitors are candidates for further study in breast cancer. PMID- 22213034 TI - Fractalkine upregulates inflammation through CX3CR1 and the Jak-Stat pathway in severe acute pancreatitis rat model. AB - Based on the function of chemokine fractalkine (FKN), acting as both adhesion and chemoattractant, FKN plays a role in acute inflammatory response. In this study, we investigated the mechanism of FKN mediated upregulation inflammation in severe acute pancreatitis (SAP) rat models. Western blot, reverse transcriptase polymerase chain reaction, and immunofluorescence demonstrated that FKN and its receptor CX3CR1 were overexpressed in cerulein-stimulated AR42J cells. AG490 and FKN-siRNA inhibited activation of Janus kinase/signal transducers and activators of transcription (Jak/Stat) in cerulein-stimulated AR42J cells. Following exposure AG490 and FKN-siRNA inhibited tumor necrosis factor-alpha expression by enzyme-linked immunosorbent assay and immunohistochemistry in vivo the SAP rat models. These results showed FKN and CX3CR1 were involved inflammatory response in cerulein-stimulated AR42J cells. FKN upregulates inflammation through CX3CR1 and the Jak/Stat pathway in SAP rat models. PMID- 22213036 TI - Genetic parameter estimates for growth traits and prolificacy in Raeini Cashmere goats. AB - The main objectives of this study were to estimate genetic and phenotypic parameters for growth traits and prolificacy in the Raeini Cashmere goat. Traits included, birth weight (BWT), weaning weight (WWT), 6-month weight (6WT), 9-month weight (9WT), 12-month weight (12WT), average daily gain from birth to weaning (ADG1), average daily gain from weaning to 6WT (ADG2), average daily gain from 6WT to 12WT (ADG3), survival rate (SR), litter size at birth (LSB) and litter size at weaning (LSW) and total litter weight at birth (LWB). Data were collected over a period of 28 years (1982-2009) at the experimental breeding station of Raeini goat, southeast of Iran. Genetic parameters were estimated with univariate models using restricted maximum likelihood (REML) procedures. In addition to an animal model, sire and threshold models, using a logit link function, were used for analyses of SR. Age of dam, birth of type, sex and of kidding had significant influence (p < 0.05 or 0.01) all the traits. Direct heritability estimates were low for prolificacy traits (0.04 +/- 0.01 for LSB, 0.09 +/- 0.02 for LSW, 0.16 +/ 0.02 for LWB and 0.05 +/- 0.02 for SR) and average daily gain (0.12 +/- 0.03 for ADG1, 0.08 +/- 0.02 for ADG2, and 0.07 +/- 0.03 for ADG3) to moderate for production traits (0.22 +/- 0.02 for BWT, 0.25 +/- 0.02 for WWT, 0.29 +/- 0.04 for 6WT, 0.30 +/- 0.02 for 9WT, 0.32 +/- 0.05 for 12WT). The estimates for the maternal additive genetic variance ratios were lower than direct heritability for BWT (0.17 +/- 0.03) and WWT (0.07 +/- 0.02). PMID- 22213037 TI - Overexpression of small GTPases directly correlates with expression of delta catenin and their coexpression predicts a poor clinical outcome in nonsmall cell lung cancer. AB - delta-catenin can affect cytoskeletal assembly, and promote cell migration by regulating the activity of small GTPases. While many malignancies have been shown to be positive for delta-catenin, it is still unclear whether delta-catenin and small GTPases are coexpressed in tumor cells, and so is the relationship between their coexpression and prognosis in the tumor patients. In this study, immunohistochemistry was performed to examine expressive levels of delta-catenin, cdc42, and Rac1 in 135 cases of nonsmall cell lung cancer (NSCLC), including 60 cases with follow-up records. Thirty samples of paired lung cancer tissues and adjacent normal lung tissues were collected to analyze mRNA and protein expression of delta-catenin and small GTPases. The effects of delta-catenin on small GTPases expression and invasive ability of lung cancer cells were also evaluated. Compared with normal lung tissues, both mRNA and protein levels of delta-catenin and small GTPases were increased in lung cancer tissues (P < 0.05), and the expression of small GTPases directly correlated with that of delta catenin (P < 0.001). In addition, delta-catenin and small GTPases tended to be coexpressed in lung adenocarcinoma, advanced stages, and primary tumors with lymph node metastasis (all P < 0.05). The patients with coexpression of delta catenin and small GTPases had a shorter survival time than those without coexpression (P < 0.05). Furthermore, delta-catenin overexpression could enhance invasive ability of lung cancer cells by upregulating protein and transcriptional level of small GTPases. Therefore, delta-catenin likely upregulates the activity of small GTPases at transcriptional level, and their coexpression may predict a poor clinical outcome in NSCLC patients. PMID- 22213038 TI - Feasibility of in vivo myelin water imaging using 3D multigradient-echo pulse sequences. AB - Quantitative myelin water imaging is able to show demyelinating processes and, therefore, provides insight into the pathology of white matter diseases such as multiple sclerosis. So far, mapping of the myelin water fraction most often was performed using single-slice multiecho spin-echo sequences. Recently, a different approach using two-dimensional multigradient-echo pulse sequences was suggested. In this work, a solution to three-dimensional in vivo myelin water fraction imaging is presented that applies multigradient-echo pulse sequences and uses non negative least squares algorithms to analyze the multicomponent T*(2) decay. The suggested method offers not only whole brain coverage but also clinically practicable acquisition times. The obtained myelin water fraction values are low (6.9% for white matter) but are able to detect demyelination in multiple sclerosis lesions. However, the clinical application of the proposed method remains questionable, because further measurements that clarify the possibility of detecting ongoing processes in lesions are needed. PMID- 22213039 TI - Rhodium-catalyzed asymmetric hydrogenation of olefins with PhthalaPhos, a new class of chiral supramolecular ligands. AB - A library of 19 binol-derived chiral monophosphites that contain a phthalic acid diamide group (PhthalaPhos) has been designed and synthesized in four steps. These new ligands were screened in the rhodium-catalyzed enantioselective hydrogenation of prochiral dehydroamino esters and enamides. Several members of the library showed excellent enantioselectivity with methyl 2-acetamido acrylate (6 ligands gave >97% ee), methyl (Z)-2-acetamido cinnamate (6 ligands gave >94% ee), and N-(1-phenylvinyl)acetamide (9 ligands gave >95% ee), whilst only a few representatives afforded high enantioselectivities for challenging and industrially relevant substrates N-(3,4-dihydronaphthalen-1-yl)-acetamide (96% ee in one case) and methyl (E)-2-(acetamidomethyl)-3-phenylacrylate (99% ee in one case). In most cases, the new ligands were more active and more stereoselective than their structurally related monodentate phosphites (which are devoid of functional groups that are capable of hydrogen-bonding interactions). Control experiments and kinetic studies were carried out that allowed us to demonstrate that hydrogen-bonding interactions involving the diamide group of the PhthalaPhos ligands strongly contribute to their outstanding catalytic properties. Computational studies carried out on a rhodium precatalyst and on a conceivable intermediate in the hydrogenation catalytic cycle shed some light on the role played by hydrogen bonding, which is likely to act in a substrate-orientation effect. PMID- 22213042 TI - SIICA-DGfI 2011 Joint Meeting: Front-line immunology with sensorial stimulations, neuromuscular activity and phago/pinocytosis. PMID- 22213040 TI - Omega-3-polyunsaturated fatty acids suppress pancreatic cancer cell growth in vitro and in vivo via downregulation of Wnt/Beta-catenin signaling. AB - BACKGROUND/AIMS: omega3-polyunsaturated fatty acids (omega3- PUFAs) are known to possess anticancer properties. However, the relationship between omega3-PUFAs and beta-catenin, one of the key components of the Wnt signaling pathway, in human pancreatic cancer remains poorly characterized. METHODS: Human pancreatic cancer cells (SW1990 and PANC-1) were exposed to two omega3-PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), to investigate the relationship between omega3-PUFAs and the Wnt/beta-catenin signaling pathway in vitro. Mouse pancreatic cancer (PANC02) cells were implanted into fat-1 transgenic mice, which express omega3 desaturases and result in elevated levels of omega3-PUFAs endogenously. The tumor size, levels of Wnt/beta-catenin signaling molecules and apoptosis levels were analyzed to examine the influence of omega3-PUFAs in vivo. RESULTS: DHA and EPA significantly inhibited cell growth and increased cell death in pancreatic cancer cells. DHA also reduced beta-catenin expression, T cell factor/lymphoid-enhancing factor reporter activity and induced beta catenin/Axin/GSK-3beta complex formation, a known precursor to beta-catenin degradation. Furthermore, Wnt3a, a natural canonical Wnt pathway ligand, reversed DHA-induced growth inhibition in PANC-1 cells. Immunohistochemical analysis showed aberrant upregulation and increased nuclear staining of beta-catenin in tumor tissues from pancreatic cancer patients. However, beta-catenin levels in tumor tissues from fat-1 transgenic mice were reduced with a significant increase in apoptosis compared with those from control mice. CONCLUSION: omega3-PUFAs may be an effective therapy for the chemoprevention and treatment of human pancreatic cancer. and IAP. PMID- 22213043 TI - Clinical and fundamental aspects of monocyte, macrophage and dendritic cell plasticity. PMID- 22213044 TI - Buy one, get one free: additional functions of GM-CSF in DC maturation. AB - The hematopoietic growth factor GM-CSF has long been known for its colony formation properties in the generation of neutrophils, macrophages and DCs. However, a study by Miah et al. in this issue of the European Journal of Immunology [Eur. J. Immunol. 2012. 42: 58-68] reports that GM-CSF also terminates its own proliferation-inducing STAT5-signaling via induction of the SOCS family member cytokine-inducible SH2-domain protein (CISH, also known as CIS). CISH levels were continuously increased during murine GM-CSF-dependent DC development in vitro and CISH, in turn, suppressed STAT5 phosphorylation to inhibit further GM-CSF signals. In addition, CISH activity promoted MHC class I- but not MHC class II-dependent antigen presentation after DC maturation, selectively supporting the priming of CTLs but not Th1 responses. This is the first demonstration of a molecular switch turning proliferating DC precursors into the differentiated immature DC stage and beyond, thereby paving the way for DC maturation. Since CISH polymorphisms critically affect human susceptibility to infectious diseases, further studies with this interesting molecule and its mutants will allow further insights into the induction of immune responses by DCs in humans. PMID- 22213045 TI - The need for littermate controls. AB - The dramatic increase in the amount of research data being produced necessarily leads to higher demands on statistical thresholds and on experimental planning. This is to avoid positive selection of multiple tested data. Here we would like to highlight the need for including littermate controls in animal experiments, in particular when genetically modified strains are analysed for quantitative phenotypes. Thus, this suggestion will have impact on most immunological experiments performed today. PMID- 22213048 TI - Airborne concentrations of chrysotile asbestos in serpentine quarries and stone processing facilities in Valmalenco, Italy. AB - Asbestos may be naturally present in rocks and soils. In some cases, there is the possibility of releasing asbestos fibres into the atmosphere from the rock or soil, subsequently exposing workers and the general population, which can lead to an increased risk of developing asbestos-related diseases. In the present study, air contaminated with asbestos fibres released from serpentinites was investigated in occupational settings (quarries and processing factories) and in the environment close to working facilities and at urban sites. The only naturally occurrence of asbestos found in Valmalenco area was chrysotile; amphibole fibres were never detected. An experimental cut-off diameter of 0.25 MUm was established for distinguishing between Valmalenco chrysotile and antigorite single fibres using selected area electron diffraction analyses. Air contamination from chrysotile fibres in the examined occupational settings was site-dependent as the degree of asbestos contamination of Valmalenco serpentinites is highly variable from place to place. Block cutting of massive serpentinites with multiple blades or discs and drilling at the quarry sites that had the highest levels of asbestos contamination generated the highest exposures to (i.e. over the occupational exposure limits) asbestos. Conversely, working activities on foliated serpentinites produced airborne chrysotile concentrations comparable with ambient levels. Environmental chrysotile concentrations were always below the Italian limit for life environments (0.002 f ml(-1)), except for one sample collected at a quarry property boundary. The present exposure assessment study should encourage the development of an effective and concordant policy for proper use of asbestos-bearing rocks and soils as well as for the protection of public health. PMID- 22213049 TI - Clinical trials and their translation in hepatology: past, present, and future. PMID- 22213051 TI - Silibinin suppresses the maintenance of colorectal cancer stem-like cells by inhibiting PP2A/AKT/mTOR pathways. AB - Silibinin, an effective chemo-preventive agent in various cancer types, suppresses cancer cell growth, but its effects on cancer stem-like cells (CSLCs) remain unclear. This study aimed to examine whether silibinin inhibited the development of CSLCs and disclose the underlying signaling. The colorectal cancer spheroid culture system was used for enriching CSLCs. The effects of silibinin on CSLCs were evaluated by counting sphere numbers, and calculating the percentage of CD133+ cells by flow cytometry and immunofluorescence both in the absence and presence of different concentrations of silibinin. The results showed the sphere number of CCS was 36 +/- 9.6 after 15 days of CSLC enrichment in spheroid culture, and the percentage of CD133+ cells increased to 18 +/- 6.4% compared to 3 +/- 0.8% before enrichment. Treatment with silibinin reduced the sphere formation to 5 +/- 3.3 and decreased the CD133+ percentage to 8 +/- 2.3%. Interestingly, treatment of silibinin suppressed the activation of the AKT Ser473/mTOR pathway in spheroid culture through suppressing the activity of protein phosphatase 2Ac subunit (PP2Ac). In a xenograft tumor model, treatment with silibinin also inhibited tumor formation rate and tumor growth. Silibinin, which inhibits colon CSLCs self-renewal and sphere formation by suppressing the PP2Ac/AKT Ser473/mTOR pathway, may be a compound for developing new strategies in modulating CSLCs in cancer therapy. PMID- 22213050 TI - PEA15 impairs cell migration and correlates with clinical features predicting good prognosis in neuroblastoma. AB - ERK and RSK2 drive proliferation and invasion of many cancers. Phosphoprotein enriched in astrocytes 15 (PEA15) binds ERK and RSK2 and high PEA15 levels can impair ERK- and RSK2-dependent transcription. PEA15 expression also inversely correlates with cell motility and invasiveness. We therefore tested PEA15 effects on neuroblastoma cells in vitro. We further analyzed PEA15 expression in the context of clinical and genetic features of neuroblastoma in tumor samples to determine its correlation with disease progression. Affymetrix microarray analysis was performed using 24 different neuroblastoma cell lines. Cell lines expressing low to intermediate levels of PEA15 were chosen for in vitro functional studies. The cell line results were verified by Affymetrix analysis of three different neuroblastic tumor types (total of 110 samples) PEA15 overexpression inhibited neuroblastoma migration in vitro. We verified that inhibition of motility required PEA15 interaction with its binding partners ERK and RSK2. Additionally, synthetic inhibitors of RSK2 suppressed integrin dependent migration. PEA15 expression correlates with clinical parameters and a 25% increase in patient survival rate. The highest PEA15 levels were found in low stage, more differentiated and less metastatic neuroblastic tumors, and correlated with lack of MYCN amplification. PEA15 blocks neuroblastoma migration through inhibition of ERK/RSK2 signaling. PEA15 expression levels correlate with favorable clinical features suggesting that PEA15 limits metastatic progression of neuroblastoma. Thus, PEA15 and its partners ERK and RSK2 are potential targets for the development of new therapeutics to impede progression of minimal residual disease in patients with high-risk neuroblastoma. PMID- 22213052 TI - Substituent effects in double-helical hydrogen-bonded AAA-DDD complexes. AB - Two series of DDD and AAA hydrogen-bond arrays were synthesized that form triply hydrogen-bonded double-helical complexes when combined in CDCl(3) solution. Derivatization of the DDD arrays with electron-withdrawing groups increases the complex association constants by up to a factor of 30 in those arrays examined. Derivatization of the AAA arrays with electron donating substituents reveals a similar magnitude effect on the complex stabilities. The effect of substitution on both types of arrays are modeled quite satisfactorily (R(2) > 0.96 in all cases) as free energy relationships with respect to the sums of their Hammett substituent constants. In all, the complex stabilities can be manipulated over more than three orders of magnitude (>20 kJ mol(-1)) using this type of modification. PMID- 22213053 TI - Patient-individual local SAR determination: in vivo measurements and numerical validation. AB - Tissue heating during magnetic resonance measurements is a potential hazard at high-field MRI, and particularly, in the framework of parallel radiofrequency transmission. The heating is directly related to the radiofrequency energy absorbed during an magnetic resonance examination, that is, the specific absorption rate (SAR). SAR is a pivotal parameter in MRI safety regulations, requiring reliable estimation methods. Currently used methods are usually based on models which are neither patient-specific nor taken into account patient position and posture, which typically leads to the need for large safety margins. In this work, a novel approach is presented, which measures local SAR in a patient-specific manner. Using a specific formulation of Maxwell's equations, the local SAR is estimated via postprocessing of the complex transmit sensitivity of the radiofrequency antenna involved. The approximations involved in the proposed method are investigated. The presented approach yields a sufficiently accurate and patient-specific local SAR measurement of the brain within a scan time of less than 5 min. PMID- 22213054 TI - A stochastic model for survival of early prostate cancer with adjustments for leadtime, length bias, and over-detection. AB - To compare the survival between screen-detected and clinically detected cancers, we applied a series of non-homogeneous stochastic processes to deal with leadtime, length bias, and over-detection by using full information on detection modes obtained from the Finnish randomized controlled trial for prostate cancer screening. The results show after 9-year follow-up the hazard ratio of prostate cancer death for screen-detected cases against clinically detected cases increased from 0.24 (95% CI: 0.16-0.35) without correction for these biases, to 0.76 after correction for leadtime and length biases, and finally to 1.03 (95% CI: 0.79-1.33) for a further adjustment for over-detection. Adjustment for leadtime and length bias but no over-detection led to a 24% reduction in prostate cancer death as a result of prostate-specific antigen test. The further calibration of over-detection indicates no gain in survival of screen-detected prostate cancers (excluding over-detected case as stayer considered in the mover stayer model) as compared with the control group in the absence of screening that is considered as the mover. However, whether the model assumption on over detection is robust should be validated with other data sets and longer follow up. PMID- 22213056 TI - Stability of polymer solar cells. AB - Organic photovoltaics (OPVs) evolve in an exponential manner in the two key areas of efficiency and stability. The power conversion efficiency (PCE) has in the last decade been increased by almost a factor of ten approaching 10%. A main concern has been the stability that was previously measured in minutes, but can now, in favorable circumstances, exceed many thousands of hours. This astonishing achievement is the subject of this article, which reviews the developments in stability/degradation of OPVs in the last five years. This progress has been gained by several developments, such as inverted device structures of the bulk heterojunction geometry device, which allows for more stable metal electrodes, the choice of more photostable active materials, the introduction of interfacial layers, and roll-to-roll fabrication, which promises fast and cheap production methods while creating its own challenges in terms of stability. PMID- 22213055 TI - The Fibrobacteres: an important phylum of cellulose-degrading bacteria. AB - The phylum Fibrobacteres currently comprises one formal genus, Fibrobacter, and two cultured species, Fibrobacter succinogenes and Fibrobacter intestinalis, that are recognised as major bacterial degraders of lignocellulosic material in the herbivore gut. Historically, members of the genus Fibrobacter were thought to only occupy mammalian intestinal tracts. However, recent 16S rRNA gene-targeted molecular approaches have demonstrated that novel centres of variation within the genus Fibrobacter are present in landfill sites and freshwater lakes, and their relative abundance suggests a potential role for fibrobacters in cellulose degradation beyond the herbivore gut. Furthermore, a novel subphylum within the Fibrobacteres has been detected in the gut of wood-feeding termites, and proteomic analyses have confirmed their involvement in cellulose hydrolysis. The genome sequence of F. succinogenes rumen strain S85 has recently suggested that within this group of organisms a "third" way of attacking the most abundant form of organic carbon in the biosphere, cellulose, has evolved. This observation not only has evolutionary significance, but the superior efficiency of anaerobic cellulose hydrolysis by Fibrobacter spp., in comparison to other cellulolytic rumen bacteria that typically utilise membrane-bound enzyme complexes (cellulosomes), may be explained by this novel cellulase system. There are few bacterial phyla with potential functional importance for which there is such a paucity of phenotypic and functional data. In this review, we highlight current knowledge of the Fibrobacteres phylum, its taxonomy, phylogeny, ecology and potential as a source of novel glycosyl hydrolases of biotechnological importance. PMID- 22213057 TI - Comparison of radioguided occult lesion localization (ROLL) and wire localization for non-palpable breast cancers: a meta-analysis. AB - Four randomized trials encompassing 449 patients of non-palpable breast cancer undergoing with radio-guided occult lesion localization (ROLL) or wire guided localization (WGL). In the fixed effects model, accurate localization, peri procedural complications, and reoperation rate were comparable between two techniques. Risk of having positive resection margins following WGL was higher. Duration of localization and surgical excision was shorter for ROLL. Volume and weight of the excised occult breast lesion was similar in WGL and ROLL groups. PMID- 22213058 TI - TP53INP1 as new therapeutic target in castration-resistant prostate cancer. AB - BACKGROUND: Prostate cancer (PC) is one of the most common malignancies in industrialized countries, and the second leading cause of cancer-related death in the United States. We recently showed that over-expression of tumor protein 53 induced nuclear protein 1 (TP53INP1), a cell stress response protein, is a worse prognostic factor in PC, particularly predictive of biological cancer relapse. Moreover, treatment of castration-sensitive (CS) LNCaP tumor cells with a TP53INP1 antisense oligonucleotide (TP53INP1 ASO) inhibits proliferation and induces apoptosis. The aim of this study was to investigate variations of TP53INP1 expression in PC during androgen withdrawal therapy and in castration resistant prostate cancer (CRPC). METHODS: Quantitative measurements of immunohistochemical expression of TP53INP1 using high-throughput densitometry, assessed on digitized microscopic tissue micro-array images were correlated with hormone therapy (HT) status in human PC. Northern blot analysis of TP53INP1 after castration was performed in LNCaP xenograft. Treatment of CR C4-2 tumor cells in vitro with TP53INP1 ASO was analyzed. We also analyzed the effect of TP53INP1 ASO treatment in vivo on tumor xenograft growth. RESULTS: TP53INP1 protein expression decreases during HT and increases after HT in human CRPC. TP53INP1 mRNA increases significantly in CR tumors of LNCaP xenograft. Moreover, treatment of CR C4-2 cells with TP53INP1 ASO downregulates TP53INP1 protein level, inhibits proliferation, and induces apoptosis. Finally, in vivo, TP53INP1 ASO treatment significantly inhibits the tumoral progression of CR C4-2 xenograft and enhances docetaxel cytotoxicity. CONCLUSIONS: These results suggest that TP53INP1 could be considered as a relevant-specific target for molecular therapy of CRPC. PMID- 22213059 TI - Targeting gold nanoshells on silica nanorattles: a drug cocktail to fight breast tumors via a single irradiation with near-infrared laser light. PMID- 22213061 TI - Complex choristoma of the lacrimal caruncle: a case report of an unusual congenital tumor with clinical and histopathological classification. AB - Rare congenital tumors can be localized in the peribulbar area. Here we report an unusual case presented in a 3-year-old child with a history of a congenital tumor in the lacrimal caruncle of the right eye, associated with epiphora and constant discomfort. A surgical resection was performed, and the final histopathological diagnosis was lacrimal caruncle complex choristoma. Choristomas are growths of apparently normal tissue in an abnormal location, which can be situated anywhere in the body, including ocular and peribulbar structures. These almost unknown congenital tumors constitute the most common conjunctival tumors in children and can be interpreted clinically as different lesions, which are only differentiated through precise histopathological analysis. PMID- 22213062 TI - Human O6 -methylguanine-DNA methyltransferase containing C145A does not prevent hepatocellular carcinoma in C3HeB/FeJ transgenic mice. AB - The prevalence of hepatocellular carcinoma (HCC) was diminished from 60% to 18% at 15 months of age in C3HeB/FeJ male transgenic mice expressing hMGMT in our previous studies. To directly test if the methyltransferase activity is required for diminished tumor prevalence, two separate lines of transgenic mice bearing an enzymatically inactive form of hMGMT were used. In these lines, cysteine 145 was substituted with alanine (C145A). Expression of the hMGMT C145A transgene in liver was demonstrated by Northern blots and Western blots. Immunohistochemistry revealed predominantly nuclear localization of the hMGMT C145A protein. hMGMT C145A transgenic mice were crossed with lacI transgenic mice to assess mutant frequencies in the presence of the mutant protein. Mutant frequencies were similar among livers of lacI * hMGMT C145A bi-transgenic mice and lacI * wild type (WT) mice. DNA sequence analysis of recovered lacI mutants revealed similar mutation spectra for hMGMT C145A and WT mice. The prevalence of HCC was also similar for the two tested lines of hMGMT C145A mice, 45% and 48% prevalence with median tumor sizes of 11 and 8 mm, and WT mice, 40% prevalence and median tumor size of 10 mm. These results provide evidence that residue C145 in hMGMT is required to reduce the prevalence of HCC in C3HeB/FeJ mice transgenic for hMGMT. PMID- 22213060 TI - Brief report: successful pregnancies but a higher risk of preterm births in patients with systemic sclerosis: an Italian multicenter study. AB - OBJECTIVE: To assess fetal and maternal outcomes in women with systemic sclerosis (SSc). METHODS: Prospectively collected data on 99 women with SSc from 25 Italian centers were analyzed retrospectively. Women with SSc were observed during 109 pregnancies (from 2000 to 2011), and outcomes were compared to those in the general obstetric population (total of 3,939 deliveries). The maternal age at conception was a mean +/- SD 31.8 +/- 5.3 years, and the median disease duration at conception was 60 months (range 2-193 months). RESULTS: SSc patients, compared to the general obstetric population, had a significantly increased frequency of preterm deliveries (25% versus 12%) and severe preterm deliveries (<34 weeks of gestation) (10% versus 5%), intrauterine growth restriction (6% versus 1%), and babies with very-low birth weight (5% versus 1%). Results of multivariable analysis showed that corticosteroid use was associated with preterm deliveries (odds ratio [OR] 3.63, 95% confidence interval [95% CI] 1.12-11.78), whereas the use of folic acid (OR 0.30, 95% CI 0.10-0.91) and presence of anti-Scl-70 antibodies (OR 0.26, 95% CI 0.08-0.85) were protective. The disease remained stable in most SSc patients, but there were 4 cases of progression of disease within 1 year from delivery, all in anti-Scl-70 antibody-positive women, 3 of whom had a disease duration of <3 years. CONCLUSION: Women with SSc can have successful pregnancies, but they have a higher-than-normal risk of preterm delivery, intrauterine growth restriction, and babies with very-low birth weight. Progression of the disease during or after pregnancy is rare, but possible. High risk multidisciplinary management should be standard for these patients, and pregnancy should be avoided in women with severe organ damage and postponed in women with SSc of recent onset, particularly if the patient is positive for anti Scl-70 antibodies. PMID- 22213064 TI - Experimental and theoretical studies on organic D-pi-A systems containing three coordinate boron moieties as both pi-donor and pi-acceptor. AB - Four linear pi-conjugated systems with 1,3-diethyl-1,3,2-benzodiazaborolyl [C(6)H(4)(NEt)(2)B] as a pi-donor at one end and dimesitylboryl (BMes(2)) as a pi acceptor at the other end were synthesized. These unusual push-pull systems contain phenylene (-1,4-C(6)H(4)-; 1), biphenylene (-4,4'-(1,1'-C(6)H(4))(2)-; 2), thiophene (-2,5-C(4)H(2)S-; 3), and dithiophene (-5,5'-(2,2'-C(4)H(2)S)(2)-; 4) as pi-conjugated bridges and different types of three-coordinate boron moieties serving as both pi-donor and pi-acceptor. Molecular structures of 2, 3, and 4 were determined by single-crystal X-ray diffraction. Photophysical studies on these systems reveal blue-green fluorescence in all compounds. The Stokes shifts for 1, 2, and 3 are notably large at 7820-9760 cm(-1) in THF and 5430-6210 cm(-1) in cyclohexane, whereas the Stokes shift for 4 is significantly smaller at 5510 cm(-1) in THF and 2450 cm(-1) in cyclohexane. Calculations on model systems 1'-4' show the HOMO to be mainly diazaborolyl in character and the LUMO to be dominated by the empty p orbital at the boron atom of the BMes(2) group. However, there are considerable dithiophene bridge contributions to both orbitals in 4'. From the experimental data and MO calculations, the pi-electron-donating strength of the 1,3-diethyl-1,3,2-benzodiazaborolyl group was found to lie between that of methoxy and dimethylamino groups. TD-DFT calculations on 1'-4', using B3LYP and CAM-B3LYP functionals, provide insight into the absorption and emission processes. B3LYP predicts that both the absorption and emission processes have strong charge-transfer character. CAM-B3LYP which, unlike B3LYP, contains the physics necessary to describe charge-transfer excitations, predicts only a limited amount of charge transfer upon absorption, but somewhat more upon emission. The excited-state (S(1)) geometries show the borolyl group to be significantly altered compared to the ground-state (S(0)) geometries. This borolyl group reorganization in the excited state is believed to be responsible for the large Stokes shifts in organic systems containing benzodiazaborolyl groups in these and related compounds. PMID- 22213063 TI - CRP and acute renal rejection: a marker to the point. AB - OBJECTIVES: C-reactive protein (CRP) is increased in end-stage renal disease patients. Recent studies have shown positive associations between inflammatory markers and cardiovascular mortality in kidney transplant recipients. The aim of the present study was to examine the correlation between CRP and early detection of renal allograft rejection. Furthermore, investigate the association between pretransplant levels of CRP with the development of acute renal allograft rejection as a possible predictive marker. METHODS: Ninety-one renal transplant recipients were sequentially analyzed. The median follow up of patients was 8 weeks. Basal and 8 weeks post transplant CRP levels were assessed. RESULTS: CRP levels were significantly higher in allograft rejection both in the pretransplant (n = 25, P = 0.001) and postransplant (n = 33, P = 0.001) phases when compared to those without rejection. By stepwise multiple regression analysis, rejection in transplanted patients was independently correlated to albumin/creatinine ratio and CRP 8 weeks after transplantation. CONCLUSION: Elevated pretransplant serum CRP level is a risk predictor for acute rejection episodes and may be a useful predictive marker in the follow-up of post-transplantation patients. PMID- 22213065 TI - Very efficient search for protein alignment--VESPA. AB - A novel approach to the problem of protein alignments is described, which in comparison with existing approaches is visibly more efficient. This approach is based on superposition of amino acid adjacency matrices of a pair of proteins, which have been modified to record the sequential order of amino acids. As a result, one obtains simultaneously all segments of the two proteins which are shifted relative to one another by one or more positions in either directions, without need of a prior exhaustive search for an alignment that included unproductive directions and unknown displacement steps. PMID- 22213066 TI - Altered HLA class I and HLA-G expression is associated with IL-10 expression in patients with cervical cancer. AB - Although high-risk human papillomaviruses (HPVs) are an important risk factor in the etiopathogenesis of cervical cancer, increasing evidence suggests that the ability to avoid immune surveillance seems to be linked to the transforming potential of HPV and a rapid progression to cancer. In other cancer models, IL-10 contributes to impair anti-tumor immune response either by downregulating human leukocyte antigen Class I (HLA-I) expression or by increasing HLA-G expression. To comprehend how these alterations could contribute to evasion of immune surveillance in cervical cancer, we analyzed HLA-I, HLA-G and IL-10 expressions by immunohistochemistry in 63 biopsies from patients with cervical intraepithelial neoplasia III (CIN-III) and cervical cancer. Immunohistochemistry showed absent or weak HLA-I expression in 50/59 cases. In these cases, a high percentage had loss of heterozygosis. IL-10 and HLA-G expression were observed in 46.6 and 27.6% of cases, respectively. Concurrent upregulation of IL-10 was found in 87.5% of HLA-G positive cases (p = 0.000). Similarly, a significant association between IL-10 expression and HLA-I downregulation was found (p = 0.028). Finally, we observed higher HLA-G expression in patients with HLA-I downregulation than in those with normal HLA-I expression (p = 0.004). Our results suggest that, in cervical cancer, the IL-10 expression may induce an immunosuppressive environment by upregulating HLA-G expression and downregulating HLA class I expression. PMID- 22213067 TI - Identification of endogenous normalizers for serum microRNAs by microarray profiling: U6 small nuclear RNA is not a reliable normalizer. PMID- 22213068 TI - Recurrent deletions of the TNFSF7 and TNFSF9 genes in 19p13.3 in diffuse large B cell and Burkitt lymphomas. AB - A single nucleotide polymorphism-chip analysis of 98 cases of aggressive B-cell lymphomas revealed a recurrent deletion at 19p13 in nine of the cases. Six further cases with deletions encompassing this region were found in array comparative genomic hybridization data of 295 aggressive B-cell lymphomas from a previous study. Three cases even showed a homozygous deletion, suggesting a tumor suppressor gene in the deleted region. Two genes encoding members of the tumor necrosis factor superfamily (TNFSF) were located in the minimally deleted region, that is, TNFSF7 and TNFSF9. As no mutations were found within the coding exons of the remaining alleles in the lymphomas with heterozygous deletions, we speculate that the deletions may mostly function through a haploinsufficiency mechanism. The cases with deletions encompassed both diffuse large B-cell lymphomas and Burkitt lymphomas, and a deletion was also found in a Hodgkin lymphoma cell line. Thus, TNFSF7 and TNFSF9 deletions are recurrent genetic lesions in multiple types of human lymphomas. PMID- 22213069 TI - Denoising sparse images from GRAPPA using the nullspace method. AB - To accelerate magnetic resonance imaging using uniformly undersampled (nonrandom) parallel imaging beyond what is achievable with generalized autocalibrating partially parallel acquisitions (GRAPPA) alone, the DEnoising of Sparse Images from GRAPPA using the Nullspace method is developed. The trade-off between denoising and smoothing the GRAPPA solution is studied for different levels of acceleration. Several brain images reconstructed from uniformly undersampled k space data using DEnoising of Sparse Images from GRAPPA using the Nullspace method are compared against reconstructions using existing methods in terms of difference images (a qualitative measure), peak-signal-to-noise ratio, and noise amplification (g-factors) as measured using the pseudo-multiple replica method. Effects of smoothing, including contrast loss, are studied in synthetic phantom data. In the experiments presented, the contrast loss and spatial resolution are competitive with existing methods. Results for several brain images demonstrate significant improvements over GRAPPA at high acceleration factors in denoising performance with limited blurring or smoothing artifacts. In addition, the measured g-factors suggest that DEnoising of Sparse Images from GRAPPA using the Nullspace method mitigates noise amplification better than both GRAPPA and L1 iterative self-consistent parallel imaging reconstruction (the latter limited here by uniform undersampling). PMID- 22213070 TI - Characterization of female germ-like cells derived from mouse embryonic stem cells through expression of GFP under the control of Figla promoter. AB - Previous studies have demonstrated that germ cells can be derived from mouse embryonic stem cells (ESCs). However, there is still no efficient system, which can visualize the stage of germ cell specification in vitro, and further to identify and enrich germ cells derived from ESCs. Figla (factor in the germline, alpha) gene encodes a germ cell specific transcription factor that coordinates the expression of the oocyte-specific zona pellucida (Zp) genes and is essential for folliculogenesis in mouse. Here, we first constructed a pFigla-EGFP recombinant plasmid that expressed enhanced green fluorescent protein (EGFP) under the control of Figla promoter, and generated and characterized an ESC line stably carrying this pFigla-EGFP reporter construct. Then the ESCs were induced to differentiate into female germ-like cells by culturing adherent embryoid bodies (EBs) in retinoic acid (RA) induction medium or transplanting ESCs under the kidney capsule with ovarian cells. A population of differentiated ESCs expressed GFP, and these cells were analyzed by RT-PCR and immunofluorescence. The GFP positive cells showed the expression of germ cell markers Vasa, meiotic specific gene Stra8, Scp3, oocyte markers Gdf9, Zp3 and Figla, indicating that this method could be used for the purification and selection of female germ cells. Our study establishes a new selective system of female germ-like cell derivation and offers an approach for further research on the development and the differentiation of germ cells derived from stem cells. PMID- 22213071 TI - New sandwich-type phthalocyaninato-metal quintuple-decker complexes. PMID- 22213072 TI - UMD-DYSF, a novel locus specific database for the compilation and interactive analysis of mutations in the dysferlin gene. AB - Mutations in the dysferlin gene (DYSF) lead to a complete or partial absence of the dysferlin protein in skeletal muscles and are at the origin of dysferlinopathies, a heterogeneous group of rare autosomal recessive inherited neuromuscular disorders. As a step towards a better understanding of the DYSF mutational spectrum, and towards possible inclusion of patients in future therapeutic clinical trials, we set up the Universal Mutation Database for Dysferlin (UMD-DYSF), a Locus-Specific Database developed with the UMD(r) software. The main objective of UMD-DYSF is to provide an updated compilation of mutational data and relevant interactive tools for the analysis of DYSF sequence variants, for diagnostic and research purposes. In particular, specific algorithms can facilitate the interpretation of newly identified intronic, missense- or isosemantic-exonic sequence variants, a problem encountered recurrently during genetic diagnosis in dysferlinopathies. UMD-DYSF v1.0 is freely accessible at www.umd.be/DYSF/. It contains a total of 742 mutational entries corresponding to 266 different disease-causing mutations identified in 558 patients worldwide diagnosed with dysferlinopathy. This article presents for the first time a comprehensive analysis of the dysferlin mutational spectrum based on all compiled DYSF disease-causing mutations reported in the literature to date, and using the main bioinformatics tools offered in UMD-DYSF. PMID- 22213073 TI - ERK5 regulates invasiveness of osteosarcoma by inducing MMP-9. AB - The purpose of this study is to determine the role of ERK5 in cellular invasion of osteosarcoma (OS). The human OS cell line (MG63, SaOS, and U2OS) and primary OS cells were used for the study. The expression of ERK5 and MMP-9 in each cell was examined by western blot or RT-PCR. To evaluate the biological role of ERK5, proliferation assay (MTT) and invasion assay (BD MatrigelTM) were performed after silencing ERK5 using siRNA. MMPs expressions were analyzed using RT-PCR and zymography after silencing ERK5. ERK5 was distinctly overexpressed in U2OS and primary OS cell. Both of them also expressed MMP-9, which was not shown in MG63 and SaOS in RT-PCR. ERK5 silencing did not suppress the proliferation of OS cells. However, ERK5 silencing significantly reduced the number of invading cells in invasion assay. The expression of MMP-9 was specifically reduced after silencing ERK5. The zymography showed that the enzyme activity of MMP-9 was also reduced after ERK5 suppression. The expression of ERK5 regulates the invasion of OS cells by inducing MMP-9 expression. Therefore, ERK5 may be a new therapeutic target in invasive OS expressing MMP-9. PMID- 22213074 TI - Local wavelet-vaguelette-based functional classification of gene expression data. AB - This paper focuses on the problem of functional statistical classification of gene expression curves. A local-wavelet-vaguelette-based functional logistic regression approach is presented. This approach is specially suitable for the classification of non-stationary singular (non-differentiable) curves. The performance of the methodology proposed is illustrated by implementing it for the classification of yeast cell-cycle temporal gene expression profiles. A simulation study is also carried out for comparison with other functional classification methodologies. PMID- 22213075 TI - Allelic loss of the loci containing the androgen synthesis gene, StAR, is prognostic for relapse in intermediate-risk prostate cancer. AB - BACKGROUND: Androgen deprivation therapy (ADT) and novel agents targeting the androgen synthesis axis (e.g., abiraterone acetate) are adjuvant therapies that are currently, or may in the future be, combined with radiotherapy to reduce the chance of disease relapse. Little is known about allelic loss or gain pertaining to genes associated with the androgen synthesis axis and whether this is prognostic in patients who receive localized radiotherapy. In this hypothesis generating study, we conducted an array comparative genomic hybridization (aCGH) analysis of 33 androgen synthesis genes to identify potential prognostic factors for radiotherapy outcome. METHODS: aCGH analysis of tumor DNA prospectively derived from frozen needle biopsies of 126 men with intermediate-risk disease who underwent image-guided radiotherapy (IGRT) to a mean dose of 76.4 Gy was conducted. Statistical analyses were conducted for allelic loss or gain in genes as potential prognostic factors relative to prostate specific antigen, Gleason score, and T-category. RESULTS: We observed that allelic losses of loci containing the genes StAR and HSD17B2 were associated with increased genetic instability (as determined by percentage genome alteration). On multivariate analyses these loci were prognostic for biochemical disease-free relapse (StAR: HR = 2.84, 95% CI: 1.44-5.61, P = 0.00269; HSD17B2: HR = 1.97, 95% CI: 1.06-3.64, P = 0.031). The results were validated in a surgical cohort of 131 intermediate risk patients. CONCLUSIONS: Allelic losses of the loci containing StAR and HSD17B2 have significant prognostic value for intermediate-risk prostate cancer. With this hypothesis generating information future studies should test StAR and HSD17B2 losses as biomarkers of androgen response in combined modality protocols. PMID- 22213076 TI - General analysis of competitive binding in drug-interceptor-DNA systems. AB - A general model of competitive binding in drug-interceptor-DNA systems has been developed in order to quantify both the interceptor and protector mechanisms. The model involves full parameterization of the basic equations governing the mutual competition between drugs binding to DNA and incorporates as partial cases various similar models existing in the literature. The generality of the model results from strict accounting of the statistical effects of the binding of the drug and interceptor with DNA according to the McGhee-von Hippel formalism, and to the strict treatment of hetero-association between the drug and interceptor, which includes formation of all possible types of self- and hetero-complexes in solution. Indirect experimental evidence is provided for the importance of the protector mechanism in drug-caffeine-DNA systems, which is sometimes ignored in the literature because of the small magnitude of the CAF-DNA binding constant. PMID- 22213077 TI - Type V collagen and protein kinase C eta down-regulation in 8701-BC breast cancer cells. AB - We previously reported that ductal infiltrating carcinomas (d.i.c.) of the human breast display profound modifications of the stromal architecture, associated with anomalous collagen composition. Among the major alterations observed in the interstitial collagen, the relative increase of type V collagen content was detected. When type V collagen was used as an "in vitro" substrate for 8701-BC d.i.c. cells, it appeared able to restrain cell growth, inhibit cell motility and invasion "in vitro", and modify the expression levels of genes coding for apoptosis factors, caspases and stress response proteins. In the present paper we demonstrate that type V collagen induces the down-regulation of protein kinase C eta, an event that may be, at least in part, responsible of the previously reported modifications of cell morphology and growth rate, and that appears to be involved in the already-observed changes of expression levels of genes encoding for anti- (Bcl-2) and pro-apoptotic factors (Bad, Dapk, Bcl-Xs) and enzymes (caspase 5 and 8). PMID- 22213078 TI - Ternary ambipolar phosphine oxide hosts based on indirect linkage for highly efficient blue electrophosphorescence: towards high triplet energy, low driving voltage and stable efficiencies. AB - The effective strategy of indirect linakge for constructing ternary ambipolar phosphine oxide (PO) hosts with the high first triplet energy levels (T(1)) was successfully demonstrated. The interplay between the chromophore, hole and electron transporting moieties was effectively restrained. Both of T(1) as high as 3.0 eV and ambipolar characteristics were perfectly realized, which consequently resulted in the highly efficient blue-emitting phosphorescent organic light-emitting diodes with low driving voltage and stable efficiencies. PMID- 22213079 TI - Protein kinase C mediated extraembryonic endoderm differentiation of human embryonic stem cells. AB - Unlike mouse embryonic stem cells (ESCs), which are closely related to the inner cell mass, human ESCs appear to be more closely related to the later primitive ectoderm. For example, human ESCs and primitive ectoderm share a common epithelial morphology, growth factor requirements, and the potential to differentiate to all three embryonic germ layers. However, it has previously been shown that human ESCs can also differentiate to cells expressing markers of trophoblast, an extraembryonic lineage formed before the formation of primitive ectoderm. Here, we show that phorbol ester 12-O-tetradecanoylphorbol 13-acetate causes human ESCs to undergo an epithelial mesenchymal transition and to differentiate into cells expressing markers of parietal endoderm, another extraembryonic lineage. We further confirmed that this differentiation is through the activation of protein kinase C (PKC) pathway and demonstrated that a particular PKC subtype, PKC-delta, is most responsible for this transition. PMID- 22213080 TI - Differential effect of isoflurane, medetomidine, and urethane on BOLD responses to acute levo-tetrahydropalmatine in the rat. AB - Levo-tetrahydropalmatine (l-THP) has shown significant promise in preclinical and clinical studies to treat drug addiction. Pharmacological MRI methods can elucidate the regional cerebral effects of l-THP, but there are potential confounds from the use of general anesthesia. To investigate the possible anesthetic-drug interactions for the pharmacological MRI result of acute l-THP, we examined acute blood oxygen level-dependent responses of both 5 and 20 mg/kg l THP in naive rats during general anesthesia achieved with three agents: isoflurane, medetomidine, and urethane. We found that with acute l-THP administration, isoflurane revealed the smallest blood oxygen level-dependent activation areas. In addition, urethane had the most activation areas; however, they were all negative. Medetomidine showed mixed positive and negative activations. Region-specific interactions were found between the l-THP-induced blood oxygen level-dependent responses and the anesthetic agents. PMID- 22213081 TI - Cell permeabilization and inhibition of voltage-gated Ca(2+) and Na(+) channel currents by nanosecond pulsed electric field. AB - Previous studies have found that nanosecond pulsed electric field (nsPEF) exposure causes long-term permeabilization of the cell plasma membrane. In this study, we utilized the whole-cell patch-clamp method to study the nsPEF effect on currents of voltage-gated (VG) Ca(2+) and Na(+) channels (I(Ca) and I(Na)) in cultured GH3 and NG108 cells. We found that a single 300 or 600 ns pulse at or above 1.5-2 kV/cm caused prolonged inhibition of I(Ca) and I(Na). Concurrently, nsPEF increased a non-inactivating "leak" current (I(leak)), presumably due to the formation of nanoelectropores or larger pores in the plasma membrane. The nsPEF effects were similar in cells that were exposed intact and subsequently brought into the whole-cell recording configuration, and in cells that were first brought into the whole-cell configuration and then exposed. Although both I(leak) and the inhibition of VG currents were enhanced at higher E-field levels, these two nsPEF effects showed relatively weak correlation with each other. In some cells, I(leak) increased 10-fold or more while VG currents remained unchanged. At longer time intervals after exposure (5-15 min), I(Ca) and I(Na) could remain inhibited although I(leak) had largely recovered. The causal relation of nsPEF inhibitory effects on VG currents and permeabilization of the plasma membrane is discussed. PMID- 22213082 TI - Expression patterns of endothelin-1 and its receptors in colorectal cancer. AB - BACKGROUND AND OBJECTIVES: Endothelin-1 (ET-1), a potent vasoconstricting peptide, plays an important role in carcinogenesis. Previous in vitro studies have shown that colorectal cancer cells produce ET-1. METHODS: ET-1 and its receptors ET-A (ET(A) R) and ET-B (ET(B) R) were analyzed in colorectal cancer cell lines and tumors by Western blot and immunohistochemistry. Also, ET-1 levels were measured by ELISA in blood samples collected before and after tumor resection. RESULTS: ET-1 was immunohistochemically expressed by tumor cells at a variable level in 39 cases tested. The adjacent normal mucosa was negative for ET 1 expression. Strong ET(A) R expression observed in the deeper infiltrating areas at the periphery of neoplastic tissue correlated significantly with tumor stage. ET(B) R levels were very low or undetectable. Western blot analysis in paired (normal, tumor) fresh-frozen samples of colorectal cancers and in four colon carcinoma cell lines confirmed these findings. In addition, lower levels of ET-1 in the peripheral circulation after the tumor resection were found by ELISA as compared to those observed before surgery. CONCLUSIONS: ET-1 and ET(A) R, but not ET(B) R, are expressed at a higher level in primary and cultured colon carcinoma cells as compared to normal colon mucosa cells. Further functional studies are needed to explore the role of ET-1/ET(A) R axis in colon carcinogenesis. PMID- 22213083 TI - Systematic review of trocar-site hernia. AB - BACKGROUND: Broad implementation of laparoscopic surgery has made trocar-related complications clinically important. Trocar-site hernia (TSH) is an uncommon, but potentially serious, complication that occasionally requires emergency surgery. This systematic review was conducted to establish the prevalence and risk factors for TSH. METHODS: The review was conducted according to the PRISMA guidelines. MEDLINE, Embase, Web of Science and the Cochrane Library were searched to 7 June 2010 for studies on TSH. RESULTS: Twenty-two articles were included. One study was a randomized clinical trial, five were prospective cohort studies and 16 were retrospective cohort studies. The prevalence of TSH is low, with a median pooled estimate of 0.5 (range 0-5.2) per cent. No meta-analysis on risk factors could be performed. Pyramidal trocars, 12-mm trocars and a long duration of surgery were identified as the most important technical risk factors for TSH. Older age and a higher body mass index were observed to be patient-related risk factors. CONCLUSION: TSH is an uncommon complication of laparoscopic surgery. The most important technical risk factors are the design and size of the trocars. The scientific evidence for recommendations to avoid TSH is sparse. PMID- 22213084 TI - Spinal cathepsin S and fractalkine contribute to chronic pain in the collagen induced arthritis model. AB - OBJECTIVE: The induction of rheumatoid arthritis (RA) by active and passive immunization of mice results in the development of pain at the same time as the swelling and inflammation, with both peripheral and central sensitization contributing to joint pain. The purpose of this study was to examine the development of pain in the rat model of collagen-induced arthritis (CIA) and to evaluate the contribution of neuroimmune interactions to established arthritis pain. METHODS: Mechanical hypersensitivity was assessed in female Lewis rats before and up to 18 days after induction of CIA by immunization with type II collagen. The effect of selective inhibitors of microglia were then evaluated by prolonged intrathecal delivery of a cathepsin S (CatS) inhibitor and a fractalkine (FKN) neutralizing antibody, from day 11 to day 18 following immunization. RESULTS: Rats with CIA developed significant mechanical hypersensitivity, which started on day 9, before the onset of clinical signs of arthritis. Mechanical hypersensitivity peaked with the severity of the disease, when significant microglial and astrocytic responses, alongside T cell infiltration, were observed in the spinal cord. Intrathecal delivery of microglial inhibitors, a CatS inhibitor, or an FKN neutralizing antibody attenuated mechanical hypersensitivity and spinal microglial response in rats with CIA. CONCLUSION: The inhibition of microglial targets by centrally penetrant CatS inhibitors and CX(3) CR1 receptor antagonists represents a potential therapeutic avenue for the treatment of pain in RA. PMID- 22213085 TI - Nanographite impurities in carbon nanotubes: their influence on the oxidation of insulin, nitric oxide, and extracellular thiols. AB - There has been growing interest in the use of modified-carbon-nanotube electrodes in applications such as the electrochemical detection of biologically significant compounds, owing to their apparent "electrocatalytic" properties and ability to enhance oxidative signals. In spite of their salient properties, little work has been done to further examine the reasons for these reported characteristics. In this report, we present clear evidence that the presence of nanographite impurities within carbon nanotubes (CNTs) is responsible for providing the previously reported enhanced electrochemical response. We have demonstrated this effect on homocysteine, N-acetyl-L-cysteine, nitric oxide, and insulin, which are important biological agents in the body. Moreover, we also showed that the influence of nanographite impurities on the electrochemistry of carbon nanotubes is prevalent among a variety of CNTs, such as single-walled CNTs, double-walled CNTs, and few-walled CNTs. Our findings will have a profound influence upon the biomedical applications of CNTs. PMID- 22213087 TI - Association of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status with total choline concentration and tumor volume in breast cancer patients: an MRI and in vivo proton MRS study. AB - The association of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) status of breast cancer patients with total choline (tCho) concentration and tumor volume was investigated using in vivo proton magnetic resonance spectroscopy and MRI at 1.5 T. Values for tCho concentration were determined in 120 locally advanced breast cancer patients (stages IIB, IIIA, IIIB, and IIIC), 31 early breast cancer patients (stage IIA), 38 patients with benign lesions, and 37 controls. Significantly higher tCho concentration and lower tumor volume were observed in early breast cancer patients compared to locally advanced breast cancer patients (P<0.05). tCho concentration and tumor volume did not correlate with age and menstruation. tCho cutoff values were obtained for the differentiation of malignant from benign breast tissues (2.54 mmol/kg); malignant versus normal (1.45 mmol/kg) and benign versus normal tissues (0.82 mmol/kg). Estrogen receptor negative patients showed significantly larger tumor volumes, indicating higher angiogenesis with aggressive tumor behavior. Nontriple negative and triple positive patients had a significantly higher tCho concentration compared to triple negative patients (P<0.05), indicating complex molecular mechanism of cell proliferation and the molecular heterogeneity of breast lesions. The results indicate the potential use of integration of breast 1H magnetic resonance spectroscopy in diagnostic workup. PMID- 22213088 TI - Hierarchical zinc oxide materials with multiple porosity prepared by ultrafast temperature gradient chemical gas-phase synthesis. AB - The preparation of materials characterized by three types of porosity could be prepared by a continuous chemical gas-phase method. The multistep formation mechanism involves a critical temperature gradient and occurs within seconds. The resulting hollow aerogel materials show superior properties as gas sensors in comparison to materials constructed from compact nanoparticles. PMID- 22213090 TI - Fine-mapping of a region of chromosome 5p15.33 (TERT-CLPTM1L) suggests a novel locus in TERT and a CLPTM1L haplotype are associated with glioma susceptibility in a Chinese population. AB - Two genome-wide association studies (GWAS) have identified 5p15.33 (TERT-CLPTM1L) as one of the susceptible regions for glioma in European background. A replication research of our group highlighted the association signals in the TERT gene of this region in a Chinese Han population. To comprehensively explore the region of glioma association at 5p15.33 and to refine the potential causal variants to a smaller critical region, we conducted a fine-mapping association study among 983 cases and 1,024 controls in a Chinese Han population. Using Hapmap3 datasets as a reference, we genotyped 16 tag SNPs across this 87.9-kb region encompassing TERT. Significant association with glioma risk was observed for rs2853677 [GG vs. GA: adjusted OR = 1.46, p = 5.51 * 10(-6), GG vs. AA: adjusted OR = 1.72, p = 7.64 * 10(-6), GG vs. GA and AA: adjusted OR = 1.96, p = 6.8 * 10(-6)] in TERT and an uncommon CLPTM1L haplotype G-T-A of rs4635969, rs6554759 and rs414965 (haplotype frequency = 0.07) was associated with higher glioma risk compared with the most common G-C-G haplotype (adjusted OR = 1.44, simulated p = 6.00 * 10(-3) under additive model). Our results indicate that sequence variants in the region flanking rs2853677 may account for the GWAS and replication signals identified in 5p15.33 for glioma susceptibility in Chinese population; besides, haplotype G-T-A in CLPTM1L also confers a risk to glioma suggesting CLPTM1L is also involved in the etiology of glioma. Additional studies especially those taking advantage of sequencing platforms are warranted to further confirm the conclusions and go deeper with our findings. PMID- 22213086 TI - Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. AB - The Hedgehog (HH)-signaling pathway mediates several processes that are deregulated in patients with metabolic syndrome (e.g., fat mass regulation, vascular/endothelial remodeling, liver injury and repair, and carcinogenesis). The severity of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome generally correlate. Therefore, we hypothesized that the level of HH-pathway activation would increase in parallel with the severity of liver damage in NAFLD. To assess potential correlations between known histologic and clinical predictors of advanced liver disease and HH-pathway activation, immunohistochemistry was performed on liver biopsies from a large, well-characterized cohort of NAFLD patients (n = 90) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Database 1 study. Increased HH activity (evidenced by accumulation of HH-ligand-producing cells and HH-responsive target cells) strongly correlated with portal inflammation, ballooning, and fibrosis stage (each P < 0.0001), supporting a relationship between HH-pathway activation and liver damage. Pathway activity also correlated significantly with markers of liver repair, including numbers of hepatic progenitors and myofibroblastic cells (both P < 0.03). In addition, various clinical parameters that have been linked to histologically advanced NAFLD, including increased patient age (P < 0.005), body mass index (P < 0.002), waist circumference (P < 0.0007), homeostatic model assessment of insulin resistance (P < 0.0001), and hypertension (P < 0.02), correlated with hepatic HH activity. CONCLUSION: In NAFLD patients, the level of hepatic HH-pathway activity is highly correlated with the severity of liver damage and with metabolic syndrome parameters that are known to be predictive of advanced liver disease. Hence, deregulation of the HH-signaling network may contribute to the pathogenesis and sequelae of liver damage that develops with metabolic syndrome. PMID- 22213091 TI - Morphology-controlled synthesis of poly(oxyethylene)silicone or alkylsilicone surfactants with explicit, atomically defined, branched, hydrophobic tails. AB - Silicone surfactants are widely used in commerce because of the unusual surface activity when compared with fluorocarbon or hydrocarbon surfactants. However, most silicone surfactants are comprised of ill-defined mixtures, which preclude the development of an understanding of structure-surface activity relationships. Herein, we report a synthetic strategy that permits exquisite control over silicone structure by using the B(C(6)F(5))(3)-catalyzed condensation of hydro- and alkoxysilanes. Six different, precise hydrophobes were then mated to hydrophilic poly(oxyethylene)s of three different molecular weights by a metal free click cyclization to generate a library of explicit silicone surfactants. These compounds were calculated to have a relatively linear value range of the hydrophilic-lipophilic balance, ranging from about 8 to about 15. The solubility of some of the compounds was too low to measure a critical micelle concentration (CMC). The others exhibited a broad range of surface tension values at the CMC that depend both on the length of the hydrophilic tail and, more importantly, the nature of the hydrophobic head group. Subtle distinctions in surfactant-related properties, which can be attributed to the three-dimensional structures, can be seen for compounds with comparable numbers of hydrocarbons and silicon groups. PMID- 22213089 TI - Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study. AB - Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A-T mutated (ATM) gene. To study genotype-phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan. In these patients, cancer occurred later in life and generally consisted of solid instead of lymphoid malignancies. The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity. Overall, the phenotypic manifestations in A-T show a continuous spectrum from severe classical childhood onset A-T to a relatively mild adult-onset disorder, depending on the presence of ATM protein and kinase activity. Each patient is left with a tremendously increased cancer risk. PMID- 22213092 TI - A minimum version of log-rank test for testing the existence of cancer cure using relative survival data. AB - Cancer survival is one of the most important measures to evaluate the effectiveness of treatment and early diagnosis. The ultimate goal of cancer research and patient care is the cure of cancer. As cancer treatments progress, cure becomes a reality for many cancers if patients are diagnosed early and get effective treatment. If a cure does exist for a certain type of cancer, it is useful to estimate the time of cure. For cancers that impose excess risk of mortality, it is informative to understand the difference in survival between cancer patients and the general cancer-free population. In population-based cancer survival studies, relative survival is the standard measure of excess mortality due to cancer. Cure is achieved when the survival of cancer patients is equivalent to that of the general population. This definition of cure is usually called the statistical cure, which is an important measure of burden due to cancer. In this paper, a minimum version of the log-rank test is proposed to test the equivalence of cancer patients' survival using the relative survival data. Performance of the proposed test is evaluated by simulation. Relative survival data from population-based cancer registries in SEER Program are used to examine patients' survival after diagnosis for various major cancer sites. PMID- 22213093 TI - Evaluation of BMP-2 gene-activated muscle grafts for cranial defect repair. AB - Large, osseous, segmental defects heal poorly. Muscle has a propensity to form bone when exposed to an osteogenic stimulus such as that provided by transfer and expression of cDNA encoding bone morphogenetic protein-2 (BMP-2). The present study evaluated the ability of genetically modified, autologous muscle to heal large cranial defects in rats. Autologous grafts (8 mm * 2 mm) were punched from the biceps femoris muscle and transduced intraoperatively with recombinant adenovirus vector containing human BMP-2 or green fluorescent protein cDNA. While the muscle biopsies were incubating with the vector, a central parietal 8 mm defect was surgically created in the calvarium of the same animal. The gene activated muscle graft was then implanted into the cranial defect. After 8 weeks, crania were examined radiographically, histologically, and by micro-computed tomography and dual energy X-ray absorptiometry. Although none of the defects were completely healed in this time, muscle grafts expressing BMP-2 deposited more than twice as much new bone as controls. Histology confirmed the anatomical integrity of the newly formed bone, which was comparable in thickness and mineral density to the original cranial bone. This study confirms the in vivo osteogenic properties of genetically modified muscle and suggests novel strategies for healing bone. PMID- 22213094 TI - Proteomic identification of PSF and p54(nrb) as TopBP1-interacting proteins. AB - TopBP1 is a BRCT domain-rich protein that is structurally and functionally conserved throughout eukaryotic organisms. It is required for the initiation of DNA replication and for DNA repair and damage signalling. To further dissect its biological functions, we explored TopBP1-interacting proteins by co immunoprecipitation assays and LC-ESI-MS-analyses. As TopBP1 binding partners we identified p54(nrb) and PSF, and confirmed the physical interactions by GST pull down assays, co-immunoprecipitations and by yeast two-hybrid experiments. Recent evidence shows an involvement of p54(nrb) and PSF in DNA double-strand break repair (DSB) and radioresistance. To get a first picture of the physiological significance of the interaction of TopBP1 with p54(nrb) and PSF we investigated in real time the spatiotemporal behaviour of the three proteins after laser microirradiation of living cells. Localisation of TopBP1 at damage sites was noticed as early as 5 s following damage induction, whereas p54(nrb) and PSF localised there after 20 s. Both p54(nrb) and PSF disappeared after 20 s while TopBP1 was retained at damage sites significantly longer suggesting different functions of the proteins during DSB recognition and repair. PMID- 22213095 TI - Conduction through viscoelastic phase in a redox-active ionic liquid at reduced temperatures. PMID- 22213097 TI - Oxygen levels epigenetically regulate fate switching of neural precursor cells via hypoxia-inducible factor 1alpha-notch signal interaction in the developing brain. AB - Oxygen levels in tissues including the embryonic brain are lower than those in the atmosphere. We reported previously that Notch signal activation induces demethylation of astrocytic genes, conferring astrocyte differentiation ability on midgestational neural precursor cells (mgNPCs). Here, we show that the oxygen sensor hypoxia-inducible factor 1alpha (HIF1alpha) plays a critical role in astrocytic gene demethylation in mgNPCs by cooperating with the Notch signaling pathway. Expression of constitutively active HIF1alpha and a hyperoxic environment, respectively, promoted and impeded astrocyte differentiation in the developing brain. Our findings suggest that hypoxia contributes to the appropriate scheduling of mgNPC fate determination. PMID- 22213096 TI - LNCaP prostate cancer cells with autocrine interleukin-6 expression are resistant to IL-6-induced neuroendocrine differentiation due to increased expression of suppressors of cytokine signaling. AB - BACKGROUND: Neuroendocrine differentiation (NED) is one of the mechanisms underlying development of castration-resistant prostate cancer (CRPC). In this study, we investigated IL-6-induced NED in two LNCaP sublines. METHODS: LNCaP S17, an LNCaP subline that secretes IL-6, and LNCaP-C3, a control subline that does not express IL-6, were analyzed for IL-6-induced NED, activation of JAK2 and STAT3 pathways, and expression of IL-6/IL-6R signaling proteins and downstream target genes. RESULTS: IL-6 did not induce NED in LNCaP-S17 cells, even though IL 6 induced NED in LNCaP-C3 cells. IL-6 activated JAK2 and STAT3 pathways in LNCaP C3 cells but not in LNCaP-S17 cells. IL-6 did not activate ERK1/2, AKT, or NF kappaB pathways in either cell line. Both LNCaP-C3 and LNCaP-S17 cell lines expressed IL-6R, gp130, and TYK2 at almost the same levels and did not express JAK1 or JAK3. The basal level of JAK2 expression was slightly higher in LNCaP-C3 cells than in LNCaP-S17 cells. Two suppressors of cytokine signaling, SOCS7 and cytokine-inducible SH2 protein (CIS), were expressed constitutively at higher levels in LNCaP-S17 cells than in LNCaP-C3 cells, while SOCS1 to SOCS6 were expressed at approximately the same levels. Using siRNA to knockdown SOCS7 and CIS expression in LNCaP-S17 cells led to increased phosphorylation of STAT3 upon IL-6 stimulation. CONCLUSIONS: LNCaP-S17 cells are resistant to exogenous IL-6 induced NED due to increased levels of CIS/SOCS7 that block activation of JAK2 STAT3 pathways. PMID- 22213099 TI - Isolation of a novel Pseudomonas sp from soil that can efficiently degrade polyethylene succinate. AB - PURPOSE: Polyethylene succinate (PES) is a biodegradable synthetic polymer and therefore widely used as a base material in plastic industry to circumvent the environmental problems related with the non-biodegradability of other polymers like polyethylene. Till date only few organisms have been reported to have the ability to degrade PES. Therefore for better management of PES-related environmental waste, the present study is targeted towards isolating mesophilic organism(s) capable of more efficient degradation of PES. RESULTS: Strain AKS2 was isolated from soil based on survival on a selection plate wherein PES was used as sole carbon source. Ribotyping and biochemical tests revealed that AKS2 is a new strain of Pseudomonas. Scanning electron and atomic force microscopic analysis of the PES films obtained after incubation with AKS2 confirmed PES degradation ability of AKS2, wherein an alteration in surface topology was observed. The kinetics of PES weight loss showed that AKS2 degrades PES maximally during its logarithmic growth phase at a rate of 1.65 mg/day. This degradation is mediated by esterase activity and may also involve cell-surface hydrophobicity. It has also been observed that AKS2 is able to degrade PES considerably even in the presence of glucose, which is likely to increase the bioremediation potential of this isolate. CONCLUSION: A new strain of Pseudomonas has been isolated from soil that is able to adhere to PES and degrade this polymer efficiently. This organism has the potential to be implemented as a useful tool for bioremediation of PES-derived materials. PMID- 22213098 TI - Identification of a functional variant in SPLUNC1 associated with nasopharyngeal carcinoma susceptibility among Malaysian Chinese. AB - Nasopharyngeal carcinoma (NPC) is a multifactorial and polygenic disease with high incidence in Asian countries. Epstein-Barr virus infection, environmental and genetic factors are believed to be involved in the tumorigenesis of NPC. The association of single nucleotide polymorphisms (SNPs) in LPLUNC1 and SPLUNC1 genes with NPC was investigated by performing a two-stage case control association study in a Malaysian Chinese population. The initial screening consisted of 81 NPC patients and 147 healthy controls while the replication study consisted of 366 NPC patients and 340 healthy controls. The combined analysis showed that a SNP (rs2752903) of SPLUNC1 was significantly associated with the risk of NPC (combined P = 0.00032, odds ratio = 1.62, 95% confidence interval = 1.25-2.11). In the subsequent dense fine mapping of SPLUNC1 locus, 36 SNPs in strong linkage disequilibrium with rs2752903 (r(2) >= 0.85) were associated with NPC susceptibility. Screening of these variants by electrophoretic mobility shift and luciferase reporter assays showed that rs1407019 located in intron 3 (r(2) = 0.994 with rs2752903) caused allelic difference in the binding of specificity protein 1 (Sp1) transcription factor and affected luciferase activity. This SNP may consequently alter the expression of SPLUNC1 in the epithelial cells. In summary, our study suggested that rs1407019 in intronic enhancer of SPLUNC1 is associated with NPC susceptibility in which its A allele confers an increased risk of NPC in the Malaysian Chinese population. PMID- 22213100 TI - Chlorostyrenes in iron-catalyzed biaryl coupling reactions. PMID- 22213101 TI - Routine prophylactic sentinel lymph node biopsy is not indicated in women undergoing prophylactic mastectomy. AB - BACKGROUND: Prophylactic mastectomies (PM) are performed to reduce the risk of breast cancer. Occasionally an occult carcinoma is found in PM specimens. Given the high morbidity of axillary lymph node dissection (ALND), some perform prophylactic sentinel lymph node biopsy (SLNB). We undertook a study to examine if prophylactic SLNB is indicated in all patients undergoing PM. METHODS: A retrospective review of all PM between 2004 and 2010 was performed. The stage of tumor on the disease side and the pathologic findings in the prophylactic breast were analyzed. The number of SLN and the frequency of lymph node metastases were evaluated. RESULTS: A total of 199 PM on 184 patients were performed: 169 contralateral PM and 30 bilateral PM. Of the 199 PM, 12 had occult carcinomas (6.0%): 10 non-invasive, 1 microinvasive and 1 T1b invasive tumor. 153 of 199 PM specimens had prophylactic SLNB, of which only 2 had a positive SLN that originated from the index side of the breast. CONCLUSIONS: Although it is not uncommon to find occult carcinomas in the prophylactic breast, it is rare for the occult carcinoma to spread to the lymph nodes. Therefore, routine prophylactic SLNB is not indicated in patients undergoing PM. PMID- 22213103 TI - Myotube orientation using strong static magnetic fields. AB - In this experiment, we evaluated the effects of strong static magnetic fields (SMF) on the orientation of myotubes formed from a mouse-derived myoblast cell line, C2C12. Myogenic differentiation of C2C12 cells was conducted under exposure to SMF at a magnetic flux density of 0-10 T and a magnetic gradient of 0-41.7 T/m. Exposure to SMF at 10 T led to significant formation of oriented myotubes. Under the high magnetic field gradient and a high value of the product of the magnetic flux density and magnetic field gradient, myotube orientation increased as the myogenic differentiation period increased. At the 3 T exposure position, where there was a moderate magnetic flux density and moderate magnetic field gradient, myotube orientation was not observed. We demonstrated that SMF induced the formation of oriented myotubes depending on the magnetic flux density, and that a high magnetic field gradient and a high value of the product of the magnetic flux density and magnetic field gradient induced the formation of oriented myotubes 6 days after myogenic differentiation. We did not detect any effect of the static magnetic fields on myogenic differentiation or cell number. To the best of our knowledge, this is the first report to demonstrate that myotubes orient to each other under a SMF without affecting the cell number and myogenic differentiation. PMID- 22213102 TI - Association of Aurora-A (STK15) kinase polymorphisms with clinical outcome of esophageal cancer treated with preoperative chemoradiation. AB - BACKGROUND: Aurora-A/STK15 is a serine/threonine kinase critical for regulated chromosome segregation and cytokinesis. We investigated the association between 2 nonsynonymous single nucleotide polymorphisms in the coding region of STK15, T91A (Phe31Ile) and G169A (Val57Ile), and clinical outcome of esophageal cancer treated with preoperative chemoradiation. METHODS: Genotypes at Phe31Ile and Val57Ile were assessed from peripheral blood lymphocytes of 190 esophageal cancer patients and were correlated to response to treatment, recurrence rate, risk of death, disease-free survival (DFS) and median survival time (MTS). RESULTS: All patients had resectable esophageal or gastroesophageal junction cancer and received preoperative chemoradiation followed by esophagectomy. The heterozygous variant Phe31/Ile variant was significantly associated with tumor recurrence (odds ratio [OR] = 4.39; 95% confidence interval [CI], 2.12-8.94; P < .001), shorter DFS (P = .0001), and shorter MTS (P = .012). For patients receiving cisplatin-based therapy, only the variant Phe31/Ile had an adverse effect on response (OR = 2.8; 95% CI, 1.01-5.17; P = .048) and MTS (P = .026). The variant 91A-169G haplotype carried a significant risk for lack of complete response (OR = 2.54; 95% CI, 1.15-5.54) and higher rate of recurrence (OR = 2.73; 95%CI, 1.00 7.29). The presence of at least 1 variant allele at each locus further increased the risk of recurrence (adjusted OR = 6.21; 95% CI, 2.28-17.11; P = <.001), and was associated significantly shorter DFS (P = .003). CONCLUSIONS: Our study shows that functional SNPs in the STK15 gene are associated with higher rate of recurrence, higher likelihood of chemoratiotherapy-resistance, shorter DFS, and shorter MTS. Confirmation of our data and understanding the mechanisms through which STK15 functional SNPs mediate resistance to chemoradiotherapy are warranted. PMID- 22213104 TI - An antiapoptotic role of sorting nexin 7 is required for liver development in zebrafish. AB - Sorting nexin (SNX) family proteins are best characterized for their abilities to regulate protein trafficking during processes such as endocytosis of membrane receptors, endosomal sorting, and protein degradation, but their in vivo functions remain largely unknown. We started to investigate the biological functions of SNXs using the zebrafish model. In this study, we demonstrated that SNX7 was essential for embryonic liver development. Hepatoblasts were specified normally, and the proliferation of these cells was not affected when SNX7 was knocked down by gene-specific morpholinos; however, they underwent massive apoptosis during the early budding stage. SNX7 mainly regulated the survival of cells in the embryonic liver and did not affect the viability of cells in other endoderm-derived organs. We further demonstrated that down-regulation of SNX7 by short interfering RNAs induced apoptosis in cell culture. At the molecular level, the cellular FLICE-like inhibitory protein (c-FLIP)/caspase 8 pathway was activated when SNX7 was down-regulated. Furthermore, overexpression of c-FLIP(S) was able to rescue the SNX7 knockdown-induced liver defect. CONCLUSION: SNX7 is a liver-enriched antiapoptotic protein that is indispensable for the survival of hepatoblasts during zebrafish early embryogenesis. PMID- 22213105 TI - Design rules: a net and Archimedean polyhedra score big for self-assembly. PMID- 22213106 TI - "Allorestriction" should be distinguished from "alloreactivity". AB - Whether or not allorestriction should be distinguished from alloreactivity depends on one's model of the TCR-ligand interaction. If the ligand is viewed as a determinant formed by a meld between peptide and the MHC-encoded restricting element, then the TCR, like the BCR, has a single combining site specific for the composite epitope (the Centric Model). If, however, one views the recognition of peptide and the MHC-encoded restricting element as independent, then interactions at two sites of the TCR must be integrated to signal the T cell (the Tritope Model). As TCR recognition of the MHC-encoded restricting element is, by definition, restricted (allele-specific), then under the Centric Model, all TCR signaling interactions with the composite epitope are due to allorestriction, which is peptide-specific. In contrast, under the Tritope Model, there are two classes of signaling interaction, allorestriction and alloreactivity. Alloreactivity is peptide-unspecific and is triggered by recognition of the allo MHC-encoded restricting element allele. Alloreactivity is incompatible with the Centric Model, under which one would predict that it does not exist. Selected data are analyzed to illustrate the importance of this distinction. PMID- 22213107 TI - T cell lessons from the rheumatoid arthritis synovium SCID mouse model: CD3-rich synovium lacks response to CTLA-4Ig but is successfully treated by interleukin-17 neutralization. AB - OBJECTIVE: To provide an intermediate step between classic arthritis models and clinical trials, the rheumatoid arthritis (RA) synovium SCID mouse model is a valuable tool for use during preclinical research. We undertook this study to investigate the validity of this humanized mouse model using anti-tumor necrosis factor (anti-TNF) and anti-interleukin-1 (anti-IL-1) treatment and to investigate the direct effect of T cells- and B cell-related therapies on the transplanted RA synovial tissue. METHODS: CB17/SCID mice were engrafted with human RA synovial tissue and systemically treated with anti-TNF, anti-IL-1, anti-IL-17, CTLA-4Ig, anti-CD20, or isotype control antibodies. RESULTS: Validation of the model with anti-TNF treatment significantly reduced serum cytokine levels and decreased histologic inflammation, whereas anti-IL-1 therapy did not show any effect on the RA synovial grafts. In mice engrafted with B cell-rich synovial tissue, anti-CD20 treatment showed clear therapeutic effects. Surprisingly, CTLA-4Ig treatment did not show any effects in this transplantation model, despite prescreening of the synovial tissue for the presence of CD3+ T cells and the costimulatory molecules CD80 and CD86. In contrast, great therapeutic potential was observed for anti-IL 17 treatment, but only when CD3+ T cells were abundantly present in the RA synovial tissue. CONCLUSION: This human RA synovium SCID mouse model enabled us to show that CTLA-4Ig lacks direct effects on T cell activation processes in the synovial tissue. Further evidence was obtained that IL-17 might indeed be an interesting therapeutic target in RA patients with CD3-rich synovial tissue. Further characterization of the RA patients' individual synovial profiles is of great importance for achieving tailored therapy. PMID- 22213108 TI - Role of very high order and degree B0 shimming for spectroscopic imaging of the human brain at 7 tesla. AB - With the advent of ultrahigh field systems (7 T), significant improvements in spectroscopic imaging (SI) studies of the human brain have been anticipated. These gains are dependent upon the achievable B0 homogeneity, both globally (sigmaB0Global, over the entire regions of interest or slice) and locally (sigmaB0Global, influencing the linewidth of individual SI voxels within the regions of interest). Typically the B0 homogeneity is adjusted using shim coils with spatial distributions modeled on spherical harmonics which can be characterized by a degree (radial dependence) and order (azimuthal symmetry). However, the role of very high order and degree shimming (e.g., 3rd and 4th degree) in MRSI studies has been controversial. Measurements of sigmaB0Global and sigmaB0Local were determined from B0 field maps of 64*64 resolution. In a 10 mm thick slice taken through the region of the subcortical nuclei, we find that in comparison to 1st-2nd degree shims, use of 1st-3rd and 1st-4th degree shims reduces sigmaB0Global by 29% and 55%, respectively. Using a SI voxel size of ~1cc with an estimate of sigmaB0Local from 3*3*3 B0 map pixels in this subcortical region, the number of pixels with sigmaB0Local of less than 5 Hz increased from 24 to 59% with 1st-3rd and 1st-4th over 1st-2nd degree shims, respectively. PMID- 22213109 TI - Discrimination and classification of ginsenosides and ginsengs using bis-boronic acid receptors in dynamic multicomponent indicator displacement sensor arrays. AB - Ginsenosides are complex natural products with a diverse array of biological activities, but their molecular recognition and sensing is challenging. A library of simple bis-boronic acid-based receptors with various spacers was synthesized for the sensing of ginsenosides. The incorporation of two boronic acids allowed the pairing of two indicators, which can simultaneously bind the receptors or two saccharides within the ginsenosides. A cross-reactive sensing array was therefore constructed using the receptors in conjunction with different pairs of indicators. LDA plots created from the colorimetric response of the hosts and indicator pairs reveal excellent classification of the ginsenosides, and the corresponding loading plots reveal the cross-reactivity of the receptors. In addition, several commercial ginseng extracts were unambiguously classified using the same sensing array. The assay reported here should be applicable to the analysis of other large saccharide-based natural products. PMID- 22213110 TI - Exome and genome analysis as a tool for disease identification and treatment: the 2011 Human Genome Variation Society scientific meeting. AB - The 2011 annual scientific meeting of the Human Genome Variation Society (HGVS) was held on the 11th of October, in Montreal, Canada. The theme of this meeting was "Exome and Genome Analysis as a Tool for Disease Identification and Treatment." In the last few years, there has been a substantial increase in the use of next-generation sequencing in identifying variants associated with both single-gene disorders and complex diseases. The advent of exome sequencing with the subsequent transition to whole genome sequencing will require methods to identify candidate causal variants both in coding and regulatory regions. As this technology slowly moves into the clinical diagnostic laboratory, the need to accurately predict the functional consequences of variants becomes more critical for the both the diagnosis and treatment of disease. This year's annual meeting focused on these issues. PMID- 22213111 TI - Organic exciton multiferroics. PMID- 22213112 TI - Finite element prediction of cartilage contact stresses in normal human hips. AB - Our objectives were to determine cartilage contact stress during walking, stair climbing, and descending stairs in a well-defined group of normal volunteers and to assess variations in contact stress and area among subjects and across loading scenarios. Ten volunteers without history of hip pain or disease with normal lateral center-edge angle and acetabular index were selected. Computed tomography imaging with contrast was performed on one hip. Bone and cartilage surfaces were segmented from volumetric image data, and subject-specific finite element models were constructed and analyzed using a validated protocol. Acetabular contact stress and area were determined for seven activities. Peak stress ranged from 7.52+/-2.11 MPa for heel-strike during walking (233% BW) to 8.66 +/- 3.01 MPa for heel-strike during descending stairs (261% BW). Average contact area across all activities was 34% of the surface area of the acetabular cartilage. The distribution of contact stress was highly non-uniform, and more variability occurred among subjects for a given activity than among activities for a single subject. The magnitude and area of contact stress were consistent between activities, although inter-activity shifts in contact pattern were found as the direction of loading changed. Relatively small incongruencies between the femoral and acetabular cartilage had a large effect on the contact stresses. These effects tended to persist across all simulated activities. These results demonstrate the diversity and trends in cartilage contact stress in healthy hips during activities of daily living and provide a basis for future comparisons between normal and pathologic hips. PMID- 22213114 TI - A length-based hierarchical model of brown trout (Salmo trutta fario) growth and production. AB - We present a hierarchical Bayesian model (HBM) to estimate the growth parameters, production, and production over biomass ratio (P/B) of resident brown trout (Salmo trutta fario) populations. The data which are required to run the model are removal sampling and air temperature data which are conveniently gathered by freshwater biologists. The model is the combination of eight submodels: abundance, weight, biomass, growth, growth rate, time of emergence, water temperature, and production. Abundance is modeled as a mixture of Gaussian cohorts; cohorts centers and standard deviations are related by a von Bertalanffy growth function; time of emergence and growth rate are functions of water temperature; water temperature is predicted from air temperature; biomass, production, and P/B are subsequently computed. We illustrate the capabilities of the model by investigating the growth and production of a brown trout population (Neste d'Oueil, Pyrenees, France) by using data collected in the field from 2005 to 2010. PMID- 22213113 TI - Thermal stability of fibroblast growth factor protein is a determinant factor in regulating self-renewal, differentiation, and reprogramming in human pluripotent stem cells. AB - Fibroblast growth factor (FGF), transforming growth factor (TGF)/Nodal, and Insulin/insulin-like growth factor (IGF) signaling pathways are sufficient to maintain human embryonic stem cells (ESCs) and induced pluripotent stem cells in a proliferative, undifferentiated state. Here, we show that only a few FGF family members (FGF2, FGF4, FGF6, and FGF9) are able to sustain strong extracellular signal-regulated kinase (ERK) phosphorylation and NANOG expression levels in human ESCs. Surprisingly, FGF1, which is reported to target the same set of receptors as FGF2, fails to sustain ERK phosphorylation and NANOG expression under standard culture conditions. We find that the failure of FGF1 to sustain ES is due to thermal instability of the wild-type protein, not receptor specificity, and that a mutated thermal-stable FGF1 sustains human ESCs and supports both differentiation and reprogramming protocols. PMID- 22213115 TI - Quantitative study of [Tyr10]nociceptin/orphanin FQ (1-11) at NOP receptors in rat periaqueductal gray and expressed NOP receptors in HEK293 cells. AB - AIM: The nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor was reported to be functionally heterogeneous. We investigated if [Tyr(10)]N/OFQ(1-11), a peptide ligand reported to selectively bind to the high affinity site of (125)I [Tyr(14)]N/OFQ in rodent brains, can be a tool for revealing the NOP receptor heterogeneity. We have previously founded an NOP receptor subset insensitive to Ro 64-6198 and (+)-5a Compound, two non-peptide NOP agonists, in rat ventrolateral periaqueductal gray (vlPAG) neurons. Here, we examined if [Tyr(10)]N/OFQ(1-11) differentiated (+)-5a Compound-sensitive and -insensitive vlPAG neurons. Certain mu-opioid (MOP) receptor ligands highly competing with [Tyr(10)]N/OFQ(1-11) in binding studies also showed high affinity at expressed heteromeric NOP-MOP receptors. We also examined if [Tyr(10)]N/OFQ(1-11) distinguished heteromeric NOP-MOP receptors from homomeric NOP receptors. MAIN METHODS: The NOP receptor activity was evaluated by G-protein coupled inwardly rectifying potassium (GIRK) currents in rat vlPAG slices, and by inhibition of cAMP accumulation in HEK293 cells expressing NOP receptors or co-expressing NOP and MOP receptors. KEY FINDINGS: In vlPAG neurons, [Tyr(10)]N/OFQ(1-11), like N/OFQ, induced GIRK currents through NOP receptors. It was less potent (EC(50): 8.98MUM) but equi-efficacious as N/OFQ. [Tyr(10)]N/OFQ(1-11) displayed different pharmacological profiles as (+)-5a Compound, and was effective in both (+)-5a Compound-sensitive and -insensitive neurons. In NOP-expressing HEK293 cells and NOP- and MOP-co-expressing cells, [Tyr(10)]N/OFQ(1-11) displayed similar concentration-response curves in decreasing cAMP accumulation. SIGNIFICANCE: [Tyr(10)]N/OFQ(1-11) is an NOP full agonist and less potent than N/OFQ. However, it can neither reveal the functional heterogeneity of NOP receptors in vlPAG neurons nor differentiate heteromeric NOP-MOP and homomeric NOP receptors. PMID- 22213116 TI - Aclidinium bromide, a novel long-acting muscarinic antagonist for COPD with improved preclinical renal and urinary safety profile. AB - AIMS: Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist currently in registration phase for the treatment of chronic obstructive pulmonary disease. Since urinary difficulty and retention have been reported for anticholinergic agents such as tiotropium and ipratropium, it is important to examine the preclinical urinary and renal safety profile of aclidinium. MAIN METHODS: The effect of aclidinium on urine and electrolyte excretion, renal function and voiding cystometry was analysed in conscious water-loaded Wistar rats (10-1000 MUg/kg, s.c.), anaesthetised Beagle dogs (1000 MUg/kg, i.v.) and anaesthetised guinea pigs (3-100MUg/kg, intratracheally), respectively. Aclidinium plasma levels were determined in an independent study. Active comparators were tiotropium (all studies) and ipratropium (cystometry only). KEY FINDINGS: Aclidinium 1000 MUg/kg had no effect on urine excretion in rats, in contrast to tiotropium 100 MUg/kg which significantly decreased this parameter (p<0.05). Aclidinium 1000 MUg/kg also had no effect on renal function in Beagle dogs. In guinea pigs, aclidinium 3-100 MUg/kg had no effect on urinary bladder function, whereas tiotropium and ipratropium 100 MUg/kg decreased the peak micturition pressure (p<0.05), increased the volume of urine retained in the bladder (p<0.01) and showed a trend to decrease the volume of urine excreted. SIGNIFICANCE: Aclidinium had no significant effect on urinary and renal function in the animal models studied. These results, together with the rapid plasma clearance of aclidinium reported previously, suggest a lower propensity to induce urinary retention in humans than tiotropium and ipratropium. PMID- 22213117 TI - Differential effects of dopaminergic neurotoxins on DNA cleavage. AB - AIMS: Environmental and endogenous toxins are considered to increase the risk of dopaminergic neurodegeneration. Parkinson's disease is a neurological disorder occurring due to the death of dopaminergic neurons in substantia nigra. The present study investigated the effect of parkinsonian neurotoxins salsolinol and rotenone on plasmid and genomic DNA. MAIN METHODS: Salsolinol or rotenone (0-1000 MUM) alone or in presence of divalent metals (copper or iron) was incubated with plasmid DNA pBR322 (1 MUg) or calf thymus DNA (1 MUg). In order to study their effects on restriction endonuclease sites, the plasmid DNA was incubated with the neurotoxins (salsolinol or rotenone), extracted and subjected to restriction enzyme digestion (BamHI, EcoRV, HindIII, SalI). KEY FINDINGS: Exposure of rotenone or salsolinol alone to the plasmid or calf thymus DNA did not induce any strand scission or damage. However, salsolinol in the presence of divalent copper induced strand scission and damage in both plasmid and genomic DNA. All of the tested restriction endonucleases linearized the plasmid DNA pre-treated with salsolinol or rotenone suggesting that these neurotoxins did not selectively damage the restriction enzyme sites in the DNA. SIGNIFICANCE: The above observations suggest that salsolinol and rotenone differentially interact with DNA in inducing damage in the presence of copper, and behave similarly in their binding to DNA by not damaging the selected restriction endonuclease cleavage sites. CONCLUSION: Risk for neuronal degeneration can be significantly augmented by the environmental and endogenous toxins in the presence of various metals due to their deleterious effects on DNA. PMID- 22213118 TI - Early phase detection of bile leak after hepatobiliary surgery: value of Gd-EOB DTPA-enhanced MR cholangiography. AB - PURPOSE: To assess the value of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MR cholangiography for the detection of bile leaks after hepatobiliary surgery. METHODS: Twenty-three patients with symptoms suggestive of bile leak underwent conventional fat-suppressed T1- and T2 weighted MR cholangiography followed by Gd-EOB-DTPA-enhanced MR cholangiography using gradient-echo (GRE) T2-weighted sequences and fat-suppressed T1-weighted 3D gradient-echo sequences 20 min after an intravenous bolus of Gd-EOB-DTPA. The results of Gd-EOB-DTPA-enhanced MR cholangiography correlated with clinical findings, surgical repair, and the results of endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiography. RESULTS: The results of Gd-EOB-DTPA-enhanced MR cholangiography were negative in 13 patients (cholecystectomy 5, liver transplantation 2, liver resection for focal lesions 2, cholangiocarcinoma 1, and partial hepatectomy after liver injury 1). In 10 patients in whom bile leaks were detected, this complication occurred after liver resection for focal lesions in 3, cholecystectomy in 4, liver transplantation in 2, and liver resection for intrahepatic cholangiocarcinoma in 1. The diagnostic accuracy of Gd-EOB-DTPA-enhanced MR for the detection or exclusion of bile leaks was 100%. CONCLUSIONS: Gd-EOB-DTPA-enhanced MR cholangiography is a highly reliable technique for the detection of bile leaks after hepatobiliary surgery and may avoid the use of other, potentially risky invasive diagnostic techniques. PMID- 22213119 TI - A versatile thiouronium-based solid-phase synthesis of 1,3,5-triazines. AB - A thiouronium-based solid-phase synthesis of a 1,3,5-triazine scaffold has been developed. The key feature of the synthesis is the use of a readily accessible solid-supported thiouronium salt as a primary precursor for the stepwise assembly of the 1,3,5-triazine substrate. The sulfur linker employed in the synthesis is stable under both acidic and basic conditions and is versatile enough to provide access to monocyclic, bicyclic, and spirocyclic compounds with the 1,3,5-triazine scaffold. By using this synthetic strategy, a representative set of 79 compounds containing the 1,3,5-triazine scaffold were prepared. PMID- 22213120 TI - The mechanism of O-O bond formation in Tanaka's water oxidation catalyst. PMID- 22213122 TI - Improvement of RNAi activity and strand selectivity of RISC formation by modified siRNA involving intercalators near 5' termini. PMID- 22213121 TI - Medical therapies with adult stem/progenitor cells (MSCs): a backward journey from dramatic results in vivo to the cellular and molecular explanations. AB - There is currently great interest in the use of mesenchymal stem/stromal cells (MSCs) for the therapy of many diseases of animals and humans. However, we are still left with the serious challenges in explaining the beneficial effects of the cells. Hence, it is essential to work backward from dramatic results obtained in vivo to the cellular and molecular explanations in order to discover the secrets of MSCs. This review will focus on recent data that have changed the paradigms for understanding the therapeutic potentials of MSCs. PMID- 22213123 TI - Down-regulation of RhoE is associated with progression and poor prognosis in hepatocellular carcinoma. AB - BACKGROUND: RhoE is an atypical member of Rho GTPases family, which is a crucial regulator of cytoskeletal dynamics, cell cycle progression, and cell proliferation. Previous studies have reported that RhoE was aberrantly expressed in several human cancers, but the role of RhoE in hepatocellular carcinoma (HCC) remained poor understood. OBJECTIVES: This study investigated the expression of RhoE and its clinical significance on the outcome of patients with HCC. METHODS: The expression of RhoE was examined in HCC patients and then the prognostic impact of the RhoE expression status was evaluated by univariate and multivariate analysis. RESULTS: RhoE was down-regulated in HCC cell lines and tissues compared with normal hepatocyte line (HL-7702) and non-cancerous liver tissues. The expression of RhoE was significantly negatively associated with serum AFP (P = 0.013) and tumor grade (P = 0.016). Furthermore, the patients with low expression of RhoE had a shorter survival (P = 0.002) than those with high expression. Univariate and multivariate analysis showed that RhoE expression was a significant and independent prognostic predictor for HCC patients (P = 0.016). CONCLUSIONS: RhoE, down-regulated in patients with HCC, could serve as an independent prognostic predictor for patients with HCC. PMID- 22213124 TI - Overexpression of 5-lipoxygenase and its relation with cell proliferation and angiogenesis in 7,12-dimethylbenz(alpha)anthracene-induced rat mammary carcinogenesis. AB - The present study was performed to investigate the critical role of 5 lipoxygenase (5-LOX) in 7,12-dimethylbenz(alpha)anthracene (DMBA)-induced rat mammary inflammation associated carcinogenesis. Female Sprague-Dawley rats at 50 days of age were treated with 7,12-dimethylbenz(alpha)anthracene (DMBA; 0.5 mg/100 g body weight) by a single tail vein injection, followed by administration of zileuton (2000 mg/kg diet) from week 7 until the termination of the study at 31 wk. 5-LOX protein expression, 5-hydroxyeicosatetraenoic acid (5-HETE), and leukotriene B4 (LTB4 ) production in rat mammary tissue were analyzed at 6, 12, and 24 wk post-DMBA injection. Rate of cell proliferation was analyzed by bromodioxyuridine labeling index (BrdU-LI). Microvessel density, level of VEGF, and MMP-2 were also measured. DMBA induces inflammation in rat mammary gland as early as 6 wk. 5-LOX is upregulated in DMBA treated rats right from 6 wk when compared with their normal counterparts. An overexpression of 5-LOX is accompanied with increase in 5-HETE, LTB4 production and high BrdU-LI with an increase of two key angiogenic factors for tumorigenesis; MMP-2 and VEGF. It was found that 5-LOX specific inhibitor brought about substantial protection against DMBA-induced mammary carcinogenesis. Histological findings showed substantial repair of hyperplastic lesions. There was a significant reduction in the rate of cell proliferation and expression of angiogenic factors, MMP-2 and VEGF. 5-LOX plays an important role in DMBA-induced inflammation associated carcinogenesis via activation of MMP-2 and VEGF. 5-LOX expression can be considered as a critical event in controlling the process of mammary tumor development. PMID- 22213125 TI - Highly crystalline and low bandgap donor polymers for efficient polymer solar cells. AB - A highly crystalline and low bandgap donor polymer, EI-PFDTBT, is developed by inserting ethylene bridging units to ensure a coplanar configuration between the side chains and the main chain. Polymer solar cells based on the EI-PFDTBT and PC(71) BM blends spincoated at elevated temperatures exhibit a power conversion efficiency of 5.1%. PMID- 22213126 TI - Low risk of type-specific carcinogenic HPV re-appearance with subsequent cervical intraepithelial neoplasia grade 2/3. AB - Carcinogenic human papillomavirus (HPV) infections are very common after sexual debut and nearly all become undetectable ("clear") within a few years. Following clearance, the long-term risks of type-specific HPV re-appearance and subsequent risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) are not well defined. In the 7-year, population-based cohort study in Guanacaste, Costa Rica, we studied how often type-specific carcinogenic HPV infections re-appeared after clearance and how often re-appearance led to CIN2+. We considered 1,740 carcinogenic HPV infections detected by MY09/11 PCR among 2,805 women (18-91 years old, median 34) who were actively followed at 6- or 12-month intervals. We identified women with one or more type-specific HPV infections that cleared and re-appeared and further defined a subgroup of "definite clearance and re appearance" (>=2 intervening negative results over a period of >=1 year). We determined the absolute risk of CIN2+ among the different groups. p values are two-sided. Only 7.7% (81/1,052) of HPV-infected women had intervening negative results. Very few (3.7%, 39/1,052) had "definite clearance and re-appearance", of which 5.1% (2/39) subsequently persisted to a diagnosis of CIN2. There were zero CIN3+ lesions. Extremely few women (2/2,805 of women in our cohort) had a type specific carcinogenic HPV infection clear, re-appear and lead to CIN2+. If confirmed, this argues against vaccination to avoid re-appearance that leads to precursor lesions and against the need of frequent HPV screening after initial negative results. PMID- 22213127 TI - Gilbert syndrome redefined: a complex genetic haplotype influences the regulation of glucuronidation. AB - Gilbert syndrome (GS) is characterized by intermittent unconjugated hyperbilirubinemia without structural liver damage, affecting about 10% of the white population. In GS the UGT1A1*28 variant reduces bilirubin conjugation by 70% and is associated with irinotecan and protease inhibitor side effects. The aim of this study was to characterize potential in vivo consequences of UGT1A gene variability in GS. Three hundred GS patients (UGT1A1*28 homozygous) and 249 healthy blood donors (HBD) were genotyped for UGT1A (UGT1A1*28, UGT1A3-66 T>C, UGT1A6*3a, UGT1A7*3) and transporter single nucleotide polymorphisms (SNPs) (SCLO1B1 p.V174A, SCLO1B1 p.N130D, ABCC2 p.I1324I, ABCC2-24 UTR) using TaqMan-5' nuclease-assays. A humanized transgenic UGT1A-SNP and corresponding wildtype mouse model were established carrying the GS-associated UGT1A variant haplotype. UGT1A transcript and protein expression, and transcriptional activation were studied in vivo. Homozygous UGT1A1*28 GS individuals were simultaneously homozygous for UGT1A3-66 T>C (91%), UGT1A6*2a (77%), and UGT1A7*3 (77%). Seventy six percent of GS and only 9% of HBD were homozygous for the variant haplotype spanning four UGT1A genes. SCLO1B1 and ABCC2 SNPs showed no differences. In transgenic humanized UGT1A SNP and wildtype mice this UGT1A haplotype led to lower UGT1A messenger RNA (mRNA) expression and UGT1A protein synthesis. UGT1A transcriptional activation by dioxin, phenobarbital, and endotoxin was significantly reduced in SNP mice. CONCLUSION: Our data redefine the genetic basis behind GS. In vivo data studying the genotype present in 76% of GS individuals suggest that transcription and transcriptional activation of glucuronidation genes responsible for conjugation and detoxification is directly affected, leading to lower responsiveness. This study suggests that GS should be considered a potential risk factor for drug toxicity. PMID- 22213128 TI - Transamidation of primary amides with amines using hydroxylamine hydrochloride as an inorganic catalyst. PMID- 22213129 TI - Risk factors for magnetic resonance imaging-detected patellofemoral and tibiofemoral cartilage loss during a six-month period: the joints on glucosamine study. AB - OBJECTIVE: To assess several baseline risk factors that may predict patellofemoral and tibiofemoral cartilage loss during a 6-month period. METHODS: For 177 subjects with chronic knee pain, 3T magnetic resonance imaging (MRI) of both knees was performed at baseline and followup. Knees were semiquantitatively assessed, evaluating cartilage morphology, subchondral bone marrow lesions, meniscal morphology/extrusion, synovitis, and effusion. Age, sex, and body mass index (BMI), bone marrow lesions, meniscal damage/extrusion, synovitis, effusion, and prevalent cartilage damage in the same subregion were evaluated as possible risk factors for cartilage loss. Logistic regression models were applied to predict cartilage loss. Models were adjusted for age, sex, treatment, and BMI. RESULTS: Seventy-nine subregions (1.6%) showed incident or worsening cartilage damage at followup. None of the demographic risk factors was predictive of future cartilage loss. Predictors of patellofemoral cartilage loss were effusion, with an adjusted odds ratio (OR) of 3.5 (95% confidence interval [95% CI] 1.3-9.4), and prevalent cartilage damage in the same subregion with an adjusted OR of 4.3 (95% CI 1.3-14.1). Risk factors for tibiofemoral cartilage loss were baseline meniscal extrusion (adjusted OR 3.6 [95% CI 1.3-10.1]), prevalent bone marrow lesions (adjusted OR 4.7 [95% CI 1.1-19.5]), and prevalent cartilage damage (adjusted OR 15.3 [95% CI 4.9-47.4]). CONCLUSION: Cartilage loss over 6 months is rare, but may be detected semiquantitatively by 3T MRI and is most commonly observed in knees with Kellgren/Lawrence grade 3. Predictors of patellofemoral cartilage loss were effusion and prevalent cartilage damage in the same subregion. Predictors of tibiofemoral cartilage loss were prevalent cartilage damage, bone marrow lesions, and meniscal extrusion. PMID- 22213130 TI - Variations in the exome of the LNCaP prostate cancer cell line. AB - BACKGROUND: The LNCaP cell line is widely used as a model for prostate cancer. However, information on protein-changing mutations, genetic heterogeneity and genetic (in)stability is largely lacking for these cells. METHODS: Next generation sequencing of the LNCaP exome revealed many single nucleotide variants (SNVs). To help identify the mutations that are most likely drivers of the oncogenic process, we developed an in silico protocol, which can be adapted for other exome analyses. RESULTS: We detected 1,802 non-synonymous SNVs and 218 small insertions and deletions in the LNCaP exome. We confirm the known mutations in the androgen receptor and the PTEN gene, but most other mutations remained undescribed until now. The presence of 38 out of 42 SNVs was confirmed in monoclonal as well as in polyclonal LNCaP derivatives. Moreover, most variants were also detectable in LNCaP mRNA. CONCLUSIONS: We provide an extensive database of genetic variations in the protein-coding part of the genome of LNCaP cells, which should be taken into consideration when using LNCaP cells or its derivatives as models for prostate cancer. From the analysis of several LNCaP derived cultures and clones, we can confirm that the cell line is heterozygous for a large number of variants and that both the variant and the wild-type allele can be simultaneously expressed as mRNA. The fact that the SNVs in the E cadherin, CDK4, Notch1, and PlexinB1 genes are absent in some of the subclones strongly indicates a degree of genetic instability. PMID- 22213131 TI - Antiplasmodial decarboxyportentol acetate and 3,4-dehydrotheaspirone from Laumoniera bruceadelpha. AB - A new spiro heterocycle, decarboxyportentol acetate (1) was isolated from the barks of Laumoniera bruceadelpha Nooteboom (Simaroubaceae), together with 3,4 dehydrotheaspirone (2), and their structures were elucidated by 2D NMR analysis. 3,4-Dehydrotheaspirone (2) showed potent antiplasmodial activity against Plasmodium falciparum 3D7. PMID- 22213132 TI - Improved diagnostics lead to identification of three new patients with congenital disorder of glycosylation-Ip. AB - Congenital disorders of glycosylation (CDG) comprise a clinically and biochemically heterogeneous group of monogenetic-inherited, multisystemic diseases that affect the biosynthesis of N- and/or O-glycans linked to glycoconjugates. Recently, we identified the first patient with a defect in the cytosolic-orientated GDP-mannose:Man(3-4) GlcNAc(2)-PP-dolichol alpha-1,2 mannosyltransferase (ALG11), who presented an accumulation of shortened dolichol linked oligosaccharides leading to CDG-Ip (ALG11-CDG). Here we describe an improved metabolic labeling method that allowed the identification of three new CDG-Ip cases that were missed so far in routine diagnostics. Although all CDG-Ip patients carry different mutations in the ALG11 gene, they share a variety of clinical syndromes like an unremarkable prenatal period followed by developmental delay, psychomotor, and mental retardation, strabismus convergens and seizures occurring in the first year of life. PMID- 22213133 TI - In vivo chromium-enhanced MRI of the retina. AB - Chromium (Cr) has been used histologically to stabilize lipid fractions in the retina and is suggested to enhance oxidizable lipids in brain MRI. This study explored the feasibility, sensitivity, and specificity of in vivo chromium enhanced MRI of retinal lipids by determining its spatiotemporal profiles and toxic effect after intravitreal Cr(VI) injection to normal adult rats. One day after 3 MUL Cr(VI) administration at 1-100 mM, the retina exhibited a dose dependent increase in T1-weighted hyperintensity until 50 mM. Time-dependently, significant T1-weighted hyperintensity persisted up to 2 weeks after 10 mM Cr(VI) administration. Three-dimensional chromium-enhanced MRI of ex vivo normal eyes at isotropic 50-MUm resolution showed at least five alternating bands across retinal layers, with the outermost layer being the brightest. This agreed with histology indicating alternating lipid contents with the highest level in the photoreceptor layer of the outer retina. Although Cr(VI) reduction may induce oxidative stress and depolymerize microtubules, manganese-enhanced MRI after chromium-enhanced MRI showed a dose-dependent effect of Cr toxicity on manganese uptake and axonal transport along the visual pathway. These results potentiated future longitudinal chromium-enhanced MRI studies on retinal lipid metabolism upon further optimization of Cr doses with visual cell viability. PMID- 22213134 TI - Improved clinical trial enrollment in adolescent and young adult (AYA) oncology patients after the establishment of an AYA oncology program uniting pediatric and medical oncology divisions. AB - BACKGROUND: Since 1975, there has been a dramatic increase in the survival rates of pediatric and older cancer patients, but adolescent and young adult (AYA) patients ages 15 to 40 years have not had a similar improvement. Data indicate a direct correlation between increased cure rates and clinical trial enrollment. METHODS: The authors previously published data indicating inferior clinical trial enrollment when AYA patients were treated at an adult oncology center versus a pediatric oncology center. To address this deficit, a joint pediatric and adult AYA Oncology Program was established in July 2006 with the primary objective of improving outcomes by increasing therapeutic clinical trial enrollment in this population. Patients who were referred to that program from July 2006 through June 2010 were examined retrospectively to establish whether clinical trial enrollment increased compared with historic controls. RESULTS: Fifty-seven patients were referred to the program from 2006 to 2010 (range, 12-16 new patients per year). Eight patients were referred for consultation only and were not treated at the University of Pittsburgh Cancer Institute or Children's Hospital of Pittsburgh. Five of 22 patients (23%) who received treatment at the pediatric cancer center were enrolled onto a clinical trial, whereas 9 of 27 patients (33%) patients who received treatment at the adult cancer center were enrolled. There was superior trial participation compared with the previous 3 years for those shared AYA patients who were treated at the adult center (P < .001). CONCLUSIONS: Data from this study demonstrated that establishing a unified AYA oncology program can lead to improved clinical trial enrollment for patients who are treated at medical oncology centers. PMID- 22213135 TI - Active conformation of seven-membered-ring benzolactams as new ACAT inhibitors: latent chirality at N5 in the 1,5-benzodiazepin-2-one nucleus. PMID- 22213136 TI - All-organic photopatterned one diode-one resistor cell array for advanced organic nonvolatile memory applications. PMID- 22213137 TI - Large gadolinium nitride cluster encapsulated inside a non-IPR carbon cage: a theoretical characterization on Gd3N@C78. PMID- 22213138 TI - Model for the correction of motion-induced phase errors in multishot diffusion weighted-MRI of the head: are cardiac-motion-induced phase errors reproducible from beat-to-beat? AB - In diffusion-weighted imaging, multishot acquisitions are problematic due to intershot inconsistencies of the phase caused by motion during the diffusion encoding gradients. A model for the motion-induced phase errors in diffusion weighted-MRI of the brain is presented, in which rigid-body and nonrigid-body motion are separated. In the model, it is assumed that nonrigid-body motion is due to cardiac pulsation, and that the motion patterns are repeatable from beat to-beat. To test the validity of this assumption, the repeatability of nonrigid body motion-induced phase errors is quantified in three healthy volunteers. Nonrigid-body motion-induced phase was found to significantly correlate (P < 0.05) with pulse-oximeter waveforms in ~83% of the pixels tested across all slices and subjects. PMID- 22213139 TI - Toward a more realistic prediction of peri-prosthetic micromotions. AB - The finite element (FE) method has become a common tool to evaluate peri prosthetic micromotions in cementless total hip arthroplasty. Often, only the peak joint load and a selected number of muscle loads are applied to determine micromotions. Furthermore, the applied external constraints are simplified (diaphyseal fixation), resulting in a non-physiological situation. In this study, a scaled musculoskeletal model was used to extract a full set of muscle and hip joint loads occurring during a walking cycle. These loads were applied incrementally to an FE model to analyze micromotions. The relation between micromotions and external loads was investigated, and how micromotions during a full loading cycle compared to those calculated when applying a peak load only. Finally, the effect of external constraints was analyzed (full model vs. diaphyseal fixation and reduced number of muscle loads). Relatively large micromotions were found during the swing phase when the hip joint forces were relatively low. Maximal micromotions, however, did concur with the peak hip joint force. Applying only a peak joint force resulted in peak micromotions similar to those found when full walking cycle loads were applied. The magnitude and direction of the micromotions depended on the applied muscle loads, but not on external constraints. PMID- 22213140 TI - Odontogenic ameloblasts-associated protein (ODAM), via phosphorylation by bone morphogenetic protein receptor type IB (BMPR-IB), is implicated in ameloblast differentiation. AB - To elucidate the function of the odontogenic ameloblast-associated protein (ODAM) in ameloblasts, we identified more than 74 proteins that interact with ODAM using protoarray. Of the identified proteins, bone morphogenetic protein receptor type IB (BMPR-IB) was physiologically relevant in differentiating ameloblasts. ODAM and BMPR-IB exhibited similar patterns of expression in vitro, during ameloblast differentiation. ODAM and BMPR-IB interacted through the C-terminus of ODAM, which resulted in increased ODAM phosphorylation in the presence of bone morphogenetic protein 2 (BMP-2). Immunoprecipitation assays using Ser-Xaa-Glu (SXE) mutants of ODAM demonstrated that the phosphorylation of ODAM by BMPR-IB occurs at this motif, and this phosphorylation is required for the activation of MAPKs. ODAM phosphorylation was detected in ameloblasts during ameloblast differentiation and enamel mineralization in vitro and involved in the activation of downstream factors of MAPKs. Therefore, the BMP-2-BMPR-IB-ODAM-MAPK signaling cascade has important roles in ameloblast differentiation and enamel mineralization. Our data suggest that ODAM facilitates the progression of tooth development in cooperation with BMPR-IB through distinct domains of ODAM. PMID- 22213141 TI - Functional role for interleukin-1 in the injured peripheral taste system. AB - The peripheral taste system presents an excellent model for studying the consequences of neural injury, for the damaged nerve and sensory cells and the neighboring, intact neural cells. Sectioning a primary afferent nerve, the chorda tympani (CT), rapidly recruits neutrophils to both sides of the tongue. The bilateral neutrophil response induces transient functional deficits in the intact CT. Normal function is subsequently restored as macrophages respond to injury. We hypothesized that macrophages produce the proinflammatory cytokine interleukin (IL)-1, which contributes to the maintenance of normal taste function after nearby injury. We demonstrate that IL-1beta protein levels are significantly increased on the injured side of the tongue at day 2 after injury. Dietary sodium deficiency, a manipulation that prevents macrophage recruitment, inhibits the elevation in IL-1beta. IL-1beta was expressed in several cell populations, including taste receptor cells and infiltrating neutrophils and macrophages. To test whether IL-1 modulates taste function after injury, we blocked signaling with an IL-1 receptor antagonist (IL-1 RA) and recorded taste responses from the intact CT. This treatment inhibited the bilateral macrophage response to injury and impaired taste responses in the intact CT. Cytokine actions in the taste system are largely unstudied. These results demonstrate that IL-1 has a beneficial effect on taste function after nearby injury, in contrast to its detrimental role in the injured central nervous system. PMID- 22213142 TI - Inhibition of cyclooxygenase-2 enhances immunotherapy against experimental brain tumors. AB - Glioblastoma multiforme is the most common and aggressive malignant brain tumor in humans, and the prognosis is very poor despite conventional therapy. Immunotherapy represents a novel treatment approach, but the effect is often weakened by release of immune-suppressive molecules such as prostaglandins. In the current study, we investigated the effect of immunotherapy with irradiated interferon-gamma (IFN-gamma)-secreting tumor cells and administration of the selective cyclooxygenase-2 (COX-2) inhibitor parecoxib as treatment of established rat brain tumors. COX-2 inhibition and immunotherapy significantly enhanced the long-term cure rate (81% survival) compared with immunotherapy alone (19% survival), and there was a significant increase in plasma IFN-gamma levels in animals treated with the combined therapy, suggesting a systemic T helper 1 immune response. COX-2 inhibition alone, however, did neither induce cure nor prolonged survival. The tumor cells were identified as the major source of COX-2 both in vivo and in vitro, and unmodified tumor cells produced prostaglandin E(2) in vitro, while the IFN-gamma expressing tumor cells secreted significantly lower levels. In conclusion, we show that immunotherapy of experimental brain tumors is greatly potentiated when combined with COX-2 inhibition. Based on our results, the clinically available drug parecoxib may be added to immunotherapy against human brain tumors. Furthermore, the discovery that IFN-gamma plasma levels can be used to determine the ongoing in vivo immune response has translational potential. PMID- 22213143 TI - Isolation and total synthesis of icumazoles and noricumazoles--antifungal antibiotics and cation-channel blockers from Sorangium cellulosum. PMID- 22213144 TI - Epithelial-mesenchymal transition and mesenchymal-epithelial transition via regulation of ZEB-1 and ZEB-2 expression in pancreatic cancer. AB - BACKGROUND AND OBJECTIES: Phenotypic plasticity of cancer cells via epithelial mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) is essential for tumor progression and metastasis. METHODS: Tissue samples were obtained from 76 pancreatic head cancers. We assessed the expression of E cadherin, vimentin, ZEB-1, and ZEB-2 by immunohistochemical and immunofluorescence staining. Next, 147 metastatic lymph nodes from 45 pancreatic cancers with low expression of E-cadherin were obtained and divided into two categories according to the maximum diameter of the metastases: 2 mm or more and less than 2 mm. RESULTS: High expressions of ZEB-1 and ZEB-2 in the primary tumors were significantly associated with repression of E-cadherin (P = 0.0007), and poorer prognosis (P = 0.0322). Forty-three (29.3%) of the 147 metastatic tumors from pancreatic cancers with low expression of E-cadherin showed high E cadherin expression. Cancer cells in the larger metastases showed high expression of E-cadherin (P = 0.0061) and low expression of ZEB-1 (P = 0.0170) and ZEB-2 (P = 0.0036) compared with those in the smaller metastases. CONCLUSIONS: In primary pancreatic tumors and metastatic lymph nodes, high and low expression of ZEB-1 and ZEB-2 was associated with mesenchymal and epithelial phenotype of cancer cells, respectively. PMID- 22213145 TI - Ars2 is overexpressed in human cholangiocarcinomas and its depletion increases PTEN and PDCD4 by decreasing microRNA-21. AB - Due to the lack of effective diagnostic tools, most patients with cholangiocarcinoma (CCA) have no chance of surgical resection. Ars2 is a protein that was reported to be important for microRNA (miR) biogenesis, and its depletion can reduce the levels of several miRs, including miR-21, which is overexpressed in CCAs. We hypothesized that Ars2 was also present in CCAs and could be an early diagnostic marker. In our experiments, Ars2, PTEN, PDCD4, and miR-21 were evaluated in 18 CCAs and paired normal tissues. ShArs2, miR-21 mimics, and Ars2 were transfected into CCA and bile duct epithelial cells either alone or together. Cell proliferation, tumorigenicity analysis and expression changes of Ars2, PTEN, PDCD4, and miR-21 were evaluated. We found that both Ars2 and miR-21 were overexpressed, with 95% sensitivity and 100% specificity, and an ROC of 0.995 in distinguishing between CCAs and paired normal tissues by qRT-PCR. PTEN and PDCD4 were reversed in immunohistochemistry, but no difference was observed using qRT-PCR. The knockdown of Ars2 in CCA cells decreased the level of miR-21, inhibited cell proliferation and prevented tumor formation in nude mice. Ars2 knockdown also led to an increase in both PTEN and PDCD4 protein levels. Both proteins decreased when the miR-21 mimic was con-transfected. However, the overexpression of Ars2 alone could not get the opposite results. Based on our data, we conclude that Ars2 is overexpressed in human CCA and may be a diagnostic marker. Ars2 depletion increases PTEN and PDCD4 protein levels via the reduction of miR-21. PMID- 22213146 TI - Coordination polymers based on [Cp*Fe(eta5-P5)]: solid-state structure and MAS NMR studies. AB - Slow diffusion reactions of the pentaphosphaferrocene [Cp*Fe(eta(5)-P(5))] (Cp*=eta(5)-C(5)Me(5) (1)) with CuX (X=Cl, Br, I) in different stoichiometric ratios and solvent mixtures result in the formation of one- and two-dimensional polymeric compounds 2-6 with molecular formula [{Cu(MU X)}{Cp*Fe(MU(3),eta(5):eta(1):eta(1)-P(5))}](n) (X=Cl (2a), I (2'c)), [{Cu(MU I)}{Cp*Fe(MU(3),eta(5):eta(1):eta(1)-P(5))}](n) (3), [{CuX}{Cp*Fe(MU(4),eta(5):eta(1):eta(1):eta(1)-P(5))}](n) (X=Cl (4a), Br (4b), I (4c), Br (4'b), I (4'c)), [{Cu(3)(MU-I)(2)(MU(3) I)}{Cp*Fe(MU(5),eta(5):eta(1):eta(1):eta(1):eta(1)-P(5))}](n) (5) and [{Cu(4)(MU X)(4)(CH(3)CN)}{Cp*Fe(MU(7),eta(5):eta(2):eta(1):eta(1):eta(1):eta(1):eta(1) P(5))}](n) (X=Cl (6a), Br (6b)), respectively. The polymeric compounds have been characterised by single-crystal X-ray diffraction analyses and, for selected examples, by magic angle spinning (MAS) NMR spectroscopy. The solid-state structures demonstrate the versatile coordination modes of the cyclo-P(5) ligand of 1, extending from two to five coordinating phosphorus atoms in either sigma or sigma-and-pi fashion. In compounds 2a, 2'c and 3, two phosphorus atoms of 1 coordinate to copper atoms in a 1,2 coordination mode (2a, 2'c) and an unprecedented 1,3 coordination mode (3) to form one-dimensional polymers. Compounds 4a-c, 4'b, 4'c and 5 represent two-dimensional coordination polymers. In compounds 4, three phosphorus atoms coordinate to copper atoms in a 1,2,4 coordination mode, whereas in 5 the cyclo-P(5) ligand binds in an unprecedented 1,2,3,4 coordination mode. The crystal structures of 6a,b display a tilted tube, in which all P atoms of the cyclo-P(5) ligand are coordinated to copper atoms in sigma- and pi-bonding modes. PMID- 22213147 TI - Mycophenolic acid augments interferon-stimulated gene expression and inhibits hepatitis C Virus infection in vitro and in vivo. AB - Mycophenolic acid (MPA) is a highly effective immunosuppressant that has broad antiviral activity against different viruses and can act in synergy with interferon-alpha (IFN-alpha) on hepatitis C virus (HCV) replication. MPA is a potent inosine monophosphate dehydrogenase (IMPDH) inhibitor but the antiviral mechanisms are less understood. The aim of this study was to investigate the inhibition of HCV infection by MPA and the molecular basis for its synergy with IFN-alpha. The role of IMPDH and interferon-stimulated genes (ISGs) was investigated in two HCV models using gain- or loss-of-function approaches. The in vivo effect of MPA treatment was studied in NOD/SCID mice engrafted with HCV replicon cells. Potent antiviral effects of MPA at clinically relevant concentrations were observed with both the subgenomic and JFH1-derived infectious HCV models. MPA treatment in mice resulted in a specific and robust inhibition of HCV replication. Ectopic expression of an MPA-resistant IMPDH2 mutant in HCV host cells completely reversed the antiproliferative effect of MPA but only partially affected the antiviral potency. However, similar to ribavirin, MPA induced expression of multiple antiviral ISGs, including interferon regulatory factor 1 (IRF1). Cotreatment of MPA with IFN-alpha resulted in additive effects on ISG expression and enhanced IFN-induced luciferase reporter activity. Knockdown of IRF1, but not IFITM3, significantly attenuated the inhibition of HCV replication by MPA. CONCLUSION: MPA exerts a potent anti-HCV effect in vitro and in mice and acts in synergy with IFN-alpha. MPA's antiviral activity partially depends on IMPDH but also involves stimulation of ISGs, providing a molecular basis for its synergy with IFN-alpha. PMID- 22213148 TI - Construction of a single polypeptide that matures and exports the lasso peptide microcin J25. AB - Roped in: The lasso peptide microcin J25 (MccJ25) is matured by two enzymes and is exported by a putative ABC transporter. We probed the function of the maturation enzymes using mutagenesis. We demonstrate that fusions of the enzymes with intervening linkers can produce MccJ25. Even a 151 kDa tripartite fusion between the ABC transporter and the two enzymes is capable of producing and exporting MccJ25. PMID- 22213149 TI - High magneto-optical activity and low optical losses in metal-dielectric Au/Co/Au SiO(2) magnetoplasmonic nanodisks. AB - Metal-dielectric Au-Co-SiO(2) magnetoplasmonic nanodisks are found to exhibit large magneto-optical activity and low optical losses. The internal architecture of the nanodisks is such that, in resonant conditions, the electromagnetic field undertakes a particular spatial distribution. This makes it possible to maximize the electromagnetic field at the magneto-optically active layers and minimize it in the other, optically lossy ones. PMID- 22213150 TI - Stereoarrays with an all-carbon quaternary center: diastereoselective desymmetrization of prochiral malonaldehydes. PMID- 22213151 TI - Time-varying view angle tilting with spiral readout gradients. AB - The conventional Fourier-transform-based spin-echo sequence with a view angle tilting gradient during data acquisition can correct the in-plane distortion induced by a chemical shift or B0 field inhomogeneity. However, when extended for 3D applications, alternate k-space sampling can be beneficial for reducing the lengthy scan time. As spiral trajectories have high k-space acquisition efficiency, we investigated the applicability of spiral trajectory on a spin-echo view angle tilting pulse sequence. Computer simulations and phantom and in vivo experiments were performed to validate the usage of spiral readout gradients in the presence of a view angle tilting gradient. The results show that as long as the readout time is comparable to Cartesian readout, the resulting images have similar quality. PMID- 22213152 TI - CD31, EDNRB and TSPAN7 are promising prognostic markers in clear-cell renal cell carcinoma revealed by genome-wide expression analyses of primary tumors and metastases. AB - Currently used clinicopathological parameters are insufficient for a reliable prediction of metastatic risk and disease-free survival (DFS) of patients with clear-cell renal cell carcinoma (ccRCC). To identify prognostic genes, the expression profiles of primary ccRCC obtained from patients with different DFS- eight synchronously, nine metachronously and seven not metastasized tumors--were determined by genome-wide expression analyses. Synchronously and metachronously metastasized primary ccRCC differed in the expression of 167 genes. Thirty-six of these genes were also differentially expressed in synchronously vs. metachronously developed pulmonary metastases analyzed in a previous study. Because of their DFS-associated deregulation that is concordant in metastases and primary ccRCC, these genes are potentially functionally involved in metastatic tumor growth and are also prognostically useful. A prognostic impact was confirmed for the genes CD31, EDNRB and TSPAN7 at the mRNA level (n=86), and for TSPAN7 at the protein level (n=106). Patients with a higher gene expression of EDNRB or TSPAN7, or with TSPAN7-positive vessels in both cores investigated on tissue microarrays had a significantly longer DFS and tumor-specific survival (TSS). Patients with a higher CD31 gene expression showed a significantly longer TSS. EDNRB was an independent prognostic marker for the DFS. CD31, EDNRB and TSPAN7 had an independent impact on the TSS. In summary, comparative analysis of primary tumors and metastases is appropriate to identify independent prognostic markers in ccRCC. Gene expression of CD31 and EDNRB, and endothelial TSPAN7 protein level are potentially useful to improve outcome prediction because of their independent prognostic impact. PMID- 22213153 TI - A double-blind, randomized, placebo-controlled, phase 2 study of maintenance enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab after first-line therapy for metastatic colorectal cancer. AB - BACKGROUND: Enzastaurin and bevacizumab have demonstrated synergistic antitumor effects and, in phase 1 studies, the combination was well tolerated. This phase 2 study assessed enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab as maintenance therapy for metastatic colorectal cancer (MCRC). METHODS: Patients with locally advanced or MCRC and stable or responding disease after completing 6 cycles of first-line chemotherapy randomly received a loading dose of enzastaurin 1125 mg, followed by 500 mg/d subsequent doses or placebo. Both arms received 5 fluorouracil/leucovorin (leucovorin 400 mg/m(2) intravenously [IV], 5 fluorouracil 400-mg/m(2) bolus, 5-fluorouracil 2400 mg/m(2) IV) plus bevacizumab 5 mg/kg IV, every 2 weeks. The primary endpoint was progression-free survival (PFS), from randomization. Overall survival (OS) and PFS were also assessed from start of first-line therapy. Enrollment was stopped, and the final analysis was conducted after 73 PFS events. RESULTS: Fifty-eight patients were randomized to enzastaurin and 59 to placebo. For the enzastaurin and placebo arms, respectively, the median cycles received were 9 and 10, and the median PFS was 5.8 and 8.1 months (hazard ratio [HR], 1.35; 95% confidence interval [CI], 0.84 2.16; P = .896). Median OS was not calculable because of high censoring (77.6% enzastaurin; 91.5% placebo). The median PFS from start of first-line therapy was 8.9 months for enzastaurin and 11.3 months for placebo (HR, 1.39; 95% CI, 0.86 2.23; P = .913). More enzastaurin patients developed thrombosis or embolism compared with placebo (15.8% and 1.7%; P = .008). One possibly enzastaurin related death occurred because of arrhythmia. CONCLUSIONS: Enzastaurin combined with bevacizumab-based therapy is tolerable, but does not improve PFS during maintenance therapy in patients with MCRC compared with bevacizumab-based therapy alone. PMID- 22213154 TI - Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus specific database. AB - Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal dominant disorder characterized by ocular and renal malformations. Mutations in the paired-box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl/PAX2. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed. PMID- 22213155 TI - Sunitinib inhibits the phosphorylation of platelet-derived growth factor receptor beta in the skin of mice with scleroderma-like features and prevents the development of the disease. AB - OBJECTIVE: Systemic sclerosis (SSc) is characterized by fibrosis of the skin and visceral organs, vascular dysfunction, and immunologic dysregulation. Platelet derived growth factors (PDGFs) have been implicated in the development of fibrosis and dysregulation of vascular function. We investigated the effects of sunitinib and sorafenib, two tyrosine kinase inhibitors that interfere with PDGF signaling, in a mouse model of diffuse SSc. METHODS: SSc was induced in BALB/c mice by subcutaneous injections of HOCl daily for 6 weeks. Mice were randomized to treatment with sunitinib, sorafenib, or vehicle. The levels of native and phosphorylated PDGF receptor beta (PDGFRbeta) and vascular endothelial growth factor receptor (VEGFR) in the skin were assessed by Western blot and immunohistochemical analyses. Skin and lung fibrosis were evaluated by histologic and biochemical methods. Autoantibodies were detected by enzyme-linked immunosorbent assay, and spleen cell populations were analyzed by flow cytometry. RESULTS: Phosphorylation of PDGFRbeta and VEGFR was higher in fibrotic skin from HOCl-injected mice with SSc than from PBS-injected mice. Injections of HOCl induced cutaneous and lung fibrosis, increased the proliferation rate of fibroblasts in areas of fibrotic skin, increased splenic B cell and T cell counts, and increased anti-DNA topoisomerase I autoantibody levels in BALB/c mice. All of these features were reduced by sunitinib but not by sorafenib. Sunitinib significantly reduced the phosphorylation of both PDGF and VEGF receptors. CONCLUSION: Inhibition of the hyperactivated PDGF and VEGF pathways by sunitinib prevented the development of fibrosis in HOCl-induced murine SSc and may represent a new SSc treatment for testing in clinical trials. PMID- 22213156 TI - Immunostimulation of sugar cane extract on neutrophils to Salmonella typhimurium infection in mice. AB - The aim of this study was to evaluate the immunomodulatory effects of sugar cane extract (SCE) on the biological activities of neutrophils in mice. Six-week-old BALB/c mice were fed 1250 mg/kg of SCE once. The generation, migration and biological functions of neutrophils and the survival rates of the mice in response to Salmonella typhimurium infection were evaluated. The results show that the numbers of both bone marrow cells and neutrophils were significantly increased in response to SCE administration (p < 0.05) compared with controls. The migration, phagocytosis and H2O2 generation of neutrophils were all significantly enhanced in SCE-treated mice (p < 0.05). After challenge with S. typhimurium (lethal dose, 50% (LD50), SCE-treated mice had a 19.2% higher survival rate and milder hepatic lesions than the controls. Additionally, fewer invasive bacteria were recovered from the spleens of SCE-treated mice. In conclusion, our results suggest that SCE has a positive regulatory effect on the biological function of mouse neutrophils that may increase host resistance against bacterial infections. PMID- 22213157 TI - Do persons with diabetes benefit from combination statin and fibrate therapy? AB - Combination fibrate-statin therapy favorably modifies the atherogenic, triglyceride-rich lipoprotein environment, common to insulin resistance, diabetes, and higher cardiovascular disease (CVD) risk. Five major fibrate randomized clinical trial (RCT) results (HHS, VA-HIT, BIP, FIELD, and ACCORD Lipid) demonstrated four consistent features: 1) the highest CVD event rates occurred in the placebo subgroups possessing atherogenic "moderate" dyslipidemia (triglycerides, > 200 mg/dL, and low high-density lipoprotein cholesterol [HDL C], < 35-40 mg/dL); 2) with this subgroup having the greatest "hypothesis generating" fibrate benefit (27% to 65% relative risk reduction, variable significance [P values ranging 0.057-0.005]); 3) those subgroups without moderate dyslipidemia had relatively lower CVD event rates; and 4) little or no benefit from fibrates. The ACCORD-Lipid results, specifically, demonstrated benefits against the background of statin therapy. Three independent meta-analyses combining the five RCTs, which provided a large sample of moderate dyslipidemia participants (i.e., 2401 on fibrates; 2270 on placebo), demonstrated a fibrate benefit with significant heterogeneity of effect across lipid subgroups (P = 0.0002). The fibrate benefit was observed in "low HDL-C only" patients, reducing CVD events by 17% (P < 0.001) or "hypertriglyceridemia-only" patients, reducing CVD events by 28% (P < 0.001), or "atherogenic (moderate) dyslipidemia" phenotype, reducing CVD events by 30% (P < 0.0001), compared with a nonsignificant 6% reduction (P = 0.13) in nonatherogenic dyslipidemia patients. Fibrate RCTs in patients with diabetes (FIELD and ACCORD-Lipid) also demonstrated significant microvascular (ie, retinopathy and nephropathy) outcome benefit possibly independent of lipid levels. PMID- 22213158 TI - Nuclear fusion-independent smooth muscle differentiation of human adipose-derived stem cells induced by a smooth muscle environment. AB - Human adipose-derived stem cells hASC have been isolated and were shown to have multilineage differentiation capacity. Although both plasticity and cell fusion have been suggested as mechanisms for cell differentiation in vivo, the effect of the local in vivo environment on the differentiation of adipose-derived stem cells has not been evaluated. We previously reported the in vitro capacity of smooth muscle differentiation of these cells. In this study, we evaluate the effect of an in vivo smooth muscle environment in the differentiation of hASC. We studied this by two experimental designs: (a) in vivo evaluation of smooth muscle differentiation of hASC injected into a smooth muscle environment and (b) in vitro evaluation of smooth muscle differentiation capacity of hASC exposed to bladder smooth muscle cells. Our results indicate a time-dependent differentiation of hASC into mature smooth muscle cells when these cells are injected into the smooth musculature of the urinary bladder. Similar findings were seen when the cells were cocultured in vitro with primary bladder smooth muscle cells. Chromosomal analysis demonstrated that microenvironment cues rather than nuclear fusion are responsible for this differentiation. We conclude that cell plasticity is present in hASCs, and their differentiation is accomplished in the absence of nuclear fusion. PMID- 22213160 TI - Mode change in the self-motion of a benzoquinone disk coupled with a NADPH system. AB - The self-motion of a benzoquinone (BQ) disk on NADPH was investigated as the coupling of an autonomous motor and an enzyme reaction. In the absence of the enzyme reaction, features of motion changed depending on the concentration of NADPH, that is, continuous motion-> intermittent oscillatory motion-> no motion. When the reverse reaction from NADP(+) to NADPH was introduced into the system with the addition of an enzyme reaction, continuous motion changed to intermittent oscillatory motion with small amplitude. The mechanism of this mode change is discussed in relation to the surface tension as a driving force and the time course of UV spectra as a window to the progress of the reaction. Characteristic features of the mode change were qualitatively reproduced by a numerical calculation. PMID- 22213161 TI - Design of transparent anodes for resonant cavity enhanced light harvesting in organic solar cells. PMID- 22213159 TI - Cediranib inhibits both the intraosseous growth of PDGF D-positive prostate cancer cells and the associated bone reaction. AB - BACKGROUND: The major cause of death in prostate cancer (PCa) cases is due to distant metastatic lesions, with the bone being the most prevalent site for secondary colonization. Utilization of small molecule inhibitors to treat bone metastatic PCa have had limited success either as monotherapies or in combination with other chemotherapeutics due to intolerable toxicities. In the current study, we developed a clinically relevant in vivo intraosseous tumor model overexpressing the platelet-derived growth factor D (PDGF D) to test the efficacy of a newly characterized vascular endothelial growth factor receptor (VEGFR)/PDGFR inhibitor, cediranib (also called AZD2171). METHODS: An intratibial injection model was established utilizing DU145 cells with or without increased PDGF D expression. Tumor-bearing mice were treated by daily gavage administration of cediranib and/or weekly i.p. injection of docetaxel for 7 weeks. Tibiae were monitored by in vivo/ex vivo X-rays and histomorphometry analysis was performed to estimate tumor volume and tumor-associated trabecular bone growth. RESULTS: Cediranib reduced intraosseous growth of prostate tumors as well as tumor associated bone responses. When compared to the standard chemotherapeutic agent docetaxel, cediranib exhibited a stronger inhibition of tumor-associated bone response. The efficacy of cediranib was further enhanced when the drug was co administered with docetaxel. Importantly, the therapeutic benefits of cediranib and docetaxel are more prominent in intraosseous prostate tumors overexpressing PDGF D. CONCLUSION: These novel findings support the utilization of cediranib, either alone or in combination with docetaxel, to treat bone metastatic PCa exhibiting PDGF D expression. PMID- 22213162 TI - Reversibly switching the function of a surface between attacking and defending against bacteria. AB - Attack or defend! A smart polymer surface has two reversibly switchable equilibrium states, a cationic N,N-dimethyl-2-morpholinone (CB-Ring) and a zwitterionic carboxy betaine (CB-OH). CB-Ring will kill bacteria upon contact under dry conditions, whereas CB-OH will release the previously attached and dead bacteria and further resist adhesion of bacteria under wet conditions. PMID- 22213163 TI - A(2a) adenosine receptor mediates HepG2 cell apoptosis by downregulating Bcl-X(L) expression and upregulating Bid expression. AB - Extracellular adenosine induced apoptosis in HepG2 cells, a human hepatoma cell line, by tuning apoptosis-mediator gene transcription. The present study aimed at identifying the responsible adenosine receptor and clarifying the signaling pathway underlying adenosine-induced HepG2 cell apoptosis. Adenosine and CGS21680, an A(2a) adenosine receptor agonist, induced HepG2 cell apoptosis, and the effect was inhibited by DMPX, an A(2a) adenosine receptor antagonist, or by knocking-down A(2a) adenosine receptors. Adenosine reduced expression of Bcl-X(L) mRNA and protein but otherwise increased expression of the Bid mRNA and protein in HepG2 cells, and those effects were also prevented by knocking-down A(2a) adenosine receptors. Adenosine caused disruption of mitochondrial membrane potentials and stimulated cytochrome c efflux from the mitochondria in HepG2 cells. Adenosine activated caspases-3 and -9 in HepG2 cells, which was significantly inhibited by knocking-down A(2a) adenosine receptors. The results of the present study indicate that extracellular adenosine downregulates Bcl-X(L) expression and upregulates Bid expression, thereby disrupting mitochondrial membrane potentials to allow cytochrome c efflux from the mitochondria, and then causing activation of caspase-9 and the effector caspase-3, as mediated via A(2a) adenosine receptors. PMID- 22213165 TI - N-bound primary nitramines based on 1,5-diaminotetrazole. AB - 1,5-Diaminotetrazole can be nitrated under very mild conditions by using nitronium tetrafluoroborate to result in 5-amino-1-nitriminotetrazole (1) in good yields. The same reaction can be performed with 1-amino-5-amino-4-methyltetrazole to yield 5-amino-4-methyl-1-nitriminotetrazole (2). Both compounds have been isolated and completely characterized by using vibrational spectroscopy, mass spectrometry, and differential scanning calorimetry. Additionally, X-ray diffraction measurements of the neutral compounds could be obtained; they indicated the structure of both compounds to be zwitterionic. Compounds 1 and 2 exhibit extremely high sensitivities to impact and friction and high positive heats of formation of 496 (1) and 453 kJ mol(-1) (2), respectively. Additionally, high-nitrogen-containing salts of 1 have been synthesized by metathesis reactions of silver 5-amino-1-nitriminotetrazolate with the corresponding halides so as to investigate the changes in sensitivity and thermal stability. All ionic compounds have been synthesized in good yields and characterized by means of vibrational and multinuclear NMR spectroscopy as well as X-ray diffraction measurements. Thermal stabilities have been evaluated by differential scanning calorimetry, whereas sensitivity measurements have been performed according to standardized Bundesanstalt fur Materialforschung und -prufung (BAM) tests. Theoretical calculations have been performed to investigate the heats of formation as well as the performance characteristics of the compounds. PMID- 22213164 TI - Multifunctions of MelB, a fungal tyrosinase from Aspergillus oryzae. AB - The pro form of melB tyrosinase from the melB gene of Aspergillus oryzae was over produced from E. coli and formed a homodimer that exhibited the spectral features of met-tyrosinase. In the presence of NH(2)OH (reductant), the proenzyme bound dioxygen to give a stable (MU-eta(2):eta(2) -peroxo)dicopper(II) species (oxy form), thus indicating that the pro form tyrosinase can function as an oxygen carrier or storage protein like hemocyanin. The pro form tyrosinase itself showed no catalytic activity toward external substrates, but proteolytic digestion with trypsin activated it to induce tyrosinase activity. Mass spectroscopy analyses, mutagenesis experiments, and colorimetry assays have demonstrated that the tryptic digestion induced cleavage of the C-terminal domain (Glu458-Ala616), although the dimeric structure of the enzyme was retained. The structural changes induced by proteolytic digestion might open the entrance to the enzyme active site for substrate incorporation. PMID- 22213166 TI - In vivo degradation and new bone formation of calcium phosphate cement-gelatin powder composite related to macroporosity after in situ gelatin degradation. AB - Calcium phosphate cement (CPC) is reported to have excellent biocompatibility and osteoconductivity. However, its biodegradability must be improved to promote bone regeneration. We have mixed gelatin powder with CPC to create a composite containing macropores with interconnectivity. Sixty rabbits were grouped as follows: 85 wt% CPC to 15 wt% gelatin powder (C15), 90 wt% CPC to 10 wt% gelatin powder (C10), 100 wt% CPC (C0) as control group and Sham group. Trabecular bone defects of distal femurs were made and implanted with the composites. The femurs were harvested for histomorphometry at 4, 12, 24 weeks after implantation, and mechanical testing at 3 days, 1, 4, 12, 24 weeks. Compared with C0, X-ray and micro-CT results of the composites revealed a progressive increase in the amount of CPC-gelatin powder composite which was replaced by trabeculae. New bone area increased from 3.8 to 18% in C10, and 4.2 to 22% in C15, residual composite area decreased from 65 to 31% in C10, and 70 to 20% in C15. The compressive strength of C15 was 9.2 MPa, which was inferior to 14.6 MPa (normal cancellous bone), but was 27.4 MPa in C10 at 1 week. Further improvement of this composite may make a suitable scaffold for bone regeneration. PMID- 22213167 TI - Integrating water-soluble graphene into porphyrin nanohybrids. PMID- 22213168 TI - Phytosterol and cholesterol precursor levels indicate increased cholesterol excretion and biosynthesis in gallstone disease. AB - In hepatocytes and enterocytes sterol uptake and secretion is mediated by Niemann Pick C1-like 1 (NPC1L1) and ATP-binding cassette (ABC)G5/8 proteins, respectively. Whereas serum levels of phytosterols represent surrogate markers for intestinal cholesterol absorption, cholesterol precursors reflect cholesterol biosynthesis. Here we compare serum and biliary sterol levels in ethnically different populations of patients with gallstone disease (GSD) and stone-free controls to identify differences in cholesterol transport and synthesis between these groups. In this case-control study four cohorts were analyzed: 112 German patients with GSD and 152 controls; two distinct Chilean ethnic groups: Hispanics (100 GSD, 100 controls), and Amerindians (20 GSD, 20 controls); additionally an 8 year follow-up of 70 Hispanics was performed. Serum sterols were measured by gas chromatography / mass spectrometry. Gallbladder bile sterol levels were analyzed in cholesterol GSD and controls. Common ABCG5/8 variants were genotyped. Comparison of serum sterols showed lower levels of phytosterols and higher levels of cholesterol precursors in GSD patients than in controls. The ratios of phytosterols to cholesterol precursors were lower in GSD patients, whereas biliary phytosterol and cholesterol concentrations were elevated as compared with controls. In the follow-up study, serum phytosterol levels were significantly lower even before GSD was detectable by ultrasound. An ethnic gradient in the ratios of phytosterols to cholesterol precursors was apparent (Germans > Hispanics > Amerindians). ABCG5/8 variants did not fully explain the sterol metabolic trait of GSD in any of the cohorts. CONCLUSION: Individuals predisposed to GSD display increased biliary output of cholesterol in the setting of relatively low intestinal cholesterol absorption, indicating enhanced whole-body sterol clearance. This metabolic trait precedes gallstone formation and is a feature of ethnic groups at higher risk of cholesterol GSD. PMID- 22213169 TI - Respiratory self-navigation for whole-heart bright-blood coronary MRI: methods for robust isolation and automatic segmentation of the blood pool. AB - Free-breathing three-dimensional whole-heart coronary MRI is a noninvasive alternative to X-ray coronary angiography. However, the existing navigator-gated approaches do not meet the requirements of clinical practice, as they perform with suboptimal accuracy and require prolonged acquisition times. Self-navigated techniques, applied to bright-blood imaging sequences, promise to detect the position of the blood pool directly in the readouts acquired for imaging. Hence, the respiratory displacement of the heart can be calculated and used for motion correction with high accuracy and 100% scan efficiency. However, additional bright signal from the chest wall, spine, arms, and liver can render the isolation of the blood pool impossible. In this work, an innovative method based on a targeted combination of the output signals of an anterior phased-array surface coil is implemented to efficiently suppress such additional bright signal. Furthermore, an algorithm for the automatic segmentation of the blood pool is proposed. Robust self-navigation is achieved by cross-correlation. These improvements were integrated into a three-dimensional radial whole-heart coronary MRI sequence and were compared with navigator-gated imaging in vivo. Self navigation was successful in all cases and the acquisition time was reduced up to 63%. Equivalent or slightly superior image quality, vessel length, and sharpness were achieved. PMID- 22213170 TI - Black currant phytoconstituents exert chemoprevention of diethylnitrosamine initiated hepatocarcinogenesis by suppression of the inflammatory response. AB - Black currant fruits containing high amounts of anthocyanins are known to possess potent antioxidant and anti-inflammatory properties. We have previously reported that anthocyanin-rich black currant skin extract (BCSE) inhibits diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats although the underlying mechanisms are not fully understood. Our present study investigates the anti-inflammatory mechanisms of BCSE during DENA rat liver carcinogenesis. Dietary BCSE (100 or 500 mg/kg) treatment for 22 wk afforded a striking inhibition of DENA-induced hepatic gamma-glutamyl transpeptidase-positive preneoplastic foci in a dose-responsive fashion. There was a significant increase in hepatic expression of heat shock proteins (HSP70 and HSP90), cyclooxygenase-2, and nuclear factor-kappaB (NF-kappaB) in DENA-exposed rat livers. Dietary BCSE dose-dependently abrogated all these elevated inflammatory markers. The possible cardiotoxicity of BCSE was assessed by monitoring cardiac functions using transthoracic echocardiography. BCSE-mediated anti-inflammatory effects during rat liver carcinogenesis have been achieved without any cardiotoxicity. Our results provide convincing evidence, for the very first time, that suppression of the inflammatory cascade through modulation of the NF-kappaB signaling pathway could be implicated, at least in part, in the chemopreventive effects of black currant bioactive phytoconstituents against experimental hepatocarcinogenesis. These results coupled with an excellent safety profile of BCSE support the development of black currant phytochemicals for the chemoprevention of inflammation-driven hepatocellular cancer. PMID- 22213171 TI - Primary excision compared with re-excision of extremity soft tissue sarcomas--is anything new? AB - BACKGROUND: Soft tissue sarcomas (STS) are rare and are commonly excised outside of a sarcoma center without appropriate preoperative planning. Studies have shown varying results in survival and outcome when comparing patients undergoing re excision to patients undergoing a single, planned excision. METHODS: This retrospective study evaluated 278 patients treated for STS of the extremities between January 2000 and July 2006. One hundred seventy-two patients had a primary excision while 106 patients had a sarcoma re-excised. Survival curves for disease-free survival, metastasis-free survival, and local recurrence-free survival were calculated using competing risk analysis for both groups. RESULTS: After adjusting for high-risk variables, our results indicate that re-excision is a proxy for smaller, low-grade tumors which tend to have a better survival profile. Death due to sarcoma and distant metastases were correlated with high grade and large tumors. The presence of positive microscopic margins was the strongest predictor of local recurrence (P < 0.05). CONCLUSIONS: There were no differences in death, metastases, or local recurrence between the two groups after adjusting for high-risk variables. Survival advantages previously reported with STS re-excision serve as proxy for tumors that have a better survival profile. PMID- 22213173 TI - Congenital and acquired neutropenias consensus guidelines on therapy and follow up in childhood from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica). AB - The management of congenital and acquired neutropenias presents some differences according to the type of the disease. Treatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is not standardized and scanty data are available on the best schedule to apply. The frequency and the type of longitudinal controls in patients affected with neutropenias are not usually discussed in the literature. The Neutropenia Committee of the Marrow Failure Syndrome Group (MFSG) of the Associazione Italiana di Emato-Oncologia Pediatrica (AIEOP) elaborated this document following design and methodology formerly approved by the AIEOP board. The panel of experts reviewed the literature on the topic and participated in a conference producing a document that includes recommendations on neutropenia treatment and timing of follow-up. PMID- 22213172 TI - The influence of prediagnostic demographic and lifestyle factors on esophageal squamous cell carcinoma survival. AB - Demographic and lifestyle factors, in particular tobacco smoking and alcohol, are well established causes of esophageal squamous cell carcinoma (ESCC); however, little is known about the effect of these factors on survival. We included all 301 patients with incident ESCC, recruited into a population-based case-control study of esophageal cancer in Australia. Detailed information about demographic and lifestyle factors was obtained at diagnosis, and deaths were identified using the National Death Index. Median follow-up for all-cause mortality was 6.4 years. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were calculated from Cox proportional hazards models, adjusted for age, sex, pretreatment AJCC tumor stage, treatment and presence of comorbidities. Two hundred and thirteen patients (71%) died during follow-up. High lifetime alcohol consumption was independently associated with poor survival. Relative to life-long nondrinkers and those consuming<1 drink/week, the HRs for those with average consumption of 7-20 drinks/week or >=21 drinks/week were 2.21 (95% CI=1.27-3.84) and 2.08 (95% CI=1.18-3.69), respectively. There was a suggestion of worse survival among current smokers (HR=1.42, 95% CI=0.89-2.28); however, the risk of early death was greatest among current smokers who reported regularly (>=7 drinks/week) consuming alcohol (HR=3.84, 95% CI=2.02-7.32). Other lifestyle factors putatively associated with risk of developing ESCC were not associated with survival. In addition to increasing disease risk, heavy alcohol consumption may be independently associated with worse survival among patients with ESCC. Future clinical follow-up studies should consider alcohol as a potential prognosticator, in addition to known clinicopathologic factors. PMID- 22213174 TI - Systematic screening and characterization of the major bioactive components of Poria cocos and their metabolites in rats by LC-ESI-MS(n). AB - Poria cocos is a well-known medicinal plant widely used in China and other East Asian countries owing to its various therapeutic effects. However, the bioactive constituents responsible for the pharmacological effects of Poria cocos and their metabolites in vivo are still unclear to date. The aim of the present study was to develop a practical method based on the combined use of the liquid chromatography coupled with electrospray ionization multistage tandem mass spectrometry (LC-ESI-MS(n) ) for the comprehensive and systematic separation and characterization of the bioactive constituents of Poria cocos extract and their metabolites in rats. Based on the proposed strategy, a total of 34 compounds were characterized from the extract of Poria cocos. Among them, eight were unambiguously identified by comparing their retention times and mass spectra with those of reference standards, and 26 were tentatively identified on the basis of their MS(n) fragmentation behaviors and molecular weight information from literatures. In vivo, seven compounds were successfully detected in rat urine whereas one was found in rat plasma. This study proposed a series of potential bioactive components and provided helpful chemical information for further research on the action mechanism of traditional Chinese medicine. PMID- 22213175 TI - The role of DNA methyltransferase 3b in esophageal squamous cell carcinoma. AB - BACKGROUND: The identification of potential tumor markers can improve therapeutic planning and patient management. The objective of this study was to highlight the role of DNA methyltransferase 3b (DNMT3b) in esophageal squamous cell carcinoma (SCC). METHODS: One hundred seventy-three esophageal SCC samples were analyzed using immunohistochemical staining to correlate the expression of DNMT3b with clinical outcome. Furthermore, a human esophageal SCC cell line, CE81T, was selected for cellular and animal experiments to investigate changes in tumor behavior and treatment response after the manipulation of DNMT3b expression. RESULTS: The incidence of nuclear DNMT3b immunoreactivity in esophageal cancer specimens was significantly higher than in nonmalignant epithelium, and this incidence was linked positively to developing distant metastasis (56% in localized disease vs 80% in distant metastasis; P = .002). Furthermore, increased expression of DNMT3b was linked significantly to lower treatment response rates (P = .002) and reduced survival rates (P = .000). Inhibition of DNMT3b expression resulted in slower cellular proliferation, increased cell death, a less invasive capacity, and less epithelial-mesenchymal-transition changes. Moreover, DNMT3b silencing vectors sensitized esophageal cancer cells to irradiation and cisplatin treatment. The current results also indicated that constitutional activation of signal transducer and activator of transcription 3 (STAT3) signaling associated with inhibited expression of suppressor of cytokine signaling 3 (SOCS3) may be the mechanism underlying more aggressive tumor growth in DNMT3b-positive esophageal cancer. CONCLUSIONS: DNMT3b was linked significantly to a poor prognosis for patients with esophageal cancer. Moreover, the current results indicated that targeting this enzyme may be a promising strategy for treating esophageal cancer, as evidenced by inhibited aggressive tumor behavior and treatment resistance. PMID- 22213177 TI - A single water molecule trapped inside hydrophobic C60. PMID- 22213176 TI - Magnetization transfer MRI in pancreatic cancer xenograft models. AB - Magnetization transfer magnetic resonance imaging measurements were performed in three pancreatic ductal adenocarcinoma mouse xenograft models. For each of 28 pancreatic ductal adenocarcinoma xenografts, MT ratios (MTRs) were calculated and compared to histologic fibrosis levels from reference standard trichrome staining. MTR was found to be significantly higher in tumors grown using BxPC-3 cell line (39.4+/-5.1, mean+/-SD) compared to the MTR for the tumors grown from Panc-1 (32.4+/-2.8) and Capan-1 (27.3+/-2.9) cell lines (P<0.05 for each comparison). Histologic measurements showed a similar trend with BxPC-3 tumors demonstrating significantly higher fibrosis levels (percentage of fibrotic tissue area, 6.48+/-2.59) when compared to Panc-1 (3.54+/-2.18) and Capan-1 (2.07+/ 1.60) tumors. MTR measurements were well correlated to quantitative fibrosis levels (r=0.69, P=0.01). Results indicated that MTR measurements offer the potential to serve as a valuable in vivo biomarker of desmoplasia in pancreatic ductal adenocarcinoma. PMID- 22213178 TI - The filler content of the dental composite resins and their influence on different properties. AB - The purpose of this study was to compare the inorganic content and morphology of one nanofilled and one nanohybrid composite with one universal microhybrid composite. The Vickers hardness, degree of conversion and scanning electron microscope of the materials light-cured using LED unit were also investigated. One nanofilled (FiltekTM Supreme XT), one nanohybrid (TPH(r)(3)) and one universal microhybrid (FiltekTM Z-250) composite resins at color A(2) were used in this study. The samples were made in a metallic mould (4 mm in diameter and 2 mm in thickness). Their filler weight content was measured by thermogravimetric analysis (TG). The morphology of the filler particles was determined using scanning electron microscope equipped with a field emission gun (SEM-FEG). Vickers hardness and degree of conversion using FT-IR spectroscopy were measured. FiltekTM Z-250 (microhybrid) composite resin shows higher degree of conversion and hardness than those of FiltekTM Supreme XT (nanofilled) and TPH(r)(3) (nanohybrid) composites, respectively. The TPH(3)(r) (nanohybrid) composite exhibits by far the lowest mechanical property. Nanofilled composite resins show mechanical properties at least as good as those of universal hybrids and could thus be used for the same clinical indications as well as for anterior restorations due to their high aesthetic properties. PMID- 22213179 TI - Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis. AB - OBJECTIVE: The intestinal inflammation observed in patients with ankylosing spondylitis (AS) is characterized by an overexpression of interleukin-23 (IL-23). IL-23 is known to regulate IL-22 production through lamina propria NKp44+ natural killer (NK) cells, which are thought to be involved in protective mucosal mechanisms. This study was undertaken to evaluate the frequency of NKp44+ NK cells and the expression of IL-22 in the ileum of AS patients. METHODS: Tissue NKp44+ NK cells, NKp46+ NK cells, and IL-22-producing cells were analyzed by flow cytometry. Quantitative gene expression analysis of IL-22, IL-23, IL-17, STAT-3, and mucin 1 (MUC-1) was performed by reverse transcriptase-polymerase chain reaction on ileal samples from 15 patients with AS, 15 patients with Crohn's disease (CD), and 15 healthy controls. NKp44, pSTAT-3, and IL-22 expression was analyzed by immunohistochemistry. RESULTS: The frequency of NKp44+ but not NKp46+ NK cells was increased in the inflamed ileum of AS patients compared to CD patients and controls. The frequency of NKp46+ NK cells was significantly increased only in CD patients. Among CD4+ lymphocytes and NKp44+ NK cell subsets, the latter were the major source of IL-22 on lamina propria mononuclear cells from AS patients. Significant up-regulation of IL-22, IL-23p19, MUC-1, and STAT-3 transcripts in the terminal ileum of patients with AS was observed. Immunohistochemical analysis confirmed the increased IL-22 and pSTAT-3 expression in inflamed mucosa from AS and CD patients. CONCLUSION: Our findings indicate that overexpression of IL-22, together with an increased number of IL-22 producing NKp44+ NK cells, occurs in the gut of AS patients, where it appears to play a tissue-protective role. PMID- 22213180 TI - Quantification of the effect of osteolytic metastases on bone strain within whole vertebrae using image registration. AB - The vertebral column is the most frequent site of metastatic involvement of the skeleton with up to 1/3 of all cancer patients developing spinal metastases. Longer survival times for patients, particularly secondary to breast cancer, have increased the need for better understanding the impact of skeletal metastases on structural stability. This study aims to apply image registration to calculate strain distributions in metastatically involved rodent vertebrae utilizing uCT imaging. Osteolytic vertebral lesions were developed in five rnu/rnu rats 2-3 weeks post intracardiac injection with MT-1 human breast cancer cells. An image registration algorithm was used to calculate and compare strain fields due to axial compressive loading in metastatically involved and control vertebrae. Tumor bearing vertebrae had greatly increased compressive strains, double the magnitude of strain compared to control vertebrae (p=0.01). Qualitatively strain concentrated within the growth plates in both tumor bearing and control vertebrae. Most interesting was the presence of strain concentrations at the dorsal wall in metastatically involved vertebrae, suggesting structural instability. Strain distributions, quantified by image registration were consistent with known consequences of lytic involvement. Metastatically involved vertebrae had greater strain magnitude than control vertebrae. Strain concentrations at the dorsal wall in only the metastatic vertebrae, were consistent with higher incidence of burst fracture secondary to this pathology. Future use of image registration of whole vertebrae will allow focused examination of the efficacy of targeted and systemic treatments in reducing strains and the related risk of fracture in pathologic bones under simple and complex loading. PMID- 22213181 TI - Effect of 17beta-estradiol and flavonoids on the regulation of expression of newly identified oestrogen responsive genes in a rat raphe nuclei-derived cell line. AB - Due to the health risks attributed to perimenopausal hormone therapy, phytoestrogens such as flavonoids are receiving widespread attention to help alleviate menopausal symptoms, including hormone-driven mood disorders. Based on our previous reporter gene study regarding their transactivational activity in raphe nuclei cells from a brain region involved in regulation of mood disturbances, we herein study their effects on the regulation of expression of 17beta-estradiol (E2)-regulated genes. DNA microarray was used to globally assess E2-induced gene expression in RNDA cells, a rat raphe nuclei-derived cellular model expressing oestrogen receptor beta. Out of 212 regulated genes, six were selected for verification and as endpoints for the effect of flavonoids on the regulation of mRNA expression in proliferating as well as differentiating RNDA cells. Under proliferative conditions, E2 up-regulated mRNA expression of Cml-5, Sox-18 and Krt-19. Similar effects were observed in response to 8 prenylnaringenin (8-PN), genistein (GEN), daidzein (DAI) and equol (EQ). In line with E2, mRNA expression of Nefm and Zdhhc-2 was down-regulated following 8-PN, GEN, DAI, EQ and naringenin treatment. No regulation was observed on Slc6a4 mRNA expression in response to E2 or the flavonoids in proliferating RNDA cells. When cells were shifted to conditions promoting differentiation, changes in cell morphology, in mRNA expression levels and in responsiveness towards E2 and the tested flavonoids were noticed. These expression studies additionally highlighted some of the genes as markers for RNDA cellular differentiation. RNDA cells should prove useful to elucidate molecular and cellular mechanisms of exogenous oestrogen receptor ligands with neural cell populations. PMID- 22213182 TI - Lanthanum chloride bidirectionally influences calcification in bovine vascular smooth muscle cells. AB - Vascular calcification (VC) is frequent prevalence in patients with chronic kidney disease (CKD) and atherosclerosis. Lanthanum carbonate is used as an orally administered phosphate-binding agent to reduce the gastrointestinal absorption of phosphate and ameliorate VC in advanced CKD. In this study, we used bovine vascular smooth muscle cells as a model VC in vitro and studied the effects of lanthanum chloride on calcium deposition. Exposure of cells to LaCl(3) at the concentration of 0.1 uM suppressed the beta-glycerophosphate-induced alkaline phosphatase activity and calcium deposition. Furthermore, LaCl(3) upregulated the beta-glycerophosphate-suppressed expression of calcium-sensing receptor. In contrast to the inhibitory effect of LaCl(3) on calcium deposition, higher level lanthanum (50 uM) was found to promote immediately precipitation of calcium phosphate in cell culture medium. At this concentration, LaCl(3) was found to induce cell apoptosis which involves caspases-9 and -3. These data indicate that the promotory effect of LaCl(3) on calcium deposition is likely mediated by induction of apoptosis. Our in vitro findings do suggest that, in the context of raised lanthanum, greater attention should be paid to potential toxic effects associated to the use of lanthanide-based drugs. PMID- 22213183 TI - Implantation site and lesion topology determine efficacy of a human neural stem cell line in a rat model of chronic stroke. AB - Stroke remains one of the most promising targets for cell therapy. Thorough preclinical efficacy testing of human neural stem cell (hNSC) lines in a rat model of stroke (transient middle cerebral artery occlusion) is, however, required for translation into a clinical setting. Magnetic resonance imaging (MRI) here confirmed stroke damage and allowed the targeted injection of 450,000 hNSCs (CTX0E03) into peri-infarct tissue, rather than the lesion cyst. Intraparenchymal cell implants improved sensorimotor dysfunctions (bilateral asymmetry test) and motor deficits (footfault test and rotameter). Importantly, analyses based on lesion topology (striatal vs. striatal + cortical damage) revealed a more significant improvement in animals with a stroke confined to the striatum. However, no improvement in learning and memory (water maze) was evident. An intracerebroventricular injection of cells did not result in any improvement. MRI-based lesion, striatal and cortical volumes were unchanged in treated animals compared to those with stroke that received an intraparenchymal injection of suspension vehicle. Grafted cells only survived after intraparenchymal injection with a striatal + cortical topology resulting in better graft survival (16,026 cells) than in animals with smaller striatal lesions (2,374 cells). Almost 20% of cells differentiated into glial fibrillary acidic protein+ astrocytes, but <2% turned into FOX3+ neurons. These results indicate that CTX0E03 implants robustly recover behavioral dysfunction over a 3 month time frame and that this effect is specific to their site of implantation. Lesion topology is potentially an important factor in the recovery, with a stroke confined to the striatum showing a better outcome compared to a larger area of damage. PMID- 22213185 TI - Spontaneous ionization of N-alkylphenothiazine molecules adsorbed in channel-type zeolites: effects of alkyl chain length and confinement on electron transfer. AB - The mere mixing of N-alkylphenothiazines with three channel-type acid zeolites with various structures (ferrierite, H-MFI, and mordenite) induces the spontaneous ionization of the heterocyclic molecule in high yield upon adsorption. The diffuse reflectance UV-visible absorption and Raman scattering spectra show that the accessibility of the highly polarizing acid sites is not indispensable to induce the spontaneous ionization process. Due to their particularly low ionization potential values (6.7 eV), the adsorption of the molecules on the external surface or in the inner volume is the key parameter to generate the radical cation. However, the ionization yield and charge stabilization are intimately correlated to the possibility of the zeolites accommodating molecules inside their channels. Moreover, the higher electrostatic field gradient induced by high confinement is required to favor the second ionization and dication formation. The alkyl chain length plays a decisive role by either slowing down the diffusion process or blocking the molecule at the pore entry. Therefore, the efficiency of the ionization process that depends on the number of adsorbed molecules decreases significantly from phenothiazine to the N alkylphenothiazines. The spectral data demonstrate that deformation of the alkyl group is necessary to allow the diffusion of the molecules into the channels. PMID- 22213186 TI - Fine-tuning conformational motion of a self-assembled metal-organic macrocycle by multiple C-H...anion hydrogen bonds. PMID- 22213184 TI - Arginine mimetics using alpha-guanidino acids: introduction of functional groups and stereochemistry adjacent to recognition guanidiniums in peptides. AB - Arginine residues are broadly employed for specific biomolecular recognition, including in protein-protein, protein-DNA, and protein-RNA interactions. Arginine recognition commonly exploits the potential for bidentate electrostatic and hydrogen-bonding interactions. However, in arginine residues, the guanidinium functional group is located at the terminus of a flexible hydrocarbon side chain, which lacks the functionality to contribute to specific arginine-mediated recognition and may entropically disfavor binding. In order to enhance the potential for specificity and affinity in arginine-mediated molecular recognition, we have developed an approach to the synthesis of peptides that incorporates an alpha-guanidino acid as a novel arginine mimetic. alpha-Guanidino acids, derived from alpha-amino acids, with guanidinylation of the amino group, were incorporated stereospecifically into peptides on solid phase via coupling of an Fmoc amino acid to diaminopropionic acid (Dap), Fmoc deprotection, guanidinylation of the amine on solid phase, and deprotection, generating a peptide containing an alpha-functionalized arginine mimetic. This approach was examined by incorporating arginine mimetics into ligands for the Src, Grb, and Crk SH3 domains at the site of the key recognition arginine. Protein binding was examined for peptides containing guanidino acids derived from Gly, L-Val, L-Phe, L-Trp, D-Val, D-Phe, and D-Trp. We demonstrate that paralogue specificity and target site affinity may be modulated with the use of alpha-guanidino acid derived arginine mimetics, generating peptides that exhibit enhanced Src specificity by selection against Grb and peptides that reverse the specificity of the native peptide ligand, with enhancements in Src target specificity of up to 15-fold (1.6 kcal mol(-1)). PMID- 22213187 TI - Pyridine-based lanthanide complexes combining MRI and NIR luminescence activities. AB - A series of novel triazole derivative pyridine-based polyamino-polycarboxylate ligands has been synthesized for lanthanide complexation. This versatile platform of chelating agents combines advantageous properties for both magnetic resonance (MR) and optical imaging applications of the corresponding Gd(3+) and near infrared luminescent lanthanide complexes. The thermodynamic stability constants of the Ln(3+) complexes, as assessed by pH potentiometric measurements, are in the range log K(LnL)=17-19, with a high selectivity for lanthanides over Ca(2+), Cu(2+), and Zn(2+). The complexes are bishydrated, an important advantage to obtain high relaxivities for the Gd(3+) chelates. The water exchange of the Gd(3+) complexes (k(ex)(298)=7.7-9.3*10(6) s(-1)) is faster than that of clinically used magnetic resonance imaging (MRI) contrast agents and proceeds through a dissociatively activated mechanism, as evidenced by the positive activation volumes (DeltaV(?)=7.2-8.8 cm(3) mol(-1)). The new triazole ligands allow a considerable shift towards lower excitation energies of the luminescent lanthanide complexes as compared to the parent pyridinic complex, which is a significant advantage in the perspective of biological applications. In addition, they provide increased epsilon values resulting in a larger number of emitted photons and better detection sensitivity. The most conjugated system PheTPy, bearing a phenyl-triazole pendant on the pyridine ring, is particularly promising as it displays the lowest excitation and triplet-state energies associated with good quantum yields for both Nd(3+) and Yb(3+) complexes. Cellular and in vivo toxicity studies in mice evidenced the non-toxicity and the safe use of such bishydrated complexes in animal experiments. Overall, these pyridinic ligands constitute a highly versatile platform for the simultaneous optimization of both MRI and optical properties of the Gd(3+) and the luminescent lanthanide complexes, respectively. PMID- 22213188 TI - Composite biological reconstruction following total calcanectomy of primary calcaneal tumors. AB - BACKGROUND: Advances in oncologic treatment modalities and wide resection have made limb salvage procedures in calcaneal malignancy or aggressive benign tumor increasingly possible. However, reconstructions of the calcaneus remain a major surgical challenge because of the rarity and specific anatomy of this condition. METHODS: we retrospectively reviewed 4 patients who had primary calcaneal tumors and underwent total calcanectomy and reconstructions with use of composite of allograft and vascularized osteocutaneous fibular grafts between 2007 and 2010. The diagnoses included chondrosarcoma in 1, fibrosarcoma in 1, aggressive osteoblastoma in 1, and giant-cell tumor in 1. Wide resection margins were achieved in all patients. The mean age at the time of the operation was 32.1 years. Patients were examined clinically and radiographically and were assessed functionally with Musculoskeletal Tumor Society (MSTS) score and American Orthopaedic Foot and Ankle Society (AOFAS) score. RESULTS: The median duration of follow-up was 24.5 months. No local recurrence occurred in this series and all patients had no evidence of disease at the time of final follow-up. Limb salvage was achieved in all patients. Revision surgery was necessary in two patients because of complications (skin flap necrosis and infection). The average MSTS 93 score and AOFAS score were 91.7% and 87.5 at the final follow-up, respectively. All fibular flaps survived and bone unions achieved successfully. The overall mean time for bone union was 9.5 months. The mean time to full-weight bearing was 7 months. CONCLUSIONS: Vascularized fibular flaps in combination with massive allografts provide an excellent option for biological reconstruction after total calcanectomy in tumor situation and have proven to be a successful limb salvage procedure, which result in earlier patient recovery and return of function. LEVEL OF EVIDENCE: Therapeutic Level IV. PMID- 22213189 TI - 2,3,4',5-tetrahydroxystilbene-2-O-beta-D-glucoside inhibits proliferation of vascular smooth muscle cells: involvement of NO/cGMP/PKG pathway. AB - The proliferation of vascular smooth muscle cells (VSMCs) induced by injury to the intima of arteries is an important etiologic factor in vascular proliferative disorders such as atherosclerosis and restenosis. 2,3,4',5-Tetrahydroxystilbene-2 O-beta-D-glucoside (TSG), an active component extracted from Polygonum multiflorum, has been found to have an antiatherosclerotic effect. The aim of this study was to investigate the effects of TSG on platelet derived growth factor (PDGF)-BB induced VSMCs proliferation and to explore the possible mechanisms of such effects. Pretreatment of VSMCs with TSG significantly inhibited PDGF-BB-induced cell proliferation in a concentration-dependent but not time-dependent manner. In addition, flow cytometry analysis of the DNA content revealed blocking of the PDGF-BB-inducible cell cycle progression by TSG. On the contrary, an inhibitory effect of TSG on VSMCs proliferation and expression of cell cycle regulators were markedly attenuated by addition of an nitric oxide (NO) synthase inhibitor, a soluble guanylate cyclase inhibitor and a cyclic GMP (cGMP)-dependent protein kinase (PKG) inhibitor: N(G)-nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4] oxadiazolo [4,3-alpha] quinoxalin-1-one (ODQ) and KT5823, respectively. It was also demonstrated that TSG enhanced NO and cGMP formation through up-regulating endothelial NO synthase expression in VSMCs. The findings indicate that TSG inhibited VSMCs proliferation induced by PDGF-BB may involve the NO/cGMP/PKG signal pathway. PMID- 22213190 TI - Role of epigenetic and miR-22 and miR-29b alterations in the downregulation of Mat1a and Mthfr genes in early preneoplastic livers in rats induced by 2 acetylaminofluorene. AB - Carcinogenesis is a multistep sequential process of clonal expansion of initiated cells associated with the accumulation of multiple cancer-specific heritable phenotypes. The acquisition of these heritable cancer-specific alterations may be triggered by mutational and/or non-mutational changes in the genome that affect the regulation of gene expression. Currently, cancer-specific epigenetically mediated changes in gene expression are regarded as driving events in tumorigenesis. In the present study, we investigated the role of gene-specific expression changes in the mechanism of rat hepatocarcinogenesis induced by the complete hepatocarcinogen 2-acetylaminofluorene (2-AAF). The results of the present study demonstrate significant alterations in gene expression, especially of Mat1a and Mthfr genes, during early stages of rat 2-AAF-induced liver carcinogenesis. Both of these genes were downregulated in the livers of 2-AAF treated male rats. Inhibition of Mat1a expression was associated with an increase in histone H3 lysine 27 trimethylation and a decrease in histone H3 lysine 18 acetylation at the gene promoter/first exon region. Additionally, we demonstrate for the first time a critical contribution of miR-22 and miR-29b microRNAs in the inhibition of Mat1a and Mthfr gene expression during 2-AAF-induced rat hepatocarcinogenesis. The downregulation of Mat1a and Mthfr genes was accompanied by marked functional alterations in one-carbon metabolism. The results of the present study suggest that downregulation of the Mat1a and Mthfr genes may be one of the main driver events that promote liver carcinogenesis by causing a profound accumulation of subsequent epigenetic abnormalities during progression of the carcinogenic process. PMID- 22213191 TI - DNA methylation of the CYP1A1 enhancer is associated with smoking-induced genetic alterations in human lung. AB - CYP1A1 (cytochrome P4501A1) catalyze the conversion of polycyclic aromatic hydrocarbons into reactive metabolites, which may induce DNA damage. We hypothesized that DNA methylation of the CYP1A1 enhancer could be involved in inter-individual differences in mRNA levels of CYP1A1 or affect the smoking induced DNA damage in human lung. Using DNA bisulfite conversion and pyrosequencing, we show that DNA methylation of the CYP1A1 enhancer is affected by smoking. In adjacent histologically normal lung from lung cancer patients (n = 120), low levels of DNA methylation of the CYP1A1 enhancer were related to high levels of smoking-induced hydrophobic DNA adduct (p < 0.03), and to the presence of TP53 or K-ras mutations in the corresponding lung tumors (p < 0.03). We found an inverse correlation between DNA methylation of the CYP1A1 enhancer and mRNA levels in vivo (Spearman r = -0.54; p < 0.0001). Thus, in lung tumor tissues, the CYP1A1 enhancer hypermethylation was associated with lower mRNA levels compared to adjacent histologically normal tissue (p < 0.0001). In vitro, using a panel of cultured human lung cells, we found hypermethylation of the CYP1A1 enhancer in cancer cell lines and an inverse correlation between DNA methylation and mRNA levels (Spearman r = -0.53; p = 0.003). Altogether, our results indicated that low levels of DNA methylation of the CYP1A1 enhancer in histologically normal human lung were associated with high CYP1A1 mRNA levels and with smoking-induced genetic alterations; thus, it may play a role in the initiation of lung carcinogenesis. PMID- 22213192 TI - Zinc finger transcription factor 191, directly binding to beta-catenin promoter, promotes cell proliferation of hepatocellular carcinoma. AB - Activation of beta-catenin, the central effector of the canonical wingless-type (Wnt) pathway, has been implicated in hepatocellular carcinoma (HCC). However, the transcription regulation mechanism of the beta-catenin gene in HCC remains unknown. Here we report that human zinc finger protein 191 (ZNF191) is a potential regulator of beta-catenin transcription. ZNF191, a Kruppel-like protein, specifically interacts with the TCAT motif, which constitutes the HUMTH01 microsatellite in the tyrosine hydroxylase (TH) gene ex vivo. We demonstrate that ZNF191 is significantly overexpressed in human HCC specimens and is associated with growth of human HCC cells. Global profiling of gene expression in ZNF191 knockdown human hepatic L02 cells revealed that the important Wnt signal pathway genes beta-catenin and cyclin D1 messenger RNAs (mRNAs) are significantly down-regulated. In agreement with transcription level, beta-catenin and cyclin D1 proteins are also down-regulated in transient and stable ZNF191 knockdown L02 and hepatoma Hep3B cell lines. Moreover, significant correlation between ZNF191 and beta-catenin mRNA expression was detected in human HCCs. Promoter luciferase assay indicated that ZNF191 can increase transcription activity of the full-length beta-catenin (CTNNB1) promoter, and nucleotide (nt) 1407/-907 of the CTNNB1 promoter exhibited the maximum transcriptional activity. Electrophoretic mobility shift assay showed that purified ZNF191 protein can directly bind to the CTNNB1 promoter, and the binding region is located at nt 1254/-1224. Finally, we demonstrate that the key binding sequence of ZNF191 in vivo is ATTAATT. CONCLUSION: ZNF191 can directly bind to the CTNNB1 promoter and activate the expression of beta-catenin and its downstream target genes such as cyclin D1 in hepatoma cell lines. This study uncovers a new molecular mechanism of transcription regulation of the beta-catenin gene in HCC. PMID- 22213193 TI - Pharmacologic strategies to target oxidative stress in heart failure. AB - Reactive oxygen species (ROS), which are involved in normal physiological functions at low concentrations, can have deleterious effects when produced in excess. Over time, ROS may result in a pathological state of imbalance known as oxidative stress. Oxidative stress has long been implicated in many diseases, and is consistently associated with poor outcomes in heart failure. Most therapies that are currently being used may provide some reduction in oxidative stress, but there is no consensus on the clinical outcomes of various antioxidants. Currently, there are no antioxidant therapies that are being used routinely to specifically target oxidative stress in patients with heart failure. This article reviews the current understanding of ROS generation, and the potential for novel pharmacologic strategies to target oxidative stress in heart failure. PMID- 22213194 TI - Development and validation of a rapid LC-MS/MS method for the determination of JCC76, a novel antitumor agent for breast cancer, in rat plasma and its application to a pharmacokinetics study. AB - JCC76 is a novel nimesulide analog that selectively inhibits the human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer cell proliferation and tumor progression. To support further pharmacological and toxicological studies of JCC76, a novel and rapid method using liquid chromatography and electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) has been developed and validated for the quantification of the compound in rat plasma. A C18 column was used for chromatographic separation, and the mobile phase was aqueous ammonium formate (pH 3.7; 5 mm)-methanol (1:9, v/v) with an isocratic elution. With a simple liquid-liquid extraction procedure using the mixture of methyl tert-butyl ether-hexane (1:2, v/v), the mean extraction efficiency of JCC76 in rat plasma was determined as 89.5-97.3% and no obvious matrix effect was observed. This method demonstrated a linear calibration range from 0.3 to 100 ng/mL for JCC76 in rat plasma and a small volume of sample consumption. The intra and inter-assay accuracy and precision were within +/-10%. The pharmacokinetics of JCC76 was also profiled using this validated method in rats. In conclusion, this rapid and sensitive method has been proven to effectively quantify JCC76 for pharmacokinetics study. PMID- 22213195 TI - Pituitary iron and volume predict hypogonadism in transfusional iron overload. AB - Hypogonadism is the most common morbidity in patients with transfusion-dependent anemias such as thalassemia major. We used magnetic resonance imaging (MRI) to measure pituitary R2 (iron) and volume to determine at what age these patients develop pituitary iron overload and volume loss. We recruited 56 patients (47 with thalassemia major, five with chronically transfused thalassemia intermedia and four with Blackfan-Diamond syndrome) to have pituitary MRIs to measure pituitary R2 and volume. Hypogonadism was defined clinically based on the timing of secondary sexual characteristics or the need for sex hormone replacement therapy. Patients with transfusional iron overload begin to develop pituitary iron overload in the first decade of life; however, clinically significant volume loss was not observed until the second decade of life. Severe pituitary iron deposition (Z > 5) and volume loss (Z < -2.5) were independently predictive of hypogonadism. Pituitary R2 correlated significantly with serum ferritin as well as liver, pancreatic, and cardiac iron deposition by MRI. Log pancreas R2* was the best single predictor for pituitary iron, with an area under the receiving operator characteristic curve of 0.88, but log cardiac R2* and ferritin were retained on multivariate regression with a combined r(2) of 0.71. Pituitary iron overload and volume loss were independently predictive of hypogonadism. Many patients with moderate-to-severe pituitary iron overload retained normal gland volume and function, representing a potential therapeutic window. The subset of hypogonadal patients having preserved gland volumes may also explain improvements in pituitary function observed following intensive chelation therapy. PMID- 22213196 TI - Survival outcomes in atypical teratoid rhabdoid tumor for patients undergoing radiotherapy in a Surveillance, Epidemiology, and End Results analysis. AB - BACKGROUND: Atypical teratoid rhabdoid tumor (ATRT) is a rare central nervous system malignancy with a poor prognosis that affects mostly young children. Although radiotherapy (RT) historically has been delayed in patients aged <3 years, emerging evidence suggests a role for RT to achieve long-term survivorship. Clinical features and age-dependent trends of RT use were evaluated for patients with ATRT. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results database was used to identify 144 patients with ATRT from 1973 to 2008. The primary endpoint was median overall survival (OS). Clinical and treatment variables were assessed for an association with OS using Cox proportional hazards models. Landmark analysis was used to correct for immortal time bias of adjuvant RT. RESULTS: The median age at diagnosis was 1 year (range, 0-67 years). Gross total resection of the primary tumor was achieved in 39% of patients, and 33% of patients received RT. From 1992 to 2008, RT use increased 2.4-fold in patients aged <=3 years. The median OS for was 10 months. In multivariate analyses, metastatic disease (hazard ratio, 2.83; 95% confidence interval, 1.53-5.23; P = .001) and RT (hazard ratio, 0.10; 95% confidence interval, 0.01-0.73; P = .02) were identified as independent predictors of survival. Landmark analysis confirmed a robust association between RT use and survival, which was attenuated in patients ages 4 to 17 years compared with younger patients. CONCLUSIONS: The current results indicated that RT may offer a significant survival benefit for patients with ATRT and that patients aged <=3 years may derive more benefit from initial RT compared with older children. The authors concluded that prospective clinical trials are needed to examine the role of RT in the initial management of ATRT in patients aged <3 years. PMID- 22213197 TI - Agonist-activated Ca2+ influx and Ca2+ -dependent Cl- channels in Xenopus ovarian follicular cells: functional heterogeneity within the cell monolayer. AB - Xenopus follicles are endowed with specific receptors for ATP, ACh, and AII, transmitters proposed as follicular modulators of gamete growth and maturation in several species. Here, we studied ion-current responses elicited by stimulation of these receptors and their activation mechanisms using the voltage-clamp technique. All agonists elicited Cl(-) currents that depended on coupling between oocyte and follicular cells and on an increase in intracellular Ca(2+) concentration ([Ca(2+) ](i)), but they differed in their activation mechanisms and in the localization of the molecules involved. Both ATP and ACh generated fast Cl(-) (F(Cl)) currents, while AII activated an oscillatory response; a robust Ca(2+) influx linked specifically to F(Cl) activation elicited an inward current (I(iw,Ca)) which was carried mainly by Cl(-) ions, through channels with a sequence of permeability of SCN(-) > I(-) > Br(-) > Cl(-). Like F(Cl), I(iw,Ca) was not dependent on oocyte [Ca(2+) ](i) ; instead both were eliminated by preventing [Ca(2+) ](i) increase in the follicular cells, and also by U73122 and 2-APB, drugs that inhibit the phospolipase C (PLC) pathway. The results indicated that F(Cl) and I(iw,Ca) were produced by the expected, PLC-stimulated Ca(2+) -release and Ca(2+) -influx, respectively, and by the opening of I(Cl(Ca)) channels located in the follicular cells. Given their pharmacological characteristics and behavior in conditions of divalent cation deprivation, Ca(2+) -influx appeared to be driven through store-operated, calcium-like channels. The AII response, which is also known to require PLC activation, did not activate I(iw,Ca) and was strictly dependent on oocyte [Ca(2+) ](i) increase; thus, ATP and ACh receptors seem to be expressed in a population of follicular cells different from that expressing AII receptors, which were coupled to the oocyte through distinct gap-junction channels. PMID- 22213198 TI - Functionalization of oxidases with peroxidase activity creates oxiperoxidases: a new breed of hybrid enzyme capable of cascade chemistry. AB - The covalent flavoprotein alditol oxidase (AldO) from Streptomyces coelicolor A3(2) was endowed with an extra catalytic functionality by fusing it to a microperoxidase. Purification of the construct resulted in the isolation of a synthetic bifunctional enzyme that was both fully covalently flavinylated and heminylated: an oxiperoxidase. Characterization revealed that both oxidase and peroxidase functionalities were active, with the construct functioning as a single-component xylitol biosensor. In an attempt to reduce the size of the oxidase-peroxidase fusion, we replaced portions of the native AldO sequence with the bacterial cytochrome c CXXCH heme-binding motif. By mutating only three residues of the AldO protein we were able to create a functional oxidase peroxidase hybrid. PMID- 22213199 TI - Immunohistochemical and immunological detection of ghrelin and leptin in rainbow trout Oncorhynchus mykiss and murray cod Maccullochella peelii peelii as affected by different dietary fatty acids. AB - In this study, we report ghrelin and leptin immunoreactive (ir) cells distribution in the gastrointestinal tract and blood ghrelin and leptin levels in rainbow trout (Oncorhynchus mykiss) and Murray cod (Maccullochella peelii peelii) fed diets with different fatty acid compositions. Juvenile rainbow trout and Murray cod were fed five iso-energetic experimental diets containing fish oil (FO) or one of the following vegetable oils (VO): olive oil (OO), sunflower oil (SO), linseed oil (LO), and palm oil (PO); as the added dietary lipid source. The presence and distribution of both ghrelin and leptin ir cells in the gastrointestinal tract were affected by the inclusion of VO. Ghrelin ir cells were found in the gastric glands of rainbow trout and in the mioenteric plexuses of the stomach of Murray cod fed FO. Ghrelin ir cells were localized in the mucosa of the intestine of rainbow trout and Murray cod fed VO. Leptin ir cells were more abundant in the epithelial lining of the mucosa folds and in the glands of the stomach of rainbow trout fed VO. Leptin immunoreactivity was detected in the gastric mioenteric plexus of Murray cod fed FO. No differences were found both in ghrelin and leptin levels in blood plasma or in the growth rates of rainbow trout and Murray cod fed the different experimental diets. These observations suggest that dietary fatty acids play a role in the peripheral feeding regulation. PMID- 22213200 TI - Promyelocytic leukemia nuclear bodies support a late step in DNA double-strand break repair by homologous recombination. AB - The PML protein and PML nuclear bodies (PML-NB) are implicated in multiple cellular functions relevant to tumor suppression, including DNA damage response. In most cases of acute promyelocytic leukemia, the PML and retinoic acid receptor alpha (RARA) genes are translocated, resulting in expression of oncogenic PML RARalpha fusion proteins. PML-NB fail to form normally, and promyelocytes remain in an undifferentiated, abnormally proliferative state. We examined the involvement of PML protein and PML-NB in homologous recombinational repair (HRR) of chromosomal DNA double-strand breaks. Transient overexpression of wild-type PML protein isoforms produced hugely enlarged or aggregated PML-NB and reduced HRR by ~2-fold, suggesting that HRR depends to some extent upon normal PML-NB structure. Knockdown of PML by RNA interference sharply attenuated formation of PML-NB and reduced HRR by up to 20-fold. However, PML-knockdown cells showed apparently normal induction of H2AX phosphorylation and RAD51 foci after DNA damage by ionizing radiation. These findings indicate that early steps in HRR, including recognition of DNA double-strand breaks, initial processing of ends, and assembly of single-stranded DNA/RAD51 nucleoprotein filaments, do not depend upon PML-NB. The HRR deficit in PML-depleted cells thus reflects inhibition of later steps in the repair pathway. Expression of PML-RARalpha fusion proteins disrupted PML-NB structure and reduced HRR by up to 10-fold, raising the possibility that defective HRR and resulting genomic instability may figure in the pathogenesis, progression and relapse of acute promyelocytic leukemia. PMID- 22213201 TI - Layer-by-layer assembly through weak interactions and their biomedical applications. AB - The surface design and control of substrates with nanometer- or micrometer-sized polymer films are of considerable interest for both fundamental and applied studies in the biomedical field because of the required surface properties. The layer-by-layer (LbL) technique was discovered in 1991 by Decher and co-workers for the fabrication of polymer multilayers constructed mainly through electrostatic interaction. The scope and applicability of this LbL assembly has been extended by introducing molecularly regular conformations of polymers or proteins by employing, for the first time, weak interactions such as van der Waals interactions and biological recognition. Since these weak interactions are the sum of the attractive or repulsive forces between parts of the same molecule, they allow macromolecules to be easily arranged into the most stable conformation in a LbL film. By applying this characteristic feature, the template polymerization of stereoregular polymers, stereoregular control of surface biological properties, drastic morphological control of biodegradable nano materials, and the development of three-dimensional cellular multilayers as a tissue model were successfully achieved. It is expected that LbL assembly using weak interactions will promote further interest into fundamental and applied studies on the design of surface chemistry in the biomedical field. PMID- 22213203 TI - Water-soluble monodispersed lanthanide oxide submicrospheres: PVP-assisted hydrothermal synthesis, size-control and luminescence properties. AB - We report a facile hydrothermal synthetic route to prepare a class of monodispersed lanthanide-based compound submicrospheres with controllable size, which employs raw lanthanide oxides as starting material, urea as precipitator and poly(N-vinyl-2-pyrrolidone) (PVP) as surfactant. Dependent on the intrinsic properties of respective lanthanide, the resulting products could be in the form of oxide, hydroxide or basic carbonate. These lanthanide hydroxides or basic carbonates can be easily transformed into their corresponding oxides by calcination, retaining the same morphology and size dispersion. The formation mechanism of these lanthanide-based compound submicrospheres is investigated and PVP plays a critical role in forming uniform and well-dispersed products. Furthermore, this method could be extended to a binary system by using two kinds of lanthanide oxides as starting material, resulting in doped-type lanthanide oxide submicrospheres (such as Y(2)O(3):Eu(3+)). The Y(2)O(3):Eu(3+) submicrospheres exhibit nearly uniform spherical morphology and narrow size distribution as well as good water solubility and sharp spectral emission at 610 nm (corresponding to the 5D(0)-7F(2) transition of Eu(3+)). This makes them attractive materials for applications in fields such as fluorescent lamps, field emission displays (FEDs) or LCDs, or as biomedical labels and molecular probes. PMID- 22213202 TI - Flavokawain B, a kava chalcone, induces apoptosis in synovial sarcoma cell lines. AB - Synovial sarcomas (SS) are soft tissue sarcomas with poor prognosis, displaying a lack of response to conventional cytotoxic chemotherapy. Although SS cell lines have moderate chemosensitivity to isofamide and doxorubicin therapy, the clinical prognosis is still poor. In this article, we showed that flavokawain B (FKB), a novel chalcone from kava extract, potently inhibits the growth of SS cell lines SYO-I and HS-SY-II through induction of apoptosis. Treatment with FKB increased caspase 8, 9, and 3/7 activity compared to vehicle-treated controls, indicating that both extrinsic and intrinsic apoptotic pathways were activated. Furthermore, FKB treatment of both cell lines resulted in increased mRNA and protein expression of death receptor-5 and the mitochondrial pro-apoptotic proteins Bim and Puma, while down-regulating the expression of an inhibitor of apoptosis, survivin in a dose-dependent manner. Our results suggest the natural compound FKB has a pro-apoptotic effect on SS cell lines. FKB may be a new chemotherapeutic strategy for patients with SS and deserves further investigation as a potential agent in the treatment of this malignancy. PMID- 22213204 TI - Efficient spectral editing at 7 T: GABA detection with MEGA-sLASER. AB - At high field (7 T) spectral editing of gamma-aminobutyric acid with MEGA-point resolved spectroscopy is inefficient due to the large chemical shift displacement error. In this article, a new pulse sequence is designed which has minimal chemical shift displacement error to perform an efficient spectral editing of the gamma-aminobutyric acid 3.0 ppm resonance at 7 T. The sequence consists of the conventional MEGA editing pulses and a semi-localized by adiabatic selective refocusing sequence. Phantom and in vivo measurements demonstrated an efficient detection of gamma-aminobutyric acid. Using ECG triggering, excellent in vivo performance of the MEGA-semi-localized by adiabatic selective refocusing (MEGA sLASER) provided well-resolved gamma-aminobutyric acid signals in 27 mL volumes in the human brain at an echo time of 74 ms within a relatively short acquisition time (5 min). Furthermore, the high efficiency of the MEGA-sLASER was demonstrated by acquiring small volumes (8 mL) at an echo time of 74 ms, as well as long echo time measurements (222 ms in 27 mL volume). PMID- 22213205 TI - Distinguishing DNA by analog-to-digital-like conversion by using optofluidic lasers. PMID- 22213206 TI - Direct preparation of sulfide semiconductor nanoparticles from the corresponding bulk powders in an ionic liquid. PMID- 22213207 TI - Elemental distribution and thermoelectric properties of layered tellurides 39R M(0.067)Sb(0.667)Te(0.266) (M=Ge, Sn). AB - The isostructural phases 39R-Ge(0.067)Sb(0.667)Te(0.266) (R3m, a=4.2649(1), c=75.061(2) A) and 39R-Sn(0.067)Sb(0.667)Te(0.266) (R3m, a=4.2959(1), c=75.392(2) A) were prepared by quenching stoichiometric melts of the pure elements and subsequent annealing at moderate temperatures. Their structures are comparable to "superlattices" synthesized by layer-by-layer deposition onto a substrate. These structures show no stacking disorder by electron microscopy. The structure of the metastable layered phases are similar to that of 39R-Sb(10)Te(3) (equivalent to Sb(0.769)Te(0.231)), which contains four A7 gray-arsenic-type layers of antimony alternating with Sb(2)Te(3) slabs. Joint refinements on single-crystal diffraction data using synchrotron radiation at several K edges were performed to enhance the scattering contrast. These refinements show that the elemental distributions at some atom positions are disordered whereas otherwise the structures are long-range ordered. The variation of the elemental concentration correlates with the variation in interatomic distance. Z-contrast scanning transmission electron microscopy (HAADF-STEM) on 39R-Ge(0.067)Sb(0.667)Te(0.266) confirms the presence of concentration gradients. The carrier-type of the isostructural metal (A7-type lamellae)-semiconductor heterostructures (Ge/Sn doped Sb(2)Te(3) slabs) varies from n-type (Ge(0.067)Sb(0.667)Te(0.266)) to p type (Sn(0.067)Sb(0.667)Te(0.266)). Although the absolute values of the Seebeck coefficient reached about 50-70 MUV/K and the electrical conductivity is relatively high, the two isotypic phases exhibit a maximal thermoelectric figure of merit (ZT) of 0.06 at 400 degrees C as their thermal conductivity (kappa~8 9.5 W/mK at 400 degrees C) lies interestingly in between that of antimony and pure Sb(2)Te(3). PMID- 22213208 TI - In vivo dopaminergic and behavioral responses to acute cocaine are altered in adenosine A(2A) receptor knockout mice. AB - Adenosine, acting on adenosine A(2A) receptors (A2ARs), regulates addictive processes induced by drugs of abuse. This study investigates the role of A(2A) adenosine receptors in neurochemical and behavioral responses to an acute cocaine challenge. Changes in the extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) of mice lacking A(2A) adenosine receptors and wild type (WT) littermates after an acute cocaine (20 mg/kg) administration were evaluated by in vivo microdialysis studies. Locomotor effects induced by cocaine were measured during the microdialysis procedure. Cocaine-evoked increases in extracellular DA were not sustained in mice lacking A(2A) Rs in comparison with wild-type mice (P < 0.05). Cocaine administration significantly increased ambulatory activity in both genotypes. However, overall locomotor activity was further increased, whereas rest and small local movement measures were significantly attenuated in the A(2A) R knockout mice compared with WT littermates (P < 0.05). Our findings support an important role for adenosine A(2A) R in modulating the acute effects of cocaine, as demonstrated by the decrease in cocaine-evoked dopaminergic transmission in the NAc. Furthermore, the results support an important antagonistic role of A(2A) R in vivo in regulating psychostimulant-induced hyperlocomotion. PMID- 22213209 TI - Anisotropic charge transport in spherulitic poly(3-hexylthiophene) films. PMID- 22213210 TI - Reirradiation to the pelvis for recurrent rectal cancer. AB - OBJECTIVES: This study investigated late toxicity and infield progression-free survival in patients with locally recurrent rectal cancer (LRRC) who had previously received irradiation to the pelvis. METHODS: Twenty-two patients were treated by reirradiation to the pelvis between January 2000 and August 2007. All patients received curative surgery with preoperative or postoperative chemoradiotherapy as an initial treatment. Five patients (23%) underwent surgical resection after reirradiation. The median follow-up duration was 20 months (range, 7-91 months). RESULTS: Two patients (9%) had grade-3 acute toxicity and eight patients (36%) had grade-3 to -4 late toxicity. The incidence of grade-3 to -4 late toxicity in the gastrointestinal and urinary system was 18% and 27%, respectively. Recurrent tumor location (axial or anterior) and surgical resection after reirradiation significantly influenced severe late toxicity (P = 0.024 and P = 0.039, respectively). In the 17 patients not undergoing surgery after reirradiation, median infield progression-free survival was 16 months. Reirradiation doses exceeding 50 Gy(alphabeta10) (equivalent dose in 2 Gy fractions) significantly increased the infield progression-free survival (P = 0.005). CONCLUSIONS: Tumor location (axial or anterior) and surgery after reirradiation may increase severe late toxicity. In addition, an EQD2 exceeding 50 Gy(alphabeta10) may improve infield control. PMID- 22213212 TI - Anticancer activity of rice callus suspension culture. AB - A multitude of natural products from plant extracts have been tested for their ability to inhibit the progression of several diseases including cancer. A novel approach of evaluating plant (rice) callus suspension cultures for anticancer activity is reported. The ability of different dilutions of rice callus suspension cultures to inhibit growth of two human cancer cell lines was tested employing varying cell numbers and different incubation times. A crystal violet assay was performed to assess cell viability of the cancer cell lines. Furthermore, microscopic analysis was carried out to determine the effect of the rice callus culture on the morphology of the cancer cells. Rice callus suspension cultures significantly inhibited the growth of human cancer and renal cell lines at densities of 5000 and 10000 cells/mL when incubated for 72 and 96 h. Rice callus suspension culture was more efficient than paclitaxel (Taxol(r)) and etoposide in selectively killing human colon and renal cancer cell lines compared with a control cell line (human lung fibroblasts). The use of plant callus suspension cultures is a novel approach for inhibiting the growth of cancer cells, which will lead to the development of new agents for selectively killing cancer cells. PMID- 22213213 TI - Determination of metformin in rat plasma by HILIC-MS/MS combined with Tecan automation and direct injection. AB - Metformin is a well-known oral antihyperglycemic drug used in treatment of type II diabetes. Analysis of metformin in biological fluids is a challenge owing to its high polarity and small molecular size, which lead to poor retention of metformin on reversed-phase liquid chromatographic columns. A high-throughput method was developed and validated for the determination of metformin in rat plasma in support of preclinical toxicology studies, using hydrophilic interaction liquid chromatography tandem mass spectrometry (HILIC-MS/MS) and Tecan automated sample preparation. Extracted samples were directly injected onto the unbounded silica column with an aqueous-organic mobile phase. This HILIC MS/MS method was validated for accuracy, precision, sensitivity, stability, matrix effect, recovery and calibration range. Acceptable intra-run and inter-run assay precision (coefficient of variation <= 3.9%) and accuracy (99.0-101.8%) were achieved over a linear range of 50-50,000 ng/mL. Metformin is stable in rat plasma for at least 6 h at room temperature, 147 days at -70 degrees C and through three freeze (-70 degrees C) and thaw cycles. Metformin is also stable in rat whole blood for at least 2 h at room temperature and in an ice-water bath. The validated method was successfully used in support of several preclinical studies where metformin is dosed together with an investigational drug substance. The ruggedness of the validated method was demonstrated by the incurred sample reproducibility test. PMID- 22213214 TI - Quantitative 31P magnetic resonance spectroscopy of the human breast at 7 T. AB - This study presents quantified levels of phosphorylated metabolites in glandular tissue of human breast using (31)P magnetic resonance spectroscopy at 7 T. We used a homebuilt (1)H/(31)P radiofrequency coil to obtain artifact-free (31)P MR spectra of glandular tissue of healthy females by deploying whole breast free induction decay (FID) detection with adiabatic excitation and outer volume suppression. Using progressive saturation, the estimated apparent T(1) relaxation time of (31)P spins of phosphocholine and phosphoethanolamine was 4.4 and 5.7 s, respectively. Quantitative measures for phosphocholine and phosphoethanolamine levels in glandular tissue were established based on MR imaging. We used a 3D (1)H image of the breast to segment the glandular tissue; this was matched to a 3D (31)P image of the B1- field of the (31)P coil to correct for differences in glandular tissue volume and B(1) inhomogeneity of the (31)P coil. The (31)P MR spectra were calibrated using a phantom with known concentration. Average levels of phosphocholine and phosphoethanolamine in 11 volunteers were 0.84 +/- 0.21 mM and 1.18 +/- 0.41 mM, respectively. In addition, data of three patients with breast cancer showed higher levels of phosphocholine and phosphoethanolamine compared with healthy volunteers. This may indicate a potential role for the use of (31)P magnetic resonance spectroscopy for characterization, prognosis, and treatment monitoring in breast cancer. PMID- 22213215 TI - Tumor-specific but not nonspecific cell-free circulating DNA can be used to monitor disease response in lymphoma. AB - Recently, nontumor specific circulating DNA was shown to be elevated in a broad range of lymphomas, implicating a role as a potential biomarker. Epstein-Barr virus' (EBV) presence within a proportion of lymphomas implies EBV-DNA has potential as a lymphoma-specific disease response biomarker. However, application would be restricted to EBV-associated lymphomas. Neither detailed comparison has been performed of lymphoma-specific versus nonspecific DNA as disease response biomarkers nor have the kinetics of circulating DNA during treatment been established, and the optimal methodology remains unknown. We prospectively evaluated DNA levels and clinical response of 63 lymphoma patients. DNA was measured in paired serum, plasma, and cell samples at five predetermined time points taken prior, during and following treatment. Both cell-free (c-f) circulating EBV-DNA (in EBV-associated lymphoma) and nonspecific c-f DNA levels (in all lymphomas) were elevated and discriminatory at presentation compared to healthy controls. Nonspecific c-f DNA was significantly associated with baseline serum lactate dehydrogenase. Within EBV-associated lymphomas at presentation, there was a strong correlation between specific and nonspecific circulating c-f DNA (r = 0.9, P < 0.0001). However, only c-f EBV-DNA correlated with clinical/radiological response. In addition, c-f EBV-DNA, and not nonspecific c-f DNA, provided an early marker of relapsed and refractory disease. Serum versus plasma, and single versus multiple-copy EBV-gene targets were equivalent. Lymphoma-specific DNA is a disease response biomarker; however, nonspecific DNA reflected neither lymphoma-specific DNA nor therapeutic response. Lymphoma disease response can be monitored by blood tests, but new lymphoma-specific biomarkers need to be identified to broaden applicability. PMID- 22213216 TI - DNA repair genes XPC, XPG polymorphisms: relation to the risk of colorectal carcinoma and therapeutic outcome with Oxaliplatin-based adjuvant chemotherapy. AB - Xeroderma pigmentosum complementation group C and G (XPC, XPG) play important roles in DNA damage repairing machinery. Genetic variations in the XPC and XPG may be associated with increased risk for colorectal carcinoma (CRC). In this study, we evaluated the relation between the XPC Lys939Gln, XPG Asp1104His polymorphisms, and CRC susceptibility in a population-based case-control study, which included 1,028 CRC cases and 1,085 controls. Compared with the corresponding wild genotypes, we found that individuals with at least one copy of the XPC Lys939Gln (AC or CC genotype) and XPG Asp1104His (GC or CC genotype) had an increased risk for CRC. In addition, the variant genotypes of the XPC Lys939Gln AC/CC (P = 0.027) or XPG Asp1104His GC/CC (P = 0.003) reduced the elevation of preoperative carcinoembryonic antigen (CEA) level. Moreover a significantly longer progression-free survival (PFS) after Oxaliplatin-based adjuvant chemotherapy was observed in patients with XPG Asp1104His wide-type GG genotype (n = 432, Log-rank test: P = 0.033). Cox proportional hazards analyses demonstrated that variant genotypes of XPG Asp1104His [hazard ratio (HR) = 1.692, 95% confidence interval (95%CI): 1.202-2.383, P = 0.003] as well as pathology grade (HR = 2.545, 95%CI: 2.139-3.030, P < 0.001), and lymph node metastases (HR = 1.851, 95%CI: 1.306-2.625, P < 0.001) were predictive of shorter PFS for the CRC patients with Oxaliplatin-based adjuvant chemotherapy. In conclusion, the current data suggested that XPC Lys939Gln and XPG Asp1104His polymorphisms might contribute to the identification of patients with increased risk for CRC. PMID- 22213217 TI - Comparing different preparation methods to study human fibrin fibers and platelets using TEM. AB - For the study of cellular ultrastructure, the sample needs to be stabilized by fixation, with the ultimate aim to preserve the native tissue organization and to protect the tissue against later stages of preparation. Chemical and freezing fixation are most used, and chemical fixation employs agents that permeate tissues and cells by diffusion and covalently bind with their major biochemical constituents to fix them. Most widely used chemical fixatives are aldehydes, e.g., formaldehyde and glutaraldehyde, which are noncoagulating, crosslinking agents. Cryofixation methods for ultrastructural studies are also popular, and high-pressure freezing immobilizes all cell constituents and arrests biological activity by removing the thermal energy from the system. In the current research, we used platelet-rich plasma (PRP) to study expansive fibrin fibers and platelet ultrastructure to compare the two fixation techniques. We also used thrombin and calcium chloride as a clotting agent to determine the technique most suitable for the formation of extensive fibrin networks. Chemically fixated fibrin fibers were more compact and condensed and also showed a banding pattern on longitudinal sections. High-pressure frozen samples were more dispersed while platelets fixated showed better preserved cellular membranes and organelle structure. PRP coagulated by addition of CaCl(2) showed blood platelets that are noticeably more activated compared with PRP; however, with thrombin, a sharp ultrastructure was seen. We conclude that PRP mixed with thrombin, and freeze substituted, is the most suitable method for the study of extensive fibrin fibers as well as platelets. PMID- 22213218 TI - Differences in vitamin D status likely explain racial disparities in breast cancer mortality rates in the Southeast. PMID- 22213219 TI - Effects of cold ischemia and inflammatory tumor microenvironment on detection of PI3K/AKT and MAPK pathway activation patterns in clinical cancer samples. AB - The accuracy of common markers for PI3K/AKT and MAPK pathway activation in preclinical and clinical cancer biomarker studies depends on phosphoepitope stability and changes of phosphorylation under ischemia. Herein, we define conditions under which phosphoepitope-specific duplex immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded tumor tissues reflects pathway activation in situ as accurately as possible, and identify activation patterns linked to mutational status, pathway dependency and tumor microenvironment in clinical tumor samples, cell culture and xenograft tissues. Systematically assessing robustness of pAKT, pERK1/2, pMEK1/2 and pmTOR detection and related markers in xenograft tissues exposed to ischemia, we show that control of preprocessing and ischemia times allows accurate interpretation of staining results. Phosphorylation patterns were then analyzed in 33 xenograft models and in 58 cases with breast cancer, including 21 paired samples of core-needle biopsies with corresponding mastectomy specimens, and 37 mastectomy samples obtained under rigorously controlled conditions minimizing ischemia time. Patterns of pAKT and pERK1/2 staining (predominant PI3K/AKT, predominant MAPK and concomitant activation) were associated with sensitivity to pathway inhibition and partially with the mutational status in cell lines and corresponding xenograft tumors. In contrast, no clear correlation between mutational status and staining patterns was observed in clinical breast cancer samples, suggesting that interaction with the human tumor microenvironment may interfere with the use of phosphoepitope specific IHC as potential markers for pathway dependency. In contrast to core needle biopsies, surgically resected breast cancer samples showed evidence of severe signal changes comparable to those effects observed in xenograft tumors exposed to controlled ischemia. PMID- 22213220 TI - Terpenoids are widespread in actinomycetes: a correlation of secondary metabolism and genome data. AB - The genomes of all bacteria with publicly available sequenced genomes have been screened for the presence of sesquiterpene cyclase homologues, resulting in the identification of 55 putative geosmin synthases, 23 homologues of 2 methylisoborneol synthases, and 98 other sesquiterpene cyclase homologues. Most of these enzymes by far were found in actinomycetes. The terpenoid volatiles from 35 strains, including 31 actinomycetes and four strains from other taxa, were collected by using a closed-loop stripping apparatus and identified by GC-MS. All of these bacteria apart from one strain encode sesquiterpene cyclase homologues in their genomes. The identified volatile terpenoids were grouped according to structural similarities and their biosynthetic relationship, and the results of these analyses were correlated to the available genome information, resulting in valuable new insights into bacterial terpene biosynthesis. PMID- 22213221 TI - Cardiac and skeletal muscle expression of mutant beta-myosin heavy chains, degree of functional impairment and phenotypic heterogeneity in hypertrophic cardiomyopathy. AB - Several mutations in distinct genes, all coding for sarcomeric proteins, have been reported in unrelated kindreds with familial hypertrophic cardiomyopathy (FHC). We have identified nine individuals from three families harboring two distinct mutations in one copy of the beta-myosin heavy chain (beta-MHC) gene. In this study, the expression of the mutant beta-myosin protein isoform, isolated from slow-twitch fibers of skeletal muscle, was demonstrated by Northern and Western blot analysis; this myosin showed a decreased in vitro motility activity and produced a lower actin-activated ATPase activity. Isometric tension, measured in single slow-twitch fibers isolated from the affected individuals, also showed a significant decrease. The degree of impairment of beta-myosin function, as well as the loss in isometric tension development, were strictly dependent on the amount of the isoform transcribed from the mutated allele. Interestingly, a strong correlation was also demonstrated between mutant beta-myosin content and clinical features of FHC. On the other hand, we were unable to detect any correlation between mutant beta-myosin expression and degree of cardiac hypertrophy, thereby strengthening the hypothesis that hypertrophy, one of the hallmarks of FHC, might not necessarily be related to the clinical evolution of this disease. These findings lend support to the notion that additional factors rather than the mutated gene may play a pathogenetic role in cardiac wall thickening, whereas the prognosis appears to be strongly related to the amount of mutant protein. PMID- 22213222 TI - Narcolepsy in the pediatric population. AB - Narcolepsy is characterized by excessive daytime sleepiness, with or without cataplexy. Associated features include sleep paralysis, hypnagogic or hypnopompic hallucinations, and disturbed nocturnal sleep. Narcolepsy is strongly associated with the HLA DQB1*0602 allele, and its symptoms stem from destruction of hypocretin-secreting neurons in the hypothalamus. Recently identified autoantibodies to Tribbles homologue 2 in some patients, as well as cases associated with H1N1 vaccination, support an autoimmune mechanism. There are many challenges in diagnosing and treating pediatric narcolepsy. Caution must also be used in interpreting polysomnography and multiple sleep latency test results in children. HLA testing is nonspecific, and no commercial test exists to measure cerebrospinal fluid hypocretin levels. Neuroimaging has not yet proven useful in primary narcolepsy. Treatment of sleepiness and cataplexy in children requires extrapolating from adult studies. Hopefully, further insights into the pathophysiology of narcolepsy will allow for new therapeutics to manage the symptoms and modify the course of the disease. PMID- 22213223 TI - From green polymers to high precision chemistry - communicating the best in polymer science. PMID- 22213224 TI - Diffusive shielding stabilizes bulk nanobubble clusters. AB - Using molecular dynamics, we study the nucleation and stability of bulk nanobubble clusters. We study the formation, growth, and final size of bulk nanobubbles. We find that, as long as the bubble-bubble interspacing is small enough, bulk nanobubbles are stable against dissolution. Simple diffusion calculations provide an excellent match with the simulation results, giving insight into the reason for the stability: nanobubbles in a cluster of bulk nanobubbles protect each other from diffusion by a shielding effect. PMID- 22213225 TI - General and controllable synthesis of novel mesoporous magnetic iron oxide@carbon encapsulates for efficient arsenic removal. AB - A facile ammonia-atmosphere pre-hydrolysis post-synthetic route that can uniformly and selectively deposit Fe(2) O(3) nanoparticles in the predefined mesopores (5.6 nm) of a bimodal (2.3, 5.6 nm) mesoporous carbon matrix is demonstrated. The mesoporous magnetic Fe(2) O(3) @C encapsulates show excellent performance for arsenic capture with remarkable adsorption capacity, fast uptake rate, easy magnetic separation, and good cyclic stability. PMID- 22213226 TI - Production of renewable aromatic compounds by catalytic fast pyrolysis of lignocellulosic biomass with bifunctional Ga/ZSM-5 catalysts. PMID- 22213227 TI - The NLRP3/ASC/Caspase-1 axis regulates IL-1beta processing in neutrophils. AB - Neutrophils play a pivotal role in the defense against bacterial, viral and fungal infections and are important mediators in the acute inflammatory response. At the same time, neutrophils are also in volved in sterile inflammatory responses that are triggered by endogenous ligands. A series of immediate effector functions and the expression of proinflammatory genes enable neutrophils to initiate the immune response against the injurious agent. Among these, interleukin-1beta (IL-1beta) plays a key role in the orchestration of the inflammatory response. Induction of IL-1beta expression leads to production of cytosolic pro-IL-1beta, which requires further processing by a proteolytic cleavage event. Caspase-1 was initially identified as the main IL-1beta converting enzyme, and the upstream events leading to caspase-1 activation were identified as so-called inflammasome complexes. Up to now, the inflammasome system has mainly been studied in macrophages, whereas the inflammasome was thought to play a redundant or no role in the cell intrinsic processing of pro-IL 1beta in neutrophils. Here, we identify the expression of the components of the NLRP3 inflammasome complex in neutrophils and show that the NLRP3 inflammasome pathway is indeed operational in neutrophils. Our findings establish the NLRP3 inflammasome as a key step in the secretion of matured IL-1beta by neutrophils. PMID- 22213228 TI - Thermodynamics of translesion synthesis across a major DNA adduct of antitumor oxaliplatin: differential scanning calorimetric study. AB - Differential scanning calorimetry (DSC) was used to measure the thermodynamic changes associated with translesion synthesis across major lesion induced in DNA by antitumor oxaliplatin [1,2-d(GG) intrastrand cross-link]. Insertion of matched nucleotides dC at the primer terminus (across unique 3'- or 5'-dG in the unplatinated template) and subsequent extensions resulted in an incremental increase in thermodynamic parameters. In contrast, incorporation of dC opposite either platinated dG in the intrastrand cross-link formed in the template strand and subsequent extensions by one nucleotide resulted only in little changes in thermodynamics. A similar thermodynamic delay was observed for a control template primer containing a dG:dT mismatch across 3'- or 5'-dG in the template and subsequent Watson-Crick primer extensions. The thermodynamic scarcity generated by either the lesion or mismatches was not localized but extended to the 5' downstream sites, which may be connected with the phenomenon termed "short-term memory" of replication errors retained by some DNA polymerases responding to DNA damages or mismatches. Interestingly, formation of the 1,2-d(GG) intrastrand cross-link of oxaliplatin altered the overall DSC profiles of the dG:dT mismatch template/primers only in a very small extent. While addition of matched nucleotide dC across either dG in the template strand was thermodynamically favored over the presence of a mismatched dT (DeltaDeltaG(0)(310) was 7.6 or 6.8 kJ mol(-1), DeltaDeltaH was 14 or 49 kJ mol(-1)), no such thermodynamic advantage was observed with the 1,2-d(GG) intrastrand cross-link of oxaliplatin at these positions (DeltaDeltaG(0)(310) was 2.8 or -0.3 kJ mol(-1), DeltaDeltaH was 4 or 9 kJ mol(-1)). The equilibrium thermodynamic data also provide insight into the processes associated with misincorporation of incorrect nucleotides during replication bypass across major cross-links of antitumor oxaliplatin. On the other hand, besides thermodynamic effects also kinetic factors play an important role in the processing of the cross-links of antitumor platinum drugs. The impact of the two effects in overall processing DNA adducts by a particular DNA polymerase will depend on its nature. PMID- 22213229 TI - Integrated laser and electron microscopy correlates structure of fluid catalytic cracking particles to Bronsted acidity. PMID- 22213230 TI - Tuning and amplification strategies for intravascular imaging coils. AB - The manufacturing of intravascular imaging coils poses several challenges. Due to their size, it can be difficult to incorporate local matching networks and signal amplifiers. The goal of this study is to investigate tuning and amplification strategies for intravascular coils and to assess the signal-to-noise benefits of incorporating a matching network and/or miniature amplifier into catheter-based intravascular imaging devices at various locations in the signal chain. The results suggest that the use of a low-noise amplifier close to the receiving coil enables the use of miniature coaxial cables to be used despite being noisy. Moreover, an improvement in the signal-to-noise ratio of over 75% is presented over conventional intravascular coil configurations where the matching circuit and low-noise amplifier are placed at the proximal end. Therefore, designing devices for intravascular applications capable of generating high signal-to-noise ratio images becomes more feasible, also allowing for significant reductions in scan time. PMID- 22213231 TI - Clinicopathological prognostic factors of superficial non-small round cell soft tissue sarcomas. AB - BACKGROUND: We undertook this study to assess the therapeutic results of superficial soft tissue sarcomas as related to the presence of microscopic invasion, and to identify prognostic factors so as to optimize the therapeutic strategy. METHODS: From 1995 to 2008, 105 patients who were treated surgically for superficial non-small round cell soft tissue sarcoma were investigated with regard to clinical results and microscopic invasion, and the influence exerted on prognosis was analyzed. We analyzed overall, metastasis-free, and local recurrence-free survival rates and determined the difference in survivorship between with and without fascia invasion. RESULTS: The 5-year overall survival rate and 5-year disease-free survival rate were 95.3% and 81.8%. For overall survival, age (P < 0.05), grade (P < 0.05), tumor size (P < 0.05), and fascial invasion (P < 0.0001) were significant unfavorable prognostic factors, while for metastasis-free survival, grade (P < 0.01) and fascial invasion (P < 0.001) were significant unfavorable prognostic factors. For local recurrence-free survival, fascial invasion alone (P < 0.01) was a significant unfavorable prognostic factor. CONCLUSIONS: Fascial invasion on pathological examination of resected specimens was identified as a significant unfavorable prognostic factor. Selecting the postoperative adjuvant therapy based on a detailed evaluation of any fascial invasion is an important part of the therapeutic strategy. PMID- 22213232 TI - Double-shelled CoMn2O4 hollow microcubes as high-capacity anodes for lithium-ion batteries. PMID- 22213233 TI - Adolescent female rats exhibiting activity-based anorexia express elevated levels of GABA(A) receptor alpha4 and delta subunits at the plasma membrane of hippocampal CA1 spines. AB - Activity-based anorexia (ABA) is an animal model for anorexia nervosa that has revealed genetic links to anxiety traits and neurochemical characteristics within the hypothalamus. However, few studies have used this animal model to investigate the biological basis for vulnerability of pubertal and adolescent females to ABA, even though the great majority of the anorexia nervosa cases are females exhibiting the first symptoms during puberty. GABAergic inhibition of the hippocampus strongly regulates anxiety as well as plasticity throughout life. We recently showed that the hippocampal CA1 of female mice undergo a dramatic change at puberty onset--from expressing virtually none of the nonsynaptic alpha4betadelta GABA(A) receptors (GABARs) prepubertally to expressing these GABARs at ~7% of the CA1 dendritic spine membranes at puberty onset. Furthermore, we showed that this change underlies the enhanced modulation of anxiety, neuronal excitability, and NMDA receptor-dependent synaptic plasticity in the hippocampus by the stress neurosteroid, THP (3alpha-OH-5alpha[beta]-pregnan-20-one or [allo]pregnanolone). Here, we used quantitative electron microscopy to determine whether ABA induction in female rats during adolescence also elevates the expression of alpha4 and delta subunits of alpha4betadelta GABARs, as was observed at puberty onset for mice. Our analysis revealed that rats also exhibit a rise of alpha4 and delta subunits of alpha4betadelta GABARs at puberty onset, in that these subunits are detectable at ~6% of the dendritic spine membranes of CA1 pyramidal cells at puberty onset (postnatal day 32-36; P32-36) but this drops to about 2% by P40-P44. The levels of alpha4 and delta subunits at the CA1 spines remained low following exposure of females to either of the two environmental factors needed to generate ABA--food restriction and access to a running wheel for 4 days--from P40 to P44. This pattern contrasted greatly from those of ABA animals, for which the two environmental factors were combined. Within the hippocampus of ABA animals, 12% of the spine profiles were labeled for alpha4, reflecting a sixfold increase, relative to hippocampi of age-matched (P44) control females (p < 0.005). Concurrently, 7% of the spine profiles were labeled for delta, reflecting a 130% increase from the control values of 3% (p = 0.01). No measurable change was detected for spine size. The observed magnitude of increase in the alpha4 and delta subunits at spines is sufficient to increase both tonic inhibition of hippocampus and anxiety during stress, thereby likely to exacerbate hyperactivity and weight loss. PMID- 22213234 TI - Shoulder muscle activation and coordination in patients with a massive rotator cuff tear: an electromyographic study. AB - Adaptive muscle activation strategies following a massive rotator cuff tear (MRCT) are inadequately understood, and the relationship among muscles during everyday activities has not been considered. Thirteen healthy subjects comprised the control group, and 11 subjects with a MRCT the patient group. Upper limb function was assessed using the Functional Impairment test-hand, neck, shoulder, and arm (FIT-HaNSA). Electromyography (EMG) was recorded from 13 shoulder muscles, comprising five muscle groups, during a shelf-lifting task. Mean FIT HaNSA scores were significantly lower in MRCT patients (p<=0.001), reflecting a severe functional deficit. In MRCT patients, EMG signal amplitude was significantly higher for the biceps brachii-brachioradialis (p < 0.001), upper trapezius-serratus anterior (p= 0.025), muscle groups and for the latissimus dorsi (p = 0.010), and teres major (p=0.007) muscles. No significant differences in the correlation among muscle groups were identified, pointing to an unchanged neuromuscular strategy following a tear. In MRCT patients, a reorganization of muscle activation strategy along the upper limb kinetic chain is aimed at reducing demand on the glenohumeral joint. Increased activation of the latissimus dorsi and teres major muscles is an attempt to compensate for the deficient rotator cuff. Re-education towards an alternate neuromuscular control strategy appears necessary to restore function. PMID- 22213235 TI - Drug interaction between lenalidomide and itraconazole. PMID- 22213236 TI - Expression of microRNAs, miR-21, miR-31, miR-122, miR-145, miR-146a, miR-200c, miR-221, miR-222, and miR-223 in patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma and its prognostic significance. AB - MicroRNAs are a class of non-coding molecules found to regulate a variety of cellular functions in health and disease. Dysregulation of microRNAs is involved in liver disease, especially hepatocarcinogenesis. Since primary hepatic malignancies are typically characterized by late diagnosis, frequent recurrence, and poor response to adjuvant therapy, there is a need for the discovery of novel biomarkers in order to achieve earlier diagnosis, predict tumor aggressiveness and response to adjuvant therapy. The purpose of this study is to evaluate the expression of certain microRNAs (miR-21, -31, -122, -145, -146a, - 200c, -221, 222 and -223) in patients with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), as well as to assess their prognostic significance. Micro-RNA expression was assessed by reverse transcription and real-time PCR (RT PCR). Clinicopathological data and survival rates were retrieved and analyzed. According to our results, miR-21, miR-31, miR-122, miR-221, miR-222 were significantly up-regulated in HCC tissues, whereas miR-145, miR-146a, miR-200c, and miR-223 were found to be down-regulated. Concerning ICC samples, miR-21, miR 31, and miR-223 were found to be over-expressed, whereas miR-122, miR-145, miR 200c, miR-221, and miR-222 were down-regulated. Additionally, expression of miR 21, miR-31, miR-122, and miR-221 in HCC correlated with cirrhosis, while miR-21 and miR-221 associated with tumor stage and poor prognosis. In ICC tissues, miR 21, miR-31, and miR-223 were found to be over-expressed, but no correlation with clinicopathological features was found. PMID- 22213237 TI - Simultaneous quantification of berberine and lysergol by HPLC-UV: evidence that lysergol enhances the oral bioavailability of berberine in rats. AB - A sensitive and simple HPLC method was developed for the simultaneous quantification of berberine and lysergol in rat plasma. The chromatographic separation was achieved on a C(18) column using isocratic elution with methanol acetonitrile-0.1% ortho-phosphoric acid (25:20:55, v/v/v), pH adjusted to 6.5 with triethylamine and detected at a UV wavelength of 230 nm. The extraction of the berberine and lysergol from the rat plasma with methylene chloride resulted in their high recoveries (82.62 and 90.17%). HPLC calibration curves for both berberine and lysergol based on the extracts from the rat plasma were linear over a broad concentration range of 50-1000 ng/mL. The limit of quantification was 50 ng/mL. Intra- and inter-day precisions were <15% and accuracy was 87.12-92.55% for berberine and 87.01-92.26% for lysergol. Stability studies showed that berberine and lysergol were stable in rat plasma for short- and long-term period for sample preparation and analysis. The described method was successfully applied to study the pharmacokinetics of berberine as well as lysergol following oral administration in Sprague-Dawley rats. The results of the study inferred that lysergol improved the oral bioavailability of berberine. PMID- 22213238 TI - The natural product betulinic acid inhibits C/EBP family transcription factors. PMID- 22213239 TI - Chemical exchange saturation transfer magnetic resonance imaging of human knee cartilage at 3 T and 7 T. AB - The sensitivity of chemical exchange saturation transfer (CEST) on glycosaminoglycans (GAGs) in human knee cartilage (gagCEST) in vivo was evaluated at 3 and 7 T field strengths. Calculated gagCEST values without accounting for B(0) inhomogeneity (~0.6 ppm) were >20%. After B(0) inhomogeneity correction, calculated gagCEST values were negligible at 3 T and ~6% at 7 T. These results suggest that accurate B(0) correction is a prerequisite for observing reliable gagCEST. Results obtained with varying saturation pulse durations and amplitudes as well as the consistency between numerical simulations and our experimental results indicate that the negligible gagCEST observed at 3 T is due to direct saturation effects and fast exchange rate. As GAG loss from cartilage is expected to result in a further reduction in gagCEST, gagCEST method is not expected to be clinically useful at 3 T. At high fields such as 7 T, this method holds promise as a viable clinical technique. PMID- 22213240 TI - Annexin A1: novel roles in skeletal muscle biology. AB - Annexin A1 (ANXA1, lipocortin-1) is the first characterized member of the annexin superfamily of proteins, so called since their main property is to bind (i.e., to annex) to cellular membranes in a Ca(2+) -dependent manner. ANXA1 has been involved in a broad range of molecular and cellular processes, including anti inflammatory signalling, kinase activities in signal transduction, maintenance of cytoskeleton and extracellular matrix integrity, tissue growth, apoptosis, and differentiation. New insights show that endogenous ANXA1 positively modulates myoblast cell differentiation by promoting migration of satellite cells and, consequently, skeletal muscle differentiation. This suggests that ANXA1 may contribute to the regeneration of skeletal muscle tissue and may have therapeutic implications with respect to the development of ANXA1 mimetics. PMID- 22213241 TI - A method for analyzing the business case for provider participation in the National Cancer Institute's Community Clinical Oncology Program and similar federally funded, provider-based research networks. AB - BACKGROUND: The Community Clinical Oncology Program (CCOP) plays an essential role in the efforts of the National Cancer Institute (NCI) to increase enrollment in clinical trials. Currently, there is little practical guidance in the literature to assist provider organizations in analyzing the return on investment (ROI), or business case, for establishing and operating a provider-based research network (PBRN) such as the CCOP. In this article, the authors present a conceptual model of the business case for PBRN participation, a spreadsheet-based tool and advice for evaluating the business case for provider participation in a CCOP organization. METHODS: A comparative, case-study approach was used to identify key components of the business case for hospitals attempting to support a CCOP research infrastructure. Semistructured interviews were conducted with providers and administrators. Key themes were identified and used to develop the financial analysis tool. RESULTS: Key components of the business case included CCOP start-up costs, direct revenue from the NCI CCOP grant, direct expenses required to maintain the CCOP research infrastructure, and incidental benefits, most notably downstream revenues from CCOP patients. The authors recognized the value of incidental benefits as an important contributor to the business case for CCOP participation; however, currently, this component is not calculated. CONCLUSIONS: The current results indicated that providing a method for documenting the business case for CCOP or other PBRN involvement will contribute to the long-term sustainability and expansion of these programs by improving providers' understanding of the financial implications of participation. PMID- 22213242 TI - Surface morphology of Diplodon expansus (Kuster, 1856; Mollusca, Bivalvia, Hyriidae) gill filaments after exposure to environmentally relevant concentrations of atrazine herbicide. AB - Brazilian endemic species Diplodon expansus (Kuster, 1856) is found in freshwater bodies in the country's southeast, in large anthropogenic influence regions especially with an extensive agriculture emphasis. One of the main pesticides used in the species occurrence region is the atrazine herbicide, which has a great contamination potential in the aquatic environment. Therefore, several studies into its toxicity in aquatic systems have been developed. However, the tested concentrations are usually very high and rarely found in the environment and the short-term exposure responses in other aquatic organisms such as native bivalves are still scarce. Thus, this study sought to consider the potential effects of environmentally realistic concentrations of atrazine herbicide on the surface morphology of gill filaments of the bivalve D. expansus under laboratory controlled conditions after short-term exposure. None of the animals died before the end of the experiment. The main alterations were observed on the frontal surface of filaments, which include mucus accumulation, cilia loss, and disruption. Mucus increased secretion and accumulation in the frontal filaments region preceded as a protective mechanism. Cilia loss and disruption on the frontal surface of the gill filament indicated that ciliated frontal cells were more sensitive to atrazine exposure and these alterations may cause gills functional damages, compromising the uptake of food particles and respiration. Therefore, higher sublethal concentrations of atrazine may compromise the survival and consequently the population of D. expansus in agriculture areas after a longer period of continuous exposure. PMID- 22213243 TI - A highly diastereo- and enantioselective reaction for constructing functionalized cyclohexanes: six contiguous stereocenters in one step. PMID- 22213244 TI - Galectin-3 deficiency prevents concanavalin A-induced hepatitis in mice. AB - We used concanavalin A (Con A)-induced liver injury to study the role of galectin 3 (Gal-3) in the induction of inflammatory pathology and hepatocellular damage. We tested susceptibility to Con A-induced hepatitis in galectin-3-deficient (Gal 3(-/-)) mice and analyzed the effects of pretreatment with a selective inhibitor of Gal-3 (TD139) in wild-type (WT) C57BL/6 mice, as evaluated by a liver enzyme test, quantitative histology, mononuclear cell (MNC) infiltration, cytokine production, intracellular staining of immune cells, and percentage of apoptotic MNCs in the liver. Gal-3(-/-) mice were less sensitive to Con A-induced hepatitis and had a significantly lower number of activated lymphoid and dendritic cells (DCs) in the liver. The level of tumor necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), and interleukin (IL)-17 and -4 in the sera and the number of TNFalpha-, IFNgamma-, and IL-17- and -4-producing cluster of differentiation (CD)4(+) cells as well as IL-12-producing CD11c(+) DCs were lower, whereas the number of IL-10-producing CD4(+) T cells and F4/80(+) macrophages were significantly higher in livers of Gal-3(-/-) mice. Significantly higher percentages of late apoptotic Annexin V(+) propidium-idodide(+) liver infiltrating MNCs and splenocytes were observed in Gal-3(-/-) mice, compared to WT mice. Pretreatment of WT C57BL/6 mice with TD139 led to the attenuation of liver injury and milder infiltration of IFNgamma- and IL-17- and -4-producing CD4(+) T cells, as well as an increase in the total number of IL-10-producing CD4(+) T cells and F4/80(+) CD206(+) alternatively activated macrophages and prevented the apoptosis of liver-infiltrating MNCs. CONCLUSIONS: Gal-3 plays an important proinflammatory role in Con A-induced hepatitis by promoting the activation of T lymphocytes and natural killer T cells, maturation of DCs, secretion of proinflammatory cytokines, down-regulation of M2 macrophage polarization, and apoptosis of MNCs in the liver. PMID- 22213245 TI - Direct assembly of preformed nanoparticles and graft copolymer for the fabrication of micrometer-thick, organized TiO2 films: high efficiency solid state dye-sensitized solar cells. AB - Solid-state dye-sensitized solar cell with 7.1% efficiency at 100 mW/cm(2) is reported, one of the highest observed for N719 dye. Excellent performance was achieved via a graft copolymer-templated, organized mesoporous TiO(2) film with a large surface area using spindle-shaped, preformed TiO(2) nanoparticles and solid polymer electrolyte. PMID- 22213246 TI - An in situ STM and DTS study of the extremely pure [EMIM]FAP/Au(111) interface. AB - Herein the structure of the interfacial layer between the air- and water-stable ionic liquid 1-ethyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate ([EMIM]FAP) and Au(111) is investigated using in situ scanning tunneling microscopy (STM), distance tunneling spectroscopy (DTS) and cyclic voltammetry (CV) measurements. The in situ STM measurements reveal that structured interfacial layers can be probed in both cathodic and anodic regimes at the IL/Au(111) interface. The structure of these layers is dependent on the applied electrode potential, the number of subsequent STM scans and the scan rate. Furthermore, first DTS results show that the tunneling barrier during the 1st STM scan does not seem to change significantly in the cathodic potential regime between the ocp (-0.2 V) and -2.0 V. PMID- 22213247 TI - Founders review 2012. PMID- 22213248 TI - Nuclear architecture and dynamics: territories, nuclear bodies, and nucleocytoplasmic trafficking. PMID- 22213249 TI - Oxidative stress and apoptosis induced by hydroxyapatite nanoparticles in C6 cells. AB - Hydroxyapatite (HA) nanoparticles have been reported to exhibit anti-tumor effects on various human cancers, but the effects of HA on glioma cells remain unclear. The aim of this study was to explore whether HA can inhibit the proliferation and induce the apoptosis of C6 cells. Use of the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that HA induced C6 cell death in a concentration-dependent and time-dependent manner. Results from hoechst 33342 staining and flow cytometry assay showed that HA induced C6 cell apoptosis significantly. Meanwhile, the flow cytometric assay gave clear indication that HA induced intracellular accumulation of reactive oxygen species (ROS). The measurement of superoxide dismutase (SOD) generation showed that HA decreased the total SOD of cellular levels. Interestingly, pretreatment of N-(mercaptopropionyl)-glycine (N-MPG), known as a type of ROS scavenger formulations, could somehow inhibit C6 cell apoptosis induced by HA. These results may provide potential anti-glioma treatment in the future. PMID- 22213250 TI - HT1001, a proprietary North American ginseng extract, improves working memory in schizophrenia: a double-blind, placebo-controlled study. AB - Evidence suggests that HT1001TM, a proprietary North American ginseng extract containing known levels of active ginsenosides, may improve cognitive function. Importantly, individuals with schizophrenia show marked deficits in working memory, which are believed to be predictive of functional outcome in this population. The present study aimed to characterize the effect of HT1001 on working memory in a group of stable individuals with schizophrenia. In a double blind, placebo-controlled study design, a total of 64 individuals satisfying DSM IV criteria for schizophrenia were randomly assigned to receive either HT100 or placebo for 4 weeks. Verbal working memory and visual working memory were assessed at baseline and again at the end of the treatment phase using the Letter Number Span Test and Visual Pattern Test, respectively. Symptoms and medication side effects were also measured at baseline and post-treatment. Visual working memory was significantly improved in the HT1001 group, but not in the placebo group. Furthermore, extrapyramidal symptoms were significantly reduced after 4 weeks treatment with HT1001, whereas no difference in extrapyramidal effects was observed in the placebo group. These results provide a solid foundation for the further investigation of HT1001 as an adjunct therapy in schizophrenia, as an improvement in working memory and a reduction in medication-related side effects has considerable potential to improve functional outcome in this population. PMID- 22213251 TI - Formal asymmetric hydration of non-activated alkenes in aqueous medium through a "chemoenzymatic catalytic system". PMID- 22213252 TI - A matter of life and death: more members of the TNF receptor family join human gammadelta T lymphocytes. PMID- 22213253 TI - Selenenylsulfide-linked homogeneous glycopeptides and glycoproteins: synthesis of human "hepatic Se metabolite A". PMID- 22213257 TI - Tuning fluorescent response of nanoscale film with polymer grafting. AB - An effective method for tuning fluorescent response of an ultrathin (5 nm) polymer film, which can be used for generation of sensing arrays, is reported. This method is distinctive in that the modification of the optical response is achieved with polymer grafting of a non-fluorescent polymer to a fluorescent film. Using this approach, a number of films demonstrating different fluorescent emission when exposed to solvent vapors were synthesized. PMID- 22213258 TI - Health policy in China. PMID- 22213259 TI - What should the government do regarding health policy-making to develop community health care in Shanghai? AB - BACKGROUND: The traditional three-stratum healthcare system, within which municipal, district and community hospitals all paid great attention to improving medical treatment service by developing medical technology, is no longer able to meet the current health needs in Shanghai. In 1997, the Chinese government called for the development of community health services to serve as a basic platform to provide public health service and basic medical cure. However, because the market oriented economic reform was based on a fee-for-service mechanism (without a strict monitoring system), most community health centers (CHCs) still put great effort into developing medical services geared to profit, rather than to provide proper medical service for all and a "quality" public health service. To try to solve the problem, some government-controlled payment (GCP) system has been implemented in CHCs gradually in districts of Shanghai. The study intended to evaluate the impact of GCP solutions already implemented, as well as the impact of the standardized GCP system with supplementary solutions, in enabling CHCs to focus on providing quality public health services and appropriate medical treatment, rather than focusing on profit and loss, in order to meet the health needs aroused by major socioeconomic transition in Shanghai. METHOD: In order to make a systematic assessment, a standardized form of GCP was piloted for 6 months in Changning, Zhabei, and Songjiang districts, representing rich urban, poor urban and rich rural districts, respectively. We employed an evaluation index system with 26 indicators, based on a systematic review of literature and two rounds of Delphi consultation. The evaluation index system investigates four main themes of the reform: the government's role, the reform measures, the performance of CHC services and satisfaction with CHC services. We conducted an evaluation of the impact of both various types of GCP implemented in recent years and the standardized GCP system used during the more recent pilot project conducted across districts with different socioeconomic profiles. Cross-sectional comparisons between the pilot districts and control districts with similar socioeconomic context were also carried out to observe further the impact of the GCP system. RESULT: Various GCP systems were implemented in 2006 in Changning and Songjiang district and in 2007 in Zhabei district. These GCP systems were standardized in April 2009 and piloted for 6 months on this new basis in these three districts (Changning, Songjiang and Zhabei). The overall "outcome" scores based on an evaluation index applied to Changning, Zhabei, and Songjiang districts have been generally improving from 2004 to 2009. The improvements in outcome were significant after the districts had implemented various GCP solutions and increased further, albeit to a lesser extent, in the three pilot districts from April 2009 to September 2009, when the GCP systems were standardized by the implementation of some supplementary solutions. Cross sectional comparisons between the pilot districts and control districts also indicated that CHC performance was consistently better in the pilot districts after the pilot period than in that of some other "control" districts. CONCLUSION: Although there have been other policies interacting with the impact of GCP, GCP reforms implemented in the pilot districts at different times (as well as the later, standardized GCP system) have been effective in enabling CHCs to focus on providing quality public health services and appropriate medical treatment, rather than concentrating upon profit and loss. The impact of the standardized GCP system was further confirmed by cross-sectional comparisons of some broad indicators, in terms of medical cost, quality of medical service, and coverage of public health service, between the pilot districts and control districts. However, uncertainties exit when looking at individual indicators. Some indicators (see pp. 11-13 and Table 5), such as the service contracting rate with CHCs and the proportion of residents with health records set up, were not sufficient to allow for reasonable estimation of the impact of the GCP. In part this was due to inconsistent data collections. Some indicators, on the other hand, such as the standard management rate of residents with hypertension, were usually affected by the changing government's role over the period. Meanwhile, variations among the three pilot districts with different socioeconomic profiles were observed by several individual indicators within the evaluation index. Further research is needed to investigate the impact of other solutions--such as user fee removal and "zero margin profit" of medicine in CHCs--in order to coordinate other policies with the GCP to improve CHCs more effectively. Longer term observation of impact of the standardized GCP system, as well as other influencing factors in Shanghai based on quality data collected on a standard basis, may help improve policy. Moreover, variations in residents' expectations of barriers in access to CHC services and in healthcare-seeking behavior need to be taken into consideration when designing GCP systems for areas with different socioeconomic profiles in order to meet the different health needs which are a consequence of the major socioeconomic changes in Shanghai (and China in general, it could be agreed). PMID- 22213260 TI - A new financial budgetary system for community health services institutions in China. AB - The separation of revenue and expenditure budgets (SREB) is a new financial budgetary system that is being implemented in community health services (CHS) institutions in some areas in China. Through literature review, it was found that, derived from the traditional separation of revenue and expenditure budgets (TSREB) implemented in administrative public services units, SREB and TSREB have something in common and yet many more differences. On the basis of some quantitative and qualitative data that were collected by field survey, it was also found that implementation of SREB in CHS institutions brings positive outcomes in terms of the quantity, quality and efficiency of services; residents' satisfaction; and the behavior of CHS institutions. The conclusion can be suggested that SREB, as a system having impact upon the incentives facing CHS institutions and the nature of governmental responsibility for developing CHS in China, will promote CHS institutions to fulfill basic service functions if implemented well. Therefore, it is a system that is worth further development and evaluation. PMID- 22213261 TI - Serve the people or close the sale? Profit-driven overuse of injections and infusions in China's market-based healthcare system. AB - Treatment by injection or infusion is widespread in China. Using the common cold as a tracer condition, we explored the reasons for over-prescription of injections and infusions in Guizhou, China. Interviews with prescribers, patients and key informants were supplemented by focus groups. These revealed how historical ideas encourage unnecessary use of percutaneous treatment: faith in the healing power of needles is locally attributed to association with acupuncture. Many patients and some staff believe that injections per se are therapeutic. However, the structure of health service financing and remuneration now reinforces this irrational faith. Market-based reforms have attempted to control costs and increase productivity with an incentive scheme which rewards prescribers financially for over-prescription in general and for use of injections and infusions in particular. Aggressive marketing has displaced oral treatment from health facilities into independent pharmacies, leaving doctors functioning mainly as injection providers. There is a need for a multi-faceted response encompassing education and reform of financial incentives to reduce the use of unnecessary treatment. PMID- 22213262 TI - Evaluating performance of local case-mix system by international comparison: a case study in Beijing, China. AB - BACKGROUND: Case-mix is an important tool for health planning and management in many countries. As a major developing country, China is considering the introduction of the case-mix system in the health reform. Beijing, the capital of China, developed a local case-mix version whose performance needs to be evaluated before utilization. OBJECTIVE: The objective of this study was to evaluate the performance of the case-mix system developed in Beijing by comparing it with those used in Australia and the U.S.A. METHOD: A total of 1.3 million inpatient records from 154 hospitals in Beijing in 2008 were grouped respectively using three case-mix systems: (i) Beijing Diagnosis Related Groups (BJ-DRGs); (ii) US based All Patient DRGs; and (iii) Australian Refined DRGs. Coefficient of variation (CV) and reduction in variance (RIV) were used to measure the performance of DRGs system. RESULTS: The BJ-DRGs produced the best CV and RIV results for expenditure. However, at the level of Major Diagnostic Category (MDC), three MDCs of BJ-DRGs gave the poorest RIVs for both expenditure and length of stay. CONCLUSIONS: Although the performance of BJ-DRGs was acceptable, further revision and improvement is needed. Comparisons with other mature DRGs versions can assist in identifying the improvement priorities of the local version. PMID- 22213266 TI - Functional polymorphism rs7072793 C > T affect individual susceptibility to breast cancer by modulating CD25 transcription activity. AB - Substantial evidence has demonstrated immune defects in breast cancer patients. They have decreased numbers of peripheral blood lymphocytes, but higher numbers of functionally suppressive CD4(+) CD25(+) Treg in both peripheral blood and tumor microenvironment. Constitutive high expression of CD25 is a pivotal characteristic of natural Treg cells. This study aims at investigating if CD25 variability affects breast carcinogenesis. Two polymorphisms (rs7072793 C > T, rs3118470 C > T) in the promoter of CD25 were selected and analyzed by a multiple independent case-control study to assess the association between CD25 genotypes and breast cancer risk. Genotyping a total of 1110 patients and 1060 healthy controls in Chinese populations showed that rs7072793 CT genotype had an odd ratio of 1.49 (95% confidence interval, 1.23-1.89) for developing breast cancer compared with CC genotype, the rs7072793 TT carriers had a further increased risk of breast cancer (OR = 2.11; 95% CI = 1.66-2.87). Furthermore, our transient transfection which focused on reporter gene expression modulated by CD25 promoter demonstrated that the presence of an rs7072793 T allele led to greater transcriptional activity than the C allele. Similarly, rs13347 T carriers were shown to have larger proportion of CD4(+) CD25(+) Tregs in the PBMCs than C carriers in the flow cytometry analysis. However, no significant differences were found in genotype frequencies at rs3118470 C > T site between cases and controls. Our findings suggest that rs7072793 C > T genetic variation in CD25 genes may be genetic modifier for developing breast cancer. PMID- 22213267 TI - Primary surgical treatment of T2 oropharyngeal carcinoma. AB - BACKGROUND: The optimal management of oropharyngeal carcinoma (OPC) is not yet proven. The aim of this study is to analyze the outcome of primary surgical management of T2 cancers of the oropharynx. METHODS: All patients treated with primary surgery for pT2 OPCs between 1984 and 2005 were evaluated retrospectively. Two hundred and twenty eight cases were assessed for disease specific survival (DSS) as well as local control (LC) estimates, with respect to tumor location, surgical technique, status of surgical margins, N classification, and adjuvant therapy. Cases were also evaluated for major complications and functional results. RESULTS: DSS was 73.2% and LC 88.9%. Carcinoma of the tonsils showed a significantly better DSS than lesions of the base of the tongue (DSS = 76.3 vs. 60.2%, P = 0.02). DSS estimates in patients with pN0-1 classification were significantly better in comparison with pN2-3 (83.6 vs. 64.5%, P = 0.018). Patients who were given adjuvant treatment had a better prognosis. The incidence of occult neck metastases was 17% and complications rate 12.7%. CONCLUSIONS: Primary surgical treatment of T2 OPC proved to be an effective treatment modality with a low rate of complications and satisfactory functional results. Complete tumor excision is essential and a neck dissection is justified. Most patients need adjuvant radiotherapy. PMID- 22213268 TI - Determination of salbutamol in human plasma and urine using liquid chromatography coupled to tandem mass spectrometry and its pharmacokinetic study. AB - A sensitive and selective liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was developed and validated for the determination of salbutamol in human plasma and urine, and successfully applied to the pharmacokinetic study of salbutamol in Chinese healthy volunteers after inhalation of salbutamol sulfate aerosol. Salbutamol and the internal standard (IS) acetaminophen in plasma and urine were extracted with ethyl acetate, separated on a C(18) reversed-phase column, eluted with mobile phase of acetonitrile-ammonium acetate (5 m m; 30:70, v/v), ionized by positive ion pneumatically assisted electrospray and detected in the multi-reaction monitoring mode using precursor -> product ions of m/z 240.2 -> 148.1 for salbutamol and 152 -> 110 for the IS. The lower limits of quantitation of salbutamol in human plasma and urine by this method were 0.02 and 1 ng/mL, respectively. The specificity, matrix effect, recovery, sensitivity, linearity, accuracy, precision and several stabilities were validated for salbutamol in human plasma and urine. In conclusion, the validation results showed that this method is robust, specific and sensitive, and can successfully fulfill the requirement of clinical pharmacokinetic study of salbutamol in healthy Chinese volunteers. PMID- 22213269 TI - Effect of transient blockade of N-methyl-D-aspartate receptors at neonatal stage on stress-induced lactate metabolism in the medial prefrontal cortex of adult rats: role of 5-HT1A receptor agonism. AB - Decreased activity of the medial prefrontal cortex (mPFC) has been considered a basis for core symptoms of schizophrenia, an illness associated with a neurodevelopmental origin. Evidence from preclinical and clinical studies indicates that serotonin (5-HT)1A receptors play a crucial role in the energy metabolism of the mPFC. This study was undertaken to determine (1) if transient blockade of N-methyl-D-aspartate receptors during the neonatal stage inhibit energy demands in response to stress, as measured by extracellular lactate concentrations, in the mPFC at the young adult stage, and (2) if tandospirone, a 5-HT1A partial agonist, reverses the effect of the neonatal insult on energy metabolism. Male pups received MK-801 (0.20 mg/kg) on postnatal days (PDs) 7-10. On PD 63, footshock stress-induced lactate levels were measured using in vivo microdialysis technique. Tandospirone (0.1, 1.0, and 5.0 mg/kg) was administered once daily for 14 days before the measurement of lactate levels. Neonatal MK-801 treatment suppressed footshock stress-induced lactate production in the mPFC, but not caudate-putamen, whereas basal lactate levels were not significantly changed in either brain region. The MK-801-induced suppression of footshock stress induced lactate production in the mPFC was attenuated by tandospirone at 1.0mg/kg/day, but not 0.1 or 5.0 mg/kg/day, which is an effect antagonized by coadministration of WAY-100635, a selective 5-HT1A antagonist. These results suggest a role for impaired lactate metabolism in some of the core symptoms of schizophrenia, for example, negative symptoms and cognitive deficits. The implications for the ability of 5-HT1A agonism to ameliorate impaired lactate production in the mPFC of this animal model are discussed. PMID- 22213270 TI - Pathological bone fractures in a 20-year old athletic male with multifocal solitary plasmacytoma of bone. PMID- 22213271 TI - Survival disparities by Medicaid status: an analysis of 8 cancers. AB - BACKGROUND: A study was undertaken to compare survival and 5-year mortality by Medicaid status in adults diagnosed with 8 select cancers. METHODS: Linking records from the Ohio Cancer Incidence Surveillance System (OCISS) with Ohio Medicaid enrollment data, the authors identified Medicaid and non-Medicaid patients aged 15 to 54 years and diagnosed with the following incident cancers in the years 1996-2002: cancer of the testis; Hodgkin and non-Hodgkin lymphoma; early stage melanoma, colon, lung, and bladder cancer; and pediatric malignancies (n = 12,703). Medicaid beneficiaries were placed in the pre-diagnosis group if they were enrolled in Medicaid at least 3 months before cancer diagnosis, and in the peri/post-diagnosis group if they enrolled in Medicaid upon or after being diagnosed with cancer. The authors also linked the OCISS with death certificates and data from the US Census. By using Cox and logistic regression analysis, they examined the association between Medicaid status and survival and 5-year mortality, respectively, after adjusting for patient covariates. RESULTS: Nearly 11% of the study population were Medicaid beneficiaries. Of those, 45% were classified in the peri/post-diagnosis group. Consistent with higher mortality, findings from the Cox regression model indicated that compared with non-Medicaid, patients in the Medicaid pre-diagnosis and peri/post-diagnosis groups experienced unfavorable survival outcomes (adjusted hazard ratio [AHR], 1.52; 95% confidence interval [CI], 1.27-1.82 and AHR, 2.01; 95% CI, 1.70-2.38, respectively). CONCLUSIONS: Medicaid status was associated with unfavorable survival, even after adjusting for confounders. The findings reflect the vulnerability of Medicaid beneficiaries and possible inadequacies in the process of care. PMID- 22213273 TI - Adiabatic turbo spin echo in human applications at 7 T. AB - Nonuniform B(1) fields in ultrahigh-field MR imaging cause severe image artifacts, when conventional radiofrequency (RF) pulses are used. Particularly in MR sequences that encompass multiple RF pulses, e.g., turbo spin echo (TSE) sequences, complete signal loss may occur in certain areas. When using a surface coil for transmitting the RF pulses, these problems become even more challenging, as the spatial B(1) field variance is substantial. As an alternative to conventional TSE sequences, adiabatic TSE sequences can be applied, which have the benefit that these sequences are insensitive to B(1) nonuniformity. In this study, we investigate the potential of using adiabatic TSE at 7 T with surface coil transceivers in human applications. The adiabatic RF pulses were tuned to deal with the constraints in B(1) strength and RF power deposition, but remained in the superadiabatic regime. As a consequence, the dynamic range in B(1) is compromised, and signal modulation is obtained over the echo train. Multidimensional Bloch simulations over the echo train and phantom measurements were obtained to assess these limitations. Still, using proper k-space sampling, we demonstrate improved image quality of the adiabatic TSE versus conventional TSE in the brain, the neck (carotid artery) and in the pelvis (prostate) at 7 T. PMID- 22213274 TI - Bending the prescription opioid dosing and mortality curves: impact of the Washington State opioid dosing guideline. AB - BACKGROUND: Opioid use and dosing for patients with chronic non-cancer pain have dramatically increased over the past decade, resulting in a national epidemic of mortality associated with unintentional overdose, and increased risk of disability among injured workers. We assessed changes in opioid dosing patterns and opioid-related mortality in the Washington State (WA) workers' compensation system following implementation of a specific WA opioid dosing guideline in April, 2007. METHODS: Using detailed computerized billing data from WA workers' compensation, we report overall prevalence of opioid prescriptions, average morphine-equivalent dose (MED)/day, and proportion of workers on disability compensation receiving opioids and high-dose (>=120 mg/day MED) opioids over the past decade. We also report the trend of unintentional opioid deaths during the same time period. RESULTS: Compared to before 2007, there has been a substantial decline in both the MED/day of long-acting DEA Schedule II opioids (by 27%) and the proportion of workers on doses >=120 md/day MED (by 35%). There was a 50% decrease from 2009 to 2010 in the number of deaths. CONCLUSIONS: The introduction in WA of an opioid dosing guideline appears to be associated temporally with a decline in the mean dose for long-acting opioids, percent of claimants receiving opioid doses >=120 mg MED per day, and number of opioid-related deaths among injured workers. PMID- 22213272 TI - Argininosuccinate synthase conditions the response to acute and chronic ethanol induced liver injury in mice. AB - Argininosuccinate synthase (ASS) is the rate-limiting enzyme in both the urea and the L-citrulline/nitric oxide (NO.) cycles regulating protein catabolism, ammonia levels, and NO. generation. Because a proteomics analysis identified ASS and nitric oxide synthase-2 (NOS2) as coinduced in rat hepatocytes by chronic ethanol consumption, which also occurred in alcoholic liver disease (ALD) and in cirrhosis patients, we hypothesized that ASS could play a role in ethanol binge and chronic ethanol-induced liver damage. To investigate the contribution of ASS to the pathophysiology of ALD, wildtype (WT) and Ass(+/-) mice (Ass(-/-) are lethal due to hyperammonemia) were exposed to an ethanol binge or to chronic ethanol drinking. Compared with WT, Ass(+/-) mice given an ethanol binge exhibited decreased steatosis, lower NOS2 induction, and less 3-nitrotyrosine (3 NT) protein residues, indicating that reducing nitrosative stress by way of the L citrulline/NO. pathway plays a significant role in preventing liver damage. However, chronic ethanol-treated Ass(+/-) mice displayed enhanced liver injury compared with WT mice. This was due to hyperammonemia, lower phosphorylated AMP activated protein kinase alpha (pAMPKalpha) to total AMPKalpha ratio, decreased sirtuin-1 (Sirt-1) and peroxisomal proliferator-activated receptor coactivator 1alpha (Pgc1alpha) messenger RNAs (mRNAs), lower fatty acid beta-oxidation due to down-regulation of carnitine palmitoyl transferase-II (CPT-II), decreased antioxidant defense, and elevated lipid peroxidation end-products in spite of comparable nitrosative stress but likely reduced NOS3. CONCLUSION: Partial Ass ablation protects only in acute ethanol-induced liver injury by decreasing nitrosative stress but not in a more chronic scenario where oxidative stress and impaired fatty acid beta-oxidation are key events. PMID- 22213275 TI - The thorny way to the mechanism of ribosomal peptide-bond formation. PMID- 22213276 TI - Magnetic helical micromachines: fabrication, controlled swimming, and cargo transport. PMID- 22213277 TI - Morphological analysis of colon goblet cells and submucosa in type I diabetic rats submitted to physical training. AB - Colon layers, especially the submucosa, as well as the secretion of goblet cells are extremely important for the functioning and transit of substances in this organ. However, the damages arising from type I diabetes and the effects of physical training, which plays crucial role in the treatment of this disease, are not yet known in these regions. To analyze the changes in colon submucosa and goblet cells of diabetic rats, as well as the effects of physical training, Wistar rats were divided into four groups: sedentary control, trained control, sedentary diabetic (SD), and trained diabetic (TD). The training protocol consisted of swimming for 60 min a day, 5 days per week, during 8 weeks. Colon samples were collected, processed, and evaluated by histochemical and ultrastructural techniques. Goblet and submucosa cells did not show alterations in shape, size, protein and carbohydrate content, in all treatment groups. Decreased amount of collagen fibers, however, was observed in the submucosa and lamina propria of SD rats, but this alteration was recovered in TDs. The ultrastructural analysis, in turn, revealed greater quantity of Golgi apparatus cisterns in SDs, distinctly than TDs, which showed improvement in this diabetic condition. Thus, physical training was responsible for the recovery of some important diabetic alterations, possibly improving the motility of substances in the large intestine. Nevertheless, it cannot be considered alone in the treatment of this disease, requiring the combined practice of other methods. PMID- 22213279 TI - Nonlinear enhancement of chiroptical response through subcomponent substitution in M4L6 cages. PMID- 22213278 TI - Evolutionary history of c-myc in teleosts and characterization of the duplicated c-myca genes in goldfish embryos. AB - c-Myc plays an important role during embryogenesis in mammals, but little is known about its function during embryonic development in teleosts. In addition, the evolutionary history of c-myc gene in teleosts remains unclear, and depending on the species, a variable number of gene duplicates exist in teleosts. To gain new insight into c-myc genes in teleosts, the present study was designed to clarify the evolutionary history of c-myc gene(s) in teleosts and to subsequently characterize DNA methylation and early embryonic expression patterns in a cyprinid fish. Our results show that a duplication of c-myc gene occurred before or around the teleost radiation, as a result of the teleost-specific whole genome duplication giving rise to c-myca and c-mycb in teleosts and was followed by a loss of the c-mycb gene in the Gasterosteiforms and Tetraodontiforms. Our data also demonstrate that both c-myc genes previously identified in carp and goldfish are co-orthologs of the zebrafish c-myca. These results indicate the presence of additional c-myca duplication in Cyprininae. We were able to identify differences between the expression patterns of the two goldfish c-myca genes in oocytes and early embryos. These differences suggest a partial sub-functionalization of c myca genes after duplication. Despite differences in transcription patterns, both of the c-myca genes displayed similar DNA methylation patterns during early development and in gametes. Together, our results clarify the evolutionary history of the c-myc gene in teleosts and provide new insight into the involvement of c-myc in early embryonic development in cyprinids. PMID- 22213280 TI - Everyday life with rheumatoid arthritis and implications for patient education and clinical practice: a focus group study. AB - OBJECTIVES: This study aimed to explore how everyday life is affected by rheumatoid arthritis (RA), in order to inform patient education and clinical practice and generate further research. METHODS: Six focus group interviews were conducted with, in total, 32 participants. Interview data were analysed using content analysis methods. RESULTS: The study showed that RA affected almost every aspect of participants' everyday lives, particularly self-identity, social relationships, work and relationships with health and social care professionals. A small number of the participants did not have these experiences, due to receiving fast diagnosis and effective medical treatment. CONCLUSION: The findings point to a need to increase knowledge about RA, support symptom management and reduce the physical, social and psychological challenges posed by RA in everyday life. An individualized and engaged approach to patient education, taking the individual experiences as the point of departure, is suggested. The results indicate directions for further research. The general implications for patient education that emerge from this study might not address the support needs of those who did not experience significant changes in everyday life. A more detailed and in-depth understanding about living with RA in the first years after diagnosis would provide a valuable supplement to the many retrospective studies, and useful knowledge in the design of patient education tailored to those who are newly diagnosed with RA. PMID- 22213281 TI - Large-scale, low-cost fabrication of Janus-type emulsifiers by selective decoration of natural kaolinite platelets. PMID- 22213282 TI - Novel therapeutic approaches for targeting tumor angiogenesis. AB - Current attempts to disrupt the complex process of tumor blood vessel formation are predominantly focused on targeting the vascular endothelial growth factor (VEGF)-VEGFR signaling pathway. Although clinically proven to inhibit VEGF and its receptors, these pharmacologic agents are selective, but not specific. Consequently, many of the approved inhibitors also impair other molecular targets leading to increased toxicity. Current efforts to unravel the complexity of tumor angiogenesis have identified several new candidates for antivascular therapy. In this review article, we identify well-established and novel angiogenic molecules and discuss benefits of the therapeutic approaches based on targeting of such factors. PMID- 22213283 TI - Growth effect of neutrophil elastase on breast cancer: favorable action of sivelestat and application to anti-HER2 therapy. AB - AIM: To investigate the relation between neutrophil elastase (NE) and proliferation of breast cancer cells and whether the NE inhibitor sivelestat could both contribute and be applied to therapy for anti-epithelial growth factor receptor 2 (HER2)-positive breast cancers. MATERIALS AND METHODS: The proliferation or inhibition of breast cancer cell line SKBR-3 by each agent was evaluated by methylthiazole tetrazolium (MTT) assay. Signal transduction and expression of signaling molecules were evaluated by Western blot analysis. RESULTS: The auto tumor progression mechanism initiated by NE through tumor growth factor-alpha (TGF-alpha) was present in breast cancer cells, and this mechanism was intensively suppressed by sivelestat. The effect of trastuzumab was suppressed, and trastuzumab-induced HER2 down-regulation was impaired by TGF alpha. TGF-alpha not only promoted cell proliferation as a ligand but also enhanced resistance to trastuzumab by impairing HER2 down-regulation. Furthermore, combined use of trastuzumab and sivelestat suppressed cell proliferation more intensively than either drug alone and did not provoke impairment by TGF-alpha of HER2-induced down-regulation. CONCLUSION: Combinatorial use of sivelestat and trastuzumab might be a novel therapeutic strategy for HER2-positive breast cancer. PMID- 22213284 TI - Chemopreventive potential of black cohosh on breast cancer in Sprague-Dawley rats. AB - BACKGROUND/AIM: This study examines the chemopreventive potential and action of the herb black cohosh on Sprague-Dawley rats. MATERIALS AND METHODS: Female Sprague-Dawley rats were treated with an extract of black cohosh enriched in triterpene glycosides (27%) at 35.7 (Group I), 7.14 (Group II), 0.714 (Group III) or 0 mg/kg b.w. for 40 weeks starting from 56 weeks of age and the incidence of benign and malignant mammary tumors was determined at the end of observation. RESULTS: Among female rats treated at 35.7 and 7.14 mg/kg b.w. there was a dose related reduction (p<0.05) of the incidence of mammary adenocarcinomas when compared to the treatment of 0.714 mg/kg b.w., with a protection index (calculated relative to the group III; PI=[total tumours * 100 animals of group III] - [total tumours * 100 animals of the group I (or group II)]/ [total tumours of group III] * 100) for mammary adenocarcinomas of 87.5 and 48.8%, respectively. Black cohosh reduced Ki-67 and cyclin D1 protein expression in fibroadenomas, by immunohistochemistry. CONCLUSION: Our results suggest that black cohosh may have chemopreventive potential for mammary cancer. PMID- 22213285 TI - The cyan fluorescent protein nude mouse as a host for multicolor-coded imaging models of primary and metastatic tumor microenvironments. AB - The tumor microenvironment (TME) has an important influence on tumor progression. For example, we have discovered that passenger stromal cells are necessary for metastasis. In this report, we describe six different cyan fluorescent protein (CFP) multicolor TME nude mouse models. The six different implantation models were used to image the TME using multiple colors of fluorescent proteins: I) Red fluorescent protein (RFP)- or green fluorescent protein (GFP)-expressing HCT-116 human colon cancer cells were implanted subcutaneously in the CFP-expressing nude mice. CFP stromal elements from the subcutaneous TME were visualized interacting with the RFP- or GFP-expressing tumors. II) RFP-expressing HCT-116 cells were transplanted into the spleen of CFP nude mice, and experimental metastases were then formed in the liver. CFP stromal elements from the liver TME were visualized interacting with the RFP-expressing tumor. III) RFP-expressing HCT-116 cancer cells were transplanted in the tail vein of CFP-expressing nude mice, forming experimental metastases in the lung. CFP stromal elements from the lung were visualized interacting with the RFP-expressing tumor. IV) In order to visualize two different tumors in the TME, GFP-expressing and RFP-expressing HCT-116 cancer cells were co-implanted subcutaneously in CFP-expressing nude mice. A 3-color TME was formed subcutaneously in the CFP mouse, and CFP stromal elements were visualized interacting with the RFP- and GFP-expressing tumors. V) In order to have two different colors of stromal elements, GFP-expressing HCT-116 cells were initially injected subcutaneously in RFP-expressing nude mice. After 14 days, the tumor, which consisted of GFP cancer cells and RFP stromal cells derived from the RFP nude mouse, was harvested and transplanted into the CFP nude mouse. CFP stromal cells invaded the growing transplanted tumor containing GFP cancer cells and RFP stroma. VI) Mouse mammary tumor (MMT) cells expressing GFP in the nucleus and RFP in the cytoplasm were implanted in the spleen of a CFP nude mouse. Cancer cells were imaged in the liver 3 days after cell injection. The dual-color dividing MMT cells and CFP hepatocytes, as well as CFP non-parenchymal cells of the liver were imaged interacting with the 2-color cancer cells. CFP-expressing host cancer-associated fibroblasts (CAFs) were predominantly observed in the TME models developed in the CFP nude mouse. Thus, the CFP nude mouse adds another color to the pallet of the TME, allowing multiple types of color-coded cancer and stromal cells to be imaged simultaneously. The multi-colored models described in this report provide new opportunities to study the cellular interactions in the live primary and metastatic TME. PMID- 22213286 TI - Color-coded real-time subcellular fluorescence imaging of the interaction between cancer and host cells in live mice. AB - Stromal cells are essential for tumor growth. Stromal cells interact with cancer cells during tumor growth and progression. We report here the development of a tri-color imageable mouse model to visualize the interaction between host cells and cancer cells. To observe subcellular cancer cell dynamics in vivo, HT-1080 human fibrosarcoma cells were labeled in the nucleus with histone H2B-green fluorescent protein (GFP) and with retroviral red fluorescent protein (RFP) in the cytoplasm. HT-1080-GFP-RFP cells were sprinkled over a skin-flap in transgenic GFP immunocompetent mice. After 24 h, the mice were imaged with an Olympus IV100 laser scanning microscope. HT-1080-GFP-RFP cells were visualized surrounded by host-derived lymphocytes and macrophages both expressing GFP. It was possible to observe host GFP macrophages contacting, engulfing, and digesting dual-color HT-1080-GFP-RFP cells in real time. The dual-color cancer cells were readily visible after being engulfed in the GFP macrophages. Other cancer cells were visualized being killed by lymphocytes. The results of this study show that differentially labeling cells with spectrally-distinct fluorescent protein can allow subcellular-resolution imaging of cell-cell interactions between host and cancer cells. PMID- 22213287 TI - Effects of vitamin D-binding protein-derived macrophage-activating factor on human breast cancer cells. AB - BACKGROUND: Searching for additional therapeutic tools to fight breast cancer, we investigated the effects of vitamin D-binding protein-derived macrophage activating factor (DBP-MAF, also known as GcMAF) on a human breast cancer cell line (MCF-7). MATERIALS AND METHODS: The effects of DBP-MAF on proliferation, morphology, vimentin expression and angiogenesis were studied by cell proliferation assay, phase-contrast microscopy, immunohistochemistry and western blotting, and chorioallantoic membrane (CAM) assay. RESULTS: DBP-MAF inhibited human breast cancer cell proliferation and cancer cell-stimulated angiogenesis. MCF-7 cells treated with DBP-MAF predominantly grew in monolayer and appeared to be well adherent to each other and to the well surface. Exposure to DBP-MAF significantly reduced vimentin expression, indicating a reversal of the epithelial/mesenchymal transition, a hallmark of human breast cancer progression. CONCLUSION: These results are consistent with the hypothesis that the known anticancer efficacy of DBP-MAF can be ascribed to different biological properties of the molecule that include inhibition of tumour-induced angiogenesis and direct inhibition of cancer cell proliferation, migration and metastatic potential. PMID- 22213288 TI - Combinations of resveratrol, cisplatin and oxaliplatin applied to human ovarian cancer cells. AB - In this study, combinations of resveratrol with platinum drugs cisplatin and oxaliplatin were administered to human ovarian A2780, A2780(cisR) and A2780(ZD0473R) cell lines with the aim of offering a means of overcoming drug resistance. Cell viability was quantified using the 3-(4,5-Dimethyl-2-thiazolyl) 2,5-diphenyl-2H-tetrazolium bromide (MTT) reduction assay. Combination indices and dose response curves were used as measures of the combined drug action. Greatest synergism was observed when resveratrol was administered first followed by the platinum drug (cisplatin or oxaliplatin) 2 h later, and the least synergism was achieved when the two types of compounds were administered as a bolus. The results can be explained by assuming that the administration of resveratrol 2 h before the platinum drug may sensitize the ovarian cancer cells to platinum-induced apoptosis, thus providing a means of overcoming drug resistance. If the results are confirmed in vivo, they may be significant clinically. PMID- 22213289 TI - Dual-mode interaction between quercetin and DNA-damaging drugs in cancer cells. AB - BACKGROUND: DNA-damaging drugs constitute standard chemotherapy regimen for advanced colorectal cancer. Here, the interactions between quercetin and 5 fluorouracil (5-FU), etoposide, and camptothecin were examined in cancer cells. MATERIALS AND METHODS: HCT116 colorectal or PPC1 prostate cancer cells were treated with quercetin and the drugs. Clonogenicity assays, cell cycle profiles, and expressions of p53, p21, BAX, survivin and cyclin B1 proteins were used to examine the effects of the treatments. RESULTS: Quercetin synergistically inhibited the clonogenicity of the wild-type cells, but inhibited the cell cycle effects of all the drugs tested. In p53-null cells, the combination of low dose 5 FU with up to 6 MUM quercetin promoted clonogenic survival. Treatment of p53-wild type cells with 50 MUM quercetin reduced drug-induced up-regulation of p53, p21 and BAX. The combination of quercetin and the drugs also reduced the levels of cyclin B1 and survivin proteins. CONCLUSION: While high doses of quercetin synergize with DNA-damaging agents, the effect of drug combination with quercetin is influenced by the effective doses and the p53 status of the cells. PMID- 22213290 TI - Mutated in colorectal cancer protein modulates the NFkappaB pathway. AB - BACKGROUND: The tumour suppressor gene 'mutated in colorectal cancer' (MCC) is silenced through promoter methylation in colorectal cancer and has been implicated as a regulator of the nuclear factor kappa B (NFkappaB) pathway. Therefore, we aimed to determine whether MCC modulates NFkappaB activation in colorectal cancer. MATERIALS AND METHODS: NFkappaB activation was assessed using luciferase reporter assays in colorectal cancer cells in vitro. MCC methylation was analysed in primary tumour specimens from patients with inflammatory bowel disease. RESULTS: Re-expression of MCC reduced NFkappaB-dependent transcription in tumour necrosis factor alpha (TNFalpha)- or lipopolysaccharide (LPS) stimulated cells. Conversely, knockdown of MCC resulted in accumulation of the inhibitor of kappa B alpha (IkappaBalpha) protein, encoded by NFKBIA, a first response gene specifically and rapidly regulated by NFkappaB pathway activation. The MCC gene is methylated in up to 6/16 of inflammatory bowel disease-associated tissue specimens, and myosin-10 and valosin-containing protein were identified as MCC-interacting proteins. CONCLUSION: These findings suggest that MCC modulates NFkappaB pathway signalling indirectly in colorectal cancer cells. PMID- 22213291 TI - Combination of glucan, resveratrol and vitamin C demonstrates strong anti-tumor potential. AB - beta-Glucans are naturally occurring carbohydrates found in plants, fungi and some bacterial species, and currently are well-established and powerful immunomodulators with beneficial properties in cancer therapy. Recent studies suggested that some additional bioactive molecules have synergistic effects when combined with glucan. In the current study, we evaluated the anticancer properties of glucan, resveratrol, vitamin C combination. We found that compared to the individual components, the combination was the strongest activator of phagocytosis and antibody formation. Using two different models of cancer treatment, our results demonstrated that the combination strongly suppressed the growth of breast and lung tumors, most likely due to the stimulation of apoptosis. PMID- 22213292 TI - The hedgehog pathway inhibitor GDC-0449 alters intracellular Ca2+ homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells. AB - AIM: Cisplatin resistance is an important issue in lung cancer. We aimed at investigating if the Hedgehog pathway inhibitor GDC-0449 is effective in cisplatin-resistant cells and if it alters intracellular Ca(2+)-homeostasis. MATERIALS AND METHODS: The cytoplasmatic ([Ca(2+)](cyto)) and endoplasmatic ([Ca(2+)])(ER) Ca(2+) concentration of HCC (adeno carcinoma of the lung) and H1339 (small cell lung carcinoma) cells were measured with the calcium indicator dye Fura-2 AM. The expression of the inositol-1,4,5-trisphosphate receptor (IP(3)R) and sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) were analyzed using western blot analysis. RESULTS: GDC-0449 inhibited cell growth in cisplatin naive and -resistant cells. In both cell types, GDC-0449 increased [Ca(2+)](cyto) and reduced endoplasmatic [Ca(2+)](ER). Cisplatin failed to considerably alter Ca(2+) homeostasis in resistant cells. The effects of GDC-0449 on intracellular Ca(2+) homeostasis were not mediated by an altered expression of IP(3)R or SERCA. CONCLUSION: GDC-0449 alters intracellular Ca(2+) homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells. PMID- 22213293 TI - Anticancer effects of synthetic phosphoethanolamine on Ehrlich ascites tumor: an experimental study. AB - BACKGROUND: Antineoplastic phospholipids (ALPs) represent a promising class of drugs with a novel mode of action undergoes rapid turnover in the cell membrane of tumors, interfering with lipid signal transduction, inducing cell death. The aim of this study was to investigate the synthetic phosphoethanolamine (Pho-s) as a new anticancer agent. MATERIALS AND METHODS: Cell viability and morphology were assessed by (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Hoechst and rhodamine staining. Apoptosis was assessed by Annexin V and propidium iodide (PI) staining, caspase-3 activity, mitochondrial membrane potential (DeltamPsi) and cell cycle analysis, combined with evaluation of tumor growth in Ehrlich Ascites Tumor (EAT) bearing mice. RESULTS: We found that Pho-s 2.30 mg/ml induced cytotoxicity in all tumor cell lines studied without affecting normal cells. In vitro studies with EAT cells indicated that Pho-s induced apoptosis, demonstrated by an increase in Annexin-V positive cells, loss of mitochondrial potential (DeltamPsi) and increased caspase-3 activity. It was also shown to increase the sub-G(1) apoptotic fraction and inhibit progression to the S phase of the cell cycle. Additionally, antitumor effects on the EAT-bearing mice showed that Pho-s, at a concentration of 35 and 70 mg/kg, inhibited tumor growth and increased the lifespan of animals without causing liver toxicity. CONCLUSION: These findings suggest that Pho-s is a potential anticancer candidate drug. PMID- 22213294 TI - Trastuzumab has opposing effects on SN-38-induced double-strand breaks and cytotoxicity in HER2-positive gastric cancer cells depending on administration sequence. AB - AIM: We investigated the effects of trastuzumab, an anti-HER2 humanized monoclonal antibody, on DNA breaks induced by SN-38, a topoisomerase-1 inhibitor, in gastric cancer cell lines positive or negative for HER2 expression. MATERIALS AND METHODS: NCI-N87 (HER2+) and MKN74 (HER2-) cells were exposed to SN-38 in the presence or absence of trastuzumab. Trastuzumab was added either prior to or after SN-38. Effects of trastuzumab on the induction of gamma-H2AX, a marker of DNA double-strand breaks, the cytotoxicity of SN-38 and cell cycle progression were determined. RESULTS: When trastuzumab was administered following SN-38, it increased gammaH2AX levels and cytotoxicity of SN-38 in NCI-N87 cells, but not in MKN74 cells. In contrast, pretreatment with trastuzumab reduced SN-38-induced gammaH2AX expression and cytotoxicity of SN-38 in NCI-N87 cells, but not in MKN74 cells. Trastuzumab delayed cell cycle progression in NCI-N87 cells only. CONCLUSION: Trastuzumab has opposing effects on SN-38-induced double-strand breaks and cytotoxicity depending on the order of administration of the two agents. PMID- 22213295 TI - Somatostatin receptor subtype 2 A (SSTR2A) and HER2 expression in gastric adenocarcinoma. AB - BACKGROUND: A possible anticancer role for somatostatin has been suggested. This study assessed the presence of somatostatin receptor subtype 2A (SSTR2A) in gastric cancer, correlating its expression with histological type, grade, human epidermal growth factor receptor 2 (HER2) expression, and disease outcome. MATERIALS AND METHODS: Gastric cancer tissues of 51 consecutive patients were collected for immunohistochemical assessment of both SSTR2A and HER2 expression. RESULTS: SSTR2A expression was observed in 38 (74.5%) cases. Prevalence of SSTR2A expression was significantly higher in well to moderately (G1-2) differentiated gastric cancer as compared to poorly (G3) differentiated tumors (96% vs. 52%; p<0.01), as well as in intestinal- than in diffuse-type cancer (97% vs. 20%; p<0.001). HER2 expression was positive in 18 (35%) patients, and it was associated with SSTR2A expression (r=0.50, p<0.001), being co-expressed in 17 (95%) out of 18 positive cases. RFS was significantly lower in patients with diffuse HER2 expression. CONCLUSION: This study demonstrated a co-localization between SSTR2A and HER2, potentially opening new therapeutic strategies for patients with gastric cancer. PMID- 22213296 TI - Inhibition of cyclin D1 by shRNA is associated with enhanced sensitivity to conventional therapies for head and neck squamous cell carcinoma. AB - BACKGROUND: Overexpression of cyclin D1 is associated with resistance to chemotherapy and radiotherapy in several types of cancer including head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Cyclin D1 was silenced in an HNSCC cell line and its effect tested in sensitizing the cells to cisplatin, in vitro as well as in vivo. The HNSCC cell line NT8e, which is a chemoresistant, cyclin D1 over-expressing cell line, was used in the study. RNAi (shRNA) against cyclin D1 was designed and cloned in a vector. RESULTS: Stable silencing of cyclin D1 resulted in delayed cell cycle progression and significantly sensitized the cells to cisplatin. Effective cell kill was achieved at a much lower therapeutic dose in vivo. CONCLUSION: Suboptimal concentrations of cisplatin could be used in vivo to eradicate xenograft tumors indicating the promise of combining vector-based cyclin D1 silencing with chemotherapy to achieve maximum tumor regression. PMID- 22213297 TI - Naringin inhibits tumor growth and reduces interleukin-6 and tumor necrosis factor alpha levels in rats with Walker 256 carcinosarcoma. AB - The flavonoid naringin is a polyphenolic compound that naturally occurs in citrus. Patients with cancer generally present features of malnutrition and cachexia. Levels of the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) are raised in patients with cancer. This study was designed to analyze the in vivo effect of naringin in the therapeutic treatment of rats bearing Walker 256 carcinosarcoma (W256). Rats were treated intraperitoneally with different doses of naringin (10, 25 and 35 mg/kg), for 50 days. At 25 mg/kg, naringin inhibited tumor growth by ~75%. With this treatment, TNF-alpha and IL-6 levels decreased (p<0.05) in comparison with the control. In addition, two rats presented complete tumor regression. Inhibition of tumor growth, survival increase and the reduction of TNF-alpha and IL-6 levels in rats bearing W256 treated with naringin strongly suggest that this compound has potential as an anticarcinogenic drug. PMID- 22213298 TI - Synthesis of trans-bis-(2-hydroxypyridine)dichloroplatinum(II) and its activity in human ovarian tumour models. AB - We report the synthesis and in vitro activity of trans-bis-(2 hydroxypyridine)dichloroplatinum(II) (coded as DH3) in humour ovarian tumour models. The compound is less active than cisplatin against the parent cell line A2780 but more so against the cisplatin-resistant A2780(cisR) cell line, thus indicating that it is better able to overcome mechanisms of resistance operating in the A2780(cisR) cell line. DH3 is marginally less active than cisplatin against ZD0473-resistant A2780(ZD0473R) cell line but with a much lower resistance factor than cisplatin. DH3 has higher platinum-DNA binding levels than cisplatin in the A2780 and A2780(ZD0473) cell lines and a lower value in the A2780(cisR) cell line. Even though DH3 has a lower activity than cisplatin, the higher platinum-DNA binding levels observed for DH3 than cisplatin in A2780 and A2780(ZD0473R) cell lines may not be entirely unexpected when we note that the two compounds are likely to differ in their nature of binding with DNA. Whereas cisplatin binds with DNA forming mainly intrastrand 1,2-Pt(GG) and 1,2-Pt(AG) adducts, DH3 is expected to form more 1,2-interstrand Pt(GG) and monofunctional adducts. The higher activity of DH3 than cisplatin in the A2780(cisR) cell line despite its lower level of platinum-DNA binding can also be seen to indicate the complexity of the situation. Although platinum-DNA binding may be an essential requirement for apoptosis, it is not sufficient to cause cell death that is actually brought about by downstream processes in the cycle. The results of interaction with pBR322 plasmid DNA combined with BamH1 digestion show that DH3 is less able to prevent BamH1 digestion than is cisplatin, indicating that cisplatin causes a greater conformational change in the DNA than DH3. CONCLUSION: DH3 is less active than cisplatin against the parent cell line A2780, but more so against the cisplatin-resistant A2780(cisR) cell line, thus indicating that it is better able to overcome mechanisms of resistance operating in the A2780(cisR) cell line. PMID- 22213299 TI - Circulating transforming growth factor-beta and epidermal growth factor receptor as related to virus infection in liver carcinogenesis. AB - BACKGROUND: The aim of our study was to improve the detection of HCC by measuring alpha-fetoprotein (AFP) in addition to other molecular markers by estimating the plasma concentration of transforming growth factor beta (TGF-beta) and epidermal growth factor receptor (EGFR). In particular, the role of hepatitis C and B viruses (HCV and HBV) infection was evaluated with relation to TGF-beta and EGFR plasma concentration. MATERIALS AND METHODS: Eighty-five patients with liver disease, 54 with hepatocellular carcinoma (HCC), 16 with liver metastasis (LM), 15 with liver cirrhosis (LC) and 30 healthy volunteers were evaluated. AFP, TGF beta and EGFR were detected with enzyme-linked immunoassay (ELISA) in plasma of all study participants. RESULTS: The mean values of TGF-beta and EGFR in all patients were much higher than in control group, p<0.0001. In HCC patients the levels of TGF-beta and EGFR were much higher than in LM and LC patients. Moreover, TGF-beta and EGFR were significantly higher in the presence of both viruses or only in the presence of HCV, p=0.002. No decrease or increase of AFP was noted in these patients. CONCLUSION: Our data suggest the reliability of TGF beta and EGFR in detecting HCC, in particular when the carcinogenesis is affected by virus infection. PMID- 22213300 TI - A high-throughput cell-based screening for L858R/T790M mutant epidermal growth factor receptor inhibitors. AB - A high-throughput 32D(L858R/T790M) cell-based assay to identify inhibitors of the L858R/T790M mutant epidermal growth factor receptor (EGFR) pathway was established. After screening, ten hits from among 60,000 compounds in our in house compound library were initially identified. In the secondary assays, one hit, 1-[2-(decyloxy)-2-oxoethyl]-3-methyl-2-[(4-methylphenoxy) methyl]-1H benzimidazol-3-ium, was confirmed to directly inhibit the kinase activity of recombinant L858R/T790M EGFR and the phosphorylation of EGFR-L858R/T790M in gefitinib-resistant H1975 cells. Thus, this high-throughput assay system may be useful for identifying novel inhibitors which suppress mutant EGFR-T790M signalling and for overcoming T790M-mediated acquired resistance for future anticancer drug discovery. PMID- 22213301 TI - Intense CD44 expression is a negative prognostic factor in tonsillar and base of tongue cancer. AB - BACKGROUND: Patients with tonsillar and base of tongue cancer, which are human papillomavirus (HPV) positive, have a better clinical outcome than those with HPV negative tumors. The identification of additional predictive markers for response to therapy could still be of great use. MATERIALS AND METHODS: Tumor markers CD44, p16, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), E-cadherin, cyclooxygenase-2 (COX 2), Ki-67, and p27 were analyzed by immunochemistry, and HPV status was tested by polymerase chain reaction (PCR) in tumors from 73 patients and correlated to survival. RESULTS: High intensity CD44 staining (p=0.006) and high EGFR expression (p=0.026) were indicators of poor prognosis, while high p16 expression (p=0.021) and younger age (p=0.002) were positive prognostic markers for disease-specific survival. Furthermore, staining of CD44 (p=0.026) and age (p=0.002) were shown to be strong prognostic markers in multivariate analysis, which should be evaluated further for possible use in clinical practice. PMID- 22213302 TI - Clinical application of MAGE A1-6 RT-nested PCR for diagnosis of lung cancer invisible by bronchoscopy. AB - BACKGROUND: The main goal of this study was to evaluate the diagnostic efficacy of melanoma-associated antigen (MAGE) A1-6 reverse transcriptase-nested polymerase chain reaction (RT-nested PCR) of bronchial washing fluid for the detection of lung cancer invisible by bronchoscopy. PATIENTS AND METHODS: To determine the expression of MAGE A1-6 gene in 75 lung carcinomas diagnosed by conventional fluoroscopy-guided lung biopsy and 58 cancer-free controls, RT nested PCR was performed of bronchial washing fluid. MAGE A1-6 RT-nested PCR data was analyzed according to tumor histology, stage, size, and compared with cytological data. RESULTS: MAGE A1-6 RT-nested PCR displayed higher sensitivity (64.0%) than that of conventional cytology (14.7%). There was no significant correlation between MAGE gene expression and histological types or clinical stage. For tumor size, detection rates were 74.0% in tumor smaller than 3 cm and 58.7% in these larger than 3 cm. CONCLUSIONS: MAGE A1-6 RT-nested PCR of bronchial washing fluid may be a useful method for diagnosis of peripheral lung cancer in clinical practice. PMID- 22213303 TI - Relationship between interval from surgery to radiotherapy and local recurrence rate in patients with endometrioid-type endometrial cancer: a retrospective mono institutional Italian study. AB - AIM: To assess the relationship between the timing of radiotherapy and the risk of local failure in patients with endometrioid-type endometrial cancer who had undergone surgery and adjuvant external pelvic radiotherapy (with or without brachytherapy), but not chemotherapy. PATIENTS AND METHODS: One hundred and seventy seven patients were analyzed in this study. The median follow-up of the survivors was 72 months. RESULTS: Radiotherapy was delivered after a median time of 14.6 weeks from surgery and the median overall treatment time was 6.4 weeks. The tumor relapsed in 32 (18.1%) patients after a median time of 21 months. The local recurrence (vaginal or central pelvic) occurred in 11 patients. The local recurrence rate was associated with tumor grade (p=0.02), myometrial invasion (p=0.046), FIGO stage (p=0.003), pathological node status (p=0.037) and time interval from surgery to radiotherapy using 9 weeks as the cut-off value (p=0.046), but not with the overall treatment time. All the local relapses occurred in patients who received adjuvant irradiation after an interval from surgery >9 weeks. CONCLUSION: The time interval from surgery to radiotherapy might affect the local recurrence rate in patients not receiving chemotherapy. Every possible effort should be made to start radiotherapy within 9 weeks, when radiotherapy only is deemed necessary as adjuvant treatment. PMID- 22213304 TI - Vinorelbine versus paclitaxel for patients with advanced non-small cell lung cancer (NSCLC) and a performance status of 2. AB - AIM: The purpose of this study was to compare two single agents paclitaxel (intravenous) versus vinorelbine (oral) in non-small cell lung cancer (NSCLC) patients with performance status (PS):2. PATIENTS AND METHODS: The patients were randomized to receive either oral vinorelbine 60 mg/m(2) on days 1, 8, 15 every 4 weeks for 4 cycles (group A) or paclitaxel 90 mg/m(2) intravenously for 1 h on days 1, 8, 15 every 4 weeks for a total of 4 cycles (group B). RESULTS: Among the 74 eligible patients (36 in arm A and 38 in arm B) in arm A, two (6%) had a partial response (95% CI, 0.7-18.7) and 5 (14%) had stable disease (95% CI, 4.7 29.5). In arm B, five (13%) had a partial response (95% CI, 4.4-28.1) and 7 (18%) had stable disease (95% CI, 7.7-34.3). No significant difference was found in terms of clinical benefit between the two groups after two cycles of treatment except for appetite in favour of paclitaxel (p=0.01). Median survival was 3.1 months (95% CI, 2.2-4.0) for arm A and 5.1 months (95% CI, 2.7-7.6) for arm B (p=0.95). Toxicity was mild and only alopecia was more profound in the patients of arm B (p=0.008). CONCLUSION: No significant difference was found in clinical benefit between PS:2 NSCLC patients treated with either vinorelbine or paclitaxel. PMID- 22213305 TI - The carcinoembryonic antigen as a potential prognostic marker for neuroendocrine carcinoma of the breast. AB - AIM: Primary neuroendocrine carcinomas of the breast (PNCB) are very rare and tumor markers for this indication are not well defined. We aim at reporting a case and providing a marker useful for prognosis and prediction of tumor recurrence for patients with PNCB. CASE REPORT: A 75-year-old woman presented with a slight painful lump in her left breast of more than 6 months duration. Prior to surgery, the serum level of carcinoembryonic antigen (CEA) (54.4 ng/ml; normal limit <5.0 ng/ml) was significantly elevated. Ultrasonography identified a hypoechoic lesion. Mammography revealed a hyperdense lesion with a well circumscribed margin. The patient underwent a modified radical mastectomy with axillary lymph node dissection. Pathology showed tumor cells with neuroendocrine features, with diffuse immunopositivity for chromogranin and synaptophysin. The tumor cells were also strongly positive for progesterone and estrogen receptor, but negative for HER-2/neu expression. The CEA value gradually decreased to the normal range within one month after surgery. Neither recurrence nor distant metastasis has been detected at 20 months after surgery and hormone therapy with letrozole. The serial CEA levels were within normal limits in the follow-up period. CONCLUSION: The serum CEA level after surgery may be a potential marker for evaluating tumor recurrence or prognosis of patients with PNCB. PMID- 22213306 TI - A population-based study of the pattern of terminal care and hospital death in patients with non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is a major cause of cancer-related death and utilization of health care resources worldwide. Significant costs are generated in the months before death, with hospitalization being a major cost driver. Moreover, hospital death causes physical and emotional distress. We analyzed factors predicting the likelihood of hospital death from NSCLC. Patients who died from NSCLC (any stage and treatment) during the recent 5-year interval up to 31.12.2010, within a defined geographical region of northern Norway, were included (n=112). Only 15% of all patients did not require any hospitalization during their last 3 months. A minority of patients (24%) died at home, 53% in hospital and 23% in nursing homes. The likelihood of hospital death was independent of initial management and time between diagnosis and death. Even 45% of patients treated with best supportive care died in hospital. Multivariate analysis showed that initial tumor stage of T4 (RR 1.64), systemic therapy during the last 3 months of life (RR 2.60) and any active therapy during the last 4 weeks (RR 1.63) significantly increased the likelihood of hospital death, while early discussion of resuscitation preferences reduced it (RR 0.21). These four parameters suggest that early focus on symptom palliation and resuscitation preferences are crucial components of strategies improving terminal care. Patients with T4 tumors might experience unsatisfactory symptom control and should be offered a part in prospective studies addressing these issues. PMID- 22213308 TI - Analysis of failures in patients with FIGO stage IIIc1-IIIc2 endometrial cancer. AB - AIM: To assess the pattern of failures in patients with FIGO stage IIIc(1) IIIc(2) endometrial cancer. PATIENTS AND METHODS: Data were retrospectively analyzed for 34 patients with this malignancy who underwent extra-fascial total hysterectomy, bilateral salpingo-oophorectomy and pelvic/para-aortic node dissection. Postoperative treatment consisted of radiotherapy in 5 patients, 6 cycles of chemotherapy in 9, and 3-4 cycles of chemotherapy followed by radiotherapy in 20. The median follow-up of survivors was 33 months (range, 6 to 133 months). RESULTS: Tumour relapsed in 14 out of 34 patients (41.2%). Median time to recurrence was 17 months (range, 9.5-42 months). Vaginal recurrence developed in 2 patients (5.9%), distant recurrence in 5 (14.7%), pelvic node recurrence in 3 (8.8%) and para-aortic recurrence in 7 (20.6%). Two patients had multiple sites of recurrence. Distant failure occurred in 11.1% of the patients who received 6 cycles of chemotherapy versus 20.0% of those who had 3-4 cycles of chemotherapy followed by radiotherapy. Five-year overall survival was 60.5%, and, in particular, it was 62.5% for stage IIIc(1) and 57.0% for stage IIIc(2). CONCLUSION: FIGO stage IIIc(1)-IIIc(2) endometrial cancer relapses in approximately 40% of cases, and distant sites and para-aortic nodes represent the most common sites of failure. PMID- 22213307 TI - Efficacy and feasibility of induction chemotherapy and radiotherapy plus cetuximab in head and neck cancer. AB - BACKGROUND: To determine the potential activity and tolerability of sequential treatment in head and neck cancer, we conducted a phase II trial based on induction chemotherapy of two cycles of taxotere, cisplatin and 5-fluorouracil followed by radiotherapy plus weekly cetuximab. PATIENTS AND METHODS: Thirty-six patients with stage III or IV squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx were treated and evaluated for response and acute toxicity. RESULTS: Eighty-one percent of patients had stage IV disease and 42% had hypopharyngeal and oral cavity primaries. The overall response rate was 81.8%, with 60.6% complete response and 33.3% partial response. Severe toxicities were febrile neutropenia (6%) during induction chemotherapy and dermatitis (48%), mucositis (33%) and dysphagia (12%) during the concurrent phase. CONCLUSION: Our protocol proved to be feasible, effective and well tolerated. This sequential strategy should be further investigated. PMID- 22213309 TI - Vitamin D and its analogs in cancer prevention and therapy. PMID- 22213310 TI - Vitamin D: potential in the prevention and treatment of lung cancer. AB - Vitamin D is a steroid hormone traditionally recognized for maintaining calcium and phosphorous homeostasis in the body. However, it is now widely accepted that it exerts several extraskeletal actions, including anti-tumorigenic and immunomodulatory effects in vitro and in vivo. There is now a huge interest in studying the modes of action of vitamin D in a wide range of infectious and chronic disease settings and its potential in cancer prevention and treatment is currently under detailed investigation. In relation to the lung, evidence from observational studies, animal models and in vitro cell culture suggest that vitamin D may play a beneficial role in pulmonary inflammation. In addition, an adequate vitamin D status may be important for lung cancer prevention. Furthermore, vitamin D or its analogs, alone or in combination with cytotoxics, have potential in the treatment of lung cancer. Vitamin D is converted to its active form locally in the lung, suggesting that it may play an important role in lung health. Here, we review the evidence from observational, clinical and experimental studies in relation to vitamin D and lung cancer. In addition, we discuss vitamin D resistance in lung tumors and the potential molecular mechanisms of vitamin D action in lung cancer cells. PMID- 22213311 TI - Ecological studies of the UVB-vitamin D-cancer hypothesis. AB - BACKGROUND/AIM: This paper reviews ecological studies of the ultraviolet-B (UVB) vitamin D-cancer hypothesis based on geographical variation of cancer incidence and/or mortality rates. MATERIALS AND METHODS: The review is based largely on three ecological studies of cancer rates from the United States; one each from Australia, China, France, Japan, and Spain; and eight multicountry, multifactorial studies of cancer incidence rates from more than 100 countries. RESULTS: This review consistently found strong inverse correlations with solar UVB for 15 types of cancer: bladder, breast, cervical, colon, endometrial, esophageal, gastric, lung, ovarian, pancreatic, rectal, renal, and vulvar cancer; and Hodgkin's and non-Hodgkin's lymphoma. Weaker evidence exists for nine other types of cancer: brain, gallbladder, laryngeal, oral/pharyngeal, prostate, and thyroid cancer; leukemia; melanoma; and multiple myeloma. CONCLUSION: The evidence for the UVB-vitamin D-cancer hypothesis is very strong in general and for many types of cancer in particular. PMID- 22213312 TI - The Scots' Paradox: can sun exposure, or lack of it, explain major paradoxes in epidemiology? AB - Five epidemiological paradoxes that have puzzled epidemiologists for a decade or more can be explained by the UVB-vitamin D hypothesis. The Scots' Paradox is examined in detail as an example. Many subsidiary factors varying over time and place influence the amount of UVB which reaches the skin of individuals and so the amount of vitamin D synthesised, while other factors influence the amount ingested. These factors are plotted leading to a common pathway that ends in vitamin D insufficiency and consequent disease. Examples suggest that the factors interact to increase mortality in Scotland in a way consistent with causation according to the criteria of Bradford Hill. It is suggested that different degrees of vitamin D insufficiency in populations can explain important differences in the health of nations and resolve health paradoxes. The analysis also shows that vitamin D insufficiency is a consequence of industrialisation and, like other consequences of industrial growth, such as water and air pollution, needs to be corrected by public health measures. Direct intervention with use of supplements and fortification of foods with vitamin D can be expected to provide considerable health gains, but progress will be slow until there is greater recognition of the vitamin D health crisis by the public, professionals and politicians. Health professionals need to be trained and motivated to encourage use of supplements, particularly by pregnant and nursing mothers, and infants. The importance of open sunny spaces and clean air that allows full penetration of UVB needs to be recognised by city planners and politicians. New advice and new fashions are needed to encourage maximum exposure of skin to summer sun without burning. Use of sunlamps to boost vitamin D synthesis could be useful. PMID- 22213314 TI - Determination of 1,25-dihydroxyvitamin D concentrations in human colon tissues and matched serum samples. AB - BACKGROUND: A novel method to measure 1,25-dihydroxyvitamin D (1,25(OH)(2)D) in human tissue was developed and validated. The objectives of this study were to determine whether 1,25(OH)(2)D is present in human colon tissue and to characterize the relationship between human colon tissue and serum 1,25(OH)(2)D concentrations. MATERIALS AND METHODS: Normal colon tissue specimens and matched serum samples were obtained from 30 patients who had undergone colectomy. Colon 1,25(OH)(2)D was measured by lipid extraction followed by enzyme immunoassay (EIA). Serum 1,25(OH)(2)D and 25-hydroxyvitamin D (25(OH)D) were measured by EIA. Vitamin D binding protein (DBP) was measured in a subset of serum and tissue samples. RESULTS: Regression analysis indicated a significant positive correlation between serum and colon 1,25(OH)(2)D concentrations (r=0.58, p=0.0008). The corresponding intercept at zero serum 1,25(OH)(2)D was 21.5 pmol/kg (95% CI=16.95-25.98; p<0.001). Colon 1,25(OH)(2)D did not correlate significantly with serum 25(OH)D. DBP levels in tissue samples were negligible. CONCLUSION: The hormone 1,25(OH)(2)D can be successfully detected in human colon at physiologically relevant concentrations, partly determined by serum 1,25(OH)(2)D. The results support the notion of in vivo synthesis of 1,25(OH)(2)D within colon tissues. PMID- 22213313 TI - 1Alpha,25-dihydroxyvitamin D3 induces de novo E-cadherin expression in triple negative breast cancer cells by CDH1-promoter demethylation. AB - BACKGROUND: The triple-negative subgroup of breast cancer includes a cluster of tumors exhibiting low E-cadherin expression (metaplastic carcinomas). In several cancer models, 1 alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) induces differentiation by increasing E-cadherin expression. The Vitamin D receptor (VDR) was evaluated as a possible therapeutic target for metaplastic carcinomas and 1alpha,25(OH)(2)D(3) effects as a differentiating agent in triple-negative breast cancer cells were assessed. MATERIALS AND METHODS: Metaplastic carcinomas were assessed for VDR expression by immunohistochemistry; differences in E-cadherin expression in triple-negative breast cancer cells were evaluated by real-time PCR, western blotting and Cadherin 1 (CDH1) methylation status. RESULTS: Most of the metaplastic carcinomas were positive for VDR expression. Furthermore, 1alpha,25(OH)(2)D(3) promoted differentiation of MDA-MB-231 cells by inducing de novo E-cadherin expression, an effect that was time- and dose-dependent. Also, E cadherin expression was due to promoter demethylation. CONCLUSION: Metaplastic carcinomas may respond to 1alpha,25(OH)(2)D(3), since they express VDR and 1alpha,25(OH)(2)D(3) induces de novo E-cadherin expression in breast cancer cells by promoter demethylation. PMID- 22213315 TI - Serum 25-hydroxyvitamin D levels in patients with vulvar cancer. AB - BACKGROUND: The anticarcinogenic potential of vitamin D 25(OH)D has been attributed to the inhibition of proliferation of cells from different carcinomas. Reduced serum levels of 25(OH)D are associated with an increased incidence of various types of cancer. The influence of serum 25(OH)D on the incidence and outcome of patients with vulvar cancer is unknown. PATIENTS AND METHODS: The serum 25(OH)D levels in 24 patients with vulvar cancer and 24 age-matched cancer free patients was investigated. The blood samples were collected between October 2009 and September 2010 and time of blood collection of each patient and control was matched to avoid seasonal variations between the pairs. RESULTS: The median 25(OH)D serum levels in the under 50 year old group of patients were significantly lower in the vulvar cancer group than the controls. The younger cancer group also had an age-related trend of lower median serum level than the older population. In the control population the trend was vice versa, yet this finding was not statistically significant. CONCLUSION: Serum 25(OH)D has a possible role in the pathogenesis and progression of vulvar cancer, but further investigations of the association of vitamin D and vulvar cancer as well as regarding its influence on patient survival and quality of life are warranted in the future. PMID- 22213316 TI - The first genome-wide view of vitamin D receptor locations and their mechanistic implications. AB - The transcription factor vitamin D receptor (VDR) is the nuclear sensor for the biologically most active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)). The physiological actions of the VDR and its ligand are not only the well-known regulation of calcium and phosphorus uptake and transport controlling bone formation, but also their significant involvement in the control of immune functions and of cellular growth and differentiation. For a general understanding of the mechanisms of 1alpha,25(OH)(2)D(3) signaling, it is essential to monitor the genome-wide location of VDR in relation to primary 1alpha,25(OH)(2)D(3) target genes. Within the last months, two chromatin immunoprecipitation sequencing (ChIP-Seq) studies using cells of the hematopoietic system, lymphoblastoids and monocytes, were published. The reports indicated the existence of 2776 and 1820 1alpha,25(OH)(2)D(3)-stimulated VDR binding sites, comparable numbers, of which, however, only 18.2% overlapped. The two studies were very different in their 1alpha,25(OH)(2)D(3) treatment times (36 h versus 40 min), but showed consensus in identifying response elements formed by a direct repeat of two hexameric binding sites with three intervening nucleotide (DR3) as major DNA contact sites of the VDR. Interestingly, when analyzed in the same way, both reports indicated that within 100 bp of their VDR ChIP-Seq peak summits only fewer than 40% contain a DR3-type response element. This review provides a detailed comparison of the insights obtained from both ChIP-Seq studies. PMID- 22213317 TI - Vitamin D receptor expression in patients with vulvar cancer. AB - The anticarcinogenic potential of vitamin D is attributed to antiproliferative and prodifferentiative effects on cells for a wide variety of carcinomas. The biological effects of 1,25(OH)(2)D (calcitriol) are mediated through a soluble receptor protein termed vitamin D receptor (VDR). However, thus far there have been no studies evaluating the association between VDR expression and vulvar cancer. Using immunohistochemical analysis, VDR expression was evaluated separately in the nucleus, cytoplasm and membrane, in vulvar cancer samples and adjacent non-pathological vulvar tissue from 48 squamous cell carcinoma patients with no prior therapy, and the association between VDR and overall survival was investigated. Overall, among the 48 vulvar cancer cases, nuclear and cytoplasmic VDR expression was present in 47 (97.9%) and 23 (47.9%) cases respectively. The median nuclear VDR expression was significantly higher as compared to the cytoplasmic VDR in the vulvar cancer tissue. No significant correlation between VDR values and the age of the patients was detected. Nuclear and cytoplasmatic VDR in the vulvar cancer tissue were also compared according to the tumor size, and no significant association between mean tumor VDR and tumor size was detected. There was no association between cytoplasmatic VDR expression and OS, but better OS was observed in patients with reduced nuclear VDR expression as compared to those with high VDR expression. VDR may be considered as a useful pathological marker. PMID- 22213318 TI - The roles of cytochrome P450 enzymes in prostate cancer development and treatment. AB - The active form of vitamin D, 1alpha,25-dihydroxyvitamin D [1alpha,25(OH)(2)D], interacts with vitamin D receptor (VDR) and induces antiproliferative, anti invasive, proapoptotic and pro-differentiation activities in prostate cancer cells. Three cytochrome P-450 (CYP) hydroxylases are responsible for vitamin D synthesis and degradation, including vitamin D-25-hydroxylase (25-OHase) in the liver, and 25(OH)D-1alpha-hydroxylase (1alpha-OHase) or CYP27B1, and 25(OH)D-24 hydroxylase (24-OHase) or CYP24A1 in the kidneys. However, it is now recognized that CYP27B1 and CYP24A1 are also expressed in many tissues and cells, including the prostate. Although at least six CYP enzymes have been identified with 25 OHase activity, the two major ones are CYP27A1 and CYP2R1, and both are expressed in the prostate, with CYP2R1 as the predominate type. This indicates that prostate tissue has the ability to activate and inactivate vitamin D in an autocrine/paracrine fashion. Recent evidence indicates that 25-hydroxyvitamin D [25(OH)D] and its analogs can bind to VDR as agonists, without converting them to 1alpha,25(OH)(2)D or the corresponding 1alpha-hydroxylated metabolites, to modulate gene expressions that will lead to cell growth arrest and other antitumor activities. This finding suggests that the circulating levels of 25(OH)D, and the autocrine synthesis of 25(OH)D may play an important role in regulating the growth of prostate cancer. Thus, in addition to 1alpha,25(OH)(2)D analogs, the presence of CYP2R1, CYP27B1 and CYP24A1 in the prostate suggests that the analogs of vitamin D and 25(OH)D, especially those that are resistant to CYP24A1 degradation, can be developed and used for the prevention and treatment of prostate cancer. PMID- 22213319 TI - Vitamin D and cellular Ca2+ signaling in breast cancer. AB - The hormone 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) regulates a variety of signaling pathways via intracellular Ca(2+). Modulation of apoptosis is emerging as a promising strategy for treatment and prevention of cancer. Cellular Ca(2+) has been implicated in triggering of apoptosis, however, the vitamin D/Ca(2+) dependent targets involved in apoptotic signaling have not been identified. Here, we review our studies on mechanisms of 1,25(OH)(2)D(3)-induced Ca(2+) signaling and Ca(2+)-mediated apoptosis in breast cancer cells. The results obtained demonstrate that 1,25(OH)(2)D(3) regulates Ca(2+) entry from the extracellular space, Ca(2+) mobilization from the intracellular stores and intracellular Ca(2+) buffering. In breast cancer cells, 1,25(OH)(2)D(3) induces the apoptotic Ca(2+) signal, a sustained increase in concentration of intracellular Ca(2+) ([Ca(2+)](i)) reaching elevated, but not cytotoxic levels. This increase in [Ca(2+)](i) is associated with activation of Ca(2+)-dependent MU-calpain and Ca(2+)/calpain-dependent caspase-12. Activation of these proteases appears to be sufficient for the execution of apoptosis in cancer cells. Normal mammary epithelial cells resist induction of apoptosis with 1,25(OH)(2)D(3) due to their large Ca(2+)-buffering capacity. The results indicate that the 1,25(OH)(2)D(3) induced cellular Ca(2+) signal can act as an apoptotic initiator that directly recruits Ca(2+)-dependent apoptotic effectors capable of executing apoptosis. These findings provide a novel rationale for evaluating the role of vitamin D in prevention and treatment of breast cancer. PMID- 22213320 TI - Process development for the practical production of eldecalcitol by linear, convergent and biomimetic syntheses. AB - Eldecalcitol [1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D(3)], an analog of calcitriol (1alpha,25-dihydroxyvitamin D(3)), possesses a hydroxypropoxy substituent at the 2beta-position of calcitriol. Eldecalcitol has potent biological effects on bone disease such as osteoporosis. The marketing of eldecalcitol has very recently started in Japan. In consideration of this, we have been investigating practical synthesis of eldecalcitol for industrial-scale production. Eldecalcitol was initially synthesized in a linear manner. The 27 step linear sequence was, however, suboptimal due to its lengthiness and low overall yield (ca. 0.03%). Next, we developed a convergent approach based on the Trost coupling reaction, in which the A-ring fragment (ene-yne part obtained in 10.4% overall yield) and the C/D-ring fragment (bromomethylene part obtained in 27.1% overall yield) are coupled to produce the triene system of eldecalcitol (15.6%). Although the overall yield of the convergent synthesis was better than that of the linear synthesis, significant improvements were still necessary. Therefore, additional biomimetic studies were investigated. Process development for the practical production of eldecalcitol is described herein. PMID- 22213321 TI - C15-functionalized 16-ene-1alpha,25-dihydroxyvitamin D3 is a new vitamin D analog with unique biological properties. AB - The Delta(16) structure as a vitamin D analog enhanced vitamin D receptor (VDR) binding affinity and induced significant cell differentiation, whereas its relative calcemic activity was reduced compared to 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)). Methodologies available to introduce a double bond at C16-C17 of the D-ring on the seco-steroidal skeleton were limited; therefore, a new synthetic strategy was developed to obtain not only the Delta(16) structure, but also a new C15-functional group. Since C15-functionalization was unprecedented in vitamin D analog studies, the hybrid structure of Delta(16) and the C15-OH group at the D-ring may provide important information on the structure activity relationship with vitamin D analogs. The synthesized 16-ene-2alpha methyl-1alpha,15alpha,25-trihydroxyvitamin D(3) showed almost 3-times higher VDR binding affinity and an equipotent level of osteocalcin promoter transactivation activity in human osteosarcoma cells as compared to 1alpha,25(OH)(2)D(3). PMID- 22213322 TI - The difference between 14-epi-previtamin D3 and 14-epi-19-norprevitamin D3: their synthesis and binding affinity for human VDR. AB - The synthesis of 14-epi-1alpha,25(OH)(2)previtamin D(3), 14-epi-19-nor 1alpha,25(OH)(2)previtamin D(3), and their 2-substituted analogs is described. The vitamin D receptor (VDR) binding affinity was further evaluated and 2alpha methyl substituted 14-epi-1alpha,25(OH)(2)previtamin D(3) had 17-fold more potent affinity than 14-epi-1alpha,25(OH)(2)previtamin D(3).In the comparison of these compounds, the effects of thermal equilibrium, with or without 19-carbon at the A ring, and their CD-ring structures are discussed. PMID- 22213323 TI - Association of genetic variants of the vitamin D receptor (VDR) with cutaneous squamous cell carcinomas (SCC) and basal cell carcinomas (BCC): a pilot study in a German population. AB - BACKGROUND: Vitamin D receptor (VDR) polymorphisms have important implications for vitamin D signalling and are associated with various malignancies. PATIENTS AND METHODS: In a German population, the frequency of several VDR polymorphisms (Apa1, Taq1, Bgl1) in basal cell carcinomas (BCCs, n=90) and cutaneous squamous cell carcinomas (SCCs, n=100) as compared to healthy controls (n=51) was analyzed. RESULTS: Impressive variations in the frequency of some VDR genotypes were found when comparing skin of cancer patients and controls. An association of the genotype AaTtBb with BCC risk was found (BCC: 45.7%, SCC: 39.8% and controls: 38.0%). The genotype aaTTBB was exclusively found in the control group (20%), which suggested that this genotype may be protective against skin carcinogenesis. Moreover, the aaTTbb genotype was associated with skin cancer risk, being found at a much higher frequency in BCCs (21%) and SCCs (17%) as compared to controls (8.0%). Comparison of the frequencies of the VDR genotypes in sunlight-exposed vs. not sunlight-exposed skin areas revealed BB 30.1% vs. 7.1% respectively in BCCs and BB 28.1% vs. 0.0% respectively in SCCs, indicating that vitamin D signalling may be of importance for photocarcinogenesis of the skin. Associations also indicated that the Apa1 and Taq1 genotypes may be of importance for photocarcinogenesis of BCCs, but not for SCCs. Comparison of the VDR genotype frequencies by age (younger than 60 years vs. 60 years or older) revealed no evidence of age-dependent variations in patients with BCCs or SCCs. CONCLUSION: VDR polymorphisms are of importance for the development of BCCs and cutaneous SCCs, but further explorations of these findings and their implications are required. PMID- 22213324 TI - Crystal structure of a vitamin D3 analog, ZK203278, showing dissociated profile. AB - The plethora of actions of 1alpha,25-dihydroxyvitamin D(3), the active form of the seco-steroid hormone vitamin D, in various systems suggested wide clinical applications in treatments for renal osteodystrophy, osteoporosis, psoriasis, cancer, autoimmune diseases and prevention of graft rejection. However, the major side-effects of hypercalcemia of VDR ligands limit their use. ZK203278, a novel synthetic analog has been shown to act as a potent immunomodulator and presents dissociated biologic profile with low calcemic side-effects. Here, we described the crystal structures of the hVDR ligand-binding domain in complex with ZK203278 and determined its correlation with its specific dissociated biologic profile. The VDR/ZK203278 structure, in comparison with VDR/1alpha,25-dihydroxyvitamin D(3), shows specific interactions of the thiazole group of ZK203278 with residues of H3, H11 and H12. These specific interactions may lead to altered selective interactions with co-regulators and consequently to the dissociated biologic profile of this novel ligand. PMID- 22213325 TI - Expression and function of the vitamin D receptor in malignant germ cell tumour of the testis. AB - Testicular germ cell tumours (TGCTs) are the most common malignancy in young men aged 18-35 years. They are clinically and histologically subdivided into seminomas and non-seminomas. 1,25-Dihydroxyvitamin D (1,25(OH)(2)D(3)) is the active form of vitamin D and exerts its actions via a specific intracellular vitamin D receptor (VDR). Several investigations in the recent years have revealed, in addition to a physiological occurrence of the VDR in various tissues, VDR expression in different human malignancies. Furthermore, 1,25(OH)(2)D(3) plays an important role in the regulation of cell proliferation and differentiation. In different normal and malignant cell types, antiproliferative and pro-differentiating effects of 1,25(OH)(2)D(3) are described. We investigated whether TGCT express the VDR, wether differences exist between the histological subtypes and if vitamin D has a function on the proliferation of tumour cells. Furthermore, we investigated the potential function of the vitamin D-regulated genes nuclear receptor co-repressor 1(NCOR1), nuclear receptor co-repressor 2 (NCOR2), thyroid receptor interacting protein 15 (TRIP15), Growth Arrest and DNA Damage (GADD45), MAP kinase-activated protein kinase 2 (MAPKAPK2), Cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1) and Cytochrome P450, family 27, subfamily B, polypeptide 1 (CYP27B1) in the pathogenesis of TGCT. We demonstrate, for the first time, that primary TGCT as well as TGCT cell lines, express VDR mRNA and protein. Vitamin D and VDR may play a role in the pathogenesis of TGCTs. Furthermore, vitamin D inhibits proliferation of TGCT cell-lines, potentially via an increase in expression of GADD45. Our data suggest that vitamin D could play a role in antitumour therapy. PMID- 22213326 TI - Correlation of prostaglandin metabolizing enzymes and serum PGE2 levels with vitamin D receptor and serum 25(OH)2D3 levels in breast and ovarian cancer. AB - BACKGROUND: Vitamin D and its active form calcitriol have multiple effects in cancer cells, such as anti-proliferative effects, induction of apoptosis and cell cycle arrest. There is a link between vitamin D metabolism and inflammatory processes, which should be considered in cancer therapy. An association between these two types of metabolism is also observed in breast and ovarian cancer. These inflammatory processes are based on an increase of cyclooxygenase-2 (COX-2) activity. The current study aimed to evaluate the expression of prostaglandin metabolising enzymes COX-2 and 15-hydroxyprostaglandin-dehydrogenase (15-PGDH) along with the vitamin D receptor (VDR) in benign and malignant breast and ovarian tissues. PATIENTS AND METHODS: VDR, COX-2, 15-PGDH and prostanoid receptor E2/E4 expression were measured in tissues by western blot analysis. Additionally, plasma 25(OH)(2)D(3) and PGE(2) levels were measured in healthy patients and cancer patients. RESULTS: We detected an elevated COX-2 and inversely a lowered VDR expression in cancer patients compared to healthy women. Breast cancer patients diagnosed during wintertime had a significantly lower serum level of 25(OH)(2)D(3); PGE(2) serum levels were higher in both types of cancer. CONCLUSION: These results support the idea of a link between prostaglandin and vitamin D metabolism in regards to their influences on breast and ovarian cancer. PMID- 22213327 TI - Influence of calcitriol on prostaglandin- and vitamin D-metabolising enzymes in benign and malignant breast cell lines. AB - BACKGROUND: Cyclooxygenase-2 (COX-2) is a potential molecular prognostic factor for breast cancer, and calcitriol [1,25(OH)(2)D(3)], the biologically active form of vitamin D, is a promising target in breast cancer therapy. MATERIALS AND METHODS: The influence of calcitriol on the proliferation and the effects of calcitriol on the expression of prostaglandin- and vitamin D-metabolising enzymes were examined in benign and malignant breast cells. RESULTS: Calcitriol inhibited the proliferation of MCF-10F and MCF-7 cells but not of invasive MDA-MB-231 cells and reduced the expression of COX-2 and 15-hydroxyprostaglandin dehydrogenase (15 PGDH) in the benign breast cell line MCF-10F. Furthermore, dysregulation in vitamin D-metabolising proteins was detected, especially in MDA-MB-231 cells. CONCLUSION: These results suggest dysregulation of vitamin D metabolism and a lack of a possible influence of calcitriol on the metabolism of prostaglandins in the malignant breast cell lines. PMID- 22213328 TI - Expression of prostaglandin- and vitamin D-metabolising enzymes in benign and malignant breast cells. AB - BACKGROUND: Cyclooxygenase-2 (COX-2) plays a crucial role in prognosis of malignancy and has been associated with carcinogenesis, particularly neoangiogenesis and tumor progression. 15-Hydroxyprostaglandin dehydrogenase (15 PGDH) is described as a tumour suppressor in cancer. The antiproliferative effects of calcitriol [1,25(OH)(2)D(3)] mediated via the vitamin D receptor (VDR) render vitamin D a promising target in breast cancer therapy. MATERIALS AND METHODS: The expression of prostaglandin (PG)-metabolizing enzymes, vitamin D metabolising enzymes and VDR were determined in benign and malignant breast cell lines using western blot analysis. RESULTS: We detected an inverse correlation between the two types of metabolism, a reduced VDR expression in the malignant breast cell lines, and therefore an insufficient induction of 24-hydroxylase in the malignant cells. CONCLUSION: We suggest the possibility of dysregulation of vitamin D-metabolizing enzymes in malignant breast cell lines. PMID- 22213329 TI - Optimal serum calcidiol concentration for cancer prevention. AB - It has been demonstrated in several studies that serum calcidiol (25 OH vitamin D(3)) concentration is in a reversed and linear relationship with cancer risk. However, there are also studies showing no such association and some even suggest the opposite. The risk of pancreatic and oesophageal cancer seems to increase, when serum calcidiol concentration increases. A bias in these studies might be that their basic assumption is linear dependence of cancer on serum calcidiol concentration. Some studies suggest a U-shaped association between the disease and the serum calcidiol concentration. Evidence, in the literature, of the relationship between serum calcidiol concentration and disease is reviewed and an optimal level of 40-80 nmol/L (16-32 ng/ml) is suggested. Serum calcidiol seems to be a better predictor of cancer development than calcitriol (1alpha, 25 (OH)(2) vitamin D(3)). A calcidiol insufficiency, as well as an insufficient solar exposure, is associated with an increased risk of several solid carcinomas. In a recent study, our group demonstrated that calcidiol is an active hormone in CYP24 (24-hydroxylase) deficient cells. In these cells, calcidiol and calcitriol act synergistically, therefore fluctuations of the serum calcidiol concentration may define the hormonal activity and cancer development. CONCLUSION: Serum calcidiol concentration and the risk of many common diseases and aging phenomena seem to show a U-shaped association suggesting a lower and upper limit for healthy serum calcidiol concentration. An imbalance of hormonal calcidiol rather than that of calcitriol is a risk factor in carcinomas and chronic diseases, which might be prevented by an optimal serum calcidiol concentration. Multiple daily dosing of cholecalcipherol or skin patches could best provide an optimal dosing and stable serum concentration. Alternatively, narrow-band UV-B lamps are a possible optimal solution, when given by trained personnel. PMID- 22213330 TI - Signature of VDR miRNAs and epigenetic modulation of vitamin D signaling in melanoma cell lines. AB - BACKGROUND: Melanoma cells express the nuclear vitamin D receptor (VDR), indicating that malignant melanoma represents a promising target for treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3)) or its analogs. We previously showed that some melanoma cell lines are resistant to the antiproliferative effects of 1,25(OH)(2)D(3) and that 1,25(OH)(2)D(3)-sensitivity can, at least in part, be restored by co-treatment with the histone deacetylase inhibitor (HDACI) Trichostatin A (TSA) or with the DNA methyltransferase inhibitor (DNMTI), 5 azacytidine (5-Aza). This study aimed at gaining further insights into the molecular mechanisms that underlie the epigenetic modulation of 1,25(OH)(2)D(3) sensitivity in melanoma cells. MATERIALS AND METHODS: The expression of VDR mRNA, protein and two candidates of VDR microRNAs (miR-125b, miR-27b) were compared in 1,25(OH)(2)D(3)-responsive (MeWo, SK-Mel28) and -resistant (SK-Mel5, IGR) melanoma cell lines and in normal human melanocytes (NHM) using real time PCR and western blot analysis. Additionally, the effect of 1,25(OH)(2)D(3), epigenetic modulating drugs (TSA, 5-Aza) and miR-125b antisense on the expression of VDR messenger RNA (mRNA)/protein, miR-125b and miR-27b was investigated. RESULTS: Treatment with 1,25(OH)(2)D(3) and/or epigenetic drugs (5-Aza, TSA) modulated the VDR mRNA expression in the 1,25(OH)(2)D(3)-responsive and - resistant melanoma cell lines and in the NHM. Treatment with 5-Aza, but not with TSA, reduced the expression of miR-125b in the 1,25(OH)(2)D(3)-responsive and -resistant melanoma cell lines and in the NHM. Treatment with 1,25(OH)(2)D(3) and/or epigenetic drugs (5-Aza, TSA) reduced the miR-27b expression in three out of four melanoma cell lines. Moreover, no difference was observed in VDR protein expression in the 1,25(OH)(2)D(3)-responsive as compared to the 1,25(OH)(2)D(3)-resistant melanoma cell lines. Transfection with miR-125b antisense did not affect the VDR mRNA/protein expression in the IGR cells. CONCLUSION: Responsiveness to 1,25(OH)(2)D(3) corresponds to the expression level of VDR mRNA which in turn might be regulated by VDR microRNAs or epigenetic modulating drugs. PMID- 22213331 TI - Vitamin D status and mortality of German hemodialysis patients. AB - AIM: The goal was to analyze the link between blood levels of calcidiol and all cause, cardiac and infectious diseases, and mortality due to cancer in hemodialysis patients. PATIENTS AND METHODS: This study retrospectively evaluated a representative sub-cohort (n=6,518) of German hemodialysis patients from the incidence cohorts 1997-2006. RESULTS: Most (58.8%) were found to be vitamin D deficient (25(OH)D<20 ng/ml), with 41.2% being severely deficient (25(OH)D<12.5 ng/ml). All-cause mortality risk more than doubled in patients with severe deficiency (adjusted odds ratio (aOR)=2.67; 95% confidence interval (CI)=2.30 3.10; p<0.0001). Comparable data were obtained for mortality from cardiac disease (aOR=1.57; 95% CI=1.30-1.88; p<0.0001), infectious disease (aOR=1.48; 95% CI=1.15 1.90; p=0.0026), and cancer (aOR=1.51; 95% CI=1.09-2.08; p=0.0121), respectively. CONCLUSION: These data highlight the need to ensure primarily adequate 25(OH)D levels in dialysis patients for an advantage of survival. PMID- 22213333 TI - Platinum(II)-bis(aryleneethynylene) complexes for solution-processible molecular bulk heterojunction solar cells. AB - Four new solution-processible small-molecular platinum(II)-bis(aryleneethynylene) complexes consisting of benzothiadiazole as the electron acceptor and triphenylamine and/or thiophene as the electron donor were conveniently synthesized and characterized by physicochemical and computational methods, and utilized as the electron-donor materials in the fabrication of solution-processed bulk heterojunction (BHJ) solar cells. The effect of different electron-donor groups in these small molecules on the optoelectronic and photovoltaic properties was also examined. The optical and time-dependent density functional theory studies showed that the incorporation of stronger electron-donor groups significantly enhanced the solar-absorption abilities of the complexes. These molecular complexes can serve as good electron donors for fabricating BHJ devices by blending them with the [6,6]-phenyl-C(71)-butyric acid methyl ester (PC(70)BM) as the electron acceptor. The best power conversion efficiency of 2.37% was achieved with the open-circuit voltage of 0.83 V, short-circuit current density of 7.10 mA cm(-2) and fill factor of 0.40 under illumination of an AM 1.5 solar cell simulator. The spin-coated thin films showed p-channel field-effect charge transport with hole mobilities of up to 2.4*10(-4) cm(2) V(-1) s(-1) for these molecules. The present work illuminates the potential of well-defined organometallic complexes in developing light-harvesting small molecules for efficient power generation in organic photovoltaics implementation. PMID- 22213332 TI - Interferon regulatory factor modulation underlies the bystander suppression of malaria antigen-driven IL-12 and IFN-gamma in filaria-malaria co-infection. AB - In areas where polyparasitism is highly prevalent, the impact of multiple parasites on the host response is underestimated. In particular, the presence of helminth infection coincident with malaria profoundly alters the production of malaria-specific IFN-gamma, IL-12p70, CXCL9, CXCL10 and CXCL11, cytokines/chemokines known to be critical in mediating malaria-specific immunity. In order to elucidate the mechanisms underlying the suppression of malaria specific cytokines/chemokines, we assessed the expression of malaria-specific IL 12Rbeta1, IL-12Rbeta2 and interferon regulatory factor (IRF)-1 in blood obtained from 18 filaria-infected (Fil(+)) and 17 filaria-uninfected (Fil(-)) individuals in a filaria-malaria co-endemic region of Mali. We found that Fil(+) individuals had significantly lower RNA expression of IRF-1 but not IL-12Rbeta1 or IL 12Rbeta2 in response to malaria antigen stimulation. We also measured the frequency of IL-12-producing DCs from these subjects and found that Fil(+) subjects had lower frequencies of IL-12(+) mDCs after malaria antigen stimulation than did the Fil(-) subjects. Modeling these data in vitro, we found that mDCs pre-exposed to live microfilariae not only produced significantly lower levels of CXCL-9, CXCL-10, IL-12p35, IL-12p40, IL-12p19 and CXCL-11 following stimulation with malaria antigen but also markedly downregulated the expression of IRF-1, IRF 2 and IRF-3 compared with microfilaria-unexposed mDCs. siRNA-inhibition of irf-1 in mDCs downregulated the production of IL-12p70 through repression of IL-12p35. Our data demonstrate that the modulation of IRFs seen in filarial (and presumably other tissue-invasive helminths) infection underlies the suppression of malaria specific cytokines/chemokines that play a crucial role in immunity to malaria. PMID- 22213335 TI - Development and validation of HPLC method for simultaneous estimation of piperine and guggulsterones in compound Unani formulation (tablets) and a nanoreservoir system. AB - An attempt has been made to develop and validate a simultaneous HPLC method for novel approach of drug release via oil-in-water (o/w) nanoemulsion formulation and Habb-e-Khardal Unani tablet containing piperine and guggul sterones E and Z as main ingredients. Nanoemulsion was prepared by titration method using sefsol 218 as an oily phase, cremophor-EL as a surfactant, transcutol as a co-surfactant and distilled water as an aqueous phase. The formulation was optimized on the basis of thermodynamic stability and dispersibilty test. The nanoformulation was evaluated for particle size, surface morphology, electrical conductivity and viscosity determination. The in vitro dissolution was carried out by dialysis bag method. Drugs were quantified using an HPLC method developed in-house with a C(18) column as stationary phase and acetonitrile and water as mobile phase at lambda(max) of 240 nm. The optimized formulation showed higher drug release, lower droplet size and less viscosity as compared with the conventional Habb-e Khardal Unani tablet. The present study illustrated the potential of nanoemulsion dosage form in improving biopharmaceutic performance of piperine and guggul sterone. The HPLC method was also found to be quite sufficient for the routine quality control of formulations containing piperine and guggul sterone E and Z as ingredients and also for in vitro drug release studies. PMID- 22213334 TI - Multiple-exchange-time xenon polarization transfer contrast (MXTC) MRI: initial results in animals and healthy volunteers. AB - Hyperpolarized xenon-129 is a noninvasive contrast agent for lung MRI, which upon inhalation dissolves in parenchymal structures, thus mirroring the gas-exchange process for oxygen in the lung. Multiple-exchange-time xenon polarization transfer contrast (MXTC) MRI is an implementation of the XTC MRI technique in four dimensions (three spatial dimensions plus exchange time). The aim of this study was to evaluate the sensitivity of MXTC MRI for the detection of microstructural deformations of the healthy lung in response to gravity-induced tissue compression and the degree of lung inflation. MXTC MRI was performed in four rabbits and in three healthy human volunteers. Two lung function parameters, one related to tissue- to alveolar-volume ratio and the other to average septal wall thickness, were determined regionally. A significant gradient in MXTC MRI parameters, consistent with gravity-induced lung tissue deformation in the supine imaging position, was found at low lung volumes. At high lung volumes, parameters were generally lower and the gradient in parameter values was less pronounced. Results show that MXTC MRI permits the quantification of subtle changes in healthy lung microstructure. Further, only structures participating in gas exchange are represented in MXTC MRI data, which potentially makes the technique especially sensitive to pathological changes in lung microstructure affecting gas exchange. PMID- 22213336 TI - Collagen fibril diameter and alignment promote the quiescent keratocyte phenotype. AB - In this study, we investigated how matrix nanotopography affects corneal fibroblast phenotype and matrix synthesis. To this end, corneal fibroblasts isolated from bovine corneas were grown on collagen nanofiber scaffolds of different diameters and alignment--30 nm aligned fibrils (30A), 300 nm or larger aligned fibrils (300A), and 30 nm nonaligned fibrils (30NA) in comparison with collagen coated flat glass substrates (FC). Cell morphology was visualized using confocal microscopy. Quantitative PCR was used to measure expression levels of six target genes: the corneal crystallin-transketolase (TKT), the myofibroblast marker-alpha-smooth muscle actin (SMA), and four matrix proteins-collagen 1 (COL1), collagen 3 (COL3), fibronectin (FN), and biglycan. It was found that SMA expression was down-regulated and TKT expression was increased on all three collagen nanofiber substrates, compared with the FC control substrates. However, COL3 and biglycan expression was also significantly increased on 300A, compared with the FC substrates. Thus matrix nanotopography down-regulates the fibrotic phenotype, promotes formation of the quiescent keratocyte phenotype, and influences matrix synthesis. These results have significant implications for the engineering of corneal replacements and for promoting regenerative healing of the cornea after disease and/or injury. PMID- 22213337 TI - Resveratrol inhibits mucin gene expression, production and secretion from airway epithelial cells. AB - The study investigated whether resveratrol significantly affects mucin gene expression, production and secretion from airway epithelial cells. Confluent NCI H292 cells were pretreated with resveratrol for 30 min and then stimulated with EGF (epidermal growth factor), PMA (phorbol 12-myristate 13-acetate) and TNF alpha (tumor necrosis factor-alpha) for 24 h, respectively. The MUC5AC gene expression and mucin protein production were measured by RT-PCR and ELISA. The effect of resveratrol on TNF-alpha- or PMA-induced activation of NF-kappaB p65 was also examined. Confluent primary rat tracheal surface epithelial (RTSE) cells were pretreated with adenosine triphosphate (ATP) for 5 min and then treated for 30 min in the presence of resveratrol to assess the effect on mucin secretion using ELISA. The results were as follows: (1) resveratrol inhibited the expression of MUC5AC gene induced by EGF or PMA or TNF-alpha from NCI-H292 cells; (2) resveratrol also inhibited the production of MUC5AC mucin protein induced by the same inducers from NCI-H292 cells; (3) resveratrol inhibited the activation of NF-kappaB p65 by TNF-alpha or PMA in NCI-H292 cells; (4) resveratrol significantly decreased ATP-induced mucin secretion from cultured RTSE cells. This result suggests that resveratrol can regulate mucin gene expression, production and secretion, by directly acting on airway epithelial cells. PMID- 22213338 TI - Prognostic impact of tumor encapsulation in patients with large hepatocellular carcinoma. PMID- 22213339 TI - Tolfenamic acid inhibits neuroblastoma cell proliferation and induces apoptosis: a novel therapeutic agent for neuroblastoma. AB - Current therapeutic options for recurrent neuroblastoma have poor outcomes that warrant the development of novel therapeutic strategies. Specificity protein (Sp) transcription factors regulate several genes involved in cell proliferation, survival, and angiogenesis. Sp1 regulates genes believed to be important determinants of the biological behavior of neuroblastoma. Tolfenamic acid (TA), a non-steroidal anti-inflammatory drug, is known to induce the degradation of Sp proteins and may serve as a novel anti-cancer agent. The objective of this investigation was to examine the anti-cancer activity of TA using established human neuroblastoma cell lines. We tested the anti-proliferative effect of TA using SH-SY5Y, CHLA90, LA1 55n, SHEP, Be2c, CMP 13Y, and SMS KCNR cell lines. Cells were treated with TA (0/25/50/100 uM) and cell viability was measured at 24, 48, and 72 h post-treatment. Selected neuroblastoma cell lines were treated with 50 uM TA for 24 and 48 h and tested for cell apoptosis using Annexin-V staining. Caspase activity was measured with caspase 3/7 Glo kit. Cell lysates were prepared and the expression of Sp1, survivin, and c-PARP were evaluated through Western blot analysis. TA significantly inhibited the growth of neuroblastoma cells in a dose/time-dependent manner and significantly decreased Sp1 and survivin expression. Apart from cell cycle (G0/G1) arrest, TA caused significant increase in the apoptotic cell population, caspase 3/7 activity, and c-PARP expression. These results show that TA effectively inhibits neuroblastoma cell growth potentially through suppressing mitosis, Sp1, and survivin expression, and inducing apoptosis. These results show TA as a novel therapeutic agent for neuroblastoma. PMID- 22213340 TI - 25-hydroxyvitamin D, vitamin D receptor gene polymorphisms, and severity of Parkinson's disease. AB - We aimed to examine associations among serum 25-hydroxyvitamin D levels, 1,25 dihyroxyvitamin D levels, vitamin D receptor polymorphisms, vitamin D binding protein gene polymorphisms, and the severity of Parkinson's disease. In 137 patients, the severity of Parkinson's disease was evaluated using Hoehn & Yahr stage and Unified Parkinson's Disease Rating Stage by neurologists and compared with 25-hydroxyvitamin D, 1,25-hydroxyvitamin D, vitamin D receptor polymorphisms, ie, FokI (rs10735810), BsmI (rs1544410), Cdx2 (rs11568820), ApaI (rs7976091), and TaqI (rs731236), and vitamin D binding protein gene polymorphisms GC1 (rs7041)/GC2 (rs4588) in a cross-sectional study. Mean +/- standard deviation levels of 25-hydroxyvitamin D were 21.1 +/- 9.0 ng/mL. Levels were deficient (<20 ng/mL) in 49% of patients. In contrast, 1,25-hydroxyvitamin D levels were considered normal in all patients. Higher circulating 25 hydroxyvitamin D levels were significantly associated with milder Parkinson's disease evaluated by Hoehn & Yahr stage (P = .002) and total Unified Parkinson's Disease Rating Stage (P = .004) even after multivariate adjustment for 8 covariates, including disease duration. However, significant associations were not observed in 1,25-hydroxyvitamin D levels. Under multivariate analysis with 25 hydroxyvitamin D as well as other 8 covariates including disease duration, carriers of vitamin D receptor FokICC genotype had a milder form of Parkinson's disease: odds ratio, 0.32; 95% confidence interval, 0.16 to 0.66, P = 0.002. These results suggest that higher 25-hydroxyvitamin D levels and the vitamin D receptor FokICC genotype may be independently associated with milder forms of Parkinson's disease. However, significant associations were not observed in 1,25 hydroxyvitamin D levels. PMID- 22213341 TI - Biochemical and proteomic characterization of alkaptonuric chondrocytes. AB - Alkaptonuria (AKU) is a rare genetic disease associated with the accumulation of homogentisic acid (HGA) and its oxidized/polymerized products which leads to the deposition of melanin-like pigments (ochronosis) in connective tissues. Although numerous case reports have described ochronosis in joints, little is known on the molecular mechanisms leading to such a phenomenon. For this reason, we characterized biochemically chondrocytes isolated from the ochronotic cartilage of AKU patients. Based on the macroscopic appearance of the ochronotic cartilage, two sub-populations were identified: cells coming from the black portion of the cartilage were referred to as "black" AKU chondrocytes, while those coming from the white portion were referred to as "white" AKU chondrocytes. Notably, both AKU chondrocytic types were characterized by increased apoptosis, NO release, and levels of pro-inflammatory cytokines. Transmission electron microscopy also revealed that intracellular ochronotic pigment deposition was common to both "white" and "black" AKU cells. We then undertook a proteomic and redox-proteomic analysis of AKU chondrocytes which revealed profound alterations in the levels of proteins involved in cell defence, protein folding, and cell organization. An increased post-translational oxidation of proteins, which also involved high molecular weight protein aggregates, was found to be particularly relevant in "black" AKU chondrocytes. PMID- 22213343 TI - Capacity building in environmental and occupational health in Sri Lanka. AB - BACKGROUND: Although environmental and occupational health (EOH) research and services in Sri Lanka have a long history, policies related to EOH are outdated. METHODS: We review the International Training and Research in Environmental and Occupational Health (ITREOH) program in Sri Lanka that commenced in 2006 as a collaboration between the University of Alabama at Birmingham and the Faculty of Medicine of the University of Kelaniya, Sri Lanka. RESULTS: The program has trained over 20 scientists in conducting EOH research. New pioneering research in EOH was initiated. The program was instrumental in furthering the training and research in EOH by initiating a MPH degree program, the first in the country. CONCLUSIONS: The program has established North-South, South-South and in-country collaborations between institutions and scientists, increasing the visibility of EOH in the future. PMID- 22213342 TI - Nicotinic acetylcholine receptors in rat forebrain that bind 18F-nifene: relating PET imaging, autoradiography, and behavior. AB - Nicotinic acetylcholine receptors (nAChRs) in the brain are important for cognitive function; however, their specific role in relevant brain regions remains unclear. In this study, we used the novel compound 18F-nifene to examine the distribution of nAChRs in the rat forebrain, and for individual animals related the results to behavioral performance on an auditory-cognitive task. We first show negligible binding of 18F-nifene in mice lacking the beta2 nAChR subunit, consistent with previous findings that 18F-nifene binds to alpha4beta2* nAChRs. We then examined the distribution of 18F-nifene in rat using three methods: in vivo PET, ex vivo PET and autoradiography. Generally, 18F-nifene labeled forebrain regions known to contain nAChRs, and the three methods produced similar relative binding among regions. Importantly, 18F-nifene also labeled some white matter (myelinated axon) tracts, most prominently in the temporal subcortical region that contains the auditory thalamocortical pathway. Finally, we related 18F-nifene binding in several forebrain regions to each animal's performance on an auditory-cued, active avoidance task. The strongest correlations with performance after 14 days training were found for 18F-nifene binding in the temporal subcortical white matter, subiculum, and medial frontal cortex (correlation coefficients, r > 0.8); there was no correlation with binding in the auditory thalamus or auditory cortex. These findings suggest that individual performance is linked to nicotinic functions in specific brain regions, and further support a role for nAChRs in sensory-cognitive function. PMID- 22213344 TI - Outcomes after liver transplantation for alcoholic hepatitis are similar to alcoholic cirrhosis: exploratory analysis from the UNOS database. AB - Data on liver transplantation for patients with alcoholic hepatitis are limited. Using the United Network for Organ Sharing database (2004-2010), adults undergoing liver transplantation for a listing diagnosis of alcoholic hepatitis were matched for age, gender, ethnicity, and model for endstage disease (MELD) score, donor risk index, and year of transplantation with three patients transplanted for a listing diagnosis of alcoholic cirrhosis. Study outcomes of graft and patient survival on follow-up were also analyzed for cohorts based on the diagnosis of the explant (46 alcoholic hepatitis and 138 alcoholic cirrhosis) and diagnosis at both listing as well as of the explant (11 alcoholic hepatitis and 33 alcoholic cirrhosis). Five-year graft and patient survival of alcoholic hepatitis and alcoholic cirrhosis patients were 75% and 73% (P = 0.97) and 80% and 78% (P = 0.90), respectively. Five-year graft and patient survival rates were also similar for cohorts based on diagnosis of the explant and diagnosis at listing as well as explant. Cox proportional regression analysis adjusting for other variables showed no impact of the etiology of liver disease (alcoholic hepatitis versus alcoholic cirrhosis) on the graft and patient survival. The causes of graft loss and patient mortality were similar in the two groups, and were not alcohol-related in any patient. CONCLUSION: Compared with alcoholic cirrhosis, patients with alcoholic hepatitis have similar posttransplantation graft and patient survival. Based on these preliminary findings, liver transplantation may be considered in a select group of patients with alcoholic hepatitis who fail to improve with medical therapy. Prospective studies are needed to assess the long-term outcome after liver transplantation in patients with alcoholic hepatitis. PMID- 22213345 TI - Evaluation of a MR-quadrupole imaging coil for spinal interventions in a vertical 1.0 T MRI. AB - The in vivo pain treatment was successfully performed with the patient in a prone position. The PD-weighted TSE with echo time = 10 ms rendered contrast-to-noise ratio values of 27 +/- 10 for needle/fat, 1.6 +/- 5 for needle/muscle, and 4 +/- 4.7 for needle/nerve tissue. The mean diameter of the needle artifact was 1.2 +/- 0.2 mm. In the T(1)-weighted gradient echo, the needle's artifact diameter was 6 +/- 2 mm; the needle's contrast-to-noise ratio relative to muscle tissue was 4 +/ 2, 7.6 +/- 1.5 for needle/fat, and 5 +/- 1 for needle/nerve tissue. With the PD weighted TSE (echo time = 10 ms) and the T(1)-weighted gradient echo, the needle was imaged reliably throughout the intervention. The butterfly surface coil is feasible for the guidance of spinal interventions in a prone patient. PMID- 22213347 TI - Innovative collagen nano-hydroxyapatite scaffolds offer a highly efficient non viral gene delivery platform for stem cell-mediated bone formation. AB - The ability of nano-hydroxyapatite (nHA) particles developed in-house to act as non-viral delivery vectors is assessed. These nHA particles are combined with collagen to yield bioactive, biodegradable collagen nano-hydroxyapatite (coll nHA) scaffolds. Their ability to act as gene-activated matrices for BMP2 delivery is demonstrated with successful transfection of mesenchymal stem cells (MSCs) resulting in high calcium production. PMID- 22213346 TI - Prognostic impact of extranodal involvement in diffuse large B-cell lymphoma in the rituximab era. AB - BACKGROUND: Extranodal involvement is considered a poor prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL); however, the prognostic impact of specific sites of involvement has not been fully elucidated. METHODS: The authors retrospectively analyzed 1221 patients treated uniformly with standard R-CHOP therapy between 2003 and 2006. Patients with distinct forms of DLBCL such as intravascular lymphoma, primary effusion lymphoma, pyothorax associated lymphoma, primary central nervous system lymphoma, and intraocular lymphoma were also excluded. The authors evaluated 26 extranodal sites of involvement with respect to prognostic impact. The median age was 64 years (range, 15-91 years). RESULTS: Univariate analysis revealed that patients with involvement of specific extranodal sites had significantly worse overall survival (OS) than did patients without such involvement; these sites included nasal cavity, paranasal sinus, lung, pleura, small intestine, peritoneum, liver, pancreas, stomach, spleen, adrenal gland, testis, bone, bone marrow, peripheral blood, skin, and subcutaneous tissue. Patients with Waldeyer ring involvement had significantly better OS. Multivariate analysis revealed that patients with the involvement of the pleura (P < .001), small intestine (P = .015), peritoneum (P = .002), adrenal gland (P < .001), testis (P = .005), bone marrow (P < .001), and peripheral blood (P = .002) had significantly worse OS, whereas those with Waldeyer ring involvement had significantly better OS (P = .038). Subgroup analysis with the nodal and/or Waldeyer patient group also showed prognostic impact of Waldeyer ring by multivariate analysis (relative risk, 0.3; P = .04). CONCLUSIONS: Extranodal involvement affects the prognosis of patients undergoing R-CHOP therapy for DLBCL. PMID- 22213348 TI - The ability to achieve meiotic maturation in the dog oocyte is linked to glycolysis and glutamine oxidation. AB - We tested the hypothesis that meiotic competence of dog oocytes is tightly linked with donor follicle size and energy metabolism. Oocytes were recovered from small (<1 mm diameter, n = 327), medium (1-<2 mm, n = 292) or large (>=2 mm, n = 102) follicles, cultured for 0, 24, or 48 hr, and then assessed for glycolysis, glucose oxidation, pyruvate uptake, glutamine oxidation, and nuclear status. More oocytes (P < 0.05) from large follicles (37%) reached the metaphase-II (MII) stage than from the small group (11%), with the medium-sized class being intermediate (18%; P > 0.05). Glycolytic rate increased (P < 0.05) as oocytes progressed from the germinal vesicle (GV) to MII stage. After 48 hr of culture, oocytes completing nuclear maturation had higher (P < 0.05) glycolytic rates than those arrested at earlier stages. GV oocytes recovered from large follicle oocytes had higher (P < 0.05) metabolism than those from smaller counterparts at culture onset. MII oocytes from large follicles oxidized more (P < 0.05) glutamine than the same stage gametes recovered from smaller counterparts. In summary, larger-sized dog follicles contain a more metabolically active oocyte with a greater chance of achieving nuclear maturation in vitro. These findings demonstrate a significant role for energy metabolism in promoting dog oocyte maturation, information that will be useful for improving culture systems for rescuing intraovarian genetic material. PMID- 22213349 TI - Feasibility of outpatient consolidation chemotherapy in older versus younger patients with acute myeloid leukemia. AB - Intensive consolidation chemotherapy for acute myeloid leukemia (AML) patients in complete remission is being increasingly administered on an outpatient basis. Although this approach has been found to be safe and feasible in younger patients, its safety in older patients remains unknown. We therefore undertook an evaluation of outpatient-based consolidation chemotherapy in older AML patients, and compared results to younger patients treated at the same institution over the same time period. The overall rate of readmission was ~50%, mostly for infections, with mean admission duration of 2 weeks. The overall mortality rate was 2.2%. Readmission rates and duration of readmission were somewhat higher in older patients, but infection rate, intensive care (ICU) admissions, and mortality rates were comparable to those in the younger patient cohort. However, we also observed that rates of febrile neutropenia, bacteremia, ICU admission, and death were significantly higher during the second consolidation, as compared with the first, in both younger and older patients. We conclude that outpatient based consolidation therapy can be safely undertaken in a substantial proportion of fit older patients with AML. PMID- 22213350 TI - Phase transformation in thiamine hydrochloride tablets: Influence on tablet microstructure, physical properties, and performance. AB - The objective of this article was to monitor phase transformation in thiamine hydrochloride, from a nonstoichiometric hydrate (NSH) to a hemihydrate (HH), in stored tablets, prepared both by direct compression and wet granulation, and to relate the storage-induced phase transformation with changes in tablet microstructure, physical properties, and performance. Raman spectroscopy revealed complete NSH -> HH transformation in tablets, within 30 h of storage at 40 degrees C/75% relative humidity. When the tablets were prepared by wet granulation of NSH alone, there was a marked increase in both tablet volume and hardness on storage. However, when microcrystalline cellulose (MCC) was included in granulation, the resulting stored tablets also exhibited a pronounced increase in disintegration time. In contrast, tablets prepared by dry processing via compression of a NSH-MCC physical mixture did not exhibit any changes in properties, despite the in situ solid form conversion. Scanning electron microscopy revealed growth of needle-like HH crystals in all stored tablets and mercury porosimetry revealed considerable changes in the pore size distribution during storage. Longer storage led to crystal growth (Ostwald ripening), causing further gradual but less dramatic changes in properties. The phase transformation and the complex interparticulate associations in the tablet influenced the changes in tablet microstructure, compact physical properties, and product behavior. PMID- 22213354 TI - Exposure of the lysine in the gamma chain dodecapeptide of human fibrinogen is not enhanced by adsorption to poly(ethylene terephthalate) as measured by biotinylation and mass spectrometry. AB - Conformational changes in adsorbed fibrinogen may enhance the exposure of platelet adhesive sites that are inaccessible in solution. To test this hypothesis, mass spectrometric methods were developed to quantify chemical modification of lysine residues following adsorption of fibrinogen to biomaterials. The quantitative method used an internal standard consisting of isotope-labeled fibrinogen secreted by human HepG2 cells in culture. Lysine residues in the internal standard were partially reacted with NHS-biotin. For the experimental samples, normal human fibrinogen was adsorbed to poly(ethylene terephthalate) (PET) particles. The adsorbed fibrinogen was reacted with NHS biotin and then eluted from the particles. Constant amounts of internal standard were added to sample fibrinogen and analyzed by liquid chromatography/tandem mass spectrometry. Biotinylation of the lysine residue in the platelet-adhesive gamma chain dodecapeptide (GCDP) was quantified by comparison with the internal standard. Approximately 80% of the GCDP peptides were biotinylated when fibrinogen was reacted with NHS-biotin in solution or adsorbed onto PET. These results are generally consistent with previous antibody binding studies and suggest that other regions of fibrinogen may be crucial in promoting platelet adhesion to materials. The results do not directly address but are consistent with the hypothesis that only activated platelets adhere to adsorbed fibrinogen. PMID- 22213355 TI - A portable cryo-plunger for on-site intact cryogenic microscopy sample preparation in natural environments. AB - We present a modern, light portable device specifically designed for environmental samples for cryogenic transmission-electron microscopy (cryo-TEM) by on-site cryo-plunging. The power of cryo-TEM comes from preparation of artifact-free samples. However, in many studies, the samples must be collected at remote field locations, and the time involved in transporting samples back to the laboratory for cryogenic preservation can lead to severe degradation artifacts. Thus, going back to the basics, we developed a simple mechanical device that is light and easy to transport on foot yet effective. With the system design presented here we are able to obtain cryo-samples of microbes and microbial communities not possible to culture, in their near-intact environmental conditions as well as in routine laboratory work, and in real time. This methodology thus enables us to bring the power of cryo-TEM to microbial ecology. PMID- 22213357 TI - Image-quality figure evaluator based on contrast-detail phantom in radiography. AB - BACKGROUND: In radiology, it is significantly important to produce adequate diagnostic information while minimally affecting the patient with the lowest amount of dose. A contrast-detail phantom is generally used to study the quality of image and the amount of radiation dose for digital X-ray imaging systems. To evaluate the quality of a phantom image, radiologists are traditionally required to manually indicate the location of the holes in each square in the phantom image. Then, the image quality figure (IQF) of the image can be evaluated. However, evaluation by the human eye is subjective as well as time-consuming, and it differs from person to person. METHODS: In this paper, an image processing based IQF evaluator is proposed to automatically measure the quality of a phantom image. Nine phantom images, each consisting of 2382 * 2212 pixels, were used as test images and were provided by Taichung Hospital, Department of Health, Executive Yuan, Taiwan, Republic of China. The IP-IQF evaluator separates the phantom image into squares and then stretches the contrast of each square to the range 0-255. After that, it splits each square into 3 * 3 equal-sized regions, and recognizes the pattern of the square based on the features computed by mean difference gradient operation and run length enhancer. Furthermore, a genetic algorithm-based parameter values-detecting algorithm is presented to compute the optimal values of the parameters used in the IP-IQF evaluator. RESULTS: The experimental results demonstrate that CoCIQ and the IP-IQF evaluator can efficiently measure the IQF of a phantom image. The IP-IQF evaluator is more effective than a radiologist and CoCIQ in evaluating the IQF of a phantom image. CONCLUSIONS: The proposed IQF evaluator is more sensitive than not only the observation of radiologists but also the computer program CoCIQ. Moreover, a genetic algorithm is provided to compute the most suitable values of the parameters used in the IQF evaluator. PMID- 22213358 TI - Photoinduced memory effect in a redox controllable bistable mechanical molecular switch. PMID- 22213359 TI - Calixarene-based nanoscale coordination cages. PMID- 22213360 TI - Live-cell dSTORM of cellular DNA based on direct DNA labeling. PMID- 22213356 TI - CD24 on thymic APCs regulates negative selection of myelin antigen-specific T lymphocytes. AB - Negative selection plays a key role in the clonal deletion of autoreactive T cells in the thymus. However, negative selection is incomplete; as high numbers of autoreactive T cells can be detected in normal individuals, mechanisms that regulate negative selection must exist. In this regard, we previously reported that CD24, a GPI-anchored glycoprotein, is required for thymic generation of autoreactive T lymphocytes. The CD24-deficient 2D2 TCR transgenic mice (2D2(+) CD24(-/-) ), whose TCR recognizes myelin oligodendrocyte glycoprotein (MOG), fail to generate functional 2D2 T cells. However, it was unclear if CD24 regulated negative selection, and if so, what cellular mechanisms were involved. Here, we show that elimination of MOG or Aire gene expression in 2D2(+) CD24(-/-) mice - through the creation of 2D2(+) CD24(-/-) MOG(-/-) or 2D2(+) CD24(/) ~Aire(-/-) mice - completely restores thymic cellularity and function of 2D2 T cells. Restoration of CD24 expression on DCs, but not on thymocytes also partially restores 2D2 T-cell generation in 2D2(+) CD24(-/-) mice. Taken together, we propose that CD24 expression on thymic antigen-presenting cells (mTECs, DCs) down regulates autoantigen-mediated clonal deletion of autoreactive thymocytes. PMID- 22213361 TI - A high-sensitivity LC-MS/MS method for the determination of 4-methyl-piperazine-1 carbodithioc acid 3-cyano-3, 3-diphenylpropyl ester hydrochloride in rat plasma and its application to a pharmacokinetics study. AB - 4-Methyl-piperazine-1-carbodithioc acid 3-cyano-3, 3-diphenylpropyl ester hydrochloride (TM208), a newly synthesized anticancer compound, was quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the first time. A simple, rapid and sensitive assay method using propranolol as internal standard (IS) after one-step precipitation with acetonitrile was developed and validated to determine TM208 in rat plasma. Separation was achieved on a reverse phase C(18) column with a mobile phase composed of methanol-water (pH4.0) containing 5 m m ammonium acetate in gradient elution mode. A triple quadrupole tandem mass spectrometer with electrospray ionization source was used as detector and operated by multiple reaction monitoring in the positive ion mode. Calibration curves were linear (r > 0.99) between 0.2 and 500 ng/mL. The quantitative limit was 0.2 ng/mL; reliable precision and accuracy were validated by relative standard deviation values in the range 3.44-13.15% and relative error values between -0.58 and -9.78%. The method was successfully applied to preclinical pharmacokinetic studies of TM208. PMID- 22213362 TI - Catalytic non-conventional trans-hydroboration: a theoretical and experimental perspective. AB - We have studied the non-conventional trans-hydroboration reaction of alkynes both experimentally and theoretically. A catalytic system based on the in situ mixture of [{Rh(cod)Cl}(2)]/PCy(3) (cod=1,5-cyclooctadiene, Cy=cyclohexyl) has been able to activate pinacolborane and catecholborane and transfer boryl and hydride groups onto the same unhindered carbon atom of the terminal alkynes. The presence of a base (Et(3)N) favored the non-conventional trans-hydroboration over the traditional cis-hydroboration. Varying the substrate had a significant influence on the reaction, with up to 99% conversion and 94% regioselectivity observed for para-methyl-phenylacetylene. Both DFT and quantum mechanical/molecular mechanical ONIOM calculations were carried out on the [RhCl(PR(3))(2)] system. To explain the selectivity towards the (Z)-alkenylboronate we explored several alternative mechanisms to the traditional cis-hydroboration, using propyne as a model alkyne. The proposed mechanism can be divided into four stages: 1) isomerization of the alkyne into the vinylidene, 2) oxidative addition of the borane reagent, 3) vinylidene insertion into the Rh-H bond, and finally 4) reductive elimination of the C-B bond to yield the 1-alkenylboronate. Calculations indicated that the vinylidene insertion is the selectivity-determining step. This result was consistent with the observed Z selectivity when the sterically demanding phosphine groups, such as PCy(3) and PiPr(3), were introduced. Finally, we theoretically analyzed the effect of the substrate on the selectivity; we identified several factors that contribute to the preference for aryl alkynes over aliphatic alkynes for the Z isomer. The intrinsic electronic properties of aryl substituents favored the Z-pathway over the E-pathway, and the aryl groups containing electron donating substituents favored the occurrence of the vinylidene reaction channel. PMID- 22213363 TI - A novel DNA intercalator, 8-methoxy pyrimido[4',5':4,5]thieno (2,3-b)quinoline 4(3H)-one induces apoptosis in cancer cells, inhibits the tumor progression and enhances lifespan in mice with tumor. AB - Polycyclic aromatic molecules such as ellipticine intercalate into double stranded DNA and interfere with physiological functions. In the present study, we evaluate the chemotherapeutic potential of MPTQ on animal models and its mode of action. In order to test the antitumor activity, monohydrochloride of MPTQ was orally administered in mice bearing tumor. Results showed a significant inhibition of tumor growth compared to that of untreated controls. More importantly, mean lifespan of tumor bearing animals treated with MPTQ was significantly higher as compared to that of untreated tumor bearing mice suggesting that the treatment affected viability of cancerous cells, but not of normal cells. Consistent with this, we find that administration of MPTQ to normal mice did not cause any major side effects as observed upon hematological and serum profiling. We also found that MPTQ induces cytotoxicity in cancer cell lines, by activating apoptosis both by intrinsic and extrinsic pathways. Thus, MPTQ could be used as a potential cancer therapeutic agent. PMID- 22213366 TI - Adiabatic pulse preparation for imaging iron oxide nanoparticles. AB - Superparamagnetic iron oxide nanoparticles produce changes in the surrounding microscopic magnetic field. A method for generating contrast based on the application of an adiabatic preparation pulse and the failure of the adiabatic condition surrounding the nanoparticles is introduced in this article. Images were obtained in the presence and absence of an adiabatic preparation pulse and the difference was obtained. With the use of an adiabatic full passage pulse, the contrast in the difference image depends linearly on iron concentration up to 1 mM. The use of an adiabatic zero passage pulse resulted in higher sensitivity to nanoparticles compared to the adiabatic full passage, while maintaining linear concentration dependence to 0.1 mM. This technique was shown to be insensitive to magnetization transfer and B(0) inhomogeneity. With its linearity with iron concentration and insensitivity to changes in the main magnetic field, the new method is well suited for quantitative iron oxide nanoparticle imaging. PMID- 22213367 TI - Longitudinal mental health impact among police responders to the 9/11 terrorist attack. AB - BACKGROUND: Among police responders enrolled in the World Trade Center Health Registry (WTCHR), Post-traumatic Stress Disorder (PTSD) was almost twice as prevalent among women as men 2-3 years after the 9/11 attacks. METHODS: Police participants in the WTCHR Wave 1 survey 2-3 years after 9/11/01, were reassessed for probable PTSD at Wave 2, 5-6 years after 9/11/01, using PCL DSM-IV criteria. RESULTS: Police participants in the Wave 2 survey included 2,527 men, 413 women. The prevalence of "Probable PTSD" was 7.8% at Wave 1 and 16.5% at Wave 2. Mean PCL scores increased from 25.1 to 29.9 for men and 28.6 to 32.2 for women. Prevalence of PTSD was higher for women than for men at Wave 1 (chi(2) = 10.882, P = 0.002), but not Wave 2 (chi(2) = 2.416, P = 0.133). Other risk factors included losing one's job after 9/11 and being disabled. CONCLUSIONS: Prevalence of probable PTSD among police doubled between 2003-2004 and 2006-2007. After the 2-year time span, the gender difference was no longer significant; prevalence of PTSD symptoms increased and there was a substantial amount of co-morbidity with other mental health problems. Further development of prevention and intervention strategies for police responders with symptoms of PTSD is needed. The observed upward trend in PCL scores over time in police officers with PCL scores less than 44, suggests that PTSD prevention and intervention strategies should be applied to all police affected by the 9/11 attacks, not limited just to those with PTSD symptoms. PMID- 22213368 TI - Hepatoprotective effect of Filipendula hexapetala Gilib. (Rosaceae) in carbon tetrachloride-induced hepatotoxicity in rats. AB - The influence of methanol extract produced from the flowers of Filipendula hexapetala Gilib. (Rosaceae) on some liver biochemical parameters in rats intoxicated with carbon tetrachloride (CTC) was evaluated in this study. The results Obtained revealed that pretreatment with the extract investigated inhibited CTC-induced liver injury by decreasing lipid peroxidation and increasing the content of reduced glutathione in a dosage dependent manner, bringing the levels of all antioxidant enzymes close to control values. The administration of CTC diminished hepatic antioxidant defense mechanisms by significant reduction of peroxidase and catalase activities. The catalase activity was significantly recovered in groups treated with the extract investigated and intoxicated with a single CTC dose. A similar impact on hepatic peroxidase activity has also been observed, indicating a partial detoxication of hydrogen peroxide by both catalase and peroxidase. PMID- 22213370 TI - Effects of the triple reuptake inhibitor amitifadine on extracellular levels of monoamines in rat brain regions and on locomotor activity. AB - Major depressive disorder is a prevalent disease, and current pharmacotherapy is considered to be inadequate. It has been hypothesized that a triple reuptake inhibitor (TRI) that activates dopamine (DA) neurotransmission in addition to serotonin and norepinephrine (NE) circuitries may result in enhanced antidepressant effects. Here, we investigated the pharmacological effects of a serotonin-preferring TRI-amitifadine (EB-1010, formerly DOV 21947). The effects of amitifadine (10 mg/kg ip.) on extracellular concentrations of monoamines and their metabolites in rat brain regions were investigated using the in vivo microdialysis technique. The effects of amitifadine on locomotor activity and stereotyped behavior were also evaluated. A major metabolite of amitifadine, the 2-lactam compound, was investigated for inhibition of monoamine uptake processes. Amitifadine markedly and persistently increased extracellular concentrations of serotonin, NE, and DA in prefrontal cortex. The extracellular concentrations of DA were also increased in the DA-rich areas striatum and nucleus accumbens. The extracellular concentrations of the metabolites of serotonin, 5 hydroxyindoleacetic acid, and DA, 3,4-dihydroxyphenylacetic and homovanillic acid, were also markedly decreased in brain regions. Amitifadine did not increase locomotor activity or stereotypical behaviors over a broad dose range. The lactam metabolite of amitifadine weakly inhibited monoamine uptake. Thus, amitifadine increased extracellular concentrations of serotonin, NE, and DA, consistent with TRI. Although amitifadine significantly increased DA in the nucleus accumbens, it did not induce locomotor hyperactivity or stereotypical behaviors. The enhancement of serotonin, NE, and DA in rat brain regions associated with depression suggest that amitifadine may have novel antidepressant activity. PMID- 22213371 TI - SWIFT-CEST: a new MRI method to overcome T2 shortening caused by PARACEST contrast agents. AB - The exchange of water molecules between the inner sphere of a paramagnetic chemical exchange saturation transfer (PARACEST) contrast agent and bulk water can shorten the bulk water T(2) through the T(2) -exchange (T(2ex) ) mechanism. The line-broadening T(2ex) effect is proportional to the agent concentration, the chemical shift of the exchanging water molecule, and is highly dependent on the water molecule exchange rate. A significant T(2ex) contribution to the bulk water linewidth can make the regions of agent uptake appear dark when imaging with conventional sequences like gradient-echo and fast spin-echo. The minimum echo times for these sequences (1-10 ms) are not fast enough to capture signal from the regions of shortened T(2) . This makes "Off" (saturation at -Deltaomega) minus "On" (saturation at +Deltaomega) imaging of PARACEST agents difficult, because the regions of uptake are dark in both images. It is shown here that the loss of bulk water signal due to T(2ex) can be reclaimed using the ultrashort echo times (<10 MUs) achieved with the sweep imaging with Fourier transform pulse sequence. Modification of the sweep imaging with Fourier transform sequence for PARACEST imaging is first discussed, followed by parameter optimization using in vitro experiments. In vivo PARACEST studies comparing fast spin-echo to sweep imaging with Fourier transform were performed using EuDOTA-(gly) 4- uptake in healthy mouse kidneys. The results show that the negative contrast caused by T(2ex) can be overcome using the ultrashort echo time achieved with sweep imaging with Fourier transform, thereby enabling fast and sensitive in vivo PARACEST imaging. PMID- 22213372 TI - Microstructures of GaN thin films grown on graphene layers. AB - Plan-view and cross-sectional transmission electron microscopy images show the microstructural properties of GaN thin films grown on graphene layers, including dislocation types and density, crystalline orientation and grain boundaries. The roles of ZnO nanowalls and GaN intermediate layers in the heteroepitaxial growth of GaN on graphene, revealed by cross-sectional transmission electron microscopy, are also discussed. PMID- 22213373 TI - Caveolin-1 overexpression is associated with simultaneous abnormal expression of the E-cadherin/alpha-beta catenins complex and multiple ErbB receptors and with lymph nodes metastasis in head and neck squamous cell carcinomas. AB - The presence of lymph node metastases is one of the most important prognostic indicators in head and neck squamous cell carcinomas (HNSCCs). An alteration of the E-cadherin-catenins complex and EGFR is essential for the invasiveness of cancer cells. Caveolin-1, the major structural protein of the caveolae, represents a scaffolding molecule for several signaling proteins including EGFR. Although caveolin-1 has been shown to play a role in inducing the invasive phenotype of cancer cells, its role appears to be cell-type specific and for some tumors it has not been defined yet. In this study we used 57 HNSCC specimens to investigate whether the abnormal expression of caveolin-1 was associated with the derangement of the E-cadherin-catenins complex and with the overexpression of ErbB receptors. We demonstrate that in HNSCCs caveolin-1 overexpression is associated with the simultaneous abnormal expression of at least one member of the E-cadherin/alpha-beta catenins complex and multiple ErbB receptors as well as with lymph node metastases. We also demonstrate that chronic stimulation of a human hypopharyngeal carcinoma cell line (FaDu) with EGF induced the internalization of beta-catenin and caveolin-1 and their co-localization with EGFR. Moreover, EGF treatment induced an increased physical interaction between EGFR/beta-catenin/caveolin-1 and between E-cadherin/beta-catenin/caveolin-1. These molecular events were associated with an increased directional motility of FaDu cells in vitro. These findings may provide new insight into the biology of HNSCC progression and help to identify subgroups of primary HNSCCs with a more aggressive behavior. PMID- 22213374 TI - A marked animal-vegetal polarity in the localization of Na(+),K(+) -ATPase activity and its down-regulation following progesterone-induced maturation. AB - The stage-VI Xenopus oocyte has a very distinct animal-vegetal polarity with structural and functional asymmetry. In this study, we show the expression and distribution pattern of Na(+),K(+) -ATPase in stage-VI oocytes, and its changes following progesterone-induced maturation. Using enzyme-specific electron microscopy phosphatase histochemistry, [(3) H]-ouabain autoradiography, and immunofluorescence cytochemistry at light microscopic level, we find that Na(+),K(+) -ATPase activity is mainly confined to the animal hemisphere. Electron microscopy histochemical results also suggest that polarized distribution of Na(+),K(+) -ATPase activity persists following progesterone-induced maturation, and it becomes gradually more polarized towards the animal pole. The time course following progesterone-induced maturation suggests that there is an initial up regulation and then gradual down-regulation of Na(+),K(+) -ATPase activity leading to germinal vesicle breakdown (GVBD). By GVBD, the Na(+),K(+) -ATPase activity is completely down-regulated due to endocytotic removal of pump molecules from the plasma membrane into the sub-cortical region of the oocyte. This study provides the first direct evidence for a marked asymmetric localization of Na(+),K(+) -ATPase activity in any vertebrate oocyte. Here, we propose that such asymmetry in Na(+),K(+) -ATPase activity in stage-VI oocytes, and their down-regulation following progesterone-induced maturation, is likely to have a role in the active state of the germinal vesicle in stage-VI oocytes and chromosomal condensation after GVBD. PMID- 22213376 TI - Sarcoidosis mimicking recurrent lymphoma. PMID- 22213377 TI - Improving hand hygiene in a paediatric hospital: a multimodal quality improvement approach. AB - BACKGROUND: Effective hand hygiene has long been recognised as an important way to reduce the transmission of bacterial and viral pathogens in healthcare settings. However, many studies have shown that adherence to hand hygiene remains low, and improvement efforts have often not delivered sustainable results. The Children's Hospital at Westmead is the largest tertiary paediatric hospital in Sydney, Australia. The hospital participated in a state-wide 'Clean hands save lives' campaign which was initiated in 2006. INTERVENTION: Strong leadership, good stakeholder engagement, readily accessible alcohol-based hand rub at the point of patient care, a multifaceted education programme, monitoring of staff, adherence to recommended hand hygiene practices and contemporaneous feedback of performance data have significantly improved and maintained compliance with hand hygiene. RESULTS: Hand hygiene compliance has increased from 23% in 2006 to 87% in 2011 (p<0.001). Sustained improvement in compliance with hand hygiene has been evident in the last 4 years. A decline in a set of hospital-acquired infections (including rotavirus, multiresistant organism transmission, and nosocomial bacteraemia) has also been noted as hand hygiene rates have improved. Monthly usage of alcohol-based hand rub has increased from 16 litres/1000 bed days to 51 litres/1000 bed days during this same period. CONCLUSION: This project has delivered sustained improvement in hand hygiene compliance by establishing a framework of multimodal evidence-based strategies. PMID- 22213378 TI - Medical errors reported by French general practitioners in training: results of a survey and individual interviews. AB - CONTEXT: French interns in general practice are, like all medical students, exposed to medical errors during their training. OBJECTIVE: To measure the professional and personal impact of medical errors on French general practitioner (GP) trainees. DESIGN, SETTING AND PARTICIPANTS: Quantitative and qualitative study of medical errors and GP trainees enrolled at Paris Diderot University. METHOD: An online anonymous questionnaire was sent to all GP trainees at Paris Diderot University and recorded semi-structured interviews were conducted with 10 volunteers. RESULTS: 70 of the 392 (18%) interns contacted replied to the questionnaire and 10 semi-structured interviews were then conducted. 97% of the participants had already made a medical error. Even with the extreme, conservative assumption that non-respondents would have reported no errors, the prevalence of self-reported medical errors in the whole sample would still have been 17%. 64% said they were at least strongly affected by their error and 74% made constructive changes to their work after the error. The interns revealed that the emotional impact of their errors were great with feelings such as guilt that could remain for more than 2 years after the event. 33% would have liked to talk more about the circumstances of their error with their superior. Most interns suggest more training on medical errors and more open-minded discussion when the error actually happens rather than formal training at the university. CONCLUSION: Medical errors remain a sensitive subject that is not broached enough in our university but interns need to talk about their experiences with their peers to improve risk management and prevent the recurrence of new errors. PMID- 22213379 TI - Medical error, incident investigation and the second victim: doing better but feeling worse? PMID- 22213380 TI - [Editorial: Pharmazie in unserer Zeit 1/2012]. PMID- 22213381 TI - Subthalamic neuronal responses to cortical stimulation. AB - BACKGROUND: Deep brain stimulation of the subthalamic nucleus alleviates motor symptoms in Parkinson's disease patients. However, some patients suffer from cognitive and emotional changes. These side effects are most likely caused by current spread to the cognitive and limbic territories in the subthalamic nucleus. The aim of this study was to identify the motor part of the subthalamic nucleus to reduce stimulation-induced behavioral side effects, by using motor cortex stimulation. METHODS: We describe the results of subthalamic nucleus neuronal responses to stimulation of the hand area of the motor cortex and evaluate the safety of this novel technique. RESULTS: Responses differed between regions within the subthalamic nucleus. In the anterior and lateral electrode at dorsal levels of the subthalamic nucleus, an early excitation (~5-45 ms) and subsequent inhibition (45-105 ms) were seen. The lateral electrode also showed a late excitation (~125-160 ms). Focal seizures were observed following motor cortex stimulation. CONCLUSIONS: To prevent seizures the current density should be lowered, so that motor cortex stimulation-evoked responses can be safely used during deep brain stimulation surgery. PMID- 22213382 TI - Nucleic acid and peptide aptamers: fundamentals and bioanalytical aspects. AB - In recent years new nucleic acid and protein-based combinatorial molecules have attracted the attention of researchers working in various areas of science, ranging from medicine to analytical chemistry. These molecules, called aptamers, have been proposed as alternatives to antibodies in many different applications. The aim of this Review is to illustrate the peculiarities of these combinatorial molecules which have initially been explored for their importance in molecular medicine, but have enormous potential in other biotechnological fields historically dominated by antibodies, such as bioassays. A description of these molecules is given, and the methods for their selection and production are also summarized. Moreover, critical aspects related to these molecules are discussed. PMID- 22213384 TI - The effects of electrospun TSF nanofiber diameter and alignment on neuronal differentiation of human embryonic stem cells. AB - Although transplantation of human embryonic stem cells (hESCs)-derived neural precursors (NPs) has been demonstrated with some success for nervous repair in small animal model, control of the survival, and directional differentiation of these cells is still challenging. Meanwhile, the notion that using suitable scaffolding materials to control the growth and differentiation of grafted hESC derived NPs raises the hope for better clinical nervous repair. In this study, we cultured hESC-derived NPs on Tussah silk fibroin (TSF)-scaffold of different diameter (i.e., 400 and 800 nm) and orientation (i.e., random and aligned) to analyze the effect of fiber diameter and alignment on the cell viability, neuronal differentiation, and neurite outgrowth of hESC-derived NPs. The results show that TSF-scaffold supports the survival, migration, and differentiation of hESC-derived NPs. Aligned TSF-scaffold significantly promotes the neuronal differentiation and neurite outgrowth of hESC-derived neurons compared with random TSF-scaffold. Moreover, on aligned 400 nm fibers cell viability, neuronal differentiation and neurite outgrowth are greater than that on aligned 800 nm fibers. Together, these results demonstrate that aligned 400 nm TSF-scaffold is more suitable for the development of hESC-derived NPs, which shed light on optimization of the therapeutic potential of hESCs to be employed for neural regeneration. PMID- 22213385 TI - Initial laboratory experience with a novel ultrasound probe for standard and single-port robotic kidney surgery: increasing console surgeon autonomy and minimizing instrument clashing. AB - BACKGROUND: The aim of this study was to evaluate a novel ultrasound probe specifically developed for robotic surgery by determining its efficiency in identifying renal tumors. METHODS: The study was carried out using the Da VinciTM surgical system in one female pig. Renal tumor targets were created by percutaneous injection of a tumor mimic mixture. Single-port and standard robotic partial nephrectomy were performed. Intraoperative ultrasound was performed using both standard laparoscopic probe and the new ProARTTM Robotic probe. Probe maneuverability and ease of handling for tumor localization were recorded. RESULTS: The standard laparoscopic probe was guided by the assistant. Significant clashing with robotic arms was noted during the single-port procedure. The novel robotic probe was easily introduced through the assistant trocar, and held by the console surgeon using the robotic PrograspTM with no registered clashing in the external operative field. The average time for grasping the new robotic probe was less than 10 s. Once inserted and grasped, no limitation was found in terms of instrument clashing during the single-port procedure. CONCLUSIONS: This novel ultrasound probe developed for robotic surgery was noted to be user-friendly when performing porcine standard and especially single-port robotic partial nephrectomy. PMID- 22213383 TI - In vitro blood-brain barrier models: current and perspective technologies. AB - Even in the 21st century, studies aimed at characterizing the pathological paradigms associated with the development and progression of central nervous system diseases are primarily performed in laboratory animals. However, limited translational significance, high cost, and labor to develop the appropriate model (e.g., transgenic or inbred strains) have favored parallel in vitro approaches. In vitro models are of particular interest for cerebrovascular studies of the blood-brain barrier (BBB), which plays a critical role in maintaining the brain homeostasis and neuronal functions. Because the BBB dynamically responds to many events associated with rheological and systemic impairments (e.g., hypoperfusion), including the exposure of potentially harmful xenobiotics, the development of more sophisticated artificial systems capable of replicating the vascular properties of the brain microcapillaries are becoming a major focus in basic, translational, and pharmaceutical research. In vitro BBB models are valuable and easy to use supporting tools that can precede and complement animal and human studies. In this article, we provide a detailed review and analysis of currently available in vitro BBB models ranging from static culture systems to the most advanced flow-based and three-dimensional coculture apparatus. We also discuss recent and perspective developments in this ever expanding research field. PMID- 22213386 TI - Fiber laser based two-photon FRET measurement of calmodulin and mCherry-E(0)GFP proteins. AB - The speed and accuracy of Forster resonance energy transfer (FRET) measurements can be improved by rapidly alternating excitation wavelengths between the donor and acceptor fluorophore. We demonstrate FRET efficiency measurements based on a fiber laser and photonic crystal fiber as the source for two-photon excitation (TPE). This system offers the potential for rapid wavelength switching with the benefits of axial optical sectioning and improved penetration depth provided by TPE. Correction of FRET signals for cross excitation and cross emission was achieved by switching the excitation wavelength with an electrically controlled modulator. Measurement speed was primarily limited by integration times required to measure fluorescence. Using this system, we measured the FRET efficiency of calmodulin labeled with Alexa Fluor 488 and Texas Red dyes. In addition, we measured two-photon induced FRET in an E(0)GFP-mCherry protein construct. Results from one-photon and two-photon excitation are compared to validate the rapid wavelength switched two-photon measurements. PMID- 22213387 TI - A general chemical ligation approach towards isopeptide-linked ubiquitin and ubiquitin-like assay reagents. PMID- 22213388 TI - Crystallographic snapshots of the bond-breaking isomerization reactions involving nickel(II) complexes with hemilabile ligands. PMID- 22213389 TI - Double or multiple/secondary peaks in pharmacokinetics: considerations and challenges from a bio-analytical perspective. PMID- 22213390 TI - Polymorphisms in GSTM1 and XPD genes predict clinical outcome in advanced oral cancer patients treated with postoperative radiotherapy. AB - Polymorphisms in metabolic and DNA repair genes may alter protein function, consequently affecting patients' response to chemo/radiotherapy. We retrospectively assessed whether polymorphisms of glutathione-S-transferase genes GSTM1 (deletion), GSTT1 (deletion), GSTP1 (Ile105Val, rs1695), and DNA repair genes hOGG1 (Ser326Cys, rs1052133), XRCC1 (Arg194Trp, rs1799782, and Arg399Gln, rs25487), XPD (Asp312Asn, rs1799793, and Lys751Gln, rs13181) can predict clinical outcome in 187 oral squamous cell carcinoma patients treated with postoperative radiotherapy. The Cox proportional hazards model was used to evaluate the role of polymorphic genotypes on relapse-free (RFS) and disease-specific (DSS) survival. Deletion polymorphism of GSTM1 gene was significantly associated with DSS. The rs1799793 variant allele showed significant protection in both DSS and RFS. Significant increase in RFS but not in DSS was observed with polymorphic rs13181. The combined analysis of GSTM1 and XPD polymorphisms revealed favorable effect on survival. GSTM1 and XPD variant alleles, independently as well as in combination may serve as important predictors of clinical outcome in radiotherapy-treated OSCC patients. PMID- 22213391 TI - Organocatalytic Diels-Alder reactions catalysed by supramolecular self-assemblies formed from chiral amines and poly(alkene glycol)s. PMID- 22213392 TI - CO metabolism, sensing, and signaling. AB - CO is a colorless and odorless gas produced by the incomplete combustion of hydrocarbons, both of natural and anthropogenic origin. Several microorganisms, including aerobic and anaerobic bacteria and anaerobic archaea, use exogenous CO as a source of carbon and energy for growth. On the other hand, eukaryotic organisms use endogenous CO, produced during heme degradation, as a neurotransmitter and as a signal molecule. CO sensors act as signal transducers by coupling a "regulatory" heme-binding domain to a "functional" signal transmitter. Although high CO concentrations inhibit generally heme-protein actions, low CO levels can influence several signaling pathways, including those regulated by soluble guanylate cyclase and/or mitogen-activated protein kinases. This review summarizes recent insights into CO metabolism, sensing, and signaling. PMID- 22213393 TI - The influence of terminal push-pull substitution on the electronic structure and optical properties of pentacenes. AB - The synthesis of 2,3-R(2)-9,10-(OMe)(2)-substituted pentacenes (R=OMe, F, Br, CN; 1-4) from 2,3-R(2)-9,10-dimethoxy-6,13-dihydro-6,13-ethanopentacene-15,16-diones (alpha-diketone-bridged precursors) by photochemically induced bis decarbonylation (Strating-Zwanenburg reaction) is described. Under matrix isolation conditions (solid Ar, 10 K) the S(1) transitions of 1 and 2 undergo hypsochromic and those of 3 and 4 bathochromic shifts compared to parent pentacene. The S(1) transition wavelengths correlate well with the difference of substituent parameters sigma(p). A computational analysis of the excited states at the CAM-B3LYP/6-311+G** level of theory provides an assignment of the electronic transitions. Photolysis in solution at room temperature yields red [R=OMe (1)], blue [R=Br (3), F (2)], and green [R=CN (4)] pentacenes. The compounds are oxygen-sensitive and have low solubility, but their formation can be monitored by UV/Vis and, in the case of R=CN, also by (1)H NMR spectroscopy. The S(1) transition in 4 does not show the typical pentacene fine structure in the electronic absorption spectrum. Photogeneration in the presence of oxygen leads to a number of photoproducts that could be identified by monitoring the reaction by (1)H NMR spectroscopy for R=OMe. PMID- 22213394 TI - Prognostic significance of MYC, BCL2, and BCL6 rearrangements in patients with diffuse large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab. AB - BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) are a biologically heterogeneous group in which various gene alterations have been reported. The aim of this study was to investigate the frequency and prognostic impact of BCL2, BCL6, and MYC rearrangements in cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-CHOP)-treated DLBCL cases. METHODS: Tissue microarrays were constructed from 239 cases of DLBCL, and the expressions of CD10, BCL6, MUM1/IRF4, and BCL2 were evaluated by immunohistochemistry. MYC, BCL2, and BCL6 rearrangements were investigated by interphase fluorescence in situ hybridization on tissue microarrays. Survival analysis was constructed from 145 R-CHOP-treated patients. RESULTS: MYC, BCL2, and BCL6 rearrangements were detected in 14 (6%), 36 (15%), and 69 (29%) of 239 DLBCL patients. Double or triple rearrangements were detected in 7 (3%) of 239 DLBCL cases. Of these, 4 had BCL2 and MYC, 2 had BCL6 and MYC, and 1 had BCL2, BCL6, and MYC rearrangements. The prognosis of these cases was extremely poor, with a median survival of 9 months. MYC rearrangement was associated with significantly worse overall survival (P = .01), especially for the cases with GC phenotype (P = .009). BCL6 rearrangement also predicted significantly shorter overall survival (P = .04), especially for the non-GC phenotype (P = .03). BCL2 rearrangement had no prognostic impact on outcome. International Prognostic Index (P = .004) and MYC rearrangement (P = .009) were independent poor prognostic factors. CONCLUSIONS: Analysis of MYC gene rearrangement along with BCL2 and BCL6 is critical in identifying high-risk patients with poor prognosis. PMID- 22213395 TI - Novel strategies for fluorine-18 radiochemistry. PMID- 22213397 TI - Combination of molecular, morphological, and interfacial engineering to achieve highly efficient and stable plastic solar cells. AB - A flexible solar device showing exceptional air and mechanical stability is produced by simultaneously optimizing molecular structure, active layer morphology, and interface characteristics. The PFDCTBT-C8-based devices with inverted architecture exhibited excellent power conversion efficiencies of 7.0% and 6.0% on glass and flexible substrates, respectively. PMID- 22213396 TI - Correction of vibration artifacts in DTI using phase-encoding reversal (COVIPER). AB - Diffusion tensor imaging is widely used in research and clinical applications, but still suffers from substantial artifacts. Here, we focus on vibrations induced by strong diffusion gradients in diffusion tensor imaging, causing an echo shift in k-space and consequential signal-loss. We refined the model of vibration-induced echo shifts, showing that asymmetric k-space coverage in widely used Partial Fourier acquisitions results in locally differing signal loss in images acquired with reversed phase encoding direction (blip-up/blip-down). We implemented a correction of vibration artifacts in diffusion tensor imaging using phase-encoding reversal (COVIPER) by combining blip-up and blip-down images, each weighted by a function of its local tensor-fit error. COVIPER was validated against low vibration reference data, resulting in an error reduction of about 72% in fractional anisotropy maps. COVIPER can be combined with other corrections based on phase encoding reversal, providing a comprehensive correction for eddy currents, susceptibility-related distortions and vibration artifact reduction. PMID- 22213398 TI - Oldenlandia diffusa extracts exert antiproliferative and apoptotic effects on human breast cancer cells through ERalpha/Sp1-mediated p53 activation. AB - Breast cancer is the most frequent tumor and a major cause of death among women. Estrogens play a crucial role in breast tumor growth, which is the rationale for the use of hormonal antiestrogen therapies. Unfortunately, not all therapeutic modalities are efficacious and it is imperative to develop new effective antitumoral drugs. Oldenlandia diffusa (OD) is a well-known medicinal plant used to prevent and treat many disorders, especially cancers. The aim of this study was to investigate the effects of OD extracts on breast cancer cell proliferation. We observed that OD extracts strongly inhibited anchorage dependent and -independent cell growth and induced apoptosis in estrogen receptor alpha (ERalpha)-positive breast cancer cells, whereas proliferation and apoptotic responses of MCF-10A normal breast epithelial cells were unaffected. Mechanistically, OD extracts enhance the tumor suppressor p53 expression as a result of an increased binding of ERalpha/Sp1 complex to the p53 promoter region. Finally, we isolated ursolic and oleanolic acids as the bioactive compounds able to upregulate p53 expression and inhibit breast cancer cell growth. These acids were greatly effective in reducing tamoxifen-resistant growth of a derivative MCF 7 breast cancer cell line resistant to the antiestrogen treatment. Our results evidence how OD, and its bioactive compounds, exert antiproliferative and apoptotic effects selectively in ERalpha-positive breast cancer cells, highlighting the potential use of these herbal extracts as breast cancer preventive and/or therapeutic agents. PMID- 22213399 TI - Risk factors for musculoskeletal disorders among farm owners and farm workers: a systematic review. AB - BACKGROUND: A systematic review was undertaken to establish risk factors for the development of musculoskeletal disorders (MSDs) among farmers. METHODS: Comprehensive electronic searches of Pubmed, Web of Science, CINAHL, SCOPUS, EMBASE, Agris Database, and Cochrane Library were carried out using a battery of key words for MSDs and farmers. The studies methods quality was assessed using a standardized checklist. RESULTS: Thirty-three studies fulfilled the inclusion criteria. The median method score was 65% of the maximum attainable score, resulting in 15 studies of higher methodological. Risks were categorized into: Work characteristics (n = 11), personal characteristics (n = 5), and psychosocial factors (n = 5). Spinal MSD risk factors include exposure to working in tree crops, vibration, postural load, being an owner operator, age, education beyond high school, suffering from asthma or depression, having <8 hr nightly sleep, bad quality sleep, and geographic location. Upper extremity MSD risk factors include being an owner operator, dust with pig workers, numbness and coldness in younger milkers and numbness in milkers >43 years, age, and body height in dairy farmers. Lower extremity MSD risk factors include, duration of farming >=10 years, working >5 hr daily in animal barns, milking >40 cows, years as a dairy farmer, farm work, age, body mass, and female gender. CONCLUSIONS: In exploring risk factors the spine was the most researched body region, followed by lower and upper extremity. Given the variance between studies, it is recommended that future studies focus on specific types of farmers and should explore specific exposures for specific body parts using standardized case definitions. PMID- 22213400 TI - Aging of methabenzthiazuron, imidacloprid, and N,N-dimethylsulfamide in silty soils and effects on sorption and dissipation. AB - Differences in soil properties can influence the fate of plant protection agents in the environment. The present study aims to investigate the sorption behavior and related aging processes of imidacloprid (IMI; insecticide), methabenzthiazuron (MBT; herbicide), and N,N-dimethylsulfamide (DMSA; degradate of the fungicide tolylfluanid) in six soils of silty texture but otherwise varying properties. The sorption behavior of these 14C-labeled compounds exhibiting different physicochemical properties was characterized by applying a three-step sequential extraction procedure. After 119 d, MBT revealed strongest sorption (K'(tot) 47.4-200.4 L/kg), followed by IMI (K'(tot) 11.7-30.6 L/kg), and DMSA with K'(tot) close to zero. Aged sorption factors (AFs) were calculated to characterize aging processes over time exhibiting a 2.6-3.5-fold (IMI), a 1.8-4.5 fold (MBT), and no (DMSA) increase of sorbed amounts within 84 d. Sorption and aging varied widely in the group of silty soils, which differed with respect to organic matter content, C/N-ratio, and microbial soil parameters. The time dependent increase of adsorption of MBT and IMI was more pronounced in those soils that had a lower organic carbon and low microbial biomass content. Concomitantly, MBT and IMI degradation decelerated, presumably because of aged sorption at inner binding sites leading to a lower accessibility. In contrast, in the soils with a higher organic carbon content a strong initial (but later still reversible) sorption of MBT and IMI, occurring presumably at outer surface sites, reduced the extent of time-dependent diffusion toward inner binding sites. PMID- 22213401 TI - A novel X-linked disorder with developmental delay and autistic features. AB - OBJECTIVE: Genomic duplications that lead to autism and other human diseases are interesting pathological lesions since the underlying mechanism almost certainly involves dosage sensitive genes. We aim to understand a novel genomic disorder with profound phenotypic consequences, most notably global developmental delay, autism, psychosis, and anorexia nervosa. METHODS: We evaluated the affected individuals, all maternally related, using childhood autism rating scale (CARS) and Vineland Adaptive scales, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) brain, electroencephalography (EEG), electromyography (EMG), muscle biopsy, high-resolution molecular karyotype arrays, Giemsa banding (G-banding) and fluorescent in situ hybridization (FISH) experiments, mitochondrial DNA (mtDNA) sequencing, X-chromosome inactivation study, global gene expression analysis on Epstein-Barr virus (EBV)-transformed lymphoblasts, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). RESULTS: We have identified a novel Xq12-q13.3 duplication in an extended family. Clinically normal mothers were completely skewed in favor of the normal chromosome X. Global transcriptional profiling of affected individuals and controls revealed significant alterations of genes and pathways in a pattern consistent with previous microarray studies of autism spectrum disorder patients. Moreover, expression analysis revealed copy number-dependent increased messenger RNA (mRNA) levels in affected patients compared to control individuals. A subset of differentially expressed genes was validated using qRT-PCR. INTERPRETATION: Xq12-q13.3 duplication is a novel global developmental delay and autism predisposing chromosomal aberration; pathogenesis of which may be mediated by increased dosage of genes contained in the duplication, including NLGN3, OPHN1, AR, EFNB1, TAF1, GJB1, and MED12. PMID- 22213403 TI - Timing of first embryonic cleavage is a positive indicator of the in vitro developmental potential of porcine embryos derived from in vitro fertilization, somatic cell nuclear transfer and parthenogenesis. AB - Evidence in many species has suggested that those embryos that cleave earliest after fertilization are more developmentally competent than those that cleave relatively later after fertilization. Herein we document this phenomenon in porcine in vitro-fertilized (IVF), somatic cell nuclear transfer (SCNT), and parthenogenetic (PA) embryos. In vitro-matured pig oocytes were used to generate IVF, SCNT, and PA embryos. At 24 hr post-activation (or insemination; hpa/hpi), embryos were visually assessed, and cleaved embryos were moved into a new culture well. This process was repeated at 30 and 48 hpa/hpi. All embryos were allowed to develop 7 days in culture. For IVF embryos, 39.9%, 24.6%, and 10.5% of fast-, intermediate-, or slow-cleaving embryos, respectively, developed into blastocysts by day 7. For SCNT embryos, 31.8% of fast-, 5.7% of intermediate-, and 2.9% of late-cleaving embryos achieved the blastocyst stage of development. For PA embryos, the percentages of those cleaved embryos that developed to blastocyst were 59.3%, 36.7%, and 7.5% for early-, intermediate-, and late-cleaving embryos, respectively. Using RNA collected from early-, intermediate-, and late-cleaving embryos, real-time PCR was performed to assess the transcript levels of 14 different genes of widely varied function. The qPCR results suggest that maternal mRNA degradation may not proceed in an appropriate pattern in slow-cleaving embryos. These findings (1) confirm that, as observed in other species, earlier cleaving porcine embryos are more successful at developing in culture than are slower-cleaving embryos, and (2) implicate mechanisms of maternal transcript destruction as potential determinants of oocyte/embryo quality. PMID- 22213404 TI - Effects of mirtazapine on sleep disturbance under neuropathic pain-like state. AB - Sleep disturbance has been reported to be one of the most frequent symptoms in patients suffered from severe pain. Benzodiazepines are effective and reduce anxiety in the hours after use, but the induced sleep tends to be less than ideal in quality, with increased Stages I-II and reduces Stages III-IV sleep. In the present study, we investigated sleep disturbance under a neuropathic pain-like state in mice using electroencephalogram (EEG)/electromyogram (EMG). In a model of neuropathic pain, sciatic nerve ligation caused a marked decrease in the latency of paw withdrawal in response to a thermal stimulus only on the ipsilateral side. Under this condition, sciatic nerve-ligated animals showed a statistically significant increase in wakefulness and a decrease in non-rapid eye movement (NREM) sleep during the light phase. Mirtazapine (MTZ) is an antidepressant, which is considered to enhance noradrenergic and serotonergic neurotransmission via antagonistic action at central alpha2-adrenergic autoreceptors and heteroreceptors. In the present binding study, MTZ showed higher affinity for histamine H1 and serotonin 5-HT(2A/2C) receptors than other receptors, including alpha2-adrenergic receptor, in the mouse brain tissue. The thermal hyperalgesia and sleep disturbance following nerve ligation were almost completely alleviated by MTZ. These findings suggest that MTZ may improve the quality of sleep as well as control pain in patients with neuropathic pain mainly through histamine H1- and serotonin 5-HT2-receptor antagonistic actions. PMID- 22213405 TI - Aripiprazole altered plasma levels of brain-derived neurotrophic factor and catecholamine metabolites in first-episode untreated Japanese schizophrenia patients. AB - OBJECTIVE: We investigated the effects of aripiprazole on plasma levels of brain derived neurotrophic factor (BDNF) and catecholamine metabolites in first-episode untreated schizophrenia patients. METHODS: The subjects were 50 Japanese first episode untreated schizophrenia patients who met the Diagnostic and Statistical Manual of Mental Disorders Text Revision criteria and were treated with aripiprazole monotherapy. Twenty-nine were males, and 21 were females. The age ranged from 21 to 42 years (mean +/- SD; 30.8 +/- 5.3 years). Plasma BDNF and catecholamine metabolites were measured by ELISA and HPLC, respectively. Psychiatric symptoms were evaluated using by Positive and Negative Syndrome Scale. RESULTS: Treatment with aripiprazole for 8 weeks significantly increased plasma BDNF levels. It also changed plasma levels of homovanillic acid and 3 methoxy-4-hydroxyphenylglycol. A negative correlation was also observed between duration of psychosis and plasma BDNF levels. No correlation was observed however between plasma BDNF levels and the dose of aripiprazole. CONCLUSIONS: To the best of our knowledge, this is the first report showing that aripiprazole increases plasma BDNF levels in first-episode untreated schizophrenia patients. Furthermore, the BDNF Val66Met polymorphism was independent of the response to aripiprazole. PMID- 22213406 TI - Evaluation of computer-assisted jaw reconstruction with free vascularized fibular flap compared to conventional surgery: a clinical pilot study. AB - BACKGROUND: The introduction of computer-assisted surgery was a milestone in functional reconstructions of facial skeletal defects. PATIENTS AND METHODS: We compared five computer-assisted and five conventional reconstructions with fibular grafts in the course of a pilot study. A rapid prototyping guide translated the computer-assisted surgery plan into intraoperative utilizable models. We intraoperatively measured the time needed for shaping the graft to the recipient site and the ischaemic time. Furthermore, the size of donor site defect compared to the required transplant length was evaluated. RESULTS: Shaping procedure and ischaemic time turned out significantly shorter when compared to conventional surgery without cutting guide (p = 0.014). Using surgical guides, there was no change between the defect size of the fibula and the necessary transplant size. In conventional surgery, a mean change of 1.92 cm occurred (p = 0.001). CONCLUSION: The surgical guide significantly reduced shaping time and consequently ischaemic time. These factors can influence flap survival. The fibular donor site defect was downsized. PMID- 22213407 TI - Using Simcyp to project human oral pharmacokinetic variability in early drug research to mitigate mechanism-based adverse events. AB - Positive allosteric modulators ('potentiators') of the alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid receptor (AMPAR) have been shown to display a mechanism-based exposure-response continuum in preclinical species with procognitive electrophysiological and behavioral effects ('efficacy') at low exposures and motor coordination disruptions at progressively higher exposures. Due to the dose-capping nature of such motor coordination deficits, an exposure threshold-mediated adverse event (C(AE) ), the adequacy of separation between the maximal total plasma compound concentration (C(max) ) at a predicted clinically efficacious oral dose and this adverse event (AE) was explored in early drug research with three AMPAR potentiators considered potential candidates for clinical trials. In vitro metabolism studies in human liver microsomes and human hepatocytes demonstrated the metabolic clearance for each compound was predominately due to cytochromes P450 (CYP). Thus, for each compound's anticipated clinically efficacious dose, human C(max) variability following oral administration was assessed using Simcyp software, which combines its virtual human populations database using extensive demographic, physiological and genomic information with routinely collected compound-specific in vitro biochemical data to simulate and predict drug disposition. Using a combination of experimentally determined recombinant human CYP intrinsic clearances for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, human binding factors, expected fraction absorbed and estimated steady-state volume of distribution, Simcyp simulations demonstrated that two of the three potentiators had acceptable projected C(max) variability (i.e. the 95th percentile C(max) did not breach C(AE) ). This evaluation aided in the selection of compounds for preclinical progression, and represents a novel application of pharmacologically based pharmacokinetic (PBPK) software approaches to predict interpatient variability. PMID- 22213408 TI - Online first all the time and more continuing medical education credit too! PMID- 22213409 TI - Biomarkers for insulin resistance and inflammation and the risk for all-cause dementia and alzheimer disease: results from the Framingham Heart Study. AB - OBJECTIVE: To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A(2) levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia. DESIGN: Prospective cohort study. SETTING: Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985-1988) and were followed up prospectively for the development of AD and all-cause dementia. PARTICIPANTS: Eight hundred forty (541 women, median age of 76 years) subjects participated in the study. MAIN OUTCOME MEASURES: We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE epsilon4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD. RESULTS: Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00-1.66; P=.054) and AD (HR, 1.33; 95% CI, 1.00-1.76; P=.050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03-2.56; P=.04) and AD (HR, 1.87; 95% CI, 1.13-3.10; P=.01) as compared with those with values less than the median. CONCLUSION: In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD. PMID- 22213410 TI - Contributions of the Framingham Heart Study to stroke and dementia epidemiologic research at 60 years. AB - The Framingham Heart Study, the longest-running prospective epidemiologic study in history, was initiated in 1948 in response to the rising toll of coronary heart disease and hypertension. During the ensuing decades, the study of other diseases, notably stroke and dementia, was added. In 1971, 5124 offspring of the original cohort of 5209 men and women were added, and a third generation of 4095 men and women were added in 2002. The 3-generation structure was used to relate a host of risk factors measured in mid and late life to the subsequent development of stroke, dementia, and cognitive decline. It has also facilitated studies of family occurrence of disease over generations particularly for genomic research. Dementia and Alzheimer disease research has proceeded from the determination of risk factors for at least moderately severe Alzheimer disease in the first generation to mild cognitive impairment and mild Alzheimer disease in the offspring and to studies of the third generation for detection of pre-mild cognitive impairment and indicators of cognitive decline in mid life. These research efforts have been facilitated by genome-wide association studies, biomarkers, and multiple measures of subclinical vascular disease. The tempo of decline has been documented by serial quantitative measures of brain structure on magnetic resonance imaging and cognitive performance by neuropsychological testing. Clinical correlation with systematic neuropathological examinations of more than 150 brains has provided important confirmation of cerebrovascular and brain tissue indices of disease. Identification of persons at heightened risk for stroke, mild cognitive impairment, Alzheimer disease, and cognitive decline years prior to disease onset may facilitate delay in disease onset and prevention. PMID- 22213411 TI - Predictors of survival in patients with Parkinson disease. AB - OBJECTIVE: To determine the life expectancy of patients with Parkinson disease (PD) in the United States and identify demographic, geographic, and clinical factors that influence survival. DESIGN: Retrospective cohort study of 138 000 Medicare beneficiaries with incident PD who were identified in 2002 and followed up through 2008. MAIN OUTCOME MEASURES: Confounder-adjusted 6-year risk of death as influenced by 3 groups of factors: (1) race, sex, and age at diagnosis; (2) geography and environmental factors; and (3) clinical conditions. We examined hospitalization diagnoses in patients with terminal PD and compared PD mortality with that of other common diseases. RESULTS: Thirty-five percent of patients with PD lived more than 6 years. Sex and race significantly predicted survival; patients who were female (HR [hazard ratio], 0.74; 95% CI, 0.73-0.75), Hispanic (HR, 0.72; 95% CI, 0.65-0.80), or Asian (HR, 0.86; 95% CI, 0.82-0.91) had a lower adjusted risk of death than white men. Dementia, diagnosed in 69.6% of cases and most often in African American patients (78.2%) and women (71.5%), was associated with a greater likelihood of death (HR, 1.72; 95% CI, 1.69-1.75). Parkinson disease mortality was greater than that of many common life-threatening diseases. Patients with terminal PD were hospitalized frequently for cardiovascular disease (18.5%) and infection (20.9%) but rarely for PD (1.0%). Regional survival rates were similar but patients with PD living in urban high industrial metal emission areas had a slightly higher adjusted risk of death (HR, 1.19; 95% CI, 1.10-1.29). CONCLUSIONS: Demographic and clinical factors impact PD survival. Dementia is highly prevalent in patients with PD and is associated with a significant increase in mortality. More research is needed to understand whether environmental exposures influence PD course or survival. PMID- 22213413 TI - How the signal-to-noise ratio influences hyperpolarized 13C dynamic MRS data fitting and parameter estimation. AB - MRS of hyperpolarized (13) C-labeled compounds represents a promising technique for in vivo metabolic studies. However, robust quantification and metabolic modeling are still important areas of investigation. In particular, time and spatial resolution constraints may lead to the analysis of MRS signals with low signal-to-noise ratio (SNR). The relationship between SNR and the precision of quantitative analysis for the evaluation of the in vivo kinetic behavior of metabolites is unknown. In this article, this topic is addressed by Monte Carlo simulations, covering the problem of MRS signal model parameter estimation, with strong emphasis on the peak amplitude and kinetic model parameters. The results of Monte Carlo simulation were confirmed by in vivo experiments on medium-sized animals injected with hyperpolarized [1-(13) C]pyruvate. The results of this study may be useful for the establishment of experimental planning and for the optimization of kinetic model estimation as a function of the SNR value. PMID- 22213414 TI - Packed with action. PMID- 22213412 TI - Multiplex imaging of an intracellular proteolytic cascade by using a broad spectrum nanoquencher. PMID- 22213418 TI - A new chemical handle for protein AMPylation at the host-pathogen interface. PMID- 22213419 TI - Solution-mediated phase transformation: significance during dissolution and implications for bioavailability. AB - Solubility improvement of poorly soluble drug compounds is a key approach to ensuring the successful development of many new drugs. Methods used to improve the solubility of drug compounds include forming a salt, cocrystal, or amorphous solid. These methods of improving solubility can often lead to a phenomenon called solution-mediated phase transformation, a phase change that is facilitated through exposure to solution. Solution-mediated phase transformation occurs in three steps: dissolution to create a supersaturated solution followed by nucleation of less soluble phase and the growth of that phase. When the growth of the less soluble phase occurs on the surface of the metastable solid, this phenomenon can cause a marked decrease in dissolution rate during in vitro dissolution evaluation, and ultimately in vivo. Therefore, transformation to a less soluble solid during dissolution is an important aspect to consider when evaluating approaches to increase the solubility of a poorly soluble drug. Identification of solution-mediated phase transformation during dissolution is reviewed for powder dissolution, rotating disk method, and channel flow-through apparatus. Types of solution-mediated phase transformation are described in this report, including those involving salts, polymorphs, amorphous solids, and cocrystals. Many experimental examples are provided. Evidence of potential solution-mediated phase transformation in vivo is discussed to better understand the relationship between in vitro dissolution evaluation and in vivo performance. PMID- 22213421 TI - Adsorption of uranyl species onto the rutile (110) surface: a periodic DFT study. AB - To model the structures of dissolved uranium contaminants adsorbed on mineral surfaces and further understand their interaction with geological surfaces in nature, we have performed periodic density funtional theory (DFT) calculations on the sorption of uranyl species onto the TiO(2) rutile (110) surface. Two kinds of surfaces, an ideal dry surface and a partially hydrated surface, were considered in this study. The uranyl dication was simulated as penta- or hexa-coordinated in the equatorial plane. Two bonds are contributed by surface bridging oxygen atoms and the remaining equatorial coordination is satisfied by H(2)O, OH(-), and CO(3)(2-) ligands; this is known to be the most stable sorption structure. Experimental structural parameters of the surface-[UO(2)(H(2)O)(3)](2+) system were well reproduced by our calculations. With respect to adsorbates, [UO(2)(L1)(x)(L2)(y)(L3)(z)](n) (L1=H(2)O, L2=OH(-), L3=CO(3)(2-), x<=3, y<=3, z<=2, x+y+2z<=4), on the ideal surface, the variation of ligands from H(2)O to OH(-) and CO(3)(2-) lengthens the U-O(surf) and U-Ti distances. As a result, the uranyl-surface interaction decreases, as is evident from the calculated sorption energies. Our calculations support the experimental observation that the sorptive capacity of TiO(2) decreases in the presence of carbonate ions. The stronger equatorial hydroxide and carbonate ligands around uranyl also result in U=O distances that are longer than those of aquouranyl species by 0.1-0.3 A. Compared with the ideal surface, the hydrated surface introduces greater hydrogen bonding. This results in longer U=O bond lengths, shorter uranyl-surface separations in most cases, and stronger sorption interactions. PMID- 22213420 TI - Functionalized self-assembling peptide nanofiber hydrogel as a scaffold for rabbit nucleus pulposus cells. AB - In this study, a new functionalized peptide RLN was designed containing the bioactive motif link N, the amino terminal peptide of link protein. A link N nanofiber scaffold (LN-NS) was self-assembled by mixing peptide solution of RLN and RADA16. The characterization of LN-NS was tested using atomic force microscopy (AFM). The biocompatibility and bioactivity of this nanofiber scaffold for rabbit nucleus pulposus cells (NPCs) were also evaluated. This designer functionalized nanofiber scaffold exhibited little cytotoxicity and promoted NPCs adhesion obviously. In three-dimensional cell culture experiments, confocal reconstructed images testified that the functionalized LN-NS-guided NPCs migration from the surface into the hydrogel considerably, in which the RADA16 scaffold did not. Moreover, the functionalized LN-NS significantly stimulated the biosynthesis of extracelluar matrices (ECM) by NPCs. Our findings demonstrate that the functionalized nanofiber scaffold containing link N had excellent biocompatibility and bioactivity with rabbit NPCs and could be useful in the nucleus pulposus regeneration. PMID- 22213422 TI - An integrated bioanalytical method development and validation approach: case studies. AB - We proposed an integrated bioanalytical method development and validation approach: (1) method screening based on analyte's physicochemical properties and metabolism information to determine the most appropriate extraction/analysis conditions; (2) preliminary stability evaluation using both quality control and incurred samples to establish sample collection, storage and processing conditions; (3) mock validation to examine method accuracy and precision and incurred sample reproducibility; and (4) method validation to confirm the results obtained during method development. This integrated approach was applied to the determination of compound I in rat plasma and compound II in rat and dog plasma. The effectiveness of the approach was demonstrated by the superior quality of three method validations: (1) a zero run failure rate; (2) >93% of quality control results within 10% of nominal values; and (3) 99% incurred sample within 9.2% of the original values. In addition, rat and dog plasma methods for compound II were successfully applied to analyze more than 900 plasma samples obtained from Investigational New Drug (IND) toxicology studies in rats and dogs with near perfect results: (1) a zero run failure rate; (2) excellent accuracy and precision for standards and quality controls; and (3) 98% incurred samples within 15% of the original values. PMID- 22213423 TI - Effect of receiving environment on the transport and fate of polybrominated diphenyl ethers near two submarine municipal outfalls. AB - The fate of contaminants entering the marine environment through wastewater outfalls depends on the contaminant's persistence and affinity for particles. However, the physical characteristics of the receiving environment, for example, current velocity and sedimentary processes, may be even more important. Because of the complexity of natural settings and the lack of appropriate comparative settings, this is not frequently evaluated quantitatively. The authors investigated the near-field accumulation of particle-reactive polybrominated diphenyl ethers (PBDEs) entering coastal waters by way of two municipal outfalls: one discharging into a high-energy, low-sedimentation environment near Victoria, BC, Canada; the other into a low-energy, high-sedimentation environment, near Vancouver, BC. The authors used 210Pb profiles in box cores together with an advection-diffusion model to determine surface mixing and sedimentation rates, and to model the depositional history of PBDEs at these sites. Surprisingly, 88 to 99% of PBDEs were dispersed beyond the near-field at both sites, but a greater proportion of PBDEs was captured in the sediment near the Vancouver outfall where rapid burial was facilitated by inorganic sediment supplied from the nearby Fraser River. Although the discharge of PBDEs was much lower from the Victoria outfall than from Vancouver, some sediment PBDE concentrations were higher near Victoria. PMID- 22213424 TI - Band-like electron transport in organic transistors and implication of the molecular structure for performance optimization. AB - The Hall effect and an increase of field-effect mobility with decreasing temperature is observerd in n-channel single-crystal organic field-effect transistors (OFETs). A quantitative analysis of these findings, together with results on different p-channel transistors, indicate the importance of the semiconductor molecular polarizability and the structure of the charge transport layers in the crystal for the observation of band-like transport in OFETs. PMID- 22213425 TI - T-maze learning in weanling lambs. AB - A major advantage of sheep models in experimental studies of neurodevelopmental disorders (e.g., with prenatal neurotoxicant exposure) is that the equivalent of all three trimesters of human brain development occurs in sheep entirely in utero. However, studies of learning and memory in sheep are limited. The goal of this study was to extend the analysis of spatial learning and memory in adolescent sheep using several traditional T-maze tasks. Both 9- and 14-week-old lambs acquired a delayed nonmatching-to-place task, but the older lambs learned the task significantly faster. In contrast, acquisition of a matching-to-place task was significantly more difficult. Lambs, like rodents, appear to have a predisposition toward learning "win-shift" spatial problems in a T-maze under appetitive motivation. Lambs also rapidly acquired a position habit and showed typical reversal learning curves. These findings support the use of T-maze tasks to assess behavioral outcomes in various sheep models. PMID- 22213427 TI - beta-Cyclodextrin/glycyrrhizic acid functionalised quantum dots selectively enter hepatic cells and induce apoptosis. AB - The use of active components from important medical herbs has proved effective in treating various cancers. Glycyrrhizic acid (GA) is one of the many interesting triterpenoic acids with anticancerogenic potential, and is known to trigger apoptosis in hepatocarcinoma cells. In this study we combined quantum dots (QDs) with GA in the presence of beta-cyclodextrin (beta-CD), and prepared beta-CD/GA functionalised QDs, which led to improved antitumor activity and induced apoptosis in hepatocarcinoma cells. These compounds showed a better selectivity for hepatic cells compared to HeLa and ECV-304 cells. Hoechst and annexin V-FITC staining and mitochondrial membrane potential (MMP) experiments proved an apoptotic effect of these compounds on HepG2 cells. At the same time, transmission electron microscopy (TEM) showed obvious features of apoptosis, for example, irregularities of nuclear shapes, mitochondria swelling, clumping and peripheral chromatin condensation, zeiosis or blebbing of the plasma membrane and formation of apoptotic bodies. It is notable that beta-CD/GA-functionalised QDs showed effective cell growth inhibition by triggering G0/G1 phase arrest and inducing apoptosis through an reactive oxygen species mediated mitochondrial dysfunction pathway. beta-CD/GA-functionalised QDs primarily induced apoptotic response in a time- and dose-dependent manner, but little apoptosis appeared with L-Cys-beta-CD-functionalised QDs or GA alone. These studies suggest that beta CD/GA-functionalised QDs have therapeutic potential against cancer. PMID- 22213426 TI - Inactivation of Ink4a/Arf leads to deregulated expression of miRNAs in K-Ras transgenic mouse model of pancreatic cancer. AB - Human pancreatic cancer (PC) is an aggressive disease, which has been recapitulated in transgenic animal model that provides unique opportunity for mechanistic understanding of disease progression and also for testing the efficacy of novel therapeutics. Emerging evidence suggests deregulated expression of microRNAs (miRNAs) in human PC, and thus we investigated the expression of miRNAs in pancreas tissues obtained from transgenic mouse models of K-Ras (K), Pdx1-Cre (C), K-Ras;Pdx1-Cre (KC), and K-Ras;Pdx1-Cre;INK4a/Arf (KCI), initially from pooled RNA samples using miRNA profiling, and further confirmed in individual specimens by quantitative RT-PCR. We found over-expression of miR-21, miR-221, miR-27a, miR-27b, and miR-155, and down-regulation of miR-216a, miR 216b, miR-217, and miR-146a expression in tumors derived from KC and KCI mouse model, which was consistent with data from KCI-derived RInk-1 cells. Mechanistic investigations revealed a significant induction of EGFR, K-Ras, and MT1-MMP protein expression in tissues from both KC and KCI mouse compared to tissues from K or C, and these results were consistent with similar findings in RInk-1 cells compared to human MIAPaCa-2 cells. Furthermore, miR-155 knock-down in RInk-1 cells resulted in the inhibition of cell growth and colony formation consistent with down-regulation of EGFR, MT1-MMP, and K-Ras expression. In addition, miR 216b which target Ras, and forced re-expression of miR-216b in RInk-1 cells showed inhibition of cell proliferation and colony formation, which was correlated with reduced expression of Ras, EGFR, and MT1-MMP. These findings suggest that these models would be useful for preclinical evaluation of novel miRNA-targeted agents for designing personalized therapy for PC. PMID- 22213428 TI - Decoupled circular-polarized dual-head volume coil pair for studying two interacting human brains with dyadic fMRI. AB - A major function of the human brain is to mediate interactions with other people. Until recently, studying social interactions as they occur within the brain was not possible due to the lack of measurable methods to observe two interacting minds simultaneously. We have developed a novel MRI dual-head volume coil pair that can scan two subjects' brains simultaneously while the subjects are socially interacting in one MRI scanner. The feasibility of using this coil for dyadic functional MRI (fMRI) study has been successfully demonstrated for the first time. Meanwhile, an innovative robust scheme for decoupling two circular polarized coils (not surface coils) is introduced in theory and validated in practice in the coil technology development. PMID- 22213429 TI - 'Neutralizing the patient': therapists' accounts of sexual boundary violations. AB - Sexual contact between psychological therapists and their clients is regarded as highly damaging, both to the clients and to the professions, and regulatory bodies impose increasingly severe sanctions upon those practitioners who are disciplined. The present study captured therapists' accounts of sexual boundary violations through interpretative phenomenological analysis of interviews with three disciplined practitioners about their relationships with clients and former clients. The results highlighted two key themes relating to (i) therapists' efforts to neutralize the power imbalances between themselves and the clients by minimizing the clients' mental health problems, stressing the conventionality of the relationships and not testing the appropriateness of the relationship with their supervisors, and (ii) a shifting identity of the therapist between hero, victim, perpetrator, which permeated their accounts as the relationship moved from success to failure. In order for a sexual boundary violation to occur, the therapist needed to generate a sense of equivalent status between themselves and the client. As the relationships failed, the therapists' accounts of the clients shifted and the inequality of the relationship re-emerged. The results are discussed in terms of implicit theories and the implications for both training and supervision in the prevention of sexual boundary violations. PMID- 22213430 TI - Templated dynamic synthesis of a [3]catenane. PMID- 22213431 TI - Methylenebisphosphonates with dienone pharmacophore: synthesis, structure, antitumor and fluorescent properties. AB - The synthesis and the antitumor activity and fluorescent properties screening of novel bisphosphonate conjugates with cytotoxic 3,5-bis((hetero)arylidene)-4 piperidone residues were performed. The facile and rapid synthetic route was based on the aza-Michael addition of NH-3,5-bis((hetero)arylidene)-4-piperidones to tetraethyl ethylidenebisphosphonate. The synthesized compounds displayed high inhibitory properties towards Caov3, A549, PC3, and KB 3-1 human carcinoma cell lines. Among those, compounds bearing 4-cyano-phenyl and 3-pyridinyl substituents were revealed as the most active drug candidates with IC(50) values in the range of 0.5-2.5 uM. Methylenebisphosphonate with 4-Me(2) N-C(6) H(4) groups in the piperidone framework possessing fluorescence properties may be of interest for visualization of BPs skeletal distribution and cellular uptake in bones and other tissues. PMID- 22213432 TI - Development of a compact capillary electrophoresis-chemiluminescence system with ultra-fast peroxyoxalate reaction to monitor the hydrolysis of rhodamine 6G. AB - A simple and effective capillary electrophoresis-chemiluminescence (CE-CL) detection system was developed based on an ultra-fast bis(2,4,6 trichlorophenyl)oxalate (TCPO) chemiluminescence (CL) reaction (0.6 s duration) that avoided overlapping peaks and peak tailing. Through a series of static injection experiments, this unusually rapid CL reaction was ascribed to the catalytic effect of imidazole in the tetrahydrofuran solvent, which has been rarely utilized in such investigations. A possible mechanism is given to explain the results. Under the optimized conditions, rhodamine 6 G (R6G) and its hydrolysis product (R6G-COOH) could be efficiently separated through electrophoresis in 7 min, with sensitive CL detection in the proposed CE-CL system. In this way, the alkaline hydrolysis of R6G was monitored, followed by estimation of relative rate constants and activation energy. This finding and application should be helpful in further study for the TCPO CL reaction, and revealed an attractive opportunity for simplifying the CE-CL system, such as in a microchip device. PMID- 22213433 TI - Characterization of the ICSI-mediated gene transfer method in the production of transgenic pigs. AB - Understanding the behavior of transgenes introduced into oocytes or embryos is essential for evaluating the methodologies for transgenic animal production. We investigated the expression pattern of a transgene transferred to porcine eggs by intracytoplasmic sperm injection-mediated gene transfer (ICSI-MGT) or pronuclear microinjection (PN injection). The introduction of the EGFP gene by ICSI-MGT yielded significantly more embryos with non-mosaic transgene expression (P < 0.01). In the ICSI-MGT group, 61.5% (24/39) of the embryos were EGFP-positive in all their component blastomeres at the morula stage, while fewer than 10% of such embryos were EGFP-positive in the PN-injection group. Using three types of transgenes, ranging from 3.0 to 7.5 kb in size, we confirmed that approximately one in four fetuses obtained by ICSI-MGT was transgenic, suggesting that ICSI-MGT is a practical method for transgenic pig production. Southern blot analysis of 12 transgenic fetuses produced by ICSI-MGT revealed that the number of integrated transgene copies varied from 1 to 300, with no correlation between transgene size and the number of integrated copies. Fluorescence in situ hybridization analysis revealed that the transgenes were randomly integrated into a single site on the host chromosomes. Together, these data indicate that multiple-copy, single-site integration of a transgene is the primary outcome of ICSI-MGT in the pig and that ICSI-MGT is less likely than PN injection to cause transgene integration in a mosaic manner. PMID- 22213434 TI - A neuroimmunological perspective on anxiety disorders. AB - OBJECTIVE: Research into psychoneuroimmunology has led to substantial advances in our understanding of the reciprocal interactions between the central nervous system and the immune system in neuropsychiatric disorders. To date, the presence of inflammatory responses and the crucial role of cytokines in major depression have been addressed in numerous studies. However, neuroinflammatory hypotheses in anxiety disorders have been studied less extensively than in major depression. There is a high research need for better understanding of both the heterogeneous role of specific cytokines in the control of anxious states and in different anxiety disorders and of the immunomodulating effects of antidepressants on anxiety. METHODS: Relevant literature was identified through a search of MEDLINE via PubMed. We discuss recent research on neuroimmunology in anxiety and make methodological recommendations for future investigation of neuroinflammatory hypotheses in anxiety disorders. RESULTS: Some accumulating evidence has indicated modulatory effects of cytokines on neuronal communication and anxiety; however, research has not revealed consistent reproducible findings. CONCLUSIONS: The availability of inflammatory biomarkers may provide an opportunity to identify patients via specific pathophysiological processes and to monitor therapeutic responses within relevant pathways. Further understanding of the neuroimmunological mechanisms to untangle the reciprocal associations between inflammation and anxiety is warranted. PMID- 22213435 TI - Comparison of risk factors for shoulder pain and rotator cuff syndrome in the working population. AB - BACKGROUND: To compare risk factors for shoulder pain without and with rotator cuff syndrome (RCS). METHODS: A total of 3,710 workers of a French region were randomly included in the cross-sectional study between 2002 and 2005. Personal and occupational risk factors were assessed during a physical examination and by a self-administered questionnaire. Multinomial logistic modeling was used for the following outcomes: no shoulder pain and no RCS (reference), shoulder pain without RCS (called "shoulder pain") and RCS, separately for men and women. RESULTS: The prevalence rates of "shoulder pain" for men and women were 28.0% and 31.1%, respectively, and the prevalence rates of RCS were 6.6% and 8.5%, respectively. In men, "shoulder pain" and RCS were associated with age, high perceived physical exertion, and arm abduction. Automatic work pace and low supervisor support were associated with "shoulder pain," and high psychological demand and low skill discretion with RCS. In women, "shoulder pain" and RCS were associated with age, repetitiveness of tasks, and low supervisor support. High perceived physical exertion and exposure to cold temperatures were associated with "shoulder pain." CONCLUSIONS: Age was more strongly associated with RCS than with shoulder pain without RCS for both genders. Biomechanical and psychosocial factors were associated with "shoulder pain" and RCS and differed between genders. PMID- 22213438 TI - Realization of a high-performance GaN UV detector by nanoplasmonic enhancement. PMID- 22213436 TI - Randomized trial of exercise effect on intrahepatic triglyceride content and lipid kinetics in nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) and alterations in hepatic lipoprotein kinetics are common metabolic complications associated with obesity. Lifestyle modification involving diet-induced weight loss and regular exercise decreases intrahepatic triglyceride (IHTG) content and very low density lipoprotein (VLDL) triglyceride (TG) secretion rate. The aim of this study was to evaluate the weight loss-independent effect of following the physical activity guidelines recommended by the Department of Health and Human Services on IHTG content and VLDL kinetics in obese persons with NAFLD. Eighteen obese people (body mass index [BMI]: 38.1 +/- 4.6 kg/m(2)) with NAFLD were randomized to 16 weeks of exercise training (45%-55% VO(2peak) , 30-60 minutes * 5 days/week; n = 12) or observation (control; n = 6). Magnetic resonance spectroscopy and stable isotope tracer infusions in conjunction with compartmental modeling were used to evaluate IHTG content and hepatic VLDL-TG and apolipoprotein B-100 (apoB-100) secretion rates. Exercise training resulted in a 10.3% +/- 4.6% decrease in IHTG content (P < 0.05), but did not change total body weight (103.1 +/- 4.2 kg before and 102.9 +/ 4.2 kg after training) or percent body fat (38.9% +/- 2.1% before and 39.2% +/- 2.1% after training). Exercise training did not change the hepatic VLDL-TG secretion rate (17.7 +/- 3.9 MUmol/min before and 16.8 +/- 5.4 MUmol/min after training) or VLDL-apoB-100 secretion rate (1.5 +/- 0.5 nmol/min before and 1.6 +/ 0.6 nmol/min after training). CONCLUSION: Following the Department of Health and Human Services recommended physical activity guidelines has small but beneficial effects on IHTG content, but does not improve hepatic lipoprotein kinetics in obese persons with NAFLD. PMID- 22213437 TI - Aging-related deficits in orexin/hypocretin modulation of the septohippocampal cholinergic system. AB - The medial septum (MS) of the basal forebrain contains cholinergic neurons that project to the hippocampus, support cognitive function, and are implicated in age related cognitive decline. Hypothalamic orexin/hypocretin neurons innervate and modulate basal forebrain cholinergic neurons and provide direct inputs to the hippocampus. However, the precise role of orexin in modulating hippocampal cholinergic transmission--and how these interactions are altered in aging--is unknown. Here, orexin A was administered to CA1 and the MS of young (3-4 months) and aged (27-29 months) Fisher 344/Brown Norway rats, and hippocampal acetylcholine efflux was analyzed by in vivo microdialysis. At both infusion sites, orexin A dose-dependently increased hippocampal acetylcholine in young, but not aged rats. Moreover, immunohistochemical characterization of the MS revealed no change in cholinergic cell bodies in aged animals, but a significant decrease in orexin fiber innervation to cholinergic cells. These findings indicate that: (1) Orexin A modulates hippocampal cholinergic neurotransmission directly and transsynaptically in young animals, (2) Aged animals are unresponsive to orexin A, and (3) Aged animals undergo an intrinsic reduction in orexin innervation to cholinergic cells within the MS. Alterations in orexin regulation of septohippocampal cholinergic activity may contribute to age-related dysfunctions in arousal, learning, and memory. PMID- 22213439 TI - Development of FRET-based dual-excitation ratiometric fluorescent pH probes and their photocaged derivatives. AB - Dual-excitation ratiometric fluorescent probes allow the measurement of fluorescence intensities at two excitation wavelengths, which should provide a built-in correction for environmental effects. However, most of the small molecule dual-excitation ratiometric probes that have been reported thus far have shown rather limited separation between the excitation wavelengths (20-70 nm) and/or a very small molar absorption coefficient at one of the excitation wavelengths. These shortcomings can lead to cross-excitation and thus to errors in the measurement of fluorescence intensities and ratios. Herein, we report a FRET-based molecular strategy for the construction of small-molecule dual excitation ratiometric probes in which the donor and acceptor excitation bands exhibit large separations between the excitation wavelengths and comparable excitation intensities, which is highly desirable for determining the fluorescence intensities and signal ratios with high accuracy. Based on this strategy, we created a coumarin-rhodamine FRET platform that was then employed to develop the first class of FRET-based dual-excitation ratiometric pH probes that have two well-resolved excitation bands (excitation separations>160 nm) and comparable excitation intensities. In addition, these pH probes may be considered as in a kind of "secured ratioing mode". As a further application of these pH probes, the dual-excitation ratiometric pH probes were transformed into the first examples of photocaged dual-excitation ratiometric pH probes to improve the spatiotemporal resolution. It is expected that the modular nature of our FRET based molecular strategy should render it applicable to other small-molecule dual dye energy-transfer systems based on diverse fluorescent dyes for the development of a wide range of dual-excitation ratiometric probes with outstanding spectral features, including large separations between the excitation wavelengths and comparable excitation intensities. PMID- 22213440 TI - Chemometric evaluation of brompheniramine-tannate complexes. AB - The objective of the current study was to evaluate the performance of Raman and near-infrared (NIR) techniques combined with chemometrics in characterizing the critical quality attributes of brompheniramine (BP)-tannate complexes. Seven complexes were prepared and evaluated for chemical interactions, solubilities, dissolutions, and spatial distributions by NIR chemical imaging (CI). Principal component analysis (PCA) was applied before either partial least squares regression (PLSR) or principal component regression (PCR) models were developed. Complexation was confirmed by Fourier transform IR analysis to yield complexes of lower drug solubilities and sustained-release characteristics in alkaline media. PCA results showed better discrimination ability by NIR than by Raman spectroscopy. Compared with PCR, the PLSR predictions errors, calculated from the Raman and NIR data with second-derivative pretreatment, showed lesser values of 2.68, 0.37, 1.79, and 5.60 and 0.58, 0.25, 0.93, and 0.58 for complex solubilities in acidic and alkaline media and percentages dissolved after 1 and 20 h, respectively. In addition, good correlation (>0.95) was obtained for predicting the drug concentration using PLSR score images explaining the validity of the NIR-CI model for spatial quantitation of BP within its tannate complexes. In conclusion, the chemometric analysis of NIR and/or Raman spectra represented an innovative approach to determine the tannate complexation variability. PMID- 22213441 TI - Vapor pressure of three brominated flame retardants determined by using the Knudsen effusion method. AB - Brominated flame retardants (BFRs) have been used in a variety of consumer products in the past four decades. The vapor pressures for three widely used BFRs, that is, tetrabromobisphenol A (TBBPA), hexabromocyclododecane (HBCD), and octabromodiphenyl ethers (octaBDEs) mixtures, were determined using the Knudsen effusion method and compared with those of decabromodiphenyl ether (BDE209). The values measured extrapolated to 298.15 K are 8.47 * 10-9, 7.47 * 10-10, and 2.33 * 10-9 Pa, respectively. The enthalpies of sublimation for these BFRs were estimated using the Clausius-Clapeyron equation and are 143.6 +/- 0.4, 153.7 +/- 3.1, and 150.8 +/- 3.2 kJ/mole, respectively. In addition, the enthalpies of fusion and melting temperatures for these BFRs were also measured in the present study. PMID- 22213442 TI - High mobility group protein AT-hook 1 (HMGA1) is associated with the development of androgen independence in prostate cancer cells. AB - BACKGROUND: We previously reported that the level of high mobility group protein AT-hook 1 (HMGA1) is low in androgen-dependent prostate cancer (PCa) cells (LNCaP), but is high in androgen-independent PCa cells (DU145 and PC-3) and that HMGA1 is a strong candidate gene playing a potential role in the progression of PCa. These findings have prompted us to evaluate the effect of HMGA1 on developing androgen independency, which is associated with the progression of PCa. METHODS: Expression of HMGA1 in PCa cells and mouse tissues was examined by Western blot. In order to examine the effect of HMGA1 on cell growth under androgen-deprived condition, we transfected HMGA1 into LNCaP cells, and siRNA into both DU145 and PC-3 cells, respectively. RESULTS: Androgen-deprivation induced an increase in the level of HMGA1 in LNCaP cells in vitro and in vivo, but did not in normal prostate tissue. Overexpression of HMGA1 maintained the cell growth of LNCaP under androgen-deprived condition. Furthermore, knockdown of HMGA1 suppressed the cell growth of DU145 and PC-3. CONCLUSIONS: These data suggest that elevated expression of HMGA1 is associated with the transition of PCa cells from androgen-sensitive to androgen-independent growth and plays a role in the cell growth of androgen-independent PCa cells. PMID- 22213443 TI - Comparison of the sequential organ failure assessment score with the King's College Hospital criteria and the model for end-stage liver disease score for the prognosis of acetaminophen-induced acute liver failure. AB - Acetaminophen-induced acute liver failure (ALF) is a complex multiorgan illness. An assessment of the prognosis is essential for the accurate identification of patients for whom survival without liver transplantation (LT) is unlikely. The aims of this study were the comparison of prognostic models [King's College Hospital (KCH), Model for End-Stage Liver Disease, Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II)] and the identification of independent prognostic indicators of outcome. We evaluated consecutive patients with severe acetaminophen-induced ALF who were admitted to the intensive care unit. At admission, demographic, clinical, and laboratory parameters were recorded. The discriminative ability of each prognostic score at the baseline was evaluated with the area under the receiver operating characteristic curve (AUC). In addition, using a multiple logistic regression, we assessed independent factors associated with outcome. In all, 125 consecutive patients with acetaminophen-induced ALF were evaluated: 67 patients (54%) survived with conservative medical management (group 1), and 58 patients (46%) either died without LT (28%) or underwent LT (18%; group 2). Group 1 patients had significantly lower median APACHE II (10 versus 14) and SOFA scores (9 versus 12) than group 2 patients (P < 0.001). The independent indicators associated with death or LT were a longer prothrombin time (P = 0.007), the inspiratory oxygen concentration (P = 0.005), and the lactate level at 12 hours (P < 0.001). The KCH criteria had the highest specificity (83%) but the lowest sensitivity (47%), and the SOFA score had the best discriminative ability (AUC = 0.79). In conclusion, for patients with acetaminophen-induced ALF, the SOFA score performed better than the other prognostic scores, and this reflected the presence of multiorgan dysfunction. A further evaluation of SOFA with the KCH criteria is warranted. PMID- 22213444 TI - Design, total chemical synthesis, and X-ray structure of a protein having a novel linear-loop polypeptide chain topology. PMID- 22213445 TI - N-isopropylacrylamide as a functional monomer for noncovalent molecular imprinting. AB - Although N-isopropylacrylamide (NIPAM) has previously been used in molecular imprinting, it has mostly been considered as an 'inert' monomer, or included for its temperature-responsive nature, rather than as a functional monomer responsible for the interactions with the template at the recognition site. A comparative study of NIPAM and other traditional, functional monomers for the imprinting of a hydrogen bond donor template, bisphenol A (BPA), is reported. Nuclear magnetic resonance titration data suggest that NIPAM forms a stronger complex with BPA than either acrylamide or methacrylic acid but a weaker complex than vinylpyridine. Molecular imprinted polymers (MIPs) were prepared using each functional monomer and compared as stationary phases for the separation of BPA from structural analogues. The NIPAM-containing MIP bound BPA with better selectivity than those prepared using acrylamide or methacrylic acid. Using NIPAM also reduces the nonspecific binding, which is found with MIPs using vinylpyridine as functional monomer. PMID- 22213446 TI - The macromolecular state of A-kinase anchoring protein. AB - The amendment of the interpretation of recently published size-exclusion chromatography (SEC) data for A-kinase anchoring protein (AKAP12) on Sephacryl S400 has led to an increase in the estimated size of the supermolecular state from 840 to at least 6000 kDa. Although size-exclusion chromatography has sufficed to demonstrate unequivocally the existence of this 190-kDa scaffold protein in a supermolecular state, any quantitative estimate of the oligomer stoichiometry is shown to be precluded by failure of this empirical procedure to incorporate allowance for any deviation from globular shape--an important consideration in view of the extended structures exhibited by other extracellular matrix proteins. PMID- 22213447 TI - Scoring optimisation of unbound protein-protein docking including protein binding site predictions. AB - The prediction of the structure of the protein-protein complex is of great importance to better understand molecular recognition processes. During systematic protein-protein docking, the surface of a protein molecule is scanned for putative binding sites of a partner protein. The possibility to include external data based on either experiments or bioinformatic predictions on putative binding sites during docking has been systematically explored. The external data were included during docking with a coarse-grained protein model and on the basis of force field weights to bias the docking search towards a predicted or known binding region. The approach was tested on a large set of protein partners in unbound conformations. The significant improvement of the docking performance was found if reliable data on the native binding sites were available. This was possible even if data for single key amino acids at a binding interface are included. In case of binding site predictions with limited accuracy, only modest improvement compared with unbiased docking was found. The optimisation of the protocol to bias the search towards predicted binding sites was found to further improve the docking performance resulting in approximately 40% acceptable solutions within the top 10 docking predictions compared with 22% in case of unbiased docking of unbound protein structures. PMID- 22213448 TI - Chemotaxis induced by SXWS tetrapeptides in Tetrahymena--overlapping chemotactic effects of SXWS sequences and their identical amino acids. AB - The chemotactic potential of SXWS peptides and the components of the extracellular domain of cytokine receptors were investigated in Tetrahymena as a functional index of substitution with different amino acids in the position 'X' of the tetrapeptide. Data obtained demonstrate that position X plays a special determining role in the ligand, SEWS and STWS possess extremely strong chemoattractant ability, and aromatic amino acids result in chemorepellent ligands. Diverse effects of structurally related molecules, for example, SNWS SDWS, demonstrate a highly sensitive discrimination potential in the applied model system. Physicochemical characteristics (hydropathy, residue size, and solvent-exposed area) of the amino acids were correlated with the chemotactic activity. Data obtained by computer-assisted conformation analysis of SXWS peptides and the highly overlapping chemotactic effects of the investigated SXWS peptides as well as the presence of the amino acids in the 'X' position indicate that member 'X' of the SXWS sequence performs a special role in interactions with the chemotaxis receptors in the membrane. PMID- 22213449 TI - Applications of isothermal titration calorimetry in pure and applied research- survey of the literature from 2010. AB - Isothermal titration calorimetry (ITC) is a biophysical technique for measuring the formation and dissociation of molecular complexes and has become an invaluable tool in many branches of science from cell biology to food chemistry. By measuring the heat absorbed or released during bond formation, ITC provides accurate, rapid, and label-free measurement of the thermodynamics of molecular interactions. In this review, we survey the recent literature reporting the use of ITC and have highlighted a number of interesting studies that provide a flavour of the diverse systems to which ITC can be applied. These include measurements of protein-protein and protein-membrane interactions required for macromolecular assembly, analysis of enzyme kinetics, experimental validation of molecular dynamics simulations, and even in manufacturing applications such as food science. Some highlights include studies of the biological complex formed by Staphylococcus aureus enterotoxin C3 and the murine T-cell receptor, the mechanism of membrane association of the Parkinson's disease-associated protein alpha-synuclein, and the role of non-specific tannin-protein interactions in the quality of different beverages. Recent developments in automation are overcoming limitations on throughput imposed by previous manual procedures and promise to greatly extend usefulness of ITC in the future. We also attempt to impart some practical advice for getting the most out of ITC data for those researchers less familiar with the method. PMID- 22213450 TI - Nonspecific interactions in AFM force spectroscopy measurements. AB - Sample-probe contact duration (dwell time) and loading force are two important parameters for the atomic force microscopy (AFM) force spectroscopy measurements of ligand-receptor interaction. A prolonged contact time may be required to initiate ligand-receptor binding as a result of slow on-rate kinetics or low reactant density. In general, increasing contact duration promotes nonspecific interactions between the substrate and the functionalized cantilever and, thus, masking the detection of the specific interactions. To reduce the nonspecific interactions in AFM force measurements requiring extended substrate-probe contact, we investigated the interaction of bovine serum albumin (BSA) functionalized cantilever with BSA-coated glass, polyethylene glycol (PEG) functionalized glass, Pluronic-treated Petri dishes and agarose beads. The frequency of nonspecific interaction between the BSA-functionalized cantilever and the different samples increased with loading force and dwell time. This increase in nonspecific adhesion can be attributed to the interaction mediated by forced unfolding of BSA. By reducing the loading force, the contact duration of the AFM probe with an agarose bead can be extended to a few minutes without nonspecific adhesion. PMID- 22213451 TI - Interaction of the non-phosphorylated peptide G7-18NATE with Grb7-SH2 domain requires phosphate for enhanced affinity and specificity. AB - Src-homology (SH2) domains are an attractive target for the inhibition of specific signalling pathways but pose the challenge of developing a truly specific inhibitor. The G7-18NATE cyclic peptide is reported to specifically inhibit the growth factor receptor bound protein 7 (Grb7) adapter protein, implicated in the progression of several cancer types, via interactions with its SH2 domain. G7-18NATE effectively inhibits the interaction of Grb7 with ErbB3 and focal adhesion kinase in cell lysates and, with the addition of a cell permeability sequence, inhibits the growth and migration of a number of breast cancer cell lines. It is thus a promising lead in the development of therapeutics targeted to Grb7. Here we investigate the degree to which G7-18NATE is specific for the Grb7-SH2 domain compared with closely related SH2 domains including those of Grb10, Grb14, and Grb2 using surface plasmon resonance. We demonstrate that G7 18NATE binds with micromolar binding affinity to Grb7-SH2 domain (K(D) = 4-6 MUm) compared with 50-200 times lower affinity for Grb10, Grb14, and Grb2 but that this specificity depends critically on the presence of phosphate in millimolar concentrations. Other differences in buffer composition, including use of Tris or 2-(N-Morpholino)ethanesulfonic acid or varying the pH, do not impact on the interaction. This suggests that under cellular conditions, G7-18NATE binds with highest affinity to Grb7. In addition, our findings demonstrate that the basis of specificity of G7-18NATE binding to the Grb7-SH2 domain is via other than intrinsic structural features of the protein, representing an unexpected mode of molecular recognition. PMID- 22213453 TI - Fabrication of an efficient light-scattering functionalized photoanode using periodically aligned ZnO hemisphere crystals for dye-sensitized solar cells. PMID- 22213454 TI - Frontotemporoparietal asymmetry and lack of illness awareness in schizophrenia. AB - INTRODUCTION: Lack of illness awareness or anosognosia occurs in both schizophrenia and right hemisphere lesions due to stroke, dementia, and traumatic brain injury. In the latter conditions, anosognosia is thought to arise from unilateral hemispheric dysfunction or interhemispheric disequilibrium, which provides an anatomical model for exploring illness unawareness in other neuropsychiatric disorders, such as schizophrenia. METHODS: Both voxel-based morphometry using Diffeomorphic Anatomical Registration through Exponentiated Lie Algebra (DARTEL) and a deformation-based morphology analysis of hemispheric asymmetry were performed on 52 treated schizophrenia subjects, exploring the relationship between illness awareness and gray matter volume. Analyses included age, gender, and total intracranial volume as covariates. RESULTS: Hemispheric asymmetry analyses revealed illness unawareness was significantly associated with right < left hemisphere volumes in the anteroinferior temporal lobe (t = 4.83, P = 0.051) using DARTEL, and the dorsolateral prefrontal cortex (t = 5.80, P = 0.003) and parietal lobe (t = 4.3, P = 0.050) using the deformation-based approach. Trend level associations were identified in the right medial prefrontal cortex (t = 4.49, P = 0.127) using DARTEL. Lack of illness awareness was also strongly associated with reduced total white matter volume (r = 0.401, P < 0.01) and illness severity (r = 0.559, P < 0.01). CONCLUSION: These results suggest a relationship between anosognosia and hemispheric asymmetry in schizophrenia, supporting previous volume-based MRI studies in schizophrenia that found a relationship between illness unawareness and reduced right hemisphere gray matter volume. Functional imaging studies are required to examine the neural mechanisms contributing to these structural observations. PMID- 22213455 TI - Developmental changes of rhesus monkeys in response to separation from the mother. AB - The development of separation response behaviors in infant rhesus macaques across the first 6 months of life was assessed. Seventeen infants underwent a neonatal assessment at 7, 14, 21, and 30 days of age which included a brief period of social isolation. At 3 and 6 months of age these same monkeys and four additional subjects were again subjected to a period of brief social isolation and also exposed to a novel environment with their sedated mother. Results indicate a developmental increase followed by a steady decline in the frequency of separation vocalizations. A modest relationship between early-infancy locomotor profiles and separation responses was also observed at several time points suggesting a possible relationship between these measures. However, stable inter individual measures of separation distress did not emerge until late in the infantile period. This could suggest that high levels of maternal contact-seeking behavior early in infancy are context specific and not a reliable index of enduring temperament. PMID- 22213456 TI - Effect of nanocoating with rhamnogalacturonan-I on surface properties and osteoblasts response. AB - Long-term stability of titanium implants are dependent on a variety of factors. Nanocoating with organic molecules is one of the methods used to improve osseointegration. Therefore, the aim of this study is to evaluate the in vitro effect of nanocoating with pectic rhamnogalacturonan-I (RG-I) on surface properties and osteoblasts response. Three different RG-Is from apple and lupin pectins were modified and coated on amino-functionalized tissue culture polystyrene plates (aminated TCPS). Surface properties were evaluated by scanning electron microscopy, contact angle measurement, atomic force microscopy, and X ray photoelectron spectroscopy. The effects of nanocoating on proliferation, matrix formation and mineralization, and expression of genes (real-time PCR) related to osteoblast differentiation and activity were tested using human osteoblast-like SaOS-2 cells. It was shown that RG-I coatings affected the surface properties. All three RG-I induced bone matrix formation and mineralization, which was also supported by the finding that gene expression levels of alkaline phosphatase, osteocalcin, and collagen type-1 were increased in cells cultured on the RG-I coated surface, indicating a more differentiated osteoblastic phenotype. This makes RG-I coating a promising and novel candidate for nanocoatings of implants. PMID- 22213457 TI - Cycloaddition functionalization of cleaved microstructures. PMID- 22213458 TI - Novel anti-ErbB3 monoclonal antibodies show therapeutic efficacy in xenografted and spontaneous mouse tumors. AB - The role of the ErbB3 receptor in signal transduction is to augment the signaling repertoire of active heterodimeric ErbB receptor complexes through activating the PI3K/AKT pathway, which in turn promotes survival and proliferation. ErbB3 has recently been proposed to be involved in acquired resistance to tyrosine kinase inhibitors (TKIs), and is therefore a promising new drug cancer target. Since ErbB3 is a kinase defective receptor, it cannot be targeted by small molecule inhibitors, whereas monoclonal antibodies may offer a viable strategy for pharmacological intervention. In this study, we have utilized DNA electroporation (DNA-EP) to generate a set of novel hybridomas directed against human ErbB3, which have been characterized for their biochemical and functional properties and selected for their ability to negatively regulate the ErbB3-mediated signaling pathway. In vitro, the anti-ErbB3 antibodies modulate the growth rate of cancer cells of different origins. In vivo they show antitumoral properties in a xenograft model of human pancreatic tumor and in the ErbB2-driven carcinogenesis genetically engineered mouse model (GEMM) for mammary tumor, the BALB/neuT. Our data confirm that downregulating the ErbB3-mediated signals with the use of anti ErbB3 monoclonal antibodies is both feasible and relevant for therapeutic purposes and provides new opportunities for novel anti-ErbB3 combinatory strategies for cancer treatment. PMID- 22213459 TI - Nucleic acid functionalized graphene for biosensing. AB - There is immense demand for complex nanoarchitectures based on graphene nanostructures in the fields of biosensing or nanoelectronics. DNA molecules represent the most versatile and programmable recognition element and can provide a unique massive parallel assembly strategy with graphene nanomaterials. Here we demonstrate a facile strategy for covalent linking of single stranded DNA (ssDNA) to graphene using carbodiimide chemistry and apply it to genosensing. Since graphenes can be prepared by different methods and can contain various oxygen containing groups, we thoroughly investigated the utility of four different chemically modified graphenes for functionalization by ssDNA. The materials were characterized in detail and the different DNA functionalized graphene platforms were then employed for the detection of DNA hybridization and DNA polymorphism by using impedimetric methods. We believe that our findings are very important for the development of novel devices that can be used as alternatives to classical techniques for sensitive and fast DNA analysis. In addition, covalent functionalization of graphene with ssDNA is expected to have broad implications, from biosensing to nanoelectronics and directed, DNA programmable, self-assembly. PMID- 22213460 TI - Effects of imidazolium room temperature ionic liquids on the fluorescent properties of norfloxacin. AB - The effects of 12 imidazolium room temperature ionic liquids (RTILs), including [C(n)mim]BF4, [C(n)mim]PF6, and [C(n)mim]Br (n = 4, 6, 8, 10), on the fluorescent properties of norfloxacin were examined. The fluorescence intensity of norfloxacin at 0.1 mg/L in methanol significantly increased with the addition of [C(n)mim]BF4 and [C(n)mim]PF6 into the solvent at 0.1-15.0%. The sensitizing effect may result from the higher viscosity of the RTILs-methanol mixture solvent than that of the methanol itself. However, the quenching effect on fluorescence of norfloxacin was observed in [C(n)mim]Br-methanol solvent. The fluorescence intensities of norfloxacin decreased with an increase in the alkyl chain length of the alkyl substituents of the imidazolium ring of RTILs. The main interaction between the RTILs and norfloxacin is not by hydrogen bonding. The fact, that some RTILs can significantly sensitize fluorescence of norfloxacin, indicates that RTILs could be a group of promising solvents for development of sensitive spectrofluorimetric methods for determination of norfloxacin at ultra-trace levels in environmental samples. PMID- 22213461 TI - Pattern of cognitive impairment in older veterans with posttraumatic stress disorder evaluated at a memory disorders clinic. AB - BACKGROUND: We determined the pattern of clinically significant cognitive impairment (CI) among older veterans with posttraumatic stress disorder (PTSD) evaluated in a memory disorders clinic. METHODS: Data were collected from 19 ethnically diverse veterans. Cognitive functioning in six domains (verbal learning, memory, attention, language, executive functioning, and information processing speed) was assessed. RESULTS: The majority of veterans (57%) demonstrated CI on a measure of single trial list learning, 44% exhibited CI on short delay memory for lists, and 31% exhibited CI in long delay memory for lists. CI on measures of memory for stories (14%) and executive functioning (6%) were less common, and none of the participants demonstrated CI on measures of attention, language, or information processing speed. CONCLUSIONS: CI on measures of single trial list learning and memory for lists are common in older patients with PTSD evaluated in a memory disorders clinic and are likely to contribute to functional deficits. PMID- 22213462 TI - Effects of indoxyl sulfate on adherens junctions of endothelial cells and the underlying signaling mechanism. AB - Uremic patients have a much higher risk of cardiovascular diseases and death. Uremic toxins are probably involved in the development of vascular endothelial dysfunction. Indoxyl sulfate (IS) is a uremic toxin that accumulates with deterioration of renal function. This study explored the effects of IS on the adherens junctions of vascular endothelial cells and revealed the underlying mechanism. Bovine pulmonary artery endothelial cells (BPAECs) were treated with IS, and the distribution of vascular endothelial cadherin (VE-cadherin), p120 catenin, beta-catenin, and stress fibers was examined by immunofluorescence. IS treatment resulted in disruption of intercellular contacts between BPAECs with prominent parallel-oriented intracellular stress fiber formation. Intracellular free radical levels which measured by flow cytometry increased after IS treatment. The antioxidant, MnTMPyP, and an ERK pathway inhibitor, U0126, both significantly prevented IS-induced disruption of intercellular contacts. Western blotting analyses demonstrated that IS-induced phosphorylation of myosin light chain kinase (MLCK) and myosin light chains (MLC) as well as activation of extracellular-signal-regulated protein kinase (ERK1/ERK2). Pretreatment with MnTMPyP prevented ERK1/2 phosphorylation. U0126 prevented the IS-induced MLCK and MLC phosphorylation. MEK-ERK acted as the upstream regulator of the MLCK-MLC pathway. These findings suggest that the superoxide anion-MEK-ERK-MLCK-MLC signaling mediates IS-induced junctional dispersal of BPAECs. PMID- 22213463 TI - The relationship between fatigue-related factors and work-related injuries in the Saskatchewan Farm Injury Cohort Study. AB - BACKGROUND: The objective was to examine the relationship between seasonal variations in sleep quantity and work-related injuries on Saskatchewan farms. METHODS: A cross-sectional analysis of data from the Saskatchewan Farm Injury Cohort Study was conducted. Analyses were restricted to workers, aged >=16 years. The primary outcome was work-related injury in the last year. Logistic regression models were used to identify associations between sleep quantity and farm injury. RESULTS: After controlling for confounding variables peak production season sleep was not associated with increased odds of injury. However, those obtaining <=5 hr sleep per night during non-peak production seasons had increased odds of injury (OR 2.42, 95% CI 1.04-5.59) compared with those sleeping >=7 hr per night. CONCLUSIONS: We identified that restricted sleep durations, in certain seasons, placed farmers, and farm workers at risk of injury. Agricultural injury intervention programs need to consider the role of seasonal-related variations in sleep on farm injury. PMID- 22213464 TI - Glycolysis in preimplantation development is partially controlled by the Warburg Effect. AB - Glucose metabolism in preimplantation embryos has traditionally been viewed from a somatic cell viewpoint. Here, we show that gene expression in early embryos is similar to rapidly dividing cancer cells. In vitro-produced pig blastocysts were subjected to deep-sequencing, and were found to express two gene variants that have been ascribed importance to cancer cell metabolism (HK2 and the M2 variant of PKM2). Development was monitored and gene expression was quantified in additional embryos cultured in low or high O(2) (5% CO(2), 5% O(2), 90% N(2) vs. 5% CO(2) in air). Development to the blastocyst stage in the two atmospheres was similar, except low O(2) resulted in more total and inner cell mass nuclei than high O(2). Of the 15 candidate genes selected that are involved in glucose metabolism, only TALDO1 and PDK1 were increased in the low O(2) environment. One paradigm that has been used to explain glycolysis under low oxygen tension is the Warburg Effect (WE). The WE predicts that expression of both HK2 and PKM2 M2 results in a slowing of glucose metabolism through the TCA cycle, thereby forcing the products of glycolysis to be metabolized through the pentose phosphate pathway and to lactic acid. This charging of the system is apparently so important to the early embryo that redundant mechanisms are present, that is, a fetal form of PKM2 and high levels of PDK1. Here, we set the framework for using the WE to describe glucose metabolism and energy production during preimplantation development. PMID- 22213465 TI - Synaptic vesicle recycling is enhanced by torsinA that harbors the DYT1 dystonia mutation. AB - Early-onset generalized dystonia, DYT1, is caused by a mutation in the gene encoding the evolutionarily conserved AAA+ ATPase torsinA. Synaptic abnormalities have been implicated in DYT1 dystonia, but the details of the synaptic pathophysiology are only partially understood. Here, we demonstrate a novel role for torsinA in synaptic vesicle recycling, using cultured hippocampal neurons from a knock-in mouse model of DYT1 dystonia (DeltaE-torsinA) and live-cell imaging with styryl FM dyes. Neurons from heterozygous DeltaE-torsinA mice released a larger fraction of the total recycling pool (TRP) during a single round of electrical stimulation than did wild-type neurons. Moreover, when the neurons were subjected to prior high activity, the time course of release was shortened. In neurons from homozygous mice, these enhanced exocytosis phenotypes were similar, but in addition the size of the TRP was reduced. Notably, when release was triggered by applying a calcium ionophore rather than electrical stimuli, neither a single nor two DeltaE-torsinA alleles affected the time course of release. Thus, the site of action of DeltaE-torsinA is at or upstream of the rise in calcium concentration in nerve terminals. Our results suggest that torsinA regulates synaptic vesicle recycling in central neurons. They also indicate that this regulation is influenced by neuronal activity, further supporting the idea that synaptic abnormalities contribute to the pathophysiology of DYT1 dystonia. PMID- 22213466 TI - P=C bonds as building blocks for three- and four-membered heterocyclic cations: synthesis, structures and mechanistic studies. AB - The activation of the P=C bond of phosphaalkenes with electrophiles is investigated as a means to prepare and characterize unusual organophosphorus compounds. Treatment of RP=CHtBu (1a: R=tBu; 1b: R=1-adamantyl) with HOTf (0.5 equiv) affords diphosphiranium salts [RP-CHtBu-PR (CH(2)tBu)]OTf ([2a]OTf and [2b]OTf), each containing a three-membered P(2)C ring. In contrast, the addition of MeOTf (0.5 equiv) to either 1a or 1b affords diphosphetanium salts [RP-CHtBu P(Me)R-CHtBu]OTf ([3a]OTf and [3b]OTf) containing four-membered P(2)C(2) heterocycles. The phosphenium triflate [tBuP(CH(2)tBu)]OTf ([5a]OTf) and methylenephosphonium triflate [tBu(Me)P=CHtBu]OTf ([7a]OTf) are identified spectroscopically as intermediates in the formation of [2a](+) and [3a](+), respectively. The phosphenium triflate intermediate can be trapped with 2-butyne to afford phosphirenium salt [MeC=CMe-tBuPCH(2)tBu]OTf ([6a]OTf). Treatment of diphosphetanium [3a]OTf with an excess MeOTf affords [Me(2)P-CHtBu-PMetBu CHtBu](OTf)(2) ([4a](OTf)(2)), a compound containing a diphosphetanium dication. The molecular structures are reported for [2a]OTf, [2b][H(OTf)(2)], [3a]I, [3b]I, [4a](OTf)(2), and [6a]OTf. PMID- 22213467 TI - Efficient poling of electro-optic polymers in thin films and silicon slot waveguides by detachable pyroelectric crystals. AB - Pyroelectric crystals are used as a conformal and detachable electric field source to efficiently pole electro-optic (E-O) polymers in both parallel-plate (transverse) and in-plane (quasi-longitudinal) configurations. Large Pockels coefficients in poled thin films and high tunability of resonance wavelength shift in hybrid polymer silicon slot waveguide ring-resonator modulators have been achieved using this method. PMID- 22213468 TI - Assessing the performance of amorphous solid dispersions. AB - The characterization and performance of stable amorphous solid dispersion systems were evaluated in 40 research papers reporting active pharmaceutical ingredient (API) dissolution and bioavailability from various systems containing polymers. The results from these studies were broadly placed into three categories: amorphous dispersions that improved bioavailability (~82% of the cases), amorphous dispersions possessing lower bioavailability than the reference material (~8% of the cases), and amorphous dispersions demonstrating similar bioavailabilities as the reference material (~10% of the cases). A comparative analysis of these studies revealed several in vitro and in vivo variables that could have influenced the results. The in vitro factors compared primarily centered on dissolution testing and equipment, content and amount of dissolution media, sink or nonsink conditions, agitation rates, media pH, dissolution characteristics of the polymer, and dispersion particle size. The in vivo factors included reference materials used for bioavailability comparisons, animal species utilized, fasting versus fed conditions, and regional differences in gastrointestinal (GI) content and volume. On the basis of these considerations, a number of recommendations were made on issues ranging from the assessment of physical stability of API-polymer dispersions to in vivo GI physiological factors that require consideration in the performance evaluation of these systems. PMID- 22213469 TI - Evaluation of combined bevacizumab plus irinotecan therapy in brain tumors using magnetic resonance imaging measures of relative cerebral blood volume. AB - Frequently, bevacizumab is combined with chemotherapeutics such as irinotecan, motivated by studies showing improved clinical outcomes compared with historical controls. However, no systematic studies have been performed to determine if and how these drugs should be combined for optimal therapeutic response. The purpose of this study was to characterize the temporal combinations of bevacizumab and irinotecan by measuring the contrast-agent enhanced tumor volumes and relative cerebral blood volume using dynamic susceptibility contrast imaging. The studies, performed in the U87 brain tumor model, show a vascular normalization window with bevacizumab monotherapy and are consistent with clinical indications of no additional benefit in the addition of irinotecan to bevacizumab therapy. PMID- 22213470 TI - A direct comparison of the diagnostic accuracy of three prostate cancer nomograms designed to predict the likelihood of a positive initial transrectal biopsy. AB - BACKGROUND: Several tools have been developed to predict the outcome of prostate biopsies performed to diagnosis prostate cancer (PCa). However, few studies have focused on the comparative accuracy of these predictive tools. We aim to establish the predictive accuracy of three commonly used nomograms by comparing their prostate biopsy outcome predictions with actual pathological results. METHODS: From January 2008 to December 2010, 708 consecutive patients with an elevated serum PSA level and/or abnormal DRE were referred to our institution. All data were collected prospectively. All patients underwent a TRUS 12-core biopsy. Probability of a positive biopsy was predicted using three online risk calculation nomograms. The discriminative ability of the nomograms was assessed via AUC and the most accurate model was calibrated and compared to actual biopsy results. RESULTS: Of 667 patients fulfilling all three nomograms criteria, 384 (57.5%) had PCa and 283 (42.5%) did not. AUC for the PCPT-CRC, SWOP-PRI, and Montreal nomograms was 0.68 (95% CI, 0.63-0.72), 0.72 (95% CI, 0.68-0.76), and 0.79 (95% CI, 0.76-0.82), respectively. A comparison of the three models' performance showed that the Montreal model provided the greatest predictive accuracy (P = 0.03). CONCLUSIONS: External validation of three commonly used nomograms designed to predict the likelihood of a positive prostate biopsy reveals the Montreal model was more accurate than either the PCPT-CRC or SWOP-PRI models. The Montreal nomogram achieves a diagnostic accuracy of 79% and is superior to PSA alone though we await further research to define the probability (of cancer) threshold above which a prostate biopsy would be advised. PMID- 22213471 TI - Selective multivessel labeling approach for perfusion territory imaging in pseudo continuous arterial spin labeling. AB - Recently, a new method for perfusion territory imaging named superselective pseudo-continuous arterial spin labeling was introduced. The method uses additional time-varying gradients to create a circular labeling spot that can be adjusted in size and thus adapted to individual arteries. In this study, the additional gradients are adjusted in such a way that an elliptical labeling spot is formed, which can be applied to label the blood in multiple vessels simultaneously in conjunction with an increased labeling efficiency compared with the original superselective approach. When compared with other selective multivessel strategies, the proposed technique allows for an improved and flexible adaption of the labeling focus to different anatomical variations of the arteries in the neck so that a total of five perfusion territories from the data acquired in three measurements can be recalculated in a reduced scan time. These include not only the perfusion territories of the cerebrum but also the perfusion territories in the cerebellum fed by individual vertebral arteries. PMID- 22213472 TI - Transvenous extraction of pacemaker leads in infective endocarditis with vegetations >=20 mm: our experience. AB - BACKGROUND: According to published evidence, treatment of infective endocarditis (IE) associated with cardiovascular implantable electronic devices (CIEDs) should include complete removal of the system. Several publications have shown that transvenous removal is an effective and safe nonthoracotomy approach in patients with large vegetations, but experiences with vegetations larger than 20 mm have rarely been reported. HYPOTHESIS: Our aim was to describe our experience in percutaneous removal of CIEDs in patients with IE with large vegetations. METHODS: The data were collected retrospectively and analyzed prospectively. We evaluated in-hospital morbidity and mortality related to percutaneous removal of vegetations >=20 mm. This included 8 cases with a follow-up period of 20 months. We removed 100% of leads in the study population. RESULTS: Two patients experienced minor complications. No patient experienced subclavian vein laceration, hemothorax and lead fracture, or severe tricuspid regurgitation. After the removal procedure, 2 patients had symptoms compatible with pulmonary embolism. Both in-hospital mortality and mortality at follow-up were zero. CONCLUSIONS: Transvenous extraction of pacing leads with larger vegetations is a feasible technique. There was a tendency toward symptomatic pulmonary embolism in patients with vegetations larger than 20 mm; however, morbidity and mortality were not influenced. We agree with the consensus that this procedure is highly useful and that the selection of the removal techniques will depend not only on the size of vegetation but also on prior cardiopulmonary conditions, concomitant cardiac surgery, atrial septal defect with risk of paradoxical embolism, center experience, and the possibility of complete removal of the device. PMID- 22213473 TI - Significant interspecies differences in induction profiles of hepatic CYP enzymes by TCDD in bank and field voles. AB - The gene expression and induction of cytochrome P450 (CYP)-enzymes following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) peroral administration was studied in the livers of two wild vole species--the bank vole (Myodes glareolus) and the field vole (Microtus agrestis). The dioxin-sensitive C57BL/6 mouse was used as a reference. Doses of 0.05, 0.5, 5.0, and 50 ug/kg were applied to ascertain a dose response relationship, and the dose of 50 ug/kg was applied to the study time course for up to 96 h. The cytochrome P450 1A1 (CYP1A1) mRNA expression showed an expected dose-dependent increase equally in both vole species. Bank voles expressed notably higher CYP2A mRNA levels as compared with field voles. Both species exhibited dose-dependent increases in putative CYP1A-, CYP2B-, and CYP2A associated activities as measured by fluorometric assays for ethoxyresorufin-O deethylase (EROD), penthoxyresorufin-O-depenthylase (PROD), and 7-ethoxycoumarin O-deethylase (ECOD), respectively. Putative CYP2A-associated coumarin-7 hydroxylase (COH) activity showed a slight increase at the two highest doses of TCDD in field voles but not in bank voles, and their basal COH activity was only one-fourth or less of that in field voles. Overall, however, bank voles tended to exhibit higher CYP-associated enzyme activities measured at the two largest doses of TCDD than field voles. A western blot analysis of aryl hydrocarbon receptor (AhR) revealed that the two vole species had differential band patterns, suggesting dissimilar structures for their AhRs. PMID- 22213474 TI - Aerobic palladium(II)-catalyzed 5-endo-trig cyclization: an entry into the diastereoselective C-2 alkenylation of indoles with tri- and tetrasubstituted double bonds. PMID- 22213475 TI - Amplified in breast cancer 1 enhances human cholangiocarcinoma growth and chemoresistance by simultaneous activation of Akt and Nrf2 pathways. AB - Transcriptional coactivator amplified in breast cancer 1 (AIB1) plays important roles in the progression of several cancers such as prostate cancer, breast cancer, and hepatocellular carcinoma. However, its role in cholangiocarcinoma (CCA), a chemoresistant bile duct carcinoma with a poor prognosis, remains unclear. In this study we found that AIB1 protein was frequently overexpressed in human CCA specimens and CCA cell lines. Down-regulation of AIB1 induced the G2/M arrest and decreased the expression of mitosis-promoting factors including Cyclin A, Cyclin B, and Cdk1 through suppressing the Akt pathway, which resulted in inhibiting CCA cell proliferation. In addition, AIB1 enhanced the chemoresistance of CCA cells at least in part through up-regulating the expression of antiapoptotic protein Bcl-2. AIB1 regulated the expression of Bcl-2 in CCA cells through activating the Akt pathway as well as suppressing intracellular reactive oxygen species (ROS). AIB1 suppressed ROS by up-regulating antioxidants such as glutathione synthetase and glutathione peroxidase, which are targets of the NF-E2 related factor 2 (Nrf2), a critical transcription factor that regulates antioxidants, detoxification enzymes, and drug efflux proteins. AIB1 also increased the expression of another two Nrf2 targets, ABCC2 and ABCG2, to enhance drug efflux. AIB1 served as an essential coactivator for Nrf2 activation by physically interacting with Nrf2 to enhance its transcriptional activity. CONCLUSION: AIB1 plays an important role in proliferation and chemoresistance of CCA through simultaneous activation of Akt and Nrf2 pathways, suggesting that AIB1 is a potential molecular target for CCA treatment. PMID- 22213476 TI - Signaling the unconditioned stimulus during the preexposure phase does not attenuate the unconditioned stimulus preexposure effect in preweanling rats. AB - The unconditioned stimulus preexposure effect (US-PE) is defined as an attenuation of the conditioned response after preexposure to the US prior to conditioning. Evidence exists that this effect can be weakened or eliminated by the presence of a signal predicting the US during the preexposure phase. This evidence has been found consistently across a variety of procedures in adult rats. The aim of the present study was to evaluate whether, in infant rats, signaling the US (LiCl) during preexposure with a salient cue (almond odor) attenuates the US-PE. During the preexposure phase, preweanling rats received three (Experiment 1) or one (Experiment 2) preexposures to LiCl, preceded by exposure to almond odor. Appropriate control groups were also included in these experiments. After preexposure, two conditioning trials were carried out in which subjects were given LiCl after saccharin consumption. During preexposure, three (Experiment 1a), although not one (Experiment 2a), contingent exposures to almond odor and LiCl resulted in a strong odor aversion. Extinction of the learned taste aversion was facilitated by prior experience with LiCl (Experiments 1b and 2b). This effect was observed regardless of whether or not LiCl was signaled by the almond odor. These results do not coincide with the associative hypotheses proposed to explain the US-PE, nor are they concurrent with alternative explanations based on the learned helplessness phenomenon. PMID- 22213477 TI - Recidivism in subgroups of serious juvenile offenders: different profiles, different risks? AB - BACKGROUND: Research has shown that the treatment of juvenile offenders is most effective when it takes into account the possible risk factors for re-offending. It may be asked whether juvenile offenders can be treated as one homogeneous group, or, if they are divisible into subgroups, whether different risk factors are predictive of recidivism. AIMS AND HYPOTHESES: Our aims were to find out whether serious juvenile offenders may be subdivided into clearly defined subgroups and whether such subgroups might differ in terms of the risk factors that predict recidivism. METHODS: In a sample of 1111 serious juvenile offenders, latent class analysis was used to identify subgroups. For each juvenile offender, 70 risk factors were registered. Severity of recidivism was measured on a 12 point scale. Analysis was then conducted to identify the risk factors that best predicted the different patterns of recidivism. RESULTS: Four distinct subgroups of juvenile offenders were identified: serious violent offenders, violent property offenders, property offenders, and sex offenders. Violent property offenders were the most serious recidivists and had the highest number of risk factors. Serious violent offenders and property offenders were characterised by overt and covert behaviour, respectively. Sex offenders differed from the other three groups in the rarity of their recidivism and in the risk factors that are present. For each of these four subgroups, a different set of risk factors was found to predict severity of recidivism. CONCLUSIONS: Differences in recidivism rates occurred in spite of the fact that most of these youngsters had been in the standard treatment programme offered to serious juvenile offenders in the Netherlands. This was not a treatment outcome study, but the indication that two of the groups identified in our study appeared to be worse after going through this programme, whereas the other two did quite well in terms of recidivism lends weight to our idea that such classification of juvenile offenders may lead to more targeted treatment programmes that would better serve both the general public and the youths concerned. PMID- 22213478 TI - Effects of short vacations, vacation activities and experiences on employee health and well-being. AB - It was investigated (1) whether employee health and well-being (H&W) improve during short vacations (4-5 days), (2) how long this improvement lasts after returning home and resuming work and (3) to what extent vacation activities and experiences explain health improvements during and after short vacations. Eighty workers reported their H&W 2 weeks before vacation (Pre), during vacation (Inter), on the day of return (Post 1) and on the third and 10th day after returning home (Post 2 and Post 3, respectively). The results showed improvements in H&W during short vacations (d=0.62), although this effect faded out rather quickly. Partial correlations and regression analyses showed that employees reported higher H&W during vacation, the more relaxed and psychologically detached they felt, the more time they spent on conversations with the partner, the more pleasure they derived from their vacation activities and the lower the number of negative incidents during vacation. Experiences of relaxation and detachment from work positively influenced H&W even after returning home. Working during vacation negatively influenced H&W after vacation. In conclusion, short vacations are an effective, although not very long lasting, 'cure' to improve employees' H&W. PMID- 22213479 TI - Ion permeable microcapsules for the release of biologically available ions for remineralization. AB - The objective of this study was to investigate the effect of chemical structure, ion concentration, and ion type on the release rate of biologically available ions useful for remineralization from microcapsules with ion permeable membranes. A heterogeneous polymerization technique was utilized to prepare microcapsules containing either an aqueous solution of K2HPO4, Ca(NO3)2, or NaF. Six different polyurethane-based microcapsule shells were prepared and characterized based on ethylene glycol, butanediol, hexanediol, octanediol, triethylene glycol, and bisphenol A structural units. Ion release profiles were measured as a function of initial ion concentration within the microcapsule, ion type, and microcapsule chemical structure. The rate of ion release increased with initial concentration of ion stored in the microcapsule over a range of 0.5-3.0M. The monomer used in the synthesis of the membrane had a significant effect on ion release rates at 3.0 M salt concentration. At 1.0 M, the ethylene glycol released ions significantly faster than the hexanediol-, octanediol-, and butanediol-based microcapsules. Ion release was fastest for fluoride and slowest for phosphate for the salts used in this study. It was concluded that the microcapsules are capable of releasing calcium, phosphate, and fluoride ions in their biologically available form. PMID- 22213481 TI - Concise review: Induced pluripotent stem cells versus embryonic stem cells: close enough or yet too far apart? AB - The state of a cell is defined by the genes it transcribes and the epigenetic landscape that regulates their expression. Pluripotent cells have markedly different epigenetic signatures when compared with differentiated cells. Permissive chromatin, high occurrence of bivalent domains, and low levels of heterochromatin allow pluripotent cells to react to distinctive stimuli and undergo changes of cell state by differentiating into various tissues. Differentiated cells can be reprogrammed by a set of transcription factors to induced pluripotent stem cells (iPSC) that convert their transcriptional and epigenetic state to pluripotency and thus closely resemble embryonic stem cells (ESC). However, questions remain on whether the epigenetic reprogramming is complete or if there are some recurring iPSC specific aberrations that impede their full pluripotency potential. For this reason, iPSC need to be closely compared with ESC, which is used as a golden standard for in vitro pluripotency. Transcribed genes, epigenetic landscape, differentiation potential, and mutational load show small but distinctive dissimilarities between these two cell types. PMID- 22213483 TI - Reversible insertion of 1,3-di-tert-butylimidazol-2-ylidene into a Ru-H bond and bimetallic activation of a N-C bond of imidazoline. PMID- 22213482 TI - Wnt3a stimulates Mepe, matrix extracellular phosphoglycoprotein, expression directly by the activation of the canonical Wnt signaling pathway and indirectly through the stimulation of autocrine Bmp-2 expression. AB - Matrix extracellular phosphoglycoprotein (MEPE) is a specific marker of mineralizing osteoblasts and osteocytes. Canonical BMP and Wnt signaling pathways are two of the strongest paracrine signals stimulating osteogenesis. Our previous results indicated that Mepe expression is stimulated by the BMP-2-signaling pathway. The specific aim of this study addressed whether Mepe expression is also controlled by Wnt signaling, and whether there is a cross-regulation between two major osteogenic signaling pathways. Treatment with Wnt3a, a canonical Wnt signaling stimulator, strongly enhanced Mepe mRNA expression. Knock-down of beta catenin with siRNA completely reversed Wnt3a-stimulated Mepe expression. The Mepe mRNA expression level was increased by overexpression of beta-catenin and Lef-1, even in the absence of Wnt3a. Highly conserved Lef-1 response elements were identified in the mouse Mepe promoter. The direct binding of Lef-1 to these elements is critical for Mepe expression, indicating that Mepe is a direct target of canonical Wnt signaling. Meanwhile, we also found that Wnt3a treatment strongly stimulated Bmp-2 expression, and that the subsequent increase in Bmp-2 protein was determined in Wnt3a-treated conditioned medium (CM). Treatment of MC3T3-E1 cells with CM stimulated phosphorylation of the Smad1/5 proteins and their downstream Dlx5 mRNA expression. The CM-mediated increases of phospho-Smad and Dlx5 expression were not blocked completely by a Wnt3a antagonist, Dkk-1, but were almost completely suppressed by the addition of a Bmp-2 antagonist, Noggin. Collectively, Wnt3a stimulates Mepe transcription directly by a canonical Wnt signaling pathway through beta-catenin and Lef-1 and indirectly through the activation of a Bmp-2 autocrine loop. PMID- 22213484 TI - A charge-transfer challenge: combining fullerenes and metalloporphyrins in aqueous environments. AB - A series of truly water-soluble C(60)/porphyrin electron donor-acceptor conjugates has been synthesized to serve as powerful mimics of photosynthetic reaction centers. To this end, the overall water-solubility of the conjugates was achieved by adding hydrophilic dendrimers of different generations to the porphyrin moiety. An important variable is the metal center of the porphyrin; we examined zinc(II), copper(II), cobalt(II), nickel(II), iron(III), and manganese(III). The first insights into electronic communication between the electron donors and the electron acceptors came from electrochemical assays, which clearly indicate that the redox processes centered either on C(60) or the porphyrins are mutually affected. Absorption measurements, however, revealed that the electronic communication in terms of, for example, charge-transfer features, remains spectroscopically invisible. The polar environment that water provides is likely to be a cause of the lack of detection. Despite this, transient absorption measurements confirm that intramolecular charge separation processes in the excited state lead to rapid deactivation of the excited states and, in turn, afford the formation of radical ion pair states in all of the investigated cases. Most importantly, the lifetimes of the radical ion pairs were found to depend strongly on several aspects. The nature of the coordinated metal center and the type of dendrimer have a profound impact on the lifetime. It has been revealed that the nature/electronic configuration of the metal centers is decisive in powering a charge recombination that either reinstates the ground state or any given multiplet excited state. Conversely, the equilibrium of two opposing forces in the dendrimers, that is, the interactions between their hydrophilic regions and the solvent and the electronic communication between their hydrophobic regions and the porphyrin and/or fullerene, is the key to tuning the lifetimes. PMID- 22213485 TI - Microparticle formation after co-culture of human whole blood and umbilical artery in a novel in vitro model of flow. AB - Cardiovascular disease (CVD) is now the largest killer in western society, and the importance of interactions between vascular endothelium and circulating blood components in disease pathogenesis is well established. Microparticles are a heterogeneous population of <1 MUm blood borne particles that arise from blebbing or shedding of cell membranes. The microparticle population includes several classes of apoptotic bodies; however, increased numbers of procoagulant microparticles have been described in plasma from people with CVD. We have previously demonstrated that interactions of monocytes and platelets with isolated inflamed endothelial cells lead to production of pro-coagulant tissue factor bearing microparticles under laminar flow conditions. Here we have investigated microparticle production after perfusion of human whole blood through intact inflamed human umbilical artery. When blood was perfused through umbilical arteries which had been pre-stimulated with tumour necrosis factor (TNFalpha) for 18 h under flow conditions, there was significantly increased production of microparticles from both platelet and non-platelet sources, in particular from erythrocytes. To determine whether microparticles generated during interactions with inflamed endothelium could induce a pro-inflammatory response in trans, we isolated microparticles by centrifugation after co-culture and incubated with isolated quiescent endothelial cells followed by measurement of reactive oxygen species formation. Microparticles derived from co-culture with inflamed endothelium induced significantly enhanced levels of reactive oxygen species (ROS). These data suggest that presence of an inflamed endothelium causes release of pro-inflammatory microparticles from circulating blood cells, which could contribute to prolonged endothelial activation and subsequent atherosclerotic changes in blood vessels subjected to inflammatory insult. PMID- 22213486 TI - Optical studies of CdS:Mn nanoparticles. AB - Cadmium sulphide nanoparticles were grown using a wet chemical method, by dissolving the reactants, cadmium chloride and sodium sulphide in water, in the presence of mercaptoethanol (ME), which was used as a capping agent. Manganese chloride was used to dope the nanoparticles. It was found that the particle size varied with different concentrations of ME. At higher concentrations of ME, smaller sized nanoparticles were synthesized. This method also reveals the high stability of nanoparticles in water. Nanoparticle properties were investigated using UV-vis absorption, photoluminescence spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy (SEM) techniques. The particle sizes were measured by the XRD technique, SEM and optical absorption spectra and were in the range 2-6 nm. PMID- 22213487 TI - Comparison of DNA apoptosis in mouse and human blastocysts after vitrification and slow freezing. AB - Vitrification is a novel cryopreservation method for mammalian blastocysts. This study was designed to compare different vitrification methods and slow freezing for their effects on survival rate and DNA integrity in mouse and human blastocysts. In Experiment 1, embryo survival and DNA integrity were compared between mouse blastocysts with collapsed and non-collapsed blastoceles. In Experiment 2, embryo survival and DNA integrity were compared between vitrified and slow-frozen mouse blastocysts. In Experiment 3, embryo survival and DNA integrity were compared between vitrified and slow-frozen human blastocysts. Fresh blastocysts were used as controls in all experiments. Higher (P < 0.05) blastocyst survival rates were obtained in mouse blastocysts vitrified with collapsed versus intact blastoceles, although DNA-integrity indices in the surviving blastocysts were the same among vitrified and fresh blastocysts. More mouse blastocysts (P < 0.05) survived after vitrification (100%) as compared to slow freezing (82.5%). DNA-integrity indices examined in the surviving blastocysts were also higher (P < 0.001) in fresh (93.6%) and vitrified/warmed (93.7%) blastocysts than in slow-frozen/thawed (75.8%) ones. More human blastocysts survived with a higher DNA-integrity index after vitrification/warming than after slow freezing/thawing. These results indicate that higher survival rates can be obtained by vitrification of blastocele collapsed blastocysts, and that vitrification causes less cell apoptosis in both mouse and human blastocysts compared to slow freezing. Vitrification of blastocysts after blastocele collapse by single laser pulse supports a higher survival rate and less DNA apoptosis, suggesting that laser blastocele collapse is a safe procedure for blastocyst vitrification. PMID- 22213488 TI - Solid-state NMR characterization of high-loading solid solutions of API and excipients formed by electrospinning. AB - A major focus area in improving pharmaceutical manufacturing is decreasing powder handling steps such as milling, granulation, and blending. One approach to go directly from active pharmaceutical ingredients (API) and excipients in solution to a formulated drug product is to use electrospinning to make solid formulations of API in a polymer. Because of the rapid evaporation rate in electrospinning, the process usually results in a well-mixed solid dispersion of drugs in the polymer. In this study, solid-state nuclear magnetic resonance is used to examine phase separation in formulations of aliskiren (SPP) and indomethacin (IND) with polyvinylpyrrolidone (PVP) prepared by electrospinning and hot-melt extrusion. It was found that 1:1 SPP-PVP, 1:1 IND-PVP, and 4:1 SPP-PVP formulations prepared by electrospinning are homogeneous solid solutions down to a 2-11 nm length scale, whereas a 4:1 SPP-PVP formulation prepared by hot-melt extrusion exhibits phase separation with domain sizes of 20-100 nm or larger. PMID- 22213489 TI - Spinal manipulation, medication, or home exercise with advice for acute and subacute neck pain: a randomized trial. AB - BACKGROUND: Mechanical neck pain is a common condition that affects an estimated 70% of persons at some point in their lives. Little research exists to guide the choice of therapy for acute and subacute neck pain. OBJECTIVE: To determine the relative efficacy of spinal manipulation therapy (SMT), medication, and home exercise with advice (HEA) for acute and subacute neck pain in both the short and long term. DESIGN: Randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00029770) SETTING: 1 university research center and 1 pain management clinic in Minnesota. PARTICIPANTS: 272 persons aged 18 to 65 years who had nonspecific neck pain for 2 to 12 weeks. INTERVENTION: 12 weeks of SMT, medication, or HEA. MEASUREMENTS: The primary outcome was participant-rated pain, measured at 2, 4, 8, 12, 26, and 52 weeks after randomization. Secondary measures were self-reported disability, global improvement, medication use, satisfaction, general health status (Short Form-36 Health Survey physical and mental health scales), and adverse events. Blinded evaluation of neck motion was performed at 4 and 12 weeks. RESULTS: For pain, SMT had a statistically significant advantage over medication after 8, 12, 26, and 52 weeks (P <= 0.010), and HEA was superior to medication at 26 weeks (P = 0.02). No important differences in pain were found between SMT and HEA at any time point. Results for most of the secondary outcomes were similar to those of the primary outcome. LIMITATIONS: Participants and providers could not be blinded. No specific criteria for defining clinically important group differences were prespecified or available from the literature. CONCLUSION: For participants with acute and subacute neck pain, SMT was more effective than medication in both the short and long term. However, a few instructional sessions of HEA resulted in similar outcomes at most time points. PRIMARY FUNDING SOURCE: National Center for Complementary and Alternative Medicine, National Institutes of Health. PMID- 22213490 TI - Comparison of natural language processing biosurveillance methods for identifying influenza from encounter notes. AB - BACKGROUND: An effective national biosurveillance system expedites outbreak recognition and facilitates response coordination at the federal, state, and local levels. The BioSense system, used at the Centers for Disease Control and Prevention, incorporates chief complaints but not data from the whole encounter note into its surveillance algorithms. OBJECTIVE: To evaluate whether biosurveillance by using data from the whole encounter note is superior to that using data from the chief complaint field alone. DESIGN: 6-year retrospective case-control cohort study. SETTING: Mayo Clinic, Rochester, Minnesota. PARTICIPANTS: 17,243 persons tested for influenza A or B virus between 1 January 2000 and 31 December 2006. MEASUREMENTS: The accuracy of a model based on signs and symptoms to predict influenza virus infection in patients with upper respiratory tract symptoms, and the ability of a natural language processing technique to identify definitional clinical features from free-text encounter notes. RESULTS: Surveillance based on the whole encounter note was superior to the chief complaint field alone. For the case definition used by surveillance of the whole encounter note, the normalized partial area under the receiver operating characteristic curve (specificity, 0.1 to 0.4) for surveillance using the whole encounter note was 92.9% versus 70.3% for surveillance with the chief complaint field (difference, 22.6%; P < 0.001). Comparison of the 2 models at the fixed specificity of 0.4 resulted in sensitivities of 89.0% and 74.4%, respectively (P < 0.001). The relative risk for missing a true case of influenza was 2.3 by using the chief complaint field model. LIMITATIONS: Participants were seen at 1 tertiary referral center. The cost of comprehensive biosurveillance monitoring was not studied. CONCLUSION: A biosurveillance model for influenza using the whole encounter note is more accurate than a model that uses only the chief complaint field. Because case-defining signs and symptoms of influenza are commonly available in health records, the investigators believe that the national strategy for biosurveillance should be changed to incorporate data from the whole health record. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention. PMID- 22213491 TI - Comparison of hospital risk-standardized mortality rates calculated by using in hospital and 30-day models: an observational study with implications for hospital profiling. AB - BACKGROUND: In-hospital mortality measures, which are widely used to assess hospital quality, are not based on a standardized follow-up period and may systematically favor hospitals with shorter lengths of stay (LOSs). OBJECTIVE: To assess the agreement between performance measures of U.S. hospitals by using risk standardized in-hospital and 30-day mortality rates. DESIGN: Observational study. SETTING: Nonfederal acute care hospitals in the United States with at least 30 admissions for acute myocardial infarction (AMI), heart failure (HF), and pneumonia from 2004 to 2006. PATIENTS: Medicare fee-for-service patients admitted for AMI, HF, or pneumonia from 2004 to 2006. MEASUREMENTS: The primary outcomes were in-hospital and 30-day risk-standardized mortality rates (RSMRs). RESULTS: Included patients comprised 718,508 admissions to 3135 hospitals for AMI, 1,315,845 admissions to 4209 hospitals for HF, and 1,415,237 admissions to 4498 hospitals for pneumonia. The hospital-level mean patient LOS varied across hospitals for each condition, ranging from 2.3 to 13.7 days for AMI, 3.5 to 11.9 days for HF, and 3.8 to 14.8 days for pneumonia. The mean RSMR differences (30 day RSMR minus in-hospital RSMR) were 5.3% (SD, 1.3) for AMI, 6.0% (SD, 1.3) for HF, and 5.7% (SD, 1.4) for pneumonia; distributions varied widely across hospitals. Performance classifications differed between the in-hospital and 30 day models for 257 hospitals (8.2%) for AMI, 456 (10.8%) for HF, and 662 (14.7%) for pneumonia. Hospital mean LOS was positively correlated with in-hospital RSMRs for all 3 conditions. LIMITATION: Medicare claims data were used for risk adjustment. CONCLUSION: In-hospital mortality measures provide a different assessment of hospital performance than 30-day mortality and are biased in favor of hospitals with shorter LOSs. PRIMARY FUNDING SOURCE: The Centers for Medicare & Medicaid Services and National Heart, Lung, and Blood Institute. PMID- 22213492 TI - Evaluation of guideline recommendations on oral medications for type 2 diabetes mellitus: a systematic review. AB - BACKGROUND: Clinical practice guidelines have an important role in guiding choices among the numerous medications available to treat type 2 diabetes mellitus, but little is known about their quality. PURPOSE: To assess whether guidelines on oral medications for type 2 diabetes are consistent with a systematic review of the current evidence and whether the consistency of the guidelines depends on the quality of guideline development. DATA SOURCES: MEDLINE, CINAHL, and guideline-specific databases were searched between July 2007 and August 2011, after the 2007 publication of a peer-reviewed systematic review on oral diabetes medications. STUDY SELECTION: Two reviewers independently screened citations to identify English-language guidelines on oral medications to treat type 2 diabetes that were applied in the United States, United Kingdom, and Canada. DATA EXTRACTION: Reviewers assessed whether the guidelines addressed and agreed with 7 evidence-based conclusions from the 2007 systematic review. Two reviewers independently rated guideline quality by using 2 domains from the Appraisal of Guidelines Research and Evaluation instrument. DATA SYNTHESIS: Of the 1000 screened citations, 11 guidelines met the inclusion criteria. Seven guidelines agreed with the conclusion that metformin is favored as the first-line agent. Ten guidelines agreed that thiazolidinediones are associated with higher rates of edema and congestive heart failure compared with other oral medications to treat type 2 diabetes. One guideline addressed no evidence-based conclusions, and 5 guidelines agreed with all 7 conclusions. The summary scores of the rigor of development (median, 28.6% [range, 16.7% to 100.0%]) and editorial independence (median, 75.0% [range, 8.3% to 100.0%]) domains varied greatly across guidelines. Guidelines that received higher quality scores contained more recommendations that were consistent with the evidence-based conclusions. LIMITATION: Only English-language guidelines targeting users in the United States, United Kingdom, and Canada that contained recommendations on oral medications were included. CONCLUSION: Not all practice guidelines on oral treatment of type 2 diabetes were consistent with available evidence from a systematic review. Guidelines judged to be of higher quality contained more recommendations consistent with evidence-based conclusions. The quality of guideline development processes varied substantially. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 22213493 TI - Distinguishing case series from cohort studies. AB - Case series are a commonly reported study design, but the label "case series" is used inconsistently and sometimes incorrectly. Mislabeling impairs the appropriate indexing and sorting of evidence. This article tries to clarify the concept of case series and proposes a way to distinguish them from cohort studies. In a cohort study, patients are sampled on the basis of exposure and are followed over time, and the occurrence of outcomes is assessed. A cohort study may include a comparison group, although this is not a necessary feature. A case series may be a study that samples patients with both a specific outcome and a specific exposure, or one that samples patients with a specific outcome and includes patients regardless of whether they have specific exposures. Whereas a cohort study, in principle, enables the calculation of an absolute risk or a rate for the outcome, such a calculation is not possible in a case series. PMID- 22213495 TI - Pain in the neck: many (marginally different) treatment choices. PMID- 22213494 TI - Advanced dementia: state of the art and priorities for the next decade. AB - Dementia is a leading cause of death in the United States. This article outlines the current understanding of advanced dementia and identifies research priorities for the next decade. Research over the past 25 years has largely focused on describing the experience of patients with advanced dementia. This work has delineated abundant opportunities for improvement, including greater recognition of advanced dementia as a terminal illness, better treatment of distressing symptoms, increased access to hospice and palliative care services, and less use of costly and aggressive treatments that may be of limited clinical benefit. Addressing those opportunities must be the overarching objective for the field in the coming decade. Priority areas include designing and testing interventions that promote high-quality, goal-directed care; health policy research to identify strategies that incentivize cost-effective and evidence-based care; implementation studies of promising interventions and policies; and further development of disease-specific outcome measures. There is great need and opportunity to improve outcomes, contain expenditures, reduce disparities, and better coordinate care for the millions of persons in the United States who have advanced dementia. PMID- 22213496 TI - Fortune favors a prepared health care system. PMID- 22213497 TI - Review of the American College of Physicians Ethics Manual, Sixth Edition. PMID- 22213498 TI - Ethics of the fathers. PMID- 22213499 TI - Chemotherapy in the Rwandan countryside: universal issues a world away. PMID- 22213500 TI - My stethoscope. PMID- 22213501 TI - Doctor and son. PMID- 22213502 TI - Redesigning after-hours primary care. PMID- 22213503 TI - Redesigning after-hours primary care. PMID- 22213504 TI - A clinical practice guideline update on the diagnosis and management of stable chronic obstructive pulmonary disease. PMID- 22213505 TI - NICE guideline for management of chronic heart failure in adults. PMID- 22213506 TI - NICE guideline for management of chronic heart failure in adults. PMID- 22213507 TI - Hip fracture: a complex illness among complex patients. PMID- 22213508 TI - Hip fracture: a complex illness among complex patients. PMID- 22213509 TI - Summaries for patients: is spinal manipulation an effective treatment for neck pain? PMID- 22213510 TI - In the clinic. Plantar fasciitis. AB - This issue provides a clinical overview of plantar fasciitis focusing on prevention, diagnosis, treatment, practice improvement, and patient information. Readers can complete the accompanying CME quiz for 1.5 credits. Only ACP members and individual subscribers can access the electronic features of In the Clinic. Non-subscribers who wish to access this issue of In the Clinic can elect "Pay for View." Subscribers can receive 1.5 category 1 CME credits by completing the CME quiz that accompanies this issue of In the Clinic. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including PIER (Physicians' Information and Education Resource) and MKSAP (Medical Knowledge and Self Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP's Medical Education and Publishing division and with assistance of science writers and physician writers. Editorial consultants from PIER and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult www.acponline.org, http://pier.acponline.org, and other resources referenced within each issue of In the Clinic. PMID- 22213511 TI - Non-coding RNAs as theranostics in human cancers. AB - Theranostics was coined originally as a term used to describe a system that combines diagnosis and therapy, aiming to provide the tools for personalized medicine. This review reasserts the grounds for regarding non-coding RNAs (ncRNA) as theranostics in human cancers. The microRNAs (miRNAs) are the most well studied ncRNAs in recent years; their pivotal role in orchestrating tumor initiation and progression has been confirmed in all types of cancers. Hence, these small ncRNAs have emerged as attractive therapeutic targets and diagnostic tool. Various approaches to use their therapeutic potential have been taken, here we summarize the most important ones. In the near future, the focus of theranostics will be shifted towards longer and mechanistically more versatile ncRNAs, and we included some recent advances supporting this view. PMID- 22213512 TI - Affinity and selectivity of [11C]-(+)-PHNO for the D3 and D2 receptors in the rhesus monkey brain in vivo. AB - Although [11C]-(+)-PHNO has enabled quantification of the dopamine-D3 receptor (D3R) in the human brain in vivo, its selectivity for the D3R is not sufficiently high to allow us to disregard its binding to the dopamine-D2 receptor (D2R). We quantified the affinity of [11C]-(+)-PHNO for the D2R and D3R in the living primate brain. Two rhesus monkeys were examined on four occasions each, with [11C]-(+)-PHNO administered in a bolus + infusion paradigm. Varying doses of unlabeled (+)-PHNO were coadministered on each occasion (total doses ranging from 0.09 to 5.61 MUg kg-1). The regional binding potential (BP(ND) ) and the corresponding doses of injected (+)-PHNO were used as inputs in a model that quantified the affinity of (+)-PHNO for the D2R and D3R, as well as the regional fractions of the [11C]-(+)-PHNO signal attributable to D3R binding. (+)-PHNO in vivo affinity for the D3R (K(d)/f(ND) ~0.23-0.56 nM) was 25- to 48-fold higher than that for the D2R (K(d)/f(ND) ~11-14 nM). The tracer limits for (+)-PHNO (dose associated with D3R occupancy ~10%) were estimated at ~0.02-0.04 MUg kg-1 injected mass for anesthetized primate and at 0.01-0.02 MUg kg-1 for awake human positron emission tomography (PET) studies. Our data enabled a rational design and interpretation of future PET studies with [11C]-(+)-PHNO. PMID- 22213513 TI - Understanding insomnia in older adults. AB - OBJECTIVE: The aims of this study were to determine the true frequency of primary insomnia (PI), sleep disorder related to another mental disorder (SDMD) and sleep disorder due to a general medical condition (SDMC) in older adults and to establish their differentiating characteristics. METHODS: This is a cross sectional study. Participants were randomly selected samples of 951 subjects who are 65 years or older. Main measures were as follows: presence (according to DSM IV-TR diagnostic criteria) of PI, SDMD, SDMC or other sleep disorders, co morbidity and psychotropic consumption. RESULTS: Of the subjects, 36.1% reported having sleep problems (95% CI: 33.0-39.2) and 37.0% reported regularly consuming a psychotropic drug. The prevalence of PI was 8.9% (95% CI: 7.1-11.0), and according to the criteria for differential diagnosis, the prevalence of SDMD was 9.3% (95% CI: 7.5-11.4) and that of SDMC was 7.0% (95%CI: 5.4-8.9). A higher percentage of PI subjects had problems in falling asleep on most days (52.5%), had frequent night-time awakenings (66.3%) and early awakenings (51.3%). In subjects with any type of insomnia, the variables that showed a statistically significant association were female gender (OR: 2.21), consumption of psychotropic drugs (OR: 1.83), presence of four or more health problems (OR: 1.88) and being single, widowed or divorced (OR: 1.43). CONCLUSIONS: Our results provide a true picture of the prevalence of insomnia in older adults on the basis of diagnostic criteria and indicate that it is a widespread, significant health problem. The peculiarities of PI, SDMD and SDMC need to be appropriately differentiated in clinical practice, and each needs a different approach to obtain the best outcome. PMID- 22213514 TI - Elaborate positioning of nanowire arrays contributed by highly adhesive superhydrophobic pillar-structured substrates. AB - Elaborate positioning of nanowire arrays can be generated upon highly adhesive superhydrophobic pillar-structured silicon substrates. The site of each nanowire can be precisely positioned by well designed tip-structured micropillars, yielding on-demand nanowire patterns. This approach might affect existing applications and enable new opportunities in organically functional devices and bio/chemical sensors. PMID- 22213515 TI - Bioinspired reversible interlocker using regularly arrayed high aspect-ratio polymer fibers. AB - A reversible interlocker that is inspired by the wing locking device of beetles is presented. It exploits the van der Waals force-assisted binding between high aspect-ratio polymer fibers. The two-layered interlocker is highly flexible and displays an extremely high shear locking force and easy normal lift-off. PMID- 22213516 TI - Delivery of active DACH-Pt anticancer species by biodegradable amphiphilic polymers using thiol-ene radical addition. AB - A biodegradable and amphiphilic copolymer, mPEG-b-P(LA-co-MAC/TMA) that contains pendant 1,2-bidentate carboxyl groups is synthesized by thiol-ene radical addition and is further used to chelate with the active anticancer species (DACH Pt) of oxaliplatin to form an mPEG-b-P(LA-co-MAC/TMA-Pt-DACH) complex. The polymer platinum complex can self-assemble into micelles. In vitro studies show that the DACH-Pt micelles display enhanced or comparable cytotoxicity against SKOV-3 and MCF-7 cancer cells, while they show reduced toxicity to HeLa cells compared with oxaliplatin. PMID- 22213517 TI - Distortion correction in EPI at ultra-high-field MRI using PSF mapping with optimal combination of shift detection dimension. AB - Despite its wide use, echo-planar imaging (EPI) suffers from geometric distortions due to off-resonance effects, i.e., strong magnetic field inhomogeneity and susceptibility. This article reports a novel method for correcting the distortions observed in EPI acquired at ultra-high-field such as 7 T. Point spread function (PSF) mapping methods have been proposed for correcting the distortions in EPI. The PSF shift map can be derived either along the nondistorted or the distorted coordinates. Along the nondistorted coordinates more information about compressed areas is present but it is prone to PSF ghosting artifacts induced by large k-space shift in PSF encoding direction. In contrast, shift maps along the distorted coordinates contain more information in stretched areas and are more robust against PSF-ghosting. In ultra-high-field MRI, an EPI contains both compressed and stretched regions depending on the B0 field inhomogeneity and local susceptibility. In this study, we present a new geometric distortion correction scheme, which selectively applies the shift map with more information content. We propose a PSF-ghost elimination method to generate an artifact-free pixel shift map along nondistorted coordinates. The proposed method can correct the effects of the local magnetic field inhomogeneity induced by the susceptibility effects along with the PSF-ghost artifact cancellation. We have experimentally demonstrated the advantages of the proposed method in EPI data acquisitions in phantom and human brain using 7-T MRI. PMID- 22213518 TI - Influence of earthworm activity on microbial communities related with the degradation of persistent pollutants. AB - Earthworms may promote the biodegradation of polycyclic aromatic hydrocarbons (PAHs) in soil, but the mechanism through which they exert such influence is still unknown. To determine if the stimulation of PAH degradation by earthworms is related to changes in microbial communities, a microcosm experiment was conducted consisting of columns with natural uncontaminated soil covered with PAH contaminated dredge sediment. Columns without and with low and high Eisenia andrei densities were prepared. Organic matter and PAH content, microbial biomass, and dehydrogenase activity (DHA) were measured in soil and sediment over time. Biolog EcoplateTM and polymerase chain reaction using denaturing gradient gel electrophoresis were used to evaluate changes in metabolic and structural diversity of the microbial community, respectively. Earthworm activity promoted PAH degradation in soil, which was significant for biphenyl, benzo[a]pyrene, and benzo[e]pyrene. Microbial biomass and DHA activity generally did not change over the experiment. Earthworm activity did change microbial community structure, but this did not affect its functioning in terms of carbon substrate consumption. Results suggest no relationship between changes in the microbial community by earthworm activity and increased PAH disappearance. The role of shifts in soil microbial community structure induced by earthworms in PAH removal needs further investigation. PMID- 22213519 TI - Altered association of interleukin-6 with sex steroids in lipid metabolism disorder in men with prostate cancer receiving androgen deprivation therapy. AB - BACKGROUND: Interleukin-6 produced in adipose tissue plays a role in lipid metabolism, and also interacts with sex steroids. This study was performed to elucidate the mechanism of lipid metabolism disorder during androgen deprivation therapy (ADT) in terms of the association of interleukin-6 with sex steroids. METHODS: Seventy-two patients with localized prostate cancer were prospectively studied based on their body-composition and blood samples before and after ADT for 6 months. RESULTS: Before ADT, serum interleukin-6 levels were inversely correlated with serum total-testosterone (rs = -0.305, P = 0.009) and dihydrotestosterone (rs = -0.380, P = 0.006) concentrations, but not correlated with adrenal androgen or estradiol levels. Pretreatment interleukin-6 levels were positively correlated with %body fat (rs = 0.349, P = 0.003) and %visceral fat (rs = 0.384, P = 0.001). After ADT, %body fat increased (P < 0.001) and lean body mass decreased (P = 0.036). After ADT, in contrast to the pretreatment relationship, interleukin-6 levels were positively correlated with total testosterone concentrations (rs = 0.343, P = 0.003), and were positively correlated also with levels of androstenedione (rs = 0.351, P = 0.002) and estoradiol (rs = 0.335, P = 0.004). Interleukin-6 levels were equivalent between before and after ADT (2.02 vs. 2.16 pg/ml, P = 0.205), but the positive correlation between interleukin-6 levels and %body or %visceral fat noted before ADT disappeared after ADT. CONCLUSIONS: Posttreatment interleukin-6 levels had a strong positive correlation with total-testosterone, androstenedione, and estradiol levels, suggesting that a regulation loop may emerge between these sex steroids and interleukin-6 during ADT. The altered association between interleukin-6 and sex steroids is possibly involved in ADT-related lipid metabolism disorder with unchanged interleukin-6 levels despite increased %body fat. PMID- 22213520 TI - Mechanism of action of cyclic oligosquaramides on DPPC phospholipid monolayers. PMID- 22213521 TI - Use of simulated annealing for the design of multiple repetition time balanced steady-state free precession imaging. AB - Balanced steady-state free precession is an ultrafast sequence with high signal to-noise efficiency, but it also generates a strong fat signal which can mask important features. One method of fat suppression is to modify the balanced steady-state free precession spectrum using multiple repetition times to create a wide stopband over the fat frequency. However, with three or more pulse repetition times, the number of parameters creates a vast search space with many local minima of a cost function. We report on the initial results of using simulated annealing to find optimal sequences for two applications of multiple pulse repetition time balanced steady-state free precession: positive contrast imaging and fat suppression. PMID- 22213522 TI - Triptycene diols: a strategy for synthesizing planar pi systems through catalytic conversion of a poly(p-phenylene ethynylene) into a poly(p-phenylene vinylene). PMID- 22213525 TI - Recent advances in amino acid analysis by capillary electrophoresis. AB - This paper describes the most important articles that have been published on amino acid analysis using CE during the period from June 2009 to May 2011 and follows the format of the previous articles of Smith (Electrophoresis 1999, 20, 3078-3083), Prata et al. (Electrophoresis 2001, 22, 4129-4138) and Poinsot et al. (Electrophoresis 2003, 24, 4047-4062; Electrophoresis 2006, 27, 176-194; Electrophoresis 2008, 29, 207-223; Electrophoresis 2010, 31, 105-121). We present new developments in amino acid analysis with CE, which are reported describing the use of lasers or light emitting diodes for fluorescence detection, conductimetry electrochemiluminescence detectors, mass spectrometry applications, and lab-on-a-chip applications using CE. In addition, we describe articles concerning clinical studies and neurochemical applications of these techniques. PMID- 22213523 TI - Interactions of multicationic bis(guanidiniocarbonylpyrrole) receptors with double-stranded nucleic acids: syntheses, binding studies, and atomic force microscopy imaging. AB - Compounds 1-3, composed of two guanidiniocarbonylpyrrole moieties linked by oligoamide bridges and differing in number and type of basic groups, were prepared. The sites and degree of protonation of 1-3 depend strongly on the pH value. The interactions of these compounds with several double-stranded (ds) DNA and dsRNA were investigated by means of UV/Vis and CD spectroscopy as well as isothermal titration microcalorimetry (ITC). These studies revealed that the binding of 1-3 to the polynucleotides is driven by three factors, the presence of aliphatic amino groups, the protonation state of the compounds, and the steric properties of the polynucleotide binding site, that is, the shape and structure of their grooves. The results obtained by all applied methods consistently indicated that receptors 1-3 bind to the minor groove of DNA, but, by contrast, to the major groove of RNA. Additionally, it was shown by atomic force microscopy (AFM) imaging that upon interaction of compound 2 with calf thymus (ct) DNA induced aggregation of the DNA occurs, leading to pronounced changes in its secondary structure. PMID- 22213526 TI - Recent advances in the application of CE to forensic sciences, an update over years 2009-2011. AB - The present article reviews and comments the applications of capillary electrophoresis in the different areas of forensic sciences covering the time from the second half of 2009 until the first part of 2011, being the latest update of previous reviews covering the years from 2001 to 2009. Numerous articles reporting applications of capillary electrophoresis to analytical problems of potential interest for the forensic researchers and scientists can be found in the most qualified journals of analytical chemistry, analytical biochemistry, pharmacology, toxicology, laboratory medicine, human genetics, etc. However, the present review has been focused on discussing only the most relevant examples of analytical applications of capillary electrophoretic and electrokinetic techniques published in the following fields: (i) illicit and abused drugs, (ii) ions and small molecules of forensic interest, (iii) proteins and peptides of forensic interest, (iv) dyes and inks, (v) forensic DNA. The present review collects and comments on 60 references. PMID- 22213530 TI - Air-stable, narrow-band-gap ambipolar C60 fullerene-hydrazone hybrid materials. AB - Fullerene-hydrazone dyads have been synthesized using the Confalone reaction followed by condensation with phenylhydrazines. Room-temperature xerographic time of-flight, ionization potential, and cyclic voltammetry measurements indicate that these narrow-band-gap (E(g)<1.5 eV), ambipolar charge-transporting dyads with balanced hole- and electron mobilities, which operate in air, are attractive materials for various optoelectronic applications. PMID- 22213531 TI - Slice-by-slice B1+ shimming at 7 T. AB - Parallel transmission has been used to reduce the inevitable inhomogeneous radiofrequency fields produced in human high-field MRI greater than 3 T. Further improvements in the transmit homogeneity and efficiency are possible by leveraging the additional degree of freedom permitted by multislice acquisitions. Compared to simple scaling of the flip angle to compensate for B1+ falloff along the radiofrequency coil, calculation of B1+ shim solutions on a slice-by-slice basis can markedly improve homogeneity and/or reduce transmitted power and global SAR. Performance measures were acquired at 7 T with a 15-channel head-only transceive array featuring elements distributed over all three logical axes, facilitating B1+ shimming over arbitrary orientations. Compared to a circularly polarized volume mode of the same coil, shimming to maximize excitation efficiency on a slice-by-slice basis yielded improvements in mean B1+ by 12.8+/ 2.4% and a reduction in standard deviation of B1+ of 16.3+/-6.8%, while reducing relative SAR by 6.2+/-3.1%. When shimming for greater uniformity, the mean and standard deviation of B1+ were further improved by 15.9+/-2.6% and 26.2+/-10.4%, respectively, at the expense of a 135+/-8% increase in global SAR. Robust multislice-shim solutions are demonstrated that can be quickly calculated, applied in real time, and reliably improve on volume coil modes. PMID- 22213532 TI - Phenolic compounds and anti-oxidant capacity of twelve morphologically heterogeneous bamboo species. AB - INTRODUCTION: Despite the growing interest in the use of bamboo for both food and health-related applications because it provides a rich source of anti-oxidants, there is still a lack of information on the responsible secondary metabolites of the great variety of bamboo species. OBJECTIVE: To extend the knowledge on secondary metabolites of different bamboo species and to link anti-oxidant capacity with the different classes of phenolic compounds that are present in the leaves. METHODOLOGY: Chromatographic profiles of 12 morphological heterogeneous bamboo species from different genera were recorded using HPLC-DAD (diode array detector) and LC-MS/MS. In addition, the in vitro anti-oxidant capacity was evaluated using a variety of anti-oxidant assays (1,1-diphenyl-2-picrylhydrazyl, Trolox-equivalent anti-oxidant capacity and oxygen radical absorbance capacity). Using partial least square (PLS) analysis as a chemometric method, the anti oxidant capacity could be linked to specific groups of polyphenols. RESULTS: Flavones and phenolic acids are the two main polyphenolic classes present in the leaf extracts of the 12 selected bamboo species. Luteolin derivatives and phenolic acids were identified as the most potent anti-oxidants. CONCLUSION: The most abundant classes of phenolic compounds present in a selection of bamboo species were flavone glycosides and phenolic acids. Luteolin flavones and phenolic acids are the main anti-oxidant phenolic compounds in bamboo leaf extract. The information obtained in this study provides further support for the development of bamboo-based anti-oxidant food applications and food supplements. PMID- 22213533 TI - Statistical approaches for conducting network meta-analysis in drug development. AB - We introduce health technology assessment and evidence synthesis briefly, and then concentrate on the statistical approaches used for conducting network meta analysis (NMA) in the development and approval of new health technologies. NMA is an extension of standard meta-analysis where indirect as well as direct information is combined and can be seen as similar to the analysis of incomplete block designs. We illustrate it with an example involving three treatments, using fixed-effects and random-effects models, and using frequentist and Bayesian approaches. As most statisticians in the pharmaceutical industry are familiar with SAS(r) software for analyzing clinical trials, we provide example code for each of the methods we illustrate. One issue that has been overlooked in the literature is the choice of constraints applied to random effects, and we show how this affects the estimates and standard errors and propose a symmetric set of constraints that is equivalent to most current practice. Finally, we discuss the role of statisticians in planning and carrying out NMAs and the strategy for dealing with important issues such as heterogeneity. PMID- 22213534 TI - Molecular mechanism of remodeling of autologous artery graft interposed to vein in rabbit. AB - Our previous study found that the artery interposed to vein did not develop atherosclerosis but rather underwent atrophic remodeling in hyperlipidemic rabbits, suggesting that local hemodynamic load was another important determinant for the development of atherosclerosis. This study focused on the cellular and molecular changes in autologous artery grafts derived from rabbits fed with high lipid diet for 1, 2, 4, 8, and 12 weeks. Thickness, area of vessel wall, and lumen area were measured and analyzed on the grafted common carotid artery (GCCA) interposed to vein and on the right common carotid artery. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling. Both elastin and collagen of GCCA were identified by the method of double stains of elastin and collagen. Reverse transcription polymerase chain reaction was used to observe matrix metalloproteinases (MMPs) mRNA expression changes in the examined arteries. The lumen area increased gradually in control common carotid artery and remained unchanged in GCCA 3 months later, since the surgery and the start of high lipid diet, while significantly increased apoptosis was evidenced from inner to outer part of GCCA. Collagen content decreased gradually and elastic fibers remained unchanged in GCCA. At 1 week after operation, the mRNA expression of MMP(2) and MMP(9) increased significantly and returned to baseline thereafter. The artery interposed to a vein underwent atrophy, characterized by increased apoptosis in the vessel wall from intima to adventitia, possibly due to low shear stress circumference and reduced vessel collagen resulting from postsurgical upregulated MMP(2) and MMP(9) expression. PMID- 22213535 TI - Ribose found in the gas phase. PMID- 22213536 TI - The UK Glow Worm Survey and the glow worm distribution map. PMID- 22213538 TI - On the Cl...N halogen bond: a rotational study of CF3Cl...NH3. AB - The rotational spectra of six isotopologues (CF(3)(35)Cl...(14)NH(3), CF(3)(37)Cl...(14)NH(3), CF(3)(35)Cl...(15)NH(3), CF(3)(37)Cl...(15)NH(3), CF(3)(35)Cl...(14)ND(3) and CF(3)(37)Cl...(14)ND(3)) of the CF(3)Cl...NH(3) adduct have been investigated and analyzed by pulsed jet Fourier transform microwave spectroscopy. Rotational, centrifugal distortion and quadrupole ((35)Cl, (37)Cl, (14)N) coupling constants have been precisely obtained. The two subunits of the complex are held together via a Cl...N halogen bond interaction. Information on the internal dynamics and on the dissociation energy of the complex is provided. PMID- 22213537 TI - Phosphofructokinase type 1 kinetics, isoform expression, and gene polymorphisms in cancer cells. AB - Kinetic analysis of PFK-1 from rodent AS-30D, and human HeLa and MCF-7 carcinomas revealed sigmoidal [fructose 6-phosphate, Fru6P]-rate curves with different V(m) values when varying the allosteric activator fructose 2,6 bisphosphate (Fru2,6BP), AMP, Pi, NH(4)(+), or K(+). The rate equation that accurately predicted this behavior was the exclusive ligand binding concerted transition model together with non-essential hyperbolic activation. PFK-1 from rat liver and heart also exhibited the mixed cooperative-hyperbolic kinetic behavior regarding activators. Lowering pH induced decreased affinity for Fru6P, Fru2,6BP, citrate, and ATP (as inhibitor); as well as decreased V(m) and increased content of inactive (T) enzyme forms. High K(+) prompted increased (Fru6P) or decreased (activators) affinities; increased V(m); and increased content of active (R) enzyme forms. mRNA expression analysis and nucleotide sequencing showed that the three PFK-1 isoforms L, M, and C are transcribed in the three carcinomas. However, proteomic analysis indicated the predominant expression of L in liver, of M in heart and MCF-7 cells, of L>M in AS-30D cells, and of C in HeLa cells. PFK-1M showed the highest affinities for F6P and citrate and the lowest for ATP (substrate) and F2,6BP; PFK-1L showed the lowest affinity for F6P and the highest for F2,6BP; and PFK-1C exhibited the highest affinity for ATP (substrate) and the lowest for citrate. Thus, the present work documents the kinetic signature of each PFK-1 isoform, and facilitates the understanding of why this enzyme exerts significant or negligible glycolysis flux-control in normal or cancer cells, respectively, and how it regulates the onset of the Pasteur effect. PMID- 22213539 TI - Transferable crosslinked chitosan membranes for human melanocyte culture. AB - Development of transferable biocompatible membranes, which can be used for melanocyte culture and transplantation, is considered a feasible approach to increase the success rate for vitiliginous treatment. In this study, a crosslinked chitosan membrane (CCM) was produced via physical crosslinking of chitosan with sodium sulfate. The physical and mechanical properties as well as growth and phenotype expression of melanocytes on the CCM were investigated. The CCM supported growth and proliferation of melanocytes with the existence of melanin granules in the cytoplasm. The melanocytes remained active after transplantation. The CCM absorbed water approximately doubled from its original weight and permitted ~2400 g/m2 per day of water vapor transmission, suggesting that the CCM can function as an efficient wound dressing. Dynamic mechanical and tensile measurement results showed that the CCM possessed favorable wet strength for cell culture, separation, transfer, and transplantation application. This transferable CCM has the potential to be applied for vitiligo treatment. PMID- 22213540 TI - One-electron oxidized copper(II) salophen complexes: phenoxyl versus diiminobenzene radical species. PMID- 22213541 TI - Deep-tissue photoacoustic tomography of a genetically encoded near-infrared fluorescent probe. PMID- 22213542 TI - Surgical resection for clinical perineural invasion from cutaneous squamous cell carcinoma of the head and neck. AB - BACKGROUND: Perineural invasion (PNI) in cutaneous squamous cell carcinoma of the head and neck (SCCHN) is associated with decreased survival. Patients with large nerve or clinical PNI present with clinical signs and symptoms or MRI evidence of cranial nerve involvement. These patients often succumb to disease that spreads into the brainstem. In our experience, when the disease extends up to the Gasserian or Geniculate ganglion, surgical resection with negative margins provides the best chance for cure. Herein we review our experience to validate our clinical observations. METHODS: We identified patients with large nerve PNI from cutaneous SCCHN between January 1996 and 2006 from a prospectively collected database. Patients who underwent surgical resection as their primary mode of therapy were included. Clinical and demographic variables were recorded. Survival analysis was performed with Kaplan-Meier curves, and the log-rank test was used for significance testing between groups. RESULTS: Twenty-one patients were identified. The mean age was 60 (range, 38-86) years, with 15 men and 6 women. Nineteen patients had a formal skull base resection, whereas 2 patients had a subcranial resection. We had 3 complications in our series: extradural hemorrhage (n = 1), cerebrospinal fluid leak (n = 1), and wound infection (n = 1). None of the patients who underwent a formal skull base resection to include the lateral cavernous sinus (ie, Gasserian ganglion) suffered ocular palsies or permanent morbidity when the orbit was preserved (n = 11). We had no surgical deaths. The average length of stay was 9 days (SD 6.3 days). The 5-year disease specific survival rate for the entire group was 64.3%. V3 involvement resulted in lower, although not significant, 5-year disease-free survival rates- 0% for those patients with involvement (n = 4) versus 66.8% for no involvement of V3 (n = 17). CONCLUSION: Appropriately planned surgical resection of PNI in cutaneous SCCHN up to the ganglion as dictated by the disease extent may improve survival without significant added morbidity. PMID- 22213543 TI - Camps 2.0: exploring the sequence and structure space of prokaryotic, eukaryotic, and viral membrane proteins. AB - Structural bioinformatics of membrane proteins is still in its infancy, and the picture of their fold space is only beginning to emerge. Because only a handful of three-dimensional structures are available, sequence comparison and structure prediction remain the main tools for investigating sequence-structure relationships in membrane protein families. Here we present a comprehensive analysis of the structural families corresponding to alpha-helical membrane proteins with at least three transmembrane helices. The new version of our CAMPS database (CAMPS 2.0) covers nearly 1300 eukaryotic, prokaryotic, and viral genomes. Using an advanced classification procedure, which is based on high-order hidden Markov models and considers both sequence similarity as well as the number of transmembrane helices and loop lengths, we identified 1353 structurally homogeneous clusters roughly corresponding to membrane protein folds. Only 53 clusters are associated with experimentally determined three-dimensional structures, and for these clusters CAMPS is in reasonable agreement with structure-based classification approaches such as SCOP and CATH. We therefore estimate that ~1300 structures would need to be determined to provide a sufficient structural coverage of polytopic membrane proteins. CAMPS 2.0 is available at http://webclu.bio.wzw.tum.de/CAMPS2.0/. PMID- 22213544 TI - An accurate pharmacophore mapping method by NMR spectroscopy. PMID- 22213545 TI - Optimal case definitions of upper extremity disorder for use in the clinical treatment and referral of patients. AB - OBJECTIVE: Experts disagree about the optimal classification of upper extremity disorders. To explore whether differential response to treatments offers a basis for choosing between case definitions, we analyzed previously published research. METHODS: We screened 183 randomized controlled trials (RCTs) of treatments for upper extremity disorders identified from the bibliographies of 10 Cochrane reviews and 4 other systematic reviews, and a search in Medline, Embase, and Google Scholar to June 2010. From these, we selected RCTs that allowed estimates of benefit (expressed as relative risks [RRs]) for >1 case definition to be compared when other variables (treatment, comparison group, followup time, outcome measure) were effectively held constant. Comparisons of RRs for paired case definitions were summarized by their ratios, with the RR for the simpler and broader definition as the denominator. RESULTS: Two RCT reports allowed within trial comparison of RRs and 13 others allowed between-trial comparisons. Together these provided 17 ratios of RRs (5 for shoulder treatments, 12 for elbow treatments, and none for wrist/hand treatments). The median ratio of RRs was 1.0 (range 0.3-1.7, interquartile range 0.6-1.3). CONCLUSION: Although the evidence base is limited, our findings suggest that for musculoskeletal disorders of the shoulder and elbow, clinicians in primary care will often do best to apply simpler and broader case definitions. Researchers should routinely publish secondary analyses for subgroups of patients by different diagnostic features at trial entry to expand the evidence base on optimal case definitions for patient management. PMID- 22213546 TI - Non-virally modified human mesenchymal stem cells produce ciliary neurotrophic factor in biodegradable fibrin-based 3D scaffolds. AB - We report the adaptation of dendrimer-based nonviral expression system for ciliary neurotrophic factor (CNTF) overproduction in human mesenchymal stem cells (hMSCs) embedded into fibrin-based three-dimensional (3D) matrix. Time-restricted neurotrophin expression enables autologous adult stem cells for additional trophic support and increases their therapeutic potential in neuroregeneration applications. Polyamidoamine (PAMAM)-NH(2) dendrimers of fourth generation effectively provided virus-free delivery and expression of CNTF-internal ribosome entry site-green fluorescent protein cassette with a transfection efficiency in hMSCs over 11%. CNTF levels in transfected cultures were 10-fold higher as compared with the control cells. Dendrimer-driven CNTF expression also persisted in hMSCs embedded into fibrin-based 3D matrix, an emerging vehicle for cell delivery or bioartificial organ formation. Nonviral modification of autologous adult stem cells with use of dendrimers is a novel tool perspective in terms of biosafety and technological availability. PMID- 22213547 TI - Electroactive electrospun polyaniline/poly[(L-lactide)-co-(epsilon-caprolactone)] fibers for control of neural cell function. AB - Blends of PAni and PLCL are electrospun to prepare uniform fibers for the development of electrically conductive, engineered nerve grafts. PC12 cell viability is significantly higher on RPACL fibers than on PLCL-only fibers, and the electrical conductivity of the fibers affects the differentiation of PC12 cells; the number of cells positively-stained and their expression level are significantly higher on RPACL fibers. PC12 cell bodies display an oriented morphology with outgrowing neurites. On RPACL fibers, the expression level of paxillin, cdc-42, and rac is positively affected and proteins including RhoA and ERK exist as more activated state. These results suggest that electroactive fibers may hold promise as a guidance scaffold for neuronal tissue engineering. PMID- 22213548 TI - Controlled deposition of a high-performance small-molecule organic single-crystal transistor array by direct ink-jet printing. AB - Ink-jet printed small-molecule organic single-crystal transistors are realized by using selective surface energy modification, precise control of volume density of ink droplets on spatially patterned areas, and a co-solvent system to control solvent evaporation properties. The single-crystal formation in bottom-contact structured transistors via direct printing is expected to permit high-density array fabrication in large-area electronics. PMID- 22213549 TI - An automated analysis of highly complex flow cytometry-based proteomic data. AB - The combination of color-coded microspheres as carriers and flow cytometry as a detection platform provides new opportunities for multiplexed measurement of biomolecules. Here, we developed a software tool capable of automated gating of color-coded microspheres, automatic extraction of statistics from all subsets and validation, normalization, and cross-sample analysis. The approach presented in this article enabled us to harness the power of high-content cellular proteomics. In size exclusion chromatography-resolved microsphere-based affinity proteomics (Size-MAP), antibody-coupled microspheres are used to measure biotinylated proteins that have been separated by size exclusion chromatography. The captured proteins are labeled with streptavidin phycoerythrin and detected by multicolor flow cytometry. When the results from multiple size exclusion chromatography fractions are combined, binding is detected as discrete reactivity peaks (entities). The information obtained might be approximated to a multiplexed western blot. We used a microsphere set with >1,000 subsets, presenting an approach to extract biologically relevant information. The R-project environment was used to sequentially recognize subsets in two-dimensional space and gate them. The aim was to extract the median streptavidin phycoerythrin fluorescence intensity for all 1,000+ microsphere subsets from a series of 96 measured samples. The resulting text files were subjected to algorithms that identified entities across the 24 fractions. Thus, the original 24 data points for each antibody were compressed to 1-4 integrated values representing the areas of individual antibody reactivity peaks. Finally, we provide experimental data on cellular protein changes induced by treatment of leukemia cells with imatinib mesylate. The approach presented here exemplifies how large-scale flow cytometry data analysis can be efficiently processed to employ flow cytometry as a high content proteomics method. PMID- 22213550 TI - Diffusion--the hidden menace in organic optoelectronic devices. PMID- 22213551 TI - Quasi-static magnetic resonance elastography at 7 T to measure the effect of pathology before and after fixation on tissue biomechanical properties. AB - Evaluation of imaging for cancer detection and localization can be achieved by correlation of gold-standard histopathology with imaging data. Usage of a 3D biomechanical-based deformable registration for correlation of the histopathology of whole-tissue specimens with ex vivo imaging necessitates measurement of the distribution of biomechanical properties in the ex vivo tissue specimen and changes that occur during pathology fixation. To measure high-resolution 3D distributions of Young's modulus (E) prefixation and postfixation, a quasi-static magnetic resonance elastography method was developed at 7 T. Use of echo-planar imaging allowed for shorter imaging times, in line with limited time frames allowable for pathology specimens. The finite element modeling algorithm produced voxel-wise E measures, and mechanical indentation was used for comparison. An initial preclinical evaluation with canine prostate specimens (n = 5) demonstrated a consistent increase in E with fixation (P < 0.002) by a factor of 4 (+/- 1). Increases were a function of distance from the tissue edge and correlated with fixation time (rho = 1, P < 0.02). The technique will be used to generate population-averaged data of E from clinical ex vivo specimens prefixation and postfixation to inform registration of whole-mount histopathology with in vivo imaging. PMID- 22213552 TI - Long-range transport of giant vesicles along microtubule networks. AB - We report on a minimal system to mimic intracellular transport of membrane bounded, vesicular cargo. In a cell-free assay, purified kinesin-1 motor proteins were directly anchored to the membrane of giant unilamellar vesicles, and their movement studied along two-dimensional microtubule networks. Motion-tracking of vesicles with diameters of 1-3 MUm revealed traveling distances up to the millimeter range. The transport velocities were identical to velocities of cargo free motors. Using total internal reflection fluorescence (TIRF) microscopy, we were able to estimate the number of GFP-labeled motors involved in the transport of a single vesicle. We found that the vesicles were transported by the cooperative activity of typically 5-10 motor molecules. The presented assay is expected to open up further applications in the field of synthetic biology, aiming at the in vitro reconstitution of sub-cellular multi-motor transport systems. It may also find applications in bionanotechnology, where the controlled long-range transport of artificial cargo is a promising means to advance current lab-on-a-chip systems. PMID- 22213553 TI - Enantioselective degradation of tebuconazole in cabbage, cucumber, and soils. AB - The enantioselective degradation of tebuconazole has been investigated to elucidate the behaviors in agricultural soils, cabbage, and cucumber fruit. Rac tebuconazole was fortified into three types of agricultural soils and sprayed foliage of cabbage and cucumber, respectively. The degradation kinetics, enantiomer fraction and enantiomeric selectivity were determined by reverse-phase high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) on a Lux amylose-2 chiral column. The process of the degradation of tebuconazole enantiomers followed first-order kinetic in the test soils and vegetables. It has been shown that the degradation of tebuconazole was enantioselective. The results indicated that the (+)-S tebuconazole showed a faster degradation in cabbage, while the (-)-R-tebuconazole dissipated faster than (+)-S-form in cucumber fruit and the test soils. PMID- 22213554 TI - Recommendations for mass spectrometry data quality metrics for open access data (corollary to the Amsterdam principles). AB - Policies supporting the rapid and open sharing of proteomic data are being implemented by the leading journals in the field. The proteomics community is taking steps to ensure that data are made publicly accessible and are of high quality, a challenging task that requires the development and deployment of methods for measuring and documenting data quality metrics. On September 18, 2010, the U.S. National Cancer Institute (NCI) convened the "International Workshop on Proteomic Data Quality Metrics" in Sydney, Australia, to identify and address issues facing the development and use of such methods for open access proteomics data. The stakeholders at the workshop enumerated the key principles underlying a framework for data quality assessment in mass spectrometry data that will meet the needs of the research community, journals, funding agencies, and data repositories. Attendees discussed and agreed up on two primary needs for the wide use of quality metrics: (i) an evolving list of comprehensive quality metrics and (ii) standards accompanied by software analytics. Attendees stressed the importance of increased education and training programs to promote reliable protocols in proteomics. This workshop report explores the historic precedents, key discussions, and necessary next steps to enhance the quality of open access data. By agreement, this article is published simultaneously in Proteomics, Proteomics Clinical Applications, Journal of Proteome Research, and Molecular and Cellular Proteomics, as a public service to the research community. The peer review process was a coordinated effort conducted by a panel of referees selected by the journals. PMID- 22213561 TI - Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011. PMID- 22213560 TI - Inhibition of platelet-derived growth factor receptor signaling regulates Oct4 and Nanog expression, cell shape, and mesenchymal stem cell potency. AB - Defining the signaling mechanisms that regulate the fate of adult stem cells is an essential step toward their use in regenerative medicine. Platelet-derived growth factor receptor (PDGFR) signaling plays a crucial role in specifying mesenchymal stem cell (MSC) commitment to mesenchymal lineages. Based on the hypothesis that selective inhibition of signaling pathways involved in differentiation may increase stem cell potency, we examined the role of PDGFR signaling in controlling the fate of human MSCs. Using a small molecular PDGFR inhibitor that induced MSCs toward a more rounded shape, expression of Oct4 and Nanog were markedly upregulated. In these PDGFR inhibitor-treated MSCs, Oct4 and Nanog expression and cell shape were regulated by janus kinase (JAK), MAPK kinase (MEK), and epidermal growth factor receptor (EGFR) signaling. Under defined differentiation conditions, these PDGFR-inhibited MSCs expressed definitive endodermal, ectodermal, and mesodermal markers. We also confirmed that depletion of individual PDGF receptors upregulated expression of Oct4A and Nanog. This study identifies PDGFR signaling as a key regulator of Oct4 and Nanog expression and of MSC potency. Thus, inhibiting these specific receptor tyrosine kinases, which play essential roles in tissue formation, offers a novel approach to unlock the therapeutic capacity of MSCs. PMID- 22213562 TI - Solution structure of the splicing factor motif of the human Prp18 protein. PMID- 22213563 TI - Pre-organization of the core structure of E-selectin antagonists. AB - A new class of N-acetyl-D-glucosamine (GlcNAc) mimics for E-selectin antagonists was designed and synthesized. The mimic consists of a cyclohexane ring substituted with alkyl substituents adjacent to the linking position of the fucose moiety. Incorporation into E-selectin antagonists led to the test compounds 8 and the 2'-benzoylated analogues 21, which exhibit affinities in the low micromolar range. By using saturation transfer difference (STD)-NMR it could be shown that the increase in affinity does not result from an additional hydrophobic contact of the alkyl substituent with the target protein E-selectin, but rather from a steric effect stabilizing the antagonist in its bioactive conformation. The loss of affinity found for antagonists 10 and 35 containing a methyl substituent in a remote position (and therefore unable to support to the stabilization of the core) further supports this hypothesis. Finally, when a GlcNAc mimetic containing two methyl substituents (52 and 53) was used, in which one methyl was positioned adjacent to the fucose linking position and the other was in a remote position, the affinity was regained. PMID- 22213564 TI - Biological plasticity in penguin heat-retention structures. AB - Insulation and vascular heat-retention mechanisms allow penguins to forage for a prolonged time in water that is much cooler than core body temperature. Wing based heat retention involves a plexus of humeral arteries and veins, which redirect heat to the body core rather than to the wing periphery. The humeral arterial plexus is described here for Eudyptes and Megadyptes, the only extant penguin genera for which wing vascular anatomy had not previously been reported. The erect-crested (Eudyptes sclateri) and yellow-eyed (Megadyptes antipodes) penguins both have a plexus of three humeral arteries on the ventral surface of the humerus. The wing vascular system shows little variation between erect crested and yellow-eyed penguins, and is generally conserved across the six extant genera of penguins, with the exception of the humeral arterial plexus. The number of humeral arteries within the plexus demonstrates substantial variation and correlates well with wing surface area. Little penguins (Eudyptula minor) have two humeral arteries and a wing surface area of ~ 75 cm(2) , whereas emperor penguins (Aptenodytes forsteri) have up to 15 humeral arteries and a wing surface area of ~ 203 cm(2) . Further, the number of humeral arteries has a stronger correlation with wing surface area than with sea water temperature. We propose that thermoregulation has placed the humeral arterial plexus under a strong selection pressure, driving penguins with larger wing surface areas to compensate for heat loss by developing additional humeral arteries. PMID- 22213565 TI - Bisphosphonate-decorated lipid nanoparticles designed as drug carriers for bone diseases. AB - A conjugate of distearoylphosphoethanolamine-polyethylene glycol with 2-(3 mercaptopropylsulfanyl)-ethyl-1,1-bisphosphonic acid (thiolBP) was synthesized and incorporated into micelles and liposomes to create mineral-binding nanocarriers for therapeutic agents. The micelles and liposomes were used to encapsulate the anticancer drug doxorubicin (DOX) and a model protein lysozyme (LYZ) by using lipid film hydration (LFH) and reverse-phase evaporation vesicle (REV) methods. The results indicated that the micelles and LFH-derived liposomes were better at DOX loading than the REV-derived liposomes, while the REV method was preferable for encapsulating LYZ. The affinity of the micellar and liposomal formulations to hydroxyapatite (HA) was assessed in vitro, and the results indicated that all the thiolBP-incorporated nanocarriers had stronger HA affinity than their counterparts without thiolBP. The thiolBP-decorated liposomes also displayed a strong binding to a collagen/HA composite scaffold in vitro. More importantly, thiolBP-decorated liposomes gave increased retention in the collagen/HA scaffolds after subcutaneously implantation in rats. The designed liposomes were able to entrap the bone morphogenetic protein-2 in a bioactive form, indicating that the proposed nanocarriers could deliver bioactive factors locally in mineralized scaffolds for bone tissue engineering. PMID- 22213566 TI - Locoregional MYCN-amplified neuroblastoma. AB - MYCN-amplification is strongly associated with other high-risk prognostic factors and poor outcome in neuroblastoma. Infrequently, amplification of MYCN has been identified in localized tumors with favorable biologic features. Outcome for these children is difficult to predict and optimal treatment strategies remain unclear. We report a 5-month-old who presented with an MYCN-amplified INSS stage 3, pelvic neuroblastoma. The tumor had favorable histology, hyperdiploidy, and lacked 1p36 and 11q23 aberrations. Although the patient met the criteria for high risk neuroblastoma, because of the discordant prognostic markers we elected to treat her according to an intermediate-risk protocol. She remains event-free more than 18 months. PMID- 22213567 TI - View angle tilting echo planar imaging for distortion correction. AB - Geometric distortion caused by field inhomogeneity along the phase-encode direction is one of the most prominent artifacts due to a relatively low effective bandwidth along that direction in magnetic resonance echo planar imaging. This work describes a method for correcting in-plane image distortion along the phase-encode direction using a view angle tilting imaging technique in spin-echo echo planar imaging. Spin-echo echo planar imaging with view angle tilting uses the addition of gradient blips along the slice-select direction, concurrently applied with the phase-encode gradient blips, producing an additional phase. This phase effectively offsets an unwanted phase accumulation caused by field inhomogeneity, resulting in the removal of image distortion along the phase-encode direction. The proposed method is simple and straightforward both in implementation and application with no scan time penalty. Therefore, it is readily applicable on commercial scanners without having any customized postprocessing. The efficacy of the spin-echo echo planar imaging with view angle tilting technique in the correction of image distortion is demonstrated in phantom and in vivo brain imaging. PMID- 22213568 TI - Controlled cell proliferation on an electrochemically engineered collagen scaffold. AB - Therapies for corneal disease and injury often rely on artificial implants, but integrating cells into synthetic corneal materials remains a significant challenge. The electrochemically formed collagen-based matrix presented here is non-toxic to cells and controls the proliferation in the corneal fibroblasts seeded onto it. Histology and biomolecular studies show a behavior similar to corneal stromal cells in a native corneal environment. Not only is this result an important first step toward developing a more realistic, multi-component artificial cornea, but it also opens possibilities for using this matrix to control and contain the growth of cells in engineered tissues. PMID- 22213569 TI - Towards an efficient protocol for the determination of triterpenic acids in olive fruit: a comparative study of drying and extraction methods. AB - INTRODUCTION: Triterpenic acids, such as maslinic acid and oleanolic acid, are commonly found in olive fruits and have been associated with many health benefits. The drying and extraction methods, as well as the solvents used, are critical factors in the determination of their concentration in plant tissues. Thus, there is an emerging need for standardisation of an efficient extraction protocol that determines triterpenic acid content in olive fruits. OBJECTIVE: To evaluate common extraction methods of triterpenic acids from olive fruits and to determine the effect of the drying method on their content in order to propose an optimum protocol for their quantification. METHODOLOGY: The efficacy of different drying and extraction methods was evaluated through the quantification of maslinic acid and oleanolic acid contents using the reversed-phase HPLC technique. RESULTS: Data showed that ultrasonic assisted extraction with ethanol or a mixture of ethanol:methanol (1:1, v/v) resulted in the recovery of significantly higher amounts of triterpenic acids than other methods used. The drying method also affected the estimated triterpenic acid content; frozen or lyophilised olive fruit material gave higher yields of triterpenic acids compared with air-dried material at both 35 degrees C and 105 degrees C. CONCLUSION: This study provides a rapid and low-cost extraction method, i.e. ultrasonic assisted extraction with an eco-friendly solvent such as ethanol, from frozen or lyophilised olive fruit for the accurate determination of the triterpenic acid content in olive fruit. PMID- 22213570 TI - A cyclodextrin-based nanoassembly with bimodal photodynamic action. AB - We have developed a supramolecular nanoassembly capable of inducing remarkable levels of cancer cell mortality through a bimodal action based on the simultaneous photogeneration of nitric oxide (NO) and singlet oxygen ((1)O(2)). This was achieved through the appropriate incorporation of an anionic porphyrin (as (1)O(2) photosensitizer) and of a tailored NO photodonor in different compartments of biocompatible nanoparticles based on cationic amphiphilic cyclodextrins. The combination of steady-state and time-resolved spectroscopic techniques showed the absence of significant intra- and interchromophoric interaction between the two photoactive centers embedded in the nanoparticles, with consequent preservation of their photodynamic properties. Photodelivery of NO and (1)O(2) from the nanoassembly on visible light excitation was unambiguously demonstrated by direct and real-time monitoring of these transient species through amperometric and time-resolved infrared luminescence measurements, respectively. The typical red fluorescence of the porphyrin units was essentially unaffected in the bichromophoric nanoassembly, allowing its localization in living cells. The convergence of the dual therapeutic action and the imaging capacities in one single structure makes this supramolecular architecture an appealing, multifunctional candidate for applications in biomedical research. PMID- 22213571 TI - A novel Ly6C/Ly6G-based strategy to analyze the mouse splenic myeloid compartment. AB - Currently, there is no standardized panel for immunophenotyping myeloid cells in mouse spleen using flow cytometry. Markers such as CD11b, CD11c, F4/80, Gr-1, Ly6C, and Ly6G have long been used to identify various splenic cell myeloid populations. Flow cytometry and fluorescence-activated cell sorting (FACS) analysis demonstrated that Ly6G/Ly6C markers are superior to Gr-1 for identifying splenic neutrophils, eosinophils, and subsets of monocytes/macrophages. Moreover, these experiments showed that F4/80 is not required for identifying these myeloid subsets and that many of the commercially available preparations of anti-F4/80 antibodies stain poorly for this antigen in spleen. Taken together, we have now developed an informative flow cytometry panel that can be combined with other cell markers to further delineate subpopulations of mouse splenic myeloid cells. This panel will be highly useful to investigators in the flow cytometry field, as there is a critical need to standardize the analysis of myeloid cell subsets. PMID- 22213572 TI - Origin of low CO2 selectivity on platinum in the direct ethanol fuel cell. PMID- 22213573 TI - American College of Physicians Ethics Manual: sixth edition. AB - Medicine, law, and social values are not static. Reexamining the ethical tenets of medicine and their application in new circumstances is a necessary exercise. The sixth edition of the American College of Physicians (ACP) Ethics Manual covers emerging issues in medical ethics and revisits older ones that are still very pertinent. It reflects on many of the ethical tensions in medicine and attempts to shed light on how existing principles extend to emerging concerns. In addition, by reiterating ethical principles that have provided guidance in resolving past ethical problems, the Manual may help physicians avert future problems. The Manual is not a substitute for the experience and integrity of individual physicians, but it may serve as a reminder of the shared duties of the medical profession. PMID- 22213574 TI - A formulation strategy for gamma secretase inhibitor ELND006, a BCS class II compound: development of a nanosuspension formulation with improved oral bioavailability and reduced food effects in dogs. AB - ELND006 is a novel gamma secretase inhibitor previously under investigation for the oral treatment of Alzheimer's disease. ELND006 shows poor solubility and has moderate to high permeability, suggesting it is a Biopharmaceutics Classification System Class II compound. The poor absolute oral bioavailability of the compound in fasted dogs (F ~11%) is attributed to poor aqueous solubility. In addition, inhibiting amyloid precursor protein but not Notch cleavage is an important goal for gamma secretase inhibitors; therefore, significant variation in bioavailability resulting from food consumption is a potential liability for this class of compounds. The objective of the present study was to determine if an ELND006 nanocrystalline formulation would offer improved and predictable pharmacokinetics. ELND006 was formulated as a nanosuspension with a mean particle size of less than 200 nm, which was stable in particle size and crystallinity for over 1 year. In addition, ELND006 nanosuspension exhibited rapid dissolution in comparison with reference active pharmaceutical ingredient (API). The in vivo performance of the ELND006 nanosuspension was tested in fed and fasted beagle dogs and compared with a gelatin capsule containing reference API. The results show that nanosizing ELND006 profoundly improved the oral bioavailability and virtually eliminated variation resulting from food intake. PMID- 22213575 TI - Are survivors of childhood cancer with an unfavourable psychosocial developmental trajectory more likely to apply for disability benefits? AB - BACKGROUND: The aim of this study was to investigate whether an unfavourable psychosocial developmental trajectory while growing up with childhood cancer is related to a smaller likelihood of labour participation in adult life. METHODS: A total of 53 childhood cancer survivors (CCS) with and 313 CCS without disability benefits, and 508 peers from the general Dutch population (reference group) completed the Course of Life Questionnaire (CoLQ) about the achievement of psychosocial developmental milestones. Differences between the three groups were tested by conducting analysis of variance with contrasts (scale scores CoLQ) and logistic regression analysis (individual milestones). Effect sizes and odds ratios were calculated. RESULTS: Compared with the reference group, both CCS with and CCS without benefits reported lower scale scores with respect to social and psychosexual development. CCS with disability benefits had lower social (d = - 0.6; p < 0.001) and psychosexual (d = -0.4; p < 0.01) scale scores than the CCS without disability benefits. CCS with disability benefits scored less favourably (p < 0.01) than peers from the general population on 14 out of 22 psychosocial milestones whereas the number was only six for those without disability benefits. CONCLUSIONS: CCS with an unfavourable developmental trajectory while growing up were more likely to apply for disability benefits in adulthood than CCS with a more favourable development. Early recognition and support are warranted. Further research is needed on risk factors of application for disability benefits. In addition, research should show whether stimulating the achievement of developmental milestones while growing up will create conditions for a better labour market position. PMID- 22213576 TI - Associations between frontal plane joint stiffness and proprioceptive acuity in knee osteoarthritis. AB - OBJECTIVE: It has been proposed that proprioceptive impairments observed in knee osteoarthritis (OA) may be associated with disease-related changes in joint mechanics. The aim of this study was to quantify joint proprioception and stiffness in the frontal plane of the knee in persons with and without knee OA and to report the associations between these 2 metrics. METHODS: Participants were 13 patients with knee OA and 14 healthy age-matched subjects. Proprioceptive acuity was assessed in varus and valgus using the threshold to detection of passive movement (TDPM) test. Passive joint stiffness was estimated as the slope of the normalized torque-angle relationship at 0 degrees joint rotation (neutral) and several rotations in varus and valgus. Analyses of variance were performed to determine the effect of OA and sex on each metric. Linear regression was used to assess the correlation between the TDPM and joint stiffness. RESULTS: The TDPM was significantly higher (P < 0.05) in the OA group compared to the control group for both varus and valgus, but significant sex differences were observed. Passive joint stiffness was significantly reduced (P < 0.05) in OA participants compared to the control group in neutral and valgus, but not varus, and significantly reduced in women compared to men. A weak negative correlation was observed between the TDPM and stiffness estimates, suggesting that poorer proprioception was associated with less joint stiffness. CONCLUSION: While both joint stiffness and proprioception were reduced in the OA population, they were only weakly correlated. This suggests that other neurophysiologic factors play a larger role in the proprioceptive deficits in knee OA. PMID- 22213577 TI - Simple, fast, bright, and stable light sources. AB - In this work we show that solution-processed light-emitting electrochemical cells (LECs) based on only an ionic iridium complex and a small amount of ionic liquid exhibit exceptionally good performances when applying a pulsed current: sub second turn-on times and almost constant high luminances (>600 cd m(-2) ) and power efficiencies over the first 600 h. This demonstrates the potential of LECs for applications in solid-state signage and lighting. PMID- 22213579 TI - On the accuracy of DFT methods in reproducing ligand substitution energies for transition metal complexes in solution: the role of dispersive interactions. AB - The performance of a series of density functionals when tested on the prediction of the phosphane substitution energy of transition metal complexes is evaluated. The complexes Fe-BDA and Ru-COD (BDA=benzylideneacetone, COD=cyclooctadiene) serve as reference systems, and calculated values are compared with the experimental values in THF as obtained from calorimetry. Results clearly indicate that functionals specifically developed to include dispersion interactions usually outperform other functionals when BDA or COD substitution is considered. However, when phosphanes of different sizes are compared, functionals including dispersion interactions, at odd with experimental evidence, predict that larger phosphanes bind more strongly than smaller phosphanes, while functionals not including dispersion interaction reproduce the experimental trends with reasonable accuracy. In case of the DFT-D functionals, inclusion of a cut-off distance on the dispersive term resolves this issue, and results in a rather robust behavior whatever ligand substitution reaction is considered. PMID- 22213578 TI - Volumetric navigators for prospective motion correction and selective reacquisition in neuroanatomical MRI. AB - We introduce a novel method of prospectively compensating for subject motion in neuroanatomical imaging. Short three-dimensional echo-planar imaging volumetric navigators are embedded in a long three-dimensional sequence, and the resulting image volumes are registered to provide an estimate of the subject's location in the scanner at a cost of less than 500 ms, ~ 1% change in contrast, and ~3% change in intensity. This time fits well into the existing gaps in sequences routinely used for neuroimaging, thus giving a motion-corrected sequence with no extra time required. We also demonstrate motion-driven selective reacquisition of k-space to further compensate for subject motion. We perform multiple validation experiments to evaluate accuracy, navigator impact on tissue intensity/contrast, and the improvement in final output. The complete system operates without adding additional hardware to the scanner and requires no external calibration, making it suitable for high-throughput environments. PMID- 22213581 TI - Synthesis and HPLC chiral recognition of regioselectively carbamoylated cellulose derivatives. AB - Four regioselective-carbamoylated cellulose derivatives having two different substituents at 2-, 3-, and 6-position were prepared and evaluated as chiral stationary phases (CSPs) for high-performance liquid chromatography. Investigations showed that the nature and arrangement of the substituents significantly influenced the chiral recognition abilities of the heterosubstituted cellulose derivatives and each derivative exhibited characteristic enantioseparation. Some racemates were better resolved on these derivatives than the corresponding homogeneously substituted cellulose derivatives including a commercial CSP, Chiralcel OD. Racemic compounds shown in this study were most effectively discriminated on cellulose 2,3-(3-chloro-4 methylphenylcarbamate)-6-(3,5-dimethylphenylcarbamate) and 2,3-(3,5 dimethylphenylcarbamate)-6-(3-chloro-4-methylphenylcarbamate). PMID- 22213582 TI - "The quest for biomarkers": are we on the right technical track? AB - The discovery phase of biomarkers of diagnostic or therapeutic interest started a decade ago with the very rapid development of proteomic investigations. In spite of the development of innovative technologies and multiple approaches, the "harvest" is still modest. Various reasons justified the encountered difficulties and most of them have been circumvented by specific sample treatments or dedicated analytical approaches. Nevertheless, the situation of very modest biomarker discovery level did not change much. This review intends to specifically analyze the main approaches used for biomarker discovery phase and evaluate related advantages and disadvantages. Thus, preliminary sample treatments such as fractionation, depletion and reduction of dynamic concentration range will critically be discussed and then the main differential expression investigation methods analyzed. Combinations of technologies are also discussed along with possible proposals to federate associations of complementary technologies for better chances of success. PMID- 22213583 TI - Developmental expression pattern of Hspb8 mRNA in the mouse brain: analysis through online databases. AB - Hspb8 is a member of the Hspb family of chaperone-like proteins. It is involved in several neural disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, hereditary distal motor neuropathy, and Charcot-Marie-Tooth's disease. In this work, we aimed to characterize its expression pattern in the mouse brain, by using the information available at online databases of high-throughput in situ hybridization. Therefore, we downloaded and analyzed the image series from these databases showing Hspb8 mRNA expression from embryonic to adult and aging stages. In early gestational embryos, Hspb8 was expressed in the hippocampal anlagen and in the ventricular layer of rhombomere 4. At perinatal stages, there appeared transitory expression in the dentate gyrus and the cerebellar cortex. From perinatal to aging stages, the neurons of the mesencephalic trigeminal nucleus and cranial motor nuclei displayed stable and strong Hspb8 expression. Additionally, along these stages there was moderate and relatively homogenous expression in the anterodorsal thalamic, lateral mammillary, arcuate hypothalamic and medial habenular nuclei, and in the locus coeruleus. In its turn, the basal ganglia, cerebellar inner granular layer and diverse sensory and reticular formation nuclei of the hindbrain contained scattered cells with strong expression. In conclusion, Hspb8 mRNA is constitutively expressed in specific brain structures across ontogeny, so that eventually they could be affected by the malfunction or deregulation of this molecule. PMID- 22213584 TI - Synthesis and characterization of photoswitchable fluorescent SiO2 nanoparticles. AB - Switchable fluorescent silica nanoparticles have been prepared by covalently incorporating a fluorophore and a photochromic compound inside the particle core. The fluorescence can be switched reversibly between an on- and off-state via energy transfer. The particles were synthesized using different amounts of the photoswitchable compound (spiropyran) and the fluorophore (rhodamine B) in a size distribution between 98 and 140 nm and were characterized in terms of size, switching properties, and fluorescence efficiency by TEM, and UV?Vis and fluorescence spectroscopy. PMID- 22213585 TI - Determination of the dipole moments of RNAse SA wild type and a basic mutant. AB - In this study, we report the effects of acidic to basic residue point mutations (5K) on the dipole moment of RNAse SA at different pHs. Dipole moments were determined by measuring solution capacitance of the wild type (WT) and the 5K mutant with an impedance analyzer. The dipole moments were then (1) compared with theoretically calculated dipole moments, (2) analyzed to determine the effect of the point mutations, and (3) analyzed for their contribution to overall protein protein interactions (PPI) in solution as quantitated by experimentally derived second virial coefficients. We determined that experimental and calculated dipoles were in reasonable agreement. Differences are likely due to local motions of residue side chains, which are not accounted for by the calculated dipole. We observed that the proteins' dipole moments increase as the pH is shifted further from their isoelectric points and that the wild-type dipole moments were greater than those of the 5K. This is likely due to an increase in the proportion of one charge (either negative or positive) relative to the other. A greater charge disparity corresponded to a larger dipole moment. Finally, the larger dipole moments of the WT resulted in greater attractive overall PPI for that protein as compared to the 5K. PMID- 22213586 TI - Differentiation efficiency of induced pluripotent stem cells depends on the number of reprogramming factors. AB - Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by retroviral overexpression of the transcription factors Oct4, Sox2, Klf4, and c Myc holds great promise for the development of personalized cell replacement therapies. In an attempt to minimize the risk for chromosomal disruption and to simplify reprogramming, several studies demonstrated that a reduced set of reprogramming factors is sufficient to generate iPSC, albeit at lower efficiency. To elucidate the influence of factor reduction on subsequent differentiation, we compared the efficiency of neuronal differentiation in iPSC generated from postnatal murine neural stem cells with either one (Oct4; iPSC(1F-NSC) ), two (Oct4, Klf4; iPSC(2F-NSC) ), or all four factors (iPSC(4F-NSC) ) with those of embryonic stem cells (ESCs) and iPSC produced from fibroblasts with all four factors (iPSC(4F-MEF) ). After 2 weeks of coculture with PA6 stromal cells, neuronal differentiation of iPSC(1F-NSC) and iPSC(2F-NSC) was less efficient compared with iPSC(4F-NSC) and ESC, yielding lower proportions of colonies that stained positive for early and late neuronal markers. Electrophysiological analyses after 4 weeks of differentiation identified functional maturity in neurons differentiated from ESC, iPSC(2F-NSC) , iPSC(4F-NSC) , and iPSC(4F-MEF) but not in those from iPSC(1F-NSC) . Similar results were obtained after hematoendothelial differentiation on OP9 bone marrow stromal cells, where factor reduced iPSC generated lower proportions of colonies with hematoendothelial progenitors than colonies of ESC, iPSC(4F-NSC) , and iPSC(4F-MEF) . We conclude that a reduction of reprogramming factors does not only reduce reprogramming efficiency but may also worsen subsequent differentiation and hinder future application of iPSC in cell replacement therapies. PMID- 22213587 TI - Breast cancer in a case of Shwachman Diamond syndrome. AB - Shwachman Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome (IBMFS) characterized by neutropenia, exocrine pancreatic dysfunction, and cancer predisposition. Patients are at risk for myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) but, unlike other IBMFS, there have been no reported cases of solid tumors. We report a novel case of a solid tumor in a patient with SDS and biallelic mutations in the Shwachman Bodian Diamond Syndrome gene (SBDS). Whether the development of breast cancer in this patient is due to SDS or an isolated case due to unknown factors requires further study. PMID- 22213588 TI - Characterisation and quantification of flavonoids in Iris germanica L. and Iris pallida Lam. resinoids from Morocco. AB - INTRODUCTION: Iris resinoid obtained from Iris germanica or Iris pallida rhizomes is widely used in the perfume industry but its chemical composition has not yet been reported. Nevertheless, very active compounds have been identified in iris rhizomes including iridals and isoflavones. OBJECTIVE: In this first study concerning iris resinoid composition, flavonoids were qualitatively and quantitatively investigated in I. germanica and I. pallida resinoids. METHODOLOGY: Resinoids were first fractionated by reverse-phase flash chromatography in order to obtain fractions containing all isoflavones. These fractions were analysed by HPLC-DAD (diode array detector) and the fractions containing isoflavones were analysed by HPLC-QTOF (quadrupole time of flight)-MS. Then, the main isoflavones were isolated and identified by NMR and high resolution mass spectroscopy (HRMS). Finally, total and individual isoflavones were quantified by HPLC-DAD at 265 nm using an external calibration method with irigenin as the external standard. RESULTS: Eight isoflavones were identified in both resinoids (irigenin, iristectorigenin A, nigricin, nigricanin, irisflorentin, iriskumaonin methyl ether, irilone, iriflogenin), one isoflavone only was identified in I. germanica resinoid (irisolidone), whereas one isoflavone (8-hydroxyirigenin), one isoflavanone (2,3-dihydroirigenin) and one benzophenone (2,6,4'-trihydroxy-4-methoxybenzophenone) only were identified in I. pallida resinoid. Isoflavones were quantified in I. germanica and I. pallida resinoids at 180 +/- 1.6 mg/g and 120 +/- 3.3 mg/g respectively. CONCLUSION: The study shows that I. germanica and I. pallida resinoids are rich in flavonoids and that these two Iris species can be distinguished by simply analysing the polyphenol fraction. PMID- 22213589 TI - Catalytic polymerization of anthracene in a recyclable SBA-15 reactor with high iron content by a Friedel-Crafts alkylation. PMID- 22213590 TI - Enhancement of photoresponse properties of conjugated polymers/inorganic semiconductor nanocomposites by internal micro-magnetic field. AB - In this paper, the effect of the internal micro-magnetic field (IMMF) on the photocurrent property of conjugated polymer/inorganic semiconductor nanocomposites is reported and analyzed. By using the redox reaction, magnetic Fe(3)O(4) nanoparticles were coated on the surface of highly active nanorods of conjugated polyaniline (PANI), forming an internal micro-magnetic electron donor (i.e., Fe(3)O(4)@PANI). After subsequent incorporation of CdS nanoparticles (serving as electron acceptors), the power conversion efficiency (PCE) of the system (Fe(3)O(4)@PANI-CdS) was found to be as high as 3.563%, contrasting sharply with the value (1.135%) of the hybrid without Fe(3)O(4) (PANI-CdS). This obvious enhancement originated from the fact that the IMMF increased the number of singlet polaron pairs through field-dependent intersystem crossing (ISC), giving a positive contribution to the photocurrent generation. Additionally, the dependence of the photocurrent on the remnant magnetization of the Fe(3)O(4)@PANI CdS nanocomposites was investigated. A percolation behavior was observed, which was due to the appearance of interpenetrating networks consisting of donor and acceptor phases, leading to the recombination of charge carriers through trapping. The outcomes of the present work might help to produce a new family of conjugated organic/inorganic semiconductor nanocomposites with designed optoelectronic performances. PMID- 22213592 TI - Competition and cooperativity in carbon dioxide sorption by amine-functionalized metal-organic frameworks. PMID- 22213591 TI - Maintenance of cartilaginous gene expression on extracellular matrix derived from serially passaged chondrocytes during in vitro chondrocyte expansion. AB - The loss of cartilaginous phenotype during in vitro expansion culture of chondrocytes is a major barrier for the application of cartilage tissue engineering. The use of matrices mimicking the in vivo extracellular matrix (ECM) microenvironment is anticipated to be an efficient method to suppress chondrocyte phenotype loss. In this study, we developed several types of ECM derived from serially passaged chondrocytes for use as cell-culture substrata and compared their effects on chondrocyte functions. Primary bovine chondrocytes and serially passaged chondrocytes (at passages 2 and 6) were cultured on tissue-culture polystyrene. After culture, the cellular components were selectively removed from the ECM deposited by the cells. The remaining ECM proteins were used as cell culture substrata. The composition of the deposited ECM depended on the culture stage of the serially passaged chondrocytes used for the ECM production. The deposited ECM supported the adhesion and proliferation of chondrocytes. The effects of the ECM on the chondrocyte dedifferentiation during in vitro passage culture differed dramatically depending on the phenotype of the chondrocytes used to produce the ECM. The primary chondrocyte-derived ECM delayed the chondrocyte dedifferentiation during in vitro passage culture and is a good candidate for chondrocyte subculture for tissue engineering. PMID- 22213593 TI - Milling-induced disorder of pharmaceuticals: one-phase or two-phase system? AB - During milling, components are subjected to shear and tensile stresses, which can result in physical phase transformations. The purpose of the work described in this report is to understand the pathway by which two test compounds, d-salicin and gamma-indomethacin, undergo a crystalline to amorphous transformation during cryomilling. The results show that the transformation cannot be described by a standard one-phase or two-phase disordering mechanism. In the one-phase model, a continuous set of states exist, linking perfect crystalline with completely amorphous material, whereas the two-phase model of disorder depicts the material as a binary mixture of crystalline and amorphous fractions. Instead, a model is proposed where two one-phase regions, defected crystalline and amorphous regions, are separated by a distinct transition. PMID- 22213594 TI - Assay validation of phosphorylated S6 ribosomal protein for a pharmacodynamic monitoring of mTOR-inhibitors in peripheral human blood. AB - BACKGROUND: Therapeutic drug monitoring (TDM) of immunosuppressive drugs after organ transplantation is based on measuring blood levels alone, which often results in under- or over-immunosuppression. Previous studies have shown the potential of measuring pharmacodynamic drug effects for TDM, but assessment of biomarkers for individual drugs is still not clinical routine. Therefore, we validated a specific assay to measure the pharmacodynamic effects of mammalian target of rapamycin (mTOR)-inhibitors on phosphorylated S6 ribosomal protein (p S6RP), a downstream target of mTOR. METHODS: Clinical relevant concentrations of sirolimus (SRL, 0.9-91.4 MUg/L), cyclosporine A (CsA, 75.1-1202 MUg/L), mycophenolate acid (MPA, 0.08-3.2 mg/L), or dexamethasone (DEX, 0.5-200 ng/mL) were added to whole-blood from healthy volunteers. Activated whole-blood was analyzed by phospho-flow cytometry to measure p-S6RP in T cells. RESULTS: Phospho flow analysis revealed that SRL suppressed p-S6RP in human T cells in a dose dependent manner with a half-maximal inhibitory concentration (IC(50)) at 19.8 nM and a maximal inhibitory effect (I(max) %) at 91.9%. Neither CsA, MPA, nor DEX inhibited mTOR-related S6RP-phosphorylation. Coefficient of variations from 0.03 to 0.05, 0.12 to 0.25, and 0.14 to 0.38 for intra-, interassay, and interindividual variability respectively, showed robustness of our assay. Furthermore, samples can be stored at RT or 4 degrees C up to 2 h after withdrawal. CONCLUSION: We validated a robust whole-blood assay that allows the specific measurement of SRL- and everolimus-induced inhibition of T cells' function through detection of p-S6RP. Future studies in organ transplanted recipients will show if this assay has the potential to enhance a TDM for mTOR inhibitor drugs in combination therapies. PMID- 22213595 TI - Psychometric analysis of the Chinese version of the Posttraumatic Growth Inventory with cancer patients in Hong Kong and Taiwan. AB - OBJECTIVE: Cancer patients in Hong Kong and Taiwan share traditional Chinese as a written form of language, but each region has its own sociocultural background. This study examined if the four-factor model (self, spiritual, life orientation, and interpersonal) of the Chinese version of the Posttraumatic Growth Inventory (PTGI-C), developed for Hong Kong cancer survivors, could be applied to cancer survivors in Taiwan. METHODS: Multisample confirmatory factor analyses (MS-CFA) were used to examine the factorial invariance of the PTGI-C among cancer survivors in Taiwan (n = 217) and Hong Kong (n = 223). RESULTS: The goodness-of fit of the four-factor model was satisfactory, chi2(180) = 372.36 (chi2/df = 2.07), goodness-of-fit index (GFI) = 0.90, adjusted GFI (AGFI) = 0.87, comparative fit index (CFI) = 0.92, Tucker-Lewis index (TLI) = 0.91, root mean square error of approximation (RMSEA) = 0.05, Akaike information criterion (AIC) = 492.36. This result suggests that the factor structure of the PTGI-C developed in Hong Kong could be applied to cancer survivors in Taiwan. The internal reliabilities of the 15-item whole scale, as well as all the subscales, were good and similar to those reported previously. Interregion comparison revealed that the Taiwan sample had higher mean 'spiritual' and 'interpersonal' posttraumatic growth subscale scores than the Hong Kong sample. CONCLUSIONS: The four-factor model of the PTGI-C is invariant among cancer survivors using traditional Chinese as a written form of the language. The differences in the degree of some posttraumatic growth dimensions may be because of differences in cultural factors and in psychosocial support for cancer patients between the two regions. PMID- 22213596 TI - Formation principles and ligand dynamics of nanoassemblies of CdSe quantum dots and functionalised dye molecules. AB - Functional dye molecules, such as porphyrins, attached to CdSe quantum dots (QDs) through anchoring meso-pyridyl substituents, form quasi-stable nanoassemblies. This fact results in photoluminescence (PL) quenching of the QDs both due to Forster resonance energy transfer (FRET) and the formation of non-radiative surface states under conditions of quantum confinement (non-FRET). The formation process is in competition with the ligand dynamics. At least two timescales are found for the formation of the assemblies: 1) one faster than 60 s attributed to saturation of empty attachment sites and 2) one slower than 600 s, which is attributed to a reorganisation of the tri-n-octylphosphine oxide (TOPO) ligand shell. Finally, this process results in almost complete exchange of the TOPO shell by porphyrin dye molecules. Following a Stern-Volmer analysis, we established a microscopic description of PL quenching and assembly formation. Based on this formalism, we determined the equilibrium constant for assembly formation between QDs and the pyridyl-functionalised dye molecules to be K ~ 10(5) - 10(7) M(-1), which is several orders of magnitude larger than that of the TOPO ligands. Our results give additional insights into the non-FRET PL quenching processes involved and show that the QD surface is inhomogeneous with respect to the involved attachment and detachment processes. In comparison with other methods, such as NMR spectroscopy, the advantage of our approach is that ligand dynamics can be investigated at extremely low ratios of dye molecules to QDs. PMID- 22213599 TI - Morphology of the eye of the southern right whales (Eubalaena australis). AB - Recently, there has been a growing interest in the anatomy and optics of the visual system of cetaceans. However, much of the new information has been focused on odontocetes, and relatively little is known about the visual anatomy of baleen whales. The aim of this study was describe the eye anatomy of the southern right whale (Eubalaena australis). Eye samples were collected from 26 calves, four adults with known body length, as well as two specimens of unknown body length that had stranded near their nursery ground at Peninsula Valdes, Argentina, over 6 years. We provide anatomical descriptions of the eyeball and extraocular structures, as well as quantitative data in the form of eyeball, corneal, scleral, and lens measurements. To explore the sensitivity of the eye to light, the f-number was estimated in one specimen. We found that the eyes of the calves differed from those of the adults in having less periorbital fat surrounding the eyeball. We also observed variations in the abundance of periorbital fat among the adult specimens. The regression analysis revealed a correlation between body length and eyeball size. By contrast, the dimensions of the cornea were only weakly correlated with body length. The estimated f-number suggests that the optical sensitivity of the Eubalaena australis eye is relatively low. However, caution had to be taken in interpreting f-number as a proxy of eye sensitivity because it depends on the lens size, which can be affected by the fixation methods used. PMID- 22213597 TI - Setting proteins free: progresses and achievements in proteomics of formalin fixed, paraffin-embedded tissues. AB - Formalin fixation, followed by paraffin embedding, is long established as the standard procedure for the stabilization and preservation of tissue architecture, essential for enabling microscopic examination and long-term storage of samples. During the years, this has led to the generation of a worldwide repository of patient tissues with associated complete clinical records. As such, this represents a golden mine for all those attempting to identify proteomic signatures of disease, aimed to the understanding of pathological processes and to the identification of new biomarkers. However, access to this resource has been hampered by the stable cross-linked network generated on tissue molecules during formalin fixation. Recently, researchers have been actively working to overcome this limitation, reaching unexpected achievements. This review aims to discuss and compare the various strategies devised for extracting full-length proteins or peptides from fixed tissues, and to provide a general perspective on studies comparing matched fixed and fresh-frozen tissue proteomes, applying proteomic techniques for biomarker discovery from archival tissues, and attempting to exploit gel-based approaches. In addition, the concomitant progresses in understanding the impact of tissue processing variables and the extent and nature of formaldehyde-induced modifications are presented. In conclusion, the future perspectives and open challenges in this field are discussed. PMID- 22213600 TI - In vivo generation of neural tumors from neoplastic pluripotent stem cells models early human pediatric brain tumor formation. AB - Recent studies have identified gene signatures in malignant tumors that are associated with human embryonic stem cells, suggesting a molecular relationship between aggressive cancers and pluripotency. Here, we characterize neural precursors (NPs) derived from transformed human embryonic stem cells (N-t-hESCs) that exhibit neoplastic features of human brain tumors. NPs derived from t-hESCs have enhanced cell proliferation and an inability to mature toward the astrocytic lineage, compared with progeny derived from normal human embryonic stem cells (N hESCs) independent of adherent or neurosphere outgrowth. Intracranial transplantation of NPs derived from N-t-hESCs and N-hESCs into NOD SCID mice revealed development of neuroectoderm tumors exclusively from the N-t-hESCs NPs and not from normal N-hESCs. These tumors infiltrated the ventricles and the cerebellum of recipient mice and displayed morphological, phenotypic, and molecular features associated with classic medulloblastoma including retention of a pluripotent signature. Importantly, N-t-hESCs did not exhibit cytogenetic changes associated with medulloblastoma, suggesting that aberrant cellular and molecular properties precede the acquisition of karyotypic changes thus underscoring the value of this model system of human medulloblastoma. Our study demonstrates that NPs from a starting population of neoplastic human pluripotent parent cells possess brain tumor-initiating cell capacity, thereby providing a model system to investigate initiation and progression of primitive human neural cancers that are difficult to assess using somatic sources. PMID- 22213601 TI - Identification of RNA-protein interaction networks using PAR-CLIP. AB - All mRNA molecules are subject to some degree of post-transcriptional gene regulation (PTGR) involving sequence-dependent modulation of splicing, cleavage and polyadenylation, editing, transport, stability, and translation. The recent introduction of deep-sequencing technologies enabled the development of new methods for broadly mapping interaction sites between RNA-binding proteins (RBPs) and their RNA target sites. In this article, we review crosslinking and immunoprecipitation (CLIP) methods adapted for large-scale identification of target RNA-binding sites and the respective RNA recognition elements. CLIP methods have the potential to detect hundreds of thousands of binding sites in single experiments although the separation of signal from noise can be challenging. As a consequence, each CLIP method has developed different strategies to distinguish true targets from background. We focus on photoactivatable ribonucleoside-enhanced CLIP, which relies on the intracellular incorporation of photoactivatable ribonucleoside analogs into nascent transcripts, and yields characteristic sequence changes upon crosslinking that facilitate the separation of signal from noise. The precise knowledge of the position and distribution of binding sites across mature and primary mRNA transcripts allows critical insights into cellular localization and regulatory function of the examined RBP. When coupled with other systems-wide approaches measuring transcript and protein abundance, the generation of high-resolution RBP binding site maps across the transcriptome will broaden our understanding of PTGR and thereby lead to new strategies for therapeutic treatment of genetic diseases perturbing these processes. PMID- 22213603 TI - Environment, developmental origins, and attention-deficit/hyperactivity disorder. PMID- 22213602 TI - Exposure to gestational diabetes mellitus and low socioeconomic status: effects on neurocognitive development and risk of attention-deficit/hyperactivity disorder in offspring. AB - OBJECTIVE: To examine the independent and synergistic effects of gestational diabetes mellitus (GDM) and low socioeconomic status (SES) on neurodevelopment and attention-deficit/hyperactivity disorder (ADHD) outcomes. DESIGN: Cohort study. SETTING: Flushing, New York. PARTICIPANTS: A total of 212 preschool children as a part of the ongoing cohort study. MAIN EXPOSURES: Gestational diabetes mellitus and low SES. MAIN OUTCOME MEASURES: Primary outcomes are ADHD diagnosis based on Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria at age 6 years and several well-validated measures of neurobehavioral outcomes, cognitive functioning, ADHD symptoms, and temperament at age 4 years. Secondary outcomes are parent and teacher reports of behavioral and emotional problems at age 6 years. Neurobehavioral measures in relation to GDM and low SES were examined using generalized estimating equations and multivariate logistic regression analyses. RESULTS: Both maternal GDM and low SES were associated with an approximately 2-fold increased risk for ADHD at age 6 years. However, the risk by GDM was greater among lower SES families than among higher SES families. Children exposed to both GDM and low SES demonstrated compromised neurobehavioral functioning, including lower IQ, poorer language, and impoverished behavioral and emotional functioning. A test of additive interaction found that the risk for ADHD increased over 14-fold (P = .006) when children were exposed to both GDM and low SES. Neither children exposed to maternal GDM alone nor those exposed to low SES alone had a notable increased risk for ADHD. CONCLUSIONS: Maternal GDM and low SES, especially in combination, heighten the risk for childhood ADHD. Long-term prevention efforts should be directed at mothers with GDM to avoid suboptimal neurobehavioral development and mitigate the risk for ADHD among their offspring. PMID- 22213604 TI - When will routine testing for human immunodeficiency virus infection be the routine for adolescents? PMID- 22213605 TI - How to fight whooping cough? PMID- 22213606 TI - Association between HIV-related risk behaviors and HIV testing among high school students in the United States, 2009. AB - OBJECTIVE: To identify the human immunodeficiency virus (HIV)-related risk behaviors associated with HIV testing among US high school students who reported ever having sexual intercourse. DESIGN: Secondary analysis of a cross-sectional study. SETTING: The 2009 national Youth Risk Behavior Survey. PARTICIPANTS: A total of 7591 US high school students who reported ever having sexual intercourse. MAIN EXPOSURES: Risk behaviors related to HIV. MAIN OUTCOME MEASURE: Having ever been tested for HIV. RESULTS: Among the 7591 students who reported ever having sexual intercourse, 22.6% had been tested for HIV. Testing for HIV was most likely to be done among students who had ever injected any illegal drug (41.3%; adjusted odds ratio, 1.70; 95% CI, 1.14-2.56), had ever been physically forced to have sexual intercourse (36.2%; adjusted odds ratio, 1.43; 95% CI, 1.19 -1.72), did not use a condom the last time they had sexual intercourse (28.7%; adjusted odds ratio, 1.28; 95% CI, 1.08-1.51), and had sexual intercourse with 4 or more persons during their life (34.7%; adjusted odds ratio, 2.32; 95% CI, 1.98 2.73). CONCLUSIONS: Most sexually active students, even among those who reported high-risk behaviors for HIV, have not been tested for HIV. New strategies for increasing HIV testing among the adolescent population, including encouraging routine voluntary HIV testing among those who are sexually active, are needed. PMID- 22213607 TI - Recent progress in understanding pediatric bipolar disorder. AB - Bipolar disorder is one of the most severe psychiatric illnesses, particularly when onset occurs during childhood or adolescence. With recent empirical evidence, questions regarding the existence of bipolar disorder among children and adolescents have given way to questions regarding prevalence. There are substantial risks inherent in misapplying diagnoses and treatments of bipolar disorder when not warranted and in withholding these diagnoses and treatments when they are warranted. As with adults, the course of bipolar disorder among children and adolescents diagnosed using unmodified diagnostic criteria is characterized by recovery and recurrence, functional impairment, suicidality, and high rates of comorbid psychiatric and medical problems. Discrepancies between increasing billing diagnoses and a stable epidemiologic prevalence of bipolar disorder suggest the possibility that diagnostic criteria are not being systematically applied in some clinical settings. Introducing new diagnoses may exacerbate rather than mitigate concerns regarding misdiagnosis and excessive use of mood-stabilizing medications. Several medications, particularly second generation antipsychotics, are efficacious for treating acute manic episodes of bipolar I disorder. However, less is known regarding the treatment of other mood states and subtypes of bipolar disorder. Psychosocial treatments provide a forum in which to educate children and families regarding bipolar disorder and its treatment, and may be especially beneficial for reducing depressive symptoms. Offspring of parents with bipolar disorder are at increased risk of developing the illness, as are youth with major depressive disorder and certain psychiatric comorbidities. Preliminary findings regarding biomarkers offer hope that, in the future, these biomarkers may inform diagnostic and treatment decisions. PMID- 22213608 TI - Early Impact of the US Tdap vaccination program on pertussis trends. AB - OBJECTIVE: To evaluate the impact of the adolescent Tdap (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine) vaccination program on pertussis trends in the United States. DESIGN: Retrospective analysis of nationally reported pertussis cases, January 1, 1990, through December 31, 2009. SETTING: United States. PARTICIPANTS: Confirmed and probable pertussis cases. Intervention The US Tdap vaccination program. MAIN OUTCOME MEASURE: Rate ratios of reported pertussis incidence (defined as incidence among 11- to 18-year-olds divided by the combined incidence in all other age groups) modeled through segmented regression analysis and age-specific trends in reported pertussis incidence over time. RESULTS: A total of 200 401 pertussis cases were reported in the United States from 1990 to 2009. Overall incidence ranged from 1.0 to 8.8 per 100,000 persons (1991 and 2004, respectively). Slope coefficients (estimated annual rate of change in rate ratios) from segmented regression showed a steady increase in pertussis incidence among adolescents 11 to 18 years old compared with all other age groups before Tdap introduction (slope = 0.22; P < .001), and a steep decreasing trend post introduction (slope = -0.48; P < .001), suggesting a direct impact of vaccination among adolescents. Indirect effects of adolescent vaccination were not observed among infants younger than 1 year. CONCLUSIONS: Changes in pertussis incidence in the United States from 2005 to 2009 revealed a divergence between 11- to 18-year-olds and other age groups, suggesting that targeted use of Tdap among adolescents reduced disease preferentially in this age group. Increased Tdap coverage in adolescents and adults is needed to realize the full direct and indirect benefits of vaccination. PMID- 22213610 TI - The dependence of radiofrequency induced pacemaker lead tip heating on the electrical conductivity of the medium at the lead tip. AB - Radiofrequency induced pacemaker lead tip heating is one of the main reasons magnetic resonance imaging (MRI) is contraindicated for patients with pacemakers. The objective of this work was to evaluate the dependence of pacemaker lead tip heating during MRI scanning on the electrical conductivity of the medium surrounding the pacemaker lead tip. The effect of conductivity was measured using hydroxyethyl cellulose, polyacrylic acid, and saline with conductivities ranging from 0 to 3 S/m which spans the range of human tissue conductivity. The maximum lead tip heating observed in polyacrylic acid was 50.4 degrees C at 0.28 S/m, in hydroxyethyl cellulose the maximum was 36.8 degrees C at 0.52 S/m, and in saline the maximum was 12.5 degrees C at 0.51 S/m. The maximum power transfer theorem was used to calculate the relative power deposited in the solution based on the characteristic impedance of the pacemaker lead and test solution impedance. The results demonstrate a strong correlation between the relative power deposited and pacemaker lead tip heating for hydroxyethyl cellulose and saline solutions. Maximum power deposition occurred when the impedance of the solution matched the pacemaker lead impedance. Pacemaker lead tip heating is dependent upon the electrical conductivity of the solution at the lead tip and should be considered when planning in vitro gel or saline experiments. PMID- 22213611 TI - Oligoprolines as scaffolds for the formation of silver nanoparticles in defined sizes: correlating molecular and nanoscopic dimensions. PMID- 22213609 TI - Hospitalizations for intussusception before and after the reintroduction of rotavirus vaccine in the United States. AB - OBJECTIVE: To determine whether hospital discharges for intussusception in children younger than 1 year have changed since the reintroduction of rotavirus vaccine in the United States. DESIGN: Serial cross-sectional analysis. SETTING: US hospitals. PARTICIPANTS: Children younger than 1 year with a discharge diagnosis of intussusception identified in the Kids' Inpatient Database, a series of nationally representative data sets of pediatric hospital discharges in the United States with 4 available years prior to vaccine reintroduction (1997, 2000, 2003, and 2006) and 1 year after (2009). MAIN EXPOSURES: Hospital discharge before vs after rotavirus vaccine reintroduction. OUTCOME MEASURES: Total number and rate of hospital discharges for infants younger than 1 year with a diagnosis of intussusception (International Classification of Diseases, Ninth Revision, Clinical Modification code 560.0). RESULTS: From 1997 to 2006, there was no change in the total number of hospital discharges for intussusception, with a small decrease in the rate of intussusception discharges (41.6 [95% CI, 36.7 46.5] to 36.5 [95% CI, 31.7-41.2] per 100,000 infants). Based on the trend, the predicted rate of discharges for intussusception in 2009 was 36.0 (95% CI, 30.2 41.8) per 100,000 infants. The measured rate of hospital discharges for intussusception in 2009 was 33.3 (95% CI, 29.0-37.6) per 100,000 infants. CONCLUSION: The reintroduction of rotavirus vaccine since 2006 has not resulted in a detectable increase in the number of hospital discharges for intussusception among US infants. PMID- 22213615 TI - Lung-to-head ratio: a need to unify the technique. PMID- 22213612 TI - Hypothalamic obesity syndrome: rare presentation of CNS+ B-cell lymphoblastic lymphoma. AB - Hypothalamic obesity syndrome can affect brain tumor patients following surgical intervention and irradiation. This syndrome is rare at diagnosis in childhood cancer, but has been reported with relapse of acute lymphoblastic leukemia. Here we present a case of hypothalamic obesity syndrome as the primary presentation of a toddler found to have CNS+ B-cell lymphoblastic lymphoma. Cytogenetic studies on diagnostic cerebrospinal fluid revealed MLL gene rearrangement (11q23). Hyperphagia and obesity dramatically improved following induction and consolidation chemotherapy. We describe a novel presentation of hypothalamic obesity syndrome in CNS B-cell lymphoblastic lymphoma, responsive to chemotherapy. PMID- 22213613 TI - The effects of media on pharmaceutically relevant transporters in the human HT-29 adenocarcinoma cell line: does culture media need to be controlled? AB - The HT-29 cell line forms a confluent monolayer with tight junctions, but displays different phenotypes when cultured for 21 days in galactose-supplemented media (differentiated) versus glucose-supplemented media (dedifferentiated). This study is aimed at elucidating how media differences might affect selected drug transporter expression and peptide-based substrate transport toward reducing this variability. A vial of HT-29 cells was amplified and cultured over several passages in four different mediums (American Type Culture Collection recommended McCoy's 5A versus Dulbecco's modified Eagle's media containing glucose, galactose, or neither carbohydrate) with normal supplementation. Transporter mRNA expression was characterized at days 5 and 21 postseeding utilizing SABiosciences quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) drug transporter arrays. Transport studies using [H]histidine, [(3) H]glycylsarcosine, [(3) H]valacyclovir, and [(3) H]carnosine were performed to assess the functional effects of oligopeptide transporter expression changes in HT-29 cells grown in each media. qRT-PCR arrays illustrated variable, media-dependent transporter expression between both the initial and differentiated time points. Permeability studies illustrated considerable media-dependent differences in both paracellular and transcellular substrate fluxes. The results demonstrate that these cells exhibit differing monolayer characteristics and genotypic/phenotypic profile properties when cultured under different media. The results suggest a need for standardization of culture methodologies for reducing inter- and intralaboratory variability. PMID- 22213616 TI - Fetal surgery for severe congenital diaphragmatic hernia? PMID- 22213618 TI - Re: Retrospective review of diagnostic performance of intracranial translucency in detection of open spina bifida at the 11-13-week scan. RR. PMID- 22213621 TI - Controlled doping of MS2 (M=W, Mo) nanotubes and fullerene-like nanoparticles. PMID- 22213622 TI - Evaluation of chemically modified SLA implants (modSLA) biofunctionalized with integrin (RGD)- and heparin (KRSR)-binding peptides. AB - Enhancing osseointegration through surface immobilization of multiple short peptide sequences that mimic extracellular matrix (ECM) proteins, such as arginine-glycine-aspartic acid (RGD) and lysine-arginine-serine-arginine (KRSR), has not yet been extensively explored. Additionally, the effect of biofunctionalizing chemically modified sandblasted and acid-etched surfaces (modSLA) is unknown. The present study evaluated modSLA implant surfaces modified with RGD and KRSR for potentially enhanced effects on bone apposition and interfacial shear strength during early stages of bone regeneration. Two sets of experimental implants were placed in the maxillae of eight miniature pigs, known for their rapid wound healing kinetics: bone chamber implants creating two circular bone defects for histomorphometric analysis on one side and standard thread configuration implants for removal torque testing on the other side. Three different biofunctionalized modSLA surfaces using poly-L-lysine-graft poly(ethylene glycol) (PLL-g-PEG) as a carrier minimizing nonspecific protein adsorption [(i) 20 pmol cm-2 KRSR alone (KRSR); or in combination with RGD in two different concentrations; (ii) 0.05 pmol cm-2 RGD (KRSR/RGD-1); (iii) 1.26 pmol cm-2 RGD (KRSR/RGD-2)] were compared with (iv) control modSLA. Animals were sacrificed at 2 weeks. Removal torque values (701.48-780.28 N mm), bone-to implant contact (BIC) (35.22%-41.49%), and new bone fill (28.58%-30.62%) demonstrated no significant differences among treatments. It may be concluded that biofunctionalizing modSLA surfaces with KRSR and RGD derivatives of PLL-g PEG polymer does not increase BIC, bone fill, or interfacial shear strength. PMID- 22213623 TI - Pt-Al2O3 interfacial bonding in implantable hermetic feedthroughs: morphology and orientation. AB - The present work examines the chemistry, microstructure, and crystallography of a Pt-Al(2)O(3) joint used in implantable hermetic feedthrough designs in neural prostheses. Pt was joined to Al(2)O(3) by passing Pt pins through green Al(2)O(3) disks and then sintering in air. This created a Pt-Al(2)O(3) joint that was prepared for the current investigation by gross sectioning and then polishing and sectioning into slices using focused ion beam milling. The slices were examined by scanning electron microscopy, transmission electron microscopy, and energy dispersive spectroscopy. Two types of interfaces in the sintered material were identified: Vitreous-bonded Pt-glass-Al(2)O(3) and direct-bonded Pt-Al(2)O(3). In the case of the former, glass formation owing to the presence of glass-forming additives (to enhance densification and suppress grain growth) and consequent wetting of both the Pt and Al(2)O(3) facilitated interfacial bonding. In the case of the latter, the interfacial planes were (002)(Pt) // (022)Al(2)O(3) [rhombohedral] or (002)(Pt) // (022 2)Al(2)O(3) [hexagonal]. The lattice mismatch was calculated to be 11% (based on the calculated d spacings) or 15% (based on the literature d spacings). Both of these suggest the establishment of semicoherent interfaces. PMID- 22213625 TI - Nanostructure-driven analyte-interface electron transduction: a general approach to sensor and microreactor design. AB - A concept describing the nanostructure-directed dynamics of acid/base interaction and the balance between physisorption and chemisorption on an extrinsic semiconductor interface is evaluated and compared for n- and p-type semiconductors. The inverse hard/soft acid/base (IHSAB) concept, as it complements the HSAB concept, defines the nature of a dominant physisorption behavior and enables the creation of a matrix of controllable interactions. The technology results in the coupling of Lewis acid/base chemistry with the extrinsic semiconductor majority carriers. Nanoporous silicon layers facilitate the application of nanostructured metal/metal oxides, which provide sensitivity and selectivity for the modified interface. Applied fractional depositions can produce a dominant reversible physisorptive (sensors) or chemisorptive (microreactors) interaction at the semiconductor interface as the nanostructures act as antennas to focus the interaction. The dynamic natures of n- and p-type silicon are evaluated and compared, by focusing on the controlled manipulation of these semiconductors as they are modified with nanostructures and interact with the gas-phase analytes. The observed semiconductor responses correlate well with the temperature dependence of the extrinsic semiconductor, the population of the donor or acceptor levels, and the inherent mobilities of electrons. The response of the modified n-type semiconductors is found to exceed that of comparable p type systems. The IHSAB concept can be extended to assess the properties of several additional semiconductor interfaces including nanowires. The results obtained not only pertain to sensor and microreactor array design, but also suggest the importance of the dynamic changes created, as the majority charge carrier concentrations are manipulated and the Fermi energies are modified through chemical interaction. PMID- 22213627 TI - Adipokines: a treasure trove for the discovery of biomarkers for metabolic disorders. AB - Adipose tissue is a major endocrine organ, releasing signaling and mediator proteins, termed adipokines, via which adipose tissue communicates with other organs. Expansion of adipose tissue in obesity alters adipokine secretion which may contribute to the development of metabolic diseases. Consequently, this correlation has emphasized the importance to further characterize the adipocyte secretion profile, and several attempts have been made to characterize the complex nature of the adipose tissue secretome by utilizing diverse proteomic profiling approaches. Although the entirety of human adipokines is still incompletely characterized, to date more than 600 potentially secretory proteins were identified providing a rich source to identify putative novel biomarkers associated with metabolic diseases. PMID- 22213626 TI - Effect of nitrogen source on biomass and bioactive compound production in submerged cultures of Eleutherococcus koreanum Nakai adventitious roots. AB - Ammonium to nitrate ratios of 0:30, 5:25, 10:20, 15:15, 20:10, 25:5, and 30:0 mM were tested to determine the optimal NH(4)(+) :NO(3)(-) ratio for improving biomass and bioactive compound production in Eleutherococcus koreanum Nakai adventitious roots using 3-L bulb-type bubble bioreactors. A high ammonium nitrogen ratio had a negative effect on root growth, and the highest fresh and dry weights were obtained when NH(4)(+):NO(3)(-) ratios were 5:25 and 10:20 (mM) after 5 weeks of culture. Although the total production of eleutherosides B and E was slightly higher at the 10:20 ratio than at the 5:25 ratio (NH(4)(+):NO(3)( )), we proposed that the optimal NH(4)(+):NO(3)(-) ratio was 5:25 mM. This ratio achieved both the highest total production of five target bioactive compounds (eleutherosides B and E, chlorogenic acid, total phenolics, and flavonoids) and the highest root biomass. Furthermore, increasing NH(4)(+):NO(3)(-) ratios to 10:20 decreased pH in the medium, interrupted the absorption of essential minerals from the culture medium, and resulted in low biomass and increased relative oxidative stress levels, which were evaluated by determining 1,1 diphenyl-2-picrylhydrazyl radical scavenging activity. Therefore, nitrate rather than ammonium nitrogen was more essential not for only biomass production but also for bioactive compound production in E. koreanum adventitious root cultures. The optimal nitrogen source ratio produced 5.63 g L(-1) of biomass and 24.41 mg of the five total bioactive compounds per gram of biomass (dry weight basis). The development of such in vitro culture technology will benefit the pilot-scale production of E. koreanum-based bioactive compounds for commercialization. PMID- 22213628 TI - Alveolar epithelial type II cells and their microenvironment in the caveolin-1 deficient mouse. AB - Caveolin-1 (Cav-1) is highly expressed in alveolar epithelial type I (AE1) and endothelial cells of the alveolar region of the lung. Interestingly, alveolar epithelial type II (AE2) cells that are progenitors of the AE1 cells do not express Cav-1. We investigated whether genetic Cav-1 deficiency alters the phenotype of AE2 cells and their microenvironment using stereology. Total number, mean volume, and subcellular composition of the AE2 cells were not altered in Cav 1(-/-) when compared with wild-type mice. The alveolar septa were thickened and contained a significantly greater volume of extracellular matrix. Thus, AE2 cells as progenitors of AE1 cells are not critically involved in the severe pulmonary phenotype in Cav-1-deficient mice. PMID- 22213629 TI - Severe thrombocytosis as initial manifestation of Caffey disease in a 4 month old infant. PMID- 22213630 TI - The triple role of fluoride ions in palladium-catalyzed Suzuki-Miyaura reactions: unprecedented transmetalation from [ArPdFL2] complexes. PMID- 22213631 TI - The role of adjuvant in mediating antigen structure and stability. AB - The purpose of this study was to probe the fate of a model antigen, a cysteine free mutant of bacteriophage T4 lysozyme, to the level of fine structural detail, as a consequence of its interaction with an aluminum (Al)-containing adjuvant. Fluorescence spectroscopy and differential scanning calorimetry were used to compare the thermal stability of the protein in solution versus adsorbed onto an Al-containing adjuvant. Differences in accessible hydrophobic surface areas were investigated using an extrinsic fluorescence probe, 8-Anilino-1 naphthalenesulfonic acid (ANS). As has been observed with other model antigens, the apparent thermal stability of the protein decreased following adsorption onto the adjuvant. ANS spectra suggested that adsorption onto the adjuvant caused an increase in exposure of hydrophobic regions of the protein. Electrostatic interactions drove the adsorption, and disruption of these interactions with high ionic strength buffers facilitated the collection of two-dimensional (15) N heteronuclear single quantum coherence nuclear magnetic resonance data of protein released from the adjuvant. Although the altered stability of the adsorbed protein suggested changes to the protein's structure, the fine structure of the desorbed protein was nearly identical to the protein's structure in the adjuvant free formulation. Thus, the adjuvant-induced changes to the protein that were responsible for the reduced thermal stability were not observed upon desorption. PMID- 22213633 TI - Mesoporous organosilica hybrids consisting of silica-wrapped pi-pi stacking columns. PMID- 22213632 TI - Effect of calcium carbonate on hardening, physicochemical properties, and in vitro degradation of injectable calcium phosphate cements. AB - The main disadvantage of apatitic calcium phosphate cements (CPCs) is their slow degradation rate, which limits complete bone regeneration. Carbonate (CO32-) is the common constituent of bone and it can be used to improve the degradability of the apatitic calcium phosphate ceramics. This study aimed to examine the effect of calcite (CaCO3) incorporation into CPCs. To this end, the CaCO3 amount (0-4-8 12 wt %) and its particle size (12.0-MUm-coarse or 2.5-MUm-fine) were systematically investigated. In comparison to calcite-free CPC, the setting time of the bone substitute was delayed with increasing CaCO3 incorporation. Reduction of the CaCO3 particle size in the initial powder increased the injectability time of the paste. During hardening of the cements, the increase in calcium release was inversely proportional to the extent of CO32- incorporation into apatites. The morphology of the carbonate-free product consisted of large needle-like crystals, whereas small plate-like crystals were observed for carbonated apatites. Compressive strength decreased with increasing CaCO3 content. In vitro accelerated degradation tests demonstrated that calcium release and dissolution rate from the set cements increased with increasing the incorporation of CO32-, whereas differences in CaCO3 particle size did not affect the in vitro degradation rate under accelerated conditions. PMID- 22213635 TI - Shape changes of Pt nanoparticles induced by deposition on mesoporous silica. AB - Polyvinylpyrollidone (PVP)-capped platinum nanoparticles (NPs) are found to change shape from spherical to flat when deposited on mesoporous silica substrates (SBA-15). Transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS), and extended X-ray absorption fine structure (EXAFS) analyses are used in these studies. The SAXS results indicate that, after deposition, the 2 nm NPs have an average gyration radius 22% larger than in solution, while the EXAFS measurements indicate a decrease in first neighbor co-ordination number from 9.3 to 7.4. The deformation of these small capped NPs is attributed to interactions with the surface of the SBA-15 support, as evidenced by X-ray absorption near-edge structure (XANES). PMID- 22213636 TI - The influence of silver nanostructures formed in situ in silica sol-gel derived films on the rate of Forster resonance energy transfer. AB - The efficiency of Forster resonance energy transfer (FRET) can be enhanced in the presence of a metal. Herein, we demonstrate the increased efficiency for a novel model sensor system where FRET is shown to occur between Rhodamine 6G in the bulk sol-gel matrix and Texas Red, which is held a fixed distance away by covalent attachment onto a silane spacer. Silver colloids are formed using light to initiate the reduction of a silver salt, which can be achieved at controlled locations within the film. Both the fluorescence intensity and lifetime maps and analysis indicate that an enhanced FRET efficiency has been achieved in the presence of silver nanoparticles. An increase in efficiency of 1.2-1.5 times is demonstrated depending on the spacer used. The novelty of our approach lies in the method of silver-nanoparticle formation, which allows for the accurate positioning of the silver nanoparticles and hence selective fluorescence enhancement within a biocompatible host material. Our work gives a practical demonstration of metal-enhanced FRET and demonstrates the ability of such systems to be developed for molecular-recognition applications that could find use in lab on-a-chip technologies. PMID- 22213637 TI - Functional protease profiling for diagnosis of malignant disease. AB - Clinical proteomic profiling by mass spectrometry (MS) aims at uncovering specific alterations within mass profiles of clinical specimens that are of diagnostic value for the detection and classification of various diseases including cancer. However, despite substantial progress in the field, the clinical proteomic profiling approaches have not matured into routine diagnostic applications so far. Their limitations are mainly related to high-abundance proteins and their complex processing by a multitude of endogenous proteases thus making rigorous standardization difficult. MS is biased towards the detection of low-molecular-weight peptides. Specifically, in serum specimens, the particular fragments of proteolytically degraded proteins are amenable to MS analysis. Proteases are known to be involved in tumour progression and tumour-specific proteases are released into the blood stream presumably as a result of invasive progression and metastasis. Thus, the determination of protease activity in clinical specimens from patients with malignant disease can offer diagnostic and also therapeutic options. The identification of specific substrates for tumour proteases in complex biological samples is challenging, but proteomic screens for proteases/substrate interactions are currently experiencing impressive progress. Such proteomic screens include peptide-based libraries, differential isotope labelling in combination with MS, quantitative degradomic analysis of proteolytically generated neo-N-termini, monitoring the degradation of exogenous reporter peptides with MS, and activity-based protein profiling. In the present article, we summarize and discuss the current status of proteomic techniques to identify tumour-specific protease-substrate interactions for functional protease profiling. Thereby, we focus on the potential diagnostic use of the respective approaches. PMID- 22213638 TI - Acid-insoluble human dentin as carrier material for recombinant human BMP-2. AB - The aim of this study is to estimate the increase of bone-inductive potency by human demineralized dentin matrix (DDM) with recombinant human bone morphogenetic protein-2 (BMP-2). Human teeth were crushed, completely demineralized in 0.6M HCl, and freeze-dried. The tooth-derived material is called DDM. The shape of DDM was a particle type and its size varied from 0.4 to 0.8 mm. The BMP-2 dose dependent study in the rat subcutaneous tissues demonstrated that the volume of induced bone and marrow increased at a dose-dependent manner. The time-course study of bone induction by the BMP-2 (5.0 MUg)/DDM (70 mg) was estimated histologically and biochemically. Histological findings showed that the BMP-2/DDM increased bone and marrow sequentially between the DDM particles. Calcium content in the BMP-2/DDM-induced tissue was compatible to the histological findings. ALP activity in the BMP-2/DDM showed a maximal value at 1 week and gradually decreased. The morphometric analysis demonstrated that the BMP-2/DDM showed 66.9%, 79.0% in the volume of bone and marrow, and 32.4%, 21.0% in that of DDM at 8, 32 weeks, respectively. We confirmed that BMP-2 significantly accelerated bone formation in the acid-insoluble human-dentin carriers. These results indicate that human DDM should be an effective carrier for delivering BMP-2 and superior scaffold for bone-forming cells. PMID- 22213639 TI - Anatomy education in Namibia: balancing facility design and curriculum development. AB - The anatomy curriculum at Namibia's first, and currently only, medical school is clinically oriented, outcome-based, and includes all of the components of modern anatomical sciences i.e., histology, embryology, neuroanatomy, gross, and clinical anatomy. The design of the facilities and the equipment incorporated into these facilities were directed toward simplification of work flow and ease of use by faculty, staff, and students. From the onset, the integration of state of the art technology was pursued to facilitate teaching and promote a student centered pedagogical approach to dissections. The program, as realized, is comprised of three 16-week semesters with seven hours of contact time per week, namely three hours of lectures and four hours of dissection laboratory and microscopy time. Set outcomes were established, each revolving around clinical cases with integrated medical imaging. The design of the facility itself was not constrained by a legacy structure, allowing the School of Medicine, in collaboration with architects and contractors, to design the building from scratch. A design was implemented that allows for the sequential processing of cadaveric material in a unidirectional flow from reception, to preparation, embalming, storage, dissection, and maceration. Importantly, the odor of formaldehyde typically associated with anatomy facilities was eliminated outside of the dissection areas and minimized within via a high-performance ventilation system. By holistically incorporating an integrated curriculum, facility design, and teaching at an early stage, the authors believe they have created a system that might serve as a model for new anatomy programs. PMID- 22213640 TI - Linking ion and neutral chemistry in C-H bond electrophilic activation: generation and detection of HO2. reactive radicals in the gas phase. PMID- 22213641 TI - Formation of enantiomeric impeller-like helical architectures by DNA self assembly and silica mineralization. PMID- 22213642 TI - Prognostic significance of high podoplanin expression after chemoradiotherapy in esophageal squamous cell carcinoma patients. AB - BACKGROUND: The correlation between high tumor podoplanin (PP) immunoreactivity and poor outcome in patients with non-chemoradiotherapy(CRT) pretreated upper aerodigestive tract squamous cell carcinoma (SCC) has been reported recently. Little is known about the implication of PP expression after CRT. Therefore, we conducted this study. METHODS: We evaluated the PP immunoreactivity in ypT3N0 esophageal SCC patients by using immunohistochemistry. The impact of PP expression intensity in tumors on patient survival was judged in combination with clinical and pathological descriptors. RESULTS: Our study included 109 males and 4 females (mean age, 57.6 years; range, 38-79 years). PP immunoreactivity was expressed in tumors in 95% of patients and 38% of patients had high PP expression. High PP expression tumors had positive association with lymphovascular invasion (LVI). Multivariate analyses revealed tumor PP immunoreactivity and circumferential resection margin (CRM) status as independent prognostic factors. Patients with positive CRM and high PP expression had shortest survival followed by those with either positive CRM or high PP expression, and then by patients with neither positive CRM nor high PP expression (5-year disease-specific survival: 5%, 20%, 40%, P < 0.001). CONCLUSION: Tumor PP immunoreactivity in conjunction with CRM status are useful markers to identify aggressive post-CRT treated ypT3N0 stage esophageal SCC. PMID- 22213643 TI - Delivery of VEGF using collagen-coated polycaprolactone scaffolds stimulates angiogenesis. AB - Establishing sufficient vascularization in scaffold remains a challenge for tissue-engineering. To improve angiogenesis, we incorporated vascular endothelial growth factor (VEGF) in collagen-coating over the porous polycaprolactone (PCL) scaffolds. The release kinetics of loaded VEGF from collagen-coated PCL (col-PCL) scaffolds was same as from scaffolds without the collagen. The bioactivity of VEGF delivered by the col-PCL scaffolds was confirmed by human umbilical vein endothelial cell (HUVEC) proliferation and chorioallantoic membrane (CAM) assay. The col-PCL scaffolds were implanted subcutaneously in mice for 7 and 14 days. At day 7, vascularization within scaffolds loaded with VEGF was superior to that in the scaffolds without VEGF. However, the vessel connectivity to host circulatory system was incomplete and restricted to the scaffold edges. At day 14, blood vessels in scaffolds reached density similar to the subcutaneous tissue and were perfusable throughout the implant thickness. Prewashing the scaffolds with saline to remove the unbound growth factor decreased the initial burst release and sustained the VEGF-mediated angiogenesis in vivo. In conclusion, our study demonstrates that physically adsorbed VEGF stimulated angiogenesis in collagen coated PCL scaffolds. PMID- 22213646 TI - Towards clinical applications of selected reaction monitoring for plasma protein biomarker studies. AB - The widespread clinical adoption of protein biomarkers with diagnostic, prognostic and/or predictive value remains a formidable challenge for the biomedical community. From discovery to validation, the path to biomarkers of clinical relevance abounds with many protein candidates, yet so few concrete examples have been substantiated. In this review, we focus on the recent adoption of selected reaction monitoring (SRM) of plasma proteins in the path to clinical use for a broad range of diseases including cancer, cardiovascular disease, genetic disorders and various metabolic disorders. Recent progress reveals a promising outlook for clinical applications using SRM, which now provides the routine analysis of clinically relevant protein markers at low nanogram per millilitre in plasma. PMID- 22213648 TI - The two faces of His-tag: immune response versus ease of protein purification. PMID- 22213647 TI - Multicolor super-resolution fluorescence imaging via multi-parameter fluorophore detection. AB - Understanding the complexity of the cellular environment will benefit from the ability to unambiguously resolve multiple cellular components, simultaneously and with nanometer-scale spatial resolution. Multicolor super-resolution fluorescence microscopy techniques have been developed to achieve this goal, yet challenges remain in terms of the number of targets that can be simultaneously imaged and the crosstalk between color channels. Herein, we demonstrate multicolor stochastic optical reconstruction microscopy (STORM) based on a multi-parameter detection strategy, which uses both the fluorescence activation wavelength and the emission color to discriminate between photo-activatable fluorescent probes. First, we obtained two-color super-resolution images using the near-infrared cyanine dye Alexa 750 in conjunction with a red cyanine dye Alexa 647, and quantified color crosstalk levels and image registration accuracy. Combinatorial pairing of these two switchable dyes with fluorophores which enhance photo activation enabled multi-parameter detection of six different probes. Using this approach, we obtained six-color super-resolution fluorescence images of a model sample. The combination of multiple fluorescence detection parameters for improved fluorophore discrimination promises to substantially enhance our ability to visualize multiple cellular targets with sub-diffraction-limit resolution. PMID- 22213650 TI - Strain-induced orientation-selective cutting of graphene into graphene nanoribbons on oxidation. PMID- 22213649 TI - Chemically extracted acellular muscle: a new potential scaffold for spinal cord injury repair. AB - Extracellular matrix is the gold standard for tissue regeneration. In this study, we directly made the extracellular matrix of the tissue or organ into scaffold for spinal cord injuries, a strategy that is seldomly tried in spinal cord engineering. The aim of this study was to determine if the chemically extracted acellular muscle could be a potential scaffold for spinal cord injury. The chemically extracted acellular muscle was implanted in the lateral hemisected adult rat thoracic spinal cord. Control rats were similarly injured. After 1 and 4 weeks, scaffold integration and biocompatibility, axon sprouting, and myelination were evaluated. The chemically extracted acellular muscle scaffolds were found to be well integrated with the host tissue. Sprouting axons grew into the full length of the scaffold in a strikingly parallel and linear fashion. A few remyelinated axons were also detected in the scaffolds. The tracing results in another six rats showed that labeled fibers entered the chemically treated muscle grafts. Furthermore, there were no apparent quantitative differences in the ED-1 and glial fibrillary acidic protein positive cells between groups. Neuron counting showed more surviving neurons in the acellular muscle treated group than those of the injured only group. Vascularization of the grafts was also confirmed. These findings clearly demonstrated that chemically extracted acellular muscle grafts provided useful biomatrices to enhance axon sprouting in the injured spinal cord. PMID- 22213651 TI - Design, implementation, and evaluation of a postgraduate Diploma in Surgical Anatomy. AB - After careful planning, a postgraduate Diploma in Surgical Anatomy was launched in 2009. This report describes the structure of the program, the challenges encountered in implementing and running the course, and results of evaluations. The qualification is targeted at junior doctors intending to become surgeons or radiologists and aims to equip them with a sound understanding of regional anatomy relevant to common diagnostic and therapeutic procedures, together with an understanding of common/important anatomical variations. The course is delivered by: (1) 24 weeks' distance learning, comprising selected readings, podcasts, multiple choice questions (MCQs), and research informed essays; and (2) two separate two-week periods of intensive campus-based learning and whole body dissection (four students per cadaver) assessed by oral examination, a class presentation of an anatomical variation, and formal MCQ examination. Campus-based instruction is delivered by two surgical anatomists with additional input from a broad range of specialist surgeons and radiologists. Anonymous student evaluations over three successive courses show that all components of the course were highly rated. The success of the program may relate to several factors: an emphasis on clinically relevant anatomy, clear learning objectives, personalized student feedback, a low student to cadaver ratio, restricted class size, a wide range of supportive material, a dedicated team of surgical/radiological instructors, efficient course administration, and endorsement by the Royal Australasian College of Surgeons. Establishing a Diploma in Surgical Anatomy program requires a dedicated team of individuals, the setting and maintenance of appropriate educational standards, and collaboration with the professional body regulating the training of surgeons. PMID- 22213653 TI - Effect of protein adsorption on the fluorescence of ultrasmall gold nanoclusters. AB - The interaction of proteins with ultrasmall gold nanoclusters (Au NCs) is investigated. Upon protein association, the fluorescence of Au NCs is significantly enhanced and, concomitantly, their luminescence lifetime is prolonged. The results stress the importance of investigating the behavior of fluorescent metal NCs in complex biological environment for advancing their bio nanotechnology applications. PMID- 22213652 TI - Tailored magnetic nanoparticles for optimizing magnetic fluid hyperthermia. AB - Magnetic Fluid Hyperthermia (MFH) is a promising approach towards adjuvant cancer therapy that is based on the localized heating of tumors using the relaxation losses of iron oxide magnetic nanoparticles (MNPs) in alternating magnetic fields (AMF). In this study, we demonstrate optimization of MFH by tailoring MNP size to an applied AMF frequency. Unlike conventional aqueous synthesis routes, we use organic synthesis routes that offer precise control over MNP size (diameter ~10 to 25 nm), size distribution, and phase purity. Furthermore, the particles are successfully transferred to the aqueous phase using a biocompatible amphiphilic polymer, and demonstrate long-term shelf life. A rigorous characterization protocol ensures that the water-stable MNPs meet all the critical requirements: (1) uniform shape and monodispersity, (2) phase purity, (3) stable magnetic properties approaching that of the bulk, (4) colloidal stability, (5) substantial shelf life, and (6) pose no significant in vitro toxicity. Using a dedicated hyperthermia system, we then identified that 16 nm monodisperse MNPs (sigma 0.175) respond optimally to our chosen AMF conditions (f = 373 kHz, H0 = 14 kA/m); however, with a broader size distribution (sigma-0.284) the Specific Loss Power (SLP) decreases by 30%. Finally, we show that these tailored MNPs demonstrate maximum hyperthermia efficiency by reducing viability of Jurkat cells in vitro, suggesting our optimization translates truthfully to cell populations. In summary, we present a way to intrinsically optimize MFH by tailoring the MNPs to any applied AMF, a required precursor to optimize dose and time of treatment. PMID- 22213654 TI - Optical resonator biosensors: molecular diagnostic and nanoparticle detection on an integrated platform. AB - Optical resonator biosensors are emerging as one of the most sensitive microsystem biodetection technology that does not require amplification or labeling of the analyte. This minireview provides a scholarly introduction to this research area and reviews current advances in molecular diagnostics and nanoparticle detection. PMID- 22213655 TI - Systems biology analysis of protein-drug interactions. AB - Drugs induce global perturbations at the molecular machinery level because their cognate targets are involved in multiple biological functions or because of off target effects. The analysis or the prediction of such systems level consequences of drug treatment therefore requires the application of systems biology concepts and methods. In this review, we first summarize the methods of chemical proteomics that can measure unbiased and proteome-wide drug protein target spectra, which is an obvious necessity to perform a global analysis. We then focus on the introduction of computational methods and tools to relate such target spectra to global models such as pathways and networks of protein-protein interactions, and to integrate them with existing protein functional annotations. In particular, we discuss how drug treatment can be mapped onto likely affected biological functions, how this can help identifying drug mechanisms of action, and how such mappings can be exploited to predict potential side effects and to suggest new indications for existing compounds. PMID- 22213658 TI - The physics, chemistry and dynamics of explosions. AB - The motivation for devoting a Theme Issue to explosions is discussed. As subsequent articles in the issue are written with the assumption that the reader has had a certain amount of previous exposure to the subject, some of the history and necessary background information are presented here. The topics on explosions that will be encountered in the remaining articles are previewed. Finally, several important future outstanding research problems, beyond those addressed in the following articles, are discussed, with the objective of complementing the coverage of explosions in this issue. PMID- 22213659 TI - Large vapour cloud explosions, with particular reference to that at Buncefield. AB - This paper first briefly surveys the energy releases in some major accidents. It then examines the analyses of the explosion at the Buncefield fuel storage site in the UK, one of the most intense accidental explosions in recent times. This followed the release of approximately 300 tonnes of winter-grade gasoline, when a 15 m high storage tank was overfilled for about 40 min before ignition of the resulting flammable mixture. The ensuing explosion was of a severity that had not been identified previously in a major hazard assessment of this type of facility. It was therefore imperative to investigate the event thoroughly and develop an understanding of the underlying mechanisms to inform future prevention, mitigation and land-use planning issues. The investigation of the incident was overseen by the Buncefield Major Incident Investigation Board. A separate Explosion Mechanism Advisory Group examined the evidence and reported on the severity of the explosion. It concluded that additional work was necessary and recommended that a two-stage project be initiated, phase 1 of which has been completed. The analyses of the damage and the derivation of explosion over pressures are described. Possible explosion mechanisms and the evidence for them at Buncefield are discussed, in the light of other major incidents. Mechanisms that are reviewed include high-speed turbulent combustion, quasi-detonations, fully developed detonations, the generation of fireballs, flame instabilites, radiative heat transfer and aspects of two-phase burning. Of particular importance is the acceleration of turbulent flames along the line of trees and hedgerows. A number of conclusions are drawn and suggestions made for further research. PMID- 22213660 TI - Gas-phase detonation propagation in mixture composition gradients. AB - The propagation of detonations through several fuel-air mixtures with spatially varying fuel concentrations is examined numerically. The detonations propagate through two-dimensional channels, inside of which the gradient of mixture composition is oriented normal to the direction of propagation. The simulations are performed using a two-component, single-step reaction model calibrated so that one-dimensional detonation properties of model low- and high-activation energy mixtures are similar to those observed in a typical hydrocarbon-air mixture. In the low-activation-energy mixture, the reaction zone structure is complex, consisting of curved fuel-lean and fuel-rich detonations near the line of stoichiometry that transition to decoupled shocks and turbulent deflagrations near the channel walls where the mixture is extremely fuel-lean or fuel-rich. Reactants that are not consumed by the leading detonation combine downstream and burn in a diffusion flame. Detonation cells produced by the unstable reaction front vary in size across the channel, growing larger away from the line of stoichiometry. As the size of the channel decreases relative to the size of a detonation cell, the effect of the mixture composition gradient is lessened and cells of similar sizes form. In the high-activation-energy mixture, detonations propagate more slowly as the magnitude of the mixture composition gradient is increased and can be quenched in a large enough gradient. PMID- 22213661 TI - Analytical studies of the dynamics of gaseous detonations. AB - The dynamics of gaseous detonation is revisited on the basis of analytical studies. Problems of initiation, quenching, pulsation and cellular structures are addressed. The objective is to improve our physical understanding of the development, stability and structure of gaseous detonations. New insights that have been gained from analytical investigations are emphasized. Specific problems discussed are the direct initiation of detonations in spherical geometry, the spontaneous soft initiation and quenching of detonations in a temperature gradient, the stability threshold and dynamics of galloping detonations, and the multi-dimensional instability threshold and cellular structures of both overdriven and near-Chapman-Jouguet detonations. It will be seen that, although there have been many accomplishments, some outstanding questions remain. PMID- 22213662 TI - Combustion waves in hydraulically resisted systems. AB - The effects of hydraulic resistance on the burning of confined/obstacle-laden gaseous and gas-permeable solid explosives are discussed on the basis of recent research. Hydraulic resistance is found to induce a new powerful mechanism for the reaction spread (diffusion of pressure) allowing for both fast subsonic as well as supersonic propagation. Hydraulic resistance appears to be of relevance also for the multiplicity of detonation regimes as well as for the transitions from slow conductive to fast convective, choked or detonative burning. A quasi one-dimensional Fanno-type model for premixed gas combustion in an obstructed channel open at the ignition end is discussed. It is shown that, similar to the closed-end case studied earlier, the hydraulic resistance causes a gradual precompression and preheating of the unburned gas adjacent to the advancing deflagration, which leads (after an extended induction period) to a localized autoignition that triggers an abrupt transition from deflagrative to detonative combustion. In line with the experimental observations, the ignition at the open end greatly encumbers the transition (compared with the closed-end case), and the deflagration practically does not accelerate up to the very transition point. Shchelkin's effect, that ignition at a small distance from the closed end of a tube facilitates the transition, is described. PMID- 22213663 TI - Explosion propagation in inert porous media. AB - Porous media are often used in flame arresters because of the high surface area to volume ratio that is required for flame quenching. However, if the flame is not quenched, the flow obstruction within the porous media can promote explosion escalation, which is a well-known phenomenon in obstacle-laden channels. There are many parallels between explosion propagation through porous media and obstacle-laden channels. In both cases, the obstructions play a duel role. On the one hand, the obstruction enhances explosion propagation through an early shear driven turbulence production mechanism and then later by shock-flame interactions that occur from lead shock reflections. On the other hand, the presence of an obstruction can suppress explosion propagation through momentum and heat losses, which both impede the unburned gas flow and extract energy from the expanding combustion products. In obstacle-laden channels, there are well-defined propagation regimes that are easily distinguished by abrupt changes in velocity. In porous media, the propagation regimes are not as distinguishable. In porous media the entire flamefront is affected, and the effects of heat loss, turbulence and compressibility are smoothly blended over most of the propagation velocity range. At low subsonic propagation speeds, heat loss to the porous media dominates, whereas at higher supersonic speeds turbulence and compressibility are important. This blending of the important phenomena results in no clear transition in propagation mechanism that is characterized by an abrupt change in propagation velocity. This is especially true for propagation velocities above the speed of sound where many experiments performed with fuel-air mixtures show a smooth increase in the propagation velocity with mixture reactivity up to the theoretical detonation wave velocity. PMID- 22213664 TI - Stability of detonation in a circular pipe with porous walls. AB - A stability analysis is carried out taking into account slightly porous walls in an idealized detonation confined to a circular pipe. The analysis is carried out using the normal-mode approach and corrections are obtained to the underlying impenetrable wall case results to account for the effect of the slight porosity. The porous walls are modelled by an acoustic boundary condition for the perturbations linking the normal velocity and the pressure components and thus replacing the conventional no-penetration boundary condition at the wall. This new boundary condition necessarily complicates the derivation of the stability problem with respect to the impenetrable wall case. However, exploiting the expressly slight porosity, the modified temporal stability can be determined as a two-point boundary value problem similar to the case of a non-porous wall. PMID- 22213665 TI - Autoignitions and detonations in engines and ducts. AB - The origins of autoignition at hot spots are analysed and the pressure pulses that arise from them are related to knock in gasoline engines and to developing detonations in ducts. In controlled autoignition engines, autoignition is benign with little knock. There are several modes of autoignition and the existence of an operational peninsula, within which detonations can develop at a hot spot, helps to explain the performance of various engines. Earlier studies by Urtiew and Oppenheim of the development of autoignitions and detonations ahead of a deflagration in ducts are interpreted further, using a simple one-dimensional theory of the generation of shock waves ahead of a turbulent flame. The theory is able to indicate entry into the domain of autoignition in an 'explosion in the explosion'. Importantly, it shows the influence of the turbulent burning velocity, and particularly its maximum attainable value, upon autoignition. This value is governed by localized flame extinctions for both turbulent and laminar flames. The theory cannot show any details of the transition to a detonation, but regimes of eventually stable or unstable detonations can be identified on the operational peninsula. Both regimes exhibit transverse waves, triple points and a cellular structure. In the case of unstable detonations, transverse waves are essential to the continuing propagation. For hazard assessment, more needs to be known about the survival, or otherwise, of detonations that emerge from a duct into the same mixture at atmospheric pressure. PMID- 22213666 TI - Some observations on the initiation and onset of detonation. AB - The results of experimental studies during which transition to detonation events occurred are presented. These observations and their interpretation are then discussed, and the conditions for the onset of detonation are described, with particular attention paid to the nature of the phenomena of deflagration-to detonation transition. The resulting implications for predicting detonation evolution using computational fluid dynamic methods in practical applications are also discussed. PMID- 22213667 TI - Plasma-assisted ignition and deflagration-to-detonation transition. AB - Non-equilibrium plasma demonstrates great potential to control ultra-lean, ultra fast, low-temperature flames and to become an extremely promising technology for a wide range of applications, including aviation gas turbine engines, piston engines, RAMjets, SCRAMjets and detonation initiation for pulsed detonation engines. The analysis of discharge processes shows that the discharge energy can be deposited into the desired internal degrees of freedom of molecules when varying the reduced electric field, E/n, at which the discharge is maintained. The amount of deposited energy is controlled by other discharge and gas parameters, including electric pulse duration, discharge current, gas number density, gas temperature, etc. As a rule, the dominant mechanism of the effect of non-equilibrium plasma on ignition and combustion is associated with the generation of active particles in the discharge plasma. For plasma-assisted ignition and combustion in mixtures containing air, the most promising active species are O atoms and, to a smaller extent, some other neutral atoms and radicals. These active particles are efficiently produced in high-voltage, nanosecond, pulse discharges owing to electron-impact dissociation of molecules and electron-impact excitation of N(2) electronic states, followed by collisional quenching of these states to dissociate the molecules. Mechanisms of deflagration to-detonation transition (DDT) initiation by non-equilibrium plasma were analysed. For longitudinal discharges with a high power density in a plasma channel, two fast DDT mechanisms have been observed. When initiated by a spark or a transient discharge, the mixture ignited simultaneously over the volume of the discharge channel, producing a shock wave with a Mach number greater than 2 and a flame. A gradient mechanism of DDT similar to that proposed by Zeldovich has been observed experimentally under streamer initiation. PMID- 22213668 TI - Astrophysical explosions: from solar flares to cosmic gamma-ray bursts. AB - Astrophysical explosions result from the release of magnetic, gravitational or thermonuclear energy on dynamical time scales, typically the sound-crossing time for the system. These explosions include solar and stellar flares, eruptive phenomena in accretion discs, thermonuclear combustion on the surfaces of white dwarfs and neutron stars, violent magnetic reconnection in neutron stars, thermonuclear and gravitational collapse supernovae and cosmic gamma-ray bursts, each representing a different type and amount of energy release. This paper summarizes the properties of these explosions and describes new research on thermonuclear explosions and explosions in extended circumstellar media. Parallels are drawn between studies of terrestrial and astrophysical explosions, especially the physics of the transition from deflagration-to-detonation. PMID- 22213669 TI - The permeability of silicone rubber to metal compounds: relevance to implanted devices. AB - Most implanted electrical devices use encapsulant as insulation. The encapsulant may remain functional for many years, bonded to the metallic surfaces, but eventually become partly detached allowing corrosion to occur. To understand whether the corrosion products will cause toxic effects, we need to know how quickly they will permeate through the encapsulant. In these experiments, silicone capsules (the encapsulant) containing metal compounds were left in jars of initially pure water for 6 months, and the concentration of the metal in the water was measured. The amount of metal depended on the type of compound; for the organometallic compounds tested, permeation was very rapid. However, for most of the other compounds, whether oxides or salts, the amount of metal was below the control level and therefore could have been the result of contamination. These compounds were tin sulfate and oxide (<102), lead nitrate and oxide (<102), copper sulfate (<103), and nitrates of bismuth (<101), chrome (<102), nickel (<103) and zinc (<102). The numbers in brackets are the maximum mass (ng) of permeated metal after 6 months. Three silver compounds were tested but without proper controls; however, the amount of permeated silver appeared to be low: silver oxide (1.3 * 102), silver nitrate (6.3 * 101), and silver chloride (6 * 100). The resolution of this method is limited by contamination that is detected by control capsules. The conclusion is that compounds that are likely corrosion products permeate through silicone encapsulant at a low rate and seem unlikely to cause toxic effects. PMID- 22213670 TI - Survival of the fittest in anatomical scholarship and the rapid evolution of Anatomical Sciences Education. PMID- 22213671 TI - A twin study of schizoaffective-mania, schizoaffective-depression, and other psychotic syndromes. AB - The nosological status of schizoaffective disorders remains controversial. Twin studies are potentially valuable for investigating relationships between schizoaffective-mania, schizoaffective-depression, and other psychotic syndromes, but no such study has yet been reported. We ascertained 224 probandwise twin pairs [106 monozygotic (MZ), 118 same-sex dizygotic (DZ)], where probands had psychotic or manic symptoms, from the Maudsley Twin Register in London (1948 1993). We investigated Research Diagnostic Criteria schizoaffective-mania, schizoaffective-depression, schizophrenia, mania and depressive psychosis primarily using a non-hierarchical classification, and additionally using hierarchical and data-derived classifications, and a classification featuring broad schizophrenic and manic syndromes without separate schizoaffective syndromes. We investigated inter-rater reliability and co-occurrence of syndromes within twin probands and twin pairs. The schizoaffective syndromes showed only moderate inter-rater reliability. There was general significant co-occurrence between syndromes within twin probands and MZ pairs, and a trend for schizoaffective-mania and mania to have the greatest co-occurrence. Schizoaffective syndromes in MZ probands were associated with relatively high risk of a psychotic syndrome occurring in their co-twins. The classification of broad schizophrenic and manic syndromes without separate schizoaffective syndromes showed improved inter-rater reliability, but high genetic and environmental correlations between the two broad syndromes. The results are consistent with regarding schizoaffective-mania as due to co-occurring elevated liability to schizophrenia, mania, and depression; and schizoaffective-depression as due to co-occurring elevated liability to schizophrenia and depression, but with less elevation of liability to mania. If in due course schizoaffective syndromes show satisfactory inter-rater reliability and some specific etiological factors they could alternatively be regarded as partly independent disorders. PMID- 22213672 TI - Enhanced binding affinity, remarkable selectivity, and high capacity of CO2 by dual functionalization of a rht-type metal-organic framework. PMID- 22213673 TI - Transparent and conducting graphene-RNA-based nanocomposites. AB - Ribonucleic acid (RNA) is proposed as a nonionic surfactant for the efficient exfoliation of graphite in thin flakes of few-layer graphene and the subsequent preparation of transparent and conducting thin films. Parameters such as the type of RNA used and the size of starting graphite flakes are demonstrated to be essential for obtaining RNA-graphene thin films of good quality. A model explaining the exfoliation of graphene by RNA in water is suggested. A number of post- and predeposition treatments (including thermal annealing, functionalization of the films, and the preoxidation of graphite) are critical to improve the performance of graphene-RNA nanocomposites as transparent conductors. The study establishes an ideal link between RNA and graphene, the fundamental building blocks for nanobiology and carbon-based nanotechnology. PMID- 22213675 TI - Integrated biofabrication for electro-addressed in-film bioprocessing. AB - Many recent advances in bioprocessing have been enabled by developments in miniaturization and microfluidics. A continuing challenge, however, is integrating multiple unit operations that require distinct spatial boundaries, especially with included labile biological components. We have suggested "biofabrication" as a means for organizing cells and biomolecules in complex configurations while preserving function of individual components. Polysaccharide films of chitosan and alginate that are assembled on-chip by electrodeposition are "smart" configurable interfaces that mediate communication between the biological systems and microfabricated devices. Here, we demonstrate the scalable performance of a production address, where incubated cells secrete antibodies, and a capture address, where secreted antibody is retained with specificity and subsequently assayed. The antibody exchange from one electro-address to another exemplifies integrated in-film bioprocessing, facilitated by the integrated biofabrication techniques used. This in-film approach enables complex processes without need for microfluidics and valving. Finally, we have shown scalability by reducing electrode sizes to a 1 mm scale without compromising film biofabrication or bioprocessing performance. The in situ reversible deposition of viable cells, productivity characterization, and capture of secreted antibodies could find use in bioprocessing applications such as clonal selection, run-to-run monitoring, initial scale-up, and areas including drug screening and biopsy analysis. PMID- 22213677 TI - A dissecting competition for medical students. AB - After repeated requests from medical students for more cadaver dissection opportunities, a voluntary dissecting "competition" was initiated for the third year medical students in 2006. This has been held annually on five occasions since, offering up to 30 dissection stations and accommodating an average of 53 students (range 40-66) per year, representing about 20-25% of the total class. Material is standardized to distal upper or lower limb specimens, each of which is dissected by one or two students during a single weekend day. Participants are required to complete their dissection in about six hours and present an appropriately labeled display together with a 300 word abstract, emphasizing clinical relevance. Dissections are judged on presentation, accuracy of identification and labeling, and relevance to the clinical abstract, taking into account the technical difficulty of the particular dissection. Judging from successive annual uptake of places and informal feedback, this is not only a popular event allowing students to focus creatively on producing a clinically relevant dissection in a relaxed learning environment but also of educational value. An unexpected outcome has been the production of many specimens suitable as prosections for future classes. A dissecting competition may be a useful method of stimulating learning for medical students interested in undertaking further dissection but it requires appropriate staff commitment and a supply of suitable cadaver specimens. PMID- 22213674 TI - The current Salmonella-host interactome. AB - Salmonella bacteria cause millions of infections and thousands of deaths every year. This pathogen has an unusually broad host range including humans, animals, and even plants. During infection, Salmonella expresses a variety of virulence factors and effectors that are delivered into the host cell triggering cellular responses through protein-protein interactions (PPI) with host cell proteins which make the pathogen's invasion and replication possible. To speed up proteomic efforts in elucidating Salmonella-host interactomes, we carried out a survey of the currently published Salmonella-host PPI. Such a list can serve as the gold standard for computational models aimed at predicting Salmonella-host interactomes through integration of large-scale biological data sources. Manual literature and database search of >2200 journal articles and >100 databases resulted in a gold standard list of currently 62 PPI, including primarily interactions of Salmonella proteins with human and mouse proteins. Only six of these interactions were directly retrievable from PPI databases and 16 were highlighted in databases featuring literature extracts. Thus, the literature survey resulted in the most complete interactome available to date for Salmonella. Pathway analysis using Ingenuity and Broad Gene Set Enrichment Analysis (GSEA) software revealed among general pathways such as MAPK signaling in particular those related to cell death as well as cell morphology, turnover, and interactions, in addition to response to not only Salmonella but also other pathogenic - viral and bacterial - infections. The list of interactions is available at http://www.shiprec.org/indicationslist.htm. PMID- 22213676 TI - Gradual pore formation in natural origin scaffolds throughout subcutaneous implantation. AB - This study used a rat subcutaneous implantation model to investigate gradual in situ pore formation in a self-regulating degradable chitosan-based material, which comprises lysozyme incorporated into biomimetic calcium phosphate (CaP) coatings at the surface to control the scaffold degradation and subsequent pore formation. Specifically, the in vivo degradation of the scaffolds, the in situ pore formation, and the tissue response were investigated. Chitosan or chitosan/starch scaffolds were studied with and without a CaP coating in the presence or absence of lysozyme for a total of six experimental groups. Twenty four scaffolds per group were implanted, and eight scaffolds were retrieved at each of three time points (3, 6, and 12 weeks). Harvested samples were analyzed for weight loss, microcomputed tomography, and histological analysis. All scaffolds showed pronounced weight loss and pore formation as a function of time. The highest weight loss was 29.8% +/- 1.5%, obtained at week 12 for CaP chitosan/starch scaffolds with lysozyme incorporated. Moreover, all experimental groups showed a significant increase in porosity after 12 weeks. At all time points no adverse tissue reaction was observed, and as degradation increased, histological analysis showed cellular ingrowth throughout the implants. Using this innovative methodology, the ability to gradually generate pores in situ was clearly demonstrated in vivo. PMID- 22213678 TI - PLA2G6 mutations in PARK14-linked young-onset parkinsonism and sporadic Parkinson's disease. AB - Mutations of PLA2G6 gene have been lately proposed to be the causative gene for PARK14 in patients with autosomal recessive young-onset parkinsonism (YOPD). The role of PLA2G6 mutations as a risk factor for Parkinson's disease is not clear. To study the PLA2G6 mutations in PARK14-linked patients and its association with the onset of sporadic Parkinson's disease (sPD), sequencing and gene dosage analyses were carried out in 25 patients (onset age ?30 years) then the identified variants were assessed in 956 sporadic PD (sPD) patients and 802 age matched healthy controls. Four genetic variants were identified; one patient had homozygous c.991G > T (p.Asp331Tyr) mutation, two had compound heterozygous c.991G > T/c.1077G > A (p.Met358IlefsX) mutation, one had single c.1976A > G (p.Asn659Ser) mutation, and one patient had an exon 1 hetero-deletion. The c.1077G > A mutation resulted in a 4-bp deletion in leukocyte mRNA by activating a cryptic splice site in exon 7. Only p.Asp331Tyr was identified in four sPD patients and four controls. The onset age for PLA2G6 mutation carriers was younger than that for sPD (29.86 +/- 8.59 vs. 56.84 +/- 11.33 years, P = 0.0002). The analysis of previously reported PARK14 patients revealed that those who carried a truncated mutation tended to have a complicated phenotype and atrophies of cortex and cerebellum. In conclusion, PLA2G6 mutation was the second common genetic cause after PRKN mutation in our YOPD patients and might be a risk factor for early-onset PD in Han Chinese. Additionally, mutation data should be interpreted carefully because even a synonymous mutation could cause abnormal mRNA splicing. PMID- 22213679 TI - Efficient gene delivery to mesenchymal stem cells by an ethylenediamine-modified polysaccharide from mulberry leaves. AB - This study investigates the use of a natural polysaccharide isolated from mulberry leaves as a nonviral gene vector. Ethylenediamine is chemically grafted to the backbone of a polysaccharide from mulberry leaves (MPS) to acquire nucleic acid binding affinity. A particle-size observation indicates that the cationic mulberry leaf polysaccharide (CMPS) can efficiently combine with plasmid transforming growth factor beta1 (TGF-beta1) to form nanoscaled particles. In addition, the electrophoresis assay indicates a retarded plasmid migration when the CMPS/pTGF-beta1 weight ratio is increased to 30:1. The in vitro cell transfection experiment is performed based on bone marrow mesenchymal stem cells (MSCs) derived from rat femurs and tibias, and the findings reveal that the complex with a CMPS/pTGF-beta1 weight ratio of 50:1 exhibits the highest cell transfection effect, which is significantly higher than that of branched poly(ethyleneimine) (PEI) (25 kDa; p = 0.001, Student's t-test) and slightly higher than Lipofectamine 2000. Moreover, the cytotoxicity assay also demonstrates that all of these tested complexes and the plasmid TGF-beta1 are nontoxic to mesenchymal stem cells (MSCs). The results of the living cell imaging confirm that more of the CMPS/plasmid TGF-beta1 nanoparticles can be taken up and at a faster rate by the MSCs than by the positive control Lipofectamine 2000; these data are consistent with the transfection efficiency data. Together, these results suggest that the CMPS/pTGF-beta1 nanoparticle can potentially be developed into a promising alternative for the transfer of therapeutic genes into cells. PMID- 22213680 TI - Digital imaging in pathology--current applications and challenges. AB - Conventional histopathology is rapidly shifting towards digital integration. Will microscopes (and pathologists) soon be obsolete? Or are we dealing with just another image modality that leaves the core of tissue diagnosis intact? This article provides an overview of current digital pathology applications and research with emphasis on whole slide imaging (WSI). Static or interactive digital pathology work stations already can be used for many purposes, e.g. telepathology expert consultations, frozen section diagnosis in remote areas, cytology screening, quality assurance, diagnostic validations for clinical trials, quantitation of hormone receptor or HER2 studies in breast cancer, or three-dimensional visualization of anatomical structures, among others. Changes of workflow in histology laboratories are beginning to enable digital image acquisition and WSI in a routine setting. WSI plays an increasing role in pathology education, glass slide boxes in medical schools are being replaced by digital slide collections; digital slide seminars and virtual microscopy are used for postgraduate and continuing medical education in pathology. Research and efforts to validate WSI systems for diagnostic settings are ongoing. PMID- 22213681 TI - The cost and cost-effectiveness of opportunistic screening for Chlamydia trachomatis in Ireland. AB - OBJECTIVE: The objective of this study was to estimate the cost and cost effectiveness of opportunistic screening for Chlamydia trachomatis in Ireland. METHODS: Prospective cost analysis of an opportunistic screening programme delivered jointly in three types of healthcare facility in Ireland. Incremental cost-effectiveness analysis was performed using an existing dynamic modelling framework to compare screening to a control of no organised screening. A healthcare provider perspective was adopted with respect to costs and included the costs of screening and the costs of complications arising from untreated infection. Two outcome measures were examined: major outcomes averted, comprising cases of pelvic inflammatory disease, ectopic pregnancy and tubal factor infertility in women, neonatal conjunctivitis and pneumonia, and epididymitis in men; and quality-adjusted life-years (QALY) gained. Uncertainty was explored using sensitivity analyses and cost-effectiveness acceptability curves. RESULTS: The average cost per component of screening was estimated at ?26 per offer, ?66 per negative case, ?152 per positive case and ?74 per partner notified and treated. The modelled screening scenario was projected to be more effective and more costly than the control strategy. The incremental cost per major outcomes averted was ?6093, and the incremental cost per QALY gained was ?94,717. For cost effectiveness threshold values of ?45,000 per QALY gained and lower, the probability of the screening being cost effective was estimated at <1%. CONCLUSIONS: An opportunistic chlamydia screening programme, as modelled in this study, would be expensive to implement nationally and is unlikely to be judged cost effective by policy makers in Ireland. PMID- 22213682 TI - Reaction engineering studies of acetone-butanol-ethanol fermentation with Clostridium acetobutylicum. AB - Acetone-butanol-ethanol (ABE) fermentation by Clostridium acetobutylicum has been extensively studied in recent years because the organism is recognized as an excellent butanol producer. A parallel bioreactor system with 48 stirred-tank bioreactors on a 12 mL scale was evaluated for batch cultivations of the strictly anaerobic, butanol-producing C. acetobutylicum ATCC 824. Continuous gassing with nitrogen gas was applied to control anaerobic conditions. Process performances of ABE batch fermentations on a milliliter scale were identical to the liter-scale stirred-tank reactor if reaction conditions were identical on the different scales (e.g., initial medium, pH, temperature, specific evaporation rates, specific power input by the stirrers). The effects of varying initial ammonia concentrations (0.1-4.4 g L(-1) ) were studied in parallel with respect to glucose consumption and butanol production of C. acetobutylicum ATCC 824 as a first application example. The highest butanol yield of 33% (mol mol(-1) ) was observed at initial ammonia concentrations of 0.5 and 1.1 g L(-1) . This is the first report on the successful application of a 48 parallel stirred-tank bioreactor system for reaction engineering studies of strictly anaerobic microorganisms at the milliliter scale. PMID- 22213683 TI - The 29th Manfred Donike workshop on doping analysis. PMID- 22213684 TI - Development of liquid chromatography-tandem mass spectrometry-based analytical assays for the determination of HIF stabilizers in preventive doping research. AB - Hypoxia-inducible factor (HIF) stabilizers increase blood haemoglobin levels after oral administration and their use in sports was recently banned by the World Anti-Doping Agency. For the support of analytical assay development, the metabolic fate of two model HIF stabilizers, based on the isoquinoline-3 carboxamide scaffold of the lead drug candidate FG-2216, was assessed by in vitro methods. The analytes were identified and characterized by liquid chromatography tandem mass spectrometry (LC-MS/MS) in positive and negative ionization mode using an API 4000 Qtrap as well as an exactive high resolution-high accuracy MS. The model HIF stabilizer N-[(1-chloro-4-hydroxy-7-isopropoxy-isoquinolin-3 carbonyl)-amino]-acetic acid (1), was converted into 3 major phase I metabolites by hydroxylation, dealkylation, and dehydrogenation. The structures of the hydroxylated and the dealkylated metabolites were confirmed by LC-coupled nuclear magnetic resonance spectroscopy. Moreover, glucuronic acid conjugates of the active drug and one of the dealkylated phase I metabolite were identified. Hydroxylation of model compound 2 (N-[(1-chloro-4-hydroxy-isoquinolin-3-carbonyl) amino]-acetic acid) yielded two metabolites, regioisomeric to the dealkylated product of 1. Mass spectral data of compounds 1 and 2, as well as a structure related analogue were included into a multi-target analytical assay based on direct injection and LC-MS/MS analysis of human urine. The method was validated for quantitative purposes. In an approach of preventive doping research, more comprehensive screening methods applying precursor ion (m/z 166) and neutral loss (-10 Da) scans were developed, allowing for the detection of unknown metabolites and structurally analogous HIF stabilizers emerging from ongoing lead structure developments. PMID- 22213685 TI - Urinary concentrations of ethyl glucuronide and ethyl sulfate as thresholds to determine potential ethanol-induced alteration of steroid profiles. AB - The suppression of steroid biotransformation resulting in a decrease of the major urinary metabolites--androsterone and etiocholanolone--and the elevation of testosterone/epitestosterone (T/E) ratios following ethanol administration is well described. At least the latter parameter T/E represents an important indicator for endogenous steroid abuse in doping control. The quantitative correlation between ethanol consumption markers and steroid profile alteration was evaluated, aiming to differentiate between permitted ethanol administration and potential steroid abuse. Steroid profiles, ethanol, ethyl glucuronide (EtG), and sulfate (EtS) were quantified after administration of ethanol (intended maximum ethanol concentration in blood was 1 mg/g) to 21 male and 15 female volunteers. EtG concentrations in urine (corrected by either specific gravity or creatinine concentration) were found to be most suitable for quantitative evaluations. Gender specific urinary EtG concentrations of 48 ug/ml (men) and 15.5 ug/ml (women) may be considered as useful thresholds for a potential ethanol induced suppression of steroids biotransformation. PMID- 22213686 TI - Unconventional layer-by-layer assembly: surface molecular imprinting and its applications. AB - Layer-by-layer assembly (LbL) is a rich, versatile, and powerful technique for fabricating multilayer thin films with controlled architecture and functions. Singly charged, uncharged, or water-repellent molecules cannot be used directly in conventional LbL assembly. This problem can be solved with unconventional LbL methods, by employing the preassembly of building blocks in solution and the use of these assemblies for LbL formation at the interface. This Concept summarizes different methods of unconventional LbL assembly, including electrostatic complex formation, hydrogen-bonded complexes, block-copolymer micelles, and pi-pi interaction complexes. These preassembly treatments endow the building blocks with enhanced abilities for advanced functionality, in particular, surface molecular imprinting, a new concept emerging from unconventional LbL. Molecular imprinting approaches are thus conceptually described based on different types of interactions and their great potential in applications is demonstrated by examples such as selective surface patterning and selective filtration. PMID- 22213688 TI - Investigation of the permeability and optical clearing ability of different analytes in human normal and cancerous breast tissues by spectral domain OCT. AB - The potential of OCT applied for early breast cancer detection attracted significant efforts. The permeability coefficients and the percentages of OCT signal enhancement for normal and cancerous breast tissues have been investigated from the experiments of 20% glucose, 40% glucose, and 20% mannitol in vitro. Obtained results indicate that the permeability coefficient in breast cancer tissue is prominently larger than that in normal breast tissue, while the optical clearing effect is just the reverse to that for each agent. The results suggest that OCT has the ability to distinguish cancer tissue from different aspect. PMID- 22213689 TI - Quality research. Outstanding publications. PMID- 22213693 TI - Simultaneous quantification of five marker compounds of Betula utilis stem bark using a validated high-performance thin-layer chromatography method. AB - A sensitive, selective and robust densitometric high-performance thin-layer chromatographic method was developed and validated for five marker compounds, namely betulin, lupeol, oleanolic acid, 3-acetyloleanolic acid and beta sitosterol, known for their various therapeutic activities. The marker compounds have been isolated from the stem bark of Betula utilis, well characterized by the spectral analysis, and their simultaneous quantitative determination carried out by high-performance thin-layer chromatography (HPTLC) method. The resolution of marker compounds was carried out on silica-gel 60 plates, using n-hexane:ethyl acetate (8:2 v/v) as the mobile phase. The HPTLC densitometry was performed at 500-nm wavelength after the post chromatographic derivatization with ceric ammonium sulfate reagent. The optimized method provided good linear relation (r>0.9960) for all the investigated analytes. The method is simple, and reproducible, which may be applied for quantitative analysis of the above mentioned marker compounds. PMID- 22213687 TI - Longevity candidate genes and their association with personality traits in the elderly. AB - Human longevity and personality traits are both heritable and are consistently linked at the phenotypic level. We test the hypothesis that candidate genes influencing longevity in lower organisms are associated with variance in the five major dimensions of human personality (measured by the NEO-FFI and IPIP inventories) plus related mood states of anxiety and depression. Seventy single nucleotide polymorphisms (SNPs) in six brain expressed, longevity candidate genes (AFG3L2, FRAP1, MAT1A, MAT2A, SYNJ1, and SYNJ2) were typed in over 1,000 70-year old participants from the Lothian Birth Cohort of 1936 (LBC1936). No SNPs were associated with the personality and psychological distress traits at a Bonferroni corrected level of significance (P < 0.0002), but there was an over representation of nominally significant (P < 0.05) SNPs in the synaptojanin-2 (SYNJ2) gene associated with agreeableness and symptoms of depression. Eight SNPs which showed nominally significant association across personality measurement instruments were tested in an extremely large replication sample of 17,106 participants. SNP rs350292, in SYNJ2, was significant: the minor allele was associated with an average decrease in NEO agreeableness scale scores of 0.25 points, and 0.67 points in the restricted analysis of elderly cohorts (most aged >60 years). Because we selected a specific set of longevity genes based on functional genomics findings, further research on other longevity gene candidates is warranted to discover whether they are relevant candidates for personality and psychological distress traits. PMID- 22213694 TI - Forced extension of delipidated red blood cell cytoskeleton with little indication of spectrin unfolding. AB - Force-extension curves obtained on intact human red blood cells (RBC) were compared with those of delipidated RBCs to assess the contribution of cytoskeletal flexibility to the extensibility of the intact membrane skeleton. The RBCs were first delipidated by treatment with phospholipase A2; tensile properties of the exposed cytoskeletal structures were measured using an atomic force microscope (AFM). The AFM probes were modified either with the Band 3 specific lectin, concanavalin A, (Con A) or anti-F-actin antibody, to localize the point of interaction between the probe and the cytoskeleton. Extension of the spectrin-based cytoskeleton reached up to 2-3 MUm with a force less than 70 pN without showing any force peaks before the final rupture of the adhesive bonds. Our interpretation of the result is that the spectrin-based network was slack enough to allow the observed degree of extension without unfolding the tetrameric spectrin molecules. The force-extension curves obtained either on Band 3-ankyrin loci or on junction nodes of the cytoskeleton were not significantly different. Experimental results were verified by computer simulation of pulling mechanics of a network model of the RBC cytoskeleton. Our experimental results are also in agreement with the theoretical prediction of Mirijanian and Voth [2008; Proc Natl Acad Sci USA 105:1204-1208]. PMID- 22213695 TI - Mutations in MECP2 exon 1 in classical Rett patients disrupt MECP2_e1 transcription, but not transcription of MECP2_e2. AB - The overwhelming majority of Rett syndrome cases are caused by mutations in the gene MECP2. MECP2 has two isoforms, termed MECP2_e1 and MECP2_e2, which differ in their N-terminal amino acid sequences. A growing body of evidence has indicated that MECP2_e1 may be the etiologically relevant isoform in Rett Syndrome based on its expression profile in the brain and because, strikingly, no mutations have been discovered that affect MECP2_e2 exclusively. In this study we sought to characterize four classical Rett patients with mutations that putatively affect only the MECP2_e1 isoform. Our hypothesis was that the classical Rett phenotype seen here is the result of disrupted MECP2_e1 expression, but with MECP2_e2 expression unaltered. We used quantitative reverse transcriptase PCR to assay mRNA expression for each isoform independently, and used cytospinning methods to assay total MECP2 in peripheral blood lymphocytes (PBL). In the two Rett patients with identical 11 bp deletions within the coding portion of exon 1, MECP2_e2 levels were unaffected, whilst a significant reduction of MECP2_e1 levels was detected. In two Rett patients harboring mutations in the exon 1 start codon, MECP2_e1 and MECP2_e2 mRNA amounts were unaffected. In summary, we have shown that patients with exon 1 mutations transcribe normal levels of MECP2_e2 mRNA, and most PBL are positive for MeCP2 protein, despite them theoretically being unable to produce the MECP2_e1 isoform, and yet still exhibit the classical RTT phenotype. Altogether, our work further supports our hypothesis that MECP2_e1 is the predominant isoform involved in the neuropathology of Rett syndrome. PMID- 22213696 TI - Copper nanoparticle-catalyzed carbon-carbon and carbon-heteroatom bond formation with a greener perspective. AB - The carbon-carbon and carbon-heteroatom bond formations constitute the backbone of organic synthesis and have been widely used in the synthesis of natural products and useful compounds. Because of growing environmental concern, more attention has been focussed on the development of greener methods. Copper is environment-friendly and comparatively inexpensive. Although the use of copper salts in catalysis has been known since the last century, this area of research has been less explored compared to other metals, such as palladium, magnesium, and zinc. This review highlights the general features of nanoparticles as catalysts with particular reference to copper and the recent developments in the copper(0) nanoparticle-catalyzed C(aryl)-C(aryl/alkynyl), C(aryl)-N, C(aryl)-O, C(aryl)-S, and C(aryl)-Se bond formations and related reactions. The mechanisms of the reactions have been outlined and discussed with respect to the active catalytic species and possible intermediates. The scope, limitations, and green aspects of the reactions have also been highlighted. The convenient methods of preparation of copper nanoparticles and their characterization are described. PMID- 22213697 TI - A benzopyrane derivative as a P-glycoprotein stimulator: a potential agent to decrease beta-amyloid accumulation in Alzheimer's disease. PMID- 22213698 TI - Simple preparative gas chromatographic method for isolation of menthol and menthone from peppermint oil, with quantitative GC-MS and (1) H NMR assay. AB - The quantitative performance of a simple home-built preparative gas chromatography (prep-GC) arrangement was tested, incorporating a micro-fluidic Deans switch, with collection of the target compound in a deactivated uncoated capillary tube. Repeat injections of a standard solution and peppermint sample were made into the prep-GC instrument. Individual compounds were eluted from the trapping capillary, and made up to constant volume. Chloronaphthalene internal standard was added in some cases. Recovered samples were quantitatively assayed by using GC-MS. Calibration linearity of GC-MS for menthol standard area response against number of injections (2-20 repeat injections) was excellent, giving R(2) of 0.996. For peppermint, menthol correlation over 2-20 repeated injections was 0.998 for menthol area ratio (versus IS) data. Menthone calibration for peppermint gave an R(2) of 0.972. (1) H NMR spectroscopy was conducted on both menthol and menthone. Good correspondence with reference spectra was obtained. About 80 MUg of isolated menthol and menthone solute was collected over a sequence of 80 repeat injections from the peppermint sample, as assayed by 600 MHz (1) H NMR analysis (~100% recovery for menthol from peppermint). A procedure is proposed for prediction of number of injections required to acquire sufficient material for NMR detection. PMID- 22213700 TI - Automating flow cytometry. PMID- 22213699 TI - Plus-end directed myosins accelerate actin filament sliding by single-headed myosin VI. AB - Myosin VI (Myo6) is unique among myosins in that it moves toward the minus (pointed) end of the actin filament. Thus to exert tension on, or move cargo along an actin filament, Myo6 is working against potentially multiple plus (barbed)-end myosins. To test the effect of plus-end motors on Myo6, the gliding actin filament assay was used to assess the motility of single-headed Myo6 in the absence and presence of cardiac myosin II (Myo2) and myosin Va (Myo5a). Myo6 alone exhibited a filament gliding velocities of 60.34 +/- 13.68 nm/s. Addition of either Myo2 or Myo5a, at densities below that required to promote plus-end movement resulted in an increase in Myo6 velocity (~100-150% increase). Movement in the presence of these plus-end myosins was minus-end directed as determined using polarity tagged filaments. High densities of Myo2 or Myo5a were required to convert to plus-end directed motility indicating that Myo6 is a potent inhibitor of Myo2 and Myo5a. Previous studies have shown that two-headed Myo6 slows and then stalls in an anchored state under load. Consistent with these studies, velocity of a two headed heavy mero myosin form of Myo6 was unaffected by Myo5a at low densities, and was inhibited at high Myo5a densities. PMID- 22213701 TI - Oxidation of benzyl alcohol by using gold nanoparticles supported on ceria foam. AB - The efficacy of using cerium oxide foams as a support for Au nanoparticles and subsequent use as oxidation catalysts have been investigated. These were synthesized using L-asparagine to produce a cerium coordination polymer foam, which was calcined to give the oxide foam. Au nanoparticles were supported on the CeO(2) foams using a sol-immobilization method. The activity of the Au/foamCeO(2) for solvent-free benzyl alcohol oxidation was superior to standard Au/CeO(2) catalysts, and the activity was found to be dependent on the crystallization time of the precursor foam. A crystallization time of 4 h was found to produce the most active catalyst, which retained activity and a high selectivity to benzaldehyde (ca. 96 %) when re-used and this is related to the structure of the material. The high activity is attributed to the greater lability of surface oxygen in the support compared with commercial CeO(2) materials. PMID- 22213702 TI - Experimental and computational active site mapping as a starting point to fragment-based lead discovery. AB - Small highly soluble probe molecules such as aniline, urea, N-methylurea, 2 bromoacetate, 1,2-propanediol, nitrous oxide, benzamidine, and phenol were soaked into crystals of various proteins to map their binding pockets and to detect hot spots of binding with respect to hydrophobic and hydrophilic properties. The selected probe molecules were first tested at the zinc protease thermolysin. They were then applied to a wider range of proteins such as protein kinase A, D-xylose isomerase, 4-diphosphocytidyl-2C-methyl-D-erythritol synthase, endothiapepsin, and secreted aspartic protease 2. The crystal structures obtained clearly show that the probe molecules populate the protein binding pockets in an ordered fashion. The thus characterized, experimentally observed hot spots of binding were subjected to computational active site mapping using HotspotsX. This approach uses knowledge-based pair potentials to detect favorable binding positions for various atom types. Good agreement between the in silico hot spot predictions and the experimentally observed positions of the polar hydrogen bond forming functional groups and hydrophobic portions was obtained. Finally, we compared the observed poses of the small-molecule probes with those of much larger structurally related ligands. They coincide remarkably well with the larger ligands, considering their spatial orientation and the experienced interaction patterns. This observation confirms the fundamental hypothesis of fragment-based lead discovery: that binding poses, even of very small molecular probes, do not significantly deviate or move once a ligand is grown further into the binding site. This underscores the fact that these probes populate given hot spots and can be regarded as relevant seeds for further design. PMID- 22213703 TI - Analysis of glycoforms on the glycosylation site and the glycans in monoclonal antibody biopharmaceuticals. AB - Therapeutic monoclonal antibodies (mAbs), immunoglobulins, have been efficiently used in the treatment of many diseases, such as cancer, inflammatory and cardiovascular diseases, and organ transplantation. mAbs are glycoprotein molecules undergoing posttranslational modifications. Glycosylation is one of the posttranslational modifications. Different glycoforms that are important for maintaining the potency of mAb drugs show various biological activities. Therefore, the profile of the glycans and glycosylation sites should be determined to produce safe, good quality, consistent mAb drugs for human use. For this reason, simple, robust, accurate, and reproducible analytical methods need to be developed. In this article, chromatographic methods for the analysis of the glycoforms on the glycosylation site and the glycans in mAb biopharmaceuticals have been evaluated. PMID- 22213705 TI - Molecular-scale interface engineering of nanocrystalline titania by co-adsorbents for solar energy conversion. AB - The use of mixed self-assembled monolayers, combining hydrophobic co-adsorbents with the sensitizer, has been demonstrated to enhance the efficiency of dye sensitized solar cells (DSCs). Herein, the influence of the anchoring groups of the co-adsorbents on the performance of the DSCs is carefully examined by selecting two model molecules: neohexyl phosphonic acid (NHOOP) and bis-(3,3 dimethyl-butyl)-phosphinic acid (DINHOP). The effect of these co-adsorbents on the photovoltaic performance (J-V curves, incident photon-to-electron conversion efficiency) is investigated. Photoelectron spectroscopy and electrochemical impedance spectroscopy are performed to assess the spatial configuration of adsorbed dye and co-adsorbent molecules. The photoelectron spectroscopy studies indicate that the ligands of the ruthenium complex, containing thiophene groups, point out away from the surface of TiO(2) in comparison with the NCS group. PMID- 22213704 TI - Isolation of synaptic terminals from Alzheimer's disease cortex. AB - Amyloid beta (Abeta) oligomers and phosphorylated tau (p-tau) aggregates are increasingly identified as potential toxic intermediates in Alzheimer's disease (AD). In cortical AD synapses, p-tau co-localizes with Abeta, but the Abeta and p tau peptide species responsible for synaptic dysfunction and demise remains unclear. The present experiments were designed to use high-speed cell sorting techniques to purify synaptosome population based on size, and then extend the method to physically isolate Abeta-positive synaptosomes with the goal of understanding the nature of Abeta and tau pathology in AD synapses. To examine the purity of size-gated synaptosomes, samples were first gated on size; particles with sizes between 0.5 and 1.5 microns were collected. Electron microscopy documented a homogenous population of spherical particles with internal vesicles and synaptic densities. Next, size-gated synaptosomes positive for Abeta were collected by fluorescence activated sorting and then analyzed by immunoblotting techniques. Sorted Abeta-positive synaptosomes were enriched for amyloid precursor protein (APP) and for Abeta oligomers and aggregates; immunolabeling for p-tau showed a striking accumulation of p-tau aggregates compared to the original homogenate and purified synaptosomes. These results confirm co-localization of Abeta and p-tau within individual synaptic terminals and provide proof of concept for the utility of flow sorting synaptosomes. PMID- 22213706 TI - Engineering and functionalization of the disulfide-constrained miniprotein min-23 as a scaffold for diagnostic application. AB - Miniproteins are scaffolds for the development of alternative non-immunoglobin binding agents for medical applications. This peptide format features high tolerance to sequence mutagenesis, excellent proteolytic stability, and fast blood pool clearance. Herein we present the total chemical synthesis of the disulfide-constrained scaffold Min-23 and its functionalization for in vitro and in vivo application. Optimized solid-phase peptide chemistry and oxidative folding strategies were developed to engineer this miniprotein with native-like disulfide configuration. High levels of serum stability and proteolytic resistance, as well as a beneficial pharmacokinetic profile for diagnostic imaging, were determined by using radiolabeling techniques such as positron emission tomography. The reported achievements highlight Min-23 as a promising scaffold for the development of novel recognition molecules for medical application. PMID- 22213707 TI - Simultaneous determination of serotonin and creatinine in urine by combining two ultrasound-assisted emulsification microextractions with on-column stacking in capillary electrophoresis. AB - This article describes the development of a rapid, simple, and sensitive analytical approach for the simultaneous determination of serotonin (5 hydroxytryptamine) and creatinine in urine samples by combining two ultrasound assisted emulsification microextractions (USAEMEs) in series with on-column stacking in CE. This serial USAEME procedure comprises analytes extraction from the donor solution (urine with K(2) CO(3) additive) to an organic solvent followed by a back-extraction from the organic phase into a small volume of hydrochloric acid. After 15 min of sample pretreatment, the acidic acceptor solution was analyzed directly on CE in the mode of capillary zone electrophoresis. The adoption of HCl as the acceptor phase not only provided effective back-extraction but also facilitated pH-mediated on-column stacking in CE analysis. About 360-fold sensitivity enhancement was achieved for serotonin detection. The limits of detection were 7.9 nM for serotonin and 13.3 MUM for creatinine, respectively. Satisfactory results were obtained with respect to precision and recovery. The proposed method has been demonstrated to be convenient and effective for the analysis of real urine samples. We believe that two USAEMEs in series will find wide applications in simplified sample pretreatment prior to CE analysis. PMID- 22213708 TI - Interpreting the evolutionary regression: the interplay between observational and biological errors in phylogenetic comparative studies. AB - Regressions of biological variables across species are rarely perfect. Usually, there are residual deviations from the estimated model relationship, and such deviations commonly show a pattern of phylogenetic correlations indicating that they have biological causes. We discuss the origins and effects of phylogenetically correlated biological variation in regression studies. In particular, we discuss the interplay of biological deviations with deviations due to observational or measurement errors, which are also important in comparative studies based on estimated species means. We show how bias in estimated evolutionary regressions can arise from several sources, including phylogenetic inertia and either observational or biological error in the predictor variables. We show how all these biases can be estimated and corrected for in the presence of phylogenetic correlations. We present general formulas for incorporating measurement error in linear models with correlated data. We also show how alternative regression models, such as major axis and reduced major axis regression, which are often recommended when there is error in predictor variables, are strongly biased when there is biological variation in any part of the model. We argue that such methods should never be used to estimate evolutionary or allometric regression slopes. PMID- 22213710 TI - Simultaneously mapping and superimposing landmark configurations with parsimony as optimality criterion. AB - All methods proposed to date for mapping landmark configurations on a phylogenetic tree start from an alignment generated by methods that make no use of phylogenetic information, usually by superimposing all configurations against a consensus configuration. In order to properly interpret differences between landmark configurations along the tree as changes in shape, the metric chosen to define the ancestral assignments should also form the basis to superimpose the configurations. Thus, we present here a method that merges both steps, map and align, into a single procedure that (for the given tree) produces a multiple alignment and ancestral assignments such that the sum of the Euclidean distances between the corresponding landmarks along tree nodes is minimized. This approach is an extension of the method proposed by Catalano et al. (2010. Phylogenetic morphometrics (I): the use of landmark data in a phylogenetic framework. Cladistics. 26:539-549) for mapping landmark data with parsimony as optimality criterion. In the context of phylogenetics, this method allows maximizing the degree to which similarity in landmark positions can be accounted for by common ancestry. In the context of morphometrics, this approach guarantees (heuristics aside) that all the transformations inferred on the tree represent changes in shape. The performance of the method was evaluated on different data sets, indicating that the method produces marked improvements in tree score (up to 5% compared with generalized superimpositions, up to 11% compared with ordinary superimpositions). These empirical results stress the importance of incorporating the phylogenetic information into the alignment step. PMID- 22213711 TI - Are Asteraceae 1.5 billion years old? A reply to heads. PMID- 22213712 TI - The effect of taxol microinjection on the microtubular structure in polar body formation of starfish oocytes. AB - In starfish oocytes, microtubules (MTs) form a spindle, which plays an important role in contributing to the selective loss of chromosomes and centrosomes to the polar bodies (PBs) during meiosis. When Taxol was locally injected near the germinal vesicle (GV) or the mitotic apparatus during meiosis I, PB formation was inhibited as mentioned below. In the oocytes, which were injected with Taxol after spindle formation, the spindle became large, and then the volume of the first PB also increased more than that of the control. In contrast, in the oocytes injected with Taxol before the spindle formation, chromosome capture and alignment were inhibited. These oocytes did not form PB, but only a bulge at the cell cortex was occasionally observed. Moreover, in the oocytes injected with Taxol before GV breakdown, the chromosomes did not gather in one place, and then two asters were observed at distant positions from the cell cortex. These results suggested that MTs lost not only the ability to obtain the bipolar attachment of chromosomes by Taxol injection but also the aster closer to the cell cortex lost its interaction with the cell cortex of the animal pole. PMID- 22213713 TI - Isosorbide as a renewable platform chemical for versatile applications--quo vadis? AB - Isosorbide is a platform chemical of considerable importance for the future replacement of fossil resource-based products. Applications as monomers and building blocks for new polymers and functional materials, new organic solvents, for medical and pharmaceutical applications, and even as fuels or fuel additives are conceivable. The conversion of isosorbide to valuable derivatives by functionalization or substitution of the hydroxyl groups is difficult because of the different configurations of the 2- and 5-positions and the resulting different reactivity and steric hindrance of the two hydroxyl groups. Although a substantial amount of work has been published using exclusively the endo or exo derivatives isomannide and isoidide, respectively, as starting material, a considerable effort is still necessary to transfer and adapt these methods for the efficient conversion of isosorbide. This Minireview deals with all aspects of isosorbide chemistry, which includes its production by catalytic processes, special properties, and chemical transformations for its utilization in biogenic polymers and other applications of interest. PMID- 22213709 TI - Pleistocene speciation in the genus Populus (salicaceae). AB - The macroevolutionary consequences of recent climate change remain controversial, and there is little paleobotanical or morphological evidence that Pleistocene (1.8-0.12 Ma) glacial cycles acted as drivers of speciation, especially among lineages with long generation times, such as trees. We combined genetic and ecogeographic data from 2 closely related North American tree species, Populus balsamifera and P. trichocarpa (Salicacaeae), to determine if their divergence coincided with and was possibly caused by Pleistocene climatic events. We analyzed 32 nuclear loci from individuals of P. balsamifera and P. trichocarpa to produce coalescent-based estimates of the divergence time between the 2 species. We coupled the coalescent analyses with paleodistribution models to assess the influence of climate change on species' range. Furthermore, measures of niche overlap were used to investigate patterns of ecological differentiation between species. We estimated the divergence date of P. balsamifera and P. trichocarpa at approximately 75 Ka, which corresponds closely with the onset of Marine Isotope Stage 4 (~76 Ka) and a rapid increase in global ice volume. Significance tests of niche overlap, in conjunction with genetic estimates of migration, suggested that speciation occurred in allopatry, possibly resulting from the environmental effects of Pleistocene glacial cycles. Our results indicate that the divergence of keystone tree species, which have shaped community diversity in northern North American ecosystems, was recent and may have been a consequence of Pleistocene era glaciation and climate change. PMID- 22213714 TI - Selective agonists for dopamine/neurotensin receptor heterodimers. AB - The neuromodulatory peptide neurotensin has been described to functionally interact with dopaminergic pathways of the human brain. We employed radioligand binding studies to investigate the physical interaction between co-expressed dopamine D(2L) or D3 and neurotensin NTS1 or NTS2 receptors. Substantial cross inhibitory effects of both receptor subtypes NTS(1) and NTS2 on the agonist binding of D(2L) or D3 were detected in the presence of neurotensin. To identify ligand-specific modulation and subtype-dependent differences, the novel dopamine receptor agonists 5 and 6 bearing the 7-OH-DPAT pharmacophore were synthesized. Exceptional ligand specificity was observed for D3-NTS2 co-expression, which gave a 20-fold decrease in affinity for biphenylcarboxamide 5 in the presence of neurotensin. Comparing the binding properties of dopaminergic compounds in the presence of neurotensin, dopamine receptor subtype-selective profiles of the cross-inhibitory effect of neurotensin were observed. PMID- 22213715 TI - Far infrared-assisted extraction followed by MEKC for the simultaneous determination of flavones and phenolic acids in the leaves of Rhododendron mucronulatum Turcz. AB - A method based on micellar electrokinetic chromatography with amperometric detection and far infrared-assisted extraction has been developed for the simultaneous determination of two flavones (rutin and farrerol) and three phenolic acids (syringic acid, vanillic acid, and 4-hydroxybenzoic acid) in the dried leaves of Rhododendron mucronulatum Turcz., a commonly used traditional Chinese medicine. The effects of some important factors such as the voltage applied on the infrared generator, irradiation time, the concentration of borate and sodium dodecylsulfate (SDS), separation voltage, and detection potential were investigated to acquire the optimum conditions. The detection electrode was a 300 MUm diameter carbon disc electrode. The five analytes could be well separated within 8 min in a 40 cm-long capillary at a separation voltage of 12 kV in a 50 mM borate buffer (pH 9.2) containing 50 mM SDS. The relationship between peak current and analyte concentration was linear over about three orders of magnitude with the detection limits (S/N=3) ranging from 0.20 to 0.46 MUM. The results indicated that far infrared irradiations significantly enhanced the extraction efficiency. The extraction time was substantially reduced to 6 min compared with 3 h for conventional hot solvent extraction. PMID- 22213716 TI - Endoscopic endonasal approach for resection of ventral skull base keratinaceous cysts. AB - BACKGROUND: Epidermoid and dermoid cysts are uncommon entities that belong in the differential diagnosis of ventral skull base lesions. The endoscopic endonasal approach is an attractive option for management of these lesions with limited morbidity. The clinical characteristics and management course from our experience is reviewed along with the relevant literature. METHODS: A prospective database of endoscopic endonasal skull base cases performed since 2003 at a tertiary referral center was reviewed for cases involving keratinaceous lesions. Data on the pathology, radiology and management of the disease was reviewed. A search of pertinent literature using Medline was performed to complement the discussion. RESULTS: Three cases of intracranial keratinaceous cysts successfully managed with the endoscopic endonasal approach. All cases presented with headache, and 1 case presented with bitemporal hemianopsia. Characteristic appearance on magnetic resonance imaging was seen in each case. All lesions were intradural with variable involvement of the suprasellar, prepontine, and premedullary cisterns. Total resection was achieved in 2 cases and near total resection in 1 case. Postoperative cerebrospinal fluid leak occurred in one case, which was controlled after revision surgery using the "gasket-seal" technique. There were no cranial nerve palsies or vascular events. CONCLUSION: The endoscopic endonasal approach allows the rhinologic surgeon to access the ventral midline skull base for the successful management of keratinaceous cysts without major complications. PMID- 22213717 TI - Furfural--a promising platform for lignocellulosic biofuels. AB - Furfural offers a promising, rich platform for lignocellulosic biofuels. These include methylfuran and methyltetrahydrofuran, valerate esters, ethylfurfuryl and ethyltetrahydrofurfuryl ethers as well as various C(10)-C(15) coupling products. The various production routes are critically reviewed, and the needs for improvements are identified. Their relative industrial potential is analysed by defining an investment index and CO(2) emissions as well as determining the fuel properties for the resulting products. Finally, the most promising candidate, 2 methylfuran, was subjected to a road trial of 90,000 km in a gasoline blend. Importantly, the potential of the furfural platform relies heavily on the cost competitive production of furfural from lignocellulosic feedstock. Conventional standalone and emerging coproduct processes-for example, as a coproduct of cellulosic ethanol, levulinic acid or hydroxymethyl furfural-are expensive and energetically demanding. Challenges and areas that need improvement are highlighted. In addition to providing a critical review of the literature, this paper also presents new results and analysis in this area. PMID- 22213718 TI - Influence of periodic nitrogen functionality on the selective oxidation of alcohols. AB - An enhancement in catalytic alcohol oxidation activity is attributed to the presence of nitrogen heteroatoms on the external surface of a support material. The same Pd particles (3.1-3.2 nm) were supported on polymeric carbon-nitrogen supports and used as catalysts to selectively oxidize benzyl alcohol. The polymeric carbon-nitrogen materials include covalent triazine frameworks (CTF) and carbon nitride (C(3)N(4)) materials with nitrogen content varying from 9 to 58 atomic percent. With comparable metal exposure, estimated by X-ray photoelectron spectroscopy, the activity of these catalysts correlates with the concentration of nitrogen species on the surface. Because the catalysts showed comparable acidic/basic properties, this enhancement cannot be ascribed to the Lewis basicity but most probably to the nature of N-containing groups that govern the adsorption sites of the Pd nanoparticles. PMID- 22213719 TI - An enhanced protein crosslink identification strategy using CID-cleavable chemical crosslinkers and LC/MS(n) analysis. AB - We describe a novel two-step LC/MS(n) strategy to effectively and confidently identify numerous crosslinked peptides from complex mixtures. This method incorporates the use of our gas-phase cleavable crosslinking reagent, disuccinimidyl-succinamyl-aspartyl-proline (SuDP), and a new data-processing algorithm CXLinkS (Cleavable Crosslink Selection), which enables unequivocal crosslink peptide selection and identification on the basis of mass measurement accuracy, high resolving power, and the unique fragmentation pattern of each crosslinked peptide. We demonstrate our approach with well-characterized monomeric and multimeric protein systems with and without database searching restrictions where inter-peptide crosslink identification is increased 8-fold over our previously published data-dependent LC/MS3 method and discuss its applicability to other CID-cleavable crosslinkers and more complex protein systems. PMID- 22213720 TI - Introduction to special section: muscle and bone in the rheumatic diseases. PMID- 22213721 TI - Osteoporosis and fractures in systemic lupus erythematosus. PMID- 22213722 TI - Muscle strength, mass, and quality in older men and women with knee osteoarthritis. AB - OBJECTIVE: To examine the relationship between knee osteoarthritis (OA) and muscle parameters in a biracial cohort of older adults. METHODS: Participants in the Health, Aging and Body Composition Study (n = 858) were included in this cross-sectional analysis. Computed tomography was used to measure muscle area, and quadriceps strength was measured isokinetically. Muscle quality (specific torque) was defined as strength per unit of muscle area for both the entire thigh and quadriceps. Knee OA was assessed based on radiographic features and knee pain. We compared muscle parameters between those with and without radiographic knee OA (+RKOA group and -RKOA group, respectively) and among 4 groups defined by +RKOA and -RKOA with and without pain. RESULTS: The mean +/- SD age was 73.5 +/- 2.9 years and the mean +/- SD body mass index (BMI) was 27.9 +/- 4.8 kg/m(2) . Fifty-eight percent of participants were women and 44% were African American. Compared to the -RKOA participants, +RKOA participants had a higher BMI (30.2 versus 26.8 kg/m(2)), larger thigh muscles (117.9 versus 108.9 cm(2)), and a greater amount of intermuscular fat (12.5 versus 9.9 cm(2) ; all P < 0.0001). In adjusted models, the +RKOA participants had significantly lower specific torque (P < 0.001), indicating poorer muscle quality, than -RKOA participants, but there was no difference between groups in quadriceps specific torque. The +RKOA without pain (P < 0.05) and the +RKOA with pain (P < 0.001) participants had lower specific torque compared to the -RKOA without pain group. There were no significant differences in quadriceps specific torque among groups. CONCLUSION: Muscle quality was significantly poorer in participants with RKOA regardless of pain status. Future studies should address how lifestyle interventions might affect muscle quality and progression of knee OA. PMID- 22213723 TI - Association of lower muscle strength with self-reported knee instability in osteoarthritis of the knee: results from the Amsterdam Osteoarthritis cohort. AB - OBJECTIVE: To determine whether muscle strength, proprioceptive accuracy, and laxity are associated with self-reported knee instability in a large cohort of knee osteoarthritis (OA) patients, and to investigate whether muscle strength may compensate for impairment in proprioceptive accuracy or laxity, in order to maintain knee stability. METHODS: Data from 283 knee OA patients from the Amsterdam Osteoarthritis cohort were used. Univariable and multivariable logistic regression analyses were performed to assess the association between muscle strength, proprioceptive accuracy (motion sense), frontal plane varus-valgus laxity, and self-reported knee instability. Additionally, effect modification between muscle strength and proprioceptive accuracy and between muscle strength and laxity was determined. RESULTS: Self-reported knee instability was present in 67% of the knee OA patients and mainly occurred during walking. Lower muscle strength was significantly associated with the presence of self-reported knee instability, even after adjusting for relevant confounding. Impaired proprioceptive accuracy and high laxity were not associated with self-reported knee instability. No effect modification between muscle strength and proprioceptive accuracy or laxity was found. CONCLUSION: Lower muscle strength is strongly associated with self-reported knee instability in knee OA patients, while impairments in proprioceptive accuracy and laxity are not. A compensatory role of muscle strength for impaired proprioceptive accuracy or high laxity, in order to stabilize the knee, could not be demonstrated. PMID- 22213724 TI - Association of larger holes in the trabecular bone at the distal radius in postmenopausal women with type 2 diabetes mellitus compared to controls. AB - OBJECTIVE: Adults with type 2 diabetes mellitus (DM) have an elevated fracture risk despite normal areal bone mineral density (aBMD). The study objective was to compare trabecular bone microarchitecture of postmenopausal women with type 2 DM and women without type 2 DM. METHODS: An extremity 1T magnetic resonance imaging system was used to acquire axial images (195 * 195 * 1,000 MUm(3) voxel size) of the distal radius of women recruited from outpatient clinics or by community advertisement. Image segmentation yielded geometric, topologic, and stereologic outcomes, i.e., number and size of trabecular bone network holes (marrow spaces), endosteal area, trabecular bone volume fraction, nodal and branch density, and apparent trabecular thickness, separation, and number. Lumbar spine (LS) and proximal femur BMD were measured with dual x-ray absorptiometry. Microarchitectural differences were assessed using linear regression and adjusted for percent body fat, ethnicity, timed up-and-go test, Charlson Index, and calcium and vitamin D intake; aBMD differences were adjusted for body mass index (BMI). RESULTS: Women with type 2 DM (n = 30, mean +/- SD age 71.0 +/- 4.8 years) had larger holes (+13.3%; P = 0.001) within the trabecular bone network than women without type 2 DM (n = 30, mean +/- SD age 70.7 +/- 4.9 years). LS aBMD was greater in women with type 2 DM; however, after adjustment for BMI, LS aBMD did not differ between groups. CONCLUSION: In women with type 2 DM, the average hole size within the trabecular bone network at the distal radius is greater compared to controls. This may explain the elevated fracture risk in this population. PMID- 22213725 TI - Matched-cohort study of body composition, physical function, and quality of life in men with idiopathic vertebral fracture. AB - OBJECTIVE: To determine the effect of 6 years of routine management on body composition, physical functioning, and quality of life, and their interrelationships, in men with idiopathic vertebral fracture. METHODS: Twenty men with idiopathic vertebral fracture (patients: mean +/- SD age 58 +/- 6 years) were age and height matched to 28 healthy controls with no known disease. The primary outcome was skeletal muscle mass (appendicular lean mass by dual x-ray absorptiometry) assessed at 2 visits (0 and 6 years). Physical functioning and quality of life domains were assessed by the Senior Fitness Test and Short Form 36 (SF-36) questionnaire at visit 2 only. Data were analyzed by repeated-measures analysis of variance, independent t-tests, and correlation. RESULTS: At visit 1, appendicular lean mass was 9% lower in patients than controls. Although patients better maintained appendicular lean mass between visits (interaction P = 0.016), at visit 2 appendicular lean mass remained 5% lower in patients than controls. Furthermore, patients' appendicular lean mass change was correlated with femoral neck bone density change (r = 0.507, P = 0.023). Physical function tests were 13 27% lower in patients compared with controls (P = 0.056 to 0.003), as were SF-36 quality of life physical domains (13-26% lower; P = 0.028 to <0.001). CONCLUSION: Despite an association between changes in muscle mass and bone density, routine management of men with idiopathic vertebral fracture does not address muscle loss. Combined with the observation of reduced physical functioning and quality of life, this study identifies novel targets for intervention in men with idiopathic vertebral fracture. PMID- 22213726 TI - Physical activity and body composition in patients with ankylosing spondylitis. AB - OBJECTIVE: Patients with ankylosing spondylitis (AS) are at risk for accelerated muscle loss and reduced physical activity. Accurate data are needed on body composition and physical activity in this patient group. The purpose of this study was to investigate body composition and objectively assessed physical activity in patients with AS. METHODS: Twenty-five AS patients (15 men, mean +/- SD age 48 +/- 11 years) were compared with 25 healthy adults matched for age, sex, and body mass index. Body composition was measured using a 3-compartment model based on air-displacement plethysmography to assess body volume and deuterium dilution to assess total body water. The fat-free mass index (FFMI; fat free mass divided by height squared) and the percent fat mass (%FM) were calculated. Daily physical activity was assessed for 7 days using a triaxial accelerometer and physical fitness with an incremental test until exertion on a bicycle ergometer. Blood samples were taken to determine C-reactive protein (CRP) level and tumor necrosis factor alpha. RESULTS: Accelerometer output (kilocounts/day) showed the same physical activity level for patients and controls (mean +/- SD 319 +/- 105 versus 326 +/- 66). There was no difference in the FFMI or %FM between the patients and controls. Physical activity was positively related to the FFMI (partial R = 0.38, P = 0.01) and inversely related to CRP level (R = -0.39, P < 0.01), independent of group. CRP level was inversely related to the FFMI, but the effect was less strong than with physical activity (partial R = -0.31, P = 0.03). CONCLUSION: Daily physical activity may help preserve fat-free mass in patients with AS. PMID- 22213728 TI - A 9-year-old girl with ankle, knee, and shoulder pain. PMID- 22213731 TI - Connectable DNA logic gates: OR and XOR logics. AB - Modern computer processors are based on semiconductor logic gates connected to each other in complex circuits. This study contributes to the development of a new class of connectable logic gates made of DNA in which the transfer of oligonucleotide fragments as input/output signals occurs upon hybridization of DNA sequences. The DNA strands responsible for a logic function form associates containing immobile DNA four-way junction structures when the signal is high and dissociate into separate strands when the signal is low. A basic set of logic gates (NOT, AND, and OR) was designed. Two NOT gates, two AND gates, and an OR gate were connected in a network that corresponds to an XOR logic function. The design of the logic gates presented here may contribute to the development of the first biocompatible molecular computer. PMID- 22213732 TI - PloGO: plotting gene ontology annotation and abundance in multi-condition proteomics experiments. AB - We describe the PloGO R package, a simple open-source tool for plotting gene ontology (GO) annotation and abundance information, which was developed to aid with the bioinformatics analysis of multi-condition label-free proteomics experiments using quantitation based on spectral counting. PloGO can incorporate abundance (raw spectral counts) or normalized spectral abundance factors (NSAF) data in addition to the GO annotation, as well as handle multiple files and allow for a targeted collection of GO categories of interest. Our main aims were to help identify interesting subsets of proteins for further analysis such as those arising from a protein data set partition based on the presence and absence or multiple pair-wise comparisons, as well as provide GO summaries that can be easily used in subsequent analyses. Though developed with label-free proteomics experiments in mind it is not specific to that approach and can be used for any multi-condition experiment for which GO information has been generated. PMID- 22213727 TI - Incident vertebral fractures among children with rheumatic disorders 12 months after glucocorticoid initiation: a national observational study. AB - OBJECTIVE: To determine the frequency of incident vertebral fractures (IVF) 12 months after glucocorticoid (GC) initiation in children with rheumatic diseases and to identify children at higher risk. METHODS: Children with rheumatic diseases initiating GC were enrolled in a prospective observational study. Annual spine radiographs were evaluated using the Genant semiquantitative method. Spine areal bone mineral density (aBMD) was measured every 6 months. Clinical features, including cumulative GC dose, back pain, disease and physical activity, calcium and vitamin D intake, and spine aBMD Z scores, were analyzed for association with IVF. RESULTS: Seven (6%) of 118 children (95% confidence interval 2.9-11.7%) had IVF. Their diagnoses were: juvenile dermatomyositis (n = 2), systemic lupus erythematosus (n = 3), systemic vasculitis (n = 1), and mixed connective tissue disease (n = 1). One child was omitted from the analyses after 4 months because of osteoporosis treatment for symptomatic IVF. Children with IVF received on average 50% more GC than those without (P = 0.030), had a greater increase in body mass index (BMI) at 6 months (P = 0.010), and had greater decrements in spine aBMD Z scores in the first 6 months (P = 0.048). Four (67%) of 6 children with IVF and data to 12 months had spine aBMD Z scores less than -2.0 at 12 months compared to 16% of children without IVF (P = 0.011). CONCLUSION: The incidence of VF 12 months following GC initiation was 6%; most children were asymptomatic. Children with IVF received more GC, had greater increases in BMI, and had greater declines in spine aBMD Z scores in the first 6 months. PMID- 22213733 TI - Clinical decision rule to predict the presence of interstitial lung disease in systemic sclerosis. AB - OBJECTIVE: To develop a clinical decision rule to predict the presence of interstitial lung disease (ILD) in systemic sclerosis (SSc; scleroderma) and to estimate the prevalence of SSc-ILD. METHODS: Patient data were extracted from the Canadian Scleroderma Research Group registry. Three algorithms for the clinical decision rule were considered based on lung auscultation, chest radiography (CXR), and % predicted forced vital capacity (FVC). High-resolution computed tomography (HRCT) scans were used as the gold standard to determine the diagnostic properties of the 3 algorithms. Multiple imputation was used to impute HRCT data when missing, thereby avoiding bias due to differential referral for HRCT. RESULTS: This study included 1,168 patients. Of the patients with HRCT scans, 65% had evidence of ILD, compared to 26% by physical examination and 22% by CXR. The FVC of those who did not have HRCT was 8.8% greater than those who did (95% confidence interval [95% CI] 6.0-11.6%). Algorithm A, which identified the presence of ILD based on crackles on lung auscultation and/or findings on CXR, had a likelihood ratio of 3.9, compared to 3.2 for Algorithm B (which included patients with FVC <70%) and 2.2 for Algorithm C (which included patients with FVC <80%). The prevalence of ILD in the cohort was estimated to be 52% (95% CI 46-59%). CONCLUSION: We developed a simple clinical decision rule to predict SSc-ILD with good test characteristics. The prevalence of ILD in a large, unselected SSc cohort was estimated to be 52%. PMID- 22213734 TI - Reaction dynamics and solution chemistry of polyoxometalates by electrospray ionization mass spectrometry. AB - Mass spectrometry both complements other analytical techniques and allows for types of analyses and experiments not possible with common analytical methods, such as NMR, IR, and UV/Vis spectroscopy. Electrospray constitutes one of the mildest forms of ionization, making it the preferred method for the analysis of large fragile or reactive ions. There is particular promise for mass spectrometry in aiding the characterization of polyoxometalates and their solutions, but caution must be taken in designing the experiments in order to yield reliable data and to avoid the temptation of over-interpreting the relevance of gas-phase data to solution chemistry. PMID- 22213735 TI - Chemical and topographical patterning of hydrogels for neural cell guidance in vitro. AB - This review focuses on hydrogels and their patterning techniques in relation to central nervous system applications, with emphasis on synthetic and natural materials and chemical and topographical patterning techniques. We describe the properties of hydrogel materials and various techniques used in hydrogel patterning methods. Also, the applicability and utilization of patterned hydrogels with neural cells is discussed. Surface chemistry and topography significantly affect cell behaviour, including cell attachment, migration and maturation. Although several patterning techniques are described in the literature, a review of techniques applicable to hydrogel materials is needed. Use of these patterned cell-hydrogel constructs might provide novel ways to treat central nervous system deficits in the future. PMID- 22213736 TI - Different protein expression profiles in cheese and clinical isolates of Enterococcus faecalis revealed by proteomic analysis. AB - The use of Enterococcus faecalis in the food industry has come under dispute because of the pathogenic potential of some strains of this species. In this study, we have compared the secretome and whole-cell proteome of one food isolate (E. faecalis DISAV 1022) and one clinical isolate (E. faecalis H1) by 2-DE and iTRAQ analyses, respectively. Extracellular protein patterns differed significantly, with only seven proteins common to both strains. Notably, only the clinical isolate expressed various well-characterized virulence factors such as the gelatinase coccolysin (GelE) and the extracellular serine proteinase V8 (SprE). Moreover, various other putative virulence factors, e.g. superoxide dismutase, choline- and chitin-binding proteins and potential moonlighting proteins, have been detected exclusively in the secretome of the clinical isolate, but not in the food isolate. The iTRAQ analysis of whole-cell proteins of the two strains highlighted a stronger expression of pathogenic traits such as an endocarditis-specific antigen and an adhesion lipoprotein in the pathogenic strain E. faecalis H1. Subsequently, six food isolates (including E. faecalis DISAV 1022) and six clinical isolates (including E. faecalis H1) were tested for the presence of gelatinase and protease activity in the culture supernatants. Both enzymatic activities were found in the clinical as well as the food isolates which clearly indicates that protease expression is strain specific and not representative for pathogenic isolates. Genetic analyses revealed that not only the gelatinase and serine protease genes but also the regulatory fsr genes must be present to allow protease expression. PMID- 22213737 TI - Impaired type I and type III interferon induction and rhinovirus control in human cystic fibrosis airway epithelial cells. AB - BACKGROUND: Rhinoviruses are important triggers of pulmonary exacerbations and possible contributors to long-term respiratory morbidity in cystic fibrosis (CF), but mechanisms leading to rhinovirus-induced CF exacerbations are poorly understood. It is hypothesised that there is a deficient innate immune response of the airway epithelium towards rhinovirus infection in CF. METHODS: Early innate immune responses towards rhinoviruses (RV-16, major-type and RV-1B, minor type) in CF and non-CF bronchial epithelial cell lines and primary nasal and bronchial epithelial cells from patients with CF (n=13) and healthy controls (n=24) were studied. RESULTS: Rhinovirus RNA expression and virus release into supernatants was increased more than tenfold in CF cells compared with controls. CF cells expressed up to 1000 times less interferon (IFN) type I (beta) and type III (lambda) mRNA and produced less than half of IFN-beta and IFN-lambda protein compared with controls. In contrast, interleukin 8 production was not impaired, indicating a selective deficiency in the innate antiviral defence system. Deficient IFN production was paralleled by lower expression of IFN-stimulated genes including myxovirus resistance A, 2',5'-oligoadenylate synthetase, viperin and nitric oxide synthase 2. Addition of exogenous type I and III IFNs, particularly IFN-beta, restored antiviral pathways and virus control in CF cells, underscoring the crucial role of these molecules. CONCLUSIONS: This study describes a novel mechanism to explain the increased susceptibility of patients with CF to rhinovirus infections. A profound impairment of the antiviral early innate response in CF airway epithelial cells was identified, suggesting a potential use of IFNs in the treatment of rhinovirus-induced CF exacerbations. PMID- 22213738 TI - Allergic rhinitis is associated with poor asthma control in children with asthma. AB - BACKGROUND: Asthma and allergic rhinitis are the two most common chronic disorders in childhood and adolescence. To date, no study has examined the impact of comorbid allergic rhinitis on asthma control in children. OBJECTIVE: To examine the prevalence of allergic rhinitis in children with asthma, and the impact of the disease and its treatment on asthma control. METHODS: A cross sectional survey in 203 children with asthma (5-18 years) using validated questionnaires on rhinitis symptoms (stuffy or runny nose outside a cold) and its treatment, and the paediatric Asthma Control Questionnaire (ACQ). Fraction of nitric oxide in exhaled air (FeNO) was measured with a Niox Mino analyser; total and specific IgE levels were assessed by the Immunocap system. RESULTS: 157 children (76.2%) had symptoms of allergic rhinitis but only 88 of these (56.1%) had been diagnosed with the condition by a physician. ACQ scores were worse in children with allergic rhinitis than in those without the condition (p=0.012). An ACQ score >= 1.0 (incomplete asthma control) was significantly more likely in children with allergic rhinitis than in those without (OR 2.74, 95% CI 1.28 to 5.91, p=0.0081), also after adjustment for FeNO levels and total serum IgE. After adjustment for nasal corticosteroid therapy, allergic rhinitis was no longer associated with incomplete asthma control (OR 0.72, 95% CI 0.47 to 1.12, p=0.150). CONCLUSION: Allergic rhinitis is common in children with asthma, and has a major impact on asthma control. The authors hypothesise that recognition and treatment of this condition with nasal corticosteroids may improve asthma control in children, but randomised clinical trials are needed to test this hypothesis. PMID- 22213739 TI - Rapid molecular detection of tuberculosis and rifampicin drug resistance: retrospective analysis of a national U.K. molecular service over the last decade. AB - BACKGROUND: Fast and reliable detection of Mycobacterium tuberculosis complex (MTBC) and drug resistance is crucial in establishing effective treatment and enforcing timely public health measures. METHODS: The authors analysed the performance of a national U.K. molecular diagnostic service over a decade, based on the use of a line probe assay (Innolipa, LiPA) compared with conventional liquid and solid cultures with rapid molecular identification and culture-based drug resistance testing. FINDINGS: Data were available for 7836 consecutive patient samples using LiPA and the reference microbiological technique (conventional liquid and solid cultures with rapid molecular identification and culture-based drug resistance testing). For all sputum specimens (n=3382) the sensitivity, specificity, positive predictive value, negative predictive value and accuracy for MTBC detection were 93.4%, 85.6%, 92.7%, 86.9% and 90.7%; the equivalent values for smear-positive sputum specimens (n=2606) were 94.7%, 80.9%, 93.9%, 83.3% and 91.3%. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy for detection of rifampicin resistance in all sputum samples (n=1667) were 92.1%, 99.3%, 89.4%, 99.5% and 98.9%, respectively; the equivalent values for smear-positive sputum specimens (n=1477) were 93.3%, 99.3%, 87.5%, 99.6% and 99%. Between January 2006 and December 2008, LiPA saved 25.3 and 32.2 days for TB diagnosis and rifampicin resistance of smear positive samples, respectively. INTERPRETATION: A molecular diagnostic service, using a non-automated line probe assay approach, provides a rapid and reliable national service for diagnosing MTBC and rifampicin resistance. PMID- 22213740 TI - Toe-out, lateral trunk lean, and pelvic obliquity during prolonged walking in patients with medial compartment knee osteoarthritis and healthy controls. AB - OBJECTIVE: To compare the time-varying behavior of maximum toe-out angle, lateral trunk lean (over the stance leg), and pelvic obliquity (rise and drop on the swing leg) during prolonged walking in participants with and without medial compartment knee osteoarthritis (OA), and to explore correlations between these gait characteristics and pain. METHODS: Twenty patients with knee OA and 20 healthy controls completed 30 minutes of treadmill walking. Toe-out, trunk lean, pelvic obliquity, and pain were measured at 5-minute intervals. RESULTS: The mean +/- SD toe-out angle was significantly smaller (P = 0.04) in patients with knee OA (6.7 +/- 2.5 degrees) than in controls (10.3 +/- 2.2 degrees). Toe-out changed significantly over time (P = 0.002), but not in a systematic way, and there was no interaction between group and time. The mean +/- SD trunk lean was higher (P = 0.03) in patients with knee OA (2.0 +/- 1.0 degrees) than in controls (0.7 +/- 0.5 degrees). Trunk lean did not change over time and there was no interaction between group and time. There were no differences for pelvic drop. The mean +/- SD pelvic rise was higher (P = 0.01) in patients with knee OA (2.8 +/- 0.9 degrees) than in controls (1.2 +/- 0.8 degrees), but did not change over time and there was no interaction. Patients experienced a small increase in pain (P < 0.001). Trunk lean and pelvic drop were correlated with pain (r = 0.49, P = 0.03 and r = 0.47, P = 0.04, respectively). CONCLUSION: Toe-out and trunk lean are consistently different between individuals with and without medial compartment knee OA during prolonged walking, and patients with greater pain have greater trunk lean. However, over 30 minutes of walking, these gait characteristics remain quite stable, suggesting they are not acute compensatory mechanisms in response to repetitive loading with subtle increases in pain. PMID- 22213741 TI - High-performance organic materials for dye-sensitized solar cells: triarylene linked dyads with a 4-tert-butylphenylamine donor. AB - A series of organic dyes were prepared that displayed remarkable solar-to-energy conversion efficiencies in dye-sensitized solar cells (DSSCs). These dyes are composed of a 4-tert-butylphenylamine donor group (D), a cyanoacrylic-acid acceptor group (A), and a phenylene-thiophene-phenylene (PSP) spacer group, forming a D-pi-A system. A dye containing a bulky tert-butylphenylene-substituted carbazole (CB) donor group showed the highest performance, with an overall conversion efficiency of 6.70%. The performance of the device was correlated to the structural features of the donor groups; that is, the presence of a tert butyl group can not only enhance the electron-donating ability of the donor, but can also suppress intermolecular aggregation. A typical device made with the CB PSP dye afforded a maximum photon-to-current conversion efficiency (IPCE) of 80% in the region 400-480 nm, a short-circuit photocurrent density J(sc) =14.63 mA cm(-2), an open-circuit photovoltage V(oc) =0.685 V, and a fill factor FF=0.67. When chenodeoxycholic acid (CDCA) was used as a co-absorbent, the open-circuit voltage of CB-PSP was elevated significantly, yet the overall performance decreased by 16-18%. This result indicated that the presence of 4-tert butylphenyl substituents can effectively inhibit self-aggregation, even without CDCA. PMID- 22213742 TI - Encapsulation of cardiac stem cells in superoxide dismutase-loaded alginate prevents doxorubicin-mediated toxicity. AB - Anthracyclines are powerful drugs available for the treatment of neoplastic diseases. Unfortunately, these chemotherapy agents cause cardiomyopathy and congestive heart failure. Doxorubicin (DOX) is a widely used anthracycline and evidence indicates that DOX-induced cardiotoxicity can be viewed as a stem cell disease, whereby the formation of reactive oxygen species (ROS) by DOX is seen to predominantly hinder cardiac stem cell (CSC) regenerative capability. Acute, early-onset and late-onset cardiotoxicity have been described and this may be reversible by the local administration of CSCs, which regenerate myocardial tissue and rescue the failing heart. CSCs are, however, particularly sensitive to oxidative stress and die rapidly by apoptosis in such adverse conditions. Therefore, this study aims to enhance CSC survival by encapsulation in an alginate hydrogel formulation containing superoxide dismutase (SOD), a reactive oxygen species scavenger. Cell survival was qualitatively and quantitatively assessed by fluorescent microscopy and assays measuring metabolic activity, cell viability, cytotoxicity and apoptosis. CSCs were cultured in DOX-conditioned cell culture medium and displayed reduced live cell numbers as well as high levels of apoptosis. Encapsulation of CSCs in alginate alone failed to prevent apoptosis. Encapsulation in SOD-loaded alginate reduced apoptosis to near-normal levels, whilst metabolic activity was returned to baseline. In conclusion, this study demonstrates that encapsulation of CSCs in SOD-loaded alginate hydrogel enhances CSC survival in the presence of DOX, raising the possibility of its application as a novel therapy for the treatment of acute and early onset DOX-induced cardiotoxicity. PMID- 22213743 TI - Encapsulation and survival of a chondrocyte cell line within xanthan gum derivative. AB - A chemical derivative of xanthan gum polysaccharide is investigated as a new artificial matrix for the encapsulation of chondrocytic cells. Toward this goal, a novel micro-droplet generator is developed to produce microcapsules. Microcapsules with an average diameter of 500 um, smooth surface, and homogeneous size distribution are obtained. ATDC5 cells encapsulated in carboxymethyl xanthan (CMX) microcapsules remain viable and are observed to proliferate for prolonged culture periods with enhanced metabolic activity. Furthermore, retention of the chondrogenic phenotype is exhibited by the cells within CMX, suggesting the ability of this material to be applied in cell-delivery therapies. PMID- 22213746 TI - Distribution of finger nodes and their association with underlying radiographic features of osteoarthritis. AB - OBJECTIVE: To determine the distribution of clinically palpable hand interphalangeal (IP) nodes at each finger and thumb joint in a population with nodes, the influence of left or right hand dominance and sex on the development of nodes, and the association between nodes and underlying radiographic features of osteoarthritis (OA). METHODS: We performed a cross-sectional analysis of participants in the Genetics of Osteoarthritis and Lifestyle (GOAL) study who had >=1 Heberden's nodes or Bouchard's nodes on clinical examination. Frequencies (%) of nodes were described for each IP joint in the hand. Associations between nodes and underlying radiographic OA were shown with odds ratios (ORs) and 95% confidence intervals. A logistic regression model was used to adjust for the following confounding factors: age, sex, body mass index, left or right hand dominance, hand trauma, occupation with heavy manual activity, and participation in sports. RESULTS: Of the 3,170 GOAL participants, 1,939 had >=1 nodes (mean age 68 years, 54% women). The distal IP joints of the index finger were the most frequently affected, followed by the thumb IP joint. Nodes were more common in dominant hands and women. There was a significant association between nodes and underlying radiographic OA (OR range 2.26-21.23). This association was stronger for joint space narrowing than for osteophytes. A dose-response relationship was found between clinical severity of Heberden's nodes and underlying radiographic change. CONCLUSION: Our study supports the positive association between nodes and radiographic OA, especially narrowing, and the influence of sex and left or right hand dominance on development of nodes. In this age group, presence of nodes may be taken as an indication of underlying small joint OA. PMID- 22213745 TI - Pleiotropic effects of the bone morphogenetic proteins on development of the enteric nervous system. AB - Formation of the enteric nervous system (ENS) from migratory neural crest-derived cells that colonize the primordial gut involves a complex interplay among different signaling molecules. The bone morphogenetic proteins (BMPs), specifically BMP2 and BMP4, play a particularly important role in virtually every stage of gut and ENS development. BMP signaling helps to pattern both the anterior-posterior axis and the radial axis of the gut prior to colonization by migratory crest progenitor cells. BMP signaling then helps regulate the migration of enteric neural crest-derived precursors as they colonize the fetal gut and form ganglia. BMP2 and -4 promote differentiation of enteric neurons in early fetal ENS development and glia at later stages. A major role for BMP signaling in the ENS is regulation of responses to other growth factors. Thus BMP signaling first regulates neurogenesis by modulating responses to GDNF and later gliogenesis through its effects on GGF-2 responses. Furthermore, BMPs promote growth factor dependency for survival of ENS neurons (on NT-3) and glia (on GGF 2) by inducing TrkC (neurons) and ErbB3 (glia). BMP signaling limits total neuron numbers, favoring the differentiation of later born neuronal phenotypes at the expense of earlier born ones thus influencing the neuronal composition of the ENS and the glia/neuron ratio. BMP2 and -4 also promote gangliogenesis via modification of neural cell adhesion molecules and promote differentiation of the circular and then longitudinal smooth muscles. Disruption of BMP signaling leads to defects in the gut and in ENS function commensurate with these complex developmental roles. PMID- 22213747 TI - Effect of pediatric bilateral cochlear implantation on language development. AB - OBJECTIVE: To examine spoken language outcomes in children undergoing bilateral cochlear implantation compared with matched peers undergoing unilateral implantation. DESIGN: Case-control, frequency-matched, retrospective cross sectional multicenter study. SETTING: Two Belgian and 3 Dutch cochlear implantation centers. PARTICIPANTS: Twenty-five children with 1 cochlear implant matched with 25 children with 2 cochlear implants selected from a retrospective sample of 288 children who underwent cochlear implantation before 5 years of age. INTERVENTION: Cochlear implantation. MAIN OUTCOME MEASURES: Performance on measures of spoken language comprehension and expression (Reynell Developmental Language Scales and Schlichting Expressive Language Test). RESULTS: On the receptive language tests (mean difference [95% CI], 9.4 [0.3-18.6]) and expressive language tests (15.7 [5.9-25.4] and 9.7 [1.5-17.9]), children undergoing bilateral implantation performed significantly better than those undergoing unilateral implantation. Because the 2 groups were matched with great care on 10 auditory, child, and environmental factors, the difference in performance can be mainly attributed to the bilateral implantation. A shorter interval between both implantations was related to higher standard scores. Children undergoing 2 simultaneous cochlear implantations performed better on the expressive Word Development Test than did children undergoing 2 sequential cochlear implantations. CONCLUSIONS: The use of bilateral cochlear implants is associated with better spoken language learning. The interval between the first and second implantation correlates negatively with language scores. On expressive language development, we find an advantage for simultaneous compared with sequential implantation. PMID- 22213748 TI - Cochlear implantation in prelingually deafened adolescents. AB - OBJECTIVES: To determine the efficacy of cochlear implantation (CI) in prelingually deafened adolescent children and to evaluate predictive variables for successful outcomes. DESIGN: Retrospective medical record review. PARTICIPANTS: Children aged 10 to 17 years with prelingual hearing loss (mean length of deafness, 11.5 years) who received a unilateral CI (mean age at CI, 12.9 years). INTERVENTION: Unilateral CI. MAIN OUTCOME MEASURES: Standard speech perception testing (Consonant-Nucleus-Consonant [CNC] monosyllabic word test and Hearing in Noise [HINT] sentence test) was performed preoperatively, 1 year postoperatively (year 1), and at the last follow-up/end of the study (EOS). RESULTS: There was a highly significant improvement in speech perception scores for both HINT sentence and CNC word testing from the preoperative testing to year 1 (mean change score, 51.10% and 32.23%, respectively; P < .001) and from the preoperative testing to EOS (mean change score, 60.02% and 38.73%, respectively; P < .001), with a significantly greater increase during the first year (P < .001). In addition, there was a highly significant correlation between improvements in performance scores on the CNC word and HINT sentence speech perception tests and both age at CI and length of deafness at the year 1 testing (P <=.009) but not from the year 1 testing to EOS testing. Adolescents with progressive deafness and those using oral communication before CI performed significantly better than age-matched peers. CONCLUSIONS: Adolescents with prelingual deafness undergoing unilateral CI show significant improvement in objective hearing outcome measures. Patients with shorter lengths of deafness and earlier age at CI tend to outperform their peers. In addition, patients with progressive deafness and those using oral communication have significantly better objective outcomes than their peers. PMID- 22213750 TI - Physical activity and performance at school: a systematic review of the literature including a methodological quality assessment. AB - OBJECTIVE: To describe the prospective relationship between physical activity and academic performance. DATA SOURCES: Prospective studies were identified from searches in PubMed, PsycINFO, Cochrane Central, and Sportdiscus from 1990 through 2010. STUDY SELECTION: We screened the titles and abstracts for eligibility, rated the methodological quality of the studies, and extracted data. MAIN EXPOSURE: Studies had to report at least 1 physical activity or physical fitness measurement during childhood or adolescence. MAIN OUTCOME MEASURES: Studies had to report at least 1 academic performance or cognition measure during childhood or adolescence. RESULTS: We identified 10 observational and 4 intervention studies. The quality score of the studies ranged from 22% to 75%. Two studies were scored as high quality. Methodological quality scores were particularly low for the reliability and validity of the measurement instruments. Based on the results of the best-evidence synthesis, we found evidence of a significant longitudinal positive relationship between physical activity and academic performance. CONCLUSIONS: Participation in physical activity is positively related to academic performance in children. Because we found only 2 high-quality studies, future high-quality studies are needed to confirm our findings. These studies should thoroughly examine the dose-response relationship between physical activity and academic performance as well as explanatory mechanisms for this relationship. PMID- 22213749 TI - Excess body mass index-years, a measure of degree and duration of excess weight, and risk for incident diabetes. AB - OBJECTIVE: To evaluate the relation between excess body mass index (BMI)-years, a measure of the degree to which an individual's BMI (calculated as weight in kilograms divided by height in meters squared) exceeds the reference BMI and the duration for which he or she carries excess BMI, and incident diabetes. DESIGN: Longitudinal analysis. SETTING: United States of America. PARTICIPANTS: A total of 8157 adolescents and young adults aged 14 to 21 years at the start of the National Longitudinal Survey of Youth 1979 with self-reported measures of height, weight, and diabetes status (type unspecified) from 1981 through 2006. MAIN EXPOSURE: Excess BMI-years, which were calculated by subtracting the [corrected] reference BMI (25.0 for adults or 85th percentile for adolescents) from the actual BMI [corrected] for each study year and cumulating excess BMI for the study duration. MAIN OUTCOME MEASURE: We conducted logistic regression models to predict presumed type 2 diabetes (after excluding presumed type 1 diabetes) as a function of age, sex, race, excess BMI-years, and specific interactions. RESULTS: A higher level of excess BMI-years was associated with an increased risk of diabetes. For example, on average, white men aged 40 years with 200 excess BMI years had 2.94 times (95% confidence interval, 2.36-3.67) higher odds of developing diabetes compared with men of the same age and race with 100 excess BMI-years. For a given level of excess BMI-years, younger compared with older and Hispanic and black compared with white individuals had higher risk of developing diabetes. Our study is limited by use of self-reported data without specification of diabetes type. CONCLUSIONS: Because younger compared with older individuals have a higher risk of self-reported diabetes for a given level of excess BMI years and cumulative exposure to excess BMI is increasing among younger US birth cohorts, public health interventions should target younger adults. PMID- 22213751 TI - Association of exclusive breastfeeding duration and fibrinogen levels in childhood and adolescence: the European Youth Heart Study. AB - OBJECTIVE: To examine the association of exclusive breastfeeding (BF) duration on serum fibrinogen levels of children and adolescents from Estonia and Sweden, controlling for other potential confounding factors that could mediate in this relationship. DESIGN: Cross-sectional study. SETTING: Estonia and Sweden. PARTICIPANTS: A total of 704 children (mean [SD] age, 9.5 [0.4] years) and 665 adolescents (15.5 [0.5] years). MAIN EXPOSURE: Exclusive BF duration was reported by the mother and categorized in the following 5 categories: never, less than 1 month, 1 to 3 months, more than 3 to 6 months, and more than 6 months. MAIN OUTCOME MEASURES: Fasting fibrinogen level. Age, sex, pubertal status, country, adiposity (sum of 5 skin-fold thicknesses), total cholesterol and triglyceride levels, blood pressure, physical activity (accelerometry), birth weight, maternal education, body mass index, and age were considered confounders in the analyses. RESULTS: Longer duration of exclusive BF was associated with lower fibrinogen levels regardless of confounders (P < .001). Mean (SD) fibrinogen levels were lower in youth who were breastfed for more than 3 months (after adjusting for all confounders, P < .01) in children (2.55 [0.04] vs 2.77 [0.03] g/L), adolescents (2.59 [0.06] vs 2.72 [0.03] g/L), boys (2.47 [0.04] vs 2.73 [0.04] g/L), and girls (2.60 [0.03] vs 2.75 [0.02] g/L), compared with groups who were not breastfed. The results did not change substantially after further adjustment for birth weight and maternal educational level. CONCLUSIONS: Exclusive BF is associated with less low-grade inflammation, as estimated by serum fibrinogen levels, in healthy children and adolescents. These findings give further support to the notion that early feeding patterns could program cardiovascular disease risk factors later in life. PMID- 22213752 TI - Child health providers' precautionary discussion of emotions during communication about results of newborn genetic screening. AB - OBJECTIVE: To demonstrate a quantitative abstraction method for Communication Quality Assurance projects to assess physicians' communication about hidden emotions after newborn genetic screening. DESIGN: Communication quality indicator analysis. SETTING: Standardized parent encounters performed in practicing physicians' clinics or during educational workshops for residents. PARTICIPANTS: Fifty-nine pediatrics residents, 53 pediatricians, and 31 family physicians. INTERVENTION: Participants were asked to counsel standardized parents about a screening result; counseling was recorded, transcribed, and parsed into statements (each with 1 subject and 1 predicate). Pairs of abstractors independently compared statements with a data dictionary containing explicit criteria definitions. OUTCOME MEASURES: Four groups of "precautionary empathy" behaviors (assessment of emotion, anticipation/validation of emotion, instruction about emotion, and caution about future emotion), with definitions developed for both "definite" and "partial" instances. RESULTS: Only 38 of 143 transcripts (26.6%) met definite criteria for at least 1 of the precautionary empathy behaviors. When partial criteria were counted, this number increased to 80 of 143 transcripts (55.9%). The most common type of precautionary empathy was the "instruction about emotion" behavior (eg, "don't be worried"), which may sometimes be leading or premature. CONCLUSIONS: Precautionary empathy behaviors were rare in this analysis. Further study is needed, but this study should raise concerns about the quality of communication services after newborn screening. PMID- 22213753 TI - The interplay of outpatient services and psychiatric hospitalization among Medicaid-enrolled children with autism spectrum disorders. AB - OBJECTIVE: To examine whether increased provision of community-based services is associated with decreased psychiatric hospitalizations among children with autism spectrum disorders (ASDs). DESIGN: Retrospective cohort study using discrete-time logistic regression to examine the association of service use in the preceding 60 days with the risk of hospitalization. SETTING: The Medicaid-reimbursed health care system in the continental United States. PARTICIPANTS: Medicaid-enrolled children with an ASD diagnosis in 2004 (N = 28 428). MAIN EXPOSURES: Use of respite care and therapeutic services, based on procedure codes. MAIN OUTCOME MEASURES: Hospitalizations associated with a diagnosis of ASD (International Classification of Diseases, 10th Revision, codes 299.0, 299.8, and 299.9). RESULTS: Each $1000 increase in spending on respite care during the preceding 60 days resulted in an 8% decrease in the odds of hospitalization in adjusted analysis. Use of therapeutic services was not associated with reduced risk of hospitalization. CONCLUSIONS: Respite care is not universally available through Medicaid. It may represent a critical type of service for supporting families in addressing challenging child behaviors. States should increase the availability of respite care for Medicaid-enrolled children with ASDs. The lack of association between therapeutic services and hospitalization raises concerns regarding the effectiveness of these services. PMID- 22213754 TI - Health-related quality of life in pediatric minor injury: reliability, validity, and responsiveness of the Pediatric Quality of Life Inventory in the emergency department. AB - OBJECTIVE: To evaluate the feasibility, reliability, validity, and responsiveness of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL) in the first 2 weeks after pediatric emergency department care of minor injury. DESIGN: Prospective cohort study. SETTING: Pediatric hospital emergency department. PARTICIPANTS: Children and adolescents with minor injury (n = 334). MAIN OUTCOME MEASURES: Child- and parent-reported clinical outcomes and PedsQL scale scores. RESULTS: The PedsQL had good to excellent internal consistency reliability (alpha range, 0.73-0.93). For each day that the clinical symptoms persisted, there were consistent decreases in mean health-related quality of life (HRQOL) scores (validity testing). There were significantly greater negative changes in mean HRQOL scores for fractures vs soft-tissue injuries and for lower vs upper extremity injuries. Clinical outcomes categorized as poor had large negative changes in HRQOL not seen in good outcome groups. Distribution-based indicators of change supported good responsiveness (effect sizes for the physical summary score, 0.01-2.44; group differences at follow-up exceeded estimates of the minimal importance difference). CONCLUSIONS: The PedsQL is feasible, reliable, and demonstrates good construct and discriminant validity and responsiveness in measuring short-term outcome after minor injury care in the pediatric emergency department. Assessing short-term outcome from the patient perspective with HRQOL measures may greatly enhance our ability to evaluate the effectiveness of emergency department care. PMID- 22213755 TI - Adolescent perceptions of risk and need for safer sexual behaviors after first human papillomavirus vaccination. AB - OBJECTIVES: To (1) examine perceptions of risk of human papillomavirus (HPV) and other sexually transmitted infections (STIs), (2) examine perceived need for safer sexual behaviors, and (3) determine factors associated with less perceived need for safer sexual behaviors, all in the context of receiving the first HPV vaccination. DESIGN: Cross-sectional baseline analysis from an ongoing longitudinal cohort study. SETTING: An urban hospital-based adolescent primary care clinic. PARTICIPANTS: Girls 13 to 21 years (for this article girls are defined as being aged 13 to 21 years) (n = 339) receiving their first HPV vaccination and their mothers (n = 235). MAIN OUTCOME MEASURES: (1) Girls' perceived risk of HPV after HPV vaccination, (2) girls' perceived risk of other STIs after vaccination, (3) girls' perceived need for continued safer sexual behaviors after vaccination, and (4) factors associated with girls' perception of less need for safer sexual behaviors. RESULTS: Mean age of girls was 16.8 years. Most participants (76.4%) were black, and 57.5% were sexually experienced. Girls perceived themselves to be at less risk for HPV than for other STIs after HPV vaccination (P < .001). Although most girls reported continued need for safer sexual behaviors, factors independently associated with perception of less need for safer sexual behaviors included adolescent factors (lower HPV and HPV vaccine knowledge and less concern about HPV) and maternal factors (lower HPV and HPV vaccine knowledge, physician as a source of HPV vaccine information, and lack of maternal communication about the HPV vaccine). CONCLUSIONS: Few adolescents perceived less need for safer sexual behaviors after the first HPV vaccination. Education about HPV vaccines and encouraging communication between girls and their mothers may prevent misperceptions among these adolescents. PMID- 22213756 TI - Picture of the month--quiz case. Fetus in fetu. PMID- 22213757 TI - Cochlear implants in children and adolescents. PMID- 22213758 TI - Communicating with parents about newborn screening: the skill of eliciting unspoken emotions. PMID- 22213759 TI - Exposure to magnetic fields during pregnancy and asthma in offspring. PMID- 22213760 TI - Observations on power-line magnetic fields associated with asthma in children. PMID- 22213761 TI - Parental smoking and childhood ear infections: a dangerous combination. PMID- 22213762 TI - Learning optimal embedded cascades. AB - The problem of automatic and optimal design of embedded object detector cascades is considered. Two main challenges are identified: optimization of the cascade configuration and optimization of individual cascade stages, so as to achieve the best tradeoff between classification accuracy and speed, under a detection rate constraint. Two novel boosting algorithms are proposed to address these problems. The first, RCBoost, formulates boosting as a constrained optimization problem which is solved with a barrier penalty method. The constraint is the target detection rate, which is met at all iterations of the boosting process. This enables the design of embedded cascades of known configuration without extensive cross validation or heuristics. The second, ECBoost, searches over cascade configurations to achieve the optimal tradeoff between classification risk and speed. The two algorithms are combined into an overall boosting procedure, RCECBoost, which optimizes both the cascade configuration and its stages under a detection rate constraint, in a fully automated manner. Extensive experiments in face, car, pedestrian, and panda detection show that the resulting detectors achieve an accuracy versus speed tradeoff superior to those of previous methods. PMID- 22213763 TI - RASL: robust alignment by sparse and low-rank decomposition for linearly correlated images. AB - This paper studies the problem of simultaneously aligning a batch of linearly correlated images despite gross corruption (such as occlusion). Our method seeks an optimal set of image domain transformations such that the matrix of transformed images can be decomposed as the sum of a sparse matrix of errors and a low-rank matrix of recovered aligned images. We reduce this extremely challenging optimization problem to a sequence of convex programs that minimize the sum of l1-norm and nuclear norm of the two component matrices, which can be efficiently solved by scalable convex optimization techniques. We verify the efficacy of the proposed robust alignment algorithm with extensive experiments on both controlled and uncontrolled real data, demonstrating higher accuracy and efficiency than existing methods over a wide range of realistic misalignments and corruptions. PMID- 22213764 TI - Ensemble segmentation using efficient integer linear programming. AB - We present a method for combining several segmentations of an image into a single one that in some sense is the average segmentation in order to achieve a more reliable and accurate segmentation result. The goal is to find a point in the "space of segmentations" which is close to all the individual segmentations. We present an algorithm for segmentation averaging. The image is first oversegmented into superpixels. Next, each segmentation is projected onto the superpixel map. An instance of the EM algorithm combined with integer linear programming is applied on the set of binary merging decisions of neighboring superpixels to obtain the average segmentation. Apart from segmentation averaging, the algorithm also reports the reliability of each segmentation. The performance of the proposed algorithm is demonstrated on manually annotated images from the Berkeley segmentation data set and on the results of automatic segmentation algorithms. PMID- 22213765 TI - Face recognition using sparse approximated nearest points between image sets. AB - We propose an efficient and robust solution for image set classification. A joint representation of an image set is proposed which includes the image samples of the set and their affine hull model. The model accounts for unseen appearances in the form of affine combinations of sample images. To calculate the between-set distance, we introduce the Sparse Approximated Nearest Point (SANP). SANPs are the nearest points of two image sets such that each point can be sparsely approximated by the image samples of its respective set. This novel sparse formulation enforces sparsity on the sample coefficients and jointly optimizes the nearest points as well as their sparse approximations. Unlike standard sparse coding, the data to be sparsely approximated are not fixed. A convex formulation is proposed to find the optimal SANPs between two sets and the accelerated proximal gradient method is adapted to efficiently solve this optimization. We also derive the kernel extension of the SANP and propose an algorithm for dynamically tuning the RBF kernel parameter while matching each pair of image sets. Comprehensive experiments on the UCSD/Honda, CMU MoBo, and YouTube Celebrities face datasets show that our method consistently outperforms the state of the art. PMID- 22213766 TI - Beyond novelty detection: incongruent events, when general and specific classifiers disagree. AB - Unexpected stimuli are a challenge to any machine learning algorithm. Here, we identify distinct types of unexpected events when general-level and specific level classifiers give conflicting predictions. We define a formal framework for the representation and processing of incongruent events: Starting from the notion of label hierarchy, we show how partial order on labels can be deduced from such hierarchies. For each event, we compute its probability in different ways, based on adjacent levels in the label hierarchy. An incongruent event is an event where the probability computed based on some more specific level is much smaller than the probability computed based on some more general level, leading to conflicting predictions. Algorithms are derived to detect incongruent events from different types of hierarchies, different applications, and a variety of data types. We present promising results for the detection of novel visual and audio objects, and new patterns of motion in video. We also discuss the detection of Out-Of- Vocabulary words in speech recognition, and the detection of incongruent events in a multimodal audiovisual scenario. PMID- 22213767 TI - A probabilistic approach to pattern matching in the continuous domain. AB - The goal of this paper is to solve the following basic problem: Given discrete noisy samples from a continuous signal, compute the probability distribution of its distance from a fixed template. As opposed to the typical restoration problem, which considers a single optimal signal, the computation of the entire probability distribution necessitates integrating over the entire signal space. To achieve this, we apply path integration techniques. The problem is studied in one and two dimensions, and an accurate solution as well as an efficient approximation scheme are provided. PMID- 22213768 TI - Calculation of dispersion energies. AB - We summarize the theory of van der Waals (dispersion) forces, with emphasis on recent microscopic approaches that permit the prediction of forces between solids and nanostructures right down to intimate contact and binding. Some connections are pointed out between microscopic theory and macroscopic Lifshitz theory. PMID- 22213769 TI - Elevated prefrontal cortex gamma-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy. AB - CONTEXT: Postmortem studies have found evidence of gamma-aminobutyric acid (GABA) deficits in fast-spiking, parvalbumin-positive interneurons in the prefrontal cortex in schizophrenia. Magnetic resonance spectroscopy studies in unmedicated patients have reported glutamine or glutamate-glutamine (Glx) elevations in this region. Abnormalities in these transmitters are thought to play a role in cognitive impairments in the illness. OBJECTIVE: To measure GABA and Glx levels in vivo in 2 prefrontal brain regions in unmedicated and medicated patients with schizophrenia and healthy controls. DESIGN: Case-control study. SETTING: Inpatient psychiatric research unit and associated outpatient clinic. PARTICIPANTS: Sixteen unmedicated patients with schizophrenia, 16 medicated patients, and 22 healthy controls matched for age, sex, ethnicity, parental socioeconomic status, and cigarette smoking. METHODS: Proton magnetic resonance spectroscopy with a 3-T system and the J-edited spin-echo difference method. The GABA and Glx levels were measured in the dorsolateral and medial prefrontal cortex and normalized to the simultaneously acquired water signal. Working memory performance was assessed in all subjects. MAIN OUTCOME MEASURES: The GABA and Glx concentrations determined by proton magnetic resonance spectroscopy. RESULTS: In the medial prefrontal cortex region, 30% elevations were found in GABA (P = .02) and Glx (P = .03) levels in unmedicated patients compared with controls. There were no alterations in the medicated patients or in either group in the dorsolateral prefrontal cortex. Both regions showed correlations between GABA and Glx levels in patients and controls. No correlations with working memory performance were found. CONCLUSIONS: To our knowledge, this study presents the first GABA concentration measurements in unmedicated patients with schizophrenia, who showed elevations in both GABA and Glx levels in the medial prefrontal cortex but not the dorsolateral prefrontal cortex. Medicated patients did not show these elevations, suggesting possible normalization of levels with antipsychotic medication. The Glx elevations agree with prior magnetic resonance spectroscopy literature, but GABA elevations were unexpected and suggest possible involvement of classes of interneurons not found to show impairments in postmortem studies. PMID- 22213770 TI - Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. AB - CONTEXT: Deep brain stimulation (DBS) may be an effective intervention for treatment-resistant depression (TRD), but available data are limited. OBJECTIVE: To assess the efficacy and safety of subcallosal cingulate DBS in patients with TRD with either major depressive disorder (MDD) or bipolar II disorder (BP). DESIGN: Open-label trial with a sham lead-in phase. SETTING: Academic medical center. Patients Men and women aged 18 to 70 years with a moderate-to-severe major depressive episode after at least 4 adequate antidepressant treatments. Ten patients with MDD and 7 with BP were enrolled from a total of 323 patients screened. Intervention Deep brain stimulation electrodes were implanted bilaterally in the subcallosal cingulate white matter. Patients received single blind sham stimulation for 4 weeks followed by active stimulation for 24 weeks. Patients then entered a single-blind discontinuation phase; this phase was stopped after the first 3 patients because of ethical concerns. Patients were evaluated for up to 2 years after the onset of active stimulation. MAIN OUTCOME MEASURES: Change in depression severity and functioning over time, and response and remission rates after 24 weeks were the primary efficacy end points; secondary efficacy end points were 1 year and 2 years of active stimulation. RESULTS: A significant decrease in depression and increase in function were associated with chronic stimulation. Remission and response were seen in 3 patients (18%) and 7 (41%) after 24 weeks (n = 17), 5 (36%) and 5 (36%) after 1 year (n = 14), and 7 (58%) and 11 (92%) after 2 years (n = 12) of active stimulation. No patient achieving remission experienced a spontaneous relapse. Efficacy was similar for patients with MDD and those with BP. Chronic DBS was safe and well tolerated, and no hypomanic or manic episodes occurred. A modest sham stimulation effect was found, likely due to a decrease in depression after the surgical intervention but prior to entering the sham phase. CONCLUSIONS: The findings of this study support the long-term safety and antidepressant efficacy of subcallosal cingulate DBS for TRD and suggest equivalent safety and efficacy for TRD in patients with BP. Trial Registration clinicaltrials.gov Identifier: NCT00367003. PMID- 22213771 TI - A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. AB - CONTEXT: There was a paucity of comparative pharmacological research for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. OBJECTIVE: To investigate which medication to administer first to antimanic medication-naive subjects. DESIGN, SETTING, AND PARTICIPANTS: The Treatment of Early Age Mania (TEAM) study recruited 6- to 15-year-old children and adolescents with DSM-IV bipolar I disorder (manic or mixed phase) at 5 US sites from 2003 to 2008 into a controlled, randomized, no-patient-choice, 8-week protocol. Blinded, independent evaluators conducted all baseline and end-point assessments. INTERVENTIONS: Subjects received a titrated schedule of lithium, divalproex sodium, or risperidone. Medications were increased weekly only if there was inadequate response, and no dose-limiting adverse effects, to maximum doses of lithium carbonate (1.1-1.3 mEq/L), divalproex sodium (111-125 MUg/mL), and risperidone (4-6 mg). MAIN OUTCOME MEASURES: Primary outcome measures were the Clinical Global Impressions for Bipolar Illness Improvement-Mania and the Modified Side Effects Form for Children and Adolescents. RESULTS: There were 279 antimanic medication-naive subjects (mean [SD] age, 10.1 [2.8] years; 50.2% female) who had the following characteristics: 100% elated mood and/or grandiosity, 77.1% psychosis, 97.5% mixed mania, 99.3% daily rapid cycling, and mean (SD) mania duration of 4.9 (2.5) years. The mean (SD) titrated lithium level was 1.09 (0.34) mEq/L, and the mean (SD) divalproex sodium level was 113.6 (23.0) MUg/mL. The mean (SD) titrated risperidone dose was 2.57 (1.21) mg. Higher response rates occurred with risperidone vs lithium (68.5% vs 35.6%; chi(2)(1) = 16.9, P < .001) and vs divalproex sodium (68.5% vs 24.0%; chi(2)(1) = 28.3, P < .001). Response to lithium vs divalproex sodium did not differ. The discontinuation rate was higher for lithium than for risperidone (chi(2)(1) = 6.4, P = .011). Increased weight gain, body mass index, and prolactin level occurred with risperidone vs lithium (F(1,212) = 45.5, P < .001; F(1,212) = 39.1, P < .001; and F(1,213) = 191.4, P < .001, respectively) and vs divalproex sodium (F(1,212) = 34.7, P < .001; F(1,212) = 45.3, P < .001; and F(1,213) = 209.4, P < .001, respectively). The thyrotropin level increased in subjects taking lithium (t(62) = 11.3, P < .001). CONCLUSIONS: Risperidone was more efficacious than lithium or divalproex sodium for the initial treatment of childhood mania but had potentially serious metabolic effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00057681 PMID- 22213772 TI - Self-reported attenuated psychotic symptoms as forerunners of severe mental disorders later in life. AB - CONTEXT: It has been suggested that attenuated psychotic symptoms (APSs) reported by people who do not have psychotic disorders signal risk for later severe mental illness. OBJECTIVE: To investigate this suggestion using follow-up assessments of hospitalization for clinical diagnoses of nonaffective psychotic and other psychiatric disorders. DESIGN: Longitudinal cohort study of self-reported APSs with outcome assessment of severe mental illness obtained through linkage with a national hospitalization case registry. SETTING: Israel. PARTICIPANTS: A stratified full probability sample of 4914 persons aged 25 to 34 years who were screened for psychopathology in the 1980s. MAIN OUTCOME MEASURE: Subsequent psychiatric hospitalization was ascertained using the psychiatric hospitalization registry, with a mean follow-up of 24 years. RESULTS: After removing subjects with diagnosable psychotic disorders at baseline, 57.2% of the remaining sample reported at least 1 weak (infrequent) APS and 14.3% reported at least 1 strong (frequent) APS in the year preceding the assessment. Self-reported APSs predicted risk of later hospitalization for nonaffective psychotic disorders, mostly during the 5 years after baseline (adjusted odds ratio = 4.31; 95% CI, 2.21-8.41; positive predictive value = 1.27%; population attributable risk fraction = 33%). Also, APSs increased the risk of later hospitalization for other psychiatric disorders, albeit to a lesser extent (adjusted odds ratio = 2.21; 95% CI, 1.02 4.82). CONCLUSIONS: Self-reported APSs signal risk for later nonaffective psychotic disorders but are not clinically useful as predictors. The difference between these population-based data and the high-risk literature in terms of the positive predictive value (1% vs 10%, respectively) and the time window of transition (5 years vs 12 months, respectively) can be attributed to the selective enrichment strategies that produce high-risk samples. PMID- 22213773 TI - 9-cis retinoic acid inhibits inflammatory responses of adherent monocytes and increases their ability to induce classical monocyte migration. AB - Patients with vitamin A/retinol deficiency are shown to be prone to infections and to suffer from increased inflammation, effects which can be remedied by vitamin A supplements. We aimed to study how human monocytes from the peripheral venous blood of healthy donors acted within the initial hours after adherence and exposure to bacterial endotoxin in the presence or absence of the 9-cis-isomer of retinoic acid (9cisRA). We found that adherent human monocytes were dominated by the CD14dimCD16+ subtype. Pretreatment with 9cisRA for 1 h significantly decreased lipopolysaccharide (LPS)-induced mRNA expression and protein release of tumor necrosis factor (TNF)alpha, interleukin (IL)-6 and chemokine ligands (CCL)3 and CCL4. In contrast, treatment with 9cisRA rapidly enhanced the production of monocyte chemoattractive protein/CCL2. 9cisRA treatment also led to enhanced migration of classical CD14high monocytes in a transwell in vitro system. We conclude that 9cisRA treatment of human adherent monocytes attenuates the inflammatory responses to LPS and induces the attraction of classical monocytes, a feature which may help explain why supplements administered to vitamin A deficient patients counteract inflammation and increases the ability to fight infections. PMID- 22213774 TI - Effect of dose and duration of micronized progesterone treatment during the first trimester on incidence of glucose intolerance and on birth weight. AB - OBJECTIVE: The aim was to investigate the potential effect of oral progesterone therapy during the first trimester on glucose metabolism and on birth weight, and to assess the existence of dose-related differences. METHODS: One hundred and fifty women with a history of imminent abortion and who used micronized progesterone (MicP) (200-600 MUg/day for 4-6 weeks), and 150 healthy pregnant women as a control group, were included in the study. Fasting blood glucose (FBG), hemoglobin A1c (HbA1c) and OGL were measured between 24 and 28 weeks of gestation. Patients were followed up to term and birth weight was recorded. RESULTS: Risk of abnormal FBG and OGL was increased by 4.5- and 9.4-fold, respectively, in patients receiving MicP (p < 0.001). Median birth weight and gestational age were 3,599 g (500) and 39.0 weeks (1.3) for the MicP exposed group and 3,120 g (210) and 39.4 weeks (1.5) for the control group, respectively. Median birth weight was significantly higher in the MicP-exposed group for a similar gestational age (p < 0.001). There were no dose-related differences between groups. CONCLUSION: MicP therapy during the first trimester of pregnancy might have undesirable effects on glucose metabolism, which stresses the need of larger studies to confirm this association. PMID- 22213775 TI - Neuroprotective role of estradiol against neuronal death induced by glucose deprivation in cultured rat hippocampal neurons. AB - Studies have reported the protective effect of estradiol (E(2)) against neuronal death induced by several insults including oxygen deprivation, mitochondrial toxins and activation of glutamate receptors. Glucose deprivation (GD) is associated with ischemia and hypoglycemia, and to date there is no effective therapeutic agent able to prevent neuronal damage induced by these conditions. In this study, we have investigated the effects of 17beta-E(2) and the selective agonists of the alpha (ERalpha) and beta (ERbeta) estrogen receptors, propyl pyrazole triol (PPT) and diarylpropionitrile (DPN), respectively, on neuronal death induced by GD in cultured rat hippocampal neurons. We have also analyzed the expression of both ER isoforms after GD. Results show that GD for 2 and 4 h reduces cell survival by 42 and 55%, respectively. Treatment with 17beta-E(2) (10 nM to 10 uM) induces a dose-dependent protective effect that is blocked by ICI 182,780, an ER antagonist, and by 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-( piperidinylethoxy)phenol]-1H'pyrazole dihydrochloride (MPP) and 4-[2-phenyl-5,7 bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP), selective ERalpha and ERbeta antagonists, respectively. The ERalpha and ERbeta agonists PPT and DPN show a similar neuroprotective effect to that of 17beta-E(2), but DPN is more efficient. In addition, hippocampal neurons under normal conditions show a higher expression of the ERbeta isoform. When exposed to GD during 4 h, the expression of both ER isoforms is increased, while only that of the ERbeta isoform significantly increases after 2 h of GD. Results demonstrate that E(2) prevents neuronal death induced by GD through its interaction with ER, although the ERbeta isoform might have a predominant role. Results also suggest that GD differentially alters the expression of ERalpha and ERbeta in hippocampal neurons. PMID- 22213776 TI - Epilepsy surgery in a pediatric population: a retrospective study of 129 children from a tertiary care hospital in a developing country along with assessment of quality of life. AB - PURPOSE: To assess the outcome of a pediatric population operated for drug resistant epilepsy from a large tertiary care center in India. METHODS: Retrospectively: quality of life (QOL); prospectively: preoperative assessment included interictal EEG, MRI (as per epilepsy protocol), video-EEG. Ictal SPECT (with subtraction) and PET were performed when required. QOL scores were assessed using the HASS or SSQ for seizure severity, Quality of Life in Childhood Epilepsy (QOLCE) for QOL, and Child Behavior Check List (CBCL) for behavior. RESULTS: 142 were operated from January 2000 to June 2011 by the senior author. 118 patients with at least 1 year of follow-up were included in the study. Mean age at surgery was 9.8 +/- 4.3 years. In addition, 40 patients underwent QOL assessment prospectively both before and after surgery. Mean duration of epilepsy was 5.3 +/ 3.3 years. A class I outcome (Engel's) was seen in 79.5% patients, class II in 8.6%, class III in 10.7%, and class IV in 1 patient. As per surgical procedures, class I outcome in patients who underwent temporal resection, hemispherotomy and extratemporal resection was 76, 87 and 72%, respectively. QOL scores correlated with duration of seizures, epileptic encephalopathy and outcome of surgery, but not with side of surgery, age and sex. CONCLUSIONS: This study, the largest reported from India, has demonstrated satisfactory results for epilepsy surgery in children. PMID- 22213777 TI - Metastatic spread outside the central nervous system of anaplastic medulloblastoma associated with a spinal-peritoneal shunt immediately after radiotherapy. PMID- 22213778 TI - Long-segment type 1 split cord malformation with two-level split cord malformation and a single dural sac at the lower split. AB - OBJECTIVE AND IMPORTANCE: Two-level bony spurs are rare and also a very long segment of bony spur is very rare. Bony spur with a single dural covering is not reported in the literature. Here, we report a case of prophylactic surgery performed on a patient with a bony spur with a single dural covering who showed a good postoperative outcome. This case highlights the importance of prophylactic surgery in such patients to avoid cord injuries. CLINICAL PRESENTATION: Since birth a 1-year-old child had had a tuft of hair at the dorsal (D6 and D7) region. The patient was examined and found to have scoliosis with convexity towards the right. There was no neurological deficit. MRI and CT spine scans showed 2-level type 1 split cord malformation (SCM) and there was a low-lying conus at the L(3 4) level. INTERVENTION: The patient was operated on at the age of 1 year and 2 separate bony septae were observed. The upper one extended from D5 to D9 and the lower one was at the D11 level. The bony spurs were excised. The filum was sectioned at the L(4-5) level by a separate incision. The patient had a good postoperative recovery. CONCLUSION: With meticulous planning and careful surgery, prophylactic surgery can have a very good outcome in long-segment and two-level type 1 SCM. PMID- 22213779 TI - Morquio's syndrome and craniocervical instability. PMID- 22213780 TI - Desmoplakin as a potential candidate for cerebrospinal fluid marker to rule out 14-3-3 false positive rates in sporadic Creutzfeldt-Jakob disease differential diagnosis. AB - BACKGROUND: The detection of a 14-3-3 elevated level in cerebrospinal fluid (CSF) is a part of the diagnostic criteria for probable sporadic Creutzfeldt-Jakob disease (sCJD), as defined by the WHO. However, some pathological conditions associated with acute neuronal damage may result in a positive 14-3-3 test and thereby reduce test specificity in sCJD. OBJECTIVE: Desmoplakin has been previously identified as up-regulated CSF protein in sCJD and these studies aimed to investigate its diagnostic utility and compare it with two known CSF markers, 14-3-3 and tau. METHODS AND RESULTS: We tested CSF levels of 14-3-3, tau and desmoplakin in 58 sCJD patients and 81 control patients including 45 cases with an elevated 14-3-3 level due to other disease than sCJD. We detected an elevated CSF level of desmoplakin in 78% of the sCJD patients, while 14-3-3 (88%) and tau (91%) showed a higher positive rate. However, the false positive rate of newly tested desmoplakin was significantly lower in comparison to 14-3-3 and tau, and it accounted for only 11% versus 56% and 35%, respectively. Further reduction of false positive rates was achieved by combination of elevated tau level with a positive desmoplakin test. Moreover, in the non-sCJD group, desmoplakin level did not correlate with the level of both above-mentioned CSF markers, whereas a clear correlation was observed in the sCJD group. CONCLUSION: Desmoplakin showed a low positive rate accompanied by a very low false positive rate. Thus, we conclude that desmoplakin is a promising candidate for supportive CSF marker to rule out 14-3-3 false positive cases in sCJD differential diagnosis. PMID- 22213781 TI - Lack of association of mouse mammary tumor virus-like sequences in Iranian breast cancer patients. AB - OBJECTIVE: The present study aimed to detect mouse mammary tumor virus (MMTV) like sequences in Iranian breast cancer patients in the city of Shiraz, located in southwest Iran. SUBJECTS AND METHODS: We searched for two MMTV genetic regions in the peripheral blood leukocytes of 300 women with breast cancer, 300 age matched healthy control subjects, and 50 breast tumor tissues. Two regions of MMTV, 660 bp and 250 bp, were searched by nested polymerase chain reactions. RESULTS: None of the above two regions were detected. There were no differences between the control group and the breast cancer group. CONCLUSION: Our findings did not show any association of MMTV-like sequences with breast cancer development in Iranian patients in Shiraz. PMID- 22213782 TI - Long-term intersession variability for single-breath diffusing capacity. AB - BACKGROUND: Characterizing long-term diffusing capacity (DL(CO)) variability is important in assessing quality control for DL(CO) equipment and patient management. Long-term DL(CO) variability has not been reported. OBJECTIVES: It was the aim of this study to characterize long-term variability of DL(CO) in a cohort of biocontrols and to compare different methods of selecting a target value. METHODS: Longitudinal DL(CO) monitoring of biocontrols was performed as part of the inhaled insulin development program; 288 biocontrols were tested twice monthly for up to 5 years using a standardized technique. Variability, expressed either as percent change or DL(CO) units, was assessed using three different target values. RESULTS: The 90th percentile for mean intersession change in DL(CO) was between 10.9 and 15.8% (2.6-4.1 units) depending on the target value. Variability was lowest when the mean of all DL(CO) tests was used as the target value and highest when the baseline DL(CO) was used. The average of the first six DL(CO) tests provided an accurate estimate of the mean DL(CO) value. Using this target, the 90th percentile for mean intersession change was 12.3% and 3.0 units. Variability was stable over time and there were no meaningful associations between variability and demographic factors. CONCLUSIONS: DL(CO) biocontrol deviations >12% or >3.0 units, from the average of the first six tests, indicate that the instrument is not within quality control limits and should be carefully evaluated before further patient testing. PMID- 22213783 TI - Balancing the risks and benefits of genomic data sharing: genome research participants' perspectives. AB - BACKGROUND: Technological advancements are rapidly propelling the field of genome research forward, while lawmakers attempt to keep apace with the risks these advances bear. Balancing normative concerns of maximizing data utility and protecting human subjects, whose privacy is at risk due to the identifiability of DNA data, are central to policy decisions. Research on genome research participants making real-time data sharing decisions is limited; yet, these perspectives could provide critical information to ongoing deliberations. METHODS: We conducted a randomized trial of 3 consent types affording varying levels of control over data release decisions. After debriefing participants about the randomization process, we invited them to a follow-up interview to assess their attitudes toward genetic research, privacy and data sharing. RESULTS: Participants were more restrictive in their reported data sharing preferences than in their actual data sharing decisions. They saw both benefits and risks associated with sharing their genomic data, but risks were seen as less concrete or happening in the future, and were largely outweighed by purported benefits. CONCLUSION: Policymakers must respect that participants' assessment of the risks and benefits of data sharing and their privacy-utility determinations, which are associated with their final data release decisions, vary. In order to advance the ethical conduct of genome research, proposed policy changes should carefully consider these stakeholder perspectives. PMID- 22213784 TI - Picasso's Weeping Woman. PMID- 22213785 TI - Progressive brain changes in children and adolescents with first-episode psychosis. AB - CONTEXT: Progressive loss of brain gray matter (GM) has been reported in childhood-onset schizophrenia; however, it is uncertain whether these changes are shared by pediatric patients with different psychoses. OBJECTIVE: To examine the progression of brain changes in first-episode early-onset psychosis and their relationship to diagnosis and prognosis at 2-year follow-up. DESIGN: Prospective, multicenter, naturalistic, 2-year follow-up study. SETTING: Six child and adolescent psychiatric units in Spain. PARTICIPANTS: A total of 110 patients and 98 healthy controls were recruited between March 1, 2003, and November 31, 2005. Magnetic resonance imaging of the brain was performed for 61 patients with schizophrenia (n = 25), bipolar disorder (n = 16), or other psychoses (n = 20) and 70 controls (both at baseline and after 2 years of follow-up). Mean age at baseline was 15.5 years (patients) and 15.3 years (controls). MAIN OUTCOME MEASURES: The GM and cerebrospinal fluid (CSF) volumes in the total brain and frontal, parietal, and temporal lobes. RESULTS: Compared with controls, patients with schizophrenia showed greater GM volume loss in the frontal lobe during the 2 year follow-up (left: -3.3 vs -0.6 cm(3), P = .004; right: -3.7 vs -0.8 cm(3), P = .005) and left frontal CSF volume increase (left: 6.7 vs 2.4 cm(3), P = .006). In addition to frontal volume, changes for total GM (-37.1 vs -14.5 cm(3), P = .001) and left parietal GM (-4.3 vs -2.2 cm(3), P = .04) were significantly different in schizophrenic patients compared with controls. No significant differences emerged for patients with bipolar disease. Greater left frontal GM volume loss was related to more weeks of hospitalization, whereas severity of negative symptoms correlated with CSF increase in patients with schizophrenia. CONCLUSIONS: Patients with schizophrenia or other psychoses showed greater loss of GM volume and increase of CSF in the frontal lobe relative to controls. Progressive changes were more evident in patients with schizophrenia than those with bipolar disorder. These changes in specific brain volumes after onset of psychotic symptoms may be related to markers of poorer prognosis. PMID- 22213786 TI - Induction of psychosis by Delta9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing. AB - CONTEXT: The aberrant processing of salience is thought to be a fundamental factor underlying psychosis. Cannabis can induce acute psychotic symptoms, and its chronic use may increase the risk of schizophrenia. We investigated whether its psychotic effects are mediated through an influence on attentional salience processing. OBJECTIVE: To examine the effects of Delta9-tetrahydrocannabinol (Delta9-THC) and cannabidiol (CBD) on regional brain function during salience processing. DESIGN: Volunteers were studied using event-related functional magnetic resonance imaging on 3 occasions after administration of Delta9-THC, CBD, or placebo while performing a visual oddball detection paradigm that involved allocation of attention to infrequent (oddball) stimuli within a string of frequent (standard) stimuli. SETTING: University center. PARTICIPANTS: Fifteen healthy men with minimal previous cannabis use. MAIN OUTCOME MEASURES: Symptom ratings, task performance, and regional brain activation. RESULTS: During the processing of oddball stimuli, relative to placebo, Delta9-THC attenuated activation in the right caudate but augmented it in the right prefrontal cortex. Delta9-Tetrahydrocannabinol also reduced the response latency to standard relative to oddball stimuli. The effect of Delta9-THC in the right caudate was negatively correlated with the severity of the psychotic symptoms it induced and its effect on response latency. The effects of CBD on task-related activation were in the opposite direction of those of Delta9-THC; relative to placebo, CBD augmented left caudate and hippocampal activation but attenuated right prefrontal activation. CONCLUSIONS: Delta9-Tetrahydrocannabinol and CBD differentially modulate prefrontal, striatal, and hippocampal function during attentional salience processing. These effects may contribute to the effects of cannabis on psychotic symptoms and on the risk of psychotic disorders. PMID- 22213787 TI - Reduced medial prefrontal responses to social interaction images in remitted depression. AB - CONTEXT: Major depressive disorder is associated with impairments in processing emotional stimuli, and residual impairments are observed during remission, possibly indicating trait vulnerability. Stimuli with social context represent a distinct class of emotional stimuli, which in healthy volunteers are associated with specific neural substrates but have not previously been studied relative to vulnerability to depression. OBJECTIVE: To explore whether individuals with remitted major depressive disorder had altered neuronal processing of social emotional stimuli. DESIGN: Cross-sectional design using functional magnetic resonance imaging, combined with a cognitive activation task. SETTING: General community of greater Manchester, England. PARTICIPANTS: Twenty-five unmedicated participants fully remitted from major depressive disorder and 29 age-matched control subjects. MAIN OUTCOME MEASURES: Neuronal responses to positive and negative social interaction images vs valence-matched images with less overt social context. RESULTS: Participants with remitted depression showed attenuated frontopolar response relative to controls for positive and negative images depicting social interactions. For negative social images, participants with remitted depression also showed reduced latero-orbitofrontal response relative to controls. CONCLUSIONS: In the absence of current symptoms, individuals with remitted major depressive disorder showed reduced frontopolar processing of stimuli showing social interactions, a reduction not seen for stimuli showing individual successes and failures and, therefore, not simply an effect of emotional valence. These results suggest a specific trait abnormality in social emotional processing associated with vulnerability to depression, which may have implications for understanding social cognition mechanisms and for developing effective psychological therapies. PMID- 22213788 TI - Autism spectrum disorders and autistic like traits: similar etiology in the extreme end and the normal variation. AB - CONTEXT: Autism spectrum disorders (ASDs) have been suggested to represent the extreme end of a normal distribution of autistic like traits (ALTs). However, the evidence of this notion is inconclusive. OBJECTIVE: To study whether there are similar genetic and/or environmental etiologies behind ASDs and ALTs. DESIGN: A nationwide twin study. PARTICIPANTS: Consenting parents of all Swedish twins aged 9 and 12 years, born between July 1, 1992, and December 31, 2001 (n = 19 208), were interviewed by telephone to screen for child psychiatric conditions, including ASDs. MAIN OUTCOME MEASURES: Two validated cutoffs for ASDs, 2 cutoffs encompassing the normal variation, and 1 continuous measure of ALTs were used with DeFries-Fulker extreme-end analyses and standard twin study methods. RESULTS: We discerned a strong correlation between the 4 cutoffs and the full variation of ALTs. The correlation was primarily affected by genes. We also found that the heritability for the 4 cutoffs was similar. CONCLUSION: We demonstrate an etiological similarity between ASDs and ALTs in the normal variation and, with results from previous studies, our data suggest that ASDs and ALTs are etiologically linked. PMID- 22213789 TI - Increased rate of amygdala growth in children aged 2 to 4 years with autism spectrum disorders: a longitudinal study. AB - CONTEXT: Precocious amygdala enlargement is commonly observed in young children with autism. However, the age at which abnormal amygdala enlargement begins and the relative growth trajectories of the amygdala and total brain remain unclear. OBJECTIVE: To determine whether the rate of amygdala growth is abnormal and disproportionate to total brain growth in very young children with autism spectrum disorders (ASDs). DESIGN: Longitudinal structural magnetic resonance imaging study. SETTING: Neuroimaging and diagnostic assessments were performed at an academic medical center. Participants were recruited from the community. PARTICIPANTS: Baseline scans were acquired in 132 boys (85 with ASD and 47 control subjects with typical development [TD]; mean age, 37 months). Longitudinal magnetic resonance images were acquired in 70 participants (45 with ASD and 25 TD controls) 1 year later. MAIN OUTCOME MEASURE: Amygdala volumes and total cerebral volumes (TCVs) were evaluated at both time points, and 1-year growth rates were calculated. RESULTS: The amygdala was larger in children with ASD at both time points, but the magnitude of enlargement was greater at time 2. The TCV was also enlarged in the children with ASD by the same magnitude at both time points. When we controlled for TCV, amygdala enlargement remained significant at both time points. The rate of amygdala growth during this 1-year interval was faster in children with ASD than in TD controls. The rate of TCV growth did not differ between groups. Post hoc exploratory analyses revealed 3 patterns of amygdala and TCV growth rates in the ASD group. CONCLUSIONS: Disproportionate amygdala enlargement is present by 37 months of age in ASD. The amygdala continues to grow at an increased rate, but substantial heterogeneity exists in amygdala and TCV growth patterns. Future studies aimed at clinical characterization of different growth patterns could have implications for choice and outcomes of treatment and behavioral therapy. PMID- 22213790 TI - Interaction between FKBP5 and childhood trauma and risk of aggressive behavior. AB - CONTEXT: Childhood trauma may predispose individuals to aggressive behavior, and both childhood trauma and aggressive behavior are associated with hypothalamic pituitary-adrenal axis dysregulation. OBJECTIVE: To determine whether there would be an interaction between genetic variation in FKBP5 and childhood trauma in predicting aggressive behavior. DESIGN: Cross-sectional study. Four FKBP5 single nucleotide polymorphisms used in previous studies (rs3800373, rs9296158, rs1360780, and rs9470080) were genotyped. Three diplotypes were derived from 2 major putatively functional haplotypes regulating protein expression that were previously associated with glucocorticoid receptor sensitivity. SETTING: Penitentiary District of Abruzzo-Molise in central Italy. PARTICIPANTS: A population of 583 male Italian prisoners recruited between 2005 and 2008. MAIN OUTCOME MEASURES: A comprehensive analysis of aggression and impulsivity was undertaken using the Brown-Goodwin Lifetime History of Aggression (BGHA) questionnaire, the Buss-Durkee Hostility Inventory (BDHI), and the Barratt Impulsiveness Scale (BIS). A history of childhood trauma was investigated with the Childhood Trauma Questionnaire. The interaction between the FKBP5 diplotypes and childhood trauma on measures of aggression was analyzed. Analyses were replicated with a second behavioral measure of aggression: violent behavior in jail. Individual single-nucleotide polymorphism analysis was performed. RESULTS: Childhood trauma had a significant effect on BGHA and BDHI scores but not on BIS scores. We observed a significant influence of the FKBP5 high-expression diplotype on both a lifetime history of aggressive behavior (BGHA) (P = .012) and violent behavior in jail (P = .025) but only in individuals exposed to childhood trauma, in particular to physical abuse. No main effect of the FKBP5 diplotypes was observed. CONCLUSION: These data suggest that childhood trauma and variants in the FKBP5 gene may interact to increase the risk of overt aggressive behavior. PMID- 22213791 TI - Operational definitions and algorithms for excessive sleepiness in the general population: implications for DSM-5 nosology. AB - CONTEXT: Excessive sleepiness (ES) is poorly defined in epidemiologic studies, although its adverse implications for safety, health, and optimal social and vocational functioning have been extensively reported. OBJECTIVE: To determine the importance of ES definition, measurement, and prevalence in the general population, together with its coexisting conditions. DESIGN: Cross-sectional telephone study. PARTICIPANTS: A total of 15 929 individuals representative of the adult general population of 15 states in the United States. MAIN OUTCOME MEASURES: Interviews were carried out using Sleep-EVAL, a knowledge-based expert system for use in epidemiologic studies, focusing on sleep, as well as physical and mental disorders, according to classification in DSM-IV and the second edition of the International Classification of Sleep Disorders. The interviews elicited information on ES, naps, frequency, duration, impairment, and distress associated with ES symptoms. RESULTS: Excessive sleepiness was reported by 27.8% (95% CI, 27.1%-28.5%) of the sample. Excessive sleepiness with associated symptoms was found in 15.6% of the participants (95% CI, 15.0%-16.2%). Adding an ES frequency of at least 3 times per week for at least 3 months despite normal sleep duration dropped the prevalence to 4.7% of the sample (95% CI, 4.4%-5.0%). The proportion of individuals having social or professional impairment and psychological distress increased with the frequency of ES symptoms during the week and within the same day. In multivariate models, the number of ES episodes per day and severity of ES were identified as the best predictors for impairment/distress. Prevalence of hypersomnia disorder was 1.5% of the participants (95% CI, 1.3%-1.7%). The most common coexisting conditions were mood and substance use disorders. CONCLUSIONS: Excessive sleepiness is an important problem in the US population, even when using restrictive criteria to define it. Hypersomnia disorder is more prevalent than previously estimated. Excessive sleepiness has to be recognized and given attention by public health authorities, scientists, and clinicians. PMID- 22213792 TI - Cerebrospinal fluid levels of beta-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. AB - CONTEXT: Early detection of prodromal Alzheimer disease (AD) is important because new disease-modifying therapies are most likely to be effective when initiated during the early stages of disease. OBJECTIVES: To assess the ability of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P tau), and beta-amyloid 1-42 (Abeta42) to predict future development of AD dementia within 9.2 years in patients with mild cognitive impairment (MCI) and to compare CSF biomarkers between early and late converters to AD. DESIGN: A clinical study with a median follow-up of 9.2 years (range, 4.1-11.8 years). SETTING: Memory disorder clinic. Patients A total of 137 patients with MCI who underwent lumbar puncture at baseline. MAIN OUTCOME MEASURE Conversion to AD dementia. RESULTS: During follow-up, 72 patients (53.7%) developed AD and 21 (15.7%) progressed to other forms of dementia. At baseline, CSF Abeta42 levels were reduced and T-tau and P-tau levels were elevated in patients who converted to AD during follow-up compared with nonconverters (P < .001). Baseline CSF Abeta42 levels were equally reduced in patients with MCI who converted to AD within 0 to 5 years (early converters) compared with those who converted between 5 and 10 years (late converters). However, CSF T-tau and P-tau levels were significantly higher in early converters vs late converters. A baseline Abeta42:P tau ratio predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 86%. CONCLUSIONS: Approximately 90% of patients with MCI and pathologic CSF biomarker levels at baseline develop AD within 9 to 10 years. Levels of Abeta42 are already fully decreased at least 5 to 10 years before conversion to AD dementia, whereas T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered Abeta metabolism precedes tau-related pathology and neuronal degeneration. PMID- 22213793 TI - AAIR or DDDR pacing for sick sinus syndrome: the physiologic conundrum. PMID- 22213794 TI - Temporary transvenous VDD pacing as a bridge to permanent pacemaker implantation in patients with sepsis and haemodynamically significant atrioventricular block. AB - AIMS: Permanent pacemaker (PM) implantation is temporarily contraindicated in patients (pts) with sepsis. In patients with symptomatic atrioventricular (AV) block and infection, prolonged VVI pacing is therefore usually ensured by a ventricular pacing lead (PL) connected to an external PM generator. In patients with normal sinus function and heart failure, the VVI mode can exacerbate haemodynamic dysfunction. A single AV PL can be attractive to achieve physiological pacing. This study was designed to assess the efficacy and safety of temporary VDD pacing as a bridge to permanent PM implantation in patients with complete AV block until control of infection. METHODS AND RESULTS: This study included eight patients with complete AV block and sepsis with negative blood culture. Due to the presence of congestive heart failure, a single bipolar AV PL connected to an external VDD PM generator. At VDD implantation, P-wave amplitude was 1.9 +/- 1.6 mV and R-wave was 11.3 +/- 5.2 mV. The ventricular pacing threshold was 0.53 +/- 0.1 V for a 0.5 ms pulse. Antibiotic therapy was instituted in all patients. A permanent VDD or DDD PM was implanted after 8 +/- 2.5 days of temporary VDD pacing. At permanent PM implantation, the mean brain natriuretic peptide level had decreased and sepsis was controlled in all patients. No recurrence of sepsis was observed with a mean follow-up of 15.8 +/- 5.3 months. CONCLUSION: Temporary VDD pacing is a safe and effective method to achieve prolonged AV physiological pacing in patients with AV block until infection has been controlled. PMID- 22213795 TI - J-wave-associated ventricular fibrillation in a patient with a subarachnoid haemorrhage. AB - We report a case of 59-year-old man with subarachnoid haemorrhage (SAH) complicated by ventricular fibrillation (VF). Continuous electrocardiogram monitoring revealed that J-waves appeared immediately before the VF. The present report is the first to describe a J-wave-associated VF as another possible mechanism of sudden cardiac death in patients with SAH. PMID- 22213796 TI - ColoGuideEx: a robust gene classifier specific for stage II colorectal cancer prognosis. AB - BACKGROUND AND AIMS: Several clinical factors have an impact on prognosis in stage II colorectal cancer (CRC), but as yet they are inadequate for risk assessment. The present study aimed to develop a gene expression classifier for improved risk stratification of patients with stage II CRC. METHODS: 315 CRC samples were included in the study. Gene expression measurements from 207 CRC samples (stage I-IV) from two independent Norwegian clinical series were obtained using Affymetrix exon-level microarrays. Differentially expressed genes between stage I and stage IV samples from the test series were identified and used as input for L1 (lasso) penalised Cox proportional hazards analyses of patients with stage II CRC from the same series. A second validation was performed in 108 stage II CRC samples from other populations (USA and Australia). RESULTS: An optimal 13 gene expression classifier (PIGR, CXCL13, MMP3, TUBA1B, SESN1, AZGP1, KLK6, EPHA7, SEMA3A, DSC3, CXCL10, ENPP3, BNIP3) for prediction of relapse among patients with stage II CRC was developed using a consecutive Norwegian test series from patients treated according to current standard protocols (n=44, p<0.001, HR=18.2), and its predictive value was successfully validated for patients with stage II CRC in a second Norwegian CRC series collected two decades previously (n=52, p=0.02, HR=3.6). Further validation of the classifier was obtained in a recent external dataset of patients with stage II CRC from other populations (n=108, p=0.001, HR=6.5). Multivariate Cox regression analyses, including all three sample series and various clinicopathological variables, confirmed the independent prognostic value of the classifier (p<=0.004). The classifier was shown to be specific to stage II CRC and does not provide prognostic stratification of patients with stage III CRC. CONCLUSION: This study presents the development and validation of a 13-gene expression classifier, ColoGuideEx, for prognosis prediction specific to patients with stage II CRC. The robustness was shown across patient series, populations and different microarray versions. PMID- 22213797 TI - The vesicular SNARE Synaptobrevin is required for Semaphorin 3A axonal repulsion. AB - Attractive and repulsive molecules such as Semaphorins (Sema) trigger rapid responses that control the navigation of axonal growth cones. The role of vesicular traffic in axonal guidance is still largely unknown. The exocytic vesicular soluble N-ethylmaleimide sensitive fusion protein attachment protein receptor (SNARE) Synaptobrevin 2 (Syb2) is known for mediating neurotransmitter release in mature neurons, but its potential role in axonal guidance remains elusive. Here we show that Syb2 is required for Sema3A-dependent repulsion but not Sema3C-dependent attraction in cultured neurons and in the mouse brain. Syb2 associated with Neuropilin 1 and Plexin A1, two essential components of the Sema3A receptor, via its juxtatransmembrane domain. Sema3A receptor and Syb2 colocalize in endosomal membranes. Moreover, upon Sema3A treatment, Syb2 deficient neurons failed to collapse and transport Plexin A1 to cell bodies. Reconstitution of Sema3A receptor in nonneuronal cells revealed that Sema3A further inhibited the exocytosis of Syb2. Therefore, Sema3A-mediated signaling and axonal repulsion require Syb2-dependent vesicular traffic. PMID- 22213798 TI - Ubiquitylation of the nuclear pore complex controls nuclear migration during mitosis in S. cerevisiae. AB - Nuclear pore complexes (NPCs) correspond to large protein transport complexes responsible for selective nucleocytoplasmic exchange. Although research has revealed much about the molecular architecture and roles of the NPC subcomplexes, little is known about the regulation of NPC functions by posttranslational modifications. We used a systematic approach to show that more than half of NPC proteins were conjugated to ubiquitin. In particular, Nup159, a nucleoporin exclusively located on the cytoplasmic side of the NPC, was monoubiquitylated by the Cdc34/SCF (Skp1-Cdc53-F-box E3 ligase) enzymes. Preventing this modification had no consequences on nuclear transport or NPC organization but strongly affected the ability of Nup159 to target the dynein light chain to the NPC. This led to defects in nuclear segregation at the onset of mitosis. Thus, defining ubiquitylation of the yeast NPC highlights yet-unexplored functions of this essential organelle in cell division. PMID- 22213799 TI - RAB-6.2 and the retromer regulate glutamate receptor recycling through a retrograde pathway. AB - Regulated membrane trafficking of AMPA-type glutamate receptors (AMPARs) is a key mechanism underlying synaptic plasticity, yet the pathways used by AMPARs are not well understood. In this paper, we show that the AMPAR subunit GLR-1 in Caenorhabditis elegans utilizes the retrograde transport pathway to regulate AMPAR synaptic abundance. Mutants for rab-6.2, the retromer genes vps-35 and snx 1, and rme-8 failed to recycle GLR-1 receptors, resulting in GLR-1 turnover and behavioral defects indicative of diminished GLR-1 function. In contrast, expression of constitutively active RAB-6.2 drove the retrograde transport of GLR 1 from dendrites back to cell body Golgi. We also find that activated RAB-6.2 bound to and colocalized with the PDZ/phosphotyrosine binding domain protein LIN 10. RAB-6.2 recruited LIN-10. Moreover, the regulation of GLR-1 transport by RAB 6.2 required LIN-10 activity. Our results demonstrate a novel role for RAB-6.2, its effector LIN-10, and the retromer complex in maintaining synaptic strength by recycling AMPARs along the retrograde transport pathway. PMID- 22213800 TI - PAI-1-regulated miR-21 defines a novel age-associated fibrogenic pathway in muscular dystrophy. AB - Disruption of skeletal muscle homeostasis by substitution with fibrotic tissue constitutes the principal cause of death in Duchenne muscular dystrophy (DMD) patients, yet the implicated fibrogenic mechanisms remain poorly understood. This study identifies the extracellular PAI-1/urokinase-type plasminogen activator (uPA) balance as an important regulator of microribonucleic acid (miR)-21 biogenesis, controlling age-associated muscle fibrosis and dystrophy progression. Genetic loss of PAI-1 in mdx dystrophic mice anticipated muscle fibrosis through these sequential mechanisms: the alteration of collagen metabolism by uPA mediated proteolytic processing of transforming growth factor (TGF)-beta in muscle fibroblasts and the activation of miR-21 expression, which inhibited phosphatase and tensin homologue and enhanced AKT signaling, thus endowing TGF beta with a remarkable cell proliferation-promoting potential. Age-associated fibrogenesis and muscle deterioration in mdx mice, as well as exacerbated dystrophy in young PAI-1(-/-) mdx mice, could be reversed by miR-21 or uPA selective interference, whereas forced miR-21 overexpression aggravated disease severity. The PAI-1-miR-21 fibrogenic axis also appeared dysregulated in muscle of DMD patients, providing a basis for effectively targeting fibrosis and muscular dystrophies in currently untreatable individuals. PMID- 22213801 TI - Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia. AB - PTEN (phosphatase and tensin homologue deleted on chromosome TEN) is the major negative regulator of phosphatidylinositol 3-kinase signaling and has cell specific functions including tumor suppression. Nuclear localization of PTEN is vital for tumor suppression; however, outside of cancer, the molecular and physiological events driving PTEN nuclear entry are unknown. In this paper, we demonstrate that cytoplasmic Pten was translocated into the nuclei of neurons after cerebral ischemia in mice. Critically, this transport event was dependent on a surge in the Nedd4 family-interacting protein 1 (Ndfip1), as neurons in Ndfip1-deficient mice failed to import Pten. Ndfip1 binds to Pten, resulting in enhanced ubiquitination by Nedd4 E3 ubiquitin ligases. In vitro, Ndfip1 overexpression increased the rate of Pten nuclear import detected by photobleaching experiments, whereas Ndfip1(-/-) fibroblasts showed negligible transport rates. In vivo, Ndfip1 mutant mice suffered larger infarct sizes associated with suppressed phosphorylated Akt activation. Our findings provide the first physiological example of when and why transient shuttling of nuclear Pten occurs and how this process is critical for neuron survival. PMID- 22213802 TI - dEHBP1 controls exocytosis and recycling of Delta during asymmetric divisions. AB - Notch signaling governs binary cell fate determination in asymmetrically dividing cells. Through a forward genetic screen we identified the fly homologue of Eps15 homology domain containing protein-binding protein 1 (dEHBP1) as a novel regulator of Notch signaling in asymmetrically dividing cells. dEHBP1 is enriched basally and at the actin-rich interface of pII cells of the external mechanosensory organs, where Notch signaling occurs. Loss of function of dEHBP1 leads to up-regulation of Sanpodo, a regulator of Notch signaling, and aberrant trafficking of the Notch ligand, Delta. Furthermore, Sec15 and Rab11, which have been previously shown to regulate the localization of Delta, physically interact with dEHBP1. We propose that dEHBP1 functions as an adaptor molecule for the exocytosis and recycling of Delta, thereby affecting cell fate decisions in asymmetrically dividing cells. PMID- 22213803 TI - The E3 ubiquitin ligase Mule acts through the ATM-p53 axis to maintain B lymphocyte homeostasis. AB - Cellular homeostasis is controlled by pathways that balance cell death with survival. Mcl-1 ubiquitin ligase E3 (Mule) is an E3 ubiquitin ligase that targets the proapoptotic molecule p53 for polyubiquitination and degradation. To elucidate the role of Mule in B lymphocyte homeostasis, B cell-specific Mule knockout (BMKO) mice were generated using the Cre-LoxP recombination system. Analysis of BMKO mice showed that Mule was essential for B cell development, proliferation, homeostasis, and humoral immune responses. p53 transactivation was increased by two- to fourfold in Mule-deficient B cells at steady state. Genetic ablation of p53 in BMKO mice restored B cell development, proliferation, and homeostasis. p53 protein was increased in resting Mule-deficient mouse embryonic fibroblasts (MEFs) and embryonic stem (ES) cells. Loss of Mule in both MEFs and B cells at steady state resulted in increased levels of phospho-ataxia telangiectasia mutated (ATM) and the ATM substrate p53. Under genotoxic stress, BMKO B cells were resistant to apoptosis, and control MEFs exhibited evidence of a physical interaction between Mule and phospho-ATM. Phospho-ATM, phospho-p53, and Brca1 levels were reduced in Mule-deficient B cells and MEFs subjected to genotoxic stress. Thus, Mule regulates the ATM-p53 axis to maintain B cell homeostasis under both steady-state and stress conditions. PMID- 22213804 TI - Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence. AB - Vigorous proliferative CD4(+) T cell responses are the hallmark of spontaneous clearance of acute hepatitis C virus (HCV) infection, whereas comparable responses are absent in chronically evolving infection. Here, we comprehensively characterized the breadth, specificity, and quality of the HCV-specific CD4(+) T cell response in 31 patients with acute HCV infection and varying clinical outcomes. We analyzed in vitro T cell expansion in the presence of interleukin-2, and ex vivo staining with HCV peptide-loaded MHC class II tetramers. Surprisingly, broadly directed HCV-specific CD4(+) T cell responses were universally detectable at early stages of infection, regardless of the clinical outcome. However, persistent viremia was associated with early proliferative defects of the HCV-specific CD4(+) T cells, followed by rapid deletion of the HCV specific response. Only early initiation of antiviral therapy was able to preserve CD4(+) T cell responses in acute, chronically evolving infection. Our results challenge the paradigm that HCV persistence is the result of a failure to prime HCV-specific CD4(+) T cells. Instead, broadly directed HCV-specific CD4(+) T cell responses are usually generated, but rapid exhaustion and deletion of these cells occurs in the majority of patients. The data further suggest a short window of opportunity to prevent the loss of CD4(+) T cell responses through antiviral therapy. PMID- 22213805 TI - Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. AB - Monocytes (Mo) and macrophages (MPhi) are emerging therapeutic targets in malignant, cardiovascular, and autoimmune disorders. Targeting of Mo/MPhi and their effector functions without compromising innate immunity's critical defense mechanisms first requires addressing gaps in knowledge about the life cycle of these cells. Here we studied the source, tissue kinetics, and clearance of Mo/MPhi in murine myocardial infarction, a model of acute inflammation after ischemic injury. We found that a) Mo tissue residence time was surprisingly short (20 h); b) Mo recruitment rates were consistently high even days after initiation of inflammation; c) the sustained need of newly made Mo was fostered by extramedullary monocytopoiesis in the spleen; d) splenic monocytopoiesis was regulated by IL-1beta; and e) the balance of cell recruitment and local death shifted during resolution of inflammation. Depending on the experimental approach, we measured a 24 h Mo/MPhi exit rate from infarct tissue between 5 and 13% of the tissue cell population. Exited cells were most numerous in the blood, liver, and spleen. Abrogation of extramedullary monocytopoiesis proved deleterious for infarct healing and accelerated the evolution of heart failure. We also detected rapid Mo kinetics in mice with stroke. These findings expand our knowledge of Mo/MPhi flux in acute inflammation and provide the groundwork for novel anti-inflammatory strategies for treating heart failure. PMID- 22213806 TI - Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL 10-producing suppressive CD4+ T cells. AB - Dendritic cells (DCs) can initiate and shape host immune responses toward either immunity or tolerance by their effects on antigen-specific CD4(+) T cells. DC asialoglycoprotein receptor (DC-ASGPR), a lectinlike receptor, is a known scavenger receptor. Here, we report that targeting antigens to human DCs via DC ASGPR, but not lectin-like oxidized-LDL receptor, Dectin-1, or DC-specific ICAM-3 grabbing nonintegrin favors the generation of antigen-specific suppressive CD4(+) T cells that produce interleukin 10 (IL-10). These findings apply to both self- and foreign antigens, as well as memory and naive CD4(+) T cells. The generation of such IL-10-producing CD4(+) T cells requires p38/extracellular signal regulated kinase phosphorylation and IL-10 induction in DCs. We further demonstrate that immunization of nonhuman primates with antigens fused to anti-DC ASGPR monoclonal antibody generates antigen-specific CD4(+) T cells that produce IL-10 in vivo. This study provides a new strategy for the establishment of antigen-specific IL-10-producing suppressive T cells in vivo by targeting whole protein antigens to DCs via DC-ASGPR. PMID- 22213807 TI - Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. AB - A direct association of islet-autoreactive T cells with beta cell destruction in human pancreatic islets from type 1 diabetes (T1D) patients has never been demonstrated, and little is known about disease progression after diagnosis. Frozen pancreas samples were obtained from 45 cadaveric T1D donors with disease durations ranging from 1 wk to >50 yr, 14 nondiabetic controls, 5 nondiabetics with islet autoantibodies, 2 cases of gestational diabetes, and 6 T2D patients. Sections were systematically analyzed for the presence of insulin-sufficient beta cells, CD8(+) insulitic lesions, and HLA class I hyperexpression. Finally, consecutive sections from HLA-A2-expressing individuals were probed for CD8 T cell reactivity against six defined islet autoantigens associated with T1D by in situ tetramer staining. Both single and multiple CD8 T cell autoreactivities were detected within individual islets in a subset of patients up to 8 yr after clinical diagnosis. Pathological features such as HLA class I hyperexpression and insulitis were specific for T1D and persisted in a small portion of the patients with longstanding disease. Insulitic lesions consistently presented in a multifocal pattern with varying degrees of infiltration and beta cell loss across affected organs. Our observations provide the first direct proof for islet autoreactivity within human islets and underscore the heterogeneous and chronic disease course. PMID- 22213808 TI - Patenting of plant varieties and plant breeding methods. AB - This article considers the relationship between patenting and plant variety rights protection, through a detailed analysis of the recent determination by the Extended Board of Appeal of the European Patent Office that methods for breeding broccoli and tomatoes were not patentable. It concludes that the right to patent agricultural innovations is increasingly located within a political context. PMID- 22213809 TI - Characterization of the wheat gene encoding a grain-specific lipid transfer protein TdPR61, and promoter activity in wheat, barley and rice. AB - The TaPR61 gene from bread wheat encodes a lipid transfer protein (LTP) with a hydrophobic signal peptide, predicted to direct the TaPR61 protein to the apoplast. Modelling of TaPR61 revealed the presence of an internal cavity which can accommodate at least two lipid molecules. The full-length gene, including the promoter sequence of a TaPR61 orthologue, was cloned from a BAC library of Triticum durum. Quantitative RT-PCR analysis revealed the presence of TaPR61 and TdPR61 mainly in grain. A transcriptional TdPR61 promoter-GUS fusion was stably transformed into wheat, barley, and rice. The strongest GUS expression in all three plants was found in the endosperm transfer cells, the embryo surrounding region (ESR), and in the embryo. The promoter is strong and has similar but not identical spatial patterns of activity in wheat, barley, and rice. These results suggest that the TdPR61 promoter will be a useful tool for improving grain quality by manipulating the quality and quantity of nutrient/lipid uptake to the endosperm and embryo. Mapping of regions important for the promoter function using transient expression assays in developing embryos resulted in the identification of two segments important for promoter activation in embryos. The putative cis-elements from the distal segment were used as bait in a yeast 1 hybrid (Y1H) screen of a cDNA library prepared from the liquid part of the wheat multinucleate syncytium. A transcription factor isolated in the screen is similar to BES1/BLZ1 from Arabidopsis, which is known to be a key transcriptional regulator of the brassinosteroid signalling pathway. PMID- 22213810 TI - Phenotyping transgenic wheat for drought resistance. AB - Realistic experimental protocols to screen for drought adaptation in controlled conditions are crucial if high throughput phenotyping is to be used for the identification of high performance lines, and is especially important in the evaluation of transgenes where stringent biosecurity measures restrict the frequency of open field trials. Transgenic DREB1A-wheat events were selected under greenhouse conditions by evaluating survival and recovery under severe drought (SURV) as well as for water use efficiency (WUE). Greenhouse experiments confirmed the advantages of transgenic events in recovery after severe water stress. Under field conditions, the group of transgenic lines did not generally outperform the controls in terms of grain yield under water deficit. However, the events selected for WUE were identified as lines that combine an acceptable yield even higher yield (WUE-11) under well irrigated conditions-and stable performance across the different environments generated by the experimental treatments. PMID- 22213811 TI - Deposition of ammonium and nitrate in the roots of maize seedlings supplied with different nitrogen salts. AB - This study measured total osmolarity and concentrations of NH(4)(+), NO(3)(-), K(+), soluble carbohydrates, and organic acids in maize seminal roots as a function of distance from the apex, and NH(4)(+) and NO(3)(-) in xylem sap for plants receiving NH(4)(+) or NO(3)(-) as a sole N-source, NH(4)(+) plus NO(3)(-), or no nitrogen at all. The disparity between net deposition rates and net exogenous influx of NH(4)(+) indicated that growing cells imported NH(4)(+) from more mature tissue, whereas more mature root tissues assimilated or translocated a portion of the NH(4)(+) absorbed. Net root NO(3)(-) influx under Ca(NO(3))(2) nutrition was adequate to account for pools found in the growth zone and provided twice as much as was deposited locally throughout the non-growing tissue. In contrast, net root NO(3)(-) influx under NH(4)NO(3) was less than the local deposition rate in the growth zone, indicating that additional NO(3)(-) was imported or metabolically produced. The profile of NO(3)(-) deposition rate in the growth zone, however, was similar for the plants receiving Ca(NO(3))(2) or NH(4)NO(3). These results suggest that NO(3)(-) may serve a major role as an osmoticant for supporting root elongation in the basal part of the growth zone and maintaining root function in the young mature tissues. PMID- 22213813 TI - Transcriptome analysis of rice mature root tissue and root tips in early development by massive parallel sequencing. AB - Despite the major physiological dissimilarities between mature root regions and their tips, differences in their gene expression profiles remain largely unexplored. In this research, the transcriptome of rice (Oryza sativa L. subsp. japonica) mature root tissue and root tips was monitored using mRNA-Seq at two time points. Almost 50 million 76 bp reads were mapped onto the rice genome sequence, expression patterns for different tissues and time points were investigated, and at least 1106 novel transcriptionally active regions (nTARs) expressed in rice root tissue were detected. More than 30 000 genes were found to be expressed in rice roots, among which were 1761 root-enriched and 306 tip enriched transcripts. Mature root tissue appears to respond more strongly to external stimuli than tips, showing a higher expression of, for instance, auxin responsive and abscisic acid-responsive genes, as well as the phenylpropanoid pathway and photosynthesis upon light. The root tip-enriched transcripts are mainly involved in mitochondrial electron transport, organelle development, secondary metabolism, DNA replication and metabolism, translation, and cellular component organization. During root maturation, genes involved in cell wall biosynthesis and modification, response to oxidative stress, and secondary metabolism were activated. For some nTARs, a potential role in root development can be put forward based on homology to genes involved in CLAVATA signalling, cell cycle regulators, and hormone signalling. A subset of differentially expressed genes and novel transcripts was confirmed using (quantitative) reverse transcription-PCR. These results uncover previously unrecognized tissue-specific expression profiles and provide an interesting starting point to study the different regulation of transcribed regions of these tissues. PMID- 22213812 TI - S-Nitrosylated proteins in pea (Pisum sativum L.) leaf peroxisomes: changes under abiotic stress. AB - Peroxisomes, single-membrane-bounded organelles with essentially oxidative metabolism, are key in plant responses to abiotic and biotic stresses. Recently, the presence of nitric oxide (NO) described in peroxisomes opened the possibility of new cellular functions, as NO regulates diverse biological processes by directly modifying proteins. However, this mechanism has not yet been analysed in peroxisomes. This study assessed the presence of S-nitrosylation in pea-leaf peroxisomes, purified S-nitrosylated peroxisome proteins by immunoprecipitation, and identified the purified proteins by two different mass-spectrometry techniques (matrix-assisted laser desorption/ionization tandem time-of-flight and two-dimensional nano-liquid chromatography coupled to ion-trap tandem mass spectrometry). Six peroxisomal proteins were identified as putative targets of S nitrosylation involved in photorespiration, beta-oxidation, and reactive oxygen species detoxification. The activity of three of these proteins (catalase, glycolate oxidase, and malate dehydrogenase) is inhibited by NO donors. NO metabolism/S-nitrosylation and peroxisomes were analysed under two different types of abiotic stress, i.e. cadmium and 2,4-dichlorophenoxy acetic acid (2,4 D). Both types of stress reduced NO production in pea plants, and an increase in S-nitrosylation was observed in pea extracts under 2,4-D treatment while no total changes were observed in peroxisomes. However, the S-nitrosylation levels of catalase and glycolate oxidase changed under cadmium and 2,4-D treatments, suggesting that this post-translational modification could be involved in the regulation of H(2)O(2) level under abiotic stress. PMID- 22213814 TI - Xylem cell death: emerging understanding of regulation and function. AB - Evolutionary, as well as genetic, evidence suggests that vascular development evolved originally as a cell death programme that allowed enhanced movement of water in the extinct protracheophytes, and that secondary wall formation in the water-conducting cells evolved afterwards, providing mechanical support for effective long-distance transport of water. The extant vascular plants possess a common regulatory network to coordinate the different phases of xylem maturation, including secondary wall formation, cell death, and finally autolysis of the cell contents, by the action of recently identified NAC domain transcription factors. Consequently, xylem cell death is an inseparable part of the xylem maturation programme, making it difficult to uncouple cell death mechanistically from secondary wall formation, and thus identify the key factors specifically involved in regulation of cell death. Current knowledge suggests that the necessary components for xylem cell death are produced early during xylem differentiation, and cell death is prevented through the action of inhibitors and storage of hydrolytic enzymes in inactive forms in compartments such as the vacuole. Bursting of the central vacuole triggers autolytic hydrolysis of the cell contents, which ultimately leads to cell death. This cascade of events varies between the different xylem cell types. The water-transporting tracheary elements rely on a rapid cell death programme, with hydrolysis of cell contents taking place for the most part, if not entirely, after vacuolar bursting, while the xylem fibres disintegrate cellular contents at a slower pace, well before cell death. This review includes a detailed description of cell morphology, function of plant growth regulators, such as ethylene and thermospermine, and the action of hydrolytic nucleases and proteases during cell death of the different xylem cell types. PMID- 22213816 TI - The role of flavonoids in root-rhizosphere signalling: opportunities and challenges for improving plant-microbe interactions. AB - The flavonoid pathway produces a diverse array of plant compounds with functions in UV protection, as antioxidants, pigments, auxin transport regulators, defence compounds against pathogens and during signalling in symbiosis. This review highlights some of the known function of flavonoids in the rhizosphere, in particular for the interaction of roots with microorganisms. Depending on their structure, flavonoids have been shown to stimulate or inhibit rhizobial nod gene expression, cause chemoattraction of rhizobia towards the root, inhibit root pathogens, stimulate mycorrhizal spore germination and hyphal branching, mediate allelopathic interactions between plants, affect quorum sensing, and chelate soil nutrients. Therefore, the manipulation of the flavonoid pathway to synthesize specifically certain products has been suggested as an avenue to improve root rhizosphere interactions. Possible strategies to alter flavonoid exudation to the rhizosphere are discussed. Possible challenges in that endeavour include limited knowledge of the mechanisms that regulate flavonoid transport and exudation, unforeseen effects of altering parts of the flavonoid synthesis pathway on fluxes elsewhere in the pathway, spatial heterogeneity of flavonoid exudation along the root, as well as alteration of flavonoid products by microorganisms in the soil. In addition, the overlapping functions of many flavonoids as stimulators of functions in one organism and inhibitors of another suggests caution in attempts to manipulate flavonoid rhizosphere signals. PMID- 22213815 TI - Low antioxidant concentrations impact on multiple signalling pathways in Arabidopsis thaliana partly through NPR1. AB - Production of reactive oxygen species (ROS) is linked to signalling in both developmental and stress responses. The level of ROS is controlled by both production and removal through various scavengers including ascorbic acid and glutathione. Here, the role of low ascorbic acid or glutathione concentrations was investigated on ozone-induced cell death, defence signalling, and developmental responses. Low ascorbic acid concentrations in vtc1 activated expression of salicylic acid (SA)-regulated genes, a response found to be dependent on the redox-regulated transcriptional co-regulator NPR1. In contrast, low glutathione concentrations in cad2 or pad2 reduced expression of SA-regulated genes. Testing different responses to jasmonic acid (JA) revealed the presence of at least two separate JA signalling pathways. Treatment of the vtc1 mutant with JA led to hyper-induction of MONODEHYDROASCORBATE REDUCTASE3, indicating that low ascorbic acid concentrations prime the response to JA. Furthermore, NPR1 was found to be a positive regulator of JA-induced expression of MDHAR3 and TAT3. The vtc1 and npr1 mutants were sensitive to glucose inhibition of seed germination; an opposite response was found in cad2 and pad2. Overall, low ascorbic acid concentrations mostly led to opposite phenotypes to low glutathione concentrations, and both antioxidants interacted with SA and JA signalling pathways. PMID- 22213817 TI - A toolset of aequorin expression vectors for in planta studies of subcellular calcium concentrations in Arabidopsis thaliana. AB - Calcium has long been acknowledged as one of the most important signalling components in plants. Many abiotic and biotic stimuli are transduced into a cellular response by temporal and spatial changes in cellular calcium concentration and the calcium-sensitive protein aequorin has been exploited as a genetically encoded calcium indicator for the measurement of calcium in planta. The objective of this work was to generate a compatible set of aequorin expression plasmids for the generation of transgenic plant lines to measure changes in calcium levels in different cellular subcompartments. Aequorin was fused to different targeting peptides or organellar proteins as a means to localize it to the cytosol, the nucleus, the plasma membrane, and the mitochondria. Furthermore, constructs were designed to localize aequorin in the stroma as well as the inner and outer surface of the chloroplast envelope membranes. The modular set-up of the plasmids also allows the easy replacement of targeting sequences to include other compartments. An additional YFP-fusion was included to verify the correct subcellular localization of all constructs by laser scanning confocal microscopy. For each construct, pBin19-based binary expression vectors driven by the 35S or UBI10 promoter were made for Agrobacterium-mediated transformation. Stable Arabidopsis lines were generated and initial tests of several lines confirmed their feasibility to measure calcium signals in vivo. PMID- 22213818 TI - Impact of the definition of peak standardized uptake value on quantification of treatment response. AB - PET-based treatment response assessment typically measures the change in maximum standardized uptake value (SUV(max)), which is adversely affected by noise. Peak SUV (SUV(peak)) has been recommended as a more robust alternative, but its associated region of interest (ROI(peak)) is not uniquely defined. We investigated the impact of different ROI(peak) definitions on quantification of SUV(peak) and tumor response. METHODS: Seventeen patients with solid malignancies were treated with a multitargeted receptor tyrosine kinase inhibitor resulting in a variety of responses. Using the cellular proliferation marker 3'-deoxy-3'-(18)F fluorothymidine ((18)F-FLT), whole-body PET/CT scans were acquired at baseline and during treatment. (18)F-FLT-avid lesions (~2/patient) were segmented on PET images, and tumor response was assessed via the relative change in SUV(peak). For each tumor, 24 different SUV(peaks) were determined by changing ROI(peak) shape (circles vs. spheres), size (7.5-20 mm), and location (centered on SUV(max) vs. placed in highest-uptake region), encompassing different definitions from the literature. Within each tumor, variations in the 24 SUV(peaks) and tumor responses were measured using coefficient of variation (CV), standardized deviation (SD), and range. For each ROI(peak) definition, a population average SUV(peak) and tumor response were determined over all tumors. RESULTS: A substantial variation in both SUV(peak) and tumor response resulted from changing the ROI(peak) definition. The variable ROI(peak) definition led to an intratumor SUV(peak) variation ranging from 49% above to 46% below the mean (CV, 17%) and an intratumor SUV(peak) response variation ranging from 49% above to 35% below the mean (SD, 9%). The variable ROI(peak) definition led to a population average SUV(peak) variation ranging from 24% above to 28% below the mean (CV, 14%) and a population average SUV(peak) response variation ranging from only 3% above to 3% below the mean (SD, 2%). The size of ROI(peak) caused more variation in intratumor response than did the location or shape of ROI(peak). Population average tumor response was independent of size, shape, and location of ROI(peak). CONCLUSION: Quantification of individual tumor response using SUV(peak) is highly sensitive to the ROI(peak) definition, which can significantly affect the use of SUV(peak) for assessment of treatment response. Clinical trials are necessary to compare the efficacy of SUV(peak) and SUV(max) for quantification of response to therapy. PMID- 22213819 TI - Impact of partial-volume effect correction on the predictive and prognostic value of baseline 18F-FDG PET images in esophageal cancer. AB - The objective of this study was to investigate the clinical impact of partial volume effect (PVE) correction on the predictive and prognostic value of metabolically active tumor volume (MATV) measurements on (18)F-FDG PET baseline scans for therapy response and overall survival in esophageal cancer patients. METHODS: Fifty patients with esophageal cancer treated with concomitant radiochemotherapy between 2004 and 2008 were retrospectively considered. PET baseline scans were corrected for PVE with iterative deconvolution incorporating wavelet denoising. MATV delineation on both original and corrected images was performed using the automatic fuzzy locally adaptive Bayesian methodology. Several parameters were extracted considering the original and corrected images: maximum and peak standardized uptake value (SUV), mean SUV, MATV, and total lesion glycolysis (TLG) (TLG = MATV * mean SUV). The predictive value of each parameter with or without correction was investigated using Kruskal-Wallis tests, and the prognostic value was determined with Kaplan-Meier curves. RESULTS: Whereas PVE correction had a significant quantitative impact on the absolute values of the investigated parameters, their clinical value within the clinical context of interest was not significantly modified-a result that was observed for both overall survival and response to therapy. The hierarchy between parameters was the same before and after correction. SUV measurements (maximum, peak, and mean) had nonsignificant (P > 0.05) predictive or prognostic value, whereas functional tumor-related measurements (MATV and TLG) were significant (P < 0.002) predictors of response and independent prognostic factors. CONCLUSION: PVE correction does not improve the predictive and prognostic value of baseline PET image-derived parameters in esophageal cancer patients. PMID- 22213820 TI - Prognostic significance of 18F-FDG PET parameters and plasma Epstein-Barr virus DNA load in patients with nasopharyngeal carcinoma. AB - The plasma concentration of Epstein-Barr virus (EBV) DNA is associated with tumor burden and prognosis in patients with nasopharyngeal carcinoma (NPC), but data on the relationship between viral load and (18)F-FDG PET functional parameters are lacking. We examined the association of (18)F-FDG PET functional parameters and EBV DNA load with the clinicopathologic characteristics and clinical outcomes of patients with NPC. METHODS: One hundred eight patients with NPC who underwent (18)F-FDG PET before treatment were included in this study. We determined total lesion glycolysis (TLG) of the primary tumor, the cervical nodes, and their combination and the maximal standardized uptake value of the primary tumor and cervical lymph nodes. EBV DNA was measured by real-time polymerase chain reaction. RESULTS: EBV DNA was significantly associated with total TLG (R(2) = 0.589). Total TLG values had the highest correlation with EBV DNA load and were significantly associated with tumor, nodal, and overall stages. However, tumor TLG greater than the median (>65 g) was the only parameter significantly associated with overall, local recurrence-free, disease-free, and distant metastasis-free survivals (P = 0.033, 0.014, <0.001, and 0.023, respectively). After allowance for potential confounders, tumor TLG retained its independent significance for overall and disease-free survival rates (P = 0.045 and 0.006, respectively). CONCLUSION: Total TLG values are primarily associated with tumor burden and clinical stage, whereas tumor TLG is the best predictor of patient survival after treatment. PMID- 22213821 TI - Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. AB - Astrocytes colocalize with fibrillar amyloid-beta (Abeta) plaques in postmortem Alzheimer disease (AD) brain tissue. It is therefore of great interest to develop a PET tracer for visualizing astrocytes in vivo, enabling the study of the regional distribution of both astrocytes and fibrillar Abeta. A multitracer PET investigation was conducted for patients with mild cognitive impairment (MCI), patients with mild AD, and healthy controls using (11)C-deuterium-L-deprenyl ((11)C-DED) to measure monoamine oxidase B located in astrocytes. Along with (11)C-DED PET, (11)C-Pittsburgh compound B ((11)C-PIB; fibrillar Abeta deposition), (18)F-FDG (glucose metabolism), T1 MRI, cerebrospinal fluid, and neuropsychologic data were acquired from the patients. METHODS: (11)C-DED PET was performed in MCI patients (n = 8; mean age +/- SD, 62.6 +/- 7.5 y; mean Mini Mental State Examination, 27.5 +/- 2.1), AD patients (n = 7; mean age, 65.1 +/- 6.3 y; mean Mini Mental State Examination, 24.4 +/- 5.7), and healthy age-matched controls (n = 14; mean age, 64.7 +/- 3.6 y). A modified reference Patlak model, with cerebellar gray matter as a reference, was chosen for kinetic analysis of the (11)C-DED data. (11)C-DED data from 20 to 60 min were analyzed using a digital brain atlas. Mean regional (18)F-FDG uptake and (11)C-PIB retention were calculated for each patient, with cerebellar gray matter as a reference. RESULTS: ANOVA analysis of the regional (11)C-DED binding data revealed a significant group effect in the bilateral frontal and bilateral parietal cortices related to increased binding in the MCI patients. All patients, except 3 with MCI, showed high (11)C-PIB retention. Increased (11)C-DED binding in most cortical and subcortical regions was observed in MCI (11)C-PIB+ patients relative to controls, MCI (11)C-PIB (negative) patients, and AD patients. No regional correlations were found between the 3 PET tracers. CONCLUSION: Increased (11)C-DED binding throughout the brain of the MCI (11)C-PIB+ patients potentially suggests that astrocytosis is an early phenomenon in AD development. PMID- 22213822 TI - PET and MRI of metastatic peritoneal and pulmonary colorectal cancer in mice with human epidermal growth factor receptor 1-targeted 89Zr-labeled panitumumab. AB - Human epidermal growth factor receptor 1 (HER1) plays an important role in the pathogenesis of colorectal cancer. Panitumumab is an anti-HER1 monoclonal antibody approved for use in colorectal cancer. However, few data exist regarding HER1 status in the corresponding distant metastases, and little corresponding information is available regarding the localization of panitumumab at primary and metastatic lesions. The utility of PET and MRI using (89)Zr-panitumumab to assess the status of HER1 in distant metastases with different metastasis models is presented in this study. METHODS: In vivo biodistribution and PET studies were performed in HER1-expressing LS-174T and HER1-negative A375 tumor xenografts. Additionally, studies were performed in different models of intraperitoneal and pulmonary metastases. MRI studies were performed for metastatic models to characterize the targeting potential of (89)Zr-panitumumab at different lesion sites. RESULTS: HER1-mediated targeting was achieved in all HER1-expressing models. The LS-174T tumor area under the curve (AUC) was 3.7-fold greater than the AUC for A375. The LS-174T tumor AUC of 204.13 +/- 9.67 was significantly greater (P < 0.001) than the LS-174T tumor AUC of 36.45 +/- 1.39 obtained from mice coinjected with 0.1 mg of panitumumab for blocking the target. Differences were observed in 2 intraperitoneal models; tumor uptake in mice with a 3-d tumor burden was more than 2-fold greater than the mice with a 7-d tumor burden. PET and MRI studies revealed HER1-mediated tumor targeting in all metastatic models. However, significant differences were observed between different LS-174T tumor models. Peak tumor uptake of approximately 40 percentage injected dose per gram (%ID/g) was observed at 3-4 d after injection for the subcutaneous tumor model, in contrast to approximately 75 %ID/g at 2 d after injection for the thoracic tumors and approximately 95 %ID/g at 1-2 d after injection for the intraperitoneal tumors. CONCLUSION: The potential utility of (89)Zr-panitumumab in assessing HER1 status in distant metastases and understanding the variations in antibody uptake at different lesion sites is demonstrated in this study. (89)Zr-panitumumab can play a vital role in patient stratification and immunotherapy and therefore warrants further investigation for clinical translation. PMID- 22213824 TI - Newsline 2012: 25 years of age. PMID- 22213825 TI - ABMS makes physician MOC status public. PMID- 22213823 TI - Quantitative PET of human urokinase-type plasminogen activator receptor with 64Cu DOTA-AE105: implications for visualizing cancer invasion. AB - Expression levels of the urokinase-type plasminogen activator receptor (uPAR) represent an established biomarker for poor prognosis in a variety of human cancers. The objective of the present study was to explore whether noninvasive PET can be used to perform a quantitative assessment of expression levels of uPAR across different human cancer xenograft models in mice and to illustrate the clinical potential of uPAR PET in future settings for individualized therapy. METHODS: To accomplish our objective, a linear, high-affinity uPAR peptide antagonist, AE105, was conjugated with DOTA and labeled with (64)Cu ((64)Cu-DOTA AE105). Small-animal PET was performed in 3 human cancer xenograft mice models, expressing different levels of human uPAR, and the tumor uptake was correlated with the uPAR expression level determined by uPAR enzyme-linked immunosorbent assay. The tumor uptake pattern of this tracer was furthermore compared with (18)F-FDG uptake, and finally the correlation between sensitivity toward 5 fluorouracil therapy and uPAR expression level was investigated. RESULTS: The uPAR-targeting PET tracer was produced in high purity and with high specific radioactivity. A significant correlation between tumor uptake of (64)Cu-DOTA AE105 and uPAR expression was found (R(2) = 0.73; P < 0.0001) across 3 cancer xenografts, thus providing a strong argument for specificity. A significantly different uptake pattern of (64)Cu-DOTA-AE105, compared with that of (18)F-FDG, was observed, thus emphasizing the additional information that can be obtained on tumor biology using (64)Cu-DOTA-AE105 PET. Furthermore, a significant correlation between baseline uPAR expression and sensitivity toward 5-fluorouracil was revealed, thus illustrating the possible potentials of uPAR PET in a clinical setting. CONCLUSION: Our results clearly demonstrate that the peptide-based PET tracer (64)Cu-DOTA-AE105 enables the noninvasive quantification of uPAR expression in tumors in vivo, thus emphasizing its potential use in a clinical setting to detect invasive cancer foci and for individualized cancer therapy. PMID- 22213826 TI - Schelbert completes service as JNM editor-in-chief. PMID- 22213827 TI - "Go with the guidelines" initiative targets pediatric dose. PMID- 22213828 TI - SNM journals' new mobile interface. PMID- 22213829 TI - Senate passes isotope production act. PMID- 22213830 TI - Molecular imaging training course debuts. PMID- 22213831 TI - Molding the future of the profession. PMID- 22213833 TI - National Institute for Health and Clinical Excellence appraisal and ageism. AB - The requirements of the UK Equality Act 2010 and some high profile criticism for using a potentially ageist methodology have prompted the National Institute for Health and Clinical Excellence (NICE) to assess the processes and methodology it uses to make appraisal decisions. This paper argues that NICE has established rigorous systems to protect against ageist decisions, has no track record of ageism and is well placed to meet the requirements of new UK equality legislation. PMID- 22213834 TI - Illness as a condition of our existence in the world: on illness and pathic existence. AB - This paper seeks to find different ways of addressing illness as an experience essential to the understanding of being a human being. As a conceptual point of departure, we suggest the notion of 'pathic existence' as developed by the German physician and philosopher Viktor von Weizsacker (1886-1957). Through an analysis of his conceptualisation of the pathic and of pathic categories, we demonstrate how this auxiliary typology may be of help in unveiling different modes of ill being, or Kranksein. Furthermore, we show how illness plays a paradigmatic role in this type of existence. We discuss how von Weizsacker's claim of illness as "a way of being human" indicates how such a view of the illness existence both differs from and touches upon other streams of thought within the philosophy of medicine and medical ethics. Finally, we highlight some of the normative implications emerging from this perspective of relevance in today's medicine. PMID- 22213832 TI - Kinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: apoptosis induction by TRAIL. AB - Here we show by computer modeling that kinetics and outcome of signal transduction in case of hetero-oligomerizing receptors of a promiscuous ligand largely depend on the relative amounts of its receptors. Promiscuous ligands can trigger the formation of nonproductive receptor complexes, which slows down the formation of active receptor complexes and thus can block signal transduction. Our model predicts that increasing the receptor specificity of the ligand without changing its binding parameters should result in faster receptor activation and enhanced signaling. We experimentally validated this hypothesis using the cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its four membrane-bound receptors as an example. Bypassing ligand-induced receptor hetero-oligomerization by receptor-selective TRAIL variants enhanced the kinetics of receptor activation and augmented apoptosis. Our results suggest that control of signaling pathways by promiscuous ligands could result in apparent slow biological kinetics and blocking signal transmission. By modulating the relative amount of the different receptors for the ligand, signaling processes like apoptosis can be accelerated or decelerated and even inhibited. It also implies that more effective treatments using protein therapeutics could be achieved simply by altering specificity. PMID- 22213835 TI - Dural arteriovenous fistulae in pediatric patients: associated conditions and treatment outcomes. AB - OBJECTIVE: Dural arteriovenous fistulae (dAVF) are rare vascular lesions of the CNS with potentially significant morbidity and mortality. Our experience in the treatment of children with dAVF is reported. DESIGN: Our neurosurgical and neurointerventional pediatric database was retrospectively reviewed for patients with dAVF. Brain arteriovenous malformations, pial fistulae, vein of Galen malformations and extracranial fistulae were excluded. Angiography was used to assess radiographic outcome in all cases. Clinical outcome was assessed by the pediatric Functional Status Scale (6=normal, maximal incapacity=30). RESULTS: Between July 2003 and June 2011, seven patients with dAVF were treated, with a mean age at presentation of 4.8 years. Presenting symptoms included facial venous prominence, headache, macrocephaly and symptoms of elevated intracranial pressure; one patient (14%) had asymptomatic dAVF discovered on imaging follow-up after craniotomy for cavernous malformation. Two cases (28%) were associated with vascular anomaly syndromes, PHACE association and PTEN associated syndrome. Venous sinus thrombosis was identified in four patients (57%) and was associated with a systemic hypercoagulable state or trauma. Complete obliteration was achieved in six of seven patients. Treatment was exclusively endovascular in six patients and by combined surgical/endovascular means in the remaining patient. No treatment complications were experienced. Functional Status Scale scores at an average of 2 years of follow-up were 6 in all patients. CONCLUSION: Treatment is effective in the obliteration of dAVF in children and is well tolerated, with patients having excellent prognoses. Genetic screening and hypercoagulable workup are indicated, particularly when other anomalies or sinus thrombosis coexist. PMID- 22213836 TI - Pial arteriovenous fistulae in pediatric patients: associated syndromes and treatment outcome. AB - OBJECTIVE: Pediatric pial arteriovenous fistulae (pAVF) are rare vascular lesions of the CNS, reported to have up to a 25% association with hereditary hemorrhagic telangiectasia. The presentation, treatment and syndromes associated with pAVF in children are reported here. DESIGN: A pediatric database for pAVF was retrospectively reviewed. Patients with carotid-cavernous fistulae, dural arteriovenous fistulae, brain arteriovenous malformations and vein of Galen malformations were excluded. Radiographic outcome was assessed using digital subtraction angiography, and clinical outcome by the Functional Status Scale (6=normal, maximal incapacity=30). RESULTS: Between July 2003 and June 2011, seven patients with pAVF (six intracranial and one spinal) were treated. Mean age was 4.2 years. The most common clinical presentation was high output cardiac failure (43%). Two patients (29%) harbored a known mutation in the RASA1 gene, associated with a hereditary vascular syndrome: capillary malformation arteriovenous malformation. No patient had hereditary hemorrhagic telangiectasia. Treatment resulted in complete lesional obliteration in six of seven patients, with treatment ongoing in the seventh. Five of seven patients had combined endovascular and surgical treatment while two underwent endovascular embolization alone. Functional Status Scale scores at the most recent follow-up were 6 in all but one patient who had presented with a pretreatment hemianopsia. CONCLUSION: Treatment is effective in obliterating pAVF in children, with an excellent prognosis seen in our cohort. Genetic screening is indicated, with capillary malformation-arteriovenous malformation being the most frequently seen syndrome. No patients had hemorrhagic hereditary telangiectasia. PMID- 22213837 TI - Perceived muscular tension predicts future neck-shoulder and arm-wrist-hand symptoms. AB - OBJECTIVES: The aim of the study was to investigate if perceived muscular tension predicts future neck-shoulder symptoms and arm-wrist-hand symptoms in symptomfree office workers. METHODS: Data were used of a prospective cohort of 1951 office workers with a follow-up duration of 2 years (the Prospective Research On Musculoskeletal disorders among Office workers (PROMO) study). Perceived muscular tension and covariates were measured using self-report at baseline and at 1-year follow-up. Symptoms were assessed every 3 months using self-report. According to their perceived muscular tension, participants were classified into three groups: 'never tensed', 'sometimes tensed' and 'often tensed'. Neck-shoulder cases and arm-wrist-hand cases were identified based on the transition of 'no' or 'sometimes' pain to 'regular' or 'prolonged' pain. Generalised estimating equations were used to estimate rate ratios (RRs) for becoming a new case. RESULTS: Perceived muscular tension predicted future neck-shoulder symptoms and arm-wrist-hand symptoms, even when adjusted for symptoms in the past. The RRs for perceived muscular tension in relation to future neck-shoulder symptoms were higher than for future arm-wrist-hand symptoms. Participants who were sometimes or often tensed had a 2.9 and 4.4 times higher risk, respectively, of becoming a future neck-shoulder case than those who were never tensed. For arm-wrist-hand symptoms, the risk of becoming a future case was 1.5 and 2.3, respectively. CONCLUSIONS: Perceived muscular tension predicted future neck-shoulder symptoms and arm-wrist-hand symptoms. Future research should further explore the concept of perceived muscular tension and what role it has in the onset of symptoms in order to make use of it in interventions to prevent symptoms. PMID- 22213838 TI - Paraquat application and respiratory health effects among South Korean farmers. AB - OBJECTIVES: Paraquat is commonly used worldwide as major herbicide. The objective of this study was to investigate the association among farmers between occupational paraquat exposure and respiratory health effects. METHODS: A cross sectional survey of health effects related to an oil spill was conducted in South Korea from 2008 to 2009. For this analysis, a total of 2882 full-time farmers were selected from the overall sample. Data collection included an interviewer administered questionnaire and spirometry testing. Logistic regression analysis and linear regression analysis were performed to evaluate the relationship between paraquat exposure and respiratory health outcomes after adjustment for potential confounders. RESULTS: The risks of self-reported physician-diagnosed asthma, chronic obstructive pulmonary disease and allergic rhinitis were non significantly increased among paraquat-applying farmers compared with non paraquat-applying farmers. Although the results of a pulmonary function test fell within normal limits, a decline in forced vital capacity and forced expiratory volume in one second was apparent among paraquat-applying farmers compared with non-paraquat-applying farmers. Forced vital capacity (beta = -5.20, p<0.001) and forced expiratory volume in one second (beta = -1.89, p = 0.010) significantly decreased with each unit increase in years of paraquat application. Paraquat applying farmers showed a significant exposure-response relationship between restrictive ventilatory defects and paraquat application years (p trend = 0.015) or lifetime days of application (p trend = 0.007). CONCLUSIONS: Our findings suggest a possible association between paraquat application and adverse respiratory health effects among farmers. PMID- 22213839 TI - Sharing the knowledge gained from occupational cohort studies: a call for action. AB - OBJECTIVES: An immense body of knowledge has been created by establishing various job-exposure matrices (JEMs) to assess occupational exposures in community- and industry-based cohort studies. These JEMs could be made available to occupational epidemiologists using knowledge-sharing technologies, thereby saving considerable amounts of time and money for researchers investigating occupation-related research questions. In this paper, the authors give an example of how a detailed JEM can be easily transformed into a job-specific module (JSM) for use in community-based studies. METHODS: OccIDEAS is operationalised as a web-based software, combining the use of JSMs with an individual expert exposure assessment to assess occupational exposures in various industries according to a set of predefined rules. The authors used a JEM focusing on endocrine-disrupting chemicals from a German study on testicular cancer in the automobile industry to create a JSM in OccIDEAS. RESULTS: The JEM was easily translated into OccIDEAS requiring about 50 h of work by an epidemiologist familiar with the German JEM to learn about the OccIDEAS structure, establish the required set of exposure rules and to translate the JEM into OccIDEAS. Language did not represent an obstacle for translation either. To make the data available in an international context, an interpreter had to translate the German tasks and exposures after they were coded into OccIDEAS. CONCLUSIONS: JEMs which are constructed based on identifying tasks that determine exposure can be easily transformed into a JSM. Occupational epidemiologists are invited to contribute to the international scope of OccIDEAS by providing their previously established JEMs to make existing data on occupational exposures widely available to the epidemiological community. PMID- 22213842 TI - New challenges for image processing research. PMID- 22213843 TI - Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS. PMID- 22213840 TI - Heavy manual work, exposure to vibration and Dupuytren's disease? Results of a surveillance program for musculoskeletal disorders. AB - INTRODUCTION: This study aimed to determine the prevalence of Dupuytren's disease in men and its relationship with work exposure, particularly heavy manual work with and without significant use of vibrating tools, using data from a surveillance program for musculoskeletal disorders. METHOD: This cross-sectional study was conducted in France between 2002 and 2005. Dupuytren's disease was diagnosed clinically by one of 83 occupational physicians. Exposure in relation to work status and occupational risk factors was assessed with a self administered questionnaire, and categorised according to vibration exposure (defined as use of vibrating tools for >=2 h/day), heavy manual work without vibration exposure (defined as use of hand tools for >=2 h/day (use of vibrating tools for >=2 h/day excluded) and Borg scale >=15/20) and no such exposure. Bivariate and multivariate associations using logistic models were recorded in men and in those with >10 years in the same job. RESULTS: Of 2161 men, 1.3% (n=27) had Dupuytren's disease (mean age 47.1+/-6.7 years). Heavy manual work without vibration exposure was significantly associated with the condition (adjusted OR (aOR) 3.9; 95% CI 1.3 to 11.5) adjusted on age and diabetes), as was use of vibrating tools (aOR 5.1; 2.1 to 12.2). These associations remained significant among subjects with >10 years in the same job, with increases in aOR of 6.1 (1.5 to 25.0) and 10.7 (3.4 to 34.6), respectively. CONCLUSION: Despite the limited number of cases, occupational exposure, including both vibration exposure and heavy manual work without significant vibration exposure, was associated with Dupuytren's disease. PMID- 22213844 TI - Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS. PMID- 22213845 TI - Critical care competence. PMID- 22213846 TI - Paget's disease: a potential predictor of breast cancer survival? PMID- 22213847 TI - Personalizing surgical risk: "To be or not to be" should not be the question. PMID- 22213848 TI - Substance abuse among surgeons: the perils of losing your credentials. PMID- 22213849 TI - Another bastion of empiricism falls? PMID- 22213850 TI - Weight loss preceding laparoscopic gastric bypass improves acute outcomes. PMID- 22213851 TI - Career phase and surgical outcomes: have you ever been experienced? PMID- 22213853 TI - Awards: Conscientious counsellors. PMID- 22213852 TI - Bandwagon forward. PMID- 22213854 TI - [Lyme borreliosis. Recommendations for diagnosis, therapy and prevention]. PMID- 22213855 TI - Endoscopy live Berlin 2011 - intestinal disease meeting. PMID- 22213856 TI - Management of atrial fibrillation with preexcitation syndrome. PMID- 22213857 TI - Calcium channel blocker (CCB) poisoning. PMID- 22213858 TI - "Aortic dissection: a review of the diagnosis and initial management". PMID- 22213859 TI - [In commemoration of Qian Yijian]. PMID- 22213860 TI - [Relationship between RAD51-g135C and XRCC3-C241T polymorphisms and prognosis of inv (16)/ t(16;16) (CBFbeta-MYH11) acute myeloid leukemia]. AB - OBJECTIVE: To investigate the impact of polymorphisms of DNA homologous recombination (HR) repair genes RAD51-G135C and XRCC3-C241T on the prognosis of acute myeloid leukemia (AML) with inv(16)/t(16;16)(CBFbeta-MYH1). METHODS: One hundred and three de novo inv(16)/t(16;16) (CBFbeta-MYH11) AML patients were followed-up and retrospectively analyzed. Polymorphisms of RAD51-G135C and XRCC3 C241T were detected by PCR-RFLP. The prognostic factors,including sex, age, white blood cell count, platelet count, hemoglobin level, karyotype, KIT mutation, RAD51-G135C and XRCC3-C241T polymorphisms at diagnosis, for complete remission (CR) achievement, overall survival (OS) and relapse-free survival (RFS) were analyzed by univariate and multivariate analyses. RESULTS: The median follow-up of all patients was 28 (1 - 106) months. The overall CR rate was 92.2%. The estimated 5-year OS and RFS rates were 43.6% (95% CI 37.7% - 49.5%) and 26.4% (95% CI 21.1% - 31.7%), and the median OS and RFS were 53 (95% CI 133.4 - 72.7) and 27 (95% CI 22.9 - 31.1) months, respectively. In multivariate analysis, higher WBC (P = 0.004) and older than 30 years of age (P = 0.035) were independent poor factors for CR achievement, the XRCC3-241T variant (P = 0.007) and higher WBC (P = 0.009) were independent poor factors for 5-year RFS, and higher WBC (P = 0.002) and trisomy 8 (P = 0.035) were independent poor factors for 5-year survival. Polymorphism of RAD51-G135C had no significant impact on the prognosis. CONCLUSION: The XRCC3-241T variant is an independent poor prognostic factor for AML with inv(16)/t(16;16)/CBFbeta-MYH11. PMID- 22213861 TI - [Probe of classification of adult acute lymphoblastic leukemia]. AB - OBJECTIVE: To investigate the biologic features of adult acute lymphoblastic leukemia (ALL), and reclassified our ALL patients according to the 2008 WHO classification. METHODS: Immunophenotype and cytogenetic/molecular genetic results were obtained by flow cytometry, R-banding and RT-PCR, respectively. RESULTS: (1) A total of 412 newly diagnosed and previously untreated adult ALL patients, were 239 males and 173 females. Among 410 patients with available immunophenotypic results, 357 were B-ALL and 53 T-ALL. Myeloid antigen (MyAg) was higher expression in B-ALL than in T-ALL, and was correlated with the expression of CD34. (2) 93 Ph + ALL patients, mainly CD10 ALL, was associated with high WBC count and MyAg and CD34 expression. MLL rearrangement was found in 12 cases, mainly pro-B ALL. (3) 299 cases could be analysed, according to the 2008 WHO classification of ALL, including 126 B-ALL with recurrent genetic abnormalities, and 120 B-ALL not otherwise specified. Among the 126 B-ALL with recurrent genetic abnormalities, 92 were Ph + ALL, 10 MLL + ALL, 11 hyperdiploid, 9 hypodiploid, 3 E2A-PBX +, and 1 TEL-AML1 +. Patients with Ph +, MLL +, hypodiploid or E2A-PBX + were associated with older age, higher WBC count, higher HGB, higher peripheral blasts and higher LDH level as compared with other patients. CONCLUSION: Combination of immunophenotype and cytogenetic-molecular profiles can provide a further detailed classification of B-ALL. PMID- 22213862 TI - [The clinical and laboratory features of 9 cases with gammadeltaT cell lymphoma or leukemia]. AB - OBJECTIVE: To analyze the clinical and laboratory features of 9 cases of gammadeltaT cell lymphoma or leukemia. METHODS: From 2007 to 2011, 9 patients with gammadeltaT-cell lymphoma/leukemia were diagnosed in our hospital. The immunophenotype of the abnormal cells were detected by flow cytometry, clonal gene rearrangement of IgH, TCRgamma, TCRdelta by PCR, chromosome karyotype analysis by G banding, acute leukemia gene and the DNA of type 1 - 8 human herpes virus by multiple nested PCR, The gammadeltaT cells were determined by T cell with TCR gammadelta chain, the malignant gammadelta T cells by the abnormal expression of T cell antigens and the precursor malignant gammadelta T cells by the expression of CD34, TDT, CD99, CD1 a or acute leukemia genes. RESULTS: In the 9 patients with gammadeltaT cell lymphoma leukemia, significant malignant gammadeltaT cells infiltration of bone marrow were found in 8 with blast morphology. 5 were diagnosed as T-ALL/LBL (gammadeltaT type) and 4 HSgammadelta TCL. The clonal gene rearrangement of TCRgamma and/or TCRB were detected in 6/6 patients. Patients either did not achieve complete remission(CR) after induction therapy or relapsed quickly after CR. Only 4/5 patients remained continuous CR(CCR) at 2, 2, 3,12 months respectively, after allogeneic hematopoietic stem cell transplantation (allo-HSCT), the fifth T-ALL (gammadeltaT) relapsed 1 month after allo-HSCT. CONCLUSIONS: The incidence of gammadelta T cell lymphoma or leukemia may be higher than reported, part of them were T-ALL/LBL with poor prognoses. FCM and clonal gene rearrangement of TCRgamma and/or TCRdelta are helpful to diagnosis. Allo-HSCT may be the only curative approach. PMID- 22213863 TI - [Monitoring of plasma concentration of imatinib mesylate in patients with chronic myeloid leukemia]. AB - OBJECTIVE: To analyze the clinical efficacy of imatinib mesylate (IM) for Ph positive or BCR-ABL positive chronic myeloid leukemia (CML) to couple the trough plasma concentrations (C mins) of IM with clinical responses and adverse events (AEs). METHODS: One hundred and one CML patients received IM therapy, and Cmins of IM were determined in 30 patients. RESULTS: (1) Cumulative complete hematological response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR) and negative BCR/ABL fusion gene rates were 96.6%, 86.5%, 77.5% and 47.2%, respectively, in CML-CP patients. In accelerated and blastic phases (AP and BC) patients, CHR, MCyR, CCyR and negative BCR-ABL fusion gene rates were 58.3%, 25.0%, 25.0%, 8.3%, respectively. (2) Mean Cmins of IM was significantly higher in the CCyR at 1 year [(1472 +/- 482) microg/L] group than in the non-CCyR at 1 years group [(1067 +/- 373) microg/L] (P < 0.05), and higher in the MMR at 1 year group than in the non-MMR at 1 years group [(1624 +/- 468) microg/L vs (1137 +/- 404) microg/L, P < 0.05]. CONCLUSION: IM significantly improves cytogenetic and molecular response, event-free survival, and overall survival for patients with Ph-positive CML. The Cmins of IM exerts a significant impact on clinical response (CCyR and MMR at 1 year). PMID- 22213864 TI - [Application of spectral karyotyping to cytogenetic analysis in acute myeloid leukemia]. AB - OBJECTIVE: To evaluate the value of spectral karyotyping (SKY) in cytogenetic analysis of acute myeloid leukemias (AML). METHODS: Nine AML patients were analyzed by R-banding and SKY. MLL, PML-RARalpha, AML1-ETO fusion genes were detected by dual fusion- fluorescence in situ hybridization (D-FISH). RESULTS: All 9 samples were successfully hybridized. SKY identified structural aberrations including 9q -, t(15;17) and ins(10;17) (q22;p11p12) ; and some numeral abnormalities. The results of SKY confirmed those of R-band karyotyping and D FISH; with more accurate localization. CONCLUSION: SKY appears to be fairly stable, accurate and sensitive, for AML cytogenetic study. PMID- 22213865 TI - [Inhibitory effect of valproic acid on xenografted Kasumi-1 tumor growth in nude mouse and its mechanism]. AB - OBJECTIVE: To investigate in vivo inhibitory effect of histone deacetylase (HDAC) inhibitor valproic acid (VPA) on xenografted Kasumi-1 tumor in nude mice and its mechanism. METHODS: Xenografted Kasumi-1 tumor mouse model was established by subcutaneous inoculation of Kasumi-1 cells. Xenotransplanted nude mice were assigned into control or VPA treatment groups. Volume of the xenografted tumors was measured and compared between the two groups. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) was applied to detection of tumor cell apoptosis. The gene expression of GM-CSF, HDAC1, Ac-H3 and survivin was studied with semi-quantitative RT-PCR and Western blotting. ChIP method was used to assay the effects of VPA on acetylation of histone H3 within GM-CSF promoter region. RESULTS: (1) VAP significantly inhibited xenografted Kasumi-1 tumor growth. The calculated inhibition rate was 57.25%. (2) Morphologic study showed that VPA induced differentiation and apoptosis of Kasumi-1 tumor cells. The apoptosis index of VAP treatment group [(3.661 +/- 0.768)%] was significantly higher than that of control group [(0.267 +/- 0.110)%]. (3) Comparing to those in control group, the level of nuclear HDAC1 protein was significantly decreased, the Ac-H3 protein expression level was increased, the mRNA and protein expression levels of GM-CSF and acetylation of histone H3 were remarkably increased, and the gene expression level of survivin significantly decreased in VPA treatment group. CONCLUSION: VAP significantly inhibits xenografted Kasumi-1 tumor growth and induces tumor cell differentiation and apoptosis. The mechanism may be decrease of survivin gene expression, inhibition of nuclear expression of HDAC, promotion of histone protein acetylation level and acetylation of histone H3 within GM-CSF promoter region, and increase of GM-CSF transcription. PMID- 22213866 TI - [Long-term follow-up of malignant clonal evolution in patients with acquired aplastic anemia]. AB - OBJECTIVE: To assess the incidence and risk factors for evolution of acquired aplastic anemia (AA) into myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). METHOD: A total of 1003 AA patients hospitalized in our institute hospital between January 1991 and December 2009 enrolled into this study. The incidence and risk factors for AA developing MDS/AML by the Kaplan-Meier method and Cox proportional hazards models, respectively. RESULTS: The median follow-up was 62 (2 - 423) months and the projected 5-year survival rate was (78.0 +/- 1.0)%. Twenty-seven patients evolved to MDS/AML, of whom 11, 6 and 10 were from NSAA, SAA and VSAA subgroups, respectively. The estimated cumulative incidence of MDS/AML transformation for these 1003 patients after diagnosis was (4.5 +/- 1.0)% at 10 year. The incidence of MDS/AML transformation in VSAA subgroup [(12.8 +/- 3.5)%] was significantly higher than in NSAA subgroup [(4.1 +/- 1.9)%] (P < 0.001) and SAA subgroup [(3.5 +/- 1.4)% ] (P = 0.008), but no difference between the latter two subgroups (P = 0.616). Age [RR = 3.527 (95% CI: 1.598 - 7.784), P = 0.002], severity of disease [RR = 5.122 (95% CI: 2.214 - 11.853), P < 0.001], the duration (days) of rhuG-CSF therapy [RR = 10.782 (95% CI: 4.600 - 25.269), P < 0.001] and exposure to ray, chemicals or drugs [RR = 3.401 (95% CI: 1.535 - 7.534), P = 0.003] were risk factors for the transformation in both univariate and multivariate analyses. CONCLUSION: Long-term follow-up is essential to assess the incidence and risk factors for evolutions of acquired AA into MDS/AML, and to administer salvage therapy for transformation in time during follow-up. PMID- 22213867 TI - [The effects and mechanisms of erythropoietin on hepcidin of human monocytes]. AB - OBJECTIVE: To investigate the in vitro effect of erythropoietin (EPO) on hepcidin of monocytes and its molecular mechanisms. METHODS: Hepcidin and signaling molecules including C/EBPalpha, Smad1/5/8, p-Smad1/5/8 and p-STAT3 were detected by real time PCR and Western blot. THP-1 monocytes were stimulated by interleukin 6 (IL-6) or lipopolysaccharide (LPS). EPO receptor (EPOR) antibody was added to observe its antagonistic effect on EPO and impact on the signaling proteins. RESULTS: EPO suppressed mRNA expression of THP-1 hepcidin of monocytes induced by 20 ng/ml IL-6 or 1 microg/ml LPS in both dose and time dependent manner. The most decrease of hepcidin expression was observed at 2 IU/ml EPO for 6 hours. EPO also down-regulated hepcidin protein induced by 20 ng/ml IL-6. At 2 IU/ml EPO for 6 hours hepcidin protein was down-regulated, as was C/EBPalpha, p-Smad1/5/8 and p STAT3. Antibody to EPOR antagonized the down-regulation of EPO on hepcidin and signaling proteins. CONCLUSIONS: Monocytes hepcidin can be reduced by EPO when stimulated by IL-6 or LPS. The mechanism of which may be at least in part, via suppression of C/EBPalpha, p-Smad1/5/8 and p-STAT3 signaling. PMID- 22213868 TI - [Efficacy of voriconazole for treatment of invasive fungal infections in 87 cases with hematologic malignancies]. PMID- 22213869 TI - [Foix syndrome secondary to chemotherapy of acute nonlymphocytic leukemia: a case report and review of the literature]. PMID- 22213870 TI - [Initial therapy of imatinib mesylate for extramedullary T lymphoblastic crisis of chronic myeloid leukemia: a case report and review of the literature]. PMID- 22213872 TI - [Survey of medical care and prognosis in patients with severe hemophilia A from certain cities in China]. PMID- 22213871 TI - [Expressions of Axl and its ligand Gas6 in acute leukemia and its relation to efficacy of induction therapy]. PMID- 22213873 TI - [Detection of the IDH1 gene mutation in acute myeloid leukemia by PCR-high resolution melting analysis]. PMID- 22213874 TI - [Treatment of thrombotic thrombocytopenic purpura with rituximab]. PMID- 22213875 TI - [Recent advances in microvesicles derived from leukemic cells and its relationship with disease progression]. PMID- 22213876 TI - [Tyrosine kinase inhibitors and leukemic stem cells in chronic myeloid leukemia]. PMID- 22213877 TI - [Chinese guidelines for the diagnosis and management of chronic lymphocytic leukemia (2011)]. PMID- 22213878 TI - [Treatment of two chronic myelomonocytic leukemia patients with Decitabine]. PMID- 22213879 TI - The political economy of maize production and poverty reduction in Zambia: analysis of the last 50 years. AB - Poverty and food security are endemic issues in much of sub-Saharan Africa. To eradicate extreme poverty and hunger in the region remains a key Millennium Development Goal. Many African governments have pursued economic reforms and agricultural policy interventions in order to accelerate economic growth that reduces poverty faster. Agricultural policy regimes in Zambia in the last 50 years (1964-2008) are examined here to better understand their likely impact on food security and poverty, with an emphasis on the political economy of maize subsidy policies. The empirical work draws on secondary sources and an evaluation of farm household data from three villages in the Kasama District of Zambia from 1986/87 and 1992/93 to estimate a two-period econometric model to examine the impact on household welfare in a pre- and post-reform period. The analysis shows that past interventions had mixed effects on enhancing the production of food crops such as maize. While such reforms were politically popular, it did not necessarily translate into household-level productivity or welfare gains in the short term. The political economy of reforms needs to respond to the inherent diversity among the poor rural and urban households. The potential of agriculture to generate a more pro-poor growth process depends on the creation of new market opportunities that most benefit the rural poor. The state should encourage private sector investments for addressing infrastructure constraints to improve market access and accelerate more pro-poor growth through renewed investments in agriculture, rural infrastructure, gender inclusion, smarter subsidies and regional food trade. However, the financing of such investments poses significant challenges. There is a need to address impediments to the effective participation of public private investors to generate more effective poverty reduction and hunger eradication programmes. This article also explores the opportunities for new public-private investments through South-South cooperation and Asia-driven growth for reducing poverty in Zambia. PMID- 22213880 TI - Gender earnings and poverty reduction: post-Communist Uzbekistan. AB - Women get less of the material resources, social status, power and opportunities for self-actualization than men do who share their social location - be it a location based on class, race, occupation, ethnicity, religion, education, nationality, or any intersection of these factors. The process of feminization of poverty in Central Asia and Uzbekistan is intimately connected to the cultural and institutional limitations that put a ceiling on women's involvement in economic activity. This article attempts to study and explore gender in the context of poverty reduction in Uzbekistan, the most populated state of Central Asia, to understand the ways and manner in which poverty and other forms of deprivation demand women's participation in variety of contexts. The study is primarily an empirical one and is based on an extensive sociological investigation in the field. PMID- 22213881 TI - The form, the permit and the photograph: an archive of mobility between South Africa and India. AB - Inspired by recent scholarship that calls for a more critical engagement with archives and knowledge production, this article plots the biography of an archive in Cape Town. Unravelling the layers of paperwork, it locates the origins of the archive in a repressive state project of excluding Indian immigrants and controlling those within the borders of the Cape Colony. The paper trail reveals documents of identity and the state's attempts to verify identity. In seeking to answer the question as to how the historian should approach such an archive of control and surveillance, it concludes that a social history and gendered approach to migration is possible and the real treasures are those documents that enter the archive beyond the limits of state intentions. PMID- 22213882 TI - Poppies for medicine in Afghanistan: lessons from India and Turkey. AB - This study examines India and Turkey as case studies relevant to the Senlis Council's 'poppies for medicine' proposal. The proposal is that Afghan farmers are licensed to produce opium for medical and scientific purposes. Here it is posited that the Senlis proposal neglects at least three key lessons from the Turkish and Indian experiences. First, not enough weight has been given to diversion from licit markets, as experienced in India. Second, both India and Turkey had significantly more efficient state institutions with authority over the licensed growing areas. Third, the proposal appears to overlook the fact that Turkey's successful transition was largely due to the use of the poppy straw method of opium production. It is concluded that, while innovative and creative policy proposals such as that of the Senlis proposal are required if Afghanistan is to move beyond its present problems, 'poppies for medicine' does not withstand evidence-based scrutiny. PMID- 22213883 TI - Crossing boundaries: women's gossip, insults and violence in sixteenth-century France. AB - Using evidence from cases recorded in the registers of the consistories of southern France, the author investigates the way in which Languedocian women policed each other's behaviour, enforcing a collective morality through gossip, sexual insult and physical confrontation. In contrast to case studies by other historians, it is argued here that gossip does appear to have been a peculiarly female activity, but far more than simply being an outlet for malice or prurience, it gave women a distinctive social role in the town. No less evident is the involvement of women in physical violence both against each other and against men, violence which, though less extreme than its male counterpart, nonetheless occupies a significant role in the proceedings of the consistories. PMID- 22213884 TI - Thinking with Montaigne: evidence, scepticism and meaning in early modern demonology. AB - In 1612 the Bordeaux witchcraft inquisitor Pierre de Lancre (1556-1631), himself linked by marriage to Michel de Montaigne (1533-1592), revealed that the essayist and sceptic was related on his mother's side to a leading authority on magic and superstition, the Flemish-Spanish Jesuit Martin Delrio (1551-1608). De Lancre confounded historians' expectations by using the revelation to defend Montaigne against his cousin's criticism. This article re-evaluates the relationships of De Lancre, Delrio and Montaigne in the light of recent scholarship, which casts demonology as a form of "resistance to scepticism" that conceals deep anxiety about the existence of the supernatural. It explores De Lancre's and Delrio's very different attitudes towards Montaigne and towards evidence and scepticism. This, in turn, reveals the different underlying preoccupations of their witchcraft treatises. It hence argues that no monocausal explanation linking scepticism to witchcraft belief is plausible. PMID- 22213885 TI - Rendering justice in witch trials: the case of the val de Liepvre. AB - The borderland of the val de Liepvre, with lands in Alsace and in the Duchy of Lorraine, and divided by religion and language, offers a rich collection of sources for the history of witchcraft persecution. The territory sharply reveals what was undoubtedly characteristic of witchcraft trials more widely. The crime of witchcraft was considered abominable before the Christian community and God, and its prosecution justified abandoning many of the safeguards and constraints in legal procedure, whether restrictions on the use of torture, the reliance on dubious testimony or even denial of advocacy to the witches. The action of the judges was nonetheless, as they understood it, the rendering of true justice, by punishing the culprits with a harshness that would expiate their crimes before the community and preserve them from damnation in the face of God's judgment. PMID- 22213886 TI - The carbon-consuming home: residential markets and energy transitions. AB - Home heating and lighting markets have played crucial and underappreciated roles in driving energy transitions. When historians have studied the adoption of fossil fuels, they have often privileged industrial actors, markets, and technologies. My analysis of the factors that stimulated the adoption of anthracite coal and petroleum during the nineteenth century reveals that homes shaped how, when, and why Americans began to use fossil fuel energy. Moreover, a brief survey of other fossil fuel transitions shows that heating and lighting markets have been critical drivers in other times and places. Reassessing the historical patterns of energy transitions offers a revised understanding of the past for historians and suggests a new set of options for policymakers seeking to encourage the use of renewable energy in the future. PMID- 22213887 TI - Body banks: a history of milk banks, blood banks, and sperm banks in the United States. PMID- 22213888 TI - Jane Austen on love and pedagogical power. AB - This essay notes initially recent prominence of theories of pedagogy that attempt to "de-mystify" it and reveal troubling power relations, and their subsequent contention that love is impossible in the student-teacher relationship. "Pedagogical" interpretations of Jane Austen's fiction, however, see pedagogy as essential to love. I argue that this is so precisely because of the power dynamics involved; drawing on Jessica Benjamin's psychoanalytic interpretation of G. W. F. Hegel's analysis of the "Lord-Bondsman," I suggest that Austen portrays the loving relationship as inherently involving the occupation and subsequent exchange of roles as superior and inferior, incarnated as "teacher" and "student." PMID- 22213889 TI - Reading embodied consciousness in "Emma". AB - The language of Emma (1815) reflects Jane Austen's developing view of embodied consciousness and her particular interest in this novel in the physical manifestations of emotions, such as blushes and nervous responses. The discursive exploration of the inner life in Emma is the product of a cultural context that features emerging brain science and Austen's own conceptualization of the psychophysical nature of emotions. This article analyzes the language of mind and emotion in Emma, to contend that Austen grapples with the implications of the idea of embodied consciousness in a narrative that contrasts mind reading with interpreting the body. PMID- 22213890 TI - Aspects of child labor in Tonna's "Helen Fleetwood". AB - This article explores the unique role of Charlotte Elizabeth Tonna's "Helen Fleetwood" (1841), one of the first social-problem novels, in shaping the concerns and strategies of the genre. Writing at a moment of cultural change in the attitude toward children, Tonna's Blakean vision of child labor as diabolical allows her to offer a daring critique of social institutions. Yet her political vision is inconsistent: although she redeems the working-class child's point of view and rehumanizes this figure, Tonna's staging of child labor as originating in a metaphysical, divine plan leads her to construct children's suffering as a justifiable and even desirable ethos. PMID- 22213891 TI - Evolution and epilepsy in "Bleak House". AB - In Charles Dickens's novels, nervous seizures trigger dreamy, clairvoyant episodes in which normally imperceptible connections and relations among events and characters come to light. During such episodes, which the neurologist John Hughlings Jackson would describe as "voluminous" states of consciousness, the boundaries of the self dissolve, and the mind becomes attuned to a range of possible identities or phantom selves. The specters unleashed in this state of nervous "dissolution" haunt Bleak House even as they illuminate relations among members of vastly different social worlds and the great institutional forces that affect the most curious events of the mind. PMID- 22213892 TI - George Eliot's interrogation of physiological future knowledge. AB - This essay tracks George Eliot's sustained interest in the epistemological problems surrounding the Victorian tendency to envision the future through the body's materiality. It argues that her nuanced criticism of phrenology in "The Lifted Veil" (1859) and "A Minor Prophet" (1865) addresses the delimiting psychological and social effects that attend an applied theory of physiological determinism. Returning to this problem in Daniel Deronda (1876), Eliot offers Mordecai's plan to posit Deronda's body as a living emblem as a radical alternative to racial iconography and typological meaning-a move that allowed her to reconcile the body's legibility with a future beyond socially inscribed possibilities. PMID- 22213893 TI - Morality's ugly implications in Oscar Wilde's fairy tales. AB - In Oscar Wilde's two volumes of fairy tales, "The Happy Prince" and Other Tales (1888) and A House of Pomegranates (1891), many central characters meet with premature death or physical disfigurement after learning a bourgeois moral lesson. In an attempt to explain this unconventional phenomenon in the fairy tale tradition, this essay examines Wilde's stories through the lens of his aesthetic ideology and demonstrates how the superficial morality of the Victorian bourgeoisie corrodes each tale's aesthetic integrity, causing the characters to either deny morality outright, assume the guise of Christian philanthropy, or die as the result of their moral reformation. PMID- 22213894 TI - What you learn is what you see: using eye movements to study infant cross situational word learning. AB - Recent studies show that both adults and young children possess powerful statistical learning capabilities to solve the word-to-world mapping problem. However, the underlying mechanisms that make statistical learning possible and powerful are not yet known. With the goal of providing new insights into this issue, the research reported in this paper used an eye tracker to record the moment-by-moment eye movement data of 14-month-old babies in statistical learning tasks. Various measures are applied to such fine-grained temporal data, such as looking duration and shift rate (the number of shifts in gaze from one visual object to the other) trial by trial, showing different eye movement patterns between strong and weak statistical learners. Moreover, an information-theoretic measure is developed and applied to gaze data to quantify the degree of learning uncertainty trial by trial. Next, a simple associative statistical learning model is applied to eye movement data and these simulation results are compared with empirical results from young children, showing strong correlations between these two. This suggests that an associative learning mechanism with selective attention can provide a cognitively plausible model of cross-situational statistical learning. The work represents the first steps in using eye movement data to infer underlying real-time processes in statistical word learning. PMID- 22213895 TI - Multisensory information boosts numerical matching abilities in young children. AB - This study presents the first evidence that preschool children perform more accurately in a numerical matching task when given multisensory rather than unisensory information about number. Three- to 5-year-old children learned to play a numerical matching game on a touchscreen computer, which asked them to match a sample numerosity with a numerically equivalent choice numerosity. Samples consisted of a series of visual squares on some trials, a series of auditory tones on other trials, and synchronized squares and tones on still other trials. Children performed at chance on this matching task when provided with either type of unisensory sample, but improved significantly when provided with multisensory samples. There was no speed-accuracy tradeoff between unisensory and multisensory trial types. Thus, these findings suggest that intersensory redundancy may improve young children's abilities to match numerosities. PMID- 22213896 TI - Onset and maturation of fetal heart rate response to the mother's voice over late gestation. AB - BACKGROUND: Term fetuses discriminate their mother's voice from a female stranger's, suggesting recognition/learning of some property of her voice. Identification of the onset and maturation of the response would increase our understanding of the influence of environmental sounds on the development of sensory abilities and identify the period when speech and language might influence auditory processing. AIM: To characterize the onset and maturation of fetal heart rate response to the mother's voice. METHODS: 143 fetuses from 29 to 40 weeks gestational age (GA) received a standardized protocol: no-sound pre voice baseline (2 min), audio recording of their mother reading a story (2 min), no-sound post-voice (2 min). The voice was delivered 10 cm above the maternal abdomen at an average of 95 dB A; heart rate was recorded continuously. RESULTS: For data analyses, fetuses were categorized into four age groups: 29-31, 32-34, 35-37, and > 37 weeks GA. Onset of response to the mother's voice occurred at 32 34 weeks GA. From 32 to 37 weeks GA, there was an initial heart rate decrease followed by an increase. At term, there was a response shift to an initial heart rate increase. The percentage of fetuses responding increased over gestation from 46% at 32-34 weeks GA to 83% at term. CONCLUSION: A relatively long latency and sustained duration of the heart rate response suggest auditory processing, the formation of neural networks, above the level of the brainstem. PMID- 22213897 TI - Measuring fetal cognitive development: when methods and conclusions don't match. PMID- 22213898 TI - Twelve-month-olds privilege words over other linguistic sounds in an associative learning task. AB - We examined whether 12-month-old infants privilege words over other linguistic stimuli in an associative learning task. Sixty-four infants were presented with sets of either word-object, communicative sound-object, or consonantal sound object pairings until they habituated. They were then tested on a 'switch' in the sound to determine whether they were able to associate the word and/or sound with the novel objects. Infants associated words, but not communicative sounds or consonantal sounds, with novel objects. The results demonstrate that infants exhibit a preference for words over other linguistic stimuli in an associative word learning task. This suggests that by 12 months of age, infants have developed knowledge about the nature of an appropriate sound form for an object label and will privilege this form as an object label. PMID- 22213899 TI - Speed of processing, anticipation, inhibition and working memory in bilinguals. AB - Literature on the so-called bilingual advantage is directed towards the investigation of whether the mastering of two languages fosters cognitive skills in the non-verbal domain. The present study aimed to evaluate whether the bilingual advantage in non-verbal skills could be best defined as domain-general or domain-specific, and, in the latter case, at identifying the basic cognitive skills involved. Bilingual and monolingual participants were divided into two different age groups (children, youths) and were tested on a battery of elementary cognitive tasks which included a choice reaction time task, a go/no-go task, two working memory tasks (numbers and symbols) and an anticipation task. Bilingual and monolingual children did not differ from each other except for the anticipation task, where bilinguals were found to be faster and more accurate than monolinguals. These findings suggest that anticipation, which has received little attention to date, is an important cognitive domain which needs to be evaluated to a greater extent both in bilingual and monolingual participants. PMID- 22213900 TI - Inhibitory control interacts with core knowledge in toddlers' manual search for an occluded object. AB - Core knowledge theories advocate the primacy of fundamental principles that constrain cognitive development from early infancy. However, there is concern that core knowledge of object properties does not constrain older preschoolers' reasoning during manual search. Here we address in detail both failure and success on two well-established search measures that require reasoning about solidity. We show that poor performance arises from an inability to engage the appropriate search strategy rather than a simple failure of core knowledge. Moreover, we demonstrate that successful search is positively correlated with inhibitory control. We believe that toddlers' manual search for an occluded object reflects a general capacity to deploy inhibition so that search behaviour can be guided by core knowledge. PMID- 22213901 TI - Subitizing and counting in typical and atypical development. AB - Enumeration performance in standard dot counting paradigms was investigated for different age groups with typical and atypically poor development of arithmetic skills. Experiment 1 showed a high correspondence between response times and saccadic frequencies for four age groups with typical development. Age differences were more marked for the counting than the subitizing range. In Experiment 2 we found a discontinuity between subitizing and counting for dyscalculic children; however, their subitizing slopes were steeper than those of typically developing control groups, indicating a dysfunctional subitizing mechanism. Across both experiments a number of factors could be identified that affect enumeration in the subitizing and the counting range differentially. These differential patterns further support the assumption of two qualitatively different enumeration processes. PMID- 22213902 TI - False-belief understanding i 2.5-year-olds: evidence for violation-of-expectation change-of-location and unexpected-contents tasks. AB - Until recently, it was generally assumed that the ability to attribute false beliefs did not emerge until about 4 years of age. However, recent reports using spontaneous- as opposed to elicited-response tasks have suggested that this ability may be present much earlier. To date, researchers have employed two kinds of spontaneous-response false-belief tasks: violation-of-expectation tasks have been used with infants in the second year of life, and anticipatory-looking tasks have been used with toddlers in the third year of life. In the present research, 2.5-year-old toddlers were tested in violation-of-expectation tasks involving a change-of-location situation (Experiment 1) and an unexpected-contents situation (Experiment 2). Results were positive in both situations, providing the first demonstrations of false-belief understanding in toddlers using violation-of expectation tasks and, as such, pointing to a consistent and continuous picture of early false-belief understanding. PMID- 22213903 TI - Using mu rhythm desynchronization to measure mirror neuron activity in infants. AB - The Mirror Neuron System hypothesis stating that observed actions are projected onto the observer's own action system assigns an important role to development, because only actions mastered by the observer can be mirrored. The purpose of the present study was to investigate whether there is evidence of a functioning mirror neuron system (MNS) in 8-month-old infants. High-density EEG was used to assess the mu rhythm desynchronization in an action observation task where the infants observed a live model. To reduce noise, ICA decompositions were used. The results show a higher desynchronization of the mu rhythm when infants observed a goal-directed action than when they observed a spatially similar non-goal directed movement. The localizations of the sources are in agreement with those proposed by the MNS hypothesis. This indicates that the MNS is functioning at this age. PMID- 22213904 TI - Near-term fetuses process temporal features of speech. AB - The perception of speech and music requires processing of variations in spectra and amplitude over different time intervals. Near-term fetuses can discriminate acoustic features, such as frequencies and spectra, but whether they can process complex auditory streams, such as speech sequences and more specifically their temporal variations, fast or relatively slow acoustic variations, is unclear. We recorded the cardiac activity of 82 near-term fetuses (38 weeks GA) in quiet sleep during a silent control condition and four 15 s streams presented at 90 dB SPL Leq: two piano melodies with opposite contours, a natural Icelandic sentence and a chimera of the sentence--all its spectral information was replaced with broadband noise, leaving its specific temporal variations in amplitude intact without any phonological information. All stimuli elicited a heart rate deceleration. The response patterns to the melodies were the same and differed significantly from those observed with the Icelandic sentence and its chimera, which did not differ. The melodies elicited a monophasic heart rate deceleration, indicating a stimulus orienting reflex while the Icelandic and its chimera evoked a sustained lower magnitude response, indicating a sustained attentional response or more focused information processing. A conservative interpretation of the data is that near-term fetuses can perceive sound streams and the rapid temporal variations in amplitude that are specific to speech sounds with no spectral variations at all. PMID- 22213905 TI - Biological motion preference in humans at birth: role of dynamic and configural properties. AB - The present study addresses the hypothesis that detection of biological motion is an intrinsic capacity of the visual system guided by a non-species-specific predisposition for the pattern of vertebrate movement and investigates the role of global vs. local information in biological motion detection. Two-day-old babies exposed to a biological motion point-light display (depicting a walking hen) and a non-biological motion display (a rotating rigid object) preferentially looked at the biological display (Experiment 1). A new group of newborns showed themselves to be capable of discriminating, following habituation, a biological motion display from a spatially scrambled version of it (Experiment 2). However, a third group of newborns, at their first exposure to such displays, did not show any preference between them (Experiment 3). Results confirm and extend previous comparative and developmental data, supporting an inborn predisposition to attend to biological motion in humans. This ability is presumably part of an evolutionarily ancient and non-species-specific system predisposing animals to preferentially attend to other animals. PMID- 22213906 TI - [Female religiosity and the education of indigenous women in the Philippines: the Beaterio-Colegio of Mother Paula of the Holy Trinity]. PMID- 22213907 TI - Human newborns match tongue protrusion of disembodied human and robotic mouths. AB - No evidence had been provided so far of newborns' capacity to give a matching response to 2D stimuli. We report evidence from 18 newborns who were presented with three types of stimuli on a 2D screen. The stimuli were video-recorded displays of tongue protrusion shown by: (a) a human face, (b) a human tongue from a disembodied mouth, and (c) an artificial tongue from a robotic mouth. Compared to a baseline condition, neonates increased significantly their tongue protrusion when seeing disembodied human and artificial tongue movements, but not when seeing a 2D full-face protruding tongue. This result was interpreted as revealing the exploration of top-heavy patterns of the 2D face that distracted infants' attention from the tongue. Results also showed progressively more accurate matching (full tongue protrusion) throughout repeated exposure to each kind of stimulus. Such findings are not in line with the predictions of the innate releasing mechanism (IRM) model or of the oral exploration hypothesis. They support the active intermodal mapping (AIM) hypothesis that emphasizes not only the importance of repeated experience, as would the associative sequence learning (ASL) hypothesis, but also predicts a differential learning and progressive correction of the response adapted to each stimulus. PMID- 22213908 TI - The acquisition of phonetic categories in bilingual infants: new data from an anticipatory eye movement paradigm. AB - Contrasting results have been reported regarding the phonetic acquisition of bilinguals. A lack of discrimination has been observed for certain native contrasts in 8-month-old Catalan-Spanish bilingual infants (Bosch & Sebastian Galles, 2003a), though not in French-English bilingual infants (Burns, Yoshida, Hill & Werker, 2007; Sundara, Polka & Molnar, 2008). At present, the data for Catalan-Spanish bilinguals constitute an exception in the early language acquisition literature. This study contributes new findings that show that Catalan-Spanish bilingual infants do not lose the capacity to discriminate native contrasts. We used an adaptation of the anticipatory eye movement paradigm (AEM; McMurray & Aslin, 2004) to explore this question. In two experiments we tested the ability of infants from Catalan and Spanish monolingual families and from Catalan-Spanish bilingual families to discriminate a Spanish-Catalan common and a Catalan-specific vowel contrast. Results from both experiments revealed that Catalan-Spanish bilingual infants showed the same discrimination abilities as those shown by their monolingual peers, even in a phonetic contrast that had not been discriminated in previous studies. Our results demonstrate that discrimination can be observed in 8-month-old bilingual infants when tested with a measure not based on recovery of attention. The high ratio of cognates in Spanish and Catalan may underlie the reason why bilinguals failed to discriminate the native vowels when tested with the familiarization-preference procedure but succeeded with the AEM paradigm. PMID- 22213910 TI - Thinking outside the cortex: social motivation in the evolution and development of language. AB - Alteration of the organization of social and motivational neuroanatomical circuitry must have been an essential step in the evolution of human language. Development of vocal communication across species, particularly birdsong, and new research on the neural organization and evolution of social and motivational circuitry, together suggest that human language is the result of an obligatory link of a powerful cortico-striatal learning system, and subcortical socio motivational circuitry. PMID- 22213911 TI - 'No fair, copycat!': what children's response to plagiarism tells us about their understanding of ideas. AB - Adults believe that plagiarizing ideas is wrong, which requires an understanding that others can have ideas and that it is wrong to copy them. In order to test when this understanding emerges, we investigated when children begin to think plagiarism is wrong. In Study 1, children aged 7, 9 and 11 years old, as well as adults, disliked someone who plagiarized compared to someone who drew an original drawing or someone who drew an identical picture by chance. Study 2 investigated the same question with younger children, focusing on children aged 3-6 years old. Children aged 5-6 years old evaluated plagiarizers negatively relative to unique drawers, but 3-4-year-olds did not. Study 3 replicated the findings from Study 2 and found that children justify their negative evaluations of plagiarizers by mentioning concerns over copying. These experiments provide evidence that, by age 5 years old, children understand that others have ideas and dislike the copying of these ideas. PMID- 22213909 TI - Is auditory discrimination mature by middle childhood? A study using time frequency analysis of mismatch responses from 7 years to adulthood. AB - Behavioural and electrophysiological studies give differing impressions of when auditory discrimination is mature. Ability to discriminate frequency and speech contrasts reaches adult levels only around 12 years of age, yet an electrophysiological index of auditory discrimination, the mismatch negativity (MMN), is reported to be as large in children as in adults. Auditory ERPs were measured in 30 children (7 to 12 years), 23 teenagers (13 to 16 years) and 32 adults (35 to 56 years) in an oddball paradigm with tone or syllable stimuli. For each stimulus type, a standard stimulus (1000 Hz tone or syllable [ba]) occurred on 70% of trials, and one of two deviants (1030 or 1200 Hz tone, or syllables [da] or [bi]) equiprobably on the remaining trials. For the traditional MMN interval of 100-250 ms post-onset, size of mismatch responses increased with age, whereas the opposite trend was seen for an interval from 300 to 550 ms post onset, corresponding to the late discriminative negativity (LDN). Time-frequency analysis of single trials revealed that the MMN resulted from phase synchronization of oscillations in the theta (4-7 Hz) range, with greater synchronization in adults than children. Furthermore, the amount of synchronization was significantly correlated with frequency discrimination threshold. These results show that neurophysiological processes underlying auditory discrimination continue to develop through childhood and adolescence. Previous reports of adult-like MMN amplitudes in children may be artefactual results of using peak measurements when comparing groups that differ in variance. PMID- 22213912 TI - Carryover effect of joint attention to repeated events in chimpanzees and young children. AB - Gaze following is a fundamental component of triadic social interaction which includes events and an object shared with other individuals and is found in both human and nonhuman primates. Most previous work has focused only on the immediate reaction after following another's gaze. In contrast, this study investigated whether gaze following is retained after the observation of the other's gaze shift, whether this retainment differs between species and age groups, and whether the retainment depends on the nature of the preceding events. In the social condition, subjects (1- and 2-year-old human children and chimpanzees) witnessed an experimenter who looked and pointed in the direction of a target lamp. In the physical condition, the target lamp blinked but the experimenter did not provide any cues. After a brief delay, we presented the same stimulus again without any cues. All subjects looked again to the target location after experiencing the social condition and thus showed a carryover effect. However, only 2-year-olds showed a carryover effect in the physical condition; 1-year-olds and chimpanzees did not. Additionally, only human children showed spontaneous interactive actions such as pointing. Our results suggest that the difference between the two age groups and chimpanzees is conceptual and not only quantitative. PMID- 22213913 TI - Three-month-old infants attribute goals to a non-human agent. AB - The present research examined whether 3-month-old infants, the youngest found so far to engage in goal-related reasoning about human agents, would also act as if they attribute goals to a novel non-human agent, a self-propelled box. In two experiments, the infants seemed to have interpreted the box's actions as goal directed after seeing the box approach object A as opposed to object B during familiarization. They thus acted as though they expected the box to maintain this goal and responded with increased attention when the box approached object B during test. In contrast, when object B was absent during familiarization and introduced afterwards, the infants' responses were consistent with their having recognized that they had no information to predict which of the two objects the box should choose during test and therefore responded similarly when the box approached either object. However, if object B was absent during familiarization and object A was in different positions but the box persistently approached it, thus demonstrating equifinal variations in its actions, the infants again acted as though they attributed to the box a goal directed towards object A and expected the box to maintain this goal even when object B was introduced and hence responded with prolonged looking when the box failed to do so during test. These results are consistent with the notion that (a) infants as young as 3 months appear to attribute goals to both human and non-human agents, and (b) even young infants can use certain behavioral cues, e.g. equifinal variations in agents' actions, to make inferences about agents' goals. PMID- 22213915 TI - [Child labor in the mining industry: historical notes]. PMID- 22213916 TI - Anna Barbara van Meerten-Schilperoort: feminist pioneer? PMID- 22213917 TI - In memoriam: Gaston P. Beunen 1945-2011. PMID- 22213918 TI - Comments on "Socio-geographical factors in vulnerability to dengue in Thai villages: a spatial regression analysis" by Tipayamongkholgul and Lisakulruk. PMID- 22213920 TI - [Health service research (13): From an interdisciplinary viewpoint--legal medicine and HSR]. PMID- 22213919 TI - Remodelling of the natural product fumagillol employing a reaction discovery approach. AB - In the search for new biologically active molecules, diversity-oriented synthetic strategies break through the limitation of traditional library synthesis by sampling new chemical space. Many natural products can be regarded as intriguing starting points for diversity-oriented synthesis, wherein stereochemically rich core structures may be reorganized into chemotypes that are distinctly different from the parent structure. Ideally, to be suited to library applications, such transformations should be general and involve few steps. With this objective in mind, the highly oxygenated natural product fumagillol has been successfully remodelled in several ways using a reaction-discovery-based approach. In reactions with amines, excellent regiocontrol in a bis-epoxide opening/cyclization sequence can be obtained by size-dependent interaction of an appropriate catalyst with the parent molecule, forming either perhydroisoindole or perhydroisoquinoline products. Perhydroisoindoles can be further remodelled by cascade processes to afford either morpholinone or bridged 4,1-benzoxazepine containing structures. PMID- 22213921 TI - [Scientific study of society and health through public health (9). "Development of health information science"]. PMID- 22213922 TI - [Public health monitoring report (6): Health crisis management following a large scale disaster--minimization of damage through information management]. PMID- 22213923 TI - [Public health monitoring report (7). On management of environmentally induced cancer in response to accidental radiation release at the First Fukushima reactor]. PMID- 22213924 TI - [Recent progress and future view in diagnostic imaging for colorectal cancer]. PMID- 22213925 TI - [Time trend of endoscopic treatment for early colorectal carcinoma]. PMID- 22213926 TI - [Alteration of surgical treatment for colorectal cancer]. PMID- 22213927 TI - [Chemotherapy for advanced colorectal cancer]. PMID- 22213928 TI - [Epidemiologic review of colorectal cancer in Japan]. PMID- 22213929 TI - [Incidence and mortality of colorectal cancer--international comparison]. PMID- 22213930 TI - [Lifestyle and environmental factors for colorectal cancer]. PMID- 22213931 TI - [Host factor of colorectal cancer]. PMID- 22213932 TI - [Hereditary colorectal cancer; familial adenomatous polyposis, MUTYH associated polyposis and Lynch syndrome]. PMID- 22213934 TI - [Oncogenes and tumor-suppressor genes]. PMID- 22213933 TI - [Molecular biology of colon cancer]. PMID- 22213935 TI - [DNA mismatch genes in colorectal cancer]. PMID- 22213936 TI - [Microsatellite instability]. PMID- 22213937 TI - [Genetics of colorectal cancer (polymorphism and chromosomal abnormality)]. PMID- 22213938 TI - [Cancer stem cell]. PMID- 22213939 TI - [Significance of microRNA in digestive system carcinoma]. PMID- 22213940 TI - [Mechanisms of colorectal carcinogenesis]. PMID- 22213941 TI - [Mechanism of carcinogenesis in the sessile serrated adenoma/polyp--carcinoma pathway in the colon]. PMID- 22213942 TI - [Inflammation and colorectal carcinogenesis including carcinogenesis of ulcerative colitis]. PMID- 22213943 TI - [Radiation-induced colorectal cancer: second primary cancer after radiotherapy]. PMID- 22213944 TI - [Single nucleotide polymorphism associated with the oncogenesis of colorectal cancer]. PMID- 22213945 TI - [Oxidative DNA damage-induced intestinal tumorigenesis in Mutyh-deficient mice]. PMID- 22213946 TI - [Introduction of invasion and metastasis in colorectal carcinoma]. PMID- 22213947 TI - [Molecular genetics associated with invasion and metastasis of colorectal cancer]. PMID- 22213948 TI - [Patterns of recurrence following curative resection for colorectal cancer-based on the data of Japanese Study Group for Postoperative Follow-up of Colorectal Cancer]. PMID- 22213949 TI - [Clinical appearance of liver metastases from colorectal cancer]. PMID- 22213950 TI - [Clinical characteristic of the pulmonary metastases from colorectal cancer]. PMID- 22213951 TI - [Characteristics of rectal cancer with lateral pelvic lymph node metastasis]. PMID- 22213952 TI - [Clinical characteristics of metastatic bone tumor and brain tumor in colorectal cancer]. PMID- 22213953 TI - [The meaning of prognostic factor for treatment of colorectal cancer: review]. PMID- 22213954 TI - [Prognostic factors for stage I colorectal cancer]. PMID- 22213955 TI - [Prognostic factor of stage II colon cancer]. PMID- 22213956 TI - [Prognostic factors of stage III colorectal cancer]. PMID- 22213957 TI - [Prognostic factors of metastasectomy for colorectal cancer]. PMID- 22213958 TI - [Impact of lymph node evaluation and prognosis in patients with colorectal cancer]. PMID- 22213959 TI - [Prognostic impact of serum carcinoembryonic antigen level in patients with colorectal cancer]. PMID- 22213960 TI - [Dihydropyrimidine dehydrogenase and thymidine phosphorylase as a prognostic factor of colorectal cancer patients]. PMID- 22213961 TI - [Recent advancement in biomarkers to predict the clinical outcome for colorectal cancer patients]. PMID- 22213962 TI - [Overview of 'General rules for clinical and pathological studies on cancer of colon, rectum and anus' and 'JSCCR guidelines 2010 for the treatment of colorectal cancer]. PMID- 22213963 TI - [Comparison of the Japanese classification 7th edition and the TNM classification 7th edition for colorectal cancer]. PMID- 22213964 TI - [Comparison between JSCCR and NCCN guidelines for the treatment of colorectal cancer]. PMID- 22213965 TI - [Examination and diagnosis of colorectal cancer (introduction and overview)]. PMID- 22213966 TI - [Pre-treatment of colonoscopy]. PMID- 22213967 TI - [Essence of endoscopic diagnosis for the depth of early colorectal cancer]. PMID- 22213968 TI - [Effectiveness of endoscopic diagnosis with magnification]. PMID- 22213969 TI - [Diagnosis of invasion depth (T stage) of rectal cancer by endoscopic ultrasonography]. PMID- 22213970 TI - [Narrow band imaging for detection of non-polypoid colorectal neoplasms]. PMID- 22213971 TI - [Strategy for early detection of colitic cancer]. PMID- 22213973 TI - [Application of PET/CT fused images in the diagnosis of colorectal cancer]. PMID- 22213972 TI - [Colorectal screening using CT colonography--current status and future prospect in Japan]. PMID- 22213974 TI - [Preoperative optimal simulation for colorectal cancer with multi-image 3D fusion virtual reality]. PMID- 22213975 TI - [Usefulness of the auto fluorescence imaging for diagnosis of colorectal cancer]. PMID- 22213976 TI - [Diffusion weighted whole body imaging with background body signal suppression (DWIBS) in nodal metastasis of colorectal cancer]. PMID- 22213977 TI - [Significance of contrast enhanced intraoperative ultrasound with Sonazoid for liver metastases from colorectal cancer]. PMID- 22213978 TI - [Pathological diagnosis of colorectal cancer according to Japanese classification of colorectal carcinoma]. PMID- 22213979 TI - [Point of handling of endoscopically resected specimens]. PMID- 22213980 TI - [Pathological evaluation of submucosal invasive colorectal cancer]. PMID- 22213981 TI - [Histological evaluation of vascular permeation in colorectal carcinoma]. PMID- 22213983 TI - [Importance and practice of UGT1A1 polymorphisms]. PMID- 22213982 TI - [Clinical significance and the handling of KRAS testing on metastatic colorectal cancer]. PMID- 22213984 TI - [Predicted difficulties at screening of hereditary colorectal cancers including the issue of genetic testing]. PMID- 22213985 TI - [Strategy of colorectal cancer treatment]. PMID- 22213986 TI - [Treatment strategy for early colorectal cancer]. PMID- 22213987 TI - [Endoscopic treatment for early colorectal carcinoma: EMR or ESD?]. PMID- 22213988 TI - [Surveillance and long-term prognosis (metastasis, recurrence) in cases with submucosal invasive carcinoma resected endoscopically]. PMID- 22213989 TI - [Treatment strategy for T1 carcinoma of the distal rectum: the possibility of a minimally invasive surgery by the identification of risk factors for an adverse outcome]. PMID- 22213990 TI - [Treatment of obstructing colorectal cancer]. PMID- 22213991 TI - [Surgical management of peritoneal carcinomatosis from colorectal cancer]. PMID- 22213992 TI - [Surgical treatment of colorectal liver metastases-operative indication]. PMID- 22213993 TI - [Surgical treatment for pulmonary metastases from colorectal cancer]. PMID- 22213994 TI - [Principle and indication of surgical treatment of locally recurrent rectal cancer]. PMID- 22213995 TI - [The role of laparoscopic surgery in the treatment of colorectal cancer]. PMID- 22213996 TI - [Current status of robotic surgery for colorectal cancer and its future perspectives]. PMID- 22213997 TI - [Adjuvant chemotherapy for stage II and III colorectal cancer]. PMID- 22213998 TI - [Adjuvant chemotherapy for stage IV colorectal cancer after R0 resection]. PMID- 22213999 TI - [Treatment strategy of chemotherapy for unresectable metastatic or recurrent colorectal cancer]. PMID- 22214000 TI - [Which chemotherapy regimens should we choose for 1st or 2nd line of metastatic colorectal cancer?]. PMID- 22214001 TI - [A review of FOLFOXIRI chemotherapy for the 1st line treatment of metastatic colorectal cancer]. PMID- 22214002 TI - [Combination of surgery and chemotherapy in the treatment of patients with colorectal liver metastases; conversion therapy]. PMID- 22214004 TI - [Efficacy of monoclonal antibodies in combination with chemotherapy in metastatic colorectal cancer]. PMID- 22214003 TI - [Development of oral drugs in the standard therapy for metastatic colorectal cancer patients]. PMID- 22214005 TI - [Issues of molecular targeted therapies in combination with chemotherapy in metastatic colorectal cancer]. PMID- 22214006 TI - [Administration-limiting factor of bevacizumab for patient with metastatic colorectal cancer]. PMID- 22214008 TI - [Selection of a molecule-target agent--present and prospect]. PMID- 22214007 TI - [Gene mutation (KRAS, BRAF, PIK3CA) and clinical benefit of anti-EGFR antibody]. PMID- 22214009 TI - [Current view and possibilities of chemotherapy sensitivity and resistance assays and metabolic enzyme analysis in individualized chemotherapy for the patients with colorectal cancer]. PMID- 22214010 TI - [Predictive marker for the efficacy of FOLFOX treatment in colon cancer (TS, ERCC1 etc)]. PMID- 22214011 TI - [Chemoradiotherapy for resectable lower rectal cancer]. PMID- 22214012 TI - [Radiotherapy for locally recurrent rectal cancer]. PMID- 22214013 TI - [Predictive and prognostic factors for the chemoradiotherapy of rectal cancer]. PMID- 22214014 TI - [Effort to reduce the adverse event due to radiotherapy for rectal cancer]. PMID- 22214015 TI - [Incidence of complications of colorectal ESD: how to prevent and manage it]. PMID- 22214016 TI - [Rash management for anti-EGFR antagonist]. PMID- 22214017 TI - [Thromboembolic events associated bevacizumab treatment]. PMID- 22214018 TI - [Chemotherapy-induced hepatotoxicity in patients with colorectal cancer liver metastases]. PMID- 22214019 TI - [FOLFOX-related hypersensitivity reactions: clinical presentation and management]. PMID- 22214020 TI - [Treatment with CPT-11 based on the UGT1A1 genetic polymorphism]. PMID- 22214021 TI - [Treatment of elderly patients with stage I-III colorectal cancers]. PMID- 22214022 TI - [Safety and efficacy of FOLFOX and FOLFIRI in elderly patients with colorectal cancer]. PMID- 22214023 TI - [Surgical management of colorectal cancer in patients with psychiatric disorders]. PMID- 22214024 TI - [Gene therapy for colorectal cancer]. PMID- 22214025 TI - [Immunotherapy for colorectal cancer--the present status and the prospects]. PMID- 22214026 TI - [Peptide vaccine treatment for colorectal cancer]. PMID- 22214027 TI - [Assessment of quality of life in cancer therapy: an overview]. PMID- 22214028 TI - [Colorectal cancer chemotherapy and QOL (benefits and problems of outpatient chemotherapy)]. PMID- 22214029 TI - [Perspective on cost-effectiveness analysis of chemotherapy for colorectal cancer]. PMID- 22214030 TI - [Quality of life after surgery for rectal cancer]. PMID- 22214031 TI - [Local communication in the treatment of colorectal cancer--for the improvement of quality of life]. PMID- 22214032 TI - [General statements: informed consent]. PMID- 22214033 TI - [Point of informed consent in surgery for colorectal cancer]. PMID- 22214034 TI - [Appropriate supporting systems and informed consent for patients with stomas]. PMID- 22214035 TI - [Summary of informed consent on chemotherapy to colorectal cancer patients]. PMID- 22214036 TI - [Significance of the national clinical database]. PMID- 22214037 TI - [Screening for colorectal cancer--present status and issues]. PMID- 22214038 TI - [Economic validity of hepatectomy for colorectal liver metastasis after chemotherapy]. PMID- 22214039 TI - [Treatment strategy for colorectal diminutive polyp]. PMID- 22214040 TI - Emerging directions in sociological research on sexuality. PMID- 22214041 TI - A new sexual revolution? Critical theory, pornography, and the Internet. AB - The "sexual revolution" was a central element of North American culture in the 1960s. Today, sex is increasingly central to mainstream culture, in large part due to the Internet, and we might wonder whether we are living through a comparable period of sexual history. In this article, I revisit the work of Herbert Marcuse-the original theorist of the sexual revolution-to ask whether it can contribute to a critical theory of sexuality in the era of digital technology. After outlining Marcuse's theory of the role of Eros in social life, I discuss two pornographic Web sites that combine eroticism and social critique. I argue that Marcuse's work is valuable for its emphasis on the intersection of sex, technology, and capitalist economy, but that it needs to be supplemented by a focus on masculinity and the male body in Internet pornography. PMID- 22214042 TI - Identity, refugeeness, belonging: experiences of sexual minority refugees in Canada. AB - This article explores the results of a qualitative community-based research project on the intersectional experiences of sexual minority refugees living in Canada. Undertaken between 2008 and 2010, this study examines sexual minority refugees' multifaceted experiences of migration, the refugee determination process, and settlement. Through an analysis of the interrelated themes of identity, refugeeness, and belonging, we hope to further investigate the ways in which Canadian refugee policies, social institutions, and dominant discourses contribute to the sociopolitical construction of sexual minority refugees. We conclude with an exploration of strategies for increasing protection of sexual minority refugees in Canada. PMID- 22214043 TI - "We are not aliens, we're people, and we have rights." Canadian human rights discourse and high school climate for LGBTQ students. AB - Canadian law protects people from discrimination on the grounds of sexual orientation, but our public schools do not fulfill their ethical and legal obligations where sexual and gender minority youth are concerned. This article reports on a national survey study on homophobia and transphobia in Canadian high schools. Participants (n = 3,607) were questioned about school climate, harassment, school attachment, and institutional interventions. We found that schools were neither safe nor respectful for sexual and gender minority students, and we argue that ongoing exposure to this situation undermines students' respect for the Charter of Rights and their faith in adults. PMID- 22214044 TI - "Kids not rights, is their craving": sex education, gay rights, and the threat of gay teachers. AB - In July 1977, the Ontario Humans Rights Commission recommended adding sexual orientation to the Code. This move was generally supported but Toronto newspapers and evangelists sought assurances that school boards could still dismiss homosexual teachers. They demanded children be shielded from gay teachers, who they accused of sexual predation. I historically link this to a reenergized fear of homosexuals which emerged during Toronto sex education debates in the 1970s. Later, influenced by Anita Bryant's Save the Children crusade, Toronto newspapers and evangelists argued gay teachers were the dangerous effect of gay rights. After the 1977 murder of Emanuel Jaques and the publication of Gerald Hannon's "Men Loving Boys, Loving Men" article, anti-gay sentiment in Toronto exploded, temporarily halting the progress of gay rights. PMID- 22214045 TI - Dissolved oxygen as a factor influencing nitrogen removal rates in a one-stage system with partial nitritation and Anammox process. AB - A biofilm system with Kaldnes biofilm carrier was used in these studies to cultivate bacteria responsible for both partial nitritation and Anammox processes. Due to co-existence of oxygen and oxygen-free zones within the biofilm depth, both processes can occur in a single reactor. Oxygen that inhibits the Anammox process is consumed in the outer layer of the biofilm and in this way Anammox bacteria are protected from oxygen. The impact of oxygen concentration on nitrogen removal rates was investigated in the pilot plant (2.1 m3), supplied with reject water from the Himmerfjarden Waste Water Treatment Plant. The results of batch tests showed that the highest nitrogen removal rates were obtained for a dissolved oxygen (DO) concentration around 3 g O2 m(-3) At a DO concentration of 4 g O2 m(-3), an increase of nitrite and nitrate nitrogen concentrations in the batch reactor were observed. The average nitrogen removal rate in the pilot plant during a whole operating period oscillated around 1.3 g N m(-2)d(-1) (0.3 +/- 0.1 kg N m(-3)d(-1)) at the average dissolved oxygen concentration of 2.3 g O2 m(-3). The maximum value of a nitrogen removal rate amounted to 1.9 g N m(-2)d(-1) (0.47 kg N m(-3)d(-1)) and was observed for a DO concentration equal to 2.5 g O2 m(-3). It was observed that increase of biofilm thickness during the operational period, had no influence on nitrogen removal rates in the pilot plant. PMID- 22214046 TI - Calibration of a 1D/1D urban flood model using 1D/2D model results in the absence of field data. AB - Recently increased flood events have been prompting researchers to improve existing coupled flood-models such as one-dimensional (1D)/1D and 1D/two dimensional (2D) models. While 1D/1D models simulate sewer and surface networks using a one-dimensional approach, 1D/2D models represent the surface network by a two-dimensional surface grid. However their application raises two issues to urban flood modellers: (1) stormwater systems planning/emergency or risk analysis demands for fast models, and the 1D/2D computational time is prohibitive, (2) and the recognized lack of field data (e.g. Hunter et al. (2008)) causes difficulties for the calibration/validation of 1D/1D models. In this paper we propose to overcome these issues by calibrating a 1D/1D model with the results of a 1D/2D model. The flood-inundation results show that: (1) 1D/2D results can be used to calibrate faster 1D/1D models, (2) the 1D/1D model is able to map the 1D/2D flood maximum extent well, and the flooding limits satisfactorily in each time-step, (3) the 1D/1D model major differences are the instantaneous flow propagation and overestimation of the flood-depths within surface-ponds, (4) the agreement in the volume surcharged by both models is a necessary condition for the 1D surface network validation and (5) the agreement of the manholes discharge shapes measures the fitness of the calibrated 1D surface-network. PMID- 22214047 TI - A combined hydraulic and biological SBR model. AB - A sequencing batch reactor (SBR) model was developed consisting of six continuous stirred tank reactors which describe the hydraulic flow patterns occurring in different SBR phases. The model was developed using the results of computational fluid dynamics (CFD) simulation studies of an SBR reactor under a selection of dynamic operational phases. Based on the CFD results, the model structure was refined and a simplified 'driver' model to allow one to mimic the flow pattern driven by the external operational conditions (influent, aeration, mixing) was derived. The resulting model allows the modeling of biological processes, settlement and hydraulic conditions of cylindrical SBRs. PMID- 22214048 TI - Hydraulic behaviour and removal efficiencies of two H-SSF constructed wetlands for wastewater reuse with different operational life. AB - This work focuses on the performance evaluation of two full-scale horizontal suburface flow constructed wetlands (H-SSF CWs) working in parallel, which have an almost equal surface area (about 2,000 m2) but with different operational lives: 8 and 3 years. Both H-SSF CWs, located in Southern Italy (Sicily), are used for tertiary treatment of the effluent of a conventional wastewater treatment plant. This study evaluates and compares H-SSF CW efficiency both in terms of water quality improvement (removal percentage) and achievement of Italian wastewater discharge and irrigation reuse limits. The mean removal percentage, for the overall operational life, of TSS, COD and BOD (80%, 63%, 58% obtained for H-SSF1 and 67%, 38%, 41% for H-SSF2), confirm the high reliability of CWs for wastewater treatment. However, despite the satisfactory removal of microbial indicators (the mean E. coli removal was up to 2.5 log unit for both beds), CWs didn't achieve the Italian limits for wastewater reuse. Information on hydraulic properties of the CWs were extracted from breakthrough curves of a non reactive tracer (NaCl). By comparing the nominal (tau(n)) and actual residence time (tau), hydraulic behaviour was revealed. PMID- 22214049 TI - Noble metal modified titania catalysts in the degradation of reactive black 5: a kinetic approach. AB - The photocatalytic degradation of Reactive Black 5 (RB 5), a di-azo dye was investigated over M/TiO2 (M = Ag, Au and Pt) photocatalysts irradiated with UV and visible light. TiO2 was prepared by sol-gel technique (Syn-TiO2). Photodeposition of metal salt precursors over Syn-TiO2 was carried out so as to obtain 1 wt% of M/TiO2 catalysts. The photodecolourization and photodegradation reactions were also compared with commercial TiO2 (Degussa P25) catalyst. Kinetic studies for the decolourization of RB 5 showed that it followed pseudo first order. Recycling of catalysts was performed to check the economic feasibility of the photocatalytic process. In order to check the applicability of M/TiO2 catalyst in the treatment of industrial effluent, real textile effluent was collected from an industry and subjected to photodegradation and the results are presented. Enhanced activity of M/TiO2 catalyst under visible light irradiation highlights its importance in the field of photocatalysis. PMID- 22214050 TI - Arsenic removal by ferric-chloride coagulation--effect of phosphate, bicarbonate and silicate. AB - Jar tests with synthetic water were carried out in order to investigate the effect of phosphate, bicarbonate and silicate on arsenic removal efficiency by in situ formed ferric hydroxide. Above 12 mg C/L inorganic carbon concentration, the adverse effect of bicarbonate was definite, and resulted in higher remaining arsenic concentration. At all pH values (7.5-7.8) and coagulant dosages (0.84 3.00 mg/L Fe) tested, the negative effect of phosphate on arsenic removal was also evident. In the presence of silicate small ferric-hydroxide colloids were formed, which were able to go through the 0.45 microm pore-size membrane. Compared to silicate-free systems, 2.5-3.5 times higher coagulant dose was needed to achieve the target arsenic concentration in the presence of 14-23 mg/L Si. At higher pH values the adverse effect of silicate was even more significant. All data were merged and multiple linear regression analysis was carried out in order to build up a robust model to predict the residual arsenic concentration if the raw water contains 50-60 microg/L initial arsenic concentration. The estimation was based on the following variables: PO4-P concentration, final pH, Si concentration, Fe(III) dose. The most important influencing factors proved to be the silicate concentration and applied coagulant dosage. PMID- 22214051 TI - Tracer studies and hydraulic behaviour of planted and un-planted vertical-flow constructed wetlands. AB - The aim of this research was to assess the hydraulic behaviour of three intermittently-fed vertical flow wetland units operated in parallel, designed for the treatment of raw wastewater generated in the city of Belo Horizonte, Brazil. The system was designed to serve 100 PE (-1 m2/PE). The first filter was planted with cattail (Typha latifolia), the second with Tifton-85 (Cynodon spp.) and the third was maintained without plants (control unit). NaCl tracer tests were conducted to determine the residence time distribution. The tests were done with water when the system was unused (clean media) and also after an 11-month operation period with wastewater (used media), using two different dosing regimes (lower and higher frequency). Results showed a strong tendency towards the hydraulic completely mixed regime. A great dispersion in the units and the presence of short circuiting and dead zones were observed. The unsaturated condition in a large volume of the filter, even during the draining stage, was confirmed for the three units. The dosing regime, the resting period duration, the age of the filter and the presence of plants were found to influence the hydraulic processes in the units. PMID- 22214052 TI - Treatment performance and microbial characteristics in two-stage membrane bioreactor applied to partially stabilized leachate. AB - A two-stage membrane bioreactor system was applied to the treatment of partially stabilized leachate from solid waste landfill in Thailand. In the system, an anoxic tank with incline tube for biomass separation from re-circulated sludge is followed by a second-stage aerobic tank in which a direct submerged hollow-fiber membrane module is used for solid-liquid separation. During steady operation of 200 days, BOD, COD, NH3 and TKN removals were found to be 99.6, 68, 89 and 86% respectively. Determination of nitrogen transforming bacteria by fluorescent in situ hybridization technique revealed a slightly higher percentage of nitrifying bacteria in the aerobic tank and a higher percentage of denitrifying bacteria in the anoxic tank respectively. Anammox-like bacteria were also detected at relatively high percentage. PMID- 22214054 TI - An application of Austrian legal requirements for CSO emissions. AB - The Austrian standard for designing combined sewer overflow (CSO) detention basins introduces the efficiency of the combined sewer overflows as an indicator for CSO pollution. Additionally criteria for the ambient water quality are defined, which comprehend six kinds of impacts. In this paper, the Austrian legal requirements are described and discussed by means of hydrological modelling. This is exemplified with the case study Innsbruck (Austria) including a description for model building and model calibration. Furthermore an example is shown in order to demonstrate how - in this case- the overall system performance could be improved by implementing a cost-effective rearrangement of the storage tanks already available at the inflow of the wastewater treatment plant. However, this guideline also allows more innovative methods for reducing CSO emissions as measures for better usage of storage volume or de-centralised treatment of stormwater runoff because it is based on a sewer system simulation. PMID- 22214053 TI - Exposure to dust, endotoxin and airborne microorganisms in wastewater sludge thermal drying units. AB - The objective of this study was to assess workers' exposure to bioaerosols in sludge drying units. Simultaneous collection of inhalable dust and airborne biological agents was carried out using rotating cup samplers (CIP 10, Arelco). Sixteen stationary and 30 personal measurements were performed in three drying plants, during summer and winter. Microbial content of air was characterized by high amounts of Gram-negative bacteria, endotoxin, and thermophilic actinomycetes. High differences between exposure levels were observed with regard to workplaces and tasks. Dryers and conveyors in operation were closed, and the monitoring task in the dryer room was associated with low levels of personal exposure, close to background levels. Conversely, cleaning and maintenance of the dryer and conveyors required the equipment to be opened, giving significantly higher task-based personal exposure levels. The fall of dried sludge into indoor containers resulted in high emission and spreading of dust. Mean personal exposure levels to fungi were moderate or low for all tasks. Based on the results of this study, appropriate means of operational control and personal protection are being developed and implemented on sites. PMID- 22214055 TI - Energy savings by reduced mixing in aeration tanks: results from a full scale investigation and long term implementation at Avedoere wastewater treatment plant. AB - The aim of this project was to investigate the potential of reducing number of mixers in the biological treatment process and thereby achieve energy and economical savings and contribute to cleaner environment. The project was carried out at Avedoere wastewater treatment plant and a full scale investigation was conducted to study the effect of reduced mixing on flow velocity, suspended solid sedimentation, concentration gradients of oxygen and SS with depth and treatment efficiency. The only negative effect observed was on flow velocity; however the velocity was above the critical velocity. The plant has been operating with 50% of its designed number of mixers since September 2007 and long term results also confirm that reduced mixing did not have any negative effect on treatment efficiency. The estimated yearly electricity saving is 0.75 GWh/year. PMID- 22214056 TI - On the use of non-negative matrix factorisation to characterise wastewater from dairy processing plants. AB - A portable field spectrometer was used to record the time-resolved ultraviolet/visible (UV/Vis) spectrum of the effluent stream at two different dairy processing plants (a Drier Plant and Cheese Factory). The spectra exhibited significant variability. As an alternative to the partial least squares regression methods usually used in the online UV/Vis field a non-negative matrix factorisation technique was employed to compress the spectral data. One of the extracted basis vectors had a physical shape associated with protein absorption. The weightings associated with the basis vector explained 80% of the variability in protein concentration as measured with traditional grab sampling techniques (increasing to 94% with a further three vectors), allowing the spectrometer to be retrospectively calibrated to continuously measure protein. PMID- 22214057 TI - Effect of upflow velocity on the performance of an inclined plate membrane bioreactor treating municipal wastewater. AB - An inclined plate membrane bioreactor (iPMBR) was introduced to meet the challenge of handling high mixed liquor suspended solids when operating at long sludge retention times. During the first 407 days of operation, the iPMBR was able to rezone more sludge (1.5-10.5 times greater) in its upstream, anoxic tank compared to its downstream, aerobic tank. This could extend membrane filtration by diverting most of the sludge from the aerobic zone. During this period, the upflow velocities through the inclined plates of the anoxic tank ranged from 2.3 x 10(-4) to 7.7 x 10(-4) m/s. After Day 407, the operating conditions were changed to determine whether the iPMBR would fail to create a sludge concentration difference between its two tanks. When the upflow velocity was increased to 1.8 x 10(-3) m/s, the sludge concentration difference between the two zones was removed. This indicated that the upflow velocity had increased sufficiently to overcome the settling velocities of most flocs, resulting in more solids being carried from the anoxic to the aerobic tank. For the configuration of this iPMBR, operating at flow rates where the upflow velocity through the inclined plates was less than 1.0 x 10(-3) m/s would be necessary to keep a significant sludge concentration difference between its two zones. PMID- 22214058 TI - Flow measurements in sewers based on image analysis: automatic flow velocity algorithm. AB - Discharges of combined sewer overflows (CSOs) and stormwater are recognized as an important source of environmental contamination. However, the harsh sewer environment and particular hydraulic conditions during rain events reduce the reliability of traditional flow measurement probes. An in situ system for sewer water flow monitoring based on video images was evaluated. Algorithms to determine water velocities were developed based on image-processing techniques. The image-based water velocity algorithm identifies surface features and measures their positions with respect to real world coordinates. A web-based user interface and a three-tier system architecture enable remote configuration of the cameras and the image-processing algorithms in order to calculate automatically flow velocity on-line. Results of investigations conducted in a CSO are presented. The system was found to measure reliably water velocities, thereby providing the means to understand particular hydraulic behaviors. PMID- 22214059 TI - The application of model predictive control of ammonia nitrogen in an activated sludge process. AB - In this paper a model predictive controller (MPC) for ammonia nitrogen is presented and evaluated in a real activated sludge process. A reduced nonlinear mathematical model based on mass balances is used to model the ammonia nitrogen in the activated sludge plant. An MPC algorithm that minimises only the control error at the end of the prediction interval is applied. The results of the ammonia MPC were compared with the results of the ammonia feedforward-PI and ammonia PI controllers from our previous study. The ammonia MPC and ammonia feedforward-PI controller give better results in terms of ammonia removal and aeration energy consumption than the ammonia PI controller because of the measurable disturbances used. On the other hand, with the ammonia MPC, comparable or even slightly poorer results than with the ammonia feedforward-PI controller are obtained. Further improvements to the MPC could be possible with an improved accuracy of the nonlinear reduced model of the ammonia nitrogen, more sophisticated control criteria used inside the controller and the extension of the problem from univariable ammonia to multivariable total nitrogen control. PMID- 22214060 TI - Comparison of nitrogen elimination rates of different constructed wetland designs. AB - In this paper the nitrogen elimination rates of different constructed wetland (CW) designs reported in literature are compared with those obtained for outdoor and indoor 2-stage vertical flow (VF) systems. The outdoor system is located about 150 km west of Vienna. Both stages are planted with Phragmites australis and the system has been operated for 4 years continuously. During this period the average value of the nitrogen elimination rate was 3.30 g N m(-2) d(-1). The indoor system comprises three parallel operated 2-stage VF systems and is located in the technical lab hall at BOKU University. The design of the indoor system resembles the outdoor system. However, there are a few differences: (1) the indoor systems are not planted, and (2) different filter media have been used for the main layer of the first stages. With the indoor system the highest nitrogen elimination rate achieved was 2.24 g N m(-2) d(-1) for the system with zeolite and impounded drainage layer. Similar results have been found in France for treating raw wastewater with VF and horizontal flow (HF) beds in series with nitrogen elimination rates of 1.89 and 2.82 g N m(-2) d(-1) for differently designed HF beds. The highest nitrogen elimination rates of 15.9 g N m(-2) d(-1) reported were for pilot-scale VF CWs treating high-strength synthetic wastewater (total nitrogen of 305 mg L(-1) in the influent) in Thailand. It has been shown that the outdoor two-stage VF CW system has one of the highest nitrogen elimination rates of CWs treating domestic wastewater. PMID- 22214061 TI - Adaptive predictive expert control of dissolved oxygen concentration in a wastewater treatment plant. AB - In this paper we present the application of adaptive predictive expert controllers to dissolved oxygen (DO) control in the aerobic reactors of a wastewater treatment plant. The control system described in this paper consists of adaptive predictive expert control loops complemented by optimisation logic. The controllers successfully cope with nonlinearity and changing operating conditions of the process by predicting the evolution of the controlled variable and adapting to changes in the process dynamics. This results in more precise and stable DO control, offering many benefits. The complementary optimisation logic maintains the air pressure in the common collector at the lowest possible level, enabling adequate DO control and thus considerably reducing energy consumption. PMID- 22214062 TI - Long-term behaviour of a two-stage CW system regarding nitrogen removal. AB - In the first two years of operation a nitrogen removal efficiency of 53% and a high average elimination rate of 1,000 g N m(-2) yr(-1) could be observed for a two-stage vertical flow (VF) constructed wetland (CW) system. The two-stage system consists of two VF beds with intermittent loading operated in series, each stage having a surface area of 10 m2. The first stage uses sand with a grain size of 2-3.2 mm for the 50 cm main layer and has a drainage layer that is impounded; the second stage sand with a grain size of 0.06-4 mm and a conventional drainage layer (with free drainage). The two-stage VF system was designed for and operated with an organic load of 40 g COD m(-2) d(-1) (i.e. 2 m2 per person equivalent). Data from the following years of operation showed that from the third year nitrogen elimination increased and stabilized. The median values of the nitrogen elimination rate in the first five years of operation have been 3.51, 2.76, 4.20, 3.84 and 4.07 g N m(-2) d(-1), the median value of the last three years being 3.8 g N m(-2) d(-1) and 1,380 g N m(-2) yr(-1), respectively, and the nitrogen removal > 60%. It can be assumed that the vegetation as well as the biofilm development in the two-stage VF CW system plays the major role for the enhancement of the nitrogen elimination rate. PMID- 22214063 TI - A two-sludge system for simultaneous biological C, N and P removal via the nitrite pathway. AB - Nitrogen removal via the nitrite pathway results in significant savings in both aeration costs and COD requirements for denitrification when compared to the conventional biological nitrogen removal process. Implementation of the nitrite pathway for simultaneous C/N/P removal in a single sludge system has a major drawback: the aeration phase disfavours denitrifying phosphorus removal. A possible configuration to overcome this issue is the utilisation of a two-sludge system where autotrophic and heterotrophic populations are physically separated. This paper experimentally demonstrates the feasibility of a nitrite-based two sludge system with sequencing batch reactors (SBR) for the treatment of urban wastewater: a heterotrophic SBR with denitrifying PAOs for P removal and an aerobic SBR for N removal. Partial nitrification was attained in the autotrophic SBR so that shortcut biological nitrogen removal was achieved by using the anoxic dephosphatation activity of DPAOs. Finally, the effect of operating this system without pH control was studied using different influent pH values (pH = 6.8, 7.5 and 8.2) and, despite some efficiency lost due to the pH fluctuations, the system was able to remove most of the C, N and P present in the wastewater. PMID- 22214064 TI - Social benchmarking to improve river ecosystems. AB - To complement physical measures or indices of river health a social benchmarking instrument has been developed to measure community dispositions and behaviour regarding river health. This instrument seeks to achieve three outcomes. First, to provide a benchmark of the social condition of communities' attitudes, values, understanding and behaviours in relation to river health; second, to provide information for developing management and educational priorities; and third, to provide an assessment of the long-term effectiveness of community education and engagement activities in achieving changes in attitudes, understanding and behaviours in relation to river health. In this paper the development of the social benchmarking instrument is described and results are presented from the first state-wide benchmark study in Victoria, Australia, in which the social dimensions of river health, community behaviours related to rivers, and community understanding of human impacts on rivers were assessed. PMID- 22214065 TI - Effect of membrane characteristics on the performance of membrane bioreactors for oily wastewater treatment. AB - Influence of membrane material and pore size on the performance of a submerged membrane bioreactor (sMBR) for oily wastewater treatment was investigated. The sMBR had a working volume of about 19 L with flat sheet modules at the same hydrodynamic conditions. Five types of micro- and ultra-polymeric membranes containing cellulose acetate (CA), cellulose nitrate (CN), polyamide (PA), polyvinylidene difluoride (PVDF) and polyethersulfone (PES) were used and their filtration performance in terms of permeability, permeate quality and fouling intensity were evaluated. Characterization of the membranes was done by performing some analysis such as pore size distribution; contact angle and scanning electronic microscopy (SEM) microphotograph on all membranes. The quality of permeates from each membrane was identified by measuring chemical oxygen demand (COD). The results showed more irreversible fouling intensity for membranes with larger pore size which can be due to more permeation of bioparticles and colloids inside the pores. Membrane characteristics have a major role in the preliminary time of the filtration before cake layer formation so that the PA with the highest hydrophilicity had the lowest permeability decline by fouling in this period. Also, the PVDF and PES membranes had better performance according to better permeate quality in the preliminary time of the filtration related to smaller pore size and also their better fouling resistance and chemical stability properties. However, all membranes resulted in the same permeability and permeate quality after cake layer formation. An overall efficiency of about 95% in COD removal was obtained for oily wastewater treatment by the membranes used in this study. PMID- 22214066 TI - Water quality management of aquifer recharge using advanced tools. AB - Managed aquifer recharge (MAR) with recycled water or other alternative resources is one of the most rapidly growing techniques that is viewed as a necessity in water-short areas. In order to better control health and environmental effects of MAR, this paper presents two case studies demonstrating how to improve water quality, enable reliable tracing of injected water and better control and manage MAR operation in the case of indirect and direct aquifer recharge. Two water quality management strategies are illustrated on two full-scale case studies, including the results of the combination of non conventional and advanced technologies for water quality improvement, comprehensive sampling and monitoring programs including emerging pollutants, tracer studies using boron isotopes and integrative aquifer 3D GIS hydraulic and hydrodispersive modelling. PMID- 22214067 TI - Treatment of wastewater from a school in a decentralized filtration system by percolation over organic packing media. AB - Based on results obtained in the laboratory a WWTP composed of a septic tank and an aerated percolating filter packed with organic media was built for a school. The system can treat 18 m3 d(-1) and was operated with a hydraulic loading rate of 0.078 (m3 m(-2) d(-1). For 360 days different operational conditions including start-up; stabilization; operation with aeration and non aeration; effect of rainy season, breaks from activities due to holidays and restart; were monitored and described in the article. Once stabilized, the system was able to remove, without the need for mechanical aeration, 97% of BOD5, 71% of COD, 93% of TKN, 11% of PO(4-)-P, 95% of TSS, 96% of VSS, in addition to having a removal efficiency of 4 log units of Faecal Coliforms (FC) and 100% helminthes eggs (HE). With this quality, the treated wastewater can be chlorinated and reused to irrigate green areas and/or in toilets. Although sanitary wastewater has a high concentration of Total-N (250 mg L(-1)) and a C/N ratio of less than 1, the system removed 65% of Total-N. Finally it was observed that after non activity periods, there was neither system failure nor the need to re-stabilize the system. PMID- 22214068 TI - Solar disinfection for the post-treatment of greywater by means of a continuous flow reactor. AB - SODIS (solar disinfection) is a low-cost alternative for water decontamination. The method is based on the exposure of water, contained in PET bottles, to direct sunlight, and mainly its UV-A and infrared components. The present research studied SODIS as a low cost alternative for the inactivation of Escherichia coli (E. coli) in treated greywater, aiming at its reuse for more noble applications. Experiments were performed in (i) batch mode (2 L PET-bottles), testing the effect of turbidity on system efficiency and, (ii) in a continuous pilot-scale reactor prototype (51 L, using interconnected 2 L-PET bottles), testing hydraulic retention times (HRT) of 18 and 24 h. Samples were exposed to an average solar radiation intensity of 518 W/m2. The results obtained indicate that the SODIS system has potential for total coliforms and E. coli inactivation in the pre treated greywater, reaching 2.1 log units E. coli inactivation in batch experiments for low turbidity samples (21 NTU), and > 2 log units inactivation of total coliforms (and E. coli, when present) for the 24 h HRT-continuous prototype. The continuous flow prototype needs more testing and structural improvements to cope with the difficulties posed by algae growth, as they complicate maintaining conditions of constant flow and make frequent maintenance inevitable. PMID- 22214069 TI - Statistical assessment of seafront and beach water quality of Mumbai, India. AB - The water quality of seafronts and beaches of Mumbai is under pressure and deteriorating due to discharge of partially treated sewage and wastewater through point and nonpoint sources. The objective of the study was to assess the water quality and to correlate physico-chemical and bacteriological parameters for establishing relationship, association and dependence on each other. The water quality parameters were selected as per SW II standards specified by Central Pollution Control Board, India and nutrient parameters as strong indicators of sewage pollution. Box and whisker plots were generated for evaluating spatio temporal variation of water quality which suggest influence of organic pollution mostly at Mahim and Dadar in the form of outliers and extremes. Pearson's correlations were estimated between parameters and found significant correlation with each other indicating influence of sewage on water quality. The water quality of beaches and seafronts were found unsafe for recreational purposes. The study suggested that designated water quality can be achieved by restricting nonpoint source through improvement in wastewater collection systems, appropriate level of treatment and proper disposal. PMID- 22214070 TI - Microalgae growth for nutrient recovery from sludge liquor and production of renewable bioenergy. AB - Proof-of-concept has been demonstrated for a process that will utilize nutrients from sludge liquor, natural light, and CO2 from biogas to grow microalgae at wastewater treatment plants. This process will reduce the impact of returning side-streams to the head of the plant. The produced algae will be fed to anaerobic digesters for increased biogas production. Dewatering of anaerobically digested sludge in centrifuges produces reject water with extremely low transmittance of light. A pretreatment procedure was developed that improved light transmittance for reject water from the FREVAR, Norway, wastewater treatment plant from 0.1% T to 77% T (670 nm, 1 cm path). Chlorella sp. microalgae were found to be suitable for growth in this pre-treated reject water. Typical nitrogen removal was 80-90 g N/kg TSS of produced microalgae. The microalgae were successfully harvested by chemically assisted flocculation followed by straining through a 33 microm sieve cloth, achieving up to 99% recovery. Harvested algae were anaerobically co-digested with wastewater sludge. The specific methane gas production (mL CH4/g VS fed) for the algae varied from less than 65% to 90% of the specific methane gas production for the wastewater sludge, depending on digester temperature, retention time and pre-treatment of the algae biomass. PMID- 22214071 TI - One-year monthly survey of rotavirus, astrovirus and norovirus in three sewage treatment plants (STPs) in Beijing, China and associated health risk assessment. AB - To evaluate the presence and distribution of the three main viruses (rotavirus, astrovirus, and norovirus) responsible for human acute gastroenteritis in sewerage systems, a one-year study was carried out in Beijing, China. A total of 96 samples of influent and effluents from three sewage treatment plants (STPs) were collected from November 2006 to October 2007. Silica was used to concentrate viral particles from water samples and a reverse transcriptase-nested polymerase chain reaction (RT-nested PCR) method was used for detection of viruses. Virus(es) could be detected in 35.4% (34/96) of the water samples analysed, where human rotavirus was the most frequently detected one (32.3%, 31/96), followed by human astrovirus (6.3%, 6/96) and human norovirus (3.1%, 3/96). According to the quantitation results of rotaviruses, which were gained by the real-time quantitative RT-PCR method with SYBR Green I, it was known that the distributions of rotaviruses in influents and effluents of three STPs were quite similar, i.e., abundant in cold weather (from October to March) and less prevalent in warm weather (from April to September). According to the estimated exposure dose and exposure frequency, as well as the acceptable annual risk level, it was shown that the rotaviruses in the reused wastewater after conventional treatment process presented potential risk to human health through both occupational and accidental exposure. PMID- 22214072 TI - Laboratory study on factors influencing nitrogen removal in marble chip biofilters incorporating nitritation and anammox. AB - It remains challenging to integrate nitritation and anammox in ecologically engineered treatment systems such as passive biofilters that are packed with natural materials and have low energy inputs. This study explored the factors influencing nitritation-anammox through parallel operation of two laboratory scale biofilters packed with large and small marble chips respectively. Clean marble chips (mainly CaCO3) had an alkalinity dissolution rate of 130 mg CaCO3/kg marble d when water pH approached 6.5. Marble chips effectively increased water pH and provided sufficient alkalinity to support nitritation-anammox in the biofilters. Ammonium and total nitrogen removal decreased by 47 and 26%, respectively, when nutrients were not amended to influent. An influent nitrite concentration above 8.9 mg N/L could inhibit anammox in thin biofilms of biofilters. Nitritation-anammox was enhanced with a hydraulic retention time of 2 d relative to 7 d, likely due to enhanced air entrainment. Size of marble chips rarely made a significant difference in nitrogen removal, possibly due to sufficient surface area available for bacterial attachment and alkalinity dissolution. PMID- 22214073 TI - Operation of a full-scale pumped flow biofilm reactor (PFBR) under two aeration regimes. AB - A novel technology suitable for centralised and decentralised wastewater treatment has been developed, extensively tested at laboratory-scale, and trialled at a number of sites for populations ranging from 15 to 400 population equivalents (PE). The two-reactor-tank pumped flow biofilm reactor (PFBR) is characterised by: (i) its simple construction; (ii) its ease of operation and maintenance; (iii) low operating costs; (iv) low sludge production; and (v) comprising no moving parts or compressors, other than hydraulic pumps. By operating the system in a sequencing batch biofilm reactor (SBBR) mode, the following treatment can be achieved: 5-day biochemical oxygen demand (BOD5), chemical oxygen demand (COD) and total suspended solids (TSS) reduction; nitrification and denitrification. During a 100-day full-scale plant study treating municipal wastewater and operating at 165 PE and 200 PE (Experiments 1 and 2, respectively), maximum average removals of 94% BOD5, 86% TSS and 80% ammonium-nitrogen (NH4-N) were achieved. During the latter part of Experiment 2, effluent concentrations averaged: 14 mg BOD5/l; 32 mg COD(filtered)/l; 14 mg TSS/l; 4.4 mg NH4-N/l; and 4.0 mg NO3-N/l (nitrate-nitrogen). The average energy consumption was 0.46-0.63 kWh/m3(treated) or 1.25-1.76 kWh/kg BOD5 removed. No maintenance was required during these experiments. The PFBR technology offers a low energy, minimal maintenance technology for the treatment of municipal wastewater. PMID- 22214074 TI - Effect of the disinfection agents chlorine, UV irradiation, silver ions, and TiO2 nanoparticles/near-UV on DNA molecules. AB - Extracellular DNA in municipal wastewater and effluents from hospitals and R&D laboratories contains antimicrobial resistance and recombinant genes that are today considered as a new class of emerging contaminants. The objective of this research was to investigate the effect of disinfection agents on the integrity of DNA molecules by using real-time PCR. Escherichia coli cell suspensions and genomic DNA in aqueous solution were exposed to increasing doses of disinfection systems, including chlorination, UV irradiation, silver ions, and TiO2 nanoparticles/near-UV. The doses resulting in damage of DNA (16S rDNA) were determined using real-time PCR and compared with the doses resulting in the inactivation of bacterial cells. Our results showed that the disinfection agents chlorine, UV, and silver significantly inhibited the amplification of a fragment of 16S rDNA, but only when applied at doses much higher than the lethal doses for E. coli bacteria. The inactivation doses of TiO2 nanoparticles/near-UV were of the same order of magnitude for both DNA and living cells. Our results raise questions about the efficacy of disinfection processes to destroy and prevent the dispersion of DNA pollutants into the environment. In addition, the damage of DNA by high levels of disinfectants may have implications for the utilization of PCR based methods for bacterial detection. PMID- 22214075 TI - Phytotreatment of sludges (Phragmites australis) for their reuse in the environment. AB - The aim of this study is the evaluation of the agronomic characteristics acquired by a phytotreated sludge coming from a wastewater treatment plant (WWTP) located in Tuscany (central Italy). The chemical characterization showed values which are within the Italian legislation limits for mixed composts. From an agronomic point of view, the sludge did not present a level of phytotoxicity, as shown by the germination index (GI% = 77). Furthermore, pathogen compounds are inexistent (Escherichia coli < 1,000 CFU/g). Different substrates (obtained by mixing the sludge with sandy agronomic soil - 0.5% w/w, 1% w/w, 2.5% w/w and 5% w/w) were prepared in order to evaluate the best mixture performance in terms of water retention capacity and plant growth. No significant differences were observed for all sludge mixtures. Different plants were tested in plots (Lepidium sativum, Cucumis sativus and Avena sativa). The best plant adaptation, measured as dry biomass production, was observed for Avena sativa. The results obtained underlined that the phytotreatment of sludge can bring about the transformation of sewage sludges into organic products that are reusable in agriculture, if previously mixed with other appropriate materials and taking into account their heavy metal content. PMID- 22214076 TI - Biological treatment of toluene contaminated wastewater by Alcaligenese faecalis in an extractive membrane bioreactor; experiments and modeling. AB - Conventional wastewater treatment methods are not efficient in treating wastewaters contaminated with volatile hydrocarbons such as benzene, toluene and xylenes (BTX). The aim of this study is to enhance the efficiency of an extractive membrane bioreactor (EMBR) in treating toluene contaminated wastewater by usage of pure culture of Alcaligenese faecalis. Toluene was used as a model of toxic contaminant because of its wide presence in wastewaters contaminated with petrol derivatives. The Haldane kinetic model adequately described the dynamic behavior of the toluene biodegradation by the strain of A. faecalis over a wide range of initial toluene concentrations (50-1,000 mg L(-1)) with kinetic constants micro(max) = 0.066 h(-1), k(s) = 91.7 mg/L and k(I) = 278.2. Overall mass transfer coefficient has been measured and described as resistance in the series model. No biofilm formed on the exterior surface of the membrane; however in previous works the layer of the biofilm on the exterior surface of the membrane acts as a mass transfer resistance. A mathematical model was developed to predict the pollutant concentration profile along the tube side of the membrane modules. PMID- 22214077 TI - Exploring the potential synergistic effects of chemical disinfectants and UV on the inactivation of free-living bacteria and treatment of biofilms in a pilot scale system. AB - The main objective of this study is to explore possible synergistic or additive effects of combinations of chemical disinfectants (sodium hypochlorite, peracetic acid, hydrogen peroxide, chlorine dioxide) and UV in their efficacy in inactivating free-living bacteria and removing biofilms. In contrast to most studies, this study examines disinfection of municipal water in a pilot-scale system using a mixed bacterial suspension, which enables a better simulation of the conditions encountered in actual industrial environments. It was shown that the combination of either hypochlorite, hydrogen peroxide, peracetic acid, or chlorine dioxide with UV yielded additive effects on the inactivation of free living bacteria. Actual synergy was observed for the combination of UV and 5 ppm hydrogen peroxide. Regarding biofilm treatment, additive effects were observed using the combination of hydrogen peroxide and UV. The promising results obtained in this study indicate that the combination of UV and chemical disinfectants can considerably reduce the amount of chemicals required for the effective disinfection and treatment of biofilms. PMID- 22214078 TI - Considerations for the mitigation of nitrate contamination: stable isotopes and insights into the importance of soil processes. AB - Nutrient management is widely promoted to minimize the impact of intensive fertilizer use on groundwater quality, however watershed-scale stable isotope studies in eastern North America suggest nitrogen transport to groundwater is dominated by non-growing season fluxes derived principally from the mineralization and nitrification of soil organic matter. In the current field scale study, delta15N ratios of nitrate in tile drain effluents from experimental potato plots treated with 300 kg/ha ammonia nitrate and those with no fertilizer both average +4.7 per thousand, close to the +4.0 per thousand ratios observed in soils of the same plots, and distinct from values near 0 per thousand for inorganic fertilizer. A source apportionment model using delta15N and delta18O in nitrate suggests that even with heavy fertilizer application, less than 10% of non-growing season N flux is derived from direct leaching of fertilizer, the remainder representing N from various sources, including residual fertilizer that has been assimilated into the broader soil organic matter pool and subsequently released via mineralization and nitrification. Factors controlling these losses could be as closely related to cropping practices as initial N application rates, providing potential opportunities for more efficiently utilizing N available in the soil profile and reducing initial N application rates. PMID- 22214079 TI - Influence of environmental factors on abundance and temporal variation of benthic fauna resources in the eutrophic Tha Chin estuary, Samut Sakhon province, Thailand. AB - The influence of environmental factors on the abundance and temporal variation of benthic fauna resources was studied in the eutrophic Tha Chin estuary located in Samut Sakhon province. The objectives were to analyze the status of abundance and temporal variation of the benthic fauna and to clarify the impacts from environmental factors (water and sediment quality). Field surveys were conducted monthly from August 2007 to March 2008 at 11 sampling stations in the estuary. Based on freshwater runoff volumes, the high-, medium-, and low-loading periods were categorized to be from August to October 2007, November to December 2007, and January to March 2008, respectively. The benthic fauna resources were composed of 57 species in eight phyla. Annelids were the dominant species (with the maximum density being 19,885 individuals/m2), followed by the mollusks. Both densities decreased during the low-loading period in 2008. Water quality deteriorated during the high-loading period. Land-based wastewater discharges decreased the levels of salinity and dissolved oxygen but dramatically increased various nutrients. Consequently, the sediment quality deteriorated during the medium-loading period. Bottom deposits during this time depicted high accumulation of acid volatile sulfides (more than 0.76 mg/g dry weight). Analyzing the environmental relationships, deposit feeders (for example, Nereis sp. and Prionospio sp.) and a clam (Arcuatula sp.) showed potential as bio indicators for environmental monitoring. The overall results revealed the importance of changes in the water and sediment qualities that had an influence on related benthic resources. The increase in the level of NH4(+)-N had a negative impact on the economic clam species, while the sedimentary TOM showed positive correlation (P < 0.05) with this increase. The succession of groups based on feeding behavior seemed to correspond with stress in eutrophication along the salinity gradient and in different estuarine parts. In addition, the economic clam population decreased noticeably during the medium-loading period, as a consequence of deteriorated sediment conditions. Thus, the land-based runoff should be controlled for the protection of resources. Further effective sustainable management will be enhanced by giving serious consideration to an eco based zoning scheme for conservation and restoration of the Tha Chin estuary. PMID- 22214080 TI - The effect of pre-ozonation and subsequent coagulation on the filtration of WWTP effluent with low-pressure membranes. AB - The impact of a pre-treatment by pre-ozonation (2-10 mg O3/L) and subsequent coagulation (FeCl3: 2-6 mg Fe3+/L) on the performance of a polymeric ultrafiltration membrane was investigated in lab scale. The performance was assessed by monitoring the flux decline during filtration of secondary effluent in Amicon test cells. During the filtration process no free dissolved ozone was in contact with the membrane. It was observed that flux decline is reduced with increasing coagulant concentration as well as with increasing ozone dosage. This effect involves a reduction in the amount of biopolymers measured by size exclusion chromatography (LC-OCD). Moreover, multi-filtration cycles revealed that pre-ozonation leads to a significant increase in irreversible fouling that might be caused by increasing colloidal iron concentrations. Phosphorus in the permeate was successfully reduced to concentrations < 60 microg/L. PMID- 22214081 TI - Application of the biotic ligand model to predict copper acute toxicity to Medaka fish in typical Chinese rivers. AB - LA50, the Lethal Accumulation of Cu on the Medaka fish (Oryzias latipes) gills that results in 50% mortality during a toxicological exposure (96 hours) in synthetic water was assessed by use of the biotic ligand model (BLM). The LA50 was employed to predict the 96 h Cu toxicity (LC50) to this fish in different natural surface waters in China. The LC50 values were predicted with errors of no more than 1.55 for the river water except for two water samples, one of which was from a tidal river and the other of which was from a river that was subject to joint metal pollution and possibly affected by other pollutants. PMID- 22214082 TI - Effect of interspecies quorum sensing on the formation of aerobic granular sludge. AB - Quorum sensing (QS) is a form of microbial communication that relies on small signal molecules to regulate group behaviors such as biofilm formation in response to population density. In this study, we attempted to apply the paradigm of bacterial QS to aerobic granular sludge (AGS) formation for wastewater treatment. An essential element of interspecies QS signals, boron, was added to a sequencing batch reactor (SBR) to stimulate AGS growth. Bioassays elaborated the activity of autoinducer-2 (AI-2). We found that boron accelerated AGS growth, resulting in improved settlement performance and increased biomass in the SBR. During continuous SBR operation, the AGS showed an obvious increase in AI-2 activity, which implies that interspecies QS was closely associated with AGS formation. Analysis of EPS showed that boron stimulated tryptophan production, and increased the hydrophobia of AGS. From these results, it was speculated that the addition of boron may have promoted the formation of boron complexed to (R) 4, 5-dihydroxy-2,3-pentanedione (DPD) as the precursor of AI-2, which resulted in accelerated interspecies QS. The results also suggested QS as a novel regulation target for the biogranulation process, such as AGS formation. PMID- 22214083 TI - Removal of 17beta-estradiol (E2) and its chlorination by-products from water and wastewater using non-imprinted polymer (NIP) particles. AB - Endocrine disrupting compounds and their chlorination by-products are two classes of emerging contaminants. Surface water and wastewater treatment technologies have limitations in removing these contaminants. This study evaluated the ability of non-imprinted polymer particles (NIP) to remove the endocrine disruptor 17beta estradiol (E2) and its chlorination by-products from water and wastewater. NIP effectively removed 98% of 10 mg/L E2 from wastewater. NIP were also effective in removing chlorination by-products of E2 by 84.9% after 10 mg/L E2 in water was chlorinated at 5 mg/L. In the presence of 5 mg/L humic acid, NIP were able to achieve removal of 10 mg/L E2 by greater than 99.9%. Furthermore, after chlorination of 10 mg/L E2 and 5 mg/L humic acid at 10 mg/L chlorine, NIP were also able to remove the chlorination by-products formed as well as the remaining E2 by greater than 99.9%. The presence of 5 mg/L humic acid did not adversely affect the adsorption efficiency. The results of this research indicate that NIPs have good potential as a final treatment step for surface water and wastewater treatment. PMID- 22214084 TI - Enhanced nutrient removal MBR system with chemical addition for low effluent TP. AB - A pilot study was conducted to test an membrane bioreactor (MBR) process for combined biological and chemical P removal to achieve a very low effluent total phosphorus (TP) concentration of 0.025 mg P/L. With the data from the pilot test, a simulation study was performed to demonstrate that: (1) the pilot system behaviour (effluent quality, MLSS, etc.) can be modelled accurately with an activated sludge model combined with a chemical precipitation model; and (2) with the calibrated model, simulation scenarios can be performed to further understand the pilot MBR process, and provide information for optimizing design and operation when applied at full-scale. Results from the pilot test indicated that the system could achieve very low effluent TP concentration through biological P removal with a limited chemical addition, and chemical addition to remove P to very low level did not affect other biological processes, i.e., organic and nitrogen removal. Simulation studies indicate that the process behaviour can be modelled accurately with an activated sludge model combined with a chemical precipitation model, and the calibrated model can be used to provide information to optimize system design and operation, e.g., chemical addition control under dynamic loading conditions is important for maintaining biological P removal. PMID- 22214085 TI - Saline sewage treatment and source separation of urine for more sustainable urban water management. AB - While energy consumption and its associated carbon emission should be minimized in wastewater treatment, it has a much lower priority than human and environmental health, which are both closely related to efficient water quality management. So conservation of surface water quality and quantity are more important for sustainable development than green house gas (GHG) emissions per se. In this paper, two urban water management strategies to conserve fresh water quality and quantity are considered: (1) source separation of urine for improved water quality and (2) saline (e.g. sea) water toilet flushing for reduced fresh water consumption in coastal and mining cities. The former holds promise for simpler and shorter sludge age activated sludge wastewater treatment plants (no nitrification and denitrification), nutrient (Mg, K, P) recovery and improved effluent quality (reduced endocrine disruptor and environmental oestrogen concentrations) and the latter for significantly reduced fresh water consumption, sludge production and oxygen demand (through using anaerobic bioprocesses) and hence energy consumption. Combining source separation of urine and saline water toilet flushing can reduce sewer crown corrosion and reduce effluent P concentrations. To realize the advantages of these two approaches will require significant urban water management changes in that both need dual (fresh and saline) water distribution and (yellow and grey/brown) wastewater collection systems. While considerable work is still required to evaluate these new approaches and quantify their advantages and disadvantages, it would appear that the investment for dual water distribution and wastewater collection systems may be worth making to unlock their benefits for more sustainable urban development. PMID- 22214086 TI - The efficiency of asset management strategies to reduce urban flood risk. AB - In this study, three asset management strategies were compared with respect to their efficiency to reduce flood risk. Data from call centres at two municipalities were used to quantify urban flood risks associated with three causes of urban flooding: gully pot blockage, sewer pipe blockage and sewer overloading. The efficiency of three flood reduction strategies was assessed based on their effect on the causes contributing to flood risk. The sensitivity of the results to uncertainty in the data source, citizens' calls, was analysed through incorporation of uncertainty ranges taken from customer complaint literature. Based on the available data it could be shown that increasing gully pot blockage is the most efficient action to reduce flood risk, given data uncertainty. If differences between cause incidences are large, as in the presented case study, call data are sufficient to decide how flood risk can be most efficiently reduced. According to the results of this analysis, enlargement of sewer pipes is not an efficient strategy to reduce flood risk, because flood risk associated with sewer overloading is small compared to other failure mechanisms. PMID- 22214087 TI - Imprinted polymers for the removal of heavy metal ions from water. AB - In wastewater treatment, the removal of heavy metals is difficult due to the limited affinity of heavy metal ions to ion exchange resins. Here imprinting polymerization is used to develop resins with high capacity and selectivity for heavy metal ions for water treatment. A random copolymer of methacrylate and methacrylamide was found to be most effective for the removal of hydrophilic metal complexes, like CdCl2, ZnCI2, and the metalloid NaH2AsO4, particularly when the porosity of these resins is increased. For hydrophobic complexes imprinting emulsion polymerization was developed and data for the effective removal of mercury dithizonate will be described. Complete removal for up to 80 ppm of cadmium and mercury with only 200 mg of imprinted resin was obtained; competition and co-imprinting experiments are described as well. PMID- 22214088 TI - Further developments in self-fertilising geotextiles for use in pervious pavements. AB - Geotextiles incorporating inorganic nutrients (particularly phosphorous) to enhance the growth of oil degrading microoganisms when geotextiles are used in pervious pavement applications have been shown to be effective in the past. However the cost and manufacturing difficulties have been a barrier to their use. A polypropylene random mat geotextile incorporating an alternative polymer additive as a source of phosphorus has been investigated as a potential self fertilising geotextile. Experiments are reported which investigate nutrient leach rates, biofilm formation and biodegradation activity. PMID- 22214089 TI - Evaluation of the importance of various operating and sludge property parameters to the fouling of membrane bioreactors. AB - A single-fibre microfiltration system was employed to investigate the importance of various operating and sludge property parameters to the membrane fouling during sludge filtration. The sludge was obtained from a submerged membrane bioreactor (SMBR). A series of comparative and correlative filtration and fouling tests were conducted on the influence of the operating variables, sludge properties and the liquid-phase organic substances on the membrane fouling development. The test results were analysed statistically with Pearson's correlation coefficients and the stepwise multivariable linear regression. According to the statistical evaluation, the membrane fouling rate has a positive correlation with the biopolymer cluster (BPC) concentration, sludge concentration (mixed liquor suspended solids, MLSS), filtration flux and viscosity, a negative correlation with the cross-flow velocity, and a weak correlation with the extracellular polymeric substances and soluble microbial products. BPC appear to be the most important factor to membrane fouling development during the sludge filtration, followed by the filtration flux and MLSS concentration. The cross flow rate also is important to the fouling control. It is argued that, during membrane filtration of SMBR sludge, BPC interact with sludge flocs at the membrane surface to facilitate the deposition of the sludge cake layer, leading to serious membrane fouling. PMID- 22214090 TI - Feasibility of UASB/trickling filter systems without final clarifiers for the treatment of domestic wastewater in small communities in Brazil. AB - The paper analyses the concept and performance of different configurations of compact UASB/TF systems, without the final clarification stage, in relation to the removal of organic matter. The experiments were carried out in two sets of UASB/TF systems operating without secondary clarifiers, as follows: (i) four shallow (2.50 m height) TFs, each one filled with a different packing material; and (ii) two deep (4.20 m height) TFs, one filled with polyethylene corrugated sheets and the other with mixed polyethylene and sponge sheets. For the conditions tested (different packing material in shallow and deep TF), the UASB/TF systems had consistently complied (90 to 100% of the results) with the Brazilian discharge standards regarding to BOD, COD, and TSS parameters. The average BOD, COD and TSS effluent concentrations stayed below 40 mg BOD L(-1), 100 mg COD L(-1) and 50 mg TSS L(-1), respectively. UASB/TF systems can constitute an attractive alternative for domestic wastewater treatment in small communities in developing countries, especially considering its operational simplicity and very low running costs. PMID- 22214091 TI - Energy requirements for waste water treatment. AB - The actual mathematical models describing global climate closely link the detected increase in global temperature to anthropogenic activity. The only energy source we can rely on in a long perspective is solar irradiation which is in the order of 10,000 kW/inhabitant. The actual primary power consumption (mainly based on fossil resources) in the developed countries is in the range of 5 to 10 kW/inhabitant. The total power contained in our nutrition is in the range of 0.11 kW/inhabitant. The organic pollution of domestic waste water corresponds to approximately 0.018 kW/inhabitant. The nutrients contained in the waste water can also be converted into energy equivalents replacing market fertiliser production. This energy equivalent is in the range of 0.009 kW/inhabitant. Hence waste water will never be a relevant source of energy as long as our primary energy consumption is in the range of several kW/inhabitant. The annual mean primary power demand of conventional municipal waste water treatment with nutrient removal is in the range of 0.003-0.015 kW/inhabitant. In principle it is already possible to reduce this value for external energy supply to zero. Such plants should be connected to an electrical grid in order to keep investment costs low. Peak energy demand will be supported from the grid and surplus electric energy from the plant can be is fed to the grid. Zero 'carbon footprint' will not be affected by this solution. Energy minimisation must never negatively affect treatment efficiency because water quality conservation is more important for sustainable development than the possible reduction in energy demand. This argument is strongly supported by economical considerations as the fixed costs for waste water infrastructure are dominant. PMID- 22214092 TI - A simplified approach for the design of infiltration trenches. AB - The use of infiltration trenches has proven to be useful to reduce runoff in urban surfaces. The design of these structures is based on the continuity equation taking into account inflow, outflow and detention water volumes. Basic procedures evaluate entering flow rates and relative volumes directly as a function of rain event characteristics, without taking into account rain-runoff processes occurring in the watershed. An improved simplified procedure, based on the kinematic model for the description of rain-runoff processes, has been developed here using a dimensionless approach. The procedure and the relative applicative design graphs are presented and discussed. PMID- 22214093 TI - Simulation of particle capture in a microfiltration membrane. AB - The present study takes an interest in the description of the fouling mechanisms by a numerical approach at the microscopic scale. At first, an X-ray tomography has enabled the modelling of the membrane structure for the numerical simulations. Next, for different particle size, a same volume of particles has been sent in the modelled membrane and the final permeability has been computed. Thus, the influence of the particle size on the fouling has been seen. An observation of the particles penetration in the membrane has been realised to detail this influence. The Hermia relations were used in order to determinate the predominant fouling mechanism or the succession of predominant fouling mechanisms. But, without an accurate calculation of the first derivative, it is not possible to define cleanly the predominant fouling mechanism for a low filtered volume. Nevertheless, the perspectives of the local approach with the numerical simulation seem interesting. PMID- 22214094 TI - A sewer ventilation model applying conservation of momentum. AB - The work presented herein was completed in an effort to characterize the forces influencing ventilation in gravity sewers and to develop a mathematical model, based on conservation of momentum, capable of accounting for friction at the headspace/pipe interface, drag at the air/water interface, and buoyancy caused by air density differences between a sewer headspace and ambient. Experiments were completed on two full scale sewer reaches in Australia. A carbon monoxide-based tracer technique was used to measure the ventilation rate within the sewer headspaces. Additionally, measurements of pressure, relative humidity, and temperature were measured in the ambient air and sewer headspace. The first location was a five kilometre long sewer outfall beginning at a wastewater treatment plant and terminating at the ocean. The second location was a large gravity sewer reach fitted with ventilation fans. At the first location the headspace was entirely sealed except for openings that were controlled during the experiments. In this situation forces acting on the headspace air manifested mostly as a pressure distribution within the reach, effectively eliminating friction at the pipe wall. At the second location, air was forced to move near the same velocity as the wastewater, effectively eliminating drag at the air/water interface. These experiments allowed individual terms of the momentum equation to be evaluated. Experimental results were compared to the proposed mathematical model. Conclusions regarding model accuracy are provided along with model application guidance and assumptions. PMID- 22214095 TI - [Introduction. The immediate and long term fortune of De Morbis Artificum Diatriba (1700-1713) by Bernardino Ramazzini]. AB - No any other classical and modern medical text had a fortune comparable to the Ramazzini's De Morbis Artificum Diatriba. The number and distribution of new editions, translations, quotations and emulations illustrate the long-term fortune of the work. In the Eighteenth, Nineteenth and Twentieth centuries a "differential impact" of Ramazzini's De morbis developed all over Europe, due to different cultural, industrial and economical contexts in which the work conquered its fame. This article analyses in particular dictionaries and academic dissertations contributing, between XVlllth and XIXth centuries, to the spreading of Ramazzini's work. PMID- 22214096 TI - [Philosophy and science in the work of Bernardino Ramazzini]. AB - The treatise DMA focuses, in particular, on diseases caused by the exposition or the contact with chemical substances. The aetiological theories and the therapeutic strategies proposed by the author, show his acquaintance with the XVllth and XVIllth centuries' latrochemistry. PMID- 22214097 TI - Bernardino Ramazzini and the new epidemics of work-related disorders. AB - Work-related diseases (such as musculoskeletal disorders, neoplasms cardiocirculatory and psycho-social problems disorders) represent an increasing problem that countries are becoming aware of. In particular, musculoskeletal disorders, affecting workers in a variety of occupations, are a major cause of lost time from work and workers' disability. The paper reviews Ramazzini's observations of musculoskeletal disorders of subjects working in the second half of the seventeenth century. He observed that several clinical pictures were linked to a variety of factors (prolonged stationary postures, unnatural postures, repetition of movements, heavy muscular performance) and stressed the need to provide workforce with hygienic measures and information about hazards and preventive measures. It is worthy to stress that Ramazzini's observations, based on original intuitions and critical reasoning, anticipate the modern approach based on epidemiological principles. PMID- 22214098 TI - [Bernardino Ramazzini's intuitions and modern occupational medicine]. AB - Bernardino Ramazzini is the recognized father of occupational medicine. His work De morbis artificum diatriba, printed in Modena in 1700, is the first comprehensive treatise on the diseases of workers. Ramazzini was the first physician to investigate systematically the relationship between work and disease. The method applied, including an accurate medical examination, an inspection to workplaces to observe workers' activities, and a collection of existing knowledge, is surprisingly up-to-date. But the most modern part of his method was the acknowledgement of the role of prevention: Ramazzini identified several precautions to limit exposure to hazards, and also recognized the fundamental role of informing and training the workers about the occupational risks and how to protect themselves. As a conclusion, the contribution of Bernardino Ramazzini to occupational medicine is not limited to the recognition of a large number of occupational diseases, but is also, and mainly, in the method developed. PMID- 22214099 TI - [Neo-'hippocratism' in Bernardino Ramazzini]. AB - Neo-hippocratism is a rational and mechanic method to explain pathological phenomena and discover the causes of diseases. Bernardino Ramazzini uses Hippocratic empirical observation to investigate the relations between the alterations of the air - due to mephitic vapours, of organic and inorganic origin - and the development of pathological processes. His notion of corruption of the atmosphere as the origin of epidemics and specific diseases, and that of prevention as the main strategy of modern medicine, is developed in medical literature and in the public medicine projects of the end of the Seventeenth century. PMID- 22214100 TI - [Disinfection in Milan at the beginning of XXth century]. AB - The authors analyse some technical and professional aspects of disinfection in Milan at the beginning of XXth century, and the work of Vittorio Maragnoli. Also the use of HCN vapours in disinfestation is here analysed. PMID- 22214101 TI - [The eclecticism in Bernardino Ramazzini: the analysis of non-medical sources of "De Morbis Artificum Diatriba"]. AB - Bernardino Ramazzini (1633-1714), the founder of occupational medicine, can be considered an eclectic author since his works ranged from physics to geology, from epidemiology to poetry. An analysis of his most famous book De Morbis Artificum Diatriba shows that about half of the authors cited by Ramazzini are not medical. In particular, "non medical" authors most cited are poets, comic playwrights, philosophers and satirists. It was not just a display of erudition. Probably Ramazzini cited them because of lack of information on workers and their diseases in medical literature. So, only "non medical" sources could provide enough information on living conditions of workers that allowed Ramazzini to systematically analyze the relationship between work and disease. This use of non medical sources is still widespread in modern industrial medicine. PMID- 22214102 TI - [The University of Modena during Bernardino Ramazzini's teaching]. AB - In 1682 Bernardino Ramazzini opened the first academic year of the renewed University of Modena. In his oration he outlined the origins of the ancient university and celebrated the great Modenese scholars of the past. The University of Modena was founded in 1175 and began to decline starting from the XIV century. In 1682, during Francesco II of Este's reign, the municipality of Modena and private legacies financed its re-establishment. Ramazzini taught medical subjects until 1700. During his tenure he frequented university colleagues, including physicist Michelangelo Fardella and physician Francesco Torti, and met the great philosopher G.W. Leibniz. His university experience was closely connected with his first scientific researches, especially the one that lead to The Workers' Diseases (Modena 1700). PMID- 22214103 TI - [For a socio-medical iconography of Ramazzini's De Morbis: the manuscript of Giovanni Grevembroch (1731-1807)]. AB - Since 2002, a group of historians of medicine in Padua has been working on the creation of a iconographic database related to the professions described by Ramazzini, founder of occupational medicine, in his 1700's De morbis artificum diatriba. A specific example of iconography relevant to De morbis can be found in a 17th century manuscript written and illustrated by Giovanni Grevembroch (1731 1807), Venetian painter probably from a family of Flemish origins. This manuscript describes typical Venetian dress and costumes, accompanied by commentaries made by the artist himself. Here we can find costumes related to some of the very same professions described by Ramazzini and a comparative analysis reveals interesting elements. First of all, in his commentary Grevembroch frequently invokes concepts very similar to those of Ramazzini, related both to the dangers of the environment characteristic of a given profession and to the illnesses typical to each profession. Moreover, analysis of Grevenbroch's images and text often provides supplemental insights into to the context of and risks associated with selected occupations. Finally, the Grevembroch manuscript also supplies supplemental material pertinent to the social and cultural life of the epoch that, even if not strictly linked to questions of occupational medicine. PMID- 22214104 TI - State of the journal, 2011. PMID- 22214105 TI - High-definition occupational therapy's competitive edge: personal excellence is the key. PMID- 22214106 TI - Accentuate the positive: reflections on empathic interpersonal interactions. PMID- 22214107 TI - Perspectives on home safety: do home safety assessments address the concerns of clients with vision loss? AB - PURPOSE: We explored the occupational performance and home safety perspectives of older adults with vision loss. Our study focused on the person-environment interaction to ascertain whether participants' concerns are addressed by three commonly used home safety assessments. METHOD: Twenty-two older adults with vision loss participated in face-to-face interviews regarding their perspectives on home safety. We compared categories generated from a content analysis of the data with the contents of three standardized home safety assessments. RESULTS: Five categories of home safety emerged from the analysis: (1) lighting, (2) contrast, (3) visual distractions, (4) glare, and (5) compensation strategies. Comparisons of content in the three home safety assessments with emerged categories revealed that study participants had specific concerns about home safety that were not thoroughly addressed in the selected assessments. CONCLUSION: The findings provide preliminary content areas that should be included in the development of a home assessment specific to the low vision population. PMID- 22214108 TI - Validity of using the Assessment of Motor and Process Skills to determine the need for assistance. AB - OBJECTIVE: This study evaluated the validity of using Assessment of Motor and Process Skills (AMPS) measures as evidence of the need for assistance in the community. METHOD: In a retrospective analysis of existing data (N = 64,466), receiver operating characteristic (ROC) curves were generated, and a split-sample method was used to validate the predictions. RESULTS: When identifying people who need assistance versus those who do not need assistance in the community, activity of daily living (ADL) motor and ADL process measures have fair and good discriminating value, respectively (areas under the ROC curves were .78 and .84). Evidence supports placing ADL motor and ADL process independence cutoff measures at 1.50 logits (sensitivity = .67, specificity = .72) and 1.00 logit (sensitivity = .81, specificity = .70), respectively. Accuracy was highest when matched motor and process decisions occurred (sensitivity = .85, specificity = .83). CONCLUSION: Evidence supports using ADL ability measures from the AMPS to provide evidence of a client's need for assistance in the community. PMID- 22214109 TI - Driving to learn in a powered wheelchair: the process of learning joystick use in people with profound cognitive disabilities. AB - The Driving to Learn project explored ways to help people with profound cognitive disabilities practice operating a joystick-operated powered wheelchair. The project used a grounded theory approach with constant comparative analysis and was carried out over 12 yr. The participants were 45 children and adults with profound cognitive disabilities. Reference groups included 17 typically developing infants and 64 participants with lesser degrees of cognitive disability. The data sources included video recordings, field notes, open interviews, and a rich mixture of literature. The findings that emerged yielded strategies for facilitating achievements, an 8-phase learning process, an assessment tool, and a grounded theory of deplateauing explaining the properties necessary for participants to exceed expected limitations and plateaus. Eight participants with profound cognitive disabilities reached goal-directed driving or higher. Participants were empowered by attaining increased control over tool use, improving their autonomy and quality of life. PMID- 22214110 TI - Correlations between quality of life and adaptation factors among people with multiple sclerosis. AB - OBJECTIVE: We examined the correlations between quality of life and three adaptation factors--adjusted self-concept, social support, and accessibility-in people with multiple sclerosis (MS). METHOD: A convenience sample of 68 participants completed the Leeds Multiple Sclerosis Quality of Life scale (LMSQoL) and a questionnaire assessing the three adaptation factors. RESULTS: We found significant moderate correlations between LMSQoL scores and adjusted self concept (r = .56, p < .0001) and LMSQoL scores and social support (r = .52, p < .0001); a significant low correlation was found between LMSQoL and accessibility (r = .36, p = .003). DISCUSSION: Adjusted self-concept, social support, and accessibility were found to be critical in participants' psychosocial adaptation to the course of MS. Occupational therapy intervention should address these adaptation factors to help clients cope with MS and promote quality of life. PMID- 22214111 TI - Effectiveness of an integrated handwriting program for first-grade students: a pilot study. AB - We developed and piloted a program for first-grade students to promote development of legible handwriting and writing fluency. The Write Start program uses a coteaching model in which occupational therapists and teachers collaborate to develop and implement a handwriting-writing program. The small-group format with embedded individualized supports allows the therapist to guide and monitor student performance and provide immediate feedback. The 12-wk program was implemented with 1 class of 19 students. We administered the Evaluation of Children's Handwriting Test, Minnesota Handwriting Assessment, and Woodcock Johnson Fluency and Writing Samples test at baseline, immediately after the Write Start program, and at the end of the school year. Students made large, significant gains in handwriting legibility and speed and in writing fluency that were maintained at 6-mo follow-up. The Write Start program appears to promote handwriting and writing skills in first-grade students and is ready for further study in controlled trials. PMID- 22214112 TI - Effects of a father-based in-home intervention on perceived stress and family dynamics in parents of children with autism. AB - Parents of children with autism report high rates of stress. Parental differences in stress are inconsistent, with most research indicating that mothers report higher levels of stress than fathers. We explored parental differences before and after an in-home training program. Fathers were taught an intervention designed to improve their child's social reciprocity and communication; they then trained mothers. Stress was assessed with the Parenting Stress Index-Short Form, and family dynamics was assessed with the Family Adaptability and Cohesion Evaluation Scales II. Both mothers and fathers reported high preintervention levels of stress. After intervention, fathers' stress was reduced, but not significantly, possibly because of the variability in fathers' scores; mothers' stress scores were significantly reduced. Parenting styles were significantly different before and after intervention. Interdisciplinary teams, including occupational therapists, nurses, and special educators, can work.together to have a positive impact on the lives of families of children with autism. PMID- 22214113 TI - Pilot study of the effectiveness of weighted vests. AB - OBJECTIVE: In this pilot study, we determined the effectiveness of a weighted vest on attention to task for second-grade general education students with difficulty attending. METHOD: We used an intervention and a control group and an ABA design to compare participants' percentage of time on task with and without a vest. Ten participants from nine elementary schools in a suburban Texas school district were randomly assigned to an intervention or a control group. Control group participants wore a nonweighted vest. Participants, classroom teachers, and research assistants who coded the data were blind as to the group to which the participants were assigned. RESULTS: A repeated measures analysis of variance indicated no significant differences between groups or between baseline, intervention, and withdrawal conditions. CONCLUSION: Our results indicated that the weighted vests were not effective in increasing time on task. These results should be generalized cautiously owing to the small sample size and participant selection process. PMID- 22214114 TI - Relationship between postural control and fine motor skills in preterm infants at 6 and 12 months adjusted age. AB - We examined the relationship between postural control and fine motor skills of preterm infants at 6 and 12 mo adjusted age. The Alberta Infant Motor Scale was used to measure postural control, and the Peabody Developmental Motor Scales II was used to measure fine motor skills. The data analyzed were taken from 105 medical records from a preterm infant follow-up clinic at an urban academic medical center in south Taiwan. Using multiple regression analyses, we found that the development of postural control is related to the development of fine motor skills, especially in the group of preterm infants with delayed postural control. This finding supports the theoretical assumption of proximal-distal development used by many occupational therapists to guide intervention. Further research is suggested to corroborate findings. PMID- 22214115 TI - Randomized controlled trial comparing tailoring methods of multimedia-based fall prevention education for community-dwelling older adults. AB - OBJECTIVE: We attempted to determine whether multimedia fall prevention education using different instructional strategies increases older adults' knowledge of fall threats and their fall prevention behaviors. METHOD: Fifty-three community dwelling older adults were randomized to iwo educational groups or a control group. Multimedia-based educational interventions to increase fall threats knowledge and encourage fall prevention behaviors had two tailoring strategies: (1) improve content realism for individual learners (authenticity group) and (2) highlight program goals and benefits while using participants' content selections (motivation group). Knowledge was measured at baseline and 1-mo follow-up. Participants recorded prevention behaviors for 1 mo. RESULTS: Intervention group participants showed greater knowledge gains and posttest knowledge than did control group participants. The motivation group engaged in more prevention behaviors over 1 mo than did the other groups. CONCLUSION: Tailoring fall prevention education by addressing authenticity and motivation successfully improved fall threats knowledge. Combining motivational strategies with multimedia education increased the effectiveness of the intervention in encouraging fall prevention behaviors. PMID- 22214117 TI - Stop the genetic dragnet. PMID- 22214118 TI - Stop the killer rocks. PMID- 22214119 TI - Can't touch this feeling. PMID- 22214116 TI - Manualization of occupational therapy interventions: illustrations from the pressure ulcer prevention research program. AB - The manualization of a complex occupational therapy intervention is a crucial step in ensuring treatment fidelity for both clinical application and research purposes. Toward the latter end, intervention manuals are essential for ensuring trustworthiness and replicability of randomized controlled trials that aim to provide evidence of the effectiveness of occupational therapy. In this article, we review the literature on the process of intervention manualization. We then illustrate the prescribed steps through our experience in implementing the University of Southern California/Rancho Los Amigos National Rehabilitation Center's collaborative Pressure Ulcer Prevention Project. In this research program, qualitative research provided the initial foundation for manualization of a multifaceted occupational therapy intervention designed to reduce the incidence of medically serious pressure ulcers in adults with spinal cord injury. PMID- 22214120 TI - Microwaves and the speed of light. PMID- 22214121 TI - A circuit in every cell. PMID- 22214122 TI - Freedom fighter. PMID- 22214124 TI - Universal alignment. PMID- 22214123 TI - Why neutrinos might wimp out. PMID- 22214125 TI - From pollen to polyester. PMID- 22214127 TI - How to see the invisible. PMID- 22214128 TI - World changing ideas: 10 new technologies that will make a difference. PMID- 22214126 TI - Swapping germs. PMID- 22214129 TI - The machine that would predict the future. PMID- 22214130 TI - This way to mars. PMID- 22214131 TI - Dazzling miniatures. PMID- 22214132 TI - After the deluge. PMID- 22214133 TI - Hidden switches in the mind. PMID- 22214134 TI - Ants & the art of war. PMID- 22214135 TI - Arm in the ice. PMID- 22214136 TI - Speaking out on the "quiet crisis". Interview by Brendan Borrell. PMID- 22214137 TI - Sacred salubriousness. PMID- 22214138 TI - The links we love. PMID- 22214139 TI - Lawsuit verdicts and settlements involving reflex sympathetic dystrophy and complex regional pain syndrome. AB - Litigation involving Reflex Sympathetic Dystrophy (RSD) or Complex Regional Pain Syndrome (CRPS), because of its complexities, is often difficult to prove or defend. In our review of 56 verdicts and settlements in the state of Florida, in cases involving a diagnosis or misdiagnosis of RSD or CRPS, over half resulted in a substantial verdict or settlement for the plaintiff. PMID- 22214140 TI - Cost-effectiveness analysis of free vascularized fibular grafting for osteonecrosis of the femoral head. AB - Management of symptomatic pre-collapse osteonecrosis of the femoral head continues to be controversial. Patients are often young and active, therefore hip preserving procedures such as free vascularized fibular grafting (FVFG) have been developed to relieve pain and restore function, thereby delaying or preventing the need for joint arthroplasty. This study compared the cost-effectiveness of FVFG to total hip arthroplasty (THA) in the young adult. A Markov decision model was created for a cost-utility analysis of FVFG compared to THA. Outcome probabilities and effectiveness, expressed in QALYs gained, were derived from existing literature. Principal outcome measures included average incremental costs, effectiveness, and net health benefits. Multivariate sensitivity analysis was used to validate the model. THA resulted in a greater average incremental cost (+$5,933) while at a lower average incremental effectiveness (-0.15 QALY) compared to FVFG. On average, THA gained 22.08 QALYs at a cost-effectiveness (C/E) ratio of $1026/QALY, whereas FVFG gained 22.23 QALYs at a C/E ratio of $752/QALY. Threshold sensitivity analysis determined that the yearly all-cause probability of revision for FVFG would have to be more than three times greater than THA before THA became more cost-effective. Free vascularized fibular grafting is a more cost-effective procedure to treat osteonecrosis in certain populations. Markov decision analysis accounts for the impact of treatment strategies over the lifetime of a patient cohort. These findings can inform clinical decision making in the absence of universally accepted management strategies. PMID- 22214141 TI - Subatmospheric pressure therapy: basic science review. AB - Subatmospheric pressure (SAP) therapy has evolved as a mainstay in the treatment of acute and chronic wounds over the past 20 years. The significant improvement in wound healing upon application of a SAP therapy system such as the Vacuum Assisted Closure (V.A.C.; KCI, San Antonio, TX) device, historically has been related to general principles such as edema reduction, bacterial clearance, and increased perfusion to the wound bed. Recent investigations have also indicated that microdeformation and regulation of biochemical mediator expression play a role in the improved outcomes seen with SAP therapy. Future studies will pursue further the mechanisms by which SAP functions to render such impressive results in wound healing. PMID- 22214142 TI - Treatment of acute proximal humerus fractures with an Evans staple. AB - The purpose of this study was to report on radiographic, objective, and functional outcomes in patients with 2- and 3-part proximal humerus fractures treated with an Evans staple. Six patients (three males and three females) who had had acute, displaced proximal humerus fractures requiring operative treatment were identified and their medical records reviewed. There were four 2-part and two 3-part fractures as described by Neer. Mean age was 68.5 (range, 57 to 73) years; mean followup was 71.1 (range, 30 to 98) months. The senior author (T.W.W.) was the treating physician who determined the treatment method. All patients were treated within 2 weeks of injury using an Evans staple (Smith & Nephew, Memphis, TN), with or without tension band. Clinical outcome measurements were fracture healing, range of motion, complications, Shoulder Pain and Disability Index (SPADI) score, and radiologic outcome. All six fractures reached clinical and radiographic union at a mean of 4.2 months without postoperative complications. Two patients required subsequent hardware removal. Mean SPADI score at last followup was 36.8 (good). Average radiologic neck/shaft angle was 110 (range, 92 to 136) degrees. The Evans staple is a valuable implant for treatment of 2- and 3-part proximal humerus fractures requiring a relatively simple surgical implantation and minimal soft tissue dissection. PMID- 22214143 TI - Total knee arthroplasty: factors associated with patient compliance with followup. AB - Total joint arthroplasty followup will become an increasingly important issue as the numbers of arthroplasty patients rise. The predictors of return for routine 1 and 2-year followup are not known. A retrospective review of 290 total knee arthroplasty patients was performed. Hospital operative records and clinical notes were used to determine demographic indicators and clinical followup compliance. Patient followup compliance decreased over time [6 months (82%), 1 year (78%), 2 year (37%)]. Using a logistic model, attendance at 6-month followup was found to be a significant positive predictor for 1-year followup. Using a multivariate model, obesity was found to be a negative predictor for 2-year followup, and compliance with 6-month and 1-year followup was found to be a positive predictor for 2-year followup. The data shows that current patient dependent followup protocols are ineffective beyond one year, with only 37% of patients returning for their 2-year visit. Inclusion of a 6-month visit may improve 1-year followup, but 2-year followup remained low. PMID- 22214144 TI - Functional outcome and complications using the intramedullary hip screw for intertrochanteric fractures. AB - We prospectively studied 110 consecutive patients with intertrochanteric hip fractures treated with the 130 degree angle, 10-mm short IMHS intramedullary hip screw (IMHS, Smith & Nephew, Richards, Memphis, TN). Surgery was performed within 36 hours from admission; all patients were mobilized immediately postoperatively. Fracture union, pre- and post-operative mobility status and complications were evaluated. Eighty patients were included in the postoperative evaluation for a mean followup of 14 (range, 9 to 25) months. Mortality was 19%. Union occurred in 79 fractures within 6 months from surgery; there was one case of screw cut-out and one case of deep venous thrombosis. Periprosthetic femoral shaft fractures were not observed. At the latest examination, the mean mobility score decreased from 8.4 +/- 1.6 to 7.1 +/- 2.1 (p = 0.0001); 26 patients (32%) fully achieved the preoperative mobility score and 54 patients (68%) achieved more than 90% of the preoperative mobility score. The IMHS intramedullary hip screw represents a reliable method for the treatment of patients with intertrochanteric hip fractures, and provides for early mobilization and rehabilitation of the patients with acceptable complications. PMID- 22214145 TI - The use of osteo-conductive stem-cells allograft in lumbar interbody fusion procedures: an alternative to recombinant human bone morphogenetic protein. AB - The use of autogenous bone graft in spinal fusion is progressively declining. Different allografts including the human bone morphogenetic protein have been proposed to facilitate fusion rates but are associated with various adverse effects. Osteocel belongs to a new class of allograft tissue material that is a re-absorbable biomaterial with allogenic mesenchymal stem cells. The purpose of the present retrospective study was to analyze the clinical effectiveness of mesenchymal stem cells allograft (Osteocel") to achieve radiological arthrodesis in adult patients undergoing lumbar interbody fusion surgery for different indications. Fifty-two consecutive patients received lumbar interbody fusion at one (69%) or two contiguous (31%) levels of lumbar spine for various indications. The mean age was 50 (range, 27 to 77) years; 60% were females; 43% were habitual smokers and 21% had previously failed surgery at the index level(s). OUTCOME MEASURES: Radiographic analyses of fusion by plain films and CT scans. Procedures performed were circumferential fusion (67%), ALIF (17%) and TLIF (16%). Followup radiographic data was analyzed to establish arthrodesis versus failure (pseudarthrosis), number of months until achievement of fusion, and possible factors affecting the fusion rate. Followup ranged from 8 to 27 (median, 14) months. Solid arthrodesis was achieved in 92.3% of patients at median followup time of 5 months (95% Cl; range, 3 to 11 months). Kaplan-Meier survival curves and Mantle-Cox test were conducted to assess the effect of various factors on the rate of fusion. Statistics showed that increasing age (older than 50 years) (p = 0.017) and habitual smoking (p = 0.015) delayed the fusion time and increased the risk of pseudarthrosis. The use of Osteocel allograft is safe and effective in adult patients undergoing lumbar interbody spinal fusion procedure. Increased age and habitual smoking delays fusion but gender, previous surgery at the index level, type of procedure and number of levels do not affect the fusion rates. PMID- 22214146 TI - Heterotopic ossification after single-incision distal biceps tendon repair with an endobutton. AB - Heterotopic ossification is rarely encountered following repair of a distal biceps tendon by an anterior approach. Although much less common than with a classic two-incision approach, a review of the literature demonstrates that heterotopic ossification may still occur following anterior single incision techniques. We describe only the second reported case to our knowledge of symptomatic heterotopic ossification following repair of a distal biceps tendon rupture with an EndoButton. PMID- 22214147 TI - Late compartment syndrome of the hand due to wasp sting in a child. AB - We report a 6-year-old girl, with no history of previous anaphylactic reaction, who sustained a wasp sting to the volar aspect of her left hand. The child did not present any symptoms at the beginning. She was first examined at the emergency department with developed compartment syndrome, after more than 24 hours later and she was urgently taken to the operating theatre. The midpalmar, thenar, and hypothenar spaces were decompressed, and the transverse carpal ligament was released. At the 11-month followup, she presented with normal function of the hand and normal 2-point discrimination in all fingers. Although the accurate mechanism of the development of compartment syndrome after a wasp sting in children is not thoroughly clear, the treatment seems to be the same as in all other cases of compartment syndrome; urgent fasciotomy. It is very important to keep in mind the possibility, even if it is extremely low, of compartment syndrome after a wasp sting in children; even of those with no history of anaphylactic reaction. PMID- 22214148 TI - Tissue sparing total femoral arthroplasty: technical note. AB - It is predicted that the number of revision hip and knee arthroplasties will double by the years 2026 and 2015, respectively. As the burden of end-stage prosthetic disease increases, there will be a greater potential need for total femoral arthroplasty. This report describes a patient with a femoral neck fracture nonunion with an ipsilateral multiply revised failed total knee arthroplasty treated by a tissue sparing total femoral arthroplasty. The technique is described, and potential benefits are reviewed. PMID- 22214149 TI - [Association analysis of polymorphisms of metabolizing enzyme genes with chronic benzene poisoning based on logistic regression and multifactor dimensionality reduction]. AB - OBJECTIVE: To explore the association of polymorphisms of metabolizing enzyme genes with chronic benzene poisoning (CBP) comprehensively by case-control design. METHODS: 152 CBP patients and 152 workers occupationally exposed to benzene without poisoning manifestations were investigated. 30 single nucleotide polymorphisms (SNPs) in 13 genes such as CYP2E1 were tested by PCR-RFLP, sequencing approaches. Logistic regression model was used to detect main effects and 2-order interaction effects of gene and/or environment. Multifactor dimensionality reduction (MDR) was used to detect high-order gene-gene or gene environment interactions. RESULTS: Based on logistic regression, the main effects of GSTP1 rs947894, EPHX1 rs1051740, CYP1A1 rs4646903, CYP2D6 rs1065852 and rs1135840 were found to be significant (P < 0.05) while the confounding factors of sex, cigarette smoking, alcohol consumption and the intensity of benzene exposure were controlled. EPHX1 rs1051740 might be associated with CBP (P = 0.06). There existed 3 types of interactions were as followed: interactions of GSTP1 rs947894 with alcohol consumption, CYP2E1 rs3813867 with EPHX1 rs3738047, EPHX1 rs3738047 with alcohol consumption(P < 0.05), while the main effects of CYP2E1 rs3813867 and EPHX1 rs3738047 were not significant (P > 0.05). The other SNPs did not show any significant associations with CBP. According to MDR, a 3 order interaction with the strongest combined effect was found, i.e. the 3-factor combination of CYP1A1 rs4646903, CYP2D6 rs1065852 and CYP2D6 rs1135840. CONCLUSION: Gene-gene, gene-environment interactions are important mechanism to genetic susceptibility of CBP. PMID- 22214150 TI - [Silica induce cell cycle changes by mitogen-activated protein kinases pathway]. AB - OBJECTIVE: To investigate the roles of mitogen-activated protein kinases (MAPK) on silica-induced cell cycle changes. METHODS: After cells were treated with 200 microg/ml silica, Western blot and Immunofluorescence assays were utilized to detect the expression of cyclin D1, CDK4 and E2F-4, Flow cytometry was used to detect cell cycle progression, the dominant negative mutants techniques were used to investigate silica-induced signal pathway and the effects of which in silica induced cell cycle changes. RESULTS: After cells were exposed to 200 microg/ml silica 24 h, the results of present study showed the proportion of cells in G1 phases was decreased. Silica-induced cell cycle alternation was markedly impaired by stable expression of a dominant negative mutants of ERK or JNK, but not p38. It was found that ERK and JNK were involved in silica-induced cyclin D1 and CDK4 overexpression and the decreased expression of E2F-4. CONCLUSION: ERK and JNK, but not p38, mediated silica-induced cell cycle changes in human embryo lung fibroblasts. PMID- 22214151 TI - [Statistical analysis of 512 in-patients with carbon monoxide poisoning]. PMID- 22214152 TI - [Oxidative damage of single-walled carbon nanotubes in striaturn and hippocampi of mice]. AB - OBJECTIVE: To study the oxidative damage of SWCNTs in striaturn and hippocampi of mice. METHODS: Forty male ICR mice were divided into experiment group (12.5 mg/kg SWCNTs) and control group (saline containing 0.1% Tween80) randomly. Each group was subdivided into 1, 7, 14 and 28 days group, 5 mice in each subgroup, then treated with tail intravenous injection for 5 continuous days. The striatum and hippocampus were isolated on the ice bath and homogenized in saline. SOD, GSH-Px, and MDA in the supernatants were measured with xanthine oxidize, GSH consumption in enzymatic reaction and TBA methods. RESULTS: After exposure to 12.5 mg/kg SWCNTs for 5 d, SOD activity in striaturn and hippocampi decreased on 1st day and reached the minimum on 7th day, then increased gradually. The SOD activity in the SWCNTs treatment groups on 7th day were significantly decreased when compared to control (P < 0.05). Comparison with control group, GSH-Px activity in striaturn obviously decreased on 7th day then increased on 14th day, the difference between 7th day and 14th day was significantly (P < 0.05). GHS-Px activity in the hippocampi in SWCNTs group on 7th day and 14th day was significantly lower than that in control group (P < 0.05), then increased to the level of control group on 28th day. MDA contents of striaturn and hippocampi in SWCNTs group reduced on 1st day, then gradually increased on 7th day and 14th day, then reduced, MDA contents on7th day and 14th day n SWCNTs group were significantly higher than that in control group (P < 0.05). CONCLUSIONS: The results of present study indicated that SWCNTs could decrease antioxidase activity and increase the Lipid peroxide in striaturn and hippocampi of mice. PMID- 22214153 TI - [The comparative study of quartz dust and bleomycin-induced pulmonary fibrosis in rats]. AB - OBJECTIVE: To compare the pulmonary alveolitis and the early fibrosis of pulmonary fibrosis induced by quartz dust and bleomycin in rats, and investigate their mechanism. METHODS: The female rats were divided into three groups: control group exposed to normal saline by the trachea; SiO2 group exposed to SiO2 by the trachea; BLM group exposed to BLM A5 by the trachea. Each half of the animals were sacrificed on the 7th and 14th day after exposure. The lungs of rats were collected to observe pulmonary alveolitis by HE staining and to observe fibrosis by saturated picric acid sirius red staining. The expression of tumor necrosis factor-alpha (TNF-alpha) and CD68 in pulmonary tissues were analyzed quantitatively by immunohistochemistry and image analysis system. RESULTS: (1) The alveolitis and pulmonary fibrosis of rats in both SiO2 group and BLM group were became more serious gradually over time, HE staining under light microscope showed that BLM group on the 7th day had the most obvious alveolitis (2.814 +/- 0.832), the saturated picric acid sirius red staining under polarized light showed that BLM group on the 14th day had the worst pulmonary fibrosis (1284.57 +/- 554.72), which were significantly higher than those (103.69 +/- 18.29 and 111.78 +/- 37.45) in control group and SiO2 group on the 7th day (P < 0.05). (2) The results of immunohistochemistry examination indicated that the expression (17.100 +/- 1.831) of TNF-alpha in the BLM group on the 7th day was significantly higher than those (0.451 +/- 0.441, 7.909 +/- 1.275 and 13.506 +/- 1.454) in control group, SiO2 group on 7th day and BLM group on 14th day (P < 0.05). The expression (22.778 +/- 2.512) of TNF-alpha in the SiO2 group on the 14th day was significantly higher than those in control group, SiO2 group on 7th day and BLM group on 14th day (P < 0.05). The expression (134.941 +/- 35.951) of CD68 in the SiO2 group on the 14th day was significantly higher than those in control group, SiO2 group on 7th day and BLM group on 14th day (P < 0.05). CONCLUSION: The early alveolitis of BLM-induced lung injury model was more serious than that of SiO2 induced lung injury model, and the fibrosis process of BLM-induced lung injury model was earlier than that of SiO2-induced lung injury model. TNF-alpha plays an important role in the course of both models, but macrophages is involved in SiO2 induced pulmonary in a more continuous way than in BLM-induced pulmonary fibrosis. PMID- 22214154 TI - [Lung transplantation for silicosis: a report of 5 cases]. AB - OBJECTIVE: To investigate the selection of recipients, operative technique, and perioperative management of lung transplantation for silicosis. METHODS: Lung transplantations (LTx) were performed for five end-stage silicosis in our hospital who were diagnosed in accordance with recommendations of the local Prophylactic Therapeutic Institution for Occupational Diseases. The chest roentgenogram and high resolution CT showed somewhat pulmonary interstitial fibrosis, pulmonary emphysema and massive opacities. The mean pulmonary artery pressure (mPAP) was > 30mmHg, NYHA III or IV. Two patients received thoracic surgery prior to LTx, one patient was ventilator-dependent. One patient received bilateral sequence lung transplantation (BSLT) under extracorporeal membrane oxygenation (ECMO) support. Four patients received single lung transplantation (SLT), 3 under ECMO support. RESULTS: Patient five died of multiple organ failure on postoperative day 8, the remaining four patients were discharged from hospital. During follow up, patient three died of severe infection 7 month postoperatively, the remaining three patients were alive for 5 years, 3 years and 2 years respectively, and lived good quality of life, especially with lower mPAP and improved lung function. Although our patients suffered low-grade chronic rejection with the manifestation of bronchiolitis obliterative syndrome (BOS). CONCLUSION: Lung transplantation is a viable option for patients with end-stage silicosis, providing acceptable quality of life and survival. Both SLT and BSLT are satisfactory approach for end-stage silicosis,and long-term survival requires further investigations. PMID- 22214155 TI - [Case-control study of relationship between polymorphisms of interleukin-4 gene and susceptibility of silicosis]. AB - OBJECTIVE: To explore the relationship between polymorphisms of interleukin-4 (IL 4) gene (-33, +45, VNTR, +429, +448) and the susceptibility of silicosis. METHODS: In a case-control study, the case group consisted of 101 patients with silicosis, and was matched with the control group (121 workers without silicosis), according to the age, sex, nationality, working place, exposure to dust. The polymorphisms of IL-4 (five locus) detected by the method of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques. RESULTS: There was no difference of age, exposure and smoking between case group and control group (P > 0.05). The two groups had good comparability. Only the GA genotype in the IL-4 (+429) locus was found, the genotypes of AA and GG were not found. The CC genotype in the IL-4 (+448) locus was found, the genotypes of CG and GG were not found. The frequencies of AA, GG and AG of IL-4 (+45) locus in the case and control groups were 55.4%, 10.9%, 33.7% and 62.0%, 11.6%, 26.4%, respectively, there was no the significant difference between case and control groups (P > 0.05). The frequencies of B1B1, B2B2 and B1B2 of IL-4 (VNTR) locus in the case and control groups were 73.3%, 1.0%, 25.7% and 68.6%, 1.7%, 29.8%, respectively, there was no the significant difference between case and control groups (P > 0.05). The frequencies of TT, CC and CT in IL-4 -33 locus in the case group were 55.4%, 11.9% and 32.7%, which were significantly higher than those (69.4%, 4.1%, 26.4%) in control group (P < 0.05). CONCLUSIONS: There was no relationship between IL-4 (+45, VNTR) genotypes and prevalence of silicosis in this study. The polymorphisms of IL-4 (+448) site were not found which may be related to the race. The relationship between genetic polymorphism of IL-4 (-33) locus and silicosis development was found, Workers with IL-4 (-33) allele C are susceptible to the silica. PMID- 22214156 TI - [Effects of high-dose N-acetylcysteine on the lung tissues of rats exposed to silica]. AB - OBJECTIVE: To explore the effects of high-dose N-acetylcysteine on the lung tissues of rats exposed to silica. METHODS: Ninety-six Wistar rats were randomly divided into model group, intervention group and control group (32 rats for each group). The rats of model group and intervention group were exposed to silica by intratracheal infusion of silica dust suspension. The rats in the intervention group were orally given high dose N-acetylcysteine. In 3, 7, 14, 28 days after exposure, eight rats in each group were sacrificed, respectively and the lung samples were collected. The pathological changes of lung were evaluated by HE and Masson staining methods. The levels of TNF-alpha and IL-8 in the BALF were detected by ELISA. RESULTS: Compared with the control group, the alveolitis and pulmonary fibrosis in the intervention group were significantly reduced. In 3, 7, 14, 28 days after exposure, the lung/body coefficients in the intervention group were 9.30 +/- 0.78, 6.29 +/- 0.74, 7.63 +/- 0.88, 6.06 +/- 1.16 respectively, which were significantly lower than those (13.84 +/- 1.61, 9.23 +/- 0.87, 11.23 +/- 1.25, 9.56 +/- 0.76, P < 0.01 ) in the model group (P < 0.01). At the different time points, the levels of TNF-alpha and IL-8 in the BALF in the intervention group were significantly higher than those in the control group (P < 0.01), but were significantly lower than those in the model group (P < 0.01). CONCLUSION: The intervention with high dose N-acetylcysteine can significantly reduce the alveolitis and the TNF-alpha and IL-8 levels in the BALF, therefore, inhibit and delay the development of pulmonary fibrosis of rats exposed to silicon dioxide. PMID- 22214157 TI - [The analysis of adverse health effects of occupational hazards factors in one solid waste landfill]. AB - OBJECTIVE: To determine occupational hazards in work sites of a large solid waste landfill and analyze their adverse health effects. METHOD: The national standardized detection methods were used to determine dust concentration, harmful gas and physical factors in worksites. Routine physical examination, pulmonary function, hearing tests and nervous system test were performed in workers for 2 consecutive years. Urine lead, cadmium and mercury contents were detected. The comet assay was use to measure DNA damage in peripheral blood lymphocytes among workers. RESULT: The main occupational hazard factors in this solid landfill are dust, harmful gas, high temperature and noise. The oxides, carbon monoxide, and noise and high temperatures in summer at some work sites exceeded the national occupational exposure limits. The prevalence of respiratory inflammation and rate of pulmonary function decrease among front-line workers and on-site technical managers are 21.2% and 11.5%, which are significantly higher than those among administrative staff (7.1% and 0) (P < 0.05). Nervous system abnormalities rate of front-line workers and on-site technical managers was 50.0%, which is significantly higher than that (26.7%) of administrative staff (P < 0.05). Because of long-term exposure to high intensity noice, hearing loss rate of bulldozer drivers was 10.3%. In addition, about 75% of workers with DNA damage in peripheral blood lymphocyte are front-line workers. CONCLUSION: Adverse health effects from occupational hazards were observed among workers in this solid waste landfill. PMID- 22214158 TI - [Clinical analysis of multiple organ dysfunction syndrome caused by acute paraquat poisoning]. AB - OBJECTIVE: To analysis clinical characteristics of the multiple organ dysfunction syndrome (MODS) caused by acute paraquat poisoning (APP). METHOD: Clinical data of 68 APP cases from Jan 2006 to Jun 2009, including age, gender, poisoning time and dosage, and MODS time, were compared in two groups, i.e. the death (37 cases) and survived (31cases) groups. It was less than 24 hours from poisoning to rescue in all cases. RESULTS: Among the 68 cases, the incident rate of ARDS was 51.47% (35 cases). The rate of acute lung injure was 97.1% (66 cases). The mortality was 54.4% (37 cases). There was no significant difference in age and gender between both groups (P > 0.05). The dosages and times from poisoning to rescue were significant different between two groups (P < 0.05, P < 0.01). In the death group, proportion of amounts (> 3) of organs related with MODS was 70.29%, which was significantly higher than that (38.71%) in survived group (P < 0.01). MODS and ALI/ARDS occurred in death group earlier than those in survival group (P < 0.05). On the other hand, cardiac, hepatic and renal damage occurred earlier than the lung injure. CONCLUSION: MODS in APP patients occurred earlier, were more sever, and caused higher mortality. The poisoning dosage and time were important prognostic factors. PMID- 22214159 TI - [Relationship between polymorphism of interleukin-8 and silicosis susceptibility]. AB - OBJECTIVE: To explore the relationship between the polymorphisms of interleukin-8 (IL-8) and the silicosis susceptibility. METHODS: The case group consisted of 101 male patients with stage I silicosis diagnosed by the Pneumoconiosis Diagnosis Expert Panel according to the Chinese National Diagnosis Criteria of Pneumoconiosis (GBZ 70-2009). The control group consisted of 121 workers without silicosis exposed to same dusts. The cases and the controls had the same dust exposure history. The peripheral venous blood was drawn from each subject. DNA was extracted from leucocytes by the salting method. The polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) techniques and PCR were used to examine polymorphism of IL-8 (Met31Arg, 781C/T, -251A/T and RA+860). RESULTS: There were no the differences of age, cumulative exposure time and smoking between the cases and the controls (P > 0.05). The frequencies of IL-8 (Met31Arg) GT genotypes in cases and controls were 12.87% and 2.48%, respectively, there was significant difference (P < 0.05). The frequencies of allele G in cases and controls were 6.44% and 2.07%, respectively, there was significant difference (P < 0.05). The frequencies of IL-8 (-251A/T) AA genotypes in cases and controls were 9.90% and 25.64%, respectively, there was significant difference (P < 0.05). The frequencies of IL-8 (781C/T) CC, CT, TT genotypes in cases and controls were 38.61%, 40.59%, 20.79% and 46.28%, 40.50%, 13.22%, respectively, there was no significant difference (P > 0.05). The frequencies of IL-8 (RA+860) GG, GC and CC genotypes in cases and controls were 75.25%, 21.78%, 2.97%, 80.17%, 14.88%, 4.96%, respectively, there was no significant difference (P > 0.05). CONCLUSIONS: IL-8 (Met31Arg and -251A/T) genetic polymorphisms might play a role in the development of silicosis. The risk of pneumoconiosis in workers carrying (Met31Arg) genotype GT is likely to increase. The risk of pneumoconiosis in workers carrying IL-8 (-251A/T) AA genotype is likely to decrease. The relationship between IL-8 781C/T and RA+860 genes polymorphisms and silicosis is not found. PMID- 22214160 TI - [The incidence of pneumoconiosis in welders feature]. PMID- 22214161 TI - [Evaluation on the prevention and control measures of pneumoconiosis in peasant laborer in Guangxi]. PMID- 22214162 TI - [Effects of rush mat dust exposure and smoking on workers' FEV1.0]. AB - OBJECTIVE: To study the effect of smoking and rush-mat dust exposure on pulmonary function. METHOD: 122 rush-mat dust exposed workers and 118 controls without dust exposure were selected. Questionnaire and FEVY1.0 measurement were performed on them. RESULTS: For dust exposure, FEV1.0% of cases (81.8% +/- 13.9%) was statistically lower than controls (95.9% +/- 15.3%) (t = -7.49, P < 0.01), the abnormal rate of FEV1.0% was 46.7% (57/122) for cases, statistically higher than controls (8.5%, 10/118), chi2 = 43.6, P < 0.01. For smoking, FEV1.0% of cases (82.02% +/- 12.9%) was statistically lower than controls (93.33% +/- 12.4%), t = 5.18, P < 0.05, the abnormal rate of FEV1.0% is 55.9% for cases, statistically higher than controls (16.7%), chi2 = 22.2, P < 0.05. The exposing ages of workers has negative correlation with FEV1.0% (R(S1) = -0.299, P = 0.0008). Exposure and smoking could affect FEV1.0% (Fe = 259.06, P < 0.01, F(s) = 42.42, P < 0.01), and their interactive effect on FEV1.0% was greater than single ones (F = 34.70, P < 0.01). CONCLUSION: Rush-mat dust exposure, smoking and their interaction have influence on FEV1.0%. PMID- 22214163 TI - [The effect of extracellular signal-regulated kinase 1/2 signaling pathway on the expression of transforming growth factor-beta1 in lung fibroblast activated by silicon dioxide]. AB - OBJECTIVE: To investigate the effect and regulation of extracellular signal regulated kinase (ERK1/2) signaling pathway on the expression of transforming growth factor-beta1 (TGF-beta1) in human embryonic lung fibroblasts induced by SiO2. METHODS: Human alveolar macrophages were collected from a silicotic patient by bronchoalveolar lavage and in the presence or absence of SiO2 (50 ug/ml) exposition for 18h, and then the conditioned supernatants were used to incubate HELF. The expressions of TGF-beta1, of the HELF acted with the conditioned AM supernatant fluid were detected with the immunocytochemistry method after treatment with PD98059 of inhibitor of ERK. RESULTS: The expression of TGF-beta1 in HELF of the SiO2 treatment group (OD value is 0.322 7 +/- 0.023 8) exceed blank group (OD value is 0.163 7 +/- 0.019 6) and AM control group (OD value is 0.240 6 +/- 0.022 5) by the immunocytochemistry method. But the expression of TGF beta1 had reduction in some extent in the PD98059 intervention group (OD value is 0.271 1 +/- 0.022 9). The values were statistically different (P < 0.05). CONCLUSION: ERK inhibitor PD98059 have inhibition effect on the expression of transforming growth factor-beta1 and expression of cytokine of human embryonic lung fibroblasts stimulated by SiO2. The study indicate that the proliferation and collagen production of HELF activated by SiO2 are mediated by ERK/MAPK signal pathway in some extent. PD98059 may antagonizes silica-induced lung fibrosis by inhibiting the expression of transforming growth factor-beta1. PMID- 22214164 TI - [Comparative study of the cytotoxicity induced by chrysotile asbestos, rock wool and substitute fibers in vitro]. AB - OBJECTIVE: To study the cytotoxicity induced by chrysotile asbestos (CA), rock wool (RW) and wollastonite (WS). METHODS: V79 cells were divided into 4 groups. i.e. CA group, WS group, RW group and control group (200 microl PBS). The exposure concentration of dusts was 100 mg/L, The cell viability was detected by MTT and lactate dehydrogenase (LDH) activity assays. The technique of scanning electron microscopy was used to examine the change of V79 cells. RESULTS: SiO2 was main constituent for 3 kinds of dusts. In MTT assay, the cell viability of RW and WS groups was 64.8% and 65.7%, respectively, which were significantly higher than that (54.5%) of CA group (P < 0.01). In LDH assay, the LDH activity of RW and WS groups [(15.7 +/- 50.9), (12.3 +/- 3.7) U/L, respectively] was significantly lower than that [(20.2 +/- 0.9) U/L] of CA group (P < 0.05). In scanning electron microscopy examination, it was found that the two ends of V79 cells in CA group contained a great deal of fibers remaining bodies, but the V79 cell appearance in RW and WS groups was normal. CONCLUSION: The cytotoxicity induced by RW and WS is significantly lower than that induced by CA for V79 cell. PMID- 22214165 TI - [Expression of epidermal growth factor receptor and the oncogene c-erbB2 on pulmonary fibrosis induced by bleomycin in rats]. AB - OBJECTIVE: To study the expression of the epidermal growth factor receptor (EGFR) and the oncogene c-erbB2 on pulmonary fibrosis induced by bleomycin (BLM) in rats. METHODS: Fifty-four Wistar rats were randomly divided into three groups, the pulmonary fibrosis group (BLM), Iressa group and the control group. There were 18 rats in each group. Control group were injected with saline 0.2-0.3 ml in trachea. Iressa group and BLM group were injected with BLM intratracheal. After the fibrosis models were build, Iressa group were given orally Iressa (200 mg/kg)1 h before modeling in Iressa group, saline were fed 10 ml/kg in BLM group and control group. The three groups were fed 5 times per week; and were sacrificed after treatment on days 1, 14 and 28 respectively. The lungs were harvested for histological studies. RESULTS: The lung tissue in Iressa group showed fibrosis and inflammatory cell infiltration, the same as shown in the BLM group. The pulmonary fibrosis score was significantly lower than the BLM group on the 28 th day (2.17 +/- 0.41 vs 3.50 +/- 0.84, P < 0.01). Compared with the control group, c-erbB2 and EGFR were hyper expressed significantly both in BLM group and Iressa group at all time points (P < 0.01); c-erbB2 expression had no changes between the Iressa group and the BLM (P > 0.05), that were gradually decreased, and was significantly different at each time point (P < 0.01). EGFR expression was increased gradually on the 14th and 28th day (0.17 +/- 0.02 and 0.28 +/- 0.04) in Iressa group ,that was significantly lower than the BLM group (0.27 +/- 0.04 and 0.34 +/- 0.02) (P < 0.01). EGFR expression increased significantly on the 28th day than on the 14th day in the Iressa group (P < 0.01). CONCLUSION: The expression of C-erbB2 and EGFR are enhanced in different stages of alveolitis and pulmonary fibrosis, c-erbB2 and EGFR may be participated in different stages of pulmonary fibrosis. PMID- 22214166 TI - [Analysis of pathogen isolated from lower respiratory tract in coalminer's pneumoconiosis patients complicated with infection]. AB - OBJECTIVE: To investigate the composition and resistance of main pathogens isolated form Lower respiratory tract in coalminer's pneumoconiosis patients complicated with infection to provide the basis for clinical treatment. METHOD: Coalminer's pneumoconiosis patients complicated with infection during 2009 to 2010 were divided into mechanical ventilation group and non mechanical ventilation group. Specimens were obtained from lower respiratory tract by fibrobronchoscopy with protected specimen brush in patients of both groups to perform isolation, culture, identification and susceptibility test of pathogen. RESULT: Total 111 patients were enrolled, 36 of them in mechanical ventilation group and 75 patients in non mechanical ventilation group. The pathogenic bacteria detection rate of patients in mechanical ventilation group was significantly higher than that of patients in non mechanical ventilation group (88.9% vs. 46.7%, P < 0.01). In non mechanical ventilation group, Mycobacterium tuberculosis was detected in 3 patients, and 27 strains of G- bacilli, 3 strains of G+ coccus, and 2 strains of fungus; and 26 strains of G- bacilli, 3 strains of G+ coccus, and 3 strains of fungus were detected in mechanical ventilation group. There was no significant difference in term of strains between the two groups (P > 0.05). Rate of resistance to main antibiotics of patients in mechanical ventilation group was higher than that of patients in non mechanical ventilation group. CONCLUSION: Resistance of pathogenic bacteria isolated from lower respiratory tract was severe in coalminer's pneumoconiosis patients complicated with infection, which was higher in patients treated with mechanical ventilation than patients without mechanical ventilation. Mycobacterium tuberculosis and fungal infection and increasing resistance prompted that clinicians must attach importance to rational drug use and keep to monitoring bacterial resistance. PMID- 22214167 TI - [A case report of successful treatment of severe acute paraquat poisoning with pulmonary aspergillus infection]. PMID- 22214168 TI - [Clinical analysis of acute bromadiolone poisoning]. PMID- 22214169 TI - [Large whole-lung lavage with paroxysmal atrial fibrillation causes and treatment]. PMID- 22214170 TI - [Lower respiratory tract of pneumoconiosis on fosfomycin antibacterial activity in vitro of fosfomycin to infected in coal worker pneumoconiosis in vitro antibacterial activity]. PMID- 22214171 TI - [Coal worker's pneumoconiosis complicated with lung cancer patients with respiratory tract of drug resistance of Pseudomonas aeruginosa]. PMID- 22214172 TI - [Long-term observation and dynamic for chest X-ray film in tin hemochromatosis cases]. PMID- 22214173 TI - [Research progress on the health effects of the man-made vitreous fibre insulation wools]. PMID- 22214174 TI - [Solid waste landfill and its occupational hazards]. PMID- 22214175 TI - Facile solution synthesis of alpha-FeF3.3H2O nanowires and their conversion to alpha-Fe2O3 nanowires for photoelectrochemical application. AB - We report for the first time the facile solution growth of alpha-FeF(3).3H(2)O nanowires (NWs) in large quantity at a low supersaturation level and their scalable conversion to porous semiconducting alpha-Fe(2)O(3) (hematite) NWs of high aspect ratio via a simple thermal treatment in air. The structural characterization by transmission electron microscopy shows that thin alpha FeF(3).3H(2)O NWs (typically <100 nm in diameter) are converted to single-crystal alpha-Fe(2)O(3) NWs with internal pores, while thick ones (typically >100 nm in diameter) become polycrystalline porous alpha-Fe(2)O(3) NWs. We further demonstrated the photoelectrochemical (PEC) application of the nanostructured photoelectrodes prepared from these converted hematite NWs. The optimized photoelectrode with a ~400 nm thick hematite NW film yielded a photocurrent density of 0.54 mA/cm(2) at 1.23 V vs reversible hydrogen electrode potential after modification with cobalt catalyst under standard conditions (AM 1.5 G, 100 mW/cm(2), pH = 13.6, 1 M NaOH). The low cost, large quantity, and high aspect ratio of the converted hematite NWs, together with the resulting simpler photoelectrode preparation, can be of great benefit for hematite-based PEC water splitting. Furthermore, the ease and scalability of the conversion from hydrated fluoride NWs to oxide NWs suggest a potentially versatile and low-cost strategy to make NWs of other useful iron-based compounds that may enable their large scale renewable energy applications. PMID- 22214176 TI - Engineering of targeted nanoparticles for cancer therapy using internalizing aptamers isolated by cell-uptake selection. AB - One of the major challenges in the development of targeted nanoparticles (NPs) for cancer therapy is to discover targeting ligands that allow for differential binding and uptake by the target cancer cells. Using prostate cancer (PCa) as a model disease, we developed a cell-uptake selection strategy to isolate PCa specific internalizing 2'-O-methyl RNA aptamers (Apts) for NP incorporation. Twelve cycles of selection and counter-selection were done to obtain a panel of internalizing Apts, which can distinguish PCa cells from nonprostate and normal prostate cells. After Apt characterization, size minimization, and conjugation of the Apts with fluorescently labeled polymeric NPs, the NP-Apt conjugates exhibit PCa specificity and enhancement in cellular uptake when compared to nontargeted NPs lacking the internalizing Apts. Furthermore, when docetaxel, a chemotherapeutic agent used for the treatment of PCa, was encapsulated within the NP-Apt, a significant improvement in cytotoxicity was achieved in targeted PCa cells. Rather than isolating high-affinity Apts as reported in previous selection processes, our selection strategy was designed to enrich cancer cell-specific internalizing Apts. A similar cell-uptake selection strategy may be used to develop specific internalizing ligands for a myriad of other diseases and can potentially facilitate delivering various molecules, including drugs and siRNAs, into target cells. PMID- 22214178 TI - Evaluation and control of respirable silica exposure during lateral drilling of concrete. PMID- 22214177 TI - Exciton scattering mechanism in a single semiconducting MgZnO nanorod. AB - Excitonic phenomena, such as excitonic absorption and emission, have been used in many photonic and optoelectronic semiconductor device applications. As the sizes of these nanoscale materials have approached to exciton diffusion lengths in semiconductors, a fundamental understanding of exciton transport in semiconductors has become imperative. We present exciton transport in a single MgZnO nanorod in the spatiotemporal regime with several nanometer-scale spatial resolution and several tens of picosecond temporal resolution. This study was performed using temperature-dependent cathodoluminescence and time-resolved photoluminescence spectroscopies. The exciton diffusion length in the MgZnO nanorod decreased from 100 to 70 nm with increasing temperature in the range of 5 and 80 K. The results obtained for the temperature dependence of exciton diffusion length and luminescence lifetime revealed that the dominant exciton scattering mechanism in MgZnO nanorod is exciton-phonon assisted piezoelectric field scattering. PMID- 22214179 TI - Excitation energy shuttling in oligothiophene-diketopyrrolopyrrole-fullerene triads. AB - The photophysical properties of a thiophene-diketopyrrolopyrrole oligomer linked to two fullerene units via alkyl linkers of different lengths have been investigated in solution. The molecules exhibit excitation energy shuttling between the singlet and triplet photoexcited states. Photoexcitation of the oligomer is followed by singlet energy transfer to the fullerene, intersystem crossing to the triplet state, and then triplet energy transfer back to the oligomer. Competing electron transfer reactions, followed by recombination to the triplet state, are energetically possible and cannot be ruled out but were not observed and seem to have a small contribution in solution. PMID- 22214180 TI - Comparison between immediate and delayed laser-treated implants surface with switching platform: a clinical retrospective study. AB - The aim of the present study was to compare immediate (Im) versus delayed (De) placement of laser-treated implants surface with switching platform to confirm the predictability and performance of this type of implant. The implants were placed in pos exodontia and healed sites at the incisor, canine, premolar, and molar regions of the maxilla or the mandible. A protocol was prepared in which patient age, sex, implant length, diameter, and use of bone graft were recorded. The study included 44 GEASS Srl (Udine, Italy) implants with laser surface and morse taper connection, placed in 27 patients (mean age: 56 years; range: 25-80 years).The survival rates were 100% in the Im group and in the De group. The patients were followed for a minimum of 12 months. Implants with laser surface and morse connection presented when placed in fresh sockets showed similar results to implants placed in mature bone after 12 months of follow-up. PMID- 22214181 TI - Can we modify maladaptive attributions for fatigue? AB - Research has shown that those with insomnia focus primarily on their sleep as a cause of daytime fatigue rather than the multitude of other possible causes of fatigue. This can create sleep-related anxiety and further perpetuate the sleep disturbance. In order to lessen the increased focus on sleep, the present study investigated whether people could learn to consider other attributions for fatigue via an information-based manipulation. Undergraduate students (N = 88) were randomized to two information groups: They either received information about common factors that could explain daytime fatigue (the fatigue information condition) or received generic sleep-related information (the control condition). Each group was tested pre- and post-intervention. Fatigue information participants were significantly more likely to consider non-sleep-related attributions for fatigue at post-intervention, relative to control participants. These results demonstrate that attributions for fatigue may be amenable to change via an information-based intervention; thus, this research explores a preliminary step toward investigating refinements to insomnia treatments. PMID- 22214182 TI - Editorial comment for Park et al. PMID- 22214183 TI - Quantitative assessment of brown adipose tissue metabolic activity and volume using 18F-FDG PET/CT and β3-adrenergic receptor activation. AB - BACKGROUND: Brown adipose tissue [BAT] metabolism in vivo is vital for the development of novel strategies in combating obesity and diabetes. Currently, BAT is activated at low temperatures and measured using 2-deoxy-2-18F-fluoro-D glucose [18F-FDG] positron-emission tomography [PET]. We report the use of beta3 adrenergic receptor-mediated activation of BAT at ambient temperatures using (R, R)-5-[2-[2,3-(3-chlorphenyl)-2-hydroxyethyl-amino]propyl]-1,3-benzodioxole-2,2 dicarboxylate, disodium salt [CL316,243] (a selective beta3-adrenoceptor agonist) and measured by 18F-FDG PET/computed tomography [CT]. METHODS: Control and CL316,243-treated (2 mg/kg) male Sprague-Dawley rats were administered with 18F FDG for PET/CT studies and were compared to animals at cold temperatures. Receptor-blocking experiments were carried out using propranolol (5 mg/kg). Dose effects of CL316,243 were studied by injecting 0.1 to 1 mg/kg 30 min prior to 18F FDG administration. Imaging results were confirmed by autoradiography, and histology was done to confirm BAT activation. RESULTS: CL316,243-activated interscapular BAT [IBAT], cervical, periaortic, and intercostal BATs were clearly visualized by PET. 18F-FDG uptake of IBAT was increased 12-fold by CL316,243 vs. 1.1-fold by cold exposure when compared to controls. 18F-FDG uptake of the CL activated IBAT was reduced by 96.0% using intraperitoneal administration of propranolol. Average 18F-FDG uptake of IBAT increased 3.6-, 3.5-, and 7.6-fold by doses of 0.1, 0.5, and 1 mg/kg CL, respectively. Ex vivo 18F-FDG autoradiography and histology of transverse sections of IBAT confirmed intense uptake in the CL activated group and activated IBAT visualized by PET. CONCLUSION: Our study indicated that BAT metabolic activity could be evaluated by 18F-FDG PET using CL316,243 at ambient temperature in the rodent model. This provides a feasible and reliable method to study BAT metabolism. PMID- 22214184 TI - Structure-function studies of a plant tyrosyl-DNA phosphodiesterase provide novel insights into DNA repair mechanisms of Arabidopsis thaliana. AB - TDP1 (tyrosyl-DNA phosphodiesterase 1), a member of the PLD (phospholipase D) superfamily, catalyses the hydrolysis of a phosphodiester bond between a tyrosine residue and the 3'-phosphate of DNA. We have previously identified and characterized the AtTDP gene in Arabidopsis thaliana, an orthologue of yeast and human TDP1 genes. Sequence alignment of TDP1 orthologues revealed that AtTDP has both a conserved C-terminal TDP domain and, uniquely, an N-terminal SMAD/FHA (forkhead-associated) domain. To help understand the function of this novel enzyme, we analysed the substrate saturation kinetics of full-length AtTDP compared with a truncated AtTDP mutant lacking the N-terminal FHA domain. The recombinant AtTDP protein hydrolysed a single-stranded DNA substrate with Km and kcat/Km values of 703+/-137 nM and (1.5+/-0.04)*10(9) M(-1).min(-1) respectively. The AtTDP-(Delta1-122) protein (TDP domain) showed kinetic parameters that were equivalent to those of the full-length AtTDP protein. A basic amino acid sequence (RKKVKP) within the AtTDP-(Delta123-605) protein (FHA domain) was necessary for nuclear localization of AtTDP. Analysis of active-site mutations showed that a histidine and a lysine residue in each of the HKD motifs were critical for enzyme activity. Vanadates, inhibitors of phosphoryl transfer reactions, inhibited AtTDP enzymatic activity and retarded the growth of an Arabidopsis tdp mutant. Finally, we showed that expression of the AtTDP gene could complement a yeast tdp1Deltarad1Delta mutant, rescuing the growth inhibitory effects of vanadate analogues and CPT (camptothecin). Taken together, the results of the present study demonstrate the structure-based function of AtTDP through which AtTDP can repair DNA strand breaks in plants. PMID- 22214185 TI - Site- and enantioselective formation of allene-bearing tertiary or quaternary carbon stereogenic centers through NHC-Cu-catalyzed allylic substitution. AB - Catalytic enantioselective allylic substitutions that result in addition of an allenyl group (<2% propargyl addition) and formation of tertiary or quaternary C C bonds are described. Commercially available allenylboronic acid pinacol ester is used. Reactions are promoted by a 5.0-10 mol % loading of sulfonate-bearing chiral bidentate N-heterocyclic carbene (NHC) complexes of copper, which exhibit the unique ability to furnish chiral products arising from the S(N)2' mode of addition. Allenyl-containing products are generated in up to 95% yield, >98% S(N)2' selectivity, and 99:1 enantiomeric ratio (er). Site-selective NHC-Cu catalyzed hydroboration of enantiomerically enriched allenes and conversion to the corresponding beta-vinyl ketones demonstrates the method's utility. PMID- 22214186 TI - Folding simulations of the A and B domains of protein G. AB - We study wild type and mutants of the A and B domain of protein G using all-atom Go-models. Our data substantiate the usefulness of such simulation for probing the folding mechanism of proteins and demonstrate that multifunnel versions of such models also allow probing of more complicated funnel landscapes. In our case, such models reproduce the experimentally observed distributions of the GA98 and GB98 mutants which differ only by one residue but fold into different structures. They also reveal details on the folding mechanism in these two proteins. PMID- 22214187 TI - A change in CD3gamma, CD3delta, CD3epsilon, and CD3zeta gene expression in T lymphocytes from benzene-exposed and benzene-poisoned workers. AB - Benzene is known to be highly toxic to a variety of cell types, including lymphocytes. A previous study showed that T-lymphocyte immune function disorder might be related to benzene exposure. To elucidate characteristics of TCR signal transduction in benzene-exposed workers, expression levels of CD3gamma, CD3delta, CD3epsilon, and CD3zeta genes in peripheral blood mononuclear cells (PBMC) were analyzed. Real-time RT-PCR using SYBR Green I was used to detect CD3 gene expression levels in PBMC from 20 benzene-exposed workers, seven workers with chronic mild benzene poisoning, five workers with chronic severe benzene poisoning and 14 healthy individuals (controls). The relative mRNA expression level was analyzed by the 2(-Deltact) * 100% method. In benzene-exposed worker cells, significantly higher CD3delta, CD3epsilon, and CD3zeta, expression levels were observed as compared with values for cells from the healthy controls. In the workers with chronic severe benzene poisoning, lymphocyte CD3gamma, CD3epsilon, and CD3zeta gene expression levels were significantly lower than in control cells. Lymphocytes from chronic mildly benzene- poisoned workers evinced two different gene expression patterns, i.e., CD3gamma and CD3epsilon levels were similar to those in the benzene-exposed worker cells, but CD3delta and CD3zeta expression levels were significantly lower relative to those in cells from chronic severely-benzene-poisoned counterparts. It remained to be determined if these reductions in expression of these genes presage or are indicative of deficiencies in the activities of T-lymphocytes in these workers. For now, it is hoped that this study may contribute to a better understanding of the disorders in cellular immunity frequently found with benzene-exposed workers. PMID- 22214189 TI - Regioselective synthesis of 3-arylamino- and 5-arylaminoisoxazoles from enaminones. AB - A highly regioselective synthesis of 3-arylamino- and 5-arylaminoisoxazoles from enaminones based on reaction condition selection is reported. 3 Arylaminoisoxazoles were produced by treating enaminones with aqueous hydroxylamine in DMF at 100 degrees C, whereas 5-arylaminoisoxazoles were synthesized by subjecting enaminones to aqueous hydroxylamine in the presence of KOH and TBAB in water under reflux. A mechanism for the regioselective synthesis of 3-arylamino- and 5-arylaminoisoxazoles is proposed. PMID- 22214188 TI - Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia. AB - BACKGROUND: Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E2 and PGD2. FINDINGS: We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE2 and PGD2 without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE2 and PGD2. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE2 and PGD2 levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE2 in non-stimulated microglia. CONCLUSION: Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation. PMID- 22214192 TI - Retention of KOH-soluble fluoride formed after application of a SnCl(2)/AmF/NaF containing mouth rinse under erosive conditions. AB - OBJECTIVE: Application of SnCl(2)/AmF/NaF containing mouth rinse showed good protection against erosion. The aim of the study was to evaluate if this is due to the amount of KOH-soluble fluoride (KOHsF) formed or its resistance under erosive conditions. METHODS: One hundred and fifty bovine enamel samples were allocated to five groups (n = 30) and were once eroded in 0.05 mol/l citric acid (5 min). Samples were stored in artificial saliva for 4 days. Samples of two groups (erosive-SnCl(2) + erosive-NaF) were eroded 6 * for 5 min. The remaining samples were stored in aqua dest deionised water. Each day the samples were treated twice for 2 min with 1 ml SnCl(2)/AmF/NaF-solution (erosive SnCl(2);neutral-SnCl(2)/AmF/NaF) or NaF-solution (erosive-NaF;neutral-NaF). The fifth group remained untreated (control). On day 5, 10 samples of each group were used for determination of KOHsF (series 1). The remaining samples were again eroded (erosive-SnCl(2) + erosive-NaF) or stored in artificial saliva (neutral SnCl(2) + neutral-NaF). KOHsF of another 10 samples of each group was measured (series 2). The last 10 samples of each group were also treated as described above and the amount of KOHsF was measured (series 3). RESULTS: In each series 1 3 KOHsF in group erosive-SnCl(2)/AmF/NaF were significantly higher. No significant loss of KOHsF between the series 1-3 was observed (except for control). CONCLUSION: SnCl(2)/AmF/NaF containing mouth rinse revealed a better formation of KOH-soluble fluoride as the NaF-solution, although the applied fluoride compound has no influence on the stability of the KOHsF under erosive conditions, leading to the conclusion that the resistance of KOHsF is not responsible for the difference in the protection against dental erosion. PMID- 22214194 TI - Fractional modeling dynamics of HIV and CD4+ T-cells during primary infection. AB - In this paper, we introduce fractional-order into a model of HIV-1 infection of CD4+ T cells. We study the effect of the changing the average number of viral particles N with different sets of initial conditions on the dynamics of the presented model. Generalized Euler method (GEM) will be used to find a numerical solution of the HIV-1 infection fractional order model. PMID- 22214193 TI - Codivergence and multiple host species use by fig wasp populations of the Ficus pollination mutualism. AB - BACKGROUND: The interaction between insects and plants takes myriad forms in the generation of spectacular diversity. In this association a species host range is fundamental and often measured using an estimate of phylogenetic concordance between species. Pollinating fig wasps display extreme host species specificity, but the intraspecific variation in empirical accounts of host affiliation has previously been underestimated. In this investigation, lineage delimitation and codiversification tests are used to generate and discuss hypotheses elucidating on pollinating fig wasp associations with Ficus. RESULTS: Statistical parsimony and AMOVA revealed deep divergences at the COI locus within several pollinating fig wasp species that persist on the same host Ficus species. Changes in branching patterns estimated using the generalized mixed Yule coalescent test indicated lineage duplication on the same Ficus species. Conversely, Elisabethiella and Alfonsiella fig wasp species are able to reproduce on multiple, but closely related host fig species. Tree reconciliation tests indicate significant codiversification as well as significant incongruence between fig wasp and Ficus phylogenies. CONCLUSIONS: The findings demonstrate more relaxed pollinating fig wasp host specificity than previously appreciated. Evolutionarily conservative host associations have been tempered by horizontal transfer and lineage duplication among closely related Ficus species. Independent and asynchronistic diversification of pollinating fig wasps is best explained by a combination of both sympatric and allopatric models of speciation. Pollinator host preference constraints permit reproduction on closely related Ficus species, but uncertainty of the frequency and duration of these associations requires better resolution. PMID- 22214196 TI - Relevance of electronic effects on the yield of CO2 from methanol oxidation. AB - The yields of products of methanol oxidation (HCHO, HCOOH, and CO(2)) were studied for carbon-supported PtRu nanoparticles having different amounts of alloyed and oxide phases. It is demonstrated that the increase in the Pt 5d-band vacancy enhances the production of CO(2), which is not directly related with the catalytic activity for CO oxidation. Results prove the relevant role of oxides and, at the same time, shed some new light on mechanistic aspects of methanol oxidation on PtRu nanocatalysts. It is also demonstrated that extrapolating from the behavior of smooth surfaces to nanoparticle systems is not always valid. PMID- 22214195 TI - Cell type specificity of female lung cancer associated with sulfur dioxide from air pollutants in Taiwan: an ecological study. AB - BACKGROUND: Many studies have examined the association between air pollutants (including sulfur dioxide [SO2], carbon monoxide [CO], nitrogen dioxide [NO2], nitric oxide [NO], ozone [O3], and particulate matter < 10 MUm [PM10]) and lung cancer. However, data from previous studies on pathological cell types were limited, especially for SO2 exposure. We aimed to explore the association between SO2 exposure from outdoor air pollutants and female lung cancer incidence by cell type specificity. METHODS: We conducted an ecological study and calculated annual average concentration of 6 air pollutants (SO2, CO, NO2, NO, O3, and PM10) using data from Taiwan Environmental Protection Administration air quality monitoring stations. The Poisson regression models were used to evaluate the association between SO2 and age-standardized incidence rate of female lung cancer by two major pathological types (adenocarcinoma [AC] and squamous cell carcinoma [SCC]). In order to understand whether there is a dose-response relationship between SO2 and two major pathological types, we analyzed 4 levels of exposure based on quartiles of concentration of SO2. RESULTS: The Poisson regression results showed that with the first quartile of SO2 concentration as the baseline, the relative risks for AC/SCC type cancer among females were 1.20 (95% confidence interval [CI], 1.04-1.37)/1.39 (95% CI, 0.96-2.01) for the second, 1.22 (95% CI, 1.04 1.43)/1.58 (95% CI, 1.06-2.37) for the third, and 1.27 (95% CI, 1.06-1.52)/1.80 (95% CI, 1.15-2.84) for the fourth quartile of SO2 concentration. The tests for trend were statistically significant for both AC and SCC at P = 0.0272 and 0.0145, respectively. CONCLUSION: The current study suggests that SO2 exposure as an air pollutant may increase female lung cancer incidence and the associations with female lung cancer is much stronger for SCC than for AC. The findings of this study warrant further investigation on the role of SO2 in the etiology of SCC. PMID- 22214197 TI - Spontaneous upper limb monoplegia secondary to probable cerebral amyloid angiopathy. AB - Cerebral amyloid angiopathy is a clinicopathological disorder characterised by vascular amyloid deposition initially in leptomeningeal and neocortical vessels, and later affecting cortical and subcortical regions. The presence of amyloid within the walls of these vessels leads to a propensity for primary intracerebral haemorrhage. We report the unusual case of a 77-year-old female who presented to our emergency department with sudden onset isolated hypoaesthesia and right upper limb monoplegia. A CT scan demonstrated a peripheral acute haematoma involving the left perirolandic cortices. Subsequent magnetic resonance imaging demonstrated previous superficial haemorrhagic events. One week following discharge the patient re-attended with multiple short-lived episodes of aphasia and jerking of the right upper limb. Further imaging demonstrated oedematous changes around the previous haemorrhagic insult. Cerebral amyloid angiopathy is an overlooked cause of intracerebral haemorrhage; the isolated nature of the neurological deficit in this case illustrates the many guises in which it can present. PMID- 22214198 TI - Risk groups defined by Recursive Partitioning Analysis of patients with colorectal adenocarcinoma treated with colorectal resection. AB - BACKGROUND: To define different prognostic groups of surgical colorectal adenocarcinoma patients derived from recursive partitioning analysis (RPA). METHODS: Ten thousand four hundred ninety four patients with colorectal adenocarcinoma underwent colorectal resection from Taiwan Cancer Database during 2003 to 2005 were included in this study. Exclusion criteria included those patients with stage IV disease or without number information of lymph nodes. For the definition of risk groups, the method of classification and regression tree was performed. Main primary outcome was 5-year cancer-specific survival. RESULTS: We identified six prognostic factors for cancer-specific survival, resulting in seven terminal nodes. Four risk groups were defined as following: Group 1 (mild risk, 1,698 patients), Group 2 (moderate risk, 3,129 patients), Group 3 (high risk, 4,605 patients) and Group 4 (very high risk, 1,062 patients). The 5-year cancer-specific survival for Group 1, 2, 3, and 4 was 86.6%, 62.7%, 55.9%, and 36.6%, respectively (p < 0.001). Hazard ratio of death was 2.13, 5.52 and 10.56 (95% confidence interval 1.74-2.60, 4.58-6.66 and 8.66-12.9, respectively) times for Group 2, 3, and 4 as compared to Group 1. The predictive capability of these grouping was also similar in terms of overall and progression-free survival. CONCLUSION: The use of RPA offered an alternative grouping method that could predict the survival of patients who underwent surgery for colorectal adenocarcinoma. PMID- 22214199 TI - P-glycoprotein at the blood-brain barrier: kinetic modeling of 11C desmethylloperamide in mice using a 18F-FDG MUPET scan to determine the input function. AB - PURPOSE: The objective of this study is the implementation of a kinetic model for 11C-desmethylloperamide (11C-dLop) and the determination of a typical parameter for P-glycoprotein (P-gp) functionality in mice. Since arterial blood sampling in mice is difficult, an alternative method to obtain the arterial plasma input curve used in the kinetic model is proposed. METHODS: Wild-type (WT) mice (pre injected with saline or cyclosporine) and P-gp knock-out (KO) mice were injected with 20 MBq of 11C-dLop, and a dynamic MUPET scan was initiated. Afterwards, 18.5 MBq of 18F-FDG was injected, and a static MUPET scan was started. An arterial input and brain tissue curve was obtained by delineation of an ROI on the left heart ventricle and the brain, respectively based on the 18F-FDG scan. RESULTS: A comparison between the arterial input curves obtained by the alternative and the blood sampling method showed an acceptable agreement. The one-tissue compartment model gives the best results for the brain. In WT mice, the K1/k2 ratio was 0.4 +/- 0.1, while in KO mice and cyclosporine-pretreated mice the ratio was much higher (2.0 +/- 0.4 and 1.9 +/- 0.2, respectively). K1 can be considered as a pseudo value K1, representing a combination of passive influx of 11C desmethylloperamide and a rapid washout by P-glycoprotein, while k2 corresponds to slow passive efflux out of the brain. CONCLUSIONS: An easy to implement kinetic modeling for imaging P-glycoprotein function is presented in mice without arterial blood sampling. The ratio of K1/k2 obtained from a one-tissue compartment model can be considered as a good value for P-glycoprotein functionality. PMID- 22214200 TI - Correlates of antiretroviral utilization among hospitalized HIV-infected crack cocaine users. AB - Despite the availability of antiretroviral therapy (ART), HIV-infected drug users, particularly crack cocaine users, continue to have high HIV-related morbidity and mortality. We conducted a cross-sectional analysis of the baseline data for hospitalized HIV-infected crack cocaine users recruited for Project HOPE (Hospital Visit Is an Opportunity for Prevention and Engagement with HIV-Positive Crack Users) in Atlanta and Miami who were eligible for ART (reported any lifetime use of ART or CD4 <350 cells/MUl). Among 350 eligible participants, whose mean age was 44.9 years (SD 7.0), 49% were male, 90% were black, and 81% were heterosexual. The median CD4 count was 144 cells/MUl, and 78 of 350 (22%) were taking ART. We conducted a multivariable logistic regression to examine individual, interpersonal, and structural factors as potential correlates of ART use. Reporting >=2 visits to outpatient HIV care in the past 6 months (AOR 7.55, 95% CI 3.80-14.99), drug or alcohol treatment in the past 6 months (AOR 2.29, 95% CI 1.06-4.94), and study site being Miami (AOR 2.99, 95% CI 1.56-5.73) were associated with ART use. Current homelessness (AOR 0.41, 95% CI 0.20-0.84) and CD4 <200 cells/MUl (AOR 0.29, 95% CI 0.15-0.55) were negatively associated with ART use. Among those taking ART, 60% had an HIV-1 viral load <400 copies/ml; this represented 9% of the eligible population. For HIV-infected crack cocaine users, structural factors may be as important as individual and interpersonal factors in facilitating ART utilization. Few HIV(+) crack cocaine users had viral suppression, but among those on ART, viral suppression was achievable. PMID- 22214201 TI - Novel dimeric DOTA-coupled peptidic Y1-receptor antagonists for targeting of neuropeptide Y receptor-expressing cancers. AB - BACKGROUND: Several peptide hormone receptors were identified that are specifically over-expressed on the cell surface of certain human tumors. For example, high incidence and density of the Y1 subtype of neuropeptide Y (NPY) receptors are found in breast tumors. Recently, we demonstrated that the use of potent radiolabeled somatostatin or bombesin receptor antagonists considerably improved the sensitivity of in vivo imaging when compared to agonists. We report here on the first DOTA-coupled peptidic Y1 receptor affine dimer antagonists. METHODS: Based on a Y1 affine dimeric peptide scaffold previously reported to competitively antagonize NPY-mediated processes, we have developed new dimeric DOTA-coupled Y1 receptor affine antagonists for scintigraphy and radiotherapy. These dimeric peptides were tested for their specific binding to Y1 expressed in SK-N-MC cells and Y2 expressed in SH-SY5Y as well as for their ability to mediate cAMP production in SK-N-MC cells. RESULTS: Introduction of two DOTA moieties at the N-termini of the dimeric NPY analogs as well as the double Asn29 replacement by Dpr(DOTA) or Lys(DOTA) (6 and 10) moiety dramatically reduced binding affinity. However, asymmetric introduction of the DOTA moiety in one segment of the peptidic heterodimer (8 and 11) resulted in suitable antagonists for receptor targeting with high binding affinity for Y1. All compounds were devoid of Y2 binding affinity. CONCLUSIONS: The design and the in vitro characterization of the first DOTA-coupled dimeric NPY receptor antagonist with high affinity and selectivity for Y1 over Y2 are described. This compound may be an excellent candidate for the imaging of Y1-positive tumors and their treatment. PMID- 22214202 TI - Molecular pathology of familial hypercholesterolemia, related dyslipidemias and therapies beyond the statins. AB - The development of the statin class of cholesterol-lowering drugs is one of the most significant success stories of modern pharmacotherapy. World-wide there are an estimated 150 million people on statins, with the emerging economies of India and China predicted to contribute significantly to that number. Notwithstanding their success, a significant number of people cannot tolerate statins because of serious side effects; of equal concern, a substantial proportion of high risk patients fail to reach cholesterol-lowering targets. For these subjects there is an urgent need for new cholesterol-lowering agents to be used alone or in combination with statins. The success of statins has been largely underpinned by knowledge of cholesterol homeostasis at a molecular level, knowledge that was first gleaned in the 1980s from Brown and Goldstein's pioneering studies of familial hypercholesterolemia (FH, OMIM 143890). Follow-up work that has identified a number of intracellular and circulating factors, all capable of disrupting LDL clearance, has revealed that the low-density lipoprotein receptor- (LDLR) mediated clearance pathway is substantially more complex than previously thought. These factors were discovered in studies of individuals with very rare inherited conditions that lead to either hypo- or hypercholesterolemia. These investigations, besides providing clearer insight into the molecular mechanisms regulating plasma LDL concentrations, have also revealed a number of novel therapeutic targets independent from statins. Consequently, a number of novel therapeutic approaches that are based on small interfering bio-molecules, including antisense oligonucleotides, are now in clinical development. These are aimed at impairing the assembly, synthesis and secretion of apolipoprotein B containing lipoproteins and/or accelerating their hepatic catabolism. The aim of this article is to focus on these recent advances in the understanding of the molecular basis of cholesterol metabolism that should herald novel cholesterol lowering agents beyond the statins. PMID- 22214203 TI - Disruption of tubulin polymerization and cell proliferation by 1-naphthylarsonic acid. AB - Arsenical compounds exhibit a differential toxicity to cancer cells. Microtubules are a primary target of a number of anticancer drugs, such as arsenical compounds. The interaction of 1-NAA (1-naphthylarsonic acid) has been investigated on microtubule polymerization under in vitro and cellular conditions. Microtubules were extracted from sheep brain. Transmission electron microscopy was used to show microtubule structure in the presence of 1-NAA. Computational docking method was applied for the discovery of ligand-binding sites on the microtubular proteins. Proliferation of HeLa cells and HF2 (human foreskin fibroblasts) was measured by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl-2H-tetrazolium bromide] assay method following their incubation with 1 NAA. Fluorescence microscopic labelling was done with the help of alpha-tubulin monoclonal antibody and Tunel kit was used to investigate the apoptotic effects of 1-NAA on the HeLa cells. 1-NAA inhibits the tubulin polymerization by the formation of abnormal polymers having high affinity to the inner cell wall. PMID- 22214204 TI - Pellicle and early dental plaque in periodontitis patients before and after surgical pocket elimination. AB - OBJECTIVE: Gingival inflammation may affect the composition of the dental pellicle and initial acquisition of bacteria, which in turn could affect the healing of the periodontal pocket. The aim of this study was to examine the dental pellicle and early supragingival biofilms in periodontitis patients with an established subgingival infiltrate before and after surgical pocket elimination. MATERIALS AND METHODS: Eleven patients with remaining pockets were selected. Samples were taken before and after surgical pocket elimination and after subsequent experimental gingivitis. Pellicle proteins were analyzed by SDS PAGE, immunoblotting and image analysis and 4-h supragingival plaque by culturing. RESULTS: The inflammatory status affected to a greater extent the concentration of plasma proteins than salivary proteins in the dental pellicle. The highest plasma protein concentrations were observed at remaining periodontal pockets where also the highest bacterial counts were found. The TVC was reduced on the gingival tooth surfaces (p < 0.05) after pocket elimination and increased slightly during experimental gingivitis. The finding of streptococci was highest on the incisal tooth surfaces and increased after surgery. Gram-negative anaerobes were sparse but seen more often before than after pocket elimination and on gingival than on incisal surfaces. CONCLUSIONS: This study suggests that increased amounts of plasma proteins in the pellicle formed in the presence of remaining periodontal pockets may foster the acquisition of bacteria, including proteolytic Gram-negative species. This, in turn, results in an increased de novo plaque formation rate. PMID- 22214205 TI - An exploratory study on assessment of gingival biotype and crown dimensions as predictors for implant esthetics comparing caucasian and Indian subjects. AB - Gingival biotype and crown dimensions may be important predictors for the esthetic outcome of surgical procedures. However, the visual distinction between "thick" and "thin" biotype may not be a suitable predictive parameter of surgical outcome. Intraoral photographs of 73 Indian and Dutch subjects were matched with respect to age and gender and were used to determine the gingival biotype (subjective assessment) and crown dimensions (objective assessment). Intraobserver and interobserver agreement was determined for subjective measurements (Cohen's kappa), and the error of the method was calculated for the objective measurements (Dahlberg formula). Intraobserver agreement for the subjective assessment of gingival biotype was adequate (kappa = 0.49-0.60), but interobserver agreement was poor (kappa = 0.10), whereas the error of the method for objective assessment of crown dimensions was small. The mean crown width length angle is smaller in Dutch as compared to Indian subjects in this sample (P < .05). Crown dimensions may be a more quantitative approach and could become a future norm to predict outcomes of implant restorative and surgical procedures, bearing in mind that cross-cultural differences may be present. PMID- 22214206 TI - Bone marrow mesenchymal stem cells in patients with beta thalassemia major: molecular analysis with attenuated total reflection-Fourier transform infrared spectroscopy study as a novel method. AB - Bone marrow mesenchymal stem cells (BM-MSCs) are the main cellular components of the bone marrow, providing a supportive cellular microenvironment to maintain healthy hematopoiesis. beta-thalassemia major (beta-TM) is characterized by anemia that is caused by a genetic defect in hemoglobin synthesis and results in ineffective erythropoiesis (IE). The alterations in the microenvironment in thalassemic bone marrow during IE can cause changes in BM-MSCs. This study aimed to investigate global structural and compositional changes in BM-MSCs in beta-TM that may provide a basis in understanding interactions of hematopoietic stem cells (HSCs)-MSCs in such a pathological bone marrow microenvironment. Following characterization of morphological, immunophenotypical, and differentiation properties, the changes in healthy and thalassemic BM-MSCs before and after bone marrow transplantation (BMT) were examined by attenuated total reflection-Fourier transform infrared (ATR-FTIR). The significant increase in lipid, protein, glycogen, and nucleic acid contents in thalassemic BM-MSCs with respect to healthy BM-MSCs was attributed to enhanced cell proliferation and BM activity during IE. The significant decreases in the content of mentioned macromolecules in post-transplant group BM-MSCs versus pre-transplant BM-MSCs was interpreted as restoring effect of BMT therapy on IE and defective BM microenvironment. These alterations were also supported by ELISA results of erythropoietin (EPO) and growth differentiation factor (GDF15) in bone marrow plasma samples as a reflection of IE and by MTT proliferation assay on BM-MSCs. Based on these changes, sampling groups were discriminated by cluster analysis. These results provide information for the studies that concentrate on interactions between HSCs MSCs in bone marrow. PMID- 22214207 TI - Comparison of a novel surface laser scanning anthropometric technique to traditional methods for facial parameter measurements. AB - This study was designed to determine if three-dimensional (3D) laser scanning techniques could be used to collect accurate anthropometric measurements, compared with traditional methods. The use of an alternative 3D method would allow for quick collection of data that could be used to change the parameters used for facepiece design, improving fit and protection for a wider variety of faces. In our study, 10 facial dimensions were collected using both the traditional calipers and tape method and a Konica-Minolta Vivid9i laser scanner. Scans were combined using RapidForm XOR software to create a single complete facial geometry of the subject as a triangulated surface with an associated texture image from which to obtain measurements. A paired t-test was performed on subject means in each measurement by method. Nine subjects were used in this study: five males (one African-American and four Caucasian females) and four females displaying a range of facial dimensions. Five measurements showed significant differences (p<0.05), with most accounted for by subject movements or amended by scanning technique modifications. Laser scanning measurements showed high precision and accuracy when compared with traditional methods. Significant differences found can be very small changes in measurements and are unlikely to present a practical difference. The laser scanning technique demonstrated reliable and quick anthropometric data collection for use in future projects in redesigning respirators. PMID- 22214209 TI - Dihalogenated sulfanilamides and benzolamides are effective inhibitors of the three beta-class carbonic anhydrases from Mycobacterium tuberculosis. AB - A series of halogenated sulfanilamides and halogenated benzolamide derivatives have been investigated as inhibitors of three beta-carbonic anhydrases (CAs, EC 4.2.1.1) from the bacterial pathogen Mycobacterium tuberculosis, mtCA 1 (Rv1284), mtCA 2 (Rv3588c) and mtCA 3 (Rv3273). All three enzymes were inhibited with efficacies between the submicromolar to the micromolar one, depending on the substitution pattern at the sulfanilamide moiety/fragment of the molecule. Best inhibitors were the halogenated benzolamides (K(I)s in the range of 0.12-0.45 MUM) whereas the halogenated sulfanilamides were slightly less inhibitory (K(I)s in the range of 0.41-4.74 MUM). This class of beta-CA inhibitors may have the potential for developing antimycobacterial agents with a diverse mechanism of action compared to the clinically used drugs for which many strains exhibit multi drug/extensive multi-drug resistance. PMID- 22214208 TI - Regulatory T cell frequencies do not correlate with breadth or magnitude of HIV-1 specific T cell responses. PMID- 22214210 TI - Synthesis and binding study of certain 6-arylalkanamides as molecular probes for cannabinoid receptor subtypes. AB - Tetrahydrocannabinol and other mixed cannabinoid (CB) receptors CB(1)/CB(2) receptor agonists are well established to elicit antinociceptive effects and psychomimetic actions, however, their potential for abuse have dampened enthusiasm for their therapeutic development. In an effort to refine a semi-rigid structural framework for CB(2) receptors binding, we designed novel compounds based on aromatic moiety and flexible linker with various amides mimicking the outlook of the endogenous anandamide which could provide as CB(2) receptor ligand. In this direction, we developed and synthesized new aryl or arylidene hexanoic acid amides and aryl alkanoic acid diamide carrying different head groups. These new compounds were tested for their affinities for human recombinant CB receptors CB(1) and CB(2) and fatty acid amide hydrolase. Although, the preliminary screening of these compounds demonstrated weak binding activity towards CB receptor subtypes at 10 umole, yet this template still could serve up as probes for further optimization and development of affinity ligand for CB receptors. PMID- 22214211 TI - Phase in nanooptics. AB - Quantitative phase measurements in imaging, microscopy, and nanooptics provide information not carried in amplitude measurements alone. In this issue of ACS Nano, Honigstein et al. present a new method in phase measurement. In this Perspective, we comment on this work and more broadly on the emerging role of phase and phase measurements in nanooptics. PMID- 22214212 TI - Parahalogenated phenols accelerate the photochemical release of nitrogen oxides from frozen solutions containing nitrate. AB - The photolysis of nitrate anion (NO(3)(-)) contained in surface ice and snow can be a regionally significant source of gas-phase nitrogen oxides and affect the composition of the planetary boundary layer. In this study, the photochemical release of nitrogen oxides from frozen solutions containing NO(3)(-) in the presence of organic compounds was investigated. Gas-phase nitrogen oxides were quantified primarily by NO-O(3) chemiluminescence detection of NO and NO(y) (=NO + NO(2) + HONO + HNO(3) + ?PAN + ?AN ...) and cavity ring-down spectroscopy of NO(2) and total alkyl nitrates (?AN). The photochemical production of gas-phase NO(y) was suppressed by the presence of formate, methanesulfonate, toluene, or phenol. In contrast, para-halogenated phenols (in the order of Cl > Br > F) promoted the conversion of NO(3)(-) to gas-phase NO(y), rationalized by acidification of the ice surface. PMID- 22214213 TI - Electrophoresis of a particle at an arbitrary surface potential and double layer thickness: importance of nonuniformly charged conditions. AB - Recent advances in material science and technology yield not only various kinds of nano- and sub-micro-scaled particles but also particles of various charged conditions such as Janus particles. The characterization of these particles can be challenging because conventional electrophoresis theory is usually based on drastic assumptions that are unable to realistically describe the actual situation. In this study, the influence of the nonuniform charged conditions on the surface of a particle at an arbitrary level of surface potential and double layer thickness on its electrophoretic behavior is investigated for the first time in the literature taking account of the effect of double-layer polarization. Several important results are observed. For instance, for the same averaged surface potential, the mobility of a nonuniformly charged particle is generally smaller than that of a uniformly charged particle, and the difference between the two depends upon the thickness of double layer. This implies that using the conventional electrophoresis theory may result in appreciable deviation, which can be on the order of ca. 20%. In addition, the nonuniform surface charge can yield double vortex in the vicinity of a particle by breaking the symmetric of the flow field, which has potential applications in mixing and/or regulating the medium confined in a submicrometer-sized space, where conventional mixing devices are inapplicable. PMID- 22214214 TI - Probing the effect of conformational constraint on phosphorylated ligand binding to an SH2 domain using polarizable force field simulations. AB - Preorganizing a ligand in the conformation it adopts upon binding to a protein has long been considered to be an effective way to improve affinity by making the binding entropy more favorable. However, recent thermodynamic studies of a series of complexes of the Grb2 SH2 domain with peptide analogues having constrained and flexible replacements for a phosphotyrosine residue revealed that less favorable binding entropies may result from constraining ligands in their biologically active conformations. Toward probing the origin of this unexpected finding, we examined the complexes of four phosphotyrosine-derived analogues with the Grb2 SH2 domain using molecular dynamics simulations with a polarizable force field. Significantly, the computed values for the relative binding free energies, entropies, and enthalpies of two pairs of constrained and unconstrained ligands reproduced the trends that were determined experimentally, although the relative differences were overestimated. These calculations also revealed that a large fraction of the ligands lacking the constraining element exist in solution as compact, macrocyclic-like structures that are stabilized by interactions between the phosphate groups and the amide moieties of the C-terminal pY+2 residues. In contrast, the three-membered ring in the constrained ligands prevents the formation of such macrocyclic structures, leading instead to globally extended, less ordered conformations. Quasiharmonic analysis of these conformational ensembles suggests that the unconstrained ligands possess significantly lower entropies in solution, a finding that is consistent with the experimental observation that the binding entropies for the unconstrained ligands are more favorable than for their constrained counterparts. This study suggests that introducing local constraints in flexible molecules may have unexpected consequences, and a detailed understanding of the conformational preferences of ligands in their unbound states is a critical prerequisite to correlating changes in their chemical structure with protein binding entropies and enthalpies. PMID- 22214216 TI - Spreading of a suspension drop on a horizontal surface. AB - Experimental studies were performed on the contact line motion of a suspension of PS particles on a glass surface. The base liquids were silicone oil and glycerin. The particle size was in the range of 1-6 MUm and the particle loading was 0.5-5 vol %. The drop shape was determined by using a drop image and its reflection and the drop outline was traced to the subpixel level. The Tanner-Voinov-Hoffman relation was valid for suspensions as well as for pure liquids. Silicone oil suspensions showed almost no noticeable change compared with the pure fluid. Glycerin suspensions showed an increase in contact line speed at low particle loading. The difference was due to the microstructure change at the contact line region, and the microstructure change was originated from the wetting characteristics of particles. Particle alignment occurred during the spreading stage for partially wetting particles. The contact line showed a stop-and-go fashioned motion due to surface irregularities. This result can be used as the boundary condition at the contact line in the numerical simulation of suspension spreading. PMID- 22214215 TI - Immune function in female B(6)C(3)F(1) mice is modulated by DE-71, a commercial polybrominated diphenyl ether mixture. AB - Polybrominated diphenyl ethers (PBDEs) are an important class of flame-retardants that are environmentally persistent and bioaccumulative. Toxicity of these compounds has become a concern because detectable levels of PBDEs are present in humans and wildlife and they are structurally similar to polychlorinated biphenyls (PCBs). This study examined the effects of the commercial penta-BDE mixture, DE-71, in adult female B(6)C(3)F(1) mice on hematology, serum clinical chemistry, thyroid hormones, tissue histology, and several immunotoxicity end points (lymphocyte proliferation, NK cell activity, splenic immunophenotypes, and SRBC-specific-IgM production). Mice were exposed via oral gavage for 28 days to achieve total administered doses (TAD) of 0, 0.5, 5, 50, or 100 mg/kg. No changes in histology, clinical chemistry, body or organ weights were observed. Serum total T3 and T4 levels were not altered by any of the DE-71 treatments. Peripheral blood monocyte numbers were decreased by the 0.5, 5, and 50 mg/kg treatments, but not by the 100 mg/kg TAD concentration. Compared to controls, mitogen-stimulated T- and B-cell proliferation was increased by the 100 mg/kg TAD concentration (ED(50) = 60 mg/kg TAD [2.14 mg/kg/day] and 58 mg/kg TAD [2.57 mg/kg/day], respectively). NK cell activity was decreased compared to controls by the 100 mg/kg TAD concentration (ED(50) = 20 mg/kg TAD [0.7 mg/kg/day]). No alterations were noted in thymic T-cell populations or in SRBC-specific-IgM production. Numbers of CD19(+)CD21(-), CD19(+)CD21(+), CD4(+)CD8(-), CD4( )CD8(+), CD4(-)CD8(-), and MHC-II(+) cells in the spleen were not affected. However, the numbers of splenic CD4(+)CD8(+) cells were decreased compared to the controls by 0.5, 5, and 100 mg/kg TAD. This study provides an assessment of the systemic toxicity and immunotoxicity of DE-71, and indicates that immune parameters are modulated at exposure concentrations lower than previously reported. PMID- 22214217 TI - Magnetism in dopant-free ZnO nanoplates. AB - It is known that bulk ZnO is a nonmagnetic material. However, the electronic band structure of ZnO is severely distorted when the ZnO is in the shape of a very thin plate with its dimension along the c-axis reduced to a few nanometers while keeping the bulk scale sizes in the other two dimensions. We found that the chemically synthesized ZnO nanoplates exhibit magnetism even at room temperature. First-principles calculations show a growing asymmetry in the spin distribution within the distorted bands formed from Zn (3d) and O (2p) orbitals with the reduction of thickness of the ZnO nanoplates, which is suggested to be responsible for the observed magnetism. In contrast, reducing the dimension along the a- or b-axes of a ZnO crystal does not yield any magnetism for ZnO nanowires that grow along c-axis, suggesting that the internal electric field produced by the large {0001} polar surfaces of the nanoplates may be responsible for the distorted electronic band structures of thin ZnO nanoplates. PMID- 22214218 TI - Tuning quantum corrections and magnetoresistance in ZnO nanowires by ion implantation. AB - Using ion implantation, the electrical as well as the magnetotransport properties of individual ZnO nanowires (NWs) can be tuned. The virgin NWs are configured as field-effect transistors which are in the enhancement mode. Al-implanted NWs reveal a three-dimensional metallic-like behavior, for which the magnetoresistance is well described by a semiempirical model that takes into account the presence of doping induced local magnetic moments and of two conduction bands. On the other hand, one-dimensional electron transport is observed in Co-implanted NWs. At low magnetic fields, the anisotropic magnetoresistance can be described in the framework of weak electron localization in the presence of strong spin-orbit scattering. From the weak localization, a large phase coherence length is inferred that reaches up to 800 nm at 2.5 K. The temperature-dependent dephasing is shown to result from a one-dimensional Nyquist noise-related mechanism. At the lowest temperatures, the phase coherence length becomes limited by magnetic scattering. PMID- 22214219 TI - Synthetic studies toward lapidilectine-type Kopsia alkaloids. AB - A rapid synthesis of the tetracyclic core of Kopsia indole alkaloids related to lapidilectine B, grandilodine C, and tenuisine A is reported. Key to the success of this route was an efficient and scalable Ugi four-component coupling to install all the necessary carbons found in the natural products. PMID- 22214220 TI - Combined inactivation of the Clostridium cellulolyticum lactate and malate dehydrogenase genes substantially increases ethanol yield from cellulose and switchgrass fermentations. AB - BACKGROUND: The model bacterium Clostridium cellulolyticum efficiently degrades crystalline cellulose and hemicellulose, using cellulosomes to degrade lignocellulosic biomass. Although it imports and ferments both pentose and hexose sugars to produce a mixture of ethanol, acetate, lactate, H2 and CO2, the proportion of ethanol is low, which impedes its use in consolidated bioprocessing for biofuels production. Therefore genetic engineering will likely be required to improve the ethanol yield. Plasmid transformation, random mutagenesis and heterologous expression systems have previously been developed for C. cellulolyticum, but targeted mutagenesis has not been reported for this organism, hindering genetic engineering. RESULTS: The first targeted gene inactivation system was developed for C. cellulolyticum, based on a mobile group II intron originating from the Lactococcus lactis L1.LtrB intron. This markerless mutagenesis system was used to disrupt both the paralogous L-lactate dehydrogenase (Ccel_2485; ldh) and L-malate dehydrogenase (Ccel_0137; mdh) genes, distinguishing the overlapping substrate specificities of these enzymes. Both mutations were then combined in a single strain, resulting in a substantial shift in fermentation toward ethanol production. This double mutant produced 8.5-times more ethanol than wild-type cells growing on crystalline cellulose. Ethanol constituted 93% of the major fermentation products, corresponding to a molar ratio of ethanol to organic acids of 15, versus 0.18 in wild-type cells. During growth on acid-pretreated switchgrass, the double mutant also produced four times as much ethanol as wild-type cells. Detailed metabolomic analyses identified increased flux through the oxidative branch of the mutant's tricarboxylic acid pathway. CONCLUSIONS: The efficient intron-based gene inactivation system produced the first non-random, targeted mutations in C. cellulolyticum. As a key component of the genetic toolbox for this bacterium, markerless targeted mutagenesis enables functional genomic research in C. cellulolyticum and rapid genetic engineering to significantly alter the mixture of fermentation products. The initial application of this system successfully engineered a strain with high ethanol productivity from cellobiose, cellulose and switchgrass. PMID- 22214221 TI - A high-spin iron(IV)-oxo complex supported by a trigonal nonheme pyrrolide platform. AB - We report the generation and characterization of a new high-spin iron(IV)-oxo complex supported by a trigonal nonheme pyrrolide platform. Oxygen-atom transfer to [(tpa(Mes))Fe(II)](-) (tpa(Ar) = tris(5-arylpyrrol-2-ylmethyl)amine) in acetonitrile solution affords the Fe(III)-alkoxide product [(tpa(Mes2MesO))Fe(III)](-) resulting from intramolecular C-H oxidation with no observable ferryl intermediates. In contrast, treatment of the phenyl derivative [(tpa(Ph))Fe(II)](-) with trimethylamine N-oxide in acetonitrile solution produces the iron(IV)-oxo complex [(tpa(Ph))Fe(IV)(O)](-) that has been characterized by a suite of techniques, including mass spectrometry as well as UV vis, FTIR, Mossbauer, XAS, and parallel-mode EPR spectroscopies. Mass spectral, FTIR, and optical absorption studies provide signatures for the iron-oxo chromophore, and Mossbauer and XAS measurements establish the presence of an Fe(IV) center. Moreover, the Fe(IV)-oxo species gives parallel-mode EPR features indicative of a high-spin, S = 2 system. Preliminary reactivity studies show that the high-spin ferryl tpa(Ph) complex is capable of mediating intermolecular C-H oxidation as well as oxygen-atom transfer chemistry. PMID- 22214222 TI - Developmental plasticity and the evolution of parasitism in an unusual nematode, Parastrongyloides trichosuri. AB - BACKGROUND: Parasitism is an important life history strategy in many metazoan taxa. This is particularly true of the Phylum Nematoda, in which parasitism has evolved independently at least nine times. The apparent ease with which parasitism has evolved amongst nematodes may, in part, be due to a feature of nematode development acting as a pre-adaptation for the transition from a free living to a parasitic life history. One candidate pre-adaptive feature for evolution in terrestrial nematodes is the dauer larva, a developmentally arrested morph formed in response to environmental signals. RESULTS: We investigated the role of dauer development in the nematode, Parastrongyloides trichosuri, which has retained a complete free-living life cycle in addition to a life cycle as a mammalian gastrointestinal parasite. We show that the developmental switch between these life histories is sensitive to the same environmental cues as dauer arrest in free-living nematodes, including sensitivity to a chemical cue produced by the free-living stages. Furthermore, we show that genetic variation for the sensitivity of the cue(s) exists in natural populations of P. trichosuri, such that we derived inbred lines that were largely insensitive to the cue and other lines that were supersensitive to the cue. CONCLUSIONS: For this parasitic clade, and perhaps more widely in the phylum, the evolution of parasitism co-opted the dauer switch of a free-living ancestor. This lends direct support to the hypothesis that the switch to developmental arrest in the dauer larva acted as a pre-adaptation for the evolution of parasitism, and suggests that the sensory transduction machinery downstream of the cue may have been similarly co-opted and modified. PMID- 22214223 TI - Prevalence and risk indicators of gingivitis and periodontitis in a multi-centre study in North Jordan: a cross sectional study. AB - BACKGROUND: There are limited data about the epidemiology and risk factors/indicators of gingivitis, aggressive periodontitis (AgP) and chronic periodontitis (CP) in Jordan. The aim of this study was to assess the prevalence and risk indicators of gingivitis, AgP and CP. METHODS: A sample of 595 subjects was randomly selected from subjects escorting out-patients attending a Medical Center, a Dental Teaching Hospital, and 2 private dental clinics. The socio demographic variables, oral hygiene habits, income, smoking and Body Mass Index (BMI) were recorded. Full mouth periodontal examination was performed, and radiographs were taken for sites with probing depth > 3 mm. RESULTS: About 76% had gingivitis, 2.2% had AgP and 5.5% had CP. Periodontitis was more frequent among males than females with a M: F ratio of 1.6:1 and the prevalence increased with age. Subjects who reported not using a tooth brush, smokers and subjects with BMI > 30 kg/m2 had significantly higher prevalence of periodontitis. The risk for periodontitis was greater among subjects who reported positive family history and subjects with <= 12 years of education. CONCLUSIONS: This is the first study to report on the prevalence of gingivitis, CP and AgP in North Jordanian. Age, low education, low frequency of tooth brushing and family history were significantly associated with increased risk of periodontitis. PMID- 22214224 TI - Low incidence of positive smooth muscle antibody and high incidence of isolated IgM elevation in Chinese patients with autoimmune hepatitis and primary biliary cirrhosis overlap syndrome: a retrospective study. AB - : BACKGROUND: Up to now, few data are available regarding the clinical characteristics of autoimmune hepatitis and primary biliary cirrhosis overlap syndrome. The study was to investigate and analyze the prevalent and clinical features of Chinese patients with this disease. METHODS: Clinical data on patients diagnosed as autoimmune hepatitis and primary biliary cirrhosis overlap syndrome in our hospital from January 2001 to December 2006 were collected and analyzed. RESULTS: Overlap syndrome of autoimmune hepatitis and primary biliary cirrhosis accounted for 10.33% of patients with autoimmune liver diseases during the past six years. For these patients with overlap syndrome, xanthochromia, lethargy and anorexia were the predominant complaints; a low incidence (14/146) of smooth muscle antibody positivity and a high incidence (37/89) of isolated IgM elevation were the main serological characteristics. CONCLUSIONS: Overlap syndrome of autoimmune hepatitis and primary biliary cirrhosis was not rare in Chinese patients with clinical manifests of autoimmune liver diseases. Overlap of the diseases should not be disregarded when isolated IgM elevation was exhibited, and smooth muscle antibody might have little diagnostic significance in the overlap syndrome. If it was difficult to make a definite diagnosis, liver biopsy was necessary. PMID- 22214225 TI - Inert coupling of IRDye800CW to monoclonal antibodies for clinical optical imaging of tumor targets. AB - BACKGROUND: Photoimmunodetection, in which monoclonal antibodies [mAbs] are labeled with fluorescent dyes, might have clinical potential for early detection and characterization of cancer. For this purpose, the dye should be coupled in an inert way to mAb. In this study, different equivalents of IRDye800CW, a near infrared fluorescent dye, were coupled to 89Zr-labeled cetuximab and bevacizumab, and conjugates were evaluated in biodistribution studies. Radiolabeled mAbs were used to allow accurate quantification for assessment of the number of dye groups that can be coupled to mAbs without affecting their biological properties. METHODS: 89Zr-cetuximab and 89Zr-bevacizumab, containing 0.5 89Zr-desferal group per mAb molecule, were incubated with 1 to 10 eq IRDye800CW at pH 8.5 for 2 h at 35 degrees C, and 89Zr-mAb-IRDye800CW conjugates were purified by a PD10 column using 0.9% NaCl as eluent. HPLC analysis at 780 nm was used to assess conjugation efficiency. In vitro stability measurements were performed in storage buffer (0.9% NaCl or PBS) at 4 degrees C and 37 degrees C and human serum at 37 degrees C. 89Zr-mAb-IRDye800CW conjugates and 89Zr-mAb conjugates (as reference) were administered to nude mice bearing A431 (cetuximab) or FaDu (bevacizumab) xenografts, and biodistribution was assessed at 24 to 72 h after injection. RESULTS: Conjugation efficiency of IRDye800CW to 89Zr-mAbs was approximately 50%; on an average, 0.5 to 5 eq IRDye800CW was conjugated. All conjugates showed optimal immunoreactivity and were > 95% stable in storage buffer at 4 degrees C and 37 degrees C and human serum at 37 degrees C for at least 96 h. In biodistribution studies with 89Zr-cetuximab-IRDye800CW, enhanced blood clearance with concomitant decreased tumor uptake and increased liver uptake was observed at 24 to 72 h post-injection when 2 or more eq of dye had been coupled to mAb. No significant alteration of biodistribution was observed 24 to 48 h after injection when 1 eq of dye had been coupled. 89Zr-bevacizumab-IRDye800CW showed a similar tendency, with an impaired biodistribution when 2 eq of dye had been coupled to mAb. CONCLUSION: Usage of 89Zr-mAbs allows accurate quantification of the biodistribution of mAbs labeled with different equivalents of IRDye800CW. Alteration of biodistribution was observed when more than 1 eq of IRDye800CW was coupled to mAbs. PMID- 22214226 TI - Diagnostic evaluation of three cardiac software packages using a consecutive group of patients. AB - PURPOSE: The aim of this study was to compare the diagnostic performance of the three software packages 4DMSPECT (4DM), Emory Cardiac Toolbox (ECTb), and Cedars Quantitative Perfusion SPECT (QPS) for quantification of myocardial perfusion scintigram (MPS) using a large group of consecutive patients. METHODS: We studied 1,052 consecutive patients who underwent 2-day stress/rest 99mTc-sestamibi MPS studies. The reference/gold-standard classifications for the MPS studies were obtained from three physicians, with more than 25 years each of experience in nuclear cardiology, who re-evaluated all MPS images. Automatic processing was carried out using 4DM, ECTb, and QPS software packages. Total stress defect extent (TDE) and summed stress score (SSS) based on a 17-segment model were obtained from the software packages. Receiver-operating characteristic (ROC) analysis was performed. RESULTS: A total of 734 patients were classified as normal and the remaining 318 were classified as having infarction and/or ischemia. The performance of the software packages calculated as the area under the SSS ROC curve were 0.87 for 4DM, 0.80 for QPS, and 0.76 for ECTb (QPS vs. ECTb p = 0.03; other differences p < 0.0001). The area under the TDE ROC curve were 0.87 for 4DM, 0.82 for QPS, and 0.76 for ECTb (QPS vs. ECTb p = 0.0005; other differences p < 0.0001). CONCLUSION: There are considerable differences in performance between the three software packages with 4DM showing the best performance and ECTb the worst. These differences in performance should be taken in consideration when software packages are used in clinical routine or in clinical studies. PMID- 22214227 TI - Use of a beta microprobe system to measure arterial input function in PET via an arteriovenous shunt in rats. AB - BACKGROUND: Kinetic modeling of physiological function using imaging techniques requires the accurate measurement of the time-activity curve of the tracer in plasma, known as the arterial input function (IF). The measurement of IF can be achieved through manual blood sampling, the use of small counting systems such as beta microprobes, or by derivation from PET images. Previous studies using beta microprobe systems to continuously measure IF have suffered from high background counts. METHODS: In the present study, a light-insensitive beta microprobe with a temporal resolution of up to 1 s was used in combination with a pump-driven femoral arteriovenous shunt to measure IF in rats. The shunt apparatus was designed such that the placement of the beta microprobe was highly reproducible. The probe-derived IF was compared to that obtained from manual sampling at 5-s intervals and IF derived from a left ventricle VOI in a dynamic PET image of the heart. RESULTS: Probe-derived IFs were very well matched to that obtained by "gold standard" manual blood sampling, but with an increased temporal resolution of up to 1 s. The area under the curve (AUC) ratio between probe- and manually derived IFs was 1.07 +/- 0.05 with a coefficient of variation of 0.04. However, image-derived IFs were significantly underestimated compared to the manually sampled IFs, with an AUC ratio of 0.76 +/- 0.24 with a coefficient of variation of 0.32. CONCLUSIONS: IF derived from the beta microprobe accurately represented the IF as measured by blood sampling, was reproducible, and was more accurate than an image-derived technique. The use of the shunt removed problems of tissue background activity, and the use of a light-tight probe with minimal gamma sensitivity refined the system. The probe/shunt apparatus can be used in both microprobe and PET studies. PMID- 22214228 TI - Combination effect of PectaSol and Doxorubicin on viability, cell cycle arrest and apoptosis in DU-145 and LNCaP prostate cancer cell lines. AB - The effect of PectaSol on Dox (Doxorubicin) cytotoxicity in terms of apoptosis and cell cycle changes in PCa (prostate cancer) cell lines (DU-145 and LNCaP) has been investigated. Combination of PectaSol and Dox resulted in a viability of 29.4 and 32.6% (P<0.001) in DU-145 and LNCaP cells. The IC50 values decreased 1.5 fold and 1.3-fold in the DU-145 and LNCaP cells respectively. In the DU-145 cells, combination of PectaSol and Dox resulted in a reduction in p27 gene and protein expression (P<0.001). In LNCaP cells, this combination increased p53, p27 and Bcl-2 expression. Treatment with both drugs in DU-145 cells led to an increase in sub-G1 arrest (54.6% compared with 12.2% in Dox). In LNCaP cells, combination of the drugs led to an increased in G2/M arrest (61.7% compared with 53.6% in Dox). Based on these findings, progressive cytotoxicity effect of Dox and PectaSol together rapidly induce cell death in DU-145 through apoptosis and in LNCaP cells through cell cycle arrest (G2/M arrest). PMID- 22214229 TI - Bowel evisceration through the bladder neck in a paraplegic female secondary to urethral coitus. AB - INTRODUCTION: Urethral coitus is rarely reported in the literature. The majority of reported cases have been secondary to vaginal agenesis or hymenal anomalies. AIM: We report a case of urethral coitus in a paraplegic patient with a patulous urethra resulting from chronic indwelling catheter use, with the unfortunate presentation of bladder rupture and evisceration per urethra. To our knowledge, this is the only report of urethral coitus due to sequelae from an indwelling catheter, as well as the only report of the subsequent complication of bowel evisceration per urethra. RESULTS: After initial temporization at an outside facility, we were able to perform primary cystorrhaphy. There was no need for bowel resection. The patient has chosen to defer her decision on permanent reconstruction. CONCLUSIONS: Urethral coitus is rare and the subsequent ramifications can be devastating, particularly in neurologically impaired patients. This unusual case speaks to the importance of properly caring for the neurogenic bladder. PMID- 22214230 TI - Nuclear and plastid haplotypes suggest rapid diploid and polyploid speciation in the N Hemisphere Achillea millefolium complex (Asteraceae). AB - BACKGROUND: Species complexes or aggregates consist of a set of closely related species often of different ploidy levels, whose relationships are difficult to reconstruct. The N Hemisphere Achillea millefolium aggregate exhibits complex morphological and genetic variation and a broad ecological amplitude. To understand its evolutionary history, we study sequence variation at two nuclear genes and three plastid loci across the natural distribution of this species complex and compare the patterns of such variations to the species tree inferred earlier from AFLP data. RESULTS: Among the diploid species of A. millefolium agg., gene trees of the two nuclear loci, ncpGS and SBP, and the combined plastid fragments are incongruent with each other and with the AFLP tree likely due to incomplete lineage sorting or secondary introgression. In spite of the large distributional range, no isolation by distance is found. Furthermore, there is evidence for intragenic recombination in the ncpGS gene. An analysis using a probabilistic model for population demographic history indicates large ancestral effective population sizes and short intervals between speciation events. Such a scenario explains the incongruence of the gene trees and species tree we observe. The relationships are particularly complex in the polyploid members of A. millefolium agg. CONCLUSIONS: The present study indicates that the diploid members of A. millefolium agg. share a large part of their molecular genetic variation. The findings of little lineage sorting and lack of isolation by distance is likely due to short intervals between speciation events and close proximity of ancestral populations. While previous AFLP data provide species trees congruent with earlier morphological classification and phylogeographic considerations, the present sequence data are not suited to recover the relationships of diploid species in A. millefolium agg. For the polyploid taxa many hybrid links and introgression from the diploids are suggested. PMID- 22214231 TI - Beneficial effect of adenosine on myocardial perfusion in patients treated with primary percutaneous coronary intervention for acute myocardial infarction. AB - The present study investigated the effects of intravenous adenosine on myocardial perfusion and segmental contractile function when used as an adjunct of primary percutaneous coronary intervention (PCI) in patients with acute ST segment elevation myocardial infarction (STEMI). Patients were randomly assigned to receive intravenous adenosine (n = 35) or saline (n = 34) within 12 h of STEMI. Myocardial contrast echocardiography (MCE) and velocity vector imaging (VVI) were performed 7 days after primary PCI. Serial echocardiography was performed on Days 7 and 30. Capillary blood volume (A; 6.34 +/- 1.98 vs 5.64 +/- 1.84 dB; P = 0.03) and myocardial blood velocity (beta; 0.13 +/- 0.04 vs 0.1 +/- 0.04/s; P = 0.01) were higher in the adenosine group than in control patients. Myocardial blood flow (A * beta) was 0.82 +/- 0.37 dB/s with adenosine compared with 0.57 +/- 0.4 dB/s in control patients (P < 0.01). Improvements were seen in the adenosine compared with the control group in terms of myocardial wall strain(-13.52 +/- 5.61% vs -11.47 +/- 5.25%, respectively; P = 0.03), strain rate (-1.08 +/- 0.52 vs -0.90 +/- 0.44/s, respectively; P = 0.03) and segmental ejection fraction (53.66 +/- 12.04% vs 48.40 +/- 14.99%, respectively; P = 0.03). There was a correlation between myocardial perfusion in apical anterior segments, peak systolic strain (P = 0.001), strain rate (P = 0.001) and segmental ejection (P < 0.001). Global contractile function was better in the adenosine-treated than control group. At the 1 month follow up, there were no significant differences between groups in terms of the incidence of recurrent angina or heart failure. The results of the present study suggest that periprocedural intravenous adenosine contributes to improvements in myocardial perfusion, segmental wall motion and global contractile function in patients with acute myocardial infarction undergoing primary PCI. PMID- 22214234 TI - Denture wearer's perception of ambient care, part 1: validation of a preliminary scale. AB - OBJECTIVE: The aim of the present study was to investigate if a preliminary Ambient Care Scale (ACS), intended to measure ambient care in complete denture wearers, had acceptable reliability and validity. MATERIALS AND METHODS: A sample of 117 patients who had received complete dentures in both jaws in the period 1997-2005 at Bergen School of Dentistry completed a questionnaire containing eight items regarding the patients' relationship with the student and clinical personnel, to what extent they were informed and consulted during treatment, waiting times and cost. In addition, information was gathered regarding demographics, The Psychological General Well-Being index (WHO-5), global ambient care, satisfaction with dentures and how patients viewed their oral health. RESULTS: Cronbach's alpha coefficient was 0.76 for the ACS, indicating acceptable internal consistency. From principle component analysis, three factors were extracted, correlating with ACS with coefficients of 0.72, 0.58 and 0.59, respectively. Acceptable construct validity was indicated by the fact that items were formulated by common agreement among three experienced prosthodontists, the extremely low frequency of missing data (<2%) and that ACS, as expected, was able to discriminate between patients satisfied and dissatisfied with their dentures (p = 0.005) and oral health (p = 0.042), but not between those who had high or low WHO-5 scores (p = 0.77). CONCLUSIONS: The ACS appears to have acceptable psychometric properties. PMID- 22214232 TI - The role of G protein gene GNB3 C825T polymorphism in HIV-1 acquisition, progression and immune activation. AB - BACKGROUND: The GNB3 C825T polymorphism is associated with increased G protein mediated signal transduction, SDF-1alpha-mediated lymphocyte chemotaxis, accelerated HIV-1 progression, and altered responses to antiretroviral therapy among Caucasian subjects. The GNB3 825T allele is highly prevalent in African populations, and as such any impact on HIV-1 acquisition or progression rates could have a dramatic impact. This study examines the association of the 825T polymorphism with HIV-1 acquisition, disease progression and immune activation in two African cohorts. GNB3 825 genotyping was performed for enrolees in both a commercial sex worker cohort and a perinatal HIV transmission (PHT) cohort in Nairobi, Kenya. Ex vivo immune activation was quantified by flow cytometry, and plasma chemokine levels were assessed by cytokine bead array. RESULTS: GNB3 genotype was not associated with sexual or vertical HIV-1 acquisition within these cohorts. Within the Pumwani cohort, GNB3 genotype did not affect HIV-1 disease progression among seroconverters or among HIV-1-positive individuals after adjustment for baseline CD4 count. Maternal CD4 decline and viral load increase in the PHT cohort did not differ between genotypes. Multi-parametric flow cytometry assessment of T cell activation (CD69, HLA-DR, CD38) and Treg frequency (CD25(+)FOXP3(+)) found no differences between genotype groups. Plasma SDF-1alpha, MIP-1beta and TRAIL levels quantified by cytokine bead array were also similar between groups. CONCLUSIONS: In contrast to previous reports, we were unable to provide evidence to suggest that the GNB3 C825T polymorphism affects HIV-1 acquisition or disease progression within African populations. Ex vivo immune activation and plasma chemokine levels were similarly unaffected by GNB3 genotype in both HIV-1-negative and HIV-1-positive individuals. The paucity of studies investigating the impact of GNB3 polymorphism among African populations and the lack of mechanistic studies make it difficult to assess the true biological significance of this polymorphism in HIV-1 infection. PMID- 22214235 TI - Impact of the apolipoprotein B/apolipoprotein A-I ratio on renal outcome in immunoglobulin A nephropathy. AB - OBJECTIVE: Serum levels of the apolipoprotein B/apolipoprotein A-I ratio (ApoB/ApoA-I) have been shown to identify patients at risk of cardiovascular disease. The aim of this study was to evaluate whether raised ApoB/ApoA-I values are also predictive of renal outcome in patients with chronic kidney disease (CKD), as similar mechanisms seem to be involved in the development of atherosclerosis and glomerulosclerosis. Only patients with immunoglobulin A nephropathy (IgAN) were included, since they represent a homogeneous group of patients with CKD. MATERIAL AND METHODS: ApoB and ApoA-I, serum albumin, urine albumin and blood pressure were measured, and a highly sensitive C-reactive protein test was carried out, in 70 patients with IgAN and in 70 age- and gender matched healthy control subjects. Patients were followed over a period of up to 11 years (median 3.8 years). End-stage renal disease (ESRD) was defined as reaching CKD stage 5 [estimated glomerular filtration rate (eGFR) <15 ml/min/1.73 m2]. RESULTS: Baseline ApoB/ApoA-I values greater than 0.9 for men and greater than 0.8 for women were associated with a risk of developing CKD stage 5 (risk ratio 5.7, p = 0.037), independently of baseline GFR and serum albumin. CONCLUSION: Patients with IgAN and an increased ApoB/ApoA-I ratio have a significantly higher risk of developing ESRD compared with patients with a low ratio. Controlled studies are warranted to demonstrate whether interventions focusing on the ApoB/ApoA-I ratio may have beneficial clinical effects. PMID- 22214236 TI - HCV coinfection does not alter the frequency of regulatory T cells or CD8+ T cell immune activation in chronically infected HIV+ Chinese subjects. AB - Regulatory T cell (Treg) is a subset of CD4(+) T cells that play a critical role in regulating the immune responses. Human immunodeficiency virus (HIV) infection is associated with T cell abnormalities and alters effector T cell function. There are a large number of patients coinfected with HIV and hepatitis C virus (HCV). Here, we evaluated the proportion of CD4(+) Treg cells expressing CD25 and FOXP3, and the status of immune activation of CD8(+) T cells in 60 Chinese patients chronically infected with HIV and/or HCV. Furthermore, we investigated the influence of highly active antiretroviral therapy (HAART) on the level of Treg cells and immune activated CD8(+) T cells. We observed that the Treg level was upregulated in HIV infection and HCV infection could not enhance this kind of upregulation significantly. The level of Treg cells was negatively correlated with CD4(+) T cell counts and positively correlated with HIV viral loads. We observed considerably elevated CD38 and HLA-DR expression in CD8(+) T cells in HIV-infected subjects but not in HCV-infected patients in comparison to that in healthy controls. There is no significant difference concerning the proportion of CD8(+) T cells expressing CD38 or HLA-DR between HIV-1-monoinfected and HIV/HCV coinfected patients. After 12-week HAART, the proportion of Treg cells dropped, but still more than the level in healthy controls. HAART could reverse the abnormal immune activation of CD8(+) T cells. The decrease of Tregs did not alter the downregulation of HIV-1-specific CTL responses in these HIV-infected patients after HAART therapy. The level of HIV virus might be the key point for the decline of CTL responses. PMID- 22214237 TI - Outdoor light at night (LAN) is correlated with eveningness in adolescents. AB - External zeitgebers synchronize the human circadian rhythm of sleep and wakefulness. Humans adapt their chronotype to the day-night cycle, the strongest external zeitgeber. The human circadian rhythm shifts to evening-type orientation when daylight is prolonged into the evening and night hours by artificial light sources. Data from a survey of 1507 German adolescents covering questions about chronotype and electronic screen media use combined with nocturnal satellite image data suggest a relationship between chronotype and artificial nocturnal light. Adolescents living in brightly illuminated urban districts had a stronger evening-type orientation than adolescents living in darker and more rural municipalities. This result persisted when controlling for time use of electronic screen media, intake of stimulants, type of school, age, puberty status, time of sunrise, sex, and population density. Time spent on electronic screen media use-a source of indoor light at night-is also correlated with eveningness, as well as intake of stimulants, age, and puberty status, and, to a lesser degree, type of school and time of sunrise. Adequate urban development design and parents limiting adolescents' electronic screen media use in the evening could help to adjust adolescents' zeitgeber to early school schedules when they provide appropriate lighting conditions for daytime and for nighttime. PMID- 22214239 TI - Control of single molecular nanodot patterns of phenyl azomethine dendrimers by statistical simulation. AB - Precisely synthesized subnanometer particles of metals or metal oxides can be prepared using dendritic polyphenyl azomethines as the template. With a goal of their arrays to a surface using a simple and quick process, such as spin-casting, statistical analyses were applied to a nanodot array of the dendrimers to obtain the relationship between the experimental condition and the results such as size, spacing, or its standard deviations. The dot patterns of a single molecular dendrimer on a substrate were able to be predicted with numerical values of the experimental parameters associated with the spin coat (concentration of the dendrimer, physical properties of solvent, the spin coating recipe, temperature of the solution, relative humidity (RH)) as the inputs for the statistical analysis. PMID- 22214238 TI - Progenitor/stem cell fate determination: interactive dynamics of cell cycle and microvesicles. AB - We have shown that hematopoietic stem/progenitor cell phenotype and differentiative potential change throughout cell cycle. Lung-derived microvesicles (LDMVs) also change marrow cell phenotype by inducing them to express pulmonary epithelial cell-specific mRNA and protein. These changes are accentuated when microvesicles isolated from injured lung. We wish to determine if microvesicle-treated stem/progenitor cell phenotype is linked to cell cycle and to the injury status of the lung providing microvesicles. Lineage depleted, Sca-1+ (Lin-/Sca-1+) marrow isolated from mice were cultured with interleukin 3 (IL-3), IL-6, IL-11, and stem cell factor (cytokine-cultured cells), removed at hours zero (cell cycle phase G0/G1), 24 (late G1/early S), and 48 (late S/early G2/M), and cocultured with lung tissue, lung conditioned media (LCM), or LDMV from irradiated or nonirradiated mice. Alternatively, Lin-/Sca-1+ cells not exposed to exogenous cytokines were separated into G0/G1 and S/G2/M cell cycle phase populations by fluorescence-activated cell sorting (FACS) and used in coculture. Separately, LDMV from irradiated and nonirradiated mice were analyzed for the presence of adhesion proteins. Peak pulmonary epithelial cell-specific mRNA expression was seen in G0/G1 cytokine-cultured cells cocultured with irradiated lung and in late G1/early S cells cocultured with nonirradiated lung. The same pattern was seen in cytokine-cultured Lin-/Sca-1 cells cocultured with LCM and LDMV and when FACS-separated Lin-/Sca-1 cells unexposed to exogenous cytokines were used in coculture. Cells and LDMV expressed adhesion proteins whose levels differed based on cycle status (cells) or radiation injury (LDMV), suggesting a mechanism for microvesicle entry. These data demonstrate that microvesicle modification of progenitor/stem cells is influenced by cell cycle and the treatment of the originator lung tissue. PMID- 22214241 TI - Computational studies for reduced graphene oxide in hydrogen-rich environment. AB - We employ molecular dynamic simulations to study the reduction process of graphene oxide (GO) in a chemically active environment enriched with hydrogen. We examine the concentration and pressure of hydrogen gas as a function of temperature in which abstraction of oxygen is possible with minimum damage to C sp(2) bonds, hence preserving the integrity of the graphene sheet. Through these studies we find chemical pathways that demonstrate beneficiary mechanisms for the quality of graphene including formation of water as well as suppression of carbonyl pair holes in favor of hydroxyl and epoxide formation facilitated by hydrogen gas in the environment. PMID- 22214240 TI - Alterations in T-lymphocyte sub-set profiles and cytokine secretion by PBMC of systemic lupus erythematosus patients upon in vitro exposure to organochlorine pesticides. AB - Chronic exposure to organochlorine pesticides (OCP) has been suspected of causing immunoregulatory abnormalities that eventually lead to development and progression of systemic lupus erythematosus (SLE), but the role of these non genetic stimuli has remained poorly understood. The objectives of the study were to quantify the levels of different OCP residues in the blood of SLE patients and to study the effects of in vitro treatment of peripheral blood mononuclear cells (PBMC) from these patients and healthy controls with OCP. Levels of different OCP residues in the blood were measured by gas-liquid chromatography. Isolated PBMC were treated in vitro with hexachlorocyclohexane (HCH), o,p' dichlorodiphenyltrichloroethane (DDT), or phytohemagglutinin-M (PHA-M) for 72 h, then stained with different dye-labeled monoclonal antibodies to analyze alterations in T-lymphocytes using flow cytometry. Levels of different T(H)1 and T(H)2 cytokines were also estimated by ELISA. Significantly higher levels of p,p' DDE and beta-HCH were detected in the blood of SLE patients than in healthy controls. HCH exposure markedly increased the percentages of CD3(+)CD4(+) T lymphocytes and expression of CD45RO(+) on CD4(+) and CD8(+) T-lymphocytes, but decreased CD4(+)CD25(+) T-lymphocytes in SLE patients. DDT exposure increased the percentages of CD3(+)CD4(+) T-lymphocytes and decreased those of CD4(+)CD25(+) T lymphocytes in SLE patients as compared to healthy controls. No significant responsiveness of patient PBMC to PHA-M stimulation was observed indicating suppression of T-lymphocytes by these OCP. Further, both HCH and DDT decreased the levels of IL-2 and IFNgamma but had no effect on IL-4 levels in SLE patients. DDT also increased significantly the levels of IL-10 in patients. It is likely that higher levels and prolonged durations of exposure to HCH and DDT may significantly influence T-lymphocyte sub-sets and cytokine expression in vivo that could lead to the development or exacerbation of SLE. PMID- 22214242 TI - Nanowire failure: long = brittle and short = ductile. AB - Experimental studies of the tensile behavior of metallic nanowires show a wide range of failure modes, ranging from ductile necking to brittle/localized shear failure-often in the same diameter wires. We performed large-scale molecular dynamics simulations of copper nanowires with a range of nanowire lengths and provide unequivocal evidence for a transition in nanowire failure mode with change in nanowire length. Short nanowires fail via a ductile mode with serrated stress-strain curves, while long wires exhibit extreme shear localization and abrupt failure. We developed a simple model for predicting the critical nanowire length for this failure mode transition and showed that it is in excellent agreement with both the simulation results and the extant experimental data. The present results provide a new paradigm for the design of nanoscale mechanical systems that demarcates graceful and catastrophic failure. PMID- 22214243 TI - Characterization of mineral oxide charging in apolar media. AB - This paper presents an investigation of the charging behavior of mineral oxide particles dispersed in apolar media. There are a growing number of applications that seek to use electrostatic effects in apolar media to control particle movement and improve aggregation stability. Progress is limited, however, by incomplete knowledge of the mechanism(s) of particle charging in these systems. It has been shown in a number of cases that the acid-base properties of both the particles and the surfactants used to stabilize charge play key roles. A mechanism for acid-base charging has previously been established for mineral oxides in aqueous systems, where the surface hydroxyl groups act as proton donors or receivers depending on the pH of the surrounding solution. In water, the pH at which the surface charge density is zero, i.e., the point of zero charge (PZC), can be used to characterize the acid-base nature of the mineral oxide particles. The current work explores the possible extension of this charging behavior to apolar systems, with the key difference that the surface hydroxyl groups of the mineral oxides react with the surfactant molecules instead of free ions in solution. The apolar charging behavior is explored by measuring the electrophoretic mobility of a series of mineral oxides dispersed in a solution of Isopar-L and AOT, a neutral surfactant in water. The electrophoretic mobility of the particles is found to scale quantitatively, with respect to both sign and magnitude, with their aqueous PZC value. This provides support for the theory of acid-base charging in apolar media and represents a method for predicting and controlling particle charge of mineral oxides dispersed in apolar media. PMID- 22214244 TI - Monosaccharides versus PEG-functionalized NPs: influence in the cellular uptake. AB - Magnetic nanoparticles (NPs) hold great promise for biomedical applications. The core composition and small size of these particles produce superparamagnetic behavior, thus facilitating their use in magnetic resonance imaging and magnetically induced therapeutic hyperthermia. However, the development and control of safe in vivo applications for NPs call for the study of cell-NP interactions and cell viability. Furthermore, as for most biotechnological applications, it is desirable to prevent unspecific cell internalization of these particles. It is also crucial to understand how the surface composition of the NPs affects their internalization capacity. Here, through accurate control over unspecific protein adsorption, size distribution, grafting density, and an extensive physicochemical characterization, we correlated the cytotoxicity and cellular uptake mechanism of 6 nm magnetic NPs coated with several types and various densities of biomolecules, such as glucose, galactose, and poly(ethylene glycol). We found that the density of the grafted molecule was crucial to prevent unspecific uptake of NPs by Vero cells. Surprisingly, the glucose-coated NPs described here showed cellular uptake as a result of lipid raft instead of clathrin-mediated cellular internalization. Moreover, these glucose functionalized NPs could be one of the first examples of NPs being endocytosed by caveolae that finally end up in the lysosomes. These results reinforce the use of simple carbohydrates as an alternative to PEG molecules for NPs functionalization when cellular uptake is required. PMID- 22214246 TI - Yttrium-90-labeled microsphere tracking during liver selective internal radiotherapy by bremsstrahlung pinhole SPECT: feasibility study and evaluation in an abdominal phantom. AB - BACKGROUND: The purpose of the study is to evaluate whether a pinhole collimator is better adapted to bremsstrahlung single photon emission computed tomography [SPECT] than parallel-hole collimators and in the affirmative, to evaluate whether pinhole bremsstrahlung SPECT, including a simple model of the scatter inside the patient, could provide a fast dosimetry assessment in liver selective internal radiotherapy [SIRT]. MATERIALS AND METHODS: Bremsstrahlung SPECT of an abdominal-shaped phantom including one cold and five hot spheres was performed using two long-bore parallel-hole collimators: a medium-energy general-purpose [MEGP] and a high-energy general-purpose [HEGP], and also using a medium-energy pinhole [MEPH] collimator. In addition, ten helical MEPH SPECTs (acquisition time 3.6 min) of a realistic liver-SIRT phantom were also acquired. RESULTS: Without scatter correction for SPECT, MEPH SPECT provided a significantly better contrast recovery coefficient [CRC] than MEGP and HEGP SPECTs. The CRCs obtained with MEPH SPECT were still improved with the scatter correction and became comparable to those obtained with positron-emission tomography [PET] for the 36-, 30- (cold), 28-, and 24-mm-diameter spheres: CRC = 1.09, 0.59, 0.91, and 0.69, respectively, for SPECT and CRC = 1.07, 0.56, 0.84, and 0.63, respectively, for PET. However, MEPH SPECT gave the best CRC for the 19-mm-diameter sphere: CRC = 0.56 for SPECT and CRC = 0.01 for PET. The 3.6-min helical MEPH SPECT provided accurate and reproducible activity estimation for the liver-SIRT phantom: relative deviation = 10 +/- 1%. CONCLUSION: Bremsstrahlung SPECT using a pinhole collimator provided a better CRC than those obtained with parallel-hole collimators. The different designs and the better attenuating material used for the collimation (tungsten instead of lead) explain this result. Further, the addition of an analytical modeling of the scattering inside the phantom resulted in an almost fully recovered contrast. This fills the gap between the performance of90Y-PET and bremsstrahlung pinhole SPECT which is a more affordable technique and could even be used during the catheterization procedure in order to optimize the90Y activity to inject. PMID- 22214245 TI - Genomics and proteomics in liver fibrosis and cirrhosis. AB - Genomics and proteomics have become increasingly important in biomedical science in the past decade, as they provide an opportunity for hypothesis-free experiments that can yield major insights not previously foreseen when scientific and clinical questions are based only on hypothesis-driven approaches. Use of these tools, therefore, opens new avenues for uncovering physiological and pathological pathways. Liver fibrosis is a complex disease provoked by a range of chronic injuries to the liver, among which are viral hepatitis, (non-) alcoholic steatohepatitis and autoimmune disorders. Some chronic liver patients will never develop fibrosis or cirrhosis, whereas others rapidly progress towards cirrhosis in a few years. This variety can be caused by disease-related factors (for example, viral genotype) or host-factors (genetic/epigenetic). It is vital to establish accurate tools to identify those patients at highest risk for disease severity or progression in order to determine who are in need of immediate therapies. Moreover, there is an urgent imperative to identify non-invasive markers that can accurately distinguish mild and intermediate stages of fibrosis. Ideally, biomarkers can be used to predict disease progression and treatment response, but these studies will take many years due to the requirement for lengthy follow-up periods to assess outcomes. Current genomic and proteomic research provides many candidate biomarkers, but independent validation of these biomarkers is lacking, and reproducibility is still a key concern. Thus, great opportunities and challenges lie ahead in the field of genomics and proteomics, which, if successful, could transform the diagnosis and treatment of chronic fibrosing liver diseases. PMID- 22214247 TI - Alterations in vasomotor systems and mechanics of resistance-sized mesenteric arteries from SHR and WKY male rats following in vivo testosterone manipulation. AB - BACKGROUND: Testosterone (T) and the sympathetic nervous system each contribute to the pathology of hypertension. Altered blood vessel reactivity is also associated with the pathology of high blood pressure. The purpose of this study was to examine the effects of T manipulation in the regulation of resistance sized blood vessel reactivity. METHODS: Adult spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) male rats at 8 weeks of age were used. The rats were divided into groups consisting of gonadally intact controls (CONT), castrate with sham implant (CAST) and castrate with T implant (CAST + T) (n = 6 to 12 per group). Following a short-term period of T treatment (approximately 4 weeks), plasma norepinephrine (NE) and plasma T were assessed by performing high performance liquid chromatography and RIA, respectively. Resistance-sized mesenteric artery reactivity was assessed on a pressurized arteriograph for myogenic reactivity (MYO), phenylephrine (PE) responsiveness and passive structural mechanics. RESULTS: SHR and WKY males exhibited similar physiological trends in T manipulation, with castration significantly lowering plasma T and NE and T replacement significantly increasing plasma T and NE. T manipulation in general resulted in significant alterations in MYO of second-order mesenteric arteries, with T replacement decreasing MYO in SHR (P < 0.05) compared to CONT, T replacement increasing MYO, and CAST decreasing MYO in WKY rats (P < 0.001) compared to CONT rats. Additionally, PE-induced constriction was significantly altered in both strains following T treatment, with the effective concentration of PE to constrict the vessel to 50% of the total diameter significantly increased in the CAST + T SHR compared to CONT (P < 0.05). Comparisons of passive structural mechanics between SHR and WKY treatment groups indicated in SHR a significantly increased wall-to-lumen ratio and decreased circumferential wall stress compared to WKY treatment groups. CONCLUSIONS: These data suggest that T and NE are involved in a complex interaction with both myogenic reactivity and structural alterations of resistance-sized blood vessels and that these factors likely contribute to the development and maintenance of hypertension. PMID- 22214249 TI - Editorial: spare the rod, spoil the industry. PMID- 22214250 TI - The role of persistent organic pollutants in the worldwide epidemic of type 2 diabetes mellitus and the possible connection to Farmed Atlantic Salmon (Salmo salar). AB - Rates of type 2 diabetes mellitus (T2DM), both in the United States and worldwide, have been rising at an alarming rate over the last two decades. Because this disease is viewed as primarily being attributable to unhealthy lifestyle habits, a great deal of emphasis has been placed on encouraging increased exercise, better dietary habits, and weight loss. Recent studies reveal that the presence of several persistent organic pollutants (POPs) can confer greater risk for developing the disease than some of the established lifestyle risk factors. In fact, evidence suggests the hypothesis that obesity might only be a significant risk factor when adipose tissue contains high amounts of POPs. Chlorinated pesticides and polychlorinated biphenyls, in particular, have been strongly linked to the development of metabolic syndrome, insulin resistance, and T2DM. In addition to reviewing the evidence associating POPs to these conditions, this article explores the possible contribution of farmed Atlantic salmon - a significant and common dietary source of POPs - with blood sugar dysregulation conditions. PMID- 22214248 TI - Up-regulation of FOXP3 and induction of suppressive function in CD4+ Jurkat T cells expressing hepatitis C virus core protein. AB - HCV (hepatitis C virus) infection is a serious health care problem that affects more than 170 million people worldwide. Viral clearance depends on the development of a successful cellular immune response against the virus. Interestingly, such a response is altered in chronically infected patients, leading to chronic hepatitis that can result in liver fibrosis, cirrhosis and hepatocellular carcinoma. Among the mechanisms that have been described as being responsible for the immune suppression caused by the virus, Treg-cells (regulatory T-cells) are emerging as an essential component. In the present work we aim to study the effect of HCV-core protein in the development of T-cells with regulatory-like function. Using a third-generation lentiviral system to express HCV-core in CD4+ Jurkat T-cells, we describe that HCV-core-expressing Jurkat cells show an up-regulation of FOXP3 (forkhead box P3) and CTLA-4 (cytotoxic T lymphocyte antigen-4). Moreover, we show that HCV-core-transduced Jurkat cells are able to suppress CD4+ and CD8+ T-cell responses to anti-CD3 plus anti-CD28 stimulation. PMID- 22214251 TI - A review of the use of mercury in historic and current ritualistic and spiritual practices. AB - Mercury (Hg) occurs naturally in the environment and has been used in numerous medicinal, commercial, and industrial applications over many centuries. Also, it has played significant historical, as well as current, ethno-medical and magico religious roles in a number of different cultures. In recent times, awareness has emerged that exposure to mercury can have serious adverse health consequences. Accompanying this, contamination of the environment by mercury is causing public health and environmental concerns. As a result, major efforts are being undertaken by industry, private organizations, and government agencies to reduce or eliminate the use of and exposure to this toxic element. However, in spite of extensive educational and socio-cultural interventions, the use of mercury in ritualistic and spiritual practices is a continuing cause for concern. PMID- 22214252 TI - Complementary and alternative medical therapies for children with attention deficit/hyperactivity disorder (ADHD). AB - Attention-deficit/hyperactivity disorder (ADHD) is a commonly diagnosed childhood disorder characterized by impulsivity, inattention, and hyperactivity. ADHD affects up to 1 in 20 children in the United States. The underlying etiologies of ADHD may be heterogeneous and diverse, and many possible risk factors in the development of ADHD have been identified. Conventional treatment usually consists of behavioral accommodations and medication, with stimulant medication most commonly being prescribed. Parents concerned about the side effects and long-term use of conventional medications are increasingly seeking alternatives to pharmacologic treatment. Complementary and alternative medicine (CAM) offers parents various treatment options for this condition, including dietary modifications, nutritional supplementation, herbal medicine, and homeopathy. CAM appears to be most effective when prescribed holistically and according to each individual's characteristic symptoms. Possible etiologies and risk factors for the condition also need to be considered when developing a treatment plan. This article serves to highlight the latest research regarding the most commonly used CAM for children with ADHD. PMID- 22214253 TI - A clinical trial testing the safety and efficacy of a standardized Eucommia ulmoides Oliver bark extract to treat hypertension. AB - BACKGROUND: A tea made from Eucommia ulmoides leaves and bark is part of the Japanese diet. Eucommia is an herbal medicine that, by increasing nitric oxide, reduced blood pressure (BP) in rats and humans in an uncontrolled clinical trial. OBJECTIVE: A controlled clinical trial was conducted to evaluate an aqueous bark extract of Eucommia standardized to eight percent pinoresinol di-beta-D-glucoside (PG) for BP reduction in humans. METHODS: Study 1: Twenty-four healthy adult subjects with a BP between 120-160/80-100 mmHg were randomized to Eucommia extract 500 mg three times daily for eight weeks. Automatic 24-hour ambulatory blood pressure monitoring (24-h ABPM) was utilized at baseline and after eight weeks. Study 2: The effect of the Eucommia extract on isoproterenol-stimulated lipolysis was evaluated in a human fat cell assay to determine whether Eucommia was a beta-adrenergic blocker. Study 3: Thirty healthy adult subjects with a BP between 120-160/80-100 mmHg were randomized to 1 g Eucommia extract three times daily for two weeks with 24-h ABPM at baseline and after two weeks. RESULTS: Study 1: There was no toxicity or any difference in BP between the two groups. Study 2: Eucommia at 0.5% w/v reduced isoproterenol-stimulated lipolysis from 2.67 to 1.4 times the buffer control (P<0.001). Study 3: The Eucommia extract was well-tolerated and reduced BP by an average of 7.5/3.9 mmHg (P<0.008). CONCLUSION: The standardized Eucommia extract reduced BP and has beta-adrenergic blocking activity. Eucommia may be an appropriate nutraceutical intervention for prehypertension. PMID- 22214254 TI - The effects of L-theanine (Suntheanine(r)) on objective sleep quality in boys with attention deficit hyperactivity disorder (ADHD): a randomized, double-blind, placebo-controlled clinical trial. AB - INTRODUCTION: The purpose of this study was to investigate the efficacy and safety of L-theanine as an aid to the improvement of objectively measured sleep quality in a population of 98 male children formally diagnosed with attention deficit/hyperactivity disorder (ADHD). METHODS: A randomized, double-blind, placebo-controlled trial was conducted involving boys, ages 8-12 years, who had been previously diagnosed with ADHD. An experienced physician confirmed the diagnosis of ADHD in each subject. Randomization was stratified based upon current use of stimulant medication to ensure an equal distribution of stimulant/non-stimulant treated subjects into active and placebo treated groups. Participants consumed two chewable tablets twice daily (at breakfast and after school), with each tablet containing 100 mg of L-theanine (total 400 mg daily Suntheanine(r), Taiyo Kagaku, Yokkaichi, Japan) or identical tasting chewable placebo for six weeks. Subjects were evaluated for five consecutive nights using wrist actigraphy at baseline, and again at the end of the six-week treatment period. The Pediatric Sleep Questionnaire (PSQ) was completed by parents at baseline and at the end of the treatment period. RESULTS: Actigraph watch data findings indicated that boys who consumed L-theanine obtained significantly higher sleep percentage and sleep efficiency scores, along with a non-significant trend for less activity during sleep (defined as less time awake after sleep onset) compared to those in the placebo group. Sleep latency and other sleep parameters were unchanged. The PSQ data did not correlate significantly to the objective data gathered from actigraphy, suggesting that parents were not particularly aware of their children's sleep quality. L-theanine at relatively high doses was well tolerated with no significant adverse events. CONCLUSIONS: This study demonstrates that 400 mg daily of L-theanine is safe and effective in improving some aspects of sleep quality in boys diagnosed with ADHD. Since sleep problems are a common co-morbidity associated with ADHD, and because disturbed sleep may be linked etiologically to this disorder, L-theanine may represent a safe and important adjunctive therapy in childhood ADHD. Larger, long-term studies looking at the wider therapeutic role of this agent in this population are warranted. PMID- 22214255 TI - Astaxanthin, cell membrane nutrient with diverse clinical benefits and anti-aging potential. AB - Astaxanthin, a xanthophyll carotenoid, is a nutrient with unique cell membrane actions and diverse clinical benefits. This molecule neutralizes free radicals or other oxidants by either accepting or donating electrons, and without being destroyed or becoming a pro-oxidant in the process. Its linear, polar-nonpolar polar molecular layout equips it to precisely insert into the membrane and span its entire width. In this position, astaxanthin can intercept reactive molecular species within the membrane's hydrophobic interior and along its hydrophilic boundaries. Clinically, astaxanthin has shown diverse benefits, with excellent safety and tolerability. In double-blind, randomized controlled trials (RCTs), astaxanthin lowered oxidative stress in overweight and obese subjects and in smokers. It blocked oxidative DNA damage, lowered C-reactive protein (CRP) and other inflammation biomarkers, and boosted immunity in the tuberculin skin test. Astaxanthin lowered triglycerides and raised HDL-cholesterol in another trial and improved blood flow in an experimental microcirculation model. It improved cognition in a small clinical trial and boosted proliferation and differentiation of cultured nerve stem cells. In several Japanese RCTs, astaxanthin improved visual acuity and eye accommodation. It improved reproductive performance in men and reflux symptoms in H. pylori patients. In preliminary trials it showed promise for sports performance (soccer). In cultured cells, astaxanthin protected the mitochondria against endogenous oxygen radicals, conserved their redox (antioxidant) capacity, and enhanced their energy production efficiency. The concentrations used in these cells would be attainable in humans by modest dietary intakes. Astaxanthin's clinical success extends beyond protection against oxidative stress and inflammation, to demonstrable promise for slowing age related functional decline. PMID- 22214257 TI - Shear modulus of monolayer graphene prepared by chemical vapor deposition. AB - We report shear modulus (G) and internal friction (Q(-1)) measurements of large area monolayer graphene films grown by chemical vapor deposition on copper foil and transferred onto high-Q silicon mechanical oscillators. The shear modulus, extracted from a resonance frequency shift at 0.4 K where the apparatus is most sensitive, averages 280 GPa. This is five times larger than those of the multilayered graphene-based films measured previously. The internal friction is unmeasurable within the sensitivity of our experiment and thus bounded above by Q(-1) <= 3 * 10(-5), which is orders-of-magnitude smaller than that of multilayered graphene-based films. Neither annealing nor interface modification has a measurable effect on G or Q(-1). Our results on G are consistent with recent theoretical evaluations and simulations carried out in this work, showing that the shear restoring force transitions from interlayer to intralayer interactions as the film thickness approaches one monolayer. PMID- 22214258 TI - Uptake of 68gallium in atherosclerotic plaques in LDLR-/-ApoB100/100 mice. AB - BACKGROUND: Atherosclerosis is a chronic inflammatory disease of artery wall characterized by infiltration of monocytes into subendothelial space and their differentiation into macrophages. Since rupture-prone plaques commonly contain high amounts of activated macrophages, imaging of the macrophage content may provide a useful tool for the evaluation of plaque vulnerability. The purpose of this study was to explore the uptake of 68gallium (68Ga) in atherosclerotic plaques in mice. METHODS: Uptake of ionic 68Ga was investigated in atherosclerotic LDLR-/-ApoB100/100 and C57BL/6N control mice at 3 h after injection. The ex vivo biodistribution of the 68Ga was assessed and autoradiography of aortic cryosections was defined. In vivo imaging of 68Ga was performed using a small animal positron emission tomography PET/CT scanner. RESULTS: Our results revealed that the uptake of 68Ga-radioactivity was higher in atherosclerotic plaques than in healthy vessel wall (ratio 1.8 +/- 0.2, p = 0.0002) and adventitia (ratio 1.3 +/- 0.2, p = 0.0011). The autoradiography signal co-localized with macrophages prominently as demonstrated by Mac-3 staining. In both mice strains, the highest level of radioactivity was found in the blood. CONCLUSIONS: We observed a moderate but significantly elevated 68Ga radioactivity uptake in the aortic plaques of atherosclerotic mice, especially at the sites rich in macrophages. While the uptake of 68Ga was promising in this animal model, the slow blood clearance may limit the usability of 68Ga as a PET tracer for clinical imaging of atherosclerotic plaques. PMID- 22214259 TI - Outcomes associated with matching patients' treatment preferences to physicians' recommendations: study methodology. AB - BACKGROUND: Patients often express strong preferences for the forms of treatment available for their disease. Incorporating these preferences into the process of treatment decision-making might improve patients' adherence to treatment, contributing to better outcomes. We describe the methodology used in a study aiming to assess treatment outcomes when patients' preferences for treatment are closely matched to recommended treatments. METHOD: Participants included patients with moderate and severe psoriasis attending outpatient dermatology clinics at the University Medical Centre Mannheim, University of Heidelberg, Germany. A self administered online survey used conjoint analysis to measure participants' preferences for psoriasis treatment options at the initial study visit. Physicians' treatment recommendations were abstracted from each participant's medical records. The Preference Matching Index (PMI), a measure of concordance between the participant's preferences for treatment and the physician's recommended treatment, was determined for each participant at t(1) (initial study visit). A clinical outcome measure, the Psoriasis Area and Severity Index, and two participant-derived outcomes assessing treatment satisfaction and health related quality of life were employed at t(1), t(2) (twelve weeks post-t(1)) and t(3) (twelve weeks post-t(2)). Change in outcomes was assessed using repeated measures analysis of variance. The association between participants' PMI scores at t(1) and outcomes at t(2) and t(3) was evaluated using multivariate regressions analysis. DISCUSSION: We describe methods for capturing concordance between patients' treatment preferences and recommended treatment and for assessing its association with specific treatment outcomes. The methods are intended to promote the incorporation of patients' preferences in treatment decision-making, enhance treatment satisfaction, and improve treatment effectiveness through greater adherence. PMID- 22214261 TI - Optimizing Illumina next-generation sequencing library preparation for extremely AT-biased genomes. AB - BACKGROUND: Massively parallel sequencing technology is revolutionizing approaches to genomic and genetic research. Since its advent, the scale and efficiency of Next-Generation Sequencing (NGS) has rapidly improved. In spite of this success, sequencing genomes or genomic regions with extremely biased base composition is still a great challenge to the currently available NGS platforms. The genomes of some important pathogenic organisms like Plasmodium falciparum (high AT content) and Mycobacterium tuberculosis (high GC content) display extremes of base composition. The standard library preparation procedures that employ PCR amplification have been shown to cause uneven read coverage particularly across AT and GC rich regions, leading to problems in genome assembly and variation analyses. Alternative library-preparation approaches that omit PCR amplification require large quantities of starting material and hence are not suitable for small amounts of DNA/RNA such as those from clinical isolates. We have developed and optimized library-preparation procedures suitable for low quantity starting material and tolerant to extremely high AT content sequences. RESULTS: We have used our optimized conditions in parallel with standard methods to prepare Illumina sequencing libraries from a non-clinical and a clinical isolate (containing ~53% host contamination). By analyzing and comparing the quality of sequence data generated, we show that our optimized conditions that involve a PCR additive (TMAC), produces amplified libraries with improved coverage of extremely AT-rich regions and reduced bias toward GC neutral templates. CONCLUSION: We have developed a robust and optimized Next-Generation Sequencing library amplification method suitable for extremely AT-rich genomes. The new amplification conditions significantly reduce bias and retain the complexity of either extremes of base composition. This development will greatly benefit sequencing clinical samples that often require amplification due to low mass of DNA starting material. PMID- 22214262 TI - Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations. AB - Myelodysplastic syndromes (MDS) are often accompanied by autoimmune phenomena. The underlying mechanisms for these associations remain uncertain, although T cell activation seems to be important. Human T-lymphotropic virus (HTLV-1) has been detected in patients with myelodysplastic syndromes, mostly in regions of the world which are endemic for the virus, and where association of HTLV-1 with rheumatological manifestation is not rare. We present here the case of a 58 year old man who presented with cytopenias, leukocytoclastic vasculitis of the skin and glomerulopathy, and was diagnosed as MDS (refractory anemia with excess blasts - RAEB 1). The patient also tested positive for HTLV-1 by PCR. After 8 monthly cycles of 5-azacytidine he achieved a complete hematologic remission. Following treatment, a second PCR for HTLV-1 was carried out and found to be negative. This is the first report in the literature of a HTLV-1-positive MDS with severe autoimmune manifestations, which was treated with the hypomethylating factor 5-azacitidine, achieving cytogenetic remission with concomitant resolution of the autoimmune manifestations, as well as HTLV-1-PCR negativity. HTLV-1-PCR negativity may be due to either immune mediated clearance of the virus, or a potential antiretroviral effect of 5-azacytidine. 5-azacytidine is known for its antiretroviral effects, although there is no proof of its activity against HTLV-1 infection in vivo. PMID- 22214263 TI - Suitability of bilateral filtering for edge-preserving noise reduction in PET. AB - BACKGROUND: To achieve an acceptable signal-to-noise ratio (SNR) in PET images, smoothing filters (SF) are usually employed during or after image reconstruction preventing utilisation of the full intrinsic resolution of the respective scanner. Quite generally Gaussian-shaped moving average filters (MAF) are used for this purpose. A potential alternative to MAF is the group of so-called bilateral filters (BF) which provide a combination of noise reduction and edge preservation thus minimising resolution deterioration of the images. We have investigated the performance of this filter type with respect to improvement of SNR, influence on spatial resolution and for derivation of SUVmax values in target structures of varying size. METHODS: Data of ten patients with head and neck cancer were evaluated. The patients had been investigated by routine whole body scans (ECAT EXACT HR+, Siemens, Erlangen). Tomographic images were reconstructed (OSEM 6i/16s) using a Gaussian filter (full width half maximum (FWHM): Gamma0 = 4 mm). Image data were then post-processed with a Gaussian MAF (FWHM: GammaM = 7 mm) and a Gaussian BF (spatial domain: GammaS = 9 mm, intensity domain: GammaI = 2.5 SUV), respectively. Images were assessed regarding SNR as well as spatial resolution. Thirty-four lesions (volumes of about 1-100 mL) were analysed with respect to their SUVmax values in the original as well as in the MAF and BF filtered images. RESULTS: With the chosen filter parameters both filters improved SNR approximately by a factor of two in comparison to the original data. Spatial resolution was significantly better in the BF-filtered images in comparison to MAF (MAF: 9.5 mm, BF: 6.8 mm). In MAF-filtered data, the SUVmax was lower by 24.1 +/- 9.9% compared to the original data and showed a strong size dependency. In the BF-filtered data, the SUVmax was lower by 4.6 +/- 3.7% and no size effects were observed. CONCLUSION: Bilateral filtering allows to increase the SNR of PET image data while preserving spatial resolution and preventing smoothing-induced underestimation of SUVmax values in small lesions. Bilateral filtering seems a promising and superior alternative to standard smoothing filters. PMID- 22214264 TI - Improving person-centred care in nursing homes through dementia-care mapping: design of a cluster-randomised controlled trial. AB - BACKGROUND: The effectiveness and efficiency of nursing-home dementia care are suboptimal: there are high rates of neuropsychiatric symptoms among the residents and work-related stress among the staff. Dementia-care mapping is a person centred care method that may alleviate both the resident and the staff problems. The main objective of this study is to evaluate the effectiveness and cost effectiveness of dementia-care mapping in nursing-home dementia care. METHODS/DESIGN: The study is a cluster-randomised controlled trial, with nursing homes grouped in clusters. Studywise minimisation is the allocation method. Nursing homes in the intervention group will receive a dementia-care-mapping intervention, while the control group will receive usual care. The primary outcome measure is resident agitation, to be assessed with the Cohen-Mansfield Agitation Inventory. The secondary outcomes are resident neuropsychiatric symptoms, assessed with the Neuropsychiatric Inventory--Nursing Homes and quality of life, assessed with Qualidem and the EQ-5D. The staff outcomes are stress reactions, job satisfaction and job-stress-related absenteeism, and staff turnover rate, assessed with the Questionnaire about Experience and Assessment of Work, the General Health Questionnaire-12, and the Maastricht Job Satisfaction Scale for Health Care, respectively. We will collect the data from the questionnaires and electronic registration systems. We will employ linear mixed effect models and cost-effectiveness analyses to evaluate the outcomes. We will use structural equation modelling in the secondary analysis to evaluate the plausibility of a theoretical model regarding the effectiveness of the dementia care mapping intervention. We will set up process analyses, including focus groups with staff, to determine the relevant facilitators of and barriers to implementing dementia-care mapping broadly. DISCUSSION: A novelty of dementia care mapping is that it offers an integral person-centred approach to dementia care in nursing homes. The major strengths of the study design are the large sample size, the cluster-randomisation, and the one-year follow-up. The generalisability of the implementation strategies may be questionable because the motivation for person-centred care in both the intervention and control nursing homes is above average. The results of this study may be useful in improving the quality of care and are relevant for policymakers. TRIAL REGISTRATION: The trial is registered in the Netherlands National Trial Register: NTR2314. PMID- 22214265 TI - The differential contribution of facial expressions, prosody, and speech content to empathy. AB - BACKGROUND: Facial expressions, prosody, and speech content constitute channels by which information is exchanged. Little is known about the simultaneous and differential contribution of these channels to empathy when they provide emotionality or neutrality. Especially neutralised speech content has gained little attention with regards to influencing the perception of other emotional cues. METHODS: Participants were presented with video clips of actors telling short-stories. One condition conveyed emotionality in all channels while the other conditions either provided neutral speech content, facial expression, or prosody, respectively. Participants judged the emotion and intensity presented, as well as their own emotional state and intensity. Skin conductance served as a physiological measure of emotional reactivity. RESULTS: Neutralising channels significantly reduced empathic responses. Electrodermal recordings confirmed these findings. The differential effect of the communication channels on empathy prerequisites was that target emotion recognition of the other decreased mostly when the face was neutral, whereas decreased emotional responses attributed to the target emotion were especially present in neutral speech. CONCLUSION: Multichannel integration supports conscious and autonomous measures of empathy and emotional reactivity. Emotional facial expressions influence emotion recognition, whereas speech content is important for responding with an adequate own emotional state, possibly reflecting contextual emotion-appraisal. PMID- 22214266 TI - Postcoital penile drug eruption in a co-trimoxazole-sensitive patient following vaginal use of triple sulfa vaginal cream by his partner. AB - INTRODUCTION: This is a report of a very rare case of proven postcoital penile drug eruption in a patient following vaginal use of triple sulfa vaginal cream by his partner. AIM: To report the rare case of cross-reaction following vaginal use of triple sulfa vaginal cream in partner. METHODS: A case of postcoital penile drug eruption in a patient following vaginal use of triple sulfa vaginal cream in his partner is presented including subjective reporting, physical examination, and laboratory evaluations. RESULTS: We report a 42-year-old man with known sensitivity to trimethoprim/sulfamethoxazole (co-trimoxazole) who developed a penile drug eruption at the glans after having intercourse with his wife, who was taking sulfathiazole/sulfacetamide/sulfabenzamide (triple sulfa) vaginal cream. The nature of the lesion was confirmed by a rechallenge test. CONCLUSION: To our knowledge, this is the fourth case of proven postcoital penile drug eruption in a patient following vaginal use of triple sulfa vaginal cream in his partner. Our case illustrates the importance of history taking. In clinical practice of urology, it is not rare to see patients who present with strange penile lesions following coitus. To reach a correct diagnosis, one should obtain a drug history of the sexual partner and allergic history of the patient in such cases. PMID- 22214268 TI - Effect of surface oxidation on the interaction of 1-methylaminopyrene with gold nanoparticles. AB - The effect of the surface chemistry of gold nanoparticles (GNPs) on the GNP-amine (-NH(2)) interaction was investigated via conjugating an amine probe--1 methylaminopyrene (MAP) chromophore--with three Au colloidal samples of the same particle size yet different surface chemistry. The surface of laser-irradiated and ligand-exchanged-irradiated GNPs is covered with acetonedicarboxylic ligands (due to laser-introduced citrate oxidization) and citrate ligands, respectively, and both surfaces contain oxidized Au species which are essentially lacking for the citrate-capped GNPs prepared by the pure chemical approach. Both laser irradiated samples show inferior adsorption capacity of MAP as compared with the purely chemically prepared GNPs. Detailed investigations indicate that MAP molecules mainly complex directly with Au atoms via forming Au-NH(2)R bonds, and the oxidization of the GNP surface strongly influences the ratio of this direct bonding to the indirect bonding originating from the electrostatic interaction between protonated amine (-NH(3)(+)) and negatively charged surface ligands. The impact of the oxidized GNP surface associated with the laser treatment is further confirmed by aging experiment on GNP-MAP conjugation systems, which straightforwardly verifies that the surface oxidation leads to the decrease in the MAP adsorption on GNPs. PMID- 22214267 TI - Evaluation of heterologous vaginal SHIV SF162p4 infection following vaccination with a polyvalent Clade B virus-like particle vaccine. AB - The vast diversity of HIV-1 infections has greatly impeded the development of a successful HIV-1/AIDS vaccine. Previous vaccine work has demonstrated limited levels of protection against SHIV/SIV infection, but protection was observed only when the challenge virus was directly matched to the vaccine strain. As it is likely impossible to directly match the vaccine strain to all infecting strains in nature, it is necessary to develop an HIV-1 vaccine that can protect against a heterologous viral challenge. In this study we investigated the ability of polyvalent and consensus vaccines to protect against a heterologous clade B challenge. Rhesus macaques were vaccinated with ConB or PolyB virus-like particle vaccines. All vaccines were highly immunogenic with high titers of antibody found in all vaccinated groups against SIV Gag. Antibody responses were also observed against a diverse panel of clade B envelopes. Following vaccination nonhuman primates (NHPs) were challenged via the vaginal route with SHIV(SF162p4). The PolyB vaccine induced a 66.7% reduction in the rate of infection as well as causing a two log reduction in viral burden if infection was not blocked. ConB vaccination had no effect on either the infection rate or viral burden. These results indicate that a polyvalent clade-matched vaccine is better able to protect against a heterologous challenge as compared to a consensus vaccine. PMID- 22214269 TI - Detection of Anaplasma phagocytophilum in ixodid ticks from equine-inhabited sites in the Southeastern United States. AB - Anaplasma phagocytophilum is a vector-borne, obligate intracellular bacterium that invades the neutrophils and eosinophils of infected individuals, causing granulocytic anaplasmosis. Equine cases have previously been reported in the United States from California, Florida, and Connecticut, but limited surveillance studies in the Southeast have been conducted. The objective of this study was to determine A. phagocytophilum prevalence in Ixodes scapularis ticks at southeastern U.S. horse-inhabited sites to evaluate the potential risk for equine exposure to A. phagocytophilum-infected ticks in these areas. Samples of I. scapularis were collected from selected barrier islands and Georgia mainland sites where feral and domestic equine populations are present, respectively. Ticks were individually tested for infection by amplification of the A. phagocytophilum ankA gene. The collective prevalence of A. phagocytophilum in I. scapularis ticks was 20% (n=808). PMID- 22214270 TI - Wild cervids are host for tick vectors of babesia species with zoonotic capability in Belgium. AB - Babesiosis is a tick-borne disease caused by different species of intraerythrocytic protozoan parasites within the genus Babesia. Different species of Babesia are described as potentially zoonotic and cause a malaria-like disease mainly in immunocompromised humans. Interest in the zoonotic potential of Babesia is growing and babesiosis has been described by some authors as an emergent zoonotic disease. The role of cervids to maintain tick populations and act as a reservoir host for some Babesia spp. with zoonotic capability is suspected. To investigate the range and infection rate of Babesia species, ticks were collected from wild cervids in southern Belgium during 2008. DNA extraction was performed for individual ticks, and each sample was evaluated for the absence of PCR inhibition using a PCR test. A Babesia spp. genus-specific PCR based on the 18S rRNA gene was applied to validated tick DNA extracts. A total of 1044 Ixodes ricinus ticks were collected and 1023 validated samples were subsequently screened for the presence of Babesia spp. DNA. Twenty-eight tick samples were found to be positive and identified after sequencing as containing DNA representing: Babesia divergens (3), B. divergens-like (5), Babesia sp. EU1 (11), Babesia sp. EU1-like (3), B. capreoli (2), or unknown Babesia sp. (4). This study confirms the presence of potentially zoonotic species and Babesia capreoli in Belgium, with a tick infection rate of 2.7% (95% CI 1.8,3.9%). Knowledge of the most common reservoir source for transmission of zoonotic Babesia spp. will be useful for models assessing the risk potential of this infection to humans. PMID- 22214271 TI - Duration of Catarina virus infection in the southern plains woodrat (Neotoma micropus). AB - Four adult male, 6 sub-adult, and 7 newborn southern plains woodrats (Neotoma micropus) each were inoculated subcutaneously with 3.1 log(10) median cell culture infectious doses (CCID(50)) of Catarina virus strain AV A0400135 (virus family Arenaviridae). The inoculated animals and the mothers of the newborn animals all became infected and remained asymptomatic. The infections in the adult male woodrats and in the mother woodrats were transient, the infections in 2 (33.3%) of the sub-adult woodrats persisted through month 4 post-inoculation, and 6 (85.7%) of the newborn woodrats were viruric through month 5 post inoculation. Collectively these findings indicate that the duration of infection in the southern plains woodrat is dependent upon age at exposure to Catarina virus. The results of this study also indicate that chronically infected woodrats persistently shed Catarina virus into the environment. PMID- 22214272 TI - A new Rickettsia species found in fleas collected from human dwellings and from domestic cats and dogs in Senegal. AB - The insects of the order Siphonaptera, commonly named fleas, are vectors of pathogens around the world. Our previous studies showed that 4.4% of acute febrile diseases in the Sine-Saloum region of Senegal were due to Rickettsia felis. The aim of this study was to explain the high prevalence of R. felis infections in two rural Senegalese populations by an entomological, systematic monitoring protocol. A total of 232 fleas from three species (Ctenocephalides felis, Echidnophaga gallinacea, and Synosternus pallidus) were collected by candle trapping and manually from pets in the villages of Dielmo and Ndiop during the year 2010. The fleas were then tested for the presence of Bartonella and Rickettsia species. No fleas were found to be positive for any Bartonella species or R. felis. Surprisingly, we found that 91.4% of S. pallidus were infected by a new Rickettsia species, which, based on sequence analysis of gltA, ompB, and two fragments of rpoB, was found to be closely related to R. felis. The results from this study did not explain the high incidence of R. felis infections in these Senegalese populations. PMID- 22214273 TI - Hantavirus pulmonary syndrome clinical findings: evaluating a surveillance case definition. AB - Clinical cases of hantavirus pulmonary syndrome (HPS) can be challenging to differentiate from other acute respiratory diseases, which can lead to delays in diagnosis, treatment, and disease reporting. Rapid onset of severe disease occurs, at times before diagnostic test results are available. This study's objective was to examine the clinical characteristics of patients that would indicate HPS to aid in detection and reporting. Test results of blood samples from U.S. patients suspected of having HPS submitted to the Centers for Disease Control and Prevention from 1998-2010 were reviewed. Patient information collected by case report forms was compared between HPS-confirmed and test negative patients. Diagnostic sensitivity, specificity, predictive values, and likelihood ratios were calculated for individual clinical findings and combinations of variables. Of 567 patients included, 36% were HPS-confirmed. Thrombocytopenia, chest x-rays with suggestive signs, and receiving supplemental oxygenation were highly sensitive (>95%), while elevated hematocrit was highly specific (83%) in detecting HPS. Combinations that maximized sensitivity required the presence of thrombocytopenia. Using a national sample of suspect patients, we found that thrombocytopenia was a highly sensitive indicator of HPS and should be included in surveillance definitions for suspected HPS. Using a sensitive suspect case definition to identify potential HPS patients that are confirmed by highly specific diagnostic testing will ensure accurate reporting of this disease. PMID- 22214274 TI - Seroepidemiology of Toxoplasma gondii infection in Tepehuanos in Durango, Mexico. AB - The epidemiology of Toxoplasma gondii infection is known to depend on a number of behavioral factors, including contact with animals and eating habits. The epidemiology in specific populations (i.e., in indigenous ethnic groups) is not well studied. We therefore investigated the presence of anti-Toxoplasma IgG and IgM antibodies in 156 Tepehuanos, an indigenous ethnic group in Durango State in northern Mexico, using ELISAs. Of the 156 Tepehuanos (mean age 31.03+/-16.71 years), 35 (22.4%) had anti-Toxoplasma IgG antibodies. IgG levels of 14-99, 100 150, and >150 IU/mL were found in 15 (42.9%), 1 (2.8%), and 19 (54.3%) anti Toxoplasma IgG-positive Tepehuanos, respectively. Also, 15 (9.6%) subjects had anti-Toxoplasma IgM antibodies. Male Tepehuanos aged 31-50 years showed a significantly higher frequency of exposure to T. gondii than female Tepehuanos of the same age. Seroprevalence of anti-T. gondii IgM antibodies was significantly higher in Tepehuanos without education than those with 7-12 years of education. Tepehuanos suffering from frequent headaches had significantly higher seroprevalences of anti-T. gondii IgG and IgM antibodies than those without this clinical feature. In addition, Tepehuanos suffering from hearing impairment had significantly higher seroprevalence of anti-T. gondii IgM antibodies than those without this clinical feature. Logistic regression analysis did not show an association of T. gondii exposure with any behavioral characteristics, including contact with cats or eating habits. The seroprevalence of T. gondii exposure in Tepehuanos is comparable to that reported in other populations in North America; however, seroprevalence in the largely rural Tepehuanos is higher than that reported in a nearby urban center. Toxoplasma may be impacting the health of Tepehuanos. This is the first report of T. gondii infection in Tepehuanos, and the results should prove useful for the design of preventive measures. PMID- 22214275 TI - A novel deletion in 2q24.1q24.2 in a girl with mental retardation and generalized hypotonia: a case report. AB - BACKGROUND: Chromosomal imbalances, recognized as the major cause of mental retardation, are often due to submicroscopic deletions or duplications not evidenced by conventional cytogenetic methods. To date, interstitial deletion of long arm of chromosome 2 have been reported for more than 100 cases, although studies reporting small interstitial deletions involving the 2q24.1q24.2 region are rare. With the widespread clinical use of comparative genomic hybridization chromosomal microarray technology, several cryptic chromosome imbalances have outlined new genotype-phenotype correlations and isolated a number of distinctive clinical conditions. RESULTS: here we report on a girl with mental retardation and generalized hypotonia. A genome-wide screen for copy number variations (CNVs) using single nucleotide polymorphisms (SNPs) array revealed a 7.5 Mb interstitial deletion of chromosome region 2q24.1q24.2 encompassing 59 genes, which was absent in parents. The gene content analysis of the deleted region and review of the literature revealed the presence of some genes that may be indicated as good candidate in generating the main clinical features of the patient. DISCUSSION: the present case represents a further patient described in the literature with an interstitial deletion of chromosome 2q24.1q24.2. Our patient shares some clinical features with the previously reported patients carriers of overlapping 2q24 deletion. Although more cases are needed to delineate the full-blown phenotype of 2q24.1q24.2 deletion syndrome, published data and present observation suggest that hemizygosity of this region results in a clinically recognizable phenotype. Considering these clinical and cytogenetic similarities, we suggest the existence of an emerging syndrome associated to 2q24.1q24.2 region. PMID- 22214276 TI - The effect of beclomethasone dipropionate in ultrafine particles on bronchial hyper-reactivity in young children. AB - AIM: Bronchial hyper-reactivity (BHR) provides a tool for asthma diagnosis, assessment of severity and response to treatment. The effect of beclomethasone dipropionate in ultrafine particles (BDP-HFA) on BHR as measured by the adenosine challenge test in young children has not yet been determined. Our aim was to determine the effect of BDP-HFA (100 MUg twice daily) on BHR as evaluated by a reduction of 20% from baseline FEV1 (PC20-FEV1) values in young asthmatic children. METHODS: Twenty-one young children (13 males), mean age 4.95 +/- 1.05 years, with partially controlled or controlled asthma completed a double-blind randomized, placebo-controlled, cross-over study. Each child received 4 weeks of treatment with either 100 MUg BDP-HFA twice daily or placebo, and after a 2-week washout period the other way around. Primary outcomes were PC20-FEV1 concentration, and the stage number at which FEV1 values dropped by 20%. RESULTS: Following 4 weeks of treatment, median PC20-FEV1 was 81.28 mg/mL while on BDP HFA, compared with 9.64 mg/mL on placebo (p < 0.001). The median increase in stages required to achieve PC20 on BDP-HFA compared with placebo was three (95% CI 2.28-4.86). CONCLUSION: Four weeks of treatment with BDP-HFA resulted in significantly decreased BHR in young children. PMID- 22214277 TI - Quantitative thermometry of nanoscale hot spots. AB - A method is described to quantify thermal conductance and temperature distributions with nanoscale resolution using scanning thermal microscopy. In the first step, the thermal resistance of the tip-surface contact is measured for each point of a surface. In the second step, the local temperature is determined from the difference between the measured heat flux for heat sources switched on and off. The method is demonstrated using self-heating of silicon nanowires. While a homogeneous nanowire shows a bell-shaped temperature profile, a nanowire diode exhibits a hot spot centered near the junction between two doped segments. PMID- 22214278 TI - Decomposition of aminotetrazole based energetic materials under high heating rate conditions. AB - A T-jump/time-of-flight mass spectrometer (T-Jump/TOFMS) is used to probe the decomposition of several aminotetrazole containing energetic materials under very high heating rates of 10(5)-10(6) K/s. The materials investigated are 5-amino-1 methyl-1H-tetrazolium dinitramide (MeHAT_DN), 1,5-diamino-4-methyl-1H-tetrazolium dinitramide (MeDAT_DN), 1,5-diamino-1H-tetrazolium nitrate (DAT_N), 1,5-diamino-4 methyl-1H-tetrazolium azide (MeDAT_N3), and 5-aminotetrazolium dinitramide (HAT_DN). Subtle differences between materials in functional group placement and anion composition allow for further understanding of the decomposition pathway of the tetrazole structure and various anions. Two decomposition pathways for the tetrazole ring are observed, which result in the primary formation of HN(3) or N(2). The N(2) formation pathway occurs when functional groups are placed symmetrically around the tetrazole ring, whereas asymmetric placement results in HN(3) production. The differing anion compositions also show effects on thermal stability of the salts, as is demonstrated by a lower decomposition temperature for the azide containing salt compared to the similar dinitramide containing material. For the decomposition of the dinitramide molecule, high temperature (N(2)O forming) and low temperature (NO(2) forming) decomposition pathways are observed, as has been previously suggested. PMID- 22214279 TI - Immunohistochemical expression of RANKL, RANK and OPG in gingival tissue of patients with periodontitis. AB - OBJECTIVES: To evaluate the expression of the receptor activator of NF-kappaB (RANK), the receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG), in the gingival tissue of patients with periodontitis. MATERIALS AND METHODS: Gingival tissue was obtained from 14 systemically healthy subjects with chronic periodontitis during conventional periodontal surgery. Immunohistochemistry was used to detect the expression of RANK, RANKL and OPG in the oral and periodontal pocket epithelium as well as in the connective tissue cells. RESULTS: RANKL was negatively expressed in both oral and periodontal pocket epithelium. OPG was also negative or weakly positive in the whole epithelium. RANK showed moderate/strong positive staining mainly in the basal and suprabasal layer of oral and periodontal pocket epithelium. In most of the cases, more than 60% of the inflammatory cell infiltrate stained for RANK and RANKL. In these cases the intensity of the stained cells ranged from moderate-to-strong. In less than half of the cases, OPG was positive in more than 60% of the stained cells of the inflammatory cell infiltrate. CONCLUSION: The RANK, RANKL and OPG proteins are differentially expressed in periodontal tissues and may play a major role in the bone loss occurring in periodontitis. PMID- 22214280 TI - A single-bout of one-hour spinning exercise increases troponin T in healthy subjects. AB - OBJECTIVES: While long-term endurance exercise is known to increase cardiac biomarkers, only a few studies on short-term exercise and these markers have been reported. The aim of this study was to investigate the acute effects of a one hour bicycle spinning on cardiac biomarkers in healthy individuals. DESIGN: Serum levels of high-sensitive troponin T (TnT), creatinine kinase MB fraction (CK-MB), N-terminal pro-brain natriuretic peptide (NT-proBNP), creatinine kinase (CK) and myoglobin were measured at baseline, 1 and 24 hour after one hour of spinning exercise in ten healthy and fit (age 31.0 +/- 6.6 years) individuals. RESULTS: TnT doubled one hour post-exercise (All values <= 5 - 9.7 +/- 6.0 ng/L, p < 0.001). Two individuals had TnT levels above upper reference limit, URL (20.7 and 20.2 ng/L, URL = 12 ng/L). Myoglobin levels increased 72% one hour post-exercise (38 +/- 20 - 66 +/- 41 mg/L, p < 0.02). TnT and myoglobin levels returned to baseline 24 hour post-exercise. Serum levels of CK-MB, NT-proBNP and CK were not significantly changed. CONCLUSIONS: A single-bout of one-hour bicycle spinning transiently increases TnT and myoglobin in healthy subjects. Some subjects even have TnT release above URL. Thus, recently performed exercise also of short duration should be taken into consideration in the evaluation of acute chest pain with release of cardiac TnT. PMID- 22214281 TI - Development of a novel multichannel port (x-Gate((r))) for reduced port surgery and its initial clinical results. AB - BACKGROUND: In order to reduce clashing between the instruments during single incision endoscopic surgery or reduced port surgery we have developed a new multichannel port with wider distance between the channels. MATERIAL AND METHODS: We used the newly developed multichannel port (x-Gate(r)) in 34 patients undergoing a variety of reduced port surgery procedures. The operation records of these patients were reviewed. RESULTS: Overall performance of x-Gate(r) was sufficient in the clinical experience. There have been no complications attributed to x-Gate(r). We found that with the x-Gate(r) the conflicts among the forceps have been drastically improved compared with other multi-channel ports we had used before, which had a shorter distance between the channels. PMID- 22214282 TI - An open, comparative study of 10% potassium hydroxide solution versus salicylic and lactic acid combination in the treatment of molluscum contagiosum in children. AB - OBJECTIVES: To evaluate and compare the safety and efficacy of 10% potassium hydroxide (KOH) solution and salicylic and lactic acid (SAL + LAC) combination in the treatment of molluscum contagiosum (MC). MATERIAL AND METHODS: 26 patients with MC randomized into two treatment groups. 12 patients treated with 10% KOH solution and 14 patients treated with SAL + LAC combination for 6 weeks. Parents of patients were instructed to apply medication once daily only to lesions at study onset. Assessment of response of the treated lesions and side effects was performed at 2, 4 and 6 weeks of the treatment. Newly acquired lesions were not included in the study. RESULTS: At the end of therapy, 83.3% (n = 10) of KOH group demonstrated complete remission and 16.7% (n = 2) of them showed partial remission; four patients (33%) developed new lesions during the study. All the patients in the SAL + LAC combination group (100%) demonstrated complete remission of study entry lesions at the end of 6 weeks with five patients (35%) acquiring new lesions during the study. Minor side effects were observed in two groups. CONCLUSIONS: 10% KOH solution and SAL + LAC combination were found to be equally effective in the treatment of MC in children. PMID- 22214284 TI - Biological properties of new viologen-phosphorus dendrimers. AB - Some biological properties of eight dendrimers incorporating both phosphorus linkages and viologen units within their cascade structure or at the periphery were investigated for the first time. In particular cytotoxicity, hemotoxicity, and antimicrobial and antifungal activity of these new macromolecules were examined. Even if for example all these species exhibited good antimicrobial properties, it was demonstrated that their behavior strongly depends on several parameters as their size and molecular weight, the number of viologen units and the nature of the terminal groups. PMID- 22214285 TI - Cyp26b1 mediates differential neurogenicity in axial-specific populations of adult spinal cord progenitor cells. AB - Utilization of endogenous adult spinal cord progenitor cells (SCPCs) for neuronal regeneration is a promising strategy for spinal cord repair. To mobilize endogenous SCPCs for injury repair, it is necessary to understand their intrinsic properties and to identify signaling factors that can stimulate their neurogenic potential. In this study, we demonstrate that adult mouse SCPCs express distinct combinatorial Hox genes and exhibit axial-specific stem cell properties. Lumbar derived neurospheres displayed higher primary sphere formation and greater neurogenicity compared with cervical- and thoracic-derived neurospheres. To further understand the mechanisms governing neuronal differentiation of SCPCs from specific axial regions, we examined the neurogenic responses of adult SCPCs to retinoic acid (RA), an essential factor for adult neurogenesis. Although RA is a potent inducer of neuronal differentiation, we found that RA enhanced the generation of neurons specifically in cervical- but not lumbar-derived cells. We further demonstrate that the differential RA response was mediated by the RA degrading enzyme cytochrome P450 oxidase b1 Cyp26b1. Lumbar cells express high levels of Cyp26b1 and low levels of the RA-synthesizing enzyme retinaldehyde dehydrogenase Raldh2, resulting in limited activation of the RA signaling pathway in these cells. In contrast, low Cyp26b1 expression in cervical spinal cord progenitor cells allows RA signaling to be readily activated upon RA treatment. The intrinsic heterogeneity and signaling factor regulation among adult SCPCs suggest that different niche factor regimens are required for site-specific mobilization of endogenous SCPCs from distinct spatial regions of the spinal cord for injury repair. PMID- 22214283 TI - Engineering endomorphin drugs: state of the art. AB - INTRODUCTION: Although endomorphins-1 (EM-1; H-Tyr-Pro-Phe-Trp-NH(2)) and -2 (EM 2; H-Tyr-Pro-Phe-Phe-NH(2)) are primarily considered agonists for the MU-opioid receptor (MOR), systematic alterations to specific residues provided antagonists and ligands with mixed MU/delta-opioid properties, suitable for application to health-related topics. While the application of endomorphins as antinociceptive agents and numerous biological endpoints were experimentally delineated in laboratory animals and in vitro, clinical use is currently absent. However, structural alterations provide enhanced stability; formation of MOR antagonists or mixed and dual MU/delta-acting ligands could find considerable therapeutic potential. AREAS COVERED: This review attempts to succinctly provide insight on the development and bioactivity of endomorphin analogues during the past decade. Rational design approaches will focus on the engineering of endomorphin agonists, antagonists and mixed ligands for their application as a multi-target ligand. EXPERT OPINION: Aside from alleviating pain, EM analogues open new horizons in the treatment of medical syndromes involving neural reward mechanisms and extraneural regulation effects on homeostasis. Highly selective MOR antagonists may be promising to reduce inflammation, attenuate addiction to drugs and excess consumption of high-caloric food, ameliorate alcoholism, affect the immune system and combat opioid bowel dysfunction. PMID- 22214286 TI - Laboratory evolution of copper tolerant yeast strains. AB - BACKGROUND: Yeast strains endowed with robustness towards copper and/or enriched in intracellular Cu might find application in biotechnology processes, among others in the production of functional foods. Moreover, they can contribute to the study of human diseases related to impairments of copper metabolism. In this study, we investigated the molecular and physiological factors that confer copper tolerance to strains of baker's yeasts. RESULTS: We characterized the effects elicited in natural strains of Candida humilis and Saccharomyces cerevisiae by the exposure to copper in the culture broth. We observed that, whereas the growth of Saccharomyces cells was inhibited already at low Cu concentration, C. humilis was naturally robust and tolerated up to 1 g . L-1 CuSO4 in the medium. This resistant strain accumulated over 7 mg of Cu per gram of biomass and escaped severe oxidative stress thanks to high constitutive levels of superoxide dismutase and catalase. Both yeasts were then "evolved" to obtain hyper-resistant cells able to proliferate in high copper medium. While in S. cerevisiae the evolution of robustness towards Cu was paralleled by the increase of antioxidative enzymes, these same activities decreased in evolved hyper-resistant Candida cells. We also characterized in some detail changes in the profile of copper binding proteins, that appeared to be modified by evolution but, again, in a different way in the two yeasts. CONCLUSIONS: Following evolution, both Candida and Saccharomyces cells were able to proliferate up to 2.5 g . L-1 CuSO4 and to accumulate high amounts of intracellular copper. The comparison of yeasts differing in their robustness, allowed highlighting physiological and molecular determinants of natural and acquired copper tolerance. We observed that different mechanisms contribute to confer metal tolerance: the control of copper uptake, changes in the levels of enzymes involved in oxidative stress response and changes in the copper-binding proteome. However, copper elicits different physiological and molecular reactions in yeasts with different backgrounds. PMID- 22214288 TI - Templated synthesis of amphiphilic nanoparticles at the liquid-liquid interface. AB - A simple and reliable method is described to produce inorganic nanoparticles functionalized asymmetrically with domains of hydrophobic and hydrophilic ligands on their respective hemispheres. These amphiphilic, Janus-type particles form spontaneously by a thermodynamically controlled process, in which the particle cores and two competing ligands assemble at the interface between two immiscible liquids to reduce the interfacial energy. The asymmetric surface chemistry resulting from this process was confirmed using contact angle measurements of water droplets on nanoparticle monolayers deposited onto hydrophobic and hydrophilic substrates-particles presenting their hydrophobic face give contact angles of ~96 degrees , those presenting their hydrophilic face ~19 degrees . The spontaneous assembly process is rationalized by a thermodynamic model, which accounts both for the energetic contributions driving the assembly and for the entropic penalties that must be overcome. Consistent with the model, amphiphilic NPs form only when there is sufficient interfacial area to accommodate them; however, this potential limitation is easily overcome by mechanical agitation of the two-phase mixture. While it is straightforward to vary the ratio of hydrophobic and hydrophilic ligands, the accumulation of amphiphilic particles at the interface is maximal for ligand ratios near 1:1. In addition to gold nanoparticles and thiolate ligands, we demonstrate the generality of this approach by extending it to the preparation of amphiphilic iron oxide nanoparticles using two types of diol-terminated ligands. Depending on the material properties of the inorganic cores, the resulting amphiphilic particles should find applications as responsive particle surfactants that respond dynamically to optical (plasmonic particles) and/or magnetic (magnetic particles) fields. PMID- 22214287 TI - Improved clinical outcome after invasive management of patients with recent myocardial infarction and proven myocardial viability: primary results of a randomized controlled trial (VIAMI-trial). AB - BACKGROUND: Patients with ST-elevation myocardial infarction (STEMI) not treated with primary or rescue percutaneous coronary intervention (PCI) are at risk for recurrent ischemia, especially when viability in the infarct-area is present. Therefore, an invasive strategy with PCI of the infarct-related coronary artery in patients with viability would reduce the occurrence of a composite end point of death, reinfarction, or unstable angina (UA). METHODS: Patients admitted with an (sub)acute myocardial infarction, who were not treated by primary or rescue PCI, and who were stable during the first 48 hours after the acute event, were screened for the study. Eventually, we randomly assigned 216 patients with viability (demonstrated with low-dose dobutamine echocardiography) to an invasive or a conservative strategy. In the invasive strategy stenting of the infarct related coronary artery was intended with abciximab as adjunct treatment. Seventy five (75) patients without viability served as registry group. The primary endpoint was the composite of death from any cause, recurrent myocardial infarction (MI) and unstable angina at one year. As secondary endpoint the need for (repeat) revascularization procedures and anginal status were recorded. RESULTS: The primary combined endpoint of death, recurrent MI and unstable angina was 7.5% (8/106) in the invasive group and 17.3% (19/110) in the conservative group (Hazard ratio 0.42; 95% confidence interval [CI] 0.18-0.96; p = 0.032). During follow up revascularization-procedures were performed in 6.6% (7/106) in the invasive group and 31.8% (35/110) in the conservative group (Hazard ratio 0.18; 95% CI 0.13-0.43; p < 0.0001). A low rate of recurrent ischemia was found in the non-viable group (5.4%) in comparison to the viable-conservative group (14.5%). (Hazard-ratio 0.35; 95% CI 0.17-1.00; p = 0.051). CONCLUSION: We demonstrated that after acute MI (treated with thrombolysis or without reperfusion therapy) patients with viability in the infarct-area benefit from a strategy of early in-hospital stenting of the infarct-related coronary artery. This treatment results in a long-term uneventful clinical course. The study confirmed the low risk of recurrent ischemia in patients without viability. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00149591. PMID- 22214289 TI - Targeting CEA in Pancreas Cancer Xenografts with a Mutated scFv-Fc Antibody Fragment. AB - BACKGROUND: Sensitive antibody-based tumor targeting has the potential not only to image metastatic and micrometastatic disease, but also to be the basis of targeted therapy. The vast majority of pancreas cancers express carcinoembryonic antigen (CEA). Thus, we sought to evaluate the potential of CEA as a pancreatic cancer target utilizing a rapidly clearing engineered anti-CEA scFv-Fc antibody fragment with a mutation in the Fc region [anti-CEA scFv-Fc H310A]. METHODS: Immunohistochemistry (IHC) with the antibody fragment was used to confirm expression of CEA on human pancreas cancer specimens. In vivo tumor targeting was evaluated by tail vein injection of I124-labeled anti-CEA scFv-Fc(H310A) into mice harboring CEA-positive and -negative xenografts. MicroPET/CT imaging was performed at successive time intervals. Radioactivity in blood and tumor was measured after the last time point. Additionally, unlabeled anti-CEA scFv Fc(H310A) was injected into CEA-positive tumor bearing mice and ex vivo IHC was performed to identify the presence of the antibody to define the microscopic intratumoral pattern of targeting. RESULTS: Moderate to strong staining by IHC was noted on 84% of our human pancreatic cancer specimens and was comparable to staining of our xenografts. Pancreas xenograft imaging with the radiolabeled anti CEA scFv-Fc(H310A) antibody demonstrated average tumor/blood ratios of 4.0. Immunolocalization demonstrated peripheral antibody fragment penetration of one to five cell diameters (0.75 to 1.5 MUm). CONCLUSIONS: We characterized a preclinical xenograft model with respect to CEA expression that was comparable to human cases. We demonstrated that the anti-CEA scFv-Fc(H310A) antibody exhibited antigen-specific tumor targeting and shows promise as an imaging and potentially therapeutic agent. PMID- 22214290 TI - A brief report of depressive symptoms and health promoting behaviors among women with infertility attending a clinical mind-body program. AB - Diagnosis of infertility or treatment for infertility can result in distress, including for some women, depressive symptoms. Integrative infertility treatment programs are gaining recognition and popularity, and many women may seek this kind of care. However, depressive symptoms may be a barrier to fully engaging in and benefiting from mind-body infertility programs. The aim of this retrospective, cross-sectional chart review, was to describe the baseline level of depressive symptoms and differences in baseline health promoting behaviors by level of depressive symptoms among women (n=104) presenting to a mind-body infertility program in the clinical setting. Depressive symptoms were assessed using the Beck Depression Inventory-II (BDI-II), and health promoting behaviors were assessed using the Health Promoting Lifestyle Profile-II (HPLP-II). The mean BDI-II score for the sample was 16.3 (+/- 8.5). Participants scoring in the moderate-severe range on the BDI-II had significantly lower scores on Spiritual Growth, Interpersonal Relations, Stress Management and Nutrition subscales of the HPLP-II. There were no significant differences on the Physical Activity or Health Responsibility subscales. These findings may have implications for the treatment of women with infertility, particularly those who seek an integrative approach to treatment. PMID- 22214292 TI - Gate-controlled nonlinear conductivity of Dirac fermion in graphene field-effect transistors measured by terahertz time-domain spectroscopy. AB - We present terahertz spectroscopic measurements of Dirac fermion dynamics from a large-scale graphene that was grown by chemical vapor deposition and on which carrier density was modulated by electrostatic and chemical doping. The measured frequency-dependent optical sheet conductivity of graphene shows electron-density dependence characteristics, which can be understood by a simple Drude model. In a low carrier density regime, the optical sheet conductivity of graphene is constant regardless of the applied gate voltage, but in a high carrier density regime, it has nonlinear behavior with respect to the applied gate voltage. Chemical doping using viologen was found to be efficient in controlling the equilibrium Fermi level without sacrificing the unique carrier dynamics of graphene. PMID- 22214291 TI - High content live cell imaging for the discovery of new antimalarial marine natural products. AB - BACKGROUND: The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, Plasmodium falciparum. METHODS: A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown in vitro in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope. RESULTS: Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts. CONCLUSION: Collectively, our results show that high-content live cell imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials. PMID- 22214295 TI - Child coping and parent coping assistance during the peritrauma period in injured children. AB - Pediatric physical injury is a very common, potentially traumatic medical event that many families face each year. The role that child or parent coping behavior plays in emotional recovery from injury is not well understood. This study described coping used by children and coping assistance implemented by parents in the early aftermath of a child's injury. Ten child-parent dyads participated in individual semistructured interviews that were audiorecorded, transcribed, and coded using hierarchical coding schemes. Study findings highlight reliance on a broad range of coping strategies. Although children and parents report some similarities in their perceptions of child coping, parents do not recognize all the coping strategies that children report. This suggests potential for improvement in parent-child communication concerning coping techniques. Parents report a limited number of coping assistance strategies, indicating a niche for preventive programs. Further research should examine coping during the peritrauma period as it relates to physical and emotional outcomes to inform secondary prevention programs. PMID- 22214296 TI - Integration of behavioral health services in a primary care clinic serving rural Appalachia: reflections on a clinical experience. AB - In the past few decades, there has been a move toward integrating behavioral health and medical services. This can be particularly beneficial for rural residents, as integration can increase access to mental healthcare in areas where there are shortages of mental health providers. Southern Appalachia is characterized by isolated areas that have shortages of both mental health and medical providers. This article discusses the experiences of a clinical psychology doctoral student integrating behavioral health services in a primary care clinic within rural Southern Appalachia. The role of the behavioral health consultant is described, including representative services and development and implementation of a clinic-wide depression protocol. Additionally, barriers to integration and recommendations for future training and practice are provided. PMID- 22214297 TI - Mano a Mano: Improving health in impoverished Bolivian communities through community-based participatory research. AB - Mano a Mano (Spanish translation: "Hand to Hand") is a nonprofit organization that is working in partnership with underserved Bolivian communities to cocreate medical infrastructures and to improve health. Using community-based participatory research (CBPR) methods, Mano a Mano engages local government and community leaders, health care providers, educators, and ordinary citizens in a manner that taps local strengths and resources to allow all participants to work together to realize this mission. After describing Bolivia's call for improved access to high quality care in its poor and underserved rural areas, we outline the Mano a Mano's CBPR approach and sequence to answer this call, the culmination of its efforts to date (including the establishment of 119 health care facilities), lessons learned, and next steps in the formal evaluation and extension of this collaborative work. PMID- 22214298 TI - Individual and family strengths: an examination of the relation to disease management and metabolic control in youth with type 1 diabetes. AB - We examined the association of youths' positive qualities, family cohesion, disease management, and metabolic control in Type 1 diabetes. Two-hundred fifty seven youth-parent dyads completed the Family Cohesion subscale of the Family Environment Scale, the Diabetes Behavior Rating Scale, 24-hour diabetes interview, and youth completed the Positive Qualities subscale of the Youth Self Report (YSR-PQ). Structural equation modeling demonstrated that YSR-PQ scores were associated with metabolic control mediated by associations with more family cohesion and better disease management. That is, youth with higher YSR-PQ scores had more cohesive families, better disease management, and, indirectly, better metabolic control. Family cohesion was indirectly associated with better metabolic control mediated by its association with better disease management, but not mediated by its association with YSR-PQ scores. Youth who reported more positive qualities, as measured by the YSR-PQ subscale, had better disease management and metabolic control through the association with more family cohesion. However, the current results did not support an alternative hypothesis that cohesive families display better diabetes management mediated by higher YSR PQ scores. PMID- 22214307 TI - A comparison of 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT. AB - BACKGROUND: Our objective was to compare 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging small or large s.c. tumor xenografts in athymic mice that display a wide range of human epidermal growth factor receptor-2 (HER2) expression using microSPECT/CT or microPET/CT. METHODS: Trastuzumab Fab were labeled with 111In or 64Cu by conjugation to 1,4,7,10-tetraazacyclododecane N, N', N'', N'''-tetraacetic acid (DOTA). The purity of 111In- and 64Cu-DOTA trastuzumab Fab was measured by SDS-PAGE and HPLC. HER2 binding affinity was determined in saturation radioligand binding assays using SKBR-3 cells (1.3 * 106 HER2/cell). MicroSPECT/CT and microPET/CT were performed in athymic mice bearing s.c. BT-20 and MDA-MB-231 xenografts with low (0.5 to 1.6 * 105 receptors/cell), MDA-MB-361 tumors with intermediate (5.1 * 105 receptors/cell) or SKOV-3 xenografts with high HER2 expression (1.2 * 106 receptors/cell) at 24 h p.i. of 70 MBq (10 MUg) of 111In-DOTA-trastuzumab Fab or 22 MBq (10 MUg) of 64Cu-DOTA trastuzumab Fab or irrelevant 111In- or 64Cu-DOTA-rituximab Fab. Tumor and normal tissue uptake were quantified in biodistribution studies. RESULTS: 111In- and 64Cu-DOTA-trastuzumab were > 98% radiochemically pure and bound HER2 with high affinity (Kd = 20.4 +/- 2.5 nM and 40.8 +/- 3.5 nM, respectively). MDA-MB-361 and SKOV-3 tumors were most clearly imaged using 111In- and 64Cu-DOTA-trastuzumab Fab. Significantly higher tumor/blood (T/B) ratios were found for 111In-DOTA trastuzumab Fab than 111In-DOTA-rituximab Fab for BT-20, MDA-MB-231 and MDA-MB 361 xenografts, and there was a direct association between T/B ratios and HER2 expression. In contrast, tumor uptake of 64Cu-DOTA-trastuzumab Fab was significantly higher than 64Cu-DOTA-rituximab Fab in MDA-MB-361 tumors but no direct association with HER2 expression was found. Both 111In- and 64Cu-DOTA trastuzumab Fab imaged small (5 to 10 mm) or larger (10 to 15 mm) MDA-MB-361 tumors. Higher blood, liver, and spleen radioactivity were observed for 64Cu-DOTA trastuzumab Fab than 111In-DOTA-trastuzumab Fab. CONCLUSIONS: We conclude that 111In-DOTA-trastuzumab Fab was more specific than 64Cu-DOTA-trastuzumab Fab for imaging HER2-positive tumors, especially those with low receptor density. This was due to higher levels of circulating radioactivity for 64Cu-DOTA-trastuzumab Fab which disrupted the relationship between HER2 density and T/B ratios. Use of alternative chelators that more stably bind 64Cu may improve the association between T/B ratios and HER2 density for 64Cu-labeled trastuzumab Fab. PMID- 22214306 TI - Yeast-based assay identifies novel Shh/Gli target genes in vertebrate development. AB - BACKGROUND: The increasing number of developmental events and molecular mechanisms associated with the Hedgehog (Hh) pathway from Drosophila to vertebrates, suggest that gene regulation is crucial for diverse cellular responses, including target genes not yet described. Although several high throughput, genome-wide approaches have yielded information at the genomic, transcriptional and proteomic levels, the specificity of Gli binding sites related to direct target gene activation still remain elusive. This study aims to identify novel putative targets of Gli transcription factors through a protein DNA binding assay using yeast, and validating a subset of targets both in-vitro and in-vivo. Testing in different Hh/Gli gain- and loss-of-function scenarios we here identified known (e.g., ptc1) and novel Hh-regulated genes in zebrafish embryos. RESULTS: The combined yeast-based screening and MEME/MAST analysis were able to predict Gli transcription factor binding sites, and position mapping of these sequences upstream or in the first intron of promoters served to identify new putative target genes of Gli regulation. These candidates were validated by qPCR in combination with either the pharmacological Hh/Gli antagonist cyc or the agonist pur in Hh-responsive C3H10T1/2 cells. We also used small-hairpin RNAs against Gli proteins to evaluate targets and confirm specific Gli regulation their expression. Taking advantage of mutants that have been identified affecting different components of the Hh/Gli signaling system in the zebrafish model, we further analyzed specific novel candidates. Studying Hh function with pharmacological inhibition or activation complemented these genetic loss-of function approaches. We provide evidence that in zebrafish embryos, Hh signaling regulates sfrp2, neo1, and c-myc expression in-vivo. CONCLUSION: A recently described yeast-based screening allowed us to identify new Hh/Gli target genes, functionally important in different contexts of vertebrate embryonic development. PMID- 22214308 TI - Decreased defluorination using the novel beta-cell imaging agent [18F]FE-DTBZ-d4 in pigs examined by PET. AB - BACKGROUND: Fluorine-18 dihydrotetrabenazine [DTBZ] analogues, which selectively target the vesicular monoamine transporter 2 [VMAT2], have been extensively studied for in vivo quantification of beta cell mass by positron-emission tomography [PET]. This study describes a novel deuterated radioligand [18F]fluoroethyl [FE]-DTBZ-d4, aimed to increase the stability against in vivo defluorination previously observed for [18F]FE-DTBZ. METHODS: [18F]FE-DTBZ-d4 was synthesized by alkylation of 9-O-desmethyl-(+)-DTBZ precursor with deuterated [18F]FE bromide ([18F]FCD2CD2Br). Radioligand binding potential [BP] was assessed by an in vitro saturation homogenate binding assay using human endocrine and exocrine pancreatic tissues. In vivo pharmacokinetics and pharmacodynamics [PK/PD] was studied in a porcine model by PET/computed tomography, and the rate of defluorination was quantified by compartmental modeling. RESULTS: [18F]FE-DTBZ d4 was produced in reproducible good radiochemical yield in 100 +/- 20 min. Radiochemical purity of the formulated product was > 98% for up to 5 h with specific radioactivities that ranged from 192 to 529 GBq/MUmol at the end of the synthesis. The in vitro BP for VMAT2 in the islet tissue was 27.0 +/- 8.8, and for the exocrine tissue, 1.7 +/- 1.0. The rate of in vivo defluorination was decreased significantly (kdefluorination = 0.0016 +/- 0.0007 min-1) compared to the non-deuterated analogue (kdefluorination = 0.012 +/- 0.002 min-1), resulting in a six fold increase in half-life stability. CONCLUSIONS: [18F]FE-DTBZ-d4 has similar PK and PD properties for VMAT2 imaging as its non-deuterated analogue [18F]FE-DTBZ in addition to gaining significantly increased stability against defluorination. [18F]FE-DTBZ-d4 is a prime candidate for future preclinical and clinical studies on focal clusters of beta cells, such as in intramuscular islet grafts. PMID- 22214309 TI - Structure of noncoding RNA is a determinant of function of RNA binding proteins in transcriptional regulation. AB - The majority of the noncoding regions of mammalian genomes have been found to be transcribed to generate noncoding RNAs (ncRNAs), resulting in intense interest in their biological roles. During the past decade, numerous ncRNAs and aptamers have been identified as regulators of transcription. 6S RNA, first described as a ncRNA in E. coli, mimics an open promoter structure, which has a large bulge with two hairpin/stalk structures that regulate transcription through interactions with RNA polymerase. B2 RNA, which has stem-loops and unstructured single stranded regions, represses transcription of mRNA in response to various stresses, including heat shock in mouse cells. The interaction of TLS (translocated in liposarcoma) with CBP/p300 was induced by ncRNAs that bind to TLS, and this in turn results in inhibition of CBP/p300 histone acetyltransferase (HAT) activity in human cells. Transcription regulator EWS (Ewing's sarcoma), which is highly related to TLS, and TLS specifically bind to G-quadruplex structures in vitro. The carboxy terminus containing the Arg-Gly-Gly (RGG) repeat domains in these proteins are necessary for cis-repression of transcription activation and HAT activity by the N-terminal glutamine-rich domain. Especially, the RGG domain in the carboxy terminus of EWS is important for the G-quadruplex specific binding. Together, these data suggest that functions of EWS and TLS are modulated by specific structures of ncRNAs. PMID- 22214310 TI - Nonischemic priapism following penile tattooing. AB - INTRODUCTION: To our knowledge, here we report the first case of nonischemic priapism following penile tattooing. AIM: To report the first case of nonischemic priapism following penile tattooing. METHODS: A case with tattooing-induced priapism is presented including subjective reporting, physical examination, and laboratory/radiologic evaluations. RESULTS: A 21-year-old man, presented with partially rigid penis of 3-month duration. On examination, the penis was half rigid, with a tattoo on its dorsal surface, and a smaller tattoo on the glans (Figure 1). The patient initially stated that the tattoo had been created years ago, but later admitted that he had it created just before the occurrence of priapism. A traditional tattooist created the tattoo manually, using a handheld needle. Bleeding from deep penile tissue for several days complicated the tattooing. Known etiologies of priapism were investigated and ruled out. Specifically, perineal injury, leukemia, sickle cell trait, thalassemia, urinary tract infection, neurogenic, neoplastic, infectious, toxic, and pharmacological causes were actively investigated and ruled out. There was no history of alcohol consumption or smoking. Aspirated penile blood was bright red. Cavernous blood gas measurements confirmed high oxygen and low carbon dioxide content, diagnostic of arterial priapism. There was no embolization facility in Kermanshah. In fact, there are few experts in superselective embolization in Iran. We referred the patient for superselective embolization. However, he underwent a nonindicated Sacher procedure. Predictably, the procedure was unsuccessful. At present, the patient continues to have priapism. Because of the painless nature of erections, moderately good preservation of erectile function during intercourses, and disappointment with former surgery, the patient declined further therapies, and he lives with his condition. CONCLUSIONS: Tattooing should be added to the etiologies of nonischemic priapism. Considering this case, we discourage penile tattooing. PMID- 22214311 TI - Correcting for a density distribution: particle size analysis of core-shell nanocomposite particles using disk centrifuge photosedimentometry. AB - Many types of colloidal particles possess a core-shell morphology. In this Article, we show that, if the core and shell densities differ, this morphology leads to an inherent density distribution for particles of finite polydispersity. If the shell is denser than the core, this density distribution implies an artificial narrowing of the particle size distribution as determined by disk centrifuge photosedimentometry (DCP). In the specific case of polystyrene/silica nanocomposite particles, which consist of a polystyrene core coated with a monolayer shell of silica nanoparticles, we demonstrate that the particle density distribution can be determined by analytical ultracentrifugation and introduce a mathematical method to account for this density distribution by reanalyzing the raw DCP data. Using the mean silica packing density calculated from small-angle X ray scattering, the real particle density can be calculated for each data point. The corrected DCP particle size distribution is both broader and more consistent with particle size distributions reported for the same polystyrene/silica nanocomposite sample using other sizing techniques, such as electron microscopy, laser light diffraction, and dynamic light scattering. Artifactual narrowing of the size distribution is also likely to occur for many other polymer/inorganic nanocomposite particles comprising a low-density core of variable dimensions coated with a high-density shell of constant thickness, or for core-shell latexes where the shell is continuous rather than particulate in nature. PMID- 22214312 TI - Early onset Parkinsonism associated with an intronic SOD1 mutation. AB - We report on a patient belonging to a large family with autosomal-dominant amyotrophic lateral sclerosis, who developed asymmetrical akineto-rigid symptoms at 33 years of age. He had no signs of lower motor neuron disease after four years of follow-up. All seven ALS patients from this family harboured a mutation located in the fourth intron of the SOD1 gene. The proband also harboured the same mutation, associated with a 40% decrease in SOD1 erythrocyte activity. This case report suggests that SOD1 mutations might be associated with marked phenotypic variability (ALS or early onset Parkinsonism in this family). PMID- 22214313 TI - Widespread neuronal and glial hyperphosphorylated tau deposition in ALS with cognitive impairment. AB - Although the biological basis of frontotemporal syndromes associated with amyotrophic lateral sclerosis (ALS) is considered to be altered metabolism of TDP 43, in ALS with cognitive impairment (ALSci) the metabolism of tau protein is also altered. This includes neuronal hyperphosphorylation (pThr(175)). Using novel polyclonal phospho-tau antibodies (pSer(208, 210), pThr(217) and pThr(175)) and antibodies directed against PHF tau (pSer(202)), TDP-43 or ubiquitin, we characterized tau deposition in ALS and ALSci. In ALS, we observed pThr(175) tau immunoreactive intraneuronal and neuritic aggregates throughout the amygdala and entorhinal cortex. In ALSci, this extended to the anterior cingulate gyrus, superior frontal cortex and substantia nigra. The pThr(217) antibody detected widespread astrocytic tau deposition, including punctuate or fibrillary aggregates, or intensely immunoreactive tufted astrocytes in the superior frontal cortex, anterior cingulate gyrus, entorhinal cortex, amygdala and basal ganglia of ALS. In ALSci, a similar but more widely distributed pThr(217) pathology was observed. There was no correlation between the extent of pathological tau deposition and TDP-43 pathology, although nuclear TDP-43 immunoreactivity was absent in neurons with tau pathology. In conclusion, ALSci is unique in possessing both tau and TDP-43 pathology. The presence of widespread astrocytic tau pathology suggests that ALSci may initially be characterized by astrocytic pathology. PMID- 22214314 TI - A novel P66S mutation in exon 3 of the SOD1 gene with early onset and rapid progression. AB - Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease in adults of unknown origin in most cases. Here we report a novel P66S mutation in exon 3 of the SOD1 gene in an apparently sporadic ALS patient with unusual early onset and rapid disease progression. Our data widen the spectrum of SOD1 mutations and clinical presentations of ALS. PMID- 22214316 TI - Subangstrom profile imaging of relaxed ZnO(10 10) surfaces. AB - Relaxation is a most basic structural behavior of free surfaces, however, direct observation of surface relaxation remains challenging in atomic-scale. Herein, single-crystalline nanoislands formed in situ on ZnO nanowires and nanobelts are characterized using aberration-corrected transmission electron microscopy combined with ab initio calculations. For the first time, displacements of both Zn and O atoms in the fresh (10 10) facets are quantified to accuracies of several picometers and the under-surface distributions of contractions and rotations of Zn-O bonds are directly measured, which unambiguously verify the theoretically predicted relaxation of ZnO (10 10) free surfaces. Finally, the surface relaxation is directly correlated with the size effects of electromechanical properties (e.g., elastic modulus and spontaneous polarization) in ZnO nanowires. PMID- 22214315 TI - Isochromosome 13 in a patient with childhood-onset schizophrenia, ADHD, and motor tic disorder. AB - BACKGROUND: A small percentage of all cases of schizophrenia have a childhood onset. The impact on the individual and family can be devastating. We report the results of genetic analyses from a patient with onset of visual hallucinations at 5 years, and a subsequent diagnosis at 9 years of schizophrenia, attention deficit hyperactivity disorder (ADHD) with hyperactivity and impulsivity, and chronic motor tic disorder. RESULTS: Karyotypic analysis found 45,XX,i(13)(q10) in all cells examined. Alpha satellite FISH of isochromosome 13 revealed a large unsplit centromeric region, interpreted as two centromeres separated by minimal or undetectable short-arm material or as a single monocentric centromere, indicating that the isochromosome likely formed post-zygotically by a short arm U type or centromeric exchange. Characterization of chromosome 13 simple tandem repeats and Affymetrix whole-genome 6.0 SNP array hybridization found homozygosity for all markers, and the presence of only a single paternal allele in informative markers, consistent with an isodisomic isochromosome of paternal origin. Analysis of two chromosome 13 schizophrenia candidate genes, D-amino acid oxidase activator (DAOA) and 5-hydroxytryptamine (serotonin) receptor 2A (5 HTR2A), failed to identify non-synonymous coding mutations but did identify homozygous risk polymorphisms. CONCLUSIONS: We report a female patient with childhood-onset schizophrenia, ADHD, and motor tic disorder associated with an isodisomic isochromosome 13 of paternal origin and a 45,XX,i(13)(q10q10) karyotype. We examined two potential mechanisms to explain chromosome 13 involvement in the patient's pathology, including reduction to homozygosity of a paternal mutation and reduction to homozygosity of a paternal copy number variation, but were unable to identify any overtly pathogenic abnormality. Future studies may consider whether epigenetic mechanisms resulting from uniparental disomy (UPD) and the lack of chromosome 13 maternal alleles lead to the patient's features. PMID- 22214317 TI - Bacterial skin and soft tissue infections: review of the epidemiology, microbiology, aetiopathogenesis and treatment: a collaboration between dermatologists and infectivologists. AB - Bacterial skin and soft tissues infections (SSTI) often determine acute disease and frequent emergency recovering, and they are one of the most common causes of infection among groups of different ages. Given the variable presentation of SSTI, a thorough assessment of their incidence and prevalence is difficult. The presence of patient-related (local or systemic) or environmental risk factors, along with the emergence of multi-drug resistant pathogens, can promote SSTI. These infections may present with a wide spectrum of clinical features and different severity, and can be classified according to various criteria. Many bacterial species can cause SSTI, but Gram-positive bacteria are the most frequently isolated, with a predominance of Staphylococcus aureus and Streptococcus pyogenes. The diagnosis of SSTI requires an extended clinical history, a thorough physical examination and a high index of suspicion. Early diagnosis is particularly important in complicated infections, which often require laboratory studies, diagnostic imaging and surgical exploration. SSTI management should conform to the epidemiology, the aetiology, the severity and the depth of the infection. Topical, oral or systemic antimicrobial therapy and drainage or debridement could be necessary, along with treatment of a significant underlying disease. This review discusses the epidemiology, the pathogenesis and the classification of bacterial SSTI, describes their associated risk factors and their clinical presentations. The authors provide a rational diagnostic and therapeutic approach to SSTI in respect of antibiotic resistance and currently available antimicrobial agents. PMID- 22214318 TI - Oral habits in a group of consecutively treated orthodontic patients, using standardized video recordings for diagnosis. AB - OBJECTIVE: To investigate the prevalence and correlation of soft tissue dysfunctions documented by standardized video recordings in a group of orthodontic patients and to evaluate orthodontic treatment changes. SUBJECTS AND METHODS: The presence of an oral habit was evaluated from standardized pre- and post-treatment video recordings of 80 consecutive patients (30 boys and 50 girls, mean age 12.2 +/- 1.7 years). Any digit-sucking habit was noted during a routine interview. Pre- and post-treatment cephalograms were traced to assess sagittal and vertical jaw and incisor relationships. Correlations and differences were tested for statistical significance using the t-test and Odds-ratio. RESULTS: 56.3% had one or more habits before treatment. The total prevalence fell during treatment. A clear correlation was found between digit sucking and atypical tongue activity. Pre-treatment cephalograms showed that patients with a habit had a larger overjet, smaller overbite, more proclined and protruded incisors, a greater ANB angle and a greater inter-maxillary angle (ML/NL) than those without a habit. Cephalometric differences between the groups after orthodontic treatment were much less pronounced. Those with an oral habit also showed a tendency for increased treatment time/number of visits. CONCLUSIONS: Standardized video recordings improved the reliability of the recordings of the oral soft tissue dysfunctions. Their overall reduction after the end of orthodontic treatment coincided with a normalization of the sagittal skeletal and dental variables. PMID- 22214319 TI - Novel alginate gel microspheres produced by impinging aerosols for oral delivery of proteins. AB - Lysozyme and insulin were encapsulated in alginate gel microspheres using impinging aerosols method. High loadings of around 50% weight/dry microspheres weight were obtained with encapsulation efficiencies of at least 48%. Environmental scanning electron microscopy revealed smooth spherical hydrated microspheres (30-60 um) in diameter. No lysozyme or insulin release was measured in simulated gastric fluid (HCl, pH 1.2, 37 degrees C). Total insulin release occurred in simulated intestinal fluid (SIF; phosphate buffer saline, pH 7.4, 37 degrees C) in 8 h following 2 h incubation in SGF and was found to retain 75% activity using the ARCHITECT(r) assay. Lysozyme was released completely in SIF in 10 h following 2 h incubation in SGF and was found to exhibit at least 80% bioactivity using the Micrococcus lysodeikticus assay. The absence of protein release in HCl and the retention of high levels of biological activity demonstrate the potential of alginate gel microspheres, for improving oral delivery of biopharmaceuticals. PMID- 22214320 TI - Mechanical characterization of microspheres - capsules, cells and beads: a review. AB - Microspheres, including microcapsules and cells or beads, are widely used to produce many functional products. Information about their mechanical properties is essential to understanding their performance during manufacturing, processing and end-use applications. The mechanical characterization of microspheres requires applying a mechanical load onto single microspheres and measuring the corresponding deformation, and theoretical modelling of the force-deformation relationship, which allows the determination of mechanical property parameters of the materials such as the elastic modulus, yield stress or failure stress/strain. This review presents the techniques developed for the characterization of microspheres, but focus is on the two most common techniques: atomic force microscopy and compression testing by micromanipulation. The merits and limitations of these techniques and their future developments required are discussed along with the four key aspects to mechanically characterize single microspheres: (i) elastic regime, (ii) plasticity, (iii) rupture behaviour and (iv) time-dependent effects, such as viscoelasticity and permeation. PMID- 22214321 TI - Enhanced percutaneous delivery of recombinant human epidermal growth factor employing nano-liposome system. AB - We encapsulated recombinant human epidermal growth factor (rhEGF) into nano liposomes (NLs) system for topical delivery. The rhEGF-loaded NLs were prepared using a high pressure homogenization method. Morphology and overall particle distribution of NLs were investigated using transmission electron microscopy (TEM) and high resolution microscope (CytoVivaTM). Particle size, zeta (zeta) potential and encapsulation efficiency were measured and the percutaneous delivery of NLs was evaluated using Franz diffusion cells and immunofluorescence confocal laser scanning microscopy (CLSM). The mean particle size, zeta potential and encapsulation efficiency of the NLs were 155.57 +/- 2.59 nm, -57.92 +/- 4.35 mV and 9.00 +/- 0.39%, respectively. TEM and microscopic analysis showed spherical, very even-sized vesicles approximately 150 nm. The skin permeation and localization of rhEGF were enhanced by NLs. CLSM image analysis provided that the NLs enhanced the permeation and localization of rhEGF in rat skin by facilitating entry through pores of skin. PMID- 22214322 TI - Hollow poly(MPC-g-PEG-b-PLA) graft copolymer microcapsule as a potential drug carrier. AB - In this article, an amphiphilic graft copolymer composed of poly(2 methacryloyloxyethyl phosphorylcholine) (PMPC) as the hydrophilic backbone, poly(L-lactic acid) (PLA) as the hydrophobic side-chains and polyethylene glycol (PEG) as the spacer was synthesized. Transmission electron microscopy revealed that the graft copolymer could self-assemble into hollow microcapsules when dialyzed in aqueous solution and particle sizes ranged from 200 to 300 nm, while the graft copolymer formed core-shell microspheres with the absence of PEG spacer. X-ray photoelectron microscope showed that MPC polymers were located at the surface of the microcapsules. The amounts of adsorbed bovine serum albumin and Fg on the microcapsules were significantly decreased than that on the conventional PLA particles (74% and 60%, respectively), well indicating the anti adhesive property of the microcapsules. Paclitaxel was chosen as a prototype anticancer drug for the encapsulation and release studies, the results showed that the drug encapsulation efficiency was 89.3 +/- 1.2% and the microcapsules exhibited controlled release behaviour. PMID- 22214323 TI - What factors control product yield in charge separation reaction from second excited state in zinc-porphyrin derivatives? AB - Intramolecular charge separation from the second singlet excited state of directly linked Zn-porphyrin-imide dyads and following charge recombination into the first singlet excited state has been investigated in the framework of a model involving three electronic states (the first and the second singlet excited and charge separated states) as well as their vibrational sublevels. Kinetics of the transitions between these states are described in terms of the stochastic point transition approach. The influence of the model parameters (free energy change of charge separation, magnitude of the reorganization energies of the medium and the high frequency intramolecular vibrations, the rate of relaxation of the medium and the intramolecular high frequency vibrational mode) on the kinetics of population of both the charge separated and the first singlet excited states has been explored. Simulations of the kinetics of the charge separated state population have allowed reproducing the distinctive features of the kinetics observed in the experiment [Wallin, S.; Monnereau, C.; Blart, E.; Gankou, J.-R.; Odobel, F.; Hammarstrom, L. J. Phys. Chem. A 2010, 114, 1709]: (i) two maxima on short time scale (hundreds of femtoseconds) and long time scale (tens of picoseconds), (ii) the magnitudes of both maxima, and (iii) the depth of the notch between the maxima. PMID- 22214324 TI - How do laboratory specialists advise clinicians concerning the use and interpretation of renal tests? AB - BACKGROUND: The aim of this study was to elucidate how laboratory specialists advise clinicians concerning renal parameters and to compare their advice with guideline recommendations. METHODS: A questionnaire was distributed to laboratory specialists in Norway and The Netherlands together with two case histories from a primary health-care setting and one from a hospital setting, simulating questions from clinicians. The investigations that laboratory specialists suggested were compared to a test panel that was predefined based on clinical practice guideline recommendations (the 'recommended test panel'). The critical differences between two test results (creatinine, estimated glomerular filtration rate [eGFR] and albumin/creatinine ratio [ACR]) and the anticipated precision of the MDRD equation were evaluated. RESULTS: Fifty-two of the 100 laboratory specialists responded, and most of these were regularly contacted by clinicians to discuss laboratory results. Less than 30% would suggest using the recommended test panel to evaluate renal function in the two primary-care patients. For creatinine and eGFR, median changes stated to signal improvement or deterioration in renal function (creatinine: -14% and +14%, respectively; eGFR: +18% and -13%, respectively) were similar to what could be calculated using information on analytical and within-subject variation from the literature. There were variable critical differences for the ACR results (median values of -50% for improvement and +67% for deterioration). Only 23% of the participants would recommend a gold standard clearance examination for a patient who was to undergo nephrotoxic chemotherapy. CONCLUSION: Questions from GPs about renal parameters are answered differently by laboratory specialists, and adherences to guideline recommendations are low on some issues. PMID- 22214325 TI - A cross-institutional examination of readiness for interprofessional learning. AB - This paper examines the readiness for and attitudes toward interprofessional (IP) education in students across four diverse educational institutions with different educational mandates. The four educational institutions (research-intensive university, baccalaureate, polytechnical institute and community college) partnered to develop, deliver and evaluate IP modules in simulation learning environments. As one of the first steps in planning, the Readiness for Interprofessional Learning Scale was delivered to 1530 students from across the institutions. A confirmatory factor analysis was used to expand upon previous work to examine psychometric properties of the instrument. An analysis of variance revealed significant differences among the institutions; however, a closer examination of the means demonstrated little variability. In an environment where collaboration and development of learning experiences across educational institutions is an expectation of the provincial government, an understanding of differences among a cohort of students is critical. This study reveals nonmeaningful significant differences, indicating different institutional educational mandates are unlikely to be an obstacle in the development of cross institutional IP curricula. PMID- 22214327 TI - Piperidine and pyrrolidine analogs as glycogen synthase activators; a patent evaluation (WO2011058122). AB - A small series of piperidine analogs that effectively activate glycogen synthase (GS) was prepared in WO2011058122. The treatment or prophylaxis of metabolic disease and disorders by these novel GS activators is claimed. These compounds represent further variations around a structural motif explored in the prior patent publications by Roche. PMID- 22214326 TI - Specific inhibition of the transcription factor Ci by a cobalt(III) Schiff base DNA conjugate. AB - We describe the use of Co(III) Schiff base-DNA conjugates, a versatile class of research tools that target C2H2 transcription factors, to inhibit the Hedgehog (Hh) pathway. In developing mammalian embryos, Hh signaling is critical for the formation and development of many tissues and organs. Inappropriate activation of the Hedgehog (Hh) pathway has been implicated in a variety of cancers including medulloblastomas and basal cell carcinomas. It is well-known that Hh regulates the activity of the Gli family of C2H2 zinc finger transcription factors in mammals. In Drosophila the function of the Gli proteins is performed by a single transcription factor with an identical DNA binding consensus sequence, Cubitus Interruptus (Ci). We have demonstrated previously that conjugation of a specific 17 base-pair oligonucleotide to a Co(III) Schiff base complex results in a targeted inhibitor of the Snail family C2H2 zinc finger transcription factors. Modification of the oligonucleotide sequence in the Co(III) Schiff base-DNA conjugate to that of Ci's consensus sequence (Co(III)-Ci) generates an equally selective inhibitor of Ci. Co(III)-Ci irreversibly binds the Ci zinc finger domain and prevents it from binding DNA in vitro. In a Ci responsive tissue culture reporter gene assay, Co(III)-Ci reduces the transcriptional activity of Ci in a concentration dependent manner. In addition, injection of wild-type Drosophila embryos with Co(III)-Ci phenocopies a Ci loss of function phenotype, demonstrating effectiveness in vivo. This study provides evidence that Co(III) Schiff base-DNA conjugates are a versatile class of specific and potent tools for studying zinc finger domain proteins and have potential applications as customizable anticancer therapeutics. PMID- 22214328 TI - Cystic echinococcosis: aspects of immune response, immunopathogenesis and immune evasion from the human host. AB - Cystic echinococcosis (CE) is a neglected infectious disease caused by the larval stage of Echinococcus granulosus. It constitutes a major public health problem in developing countries. During CE, the distinguishing feature of the host-parasite relationship is that chronic infection coexists with detectable humoral and cellular responses against the parasite. In order to establish successfully an infection, E. granulosus releases molecules that directly modulate the host immune responses favoring a strong anti-inflammatory response and perpetuating parasite survival in the host. In vitro and in vivo immunological approaches, together with molecular biology and immunoproteomic technologies provided us exciting insights into the mechanisms involved in the initiation of E. granulosus infection and the consequent induction and regulation of the immune response. Here, we review some of the recent developments and discuss how these observations helped to understand the immunology of E. granulosus infection in man. Although the last decade has clarified many aspects of host-relationship in human CE, establishing the full mechanisms that cause the disease require more studies. We need to define more clearly the events that manipulate the host immune response to protect the E. granulosus from elimination and minimizing severe pathology in the host. PMID- 22214329 TI - Wolbachia and its implications for the immunopathology of filariasis. AB - Filarial infections are characterized by immunopathological phenomena, that are responsible for the onset of often dramatic pathological outcomes, such as blindness (Onchocerca volvulus) and elephantiasis (W. bancrofti). In addition, the long-term survival (as long as 10 years) of these parasites in otherwise immunocompetent hosts indicates that these nematodes are capable of manipulating the host immune response. The ground-breaking discovery of the bacterial endosymbiont Wolbachia, which resides in most filarial nematodes causing disease, has led to increasing interest in the role it may play in immuno-modulation, pro inflammatory pathology and other aspects of filarial infection. Indeed, Wolbachia has been shown to be responsible for exacerbating inflammation (as in river blindness), while at the same time blocking efficient elimination of parasites through the host immune response (Onchocerca ochengi). While studies aimed at identifying Wolbachia as a potential target for anti-filarial therapy are at the forefront of current research, understanding its role in the immunology of filarial infection is a fascinating field that has yet to uncover many secrets. PMID- 22214330 TI - Toxocara infection and its association with allergic manifestations. AB - Toxocara canis and Toxocara cati are roundworms of dogs and cats that can also infect humans worldwide. Although these parasites do not reach the adult stage in the human host the larvae migrate to different organs and can persist for many years. Migration of larvae through the lungs may result in respiratory distress such as wheezing, coughs, mucous production and hyper-reactivity of the airways. Epidemiological and experimental studies suggest that infection with this helminth contributes to the development of allergic manifestations, including asthma. These findings are however conflicting since in others studies no association between these two immunopathologies has been found. This article reviews information on Toxocara spp. and findings from epidemiological and experimental studies on the association between Toxocara infection and allergic manifestations. In addition, the immunological mechanisms and the factors involved in the helminth allergy-association are discussed. PMID- 22214331 TI - Immunomodulation in trichinellosis: does Trichinella really escape the host immune system? AB - This review describes different aspects of the host immune response to Trichinella. The role of antibodies, T cells, mast cells, eosinophils and neutrophils in immune reaction to this nematode is considered, in the light of the recent data derived from experimental models, both in in vivo and in vitro. The knowledge of immune response mechanisms against Trichinella is fundamental to understand how the parasite can escape such mechanisms. The principal evasion mechanisms of host immune response occurring in trichinellosis are described, some of which are shared by other parasites, some others are peculiar of this parasite, but particular attention is focused on immunomodulation and the possibilities to exploit this parasite ability to verify the effects on immuno mediated diseases. In conclusion, some considerations on the actual ability to escape the host immune response by the parasite are discussed, taking into account the recent data that shows that the parasite might rather drive immune system of the host towards a less dangerous response. PMID- 22214332 TI - Schistosoma mansoni antigens as modulators of the allergic inflammatory response in asthma. AB - Epidemiologic evidence has accumulated suggesting that helminth infection or their products protect against the development of autoimmune and allergic diseases. The mechanisms underlying this protection may include regulatory cells and cytokines. Both helminth infection and allergic diseases drive the immune system toward the Th2 type response with high production of IgE. However, while this antibody response is associated with the pathogenesis of allergic diseases, IgE production in regions endemic for parasite diseases, such as schistosomiasis, might be associated with a protection against infection. In individuals chronically exposed to Schistosoma sp infection, regulatory cells and cytokines which may develop to protect the host against harmful parasite antigens may also protect the host against allergic diseases. We have demonstrated that helminthic infections are associated with a poor response to allergy skin-prick tests and with low asthma pathology. This review summarizes the immune response that is associated with the pathology of allergic diseases such as asthma and with the resistance to helminth infections. Moreover, it is discussed how helminth infection, particularly Schistosoma mansoni or their products may influence the development of atopic asthma. PMID- 22214333 TI - Immunomodulatory properties of ES-62, a phosphorylcholine-containing glycoprotein secreted by Acanthocheilonema viteae. AB - Filarial nematodes are parasites that have the ability to persist in their hosts for extended periods of time due to the employment of various mechanisms to divert or down-regulate the host's immune responses. One of these mechanisms is the production of immunomodulatory excretory-secretory (ES) products. This review will discuss the properties of one such product, ES-62, which over the years, has been shown to interact with and modulate the activities of a variety of cells of the immune system including B and T lymphocytes, dendritic cells, macrophages and mast cells. Overall, ES-62 diverts the immune system towards an anti-inflammatory phenotype and consistent with this it has been shown to have therapeutic potential in models of inflammatory disease associated with autoimmunity and allergy. PMID- 22214334 TI - Incidence and prevalence of hypothyroidism in patients affected by chronic heart failure: role of amiodarone. AB - BACKGROUND: It has been demonstrated that hypothyroidism can lead to significant hemodynamic alterations favoring the onset of chronic heart failure (CHF) as well as its progression. Furthermore, amiodarone, an iodine-containing antiarhythmic drug frequently used in CHF patients, is often the cause of primary hypothyroidism. AIM OF THE STUDY: To define the prevalence and incidence of hypothyroidism in a group of CHF outpatients in stable clinical conditions, with particular reference to the role of amiodarone therapy. RESULTS: Among the 422 enrolled patients (326 males, aged 65+/-12 years), 51 (12%) had a previous diagnosis of hypothyroidism while 21 (5%) were newly diagnosed at the enrolment. Then, the overall prevalence of hypothyroidism at the first evaluation was 17%and, as expected, it was significantly higher in females than males (33% vs 13%; p < 0.001). During follow-up (median 28 months) hypothyroidism occurred in further 19 patients (incidence rate: 26/1000/year) and it was mainly attributable to amiodarone therapy. Considering all together the hypothyroid patients, either those affected by thyroid failure at the enrolment than those developing hypothyroidism during the follow-up, levothyroxine therapy was continued or started in 69% of them; however, normal serum TSH values were obtained only in 76% of treated cases (mean levothyroxine dose: 69+/-44 mcg/day). In any case, in the group of patients affected by hypothyroidism a significantly greater occurrence of heart failure progression was observed. CONCLUSIONS: Hypothyroidism, especially the subclinical form, frequently occurs in patients affected by CHF receiving amiodarone therapy. Given the unfavorable impact of hypothyroidism on the progression and prognosis of CHF, and the opportunity to adequately manage thyroid failure by means of levothyroxine replacement therapy without the need to withdraw amiodarone, we recommend regular testing of thyroid function in CHF patients, in particular in those submitted to amiodarone therapy, in order to early diagnose a condition of hypothyroidism and titrate substitutive treatment. PMID- 22214335 TI - Glucocorticoid analogues: potential therapeutic alternatives for treating inflammatory muscle diseases. AB - Glucocorticoids (GCs) have been prescribed to treat a variety of diseases, including inflammatory myopathies and Duchenne muscular dystrophy for over 50 years. However, their prescription remains controversial due to the significant side effects associated with the chronic treatment. It is a common belief that the clinical efficacy of GCs is due to their transrepression of pro-inflammatory genes through inhibition of inflammatory transcription factors (i.e. NF-kappaB, AP-1) whereas the adverse side effects are attributed to the glucocorticoid receptor (GR)-mediated transcription of target genes (transactivation). The past decade has seen an increased interest in the development of GR modulators that maintain the effective anti-inflammatory properties but lack the GR-dependent transcriptional response as a safe alternative to traditional GCs. Many of these analogues or "dissociative" compounds show potential promise in in vitro studies but fail to reach human clinical trials. In this review, we discuss molecular effects of currently prescribed GCs on skeletal muscle and also discuss the current state of development of GC analogues as alternative therapeutics for inflammatory muscle diseases. PMID- 22214336 TI - Regulation of leptin receptor expression in human polarized Caco-2/15 cells. AB - BACKGROUND: Leptin receptors (LEPR) are expressed in intestinal epithelial cells from the duodenum to the colon. Since their role is fundamental for the proper control of nutrient absorption, mucus secretion and mucosa renewal, the regulation of LEPR expression is for the first time investigated as a function of various potential effectors. METHODOLOGY/PRINCIPAL FINDINGS: Fully differentiated Caco-2/15 cells were incubated for 24 hours with nutrients [carbohydrates, fatty acids (FA), amino acids and sterols], hormones (leptin, insulin, hydrocortisone and epithelial growth factor), inflammatory agents (Interferon-gamma, LPS, TNF alpha), and PPAR agonists (rosiglitazone and WY14643). Levels of LEPR mRNA and protein expressions were measured by RT-PCR and Western blots, respectively. RESULTS: Long (219.1) and short (219.3) isoforms of the LEPR were detected in Caco-2/15 cells, while absence of the isoform 219.2 was noted. Their gene expression was modulated by carbohydrates, FA, PPAR agonists, biliary salts, insulin and leptin itself. On the other hand, LEPR protein expression was modulated by FA, cholesterol, biliary salts, PPAR agonists and insulin. Interestingly, the same effectors may have opposite effects on the short and the long LEPR isoforms, as well as on mRNA and protein levels. Finally, Caco-2/15 cells were found to be sensitive to the effector location, i.e. apical or basolateral compartment. CONCLUSIONS/SIGNIFICANCE: Our results suggest that (i) the expression of LEPR in Caco-2/15 cell line is not constitutive; (ii) the agents present in the apical or basolateral medium have different effects on LEPR mRNA and/or protein levels; and (iii) short and long isoforms of LEPR follow different patterns of regulation. PMID- 22214337 TI - Immune modulation by regulatory T cells in Helicobacter pylori-associated diseases. AB - Regulatory T cells (Treg) have the ability to suppress the activity of most other lymphoid cells as well as dendritic cells through cell-cell contact dependent mechanisms, which have not yet been fully defined. Treg are a key component of a functional immune system, and Treg deficiency is associated with severe autoimmunity and allergies. Antigen-specific Treg accumulate in gastric tissue during both Helicobacter pylori-induced gastritis and peptic ulcer disease (PUD). Several studies suggest that the local Treg response protects the gastric mucosa from exaggerated inflammation and tissue damage, and the risk of PUD is inversely related to Treg frequencies. At the same time the reduction of the inflammatory response achieved by Treg leads to increased bacterial density. Furthermore, the inability to mount a protective inflammatory response will lead to chronic infection and in some patients to the development of atrophic gastritis and gastric cancer progression. Treg actively infiltrate gastric adenocarcinomas and are predicted to promote tumor escape from cytotoxic immune responses. In addition, the presence of a potent Treg response will probably be an obstacle when constructing a future therapeutic vaccine against H. pylori. In this article, we will review the proposed mechanisms of action for Treg, their accumulation in the gastric mucosa in the different H. pylori-associated diseases, and how they may affect the immune response induced by H. pylori infection and the course of PUD and gastric adenocarcinomas. PMID- 22214338 TI - Loss of correlations among proteins in brains of the Ts65Dn mouse model of down syndrome. AB - The Ts65Dn mouse model of Down syndrome (DS) is trisomic for orthologs of 88 of 161 classical protein coding genes present on human chromosome 21 (HSA21). Ts65Dn mice display learning and memory impairments and neuroanatomical, electrophysiological, and cellular abnormalities that are relevant to phenotypic features seen in DS; however, little is known about the molecular perturbations underlying the abnormalities. Here we have used reverse phase protein arrays to profile 64 proteins in the cortex, hippocampus, and cerebellum of Ts65Dn mice and littermate controls. Proteins were chosen to sample a variety of pathways and processes and include orthologs of HSA21 proteins and phosphorylation-dependent and -independent forms of non-HSA21 proteins. Protein profiles overall show remarkable stability to the effects of trisomy, with fewer than 30% of proteins altered in any brain region. However, phospho-proteins are less resistant to trisomy than their phospho-independent forms, and Ts65Dn display abnormalities in some key proteins. Importantly, we demonstrate that Ts65Dn mice have lost correlations seen in control mice among levels of functionally related proteins, including components of the MAP kinase pathway and subunits of the NMDA receptor. Loss of normal patterns of correlations may compromise molecular responses to stimulation and underlie deficits in learning and memory. PMID- 22214339 TI - Multiple exciton generation and recombination dynamics in small Si and CdSe quantum dots: an ab initio time-domain study. AB - Multiple exciton generation and recombination (MEG and MER) dynamics in semiconductor quantum dots (QDs) are simulated using ab initio time-dependent density functional theory in combination with nonadiabatic molecular dynamics. The approach differs from other MEG and MER theories because it provides atomistic description, employs time-domain representation, allows for various dynamical regimes, and includes electron-phonon interactions. MEG rapidly accelerates with energy, reflecting strong energy dependence of double exciton (DE) density of states. At early times, MEG is Gaussian rather than exponential. Exponential dynamics, assumed in rate theories, starts at a later time and becomes more important in larger QDs. Phonon-assisted MEG is observed at energies below the purely electronic threshold, particularly in the presence of high frequency ligand vibrations. Coupling to phonons is essential for MER since higher-energy DEs must relax to recombine into single excitons (SEs), and SEs formed during MERs must lose some of their energy to avoid recreating DEs. MER simulated starting from a DE is significantly slower than MER involving an optical excitation of a SE, followed by MEG and then MER. The latter time scale agrees with experiment, emphasizing the importance of quantum-mechanical superpositions of many DEs for efficient MER. The detailed description of the interplay between MEG and MER coupled to phonons provides important insights into the excited state dynamics of semiconductor QDs and nanoscale materials in general. PMID- 22214340 TI - Very high thermopower of Bi nanowires with embedded quantum point contacts. AB - Quantum confinement effects in bismuth (Bi) nanowires (NWs) are predicted to impart them with high thermopower values and hence make them efficient thermoelectric materials. Yet, boundary scattering of charge carriers in these NWs operating in the diffusion transport regime mask any quantum effects and impede their use for nanoscale thermoelectric applications. Here we demonstrate quantum confinement effects in Bi NWs by forming in their structure ballistic quantum point contacts (QPCs) leading to exceptionally high thermopower values (S > 2 mV/K). The power factor, S(2)G, of the QPCs is maximized at G ~ 0.25G(0) (where G(0) is the quantum of conductance) within agreement with a one-band model with step edge characteristics. PMID- 22214341 TI - Determination of cell survival after irradiation via clonogenic assay versus multiple MTT Assay--a comparative study. AB - For studying proliferation and determination of survival of cancer cells after irradiation, the multiple MTT assay, based on the reduction of a yellow water soluble tetrazolium salt to a purple water insoluble formazan dye by living cells was modified from a single-point towards a proliferation assay. This assay can be performed with a large number of samples in short time using multi-well-plates, assays can be performed semi-automatically with a microplate reader. Survival, the calculated parameter in this assay, is determined mathematically. Exponential growth in both control and irradiated groups was proven as the underlying basis of the applicability of the multiple MTT assay. The equivalence to a clonogenic survival assay with its disadvantages such as time consumption was proven in two setups including plating of cells before and after irradiation. Three cell lines (A 549, LN 229 and F 98) were included in the experiment to study its principal and general applicability. PMID- 22214342 TI - Association of polymorphisms in survivin gene with the risk of hepatocellular carcinoma in Chinese han population: a case control study. AB - BACKGROUND: Survivin, one of the strongest apoptosis inhibitors, plays a critical role in the development and progression of hepatocellular carcinoma (HCC). By comparison, relatively little is known about the effect of survivin gene polymorphisms on HCC susceptibility. Our study aimed to investigate the association of survivin gene polymorphisms with the risk of HCC in Chinese han population. METHODS: A case-control study was conducted in Chinese han population consisting of 178 HCC cases and 196 cancer-free controls. Information on demographic data and related risk factors was collected for all subjects. Polymorphisms of the survivin gene, including three loci of rs8073069, rs9904341 and rs1042489, were selected and genotyped by a polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) technique. Association analysis of genotypes/alleles and haplotypes from these loci with the risk of HCC was conducted under different genetic models. RESULTS: Using univariate analysis of rs8073069, rs9904341 and rs1042489 under different genetic models, no statistically significant difference was found in genotype or allele distribution of HCC cases relative to the controls (P > 0.05). Linkage disequilibrium (LD) analysis showed that these loci were in LD. Multivariate logistic regression indicated that with no G-C-T haplotype as reference, the haplotype of G-C-T from these loci was associated with a lower risk for HCC under the recessive model (OR = 0.46, 95% confidence interval (CI): 0.24~0.90, P = 0.023). Both HBsAg+ and the medical history of viral hepatitis type B were risk factors for HCC. However, no statistically significant haplotype-environment interaction existed. CONCLUSIONS: No association between rs8073069, rs9904341 or rs1042489 in survivin gene and the risk of HCC is found in Chinese han population, but rs8073069G-rs9904341C- rs1042489T is perhaps a protective haplotype for HCC. PMID- 22214343 TI - The female menstrual cycle does not influence testosterone concentrations in male partners. AB - BACKGROUND: The time of ovulation has since long been believed to be concealed to male heterosexual partners. Recent studies have, however, called for revision of this notion. For example, male testosterone concentrations have been shown to increase in response to olfactory ovulation cues, which could be biologically relevant by increasing sexual drive and aggressiveness. However, this phenomenon has not previously been investigated in real-life human settings. We therefore thought it of interest to test the hypothesis that males' salivary testosterone concentrations are influenced by phases of their female partners' menstrual cycle; expecting a testosterone peak at ovulation. METHODS: Thirty young, healthy, heterosexual couples were recruited. During the course of 30-40 days, the women registered menses and ovulation, while the men registered sexual activity, physical exercise, alcohol intake and illness (confounders), and obtained daily saliva samples for testosterone measurements. All data, including the registered confounders, were subjected to multiple regression analysis. RESULTS: In contrast to the hypothesis, the ovulation did not affect the testosterone levels, and the resulting testosterone profile during the menstrual cycle was on the average flat. The specific main hypothesis, that male testosterone levels on the day of ovulation would be higher than day 4 of the cycle, was clearly contradicted by a type II error(beta)-analysis (< 14.3% difference in normalized testosterone concentration; beta = 0.05). CONCLUSIONS: Even though an ovulation-related salivary testosterone peak was observed in individual cases, no significant effect was found on a group level. PMID- 22214345 TI - The effects of whole-body vibration training on gait and walking ability - a systematic review comparing two quality indexes. AB - BACKGROUND: Whole-body vibration (WBV) training has been introduced in the last decade and become a popular training method and may increase muscle performance. OBJECTIVES: To evaluate the evidence degree of the effect of WBV training on gait and walking ability by a critical examination of scientific studies. In addition, a minor objective was to compare two quality indexes. METHOD: Literature search in Scopus; quality assessments with The Risk of Bias and The PEDro Scale; and evidence appraisal according to GRADE. RESULT: Ten studies with varying populations using gait-related measurements after at least 1-month WBV intervention were included. Only two studies report significant positive effects. This is defined as low-quality evidence. Eighty percent and 90% of the studies were rated as high quality according to The PEDro Scale and The Risk of Bias, respectively. DISCUSSION: The low-quality evidence indicates a need for further research. A standardized training protocol would make comparisons and conclusions of WBV training more reliable and feasible. CONCLUSION: There is low-quality evidence for WBV training having effects on gait and walking ability. Further research is needed. The evidence did not alter between the quality indexes. PMID- 22214344 TI - Use of [18F]FDOPA-PET for in vivo evaluation of dopaminergic dysfunction in unilaterally 6-OHDA-lesioned rats. AB - BACKGROUND: We evaluated the utility of L-3,4-dihydroxy-6-[18F]fluoro phenylalanine ([18F]FDOPA) positron emission tomography (PET) as a method for assessing the severity of dopaminergic dysfunction in unilaterally 6 hydroxydopamine (6-OHDA)-lesioned rats by comparing it with quantitative biochemical, immunohistochemical, and behavioral measurements. METHODS: Different doses of 6-OHDA (0, 7, 14, and 28 MUg) were unilaterally injected into the right striatum of male Sprague-Dawley rats. Dopaminergic functional activity in the striatum was assessed by [18F]FDOPA-PET, measurement of striatal dopamine (DA) and DA metabolite levels, tyrosine hydroxylase (TH) immunostaining, and methamphetamine-induced rotational testing. RESULTS: Accumulation of [18F]FDOPA in the bilateral striatum was observed in rats pretreated with both aromatic L amino acid decarboxylase and catechol-O-methyltransferase (COMT) inhibitors. Unilateral intrastriatal injection of 6-OHDA produced a significant site-specific reduction in [18F]FDOPA accumulation. The topological distribution pattern of [18F]FDOPA accumulation in the ipsilateral striatum agreed well with the pattern in TH-stained corresponding sections. A significant positive relationship was found between Patlak plot Ki values and striatal levels of DA and its metabolites (r = 0.958). A significant negative correlation was found between both Ki values (r = -0.639) and levels of DA and its metabolites (r = -0.719) and the number of methamphetamine-induced rotations. CONCLUSIONS: Ki values determined using [18F]FDOPA-PET correlated significantly with the severity of dopaminergic dysfunction. [18F]FDOPA-PET makes it possible to perform longitudinal evaluation of dopaminergic function in 6-OHDA-lesioned rats, which is useful in the development of new drugs and therapies for Parkinson's disease (PD). PMID- 22214346 TI - SimReg1 is a master switch for biosynthesis and export of simocyclinone D8 and its precursors. AB - Analysis of the simocyclinone biosynthesis (sim) gene cluster of Streptomyces antibioticus Tu6040 led to the identification of a putative pathway specific regulatory gene simReg1. In silico analysis places the SimReg1 protein in the OmpR-PhoB subfamily of response regulators. Gene replacement of simReg1 from the S. antibioticus chromosome completely abolishes simocyclinone production indicating that SimReg1 is a key regulator of simocyclinone biosynthesis. Results of the DNA-shift assays and reporter gene expression analysis are consistent with the idea that SimReg1 activates transcription of simocyclinone biosynthesis, transporter genes, regulatory gene simReg3 and his own transcription. The presence of extracts (simocyclinone) from S. antibioticus Tu6040 * pSSimR1-1 could dissociate SimReg1 from promoter regions. A preliminary model for regulation of simocyclinone biosynthesis and export is discussed. PMID- 22214347 TI - Peripheral blood gene expression: it all boils down to the RNA collection tubes. AB - BACKGROUND: Gene expression profiling from peripheral blood is a valuable tool for biomarker discovery in clinical studies. Different whole blood RNA collection and processing methods are highly variable and might confound comparisons of results across studies. The main aim of the study was to compare genome-wide gene expression profiles obtained from the two widely used commercially available whole blood RNA collection systems - PAXgeneTM and TempusTM tubes. Comparisons of present call rates, variances, correlations and influence of globin reduction across the two collection systems was performed using in vivo glucocorticoid stimulation in 24 peripheral blood samples from three individuals. RESULTS: RNA quality, yield and numbers of detected transcripts from the two RNA collection systems was comparable, with no significant differences between the tube types. Globin reduction resulted in a significant increase in present call rates (p = 8.17 * 10-5 and p = 1.95 * 10-3 in PAXgeneTM and TempusTM tubes respectively) and significant decrease in gene expression variance in both RNA collection tubes (p = 0.0025 and p = 0.041 in PAXgeneTM and TempusTM tubes respectively). Comparisons of glucocorticoid receptor-stimulated gene expression profiles between the two collection tube systems revealed an overlap of only 17 to 54%, depending on the stringency level of the statistical thresholds. This overlap increased by 1-8% when the RNA samples were processed to remove the globin mRNA. CONCLUSION: RNA obtained from PAXgeneTM and TempusTM tubes was comparable in terms of quality and yield, however, detectable gene expression changes after glucocorticoid receptor stimulation were distinct, with an overlap of only up to 46% between the two collection systems. This overlap increased to 54% when the samples were depleted of globin mRNA and drastically reduced to 17-18% when only gene expression differences with a fold change greater than 2.0 were assessed. These results indicate that gene expression profiles obtained from PAXgeneTM and TempusTM differ drastically and should not be analyzed together. These data suggest that researchers must exert caution while interpreting expression profiles obtained through different RNA collection tubes. PMID- 22214348 TI - SUVref: reducing reconstruction-dependent variation in PET SUV. AB - BACKGROUND: We propose a new methodology, reference Standardised Uptake Value (SUVref), for reducing the quantitative variation resulting from differences in reconstruction protocol. Such variation that is not directly addressed by the use of SUV or the recently proposed PERCIST can impede comparability between positron emission tomography (PET)/CT scans. METHODS: SUVref applies a reconstruction protocol-specific phantom-optimised filter to clinical PET scans for the purpose of improving comparability of quantification. The ability of this filter to reduce variability due to differences in reconstruction protocol was assessed using both phantom and clinical data. RESULTS: SUVref reduced the variability between recovery coefficients measured with the NEMA image quality phantom across a range of reconstruction protocols to below that measured for a single reconstruction protocol. In addition, it enabled quantitative conformance to the recently proposed EANM guidelines. For the clinical data, a significant reduction in bias and variance in the distribution of differences in SUV, resulting from differences in reconstruction protocol, greatly reduced the number of hot spots that would be misclassified as undergoing a clinically significant change in SUV. CONCLUSIONS: SUVref significantly reduces reconstruction-dependent variation in SUV measurements, enabling increased confidence in quantitative comparison of clinical images for monitoring treatment response or disease progression. This new methodology could be similarly applied to reduce variability from scanner hardware. PMID- 22214349 TI - RAD tag sequencing as a source of SNP markers in Cynara cardunculus L. AB - BACKGROUND: The globe artichoke (Cynara cardunculus L. var. scolymus) genome is relatively poorly explored, especially compared to those of the other major Asteraceae crops sunflower and lettuce. No SNP markers are in the public domain. We have combined the recently developed restriction-site associated DNA (RAD) approach with the Illumina DNA sequencing platform to effect the rapid and mass discovery of SNP markers for C. cardunculus. RESULTS: RAD tags were sequenced from the genomic DNA of three C. cardunculus mapping population parents, generating 9.7 million reads, corresponding to ~1 Gbp of sequence. An assembly based on paired ends produced ~6.0 Mbp of genomic sequence, separated into ~19,000 contigs (mean length 312 bp), of which ~21% were fragments of putative coding sequence. The shared sequences allowed for the discovery of ~34,000 SNPs and nearly 800 indels, equivalent to a SNP frequency of 5.6 per 1,000 nt, and an indel frequency of 0.2 per 1,000 nt. A sample of heterozygous SNP loci was mapped by CAPS assays and this exercise provided validation of our mining criteria. The repetitive fraction of the genome had a high representation of retrotransposon sequence, followed by simple repeats, AT-low complexity regions and mobile DNA elements. The genomic k-mers distribution and CpG rate of C. cardunculus, compared with data derived from three whole genome-sequenced dicots species, provided a further evidence of the random representation of the C. cardunculus genome generated by RAD sampling. CONCLUSION: The RAD tag sequencing approach is a cost-effective and rapid method to develop SNP markers in a highly heterozygous species. Our approach permitted to generate a large and robust SNP datasets by the adoption of optimized filtering criteria. PMID- 22214350 TI - Roadmap and standard operating procedures for biobanking and discovery of neurochemical markers in ALS. AB - Despite major advances in deciphering the neuropathological hallmarks of amyotrophic lateral sclerosis (ALS), validated neurochemical biomarkers for monitoring disease activity, earlier diagnosis, defining prognosis and unlocking key pathophysiological pathways are lacking. Although several candidate biomarkers exist, translation into clinical application is hindered by small sample numbers, especially longitudinal, for independent verification. This review considers the potential routes to the discovery of neurochemical markers in ALS, and provides a consensus statement on standard operating procedures that will facilitate multicenter collaboration, validation and ultimately clinical translation. PMID- 22214351 TI - Spatial clustering of amyotrophic lateral sclerosis and the potential role of BMAA. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative syndrome which has no known cause, except for a small proportion of cases which are genetically inherited. The development of ALS likely involves both genetic and environmental risk factors. Environmental risk factors implicated in ALS have included heavy metals, trauma, pesticides, electrical injuries, electromagnetic radiation and the cyanobacterial-derived neurotoxin beta-N-methylamino-L-alanine (BMAA). To investigate possible environmental risks, a number of epidemiological studies of ALS have been conducted. Some of these studies employ spatial analysis techniques that examine for spatial clusters of ALS and can help guide further research into identifying environmental exposures. Despite identifying geographical disparities in the distribution of ALS cases, these studies have not provided any clear associations with environmental factors. We review the literature on important studies of spatial clustering of ALS and explore the hypothesized link between the neurotoxin BMAA and ALS. PMID- 22214352 TI - Respiratory exercise in amyotrophic lateral sclerosis. AB - We have evaluated the potential role of respiratory exercise by implementing specific inspiratory muscle training in a selected population of early-affected amyotrophic lateral sclerosis (ALS) patients. We studied 26 patients with ALS with normal respiratory function using two groups of patients in a parallel, control-group, randomized, delayed-start design. Patients in the first group (G1) started the active inspiratory exercise programme at entry and were followed for eight months, while the second group (G2) of patients followed a placebo exercise programme for the first four months and then active exercise for the second four month period. The primary outcome measure was the ALSFRS. Respiratory tests, neurophysiological measurements, fatigue and quality of life scales were secondary outcomes. Analysis of covariance was used to compare changes between and within groups. Results showed that there was no significant difference between the two patient groups. Within-group analysis suggested that inspiratory exercise promotes a transient improvement in the respiratory subscore and in the maximal voluntary ventilation, peak expiratory flow, and sniff inspiratory pressure. In conclusion, there was no clear positive or negative outcome of the respiratory exercise protocol we have proposed, but we cannot rule out a minor positive effect. Exercise regimes merit more detailed clinical evaluation in ALS. PMID- 22214353 TI - Non-invasive ventilation and gastrostomy may not impact overall quality of life in patients with ALS. AB - Non-invasive positive pressure ventilation (NIPPV) may improve health-related quality of life (HRQoL) in patients with ALS. The effect of percutaneous endoscopic gastrostomy (PEG) on HRQoL is not known. Instruments measuring QoL more broadly have not been used to assess effects of these interventions. This study was undertaken to do so via the ALS-Specific Quality of Life Instrument revised (ALSSQOL-R). A retrospective review was carried out of ALS patients who had undergone one QoL assessment prior to NIPPV or PEG initiation and two assessments following one of these interventions. Random coefficients models were developed. Twenty-two patients met criteria for inclusion: six NIPPV, 11 PEG, and five NIPPV + PEG. The ALSSQoL-R did not change significantly following NIPPV or PEG or both. Function declined in all three groups over the same time-period. In conclusion, overall QoL in ALS does not appear to change after NIPPV or PEG. This may reflect the impact of non-health-related factors or may be due to a response shift. QoL instruments that include domains outside of health status may not be sensitive to changes from single interventions. Larger, prospective studies are needed. PMID- 22214354 TI - Formal ventilation patient education for ALS predicts real-life choices. AB - Our objective was to evaluate a single-session, hands-on education programme on mechanical ventilation for ALS patients and caregivers in terms of knowledge, change in affect and to determine whether ventilator decisions made after the education sessions predict those made later in life. Questionnaires were administered to 26 patients and 26 caregivers on four separate occasions. The questionnaires assessed knowledge of ventilatory support, feedback on the nature of the education programme, as well as self-reported emotional well-being. All patients were followed until their death or until initiation of invasive ventilation. Both groups demonstrated significant improvements in knowledge as a result of the education session which was retained after one month. There was no change in patient or caregiver reports' self-reported emotional well-being. The choices of ventilatory support expressed at one month (T4) accurately predicted the real-life clinical choices made by 76% of patients. Any difference resulted from choosing palliative care. Hands-on patient and caregiver education results in improved knowledge, assists in decision-making with respect to ventilatory support, and is not associated with a worsening of affect. It also provides for an accurate prediction of real-life choices and avoids undesired life support interventions and critical care admissions. PMID- 22214355 TI - No evidence for a large difference in ALS frequency in populations of African and European origin: a population based study in inner city London. AB - Abstract Previous studies have suggested a lower incidence of ALS in people of African origin. We used a population based register in an urban setting from inner city London postcodes where there is a large population of people of African ancestry to compare the frequency of ALS in people of European and African origin. Population statistics stratified by age, gender and ethnicity were obtained from the 2001 census. Incidence and prevalence were calculated in each ethnic group. Results showed that in a population of 683,194, of which 22% were of African ancestry, 88 individuals with ALS were identified over a seven year period, including 14 people with African ancestry. The adjusted incidence in people of African ancestry was 1.35 per 100,000 person-years (95% CI 0.72-2.3) and in those of European ancestry 1.97 per 100,000 person-years (95% CI 1.55 2.48). In conclusion, in this small population based study we could not detect a difference in rates of ALS between people of African ancestry and those of European ancestry. PMID- 22214356 TI - Amyotrophic lateral sclerosis and frontotemporal dementia: A behavioural and cognitive continuum. AB - Our objective was to compare the cognitive and behavioural profile of patients with amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD), and to explore the continuum between these disorders according to neuropsychological and behavioural performance using novel methods of testing and analysis. Twenty patients with ALS, 20 bvFTD patients and 20 healthy controls completed a neuropsychiatric and neuropsychological assessment including cognitive screening, working memory, inhibitory control, decision making and emotion recognition. The resulting neuropsychological and behavioural data were analysed by Rasch analysis. ALS patients showed a similar profile to bvFTD patients on tests of working memory, inhibitory control and behavioural measures. Nine ALS patients (45%) had cognitive impairment and five (25%) met criteria for bvFTD. Even in a subset of MND patients with no impairment on the ACE-R, subtle impairment of inhibitory control together with moderate to severe apathy, were found. The Rasch analysis confirmed that all patients could be ranked on the same continuum, based on their neuropsychological performance and behaviour. Thus, the cognitive and behavioural profiles of ALS mirror those seen in bvFTD. Impaired inhibitory control and behavioural changes suggest subtle orbitofrontal dysfunction in ALS. The Rasch analysis revealed a clear overlap between bvFTD and ALS. PMID- 22214357 TI - Clinical analysis and outcomes of amyotrophic lateral sclerosis with demyelinating polyneuropathy. AB - Abnormalities of both motor and sensory nerve action potentials, similar to those found in demyelinating polyneuropathy, may occur in patients with amyotrophic lateral sclerosis (ALS). We analyzed the clinical features of unusual ALS patients with demyelinating polyneuropathy (DPN) to delineate the characteristics and outcomes of this rare condition. We reviewed three ALS patients with DPN who were confirmed to meet the electrophysiological nerve conduction criteria for DPN among 157 patients with ALS. At the initial neurological examination, one patient had both subjective sensory symptoms and abnormal results of sensory examinations, and one patient had sensory symptoms. Motor weakness of the limbs was present in all patients, and fasciculation was present in two patients. Anti GalNAc-GD1a IgG antibodies were evident in one. Sural nerve biopsy showed a moderate, marginal reduction in myelin thickness, and teased fiber analysis revealed segmental demyelination and remyelination, but axonal degeneration was found in one patient. The mean interval from disease onset to respiratory failure or death in our three patients and seven previously documented ALS patients with DPN was 43.1 +/- 18.7 months. Our findings suggest that survival in ALS with DPN is similar to that in classic ALS. PMID- 22214358 TI - IBP is a form of PLS and should be distinguished from PBP. PMID- 22214359 TI - ALSUntangled No. 14: Mototab. AB - In conclusion, given the lack of demonstrated effectiveness, and the above documented concerns about product safety and supplier identity and reliability, ALSUntangled does not support the use of mototab for amyotrophic lateral sclerosis or any other motor neuron disease. If Oslo Health Solutions ever contacts us with additional useful information on this product we will gladly publish an addendum to this investigation. PMID- 22214360 TI - Microporous polystyrene particles for selective carbon dioxide capture. AB - This study presents the synthesis of microporous polystyrene particles and the potential use of these materials in CO(2) capture for biogas purification. Highly cross-linked polystyrene particles are synthesized by the emulsion copolymerization of styrene (St) and divinylbenzene (DVB) in water. The cross link density of the polymer is varied by altering the St/DVB molar ratio. The size and the morphology of the particles are characterized by scanning and transmission electron microscopy. Following supercritical point drying with carbon dioxide or lyophilization from benzene, the polystyrene nanoparticles exhibit a significant surface area and permanent microporosity. The dried particles comprising 35 mol % St and 65 mol % DVB possess the largest surface area, ~205 m(2)/g measured by Brunauer-Emmett-Teller and ~185 m(2)/g measured by the Dubinin-Radushkevich method, and a total pore volume of 1.10 cm(3)/g. Low pressure measurements suggest that the microporous polystyrene particles exhibit a good separation performance of CO(2) over CH(4), with separation factors in the range of ~7-13 (268 K, CO(2)/CH(4) = 5/95 gas mixture), which renders them attractive candidates for use in gas separation processes. PMID- 22214361 TI - Dental anxiety and temperament in 15-year olds. AB - OBJECTIVE: The aim of the present study was to analyze the prevalence of dental anxiety and its association with temperament, sociodemographic factors and previous painful and unpleasant experiences of dental care among 15-year old individuals. MATERIALS AND METHODS: The sample included 263 randomly selected 15 year old individuals living in the municipality of Jonkoping, Sweden. The school, parental and adolescent consent was acquired. Three self-reported questionnaires were used, one included items of sociodemography, while the others dealt with dental anxiety assessed by the Dental Fear Survey (DFS) and temperament assessed by an adapted version of The EAS Temperament Survey for Children modified for adults, the EASI temperament survey. RESULTS: The results showed that 6.5% of the adolescents were classified as dentally anxious and with girls proportionally more fearful than boys. The three temperaments activity, impulsivity and emotionality were significantly correlated with dental anxiety. A hierarchical multiple linear regression analysis showed that pain at the last dental appointment or previous pain experiences during dental care treatment were the strongest predictors regarding dental anxiety in 15-year olds. The temperament dimensions activity and impulsivity were also significantly predictive of dental anxiety. CONCLUSIONS: Although some of the temperament dimensions are correlated with dental anxiety, which may emphasize an important finding with regard to personality, this study showed that previous pain experiences during dental care treatment is a strong predictor for high dental anxiety in 15-year olds. PMID- 22214362 TI - Comparison between 68Ga-bombesin (68Ga-BZH3) and the cRGD tetramer 68Ga-RGD4 studies in an experimental nude rat model with a neuroendocrine pancreatic tumor cell line. AB - OBJECTIVES: Receptor scintigraphy gains more interest for diagnosis and treatment of tumors, in particular for neuroendocrine tumors (NET). We used a pan-Bombesin analog, the peptide DOTA-PEG2-[D-tyr6, beta-Ala11, Thi13, Nle14] BN(6-14) amide (BZH3). BZH3 binds to at least three receptor subtypes: the BB1 (Neuromedin B), BB2 (Gastrin-releasing peptide, GRP), and BB3. Imaging of alphanubeta3 integrin expression playing an important role in angiogenesis and metastasis was accomplished with a 68Ga-RGD tetramer. The purpose of this study was to investigate the kinetics and to compare both tracers in an experimental NET cell line. METHODS: This study comprised nine nude rats inoculated with the pancreatic tumor cell line AR42J. Dynamic positron emission tomography (PET) scans using 68Ga-BZH3 and 68Ga-RGD tetramer were performed (68Ga-RGD tetramer: n = 4, 68Ga BZH3: n = 5). Standardized uptake values (SUVs) were calculated, and a two-tissue compartmental learning-machine model (calculation of K1 - k4 vessel density (VB) and receptor binding potential (RBP)) as well as a non-compartmental model based on the fractal dimension was used for quantitative analysis of both tracers. Multivariate analysis was used to evaluate the kinetic data. RESULTS: The PET kinetic parameters showed significant differences when individual parameters were compared between groups. Significant differences were found in FD, VB, K1, and RBP (p = 0.0275, 0.05, 0.05, and 0.0275 respectively). The 56- to 60-min SUV for 68Ga-BZH3, with a range of 0.86 to 1.29 (median, 1.19) was higher than the corresponding value for the 68Ga-RGD tetramer, with a range of 0.78 to 1.31 (median, 0.99). Furthermore, FD, VB, K1, and RBP for 68Ga-BZH3 were generally higher than the corresponding values for the 68Ga-RGD tetramer, whereas k3 was slightly higher for 68Ga-RGD tetramer. CONCLUSIONS: As a parameter that reflects receptor binding, the increase of K1 for 68Ga-BZH3 indicated higher expression of bombesin receptors than that of the alphanubeta3 integrin in neuroendocrine tumors. 68Ga-BZH3 seems better suited for diagnosis of NETs owing to higher global tracer uptake. PMID- 22214363 TI - Discovery of a novel class of potent and orally bioavailable sphingosine 1 phosphate receptor 1 antagonists. AB - A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species. PMID- 22214364 TI - Formation of NDMA and halogenated DBPs by chloramination of tertiary amines: the influence of bromide ion. AB - The formation of NDMA and other DBPs (including THMs, HANs, and HKs) has been investigated by chloramination of several tertiary amines in the absence and presence of bromide ion. NDMA formation from the most reactive tertiary amines (e.g., dimethylaminomethylfurfuryl alcohol or DMP30) was enhanced in the presence of bromide due to the formation of brominated oxidant species such as bromochloramine (NHBrCl) and the hypothetical UDMH-Br as an intermediate. The formation of NDMA by chloramination of less reactive model compounds was inhibited in the presence of bromide. This can be explained by competitive reactions leading to the production of brominated DBPs (i.e., THMs). In the presence of bromide, the formation of brominated THMs during chloramination can be attributed to the presence of small amounts of HOBr produced by the decomposition of chloramines and bromamines. The results are of particular interest to understand NDMA formation mechanisms, especially during chloramination of wastewaters impacted by anthropogenic tertiary amines and containing bromide ion. PMID- 22214365 TI - Surface second-harmonic generation from vertical GaP nanopillars. AB - We report on the experimental observation and analysis of second-harmonic generation (SHG) from vertical GaP nanopillars. Periodic arrays of GaP nanopillars with varying diameters ranging from 100 to 250 nm were fabricated on (100) undoped GaP substrate by nanosphere lithography and dry etching. We observed a strong dependence of the SHG intensity on pillar diameter. Analysis of surface and bulk contributions to SHG from the pillars including the calculations of the electric field profiles and coupling efficiencies is in very good agreement with the experimental data. Complementary measurements of surface optical phonons by Raman spectroscopy are also in agreement with the calculated field intensities at the surface. Finally, polarization of the measured light is used to distinguish between the bulk and surface SHG from GaP nanopillars. PMID- 22214366 TI - Conformations of the glycine tripeptide analog Ac-Gly-Gly-NHMe: a computational study including aqueous solvation effects. AB - A computational study of the conformational preferences of the glycine tripeptide analog, Ac-Gly-Gly-NHMe, has been carried out. The molecule is considered in isolation as well as with a continuum model of aqueous solvation. In the absence of solvent, several low-energy conformers are found that exhibit turnlike structures including type I and type II beta turns. Upon consideration of aqueous solvation, two conformers, corresponding to the type I and II turn structures are found to be significantly lower in energy than all others. Results from ab initio molecular orbital theory calculations at MP2/aug-cc-pVTZ//MP2/6-311+G(d,p) are compared with those from density functional theory with B3LYP, omegaB97X-D, B97 D, and M06-2X as well as several empirical force fields. PMID- 22214367 TI - Towards an automated detection of oestrus in dairy cattle. AB - Heat detection is a key factor in the profitability of dairy herds. However, this detection demands a significant part of the breeder's working time and is made difficult by the short duration and the discrete behavioural changes associated with oestrus in modern dairy cows. Progress has been made in monitoring cow with electronics, biosensors and computer. As a result, automated heat detection systems have been developed. Currently available tools are automated detectors of standing heat, activity-metres and automated in-line systems measuring milk progesterone. Camera-software systems and monitoring of body temperature are being developed and may also be used as heat detection tools. The heat detection rate of most systems is above 80% with a specificity of detection generally higher than 90%. The accuracy, however, may vary considerably depending on the tool and model developed. The initial investment of several thousands of euros required for these automated systems becomes a source of profit in large herds, provided the recorded data are properly managed. PMID- 22214370 TI - Evaluation of sexual function in Brazilian women with recurrent vulvovaginal candidiasis and localized provoked vulvodynia. AB - INTRODUCTION: Recurrent vulvovaginitis is an important trigger for inflammatory processes that in many cases may result in vulvovaginal pain. Vulvodynia, a vulvar disorder, can also cause a lot of pain in the female genitals. The sexual function in women with vulvodynia or recurrent vulvovaginitis will possibly be negatively affected and therefore should be evaluated. AIM: To assess sexual function in women with recurrent vulvovaginal candidiasis (RVVC) and localized provoked vulvodynia (LPV) in comparison with women without lower genital tract dysfunction. METHODS: A 1-year cross-sectional study evaluated sexual function in 58 women (11 with RVVC, 18 with LPV, and 29 controls) seen at a university outpatient clinic. Sexual function was assessed by taking into account the results obtained from the application of the Female Sexual Function Index (FSFI) questionnaire. Kruskal-Wallis, Mann-Whitney, chi-square, and Fisher's tests were used for statistical analysis. MAIN OUTCOME MEASURE: FSFI, a validated questionnaire in Portuguese. RESULTS: There were no significant differences in the three groups with respect to age, marital status, schooling, race, body mass index, contraceptive method, and parity. The FSFI questionnaire total score found was 25.51 (+/-5.12), 21.17 (+/-5.15), and 29.56 (+/-3.87) for the RVVC, LPV, and control groups, respectively. The scores were significantly statistically lower in the study groups compared with the control group (P<0.05). Women with RVVC and LPV also had lower total scores compared with 26.55 values, considered a cutoff score for sexual dysfunction in literature. The LPV group showed a significant difference and scored worse in the domains of arousal, lubrication, orgasm, satisfaction, and pain but not in the domain of sexual desire. The same occurred with the RVVC group but only for the domains of orgasm and satisfaction. CONCLUSION: Women with RVVC and LPV had significantly more symptoms of sexual dysfunction than women without lower genital tract diseases. PMID- 22214369 TI - Transient expression of mouse pro-alpha3(V) collagen gene (Col5a3) in wound healing. AB - The alpha3(V) chain is poorly characterized among type V collagen chains. Pro alpha3(V) collagen is expressed in newly synthesized bone as well as in the superficial fascia of developing muscle. Present study examined the expression in a mouse model of wound healing. Real-time reverse transcriptase polymerase chain reaction and in situ hybridization revealed transient expression of pro-alpha3(V) chain at a lower level than other fibrillar collagen genes after injury. Immunohistochemistry showed a similar expression pattern in the injured skin. In addition, electron microscopy showed that pro-alpha3(V) chain was localized in the amorphous nonfibrillar region, but not in fine or dense fibrils. The pro alpha3(V) chain co-localized with heparan sulfate, which appeared in the skin after injury and might bind via an acidic segment of the pro-alpha3(V) chain. The matrix containing the pro-alpha3(V) chain may therefore be needed for the initiation of wound healing. PMID- 22214368 TI - Analgesia or addiction?: implications for morphine use after spinal cord injury. AB - Opioid analgesics are among the most effective agents for treatment of moderate to severe pain. However, the use of morphine after a spinal cord injury (SCI) can potentiate the development of paradoxical pain symptoms, and continuous administration can lead to dependence, tolerance, and addiction. Although some studies suggest that the addictive potential of morphine decreases when it is used to treat neuropathic pain, this has not been studied in a SCI model. Accordingly, the present studies investigated the addictive potential of morphine in a rodent model of SCI using conditioned place preference (CPP) and intravenous self-administration paradigms. A contusion injury significantly increased the expression of a CPP relative to sham and intact controls in the acute phase of injury. However, contused animals self-administered significantly less morphine than sham and intact controls, but this was dose-dependent; at a high concentration, injured rats exhibited an increase in drug-reinforced responses over time. Exposure to a high concentration of morphine impeded weight gain and locomotor recovery. We suggest that the increased preference observed in injured rats reflects a motivational effect linked in part to the drug's anti-nociceptive effect. Further, although injured rats exhibited a suppression of opiate self administration, when given access to a high concentration, addictive-like behavior emerged and was associated with poor recovery. PMID- 22214372 TI - Role of heparin on serum VEGF levels and local VEGF contents in reducing the severity of experimental severe acute pancreatitis in rats. AB - OBJECTIVE: The aims of this study were to examine the effects of prophylactic heparin treatment during taurocholate-induced pancreatitis in rats and its impact on serum VEGF levels and local VEGF contents within the pancreas. METHODS: Severe acute pancreatitis (SAP) was induced by injecting 4% sodium taurocholate into the pancreatic duct. Heparin at a dose of 150 IU/kg s.c. was administered 30 min before the operation. The rats were sacrificed 1 h, 3 h, 6 h and 12 h (n = 5 per time point) after the onset of pancreatitis. The severity of pancreatitis, serum VEGF levels and local VEGF contents were evaluated with and without heparin pretreatment. RESULTS: The serum VEGF levels increased at an early phase of pancreatitis, and the highest level was found at 12 h after inducing pancreatitis. The gray value of the local VEGF showed a remarkable increase from the onset of the pancreatitis. However, the gray value of VEGF did not show an increase over time but maintained a high level during the entire process. Prophylactic heparin treatment significantly improved the morphologic changes, myeloperoxidase (MPO), TNF-alpha and malondialdehyde (MDA) activities. Meanwhile, it decreased the serum VEGF levels and the contents of VEGF within the pancreatic tissue. CONCLUSIONS: The present study suggests that prophylactic heparin ameliorates the severity of taurocholate-induced pancreatitis via its anti inflammatory properties. These protective effects may be partly due to decreasing serum VEGF levels and VEGF contents within the pancreas. PMID- 22214374 TI - Integrated SDS removal and peptide separation by strong-cation exchange liquid chromatography for SDS-assisted shotgun proteome analysis. AB - We report an improved shotgun method for analyzing proteomic samples containing sodium dodecyl sulfate (SDS). This method is based on the use of strong-cation exchange (SCX) liquid chromatography (LC) for SDS removal that can be integrated with peptide separation as the first dimension of the two-dimensional LC tandem mass spectrometry workflow. To optimize the performance of SDS removal, various experimental conditions, including the concentrations of chemical reagents and salts in the sample, the SDS concentration, and the SCX mobile phase composition, were investigated. It was found that a peptide recovery rate of about 90% could be achieved while removing SDS efficiently. One key finding was that, by increasing the SDS concentration to a certain level (0.5%) in the digested peptide sample, the sample recovery rate could be increased. The peptide recovery rate of BSA digests was found to be 90.6 +/- 1.0% (n = 3), and SDS in the SCX fractions collected was not detectable by pyrolysis GC-MS, i.e., below the detection limit of 0.00006% for the undesalted SCX fractions. The peptide recovery rates were found to be 90.9% +/- 2.7 (n = 3) and 89.5% +/- 0.5% (n = 3) for the digests of the membrane-protein-enriched fractions of E. coli cell lysates and the MCF-7 breast cancer cell line, respectively. Compared to the methods that use acid-labile surfactants, such as RapiGest and PPS, for the MCF-7 membrane fraction sample, the SDS method identified, on average (n = 3), more peptides (~5%) and proteins (~16%) than the RapiGest method, while the RapiGest method identified more peptides (~21%) and proteins (~7%) from the E. coli membrane fraction than the SDS method. In both cases, the two methods identified more peptides and proteins than the PPS method. Since SCX is widely used as the first dimension of 2D-LC MS/MS, integration of SDS removal with peptide separation in SCX does not add any extra steps to the sample handling process. We demonstrated the application of this method for 2D-LC MS/MS profiling of the MCF 7 membrane protein fraction and identified 6889 unique peptides, corresponding to 2258 unique proteins or protein groups from two replicate experiments with a false peptide discovery rate of ~0.8%, compared to 5172 unique peptides and 1847 unique proteins identified by the RapiGest method. PMID- 22214375 TI - Alveolar adenoma of the lung: unusual diagnosis of a lesion positive on PET scan. A case report. AB - The authors report a clinical case of alveolar adenoma presenting as a solitary pulmonary nodule which was positive to PET and deeply located in the lung. Few cases of alveolar adenomas have been reported in literature; these lesions are considered pulmonary neoplasms with benign behaviour, usually presenting as a peripheral or subpleural coin lesion; the PET activities of such neoplasms were unknown.The present clinical case was singular for the deep location of the nodule and its tight adhesion to left inferior pulmonary vein requiring a lobectomy. In addition, alveolar adenoma PET behaviour has been reported as light positivity. PMID- 22214376 TI - Detection beyond the Debye screening length in a high-frequency nanoelectronic biosensor. AB - Nanosensors based on the unique electronic properties of nanotubes and nanowires offer high sensitivity and have the potential to revolutionize the field of Point of-Care (POC) medical diagnosis. The direct current (dc) detection of a wide array of organic and inorganic molecules has been demonstrated on these devices. However, sensing mechanism based on measuring changes in dc conductance fails at high background salt concentrations, where the sensitivity of the devices suffers from the ionic screening due to mobile ions present in the solution. Here, we successfully demonstrate that the fundamental ionic screening effect can be mitigated by operating single-walled carbon nanotube field effect transistor as a high-frequency biosensor. The nonlinear mixing between the alternating current excitation field and the molecular dipole field can generate mixing current sensitive to the surface-bound biomolecules. Electrical detection of monolayer streptavidin binding to biotin in 100 mM buffer solution is achieved at a frequency beyond 1 MHz. Theoretical modeling confirms improved sensitivity at high frequency through mitigation of the ionic screening effect. The results should promise a new biosensing platform for POC detection, where biosensors functioning directly in physiologically relevant condition are desired. PMID- 22214377 TI - Failure of annexin-based apoptosis imaging in the assessment of antiangiogenic therapy effects. AB - BACKGROUND: Molecular apoptosis imaging is frequently discussed to be useful for monitoring cancer therapy. We demonstrate that the sole assessment of therapy effects by apoptosis imaging can be misleading, depending on the therapy effect on the tumor vasculature. METHODS: Apoptosis was investigated by determining the uptake of Annexin Vivo by optical imaging (study part I) and of 99 mTc-6 hydrazinonicotinic [HYNIC]-radiolabeled Annexin V by gamma counting (study part II) in subcutaneous epidermoid carcinoma xenografts (A431) in nude mice after antiangiogenic treatment (SU11248). Optical imaging was performed by optical tomography (3D) and 2D reflectance imaging (control, n = 7; therapy, n = 6). Accumulation of the radioactive tracer was determined ex vivo (control, n = 5; therapy, n = 6). Tumor vascularization was investigated with an optical blood pool marker (study part I) and contrast-enhanced ultrasound (both studies). Data were validated by immunohistology. RESULTS: A significantly higher apoptosis rate was detected in treated tumors by immunohistological terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining (area fraction: control, 0.023 +/- 0.015%; therapy, 0.387 +/- 0.105%; P < 0.001). However, both 2D reflectance imaging using Annexin Vivo (control, 13 +/- 15 FI/cm2; therapy, 11 +/ 7 FI/cm2) and gamma counting using 99 mTc-HYNIC-Annexin V (tumor-to-muscle ratio control, 5.66 +/- 1.46; therapy, 6.09 +/- 1.40) failed in showing higher accumulation in treated tumors. Optical tomography even indicated higher probe accumulation in controls (control, 81.3 +/- 73.7 pmol/cm3; therapy, 27.5 +/- 34.7 pmol/cm3). Vascularization was strongly reduced after therapy, demonstrated by contrast-enhanced ultrasound, optical imaging, and immunohistology. CONCLUSIONS: The failure of annexin-based apoptosis assessment in vivo can be explained by the significant breakdown of the vasculature after therapy, resulting in reduced probe/tracer delivery. This favors annexin-based apoptosis imaging only in therapies that do not severely interfere with the vasculature. PMID- 22214379 TI - Immobilization of anode-attached microbes in a microbial fuel cell. AB - Current-generating (exoelectrogenic) bacteria in bioelectrochemical systems (BESs) may not be culturable using standard in vitro agar-plating techniques, making isolation of new microbes a challenge. More in vivo like conditions are needed where bacteria can be grown and directly isolated on an electrode. While colonies can be developed from single cells on an electrode, the cells must be immobilized after being placed on the surface. Here we present a proof-of-concept immobilization approach that allows exoelectrogenic activity of cells on an electrode based on applying a layer of latex to hold bacteria on surfaces. The effectiveness of this procedure to immobilize particles was first demonstrated using fluorescent microspheres as bacterial analogs. The latex coating was then shown to not substantially affect the exoelectrogenic activity of well-developed anode biofilms in two different systems. A single layer of airbrushed coating did not reduce the voltage produced by a biofilm in a microbial fuel cell (MFC), and more easily applied dip-and-blot coating reduced voltage by only 11% in a microbial electrolysis cell (MEC). This latex immobilization procedure will enable future testing of single cells for exoelectrogenic activity on electrodes in BESs. PMID- 22214378 TI - Human chorionic gonadotropin and its relation to grade, stage and patient survival in ovarian cancer. AB - BACKGROUND: An influence of gonadotropins (hCG) on the development of ovarian cancer has been discussed. Therefore, we quantified serum hCG levels in patients with benign and malignant ovarian tumors and the hCG expression in ovarian cancer tissue in order to analyze its relation to grade, stage, gonadotropin receptor (LH-R, FSH-R) expression and survival in ovarian cancer patients. METHODS: Patients diagnosed and treated for ovarian tumors from 1990 to 2002 were included. Patient characteristics, histology including histological subtype, tumor stage, grading and follow-up data were available. Serum hCG concentration measurement was performed with ELISA technology, hCG tissue expression determined by immunohistochemistry. RESULTS: HCG-positive sera were found in 26.7% of patients with benign and 67% of patients with malignant ovarian tumors. In addition, significantly higher hCG serum concentrations were observed in patients with malignant compared to benign ovarian tumors (p = 0.000). Ovarian cancer tissue was positive for hCG expression in 68%. We identified significant differences in hCG tissue expression related to tumor grade (p = 0.022) but no differences with regard to the histological subtype. In addition, mucinous ovarian carcinomas showed a significantly increased hCG expression at FIGO stage III compared to stage I (p = 0.018). We also found a positive correlation of hCG expression to LH-R expression, but not to FSH-R expression. There was no significant correlation between tissue hCG expression and overall ovarian cancer patient survival, but subgroup analysis revealed an increased 5-year survival in LH-R positive/FSH-R negative and hCG positive tumors (hCG positive 75.0% vs. hCG negative 50.5%). CONCLUSIONS: Serum human gonadotropin levels differ in patients with benign and malignant ovarian tumors. HCG is often expressed in ovarian cancer tissue with a certain variable relation to grade and stage. HCG expression correlates with LH-R expression in ovarian cancer tissue, which has previously been shown to be of prognostic value. Both, the hormone and its receptor, may therefore serve as targets for new cancer therapies. PMID- 22214380 TI - Assessing the impact of ionizing radiation on aquatic invertebrates: a critical review. AB - There is growing scientific, regulatory and public concern over anthropogenic input of radionuclides to the aquatic environment, especially given the issues surrounding existing nuclear waste, future energy demand and past or potential nuclear accidents. A change in the approach to how we protect the environment from ionizing radiation has also underlined the importance of assessing its impact on nonhuman biota. This review presents a thorough and critical examination of the available information on the effects of ionizing radiation on aquatic invertebrates, which constitute approximately 90% of extant life on the planet and play vital roles in ecosystem functioning. The aim of the review was to assess the progress made so far, addressing any concerns and identifying the knowledge gaps in the field. The critical analysis of the available information included determining yearly publications in the field, qualities of radiation used, group(s) of animals studied, and levels of biological organization at which effects were examined. The overwhelming conclusion from analysis of the available information is that more data are needed in almost every area. However, in light of the current priorities in human and environmental health, and considering regulatory developments, the following are areas of particular interest for future research on the effects of ionizing radiation on nonhuman biota in general and aquatic invertebrates in particular: (1) studies that use end points across multiple levels of biological organization, including an ecosystem level approach where appropriate, (2) multiple species studies that produce comparable data across phylogenetic groups, and (3) determination of the modifying (i.e. antagonistic, additive or synergistic) effects of biotic and abiotic factors on the impact of ionizing radiation. It is essential that all of these issues are examined in the context of well-defined radiation exposure and total doses received and consider the life stages and life span of the species studied. The review also provides future directions for studies in this stimulating area of research to protect human and environmental health. PMID- 22214381 TI - Radiation sensitivity of esophageal adenocarcinoma: the contribution of the RNA binding protein RNPC1 and p21-mediated cell cycle arrest to radioresistance. AB - Radiation combined with chemotherapy (neo-CRT) is increasingly the standard of care for the treatment of esophageal cancer, either as neoadjuvant therapy in multimodal protocols or as primary therapy. Unfortunately, ~60% of patients demonstrate little or no response to neo-CRT. Accordingly, understanding the molecular mechanisms of resistance to therapy may underpin significant advances through the identification of nonresponders either before or early in treatment. We previously identified the RNPC1 gene, which is important in stabilizing p21, as being upregulated in the tumors of esophageal cancer patients who had a poor response to neo-CRT. We hypothesize that RNPC1 contributes to resistance to radiation therapy through a p21-mediated cell cycle accumulation/arrest mechanism. Analysis revealed that p53 and RNPC1 expression were highest in the JH EsoAd1 cell line and lowest in OE19 cells. This was associated with accumulation of cells in G0/G1. p21 expression, which was highest in OE19 cells and lowest in OE33 cells, was associated with relative intrinsic sensitivity to radiation. OE33 cells were transfected with a plasmid (pCMV6-AC-GFP) encoding a C-terminal GFP tagged RNPC1, and overexpression was confirmed by qPCR and fluorescence microscopy. Overexpression of RNPC1-GFP resulted in significantly increased levels of the p21 transcript and protein through a direct physical interaction between the RNPC1 protein and the p21 transcript. Furthermore, RNPC1 overexpression led to significant G0/G1 cell cycle accumulation and significantly enhanced cellular resistance to radiation. We conclude that RNPC1 contributes to tumor resistance to radiotherapy, which likely occurs through a p21-mediated G0/G1 accumulation mechanism. Therefore, RNPC1 may represent a potential therapeutic target for enhancing tumor sensitivity to radiation. PMID- 22214382 TI - It can't hurt to ask; a patient-centered quality of service assessment of health canada's medical cannabis policy and program. AB - BACKGROUND: In 2001 Health Canada responded to a series of Ontario court decisions by creating the Marihuana Medical Access Division (MMAD) and the Marihuana Medical Access Regulations (MMAR). Although Health Canada has conducted a small number of stakeholder consultations, the federal government has never polled federally authorized cannabis patients. This study is an attempt to learn more about patient needs, challenges and experiences with the MMAD. METHODS: Launched in the spring of 2007, Quality of Service Assessment of Health Canada's Medical Cannabis Policy and Program pairs a 50 question online survey addressing the personal experiences of patients in the federal cannabis program with 25 semi guided interviews. Data gathering for this study took place from April 2007 to Jan. 2008, eventually garnering survey responses from 100 federally-authorized users, which at the time represented about 5% of the patients enrolled in Health Canada's program. This paper presents the results of the survey portion of the study. RESULTS: 8% of respondents report getting their cannabis from Health Canada, while 66% grow it for themselves. >50% report that they frequent compassion clubs or dispensaries, which remain illegal and unregulated in Canada. 81% of patients would chose certified organic methods of cultivation; >90% state that not all strains are equally effective at relieving symptoms, and 97% would prefer to obtain cannabis from a source where multiple strains are available. Of the 48 patients polled that had tried the Health Canada cannabis supply, >75% rank it as either "1" or "2" on a scale of 1-10 (with "1" being "very poor", and 10 being "excellent"). DISCUSSION: 72% of respondents report they are either "somewhat" or "totally unsatisfied" with Canada's medical cannabis program. These survey results and relevant court decisions suggest that the MMAR are not meeting the needs of most of the nation's medical cannabis patient community. It is hoped this research will help inform policy changes that will better address the needs of Canada's critically and chronically ill medical cannabis patient population, including the integration of community-based dispensaries into this novel healthcare delivery model. PMID- 22214383 TI - Structure and catalytic mechanism of nicotinate (vitamin B3) degradative enzyme maleamate amidohydrolase from Bordetella bronchiseptica RB50. AB - The penultimate reaction in the oxidative degradation of nicotinate (vitamin B(3)) to fumarate in several species of aerobic bacteria is the hydrolytic deamination of maleamate to maleate, catalyzed by maleamate amidohydrolase (NicF). Although it has been considered a model system for bacterial degradation of N-heterocyclic compounds, only recently have gene clusters that encode the enzymes of this catabolic pathway been identified to allow detailed investigations concerning the structural basis of their mechanisms. Here, the Bb1774 gene from Bordetella bronchiseptica RB50, putatively annotated as nicF, has been cloned, and the recombinant enzyme, overexpressed and purified from Escherichia coli, is shown to catalyze efficiently the hydrolysis of maleamate to maleate and ammonium ion. Steady-state kinetic analysis of the reaction by isothermal titration calorimetry (ITC) established k(cat) and K(M) values (pH 7.5 and 25 degrees C) of 11.7 +/- 0.2 s(-1) and 128 +/- 6 MUM, respectively. The observed K(D) of the NicF.maleate (E.P) complex, also measured by ITC, is approximated to be 3.8 +/- 0.4 mM. The crystal structure of NicF, determined at 2.4 A using molecular replacement, shows that the enzyme belongs to the cysteine hydrolase superfamily. The structure provides insight concerning the roles of potential catalytically important residues, most notably a conserved catalytic triad (Asp29, Lys117, and Cys150) observed in the proximity of a conserved non proline cis-peptide bond within a small cavity that is likely the active site. On the basis of this structural information, the hydrolysis of maleamate is proposed to proceed by a nucleophilic addition-elimination sequence involving the thiolate side chain of Cys150. PMID- 22214384 TI - Comparative analysis of deutocerebral neuropils in Chilopoda (Myriapoda): implications for the evolution of the arthropod olfactory system and support for the Mandibulata concept. AB - BACKGROUND: Originating from a marine ancestor, the myriapods most likely invaded land independently of the hexapods. As these two evolutionary lineages conquered land in parallel but separately, we are interested in comparing the myriapod chemosensory system to that of hexapods to gain insights into possible adaptations for olfaction in air. Our study connects to a previous analysis of the brain and behavior of the chilopod (centipede) Scutigera coleoptrata in which we demonstrated that these animals do respond to volatile substances and analyzed the structure of their central olfactory pathway. RESULTS: Here, we examined the architecture of the deutocerebral brain areas (which process input from the antennae) in seven additional representatives of the Chilopoda, covering all major subtaxa, by histology, confocal laser-scan microscopy, and 3D reconstruction. We found that in all species that we studied the majority of antennal afferents target two separate neuropils, the olfactory lobe (chemosensory, composed of glomerular neuropil compartments) and the corpus lamellosum (mechanosensory). The numbers of olfactory glomeruli in the different chilopod taxa ranged from ca. 35 up to ca. 90 and the shape of the glomeruli ranged from spheroid across ovoid or drop-shape to elongate. CONCLUSION: A split of the afferents from the (first) pair of antennae into separate chemosensory and mechanosensory components is also typical for Crustacea and Hexapoda, but this set of characters is absent in Chelicerata. We suggest that this character set strongly supports the Mandibulata hypothesis (Myriapoda + (Crustacea + Hexapoda)) as opposed to the Myriochelata concept (Myriapoda + Chelicerata). The evolutionary implications of our findings, particularly the plasticity of glomerular shape, are discussed. PMID- 22214385 TI - Fabrication of heterogeneous double-ring-like structure arrays by combination of colloidal lithography and controllable dewetting. AB - We report a novel technique for fabricating the heterogeneous double-ring-like structural array by colloidal lithography and two-step dewetting process. First, the 2D non-closed-packed (ncp) silica sphere arrays were obtained by lift-up lithography. Then, the ncp sphere array transferred onto the Rhodamine B (RB)@poly(vinyl alcohol) (PVA) film was used for the mask during reactive ion etching (RIE) process. Sequentially, the substrate with RB@PVA ring-like structure arrays under the silica sphere was dip-coated from poly(N vinylcarbazole) (PVK) chloroform solution with certain concentration. Due to the presence of ordered 2D sphere arrays, the two-step dewetting behavior happened on top of the sphere and the silicon wafer between adjacent spheres, respectively. After removing the silica sphere arrays by hydrofluoric acid, the RB@PVA/PVK heterogeneous double-ring-like structure array was exhibited on the substrate. We characterized this particular structure by SEM, AFM, and fluorescence spectrum, which prove that both the inner RB@PVA ring and outer PVK ring are independent without any reaction. Accordingly, this method could be extended to other materials owing to its universality. These unique structural arrays have potential application in optoelectronic devices, surface photocatalysis, and surface enhanced Raman scattering (SERS). PMID- 22214386 TI - Transbilayer phospholipids molecular imaging. AB - Nuclear medicine has become a key part of molecular imaging. In the present review article, we focus on the transbilayer phospholipids as exquisite targets for radiolabelled probes in molecular imaging. Asymmetry of phospholipid distribution is a characteristic of mammalian cell membranes. Phosphatidylcholine and sphyngomyelin cholinophospholipids are primarily located within the external leaflet of the cell membrane. Phosphatidylserine and phosphatidylethanolamine aminophospholipids, and also phosphatidylinositol are primarily located within the internal leaflet of the cell membrane. New radiolabelled tracers have been designed in preclinical and clinical research for PET-CT and SPECT-CT molecular imaging of transbilayer phospholipids. PMID- 22214388 TI - Pentraxin-3 levels in gingival crevicular fluid during orthodontic tooth movement in young and adult patients. AB - OBJECTIVES: To measure the levels of pentraxin-3 (PTX-3) in gingival crevicular fluid (GCF) in orthodontic young and adult patients in the first 2 weeks after the orthodontic appliance to determine whether those changes occur during orthodontic treatment and if those values could be the expression of an inflammatory state. MATERIALS AND METHODS: GCF samples were collected with paper strips from 16 orthodontic young patients and 13 orthodontic adult patients from an upper canine requiring distalization as a test tooth. A contralateral canine was used as a control tooth. The absorbed volume was eluted in 100 uL phosphate buffered saline (pH = 7.2). PTX-3 levels in GCF were determined using a commercial enzyme-linked immunosorbent assay kit, and the results were expressed in ng/mL. RESULTS: The results showed an increase of GCF levels of PTX-3 from 1 hour before the orthodontic appliance to a maximum at 24 hours, followed by a decrease in both groups of adult and young patients. CONCLUSIONS: The results suggest PTX-3 involvement in periodontal orthodontic remodeling and the aseptic inflammation induced by the orthodontic forces. PMID- 22214387 TI - The association between active participation in a sports club, physical activity and social network on the development of lung cancer in smokers: a case-control study. AB - BACKGROUND: This study analyses the effect of active participation in a sports club, physical activity and social networks on the development of lung cancer in patients who smoke. Our hypothesis is that study participants who lack social networks and do not actively participate in a sports club are at a greater risk for lung cancer than those who do. METHODS: Data for the study were taken from the Cologne Smoking Study (CoSmoS), a retrospective case-control study examining potential psychosocial risk factors for the development of lung cancer. Our sample consisted of n = 158 participants who had suffered lung cancer (diagnosis in the patient document) and n = 144 control group participants. Both groups had a history of smoking.Data on social networks were collected by asking participants whether they participated in a sports club and about the number of friends and relatives in their social environment. In addition, sociodemographic data (gender, age, education, marital status, residence and religion), physical activity and data on pack years (the cumulative number of cigarettes smoked by an individual, calculated by multiplying the number of cigarettes smoked per day by the number of years the person has smoked divided by 20) were collected to control for potential confounders. Logistic regression was used for the statistical analysis. RESULTS: The results reveal that participants who are physically active are at a lower risk of lung cancer than those who are not (adjusted OR = 0.53*; CI = 0.29-0.97). Older age and lower education seem also to be risk factors for the development of lung cancer. The extent of smoking, furthermore, measured by pack years is statistically significant. Active participation in a sports club, number of friends and relatives had no statistically significant influence on the development of the cancer. CONCLUSIONS: The results of the study suggest that there is a lower risk for physically active participants to develop lung cancer. In the study sample, physical activity seemed to have a greater protective effect than participation in a sports club or social network of friends and relatives. Further studies have to investigate in more detail physical activity and other club participations. PMID- 22214389 TI - Alveolar bone loss around lower incisors during surgical orthodontic treatment in mandibular prognathism. AB - OBJECTIVES: To evaluate the alveolar bone loss around lower incisors incurred during surgical orthodontic treatment in individuals with mandibular prognathism. MATERIALS AND METHODS: The samples consisted of 25 patients (13 men, 12 women; mean ages: 26.3 +/- 2.7 years) treated with jaw surgery and orthodontic treatment. Lateral and frontal cephalograms and cone-beam computed tomography (CBCT) images of the patients were obtained before treatment (T0) and after presurgical orthodontic treatment (T1) and after debonding (T2). After measurement of variables, repeated-measures analysis of variance with Bonferroni's multiple comparison test and Pearson and Spearman correlation analysis were performed. RESULTS: The lower central and lateral incisors showed that the vertical alveolar bone level and the alveolar bone thickness of the labial and lingual plates were reduced after presurgical orthodontic treatment but were not deteriorated during postsurgical orthodontic treatment. CONCLUSION: Excessive forward movement of lower incisors during presurgical orthodontic treatment could cause alveolar bone loss around the lower incisors; thus, special care should be considered in individuals with mandibular prognathism. PMID- 22214390 TI - A comparison of the MARA and the AdvanSync functional appliances in the treatment of Class II malocclusion. AB - OBJECTIVES: To determine the skeletal and dentoalveolar effects produced by the MARA and the AdvanSync functional appliances in the treatment of growing patients with Class II malocclusion. MATERIALS AND METHODS: A retrospective study was conducted using lateral cephalograms of patients consecutively treated with MARA (n = 40) and AdvanSync (n = 30) during their skeletal growth spurt as evaluated by the improved cervical vertebral maturation method. A comparison was made with 24 untreated Class II control subjects obtained from the University of Michigan growth study and matched with the experimental groups for skeletal age, sex, and craniofacial morphology. Cephalograms were taken at three time points: (T1) pretreatment, (T2) postfunctional appliance treatment, and (T3) fixed orthodontic treatment completion. Treatment changes were evaluated between the time points using 35 variables. Data were analyzed using one-way analysis of variance and Scheffe's post hoc test. RESULTS: At the postfunctional appliances' phase (T2-T1), both appliances showed significant increases in total mandibular length, ramus height, and anterior/posterior facial height. The AdvanSync resulted in significant restriction of maxillary growth, 1 degrees more than MARA. This effect continued during the fixed orthodontic treatment stage (T3-T2). The net changes (T3-T1) revealed significant mandibular growth enhancement with MARA (+2.7mm) and significant headgear effect with AdvanSync. Both appliances caused 5 degrees flaring in mandibular incisors as well as significant decreases in overjet and overbite. The treatment time for AdvanSync was 1 year less than MARA. CONCLUSION: The MARA and the AdvanSync resulted in normalization of the Class II malocclusion. The AdvanSync showed more headgear effect but less mandibular length enhancement than MARA did. Both appliances showed similar dentoalveolar changes. PMID- 22214391 TI - The growing burden of Alzheimer's disease. AB - Most dementias in people at least 65 years of age are attributable to Alzheimer's disease (AD). While approximately 5.4 million Americans are now believed to have AD, the AD population is expected to nearly triple over the next 40 years, reaching approximately 14.5 million. Presently, there is no cure for AD, but a 2 year delay in AD onset would reduce the expected prevalence by 1.94 million within 50 years. The most important risk factor for AD is age, followed by presence of the apolipoprotein E-4 allele. Other risk factors for AD include sex (female), history of head trauma, family history of Down syndrome or dementia, and cerebrovascular risk factors. The initial neurodegenerative process that causes AD is unknown. However, it is accepted that the presence of amyloid plaques, neurofibrillary tangles, neuronal loss (and synapses), and cerebral amyloid angiopathy are the central pathogenic events. There is selective vulnerability of the limbic system and heteromodal association areas in AD pathology. The most affected neurotransmitter in AD is acetylcholine, as enzymes that are part of its metabolic pathway are depleted. The clinical presentation of AD is heterogeneous and insidious, and the psychological and financial effects of AD on caregivers and family members are significant. PMID- 22214392 TI - Effective pharmacological management of Alzheimer's disease. AB - Alzheimer's dementia represents organ failure of the brain. It denotes a clinical milestone that is the result of a pathological process, Alzheimer's disease (AD), which over 1 or more decades has wrought insidious destruction, and finally overwhelmed the brain's capacities to compensate. It is incurable, progressive, and follows an individual pace and course. AD is particularly demanding and devastating to family and caregivers, and patients, all of whom suffer psychologically and emotionally. The cholinesterase inhibitors (ChEIs) donepezil, galantamine, and rivastigmine and the N-methyl- D-aspartate receptor antagonist memantine are approved by the US Food and Drug Administration for AD; they are often used in combination once the disease reaches moderate stages. The relatively good safety profile of these medications, along with their efficacy in alleviating symptoms, is supported by several level-I evidence-grade, short-term, randomized, placebo-controlled trials (RCTs). However, these studies are of limited value in assessing the real-world clinical and economic impact of AD therapies. Long-term, observational studies can provide complementary information to results from short-term clinical trials and more accurately assess practical long-term benefits, risks, costs, and effects on clinically meaningful end points. There is now accumulating and convergent evidence from short- and long term RCTs, longer-term open-label extensions of RCTs, and long-term observational studies that ChEIs and memantine reduce decline in cognition and daily function, and delay nursing home placement. Optimal care in AD is multifactorial; it includes early diagnosis and multidisciplinary care with educational and nonpharmacological interventions, while ensuring safety, treating comorbidities, caring for caregivers, and appropriate initiation and maintenance of combination therapy. PMID- 22214393 TI - The costs of Alzheimer's disease and the value of effective therapies. AB - Every 69 seconds, a person in the United States develops Alzheimer's disease (AD). By 2050, this rate is expected to double. Total direct costs of AD and dementia (AD/D) are estimated at $183 billion, and are expected to increase to $1.1 trillion by 2050. In 2010, unpaid care was valued at an estimated $202 billion. Caregivers of patients with AD are usually family members, and provide up to 70 hours of care per week. By delaying institutionalization of an AD patient, a savings of $2029 per month in direct healthcare costs could be realized; therefore, caregiver support is a significant factor in controlling costs. It is important for those with AD/D to have prescription plans that optimize access to AD/D therapies. Among older adults who previously did not have prescription coverage, 80% are now enrolled in Medicare Part D. Three preferred AD/D agents (donepezil, extended release galantamine hydrochloride, and memantine hydrochloride) have been identified by an expert panel. It is important, given the clinical course of AD, especially with progression to moderate-to-severe disease, that physicians continue to have access to preferred medications as demonstrated through evidence-based clinical evaluations. Many Medicare Part D beneficiaries are subject to a gap in prescription coverage known as the "donut hole," including 64% of patients with AD. Because of the increased out-of-pocket expenditures associated with this coverage gap, some patients stop taking their medication completely or reduce medication use. It is critical to avoid lapses in maintenance therapy, as functional and cognitive abilities cannot be regained. Numerous clinical trials have demonstrated the pharmacoeconomic benefits of appropriate and preferred AD therapies; greater therapeutic availability may lead to better adherence and therefore improved outcomes. PMID- 22214394 TI - Measurement of metabolic tumor volume: static versus dynamic FDG scans. AB - BACKGROUND: Metabolic tumor volume assessment using positron-emission tomography [PET] may be of interest for both target volume definition in radiotherapy and monitoring response to therapy. It has been reported, however, that metabolic volumes derived from images of metabolic rate of glucose (generated using Patlak analysis) are smaller than those derived from standardized uptake value [SUV] images. The purpose of this study was to systematically compare metabolic tumor volume assessments derived from SUV and Patlak images using a variety of (semi )automatic tumor delineation methods in order to identify methods that can be used reliably on (whole body) SUV images. METHODS: Dynamic [18F]-fluoro-2-deoxy-D glucose [FDG] PET data from 10 lung and 8 gastrointestinal cancer patients were analyzed retrospectively. Metabolic tumor volumes were derived from both Patlak and SUV images using five different types of tumor delineation methods, based on various thresholds or on a gradient. RESULTS: In general, most tumor delineation methods provided more outliers when metabolic volumes were derived from SUV images rather than Patlak images. Only gradient-based methods showed more outliers for Patlak-based tumor delineation. Median measured metabolic volumes derived from SUV images were larger than those derived from Patlak images (up to 59% difference) when using a fixed percentage threshold method. Tumor volumes agreed reasonably well (< 26% difference) when applying methods that take local signal-to-background ratio [SBR] into account. CONCLUSION: Large differences may exist in metabolic volumes derived from static and dynamic FDG image data. These differences depend strongly on the delineation method used. Delineation methods that correct for local SBR provide the most consistent results between SUV and Patlak images. PMID- 22214396 TI - Bismuth pyrostannate, Bi2Sn2O7, from the first structurally characterized heterobimetallic Bi:Sn alkoxides. AB - The first heterobimetallic Bi:Sn alkoxide complexes [Bi(2)SnO(OCH(CF(3))(2))(5)(O(t)Bu)(3)(THF)] (1) and [BiSnO(OCH(CF(3))(2))(3)(O(t)Bu)(2)](2) (2) are described. The complexes were obtained through mixing and heating equimolar quantities of the component alkoxides, Bi(OCH(CF(3))(2))(3) and Sn(O(t)Bu)(4), under solvent-free conditions (1) and in THF (2). The solid-state structures were determined by single crystal X-ray diffraction showing ligand redistribution from Bi(III) to Sn(IV) in the two molecular species. Compound 2 behaves as a single-source precursor for the thermolytic formation of bismuth pyrostannate, Bi(2)Sn(2)O(7). PMID- 22214395 TI - Structure-activity relationships of cyanoquinolines with corrector-potentiator activity in DeltaF508 cystic fibrosis transmembrane conductance regulator protein. AB - Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, DeltaF508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified cyanoquinolines with both corrector ("Co", normalizing DeltaF508-CFTR targeting) and potentiator ("Po", normalizing DeltaF508-CFTR channel gating) activities. Here, we synthesized and characterized 24 targeted cyanoquinoline analogues to elucidate the conformational requirements for corrector and potentiator activities. Compounds with potentiator-only, corrector only, and dual potentiator-corrector activities were found. Molecular modeling studies (conformational search => force-field lowest energy assessment => geometry optimization) suggest that (1) a flexible tether and (2) a relatively short bridge between the cyanoquinoline and arylamide moieties are important cyanoquinoline-based CoPo features. Further, these CoPo's may adopt two distinct pi-stacking conformations to elicit corrector and potentiator activities. PMID- 22214397 TI - Molecular insight into the ligand-IgG interactions for 4-mercaptoethyl-pyridine based hydrophobic charge-induction chromatography. AB - Hydrophobic charge-induction chromatography (HCIC) with 4-mercaptoethyl-pyridine (MEP) as the ligand is a novel technology for antibody purification. In the present work, the molecular simulation methods were used to investigate the interactions between MEP ligand and Fc fragment of IgG (Fc-A). Six ligands with different structures of spacer arm were studied with molecular docking and dynamics simulation at neutral and acidic pH. The binding modes and the interaction energies were analyzed. The results indicated that all ligands tested could bind into the selected pocket on the C(H2) domain of Fc-A at neutral pH. The pyridine ring on the top of MEP ligands acts as a major role to provide the hydrophobic association and hydrogen bond for the ligand-IgG binding; meanwhile, the sulfone group on the spacer arm might form the additional hydrogen bond and enhance the binding of ligand onto the surface of IgG. The replacements of thioether sulfur atom on the spacer arm with either nitrogen or oxygen atom seem to have little influence on the binding. The influences of pH on the ligand-IgG interactions were also studied with the molecular dynamics simulation. It was found that MEP ligands would departed from the surface of Fc-A at low pH due to the electrostatic repulsion. The ligands with a sulfone group on the spacer arm would weaken the electrostatic repulsion and need more acidic conditions for the departing of ligand. The molecular simulation results were in agreement with some experimental observations, which would be useful to elucidate the molecular mechanism of HCIC and design a novel ligand to improve the efficiency of antibody separation. PMID- 22214398 TI - Two-dimensional electronic spectroscopy reveals the dynamics of phonon-mediated excitation pathways in semiconducting single-walled carbon nanotubes. AB - Electronic two-dimensional Fourier transform (2D-FT) spectroscopy is applied to semiconducting single-walled carbon nanotubes and provides a spectral and time domain map of exciton-phonon assisted excitations. Using 12 fs long pulses, we resolve side-bands above the E(22) transition that correspond with the RBM, G, G', 2G and other multiphonon modes. The appearance of 2D-FT spectral cross-peaks explicitly resolves discrete phonon assisted population transfer that scatters excitations to the E(22) (Gamma-pt) state, often through a second-order exciton phonon coupling process. All 2D-FT peaks exhibit a strong peak amplitude modulation at the G-band period (21 fs) which we show originates from an impulsive stimulated Raman process that populates a ground-state G-band vibrational coherence over a 1.3 ps phonon lifetime. PMID- 22214399 TI - Change in kinesiophobia and its relation to activity limitation after multidisciplinary rehabilitation in patients with chronic back pain. AB - PURPOSE: To explore the change in kinesiophobia in relation to activity limitation after a multidisciplinary rehabilitation programme in patients with chronic back pain. METHOD: A prospective cohort study was made including 265 patients. Data were collected at baseline, after rehabilitation, and at 6-months follow-up. Outcome measures were the Tampa Scale for kinesiophobia (TSK) and the disability rating index (DRI). The smallest detectable change (SDC) in TSK was set to 8 scores. Relationships between kinesiophobia and activity limitation/physical ability were explored with regard to subgroups with high, medium and low baseline TSK scores, and for those patients who did or did not reach the SDC in TSK. RESULTS: Improvements in TSK showed high effect sizes in the groups with high and medium baseline TSK scores. Improvements in DRI showed medium effect sizes in all three TSK subgroups. One third of the patients reached the SDC in TSK, and this group also improved significantly more in DRI. The correlation between change in TSK and change in DRI was low. Half of the patients with high TSK score at baseline remained having high DRI at follow-up. CONCLUSIONS: Improvement in physical ability was not related to the initial degree of kinesiophobia but to the SDC in TSK. To prevent patients with high kinesiophobia from preserving high activity limitations, it might be useful to include targeted treatment of kinesiophobia. PMID- 22214400 TI - Polymorphisms in sequence of permanent tooth emergence: a cross-sectional study on Jordanian children and adolescents. AB - OBJECTIVE: This study aimed at providing the norms of polymorphic gender- variation in the sequence of permanent tooth emergence in Jordanian children and adolescents. MATERIALS AND METHODS: A total of 2650 Jordanian children and adolescents (1232 males and 1418 females) aged 4-16 years were examined for permanent tooth emergence. By counting the cases of present-absent and absent present across all possible intra-arch tooth pairs, the frequencies of sequence polymorphisms were calculated and expressed as percentages in and arch-specific matrices. RESULTS: Sequence polymorphisms were more common in tooth pairs in phase II than in phase I of permanent tooth emergence and only rarely did teeth in phase I reverse sequence with teeth in phase II. In addition, maxillary and mandibular polymorphisms were most common in the sequences of canine-second premolar and first premolar-canine, respectively. Furthermore, central incisor first molar and second molar-second premolar sequences were much more common in the mandible than in the maxilla. It was noticed that males and females had more similar frequencies of polymorphic sequences in the maxillary than in the mandibular tooth pairs. CONCLUSIONS: This study presented the norms of pairwise sequence polymorphisms in permanent tooth emergence in the Jordanians. Such norms are adequately useful for the evaluation and prediction of tooth emergence sequence in individual children and valuable in the assessment of emergence sequence problems in pediatric dentistry and in planning and following-up orthodontic treatment. PMID- 22214401 TI - Impact of using the Model of Human Occupation: a survey of occupational therapy mental health practitioners' perceptions. AB - AIM: While little is known about how occupational therapists perceive the use of occupation-focused theory in their practice, evidence indicates that it has been called for in the profession. To date, the Model of Human Occupation (MOHO) is the most widely used model internationally. The aim of this study is to document practitioners' perceptions of how using MOHO impacted on their practice. METHODS: A descriptive study using an Internet-based survey study design was conducted with 429 therapists in six National Health Service (NHS) trusts in the UK. RESULTS: Of the 429 therapists, 262 completed the survey, for a response rate of 61.07%. Most were female (85.5%) with a varying range of years of experience. Most worked in community and/or inpatient mental health settings; 92.1% responded that they use MOHO as their primary model. Therapists reported using MOHO moderately to greatly improve their assessment, goal setting, and conduct of relevant interventions as well as professional identity as an OT in their mental health occupational therapy practice. CONCLUSION/IMPLICATIONS: This study examined therapists' perceived impact of using an occupation-focused model in mental health practice. The findings of this study provided promising results. Findings suggest that the utilization of MOHO increases service for clients and professional stature and identity for therapists. PMID- 22214402 TI - Erectile dysfunction and premature ejaculation in men who have sex with men. AB - INTRODUCTION: Quantitative research into sexual function and dysfunction in men who have sex with men (MSM) has been sparse due in large part to a lack of validated, quantitative instruments for the assessment of sexuality in this population. AIM: To assess prevalence and associations of erectile problems and premature ejaculation in MSM. METHODS: MSM were invited to complete an online survey of sexual function. Ethnodemographic, sexuality, and health-related factors were assessed. MAIN OUTCOME MEASURE: Participants completed a version of the International Index of Erectile Function modified for use in MSM (IIEF-MSM) and the Premature Ejaculation Diagnostic Tool (PEDT). Total score on the erectile function (EF) domain of the IIEF-EF (IIEF-MSM-EF) was used to stratify erectile dysfunction (ED) severity (25-30 = no ED, 16-24 mild or mild moderate ED, 11-15 moderate ED, and <=10 severe ED). PEDT scores were used to stratify risk of premature ejaculation (PE, diagnosed as PEDT score >=9). RESULTS: Nearly 80% of the study cohort of 2,640 men resided in North America. The prevalence of ED was higher in older men whereas the prevalence of PE was relatively constant across age groups. Multivariate logistic regression revealed that increasing age, HIV seropositivity, prior use of erectogenic therapy, lower urinary tract symptoms (LUTS), and lack of a stable sexual partner were associated with greater odds of ED. A separate multivariate analysis revealed that younger age, LUTS, and lower number of lifetime sexual partners were associated with greater odds of PE. CONCLUSIONS: Risk factors for sexual problems in MSM are similar to what has been observed in quantitative studies of non-MSM males. Urinary symptoms are associated with poorer sexual function in MSM. PMID- 22214403 TI - Impact of stigma, culture and law on healthcare providers after occupational exposure to HIV and hepatitis C. AB - Worldwide, approximately three million needlestick or sharps injuries occur annually during healthcare procedures, with an estimated 18-35 healthcare professionals (HCPs) acquiring HIV each year as a result. This qualitative study examined the lived experience of occupational exposure to HIV or hepatitis C reported by four HCPs working in a tertiary care hospital in United Arab Emirates (UAE). Findings were based on interviews conducted as part of a larger two-year study investigating an intervention to improve the reporting and management of blood and body fluid exposures (BBFE) in the hospital. The data showed that due to cultural differences, individuals exposed to the same disease within the same legal system could have different concerns. Five themes arose from the data: (1) experiencing the unexpected, (2) inevitability and finality, (3) impact of stigma, (4) responsibility and risk and (5) legal and financial implications. The participants' most important concerns and causes of stress arising from occupational BBFE were related to the social implications (i.e., stigma; legal and financial costs) rather than the biological consequences of the disease. Social implications like these may negatively impact on reporting of occupational BBFE in UAE, but may need to be addressed at a societal rather than organisational level. PMID- 22214404 TI - Calcium [13C]carbonate breath test for quantitative measurement of total gastric acid in rats. AB - OBJECTIVE: A traditional measurement of gastric acid, involving nasogastric intubation of stomach and acid suction, has been suggested as a gold standard. However, this causes the patient discomfort and cost increase, and is 'time consuming'. MATERIAL AND METHODS: A calcium [(13)C]carbonate (Ca(13)CO(3)) breath test was carried out in rats without or with concomitant drugs omeprazole (OMP) and pentagastrin (PG) known as an inhibitor and an inducer of acid, respectively. This test was aimed at evaluating a correlation between the breath response and the total amount of gastric acid. To search for an absorption pathway of (13)CO(2) gas produced by the reaction of Ca(13)CO(3) with hydrochloric acid in the stomach of rats, we compared the breath responses after intra-gastric administration of (13)CO(2) gas and sodium [(13)C]bicarbonate (NaH(13)CO(3)). RESULTS: A linear relationship of the breath parameter (breath-C(max)) with the dose of Ca(13)CO(3) was obtained in the range of 4-200 umol/kg. However, theses parameters were saturated at >200 umol/kg. The direct correlation between the breath-C(max) and the total amount of gastric acid in rats with or without OMPs or PG (r = 0.994) demonstrated that the change in breath response is an accurate or sensitive indicator of the total amount of gastric acid. (13)CO(2) gas generated in the rat stomach was likely to diffuse across the stomach wall as (13)CO(2) gas directly into the blood plasma. CONCLUSIONS: The present study showed that Ca(13)CO(3) breath test is a good tool to accurately predict the total amount of gastric acid. PMID- 22214406 TI - Catching and correcting near misses: the collective vigilance and individual accountability trade-off. AB - Despite the focus on patient safety and quality health care for the last two decades, there is still limited understanding of how interprofessional interactions at an organizational or work unit level influence how clinicians perceive and respond to safety events and errors. Within the rubric of safety events, there has been a growing interest in near misses as precursors to adverse events in health care. Given the interactive nature of the variety of professionals working together in the delivery of health care, understanding how the different clinicians experience and respond to near misses in practice is important. A constructivist grounded theory approach was employed for this study which included semi-structured interviews with 24 participants in a large teaching hospital in Canada. Findings from this study provide a deeper understanding into how different clinicians experience and respond to near misses in clinical practice. This understanding indicates that collective vigilance can potentially create risk by eroding individual professional accountability through reliance on other team members to catch and correct their errors. Further research is needed to explore in more depth the trade-offs between collective vigilance and individual accountability by relying on others to catch and correct the potentially harmful errors and avert negative outcomes. PMID- 22214407 TI - Metabolite proving fungal cleavage of the aromatic core part of a fluoroquinolone antibiotic. AB - Liquid cultures of the basidiomycetous fungus Gloeophyllum striatum were employed to study the biodegradation of pradofloxacin, a new veterinary fluoroquinolone antibiotic carrying a CN group at position C-8. After 16 days of incubation, metabolites were purified by micro-preparative high-performance liquid chromatography. Four metabolites could be identified by co-chromatography with chemically synthesized standards. The chemical structures of three compounds were resolved by 1H-nuclear magnetic resonance spectroscopy plus infrared spectroscopy in one case. All metabolites were confirmed by high resolution mass spectrometry-derived molecular formulae. They comprised compounds in which the carboxyl group or the fluorine atom had been exchanged for a hydroxyl group. Furthermore, replacement of the CN group and the intact amine moiety by a hydroxyl group as well as degradation of the amine substituent were observed. The chemical structure of a catechol-type fluoroquinolone metabolite (F-5) could be fully defined for the first time. The latter initiated a hypothetical degradation sequence providing a unique metabolite, F-13, which consisted of the cyclopropyl substituted pyridone ring still carrying C-7 and C-8 of pradofloxacin, now linked by a double bond and substituted by a hydroxyl and the CN group, respectively. Most likely, all reactions were hydroxyl radical-driven. Metabolite F-13 proves fungal cleavage of the aromatic fluoroquinolone core for the first time. Hence, two decades after the emergence of the notion of the non-biodegradability of fluoroquinolones, fungal degradation of all key structural elements has been proven. PMID- 22214405 TI - NADPH oxidase-derived H(2)O(2) contributes to angiotensin II-induced aldosterone synthesis in human and rat adrenal cortical cells. AB - BACKGROUND: The Renin-Angiotensin-Aldosterone-System plays a pivotal role in hypertension. Angiotensin II (Ang II) is a major regulator of aldosterone synthesis and secretion, and it is known to facilitate reactive oxygen species (ROS) generation in many cell types. AIMS: Here, we assessed the role of ROS signaling in Ang II-induced aldosterone synthesis by focusing on the regulation of aldosterone synthase (CYP11B2), a cytochrome P450 oxidase that catalyzes the final step in aldosterone biosynthetic pathway. RESULTS: Ang II increased CYP11B2 activity, mRNA and protein with a concomitant elevation of 6-Carboxy- 2',7' dichlorodihydrofluorescein diacetate fluorescence, malondialdehyde and protein carbonyl levels (indices of ROS), NADPH oxidase (Nox) activity, and H(2)O(2) levels in human and rat adrenal cortical cells. The expression of nuclear receptor related 1 protein, a transcription factor known to regulate CYP11B2 expression, was also augmented by Ang II. These Ang II-evoked effects were either abolished or attenuated by pretreatment of cells with either Ang II type I receptor (AT(1)R) antagonist, or antioxidants or Nox inhibitor or siRNA silencing of Nox1, 2 and 4, or inhibitors of phospholipase C and protein kinase C. Exogenous H(2)O(2) mimicked the facilitatory effects of Ang II on CYP11B2 activity, mRNA, and protein expression, and these changes were significantly reduced by PEG-catalase. INNOVATION: ROS, particularly H(2)O(2), is identified as a key regulator of aldosterone production. CONCLUSION: Our results suggest that Ang II facilitates CYP11B2 activity and the ensuing aldosterone production via activation of AT(1)R-Nox-H(2)O(2) signaling pathway. PMID- 22214409 TI - State and certifying boards/associations: CE and competency requirements. PMID- 22214410 TI - 23rd annual survey of state boards of nursing and selected national professional certifying boards/associations. PMID- 22214408 TI - Proteomic profiling of H-Ras-G12V induced hypertrophic cardiomyopathy in transgenic mice using comparative LC-MS analysis of thin fresh-frozen tissue sections. AB - Determination of disease-relevant proteomic profiles from limited tissue specimens, such as pathological biopsies and tissues from small model organisms, remains an analytical challenge and a much needed clinical goal. In this study, a transgenic mouse disease model of cardiac-specific H-Ras-G12V induced hypertrophic cardiomyopathy provided a system to explore the potential of using mass spectrometry (MS)-based proteomics to obtain a disease-relevant molecular profile from amount-limited specimens that are routinely used in pathological diagnosis. Our method employs a two-stage methanol-assisted solubilization to digest lysates prepared from 8-MUm-thick fresh-frozen histological tissue sections of diseased/experimental and normal/control hearts. Coupling this approach with a nanoflow reversed-phase liquid chromatography (LC) and a hybrid linear ion trap/Fourier transform-ion cyclotron resonance MS resulted in the identification of 704 and 752 proteins in hypertrophic and wild-type (control) myocardium, respectively. The disease driving H-Ras protein along with vimentin were unambiguously identified by LC-MS in hypertrophic myocardium and cross validated by immunohistochemistry and western blotting. The pathway analysis involving proteins identified by MS showed strong association of proteomic data with cardiovascular disease. More importantly, the MS identification and subsequent cross-validation of Wnt3a and beta-catenin, in conjunction with IHC identification of phosphorylated GSK-3beta and nuclear localization of beta catenin, provided evidence of Wnt/beta-catenin canonical pathway activation secondary to Ras activation in the course of pathogenic myocardial hypertrophic transformation. Our method yields results indicating that the described proteomic approach permits molecular discovery and assessment of differentially expressed proteins regulating H-Ras induced hypertrophic cardiomyopathy. Selected proteins and pathways can be further investigated using immunohistochemical techniques applied to serial tissue sections of similar or different origin. PMID- 22214411 TI - Assigning continuing education credit to enduring materials. AB - Accreditation and approval criteria require that provider units calculate credit for enduring materials in a logical and defensible manner. Many nurses use enduring materials to stay up-to-date in their areas of practice. Most professional nursing journals include at least one article that is available for continuing education credit. Face-to-face activities do not fit into the budgets or schedules of many nurses. PMID- 22214412 TI - Continuing nursing education: a partnership between learner and teacher. AB - Learners and educators both need to be invested in making continuing nursing education a meaningful and rewarding experience. PMID- 22214413 TI - When funds for professional development are scarce. AB - This column describes an approach to sustaining interprofessional education for perioperative staff when budgetary cuts in professional education significantly limit professional development. PMID- 22214414 TI - Using algorithmic practice maps to teach emergency preparedness skills to nurses. AB - In 2004, The George Washington University received funding from the U.S. Department of Homeland Security to develop a web-based emergency preparedness course for nurses. The purpose of the course was to provide training that would be accessible regardless of work setting or location. In designing the course, the development team used algorithmic decision making as a conceptual framework to transcend the linear, didactic focus of traditional online preparedness training to provide learners with a learning experience crafted around the decision-making process. This article describes the design of the algorithmic practice maps underlying this course and provides a replicable structure for those interested in developing similar offerings for nurses. PMID- 22214417 TI - Short-term clinicopathological outcome of neoadjuvant chemohormonal therapy comprising complete androgen blockade, followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy in Japanese patients with high-risk localized prostate cancer. AB - BACKGROUND: To assess the outcome of neoadjuvant chemohormonal therapy comprising complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy in Japanese patients with a high risk of localized prostate cancer (PCa). METHODS: Complete androgen blockade followed by 6 cycles of docetaxel (30 mg/m2) with estramustine phosphate (560 mg) were given to 18 PCa patients before radical prostatectomy. Subsequently, the clinical and pathological outcomes were analyzed. RESULTS: No patients had severe adverse events during chemohormonal therapy, and hence they were treated with radical prostatectomy. Two patients (11.1%) achieved pathological complete response. Surgical margins were negative in all patients. At a median follow-up of 18 months, 14 patients (77.8%) were disease-free without PSA recurrence. All 4 patients with PSA recurrence had pathologic T3b or T4 disease and 3 of these 4 patients had pathologic N1 disease. CONCLUSION: We found that neoadjuvant chemohormonal therapy with complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy was safe, feasible, and associated with favorable pathological outcomes in patients with a high risk of localized PCa. PMID- 22214418 TI - Decreased pre-surgical CD34+/CD144+ cell number in patients undergoing coronary artery bypass grafting compared to coronary artery disease-free valvular patients. AB - BACKGROUND: Cardiovascular disease has been linked to endothelial progenitor cell (EPC) depletion and functional impairment in atherosclerosis and aortic stenosis. EPCs may play a pivotal role in vascular grafting. However, the EPC depletion in coronary artery bypass grafting (CABG) patients has not been compared to coronary artery disease-free valvular replacement patients with aortic stenosis. METHODS: We aimed to assess the basal number of CD34+/KDR+ and CD34+/CD144+ cells in CABG patients, compared to aortic stenosis valvular replacement patients. 100 patients (51 CABG and 49 valvular surgery ones) were included in the present study. All CABG or valvular patients had angiographic demonstration of the presence or the absence of coronary artery disease, respectively. Numbers of CD34+/KDR+ and CD34+/CD144+ were assessed by flow cytometry of pre-surgical blood samples. RESULTS: We found a lower number of CD34+/CD144+ cells in CABG patients compared to valvular patients (0.21 +/- 0.03% vs. 0.47 +/- 0.08%), and this difference remained statistically significant after the P was adjusted for multiple comparisons (P = 0.01428). Both groups had more EPCs than healthy controls. CONCLUSIONS: Pre-surgical CD34+/CD144+ numbers are decreased in CABG patients, compared to valvular patients with absence of coronary disease. PMID- 22214419 TI - PET kinetics of radiolabeled antidepressant, [N-methyl-11C]mirtazapine, in the human brain. AB - BACKGROUND: We compared six kinetic models with and without the requirement of arterial cannulation for estimating the binding potential of [N-methyl 11C]mirtazapine in the living human brain. METHODS: Distribution volumes of [N methyl-11C]mirtazapine in brain regions were estimated using single- and two tissue compartment models as well as a graphical plasma input model. The two tissue compartment model provided a direct estimate of the binding potentials of [N-methyl-11C]mirtazapine in brain regions, while binding potentials of the single-tissue compartment model and the graphical plasma input model were estimated indirectly from ratios of distribution volumes in brain regions. We obtained also direct estimates of binding potentials using a graphical reference tissue model and two nonlinear reference tissue models. RESULTS: The two-tissue compartment model required several fits with different initial guesses for avoiding negative values of parameters. Despite the extra fits, estimates of distribution volumes and binding potentials of [N-methyl-11C]mirtazapine obtained by the two-tissue compartment model were far more variable than those produced by the other methods. The graphical plasma input method and the graphical reference tissue method provided estimates of the binding potential that correlated closely, but differed in magnitude. The single-tissue compartment model provided relatively low estimates of binding potentials with curves that failed to fit the data as well as the three other methods that used the entire series of positron emission tomography data. The reference tissue method and the simplified reference tissue method provided similar, consistent estimates of binding potentials. However, certain assumptions of the simplified reference tissue method may not be fulfilled by the radioligand. CONCLUSION: The reference tissue method is appropriate for estimating the binding potential of [N-methyl 11C]mirtazapine in regions of the human brain so that the binding potential of [N methyl-11C]mirtazapine can be estimated without arterial cannulation. PMID- 22214420 TI - Playing with peptides: how to build a supramolecular peptide nanostructure by exploiting helix...helix macrodipole interactions. AB - A novel method to build bicomponent peptide self-assembled monolayers (SAMs) has been developed, by exploiting helix...helix macrodipole interactions. In this work, a peptide-based self-assembled monolayer composed of two helical peptides was immobilized on a gold surface. Specifically, a pyrene-containing octapeptide, devoid of any sulfur atom (A8Pyr), and a hexapeptide, functionalized at the N terminus with (S,R) lipoic acid, for binding to gold substrates (SSA4WA) via a Au S linkage, have been employed. Both peptides investigated attain a helical structure, because they are almost exclusively formed by strongly folding inducer C(alpha)-tetrasubstituted alpha-amino acids. We demonstrate that the two peptides generate a stable supramolecular nanostructure (a densely packed bicomponent peptide monolayer), where A8Pyr is incorporated into the SSA4WA palisade by exploiting helix...helix macrodipole interactions. The presence of both peptides on the gold surface was investigated by spectroscopic and electrochemical techniques, while the morphology of the monolayer was analyzed by ultra high vacuum scanning tunnelling microscopy. The composition of the bicomponent SAM on the surface was studied by a combination of electrochemical and spectroscopic techniques. In particular, the amount of Au-S linkages from the sulfur-containing peptides was quantified from reductive desorption of the peptide-based SAM, while the amount of A8Pyr was estimated by fluorescence spectroscopy. The antiparallel orientation of the A8Pyr and SSA4WA peptide chains minimizes the interaction energy between the helix dipoles, suggesting that this kind of electrostatic phenomenon is the driving force that stabilizes the bicomponent SAM. PMID- 22214421 TI - Loop-mediated isothermal amplification (LAMP): early detection of Toxoplasma gondii infection in mice. AB - BACKGROUND: Toxoplasmosis is a widespread zoonotic parasitic disease that occurs in both animals and humans. Traditional molecular assays are often difficult to perform, especially for the early diagnosis of Toxoplasma gondii infections. Here, we established a novel loop-mediated isothermal amplification targeting the 529 bp repeat element (529 bp-LAMP) to detect T. gondii DNA in blood samples of experimental mice infected with tachyzoites of the RH strain. FINDINGS: The assay was performed with Bst DNA polymerase at 65 degrees C for 1 h. The detection limit of the 529 bp-LAMP assay was as low as 0.6 fg of T. gondii DNA. The sensitivity of this assay was 100 and 1000 fold higher than that of the LAMP targeting B1 gene (B1-LAMP) and nested PCR targeting 529 bp repeat element (529 bp-nested PCR), respectively. The specificity of the 529 bp-LAMP assay was determined using the DNA samples of Trypanosoma evansi, Plasmodium falciparum, Paragonimus westermani, Schistosoma japonicum, Fasciola hepatica and Angiostrongylus cantonensis. No cross-reactivity with the DNA of any parasites was found. The assay was able to detect T. gondii DNA in all mouse blood samples at one day post infection (dpi). CONCLUSIONS: We report the following findings: (i) The detection limit of the 529 bp-LAMP assay is 0.6 fg of T. gondii DNA; (ii) The assay does not involve any cross-reactivity with the DNA of other parasites; (iii) This is the first report on the application of the LAMP assay for early diagnosis of toxoplasmosis in blood samples from experimentally infected mice. Due to its simplicity, sensitivity and cost-effectiveness for common use, we suggest that this assay should be used as an early diagnostic tool for health control of toxoplasmosis. PMID- 22214422 TI - Silicon nanowire Esaki diodes. AB - We report on the fabrication and characterization of silicon nanowire tunnel diodes. The silicon nanowires were grown on p-type Si substrates using Au catalyzed vapor-liquid-solid growth and in situ n-type doping. Electrical measurements reveal Esaki diode characteristics with peak current densities of 3.6 kA/cm(2), peak-to-valley current ratios of up to 4.3, and reverse current densities of up to 300 kA/cm(2) at 0.5 V reverse bias. Strain-dependent current voltage (I-V) measurements exhibit a decrease of the peak tunnel current with uniaxial tensile stress and an increase of 48% for 1.3 GPa compressive stress along the <111> growth direction, revealing the strain dependence of the Si band structure and thus the tunnel barrier. The contributions of phonons to the indirect tunneling process were probed by conductance measurements at 4.2 K. These measurements show phonon peaks at energies corresponding to the transverse acoustical and transverse optical phonons. In addition, the low-temperature conductance measurements were extended to higher biases to identify potential impurity states in the band gap. The results demonstrate that the most likely impurity, namely, Au from the catalyst particle, is not detectable, a finding that is also supported by the excellent device properties of the Esaki diodes reported here. PMID- 22214423 TI - Effects of paraoxonase activity and gene polymorphism on coronary vasomotion. AB - BACKGROUND: Paraoxonase 1 [PON1] is recognized as a protective enzyme against LDL oxidation, and PON1 polymorphism has been described as a factor influencing coronary heart disease [CHD] free survival. As coronary vasoreactivity is a surrogate of future cardiovascular events, we aimed at assessing the respective effect of the PON1 genotype and activity on coronary vasoreactivity in a population of type 2 diabetic patients. METHODS: Nineteen patients with type 2 diabetes mellitus underwent 82Rb cardiac PET/CT to quantify myocardial blood flow [MBF] at rest, during cold pressor testing [CPT], and during adenosine-induced hyperaemia to compute myocardial flow reserve [MFR]. They were allocated according to Q192R and L55M polymorphisms into three groups (wild-type and LM/QR heterozygotes, MM homozygotes, and RR homozygotes) and underwent a measurement of plasmatic PON1 activity. Relations between rest-MBF, stress-MBF, MFR, and MBF response to CPT and PON1 genotypes and PON1 activity were assessed using Spearman's correlation and multivariate linear regression analysis. RESULTS: Although PON1 activity was significantly associated with PON1 polymorphism (p < 0.0001), there was no significant relation between the PON1 genotypes and the rest-MBF, stress-MBF, or MBF response to CPT (p >= 0.33). The PON1 activity significantly correlated with the HDL plasma level (rho = 0.63, p = 0.005), age (rho = -0.52, p = 0.027), and MFR (rho = 0.48, p = 0.044). Moreover, on multivariate analysis, PON1 activity was independently associated with MFR (p = 0.037). CONCLUSION: Our study supports an independent association between PON1 activity and MFR. Whether PON1 contributes to promote coronary vasoreactivity through its antioxidant activity remains to be elucidated. This putative mechanism could be the basis of the increased risk of CHD in patients with low PON1 activity. PMID- 22214424 TI - Improving care for patients with type 2 diabetes: applying management guidelines and algorithms, and a review of new evidence for incretin agents and lifestyle intervention. AB - Diabetes affects an estimated 25.8 million US adults, or 8.3% of the population. By 2050, the prevalence of type 2 diabetes mellitus (T2DM) in the United States may be as high as 1 in 3 adults. This paper summarizes key national treatment goals, guidelines, and algorithms for T2DM management in a way that clarifies their similarities and areas of disparity, for use by managed care organizations and other healthcare professionals. In addition, the role of long-standing and newer classes of antihyperglycemic agents, including incretin-related agents, bromocriptine, and colesevelam, will be reviewed, as will emerging research on the role of lifestyle intervention in T2DM and prediabetes. Lastly, comparative and long-term clinical efficacy data on incretin therapy, reported at the American Diabetes Association's 2011 71st Scientific Sessions, will be summarized. Although the treatment landscape for T2DM has increased substantially in complexity, major guidelines have similar goals. While established, relatively inexpensive, and thoroughly investigated antihyperglycemic agents maintain popularity, incretin-based agents offer glycemic efficacy along with other benefits relative to weight loss or neutrality and low rates of hypoglycemia. In addition, the feasibility of matching patients to appropriate lifestyle intervention, for both diabetes and diabetes prevention, is increasing. PMID- 22214425 TI - Decision support tools to optimize economic outcomes for type 2 diabetes. AB - As the costs of type 2 diabetes mellitus (T2DM) care and related clinical trials continue to rise, economically viable methods are being sought to effectively predict the relative utility of various treatment options. The high price of clinical trials has led to the development of alternative methods to collect and consolidate data. Comparative effectiveness research (CER) synthesizes existing evidence to address knowledge gaps and drive patient-focused clinical decisions and outcomes. CER methods compare the health outcomes and costs associated with interventions to determine the option with the maximum patient benefit at optimal cost. In addition to traditional CER approaches such as systematic reviews, meta analyses, and retrospective claims analyses, Markov modeling and Bayesian analysis can be applied to predict patient outcomes in scenarios where clinical trials are not feasible. Additionally, cost-benefit, cost-effectiveness, and cost utility analyses comprise "cost-effectiveness analyses." Cost-benefit analysis looks solely at monetary value, while cost-effectiveness and cost-utility analyses include gains in health and quality of life, providing a ratio of cost to benefit. This paper will discuss a range of approaches to CER including Markov modeling, mixed treatment comparisons, the Archimedes model, and Bayesian statistics, and provide guidance in interpreting data from these studies in a managed care context, with a particular focus on evaluating treatments for T2DM. It will also provide guidance on common indices of comorbidity used in health economics research. Data from these models can be used to reduce treatment costs and improve the overall quality of population-level health. PMID- 22214426 TI - Diabetes benefit management: evolving strategies for payers. AB - Over the next quarter century, the burden of type 2 diabetes mellitus (T2DM) is expected to at least double. Currently, 1 in every 10 healthcare dollars is spent on diabetes management; by 2050, it has been projected that the annual costs of managing T2DM will rise to $336 billion. Without substantial, systemic changes, T2DM management costs will lead to a potentially untenable strain on the healthcare system. However, the appropriate management of diabetes can reduce associated mortality and delay comorbidities. In addition, adequate glycemic control can improve patient outcomes and significantly reduce diabetes-related complications. This article provides an overview of key concepts associated with a value-based insurance design (VBID) approach to T2DM coverage. By promoting the use of services or treatments that provide high benefits relative to cost, and by alternatively discouraging patients from utilizing services whose benefits do not justify their cost, VBID improves the quality of healthcare while simultaneously reining in spending. VBID initiatives tend to focus on chronic disease management and generally target prescription drug use. However, some programs have expanded their scope by incorporating services traditionally offered by wellness and disease management programs. The concept of VBID is growing, and it is increasingly being implemented by a diverse and growing number of public and private entities, including pharmacy benefit managers, health plans, and employers. This article provides key background on VBID strategies, with a focus on T2DM management. It also provides a road map for health plans seeking to implement VBID as part of their programs. PMID- 22214428 TI - Mechanistic insights into polar monomer insertion polymerization from acrylamides. AB - N-Isopropyl acrylamide (NIPAM), N,N-dimethyl acrylamide (DMAA), and 2 acetamidoethyl acrylate (AcAMEA) were copolymerized with ethylene employing [(P^O)PdMe(DMSO)] (1-DMSO; P^O = kappa(2)-P,O-Ar(2)PC(6)H(4)SO(2)O with Ar = 2 MeOC(6)H(4)) as a catalyst precursor. Inhibition studies with nonpolymerizable polar additives show that reversible kappa-O-coordination of free amide retards polymerization significantly. Retardation of polymerization increases in the order ethyl acetate ? methyl ethyl sulfone < acetonitrile < N,N-dimethylacetamide ~ N-methylacetamide ~ propionic acid < dimethylsulfoxide. Pseudo-first-order rate constants for the insertion into 1-DMSO were determined to increase in the order DMAA < AcAMEA < NIPAM < methyl acrylate. Exposure of 1-DMSO to NIPAM resulted in the formation of consecutive insertion products [(P^O)Pd(C(6)H(11)NO(2))(n)Me] (n <= 3), as determined by electrospray ionization mass spectrometry. The solid state structure of the methanol adduct of the 2,1-insertion product of NIPAM into 1-DMSO, [(P^O)Pd{eta(1)-CH(CONHiPr)CH(2)CH(3)}(kappa(1)-O-MeOD)] (2-MeOD), was determined by single crystal X-ray diffraction. Both 2,1- and 1,2-insertions of DMAA into the Pd-Me bond of a [(P^O)PdMe] fragment occur to afford a ca. 4:1 mixture of chelates [(P^O)Pd{kappa(2)-C,O-C(CH(2)CH(3))C(O)NMe(2)}] (3) and [(P^O)Pd{kappa(2)-C,O-CH(2)C(CH(3))C(O)NMe(2)}] (4). The four-membered chelate of 3 is opened by coordination of 2,6-lutidine (3 + 2,6-lutidine ? 3-LUT) with DeltaH degrees = -41.8(10.5) kJ and DeltaS degrees = -115(37) J mol(-1) K(-1). PMID- 22214429 TI - Differences in physical fitness and gross motor coordination in boys aged 6-12 years specializing in one versus sampling more than one sport. AB - The Developmental Model of Sports Participation proposes two pathways towards expertise in sports between 6 and 12 years of age: early specialization and early diversification. This study investigated the effect of sampling various sports and of spending many or few hours in sports on fitness and gross motor coordination. Altogether, 735 boys in three age groups (6-8, 8-10, and 10-12 years) were profiled using a fitness test battery. A computerized physical activity questionnaire was used to obtain data on sports participation. In the eldest group, (M)ANCOVA showed a positive effect of sampling various sports on strength, speed, endurance, and gross motor coordination (P < 0.05). A positive effect of many hours per week spent in sports was apparent in every age group. These data suggest an acute positive effect of many hours in sports and a latent positive effect of early sampling on fitness and gross motor coordination. Multiple comparisons revealed that boys aged 10-12 years, who spent many hours in various sports, performed better on standing broad jump (P < 0.05) and gross motor coordination (P < 0.05) than boys specializing in a single sport. Therefore, our results highlight the importance of spending many hours in sports and sampling various sports in the development of fitness and gross motor coordination. PMID- 22214427 TI - Volumetric and MGMT parameters in glioblastoma patients: survival analysis. AB - BACKGROUND: In this study several tumor-related volumes were assessed by means of a computer-based application and a survival analysis was conducted to evaluate the prognostic significance of pre- and postoperative volumetric data in patients harboring glioblastomas. In addition, MGMT (O6-methylguanine methyltransferase) related parameters were compared with those of volumetry in order to observe possible relevance of this molecule in tumor development. METHODS: We prospectively analyzed 65 patients suffering from glioblastoma (GBM) who underwent radiotherapy with concomitant adjuvant temozolomide. For the purpose of volumetry T1 and T2-weighted magnetic resonance (MR) sequences were used, acquired both pre- and postoperatively (pre-radiochemotherapy). The volumes measured on preoperative MR images were necrosis, enhancing tumor and edema (including the tumor) and on postoperative ones, net-enhancing tumor. Age, sex, performance status (PS) and type of operation were also included in the multivariate analysis. MGMT was assessed for promoter methylation with Multiplex Ligation-dependent Probe Amplification (MLPA), for RNA expression with real time PCR, and for protein expression with immunohistochemistry in a total of 44 cases with available histologic material. RESULTS: In the multivariate analysis a negative impact was shown for pre-radiochemotherapy net-enhancing tumor on the overall survival (OS) (p = 0.023) and for preoperative necrosis on progression free survival (PFS) (p = 0.030). Furthermore, the multivariate analysis confirmed the importance of PS in PFS and OS of patients. MGMT promoter methylation was observed in 13/23 (43.5%) evaluable tumors; complete methylation was observed in 3/13 methylated tumors only. High rate of MGMT protein positivity (> 20% positive neoplastic nuclei) was inversely associated with pre-operative tumor necrosis (p = 0.021). CONCLUSIONS: Our findings implicate that volumetric parameters may have a significant role in the prognosis of GBM patients. Furthermore, volumetry could help not only to improve the prediction of outcome but also the outcome itself by identifying patients at high risk of treatment failure and, thus, seek alternative treatment for these patients. In this small series, MGMT protein was associated with less aggressive tumor characteristics. PMID- 22214430 TI - Microscopic structures of tri-n-butyl phosphate/n-octane mixtures by X-ray and neutron scattering in a wide q range. AB - Tri-n-butyl phosphate (TBP) is an important extractant for separating hexavalent uranium and tetravalent plutonium from used nuclear fuel by solvent extraction. In such solvent extractions using TBP, the organic phase occasionally separates into two organic phases, namely, light and heavy organic phases. The latter one in particular is called the third phase. The purpose of this work is to elucidate the mechanism whereby the third phase forms in biphasic liquid-liquid solvent extraction of heavy metal ions. Toward this end, small- and wide-angle X-ray and neutron scattering (SWAXS and SWANS) experiments were conducted to examine the microscopic structures of TBP/octane mixtures. These investigations of solute associations in TBP-containing organic phases before extraction of heavy metal ions provide insights into system performance. After the extraction of heavy metal ions, for example, the microscopic structures formed in the organic phase are likely to be correlated with the initial microscopic structures, which are revealed here. SWAXS and SWANS, with accurate estimations of incoherent scattering intensities for all solution samples, revealed the following: (i) TBP self-associates in octane, and the average distance between two TBP molecules in the TBP assemblies is evaluated as 0.9-1.0 nm; (ii) the shape of the TBP assembly is ellipsoidal; and (iii) the attractive interaction among TBP assemblies in octane is miniscule, and thus, they tend to be dispersed homogeneously due to the excluded volume effect. PMID- 22214431 TI - Avenues for the development of therapeutics that target trace amine associated receptor 1 (TAAR1). PMID- 22214432 TI - Experimental alpha-particle radioimmunotherapy of breast cancer using 227Th labeled p-benzyl-DOTA-trastuzumab. AB - BACKGROUND: The aim of the present study was to explore the biodistribution, normal tissue toxicity, and therapeutic efficacy of the internalizing low-dose rate alpha-particle-emitting radioimmunoconjugate 227Th-trastuzumab in mice with HER2-expressing breast cancer xenografts. METHODS: Biodistribution of 227Th trastuzumab and 227Th-rituximab in nude mice bearing SKBR-3 xenografts were determined at different time points after injection. Tumor growth was measured after administration of 227Th-trastuzumab, 227Th-rituximab, cold trastuzumab, and saline. The toxicity of 227Th-trastuzumab was evaluated by measurements of body weight, blood cell, and clinical chemistry parameters, as well as histological examination of tissue specimens. RESULTS: The tumor uptake reached peak levels of 34% ID/g (4.6 kBq/g) 3 days after injection of 400 kBq/kg of 227Th-trastuzumab. The absorbed radiation dose to tumor was 2.9 Gy, while it was 2.4 Gy to femur due to uptake of the daughter nuclide 223Ra in bone; the latter already explored in clinical phases I and II trials without serious toxicity. A significant dose dependent antitumor effect was observed for dosages of 200, 400, and 600 kBq/kg of 227Th-trastuzumab but no effect of 400 and 600 kBq/kg 227Th-rituximab (non tumor binding). No serious delayed bone marrow or normal organ toxicity was observed, but there was a statistical significant reduction in blood cell parameters for the highest-dose group of 227Th-trastuzumab treatment. CONCLUSION: Internalizing 227Th-trastuzumab therapy was well tolerated and resulted in a dose dependent inhibition of breast cancer xenograft growth. These results warrant further preclinical studies aiming at a clinical trial in breast cancer patients with metastases to bone. PMID- 22214434 TI - Sexual risk history and condom use among people living with HIV/AIDS in Ogun State, Nigeria. AB - INTRODUCTION: The majority of human immunodeficiency virus (HIV) infections are acquired through unprotected sex between partners; only male or female condoms can reduce the chances of infection with HIV during a sexual act. AIM: This study was therefore designed to describe sexual risk history and identify factors associated with condom use among people living with HIV/acquired immunodeficiency syndrome (AIDS) (PLWHAs) in Ogun State, Nigeria. MAIN OUTCOME MEASURES: Main outcome measures are sexual and HIV risk history, safe sex practices, and condom use. METHODS: This study is an analytical cross-sectional study. A total sample of all people living with HIV/AIDS attending secondary health facilities in Ogun State were recruited into the study. RESULT: A total of 637 were interviewed; median age at first sexual intercourse among the study participants was 19 years (mean age = 18.95, standard deviation [SD] = 4.148) with a median of two lifetime sexual partners (mean = 3.22, SD = 3.57). Majority (71.4%) of the respondents had not been diagnosed with a sexually transmitted infection other than HIV. Precisely 47.7% of men and 52.3% of women had two or more sexual partners in the last 6 months. Men were statistically significantly more likely to have multiple sexual partners when compared with women (P = 0.00). Significantly more women (69.8%) than men (30%) had sexual partners whose HIV status they did not know (P = 0.006). Predictors of condom use were individuals who had multiple sexual partners (odds ratio [OR] = 1.41, confidence interval [CI] = 1.05-1.83) and married (OR = 3.13, CI = 1.15-8.51) with higher level of education (OR = 2.78, CI = 1.39-5.79), with knowledge of partner's serostatus (OR = 2.53, CI = 1.50-4.28), and awareness of reinfection (OR = 1.90, CI = 1.22-2.95). CONCLUSION: The study indicates that the establishment of effective safe sex practices and condom use behavior among PLWHAs in low-income countries such as the study population requires adequate health education on the transmission of HIV/AIDS and the understanding of the dynamics of family life and gender issues. PMID- 22214435 TI - Reasons for replacement of restorations: dentists' perceptions. AB - OBJECTIVE: This study aimed at evaluating dentists' perceived reasons for replacement of restorations and ascertaining the differences arising from dentists' gender, time since graduation and working sector (salaried vs private). MATERIALS AND METHODS: A postal questionnaire was sent to a total of 592 working age general dental practitioners in Finland, 57% (n = 339) responded. The dentists were asked to rank in order of priority the six most common reasons for replacement of composite in the incisors and posterior teeth and amalgam in the posterior tooth from a list of 12 reasons. Ranking order 1 was worth six points and order 6 one point; the non-ranked reasons were equal to zero. Differences in the means of the summed scores of caries-related (RC), fracture- and failure related (RF) and miscellaneous (RO) groups were evaluated by ANOVA. The level of significance was set at p = 0.05. RESULTS: For each of three restorations, the RF group comprised 48-56% of the sum-scores. Of the single reasons, secondary caries predominated (20-24%). For composite restorations in the incisors, the mean sum score of the RO group was greater for private-sector dentists (p = 0.04). For composite restorations in the posterior teeth, the mean sum-score of RF group was higher for male than female dentists (p = 0.009). For amalgam, mean score for RF was 10.2, followed by RC (8.5) and RO (1.1). CONCLUSION: Secondary caries and various fractures and failures predominate as dentists' perceived reasons for replacement of restorations. Private dentists included miscellaneous reasons as one of their six reasons more often than did the salaried dentists. The complex process of treatment planning and decision-making is influenced by many as of yet unknown factors, calling for emphasis on investigating of perceptions. PMID- 22214436 TI - Experimental-computational study of shear interactions within double-walled carbon nanotube bundles. AB - The mechanical behavior of carbon nanotube (CNT)-based fibers and nanocomposites depends intimately on the shear interactions between adjacent tubes. We have applied an experimental-computational approach to investigate the shear interactions between adjacent CNTs within individual double-walled nanotube (DWNT) bundles. The force required to pull out an inner bundle of DWNTs from an outer shell of DWNTs was measured using in situ scanning electron microscopy methods. The normalized force per CNT-CNT interaction (1.7 +/- 1.0 nN) was found to be considerably higher than molecular mechanics (MM)-based predictions for bare CNTs (0.3 nN). This MM result is similar to the force that results from exposure of newly formed CNT surfaces, indicating that the observed pullout force arises from factors beyond what arise from potential energy effects associated with bare CNTs. Through further theoretical considerations we show that the experimentally measured pullout force may include small contributions from carbonyl functional groups terminating the free ends of the CNTs, corrugation of the CNT-CNT interactions, and polygonization of the nanotubes due to their mutual interactions. In addition, surface functional groups, such as hydroxyl groups, that may exist between the nanotubes are found to play an unimportant role. All of these potential energy effects account for less than half of the ~1.7 nN force. However, partially pulled-out inner bundles are found not to pull back into the outer shell after the outer shell is broken, suggesting that dissipation is responsible for more than half of the pullout force. The sum of force contributions from potential energy and dissipation effects are found to agree with the experimental pullout force within the experimental error. PMID- 22214438 TI - A reactive lesion (pyogenic granuloma) associated with dental implant: a case report. PMID- 22214437 TI - Testing differences: the implementation of Western HIV testing norms in sub Saharan Africa. AB - This paper examines the implementation of Western HIV testing norms - counselling, consent and confidentiality ('3Cs') - in Malawi, a high prevalence, rural African setting. It considers the differential perspectives of three categories of stakeholders: proponents, implementers and intended beneficiaries. The proponents are members of the 'Counseling and Testing Establishment'. For them, the 3Cs are human rights imports that are worth defending formally, but not always worth prioritising in practice. The implementers are HIV Counsellors. For them, knowledge of the 3Cs as Western biomedical jargon distinguishes them from villagers, but places them in situations where the ethics of testing conflict with their moral concerns for those whom they were trained to help, thus they adapt them in practice. And the intended beneficiaries, the rural Malawians whose rights are meant to be protected by the 3Cs, perceive the norms as protecting themselves as individuals, but as harming rather than benefitting their communities. The case study of Malawi illustrates a tension between Western, individual rights-oriented public health norms and local concerns for the health and wellbeing of the imagined communities that they are meant to benefit. PMID- 22214439 TI - Cationic lipids percentage and processing temperature are critical in designing siRNA lipid nanoparticles. AB - To design a clinically viable small interfering RNA (siRNA) formulation, it is essential to understand the in vivo siRNA delivery mechanism during the product development. However, majority of reported siRNA delivery studies are based on testing only isolated factors, with ambiguous interpretation of often in vitro transfection results. Correlating physicochemical properties with in vivo transfection efficiency thus represents an important step towards rational design of siRNA delivery systems. In this study, design of experiments studies were applied to probe formulation attributes and process parameters, with in vivo activities evaluated as a primary response along with physicochemical properties. Statistical analysis was performed to identify the significance of each input factor towards the in vivo transfection efficiency using a Positive Readout System. The interactions between these factors were also analyzed. Our results indicated that among the formulation factors evaluated, the percentage of cationic lipid is of most significant effect. During the process, temperature stands out as the most significant factor impacting the in vivo activities. These results shed light on our design of siRNA lipid nanoparticle formulations in the early development stage. PMID- 22214440 TI - Development and application of a HPLC method for eight sunscreen agents in suncare products. AB - This work describes the development, validation and application of a simple and fast high-performance liquid chromatography-with diode array dectection (HPLC DAD) method for the determination of eight sunscreen agents: benzophenone-3, octocrylene, ethylhexyl methoxycinnamate, ethylhexyl salicylate, homosalate (used in two isomeric forms), butyl methoxydibenzoylmethane, 4-methylbenzylidene camphor and ethylhexyl dimethyl PABA in sunscreen formulations. The separation of the eight sunscreen compounds was achieved using an ACE C18 column (250 * 4.6 mm, 5 MUm), with a column temperature 20 degrees C, and a mobile phase of 88 : 12 (v/v) methanol-water with isocratic elution. Column temperature strongly influences the retention time and resolution of the compounds. The flow rate was 1.0 mL min(-1) and quantitation was performed by external calibration at the maximum wavelength of each compound. The sample preparation was simple and consisted basically of sample dilution with methanol, centrifugation and filtration in syringe filters before quantitation. Total run time was 18 min. The method was validated according to the parameters: linear range, linearity, selectivity, intra-day and inter-day precision and accuracy. Ten samples of sunscreen emulsions commercially available in Brazil (SPF 30) from different manufacturers were analysed using the proposed method. The number of the sunscreen agents varied between one and five in a single sample. The concentrations of all compounds were in the range of 0.9-10% (w/w) and were in accordance with the current Brazilian legislation. PMID- 22214441 TI - Beta glucan: a valuable functional ingredient in foods. AB - beta-Glucan is a valuable functional ingredient and various extraction techniques are available for its extraction. Choice of an appropriate extraction technique is important as it may affect the quality, structure, rheological properties, molecular weight, and other functional properties of the extracted beta-glucan. These properties lead to the use of beta-glucan into various food systems and have important implications in human health. This review focuses on the extraction, synthesis, structure, molecular weight, and rheology of beta-glucan. Furthermore, health implications and utilization of beta-glucan in food products is also discussed. PMID- 22214433 TI - SSR markers in transcripts of genes linked to post-transcriptional and transcriptional regulatory functions during vegetative and reproductive development of Elaeis guineensis. AB - BACKGROUND: The oil palm (Elaeis guineensis Jacq.) is a perennial monocotyledonous tropical crop species that is now the world's number one source of edible vegetable oil, and the richest dietary source of provitamin A. While new elite genotypes from traditional breeding programs provide steady yield increases, the long selection cycle (10-12 years) and the large areas required to cultivate oil palm make genetic improvement slow and labor intensive. Molecular breeding programs have the potential to make significant impacts on the rate of genetic improvement but the limited molecular resources, in particular the lack of molecular markers for agronomic traits of interest, restrict the application of molecular breeding schemes for oil palm. RESULTS: In the current study, 6,103 non-redundant ESTs derived from cDNA libraries of developing vegetative and reproductive tissues were annotated and searched for simple sequence repeats (SSRs). Primer pairs from sequences flanking 289 EST-SSRs were tested to detect polymorphisms in elite breeding parents and their crosses. 230 of these amplified PCR products, 88 of which were polymorphic within the breeding material tested. A detailed analysis and annotation of the EST-SSRs revealed the locations of the polymorphisms within the transcripts, and that the main functional category was related to transcription and post-transcriptional regulation. Indeed, SSR polymorphisms were found in sequences encoding AP2-like, bZIP, zinc finger, MADS box, and NAC-like transcription factors in addition to other transcriptional regulatory proteins and several RNA interacting proteins. CONCLUSIONS: The identification of new EST-SSRs that detect polymorphisms in elite breeding material provides tools for molecular breeding strategies. The identification of SSRs within transcripts, in particular those that encode proteins involved in transcriptional and post-transcriptional regulation, will allow insight into the functional roles of these proteins by studying the phenotypic traits that cosegregate with these markers. Finally, the oil palm EST-SSRs derived from vegetative and reproductive development will be useful for studies on the evolution of the functional diversity within the palm family. PMID- 22214442 TI - Interactions between polyphenols and macromolecules: quantification methods and mechanisms. AB - Non-covalent and covalent associations of polyphenols with food macromolecules are two of the most fundamental factors affecting the quality of polyphenol-rich food products. This review therefore describes the biochemical bases of associations between polyphenols and macromolecules, that is, proteins and polysaccharides. Our intent is to provide a level of understanding that can be used to underpin future research directions. This will help to resolve existing issues that limit organoleptic and nutritional qualities of polyphenol-rich foods and drinks. It will also allow a better understanding of the functional consequences of these interactions on food/biological systems. The methods used to study non-covalent and covalent interactions are described, and the limiting factors of each method are emphasized. The biochemical mechanisms of interaction between polyphenols and macromolecules are also described. In processed food, non covalent polyphenol/macromolecule interactions are largely due to weak associations, and result from a combination of hydrogen bonds and hydrophobic interactions. The biochemical mechanisms for covalent interactions involve oxidation of phenolic compounds, whether enzymatically mediated or not, with the formation of o-quinones or o-semi-quinones, or the cleavage of procyanidin interflavanic bonds in acid medium with the formation of carbocations. The effects of factors such as polyphenol structure, macromolecule structure, relative concentrations of both polyphenol and macromolecule, solvent composition, ionic strength, temperature, and pH are discussed. PMID- 22214443 TI - Date fruits (Phoenix dactylifera Linn): an emerging medicinal food. AB - Date palm is one of the oldest trees cultivated by man. In the folk-lore, date fruits have been ascribed to have many medicinal properties when consumed either alone or in combination with other herbs. Although, fruit of the date palm served as the staple food for millions of people around the world for several centuries, studies on the health benefits are inadequate and hardly recognized as a healthy food by the health professionals and the public. In recent years, an explosion of interest in the numerous health benefits of dates had led to many in vitro and animal studies as well as the identification and quantification of various classes of phytochemicals. On the basis of available documentation in the literature on the nutritional and phytochemical composition, it is apparent that the date fruits are highly nutritious and may have several potential health benefits. Although dates are sugar-packed, many date varieties are low GI diet and refutes the dogma that dates are similar to candies and regular consumption would develop chronic diseases. More investigations in these areas would validate its beneficial effects, mechanisms of actions, and fully appreciate as a potential medicinal food for humans all around the world. Therefore, in this review we summarize the phytochemical composition, nutritional significance, and potential health benefits of date fruit consumption and discuss its great potential as a medicinal food for a number of diseases inflicting human beings. PMID- 22214444 TI - Fruit quality: new insights for biotechnology. AB - At ripening fruits undergo many changes which include the development of color and aroma and improvements in flavor and texture that make them attractive to potential consumers. Fruits provide an important source of health-related substances, plus minerals and vitamins, and the quality of a fruit is influenced by variety, nutritional status, and environmental conditions during plant growth and fruit development. Ripening is considered to be the main process in fruit development, and all studies had been focused on this process which included physicochemical, biochemical, and molecular analysis. With the development of genomic analysis the strategies to study fruit ripening have been changing and now there are new perspectives and opportunities. The objective of this review is to describe the state of the art in the studies related to fruit ripening with emphasis in molecular studies. PMID- 22214446 TI - Synthesis and antinociceptive behaviors of new methyl and hydroxyl derivatives of phencyclidine. AB - Phencyclidine (I) and its derivatives show such pharmacological behaviors as analgesic, anticonsulvant, anti-anxiety and antidepressant, while interacting with central nervous system. In this study, new methyl and hydroxyl derivatives of PCP were synthesized and their antinociceptive behaviors in animals were examined by measuring the number of writhing in a writhing test of visceral pain and the pain scores in Formalin test. Compared to control and PCP groups, findings in experimental groups indicated the new synthesized analogues (compounds II, III and V, 10 mg/kg) of PCP were able to produce more analgesic effects in formalin and writhing tests, especially for compound V. It was concluded that the new synthesized derivatives of PCP could substantially and respectively diminish acute and chronic pains. PMID- 22214447 TI - Ginsenoside Rg1 attenuates lipopolysaccharide-induced inflammatory responses via the phospholipase C-gamma1 signaling pathway in murine BV-2 microglial cells. AB - BACKGROUND AND PURPOSE: Microglial activation plays an important role in neurodegenerative diseases by producing an array of proinflammatory enzymes and cytokines. Ginsenoside Rg1 (Rg1), a well-known Chinese herbal medicine, has been well recognized for its anti-inflammatory effect. This study sought to determine the anti-inflammatory effects of Rg1 and its underlying mechanisms in lipopolysaccharide (LPS)-stimulated murine BV-2 microglial cells. EXPERIMENTAL APPROACH: Murine BV-2 microglial cells were treated with Rg1 (10, 20, and 40 MUM) and/or LPS (1 MUg.ml(-1)). The mRNA and protein levels of proinflammatory proteins and cytokines were analysed by RT-PCR assay and double immunofluorescence labeling, respectively. Phosphorylation levels of mitogen activated protein kinases (MAPKs) cascades, inhibitor kappaB-alpha (IkappaB alpha) and cyclic AMP- responsive element (CRE)-binding protein (CREB) were measured by western blot. U73122 (5 MUM), a specific phospholipase C (PLC) inhibitor, was used to determine if PLC signaling pathway might be involved in Rg1's action on activated BV-2 cells. KEY RESULTS: Pretreatment with Rg1 significantly attenuated the LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta) and nuclear factor-kappaB (NF-kappaB) in BV 2 cells. U73122 blocked the effects of Rg1 on LPS-induced microglial activation. In addition, PLC-gamma1 inhibition partially abolished the inhibitory effect of Rg1 on the phosphorylation of IkappaB-alpha, CREB, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and p38 mitogen activated protein kinase (p38 MAPK). CONCLUSION AND IMPLICATIONS: This investigation demonstrates that Rg1 significantly attenuates overactivation of microglial cells by repressing expression levels of neurotoxic proinflammatory mediators and cytokines via activation of PLC-gamma1 signaling pathway. PMID- 22214448 TI - Zinc metallo-enzymes as target for drug design. PMID- 22214449 TI - Structure based drug design of angiotensin-I converting enzyme inhibitors. AB - Cardiovascular disease (CVD) is responsible for ~27% of deaths worldwide, with 80% of these occuring in developing countries. Hypertension is one of the most important treatable factors in the prevention of CVD. Angiotensin-I converting enzyme (ACE) is a two-domain dipeptidylcarboxypeptidase that is a key regulator of blood pressure as a result of its critical role in the reninangiotensin- aldosterone and kallikrien-kinin systems. Consequently, ACE is an important drug target in the treatment of CVD. ACE is primarily known for its ability to cleave angiotensin-I to the vasoactive octapeptide angiotensin-II, but is also able to cleave a number of other substrates including the vasodilator bradykinin and N acetyl-seryl-aspartyl-lysyl-proline (acetyl-SDKP), a physiological modulator of hematopoiesis. Numerous ACE inhibiors are available clinically, and these are generally effective in treating hypertension. However some adverse effects are associated with ACE inhibition, such as the persistent dry cough and the potentially fatal angioedema. The solution of ACE crystal structures over the last decade has facilitated rational drug design which has contributed to the development of domain-selective ACE inhibitors, the most notable of which include RXP407 (N-domain) and RXPA380 (C-domain), which in principle may herald new therapeutic approaches for ACE inhibition. Additionally, dual inhibitors to ACE and other targets such as neprilysin, endothelin converting enzyme and chymase have been developed. The success of ACE inhibitors has also led to the search for novel inhibitors in food and natural products and the structure guided screening of such libraries may well reveal a number of new ACE inhibitors. PMID- 22214451 TI - Inhibition of bacterial carbonic anhydrases and zinc proteases: from orphan targets to innovative new antibiotic drugs. AB - Zinc-containing enzymes, such as carbonic anhydrases (CAs) and metalloproteases (MPs) play critical functions in bacteria, being involved in various steps of their life cycle, which are important for survival, colonization, acquisition of nutrients for growth and proliferation, facilitation of dissemination, invasion and pathogenicity. The development of resistance to many classes of clinically used antibiotics emphasizes the need of new antibacterial drug targets to be explored. There is a wealth of data regarding bacterial CAs and zinc MPs present in many pathogenic species, such as Neisseria spp., Helycobacter pylori Escherichia coli, Mycobacterium tuberculosis, Brucella spp., Streptococcus pneumoniae, Salmonella enterica, Haemophilus influenzae, Listeria spp, Vibrio spp., Pseudomonas aeruginosa, Legionella pneumophila, Streptomyces spp., Clostridium spp., Enterococcus spp., etc. Some of these enzymes have been cloned, purified and characterized by crystallographic techniques. However, for the moment, few potent and specific inhibitors for bacterial MPs have been reported except for Clostridium histolyticum collagenase, botulinum and tetanus neurotoxin and anthrax lethal factor, which will be reviewed in this article. Bacteria encode alpha-,beta-, and/or gamma-CA families, but up to now only the first two classes have been investigated in some detail in different species. The alpha CAs from Neisseria spp. and H. pylori as well as the beta-class enzymes from E. coli, H. pylori, M. tuberculosis, Brucella spp., S. pneumoniae, S. enterica and H. influenzae have been cloned and characterized. The catalytic/inhibition mechanisms of these CAs are well understood as X-ray crystal structures are available for some of them, but no adducts of these enzymes with inhibitors have been characterized so far. In vitro and in vivo studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates have been reported. Only for Neisseria spp., H. pylori, B. suis and S. pneumoniae CAs it has been possible to evidence inhibition of bacterial growth in vivo. Thus, bacterial CAs and MPs represent at this moment very promising targets for obtaining antibacterials devoid of the resistance problems of the clinically used such agents but further studies are needed to validate these and other less investigated enzymes as novel drug targets. PMID- 22214452 TI - Carbonic anhydrase IX as a target for designing novel anticancer drugs. AB - Carbonic anhydrase IX (CA IX) is a tumor associated protein, since it is highly expressed in a multitude of carcinomas, while it is present in a limited number of normal tissues. It is a multi-domain protein consisting of an N-terminal proteoglycan-like (PG) domain, a catalytic domain, a trans-membrane portion (TM) and an intracytoplasmatic (IC) segment. These domains have peculiar biochemical and physiological features. Among these, only the PG domain is unique among the CA family. This review focuses on the most recent molecular and catalytic features uncovered of this enzyme, the role of its different domains in tumor physiology, and its three dimensional structure which has recently been solved. In addition, we present recent advances in the development of antibodies and small inhibiting molecules able to target CA IX for diagnostic and therapeutic applications. PMID- 22214453 TI - Molecular response to hypericin-induced photodamage. AB - Hypericin (Hyp) is used as a powerful natural photosensitizer in photodynamic therapy (PDT). After selective accumulation in tumor tissue, vessels and matrix, and activated by visible light, it destroys the tumor mainly via generation of reactive oxygen species. After photoactivation, molecular biological mechanisms lead to different cellular endpoints: "biostimulation" (increased proliferation rate), repair of the damage leading to rescue of the cells, autophagy, apoptosis and necrosis. Growth stimulation after low-dose Hyp-PDT seems to be induced via the p38 or JNK survival pathways. Since both pathways are also activated by stress, modification of these pathways may also contribute to rescue mechanisms as well as to damage processing. By increasing PDT doses beyond sublethal damage, stress response pathways are activated such as the ER-stress pathway with disruption of Ca2+ homeostasis and unfolded protein response. This leads either to apoptosis or autophagic cell death, dependent on the availability of Bax/Bak. Apoptosis triggered directly at the mitochondria or by the ER-stress response is executed via the mitochondrial pathway, whereas in some cases, the receptor mediated pathway is preferred. If the damage is too severe, the cellular energy level low and /or the cytoplasma membrane leaky, cells will die necrotically. The different modes of cellular responses depend mainly on the PDT-protocol, photosensitizer localisation, cellular damage protection and the available intracellular energy. PMID- 22214450 TI - Glutamate carboxypeptidase II in diagnosis and treatment of neurologic disorders and prostate cancer. AB - Glutamate carboxypeptidase II (GCPII) is a membrane-bound binuclear zinc metallopeptidase with the highest expression levels found in the nervous and prostatic tissue. Throughout the nervous system, glia-bound GCPII is intimately involved in the neuron-neuron and neuron-glia signaling via the hydrolysis of N acetylaspartylglutamate (NAAG), the most abundant mammalian peptidic neurotransmitter. The inhibition of the GCPII-controlled NAAG catabolism has been shown to attenuate neurotoxicity associated with enhanced glutamate transmission and GCPII-specific inhibitors demonstrate efficacy in multiple preclinical models including traumatic brain injury, stroke, neuropathic and inflammatory pain, amyotrophic lateral sclerosis, and schizophrenia. The second major area of pharmacological interventions targeting GCPII focuses on prostate carcinoma; GCPII expression levels are highly increased in androgen-independent and metastatic disease. Consequently, the enzyme serves as a potential target for imaging and therapy. This review offers a summary of GCPII structure, physiological functions in healthy tissues, and its association with various pathologies. The review also outlines the development of GCPII-specific small molecule compounds and their use in preclinical and clinical settings. PMID- 22214454 TI - Non polymeric nanoparticles for photodynamic therapy applications: recent developments. AB - Photodynamic therapy has emerged as an alternative to chemotherapy and radiotherapy for cancer treatment. Nanoparticles have recently been proposed as effective carriers for photosensitizers. Depending on their chemical composition, these can be used for diagnosis and therapy due to the selective accumulation of the photosensitizer in cancer cells in vitro or in tumors in vivo. Multifunctional nanoplatforms combining several applications within the same nano object emerge as potential important theranostic tools. This review, based on the chemical nature of the nanoparticles will discuss recent advances in the area of non polymeric nanoparticles for photodynamic therapy applications. PMID- 22214455 TI - The chlorophyll catabolite pheophorbide a as a photosensitizer for the photodynamic therapy. AB - Pheophorbide a is a clorophyll catabolite that recently has drawn the attention of several investigators for its potential in photodynamic therapy. In this review we summarize its photophysical properties, phototoxicity, cellular localization, biodistribution and PDT activity as a free or conjugated molecule. PMID- 22214457 TI - Modulation of ascorbic acid-induced DNA cleavage by polyamide: cleavage manner, kinetics and mechanism. AB - Manipulation of DNA presents a great interest in biotechnology and therapeutics. The molecules that damage DNA selectively offer new prospects for controlled manipulation of DNA. The conjugations of DNA-code reading molecules such as polyamides to reagents that induce DNA damages provide an approach to reach this goal. In this work, a new compound which contained polyamide and ascorbic acid conjugated by flexible linker (polyamide-Vc), was successfully synthesized, characterized, and evaluated as DNA cleavage agent, compared with that by using ascorbic acid molecule. The kinetics data showed that polyamide-Vc successfully promoted the cleavage of plasmid DNA, with k(max) of 0.314 h(-1) and K(d) of 0.105 mM. The evaluation of DNA linearization elicited that the activity of cleaving double-strand in the supercoiled pUC18 plasmid DNA by polyamide-Vc was enhanced remarkably, achieving n1/n2 ratio of 13.9 at 1.2 mM for 1 h. The introduction of polyamide to Vc could also partially weaken the inhibition of hydrogen radical to double-strand cleavage process because of its good binding activity to DNA. We anticipate that this work could provide a method for improving the efficiency of double-strand cleavage, especially to oxidative cleavage agents. PMID- 22214456 TI - Porphyrin photosensitised processes in the prevention and treatment of water- and vector-borne diseases. AB - Water- and vector-borne diseases are a global burden which is estimated to cause several million deaths and innumerable cases of sickness every year. These infectious illnesses are emerging or resurging as a result of several factors, such as changes in climate, in public health and demography policy, as well as the spread of resistance to insecticide and drug, and genetic changes in pathogens. Integrated prevention strategies must be developed and implemented in endemic disease areas to reverse the trend of emergent/resurgent water- and vector-borne diseases. With this perspective porphyrins and their analogues, that have been shown to act as very efficient photosensitising agents against a broad number of microbial pathogens (bacteria, fungi, protozoa) and parasitic animals, could represent an important tool for the prevention and control of these pathologies. The application of photosensitised processes can be exploited to address environmental problems of high significance, including the decontamination of waste waters, the disinfection of fish-farming tanks and the control of populations of noxious insects. Such diversified applications take advantage of the availability of a truly large number of porphyrin derivatives with chemical structures which can be tailored to comply with the physical and chemical properties, as well as the biological features of several milieus. In addition, the property typical of porphyrins to absorb essentially all the wavelengths in the sun emission spectrum allows the promotion of processes largely based on natural resources with significant energy saving and low impact on the ecosystems. PMID- 22214458 TI - Novel biotransformation process of podophyllotoxin to 4 beta-sulfur-substituted podophyllum derivates with anti-tumor activity by Penicillium purpurogenum Y.J. Tang. AB - According to the structure-function relationship of podophyllotoxin (PTOX) and its analogue of 4'- demethylepipodophyllotoxin (DMEP), the 4 beta-substitution of sulfur-containing heterocyclic compounds with a carbon-sulfur bond at 4 position of PTOX or DMEP is an essential modification direction for improving the anti tumor activity. So, four novel 4 beta-sulfursubstituted podophyllum derivatives (i.e., 4beta -(1,2,4-triazole-3-yl)sulfanyl-4-deoxy-podophyllotoxin (4-MT-PTOX), 4beta-(1,3,4- thiadiazole-2-yl)sulfanyl-4-deoxy-podophyllotoxin (4-MTD-PTOX), 4beta-(1,2,4-triazole-3-yl)sulfanyl-4-deoxy-4' -demethylepipodophyllotoxin (4-MT DMEP), and 4beta-(1,3,4-thiadiazole-2-yl)sulfanyl-4-deoxy-4' demethylepipodophyllotoxin (4-MTD-DMEP)) were designed and then successfully biosynthesized in this work. In the novel sulfur-substituted biotransformation processes, PTOX and DMEP was linked with sulfur-containing compounds (i.e., 3 mercapto-1,2,4-triazole (MT) and 2-mercapto-1,3,4-thiadiazole (MTD)) at 4 position of cycloparaffin to produce 4-MT-PTOX (1), 4-MTD-PTOX (2), 4-MT-DMEP (3), and 4-MTD-DMEP (4) by Penicillium purpurogenum Y.J. Tang, respectively, which was screened out from Diphylleia sinensis Li (Hubei, China). All the novel compounds exhibited promising in vitro bioactivity, especially 4-MT-PTOX (1). Compared with etoposide (i.e., a 50 % effective concentration [EC(50)] of 25.72, 167.97, and 1.15 M), the EC(50) values of 4-MT-PTOX (1) against tumor cell line BGC-823, A549 and HepG2 (i.e., 0.28, 0.76, and 0.42 M) were significantly improved by 91, 221 and 2.73 times, respectively. Moreover, the EC(50) value of 4 MT-PTOX (1) against the normal human cell line HK-2 (i.e., 182.4 MUM) was 19 times higher than that of etoposide (i.e., 9.17 MUM). Based on the rational design, four novel 4 beta-sulfur-substituted podophyllum derivatives with superior in vitro anti-tumor activity were obtained for the first time. The correctness of structure-function relationship and rational drug design was strictly demonstrated by the in vitro biological activity tests. PMID- 22214459 TI - Diketoacid inhibitors of HIV-1 integrase: from L-708,906 to raltegravir and beyond. AB - HIV-1 integrase is one of the three viral enzymes essential to HIV replication. Consequently the development of therapeutics targeting this enzyme has been a major focus of antiretroviral research over the past two decades. Several classes of integrase inhibitors have been identified; of these the diketoacids (DKAs) show greatest promise: raltegravir (Merck & Co) has been approved by the US Food and Drug Administration (FDA) for HIV-1 therapy, while elvitegravir (Gilead Sciences/ Japan Tobacco) has reached phase III clinical trials. This review considers the development of DKA-based inhibitors from early screening studies through to the release of raltegravir. SAR data collated from numerous studies are compared and analysed, shedding light on the geometric and electronic requirements for effective binding to HIV-1 integrase. This information will in turn aid the rational design of future generations of integrase inhibitors. PMID- 22214460 TI - Hot topic: targeting tumor angiogenesis: an update. PMID- 22214461 TI - Inflammation and antiangiogenesis in cancer. AB - The immune system regulates angiogenesis in cancer by means of pro- and anti angiogenesis activities. In fact, both innate (macrophages, granulocytes, mast cells, dendritic cells, natural killer cells, and platelets) and adaptive (T and B lymphocytes) immune cells synthesize several pro- and anti-angiogenic mediators. Moreover, in pre-clinical models, a synergy has been observed between antiangiogenic molecules and immunotherapy. In this review article, we will focus on some angiogenenic and anti-angiogenic molecules properties of immune cells that may be utilized for a potential parmacological use as anti-angiogenic agents in cancer. PMID- 22214462 TI - Sorafenib (BAY 43-9006) in hepatocellular carcinoma patients: from discovery to clinical development. AB - Angiogenesis and signaling through the RAS/RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinoma (HCC). Sorafenib (Nexavar), a novel bi-aryl urea BAY 43-9006, is an orally administered multikinase inhibitor with activity against RAS/RAF kinases multikinase inhibitor with activity against RAF kinases and several receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. It is involved in angiogenic pathway and cell proliferation. Sorafenib has demonstrated potent anti-tumor activity in in vitro studies, preclinical xenograft models of different tumor types and human clinical trials. This review summarizes the history of sorafenib from its discovery by the medicinal chemistry approach through to clinical development and ongoing trials on the combination between sorafenib and trans-arterial chemoembolization (TACE) in HCC patients. PMID- 22214463 TI - Efficacy and safety of bevacizumab in glioblastomas. AB - Glioblastoma multiforme (GBM) is a common and malignant primary brain tumor arising from glial precursors the survival of which is estimated to be about 14 months after diagnosis despite current standard care with radiotherapy, surgery, and chemotherapies. Therapeutic approaches were greatly improved in the last years; however, GBM still represents the most lethal subtype of glioma. Actually, it has been estimated that only about 3.4% of patients will survive at the most five years when obtaining the best outcome from treatment; however, this depends on tumor resistance, which is generally related to repairing radiation injury, and self- improving cell growth repair and survival. All GBMs recur after initial therapy, limiting patients ? survival at 20-25% within 1 year after diagnosis of recurrent disease. Moreover, for recurrent GBM response rates are less than 10% (ranging from 5% to 9%), and progression free survival at 6-month (PFS-6) rates ranges between 9% and 28% (median 15%). The development of targeted therapy based on tumor vascular blockade led to the approval of bevacizumab for recurrent or progressive glioblastoma, since it was proven that this offers a new opportunity for patients suffering from this malignancy. Bevacizumab is a recombinant antivascular monoclonal antibody binding to circulating Vascular Endothelial Growth Factor (VEGF) preventing this cytokine from reaching its receptors (VEGFR1 and VEGFR2) on endothelium, resulting in an inhibition of cells proliferation and vessels sprouting. The aim of this review is to address bevacizumab mode of action in malignant gliomas and provide a summary on currently available data on efficacy and safety. PMID- 22214464 TI - Bevacizumab in non small cell lung cancer: development, current status and issues. AB - Bevacizumab is a monoclonal antibody directed against Vascular Endothelial Growth Factor (VEGF). Evidence about its efficacy in addition to first-line chemotherapy in non-small-cell-lung-cancer (NSCLC) has been produced by two large randomized phase III clinical trials (ECOG 4599 and AVAiL), conducted in a clinically selected population with non-squamous histology and without major risk factors for bleeding. In the ECOG 4599 trial, the addition of bevacizumab (15 mg/kg) to carboplatin plus paclitaxel produced a statistically significant and clinically relevant improvement in overall survival (OS), that was the primary endpoint of the trial (12.3 months vs 10.3 months, HR 0.79; p=0.003). Furthermore, patients receiving bevacizumab showed a significant improvement in progression-free survival (PFS) and in objective response rates. Treatment with bevacizumab was well tolerated by the majority of patients, but was still associated with increased risk of clinically significant bleeding (4.4% vs 0.7%, p0.001). In the AVAiL trial the addition of bevacizumab (at the dose of 7.5 and 15 mg/kg) to cisplatin plus gemcitabine produced a small improvement in PFS, but no differences in OS. Information from retrospective analysis and two large observational studies (SAIL and ARIES) have confirmed the safety profile of first line bevacizumab with a wide range of chemotherapy partners, but whether its efficacy is comparable when combined with the different regimens is still unknown. The identification of predictive factors of efficacy would be relevant for the optimal use of the drug, but to date we have no conclusive data in this direction. PMID- 22214465 TI - mTOR as a target of everolimus in refractory/relapsed Hodgkin lymphoma. AB - Despite impressive treatment advances, few options for refractory or relapsed Hodgkin Lymphoma (HL) are available and there is a need for new compounds development. A number of promising agents with multiple mechanisms of action are under investigation. Microenvironment and neoangiogenesis are acquiring a rising relevance in the pathophysiology and progression of HL. Everolimus (RAD001) is an oral antineoplastic agent derived from rapamycin, a macrocyclic lactone antibiotic, targeting the mammalian target of rapamycin (mTOR). Although the importance of mTOR signaling in the deregulated cell growth of human neoplastic cells has been recognized, this pathway is also emerging as a key regulator of the tumor response to hypoxia, as well as endothelial and stromal cells function, thereby regulating neoangiogenesis. Furthermore, mTOR plays an important role in anticancer drug resistance. The actions of everolimus within the mTOR pathway in HL result in decreased protein synthesis and cell cycle arrest, as well as in decreased angiogenesis. Everolimus has shown preliminary evidence of efficacy as a single-agent in heavily pretreated relapsed/refractory HL, with an overall fair safety profile. The purpose of this review is to discuss the employment of everolimus as an antiproliferative and antiangiogenic agent in HL and to report the critical role of the mTOR pathway and angiogenesis in this malignancy. PMID- 22214466 TI - The pharmacological pathways of GnRH mediating the inhibition of mammary tumours: implications in humans and domestic animals. AB - The Gonadotropin-Releasing Hormone (GnRH) exists in two isoforms, GnRH-I and GnRH II, in most vertebrates, including humans. Both of these isoforms and their respective receptors have been found in many healthy and pathologic extra nervous system tissues, such as cells found in cancers of the reproductive systems and, in particular, in breast cancer. GnRH analogues are used as therapeutic agents in the case of sex-hormone-dependent tumours. Besides acting as suppressors of steroidogenesis, GnRH analogues seem to interfere with mitogenic signal transduction pathways, thus behaving as negative regulators of tumour growth and progression. GnRH analogues counteract the proliferating effects of both epidermal growth factor (EGF) and insulin like growth factor (IGF-I); additionally, it affects the mitogen-activated protein kinase (MAPK) cascade and modulates the activity of the urokinase-type plasminogen activator (uPA)/plasminogen activator inhibitory (PAI) system, which is involved in the process of metastasis. In addition, GnRH analogues decrease the expression of many growth factors involved in the development of human uterine myomas (as well as endometriotic tissue), such as the vascular endothelial growth factor (VEGF), which is deeply implied in the angiogenesis of many benign and malignant tumours, including breast cancer. Angiogenesis is one of the primary processes leading to the progression and metastasis of breast cancer cells, and a key therapeutic goal in the fight against tumours is the blocking of new vessel sprouts. Given these premises, this review provides an update on the background of anti-neoplastic properties of GnRH analogues.. PMID- 22214467 TI - Immunotherapy for metastatic colorectal cancer: present status and new options. AB - Although no immunotherapeutic treatment is approved for colorectal cancer (CRC) patients, promising results from clinical trials suggest that several immunotherapeutic strategies may prove efficacious and applicable to this group of patients. This review describes the immunogenicity of CRC and presents the most interesting strategies investigated so far: cancer vaccination including antigen-defined vaccination and dendritic cell vaccination, chemo-immunotherapy, and adoptive cell transfer. Future treatment options as well as the possibility of combining existing therapies will be discussed along with the challenges presented by tumor escape mechanisms. PMID- 22214469 TI - Lower striatal dopamine D2/3 receptor availability in obese compared with non obese subjects. AB - BACKGROUND: Obesity is a result of a relative excess in energy intake over energy expenditure. These processes are controlled by genetic, environmental, psychological and biological factors. One of the factors involved in the regulation of food intake and satiety is dopaminergic signalling. A small number of studies have reported that striatal dopamine D2/D3 receptor [D2/3R] availability is lower in morbidly obese subjects. METHODS: To confirm the role of D2/3R in obesity, we measured striatal D2/3R availability, using [123I]IBZM SPECT, in 15 obese women and 15 non-obese controls. RESULTS: Striatal D2/3R availability was 23% (p = 0.028) lower in obese compared with non-obese women. CONCLUSION: This study is an independent replication of the finding that severely obese subjects have lower striatal D2/3R availability. Our findings invigorate the evidence for lower striatal D2/3R availability in obesity and confirm the role of the striatal dopaminergic reward system in obesity. PMID- 22214470 TI - The immune score as a new possible approach for the classification of cancer. AB - The outcome prediction in cancer is usually achieved by evaluating tissue samples obtained during surgical removal of the primary tumor focusing on their histopathological characteristics. Tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N), and evidence for metastases (M). However, this classification provides limited prognostic information in estimating the outcome in cancer and does not predict response to therapy. It is recognized that cancer outcomes can vary significantly among patients within the same stage. Recently, many reports suggest that cancer development is controlled by the host's immune system underlying the importance of including immunological biomarkers for the prediction of prognosis and response to therapy. Data collected from large cohorts of human cancers demonstrated that the immune-classification has a prognostic value that may be superior to the AJCC/UICC TNM-classification. Thus, it is imperative to begin incorporating immune scoring as a prognostic factor and to introduce this parameter as a marker to classify cancers, as part of the routine diagnostic and prognostic assessment of tumors. At the same time, the inherent complexity of quantitative immunohistochemistry, in conjunction with variable assay protocols across laboratories, the different immune cell types analyzed, different region selection criteria, and variable ways to quantify immune infiltration underscore the urgent need to reach assay harmonization. In an effort to promote the immunoscore in routine clinical settings worldwide, the Society for Immunotherapy of Cancer (SITC), the European Academy of Tumor Immunology, the Cancer and Inflammation Program, the National Cancer Institute, National Institutes of Health, USA and "La Fondazione Melanoma" will jointly initiate a task force on Immunoscoring as a New Possible Approach for the Classification of Cancer that will take place in Naples, Italy, February 13th, 2012. The expected outcome will include a concept manuscript that will be distributed to all interested participants for their contribution before publication outlining the goal and strategy to achieve this effort; a preliminary summary to be presented during the "Workshop on Tumor Microenvironment" prior to the SITC annual meeting on October 24th - 25th 2012 in Bethesda, Maryland, USA and finally a "Workshop on Immune Scoring" to be held in Naples in December of 2012 leading to the preparation of a summary document providing recommendations for the harmonization and implementation of the Immune Score as a new component for the classification of cancer. PMID- 22214471 TI - Synthesis of TiO2 nanocoral structures in ever-changing aqueous reaction systems. AB - A far-from-equilibrium strategy is developed to synthesize coral-like nanostructures of TiO(2) on a variety of surfaces. TiO(2) nanocoral structures consist of anatase base film and rutile nanowire layers, and they are continuously formed on substrates immersed in aqueous TiOSO(4)-H(2)O(2). The sequential deposition of TiO(2) starts with hydrolysis and condensation reactions of titanium peroxocomplexes in the aqueous phase, resulting in deposition of amorphous film. The film serves as adhesive interface on which succeeding growth of rutile nanowires to occur. This initial deposition reaction is accompanied by shift in pH of the reaction media, which is favorable condition for the growth of rutile nanocrystals. During the growth of rutile nanocoral layers, the amorphous base films are transformed to anatase phase. These sequential deposition reactions occur at temperatures as low as 80 degrees C, and the mild synthetic condition allows the use of a wide range of substrates such as ITO (indium tin oxide), glass, and even organic polymer films. The thickness of nanocoral layer is controllable by repeating the growth reaction of rutile nanocorals. TiO(2) nanocorals show photocatalytic activity as demonstrated by site-specific reduction of Ag(I) ions, which proceeds preferentially on the rutile nanowire layer. The rutile nanowire layer also shows photocatalytic decomposition of acetaldehyde, which is promoted upon increase of the thickness of the nanowire layer. The use of temporally transforming reaction media allows the formation of biphasic TiO(2) nanocoral structures, and the concept of nonequilibrium synthetic approach would be widely applicable to developing structurally graded inorganic nanointerfaces. PMID- 22214468 TI - Congenital diaphragmatic hernia. AB - Congenital Diaphragmatic Hernia (CDH) is defined by the presence of an orifice in the diaphragm, more often left and posterolateral that permits the herniation of abdominal contents into the thorax. The lungs are hypoplastic and have abnormal vessels that cause respiratory insufficiency and persistent pulmonary hypertension with high mortality. About one third of cases have cardiovascular malformations and lesser proportions have skeletal, neural, genitourinary, gastrointestinal or other defects. CDH can be a component of Pallister-Killian, Fryns, Ghersoni-Baruch, WAGR, Denys-Drash, Brachman-De Lange, Donnai-Barrow or Wolf-Hirschhorn syndromes. Some chromosomal anomalies involve CDH as well. The incidence is < 5 in 10,000 live-births. The etiology is unknown although clinical, genetic and experimental evidence points to disturbances in the retinoid-signaling pathway during organogenesis. Antenatal diagnosis is often made and this allows prenatal management (open correction of the hernia in the past and reversible fetoscopic tracheal obstruction nowadays) that may be indicated in cases with severe lung hypoplasia and grim prognosis. Treatment after birth requires all the refinements of critical care including extracorporeal membrane oxygenation prior to surgical correction. The best hospital series report 80% survival but it remains around 50% in population-based studies. Chronic respiratory tract disease, neurodevelopmental problems, neurosensorial hearing loss and gastroesophageal reflux are common problems in survivors. Much more research on several aspects of this severe condition is warranted. PMID- 22214472 TI - Quantitative PCR-based genome size estimation of the astigmatid mites Sarcoptes scabiei, Psoroptes ovis and Dermatophagoides pteronyssinus. AB - BACKGROUND: The lack of genomic data available for mites limits our understanding of their biology. Evolving high-throughput sequencing technologies promise to deliver rapid advances in this area, however, estimates of genome size are initially required to ensure sufficient coverage. METHODS: Quantitative real-time PCR was used to estimate the genome sizes of the burrowing ectoparasitic mite Sarcoptes scabiei, the non-burrowing ectoparasitic mite Psoroptes ovis, and the free-living house dust mite Dermatophagoides pteronyssinus. Additionally, the chromosome number of S. scabiei was determined by chromosomal spreads of embryonic cells derived from single eggs. RESULTS: S. scabiei cells were shown to contain 17 or 18 small (< 2 MUM) chromosomes, suggesting an XO sex-determination mechanism. The average estimated genome sizes of S. scabiei and P. ovis were 96 (+/- 7) Mb and 86 (+/- 2) Mb respectively, among the smallest arthropod genomes reported to date. The D. pteronyssinus genome was estimated to be larger than its parasitic counterparts, at 151 Mb in female mites and 218 Mb in male mites. CONCLUSIONS: This data provides a starting point for understanding the genetic organisation and evolution of these astigmatid mites, informing future sequencing projects. A comparitive genomic approach including these three closely related mites is likely to reveal key insights on mite biology, parasitic adaptations and immune evasion. PMID- 22214474 TI - Recognizing the link between chronic kidney disease and cardiovascular disease. AB - The prevalence of chronic kidney disease (CKD) is rising in the United States, and cardiovascular disease (CVD) is increasingly recognized to occur at elevated rates in patients with CKD compared with the general population. The impact of CVD in patients with CKD is significant, inversely related to the level of kidney function, and exaggerated when compared with matched patients without CKD. CKD is associated with an increased risk of CVD, CVD events, and death, but the prevalence of traditional CVD risk factors is also increased compared with the general population. Proteinuria, hypertension, dyslipidemia, and diabetes are common in patients with CKD and contribute directly to CVD events. CKD-related factors (eg, disorders of electrolyte and mineral metabolism, anemia, and vascular calcification) also contribute to mortality associated with CKD. PMID- 22214473 TI - Brain perfusion CT compared with15O-H2O-PET in healthy subjects. AB - BACKGROUND: Regional cerebral blood flow [rCBF] measurements are valuable for identifying angiogenically active tumours, and perfusion computed tomography [CT] has been suggested for that purpose. This study aimed to validate rCBF measurements by perfusion CT with positron-emission tomography [PET] and15O labelled water [15O-H2O] in healthy subjects. METHODS: RCBF was measured twice in 12 healthy subjects with15O-H2O PET and once with perfusion CT performed over the basal ganglia. Matching rCBF values in regions of interest were compared. RESULTS: Measured with perfusion CT, rCBF was significantly and systematically overestimated. White matter rCBF values were 17.4 +/- 2.0 (mean +/- SD) mL min-1 100 g-1 for PET and 21.8 +/- 3.4 mL min-1 100 g-1 for perfusion CT. Grey matter rCBF values were 48.7 +/- 5.0 mL min-1 100 g-1 for PET and 71.8 +/- 8.0 mL min-1 100 g-1 for perfusion CT. The overestimation of grey matter rCBF could be reduced from 47% to 20% after normalization to white matter rCBF, but the difference was still significant. CONCLUSION: RCBF measured with perfusion CT does contain perfusion information, but neither quantitative nor relative values can substitute rCBF measured by15O-H2O PET yet. This, however, does not necessarily preclude a useful role in patient management. PMID- 22214475 TI - Optimizing outcomes in patients with cardiovascular disease and chronic kidney disease. AB - Chronic kidney disease (CKD) is an independent risk factor for the development of cardiovascular disease (CVD). Often, CKD and CVD coexist, and patients warrant optimal pharmacotherapy to reduce the risk of future cardiovascular (CV) events. Randomized trials have evaluated the role of antihypertensive therapy and lipid lowering therapy as means to reduce CVD in patients with CKD. Many clinical trials support the role of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in the CKD population. In addition, many clinical trials have evaluated the role of statin therapy in reducing CV events in early- and late-stage CKD. The struggle with interpreting results from these trials is that there are a number of different CV composite end points and a lack of consistency in defining CKD, especially in some post hoc subanalyses. Overall, ACEI/ARB therapy is supported by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) hypertension guidelines and statin therapy is supported by the Adult Treatment Panel (ATP) III and NKF KDOQI dyslipidemia guidelines to optimally manage patients with CKD and CV risk factors. Questions remain as to the optimal role of statin therapy in patients with CKD receiving dialysis. JNC 8 and ATP IV guidelines will be available in the next year, and it is expected that there will be specific recommendations on both hypertension and dyslipidemia management in the CKD population. PMID- 22214476 TI - Management of cardiovascular disease in chronic kidney disease: implications for managed care. AB - Despite the rising incidence of chronic kidney disease (CKD), this condition remains underrecognized and is costly to treat. Care of CKD accounts for a substantial portion of US Medicare spending, with major costs primarily associated with hospitalization and drug therapy. The leading cause of death and hospitalization in patients with CKD is cardiovascular disease (CVD). Strategies to improve identification of CKD have proved to be cost-effective in the highest risk patients (eg, those with diabetes), but determining the most appropriate way to identify high-risk patients remains a significant challenge. There is also evidence to suggest that referral to a specialist once the estimated glomerular filtration rate reaches approximately 60 mL/min/1.73 m2 is cost-effective, especially when patients are greater than 50 years of age and/or have diabetes. Individualized patient care has shown to be cost-effective (or even cost saving), and associated with improved outcomes, such as reduced incidence of CVD events and mortality. Individualized care centers treat numerous comorbidities (eg, hypertension, diabetes, albuminuria, dyslipidemia) in a given patient to prevent the downstream consequences of worsening CVD. Ensuring access to specialist care and effective therapies, along with adherence to such therapies, appears to be a cost-effective, or even cost-saving, strategy based on current available evidence. PMID- 22214478 TI - Supramolecular control of photochemical and electrochemical properties of two oligothiophene derivatives at the air/water interface. AB - Two geometric isomers of oligothiophene derivatives containing two crowned styryl fragments in 2- or 3-positions of thiophene rings are able to form stable monolayers on the water subphase. The organizing of crown-containing oligothiophenes in monolayers is guided by the pi-stacking interaction of hydrophobic styrylthiophene fragments and interaction of hydrophilic macrocycles with the water subphase. The difference in structure of oligothiophene molecules leads to the formation of distinct monolayer architectures with various electrochemical and optical characteristics. PMID- 22214477 TI - Highly luminescent (Zn,Cd)Te/CdSe colloidal heteronanowires with tunable electron hole overlap. AB - We report the synthesis of ultranarrow (Zn,Cd)Te/CdSe colloidal heteronanowires, using ZnTe magic size clusters as seeds. The wire formation starts with a partial Zn for Cd cation exchange, followed by self-organization into segmented heteronanowires. Further growth occurs by inclusion of CdSe. The heteronanowires emit in the 530 to 760 nm range with high quantum yields. The electron-hole overlap decreases with increasing CdSe volume fraction, allowing the optical properties to be controlled by adjusting the heteronanowire composition. PMID- 22214479 TI - Internal construct validity of the Shirom-Melamed Burnout Questionnaire (SMBQ). AB - BACKGROUND: Burnout is a mental condition defined as a result of continuous and long-term stress exposure, particularly related to psychosocial factors at work. This paper seeks to examine the psychometric properties of the Shirom-Melamed Burnout Questionnaire (SMBQ) for validation of use in a clinical setting. METHODS: Data from both a clinical (319) and general population (319) samples of health care and social insurance workers were included in the study. Data were analysed using both classical and modern test theory approaches, including Confirmatory Factor Analysis (CFA) and Rasch analysis. RESULTS: Of the 638 people recruited into the study 416 (65%) persons were working full or part time. Data from the SMBQ failed a CFA, and initially failed to satisfy Rasch model expectations. After the removal of 4 of the original items measuring tension, and accommodating local dependency in the data, model expectations were met. As such, the total score from the revised scale is a sufficient statistic for ascertaining burnout and an interval scale transformation is available. The scale as a whole was perfectly targeted to the joint sample. A cut point of 4.4 for severe burnout was chosen at the intersection of the distributions of the clinical and general population. CONCLUSION: A revised 18 item version of the SMBQ satisfies modern measurement standards. Using its cut point it offers the opportunity to identify potential clinical cases of burnout. PMID- 22214480 TI - Binding of TS1, an anti-keratin 8 antibody, in small-cell lung cancer after 177Lu DOTA-Tyr3-octreotate treatment: a histological study in xenografted mice. AB - BACKGROUND: Small-cell lung carcinoma (SCLC) is an aggressive malignancy characterised by an early relapse, a tendency towards drug resistance, and a high incidence of metastasis. SCLC cells are of neuroendocrine origin and express high levels of somatostatin receptors; therefore, future treatment might involve targeting tumours with radiolabelled somatostatin analogues. This therapy induces abundant necrotic patches that contain exposed keratins; thus, keratin 8, which is one of the most abundant cytoskeletal proteins may represent an interesting secondary target for SCLC. This study aimed to investigate the effects of177Lu DOTA-Tyr3-octerotate and the binding of the monoclonal anti-keratin 8 antibody, TS1, in vitro in treated SCLC- and midgut-xenografted mouse models. METHODS: NCI H69- and GOT1-xenotransplanted mice were treated with three doses of 30 MBq177Lu DOTA-Tyr3-octreotate administered 24 h apart. Mice xenotransplanted with NCI-H69 were sacrificed 1, 5, 12, 20 and 150 days post-injection or when the tumour had regrown to its original size. GOT1-xenotransplanted mice were sacrificed 3 days post-injection. Immunohistochemistry was performed to evaluate TS1 staining in tumours and in seven human biopsies of primary SCLC from pulmonary bronchi. Central cell density and nucleus size were determined in NCI-H69 sections. RESULTS: Twelve days after177Lu-DOTA-Tyr3-octerotate treatment, the SCLC xenograft response was extensive. Twenty days after treatment, one of three analysed tumours displayed complete remission. The other two tumours showed 1/4 the cell density of untreated controls and cell nuclei were about three times larger than those of untreated controls. At 150 days after treatment, one of four mice exhibited complete remission. Treated tumours displayed increased TS1 antibody accumulation and high TS1 binding in necrotic patches. All seven human SCLC biopsies displayed necrotic areas with TS1 staining. CONCLUSIONS: Radiation treatment with three injections of 30 MBq177Lu-DOTA-Tyr3-octreotate had pronounced effects on tumour cell density and cell nuclei, which indicated mitotic catastrophe. Despite these anti-tumour effects, two of three SCLC tumours recurred. Further studies should investigate the nature of tumour cell survival and develop more effective treatments. High TS1 accumulation in tumour sections in vitro after177Lu-DOTA-Tyr3-octerotate treatment indicated that TS1 might represent a promising secondary therapeutic strategy. PMID- 22214481 TI - Curve and instep kick kinematics in elite female footballers. AB - The three-dimensional kinematics of international female footballers performing a simulated direct free kick (curve kick) were compared with those of an instep kick. Reflective markers attached to the participants were tracked by 17 Vicon cameras sampling at 250 Hz. Foot velocity at ball impact did not differ between the two types of kick, but the way in which foot velocity was generated did differ, with instep kicks using a faster approach velocity and greater linear velocities of the hip and knee, and curve kicks using a greater knee angular velocity at impact. In both types of kick, peak knee angular velocity and peak ankle linear velocity occurred at ball impact, providing biomechanical support to the common coaching recommendation of kicking through the ball. To achieve a curved ball trajectory, players should take a wide approach angle, point the support foot to the right of the intended target (for right-footed players), swing the kicking limb across the face of the goal, and impact the ball with the foot moving upwards and in an abducted position. This information will be useful to coaches and players in identifying the fundamental coaching points necessary to achieve a curved trajectory of the ball compared with the more commonly described instep kick kinematics. PMID- 22214483 TI - siRNA against presenilin 1 (PS1) down regulates amyloid beta42 production in IMR 32 cells. AB - BACKGROUND: One of the pathological hallmarks of Alzheimer's disease (AD) is the deposition of the ~4 kDa amyloid beta protein (Abeta) within lesions known as senile plaques. Abeta is also deposited in the walls of cerebral blood vessels in many cases of AD. A substantial proportion of the Abeta that accumulates in the AD brain is deposited as Amyloid, which is highly insoluble, proteinaceous material with a beta-pleated-sheet conformation and deposited extracellularly in the form of 5-10 nm wide straight fibrils. As gamma-secretase catalyzes the final cleavage that releases the Abeta42 or 40 from amyloid beta -protein precursor (APP), therefore, it is a potential therapeutic target for the treatment of AD. gamma-Secretase cleavage is performed by a high molecular weight protein complex containing presenilins (PSs), nicastrin, Aph-1 and Pen-2. Previous studies have demonstrated that the presenilins (PS1 and PS2) are critical components of a large enzyme complex that performs gamma-secretase cleavage. METHODS: In this study we used RNA interference (RNAi) technology to examine the effects of small interfering RNA (siRNA) against PS1 on expression levels of PS1 and Abeta42 in IMR-32 Cells using RTPCR, western blotting and immunofluorescence techniques. RESULTS: The results of the present study showed down regulation of PS1 and Abeta42 in IMR32 cells transfected with siRNA against PS1. CONCLUSION: Our results substantiate the concept that PS1 is involved in gamma-secretase activity and provides the rationale for therapeutic strategies aimed at influencing Abeta42 production. PMID- 22214484 TI - Osseointegrated dental implants in growing children: a literature review. AB - Edentulism is usually associated with the aging patient. However, total or partial tooth loss also affects young individuals, mainly as a result of trauma, decay, anodontia, or congenital and acquired jaw defects involving the alveolar processes. For elderly patients, the use of oral implants has become an accepted treatment modality for edentulism, and most of today's knowledge regarding implants is based on such practice. There has been hesitation to perform implant therapy for growing children; hence, few children to date have been provided with implant-supported construction. Consequently, little is known about the outcome of the osseointegration procedure in young patients, and until now, only a limited number of case presentations have been reported. This article reviews the current literature to discuss the use of dental implants in growing patients and the influence of maxillary and mandibular skeletal and dental growth on the stability of those implants. The literature review was performed through Science Direct, Wileys Blackwell Synergy, PubMed, Google, Embase, Medknow publications, and Springer for references published from 1963 to 2011. It is recommended to wait for the completion of dental and skeletal growth, except for severe cases of ectodermal dysplasia. PMID- 22214486 TI - In vitro study of transporters involved in intestinal absorption of inorganic arsenic. AB - Inorganic arsenic (iAs) [As(III)+As(V)] is a drinking water contaminant, and human exposure to these arsenic species has been linked with a wide range of health effects. The main path of exposure is the oral route, and the intestinal epithelium is the first physiological barrier that iAs must cross in order to be absorbed. However, there is a lack of information about intestinal iAs absorption. The aim of this study was to evaluate the participation of certain transporters [glucose transporters (GLUT and SGLT), organic anion transporting polypeptides (OATPs), aquaporins (AQPs), and phosphate transporters (NaPi and PiT)] in intestinal absorption of As(V) and As(III), using the Caco-2 cell line as a model of the intestinal epithelium. For this purpose, the effects of chemical inhibition and gene silencing of the transporters of interest on iAs uptake were evaluated, and also the differential expression of these transporters after treatment with iAs. The results show that chemical inhibition using rifamycin SV (OATP inhibitor), phloridzin (SGLT inhibitor), phloretin (GLUT and AQP inhibitor), and copper sulfate (AQP inhibitor) leads to a significant reduction in the apparent permeability and cellular retention of As(III). RT-qPCR indicates up-regulation of GLUT2, GLUT5, OATPB, AQP3, and AQP10 after exposure to As(III), while exposure to As(V) increases the expression of sodium-dependent phosphate transporters, especially NaPiIIb. Gene silencing of OATPB, AQP10, and GLUT5 for As(III) and NaPiIIb for As(V) significantly reduces uptake of the inorganic forms. These results indicate that these transporters may be involved in intestinal absorption of iAs. PMID- 22214485 TI - The upregulation of thiamine (vitamin B1) biosynthesis in Arabidopsis thaliana seedlings under salt and osmotic stress conditions is mediated by abscisic acid at the early stages of this stress response. AB - BACKGROUND: Recent reports suggest that vitamin B1 (thiamine) participates in the processes underlying plant adaptations to certain types of abiotic and biotic stress, mainly oxidative stress. Most of the genes coding for enzymes involved in thiamine biosynthesis in Arabidopsis thaliana have been identified. In our present study, we examined the expression of thiamine biosynthetic genes, of genes encoding thiamine diphosphate-dependent enzymes and the levels of thiamine compounds during the early (sensing) and late (adaptation) responses of Arabidopsis seedlings to oxidative, salinity and osmotic stress. The possible roles of plant hormones in the regulation of the thiamine contribution to stress responses were also explored. RESULTS: The expression of Arabidopsis genes involved in the thiamine diphosphate biosynthesis pathway, including that of THI1, THIC, TH1 and TPK, was analyzed for 48 h in seedlings subjected to NaCl or sorbitol treatment. These genes were found to be predominantly up-regulated in the early phase (2-6 h) of the stress response. The changes in these gene transcript levels were further found to correlate with increases in thiamine and its diphosphate ester content in seedlings, as well as with the enhancement of gene expression for enzymes which require thiamine diphosphate as a cofactor, mainly alpha-ketoglutarate dehydrogenase, pyruvate dehydrogenase and transketolase. In the case of the phytohormones including the salicylic, jasmonic and abscisic acids which are known to be involved in plant stress responses, only abscisic acid was found to significantly influence the expression of thiamine biosynthetic genes, the thiamine diphosphate levels, as well as the expression of genes coding for main thiamine diphosphate-dependent enzymes. Using Arabidopsis mutant plants defective in abscisic acid production, we demonstrate that this phytohormone is important in the regulation of THI1 and THIC gene expression during salt stress but that the regulatory mechanisms underlying the osmotic stress response are more complex. CONCLUSIONS: On the basis of the obtained results and earlier reported data, a general model is proposed for the involvement of the biosynthesis of thiamine compounds and thiamine diphosphate dependent enzymes in abiotic stress sensing and adaptation processes in plants. A possible regulatory role of abscisic acid in the stress sensing phase is also suggested by these data. PMID- 22214487 TI - IPS-Empress II inlay-retained fixed partial denture reinforced with zirconia bar: three-dimensional finite element and in-vitro studies. AB - OBJECTIVE: This study evaluated von Mises stress distribution, flexural strength and interface micrographs of IPS-Empress II (IPS) inlay-retained fixed partial dentures (IRFPD) reinforced with Zirconia bars (Zb). MATERIALS AND METHODS: In the Finite element analysis, six three-dimensional models of IRFPD were designed using Solid Works 2006. Five models were reinforced with different Zb and a model without Zb was considered as a control. The bridges were loaded by 200 and 500 N forces at the middle of the pontic on the occlusal surface. Subsequently, von Mises stress and displacement of the models were evaluated along a defined path. In the experimental part, 21 bar shape specimens were fabricated from lithium disilicate and zirconia ceramic in three different designs. The zirconia-IPS interfaces and the fractured surfaces of flexural test were observed using SEM. RESULTS: In the connector area, von Mises stress and displacement of the models with Zb under a load of 500 N were decreased compared to the model without the Zb; however, this difference was not considerable at a load of 200 N. In the mesial connector, Von Mises stress and displacement was decreased from 12.5 Mpa for the control model tested at 500 N to 7.0 Mpa for the model with Zb and from 0.0050-0.0041 mm, respectively. SEM analyses showed that, before fracture, interfacial gaps were not observed along the interfaces, but initiated cracks propagated along the interfaces after flexural loading. CONCLUSION: IPS IRFPD reinforced by Zb can tolerate higher stresses while still functioning effectively and the interfaces may have desirable adaption. PMID- 22214489 TI - Current insulin analogues in the treatment of diabetes: emphasis on type 2 diabetes. AB - INTRODUCTION: Although traditionally used as a final treatment option, early use of insulin is a therapeutic option after metformin failure in type 2 diabetes. Injection of native insulin lacks the rapid onset of action after food ingestion and the chronic maintenance of a steady-state low-level basal insulin in fasting periods. These limitations have fuelled the development of insulin analogues, which mainly fall into two different categories: short-acting and long-acting analogues. AREAS COVERED: We review the recent literature investigating the efficacy and safety of insulin analogues in human diabetes, with emphasis on type 2 diabetes, as about 30% of these patients are being treated with insulin. We also examine novel developments in this area, including the new long-acting basal analogues whose longer duration of action might reduce dosing frequency to three times a week. EXPERT OPINION: Insulin analogues show some advantage compared with native insulin. However, improvements in reducing their pharmacological variability would be expected to lower the risk of hypoglycemia and hyperglycemia, as well as to simplify and perhaps also encourage optimal insulin titration in real-life clinical practice. Extending the duration of insulin effect would also allow for greater flexibility and potentially reduce the frequency of blood glucose monitoring. PMID- 22214488 TI - Bioactivity-based screening methods for antibiotics residues: a comparative study of commercial and in-house developed kits. AB - Two bioactivity-based screening methods for antibiotic residue analysis (FAST Antimicrobial Screening Test and PremiTest) were compared, in terms of sensitivity, with a new in-house developed tube test assay using Escherichia coli. Tests were performed using antibiotic standards, spiked samples and real incurred samples. The minimum inhibitory concentration (MIC) for several antibiotics was established and compared with maximum residue levels (MRLs) in samples. The results of all evaluated tests are compared with liquid chromatography-tandem mass spectrometry multi-residue screening tests to compare parameters such as sample preparation, cost, time of analysis and confidence in results. For all tests, values of half the maximum residue limit (0.5 * MRL) were considered as a satisfactory target for a screening method. The potential and limitations of each method are discussed to indicate more rational and effective strategies for high-throughput residue monitoring and surveillance programmes. It was concluded that bioactivity-based screening methods are a useful tool, but the best compromise between minimum performance limits, cost and selectivity must be taken into account. For laboratories equipped with mass spectrometry, multi-class screening methods provide more specific responses with high sensitivity. PMID- 22214490 TI - Anisotropic third-order optical nonlinearity of a single ZnO micro/nanowire. AB - We report a systematic study about the anisotropic third-order optical nonlinearity of a single ZnO micro/nanowire by using the Z-scan method with a femtosecond laser. The two-photon absorption coefficient and nonlinear refraction index, which are measured as a function of polarization angle and sample orientation angle, exhibit oscillation curves with a period of pi/2, indicating a highly polarized optical nonlinearity of the ZnO micro/nanowire. Further studies show that the polarized optical nonlinearity of the ZnO micro/nanowire is highly size-dependent. The results indicate that ZnO nanowire has great potential in applications of nanolasers, all-optical switching and polarization-sensitive photodetectors. PMID- 22214491 TI - 18F-fluoride PET: changes in uptake as a method to assess response in bone metastases from castrate-resistant prostate cancer patients treated with 223Ra chloride (Alpharadin). AB - BACKGROUND: A qualitative assessment of conventional bone scintigraphy with 99mTc methylene diphosphonate is perceived as an insensitive method for monitoring the treatment response of bone metastases, and we postulated that semi-quantitative 18F-fluoride positron emission tomography (PET) might serve as a suitable alternative biomarker of the treatment response. METHODS: Five patients with castrate-resistant prostate cancer and bone metastases with no known soft tissue disease received 100 kBq/kg of radium-223 (223Ra)-chloride (Alpharadin) therapy at 0 and 6 weeks and had whole body 18F-fluoride PET scans at baseline, 6 and 12 weeks with concurrent prostatic-specific antigen (PSA) and alkaline phosphatase (ALP) measurements. A qualitative comparison of the PET scans was performed blinded to the PSA and ALP results. A semi-quantitative comparison was made by measuring the maximum standardised uptake values (SUVmax) in five bone metastases in each patient. The means of the five SUVmax measurements in each subject were used as a quantitative measure of global metastatic activity at each time point. RESULTS: Three patients showed a PSA decline at 12 weeks (-44%, -31%, -27% reduction) whilst two patients showed PSA increases (+10%, +17%). All five patients showed a reduction in ALP of greater than 25%. The qualitative assessment of the 18F-fluoride scans recorded a stable disease in each case. However, the semi-quantitative assessment showed agreement with the PSA decline in three patients (-52%, -75%, -49%) and minimal change (+12%, -16%) in two patients with increased PSA at 12 weeks. Four patients showed similar reductions in mean SUVmax and ALP at 12 weeks. CONCLUSIONS: The semi-quantitative 18F fluoride PET is more accurate than the qualitative comparison of scans in assessing response in bone metastases, correlating with the PSA response and ALP activity and offering a potential imaging biomarker for monitoring treatment response in bone metastases following treatment with 223Ra-chloride. PMID- 22214492 TI - Are daily fluctuations in perceived environment associated with walking? AB - The physical environment is thought to influence walking; however, daily variations in perceived environment have received little attention. The current study sought to examine if key within-person factors (i.e., implementation intentions, social support, affect and self-efficacy) would be associated with walking and if perceived access to supportive environments (e.g., access to nice walking paths) and perceived environmental barriers (e.g., bad weather and safety issues) were uniquely associated with walking after controlling for other constructs. Participants (N = 14, 50.0% men, 78.6% White, M age = 59.4 +/- 6.4) were in the intervention arm of an 8-week controlled trial promoting walking via personal digital assistants. Participants completed electronic surveys twice a day (total entries = 804) in which they reported brisk walking levels and psychosocial and environmental factors. Multilevel modelling was used to examine within-person variations in constructs as determinants of walking. Results suggested that daily variations in implementation intentions, social support and positive affect were positively associated with walking. Further, perceived access to supportive environments, though not perceived environmental barriers, was positively associated with walking after controlling for other constructs (p < 0.05). Future research should explore intervention components that target context-specific information about perceived access to supportive environments as part of a broader perspective on intervention development. PMID- 22214493 TI - mTOR inhibitors: A novel class of anti-cancer agents. PMID- 22214494 TI - Effects of crystallization and dopant concentration on the emission behavior of TiO2:Eu nanophosphors. AB - Uniform, spherical-shaped TiO2:Eu nanoparticles with different doping concentrations have been synthesized through controlled hydrolysis of titanium tetrabutoxide under appropriate pH and temperature in the presence of EuCl3.6H2O. Through air annealing at 500 degrees C for 2 h, the amorphous, as-grown nanoparticles could be converted to a pure anatase phase. The morphology, structural, and optical properties of the annealed nanostructures were studied using X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray spectroscopy [EDS], and UV-Visible diffuse reflectance spectroscopy techniques. Optoelectronic behaviors of the nanostructures were studied using micro-Raman and photoluminescence [PL] spectroscopies at room temperature. EDS results confirmed a systematic increase of Eu content in the as-prepared samples with the increase of nominal europium content in the reaction solution. With the increasing dopant concentration, crystallinity and crystallite size of the titania particles decreased gradually. Incorporation of europium in the titania particles induced a structural deformation and a blueshift of their absorption edge. While the room temperature PL emission of the as-grown samples is dominated by the 5D0 - 7Fj transition of Eu+3 ions, the emission intensity reduced drastically after thermal annealing due to outwards segregation of dopant ions. PMID- 22214495 TI - Nanostructure of complexes between cationic lipids and an oppositely charged polyelectrolyte. AB - The morphology of aqueous solutions of polyelectrolytes and oppositely charged lipids is the subject of extensive colloid science research, because of their application in industry and medicine, the latter especially for gene therapy. In this work, we show that complexes of two different cationic lipids with the polyelectrolyte sodium poly(acrylic acid), PAA, share similar morphology with the complexes of those lipids with nucleic acids, implying a broader and universal packing phenomenon. We characterized by direct-imaging cryogenic-temperature transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS), and zeta (zeta)-potential two cationic lipids, 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) and bis(11-ferrocenylundecyl) dimethylammonium bromide (BFDMA), which are used in gene transfection, at equivalent lipid/polyelectrolyte charge ratio. Our results revealed that, for both types of complexes, onion-like multilamellar nanostructures formed, which exhibited similar morphology as in complexes of DNA or oligonucleotides (lipoplexes), based on the same lipids. Our findings suggest that the onion-like packing may be energetically favorable for a wide range of polyelectrolyte-liposome systems, from oligonucleotides and DNA to PAA. PMID- 22214497 TI - Effects of internal low-dose irradiation from 131I on gene expression in normal tissues in Balb/c mice. AB - BACKGROUND: The aim of this study was to investigate the global gene expression response of normal tissues following internal low absorbed dose irradiation of 131I. METHODS: Balb/c mice were intravenously injected with 13 to 260 kBq of 131I and euthanized 24 h after injection. Kidneys, liver, lungs, and spleen were surgically removed. The absorbed dose to the tissues was 0.1 to 9.7 mGy. Total RNA was extracted, and Illumina MouseRef-8 Whole-Genome Expression BeadChips (Illumina, Inc., San Diego, California, USA) were used to compare the gene expression of the irradiated tissues to that of non-irradiated controls. The Benjamini-Hochberg method was used to determine differentially expressed transcripts and control for false discovery rate. Only transcripts with a modulation of 1.5-fold or higher, either positively or negatively regulated, were included in the analysis. RESULTS: The number of transcripts affected ranged from 260 in the kidney cortex to 857 in the lungs. The majority of the affected transcripts were specific for the different absorbed doses delivered, and few transcripts were shared between the different tissues investigated. The response of the transcripts affected at all dose levels was generally found to be independent of dose, and only a few transcripts showed increasing or decreasing regulation with increasing absorbed dose. Few biological processes were affected at all absorbed dose levels studied or in all tissues studied. The types of biological processes affected were clearly tissue-dependent. Immune response was the only biological process affected in all tissues, and processes affected in more than three tissues were primarily associated with the response to stimuli and metabolism. CONCLUSION: Despite the low absorbed doses delivered to the tissues investigated, a surprisingly strong response was observed. Affected biological processes were primarily associated with the normal function of the tissues, and only small deviations from the normal metabolic activity in the tissues were induced. PMID- 22214496 TI - Real-time PCR of the mammalian hydroxymethylbilane synthase (HMBS) gene for analysis of flea (Ctenocephalides felis) feeding patterns on dogs. AB - BACKGROUND: Precise data on quantitative kinetics of blood feeding of fleas, particularly immediately after contact with the host, are essential for understanding dynamics of flea-borne disease transmission and for evaluating flea control strategies. Standard methods used are inadequate for studies that simulate early events after real-life flea access to the host. METHODS: Here, we developed a novel quantitative polymerase chain reaction targeting mammalian DNA within fleas to quantify blood consumption with high sensitivity and specificity. We used primers and fluorescent probes that amplify the hydroxymethylbilane synthase (HMBS) gene, an evolutionary divergent gene that is unlikely to be detected in insects by mammalian-specific primers and probes. To validate this assay, fleas were placed on dogs, allowed to distribute in the hair, and removed at specific time points with single-use combs. Fleas were then immediately homogenized by vigorous shaking with ceramic beads in guanidinium-based DNA preservation buffer for DNA extraction. RESULTS: The specificity of this assay was ascertained by amplification of canine, feline and equine blood with differential product melting temperatures (Tm), and lack of amplification of bovine and porcine blood and of adult fleas reared from larvae fed with bovine blood. Sensitivity of the assay was established by limiting dilution and detection of single copies of HMBS DNA equivalent to 0.043 nL blood. Application of the assay indicated that after 15 minutes on a dog, male and female fleas had ingested low, but similar amounts of approximately 1.1. nL blood. Saturation uptake of 118 and 100 nL blood per flea was found at 30 and 60 min on the dog, respectively. CONCLUSIONS: The HMBS PCR method developed here offers the advantages of both exquisite sensitivity and specificity that make it superior to other approaches for quantification of blood ingested by fleas. The capability to detect minute quantities of blood in single fleas, particularly immediately after colonization of the host, will provide a superior tool for studying flea-host interactions, flea-borne disease transmission, and flea control strategies. PMID- 22214498 TI - Imaging in the age of molecular medicine. PMID- 22214499 TI - Investigation of superparamagnetic iron oxide nanoparticles for MR-visualization of surgical implants. AB - For the development of a surgical mesh implant that is visible in magnetic resonance imaging (MRI), superparamagnetic iron oxides (SPIOs) are integrated into the material of the mesh. In order to get a high quality mesh regarding both mechanical and imaging properties, a narrow size distribution and homogenous spatial distribution, as well as a strong magnetization of SPIOs within the filament of the mesh are required. In this work, six different samples of SPIOs composed of a magnetite core are synthesized with and without stabilizing dodecanoic acid and analyzed using a superconducting quantum interference device (SQUID), transmission electron microscope (TEM) and a magnetic force microscope (MFM) to determine the properties that are beneficial for the assembly and imaging of the implant. These analyses show the feasibility of visualization of surgical implants with incorporated SPIOs and the influence of the agglomeration of SPIOs on their magnetization and on a homogenous spatial distribution within the polymer of the mesh. PMID- 22214500 TI - Monitoring molecular, functional and morphologic aspects of bone metastases using non-invasive imaging. AB - Bone is among the most common locations of metastasis and therefore represents an important clinical target for diagnostic follow-up in cancer patients. In the pathogenesis of bone metastases, disseminated tumor cells proliferating in bone interact with the local microenvironment stimulating or inhibiting osteoclast and osteoblast activity. Non-invasive imaging methods monitor molecular, functional and morphologic changes in both compartments of these skeletal lesions - the bone and the soft tissue tumor compartment. In the bone compartment, morphologic information on skeletal destruction is assessed by computed tomography (CT) and radiography. Pathogenic processes of osteoclast and osteoblast activity, however, can be imaged using optical imaging, positron emission tomography (PET), single photon emission CT (SPECT) and skeletal scintigraphy. Accordingly, conventional magnetic resonance imaging (MRI) and CT as well as diffusion- weighted MRI and optical imaging are used to assess morphologic aspects on the macroscopic and cellular level of the soft tissue tumor compartment. Imaging methods such as PET, MR spectroscopy, dynamic contrast-enhanced techniques and vessel size imaging further elucidate on pathogenic processes in this compartment including information on metabolism and vascularization. By monitoring these aspects in bone lesions, new insights in the pathogenesis of skeletal metastases can be gained. In translation to the clinical situation, these novel methods for the monitoring of bone metastases might be applied in patients to improve follow-up of these lesions, in particular after therapeutic intervention. This review summarizes established and experimental imaging techniques for the monitoring of tumor and bone cell activity including molecular, functional and morphological aspects in bone metastases. PMID- 22214501 TI - Imaging of hypoxia using PET and MRI. AB - Tumor hypoxia is the result of an inadequate supply of oxygen to tumor cells which can be caused by multiple factors. It is associated with aggressive local tumor growth and invasion, increased risk of metastasis, higher resistance to radiotherapy (RT) and chemotherapy, overall resulting in a poor clinical prognosis. Many locally advanced solid tumors may exhibit hypoxic and/or anoxic tissue areas that are heterogeneously distributed within the tumor mass. As hypoxia is a negative prognostic factor concerning response to radiotherapy and chemotherapy, in vivo measurement of tumor hypoxia could be helpful to identify patients with worse prognosis or patients that could benefit from appropriate treatments such as intensity modulated radiotherapy (IMRT) that may accurately conform the dose distribution to small intratumoral regions showing differences in the oxygen level. A manifold of different methods to assess the oxygen tension (pO2) in tissues have been developed, each of them offering advantages as well as drawbacks. They range from invasive direct measurement techniques of the pO2 in tissue by using a polarographic electrode, to non-invasive imaging techniques such as positron emission tomography (PET) or magnetic resonance imaging (MRI). This article provides an overview over the various methods, with a particular emphasis on PET and MRI for imaging of hypoxia, and reviews their performance in preclinical and clinical studies. PMID- 22214502 TI - Cellular and subcellular imaging in live mice using fluorescent proteins. AB - Fluorescent proteins have revolutionized in vivo biology. Due to their intrinsic brightness, multiple colors, and ease of genetic manipulation, fluorescent proteins have been demonstrated to be the reporters of choice for in vivo imaging. The present report reviews applications of fluorescent proteins for imaging cancer progression, gene expression, angiogenesis, stem cells, bacterial infection, Leishmania infection, and asthma, at the cellular and subcellular level in live mice. With fluorescent-protein-expressing cells and a highly sensitive small animal imaging system, cellular and subcellular dynamics can now be observed in live mice in real time. Such imaging possibilities can provide new visual targets for novel drug therapy. Fluorescent proteins thus enable both micro as well as macro imaging technology and thereby provide the basis for the new field of in vivo cell biology. PMID- 22214503 TI - Theranostic systems and strategies for monitoring nanomedicine-mediated drug targeting. AB - Nanomedicine formulations are considered to be superior to standard low-molecular weight drugs because of an increased drug accumulation at the pathological site and a decreased localization to healthy non-target tissues, together leading to an improved balance between the efficacy and the toxicity of (chemo-) therapeutic interventions. To better understand and further improve nanomedicine-mediated drug targeting, it is important to design systems and strategies which are able to provide real-time feedback on the localization, the release and the therapeutic efficacy of these formulations. The advances made over the past few years with regard to the development of novel imaging agents and techniques have provided a broad basis for the design of theranostic nanomedicine materials, i.e. multicomponent carrier constructs in which drugs and imaging agents are combined, and which can be used to address issues related to drug localization, drug release and drug efficacy. Here, we summarize several recent efforts in this regard, and we show that theranostic systems and strategies hold significant potential for monitoring and improving nanomedicine-mediated drug targeting. PMID- 22214504 TI - Imaging in the age of molecular medicine: monitoring of anti-angiogenic treatments. AB - Angiogenesis is a complex multistep process and a crucial pre-requisite for tumor growth, invasion and metastasis. A profound knowledge of the mechanisms including the elucidation of markers for angiogenic vessels is essential for the generation of new anti-angiogenic chemotherapeutic agents and the improvement of specific imaging techniques. During the last decades, numerous angiogenesis inhibitors have been developed and some of them have shown promising results in preclinical and clinical trials. However, the response to anti-angiogenic treatment is often delayed and shows high inter-individual variations. In order to improve anti angiogenic therapy, new specific surrogate markers are necessary that allow the characterization of different angiogenic steps, especially at the early stage. In this respect, non-invasive imaging is a potent tool for characterizing the tumor vascularization and for sensitive and longitudinal treatment monitoring. In particular, new molecular imaging techniques might ultimately improve the characterization of the angiogenic tumor phenotype and stage. This review summarizes the current status of different imaging modalities e.g. MRI, CT, US, nuclear and optical imaging with respect to the imaging of tumor angiogenesis and of anti-angiogenic treatments. It also includes new approaches in molecular imaging, which give deep insight into the tumor stage and the response of tumor vessels to anti-angiogenic therapy. Thus, this may lead to a more personalized cancer therapy in future. PMID- 22214505 TI - Translational optical imaging in diagnosis and treatment of cancer. AB - In cancer imaging, many different modalities are used that each have their specific features, leading to the combined use of different techniques for the detection, staging and treatment evaluation of cancer. Optical imaging using near infrared fluorescence light is a new imaging modality that has recently emerged in the field of cancer imaging. After extensive preclinical research, the first steps of translation to the clinical practice are currently being made. In this article, we discuss the preclinical and clinical results of near-infrared optical imaging for non-invasive detection and classification of tumors, therapy monitoring, sentinel lymph node procedures, and image-guided cancer surgery. Widespread availability of imaging systems and optical contrast agents will enable larger studies on their clinical benefit and can help establish a definitive role in clinical practice. PMID- 22214506 TI - Apoptosis imaging to monitor cancer therapy: the road to fast treatment evaluation? AB - Molecular imaging of biological processes may allow detection of therapy effects before the tumor is reduced in size. The most frequently used PET tracer in oncology, 2-[18F]fluoro-2-deoxyglucose (FDG), suffers from low specificity due to uptake in inflammatory cells. The proliferation marker, 3'-[18F]fluoro-3'-deoxy-L thymidine (FLT), is less influenced by the inflammatory response following therapy but here disease- and drug-specific effects need to be considered. Since cancer therapy mainly intends to eliminate cancer cells, imaging of cell death offers a direct way to image therapy response. This review gives an overview of the radiopharmaceutical development and in vivo evaluation of radioligands that have emerged so far for detection and assessment of apoptosis and necrosis. Two radiopharmaceuticals that can image cell death have made it to clinical trials for follow up of tumor treatment: i) 99mTc-and 123I-labelled AnxA5 for the response to treatment of for example lymphoma and lung cancer and ii) 18F-ML10 for the evaluation of brain tumors post-radiation. Other agents need further optimization. PMID- 22214507 TI - Enzymatically activatable diagnostic probes. AB - Molecular imaging of disease development, progression and treatment is seen as key to further advancement in the understanding and triumph over illness. The role of enzymes is to catalyze the biochemical reactions that help regulate health, and when dysregulated in complex organisms lead to or indicate disease. The ability to image the action of these proteins for diagnostic purposes opens a window for the researcher and clinician to witness specifc molecular events in vitro and in vivo. Such probes have been developed and deployed for the optical, radionuclide and magnetic resonance modalities and offer significant benefits over conventional agents. The signal of enzymatically-activated probes is regulated by the specific activity of the desired enzyme. This allows for a higher signal to background ratio over non-specific and targeted agents. It also enables the modulation of contrast agent distribution (and even cellular accumulation) following enzymatic activity. This review summarizes the strategies and probes in development and use in this emergent field of molecular imaging, with a particular focus on the research and medical relevance of these advances. PMID- 22214508 TI - Mini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflammation. AB - BACKGROUND: Vascular adhesion protein-1 (VAP-1) is an adhesion molecule that plays a key role in recruiting leucocytes into sites of inflammation. We have previously shown that 68Gallium-labelled VAP-1-targeting peptide (68Ga-DOTAVAP P1) is a positron emission tomography (PET) imaging agent, capable of visualising inflammation in rats, but disadvantaged by its short metabolic half-life and rapid clearance. We hypothesised that prolonging the metabolic half-life of 68Ga DOTAVAP-P1 could further improve its imaging characteristics. In this study, we evaluated a new analogue of 68Ga-DOTAVAP-P1 modified with a mini-polyethylene glycol (PEG) spacer (68Ga-DOTAVAP-PEG-P1) for in vivo imaging of inflammation. METHODS: Whole-body distribution kinetics and visualisation of inflammation in a rat model by the peptides 68Ga-DOTAVAP-P1 and 68Ga-DOTAVAP-PEG-P1 were evaluated in vivo by dynamic PET imaging and ex vivo by measuring the radioactivity of excised tissues. In addition, plasma samples were analysed by radio-HPLC for the in vivo stability of the peptides. RESULTS: The peptide with the mini-PEG spacer showed slower renal excretion but similar liver uptake as the original peptide. At 60 min after injection, the standardised uptake value of the inflammation site was 0.33 +/- 0.07 for 68Ga-DOTAVAP-P1 and 0.53 +/- 0.01 for 68Ga-DOTAVAP-PEG-P1 by PET. In addition, inflammation-to-muscle ratios were 6.7 +/- 1.3 and 7.3 +/- 2.1 for 68Ga-DOTAVAP-P1 and 68Ga-DOTAVAP-PEG-P1, respectively. The proportion of unchanged peptide in circulation at 60 min after injection was significantly higher for 68Ga-DOTAVAP-PEG-P1 (76%) than for 68Ga-DOTAVAP-P1 (19%). CONCLUSION: The eight-carbon mini-PEG spacer prolonged the metabolic half-life of the 68Ga DOTAVAP-P1 peptide, leading to higher target-to-background ratios and improved in vivo PET imaging of inflammation. PMID- 22214509 TI - Increased graphitization in electrospun single suspended carbon nanowires integrated with carbon-MEMS and carbon-NEMS platforms. AB - Single suspended carbon nanowires (CNWs) integrated on carbon-MEMS (CMEMS) structures are fabricated by electrospinning of SU-8 photoresist followed by pyrolysis. These monolithic CNW-CMEMS structures enable fabrication of very high aspect ratio CNWs of predefined length. The CNWs thus fabricated display core shell structures having a graphitic shell with a glassy carbon core. The electrical conductivity of these CNWs is increased by about 100% compared to glassy carbon as a result of enhanced graphitization. We suggest some tunable fabrication and pyrolysis parameters that may improve graphitization in the resulting CNWs, making them a good replacement for several carbon nanostructure based devices. PMID- 22214510 TI - A systematic review of economic evaluations of interventions to tackle cardiovascular disease in low- and middle-income countries. AB - BACKGROUND: Low-and middle-income countries are facing both a mounting burden of cardiovascular disease (CVD) as well as severe resource constraints that keep them from emulating some of the extensive strategies pursued in high-income countries. There is thus an urgency to identify and implement those interventions that help reap the biggest reductions of the CVD burden, given low resource levels. What are the interventions to combat CVDs that represent good "value for money" in low-and middle-income countries? This study reviews the evidence-base on economic evaluations of interventions located in those countries. METHODS: We conducted a systematic literature review of journal articles published until 2009, based on a comprehensive key-word based search in generic and specialized electronic databases, accompanied by manual searches of expert databases. The search strategy consisted of freetext and MeSH terms related to economic evaluation and cardiovascular disease. Two independent reviewers verified fulfillment of inclusion criteria and extracted study characteristics. RESULTS: Thirty-three studies met the selection criteria. We find a growing research interest, in particular in most recent years, if from a very low baseline. Most interventions fall under the category primary prevention, as opposed to case management or secondary prevention. Across the spectrum of interventions, pharmaceutical strategies have been the predominant focus, and, taken at face value, these show significant positive economic evidence, specifically when compared to the counterfactual of no interventions. Only a few studies consider non-clinical interventions, at population level. Almost half of the studies have modelled the intervention effectiveness based on existing risk-factor information and effectiveness evidence from high-income countries. CONCLUSION: The cost effectiveness evidence on CVD interventions in developing countries is growing, but remains scarce, and is biased towards pharmaceutical interventions. While the burden of cardiovascular disease is growing in these countries, future research should put greater emphasis on non-clinical interventions than has hitherto been the case. Significant differences in outcome measures and methodologies prohibit a direct ranking of the interventions by their degree of cost-effectiveness. Considerable caution should be exercised when transferring effectiveness estimates from developed countries for the purpose of modelling cost effectiveness in developing countries. New local CVD risk factor and intervention follow-up studies are needed. Some pharmaceutical strategies appear cost effective while clarifications are needed on the diagnostic approach in single high-risk factor vs. absolute risk targeting, the role of patient compliance, and the potential public health consequences of large-scale medicalization. PMID- 22214511 TI - The benefits of specific immunoglobulin E testing in the primary care setting. AB - A common link among allergic diseases remains the many allergens that can provoke symptoms. The National Institutes of Health Guidelines for the Diagnosis and Management of Asthma and Guidelines for the Diagnosis and Management of Food Allergy support the use of in vivo (skin prick) or in vitro (blood) specific immunoglobulin E (IgE) testing, along with a detailed clinical history and physical examination, to document an allergy diagnosis. The initial responsibility of diagnosing allergic diseases falls principally on primary care providers, for whom skin prick testing is impractical. Access to in vitro testing provides a valuable diagnostic tool, in conjunction with patient history, for comprehensive allergy and asthma management, which can result in significant clinical and economic benefits and improved patient outcomes. Identification of specific allergens in patients enhances management through education, targeted allergen avoidance, pharmacotherapy, and immunotherapy. The utilization of specific IgE in vitro allergy testing may also drive efficient and effective utilization of healthcare resources. Testing can facilitate a close collaboration between the primary care provider and the allergy specialist, who is experienced in interpreting allergy tests and correlating them with clinical history, conducting food and drug challenges, educating about environmental controls, and managing chronic or recurrent conditions where allergy is not easily recognized. As healthcare reimbursement moves from fee-for-service to fee-for-outcomes, cooperative, comprehensive, and outcome-based patient management will gain in importance. PMID- 22214512 TI - Manipulating thermal conductance at metal-graphene contacts via chemical functionalization. AB - Graphene-based devices have garnered tremendous attention due to the unique physical properties arising from this purely two-dimensional carbon sheet leading to tremendous efficiency in the transport of thermal carriers (i.e., phonons). However, it is necessary for this two-dimensional material to be able to efficiently transport heat into the surrounding 3D device architecture in order to fully capitalize on its intrinsic transport capabilities. Therefore, the thermal boundary conductance at graphene interfaces is a critical parameter in the realization of graphene electronics and thermal solutions. In this work, we examine the role of chemical functionalization on the thermal boundary conductance across metal/graphene interfaces. Specifically, we metalize graphene that has been plasma functionalized and then measure the thermal boundary conductance at Al/graphene/SiO(2) contacts with time domain thermoreflectance. The addition of adsorbates to the graphene surfaces are shown to influence the cross plane thermal conductance; this behavior is attributed to changes in the bonding between the metal and the graphene, as both the phonon flux and the vibrational mismatch between the materials are each subject to the interfacial bond strength. These results demonstrate plasma-based functionalization of graphene surfaces is a viable approach to manipulate the thermal boundary conductance. PMID- 22214513 TI - Bromine-sensitized solar photolysis of CO2. AB - Direct photochemical reduction of CO(2) has generally been accomplished by using transition-metal compounds as electron transfer reagents. Here, we show that elemental bromine can function as an alternative photosensitizer. When sunlight is tightly focused on mixtures of CO(2) and Br(2), in the presence of a polar adsorbent such as silica gel, glass wool, alumina, or titania, a metastable red adduct is formed within seconds and concentrates at the point of illumination. Further illumination causes deposition of a stable black film on the polar adsorbent. Mass spectrometry of the cold-trapped red intermediate shows clusters of peaks corresponding to the expected distribution of isotopomers of C(2)O(4)Br(4)(+), as well as of C(2)O(4)Br(3)(+). DFT computations indicate that the lowest-energy species with the formula C(2)O(4)Br(4) is trans-2,4-dibromo-2,4 dihypobromo-1,3-dioxetane. Formation of this molecule from (2CO(2) + 2Br(2)) would require a minimum of 3 visible photons, two of which would hypothetically be used in formation of as-yet undetected CO(2)Br(2) and the third, in a subsequent photodimerization. By elemental analysis, the final amorphous solid product contains a C/Br atomic ratio >12, suggesting that Br(2) is acting photocatalytically. Even with a poorly optimized optical system, the reaction rate has reached as high as 1.6 mg reduced C with 40 s of solar collection using a 30 cm diameter paraboloid reflector. This rate is consistent with the storage of approximately 1% of incident solar energy. PMID- 22214514 TI - White fat, factitious hyperglycemia, and the role of FDG PET to enhance understanding of adipocyte metabolism. AB - The development of a hybrid PET/CT led to the recognition of the enhanced glycolysis in brown fat. We report a previously unrecognized mechanism for altered fluorodeoxyglucose (FDG) biodistribution with diffuse white adipose tissue uptake. This occurred during a restaging scan for cervical cancer following administration of insulin in the setting of measured hyperglycemia. The patient's blood sugar normalized, but she experienced symptoms and signs of hypoglycemia. A subsequent history indicated that the patient received intravenous high-dose vitamin C just prior to arrival. Ascorbic acid is a strong reducing agent and can cause erroneous false positive portable glucometer readings. Accordingly, it is likely the patient was euglycemic on arrival and was administered FDG during a period of insulin-induced hypoglycemia. Prominent diffuse white adipose tissue, gastric mucosal, myocardial, and very low hepatic and muscle activity were observed. The case provides insight into the metabolic changes that occur during hypoglycemia and the potential danger of relying on portable glucometer readings. We discuss the potential biological basis of this finding and provide recommendations on the avoidance of this complication. PMID- 22214515 TI - How slowing senescence translates into longer life expectancy. AB - Mortality decline has historically been largely a result of reductions in the level of mortality at all ages. A number of leading researchers on ageing, however, suggest that the next revolution of longevity increase will be the result of slowing down the rate of ageing. In this paper, we show mathematically how varying the pace of senescence influences life expectancy. We provide a formula that holds for any baseline hazard function. Our result is analogous to Keyfitz's 'entropy' relationship for changing the level of mortality. Interestingly, the influence of the shape of the baseline schedule on the effect of senescence changes is the complement of that found for level changes. We also provide a generalized formulation that mixes level and slope effects. We illustrate the applicability of these models using recent mortality decline in Japan and the problem of period to cohort translation. PMID- 22214516 TI - Endothelial-monocyte activating polypeptide II disrupts alveolar epithelial type II to type I cell transdifferentiation. AB - BACKGROUND: Distal alveolar morphogenesis is marked by differentiation of alveolar type (AT)-II to AT-I cells that give rise to the primary site of gas exchange, the alveolar/vascular interface. Endothelial-Monocyte Activating Polypeptide (EMAP) II, an endogenous protein with anti-angiogenic properties, profoundly disrupts distal lung neovascularization and alveolar formation during lung morphogenesis, and is robustly expressed in the dysplastic alveolar regions of infants with Bronchopulmonary dysplasia. Determination as to whether EMAP II has a direct or indirect affect on ATII -> ATI trans-differentiation has not been explored. METHOD: In a controlled nonvascular environment, an in vitro model of ATII -> ATI cell trans-differentiation was utilized to demonstrate the contribution that one vascular mediator has on distal epithelial cell differentiation. RESULTS: Here, we show that EMAP II significantly blocked ATII > ATI cell transdifferentiation by increasing cellular apoptosis and inhibiting expression of ATI markers. Moreover, EMAP II-treated ATII cells displayed myofibroblast characteristics, including elevated cellular proliferation, increased actin cytoskeleton stress fibers and Rho-GTPase activity, and increased nuclear:cytoplasmic volume. However, EMAP II-treated cells did not express the myofibroblast markers desmin or alphaSMA. CONCLUSION: Our findings demonstrate that EMAP II interferes with ATII -> ATI transdifferentiation resulting in a proliferating non-myofibroblast cell. These data identify the transdifferentiating alveolar cell as a possible target for EMAP II's induction of alveolar dysplasia. PMID- 22214517 TI - Dental implants: early versus standard two-stage loading (animal study). AB - Direct bone formation on the implant surface is a treatment goal in implant dentistry. It was always thought that a healing period of 3 months for the lower jaw and 5-6 months for the upper jaw was required for osseointegration to occur. Recent studies, however, show that with the early loading protocol, osseointegration is possible as well. The goal of this study was to evaluate clinical, histologic, and histomorphometric parameters of implants with early loading protocols and implants that did not undergo the early loading protocol. In this experimental study, the first to the fourth premolar teeth were extracted from the lower jaws of 3 dogs. After a healing period of 3 months, 12 BioHorizons internal implants 4.5 * 10.5 mm were placed in the mandible of the dogs. The implant stability quotient (ISQ) was recorded. After 3 weeks, half of the implants were exposed, and after recording ISQ, polycarbonate crowns were placed on them and occlusion was adjusted so that there was no contact in centric occlusion and no lateral movement with the opposing teeth. After 3 months, the ISQs were recorded for all the implants. Bleeding upon probing and pocket depths were measured for the early loading implants. All the implants were removed using a trephine bur, and cross-sections of 150 MUm were prepared, from which the bone implant contact (BIC) and the type of bone around them were obtained. Statistical analysis was conducted with independent t test, paired t test, and repeated analysis of variance. The BIC for the early loaded group was 46.17% +/- 12.89%, and for the unloaded group was 44.4% +/- 10.45%. This difference was not statistically significant (P = .811). The ISQ for the implants in the early loaded group (before they were removed) was 71 +/- 7.35 and that of the unloaded group was 66.75 +/- 11.86 .These differences were statistically insignificant. With regard to the result of this study, and the fact that the 2 groups showed no statistically significant differences in a number of major aspects, such as BIC and ISQ, it seems possible to load implants with an earlier than usual protocol with no adverse effects on implant success. It is necessary, however, to follow certain protocols for this type of loading. PMID- 22214518 TI - Factors influencing injury severity score regarding Thai military personnel injured in mass casualty incident April 10, 2010: lessons learned from armed conflict casualties: a retrospective study. AB - BACKGROUND: Political conflicts in Bangkok, Thailand have caused mass casualties, especially the latest event April 10, 2010, in which many military personnel were injured. Most of them were transferred to Phramongkutklao Hospital, the largest military hospital in Thailand. The current study aimed to assess factors influencing Injury Severity Score (ISS) regarding Thai military personnel injured in the mass casualty incident (MCI) April 10, 2010. METHODS: A total of 728 injured soldiers transferred to Phramongkutklao Hospital were reviewed. Descriptive statistics was used to display characteristics of the injuries, relationship between mechanism of injury and injured body regions. Multiple logistic regressions were used to calculate the adjusted odds ratio (adjusted OR) of ISS comparing injured body region categories. RESULTS: In all, 153 subjects defined as major data category were enrolled in this study. Blast injury was the most common mechanism of injury (90.2%). These victims displayed 276 injured body regions. The most common injured body region was the extremities (48.5%). A total of 18 patients (11.7%) had an ISS revealing more than 16 points. Three victims who died were expected to die due to high Trauma and Injury Severity Score (TRISS). However, one with high TRISS survived. Factors influencing ISS were age (p = 0.04), abdomen injury (adjusted OR = 29.9; 95% CI, 5.8-153.5; P < 0.01), head & neck injury (adjusted OR = 13.8; 95% CI, 2.4-80.4; P < 0.01) and chest injury (adjusted OR = 9.9; 95% CI, 2.1-47.3; P < 0.01). CONCLUSIONS: Blast injury was the most common mechanism of injury among Thai military personnel injured in the MCI April 10, 2010. Age and injured body region such as head & neck, chest and abdomen significantly influenced ISS. These factors should be investigated for effective medical treatment and preparing protective equipment to prevent such injuries in the future. PMID- 22214519 TI - Efficient in vitro encapsulation of protein cargo by an engineered protein container. AB - An engineered variant of lumazine synthase, a nonviral capsid protein with a negatively charged luminal surface, is shown to encapsulate up to 100 positively supercharged green fluorescent protein (GFP) molecules in vitro. Packaging can be achieved starting either from intact, empty capsids or from capsid fragments by incubation with cargo in aqueous buffer. The yield of encapsulated GFP correlates directly with the host/guest mixing ratio, providing excellent control over packing density. Facile in vitro loading highlights the unusual structural dynamics of this novel nanocontainer and should facilitate diverse biotechnological and materials science applications. PMID- 22214520 TI - Radical/pi-bond addition between o-benzyne and cyclic C5 hydrocarbons. AB - Recent theoretical investigations of the radical/pi-bond addition between single ring aromatic hydrocarbons highlight the importance of this category of reactions for the formation of PAH intermediates and soot. The present investigation extends the theory of the radical/pi-bond addition reactions to the o-benzyne + cyclic C(5) hydrocarbons systems. The calculations, performed using the uB3LYP/6 311+G(d,p) method, have addressed the possible role of the reaction between o benzyne and cyclopentadiene in the formation of indene through the fragmentation of the bicyclo intermediate benzonorbornadiene. The complex potential energy surface for the reaction between o-benzyne and cyclopentadienyl radical was also investigated. In this case, the formation of the bicyclo benzonorbornadienyl radical and its subsequent fragmentation to indenyl radical and acetylene is not the main reaction pathway, although it could be relevant at relatively high temperatures. At lower temperatures, the isomerization reactions, which lead to the formation of a variety of multiring compounds, are dominant. PMID- 22214521 TI - Clinicopathologic and immunohistochemical features of oral neurofibroma. AB - OBJECTIVE: The purposes of this study were to assess clinical, histopathological and immunohistochemical features of 22 oral neurofibromas (NFs) and discuss with previously described literature, addressing the main aspects regarding the differential diagnosis. MATERIALS AND METHODS: Immunohistochemical reactions included S-100, CD34, GLUT-1, EMA, Ki-67, p53 and Collagen IV and histochemical reactions for Alcian blue. RESULTS: Clinically, the preferential location was the maxillary bones, tongue and buccal mucosa. Microscopically, widely spread spindle shaped cells with scant cytoplasm and elongated nuclei were observed. Immunostaining revealed that the tumor cells weakly expressed GLUT-1, Collagen IV, Ki-67 and p53. They were variably positive for CD34, S-100 protein and membrane epithelial antigen (EMA). CONCLUSIONS: The different types of nerve sheath cells observed in the present series reinforce the presence of heterogeneous population in NFs. The strong positivity for S-100 suggests that the lesions were more composed by S-100-positive Schwann cells than other cells. Besides, the high number of CD34-positive cells suggests that this marker can be useful for the differential diagnosis of NFs against PEN, traumatic neuromas and Schwannomas. Finally, the low immunostaining for p53 and Ki-67 may indicate that NFs massively composed by S-100-positive Schwann cells present low potential of aggressiveness and malignant transformation. PMID- 22214522 TI - Method development for the control determination of mercury in seafood by solid sampling thermal decomposition amalgamation atomic absorption spectrometry (TDA AAS). AB - A very simple and rapid method for the determination of total mercury in fish samples using the Direct Mercury Analyser DMA-80 was developed. In this system, a previously weighted portion of fresh fish is combusted and the released mercury is selectively trapped in a gold amalgamator. Upon heating, mercury is desorbed from the amalgamator, an atomic absorption measurement is performed and the mercury concentration is calculated. Some experimental parameters have been studied and optimised. In this study the sample mass was about 100.0 mg. The relative standard deviation was lower than 8.0% for all measurements of solid samples. Two calibration curves against aqueous standard solutions were prepared through the low linear range from 2.5 to 20.0 ng of Hg, and the high linear range from 25.0 to 200.0 ng of Hg, for which a correlation coefficient better than 0.997 was achieved, as well as a normal distribution of the residuals. Mercury reference solutions were prepared in 5.0% v/v nitric acid medium. Lyophilised fish tissues were also analysed; however, the additional procedure had no advantage over the direct analysis of the fresh fish, and additionally increased the total analytical process time. A fish tissue reference material, IAEA-407, was analysed and the mercury concentration was in agreement with the certified value, according to the t-test at a 95% confidence level. The limit of quantification (LOQ), based on a mercury-free sample, was 3.0 ug kg(-1). This LOQ is in accordance with performance criteria required by the Commission Regulation No. 333/2007. Simplicity and high efficiency, without the need for any sample preparation procedure, are some of the qualities of the proposed method. PMID- 22214523 TI - Rapalogs in viral cancers. AB - At present, 150 clinical trials are registered with the National Cancer Institute, which investigate the efficacy of inhibitors of the PI3K/Akt/mTOR pathway against multiple cancers. Efficacy varies not so much with drug action, but with tumor type, as different cancer types (and different pre-clinical models) exhibit widely differing susceptibilities to mTOR inhibitors, such as rapamycin. Viral cancers appear to be among the most mTOR-addicted and most rapamycin-sensitive cancers. We discuss the different mTOR inhibitors that are currently available and in clinical trials. We also speculate how the molecular makeup of viral cancers could guide the selection and use of known and novel mTOR inhibitors to treat virus-associated malignancies. PMID- 22214524 TI - Nontoxic and abundant copper zinc tin sulfide nanocrystals for potential high temperature thermoelectric energy harvesting. AB - Improving energy/fuel efficiency by converting waste heat into electricity using thermoelectric materials is of great interest due to its simplicity and reliability. However, many thermoelectric materials are composed of either toxic or scarce elements. Here, we report the experimental realization of using nontoxic and abundant copper zinc tin sulfide (CZTS) nanocrystals for potential thermoelectric applications. The CZTS nanocrystals can be synthesized in large quantities from solution phase reaction and compressed into robust bulk pellets through spark plasma sintering and hot press while still maintaining nanoscale grain size inside. Electrical and thermal measurements have been performed from 300 to 700 K to understand the electron and phonon transports. Extra copper doping during the nanocrystal synthesis introduces a significant improvement in the performance. PMID- 22214526 TI - Graphene-multilayer graphene nanocomposites as highly efficient thermal interface materials. AB - We found that the optimized mixture of graphene and multilayer graphene, produced by the high-yield inexpensive liquid-phase-exfoliation technique, can lead to an extremely strong enhancement of the cross-plane thermal conductivity K of the composite. The "laser flash" measurements revealed a record-high enhancement of K by 2300% in the graphene-based polymer at the filler loading fraction f = 10 vol %. It was determined that the relatively high concentration of the single-layer and bilayer graphene flakes (~10-15%) present simultaneously with the thicker multilayers of large lateral size (~1 MUm) were essential for the observed unusual K enhancement. The thermal conductivity of the commercial thermal grease was increased from an initial value of ~5.8 W/mK to K = 14 W/mK at the small loading f = 2%, which preserved all mechanical properties of the hybrid. Our modeling results suggest that graphene-multilayer graphene nanocomposite used as the thermal interface material outperforms those with carbon nanotubes or metal nanoparticles owing to graphene's aspect ratio and lower Kapitza resistance at the graphene-matrix interface. PMID- 22214525 TI - Detailed interrogation of trypanosome cell biology via differential organelle staining and automated image analysis. AB - BACKGROUND: Many trypanosomatid protozoa are important human or animal pathogens. The well defined morphology and precisely choreographed division of trypanosomatid cells makes morphological analysis a powerful tool for analyzing the effect of mutations, chemical insults and changes between lifecycle stages. High-throughput image analysis of micrographs has the potential to accelerate collection of quantitative morphological data. Trypanosomatid cells have two large DNA-containing organelles, the kinetoplast (mitochondrial DNA) and nucleus, which provide useful markers for morphometric analysis; however they need to be accurately identified and often lie in close proximity. This presents a technical challenge. Accurate identification and quantitation of the DNA content of these organelles is a central requirement of any automated analysis method. RESULTS: We have developed a technique based on double staining of the DNA with a minor groove binding (4'', 6-diamidino-2-phenylindole (DAPI)) and a base pair intercalating (propidium iodide (PI) or SYBR green) fluorescent stain and color deconvolution. This allows the identification of kinetoplast and nuclear DNA in the micrograph based on whether the organelle has DNA with a more A-T or G-C rich composition. Following unambiguous identification of the kinetoplasts and nuclei the resulting images are amenable to quantitative automated analysis of kinetoplast and nucleus number and DNA content. On this foundation we have developed a demonstrative analysis tool capable of measuring kinetoplast and nucleus DNA content, size and position and cell body shape, length and width automatically. CONCLUSIONS: Our approach to DNA staining and automated quantitative analysis of trypanosomatid morphology accelerated analysis of trypanosomatid protozoa. We have validated this approach using Leishmania mexicana, Crithidia fasciculata and wild-type and mutant Trypanosoma brucei. Automated analysis of T. brucei morphology was of comparable quality to manual analysis while being faster and less susceptible to experimentalist bias. The complete data set from each cell and all analysis parameters used can be recorded ensuring repeatability and allowing complete data archiving and reanalysis. PMID- 22214527 TI - A new time-series methodology for estimating relationships between elderly frailty, remaining life expectancy, and ambient air quality. AB - BACKGROUND: Many publications estimate short-term air pollution-mortality risks, but few estimate the associated changes in life-expectancies. OBJECTIVE AND METHODS: We present a new methodology for analyzing time series of health effects, in which prior frailty is assumed to precede short-term elderly nontraumatic mortality. The model is based on a subpopulation of frail individuals whose entries and exits (deaths) are functions of daily and lagged environmental conditions: ambient temperature/season, airborne particles, and ozone. This frail susceptible population is unknown; its fluctuations cannot be observed but are estimated using maximum-likelihood methods with the Kalman filter. We used an existing 14-y set of daily data to illustrate the model and then tested the assumption of prior frailty with a new generalized model that estimates the portion of the daily death count allocated to nonfrail individuals. RESULTS: In this demonstration dataset, new entries into the high-risk pool are associated with lower ambient temperatures and higher concentrations of particulate matter and ozone. Accounting for these effects on antecedent frailty reduces this at-risk population, yielding frail life expectancies of 5-7 days. Associations between environmental factors and entries to the at-risk pool are about twice as strong as for mortality. Nonfrail elderly deaths are seen to make only small contributions. CONCLUSIONS: This new model predicts a small short lived frail population-at-risk that is stable over a wide range of environmental conditions. The predicted effects of pollution on new entries and deaths are robust and consistent with conventional morbidity/mortality times-series studies. We recommend model verification using other suitable datasets. PMID- 22214528 TI - Imaging the effect of receptor for advanced glycation endproducts on angiogenic response to hindlimb ischemia in diabetes. AB - BACKGROUND: Receptor for advanced glycation endproducts (RAGE) expression contributes to the impaired angiogenic response to limb ischemia in diabetes. The aim of this study was to detect the effect of increased expression of RAGE on the angiogenic response to limb ischemia in diabetes by targeting alphavbeta3 integrin with 99mTc-labeled Arg-Gly-Asp (RGD). METHODS: Male wild-type (WT) C57BL/6 mice were either made diabetic or left as control for 2 months when they underwent femoral artery ligation. Four groups were studied at days 3 to 7 after ligation: WT without diabetes (NDM) (n = 14), WT with diabetes (DM) (n = 14), RAGE-/- NDM (n = 16), and RAGE-/- DM (n = 14). Mice were injected with 99mTc HYNIC-RGD and imaged. Count ratios for ischemic/non-ischemic limbs were measured. Muscle was stained for RAGE, alphavbeta3, and lectins. RESULTS: There was no difference in count ratio between RAGE-/- and WT NDM groups. Mean count ratio was lower for WT DM (1.38 +/- 0.26) vs. WT NDM (1.91 +/- 0.34) (P<0.001). Mean count ratio was lower for the RAGE-/- DM group than for RAGE-/- NDM group (1.75 +/- 0.22 vs. 2.02 +/- 0.29) (P<0.001) and higher than for the WT DM group (P<0.001). Immunohistopathology supported the scan findings. CONCLUSIONS: In vivo imaging of alphavbeta3 integrin can detect the effect of RAGE on the angiogenic response to limb ischemia in diabetes. PMID- 22214529 TI - Changing memory of food enjoyment to increase food liking, choice and intake. AB - Novel ways to increase liking and intake of food are needed to encourage acceptance of healthier food. How enjoyable we remember food to have been is likely to be a significant predictor of food choice. Two studies examined whether remembered enjoyment of eating a food can be increased and whether this makes individuals more likely to eat that food in the future. In Study One, a simple manipulation of instructing participants to rehearse what they found enjoyable about a food immediately after eating it was used to increase remembered enjoyment (relative to controls). In a separate study; Study Two, the effect of increasing remembered enjoyment on food choice was tested by examining whether the manipulation to increase remembered enjoyment resulted in participants choosing to eat more of a food as part of a later buffet lunch. The experimental manipulation increased remembered enjoyment for the food (Study One). A change in remembered enjoyment was shown to have a significant effect on the amount of a food participants chose to eat the following day for lunch (Study Two). The present studies suggest that remembered enjoyment can be increased via a simple act of rehearsal, resulting in a later increase in the amount of food chosen and eaten. Interventions based on altering remembered enjoyment of healthy food choices warrant further investigation. PMID- 22214530 TI - Development of a novel 96-microwell assay with high throughput for determination of olmesartan medoxomil in its tablets. AB - A novel 96-microwell-based spectrophotometric assay has been developed and validated for determination of olmesartan medoxomil (OLM) in tablets. The formation of a colored charge-transfer (CT) complex between OLM as a n-electron donor and 2, 5-dichloro-3, 6-dihydroxy-1, 4-benzoquinone (p-chloranilic acid, pCA) as a pi-electron acceptor was investigated, for the first time, and employed as a basis in the development of the proposed assay. The proposed assay was carried out in 96-microwell plates. The absorbance of the colored-CT complex was measured at 490 nm by microwell-plate absorbance reader. The optimum conditions of the reaction and the analytical procedures of the assay were established. Under the optimum conditions, linear relationship with good correlation coefficient was found between the absorbance and the concentration of OLM in the range of 1-200 MUg ml-1. The limits of detection and quantitation were 0.3 and 1 MUg ml-1, respectively. No interference was observed from the additives that are present in the pharmaceutical formulation or from hydrochlorothiazide and amlodipine that are co-formulated with OLM in some formulations. The assay was successfully applied to the analysis of OLM in tablets with good accuracy and precision. The assay described herein has great practical value in the routine analysis of OLM in quality control laboratories, as it has high throughput property, consumes minimum volume of organic solvent thus it offers the reduction in the exposures of the analysts to the toxic effects of organic solvents, and reduction in the analysis cost by 50-fold. Although the proposed assay was validated for OLM, however, the same methodology could be used for any electron donating analyte for which a CT reaction can be performed. PMID- 22214531 TI - Direct measurements of lateral variations of Schottky barrier height across "end on" metal contacts to vertical Si nanowires by ballistic electron emission microscopy. AB - Ballistic electron emission microscopy measurements on individual "end-on" Au Schottky contacts to vertical Si nanowires (NWs) indicate that the local Schottky barrier height at the contact edge is 23 +/- 3 meV lower than at the contact center. Finite-element electrostatic simulations suggest that this is due to a larger interface electric field at the contact edge resulting from (equilibrium) positive charge in Si/SiO(2) interface states near the Au/NW contact, induced by local band bending due to the high work function Au film. PMID- 22214532 TI - Short communication: analysis of the integrase gene from HIV type 1-positive patients living in a rural area of West Cameroon. AB - Major mutations associated with HIV-I integrase inhibitors (INI) resistance are rare in INI-naive patients. However, polymorphisms at positions that may influence the genetic barrier and/or drive the selection of specific INI resistance pathways are common in HIV non-B subtypes. The aim was to evaluate the presence of natural polymorphisms and/or INI resistance mutations in HIV-1 non-B subtype samples obtained from INI-naive patients living in rural west Cameroon. Thirty-three HIV-1 non-B samples were obtained from INI-naive African women and, as controls, 15 samples of HIV-1 subtype B were obtained from antiretroviral naive Italian patients. The integrase gene was amplified and sequenced using Trugene Core Reagents. Several amino acid positions in B and non-B subtypes were found to be polymorphic. Interestingly, two patients infected with the CRF02_AG subtype had the resistance mutations N155H and E157Q/E and 12% of African samples had an amino acid substitution at position 143. Silent mutations leading to a higher increment of genetic barriers were detected at 140 and 151 positions in non B-subtypes. Although most polymorphisms may have little effect on INI susceptibility, the IN gene variations found in the present study should be taken into consideration as they may facilitate or delay the emergence of variants fully resistant to INIs. PMID- 22214533 TI - Glycotechnology for decontamination of biological agents: a model study using ricin and biotin-tagged synthetic glycopolymers. AB - Two types of biotin-tagged glycopolymers carrying lactose or glucose in clusters along the polyacrylamide backbone were prepared and subjected to decontamination analyses with the plant toxin ricin. A buffer solution containing the toxin was treated with one glycopolymer followed by streptavidin-magnetic particles. Supernatant solutions were analyzed with surface plasmon resonance and capillary electrophoresis, and revealed that the lactose glycopolymer "captured" this toxin more effectively than the glucose polymer. Free toxin was not detectable in the supernatant after treatment with the glycopolymer and magnetic particles; >99% decontamination was achieved for this potentially fatal biological toxin. PMID- 22214534 TI - Syndecan-1 antigen, a promising new target for triple-negative breast cancer immuno-PET and radioimmunotherapy. A preclinical study on MDA-MB-468 xenograft tumors. AB - BACKGROUND: Overexpression of syndecan-1 (CD138) in breast carcinoma correlates with a poor prognosis and an aggressive phenotype. The objective of this study was to evaluate the potential of targeting CD138 by immuno-PET imaging and radioimmunotherapy (RIT) using the antihuman syndecan-1 B-B4 mAb radiolabeled with either 124I or 131I in nude mice engrafted with the triple-negative MDA-MB 468 breast cancer cell line. METHOD: The immunoreactivity of 125I-B-B4 (80%) was determined, and the affinity of 125I-B-B4 and the expression of CD138 on MDA-MB 468 was measured in vitro by Scatchard analysis. CD138 expression on established tumors was confirmed by immunohistochemistry. A biodistribution study was performed in mice with subcutaneous MDA-MB-468 and 125I-B-B4 at 4, 24, 48, 72, and 96 h after injection and compared with an isotype-matched control. Tumor uptake of B-B4 was evaluated in vivo by immuno-PET imaging using the 124I-B-B4 mAb. The maximum tolerated dose (MTD) was determined from mice treated with 131I B-B4 and the RIT efficacy evaluated. RESULTS: 125I-B-B4 affinity was in the nanomolar range (Kd = 4.39 +/- 1.10 nM). CD138 expression on MDA-MB-468 cells was quite low (Bmax = 1.19 * 104 +/- 9.27 * 102 epitopes/cell) but all expressed CD138 in vivo as determined by immunohistochemistry. The tumor uptake of 125I-B B4 peaked at 14% injected dose (ID) per gram at 24 h and was higher than that of the isotype-matched control mAb (5% ID per gram at 24 h). Immuno-PET performed with 124I-B-B4 on tumor-bearing mice confirmed the specificity of B-B4 uptake and its retention within the tumor. The MTD was reached at 22.2 MBq. All mice treated with RIT (n = 8) as a single treatment at the MTD experienced a partial (n = 3) or complete (n = 5) response, with three of them remaining tumor-free 95 days after treatment. CONCLUSION: These results demonstrate that RIT with 131I-B-B4 could be considered for the treatment of metastatic triple-negative breast cancer that cannot benefit from hormone therapy or anti-Her2/neu immunotherapy. Immuno PET for visualizing CD138-expressing tumors with 124I-B-B4 reinforces the interest of this mAb for diagnosis and quantitative imaging. PMID- 22214535 TI - Imaging technologies for preclinical models of bone and joint disorders. AB - Preclinical models for musculoskeletal disorders are critical for understanding the pathogenesis of bone and joint disorders in humans and the development of effective therapies. The assessment of these models primarily relies on morphological analysis which remains time consuming and costly, requiring large numbers of animals to be tested through different stages of the disease. The implementation of preclinical imaging represents a keystone in the refinement of animal models allowing longitudinal studies and enabling a powerful, non-invasive and clinically translatable way for monitoring disease progression in real time. Our aim is to highlight examples that demonstrate the advantages and limitations of different imaging modalities including magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), single-photon emission computed tomography (SPECT) and optical imaging. All of which are in current use in preclinical skeletal research. MRI can provide high resolution of soft tissue structures, but imaging requires comparatively long acquisition times; hence, animals require long-term anaesthesia. CT is extensively used in bone and joint disorders providing excellent spatial resolution and good contrast for bone imaging. Despite its excellent structural assessment of mineralized structures, CT does not provide in vivo functional information of ongoing biological processes. Nuclear medicine is a very promising tool for investigating functional and molecular processes in vivo with new tracers becoming available as biomarkers. The combined use of imaging modalities also holds significant potential for the assessment of disease pathogenesis in animal models of musculoskeletal disorders, minimising the use of conventional invasive methods and animal redundancy. PMID- 22214536 TI - Ent-7alpha-acetoxytrachyloban-18-oic acid and ent-7alpha-hydroxytrachyloban-18 oic acid from Xylopia langsdorfiana A. St-Hil. & Tul. modulate K(+) and Ca(2+) channels to reduce cytosolic calcium concentration on guinea pig ileum. AB - In this study we investigated the mechanism underlying the spasmolytic action of ent-7alpha-acetoxytrachyloban-18-oic acid (trachylobane-360) and ent-7alpha hydroxytrachyloban-18-oic acid (trachylobane-318), diterpenes obtained from Xylopia langsdorfiana, on guinea pig ileum. Both compounds inhibited histamine induced cumulative contractions (slope=3.5+/-0.9 and 4.4+/-0.7) that suggests a noncompetitive antagonism to histaminergic receptors. CaCl(2)-induced contractions were nonparallelly and concentration-dependently reduced by both diterpenes, indicating blockade of calcium influx through voltage-dependent calcium channels (Ca(v)). The Ca(v) participation was confirmed since both trachylobanes equipotently relaxed ileum pre-contracted with S-(-)-Bay K8644 (EC(50)=3.5+/-0.7*10-(5) and 1.1+/-0.2*10-(5)M) and KCl (EC(50)=5.5+/-0.3*10-(5) and 1.4+/-0.2*10-(5)M). K(+) channels participation was confirmed since diterpene induced relaxation curves were significantly shifted to right in the presence of 5mM tetraethylammonium (TEA(+)) (EC(50)=0.5+/-0.04*10-(4) and 2.0+/-0.5*10-(5)M). ATP-sensitive K(+) channel (K(ATP)), voltage activated K(+) channels (K(V)), small conductance calcium-activated K(+) channels (SK(Ca)) or big conductance calcium-activated K(+) channels (BK(Ca)) did not seem to participate of trachylobane-360 spasmolytic action. However trachylobane-318 modulated positively K(ATP), K(V) and SK(Ca) (EC(50)=1.1+/-0.3*10-(5), 0.7+/-0.2*10-(5) and 0.7+/-0.2*10-(5)M), but not BK(Ca). A fluorescence analysis technique confirmed the decrease of cytosolic calcium concentration ([Ca(2+)](c)) induced by both trachylobanes in ileal myocytes. In conclusion, trachylobane-360 and trachylobane 318 induced spasmolytic activity by K(+) channel positive modulation and Ca(2+) channel blockade, which results in [Ca(2+)](c) reduction at cellular level leading to smooth muscle relaxation. PMID- 22214538 TI - Reducing the energy penalty costs of postcombustion CCS systems with amine storage. AB - Carbon capture and storage (CCS) can significantly reduce the amount of CO(2) emitted from coal-fired power plants but its operation significantly reduces the plant's net electrical output and decreases profits, especially during times of high electricity prices. An amine-based CCS system can be modified adding amine storage to allow postponing 92% of all its energy consumption to times of lower electricity prices, and in this way has the potential to effectively reduce the cost of CO(2) capture by reducing the costs of the forgone electricity sales. However adding amine-storage to a CCS system implies a significant capital cost that will be outweighed by the price-arbitrage revenue only if the difference between low and high electricity prices is substantial. In this paper we find a threshold for the variability in electricity prices that make the benefits from electricity price arbitrage outweigh the capital costs of amine-storage. We then look at wholesale electricity markets in the Eastern Interconnect of the United States to determine profitability of amine-storage systems in this region. Using hourly electricity price data from years 2007 and 2008 we find that amine storage may be cost-effective in areas with high price variability. PMID- 22214537 TI - Endocannabinoid signaling, glucocorticoid-mediated negative feedback, and regulation of the hypothalamic-pituitary-adrenal axis. AB - The hypothalamic-pituitary-adrenal (HPA) axis regulates the outflow of glucocorticoid hormones under basal conditions and in response to stress. Within the last decade, a large body of evidence has mounted indicating that the endocannabinoid system is involved in the central regulation of the stress response; however, the specific role endocannabinoid signaling plays in phases of HPA axis regulation, and the neural sites of action mediating this regulation, were not mapped out until recently. This review aims to collapse the current state of knowledge regarding the role of the endocannabinoid system in the regulation of the HPA axis to put together a working model of how and where endocannabinoids act within the brain to regulate outflow of the HPA axis. Specifically, we discuss the role of the endocannabinoid system in the regulation of the HPA axis under basal conditions, activation in response to acute stress, and glucocorticoid-mediated negative feedback. Interestingly, there appears to be some anatomical specificity to the role of the endocannabinoid system in each phase of HPA axis regulation, as well as distinct roles of both anandamide and 2 arachidonoylglycerol in these phases. Overall, the current level of information indicates that endocannabinoid signaling acts to suppress HPA axis activity through concerted actions within the prefrontal cortex, amygdala, and hypothalamus. PMID- 22214539 TI - Karyotyping of human chondrocytes in scaffold-assisted cartilage tissue engineering. AB - Scaffold-assisted autologous chondrocyte implantation (ACI) is an effective clinical procedure for cartilage repair. The aim of our study was to evaluate the chromosomal stability of human chondrocytes subjected to typical cell culture procedures needed for regenerative approaches in polymer-scaffold-assisted cartilage repair. Chondrocytes derived from post mortem donors and from donors scheduled for ACI were expanded, cryopreserved and re-arranged in polyglycolic acid (PGA)-fibrin scaffolds for tissue culture. Chondrocyte redifferentiation was analyzed by electron microscopy, histology and gene expression analysis. Karyotyping was performed using GTG banding and fluorescence in situ hybridization on a single cell basis. Chondrocytes showed de- and redifferentiation accompanied by the formation of extracellular matrix and induction of typical chondrocyte marker genes like type II collagen in PGA-fibrin scaffolds. Post mortem chondrocytes showed up to 1.7% structural and high numbers of numerical (up to 26.7%) chromosomal aberrations, while chondrocytes from living donors scheduled for ACI showed up to 1.8% structural and up to 1.3% numerical alterations. Cytogenetically, cell culture procedures and PGA-fibrin scaffolds did not significantly alter chromosomal integrity of the chondrocyte genome. Human chondrocytes derived from living donors subjected to regenerative medicine cell culture procedures like cell expansion, cryopreservation and culture in resorbable polymer-based scaffolds show normal chromosomal integrity and normal karyotypes. PMID- 22214540 TI - Autoinhibition mechanism of the plasma membrane calcium pump isoforms 2 and 4 studied through lipid-protein interaction. AB - The autoinhibition/activation of the PMCA (plasma membrane Ca2+-ATPase) involves conformational changes in the membrane region of the protein that affect the amount of lipids directly associated with the transmembrane domain. The lipid protein-dependence of PMCA isoforms 2 and 4 expressed and obtained in purified form from Saccharomyces cerevisiae was investigated using the phosphatidylcholine analogue [125I]TID-PC/16 {l-O-hexadecanoyl-2-O-[9-[[[2-[125I]iodo-4 (trifluoromemyl-3H-diazirin-3-yl)benzyl]oxy]carbonyl]nonanoyl]-sn-glycero-3 phosphocholine}, which was incorporated into mixtures of dimyristoylphosphatidylcholine and the non-ionic detergent C12E10 [deca(ethylene glycol) dodecyl ether]. We found no differences between the recombinant PMCA4 and PMCA purified from erythrocytes (ePMCA). However, titration of the half-maximal activation by Ca2+/calmodulin of PMCA2 showed 30-fold higher affinity than PMCA4. PMCA2 exhibited a lower level of labelling in the autoinhibited conformation relative to PMCA4, indicating that the lower autoinhibition was correlated with a lower exposure to lipids in the autoinhibited state. Analysis of the lipid protein stoichiometry showed that the lipid annulus of PMCA varies: (i) in accordance to the conformational state of the enzyme; and (ii) depending on the different isoforms of PMCA. PMCA2 during Ca2+ transport changes its conformation to a lesser extent than PMCA4, an isoform more sensitive to modulation by calmodulin and acidic phospholipids. This is the first demonstration of a dynamic behaviour of annular lipids and PMCA. PMID- 22214541 TI - GuiTope: an application for mapping random-sequence peptides to protein sequences. AB - BACKGROUND: Random-sequence peptide libraries are a commonly used tool to identify novel ligands for binding antibodies, other proteins, and small molecules. It is often of interest to compare the selected peptide sequences to the natural protein binding partners to infer the exact binding site or the importance of particular residues. The ability to search a set of sequences for similarity to a set of peptides may sometimes enable the prediction of an antibody epitope or a novel binding partner. We have developed a software application designed specifically for this task. RESULTS: GuiTope provides a graphical user interface for aligning peptide sequences to protein sequences. All alignment parameters are accessible to the user including the ability to specify the amino acid frequency in the peptide library; these frequencies often differ significantly from those assumed by popular alignment programs. It also includes a novel feature to align di-peptide inversions, which we have found improves the accuracy of antibody epitope prediction from peptide microarray data and shows utility in analyzing phage display datasets. Finally, GuiTope can randomly select peptides from a given library to estimate a null distribution of scores and calculate statistical significance. CONCLUSIONS: GuiTope provides a convenient method for comparing selected peptide sequences to protein sequences, including flexible alignment parameters, novel alignment features, ability to search a database, and statistical significance of results. The software is available as an executable (for PC) at http://www.immunosignature.com/software and ongoing updates and source code will be available at sourceforge.net. PMID- 22214542 TI - Analysis of human immune responses in quasi-experimental settings: tutorial in biostatistics. AB - BACKGROUND: Human immunology is a growing field of research in which experimental, clinical, and analytical methods of many life science disciplines are utilized. Classic epidemiological study designs, including observational longitudinal birth cohort studies, offer strong potential for gaining new knowledge and insights into immune response to pathogens in humans. However, rigorous discussion of methodological issues related to designs and statistical analysis that are appropriate for longitudinal studies is lacking. METHODS: In this communication we address key questions of quality and validity of traditional and recently developed statistical tools applied to measures of immune responses. For this purpose we use data on humoral immune response (IR) associated with the first cryptosporidial diarrhea in a birth cohort of children residing in an urban slum in south India. The main objective is to detect the difference and derive inferences for a change in IR measured at two time points, before (pre) and after (post) an event of interest. We illustrate the use and interpretation of analytical and data visualization techniques including generalized linear and additive models, data-driven smoothing, and combinations of box-, scatter-, and needle-plots. RESULTS: We provide step-by-step instructions for conducting a thorough and relatively simple analytical investigation, describe the challenges and pitfalls, and offer practical solutions for comprehensive examination of data. We illustrate how the assumption of time irrelevance can be handled in a study with a pre-post design. We demonstrate how one can study the dynamics of IR in humans by considering the timing of response following an event of interest and seasonal fluctuation of exposure by proper alignment of time of measurements. This alignment of calendar time of measurements and a child's age at the event of interest allows us to explore interactions between IR, seasonal exposures and age at first infection. CONCLUSIONS: The use of traditional statistical techniques to analyze immunological data derived from observational human studies can result in loss of important information. Detailed analysis using well-tailored techniques allows the depiction of new features of immune response to a pathogen in longitudinal studies in humans. The proposed staged approach has prominent implications for future study designs and analyses. PMID- 22214544 TI - Improving AFM images with harmonic interference by spectral analysis. AB - Atomic force microscopy (AFM) is one of the most sensitive tools for nanoscale imaging. As such, it is very sensitive to external noise sources that can affect the quality of collected data. The intensity of the disturbance depends on the noise source and the mode of operation. In some cases, the internal noise from commercial AFM controllers can be significant and difficult to remove. Thus, a new method based on spectrum analysis of the scanned images is proposed to reduce harmonic disturbances. The proposal is a post-processing method and can be applied at any time after measurements. This article includes a few methods of harmonic cancellation (e.g., median filtering, wavelet denoising, Savitzky-Golay smoothing) and compares their effectiveness. The proposed method, based on Fourier transform of the scanned images, was more productive than the other methods mentioned before. The presented data were achieved for images of conductive layers taken in a contact AFM mode. PMID- 22214543 TI - Understanding patient acceptance and refusal of HIV testing in the emergency department. AB - BACKGROUND: Despite high rates of patient satisfaction with emergency department (ED) HIV testing, acceptance varies widely. It is thought that patients who decline may be at higher risk for HIV infection, thus we sought to better understand patient acceptance and refusal of ED HIV testing. METHODS: In-depth interviews with fifty ED patients (28 accepters and 22 decliners of HIV testing) in three ED HIV testing programs that serve vulnerable urban populations in northern California. RESULTS: Many factors influenced the decision to accept ED HIV testing, including curiosity, reassurance of negative status, convenience, and opportunity. Similarly, a number of factors influenced the decision to decline HIV testing, including having been tested recently, the perception of being at low risk for HIV infection due to monogamy, abstinence or condom use, and wanting to focus on the medical reason for the ED visit. Both accepters and decliners viewed ED HIV testing favorably and nearly all participants felt comfortable with the testing experience, including the absence of counseling. While many participants who declined an ED HIV test had logical reasons, some participants also made clear that they would prefer not to know their HIV status rather than face psychosocial consequences such as loss of trust in a relationship or disclosure of status in hospital or public health records. CONCLUSIONS: Testing for HIV in the ED as for any other health problem reduces barriers to testing for some but not all patients. Patients who decline ED HIV testing may have rational reasons, but there are some patients who avoid HIV testing because of psychosocial ramifications. While ED HIV testing is generally acceptable, more targeted approaches to testing are necessary for this subgroup. PMID- 22214545 TI - Endoscopic submucosal enucleation of small gastric gastrointestinal stromal tumors with cross-shaped incision: report of sixty-nine cases. AB - BACKGROUND/AIMS: Gastric gastrointestinal stromal tumors (gastric GISTs) are the most common gastric submucosal tumors with potential for malignant transformation. Our aim was to assess the efficacy and safety of ESE for gastric GISTs. METHODOLOGY: Small gastric GISTs were dealt with ESE between May 2007 and October 2010. RESULTS: A total of 69 patients (42 men, 27 women; mean age 47.28+/ 10.10 years) were treated. The mean diameter of the specimens was 1.87+/-0.57cm (range 0.7-3.0cm). The rates of intra-operative bleeding, delayed bleeding, perforation and surgery related complications were 7.25% (5/69), 1.45% (1/69), 33.33% (23/69) and 5.80% (4/69), respectively. The rate of perforation was 43.2% (19/44) at the fundus of the stomach and 16% (4/25) at the body (p=0.02). The mean time of the procedure was 41.07+/-10.79 minutes. Nineteen patients with perforation were treated by titanium clips and the rest by laparoscopy. Immunohistochemistry revealed that the positive rates of CD117 and CD34 were 88.41% and 68.12%, respectively. The gastric GISTs were all at low risk. At a mean follow-up period of 17.97+/-10.75 months (range 1 to 40 months) all of the patients were disease free. CONCLUSIONS: ESE with a cross-shaped incision is possibly a very good choice for small gastric GISTs. PMID- 22214546 TI - Radioimmunotherapy consolidation and rituximab maintenance in the initial treatment of follicular lymphoma. AB - Several reports have documented similar efficacies and tolerable toxicities of radioimmunotherapy (RIT) consolidation and rituximab maintenance after initial R chemotherapy of follicular lymphoma. The relative merits of these two interventions are currently under discussion. We now raise the question whether both RIT consolidation and rituximab maintenance should be used together aiming to augment the results achievable with R-chemotherapy. PMID- 22214547 TI - Nanotoxicology: in vitro-in vivo dosimetry. PMID- 22214548 TI - Trending now: using social media to predict and track disease outbreaks. PMID- 22214549 TI - Mechanism of quantum dot luminescence excitation within implanted SiO2:Si:C films. AB - Results of the investigation of photoluminescence (PL) mechanisms for silicon dioxide films implanted with ions of silicon (100 keV; 7 * 10(16) cm(-2)) and carbon (50 keV; 7 * 10(15)-1.5 * 10(17) cm(-2)) are presented. The spectral, kinetic and thermal activation properties of the quantum dots (Si, C and SiC) formed by a subsequent annealing were studied by means of time-resolved luminescence spectroscopy under selective synchrotron radiation excitation. Independent quantum dot PL excitation channels involving energy transfer from the SiO(2) matrix point defects and excitons were discovered. A resonant mechanism of the energy transfer from the matrix point defects (E' and ODC) is shown to provide the fastest PL decay of nanosecond order. The critical distances (6-9 nm) of energy transport between the bulk defects and nanoclusters were determined in terms of the Inokuti-Hirayama model. An exchange interaction mechanism is realized between the surface defects (E(s)'-centres) and the luminescent nanoparticles. The peculiarities of an anomalous PL temperature dependence are explained in terms of a nonradiative energy transfer from the matrix excitons. It is established that resonant transfer to the luminescence centre triplet state is realized in the case of self-trapped excitons. In contrast, the PL excitation via free excitons includes the stages of energy transfer to the singlet state, thermally activated singlet-triplet conversion and radiative recombination. PMID- 22214550 TI - Reduction and functionalization of graphene oxide sheets using biomimetic dopamine derivatives in one step. AB - An easy and environmentally friendly chemical method for the simultaneous reduction and noncovalent functionalization of graphene oxide (GO) using dopamine derivatives is described. The reaction takes place at room temperature under ultrasonication of an aqueous suspension of GO and a dopamine derivative. X-ray photoelectron spectroscopy, FT-IR spectroscopy, and cyclic voltammetry characterizations revealed that the resulting material consists of graphene functionalized with the dopamine derivative. This one-step protocol is applied for simultaneous reduction and functionalization of graphene oxide with a dopamine derivative bearing an azide function. The chemical reactivity of the azide function was demonstrated by a postfunctionalization with ethynylferrocene using the Cu(I) catalyzed 1,3-dipolar cyloaddition. PMID- 22214551 TI - Income inequality and obesity prevalence among OECD countries. AB - Using recent pooled data from the World Health Organization Global Infobase and the World Factbook compiled by the Central Intelligence Agency of the United States, this study assesses the relation between income inequality and obesity prevalence among 31 OECD countries through a series of bivariate and multivariate linear regressions. The United States and Mexico well lead OECD countries in both obesity prevalence and income inequality. A sensitivity analysis suggests that the inclusion or exclusion of these two extreme cases can fundamentally change the findings. When the two countries are included, the results reveal a positive correlation between income inequality and obesity prevalence. This correlation is more salient among females than among males. Income inequality alone is associated with 16% and 35% of the variations in male and female obesity rates, respectively, across OECD countries in 2010. Higher levels of income inequality in the 2005-2010 period were associated with a more rapid increase in obesity prevalence from 2002 to 2010. These associations, however, virtually disappear when the US and Mexico have been excluded from the analysis. Findings from this study underscore the importance of assessing the impact of extreme cases on the relation between income inequality and health outcomes. The potential pathways from income inequality to the alarmingly high rates of obesity in the cases of the US and Mexico warrant further research. PMID- 22214552 TI - Structural, spectroscopic, magnetic and electrical characterization of Ca-doped polycrystalline bismuth ferrite, Bi(1-x)Ca(x)FeO(3-x/2) (x <= 0.1). AB - The crystal structure and physical properties of multiferroic polycrystalline Ca(2+)-doped BiFeO(3) samples have been investigated. The present experimental investigation suggests that Bi(1-x)Ca(x)FeO(3-x/2) (x <= 0.1) can be considered as a solid solution between BiFeO(3) and CaFeO(2.5). The oxidation state of Fe in these materials is + 3 and charge balance occurs through the creation of oxygen vacancies. For each composition, two structural phase transitions are revealed as anomalies in the variable-temperature in situ x-ray diffraction data which is consistent with the well-established high-temperature structural transformation in pure BiFeO(3). All compositions studied show antiferromagnetic behaviour along with a ferromagnetic component that increases with Ca(2+) doping. The resistivities of the Bi(1-x)Ca(x)FeO(3-x/2) samples at room temperature are of the order of 10(9) Omega cm and decrease with increasing Ca(2+) content. Arrhenius plots of the resistivity show two distinct linear regions with activation energies in the range of 0.4-0.7 and 0.03-0.16 eV. A correlation has been established between the critical temperatures associated with the structural phase transitions and the multiferroic properties. A composition of x = 0.085 is predicted to show maximum magneto-electric coupling. PMID- 22214553 TI - Electroless synthesis of 3 nm wide alloy nanowires inside Tobacco mosaic virus. AB - We show that 3 nm wide cobalt-iron alloy nanowires can be synthesized by simple wet chemical electroless deposition inside tubular Tobacco mosaic virus particles. The method is based on adsorption of Pd(II) ions, formation of a Pd catalyst, and autocatalytic deposition of the alloy from dissolved metal salts, reduced by a borane compound. Extensive energy-filtering TEM investigations at the nanoscale revealed that the synthesized wires are alloys of Co, Fe, and Ni. We confirmed by high-resolution TEM that our alloy nanowires are at least partially crystalline, which is compatible with typical Co-rich alloys. Ni traces bestow higher stability, presumably against corrosion, as also known from bulk CoFe. Alloy nanowires, as small as the ones presented here, might be used for a variety of applications including high density data storage, imaging, sensing, and even drug delivery. PMID- 22214554 TI - Atherosclerosis predictor? Circulating levels of POPs linked to arterial effects. PMID- 22214556 TI - Fructose 2,6-bisphosphate is essential for glucose-regulated gene transcription of glucose-6-phosphatase and other ChREBP target genes in hepatocytes. AB - Glucose metabolism in the liver activates the transcription of various genes encoding enzymes of glycolysis and lipogenesis and also G6pc (glucose-6 phosphatase). Allosteric mechanisms involving glucose 6-phosphate or xylulose 5 phosphate and covalent modification of ChREBP (carbohydrate-response element binding protein) have been implicated in this mechanism. However, evidence supporting an essential role for a specific metabolite or pathway in hepatocytes remains equivocal. By using diverse substrates and inhibitors and a kinase deficient bisphosphatase-active variant of the bifunctional enzyme PFK2/FBP2 (6 phosphofructo-2-kinase-fructose-2,6-bisphosphatase), we demonstrate an essential role for fructose 2,6-bisphosphate in the induction of G6pc and other ChREBP target genes by glucose. Selective depletion of fructose 2,6-bisphosphate inhibits glucose-induced recruitment of ChREBP to the G6pc promoter and also induction of G6pc by xylitol and gluconeogenic precursors. The requirement for fructose 2,6-bisphosphate for ChREBP recruitment to the promoter does not exclude the involvement of additional metabolites acting either co-ordinately or at downstream sites. Glucose raises fructose 2,6-bisphosphate levels in hepatocytes by reversing the phosphorylation of PFK2/FBP2 at Ser32, but also independently of Ser32 dephosphorylation. This supports a role for the bifunctional enzyme as the phosphometabolite sensor and for its product, fructose 2,6-bisphosphate, as the metabolic signal for substrate-regulated ChREBP-mediated expression of G6pc and other ChREBP target genes. PMID- 22214558 TI - Impact of NEDO project on microdosing clinical studies: toward the eIND study in Japan. PMID- 22214557 TI - Self-organizing tissue-engineered constructs in collagen hydrogels. AB - A novel self-organizing behavior of cellularized gels composed of collagen type 1 that may have utility for tissue engineering is described. Depending on the starting geometry of the tissue culture well, toroidal rings of cells or hollow spheroids were prompted to form autonomously when cells were seeded onto the top of gels and the gels released from attachment to the culture well 12 to 24 h after seeding. Cells within toroids assumed distinct patterns of alignment not seen in control gels in which cells had been mixed in. In control gels, cells formed complex three-dimensional arrangements and assumed relatively higher levels of heterogeneity in expression of the fibronectin splice variant ED-A--a marker of epithelial mesenchymal transformation. The tissue-like constructs resulting from this novel self-organizing behavior may have uses in wound healing and regenerative medicine, as well as building blocks for the iterative assembly of synthetic biological structures. PMID- 22214559 TI - The relationship of depression and disease stage to patient perceptions of Parkinson's disease. AB - The present study aimed to perform an in-depth exploration of perceptions of Parkinson's disease (PD) and their relationship to depression and disease stage using semi-structured interviews. 37 participants with PD formed four groups: depressed and non-depressed with either mild or moderate-severe stage PD. Interviews were analysed using Framework Analysis. Moderate-severe stage patients reported a greater variety of perceptions than those with mild symptoms. Depressed and non-depressed patients differed in their perceptions of the consequences, treatment control and emotional reaction to PD. Helping patients to adjust life goals to accommodate PD and employ adaptive coping strategies may help to relieve depressive symptoms in PD. PMID- 22214560 TI - Tailoring impact toughness of poly(L-lactide)/poly(epsilon-caprolactone) (PLLA/PCL) blends by controlling crystallization of PLLA matrix. AB - Melt blending poly(L-lactide) (PLLA) with various biodegradable polymers has been thought to be the most economic and effective route to toughen PLLA without compromising its biodegradability. Unfortunately, only very limited improvement in notched impact toughness can be achieved, although most of these blends show significant enhancement in tensile toughness. In this work, biodegradable poly(epsilon-caprolactone) (PCL) was used as an impact modifier to toughen PLLA and a nucleating agent was utilized to tailor the crystallization of PLLA matrix. Depending on the nucleating agent concentrations in the matrix and mold temperatures in injection molding, PLLA/PCL blends with a wide range of matrix crystallinity (10-50%) were prepared by practical injection molding. The results show that there is a linear relationship between PLLA matrix crystallinity and impact toughness. With the increase in PLLA crystalline content, toughening becomes much easier to achieve. PLLA crystals are believed to provide a path for the propagation of shear yielding needed for effective impact energy absorption, and then, excellent toughening effect can be obtained when these crystals percolate through the whole matrix. This investigation provides not only a new route to prepare sustainable PLLA products with good impact toughness but also a fresh insight into the importance of matrix crystallization in the toughening of semicrystalline polymers with a flexible polymer. PMID- 22214561 TI - The 'patient journey' of adults with sudden-onset acquired hearing impairment: a pilot study. AB - OBJECTIVE: A previous study examined the 'patient journey' of adults with gradual onset acquired hearing impairment. This study examined the same for adults with sudden-onset acquired hearing impairment, and assessed differences. STUDY DESIGN: Data were collected from 16 audiologists, using the Ida Institute template, and from four adults with sudden-onset acquired hearing impairment, through semi structured interviews. Data were analysed using thematic analysis and presented using a process mapping model. RESULTS: A patient journey template for sudden onset acquired hearing impairment was developed based on the professionals' and patients' perspectives. The main difference between these two groups' perspectives was seen in the self-evaluation phase: some stages within this phase were recognised by the patients but not by the professionals. The main difference between the current and the previous study was the absence of a pre-awareness phase in the journey described by patients with sudden-onset acquired hearing impairment, compared with that described by patients with gradual-onset acquired hearing impairment. CONCLUSION: Patient journey templates could be useful counselling tools for ear and hearing healthcare specialists. However, such templates should be used only as a baseline; it is important to take a detailed case history to understand each patient's unique experience, including the psychosocial impact of hearing impairment. PMID- 22214562 TI - Landau level spectrum for bilayer graphene in a tilted magnetic field. AB - We consider a graphene bilayer in a constant magnetic field of arbitrary orientation, i.e., tilted with respect to the graphene plane. In the low energy approximation to the tight-binding model with Peierls substitution, we find the Landau level spectrum analytically in terms of spheroidal functions and the respective eigenvalues. We compare our result to the perpendicular and purely in plane field cases. In the limit of perpendicular field we reproduce the known equidistant spectrum for Landau levels. In the opposite limit of large in-plane field this spectrum becomes two-fold degenerate, which is a consequence of Dirac point splitting induced by the in-plane field. PMID- 22214563 TI - Optimal integration of shading and binocular disparity for depth perception. AB - We explore the relative utility of shape from shading and binocular disparity for depth perception. Ray-traced images either featured a smooth surface illuminated from above (shading-only) or were defined by small dots (disparity-only). Observers judged which of a pair of smoothly curved convex objects had most depth. The shading cue was around half as reliable as the rich disparity information for depth discrimination. Shading- and disparity-defined cues where combined by placing dots in the stimulus image, superimposed upon the shaded surface, resulting in veridical shading and binocular disparity. Independently varying the depth delivered by each channel allowed creation of conflicting disparity-defined and shading-defined depth. We manipulated the reliability of the disparity information by adding disparity noise. As noise levels in the disparity channel were increased, perceived depths and variances shifted toward those of the now more reliable shading cue. Several different models of cue combination were applied to the data. Perceived depths and variances were well predicted by a classic maximum likelihood estimator (MLE) model of cue integration, for all but one observer. We discuss the extent to which MLE is the most parsimonious model to account for observer performance. PMID- 22214564 TI - Relative flattening between velvet and matte 3D shapes: evidence for similar shape-from-shading computations. AB - Among other cues, the visual system uses shading to infer the 3D shape of objects. The shading pattern depends on the illumination and reflectance properties (BRDF). In this study, we compared 3D shape perception between identical shapes with different BRDFs. The stimuli were photographed 3D printed random smooth shapes that were either painted matte gray or had a gray velvet layer. We used the gauge figure task (J. J. Koenderink, A. J. van Doorn, & A. M. L. Kappers, 1992) to quantify 3D shape perception. We found that the shape of velvet objects was systematically perceived to be flatter than the matte objects. Furthermore, observers' judgments were more similar for matte shapes than for velvet shapes. Lastly, we compared subjective with veridical reliefs and found large systematic differences: Both matte and velvet shapes were perceived more flat than the actual shape. The isophote pattern of a flattened Lambertian shape resembles the isophote pattern of an unflattened velvet shape. We argue that the visual system uses a similar shape-from-shading computation for matte and velvet objects that partly discounts material properties. PMID- 22214565 TI - Big biking payoff: alternative transportation could net Midwest over $8 billion. PMID- 22214566 TI - Direct growth of oxide nanowires on CuOx thin film. AB - Oxide nanowires were directly grown on a CuO(x) thin film deposited by plasma enhanced atomic layer deposition without additional metal catalysts. Oxide nanowires would exhibit metal-catalyst-free growth on the CuO(x) thin film with oxide materials diffused on the top. Through a focused ion beam and transmission electron microscopy, we could verify that SnO(2) and ZnO nanowires were grown as single-crystalline structures just above the CuO(x) thin film. Bottom-gate structural SnO(2) and ZnO nanowire transistors exhibited mobilities of 135.2 and 237.6 cm(2) V(-1) s(-1), respectively. We anticipate that a variety of large-area and high-density oxide nanowires can be grown at low cost by using the CuO(x) thin film. PMID- 22214567 TI - Quaternary Heusler compounds Co(2-x)Rh(x)MnZ (Z = Ga, Sn, Sb): crystal structure, electronic structure, and magnetic properties. AB - Within the huge family of Heusler compounds only a few quaternary derivatives are known that crystallize in the F43m space group. In this work, the yet unreported compounds CoRhMnZ (Z = Ga, Sn, Sb) and the alloy Co(0.5)Rh(1.5)MnSb were investigated in detail by experimental techniques and theoretical methods. The ab initio calculations predict the CoRhMnZ compounds to be half-metallic ferromagnets or to be close to the half-metallic ferromagnetic state. Calculations of the elastic constants show that the cubic structure is stable in compounds containing Mn. Both calculations and experiment reveal that Mn cannot be exchanged by Fe (CoRhFeGa). The low temperature magnetization of the compounds is in the range of 3.4-5.5 MU(B) depending on the composition. The best agreement between experiment and calculation has been achieved for CoRhMnSn (5 MU(B)). The other compounds are also cubic but tend to anti-site disorder. Compared to Co(2)MnSn it is interesting to note that the magnetic properties and half metallicity are preserved when replacing one of the 'magnetic' Co atoms by a 'non magnetic' Rh atom. This allows us to increase the spin-orbit interaction at one of the lattice sites while keeping the properties as a precondition for applications and physical effects relying on a large spin-orbit interaction. The Curie temperatures were determined from measurements in induction fields of up to 1 T by applying molecular field fits respecting the applied field. The highest Curie temperature was found for CoRhMnSn (620 K) that makes it, together with the other well defined properties, attractive for above room temperature spintronic applications. PMID- 22214568 TI - Dye surface coating enables visible light activation of TiO2 nanoparticles leading to degradation of neighboring biological structures. AB - Biologically and chemically modified nanoparticles are gaining much attention as a new tool in cancer detection and treatment. Herein, we demonstrate that an alizarin red S (ARS) dye coating on TiO2 nanoparticles enables visible light activation of the nanoparticles leading to degradation of neighboring biological structures through localized production of reactive oxygen species. Successful coating of nanoparticles with dye is demonstrated through sedimentation, spectrophotometry, and gel electrophoresis techniques. Using gel electrophoresis, we demonstrate that visible light activation of dye-TiO2 nanoparticles leads to degradation of plasmid DNA in vitro. Alterations in integrity and distribution of nuclear membrane associated proteins were detected via fluorescence confocal microscopy in HeLa cells exposed to perinuclear localized ARS-TiO2 nanoparticles that were photoactivated with visible light. This study expands upon previous studies that indicated dye coatings on TiO2 nanoparticles can serve to enhance imaging, by clearly showing that dye coatings on TiO2 nanoparticles can also enhance the photoreactivity of TiO2 nanoparticles by allowing visible light activation. The findings of our study suggest a therapeutic application of dye coated TiO2 nanoparticles in cancer research; however, at the same time they may reveal limitations on the use of dye assisted visualization of TiO2 nanoparticles in live-cell imaging. PMID- 22214570 TI - [University cooperation for new pharmacy education]. PMID- 22214569 TI - Artificial food color additives and child behavior. PMID- 22214571 TI - [Cooperation of medical and pharmaceutical sciences between private and national universities to educate professionals in the fields of drug development and rational pharmacotherapy]. AB - Cooperation in education and research in medical and pharmaceutical sciences between Kobe Pharmaceutical University and Kobe University was started in 2008 for training professionals in drug development and rational pharmacotherapy. Initially, we started a two-year pharmacy residency program. Our pharmacy residents can attend lectures at our universities, and they also help pharmacist preceptors educate undergraduate pharmacy students in practical training. As curricula for cooperative education of pharmacy, nursing and medical students, we developed two new elective subjects (early exposure to clinical training for first year students and IPW (inter-professional work) seminar for fifth year pharmacy students) to learn about the roles of health care professionals in a medical team. Cooperative research between faculty members and graduate students is also in progress. For faculty and staff developments, invited lectures by clinical pharmacy and medical professors from the United States on the clinical education system in pharmacy and medicine in the United States have been held. This systematic cooperation will contribute to the promotion of a new curriculum for inter-professional education in the health-science fields. PMID- 22214572 TI - [Cooperation between extension project and pharmacy education in Kobe Pharmaceutical University]. AB - In Kobe Pharmaceutical University, postgraduate continuing professional development (CPD) has been held every year since 1975. Kobe Pharmaceutical University Extension Center was established in June 2007. Kobe Pharmaceutical Extension Center is accredited as a credentialing body (G07) by the Council on Pharmacist Credentials. The extension project of Kobe Pharmaceutical University works together with the alumni association to provide ongoing opportunities for increasing pharmacist competence and professionalism. The extension program is continuing to develop expanded links with pharmacy education. PMID- 22214573 TI - [Development of an advanced education program for community medicine by Nagasaki pharmacy and nursing science union consortium]. AB - The Nagasaki University School of Pharmaceutical Sciences has conducted a project concerning "development of an advanced education program for community medicine" for its students in collaboration with the University's School of Nursing Sciences, the University of Nagasaki School of Nursing Sciences, and the Nagasaki International University School of Pharmaceutical Sciences. The project was named "formation of a strategic base for the integrated education of pharmacy and nursing science specially focused on home-healthcare and welfare", that has been adopted at "Strategic University Cooperative Support Program for Improving Graduate" by the Ministry of Education, Culture, Sports, Science and Technology, Japan from the 2009 academic year to the 2011 academic year. Our project is a novel education program about team medical care in collaboration with pharmacist and nurse. In order to perform this program smoothly, we established "Nagasaki pharmacy and nursing science union consortium (Nagasaki University, The University of Nagasaki, Nagasaki International University, Nagasaki Pharmaceutical Association, Nagasaki Society of Hospital Pharmacists, Nagasaki Nursing Association, Nagasaki Medical Association, Nagasaki Prefectural Government)". In this symposium, we introduce contents about university education program and life learning program of the project. PMID- 22214574 TI - ["Pharmacy 3.0" and the meaning of vital signs for pharmacists]. AB - In Japan, the proportion of elderly people had reached up to 23% in 2009. The number of elderly people in long-term nursing homes or nursing facilities will increase in the next decade. By 2025, the majority of the elderly people would have developed cancer, stroke, cardio-vascular diseases, and dementia. Almost all of them would be treated with prescribed drugs. They would also have dysphagia and have difficulties in remembering their medications in the long term. Therefore, for the benefit of such a community, the work force, especially in the field of drug distribution, will need to be increased to prevent the incidence of patients who forget to take their medications. Further, the educational curriculum for pharmaceutical students has been changed to a new version, and some Japanese pharmacy shops have been switching over to "Pharmacy 3.0," which is the next generation model. In this pharmacy, the pharmacists will play an additional new role; they will not only dispense drugs but also support home recuperation leveraging some vital signs and physical assessments. In my opinion, this novel scheme of medical service developed with pharmacists playing this new role may be a boon to the patient/elderly community in Japan who are facing the collapse of healthcare systems. In conclusion, Collaborative Drug Therapy Management (CDTM) in the practice of the pharmacists is essential for increasing the efficiency of the Japanese healthcare systems. PMID- 22214575 TI - [Cooperation among pharmaceutical, medical and nursing schools aimed at 6-year pharmaceutical education]. AB - Eleven universities which have pharmacy, medical or nursing school, have cooperated in an attempt to build the human and material systems for 6-year pharmacy education and to apply them to practical pharmacy educations. Members are Nagoya City University, Gifu Pharmaceutical University, University of Shizuoka, Aichi Gakuin University, Kinjo Gakuin University, Meijo University, Suzuka University of Medical Science, Hamamatsu University School of Medicine, Mie University, Aichi Medical University and Fujita Health University. Tokai Cooperation Center for Clinical Pharmacy Education, the steering committee and 5 subcommittees established following projects; 1) WEB-based system for supplementary lesson of natural science (for freshmen), 2) FD (Faculty Development) activity (for teachers), 3) WEB-based data-base system of disease case for PBL (Problem-based Learning) and methods for practice of physical assessment (for 4th grade students), 4) WEB-based system for practical pharmacy training (for 5th grade students), 5) Matching and WEB system for graduation practice at university hospital (for 6th grade students). PMID- 22214576 TI - [Merits of university-cooperation for preparing the contents of clinical case discussions]. AB - Clinical case discussions based on the problem-based learning are one of the indispensable practices in the course of 6-year pharmacy education program. To perform the effective learning in clinical case discussions, it is important to prepare the cases in which quality and quantity are sufficient for practical use. Under the support of University Cooperation Program from Ministry of Education, Culture, Sports, Science and Technology, we tried to prepare educational cases from the cases of real patients, and to construct the database system for inter university utilization of educational cases. In this review, I describe the achievements in our three-year activities. PMID- 22214577 TI - [Recent advance in research of new anti-infectious agents-discovery chemical biology and development-]. PMID- 22214578 TI - [Mode of action of microbial anti-MRSA agents]. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is known as a major nosocomial pathogen that has also developed resistance to many antibiotics. Moreover, MRSA resistance to a last-resort antibiotic, vancomycin, has been reported. Therefore, new anti-infectious agents to prevent and treat MRSA infection are needed. Based on this background, our group has focused on the discovery of new microbial agents active against MRSA infection. Viridicatumtoxin and spirohexaline, produced by Penicillium sp. FKI-3368, were isolated as inhibitors of undecaprenyl pyrophosphate (UPP) synthase of Staphylococcus aureus, which was involved in cell wall synthesis. Viridicatumtoxin and spirohexaline with a pentacyclic spiro skeleton inhibited UPP synthase activity with an IC(50) value of 4.0 and 9.0 uM, respectively. Actually, the growth of gram-positive bacteria including MRSA was strongly inhibited by the compounds. Our computational modeling experiments indicated that spirohexaline A was inserted into the substrate pocket of UPP synthase and interacted with Glu(88) via a carbamoyl group of the compound, with Ala(76), Met(54) and Asn(35) via three hydroxyl groups, and with certain hydrophobic amino acids via a spiro ring. Cyslabdan, produced by Streptomyces sp. K04-0144, was isolated as a potentiator of beta-lactam imipenem activity against MRSA. The compound consisted of a labdan skeleton and an N-acetylcysteine. Cyslabdan potentiated imipenem activity by over 1000 fold, drastically reducing the MIC value of imipenem against MRSA from 16 to 0.03 ug/mL. The binding proteins of cyslabdan were investigated in the lysate of MRSA to identify FemA, which was involved in the formation of the pentaglycine interpeptide bridge in MRSA peptidoglycan. PMID- 22214579 TI - [Physiological role of bacterial multidrug efflux pumps]. AB - Since the discovery of antibiotics, the battle between humans and drug resistant bacteria has never stopped. Bacteria have developed various ways to resist the toxic effects of antibiotics and other drugs. Multidrug efflux pumps are integral membrane proteins that utilize cellular energy to extrude antibiotics or biocides actively out of the cell. In this symposium, I first introduce the post-genomic approach to analyze all putative drug efflux genes. Next, I discuss the regulation of drug efflux pumps responding to environmental signals. I also introduce the physiological roles of drug efflux pumps in virulence, which is an ongoing research area. Multidrug efflux pumps have greater clinical relevance than has previously been thought, because there is now accumulating evidence that certain classes of efflux pumps not only confer resistance to drugs used in therapy but also have a role in bacterial pathogenicity. PMID- 22214580 TI - [Two-component signal transduction as attractive drug targets in pathogenic bacteria]. AB - Gene clusters contributing to processes such as cell growth and pathogenicity are often controlled by two-component signal transduction systems (TCSs). TCS consists of a histidine kinase (HK) and a response regulator (RR). TCSs are attractive as drug targets for antimicrobials because many HK and RR genes are coded on the bacterial genome though few are found in lower eukaryotes. The HK/RR signal transduction system is distinct from serine/threonine and tyrosine phosphorylation in higher eukaryotes. Specific inhibitors against TCS systems work differently from conventional antibiotics, and developing them into new drugs that are effective against various drug-resistant bacteria may be possible. Furthermore, inhibitors of TCSs that control virulence factors may reduce virulence without killing the pathogenic bacteria. Previous TCS inhibitors targeting the kinase domain of the histidine kinase sensor suffered from poor selectivity. Recent TCS inhibitors, however, target the sensory domains of the sensors blocking the quorum sensing system, or target the essential response regulator. These new targets are introduced, together with several specific TCSs that have the potential to serve as effective drug targets. PMID- 22214581 TI - [Studies for the development of novel anti-MRSA/VRE drugs]. AB - The widespread emergence of multidrug-resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) is a high threat for human health. In the course of screening for active compounds against the above drug-resistant bacteria from microbial metabolites, we discovered three kinds of novel compounds designated tripropeptins, pargamicin, and amycolamicin. Tripropeptin C (TPPC), major component of tripropeptins, is the most promising compound because it is efficacious against MRSA and VRE both in vitro and in a mouse septicemia model, and shows no cross-resistance to available drugs including vancomycin. Studies of incorporation of radioactive macromolecular precursors and accumulation of UDP MurNAc-pentapeptide in the cytoplasm in S. aureus Smith revealed that TPPC is a cell wall synthesis inhibitor. Antimicrobial activity of TPPC was weakened by addition of prenylpyrophosphates but not with prenylphosphates, UDP-linked sugars, or the pentapeptide of peptidoglycan. Direct interaction between TPPC and undecaprenyl pyrophosphate (C(55)-PP) was observed by mass spectrometry and thin layer chromatography, and TPPC inhibits C(55)-PP phosphatase, which plays a crucial role in peptidoglycan synthesis at an IC(50) of 0.03-0.1 uM in vitro. From the analysis of accumulation of lipid carrier-related compounds, TPPC caused accumulation of C(55)-PP in situ, leading to the accumulation of a glycine-added lipid intermediate, suggesting a distinct mode of action from that of clinically important drugs such as vancomycin, daptomycin, and bacitracin. TPPC might represent a promising novel class of antibiotic against MRSA and VRE infections. PMID- 22214582 TI - [Development of anti-HIV agents based on chemical biology]. AB - Recently, highly active anti-retroviral therapy (HAART), which involves a combinational use of reverse transcriptase inhibitors and HIV protease inhibitors, has brought us a great success in the clinical treatment of AIDS patients. However, HAART has several serious clinical problems. These drawbacks encouraged us to find novel drugs and increase repertoires of anti-HIV agents with various action mechanisms. The recent disclosing of the dynamic supramolecular mechanism in HIV-entry has provided potentials to find a new type of drugs. To date, we have synthesized HIV-entry inhibitors, especially coreceptor CXCR4 antagonists. In addition, CD4 mimics in consideration of synergic effects with other entry inhibitors or neutralizing antibodies have been developed. The development of the above anti-HIV agents is based on the concept of reverse chemical genomics, in which target molecules are fixed. On the other hand, based on the concept of forward chemical genomics, in which active compounds are searched according to the screening of random libraries, effective peptide leads such as integrase inhibitors derived from fragment peptides of HIV 1 Vpr have been discovered. As such, from a point of view on chemical biology, anti-HIV leads have been found utilizing reverse and forward chemical genomics. Furthermore, antibody-based therapy or AIDS vaccine is still thought to be a promising treatment. Thus, peptidic antigen molecules based on artificial remodeling of the dynamic structures of a surface protein gp41 in HIV fusion have been developed. The present chemical biology approaches would be essential for discovery of anti-HIV agents in consideration of cocktail therapy of AIDS. PMID- 22214583 TI - [Identification of novel therapeutically effective antibiotics using silkworm infection model]. AB - Most antibiotics obtained by in vitro screening with antibacterial activity have inappropriate properties as medicines due to their toxicity and pharmacodynamics in animal bodies. Thus, evaluation of the therapeutic effects of these samples using animal models is essential in the crude stage. Mammals are not suitable for therapeutic evaluation of a large number of samples due to high costs and ethical issues. We propose the use of silkworms (Bombyx mori) as model animals for screening therapeutically effective antibiotics. Silkworms are infected by various pathogenic bacteria and are effectively treated with similar ED(50) values of clinically used antibiotics. Furthermore, the drug metabolism pathways, such as cytochrome P450 and conjugation systems, are similar between silkworms and mammals. Silkworms have many advantages compared with other infection models, such as their 1) low cost, 2) few associated ethical problems, 3) adequate body size for easily handling, and 4) easier separation of organs and hemolymph. These features of the silkworm allow for efficient screening of therapeutically effective antibiotics. In this review, we discuss the advantages of the silkworm model in the early stages of drug development and the screening results of some antibiotics using the silkworm infection model. PMID- 22214584 TI - [Novel approach of cyclodextrin-based pharmaceutical formulation]. AB - The alpha-, beta-, and gamma-CyDs are the most common natural CyDs, consisting of six, seven, and eight glucose units, respectively. Among the natural CyDs, bioadaptable gamma-cyclodextrin (gamma-CyD) is useful to improve the undesired properties of drug molecules through the formation of inclusion complex. Recently, various kinds of CyD derivatives such as hydrophilic, hydrophobic, amphiphatic and anionic CyDs have been developed, anticipating the design of CyD based drug delivery system. The objective of this contribution is to outline our recent findings on the combinational use of gamma-CyD and functional ingredients, focusing on the ability to increase the drug absorption, the ability to control the rate and time profiles of drug release, and the ability to deliver a drug to a targeted site. In addition, the multi-functional characteristic of hydroxyalkylated CyDs, in particular, 2-hydroxypropyl-beta-CyD (HP-beta-CyD) is applicable to design the novel pharmaceutical formulation, focusing on the ability to form hydrophilic nano-particles. Moreover, some amphiphatic CyDs such as 2,6-di-O-methyl-beta-CyD (DM-beta-CyD) and 2-hydroxybutyl-beta-CyD (HB-beta CyD) are useful to control the crystallization and polymorphic transition of solid drugs and will provide an opportunity to isolate labile intermediate metastable polymorphs. On the basis of above-mentioned knowledge, this review explores the use of CyDs to better understand their pharmaceutical applications as well as their limitations in the approach of CyD-based drug delivery system. PMID- 22214585 TI - [Role of microRNAs in the regulation of cytochrome P450s and transcriptional factors]. AB - MicroRNAs (miRNAs) are endogenous ~22-nucleotide non-coding RNAs that regulate gene expression through the translational repression or degradation of target mRNAs. The human genome contains over 1400 miRNAs and over 60% of human mRNAs are predicted to be targets of miRNAs. The miRNAs have roles in fine-tuning the expression of their target genes forming intricate networks. Research on miRNA is growing exponentially, and it is now clear that miRNAs can potentially regulate every aspect of cellular processes such as differentiation, proliferation and apoptosis as well as a large range of physiological processes such as development, immune response, metabolism, tumor formation, and disease development. The roles of miRNAs in the metabolism of xenobiotics and endobiotics have only recently been revealed. This review describes the current knowledge on the regulation of cytochrome P450s and transcriptional factors by miRNAs, and its physiological and clinical significance, which were disclosed in our studies. The miRNA expression is readily altered by chemicals, carcinogens, drugs, hormones, stress, or diseases, and the dysregulation of specific miRNAs might lead to changes in the drug metabolism potency or pharmacokinetics as well as pathophysiological changes. Utilizing miRNAs opens a new era in the fields of drug metabolism and pharmacokinetics as well as toxicology. PMID- 22214586 TI - [Development of novel types of biologically active compounds based on natural products and biomolecules]. AB - Enzyme inhibitors have been utilized as useful tools for elucidating the function and structure of specific enzymes and for cell biology studies. Recently, chemical screening from natural sources and compound libraries has led to the rapid discovery of enzyme inhibitors. To create more useful inhibitors with high enzyme selectivity, and molecular probes for analyzing the precise mode of actions for enzymes, synthetic approaches based on natural products and bio molecules are considered to have an important role in medicinal chemistry and chemical biology. In this review, the "focused library approach" for the development of inhibitors and modulators for enzymes related to protein phosphorylations and de-phosphorylations was introduced. As protein kinase C modulators, we constructed a focused library with the conformationally constrained 1,2-diacylglycerol (DAG) motif as the core structure. Among the synthesized compounds, we found some characteristic molecules with different binding affinity to the C1 domain and activation ability for PKCalpha. As inhibitors for the dual-specificity protein phosphatase VHR, the neutral phosphate-mimicking core structure was designed based on natural product RK-682. Among the derivatives of the constructed focused library, including the neutral core structure stated above, we found the selective inhibitor for VHR, which showed cell cycle arresting activity for NIH3T3 cells and inhibitory activity for the de-phosphorylation of ERK and JNK. PMID- 22214587 TI - [Clinical usefulness of the new Japanese glomerular filtration rate equation for initial and individualized dosage adjustment concentrations of vancomycin]. AB - To clarify whether the new Japanese glomerular filtration rate (eGFR) equation was able to accurately determine the initial and individualized dosage adjustment concentrations of vancomycin (VCM), the predictive performance for VCM concentrations using the eGFR and Cockcroft-Gault (CG) equations was compared. Data were retrospectively collected from clinical records of 90 patients with MRSA infection whose trough and peak VCM concentrations had been determined. The predicted VCM initial and individualized dosage adjustment concentrations were performed with the 2-compartment linear model using pharmacokinetic parameter means and their individual values via Bayesian estimation, respectively. The prediction error (PE) and its absolute value (APE) between the observed and predicted VCM concentrations were calculated as indices of bias and accuracy in predictive performance, respectively. In the initial dosage adjustment of VCM, the PE value, calculated with the eGFR equation in trough and peak VCM concentrations of patients whose BMI were 18.5 kg/m(2) and higher, was significantly smaller than that calculated with the CG equation. In particular, both PE and APE values obtained from the eGFR calculated concentrations from nonelderly patients (younger than 65 years old) were significantly improved compared with those from the CG equation. In the individualized dosage adjustment of VCM, the eGFR equation gave a significantly smaller PE value in nonelderly patients' trough concentrations than the CG equation. These findings provide useful information for adjusting the VCM dosage to achieve optimal therapeutic efficacy in patients with MRSA infection. PMID- 22214588 TI - [Prediction of systemic exposure of ketoprofen tapes by in vitro release test and pharmacokinetic model analysis: comparison between brand-name and generic formulations]. AB - Topical dermatological formulations of non-steroidal anti-inflammatory drugs (NSAIDs) are reported to show their pharmacological effect partially through the systemic circulation, and to induce systemic side effects. However, pharmaceutical equivalence and pharmacokinetic bioequivalence between brand-name and generic products are not required. Therefore, we aimed to predict systemic drug exposure from brand-name and nine generic ketoprofen tapes. In vitro release profiles were examined using the paddle-over-disk method, then analyzed by the W. I. Higuchi equation incorporating an initial burst effect. Pharmacokinetic parameters were estimated from observed release profiles and the reported time plasma concentration profile of the brand-name product. Plasma concentration profiles of generic products were predicted from the observed release profiles and the pharmacokinetic parameters of the brand-name product. In vitro release profiles differed markedly, and estimated release rates for initial burst effect and at 24 hours ranged from 4.20 to 88.75% and from 45.27 to 95.83%, respectively. The predicted plasma concentration profile of each product reflected its release profile, and estimated C(max) ranged from 61.70 to 290.30 ng/mL (0.46- to 2.15-fold vs. brand-name product). Generic products were classified into three types, i.e., systemic exposure comparable with, higher than and lower than that of brand-name product. C(max) was predicted to increase with enhanced skin permeability for all products, but the increase rates differed among products. These results suggest that safety and efficacy differ between brand-name and generic ketoprofen tapes. Healthcare professionals should carefully monitor systemic side effects, especially when switching from brand name to generic products for which higher systemic exposure is predicted. PMID- 22214589 TI - [Mechanism of interaction between risperidone and tea catechin (2) influence of presence of galloyl group in catechin on insoluble complex formation with risperidone]. AB - The influence of the presence of a galloyl group in catechin on complexation with risperidone (RISP) was examined using (--)-epigallocatechin gallate (EGCg) and (- )-epigallocatechin (EGC), which are present in green tea as tea catechins. By quantitative analysis using HPLC, it was found that EGCg formed an insoluble complex with RISP for concentration dependence, whereas EGC did not. The large contribution of the galloyl group of catechin to form an insoluble complex with RISP was recognized in this study. In a molecular modeling study, it was found that the EGCg-R complex (EGCg with RISP) formed three hydrogen bonds between the hydroxyl groups of EGCg and the two N atoms and an O atom of RISP. The hydrogen bond between the hydroxyl group of the galloyl ring in EGCg and the N atom of the piperidine ring in RISP stabilized EGCg-R more energetically. The EGC-R complex (EGC with RISP) also formed three hydrogen bonds, but the N atom of the piperidine ring in RISP did not participate in hydrogen bond formation. According to the calculation using the COSMO-RS method, the water solubility of the EGCg-R complex was 1/26 that of the EGC-R complex. Therefore, the EGCg-R complex was difficult to dissolve in water. In the (1)H-NMR spectra of RISP in DMSO-d(6), although chemical shifts of protons near the N atom on the piperidine ring moved downfield on the addition of EGCg, no change in chemical shifts of these protons was observed on the addition of EGC. Therefore, based on these results, the galloyl group of EGCg contributes to the formation of an insoluble complex between tea catechin and RISP, and this insoluble complex is stabilized by the hydrogen bond between the hydroxyl group of the galloyl ring in EGCg and the N atom of the piperidine ring in RISP. PMID- 22214591 TI - Discovery of the "RNA continent" through a contrarian's research strategy. AB - The International Human Genome Sequencing Consortium completed the decoding of the human genome sequence in 2003. Readers will be aware of the paradigm shift which has occurred since then in the field of life science research. At last, mankind has been able to focus on a complete picture of the full extent of the genome, on which is recorded the basic information that controls all life. Meanwhile, another genome project, centered on Japan and known as the mouse genome encyclopedia project, was progressing with participation from around the world. Led by our research group at RIKEN, it was a full-length cDNA project which aimed to decode the whole RNA (transcriptome) using the mouse as a model. The basic information that controls all life is recorded on the genome, but in order to obtain a complete picture of this extensive information, the decoding of the genome alone is far from sufficient. These two genome projects established that the number of letters in the genome, which is the blueprint of life, is finite, that the number of RNA molecules derived from it is also finite, and that the number of protein molecules derived from the RNA is probably finite too. A massive number of combinations is still involved, but we are now able to understand one section of the network formed by these data. Once an object of study has been understood to be finite, establishing an image of the whole is certain to lead us to an understanding of the whole. Omics is an approach that views the information controlling life as finite and seeks to assemble and analyze it as a whole. Here, I would like to present our transcriptome research while making reference to our unique research strategy. PMID- 22214592 TI - Dissection and cytological mapping of barley chromosome 2H in the genetic background of common wheat. AB - We used gametocidal (Gc) chromosomes 2C and 3C(SAT) to dissect barley 2H added to common wheat. The Gc chromosome induces chromosomal breakage resulting in chromosomal aberrations in the progeny of the 2H addition line of common wheat carrying the monosomic Gc chromosome. We conducted in situ hybridization to select plants carrying structurally rearranged aberrant 2H chromosomes and characterized them by sequential C-banding and in situ hybridization. We established 66 dissection lines of common wheat carrying single aberrant 2H chromosomes. The aberrant 2H chromosomes were of either deletion or translocation or complicated structural change. Their breakpoints were distributed in the short arm (2HS), centromere (2HC) and the long arm (2HL) at a rough 2HS/2HC/2HL ratio of 2:1:2. We conducted PCR analysis of the 66 dissection lines using 115 EST markers specific to chromosome 2H. Based on the PCR result, we constructed a physical or cytological map of chromosome 2H that were divided into 34 regions separated by the breakpoints of the aberrant 2H chromosomes. Forty-seven markers were present in 2HS and 68 in 2HL. We compared the 2H cytological map with a previously reported 2H genetic map using 44 markers that were used in common to construct both maps. The order of markers in the distal region was the same on both maps but that in the proximal region was somewhat contradictory between the two maps. We found that the markers distributed rather evenly in the genetic map were actually concentrated in the distal regions of both arms as revealed by the cytological map. We also recognized an EST-marker or gene-rich region in the 2HL interstitial region slightly to the telomere. PMID- 22214593 TI - Heteroplasmy and expression of mitochondrial genes in alloplasmic and euplasmic wheat. AB - The plant chondriome confers a complex nature. The atp4 gene (formerly called orf25) of Aegilops crassa (CR) harbors the promoter sequence of the rps7 gene from common wheat (Triticum aestivum cv. Chinese Spring, CS). The rps7 gene of CR has the promoter sequence of CS atp6. The atp6 gene of CR contains an unknown sequence inside of its coding region. Since repeat sequences have been found around the breaking points, these structural alterations are most likely generated through homologous recombination. In this study, PCR analysis was performed to detect structural alterations in each of three lines: euplasmic lines of Ae. crassa, Chinese Spring, and alloplasmic Chinese Spring wheat with the cytoplasm of Ae. crassa ((cr)-CS). We found that each of these lines contained both genotypes, although mitochondrial genotypes of CR in Chinese Spring wheat and CS genotypes in Ae. crassa were still retained as minor fractions (less than 10%). On the other hand, CS mitochondrial gene frequencies in ((cr)-CS) were shown to be ca. 30%. SNP analysis after DNA sequencing of these genes indicated that minor types of all three mitochondrial genes in alloplasmic wheat contained the mitochondrial gene types from pollens. Since the frequencies of paternal mitochondrial gene types in F(1) were about 20%, successive backcrossing increased the frequencies of paternal mitochondrial gene types to around 30% in alloplasmic wheat. Expression profiles of these mitochondrial genes were quantitatively analyzed by RT-PCR. Transcripts of paternal mitochondrial gene types were scarcely found. This suggests that minor fractions including paternal mitochondrial gene types are maintained and silenced in the descendants. PMID- 22214590 TI - Reflections on the theory of "silver bullet" octreotide tracers: implications for ligand-receptor interactions in the age of peptides, heterodimers, receptor mosaics, truncated receptors, and multifractal analysis. AB - The classical attitude of Nuclear Medicine practitioners on matters of peptide receptor interactions has maintained an intrinsic monogamic character since many years. New advances in the field of biochemistry and even in clinical Nuclear Medicine have challenged this type of thinking, which prompted me to work on this review. The central issue of this paper will be the use of somatostatin analogs, i.e., octreotide, in clinical imaging procedures as well as in relation to neuroendocirne tumors. Newly described characteristics of G-protein coupled receptors such as the formation of receptor mosaics will be discussed. A small section will enumerate the regulatory processes found in the cell membrane. Possible new interpretations, other than tumor detection, based on imaging procedures with somatostatin analogs will be presented. The readers will be taken to situations such as inflammation, nociception, mechanosensing, chemosensing, fibrosis, taste, and vascularity where somatostatin is involved. Thyroid associated orbitopathy will be used as a model for the development of multi-agent therapeutics. The final graphical summary depicts the multifactorial properties of ligand binding. PMID- 22214594 TI - Comparative genome mapping among Populus adenopoda, P. alba, P. deltoides, P. euramericana and P. trichocarpa. AB - Among the genus Populus, the sections Populus (white poplar), Aigeiros Duby (black poplar) and Tacamahaca Spach contain many tree species of economical and ecological important properties. Two parental maps for the inter-specific hybrid population of Populus adenopoda * P. alba (two species of Populus section) were constructed based on SSR and SRAP markers by means of a two-way pseudo-test cross mapping strategy. The same set of SSR markers developed from the P. trichocarpa (belonging to Tacamahaca section) genome which were used to construct the maps of P. deltoides and P. euramericana (two species of Aigeiros section) was chosen to analyze the genotype of the experimental population of P. adenopoda * P. alba. Using the mapped SSR markers as allelic bridges, the alignment of the white and black poplar maps to each other and to the P. trichocarpa physical map was conducted. The alignment showed high degree of marker synteny and colinearity and the closer relationship between Aigeiros and Tacamahaca sections than that of Populus and Tacamahaca. Moreover, there was evidence for the chromosomal duplication and inter-chromosomal reorganization involving some poplar linkage groups, suggesting a complicated course of fission or fusion in one of the lineages. A poplar consensus map based on the comparisons could be constructed will be useful in practical applications including marker assisted selection. PMID- 22214595 TI - Expression profile of mouse Mterfd2, a novel component of the mitochondrial transcription termination factor (MTERF) family. AB - Mterfd2 is a component of mitochondria transcription termination factor (MTERF) family which belongs to the MTERF4 subfamily. In this report, we characterized the expression profile of mouse Mterfd2 during embryogenesis by in situ hybridization (ISH), quantitative real-time PCR (qRT-PCR) and northern blot. The whole mount ISH at E9.5, E10.5 and E11.5 showed that Mterfd2 was dynamically expressed in the brain. Besides, at E9.5 and E10.5 stages, Mterfd2 was persistently expressed in the lateral plate mesoderm and heart; at E10.5 and E11.5 stages, it showed an abundant expression in the limb buds. The tissue ISH of E13.5 and E15.5 suggested that Mterfd2 was ubiquitously expressed, and has the higher expression in the forebrain, diencephalon, midbrain, spinal cord, dorsal root ganglion, tongue, lung, liver and kidney. This ubiquitous expression profile in the late embryogenesis was further confirmed by qRT-PCR and northern blot at E12.5, E15.5 and E18.5 stages. Besides, the results of co-location of EGFP Mterfd2 fusion protein indicated that Mterfd2 was targeted to the mitochondria. Collectively, these data suggested that Mterfd2 showed a dynamic expression pattern during embryogenesis. It might play an important role in the organ differentiation which was probably resulted from its role in the mitochondrial transcription regulation. PMID- 22214596 TI - Evolutionary diversification of DYX1C1 transcripts via an HERV-H LTR integration event. AB - DYX1C1 is a candidate gene for developmental dyslexia and has three alternative pre-mRNA spliced forms in the human genome. One of the transcripts contains an HERV-H LTR that could affect the expression level of DYX1C1. We speculate that the HERV-H LTR integrated into the DYX1C1 locus in the catarrhine lineage after its divergence from the platyrrhine lineage. Reverse transcription-PCR of the HERV-H LTR-related transcript produced four alternative forms from several human tissues. All of alternative forms were also identified in various rhesus macaque tissues. Through sequencing analysis of various primate DNA samples, we found that a part of the HERV-H LTR sequence was duplicated within the DYX1C1 exon 9 only in catarrhines. However, the duplication event did not cause frameshift mutation of the DYX1C1 transcript. Taken together, this HERV-H LTR insertion into DYX1C1 has contributed to transcript diversification of DYX1C1 during primate evolution. PMID- 22214597 TI - Interconnected bis-silylenes: a new dimension in organosilicon chemistry. AB - The past two decades have brought remarkable advances in organosilicon chemistry with the isolation of stable silylenes, persila-allene, and disilynes. The extension of this list gives an impression that it will continue to flourish. The judicous employment of sterically appropriate ligands has enabled the synthesis and isolation of compounds with low-valent silicon. Recently, for example, interconnected bis-silylenes were isolated where the two Si atoms are connected by a sigma-bond and each Si atom is possessing a lone pair of electrons. The formal oxidation state of each Si atom in the interconnected bis-silylene is +1, so bis-silylenes can be considered as the valence isomers of disilynes. In this Account, we describe the synthesis of interconnected bis-silylenes and assess their potential as a new building block in organosilicon chemistry. In 2009, we reported the isolation of a bis-silylene ((PhC(NtBu)(2))(2)Si(2)) stabilized by a sterically bulky benz-amidinato ligand with tBu substituents on the nitrogen atoms. Prior to our work, Robinson and co-workers described the synthesis of a N heterocyclic carbene stabilized bis-silylene. In following years, just two more interconnected bis-silylenes have been reported. Density functional theory calculations to establish the geometric and electronic structures of the reported bis-silylenes have shown that the Wiberg bond index (WBI) for all the reported bis-silylenes is ~1. The synthesis of stable (PhC(NtBu)(2))(2)Si(2) prompted explorations of its reactivity. An important facet of silylene chemistry involves oxidative addition at the Si(II) center with unsaturated substrates, a reaction also available for bis-silylenes. Due to the three reaction sites (two lone pairs of electrons and a labile Si(I)-Si(I) single bond) in the interconnected bis silylenes, we expect novel product formation. A labile Si-Si bond facilitates the reactions of (PhC(NtBu)(2))(2)Si(2) with diphenyl alkyne or adamantyl phosphaalkyne which afforded 1,4- disilabenzene and 1,3-disilacarbaphosphide (CSi(2)P) derivatives, respectively. The former is a noteworthy addition to the silicon analogues of benzene, and the latter serves as a heavy cyclobutadiene. With white phosphorus, a cyclic Si(2)P(2) derivative, an analogue of cyclobutadiene was obtained. The most predominant structural feature of these heavy cyclobutadienes is the presence of two-coordinate P atoms. PMID- 22214598 TI - Density-functional-theory investigation of pressure induced semiconductor-metal transitions in the ferromagnetic semiconductor HgCr2Se4. AB - We investigate the electronic structures of the ferromagnetic semiconductor HgCr(2)Se(4) by using a modified Becke and Johnson exchange potential. The energy gap calculated with the experimental lattice structure is in good agreement with the experimental value. When the pressure reaches 9.0 GPa, HgCr(2)Se(4) becomes a so-called spin gapless semiconductor due to the closure of the spin non conservation energy gap, and when the pressure increases to 11.4 GPa, the spin conservation energy gap closes, leading to a semiconductor-semimetal transition. PMID- 22214599 TI - Insulin immuno-neutralization in fed chickens: effects on liver and muscle transcriptome. AB - Chickens mimic an insulin-resistance state by exhibiting several peculiarities with regard to plasma glucose level and its control by insulin. To gain insight into the role of insulin in the control of chicken transcriptome, liver and leg muscle transcriptomes were compared in fed controls and "diabetic" chickens, at 5 h after insulin immuno-neutralization, using 20.7K-chicken oligo-microarrays. At a level of false discovery rate <0.01, 1,573 and 1,225 signals were significantly modified by insulin privation in liver and muscle, respectively. Microarray data agreed reasonably well with qRT-PCR and some protein level measurements. Differentially expressed mRNAs with human ID were classified using Biorag analysis and Ingenuity Pathway Analysis. Multiple metabolic pathways, structural proteins, transporters and proteins of intracellular trafficking, major signaling pathways, and elements of the transcriptional control machinery were largely represented in both tissues. At least 42 mRNAs have already been associated with diabetes, insulin resistance, obesity, energy expenditure, or identified as sensors of metabolism in mice or humans. The contribution of the pathways presently identified to chicken physiology (particularly those not yet related to insulin) needs to be evaluated in future studies. Other challenges include the characterization of "unknown" mRNAs and the identification of the steps or networks, which disturbed tissue transcriptome so extensively, quickly after the turning off of the insulin signal. In conclusion, pleiotropic effects of insulin in chickens are further evidenced; major pathways controlled by insulin in mammals have been conserved despite the presence of unique features of insulin signaling in chicken muscle. PMID- 22214601 TI - Anti-inflammatory effects of epidermal growth factor on the immature human intestine. AB - The inflammatory response of the preterm infants' intestine underlines its inability to respond to hemodynamic stress, microbes, and nutrients. Recent evidence suggests that exogenous epidermal growth factor (EGF) exerts a therapeutic influence on neonatal enteropathies. However, the molecular mechanisms underlying the beneficial effects of EGF remain to be clarified. The purpose of this study was to evaluate the impact of EGF on the gene expression profiles of the developing human small and large intestine at midgestation in serum-free organ cultures using microarrays. The gene expression profiles of cultured human fetal ileal and colonic explants were investigated in the absence or presence of a physiological concentration of 50 ng/ml EGF for 48 h. Data were analyzed with the Ingenuity Pathway Analysis (IPA) software and confirmed by qPCR. We found a total of 6,474 differentially expressed genes in the two segments in response to EGF. IPA functional analysis revealed that in addition to differentially modulating distinct cellular, molecular, and physiological functions in the small and large intestine, EGF regulated the inflammatory response in both intestinal segments in a distinct manner. For instance, several intestinal-derived chemokines such as CCL2, CCL25, CXCL5, and CXCL10 were found to be differentially regulated by EGF in the immature ileum and colon. The findings showing the anti-inflammatory influence of exogenous EGF suggests a mechanistic basis for the beneficial effects of EGF on neonatal enteropathies. These results reinforce growing evidence that by midgestation, the human small intestine and colon rely on specific and distinct regulatory pathways. PMID- 22214600 TI - The miR-29 family: genomics, cell biology, and relevance to renal and cardiovascular injury. AB - The human miR-29 family of microRNAs has three mature members, miR-29a, miR-29b, and miR-29c. miR-29s are encoded by two gene clusters. Binding sites for several transcriptional factors have been identified in the promoter regions of miR-29 genes. The miR-29 family members share a common seed region sequence and are predicted to target largely overlapping sets of genes. However, the miR-29 family members exhibit differential regulation in several cases and different subcellular distribution, suggesting their functional relevance may not be identical. miR-29s directly target at least 16 extracellular matrix genes, providing a dramatic example of a single microRNA targeting a large group of functionally related genes. Strong antifibrotic effects of miR-29s have been demonstrated in heart, kidney, and other organs. miR-29s have also been shown to be proapoptotic and involved in the regulation of cell differentiation. It remains to be explored how various cellular effects of miR-29s determine functional relevance of miR-29s to specific diseases and how the miR-29 family members may function cooperatively or separately. PMID- 22214602 TI - Prospective study of the risk of not using prophylactic antibiotics in nasal packing for epistaxis. AB - BACKGROUND: There is wide variation in UK prescribing practice regarding prophylactic antibiotics for nasal packing in spontaneous epistaxis. There are few published cases of infective complications in such patients. METHOD: This prospective study examined 149 consecutive patients admitted to a tertiary otorhinolaryngology centre with spontaneous epistaxis, who underwent nasal packing, over a six-month period. In the first three-month period, 78 patients were routinely prescribed prophylactic antibiotics; in the second three months, 71 patients were not routinely prescribed antibiotics. Exclusion criteria included antibiotics prescribed for unrelated pathology and post-operative epistaxis. Signs and symptoms of acute otitis media, sinusitis and toxic shock syndrome were assessed using clinical examination and a questionnaire. RESULTS: Fourteen of the 149 patients experienced otalgia, most commonly following posterior nasal packing. No patient in either group had evidence of any infective complication. CONCLUSION: We do not recommend the routine prescription of prophylactic antibiotics for patients undergoing nasal packing for spontaneous epistaxis. PMID- 22214603 TI - Two selected models of missense mutations in mice for the study of learning behaviour. AB - A large number of genome-wide association studies have linked missense mutations, mutations altering the amino acid sequence of proteins, with cognitive impairment in humans. However, these studies are correlative. As there may be multiple mutations for one particular patient, it is essential to address the functional impact of a missense mutation in a model system. The most suitable model system is the generation of knock-in mice with the homologous missense mutation followed by behavioural phenotyping. Here, we review selected mutants demonstrating an impact of single mutations on learning and memory in mice and discuss the relevance of such studies for understanding the role of these polymorphisms in human behaviour. We conclude that using these animal models has been instrumental in decoding the mechanisms underlying behaviour, and assists the design of therapeutic strategies for humans. PMID- 22214604 TI - Dietary patterns: the importance of sex differences. PMID- 22214605 TI - The traveling Libby legacy: Minnesota community exhibits nonoccupational health impacts consistent with asbestos damage. PMID- 22214606 TI - Extended scaling in the magnetic critical phenomenology of the sigma-phase Fe0.53 Cr0.47 and Fe0.52-V0.48 alloys. AB - The magnetization of the sigma-phase Fe(0.53)Cr(0.47) and Fe(0.52)V(0.48) alloys was studied as a function of temperature and field. The experiments show that both materials behave magnetically as re-entrant spin glass systems. Field versus temperature diagrams were obtained where the locations of the paramagnetic phase, the intermediate ferromagnetic-like phase and the spin glass fundamental state were displayed. These diagrams are in qualitative agreement with the predictions of the mean field theory for the interplay between the ferromagnetic and spin glass orderings. The critical phenomenology near the para-ferromagnetic transition could be investigated. It was found that the paramagnetic susceptibility is quite well described by the extended scaling scheme, where the reduced temperature is written as tau = (T - T(c))/T. The value obtained for the susceptibility critical exponent gamma is intermediate between the prediction of the 3D Heisenberg universality class and the large values observed in spin glasses, as previously found in other re-entrant systems. The data do not confirm the validity of the extended scaling in the ferromagnetic-like phase. Using either the conventional or extended scaling protocols, the exponents beta and delta were found to have values close to those reported for spin glass transitions. Despite the relevance of disorder and the anomalous values determined for beta, gamma and delta, the Widom scaling relation holds as an equality. PMID- 22214607 TI - Review of the literature: the longest documented left main coronary artery. PMID- 22214608 TI - Spectroscopy and imaging of arrays of nanorods toward nanopolarimetry. AB - The polarization dependence of the optical scattering properties of two dimensional arrays of metal nanostructures with sub-wavelength dimensions (nanoantennas) has been investigated. Arrays of 500 nm * 100 nm gold nanorods covering a 100 * 100 um(2) area were fabricated with varying orientations on an electrically conductive substrate. The experimental and computational analysis of the angularly organized nanorods suggest potential use toward the development of an integrated polarimeter. Using the gold nanorods on a transparent substrate as a preliminary system, we show that in the proper spectral range the scattering properties of the structures may be tuned for such an application. PMID- 22214609 TI - On the pleiotropic structure of the genotype-phenotype map and the evolvability of complex organisms. AB - Analyses of effects of mutants on many traits have enabled estimates to be obtained of the magnitude of pleiotropy, and in reviews of such data others have concluded that the degree of pleiotropy is highly restricted, with implications on the evolvability of complex organisms. We show that these conclusions are highly dependent on statistical assumptions, for example significance levels. We analyze models with pleiotropic effects on all traits at all loci but by variable amounts, considering distributions of numbers of traits declared significant, overall pleiotropic effects, and extent of apparent modularity of effects. We demonstrate that these highly pleiotropic models can give results similar to those obtained in analyses of experimental data and that conclusions on limits to evolvability through pleiotropy are not robust. PMID- 22214610 TI - Mitochondrial genome maintenance: roles for nuclear nonhomologous end-joining proteins in Saccharomyces cerevisiae. AB - Mitochondrial DNA (mtDNA) deletions are associated with sporadic and inherited diseases and age-associated neurodegenerative disorders. Approximately 85% of mtDNA deletions identified in humans are flanked by short directly repeated sequences; however, mechanisms by which these deletions arise are unknown. A limitation in deciphering these mechanisms is the essential nature of the mitochondrial genome in most living cells. One exception is budding yeast, which are facultative anaerobes and one of the few organisms for which directed mtDNA manipulation is possible. Using this model system, we have developed a system to simultaneously monitor spontaneous direct-repeat-mediated deletions (DRMDs) in the nuclear and mitochondrial genomes. In addition, the mitochondrial DRMD reporter contains a unique KpnI restriction endonuclease recognition site that is not present in otherwise wild-type (WT) mtDNA. We have expressed KpnI fused to a mitochondrial localization signal to induce a specific mitochondrial double strand break (mtDSB). Here we report that loss of the MRX (Mre11p, Rad50p, Xrs2p) and Ku70/80 (Ku70p, Ku80p) complexes significantly impacts the rate of spontaneous deletion events in mtDNA, and these proteins contribute to the repair of induced mtDSBs. Furthermore, our data support homologous recombination (HR) as the predominant pathway by which mtDNA deletions arise in yeast, and suggest that the MRX and Ku70/80 complexes are partially redundant in mitochondria. PMID- 22214611 TI - "Calling cards" for DNA-binding proteins in mammalian cells. AB - The ability to chronicle transcription-factor binding events throughout the development of an organism would facilitate mapping of transcriptional networks that control cell-fate decisions. We describe a method for permanently recording protein-DNA interactions in mammalian cells. We endow transcription factors with the ability to deposit a transposon into the genome near to where they bind. The transposon becomes a "calling card" that the transcription factor leaves behind to record its visit to the genome. The locations of the calling cards can be determined by massively parallel DNA sequencing. We show that the transcription factor SP1 fused to the piggyBac transposase directs insertion of the piggyBac transposon near SP1 binding sites. The locations of transposon insertions are highly reproducible and agree with sites of SP1-binding determined by ChIP-seq. Genes bound by SP1 are more likely to be expressed in the HCT116 cell line we used, and SP1-bound CpG islands show a strong preference to be unmethylated. This method has the potential to trace transcription-factor binding throughout cellular and organismal development in a way that has heretofore not been possible. PMID- 22214612 TI - Extravascular lung water index improves the diagnostic accuracy of lung injury in patients with shock. AB - INTRODUCTION: The diagnosis of acute lung injury (ALI) may be more robust if more accurate physiological markers can be identified. Extravascular lung water (EVLW) is one possible marker, and it has been shown to correlate with respiratory function and mortality in patients with sepsis. Whether EVLW confers diagnostic value in a general population with shock, as well as which index performs best, is unclear. We investigated the diagnostic accuracy of various EVLW indices in patients with shock. METHODS: We studied a prospective, observational cohort of 51 patients with shock admitted to a tertiary ICU. EVLW was measured within 6 hours of ICU admission and indexed to actual body weight (EVLW/ABW), predicted body weight (EVLW/PBW) and pulmonary blood volume (EVLW/PBV). The relationship of these indices to the diagnosis and severity of lung injury and ICU mortality were studied. Positive and negative likelihood ratios, pre- and posttest odds for diagnosis of lung injury and mortality were calculated. RESULTS: All EVLW indices were higher among patients with lung injury and significantly correlated with respiratory parameters. Furthermore, all EVLW indices were significantly higher in nonsurvivors. The use of EVLW improves the posttest OR for the diagnosis of ALI, acute respiratory distress syndrome (ARDS) and severe lung injury (sLI) by up to eightfold. Combining increased EVLW and a diagnosis of ALI, ARDS or sLI increases the posttest odds of ICU mortality. EVLW/ABW and EVLW/PBV demonstrated the best diagnostic performance in this population. CONCLUSIONS: EVLW was associated with degree of lung injury and mortality, regardless of the index used, confirming that it may be used as a bedside indicator of disease severity. The use of EVLW as a bedside test conferred added diagnostic value for the identification of patients with lung injury. PMID- 22214613 TI - Interactions between atrial electrical remodeling and autonomic remodeling: how to break the vicious cycle. AB - BACKGROUND: The mechanism(s) underlying the maintenance of atrial fibrillation (AF) during the first few hours after AF was initiated remains poorly understood. OBJECTIVE: To investigate the roles of the intrinsic cardiac autonomic nervous system in the maintenance of AF at the early stage. METHODS: In 10 anesthetized dogs, we attached multielectrode catheters on atria and pulmonary veins. Microelectrodes inserted into the anterior right ganglionated plexi recorded neural activity. At baseline, programmed stimulation determined the effective refractory period (ERP) and window of vulnerability (WOV), a measure of AF inducibility. For the next 6 hours, AF was simulated by rapid atrial pacing (RAP) and the same parameters were measured hourly during sinus rhythm. A circular catheter was positioned in the superior vena cava for high-frequency stimulation (20 Hz) of the adjacent vagal preganglionics. During 4-6 hours of RAP, we delivered low-level vagal stimulation in the superior vena cava (LL-SVCS), 50% below that which induced slowing of the sinus rate. RESULTS: During the 6-hour RAP, there was a progressive decrease in the ERP and an increase in ERP dispersion, WOV, and neural activity. With LL-SVCS during 4-6-hour RAP, ERP, WOV, and neural activity returned toward baseline levels (all P <.05, compared with the third-hour RAP values). CONCLUSIONS: RAP not only induces atrial electrical remodeling but also promotes autonomic remodeling. These 2 remodeling processes may form a vicious cycle and each may perpetuate the other. These findings may help to explain how AF maintains itself in its very early stage. LL-SVCS both reversed remodeling processes and can potentially break the vicious cycle of "AF begets AF" in the first few hours of AF. PMID- 22214614 TI - Predictors of long-term success after catheter ablation of atriofascicular accessory pathways. AB - BACKGROUND: Electrophysiologic characteristics, mapping strategies, and acute success rates of radiofrequency catheter ablation of atriofascicular accessory pathways are well described. However, data on long-term prognosis and predictors for freedom from arrhythmias are lacking. OBJECTIVE: To report our 20-year single center experience on ablation of atriofascicular fibers. METHOD: Between 1992 and 2010, 34 patients with atriofascicular accessory pathways underwent catheter ablation at our institution because of symptomatic antidromic atrioventricular reentrant tachycardias. Radiofrequency procedures were retrospectively analyzed, and patients were followed for recurrences of tachyarrhythmias. Electrocardiograms (before and after ablation and at follow-up) were analyzed for each patient. RESULTS: Successful catheter ablation of the atriofascicular fiber was achieved in 23 (68%) patients. Mechanical block during mapping occurred in 3 (9%) patients, and in 2 of them ablation was performed at the site of mechanical block. Mere modification of conduction properties of the pathway without complete block was achieved in 5 patients (15%). Fast pathway ablation was performed in 2 (6%) of the patients ablated in the early 1990s. During follow-up of 9.3 +/- 5.5 years, 24 patients (71%) remained free of tachyarrhythmias, 7 reported significant improvement, and 3 (9%) had no change in symptoms after ablation. Long-term success was identical between patients from the first (1992-1999) and second (2000-2010) decade (12 of 17 [71%] vs 12 of 17 [71%]). It was 87% in those with complete block of the atriofascicular fiber while all patients with mechanical block during mapping reported recurrences. Fast pathway ablation was complicated by complete atrioventricular block in 1 patient, who required pacemaker implantation 18 years after ablation owing to loss of conduction properties of the atriofascicular fiber over the years. On analyzing patients with preexcitation before ablation (n = 16; 47%), we found that the PR interval after ablation was significantly longer only in those without recurrence (162 +/- 21 ms vs 134 +/- 21 ms; P = .042). None of the other analyzed electrocardiographic parameters, including PR, QRS duration, and preexcitation, had prognostic impact. CONCLUSION: Acute success of complete ablation of atriofascicular pathways is associated with excellent long-term success (87%). Mere modification of conduction properties of atriofascicular fibers or ablation at the sites of mechanical block are less promising end points of ablation with high recurrence rates. Technical innovations during decades may not further improve long-term outcome in these patients. PMID- 22214616 TI - Efficacy of contrast-enhanced ultrasonography in radiofrequency ablation for hepatocellular carcinoma. AB - OBJECTIVE: Local recurrence after radiofrequency ablation (RFA) is a major problem that needs to resolved to increase the survival rate of hepatocellular carcinoma (HCC). CE-US with Sonazoid((r)), the second-generation contrast media, can detect smaller HCC lesions and the detection rate of ultrasonically unrecognized hypervascular HCC was improved by CE-US. The aim of the present study was to evaluate the role of CE-US with Sonazoid((r)) in improving radicality and reducing local recurrence after RFA for HCC. PATIENTS AND METHODS: A total of 102 nodules treated by RFA at our hospital from January 2006 to October 2009 were enrolled: 31 nodules were treated without CE-US, since CE-US was not yet available (Group A), and 71 nodules were treated with a combination of RFA and CE-US with Sonazoid((r)) (Group B). RESULTS: The clinical characteristics (sex, virus marker, Child-Pugh grade, with or without transcatheter arterial infusion chemotherapy with lipiodol, and T factor) did not differ significantly between group A and group B. Mean age was significantly older and tumor size was significantly larger in group B. Group B had significantly better radicality compared with group A. The non-local recurrence rate was significantly higher in group B as compared with group A. CONCLUSION: CE US with Sonazoid((r)) greatly helps to improve RFA efficacy in HCC treatment. We suggest that the ability of CE-US with Sonazoid((r)) to detect an accurate area of HCC before RFA and to immediately detect a residual tumor during RFA might contribute to an increase of the radicality and reduction of local recurrence after RFA. PMID- 22214617 TI - A multicenter study to clarify the optimal HCV-RNA negative period during combined therapy with pegylated interferon plus ribavirin in patients with chronic hepatitis caused by HCV genotype 2. AB - OBJECTIVE: A multicenter open trial was performed to clarify the optimal duration of combined pegylated interferon (Peg-IFN) plus ribavirin therapy in patients with chronic hepatitis caused by HCV genotype 2. METHODS: A total of 100 patients seen between 2005 and 2007 received the combination therapy for 4 to 52 weeks. The cutoff value of the HCV-RNA-negative (titers under 1.7 Log IU/mL) period during the therapy to predict sustained virological response (SVR) was determined by ROC curve and multivariate logistic regression analyses. The result was validated in 48 patients between 2008 and 2009. RESULTS: SVR was achieved in 78 patients. Serum HCV-RNA titers decreased to less than 1.7 Log IU/mL at 4 weeks of the therapy in 60 patients. The SVR rate in these patients was 85%, which was significantly higher than that of remaining 40 patients with a SVR rate of 68%. An HCV-RNA-negative period of >=17 weeks was selected as the cutoff value, which showed a significant odds ratio of 4.77 for SVR. Among the 35 patients who showed a decrease of the serum HCV-RNA of less than 1.7 Log IU/mL between 8 and 16 weeks of therapy, the SVR rate was significantly higher in 16 patients with a serum HCV RNA-negative period of >=17 weeks (94%) than in 19 patients in whom the period was less than 17 weeks (63%). Similar results were obtained in the subsequent validation study. CONCLUSION: Prolonged combined Peg-IFN plus ribavirin therapy, with an HCV-RNA-negative period of >=17 weeks, yielded good therapeutic outcomes in patients with chronic HCV genotype 2 hepatitis. PMID- 22214618 TI - Increased risk of ischemic stroke in patients with systemic lupus erythematosus: a nationwide population-based study. AB - BACKGROUND: Systemic lupus erythematosus (SLE) has been reported to be associated with an increased risk of cardiovascular disease. However, most studies have been criticized for either a small sample size or the lack of a prospective control. Our study investigated the relationship of SLE and the subsequent development of ischemic stroke using a nationwide, population-based database in an Asian population. METHODS: From 2000 to 2007, we identified a study cohort consisting of a total of 11,637 newly diagnosed SLE patients using the National Health Insurance Research Database in Taiwan. A control cohort of 58,185 subjects without SLE, matched for age, gender, and comorbidities were selected for comparison to observe the occurrence of ischemic stroke in these two groups. RESULTS: During a follow-up period of up to 7 years, ischemic stroke developed in 258 (2.22%) of the patients with SLE and in 873 (1.5%) of patients in the comparison cohort. Kaplan-Meier analysis also revealed a tendency of SLE patients toward ischemic stroke development (log rank test, p = 0.001). After Cox model adjustment for patients' demographic characteristics and selected comorbidities, patients with SLE were found to have a 1.67-fold (95% CI, 1.45 to 1.91) higher risk of developing ischemic stroke. CONCLUSION: Patients with SLE have an increased risk of stroke. PMID- 22214619 TI - Prehypertension in children and adolescents: association with body weight and neck circumference. AB - OBJECTIVE: The present study was undertaken to investigate the role of neck circumference (NC) in predicting prehypertension in children and adolescents. METHODS: We conducted a cross-sectional study including 6,802 children and adolescents (3,631 boys and 3,171 girls) aged 5-18 years. Main anthropometric data and related information were collected. RESULTS: The prevalence of prehypertension was 14.4%, 16.4% and 17.1% in normal weight, overweight and obese group respectively. Among the participants with normal body mass index (BMI), higher NC was significantly associated with increased odds of prehypertension (OR: 1.439; 95% CI: 1.118 to 1.853) after adjustment for age, gender, BMI and WC. Significant associations between NC and either systolic blood pressure (SBP) (beta=0.581 mmHg) or diastolic blood pressure (DBP) (beta=0.236 mmHg) were found in the linear regression. No significant ORs were observed either in overweight or in obese categories. CONCLUSION: We concluded that additional measure of NC might expand the ability of BMI for the identification of prehypertension in normal weight children and adolescents. PMID- 22214621 TI - A retrospective analysis of 111 cases of pneumococcal pneumonia: clinical features and prognostic factors. AB - OBJECTIVE: Streptococcus pneumoniae is an important and common pathogen of acute pneumonia. The urinary pneumococcal antigen test has been increasingly used for the diagnosis of pneumococcal pneumonia, but there have been few studies on pneumococcal pneumonia after this test became prevalent. The present study was conducted to characterize the clinical features of pneumococcal pneumonia after the introduction of the urinary antigen test. METHODS: We retrospectively analyzed 111 cases from 105 patients with pneumococcal pneumonia in our hospital between 2007 and 2010, and collected data regarding background characteristics, laboratory data, isolated bacteria, and clinical courses. RESULTS: The cases analysed included 77 of community-acquired pneumonia (CAP), 21 of healthcare associated pneumonia (HCAP), and 13 of hospital-acquired pneumonia (HAP). Penicillin-resistant Streptococcus pneumoniae was isolated in 12.5 and 55.6% of non-HAP and HAP cases, respectively. When the cases were divided into 5 groups according to A-DROP scores (0, 1, 2, 3 and 4 points), critical events occurred at 0, 0, 8.7, 15.4, and 75.0% in groups of cases of 0, 1, 2, 3, and 4 points, respectively. Similarly, critical events occurred at 66.7, 4.7, 3.8, and 9.1% in groups of cases according to WBC counts of <4,000, 4,000-9,999, 10,000-19,999, and >=20,000 cells/uL, respectively. CONCLUSION: Most of the pneumococcal pneumonia cases occurred as CAP and were treated successfully. HAP cases were frequently penicillin resistant. Elevated A-DROP scores and decreased WBC counts were found to be predictive of critical events. PMID- 22214620 TI - Progression of cognitive dysfunction in elderly chronic kidney disease patients in a veteran's institution in central Taiwan: a 3-year longitudinal study. AB - OBJECTIVE: A strong positive correlation between estimated glomerular filtration rate (eGFR) multiplied by follow-up time and memory function has been demonstrated previously. The purpose of this study was to investigate the factors affecting progression of cognitive dysfunction in the elderly with different levels of kidney function. METHODS: In April 2002, a prospective study on progression of cognitive function was conducted on 356 elderly people. All participants received a comprehensive geriatric assessment, serum biochemical test, homeostasis model assessment (HOMA), and a genetic polymorphism study, including polymorphism of apolipoprotein E (APOE), Cystatin, C-reactive protein (CRP) and tumor necrosis factor (TNF). Lean body mass-adjusted eGFR was used to evaluate severity of chronic kidney disease (CKD), and a clinical dementia rating scale was used to assess cognitive dysfunction. Patients were stratified according to eGFR (>=49 mL/min and <49 mL/min). RESULTS: Using multivariate logistic regression models, older age (OR=1.27, 95% CI=1.00-1.61) was associated with a high risk for progression of cognitive function in patients with a relatively low eGFR. In patients with lower eGFR, higher mini-mental state examination (MMSE) scores (OR=0.23, 95% CI=0.10-0.54) were correlated with a low risk for progression of cognition, while in patients with higher eGFR, higher MMSE scores (OR=0.39, 95% CI=0.23-0.65) were less correlated with cognitive dysfunction. However, elevated serum plasminogen activator inhibitor-1 (PA1-1) was associated with a high risk for cognitive dysfunction (OR=1.06, 95% CI=1.01 1.11) in patients with a better eGFR. CONCLUSION: Age, MMSE score and serum PAI-1 were found to be factors that predicted cognitive dysfunction at different functional levels of CKD. PMID- 22214622 TI - Oral intake 6 months after acute ischemic stroke. AB - OBJECTIVE: It remains unclear which patients with acute stroke need percutaneous endoscopic gastrostomy (PEG) placement and when it should be performed. The aim of this study was to identify the predictors for oral intake 6 months after onset in stroke patients. METHODS: Data were obtained from a prospectively registered database of 738 acute ischemic stroke patients both with and without a history of stroke. Patients who survived for 6 months and replied to a questionnaire were divided into two groups: those with oral intake 6 months after onset and those without. Predictors for oral intake 6 months after onset were analyzed. RESULTS: Forty-five patients died during their hospital stay, 145 did not reply to the questionnaire, and 23 died during follow-up. Of the residual 525 patients, 485 (92.4%) had oral intake after 6 months. On multivariate analysis, modified Rankin Scale score 0 before admission (OR 2.70, 95% CI 1.10-6.61) and National Institutes of Health Stroke Scale (NIHSS) score <=9 on day 10 (OR 21.12, 95% CI 5.04-88.39) were independent predictors for oral intake after 6 months, while NIHSS score on admission was not. CONCLUSION: Clinicians should be cautious about PEG placement for stroke patients who were independent prior to their stroke and whose stroke severity decreases 10 days after admission, because their swallowing dysfunction may improve within a brief period. PMID- 22214623 TI - Clinical characteristics of tertiary hospital patients from whom Acinetobacter calcoaceticus-Acinetobacter baumannii complex strains were isolated. AB - OBJECTIVE: Acinetobacter baumannii is a worldwide nosocomial pathogen that has become increasingly common over the past few decades, and strains of multidrug resistant A. baumannii have been increasing. The aim of this study was to assess the clinical characteristics of A. calcoaceticus-A. baumannii complex (Acb complex) strains and to determine the risk factors of this infection. METHODS: The medical records of 121 patients at Nagasaki University Hospital from whom Acb complex had been isolated between January 2007 and December 2009 were retrospectively reviewed. Patient backgrounds, sensitivity to antibiotics, risk factors for infection, and prognosis were evaluated. RESULTS: Lower respiratory isolates accounted for 73% (147 strains) of all 201 isolates. Most of the isolates were sensitive to carbapenems. Of the 121 patients (74 males and 47 females; mean age: 62.1 years), 48 (39.7%) had malignancy and 75 (62.0%) were treated with antibiotics prior to isolation. Thirty-seven of the patients in this study (30.6%) were infected by Acb complex and the most frequent clinical manifestation was pneumonia (18 cases; 48.6%). Approximately 60% of infected patients were treated with beta-lactam agent in combination with beta-lactamase inhibitors or carbapenems. The mortality rate of infected patients was significantly higher than that of colonized patients (infected: 24.3%, colonized: 6.0%, p<0.05). Risk factors for Acb complex infection include being over 60 years of age, chronic liver disease, and the use of first-generation cephalosporins prior to isolation. CONCLUSION: Acb complex was relatively sensitive to antibiotics. The appropriate usage of antibiotics should be continued for the prevention of drug resistance in Acb complex. PMID- 22214624 TI - Clinical characteristics and risk factors for mortality in patients with bacteremia caused by Pseudomonas aeruginosa. AB - OBJECTIVE: The mortality rates for bacteremia due to Pseudomonas aeruginosa remain high. In our hospital, we performed retrospective analyses to determine risk factors for mortality among patients with bacteremia caused by P. aeruginosa. MATERIALS AND METHODS: This retrospective cohort study was conducted among adult patients with bacteremia due to P. aeruginosa at Jikei University Hospital. We analyzed factors, such as age, gender, underlying disease, initial antimicrobial treatment, and primary site of infection to determine which of these were predictive of mortality in patients with P. aeruginosa bacteremia. RESULTS: One hundred and thirty-four patients with P. aeruginosa bacteremia were identified between April 2003 and March 2010. The 30-day mortality rate among all patients with P. aeruginosa bacteremia was 20.9%. The most common underlying disease was leukemia (20.9%), and the most common primary site of infection was the urinary tract (24.6%). Seventy-one patients (65.7%) were treated with an appropriate initial antimicrobial regimen for P. aeruginosa bacteremia. However, these patients had similar 30-day mortality to that observed in patients not administered appropriate antibiotics. This study revealed that risk factors for the 30-day mortality were thrombocytopenia and polymicrobial P. aeruginosa bacteremia (p<0.01). CONCLUSION: Thrombocytopenia and polymicrobial bacteremia were associated with a greater incidence of 30-day mortality among patients with P. aeruginosa bacteremia. On the other hand, age, underlying disease, and inappropriate initial empirical antimicrobial treatment did not affect mortality. PMID- 22214625 TI - Sarcoidosis manifesting as cardiac sarcoidosis and massive splenomegaly. AB - Sarcoidosis is a multisystemic granulomatous disease of unknown etiology. We report an unusual case of sarcoidosis in a woman presenting with cardiac sarcoidosis and massive splenomegaly with a familial history of cardiac sarcoidosis. Cardiac sarcoidosis was diagnosed based on electrocardiogram, echocardiogram, 18F-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET) and skin histological findings. We performed splenectomy to rule out malignant lymphoma, and histological findings confirmed sarcoidosis. After splenectomy, we initiated prednisolone therapy. After 20 months of diagnosis, she was symptom free. Echocardiography and 18F-FDG-PET may be a key diagnostic tool and prednisolone therapy may be safe, effective, and feasible for cardiac sarcoidosis. PMID- 22214626 TI - Congenital absence of the left circumflex artery associated with inferior myocardial infarction. AB - Congenital absence of the left circumflex artery is a rare anomaly of the coronary arteries. A 52-year-old man who developed acute inferior myocardial infarction underwent coronary angiography which revealed the absence of the left circumflex artery and that the surrounding structures were supplied by the infarct-related super-dominant right coronary artery. Two stents were implanted into the right coronary artery and one stent into the mid portion of the left anterior descending artery. Follow-up coronary angiography at 67 months showed no detectable restenosis, and 64-slice multidetector computed tomography confirmed the absence of the left circumflex artery. The circumflex artery as a terminal extension of a culprit right coronary artery has not been previously reported. PMID- 22214627 TI - Primary leiomyosarcoma of the pulmonary artery: a case of a 20-month survivor after incomplete surgical resection. AB - We report a 53-year-old man who presented with dyspnea and low-grade fever. Cardiac ultrasound showed pulmonary hypertension and an ill-defined echogenic mass within the pulmonary trunk. Computed tomography scan revealed an inhomogeneous mass which filled the main pulmonary trunk with near-total occlusion, and extended into both pulmonary arteries. Anticoagulant therapy was administered based on a presumptive diagnosis of pulmonary thromboembolism. Positron-emission tomography scan was useful for differentiating the mass, which was determined as a pulmonary artery sarcoma by surgical resection. Although complete resection was impossible, the patient survived for 20 months with adjuvant chemotherapy and medical treatment. PMID- 22214628 TI - Slowly progressive insulin-dependent diabetes in a patient with primary biliary cirrhosis with portal hypertension-type progression. AB - A 73-year-old woman had previously been diagnosed with CREST syndrome, PBC and diabetes. Hepatic fibrosis was not evident, in spite of the transudative ascites and active esophageal varices. ACA were positive, whereas AMA and anti-gp210 antibodies were negative. She showed low urinary excretion of C-peptide and was weakly positive for anti-GAD antibody. She was diagnosed with a form of PBC that progresses via portal hypertension rather than liver failure and with SPIDDM. Her HLA type did not contain risk allele for IDDM or PBC. SPIDDM should be considered when patients with PBC with portal hypertension-type progression develop diabetes. PMID- 22214629 TI - Eplerenone improved hypokalemia in a patient with Gitelman's syndrome. AB - A 47-year-old woman presented with hypokalemia (2.4 mmol/L). She also had hypomagnesemia, hypocalciuria, and hyperreninemic hyperaldosteronism. Sequence analysis revealed a compound heterozygous mutation, R655C and R955Q, in the SLC12A3 gene. These findings were compatible with Gitelman's syndrome (GS). Eplerenone, a selective aldosterone blocker, in combination with oral potassium chloride improved serum potassium level (3.6 mmol/L) with no apparent adverse effect. Although eplerenone has an advantage over spironolactone for its selective affinity for the aldosterone receptor, the efficacy and safety of eplerenone for GS is little understood. Our observation suggests that eplerenone is a useful treatment option for GS. PMID- 22214630 TI - A case of adenoid cystic carcinoma presenting as Garcin's syndrome without mass formation. AB - Adenoid cystic carcinoma (ACC) is a malignant neoplasm that commonly arises in the major or minor salivary gland and usually forms mass lesions. Here, we report a case of ACC involving a 56-year-old man, who displayed right multiple cranial nerve palsies with ipsilateral severe facial pain but not any mass formation. Right submaxillary gland biopsy after repeated challenges at last revealed the primary focus of ACC with perineural invasion and without lymph node metastasis. The neurological manifestations were considered to be attributed to the perineural spread of ACC. It is extremely rare for ACC to show Garcin's syndrome without mass formation. PMID- 22214632 TI - Alcohol-responsive writer's cramp. AB - Writer's cramp is a rare movement disorder of unknown etiology, in which a cramp is elicited primarily or exclusively with writing. We describe a patient with primary writer's cramp that was completely improved by drinking a small amount of alcohol. Although it is unclear how "alcohol" ameliorated the dystonia, this case suggests that alcohol might reverse the pathophysiologic changes in the entire basal ganglia circuit. In addition, we cannot rule out the possibility that the anxiolytic influence of alcohol may contribute to the beneficial effects on dystonia. PMID- 22214631 TI - A novel GJA1 mutation in oculodentodigital dysplasia with progressive spastic paraplegia and sensory deficits. AB - Oculodentodigital dysplasia (ODDD) is a rare autosomal dominant inherited disorder mainly affecting the development of the face, eyes, dentition, limbs, hair and heart. GJA1 (the gap junction protein alpha-1) has been determined to be a causative gene of ODDD, mapped to chromosome 6q22-24 identified as the connexin 43 gene (Cx43). We found a novel GJA1 mutation (W25C) as the possible causative gene in this sporadic ODDD patient with neurological features of motor deficits by pyramidal tract signs, and sensory deficits due to peripheral nerve disturbance. It is also notable that the MRI of this patient demonstrated widespread aberrant signal lesions in the brain and brainstem. PMID- 22214633 TI - Elderly-onset neuromyelitis optica which developed after the diagnosis of prostate adenocarcinoma and relapsed after a 23-valent pneumococcal polysaccharide vaccination. AB - We report a case of elderly-onset neuromyelitis optica (NMO) positive for the anti-aquaporin-4 (AQP-4) antibody; symptoms developed after the diagnosis of prostate adenocarcinoma and relapsed after a 23-valent pneumococcal polysaccharide vaccination. We suggest that activation of CD4-positive T cells and secretion of interferon-gamma induced by adenocarcinoma and complement activation induced by vaccination are responsible for the onset and relapse of NMO, even if a patient is positive for the anti-AQP-4 antibody. This case supports the previous experimental finding that the anti-AQP-4 antibody does not cause NMO-like lesions when injected alone, but does so after the induction of T cell-mediated experimental autoimmune encephalomyelitis or when co-injected with human complement. PMID- 22214634 TI - Churg-Strauss syndrome complicated by chronic periaortitis: a case report and review of the literature. AB - We present a case of Churg-Strauss syndrome complicated by chronic periaortitis. A 68-year-old man presented with wheezing, dyspnea, purpurae, and numbness of the extremities. Antineutrophil cytoplasmic antibodies were absent; however, eosinophilia, a pulmonary infiltrative shadow on chest X-ray, eosinophilic vasculitis on histologic examination of skin and kidney, and mononeuritis multiplex were detected. Churg-Strauss syndrome was diagnosed. Contrast-enhanced abdominal computed tomography revealed a periaortic soft tissue mass extending from the subphrenic abdominal aorta to the proximal area of the bilateral iliac arteries. This indicated chronic periaortitis, probably caused by vasculitic activities. Both disorders improved with steroid therapy. PMID- 22214635 TI - The role of Chlamydia and Chlamydophila infections in reactive arthritis. AB - Chlamydia trachomatis and Chlamydophila pneumoniae are human pathogens; the former being the etiologic agent for trachoma as well as a prevalent sexually transmitted bacterium, while C. pneumoniae is a respiratory pathogen responsible for community-acquired pneumonia. Patients with reactive arthritis show evidence of present or past Chlamydial infection. Chlamydia spp., has been strongly implicated as a triggering factor for reactive arthritis. We describe the simultaneous occurrence of C. pneumoniae and C. trachomatis infections in a subject with reactive arthritis. We suggest treatment for a patient with Chlamydia-associated arthritis to define a means by which persistent organisms can be induced to return to the active developmental cycle, thereby making them more accessible to antibiotic activity. PMID- 22214636 TI - Multifocal Langerhans cell histiocytosis in an adult. PMID- 22214637 TI - Nifedipine-induced gingival hypertrophy. PMID- 22214638 TI - Encapsulating peritoneal sclerosis. PMID- 22214639 TI - Tension pneumomediastinum in a patient with interstitial pneumonia. PMID- 22214640 TI - Oropharyngeal metastasis of cardiogenic angiosarcoma. PMID- 22214641 TI - Brain abnormality in mild legionellosis. PMID- 22214642 TI - Uterine carcinosarcoma with scalp metastasis; a rare presentation. PMID- 22214643 TI - Obstructive uropathy caused by atherosclerotic abdominal aortic aneurysm. PMID- 22214644 TI - Reversible cerebral vasoconstriction syndrome and subarachnoid hemorrhage; which occurs first? PMID- 22214646 TI - Virulence: The first two years. PMID- 22214647 TI - Long-term exposure to traffic-related air pollution associated with blood pressure and self-reported hypertension in a Danish cohort. AB - BACKGROUND: Short-term exposure to air pollution has been associated with changes in blood pressure (BP) and emergency department visits for hypertension, but little is known about the effects of long-term exposure to traffic-related air pollution on BP and hypertension. OBJECTIVES: We studied whether long-term exposure to air pollution is associated with BP and hypertension. METHODS: In 1993-1997, 57,053 participants 50-64 years of age were enrolled in a population based cohort study. Systolic and diastolic BP (SBP and DBP, respectively) were measured at enrollment. Self-reported incident hypertension during a mean follow up of 5.3 years was assessed by questionnaire. We used a validated dispersion model to estimate residential long-term nitrogen oxides (NO(x)), a marker of traffic-related air pollution, for the 1- and 5-year periods prior to enrollment and before a diagnosis of hypertension. We conducted a cross-sectional analysis of associations between air pollution and BP at enrollment with linear regression, adjusting for traffic noise, measured short-term NO(x), temperature, relative humidity, and potential lifestyle confounders (n = 44,436). We analyzed incident hypertension with Cox regression, adjusting for traffic noise and potential confounders. RESULTS: A doubling of NO(x) exposure during 1- and 5-year periods preceding enrollment was associated with 0.53-mmHg decreases [95% confidence interval (CI): -0.88, -0.19 mmHg] and 0.50-mmHg decreases (95% CI: 0.84, -0.16 mmHg) in SBP, respectively. Long-term exposure also was associated with a lower prevalence of baseline self-reported hypertension (per doubling of 5 year mean NO(x): odds ratio = 0.96; 95% CI: 0.91, 1.00), whereas long-term NO(x) exposure was not associated with incident self-reported hypertension during follow-up. CONCLUSIONS: Long-term exposure to traffic-related air pollution was associated with a slightly lower prevalence of BP at baseline, but was not associated with incident hypertension. PMID- 22214648 TI - High magnetic field quantum transport in Au nanoparticle-cellulose films. AB - We report the magneto-transport properties of cellulose films comprising interconnected networks of gold nanoparticles (Au NPs). Cellulose is a biopolymer that can be made electrically conducting by cellulose regeneration in Au NP dispersions. The mechanism of electronic conduction in the Au-cellulose films changes from variable range hopping to metallic-like conduction with decreasing resistivity. Our experiments in high magnetic fields (up to 45 T) reveal negative magnetoresistance in the highly resistive films. This is attributed to the spin polarization of the Au NPs and the magnetic field induced suppression of electron spin flips during spin-polarized tunneling in the NP network. PMID- 22214650 TI - Interaction between phonemic abilities and syllable congruency effect in young readers. AB - This study investigated whether and to what extent phonemic abilities of young readers (Grade 5) influence syllabic effects in reading. More precisely, the syllable congruency effect was tested in the lexical decision task combined with masked priming in eleven-year-old children. Target words were preceded by a pseudo-word prime sharing the first three letters that either corresponded to the syllable (congruent condition) or not (incongruent condition). The data showed that the syllable priming effect interacted with the score of phonemic abilities. In children with good phonemic skills, word recognition was delayed in the congruent condition compared to the incongruent condition, while it was speeded up in children with weaker phonemic skills. These findings are discussed in a lexical access model including syllable units. PMID- 22214649 TI - Relationship between dose, drug levels, and D2 receptor occupancy for the atypical antipsychotics risperidone and paliperidone. AB - Blockade of D2 family dopamine receptors (D2Rs) is a fundamental property of antipsychotics, and the degree of striatal D2R occupancy has been related to antipsychotic and motor effects of these drugs. Recent studies suggest the D2R occupancy of antipsychotics may differ in extrastriatal regions compared with the dorsal striatum. We studied this issue in macaque monkeys by using a within subjects design. [(18)F]fallypride positron emission tomography scans were obtained on four different doses of risperidone and paliperidone (the 9-OH metabolite of risperidone) and compared with multiple off-drug scans in each animal. The half-life of the two drugs in these monkeys was determined to be between 3 and 4 h, and drug was administered by a constant infusion through an intragastric catheter. The D2R occupancy of antipsychotic was determined in the caudate, putamen, ventral striatum, and four prefrontal and temporal cortical regions and was related to serum and cerebrospinal fluid drug levels. Repeated 2 week treatment with risperidone or paliperidone did not produce lasting changes in D2R binding potential in any region examined. As expected, D2R binding potential was highest in the caudate and putamen and was approximately one-third that level in the ventral striatum and 2% of that level in the cortical regions. We found dose-dependent D2R occupancy for both risperidone and paliperidone in both basal ganglia and cortical regions of interest. We could not find evidence of regional variation in D2R occupancy of either drug. Comparison of D2R occupancy and serum drug levels supports a target of 40 to 80 ng/ml active drug for these two atypical antipsychotics. PMID- 22214651 TI - Pressure induced magnetic phase separation in La0.75Ca0.25MnO3 manganite. AB - The pressure dependence of the Curie temperature T(C)(P) in La(0.75)Ca(0.25)MnO(3) was determined by neutron diffraction up to 8 GPa, and compared with the metallization temperature T(IM)(P) (Postorino et al 2003 Phys. Rev. Lett. 91 175501). The behavior of the two temperatures appears similar over the whole pressure range, suggesting a key role of magnetic double-exchange also in the pressure regime where the superexchange interaction is dominant. The coexistence of antiferromagnetic and ferromagnetic peaks at high pressure and low temperature indicates a phase separated regime which is well reproduced with a dynamical mean-field calculation for a simplified model. A new P-T phase diagram has been proposed on the basis of the whole set of experimental data. PMID- 22214652 TI - Dietary arginine supplementation alleviates immune challenge induced by Salmonella enterica serovar Choleraesuis bacterin potentially through the Toll like receptor 4-myeloid differentiation factor 88 signalling pathway in weaned piglets. AB - The present study evaluated whether dietary arginine (Arg) supplementation could attenuate immune challenge induced by Salmonella enterica serovar Choleraesuis C500 (S.C500) through the Toll-like receptor (TLR) 4-myeloid differentiation factor 88 (Myd88) signalling pathway in weaned piglets. A total of thirty-six weaned pigs were randomly allocated into six groups with six replicates per group. Pigs were subjected to three dietary treatments (namely two groups per treatment) in the first week (0-7 d) and fed with diets containing 0, 0.5 and 1.0 % l-Arg, respectively. On day 8, pigs were injected intramuscularly either with S.C500 or sterile saline. Serum samples were collected at day 8 (before injection), and at 1, 3 and 10 d post-injection, pigs were killed for evaluation of tissue gene expression following the last blood collection. Piglets fed the diets with 0.5 or 1.0 % Arg supplementation had a higher concentration of serum Arg (P < 0.05). S.C500-challenged piglets had higher (P < 0.05) serum antibody levels during the days 9-18. Weight gain and feed intake were decreased remarkably (P < 0.01) after the injection of S.C500, and 0.5 or 1.0 % Arg supplementation tended to alleviate the inhibition. The S.C500 challenge significantly enhanced (P < 0.05) serum C-reactive protein (CRP), interferon gamma and IL-12 concentrations, but Arg supplementation attenuated (P < 0.05) the increase in CRP level. The mRNA expression of TLR4, TLR5, Myd88, p65 NF-kappaB and TNF-alpha was up-regulated (P < 0.05) by the S.C500 challenge in different tissues, but was down-regulated (P < 0.05) by Arg supplementation. In conclusion, Arg supplementation could inhibit the excessive activation of the TLR4-Myd88 signalling pathway and thus attenuated the negative effects caused by the immune challenge of S.C500. PMID- 22214653 TI - Mixed metals toxicity: more than the sum of its parts? PMID- 22214654 TI - Immunohistochemical localization of serotonin in the brain during natural sex change in the hermaphroditic goby Lythrypnus dalli. AB - The neurotransmitter serotonin (5-HT) may play a central role in the inhibition of socially regulated sex change in fish because of its known modulation of both aggressive and reproductive behavior. This is the first study to use immunohistochemical techniques to examine the morphometry of serotonergic neurons at different times during sex change. Using a model species wherein sex change is socially regulated via agonistic social interactions (the bluebanded goby, Lythrypnus dalli), we sampled brains of males and females with different social status, and of females at different times during sex change. Consistent with previous studies on other teleosts, immunoreactive neurons were found in the posterior periventricular nucleus (NPPv), the nucleus of the lateral recess (NRL), the nucleus of the posterior recess (NRP) and in the raphe nucleus. We measured the total area of NPPv, NRL, NRP, and the number and mean cell area of serotonergic neurons in the raphe nucleus. There was no significant difference in any of the brain regions between males, females or sex changing fish, but there was a slight increase in the number of dorsal raphe neurons in the brain of sex changers 2h after male removal. The results show that in L. dalli the serotonergic system does not present any morphological sex and status differences, nor any dramatic modifications during sex change. These data, together with previous results, do not support the hypothesis that serotonin inhibits socially regulated sex change. PMID- 22214655 TI - The disintegration behaviour of capsules in fed subjects: a comparison of hypromellose (carrageenan) capsules and standard gelatin capsules. AB - Two-piece hard shell capsules made from hypromellose (or hydroxypropyl methylcellulose, HPMC) containing carrageenan as a gelling agent have been proposed as an alternative to conventional gelatin capsules for oral drug delivery. We have previously compared the disintegration of hypromellose(carrageenan) (Quali-V((r))) and gelatin capsules (Qualicaps) in fasted human subjects using the technique of gamma scintigraphy. This second study used the same technique with both fasted and fed human subjects. Size 0 capsules were filled with powder plugs made from lactose and did not contain croscarmellose as in the original study. The capsules were separately radiolabelled with indium-111 and technetium-99m. Both capsules were administered simultaneously with 180ml water to eight healthy male subjects following an overnight fast. Each volunteer was positioned in front of the gamma camera and sequential 60s images were acquired in a continuous manner for 30min. The mean (+/-S.D.) disintegration time in the fasted state for the hypromellose(carrageenan) capsules was 8+/-2min and for gelatin 7+/-3min. These results were not statistically different from the data in the original study and show that the removal of the croscarmellose had no effect on the results. The mean (+/-S.D.) disintegration time in the fed state for the hypromellose(carrageenan) capsules was 16+/-5min and for the gelatin capsules was 12+/-4min. There was no statistical difference between the hypromellose(carrageenan) and gelatin capsules in either the fed or fasted state. PMID- 22214656 TI - Characterization of nanometer-scale porosity in reservoir carbonate rock by focused ion beam-scanning electron microscopy. AB - Sedimentary carbonate rocks are one of the principal porous structures in natural reservoirs of hydrocarbons such as crude oil and natural gas. Efficient hydrocarbon recovery requires an understanding of the carbonate pore structure, but the nature of sedimentary carbonate rock formation and the toughness of the material make proper analysis difficult. In this study, a novel preparation method was used on a dolomitic carbonate sample, and selected regions were then serially sectioned and imaged by focused ion beam-scanning electron microscopy. The resulting series of images were used to construct detailed three-dimensional representations of the microscopic pore spaces and analyze them quantitatively. We show for the first time the presence of nanometer-scale pores (50-300 nm) inside the solid dolomite matrix. We also show the degree of connectivity of these pores with micron-scale pores (2-5 MUm) that were observed to further link with bulk pores outside the matrix. PMID- 22214658 TI - Paul Epstein: 1943-2011. PMID- 22214657 TI - Effect of distributing an evidence-based guideline for prevention of osteoporosis on health education programs in municipal health centers: a randomized controlled trial. AB - BACKGROUND: Current health education programs for osteoporosis prevention are not strictly evidence-based. We assessed whether distribution of an evidence-based guideline improved such programs at municipal health centers. METHODS: This randomized controlled trial evaluated 100 municipal health centers throughout Japan that were randomly selected from those that planned to revise osteoporosis prevention programs. The implementation status of educational items recommended by the guideline was assessed before and after the intervention by evaluators blinded to the allocation. After the pre-intervention assessment, centers were randomly allocated in a 1:1 ratio to intervention and control groups by a minimization method defining region and city/town as stratification factors. Centers in the intervention group were given copies of the guideline; centers in the control group were instructed to use any information except the guideline. Analyses were performed on an intention-to-treat basis. RESULTS: The guideline was used by 50% of the intervention group. Before the intervention, there was no significant difference in the evidence-based status of health education between the groups. The post-intervention assessment showed that the implementation rates of health education on dietary calcium intake for postmenopausal women and exercise for elderly persons were higher in the intervention group. Specific advice on intakes of calcium and vitamin D and exercise became more evidence based in the intervention group. CONCLUSIONS: The findings suggest that the guideline helped healthcare professionals to improve health education programs by making them more evidence-based. However, the improvements seemed to be limited to items that the professionals felt prepared to improve. PMID- 22214659 TI - Arabidopsis ubiquitin conjugase UBC32 is an ERAD component that functions in brassinosteroid-mediated salt stress tolerance. AB - Plants modify their growth and development to protect themselves from detrimental conditions by triggering a variety of signaling pathways, including the activation of the ubiquitin-mediated protein degradation pathway. Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is an important aspect of the ubiquitin-proteasome system, but only a few of the active ERAD components have been reported in plants. Here, we report that the Arabidopsis thaliana ubiquitin-conjugating enzyme, UBC32, a stress-induced functional ubiquitin conjugation enzyme (E2) localized to the ER membrane, connects the ERAD process and brassinosteroid (BR)-mediated growth promotion and salt stress tolerance. In vivo data showed that UBC32 was a functional ERAD component that affected the stability of a known ERAD substrate, the barley (Hordeum vulgare) powdery mildew O (MLO) mutant MLO-12. UBC32 mutation caused the accumulation of bri1-5 and bri1 9, the mutant forms of the BR receptor, BRI1, and these mutant forms subsequently activated BR signal transduction. Further genetic and physiological data supported the contention that UBC32 plays a role in the BR-mediated salt stress response and that BR signaling is necessary for the plant to tolerate salt. Our data indicates a possible mechanism by which an ERAD component regulates the growth and stress response of plants. PMID- 22214660 TI - What makes the engine hum: Rad6, a cell cycle supercharger. AB - Deregulated CDK activity drives cell proliferation of the majority of human tumors, making CDKs highly relevant research subjects. Cdc28 controls cell cycle progression in the budding yeast Saccharomyces cerevisiae, but the identity of many genes that function in conjunction with CDC28 to regulate the cell cycle and cell viability remains obscure. In a recent study, we used a chemical-genetic screen to identify the genetic network of CDC28. Through this analysis, we discovered that the Rad6-Bre1 pathway functions in this network and links ubiquitin levels to cell cycle progression by increasing transcription of cyclin genes. Thus, Rad6 boosts the activity of the cell cycle machinery. PMID- 22214663 TI - Mutant p53 subverts PLK2 function in a novel, reinforced loop of corruption. PMID- 22214662 TI - The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and activation, leading to G1 arrest. AB - Cellular stresses, including growth factor deprivation, inflammatory cytokines or viral infection promote RAX/PACT-dependent activation of the double-stranded RNA dependent protein kinase, PKR, to phosphorylate eIF2alpha, resulting in translation inhibition and apoptosis. In addition, PKR has been reported to regulate p53, STAT1 and NFkappaB. Here, we report that RAX/PACT interacts with the SUMO E2 ligase Ubc9 to stimulate p53-Ubc9 association and reversible p53 sumoylation on lysine 386. In addition, expression of RAX/PACT in a variety of cell lines promotes p53 stability and activity to increase p53 target gene expression. Significantly, while the expression of RAX/PACT, PKR or p53 alone has little effect on the cell cycle of p53-null H1299 cells, co-expression of p53 with either RAX/PACT or PKR promotes a 25-35% increase of cells in G1. In contrast, co-expression of RAX/PACT with the sumoylation-deficient p53(K386R) mutant or with the desumoylase SENP1 fails to induce such a G1 arrest. Furthermore, co-expression of p53, RAX/PACT and the dominantnegative PKR(K296R) mutant inhibits RAX/PACT-induced, p53-dependent G1 growth arrest and expression of RAX/PACT in pkr(+/+) but not pkr(-/-) MEF cells promotes p53 and p21 expression following gamma irradiation. Significantly, p53 stability is decreased in cells with reduced RAX/PACT or PKR following doxorubicin treatment, and expression of exogenous RAX/ PACT promotes phosphorylation of wild-type but not p53(K386R) on serine 392. Collectively, results indicate that, in response to stress, the RAX/PACT-PKR signaling pathway may inhibit p53 protein turnover by a sumoylation-dependent mechanism with promotion of p53 phosphorylation and translational activation leading to G1 cell cycle arrest. PMID- 22214664 TI - Providing the TORC for cell cycle progression in neoplastic mast cells. PMID- 22214661 TI - Deconvoluting mTOR biology. AB - In metazoans, TOR is an essential protein that functions as a master regulator of cellular growth and proliferation. Over the past decade, there has been an explosion of information about this critical master kinase, ranging from the composition of the TOR protein complex to its ability to act as an integrator of numerous extracellular signals. Unfortunately, this plethora of information has also raised numerous questions regarding TOR function. Currently, the prevailing view is that mammalian TOR (mTOR) exists in at least two molecular complexes, mTORC1 and mTORC2, which are largely defined by the presence of either RAPTOR or RICTOR. However, additional co-factors have been identified for each complex, and their importance in mediating mTOR signals has been incompletely elucidated. Similarly, there are differences in mTOR function that reflect the tissue of origin. In this review, we present an alternative view to mTOR complex formation and function, which envisions mTOR regulation and signal propagation as a reflection of cell type- and basal state-dependent conditions. The re interpretation of mTOR biology in this framework may facilitate the design of therapies most likely to effectively inhibit this central regulator of cell behavior. PMID- 22214665 TI - A new chronological survival assay in mammalian cell culture. PMID- 22214666 TI - The shark in us: learning about the evolution of the p53 regulatory circuit. PMID- 22214667 TI - MiR-34 and SNAIL: another double-negative feedback loop controlling cellular plasticity/EMT governed by p53. PMID- 22214668 TI - The evolution of the p53 family of genes. PMID- 22214669 TI - Bipolar disorder: kinesin-12 to the rescue. PMID- 22214670 TI - Lead and cadmium levels and balance and vestibular dysfunction among adult participants in the National Health and Nutrition Examination Survey (NHANES) 1999-2004. AB - BACKGROUND: Few studies have been conducted to identify risk factors for balance and vestibular dysfunction in general populations, but previous studies have reported evidence of adverse effects of lead and cadmium on balance control in high-risk groups. OBJECTIVE: We evaluated the relationship between blood lead and cadmium levels and balance and vestibular dysfunction in a general population study. METHODS: We analyzed data from the 1999-2004 National Health and Nutrition Examination Survey (NHANES) of 5,574 adults >= 40 years of age. Balance dysfunction was evaluated by the Romberg Test of Standing Balance on Firm and Compliant Support Surfaces, which examines the ability to stand unassisted using four test conditions to evaluate vestibular system, vision, and proprioception inputs that contribute to balance. Blood levels of lead and cadmium were measured by atomic absorption spectrometry. Associations were estimated using logistic regression models adjusted for potential confounders. Associations with time to loss of balance were estimated using adjusted Cox proportional hazard models. RESULTS: The adjusted odds ratio (OR) for balance dysfunction in association with the highest quintile (3.3-48 ug/dL) versus the lowest quintile (< 1.2 ug/dL) of lead was 1.42 [95% confidence interval (CI): 1.07, 1.89]. The corresponding OR for cadmium (0.9-7.4 ug/L vs. < 0.2 ug/L) was 1.27 (95% CI: 1.01, 1.60). The adjusted hazard ratio for time to failure for the most physiologically challenging balance test among subjects with the highest vs. lowest quintiles of blood lead was 1.24 (95% CI: 1.04, 1.48). Cadmium levels were not associated with time to failure. CONCLUSIONS: Our findings suggest that blood lead and cadmium levels may be associated with balance and vestibular dysfunction in a general sample of U.S. adults. PMID- 22214672 TI - The conference was a full success and everybody seemed to enjoy the days of scientific debate, communication and friendship. Preface. PMID- 22214673 TI - Laudatio for the 2011 Fahraeus Awardee: Prof. Dr. Hans Walter Reinhart. PMID- 22214674 TI - Peculiar red cell shapes: Fahraeus Lecture 2011. PMID- 22214676 TI - Viscosity, platelet activation, and hematocrit: progress in understanding their relationship with clinical and subclinical vascular disease. PMID- 22214675 TI - Nonlinear cardiovascular regulation consequent to changes in blood viscosity. AB - Increasing blood and plasma viscosity is generally associated with pathological conditions, and increased cardiovascular risk, a perception based in part on studies where blood viscosity is increased to extreme values attained by hemoconcentration. Present studies, supported by epidemiological studies in humans, show that moderate increases in Hct improve cardiovascular function and vice versa. This result is due to the nonlinear regulation of peripheral vascular resistance arising from the increased production of nitric oxide following the increase of shear stress on the vascular wall due to increasing blood viscosity. Similar effects are found in when plasma viscosity is increased in the extremely hemodiluted circulation. In both cases there is an effect at the arteriolar/capillary level, leading to a condition of improved microvascular function and supra perfusion that facilitates clearance of metabolic waste products, while maintaining oxygen delivery. Application of these findings to the design of viscogenic plasma expanders suggests a new approach for the treatment of hemorrhage that in part replaces the use of blood transfusions, making it feasible to lower the transfusion trigger to levels below than normally considered safe. PMID- 22214677 TI - Contrast-enhanced ultrasound improves real-time imaging of ablation region during radiofrequency ablation: preliminary results. AB - PURPOSE: To assess the added value of depicting tumour microvascularisation, using dynamic contrast enhanced (CEUS), during radiofrequency ablation, as a means of achieving a complete ablation (CA) of malignant liver lesions. MATERIAL AND METHODS: 18 consecutive patients (2 female, 16 male, age range 52-79 years, mean 64.1 +/- 9.9 years) with 22 histologically confirmed hepatic malignancies (HCC: n = 10, liver metastases: n = 12) underwent RFA. Before RFA treatment, conventional US, CEUS and contrast enhanced CT (ceCT) of the liver were performed. During the CT-guided RFA procedure, CEUS was performed to asses the ablation defect. In case of partial ablation a subsequent ablation was performed with a corrected electrode position and evaluated again using CEUS. This procedure was repeated until a CA was achieved. The number of ablations per patient was recorded. Secondary efficacy parameters assessed were lesion detectability in the different imaging modalities and contrast phases. RESULTS: Overall intraprocedural CEUS led to a change in therapeutic management in 59% of cases, resulting in 17 additional ablation cycles. Lesion detectability during CT Fluoroscopy was the sole statistical significant predictor of incomplete ablations (p = 0.008). The mean number of ablations for detectable lesions was 1.27 vs. 2.27 ablations for not detectable lesions (p = 0.002). The combined CT and CEUS RFA procedure led to a CA for all treated lesions in follow up 3 month post intervention. CONCLUSION: CEUS does allow a reliable and immediate assessment of therapeutic efficacy of percutaneous RFA procedures of malignant liver lesions, through the continuous dynamic evaluation of tumour microcirculation. PMID- 22214678 TI - Evaluation of the microcirculation of hepatocellular carcinomas using contrast enhanced ultrasound with intraarterial and intravenous contrast application during transarterial chemoembolization with drug-eluting beads (DEB-TACE): preliminary data. AB - PURPOSE: The objective was the evaluation of microcirculation in hepatocellular carcinomas (HCC) in vivo by dynamic contrast-enhanced ultrasound (CEUS) after intravenous (i.v.) and intraarterial (i.a.) application of contrast agent during transarterial chemoembolization (TACE) using drug-eluting beads (DEB). PATIENTS AND METHODS: Eleven patients with HCC underwent CEUS directly before and immediately after DEB-TACE. The sonographic contrast agent was injected through the microcatheter intraarterially and intravenously. The grade of hypervascularization was evaluated before Bead application. The percentage of devascularization after Bead application was calculated and quantitative devascularization was carried out using time intensity curves (TIC). These results were compared to postinterventional angiography after Bead application and postprocedural computed tomography. RESULTS: The hypervascularization of HCC was marginal improved after i.a. contrast application compared to i.v. application (p = 0.163). The reduction of vascularization after Bead application correlated significant between i.a. and i.v. contrast application (p = 0.007) and decreased significant using TIC analysis (p = 0.003). Postinterventional angiography related with CEUS after i.a. sonographic contrast agent application. Extrahepatic tumor-feeding arteries were detected by a mismatch between i.a. and i.v. CEUS in one case. CONCLUSION: Quantification of the reduction of microvascularization using TIC analysis may be a valuable periinterventional tool during DEB-TACE. Intraprocedural CEUS with i.a. and i.v. ultrasound contrast agent injection may help finding extrahepatic tumor-feeding arteries. PMID- 22214679 TI - Image fusion of contrast enhanced ultrasound (CEUS) with computed tomography (CT) or magnetic resonance imaging (MRI) using volume navigation for detection, characterization and planning of therapeutic interventions of liver tumors. AB - AIM: To evaluate, whether image fusion of contrast enhanced ultrasound (CEUS) with CT or MRI affects the diagnosis and characterization of liver lesions or the therapeutic strategy of surgical or interventional procedures compared to the preliminary diagnosis. MATERIAL AND METHODS: In a retrospective study the image fusion scans of CEUS with contrast enhanced CT or MRI of 100 patients (71 male, mean age 59 years, 0.3-85 years) with benign or malignant liver lesions were evaluated. Fundamental B-scan, color Doppler imaging and CEUS were performed in all patients by an experienced examiner using a multifrequency convex transducer (1-5 MHz, LOGIQ 9/GE) and volume navigation (Vnav). After a bolus injections of up to 2.4 ml SonoVue(r) (BRACCO, Italy) digital raw data was stored as cine-loops up to 5 min. In 74 patients, CEUS was fused with a pre-existing ceCT, in 26 patients a ceMRI was used. RESULTS: In all 100 patients (100%) the image quality in all modalities (ceCT, ceMRI and CEUS) was excellent or with only minor diagnostic limitations. Regarding the number of lesions revealed in image fusion of CEUS/ceCT/ceMRI and the preceding diagnostic method, concordant results were found in 84 patients. In 12 patients, additional lesions were found using fusion imaging causing subsequently a change of the therapeutical strategy. In 15 out of 21 patients with either concordant or discordant results regarding the number of lesions, image fusion allowed a definite diagnosis due to a continuous documentation of the microcirculation of the tumor and its contrast enhancement. A significant coherency (p < 0.05) among image fusion with either ceCT or ceMRI and CEUS and a subsequent change of therapeutic strategy was found. CONCLUSION: Image fusion with volume navigation (VNav) of CEUS with ceCT or ceMRI frequently allows a definite localization and diagnosis of hepatic lesions in patients with primary hepatic carcinoma or metastatic diseases. This might cause a change of the therapeutic strategy in many patients with hepatic lesions. PMID- 22214680 TI - Contrast-enhanced ultrasonography (CEUS) using early dynamic in microcirculation for localization of pathological parathyroid glands: first-line or complimentary diagnostic modality? AB - BACKGROUND: Contrast-enhanced ultrasonography (CEUS) represents a new diagnostic tool to localize pathological parathyroid glands. The aim of this study was to differentiate the capability of CEUS as first-line or complimentary modality for the detection of hyperfunctioning parathyroid glands. METHODS: Sixty patients with pHPT were admitted to the University Hospital Regensburg between 8/2009 and 3/2011. Conventional and contrast-enhanced ultrasonography (CEUS) using a linear probe (6-9 MHz, LOGIQ E9/GE) was performed in all patients preoperatively. The sensitivity of CEUS was analyzed to determine its potential as first line or complimentary diagnostic procedure. RESULTS: Using CEUS 98.3% of all pathological glands could be detected in the correct quadrant whereas conventional ultrasonography (70%) (p < 0.001) revealed less sensitivity. In all patients CEUS indicated a correct side localization of the hyperfunctioning parathyroid gland. The advantage of CEUS was the detection of the early dynamic on the capillary level immediately after contrast injection. Overall, CEUS permit minimally invasive video-assisted parathyroidectomy in 45 patients. 15 patients required conventional procedure due to concomitant goiter. All patients showed normal calcium and parathyroid hormone serum levels three months after surgery. CONCLUSIONS: CEUS represents a highly sensitive diagnostic modality for localization of pathologic parathyroid glands in patients with pHPT. Nevertheless, it can only be recommended as first-line diagnostic procedure in specialized clinical centers with experienced investigators. PMID- 22214681 TI - Improving the follow up after EVAR by using ultrasound image fusion of CEUS and MS-CT. AB - PURPOSE: To evaluate whether the image fusion with contrast enhanced ultrasound (CEUS) and CT affects the diagnosis of endoleaks in unclear cases. METHODS AND MATERIALS: 35 patients with follow-up examinations after endovascular aneurysm repair (EVAR) were included in this retrospective study. Mean patient age was 73 years (range 54-83 y). B-scan, colour doppler and CEUS (1.2 ml SonoVue(r), Bracco Imaging Germany) were performed in all patients by an experienced examiner using two different high-end ultrasound system (Siemens ACUSON S2000TM, Siemens Healthcare, Erlangen, Germany or Logic E9, GE Healthcare, Milwaukee,WI, USA) with a multifrequency curved array transducer. The examiner was initially blinded to the CT results. Additional image fusion with CT-angiography (CTA) was then performed. The ultrasound examinations were later read by two blinded unbiased investigators with more than five years of clinical ultrasound in consensus. RESULTS: All patients were examined using all diagnostic ultrasound tools of the study. The results show that image fusion is easy and convenient to perform. Conventional ultrasound examination with B-scan and colour Doppler examination detected one Type I and one Type II endoleak, contrast enhanced ultrasound detected one Type I and three Type II endoleaks after EVAR whereas CTA depicted one Type I and two Type II endoleaks. Ultrasound image fusion with CT-angiography confirmed one Type I and three Type II endoleaks. CONCLUSION: In comparison to conventional ultrasound and CTA the use of CEUS improved the visualization and classification of endoleaks. CEUS shows even small blood flow which can be depicted due to the real time imaging of endoleaks. In unclear cases additional ultrasound image fusion with CEUS and CT angiography improves the visualisation of small endoleaks and this may cause a change in the follow-up interval. CEUS is a good alternative to CT in the detection and follow-up of endoleaks, especially in patients with contraindications to CT contrast agents due to allergies or renal failure, enabling reduced additional costs and exposure to radiation. PMID- 22214682 TI - Acoustic radiation force impulse imaging of the testes: a preliminary experience. AB - PURPOSE: Acoustic radiation force impulse imaging (ARFI) is a newly developed technique for the sonographic quantification of tissue elasticity. It has been used in the assessment of various abdominal organs. The testes are extraabdominal organs with limited overlying tissue, making them ideally suited to ARFI assessment. To our knowledge no published data exist on ARFI elastography of the testes. METHOD: 23 male volunteers (mean age 45.13 +/- 17.3, range 23-75) with no known testicular pathology underwent normal B-mode sonography with ARFI elastometry of both testes using a Siemens Acuson S2000TM (Siemens Healthcare, Germany) system. 15 measurements were performed on each testis; 5 each in the upper pole, middle portion and lower pole. Results were statistically evaluated. RESULTS: 95% of the SWV values were found to lie within the reference interval ranging from 0.62 to 1.01 m/s. There was a significant association between measured SWV and age (P = 0.0056) and testicular volume (P = 0.0003). CONCLUSION: ARFI elastometry proved to be feasible in the assessment of testicular stiffness. Older age and lower testicular volumes were associated with increased parenchymal stiffness. Further studies with more subjects may be required to define the normal range of values for each age group. PMID- 22214683 TI - Assessment of bone microcirculation by contrast-enhanced ultrasound (CEUS) and [18F]-positron emission tomography/computed tomography in free osseous and osseocutaneus flaps for mandibular reconstruction: preliminary results. AB - PURPOSE: Postsurgical evaluation of bone microcirculation in osseous and osseocutaneus free flaps by contrast enhanced ultrasound (CEUS) with time intensity curve (TIC) analysis and [18F]-positron emission tomography/computed tomography (Fluoride-PET/CT). PATIENTS AND METHODS: 10 patients with osseous or osseocutaneus microvascular flaps were evaluated with CEUS. Ultrasound was carried out by an experienced examiner with a high resolution linear probe (6-9 MHz, LOGIQ E9, GE) after intravenous bolus injection of 2.4 ml SonoVue(r) (BRACCO, Germany). Time intensity curves (TIC) in selected regions of interest (ROI) were analyzed and compared with the evaluation of [18F]-positron emission tomography/computed tomography and the clinical course for at least 2 month. RESULTS: 9/10 patients showed evidence for soft tissue and osseous microcirculation of the transplants in CEUS correlating with the clinical course. The soft tissue parts of the transplant showed a mean value of 84% (range 51-98%) and the bone parts a mean value of 39% (range 11-75%) for the Area under the curve (AuC) compared with the AuC for the anastomotic vessel region. Mean values for time to peak (TTP) were 27,1 sec (range 8.7-52.0 sec) for the anastomotic vessels, 29.3 sec (range 7.9-62.0 sec) for the soft tissue of and 32.0 sec (range 7.4-69.0 sec) for the transplant bone. In 1/10 patients flap failure occurred, after denudation the bone was left as an avascular transplant. AuC showed a mean value of 0.5 % for the bone region compared with the vessel region. Fluoride PET/CT assessed bone vitality in 7 patients as "good" in 1 patient as "uncertain" and in 1 patient as "poor". CEUS assessment was corresponding with Fluoride PET/CT in 4 patients, clinical assessment in 6 patients. CONCLUSION: Fluoride PET/CT is a valuable tool to make an indirect statement about the perfusion of the transplanted bone and was used as control in this study. CEUS is a new and promising method for the evaluation of microcirculation of buried free microvascular bone grafts and the osseous part of osseocutaneous flaps and may be used for a steady monitoring in the first postoperative days. PMID- 22214684 TI - Contrast-enhanced ultrasound for differential diagnosis of suspected GvHD in patients after allogeneic transplantation. AB - GvHD is a serious complication in patients after allo-SCT, presenting with unspecific symptoms such as abdominal pain or cramps and diarrhea. Early diagnosis of GvHD, after differentiation from other causes leading to the same symptoms, such as viral or bacterial enteritis, is highly important because the time needed for diagnosing GvHD is directly correlated to a worsening of the outcome. We examined 23 patients presenting with the abdominal symptoms mentioned above, of whom 20 had received an allo-SCT in their history and were thus potential candidates for enteric GvHD. The other three patients were included because they also presented with abdominal symptoms similar to those of GvHD, which could be ruled out due to their history. We wanted to evaluate CEUS in these patients as an additional subgroup to gain more data on the value of CEUS in early detection of enteral GvHD and in the differentiation of GvHD against other causes of abdominal discomfort. All patients underwent CEUS with particular attention to penetration of the intravenously applied microbubbles in the bowel lumen. In the patients having allo-SCT in their history we strove to achieve histological confirmation of GvHD of the GI-tract. The resulting examinations were documented digitally. Out of 17 patients with confirmed GvHD of the GI tract, 14 showed penetration of the intravenously applied microbubbles into the bowel lumen, leading to a sensitivity and specificity of 82% and 100% for transmural bubble penetration for GvHD of the GI-Tract, since the patients without GvHD of the GI tract showed no transmural bubble penetration. In patients with viral or bacterial infections of the GI tract, no transmural penetration of the microbubbles into the bowel lumen was observed. For microbubble penetration as a criterion for GvHD of the GI-Tract, this leads to a negative predictive value (NPV) of 67%, and a positive predicative value (PPV) of 100%. PMID- 22214685 TI - Quantitative evaluation of microvascular blood flow by contrast-enhanced ultrasound (CEUS). AB - Ultrasound contrast agents consist of tiny gas-filled microbubbles the size of red blood cells. Due to their size distribution, they are purely intravascular tracers which do not extravasate into the interstitial fluid, and thus they are perfect agents for imaging blood distribution and flow. Using ultrasound scanners with contrast-specific software, the specific microbubble-derived echo signals can be separated from tissue signals in realtime, allowing selective imaging of the contrast agent. The signal intensity obtained lies in a linear relationship to the amount of microbubbles in the target organ, which allows easy and reliable assessment of relative blood volume. Imaging of the contrast wash-in and wash-out after bolus injection, or more precisely using the flash-replenishment technique, allows assessment of regional blood flow velocity. Commercially available quantification software packages can calculate time-related intensity values from the contrast wash-in and wash-out phase for each image pixel from stored video clips. After fitting of a mathematical model curve according to the respective kinetic model (bolus or flash-replenishment kinetics), time/intensity curves (TIC) can be calculated from single pixels or user-defined regions of interest (ROI). Characteristic parameters of these TICs (e.g. peak intensity, area under the curve, wash-in rate, etc.) can be displayed as color-coded parametric maps on top of the anatomical image, to identify cold and hot spots with abnormal perfusion. PMID- 22214686 TI - Exercise limitation, exercise testing and exercise recommendations in sickle cell anemia. AB - Sickle cell anemia (SCA or SS homozygous sickle cell disease) is an inherited blood disorder caused by single nucleotide substitution in the beta-globin gene that renders their hemoglobin (HbS) much less soluble than normal hemoglobin (HbA) when deoxygenated. The polymerization of HbS upon deoxygenation is the basic pathophysiologic event leading to RBC sickling, hemolysis, vasoocclusion and ultimately to chronic organ damage. The metabolic changes imposed by exercise may initiate sickling and vaso-occlusive episodes. Further, in patients with SCA, exercise limitation may be related to anemia or chronic complications such as pulmonary vascular disease, congestive heart failure and chronic parenchymal lung disease. Few studies have investigated the cardiorespiratory responses of patients with SCA during either symptom-limited maximal exercise test on cyclo ergometer or during a six minute walk test. Therefore, patients are advised to start exercise slowly and progressively, to maintain adequate hydration during and after exercise, to avoid cold exposure or sudden change in temperature, and to avoid sports associated with mechanical trauma. There are, however, lack of evidence to allow practitioners to prescribe an exercise program for patients with SCA, and individuals are usually encouraged to exercise on a symptom-limited basis. Finally, this review will also highlight the basic principles that are often used for exercise practice and could be used for exercise prescription and rehabilitation in patients with sickle cell anemia. PMID- 22214687 TI - Effects of age on hemorheological responses to acute endurance exercise. AB - The purpose of this investigation was to examine the effects of age on the acute responses of hemorheological variables and biochemical parameters to a single bout of sub-maximal endurance exercise. Fifteen young (20-30 years), 15 middle aged (40-50 years) and 12 old (60-70 years) male subjects participated in the study. All subjects performed one single bout of endurance exercise encompassed 30-min cycling at 70-75% of maximal heart rate which was followed by 30-min recovery. Three blood samples were taken before, immediately after exercise and after 30-min recovery. Resting levels of hematocrit, red blood cells count, plasma albumin and fibrinogen concentrations, plasma viscosity and whole blood viscosity were significantly different among the three groups (P < 0.01). Thirty minutes of cycling resulted in significant increases (P < 0.05) in all parameters; while these changes were temporary and returned to pre-exercise level at the end of recovery. Responses of all parameters to exercise and recovery were not significantly different among the three groups (P > 0.05). Fibrinogen changes during exercise and recovery were corrected for exercise- and recovery-induced changes in plasma volume. Data analysis showed effects of exercise and recovery only for raw data (P > 0.05). In addition, raw and corrected fibrinogen data in response to exercise and recovery were not age-related. Our results demonstrate that age does not affect the hemorheological responses to an acute endurance exercise in healthy men. PMID- 22214688 TI - Nitric oxide, erythrocytes and exercise. AB - Nitric oxide (NO) is accepted to be an important factor affecting the degree of vascular tone in various portions of the circulation. Until recently, research in this area has focused on endothelial cells as a NO source, and there is general agreement that: 1) the level of wall shear stress is the primary determinant of endothelial nitric oxide synthase (eNOS) expression; 2) exercise training induces changes of endothelial cell NO synthesizing activity; 3) phosphorylation patterns of eNOS are altered following exercise episodes. However, there is now a growing body of evidence for the existence of similar nitric oxide synthesizing mechanisms in human red blood cells (RBC). Erythrocyte NOS activity has been demonstrated to be induced by applied shear stress and mechanical deformation of RBC, and there are closely linked increases of intracellular nitric oxide levels and of release of NO into the suspending phase. In brief, the RBC is an enzymatic source of NO that is dependent on flow dynamics and from which NO is released in very close proximity to vessel walls. Although reports regarding the influence of exercise on RBC nitric oxide synthesizing mechanisms are not yet concordant, it seems logical to suggest that this source of NO may play a role in the regulation of local blood flow dynamics during exercise. PMID- 22214689 TI - Interrelationships among body composition, blood rheology and exercise performance. AB - It is well known that body composition influences blood rheology (higher blood viscosity and RBC aggregation in obese individuals). On the other hand, blood rheology is related to exercise performance (the fitter the athlete the more fluid the blood). The 'paradox of hematocrit' is that most of the time trained athletes have a lower hematocrit while doping aims at increasing it, a situation which seems to challenge physiology and can be explained by the fact that systemic hematocrit may have poor physiological relevance at the microcirculatory level in exercising muscles. However, recent studies dealing with the marked differences among hemorheologic profiles observed in selected sports lead to the concept that the relationships between hemorheology and performance on one hand and body composition and hemorheology on the other hand are more complex and somewhat different according to the variety of exercise and the physiological and/or pathophysiological background. Increased fat mass, but also fat free mass independently of fat mass, are both correlated to impairments of blood fluidity, consistent with the emerging concept that beside increases in fat mass, increases in fat free mass may also be related to metabolic and circulatory disturbances. PMID- 22214690 TI - Effects of exercise training on blood rheology: a meta-analysis. AB - Regular exercise has been reported to improve blood rheology, but all the studies investigating this issue included a reduced number of subjects, and thus it was logic to perform a meta-analysis of them in order to better characterize this physiological effect. Research was handed on Medline from 1950 to 2010. Studies were selected if they were in English and if they had one or several of these following outcomes: lactate, blood viscosity, RBC rigidity, hematocrit (%), RBC aggregation, fibrinogen and plasma viscosity. They were also kept if they included exercise in their protocol. Results were computed with the fixed effect model and the weighting method was the inverse variance. 11 studies with 175 people were found and included in this meta-analysis. None of these studies had the whole mentioned outcomes. The meta-analysis shows significant effects on on RBC aggregation (-0.59 CI 95% [-0.72; -0.46]), whole blood viscosity (-0.30 [ 0.31; -0.28] p < 0.001) and hematocrit (-0.296%; CI 95% [-0.57; -0.01]). Aggregation, hematocrit and viscosity data showed significant heterogeneity, aggregation I(2) = 94.95%, hematocrit I(2) = 96.46%, viscosity I(2) = 99.25%. RBC aggregation (0.53 CI 95% [0.40; 0.66]). Three studies could be included for an intervention versus control analysis which shows significant effects on hematocrit (-1.06% CI 95% [-1.43; -0.68]) but not on aggregation, with again a significant heterogeneity (hematocrit I(2) = 96.46%). These results confirm that regular exercise decreases hematocrit and RBC aggregation, but the heterogeneity which is evidenced should be pointed out. This heterogeneity will require a new computation taking into account a "random effect" by using a pooling method. In addition, this heterogeneity leads to conclude that more studies are needed to further analyze these effects which are described by a low number of articles, which could explain some of the non-significant results. PMID- 22214691 TI - Blood rheology and body composition as determinants of exercise performance in female rugby players. AB - Athletes involved in rugby are characterized by a very specific pattern of body composition with an unusually important muscle mass. In a preceding study about rugbymen we evidenced that they exhibit a correlation between red blood cell aggregability and the amount of body fat although it remains within a normal range, and that red cell rigidity was correlated to isometric adductor strength. We had the opportunity of studying the relationships among exercise performance, body composition and hemorheology in 19 female rugby players (age 19-26, mean: 24.47 +/- 0.67 yr) practising 4 - 10 hr/wk (mean 7.15 +/- 0.3) since 1-12 yr (mean 4,05 +/- 0,694). VO2max was not related by its own to blood rheology, either hematocrit (r = -0.0717 p = 0.7706) or plasma viscosity (r = 0.0144; p = 0.9533), but other markers of performance exhivited a correlation with red cell rheology. Relationships between fitness and body composition were evidenced. Isometric handgrip strength was negatively correlated to red blood cell aggregability (Myrenne M, r = -0.57839; p = 0.00948 M1 r = -0.58910; p = 0.00795). Adductor isometric strength was negatively correlated to red blood cell aggregability Myrenne M (r = -0.5033; p = 0.0280) but not to M1 (r = -0.4227; p = 0.0714). Fat mass is a major determinant of the maximal oxygen consumption VO2max either measured by a field test (r = -0.766; p = 0.00013) or exercise test (r = 0.575; p = 0.00994) and was also negatively correlated to both handgrip (r = 0.4918; p = 0.0325) and RBC aggregability M (r = -0.57839; p = 0.00948 and M1 r = -0.5891; p = 0.00795). Independently of fat mass, FFM appears to be a determinant of blood viscosity (r = 0.4622; p = 0.0463) due to its correlation with RBC rigidity (r = 0.4781; p = 0.0384). Thus, trained young women exercising 4-10 hr/wk and thus exhibiting a low percentage of body fat exhibit clear relationships between body composition and hemorheology, but fat mass being low, the parameter correlated with blood rheology is in this case fat-free mass, consistent with recent findings indicating that high fat mass in women is sometimes correlated with parameters of the metabolic syndrome such as insulin resistance or inflammation. In addition, parameters quantifying fatness even within such a physiological range are in this sample negatively related with exercise performance. PMID- 22214692 TI - Body composition and exercise performance as determinants of blood rheology in middle-aged patients exhibiting the metabolic syndrome. AB - Aerobic capacity and performance are associated with increased blood fluidity, while sedentarity leads to decreased exercise performance, and blood hyperviscosity. We aimed at investigating the relationships among body composition, blood rheology and exercise performance in this situation. In 46 sedentary subjects (53.09 +/- 1.79 yr old; BMI = 32,35 +/- 0,80) attending our unit for an exercise prescription we performed an exercise test to assess aerobic capacity, together with blood lipid profile and blood viscosity (MT 90 viscometer, Myrenne erythroaggregometer). The maximal aerobic capacity VO2max was not correlated to blood rheology but its changes were negatively correlated to those of plasma viscosity (r = -0.679) and pre-training VO2max values were negatively correlated to the BMI (r = -0.45873; p = 0.00430) and fatness (waist circumference r = -0.53476; p = 0.00406). Hemorheological parameters were as expected correlated to blood lipids. The main determinant of the RBC rigidity index Tk was HDL-cholesterol (r = -0.70026; p = 0.00121). The main determinant of M1 is HDL-cholesterol (r = -0.5157; p = 0.0238). RBC aggregability "M" is negatively correlated to total cholesterol (r = -0.758932; p = 0.000105); HDL cholesterol (r = -0.62232; p = 0.00444); LDL-cholesterol (r = -0.64486; p = 0.00386). Whole blood viscosity is correlated to triglycerides (r = 0.8569; p = 0.00000140) and negatively correlated to HDL-cholesterol (r = -0.5622; p = 0.0122). Waist circumference (an index of abdominal fatness) is correlated to blood viscosity (r = 0.597; p = 0.00888). The waist to hip ratio is correlated to Hct (r = 0.70075 p = 0.00120) and to blood viscosity (r = 0.8124334; p = 0.0000420). Fat-free mass is correlated to blood viscosity (r = 0.66528; p = 0.00137) and hematocrit (r = 0.64350; p = 0.00220). Hip circumference is negatively correlated to plasma viscosity (r = -0.5007; p = 0.0290). Therefore, this study confirms that hemorheological parameters are influenced by blood lipids, that changes in plasma viscosity are correlated to those of aerobic capacity, and that abdominal fat mass is associated with a worsening of blood rheology and of exercise performance. By contrast, gluteal fat (a factor associated with favorable lipid profile and high insulin sensitivity) is associated with a decrease in plasma viscosity, and fat-free mass is associated with higher blood viscosity and hematocrit, consistent with recent literature linking its size in abdominal obesity with a deleterious metabolic profile. PMID- 22214693 TI - Blood rheology and body composition as determinants of exercise performance in male soccer players. AB - The aim of this study was to assess on a large series of soccer players our previous reports on blood rheology and exercise performance. In 99 soccer players (Age 24,17 +/- 0,42 yr; weight 75,87 +/- 0,89 kg; VO2max 46,86 +/- 0,95 mL/min/kg) an exercise test was performed for measuring maximal aerobic capacity and we measured blood viscosity at high shear rate (MT90 viscometer) and RBC aggregation (Myrenne MK1). The French questionnaire developped by the consensus group on overtraining of the French Society of Sports Medicine (SFMS) was also employed. The only hemorheologic statistical determinant of VO2max was hematocrit (Hct r = -0.2439; p = 0.0303). The lactate threshold 2 mmol/l was negatively correlated to M1 (r = -0.43224; p = 0.00847). There was a borderline correlation between the overtraining score at the questionnaire of the SFMS and plasma viscosity (r = 0.3080; p = 0.0532). Therefore, our study confirms that aerobic capacity in this sport is negatively correlated to hematocrit, that RBC aggregation is positively associated with blood lactate accumulation in blood during exercise, and that plasma viscosity is one of the parameters that increase when the athlete is on the edge of the overtraining syndrome. These data are consistent with previous reports about soccer players but caution is needed to extrapolate to other sports. PMID- 22214694 TI - Cardiovascular dynamics during exercise are related to blood rheology. AB - BACKGROUND: The principal determinants of oxygen uptake (VO2) kinetics are controversial, with dynamic changes in central and peripheral factors mediating oxygen supply and utilisation suggested to be limiting. The aim of this study was to determine whether important parameters of blood rheology were related to the exercise-induced time-course changes in VO2 and cardiac output (Qc), or steady state arteriovenous oxygen difference (a-vO2D) during submaximal cycling. METHODS AND RESULTS: Blood was collected from ten healthy, recreationally active males and females (age: 21.7 +/- 1.3 yr; body mass index: 22.7 +/- 2.0 kg . m(-2)), before each subject cycled at 105% of the first ventilatory threshold. Red blood cell aggregation was negatively correlated with steady-state VO2 during exercise and the a-vO2D at rest (r = -0.73, p < 0.05), and positively correlated to Qc at rest (r = 0.71, p < 0.05). Blood viscosity at various shear rates was negatively correlated with the time constant of VO2 (all p < 0.01) on-transient kinetics. Red blood cell deformability at various shear stress was positively correlated to the time constant of VO2 (all p < 0.05) on-transient kinetics. CONCLUSIONS: The findings of the present study suggest that the rheological properties of blood may modulate, at least in part, the rate of change in the uptake and/or utilisation of oxygen at the onset of exercise. PMID- 22214695 TI - Correlation between postischemic vasodilation of the arteria brachialis and of the postischemic hyperemia in the adjacent microvascular bed. AB - BACKGROUND: Endothelial cells secrete different mediators depending on biochemical and/or biophysical conditions, which can lead to vasodilation or vasoconstriction, respectively. Impaired endothelial responsiveness to specific vasodilator stimuli has been used as a surrogate marker of cardiovascular risk. Multiple methods allow testing endothelial responses in both microvessels and conduit arteries, but it is still unclear whether there is a relationship in endothelial function between these two different vascular beds. MATERIAL AND METHODS: In order to examine, whether such macrocirculatory data might correlate with data obtained in the supplied microvessels, a parallel investigation in the brachial artery (BA) and the supplied nailfold capillaries was performed. The duration and amplitude of the postischemic hyperemia (stasis in the vasculature of the left arm using a blood pressure cuff for 3 minutes) were measured (ultrasound technique) and simultaneously the amplitude and duration of the postischemic hyperemia in ipsilateral nailfold capillaries (intravital capillaroscopy). RESULTS: There was absolutely no correlation between the duration (n = 153, r = 0.076, p = 0.3493) of the diameter increase in the BA and in ipsilateral nailfold capillaries. CONCLUSION: The regulation of the cutaneous microcirculation did not follow diameter changes of the conduit artery (BA) but seems to be dominated by the precapillary arterioles. PMID- 22214696 TI - Osteocutaneous free flaps: a critical analysis of quantitative evaluation of bone microcirculation with contrast-enhanced high resolution ultrasound (hrCEUS) and TIC analysis. AB - PURPOSE: Osteocutaneous free flaps (OFF) are widely used to reconstruct large bone defects in trauma and cancer surgery. Currently no monitoring method is available to detect blood circulation around and inside the bone after transplantation. Therefore we used for the first time contrast-enhanced high resolution ultrasound (hrCEUS) to gain evidence for the microcirculation of the transplanted bone. MATERIALS AND METHODS: 15 patients transplanted with OFF because of large bone defects at different sites were examined postoperatively with hrCEUS with a high resolution linear probe (6-9 MHz, LOGIQ E9/GE) and a bolus injection of 2.4 ml of contrast agent (SonoVue(r), Bracco, Italy). Operation and examination were performed by either an experienced plastic surgeon or an experienced ultrasound examiner. Microcirculation of the periost and bone was analyzed in different regions of interest (ROIs) and quantitative microcirculation analysis was performed using time intension curve analysis (TIC). We further analyzed clinical outcome of the patients in respect to revision-surgery, necrosis of the OFF and flap survival as well as viability on standard x-rays 2 months after surgery. RESULTS: The most representative parameter by TIC analysis of hrCEUS were the area under the curve (AUC) and the time to peak (Ttop). The AUC of the periost and central part of the bone showed a high correlation (Pearson's r = 0.831). Mean AUC for the periost was 163.92 dB +/ 49.44 and for the central part of the bone 70.42 dB +/- 25.33. The Ttop of the periosteal ROI was 33.04 sec. +/- 6.71 and the bone ROI 41.01 sec. +/- 9.24. There was a high correlation of the Ttop of the periost and bone (Pearson's r = 0.937). One revision had to be performed due to haematoma and microcirculation defect of the distal part of the transplanted bone graft which was detected early by hrCEUS and the distal part of the avital bone could be removed timely. CONCLUSION: For the first time we could show that hrCEUS is a reliable method to evaluate the viability of OFF. The AUC and Ttop seem to be a valuable parameter to detect the microcirculation around and inside the bone transplant. PMID- 22214697 TI - Peripheral hemorheological and vascular correlates of coronary blood flow. AB - The slow coronary flow phenomenon (SCF), a condition described by the presence of inappropriate delay in the progression of intracoronary contrast during angiography in the absence of stenoses, has been shown in some patients presenting with chest pain. While several conditions leading to "secondary" slow flow are known, there are no definitive conclusions regarding the exact pathogenesis of "primary" SCF. The present paper outlines the mechanisms that may lead to SCF, emphasizing the role of hemorheological and vascular factors in the pathogenesis of this phenomenon. Small vessel dysfunction has been proposed in the pathogenesis of SCF since the first description of this syndrome in 1972. Abnormalities in coronary microvascular function result from increased microvascular resistances and impaired endothelial release of vasoactive substances, especially in production and bioavailability of endothelium derived NO. Inflammatory conditions (increased levels of C-reactive protein, interleukin 6 and adhesion molecules) and metabolic abnormalities such as impaired glycemic control, hyperuricemia and elevated serum gamma-glutamyltransferase were also found to contribute to microvascular dysfunction in patients with SCF. New studies have also indicated that increased blood viscosity and one of its major determinants, erythrocyte aggregation, is associated with the SCF. Rheological variables play a role in the control of shear stress and contribute to blood flow velocity changes. Although platelets do not have a significant influence on blood viscosity, it has been demonstrated that they are involved in the development of SCF. Increased mean platelet volume (MPV), an indicator of platelet activation and platelet aggregability is also significantly higher in patients with SCF compared with patients with normal coronary flow. PMID- 22214698 TI - Gene therapy with iNOS enhances regional contractility and reduces delayed contrast enhancement in a model of postischemic congestive heart failure. AB - AIMS: The purpose of this study was to evaluate the effect of transient local myocardial gene transfer of iNOS on cardiac function in a large mammal animal model of heart failure induced by chronic ischemia. METHODS: Chronic myocardial ischemia was induced using a minimally invasive model in 16 landrace pigs. Upon demonstration of heart failure, eight animals were treated with liposome-mediated iNOS-gene-transfer by local intramyocardial injection; eight animals received a sham procedure to serve as control. RESULTS: The transmurality of late enhancement (control: 46.4%, iNOS: 35.9%; p < 0.05) was significantly decreased in the ischemic area in the iNOS-treated group. Wall thickness at end-systole (6.8 mm vs. 5.9 mm, p < 0.001) and at end-diastole (5.4 mm vs. 4.2 mm, p < 0.001) were significantly higher in the therapy group. Additionally, the regional wall motion at the level of the ischemic region was 3.5 mm in the therapy group while it was significantly less (3.0 mm, p < 0.001) in the control group. CONCLUSIONS: Our findings demonstrate that transient iNOS overexpression potentially leads to a significant decrease of regional late enhancement with a positive effect on regional cardiac function in the ischemic area in a large animal model of postischemic heart failure. PMID- 22214699 TI - Hypoxic downregulation of cellular proliferation and loss of phenotype stability in human osteoblasts is mediated by HIF-1alpha. AB - Both, skeletal development and fracture healing depend on an orchestrated sequence of cellular growth and differentiation processes. Regional changes in tissue oxygen tension were proposed as key regulators of osteoblast proliferation and phenotype. Hypoxia results in the stabilization of hypoxia-inducible factor 1alpha (HIF-1alpha), thus influencing expression of a multitude of genes required for cellular adaptation. In the present study we dissected the effects of HIF 1alpha on cellular proliferation and gene expression of primary human osteoblasts. Primary human osteoblasts were studied by transfecting siRNA and plasmids coding for human HIF-1alpha. Gene expression was analyzed by western blot and quantitative PCR. Functional assays were performed to study HIF-1alpha function, i.e. proliferation and cell cycle analysis. As previously reported exposure to hypoxia led to a stabilization of HIF-1alpha on protein level and resulted in reduced rates of proliferation and osteocalcin expression. Furthermore, the expression of the proproliferative gene survivin was significantly reduced (p < 0.01). Knock down of HIF-1alpha attenuated hypoxic downregulation of proliferation (p < 0.05), and osteocalcin (p < 0.05) as well as survivin (p < 0.05) expression significantly. Importantly, the isolated overexpression of HIF-1alpha impaired proliferative activity and led to significantly reduced rates of expression of osteocalcin (p < 0.05) and survivin (p < 0.01). The present study shows that HIF-1alpha might reduce proliferation and survivin expression in primary human osteoblasts independently from cellular hypoxia. Furthermore, HIF-1alpha promoted the loss of the characteristic osteoblastic marker, osteocalcin in vitro. These findings underline the important role of HIF-1alpha in bone physiology and pathophysiology. Modulating HIF-1alpha function in hypoxic environments could be of value for future therapeutic approaches. PMID- 22214700 TI - Chronic pharmacological preconditioning against ischemia. AB - Despite decades of research and thousands of experimental publications, acute preconditioning strategies have yet to be implemented in clinical practice. While some have attributed this to a failure of the experimental studies to mimic the clinical environment, others have suggested that acute preconditioning strategies themselves may possess physiological limitations. In particular, there is evidence to suggest a reduced efficacy of acute preconditioning in the aged heart and in disease states, such as diabetes, hypertension, hyperlipidemia, and atherosclerosis. In addition, pharmacologic agent commonly used in clinical practice, such as sulfonylureas and non-steroidal anti-inflammatory agents may interfere with acute preconditioning signaling pathways. Such considerations may preclude the translation of acute preconditioning strategies to the clinical setting. This has led some to shift attention to alternate strategies of cardioprotection, one such strategy being the possibility of generating a prolonged state of cardioprotection. Although preliminary, studies to date have suggested that sustained preconditioning strategies may not be associated with the same drawbacks as acute preconditioning. Further, cardioprotective signaling pathways that elicit the sustained preconditioning response may be distinct from acute signaling pathways, which permit pharmacologic targeting of these pathways in the future. Additionally, sustained preconditioning strategies may be clinically applicable in the setting of acute myocardial infarction, a setting where acute preconditioning strategies are inherently limited. This review will briefly discuss the current data regarding sustained preconditioning strategies, including those in humans, and discuss the goal of future studies in this setting. PMID- 22214701 TI - Microcirculation and blood rheology in patients with cerebrovascular disorders. AB - We estimated hemorheological parameters of vein blood samples and cutaneous microvascular blood flow in patients with acute ischemic stroke and in controls. The worsened blood rheological properties were registered in patients with stroke: the enhanced whole blood viscosity was due to the substantial increase of plasma viscosity and the impairment of microrheological blood properties: elevated erythrocyte aggregability and decreased deformability compared to the healthy group. The decrease of oxygen consumption fixed by rheological methods and by laser Doppler flowmetry led us to conclude that the tissue hypoxia took place in patients with stroke. The regulatory mechanisms aimed to maintain blood supply to tissue were activated under cerebral infarction and the impact of unfavorably changed rheological blood properties was markedly enhanced. Revealed close interrelations between rheological and microcirculation parameters testified the important role of hemorheological factors in maintenance of microvascular blood flow and oxygen delivery to tissue. PMID- 22214702 TI - Activation of N-methyl D-aspartate (NMDA) receptors has no influence on rheological properties of erythrocytes. AB - PURPOSE: Red blood cells (RBCs) express N-methyl D-aspartate (NMDA) receptors on their surface. We tested if NMDA receptor activation or inhibition had an influence on RBC deformability and aggregability. METHODS: Heparinized blood was drawn from healthy volunteers and centrifuged. RBCs were washed twice and resuspended with a hematocrit of 30% in a same buffer solution containing 3% dextran 70. Aliquots were prepared: a) control; b) containing 100 MUM homocysteic acid (NMDA receptor agonist); c) 100 MUM memantine (NMDA receptor inhibitor) and 100 MUM homocysteic acid. RBC suspension viscometry (Contraves LS-30) was done at 37 degrees C with shear rates of 37.6 s(-1) and 0.1 s(-1). RBC aggregability was assessed with a Myrenne aggrometer and sedimentation rate. RESULTS: Neither NMDA receptor activation nor inhibition had an influence on biophysical properties of RBCs. RBC suspension viscosity at a shear rate of 37.6 s(-1) was 3.62 +/- 0.16, 3.61 +/- 0.13, and 3.62 +/- 0.16 mPa.s for control, homocysteic acid, and memantine + homocysteic acid, respectively, indicating an unchanged RBC deformability. The RBC aggregability parameters (low shear viscosity, Myrenne aggregometry at stasis (M) and 3 s(-1) (M1), and the sedimentation rate) showed no influence of either memantine and/or homocysteic acid. A large interindividual variability in RBC aggregability was observed. A good correlation was found between M, M1 and sedimentation values, but not with low shear viscosity values. CONCLUSIONS: An activation or inhibition of NMDA receptors on RBCs has no influence on their deformability and aggregability. RBC aggregability varies largely among individuals, which was consistently detected by the sedimentation rate and the Myrenne aggregometer, but not by low shear viscosity, which should not be used for this purpose. PMID- 22214703 TI - Lipid A decreases human erythrocytes deformability by increasing intracellular Ca(2+): effects of verapamil, staurosporine and the rho-kinase inhibitor Y-27632. AB - There are several reports demonstrating an involvement of bacterial toxins in the rigidity of red blood cells (RBC). The present study investigates the influence of E. coli F-583-Rd lipid A on RBC deformability under mechanical shear stress. Verapamil (Ca(2+) channel inhibitor), staurosporine (protein kinase inhibitor) and Y-27632 (rho-kinase inhibitor) were used to modify the effect of lipid A on RBC deformability. We also determined if E. coli F-583-Rd Lipid A could induce an increase of intracellular Ca(2+) concentration. For the deformation measurements RBC (10 adult donors) were incubated with E. coli F-583-Rd lipid A (100 MUg/ml) and also co-incubated with either verapamil (10(-7) mol/l), staurosporine (10(-7) mol/l) or Y-27632 (10(-7) mol/l). The deformation of the RBC under different shear stresses (0.6-60 Pa) was measured by a shear stress diffractometer (Rheodyne SSD). Intracellular Ca(2+) was determinded by flow cytometry in RBC incubated with Lipid A and labeled with fluorescent Fluo-4/AM which binds intracellular Ca(2+) with high affinity resulting in enhanced green fluorescence intensity. At increasing shear stresses Lipid A induced a significantly lower elongation. Co-incubation of the erythrocytes with verapamil or staurosporine inhibited lipid A induced decrease in elongation while Y-27632 had no effect. Verapamil, Staurosporine and Y-27632 did not influence the elongation response of the cells under control conditions. Lipid A induced a marked increase in fluorescence Fluo-4/AM indicating increased intracellular Ca(2+). These results suggest that E. coli F-583-Rd lipid A is able to influence red blood cell rigidity by a rapid and significant increase of intracellular Ca(2+) concentration. Verapamil and staurosporine abolished the decrease in deformability of Lipid A incubated RBC. PMID- 22214704 TI - Relevance of erythrocyte deformability to the concentration of soluble cell adhesion molecules and glomerular filtration rate in patients with untreated essential hypertension. AB - Relationship between erythrocyte deformability and: a) soluble cell adhesion molecules concentration, b) glomerular filtration rate (eGFR) has been investigated in three study groups: a group of 20 patients with diagnosed arterial hypertension, a group of 20 individuals with exclusively hypercholesterolemia and a group of 22 healthy persons. The individuals with hypertension or hypercholesterolemia were free of any other cardiovascular disease risk factor and were not on any therapy prior to entering the study. Clinical and laboratory data included systolic and diastolic blood pressure (obtained by ABPM), lipids profile, eGFR, red blood cell (RBC) deformability (assessed by shear stress laser diffractometry) and levels of circulating soluble vascular adhesion molecules-1 (sVCAM-1) as well as soluble intracellular adhesion molecules-1 (sICAM-1). In the group of hypertensives, RBC deformability and concentration of circulating soluble adhesion molecules showed statistically significant negative correlations: RBC deformability decreases with increasing level of: a) sVCAM-1, R = -0.61, p < 0.002, b) sIVCAM-1, R = -0.53, p < 0.009. In parallel, statistically significant increase of eGFR was observed with rising erythrocyte deformability, R = 0.60, p < 0.005. In the groups of healthy individuals and patients with hypercholesterolemia there was no sign of any correlations between the considered parameters. The observed correlations suggest that in patients diagnosed exclusively with hypertension, firstly, erythrocyte deformability may serve as a marker of endothelial dysfunction and, secondly, red blood cells may be mediators of adverse changes in kidneys. PMID- 22214705 TI - The influence of on-pump and off-pump coronary artery bypass grafting on hemorheological parameters. AB - Conditions during coronary artery bypass grafting (CABG) performed on beating heart (off-pump) are more physiological than using extracorporeal perfusion (on pump). The present study aims to examine the hemorheological aspects of the two techniques. Blood samples were taken from patients undergoing on-pump (n = 25) and off-pump (n = 22) CABG, upon arrival to the operating theatre, after 20 and 40 minutes during the operation, after closing the thorax, on the 1st and 2nd postoperative days, and during the 2nd and 6th month control check-ups. Hematocrit (Hct), plasma and whole blood viscosity (PV, WBV; Hevimet 40 capillary viscometer), red blood cell (RBC) aggregation (Myrenne RBC aggregometer, LORCA) and deformability (LORCA, Carat FT-1 filtrometer), and platelet aggregation (Carat TX4 aggregometer) were determined. The morphology of red blood cells was investigated by scanning electron microscopy (SEM). Hct, PV, WBV and RBC aggregation decreased significantly during the early phase of the surgery, they started to recover during the postoperative period, and reached the baseline values by the 2nd and 6th month control check-ups. These parameters were significantly lower in samples taken after 20 and 40 minutes in the on-pump group. SEM showed rather damaged and malformed cells in case of on-pump surgery. Ektacytometry showed no significant difference, but RBC deformability was impaired during on-pump surgery when measured by filtrometry. The decrease in platelet aggregation was more pronounced by the end of surgery in case of on-pump technique. During CABG rheological parameters change less when using the off-pump method, and mechanical damage of RBCs are also smaller. The off-pump technique seems to be favorable from a hemorhelogical point of view. PMID- 22214706 TI - Designing multifunctional polymers for cardiovascular implants. AB - Polymer-based biomaterials are extensively used in all disciplines of clinical medicine and innovations in biomaterial science are building a product pipeline, e.g., of future cardiovascular implants. Still, cardiovascular applications demand a number of extensive requirements of properties and functions to be fulfilled by the polymer matrix. This report provides an overview on some of these issues and how they can be addressed by a tailored design of novel polymer based biomaterials. Multifunctional shape-memory polymers are highlighted as a class of materials that combine biocompatibility and the capability for stimuli induced active movements for anchoring of implants with a controlled degradation and drug release profile to enable a functional regeneration of the tissue at the application site. PMID- 22214707 TI - Tissue engineering of small-diameter vascular grafts: a literature review. AB - For the treatment of cardiovascular disease, functional arterial blood vessel prostheses with an inner diameter less than 6 mm are needed. This article gives an overview of the preparation of such vascular grafts by means of tissue engineering. PMID- 22214708 TI - Hemocompatibility of soft hydrophobic poly(n-butyl acrylate) networks with elastic moduli adapted to the elasticity of human arteries. AB - Small calibre vascular prostheses (<6 mm) still lack medium and long term patency. Inelasticity of the prosthesis is one of the characteristics, which is involved in the mechanisms of failure (e.g. the development of neointimal hyperplasia at the distal anastomosis). Here we report about covalently crosslinked poly(n-butyl acrylate) networks (cPnBA) with adjustable elastic moduli, which can be tailored to values of human arteries (between 100 and 1000 kPa). Motivated by the potential application of such polymer networks as cardiovascular prosthesis, adhesion, activation and thrombus formation of human platelets on cPnBA networks were evaluated. All cPnBA-samples displayed a high thrombogenicity compared to the control (silicone). Significantly less platelets adhered on the surface of the soft cPnBA04 than on cPnBA73. All cPnBA samples displayed a higher number of platelet aggregates and a lower number of inactivated platelets in comparison to the control. While the elastic modulus of cPnBA networks could be successfully adjusted to that of human arteries, the tested polymers did not show an optimal hemocompatibility. Future studies aim at improving the biofunctionality by surface modification of these polymer networks. PMID- 22214709 TI - An advanced cone-and-plate reactor for the in vitro-application of shear stress on adherent cells. AB - Endothelial cells (ECs) are permanently exposed to the blood flow and the resulting shear stress, its magnitude varying with the EC site in the blood stream. Along with other mechanical stimuli like vessel wall stretching or hydrostatic blood pressure, this shear stress modulates the endothelial cell function, morphology and gene expression. Here, we describe our improved cone-and plate reactor that applies up to 10 dyn/cm(2) uniform wall shear stress on a defined, ring-shaped region on a culture dish. At the same time, a hydrostatic pressure of up to 195 mmHg can be applied by increasing the atmospheric pressure in the incubator box. Gas composition can be controlled additionally, used for maintaining CO2-homeostasis or inducing hypoxic conditions. For better comparability, six cone-and-plate systems can be used at the same time at different rotational velocities. The effects on cell morphology, cytoskeleton and cell alignment can be monitored during application using a laser scanning microscope. Flow conditions have been studied and a sufficient area of uniform wall shear stress could be shown. To exceed 10 dyn/cm2, we suggest an increase in medium viscosity. PMID- 22214710 TI - Alterations of serum erythropoietin and thrombopoietin levels in patients undergoing Coronary Artery Bypass Grafting (CABG). AB - INTRODUCTION: The hormones erythropoietin (EPO) and thrombopoietin (TPO) are main regulators of erythro- and thrombopoiesis. Cell loss caused by operative procedures may alter serum levels of the hormones, resulting in well known phenomenons like reactice thrombocytosis. MATERIAL AND METHODS: Blood samples from 10 patients (mean age 63 +/- 9 years) were obtained before and at day 1, 5 and 10 after coronary artery bypass grafting (CABG). EPO and TPO levels were determined by commercially available ELISA-Kits (R&D Systems, Germany). In addition, platelet count (PC) and hemoglobin concentration (Hb) were determined. RESULTS: Prior to CABG, EPO (13.2 +/- 8.2 mU/mL), TPO (189 +/- 52 pg/mL), Hb (8.8 +/- 1.1 mmol/L) and PC (254 +/- 121/nL) were within a normal range. At day 1 after surgery, Hb and PC were significantly decreased to 6.6 +/- 0.9 mmol/L and 138 +/- 70/nL. In contrast, EPO and TPO were significantly elevated to 32 +/- 18 mU/mL and 336 +/- 96 pg/mL, respectively, in spite of hemodilution. In particular, TPO elevation was followed by a significant increase in PC (342 +/- 144/nL) at day 10 after surgery compared to preoperative values. CONCLUSIONS: Appropriate to the decrease in hemoglobin concentration and platelet count, clear alterations of serum erythropoietin and thrombopoietin levels could postoperatively be observed. EPO levels showed an inverse correlation to hemoglobin concentrations, whereas a disturbed thrombopoietin feedback mechanism resulted in the phenomenon of reactive thrombocytosis. PMID- 22214711 TI - Evidence that the degree of band 3 phosphorylation modulates human erythrocytes nitric oxide efflux--in vitro model of hyperfibrinogenemia. AB - Recent evidence has shown that plasma fibrinogen, a major cardiovascular risk factor, interacts with the erythrocyte membrane and acts to influence blood flow via erythrocyte nitric oxide (NO) modulation. In the present pioneer in-vitro study, whole blood samples were harvested from healthy subjects and aliquots were incubated in the absence (control aliquots) and presence of fibrinogen at different degrees of band 3 phosphorylation, and the levels of NO, nitrite, nitrate and S-nitroglutathione (GSNO) were determined. Hyperfibrinogenemia interferes with erythrocyte NO mobilization without changing its efflux in a way that seems to be dependent of the degree of band 3 phosphorylation. In presence of higher fibrinogen concentrations the NO efflux is reinforced when band 3 is phosphorylated (p < 0.001). Higher levels of nitrite, nitrate and GSNO were documented (p < 0.05). However, the mechanisms by which fibrinogen signalling modulates erythrocyte function remain to be clarified and are currently under study. These conditions may be considered an approach to be followed in blood storage for transfusions. PMID- 22214713 TI - Support of HUVEC proliferation by pro-angiogenic intermediate CD163+ monocytes/macrophages: a co-culture experiment. AB - So called intermediate (MO2) monocytes/macrophages possess anti-inflammatory properties and express the MO lineage marker CD163. On a hydrophilic, acrylamide based hydrogel human intermediate (CD14++ CD16+) CD163++ monocytes/macrophages (aMO2) which were angiogenically stimulated, maintained a pro-angiogenic and non inflammatory status for at least 14 days. Here we explored, whether this aMO2 subset can positively influence the proliferation of human umbilical venous endothelial cells (HUVECs) without switching back into a pro-inflammatory (MO1) phenotype. aMO2 or HUVEC were seeded alone on glass cover slips (0.5 * 10(5) cells / 1.33 cm(2)) in a HUVEC specific cell culture medium (EGM-2) for 3 hrs, 24 hrs and 72 hrs or under co-culture conditions (0.5 * 10(5) HUVEC + 0.25 * 10(5) aMO2 / 1.33 cm(2)) in EGM-2 for the same time window as well (n = 6 each). Under co-culture conditions the numbers of adherent HUVEC per unit area were significantly higher (p < 0.01; 525 +/- 52 HUVEC/mm(2)) compared to control mono cultures (473 +/- 76 HUVEC/mm(2)) after 72 hrs of cultivation and showed their typically spread morphology. The aMO2 remained in their subset status and secreted VEGF-A165 without release of pro-inflammatory cytokines until the end of the 72 hrs cultivation time period, thereby supporting the HUVEC proliferation. These in vitro results might indicate that this MO subset can be used as cellular delivery system for pro-angiogenic and non-inflammatory mediators to support the endothelialisation of biomaterials like e.g. cPnBA. PMID- 22214712 TI - Hematological changes in case of chronic cadmium intoxication and monensin detoxication. Relationship with rheological variables. AB - The study evaluated the affect of chronic cadmium (Cd) and monensin treatment on some hematological parameters and its relationship with the rheological variables. Adult male mice were subjected to chronic treatment with cadmium acetate [Cd(CH3COO)2 * 2H2O] (group 1), Cd(CH3COO)2 * 2H2O followed by treatment with low dose monensin (group 2) and Cd(CH3COO)2 * 2H2O followed by high dose monensin treatment (group 3). Cd(CH3COO)2 * 2H2O and deprotonated monensin were dissolved in distilled water and given daily to the experimental animals. Mice drinking distilled water served as a control group (group 4). Hematological parameters and erythrocyte morphology were evaluated in parallel with whole blood viscosity (WBV). Cd treatment reduced Hb and increased RDW. The addition of high dose monensin significantly improved erythrocytic indices compared to the control. Erythrocyte anisocytosis was observed in blood smears of Cd-treated mice corresponding to the increased RDW. WBV was significantly elevated in the experimental groups in the whole range of shear rates compared to the control group and in groups 2 and 3 was lower than in group 1 but remained higher compared to group 4. Correlations were found between WBV and RBC, Hb, Hct, MCV and RDW. The results suggest that hemorheological parameters such as WBV should be monitored in parallel with the hematological parameters when monensin is applied and heavy metal intoxication is suspected. PMID- 22214715 TI - Experimental evaluation of mechanical and electrical properties of RBC suspensions in Dextran and PEG under flow II. Role of RBC deformability and morphology. AB - Mechanical and electrical properties of the normal RBCs suspensions and of hardened after treatment with glutaraldehyde (0.01-2.5%) RBCs in isotonic physiological solution and Dextran 70,000 (Dextran 70) and Polyethylene glycol 35,000 (PEG) and adjusted to hematocrit of 40%, were evaluated. Apparent viscosity and conductivity were measured under steady and transient flow regimes at low shear rates and at different local structure of the flow at 37 degrees C. A time course of conductivity was recorded in parallel with the rheological properties of the RBC suspensions and conductivity and apparent viscosity dependences on shear rates were studied and compared at different concentrations of Dextran 70, PEG and glutaraldehyde. Low shear viscosity decreased after RBCs treatment with glutaraldehyde and at 0.5-2.5% it is constant. Echinocytes are observed at low Dextran 70 and PEG concentrations while spherocytes are found mainly in smears treated with higher concentrations. The results show that the apparent viscosity and conductivity of RBCs suspensions in Dextran 70 and PEG are strongly influenced by flow, shear rates, concentration, cell deformability and morphology and the method is sensitive to study the mechanical and electrical properties of RBC suspension and to provide experimental description of RBCs and other cell-to-cell interactions. PMID- 22214714 TI - Macro- and microrheological parameters of blood in patients with cerebral and peripheral atherosclerosis: the molecular change mechanisms after pentoxifylline treatment. AB - This study was designed to evaluate hemorheological changes in patients with cerebrovascular disease (CVD) and peripheral arterial disease (PAD) after 4 weeks of pentoxifylline therapy as well as to study red blood cell microrheological variables after the cell incubation with pentoxifylline and some phosphodiesterase (PDE) activity inhibitors. The patients with CVD (n = 50) and PAD (n = 33) were treated with pentoxifylline (400 mg, thrice a day) for 4 weeks. Before and after drug therapy the hemorheological measurements including plasma and whole blood viscosity, red blood cell aggregation (RBCA) and deformability (RBCD) were completed. In vitro study RBCs were incubated with: 1) Vinpocetine- inhibitor PDE-1, 10 MUM; 2) Rolipram--PDE-4, 10 MUM; 3) Isobutyl-methylxanthine (IBMX)--nonselective PDE inhibitor, 100 MUM and with pentoxifylline, 10 MUM The cell incubation was performed at 37 degrees C for 15 min. There were the positive changes of hemorheological profile after 4 weeks of the pentoxifylline therapy both in CVD and PAD patients. The marked RBCD changes were observed after the in vitro cell pentoxifylline treatment as well. Perhaps it is connected with the inhibition of the phosphodiesterase activity in RBCs. An application of drugs and chemicals that can inhibit the PDE activity resulted in RBCD rise and RBCA decrease. The experiments with the use of selective PDE inhibitors have revealed the similar red cell deformability changes. Vinpocetine increased RBCD significantly (p < 0.05). PDE-4 inhibitor--Rolipram stimulated RBCD by 15% (p < 0.05). Some more effective was IBMX. After cell incubation with it a significant rise of the deformability (by 27%; p < 0.05) was found. All drugs, having PDE activity decreased RBCA, but the most pronounced effect had Vinpocetine (50%; p < 0.05). Thus, administered pentoxifylline, daily (1200 mg), during four weeks improves hemorheological profile and especially its microrheological part as well as the blood transport capacity in subjects with cerebral and peripheral vascular disorders. It is most probably red cell microrheological control mechanisms may be associated with the phosphodiesterase activity alterations. PMID- 22214716 TI - Metabolic depletion decreases the aggregability of erythrocytes. AB - We studied the influence of metabolic depletion on red blood cell (RBC) aggregability, which is a determinant of blood flow. Heparinized blood was stored at room temperature for 0, 24, and 48 h. RBCs were washed twice and resuspended in Tris-buffer containing 3% dextran 70 (hematocrit 30%). Suspension viscosities were measured at 37 degrees C and shear rates of 37.6 and 0.1 s(-1), RBC aggregability was analysed by the sedimentation rate, direct microscopic visualization and a Myrenne aggregometer. RBCs in autologous plasma showed an increasing echinocytic shape transformation, which was reversible in buffer. The viscosities of RBC suspensions in buffer remained unchanged at both low (0.1 s( 1)) and high shear rate (37.6 s(-1)), the latter result indicating an unchanged RBC deformability. RBC aggregability decreased: The RBC sedimentation rates were 40.7 +/- 5.0, 29.3 +/- 13.4, and 13.3 +/- 11.2 mm/h (p < 0.001) at 0, 24, and 48 h, respectively, which correlated well with the visual aggregability index and the Myrenne aggregation parameters M and M1. We conclude that metabolic depletion for 48 h leads to RBC swelling and a reversible echinocytic shape transformation. These ATP-depleted, but normally shaped RBCs had a decreased aggregability. In contrast to all other methods used, low shear viscosity was inaccurate and should not be used to test RBC aggregability. PMID- 22214717 TI - Erythrocyte as a link between basic and clinical research. AB - We review the major hemorheological experimental studies that show the erythrocyte aggregation as a link between basic and clinical research. The results of the clinical cross-sectional and longitudinal studies presented here will highlight the possible association between erythrocyte aggregation and plasma fibrinogen. Basic studies conducted in vitro are also mentioned as for its relevance in answering questions raised in clinical settings, as well as and in understanding the underlying influent factors in the erythrocyte tendency to aggregate and disaggregate. PMID- 22214718 TI - In vitro angiogenic potency in human microvascular endothelial cells derived from myocardium, lung and skin. AB - Human microvascular endothelial cells derived from myocardium (HCMEC), lung (HPMEC) and foreskin (HDMEC) showed different angiogenic potency when cultivated in their original growth media provided by the distributors. In order to standardize microenvironmental conditions in an all-in-one assay of angiogenesis the aim of this study was to find one optimal growth medium for the endothelial cells derived from the different organs. Therefore each endothelial cell type was cultivated under identical conditions in the different original growth media as well as in several media formulations of the original growth media. Results reveal that even if cultivated in the same growth medium under exactly the same cultivation conditions--over a prolonged time period of 60 days--the endothelial cells still showed different angiogenic potency. This is due to a combination of extrinsic factors, i.e. the isolation procedure and in particular the growth medium, as well as to intrinsic differences between cells of diverse origin. PMID- 22214719 TI - Endothelium and hyperviscosity. AB - The role of viscosity, and of interindividual variations in this parameter, in the pathophysiology of cardiovascular disease remain incompletely understood. Any speculation regarding the possible impact of "hemorheological" therapies is therefore even more complex. In the last years, the debate regarding the relationship between increased viscosity and atherogenesis has been opened again. While the traditional view postulates that an increased blood viscosity has invariably a negative impact on tissue perfusion and therefore should be considered as a risk factor (when not as a true disease), a more recent hypothesis has been formulated based on the observation that small increases in viscosity actually have vasodilatory effects, potentially improving tissue perfusion. PMID- 22214720 TI - Association between hemorheological alterations and metabolic syndrome. AB - The contribution of hemorheological alterations in the prothrombotic condition in patients with metabolic syndrome (MS) remains a question of debate. We aimed to determine the association between MS and hemorheological parameters by means of a case-control study in 61 MS patients and 89 controls without MS. We determined blood viscosity at 230 s(-1) (Brookfield DVIII viscosimeter); plasma viscosity (Fresenius capillary plasma viscosimeter); erythrocyte aggregation at stasis and 3 s(-1) (MA-1 erythrocyte aggregometer); erythrocyte deformability (Rheodyn SSD at shear stresses of 12, 30 and 60 Pascals) and fibrinogen, along with anthropometric, lipidic and inflammatory parameters. MS patients showed increased blood viscosity (p = 0.018), plasma viscosity (p < 0.001), fibrinogen (p < 0.001), erythrocyte aggregation (p < 0.001), and decreased erythrocyte deformability (p = 0.033). In the multivariate regression analysis, fibrinogen and triglycerides predicted plasma viscosity and erythrocyte aggregability, whereas erythrocyte deformability was associated with alterations in the hydrocarbonate metabolism. Blood viscosity related to abdominal obesity. The logistic regression analysis revealed that of all the MS components, only hypertriglyceridemia independently predicts plasma hyperviscosity (OR 3.75 CI 1.44-9.77 p = 0.007) and erythrocyte hyperaggregability (OR 2.41 CI 1.00-5.80 p = 0.050). Erythrocyte hyperaggregability (EA > 8.23) and hyperfibrinogenemia (fibrinogen > 358 mg/dL) were independent predictors of MS: OR 3.34, 95% CI 1.40 7.93, p = 0.006 and OR 2.42 95% CI 1.04-5.66, p = 0.041, respectively. We conclude that MS is associated with an altered hemorheological profile related to inflammatory, lipidic and glucose intolerance parameters which could favor the development of thrombo-embolic and athero-thrombotic events in MS patients. PMID- 22214721 TI - Hemorheology and vascular reactivity in patients with diabetes mellitus type 2. AB - The study aimed to investigate the hemorheological parameters in patients with diabetes mellitus type 2 and to estimate their relationship with the cerebral and cutaneous blood flow and their responses to postural changes. The basic hemorheological constituents: hematocrit (Ht), fibrinogen (Fib), whole blood (WBV) and plasma viscosity (PV) were examined in 20 patients with diabetes mellitus type 2 and in 10 healthy age and sex matched controls. Blood flow velocity in the middle cerebral artery (MCA) was measured by transcranial Doppler monitoring at rest and during 5-min head-up tilt. Also laser Doppler-recorded tiptoe skin blood flow was investigated and venoarteriolar reflex perfusion responses to postural impact was monitored. Significant increase of Fib and WBV at shear rates of 0.0237 s(-1) to 128.5 s(-1) in the patients in comparison to controls was found. The postural challenge caused decrease of the cerebral blood flow velocity and increase of the resistance index (RI) in the diabetic patients. The initial mean skin perfusion values of the tiptoes and the venoarteriolar constriction response indices were significantly higher in the diabetes group. In the patients with diabetes mellitus type 2 the increased blood viscosity values were associated with impaired cerebrovascular and peripheral vascular responces. PMID- 22214722 TI - Hemorheology and heart rate variability in patients with diabetes mellitus type 2. AB - Our study aimed to investigate the relationship between hemorheological parameters and heart rate variability (HRV) in patients with diabetes mellitus type 2. Hemorheological variables, including hematocrit (Ht), fibrinogen (Fib), whole blood (WBV) and plasma viscosity (PV) at shear rates of 0.0237 s(-1) to 128.5 s(-1) were examined in 20 patients with diabetes mellitus type 2 and in 10 control subjects. They all underwent non-invasive short-term monitoring of heart rate at rest and after passive head-up tilt. Measurement of the R-R intervals and calculation of the time domain parameters and the power spectral data were performed by our softwear, using fast Fourier transformation. Significant increase of Fib and WBV in the patients in comparison to controls was found within the range of shear rates 0.0237 s(-1) to 128.5 s(-1). In the diabetic patients parallel decrease of the total power (TP), the low frequency spectral power (LF) and of the mean RR and mild increase of the low frequency-high frequency ratio (LF/HF) at rest were established. This tendency was kept after the passive tilt. In patients with diabetes mellitus type 2 the increased blood viscosity was associated with reduced HRV. PMID- 22214723 TI - Limitation of in vivo models investigating angiogenesis in breast cancer. AB - MSCs reside within their niche and pathologic conditions such as hypoxia and inflammation can lead to mobilization and migration of Mesenchymal Stem Cells (MSCs). Xenograft animal models using immundeficient mouse demonstrated that MSCs migrated to and distributed throughout the tumors and were found to engraft into tumor stroma and vasculature. In contrast, MSCs primarily incorporated within tumor-capsula and did not invade the tumor using immuncompetent tumor allograft models. Here we hypothesize that MSCs migrate primarily towards an inflammatory milieu independent of the underlying biological process causing the inflammation. Murine MSCs (mASCs) were isolated from subcutaneous fat tissues and transduced at passage 0 with lentiviral vector encoding green fluorescent protein (GFP) and luciferase reporter. Breast cancer was established in BALB/c mice by subcutaneous injection of 4T1 cells into the left mammary fat pad. E. coli were injected subcutaneously in the right 4th mammary fat pad. After 24 h luciferase labeled mASCs were administered intraperitoneal (i.p.) and monitored with IVIS Bioluminescence camera for 72 hours. Control group received either tumor implantation or E. coli injection. MSCs significantly migrated towards tumor when compared to control mice without tumor or inflammatory process. However, mASCs injected in 4T1 bearing mice with E. coli only migrated towards the bacterial inflammatory focus. Our results substantiate the notation the MSCs response predominantly to the inflammatory milieu created by bacteria or tumor rather than specifically to the tumor. Thus, it is suggested that the migration of MSCs in immunodeficient mice depends on cancer secreted cytokines due to the lack of the inflammatory response by the immune system. Therefore, in vivo studies investigating the role of MSCs in tumor angiogenesis have shown controversy results and should be interpreted with caution in terms of tumor secreted cytokine dependent stem cell migration. PMID- 22214724 TI - ARFI-based tissue elasticity quantification and kidney graft dysfunction: first clinical experiences. AB - BACKGROUND AND PURPOSE: Beyond the medical history, the clinical exam and lab findings, non-invasive ultrasound parameters such as kidney size and Doppler values (e.g. the resistive index) are important tools assisting clinical decision making in the monitoring of renal allografts. The gold standard for the diagnosis of renal allograft dysfunction remains the renal biopsy; while an invasive procedure, the justifiable necessity for this derives from its definitive nature a requirement beyond the synopses of all non-invasive tools. "Acoustic Radiation Force Impulse Imaging"(ARFI)-quantification is a novel ultrasound-based technology measuring tissue elasticity properties. So far experience related to this new method has not been reported in renal transplant follow-up. The purpose of this study was to evaluate changes in ARFI-measurements between clinically stable renal allografts and biopsy-proven transplant dysfunction. METHODS: We employed "Virtual TouchTM tissue quantification" (Siemens Acuson, S2000) for the quantitative measurement of tissue stiffness in the cortex of transplant kidneys. We performed initial baseline and later disease-evaluative ultrasound examinations in 8 renal transplant patients in a prospective study design. Patients were first examined during stable allograft function with a routine post transplant renal ultrasound protocol. A second follow-up examination was carried out on subsequent presentation with transplant dysfunction prior to allograft biopsy and histological evaluation. All patiens were examined using ARFI quantification (15 measurements/kidney). Resistive indices (RI) were calculated using pulsed-wave Doppler ultrasound, and transplant kidney size was measured on B-mode ultrasound images. All biopsies were evaluated histologically by a reference nephropathologist unaware of the results of the ultrasound studies. Histopathological diagnoses were based on biopsy results, taking clinical and laboratory findings into account. Finally we calculated the relative changes in ARFI-quantification, resistive indices and the absolute change of kidney size on a percentage basis at these defined assessment times and compared the results with the final pathologic diagnosis. RESULTS: Histological results enumerated five cases of acute T-cell-mediated rejection, one case of calcineurin inhibitor toxicity and two cases of acute tubular necrosis. Calcineurin inhibitor toxicity and acute tubular necrosis were subsumed as "other pathologies". Mean ARFI-values showed an average increase of more than 15% percent in transplants with histologically proven acute rejection whereas no increase was seen in transplants with other pathologies. Mean RI-values showed no increase either in the diagnostic group of acute rejection, nor in the group with other pathologies. Kidney size showed a mean absolute increase of 0.5 centimetres in allografts with acute rejection, whereas a mean decrease of 0.17 centimetres was seen in the group with other pathologies. CONCLUSION: As shown before in other studies, RI values and kidney size are of doubtful utility in the evaluation of kidney allograft dysfunction. ARFI-based elasticity measurement shows promise as a complementary non-invasive parameter in follow-on diagnosis of renal allograft rejection. PMID- 22214725 TI - Improved visualization of renal lesions using three-dimensional ultrasound--a feasibility study. AB - PURPOSE: To evaluate the potential benefit of three-dimensional ultrasound in the assessment of renal lesions. MATERIALS AND METHODS: 21 patients with unclear renal findings were prospectively included in the study. Every patient was examined using two-dimensional (2D) ultrasound (US), X-plane technique (simultaneous display of main image and second image at a plane at right angles to the first), and real time three-dimensional (3D) US. The imaging model used were standard gray scale-, duplex- and contrast-enhanced ultrasound (CEUS). All acquisitions were compared to each other with regard to image quality and identifiability of renal lesions. Additionally, when using the X-plane technique the quality of the first and the second image were analysed separately. The assessment was done using a subjective 6 point scale (1 = best). RESULTS: All acquisitions were successfully performed and no patient had to be excluded. Image quality of real time 3D-US (score: 2.4 +/- 0.73) was slightly inferior to 2D-US and X-plane technique (main image) with a score of 2.2 +/- 0.43 and 2.2 +/- 0.5, respectively. The image quality of second image in the X-plane mode -due to a lower spatial resolution- was lower with a score of 3.2 +/- 0.5. Real time 3D-US and X-plane technique allowed for better identifiability (score: 1.4 +/- 0.59 and 1.9 +/- 0.53) of renal lesions compared to 2D-US (score: 2.5 +/- 0.6). The most marked difference was observed between the simultaneous use of real time 3D-US and X-plane technique versus 2D-US in case of renal cell carcinoma, especially with regard to extra-capsular tumor extension (score: 1.6 +/- 0.52, 1.8 +/- 0.71, and 3.0 +/- 0.52, respectively). CONCLUSION: Assessment of renal lesions using real time 3D-US is feasible and improves the identifiability of renal lesions. PMID- 22214728 TI - The Hall effect in the organic conductor TTF-TCNQ: choice of geometry for accurate measurements of a highly anisotropic system. AB - We have measured the Hall effect on recently synthesized single crystals of the quasi-one-dimensional organic conductor TTF-TCNQ (tetrathiafulvalene tetracyanoquinodimethane), a well known charge transfer complex that has two kinds of conductive stacks: the donor (TTF) and the acceptor (TCNQ) chains. The measurements were performed in the temperature interval 30 K < T < 300 K and for several different magnetic field and current directions through the crystal. By applying the equivalent isotropic sample approach, we have demonstrated the importance of the choice of optimal geometry for accurate Hall effect measurements. Our results show, contrary to past belief, that the Hall coefficient does not depend on the geometry of measurements and that the Hall coefficient value is approximately zero in the high temperature region (T > 150 K), implying that there is no dominance of either the TTF or the TCNQ chain. At lower temperatures our measurements clearly prove that all three phase transitions of TTF-TCNQ could be identified from Hall effect measurements. PMID- 22214729 TI - Source attribution of human campylobacteriosis using a meta-analysis of case control studies of sporadic infections. AB - Campylobacter spp. is a widespread and important cause of human illness worldwide. Disease is frequently associated with foodborne transmission, but other routes of exposure, such as direct contact with live animals and person-to person transmission, are also recognized. Identifying the most important sources of human disease is essential for prioritizing food safety interventions and setting public health goals. Numerous case-control studies of sporadic infections of campylobacteriosis have been published. These studies investigated a variety of potential risk factors for disease, often using different methodologies and settings. Systematic reviews (SRs) consist of a formal process for literature review focused on a specific research question, and include the identification of relevant literature, quality assessment of relevant studies, summarization or statistical analysis of data, and conclusions. With the objective of identifying the most important risk factors for human sporadic campylobacteriosis, we performed a SR of case-control studies of human sporadic cases and a meta analysis of the obtained results. A combined SR focusing on Salmonella and Campylobacter studies was performed and the results analysed separately. From 1295 identified references, 131 passed the relevance screening, 73 passed the quality assessment stage, and data was extracted from 72 studies. Of these, 38 focused on campylobacteriosis. Information on exposures of cases and controls, and estimated odds ratios for investigated risk factors were collected and analysed. In the meta-analysis, heterogeneity between the studies and possible sources of bias were investigated, and pooled odds ratios for identified risk factors were estimated. Results suggest that travelling abroad, eating undercooked chicken, environmental sources, and direct contact with farm animals were significant risk factors for campylobacteriosis. Sub-analyses by geographical region, age group, and study period were performed, and differences were discussed. PMID- 22214730 TI - New Zealand green-lipped mussels (Perna canaliculus) enhance non-haem iron absorption in vitro. AB - Fe bioavailability can be manipulated by the nutritional composition of a meal. Ascorbic acid and unidentified components of meat, fish and poultry, but particularly beef, all appear to enhance the absorption of non-haem Fe. The aim of the present study is to identify whether extracts of green-lipped mussels (GLM; Perna canaliculus) enhance non-haem Fe absorption in Caco-2 cells and to compare the effect with that of beef. Raw GLM and raw beef homogenates were digested in vitro with pepsin at pH 2, and pancreatin and bile salts at pH 7. Tracer 55Fe was used to measure cellular Fe uptake. Ascorbic acid was used as a positive control and egg albumin, exposed to the same in vitro digestion process, was used as a negative control. Caco-2 cell monolayers were incubated with treatments for 60 min. All values were standardised per MUg of GLM, egg albumin, beef or ascorbic acid. The results showed that ascorbic acid enhanced non-haem Fe absorption to the highest degree. Beef and GLM digestates both significantly enhanced Fe absorption compared with egg albumin. In conclusion, GLM digestate significantly enhances non-haem Fe uptake in Caco-2 cells with a similar magnitude to that of beef. PMID- 22214731 TI - Increasing health awareness to decreasing nonparticipation bias in health studies. PMID- 22214733 TI - Two-thirds of methodological research remained unpublished after presentation at Cochrane Colloquia: an empirical analysis. AB - OBJECTIVES: To determine the extent to which abstracts of methodology research, initially presented at annual meetings of The Cochrane Collaboration, have been published as full reports and over what period of time. A secondary aim was to explore whether full publication varied in different methodological subject areas. STUDY DESIGN AND SETTING: The Cochrane Methodology Register (CMR) was searched for all abstracts reporting methodology research, presented at the 11 Cochrane Colloquia from 1997 to 2007. EMBASE, PubMed, and CMR were searched for full publications of the same research. RESULTS: We identified 908 eligible conference abstracts and found full publications for 312 (34.4%) of these, almost half of which (47.1%) had appeared by the end of the first year after the relevant Colloquium. The proportion of abstracts that had not been published by 3 years was 69.7%, falling to 66.2% at 5 years. Publication varied considerably between different methodological areas. CONCLUSION: Approximately two-thirds of methodological research studies presented at Cochrane Colloquia remain unpublished as full papers at least 5 years later. This highlights the importance of searching conference abstracts if one wishes to find as comprehensive and complete a sample of methodological research as possible. PMID- 22214734 TI - Development and validation of clinical prediction models: marginal differences between logistic regression, penalized maximum likelihood estimation, and genetic programming. AB - OBJECTIVE: Many prediction models are developed by multivariable logistic regression. However, there are several alternative methods to develop prediction models. We compared the accuracy of a model that predicts the presence of deep venous thrombosis (DVT) when developed by four different methods. STUDY DESIGN AND SETTING: We used the data of 2,086 primary care patients suspected of DVT, which included 21 candidate predictors. The cohort was split into a derivation set (1,668 patients, 329 with DVT) and a validation set (418 patients, 86 with DVT). Also, 100 cross-validations were conducted in the full cohort. The models were developed by logistic regression, logistic regression with shrinkage by bootstrapping techniques, logistic regression with shrinkage by penalized maximum likelihood estimation, and genetic programming. The accuracy of the models was tested by assessing discrimination and calibration. RESULTS: There were only marginal differences in the discrimination and calibration of the models in the validation set and cross-validations. CONCLUSION: The accuracy measures of the models developed by the four different methods were only slightly different, and the 95% confidence intervals were mostly overlapped. We have shown that models with good predictive accuracy are most likely developed by sensible modeling strategies rather than by complex development methods. PMID- 22214735 TI - Classic and non-classic forms of mitral valve prolapse. AB - OBJECTIVE: To investigate the significance of the established distinction between classic and non-classic forms of mitral valve prolapsed (MVP). METHODS: We included in this prospective study all patients examined in our preventive cardiology outpatient clinics during the biannual period October 2004-October 2006. We examined in total 10.818 patients, 238 of whom (2.2%) were diagnosed for MVP. We noted relevant demographic and clinical data (gender, age of diagnosis, symptoms, need for hospitalization) and performed statistical comparisons between patients with the classic and those with the non-classic form. Follow-up controls were performed three years afterwards. RESULTS: Patients with the classic form had an earlier age of first diagnosis, more prominent symptoms, and more frequently diagnosis for other disorders (atrial septal defect, ventricular septal defect, Marfan syndrome, Ehlers-Danlos syndrome) than the rest of the patients; however, there were no significant differences as far as certain major complications (stroke, death, submission to surgery) were concerned. CONCLUSION: The classic form of mitral valve prolapse is more tightly associated with morbid complications, and a more frequent follow-up control in this group of patients may be useful. PMID- 22214736 TI - [The effect of hemodialysis on right ventricular functions in patients with end stage renal failure]. AB - OBJECTIVE: The aim of this study was to evaluate the effects of hemodialysis (HD) on right ventricular echocardiographic parameters in patients with end-stage renal failure (ESRF). METHODS: Forty-three uremic patients who underwent echocardiography before and 30 minutes after dialysis included in this prospective observational study. Right ventricular systolic function was evaluated using tricuspid annular plane systolic excursion (TAPSE) by M-mode echocardiography and tricuspid lateral annular systolic velocity (Sa) by tissue Doppler echocardiography whereas diastolic function was evaluated using tricuspid early (E) and late (A) diastolic flow velocities by conventional and tricuspid lateral annular early (Ea) and late (Aa) diastolic velocities by tissue Doppler echocardiography. Myocardial performance index was taken as an indicator of global functions. Paired t test or Wilcoxon test were used for statistical analysis where appropriate. RESULTS: E decreased significantly (68 +/- 13 cm/s and 56 +/- 12 cm/s before and after HD, respectively; p<0.0001) but A did not (p=0.797).TAPSE was 1.84 +/- 0.34 cm before HD and showed a significant increase to 2.03 +/- 0.20 cm after HD (p=0.006). Right ventricular MPI, Sa and Aa did not change significantly by dialysis (p=0.504; p=0.118 and p=0.150 respectively) whereas Ea decreased to 8.8 +/- 2.5 cm/s from 11.3 +/- 3.4 cm/s (p<0.001). Ea/Aa ratio also decreased significantly to 0.69 +/- 0.35 from 0.84 +/- 0.44 with HD (p=0.007). CONCLUSION: The results of this study indicates that parameters of right ventricular systolic function such as Sa and MPI are independent of preload whereas the conventional and tissue Doppler parameters of right ventricular diastolic function are preload dependent in patients with end-stage renal failure who undergo regular hemodialysis. PMID- 22214737 TI - [Clinical and hemodynamic features of Eisenmenger syndrome patients at the time of first admission: a tertiary referral-center experience]. AB - OBJECTIVE: In this study, patients admitted with the diagnosis of Eisenmenger syndrome (ES) in a tertiary referral center were analyzed. METHODS: The data of 20 consecutive patients (mean age: 27.6+1.8 years, 7 male and mean follow-up time: 35.6 +/- 9.1 months) with ES were retrospectively analyzed. Demographic characteristics, symptoms, physical examination, laboratory and hemodynamic parameters were analyzed at the time of first admission. RESULTS: The most frequent underlying heart diseases were ventricular septal defect (VSD) with complex congenital disease (n:8, 40%) and isolated VSD (n:7, 35%). 6-minute walking test distance was 347.9 +/- 33.7 meters and 15 patients (75%) had a functional capacity of NYHA Class III, at the time of admission. ES was diagnosed with catheterization in all patients and mean systolic pulmonary arterial pressure measured by catheterization was 112 +/- 6.8 mmHg. Pulmonary function tests, FVC (forced vital capacity), FEV1 (forced expiratory volume), FEV1/FVC values were respectively, 3.1 +/- 0.4, 2.5 +/- 0.4 L and 76.7 +/- 3.3%. Metabolic tests were performed in all patients at the first visit. Mean VO2 max was 16.7 +/ 1.0 ml / kg/min and VE/VCO2 rate was 53.9 +/- 3.2%. Although PH and partial pressure of carbon dioxide levels were within normal range in blood gas analysis, oxygen saturation and partial pressure of oxygen levels were low. CONCLUSION: The most common underlying heart disease of ES patients is VSD. In this cases exercise capacity is restricted and this restriction is reflected in laboratory parameters. PMID- 22214738 TI - [The effect of levosimendan and dobutamine treatment on QT dispersion in patients with decompensated heart failure: a prospective study]. AB - OBJECTIVE: We investigated the effect of intravenous levosimendan on QT dispersion compared with intravenous dobutamine in patients with acute decompensated heart failure. METHODS: This prospective cohort study included 38 patients who were admitted with acute decompensated heart failure (New York Heart Association functional class III-IV). Twenty-five patients (11 men, 14 women; mean age 70.5 +/- 11.13 years) were treated with levosimendan infusion and 13 patients (5 men, 8 women; mean age 71.08 +/- 6.86 years) were treated with dobutamine infusion. Intravenous levosimendan was administered with an initial bolus dose of 12 MUg/kg for 10 min, followed by a continuous infusion of 0.1 MUg/kg/min for 1 hour and 0.1 MUg/kg/min 23 hours. Intravenous dobutamine was administered with a continuous dose of 10 MUg/kg /min for 24 hours. Transthoracic echocardiography was performed and electrocardiograms were obtained before and after drug infusions. QTc dispersion was defined as the difference between the maximum and the minimum QT intervals and the value was corrected for heart rate. Chi-square test, Wilcoxon test and Mann-Whitney U tests were used for data analysis. RESULTS: No significant differences were found before and after treatment of both levosimendan and dobutamine with respect to minimum QT intervals, maximum QT and QT dispersions. (Pretreatment and 24th hour values of levosimendan group were; 0.43 +/- 0.04 s, 0.44 +/- 0.04s; 0.49 +/- 0.05s, 0.50 +/ 0.05s; 0.06 +/- 0.03s, 0.06 +/- 0.03s; in dobutamine group values are - 0.39 +/- 0.05 s, 0.41 +/- 0.05s; 0.45 +/- 0.05s, 0.48 +/- 0.05s; 0.06 +/- 0.04s, 0.06 +/- 0.04s, respectively) (p>0.05). No side effects related to drugs were seen during follow-up in all two treatment groups. CONCLUSION: Our results suggest that, therapeutic doses of levosimendan infusion do not have a significant effect on QT parameters - the predictors of arrhythmias-, in patients with decompensated heart failure when compared with dobutamine infusion. PMID- 22214739 TI - Impact of emergency services and ambulance type on pain-to-balloon time in the acute myocardial infarction: an observational study. AB - OBJECTIVE: The objective of this study was to evaluate the role of first contact emergency departments and ambulances on transport duration, pain-to-balloon time, door-to-balloon time and first contact-to-balloon time in acute myocardial infarction (AMI) patients. METHODS: The study was a prospective and observational investigation. A total of 374 AMI patients initially admitted to primary coronary intervention (PCI) incapable centers were included in this study. Patients were classified according to initial presentation site (daily clinic, public hospital or private hospital) and transport manner (public or private ambulance). All groups were compared by the Kruskal-Wallis and Mann-Whitney U tests statistically according to their characteristics, transport duration and pain-to-balloon time. RESULTS: A majority of the patients were initially admitted to public (40.1%) or private hospitals (47.1%). The average door-to-balloon time was 45.0 +/- 18.5 min and the mean pain-to-balloon time was 310.6 +/- 160.8 min. Nearly half of the patients initially admitted to daily clinics were first transported to PCI incapable centers, leading to delayed admission to PCI-capable centers and increased pain-to-balloon and first contact-to-balloon times (361.7 +/- 194.5 min, p=0.01 and 279.7+/-158.2 min, p<0.001). Patients admitted to private hospitals experienced shorter average pain-to-balloon and first contact-to balloon times (277.5 +/- 148.6 min, p=0.01 and 157.4 +/- 83.1 min, p<0.001). Patients transported by private ambulances also experienced shorter waiting times and shorter pain-to-balloon times (107.4 +/- 70.4 and 270.1 +/- 150.4 min, p<0.001). CONCLUSION: Physicians and healthcare professionals in first contact emergency departments and ambulance type appear to be factors in the increased pain-to-balloon time. AMI patients are often initially admitted to PCI-incapable centers, leading to delayed admission to PCI-capable centers and increased pain to-balloon time. PMID- 22214740 TI - Amount of ST wave resolution in patients with and without spontaneous coronary reperfusion in the infarct -related artery after primary PCI: an observational study. AB - OBJECTIVE: In patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), a patent infarct-related artery (IRA) on initial angiography was associated with better angiographic results and improved prognosis compared with patients without spontaneous reflow. The role of systematic emergency PCI in patients with spontaneous reperfusion during myocardial infarction is debated. We compared the amount of ST wave resolution (STR) in patients with and without spontaneous coronary reperfusion (SCR) in the infarct related artery. METHODS: This study was designed as an observational cohort study. One hundred sixty-one consecutive patients (121 males, 40 females, with a mean age of 56+/-10 years) who had STEMI and treated with primary PCI without previous thrombolytic therapy were included in the study. All patients were treated with primary PCI within 12 hours from the onset of the symptoms and had stent implantation in the culprit lesion. ST wave resolution was measured as percent resolution of ST segment elevation from electrocardiogram (ECG), before and after PCI, classified as complete (>70%), partial (30% to 70%), or absent (<30%). SCR was defined as a TIMI grade III flow in the IRA on baseline coronary angiogram. The amount of ST wave resolution (STR) in patients with and without SCR in the IRA was compared. We used Chi-square test, Student's t-test and the Mann-Whitney U test for statistical analysis. RESULTS: At the baseline coronary angiography 40 (25%) patients had SCR and 121 patients (75%) had TIMI flow grade 0, 1 or 2 (non-SCR group). ST segment resolution amount was significantly higher in patients without SCR (53+/-17 versus 13+/-23 mm; p<0.001). In fact; in five patients whom had patent infarct related artery in initial angiography, ST segment elevation increased according to pre-PCI ECG. CONCLUSION: Mean ST wave resolution was lower in patients with spontaneous coronary reperfusion who were treated with primary PCI compared to their counterparts who did not have spontaneous coronary reperfusion on initial coronary angiography. PMID- 22214741 TI - Association between mean platelet volume and coronary artery calcification in patients without overt cardiovascular disease: an observational study. AB - OBJECTIVE: Platelets have an important role in the pathogenesis of atherothrombosis. It has been shown that platelet size measured by mean platelet volume (MPV), correlates with their reactivity and is still regarded as an easy, useful tool for indirect monitoring of platelet activity in different situations. Coronary artery calcification (CAC) has long been known to occur as a part of the atherosclerotic process. The aim of this study was to determine whether an association exists between MPV and CAC. METHODS: In this observational study, we enrolled 259 participants with at least one cardiac risk factor but with unknown cardiovascular disease. Coronary calcification was assessed by multislice computerized tomography and MPV was measured in a blood sample collected in EDTA tubes. Statistical analysis was performed using Kruskal-Wallis, Chi-square, correlation tests and multiple regression analysis. RESULTS: Calcium scores ranged from 0 to 735. There was a significant relation between CAC and MPV (r=0.24, p=0.02), age (r=0.32, p<0.001), hypertension (r=0.19, p=0.03), diabetes (r=0.16, p=0.005), smoking (r=0.17, p=0.001). In linear regression analysis, MPV (beta=0.4, 95%CI 19.8- 31.1, p<0.001), age (beta=0.13, 95%CI 0.23-2.4, p=0.01) and smoking (beta=0.12, 95%CI 3.2-15.1, p=0.02) independently associated with CAC. In addition, there were significant differences in MPV between significant CAC group compared to the minimal and none (10.2 +/- 2.4 versus 8.1 +/- 0.9 and 7.6 +/- 1.3; p<0.001). CONCLUSION: We have found significant association between MPV and CAC. Although this study is purely correlative and no causative conclusions can be drawn, it may suggest that higher MPV may reflect increased atherosclerotic burden and cardiovascular risk. PMID- 22214742 TI - Association between C-reactive protein, carotid intima-media thickness and P-wave dispersion in obese premenopausal women: an observational study. AB - OBJECTIVE: The aim of the present study was to evaluate P-wave dispersion (PWD) in obese women, and to investigate the relationship between P-wave measurements, high sensitive C-reactive protein (hsCRP), carotid intima-media thickness (CIMT) and echocardiographic findings. METHODS: Forty-four patients with obese premenopausal women and 30 females with normal weight were enrolled this cross sectional, observational study. Results of anthropometric measurements, laboratory assays, electrocardiographic and echocardiographic findings were recorded for each participant. Student t, Mann-Whitney U and Pearson Chi-square tests, and Spearman correlation analysis were used for statistical analysis. Multiple regression analysis was used to identify independent factors associated with PWD development. RESULTS: The obese group had significantly higher values for PWD (41.8 +/- 11.8 ms vs. 28.5 +/- 9.3ms; p<0.001) as well as for P max (105.2 +/- 14.3 ms vs. 89.0 +/- 13.3 ms; p<0.001). Correlation analyses revealed the presence of a positive correlation between PWD and each of insulin, systolic blood pressure, diastolic blood pressure, hsCRP, CIMT, left atrial diameter (LAD), waist circumference, waist to hip ratio and body mass index in obese participants. The only significant association that was observed on multiple linear regression analysis, after adjustments for confounding risk factors, was between LAD and PWD (beta=4.290, 95% CI:1.870-9.720, p=0.032). CONCLUSION: We found that increased PWD values in obese patients are correlated positively with hsCRP, CIMT and abdominal obesity. However, independent and significant association was found only between LAD and PWD. PMID- 22214743 TI - Hypertension prevalence and risk factors among adult population in Afyonkarahisar region: a cross-sectional research. AB - OBJECTIVE: Hypertension is a major public health problem worldwide with increasing prevalence. The purpose of this study was to examine the prevalence of hypertension and related risk factors among adult population in Afyonkarahisar region. METHODS: In this cross-sectional research, regarding the population distribution totally 2035 subjects, randomly selected from 75 different parts of our city, both the urban and the rural areas, were included in this epidemiologic research. After the administration of a questionnaire to the subjects, blood samples were taken and physical examinations were performed. Socio-demographic features, diabetes mellitus (DM), hypertension, family history of hypertension, coronary heart disease (CHD), smoking, and number of births were evaluated as possible risk factors for hypertension. Statistical analysis was performed using Student's t-test, Chi-square test and binary logistic regression analysis. RESULTS: The overall prevalence of hypertension was 24.2% (31.3% in women, 14.1% in men, p<0.001). Its prevalence increased with age (from 2.2% to 50.4%, p<0.001). Age, gender, DM, family history of hypertension, body mass index (BMI), CHD and income levels were significant risk factors. Diabetic patients had 2.35 times (95%CI 1.70-3.25: p<0.0001) more risk, people who had positive family history 2.23 times (95%CI 1.62-3.07: p<0.0001) more risk and those with high BMI 2.15 times (95%CI 1.66-2.78: p<0.0001) more risk to develop HT than who did not have these factors. In addition, women have 2.74 times (95%CI 2.08-3.62: p<0.0001), more risk than men for HT. We determined CHD and low income as other risk factors for HT (OR=2.32, 95%CI 1.48-3.64: p<0.0001) and OR=1.47, 95%CI 1.08 2.02: p=0.016 respectively). CONCLUSION: Hypertension is an important health problem in our region. We think that it is possible to reduce the hypertension prevalence with lifestyle changes and educating people, regarding the risk factors. PMID- 22214744 TI - [Prevalence of metabolic syndrome, its relationship with mental health (anger) and sociodemographic characteristics in women residing in central district of Malatya: a cross-sectional observational study]. AB - OBJECTIVE: The purpose of this study is to determine prevalence of metabolic syndrome (MetS) and its relationship with mental health (anger) and sociodemographic characteristics in women residing central district of Malatya. METHODS: This cross-sectional observational study was conducted between April and September 2008. The relationships between MetS and mental health (anger) and sociodemographic properties were examined. Chi-square and Student t-test were used for the statistical analysis. RESULTS: Mean age of the women included in this study was 41.9 +/- 12.7 years. MetS prevalence was 30.9%, for the age group of 60 and over prevalence was 61.3%. There was a statistically meaningful relation between MetS prevalence and the educational background, marital status, body-mass index (BMI) and family type (p<0.05). There was no significant relationship between MetS and anger status in the study group (p>0.05). The most common MetS parameters findings of our study were abdominal obesity (45.6%, waist circumference>88 cm) and low high-density lipoprotein cholesterol. Among MetS diagnosed women included in this study the most common finding was fasting blood glucose (76.7%), which were followed by high triglycerides (69.4%) and hypertension (63.5%). CONCLUSION: Taking control over or avoiding obesity plays a crucial role in prevention of MetS development. There was a significant relationship between MetS prevalence and education, BMI and family type in the study group. In the current study, there was no any significant relation between MetS and anger scale. PMID- 22214745 TI - Anemia in heart failure. AB - Chronic heart failure is a common problem and a major cause of death, hospital admission, poor physical function and impaired quality of life. In addition to the direct effect of heart failure on prognosis, several modifiable and non modifiable factors contribute to the worse prognosis in heart failure. Anemia, which is common in patients with heart failure, may represent a modifiable risk factor for adverse outcome. It is also a marker for co-morbidity burden and greater disease severity. If anemia is a marker, treatment may not obviate the increased risk associated with anemia, but if it is a mediator, treatment may be helpful to reduce morbidity and mortality in heart failure. As anemia has been identified as an independent prognostic factor of both morbidity and mortality for patients with congestive heart failure, there is an increased interest in the hypothesis that the correction of anemia with erythropoietin or iron supplementation might lead to an improvement on patients' symptoms and functional status. Large randomized trials are necessary to show the effect of anemia and the specific treatments on the outcome in these patients. This article reviews the mechanisms, impact on outcomes and therapy of anemia in patients with heart failure. PMID- 22214748 TI - [Regulatory mechanisms for stress response and pathogenesis of facultative intracellular bacteria]. PMID- 22214747 TI - Myeloperoxidase-derived oxidants inhibit sarco/endoplasmic reticulum Ca2+-ATPase activity and perturb Ca2+ homeostasis in human coronary artery endothelial cells. AB - The sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) plays a critical role in Ca(2+) homeostasis via sequestration of this ion in the sarco/endoplasmic reticulum. The activity of this pump is inhibited by oxidants and impaired in aging tissues and cardiovascular disease. We have shown previously that the myeloperoxidase (MPO)-derived oxidants HOCl and HOSCN target thiols and mediate cellular dysfunction. As SERCA contains Cys residues critical to ATPase activity, we hypothesized that HOCl and HOSCN might inhibit SERCA activity, via thiol oxidation, and increase cytosolic Ca(2+) levels in human coronary artery endothelial cells (HCAEC). Exposure of sarcoplasmic reticulum vesicles to preformed or enzymatically generated HOCl and HOSCN resulted in a concentration dependent decrease in ATPase activity; this was also inhibited by the SERCA inhibitor thapsigargin. Decomposed HOSCN and incomplete MPO enzyme systems did not decrease activity. Loss of ATPase activity occurred concurrent with oxidation of SERCA Cys residues and protein modification. Exposure of HCAEC, with or without external Ca(2+), to HOSCN or HOCl resulted in a time- and concentration dependent increase in intracellular Ca(2+) under conditions that did not result in immediate loss of cell viability. Thapsigargin, but not inhibitors of plasma membrane or mitochondrial Ca(2+) pumps/channels, completely attenuated the increase in intracellular Ca(2+) consistent with a critical role for SERCA in maintaining endothelial cell Ca(2+) homeostasis. Angiotensin II pretreatment potentiated the effect of HOSCN at low concentrations. MPO-mediated modulation of intracellular Ca(2+) levels may exacerbate endothelial dysfunction, a key early event in atherosclerosis, and be more marked in smokers because of their higher SCN(-) levels. PMID- 22214749 TI - [Analysis of molecular mechanisms of the virulence and growth coordination of Mycobacterium tuberculosis]. PMID- 22214750 TI - A biomechanical simulation of ureteral flow during peristalsis using intraluminal morphometric data. AB - Reflux nephropathy and vesicoureteral reflux are two of the most important abnormalities in the upper urinary system in which toxins and bacteria from the bladder infect the ureter and the kidney and initiate renal scar formation. A quantitative analysis that characterizes urine flow will further help our understanding of the ureter and also assist in the design of flow aided devices such as valves and stents to correct reflux situations. Here, A numerical simulation with fluid-structure interactions (FSI) using arbitrary Lagrangian Eulerian (ALE) formulation and adaptive mesh procedure was introduced and solved to perform ureteral flow analysis. Incompressible Navier-Stokes equations were utilized as the governing equations of fluid domain. Ureteral in-vivo morphometric data during peristalsis were used to construct the presented model. A nonlinear material model was used to exhibit ureteral wall mechanical properties. Direct coupling method was used to solve the solid, fluid and interface equations simultaneously. Results showed that recirculation regions formed against the jet flow, neighboring the bolus peak. Through wave propagation, separation occurred behind the moving bolus on the wall and ureteropelvic reflux began from that location and extended upstream to the ureteral inlet. The maximum luminal pressure consistently occurred behind the urine bolus during peristalsis. The measured magnitude of maximum volumetric flow rate resulted from isolated bolus transportation was 0.92 ml/min. In conclusion; due to presence of fluid inertial forces during peristalsis, the function of ureteropelvic junction in prevention of reflux is significant, especially at the beginning of peristaltic wave propagation. Moreover, modeling of ureteral function using imaging data will be valuable and it may help physicians to diagnose and cure the abnormalities. PMID- 22214751 TI - The role of weather on the relation between influenza and influenza-like illness. AB - Influenza epidemics, enabled by viral antigenic drift, occur invariably each winter in temperate climates. However, attempts to correlate the magnitude of virus change and epidemic size have been unsatisfactory. The incidence of influenza is not typically measured directly, but rather derived from the incidence of influenza-like illness (ILI), a clinical syndrome. Weather factors have been shown to influence the manifestation of influenza-like symptoms. We fitted an influenza transmission model to time series of influenza-like illness as monitored from 2003 to 2010 by two independent symptomatic surveillance systems (Influenzanet and EISN) in three European countries. By assuming that seasonality only acts upon the manifestation of symptoms, the model shows a significant correlation between the absolute humidity and temperature at the time of infection, and the proportion of influenza infections fulfilling the clinical ILI case definition, the so-called ILI factor. When a weather-dependent ILI factor is included in the model, the epidemic size of influenza-like illness becomes dependent not only on the susceptibility of the population at the beginning of the epidemic season but also on the weather conditions during which the epidemic unfolds. The combination reduces season-to-season variation in epidemic size and, interestingly, leads to a non-monotonic trend whereby the largest ILI epidemic occurs for moderate initial susceptibility. PMID- 22214753 TI - Can indoor swimming alter hormones in boys? PMID- 22214752 TI - Acute modafinil exposure reduces daytime sleepiness in abstinent methamphetamine dependent volunteers. AB - The purpose of this study was to evaluate the effects of acute, oral modafinil (200 mg) exposure on daytime sleepiness in methamphetamine (Meth)-dependent individuals. Eighteen Meth-dependent subjects were enrolled in a 7-d inpatient study and were administered placebo or modafinil on day 6 and the counter condition on day 7 (randomized) of the protocol. Subjects completed several subjective daily assessments (such as the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Beck Depression Inventory and visual analogue scale) throughout the protocol as well as objective assessments on days 5-7, when the Multiple Sleep Latency Test was performed. The results of the current study suggest that short-term abstinence from Meth is associated with increased daytime sleepiness and that a single dose of 200 mg modafinil reduces daytime somnolence in this population. In addition, a positive correlation was found between subjective reporting of the likelihood of taking a nap and craving and desire for Meth, as well as the likelihood of using Meth and whether Meth would make the participant feel better. The results of this study should be considered when investigating candidate medications for Meth-dependence, especially in those individuals who attribute their Meth use to overcoming deficits resulting from sleep abnormalities. PMID- 22214754 TI - Effect of reporting bias on meta-analyses of drug trials: reanalysis of meta analyses. AB - OBJECTIVE: To investigate the effect of including unpublished trial outcome data obtained from the Food and Drug Administration (FDA) on the results of meta analyses of drug trials. DESIGN: Reanalysis of meta-analyses. DATA SOURCES: Drug trials with unpublished outcome data for new molecular entities that were approved by the FDA between 2001 and 2002 were identified. For each drug, eligible systematic reviews containing at least one meta-analysis were identified by searches of Medline, Embase, and the Cochrane Library in November 2010. Selection criteria Eligible systematic reviews were done after FDA approval of the drug, were published in English, and had outcomes and comparators that were the same as those of the trials with unpublished FDA trial outcomes, and the characteristics of participants in the systematic reviews were consistent with the FDA approved indication for the drug. Clinical guidelines, conference proceedings, duplicate systematic reviews, and systematic reviews in which included trials were not referenced or that combined trials across multiple drug classes were excluded. Systematic reviews using non-standard meta-analytic techniques (such as Bayesian or network meta-analyses) and those that used inappropriate or invalid methods for calculation of summary statistics (such as unweighted pooled analyses) were also excluded. DATA EXTRACTION: Two authors independently extracted data from both the published systematic reviews and the FDA's medical and statistical reviews of the trials submitted to FDA. MAIN OUTCOME MEASURE: Summary statistics (risk ratios, odds ratios, or weighted mean differences) for relevant outcomes with and without unpublished FDA trial data. RESULTS: 42 meta-analyses (41 efficacy outcomes, one harm outcome) for nine drugs across six drug classes were reanalysed. Overall, addition of unpublished FDA trial data caused 46% (19/41) of the summary estimates from the meta-analyses to show lower efficacy of the drug, 7% (3/41) to show identical efficacy, and 46% (19/41) to show greater efficacy. The summary estimate of the single harm outcome showed more harm from the drug after inclusion of unpublished FDA trial data. CONCLUSION: The effect of including unpublished FDA trial outcome data varies by drug and outcome. Unpublished FDA trial outcome data should be available and included in meta-analysis. Making these data easily accessible is particularly important because the effects of including unpublished data vary. PMID- 22214755 TI - Publication of NIH funded trials registered in ClinicalTrials.gov: cross sectional analysis. AB - OBJECTIVE: To review patterns of publication of clinical trials funded by US National Institutes of Health (NIH) in peer reviewed biomedical journals indexed by Medline. DESIGN: Cross sectional analysis. SETTING: Clinical trials funded by NIH and registered within ClinicalTrials.gov (clinicaltrials.gov), a trial registry and results database maintained by the US National Library of Medicine, after 30 September 2005 and updated as having been completed by 31 December 2008, allowing at least 30 months for publication after completion of the trial. MAIN OUTCOME MEASURES: Publication and time to publication in the biomedical literature, as determined through Medline searches, the last of which was performed in June 2011. RESULTS: Among 635 clinical trials completed by 31 December 2008, 294 (46%) were published in a peer reviewed biomedical journal, indexed by Medline, within 30 months of trial completion. The median period of follow-up after trial completion was 51 months (25th-75th centiles 40-68 months), and 432 (68%) were published overall. Among published trials, the median time to publication was 23 months (14-36 months). Trials completed in either 2007 or 2008 were more likely to be published within 30 months of study completion compared with trials completed before 2007 (54% (196/366) v 36% (98/269); P<0.001). CONCLUSIONS: Despite recent improvement in timely publication, fewer than half of trials funded by NIH are published in a peer reviewed biomedical journal indexed by Medline within 30 months of trial completion. Moreover, after a median of 51 months after trial completion, a third of trials remained unpublished. PMID- 22214756 TI - Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study. AB - OBJECTIVE: To examine compliance with mandatory reporting of summary clinical trial results (within one year of completion of trial) on ClinicalTrials.gov for studies that fall under the recent Food and Drug Administration Amendments Act (FDAAA) legislation. DESIGN: Registry based study of clinical trial summaries. DATA SOURCES: ClinicalTrials.gov, searched on 19 January 2011, with cross referencing with Drugs@FDA to determine for which trials mandatory reporting was required within one year. Selection criteria Studies registered on ClinicalTrials.gov with US sites which completed between 1 January and 31 December 2009. MAIN OUTCOME MEASURE: Proportion of trials for which results had been reported. RESULTS: The ClinicalTrials.gov registry contained 83,579 entries for interventional trials, of which 5642 were completed within the timescale of interest. We identified trials as falling within the mandatory reporting rules if they were covered by the FDAAA (trials of a drug, device, or biological agent, which have at least one US site, and are of phase II or later) and if they investigated a drug that already had approval from the Food and Drug Administration. Of these, 163/738 (22%) had reported results within one year of completion of the trial compared with 76/727 (10%) trials that were not subject to mandatory reporting (95% confidence interval for the difference in proportions 7.8% to 15.5%; chi(2) test, P = 2.6 * 10(-9)). Later phase trials were more likely to report results (P = 4.4 * 10(-11)), as were industry funded trials (P = 2.2 * 10(-16)). CONCLUSION: Most trials subject to mandatory reporting did not report results within a year of completion. PMID- 22214757 TI - Understanding why evidence from randomised clinical trials may not be retrieved from Medline: comparison of indexed and non-indexed records. AB - OBJECTIVE: To explore why reports that seem to describe randomised controlled trials are sometimes not indexed ("tagged") with RCT (randomised controlled trial) [pt] (publication type) in Medline. Design Cross sectional study. SETTING: The Cochrane Collaboration and US National Library of Medicine worked together to identify and retag records of randomised controlled trials with RCT [pt], 1994 to 2006. Data source Published reports entered into Medline in 2005. MAIN OUTCOME MEASURES: Type of trial information presented (for example, main results, design, and methods), trial design, and other Medline indexing terms applied. RESULTS: 572/591 (97%) untagged records and 578/594 (97%) tagged records contained information from randomised controlled trials. Type of trial information and design differed between untagged and tagged reports. Fewer than half (234/572, 41%, 95% confidence interval 37% to 45%) of untagged reports but most tagged reports (526/578, 91%, 89% to 93%) described the main results of the trial. Untagged reports were more likely than tagged reports to contain information on design and methods, baseline characteristics, long term follow-up, and secondary analyses. Untagged reports of main results were more likely than tagged reports to be from trials using a crossover design (36% v 10%, difference 25%, 95% confidence interval 19% to 32%). The Medical Subject Heading "Randomized Controlled Trials" was the most common clinical trial term applied to untagged reports, although more than half of untagged reports had no indexing related to trials. CONCLUSION: Based on the results for 2005, at least 3000 records describing randomised controlled trials but not indexed using RCT [pt] may have been entered into Medline between 2006 and 2011. Researchers and healthcare decision makers relying on using RCT [pt] may be missing important evidence in their searches, particularly for design and methods, baseline characteristics, long term follow-up, and secondary data analyses. PMID- 22214758 TI - Assessment of publication bias, selection bias, and unavailable data in meta analyses using individual participant data: a database survey. AB - OBJECTIVE: To examine the potential for publication bias, data availability bias, and reviewer selection bias in recently published meta-analyses that use individual participant data and to investigate whether authors of such meta analyses seemed aware of these issues. DESIGN: In a database of 383 meta-analyses of individual participant data that were published between 1991 and March 2009, we surveyed the 31 most recent meta-analyses of randomised trials that examined whether an intervention was effective. Identification of relevant articles and data extraction was undertaken by one author and checked by another. RESULTS: Only nine (29%) of the 31 meta-analyses included individual participant data from "grey literature" (such as unpublished studies) in their primary meta-analysis, and the potential for publication bias was discussed or investigated in just 10 (32%). Sixteen (52%) of the 31 meta-analyses did not obtain all the individual participant data requested, yet five of these (31%) did not mention this as a potential limitation, and only six (38%) examined how trials without individual participant data might affect the conclusions. In nine (29%) of the meta-analyses reviewer selection bias was a potential issue, as the identification of relevant trials was either not stated or based on a more selective, non-systematic approach. Investigation of four meta-analyses containing data from >=10 trials revealed one with an asymmetric funnel plot consistent with publication bias, and the inclusion of studies without individual participant data revealed additional heterogeneity between trials. CONCLUSIONS: Publication, availability, and selection biases are a potential concern for meta-analyses of individual participant data, but many reviewers neglect to examine or discuss them. These issues warn against uncritically viewing any meta-analysis that uses individual participant data as the most reliable. Reviewers should seek individual participant data from all studies identified by a systematic review; include, where possible, aggregate data from any studies lacking individual participant data to consider their potential impact; and investigate funnel plot asymmetry in line with recent guidelines. PMID- 22214759 TI - Impact of document type on reporting quality of clinical drug trials: a comparison of registry reports, clinical study reports, and journal publications. AB - OBJECTIVE: To investigate to what extent three types of documents for reporting clinical trials provide sufficient information for trial evaluation. DESIGN: Retrospective analysis DATA SOURCES: Primary studies and corresponding documents (registry reports, clinical study reports, journal publications) from 16 health technology assessments of drugs conducted by the German Institute for Quality and Efficiency in Health Care between 2006 and February 2011. Data analysis We assessed reporting quality for each study and each available document for six items on methods and six on outcomes, and dichotomised them as "completely reported" or "incompletely reported." For each document type, we calculated the proportion of studies with complete reporting for methods and outcomes, per item and overall, and compared the findings. RESULTS: We identified 268 studies. Publications, study reports and registry reports were available for 192 (72%), 101 (38%), and 78 (29%) studies, respectively. Reporting quality was highest in study reports, which overall provided complete information for 90% of items (1086/1212). Registry reports provided more complete information on outcomes than on methods (overall 330/468 (71%) v 147/468 (31%)); the same applied to publications (594/1152 (52%) v 458/1152 (40%)). In the matched pairs analysis, reporting quality was poorer in registry reports than in study reports for overall methods and outcomes (P<0.001 in each case). Compared with publications, reporting quality was poorer in registry reports for overall methods (P<0.001), but better for outcomes (P=0.005). CONCLUSION: Registry reports and publications insufficiently report clinical trials but may supplement each other. Measures to improve reporting include the mandatory worldwide implementation of adequate standards for results registration. PMID- 22214760 TI - Missing clinical trial data. PMID- 22214761 TI - Amorphous nanosilicas induce consumptive coagulopathy after systemic exposure. AB - We previously reported that well-dispersed amorphous nanosilicas with particle size 70 nm (nSP70) penetrate skin and produce systemic exposure after topical application. These findings underscore the need to examine biological effects after systemic exposure to nanosilicas. The present study was designed to examine the biological effects. BALB/c mice were intravenously injected with amorphous nanosilicas of sizes 70, 100, 300, 1000 nm and then assessed for survival, blood biochemistry, and coagulation. As a result, injection of nSP70 caused fatal toxicity, liver damage, and platelet depletion, suggesting that nSP70 caused consumptive coagulopathy. Additionally, nSP70 exerts procoagulant activity in vitro associated with an increase in specific surface area, which increases as diameter reduces. In contrast, nSP70-mediated procoagulant activity was absent in factor XII-deficient plasma. Collectively, we revealed that interaction between nSP70 and intrinsic coagulation factors such as factor XII, were deeply related to nSP70-induced harmful effects. In other words, it is suggested that if interaction between nSP70 and coagulation factors can be suppressed, nSP70 induced harmful effects may be avoided. These results would provide useful information for ensuring the safety of nanomaterials (NMs) and open new frontiers in biological fields by the use of NMs. PMID- 22214762 TI - A functional cooperativity between Aurora A kinase and LIM kinase1: implication in the mitotic process. AB - Aurora kinase A (Aur-A), a mitotic kinase, regulates initiation of mitosis through centrosome separation and proper assembly of bipolar spindles. LIM kinase 1 (LIMK1), a modulator of actin and microtubule dynamics, is involved in the mitotic process through inactivating phosphorylation of cofilin. Phosphorylated LIMK1 is recruited to the centrosomes during early prophase, where it colocalizes with gamma-tubulin. Here, we report a novel functional cooperativity between Aur A and LIMK1 through mutual phosphorylation. LIMK1 is recruited to the centrosomes during early prophase and then to the spindle poles, where it colocalizes with Aur-A. Aur-A physically associates with LIMK1 and activates it through phosphorylation, which is important for its centrosomal and spindle pole localization. Aur-A also acts as a substrate of LIMK1, and the function of LIMK1 is important for its specific localization and regulation of spindle morphology. Taken together, the novel molecular interaction between these two kinases and their regulatory roles on one another's function may provide new insight on the role of Aur-A in manipulation of actin and microtubular structures during spindle formation. PMID- 22214763 TI - Monitoring APC/C activity in the presence of chromosomal misalignment in unperturbed cell populations. AB - Chromosome segregation is under strict control of the spindle assembly checkpoint (SAC). The SAC regulates anaphase-promoting complex/cyclosome (APC/C)-dependent proteolysis of securin and cyclin B. Unattached or misaligned chromosomes trigger SAC-mediated mitotic delay by stabilizing securin and cyclin B due to inhibition of APC/C until the problem is solved. Here we present a hitherto unavailable model facilitating the simultaneous depiction of chromosome movements and pulse chased cyclin B proteolysis in every single cell within a cell population. During chromosome misalignment, we observed slow cyclin B degradation, which changed to fast degradation once the SAC was satisfied, initiating chromosome separation and mitotic exit. Slow degradation during a SAC-mediated mitotic delay is part of a tightly regulated balance between cyclin B synthesis and degradation. Since chromosomal misalignment is a rare event, the ability to study entire cell populations enabled us to monitor for the first time SAC surveillance in living cells without the need of highly artificial perturbation by spindle poisons. PMID- 22214764 TI - Interaction between ZBP-89 and p53 mutants and its contribution to effects of HDACi on hepatocellular carcinoma. AB - ZBP-89, a zinc finger transcription factor, participates in histone deacetylases inhibitors (HDACi)-mediated growth arrest and apoptosis in cancer cells. p53 mutants may interact with ZBP-89 that transcriptionally regulates p21(Waf1) (p21). However, this interaction and its consequence in cancer treatments are poorly understood. In this study, we demonstrate that ZBP-89 is essentially required in HDACi-mediated p21 upregulation in hepetocellular carcinoma (HCC). Overexpression of ZBP-89 protein enhanced the lethal effectiveness of Trichostatin A (TSA). p53 mutant p53(G245D), but not p53(R249S), directly bound to ZBP-89 and prevented its translocation from cytoplasm to nucleus. Furthermore, p53(G245D) was shown to have a similar pattern of subcellular localization to ZBP 89 in tissues of HCC patients in Hong Kong. Functionally, the cytoplasmic accumulation of ZBP-89 by p53(G245D) significantly abrogated the induction of p21 caused by sodium butyrate (NaB) treatment and protected cells from TSA-induced death. The activations of several apoptotic proteins, such as Bid and PARP, were involved in p53(G245D)-mediated protection. Moreover, the resistance to HDACi in p53(G245D)-expressing cells was reversed by overexpression of ZBP-89. Taken together, these data suggest a potential mechanism via which mutant p53 enables tumor cells to resist chemotherapy and, therefore, establish a plausible link between mutant p53 binding to ZBP-89 and a decreased chemosensitivity of HCC cells. PMID- 22214765 TI - Aging reverses the role of the transient receptor potential vanilloid-1 channel in systemic inflammation from anti-inflammatory to proinflammatory. AB - Studies in young rodents have shown that the transient receptor potential vanilloid-1 (TRPV1) channel plays a suppressive role in the systemic inflammatory response syndrome (SIRS) by inhibiting production of tumor necrosis factor (TNF)alpha and possibly by other mechanisms. We asked whether the anti inflammatory role of TRPV1 changes with age. First, we studied the effect of AMG517, a selective and potent TRPV1 antagonist, on aseptic, lipopolysaccharide (LPS)-induced SIRS in young (12 wk) mice. In agreement with previous studies, AMG517 increased LPS-induced mortality in the young. We then studied the effects of TRPV1 antagonism (AMG517 or genetic deletion of TRPV1) on SIRS in middle-aged (43-44 wk) mice. Both types of TRPV1 antagonism delayed and decreased LPS-induced mortality, indicating a reversal of the anti-inflammatory role of TRPV1 with aging. In addition, deletion of TRPV1 decreased the serum TNFalpha response to LPS, suggesting that the suppressive control of TRPV1 on TNFalpha production is also reversed with aging. In contrast to aseptic SIRS, polymicrobial sepsis (induced by cecal ligation and puncture) caused accelerated mortality in aged TRPV1-deficient mice as compared with wild-type littermates. The recovery of TRPV1-deficient mice from hypothermia associated with the cecal ligation and puncture procedure was delayed. Hence, the reversal of the anti-inflammatory role of TRPV1 found in the aged and their decreased systemic inflammatory response are coupled with suppressed defense against microbial infection. These results caution that TRPV1 antagonists, widely viewed as new-generation painkillers, may decrease the resistance of older patients to infection and sepsis. PMID- 22214766 TI - Combined effect of cyclin D3 expression and abrogation of cyclin D1 prevent mouse skin tumor development. AB - We have previously demonstrated that ras-mediated skin tumorigenesis depends on signaling pathways that act preferentially through cyclin D1 and D2. Interestingly, the expression of cyclin D3 inhibits skin tumor development, an observation that conflicts with the oncogenic role of D-type cyclins in the mouse epidermis. Here, we show that simultaneous up and downregulation of particular members of the D-type cyclin family is a valuable approach to reduce skin tumorigenesis. We developed the K5D3/cyclin D1(-/-) compound mouse, which overexpresses cyclin D3 but lacks expression of cyclin D1 in the skin. Similar to K5D3 transgenic mice, keratinocytes from K5D3/cyclin D1(-/-) compound mice show a significant reduction of cyclin D2 levels. Therefore, this model allows us to determine the effect of cyclin D3 expression when combined with reduced or absent expression of the remaining two members of the D-type cyclin family in mouse epidermis. Our data show that induced expression of cyclin D3 compensates for the reduced level of cyclin D1 and D2, resulting in normal keratinocyte proliferation. However, simultaneous ablation of cyclin D1 and downregulation of cyclin D2 via cyclin D3 expression resulted in a robust reduction in ras-mediated skin tumorigenesis. We conclude that modulation of the levels of particular members of the D-type cyclin family could be useful to inhibit tumor development and, in particular, ras-mediated tumorigenesis. PMID- 22214767 TI - Bisphenol A and its analogues activate human pregnane X receptor. AB - BACKGROUND: Bisphenol A (BPA) is a base chemical used extensively in many consumer products. BPA and its analogues are present in environmental and human samples. Many endocrine-disrupting chemicals, including BPA, have been shown to activate the pregnane X receptor (PXR), a nuclear receptor that functions as a master regulator of xenobiotic metabolism. However, the detailed mechanism by which these chemicals activate PXR remains unknown. OBJECTIVE: We investigated the mechanism by which BPA interacts with and activates PXR and examined selected BPA analogues to determine whether they bind to and activate PXR. METHODS: Cell based reporter assays, in silico ligand-PXR docking studies, and site-directed mutagenesis were combined to study the interaction between BPA and PXR. We also investigated the influence of BPA and its analogues on the regulation of PXR target genes in human LS180 cells. RESULTS: We found that BPA and several of its analogues are potent agonists for human PXR (hPXR) but do not affect mouse PXR activity. We identified key residues within hPXR's ligand-binding pocket that constitute points of interaction with BPA. We also deduced the structural requirements of BPA analogues that activate hPXR. BPA and its analogues can also induce PXR target gene expression in human LS180 cells. CONCLUSIONS: The present study advances our understanding of the mechanism by which BPA interacts with and activates human PXR. Activation of PXR by BPA may explain some of the adverse effects of BPA in humans. PMID- 22214768 TI - Size-selected epitaxial nanoislands underneath graphene moire on Rh(111). AB - We use in situ scanning tunneling microscopy (STM) to investigate intercalation of the ferromagnetic 3d metals Ni and Fe underneath a graphene monolayer on Rh(111). Upon thermal annealing of graphene/Rh(111) with the deposited metal on top, we observe the formation of epitaxial monatomic nanoislands grown pseudomorphically on Rh(111) and covered by graphene. The size and shape of intercalated nanoislands is strongly influenced by the local spatial variation of the graphene-Rh bonding strength. In particular, the side length of the intercalated nanoislands shows maxima around discrete values imposed by the periodicity of the graphene moire. Intercalation can be performed efficiently and without any visible damage of the graphene overlayer in the studied temperature range between 670 and 870 K. We identify the main intercalation path to be via diffusion through pre-existing lattice defects in graphene, accompanied by the second mechanism which is based on the material diffusion via metal-generated defects followed by the defect healing of the graphene lattice. We deem these graphene-capped and sharply confined ferromagnetic nanoislands interesting in the fields of spintronics and nanomagnetism. PMID- 22214770 TI - The Josephson effect between triplet superconductors through a finite ferromagnetic barrier. AB - Charge and spin transport in a junction involving two triplet superconductors and a ferromagnetic barrier are studied. We use Bogoliubov-de Gennes wavefunctions to construct the Green's function, from which we obtain the Josephson currents in terms of the Andreev reflection coefficients. We focus on the consequences of a finite barrier width for the occurrence of 0-pi transitions and for the spin currents, and examine the appropriateness of the common delta-function approximation for the tunneling region. PMID- 22214771 TI - Chronic obstructive pulmonary disease and cancer risk: a Danish nationwide cohort study. AB - INTRODUCTION: Little is known about the risk of cancer in patients with chronic obstructive pulmonary disease (COPD), including which cancer sites are most affected. We examined the short- and long-term risk of lung and extrapulmonary cancer in a nationwide cohort of COPD patients. METHODS: We linked the Danish National Registry of Patients and the nationwide cancer registry, and examined the incidence of various cancers in 236,494 individuals with a first incident hospital contact with COPD during 1980-2008. The observed cancer incidence in this cohort was compared with the expected incidence in the general population on the basis of national age-, sex-, and site-specific incidence rates. RESULTS: Median follow-up was 3.5 years. During the first year of follow-up, 9434 cancers were diagnosed in COPD patients [standardized incidence ratio (SIR) = 3.1; 95% CI 3.0 to 3.2]. The 1-year SIR was 8.5 (8.2-8.9) for lung cancer, 5.1 (5.0-5.2) for all tobacco-related cancers, and 1.9 (1.9-2.0) for other cancers. In the following years, cancer incidence was increased 1.4-fold (1.4-1.5) in COPD patients. These patients had an increased risk of developing tobacco-related cancers (SIR = 2.1; 95% CI 2.0-2.1), including cancers of the lung, larynx, tongue, oral cavity, pharynx, esophagus, stomach, liver, pancreas, cervix uteri, and urinary tract (with SIRs ranging between 1.3 and 2.8). CONCLUSIONS: Patients with first-time hospital-diagnosed COPD are at considerably increased risk of developing both lung cancer and extrapulmonary cancers. Physicians should be aware of cancer in COPD patients. PMID- 22214769 TI - Molecular mechanisms of cell segregation and boundary formation in development and tumorigenesis. AB - The establishment and maintenance of precisely organized tissues requires the formation of sharp borders between distinct cell populations. The maintenance of segregated cell populations is also required for tissue homeostasis in the adult, and deficiencies in segregation underlie the metastatic spreading of tumor cells. Three classes of mechanisms that underlie cell segregation and border formation have been uncovered. The first involves differences in cadherin-mediated cell cell adhesion that establishes interfacial tension at the border between distinct cell populations. A second mechanism involves the induction of actomyosin mediated contraction by intercellular signaling, such that cortical tension is generated at the border. Third, activation of Eph receptors and ephrins can lead to both decreased adhesion by triggering cleavage of E-cadherin, and to repulsion of cells by regulation of the actin cytoskeleton, thus preventing intermingling between cell populations. These mechanisms play crucial roles at distinct boundaries during development, and alterations in cadherin or Eph/ephrin expression have been implicated in tumor metastasis. PMID- 22214772 TI - Spatial and temporal patterns in antimicrobial resistance of Salmonella Typhimurium in cattle in England and Wales. AB - Salmonella is the second most commonly reported human foodborne pathogen in England and Wales, and antimicrobial-resistant strains of Salmonella are an increasing problem in both human and veterinary medicine. In this work we used a generalized linear spatial model to estimate the spatial and temporal patterns of antimicrobial resistance in Salmonella typhimurium in England and Wales. Of the antimicrobials considered we found a common peak in the probability that an S. typhimurium incident will show resistance to a given antimicrobial in late spring and in mid to late autumn; however, for one of the antimicrobials (streptomycin) there was a sharp drop, over the last 18 months of the period of investigation, in the probability of resistance. We also found a higher probability of resistance in North Wales which is consistent across the antimicrobials considered. This information contributes to our understanding of the epidemiology of antimicrobial resistance in Salmonella. PMID- 22214773 TI - Summit ties sustainability to improved public health. PMID- 22214774 TI - Cefoxitin as an alternative to carbapenems in a murine model of urinary tract infection due to Escherichia coli harboring CTX-M-15-type extended-spectrum beta lactamase. AB - We investigated the efficiency of the cephamycin cefoxitin as an alternative to carbapenems for the treatment of urinary tract infections (UTIs) due to Escherichia coli producing CTX-M-type extended-spectrum beta-lactamases. The susceptible, UTI-inducing E. coli CFT073-RR strain and its transconjugant CFT073 RR Tc (pbla(CTX-M-15)), harboring a bla(CTX-M-15) carrying-plasmid, were used for all experiments. MICs of cefoxitin (FOX), ceftriaxone (CRO), imipenem (IMP), and ertapenem (ETP) for CFT073-RR and CFT073-RR Tc (pbla(CTX-M-15)) were 4 and 4, 0.125 and 512, 0.5 and 0.5, and 0.016 and 0.032 MUg/ml, respectively. Bactericidal activity was similarly achieved in vitro against the two strains after 3 h of exposure to concentrations of FOX, IMI, and ETP that were 2 times the MIC, whereas CRO was not bactericidal against CFT073-RR Tc (pbla(CTX-M-15)). The frequencies of spontaneous mutants of the 2 strains were not higher for FOX than for IMP or ETP. In the murine model of UTIs, mice infected for 5 days were treated over 24 h. Therapeutic regimens in mice (200 mg/kg of body weight every 3 h or 4 h for FOX, 70 mg/kg every 6 h for CRO, 100 mg/kg every 2 h for IMP, and 100 mg/kg every 4 h for ETP) were chosen in order to reproduce the percentage of time that free-drug concentrations above the MIC are obtained in humans with standard regimens. All antibiotic regimens produced a significant reduction in bacterial counts (greater than 2 log(10) CFU) in kidneys and bladders for both strains (P < 0.001) without selecting resistant mutants in vivo, but the reduction obtained with CRO against CFT073-RR Tc (pbla(CTX-M-15)) in kidneys was significantly lower than that obtained with FOX. In conclusion, FOX appears to be an effective therapeutic alternative to carbapenems for the treatment of UTIs due to CTX-M-producing E. coli. PMID- 22214775 TI - MpeR regulates the mtr efflux locus in Neisseria gonorrhoeae and modulates antimicrobial resistance by an iron-responsive mechanism. AB - Previous studies have shown that the MpeR transcriptional regulator produced by Neisseria gonorrhoeae represses the expression of mtrF, which encodes a putative inner membrane protein (MtrF). MtrF works as an accessory protein with the Mtr efflux pump, helping gonococci to resist high levels of diverse hydrophobic antimicrobials. Regulation of mpeR has been reported to occur by an iron dependent mechanism involving Fur (ferric uptake regulator). Collectively, these observations suggest the presence of an interconnected regulatory system in gonococci that modulates the expression of efflux pump protein-encoding genes in an iron-responsive manner. Herein, we describe this connection and report that levels of gonococcal resistance to a substrate of the mtrCDE-encoded efflux pump can be modulated by MpeR and the availability of free iron. Using microarray analysis, we found that the mtrR gene, which encodes a direct repressor (MtrR) of mtrCDE, is an MpeR-repressed determinant in the late logarithmic phase of growth when free iron levels would be reduced due to bacterial consumption. This repression was enhanced under conditions of iron limitation and resulted in increased expression of the mtrCDE efflux pump operon. Furthermore, as judged by DNA-binding analysis, MpeR-mediated repression of mtrR was direct. Collectively, our results indicate that both genetic and physiologic parameters (e.g., iron availability) can influence the expression of the mtr efflux system and modulate levels of gonococcal susceptibility to efflux pump substrates. PMID- 22214776 TI - Transferable multidrug resistance plasmid carrying cfr associated with tet(L), ant(4')-Ia, and dfrK genes from a clinical methicillin-resistant Staphylococcus aureus ST125 strain. AB - A multidrug resistance (MDR) conjugative plasmid of ca. 50 kb (designated pERGB) was detected in a linezolid and methicillin-resistant Staphylococcus aureus strain with sequence type 125 (ST125-MRSA-IVc). This strain was detected in two patients with chronic obstructive pulmonary disease, previously treated with multiple antimicrobials, including linezolid. pERGB was transferable by conjugation and carried the resistance genes cfr (oxazolidinones, phenicols, lincosamides, pleuromutilins, and streptogramin A), ant(4')-Ia (tobramycin), tet(L) (tetracycline), and dfrK (trimethoprim). A novel genetic structure, linking all of these resistance genes for the first time, was elucidated through sequencing of a 15,259-bp fragment from pERGB. Active surveillance to prevent the dissemination of such highly concerning MDR transferable elements is needed. PMID- 22214777 TI - Hepatitis C virus RNA elimination and development of resistance in replicon cells treated with BMS-790052. AB - BMS-790052, a first-in-class hepatitis C virus (HCV) replication complex inhibitor, targeting nonstructural protein 5A (NS5A), displays picomolar to nanomolar potency against genotypes 1 to 5. This exceptional potency translated into robust anti-HCV activity in clinical studies with HCV genotype 1-infected subjects. To date, all BMS-790052-associated resistance mutations have mapped to the N-terminal region of NS5A. To further characterize the antiviral activity of BMS-790052, HCV replicon elimination and colony formation assays were performed. Replicon was cleared from genotype 1a and 1b replicon cells in a time- and dose dependent manner. Elimination of the genotype 1a replicon required longer treatment durations and higher concentrations of BMS-790052 than those for the genotype1b replicon. Single amino acid substitutions that conferred relatively low levels of resistance were observed at early time points and at low doses. Higher doses and longer treatment durations yielded mutations that conferred greater levels of resistance, including linked amino acid substitutions. Replicon cells that survived inhibitor treatment remained fully sensitivity to pegylated alpha interferon (pegIFN-alpha) and other HCV inhibitors. Moreover, genotype 1a replicon elimination was markedly enhanced when pegIFN-alpha and BMS-790052 were combined. Resistant variants observed in this study were very similar to those observed in a multiple ascending dose (MAD) monotherapy trial of BMS-790052, validating replicon elimination studies as a model to predict clinical resistance. Insights gained from the in vitro anti-HCV activity and resistance profiles of BMS-790052 will be used to help guide the clinical development of this novel HCV inhibitor. PMID- 22214778 TI - In vitro antibacterial activity of the ceftazidime-avibactam (NXL104) combination against Pseudomonas aeruginosa clinical isolates. AB - The beta-lactamase inhibitor avibactam (NXL104) displays potent inhibition of both class A and C enzymes. The in vitro antibacterial activity of the combination ceftazidime-avibactam was evaluated against a clinical panel of Pseudomonas aeruginosa isolates. Avibactam offered efficient protection from hydrolysis since 94% of isolates were susceptible to ceftazidime when combined with 4 MUg/ml avibactam, compared with 65% susceptible to ceftazidime alone. Ceftazidime-avibactam also demonstrated better antipseudomonal activity than imipenem (82% susceptibility), a common reference treatment. PMID- 22214779 TI - Clonally related Neisseria gonorrhoeae isolates with decreased susceptibility to the extended-spectrum cephalosporin cefotaxime in Amsterdam, the Netherlands. AB - From 2006 to 2008, Neisseria gonorrhoeae isolates were identified with decreased susceptibility to the extended-spectrum cephalosporin (ESC) cefotaxime among visitors of the Amsterdam sexually transmitted infections (STI) clinic, the Netherlands. Spread, clonality, and characteristics of 202 isolates were examined using antibiograms, conventional penA mosaic gene PCR, and N. gonorrhoeae multiple-locus variable-number tandem repeat analysis (NG-MLVA). A strictly defined subset was further characterized by N. gonorrhoeae multiantigen sequence typing (NG-MAST) and sequencing of ESC resistance determinants (penA, mtrR, and porB1b). Seventy-four N. gonorrhoeae isolates with a cefotaxime MIC of >0.125 MUg/ml (group A), 54 with a cefotaxime MIC of 0.125 MUg/ml (group B), and a control group of 74 with a cefotaxime MIC of <0.125 MUg/ml (group C) were included. Fifty-three clonally related penA mosaic-positive isolates (penicillin binding protein 2 type XXXIV) were identified in group A (n = 47 isolates; 64%) and B (n = 6 isolates; 11%). The 53 penA mosaic-positive isolates were predominantly NG-MAST ST1407 (87%) and contained an mtrR promoter A deletion (98%) and porB1b alterations G101K/A102N. All were assigned to the same NG-MLVA cluster that comprised in total 56 isolates. A correlation was found between decreased cefotaxime susceptibility and ST1407 that was highly prevalent among visitors of the Amsterdam STI clinic. The rapid spread of this strain, which also has been identified in many other countries, might be facilitated by high-risk sexual behavior and should be monitored closely to identify potential treatment failure. Quality-assured surveillance of ESC susceptibility on the national and international levels and exploration of new drugs and/or strategies for treatment of gonorrhea are crucial. PMID- 22214781 TI - Amyloid-beta oligomers in cerebrospinal fluid are associated with cognitive decline in patients with Alzheimer's disease. AB - Oligomers of the amyloid-beta peptide (Abeta) are thought to be the most toxic form of Abeta and are linked to the development of Alzheimer's disease (AD). Here, we used a flow cytometric approach for the detection and assessment of oligomers in cerebrospinal fluid (CSF) from AD patients and other neurological disorders. 30 CSF samples from patients suffering from AD (n = 14), non-demented controls (n = 12), and other neurological disorders (dementia with Lewy bodies, n = 2; vascular dementia, n = 1; primary progressive aphasia, n = 1) were analyzed for the presence of Abeta-oligomers by flow cytometry. The CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-beta (Abeta)42 were determined using ELISA. CSF Abeta-oligomer levels in AD patients were elevated in comparison to the non-AD group (p = 0.073). The ratio Abeta-oligomers/Abeta42 was significantly elevated in AD subjects compared to non-AD subjects (p = 0.001). Most important, there was a negative correlation between the amount of Abeta oligomers and the Mini-Mental Status Exam score (r = -0.65; p = 0.013) in AD patients. The detection of Abeta-oligomers using flow cytometry analysis seems to be useful in assessing the stage of AD. This is a novel and important finding as none of the currently used CSF biomarkers are clearly associated with dementia severity. PMID- 22214780 TI - Lactoferrin inhibits Porphyromonas gingivalis proteinases and has sustained biofilm inhibitory activity. AB - Porphyromonas gingivalis is a bacterial pathogen associated with chronic periodontitis that results in destruction of the tooth's supporting tissues. The major virulence determinants of P. gingivalis are its cell surface Arg- and Lys specific cysteine proteinases, RgpA/B and Kgp. Lactoferrin (LF), an 80-kDa iron binding glycoprotein found in saliva and gingival crevicular fluid, is believed to play an important role in innate immunity. In this study, bovine milk LF displayed proteinase inhibitory activity against P. gingivalis whole cells, significantly inhibiting both Arg- and Lys-specific proteolytic activities. LF inhibited the Arg-specific activity of purified RgpB, which lacks adhesin domains, and also inhibited the same activity of the RgpA/Kgp proteinase-adhesin complexes in a time-dependent manner, with a first-order inactivation rate constant (k(inact)) of 0.023 min(-1) and an inhibitor affinity constant (K(I)) of 5.02 MUM. LF inhibited P. gingivalis biofilm formation by >80% at concentrations above 0.625 MUM. LF was relatively resistant to hydrolysis by P. gingivalis cells but was cleaved into two major polypeptides (53 and 33 kDa) at R(284) to S(285), as determined by in-source decay mass spectrometry; however, these polypeptides remained associated with each other and retained inhibitory activity. The biofilm inhibitory activity of LF against P. gingivalis was not attributed to direct antibacterial activity, as LF displayed little growth inhibitory activity against planktonic cells. As the known RgpA/B and Kgp inhibitor N-alpha-p-tosyl-l-lysine chloromethylketone also inhibited P. gingivalis biofilm formation, the antibiofilm effect of LF may at least in part be attributable to its antiproteinase activity. PMID- 22214783 TI - Down-regulation of amyloid-beta through AMPK activation by inhibitors of GSK 3beta in SH-SY5Y and SH-SY5Y-AbetaPP695 cells. AB - Glycogen synthase kinase 3beta (GSK-3beta) plays a critical role in the pathogenesis of Alzheimer's disease (AD), implicating amyloid-beta (Abeta) production, neurofibrillary tangle formation, and neuronal apoptosis. The activation of 5' AMP-activated protein kinase (AMPK) has been linked to aberrant processing of amyloid-beta protein precursor (AbetaPP), and AMPK signaling controls Abeta metabolism. It is possible that GSK-3beta regulated the activation of the AMPK pathway. To test this hypothesis, the influence of GSK-3beta on the expression of AbetaPP cleavage enzyme (BACE), Abeta, and AMPK in the SH-SY5Y and AbetaPP695 cells line through three inhibitors of GSK-3beta was analyzed. Expression of Abeta, AMPK, and pAMPK172 was measured by Western blot, and BACE was tested by Western blot and RT-PCR. This study demonstrated that suppression of GSK-3beta activity, through specific inhibitors, dramatically down-regulated Abeta generation in human SH-SY5Y and SH-SY5Y-AbetaPP695 cells by enhancing AMPK activity to down-regulate Abeta. These results suggest GSK-3beta inhibitors may be promising agents in the prevention and treatment of AD. PMID- 22214784 TI - Angiotensin-converting enzyme and progression of white matter lesions and brain atrophy--the SMART-MR study. AB - High levels of angiotensin-converting-enzyme (ACE) may increase the risk of dementia through blood pressure elevation and subsequent development of cerebral small-vessel disease. However, high ACE levels may also decrease this risk through amyloid degradation which prevents brain atrophy. Within the SMART-MR study, a prospective cohort study among patients with symptomatic atherosclerotic disease, serum ACE levels were measured at baseline and a 1.5 Tesla brain MRI was performed at baseline and after on average (range) 3.9 (3.0-5.8) years of follow up in 682 persons (mean age 58 +/- 10 years). Brain segmentation was used to quantify total, deep, and periventricular white matter lesion (WML) volume, and total brain, cortical gray matter and ventricular volume (%ICV). Lacunar infarcts were rated visually. Regression analyses were used to examine the prospective associations between serum ACE and brain measures. Patients with the highest serum ACE levels (>43.3 U/L) had borderline significantly more progression of deep WML volumes than patients with the lowest ACE levels (<21.8 U/L); mean difference (95% CI) in change was 0.20 (-0.02; 0.43) %ICV. On the contrary, patients with the highest serum ACE levels had significantly less progression of cortical brain atrophy than patients with the lowest ACE levels; mean difference (95% CI) in change was 0.78 (0.21; 1.36) %ICV. Serum ACE was not associated with subcortical atrophy, periventricular WML, or lacunar infarcts. Our results show that higher ACE activity is associated with somewhat more progression of deep WML volume, but with less progression of cortical brain atrophy. This suggests both detrimental and beneficial effects of high ACE levels on the brain. PMID- 22214782 TI - Down syndrome and dementia: seizures and cognitive decline. AB - The objective of this study was to determine the association of seizures and cognitive decline in adults with Down syndrome (DS) and Alzheimer's-type dementia. A retrospective data analysis was carried out following a controlled study of antioxidant supplementation for dementia in DS. Observations were made at baseline and every 6 months for 2 years. Seizure history was obtained from study records. The primary outcome measures comprised the performance-based Severe Impairment Battery (SIB) and Brief Praxis Test (BPT). Secondary outcome measures comprised the informant-based Dementia Questionnaire for Mentally Retarded Persons and Vineland Adaptive Behavior Scales. Because a large proportion of patients with seizures had such severe cognitive decline as to become untestable on the performance measures, time to "first inability to test" was measured. Adjustments were made for the potentially confounding co-variates of age, gender, APOE4 status, baseline cognitive impairment, years since dementia onset at baseline, and treatment assignment. The estimated odds ratio for the time to "first inability to test" on SIB comparing those with seizures to those without is 11.02 (95% CI: 1.59, 76.27), a ratio that is significantly different from 1 (p = 0.015). Similarly, we estimated an odds ratio of 9.02 (95% CI: 1.90, 42.85) on BPT, a ratio also significantly different than 1 (p = 0.006). Results from a secondary analysis of the informant measures showed significant decline related to seizures. We conclude that there is a strong association of seizures with cognitive decline in demented individuals with DS. Prospective studies exploring this relationship in DS are indicated. PMID- 22214785 TI - Effect of disease severity on neural compensation of item and associative recognition in mild cognitive impairment. AB - It is proposed that the prodromal phase of Alzheimer's disease is associated with additional brain activation in key regions involved in memory, reflecting compensatory brain plasticity. Very little is known, however, about the evolution of these compensatory mechanisms as the brain acquires more damages. We conducted an fMRI memory study measuring brain activation related to old/new (item recognition) and intact/rearranged (associative recognition) word-pair recognition paradigms in 26 persons with mild cognitive impairment (MCI) and 14 healthy older adults. The Mattis Dementia Rating Scale was used to divide persons with MCI into those with higher and lower cognitive performances. Results indicated more brain activation in MCIs than in controls but disease severity determined which cognitive process was associated with larger activation: Persons with less severe MCI showed hyperactivation during associative recognition only, whereas persons with more severe MCI showed hyperactivation during item recognition only. These hyperactivations were found mainly in brain areas that are typically associated with retrieval mode (e.g., bilateral prefrontal cortex). These findings indicate that neural plasticity occurs during the entire MCI phase but that it is associated with different cognitive components. As they progress in the disease, individuals with MCI will experience a breakdown in the compensatory mechanisms for associative recognition accompanied by emergence of compensatory mechanisms for item recognition. PMID- 22214787 TI - Pyrolytic carbon coating for cytocompatibility of titanium oxide nanoparticles: a promising candidate for medical applications. AB - Nanoparticles for biomedical use must be cytocompatible with the biological environment that they are exposed to. Current research has focused on the surface functionalization of nanoparticles by using proteins, polymers, thiols and other organic compounds. Here we show that inorganic nanoparticles such as titanium oxide can be coated by pyrolytic carbon (PyC) and that the coating has cytocompatible properties. Pyrolization and condensation of methane formed a thin layer of pyrolytic carbon on the titanium oxide core. The formation of the PyC shell retards coalescence and sintering of the ceramic phase. Our MTT assay shows that the PyC-coated particles are cytocompatible at employed doses. PMID- 22214788 TI - Role of hepatic de novo lipogenesis in the development of fasting-induced fatty liver in the American mink (Neovison vison). AB - American mink (Neovison vison) develop fatty liver quickly in response to food deprivation, which results in preferential mobilisation of n-3 PUFA. The altered n-3:n-6 PUFA ratio in the liver may activate the endocannabinoid system resulting in increased lipid synthesis. The objective of the present study was to investigate the effects of feeding intensity (80 or 120% RDA), dietary fat source (n-3, n-6 or n-9 fatty acids (FA)) and short-term fasting (1-7 d) on hepatic de novo lipogenesis (DNL) and the development of fatty liver in mink. Significantly elevated expression of mRNA encoding for acetyl-CoA carboxylase-1 (ACC-1) and FA synthase (FAS) was observed in the liver of mink fasted for 5-7 d, while upon re feeding for 28 d after a 7 d food deprivation, DNL returned to pre-fasting levels. The females had a higher expression of ACC-1 and FAS mRNA than the males. In the non-fasted animals, dietary fat source and feeding intensity had significant effects on ACC-1 mRNA. The highest levels were observed in the mink fed the rapeseed oil (n-9) diet at 80% RDA, while the lowest levels were seen when the same diet was fed at 120% RDA. For FAS, the highest gene expression was seen in the fasted mink fed at 80% RDA and the lowest in the non-fasted mink fed at 80%. It is concluded that short-term food deprivation induces hepatic lipidosis in mink and that during this process, hepatic DNL further exacerbates liver fat accumulation. PMID- 22214789 TI - Extraarticular fractures of the middle phalanx with no associated tendon injury or extensive skin loss: the "soft-tissue crush" as a prognostic factor. AB - According to Chow et al's classification, type I fractures of the middle phalanx have no associated tendon injury or extensive skin loss, which required reconstruction. Despite the favorable soft-tissue conditions, a rate of poor outcome as 25% has been observed, and the reason for this is unknown. The aim of this study is to test our hypothesis that type I fractures may be subclassified into following 2 types: type IA and type IB, based on the absence or presence of concurrent significant "soft-tissue crush," respectively. Type IB fractures are hypothesized to have a worse outcome. Significant soft-tissue crush is diagnosed clinically by the presence of severe swelling and/or superficial skin injury (not requiring reconstruction). In a prospective study, 29 type I extraarticular fractures of the middle phalanx in adult industrial workers were included and classified into the following 2 groups: type IA (n = 16 fingers) and type IB (n = 13 fingers). All were treated with closed reduction and longitudinal Kirschner wire fixation. The outcome in range of motion was measured, and time to return to work was recorded. At final follow-up, the mean total active motion of the injured fingers was 241.3 degrees in group IA and 186.9 degrees in group IB (P < 0.001 by Mann-Whitney U test). Furthermore, group A patients returned to work earlier than group B (15.1 vs. 26.8 weeks, P < 0.001 by Mann-Whitney U test). It was concluded that severe swelling and superficial skin injury significantly affect the outcome of type I extraarticular fractures of the middle phalanx treated by closed reduction and longitudinal Kirschner wire fixation. PMID- 22214790 TI - Current applications of 3-d intraoperative navigation in craniomaxillofacial surgery: a retrospective clinical review. AB - Intraoperative navigation is a tool that provides surgeons with real-time, interactive access to their patient's diagnostic imaging studies while in the operating room. This modality allows for anatomic localization and facilitates intraoperative planning and diagnosis. The application of intraoperative navigation to neurosurgery, otolaryngology, and orthopedic surgery has been well documented; however, only isolated reports have analyzed its potential in the field of craniomaxillofacial surgery. Advancements in 3-dimensional navigational systems have greatly improved the accuracy of the technology, further broadening its scope. In this article, we evaluate a series of 101 craniomaxillofacial cases in which intraoperative navigation was used. The most common application was for intraorbital cases, such as enophthalmos and acute orbital fracture repairs. Other applications included tumor resection, osteotomy design, pathology localization, and craniotomy design. The major limitations of this technology have been its cost and the fact that it cannot reliably be used for soft-tissue reconstruction currently. PMID- 22214786 TI - Cytokines and brain excitability. AB - Cytokines are molecules secreted by peripheral immune cells, microglia, astrocytes and neurons in the central nervous system. Peripheral or central inflammation is characterized by an upregulation of cytokines and their receptors in the brain. Emerging evidence indicates that pro-inflammatory cytokines modulate brain excitability. Findings from both the clinical literature and from in vivo and in vitro laboratory studies suggest that cytokines can increase seizure susceptibility and may be involved in epileptogenesis. Cellular mechanisms that underlie these effects include upregulation of excitatory glutamatergic transmission and downregulation of inhibitory GABAergic transmission. PMID- 22214791 TI - Sternal reconstruction with omental and pectoralis flaps: a review of 415 consecutive cases. AB - BACKGROUND: Sternal wound infections are a life-threatening complication of cardiovascular surgery, and management can present a great challenge for the plastic surgeon. Successful treatment involves a multidisciplinary approach, immediate detection, meticulous debridement, and delivery of vascularized tissue to the infected wound bed. METHODS: Twenty-nine years experience of a single surgeon in 415 sternal wound reconstructions is retrospectively analyzed. Flap choice was based on the amount of vascularized tissue required. Low-risk, early infections were treated with debridement and a single flap. Large, high-risk wounds were treated with multiple debridements and covered with a combination of flaps to reduce infection and eliminate dead space. RESULTS: Immediate wound closure with aggressive debridement and flap coverage in a single-stage early in the series (first 12 patients, 1980-1981) led to a mortality rate of 25% due to sepsis and cardiovascular instability. Thereafter, treatment was altered, and patient stability and wound preparation were emphasized, often requiring multiple debridements (91% of all patients). Nine percent of patients, with early low-risk infections, underwent single-stage rewiring and coverage with pectoralis or omental flaps. Coverage of multiple debrided purulent wounds was performed using pectoralis major flap (37% of total number of patients), omentum (18%), a pectoralis/omentum combination (34%), or rectus abdominis flap (2%). A multistage approach and use of 2 flaps for coverage resulted in a 1.5% mortality due to sepsis, 2.5% infection rate, 1.5% skin necrosis rate, and 1.5% hematoma/seroma rate. The use of multiple flaps in large, complex wounds resulted in a complication rate similar to smaller wounds covered with a single flap. In all, 3.5% of the patients required a salvage operation with alternate flaps. CONCLUSION: This large series demonstrates the importance of early detection of infection, meticulous staged debridement of nonviable tissue, and elimination of dead space with multiple vascularized flaps. PMID- 22214792 TI - Treatment algorithm of galactorrhea after augmentation mammoplasty. AB - Galactorrhea is a known complication of breast surgery, particularly reduction mammoplasty. However, in augmentation mammoplasty, it is a rare event. There are only a few case reports concerning galactorrhea after augmentation mammoplasty. In this report, we present a case of galactorrhea that occurred at 2 weeks postoperatively in a 34-year-old woman who had undergone augmentation mammoplasty with silicone implants via a transaxillary approach. Endocrinologic tests including serum prolactin level, routine blood work, and breast ultrasonography were all normal. The authors decided to manage conservatively with close observation. After 1 month, the symptom resolved without sequelae, and no recurrence has been reported. PMID- 22214793 TI - Smile train: changing the world one smile at a time. AB - Smile Train was founded with one, clear aim--to help as many children as possible who are needlessly suffering with unrepaired clefts. Its unique "teach-a-man-to fish" strategy supports local medical professionals to provide free, safe, and high-quality cleft care by offering free education and training opportunities, free equipment, and financial support for cleft treatment. Smile Train is continuing to expand its reach and enhance its ability to serve by developing and implementing new and innovative approaches in the delivery of comprehensive cleft care, so that each and every child born into the world with a cleft has the opportunity to live a full, productive life. PMID- 22214794 TI - The thoracodorsal artery and vein as recipient vessels for microsurgical breast reconstruction. AB - Recipient vessels for microsurgical breast reconstructions include the internal mammary and thoracodorsal systems. This review will focus on the advantages of the thoracodorsal artery and vein. PMID- 22214795 TI - Significant predictors of complications after sternal wound reconstruction: a 21 year experience. AB - BACKGROUND: We sought to identify patient comorbidities that predict complications after tissue flap sternal reconstruction. METHODS: A retrospective study, December 1989 to December 2010, analyzed numerous comorbidities, including diabetes mellitus (DM), hypertension (HTN), coronary artery disease, congestive heart failure (CHF), and renal insufficiency, as independent risk factors for postoperative complications. Pearson chi2 test, Fisher exact test, 2-sample t test, and median-unbiased estimation were used for data analysis. Significance was P<=0.05. RESULTS: In all, 106 patients received 161 sternal tissue flap repairs. Nineteen patients (18%) required reoperation because of complications, including recurrent wound infection, tissue necrosis, wound dehiscence, mediastinitis, and hematoma formation. Our analysis found DM, HTN, and CHF as significant predictors of complications after sternal reconstruction (P=0.014, 0.012, and 0.006). CONCLUSIONS: Results suggest DM, HTN, and CHF may contribute to complications after tissue flap repair of sternal wounds, possibly through impaired perfusion and healing of repairs. PMID- 22214796 TI - Inferior oblique muscle origin: horizontal location in relation to ala nasi and its gender difference. AB - We studied the horizontal location of the inferior oblique muscle (IOM) origin in relation to the ipsilateral ala nasi and compared the results between genders in 76 orbits of 38 Japanese cadavers. Consequently, the IOM origin was located 1.2 mm laterally to the vertical line through the lateral margin of the ipsilateral ala nasi. No significant difference was noted between genders (males, 1.3 mm; females, 0.9 mm; P = 0.257, Student t test) or between sides (right, 1.1 mm; left, 1.3 mm; P = 0.570, Student t test). In contrast, the mean interalae-nasi distance was 39.8 mm and was significantly greater in males than that in females (males, 40.8 mm; females, 38.6 mm; P = 0.049, Student t test). The ala nasi can be used as a reference point irrespective of gender or side for identifying the IOM origin during oculoplastic surgery. PMID- 22214797 TI - Autologous blood use for free flap breast reconstruction: a comparative evaluation of a preoperative blood donation program. AB - BACKGROUND: New insights into potential adverse effects of banked blood and improved infectious surveillance have led to questions regarding the utility of preoperative autologous blood donation. METHODS: A retrospective chart review of 153 patients undergoing abdominal free flap breast reconstruction was performed with the goal of determining the effect of an autologous blood donation program on clinical outcomes. Demographic and premorbid conditions were evaluated along with outcome variables including complication and transfusion rates. RESULTS: As expected, the autologous blood donor group (n = 96) was more likely to receive a blood transfusion of any kind compared with the nondonors (98% vs. 18%, P < 0.0001). Surprisingly, the mean number of allogeneic transfusions was not decreased (0.26 vs. 0.84, P = 0.066). The mean number of complications between groups were comparable (0.53 vs. 0.57, P = 0.687). CONCLUSION: We found neither significant benefit nor adverse effect from the practice of autologous blood banking for free flap breast reconstruction. The practice should be considered safe but not routinely recommended for free flap breast surgery. PMID- 22214798 TI - Dynamic reconstruction of full-thickness abdominal wall defects using free innervated vastus lateralis muscle flap combined with free anterolateral thigh flap. AB - Reconstruction of full-thickness abdominal wall defects remains a difficult surgical challenge. Although various reconstructive methods, including artificial mesh, pedicled and free flaps, have been reported, most reported reconstruction of only the fascia layer, leaving the resected rectus abdominis muscle unreconstructed. However, recent studies suggested the importance of dynamic reconstruction with functional muscle in preventing abdominal hernia in the long term. According to the principle of reconstructive surgery, "replace lost tissue with similar tissue," a functionally and aesthetically ideal reconstruction is to reconstruct all components of the abdominal wall structure, including skin, subcutaneous fat, fascia, and muscle. We present 2 cases with full-thickness abdominal wall defects in the upper abdominal region, which we reconstructed with a free innervated vastus lateralis muscle flap combined with a free anterolateral thigh flap. The motor nerve of the vastus lateralis muscle was sutured with the intercostal nerve, and reinnervation was confirmed by electromyography. This method allows reconstruction of all components of the abdominal wall with a single flap, and dynamic reconstruction is achieved which will reduce the risk of postoperative hernia. We believe this method can be a good option for reconstruction of full-thickness abdominal wall defects with long-term stability. PMID- 22214799 TI - Blepharoplasty revealing orbital lymphoma. AB - Blepharoplasty is a frequent request in consultations of plastic surgery. Patients are often presenting with a progressive swelling of the eyelids. For functional or aesthetic reasons, we commonly perform a superior and/or inferior blepharoplasty to correct this problem. We present the case of a 72-year-old woman who consulted us with a prominent unattractive swelling of both lower eyelids. Because of the atypical and suspicious presentation, supplementary examinations were conducted, and the fat was also sent for analysis. A diagnosis of unilateral orbital lymphoma was obtained. The patient was treated as a primarily localized lymphoma with a positive outcome. When correctly diagnosed and treated, orbital lymphomas can have a very good prognosis. PMID- 22214800 TI - Reconstruction of massive oncologic defects following extremity amputation: a 10 year experience. AB - BACKGROUND: Oncologic defects resulting from extremity amputations are often extensive and require substantial soft tissue for reconstruction. METHODS: A review of all patients, who underwent an external hemipelvectomy, forequarter amputation, or hindquarter amputation from 2001 to 2010 at the MD Anderson Cancer Center, was performed. RESULTS: A total of 50 patients were identified; of them, 21 underwent external hemipelvectomy, 22 had forequarter amputation, and 7 had hindquarter amputation. The mean defect size was 644 cm; defects were repaired using fillet flaps (n = 22, 44%), free flaps (n = 4, 8%), or local/regional flaps (n = 24, 48%). Of the fillet flaps, 16 were free flaps and the remaining were pedicled flaps. In all, 29 patients (58%) received preoperative radiation therapy, and 26 patients (52%) received preoperative chemotherapy. Two patients (4%) received postoperative radiation therapy, and 1 patient (2%) received postoperative chemotherapy. Three patients received both pre- and postoperative radiation therapy, and 10 patients were treated with both pre- and postoperative chemotherapy. Patients undergoing free flap reconstruction had significantly fewer complications compared with patients reconstructed using other modalities (2/20 vs. 13/30; P = 0.003). The majority of patients achieved excellent postoperative function, with 73% of upper extremity patients functioning independently and 57% of lower extremity amputees ambulating. CONCLUSIONS: Reconstruction for extensive defects following oncologic extremity amputation is often optimally done using free tissue transfer, particularly by salvaging "spare parts" from the amputated limb for a free fillet flap. PMID- 22214801 TI - The role of preoperative radiological assessment of vascular injury on surgical decision making in mutilating injuries of the upper extremity. AB - Preoperative assessment of the extent of vascular injury is important in patients with mutilating injuries of the upper extremity. The aim of this report was to discuss the influence of computed tomography angiography (CTA) and digital subtraction angiography (DSA) on the operating room decision-making in mutilating injuries and limb-salvage procedures of the traumatic upper extremity. Four DSA and 3 CTA were performed in 7 patients with a mean age of 28.3 (range, 4-48) years. The results of the DSA and CTA altered the preoperative planning. In 5 patients, the reconstructive decision of the type of flap was altered, whereas in all 7 patients, either the level or type of anastomosis was changed after radiologic investigations. The mean follow-up period was 37.8 months. During the follow-up period, all patients underwent subsequent procedures such as sensory restoration, tendon reconstruction, or capsulotomy. The effects of radiologic results in which flap selection, target donor vessel, and level and type of anastomosis have changed are discussed in correlation with intraoperative findings. PMID- 22214802 TI - The anterolateral thigh perforator flap for reconstruction of knee defects. AB - INTRODUCTION: Large defects around the knee remain challenging reconstructive problems. We report our experience with the use of the anterolateral thigh perforator flap for various defects in this area, based on the anatomy seen intraoperatively. METHODS AND MATERIALS: Eight knee defects were reconstructed with the anterolateral thigh flap in accordance with our algorithm. Of them, 6 were performed as pedicled flaps and 2 as free flaps. For the pedicled flaps, 1 patient was reconstructed with an anterolateral thigh rotation flap, 3 patients with a directly transposed distally based anterolateral thigh flap, 2 patients with a "propeller" distally based anterolateral thigh flap. In the 2 patients reconstructed with the free anterolateral thigh flaps, the intramuscular part of the descending branch of the lateral circumflex femoral artery was used as the recipient vessel. RESULTS: Reconstruction was successfully performed in all patients. Defects limited to the patella and above can be covered by antegrade anterolateral thigh rotation flaps. For larger defects, the distally based flap is needed. This can be used in cases where the perforators arise from the descending branch of the lateral circumflex femoral artery, either as a direct advancement or propeller flaps. In cases where the perforators are not usable or arises from the oblique branch of the lateral circumflex femoral artery, reconstruction was completed as a free flap. In such instances, the distal descending branch provides a reliable recipient vessel. CONCLUSION: The anterolateral thigh flap offers a versatile and reliable option for defects around the knee. Its use requires a certain degree of reconstructive flexibility as the anatomic variations of the flap may require the flap to be transferred as a free flap in some cases. PMID- 22214803 TI - Long-term results of arterial sympathectomy and artery reconstruction with vein bypass technique as a salvage procedure for severe digital ischemia. AB - The aim of this study is to present a combined treatment of arterial sympathectomy and artery reconstruction with vein bypass technique in patients with severe digital ischemia. In all, 22 patients representing 53 digits received treatment during a 15-year period. Skin color and trophic changes including ulcers, necrosis, and amputation; pain level according to the visual analog scale; and functional assessment based on the disabilities of the arm, shoulder, and hand questionnaire were recorded. After surgery, the skin discoloration improved, and the trophic changes healed in the majority of patients. Amputation was required in 2 cases. Pain and function improved significantly postoperatively. Based on the results of this study, vascular reconstruction combined with sympathectomy may be indicated on an individualized basis for patients with digital ischemia. This procedure can lead to healing of skin trophic changes, diminution of pain, avoidance of amputation, and long-term improvement in life quality. PMID- 22214804 TI - [microRNA in autoimmune disorders]. AB - microRNAs, short ribonucleic acid molecules which is typically 20-25 nucleotides long, can bind to complementary sequences in the three prime untranslated regions of target mRNAs, leading to the inhibition of translation or degradation of the mRNA. Theologically, human genome may have more than 1000 microRNAs, which target about 60% of human mRNAs. Thus, microRNAs have been implicated in the pathogenesis of various disorders. This paper discusses the present day understanding about the expression and role in various autoimmune diseases including rheumatoid arthritis, Sjogren syndrome, polymyositis/dermatomyositis, systemic lupus erythematosus, scleroderma, type I diabetis, and psoriasis. For example, the expression of miR-29, which targets type I collagen mRNA, is reported to be down-regulated in cultured dermal fibroblasts derived from scleroderma skin, contributing to excessive collagen production in this disease. Supplementation of the microRNA results in the decrease of collagen expression in scleroderma fibroblasts. In addition, serum miR-29a levels are significantly decreased in the very early stage of scleroderma. Investigation of the involvement of microRNAs in the pathogenesis of each autoimmune disease may lead to develop new biomarker and new therapeutic approach. PMID- 22214805 TI - [The mechanism of the efficiency of leukocytapheresis on rheumatoid arthritis]. AB - Several clinical trials revealed that leukocytapheresis (LCAP) was safe and effective therapy for patients with rheumatoid arthritis (RA). In this article, the mechanism of the efficiency of LCAP on RA is reviewed. The counts of activated CD4(+) T cells and CD4(+)CD29(+) T cells were significantly reduced in the synovial fluid after LCAP. Serum tumor necrosis factor alpha, interleukin (IL)-15 and RANTES were significantly reduced, while serum IL-10 significantly increased and this level increased significantly only in the responder group after treatment. P-glycoprotein (Pgp), which causes drug resistance by exclusion of intracellular drugs, expression on Th1 cells following LCAP therapy was significantly decreased after 4 sessions of treatment and 6 months after the last procedure in the responder group. Moreover, remarkable improvements of regulatory T cell (Treg) function were observed in good responders. Our findings suggest that LCAP may cause a reduction of activated T cells from affected joints, down regulation of Pgp on helper T cells and restoration of Treg function, and that may modify the abnormal cytokine balance. These findings may explain some of the mechanisms by which the articular symptoms are improved by LCAP. PMID- 22214806 TI - [Autoimmunity to glycolytic enzyme in rheumatoid arthritis]. AB - Prognosis of rheumatoid arthritis (RA) patients has significantly improved with the recent use of biologics targeting TNFalpha, IL-6, and co-stimulatory molecule. In US and Europe, clear therapeutic benefit of anti-CD20 antibodies is also confirmed. As a disease specific marker, rheumatoid factor and anti citrullinated protein antibody are crucial in RA, although the pathology of them is not defined. Here we focus on glycolytic enzyme such as glucose-6-phospate isomerase, that is confirmed as arthritogenic in two different mouse models, and discuss about pathogenic relevance to RA. PMID- 22214807 TI - [Topics of glucocorticoids--centered on therapy for rheumatoid arthritis]. AB - Glucocorticoids (steroids) have been widely used for the treatment of patients with rheumatoid arthritis (RA) since Hench had attempted to administer cortisone (Kendall's compound E) to an active RA patient in 1948. Rheumatologists even in the 21st century can learn a lot from the history of steroid. In this feature article on steroid, a brief outline of 11beta-hydroxysteroid dehydrogenase type 1, a tissue-specific regulator of steroid response, is presented. The isozyme re activates inactive cortisone (compound E) to active cortisol (compound F), and seems to play an important role particularly in adipose tissue. In addition, I give an account of non-genomic mechanisms of steroid, which might be relevant to early and rapid effects during methylprednisolone pulse therapy. As for the field of practical rheumatology, rates and dosages of steroid administration for RA in Japan are shown, by looking into 3 large observational cohort researches and post marketing surveillance programs for several biologics. The definition or an appropriate interpretation of medical/technical terms such as 'effectiveness' in the clinical setting and 'low-dose' steroid is also described. PMID- 22214808 TI - [Immune mechanisms involved in the development and eradication of anti-factor VIII alloantibodies in hemophilia]. AB - Hemophilia A is an X-linked hereditary bleeding disorder caused by a congenital deficiency in blood coagulation factor VIII (FVIII). Therapy to prevent or treat bleeding is replacement of FVIII. The most significant complication of treatment in patients with hemophilia A is the development of alloantibodies that inhibit FVIII activity, termed inhibitors. In the presence of inhibitors, replacement of the missing clotting factor with FVIII preparations becomes less effective. Once replacement therapy is ineffective, morbidity increases. It remains unsolved to prevent inhibitor formation. The only strategy is long-term administration of a large quantity of FVIII in an attempt to eradicate the inhibitors through immune tolerance. However, little is known about the mechanisms involved in the induction of tolerance. This review will focus on the current understanding of why inhibitors develop and can be eradicated. The development of inhibitors by intravenous infusions of FVIII without adjuvant poses an intriguing challenge to immunologists. PMID- 22214809 TI - [Anti-rheumatic therapy in patients with rheumatoid arthritis undergoing hemodialysis]. AB - Hemodialysis (HD) patients have been increasing recently. Some rheumatoid arthritis (RA) patients need hemodialysis (HD), though the proportion is not high. At present, such patients are almost treated with corticosteroids and/or nonsteroidal anti-inflammatory drugs alone, even if they have a high disease activity that would require disease-modifying anti-rheumatic drug (DMARD) therapy, partly because the safety of DMARDs in RA patients with end-stage renal disease has not been confirmed. Their joint destruction would be inevitable and lead to impaired activities of daily living. As there are no guidelines for the use of DMARDs in HD patients, here I reviewed the previous reports about the treatment of DMARDs including biologics for patients with RA undergoing HD. PMID- 22214810 TI - The effects of disease modifying anti-rheumatic drugs on osteoclastogenesis and bone destruction in rheumatoid arthritis. AB - Finding the means to ameliorate and prevent bone destruction as well as control inflammation is an urgent issue in the treatment of rheumatoid arthritis (RA). Recently, it has been demonstrated that osteoclastogenesis plays an important role in the bone destruction and pathogenesis of RA. Here, we review the effects of disease modifying anti-rheumatic drugs (DMRAD) on the amelioration of bone destruction and osteoclastogenesis. PMID- 22214811 TI - [Tuberculous peritonitis during etanercept therapy for rheumatoid arthritis]. AB - In August 2010, a 73-year-old woman with rheumatoid arthritis receiving etanercept (ETN) therapy for two years, developed high-fever and abdominal fullness. Though she had not been exposed to tuberculosis, isoniazid prophylaxis was administrated. Antibiotics were not effective. CT images revealed the massive ascites and peritonitis, and Ga scintigraphy demonstrated notable uptake in the peritoneum. Ascites analysis showed an elevated adenosine deaminase activity value (104.9 IU/l) without malignant cells. Moreover, PCR and culture for Mycobacterium tuberculosis were positive. Finally, a diagnosis of tuberculous peritonitis was established. After initiating a standard anti-tuberculosis regimen with four drugs, her clinical condition ameliorated and ascites promptly regressed. Although the tuberculous peritonitis during ETN therapy is rare, this report emphasized the importance of initial suspicion of tuberculosis in these patients with tumor necrosis factor inhibitors such as ETN. PMID- 22214812 TI - [A case of slowly progressive type 1 diabetes mellitus developing myeloperoxidase specific anti-neutrophil cytoplasmic antibody-associated vasculitis with hypertrophic pachymeningitis manifesting as multiple cranial nerve palsy]. AB - We report a 63-year-old man with a 35-year history of slowly progressive type 1 diabetes mellitus (SPIDDM), complicated with myeloperoxidase-specific anti neutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis presenting alveolar hemorrhage and pachymeningitis. The patient was first diagnosed as having DM at age of 28 years old and deteriorated secretion of insulin and the typical clinical course led us to the diagnosis of SPIDDM. When he was 58 years old, he suffered from fever, headache, and alveolar hemorrhage. He was diagnosed as having MPO-ANCA associated vasculitis based on a high titer of MPO-ANCA and histological findings of lung biopsy. Treatment with steroid pulse therapy, followed by oral prednisolone and oral cyclophosohamide, resulted in clinical improvement. Five years later, he complained of double vision. A gadolinium enhanced magnetic resonance imaging (MRI) study of the brain showed normal. Two months later, he developed right cranial nerve V~XII palsy. A second MRI study revealed thickening of the right temporal region and cerebellar dura mater, leading us to the diagnosis of hypertrophic pachymeningitis. He responded well to oral prednisolone (50 mg/day) and intravenous cyclophosohamide (500 mg). This is the first case report of SPIDDM complicated with MPO-ANCA-associated vasculitis, manifesting as alveolar hemorrhage and hypertrophic pachymeningitis. PMID- 22214813 TI - Clearance-dependent underprediction of in vivo intrinsic clearance from human hepatocytes: comparison with permeabilities from artificial membrane (PAMPA) assay, in silico and caco-2 assay, for 65 drugs. AB - Underprediction of in vivo intrinsic clearance (CLint) from suspended human hepatocytes has recently been shown to be clearance-dependent although the mechanistic basis is currently unknown. One possible explanation is rate limiting transmembrane (passive) permeation into hepatocytes in vitro; evidence to support this has been minor to date, but there has not been a systematic exploration of the impact of passive permeability in vitro. To investigate the relationship between underprediction of in vivo CLint and potentially rate limiting permeability, permeability constants (Px, collated from published studies and determined experimentally in this study), using three alternative methodologies (parallel artificial membrane permeability assay (PAMPA), caco-2 permeability assay and calculated using an empirical model) were compared with CLint from suspended human hepatocytes for 65 drugs from a recently reported database of clearance predictions. Although there was an approximate correspondence between hepatocyte CLint and permeability measured by PAMPA (but not by caco-2 or modelling), prediction accuracy was not dependent on the relative permeability (measured as the ratio of CLint to permeability), indicating the absence of a general rate limitation by passive hepatocyte uptake on metabolic clearance. Further investigation into rate-dependent CLint in hepatocytes is required. PMID- 22214814 TI - Bisphenol A in thermal paper receipts: an opportunity for evidence-based prevention. PMID- 22214815 TI - CYP3A5 genotype-phenotype analysis in the human kidney reveals a strong site specific expression of CYP3A5 in the proximal tubule in carriers of the CYP3A5*1 allele. AB - Interindividual variability in the drug-metabolizing activity of the CYP3A5 enzyme is mainly due to a single nucleotide polymorphism in CYP3A5, leading to low expression in homozygous CYP3A5*3/*3 individuals compared with CYP3A5*1 allele carriers. In the human kidney, expression of CYP3A5 has been implicated in blood pressure regulation and calcineurin inhibitor-associated nephrotoxicity. The effect of the CYP3A5*1/*3 polymorphism on the expression level and protein distribution within the human kidney is not well characterized. Therefore, we performed a genotype-phenotype analysis of CYP3A5 mRNA and protein expression in the human kidney. To this end, we analyzed sections of normal kidney tissue obtained from 93 white individuals undergoing nephrectomy by quantitative mRNA expression analysis. Qualitative protein expression analysis of CYP3A5 was performed by immunohistochemistry. Mean renal mRNA expression of carriers of the CYP3A5*1 (n = 12) allele was more than 18-fold higher than that of CYP3A5*3/*3 carriers (n = 81, p < 0.001). Immunohistochemical analysis demonstrated CYP3A5 protein in all epithelia of the nephron in kidney sections with the CYP3A5*3/*3 genotype. In carriers of the CYP3A5*1 allele, a strong increase in protein expression of CYP3A5 was detected, and this was confined to the proximal tubule. This study confirms a significant effect of the CYP3A5*1/*3 polymorphism on CYP3A5 expression in the normal human kidney and reveals a strong nephron segment specific difference in the CYP3A5 protein expression limited to the proximal tubule. PMID- 22214816 TI - NtSCP1 from tobacco is an extracellular serine carboxypeptidase III that has an impact on cell elongation. AB - The leaf extracellular space contains several peptidases, most of which are of unknown function. We isolated cDNAs for two extracellular serine carboxypeptidase III genes from tobacco (Nicotiana tabacum), NtSCP1 and NtSCP2, belonging to a phylogenetic clade not yet functionally characterized in plants. NtSCP1 and NtSCP2 are orthologs derived from the two ancestors of tobacco. Reverse transcription-polymerase chain reaction analysis showed that NtSCP1 and NtSCP2 are expressed in root, stem, leaf, and flower tissues. Expression analysis of the beta-glucuronidase reporter gene fused to the NtSCP1 transcription promoter region confirmed this expression profile. Western blotting of NtSCP1 and expression of an NtSCP1-green fluorescent protein fusion protein showed that the protein is located in the extracellular space of tobacco leaves and culture cells. Purified His-tagged NtSCP1 had carboxypeptidase activity in vitro. Transgenic tobacco plants overexpressing NtSCP1 showed a reduced flower length due to a decrease in cell size. Etiolated seedlings of these transgenic plants had shorter hypocotyls. These data provide support for a role of an extracellular type III carboxypeptidase in the control of cell elongation. PMID- 22214818 TI - Magnetism and superconductivity in Eu0.2Sr0.8(Fe0.86Co0.14)2As2 probed by 75As NMR. AB - We report bulk superconductivity (SC) in Eu(0.2)Sr(0.8)(Fe(0.86)Co(0.14))(2)As(2) single crystals by means of electrical resistivity, magnetic susceptibility and specific heat measurements with T(c) is approximately equal to 20 K and an antiferromagnetic (AFM) ordering of Eu(2+) moments at T(N) is approximately equal to 2.0 K in zero field. (75)As NMR experiments have been performed in the two external field directions (H is parallel to ab) and (H is parallel to c). (75)As NMR spectra are analysed in terms of first-order quadrupolar interaction. Spin lattice relaxation rates (1/T(1)) follow a T(3) law in the temperature range 4.2 15 K. There is no signature of a Hebel-Slichter coherence peak just below the SC transition, indicating a non-s-wave or s(+/-) type of superconductivity. In the temperature range 160-18 K 1/T(1)T follows the C/(T+theta) law reflecting 2D AFM spin fluctuations. PMID- 22214817 TI - The effect of a genetically reduced plasma membrane protonmotive force on vegetative growth of Arabidopsis. AB - The plasma membrane proton gradient is an essential feature of plant cells. In Arabidopsis (Arabidopsis thaliana), this gradient is generated by the plasma membrane proton pump encoded by a family of 11 genes (abbreviated as AHA, for Arabidopsis H(+)-ATPase), of which AHA1 and AHA2 are the two most predominantly expressed in seedlings and adult plants. Although double knockdown mutant plants containing T-DNA insertions in both genes are embryonic lethal, under ideal laboratory growth conditions, single knockdown mutant plants with a 50% reduction in proton pump concentration complete their life cycle without any observable growth alteration. However, when grown under conditions that induce stress on the plasma membrane protonmotive force (PMF), such as high external potassium to reduce the electrical gradient or high external pH to reduce the proton chemical gradient, aha2 mutant plants show a growth retardation compared with wild-type plants. In this report, we describe the results of studies that examine in greater detail AHA2's specific role in maintaining the PMF during seedling growth. By comparing the wild type and aha2 mutants, we have measured the effects of a reduced PMF on root and hypocotyl growth, ATP-induced skewed root growth, and rapid cytoplasmic calcium spiking. In addition, genome-wide gene expression profiling revealed the up-regulation of potassium transporters in aha2 mutants, indicating, as predicted, a close link between the PMF and potassium uptake at the plasma membrane. Overall, this characterization of aha2 mutants provides an experimental and theoretical framework for investigating growth and signaling processes that are mediated by PMF-coupled energetics at the cell membrane. PMID- 22214819 TI - Fanconi-Bickel syndrome: GLUT2 mutations associated with a mild phenotype. AB - Fanconi-Bickel syndrome (FBS, OMIM #227810), a congenital disorder of carbohydrate metabolism, is caused by mutations in GLUT2 (SLC2A2), the gene encoding the glucose transporter protein-2. The typical clinical picture is characterized by hepatorenal glycogen accumulation resulting in hepato- and nephromegaly, impaired utilization of glucose and galactose, proximal tubular nephropathy, rickets, and severe short stature. We report on two siblings with FBS and an unusually mild clinical course. A 9.5-year-old boy with failure to thrive was diagnosed at the age of 9 months, his younger sister (4.5 years) was investigated in the first months of life and also diagnosed with FBS. Both patients were found to be compound heterozygous for the novel GLUT2 (SLC2A2) mutations c.457_462delCTTATA (p.153_4delLI) and c.1250C>G (p.P417R). On a diet restricted in free glucose and galactose, both children showed normal growth. Hepatomegaly, nephromegaly and hypophosphatemic rickets have never been observed. Glucosuria and tubular proteinuria were only mild compared to previously reported patients with FBS. This report describes an unusually mild phenotype of FBS expanding the spectrum of this disease. Some clinical signs that have been considered hallmarks of FBS like hepatomegaly and short stature may be absent in this condition. As a consequence, clinicians will have to look for GLUT2 mutations even in patients with isolated glucosuria. PMID- 22214820 TI - Eight years of Legionnaires' disease transmission in travellers to a condominium complex in Las Vegas, Nevada. AB - Travel is a risk factor for Legionnaires' disease. In 2008, two cases were reported in condominium guests where we investigated a 2001 outbreak. We reinvestigated to identify additional cases and determine whether ongoing transmission resulted from persistent colonization of potable water. Exposures were assessed by matched case-control analyses (2001) and case-series interviews (2008). We sampled potable water and other water sources. Isolates were compared using sequence-based typing. From 2001 to 2008, 35 cases were identified. Confirmed cases reported after the cluster in 2001-2002 were initially considered sporadic, but retrospective case-finding identified five additional cases. Cases were more likely than controls to stay in tower 2 of the condominium [matched odds ratio (mOR) 6.1, 95% confidence interval (CI) 1.6-22.9]; transmission was associated with showering duration (mOR 23.0, 95% CI 1.4-384). We characterized a clinical isolate as sequence type 35 (ST35) and detected ST35 in samples of tower 2's potable water in 2001, 2002, and 2008. This prolonged outbreak illustrates the importance of striving for permanent Legionella eradication from potable water. PMID- 22214821 TI - Remediating soil lead with fish bones. PMID- 22214822 TI - Mapping of near field light and fabrication of complex nanopatterns by diffraction lithography. AB - We report a single-step lithographic approach for precisely mapping near field light diffraction in photoresist and fabricating complex subwavelength structures. This method relies on the diffraction of UV light from opaque patterns on a photomask, and utilizes the central diffraction maximum (known as the 'Poisson spot' for an opaque disk) and its higher orders. By correlating pattern geometries with the resulting diffraction, we demonstrate that the near field light intensity can be quantified to high precision and is in good agreement with theory. The method is further extended to capture higher order diffraction, which is utilized to fabricate unconventional subwavelength nanostructures with three-dimensional topographies. The simplicity of this process and its capability for light mapping suggest it to be an important tool for near field optical lithography. PMID- 22214823 TI - Optimization of polysaccharides from Panax japonicus C.A. Meyer by RSM and its anti-oxidant activity. AB - Response surface method (RSM) was used to optimize the extraction conditions of polysaccharides from the rhizomes of Panax japonicus C.A. Meyer. A three-level, three-variable Box-Behnken design (BBD) was applied for experimental design and analyzed of the results to obtain the optimal processing parameters. RSM analysis indicated good correspondence between experimental and predicted values. The optimal condition for the yield of polysaccharide was extraction time 3.74 h, extraction temperature 93.90 degrees C and ratio of water to raw material 40.22. Polysaccharide was analyzed by chemical methods and Fourier transform infrared (FT-IR). IR spectra indicated the presence of uronic acids and alpha-pyranose of the glucose residue. The antioxidant activities of Panax japonicus polysaccharides (PJP) were investigated including scavenging activity of hydrogen peroxide, 2,2-diphenyl-1-picryl-hydrazyl (DPPH) and free radicals of superoxide anion in vitro. The results of antioxidant activity exhibited PJP had a good potential for antioxidant. PMID- 22214824 TI - Antidiabetic activity of Taxus cuspidata polysaccharides in streptozotocin induced diabetic mice. AB - In present study, crude polysaccharides (TCPs) were obtained by hot water extraction and ethanol precipitation from the Taxus cuspidata. With a purpose of finding valuable and economical drug for diabetes, TCPs was administered orally at three doses [50, 100 and 200 mg/kg body weight (b.w.)] to the diabetic mice induced by streptozotocin (STZ). The body weight, fasting blood glucose (FBG), fasting serum insulin (FINS), lipid peroxidation and superoxide dismutase (SOD) activity, as well as glucose tolerance were evaluated in normal and STZ-induced diabetic mice. TCPs could dose-dependently significantly increase the body weight of diabetic mice, and reverse the decrease of SOD and the increase of thiobarbituric acid reactive substances (TBARS) in kidney and liver of diabetic mice as compared to those in control group. Meanwhile, the level of FBG markedly decreased in diabetic mice administrated with TCPs, followed by the enhancement of FINS level especially at the higher dose. Furthermore, glibenclamide and TCPs significantly suppressed the rise in blood glucose after 30 min in the acute glucose tolerance test. These results indicated that TCPs could be developed to a potential anti-diabetic drug in the future. PMID- 22214825 TI - Immunomodulatory and antioxidant effects of carboxymethylpachymaran on the mice infected with PCV2. AB - The objective of the current study is to investigate the protective effect of carboxymethylpachymaran (CMP) on the immune system of mice via multiple infections with porcine circovirus type 2 (PCV2). The in vivo results showed that CMP administration significantly improved the spleen or thymus index, promoted the proliferation activities of T or B lymphocytes, and increased the production of glutathione, the superoxidase dismutase capacity, and the total antioxidant capacity in the spleen or thymus of PCV2-infected mice. The administration of different CMP doses to PVC2-inoculated mice resulted in the upregulation of IL-2 and IFN-alpha or the downregulation of IL-10 levels in the serum. These findings suggest that CMP has potential applications in regulating immunological functions to overcome the immunosuppresion caused by PCV2 infection in mice. The findings may also prove useful in designing effective therapies against PCV2 infection. PMID- 22214826 TI - Dietary patterns and bone mineral status in young adults: the Northern Ireland Young Hearts Project. AB - Studies of individual nutrients or foods have revealed much about dietary influences on bone. Multiple food or nutrient approaches, such as dietary pattern analysis, could offer further insight but research is limited and largely confined to older adults. We examined the relationship between dietary patterns, obtained by a posteriori and a priori methods, and bone mineral status (BMS; collective term for bone mineral content (BMC) and bone mineral density (BMD)) in young adults (20-25 years; n 489). Diet was assessed by 7 d diet history and BMD and BMC were determined at the lumbar spine and femoral neck (FN). A posteriori dietary patterns were derived using principal component analysis (PCA) and three a priori dietary quality scores were applied (dietary diversity score (DDS), nutritional risk score and Mediterranean diet score). For the PCA-derived dietary patterns, women in the top compared to the bottom fifth of the 'Nuts and Meat' pattern had greater FN BMD by 0.074 g/cm(2) (P = 0.049) and FN BMC by 0.40 g (P = 0.034) after adjustment for confounders. Similarly, men in the top compared to the bottom fifth of the 'Refined' pattern had lower FN BMC by 0.41 g (P = 0.049). For the a priori DDS, women in the top compared to the bottom third had lower FN BMD by 0.05 g/cm(2) after adjustments (P = 0.052), but no other relationships with BMS were identified. In conclusion, adherence to a 'Nuts and Meat' dietary pattern may be associated with greater BMS in young women and a 'Refined' dietary pattern may be detrimental for bone health in young men. PMID- 22214827 TI - In silico cloning of genes encoding neuropeptides, neurohormones and their putative G-protein coupled receptors in a spider mite. AB - The genome of the spider mite was prospected for the presence of genes coding neuropeptides, neurohormones and their putative G-protein coupled receptors. Fifty one candidate genes were found to encode neuropeptides or neurohormones. These include all known insect neuropeptides and neurohormones, with the exception of sulfakinin, corazonin, neuroparsin and PTTH. True orthologs of adipokinetic hormone (AKH) were neither found, but there are three genes encoding peptides similar in structure to both AKH and the AKH-corazonin-related peptide. We were also unable to identify the precursors for pigment dispersing factor (PDF) or the recently discovered trissin. However, the spider mite probably does have such genes, as we found their putative receptors. A novel arthropod neuropeptide gene was identified that shows similarity to previously described molluscan neuropeptide genes and was called EFLamide. A total of 65 putative neuropeptide GPCR genes were also identified, of these 58 belong to the A-family and 7 to the B-family. Phylogenetic analysis showed that 50 of them are closely related to insect GPCRs, which allowed the identification of their putative ligand in 39 cases with varying degrees of certainty. Other spider mite GPCRs however have no identifiable orthologs in the genomes of the four holometabolous insect species best analyzed. Whereas some of the latter have orthologs in hemimetabolous insect species, crustaceans or ticks, for others such arthropod homologs are currently unknown. PMID- 22214830 TI - "Doping" a modern problem of psychotropic substances misuse. PMID- 22214828 TI - Actinobacteria associated with the marine sponges Cinachyra sp., Petrosia sp., and Ulosa sp. and their culturability. AB - Actinobacteria associated with 3 marine sponges, Cinachyra sp., Petrosia sp., and Ulosa sp., were investigated. Analyses of 16S rRNA gene clone libraries revealed that actinobacterial diversity varied greatly and that Ulosa sp. was most diverse, while Cinachyra sp. was least diverse. Culture-based approaches failed to isolate actinobacteria from Petrosia sp. or Ulosa sp., but strains belonging to 10 different genera and 3 novel species were isolated from Cinachyra sp. PMID- 22214831 TI - [Comorbidity of substance use with mental disorders]. AB - This contribution reviews the international literature about dual diagnosis, meaning patients who have simultaneously mental health problems and substance use disorders and discusses epidemiology, clinical characteristics, but primarily etiopathogenesis and different treatment models and interventions. The epidemiological data coming from large-scale studies in the general population in USA, Australia and UK demonstrate the close relationship between mental health problems and substance use disorders. Also, the results from Greek research projects support this close relationship, but their research designs have significant limitations. Multiple and high risks are common in this population, like violent or suicidal behavior, self-harm, physical problems, while they appear less responsive to treatment. Subsequently, different models for etiopathogenesis of dual diagnosis have been suggested: (a) Causal relationship: secondary substance use disorder is subsequent of primary mental illness (self medication hypothesis, supersenstivity model) or vice versa (alcohol, cannabis, and cocaine use trigger or contribute to development of mental illness). (b) Third factor as the cause of both mental and substance use disorders (genetic factor, neuropathology, traumatic experience, personality characteristics, multiple factors). (c) Comorbidty is due to chance. (d) Each disorder mutually exacerbates the other, regardless the cause. Here, the relationship between alcohol and depression is discussed further as example. The ideas and the research-evidence which support each of these models are presented. Also there is an overview of different treatment models: (a) Consecutive treatment: mental health treatment and substance misuse treatment are provided consecutively. (b) Parallel treatments: the patient attends programs of both mental health and substance use services simultaneously. (c) Integrated treatment: the same clinical team addresses both mental health issues and substance use disorders. The first two models have significant weaknesses due to lack of focus on the interaction of the different disorders or to administrative and managerial barriers. On the other hand, integrated programs appear to overcome these limitations. They use modified interventions provided by the same team in order to address the multiple needs of the patients. Different types of integrated programs are discussed. More pragmatist inter ventions should also be taken into consideration. It is expected that some direction for research and clinical practice to Greece will emerge from this contribution. PMID- 22214832 TI - [A study of eating attitudes in Nutrition and Dietetics senior students]. AB - The aim of the study was to investigate eating attitudes and related factors in a sample of senior female students of Harokopeion University, Nutrition and Dietetics Department (ND). The group of ND students was compared to a relative sample of female senior students of Technological Institute of Athens, Health Visitor's School (HV). Sixty five ND and 60 HV female senior students were approached af ter lectures. From the 55 ND and the 46 HV students that were eligible to be included in the study, 44 ND and 37 HV students agreed to participate. Ten ND and 14 HV students were excluded because they were either older than 25 years or suffering from a chronic physical or mental disorder. Eleven ND and 9 HV students refused to participate mainly because the did not wanted to be weighted by the researchers. Eating Attitudes Test (EAT-26), and two questionnaires for demographic, clinical and nutritional data were administered to all participants. Also each student was asked to pinpoint on a set of 12 male and female figures the figure that was more likely to represent their own body as well as their ideal female and male body. The ND group scored lower in the mean EAT-26 total score (p=0.03) and oral control subscale (p=0.01) than the HV group. EAT-26 score in the ND group correlated positively with self figure (Kendall's tau-b=0.2, p=0.04) and body dissatisfaction (Kendall's tau-b=0.3, p=0.01). The difference between the ideal female figure and the self figure was used as an indication of body dissatisfaction. Logistic regression analysis showed that avoidance of dinner (OR= 0.7, sig=0.03), choosing leaner ideal women figure (OR= 2.1, sig=0.03) and larger self image (OR=0.5, sig=0.001) were the three factors that could predict high EAT-26 total scores (EAT-26 >=20) in the group of senior female students from both university departments. In conclusion, Nutrition and Dietetics senior female students showed less disordered eating attitudes than senior female Health Visitor's students. Furthermore, the estimation of the ideal female body figure as compared to the perception of the participant's own body figure was significantly related to disordered eating attitudes in the total sample of female university students. PMID- 22214833 TI - [Fibromyalgia in adults-a mainly psychosomatic entity]. AB - This paper presents the clinical entity of fibromyalgia and is a review of the research data on its pathogenesis and treatment. Current data indicate that bio genetic factors associated mainly with the mechanisms of pain, combined with serious stressfull experiences, may be responsible for causing the disease. The contribution of neurotransmitters (such as substance P), of hormones (in particular of the hypothalamus-pituitar y axis), of sleep disturbance, of brain circuits linked to the perception of pain is discussed. The treatment of fibromyalgia is complex and involves in particular antidepressant therapy in combination with psychoeducational cognitive and behavioral interventions and rehabilitation programs. In the diagnosis and treatment of the disease, which, without assistance can become torturing, many specialties of health professionals are involved. PMID- 22214834 TI - [A review of the effects of lithium on cognitive functions: primary effects]. AB - Lithium has well-documented beneficial effects on the acute and prophylactic treatment of bipolardisorder. Its value as an add-on treatment of unipolar depression is also established. Additionally, amultitude of recent experimental data indicate that lithium has pronounced neuroprotective andneurotrophic action: given this neuroprotective profile, it is reasonable to expect this substanceto have beneficial effects on cognitive functioning. However, the hypothesis that lithium may act Lithium has well-documented beneficial effects on the acute and prophylactic treatment of bipolar disorder. Its value as an add-on treatment of unipolar depression is also established. Additionally, a multitude of recent experimental data indicate that lithium has pronounced neuroprotective and neurotrophic action: given this neuroprotective profile, it is reasonable to expect this substance to have beneficial effects on cognitive functioning. However, the hypothesis that lithium may act as a cognitive enhancer is at odds with clinical data which suggest that it has a "cognitive blurring" action and a specific, detrimental effect on memory. The aim of this review was to re-examine the findings of older clinical and experimental studies and integrate them with recent clinical and experimental data, addressing the primary effects of lithium on learning, memory, attention and executive functioning. On the basis of this integration we suggest that the relevant findings do not uphold the picture of persistent cognitive compromise attached to lithium treatment. Furthermore, based on recent data from our own and other laboratories, we propose the hypothesis that lithium may, under specific circumstances, act as a cognitive enhancer. PMID- 22214835 TI - Lung and pleural fibrosis in asbestos-exposed workers: a risk factor for pneumonia mortality. AB - Lungs exposed to occupational dust may be especially vulnerable to fatal infections. We followed up asbestos-exposed workers (n=590) originally screened for lung cancer with computed tomography and scored for pleuropulmonary fibrosis. We checked these workers' influenza and pneumonia mortality data (ICD-10 codes J10-J18) in the national register. In total, 191 deaths, including 43 deaths from infectious pneumonia, occurred in 6158 person-years of follow-up (mean follow-up time 10.44 years). 'Some interstitial fibrosis' [hazard ratio (HR) 2.26, 95% confidence interval (CI) 0.98-5.19, P=0.06] and 'definite interstitial fibrosis' (HR 3.70, 95% CI 1.22-11.23, P=0.02) were associated with an increased risk of death from pneumonia compared to no fibrosis. Asbestosis patients, i.e. those with both asbestos exposure and lung fibrosis, therefore appear to be particularly at risk for death from pneumonia. These patients should be vaccinated against influenza and Pneumococcus. PMID- 22214836 TI - Chlamydophila pneumoniae infection induces alterations in vascular contractile responses. AB - Chlamydophila pneumoniae infection has been associated in previous studies with coronary artery disease. The live bacterium has been detected within atherosclerotic plaques and can induce the structural remodeling of the vessel wall. However, the direct effects of infection on the contractile characteristics of the arteries remain unknown. Left anterior descending coronary arteries isolated from porcine hearts were dissected and placed in culture medium for 72 hours before infection with C. pneumoniae. Contractile responses to high molar KCl and u46619 levels and relaxation responses to bradykinin and sodium nitroprusside were assessed at days 5 and 10 postinfection. C. pneumoniae induced decreases in both KCl- and u46619-induced contractile responses at both time points. The altered contractile responses coincided with a down-regulation of L type Ca(2+) channels at both time points and inositol 1,4,5-triphosphate receptor (IP3R) levels at day 10 postinfection. Infection also induced attenuation of the endothelial-dependent relaxation response to bradykinin at day 10 postinfection. A decrease in endothelial nitric oxide synthase expression levels was noted at day 10 postinfection. Furthermore, an increase in superoxide production combined with an increase in p22phox expression levels was also observed at this time point. These findings indicate that C. pneumoniae infection can directly alter the vascular contractile responses in porcine coronary arteries, providing additional evidence for the role of C. pneumoniae infection in cardiovascular disease. PMID- 22214837 TI - Glucocorticoid-induced tumor necrosis factor receptor family-related protein exacerbates collagen-induced arthritis by enhancing the expansion of Th17 cells. AB - Rheumatoid arthritis (RA), a chronic autoimmune form of inflammatory joint disease, progressively affects multiple joints with pathological changes in the synovia, cartilage, and bone. Numerous studies have suggested a critical role for glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) in the pathogenesis of autoimmune arthritis by modulating both innate and adaptive immune reactions, but the underlying mechanisms by which GITR activation promotes arthritic progression remain largely unclear. In this study, we found that collagen-induced arthritis mice treated with the ligand of GITR (GITRL) displayed an earlier onset of arthritis with a markedly increased severity of arthritic symptoms and joint damage, in which significantly increased Th17 cells in both spleen and draining lymph nodes were observed. Notably, results showed that a marked expansion of Th17 cells with increased RORgammat mRNA expression was induced from naive CD4(+) T cells when cultured with GITRL. Consistently, normal mice that were treated with GITRL were found to display a substantial expansion of splenic Th17 cells. Furthermore, we detected elevated serum levels of GITRL in patients with RA, which were positively correlated with an increase in interleukin-17 production. Taken together, the results from this study have revealed a new function of GITRL in exacerbating autoimmune arthritis via the enhancement of the expansion of Th17 cells. PMID- 22214840 TI - Homogeneity of Ge-rich nanostructures as characterized by chemical etching and transmission electron microscopy. AB - The extension of SiGe technology towards new electronic and optoelectronic applications on the Si platform requires that Ge-rich nanostructures be obtained in a well-controlled manner. Ge deposition on Si substrates usually creates SiGe nanostructures with relatively low and inhomogeneous Ge content. We have realized SiGe nanostructures with a very high (up to 90%) Ge content. Using substrate patterning, a regular array of nanostructures is obtained. We report that electron microscopy reveals an abrupt change in Ge content of about 20% between the filled pit and the island, which has not been observed in other Ge island systems. Dislocations are mainly found within the filled pit and only rarely in the island. Selective chemical etching and electron energy-loss spectroscopy reveal that the island itself is homogeneous. These Ge-rich islands are possible candidates for electronic applications requiring locally induced stress, and optoelectronic applications which exploit the Ge-like band structure of Ge-rich SiGe. PMID- 22214841 TI - A novel lectin domain-containing protein (LvCTLD) associated with response of the whiteleg shrimp Penaeus (Litopenaeus) vannamei to yellow head virus (YHV). AB - When using mRNA from gills of normal whiteleg shrimp Penaeus (Litopenaeus) vannamei as the tester and mRNA from yellow head virus (YHV)-infected shrimp as the driver, subtractive suppression hybridization (SSH) revealed that a novel EST clone of 198 bp with a putative C-type lectin-like domain (CTLD) was downregulated in YHV-infected shrimp. The clone nucleotide sequence had 99% identity with one contig MGID1052359 (1,380 bp) reported in an EST database of P. vannamei, and the presence of this target in normal shrimp was confirmed by RT PCR using primers designed from the MGID1052359 sequence. Analysis of the primary structure of the deduced amino acid (a.a.) sequence of the contig revealed a short portion (40 a.a. residues) at its N-terminus with high similarity to a low density lipoprotein receptor (LDLR) class A domain and another 152 a.a. residues at its C-terminus with high similarity to a C-type lectin domain. Thus, the clone was named LvCTLD and three recombinant proteins (LvCTLD, the LDLR domain and the CTLD domain) were synthesized in a bacterial system based on its sequence. An in vitro encapsulation assay revealed that Sepharose 4B beads coated with rLvCTLD were encapsulated by shrimp hemocytes and that melanization followed by 24 h post encapsulation. The encapsulation activity of rLvCTLD was inhibited by 100 mM galactose, but not mannose or EDTA. In vivo injection of rLvCTLD or rLvCTLD plus YHV resulted in a significant elevation of PO activity in the hemolymph of the challenged shrimp when compared to shrimp injected with buffer, suggesting that rLvCTLD could activate the proPO system. An ELISA test revealed that rLvCTLD could bind to YHV particles in the presence of shrimp hemolymph. Phylogenetic analysis suggested that the LvCTLD sequence was more closely related to an antiviral gene found in Penaeus monodon (PmAV) than to other reported shrimp lectins. Taken together, we conclude that a novel shrimp LvCTLD is a host recognition molecule involved in the shrimp defense mechanism against YHV via recruitment of hemocytes, probably at the site of viral infection, and via activation of the proPO system. PMID- 22214838 TI - Neural stem cell depletion and CNS developmental defects after enteroviral infection. AB - Coxsackieviruses are significant human pathogens causing myocarditis, meningitis, and encephalitis. We previously demonstrated the ability of coxsackievirus B3 (CVB3) to persist within the neonatal central nervous system (CNS) and to target neural stem cells. Given that CVB3 is a cytolytic virus and may therefore damage target cells, we characterized the potential reduction in neurogenesis within the developing brain and the subsequent developmental defects that occurred after the loss of these essential neural stem cells. Neonatal mice were inoculated with a recombinant CVB3 expressing eGFP (eGFP-CVB3), and alterations in neurogenesis and brain development were evaluated over time. We observed a reduction in proliferating cells in CNS neurogenic regions simultaneously with the presence of nestin(+) cells undergoing apoptosis. The size of the brain appeared smaller by histology, and a permanent decrease in brain wet weight was observed after eGFP CVB3 infection. We also observed an inverse relationship between the amount of virus material and brain wet weight up to day 30 postinfection. In addition, signs of astrogliosis and a compaction of the cortical layers were observed at 90 days postinfection. Intriguingly, partial brain wet weight recovery was observed in mice treated with the antiviral drug ribavirin during the persistent stage of infection. Hence, long-term neurological sequelae might be expected after neonatal enteroviral infections, yet antiviral treatment initiated long after the end of acute infection might limit virus-mediated neuropathology. PMID- 22214842 TI - Dietary supplementation with n-3 PUFA does not promote weight loss when combined with a very-low-energy diet. AB - Obesity is associated with elevated levels of inflammation and metabolic abnormalities which are linked to CVD. The aim of the present study was to investigate whether long-chain n-3 PUFA (LCn-3PUFA), combined with a very-low energy diet (VLED), facilitated weight loss and weight maintenance, and improvements in blood lipids and inflammatory mediators. This was a double-blind, randomised, controlled trial with two parallel groups. For 14 weeks, one group consumed 6 * 1 g capsules/d of monounsaturated oil (placebo group, PB), and the other group consumed 6 * 1 g capsules/d of LCn-3PUFA (fish oil group, FO), each comprising 70 mg EPA and 270 mg DHA. Both groups were on VLED for 4 weeks (n 14 PB, n 18 FO), which was then followed by 10 weeks of weight maintenance (n 12 PB, n 17 FO). Fasting blood samples, anthropometric measurements and 3 d food diaries were collected at baseline, at 4 and 14 weeks. A greater-than-2-fold increase occurred in plasma levels of EPA and DHA in the FO group (P < 0.001). At 4 weeks, the mean weight loss was -6.54 (SD 2.08) kg (-6.9%) for PB and -6.87 (SD 1.83) kg (-7.7%) for FO. At week 14, after the maintenance phase, there was a further mean decrease in weight, -1.57 (SD 3.7) kg (1.85%) for PB and -1.69 (SD 2.32) kg ( 1.9%) for FO. Both groups experienced improved metabolic profiles and there was a significant reduction in fat mass for the FO group at week 14 but not for PB. However, it would appear that supplementation with LCn-3PUFA had no significant effect on weight loss or weight maintenance over the 14 weeks. PMID- 22214843 TI - Teaching an old dog new tricks: potential antiatherothrombotic use for statins. AB - Thrombotic complications represent a highly significant component of morbidity and mortality associated with hypercholesterolemia and atherosclerosis. In this issue of the JCI, Owens et al. report possible mechanisms underlying the prothrombotic, proinflammatory state accompanying hypercholesterolemia. Using rodent, monkey, and human subjects, they show that circulating oxidized LDL and circulating monocyte-derived tissue factor are important instigating factors driving the thrombotic, inflammatory phenotype and, surprisingly, that statin therapy ameliorated the phenotype even in the absence of lowering cholesterol levels. The studies raise the intriguing possibility that therapies directed at pathways generating oxidant stress or pathways involved in transmitting oxidized LDL-mediated signals in circulating platelets and monocytes could have antiatherothrombotic potential, probably with minimal anticoagulant and hemorrhagic potential. PMID- 22214844 TI - Severe dermatitis with loss of epidermal Langerhans cells in human and mouse zinc deficiency. AB - Zinc deficiency can be an inherited disorder, in which case it is known as acrodermatitis enteropathica (AE), or an acquired disorder caused by low dietary intake of zinc. Even though zinc deficiency diminishes cellular and humoral immunity, patients develop immunostimulating skin inflammation. Here, we have demonstrated that despite diminished allergic contact dermatitis in mice fed a zinc-deficient (ZD) diet, irritant contact dermatitis (ICD) in these mice was more severe and prolonged than that in controls. Further, histological examination of ICD lesions in ZD mice revealed subcorneal vacuolization and epidermal pallor, histological features of AE. Consistent with the fact that ATP release from chemically injured keratinocytes serves as a causative mediator of ICD, we found that the severe ICD response in ZD mice was attenuated by local injection of soluble nucleoside triphosphate diphosphohydrolase. In addition, skin tissue from ZD mice with ICD showed increased levels of ATP, as did cultured wild-type keratinocytes treated with chemical irritants and the zinc-chelating reagent TPEN. Interestingly, numbers of epidermal Langerhans cells (LCs), which play a protective role against ATP-mediated inflammatory signals, were decreased in ZD mice as well as samples from ZD patients. These findings suggest that upon exposure to irritants, aberrant ATP release from keratinocytes and impaired LC dependent hydrolysis of nucleotides may be important in the pathogenesis of AE. PMID- 22214845 TI - Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine. AB - Herpes simplex virus type 1 (HSV-1) not only causes painful recurrent oral-labial infections, it can also cause permanent brain damage and blindness. There is currently no HSV-1 vaccine. An effective vaccine must stimulate coordinated T cell responses, but the large size of the genome and the low frequency of HSV-1 specific T cells have hampered the search for the most effective T cell antigens for inclusion in a candidate vaccine. We have now developed what we believe to be novel methods to efficiently generate a genome-wide map of the responsiveness of HSV-1-specific T cells, and demonstrate the applicability of these methods to a second complex microbe, vaccinia virus. We used cross-presentation and CD137 activation-based FACS to enrich for polyclonal CD8+ T effector T cells. The HSV-1 proteome was prepared in a flexible format for analyzing both CD8+ and CD4+ T cells from study participants. Scans with participant-specific panels of artificial APCs identified an oligospecific response in each individual. Parallel CD137-based CD4+ T cell research showed discrete oligospecific recognition of HSV 1 antigens. Unexpectedly, the two HSV-1 proteins not previously considered as vaccine candidates elicited both CD8+ and CD4+ T cell responses in most HSV-1 infected individuals. In this era of microbial genomics, our methods - also demonstrated in principle for vaccinia virus for both CD8+ and CD4+ T cells - should be broadly applicable to the selection of T cell antigens for inclusion in candidate vaccines for many pathogens. PMID- 22214846 TI - Pivotal role of the CCL5/CCR5 interaction for recruitment of endothelial progenitor cells in mouse wound healing. AB - BM-derived endothelial progenitor cells (EPCs) are critical and essential for neovascularization in tissue repair and tumorigenesis. EPCs migrate from BM to tissues via the bloodstream, but specific chemotactic cues have not been identified. Here we show in mice that the absence of CCR5 reduced vascular EPC accumulation and neovascularization, but not macrophage recruitment, and eventually delayed healing in wounded skin. When transferred into Ccr5-/- mice, Ccr5+/+ BM cells, but not Ccr5-/- cells, accumulated in the wound site, were incorporated into the vasculature, and restored normal neovascularization. Consistent with these observations, CCL5 induced in vitro EPC migration in a CCR5 dependent manner. Moreover, expression of VEGF and TGF-beta was substantially diminished at wound sites in Ccr5-/- mice, which suggests that EPCs are important not only as the progenitors of endothelial cells, but also as the source of growth factors during tissue repair. Taken together, these data identify the CCL5/CCR5 interaction as what we believe to be a novel molecular target for modulation of neovascularization and eventual tissue repair. PMID- 22214847 TI - CBX7 is a tumor suppressor in mice and humans. AB - The CBX7 gene encodes a polycomb group protein that is known to be downregulated in many types of human cancers, although the role of this protein in carcinogenesis remains unclear. To shed light on this issue, we generated mice null for Cbx7. Mouse embryonic fibroblasts derived from these mice had a higher growth rate and reduced susceptibility to senescence compared with their WT counterparts. This was associated with upregulated expression of multiple cell cycle components, including cyclin E, which is known to play a key role in lung carcinogenesis in humans. Adult Cbx7-KO mice developed liver and lung adenomas and carcinomas. In in vivo and in vitro experiments, we demonstrated that CBX7 bound to the CCNE1 promoter in a complex that included HDAC2 and negatively regulated CCNE1 expression. Finally, we found that the lack of CBX7 protein expression in human lung carcinomas correlated with CCNE1 overexpression. These data suggest that CBX7 is a tumor suppressor and that its loss plays a key role in the pathogenesis of cancer. PMID- 22214848 TI - Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia. AB - Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder. Patients have episodes that last 1 to 4 hours and are precipitated by alcohol, coffee, and stress. Previous research has shown that mutations in an uncharacterized gene on chromosome 2q33-q35 (which is termed PNKD) are responsible for PNKD. Here, we report the generation of antibodies specific for the PNKD protein and show that it is widely expressed in the mouse brain, exclusively in neurons. One PNKD isoform is a membrane-associated protein. Transgenic mice carrying mutations in the mouse Pnkd locus equivalent to those found in patients with PNKD recapitulated the human PNKD phenotype. Staining for c-fos demonstrated that administration of alcohol or caffeine induced neuronal activity in the basal ganglia in these mice. They also showed nigrostriatal neurotransmission deficits that were manifested by reduced extracellular dopamine levels in the striatum and a proportional increase of dopamine release in response to caffeine and ethanol treatment. These findings support the hypothesis that the PNKD protein functions to modulate striatal neuro-transmitter release in response to stress and other precipitating factors. PMID- 22214849 TI - An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. AB - Mutations in the gene encoding the p110alpha subunit of PI3K (PIK3CA) that result in enhanced PI3K activity are frequently observed in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis, we generated mice in which a PIK3CA mutation commonly detected in human cancers (the H1047R mutation) could be conditionally knocked into the endogenous Pik3ca locus. Activation of this mutation in the mouse ovary revealed that alone, Pik3caH1047R induced premalignant hyperplasia of the ovarian surface epithelium but no tumors. Concomitantly, we analyzed several human ovarian cancers and found PIK3CA mutations coexistent with KRAS and/or PTEN mutations, raising the possibility that a secondary defect in a co-regulator of PI3K activity may be required for mutant PIK3CA to promote transformation. Consistent with this notion, we found that Pik3caH1047R mutation plus Pten deletion in the mouse ovary led to the development of ovarian serous adenocarcinomas and granulosa cell tumors. Both mutational events were required for early, robust Akt activation. Pharmacological inhibition of PI3K/mTOR in these mice delayed tumor growth and prolonged survival. These results demonstrate that the Pik3caH1047R mutation with loss of Pten is enough to promote ovarian cell transformation and that we have developed a model system for studying possible therapies. PMID- 22214850 TI - Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin. AB - Hypercholesterolemia is a major risk factor for atherosclerosis. It also is associated with platelet hyperactivity, which increases morbidity and mortality from cardiovascular disease. However, the mechanisms by which hypercholesterolemia produces a procoagulant state remain undefined. Atherosclerosis is associated with accumulation of oxidized lipoproteins within atherosclerotic lesions. Small quantities of oxidized lipoproteins are also present in the circulation of patients with coronary artery disease. We therefore hypothesized that hypercholesterolemia leads to elevated levels of oxidized LDL (oxLDL) in plasma and that this induces expression of the procoagulant protein tissue factor (TF) in monocytes. In support of this hypothesis, we report here that oxLDL induced TF expression in human monocytic cells and monocytes. In addition, patients with familial hypercholesterolemia had elevated levels of plasma microparticle (MP) TF activity. Furthermore, a high-fat diet induced a time-dependent increase in plasma MP TF activity and activation of coagulation in both LDL receptor-deficient mice and African green monkeys. Genetic deficiency of TF in bone marrow cells reduced coagulation in hypercholesterolemic mice, consistent with a major role for monocyte-derived TF in the activation of coagulation. Similarly, a deficiency of either TLR4 or TLR6 reduced levels of MP TF activity. Simvastatin treatment of hypercholesterolemic mice and monkeys reduced oxLDL, monocyte TF expression, MP TF activity, activation of coagulation, and inflammation, without affecting total cholesterol levels. Our results suggest that the prothrombotic state associated with hypercholesterolemia is caused by oxLDL-mediated induction of TF expression in monocytes via engagement of a TLR4/TLR6 complex. PMID- 22214851 TI - Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression. AB - Increased expression of the regulatory subunit of HIFs (HIF-1alpha or HIF-2alpha) is associated with metabolic adaptation, angiogenesis, and tumor progression. Understanding how HIFs are regulated is of intense interest. Intriguingly, the molecular mechanisms that link mitochondrial function with the HIF-regulated response to hypoxia remain to be unraveled. Here we describe what we believe to be novel functions of the human gene CHCHD4 in this context. We found that CHCHD4 encodes 2 alternatively spliced, differentially expressed isoforms (CHCHD4.1 and CHCHD4.2). CHCHD4.1 is identical to MIA40, the homolog of yeast Mia40, a key component of the mitochondrial disulfide relay system that regulates electron transfer to cytochrome c. Further analysis revealed that CHCHD4 proteins contain an evolutionarily conserved coiled-coil-helix-coiled-coil-helix (CHCH) domain important for mitochondrial localization. Modulation of CHCHD4 protein expression in tumor cells regulated cellular oxygen consumption rate and metabolism. Targeting CHCHD4 expression blocked HIF-1alpha induction and function in hypoxia and resulted in inhibition of tumor growth and angiogenesis in vivo. Overexpression of CHCHD4 proteins in tumor cells enhanced HIF-1alpha protein stabilization in hypoxic conditions, an effect insensitive to antioxidant treatment. In human cancers, increased CHCHD4 expression was found to correlate with the hypoxia gene expression signature, increasing tumor grade, and reduced patient survival. Thus, our study identifies a mitochondrial mechanism that is critical for regulating the hypoxic response in tumors. PMID- 22214852 TI - Editorial position on publishing articles on human organ transplantation. AB - The practice of transplanting organs from executed prisoners in China appears to be widespread. We vigorously condemn this practice and, effective immediately, will not consider manuscripts on human organ transplantation for publication unless appropriate non-coerced consent of the donor is provided and substantiated. PMID- 22214854 TI - Comparison of vacancy and antisite defects in GaAs and InGaAs through hybrid functionals. AB - The formation energies and charge transition levels of vacancy and antisite defects in GaAs and In(0.5)Ga(0.5)As are calculated through hybrid density functionals. In As-rich conditions, the As antisite is the most stable defect in both GaAs and InGaAs, except for n-type GaAs for which the Ga vacancy is favored. The Ga antisite shows the lowest formation energy in Ga-rich conditions. The As antisite provides a consistent interpretation of the defect densities measured at mid-gap for both GaAs/oxide and InGaAs/oxide interfaces. PMID- 22214853 TI - Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. AB - The hormone glucagon has long been dismissed as a minor contributor to metabolic disease. Here we propose that glucagon excess, rather than insulin deficiency, is the sine qua non of diabetes. We base this on the following evidence: (a) glucagon increases hepatic glucose and ketone production, catabolic features present in insulin deficiency; (b) hyperglucagonemia is present in every form of poorly controlled diabetes; (c) the glucagon suppressors leptin and somatostatin suppress all catabolic manifestations of diabetes during total insulin deficiency; (d) total beta cell destruction in glucagon receptor-null mice does not cause diabetes; and (e) perfusion of normal pancreas with anti-insulin serum causes marked hyperglucagonemia. From this and other evidence, we conclude that glucose-responsive beta cells normally regulate juxtaposed alpha cells and that without intraislet insulin, unregulated alpha cells hypersecrete glucagon, which directly causes the symptoms of diabetes. This indicates that glucagon suppression or inactivation may provide therapeutic advantages over insulin monotherapy. PMID- 22214855 TI - Composite B-cell and T-cell lineage post-transplant lymphoproliferative disorder of the lung with unusual cutaneous manifestations of mycosis fungoides. AB - We present the case of a 17-year-old male kidney transplant recipient who presented initially with dermatologic symptoms and was found to have histologic changes in the skin that were consistent with mycosis fungoides. Shortly after this diagnosis was made, imaging studies demonstrated multifocal interstitial and airspace consolidation in both lungs. Physical examination revealed no lymphadenopathy or hepatosplenomegaly, but an open lung biopsy revealed an Epstein-Barr virus (EBV)-negative monomorphic T-cell posttransplant lymphoproliferative disorder (PTLD) with a concomitant EBV-positive B-cell PTLD involving the same lesion of the lung. Polymerase chain reaction analysis demonstrated clonal T-cell receptor gene rearrangements in both the skin and the lung biopsies. Interestingly, 1 clone was shared between the skin and lung while a second clone was present only in the lung. To our knowledge, this is the first reported case of a PTLD presenting in the skin in which there was a subsequent discovery of composite, bilineal B- and T-cell PTLD of the lung. PMID- 22214856 TI - Long-term immunosuppressive therapy with cyclosporine plus prednisolone for necrotizing meningoencephalitis in a Pekingese dog. AB - A 4-year-old intact female Pekingese dog was presented with ataxia and seizure episodes. Based on magnetic resonance imaging and cerebrospinal fluid analysis results, meningoencephalitis of unknown etiology was suspected. The present case survived for 1,096 days under cyclosporine plus prednisolone therapy and was definitively diagnosed with necrotizing meningoencephalitis. This report describes the clinical findings, serial magnetic resonance imaging characteristics and pathologic features of a necrotizing meningoencephalitis and long-term survival after cyclosporine with prednisolone therapy. PMID- 22214857 TI - Evaluation of recombinant 28 kDa outer membrane protein of Brucella abortus for the clinical diagnosis of bovine brucellosis in Korea. AB - Brucella spp. are Gram-negative, facultative, intracellular coccobacilli that are pathogenic to a variety of mammals, including ruminants and humans. The conventional serological test for diagnosing brucellosis in cattle in Korea is the standard tube agglutination test. However, agglutination tests sometimes give false-positive results due to cross-reactions with other pathogens. The outer membrane proteins of Brucella species have been extensively studied for their immunogenicity and serodiagnostic applications. However, an application of B. abortus OMPs for serodiagnosis has not been successfully established. In this study, cloning and expression of B. abortus Omp28, a group 3 antigen, were accomplished by PCR amplification cloning into a pMAL expression system, and purification of a recombinant Omp28 (rOmp28). The immunogenicity of rOmp28 was confirmed by Western blot analysis with Brucella-positive bovine serum. To determine whether rOmp2 has a potential benefit for use in the serodiagnosis of bovine brucellosis, rOmp28-based ELISA and latex bead agglutination test were performed. B. abortus positive (n=122) or negative (n=88) from TAT were positive (118/122, 96.7%) or negative (84/88, 95.4%) in ELISA and were positive (94/122, 77%) or negative (71/88, 81.7%) in that the latex bead agglutination test, respectively. The sensitivity, specificity and accuracy were 96.7, 95.4, 96.2% in ELISA and 77, 80.6, 78.5% in latex bead agglutination test, respectively. These findings suggest that the rOmp28 of B. abortus might be a good candidate for developing serological diagnostic tools for bovine brucellosis. PMID- 22214858 TI - GH-producing mammary tumors in two dogs with acromegaly. AB - Two intact female dogs were admitted for growing mammary tumors. They had symptoms of acromegaly including weight gain, enlargement of the head, excessive skin folds, and inspiratory stridor. Serum concentrations of growth hormone (GH), insulin-like growth factor-I (IGF-I), and insulin were elevated in the two cases. From these findings, both dogs were diagnosed with acromegaly. In case 1, the GH, IGF-I, and insulin levels subsided after removal of the focal benign mammary tumors and ovariohysterectomy. In case 2, those levels subsided after removal of only focal mammary carcinoma. In both cases, immunohistochemical investigations for GH were positive in the mammary tumor cells but not in the normal mammary glands. We concluded that GH-producing mammary tumors caused the present acromegaly. PMID- 22214860 TI - Deep granulomatous dermatitis of the fin caused by Fusarium solani in a false killer whale (Pseudorca crassidens). AB - A 10-year-old female false killer whale (Pseudorca crassidens) developed skin lesions in the left breast fin. Histopathologically, the lesions consisted of multiple granulomas spread diffusely into the deep dermis and bone; characteristically, each granuloma had septate, branching fungal hyphae and chlamydospores surrounded by eosinophilic Splendore-Hoeppli materials. Macrophages, epithelioid cells and multinucleated giant cells in the granulomas reacted mainly to anti-SRA-E5 antibody against human macrophage scavenger receptor type I. Fusarium solani was isolated and its gene was detected from the skin samples. Mycotic skin lesions by Fusarium spp. reported so far in marine mammals were regarded as superficial dermatitis; therefore, the present case is very uncommon in that the lesions spread deeper into the skin. PMID- 22214859 TI - Ehrlichia canis infection in two dogs that emigrated from endemic areas. AB - Two dogs, emigrated from Zambia and China to Japan, were diagnosed with Ehrlichia canis infection. Both cases had thrombocytopenia, non-regenerative anemia, and hypergloblinemia with polyclonal gammopathy. Case 1 had ataxia of the hind limbs. Severe meningitis was revealed by magnetic resonance imaging examination. Intracytoplasmic inclusions were observed in mononuclear cells of cerebrospinal fluid. Case 2 had a history of bilateral epistaxis, and severe pancytopenia was noticed in complete blood count. Diagnosis was finally achieved by nested polymerase chain reaction and sequence analysis. Thus, even in non-endemic areas, E. canis infection should be included in the differential diagnosis of clinically ill dogs that emigrated from endemic areas. PMID- 22214861 TI - Therapeutic efficacy of ABT-737, a Bcl-2 inhibitor, in a canine melanoma cell line. AB - The small molecule inhibitor, ABT-737, inhibits Bcl-2 that is overexpressed in many tumor cell lines and, in combination with an anticancer drug, can strongly enhance proapoptotic activity. In the present study, we evaluated the inhibitory activity of ABT-737 on the survival of a canine melanoma cell line (MCM-N1). MCM N1 cell viability was decreased following 24- and 48-hr culture with ABT-737, depending on ABT-737 concentration, while cell viability was unchanged in controls. ABT-737 synergized with carboplatin to promote cell death. Notably, approximately 50% of MCM-N1 cells survived following culture with 2-4 ug/ml of carboplatin; whereas, less than 20% of MCM-N1 cells survived following culture with ABT-737 (1 mM) plus carboplatin (2-10 ug/ml). PMID- 22214862 TI - Epitope mapping of a monoclonal antibody against the Gp85 of avian leukosis virus subgroup J. AB - Avian leukosis virus subgroup J poses a great threat to the poultry industry in China. To reduce the economic losses, a quick method for detection of ALV-J antigen is required for diagnosis and identification of the congenitally transmitting hens. In this study, we report the production and evaluation of one monoclonal antibody (MAb) suitable for achieving these goals. The gp85 gene of avian leukosis virus subgroup J CAUHM01 China isolates was subcloned into the expression vectors pGEX-6p-1 and pET28a and successfully expressed in E. coli. After immunizing BALB/c mice with recombinant His-Jgp85 protein, splenic cells from immunized mice were fused with SP2/0 myeloma cells to produce hybridomas. We isolated and characterized one ALV-J gp85-specific MAb by determining its titer, affinity and IgG subclass. In addition, we performed epitope mapping and determined the epitope for the MAb 1E3 to be 81-92 aa of ALV-J gp85 protein (LPWDPQELDILG). Bioinformatics analysis and IFA studies revealed that this epitope is conserved among all ALV-J isolates and that this antibody could serve as a useful reagent for ALV-J detection and diagnosis. PMID- 22214863 TI - A case report of traumatic neuroma of the cervical spinal cord in a dog. AB - Traumatic neuroma of the cervical spinal cord was diagnosed in a 14-year-old male mixed-breed dog. A gross view showed two intradural extramedullary masses, measuring 1 and 0.6 cm in length and 0.7 and 0.4 cm in diameter, attached to the left side of the spinal cord at the level of the sixth and seventh cervical vertebrae. Microscopically, the cervical spinal masses comprised interlacing fascicles of axons and Schwann cells surrounded by collagenous stroma. Immunohistochemically, the fascicles were stained positively for neurofilament and S-100 proteins. Ultrastructurally, variably sized myelinated fibers and onion bulb-like structures were observed. To our knowledge, this is the first report of a traumatic neuroma in the cervical spinal cord of a dog. PMID- 22214864 TI - An outbreak of canine distemper virus in tigers (Panthera tigris): possible transmission from wild animals to zoo animals. AB - Canine distemper virus (CDV), a morbillivirus that causes one of the most contagious and lethal viral diseases known in canids, has an expanding host range, including wild animals. Since December 2009, several dead or dying wild raccoon dogs (Nyctereutes procyonoides) were found in and around one safari-style zoo in Japan, and CDV was isolated from four of these animals. In the subsequent months (January to February 2010), 12 tigers (Panthera tigris) in the zoo developed respiratory and gastrointestinal diseases, and CDV RNA was detected in fecal samples of the examined tigers. In March 2010, one of the tigers developed a neurological disorder and died; CDV was isolated from the lung of this animal. Sequence analysis of the complete hemagglutinin (H) gene and the signal peptide region of the fusion (F) gene showed high homology among these isolates (99.8 100%), indicating that CDV might have been transmitted from raccoon dog to tiger. In addition, these isolates belonged to genotype Asia-1 and had lower homology (<90%) to the vaccine strain (Onderstepoort). Seropositivity of lions (Panthera leo) in the zoo and wild bears (Ursus thibetanus) captured around this area supported the theory that a CDV epidemic had occurred in many mammal species in and around the zoo. These results indicate a risk of CDV transmission among many animal species, including large felids and endangered species. PMID- 22214865 TI - Inhibitory effects of pentosan polysulfate sodium on MAP-kinase pathway and NF kappaB nuclear translocation in canine chondrocytes in vitro. AB - Pentosan polysulfate sodium (PPS) has a heparin-like structure and is purificated from the plant of European beech wood. PPS has been used for the treatment of interstitial cystitis for human patients. Recent years, it was newly recognised that PPS reduce pain and inflammation of OA. The molecular biological mechanism of PPS to express its clinical effects is not fully understood. The purpose of the present study is to investigate a mechanism of action of PPS on inflammatory reaction of chondrocytes in vitro. It was evaluated that effects of PPS on interleukin (IL)-1beta-induced phosphorylation of mitogen-actiated protein kinases (MAPKs), such as p38, extracellular signal-regulated kinase (ERK) and c Jun N-terminal kinase (JNK), nuclear translocation of nuclear factor-kappa B (NF kappaB), and matrix metalloproteinase (MMP)-3 production in cultured articular chondrocytes. As a result, in the presence of PPS existence, IL-1beta-induced phosphorylation of p38 and ERK were certainly inhibited, while JNK phosphorylation was not affected. Nuclear translocation of NF-kappaB and MMP-3 production were suppressed by PPS pretreatment prior to IL-1beta stimulation. In conclusion, it is strongly suggested that PPS treatment prevents inflammatory intracellular responses induced by IL-1 beta through inhibition of phosphorylation of certain MAPKs, p38 and ERK and then nuclear translocation of NF-kappaB in cultured chondrocytes. These PPS properties may contribute to suppressive consequence of catabolic MMP-3 synthesis. These data might translate the clinical efficacy as PPS treatment could inhibit the cartilage catabolism and related clinical symptoms of OA in dogs. PMID- 22214866 TI - A moderate decline in U937 cell GSH levels triggers PI3 kinase/Akt-dependent Bad phosphorylation, thereby preventing an otherwise prompt apoptotic response. AB - We report that a moderate decline in GSH levels causes remarkable changes in Bad sub-cellular localization. An about 30% reduction of the GSH pool, regardless of whether mediated by diamide or DL-buthionine-[S,R]-sulfoximine, indeed promoted loss of the fraction of Bad normally associated with the mitochondria of untreated U937 cells via a phosphatidylinositol 3-kinase (PI3K)-dependent mechanism. Interestingly, inhibition of this pathway was associated with an unexpected delayed lethal response, preceded by the translocation and enforced accumulation of Bad and Bax in the mitochondrial compartment, prevented by inhibitors of mitochondrial permeability transition and characterized by morphological and biochemical features of apoptosis. Collectively, the results herein presented demonstrate that mild redox imbalance associated with a slight reduction of the GSH pool commits U937 cells to apoptosis, however prevented by events leading to PI3K/Akt-dependent mitochondrial loss of Bad. PMID- 22214868 TI - Involuntary psychiatric treatment in modern Greece. PMID- 22214867 TI - Preventive and therapeutic effects of oleuropein against carbon tetrachloride induced liver damage in mice. AB - Olives and olive products, an inevitable part of the Mediterranean diet, possess various beneficial effects, such as a decreased risk of cardiovascular disease and cancer. Oleuropein is a non-toxic secoiridoid found in the leaves and fruits of olive (Olea europaea L.). In this study, we have investigated the hepatoprotective activity of oleuropein in carbon tetrachloride (CCl(4))-induced liver injury in male BALB/cN mice. Oleuropein in doses of 100 and 200mg/kg was administered intraperitoneally (ip) once daily for 3 consecutive days, prior to CCl(4) administration (the preventive treatment), or once daily for 2 consecutive days 6h after CCl(4) intoxication (the curative treatment). CCl(4) intoxication resulted in a massive hepatic necrosis and increased plasma transaminases. Liver injury was associated with oxidative/nitrosative stress evidenced by increased nitrotyrosine formation as well as a significant decrease in superoxide dismutase activity and glutathione levels. CCl(4) administration triggered inflammatory response in mice livers by inducing expression of nuclear factor-kappaB, which coincided with the induction of tumor necrosis factor-alpha, cyclooxygenase-2 and inducible nitric oxide synthase. In both treatment protocols, oleuropein significantly attenuated oxidative/nitrosative stress and inflammatory response and improved histological and plasma markers of liver damage. Additionally, in the curative regimen, oleuropein prevented tumor necrosis factor-beta1-mediated activation of hepatic stellate cells, as well as the activation of caspase-3. The hepatoprotective activity of oleuropein was, at least in part, achieved through the NF-E2-related factor 2-mediated induction of heme oxygenase-1. The present study demonstrates antioxidant, anti-inflammatory, antiapoptotic, and antifibrotic activity of oleuropein, with more pronounced therapeutic than prophylactic effects. PMID- 22214869 TI - [The role of immune system in depression]. AB - Although there are many papers which examine the role of immune system in the pathophysiology of depression, it is not clear the relationship between depression and immune system. It seems that inflammation is strongly related with depression. Proinflammatory cytokines play crucial role in thepresence of depression. Administration of proinflammatory cytokines to treat medical diseases induce depressive symptoms in humans. Patients diagnosed with depression tend to have high levels of cytokine activity and impaired immune response, as well as those patients suffering from inflammatory processes. Proinflammatory cytokines interfere with the body's feedback loop to reduce circulating corticosteroids during the stress response. Proinflammatory cytokines may also diminish neurotrophic support and monoamine neurotransmission that can lead to neuronal apoptosis and glial damage. This happens because cytokines cause reduction of the levels of brain derived neurotrophic factor (BDNF), which is the primary neurotrophin of the hippocampus. They also induce the enzyme indoleamine 2,3 dioxygenase (IDO), which breaks down tryptophan, the primary amino acid precursor of serotonin, into kynurenine. Consequently, serotonin is reduced in the brain. Stress, which can precipitate depression, can also promote inflammatory responses through effects on sympathetic and parasympathetic nervous system pathways. The antidepressant drugs reduce the serum levels of proinflammatory cytokines. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Except from cytokines, there are other factors of immune system which play crucial role in the pathogenesis of depression. These factors include free radicals of oxygen, the balance between omega3and omega6 lipid acids, the increased levels of positive acute phase proteins and the reduction of negative acute phase proteins. The research in the domain of psychoneuroimmunology suggest that targeting proinflammatory cytokines and their signaling pathways might represent a novel strategy to treat depression. PMID- 22214870 TI - [Intellectual representations and brain]. AB - The present paper aims at presenting and discussing a naturalistic version of the representational- computational theory of mind (r-c.t.m.). In this paper the term "mind" refers to any complex system whose outputs (behaviours) are characterized by reasonability and intentionality. According to the r-c.t.m., the human brain is a mind continuously creating and containing representations of objects in two forms: image - like and proposition - like representations. Brain representations per se, may be largely distributed functional webs of neurons; each web, as a whole, is either in a state of activation or in a certain degree of readiness for activation. The brain representations are constantly composed from simpler ones, via the recursive engagement of a finite number of programs, either innate or created through learning mechanisms. Concerning proposition - like representations there may be programs that classify the representations of linguistic objects (i.e. words, phrases) into lexical or syntactical categories and combine them according to grammatical patterns. In the present text, some indices (psychological, neuroscientific, from the domain of linguistics and artificial intelligence) are presented that are supportive of the r-c.t.m.; furthermore some weak points of this theory are discussed along with some alternative views concerning the representational activity of the brain. PMID- 22214871 TI - [The role of family and socio-cultural factors in the development of eating disorders]. AB - A great number of publications in the international literature have revealed the possible part of biological factors in eating disorders and as well as characteristics of the patients' personality that favour or contribute in the development of these disorders. The research in etiology, however, includes the examination of family and socio-cultural factors. The aim of the present paper was to concentrate bibliographic data related to the family and socio-cultural factors that form the conditions under which anorexia nervosa and bulimia nervosa develop, excluding articles about binge-eating disorder. Articles from 1995 to 2005 were included through search in the files of the electronic database Medline (PubMed) on terms of inventory (MESH) for both disorders. About the role of the family environment, it was found that the factors studied more were family dysfunction, overprotection and sexual or physical abuse. As for the socio cultural factors it is not perfectly clear whether the western standards of life are linked to the development of these disorders or if there is simply a lack of culturally sensitive instruments to detect these disorders in their different possible forms in the non-western world. An important finding is that there are not enough researches to show clearly any negative part played by the mass media. PMID- 22214872 TI - [Reliability and validity of the Greek version of the Alcohol Use Disorders Identification Test (AUDIT)]. AB - Problems associated with alcohol abuse are recognised by the World Health Organization as a major health issue. Because of the size and severity of the problem, early detection is very important.This requires easy to use and specific tools. One of these is the Alcohol Use Disorders IdentificationTest (AUDIT). AUDIT was translated and back-translated from its original language by two Englishspeaking psychiatrists. The tool contains 10 questions. A score >=11 is an indication of serious abuse/dependence. In the study, 218 subjects took part: 128 were males and 90 females. From the218 individuals, 109 fulfilled the criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), and presented requesting admission; 109 subjects were healthy controls. Internal reliability (Cronbach a) was 0.80 for the controls and0.80 for the alcohol dependent individuals. Controls had significantly lower average scores when compared to the alcoholics. The questionnaire's sensitivity for scores >8 was 0.98 and its specificity was 0.94 for the same score. Iotan conclusion, the Greek version of AUDIT has increased internalreliability and validity and is easy to use and can be very useful in detection alcohol problems in sensitive populations. PMID- 22214873 TI - [The influence of Mozart's and Beethoven's music on reverse mnemonic recall tasks]. AB - The aim of this paper is to investigate one of the most well-known phenomena in the field of music psychology: the influence of Mozart's music (Mozart effect). Today the Mozart effect is generally related to every kind of short-term or long term positive influence of music on men and animals. Here it is examined in relation to cognitive tasks and par ticularly in relation to reverse mnemonic recall tasks. Twenty-four volunteers, aged 50-55 participated in all 3 ten-minute conditions of the experiment which were Mozart's Allegro con spirito K.448, Beethoven's Rondo-Allegro opus 61 and ten minutes of silence without any recorded acoustic stimulus. The individuals were randomly separated in six groups. The examination material were three improvised groups of series consisted of one-digit numbers from 2 to 9 digits, which were read in a rate of one digit per second. Results indicated that the majority of the participants did not show any increase in the number of digits that they could recall due to the listening of Mozart's piece. Also, no statistically significant difference was found between the three conditions associated with listening to a morphologically similar excerpt by Beethoven. What was however found was that individuals who strongly preferred the Mozart condition scored better than the others (p=0,005). Finally, it seems that participants who had attended even basic music studies remembered more digits in all three conditions of the experiment than the others who had never studied music before (p=0,000). PMID- 22214874 TI - [Depression in schizophrenia: diagnosis, epidemiology, predisposing factors]. AB - The observation and debates concerning the coexistence of depression and schizophrenia date back to Kraepelin and Bleuler. Both recognized that among the basic symptoms of 'dementia praecox' and "schizophrenia", are the flattening of affect and the depressed affect and both included in their clinical descriptions of schizophrenia the depressive symptoms. During the recent years this observation has been made official, with the inclusion of diagnoses like schizoaffective psychosis as well as the post psychotic or post schizophrenic depression in the international disease categorization systems DSM and ICD. Several theories have been proposed to explain the relation of depression and schizophrenia, especially when there both appear simultaneously in the same patient. Depression can be present during the prepsychotic prodromal phase, during the acute phase or after the remission of the psychotic features. In addition depressive symptoms could be part of the clinical picture of chronic stabilized patients. Depression in schizophrenia is defined in different ways, i.e. through the criteria of DSM and ICD, through the relevant items of psychopathological scales or through the total rating of depression scales if the score exceeds a certain cut-off. Since the existing depression scales have been created to evaluate depressed patients and therefore there were questions of validity of their use in schizophrenic patients, recently it has been proposed a special scale to evaluate depression specifically in schizophrenic patients (Calgary Depression Scale for Schizophrenia). This scale has been standardized in a Greek sample. In general, according to the existing studies 7-70% of all schizophrenic patients suffer from some form of clinically relevant depression and the median frequency from all the available studies is 25%. The frequency of depression in new schizophrenic patients is 21-24% during the acute phase and it seems that this frequency progressively decreases with the time and stabilizes around 8% in remitted patients. These frequencies may vary upwards depending on the definition of depression. One in four schizophrenic patients with depression presents with suicide ideation and therefore requires appropriate identification and management. As far as predisposing factors for the appearance of depression concerns, the existing data are inadequate and contradictory to extract safe conclusions and therefore further research is in line. PMID- 22214875 TI - Downscaling climate models: sharpening the focus on local-level changes. PMID- 22214876 TI - Local health departments: time of challenge and change. PMID- 22214877 TI - Novel approach to the fabrication of Au/silica core-shell nanostructures based on nanosecond laser irradiation of thin Au films on Si. AB - We demonstrate the possibility of producing Au/SiO(2) core-shell nanoparticles by nanosecond laser irradiation of thin (5 and 20 nm) Au films on Si. The Au/Si eutectic reaction and dewetting process caused by the fast melting and solidification dynamics induced by the nanosecond laser irradiations are investigated as the origin of the formation of core-shell nanoparticles. Using several microscopic techniques (Rutherford backscattering spectrometry, scanning electron microscopy, atomic force microscopy, transmission electron microscopy, and energy filtered transmission electron microscopy) the formation and evolution of the core-shell structures are investigated as a function of the laser fluence in the 500-1500 mJ cm(-2) range for both film thicknesses. In particular, the mean height and diameter and surface density evolution of the core-shell structures are quantified and correlated to the laser fluence and Au film thickness. PMID- 22214878 TI - Myofibroblasts in the infarct area: concepts and challenges. AB - Myofibroblasts are differentiated fibroblasts that hold a key role in wound healing and remodeling following myocardial infarction (MI). A large repertoire of stimuli, such as mechanical stretch, growth factors, cytokines, and vasoactive peptides, induces myofibroblast differentiation. Myofibroblasts are responsible for the production and deposition of collagen, leading to the establishment of a dense extracellular matrix that strengthens the infarcted tissue and minimizes dilatation of the infarct area. In addition, cells contributing to fibrosis act on sites distal from the infarct area and promote collagen deposition in noninfarcted tissue, thus contributing to adverse remodeling and consequently to the development of congestive heart failure (CHF). Current drugs that are used to treat post-MI CHF do influence fibroblasts and myofibroblasts; however, their therapeutic efficacy is far from being regarded as ideal. Novel therapeutic agents targeting (myo)fibroblasts are being developed to successfully prevent the cardiac remodeling of sites remote from the infarct area and therefore hinder the establishment of CHF. The purpose of this review article is to discuss the basic concepts of the myofibroblasts' actions in cardiac wound healing processes, factors that influence them, currently available pharmacological agents, and future challenges in this area. PMID- 22214879 TI - Electrophysiological measurements and analysis of nociception in human infants. AB - Pain is an unpleasant sensory and emotional experience. Since infants cannot verbally report their experiences, current methods of pain assessment are based on behavioural and physiological body reactions, such as crying, body movements or changes in facial expression. While these measures demonstrate that infants mount a response following noxious stimulation, they are limited: they are based on activation of subcortical somatic and autonomic motor pathways that may not be reliably linked to central sensory processing in the brain. Knowledge of how the central nervous system responds to noxious events could provide an insight to how nociceptive information and pain is processed in newborns. The heel lancing procedure used to extract blood from hospitalised infants offers a unique opportunity to study pain in infancy. In this video we describe how electroencephalography (EEG) and electromyography (EMG) time-locked to this procedure can be used to investigate nociceptive activity in the brain and spinal cord. This integrative approach to the measurement of infant pain has the potential to pave the way for an effective and sensitive clinical measurement tool. PMID- 22214880 TI - Affinity analysis of DNA aptamer-peptide interactions using gold nanoparticles. AB - Gold nanoparticles (AuNPs) were used as colorimetric probe and fluorescence quencher for affinity analysis of DNA aptamers toward their target mucin 1 (MUC1) peptide. Single-stranded DNA (ssDNA) aptamer-coated AuNPs showed increased stability (i.e., more resistant to aggregation induced by NaCl) in the presence of their target peptide due to the increase in steric protection conferred by the ssDNA-peptide complexes formed on the AuNPs. Based on changes in the UV-vis extinction spectrum of AuNPs (a measure of AuNPs aggregation) and fluorescence restoration of CY5-ssDNA upon ssDNA-peptide complex formation, the formation of the complexes and ssDNA sequence-dependent dissociation constant (K(d)) were determined. Besides the UV-vis and fluorescence measurements, the hydrodynamic diameters, zeta potential measurements, and transmission electron microscopy (TEM) images of AuNPs after various coatings supported the assay principle. The methodology presented herein provides a rapid and sensitive alternative solution for the identification of high affinity binders from systematic evolution of ligands by exponential enrichment (SELEX). PMID- 22214881 TI - A solid phase assay for topoisomerase I interfacial poisons and catalytic inhibitors. AB - We report a mechanism-based screening technique to rapidly identify eukaryotic topoisomerase I targeting agents. The method is based on genetic tagging of topoisomerase I to immobilize the enzyme on a solid surface in a microtiter well format. DNA is added to the wells, and retained DNA is detected by Pico Green fluorescence. Compounds that result in an increase in Pico Green staining represent potential topoisomerase interfacial poisons, whereas those that reduce fluorescence report catalytic inhibitors; therefore, the solid phase assay represents a "bimodal" readout that reveals mechanisms of action. The method has been demonstrated to work with known interfacial poisons and catalytic inhibitors. This method is rapid, robust, economical, and scalable for large library screens. PMID- 22214882 TI - Mammary gene expression and activity of antioxidant enzymes and concentration of the mammalian lignan enterolactone in milk and plasma of dairy cows fed flax lignans and infused with flax oil in the abomasum. AB - The objectives of the study were to investigate the effects of dietary supplementation of flax hulls and/or flax oil on the activity of antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX)) in plasma and the mammary gland and the relative mRNA abundance of antioxidant genes in the mammary gland of dairy cows. A total of eight dairy cows were used in a replicated 4 * 4 Latin square design. There were four treatments: control with no flax hulls (CONT), 9.88% flax hulls in the DM (HULL), control with 500 g flax oil/d infused in the abomasum (COFO), 9.88% flax hulls in the DM and 500 g flax oil/d infused in the abomasum (HUFO). Plasma GPX activity tended to decrease with flax oil supplementation. Cows fed HULL had higher levels of CAT, GPX1 and SOD1 mRNA in the mammary gland and lower mRNA abundance of GPX3, SOD2 and SOD3 compared with those fed CONT. Abundance of CAT, GPX1, GPX3, SOD2 and SOD3 mRNA was down-regulated in the mammary gland of cows fed HUFO compared to those fed CONT. The mRNA abundance of CAT, GPX1, GPX3 and SOD3 was lower in the mammary gland of cows fed COFO than in the mammary gland of cows fed CONT. The present study demonstrates that flax hulls contribute to increasing the abundance of some antioxidant genes, which can contribute to protecting against oxidative stress damage occurring in the mammary gland and other tissues of dairy cows. PMID- 22214884 TI - Culture and social support provision: who gives what and why. AB - The present research examined cultural differences in the type and frequency of support provided as well as the motivations underlying these behaviors. Study 1, an open-ended survey, asked participants about their social interactions in the past 24 hours and found that European Americans reported providing emotion focused support more frequently than problem-focused support, whereas Japanese exhibited the opposite pattern. Study 2, a closed-ended questionnaire study, found that, in response to the close other's big stressor, European Americans provided more emotion-focused support whereas Japanese provided equivalent amounts of emotion-focused and problem-focused support. In addition, Study 2 examined motivational explanations for these differences. Social support provision was motivated by the goal of closeness and increasing recipient self esteem among European Americans, but only associated with the motive for closeness among Japanese. These studies illustrate the importance of considering cultural context and its role in determining the meaning and function of various support behaviors. PMID- 22214883 TI - Measurement of cytosolic Ca2+ in isolated contractile lymphatics. AB - Lymphatic vessels comprise a multifunctional transport system that maintains fluid homeostasis, delivers lipids to the central circulation, and acts as a surveillance system for potentially harmful antigens, optimizing mucosal immunity and adaptive immune responses. Lymph is formed from interstitial fluid that enters blind-ended initial lymphatics, and then is transported against a pressure gradient in larger collecting lymphatics. Each collecting lymphatic is made up of a series of segments called lymphangions, separated by bicuspid valves that prevent backflow. Each lymphangion possesses a contractile cycle that propels lymph against a pressure gradient toward the central circulation. This phasic contractile pattern is analogous to the cardiac cycle, with systolic and diastolic phases, and with a lower contraction frequency. In addition, lymphatic smooth muscle generates tone and displays myogenic constriction and dilation in response to increases and decreases in luminal pressure, respectively. A hybrid of molecular mechanisms that support both the phasic and tonic contractility of lymphatics are thus proposed. Contraction of smooth muscle is generally regulated by the cytosolic Ca(2+) concentration ([Ca(2+)](i)) plus sensitivity to Ca(2+) of the contractile elements in response to changes in the environment surrounding the cell. [Ca(2+)](i) is determined by the combination of the movement of Ca(2+) through plasma membrane ligand or voltage gated Ca(2+) channels and the release and uptake of Ca(2+) from internal stores. Cytosolic Ca(2+) binds to calmodulin and activates enzymes such as myosin light chain (MLC) kinase (MLCK), which in turn phosphorylates MLC leading to actin-myosin-mediated contraction. However, the sensitivity of this pathway to Ca(2+) can be regulated by the MLC phosphatase (MLCP). MLCP activity is regulated by Rho kinase (ROCK) and the myosin phosphatase inhibitor protein CPI-17. Here, we present a method to evaluate changes in [Ca(2+)](i) over time in isolated, perfused lymphatics in order to study Ca(2+)-dependent and Ca(2+)-sensitizing mechanisms of lymphatic smooth muscle contraction. Using isolated rat mesenteric collecting lymphatics we studied stretch-induced changes in [Ca(2+)](i) and contractile activity. The isolated lymphatic model offers the advantage that pressure, flow, and the chemical composition of the bath solution can be tightly controlled. [Ca(2+)](i) was determined by loading lymphatics with the ratiometric, Ca(2+)-binding dye Fura-2. These studies will provide a new approach to the broader problem of studying the different molecular mechanisms that regulate phasic contractions versus tonic constriction in lymphatic smooth muscle. PMID- 22214885 TI - Benefiting from misfortune: when harmless actions are judged to be morally blameworthy. AB - Dominant theories of moral blame require an individual to have caused or intended harm. However, the current four studies demonstrate cases where no harm is caused or intended, yet individuals are nonetheless deemed worthy of blame. Specifically, individuals are judged to be blameworthy when they engage in actions that enable them to benefit from another's misfortune (e.g., betting that a company's stock will decline or that a natural disaster will occur). Evidence is presented suggesting that perceptions of the actor's wicked desires are responsible for this phenomenon. It is argued that these results are consistent with a growing literature demonstrating that moral judgments are often the product of evaluations of character in addition to evaluations of acts. PMID- 22214886 TI - Rotavirus vaccine series completion and adherence to vaccination schedules among infants in managed care in the United States. AB - BACKGROUND: Two rotavirus vaccines are currently approved in the United States: 3 dose RotaTeq (RV5; Merck & Co., Inc., Whitehouse Station, NJ, USA) is administered at ages 2, 4, and 6 months; and 2-dose Rotarix (RV1; GlaxoSmithKline, Research Triangle Park, NC, USA) is administered at ages 2 and 4 months. Our objective was to compare rotavirus vaccine series completion and dosing schedule compliance between cohorts of infants who received these vaccines. METHODS: Infants aged less than 1 year who initiated a rotavirus vaccine series between 01 January 2009 and 30 June 2009 were identified in US health insurance claims data. Cohorts were formed based on vaccine brand use. Series completion and compliance with the FDA-approved and ACIP-recommended harmonized schedules were analyzed descriptively and a log binomial model was used to estimate the difference in series completion by vaccine brand while adjusting for demographic variables. RESULTS: Among infants in the RV1 and RV5 cohorts (N=55,584), 84.3% completed a full series. A greater proportion of the RV1 cohort than the RV5 cohort completed their series (91.0% vs. 83.4%; P<0.001; multivariate-adjusted relative risk 1.07; 95% CI 1.06-1.08). In the RV1 and RV5 cohorts, respectively, 75.0% and 59.5% of infants were fully compliant with the FDA-approved administration schedule for their vaccine (P<0.001); 83.3% and 76.4% of infants were fully compliant with the harmonized schedule (P<0.001). CONCLUSIONS: The proportion of infants that completed the series was greater and compliance with respective FDA-approved and harmonized dosing schedules was higher among infants vaccinated with RV1 than among infants who received RV5. PMID- 22214887 TI - Development of a novel in-water vaccination protocol for DNA adenine methylase deficient Salmonella enterica serovar Typhimurium vaccine in adult sheep. AB - Intensive livestock production is associated with an increased incidence of salmonellosis. The risk of infection and the subsequent public health concern is attributed to increased pathogen exposure and disease susceptibility due to multiple stressors experienced by livestock from farm to feedlot. Traditional parenteral vaccine methods can further stress susceptible populations and cause carcass damage, adverse reactions, and resultant increased production costs. As a potential means to address these issues, in-water delivery of live attenuated vaccines affords a low cost, low-stress method for immunization of livestock populations that is not associated with the adverse handling stressors and injection reactions associated with parenteral administration. We have previously established that in-water administration of a Salmonella enterica serovar Typhimurium dam vaccine conferred significant protection in livestock. While these experimental trials hold significant promise, the ultimate measure of the vaccine will not be established until it has undergone clinical testing in the field wherein environmental and sanitary conditions are variable. Here we show that in-water administration of a S. Typhimurium dam attenuated vaccine was safe, stable, and well-tolerated in adult sheep. The dam vaccine did not alter water consumption or vaccine dosing; remained viable under a wide range of temperatures (21-37 degrees C); did not proliferate within fecal-contaminated trough water; and was associated with minimal fecal shedding and clinical disease as a consequence of vaccination. The capacity of Salmonella dam attenuated vaccines to be delivered in drinking water to protect livestock from virulent Salmonella challenge offers an effective, economical, stressor-free Salmonella prophylaxis for intensive livestock production systems. PMID- 22214888 TI - Enterovirus type 71 neutralizing antibodies in the serum of macaque monkeys immunized with EV71 virus-like particles. AB - Enterovirus type 71 (EV71) is a virulent form of enteroviruses causing hospitalizations for children less than three years of age. Currently there are no anti-viral therapies or vaccines available for EV71. Due to the high risk of poliomyelitis-like paralysis and fatal encephalitis, an effective vaccine to EV71 could potentially prevent virus-induced morbidity and mortality. In this study, we first tested a potential EV71 vaccine candidate based on virus-like particles (VLP). We vaccinated macaque monkeys to validate the immunogenicity of the VLP vaccine to EV71. We detected the VLP or EV71-specific antibodies, neutralization titers, ELISPOT, and T cell response to find their immune responses to EV71. When the VLP vaccine adjuvanted with alum was given to macaque monkeys, these monkeys developed both specific humoral and cellular immune responses to EV71. Despite lower neutralizing antibodies to EV71 were found in sera of VLP-immunized monkeys than monkeys vaccinated with inactivated EV71, VLP-based vaccine generated a memory immune response to EV71. Hence, VLP-based EV71 vaccine is a potential vaccine against EV71 infection. PMID- 22214889 TI - The determinants of 2009 pandemic A/H1N1 influenza vaccination: a systematic review. AB - BACKGROUND: Pandemic A/H1N1 influenza vaccine coverage varied widely across countries. To understand the factors influencing pandemic influenza vaccination and to guide the development of successful vaccination programs for future influenza pandemics, we identified and summarized studies examining the determinants of vaccination during the 2009 influenza pandemic. METHODS: We performed a systematic literature review using the PubMED electronic database from June 2009 to February 2011. We included studies examining an association between a possible predictive variable and actual receipt of the pandemic A/H1N1 influenza vaccine. We excluded studies examining intention or willingness to receive the vaccine. RESULTS: Twenty-seven studies were identified from twelve countries. Pandemic influenza vaccine coverage varied from 4.8% to 92%. Coverage varied by population sub-group, country, and assessment method used. Most studies used questionnaires to estimate vaccine coverage, however seven (26%) used a vaccination registry. Factors that positively influenced pandemic influenza vaccination were: male sex, younger age, higher education, being a doctor, being in a priority group for which vaccination was recommended, receiving a prior seasonal influenza vaccination, believing the vaccine to be safe and/or effective, and obtaining information from official medical sources. CONCLUSIONS: Vaccine coverage during the pandemic varied widely across countries and population sub-groups. We identified some consistent determinants of this variation that can be targeted to increase vaccination during future influenza pandemics. PMID- 22214890 TI - Determinants of care costs of patients with dementia or cognitive impairment. AB - INTRODUCTION: Dementia causes a high burden on patients, caregivers, and societies. Decision analytic models to support allocation of resources are often developed making use of cost-of-illness (COI) studies. However, current COI study estimates are highly variable due to care setting and methodological issues. We aim to explore variables explaining the variation of (formal and informal) health care costs of cognitive disorders, using a broad spectrum of variables, including patient, caregiver, and social context variables. METHODS: A bottom-up COI study design was used in which a societal viewpoint and a validated method to measure and value informal care was applied. Data were analyzed using univariate, multivariate, and forward regression analyses. RESULTS: The average 1-year health care sector costs were &OV0556;26,140 ($34,505 or L17,775) and &OV0556;11,931 ($15,749 or L8113) for patient and family. The analyses indicated that cognitive functioning, caregiver burden, patient sex, and instrumental activities of daily living were significantly associated with care costs independently. CONCLUSIONS: Cognitive functioning and instrumental activities of daily living are important variables to include in health care decision models. We recommend also including caregiver burden and patient sex in decision models for health policy decision makers to fully reflect the heterogeneity of the disease progression of cognitive disorders. PMID- 22214891 TI - Local suppression of ferroelectricity at PbTiO3 surface steps: a density functional theory study. AB - Ab initio (first-principles) density functional theory (DFT) calculations are performed within the local density approximations (LDA) to investigate the ferroelectricity at PbTiO(3) surface steps consisting of (001) and (100) surfaces with a spontaneous polarization along [100]. For both the PbO- and TiO(2) terminated surface steps, the [100] polarization is suppressed and the [001] polarization appears at their upper terraces, which results in a rotation of polarizations at the surface steps. The polarization rotation is induced by the local variation of the covalent Pb-O bond due to the charge redistribution at the surface steps. Furthermore, we investigate the interaction of the surface steps. Although surface steps with the same polarization configuration exhibit little interaction, steps of different types interact with each other strongly, suppressing the ferroelectricity, especially on the upper terrace. PMID- 22214892 TI - Out of sight but not out of mind: how to search for unpublished clinical trial evidence. PMID- 22214893 TI - Minimum safe staffing levels may be set for emergency departments and elderly care wards. PMID- 22214894 TI - UK launches inquiry into safety of PIP breast implants. PMID- 22214895 TI - MPs are urged to end inaction on social care reform. PMID- 22214896 TI - Hanover bans e-cigarette use in civic offices amid calls for better safety data. PMID- 22214897 TI - Simultaneous Doppler tracing of transmitral inflow and mitral annular velocity as an estimate of elevated left ventricular filling pressure in patients with atrial fibrillation. AB - BACKGROUND: The time interval between the onset of early transmitral flow velocity (E) and that of early diastolic mitral annular velocity (e') (T(E-e')) is a good predictor of elevated left ventricular (LV) filling pressure in patients with sinus rhythm. Although the evaluation of LV filling pressure using E/e' has been challenging in atrial fibrillation (AF), the usefulness of T(E-e') is unknown. METHODS AND RESULTS: E and e' were simultaneously recorded using dual Doppler echocardiography in 45 AF patients (30 men; mean age, 69 +/- 9 years). E/e' and T(E-e') were calculated and compared with the pulmonary capillary wedge pressure (PCWP), which was measured invasively. E/e' and T(E/e') correlated with PCWP (E/e', r=0.57, P<0.001; T(E-e'), r=0.77, P<0.001). Using receiver operating characteristic analysis, the optimal cut-off for T(E-e') was 34 ms (sensitivity, 95%; specificity, 88%) and that for E/e' was 14.6 (sensitivity, 50%; specificity, 84%) in order to predict >12-mmHg PCWP. When the combined cut-offs of T(E-e') >34 ms and E/e' >14.6 were used, the sensitivity and specificity of predicting elevated PCWP were improved to 100% and 88%, respectively. CONCLUSIONS: In AF patients, the simultaneous recording of E and e' using dual Doppler echocardiography and the analysis of T(E-e'), in addition to E/e', improved the accuracy of evaluation of LV filling pressure. PMID- 22214898 TI - Compound and digenic heterozygosity in desmosome genes as a cause of arrhythmogenic right ventricular cardiomyopathy in Japanese patients. AB - BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary disorder mostly caused by desmosome gene mutations. Recent comprehensive desmosome mutation analyses of Caucasian ARVC patients have revealed the presence of not only a single heterozygous mutation, but also compound and digenic heterozygosity. However, the genetic basis of Japanese ARVC remains poorly elucidated. METHODS AND RESULTS: The subjects were 7 definite and 1 possible ARVC probands (6 males, 16-76 years of age), and their family members. Genetic screening for major ARVC-causing genes (junction plakoglobin, desmoplakin, plakophilin-2 (PKP2), desmoglein-2 (DSG2), and desmocollin-2) was performed. We identified 3 cases of compound heterozygosities (Case 1: DSG2 S194L and DSG2 R292C; Case 2: PKP2 2489+1G>A and PKP2 D812N; Case 3: PKP2 M565R and PKP2 D812N) and 1 of digenic heterozygosity (Case 4: PKP2 1728_1729insGATG and DSG2 R292C) among the definite ARVC patients. All family members we investigated have remained asymptomatic. They carried, if any, only a single variant, indicating that the probands carry in trans compound heterozygosity. These results suggest that each of these variants alone may not be sufficient and second variants may be required to manifest overt ARVC in Japanese patients. CONCLUSIONS: Our comprehensive genetic analysis of desmosome genes identified 3 cases of compound heterozygosities in trans and 1 of digenic heterozygosity among 7 definite Japanese ARVC patients, providing novel insights into the genetic basis of Japanese ARVC. PMID- 22214899 TI - Impact of left ventricular afterload on longitudinal dyssynchrony in patients with severe aortic stenosis and preserved ejection fraction. AB - BACKGROUND: The purpose of this study was to investigate whether patients with severe aortic stenosis (AS) and preserved ejection fraction (EF) have dyssynchrony and whether it improves after aortic valve replacement (AVR). METHODS AND RESULTS: We studied 30 consecutive patients with severe AS and preserved EF undergoing AVR. For baseline comparison, we studied 17 EF-matched patients with mild-to-moderate AS, and 18 EF-matched normal volunteers. Longitudinal dyssynchrony was determined as the standard deviation for time-to peak speckle-tracking strain in apical 4- and 2-chamber views at the basal- and mid-levels. Radial and circumferential dyssynchrony was determined as the difference for time-to-peak strain between the anteroseptum and posterior wall from the mid-left ventricular (LV) short-axis view. Each of the myocardial functions was also evaluated by averaging each peak systolic strain. Longitudinal dyssynchrony and function in patients with severe AS was significantly worse than in the patients with mild-to-moderate AS and the controls (94 +/- 46 vs. 66 +/- 18 ms* and 52 +/- 17 ms*, and 12.5 +/- 3.7% vs. 16 +/- 3.5%* and 18.7 +/- 3.7%*, respectively, *P<0.05, vs. severe AS). In contrast, radial and circumferential dyssynchrony were similar for the 3 groups. Importantly, the dyssynchrony of patients with severe AS significantly improved after AVR from 94 +/- 46 ms to 68 +/- 22 ms (P<0.005). CONCLUSIONS: Significant longitudinal dyssynchrony was present in patients with severe AS and preserved EF, and it improved after AVR. PMID- 22214900 TI - Endothelial progenitor cell mobilization and platelet microparticle release are influenced by clopidogrel plasma levels in stable coronary artery disease. AB - BACKGROUND: Increased numbers of endothelial (EMP) and platelet (PMP) microparticles have been related to cardiovascular risk factors and coronary artery disease. Little is known about the early effects of statins and clopidogrel on these new biomarkers of vascular homeostasis. The aim of the present study was to evaluate pharmacokinetic interactions between atorvastatin and clopidogrel and their effects, alone or combined, on EMP, PMP, and endothelial progenitor cells (EPC). METHODS AND RESULTS: A prospective open-label study enrolled subjects with stable coronary disease (n=26). Drugs were given daily for 3 weeks (atorvastatin 80 mg, visits 1-3; clopidogrel 75 mg, visits 2 4). Counts of EPC (CD34+/CD133+/KDR+), EMP (CD51+) and PMP (CD42+/CD31+), and pharmacokinetic parameters over 24h were assessed at each visit. Atorvastatin plasma concentrations were increased by concomitant therapy with clopidogrel (maximum serum concentration [C(max)], P=0.002; area under the clopidogrel or atorvastatin plasma concentration vs. time curve from 0 to the last detectable concentration [AUC(last)], P=0.03). After atorvastatin withdrawal there was an increase in clopidogrel plasma concentrations (C(max), P=0.009; AUC(last), P=0.039). PMP were inversely correlated with clopidogrel C(max) on visit 3 (rho= 0.57, P=0.006) and on visit 4 (rho=-0.54, P=0.01), and with clopidogrel AUC(last) on visit 3 (rho=-0.44, P=0.04), and on visit 4 (rho=-0.57, P=0.005). In addition, clopidogrel C(max) was correlated with EPC (CD133+/KDR+) on visit 4 (rho=0.48, P=0.025). No correlations of atorvastatin and MP or EPC were found. CONCLUSIONS: The balance between platelet MP release and EPC mobilization seems influenced by clopidogrel plasma levels, suggesting a protective mechanism on coronary artery disease. PMID- 22214901 TI - Effect and safety of landiolol in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. PMID- 22214902 TI - Magnetic resonance imaging reveals slow-down of global cerebral oxygen metabolism in multiple sclerosis. PMID- 22214903 TI - Characterisation of the contribution of the GABA-benzodiazepine alpha1 receptor subtype to [(11)C]Ro15-4513 PET images. AB - This positron emission tomography (PET) study aimed to further define selectivity of [(11)C]Ro15-4513 binding to the GABARalpha5 relative to the GABARalpha1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARalpha1-selective agonist, on [(11)C]Ro15-4513, which shows selectivity for GABARalpha5, and the nonselective benzodiazepine ligand [(11)C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [(11)C]Ro15-4513 time-activity curves was used to describe distribution volume (V(T)) differences in regions populated by different GABA receptor subtypes. Those with low alpha5 were best fitted by one-tissue compartment models; and those with high alpha5 required a more complex model. The heterogeneity between brain regions suggested spectral analysis as a more appropriate method to quantify binding as it does not a priori specify compartments. Spectral analysis revealed that zolpidem caused a significant V(T) decrease (~10%) in [(11)C]flumazenil, but no decrease in [(11)C]Ro15-4513 binding. Further analysis of [(11)C]Ro15-4513 kinetics revealed additional frequency components present in regions containing both alpha1 and alpha5 subtypes compared with those containing only alpha1. Zolpidem reduced one component (mean+/-s.d.: 71%+/-41%), presumed to reflect alpha1-subtype binding, but not another (13%+/-22%), presumed to reflect alpha5. The proposed method for [(11)C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands. PMID- 22214905 TI - Promising application of dynamic nuclear polarization for in vivo (13)C MR imaging. AB - Use of hyperpolarized (13)C in magnetic resonance (MR) imaging is a new technique that enhances signal tens of thousands-fold. Recent in vivo animal studies of metabolic imaging that used hyperpolarized (13)C demonstrated its potential in many applications for disease indication, metabolic profiling, and treatment monitoring. We review the basic physics for dynamic nuclear polarization (DNP) and in vivo studies reported in prostate cancer research, hepatocellular carcinoma research, diabetes and cardiac applications, brain metabolism, and treatment response as well as investigations of various DNP (13)C substrates. PMID- 22214906 TI - MR contrast in mouse lymph nodes with subcutaneous administration of iron oxide particles: size dependency. AB - PURPOSE: We investigated the spatiotemporal changes in signal in draining lymph nodes of mice to ascertain the size-dependent effects of variously sized particles of iron oxide used to enhance magnetic resonance (MR) lymphography. MATERIALS AND METHODS: We injected iron oxide particles of 50-, 100-, 200-, or 1,000-nm diameter into the footpads of individual mice and obtained sequential MR images of the popliteal and inguinal lymph nodes with 11.7 tesla up to 6 weeks after particle administration. RESULTS: Up to 30 min after administration of particles smaller than 100 nm, we observed a marked reduction in signal in the popliteal node that spread from the periphery at first observation toward the center of the node in subsequent measurements and persisted up to 6 weeks. In contrast, 1,000-nm particles caused dot-like areas of hypointensity in the popliteal lymph node, primarily in the inner portion, that appeared after 2 days. In the inguinal lymph nodes, signal changes occurred after 2 days for 50- and 100 nm particles and after one week for 1,000-nm particles. For 1,000-nm particles, areas of hypointensity were visible in the inner portion and not the periphery of the inguinal lymph node up to 6 weeks. In this study, we demonstrate the strong dependence of MR imaging contrast in draining lymph nodes on the size of the particle-shaped contrast agents injected subcutaneously. Particle size represented passive and active targeting effects, so micron-sized particles produced delayed enhancement. CONCLUSION: Choosing the size of iron oxide particles for MR imaging contrast depends on the objective of observation, such as identifying the morphology or migration of immune cells in the lymph node. PMID- 22214904 TI - White-matter astrocytes, axonal energy metabolism, and axonal degeneration in multiple sclerosis. AB - In patients with multiple sclerosis (MS), a diffuse axonal degeneration occurring throughout the white matter of the central nervous system causes progressive neurologic disability. The underlying mechanism is unclear. This review describes a number of pathways by which dysfunctional astrocytes in MS might lead to axonal degeneration. White-matter astrocytes in MS show a reduced metabolism of adenosine triphosphate-generating phosphocreatine, which may impair the astrocytic sodium potassium pump and lead to a reduced sodium-dependent glutamate uptake. Astrocytes in MS white matter appear to be deficient in beta(2) adrenergic receptors, which are involved in stimulating glycogenolysis and suppressing inducible nitric oxide synthase (NOS2). Glutamate toxicity, reduced astrocytic glycogenolysis leading to reduced lactate and glutamine production, and enhanced nitric oxide (NO) levels may all impair axonal mitochondrial metabolism, leading to axonal degeneration. In addition, glutamate-mediated oligodendrocyte damage and impaired myelination caused by a decreased production of N-acetylaspartate by axonal mitochondria might also contribute to axonal loss. White-matter astrocytes may be considered as a potential target for neuroprotective MS therapies. PMID- 22214907 TI - Multiple-animal MR imaging using a 3T clinical scanner and multi-channel coil for volumetric analysis in a mouse tumor model. AB - PURPOSE: Multiple small-animal magnetic resonance (MR) imaging to measure tumor volume may increase the throughput of preclinical cancer research assessing tumor response to novel therapies. We used a clinical scanner and multi-channel coil to evaluate the usefulness of this imaging to assess experimental tumor volume in mice. METHODS: We performed a phantom study to assess 2-dimensional (2D) geometric distortion using 9-cm spherical and 32-cell (8*4 one-cm(2) grids) phantoms using a 3-tesla clinical MR scanner and dedicated multi-channel coil composed of 16 5-cm circular coils. Employing the multi-channel coil, we simultaneously scanned 6 or 8 mice bearing sarcoma 180 tumors. We estimated tumor volume from the sum of the product of tumor area and slice thickness on 2D spin echo images (repetition time/echo time, 3500/16 ms; in-plane resolution, 0.195*0.195*1 mm(3)). After MR acquisition, we excised and weighed tumors, calculated reference tumor volumes from actual tumor weight assuming a density of 1.05 g/cm(3), and assessed the correlation between the estimated and reference volumes using Pearson's test. RESULTS: Two-dimensional geometric distortion was acceptable below 5% in the 9-cm spherical phantom and in every cell in the 32 cell phantom. We scanned up to 8 mice simultaneously using the multi-channel coil and found 11 tumors larger than 0.1 g in 12 mice. Tumor volumes were 1.04+/-0.73 estimated by MR imaging and 1.04+/-0.80 cm(3) by reference volume (average+/ standard deviation) and highly correlated (correlation coefficient, 0.995; P<0.01, Pearson's test). CONCLUSION: Use of multiple small-animal MR imaging employing a clinical scanner and multi-channel coil enabled accurate assessment of experimental tumor volume in a large number of mice and may facilitate high throughput monitoring of tumor response to therapy in preclinical research. PMID- 22214908 TI - Diffusion tensor imaging of the corticospinal tract in patients with brain neoplasms. AB - PURPOSE: To maximize the extent of tumor resection and minimize postoperative neurological deficits in patients with brain neoplasms, it is very important to evaluate the integrity of the corticospinal tract (CST) before surgery. We attempted to determine whether CST abnormality in these patients correlates with clinical motor weakness. METHODS: We retrospectively evaluated 19 patients (16 men, 3 women, aged 39 to 70 years) with pathologically proven brain neoplasms with lesions adjacent to the posterior limb of the internal capsule and categorized their motor function as normal or abnormal based on clinical assessment. After correcting raw diffusion tensor image (DTI) data for motion and eddy-current artifacts, we computed fractional anisotropy (FA) and apparent diffusion coefficient (ADC) maps. We manually segmented the CST from the level of the cerebral peduncle to the internal capsule, used the segmented CST as the mask for FA and ADC measurements, and compared normalized FA (nFA) and ADC (nADC) values relative to the contralateral normal side using a 2-tailed, unpaired t test. RESULTS: Compared with the normalized values for patients with normal motor function, patients with abnormal motor function demonstrated significantly decreased FA (P<0.001, 0.65+/-0.09 versus 0.85+/-0.08) and significantly increased ADC (P<0.01, 1.49+/-0.17 versus 1.23+/-0.22). CONCLUSION: DTI metrics can be used for preoperative evaluation of the integrity of the CST microstructure. PMID- 22214909 TI - Gd-EOB-DTPA-enhanced MR imaging findings of hepatocellular adenoma: correlation with pathological findings. AB - We report a case of a 28-year-old woman with hepatocellular adenoma and correlate findings of pathology and magnetic resonance (MR) imaging with gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) enhancement. In the hepatobiliary phase, the peripheral region of the tumor that corresponded with proliferating hepatocytes with steatosis showed slight hypointensity compared with the surrounding liver parenchyma, and the central region of the tumor that corresponded with cellular areas showed isointensity. PMID- 22214910 TI - MR imaging of uterine adenosarcoma: case report and literature review. AB - We report a case of uterine adenosarcoma demonstrated on magnetic resonance (MR) imaging. A 74-year-old woman with a large uterine mass underwent MR examination before total abdominal hysterectomy. Imaging revealed a markedly enlarged uterus with thin myometrium occupied by a large polypoid mass. The mass contained solid components with low intensity on T(1)-weighted images and high intensity on T(2) weighted images compared to the myometrium and areas of small cysts. PMID- 22214911 TI - Cardiac rupture in acute myocardial infarction: post-mortem MR imaging. AB - We assessed acute myocardial infarction (AMI) with cardiac rupture in an autopsy using magnetic resonance (MR) imaging in vitro and histological staining. Cardiac MR imaging in vitro generated high resolution images of myocardial thinning, rupture, and epicardial hemorrhage. High signal intensity (SI) on T(1) weighted images (WI) and low SI on T(2)WI of the rupture site corresponded with acute myocardial necrosis, edema, and hemorrhage. A rupture site rich in erythrocytes after AMI might affect SI on T(1) and T(2)WI in cardiac MR imaging. PMID- 22214912 TI - Improved SNR of magnetic resonance microimaging using a cooled resonance circuit at 0.3T. AB - Because it is noninvasive, magnetic resonance microimaging (MRMI) can be used for 3-dimensional measurement of living tissues for cell engineering. Thermal noise in the resonance circuit of the radiofrequency (RF) system of the MRMI cannot become ignored as the signal diminishes in accordance with decreasing sample size, and cooling the RF coil of the receiver circuit can effectively reduce thermal noise. We used a low temperature normal conductor circuit to reduce noise and confirmed improved signal-to-noise ratio for a conventional microimaging system at low B(0) field (0.3T) with low cost. PMID- 22214913 TI - Gd-DTPA-based MR-visible polymer for direct visualization of interventional devices. AB - We developed a Gd-DTPA (gadolinium(III)-diethylenetriaminepentaacetic acid)-based coating copolymer of hydrophilic and hydrophobic subunits to obtain visibility, hydrophilicity, and durability for passive visualization of catheters used in MR guided interventions. We then examined a metal-free catheter coated with the polymer in a phantom and in porcine brain tissue ex vivo. Successful visualization of the coated device demonstrated the applicability of the new coating technique for visualizing catheters used in MR-guided interventions. PMID- 22214914 TI - Anatomical details of the brainstem and cranial nerves visualized by high resolution readout-segmented multi-shot echo-planar diffusion-weighted images using unidirectional MPG at 3T. AB - We compared diffusion-weighted imaging (DWI) with readout-segmented multi-shot echo-planar imaging (rs-EPI) and single-shot EPI, both using unidirectional motion-probing gradient, in 10 patients for visualization of the anatomical structures in the brainstem. DWI by rs-EPI was significantly better than DWI by single-shot EPI for visualizing the medial longitudinal fasciculus, lateral lemniscus, corticospinal tract, and seventh/eighth cranial nerves and offered significantly less distortion of the brainstem. PMID- 22214916 TI - The evolution of psychosomatic thinking: From the psychoanalytic approach to current theories. PMID- 22214915 TI - DiI-labeling of DRG neurons to study axonal branching in a whole mount preparation of mouse embryonic spinal cord. AB - Here we present a technique to label the trajectories of small groups of DRG neurons into the embryonic spinal cord by diffusive staining using the lipophilic tracer 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). The comparison of axonal pathways of wild-type with those of mouse lines in which genes are mutated allows testing for a functional role of candidate proteins in the control of axonal branching which is an essential mechanism in the wiring of the nervous system. Axonal branching enables an individual neuron to connect with multiple targets, thereby providing the physical basis for the parallel processing of information. Ramifications at intermediate target regions of axonal growth may be distinguished from terminal arborization. Furthermore, different modes of axonal branch formation may be classified depending on whether branching results from the activities of the growth cone (splitting or delayed branching) or from the budding of collaterals from the axon shaft in a process called interstitial branching (Fig. 1). The central projections of neurons from the DRG offer a useful experimental system to study both types of axonal branching: when their afferent axons reach the dorsal root entry zone (DREZ) of the spinal cord between embryonic days 10 to 13 (E10-E13) they display a stereotyped pattern of T or Y-shaped bifurcation. The two resulting daughter axons then proceed in rostral or caudal directions, respectively, at the dorsolateral margin of the cord and only after a waiting period collaterals sprout from these stem axons to penetrate the gray matter (interstitial branching) and project to relay neurons in specific laminae of the spinal cord where they further arborize (terminal branching). DiI tracings have revealed growth cones at the dorsal root entry zone of the spinal cord that appeared to be in the process of splitting suggesting that bifurcation is caused by splitting of the growth cone itself (Fig. 2), however, other options have been discussed as well. This video demonstrates first how to dissect the spinal cord of E12.5 mice leaving the DRG attached. Following fixation of the specimen tiny amounts of DiI are applied to DRG using glass needles pulled from capillary tubes. After an incubation step, the labeled spinal cord is mounted as an inverted open-book preparation to analyze individual axons using fluorescence microscopy. PMID- 22214917 TI - [Comorbid anxiety and depression: Diagnostic issues and treatment management]. AB - Epidemiological data show that besides the high prevalence of anxiety and depressive disorders in the general population, comorbidity between the two is a very frequent phenomenon. There is a variety in the clinical presentation of comorbidity. Comorbidity may be present as the full clinical picture of the two syndromes or as limited symptoms from both two syndromes. Anxiety disorders usually are the first manifestation. The impact of comorbidity is reflected in the severity of the disorder, the chronicity and persistency of its course, the more functional impairment and the worse quality of patient's life. There is interplay between several genetic, neurobiological and environmental risk factors leading to comorbidity. Disturbances of the serotoninergic and noradrenergic systems, as well as of the hypothalamic-pituitary-adrenal axis have been implicated in the pathophysiology of comorbidity. Treatment with novel antidepressants and anxiolytics, as well as psychotherapeutic approaches has proven to be effective for the management of comorbid anxiety and depression. PMID- 22214918 TI - [Biological factors associated with depression in patients with type IotaIota diabetes mellitus]. AB - This study was undertaken in order to identify the prevalence and factors associated with depression in a group of patients with type II diabetes mellitus. 200 patients (127 women/73 men) with type II diabetes mellitus, from Diabetic Clinic of 1st Propedeutic Medical Department of Aristotle's University of Thessaloniki, AHEPA Hospital, were enrolled in our study. Patients, sex, age, duration of diabetes, antidiabetic treatment, diabetic complications, body mass index (BMI), waist circumference, blood pressure, smoking, physical exercise and alcohol intake were assessed. BDI-II(Beck Depression Inventory-II) scale was used to measure the presence of depression. Prevalence of depression was high in the total of our patients (31.5%) and also in men (26%) and women (34.6%) separately. Depression appeared not to be related to patients' age, duration of diabetes, smokingand physical exercise, in the total of them (p>0.05). Patients, who were prescribed insulin, seemed to be more often depressed compared to those undertaking oral antidiabetic medication. The presence of depression was statistically significant increased in patients with diabetic complicationsin the total (p=0.013) and in men (p=0.001), while it was almost significantly increased in patients with diabetic nephropathy (p=0.052) and stroke (p=0.097). Depression was statistically significant related to obese patients compared to normal weight patients, in the total (p=0.003), and in menseparately (p=0.013), and also statistically significant was the relationship of depression with central obesity in the total (p=0.011) and in men (p=0.014). Statistically important was the relationship of arterial hypertension with depression in diabetic men (p=0.030), while in the limits of statistical importance was the relationship between depression and modest to heavy alcohol consumption in women (p=0.063). In a clinical aspect, depression seems to influence the development of type II diabetes mellitus, as it is shown by the significant association of diabetic complications anddepressive symptoms. The development of depression has often been considered a secondary response to the onset of complications, but depression might also play a primary role in the development or exacerbation of diabetic complications. It would be reasonable to speculate that obesity and arterial hypertension are biological variables that may interact with depression to produce diabetic complications. Further studies are needed to identify the pathways that mediate this association. These observations demonstrate that depression has a significant role in the development of type II diabetes mellitus, implying the necessity of its diagnosis and treatment, for the most optimal confrontation of the diabetic patient. PMID- 22214919 TI - [Help-seeking from a Community Mental Health Centre]. AB - Help-seeking is a multi-dimensional process. Individual, family and social factors all may be relevant in determining if and when help is sought. This study explored the possible factors affecting the help-seeking behaviour of individuals with mental health problems and their first contact with a mental health professional. Iotandividuals, who sought help from the Community Mental Health Centre (CMHC) during 2003-2007, completed a questionnaire and information was obtained on a number of variables including demographic characteristics. Women, compared to men, seek help from the CMHC at a greater frequency. Individuals with psychotic symptoms don't seek help initially from a CMHC and they used to visit other mental health services. The percentage of individuals diagnosed with psychosis, emotional and anxiety disorders, seeking help for the first time in their lives 12 months after the onset of psychopathology, was high. Delays in initiating treatment are often prolonged and the duration of untreated disorder is associated with substantial functional decline and poorer quality of life. Reduction of these delays will require clearer understanding of the contributing factors. PMID- 22214920 TI - [Depression in schizophrenia: Relationship with other symptoms, differential diagnosis, prognosis,treatment]. AB - The relationship between depressive symptoms and other symptom categories in schizophrenia have been studied by many authors. According to the existing studies depression in schizophrenic patients is related to the presense of positive symptoms, especifically delusions and hallucinations.As far as negative symptoms concerns it seems that there coexist with the depressive symptoms in any phase of the disease at least in a subgroup of schizophrenic patients. In addition, according to the pyramidal model of Kay, when positive and depressive symptoms coexist, they create theclinical picture of the paranoid subtype of schizophrenia. The same holds for the combination of negative and depressive symptoms, which most frequently describe the residual subtype of the disease. Extrapyramidal symptoms are side effects of antipsychotic drugs (especially the classicalones). According to the existing literature it seems that antipyramidal side effects appear more often in schizophrenic patients with depressive symptoms. The differential diagnosis of depressive symptoms in schizophrenic patients should start with the evaluation of possible presence of organiccauses like somatic disease, medication induced extrapyramidal symptoms, substance abuse. Yet, symptoms of depression need to be differentiated from the negative symptoms of schizophrenia. Psychiatric syndromes like schizoaffective disorder, bipolar disorder and depression with psychotic features need to be also considered. In this case is very important to identify accurately the duration of depressive symptoms as well as the succession of appearance of the depressive vs. psychotic symptoms. Depressive symptoms appear to be bad prognostic sign for the long-term outcome of schizophrenia, because of the increased risk for suicide but also because of the worsening of the quality of life and the general wellbeing of the schizophrenic patient. Depressive symptoms during the acute phase of the disease usually respond to antipsychotic therapy, but in some cases the treating physician may consider the use of atypical antipsychotics. In the case of post psychotic depression the concurrent administration of antidepressants is indicated. PMID- 22214921 TI - [Psychological dimension of cancer genetics: Doctor-patient communication]. AB - Cancer is a disease that threatens life and body integrity. A method of cancer prediction is genetic testing, thus the primary detection of individuals who have oncogenes and are at risk of a hereditary cancer. Genetic counseling is the translation of technical information by physicians and the analysis of the problems subsequent to this information, into the therapeutic relationship. Generally, the communication between medical staff and patient must follow certain rules. There are two goals; the physician's comfort when he is dealing with giving news, especially bad news and the maintenance of patient's hope during making decisions for his health and his life. Communication skills focus on emotional reaction and empathy towards the patient. PMID- 22214922 TI - Molecular phylogenetics and historical biogeography of the west-palearctic common toads (Bufo bufo species complex). AB - In most pan-Eurasiatic species complexes, two phenomena have been traditionally considered key processes of their cladogenesis and biogeography. First, it is hypothesized that the origin and development of the Central Asian Deserts generated a biogeographic barrier that fragmented past continuous distributions in Eastern and Western domains. Second, Pleistocene glaciations have been proposed as the main process driving the regional diversification within each of these domains. The European common toad and its closest relatives provide an interesting opportunity to examine the relative contributions of these paleogeographic and paleoclimatic events to the phylogeny and biogeography of a widespread Eurasiatic group. We investigate this issue by applying a multiproxy approach combining information from molecular phylogenies, a multiple correspondence analysis of allozyme data and species distribution models. Our study includes 304 specimens from 164 populations, covering most of the distributional range of the Bufo bufo species complex in the Western Palearctic. The phylogenies (ML and Bayesian analyses) were based on a total of 1988 bp of mitochondrial DNA encompassing three genes (tRNAval, 16S and ND1). A dataset with 173 species of the family Bufonidae was assembled to estimate the separation of the two pan-Eurasiatic species complexes of Bufo and to date the main biogeographic events within the Bufo bufo species complex. The allozyme study included sixteen protein systems, corresponding to 21 presumptive loci. Finally, the distribution models were based on maximum entropy. Our distribution models show that Eastern and Western species complexes are greatly isolated by the Central Asian Deserts, and our dating estimates place this divergence during the Middle Miocene, a moment in which different sources of evidence document a major upturn of the aridification rate of Central Asia. This climate-driven process likely separated the Eastern and Western species. At the level of the Western Palearctic, our dating estimates place most of the deepest phylogenetic structure before the Pleistocene, indicating that Pleistocene glaciations did not have a major role in splitting the major lineages. At a shallow level, the glacial dynamics contributed unevenly to the genetic structuring of populations, with a strong influence in the European-Caucasian populations, and a more relaxed effect in the Iberian populations. PMID- 22214923 TI - A mosaic de novo duplication of 17q21-25 is associated with GH insensitivity, disturbed in vitro CD28-mediated signaling, and decreased STAT5B, PI3K, and NF kappaB activation. AB - OBJECTIVE: The established causes of GH insensitivity include defects of the GH receptor and STAT5B. The latter condition is also characterized by severe immunodeficiency. A recent case with short stature, GH resistance, and immunodeficiency due to an IkappaB mutation suggests that the NF-kappaB pathway may interact with STAT5B signaling. DESIGN: Here, we present a case of a short child with several congenital anomalies as well as GH insensitivity and mild immunodeficiency associated with a mosaic de novo duplication of chromosome 17q21 25, suggesting that overexpression of one of the duplicated genes may be implicated in GH resistance. METHODS AND RESULTS: In vitro studies on blood lymphocytes showed disturbed signaling of the CD28 pathway, involving NF-kappaB and related proteins. Functional studies on cultured skin fibroblasts revealed that NF-kappaB activation, PI3K activity, and STAT5 phosphorylation in response to GH were suppressed, while the sensitivity to GH in terms of MAPK phosphorylation was increased. An in silico analysis of the duplicated genes showed that MAP3K3 and PRKCA are associated with the NF-kappaB pathway. Baseline MAP3K3 expression in T-cell blasts (TCBs) was normal, but PRKCA expression in TCBs and fibroblasts was significantly higher than that in control cells. CONCLUSIONS: We conclude that the 17q21-25 duplication is associated with GH insensitivity and disturbed STAT5B, PI3K, and NF-kappaB signaling, possibly due to PRKCA mRNA overexpression. PMID- 22214925 TI - Iterative Development of an Application to Support Nuclear Magnetic Resonance Data Analysis of Proteins. AB - The CONNecticut Joint University Research (CONNJUR) team is a group of biochemical and software engineering researchers at multiple institutions. The vision of the team is to develop a comprehensive application that integrates a variety of existing analysis tools with workflow and data management to support the process of protein structure determination using Nuclear Magnetic Resonance (NMR). The use of multiple disparate tools and lack of data management, currently the norm in NMR data processing, provides strong motivation for such an integrated environment. This manuscript briefly describes the domain of NMR as used for protein structure determination and explains the formation of the CONNJUR team and its operation in developing the CONNJUR application. The manuscript also describes the evolution of the CONNJUR application through four prototypes and describes the challenges faced while developing the CONNJUR application and how those challenges were met. PMID- 22214924 TI - Salivary cortisol as a diagnostic tool for Cushing's syndrome and adrenal insufficiency: improved screening by an automatic immunoassay. AB - BACKGROUND: Salivary cortisol is increasingly used to assess patients with suspected hypo- and hypercortisolism. This study established disease-specific reference ranges for an automated electrochemiluminescence immunoassay (ECLIA). METHODS: Unstimulated saliva from 62 patients with hypothalamic-pituitary disease was collected at 0800 h. A peak serum cortisol level below 500 nmol/l during the insulin tolerance test (ITT) was used to identify hypocortisolism. Receiver operating characteristic (ROC) analysis allowed establishment of lower and upper cutoffs with at least 95% specificity for adrenal insufficiency and adrenal sufficiency. Saliva from 40 patients with confirmed hypercortisolism, 45 patients with various adrenal masses, and 115 healthy subjects was sampled at 2300 h and after low-dose dexamethasone suppression at 0800 h . ROC analysis was used to calculate thresholds with at least 95% sensitivity for hypercortisolism. Salivary cortisol was measured with an automated ECLIA. RESULTS: When screening for secondary adrenal insufficiency, a lower cutoff of 3.2 nmol/l and an upper cutoff of 13.2 nmol/l for unstimulated salivary cortisol allowed a highly specific diagnosis (i.e. similar to the ITT result) in 26% of patients. For identification of hypercortisolism, cutoffs of 6.1 nmol/l (sensitivity 95%, specificity 91%, area under the curve (AUC) 0.97) and 2.0 nmol/l (sensitivity 97%, specificity 86%, AUC 0.97) were established for salivary cortisol at 2300 h and for dexamethasone-suppressed salivary cortisol at 0800 h. CONCLUSIONS: The newly established thresholds facilitated initial screening for secondary adrenal insufficiency and allowed excellent identification of hypercortisolism. Measurement by an automated immunoassay will allow broader use of salivary cortisol as a diagnostic tool. PMID- 22214926 TI - Directed self-assembly of nanogold using a chemically modified nanopatterned surface. AB - Electron-beam lithography (EBL) was used to define an aminosilane nanopatterned surface in order to electrostatically self-assemble gold nanoparticles (Au NPs). The chemically modified nanopatterned surfaces were immersed into a Au NP solution to allow the Au NPs to self-assemble. Equilibrium self-assembly was achieved in only 20 min. The number of Au NPs that self-assembled on an aminosilane dot was controlled by manipulating the diameters of both the Au NPs and the dots. Adding salt to the Au NP solution enabled the Au NPs to self assemble in greater numbers on the same sized dot. However, the preparation of the Au NP solution containing salt was sensitive to spikes in the salt concentration. These spikes led to aggregation of the Au NPs and non-specific deposition of Au NPs on the substrate. The Au NP patterned surfaces were immersed in a sodium hydroxide solution in order to lift-off the patterned Au NPs, but no lift-off was observed without adequate physical agitation. The van der Waals forces are too strong to allow for lift-off despite the absence of electrostatic forces. PMID- 22214927 TI - Efficiency of antibiotic-loaded polymethylmethacrylate rods for treatment of the implant-related infections in rat spine. AB - STUDY DESIGN: A study of local treatment of the implant-related infections in animal spine. OBJECTIVE: : This study aims to investigate the efficiency of antibiotic-loaded polymethylmethacrylate rods for treatment of the implant related infections. SUMMARY OF BACKGROUND DATA: Today's implant-related vertebral infections are challenging in spinal surgery. In addition to resolving this problem, systemic antibiotic treatment is necessary to study and develop the effectiveness of locally applied treatment methods. METHODS: Twenty-four female white Sprague Dawley rats were randomized in 3 different groups, each consisting of 8 animals. Under general anesthesia, 3 mm titanium microscrew was implanted in the thoracic vertebra. All 3 groups were inoculated with the same concentration of Staphylococcus aureus (10 colony-forming units/10 MUL). Group 1 was assigned as a control group and received no additional therapy, group 2 was given single intraperitoneal doses of vancomycin, and group 3 was implanted vancomycin buffered acrylic rods. RESULTS: The results were analyzed by Fischer exact test. The comparison between the groups revealed a significantly higher therapeutic effect (P<0.05) in the local therapy group and in the systematic treatment group compared with the control group. The success of the treatment in the systemic treatment group was statistically not significantly different (P>0.05) compared with the outcome of the locally treated group. CONCLUSIONS: This study shows the success of antibiotic-loaded polymethylmethacrylate rods for the treatment of the spinal implant infections. Further research involving clinical studies is required to increase the efficacy and the clinical applicability of the technique. PMID- 22214928 TI - Use of autogenous bone graft compared with RhBMP in high-risk patients: a comparison of fusion rates and time to fusion. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To evaluate whether recombinant human bone morphogenetic protein (rhBMP-2) can improve fusion rates and time to fusion in high-risk patients when compared with autograft in lumbar posterolateral fusion. SUMMARY OF BACKGROUND DATA: The use of rhBMP-2 in the general population for posterolateral fusion has resulted in relatively good reported outcomes; however, it is currently considered "off-label" use. Few studies, however, have determined the outcomes of rhBMP-2 when used in patients with numerous risk factors for a pseudarthrosis. METHODS: One hundred ninety-five patients were divided into 4 groups depending on fusion material and the presence/absence of fusion-related risk factors for nonunions; group A was defined as rhBMP-2 used in the presence of high-risk factors (FRRF), group B was defined as rhBMP-2 used in the absence of FRRF, group C was defined as autograft used in the presence of FRRF, and group D was defined as autograft used in the absence of FRRF. The time to fusion, fusion rate were compared between each group. RESULTS: The time to fusion was significantly faster in group B than in group D in patients with no history of smoking (P<0.05), hypertension (P<0.01), or other significant comorbidity (P<0.05). The time to complete fusion was also significantly faster in group B than in group D in patients under the age of 65 (P<0.05), patients undergoing primary surgery (P<0.05), single-level surgery (P<0.01), no smoking history (P<0.05), no diabetes mellitus (P<0.01), no hypertension (P=0.001), no osteoporosis (P<0.01), and no significant comorbidity (P<0.01). Although the fusion rate was higher in group B than in group D, with the exception of sex and single-level surgery, there were no significant differences between groups B and D. Although initial fusion mass and time to solid fusion was faster in group A than in group C, there were no significant differences between groups A and C. In addition, fusion rates were higher in group C than in group A, looking at all factors except revision surgery, but the differences were not statistically significant. CONCLUSIONS: With relative low dosage of rhBMP-2 compared with the dose used in Food and Drug Administration trial, in patients without fusion-related risk factors, rhBMP-2 may lead to acceptable fusion rates and faster fusion time when compared with autograft. Therefore, rhBMP-2 may serve as an acceptable alternative to autogenous bone graft in patients without fusion-related risk factors undergoing instrumented posterolateral lumbar fusions. When compared with patients with fusion-related risk factors, the use of rhBMP-2 was comparable with autograft but was not sufficient to overcome all aspects of the weakened osteoinductive capacity encountered in patients with these risk factors. PMID- 22214929 TI - New class of Preyssler-lanthanide complexes with modified and extended structures tuned by the lanthanide contraction effect. AB - A family of polyoxometalate compounds based on Preyssler anions and lanthanide cations, K(5)Na(5)[{Pr(4)(H(2)O)(12)(pydc)(4)}{Na(H(2)O)P(5)W(30)O(110)}].46H(2)O (1, H(2)pydc = pyridine-2,6-dicarboxylic acid), Na(7)[{Pr(4)(H(2)O)(20)(pydc)(2)(Ac)}{Na(H(2)O)P(5)W(30)O(110)}].23H(2)O (2), and Na(10)H(2) [{Ln(2)(H(2)O)(10)(pydc)(2)}{Na(H(2)O)P(5)W(30)O(110)}].XH(2)O (Ln = Sm 3, Eu 4, Gd 5; X = 11 for 3 and 5, 13 for 4), have been synthesized and characterized by elemental analysis and single crystal X-ray diffraction. Compound 1 exhibits a two-dimensional honeycomb layer which is built up from unique {Pr(4)} metallacycles and Preyssler anions. Remarkably, the strong involvement of the sodium countercations leads to the formation of a unique three dimensional open architecture with one-dimensional channels. The 2D grid layer of compound 2 is constructed by the longest currently known rare-earth metal clusters {Pr(8)} and Preyssler anions. Isostructural compounds 3, 4, and 5, obtained by introduction of the intermediate lanthanide ions into the above reaction system, exhibit bisupporting [{Ln(2)(H(2)O)(10)(pydc)(2)}{Na(H(2)O)P(5)W(30)O(110)}](12-) polyoxometalate cluster structures. The magnetic properties of compounds 1 and 2 and the luminescent properties of compounds 3 and 4 are discussed in this paper. PMID- 22214930 TI - Recognition of epidermal transglutaminase by IgA and tissue transglutaminase 2 antibodies in a rare case of Rhesus dermatitis. AB - Tissue transglutaminase 2 (tTG2) is an intestinal digestive enzyme which deamidates already partially digested dietary gluten e.g. gliadin peptides. In genetically predisposed individuals, tTG2 triggers autoimmune responses that are characterized by the production of tTG2 antibodies and their direct deposition into small intestinal wall. The presence of such antibodies constitutes one of the major hallmarks of the celiac disease (CD). Epidermal transglutaminase (eTG) is another member of the transglutaminase family that can also function as an autoantigen in a small minority of CD patients. In these relatively rare cases, eTG triggers an autoimmune reaction (a skin rash) clinically known as dermatitis herpetiformis (DH). Although the exact mechanism of CD and DH pathogenesis is not well understood, it is known that tTG2 and eTG share antigenic epitopes that can be recognized by serum antibodies from both CD and DH patients. In this study, the confocal microscopy examination of biopsy samples from skin lesions of two rhesus macaques (Macaca mulatta) with dermatitis (Table 1, Fig. 1 and 2) was used to study the affected tissues. In one animal (EM96) a spectral overlap of IgA and tTG2 antibodies (Fig. 3) was demonstrated. The presence of double-positive tTG2+IgA+ cells was focused in the deep epidermis, around the dermal papillae. This is consistent with lesions described in DH patients. When EM96 was placed on a gluten-free diet, the dermatitis, as well as tTG2+IgA+ deposits disappeared and were no longer detectable (Figs. 1-3). Dermatitis reappeared however, based on re introduction of dietary gluten in EM96 (not shown). In other macaques including animal with unrelated dermatitis, the tTG2+IgA+ deposits were not detected. Gluten-free diet-dependent remission of dermatitis in EM96 together with presence of tTG2+IgA+ cells in its skin suggest an autoimmune, DH-like mechanism for the development of this condition. This is the first report of DH-like dermatitis in any non-human primate. PMID- 22214931 TI - Carnosic acid, a pro-electrophilic compound, inhibits LPS-induced activation of microglia. AB - In the previous studies, we reported that carnosic acid (CA) protects cortical neurons by activating the Keap1/Nrf2 pathway, which activation is initiated by S alkylation of the critical cysteine thiol of the Keap1 protein by the "electrophilic"quinone-type CA. Here, we found that the pro-electrophilic CA inhibited the in vitro lipopolysaccharide (LPS)-induced activation of cells of the mouse microglial cell line MG6. LPS induced the expression of IL-1beta and IL 6, typical inflammatory cytokines released from microglial cells. CA inhibited the NO production associated with a decrease in the level of inducible NO synthase. Neither CA nor LPS affected cell survival at the concentrations used here. These actions of CA seemed to be mediated by induction of phase 2 genes (gclc, gclm, nqo1 and xct). We propose that an inducer of phase 2 genes may be a critical regulator of microglial activation. Thus, CA is a unique pro electrophilic compound that provides both a protective effect on neurons and an anti-inflammatory one on microglia through induction of phase 2 genes. PMID- 22214932 TI - Traces of certain drug molecules can enhance heme-enzyme catalytic outcomes. AB - We report that trace amounts (nano- to picomolar concentrations) of dapsone and amiodarone in reaction mixtures of structurally and functionally distinct heme enzymes gave increased product formation rates from diverse substrates. These enhancements are found to be lowered by mild radical quenchers; a lowering well differentiated from heme active site inhibitions. Based on the non-specific nature of the activations in the diverse heme enzyme reactions studied, a generic mechanism is proposed to explain additive-based activity enhancements in heme enzymology. PMID- 22214933 TI - Uridine adenosine tetraphosphate (Up4A) is a strong inductor of smooth muscle cell migration via activation of the P2Y2 receptor and cross-communication to the PDGF receptor. AB - The recently discovered dinucleotide uridine adenosine tetraphosphate (Up(4)A) was found in human plasma and characterized as endothelium-derived vasoconstrictive factor (EDCF). A further study revealed a positive correlation between Up(4)A and vascular smooth muscle cell (VSMC) proliferation. Due to the dominant role of migration in the formation of atherosclerotic lesions our aim was to investigate the migration stimulating potential of Up(4)A. Indeed, we found a strong chemoattractant effect of Up(4)A on VSMC by using a modified Boyden chamber. This migration dramatically depends on osteopontin secretion (OPN) revealed by the reduction of the migration signal down to 23% during simultaneous incubation with an OPN-blocking antibody. Due to inhibitory patterns using specific and unspecific purinoreceptor inhibitors, Up(4)A mediates it's migratory signal mainly via the P2Y(2). The signaling behind the receptor was investigated with luminex technique and revealed an activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway. By use of the specific PDGF receptor (PDGFR) inhibitor AG1296 and siRNA technique against PDGFR beta we found a strongly reduced migration signal after Up(4)A stimulation in the PDGFR-beta knockdown cells compared to control cells. In this study, we present substantiate data that Up(4)A exhibits migration stimulating potential probably involving the signaling cascade of MEK1 and ERK1/2 as well as the matrix protein OPN. We further suggest that the initiation of the migration process occurs predominant through direct activation of the P2Y(2) by Up(4)A and via transactivation of the PDGFR. PMID- 22214934 TI - Phase and electrical behaviour in Bi4NbO8.5. AB - A study of phase and electrical behaviour in the bismuth niobate, Bi(4)NbO(8.5), using x-ray and neutron powder diffraction, thermogravimetric analysis (TGA), x ray photoelectron spectroscopy (XPS) and ac impedance spectroscopy is presented. Two polymorphs were identified in this composition, a tetragonal phase (type III), which can appear at temperatures above 800 degrees C and a pseudo-cubic phase (type II) evident at lower temperatures. The defect structure analysis of the type II phase is consistent with the existence of chains of niobate polyhedra, which facilitate electronic conduction at low temperatures. The appearance of the type III phase is strongly dependent on experimental conditions and TGA and XPS measurements suggest a likely association with change in oxygen stoichiometry. PMID- 22214936 TI - Endocytic uptake of FITC-albumin by human alveolar epithelial cell line A549. AB - The uptake mechanism of FITC-labeled albumin (FITC-albumin) was examined in human alveolar epithelial cell line A549. FITC-albumin uptake by A549 cells was time- and temperature-dependent, and was markedly suppressed at 4 degrees C compared with that at 37 degrees C. The uptake was saturable, and was mediated by a high affinity, low-capacity system and by a low-affinity, high-capacity system. In the following experiments, we focused on the low-affinity system. FITC-albumin uptake was markedly inhibited by metabolic inhibitors and by a vacuolar H+-ATPase, bafilomycin A1. The uptake was inhibited by clathrin-mediated endocytosis inhibitors (phenylarsine oxide and chlorpromazine). Potassium depletion and hypertonicity that inhibit clathrin-mediated endocytosis also decreased FITC albumin uptake. On the other hand, caveolae-mediated endocytosis inhibitors (indomethacin and nystatin) did not affect FITC-albumin uptake. In addition, FITC albumin uptake was inhibited by macropinocytosis inhibitors such as 5-(N-ethyl-N isopropyl) amiloride. These results suggest that the low-affinity system of FITC albumin uptake is mediated by endocytosis in A549 cells, predominantly via a clathrin-mediated pathway. Macropinocytosis, but not caveolae-mediated endocytosis, may also be involved. Considering our previous findings, albumin may be transported by a similar mechanism and/or pathway in rat and human alveolar epithelial cells. PMID- 22214937 TI - The impact of pharmacogenomics research on drug development. AB - Over the last two decades, identification of polymorphisms that influence human diseases has begun to have an impact on the provision of medical care. The promise of genetics lies in its ability to provide insight into an individual's susceptibility to disease, the likely nature of the disease and the most appropriate therapy. For much of its history, pharmacogenomics (PGx) has been limited to relatively simple phenotypes such as plasma drug levels. Progress in genetic technologies has broadened the scope of exploratory PGx and its implementation into safety and efficacy studies, impacting a broad spectrum of drug discovery and development activities. Recent PGx data show the ability of this approach to generate information that can be applied to target selection, dose selection, efficacy determination and safety issues. This in turn will lead to significant opportunities to influence the approaches to drug discovery, clinical development and the probability of success. In particular, adverse drug reactions are critical issues for pharmaceutical companies and for the patients who will benefit from these new medicines. In this review, we outline current progress in PGx, using examples to highlight the influence of polymorphisms, and discuss contemporary challenges for both researchers and clinicians. PMID- 22214938 TI - Spectrophotometric detection of tyrosinase activity based on boronic acid functionalized gold nanoparticles. AB - A spectrophotometric method for the detection of tyrosinase activity is developed by utilizing the product-triggered aggregation of boronic acid-functionalized gold nanoparticles. Based on the changes of absorbance in UV-visible spectra, the assay shows extremely high sensitivity and lowered limit of detection of 1 * 10( 10) u mL(-1). PMID- 22214939 TI - Herbivore-induced blueberry volatiles and intra-plant signaling. AB - Herbivore-induced plant volatiles (HIPVs) are commonly emitted from plants after herbivore attack. These HIPVs are mainly regulated by the defensive plant hormone jasmonic acid (JA) and its volatile derivative methyl jasmonate (MeJA). Over the past 3 decades researchers have documented that HIPVs can repel or attract herbivores, attract the natural enemies of herbivores, and in some cases they can induce or prime plant defenses prior to herbivore attack. In a recent paper, I reported that feeding by gypsy moth caterpillars, exogenous MeJA application, and mechanical damage induce the emissions of volatiles from blueberry plants, albeit differently. In addition, blueberry branches respond to HIPVs emitted from neighboring branches of the same plant by increasing the levels of JA and resistance to herbivores (i.e., direct plant defenses), and by priming volatile emissions (i.e., indirect plant defenses). Similar findings have been reported recently for sagebrush, poplar, and lima beans. Here, I describe a push-pull method for collecting blueberry volatiles induced by herbivore (gypsy moth) feeding, exogenous MeJA application, and mechanical damage. The volatile collection unit consists of a 4 L volatile collection chamber, a 2-piece guillotine, an air delivery system that purifies incoming air, and a vacuum system connected to a trap filled with Super-Q adsorbent to collect volatiles. Volatiles collected in Super-Q traps are eluted with dichloromethane and then separated and quantified using Gas Chromatography (GC). This volatile collection method was used in my study to investigate the volatile response of undamaged branches to exposure to volatiles from herbivore-damaged branches within blueberry plants. These methods are described here. Briefly, undamaged blueberry branches are exposed to HIPVs from neighboring branches within the same plant. Using the same techniques described above, volatiles emitted from branches after exposure to HIPVs are collected and analyzed. PMID- 22214940 TI - Probing the floor of the optic nerve head in glaucoma. PMID- 22214941 TI - Dermatofibrosarcoma protuberans. PMID- 22214942 TI - Evaluation of macular thickness by SD-OCT. PMID- 22214943 TI - Pars plana width and sclerotomy sites. PMID- 22214944 TI - Webcasts for resident education. PMID- 22214946 TI - Demodex blepharitis. PMID- 22214948 TI - Phakic intraocular collamer lens. PMID- 22214949 TI - Keratoprosthesis surveillance cultures. PMID- 22214951 TI - Visual field loss. PMID- 22214953 TI - Vitreous incarceration in sclerotomies. PMID- 22214956 TI - Displacement of the retina. PMID- 22214958 TI - Screening for hydroxychloroquine toxicity. PMID- 22214960 TI - Restrictive strabismus. PMID- 22214961 TI - Airway resistance, inflammation and oxidative stress following exposure to diesel exhaust particle in angiotensin II-induced hypertension in mice. AB - Exposure to particulate matter is a risk factor for respiratory and cardiovascular diseases. However, the mechanisms underlying these effects are not well understood. Here, we compared the impact of diesel exhaust particles (DEP) on airway resistance, inflammation and oxidative stress in normal mice, or mice made hypertensive by implanting osmotic minipump infusing angiotensin II. On day 13 after the onset of infusion, angiotensin II induced significant increase in heart rate (P<0.05) and systolic blood pressure (P<0.0001). On the same day, mice were intratracheally instilled with either DEP (15 MUg/mouse) or saline. Twenty four hour later, the measurement of airway reactivity to methacholine (0-10mg/ml) in vivo by a forced oscillation technique showed a significant and dose dependent increase in airway resistance in normotensive mice exposed to DEP compared to those exposed to saline. In hypertensive mice, there was no difference in airway resistance in DEP versus saline exposed mice. However, following exposure to DEP, airway resistance significantly increased in normotensive versus hypertensive mice. Bronchoalveolar lavage (BAL) fluid analysis showed a significant increase in macrophage numbers in normotensive mice exposed to DEP compared to those exposed to saline, and to hypertensive mice exposed to DEP. Neutrophil numbers were significantly increased in both normotensive and hypertensive mice exposed to DEP compared with their respective control groups. Superoxide dismutase activity was significantly decreased following DEP exposure in both normotensive and hypertensive mice compared to their respective controls. However, total proteins, a marker for increase of epithelial permeability, and malondialdehyde, a reflection of lipid peroxidation, were only increased in normotensive mice exposed to DEP. Therefore, our data suggest that DEP do not aggravate airway resistance and inflammation in angiotensin II-induced hypertensive mice. On the contrary, at the dose of DEP and time point investigated, airway resistance, inflammation and oxidative stress are increased in normotensive compared to hypertensive mice. PMID- 22214962 TI - Prevalence of human papillomavirus in breast cancer: a systematic review. AB - OBJECTIVE: We performed a systematic review and meta-analyses to estimate the prevalence of human papillomavirus (HPV) in breast carcinoma and to explore the reasons for the ongoing controversies about this issue. MATERIALS AND METHODS: A comprehensive search of the Cochrane Library, MEDLINE, CANCERLIT, LILACS, and EMBASE databases was performed for papers published from January 1990 to January 2011. The medical subject heading terms were searched for the following: breast neoplasm, breast lesions, breast cancer, and HPV or human papillomavirus. Statistical analysis was performed using REVMAN 5.0. RESULTS: Twenty-nine primary studies, including 2211 samples, were analyzed. Overall, HPV prevalence in patients with breast cancer was 23.0% (95% CI, 21.2%-24.8%). The prevalence of HPV ranged from 13.4% (95% CI, 10.2%-16%) in Europe to 42.9% (95% CI, 36.4% 49.4%) in North America and Australia. The prevalence of HPV in controls was 12.9%. Combinations of 9 case-control studies showed that breast cancer was associated with HPV (odds ratio, 5.9; 95% CI, 3.26-10.67). CONCLUSION: We found a high prevalence of HPV DNA in breast cancer. There is strong evidence to suggest that HPV has an important role in the development of breast cancer. PMID- 22214963 TI - Type II versus type III fertility-sparing abdominal radical trachelectomy for early-stage cervical cancer: a comparison of feasibility of surgical outcomes. AB - OBJECTIVE: The purpose of this study was to compare surgical outcomes using modified (type II) and traditional (type III) abdominal radical trachelectomy (ART) for fertility-sparing surgery in early cervical cancer. METHODS: A prospectively maintained database of ART procedures was analyzed. Data were collected regarding age, stage, histology, operative outcome, surgical complication, and fertility outcome. RESULTS: We performed 23 fertility-sparing ARTs for patients with International Federation of Gynecology and Obstetrics stages IA to IB1 tumors of less than 2 cm between 2006 and 2010. Type III ART was attempted in 8 patients and modified ART in 15 patients. The median operating time was greater in the type III group compared with that in the type II group (305 vs 247 minutes; P < 0.02). The median surgical blood loss was greater in the type III ART group (580 mL; range, 250-988 mL) compared with that in the modified type II group (366 mL; range, 200-850 mL; P < 0.05). The median time to recovery of bladder dysfunction was less in the type II group (9 days; range, 3-10 days) than that in the type III group (13 days; range, 10-23 days; P < 0.01). There were no recurrences at the time of this report. CONCLUSIONS: Type II ART provides surgical and pathological outcomes with better recovery of bladder function similar to those in type III ART. For patients with early cervical cancer who wish to preserve reproductive function, type II ART is a feasible and safe operation. PMID- 22214964 TI - The utility of human epididymal protein 4, cancer antigen 125, and risk for malignancy algorithm in ovarian cancer and endometriosis. AB - BACKGROUND: In women with pelvic mass, cancer antigen 125 (CA125) had not achieved satisfactory sensitivity and specificity in the detection of ovarian cancer, particularly in patients with underlying endometriosis. The aim of this study was to determine the diagnostic potential of human epididymal protein 4 (HE4), the combination of HE4+CA125, and the Risk of Ovarian Malignancy Algorithm (ROMA) for patients with pelvic mass, particularly in differentiating endometriosis from carcinoma. METHODS: A prospective cross-sectional study was conducted at the Clinic for Gynecology and Obstetrics, Clinical Center of Serbia. Serum samples were obtained preoperatively from 108 women undergoing surgery for pelvic mass; 29 of them had ovarian carcinoma, and 79 had a nonmalignant ovarian disease (39 with benign tumor, 20 with endometriosis, 20 healthy controls). Sera were analyzed for the levels of HE4 and CA125 and were then compared with the final pathologic results. The diagnostic performance of HE4 and CA125 was estimated using receiver operating characteristic curve and area under the receiver operating characteristic curve. RESULTS: The level of HE4 and CA125 was significantly higher among the patients with malignant tumors, compared with patients with nonmalignant disease. At the predefined specificity of 95%, HE4 and CA125 showed sensitivity of 65.5% and 58.6%, respectively, whereas the combination of HE4+CA125 reached 68.9% at the same specificity. Importantly, the level of HE4 did not differ significantly between the patients with endometriosis and with other nonmalignant diseases (which was not the case with CA125). Risk of Ovarian Malignancy Algorithm classified 96% of benign premenopausal cases as at low risk for ovarian cancer. CONCLUSIONS: HE4 showed satisfactory capability of distinguishing endometriosis from ovarian cancer, which CA125 lacked. The Risk of Ovarian Malignancy Algorithm score proved to be useful in excluding malignant diagnosis in premenopausal women. PMID- 22214965 TI - Assessment of invasion in lung adenocarcinoma classification, including adenocarcinoma in situ and minimally invasive adenocarcinoma. AB - Classification of adenocarcinoma has undergone recent evaluation to better align histological classification with clinical outcomes. One terminology, in particular, that of bronchioloalveolar carcinoma (BAC), has been debated for many decades. Although initial discussion surrounded the cell-of-origin of this tumor, more recent confusion has been generated from the use of this term both as a pattern of growth within an otherwise invasive adenocarcinoma and as a term for a pre-invasive tumor synonymous with adenocarcinoma in situ. As a result, adenocarcinomas with quite different radiology, gross morphology and metastatic potential have been associated with the BAC term. Focusing on invasion and using an illustrative case, we will explore the current recommendations that incorporate assessment of invasion to clarify the confusion caused by the different uses of the historical term 'BAC'. PMID- 22214966 TI - Role of molecular studies in the diagnosis of lung adenocarcinoma. AB - Molecular alterations in adenocarcinoma of the lung have resulted in new therapeutic options for treatment of high-stage disease. Such changes are usually mutually exclusive and can be documented in small specimen samples. Most analyses are DNA-based, utilizing sequencing or fluorescence in situ hybridization to observe amplifications or translocations. Particular success in theranostics has focused on epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase gene (ALK), and BRAF gene changes, each allowing personalized therapies. Interestingly, these molecular changes have correlated with distinct, although not unique, demographics, histopathologies, and response to pharmacological agents. PMID- 22214967 TI - Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other non-small cell carcinomas. AB - Small cell lung cancer (SCLC) comprises 14% of all lung cancers, and >30,000 new cases are diagnosed per year in the United States. SCLC is one of the most distinctive malignancies in the entire field of oncology with characteristic clinical properties, responsiveness to specific chemotherapy, genetic features and a highly reliable pathological diagnosis. SCLC is defined by light microscopy, and the most important stain is a good-quality hematoxylin and eosin (H&E)-stained section. The vast majority of cases can be diagnosed on H&E alone; however, in problem cases, immunohistochemistry can be very helpful in making the distinction from other tumors. Cytology is also a powerful tool, often being more definitive than small biopsies with scant tumor cells, crush artifact and/or necrosis. As virtually all SCLCs present in advanced stages, most patients are diagnosed based on small biopsy and cytology specimens. Historically, there has been significant evolution in the histological subclassification of SCLC dating from 1962 when Kreyberg proposed the oat cell and polygonal cell types. The current subclassification recognizes only two subtypes: pure SCLC and combined SCLC. Pathologists need to do their best to make a diagnosis of SCLC or other histological types of lung cancer and this can be achieved in most cases. This review will address some of the diagnostic problems that occur in the minority of cases and outline practical ways to address them. Brief reference will be made to other neuroendocrine lung tumors with an overview of the molecular pathogenesis of this spectrum of tumors. PMID- 22214968 TI - Necrotizing granulomatous inflammation: what does it mean if your special stains are negative? AB - Necrotizing granulomas are commonly encountered in surgically resected specimens. The majority will be proven infectious with special stains for microorganisms. These need to be distinguished from other granulomatous processes such as Wegener's granulomatosis (WG). Although there may be histological overlap between these different processes, the identification of a true necrotizing vasculitis is specific to WG in the context of necrotizing granulomas. Otherwise, the combination of histological features should lead to a specific diagnosis. Despite a thorough histological examination and assessments of special stains, a significant proportion of necrotizing granulomas will appear infectious with no obvious infectious etiology. There are only few clinically available ancillary tests that can be performed on paraffin-embedded tissue and include real-time PCR for tuberculous mycobacteria. Despite correlation with clinical, serological and other microbiological studies, some necrotizing granulomas remain unexplained. Patients with such granulomas appear not to require any additional treatment and do experience a favorable outcome. PMID- 22214969 TI - Current histological diagnosis of lymphomatoid granulomatosis. AB - The current histological criteria for the diagnosis of lymphomatoid granulomatosis (LYG) are reviewed and summarized. The majority of patients present with multiple bilateral nodules involving the lung. Key histologic features necessary for the diagnosis include a mixed mononuclear cell infiltrate that shows vascular infiltration, appreciable numbers of T-cells, and variable numbers of CD20-positive B cells that show positivity for EBER by in situ hybridization. PMID- 22214970 TI - Utility of small biopsies for diagnosis of lung nodules: doing more with less. AB - Small biopsies obtained by core needle or bronchoscopy are commonly used for diagnosis of lung nodules. This review provides guidance in two key areas of interpretation of small lung biopsies. The first part answers common questions regarding the immunohistochemical subclassification of non-small cell lung carcinomas that cannot be classified by standard criteria on hematoxylin-eosin stained sections of small lung biopsies. The second part discusses common benign entities that can be diagnosed in core needle biopsies of lung nodules, such as granulomatous inflammation, parenchymal scars and organizing pneumonia. The approach to cases in which malignant cells are absent and features of a specific benign diagnosis are lacking is also addressed. PMID- 22214971 TI - Hypersensitivity pneumonia: the role of lung biopsy in diagnosis and management. AB - Hypersensitivity pneumonia is a form of diffuse interstitial lung disease resulting from sensitization to an inhaled antigen. Clinical and radiological features are relatively nonspecific, overlapping significantly with other forms of diffuse interstitial lung disease. Establishing the diagnosis in the absence of lung biopsy is challenging and is heavily dependent on being able to identify a specific antigenic exposure. Lung biopsy is especially important in diagnosing hypersensitivity pneumonia in patients for whom no incriminating exposure has been elucidated. Surgical lung biopsies show a classical combination of findings in the majority of patients, which include an airway-centered, variably cellular chronic interstitial pneumonia, a lymphocyte-rich chronic bronchiolitis, and poorly formed non-necrotizing granulomas distributed mainly within the peribronchiolar interstitium. The bronchiolitis may include variable degrees of peribronchiolar fibrosis and hyperplasia of the bronchiolar epithelium ('peribronchiolar metaplasia'), a characteristic but a nonspecific finding. In some patients, granulomatous inflammation may be lacking, resulting in a histological appearance resembling nonspecific interstitial pneumonia. Late-stage fibrotic hypersensitivity pneumonia results in clinical, radiological, and histological findings that closely mimic usual interstitial pneumonia. The presence of established collagen fibrosis, especially when associated with architectural distortion in the form of honeycomb change, is associated with shorter survivals. PMID- 22214972 TI - Smoking-related interstitial fibrosis (SRIF), pathogenesis and treatment of usual interstitial pneumonia (UIP), and transbronchial biopsy in UIP. AB - This review focuses on three selected topics of current interest that are related to chronic fibrosing lung disorders and are important for pathologists. First, the clinical and pathologic features of smoking-related interstitial fibrosis (SRIF) are highlighted. SRIF is a common finding in smokers that has striking histologic changes but only mild associated clinical manifestations. It is characterized by marked alveolar septal fibrosis composed of a distinct form of hyalinized collagen deposition. The process is present mainly in subpleural and centrilobular parenchyma and is associated with emphysema and respiratory bronchiolitis. Second, important aspects of the pathogenesis and treatment of usual interstitial pneumonia (UIP) are reviewed. The current theory proposes that UIP is caused by tiny foci of acute lung injury (manifest pathologically by fibroblast foci) that occur and recur in the interstitium over many years. Inflammation may be present as a secondary phenomenon, but is not the primary cause, and therefore anti-inflammatory agents have little effect. The recurrent injury leads to permanent fibrosis, through a process that is considered to represent a form of abnormal wound healing. Multiple therapies have been attempted that are aimed largely at interrupting the fibrosing process, but none have been successful. The cause of the injury is unknown, but a role for aspiration due to gastroesophageal reflux is a popular current theory, and there is some evidence that anti-reflux therapy may be beneficial. Genetic predisposition has been implicated in the etiology of familial cases, and there is evidence that telomere shortening may be important in sporadic cases. Third, the use of transbronchial biopsy (TBB) in diagnosing UIP is reviewed. TBB can provide a surprising amount of information and is especially useful in certain situations, such as elderly or very sick patients in whom surgical lung biopsy carries increased morbidity and mortality. PMID- 22214973 TI - Rapid increase in the national treatment costs for hepatitis A infections in Korea. AB - The number of symptomatic hepatitis A cases has progressively been increasing during the last several years in Korea. Available cost estimates indicate a growing burden to the public. The purpose of this study was to determine the extent of treatment costs for patients with hepatitis A and to analyze the influential factors with nationwide data. We collected data on 72,921 patients with hepatitis A from 5-year National Health Insurance claim archives between 2004 and 2008. Multiple regression analyses were conducted to examine influential factors affecting treatment costs for hepatitis A. Total treatment costs for patients with hepatitis A during the 5-year period were US$47,902,087 and increased significantly each year. In total, 91.4% of treatment costs were used for hospitalization, and the proportion of inpatients increased gradually throughout the study period. The most influential factor on treatment costs was treatment duration. Our results show that the soaring number of patients with hepatitis A followed by the hospitalization-focused treatment practice is a major factor associated with the rapid increase in treatment costs. Appropriate policies should be promptly developed to control treatment costs and economic burden of hepatitis A infections. PMID- 22214974 TI - Method to measure tone of axial and proximal muscle. AB - The control of tonic muscular activity remains poorly understood. While abnormal tone is commonly assessed clinically by measuring the passive resistance of relaxed limbs, no systems are available to study tonic muscle control in a natural, active state of antigravity support. We have developed a device (Twister) to study tonic regulation of axial and proximal muscles during active postural maintenance (i.e. postural tone). Twister rotates axial body regions relative to each other about the vertical axis during stance, so as to twist the neck, trunk or hip regions. This twisting imposes length changes on axial muscles without changing the body's relationship to gravity. Because Twister does not provide postural support, tone must be regulated to counteract gravitational torques. We quantify this tonic regulation by the restive torque to twisting, which reflects the state of all muscles undergoing length changes, as well as by electromyography of relevant muscles. Because tone is characterized by long lasting low-level muscle activity, tonic control is studied with slow movements that produce "tonic" changes in muscle length, without evoking fast "phasic" responses. Twister can be reconfigured to study various aspects of muscle tone, such as co-contraction, tonic modulation to postural changes, tonic interactions across body segments, as well as perceptual thresholds to slow axial rotation. Twister can also be used to provide a quantitative measurement of the effects of disease on axial and proximal postural tone and assess the efficacy of intervention. PMID- 22214975 TI - Mechanistic insight into formation and changes of nanoparticles in MgF2 sols evidenced by liquid and solid state NMR. AB - The fluorolytic sol-gel reaction of magnesium methoxide with HF in methanol was studied by (19)F, (1)H and (13)C liquid and solid state NMR. In (19)F NMR five different species were identified, three of which belong to magnesium fluoride nanoparticles, i.e. NMR gave access to local structures of solid particles in suspensions. The long-term evolution of (19)F signals was followed and along with (19)F MAS NMR experiments of sols rotating at 13 kHz mechanistic insights into the ageing processes were obtained. PMID- 22214976 TI - Single nanoparticle detectors for biological applications. AB - Nanoparticle research has become increasingly important in the context of bioscience and biotechnology. Practical use of nanoparticles in biology has significantly advanced our understanding about biological processes in the nanoscale as well as led to many novel diagnostic and therapeutic applications. Besides, synthetic and natural nanoparticles are of concern for their potential adverse effect on human health. Development of novel detection and characterization tools for nanoparticles will impact a broad range of disciplines in biological research from nanomedicine to nanotoxicology. In this article, we discuss the recent progress and future directions in the area of single nanoparticle detectors with an emphasis on their biological applications. A brief critical overview of electrical and mechanical detection techniques is given and a more in-depth discussion of label-free optical detection techniques is presented. PMID- 22214977 TI - The influence of active and passive smoking during pregnancy on umbilical cord blood levels of vitamins A and E and neonatal anthropometric indices. AB - Smoking during pregnancy has been shown to be detrimental for the developing fetus. The effects of active and passive maternal smoking on umbilical cord serum levels of vitamin A and vitamin E were examined. Secondary measures included anthropometric parameters in the newborn. Maternal and umbilical cord serum levels of vitamins A and E were measured at delivery. The mothers were assigned to three groups: non-smoking (n 12); passive smoking (n 13); active smoking (n 18). Based on multivariate linear regressions, active smoking during pregnancy was associated with increased umbilical cord serum levels of vitamin A and vitamin E. While enhanced circulating levels of vitamin A in cord blood were also found in non-smoking mothers exposed to tobacco smoke during pregnancy, those of vitamin E were not influenced. Further, an inverse association between smoking behaviour during pregnancy and birth length was observed, with shortest length in active smokers followed by passive smoking mothers. Active and passive maternal smoking behaviour during pregnancy increases the fetal demand for antioxidant compounds in order to counteract the oxidative burden by cigarette smoke. Against this background, the observed increase in umbilical cord serum levels of vitamins A and E may subserve antioxidative processes in response to tobacco smoke-induced oxidative stress. This would reduce the availability of vitamins A and E for fetal maturation, which is critical inasmuch as both compounds are indispensable for the developing fetus. However, due to the cross-sectional nature of our observation, this line of reasoning definitely requires validation in cause effect experiments in the future. PMID- 22214978 TI - Planar and three-dimensional printing of conductive inks. AB - Printed electronics rely on low-cost, large-area fabrication routes to create flexible or multidimensional electronic, optoelectronic, and biomedical devices. In this paper, we focus on one- (1D), two- (2D), and three-dimensional (3D) printing of conductive metallic inks in the form of flexible, stretchable, and spanning microelectrodes. Direct-write assembly is a 1-to-3D printing technique that enables the fabrication of features ranging from simple lines to complex structures by the deposition of concentrated inks through fine nozzles (~0.1 - 250 MUm). This printing method consists of a computer-controlled 3-axis translation stage, an ink reservoir and nozzle, and 10x telescopic lens for visualization. Unlike inkjet printing, a droplet-based process, direct-write assembly involves the extrusion of ink filaments either in- or out-of-plane. The printed filaments typically conform to the nozzle size. Hence, microscale features (< 1 MUm) can be patterned and assembled into larger arrays and multidimensional architectures. In this paper, we first synthesize a highly concentrated silver nanoparticle ink for planar and 3D printing via direct-write assembly. Next, a standard protocol for printing microelectrodes in multidimensional motifs is demonstrated. Finally, applications of printed microelectrodes for electrically small antennas, solar cells, and light-emitting diodes are highlighted. PMID- 22214979 TI - An analysis of the New York University Emergency Department Algorithm's suitability for use in gauging changes in ED usage patterns. AB - BACKGROUND: The Emergency Department Algorithm (EDA) developed at New York University uses administrative discharge data to distill hundreds of International Classification of Diseases-9 codes for emergency department (ED) visits into 4 categories, making it attractive to researchers and policy makers. The EDA has been used to analyze patterns of ED visits in a wide variety of locations and populations. However, there are concerns regarding the validity and use of the EDA for research and policy. OBJECTIVE: To explain the findings of previous EDA users that it appears to lack sensitivity in detecting changes in ED utilization patterns. STUDY DESIGN: Mathematical simulation was used to analyze and explain the performance of the EDA in detecting differences in utilization patterns across hypothetical ED populations. Sensitivity analysis was used to illustrate the magnitude of changes in EDA outputs relative to changes in ED populations using a national sample of actual ED patients. RESULTS: The vast majority of possible EDA outputs are clustered so tightly as to show no significant change in outputs between different hypothetical populations. Sensitivity analysis shows that changes in EDA outputs are not nearly as great as the magnitude of the input differences across real-world populations. CONCLUSIONS: The EDA categorizes a very large variety of ED visits into a relatively small group of outputs. Its operating characteristics suggest that the EDA is insufficiently sensitive to changes in ED utilization patterns to be useful in assessing interventions to change them. This finding should caution potential users to consider the EDA's limitations before using it. PMID- 22214980 TI - Understanding the challenges of adjuvant treatment measurement and reporting in breast cancer: cancer treatment measuring and reporting. AB - BACKGROUND: Healthcare accrediting organizations and insurers increasingly require reporting of clinical data, and cancer treatment is one area of enhanced scrutiny. OBJECTIVES: To compare rates of received versus reported adjuvant breast cancer treatments, and to assess barriers to measuring and reporting treatments to the tumor registry (TR) of a high-volume medical center with both hospital-based and community-based oncologists. RESEARCH DESIGN: We calculated rates of received treatments using data collected using chart abstraction (N=115) and compared these with rates of reported treatments from the TR (N=535). We conducted 31 indepth interviews with clinical and administrative informants. Asking about perceptions of the TR, current reporting methods, and reporting barriers. Interviews were recorded, transcribed, and analyzed using deductive and inductive methods. RESULTS: : Rates of reported versus received treatments were radiation therapy after breast-conserving surgery 22% versus 84% (P < 0.0001); chemotherapy for stage 2 or 3: 17% versus 79% (P < 0.0001); hormonal therapy for stage 2 or 3: 1% versus 91% (P < 0.0001). Comparing community-based versus hospital-based oncologists' rates reported to the TR, we found the following differences: radiation therapy post-breast conserving surgery 12% versus 32% (< 0.0001); chemotherapy 8% versus 29% (< 0.0001); and hormonal therapy 0% versus 3% (0.09). We found 4 key barriers to measuring and reporting poor understanding about the TR, limited information technology capabilities, poor communication, and mistrust. CONCLUSIONS: : Efforts to improve cancer care quality by improved treatment reporting must overcome key barriers, especially those involving information exchange and mistrust. Communications between the TR and oncology practices must improve to facilitate better treatment measurement and reporting. PMID- 22214981 TI - Allylic alcohols as synthetic enolate equivalents: isomerisation and tandem reactions catalysed by transition metal complexes. AB - Allylic alcohols can be isomerised into carbonyl compounds by transition metal complexes. In the last few years, catalyst design and development have resulted in highly efficient isomerisations under mild reaction conditions, including enantioselective versions. In addition, the isomerisation of allylic alcohols has been combined with C-C bond forming reactions when electrophiles such as aldehydes or imines were present in the reaction mixture. Also, C-F bonds can be formed when electrophilic fluorinating reagents are used. Thus, allylic alcohols can be treated as latent enol(ate)s. In this article, we highlight the latest developments concerning the isomerisation of allylic alcohols into carbonyl compounds, focusing in particular on tandem isomerisation/C-C or C-heteroatom bond formation processes. Significant attention is given to the mechanistic aspects of the reactions. PMID- 22214982 TI - Differential protective effects of quercetin, resveratrol, rutin and epigallocatechin gallate against mitochondrial dysfunction induced by indomethacin in Caco-2 cells. AB - The beneficial effects of dietary polyphenols on health are due not only to their antioxidant properties but also to their antibacterial, anti-inflammatory and/or anti-tumoral activities. It has recently been proposed that protection of mitochondrial function (which is altered in several diseases such as Alzheimer, Parkinson, obesity and diabetes) by these compounds, may be important in explaining the beneficial effects of polyphenols on health. The aim of this study was to evaluate the protective effects of dietary polyphenols quercetin, rutin, resveratrol and epigallocatechin gallate against the alterations of mitochondrial function induced by indomethacin (INDO) in intestinal epithelial Caco-2 cells, and to address the mechanism involved in such damaging effect by INDO, which generates oxidative stress. INDO concentration dependently decreases cellular ATP levels and mitochondrial membrane potential in Caco-2 cells after 20min of incubation. INDO also inhibits the activity of mitochondrial complex I and causes accumulation of NADH; leading to overproduction of mitochondrial O(2)()(-), since it is prevented by pyruvate. Quercetin (0.01mg/ml), resveratrol (0.1mg/ml) and rutin (1mg/ml) protected Caco-2 cells against INDO-induced mitochondrial dysfunction, while no protection was observed with epigallocatechin gallate. Quercetin was the most efficient in protecting against mitochondrial dysfunction; this could be due to its ability to enter cells and accumulate in mitochondria. Additionally its structural similarity with rotenone could favor its binding to the ubiquinone site of complex I, protecting it from inhibitors such as INDO or rotenone. These findings suggest a possible new protective role for dietary polyphenols for mitochondria, complementary of their antioxidant property. This new role might expand the preventive and/or therapeutic use of PPs in conditions involving mitochondrial dysfunction and associated with increased oxidative stress at the cellular or tissue levels. PMID- 22214983 TI - Effects of phthalates on 3beta-hydroxysteroid dehydrogenase and 17beta hydroxysteroid dehydrogenase 3 activities in human and rat testes. AB - The 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17beta-hydroxysteroid dehydrogenase 3 (17beta-HSD3) are involved in the reactions that culminate in androgen biosynthesis in Leydig cells. Human and rat testis microsomes were used to investigate the inhibitory potencies on 3beta-HSD and 17beta-HSD3 activities of 14 different phthalates with various carbon numbers in the ethanol moiety. The results demonstrated that the half-maximal inhibitory concentrations (IC(50)s) of dipropyl (DPrP), dibutyl (DBP), dipentyl (DPP), bis(2-butoxyethyl) (BBOP) and dicyclohexyl (DCHP) phthalate were 123.0, 24.1, 25.5, 50.3 and 25.5MUM for human 3beta-HSD activity, and 62.7, 30.3, 33.8, 82.6 and 24.7MUM for rat 3beta-HSD activity, respectively. However, only BBOP and DCHP potently inhibited human (IC(50)s, 23.3 and 8.2MUM) and rat (IC(50)s, 30.24 and 9.1MUM) 17beta-HSD3 activity. Phthalates with 1-2 or 7-8 carbon atoms in ethanol moieties had no effects on both enzyme activities even at concentrations up to 1mM. The mode of action of DCHP on 3beta-HSD activity was competitive with the substrate pregnenolone but noncompetitive with the cofactor NAD+. The mode of action of DCHP on 17beta-HSD3 activity was competitive with the substrate androstenedione but noncompetitive with the cofactor NADPH. In summary, our results showed that there are clear structure-activity responses for phthalates in the inhibition of both 3beta-HSD and 17beta-HSD3 activities. The length of carbon chains in the ethanol moieties of phthalates may determine the potency to inhibit these two enzymes. PMID- 22214984 TI - Direct detection of the acetate-forming activity of the enzyme acetate kinase. AB - Acetate kinase, a member of the acetate and sugar kinase-Hsp70-actin (ASKHA) enzyme superfamily, is responsible for the reversible phosphorylation of acetate to acetyl phosphate utilizing ATP as a substrate. Acetate kinases are ubiquitous in the Bacteria, found in one genus of Archaea, and are also present in microbes of the Eukarya. The most well characterized acetate kinase is that from the methane-producing archaeon Methanosarcina thermophila. An acetate kinase which can only utilize PP(i) but not ATP in the acetyl phosphate-forming direction has been isolated from Entamoeba histolytica, the causative agent of amoebic dysentery, and has thus far only been found in this genus. In the direction of acetyl phosphate formation, acetate kinase activity is typically measured using the hydroxamate assay, first described by Lipmann, a coupled assay in which conversion of ATP to ADP is coupled to oxidation of NADH to NAD(+) by the enzymes pyruvate kinase and lactate dehydrogenase, or an assay measuring release of inorganic phosphate after reaction of the acetyl phosphate product with hydroxylamine. Activity in the opposite, acetate-forming direction is measured by coupling ATP formation from ADP to the reduction of NADP(+) to NADPH by the enzymes hexokinase and glucose 6-phosphate dehydrogenase. Here we describe a method for the detection of acetate kinase activity in the direction of acetate formation that does not require coupling enzymes, but is instead based on direct determination of acetyl phosphate consumption. After the enzymatic reaction, remaining acetyl phosphate is converted to a ferric hydroxamate complex that can be measured spectrophotometrically, as for the hydroxamate assay. Thus, unlike the standard coupled assay for this direction that is dependent on the production of ATP from ADP, this direct assay can be used for acetate kinases that produce ATP or PP(i). PMID- 22214985 TI - Face and construct validity of the Gait Deviation Index in adults with spastic cerebral palsy. AB - OBJECTIVE: To investigate face and construct validity of the Gait Deviation Index (GDI) in adults with spastic cerebral palsy. The International Classification of Functioning, Disability and Health (ICF) was used as a framework, defining gait and walking as the manner or style of walking ("body function"), and the execution of gait ("activity"), respectively. DESIGN: A cross-sectional study. METHODS: PARTICIPANTS: 66 adults with spastic cerebral palsy, mean age 37 years, and previously collected data on 50 healthy adults (reference population). VARIABLES: GDI from three-dimensional gait analysis, Gross Motor Function Classification System (GMFCS), 6-min walk test (6MWT), Timed Up and Go (TUG), and Physiological Cost Index (PCI). RESULTS: Mean GDI was 74.3 in adults with cerebral palsy, and 101.1 in the reference population. A significant difference in GDI was found between the reference population and GMFCS level I (p < 0.001), between I and II (p < 0.001), but not between II and III (p = 0.633). The associations between GDI and 6MWT, TUG and PCI were r = 0.30, r = -0.30, and r = 0.56, respectively. CONCLUSION: GDI demonstrated similar distributional properties as those reported in children with cerebral palsy, suggesting satisfactory face validity. Low correlations between GDI and 6MWT/TUG reflect that gait and functional walking/mobility are different constructs, implicating the importance of selecting outcomes in all ICF domains when evaluating walking ability in adults with spastic cerebral palsy. PMID- 22214987 TI - Use of cellular electrical impedance sensing to assess in vitro cytotoxicity of anticancer drugs in a human kidney cell nephrotoxicity model. AB - Nephrotoxicity is one of the major concerns for anticancer drug safety because most drugs are metabolized and excreted by the kidneys. Convenient tools able to perform rapid in vitro cytotoxicity analysis and identify drug side effects in kidney cells during early phases of drug discovery could be beneficial to drug development programs. Here we developed an electrical cell-substrate impedance sensing system (ECIS) capable of continuously measuring the dosage and time response of human proximal tubular epithelial (HK2) cells exposed to four drugs throughout the experimental period. These drugs induced HK2 cell apoptosis/death in a dose-dependent manner, although with very different dose-response effects. DDP (50 MUM) was the most cytotoxic and induced obvious HK2 cell apoptosis rapidly after exposure. The other three drugs had much lower cytotoxicity, even at concentrations approaching 1 mM. The results obtained from our ECIS system correlated well with conventional in vitro assays such as flow cytometry and cell viability assays. Notably, the continuous and automatic measurements provided by ECIS system allow for better resolution for drugs with different temporal toxicity profiles. Furthermore, we investigated the effect of DDP's antidotes, glutathione and sodium subsulfite, on DDP-induced cytotoxicity, both of which decreased nephrotoxicity of DDP in a dose-dependent manner. Overall this study illustrates the convenience of ECIS for direct, continuous assessment of the cytotoxicity of anticancer drugs in vitro. ECIS has the potential to become a useful, non-invasive analytical method for early evaluation of drugs and antidotes of toxins. PMID- 22214989 TI - Comparative study of the polyvinyl siloxane technique with resin-splinted transfer copings used for multiple implant abutment impressions. AB - STATEMENTS OF PROBLEM: The lack of passivity in implant dentistry may result in failures. Therefore, impression is the first procedure in the fabrication of a passive prosthesis. The aim of this study is to compare the polyvinyl siloxane technique with a resin-splinted transfer copings used for multiple implant abutment impression. METHODS: A master cast was obtained from an edentate ridge. From the master cast, 30 casts were obtained using 3 different impression techniques. Control technique was made with polyvinyl siloxane. Resin-splinted transfer copings in condensation siloxane or irreversible hydrocolloid were used as test. The distances between analogs were obtained using a profile projector. Statistical analysis was carried out using 1-way analysis of variance. RESULTS: No significant difference among the 3 impression techniques (P > 0.05) was observed. CONCLUSION: Resin-splinted transfer copings in condensation siloxane or irreversible hydrocolloid produced impressions as accurately as polyvinyl siloxane. PMID- 22214990 TI - Monocytes: super cells for bone regeneration. AB - Monocytes are progenitor cells that lead the inflammatory cascade reaction responsible for guiding revascularization and regeneration of tissue at injury sites. They do this by secreting inductive cytokines responsible for endothelial cell migration. When released into the peripheral blood, monocytes enter tissues and become macrophages. Monocytes also trigger the body's defense mechanism against microbial invasion by lysing and removing cell debris and dead tissue. The aim of this article is to explain the role of monocytes in the processes of bone healing and regeneration and describe their interaction with stem cells and other entities. Results of a pilot histomorphometric study in which concentrated monocytes were combined with demineralized allograft material to augment implant placement sites in 2 patients also are presented. PMID- 22214992 TI - Ba2AgInS4 and Ba4MGa5Se12 (M = Ag, Li): syntheses, structures, and optical properties. AB - The first two members in alkaline-earth/group XI/group XIII/chalcogen system, namely Ba(2)AgInS(4) and Ba(4)AgGa(5)Se(12), were synthesized along with a Li analogue Ba(4)LiGa(5)Se(12). Ba(2)AgInS(4) crystallizes in space group P2(1)/c. It contains [AgInS(4)](4-) layers built from AgS(3) triangles and InS(4) tetrahedra with Ba(2+) cations inserted between the layers. Ba(4)AgGa(5)Se(12) and Ba(4)LiGa(5)Se(12) adopt two closely-related structure types in space group P4[combining macron]2(1)c with structural difference originating from the different positions of Ag and Li in them. The three-dimensional framework in Ba(4)AgGa(5)Se(12) is composed of GaSe(4) tetrahedra with the Ba and Ag atoms occupying the large and small channels respectively, whereas that in Ba(4)LiGa(5)Se(12) is built from LiSe(4) and GaSe(4) tetrahedra with channels to accommodate the Ba atoms. As deduced from the diffuse reflectance spectra measurement, the optical band gaps were 2.32 (2) eV, 2.52 (2) eV, and 2.65 (2) eV for Ba(2)AgInS(4), Ba(4)AgGa(5)Se(12), and Ba(4)LiGa(5)Se(12), respectively. PMID- 22214993 TI - Mouse sperm cryopreservation and recovery using the I.Cryo kit. AB - Thousands of new genetically modified (GM) strains of mice have been created since the advent of transgenesis and knockout technologies. Many of these valuable animals exist only as live animals, with no backup plan in case of emergency. Cryopreservation of embryos can provide this backup, but is costly, can be a lengthy procedure, and generally requires a large number of animals for success. Since the discovery that mouse sperm can be successfully cryopreserved with a basic cryoprotective agent (CPA) consisting of 18% raffinose and 3% skim milk, sperm cryopreservation has become an acceptable and cost-effective procedure for archiving, distributing and recovery of these valuable strains. Here we demonstrate a newly developed I*Cryo kit for mouse sperm cryopreservation. Sperm from five commonly-used strains of inbred mice were frozen using this kit and then recovered. Higher protection ratios of sperm motility (> 60%) and rapid progressive motility (> 45%) compared to the control (basic CPA) were seen for sperm frozen with this kit in 5 inbred mouse strains. Two cell stage embryo development after IVF with the recovered sperm was improved consistently in all 5 mouse strains examined. Over a 1.5 year period, 49 GM mouse lines were archived by sperm cryopreservation with the I*Cryo kit and later recovered by IVF. PMID- 22214994 TI - First prokaryotic biodiversity assessment using molecular techniques of an acidic river in Neuquen, Argentina. AB - Two acidic hot springs close to the crater of Copahue Volcano (Neuquen, Argentina) are the source of the Rio Agrio. The river runs several kilometres before flowing into Caviahue Lake. Along the river, temperature, iron, other metal and proton concentrations decrease gradually with distance downstream. From the source to the lake and depending on the season, pH can rise from 1.0 (or even less) to about 4.0, while temperature values decrease from 70 degrees C to 15 degrees C. Water samples were taken from different stations on the river selected according to their physicochemical parameters. In order to assess prokaryotic biodiversity throughout the water column, different and complementary molecular biology techniques were used, mainly in situ hybridisation and 16S rRNA gene cloning and sequencing. All microorganisms found are typical of acidic environments. Sulphur-oxidizing bacteria like Acidithiobacillus thiooxidans and Acidithiobacillus albertensis were detected in every station. Moderately thermophile iron- and sulphur-oxidizing bacteria like members of Alicyclobacillus and Sulfobacillus genera were also ubiquitous. Strict iron-oxidizing bacteria like Leptospirillum and Ferrimicrobium were present at the source of the river, but disappeared downstream where iron concentrations were much lower. Iron oxidizing, mesophilic Ferroplasma spp. were the main archaea found. The data presented in this work represent the first molecular assessment of this rare natural acidic environment. PMID- 22214995 TI - Single-layer graphene sound-emitting devices: experiments and modeling. AB - Single-layer graphene (SLG) was demonstrated to emit sound. The sound emission from SLG had a significant flat frequency response in the wide ultrasound range from 20 kHz to 50 kHz. SLG can produce a sound pressure level (SPL) as high as 95 dB at a distance of 5 cm with a sound frequency of 20 kHz. The SPL value is among the highest reported to date for sound-emitting devices (SEDs) based on the thermoacoustic effect. A theoretical model was established to analyze the sound emission from SLG. The theoretical results are in good agreement with the experimental results. Conventional acoustic devices with a large size can be reduced to the nano-scale by using this novel SLG-SED material. It has the potential to be widely used in speakers, buzzers, earphones, ultrasonic transducer, etc. PMID- 22214996 TI - Rare-earth metal bis(alkyl)s that bear a 2-pyridinemethanamine ligand: dual catalysis of the polymerizations of both isoprene and ethylene. AB - New pyridinemethanamido-ligated rare-earth metal bis(alkyl) complexes [C(5)H(4)N CH(Me)-NC(6)H(3)((i)Pr)(2)]Ln(CH(2)SiMe(3))(2)(THF) (Ln = Sc (1), Y (2), Lu (3)) have been prepared at 0 degrees C via a protonolysis reaction between rare-earth metal tris(alkyl)s and the corresponding 2-pyridinemethanamine ligand and fully characterized by NMR and X-ray diffraction analysis. Bis(alkyl) complexes 1-3 are analogous monomers of THF solvate, where the ligand bonds to the metal center in a kappaN:kappaN-bidentate mode. Complexes 1-3, in combination with [Ph(3)C][B(C(6)F(5))(4)], showed a good activity towards isoprene polymerization to give polyisoprene with a main 3,4-selectivity (60%-66%); in particular the yttrium catalyst system, 2/[Ph(3)C][B(C(6)F(5))(4)], displayed a living mode. By contrast, only the precatalyst 2 exhibited activity for isoprene polymerization in the presence of [PhNMe(2)H][B(C(6)F(5))(4)]. The influence of alkylaluminium (AlR(3), R = Me, Et, (i)Bu) and the metal center on the polymerization of isoprene was also studied, and it was found that addition of AlMe(3) to the catalyst systems could lead to a dramatic change in the microstructure of the polymer from 3,4-specific to 1,4-selective (89%-95%), but the ionic radius of the central metal had little influence on the selectivity. In addition, by using the 1(Sc)/[Ph(3)C][B(C(6)F(5))(4)]/10 Al(i)Bu(3), the polymerization of ethylene was also achieved with moderate activity (up to 3.2* 10(5) g (PE) mol(Sc)(-1) h(-1) bar(-1)) and narrow polydispersity (M(w)/M(n) = 1.19-1.28); while the effect of temperature on the activity was discussed. Such dual catalysis for the polymerizations of both isoprene and ethylene is rare. PMID- 22214997 TI - Soft lithographic functionalization and patterning oxide-free silicon and germanium. AB - The development of hybrid electronic devices relies in large part on the integration of (bio)organic materials and inorganic semiconductors through a stable interface that permits efficient electron transport and protects underlying substrates from oxidative degradation. Group IV semiconductors can be effectively protected with highly-ordered self-assembled monolayers (SAMs) composed of simple alkyl chains that act as impervious barriers to both organic and aqueous solutions. Simple alkyl SAMs, however, are inert and not amenable to traditional patterning techniques. The motivation for immobilizing organic molecular systems on semiconductors is to impart new functionality to the surface that can provide optical, electronic, and mechanical function, as well as chemical and biological activity. Microcontact printing (MUCP) is a soft lithographic technique for patterning SAMs on myriad surfaces. Despite its simplicity and versatility, the approach has been largely limited to noble metal surfaces and has not been well developed for pattern transfer to technologically important substrates such as oxide-free silicon and germanium. Furthermore, because this technique relies on the ink diffusion to transfer pattern from the elastomer to substrate, the resolution of such traditional printing is essentially limited to near 1 MUm. In contrast to traditional printing, inkless MUCP patterning relies on a specific reaction between a surface-immobilized substrate and a stamp-bound catalyst. Because the technique does not rely on diffusive SAM formation, it significantly expands the diversity of patternable surfaces. In addition, the inkless technique obviates the feature size limitations imposed by molecular diffusion, facilitating replication of very small (<200 nm) features. However, up till now, inkless MUCP has been mainly used for patterning relatively disordered molecular systems, which do not protect underlying surfaces from degradation. Here, we report a simple, reliable high throughput method for patterning passivated silicon and germanium with reactive organic monolayers and demonstrate selective functionalization of the patterned substrates with both small molecules and proteins. The technique utilizes a preformed NHS-reactive bilayered system on oxide-free silicon and germanium. The NHS moiety is hydrolyzed in a pattern-specific manner with a sulfonic acid modified acrylate stamp to produce chemically distinct patterns of NHS-activated and free carboxylic acids. A significant limitation to the resolution of many MUCP techniques is the use of PDMS material which lacks the mechanical rigidity necessary for high fidelity transfer. To alleviate this limitation we utilized a polyurethane acrylate polymer, a relatively rigid material that can be easily functionalized with different organic moieties. Our patterning approach completely protects both silicon and germanium from chemical oxidation, provides precise control over the shape and size of the patterned features, and gives ready access to chemically discriminated patterns that can be further functionalized with both organic and biological molecules. The approach is general and applicable to other technologically-relevant surfaces. PMID- 22214998 TI - Broad disruption of brain white matter microstructure and relationship with neuropsychological performance in male patients with severe alcohol dependence. AB - AIMS: In the last years, refined magnetic resonance diffusion tensor imaging (DTI) methods have become available to study microstructural alterations in the human brain. We investigated to what extent white matter tissue abnormalities are present in male patients after chronic, excessive alcohol consumption and if these alterations are correlated with measures of alcohol consumption and neuropsychological performance. METHODS: Twenty-four detoxified adult male patients with severe alcohol dependence and 23 healthy male control subjects were included in the study. Neuropsychological tests were assessed for executive function, attention, memory and visuospatial function. DTI was acquired and preprocessing of the data was performed using tract-based spatial statistics. Group differences of fractional anisotropy (FA) as well as correlation analyses with neuropsychological measures and drinking history were calculated. RESULTS: Performance in alcoholic patients was significantly poorer in tests of non-verbal reasoning and attention. In detoxified alcoholic patients, lower FA was primarily found in the body of the corpus callosum, but these findings did not correlate directly with behavioral measures. However, executive and psychomotor performance (Trail-Making Test) correlated significantly with FA in right anterior cingulate and left motor areas. CONCLUSION: These findings provide further evidence for reduced integrity of interhemispheric connections in male patients with severe alcohol dependence, and neurocognitive performance was in part correlated with FA. PMID- 22215000 TI - Do co-morbid anxiety disorders predict drinking outcomes in women with alcohol use disorders? AB - AIMS: It is unclear whether co-morbid anxiety disorders predict worse drinking outcomes during attempts to change drinking behavior. Studies have yielded mixed results, and have rarely examined drinking outcomes based on a specific type of anxiety disorder. Women with alcohol use disorders (AUDs) are of particular interest as they are at risk for co-morbid anxiety [Kessler et al. (1997) Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the national co-morbidity survey. Arch Gen Psychiat 54:313-21]. METHODS: Participants were 260 women with AUDs participating in an alcohol-treatment outcome studies. The Timeline Follow-Back was used to assess drinking frequency (percent days drinking) prior, within and 6 months post treatment. The current study tested the hypothesis that having at least one lifetime anxiety disorder diagnosed at baseline using the Structured Clinical Interview for DSM Disorders would be associated with more drinking at all study time points. Exploratory analyses examined patterns of drinking outcomes by specific anxiety diagnoses. RESULTS: Lifetime anxiety diagnosis was linked to poorer drinking outcomes post-treatment (beta = 0.15, P = 0.020), despite less frequent drinking prior to treatment. Analyses by specific anxiety diagnosis indicated that generalized anxiety disorder predicted poorer drinking outcomes within treatment (beta = 0.14, P = 0.018) and during follow-up (beta = 0.16, P = 0.014). CONCLUSION: Co-morbid anxiety problems complicate treatment for AUDs among women. Further, specific anxiety disorders should be evaluated as distinct constructs as evidenced by the differential outcomes related to generalized anxiety disorder. Implications for treatment development for women with AUDs are discussed. PMID- 22214999 TI - Reduction of ethanol consumption in alcohol-preferring rats by dual expression gene transfer. AB - AIMS: To mimic, in an animal model of alcoholism, the protective phenotype against alcohol consumption observed in humans carrying a fast alcohol dehydrogenase (ADH1B*2) and an inactive aldehyde dehydrogenase (ALDH2*2). METHODS: We developed a multiple expression cassette adenoviral vector (AdV ADH/asALDH2) encoding both a fast rat ADH and an antisense RNA against rat ALDH2. A control adenoviral vector (AdV-C) containing intronic non-coding DNA was also developed. These adenoviral vectors were administered intravenously to rats bred as high alcohol-drinkers (University of Chile bibulous) that were previously rendered alcohol dependent by a 75-day period of voluntary 10% ethanol intake. RESULTS: Animals administered AdV-ADH/asALDH2 showed a 176% increase in liver ADH activity, whereas liver ALDH2 activity was reduced by 24%, and upon the administration of a dose of ethanol (1 g/kg, i.p.), these showed arterial acetaldehyde levels that were 400% higher than those of animals administered AdV C. Rats that received the AdV-ADH/asALDH2 vector reduced by 60% their voluntary ethanol intake versus controls. CONCLUSION: This study provides evidence that the simultaneous increase of liver ADH and a reduction of ALDH activity by gene transfer could constitute a potential therapeutic strategy for the treatment of alcoholism. PMID- 22215001 TI - Patterns of alcohol use in early adolescence predict problem use at age 16. AB - AIMS: Teenagers in the UK report some of the highest rates of alcohol use in Europe. We identify patterns of alcohol use in early adolescence and relate these to hazardous and harmful alcohol use at age 16. METHODS: In a UK birth cohort, we analysed repeated measures of alcohol use from age 13 to 15 in a sample of 7100 adolescents. Data on drinking frequency and typical consumption when drinking were modelled separately using a pair of latent class models. Classes of alcohol use behaviour were contrasted across a range of risk factors and then to hazardous and harmful alcohol use as assessed using the Alcohol Use Disorders Identification Test scale at age 16. RESULTS: Heterogeneity in drinking frequency and consumption could each be captured with three classes corresponding to low, medium and high levels. In total, 14.2% were classified as high-frequency and 8.9% as high consumption alcohol users. Socio-demographic factors, maternal substance use and the young persons' use of tobacco and cannabis were associated with class membership. At age 16, 29% were drinking hazardously and a further 5.6% were assessed as harmful drinkers. Young people in the high drinking frequency or consumption class had a 9-fold increased risk of reporting harmful drinking at age 16. CONCLUSIONS: By the age of 16, a substantial proportion of teenagers in this sample were drinking at levels that could be considered hazardous or harmful for an adult. Patterns of alcohol exposure in early adolescence were strongly associated with later alcohol use. Altering drinking patterns in middle adolescence has the potential to reduce harmful use in later adolescence. PMID- 22215002 TI - Efficacy and safety of pregabalin in the treatment of alcohol withdrawal syndrome: a randomized placebo-controlled trial. AB - AIMS: The objective of this study was to collect preliminary data on the efficacy and safety of pregabalin in attenuating the severity of alcohol withdrawal symptoms during detoxification treatment in alcohol dependence. METHODS: Forty two alcohol-dependent patients with an alcohol withdrawal syndrome (AWS) were included in the prospective randomized double-blind placebo-controlled trial during inpatient alcohol detoxification. For 6 days, participants either received pregabalin or placebo according to a fixed dose schedule starting with 300 mg/day. Depending on the score of the AWS Scale (AWSS), diazepam was additionally administered as a rescue medication. The primary endpoint was the total amount of diazepam required from Day 2 to 6 of detoxification treatment in each of the two groups. Secondary outcome variables were the difference in AWSS and Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores between Day 2 and 6, tolerability and safety data, drop-out rates as well as changes in the neuropsychological scales. RESULTS: Pregabalin and placebo were equally safe and well tolerated. However, no statistically significant difference was found comparing the total amount of additional diazepam medication required in the two study groups. Pregabalin and placebo also showed similar efficacy according to alterations of scores of the AWSS, CIWA-Ar and neuropsychological scales. The frequency of adverse events and drop-outs did not differ between the both treatment groups. CONCLUSIONS: The study demonstrates the relative safety of pregabalin in the treatment of AWS. However, the results do not provide evidence in favor of pregabalin compared with placebo concerning its efficacy in the treatment of AWS. PMID- 22215003 TI - Lead and ethanol co-exposure lead to blood oxidative stress and subsequent neuronal apoptosis in rats. AB - AIMS: The present study was aimed at investigating chronic exposure to lead and ethanol, individually and in combination with blood oxidative stress leading to possible brain apoptosis in rats. METHODS: Rats were exposed to lead (0.1% w/v in drinking water) or ethanol (1 and 10%) either individually or in combination for four months. Biochemical variables indicative of oxidative stress (blood and brain) and brain apoptosis were examined. Native polyacrylamide agarose gel electrophoresis was carried out in brain homogenates for glucose-6-phosphate dehydrogenase (G6PD) analysis, whereas western blot analysis was done for the determination of apoptotic markers like Bax, Bcl-2, caspase-3, cytochrome c and p53. RESULTS: The results suggest that most pronounced increase in oxidative stress in red blood cells and brain of animals co-exposed to lead and 10% ethanol compared all the other groups. Decrease in G6PD activity followed the same trend. Upregulation of Bax, cytochrome c, caspase-3, p53 and down-regulation of Bcl-2 suggested apoptosis in the rat brain co-exposed to lead and ethanol (10%) compared with their individual exposures. Significantly high lead accumulation in blood and brain during co-exposure further support synergistic toxicity. CONCLUSION: The present study thus suggests that higher consumption of ethanol during lead exposure may lead to brain apoptosis, which may be mediated through oxidative stress. PMID- 22215004 TI - Bilateral renal cortical necrosis following binge drinking. AB - Renal cortical necrosis (RCN) is a rare cause of acute kidney injury secondary to ischemic necrosis of the renal cortex. Acute tubular necrosis after binge drinking is usually attributed to volume depletion, idiosyncratic reaction to alcohol, rhabdomyolysis or a combination with non-steroidal anti-inflammatory drugs. Binge drinking itself as a cause of RCN has not yet been reported. We report a case of a 25-year-old Asian male who developed bilateral RCN following binge drinking. PMID- 22215005 TI - Self-reported life satisfaction and alcohol use: a 15-year follow-up of healthy adult twins. AB - AIMS: To study the bidirectional relationships between life satisfaction (LS) and alcohol use. METHODS: Health questionnaires were administered in 1975, 1981 and 1990 to a population-based sample of healthy Finnish twins aged 18-45 at baseline (n = 14,083). These included a LS scale and three indicators for adverse alcohol use: binge drinking, passing out and high consumption (women/men >=400/800 g/month). In longitudinal analyses, logistic regression, pair-wise case-control analyses and growth models were applied. RESULTS: All alcohol indicators increased the age-adjusted risk of becoming dissatisfied regardless of study period [binge drinking odds ratio (OR)(1975-1990 )= 1.29; 95% confidence interval (CI) 1.12-1.50; high consumption OR(1975-1990 )= 1.60; 1.29-1.99 and passing out OR(1981-1990 )= 2.01; 1.57-2.57]. Also, the dissatisfied had an increased subsequent risk for adverse alcohol use. The risk for passing out due to drinking (OR(1975-1990 )= 1.50; 1.22-1.86) was increased regardless of study period, while high consumption (OR(1975-1981 )= 1.97; 1.40-2.77; OR(1981-1990 )= 2.48; 1.50 4.12) and binge drinking (OR(1975-1981 )= 1.37; 1.12-1.67) showed some variation by the study period. Predictions remained after multiple adjustments. Longitudinally, high consumption predicted dissatisfaction somewhat more strongly than vice versa. The change/levels within the whole range of LS and alcohol consumption were only slightly associated in the entire study population. CONCLUSION: Life dissatisfaction and adverse alcohol use reciprocally predict each other prospectively. The heavier the alcohol use the stronger the relationship. PMID- 22215006 TI - Synthesis and optical properties of II-VI 1D nanostructures. AB - 1D nanostructures from II-VI semiconductors have been demonstrated to exhibit outstanding optical properties with strong promise for novel optoelectronic devices with augmented performance and functionalities. Herein, we present a comprehensive review discussing important topics pertinent to the fundamental properties and applications of II-VI 1D nanostructures. With practical applications in mind, the considerations, principles and experimental techniques on the sample preparation of high quality 1D nanostructures are highlighted. Fundamentals on the optical properties of II-VI materials, along with relevant investigation techniques and recent progress in the field, are also extensively discussed. With the steady development of their synthesis, characterization and device fabrication, it is strongly expected that II-VI 1D nanostructures will assume a unique position in future technology. PMID- 22215007 TI - Spatial heterogeneity of passive electrical transfer properties of neuronal dendrites due to their metrical asymmetry. AB - The complex and diverse geometry of neuronal dendrites determines the different morphological types of neurons and influences the generation of complex and diverse discharge patterns at the cell output. The recent finding that each temporal pattern has its spatial signature in the form of a combination of high- and low-depolarization states of asymmetrical dendritic branches with active membrane properties raises the question of the nature of such characteristic spatial heterogeneity of electrical states. To answer this, we consider passive dendrites as a conventional reference case using the known current transfer functions, which we complete by corresponding parametric sensitivity functions. These functions for metrically asymmetrical bifurcations of different sizes, as the simplest elements constituting arborizations of arbitrary geometry, are analyzed under different membrane conductivity conditions related to the intensity of activation of ion channels. Characteristic relationships are obtained on the one hand among the size (branch lengths), metrical asymmetry (difference between sister branches in length and/or diameter), and membrane conductivity, and on the other hand, for the difference between the branches in their current transfer effectiveness as an indicator of their electrical asymmetry (heterogeneity). These relationships (i) allow the introduction of a biophysically based criterion for the electrical distinction between metrically asymmetrical branches, (ii) show how the difference first increases and then decreases with increasing membrane conductivity, and (iii) show that the greatest electrical heterogeneity occurs in a lower or higher range of conductivity, corresponding to larger or smaller bifurcation size. As a consequence, the characteristic low-, medium-, and high-conductance states are derived such that metrically asymmetrical parts of simple and complex trees are electrically distinct when the membrane conductivity lies in the size-related medium range, and indistinct otherwise. PMID- 22215008 TI - Influence of connection type on phase synchrony: analysis of a neural mass model. AB - Empirical studies have demonstrated synchronized frontal and parietal electrophysiological signals at 22-34 Hz during a conjunctive visual search task and at 36-56 Hz during a pop-out visual search task. Bidirectional (conjunctive) versus unidirectional (pop-out) information transfer between neuronal populations is hypothesized to underly this difference in synchronization frequency. This study modeled the influence of connection type (i.e., unidirectional vs. bidirectional) on phase synchrony between two neural populations using a neural mass model. Phase-locking values (PLVs) were used as the measure of synchrony between populations. Consistent with the connectivity hypothesis, the model revealed greater PLVs at 22-34 Hz when the two populations were connected bidirectionally than unidirectionally, but greater PLVs at 34-52 Hz when connected unidirectionally than bidirectionally. The model suggests that inter population connectivity also changes with bottom-up versus top-down control of attention. PMID- 22215009 TI - Application of a mouse ligated Peyer's patch intestinal loop assay to evaluate bacterial uptake by M cells. AB - The inside of our gut is inhabited with enormous number of commensal bacteria. The mucosal surface of the gastrointestinal tract is continuously exposed to them and occasionally to pathogens. The gut-associated lymphoid tissue (GALT) play a key role for induction of the mucosal immune response to these microbes. To initiate the mucosal immune response, the mucosal antigens must be transported from the gut lumen across the epithelial barrier into organized lymphoid follicles such as Peyer's patches. This antigen transcytosis is mediated by specialized epithelial M cells. M cells are atypical epithelial cells that actively phagocytose macromolecules and microbes. Unlike dendritic cells (DCs) and macrophages, which target antigens to lysosomes for degradation, M cells mainly transcytose the internalized antigens. This vigorous macromolecular transcytosis through M cells delivers antigen to the underlying organized lymphoid follicles and is believed to be essential for initiating antigen specific mucosal immune responses. However, the molecular mechanisms promoting this antigen uptake by M cells are largely unknown. We have previously reported that glycoprotein 2 (Gp2), specifically expressed on the apical plasma membrane of M cells among enterocytes, serves as a transcytotic receptor for a subset of commensal and pathogenic enterobacteria, including Escherichia coli and Salmonella enterica serovar Typhimurium (S. Typhimurium), by recognizing FimH, a component of type I pili on the bacterial outer membrane. Here, we present a method for the application of a mouse Peyer's patch intestinal loop assay to evaluate bacterial uptake by M cells. This method is an improved version of the mouse intestinal loop assay previously described. The improved points are as follows: 1. Isoflurane was used as an anesthetic agent. 2. Approximately 1 cm ligated intestinal loop including Peyer's patch was set up. 3. Bacteria taken up by M cells were fluorescently labeled by fluorescence labeling reagent or by overexpressing fluorescent protein such as green fluorescent protein (GFP). 4. M cells in the follicle-associated epithelium covering Peyer's patch were detected by whole-mount immunostainig with anti Gp2 antibody. 5. Fluorescent bacterial transcytosis by M cells were observed by confocal microscopic analysis. The mouse Peyer's patch intestinal loop assay could supply the answer what kind of commensal or pathogenic bacteria transcytosed by M cells, and may lead us to understand the molecular mechanism of how to stimulate mucosal immune system through M cells. PMID- 22215010 TI - [NSI+] determinant has a pleiotropic phenotypic manifestation that is modulated by SUP35, SUP45, and VTS1 genes. AB - We recently discovered the novel non-chromosomal determinant in Saccharomyces cerevisiae [NSI(+)] (nonsense suppression inducer), which causes omnipotent nonsense suppression in strains where the Sup35 N-terminal domain is deleted. [NSI(+)] possesses yeast prion features and does not correspond to previously identified yeast prion determinants. Here, we show that [NSI(+)] enhances nonsense codon read-through and inhibits vegetative growth in S. cerevisiae. Using a large-scale overexpression screen to identify genes that impact the phenotypic effects of [NSI(+)], we found that the SUP35 and SUP45 genes encoding the translation termination factors eRF3 and eRF1, respectively, modulate nonsense suppression in [NSI(+)] strains. The VTS1 gene encodes an NQ-enriched RNA-binding protein that enhances nonsense suppression in [NSI(+)] and [nsi(-)] strains. We demonstrate that VTS1 overexpression, like [NSI(+)] induction, causes translational read-through and growth defects in S. cerevisiae. PMID- 22215012 TI - IL-31 expression by inflammatory cells is preferentially elevated in atopic dermatitis. PMID- 22215013 TI - Effects of silver-based wound dressings on the bacterial flora in chronic leg ulcers and its susceptibility in vitro to silver. AB - Silver-based dressings have been used extensively in wound management in recent years, but data on their antimicrobial activity in the clinical setting are limited. In order to explore their effects on chronic leg ulcer flora, 14 ulcers were cultured after at least 3 weeks treatment with Aquacel Ag((r)) or Acticoat((r)). Phenotypic and genetic silver resistance were investigated in a total of 56 isolates. Silver-based dressings had a limited effect on primary wound pathogens, which were present in 79% of the cultures before, and 71% after, treatment. One silver-resistant Enterobacter cloacae strain was identified (silver nitrate minimal inhibitory concentration (MIC) > 512 mg/l, positive for silE, silS and silP). Further studies in vitro showed that inducible silver resistance was more frequent in Enterobacteriaceae with cephalosporin-resistance and that silver nitrate had mainly a bacteriostatic effect on Staphylococcus aureus. Monitoring of silver resistance should be considered in areas where silver is used extensively. PMID- 22215014 TI - A case of epidermolysis bullosa acquisita associated with laryngeal stenosis. PMID- 22215015 TI - Narrow-band ultraviolet B treatment for diphenylcyclopropenone-induced vitiliginous lesions. PMID- 22215016 TI - Foamy virus vector-mediated gene correction of a mouse model of Wiskott-Aldrich syndrome. AB - The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by eczema, thrombocytopenia and immunodeficiency. Hematopoietic cell transplantation can cure the disease and gene therapy is being tested as an alternative treatment option. In this study, we assessed the use of foamy virus (FV) vectors as a gene transfer system for WAS, using a Was knockout (KO) mouse model. Preliminary experiments using FV vectors expressing the green fluorescent protein under the transcriptional control of the endogenous WAS promoter or a ubiquitously acting chromatin opening element allowed us to define transduction conditions resulting in high (>40%) and long-term in-vivo marking of blood cells after transplantation. In following experiments, Was KO mice were treated with FV vectors containing the human WAS complementary DNA (cDNA). Transplanted animals expressed the WAS protein (WASp) in T and B lymphocytes, as well as platelets and showed restoration of both T-cell receptor-mediated responses and B-cell migration. We also observed recovery of platelet adhesion and podosome formation in dendritic cells (DCs) of treated mice. These data demonstrate that FV vectors can be effective for hematopoietic stem cell (HSC)-directed gene correction of WAS. PMID- 22215017 TI - Combined Tbet and IL12 gene therapy elicits and recruits superior antitumor immunity in vivo. AB - We have recently shown that intratumor (i.t.) injection of syngenic dendritic cells (DC) engineered to express the transcription factor Tbet (TBX21) promotes protective type-1 T cell-mediated immunity via a mechanism that is largely interleukin (IL)-12p70-independent. Since IL-12 is a classical promoter of type-1 immunity, the current study was undertaken to determine whether gene therapy using combined Tbet and IL-12 complementary DNA (cDNA) would yield improved antitumor efficacy based on the complementary/synergistic action of these biologic modifiers. Mice bearing established subcutaneous (s.c.) tumors injected with DC concomitantly expressing ectopic Tbet and IL12 (i.e., DC.Tbet/IL12) displayed superior (i) rates of tumor rejection and extended overall survival, (ii) cross-priming of Tc1 reactive against antigens expressed within the tumor microenvironment, and (iii) infiltration of CD8(+) T cells into treated tumors in association with elevated locoregional production of CXCR3 ligand chemokines. In established bilateral tumor models, i.t. delivery of DC.Tbet/IL12 into a single lesion led to slowed growth or regression at both tumor sites. Furthermore, DC.Tbet/IL12 pulsed with tumor antigen-derived peptides and injected as a therapy distal to the tumor site prevented tumor growth and activated robust antigen specific Tc1 responses. These data support the translation use of combined Tbet and IL-12p70 gene therapy in the cancer setting. PMID- 22215018 TI - Concomitant intravenous nitroglycerin with intracoronary delivery of AAV1.SERCA2a enhances gene transfer in porcine hearts. AB - SERCA2a gene therapy improves contractile and energetic function of failing hearts and has been shown to be associated with benefits in clinical outcomes, symptoms, functional status, biomarkers, and cardiac structure in a phase 2 clinical trial. In an effort to enhance the efficiency and homogeneity of gene uptake in cardiac tissue, we examined the effects of nitroglycerin (NTG) in a porcine model following AAV1.SERCA2a gene delivery. Three groups of Gottingen minipigs were assessed: (i) group A: control intracoronary (IC) AAV1.SERCA2a (n = 6); (ii) group B: a single bolus IC injection of NTG (50 ug) immediately before administration of intravenous (IV) AAV1.SERCA2a (n = 6); and (iii) group C: continuous IV NTG (1 ug/kg/minute) during the 10 minutes of AAV1.SERCA2a infusion (n = 6). We found that simultaneous IV infusion of NTG and AAV1.SERCA2a resulted in increased viral transduction efficiency, both in terms of messenger RNA (mRNA) as well as SERCA2a protein levels in the whole left ventricle (LV) compared to control animals. On the other hand, IC NTG pretreatment did not result in enhanced gene transfer efficiency, mRNA or protein levels when compared to control animals. Importantly, the transgene expression was restricted to the heart tissue. In conclusion, we have demonstrated that IV infusion of NTG significantly improves cardiac gene transfer efficiency in porcine hearts. PMID- 22215020 TI - A [2+2] cross-photodimerisation of photostable olefins via a three-component cocrystal solid solution. AB - A ditopic hydrogen-bond-donor template in the form of resorcinol facilitates a [2+2] cross-photodimerisation of 4-Cl-stilbazole and 4-Me-stilbazole in a rare cocrystal solid solution. A photoreaction does not proceed with the olefins individually or as a solid solution composed solely of the two olefins. PMID- 22215019 TI - Co-administration with the pharmacological chaperone AT1001 increases recombinant human alpha-galactosidase A tissue uptake and improves substrate reduction in Fabry mice. AB - Fabry disease is an X-linked lysosomal storage disorder (LSD) caused by mutations in the gene (GLA) that encodes the lysosomal hydrolase alpha-galactosidase A (alpha-Gal A), and is characterized by pathological accumulation of the substrate, globotriaosylceramide (GL-3). Regular infusion of recombinant human alpha-Gal A (rhalpha-Gal A), termed enzyme replacement therapy (ERT), is the primary treatment for Fabry disease. However, rhalpha-Gal A has low physical stability, a short circulating half-life, and variable uptake into different disease-relevant tissues. We hypothesized that coadministration of the orally available, small molecule pharmacological chaperone AT1001 (GR181413A, 1 deoxygalactonojirimycin, migalastat hydrochloride) may improve the pharmacological properties of rhalpha-Gal A via binding and stabilization. AT1001 prevented rhalpha-Gal A denaturation and activity loss in vitro at neutral pH and 37 degrees C. Coincubation of Fabry fibroblasts with rhalpha-Gal A and AT1001 resulted in up to fourfold higher cellular alpha-Gal A and ~30% greater GL-3 reduction compared to rhalpha-Gal A alone. Furthermore, coadministration of AT1001 to rats increased the circulating half-life of rhalpha-Gal A by >2.5-fold, and in GLA knockout mice resulted in up to fivefold higher alpha-Gal A levels and fourfold greater GL-3 reduction than rhalpha-Gal A alone. Collectively, these data highlight the potentially beneficial effects of AT1001 on rhalpha-Gal A, thus warranting clinical investigation. PMID- 22215021 TI - Lightning safety of animals. AB - This paper addresses a concurrent multidisciplinary problem: animal safety against lightning hazards. In regions where lightning is prevalent, either seasonally or throughout the year, a considerable number of wild, captive and tame animals are injured due to lightning generated effects. The paper discusses all possible injury mechanisms, focusing mainly on animals with commercial value. A large number of cases from several countries have been analyzed. Economically and practically viable engineering solutions are proposed to address the issues related to the lightning threats discussed. PMID- 22215022 TI - A randomized trial comparing 2 types of in-home rehabilitation for chronic obstructive pulmonary disease: a pilot study. AB - BACKGROUND: Pulmonary rehabilitation has been shown to be effective for improving quality of life and function in patients with chronic obstructive pulmonary disease (COPD) but has not been studied extensively in homebound patients. Furthermore, little is known about the effectiveness of specific types of home based interventions. PURPOSE: The purpose of this study was to examine the effectiveness of in-home rehabilitation programs for individuals with COPD considered homebound according to Medicare definition and to compare outcomes of 2 different rehabilitation interventions. METHODS: Patients were randomly assigned to 2 home-based interventions including aerobic conditioning (group A) or functional strength training (group B), which were conducted over 8 weeks. In addition, all patients received COPD self-management education. Outcome measures were collected after completion of the intervention and after 16 weeks and included the Chronic Respiratory Questionnaire (CRQ), Geriatric Depression Scale, and 2-minute walk test. RESULTS: Of 41 patients enrolled, 24 completed the 8-week intervention. On average, all CRQ quality-of-life domains improved in both groups, with the largest improvements in the CRQ-dyspnea domain. Overall, at 16 weeks, 80% of group A and 71% of group B patients had clinically significant improvements in the CRQ-dyspnea domain. Furthermore, depression scores improved in both groups. Only group A had a clinically significant improvement in walking distance. CONCLUSION: The results of this pilot study suggest that both forms of home-based rehabilitation may improve disease-specific quality of life in homebound patients with COPD. PMID- 22215024 TI - Multiplexed fluorometric immunoassay testing methodology and troubleshooting. AB - To ensure the quality of animal models used in biomedical research we have developed a number of diagnostic testing strategies and methods to determine if animals have been exposed to adventitious infectious agents (viruses, mycoplasma, and other fastidious microorganisms). Infections of immunocompetent animals are generally transient, yet serum antibody responses to infection often can be detected within days to weeks and persist throughout the life of the host. Serology is the primary diagnostic methodology by which laboratory animals are monitored. Historically the indirect enzyme-linked immunosorbent assay (ELISA) has been the main screening method for serosurveillance. The ELISA is performed as a singleplex, in which one microbial antigen-antibody reaction is measured per well. In comparison the MFIA is performed as a multiplexed assay. Since the microspheres come in 100 distinct color sets, as many as 100 different assays can be performed simultaneously in a single microplate well. This innovation decreases the amount of serum, reagents and disposables required for routine testing while increasing the amount of information obtained from a single test well. In addition, we are able to incorporate multiple internal control beads to verify sample and system suitability and thereby assure the accuracy of results. These include tissue control and IgG anti-test serum species immunoglobulin (alphaIg) coated bead sets to evaluate sample suitability. As in the ELISA and IFA, the tissue control detects non-specific binding of serum immunoglobulin. The alphaIg control (Serum control) confirms that serum has been added and contains a sufficient immunoglobulin concentration while the IgG control bead (System Suitability control), coated with serum species immunoglobulin, demonstrates that the labeled reagents and Luminex reader are functioning properly. PMID- 22215023 TI - Stress regulation of the PAN-proteasome system in the extreme halophilic archaeon Halobacterium. AB - In Archaea, the importance of the proteasome system for basic biological processes is only poorly understood. Proteasomes were partially purified from Halobacterium by native gradient density ultracentrifugation. The peptidase activity profiles showed that the 20S proteasome accumulation is altered depending on the physiological state of the cells. The amount of active 20S particles increases in Halobacterium cells as a response to thermal and low salt stresses. In the same conditions, Northern experiments showed a positive transcriptional regulation of the alpha and beta proteasome subunits as well as of the two proteasome regulatory ATPases, PANA and PANB. Co-immunoprecipitation experiments demonstrated the existence of a physical interaction between the two Proteasome Activating Nucleotidase (PAN) proteins in cell extracts. Thus, a direct regulation occurs on the PAN-proteasome components to adjust the protein degradation activity to growth and environmental constraints. These results also indicate that, in extreme halophiles, proteasome mediated proteolysis is an important aspect of low salt stress response. The tri-peptide vinyl sulfone inhibitor NLVS was used in cell cultures to study the in vivo function of proteasome in Halobacterium. The chemical inhibition of proteasomes was measured in the cellular extracts. It has no effect on cell growth and mortality under normal growth conditions as well as under heat shock conditions. These results suggest that the PAN activators or other proteases compensate for loss of proteasome activity in stress conditions. PMID- 22215025 TI - Olefin cross-metathesis for the synthesis of heteroaromatic compounds. AB - The olefin metathesis reaction has underpinned spectacular achievements in organic synthesis in recent years. Arguably, metathesis has now become the foremost choice for a carbon-carbon double bond disconnection. Despite this general utility, de novo routes to heteroaromatic compounds using the cross metathesis (CM) reaction have only recently emerged as an efficient strategy. This approach allows a convergent union of simple, functionalised, three- to four carbon olefinic core building blocks, to generate furans, pyrroles and pyridines with a high degree of control of substitution pattern in the product. PMID- 22215026 TI - A long-term stable Pt counter electrode modified by POM-based multilayer film for high conversion efficiency dye-sensitized solar cells. AB - A long-term stable Pt counter electrode modified by POM-based multilayer film has been fabricated by the electrochemical deposition method, which can markedly increase short-circuit photocurrent, open-circuit voltage and the conversion efficiency when used in dye-sensitized solar cells (DSSCs). PMID- 22215028 TI - 1-(Fluoroalkylidene)-1,1-bisphosphonic acids are potent and selective inhibitors of the enzymatic activity of Toxoplasma gondii farnesyl pyrophosphate synthase. AB - alpha-Fluorinated-1,1-bisphosphonic acids derived from fatty acids were designed, synthesized and biologically evaluated against Trypanosoma cruzi, the etiologic agent of Chagas disease, and against Toxoplasma gondii, the agent responsible for toxoplasmosis, and also towards the target parasitic enzymes farnesyl pyrophosphate synthase of T. cruzi (TcFPPS) and T. gondii (TgFPPS). Interestingly, 1-fluorononylidene-1,1-bisphosphonic acid (compound 43) proved to be an extremely potent inhibitor of the enzymatic activity of TgFPPS at the low nanomolar range, exhibiting an IC(50) of 30 nM. This compound was two-fold more potent than risedronate (IC(50) = 74 nM) that was taken as a positive control. This enzymatic activity was associated with a strong cell growth inhibition against tachyzoites of T. gondii, with an IC(50) value of 2.7 MUM. PMID- 22215029 TI - Visualization of vascular Ca2+ signaling triggered by paracrine derived ROS. AB - Oxidative stress has been implicated in a number of pathologic conditions including ischemia/reperfusion damage and sepsis. The concept of oxidative stress refers to the aberrant formation of ROS (reactive oxygen species), which include O(2)(*-), H(2)O(2), and hydroxyl radicals. Reactive oxygen species influences a multitude of cellular processes including signal transduction, cell proliferation and cell death. ROS have the potential to damage vascular and organ cells directly, and can initiate secondary chemical reactions and genetic alterations that ultimately result in an amplification of the initial ROS-mediated tissue damage. A key component of the amplification cascade that exacerbates irreversible tissue damage is the recruitment and activation of circulating inflammatory cells. During inflammation, inflammatory cells produce cytokines such as tumor necrosis factor-alpha (TNFalpha) and IL-1 that activate endothelial cells (EC) and epithelial cells and further augment the inflammatory response. Vascular endothelial dysfunction is an established feature of acute inflammation. Macrophages contribute to endothelial dysfunction during inflammation by mechanisms that remain unclear. Activation of macrophages results in the extracellular release of O(2)(*-) and various pro-inflammatory cytokines, which triggers pathologic signaling in adjacent cells. NADPH oxidases are the major and primary source of ROS in most of the cell types. Recently, it is shown by us and others that ROS produced by NADPH oxidases induce the mitochondrial ROS production during many pathophysiological conditions. Hence measuring the mitochondrial ROS production is equally important in addition to measuring cytosolic ROS. Macrophages produce ROS by the flavoprotein enzyme NADPH oxidase which plays a primary role in inflammation. Once activated, phagocytic NADPH oxidase produces copious amounts of O(2)(*-) that are important in the host defense mechanism. Although paracrine-derived O(2)(*-) plays an important role in the pathogenesis of vascular diseases, visualization of paracrine ROS-induced intracellular signaling including Ca(2+) mobilization is still hypothesis. We have developed a model in which activated macrophages are used as a source of O(2)(*-) to transduce a signal to adjacent endothelial cells. Using this model we demonstrate that macrophage-derived O(2)(*-) lead to calcium signaling in adjacent endothelial cells. PMID- 22215030 TI - Visualizing proteins and macromolecular complexes by negative stain EM: from grid preparation to image acquisition. AB - Single particle electron microscopy (EM), of both negative stained or frozen hydrated biological samples, has become a versatile tool in structural biology. In recent years, this method has achieved great success in studying structures of proteins and macromolecular complexes. Compared with electron cryomicroscopy (cryoEM), in which frozen hydrated protein samples are embedded in a thin layer of vitreous ice, negative staining is a simpler sample preparation method in which protein samples are embedded in a thin layer of dried heavy metal salt to increase specimen contrast. The enhanced contrast of negative stain EM allows examination of relatively small biological samples. In addition to determining three-dimensional (3D) structure of purified proteins or protein complexes, this method can be used for much broader purposes. For example, negative stain EM can be easily used to visualize purified protein samples, obtaining information such as homogeneity/heterogeneity of the sample, formation of protein complexes or large assemblies, or simply to evaluate the quality of a protein preparation. In this video article, we present a complete protocol for using an EM to observe negatively stained protein sample, from preparing carbon coated grids for negative stain EM to acquiring images of negatively stained sample in an electron microscope operated at 120kV accelerating voltage. These protocols have been used in our laboratory routinely and can be easily followed by novice users. PMID- 22215032 TI - Item-level psychometrics and predictors of performance for Spanish/English bilingual speakers on an object and action naming battery. AB - PURPOSE: There is a pressing need for psychometrically sound naming materials for Spanish/English bilingual adults. To address this need, in this study the authors examined the psychometric properties of An Object and Action Naming Battery (An O&A Battery; Druks & Masterson, 2000) in bilingual speakers. METHOD: Ninety-one Spanish/English bilinguals named O&A Battery items in English and Spanish. Responses underwent a Rasch analysis. Using correlation and regression analyses, the authors evaluated the effect of psycholinguistic (e.g., imageability) and participant (e.g., proficiency ratings) variables on accuracy. RESULTS: Rasch analysis determined unidimensionality across English and Spanish nouns and verbs and robust item-level psychometric properties, evidence for content validity. Few items did not fit the model, there were no ceiling or floor effects after uninformative and misfit items were removed, and items reflected a range of difficulty. Reliability coefficients were high, and the number of statistically different ability levels provided indices of sensitivity. Regression analyses revealed significant correlations between psycholinguistic variables and accuracy, providing preliminary construct validity. The participant variables that contributed most to accuracy were proficiency ratings and time of language use. CONCLUSIONS: Results suggest adequate content and construct validity of O&A items retained in the analysis for Spanish/English bilingual adults and support future efforts to evaluate naming in older bilinguals and persons with bilingual aphasia. PMID- 22215031 TI - Specificity of training in the lingual musculature. AB - PURPOSE: Training specificity for a number of exercise parameters has been demonstrated for the limb musculature. The current study is a Phase I exploration of training specificity in the lingual musculature. METHOD: Twenty-five healthy participants were assigned to 1 of 5 training conditions. Four groups completed 4 weeks of lingual exercise targeting strength, endurance, power, or speed; a control group did not exercise. Performance measures of strength, endurance, power, and speed were obtained before and after training. RESULTS: Although statistically significant group effects were not detected, specificity was observed with respect to effect size for the performance variables of strength, endurance, and power. Further evidence of specificity was provided by the finding that training isotonic endurance did not increase performance on an isometric endurance task. Speed training did not improve performance on any of the outcome measures, nor did speed increase following training with any of the exercises. CONCLUSIONS: The findings provide initial evidence that training specificity may be observed in the lingual musculature. The reported effect sizes can inform future studies examining the benefit of training muscle functions underlying speech and swallowing. PMID- 22215033 TI - Early language and behavioral regulation skills as predictors of social outcomes. AB - PURPOSE: In the present study, the authors examined the prospective associations among early language skills, behavioral regulation skills, and 2 aspects of school-age social functioning (adaptability and social skills). METHOD: The study sample consisted of children with and without a familial risk for dyslexia. The authors analyzed the relations among children's language (at age 2;6 [years;months] and age 5;0), behavioral regulation skills (at age 5;0), and social functioning (at age 8;0) using structural equation modeling. Subgroups of children with respect to language and behavioral regulation skills (at age 5;0) were identified through the use of mixture modeling. RESULTS: Among at-risk children, behavioral regulation skills mediated the association between early language skills and social outcomes. A subgroup of children with poor regulatory and weak language skills scored lower in adaptability, whereas a subgroup having only poor language skills (with normal behavioral regulation) did not differ from a group with age-appropriate skills. CONCLUSIONS: The present findings indicate that behavioral regulation skills play an important role in predicting social outcomes among children at risk for language difficulties. Furthermore, it is suggested that various aspects of social functioning may be influenced differently by self-regulation skills and that predictive relationships vary with the degree of language development deficits and accompanying risks. PMID- 22215034 TI - Developing a single comparison stimulus for matching breathy voice quality. AB - PURPOSE: In this experiment, a single comparison stimulus was developed as a reference in a perceptual matching task for the quantification of breathy voice quality. Perceptual judgments of a set of synthetic voice samples were compared to previous data obtained using multiple comparison stimuli "customized" for different voices (Patel, Shrivastav, & Eddins, 2010). METHOD: Five male and 5 female samples of the vowel /a/ were selected from the Kay Elemetrics Disordered Voice Database and resynthesized using a Klatt synthesizer. Eleven samples were created for each base voice by manipulating the aspiration noise level. Five samples from each continuum were evaluated in a perceptual matching task in which a single sawtooth and noise comparison stimulus was used to obtain breathiness judgments. Linear regression was used to compare measurements obtained using the new comparison stimulus against the customized comparison stimuli. RESULTS: Results indicated that the noncustomized sawtooth comparison provides reliability and perceptual distances between stimuli similar to those obtained using customized comparison stimuli. CONCLUSION: A single-variable matching task using a single comparison stimulus can be used to obtain perceptual estimates of breathiness across voices and experiments in a laboratory setting. This technique will help develop models of voice-quality perception. PMID- 22215035 TI - Asynchronous vowel-pair identification across the adult life span for monaural and dichotic presentations. AB - PURPOSE: Temporal order abilities decrease with age. Declining temporal processing abilities may influence the identification of rapid vowel sequences. Identification patterns for asynchronous vowel pairs were explored across the life span. METHOD: Young, middle-aged, and older listeners completed temporal order tasks for pairs of 70-ms and 40-ms vowel stimuli. For a given vowel duration, naturally spoken vowels were equated for duration, intensity, and fundamental frequency. Listeners completed monaural and dichotic temporal order tasks that involved identifying the vowel pair in the correct order. The stimulus onset asynchrony that yielded 50% accuracy for identifying the vowel pair in the correct order was used to equate performance among listeners. Vowel identification response patterns were determined at this stimulus onset asynchrony threshold. RESULTS: Vowel identification patterns were largely consistent across age groups. Older listeners were influenced by the order of certain vowel pairs. Not all vowel pairs were identified equally well. Vowel dominance patterns were also observed, with /a/ being identified most accurately for the vowel pairs tested. Formant dynamics explained, in part, identification and confusion patterns. CONCLUSION: Vowel identification accuracy patterns were reasonably similar across the life span, regardless of presentation mode, vowel duration, or effect of considerable stimulus exposure. Large effects of vowel order were observed, particularly for older listeners. PMID- 22215036 TI - The intelligibility in Context Scale: validity and reliability of a subjective rating measure. AB - PURPOSE: To describe a new measure of functional intelligibility, the Intelligibility in Context Scale (ICS), and evaluate its validity, reliability, and sensitivity using 3 clinical measures of severity of speech sound disorder: (a) percentage of phonemes correct (PPC), (b) percentage of consonants correct (PCC), and (c) percentage of vowels correct (PVC). METHOD: Speech skills of 120 preschool children (109 with parent-/teacher-identified concern about how they talked and made speech sounds and 11 with no identified concern) were assessed with the Diagnostic Evaluation of Articulation and Phonology (Dodd, Hua, Crosbie, Holm, & Ozanne, 2002). Parents completed the 7-item ICS, which rates the degree to which children's speech is understood by different communication partners (parents, immediate family, extended family, friends, acquaintances, teachers, and strangers) on a 5-point scale. RESULTS: Parents' ratings showed that most children were always (5) or usually (4) understood by parents, immediate family, and teachers, but only sometimes (3) by strangers. Factor analysis confirmed the internal consistency of the ICS items; therefore, ratings were averaged to form an overall intelligibility score. The ICS had high internal reliability (alpha = .93), sensitivity, and construct validity. Criterion validity was established through significant correlations between the ICS and PPC (r = .54), PCC (r = .54), and PVC (r = .36). CONCLUSIONS: The ICS is a promising new measure of functional intelligibility. These data provide initial support for the ICS as an easily administered, valid, and reliable estimate of preschool children's intelligibility when speaking with people of varying levels of familiarity and authority. PMID- 22215038 TI - Written narrative characteristics in adults with language impairment. AB - PURPOSE: Adults with language-based disabilities are known to have deficits in oral language; however, less is known about their written language skills. Two studies were designed to characterize the writing of adults with language-based disabilities. METHOD: In Study 1, 60 adults, 30 with language impairment and 30 with typical language, completed written narratives. Forty-one written language measures were analyzed. In Study 2, the measures that had the most potential for reliably indexing deficits were analyzed in an additional 77 adults. RESULTS: Three measures that showed significant between-group differences and had robust effect sizes in Study 1, total number of verbs, 1-part verbs, and errors, were applied to the samples in Study 2. A group difference for percentage of errors was replicated in the second sample. A discriminant analysis identified 75% of the adults with language impairment and 30% of the adults with typical language as having an impairment based on the percent of written errors. CONCLUSIONS: The writing task revealed consistent group differences in written errors and is clinically applicable in describing a client's writing. However, the number of written errors was not robust enough to identify whether an adult had a language impairment or not. PMID- 22215037 TI - Informational masking and spatial hearing in listeners with and without unilateral hearing loss. AB - PURPOSE: This study assessed selective listening for speech in individuals with and without unilateral hearing loss (UHL) and the potential relationship between spatial release from informational masking and localization ability in listeners with UHL. METHOD: Twelve adults with UHL and 12 normal-hearing controls completed a series of monaural and binaural speech tasks that were designed to measure informational masking. They also completed a horizontal localization task. RESULTS: Monaural performance by participants with UHL was comparable to that of normal-hearing participants. Unlike the normal-hearing participants, the participants with UHL did not exhibit a true spatial release from informational masking. Rather, their performance could be predicted by head shadow effects. Performance among participants with UHL in the localization task was quite variable, with some showing near-normal abilities and others demonstrating no localization ability. CONCLUSION: Individuals with UHL did not show deficits in all listening situations but were at a significant disadvantage when listening to speech in environments where normal-hearing listeners benefit from spatial separation between target and masker. This inability to capitalize on spatial cues for selective listening does not appear to be related to localization ability. PMID- 22215039 TI - Cochlear implant in the second year of life: lexical and grammatical outcomes. AB - PURPOSE: The authors studied the effect of the cochlear implant (CI) on language comprehension and production in deaf children who had received a CI in the 2nd year of life. METHOD: The authors evaluated lexical and morphosyntactic skills in comprehension and production in 17 Italian children who are deaf (M = 54 months of age) with a CI and in 2 control groups of children with normal hearing (NH; 1 matched for chronological age and the other whose chronological age corresponded to the duration of CI activation). The authors also compared children with unilateral CI to children with bilateral CI. RESULTS: Children with CI appeared to keep pace with NH children matched for time since CI activation in terms of language acquisition, and they were similar to same-age NH children in lexical production. However, children with CI showed difficulties in lexical comprehension when a task required phonological discrimination as well as in grammar comprehension and production. Children with bilateral CI showed better comprehension than did children with unilateral CI; the 2 groups were similar for production. CONCLUSIONS: Activation of CI in the 2nd year of life may provide children who are deaf with a good opportunity to develop language skills, although some limitations in phonological and morphological skills are still present 3 years after auditory reafferentation. PMID- 22215040 TI - Measuring speech recognition in children with cochlear implants in a virtual classroom. AB - PURPOSE: To determine the feasibility of using a virtual auditory test material to evaluate reverberation and noise effects on speech recognition of pediatric cochlear implant (CI) users and to compare their performance with that of children with normal hearing. METHOD: Virtual test materials representing nonreverberant and reverberant environments were used to measure speech recognition of 7 children with CIs in quiet and in noise, and of 18 children with normal hearing in the quiet condition. Performance of CI users in noise (signal to-noise ratio resulting in 50% performance) was compared to normative data from a previous study (Neuman, Wroblewski, Hajicek, & Rubinstein, 2010). For CI users, stimuli were sent directly to the CI speech processor via auxiliary input, whereas children with normal hearing were tested using insert phones. RESULTS: The speech recognition of children with CIs decreased significantly in the reverberant condition. There were individual differences in susceptibility to reverberation. Children with CIs also required higher signal-to-noise ratios than children with normal hearing in the reverberant condition. CONCLUSION: Direct connect testing with reverberant test materials allows assessment of speech recognition under conditions typical of classrooms and could be useful in identifying children with CIs whose performance decreases significantly in the presence of reverberation and noise. PMID- 22215041 TI - Fibronectin molecular status determination useful to differentiate between rheumatoid arthritis and systemic lupus erythematosus patients. AB - To find whether the plasma fibronectin (FN) molecular status can be useful to differentiate between rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The expression of plasma FN domains was determined by ELISA using monoclonal domain-specific antibodies. FN molecular forms were revealed by immunoblotting and analyzed by densitometry. The following findings were found: (1) Mean values of (Fibrin-Heparin)FN concentration were lower in SLE and RA patients than in normal plasmas. The cut off points at 31 mg/l in SLE and at 45 mg/l in RA showed a sensitivity and specificity of 54, 55 and 75%, respectively. (2) Mean values of concentrations of (CBD)FN and (Ct)FN were lower in SLE than those in normal and RA plasmas. Quantified data showed the cut off points of (CBD)FN and (Ct)FN at 200 mg/l (58% of sensitivity, 56% of specificity) and 350 mg/l (58% of sensitivity, 58% of specificity) in SLE, as well as at 295 mg/l (52% of sensitivity, 51% of specificity) and 460 mg/l in RA (70% of sensitivity, 73% of specificity). (3) The plasma FN immunopatterns, characterized by the presence of high-molecular (260-310 kDa) and/or low-molecular (158-209 kDa) FN bands, were specific only for SLE samples. The analysis of plasma FN status revealed by its Fibrin-Heparin-, CBD- and Ct-domain reactivity with monoclonal antibody and immunoblotting can be helpful to differentiate the SLE in respect to RA and normal plasmas. PMID- 22215042 TI - High risk of osteonecrosis of the femoral head in autoimmune disease patients showing no immediate increase in hepatic enzyme under steroid therapy. AB - Aim of the study is to determine the relationship between liver function and the incidence of ONF after steroid therapy in AID patients. The present study investigated 58 AID patients who had received high-dose systemic steroid therapy to determine whether a correlation exists between parameters of hepatic function and steroid-induced ONF at the precise time-point when steroid-induced ONF develops. The patients were divided into two groups on the basis of MRI findings: ONF (n = 31) and non-ONF (n = 27). The ONF group showed no increase in AST, ALT, or LDH within 4 weeks after the commencement of steroid therapy. By contrast, the non-ONF group showed an immediate and significant increase in all of these parameters. In the ONF group, hepatic steatosis and elevated triglyceride levels were also observed. Following 4 weeks of steroid therapy, there were no significant differences in biochemical data between two groups. Patients showing no immediate increase in ALT and AST in response to steroid therapy were at high risk of ONF. These findings provide important insights into the pathogenesis of steroid-induced ONF and may facilitate the development of prevention strategies in patients with AID. PMID- 22215043 TI - Early diagnosis of rheumatoid arthritis: an introduction to the newly designed Iran Criteria for Rheumatoid Arthritis. AB - More than 14 years of clinical practice in rheumatology led the author to discover the prognostic role of anti-citrullinated protein antibody (ACPA) as well as the erosions found by MRI, in detecting the RA patients resulting in establishing a new set of criteria by revising the 1987 ACR classification-Iran Criteria for Rheumatoid Arthritis. Medical records of 243 patients at the outpatient Rheumatology Clinic of the author (private sector) were reviewed for the data on the criteria of the 1987 ACR, 2010 ACR/European League against Rheumatism (EULAR), and Iran Criteria for RA. In addition to modifying the 1987 ACR classification, Iran Criteria for RA adds some additional information to the ACR criteria (including ACPA and bony erosions detected by MRI), and any patient who satisfies 6 out of 12 points is considered as a definite RA patient. Sensitivity of the three classifications was calculated considering the clinical diagnosis by a single rheumatologist as the gold standard. A total of 63 male and 180 female patients with a mean follow-up duration of 28.24 +/- 50.19 months were considered. Mean age at diagnosis and mean disease duration were 49.16 +/- 15.38 years and 7.04 +/- 6.87 months, respectively. The sensitivity for Iran Criteria for RA, 1987 ACR classification, and 2010 ACR/EULAR criteria were calculated as 98.4, 59.7, and 66.3%, respectively. Comparing Iran Criteria for RA with ACR and ACR/EULAR criteria, it was concluded that our newly introduced criteria is a more sensitive instrument in determining RA patients in the early stages of the disease. PMID- 22215044 TI - Year in review in Intensive Care Medicine 2011: I. Nephrology, epidemiology, nutrition and therapeutics, neurology, ethical and legal issues, experimentals. PMID- 22215046 TI - A CELLULOSE SYNTHASE (CESA) gene essential for gametophore morphogenesis in the moss Physcomitrella patens. AB - In seed plants, different groups of orthologous genes encode the CELLULOSE SYNTHASE (CESA) proteins that are responsible for cellulose biosynthesis in primary and secondary cell walls. The seven CESA sequences of the moss Physcomitrella patens (Hedw.) B. S. G. form a monophyletic sister group to seed plant CESAs, consistent with independent CESA diversification and specialization in moss and seed plant lines. The role of PpCESA5 in the development of P. patens was investigated by targeted mutagenesis. The cesa5 knockout lines were tested for cellulose deficiency using carbohydrate-binding module affinity cytochemistry and the morphology of the leafy gametophores was analyzed by 3D reconstruction of confocal images. No defects were identified in the development of the filamentous protonema or in production of bud initials that normally give rise to the leafy gametophores. However, the gametophore buds were cellulose deficient and defects in subsequent cell expansion, cytokinesis, and leaf initiation resulted in the formation of irregular cell clumps instead of leafy shoots. Analysis of the cesa5 knockout phenotype indicates that a biophysical model of organogenesis can be extended to the moss gametophore shoot apical meristem. PMID- 22215047 TI - Leukotriene B(4) receptors BLT1 and BLT2 are involved in interleukin-8 production in human neutrophils induced by Trichomonas vaginalis-derived secretory products. AB - OBJECTIVE AND METHOD: Trichomonas vaginalis is a flagellated protozoan parasite that causes human trichomoniasis. Although T. vaginalis itself can secrete lipid mediator leukotriene (LT) B(4) leading to neutrophil activation, information regarding the signaling mechanism involved in neutrophil activation induced by T. vaginalis-secreted LTB(4) is limited. We investigated whether LTB(4) contained in the T. vaginalis-derived secretory products (TvSP) is closely involved in interleukin (IL)-8 production in human neutrophils via LTB(4) receptors BLT1 or BLT2. RESULTS: T. vaginalis produced more than 714 pg/ml of LTB(4) per 1 * 10(7) trichomonads. The ability of trichomonads to secrete LTB(4) was inhibited by treatment of trichomonads with the 5-lipo-oxygenease inhibitor AA861, but not the cyclo-oxygenease I inhibitor FR122047. When neutrophils were incubated with TvSP obtained from 1 * 10(7) trichomonads, IL-8 protein secretion was significantly increased compared to results for cells incubated with medium alone. The stimulatory effect of TvSP on IL-8 production was strongly inhibited by pretreatment of TvSP with lipase, although pretreatment with heat or proteinase K showed little inhibitory effect. Moreover, TvSP-induced IL-8 production was efficiently inhibited when trichomonads were pretreated with AA861 or when neutrophils were pretreated with antagonists for BLT1 or BLT2. CONCLUSION: Our results suggest that LTB(4) receptors BLT1 and BLT2 are involved in IL-8 production in neutrophils induced by T. vaginalis. PMID- 22215048 TI - Mathematical modeling in immunotherapy of cancer: personalizing clinical trials. PMID- 22215051 TI - Is serum IL-17A a useful systemic biomarker in patients with Langerhans cell histiocytosis? PMID- 22215052 TI - Antisense oligonucleotides shed new light on the pathogenesis and treatment of spinal muscular atrophy. PMID- 22215053 TI - Multifunctional theranostic nanoparticles for brain tumors. PMID- 22215055 TI - A rapid room temperature chemical route for the synthesis of graphene: metal mediated reduction of graphene oxide. AB - A rapid and facile route for the synthesis of reduced graphene oxide sheets (rGOs) at room temperature by the chemical reduction of graphene oxide using Zn/acid in aqueous solution is demonstrated. PMID- 22215056 TI - Improving completeness of electronic problem lists through clinical decision support: a randomized, controlled trial. AB - BACKGROUND: Accurate clinical problem lists are critical for patient care, clinical decision support, population reporting, quality improvement, and research. However, problem lists are often incomplete or out of date. OBJECTIVE: To determine whether a clinical alerting system, which uses inference rules to notify providers of undocumented problems, improves problem list documentation. STUDY DESIGN AND METHODS: Inference rules for 17 conditions were constructed and an electronic health record-based intervention was evaluated to improve problem documentation. A cluster randomized trial was conducted of 11 participating clinics affiliated with a large academic medical center, totaling 28 primary care clinical areas, with 14 receiving the intervention and 14 as controls. The intervention was a clinical alert directed to the provider that suggested adding a problem to the electronic problem list based on inference rules. The primary outcome measure was acceptance of the alert. The number of study problems added in each arm as a pre-specified secondary outcome was also assessed. Data were collected during 6-month pre-intervention (11/2009-5/2010) and intervention (5/2010-11/2010) periods. RESULTS: 17,043 alerts were presented, of which 41.1% were accepted. In the intervention arm, providers documented significantly more study problems (adjusted OR=3.4, p<0.001), with an absolute difference of 6277 additional problems. In the intervention group, 70.4% of all study problems were added via the problem list alerts. Significant increases in problem notation were observed for 13 of 17 conditions. CONCLUSION: Problem inference alerts significantly increase notation of important patient problems in primary care, which in turn has the potential to facilitate quality improvement. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01105923. PMID- 22215057 TI - Systematic review and evaluation of web-accessible tools for management of diabetes and related cardiovascular risk factors by patients and healthcare providers. AB - OBJECTIVE: To identify and evaluate the effectiveness, clinical usefulness, sustainability, and usability of web-compatible diabetes-related tools. DATA SOURCES: Medline, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, world wide web. STUDY SELECTION: Studies were included if they described an electronic audiovisual tool used as a means to educate patients, care givers, or clinicians about diabetes management and assessed a psychological, behavioral, or clinical outcome. DATA EXTRACTION: Study abstraction and evaluation for clinical usefulness, sustainability, and usability were performed by two independent reviewers. RESULTS: Of 12,616 citations and 1541 full-text articles reviewed, 57 studies met inclusion criteria. Forty studies used experimental designs (25 randomized controlled trials, one controlled clinical trial, 14 before-after studies), and 17 used observational designs. Methodological quality and ratings for clinical usefulness and sustainability were variable, and there was a high prevalence of usability errors. Tools showed moderate but inconsistent effects on a variety of psychological and clinical outcomes including HbA1c and weight. Meta regression of adequately reported studies (12 studies, 2731 participants) demonstrated that, although the interventions studied resulted in positive outcomes, this was not moderated by clinical usefulness nor usability. LIMITATION: This review is limited by the number of accessible tools, exclusion of tools for mobile devices, study quality, and the use of non-validated scales. CONCLUSION: Few tools were identified that met our criteria for effectiveness, usefulness, sustainability, and usability. Priority areas include identifying strategies to minimize website attrition and enabling patients and clinicians to make informed decisions about website choice by encouraging reporting of website quality indicators. PMID- 22215059 TI - Sensitivity of the saline load test with and without methylene blue dye in the diagnosis of artificial traumatic knee arthrotomies. AB - OBJECTIVES: To determine whether methylene blue dye significantly improves the sensitivity of the saline load test for detection of a traumatic arthrotomy of the knee. DESIGN: Randomized, prospective. SETTING: Orthopaedic department, tertiary care medical center. PATIENTS/PARTICIPANTS: Subjects scheduled for elective outpatient knee arthroscopy were prospectively enrolled and randomized to a normal saline group or a methylene blue group. A total of 58 subjects were enrolled (methylene blue 29, normal saline 29). INTERVENTION: In the course of routine elective knee arthroscopy, a standard inferior lateral arthrotomy was created and then normal saline or methylene blue solution was injected while observing for fluid outflow from the arthrotomy site. MAIN OUTCOME MEASUREMENTS: The volume of fluid injected at the time of outflow was recorded with 180 mL set as the maximum injection volume. RESULTS: The false-negative rate was 67% (methylene blue 69%, normal saline 66%). In patients with a positive test, mean volume of injected fluid at outflow was 105 mL in the methylene blue group and 95 mL in the normal saline group (P = 0.61). CONCLUSIONS: The sensitivity of the saline load test is unacceptably low. The addition of methylene blue does not improve the diagnostic value of the saline load test. Therefore, these results indicate that the saline load test, regardless of the inclusion of methylene blue, is not an accurate test for diagnosing small traumatic knee arthrotomies. LEVEL OF EVIDENCE: Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 22215058 TI - Update on biologic pathways in inflammatory bowel disease and their therapeutic relevance. AB - Results of recent genetic and immunologic studies have brought to the forefront several biologic pathways that allow for a better understanding of the mechanisms of tissue homeostasis, on the one hand, and inflammatory bowel disease (IBD) on the other. The explosion of research activity as a result of these newly identified targets is bringing the pathogenesis of these complex disorders into focus as well as creating new therapeutic opportunities. The greatest advances with perhaps the largest impact on our understanding of the etiology of Crohn's disease are those related to bacterial sensing, such as through nucleotide binding oligomerization domain-containing protein 2 (NOD2) and its relationships to autophagy and the unfolded protein response as a consequence of endoplasmic reticulum stress. Interestingly, it appears as though these pathways, which are rooted in microbial sensing and regulation, are interrelated. Genetic studies have also renewed interest in previously studied pathways in IBD, such as the formation and function of the inflammasome and its relationship to interleukin (IL) 1-beta signaling. With the recent success of therapeutic agents designed to block tumor necrosis factor, the IL-12/23 pathways, and lymphocyte homing, insights have been gained into the biologic relevance and impact of these various inflammatory pathways in IBD. In this review, the exciting recent advances in these biologic pathways of IBD are discussed, particularly in light of their therapeutic relevance. PMID- 22215060 TI - Structural analysis of secretory phospholipase A2 from Clonorchis sinensis: therapeutic implications for hepatic fibrosis. AB - Hepatic fibrosis is a common complication of the infection by the parasite, Clonorchis sinensis. There is a high incidence of this disease in the Asian countries with an increased risk of conversion to cancer. A secretory phospholipase A(2) (PLA(2)) enzyme from the parasite is implicated in the pathology. This is an attractive drug target in the light of extensive structural characterization of this class of enzyme. In this study, the structure of the enzyme was modeled based on its sequence homology to the group III bee venom PLA(2). On analysis, the overall structure essentially is comprised of three helices, two sets of beta-wings and an elongated C-terminal extension. The structure is stabilized by four disulfide bonds. The structure is comprised of a calcium binding loop, active site and a substrate binding hydrophobic channel. The active site of the enzyme shows the classical features of PLA(2) with the participation of the three residues: histidine-aspartic acid-tyrosine in hydrogen bond formation. This is an interesting variation from the house keeping group III PLA(2) enzyme of human which has a histidine-aspartic acid and phenylalanine arrangement at the active site. This difference is therefore an important structural parameter that can be exploited to design specific inhibitor molecules against the pathogen PLA(2). Likewise, there are certain unique structural features in the hydrophobic channel and the putative membrane binding surface of the PLA(2) from Clonorchis sinensis that not only help understand the mechanism of action but also provide knowledge for a targeted therapy of liver fibrosis caused by the parasite. PMID- 22215061 TI - Two types of fatigue in cancer patients. PMID- 22215062 TI - Cetuximab-based therapy in elderly comorbid patients with metastatic colorectal cancer. AB - BACKGROUND: Clinical trials under-represent patients (pts) >65 years. Non interventional studies (NISs) help to evaluate therapies in daily practice. This NIS evaluates efficacy and safety of cetuximab in combination with chemotherapy in metastatic colorectal cancer (mCRC) pts aged >65 years vs <= 65 years. METHODS: A total of 657 pts were recruited into the NIS and analysed applying descriptive statistics and chi(2) or Fisher's exact test. RESULTS: A total of 309 and 305 pts aged <= 65 and >65 years, respectively, were documented; 80% showing a reduced ECOG status of 1-2 and 95% having received at least one palliative treatment. Cetuximab was combined with irinotecan according to approval status. Grade III/IV toxicities occurred in 20% of pts without any difference between age groups although the older pts had significantly more pre-existing comorbidities (P=0.001). A total of 64.2% of the pts developed skin rash, which was strongly related to response (P<0.0002) without any difference between age groups (P=0.34). The objective response rates were 37.9% for ages 18-65 years vs 35.4% for >65 years. Progression-free survival (PFS) did not differ between pts 18-65 years old (6.5 months) in comparison with pts >65 years (7.0 months). In a multivariate analysis only ECOG status had a negative impact on PFS (HR: 0,675; 95% Cl, 0.53-0.87; P=0.0019). CONCLUSION: This NIS reports one of the largest mCRC collectives >65 years and reduced performance status. Cetuximab has a similar efficacy and safety profile for pts aged <= 65 and >65 years. PMID- 22215064 TI - Alcohol intake and mortality among women with invasive breast cancer. AB - BACKGROUND: Alcohol intake has consistently been associated with increased breast cancer incidence in epidemiological studies. However, the relation between alcohol and survival after breast cancer diagnosis is less clear. METHODS: We investigated whether alcohol intake was associated with survival among 3146 women diagnosed with invasive breast cancer in the Swedish Mammography Cohort. Alcohol consumption was estimated using a food frequency questionnaire. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: From 1987 to 2008 there were 385 breast cancer specific deaths and 860 total deaths. No significant association was observed between alcohol intake and breast cancer-specific survival. Women who consumed 10 g per day (corresponding to approximately 0.75 to 1 drinks) or more of alcohol had an adjusted HR (95% CI) of breast cancer-specific death of 1.36 (0.82 2.26;p(trend)=0.47) compared with non-drinkers. A significant inverse association was observed between alcohol and non-breast cancer deaths. Those who consumed 3.4 9.9 g per day of alcohol had a 33% lower risk of death compared with non-drinkers (95% CI 0.50-0.90;p(trend)=0.04). CONCLUSION: Our findings suggest that alcohol intake up to approximately one small drink per day does not negatively impact breast cancer-specific survival and a half drink per day is associated with a decreased risk of mortality from other causes. PMID- 22215065 TI - Targeting the endothelin axis with atrasentan, in combination with IFN-alpha, in metastatic renal cell carcinoma. AB - BACKGROUND: The endothelin system is involved in tumour growth. Atrasentan, a selective endothelin-A-receptor antagonist, blocks endothelin signalling. This phase I trial studied combining treatment of interferon-alpha (IFN-alpha) with atrasentan in renal cell carcinoma (RCC). PATIENTS AND METHODS: This study evaluated the safety and tolerance of IFN-alpha (9MU subcutaneously (s.c.) three times a week) in combination with atrasentan (2.5, 5 and 10 mg orally once daily) in untreated metastatic RCC. Cohort 10 mg was extended to obtain insights in efficacy and pharmacodynamics. RESULTS: Observed toxicities mainly consisted of known IFN-like toxicities (anorexia, chills, fever, fatigue and nausea), and of nasal congestion (associated to atrasentan). None of these toxicities were considered dose limiting. Cohort 10 mg was extended up to 32 patients; in a subset of patients treated according to the protocol (n=27), median overall survival (OS) was 17.3 months. One patient (3.1%) showed a partial response lasting 14.3 months. In an exploratory analysis, we observed that in the subset of patients with declining vascular endothelial growth factor (VEGF) levels (in combination with rising Endothelin-1 levels), median OS was 22.2 months compared with 2.2 months in patients with increasing VEGF levels. CONCLUSION: Combination treatment of IFN-alpha 9MU-alpha s.c. three times a week and atrasentan 10 mg once daily is tolerated. Clinical activity, especially OS, and biomarkers in our view warrant further studies targeting the endothelin axis. PMID- 22215066 TI - Towards dual photodynamic and antiangiogenic agents: design and synthesis of a phthalocyanine-chalcone conjugate. AB - A phthalocyanine-chalcone conjugate has been designed to combine the vascular disrupting effect of chalcones with the photodynamic effect of phthalocyanines. This potential dual photodynamic and antiangiogenic agent was obtained by the condensation of a tetrahydroxylated non-peripherally substituted Zn(ii) phthalocyanine with an amino chalcone converted into the corresponding activated isocyanate. The conjugate was fully characterized. PMID- 22215067 TI - Microwave plasma synthesis of lanthanide zirconates from microwave transparent oxides. AB - Lanthanide zirconate phases Ln(2)Zr(2)O(7) and Ln(4)Zr(3)O(12) (Ln = Y, La, Gd, Dy, Ho, Yb) have been prepared using a microwave induced plasma methodology, which allows rapid synthesis using materials which do not couple directly with microwaves at room temperature. We describe the measurement of heating profiles of the precursor binary metal oxides which can be used to identify conditions conducive to the synthesis of more complex oxides. Uncontrolled heating which can be a feature of microwave synthesis of ceramics is not observed, allowing reproducible synthesis. Conventionally these phases are prepared at >1400 degrees C over hours or days and are being investigated for applications including the immobilisation of nuclear waste where rapid processing is important. Using the microwave plasma method, phase-pure materials have been prepared in minutes. Furthermore, it is clear that Ln(2)Zr(2)O(7) and Ln(4)Zr(3)O(12) also exhibit significant plasma-promoted dielectric heating (e.g. >2200 degrees C for Dy(4)Zr(3)O(12)) which is typically greater than either of the respective precursors, thus providing a driving force to rapidly complete the reaction. PMID- 22215068 TI - Specimen preparation, imaging, and analysis protocols for knife-edge scanning microscopy. AB - Major advances in high-throughput, high-resolution, 3D microscopy techniques have enabled the acquisition of large volumes of neuroanatomical data at submicrometer resolution. One of the first such instruments producing whole-brain-scale data is the Knife-Edge Scanning Microscope (KESM), developed and hosted in the authors' lab. KESM has been used to section and image whole mouse brains at submicrometer resolution, revealing the intricate details of the neuronal networks (Golgi), vascular networks (India ink), and cell body distribution (Nissl). The use of KESM is not restricted to the mouse nor the brain. We have successfully imaged the octopus brain, mouse lung, and rat brain. We are currently working on whole zebra fish embryos. Data like these can greatly contribute to connectomics research; to microcirculation and hemodynamic research; and to stereology research by providing an exact ground-truth. In this article, we will describe the pipeline, including specimen preparation (fixing, staining, and embedding), KESM configuration and setup, sectioning and imaging with the KESM, image processing, data preparation, and data visualization and analysis. The emphasis will be on specimen preparation and visualization/analysis of obtained KESM data. We expect the detailed protocol presented in this article to help broaden the access to KESM and increase its utilization. PMID- 22215069 TI - Diversity oriented and chemoenzymatic synthesis of densely functionalized pyrrolidines through a highly diastereoselective Ugi multicomponent reaction. AB - A highly diastereoselective Ugi reaction involving a chiral cyclic imine, two enantiomerically pure isocyanides and various carboxylic acids was employed for the synthesis of polyfunctionalized pyrrolidines. Both chiral substrates have been efficiently prepared by chemoenzymatic methodologies from readily available achiral substrates. This highly convergent approach can find an application in the fragment-based drug discovery process. PMID- 22215070 TI - Internal loop photobiodegradation reactor (ILPBR) for accelerated degradation of sulfamethoxazole (SMX). AB - The internal loop photobiodegradation reactor (ILPBR) was evaluated for the degradation of the pharmaceutical sulfamethoxazole (SMX) using batch experiments following three protocols: photolysis alone (P), biodegradation alone (B), and intimately coupled photolysis and biodegradation (P&B). SMX was removed more rapidly by P&B than by either P or B alone, and the corresponding dissolved organic carbon (DOC) removals by P&B also were higher. The faster SMX removal probably was due to a synergy between photolysis and the rapid biodegradation of SMX by the biofilm. The greater DOC removal was brought about by the presence of biofilm bacteria able to biodegrade photolysis products. Ammonium N released during photolysis of SMX gave more evidence for the formation of intermediates and was enough in P&B experiments to support bioactivity when no other N was supplied. Clone libraries performed on the biofilms before and after the P&B experiments showed profound changes in the microbial community. Whereas Rhodopirellula baltica and Methylibium petroleiphilum PM1 dominated the biofilm after the B experiments, they were replaced by Micrococcus luteus, Delftia acidovorans, and Oligotropha carboxidovorans after the P&B experiments. The changes in microbial community structure mirrored the change in function in the P&B experiments: SMX biodegradation (presumably the roles of R. baltica and M. petroleiphilum) was out-competed by SMX photolysis, but biodegradation of photolysis products (most likely by M. luteus and D. acidovorans) became important. The higher removal rates of SMX and DOC, as well as the changes in microbial community structure, confirm the value of intimately coupling photolysis with biodegradation in the ILPBR. PMID- 22215071 TI - Directed evolution and structural prediction of cellobiohydrolase II from the thermophilic fungus Chaetomium thermophilum. AB - Cellulases can be engineered with enhanced properties for broad use in scientific and industrial applications. In this study, the wild-type cbh2 gene of the thermophilic fungus Chaetomium thermophilum encoding cellobiohydrolase II (CBHII) was mutagenized through in vitro directed evolution. The resulting Pichia pastoris yeast library was screened, and two transformants were selected for enhanced CBHII activities that were not attributed to increased gene copy numbers. The optimum fermentation times of the two mutant transformants were shortened to 4-5 days after methanol induction compared to 6 days for the wild type. The optimum reaction temperature (60 degrees C) and pH level (5 or 6) of the mutant CBHII proteins, designated CBHIIX16 and CBHIIX305, were higher than those of wild-type CBHII (50 degrees C and pH 4). Kept at 80 degrees C for 1 h, CBHIIX16 and CBHIIX305 retained >50% of their activities, while the wild-type CBHII lost all activity. Sequence analysis of CBHIIX16 and CBHIIX305 revealed that they contained five and six mutated amino acids, respectively. Structural modeling confirmed the presence of carbohydrate binding type-1 and catalytic domains, where the hydrogen bond numbers between the 227th and 203rd amino acids were increased, which perhaps contributed to the elevated enzyme stability. Therefore, the two CBHII mutants selected for increased enzymatic activities also demonstrated elevated optimum reaction temperature and pH levels and enhanced thermal stability. These properties may be beneficial in practical applications for CBHII. PMID- 22215072 TI - Aerobic bioreduction of nickel(II) to elemental nickel with concomitant biomineralization. AB - Although microorganisms have the potential to reduce metals, products with elementary forms are unusual. In the present study, a strain of Pseudomonas sp. MBR was tested for its ability to reduce metal ions to their elementary forms coupled to biomineralization under aerobic conditions. The Pseudomonas sp. MBR strain was able to reduce metals such as Fe(III), Mn(II), Cu(II), Ni(II), Cd(II), Co(II), Al(III), Se(IV), and Te(IV) as electron acceptors to elementary forms using citrate, lactate, pyruvate, succinate, malate, glucose, or ethanol as electron donors. Growth and reduction during biomineralization occurred within the pH range of 6.0 to 11.0 and temperature range of 4 to 40 degrees C, with an optimum growth temperature of 28 degrees C. The resistance of Ni(II) varied from 0.5 to 5 mM. Ni(II) reduction was still observed when nitrate was present in addition to oxygen as a potential electron acceptor. The Ni(II) reduction efficiency was related with the molar ratio of the electron donor to Ni(II). Unlike other dissimilatory metal-reducing bacteria, which oxidizes organic matter with Fe(III) or Mn(IV) as the sole electron acceptor coupled to energy production under facultative anaerobic conditions, this strain used oxygen as an electron acceptor combined with metal reduction. The aerobic metal reduction may relate to a co-metabolic reduction. Transmission electron microscopy images demonstrated that the cells had the ability to accumulate heavy metals, and that the detoxicity mechanism was intracellular metal reduction. These results suggested that the use of Pseudomonas sp. MBR could be promising for toxic heavy metal bioremediation and biological metallurgy. PMID- 22215073 TI - Conventional transarterial chemoembolisation in combination with sorafenib for patients with hepatocellular carcinoma: a pilot study. AB - OBJECTIVES: To investigate the safety of transarterial chemoembolisation (TACE) in combination with sorafenib in patients with hepatocellular carcinoma (HCC). METHODS: Patients with Child-Pugh A/B liver function, ECOG performance status 0-2 and HCC treatable with TACE received continuous sorafenib 800 mg/day, and TACE with doxorubicin (75, 50 and 25 mg/m(2) according to serum bilirubin: <1.5, 1.5 3, and >3 mg/dL) and lipiodol 2 weeks after sorafenib initiation and repeated every 4 weeks. RESULTS: Fifteen patients were included (Child-Pugh A/B, n = 12/3; Barcelona Clinic Liver Cancer-A/B/C, n = 1/9/5; ECOG 0/2, n = 14/1). Median time on sorafenib was 5.2 months (2.6-7.4 months); median number of TACE sessions was 3. Common adverse events were abdominal pain (n = 14), weight loss (n = 13), alopecia (n = 12), fatigue (n = 12) and hyperbilirubinaemia (n = 11). There were 32 serious adverse events (grade >= 3); 9/10-unscheduled hospital admissions and 4/5 deaths were considered TACE-related. The study was stopped prematurely because of safety concerns. At 6 months, 2 and 5 patients had complete or partial responses; 1 had stable disease. Median overall survival was 10.6 months (95% CI: 5.2-16 months). CONCLUSION: These findings do not support use of an intensive, high-dose doxorubicin-based TACE regimen in combination with sorafenib in this study population. KEY POINTS: * Transarterial chemoembolisation (TACE) is widely used in patients with hepatocellular carcinoma (HCC) * Various antiangiogenic and other agents have been used to augment this treatment * We tested lipiodol-TACE with bilirubin-adjusted doxorubicin dosing in combination with sorafenib * This trial was stopped prematurely because of safety reasons * Our safety results do not support the combination of sorafenib with this TACE regimen. PMID- 22215074 TI - Extracardiac findings detected by cardiac magnetic resonance imaging. AB - OBJECTIVE: To determine the prevalence and importance of extracardiac findings (ECF) in patients undergoing clinical CMR and to test the hypothesis that the original CMR reading focusing on the heart may underestimate extracardiac abnormalities. METHODS: 401 consecutive patients (mean age 53 years) underwent CMR at 1.5 T. Main indications were ischaemic heart disease (n = 183) and cardiomyopathy (n = 164). All CMR sequences, including scout images, were reviewed with specific attention to ECF in a second reading by the same radiologist who performed the first clinical reading. Potentially significant findings were defined as abnormalities requiring additional clinical or radiological follow-up. RESULTS: 250 incidental ECF were detected, of which 84 (34%) had potentially significant ECF including bronchial carcinoma (n = 1), lung consolidation (n = 7) and abdominal abnormalities. In 166 CMR studies (41%) non significant ECF were detected. The number of ECF identified at second versus first reading was higher for significant (84 vs. 47) and non-significant (166 vs. 36) findings (P < 0.00001). CONCLUSIONS: About one fifth of patients undergoing CMR were found to have potentially significant ECF requiring additional work-up. The second dedicated reading detected significantly more ECF compared with the first clinical reading emphasising the importance of active search for extracardiac abnormalities when evaluating CMR studies. KEY POINTS: * Many patients undergoing cardiac MR have significant extracardiac findings (ECF) * These impact on management and require additional work-up. * Wide review of scout and cine sequences will detect most ECFs. * Education of radiologists is important to identify ECFs on CMR studies. PMID- 22215075 TI - Tracking hypoxic signaling within encapsulated cell aggregates. AB - In Diabetes mellitus type 1, autoimmune destruction of the pancreatic beta-cells results in loss of insulin production and potentially lethal hyperglycemia. As an alternative treatment option to exogenous insulin injection, transplantation of functional pancreatic tissue has been explored. This approach offers the promise of a more natural, long-term restoration of normoglycemia. Protection of the donor tissue from the host's immune system is required to prevent rejection and encapsulation is a method used to help achieve this aim. Biologically-derived materials, such as alginate and agarose, have been the traditional choice for capsule construction but may induce inflammation or fibrotic overgrowth which can impede nutrient and oxygen transport. Alternatively, synthetic poly(ethylene glycol) (PEG)-based hydrogels are non-degrading, easily functionalized, available at high purity, have controllable pore size, and are extremely biocompatible. As an additional benefit, PEG hydrogels may be formed rapidly in a simple photo crosslinking reaction that does not require application of non-physiological temperatures. Such a procedure is described here. In the crosslinking reaction, UV degradation of the photoinitiator, 1-[4-(2-Hydroxyethoxy)-phenyl]-2-hydroxy-2 methyl-1-propane-1-one (Irgacure 2959), produces free radicals which attack the vinyl carbon-carbon double bonds of dimethacrylated PEG (PEGDM) inducing crosslinking at the chain ends. Crosslinking can be achieved within 10 minutes. PEG hydrogels constructed in such a manner have been shown to favorably support cells, and the low photoinitiator concentration and brief exposure to UV irradiation is not detrimental to viability and function of the encapsulated tissue. While we methacrylate our PEG with the method described below, PEGDM can also be directly purchased from vendors such as Sigma. An inherent consequence of encapsulation is isolation of the cells from a vascular network. Supply of nutrients, notably oxygen, is therefore reduced and limited by diffusion. This reduced oxygen availability may especially impact beta-cells whose insulin secretory function is highly dependent on oxygen. Capsule composition and geometry will also impact diffusion rates and lengths for oxygen. Therefore, we also describe a technique for identifying hypoxic cells within our PEG capsules. Infection of the cells with a recombinant adenovirus allows for a fluorescent signal to be produced when intracellular hypoxia-inducible factor (HIF) pathways are activated. As HIFs are the primary regulators of the transcriptional response to hypoxia, they represent an ideal target marker for detection of hypoxic signaling. This approach allows for easy and rapid detection of hypoxic cells. Briefly, the adenovirus has the sequence for a red fluorescent protein (Ds Red DR from Clontech) under the control of a hypoxia-responsive element (HRE) trimer. Stabilization of HIF-1 by low oxygen conditions will drive transcription of the fluorescent protein (Figure 1). Additional details on the construction of this virus have been published previously. The virus is stored in 10% glycerol at -80 degrees C as many 150 MUL aliquots in 1.5 mL centrifuge tubes at a concentration of 3.4 x 10(10) pfu/mL. Previous studies in our lab have shown that MIN6 cells encapsulated as aggregates maintain their viability throughout 4 weeks of culture in 20% oxygen. MIN6 aggregates cultured at 2 or 1% oxygen showed both signs of necrotic cells (still about 85-90% viable) by staining with ethidium bromide as well as morphological changes relative to cells in 20% oxygen. The smooth spherical shape of the aggregates displayed at 20% was lost and aggregates appeared more like disorganized groups of cells. While the low oxygen stress does not cause a pronounced drop in viability, it is clearly impacting MIN6 aggregation and function as measured by glucose-stimulated insulin secretion. Western blot analysis of encapsulated cells in 20% and 1% oxygen also showed a significant increase in HIF-1alpha for cells cultured in the low oxygen conditions which correlates with the expression of the DsRed DR protein. PMID- 22215076 TI - Clinical grading of the pivot shift test correlates best with tibial acceleration. AB - PURPOSE: Recently, different measurement systems have been developed to quantitatively measure the pivot shift in vivo. These systems lack validation and a large inter-examiner variability for the manually performed pivot shift test exists. The purpose of this study was to perform objective measurements of the pivot shift using three different measurement devices and to examine the correlation of the measurements with clinical grading of the pivot shift. METHODS: A cadaver knee on a whole lower body specimen was prepared to display a high-grade pivot shift. The pivot shift tests were performed three times by 12 blinded expert surgeons using their preferred technique. Simultaneous data samplings were recorded using three different measurement devices: (1) electromagnetic tracking system using bone-attached and skin-fixed sensors, respectively, (2) triaxial accelerometer system, and (3) simple image analysis. The surgeons graded the knee clinically using pivot shift grades I-III. Correlations were calculated using the Spearman's rank correlation coefficient. RESULTS: The expert surgeons average clinical grading was 2.3 (SD +/- 0.5). Clinical grading displayed best correlation with the acceleration of reduction as measured by electromagnetic tracking system with bone-attached sensors (r = 0.67, P < 0.05). Similar correlation coefficient was found for the acceleration of reduction (r = 0.58, P = 0.05) and the "jerk" component of acceleration (r = 0.61, P < 0.05) measured by means of the triaxial accelerometer system. CONCLUSION: The pivot shift can be quantified by several in vivo measurement devices. Best correlation with clinical grading was found with tibial acceleration parameters. Future studies will have to analyze how quantitative parameters can be utilized to standardize clinical grading of the pivot shift. LEVEL OF EVIDENCE: Diagnostic study, Level II. PMID- 22215077 TI - The KneeKG system: a review of the literature. AB - PURPOSE: Accurately quantifying knee joint motion is not simple. Skin movement over the medial and lateral femoral condyles is the greatest obstacle to obtaining accurate movement data non-invasively. The KneeKGTM system was developed with the objective of providing high reliability movement analysis. The goal of this manuscript is to review the technical details, clinical evidence, and potential applications of this system for evaluation of rotational knee laxity. METHODS: A comprehensive review of the MEDLINE database was carried out to identify all clinical and biomechanical studies related to KneeKGTM system. RESULTS: The KneeKGTM system non-invasively quantifies knee abduction/adduction, axial rotation, and relative translation of the tibia and femur. The accuracy and reproducibility of the system have been assessed. The average accuracy of the acquisition is 0.4 degrees for abduction/adduction, 2.3 degrees for axial rotation, 2.4 mm for anteroposterior translation, and 1.1 mm for axial translation. This clinical tool enables an accurate and objective assessment of the tri-planar function of the knee joint. The measured biomechanical parameters are sensitive to changes in gait due to knee osteoarthritis and ACL deficiency. CONCLUSION: The KneeKGTM system provides reliable movement analysis. This system has the potential to improve understanding the biomechanical consequences of trauma or degenerative changes of the knee as well as more accurately quantify rotational laxity as detected by a positive pivot-shift test. PMID- 22215078 TI - Photoswitchable gel assembly based on molecular recognition. AB - The formation of effective and precise linkages in bottom-up or top-down processes is important for the development of self-assembled materials. Self assembly through molecular recognition events is a powerful tool for producing functionalized materials. Photoresponsive molecular recognition systems can permit the creation of photoregulated self-assembled macroscopic objects. Here we demonstrate that macroscopic gel assembly can be highly regulated through photoisomerization of an azobenzene moiety that interacts differently with two host molecules. A photoregulated gel assembly system is developed using polyacrylamide-based hydrogels functionalized with azobenzene (guest) or cyclodextrin (host) moieties. Reversible adhesion and dissociation of the host gel from the guest gel may be controlled by photoirradiation. The differential affinities of alpha-cyclodextrin or beta-cyclodextrin for the trans-azobenzene and cis-azobenzene are employed in the construction of a photoswitchable gel assembly system. PMID- 22215079 TI - Metal-adeninate vertices for the construction of an exceptionally porous metal organic framework. AB - Metal-organic frameworks comprising metal-carboxylate cluster vertices and long, branched organic linkers are the most porous materials known, and therefore have attracted tremendous attention for many applications, including gas storage, separations, catalysis and drug delivery. To increase metal-organic framework porosity, the size and complexity of linkers has increased. Here we present a promising alternative strategy for constructing mesoporous metal-organic frameworks that addresses the size of the vertex rather than the length of the organic linker. This approach uses large metal-biomolecule clusters, in particular zinc-adeninate building units, as vertices to construct bio-MOF-100, an exclusively mesoporous metal-organic framework. Bio-MOF-100 exhibits a high surface area (4,300 m(2) g(-1)), one of the lowest crystal densities (0.302 g cm( 3)) and the largest metal-organic framework pore volume reported to date (4.3 cm(3) g(-1)). PMID- 22215081 TI - Violation of a Leggett-Garg inequality with ideal non-invasive measurements. AB - The quantum superposition principle states that an entity can exist in two different states simultaneously, counter to our 'classical' intuition. Is it possible to understand a given system's behaviour without such a concept? A test designed by Leggett and Garg can rule out this possibility. The test, originally intended for macroscopic objects, has been implemented in various systems. However to date no experiment has employed the 'ideal negative result' measurements that are required for the most robust test. Here we introduce a general protocol for these special measurements using an ancillary system, which acts as a local measuring device but which need not be perfectly prepared. We report an experimental realization using spin-bearing phosphorus impurities in silicon. The results demonstrate the necessity of a non-classical picture for this class of microscopic system. Our procedure can be applied to systems of any size, whether individually controlled or in a spatial ensemble. PMID- 22215080 TI - Existence of long-lasting experience-dependent plasticity in endocrine cell networks. AB - Experience-dependent plasticity of cell and tissue function is critical for survival by allowing organisms to dynamically adjust physiological processes in response to changing or harsh environmental conditions. Despite the conferred evolutionary advantage, it remains unknown whether emergent experience-dependent properties are present in cell populations organized as networks within endocrine tissues involved in regulating body-wide homeostasis. Here we show, using lactation to repeatedly activate a specific endocrine cell network in situ in the mammalian pituitary, that templates of prior demand are permanently stored through stimulus-evoked alterations to the extent and strength of cell-cell connectivity. Strikingly, following repeat stimulation, evolved population behaviour leads to improved tissue output. As such, long-lasting experience dependent plasticity is an important feature of endocrine cell networks and underlies functional adaptation of hormone release. PMID- 22215082 TI - Inhibition of specific gene expressions by protein-mediated mRNA interference. AB - RNA interference mediated by RNA such as antisense RNA, short interfering RNA and micro RNA is well documented to regulate specific gene expression at the level of messenger RNA. However, RNA interference mediated by proteins has not been reported. Here we identify the MazF-hw mRNA interferase from a superhalophilic archaeon that cleaves RNA at a specific seven-base sequence (UUACUCA). This sequence was found unusually abundant in the mRNAs for rhodopsin transcription activator and some membrane proteins of the archaeon, suggesting that the expression of these proteins is regulated by MazF-hw. When all of the seven-base cleavage sites in essential genes in Escherichia coli were eliminated, the cells were no longer sensitive to MazF-hw, demonstrating that specific gene expression can be regulated by a sequence-specific mRNA interferase. These findings demonstrate that mRNA interference can be mediated not only by RNA but also by proteins to effectively silence specific gene expression in cells. PMID- 22215084 TI - Approaching the ideal elastic limit of metallic glasses. AB - The ideal elastic limit is the upper bound to the stress and elastic strain a material can withstand. This intrinsic property has been widely studied for crystalline metals, both theoretically and experimentally. For metallic glasses, however, the ideal elastic limit remains poorly characterized and understood. Here we show that the elastic strain limit and the corresponding strength of submicron-sized metallic glass specimens are about twice as high as the already impressive elastic limit observed in bulk metallic glass samples, in line with model predictions of the ideal elastic limit of metallic glasses. We achieve this by employing an in situ transmission electron microscope tensile deformation technique. Furthermore, we propose an alternative mechanism for the apparent 'work hardening' behaviour observed in the tensile stress-strain curves. PMID- 22215083 TI - Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model. AB - With ageing, there is a loss of adult stem cell function. However, there is no direct evidence that this has a causal role in ageing-related decline. We tested this using muscle-derived stem/progenitor cells (MDSPCs) in a murine progeria model. Here we show that MDSPCs from old and progeroid mice are defective in proliferation and multilineage differentiation. Intraperitoneal administration of MDSPCs, isolated from young wild-type mice, to progeroid mice confer significant lifespan and healthspan extension. The transplanted MDSPCs improve degenerative changes and vascularization in tissues where donor cells are not detected, suggesting that their therapeutic effect may be mediated by secreted factor(s). Indeed, young wild-type-MDSPCs rescue proliferation and differentiation defects of aged MDSPCs when co-cultured. These results establish that adult stem/progenitor cell dysfunction contributes to ageing-related degeneration and suggests a therapeutic potential of post-natal stem cells to extend health. PMID- 22215085 TI - Structure-based mutagenesis reveals the albumin-binding site of the neonatal Fc receptor. AB - Albumin is the most abundant protein in blood where it has a pivotal role as a transporter of fatty acids and drugs. Like IgG, albumin has long serum half-life, protected from degradation by pH-dependent recycling mediated by interaction with the neonatal Fc receptor, FcRn. Although the FcRn interaction with IgG is well characterized at the atomic level, its interaction with albumin is not. Here we present structure-based modelling of the FcRn-albumin complex, supported by binding analysis of site-specific mutants, providing mechanistic evidence for the presence of pH-sensitive ionic networks at the interaction interface. These networks involve conserved histidines in both FcRn and albumin domain III. Histidines also contribute to intramolecular interactions that stabilize the otherwise flexible loops at both the interacting surfaces. Molecular details of the FcRn-albumin complex may guide the development of novel albumin variants with altered serum half-life as carriers of drugs. PMID- 22215086 TI - Advantage of rare infanticide strategies in an invasion experiment of behavioural polymorphism. AB - Killing conspecific infants (infanticide) is among the most puzzling phenomena in nature. Stable polymorphism in such behaviour could be maintained by negative frequency-dependent selection (benefit of rare types). However, it is currently unknown whether there is genetic polymorphism in infanticidal behaviour or whether infanticide may have any fitness advantages when rare. Here we show genetic polymorphism in non-parental infanticide. Our novel invasion experiment confirms negative frequency-dependent selection in wild bank vole populations, where resource benefits allow an infanticidal strategy to invade a population of non-infanticidal individuals. The results show that infanticidal behaviour is highly heritable with genetic correlation across the sexes. Thus, a positive correlative response in male behaviour is expected when selection operates on females only and vice versa. Our results, on one hand, demonstrate potential benefits of infanticide, and on the other, they open a new perspective of correlative evolution of infanticide in females and males. PMID- 22215087 TI - Measurement of finite-frequency current statistics in a single-electron transistor. AB - Electron transport in nanoscale structures is strongly influenced by the Coulomb interaction that gives rise to correlations in the stream of charges and leaves clear fingerprints in the fluctuations of the electrical current. A complete understanding of the underlying physical processes requires measurements of the electrical fluctuations on all time and frequency scales, but experiments have so far been restricted to fixed frequency ranges, as broadband detection of current fluctuations is an inherently difficult experimental procedure. Here we demonstrate that the electrical fluctuations in a single-electron transistor can be accurately measured on all relevant frequencies using a nearby quantum point contact for on-chip real-time detection of the current pulses in the single electron device. We have directly measured the frequency-dependent current statistics and, hereby, fully characterized the fundamental tunnelling processes in the single-electron transistor. Our experiment paves the way for future investigations of interaction and coherence-induced correlation effects in quantum transport. PMID- 22215088 TI - Synthetic quorum-sensing circuit to control consortial biofilm formation and dispersal in a microfluidic device. AB - To utilize biofilms for chemical transformations in biorefineries they need to be controlled and replaced. Previously, we engineered the global regulator Hha and cyclic diguanylate-binding BdcA to create proteins that enable biofilm dispersal. Here we report a biofilm circuit that utilizes these two dispersal proteins along with a population-driven quorum-sensing switch. With this synthetic circuit, in a novel microfluidic device, we form an initial colonizer biofilm, introduce a second cell type (dispersers) into this existing biofilm, form a robust dual species biofilm and displace the initial colonizer cells in the biofilm with an extracellular signal from the disperser cells. We also remove the disperser biofilm with a chemically induced switch, and the consortial population could tune. Therefore, for the first time, cells have been engineered that are able to displace an existing biofilm and then be removed on command allowing one to control consortial biofilm formation for various applications. PMID- 22215090 TI - Synthesis and characterisation of BODIPY radical anions. AB - The redox processes associated with BODIPY analogues are studied by electrochemical and spectroscopic methods revealing a characteristic profile for the persistent BODIPY radical and quenching of fluorescence upon reduction. PMID- 22215089 TI - Helicobacter pylori regulates iNOS promoter by histone modifications in human gastric epithelial cells. AB - Inducible nitric oxide synthase (iNOS) expression is altered in gastrointestinal diseases. Helicobacter pylori (Hp) infection may have a critical role in iNOS disregulation. We undertook this study to investigate possible chromatin changes occurring early during iNOS gene activation as a direct consequence of Hp-gastric cells interaction. We show that Hp infection is followed by different expression and chromatin modifications in gastric cells including (1) activation of iNOS gene expression, (2) chromatin changes at iNOS promoter including decreased H3K9 methylation and increased H3 acetylation and H3K4 methylation levels, (3) selective release of methyl-CpG-binding protein 2 from the iNOS promoter. Moreover, we show that Hp-induced activation of iNOS is delayed, but not eliminated, by the treatment with LSD1 inhibitors. Our data suggest a role for specific chromatin-based mechanisms in the control of human iNOS gene expression upon Hp exposure. PMID- 22215091 TI - Percutaneous electrode placement for spinal cord stimulation in a patient with spinal fusion: a technical report. AB - A spinal cord stimulation (SCS) trial was attempted to alleviate left knee pain in a patient with spinal fusion from T12 to L4. Good paresthesia coverage for the knee pain was attained with SCS. However, while removing the needle used for electrode placement, the needle became fixed in the bony supplementary tissue. Moreover, while attempting to remove the needle using Kelly forceps, the hub of the needle became blocked. Without the hub, we had no choice but to use a pneumatic drill for removing the needle. Accordingly, the supplementary bone tissue was drilled under real-time imaging, using a pneumatic drill with a 3.2-mm drill bit, and another epidural needle was inserted through the hole. We consider that, in patients with spinal fusion, making a borehole with a pneumatic drill for introducing the epidural needle for percutaneous SCS electrode placement may be advisable in order to avoid the above-mentioned difficulties. PMID- 22215092 TI - Setting priorities. PMID- 22215093 TI - Analysis of health-related quality of life in children with immune thrombocytopenia and their parents using the kids' ITP tools. AB - The diagnosis, treatment, and prognosis of immune trombocytopenic purpura (ITP) have been extensively studied, but data on its effect on health-related quality of life in children remain sparse. To shed more light on this issue, we administered the Kids' ITP Tools (KIT) questionnaire to 17 children with ITP attending a tertiary pediatric medical center and their parents (n=34). The mean KIT score was significantly lower in the parents' group than in the children's group (P=0.000). The main domains of concern for the parents were disease side effects and their child's future; the children were mostly concerned about the need to restrict physical activities. The presence of acute versus chronic disease had no impact on the KIT score in either group. These findings stress the need to develop different interventional programs for children with ITP and their parents to provide appropriate support to each. PMID- 22215094 TI - Clinical features, prognostic factors, and their relationship with antiplatelet antibodies in children with immune thrombocytopenia. AB - We investigated and evaluated the demographics, clinical and laboratory features, treatment responses, and disease duration of 25 children with immune thrombocytopenia (ITP) eligible for detection of antiplatelet antibodies. We found that patients without antecedent of preceding infection (API) were more likely to have anti-GPIa/IIa than those with API (42.9% vs. 5.5%, P=0.048). Age groups of <2 years and 2 to 10 years were more likely to show response (R) or complete response (CR) to given treatments, whereas none of the patients whose onset age >10 years showed R or CR to given treatments (88.9% and 100% vs 0%, P=0.001). The percentage of newly diagnosed ITP was higher in age groups of <2 years (100%) and in 2 to 10 years (90%) than the age group of >10 years (16.7%, P=0.001). Patients without API (71.4%) were more likely to develop chronic ITP than those with API (5.6%, P=0.002). In conclusion, younger age was a favorable prognostic factor, especially in patients <2 years of age with respect to treatment responses and disease duration. In addition, API was associated with a short disease course as well as absence of anti-GPIa/IIa. PMID- 22215096 TI - Gene dose effects of GSTM1, GSTT1 and GSTP1 polymorphisms on outcome in childhood acute lymphoblastic leukemia. AB - Children with acute lymphoblastic leukemia (ALL) react very differently to chemotherapy. One explanation for this is inherited genetic variation. The glutathione S-transferase (GST) enzymes inactivate a number of chemotherapeutic drugs administered in childhood ALL therapy. Two multiplexing methods were applied for genotyping the GSTM1 and GSTT1 genes (distinguishing between 0, 1, or 2 gene copies) and the GSTP1 313 A>G polymorphism, simultaneously. A total of 263 childhood ALL patients were genotyped. No gene dose effect on outcome was demonstrated with either GST polymorphisms. Grouping of GSTM1 and GSTT1 into poor (0 or 1 gene copy)-and good metabolizers (at least 2 gene copies)-showed that the poor metabolizers had a trend toward a better outcome (event-free survival =91.8%) compared with the good metabolizers (event-free survival =83.2%). Similarly, in the adjusted analysis the good metabolizers demonstrated a 2.2-fold higher risk trend of experiencing an event (resistant disease or relapse) compared with the poor metabolizers (P=0.066; hazard ratio =2.248; 95% confidence interval, 0.948-5.327). In conclusion, our results suggest that the combined gene dose of GSTM1 and GSTT1 may influence outcome in childhood ALL. PMID- 22215095 TI - Bacteremia in children with sickle hemoglobinopathies. AB - BACKGROUND: Bacteremia is one of the most feared infectious complications of sickle cell disease, and it is associated with a high mortality rate in children. The objective of our study was to investigate the proportion of bacteremia among febrile children with sickle hemoglobinopathies and the clinical factors associated with bacteremia. METHODS: Clinical and microbiological data from children with sickle hemoglobinopathies being followed up at the Pediatric Hematology Clinic at the University of Rochester Medical Center in Rochester, New York, were retrospectively analyzed. The data were collected from medical records covering the time period of June 1997 to December 2006, which included the periods before and after the introduction of routine heptavalent pneumococcal conjugate vaccine usage. Proportions of positive blood cultures among febrile children, the types of organisms causing bacteremia, and clinical and sociodemographic factors were analyzed by chi and t tests as appropriate. RESULTS: The overall proportion of positive blood cultures was 3.8%; 1% was considered to yield true pathogens. Pneumococcal bacteremia decreased from 0.7% in the pre-pneumococcal conjugate vaccine-7 era to 0.2% in the post-pneumococcal conjugate vaccine-7 era; however, the difference was not statistically significant. Pathogens other than pneumococcus were responsible for most bacteremic episodes. No clinical or social factors were found to have statistically significant associations with positive blood cultures. CONCLUSIONS: Approximately 1% of children with sickle hemoglobinopathies with fever have bacteremia despite current penicillin prophylaxis and pneumococcal immunization, although most episodes are due to nonpneumococcal pathogens. Prompt evaluation of such febrile children with sickle hemoglobinopathies remains warranted. PMID- 22215097 TI - Pandemic H1N1 influenza infection in children with acute leukemia: a single center experience. AB - In English literature, there are only 2 specific series of pandemic H1N1 influenza infection in children with leukemia. To increase knowledge about pandemic influenza in children with leukemia and better understand the risk factors for severe disease, we have presented the clinical characteristics of 8 children with acute leukemia and pandemic influenza treated at our center. The mean age of the children (4 girls and 4 boys) was 6.7+/-2.0 years (range, 4 to 10 y). All these children [3 acute lymphoblastic leukemia and 5 acute myeloid leukemia (AML) cases] were receiving chemotherapy during the course of infection, except 1 who was found to be H1N1 positive at the same time that she was diagnosed with AML. Among the other 7 patients undergoing chemotherapy, 4 were receiving induction, 1 was receiving consolidation, and 2 were undergoing maintenance chemotherapy. In our series, 1 patient with AML had a fatal course. She had recently received a chemotherapy bloc. Her neutrophil count was 0 during the course of H1N1 infection. She developed acute respiratory distress syndrome within a short time after the symptoms commenced and she died within 4 days. In conclusion, the clinical course of H1N1 infection may be fatal in rare cases of leukemic children receiving chemotherapy. Thus, vaccination is advisable for all leukemic children, especially for those under maintenance chemotherapy, as it might be life saving during such pandemics. PMID- 22215098 TI - Efficacy of deferasirox in North Indian beta-thalassemia major patients: a preliminary report. AB - Deferasirox (DFX) is a relatively new iron chelator approved by the US Food and Drug Administration for treatment of children >2 years of age. Prospective studies in Asian Indian children are limited. The beta-thalassemia patients receiving regular transfusions in the thalassemia ward of an advanced pediatric center were included in this study. Monitoring of side effects was carried out by assessing monthly transaminases and serum creatinine levels. Hemoglobin levels were determined before blood transfusion. Thirty patients of transfusion dependent thalassemia were eligible for the final analysis. The male:female ratio was 3.3:1, and ages ranged from 2.0 to 21 years. The serum ferritin (SF) level at the start of therapy was 2657.7+/-1414.6 (mean+/-SD). The mean dose of DFX was 21.57 mg/kg/d (range, 17.2 to 27.2 mg/kg/d). Common side effects noted were gastrointestinal manifestations in 5 (16.6%) and skin rash in 2 (6.6%) patients. There was an increase in serum creatinine in 2 patients, and treatment was interrupted in 1. Reversible cytopenia was observed in 1 patient. In 13/30 patients, an initial increase in SF was observed. A decrease in SF levels compared with initial value was seen in only 8 patients at a follow-up of 24 months, at a median dose of 28.8 mg/kg/d. Thus, DFX is a relatively safe oral iron chelator that can be used in Asian Indians, with gastrointestinal problems like diarrhea and abdominal pain as the most common side effects. Treatment requires individualization with careful dose escalation and proper monitoring. PMID- 22215099 TI - Primary follicular lymphoma of the testis in children and adolescents. AB - This study reports 6 cases of primary follicular lymphoma of the testis (PFLT) in children and adolescents correlated with clinical presentation, pathologic features, treatment, and outcome. All 6 patients (age, 3 to 16 y; median, 4 y) had PFLT grade 3 with disease limited to the testis, completely resected and treated with 2 courses of chemotherapy (cyclophosphamide, vincristine, prednisone, doxorubicin). Event-free survival was 100% (follow-up: median, 73 mo; mean, 53 mo; range, 6 to 96 mo). In conclusion, clinical outcome in children and adolescents with PFLT is excellent with treatment including complete surgical resection and 2 courses of cyclophosphamide, vincristine, prednisone, doxorubicin. PMID- 22215100 TI - Acute upper GI bleed in a 4-year-old boy: a case of atypical Burkitt lymphoma in a 4 year old. PMID- 22215101 TI - Extraneural metastasis of a nongerminomatous germ cell tumor of the central nervous system in a pediatric patient with a ventriculoperitoneal shunt: a case report and review of the literature. AB - We describe the case of a 7-year-old white boy who presented with a mixed malignant germ cell tumor with predominant embryonal carcinoma component. The patient underwent right ventriculoperitoneal (VP) shunt placement for hydrocephalus at the time of diagnosis. He received multiagent chemotherapy followed by second-look surgery. Despite an initial response to chemotherapy, the patient had metastatic progression of disease within the craniospinal axis. He received craniospinal radiation and high-dose chemotherapy. Although, he had resolution of central nervous system (CNS) disease, follow-up off treatment revealed extra-abdominal metastases. This is a rare case to discuss abdominal metastasis of a CNS germ cell tumor in a patient with a VP shunt. The influence of VP shunt placement on treatment and management decisions of patients with CNS tumors will be discussed. PMID- 22215102 TI - Elevated serum cytokine levels using cytometric bead arrays predict culture positive infections in childhood oncology patients with febrile neutropenia. AB - Neutropenic patients with bacteraemia need prolonged intravenous antibiotic treatment. Using cytometric bead array technology, we show in children with febrile neutropenia that bacteraemia is associated with an elevation of at least 1 of 3 plasma cytokines plus C-reactive protein. The combination of interleukin (IL)-8, IL-6, IL-10, and C-reactive protein values above operator-defined cutoff levels identified 15 of 16 episodes of bacteraemia, making this a potentially useful technique in identifying high-risk patients who should not be discharged early from hospital. Furthermore, low risk of bacteraemia may be predicted by a combination of below threshold cytokines and negative clinical examination. PMID- 22215103 TI - Personalised cancer follow-up: risk stratification, needs assessment or both? PMID- 22215105 TI - Developing and paying for medicines for orphan indications in oncology: utilitarian regulation vs equitable care? AB - Despite 'orphan drug' legislation, bringing new medicines for rare diseases to market and securing funding for their provision is sometimes both costly and problematic, even in the case of medicines for very rare 'ultra orphan' oncological indications. In this paper difficulties surrounding the introduction of a new treatment for osteosarcoma exemplify the challenges that innovators can face. The implications of current policy debate on 'value-based' medicines pricing in Europe, North America and elsewhere are also explored in the context of sustaining research into and facilitating cancer patient access to medicines for low-prevalence indications. Tensions exist between utilitarian strategies aimed at optimising the welfare of the majority in the society and minority interest-focused approaches to equitable care provision. Current regulatory and pricing strategies should be revisited with the objective of facilitating fair and timely drug supply to patients without sacrificing safety or overall affordability. Failures effectively to tackle the problems considered here could undermine public interests in developing better therapies for cancer patients. PMID- 22215104 TI - Beyond trastuzumab: novel therapeutic strategies in HER2-positive metastatic breast cancer. AB - The use of trastuzumab, a monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2) alteration present in 25 to 30% of breast cancers, has been associated with improved survival outcomes in both the adjuvant and metastatic settings. However, despite the robust clinical efficacy of trastuzumab in HER2-positive metastatic breast cancer (MBC), primary and secondary resistance remains a clinical challenge. Although lapatinib has demonstrated modest activity in this setting, trials reported to date have yet to demonstrate improvements in overall survival with its use. Novel therapeutic strategies to circumvent trastuzumab resistance are warranted, and agents targeting the HER, vascular endothelial growth factor, heat shock protein 90, phosphoinositide 3 kinase/Akt/mammalian target of rapamycin, and insulin-like growth factor-1 receptor pathways represent rational approaches in the management of HER2-positive disease. In this review, early-phase and emerging trial data surrounding the use of these promising agents in HER2-positive MBC will be discussed. PMID- 22215107 TI - A rare case of primary bone xanthoma of the clivus. AB - Primary bone xanthoma is a rare type of tumor, and those developing primarily within the skull are even more unusual. In this case, a primary bone xanthoma of the clivus without endocrine or metabolic complications represents the first of this type to be reported. The patient, a 24-year-old woman, initially experienced frequent headaches. Subsequent skull tomography and bone-window computed tomography (CT) revealed a clearly demarcated osteolytic lesion in the clivus. T1 weighted magnetic resonance imaging (MRI) exhibited low intensity, and T2 weighted MRI showed iso-high intensity and a heterogeneously faint contrast effect. The tumor was completely resected, after which the patient's headaches disappeared completely. Because xanthoma is devoid of neoplastic features, it does not necessarily require aggressive therapy. Therefore, it is very important to understand the characteristics of its clinical symptoms and to give due consideration to differential diagnosis based on pathological presentations and imaging features. This study introduces information regarding a bone xanthoma originating within the skull, together with a review of bone xanthoma literature. PMID- 22215106 TI - Salinomycin inhibits prostate cancer growth and migration via induction of oxidative stress. AB - BACKGROUND: We have shown that a sodium ionophore monensin inhibits prostate cancer cell growth. A structurally related compound to monensin, salinomycin, was recently identified as a putative cancer stem cell inhibitor. METHODS: The growth inhibitory potential of salinomycin was studied in a panel of prostate cells. To get insights into the mechanism of action, a variety of assays such as gene expression and steroid profiling were performed in salinomycin-exposed prostate cancer cells. RESULTS: Salinomycin inhibited the growth of prostate cancer cells, but did not affect non-malignant prostate epithelial cells. Salinomycin impacted on prostate cancer stem cell functions as evidenced by reduced aldehyde dehydrogenase activity and the fraction of CD44(+) cells. Moreover, salinomycin reduced the expression of MYC, AR and ERG, induced oxidative stress as well as inhibited nuclear factor-kappaB activity and cell migration. Furthermore, profiling steroid metabolites revealed increased levels of oxidative stress inducing steroids 7-ketocholesterol and aldosterone and decreased levels of antioxidative steroids progesterone and pregnenolone in salinomycin-exposed prostate cancer cells. CONCLUSION: Our results indicate that salinomycin inhibits prostate cancer cell growth and migration by reducing the expression of key prostate cancer oncogenes, inducing oxidative stress, decreasing the antioxidative capacity and cancer stem cell fraction. PMID- 22215108 TI - MISSION LentiPlex pooled shRNA library screening in mammalian cells. AB - RNA interference (RNAi) is an intrinsic cellular mechanism for the regulation of gene expression. Harnessing the innate power of this system enables us to knockdown gene expression levels in loss of gene function studies. There are two main methods for performing RNAi. The first is the use of small interfering RNAs (siRNAs) that are chemically synthesized, and the second utilizes short-hairpin RNAs (shRNAs) encoded within plasmids. The latter can be transfected into cells directly or packaged into replication incompetent lentiviral particles. The main advantages of using lentiviral shRNAs is the ease of introduction into a wide variety of cell types, their ability to stably integrate into the genome for long term gene knockdown and selection, and their efficacy in conducting high throughput loss of function screens. To facilitate this we have created the LentiPlex pooled shRNA library. The MISSION LentiPlex Human shRNA Pooled Library is a genome-wide lentiviral pool produced using a proprietary process. The library consists of over 75,000 shRNA constructs from the TRC collection targeting 15,000+ human genes. Each library is tested for shRNA representation before product release to ensure robust library coverage. The library is provided in a ready-to-use lentiviral format at titers of at least 5 x 10(8) TU/ml via p24 assay and is pre-divided into ten subpools of approximately 8,000 shRNA constructs each. Amplification and sequencing primers are also provided for downstream target identification. Previous studies established a synergistic antitumor activity of TRAIL when combined with Paclitaxel in A549 cells, a human lung carcinoma cell line. In this study we demonstrate the application of a pooled LentiPlex shRNA library to rapidly conduct a positive selection screen for genes involved in the cytotoxicity of A549 cells when exposed to TRAIL and Paclitaxel. One barrier often encountered with high-throughput screens is the cost and difficulty in deconvolution; we also detail a cost-effective polyclonal approach utilizing traditional sequencing. PMID- 22215109 TI - Minimally invasive technology. PMID- 22215110 TI - Hypertension complicating 131I-meta-iodobenzylguanidine therapy for neuroblastoma. AB - PURPOSE: Radiolabelled meta-iodobenzylguanidine (mIBG), used as targeted therapy for neuroblastoma, is known to have effects on blood pressure (BP). In this study we audited BP changes in patients receiving (131)I-mIBG therapy for neuroblastoma to identify BP-related adverse events (AE) and possible predictive factors. METHODS: Between 2003 and 2010, 50 patients with neuroblastoma received 110 (131)I-mIBG administrations. BP measurements before and after administration were compared with age- and sex-matched centile values. AE were analysed, and possible predisposing factors identified. RESULTS: This population had a baseline BP distribution higher than that of their age- and sex-matched peers, with 16% of preadministration systolic BP values above the 95th centile. Changes in BP after administration showed an approximately normal distribution with similar numbers of reduced and increased values. Four AE, all related to hypertension, occurred with one patient having generalized seizures. One AE was immediate, others occurred between 20 and 25 h after administration. No significant association between AE and patient age or sex was demonstrated. However, a significant association between AE and high preadministration BP was shown, both above the 90th centile (p = 0.0022) and above the 95th centile (p = 0.0135). CONCLUSION: Clinically relevant hypertension following (131)I-mIBG therapy affected less than 5% of administrations, but was more common in those patients with preexisting hypertension. As hypertensive episodes may occur many hours after treatment, close monitoring of BP needs to be continued for at least 48 h after administration of (131)I-mIBG. PMID- 22215111 TI - Spatial mapping of city-wide PBDE levels using an exponential decay model. AB - Passive air samplers (PAS) consisting of polyurethane foam (PUF) disks were deployed at 6 outdoor air monitoring stations in different land use categories (commercial, industrial, residential and semi-rural) to assess the spatial distribution of polybrominated diphenyl ethers (PBDEs) in the Brisbane airshed. Air monitoring sites covered an area of ~1143 km(2) and PAS were allowed to accumulate PBDEs in the city's airshed over three consecutive seasons commencing in the winter of 2008. The average sum of five (?(5)) PBDEs (BDEs 28, 47, 99, 100 and 209) levels were highest at the commercial and industrial sites (12.7 +/- 5.2 ng PUF(-1)), which were relatively close to the city center and were a factor of 8 times higher than residential and semi-rural sites located in outer Brisbane. To estimate the magnitude of the urban 'plume' an empirical exponential decay model was used to fit PAS data vs. distance from the CBD, with the best correlation observed when the particulate bound BDE-209 was not included (?(5) 209) (r(2) = 0.99), rather than ?(5) (r(2) = 0.84). At 95% confidence intervals the model predicts that regardless of site characterization, ?(5)-209 concentrations in a PAS sample taken between 4-10 km from the city centre would be half that from a sample taken from the city centre and reach a baseline or plateau (0.6 to 1.3 ng PUF(-1)), approximately 30 km from the CBD. The observed exponential decay in ?(5)-209 levels over distance corresponded with Brisbane's decreasing population density (persons/km(2)) from the city center. The residual error associated with the model increased significantly when including BDE-209 levels, primarily due to the highest level (11.4 +/- 1.8 ng PUF(-1)) being consistently detected at the industrial site, indicating a potential primary source at this site. Active air samples collected alongside the PAS at the industrial air monitoring site (B) indicated BDE-209 dominated congener composition and was entirely associated with the particulate phase. This study demonstrates that PAS are effective tools for monitoring citywide regional differences however, interpretation of spatial trends for POPs which are predominantly associated with the particulate phase such as BDE-209, may be restricted to identifying 'hotspots' rather than broad spatial trends. PMID- 22215112 TI - Skeletal muscle gender dimorphism from proteomics. AB - Gross contraction in skeletal muscle is primarily determined by a relatively small number of contractile proteins, however this tissue is also remarkably adaptable to environmental factors such as hypertrophy by resistance exercise and atrophy by disuse. It thereby exhibits remodeling and adaptations to stressors (heat, ischemia, heavy metals, etc.). Damage can occur to muscle by a muscle exerting force while lengthening, the so-called eccentric contraction. The contractile proteins can be damaged in such exertions and need to be repaired, degraded and/or resynthesized; these functions are not part of the contractile proteins, but of other much less abundant proteins in the cell. To determine what subset of proteins is involved in the amelioration of this type of damage, a global proteome must be established prior to exercise and then followed subsequent to the exercise to determine the differential protein expression and thereby highlight candidate proteins in the adaptations to damage and its repair. Furthermore, most studies of skeletal muscle have been conducted on the male of the species and hence may not be representative of female muscle. In this article we present a method for extracting proteins reproducibly from male and female muscles, and separating them by two-dimensional gel electrophoresis followed by high resolution digital imaging. This provides a protocol for spots (and subsequently identified proteins) that show a statistically significant (p < 0.05) two-fold increase or decrease, appear or disappear from the control state. These are then excised, digested with trypsin and separated by high-pressure liquid chromatography coupled to a mass spectrometer (LC/MS) for protein identification (LC/MS/MS). This methodology (Figure 1) can be used on many tissues with little to no modification (liver, brain, heart etc.). PMID- 22215113 TI - Kv1.2 potassium channel inhibitors from Chukrasia tabularis. AB - Eighteen new limonoids, chubularisins A-R (1-18), along with eleven known analogues, were isolated from the stem bark of Chukrasia tabularis. The structures of 1-18 were elucidated on the basis of spectroscopic data and chemical evidence. Compound 1 represented the first example of 8,9,12-orthoester of phragmalin limonoids. Interestingly, compounds 4, 8, and 22 exhibited potent and selective inhibition against the delayed rectifier (I(K)) K(+) current with IC(50) values of 0.61, 2.03, and 2.15 MUM, respectively. PMID- 22215114 TI - Diagnostic value of F-wave inversion in patients with early carpal tunnel syndrome. AB - Routine electrophysiological studies usually give normal results in patients with early stage carpal tunnel syndrome (CTS). Diagnostic significance of the F-wave inversion (the median of F-wave minimal latencies (FWML) exceeds a normal ipsilateral ulnar FWML by 1ms) has not been previously reported in early stage CTS. In this study, our primary aim was to investigate the diagnostic value of F wave inversion in early stage CTS. Additionally, we aimed to demonstrate any possible relationship between F-wave inversion and symptom scores of the Boston questionnaire and functional capacity in early stage CTS. The study included 60 early stage CTS patients who presented with a median sensory nerve conduction velocity of >=50m/s. The symptom severity and functional status of the patients were assessed by using the Boston questionnaire. The control group consisted of 45 healthy volunteers. We compared early stage CTS patients and healthy control subjects in terms of the results obtained from median-ulnar FWML. Existence of F wave inversion was found in 32 (53.3%) of the early stage CTS patients and in 3 (8.7%) of the healthy controls (p=0.001). It was also found to be positively correlated with the Boston questionnaire scores (p=0.001, r=0.41) and functional capacity scores (p=0.001, r=0.41). The sensitivity and specificity of F-wave inversion for the diagnosis of early stage CTS were calculated as 53.3% and 93.3%, respectively. The addition of F-wave inversion measurement to the set of the routine nerve conduction studies can increase the reliability of the electrophysiological studies in patients with early stage CTS. PMID- 22215115 TI - D-Cycloserine enhances spatial memory in spontaneous place recognition in rats. AB - The effects of D-cycloserine (DCS), an exogenous partial agonist of N-methyl-D aspartate (NMDA) receptor-associated glycine site, on spatial memory were investigated using spontaneous place recognition (SPR) test. In SPR test, rats were allowed to explore an arena where two identical objects were presented for 5 min (sample phase), and after a delay of 24 h they were placed again in the same arena but one of the two objects was moved to a novel place (test phase, 4 min). Systemic administration of DCS before the sample phase, immediately after the sample phase, and before the test phase caused rats' significant preference for the object in a novel place in the test phase, although in this condition rats without DCS treatment did not show any preference. DCS affected neither total object exploration time nor locomotor activity in the arena during testing. Results suggest the possibility that DCS can facilitate various processes of spatial memory including encoding, consolidation and retrieval, and that NMDA receptors play an important role in these memory processes. PMID- 22215116 TI - Interleukin-1beta does not affect the energy metabolism of rat organotypic hippocampal-slice cultures. AB - The aim of this study was to examine the effect of the archetypal pro inflammatory cytokine, interleukin-1beta (IL-1beta), on high-energy phosphate levels within an ex vivo rat organotypic hippocampal-slice culture (OHSC) preparation using phosphorus ((31)P) magnetic resonance spectroscopy (MRS). Intrastriatal microinjection of IL-1beta induces a chronic reduction in the apparent diffusion coefficient (ADC) of tissue water, which may be indicative of metabolic failure as established by in vivo models of acute cerebral ischaemia. The OHSC preparation enables examination of the effects of IL-1beta on brain parenchyma per se, independent of the potentially confounding effects encountered in vivo such as perfusion changes, blood-brain barrier (BBB) breakdown and leukocyte recruitment. (31)P MRS is a technique that can detect multiple high energy phosphate metabolites within a sample non-invasively. Here, for the first time, we characterise the energy metabolism of OHSCs using (31)P MRS and demonstrate that IL-1beta does not compromise high-energy phosphate metabolism. Thus, the chronic reduction in ADC observed in vivo is unlikely to be a consequence of metabolic failure. PMID- 22215117 TI - Comparison between conventional and automated software-guided ultrasound assessment of bilateral common carotids intima-media thickness in patients with rheumatic diseases. AB - Over the last decade, a growing number of studies have been published supporting the high prevalence of atherosclerosis in rheumatic patients with chronic inflammatory diseases. Ultrasound (US) represents the imaging technique of choice for revealing early atherosclerotic changes at carotids level. New US software, mainly developed to rectify its operator dependence, requires a comparison with conventional technique. The main aim of the present study was to compare conventional and software-guided US in the assessment of intima-media thickness (IMT) of common carotids. Thirty-two consecutive patients with chronic inflammatory rheumatic conditions, presenting at the outpatient clinics of the Rheumatology Department--Universita Politecnica delle Marche, Italy--were enrolled in the present study. The patients underwent a US assessment of the IMT of the posterior wall of common carotids using a My Lab 70 XVG system (Esaote SpA, Genoa, Italy) equipped with a 4-13 MHz linear probe. The US examinations were performed by two sonographers. One of them used the conventional manual approach and the second sonographer adopted a software-guided technique (named RF QIMT technology). Inter-observer reliability was determined using intra-class correlation coefficient (ICC) and the Bland-Altman plot. Agreement between the two methods was high with ICC value of 0.74 (0.69 and 0.77 for the right and left common carotid, respectively). The Bland-Altman plot showed minimal proportional error and high limits of agreement. Substantial inter-observer agreement rates for the assessment of the IMT were achieved. Further studies are encouraged to confirm these results in a larger cohort of patients. PMID- 22215118 TI - Successful treatment of adult-onset Still's disease with tocilizumab monotherapy: two case reports and literature review. AB - Adult-onset Still's disease (AOSD) is a systemic inflammatory disease of unknown etiology. Recently, it has been reported that quite a few cases of refractory AOSD were successfully treated with tocilizumab (TCZ) and corticosteroids were withdrawn in some of these patients. We report two AOSD patients who were treated successfully with TCZ monotherapy; thus, avoiding corticosteroid treatment. Because both of the patients refused to take corticosteroids, we planned to treat them with 8 mg/kg of TCZ monotherapy at weeks 0, 2, 6 and subsequently every 4 weeks. The efficacy of TCZ was assessed by patients' clinical symptoms such as fever, arthralgia, skin eruptions, and laboratory markers such as serum levels of CRP, ferritin, and IL-6. We also reviewed 14 previous case reports including 30 cases who had been treated with TCZ for AOSD. Our patients responded rapidly and have been maintained in clinical remission without corticosteroid treatment. In the literature review, concomitant corticosteroid treatment described in 13 cases was successfully tapered in 7 and discontinued in 6 cases. TCZ monotherapy can be a candidate for the first-line therapy for some AOSD patients. PMID- 22215119 TI - Effect of aerobic training on plasma cytokines and soluble receptors in elderly women with knee osteoarthritis, in response to acute exercise. AB - The aim of this study was to evaluate levels of interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and soluble forms of the TNF-alpha receptor (sTNFR1 and sTNFR2) from plasma taken from the peripheral blood of elderly individuals presenting with osteoarthritis (OA) of the knee. These patients underwent aerobic treatment through the use of physical exercises. The study consisted of a longitudinal analysis of older individuals presenting clinical and radiographic diagnosis of knee OA that were submitted to 12 weeks of aerobic treatment. The individuals were evaluated during acute exercise or after chronic exercise. During acute exercise (walking slowly on the mat), blood samples of the patients were collected before, immediately after, and 30 min following the end of training. After chronic exercise (aerobic walking training, three times/week for 12 weeks), patient blood samples were obtained for comparison. Additionally, clinical and functional assessments (WOMAC test and 6-min walk) were performed at the end of all physical exercises. Plasma concentrations of cytokines and soluble receptors were measured by ELISA. Aerobic training increased the plasma concentration of sTNR1; however, it decreased the plasma concentration of sTNFR2, when compared with levels of resting patients. Acute exercise differentially affects the levels of sTNFR1 dependent on when the samples were taken, before and after aerobic training. However, the levels of sTNFR2 were not affected by training. For the population studied, we observed differences in the levels of sTNFR1 and sTNFR2 following acute and chronic exercise. Other additional factors, like the level of inactivity of the individual and the type of physical exercise that patients are exposed to, need to be considered as well. The variation in the levels of soluble receptors correlated with functional improvement; however, the inflammatory osteoarthritis markers (IL-6 and TNF-alpha) were unaffected by the walking exercises. PMID- 22215120 TI - Anti-cyclic citrullinated peptide antibodies in scleroderma patients. AB - Anti-CCP (cyclic citrullinated peptide) is considered the most useful laboratory tool in the diagnosis of rheumatoid arthritis (RA). Some authors have also found this autoantibody in patients with scleroderma (SSc). The study aimed to investigate the prevalence of anti-CCP antibodies in SSc patients from Southern Brazil and their association with clinical and serological profile of the disease. We studied 76 patients with SSc and 100 healthy volunteers for presence of anti-CCP. SSc patients charts were reviewed for clinical and laboratory data. In the SSc group, the diffuse form was present in 20.5%; 62.8% had the limited form; 14.1% had overlap with systemic lupus or polymyositis and 2.5% had SSc sine scleroderma. Anti-CCP was found in nine of 78 (11.5%) SSc patients and in one of 100 healthy volunteers (p = 0.0054). No relationship was found with arthritis, skin Rodnan m score, esophageal dysmotility, myocarditis, pulmonary hypertension and lung fibrosis. Positive association was observed with arthralgias (p = 0.02). Also, no relationship was noted with the presence of anti-centromere antibodies, anti-Scl-70, anti-RNP or rheumatoid factor. Anti-CCP are more common in SSc patients than in controls. Arthralgias but not arthritis or rheumatoid factor are more frequent in anti-CCP positive patients. PMID- 22215121 TI - Impact of recurrent lupus nephritis on lupus kidney transplantation: a 20-year single center experience. AB - This study was conducted to delineate the frequency of recurrent lupus nephritis in a Chinese kidney transplant cohort and to estimate its impact on long-term transplant outcomes. A total of 32 lupus transplant patients were enrolled in this study, and the medical records were retrospectively reviewed. Patients with unexplained graft abnormalities were subjected to allograft biopsy. Recurrent lupus nephritis was diagnosed by light microscopy, immunofluorescence, and electron microscopy. In addition, to determine the clinical manifestations of recurrent lupus GN in these patients, serum original systemic lupus erythematosus disease activity index (SLEDAI) scores while undergoing allograft biopsy were evaluated. In total, six out of 32 patients (18.8%; mean age, 40.5 +/- 9.1 years) were diagnosed as having recurrent lupus nephritis and the mean time at diagnosis was 5.1 +/- 4.9 years post-transplantation. According to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 criteria, three of the six cases (50%) were defined as class I, one was class II, one was class IV, and one was class III + V. The graft and patient survival rates of recurrent lupus nephritis (n = 6) were not different from those of patients with other diagnostic entities. Although recurrent lupus nephritis was not uncommon, it did not appear to have a strong negative impact on long-term outcome in Chinese kidney transplant patients. The recurrence was potentially treatable and should not be precluded for receiving transplantation. PMID- 22215122 TI - Regional cerebral perfusion and ischemic status after standard superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery in ischemic cerebrovascular disease. AB - BACKGROUND AND PURPOSE: Standard superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery is an effective treatment for ischemic cerebrovascular diseases, including moyamoya disease and occlusive cerebrovascular disease. Our purpose in this study was to evaluate the ischemic status based on the imaging modality of computed tomographic perfusion (CTP) before and after STA-MCA bypass in patients with moyamoya disease and occlusive cerebrovascular disease. METHODS: CTP was performed on 19 patients, comprising 10 patients with moyamoya disease and nine patients with occlusive cerebrovascular disease, preoperatively and on the third postoperative day. According to the regional cerebral microcirculatory change and modality of CTP, the regional cerebral ischemic status was graded into two stages with four substages (I1, I2, II1, and II2) to indicate the regional cerebral perfusion and ischemic status of the patients. The ischemic status was analyzed in all 19 patients according to those stages preoperatively and postoperatively. RESULTS: Among the 19 patients, nine (47.4%) showed improvement in the regional cerebral ischemic status, six (31.6%) showed no change, and four (21.1%) showed deterioration. Both improvement and no change in the regional cerebral ischemic status were regarded as effective, while deterioration was regarded as ineffective, meaning that 15 (78.9%) patients were effective and four (21.1%) patients were ineffective. The effective rate for moyamoya disease (one of ten, 90.0%) was significantly higher than that for occlusive cerebrovascular disease (three of nine, 66.7%). Postoperatively, only one patient (case N11) exhibited deterioration of symptoms, which presented as right hemiplegia and aphasia, and no obvious changes in symptoms were observed for the other patients in the transient period. CONCLUSIONS: This study has shown that STA-MCA bypass is an effective and safe way to improve the regional cerebral perfusion and ischemic status in ischemic cerebrovascular diseases. The stage based on the regional cerebral microcirculatory change and presentation of CTP can directly reflect the pathological mechanism underlying the regional cerebral ischemic status. PMID- 22215124 TI - Wittig-olefination via an yttrium-coordinated betaine. AB - We report the synthesis of an yttrium phosphonium methylide complex and its reaction with benzophenone to form an excedingly rare hydrocarbon soluble metal coordinated betaine. While this reaction models the C-C sigma-bond formation step of the Wittig reaction under salt-conditions, addition of Ph(3)P=O to the betaine complex results in formation of 1,1-diphenylethene. PMID- 22215123 TI - High prevalence of pelvic floor muscle dysfunction in hospitalized elderly women with urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: The purpose of this study was to determine pelvic floor muscle (PFM) function in hospitalized elderly women with urinary incontinence (UI). METHODS: A cross-sectional study was performed using data of 704 patients, routinely collected by means of a clinical UI assessment. RESULTS: Only 25.5% of the patients were able to perform normal PFM contractions (Oxford grading scale score >=3); 74.5% were unable to contract their PFM or showed weak PFM activity without circular contraction or elevation of the vagina. Vulvovaginal mucosal dystrophy was noted in 84% of the patients. A significant positive correlation of PFM function was found to cognitive status (MMSE score), mobility (Tinetti performance score), and history of previous PFM training; a negative correlation of PFM function was found to patients' age and vulvovaginal mucosal dystrophy, and no significant correlation to body mass index, parity, or history of hysterectomy. CONCLUSIONS: Targeted clinical UI assessment including digital vaginal palpation should be performed in all incontinent elderly women in order to detect PFM dysfunction and to optimize therapeutic measures. PMID- 22215125 TI - Conservative treatment of a pathological fracture in a 3-year-old boy with primary hyperoxaluria type I. AB - Primary hyperoxaluria type I is a rare inherited disease that presents a disturbed metabolism of glyoxylate. Consequently, patients suffer from hyperoxaluria, leading to renal failure and subsequent skeletal calcium oxalate deposition. Areas with high concentrations of calcium oxalate, so-called dense metaphyseal bands, are at risk for pathological fracturing. The primary disease is treated by combined liver-kidney transplantation, although pathological fracturing also occurs in the posttransplant period. In the current case, we present a 3-year-old boy with a pathological fracture of his right femur, 2 years after liver-kidney transplantation. We opted for a conservative regime, leading to good fracture healing. As there are limited data in the literature regarding treatment of fractures in these patients, it is important to notify the outcome of conservative treatment of pathological fractures in patients with primary hyperoxaluria type I. PMID- 22215126 TI - Insulin resistance/hyperinsulinemia and cancer mortality: the Cremona study at the 15th year of follow-up. AB - Type 2 diabetes is associated with risk of cancer. Hyperinsulinemia and insulin resistance may be the link with cancer, but whether this is independent of the diabetes status, obesity/visceral obesity and metabolic syndrome is uncertain and the present study wanted to address this issue. Fifteen-year all-cause, CVD and cancer mortality data were obtained through the Regional Health Registry in 2,011 out of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes mellitus in Italy in which anthropometric and metabolic characteristics were collected. During the 15-year observation period, 495 deaths were registered: 221 CVD related and 180 cancer related. Age and sex were independently associated with all-cause, cancer and CVD mortality rates. Age and sex-adjusted analysis showed that HOMA-IR, cigarette smoking and diabetes were independently associated with all-cause mortality; HOMA-IR, systolic blood pressure and fibrinogen were independently associated with CVD mortality; HOMA-IR and smoking habit were independently associated with cancer mortality. Individuals in the highest quintile of serum insulin had a 62% higher risk of cancer mortality (HR = 1.62 95% CI: 1.19-2.20; P < 0.0022) and 161% higher risk of gastrointestinal cancer mortality (HR = 2.61 95% CI: 1.73-3.94; P < 0.0001). Age- and sex-adjusted analysis showed that hyperinsulinemia/insulin resistance is associated with cancer mortality independently of diabetes, obesity/visceral obesity and the metabolic syndrome. PMID- 22215127 TI - Lipid accumulation in overweight type 2 diabetic subjects: relationships with insulin sensitivity and adipokines. AB - Adipokines are known to play a fundamental role in the etiology of obesity, that is, in the impaired balance between increased feeding and decreased energy expenditure. While the adipokine-induced changes of insulin resistance in obese diabetic and nondiabetic subjects are well known, the possible role of fat source in modulating insulin sensitivity (IS) remains controversial. The aim of our study was to explore in overweight type 2 diabetic patients (T2DM) with metabolic syndrome IS in different energy storage conditions (basal and dynamic) for relating it to leptin and adiponectin. Sixteen T2DM (5/11 F/M; 59 +/- 2 years; 29.5 +/- 1.1 kg/m(2)) and 16 control (CNT 5/11; 54 +/- 2; 29.1 +/- 1.0) underwent an oral glucose tolerance test. Fasting IS was measured by QUICKI, while the dynamic one with OGIS. The insulinogenic index (IGI) described beta cell function. Also, the lipid accumulation product parameter (LAP) was assessed. LAP accounts for visceral abdominal fat and triglycerides, and it is known to be related to IS. Possible interrelationships between LAP and adipokines were explored. In T2DM and CNT, adiponectin (7.4 +/- 0.5 vs. 7.8 +/- 0.9 MUg/mL), leptin (13.3 +/- 3.0 vs. 12.4 +/- 2.6 ng/mL), and QUICKI (0.33 +/- 0.01 vs. 0.33 +/- 0.01) were not different (P > 0.40), at variance with OGIS (317 +/- 11 vs. 406 +/- 13 mL/min/m(2); P = 0.006) and IGI (0.029 +/- 0.005 vs. 0.185 +/- 0.029 * 10(3) pmolI/mmolG; P = 0.00001). LAP was 85 +/- 15 cm * mg/dL in T2DM and 74 +/- 10 in CNT (P > 0.1), correlated with OGIS in all subjects (R = -0.42, P = 0.02) and QUICKI (R = -0.56, P = 0.025) in T2DM. Leptin correlated with QUICKI (R = 0.45, P = 0.009), and adiponectin correlated with OGIS (R = 0.43, P = 0.015). In overweight T2DM, insulin sensitivity in basal condition appears to be multifaceted with respect to the dynamic one, because it should be more fat related. Insulin sensitivity appears to be incompletely described by functions of fasting glucose and insulin values alone and the use of other indices, such as LAP could be suggested. PMID- 22215128 TI - Dosimetric integration of daily mega-voltage cone-beam CT for image-guided intensity-modulated radiotherapy. AB - PURPOSE: The goal of this work was to compare different methods of incorporating the additional dose of mega-voltage cone-beam CT (MV-CBCT) for image-guided intensity modulated radiotherapy (IMRT) of different tumor entities. MATERIAL AND METHODS: The absolute dose delivered by the MV-CBCT was calculated and considered by creating a scaled IMRT plan (scIMRT) by renormalizing the clinically approved plan (orgIMRT) so that the sum with the MV-CBCT dose yields the same prescribed dose. In the other case, a newly optimized plan (optIMRT) was generated by including the dose distribution of the MV-CBCT as pre-irradiation. Both plans were compared with the orgIMRT plan and a plan where the last fraction was skipped. RESULTS: No significant changes were observed regarding the 95% conformity index of the target volume. The mean dose of the organs at risk (OAR) increased by approx. 7% for the scIMRT plan and 5% for the optIMRT plan. A significant increase of the mean dose to the outline contour was observed, ranging from 3.1 +/- 1.3% (optIMRT) to 13.0 +/- 6.1% (scIMRT) for both methods over all entities. If the dose of daily MV-CBCT would have been ignored, the additional dose accumulated to nearly a whole treatment fraction with a general increase of approx. 10% to the OARs and approx. 4% to the target volume. CONCLUSION: Both methods of incorporating the additional MV-CBCT dose into the treatment plan are suitable for clinical practice. The dose distribution of the target volume could be achieved as conformal as with the orgIMRT plan, while only a moderate increase of mean dose to OAR was observed. PMID- 22215129 TI - Cerebral blood flow velocity in early-onset neonatal sepsis and its clinical significance. AB - Chorioamnionitis is a known risk factor for neurological damage in newborns. The present study aimed at assessing the changes in cerebral blood flow velocity (CBFV) in early-onset neonatal sepsis (EONS) and determining its predictive value as well as prognostic significance. Inborn neonates with antenatal risk factors for chorioamnionitis were followed up for development of EONS, diagnosed by presence of clinical signs along with positive blood culture and/or elevated interleukin-6 (IL-6) concentrations (>=50 pg/mL) in umbilical cord blood. Comparison group was formed by asymptomatic neonates who had risk factors for chorioamnionitis but did not develop EONS and cord blood IL-6 concentrations were <50 pg/mL. CBFV (resistance and pulsatility indices, peak systolic flow velocity, and vascular diameter) of internal carotid, vertebral, and middle cerebral arteries was assessed by transcranial Doppler ultrasonography within 24 h of birth. The babies were kept under clinical and radiological follow-up for a minimum period of 6 months. Data were analyzed by SPSS 16.0. Final study group contained 55 neonates with sepsis and 35 asymptomatic control neonates. Blood culture was positive in 27 babies of the sepsis group with a preponderance of Gram-negative bacterial isolation. Significantly lower resistance, vasodilatation, and higher blood flow were noted in all the cerebral arteries of the sepsis group. Increase in CBFV was correlated with elevated IL-6 concentrations. CBFV parameters showed significant predictive accuracy as early diagnostic markers of EONS. Among the sepsis group, 14 patients showed signs of intracranial hemorrhage during the hospital stay of which four expired and six showed signs of ventricular dilatation during follow-up. These patients had significantly higher CBFV compared to those who survived. Assessment of CBFV at early hours of birth can be adopted as an additional bedside, non-invasive investigation with immediate diagnostic and late prognostic significance. PMID- 22215130 TI - The use of chloride-sodium ratio in the evaluation of metabolic acidosis in critically ill neonates. AB - Acid-base disturbances have been usually evaluated with the traditional Henderson Hasselbach method and Stewart's physiochemical approach by quantifying anions of tissue acids (TA). It is hypothesized that an increase in tissue acids during metabolic acidosis would cause a compensatory decrease in the plasma chloride (Cl) relative to sodium (Cl-Na ratio) in order to preserve electroneutral balance. Therefore, we aimed to investigate the use of Cl-Na ratio as a bedside tool to evaluate the identifying raised TA in neonates as an alternative to complex calculations of Stewart's physiochemical approach. This retrospective study was conducted between January 2008 and December 2009. Infants were included in the study when blood gas analysis reveals a metabolic acidosis; pH <7.25 and sHCO(3) concentration was <22 mEq/L. The Cl-Na ratio, sodium-chloride difference (Diff(NaCl)), anion gap (AG), albumin-corrected AG (AG(corr)), strong ion difference (SID), unmeasured anions (UMA), and TA were calculated at each episode of metabolic acidosis. A total of 105 metabolic acidosis episodes occurred in 59 infants during follow-up. Hypochloremic metabolic acidosis occurred in 17 (16%) of samples, and all had increased TA. The dominant component of TA was UMA rather than lactate. There was a negative correlation between the Cl-Na ratio and SID, AG(corr), UMA, and TA. Also, there was a positive correlation between Diff(NaCl) and SID, AG(corr), UMA, and TA. Base deficit and actual bicarbonate performed poorly in identifying the TA. In conclusion, our study suggested that Diff(NaCl) and Cl-Na ratio are simple and fast, and may be an alternative method to complex Stewart's physiochemical approach in identifying raised UMA and TA in critically ill neonates. PMID- 22215132 TI - Epigenetics: Dynamic DNA methylation. PMID- 22215133 TI - Live-cell imaging of migrating cells expressing fluorescently-tagged proteins in a three-dimensional matrix. AB - Traditionally, cell migration has been studied on two-dimensional, stiff plastic surfaces. However, during important biological processes such as wound healing, tissue regeneration, and cancer metastasis, cells must navigate through complex, three-dimensional extracellular tissue. To better understand the mechanisms behind these biological processes, it is important to examine the roles of the proteins responsible for driving cell migration. Here, we outline a protocol to study the mechanisms of cell migration using the epithelial cell line (MDCK), and a three-dimensional, fibrous, self-polymerizing matrix as a model system. This optically clear extracellular matrix is easily amenable to live-cell imaging studies and better mimics the physiological, soft tissue environment. This report demonstrates a technique for directly visualizing protein localization and dynamics, and deformation of the surrounding three-dimensional matrix. Examination of protein localization and dynamics during cellular processes provides key insight into protein functions. Genetically encoded fluorescent tags provide a unique method for observing protein localization and dynamics. Using this technique, we can analyze the subcellular accumulation of key, force generating cytoskeletal components in real-time as the cell maneuvers through the matrix. In addition, using multiple fluorescent tags with different wavelengths, we can examine the localization of multiple proteins simultaneously, thus allowing us to test, for example, whether different proteins have similar or divergent roles. Furthermore, the dynamics of fluorescently tagged proteins can be quantified using Fluorescent Recovery After Photobleaching (FRAP) analysis. This measurement assays the protein mobility and how stably bound the proteins are to the cytoskeletal network. By combining live-cell imaging with the treatment of protein function inhibitors, we can examine in real-time the changes in the distribution of proteins and morphology of migrating cells. Furthermore, we also combine live-cell imaging with the use of fluorescent tracer particles embedded within the matrix to visualize the matrix deformation during cell migration. Thus, we can visualize how a migrating cell distributes force generating proteins, and where the traction forces are exerted to the surrounding matrix. Through these techniques, we can gain valuable insight into the roles of specific proteins and their contributions to the mechanisms of cell migration. PMID- 22215134 TI - A microfluidic method to study demulsification kinetics. AB - We present the results of experiments studying droplet coalescence in a dense layer of emulsion droplets using microfluidic circuits. The microfluidic structure allows direct observation of collisions and coalescence events between oil droplets dispersed in water. The coalescence rate of a flowing hexadecane-in water emulsion was measured as a function of the droplet velocity and droplet concentration from image sequences measured with a high-speed camera. A trajectory analysis of colliding droplet pairs allows evaluation of the film drainage profile and coalescence time t(c.) The coalescence times obtained for thousands of droplet pairs enable us to calculate coalescence time distributions for each set of experimental parameters, which are the mean droplet approach velocity (v(0)), the mean dispersed phase fraction (phi) and the mean hydraulic diameter of a droplet pair (d(p)). The expected value E(t(c)) of the coalescence time distributions scales as E(t(c)) is proportional to (v(0))(-0.105+/ 0.043)(d(p))(0.562+/-0.287), but is independent of phi. We discuss the potential of the procedure for the prediction of emulsion stability in industrial applications. PMID- 22215131 TI - Epigenetics and the environment: emerging patterns and implications. AB - Epigenetic phenomena in animals and plants are mediated by DNA methylation and stable chromatin modifications. There has been considerable interest in whether environmental factors modulate the establishment and maintenance of epigenetic modifications, and could thereby influence gene expression and phenotype. Chemical pollutants, dietary components, temperature changes and other external stresses can indeed have long-lasting effects on development, metabolism and health, sometimes even in subsequent generations. Although the underlying mechanisms remain largely unknown, particularly in humans, mechanistic insights are emerging from experimental model systems. These have implications for structuring future research and understanding disease and development. PMID- 22215135 TI - Protocols for vaginal inoculation and sample collection in the experimental mouse model of Candida vaginitis. AB - Vulvovaginal candidiasis (VVC), caused by Candida species, is a fungal infection of the lower female genital tract that affects approximately 75% of otherwise healthy women during their reproductive years. Predisposing factors include antibiotic usage, uncontrolled diabetes and disturbance in reproductive hormone levels due to pregnancy, oral contraceptives or hormone replacement therapies. Recurrent VVC (RVVC), defined as three or more episodes per year, affects a separate 5 to 8% of women with no predisposing factors. An experimental mouse model of VVC has been established and used to study the pathogenesis and mucosal host response to Candida. This model has also been employed to test potential antifungal therapies in vivo. The model requires that the animals be maintained in a state of pseudoestrus for optimal Candida colonization/infection. Under such conditions, inoculated animals will have detectable vaginal fungal burden for weeks to months. Past studies show an extremely high parallel between the animal model and human infection relative to immunological and physiological properties. Differences, however, include a lack of Candida as normal vaginal flora and a neutral vaginal pH in the mice. Here, we demonstrate a series of key methods in the mouse vaginitis model that include vaginal inoculation, rapid collection of vaginal specimens, assessment of vaginal fungal burden, and tissue preparations for cellular extraction/isolation. This is followed by representative results for constituents of vaginal lavage fluid, fungal burden, and draining lymph node leukocyte yields. With the use of anesthetics, lavage samples can be collected at multiple time points on the same mice for longitudinal evaluation of infection/colonization. Furthermore, this model requires no immunosuppressive agents to initiate infection, allowing immunological studies under defined host conditions. Finally, the model and each technique introduced here could potentially give rise to use of the methodologies to examine other infectious diseases of the lower female genital tract (bacterial, parasitic, viral) and respective local or systemic host defenses. PMID- 22215136 TI - Ethnicity, plasma phospholipid fatty acid composition and inflammatory/endothelial activation biomarkers in the Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND/OBJECTIVES: It has been recognized that certain long-chain polyunsaturated fatty acids (LC-PUFAs) are involved in inflammation and its resolution. It has also been shown that ethnicity may be a factor in affecting systemic inflammation, and limited evidence suggests it may influence plasma LC PUFA composition. Given the links among these three factors, we aim to determine ethnicity-based differences in plasma LC-PUFA composition among White, Black, Hispanic and Chinese participants, and whether such differences contribute to variations in markers of inflammation and endothelial activation in a sub-cohort of the Multi-Ethnic Study of Atherosclerosis (MESA). SUBJECTS/METHODS: Plasma phospholipid LC-PUFAs levels (%) were determined in 2848 MESA participants using gas chromatography-flame ionization detection. Enzyme immunoassays determined inflammatory markers levels for high-sensitivity C-reactive protein (n=2848), interleukin-6 (n=2796), soluble tumor necrosis factor-alpha receptor type 1 (n=998), and endothelial activation markers soluble intercellular adhesion molecule-1 (n=1192) and soluble E-selectin (n=998). The modifying influence of ethnicity was tested by linear regression analysis. RESULTS: Chinese adults were found to have the highest mean levels of plasma eicosapentaenoic acid (EPA, 1.24%) and docosahexaenoic acid (DHA, 4.95%), and the lowest mean levels of gamma linolenic (0.10%), dihomo-gamma-linolenic (DGLA, 2.96%) and arachidonic (10.72%) acids compared with the other ethnicities (all P <= 0.01). In contrast, Hispanics had the lowest mean levels of plasma EPA (0.70%) and DHA (3.49%), and the highest levels of DGLA (3.59%; all P <= 0.01). Significant differences in EPA and DHA among ethnicities were attenuated following adjustment for dietary non-fried fish and fish oil supplementation. Ethnicity did not modify the associations of LC PUFAs with markers of inflammation or endothelial activation (all P (interaction)>0.05). CONCLUSIONS: The absence of a modifying effect of ethnicity indicates that the putative benefits of LC-PUFAs with respect to inflammation are pan-ethnic. Future longitudinal studies may elucidate the origin(s) of ethnicity based differences in LC-PUFA composition and whether certain patterns, that is, high plasma levels of DGLA and low levels of EPA/DHA, contribute to inflammation associated health outcomes. PMID- 22215138 TI - Expression of ERp5 and GRP78 on the membrane of chronic lymphocytic leukemia cells: association with soluble MICA shedding. AB - MICA is a ligand of the activating receptor NKG2D, expressed by NK and T cells. MICA expression is induced in cancer cells favoring their elimination by the immune system; however, many advanced tumors shed soluble MICA (sMICA), which impairs NKG2D-mediated cytotoxicity. ERp5 and GRP78 are endoplasmic reticulum resident proteins that are translocated to the surface of epithelial tumor cells where they interact with MICA and are involved in sMICA shedding. In this study, we analyze the role of ERp5 and GRP78 in sMICA shedding in chronic lymphocytic leukemia (CLL). Immunofluorescence and flow cytometry analyses showed that ERp5 and GRP78 were significantly expressed on the surface of B cells and leukemia cells, but they were not expressed on T cells. The expression of ERp5 and GRP78 was significantly higher in leukemia cells than in B cells from controls. ERp5 and GRP78 co-localized with MICA on the surface of leukemia cells and the levels of expression of ERp5 and GRP78 correlated with the level of expression of membrane-bound MICA in CLL patients. Associated with higher expression of membrane-bound ERp5 and GRP78, serum sMICA levels were approximately threefold higher in patients than in controls. Elevated sMICA levels in CLL patients were associated with the down-modulation of NKG2D surface expression on CD8 T cells. Finally, pharmacological inhibition of B cell lines and stimulated leukemia cells showed that ERp5 activity is involved in sMICA shedding in CLL. In conclusion, these results uncover a molecular mechanism which regulates MICA protein shedding and immune evasion in CLL. PMID- 22215139 TI - Ring-opening reactions of 1,4-diazabicyclo[2.2.2]octane (DABCO) derived quaternary ammonium salts with phenols and related nucleophiles. AB - 1,4-Diazabicyclo[2.2.2]octane (DABCO) has been evaluated as a starting material for the synthesis of 1-alkyl-4-(2-phenoxyethyl)piperazines and related derivatives. We found that 1-alkyl-1,4-diazabicyclo[2.2.2]octan-1-ium salts, resulting from the alkylation of DABCO, efficiently react with a variety of nucleophiles in polyethyleneglycol (PEG) or diglyme at high temperatures to give piperazine products resulting from the nucleophilic ring-opening reaction. The benzylation side reaction was found to be relevant with softer nucleophiles when using 1-benzyl-1,4-diazabicyclo[2.2.2]octan-1-ium salts, while other types of alkylations were not observed. One-pot methodologies allow for the synthesis of piperazines directly from primary alcohols, alkyl halides or sulfonates, using phenols, or other nucleophile sources, and DABCO. PMID- 22215137 TI - Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. AB - PURPOSE: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immunosuppressive cells that are upregulated in cancer. Little is known about the prevalence and importance of MDSC in pancreas adenocarcinoma (PA). EXPERIMENTAL DESIGN: Peripheral blood, bone marrow, and tumor samples were collected from pancreatic cancer patients, analyzed for MDSC (CD15(+)CD11b(+)) by flow cytometry and compared to cancer-free controls. The suppressive capacity of MDSC (CD11b(+)Gr-1(+)) and the effectiveness of MDSC depletion were assessed in C57BL/6 mice inoculated with Pan02, a murine PA, and treated with placebo or zoledronic acid, a potent aminobisphosphonate previously shown to target MDSC. The tumor microenvironment was analyzed for MDSC (Gr1(+)CD11b(+)), effector T cells, and tumor cytokine levels. RESULTS: Patients with PA demonstrated increased frequency of MDSC in the bone marrow and peripheral circulation which correlated with disease stage. Normal pancreas tissue showed no MDSC infiltrate, while human tumors avidly recruited MDSC. Murine tumors similarly recruited MDSC that suppressed CD8(+) T cells in vitro and accelerated tumor growth in vivo. Treatment with zoledronic acid impaired intratumoral MDSC accumulation resulting in delayed tumor growth rate, prolonged median survival, and increased recruitment of T cells to the tumor. This was associated with a more robust type 1 response with increased levels of IFN-gamma and decreased levels of IL-10. CONCLUSIONS: MDSC are important mediators of tumor-induced immunosuppression in pancreatic cancer. Inhibiting MDSC accumulation with zoledronic acid improves the host anti-tumor response in animal studies suggesting that efforts to block MDSC may represent a novel treatment strategy for pancreatic cancer. PMID- 22215140 TI - Salinimonas lutimaris sp. nov., a polysaccharide-degrading bacterium isolated from a tidal flat. AB - A Gram-negative, non-motile, non-endospore-forming bacterial strain, designated DPSR-4(T), was isolated from a tidal flat sediment on the southern coast of Korea. Strain DPSR-4(T) grew optimally at 25-30 degrees C, at pH 7.0-7.5 and in the presence of 2% (w/v) NaCl. A Neighbour-Joining phylogenetic tree based on 16S rRNA gene sequences revealed that strain DPSR-4(T) clustered with Salinimonas chungwhensis BH030046(T) by a high bootstrap resampling value of 99.7%. Strain DPSR-4(T) exhibited 96.2% 16S rRNA gene sequence similarity to that of S. chungwhensis BH030046(T) and 93.7-96.6% sequence similarity to the sequences of type strains of Alteromonas species. Strain DPSR-4(T) contained Q-8 as the predominant ubiquinone and iso-C(15:0) 2-OH and/or C(16:1) omega7c, C(16:0) and C(18:1) omega7c as the major fatty acids. The major polar lipids detected in strain DPSR-4(T) and S. chungwhensis KCTC 12239(T) were phosphatidylglycerol, phosphatidylethanolamine and an unidentified phospholipid. The DNA G+C content was 53.4 mol%. Differential phenotypic properties and phylogenetic distinctiveness of strain DPSR-4(T) demonstrated that this strain is distinguishable from the sole recognized species of the genus Salinimonas, S. chungwhensis. On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain DPSR-4(T) is considered to represent a novel species of the genus Salinimonas, for which the name Salinimonas lutimaris sp. nov. is proposed. The type strain is DPSR-4(T) (KCTC 23464(T), CCUG 60743(T)). PMID- 22215141 TI - RLS relieved by tobacco chewing: paradoxical role of nicotine. PMID- 22215142 TI - Successful treatment of severe disruptive disorder featuring symptoms of the Kluver-Bucy Syndrome following a massive right temporal-parietal hemorrhage. AB - We know little about effective treatment for patients suffering from partial or complete Kluver-Bucy Syndrome (KBS) and other disruptive behaviors following a stroke. Reported cases have shown that certain medication, given alone or combined, can be partially effective. In this specific case study, we will try to demonstrate the effectiveness of a combination of carbamazepine, clonidine, quetiapine and methylphenidate in the alleviating of these symptoms. The wide range of symptoms found in KBS led us to use several kinds of psychotropic medication in spite of the inherent risks associated to polypharmacy. PMID- 22215144 TI - Dose correction for the Michaelis-Menten approximation of the target-mediated drug disposition model. AB - The Michaelis-Menten (M-M) approximation of the target-mediated drug disposition (TMDD) pharmacokinetic (PK) model was derived based on the rapid binding (RB) or quasi steady-state (QSS) assumptions that implied that the target and drug binding and dissociation were in equilibrium. However, the initial dose for an IV bolus injection for the M-M model did not account for a fraction bound to the target. We postulated a correction to an initial condition that was consistent with the assumptions underlying the M-M approximation. We determined that the difference between the injected dose and one that should be used for the initial condition is equal to the amount of drug bound to the target upon reaching the equilibrium. We also observed that the corrected initial condition made the internalization rate constant an identifiable parameter that was not for the original M-M model. Finally, we performed a simulation exercise to check if the correction will impact the model performance and the bias of the M-M parameter estimates. We used literature data to simulate plasma drug concentrations described by the RB/QSS TMDD model. The simulated data were refitted by both models. All the parameters estimated from the original M-M model were substantially biased. On the other hand, the corrected M-M is able to accurately estimate these parameters except for equilibrium constant K(m). Weighted sum of square residual and Akaike information criterion suggested a better performance of the corrected M-M model compared with the original M-M model. Further studies are necessary to determine the importance of this correction for the M-M model applications to analysis of TMDD driven PK data. PMID- 22215143 TI - Effect of MK-801-induced impairment of inhibitory avoidance learning in zebrafish via inactivation of extracellular signal-regulated kinase (ERK) in telencephalon. AB - N-Methyl-D-aspartate (NMDA) receptors are implicated in a wide range of complex behavioral functions, including cognitive activity. Numerous studies have shown that using the repetitive administration of a noncompetitive NMDA receptor antagonist, MK-801, induces amnesia in rodents. In this study, the effect of a subchronic MK-801 treatment on the cognitive function of zebrafish was evaluated using a novel inhibitory avoidance task. First, we established a new system to investigate the inhibitory avoidance learning of zebrafish where they were trained to refrain from swimming from a shallow compartment to a deep compartment in order to avoid electric shock. Second, we found that blocking NMDA receptors by MK-801 could significantly attenuate the inhibitory avoidance behavior of the zebrafish and alter the telencephalic extracellular signal-regulated kinase (ERK) phosphorylation level 90 min after the inhibitory avoidance training. These results suggest that the formation of long-term emotional memory is possibly mediated by ERK activation in the telencephalon of zebrafish. PMID- 22215145 TI - Optic nerve sheath solitary fibrous tumor. PMID- 22215146 TI - Polymorphisms of peroxiredoxin 1, 2 and 6 are not associated with esophageal cancer. AB - PURPOSE: Peroxiredoxins, which reduced intracellular peroxides as a noval kind of antioxidant protein, were extensively expressed in various types of cancers and were thought as a biomarker of cancer cells. In this work, we performed genotyping analyses for tag SNP of Prdx 1, 2 and 6, and then evaluated the association with susceptibility and clinic stage of esophageal squamous cell carcinoma (ESCC) in a case-control study. METHODS: The protein level of these Prdx isoforms in ESCC cancer samples was evaluated by Western blot. Then 356 ESCC cancer cases and 315 controls were genotyped by SNPshot assay. Differences in frequencies of the genotypes of the SNPs variant between the cases and controls were evaluated by using the chi-square test. RESULTS: Our result of Western blot confirmed the aberrant expression of Prdx 1, 2 and 6 in ESCC samples, which was coincident with other studies. After genotyping by SNPshot assay, the result showed that the allele and genotype frequencies did not differ between the patients and controls. And no association between the polymorphism and the progression of ESCC including tumor grade and stage was found. CONCLUSIONS: Our data suggested that polymorphisms of Prdx 1, 2 and 6 were not associated with esophageal cancer. PMID- 22215147 TI - Increased expression of CD147 and MMP-9 is correlated with poor prognosis of salivary duct carcinoma. AB - PURPOSE: The aim of this study was to investigate expression of CD147 and MMP-9 in salivary duct carcinoma (SDC) so as to determine whether these two genes may be correlated with poor prognosis of SDC. METHODS: We examined the significance of the CD147 and MMP-9 expression in SDC (n = 35), non-cancerous salivary tissue (n = 20) in previously untreated patients using immunohistochemical staining. Furthermore, we analyzed the correlation between the expression of these two genes and various clinicopathologic factors including survival status of patients with SDC. RESULTS: Positive stain of CD147 and MMP-9 was seen in all 35 cases of tumor samples. A statistical correlation was observed between CD147 and MMP-9 expression in SDC tissues. The incidences of high expression were 45.71% for CD147 and 51.43% for MMP-9 in 35 SDC tissues, respectively. High expression of CD147 and MMP-9 was significantly correlated with clinical feature and shorter progression-free survival (PFS) (P (CD147) = 0.031; P (MMP-9) = 0.020) and overall survival (OS) (P (CD147) = 0.044; P (MMP-9) = 0.013). CONCLUSION: CD147 and MMP-9 expression is correlated with invasion, metastasis and shorter PFS/OS of SDC. Patients with high expression of CD147 and MMP-9 had poor prognosis than SDC patients with low expression. PMID- 22215148 TI - Association of NQO1 rs1800566 polymorphism and the risk of colorectal cancer: a meta-analysis. AB - INTRODUCTION: NAD(P)H:quinone oxidoreductase 1 (NQO1) rs1800566 polymorphism is found to have a lower enzymatic activity, which may result in increased incidence of several kinds of carcinomas including colorectal cancer. Results from published studies on the association of NQO1 rs1800566 genetic polymorphism with the risk of colorectal cancer are inconsistent. We performed a meta-analysis to summarize the possible association. MATERIALS AND METHODS: All eligible published studies were searched from PubMed and Elsevier ScienceDirect. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were analyzed for additive, dominant, and recessive models to assess the association using fixed- or random-effect model. RESULTS: We identified 12 case-control studies that include 5,525 cases and 6,272 controls for the present meta-analysis. Significant associations between NQO1 rs1800566 genetic polymorphism and risk of colorectal cancer were observed in additive (OR = 1.09, 95% CI = 1.02-1.16, p = 0.009) and dominant models (OR = 1.12, 95% CI = 1.04-1.21, p = 0.004 for TT + CT vs. CC). Moreover, in the subgroup analysis based on ethnicity, significant associations were observed in Caucasians but not in Asians. CONCLUSIONS: This meta-analysis provided evidence that NQO1 rs1800566 genetic polymorphism was associated with increased risk of colorectal cancer and that the T allele probably acts as an important risk factor. PMID- 22215149 TI - Anatomical versus nonanatomical resection of colorectal liver metastases: a meta analysis. AB - PURPOSE: The purpose of the study was to compare anatomical resection (AR) versus nonanatomical resection (NAR) for colorectal liver metastases (CLM) with respect to perioperative and oncological outcomes. METHODS: Literature search was performed to identify comparative studies reporting outcomes for both AR and NAR for CLM. Pooled odds ratios (OR) and weighted mean differences (WMD with 95% confidence intervals (95% CI) were calculated using either the fixed effects model or random effects model. RESULTS: Seven nonrandomized controlled studies matched the selection criteria and reported on 1,662 subjects, of whom 989 underwent AR, and 673 underwent NAR for CLM. Compared with the perioperative results, NAR reduced the operation time (WMD, 0.39; 95% CI, 1.97-79.17) and blood transfusion requirement (OR, 2.98; 95% CI, 1.87-4.74), whereas postoperative morbidity and mortality were similar between the two groups. With respect to oncologic outcomes, there was no significant difference in surgical margins, overall survival and disease-free survival between the two groups. CONCLUSIONS: NAR is a safe procedure for CLM and does not compromise oncological outcomes. However, the findings have to be carefully interpreted due to the lower level of evidence. PMID- 22215150 TI - Dissection and culture of chick statoacoustic ganglion and spinal cord explants in collagen gels for neurite outgrowth assays. AB - The sensory organs of the chicken inner ear are innervated by the peripheral processes of statoacoustic ganglion (SAG) neurons. Sensory organ innervation depends on a combination of axon guidance cues and survival factors located along the trajectory of growing axons and/or within their sensory organ targets. For example, functional interference with a classic axon guidance signaling pathway, semaphorin-neuropilin, generated misrouting of otic axons. Also, several growth factors expressed in the sensory targets of the inner ear, including Neurotrophin 3 (NT-3) and Brain Derived Neurotrophic Factor (BDNF), have been manipulated in transgenic animals, again leading to misrouting of SAG axons. These same molecules promote both survival and neurite outgrowth of chick SAG neurons in vitro. Here, we describe and demonstrate the in vitro method we are currently using to test the responsiveness of chick SAG neurites to soluble proteins, including known morphogens such as the Wnts, as well as growth factors that are important for promoting SAG neurite outgrowth and neuron survival. Using this model system, we hope to draw conclusions about the effects that secreted ligands can exert on SAG neuron survival and neurite outgrowth. SAG explants are dissected on embryonic day 4 (E4) and cultured in three-dimensional collagen gels under serum-free conditions for 24 hours. First, neurite responsiveness is tested by culturing explants with protein-supplemented medium. Then, to ask whether point sources of secreted ligands can have directional effects on neurite outgrowth, explants are co-cultured with protein-coated beads and assayed for the ability of the bead to locally promote or inhibit outgrowth. We also include a demonstration of the dissection (modified protocol) and culture of E6 spinal cord explants. We routinely use spinal cord explants to confirm bioactivity of the proteins and protein-soaked beads, and to verify species cross-reactivity with chick tissue, under the same culture conditions as SAG explants. These in vitro assays are convenient for quickly screening for molecules that exert trophic (survival) or tropic (directional) effects on SAG neurons, especially before performing studies in vivo. Moreover, this method permits the testing of individual molecules under serum-free conditions, with high neuron survival. PMID- 22215153 TI - The cover. Viewpoints. PMID- 22215151 TI - Sox9/Sox6 and Sp1 are involved in the insulin-like growth factor-I-mediated upregulation of human type II collagen gene expression in articular chondrocytes. AB - Type II collagen is a marker of articular cartilage encoded by the COL2A1 gene. The nature of the trans factors involved in the upregulation of this gene by insulin-like growth factor-I (IGF-I) remains unclear. We found that IGF-I increased type II collagen synthesis by a transcriptional control mechanism involving a 715-bp region within the COL2A1 first-intron specific enhancer. The overproduction of L-Sox5/Sox6/Sox9 and Sp1 and decoy experiments targeting these factors demonstrated their action in concert in IGF-I trans-activation. These results were supported by the data obtained in knockdown experiments in which siRNA against Sox9/Sox6 and Sp1 prevented the IGF-I-induced increase in collagen II production. Indeed, each of these trans-activators increased the expression of others. IGF-I increased the binding of Sox9 and Sp1/Sp3 to their cis elements in the enhancer, and we provide the first evidence of Sox9 interaction with the promoter by chromatin immunoprecipitation. Interactions with COL2A1 were also observed for Sp1, p300/CBP, and Tip60. Finally, a physical interaction between Sox9, p300, Sp3, and Sp1 was detected. These data demonstrate the role of Sox9, Sp1/Sp3, and euchromatin-associated factors (p300, Tip60) in the IGF-I-induced upregulation of COL2A1, indicating possible use of this growth factor in articular cartilage engineering applications to promote repair in patients with degenerative diseases, such as osteoarthritis. PMID- 22215152 TI - The mitogen-activated protein kinase (MAPK) cascade controls phosphatase and tensin homolog (PTEN) expression through multiple mechanisms. AB - The mitogen-activated protein kinase (MAPK) and PI3K pathways are regulated by extensive crosstalk, occurring at different levels. In tumors, transactivation of the alternate pathway is a frequent "escape" mechanism, suggesting that combined inhibition of both pathways may achieve synergistic antitumor activity. Here we show that, in the M14 melanoma model, simultaneous inhibition of both MEK and mammalian target of rapamycin (mTOR) achieves synergistic effects at suboptimal concentrations, but becomes frankly antagonistic in the presence of relatively high concentrations of MEK inhibitors. This observation led to the identification of a novel crosstalk mechanism, by which either pharmacologic or genetic inhibition of constitutive MEK signaling restores phosphatase and tensin homolog (PTEN) expression, both in vitro and in vivo, and inhibits downstream signaling through AKT and mTOR, thus bypassing the need for double pathway blockade. This appears to be a general regulatory mechanism and is mediated by multiple mechanisms, such as MAPK-dependent c-Jun and miR-25 regulation. Finally, PTEN upregulation appears to be a major effector of MEK inhibitors' antitumor activity, as cancer cells in which PTEN is inactivated are consistently more resistant to the growth inhibitory and anti-angiogenic effects of MEK blockade. PMID- 22215154 TI - Scientists, officials eye tools aimed at combating abuse of painkillers. PMID- 22215155 TI - Researchers still seek clinical benefit in raising levels of good cholesterol. PMID- 22215156 TI - IOM panel urges lifespan study of breast cancer risk. PMID- 22215157 TI - Prematurity and mortality in childhood and early adulthood. PMID- 22215158 TI - Time-limited trials. PMID- 22215159 TI - POLST Registry do-not-resuscitate orders and other patient treatment preferences. PMID- 22215160 TI - Reversals of established medical practices: evidence to abandon ship. PMID- 22215161 TI - Where are the health care cost savings? PMID- 22215162 TI - Two years and counting: how will the effects of the Affordable Care Act be monitored? PMID- 22215163 TI - Withholds to slow Medicare spending: a better deal than cuts. PMID- 22215164 TI - A piece of my mind. A physician goes to Washington... and safely returns. PMID- 22215166 TI - Bariatric surgery and long-term cardiovascular events. AB - CONTEXT: Obesity is a risk factor for cardiovascular events. Weight loss might protect against cardiovascular events, but solid evidence is lacking. OBJECTIVE: To study the association between bariatric surgery, weight loss, and cardiovascular events. DESIGN, SETTING, AND PARTICIPANTS: The Swedish Obese Subjects (SOS) study is an ongoing, nonrandomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden of 2010 obese participants who underwent bariatric surgery and 2037 contemporaneously matched obese controls who received usual care. Patients were recruited between September 1, 1987, and January 31, 2001. Date of analysis was December 31, 2009, with median follow-up of 14.7 years (range, 0-20 years). Inclusion criteria were age 37 to 60 years and a body mass index of at least 34 in men and at least 38 in women. Exclusion criteria were identical in surgery and control patients. Surgery patients underwent gastric bypass (13.2%), banding (18.7%), or vertical banded gastroplasty (68.1%), and controls received usual care in the Swedish primary health care system. Physical and biochemical examinations and database cross-checks were undertaken at preplanned intervals. MAIN OUTCOME MEASURES: The primary end point of the SOS study (total mortality) was published in 2007. Myocardial infarction and stroke were predefined secondary end points, considered separately and combined. RESULTS: Bariatric surgery was associated with a reduced number of cardiovascular deaths (28 events among 2010 patients in the surgery group vs 49 events among 2037 patients in the control group; adjusted hazard ratio [HR], 0.47; 95% CI, 0.29-0.76; P = .002). The number of total first time (fatal or nonfatal) cardiovascular events (myocardial infarction or stroke, whichever came first) was lower in the surgery group (199 events among 2010 patients) than in the control group (234 events among 2037 patients; adjusted HR, 0.67; 95% CI, 0.54-0.83; P < .001). CONCLUSION: Compared with usual care, bariatric surgery was associated with reduced number of cardiovascular deaths and lower incidence of cardiovascular events in obese adults. PMID- 22215165 TI - Effect of dietary protein content on weight gain, energy expenditure, and body composition during overeating: a randomized controlled trial. AB - CONTEXT: The role of diet composition in response to overeating and energy dissipation in humans is unclear. OBJECTIVE: To evaluate the effects of overconsumption of low, normal, and high protein diets on weight gain, energy expenditure, and body composition. DESIGN, SETTING, AND PARTICIPANTS: A single blind, randomized controlled trial of 25 US healthy, weight-stable male and female volunteers, aged 18 to 35 years with a body mass index between 19 and 30. The first participant was admitted to the inpatient metabolic unit in June 2005 and the last in October 2007. INTERVENTION: After consuming a weight-stabilizing diet for 13 to 25 days, participants were randomized to diets containing 5% of energy from protein (low protein), 15% (normal protein), or 25% (high protein), which they were overfed during the last 8 weeks of their 10- to 12-week stay in the inpatient metabolic unit. Compared with energy intake during the weight stabilization period, the protein diets provided approximately 40% more energy intake, which corresponds to 954 kcal/d (95% CI, 884-1022 kcal/d). MAIN OUTCOME MEASURES: Body composition was measured by dual-energy x-ray absorptiometry biweekly, resting energy expenditure was measured weekly by ventilated hood, and total energy expenditure by doubly labeled water prior to the overeating and weight stabilization periods and at weeks 7 to 8. RESULTS: Overeating produced significantly less weight gain in the low protein diet group (3.16 kg; 95% CI, 1.88-4.44 kg) compared with the normal protein diet group (6.05 kg; 95% CI, 4.84 7.26 kg) or the high protein diet group (6.51 kg; 95% CI, 5.23-7.79 kg) (P = .002). Body fat increased similarly in all 3 protein diet groups and represented 50% to more than 90% of the excess stored calories. Resting energy expenditure, total energy expenditure, and body protein did not increase during overfeeding with the low protein diet. In contrast, resting energy expenditure (normal protein diet: 160 kcal/d [95% CI, 102-218 kcal/d]; high protein diet: 227 kcal/d [95% CI, 165-289 kcal/d]) and body protein (lean body mass) (normal protein diet: 2.87 kg [95% CI, 2.11-3.62 kg]; high protein diet: 3.18 kg [95% CI, 2.37-3.98 kg]) increased significantly with the normal and high protein diets. CONCLUSIONS: Among persons living in a controlled setting, calories alone account for the increase in fat; protein affected energy expenditure and storage of lean body mass, but not body fat storage. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00565149. PMID- 22215167 TI - International variation in and factors associated with hospital readmission after myocardial infarction. AB - CONTEXT: ST-segment elevation myocardial infarction (STEMI) treatment has improved outcomes and shortened hospital stay. Recently, 30-day readmission rates have been proposed as a metric for care of patients with STEMI. However, international rates and predictors of 30-day readmission after STEMI have not been studied. OBJECTIVE: To determine international variation in and predictors of 30-day readmission rates after STEMI and country-level care patterns. DESIGN, SETTING, AND PATIENTS: Post hoc analysis of the Assessment of Pexelizumab in Acute Myocardial Infarction trial that enrolled 5745 patients with STEMI at 296 sites in the United States, Canada, Australia, New Zealand, and 13 European countries from July 13, 2004, to May 11, 2006. Multivariable logistic regression analysis was used to identify independent predictors of all-cause and nonelective 30-day postdischarge readmission. MAIN OUTCOME MEASURES: Predictors of 30-day postdischarge all-cause and nonelective readmissions. RESULTS: Of 5571 patients with STEMI who survived to hospital discharge, 631 (11.3%) were readmitted within 30 days. Thirty-day readmission rates were higher for the United States than other countries (14.5% vs 9.9%; P < .001). Median length of stay was shortest for US patients (3 days; interquartile range, 2-4 days) and longest for Germany (8 days; interquartile range, 6-11 days). In multivariable regression, the predictors of 30-day readmission included multivessel disease (odds ratio [OR], 1.97; 95% CI, 1.65-2.35) and US location (OR, 1.68; 95% CI, 1.37-2.07). Excluding elective readmission for revascularization, US enrollment was still an independent predictor of readmission (OR, 1.53; 95% CI, 1.20-1.96). After adjustment of the models for country-level median length of stay, US location was no longer an independent predictor of 30-day all-cause or nonelective readmission. Location in the United States was not a predictor of in-hospital death (OR, 0.88; 95% CI, 0.60-1.30) or 30-day postadmission death (OR, 1.0; 95% CI, 0.72-1.39). CONCLUSIONS: In this multinational study, there was variation across countries in 30-day readmission rates after STEMI, with readmission rates higher in the United States than in other countries. However, this difference was greatly attenuated after adjustment for length of stay. PMID- 22215168 TI - Update: A 52-year-old woman with disabling peripheral neuropathy. PMID- 22215169 TI - Overeating and overweight: extra calories increase fat mass while protein increases lean mass. PMID- 22215172 TI - JAMA patient page. Ulcerative colitis. PMID- 22215170 TI - Inadequacy of BMI as an indicator for bariatric surgery. PMID- 22215173 TI - Paediatric trauma patients and attention deficit hyperactivity disorder: correlation and significance. AB - INTRODUCTION: Trauma is one of the leading reasons for emergency department (ED) visits in children. Hyperactivity, inattentiveness and impulsiveness may contribute to injury proneness. The aim of this study was to evaluate the prevalence and role of attention deficit hyperactivity disorder (ADHD) in children with trauma. METHODS: Trauma patients aged 3-17 attending the ED were included in the study group. Parents were informed after medical care had been given to their children, and demographic data and information about the trauma were collected. Later, parents were asked to complete the Conners' Parent Rating Scales-Revised questionnaire for ADHD symptoms. The control group consisted of children of similar age and sociocultural characteristics who attended the hospital for reasons other than trauma. Cases in which the child apparently had no active role in the trauma or where the parents did not complete the Conners' Parent Rating Scales-Revised questionnaire were excluded from the study. RESULTS: Fifty-five children were included in the study group (mean age 7.49 (range 3-14; SD 3.3); 33 (60%) were male). The control group was statistically similar to the study group. The most common trauma mechanism was falls (n=31, 56.4%). All the subscale scores were significantly higher in the study group, and previous trauma related ED visits were associated with significantly higher subscale scores. CONCLUSION: The data suggest that children who make repeated trauma-related ED visits have a predisposition to ADHD, and they may benefit from screening for this disorder while in the ED. PMID- 22215174 TI - The ABC of handover: a qualitative study to develop a new tool for handover in the emergency department. AB - OBJECTIVES: This study identifies best practice for shift handover and introduces a new tool used to hand over clinical and operational issues at the end of a shift in the emergency department (ED). METHODS: Literature review, semi structured interviews and observations of handover were used to develop a standardised process for handover. Participants were ED middle grades, consultants and senior nurses. Interviews were used to identify agreed best practice and derive a tool to classify the information into relevant sections. RESULTS: Interviews identified a variety of perceived current deficits in handover including a lack of standardised practice and structure. Participants provided examples of poor handover that were thought to have led to adverse events; these included delay in investigations and treatment for patients who were handed over with brief or inaccurate information. There was wide variation in the understanding of the meaning and purpose of shift handover, and differences were apparent according to the level of experience of the middle grades interviewed. The experts' responses were used to reach a unifying 'best practice' for the content of handover. This was then grouped under ABCDE headings to develop the ABC of handover tool. CONCLUSIONS: A simple tool was developed to provide the basis for medical shift handover, which includes clinical and operational information necessary for efficiency and organisation of the next shift. The ABC of handover classifies shift information to be handed over under the ABCDE headings, which are easy to remember and highly relevant to emergency medicine. PMID- 22215177 TI - Energy cost and mechanical work of walking during load carriage in soldiers. AB - In the military context, soldiers carry equipments of total mass often exceeding 30%-40% of their body mass (BM) and complexly distributed around their body (backpack, weapons, electronics, protections, etc.), which represents severe load carrying conditions. PURPOSE: This study aimed to better understand the effects of load carriage on walking energetics and mechanics during military-type walking. METHODS: Ten male infantrymen recently retired from the French Foreign Legion performed 3-min walking trials at a constant speed of 4 km.h(-1) on an instrumented treadmill, during which walking pattern spatiotemporal parameters, energy cost (C(W)), external mechanical work (W(ext)), and the work done by one leg against the other during the double-contact period (W(int,dc)) were specifically assessed. Three conditions were tested: (i) light sportswear (SP, reference condition considered as unloaded), (ii) battle equipment (BT, ~22 kg, ~27% of subjects' BM, corresponding to a military intermediate load), and (iii) road march equipment (RM, ~38 kg, ~46% of subjects' BM, corresponding to a military high load). RESULTS: Repeated-measures ANOVA showed that military equipment carriage significantly (i) altered the spatiotemporal pattern of walking (all P < 0.01), (ii) increased absolute gross and net CW (P < 0.0001), and (iii) increased both absolute and mass-relative W(ext) (P < 0.01) and W(int,dc) (P < 0.0001) but did not alter the inverted pendulum recovery or locomotor efficiency. CONCLUSIONS: Military equipments carriage induced significant changes in walking mechanics and energetics, but these effects appeared not greater than those reported with loads carried around the waist and close to the center of mass. This result was not expected because the latter has been hypothesized to be the optimal method of load carriage from a metabolic standpoint. PMID- 22215178 TI - Ethnic-specific determinants of exercise capacity in a healthy high-risk population. AB - PURPOSE: African Americans (AA) have been shown to have lower exercise capacities and a higher prevalence of related risk for cardiovascular disease (CVD) compared to European Americans (EA). Broad biopsychosocial models that may inform the design of ethnic-specific exercise programs have not been well examined. We thus examined exercise capacity and its biopsychosocial correlates in a healthy population of AA and EA at increased risk of CVD. METHODS: Subjects underwent maximal graded treadmill testing with gated single-photon emission computed tomography (SPECT); exercise capacity was expressed in MET-minutes. Medical history, psychosocial variables, general well-being, physical activity, and anthropometrics were assessed. Peak filling rate, a measure of left ventricular function, and ejection fraction were obtained from SPECT imaging, and the presence of silent ischemia was determined from the treadmill and SPECT imaging. RESULTS: The sample (N = 1054) was 47% AA and 60% female. Mean age was 52.1 +/- 9 yr for AA and 49.9 +/- 10 yr for EA. Body mass index (BMI) was 32.5 +/- 6.7 kg.m( 2) for AA and 29 +/- 5.3 kg.m(-2) for EA. AA achieved a mean maximal exercise level of 31 MET.min less than EA did. In separate regression models by race, BMI (r(2) = 0 .30), age (r(2) = 0 .07), and sex (r(2) = 0 .03) explained 40% of the variance in MET-minutes in AA and 36% in EA, with a similar hierarchy of associated variables. The remaining variables had minimal effect on exercise capacity in either group. CONCLUSIONS: BMI, older age, and female sex together contribute most to exercise capacity in both ethnicities. Hypothetically important biopsychosocial variables that may help shape ethnic-specific exercise programs add little to the prediction of exercise capacity. Thus, programs designed to reduce disparities in exercise capacity still need to first and foremost be geared to the age and sex demographics and address obesity. PMID- 22215179 TI - Effect of long-term vigorous physical activity on healthy adult knee cartilage. AB - INTRODUCTION: Whether participation in long-term vigorous physical activity affects knee cartilage is unclear and may depend on the state of knee health. We examined the association between vigorous physical activity during a decade and the subsequent changes in knee cartilage among healthy adults. We then examined whether this effect differed in those with and without bone marrow lesions (BMLs), as an indicator of preclinical joint damage. METHODS: A total of 297 healthy adults age 50-79 yr were recruited. Physical activity was assessed via questionnaire at baseline (1990-1994) and at follow-up (2003-2004), and a score for persistence of vigorous physical activity score was determined. Each subject underwent knee magnetic resonance imaging in 2003-2004 and in 2006-2007. Cartilage volume, defects, and BMLs were measured using validated methods. RESULTS: Persistent participation in vigorous physical activity was associated with worsening of medial knee cartilage defects (odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.0-2.3). In the subgroup with BMLs, but not in those without BML, persistent vigorous physical activity was associated with a significant worsening of medial knee cartilage defects (OR = 3.4, 95% CI = 1.0 16.5) and a trend toward an increased rate of loss of medial knee cartilage volume (21.6 mm.yr, 95% CI = -0.4 to 43.6). CONCLUSIONS: In knees with BMLs, persistent participation in vigorous physical activity was associated with adverse cartilage changes in the medial compartment. This suggests that the long term effects of vigorous physical activity may depend on the preexisting health of the joint. PMID- 22215180 TI - Breaks in sedentary time during childhood and adolescence: Iowa bone development study. AB - PURPOSE: The frequency of interruptions in sedentary time (sedentary breaks) is an aspect of sedentary behaviors that may be associated with metabolic health outcomes. The aim of this study was to describe the change in the frequency of sedentary breaks during a 10-yr period from ages 5 to 15 yr. METHODS: The longitudinal Iowa Bone Development Study has collected accelerometry data at approximately 5, 8, 11, 13, and 15 yr. Data from participants who wore an accelerometer at least 10 h.d(-1) and 3 d per data collection episode were used (423 children at age 5 yr, 550 children at age 8 yr, 520 children at age 11 yr, 454 children at age 13 yr, and 344 children at age 15 yr). The frequency of sedentary breaks was determined based on accelerometry data and compared by weekday/weekend, period during the day, gender, and data collection episode. RESULTS: The frequency of sedentary breaks decreased by >200 times per day during a 10-yr period from ages 5 to 15 yr. Linear regression models estimated a 1.84 times-per-hour decrease per year for boys and a 2.04-times-per-hour decrease per year for girls (P values < 0.0001). Both boys and girls showed significantly fewer breaks on weekdays from morning to 3:00 p.m. than on weekends from morning to 3:00 p.m. (P values < 0.0001). The frequency of sedentary breaks was slightly higher among boys than among girls (gender difference <= 2 times per hour; P values < 0.01 at ages 11, 13, and 15 yr). CONCLUSIONS: Breaks in sedentary time notably decrease during childhood and adolescence. During school hours, boys and girls have fewer breaks in sedentary time than during any other period of weekday or weekend day. PMID- 22215181 TI - Mechanisms of fatigue and task failure induced by sustained submaximal contractions. AB - PURPOSE: The present study was designed to investigate whether central neural mechanisms limit the duration of a sustained low-force isometric contraction and the maximal force-generating capacity of the knee extensors. METHODS: Fourteen healthy males (28 +/- 7 yr) were asked to sustain, until voluntary exhaustion, an isometric contraction with their right knee extensor muscles at a target force equal to 20% of their maximal voluntary contraction (MVC) force. At task failure, the muscle was immediately electrically stimulated for 1 min aiming the same target force (20% MVC force). Subsequently, subjects were asked to resume the voluntary contraction for as long as possible. Knee extensor neuromuscular function was assessed before and after the entire protocol for comparison. RESULTS: When electrically stimulated at the point of task failure, all subjects developed the 20% MVC force target, indicating that lack of force-generating capacity from peripheral impairment had not limited the duration of the first task. We observed a reduction in MVC force after the entire protocol (-57% +/- 12%), which correlated with a decrease in potentiated peak doublet force (-48% +/ 17%, P < 0.001). The level of voluntary activation, as quantified with the interpolated twitch technique, was slightly depressed after the entire protocol (from 93% +/- 7% to 87% +/- 10%, P < 0.01). CONCLUSIONS: It follows that task failure from a sustained isometric contraction is mainly affected by central/motivational factors, whereas MVC force loss is largely explained by the extent of contractile failure of the muscle. PMID- 22215182 TI - Effect of exercise on bone status and body composition in Japanese students. AB - PURPOSE: We evaluated the effect of exercise on stiffness and fat-free mass (FFM), which consists of bone and muscle, in Japanese students. It is uncertain whether exercise or sports activities will help to accumulate overall peak bone mass in Japanese adolescents. METHODS: A total of 710 Japanese students (age = 15 20 yr) were enrolled. Students who regularly engage in physical exercise were assigned to an exercise group; other students were assigned to a nonexercise group. Body composition, including height, weight, waist circumference, hip circumference, body mass index, and waist-to-hip ratio, were measured and calculated. Lung volume, body volume, and body fat percentage were evaluated by air displacement plethysmography. Fat mass and FFM were derived from body fat percentage and body weight. Bone status, such as speed of sounds, broadband ultrasound attenuation, and stiffness, which is defined as bone density, was assessed by quantitative ultrasound. RESULTS: In both sexes, height, weight, body mass index, circumferences, waist-to-hip ratio, lung volume, and body volume between the exercise and nonexercise groups did not show any significant differences. FFM, speed of sounds, broadband ultrasound attenuation, and stiffness in the exercise group were statistically higher than those in the nonexercise group (P < 0.05). Although stiffness positively correlated with age with the exception of the nonexercise group in females (P < 0.01), stiffness correlated with FFM in the exercise and nonexercise groups in both sexes (P < 0.01). CONCLUSIONS: Ours is the first analysis of a trend in peak bone mass, including the effect of exercise in Japanese students. For Japanese pubertal females who did not have a history of regular exercise, stiffness slowly decreased with age. Exercise habits in early childhood are important in the relationship between stiffness and FFM. PMID- 22215183 TI - Skeletal and hormonal responses to vitamin D supplementation during sunlight deprivation in Antarctic expeditioners. AB - Sunlight deprivation results in vitamin D deficiency but serum vitamin D levels can be maintained above 50 nmol/L when supplemented with 50,000 IU at least every alternate month. INTRODUCTION: Antarctic expeditioners are exposed to prolonged sunlight deprivation resulting in vitamin D deficiency. We hypothesised that monthly dosing of 50,000 IU vitamin D (~1,600 IU daily) will increase serum 25 hydroxyvitamin D (25(OH)D), suppress parathyroid hormone (PTH) and improve bone mineral density (BMD), 50,000 IU alternate months (~800 IU daily) will maintain these measures, while a single 50,000 IU dose pre-departure (~1,00 IU daily) will not be protective. METHODS: This was a randomised double-blind study involving 110 healthy adults: 91 males, mean age 41 years (range 24-65 years) working in Antarctica for up to 12 months, who we administered 50,000 IU vitamin D3 monthly, alternate months or a single dose pre-departure. Serum 25(OH)D, PTH, osteocalcin, CTx and calcium were assessed at baseline, mid- and end of expedition. Proximal femur and lumbar spine BMD were assessed pre- and post-expedition. RESULTS: Baseline 25(OH)D was 59 +/- 14 nmol/L. By mid-expedition, 25(OH)D increased by 7 nmol/L in those supplemented monthly (p < 0.05) and remained unchanged in those supplemented in alternate months. In those given a single dose pre-departure, 25(OH)D decreased by 8 nmol/L (p < 0.05) and PTH increased by 27% (p < 0.09). Serum osteocalcin increased by ~22% in all groups but BMD remained unchanged. If serum 25(OH)D was >50 nmol/L at baseline, 25(OH)D was maintained above this level with all regimens. If 25(OH)D was <50 nmol/L at baseline, monthly or alternate month regimens were needed to achieve levels >50 nmol/L, the single pre-departure dose was ineffective. CONCLUSION: During sunlight deprivation of up to 12 months, serum 25(OH)D levels can be maintained above 50 nmol/L when expeditioners are provided with 50,000 I U at least every alternate month. PMID- 22215184 TI - Association of CDX1 binding site of periostin gene with bone mineral density and vertebral fracture risk. AB - SUMMARY: Periostin (POSTN) as a regulator of osteoblast differentiation and bone formation may affect susceptibility to osteoporosis. This study suggests POSTN as a candidate gene for bone mineral density (BMD) variation and vertebral fracture risk, which could better our understanding about the genetic pathogenesis of osteoporosis and will be useful in clinic in the future. INTRODUCTION: The genetic determination of osteoporosis is complex and ill-defined. Periostin (POSTN), an extracellular matrix secreted by osteoblasts and a regulator of osteoblast differentiation and bone formation, may affect susceptibility to osteoporosis. METHODS: We adopted a tag-single nucleotide polymorphism (SNP) based association method followed by imputation-based verification and identification of a causal variant. The association was investigated in 1,572 subjects with extreme-BMD and replicated in an independent population of 2,509 subjects. BMD was measured by dual X-ray absorptiometry. Vertebral fractures were identified by assessing vertebral height from X-rays of the thoracolumbar spine. Association analyses were performed with PLINK toolset and imputation analyses with MACH software. The top imputation finding was subsequently validated by genotyping. Interactions between POSTN and another BMD-related candidate gene sclerostin (SOST) were analyzed using MDR program and validated by logistical regression analyses. The putative transcription factor binding with target sequence was confirmed by electrophoretic mobility shift assay (EMSA). RESULTS: Several SNPs of POSTN were associated with BMD or vertebral fractures. The most significant polymorphism was rs9547970, located at the -2,327 bp upstream (P = 6.8 * 10(-4)) of POSTN. Carriers of the minor allele G per copy of rs9547970 had 1.33 higher risk of vertebral fracture (P = 0.007). An interactive effect between POSTN and SOST upon BMD variation was suggested (P < 0.01). A specific binding of CDX1 to the sequence of POSTN with the major allele A of rs9547970 but not the variant G allele was confirmed by EMSA. CONCLUSIONS: Our results suggest POSTN as a candidate gene for BMD variation and vertebral fracture risk. PMID- 22215185 TI - Photoprocesses of chlorin e6 glucose derivatives. AB - The ground and excited state processes of chlorin e6, the monomethyl ester C1, the glucose derivative C2 and the 3-heptylchlorin-glucose C3, were studied in solvents of lower and higher polarity. The excited singlet and lowest triplet states of C1-C3 were characterized by spectroscopic methods for several conditions. The quantum yields of formation of singlet molecular oxygen and the other triplet properties of the three chlorins and chlorin e6 are similar, whereas the fluorescence quantum yield decreases on going from C1 to C3. Time resolved optoacoustic experiments revealed a ca. 30 kJ mol(-1) higher triplet level for C3 with respect to C1/2. PMID- 22215186 TI - Latent tuberculosis infection in children: diagnostic approaches. AB - Tuberculosis (TB) remains an important public health problem and a leading infectious cause of death. Diagnosis and treatment of latent tuberculosis infection (LTBI) is important for TB control and elimination. Nevertheless, the diagnosis of LTBI in both adults and children remains complex, since there is no gold standard. The development of interferon gamma release assays was a major breakthrough in the diagnosis of LTBI. The evaluation of IGRAs in the diagnosis of LTBI in children is proven to be difficult since childhood TB differs from adults as immune responses vary with age. Separate studies assessing IGRAs performance in children are still limited, and only a few of them divide results by narrow age groups Nevertheless, new approaches are being exploited by the ongoing research for the development of more efficient diagnostic tools. It is likely that many changes in both the diagnosis and management of LTBI will occur in the near future. We believe that better understanding of the immunopathology of latency can ultimately lead to the development of more effective strategies in TB control. In the present review we summarize current data on diagnosis of LTBI in children, underscoring the existing challenges and limitations. PMID- 22215187 TI - Evaluation of an immunodot blot technique for the detection of antibodies against Taenia solium larval antigens. AB - Immunodiagnostic tests represent an important tool for diagnosis of cysticercosis, the disease caused by cysticerci of Taenia solium. Accurate diagnosis of neurocysticercosis (NCC) requires costly neuroimaging techniques (magnetic resonance imaging and computed tomography), which are seldom affordable for people in endemic countries. Hence, new low-cost diagnostic methods offering good sensitivity and specificity are needed. Here, we studied four immunodiagnostic tests immunodot blot Tsol-p27, a commercial ELISA, and Western blot Tsol-p27/TsolHSP36, and compared them with a commercial enzyme-linked immunoelectrotransfer blot (EITB) that we regarded as the gold standard method. The analyzed serum samples were obtained from 160 patients: 94 epileptics suspected of NCC, six individuals confirmed NCC-positive, and 60 with positive (30) or negative (30) serology for Chagas diseases. Of the 100 serum samples from epileptic patients, 13 were positive and 87 negative by EITB. Compared to Western blot Tsol-p27, immunodot blot Tsol-p27 offered similar specificity (97.8% vs. 95.6%) but better sensitivity (86.7% vs. 76.4%). The ELISA was similar to the immunodot blot Tsol-p27 regarding both sensitivity and specificity. Western blot TsolHSP36 provided the lowest sensitivity (61.9%) and specificity (86.1%). None of the antibodies in the serum samples from the Chagas control groups were recognized by immunodot blot Tsol-p27. Our results indicate that the immunodot blot Tsol-p27 provides good sensitivity and specificity. Furthermore, considering the simplicity and low cost of this test, it might be preferable as a diagnostic method in poorly equipped laboratories in endemic countries. PMID- 22215188 TI - Antiplasmodial activity of flavonol quercetin and its analogues in Plasmodium falciparum: evidence from clinical isolates in Bangladesh and standardized parasite clones. AB - Malaria is still a major threat in many parts of the world with resistance spreading to almost all classes of antimalarials. The limited arsenal of available antimalarial drugs emphasizes the urgent need for novel antimalarial compounds. Owing to the fact that novel leads from nature have traditionally played a pivotal role in the development of various classes of antimalarials, we investigated a set of eight naturally occurring dietary flavonoids and their analogues for their antiplasmodial activity on clinical field isolates in southeastern Bangladesh and culture-adapted chloroquine-sensitive and chloroquine resistant parasite clones. Except for taxifolin, all the other flavonoids had 50% inhibitory concentrations below 14 MUM, both in the field and laboratory-adapted parasites. Neither of the flavonoids showed any activity correlation with chloroquine. The quercetin analogue rutin (7.10 +/- 10.32 MUM) was the most active substance in field isolates as well as laboratory-adapted cultures (3.53 +/- 13.34 MUM in 3D7 and 10.38 +/- 15.08 MUM in K1), providing the first evidence of its activity against Plasmodium falciparum parasites. Thus, our results provide important evidence of the antimalarial activity of flavonoids in traditional use and thus warrant further investigation of these compounds as potential antiplasmodial agents. PMID- 22215189 TI - Cloning and characterization of a novel cathepsin B-like cysteine proteinase from Angiostrongylus cantonensis. AB - Cysteine protease plays a key role in host-parasite interactions. In this study, we identified a novel gene encoding a cathepsin B-like cysteine protease (AcCBL1) from the cDNA library of Angiostrongysus cantonensis fourth-stage larvae (L4) and characterized its biological role in the parasite. Sequence and phylogeny analysis showed that AcCBL1 is related to other cathepsin B family members with the conserved catalytic triad (Cys, His, Asn) and diagnostic occluding loop. In addition, the sequence contains a specific "hemoglobinase motif" and might have a hemoglobinase (Hb)-degrading function. The recombinant AcCBL1 (rAcCBL1) exhibited the protease activity by gelation SDS/PAGE assay; rAcCBL1 can cleave the fluorogenic substrate Z-Arg-Arg-AMC, and the optimum pH was 5.5. The enzyme can hydrolyse several host proteins including Hb and human IgG in acidic pH, but low levels of hydrolysis were observed in neutral pH. Reverse transcription polymerase chain reaction revealed that AcCBL1 expression was detected throughout various developmental stages, L3, L4, adult male and female worms. Western blotting analysis indicated that AcCBL1 was an excretory/secretory product of L4 in mature form of protease. Immunolocalization demonstrated that AcCBL1 was mainly localized in the intestine of L4. These results suggest that rAcCBL1 may play an important role in the parasite nutrition uptake. PMID- 22215190 TI - Adjuvant effect of ginsenoside-based nanoparticles (ginsomes) on the recombinant vaccine against Eimeria tenella in chickens. AB - An experiment was conducted to study the adjuvant effect of ginsomes on the recombinant profilin in coccidian-infected breeding birds. Three-day-old chickens were vaccinated with Eimeria tenella recombinant profilin antigen (10, 50, and 100 MUg per chicken) with or without 50 MUg ginsomes per chicken. The boost vaccination was carried out 14 days later. Two weeks after the booster, the chickens were challenged with 1.5 * 10(4) homologous sporulated oocysts. The specific antibody response, lymphocyte proliferation, and IL-1 release from lymphocyte were measured at 1-42 days after boost vaccination. Seven days post challenge, the rate of survival, body weight gains (BWG) were examined then all chickens were sacrificed and lesion scores and oocysts per gram were monitored to evaluate the protective effects of the vaccination after challenge. Compared with the group of vaccinating with profilin only, groups of 50 and 100 MUg antigen plus ginsomes significantly enhanced lymphocyte proliferation and IL-1 secretion. The profilin specific antibody level in the four vaccinated groups was significantly higher than in the control group and in groups vaccinated with profilin containing ginsomes than profilin only. In the groups vaccinated with profilin plus ginsomes, the BWG was significantly higher than that of group of profilin only, but there was no significant difference between profilin plus adjuvant ginsomes, diclazuril medicated and uninfected-unmedicated-unvaccinated control groups. The lesion scores in groups immunized with profilin plus ginsomes was significantly lower than that both of groups unimmunized-challenged unmedicated control and group vaccinated with profilin only. Oocyst excretion in groups vaccinated with 50 or 100 MUg profilin plus ginsomes was lower than that of groups vaccinated with profilin only. These results demonstrate that the adjuvant ginsomes can promote subunit vaccine to induce a strong immune response and protective effects. PMID- 22215191 TI - Ultrastructural analysis of miltefosine-induced surface membrane damage in adult Schistosoma mansoni BH strain worms. AB - Schistosomiasis is an infectious parasitic disease caused by helminths from the genus Schistosoma; it affects over 200 million people globally and is endemic in 70 countries. In Brazil, 6 million individuals are infected with Schistosoma mansoni. Furthermore, as the prevalence of S. mansoni infections is increasing, approximately 26 million citizens in 19 Brazilian states are at risk for infection. Schistosomiasis disease control involves predominately the administration of a single drug, praziquantel. Although praziquantel exhibits chemotherapeutic efficacy and safety, its massive use in endemic zones, the possibility of the emergence of drug-resistant Schistosoma parasites, and the lack of another efficacious antischistosomal drug demand the discovery of new schistosomicidal compounds. First developed as anti-tumor drug, miltefosine is an alkylphospholipid derivative that exhibits bioactivity against Leishmania and Trypanosoma parasites, free-living protozoa, bacteria, and fungi. With its anti parasite activity, miltefosine was the first orally administered drug against visceral and cutaneous leishmaniasis approved. Previously, by means of the MTT cytotoxic assay and a DNA fragmentation test, we verified that, at doses of 100 and 200 MUM (40 and 80 MUg/mL), miltefosine exhibited in vitro schistosomicidal activity against adult S. mansoni worms. Here, we present ultrastructural evidence of rapid, severe miltefosine-induced surface membrane damage in S. mansoni following drug treatment. The number of dead parasites was concentration- and time-dependent following miltefosine treatment. At a miltefosine concentration of 200 MUM (~80 MUg/mL), in vitro parasite killing was initiated as early as 3 h post-incubation, and it was maximal after 24 h of treatment. The parasite death was preceded by progressive surface membrane damage, characterized by tegument peeling, spine reduction and erosion, blister formation and rupture, and the emergence of holes. According to our present results, miltefosine is very effective at inducing membrane destruction of S. mansoni with a short onset of pharmacological action. PMID- 22215192 TI - Curcumin treatment provides protection against Trypanosoma cruzi infection. AB - Trypanosoma cruzi, the etiologic agent of Chagas disease, causes an acute myocarditis and chronic cardiomyopathy. The current therapeutic agents for this disease are not always effective and often have severe side effects. Curcumin, a plant polyphenol, has demonstrated a wide range of potential therapeutic effects. In this study, we examined the effect of curcumin on T. cruzi infection in vitro and in vivo. Curcumin pretreatment of fibroblasts inhibited parasite invasion. Treatment reduced the expression of the low density lipoprotein receptor, which is involved in T. cruzi host cell invasion. Curcumin treatment of T. cruzi infected CD1 mice reduced parasitemia and decreased the parasitism of infected heart tissue. This was associated with a significant reduction in macrophage infiltration and inflammation in both the heart and liver; moreover, curcumin treated infected mice displayed a 100% survival rate in contrast to the 60% survival rate commonly observed in untreated infected mice. These data are consistent with curcumin modulating infection-induced changes in signaling pathways involved in inflammation, oxidative stress, and apoptosis. These data suggest that curcumin and its derivatives could be a suitable drug for the amelioration of chagasic heart disease. PMID- 22215193 TI - Hepatosplenic morbidity due to Schistosoma mansoni in schoolchildren on Ukerewe Island, Tanzania. AB - The study was conducted to assess infection intensity and morbidity due to Schistosoma mansoni in schoolchildren on Ukerewe Island in Lake Victoria, Tanzania, East Africa. Three hundred and sixty pupils who have never been treated previously were enrolled (180 males/180 females, age 6-17 years [median 10 years]) in three different schools of the island. Double stool samples were collected from each pupil and egg excretion was classified according to WHO recommendations. Ultrasound investigations were performed in accordance with the WHO Niamey-Belo-Horizonte protocol. Male (112/180, 62.2%) and female (104/180; 57.7%) pupils were infected (difference, not significant [n.s.]). In the positive 216 cases, egg excretion varied from 1 to 2,440 eggs per gramme stool (epg) [median 165 epg]. There were 69/216 (31.9%) who had a low grade, 105/216 (53.2%) had a moderate and 42/216 (14.8%) had a heavy infection. There was no significant difference between male and female sex nor with regard to age groups. There were 354/360 children who underwent sonography: 321 (90.7%) had splenomegaly, 316 (89.3%) showed a left lobe and 109 (30.9%) had a right lobe hepatomegaly. Overt signs of portal fibrosis (PF) were present in 19 children (5.4%) out of whom 11 presented with echogenic thickening of peripheral portal and 8 with thickening of central portal branches. Non-specific portal wall changes were seen in 6 children (1.7%). Association of PF to quantitative egg excretion was not seen (median in PF, 172 epg vs. median in non PF, 168 epg; difference, n.s.). Portal vein dilatation was seen in 101/354 (28.5%) cases. In Ukerewe, the prevalence of S. mansoni infection and infection intensity in children is high, yet overt hepatic morbidity is low as compared to other endemic foci. Non-specific ultrasonographic abnormalities including hepatosplenomegaly and portal vein dilatation were seen frequently but the fraction attributable to schistosomiasis is difficult to assess. PMID- 22215194 TI - Responses of the humid zone ecotype of the Nigerian West African Dwarf sheep to mixed infections with Haemonchus contortus and Trichostrongylus colubriformis. AB - The responses of the Nigerian West African Dwarf sheep to experimental infections with two of its most important gastrointestinal (GI) nematodes, namely, Haemonchus contortus and Trichostrongylus colubriformis were studied by means of two measures of parasitological response, namely, faecal egg count (FEC) and worm burden (Wb), and three measures of host pathology, namely, packed cell volume (PCV), body weight (Bwt) and body condition score (BCS). Following exposure to weekly escalating infections (60% H. contortus and 40% T. colubriformis) starting with single doses of 500 infective larvae (L(3)) at week 1, 1,000 L(3) at week 2, 2,000 L(3) at week 3 and 4,000 L(3) at week 4, two distinctive worm burden response phenotypes were readily recognisable, namely, low Wb (LWb) and high Wb (HWb) phenotypes. The percentage of inoculums (adults and immature stages) recovered at necropsy were 3.75% and 33.08% respectively for H. contortus and T. colubriformis. The results showed that the FECs of the lambs belonging to the LWb phenotype were significantly lower than the FECs of their HWb counterpart. Among the measures of host pathology tested, the LWb phenotype sheep had similar Bwt, PCV and BCS to the uninfected control sheep, whereas the HWb phenotype sheep had significantly lower values than their LWb counterparts and the control sheep towards the end of the experiment. There was a highly significant positive correlation between worm burden transformed as log(10) (Wb + 10) and the average of D56 and D59 FECs. A highly significant negative correlation also was obtained between log(10) (Wb + 10) and the PCV, Bwt and BCS. The low percentage of H. contortus inoculums recovered at necropsy suggested that the sheep may be resistant to their most important GI nematode, H. contortus but less so to T. colubriformis. PMID- 22215195 TI - Mosquito larvicidal and pupicidal efficacy of Solanum xanthocarpum (Family: Solanaceae) leaf extract and bacterial insecticide, Bacillus thuringiensis, against Culex quinquefasciatus Say (Diptera: Culicidae). AB - The bio-efficacy of Solanum xanthocarpum leaf extract and bacterial insecticide, Bacillus thuringiensis, were assessed against the first to fourth instar larvae and pupae of Culex quinquefasciatus, under the laboratory conditions. The medicinal plants were collected from the outskirt Bharathiar University, Coimbatore, Tamil Nadu, India. The shade dried plant materials were extracted by employing the Soxhlet apparatus with ethanol (organic solvent) for 8 h and filtered. The extracts were concentrated at reduced temperature on a rotary evaporator and stored at a temperature of 4 degrees C. Both S. xanthocarpum and B. thuringiensis show varied degree of larvicidal and pupicidal activity against various stages of C. quinquefasciatus. The LC(50) and LC(90) of S. xanthocarpum against the first to fourth instar larvae and pupae were 155.29, 198.32, 271.12, 377.44, and 448.41 ppm and 687.14, 913.10, 1,011.89, 1,058.85, and 1,141.65 ppm, respectively. On the other hand, the LC(50) values of B. thuringiensis against the first to fourth instar larvae and pupae were 133.88, 157.14, 179.44, 206.80, and 240.74 ppm; the LC(90) values were 321.04, 346.89, 388.86, 430.95, and 492.70 ppm, respectively. However, the combined treatment of S. xanthocarpum + B. thuringiensis (1:2) material shows highest larvicidal and pupicidal activity of the LC(50) values 126.81, 137.62, 169.14, 238.27, and 316.02 ppm and the LC(90) values 476.36, 613.49, 705.29, 887.85, and 1,041.73 ppm against C. quinquefasciatus in all the tested concentrations than the individuals and clearly established that there is a substantial amount of synergist act. Therefore, the present investigation clearly exhibit that both S. xanthocarpum and B. thuringiensis materials could serve as a potential of highest mortality rate against the mosquito larvae laboratory as well as the field conditions. Since C. quinquefasciatus is a ditch breeder vector mosquito, this is a user and eco-friendly biopesticide for the control of mosquito vector management program. PMID- 22215196 TI - Amoebicidal activity of the rhizomes and aerial parts of Allium sivasicum on Entamoeba histolytica. AB - Amebiasis is a severe illness caused by Entamoebachistolytica. The aim of this study is to evaluate the in vitro amebicidal activity of the rhizomes and aerial parts of Allium sivasicum, an endemic plant species from the flora of Turkey. Both extracts showed a time- and dose-dependent amebicidal action on the trophozoites. Among the extracts tested, rhizomes of A. sivasicum showed the strongest amebicidal effect on the trophozoites. In the presence of the rhizome extract at 2.0 mg/ml concentration, all of the trophozoites available in media have completely been killed within the 72nd hour. At 4.0 mg/ml extract concentration, all of the trophozoites available in media have completely been killed by the rhizome extract from the time of 24th hour. At 32.0 mg/ml extract concentration, 73.7% of the trophozoites were successfully killed by the extract within the first experimental hour. Aerial part extract at 4.0 mg/ml concentration completely killed the trophozoited within the 48th hour of the experimental procedure. At 8.0 mg/ml extract concentration, all of the trophozoites available in media have completely been killed by the aerial part extract from the time of 24th hour. At 32.0 mg/ml extract concentration, 67.7% of the trophozoites were successfully killed by the extract within the first experimental hour. These results suggest that the plant species evaluated here is a potential therapeutic drug for the treatment of Entamoeba infections, but it still needs to be evaluated quantitatively for determining the active phytochemicals. PMID- 22215197 TI - Rapamycin and a hyaluronic acid-carboxymethylcellulose membrane did not lead to reduced adhesion formations in a rat abdominal adhesion model. AB - PURPOSE: Rapamycin, an immunosuppressive in transplant surgery, has an additional antiproliferative effect. The aim of this study was to investigate the potential protective effects of rapamycin on postoperative adhesion development. METHODS: Ten rats per group underwent midline incision laparotomy and adhesion induction including bowel sutures. Therapy groups received daily intraperitoneal rapamycin injections (1.5 mg/kg body weight) for 3 weeks postoperatively. Controls were rats without any postoperative treatment, rats receiving the rapamycin solvent or a hyaluronic acid-carboxymethylcellulose membrane (Seprafilm(TM)). RESULTS: Postoperative rapamycin application led to enhanced adhesion development and there was a higher rate of wound infections. In addition, Seprafilm(TM) did not reduce adhesions, in subgroups there were even more. CONCLUSIONS: Rapamycin is not recommendable for perioperative immunosuppression, it enhances adhesion development and leads to a higher rate of wound infections. Surprisingly, the established Seprafilm(TM) membrane led to more adhesions in our experimental setting. PMID- 22215198 TI - Postnatal neuro-development of fetuses with absent end-diastolic flow in the umbilical artery and/or fetal descending aorta. AB - OBJECTIVE: To determine whether absence of end-diastolic flow in the umbilical artery and/or fetal aorta impacts postnatal neuro-development in preterm-born children. METHODS: The study group, consisting of 43 fetuses with absent end diastolic flow in the umbilical artery and/or fetal aorta, was compared with a control group, consisting of 30 fetuses, matching for gestational age but with normal doppler-flow results. The children's neuro-developmental status was assessed using the 'Munich functional developmental diagnostics' (MFDD), between the 2nd and 3rd year of life. RESULTS: Gestational age at birth was 33 + 6 weeks in the study group and 34 + 4 weeks in the control group. A brain-sparing effect was observed in 37.3% of fetuses in the study group compared with 10.0% in the control group (p = 0.014). For all seven MFDD domains, the number of children with deficiencies was higher in the study group. For the domains perception, active speech and comprehension this effect was statistically significant (p < 0.05). Overall, 30.2% of children in the study group and 16.7% of the control group had pathologic test results (p < 0.013). CONCLUSION: Pathological doppler flow in the umbilical artery and/or fetal descending aorta in preterm born children is associated with neuro-developmental deficiencies. Intensive pediatric care is recommended to mitigate these deficiencies during early childhood. PMID- 22215200 TI - Copper-catalyzed asymmetric ring opening of oxabicyclic alkenes with organolithium reagents. AB - A highly efficient method is reported for the asymmetric ring opening of oxabicyclic alkenes with organolithium reagents. Using a copper/chiral phosphoramidite complex together with a Lewis acid (BF(3).OEt(2)), full selectivity for the anti isomer and excellent enantioselectivities were obtained for the ring opened products. PMID- 22215199 TI - Peritoneal relative to venous serum biomarker concentrations for diagnosis of ectopic pregnancy. AB - PURPOSE: To retrospectively analyze the relationships of peritoneal serum relative to venous serum (R (p/v)) ratios for human chorionic gonadotropin, CA 125, and creatine kinase to the ectopic pregnancy (EP). METHODS: Intra-abdominal fluid and venous blood samples of 118 subjects with suspected EP were obtained for biomarker measurements. R (p/v-hCG) >1 was considered indicative of EP, and final diagnosis was based on surgical finding of an ectopic chorionic villous or gynecological ultrasound finding of an intrauterine gestational sac. RESULTS: R (p/v-hCG) and R (p/v-CA-125) were both significantly greater for abortive as compared to ruptured EP and for the absence as compared to presence of active bleeding. However, neither ratio differed significantly between ampullary and isthmic EP. R (p/v-hCG) and R (p/v-CA-125) correlated negatively with hemoperitoneum volume. R (p/v-hCG) exhibited only modest predictive value for rupture. However, with R (p/v-CA-125) as the diagnostic criterion for rupture, sensitivity and specificity were 66.7 and 100%, respectively; in patients initially diagnosed with EP, R (p/v-CA-125) values <22.43 effectively predicted rupture. R (p/v-CK) did not exhibit significant diagnostic value. CONCLUSIONS: R (p/v-hCG) values >1 combined with positive culdocentesis test findings reliably indicate the presence of EP. In patients initially diagnosed with EP, R (p/v-CA 125) values <22.43 predict tubal rupture. PMID- 22215201 TI - Assessing hepatic metabolic changes during progressive colonization of germ-free mouse by 1H NMR spectroscopy. AB - It is well known that gut bacteria contribute significantly to the host homeostasis, providing a range of benefits such as immune protection and vitamin synthesis. They also supply the host with a considerable amount of nutrients, making this ecosystem an essential metabolic organ. In the context of increasing evidence of the link between the gut flora and the metabolic syndrome, understanding the metabolic interaction between the host and its gut microbiota is becoming an important challenge of modern biology. Colonization (also referred to as normalization process) designates the establishment of micro-organisms in a former germ-free animal. While it is a natural process occurring at birth, it is also used in adult germ-free animals to control the gut floral ecosystem and further determine its impact on the host metabolism. A common procedure to control the colonization process is to use the gavage method with a single or a mixture of micro-organisms. This method results in a very quick colonization and presents the disadvantage of being extremely stressful. It is therefore useful to minimize the stress and to obtain a slower colonization process to observe gradually the impact of bacterial establishment on the host metabolism. In this manuscript, we describe a procedure to assess the modification of hepatic metabolism during a gradual colonization process using a non-destructive metabolic profiling technique. We propose to monitor gut microbial colonization by assessing the gut microbial metabolic activity reflected by the urinary excretion of microbial co-metabolites by (1)H NMR-based metabolic profiling. This allows an appreciation of the stability of gut microbial activity beyond the stable establishment of the gut microbial ecosystem usually assessed by monitoring fecal bacteria by DGGE (denaturing gradient gel electrophoresis). The colonization takes place in a conventional open environment and is initiated by a dirty litter soiled by conventional animals, which will serve as controls. Rodents being coprophagous animals, this ensures a homogenous colonization as previously described. Hepatic metabolic profiling is measured directly from an intact liver biopsy using (1)H High Resolution Magic Angle Spinning NMR spectroscopy. This semi-quantitative technique offers a quick way to assess, without damaging the cell structure, the major metabolites such as triglycerides, glucose and glycogen in order to further estimate the complex interaction between the colonization process and the hepatic metabolism. This method can also be applied to any tissue biopsy. PMID- 22215202 TI - Chronic hypobaric hypoxia mediated skeletal muscle atrophy: role of ubiquitin proteasome pathway and calpains. AB - The most frequently reported symptom of exposure to high altitude is loss of body mass and decreased performance which has been attributed to altered protein metabolism affecting skeletal muscles mass. The present study explores the mechanism of chronic hypobaric hypoxia mediated skeletal muscle wasting by evaluating changes in protein turnover and various proteolytic pathways. Male Sprague-Dawley rats weighing about 200 g were exposed to hypobaric hypoxia (7,620 m) for different durations of exposure. Physical performance of rats was measured by treadmill running experiments. Protein synthesis, protein degradation rates were determined by (14)C-Leucine incorporation and tyrosine release, respectively. Chymotrypsin-like enzyme activity of the ubiquitin-proteasome pathway and calpains were studied fluorimetrically as well as using western blots. Declined physical performance by more than 20%, in terms of time taken in exhaustion on treadmill, following chronic hypobaric hypoxia was observed. Compared to 1.5-fold increase in protein synthesis, the increase in protein degradation was much higher (five-folds), which consequently resulted in skeletal muscle mass loss. Myofibrillar protein level declined from 46.79 +/- 1.49 mg/g tissue at sea level to 37.36 +/- 1.153 (P < 0.05) at high altitude. However, the reduction in sarcoplasmic proteins was less as compared to myofibrillar protein. Upregulation of Ub-proteasome pathway (five-fold over control) and calpains (three-fold) has been found to be important factors for the enhanced protein degradation rate. The study provided strong evidences suggesting that elevated protein turnover rate lead to skeletal muscle atrophy under chronic hypobaric hypoxia via ubiquitin-proteasome pathway and calpains. PMID- 22215203 TI - CYP3A5 and NAT2 gene polymorphisms: role in childhood acute lymphoblastic leukemia risk and treatment outcome. AB - Susceptibility to acute lymphoblastic leukemia can be highly influenced by genetic polymorphisms in metabolizing enzyme genes of environmental carcinogens. This study aimed to evaluate the impact of the CYP3A5 and NAT2 metabolizing enzyme polymorphisms on the risk of childhood acute lymphoblastic leukemia. The analysis was conducted on 204 ALL patients and in 364 controls from a Brazilian population, using PCR-RFLP. The CYP3A5 3 polymorphic homozygous genotype was more frequent among ALL patients and the 3 allele variant was significantly associated with increased risk of childhood ALL (OR = 0.29; 95% CI, 0.14-0.60). The homozygous polymorphic genotype for the 6 allele variant was extremely rare and found in only two individuals. The heterozygous frequencies were similar for the ALL group and the control group. No significant differences were observed between the groups analyzed regarding NAT2 variant polymorphisms. None of the polymorphisms analyzed was related to treatment outcome. The results suggest that CYP3A5 3 polymorphism may play an important role in the risk of childhood ALL. PMID- 22215206 TI - Cannabinoid CB1 receptor activation, pharmacological blockade, or genetic ablation affects the function of the muscarinic auto- and heteroreceptor. AB - Different types of presynaptic inhibitory Galpha(i/o) protein-coupled receptors usually do not act independently of each other but rather pre-activation of receptor X impairs the effect mediated via receptor Y. It is, however, unknown whether this interaction extends to the cannabinoid CB(1) receptor on cholinergic neurones and hence we studied whether its activation, pharmacological blockade, or genetic inactivation affects the function of other presynaptic inhibitory receptors. The electrically evoked acetylcholine or noradrenaline release was determined in superfused rodent tissues preincubated with (3)H-choline or (3)H noradrenaline. The muscarinic M(2) receptor, Galpha(i), and Galpha(o) proteins were determined in hippocampal synaptosomes by Western blotting. Hippocampal anandamide and 2-arachidonoyl glycerol levels were determined by LC-MS/MS. The inhibitory effect of the muscarinic receptor agonist oxotremorine on acetylcholine release in hippocampal slices was increased by genetic CB(1) receptor ablation (mouse) and the CB(1) antagonist rimonabant (rat but not mouse) and decreased by a cannabinoid receptor agonist (mouse). In mouse tissues, CB(1) receptor ablation also increased the effect of a delta opioid receptor agonist on acetylcholine release in the hippocampus and the effect of oxotremorine on noradrenaline release in the vas deferens. CB(1) receptor ablation, to a very slight extent, increased Galpha(o) protein levels without affecting either Galpha(i) and M(2) receptor protein or the levels of anandamide and 2 arachidonoyl glycerol in the hippocampus. In conclusion, the CB(1) receptor shows an inhibitory interaction with the muscarinic and delta opioid receptor on cholinergic neurones in the rodent hippocampus and with the muscarinic receptor on noradrenergic neurones in the mouse vas deferens. PMID- 22215207 TI - Sildenafil, a phosphodiesterase type 5 inhibitor, enhances the antidepressant activity of amitriptyline but not desipramine, in the forced swim test in mice. AB - The cholinergic theory of depression highlights the involvement of muscarinic acetylcholine receptors in the neurobiology of mood disorders. The present study was designed to investigate the effect of sildenafil, a phosphodiesterase type 5 inhibitor which exhibits cholinomimetic properties, alone and in combination with scopolamine in the forced swim test in mice. Moreover, we assessed the ability of sildenafil to modify the antidepressant activity of two tricyclic antidepressants with distinct cholinolytic activity, amitriptyline and desipramine. Swim sessions were conducted by placing mice in glass cylinders filled with water for 6 min and the duration of behavioral immobility during the last 4 min of the test was evaluated. Locomotor activity was measured with photoresistor actimeters. To evaluate the potential pharmacokinetic interaction between amitriptyline and sildenafil, brain and serum concentrations of amitriptyline were determined by HPLC. Sildenafil (1.25-20 mg/kg) as well as scopolamine (0.5 mg/kg) and its combination with sildenafil (1.25 mg/kg) did not affect the total immobility time duration. However, joint administration of scopolamine with sildenafil at doses of 2.5 and 5 mg/kg significantly reduced immobility time as compared to control group. Moreover, co-administration of scopolamine with sildenafil at the highest dose (5 mg/kg) significantly decreased immobility time as compared to scopolamine treated group. Sildenafil (1.25, 2.5 and 5 mg/kg) significantly enhanced the antidepressant activity of amitriptyline (5 mg/kg). No changes in anti-immobility action of desipramine (20 mg/kg) in combination with sildenafil (5, 10 and 20 mg/kg) were observed. Sildenafil did not affect amitriptyline level in both brain and serum. In conclusion, the present study suggests that sildenafil may enhance the activity of antidepressant drugs which exhibit cholinolytic activity. PMID- 22215209 TI - Ionic liquids with metal chelate anions. AB - A series of stable (air, water stable and with good thermal stability) and hydrophobic ionic liquids based upon metal chelate anions were synthesized, which were shown to be effective, mild, and easy to recycle catalysts at the same time stable solvents for the oxidation of cyclohexene. PMID- 22215208 TI - Kynurenic acid: a metabolite with multiple actions and multiple targets in brain and periphery. AB - It is usually assumed that kynurenic acid (KYNA) modifies neuronal function because it antagonizes the glycine site of the NMDA receptors and/or the neuronal cholinergic alpha7 nicotine receptors. It is not clear, however, whether the basal levels of KYNA found in brain extracellular spaces are sufficient to interact with these targets. Another reported target for KYNA is GPR35, an orphan receptor negatively coupled to G(i) proteins. GPR35 is expressed both in neurons and other cells (including glia, macrophages and monocytes). KYNA affinity for GPR35 in native systems has not been clarified and the low-affinity data widely reported in the literature for the interaction between KYNA and human or rat GPR35 have been obtained in modified expression systems. Possibly by interacting with GPR35, KYNA may also reduce glutamate release in brain and pro-inflammatory cytokines release in cell lines. The inhibition of inflammatory mediator release from both glia and macrophages may explain why KYNA has analgesic effects in inflammatory models. Furthermore, it may also explain why, KYNA administration (200 mg/kg ip * 3 times) to mice treated with lethal doses of LPS, significantly reduces the number of deaths. Finally, KYNA has been reported as an agonist of aryl hydrocarbon receptor (AHR), a nuclear protein involved in the regulation of gene transcription and able to cause immunosuppression after binding with dioxin. Thus, KYNA has receptors in the nervous and the immune systems and may play interesting regulatory roles in cell function. PMID- 22215212 TI - Pharyngeal squamous cell papilloma in adult Japanese: comparison with laryngeal papilloma in clinical manifestations and HPV infection. AB - A number of reports have investigated the relationship between laryngeal papilloma and human papilloma virus (HPV) infection. On the other hand, it is unclear whether the HPV infection is involved in the occurrence of pharyngeal papilloma. We hypothesized that HPV infection was involved in the occurrence of pharyngeal papilloma similarly to laryngeal papilloma. To verify this hypothesis, we investigated the presence of HPV infection. Furthermore, clinical manifestations of pharyngeal papilloma, which had rarely been reported, were discussed. A male-to-female ratio, solitary or multiple occurrences, and koilocytosis were examined in cases with pharyngeal papilloma. HPV DNA was examined with unfixed surgically resected specimens of pharyngeal papilloma. A screening test by the liquid-phase hybridization method was carried out for the HPV high-risk group (16, 18, 31, 33, 35, 39, 45, 51, 56, 58, 59, and 68) and HPV low-risk group (6, 11, 42, 43, 44). As a control, 15 cases with laryngeal papilloma for which the same screening test was carried out were employed. Pharyngeal papilloma occurred as a solitary lesion more often, whereas laryngeal papilloma occurred as multiple tumors more frequently. The HPV infection rate was 0% in pharyngeal papilloma cases, which was in stark contrast with 66.7% in the HPV low-risk group in laryngeal papilloma cases. Pharyngeal papilloma occurred as a solitary lesion in females more frequently. Contrary to our hypothesis, the involvement of HPV infection was unlikely in the occurrence of pharyngeal papilloma. PMID- 22215213 TI - AFLP based assessment of genetic relationships among shiitake (Lentinula ssp.) mushrooms. AB - Despite the economical importance of shiitake (Lentinula ssp.) mushrooms, until the present date little information exists on cultivated and wild species in correlation with geographic origin applying molecular techniques. Use of a high resolution molecular tool like AFLP for assessing genetic similarity and geographical diversity would be an important step towards understanding of different Lentinula species. Thirteen wild and 17 cultivated accessions of 3 Lentinula species were analysed with 64 EcoRI-MseI primer combinations and finally 32 reproducible and polymorphic primer combinations were considered for the analysis. A total of 816 informative AFLP markers were generated and scored as binary data. These data were analysed using various method packages for cluster analysis, genetic diversity and genetic differentiation. Percentage polymorphism was high (62.99%) among the species studied. Different clustering analysis segregated the wild and the cultivated species into two major branches, with the wild samples being further grouped according to their geographic location. Overall polymorphisms among cultivated strains in the USA were higher than that of the cultivated strains in Japan (58.9%). PMID- 22215214 TI - Quantitative assessment of the effect of MTHFR polymorphisms on the risk of lung carcinoma. AB - Published studies on the relationships between 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and lung cancer risk have been conflicting. To derive a more precise estimation of the relationship, a meta-analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between MTHFR C677T and A1298C polymorphisms and lung cancer risk. A total of 15 studies including 10,753 cases and 11,275 controls described C677T genotypes, among which 11 articles totalling 6,161 cases and 7,684 controls described A1298C genotypes, were also involved in this meta analysis. Overall, no significantly elevated lung cancer risk was found in any genetic models when all studies were pooled. For C677T polymorphism: (TT vs. CC: OR = 1.17, 95% CI = 0.97-1.42; TC vs. CC: OR = 1.06, 95% CI = 0.94-1.20; dominant model: OR = 1.09, 95% CI = 0.96-1.24; and recessive model: OR = 1.08, 95% CI = 0.95-1.24); for A1298C polymorphism: (CC vs. AA: OR = 1.04, 95% CI = 0.91-1.19; AC vs. AA: OR = 0.98, 95% CI = 0.91-1.06; dominant model: OR = 0.99, 95% CI = 0.92-1.06; and recessive model: OR = 1.05, 95% CI = 0.92-1.20). In the subgroup analyses, the results showed that 677T varients could decrease lung cancer risk in female (OR = 0.63, 95% CI = 0.41-0.95, P-value = 0.03, 677CC as reference). No evidence of any associations of MTHFR A1298C polymorphism with lung cancer was found in overall or subgroup analyses. Our meta-analysis supports that the common polymorphisms of C677T and A1298C in MTHFR gene are not susceptibility gene for lung cancer from currently available evidence. PMID- 22215216 TI - Proteomics changes in adhesion molecules: a driving force for vascular smooth muscle cell phenotypic switch. AB - Vascular smooth muscle cells (VSMCs), if activated by growth factors as a consequence of vessel injuries, acquire the ability to proliferate and migrate thus contributing to the formation of neointima and atherosclerotic plaque. In this study, a gel-free and label-free proteomic approach was proposed to highlight factors modulated during VSMC activation. Twenty proteins, differentially expressed between quiescent and activated cells, were identified. A constellation of elements, that move together and are closely and functionally related, was visualized. The great majority of them are involved in cell migration and in adhesion formation, suggesting a pivotal role of these protein complexes on the phenotypic modulation. This study represents a first step to ascertain the precise actors of cell activation, their roles and interactions. PMID- 22215215 TI - Artesunate inhibits cell proliferation and decreases growth hormone synthesis and secretion in GH3 cells. AB - To determine the effect of artesunate (ART) on the rat pituitary adenoma GH3 cell line to evaluate its potential as a novel agent in growth hormone (GH) adenoma and to investigate its underlying mechanisms of action. The MTT assay was used to assess cell proliferation. DAPI staining was used to visualise apoptotic changes in the nucleus. We also analyzed cell apoptosis and cell cycle stage by flow cytometry, semi-quantitative RT-PCR analysis for the expression of GH mRNA and apoptosis-induced factor (AIF) mRNA, analysis of GH protein by western blot, ELISA detection of secreted GH, and the caspase inhibition assay. We found that ART inhibited the proliferation of GH3 cells in a dose- and time-dependent manner, with an IC50 of 9.53 +/- 4.12 MUM. The IC50s of ART against of two normal cell lines (mouse embryonic fibroblasts, and rat bone mesenchymal cells) were much higher than the IC50 recorded for the GH3 cells. ART induced apoptosis and blocked GH3 at G2/M arrest. The pan caspase inhibitor V-ZAD-FMK partly attenuated the inhibitory effect of ART. ART increased the expression of AIF mRNA and reduced GH mRNA levels, GH synthesis and the secretion of GH level in GH3 cells. ART can inhibit proliferation and induce apoptosis in GH3 cells by caspase dependent pathways. Additionally, ART can inhibit GH synthesis and secretion. Thus, we propose ART as a probably anti-tumour candidate drug in the treatment of GH adenoma. PMID- 22215217 TI - [History of treatment of schizophrenic forensic patients prior to admission: a comparison with schizophrenic general psychiatric patients]. AB - BACKGROUND: The number of schizophrenic patients admitted to forensic hospitals according to section 63 of the German Criminal Code has increased continuously over the past years. Prior to admission to a forensic ward, two thirds of schizophrenic patients have been admitted to a general psychiatric institution at least once. Among other factors, forensic admission is seen as a consequence of insufficient pretreatment in general psychiatry. This study aims to identify differences regarding the history of treatment of forensic and general psychiatric patients diagnosed with schizophrenia. METHOD: The matched samples include 72 male patients from forensic wards and 72 male patients from general psychiatry diagnosed with schizophrenia. The history of psychiatric treatment was reconstructed by interviewing the patients as well as the outpatient psychiatrists and by analyzing these patients' medical records. RESULTS: Both groups showed similar risk factors, however, forensic patients had a higher number of previous convictions and were convicted more often for violent offences. Furthermore, the data indicate that forensic patients are less integrated into psychiatric care and showed a lower rate of treatment compliance prior to admission to a forensic ward. CONCLUSIONS: The results provide support for the arrangement of an intensive outpatient aftercare, especially for schizophrenic patients with comorbid substance abuse disorders and previous convictions for violent offences. PMID- 22215218 TI - [Cranioplasty after supratentorial decompressive craniectomy: when is the optimal timing]. AB - BACKGROUND: The purpose of this study was to evaluate the outcome and complication rates of different cranioplastic procedures. PATIENTS AND METHODS: This study retrospectively reviewed 242 consecutive patients who underwent cranioplasty. The indications for craniectomy, the timing and materials employed for the cranial repair procedures were analysed in all patients as well as their early and long-term results. The immediate patient's outcome after cranioplasty was assessed by reviewing medical records and the late outcome was evaluated with a telephone questionnaire. The patients were divided into three groups depending on the timing of cranioplasty [ultra early group (until 6 weeks), early group (7 12 weeks) and delayed group (after 13 weeks following craniectomy)]. RESULTS: The ultra early cranioplasty in the form of reimplantation of the patient's own skull flap led to a rapid improvement of the patient's neurological function and late outcome. The analysis of the registered postoperative complications revealed that there were no significant differences between the groups examined. CONCLUSION: This study found that ultra early cranioplasty by reimplanting the patient's own previously removed and frozen skull bone was a safe and successful strategy. PMID- 22215219 TI - [Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids]. PMID- 22215220 TI - [Schizophrenia: more than just a "disturbance of the integrity of the self"]. PMID- 22215221 TI - [Service structure and cooperation in mental health care]. AB - BACKGROUND: This study assesses exemplarily the regional structure of mental health services and the practice of cooperation of mental health service providers. The aim is to identify starting points for improving mental health care. METHOD: (1) Mapping of mental health services in four exemplary regions (urban/rural, East/West Germany) using the European Service Mapping Schedule. (2) Analysis of the practice of cooperation in mental health care using focus groups and a postal survey of psychiatrists and psychotherapists working in private practice. RESULTS: All surveyed regions have a well-developed and complex service system available. Cooperation in mental health care takes place in flexible networks rather than in fixed relationships. An explicit concept of cooperation does not exist. Time and resources promote cooperation. Psychiatrists and psychotherapists working in outpatient care mainly cooperate among themselves and rarely on an interdisciplinary basis. In particular psychotherapists are usually not part of cooperation networks. CONCLUSIONS: Improvements in mental health care are more likely to be achieved through improving cooperation rather than just developing additional services. Starting points for improvements include-beyond the increase of resources for cooperation - the training of medical students and psychiatrists in cooperation practice, reimbursement of cooperation and coordination and the implementation of systematic coordination of service networks. PMID- 22215222 TI - [Persons held in preventive detention (S 66 Criminal Code): characteristics of offenders and the impact on prospects for successful completion of therapy]. AB - With its verdict in May 2011 the German Federal Constitutional Court declared the current law for preventive detention unconstitutional and obliged the legislative bodies to undertake a freedom- and treatment-oriented reform. Psychiatrists and psychotherapists are bound to provide therapeutic concepts. Currently there is a lack of information on the intended clientele. In our study we examined 26 persons serving preventive detention, 32 regular prisoners and 29 non-delinquent probands. The groups were matched according to age and intelligence. We gathered sociodemographic data, criminal records and conducted the tests SCID I, SCID II und PCL-R, K-FAF and BIS-11 to obtain diagnoses and characteristics. Based on this information, the HCR-20 and GAF were performed. In comparison to regular prisoners and non-delinquents, the group of those serving preventive detention is characterised by medium to advanced age, antisociality, psychopathy, substance abuse or addiction, aggressivity, a strong criminal record, years of imprisonment, insufficient educational and vocational training and a high risk of recidivism. In our examination of persons serving preventive detention, we demonstrate that this clientele is a group of recidivists difficult to treat. The current laws and a lack of early intervention programs have prevented and delayed their timely and possibly successful treatment. From a psychiatric point of view, there is a strong need for new therapeutic concepts to meet this challenge. PMID- 22215223 TI - [Obituary for Eberhard Lungershausen (15 March 1931 to 21 June 2011)]. PMID- 22215225 TI - Cigarette smoking and white matter microstructure. AB - RATIONALE: Diffusion tensor imaging has been used before in testing associations between cigarette smoking and white matter integrity, with inconsistent results. Published reports indicate higher fractional anisotropy (FA, a measure of linear water diffusion) in some brain regions and lower FA in others in adult smokers compared to nonsmokers. Adolescent smokers exhibited elevated FA at several brain regions and a positive correlation of FA in the genu corpus callosum with exposure to smoking (pack-years). OBJECTIVE: To help resolve prior discrepancies, we studied adults, sampling multiple brain regions, and testing for relationships to clinical features of nicotine dependence and exposure to smoking. METHODS: Brain MRI scans (1.5 T) were acquired, and FA and apparent diffusion coefficient (ADC, a measure of random diffusion) were assayed in corpus callosum and prefrontal white matter, corona radiata, internal capsule, cingulum bundle, and hippocampal perforant fibers in 18 smokers (33.7 +/- 7.9 years of age) and 18 age and gender-matched nonsmokers. RESULTS: ADC showed no group difference, but smokers had higher (4.3-21.1%) FA than nonsmokers. The differences were significant in right prefrontal white matter, cingulum, and genu corpus callosum. FA in several regions was negatively correlated with nicotine dependence or cigarettes/day. CONCLUSIONS: Combined with earlier findings, these results suggest a model of changing trajectories whereby FA is higher with tobacco exposure during adolescence and declines with continued smoking in adulthood. This notion is supported by the observation that, at multiple sampling sites, participants who had started smoking earlier in life had higher FA than those who had started later. PMID- 22215226 TI - Acute bacterial prostatitis: how to prevent and manage chronic infection? AB - We conducted a retrospective analysis of acute bacterial prostatitis (ABP) to evaluate the factors of progressing to chronic infection and chronic pelvic pain syndrome IIIa (CPPS IIIa) from ABP. The clinical records of 480 cases compatible with a confirmed diagnosis of ABP from five urological centers between 2001 and 2010 were reviewed. We defined chronic infection (CI) as a progression to chronic bacterial prostatitis (II), epididymo-orchitis, and showing persistent pyuria and bacteriuria after treatment of ABP in admission periods when followed up at 3 months or more. Results were analyzed according to two categories: category I, developed to CI (group A, n = 49) versus recovered without CI or CPPS IIIa (group C, n = 385); and category II, developed to CPPS IIIa (group B, n = 46) versus recovered without CI or CPPS IIIa (group C, n = 385). Of the 480 ABP patients, 10.2% (49/480) progressed to CI and 9.6% (46/480) progressed to CPPS IIIa. The frequency of CI was 11.3% (49/434) and that of CPPS IIIa was 10.7% (46/431). The factors that affected progression to CI were diabetes, prior manipulation, not doing cystostomy, and urethral catheterization (P < 0.05). The factors that affected progression to CPPS IIIa were the same as CI, but prostate volume was included in the CPPS IIIa group (P < 0.05). The identification and characterization of these factors may accelerate the development of preventive, diagnostic, and therapeutic strategies for the treatment of CI and CPPS IIIa from ABP. PMID- 22215227 TI - Antibodies against mumps virus component proteins. AB - The neutralization (NT) test is regarded as the most reliable method for detection of protective antibodies, but is labor-intensive and time consuming. Enzyme-linked immunosorbent assay (EIA) is frequently used in sero epidemiological studies because of its simplicity and ease of use. In this study, immunofluorescent (IF) antibodies against nucleocapsid (N), fusion (F), and hemagglutinin-neuraminidase (HN) proteins were investigated in comparison with NT and EIA antibodies. The antibody against N protein was dominant in serum samples obtained from patients with a previous history of mumps infection. Titers of antibodies against F and HN proteins were very low. Many serum samples were positive for EIA but negative for NT, and no significant correlation was noted between NT and EIA antibodies. Among the three component proteins, correlation of EIA and IF antibodies with N protein was relatively good. After vaccination with mumps vaccine, EIA positivity was closely related to the IF antibodies against N protein, and after vaccination NT-positive sera became positive for IF antibodies against F and HN proteins. IF antibodies against F and HN proteins were considered to have a strong association with NT antibodies, and those against N protein were considered to have a strong association with EIA antibodies. PMID- 22215228 TI - In vivo efficacy and pharmacokinetics of biapenem in a murine model of ventilator associated pneumonia with Pseudomonas aeruginosa. AB - Biapenem (BIPM) has high bactericidal activity against Pseudomonas aeruginosa and similar activity in vitro as meropenem (MEPM). We used a murine model to examine the efficacy of biapenem against ventilator-associated pneumonia (VAP) caused by P. aeruginosa. Mice were treated by intraperitoneal injection with 100 mg/kg BIPM or MEPM every 12 h beginning 12 h after inoculation with P. aeruginosa. Survival was evaluated for 7 days, and 24 h after infection, lung histopathology was analyzed and the number of viable bacteria in the lungs and blood was counted. In addition, the pharmacokinetics of BIPM and MEPM were analyzed after the initial treatment. BIPM and MEPM significantly prolonged survival compared to control (P < 0.05). The lungs of mice treated with BIPM or MEPM had significantly fewer viable bacteria (3.54 +/- 0.28 vs. 3.77 +/- 0.14 log(10) CFU/ml) than in the lungs of control mice (6.65 +/- 0.57 log(10) CFU/ml) (P < 0.05). Furthermore, viable bacteria were not detected in the blood of mice treated with BIPM or MEPM (control 2.85 +/- 0.85 log(10) CFU/ml) (P < 0.05). Histopathological examination of lung specimens indicated that BIPM and MEPM prevent the progression of lung inflammation, including alveolar neutrophil infiltration and hemorrhage. The % time above MIC for BIPM and MEPM was 15.4% and 18.3% in plasma and 19.8% and 19.8% in lungs, respectively. These results show that BIPM and MEPM significantly prolongs survival and reduces the number of viable bacteria in a murine model of VAP caused by P. aeruginosa. Therefore, BIPM might be a potent and effective treatment for VAP caused by this bacterium. PMID- 22215229 TI - A bioinspired self assembled dimeric porphyrin pocket that binds electron accepting ligands. AB - A binding pocket consisting of two zinc porphyrins self assembled by Watson-Crick base pairing is presented. The porphyrin binding pocket is located in the confined environment of a lipid membrane whereas the DNA is located in the water phase. Bidentate electron accepting ligands are shown to coordinate in-between the two porphyrins. PMID- 22215230 TI - Resource limitation and the role of a hemiparasite on a restored prairie. AB - Hemiparasitic plants tend to thrive in and significantly affect plant communities in low-nutrient, high-light environments. Hemiparasites are assumed to be weak competitors for light but strong parasites, leading to the prediction that effects on hosts and communities should be a function of resource supply. We investigated the effects of light and mineral nutrients on hemiparasite-host relations in two experiments. Removal of the hemiparasite, addition of fertilizer, and full sun significantly increased total aboveground dry mass in small plots on a restored tallgrass prairie. After 3 years, removal of Pedicularis canadensis almost doubled the mass of grasses and had smaller effects on forb species, but the impact of the parasite was independent of resource level. Fertilizer increased grass growth only in full sun, increased non-legume forb growth only when shade was applied, and tended to depress legume growth when shaded. Light manipulation did not affect the hemiparasite across 4 years of manipulation but fertilizer increased P. canadensis shoot mass. A complementary greenhouse experiment with Andropogon gerardii as host produced qualitatively similar effects and showed that shade reduced root growth of both the host and the parasite. These results do not support common assumptions regarding hemiparasite-host relations under field conditions but indicate that a small hemiparasite can significantly affect prairie productivity regardless of resource supply. PMID- 22215231 TI - New insights into the role of plant formins: regulating the organization of the actin and microtubule cytoskeleton. AB - Formins are well-known as important regulators participating in the organization of the actin cytoskeleton in organisms. For many years in the past, research on plant formins is more difficult than that in other eukaryotic formins and is limited to class I formins. Nevertheless, positive progress has been made in plant formin research recently, especially the investigations on class II formins. New functions of plant formins are identified gradually, such as regulating cell division and affecting diffuse cell expansion. More significantly, plant formins are also verified to interact with microtubules in vivo and in vitro. They may probably function as linking proteins between microtubules and microfilaments to participate in various cellular processes. PMID- 22215232 TI - Growth control by cell wall pectins. AB - Plant cell growth is controlled by the balance between turgor pressure and the extensibility of the cell wall. Several distinct classes of wall polysaccharides and their interactions contribute to the architecture and the emergent features of the wall. As a result, remarkable tensile strength is achieved without relinquishing extensibility. The control of growth and development does not only require a precisely regulated biosynthesis of cell wall components, but also constant remodeling and modification after deposition of the polymers. This is especially evident given the fact that wall deposition and cell expansion are largely uncoupled. Pectins form a functionally and structurally diverse class of galacturonic acid-rich polysaccharides which can undergo abundant modification with a concomitant change in physicochemical properties. This review focuses on homogalacturonan demethylesterification catalyzed by the ubiquitous enzyme pectin methylesterase (PME) as a growth control module. Special attention is drawn to the recently discovered role of this process in primordial development in the shoot apical meristem. PMID- 22215233 TI - Contribution of CSF cytology in the diagnostic work-up of breast cancer patients with neurological symptoms: a retrospective analysis over two decades. AB - The aim of this study was to evaluate the contribution of cytological analysis of cerebrospinal fluid (CSF) in the diagnostic work-up of breast cancer patients who present with neurological symptoms suspected for central nervous system (CNS) metastases. In the period 1989-2009, a total of 81 patients with breast cancer underwent CSF cytological examination. Relevant tumour characteristics, clinical presentation and radiological findings were scored. The CSF cytological diagnosis was classified according to the 1996 NCI-sponsored conference approach as malignant, suspicious for malignancy, atypical, benign or inadequate. During the course of 20 years, 145 CSF cytological examinations were performed. Relatively common neurological symptoms resulting in cytological CSF examination were headache (n = 25), nausea and vomiting (n = 19), sensory disturbances (n = 16), and cranial nerve dysfunction (n = 16). Of these, headache and nausea/vomiting were most often associated with malignant cells in the CSF (CSF(+)) (in 48 and 53% of the cases, respectively). The 4 patients with both headache and confusion/altered mental status all had CSF(+). In 10 patients, CSF(+) was found despite the absence of radiological evidence for metastasis in/around the CNS. In our series, repeated CSF analysis appeared to have limited additional value, and CSF(+) was strongly correlated with shorter survival. A substantial number of patients with neurological symptoms but without radiological abnormalities can have CSF(+). In our series, the additional value of repeated cytological examination of CSF was limited. Our study underscores the value of CSF cytology as a tool for the unequivocal diagnosis of metastatic spread of breast cancer to the CNS, and confirms that CSF(+) is a strong predictor of poor survival. PMID- 22215234 TI - Si-free enolate Claisen rearrangements of enamido substrates. AB - alpha-Alkyl beta-amino esters are available in high diastereoselectivity through a silicon-free Claisen enolate [3,3]-sigmatropic rearrangement of enamide esters. Optimisation studies have probed the crucial role of the initial enolisation and the nature of the enamide N-centre. The demonstration of chirality transfer and the formation of beta-proline systems, is also presented. PMID- 22215235 TI - Diagnosis and treatment of upper limb apraxia. AB - Upper limb apraxia, a disorder of higher motor cognition, is a common consequence of left-hemispheric stroke. Contrary to common assumption, apraxic deficits not only manifest themselves during clinical testing but also have delirious effects on the patients' everyday life and rehabilitation. Thus, a reliable diagnosis and efficient treatment of upper limb apraxia is important to improve the patients' prognosis after stroke. Nevertheless, to date, upper limb apraxia is still an underdiagnosed and ill-treated entity. Based on a systematic literature search, this review summarizes the current tools of diagnosis and treatment strategies for upper limb apraxia. It furthermore provides clinicians with graded recommendations. In particular, a short screening test for apraxia, and a more comprehensive diagnostic apraxia test for clinical use are recommended. Although currently only a few randomized controlled studies investigate the efficacy of different apraxia treatments, the gesture training suggested by Smania and colleagues can be recommended for the therapy of apraxia, the effects of which were shown to extend to activities of daily living and to persist for at least 2 months after completion of the training. This review aims at directing the reader's attention to the ecological relevance of apraxia. Moreover, it provides clinicians with appropriate tools for the reliable diagnosis and effective treatment of apraxia. Nevertheless, this review also highlights the need for further research into how to improve diagnosis of apraxia based on neuropsychological models and to develop new therapeutic strategies. PMID- 22215236 TI - Detection of clinical and subclinical retinal abnormalities in neurosarcoidosis with optical coherence tomography. AB - The aim of this work was to determine if neurosarcoidosis (NS) patients exhibit quantitative and/or qualitative in vivo evidence of retinal abnormalities on optical coherence tomography (OCT). Retinal imaging was performed using spectral domain Cirrus HD-OCT in 20 NS patients (40 eyes) and 24 age-matched healthy controls (48 eyes). Study participants also underwent magnetic resonance imaging of the brain and spine, cerebrospinal fluid (CSF) analysis, and detailed neurological and ophthalmological evaluation. Quantitative OCT abnormalities of average macular thickness (AMT), peri-papillary retinal nerve fiber layer (RNFL) thickness, or both, were detectable in 60% of NS patients. Of NS patients with ocular symptomatology, 75% demonstrated quantitative OCT abnormalities, while only 25% had detectable abnormalities on detailed ophthalmological assessment. Furthermore, 33% of NS patients without ocular symptoms had quantitative OCT changes, while only 8% had abnormal ophthalmologic examination. RNFL and macular thinning and swelling were significant in the NS cohort compared to healthy controls (variance ratio testing; RNFL: p = 0.02, AMT: p = 0.006). AMT also correlated inversely with disease duration (r (s) = -0.65, p = 0.002). Patient proportions with OCT abnormalities did not differ according to NS subtype (myelopathic, meningeal, or encephalitic NS), CSF findings, or immunotherapy exposure. No qualitative OCT abnormalities were detected. Retinal abnormalities occur in all NS subtypes, and may be clinical or subclinical. Our findings suggest OCT may enable greater detection of retinal abnormalities in NS than ophthalmological assessment alone, and have implications for the assessment of ocular involvement in NS, and sarcoidosis in general. Longitudinal NS studies utilizing OCT are warranted. PMID- 22215237 TI - Obstructive sleep apnea linked to wake-up strokes. AB - Obstructive sleep apnea (OSA) has been considered as one of the risk factors for ischemic stroke, but the impact of OSA on wake-up stroke (WUS) is not well studied. We aimed to determine the relationship between OSA and WUS. We prospectively recruited 71 patients with mild to moderate ischemic stroke during hospitalization. Patients were classified into WUS and non-WUS. A full-night sleep respiratory study was performed between 3 and 14 days after stroke onset. Demographic data, sleep respiratory data, heart rate variability, stroke risk factors, stroke classification and sleep-related scales were recorded. We compared the differences in the variables between the two groups and determined the independent variables associated with WUS. Of the 71 patients, 26 (36.6%) had WUS. The patients with WUS had a significantly higher apnea-hypopnea index (23.1 +/- 19.4 vs. 12.5 +/- 11.9, p = 0.016), obstructive apnea index (7.8 +/- 9.7 vs. 3.0 +/- 4.0, p = 0.021) and lower mean blood oxygen saturation (95.1 +/- 1.5 vs. 95.8 +/- 1.3, p = 0.046) than the non-WUS patients. There were no significant differences in demographic data, stroke risk factors, sleep-related scales or heart rate variability. Logistic regression revealed that severe sleep-disordered breathing (apnea-hypopnea index >=30) was the only independent variable associated with WUS (OR 6.065, 95% CI 1.451-25.350; p = 0.014). We conclude that in patients with mild to moderate ischemic stroke, OSA is the only risk factor associated with WUS, which cannot be distinguished clinically from non-WUS. PMID- 22215238 TI - Inferior vestibular neuritis. AB - Vestibular neuritis (VN) mostly involves the superior portion of the vestibular nerve and labyrinth. This study aimed to describe the clinical features of VN involving the inferior vestibular labyrinth and its afferents only. Of the 703 patients with a diagnosis of VN or labyrinthitis at Seoul National University Bundang Hospital from 2004 to 2010, we retrospectively recruited 9 patients (6 women, age range 15-75) with a diagnosis of isolated inferior VN. Diagnosis of isolated inferior VN was based on torsional downbeating spontaneous nystagmus, abnormal head-impulse test (HIT) for the posterior semicircular canal (PC), and abnormal cervical vestibular-evoked myogenic potentials (VEMP) in the presence of normally functioning horizontal and anterior semicircular canals, as determined by normal HIT and bithermal caloric tests. All patients presented with acute vertigo with nausea, vomiting, and imbalance. Three patients also had tinnitus and hearing loss in the involved side. The rotation axis of torsional downbeating spontaneous nystagmus was best aligned with that of the involved PC. HIT was also positive only for the involved PC. Cervical VEMP was abnormal in seven patients, and ocular VEMP was normal in all four patients tested. Ocular torsion and subjective visual vertical tests were mostly within the normal range. Since isolated inferior VN lacks the typical findings of much more prevalent superior VN, it may be mistaken for a central vestibular disorder. Recognition of this rare disorder may help avoid unnecessary workups in patients with acute vestibulopathy. PMID- 22215239 TI - Glycine receptor antibodies are detected in progressive encephalomyelitis with rigidity and myoclonus (PERM) but not in saccadic oscillations. AB - Glycine receptor (GlyR) antibodies were recently identified in a few patients with progressive encephalomyelitis with rigidity and myoclonus (PERM); none of these patients had antibodies against glutamic acid decarboxylase (GAD). An inhibitory glycinergic transmission defect has also been implicated in the mechanism underlying saccadic oscillations, including ocular flutter or opsoclonus; GlyR antibodies have not been reported in these patients. The purpose was to determine whether GlyR antibodies are found in patients with PERM, ocular flutter syndrome (OFS), and opsoclonus-myoclonus syndrome (OMS). GlyR antibodies were first measured in archived sera and CSF from five patients, including one patient with GAD antibody-positive PERM, two patients with OFS, and two patients with OMS. GlyR antibodies were also measured in archived sera from nine other adult patients with OMS. GlyR antibodies and GAD antibodies were both found at high titers in the serum and CSF of the patient with PERM, and their levels paralleled disease activity over time. GlyR antibodies were not found at significant levels in 13 patients with saccadic oscillations. GlyR and GAD antibodies can co-exist in PERM and follow the clinical course. Although saccadic oscillations are a feature of this condition, GlyR antibodies are not commonly found in patients with isolated saccadic oscillations. PMID- 22215240 TI - Sciatic endometriosis presenting as periodic (catamenial) sciatic radiculopathy. PMID- 22215242 TI - The concept of a near-field Raman probe. AB - This article considers the possibility to use tips, which are functionalised by Raman active molecules, as new Raman probes for near-field optics in such a way that the Raman spectrum can be recorded of such a tip. If the Raman spectrum of the probe molecules is sensitive to their immediate environment, the probe can be used to map a surface by its local influence on the Raman spectrum of the probe. This new concept may be very promising for the investigation of specific interactions at the nanoscale by an optical response. Examples of the sensitivity of such a probe to the local environment are presented as a basis for further development of such a probe. PMID- 22215241 TI - When is neuromyelitis optica diagnosed after disease onset? AB - To diagnose neuromyelitis optica (NMO), the 2006 NMO diagnostic criteria is commonly used. However, adequate studies about the time course of NMO according to the criteria have been lacking. The aim of the study was to identify the interval between disease onset and diagnosis of NMO, as well as the clinical characteristics and time course, according to the 2006 NMO diagnostic criteria in Japanese patients with NMO. Clinical progression and time course of 43 Japanese patients with NMO who fulfilled the 2006 NMO diagnostic criteria with mean disease duration of 14.2 years were investigated retrospectively. The initial inflammatory event was myelitis in 44.2% (long extensive transverse myelitis [LETM] in 14.3%), optic neuritis in 41.9%, and concurrent myelitis and optic neuritis in 9.3% of the patients. The presence of LETM and anti-aquaporin-4 antibody seropositivity by the end of the observation period was found in 85.7 and 93.0% of the patients, respectively. Among the patients whose medical information were sufficiently available, the median intervals between NMO onset and the time until development of both optic neuritis and myelitis, LETM, or fulfillment of the 2006 NMO criteria were 16.5, 35.1, and 27.8 months, respectively. The development of diagnostic method at an early stage of NMO may be needed in order to initiate early treatment. PMID- 22215243 TI - Laparoscopic paraesophageal hernia repair: defining long-term clinical and anatomic outcomes. AB - OBJECTIVE: We recently reported in a multi-institutional, randomized study of laparoscopic paraesophageal hernia repair (LPEHR) that the anatomic recurrence rate at a median of approximately 5 years was >50%. This study focuses exclusively on the symptomatic response to LPEHR and its relationship with the development of a recurrent hernia. METHODS: During 2002 to 2005, 108 patients underwent LPHER with or without biologic mesh. A standardized symptom severity questionnaire, SF-36 health survey, and upper gastrointestinal series were performed at baseline, 6 months, and during 2008-2009. RESULTS: Of 108 patients, 72 (average age of 68 +/- 10 years) underwent clinical assessment, and 60 of them also had radiologic studies at a median follow-up of 58 (40-78) months. Radiographic recurrence (>= 20 mm) was 14% at 6 months and 57% at the time of follow-up, and the average recurrence size was 40 +/- 10 mm. All symptoms were significantly improved at long-term follow-up and, with the exception of heartburn, were unaffected by the presence or size of the recurrence. Two patients (3%) with recurrent symptoms related to their hernia underwent reoperation. CONCLUSION: Despite frequent radiologic recurrences after LPEHR, symptoms remain well controlled, patient satisfaction is high, and the need for reoperation is low. PMID- 22215244 TI - What is the duct of Luschka?--A systematic review. AB - BACKGROUND: Subvesical bile ducts (frequently termed incorrectly "ducts of Luschka") have gained increased clinical recognition in the era of laparoscopic cholecystectomy. Though cited frequently and discussed in the literature, the original description by Hubert von Luschka and many anatomic details of these subvesical bile ducts remain ill-defined. STUDY DESIGN: A systematic literature search was conducted including publications that described either radiographic features or gross anatomy of bile ducts in close contact with the gallbladder fossa. Of 2,545 publications identified from electronic databases, 116 met inclusion criteria. RESULTS: Of 116 articles, 13 incorporated a prevalence study design. These 13 articles investigated 3,996 patients, of whom 156 were diagnosed with a subvesical duct for a prevalence of 4%. The prevalence in articles focusing on subvesical bile ducts was greater than in articles studying biliary anatomy in general (10% versus 3%; p<0.0001). Furthermore, of 116 articles, 54 provided detailed anatomic information identifying 238 subvesical ducts, most of which represented accessory ducts. The origin and drainage of these ducts were limited primarily to the right lobe of the liver, but great variation was seen. The mean diameter of the subvesical ducts was 2 mm (range 1-18 mm). CONCLUSIONS: The term "ducts of Luschka" should be abandoned and should be replaced by the correct term of "subvesical bile duct". The variability in anatomic location of subvesical bile ducts puts them at risk during hepato-biliary operations. A better understanding of ductal anatomy is elemental in preventing and managing operative injury to the subvesical ducts. This review debunks common myths about the so-called "duct of Luschka" and offers a systematic overview of the anatomy of the subvesical bile duct. PMID- 22215245 TI - Differences of the lymphatic distribution and surgical outcomes between remnant gastric cancers and primary proximal gastric cancers. AB - BACKGROUND: Although remnant gastric cancer (RGC) following distal gastrectomy is located in the proximal stomach, little is known about the differences of the lymphatic distribution and surgical outcomes between RGC and primary proximal gastric cancer (PGC). METHODS: Between 1997 and 2008, 1,149 patients underwent gastrectomy for gastric cancer. Of these, 33 (2.9%) RGC patients and 207 (18.5%) PGC patients were treated at our department. We reviewed their hospital records retrospectively. RESULTS: Compared with the PGC patients, those with RGC had a slightly higher age at onset (p=0.09), higher incidence of undifferentiated cancer (p=0.06), higher incidence of vascular invasion (p=0.09), and higher incidence of T4 (p=0.07). Gastrectomy for RGC involved greater blood loss (p<0.005), longer surgical duration (p=0.01), combined resection, and high incidence of complications. However, the survival rate for RGC patients was similar to that for PGC patients (p=0.67). 2) Patients with RGC had a different pattern of lymph node metastasis compared with that in PGC. Particularly in advanced RGC with pT2-T4 tumors, RGC frequently demonstrated jejunal mesentery lymph node metastases (RGC vs. PGC, 35% vs. 0%) and splenic hilar lymph node metastases (RGC vs. PGC, 17% vs. 10%). The jejunal mesentery lymph node metastases were detected only following Billroth II reconstruction (Billroth I vs. Billroth II, 0% vs. 67%). CONCLUSION: Although the clinical behaviors of the two gastric cancers were different, the survival rates were similar. The pattern of metastasis indicates that the jejunal mesentery and splenic hilar lymph nodes should be specifically targeted for en bloc resection during complete gastrectomy in RGC. PMID- 22215246 TI - Analytical methods for tracing plant hormones. AB - Plant hormones play important roles in regulating numerous aspects of plant growth, development, and response to stress. In the past decade, more analytical methods for the accurate identification and quantitative determination of trace plant hormones have been developed to better our understanding of the molecular mechanisms of plant hormones. As sample preparation is often the bottleneck in analysis of plant hormones in biological samples, this review firstly discusses sample preparation techniques after a brief introduction to the classes, roles, and methods used in the analysis of plant hormones. The analytical methods, especially chromatographic techniques and immuno-based methods, are reviewed in detail, and their corresponding advantages, limitations, applications, and prospects are also discussed. This review mainly covers reports published from 2000 to the present on methods for the analysis of plant hormones. PMID- 22215249 TI - Comparison of two methods of reciprocal recurrent selection in maize (Zea mays L.). AB - Reciprocal recurrent selection (RRS) was proposed for simultaneously improving two populations and their cross. A modification of the classical full-sib RRS (FS RRS) was proposed in which the performance of full-sibs and S(2) families is combined in a selection index (FS-S(2)-RRS). The Mediterranean corn borer (MCB) is the main corn borer species in the Mediterranean and adjacent areas and produces important yield losses. We started two RRS programs (FS-RRS and FS-S(2) RRS) from the same maize population in which the selection criterion was grain yield under artificial infestation with MCB eggs. Original populations, two cycles of selection derived from them by both RRS methods, and population crosses were evaluated under MCB attack and under insecticide treatment in three different environments. The objective was to compare the efficiency of the FS-RRS and the FS-S(2)-RRS methods for improving grain yield. We found that the FS-S(2) RRS method was successful for improving the yield of the population cross under optimum conditions (the regression coefficient over cycles was b = 0.87** Mg ha( 1) cycle(-1)) without losing yield under high pressure of MCB attack (b = 0.07). On the contrary, FS-RRS failed to improve the yield of the population cross under optimum conditions (b = 0.65) and tended to decrease the yield under high levels of MCB attack (b = -0.26). We conclude that for developing high yielding and stable varieties, FS-S(2)-RRS is more efficient than the classical FS-RRS method. PMID- 22215248 TI - Genetic dissection of fruit quality traits in the octoploid cultivated strawberry highlights the role of homoeo-QTL in their control. AB - Fruit quality traits are major breeding targets in the Rosaceae. Several of the major Rosaceae species are current or ancient polyploids. To dissect the inheritance of fruit quality traits in polyploid fleshy fruit species, we used a cultivated strawberry segregating population comprising a 213 full-sibling F1 progeny from a cross between the variety 'Capitola' and the genotype 'CF1116'. We previously developed the most comprehensive strawberry linkage map, which displays seven homoeology groups (HG), including each four homoeology linkage groups (Genetics 179:2045-2060, 2008). The map was used to identify quantitative trait loci (QTL) for 19 fruit traits related to fruit development, texture, colour, anthocyanin, sugar and organic acid contents. Analyses were carried out over two or three successive years on field-grown plants. QTL were detected for all the analysed traits. Because strawberry is an octopolyploid species, QTL controlling a given trait and located at orthologous positions on different homoeologous linkage groups within one HG are considered as homoeo-QTL. We found that, for various traits, about one-fourth of QTL were putative homoeo-QTL and were localised on two linkage groups. Several homoeo-QTL could be detected the same year, suggesting that several copies of the gene underlying the QTL are functional. The detection of some other homoeo-QTL was year-dependent. Therefore, changes in allelic expression could take place in response to environmental changes. We believe that, in strawberry as in other polyploid fruit species, the mechanisms unravelled in the present study may play a crucial role in the variations of fruit quality. PMID- 22215250 TI - Computer-aided diagnosis for detection of lacunar infarcts on MR images: ROC analysis of radiologists' performance. AB - The purpose of this study was to retrospectively evaluate radiologist performance in detection of lacunar infarcts on T1- and T2-weighted images, without and with the use of a computer-aided diagnosis (CAD) scheme. Thirty T1-weighted and 30 T2 weighted MR images obtained from 30 patients were used for assessing observer performance. These images were acquired using the fast spin-echo sequence with a 1.5-T MR imaging scanner. The group included 15 patients (age range, 48-83 years; mean age, 67.2 years; 10 men and five women) with a lacunar infarct and 15 patients (age range, 39-76 years; mean age, 64.0 years; eight men and seven women) without lacunar infarcts. Nine radiologists participated in the study. The radiologists initially interpreted the T1- and T2-weighted images without and then with the use of CAD, which indicated their confidence levels regarding the presence (or absence) of lacunar infarcts and the most likely position of a lesion on each MR scan. The observers' performance without and with the computer output was evaluated by performing receiver operating characteristic analysis. For the nine radiologists, the mean area under the best-fit binormal receiver operating characteristic curve plotted for unit square values of radiologists who interpreted the images without and with the scheme were 0.891 and 0.937, respectively. The performance of the radiologists improved significantly when they used the computer output (p=0.032). The CAD scheme has potential to improve the accuracy of radiologists' performance in detection of lacunar infarcts. PMID- 22215251 TI - Comparison of neurogenesis in the dentate gyrus between the adult and aged gerbil following transient global cerebral ischemia. AB - In the present study, we compared differences in cell proliferation, neuroblast differentiation and neuronal maturation in the hippocampal dentate gyrus (DG) between the adult and aged gerbil induced by 5 min of transient global cerebral ischemia using Ki-67 and BrdU (markers for cell proliferation), doublecortin (DCX, a marker for neuroblast differentiation) and neuronal nuclei (NeuN, a marker for mature neuron). The number of Ki-67-immunoreactive (+) cells in the DG of both the groups peaked 7 days after ischemia/reperfusion (I/R). However, the number in the aged DG was 40.6 +/- 1.8% of that in the adult DG. Thereafter, the number decreased with time. After ischemic damage, DCX immunoreactivity and its protein level in the adult and aged DG peaked at 10 and 15 days post-ischemia, respectively. However, DCX immunoreactivity and its protein levels in the aged DG were much lower than those in the adult. DCX immunoreactivity and its protein level in the aged DG were 11.1 +/- 0.6% and 34.4 +/- 2.1% of the adult DG, respectively. In addition, the number of Ki-67+ cells and DCX immunoreactivity in both groups were similar to those in the sham at 60 days postischemia. At 30 days post-ischemia, the number of BrdU+ cells and BrdU+/NeuN+ cells in the adult-group were much higher (281.2 +/- 23.4% and 126.4 +/- 7.4%, respectively) than the aged group (35.6 +/- 6.8% and 79.5 +/- 6.1%, respectively). These results suggest that the ability of neurogenesis in the ischemic aged DG is much lower than that in the ischemic adult DG. PMID- 22215252 TI - The construction of glucose biosensor based on platinum nanoclusters-multiwalled carbon nanotubes nanocomposites. AB - One-step synthesis method was proposed to obtain the nanocomposites of platinum nanoclusters and multiwalled carbon nanotubes (PtNCs-MWNTs), which were used as a novel immobilization matrix for the enzyme to fabricate glucose biosensor. The fabrication process of the biosensor was characterized by cyclic voltammetry, electrochemical impedance spectroscopy, atomic force microscopy and scanning electron microscope. Due to the favorable characteristic of PtNCs-MWNTs nanocomposites, the biosensor exhibited good characteristics, such as wide linear range (3.0 MUM-12.1 mM), low detection limit (1.0 MUM), high sensitivity (12.8 MUA mM-1), rapid response time (within 6 s). The apparent Michaelis-Menten constant (K(app)(m)) is 2.1 mM. The performance of the resulting biosensor is more prominent than that of most of the reported glucose biosensors. Furthermore, it was demonstrated that this biosensor can be used for the assay of glucose in human serum samples. PMID- 22215253 TI - Characterization of xyn10J, a novel family 10 xylanase from a compost metagenomic library. AB - A gene encoding an extracellular xylanase was cloned from a compost metagenomic library. The xylanase gene, xyn10J, was 1,137 bp in length and was predicted to encode a protein of 378 amino acid residues with a putative signal peptide of 27 amino acid residues. The molecular mass of the mature Xyn10J was calculated to be 39,882 Da with a pI of 6.09. Xyn10J had a motif GVKVHFTEMDI characteristic of most members of glycosyl hydrolase family 10. The amino acid sequence of Xyn10J showed 60.0% identity to that of XynH, a xylanase from an uncultured soil bacterium and 55% identity to XylC of Cellvibrio mixtus. Site-directed mutagenesis of the expected active site based on the sequence analysis indicated that an aspartic acid residue (Asp207), in addition to the identified catalytic residues Glu165 and Glu270, plays a crucial role for the catalytic activity. The purified Xyn10J had a mass of about 40 kDa and was optimally active at pH 7.0 and 40 degrees C. Xyn10J hydrolyzed beechwood xylan > birchwood xylan > oat spelt xylan > arabinoxylan. Xyn10J hydrolyzed xylotetraose and xylohexaose exclusively to xylobiose, xylopentaose, and xylotriose mainly to xylobiose with transglycosylation activity. The saccharification of reed (Phragmites communis) powder by commercial enzymes was significantly increased by the addition of a small amount of Xyn10J to the commercial preparation. Xyn10J is the first xylanase screened directly from a compost metagenomic library, and the enzyme has the potential to be used in the conversion of biomass to fermentable sugars for biofuel production. PMID- 22215254 TI - Lyophilization is suitable for storage and shipment of fresh tissue samples without altering RNA and protein levels stored at room temperature. AB - Lyophilization has been widely used for preservation, such as in food industry, pharmacy, biotechnology and tissues engineering, etc. However, there is no report on whether it could affect stability of RNA and protein levels in biological tissue samples. Herein we show that lyophilization can be used for storage of biological tissue samples without loss of bioactivities even stored at room temperature for 7-14 days. To address this issue, C57BL mouse tissues were prepared and dried by lyophilization and a baking method, respectively, followed by examination of morphological structure and total proteins by SDS-PAGE as well as gelatin zymography. Subsequently, the stability of RNAs and proteins, which were lyophilized and stored at room temperature (23 degrees C) for 14 days was further examined by RT-PCR, SDS-PAGE and western blot. Results demonstrated that lyophilization did not alter total protein activities of various tissues, including enzyme activities, immunoreactivities and phosphorylation, and did not affect several RNAs in lyophilized tissues. Taken together, lyophilization may represent a valuable approach for preservation and long-distance shipment of biological samples, particularly for the international exchange of biological samples without altering their bioactivities. PMID- 22215255 TI - Comparison of different screening methods for chloroquine/hydroxychloroquine retinopathy: multifocal electroretinography, color vision, perimetry, ophthalmoscopy, and fluorescein angiography. AB - PURPOSE: To compare various screening methods for the early diagnosis of retinal dysfunction in patients with long-term chloroquine (CQ) and hydroxychloroquine (HCQ) treatment. METHODS: Twenty patients with long-term CQ/HCQ treatment underwent ophthalmologic evaluation including visual acuity testing, ophthalmoscopy, fluorescein angiography, color vision tests, visual field and multifocal electroretinography (mfERG). RESULTS: In 14 patients, retinal dysfunction was indicated in the mfERG (reduced amplitudes and/or delayed implicit times) in the parafoveal area. Towards the periphery, the function was normal or only moderately reduced. Ophthalmoscopy and fluorescein angiography identified pathologic retinal changes in seven of these 14 patients. Six patients had normal mfERG, ophthalmoscopy, and fluorescein angiography. Results of color vision and visual field testing were variable even in patients with morphologic alterations. CONCLUSION: The use of mfERG may detect retinal dysfunction in a considerable number of eyes with normal ophthalmocopy and fluorescein angiography. The higher variability of color vision and visual field testing results suggests the use of mfERG as primary screening tool for retinal dysfunction in long-term CQ/HCQ treatment. PMID- 22215256 TI - Transitioning from Stratus OCT to Cirrus OCT using Lin's concordance coefficient. PMID- 22215257 TI - Optical coherence tomography measurements with the LENTIS Mplus multifocal intraocular lens. AB - BACKGROUND: To investigate optical coherence tomography (OCT) measurements following implantation of the LENTIS Mplus multifocal IOL, compared with a control group. METHODS: OCT scans were performed on 50 eyes with the Topcon 3D OCT-1000 in two groups of patients. The first group consisted of patients following implantation of the LENTIS Mplus, and a second group of age-matched control eyes following implantation of a monofocal aspheric IOL. Macular thickness and macular volume values were compared between groups and assessment for any onscreen visible artifacts. RESULTS: OCT scans were successfully performed in all 50 eyes with no visible artifacts in either group during scan acquisitions. There were no statistically significant differences (p > 0.05) in any measured or calculated macular thickness or volume values between the two groups. CONCLUSIONS: OCT measurements with the Topcon 3D OCT-1000 is possible and free from visible artifacts in eyes which have had the LENTIS Mplus multifocal IOL implanted. Macular thickness and volume values were similar to those of an age-matched control group of monofocal aspheric IOLs. PMID- 22215258 TI - Rosiglitazone attenuates activation of human Tenon's fibroblasts induced by transforming growth factor-beta1. AB - PURPOSE: To investigate the influence of rosiglitazone on activation of human Tenon's fibroblasts (HTFs) and to access the possible mechanism. METHODS: Cultured human Tenon's fibroblasts were pretreated in two different concentrations of rosiglitazone (5 MUmol/l and 10 MUmol/l) before being stimulated with 5 ng/ml transforming growth factor beta1 (TGF-beta1). The viability and proliferation of cells were accessed by cell count kit-8 assay; Cell migration was examined by the wound closure assay; Alpha smooth muscle actin (alpha-SMA), connective tissue growth factor (CTGF) and type I collagen (COL I) transcription were detected by RT-qPCR; The expression and localization of alpha SMA protein were examined by Western-blot analysis and Immunofluorescence staining; Western-blot analysis was also used to check the expression of CTGF, COL I peroxisome proliferator-activated receptor gamma (PPAR-gamma), and phosphorylation of the signaling protein Smad2/3 RESULTS: Rosiglitazone is able to attenuate the up-regulation of alpha-SMA, CTGF, and COL I transcription, as well as affect protein expression, proliferation, and migration of cells; rosiglitazone also can increase PPAR-gamma expression and attenuate Smad2/3 phosphorylation. CONCLUSIONS: Rosiglitazone can effectively attenuate activation of HTFs induced by TGF-beta1 without obvious toxicity. The possible mechanism might be that rosiglitazone interferes with TGF-beta/Smad signaling pathway. PMID- 22215259 TI - The clinical efficacy of a topical dorzolamide in the management of cystoid macular edema in patients with retinitis pigmentosa. AB - BACKGROUND: Cystoid macular edema (CME) is one of the common complications of retinitis pigmentosa (RP), and is responsible for patient complications such as blurred and reduced visual acuity and for subsequent atrophic changes in the fovea. The objective of this work was to evaluate the clinical efficacy of a topical dorzolamide (a carbonic anhydrase inhibitor) in CME associated with RP. METHODS: Sixteen eyes of nine patients with CME secondary to typical forms of RP were included in the study. Baseline visual acuity, visual field, and optical coherence tomography (OCT) measurements were obtained for all patients. All patients used 1% dorzolamide three times daily in each eye. Patients underwent follow-up exams at 1, 3, and 6 months after treatment. The response to treatment was monitored by visual acuity and visual field measurement testing using the Humphrey Field Analyzer (HFA: the central 10-2 Program); in addition, foveal thickness was measured by OCT. Evaluation of macular sensitivity calculated by HFA as the average of 12 central points. RESULTS: Thirteen (81.3%) of 16 eyes showed a clear decrease in retinal thickness after treatment. Evaluation of macular sensitivity, calculated by HFA as the average of 12 central points (with the exception of foveal point data, showed an improvement of more than 1.0 dB in nine (56.3%) of 16 eyes. Moreover, both the mean deviation value and macular sensitivity were significantly improved. No severe side-effects were seen in any of the patients examined. CONCLUSIONS: The results demonstrated that a topical dorzolamide is effective for the treatment of CME in patients with RP, and that the positive treatment effects last for up to 6 months. PMID- 22215262 TI - The study of single anticancer peptides interacting with HeLa cell membranes by single molecule force spectroscopy. AB - To determine the effects of biophysical parameters (e.g. charge, hydrophobicity, helicity) of peptides on the mechanism of anticancer activity, we applied a single molecule technique-force spectroscopy based on atomic force microscope (AFM)-to study the interaction force at the single molecule level. The activity of the peptide and analogs against HeLa cells exhibited a strong correlation with the hydrophobicity of peptides. Our results indicated that the action mode between alpha-helical peptides and cancer cells was largely hydrophobicity dependent. PMID- 22215263 TI - Microarray profiling of diaphyseal bone of rats suffering from hypervitaminosis A. AB - Vitamin A is the only known compound that produces spontaneous fractures in rats. In an effort to resolve the molecular mechanism behind this effect, we fed young male rats high doses of vitamin A and performed microarray analysis of diaphyseal bone with and without marrow after 1 week, i.e., just before the first fractures appeared. Of the differentially expressed genes in cortical bone, including marrow, 98% were upregulated. In contrast, hypervitaminotic cortical bone without marrow showed reduced expression of 37% of differentially expressed genes. Gene ontology (GO) analysis revealed that only samples containing bone marrow were associated with a GO term, which principally represented extracellular matrix. This is consistent with the histological findings of increased endosteal/marrow osteoblast number. Fourteen genes, including Cyp26b1, which is known to be upregulated by vitamin A, were selected and verified by real-time PCR. In addition, immunohistochemical staining of bone sections confirmed that the bone specific molecule osteoadherin was upregulated. Further analysis of the major gene-expression changes revealed apparent augmented Wnt signaling in the sample containing bone marrow but reduced Wnt signaling in cortical bone. Moreover, induced expression of hypoxia-associated genes was found only in samples containing bone marrow. Together, these results highlight the importance of compartment-specific analysis of bone and corroborate previous observations of compartment-specific effects of vitamin A, with reduced activity in cortical bone but increased activity in the endosteal/marrow compartment. We specifically identify potential key osteoblast-, Wnt signaling-, and hypoxia-associated genes in the processes leading to spontaneous fractures. PMID- 22215264 TI - Alteration in P-glycoprotein functionality affects intrabrain distribution of quinidine more than brain entry-a study in rats subjected to status epilepticus by kainate. AB - This study aimed to investigate the use of quinidine microdialysis to study potential changes in brain P-glycoprotein functionality after induction of status epilepticus (SE) by kainate. Rats were infused with 10 or 20 mg/kg quinidine over 30 min or 4 h. Plasma, brain extracellular fluid (brain ECF), and end-of experiment total brain concentrations of quinidine were determined during 7 h after the start of the infusion. Effect of pretreatment with tariquidar (15 mg/kg, administered 30 min before the start of the quinidine infusion) on the brain distribution of quinidine was assessed. This approach was repeated in kainate-treated rats. Quinidine kinetics were analyzed with population modeling (NONMEM). The quinidine microdialysis assay clearly revealed differences in brain distribution upon changes in P-glycoprotein functionality by pre-administration of tariquidar, which resulted in a 7.2-fold increase in brain ECF and a 40-fold increase in total brain quinidine concentration. After kainate treatment alone, however, no difference in quinidine transport across the blood-brain barrier was found, but kainate-treated rats tended to have a lower total brain concentration but a higher brain ECF concentration of quinidine than saline-treated rats. This study did not provide evidence for the hypothesis that P-glycoprotein function at the blood-brain barrier is altered at 1 week after SE induction, but rather suggests that P-glycoprotein function might be altered at the brain parenchymal level. PMID- 22215266 TI - Utilization of hepatocellular carcinoma surveillance among American patients: a systematic review. AB - BACKGROUND: Although surveillance for hepatocellular carcinoma (HCC) is recommended in high-risk patients, several studies have suggested it is being underutilized in clinical practice. The aim of our study was to quantify utilization rates for HCC surveillance among patients with cirrhosis and summarize patterns of association between utilization rates and patient socio demographic characteristics. DATA SOURCES: We performed a systematic literature review using the Medline database from January 1990 through March 2011 and a manual search of national meeting abstracts from 2008-2010. METHODS: Two investigators independently extracted data on patient populations, study methods, and results using standardized forms. A pooled surveillance rate with 95% confidence intervals was calculated. Pre-specified subgroup analysis was performed to find correlates of surveillance utilization. RESULTS: We identified nine studies that met inclusion criteria. The pooled surveillance rate was 18.4% (95%CI 17.8%-19.0%). Surveillance rates were significantly higher among patients followed in subspecialty gastroenterology clinics compared to those followed in primary care clinics (51.7% vs. 16.9%, p < 0.001). Non-Caucasians and patients of low socioeconomic status had lower surveillance rates than their counterparts. CONCLUSIONS: Utilization rates for HCC surveillance are low, although they are significantly higher among patients followed in subspecialty clinics. Current studies fail to determine why HCC surveillance is not being performed. Future efforts should focus on identifying appropriate intervention targets to increase surveillance rates and reduce socio-demographic disparities. PMID- 22215265 TI - Impact of delaying blood pressure control in patients with Type 2 diabetes: results of a decision analysis. AB - BACKGROUND: In patients with diabetes, delays in controlling blood pressure are common, but the harms of delays have not been quantified. OBJECTIVE: To estimate the harms of delays in controlling systolic blood pressure in middle-aged adults with newly diagnosed Type 2 diabetes. DESIGN: Decision analysis using diabetes complication equations from the United Kingdom Prospective Diabetes Study (UKPDS). PARTICIPANTS: Hypothetical population of adults aged 50 to 59 years old with newly diagnosed Type 2 diabetes based on characteristics from the National Health and Nutrition Examination Surveys. INTERVENTION: Delays in lowering systolic blood pressure from 150 (uncontrolled) to 130 mmHg (controlled). MAIN MEASURES: Lifetime complication rates (amputation, congestive heart failure, end stage renal disease, ischemic heart disease, myocardial infarction, and stroke), average life expectancy and quality-adjusted life expectancy (QALE). KEY RESULTS: Compared to a lifetime of controlled blood pressure, a lifetime of uncontrolled blood pressure increased complications by 1855 events per 10,000 patients and decreased QALE by 332 days. A 1-year delay increased complications by 14 events per 10,000 patients and decreased QALE by 2 days. A 10-year delay increased complications by 428 events per 10,000 patients and decreased QALE by 145 days. Among complications, rates of stroke and myocardial infarction increased to the greatest extent due to delays. With a 20-year delay in achieving controlled blood pressure, a baseline blood pressure of 160 mmHg decreased QALE by 477 days, whereas a baseline of 140 mmHg decreased QALE by 142 days. CONCLUSIONS: Among middle-aged adults with diabetes, the harms of a 1-year delay in controlling blood pressure may be small; however, delays of ten years or more are expected to lower QALE to the same extent as smoking in patients with cardiovascular disease. PMID- 22215268 TI - Missing the tree for the forest: a case of secondary spontaneous pneumothorax. PMID- 22215267 TI - Medical students' attention to multiple risk behaviors: a standardized patient examination. AB - BACKGROUND: Risk behaviors tend to cluster, particularly among smokers, with negative health effects. To optimize patients' health and wellbeing, health care providers ideally would assess and intervene upon the multiple risks with which patients may present. OBJECTIVE: This study examined medical students' skills in assessing and treating multiple risk behaviors. DESIGN: Using a randomized experimental design, medical students' counseling interactions were evaluated with a standardized patient presenting with sexual health concerns and current tobacco use with varied problematic drinking status (alcohol-positive or alcohol negative). PARTICIPANTS: One hundred and fifty-six third-year medical students. MAIN MEASURES: Student and standardized patient completed measures evaluated student knowledge, attitudes, and clinical performance. KEY RESULTS: Overall, most students assessed tobacco use (85%); fewer assessed alcohol use (54%). Relative to the alcohol-negative case, students seeing the alcohol-positive case were less likely to assess sexually transmitted disease history (80% vs. 91%, p = 0.042), or patients' readiness to quit smoking (41% vs. 60%, p = 0.025), and endorsed greater attitudinal barriers to tobacco treatment (p = 0.030). Patient satisfaction was significantly lower for the alcohol-positive than the alcohol negative case; clinical performance ratings moderated this relationship. CONCLUSIONS: When presented with a case of multiple risks, medical students performed less effectively and received lower patient satisfaction ratings. Findings were moderated by students' overall clinical performance. Paradigm shifts are needed in medical education that emphasize assessment of multiple risks, new models of conceptualizing behavior change as a generalized process, and treatment of the whole patient for optimizing health outcomes. PMID- 22215269 TI - Number of first-contact access components required to improve preventive service receipt in primary care homes. AB - BACKGROUND: A fundamental aim of primary care redesign and the patient-centered medical home is improving access to care. Patients who report having a usual site of care and usual provider are more likely to receive preventive services, but less is known about the influence of specific components of first-contact access (e.g., availability of appointments, advice by telephone) on preventive services receipt. OBJECTIVE: To examine the relationship between number of first-contact access components and receipt of recommended preventive services. DESIGN: Secondary survey data analysis. PARTICIPANTS: Five thousand five hundred and seven insured adults who had continuity with a usual primary care physician and participated in the 2003-2006 round of the Wisconsin Longitudinal Survey. MAIN MEASURES: Using multivariable logistic regression, we calculated adjusted risk ratios, adjusted predicted probabilities and 95% confidence intervals for each preventive service. KEY RESULTS: Experiencing more first-contact access components was significantly associated with a higher rate of receiving cholesterol tests, flu shots and prostate exams but not mammography. There was variation in the number of components needed (between two and seven) to achieve a significant difference. CONCLUSIONS: Having an increasing number of first-access components in a primary care office may improve preventive services receipt, and more components may be required for those services requiring greater provider contact (e.g., prostate exam) versus those that require less (e.g., mammography). In primary care redesign, the largest gains in preventive services receipt likely will come with redesign of multiple components simultaneously. While our study is a necessary step towards broadly understanding the relationship between first contact access and preventive service receipt, other important questions remain. Certain components may drive greater improvements in the receipt of different services, and the effect of some of these components may depend on individual patient characteristics. Further research is critical for understanding redesign strategies that may optimize preventive service delivery. PMID- 22215270 TI - What patients say about their doctors online: a qualitative content analysis. AB - BACKGROUND: Doctor rating websites are a burgeoning trend, yet little is known about their content. OBJECTIVE: To explore the content of Internet reviews about primary care physicians. DESIGN: Qualitative content analysis of 712 online reviews from two rating websites. We purposively sampled reviews of 445 primary care doctors (internists and family practitioners) from four geographically dispersed U.S. urban locations. We report the major themes, and because this is a large sample, the frequencies of domains within our coding scheme. RESULTS: Most reviews (63%) were positive, recommending the physician. We found a major distinction between global reviews, "Dr. B is a great doctor." vs. specific descriptions which included interpersonal manner, "She always listens to what I have to say and answers all my questions."; technical competence "No matter who she has recommended re: MD specialists, this MD has done everything right."; and/or systems issues such as appointment and telephone access. Among specific reviews, interpersonal manner "Dr. A is so compassionate." and technical competence "He is knowledgeable, will research your case before giving you advice." comments tended to be more positive (69% and 80%, respectively), whereas systems-issues comments "Staff is so-so, less professional than should be..." were more mixed (60% positive, 40% negative). CONCLUSIONS: The majority of Internet reviews of primary care physicians are positive in nature. Our findings reaffirm that the care encounter extends beyond the patient-physician dyad; staff, access, and convenience all affect patient's reviews of physicians. In addition, negative interpersonal reviews underscore the importance of well perceived bedside manner for a successful patient-physician interaction. PMID- 22215271 TI - Cost-effectiveness of long-term outpatient buprenorphine-naloxone treatment for opioid dependence in primary care. AB - BACKGROUND: Primary care physicians with appropriate training may prescribe buprenorphine-naloxone (bup/nx) to treat opioid dependence in US office-based settings, where many patients prefer to be treated. Bup/nx is off patent but not available as a generic. OBJECTIVE: We evaluated the cost-effectiveness of long term office-based bup/nx treatment for clinically stable opioid-dependent patients compared to no treatment. DESIGN, SUBJECTS, AND INTERVENTION: A decision analytic model simulated a hypothetical cohort of clinically stable opioid dependent individuals who have already completed 6 months of office-based bup/nx treatment. Data were from a published cohort study that collected treatment retention, opioid use, and costs for this population, and published quality-of life weights. Uncertainties in estimated monthly costs and quality-of-life weights were evaluated in probabilistic sensitivity analyses, and the economic value of additional research to reduce these uncertainties was also evaluated. MAIN MEASURES: Bup/nx, provider, and patient costs in 2010 US dollars, quality adjusted life years (QALYs), and incremental cost-effectiveness (CE) ratios ($/QALY); costs and QALYs are discounted at 3% annually. KEY RESULTS: In the base case, office-based bup/nx for clinically stable patients has a CE ratio of $35,100/QALY compared to no treatment after 24 months, with 64% probability of being < $100,000/QALY in probabilistic sensitivity analysis. With a 50% bup/nx price reduction the CE ratio is $23,000/QALY with 69% probability of being < $100,000/QALY. Alternative quality-of-life weights result in CE ratios of $138,000/QALY and $90,600/QALY. The value of research to reduce quality-of-life uncertainties for 24-month results is $6,400 per person eligible for treatment at the current bup/nx price and $5,100 per person with a 50% bup/nx price reduction. CONCLUSIONS: Office-based bup/nx for clinically stable patients may be a cost effective alternative to no treatment at a threshold of $100,000/QALY depending on assumptions about quality-of-life weights. Additional research about quality of-life benefits and broader health system and societal cost savings of bup/nx therapy is needed. PMID- 22215272 TI - Subjective social status and functional decline in older adults. AB - BACKGROUND: It is unknown whether subjective assessment of social status predicts health outcomes in older adults. OBJECTIVE: To describe the relationship between subjective social status and functional decline in older adults. DESIGN: Longitudinal cohort study. SETTING: The Health and Retirement Study, a nationally representative survey of community-dwelling older adults (2004-2008). PARTICIPANTS: Two thousand five hundred and twenty-three community-dwelling older adults. MAIN MEASURES: Self-report of social status (SSS), categorized into three groups, reported by participants who marked a 10-rung ladder to represent where they stand in society. Four-year functional decline (new difficulty in any of five activities of daily living, mobility decline and/or death) KEY RESULTS: Mean age was 64; 46% were male, 85% were white. At baseline, lower SSS was associated with being younger, unmarried, of nonwhite race/ethnicity, higher rates of chronic medical conditions and ADL impairment (P < 0.01). Over 4 years, 50% in the lowest SSS group declined in function, compared to the middle and highest groups (28% and 26%), P-trend <0.001. Those in the lowest rungs of SSS were at increased risk of 4-year functional decline (unadjusted RR = 1.91, CI 1.-9-2.46). The relationship between a subjective belief that one is worse off than others and functional decline persisted after serial adjustment for demographics, objective SES measures, and baseline health and functional status (RR 1.36, CI 1.08-1.73). CONCLUSIONS: In older adults, the belief that one is in the lowest rungs of social status is a measure of socioeconomic distress and of significant risk for functional decline. These findings suggest that self-report of low subjective social status may give clinicians additional information about which older adults are at high risk for future functional decline. PMID- 22215273 TI - Can integrating health literacy into the patient-centered medical home help us weather the perfect storm? AB - Improving health literacy is one key to buoying our nation's troubled health care system. As system-level health literacy improvement strategies take the stage among national priorities for health care, the patient-centered medical home (PCMH) model of care emerges as a compelling avenue for their widespread implementation. With a shared focus on effective communication and team-based care organized around patient needs, health literacy principles and the PCMH are well aligned. However, their synergy has received little attention, even as PCMH demonstration projects and health literacy interventions spring up nationwide. While many health literacy interventions are limited by their focus on a single point along the continuum of care, creating a "room" for health literacy within the PCMH may finally provide a multi-dimensional, system-level approach to tackling the full range of health literacy challenges. Increasing uptake coupled with federal support and financial incentives further boosts the model's potential for advancing health literacy. On the journey toward a revitalized health care system, integrating health literacy into the PCMH presents a promising opportunity that deserves consideration. PMID- 22215274 TI - Religious values and healthcare accommodations: voices from the American Muslim community. AB - BACKGROUND: Minority populations receive a lower quality healthcare in part due to the inadequate assessment of, and cultural adaptations to meet, their culturally informed healthcare needs. The seven million American Muslims, while ethnically and racially diverse, share religiously informed healthcare values that influence their expectations of healthcare. There is limited empirical research on this community's preferences for cultural modifications in healthcare delivery. OBJECTIVE: Identify healthcare accommodations requested by American Muslims. METHODS: Using community-based participatory research (CBPR) methods, we partnered with four community organizations in the Greater Detroit area to design and conduct thirteen focus groups at area mosques serving African American, Arab American, and South Asian American Muslims. Qualitative content analysis utilized a framework team-based approach. KEY RESULTS: Participants reported stigmatization within the healthcare system and voiced the need for culturally competent healthcare providers. In addition, they identified three key healthcare accommodations to address Muslim sensitivities: the provision of (1) gender concordant care, (2) halal food and (3) a neutral prayer space. Gender concordance was requested based on Islamic conceptions of modesty and privacy. Halal food was deemed to be health-promoting and therefore integral to the healing process. Lastly, a neutral prayer space was requested to ensure security and privacy during worship. CONCLUSIONS: This study informs efforts to deliver high-quality healthcare to American Muslims in several ways. We note three specific healthcare accommodations requested by this community and the religious values underlying these requests. Healthcare systems can further cultural sensitivity, engender trust, and improve the healthcare experiences of American Muslims by understanding and then attempting to accommodate these values as much as possible. PMID- 22215275 TI - Upregulation of SDF-1 is associated with atherosclerosis lesions induced by LDL concentration polarization. AB - Previous numerical simulations on low-density lipoprotein (LDL) concentration polarization in the arterial system indicated that LDL concentration polarization might play an important role in the genesis and development of atherosclerosis. To date, no in vivo experiments have examined this question directly, and the molecular mechanisms are unknown. In this study, ten rabbits were treated with gel-silica loop to develop a defined local stenosis in the straight segment of the left carotid artery. Both numerical simulation and experiment measurements showed that the concentration of LDL was about 35% higher at the blood/arterial wall interface than in the lumen on the distal side of the stenosis. Atherosclerotic lesions with abundant lipid deposits were observed and stromal derived factor-1 (SDF-1) was detected at the distal end of the stenosis, while the straight segment was plaque-free. In vitro studies demonstrated that LDL induced SDF-1 expression in endothelial cells and increased monocyte adhesion to endothelial cells in a dose-dependent manner. The adhesion was suppressed when endothelial cells were pretreated with SDF-1 antibody. These results suggested LDL concentration polarization contributed to the localization of atherosclerosis and to the expression of SDF-1. In turn, SDF-1 facilitated plaque formation. PMID- 22215276 TI - Microtechnology for mimicking in vivo tissue environment. AB - Microtechnology provides a new approach for reproducing the in vivo environment in vitro. Mimicking the microenvironment of the natural tissues allows cultured cells to behave in a more authentic manner, and gives researchers more realistic platforms to study biological systems. In this review article, we discuss the physiochemical aspects of in vivo cellular microenvironment, and relevant technologies that can be used to mimic those aspects. Secondly we identify the core methods used in microtechnology for biomedical applications. Finally we examine the recent application areas of microtechnology, with a focus on reproducing the functions of specific organs, or whole-body response such as homeostasis or metabolism-dependent toxicity of drugs. These new technologies enable researchers to ask and answer questions in a manner that has not been possible with conventional, macroscale technologies. PMID- 22215277 TI - Automated detection of dual p16/Ki67 nuclear immunoreactivity in liquid-based Pap tests for improved cervical cancer risk stratification. AB - The Papanicolau (Pap) test is a routine cytological procedure for early detection of dysplastic lesions in cervical epithelium. A reliable screening method is crucial for triage of women at risk; however manual screening and interpretation are associated with relatively low sensitivity and substantial interobserver diagnostic variability. P16 and Ki67 biomarkers have been recently proposed as adjunctive tools in the diagnosis of high-risk human papillomavirus (hrHPV) associated dysplasias to supplement the morphological characteristics of cells by additional colorimetric features. In this study, an automated technique for the evaluation of dual p16/Ki67 immunoreactivity in cervical cell nuclei is introduced. Smears stained with p16 and Ki67 antibodies were digitized, and analyzed by algorithms we developed. Gradient-based radial symmetry operator and adaptive processing of symmetry image were employed to obtain the nuclear mask. This step was followed by the extraction of features including pixel data and immunoreactivity signature from each nucleus. The features were analyzed by two support vector machine classifiers to assign a nucleus into one of four types of immunoreactivity: p16 positive (p16(+)/Ki67(-)), Ki67 positive (p16(-)/Ki67(+)), dual p16/Ki67 positive (p16(+)/Ki67(+)) and negative (p16(-)/Ki67(-)), respectively. Results obtained by our method correlated well with readings by two cytopathologists (n = 18,068 cells); p16(+)/Ki67(+) nuclei were classified with respective precisions of 77.1% and 82.6%. Specificity in identification of p16( )/Ki67(-) nuclei was better than 99.5%, and the sensitivity in detection of all immunopositive nuclei was 86.3 and 89.4%, respectively. We found that the quantitative characterization of immunoreactivity provided by the additional highlighting of classified nuclei can positively impact the efficacy and screening outcome of the Pap test. PMID- 22215278 TI - A numerical investigation of blood damage in the hinge area of aortic bileaflet mechanical heart valves during the leakage phase. AB - Previous experimental and numerical blood studies have shown that high shear stress levels, long exposure times to these shear stresses, and flow recirculation promote thromboembolism. Artificial heart valves, in particular bileaflet mechanical heart valves (BMHVs), are prone to developing thromboembolic complications. These complications often form at the hinge regions of BMHVs and the associated geometry has been shown to affect the local flow dynamics and the associated thrombus formation. However, to date no study has focused on simulating the motion of realistically modeled blood elements within the hinge region to numerically estimate the hinge-related blood damage. Consequently, this study aims at (a) simulating the motion of realistically modeled platelets during the leakage (mid-diastole) phase in different BMHV hinge designs placed in the aortic position and (b) quantitatively comparing the blood damage associated with different designs. Three designs are investigated to assess the effects of hinge geometry and dimensions: a 23 mm St. Jude Medical RegentTM valve hinge with two different gap distances between the leaflet ear and hinge recess; and a 23 mm CarboMedics (CM) aortic valve hinge. The recently developed lattice-Boltzmann method with external boundary force method is used to simulate the hinge flow and capture the dynamics and surface shear stresses of individual platelets. A blood damage index (BDI) value is then estimated based on a linear shear stress exposure time BDI model. The velocity boundary conditions are obtained from previous 3D large-scale simulations of the hinge flow fields. The trajectories of the blood elements in the hinge region are found to be qualitatively similar for all three hinges, but the shear stresses experienced by individual platelets are higher for the CM hinge design, leading to a higher BDI. The results of this study are also shown to be in good agreement with previous studies, thus validating the numerical method for future research in BMHV flows. This study provides a general numerical tool to optimize the hinge design based on both hemodynamic and thromboembolic performance. PMID- 22215279 TI - TGFbeta modulates cell-to-cell communication in early epithelial-to-mesenchymal transition. AB - AIMS/HYPOTHESIS: A key pathology in diabetic nephropathy is tubulointerstitial fibrosis. The condition is characterised by increased deposition of the extracellular matrix, fibrotic scar formation and declining renal function, with the prosclerotic cytokine TGF-beta1 mediating many of these catastrophic changes. Here we investigated whether TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) plays a role in alterations in cell adhesion, cell coupling and cell communication in the human renal proximal tubule. METHODS: Whole-cell and cell compartment abundance of E-cadherin, N-cadherin, snail, vimentin, beta catenin and connexin-43 was determined in human kidney cell line (HK)2 and human proximal tubule cells with or without TGF-beta1, using western blotting and immunocytochemistry, followed by quantification by densitometry. The contribution of connexin-43 in proximal tubule cell communication was quantified using small interfering RNA knockdown, while dye-transfer was used to assess gap junctional intercellular communication (GJIC). Functional tethering was assessed by single cell force spectroscopy with or without TGF-beta1, or by immunoneutralisation of cadherin ligation. RESULTS: High glucose (25 mmol/l) increased the secretion of TGF-beta1 from HK2 cells. Analysis confirmed early TGF-beta1-induced morphological and phenotypical changes of EMT, with altered levels of adhesion and adherens junction proteins. These changes correlated with impaired cell adhesion and decreased tethering between coupled cells. Impaired E-cadherin mediated adhesion reduced connexin-43 production and GJIC, these effects being mimicked by neutralisation of E-cadherin ligation. Upregulation of N-cadherin failed to restore adhesion or connexin-43-mediated GJIC. CONCLUSIONS/INTERPRETATION: We provide compelling evidence that TGF-beta1-induced EMT instigates a loss of E-cadherin, cell adhesion and ultimately of connexin mediated cell communication in the proximal tubule under diabetic conditions; these changes occur ahead of overt signs of renal damage. PMID- 22215280 TI - High-resolution manometry of pharyngeal swallow pressure events associated with effortful swallow and the Mendelsohn maneuver. AB - Effortful swallow and the Mendelsohn maneuver are two common strategies to improve disordered swallowing. We used high-resolution manometry (HRM) to quantify the effects of these maneuvers on pressure and timing characteristics. Fourteen normal subjects swallowed multiple, 5-ml water boluses using three techniques: normal swallow, effortful swallow, and the Mendelsohn maneuver. Maximum pressure, rate, duration, area integral, and line integral were determined for the velopharynx and tongue base. Minimum pressure, duration of pressure-related change, duration of nadir pressure, maximum preopening and postclosure pressure, area integral, and line integral were recorded for the upper esophageal sphincter (UES). Area and line integrals of the velopharyngeal pressure curve significantly increased with the Mendelsohn maneuver; the line integral increased with the effortful swallow. Preopening UES pressure decreased significantly for the Mendelsohn, while postclosure pressure tended to increase insignificantly for both maneuvers. UES area and line integrals as well as nadir UES pressure duration increased with both maneuvers. Maneuver-dependent changes were observed primarily at the velopharynx and UES. These regions are critical to safe swallowing, as the velopharynx provides positive pressure at the bolus tail while the UES allows a bolus to enter the esophagus without risk of regurgitation. Integrals were more responsive than maximum pressure or duration and should be investigated further. PMID- 22215281 TI - Distal esophageal spasm. AB - Distal esophageal spasm (DES) is an uncommon esophageal motility disorder associated with dysphagia and/or chest pain. Its pathophysiology implies an impairment of esophageal inhibitory neural function. Using conventional manometry, DES was defined by the presence of simultaneous esophageal contractions. With the introduction of high-resolution manometry and esophageal pressure topography (EPT) in clinical practice, rapidly propagated contractions are nonspecific of esophageal spasm. Hence, a more physiological and clinically relevant definition was proposed. Distal latency (DL) measures the period of inhibition that precedes contraction in the distal esophagus immediately proximal to the esophagogastric junction (EGJ). Premature contractions, defined as reduced DL, appeared to be much more specific for DES in EPT. Premature contractions with normal EGJ relaxation constitute DES, while premature contractions with impaired EGJ relaxation are diagnostic of spastic achalasia. Because of the interaction between DES and gastroesophageal reflux disease, 24-h esophageal pH monitoring should also be considered in patient evaluation. Medical treatment of DES aims to compensate for the deficient inhibitory neural function. Sildenafil, which blocks nitric oxide degradation and thus prolongs esophageal muscle relaxation, is a promising treatment. Endoscopic injection of botulinum toxin in the esophageal muscle is also an interesting therapeutic option. Finally, extended surgical myotomy might be discussed in extreme cases after failure of other therapeutic options. PMID- 22215282 TI - Growing up with cystic fibrosis: achievement, life satisfaction, and mental health. AB - PURPOSE: Significant improvements in survival of patients with cystic fibrosis lead clinicians and researchers to focus on how patients can be enabled to lead as normal a life as possible throughout their entire life span. The study aimed at analyzing the vocational and social achievement, life satisfaction, and psychological well-being of adolescents and adults with cystic fibrosis. METHODS: During a routine clinic visit, 670 German patients with cystic fibrosis (12-64 years, M = 23.1) completed questionnaires on their vocational and social achievement, life satisfaction, and symptoms of anxiety and depression. Cross sectional analyses were applied across four age-groups (12-20 years, 21-30 years, 31-40 years, and 41 years and older). RESULTS: Most patients with cystic fibrosis reached employment and independence from their parents during adulthood. Life satisfaction was negatively associated with age, with the largest difference between the second and third life decade. A strong negative association of anxious and depressive symptoms with life satisfaction was found. Lung function was significantly positively related to life satisfaction, even though this association was less pronounced. CONCLUSIONS: Most patients with cystic fibrosis achieve ordinary social and vocational development into adulthood. A favorable mental health status seems more important than pulmonary function to maintain a good satisfaction with life. PMID- 22215283 TI - Supplementation of poultry feeds with dietary zinc and other minerals and compounds to mitigate nitrogen emissions--a review. AB - One of the environmental challenges that the poultry industry has been faced with is ammonia emission from manure. One way to reduce nitrogen excretion and emissions is supplementing dietary trace minerals to inhibit the activity of microbial uricase, a key enzyme converting nitrogen compounds in the manure into ammonia. Several dietary minerals are commercially available as economic alternatives for reducing ammonia emissions in poultry. In this review, we discuss different mineral elements including zinc as feed amendment minerals that could be used to reduce ammonia emission. Issues discussed include potential for inhibiting microbial uricase, dietary supplementation levels, growth performance, toxicity, their influence on manure nitrogen emission, and potential mineral accumulation in soil. In addition, we discuss other minerals and compounds that have the potential to reduce ammonia volatilization by inhibiting microbial uricase and growth of uric acid-utilizing microorganisms. PMID- 22215284 TI - SUICIDALITY in the perinatal period: comparison of two self-report instruments. Results from PND-ReScU. AB - The aim of this study was to assess suicidality in a non-clinical sample during the perinatal period and to report suicidality rates in women with major or minor depressive episode (MmD), assessed with the SCID, during the perinatal period. Women (1,066) were recruited at the third month of pregnancy and followed until the 12th month postpartum (N = 500). Suicidality was assessed with the MOODS-SR and with item 10 of the EPDS at different time-points during the perinatal period. The period prevalence of suicidality was 6.9% (95% CI: 6.0-7.8) during pregnancy and 4.3% (95% CI: 3.4-5.2) during postpartum, assessed with the MOODS SR, and was 12.0% (95% CI: 10.8-13.2) during pregnancy and 8.6% (95% CI: 7.4-9.8) during the postpartum period, assessed with the EPDS. The prevalence of suicidality in women who had MmD during pregnancy was 26.4% and 34.1%, assessed with the MOODS-SR and the EPDS, respectively, while it was 18.4% (MOODS-SR) and 30.6% (EPDS) during the postpartum period. Clinicians should assess suicidality in women presenting with MmD during the whole perinatal period. Furthermore, suicidality should be assessed in women with a previous history of psychiatric disorder that reported a lifetime suicidal ideation. PMID- 22215285 TI - Untreated prenatal maternal depression and the potential risks to offspring: a review. AB - Research exploring the effects of prenatal maternal depression on a developing fetus and child is underrepresented in the literature. Empirical papers have typically focused on the effects of postpartum depression (after birth) instead of prepartum depression (before birth). Disparate empirical findings have produced ongoing debate regarding the effects of prenatal depression on a developing fetus and later in infancy and early childhood. Even more controversial is determining the role of antidepressant medication on offspring outcomes and whether research that does not include the proper control population (e.g., unmedicated depressed participants) can adequately address questions about risks and benefits of treatment during pregnancy. The current review systematically summarizes the literature focusing on unmedicated prenatal depression and offspring outcome and concludes that prepartum depression is highly prevalent, is associated with negative outcomes in offspring, and remains understudied. PMID- 22215286 TI - Prenatal health behaviors and postpartum depression: is there an association? AB - Postpartum depression is a prevalent mental disorder; however, scarce research has examined its association with prenatal health behaviors. This study investigated the associations of cigarette smoking, caffeine intake, and vitamin intake during pregnancy with postpartum depressive symptoms at 8 weeks after childbirth. Using a prospective cohort study design, participants were recruited from the postpartum floor at a hospital for women and newborns located in a northeastern city, from 2005 through 2008. Eligible women who were at least 18 years old and spoke English were interviewed in person while hospitalized for childbirth (N = 662). A follow-up home interview was conducted at 8 weeks postpartum with a 79% response rate (N = 526). Hierarchical regression analyses showed that smoking cigarettes anytime during pregnancy and not taking prenatal vitamins in the first trimester were significantly associated with worse depressive symptoms (Edinburgh Postnatal Depression Scale). Moreover, having a colicky infant, an infant that refuses feedings, being stressed out by parental responsibility, and having difficulty balancing responsibilities were stressors associated with worse depressive symptoms. Primary health care providers should consider evaluating women for risk of postpartum depression during their first prenatal visit, identifying prenatal health behaviors such as smoking and taking prenatal vitamins. PMID- 22215287 TI - Persistent postnatal depression after preterm delivery. PMID- 22215288 TI - Effect of inter-repetition rest on ratings of perceived exertion during multiple sets of the power clean. AB - The purpose of this study was to examine the effects of inter-repetition rest (IRR) on ratings of perceived exertion (RPE) in the power clean exercise in a multiple set protocol using peak power as an indication of fatigue. Ten resistance-trained males participated in four testing sessions which consisted of determination of a one repetition maximum (1RM) in the power clean exercise (session 1) and performance of three sets of six repetitions at 80% of 1RM with 0 (P0), 20 (P20), or 40 s (P40) IRR (sessions 2-4). Fatigue during all three conditions was indicated by a significant decrease in power of 9.0% (P0), 3.0% (P20) and 2.1% (P40), respectively. Significant difference in the rate of power decrease in P40 indicates less fatigue in comparison to P0 and P20. P40 resulted in a significantly lower RPE compared to P0 and P20 (7.43 +/- 0.34, 6.46 +/- 0.47, and 5.30 +/- 0.55, respectively). RPE increased significantly (p <= 0.01) within each set (5.26 +/- 0.37, 6.46 +/- 0.44, and 7.46 +/- 0.53; sets 1, 2, and 3, respectively). Significant difference in average RPE between the conditions indicates that RPE is not a determinant of intensity (% of 1RM) but the rate of fatigue (decreases in peak power). In addition, the fact that RPE increased between sets 1, 2 and 3 during all conditions support the same conclusion. The results demonstrate that increasing IRR in power clean training decreases the perception of effort and is inversely related to the rate of fatigue. PMID- 22215289 TI - Is nurse interpretation of the ECG QRS width reliable? AB - Electrocardiogram (ECG) data are critical in formulating management strategies following sodium channel antagonist overdose. Poison centers frequently rely on verbal reports of the ECG obtained from bedside nurses. No previous study has addressed the quality of ECG data obtained in this manner. Therefore, we sought to test the ability of nurses to recognize and measure a widened QRS complex, the hallmark of myocardial sodium channel toxicity. Thirty-six emergency department and critical care nurses employed at a tertiary care hospital participated in this prospective study. The study subjects were divided into three groups and asked to interpret 12 ECGs (five normal and seven wide QRS). For each ECG, participants (1) determined if the QRS was narrow or wide and (2) measured the QRS duration. The groups differed in delivery of instruction regarding QRS measurement. Group 1 received visual instructions; group 2 received scripted verbal instructions, and group 3 served as controls, receiving no specific QRS measurement instructions. The nurse data was compared with physician interpretation (consensus of three physicians). Between-group analysis tested for impact of potential real-time educational intervention. Overall, the nurses identified a wide QRS complex most of the time (77%), but had difficulty in accurately measuring the QRS duration (44%). Real-time visual or verbal instruction did not improve accuracy (p = NS between groups). The results suggest that verbal ECG data from nurse callers is not sufficient to make an accurate clinical assessment in the setting of sodium channel poisoning. PMID- 22215290 TI - Sensitive and rapid HPLC quantification of tenofovir from hyaluronic acid-based nanomedicine. AB - The purpose of this study was to develop and validate a rapid, sensitive, and specific reversed-phase high-performance liquid chromatography method for the quantitative determination of native tenofovir (TNF) for various applications. Different analytical performance parameters such as linearity, precision, accuracy, limit of quantification (LOQ), limit of detection (LOD), and robustness were determined according to International Conference on Harmonization (ICH) guidelines. A BridgeTM C18 column (150 * 4.6 mm, 5 MUm) was used as stationary phase. The retention time of TNF was 1.54 +/- 0.03 min (n = 6). The assay was linear over the concentration range of 0.1-10 MUg/mL. The proposed method was sensitive with LOD and LOQ values equal to 50 and 100 ng/mL, respectively. The method was accurate with percent mean recovery from 95.41% to 102.90% and precise as percent RSD (relative standard deviation) values for intra-day, and inter-day precision were less than 2%. This method was utilized for the estimation of molar absorptivity of TNF at 259 nm (epsilon(259) = 12,518 L/mol/cm), calculated from linear regression analysis. The method was applied for determination of percentage of encapsulation efficiency (22.93 +/- 0.04%), drug loading (12.25 +/- 1.03%), in vitro drug release profile in the presence of enzyme (43% release in the first 3 h) and purification analysis of hyaluronic acid-based nanomedicine. PMID- 22215291 TI - Passive transdermal systems whitepaper incorporating current chemistry, manufacturing and controls (CMC) development principles. AB - In this whitepaper, the Manufacturing Technical Committee (MTC) of the Product Quality Research Institute has updated the 1997 Transdermal Drug Delivery Systems Scale-Up and Post Approval Change workshop report findings to add important new product development and control principles. Important topics reviewed include ICH harmonization, quality by design, process analytical technologies, product and process validation, improvements to control of critical excipients, and discussion of Food and Drug Administration's Guidance on Residual Drug in Transdermal and Related Drug Delivery Systems as well as current thinking and trends on in vitro-in vivo correlation considerations for transdermal systems. PMID- 22215292 TI - Microchip for sustained drug delivery by diffusion through microchannels. AB - To enable sustained drug delivery, we prepared microchips of simple structure for drug release based on diffusion through microchannels. The microchips were fabricated with poly(methyl methacrylate), embedded with one or more microwells and microchannels of controlled length. The channels were filled with biocompatible polymer, poly(ethylene glycol), to serve as a drug diffusion barrier. The wells served as drug reservoirs and were filled with a fine powder of a model compound, fluorescein. Three different drug delivery microchip designs were prepared, each equipped with a channel of 1, 4, or 8 mm length. Drug release from these devices all exhibited a delay followed by sustained release over time. As the channel length increased from 1 to 8 mm, the onset time and duration of drug release also increased from 0.5 to 7 day and from 11 days to 28, respectively. We also prepared microchips equipped with multiple microwells, each connected to a channel of different length. In this way, a chip with channels of 1, 4, and 8 mm length exhibited a continuous drug release from 0.5 to 35 days. A future study is in progress to develop the microchips made of biodegradable materials. Therefore, we conclude that a microchip embedded with multiple sets of microwells and microchannels of different length can be designed to enable sustained drug release for controlled and prolonged periods of time. PMID- 22215293 TI - Quantitative analysis of colonization with real-time PCR to identify the role of Oxalobacter formigenes in calcium oxalate urolithiasis. AB - The objective of the study was to quantitatively measure the number of Oxalobacter formigenes (O. formigenes) colonizations in the gastrointestinal tract in calcium oxalate-forming patients with real-time polymerase chain reaction (PCR). Calcium oxalate-forming patients (n: 27) were included in the study. Serum calcium, sodium, potassium, urea and creatinine levels, as well as 24 h urine levels of calcium and oxalate were measured. The numbers of O. formigenes colonies in stool samples were detected by real-time PCR. One or two metabolic abnormalities were detected in 15 of 27 patients. The O. formigenes levels in patients with metabolic disturbance were significantly decreased when compared to the patients with no metabolic abnormalities (p: 0.038). The undetectable levels of O. formigenes were encountered in one of five patients with hypercalciuria, in three of four patients with hyperoxaluria and in four of six patients with both hypercalciuria and hyperoxaluria. In nine patients with a history of stone recurrence, O. formigenes colonization was significantly lower than the patients with the first stone attack (p: 0.001). O. formigenes formation ceased or significantly diminished in patients with calcium oxalate stones with a coexistence of both hyperoxaluria and hypercalciuria. The measurement of O. formigenes colonies by real-time PCR seemed to be an inconvenient and expensive method. For this reason, the real-time PCR measurements can be spared for the patients with stone recurrences and with metabolic abnormalities like hypercalciuria and hyperoxaluria. The exact measurement of O. formigenes may also help more accurate programming of O. formigenes-based treatments. PMID- 22215295 TI - [Anatomical and pathophysiological features and treatment of elbow luxation in rabbits]. AB - OBJECTIVE: Functional anatomical evaluation of elbow luxation in rabbits and the comparison of this lesion to cats and dogs. MATERIAL AND METHODS: The relative frequency of elbow luxation and the most common direction of antebrachial bone dislocation in rabbits were compared catamnestically with data in dogs and cats. Goniometric evaluation of the range of motion of the elbow was carried out in 14 rabbits. This was followed by visualisation of the anatomical structures of cadaver elbows and measurement of the subchondral bone density of the elbow using computed tomographic osteoabsorptiometry in seven rabbits and seven cats. Finally, the stabilisation of the elbow joint using wire to replace the collateral ligaments was evaluated in cadaver specimens. RESULTS: Rabbits undergo elbow luxation approximately four times more often than cats and dogs when compared to luxation of the hip joint. Caudal elbow luxation is most commonly seen in rabbits. The elbow functions as a "snap joint" because of the eccentric insertion of the collateral ligaments and has good lateral stability, which is afforded by a sagittal crest of the humeral condyle. Computed tomographic osteoabsorptiometry showed that the caudal region of the elbow joint undergoes the most mechanical stress. CONCLUSIONS AND CLINICAL RELEVANCE: The anatomical structure of the elbow of rabbits allows primarily sagittal movement; excessive force poses a risk of injury to the cranial aspect of the joint capsule and the humeroulnar ligaments. When closed reduction and a Velpeau sling do not provide stabilisation for the treatment of elbow luxation, transosseus replacement of the humeroulnar collateral ligaments may be indicated. PMID- 22215294 TI - The efficacy and safety of ureteroscopy for ureteral calculi in pregnancy: our experience in 32 patients. AB - The aim of this study was to investigate the efficacy and safety of ureteroscopy (URS) in pregnant women. A retrospective analysis was performed on 32 pregnant patients referred to our center between April 2005 and November 2010 with hydronephrosis requiring surgical intervention. A semirigid URS of 9.5 F was used in all patients. The mean age of patients was 27.8 years (range 20-39), and the mean gestation duration was 24 weeks (15-34). The ultrasound findings were diagnostic of obstructive ureteral calculi in 16 (50%) patients and the mean stone diameter was 8 mm. Spinal anaesthesia was performed in 22 (68.8%) patients, while general anaesthesia was performed in 7 (21.8%) patients. Ureteric stones were found in 27 (84.3%) patients during endoscopy, 10 being distal, 9 middle and 8 proximal. There were no stones in five patients. The stones were fragmented with pneumatic lithotripsy in 8 patients and with holmium laser in 17 patients and the fragments were retracted with forceps. Of the 32 patients, 19 (59.4%) required JJ stent insertion peroperatively. There was no serious complication intraoperatively, while urinary tract infection developed in four and renal colic in two patients postoperatively. In one patient, sepsis developed postoperatively, and improved with appropriate treatment. All babies were born normally. Semirigid ureteroscopy for diagnosing and treating ureteral calculi by intracorporeal pneumatic or holmium laser lithotripsy is a safe and reasonable treatment option for pregnant patients. PMID- 22215296 TI - Solid phase gastric emptying times in the dog measured by 13C-sodium-acetate breath test and 99mTechnetium radioscintigraphy. AB - OBJECTIVE: The aim of the study was to assess solid gastric emptying via non invasive 13C-sodium acetate breath test and compare this technique to 99mTechnetium scintigraphy in 12 healthy adult dogs. MATERIAL AND METHODS: The dogs were fed a test meal containing either 100mg 13C-sodium acetate or 150-250 MBq 99mTechnetium albumin colloid. Breath test and scintigraphy were performed on two consecutive days; this set of procedures was repeated in all dogs. Breath samples and scintigrams were obtained at baseline and every 15minutes for 4 hours, then every 30 minutes for another 2 hours. 25%, 50% and 75% gastric emptying times for breath test (Gt25%b, Gt50%b, Gt75%b) and scintigraphy (Gt25%s, Gt50%s, Gt75%s) were calculated and compared. RESULTS: The mean (+/-SD) Gt50%b and Gt50%s were 165 (+/-28.1) and 71 (+/-16.6)minutes, respectively. There was a significant correlation at all three gastric emptying times between breath test and scintigraphy. Conclusion and clinical significance: While gastric emptying times between both methods varied considerably, both methods correlated significantly showing that the gastric emptying breath test can be used to assess gastric emptying times in dogs. PMID- 22215297 TI - [Treatment and management of Chlamydophila felis infections in cats]. AB - Chlamydophila felis is a common organism among cats and has been detected in up to 60% of cats with conjunctivitis or upper respiratory tract disease. Transmission is mainly caused by direct contact to symptomatic cats. Nevertheless, carriers without current clinical signs are able to shed the organism and, therefore, are a source of infection as well. Treatment and management of infection may be difficult as cats often live in close contact with shedding cats. The most common problem in multi-cat households is re-infection. The intracellular occurrence of Chlamydophila felis requires antibiotics that exhibit a good intracellular efficacy. In this review article, currently used treatment and management regimes are described and compared to each other. PMID- 22215298 TI - [Treatment options for canine atopic dermatitis]. AB - In this review evidence for efficacious treatments of canine atopic dermatitis is summarized on the basis of randomised controlled studies. For severely affected cases topical or systemic glucocorticoids or calcineurin inhibitors such as cyclosporin or tacrolimus can be used in addition to avoidance of flare factors, allergen-specific immunotherapy, a good flea control, dietetic measures, essential fatty acids and shampoos. To prevent recurrences long-term use of especially allergen-specific immunotherapy, essential fatty acids and antihistamines can be helpful. In some cases intermittent therapy with topical or systemic glucocorticoids at low dose may also be useful. Essential fatty acids and antihistamines may reduce the needed glucocorticoid dose. PMID- 22215299 TI - [Nodular lesions in the lung of a dog with eosinophilic bronchopneumopathy]. PMID- 22215300 TI - [Bronchial adenocarcinoma and possible differential diagnosis in an ornamental cock (Gallus gallus domesticus)]. PMID- 22215301 TI - [Subcutaneous sparganosis in an Australian green tree frog (Litoria caerulea)]. PMID- 22215302 TI - [Diagnostic investigation of the liver with ultrasound - current state]. PMID- 22215304 TI - Design and synthesis of caged fluorescent nucleotides and application to live cell RNA imaging. AB - A binary photocontrolled nucleic acid probe that contains a nucleotide modified with one photolabile nitrobenzyl unit and two hybridization-sensitive thiazole orange units has been designed for area-specific fluorescence imaging of RNA in a cell. The synthesized probe emitted very weak fluorescence regardless of the presence of the complementary RNA, whereas it showed hybridization-sensitive fluorescence emission at 532 nm after photoirradiation at 360 or 405 nm for uncaging. Fluorescence suppression of the caged probe was attributed to a decrease in the duplex-formation ability. Caged fluorescent nucleotides with other emission wavelengths (622 and 724 nm) were also synthesized in this study; they were uncaged by 360 nm irradiation, and emitted fluorescence in the presence of the complementary RNA. Such probes were applied to area-specific RNA imaging in a cell. Only probes in the defined irradiation area were activated by uncaging irradiation, and subnuclear mRNA diffusion in a living cell was monitored. PMID- 22215305 TI - Successful treatment of Nocardia pneumonia with cytomegalovirus retinitis coinfection in a renal transplant recipient. AB - Nocardiosis is a rare opportunistic infection, especially seen in immunocompromised patients, including renal allograft recipients. Primary pulmonary infection is the most common clinical pattern and can easily result in disseminated Nocardia infection if treatment therapy is not adequate at the beginning. We report a case of pulmonary nocardiosis associated with cytomegalovirus retinitis in a renal transplant recipient, followed by chronic allograft dysfunction. Our patient was a 50-year-old male renal allograft recipient, with diabetes mellitus and hypertension, who was diagnosed with pneumonia and cytomegalovirus retinitis. High-resolution computed tomography scan of the thorax and bronchoscopy revealed nocardial pneumonia. The patient responded well to ceftriaxone and was later switched to oral minocycline. To our knowledge, this is the first report of a successful treatment of co-infection with Nocardia pneumonia and cytomegalovirus retinitis in a renal transplant patient, with early diagnosis and prompt treatment. PMID- 22215306 TI - Indocyanine green (ICG)-based fluorescence navigation system for discrimination of kidney cancer from normal parenchyma: application during partial nephrectomy. AB - PURPOSE: To determine the definite border between normal and tumor kidney tissues during partial nephrectomy (PN) procedures using intraoperative indocyanine green (ICG)-based fluorescence imaging. METHODS: Sixteen potential candidates for PN with organ-confined, small renal masses treated between July 2008 and June 2011 at Shimane University Hospital were enrolled. An ICG-based fluorescence navigation (FN) system was used to evaluate the border between the tumor and normal kidney parenchyma (step 1), the cavity following tumor excision (step 2), and the negative surgical margin of resected tissues (step 3). The R.E.N.A.L nephrometry score (RNS) was applied to evaluate the correlation between tumor anatomy and ICG-based fluorescence imaging. RESULTS: In step 1, in vivo probing revealed 14 tumors with a mean RNS of 7 points that showed quite low ICG fluorescence signals in the tumor mass as compared with normal kidney parenchyma. In step 2, in vivo probing around the bed revealed highly fluorescent signals with no remnant tumor residing in 10 cases with a mean RNS of 6 points. In step 3, ex vivo probing revealed cancer tissues involving normal parenchyma that were completely excised with minimum amounts of normal parenchyma in all 16 resected specimens. CONCLUSIONS: ICG-based FN system was very helpful for confirming negative margin status in even the most complex cases. Further evaluations may open the door for widespread use of this ICG-based FN system as a feasible and attractive alternative during a PN procedure. PMID- 22215307 TI - pH-Induced molten globule state of Rhizopus niveus lipase is more resistant against thermal and chemical denaturation than its native state. AB - Here, we have characterized four pH-dependent states: alkaline state, "B" (pH 9.0), native state, "N" (pH 7.4), acid-induced state, "A" (pH 2.2) and molten globule state, "MG" (pH 1.8) of Rhizopus niveus lipase (RNL) by CD, tryptophanyl fluorescence, ANS binding, DLS, and enzyme activity assay. This "MG" state lacks catalytic activity and tertiary structure but it has native-like significant secondary structure. The "R (h)" of all the four states of RNL obtained from DLS study suggests that the molecular compactness of the protein increases as the pH of solution decreases. Kinetic analysis of RNL shows that it has maximum catalytic efficiency at state "B" which is 15-fold higher than state "N." The CD and tryptophanyl fluorescence studies of RNL on GuHCl and temperature-induced unfolding reveal that the "MG" state is more stable than the other states. The DSC endotherms of RNL obtained at pH 9.0, 7.4, and 2.2 were with two transitions, while at pH 1.8 it showed only a single transition. PMID- 22215308 TI - The influence of walking with an orthosis on bone mineral density by determination of the absolute values of the loads applied on the limb. AB - Spinal cord injury is damage to the spinal cord that results in loss of mobility and sensation below the level of injury. Most patients use various types of orthoses to stand and walk. It has been claimed that walking and standing with orthosis reduces bone osteoporosis, improves joint range of motion and decreases muscle spasm. Unfortunately, there are discrepancies regarding the clinical effects of walking and standing on bone mineral density. The aim of this research was to find the absolute values of the loads transmitted by body and orthosis in walking with use of an orthosis. 5 normal subjects were recruited to stand and walk with a new design of reciprocal gait orthosis. The loads transmitted through the orthosis and anatomy was measured by use of strain gauge and motion analysis systems. It has been shown that the loads applied on the anatomy were significantly more than that transmitted through the orthosis. Moreover, the patterns of the forces and moments of the orthosis and body completely differed from each other. As the most part of the loads applied on the complex transmitted by anatomy in walking with an orthosis, walking with orthosis can influence bone mineral density. PMID- 22215309 TI - Upregulation of a disintegrin and metalloprotease 8 influences tumor metastasis and prognosis in patients with osteosarcoma. AB - To investigate the clinicopathological and prognostic value of a disintegrin and metalloprotease 8 (ADAM8) in osteosarcoma. ADAM8 expression in osteosarcoma tissues was examined by immunohistochemistry in 69 patients. ADAM8 was positively expressed in 61 of 69 (88.4%) osteosarcoma specimens with cytoplasmic staining, and also increased in the specimens with recurrence (P = 0.008) and metastasis (P = 0.002). Patients with strong ADAM8 expression had significantly poorer overall survival (OS) and disease-free survival (DFS) (both P < 0.001) when compared with the patients with the weak expression of ADAM8. On multivariate analysis, ADAM8 expression was found to be an independent prognostic factor for both OS (P < 0.001) and DFS (P < 0.001). Our results suggest for the first time that ADAM8 might be applied as a novel marker for the prediction of recurrence and metastasis potency and a significant indicator of poor prognosis for patients with osteosarcoma. PMID- 22215310 TI - A proposed new technique in prostate cancer tissue bio-banking: our experience with a new protocol. AB - The aim of our study, beyond validating a method of collecting and storing biological samples from patients with prostate cancer, was to validate an innovative biopsy method for the creation of a biobank of prostatic frozen tissues. Patients referred to our hospital between November 2008 and March 2010 to undergo radical prostatectomy were invited to participate in the study. Each patient's data were stored in two databases (personal information and clinical database) while samples of urine, blood and its derivatives, fresh material and formalin-processed tissue were stored in a correlated biobank. The proposed method for collecting fresh material was to take samples of the neoplastic tissue by carrying out targeted biopsies in the area indicated by the biopsy mapping as the site of the malignancy, under manual palpation to identify the neoplastic nodule. The site of sampling was marked by an injection of India ink. 55 patients agreed to participate in the study. In 43 cases biopsies were correct, with a mean of 48% of core involved by tumour (range, 10-90%). Overall the tumour detection rate was 78.2%. The protocol for collecting biological material and the new method for collecting fresh tissue reduce internal steps and staff involved, thereby reducing all those variables that cause heterogeneity of material and changes in its quality. This process provides high quality, low cost material for research on prostate cancer. The features of the collection protocol mean that the protocol can also be used in non-academic centres with only limited research funds. PMID- 22215312 TI - [Radiographic location of the tibial cranial cruciate ligament attachment in middle- to large breed dogs]. AB - OBJECTIVE: Investigation of the radiographic cranio-caudal (cc) and medio-lateral (ml) location of the tibial centroid of the attachment area of the CCL (ACCL). MATERIAL AND METHODS: In 46 tibiae from orthopedically healthy dogs (22-50kg) the tibial plateau was stripped of all soft tissue, degreased with acetone and the contour of the ACCL was marked with ink stain. The CCL was completely resected and one pin each was placed at the most medial, lateral, cranial and caudal extensions of the ACCL. On digital images of each tibial plateau the previously marked contour of the ACCL was traced. Using custom-made image analysis software the two-dimensional centroid of the ACCL was determined and transferred to standard radiographs in two planes of each tibia. The cc location of the centroid of the ACCL was measured starting at the intercondylar tubercles. The proximal tibial extension (TibEx) was obtained and linear regression analysis was applied to develop a mathematical first order equation for the calculation of the cc location of the centroid based on the proximal tibial depth in the individual stifle. The ml location of the centroid was measured in relation to the medial intercondylar tubercle. RESULTS: A statistically significant (p<0.001) correlation was found between the TibEx and the anatomical cc location of the centroid. Linear regression analysis revealed a first order linear equation for calculation of the individual cc location of the centroid in mm to be: 0.28 x TibEx - 4 in mm with an R2 of 0.83. The median ml location of the centroid in relation to the medial intercondylar tubercle was 0mm whereas 90% were located 1 mm medial and 1 mm lateral to the medial intercondylar tubercle. CONCLUSION: The radiographic location of the centroid of the ACCL can be individually determined on standard stifle radiographs. CLINICAL RELEVANCE: With the help of these data the location of a tibial drill tunnel in anatomic reconstruction of the ruptured CCL may be evaluated either intra-operatively with fluoroscopy or postoperatively on two plane standard stifle radiographs and the placement could be corrected when necessary. PMID- 22215311 TI - Employment experience of cancer survivors 2 years post-diagnosis in the Study of Cancer Survivors-I. AB - INTRODUCTION: A large percentage of cancer survivors are in the workforce and it is important to understand their experiences and challenges in the workplace and work status changes. METHOD: We utilized multivariate logistic regression to evaluate sociodemographic, clinical, and psychosocial measures as potential predictors of having at least one negative work-related experience and reporting a reduction in workload among cancer survivors 2 years post-diagnosis in the longitudinal Study of Cancer Survivors-I. RESULT: Many cancer survivors (62%) reported having at least one negative work-related experience 2 years post diagnosis; they were more likely to be male (OR = 1.70, 95% CI = 1.32-2.18), have lower household income (>$80,000 vs. <$20,000; OR = 0.53, 95% CI = 0.35-0.79), be farther from diagnosis (OR = 1.06, 95% CI = 1.02-1.10), and have deteriorating physical (OR = 0.96, 95% CI = 0.94-0.98) and mental (OR = 0.94, 95% CI = 0.92 0.96) health. Among those employed full-time 1 year post-diagnosis, older age (65+ vs. <55; OR = 2.71, 95% CI = 1.18-6.24), negative work-related experiences (2+ vs. 0; OR = 1.78, 95% CI = 1.00-3.14), and deteriorating physical (OR = 0.93, 95% CI = 0.90-0.95) and mental (OR = 0.97, 95% CI = 0.95-0.99) health were associated with reporting a reduced workload 2 years post-diagnosis. DISCUSSIONS: Several sociodemographic and psychosocial characteristics were associated with negative work-related experiences and reduced workload in this population of cancer survivors who were working 1 to 2 years post-diagnosis. Additional research is needed to determine if these experiences and predictors are consistent in other cancer survivor populations. IMPLICATIONS FOR CANCER SURVIVORS: Being aware that some working cancer survivors may have negative work related experiences and/or may not maintain full employment in later survivorship years may enable cancer survivors and employers to improve survivors' experiences at work. PMID- 22215313 TI - Canine status epilepticus due to acute intoxication. AB - OBJECTIVES: The purpose of this study was to describe the type of toxin ingested, clinical presentation and outcome of dogs with status epilepticus (SE) due to acute poisoning presented to a large referral veterinary hospital. MATERIALS AND METHODS: Retrospective case series. Medical records of all dogs suffering from SE were reviewed (Jan 1, 2002 to April 30, 2009). RESULTS: Fourteen dogs with SE due to acute intoxication were identified. Toxicological analyses (qualitative analysis with gas chromatography/mass spectrometry; n=11) detected poisonings with carbofuran, crimidine, paraoxone, metaldehyde, strychnine and diazinon. In the other three cases the uptake of a known poison was observed (zink phosphide, metaldehyde). None of the dogs showed evidence of neurological disease up to the day of presentation. The dogs were hospitalised for 2-10 days (median 5 days). The survival rate was 85.7%. None of the dogs experienced any more seizures after discharge (median observation period 2.6 years). CONCLUSION AND CLINICAL RELEVANCE: Ancillary to the acute clinical presentation, preliminary reports (possible uptake of poisonous material) and an inconspicuous medical history may suggest a tentative diagnosis. Managed adequately, these patients can have a high survival rate. Clinicians should also keep uncommon intoxications in mind. PMID- 22215314 TI - Comparison of clomipramine and fluoxetine treatment of dogs with tail chasing. AB - OBJECTIVE: The aim of the study was to determine the response to treatment with clomipramine and fluoxetine in dogs with tail chasing. MATERIAL AND METHODS: Twenty-five client owned dogs with tail chasing were included in this study. Diagnosis of tail chasing was made on the basis of the dog's behavioral history, clinical signs, and results of laboratory parameters. The study had a randomized, placebo-controlled, double-blind design. Dogs were allocated to three groups. During 12 weeks, dogs of one group were given 2mg/kg clomipramine hydrochloride orally, dogs of the second group received 1mg/kg fluoxetine orally and placebo was administered to control dogs. Changes in signs of tail chasing were weekly reported by the owners. Treatment was assessed in four intervals: weeks 1-3, 4-6, 7-9, and weeks 10-12, respectively. RESULTS: German shepherd dogs and Anatolian sheepdogs were overrepresented. In all four intervals improvement of tail chasing did not differ significantly between clomipramine and fluoxetine (p>0.05). Improvement of behavior in the clomipramine group was significantly better than in the placebo group between weeks 1-3 and 4-6 and between weeks 7-9 and 10-12 (p<0.05). Furthermore, there was a significantly better improvement in the fluoxetine group between weeks 7-9 and weeks 10-12 when compared to the placebo group (p<0.05). CONCLUSION AND CLINICAL RELEVANCE: Clomipramine and fluoxetine seem to be equally effective in the treatment of tail chasing. Treated dogs responded well to the drugs and both drugs did not show superiority over each other. PMID- 22215315 TI - [New drugs for small animals in 2009]. AB - In 2009, five active pharmaceutical ingredients were released on the German market for small animals. Those are the analgesic Buprenorphin (Buprenovet(r)), the cytostatic Masitinib (Masivet(r)), the antiepileptic Phenobarbital (Phenoleptil(r)) and the cyclooxygenase-2-inhibitors Mavacoxib (Trocoxil(r)) and Robenacoxib (Onsior(r)). Six additional substances were authorized for additional species. Benazepril, Cefalexin, Ivermectin und Ramipril are now available for cats, Emodepsid in combination with Praziquantel is likewise authorized for dogs and the combination Imidaclopird + Moxidectin is now also available for ferrets. Furthermore, two new preparations with an interesting new pharmaceutical form were added to the market for small animals. In addition seven active pharmaceutical ingredients with approval for use in human medicine which are of potential interest for veterinary medicine, entered the market in 2009. Those are the antiepileptic Eslicarbazepinacetat, the antihemorrhagic Romiplostim, the anticoagulant Prasugrel, the vasopressin-antagonist Tolvaptan as well as the cytostatics Azacitidin, Plerixafor and Vinflunin. PMID- 22215316 TI - [Recommendations for the veterinary care and assessment of bird of prey collections]. AB - Legislation from a new regulation of the Federal Nature Conservation Act that became effective on March 1, 2010 requires a written program for veterinary prophylaxis, treatment and nutrition for zoo and animal collections. As a result of this act, veterinary care is now obligatory for all captive birds of prey kept within either private or commercial collections, independent on the number of birds involved. The legal requirements of the Act will shortly be introduced and recommendations for the veterinary care of bird of prey collections are provided. Firstly, risk assessment of different husbandry systems (falconry birds, show birds, breeding stock, rehabilitation) is performed and veterinary care programs are provided based upon these assessments. Additionally, instructions for anamnestic ascertainments, work flow, feeding, quarantine, cleaning and disinfection procedures as well as prophylactic measures such as vaccination are provided. As husbandry, in particular the size and equipment of cages is important for the health and welfare of the birds, species specific housing, care and protection measures are also discussed. Veterinarians will be able to refer to these guidelines and can use them in the future for collection management. PMID- 22215317 TI - [Trichomonas-associated enteritis in a puppy with parvovirosis]. PMID- 22215318 TI - [Treatment of a Candida-dermatitis in an African spurred tortoise (Geochelone sulcata)]. PMID- 22215319 TI - [Ovarian cysts in the bitch]. PMID- 22215320 TI - Copper chitosan nanocomposite: synthesis, characterization, and application in removal of organophosphorous pesticide from agricultural runoff. AB - PURPOSE: Removal of malathion from agricultural runoff was studied using novel copper-coated chitosan nanocomposite (CuCH)-a biopolymeric waste obtained from marine industry. METHODS: Synthesis and characterization of the adsorbent using different spectral techniques like Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy, energy-dispersive X-ray spectroscopy, Brunauer, Emmett, and Teller surface analyzer have been carried out. Equilibrium studies have been carried out to optimize the dose rate, pH, and the reaction time. Parathion and methyl parathion removal were also evaluated by CuCH in the batch mode. Using gas chromatography-mass spectrometry (GC-MS) and FTIR studies suitable mechanism for adsorption has been suggested. RESULTS: The particle size of the adsorbent ranged from 700 to 750 nm. The surface area was found to be 20 m(2) g(-1) with a pore volume of 0.11 cc g(-1). The maximum adsorption capacity of malathion by CuCH was found to be 322.6 +/- 3.5 mg g(-1) at an optimum pH of 2.0. Presence of copper ions enhanced the adsorption capacity of the adsorbent. The reaction was found to follow pseudo second-order kinetics with a rate constant of 0.53 g mg(-1) min(-1). Evidence from FTIR indicated that copper ions form a dithionate complex with malathion during the adsorption stage. The adsorbent was found to remove malathion completely from spiked concentration of 2 mg l(-1) in the agricultural run-off samples. It was also found that CuCH removed other organophospurous pesticides like methyl parathion and parathion under prevailing conditions. CONCLUSIONS: The results indicated that CuCH could be applied for the removal of organophosphorous pesticides. PMID- 22215321 TI - Study on the spectral and Cu (II) binding characteristics of DOM leached from soils and lake sediments in the Hetao region. AB - INTRODUCTION: Dissolved organic matter (DOM) is the most active component in environmental system and its chemical and structural characteristics most likely influence its biodegradation. Four surface soil (0-20 cm) and three core sediment samples (0-10 cm) were collected from Wuliangsuhai Lake. The objectives of this study were to investigate the spectral properties and humification degree of DOM and to determine and discuss comparatively the complexing capacities and stability constants of DOM by Cu (II) in the Hetao region. MATERIALS AND METHODS: In this study, fluorescence spectra and fluorescence quenching methods were used to evaluate the humification degree of DOM and calculate the complexing capacities and the stability constants between DOM and Cu (II). RESULTS AND DISCUSSION: Two defined peaks, at wavelengths of 260~300 nm (peak I) and 300~350 nm (peak II), could be identified for soil DOM at a Deltalambda value of 30 nm. In sediment DOM extracts, a third peak (III) was observed near 364 nm. The results show that there is a significant difference in the structure of DOM because of different sources. The humification degree is significantly higher for soil samples than those of sediment samples. The FT-IR spectra of DOM show that structure in sediment DOM is more functional groups than those in soil DOM. DOM has a stronger Cu binding affinity in soils than in sediment in the Hetao region, which may lead to potentially significant influence on the migration and transformation of Cu (II). PMID- 22215322 TI - Fibrin-embedded adipose derived stem cells enhance skin flap survival. PMID- 22215325 TI - Quantitative comparison of cis-regulatory element (CRE) activities in transgenic Drosophila melanogaster. AB - Gene expression patterns are specified by cis-regulatory element (CRE) sequences, which are also called enhancers or cis-regulatory modules. A typical CRE possesses an arrangement of binding sites for several transcription factor proteins that confer a regulatory logic specifying when, where, and at what level the regulated gene(s) is expressed. The full set of CREs within an animal genome encodes the organism's program for development, and empirical as well as theoretical studies indicate that mutations in CREs played a prominent role in morphological evolution. Moreover, human genome wide association studies indicate that genetic variation in CREs contribute substantially to phenotypic variation. Thus, understanding regulatory logic and how mutations affect such logic is a central goal of genetics. Reporter transgenes provide a powerful method to study the in vivo function of CREs. Here a known or suspected CRE sequence is coupled to heterologous promoter and coding sequences for a reporter gene encoding an easily observable protein product. When a reporter transgene is inserted into a host organism, the CRE's activity becomes visible in the form of the encoded reporter protein. P-element mediated transgenesis in the fruit fly species Drosophila (D.) melanogaster has been used for decades to introduce reporter transgenes into this model organism, though the genomic placement of transgenes is random. Hence, reporter gene activity is strongly influenced by the local chromatin and gene environment, limiting CRE comparisons to being qualitative. In recent years, the phiC31 based integration system was adapted for use in D. melanogaster to insert transgenes into specific genome landing sites. This capability has made the quantitative measurement of gene and, relevant here, CRE activity feasible. The production of transgenic fruit flies can be outsourced, including phiC31-based integration, eliminating the need to purchase expensive equipment and/or have proficiency at specialized transgene injection protocols. Here, we present a general protocol to quantitatively evaluate a CRE's activity, and show how this approach can be used to measure the effects of an introduced mutation on a CRE's activity and to compare the activities of orthologous CREs. Although the examples given are for a CRE active during fruit fly metamorphosis, the approach can be applied to other developmental stages, fruit fly species, or model organisms. Ultimately, a more widespread use of this approach to study CREs should advance an understanding of regulatory logic and how logic can vary and evolve. PMID- 22215326 TI - Recurrent salivary gland cancer. AB - OPINION STATEMENT: Salivary gland cancer is the most diverse cancer in the body consisting of up to 24 different pathologic subtypes. Although these cancers arise within a common group of glands in the head and neck region, these diverse cancers differ substantially in clinical behavior. As a result, salivary cancers are often categorized as low, intermediate, or high-risk for recurrence and metastasis based on histopathologic subtype and tumor stage. Appropriate risk classification of a given salivary tumor provides a useful guide to the physicians who determine the appropriate treatment regimen. Low-risk tumors can be treated successfully with surgery alone, whereas intermediate and high-risk tumors often require multimodality therapy. Recurrent salivary cancer should be considered high-risk by definition, especially if previously treated with appropriate therapy, and therefore requires aggressive multimodality therapy in order to achieve adequate local control and disease-free survival. PMID- 22215324 TI - Treatment options for cerebral vasospasm in aneurysmal subarachnoid hemorrhage. AB - Cerebral vasospasm occurs frequently after aneurysmal subarachnoid and contributes to delayed cerebral ischemia. In this article we address systematic problems with the literature on vasospasm and then review both established and experimental treatment options. PMID- 22215327 TI - [Growth and pulmonary function in Chilean children and adolescents with cystic fibrosis]. AB - BACKGROUND: Nutrition influences morbidity and mortality in patients with cystic fibrosis (CF), affecting their lung function. AIM: To characterize the nutritional status of a group of CF patients and to analyze its evolution and relationship to lung function. PATIENTS AND METHODS: A retrospective cohort of CF children and adolescents attended in our institution for 15 years, was analyzed. Age and form of presentation, mutation, weight and stature (measured annually at least), microbial colonization and forced expiratory volume in the first second (FEV(1)) were registered. RESULTS: We gathered information about 33 patients, 64% males, diagnosed at 23.8 +/- 45.6 months old (range 1-216), 85% had a genetic study (10 children had one or more Df508 alleles) and 94% had pancreatic insufficiency. In their last visit they were 13.0 +/- 5.8 years old, their body mass index z-score (BMIz) was -0.25 +/- 1.2 and their FEV(1) was 80.4 +/- 28.6%. According to BMI: 73% were eutrophic, 18% undernourished and 9% were overweight. According to weight/ for height index (WH), the figures for eutrophy, undernutrition and overweight were 70, 6 and 24%, respectively. Only 12% had short stature. Those with P. aeruginosa infection had lower BMI. There was a positive correlation between FEV(1) and BMIz (+0.46, p = 0.02), but not with WH. During follow-up, there was a gradual deterioration of weight, height, and BMIz after 10-12 years of age and an overall gradual FEV(1) decrease. CONCLUSIONS: The prevalence of malnutrition in these patients with CF is high; undernutrition is higher if defined by BMIz and unlike WH, correlates to lung function. Nutritional deterioration starts before adolescence. PMID- 22215328 TI - [Hyponatremia on admission to the emergency room as a risk factor for hospital mortality]. AB - BACKGROUND: Patients who develop hyponatremia during their hospitalization have higher hospital mortality. AIM: To determine if the presence of hyponatremia on admission to the emergency room is a risk factor for hospital mortality. PATIENTS AND METHODS: Two hundred forty five patients consecutively admitted to the emergency room and then transferred to the Medicine Department, where they finally died, were matched for age and gender with 245 control subjects admitted to the emergency room and hospitalized in the Medicine Department at the same time, but survived. The dependent variable was death, and the exposure variable was hyponatremia. Admission diagnosis and Charlson comorbidity index was considered as confounding variables. RESULTS: Hyponatremia at admission occurred in 30 and 17% of patients who died and survived, respectively, rendering an adjusted odds ratio for death of 2.13 (95% confidence intervals = 1.27-3.57). Charlson Comorbidity Index according to age score was higher in subjects with hyponatremia compared to those without hyponatremia (8.1 +/- 3.1 and 7.2 +/- 2.8; p = 0.01). Multivariate analysis showed that age, gender, length of stay, cause of hospitalization and chronic diseases did not significantly modify the effect of hyponatremia on hospital mortality. CONCLUSIONS: Hyponatremia on admission at emergency room had a significant association with hospital mortality. Subjects with hyponatremia had a higher Charlson Comorbidity Index score. PMID- 22215329 TI - [Prognostic value of extracapsular lymph node involvement among patients with gastric cancer]. AB - BACKGROUND: Extracapsular lymph node involvement has a negative prognosis in malignant tumors. AIM: To assess the prognostic importance of extracapsular lymph node involvement in patients with gastric cancer with lymph node metastases. MATERIAL AND METHODS: Clinical and morphological features and survival of patients with gastric cancer and lymph node involvement operated between 1986 and 2003, were analyzed. Patients with and without extracapsular involvement were compared. RESULTS: During the study period, 459 gastrectomies were performed, 312 patients (68%) had lymph node involvement and 144 (31%) had extracapsular involvement. Patients with and without extracapsular involvement were followed for a median of 10 (range 1 to 120) and 41 (range 1 to 193) months, respectively. Five years actuarial survival for patients with and without extracapsular involvement was 23 and 40% respectively. Extracapsular lymph node involvement and level of wall infiltration were identified as prognostic factors using a multivariate analysis. CONCLUSIONS: Extracapsular lymph node involvement is an independent risk factor for mortality among patients with gastric cancer. PMID- 22215330 TI - [Quality of life of older people living in Antofagasta, Chile]. AB - BACKGROUND: As basic needs of older people are covered, the concern about the determinants of their quality of life becomes preeminent. AIM: To evaluate the relationship between self-reported quality of life and related variables. MATERIAL AND METHODS: The Quality of Life Survey for older people developed by the World Health Organization (WHOQOL-Old), the reduced scale of Ryff Psychological Well Being, the Functional Social Support Questionnaire, the SF-12 and GHQ12 general health surveys were applied to 406 older adults aged 71 +/- 7 years (83% women), that were members of older people organizations and lived in Antofagasta, Chile. RESULTS: Older people that perceived themselves as sick had significantly lower quality of life scores. Self-acceptance, social support, autonomy and having a purpose in life also influenced the perception of quality of life. CONCLUSIONS: Health issues and the sense of self efficacy are determinants of the quality of life of these older subjects. PMID- 22215331 TI - [Results of pancreaticoduodenectomy in the treatment of periampullary tumors]. AB - BACKGROUND: The diagnosis and treatment of periampullary tumors represents a challenge for current medicine. AIM: To review the results of pancreaticoduodenectomy (PDD) in the treatment of periampullary tumors and to identify risk factors that impact the long-term survival. PATIENTS AND METHODS: We performed a retrospective study of patients who underwent a PDD for periampullary tumors between 1993 and 2009. We reviewed perioperative results and long term survival. We performed a multivariate analysis for long-term survival. RESULTS: A PDD was performed in 181 patients aged 58 +/- 12 years (98 females). Pyloric preservation was done in 53% and a pancreatogastric anastomosis was used in 94% of cases. Morbidity was 62% and postoperative mortality was 5.5%. Pancreatic cancer was the most frequent pathological finding in 41%, followed by ampullary cancer in 28% and distal bile duct cancer in 16%. Median survival was 17 months, with a five years survival of 24%. Survival for ampullary tumors was 28 months with a five years survival of 32%. The median and five years survival were 14 months and 16% for bile duct cancer and 11 months and 14% for pancreatic cancer. Multivariate analysis identified tumor type (pancreas /bile duct) and lymph node dissemination as independent predictors of mortality. CONCLUSIONS: One quarter of patients experienced long term survival. Mortality predictors were tumor type and lymph node dissemination. PMID- 22215332 TI - [Functional endoscopic evaluation of swallowing among hospitalized patients]. AB - BACKGROUND: Swallowing disorders are common in hospitalized patients. Functional endoscopic evaluation of swallowing (FEES) is a simple, safe and effective test for the diagnosis and monitoring of these disorders. AIM: To report the results of functional endoscopic swallowing evaluation. MATERIAL AND METHODS: Retrospective review of all records of functional swallowing evaluation procedures performed in a 6 months period. RESULTS: A total of 327 evaluations were analyzed. Sixty seven percent were performed for the first time in a patient and 32.4% were follow-up evaluations. Mean age of patients was 73 +/- 17 (SD) years and 56% were male. Twenty nine percent had prolonged orotracheal intubation (> 48 hours). Swallowing was evaluated as normal, mildly, moderately and severely altered in 8.2, 27, 27 and 38% of cases, respectively. Age (> 50 years) and orotracheal intubation were the most important predictors of severity (p = 0,01). Oral feeding was achieved during hospital stay in 78 and 55 % of patients with moderate or severe swallowing disorders, respectively, after a delay of 8.7 and 14.3 days, respectively. Having a severe swallowing disorder during the first evaluation, increased fourfold the risk of gastrostomy. CONCLUSIONS: Most hospitalized patients with swallowing disorders achieve oral feeding before leaving hospital. Safe oral feeding is delayed as swallowing disorder is of greater severity. PMID- 22215333 TI - [Detection and management of non-motor symptoms in Parkinson's disease: impact on their prevalence]. AB - BACKGROUND: Non-motor symptoms are common among patients with Parkinson disease and include cognitive, psychiatric, sleep and autonomic dysfunctions. AIM: To determine if the detection of non-motor symptoms along with the appropriate referral to an specialist has an impact on their prevalence after one year follow up. MATERIAL AND METHODS: We included 60 patients diagnosed with Parkinson's disease attending to the Movement Disorder Clinic. The presence of non-motor symptoms was determined by the non-motor symptom questionnaire (NMSQuest). RESULTS: The mean NMSQuest scores at baseline and at one year follow up were 12.6 +/- 6.2 and 9.9 +/- 5.6, respectively (p < 0.01). The non-motor symptoms that showed a statistically significant differences in frequency between baseline and the final assessment, were constipation (p = 0.04), urinary urgency (p = 0.02), hallucinations (p = 0.04), dizziness (p = 0.02) and vivid dreams (p = 0.04). CONCLUSIONS: Intentional search for non-motor symptoms in patients with Parkinson's disease along with a multidisciplinary approach has an impact on their prevalence. The change in specific symptoms is probably related to adjustments in dopaminergic management. PMID- 22215334 TI - [Ankle-brachial index in the assessment of cardiovascular risk among HIV infected patients]. AB - BACKGROUND: Vascular risk is an important cause of morbidity and mortality in HIV infected patients. AIM: To study the value of the ankle-brachial index (ABI) in vascular risk stratification in a cohort of people with HIV infection. PATIENTS AND METHODS: Vascular risk was calculated in all the patients that agreed to participate in the study and clinical reports were reviewed retrospectively. Ten year risk of fatal myocardial infarction was calculated according to Framingham equation, National Cholesterol Education Program (NCEP) III and Systematic Coronary Risk Evaluation (SCORE) project score. ABI was calculated measuring resting systolic blood pressure at the ankle, that was compared with the systolic brachial pressure. The ratio of the two pressures defined ABI, that was considered abnormal if it was <= 0.9 or >= 1.3. RESULTS: A total of 231 HIV infected patients aged 23 to 82 years (80% males) were enrolled. Ten years risk according to Framingham equation was 8.4%, 95% confidence intervals (CI): 7.54 9.15 and according to SCORE scale was 0.8%, 95% CI: 0.62-1.01. According to NCEP III 9% of patients had a high or very high cardiovascular risk. Median ABI was 1.17 (95% CI intervals: 1.16-1.19) and 58 patients (25%) had an abnormal value. Using ABI results, approximately 20% of patients were re-classified as having a high vascular risk. CONCLUSIONS: ABI identified approximately 20% of this cohort of HIV infected subjects as having high vascular risk. PMID- 22215335 TI - [A pilot study on physical training of patients in hemodialysis]. AB - BACKGROUND: Exercise training during the dialytical procedure may have positive cardiovascular effects and prevent or revert muscle wasting in patients undergoing chronic hemodialysis. AIM: To evaluate the effects of an exercise training program in patients undergoing chronic hemodialysis. MATERIAL AND METHODS: Fifteen patients on chronic hemodialysis aged 21 to 69 years (three females) were included in the study. Nine of these were included in an exercise training program. During 16 weeks, exercise sessions were carried out during each dialytical procedure that included a warm-up period, aerobic exercises done using standing cycles, and resistance exercises, performed using Thera-Band((r)) elastic bands and loops. Borg scale was used to control the intensity of training. At baseline and at the end of the study, a blood sample prior and after the dialytical procedure was obtained to measure C reactive protein, tumor necrosis factor alpha and interleukin 6. Quadriceps muscle strength, six minutes' walk and quality of life using the SF-36 questionnaire, were also measured. RESULTS: Four experimental subjects did not complete the study period, two that withdrew before starting, one due to problems with the venous access and one that decided to withdraw after 1 month of training. Among the five patients that finished the training period, significant improvements in the six minutes' walk and quadriceps strength were observed in the experimental group. No significant changes were observed among controls. No changes were observed in either group in C reactive protein, tumor necrosis factor and interleukin 6 levels or quality of life. CONCLUSIONS: Among patients undergoing chronic hemodialysis exercise training improves endurance and muscle strength. PMID- 22215336 TI - [Erdhei-Chester disease: report of one case]. AB - We report a 76-year-old male who was admitted due to progressive congestive heart failure lasting several months. An echocardiogram showed a large pericardial effusion with early signs of pericardial tamponade and an irregular surface suggestive of cancer infiltration. The patient was operated, creating a pericardial window and draining 1,200 ml of a brownish yellow fluid with abundant cellularity. Pericardial biopsy showed infiltration by CD68 (+), CD1a (-) and S100 (-) cells. Twenty-eight months earlier, due to fatigue, dyspnea, and a non specific inflammatory process, an enhanced-contrast-scan showed that aorta was coated with a hypodense tissue that began near the aortic valve and extended until the inferior mesenteric artery, with stenosis of the left subclavian, celiac axis, renal and upper mesenteric arteries. An angioplasty and stent placing was carried out in the last two arteries. Both kidneys had the appearance of "hairy kidneys". A bone scan showed increased uptake in femurs and tibiae and X-ray examination showed osteosclerosis in metaphysis and diaphysis. The diagnosis of Erdheim-Chester disease (non-Langerhans-cell histiocytosis) was made and the patient was treated with steroids and methotrexate. PMID- 22215337 TI - [Congenital adrenal hyperplasia causing male infertility. Report of one case]. AB - In males, congenital adrenal hyperplasia due to 21 hydroxylase deficiency is associated to normal fertility or infertility caused by a hypogonadotrophic hypogonadism (HH) or gonadal damage caused by intratesticular adrenal remnants. We report a 29-year-old male with azoospermia, without any important personal or family background. Physical examination was normal, his height was 150 cm and his testicular volume was 10 ml (normal 15 to 25 ml). Laboratory showed a normal testosterone and FSH and LH in the low normal limit. These results discarded a HH, whose diagnostic requirements are a low testosterone and inadequately normal or low gonadotrophins. A testicular biopsy was informed as compatible with HH. A 21 hydroxylase deficiency was suspected and confirmed with extremely high levels of 17 hydroxyprogesterone at baseline and after stimulation with fast acting ACTH. Clomiphene citrate did not increase testosterone or gonatrophin levels. Testicular ultrasound discarded the presence of adrenal nodules. Betametasone therapy resulted in a normal testicular development, normalization of sperm count, reduction of 17 hydroxyprogesterone and testosterone levels with an ulterior rise of the latter. Spontaneous paternity was achieved twice. It must be remembered that in cases of azoospermia due to congenital adrenal hyperplasia, testosterone produced by adrenal glands hinders the laboratory diagnosis of HH. PMID- 22215338 TI - [Virilization caused by an ovarian tumor. Report of one case]. AB - We report a 76-year-old woman with a virilization syndrome characterized by progressive androgenic alopecia, clitoris enlargement and hirsutism predominating in the face. Plasma testosterone was 711 ng/dl. Magnetic resonance imaging showed slightly enlarged ovaries with a cyst in the left. A bilateral oophorectomy was performed, demonstrating the presence of a Leydig cell hilar tumor in the right ovary. The patient had a good postoperative evolution with reduction of androgen levels and reversion of alopecia. PMID- 22215339 TI - [Hybrid management of an infectious pseudoaneurysm. Report of one case]. AB - We report a 61-year-old male with a four months history of progressive back pain, fever, weight loss and hematuria. A CAT scan showed a spondylitis with destruction of L1 and L2 vertebral bodies and a big pseudoaneurysm of the posterior wall of the visceral aorta. A hybrid approach was used to repair the lesion in two stages; a surgical superior mesenteric artery revascularization followed by the placement of an endovascular stent graft in the affected segment of the aorta 48 hours later, excluding the lesion from circulation. In the postoperative period, no evidence of mesenteric vascular insufficiency was detected but the patient developed a systemic inflammatory response that was managed adequately. A CAT scan performed one month later confirmed the exclusion of the pseudoaneurysm. One year after surgery, the patient is able to walk and without evidences of infection or pseudoaneurysm. PMID- 22215340 TI - [Evaluation of public health risk. A new instrument for environmental management in Chile]. AB - One of the main challenges in environmental management is to prevent the public health impact of projects that can cause pollution. To tackle this problem, the new Chilean bill on environmental management has defined the need to determine the potential health risks of a given Project. This paper gives a summary of the method used for risk evaluation and its evolution. Its incorporation in the Environmental Impact Evaluation System is proposed, to guarantee an effective prevention of the potential risks on health of new projects. PMID- 22215341 TI - [A consensus definition of internal medicine and the internist]. AB - Internal Medicine is a basic clinical specialty in Medicine, but due to it's vast field of action it is quite difficult to define. This consensus article analyzes different definitions and proposes a current definition while analyzing several aspects of the specialty along with its strengths and weaknesses. We propose to define Internal Medicine as a clinical specialty devoted to the comprehensive care of adults, from adolescence to senility, particularly the diagnosis and non surgical treatment as well as primary and secondary prevention of their diseases, in hospital or ambulatory settings. We propose to define Internal Medicine as a clinical specialty devoted to the comprehensive care of adults in hospital or ambulatory settings, from adolescence to end of life, in terms of prevention, diagnosis and non-surgical treatments of disease. PMID- 22215342 TI - [Mathematical simulation of mild brain injury in children heading soccer balls]. AB - BACKGROUND: Heading professional soccer balls can generate mild traumatic brain injury in children. The long-term consequences could include difficulty in solving problems and deficits in memory and language. AIM: To assess the impact of a professional adult soccer ball on a child's head, using the finite element method and dynamic effects to predict brain damage. MATERIAL AND METHODS: The minimum conditions of an adult game were considered: the ball speed was 6 m/s and the diffuse blow was 345 and 369 Newtons (N), on the forehead and top of the head, respectively. A head was modeled in order to know the stresses, strains and displacements generated by the impacts. The extent of the alteration was determined by comparing the strength of brain tissue, with predictions of computed stresses. The geometric characteristics of the head were transferred from medical images. The input data of the materials of a child's head was obtained from the literature. RESULTS: In the case of heading with the forehead, mathematical simulation showed frontal lobe alterations, with brain stresses between 0.064 and 0.059 N/mm(2). When the heading was with the upper head zone, the brain alterations were in the parietal lobe, with stresses between 0.089 and 0.067 N/mm(2). In the cerebral spinal fluid the pressure was 3.61 to 3.24 N/mm(2). CONCLUSIONS: The mathematical simulations reveal evidence of brain alterations caused by a child heading adult soccer balls. The model presented is an economical and quick tool that can help predict brain damage. It demonstrates the ability of the cerebral spinal fluid (CSF) to absorb shock loads. PMID- 22215343 TI - [Ethical aspects of academic management in a faculty of medicine]. AB - This article states that the incorporation of ethical issues such as bioethics and principles of good practice, facilitates the academic management in a Faculty of Medicine. It presents some interesting aspects necessary to carry out a quality academic management that serves the university mission and its educational and research project. It underlines good practices regarding not only professional relations but also organizational aspects. It includes an analysis of academic management and its association with quality and leadership, it reflects on the ethical values of quality work and on the theory of functional or interactional leadership, a key element to boost the development of a university health institution. PMID- 22215344 TI - [Re-certification of medical specialties in Chile: the role of scientific medical societies]. PMID- 22215345 TI - [Post-anesthesia recovery. A perspective of patients]. PMID- 22215346 TI - [The first 4000 cardiac surgeries performed in Concepcion, Chile]. PMID- 22215347 TI - Drug shortages--Congress listens, FDA acts. PMID- 22215348 TI - Solid data lacking on HIT and patient safety. PMID- 22215349 TI - REMS review explores programs' burdens. PMID- 22215352 TI - Global reach of online direct-to-consumer drug advertising. PMID- 22215353 TI - Physical compatibility of calcium gluconate and magnesium sulfate injections. PMID- 22215354 TI - Surviving in a cofunded faculty appointment. PMID- 22215355 TI - Billing for pharmacists' services provided to ambulatory care patients. PMID- 22215356 TI - Aztreonam lysine for inhalation: new formulation of an old antibiotic. AB - PURPOSE: The pharmacology, safety, efficacy, pharmacokinetics, pharmacodynamics, current place in therapy, and potential future therapeutic uses of inhaled aztreonam are reviewed. SUMMARY: Inhaled aztreonam, a newly formulated lysine salt of the original monobactam antibiotic, is approved for the treatment of respiratory symptoms in patients with cystic fibrosis (CF) who are colonized with Pseudomonas aeruginosa. Its spectrum of activity is limited to susceptible gram negative organisms, including P. aeruginosa. Lyophilized aztreonam lysine is diluted with 0.17% sodium chloride and administered using the Altera nebulizer system, which produces appropriate-sized particles for proper deposition in the lungs to achieve high sputum and low systemic concentrations. Mean sputum drug concentrations are highest 10 minutes after dose administration, and plasma concentrations peak one hour after inhalation. Aztreonam is excreted via active tubular secretion and glomerular filtration. Caution is advised in patients with renal or hepatic impairment, breastfeeding women, and patients age 65 years or older. Like the older i.v. formulation, inhaled aztreonam displays time-dependent killing. Phase III clinical trials have shown improvements in respiratory symptoms, decreased P. aeruginosa sputum density, prolonged time intervals between antibiotic treatments, and efficacy without the development of resistance in the face of repeated exposures. This formulation is available only from select specialty pharmacies and should only be used with the Altera nebulizer system. CONCLUSION: Inhaled aztreonam has shown efficacy and safety in patients seven years of age or older with CF who have P. aeruginosa airway infections. This product may complement existing therapies and offers the advantage of a new inhaled formulation to aid in treatment regimens. PMID- 22215357 TI - Practical considerations for optimal transdermal drug delivery. AB - PURPOSE: The properties of various transdermal drug delivery system (TDDS) products are reviewed, with safety recommendations and guidance on addressing questions frequently posed by patients and caregivers. SUMMARY: Drug delivery via a TDDS can offer many advantages over other methods of administration, but those benefits can be compromised by improper use or alteration of medication patches or a lack of awareness of the properties of different patch types (reservoir, matrix, drug-in-adhesive). To assess current TDDS technologies and recommended practices for safe and effective use of medication patches, a literature search for articles on commonly used TDDS products available in the United States was conducted; supplemental information was obtained from package inserts and through direct communication with manufacturers. In addition to recommendations on the site and duration of TDDS application and proper patch disposal, clinicians must consider (1) potential problems with cutting patches as a method of dosage adjustment, (2) safety concerns related to the electric conductivity of metal containing patches, (3) appropriate strategies for managing patch adhesion failures, and (4) the advisability of writing on patches for medication safety or compliance reasons. Clinicians should also be prepared to counsel patients about TDDS-specific recommendations on the avoidance of sunlight and other external heat sources during the use of a medication patch. CONCLUSION: Practical considerations related to transdermal drug delivery include the appropriateness of cutting patches, the implications of their containing metallic components, and whether they may be covered with tape or written on. Manufacturers of patches provide some useful information on these topics. PMID- 22215358 TI - Deep vein thrombosis associated with a single dose of romiplostim in a high-risk patient. AB - PURPOSE: The case of a patient who developed thrombosis after receiving a single dose of romiplostim is reported. SUMMARY: A 63-year-old, 76-kg Caucasian man arrived at our clinic complaining of right-lower-extremity edema and redness. The patient had a complicated cardiac history, including two coronary artery bypass grafts and five percutaneous coronary interventions. The patient had a history of stage IV marginal zone lymphoma of the distal stomach and proximal duodenum and stage IV mantle cell lymphoma, both of which were successfully treated. He also underwent peripheral blood autologous bone marrow transplantation. Over a year later, the patient was found to have profound thrombocytopenia, with a platelet count of <5 * 10(9)/L. A bone marrow biopsy was negative for active lymphoma but suggested idiopathic thrombocytopenia purpura (ITP). One week after receiving a single subcutaneous dose (1 MUg/kg) of romiplostim, the patient complained of lower-right-extremity edema and redness. Suspicion of a deep vein thrombosis (DVT) was confirmed with a Doppler study. At the time of his DVT, his platelet count was 51 * 10(9)/L. The patient was given enoxaparin 1 mg/kg subcutaneously twice daily for six months. Romiplostim was discontinued after the first dose; however, the patient continues to take danazol. Since then, the patient's platelet count has consistently remained above 50 * 10(9)/L. The patient had no further venous thromboembolic events. CONCLUSION: A 63-year-old man with a history of cardiovascular disease and prior malignancy developed a DVT after receiving a single dose of romiplostim for the treatment of ITP. PMID- 22215359 TI - Pharmacokinetics of tacrolimus and mycophenolate mofetil in renal transplant recipients on a corticosteroid-free regimen. AB - PURPOSE: The pharmacokinetics of both tacrolimus and mycophenolic acid in renal transplant recipients on a corticosteroid-free regimen was evaluated. METHODS: Upon administration of steady-state morning tacrolimus and mycophenolate mofetil doses, 28 patients for whom at least three months had passed after renal transplantation underwent serial blood sample collection over a 12-hour dosing period. Whole blood concentrations of tacrolimus were measured, as were mycophenolic acid, mycophenolic acid 7-0-glucuronide (MPAG), and acyl glucuronide MPAG (AcMPAG) concentrations. Pharmacokinetic parameters were then analyzed by conventional noncompartmental modeling. RESULTS: The mean +/- S.D. pharmacokinetic parameters for tacrolimus, normalized to a dose of 1 mg, were as follows: area under the concentration-time curve (AUC), 52.6 +/- 24.8 MUg . hr/L/mg; maximum concentration (C(max)), 8.0 +/- 3.3 MUg/L/mg; time to C(max) (t(max)), 1.8 +/- 1.0 hr; and minimum concentration (C(min)), 2.6 +/- 1.4 MUg/L/mg. The mean +/- S.D. pharmacokinetic parameters for mycophenolic acid, normalized to a mycophenolate mofetil dose of 1 g, were AUC, 26.9 +/- 13.2 MUg .hr/mL/g; C(max), 17.5 +/- 5.4 MUg/mL/g; t(max), 0.9 +/- 0.6 hr; and C(min), 1.5 +/- 1.1 MUg/mL/g. The free fraction of mycophenolic acid was 1.8% +/- 0.7%. AUC ratios of MPAG:mycophenolic acid and AcMPAG:mycophenolic acid were 13.0 +/- 5.8 and 0.1 +/- 0.2, respectively. CONCLUSION: Overall exposure and C(min) values for tacrolimus were similar but C(max) values were higher than those documented in renal transplant patients treated with corticosteroid-based regimens. This may have clinical implications in corticosteroid-free patients experiencing symptoms of tacrolimus toxicity despite trough levels within target ranges. Mycophenolic acid exposure increased with time, but AUC values fell within the range expected for patients receiving concurrent corticosteroids. PMID- 22215360 TI - Billing for outpatient transplant pharmacy services. AB - PURPOSE: The economic impact of out-patient pharmacy services in a transplant program was evaluated. METHODS: Full-time kidney transplant pharmacy services were implemented at Providence Sacred Heart Medical Center (PSHMC) in the fall of 2008, with two pharmacists combining hours to provide one full-time-equivalent position. At PSHMC, posttransplantation patients are seen three times per week. The number of patient visits with pharmacists for 2010 was compared with the total number of patient visits. The face-to-face time spent with the patient was translated to a level of billing that was associated with a set reimbursement schedule. For each patient encounter in which a pharmacist was involved, the incremental difference between the nursing and pharmacy levels of billing was examined, as were the levels most often billed by pharmacists. The difference in billing levels between pharmacists and nurses for the same patient encounter was also evaluated. RESULTS: Overall, pharmacist visits accounted for 208 (22%) of the 994 out-patient kidney transplant visits in 2010, with pharmacists billing at a higher level of acuity compared with nursing for the same patient encounter 48% of the time. This translated to an approximate increase of $100 per patient visit. For the one-year study period, pharmacists utilizing facility- fee billing increased out-patient reimbursement by approximately $10,000. CONCLUSION: By utilizing outpatient facility-fee billing for pharmacy services, the transplant program at PSHMC increased reimbursement in the outpatient setting. PMID- 22215361 TI - Cost-effectiveness of posaconazole versus fluconazole for prevention of invasive fungal infections in U.S. patients with graft-versus-host disease. AB - PURPOSE: The results of a pharmacoeconomic study of the cost-effectiveness of posaconazole versus fluconazole in preventing invasive fungal infections (IFIs) in patients with graft-versus-host disease (GVHD) are reported. METHODS: The results of a randomized clinical trial suggested that posaconazole may be as effective as fluconazole for the prevention of IFIs in recipients of allogeneic cell transplants who develop severe GVHD and that posaconazole may be superior to fluconazole in reducing IFI-related deaths. Using published data from that trial and data from secondary sources, an economic model was developed to estimate the costs, IFIs avoided, and life-years saved with posaconazole versus fluconazole therapy. The results of the modeled 112-day treatment simulation were extrapolated to a lifetime horizon. RESULTS: In the modeled simulation, posaconazole therapy was associated with a lower probability of IFI development (0.05 versus 0.09), increased discounted life-years (7.87 life-years versus 7.66 life-years), and higher discounted costs per patient ($8,860 versus $5,710 in 2006 U.S. dollars) relative to fluconazole therapy. The estimated incremental cost-effectiveness of posaconazole versus fluconazole for IFI prophylaxis was $85,300 per IFI avoided and $15,300 per life-year saved. A sensitivity analysis indicated a 90% probability that the use of posaconazole for this purpose would be cost-effective at a threshold of $50,000 per life-year saved. CONCLUSION: Posaconazole is in the range of currently accepted criteria for cost- effectiveness relative to fluconazole for the prevention of IFIs among patients with GVHD. PMID- 22215362 TI - Value of pharmacy residency training: a survey of the academic medical center perspective. AB - PURPOSE: The results of a survey assessing the views of pharmacy directors, medical center executives, and pharmacists on the value of residency programs to their institutions are reported. METHODS: In a two-phase survey entailing face-to face interviews and the use of an electronic questionnaire, representatives of the pharmacy departments and executive staffs of eight academic medical centers were asked to rate the impact of pharmacy residency programs in areas such as educational and research innovation, quality-of-care and cost outcomes, and opportunities for revenue generation. RESULTS: Seven hospital administrators, eight directors of pharmacy, 122 pharmacists serving as residency preceptors, and 91 nonpreceptor pharmacists participated in the survey. The survey responses indicated that hospital administrators view pharmacy residency programs as important contributors to their institutions' prestige, academic success, and capacity for delivering educational programs. All directors of pharmacy surveyed were in agreement that the costs associated with conducting a pharmacy residency program are outweighed by the cost savings achieved through resident contributions to patient care and medication error prevention. A large majority (90%) of preceptor pharmacists agreed or strongly agreed that residents help reduce medication errors by educating prescribers and other activities that promote rational medication use; only about half of nonpreceptor pharmacists shared that view, although 65% of nonpreceptors acknowledged the contributions of residents to overall pharmacy department success. CONCLUSION: All groups of survey respondents viewed residency programs as important assets to their institutions, especially in the areas of institutional prestige, staff recruitment, and professional development and education. PMID- 22215363 TI - Effect of delayed diagnosis on severity of Pott's disease. AB - PURPOSE: We analysed delay in diagnosis (DID) and disease severity in patients with vertebral tuberculosis (TB) in India. METHODS: We interviewed 228 patients with vertebral TB and reviewed their diagnostic magnetic resonance images (MRIs). We examined patient characteristics at the time of presentation and associations between socioeconomic background, access to care, DID and radiographic disease severity at the time of diagnosis. RESULTS: The most common presenting symptom was localised back pain (84%), followed by fever (40%) and pain elsewhere (28%). The median DID was five months [interquartile range (IQR) 3-9]. In multivariate logistic regression, Muslim and older patients had a higher risk of extreme (more than ten months) DID [adjusted odds ratio (aOR) 2.91; 95% confidence interval (CI) 1.20-7.08 and 2.33; 95% CI 1.23-4.94, respectively]. One hundred and two patients (64%) had vertebral abscesses. Median local kyphotic deformity was 11.7 degrees (IQR 0-18.5 degrees ). Fifty-four (34%) patients had radiologically severe disease at the time of diagnosis. Older patients and those with higher education were less likely to have severe disease at the time of diagnosis (aOR 0.32; 95% CI 0.13-0.76 and 0.20 95% CI 0.06-0.62, respectively). Patients who experienced extreme DID were more likely to have severe disease (aOR 2.67; 95% CI 1.05-6.99). CONCLUSIONS: Most patients in this cohort experienced long delays in diagnosis, and such delay was significantly associated with the presence of severe disease. Clinicians in TB-endemic areas must consider vertebral TB early and obtain imaging in patients who complain of persistent back pain. Improved diagnostic criteria are needed to identify patients at higher risk of disease. PMID- 22215364 TI - The surgical treatment and related management for post-tubercular kyphotic deformity of the cervical spine or the cervico-thoracic spine. AB - PURPOSE: The outcomes of surgical treatment and related complications of post tubercular kyphotic (PTK) deformity of the cervical spine or the cervico-thoracic spine were evaluated. METHODS: From January 2005 to October 2010, 12 cases with PTK (7 males, 5 females) with an average age of 30 years (range 21-43 years) formed the study group. There were ten patients with cervical deformities and two with cervico-thoracic kyphosis. Neurological function of all the patients was evaluated by the Japanese Orthopaedic Association (JOA) score and visual analogue scale (VAS) score. Two patients with severe cervico-thoracic deformity received modified skeleton traction pre-operatively. Ten patients underwent anterior debridement and reconstruction, using iliac crest or cages with autografts, while two patients with cervico-thoracic kyphosis received posterior instrumentation and fusion. RESULTS: The mean pre-operative focal kyphotic angle was 42.58 degrees (range 30-67 degrees ), reducing to -8 degrees (range -15-11 degrees ) postoperatively (at the last follow-up visit). The average operating time was 117.50 min (80-200 min) with an average blood loss of 110 ml (range 50-300 ml). Neurological assessment of all the patients, using the Japanese Orthopaedic Association (JOA) score and visual analogue scale (VAS) score, was improved significantly after surgery. All patients had solid fusion and no major complication was observed in the follow-up. CONCLUSION: One-stage anterior debridement, instrumentation and fusion for cervical spinal TB and single posterior instrumentation for cervico-thoracic spinal TB followed by chemotherapy is practical to correct PTK. The procedure has the advantage of lower blood loss, effective kyphosis correction and minimal complications. To patients with severe deformity, skeletal traction seemed indispensible. PMID- 22215365 TI - Surgical treatment of spondylodiscitis. An update. AB - CONCEPT: Spondylodiscitis refers to an infection affecting the intervertebral disk, the vertebral body or the posterior arch of the vertebra being aetiologically, pyogenic, granulomatous (tuberculosis, brucellosis, or fungal infection) or parasitic. DIAGNOSIS: Spondylodiscitis diagnosis is based on clinical symptoms, a combination of erythrocyte sedimentation rate with C reactive protein (CRP) tests and, less useful, leukocytosis. Blood culture is also a very cost-effective method of identifying organisms. Plain radiographs are useful, however changes may take several months to appear. Radionuclide tests are currently less used; nevertheless, fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) shows encouraging results particularly when magnetic resonance images (MRI) are unconvincing in the distinction between degenerative changes and infection. MRI with gadolinium enhancement is the choice for image diagnosis. MANAGEMENT: Medical management is usually the basis for treatment, alone or in combination with surgery. Surgical approach, either by endoscopy or open, is indicated for biopsy when clinical evolution is unsatisfactory and no micro-organism has been isolated, and also whenever a root, spinal cord or dural compression is seen on MRI; spinal instability or severe deformity are also clear indications for surgical treatment. Less invasive surgery either CT-scan guided or, particularly, by endoscopy has good results. However open surgery is still the standard. The anterior approach allows for anterior disc and bone debridement. The posterior approach is indicated when posterior elements are involved or in the presence of an epidural abscess. Although good results have been claimed, the use of instrumentation in the presence of an infected focus is controversial, as the use of cages or BMPs are. PMID- 22215366 TI - Management of infectious discitis. Outcome in one hundred and eight patients in a university hospital. AB - PURPOSE: The optimal management of pyogenic discitis is not agreed on. We conducted a retrospective, cross-sectional, observational study in which all patients with discitis who attended Hospital San Carlos Madrid from January 1999 to January 2009 were included. METHODS: We identified 108 consecutive adult patients with infectious discitis. There were 49 men and 59 women with an average age of 67,5 (+/- 16,89) years in the study group. Mean follow-up interval was 6,06 (12,5-2) years. 78 patients had spontaneous discitis and 30 patients had postoperative discitis. Inclusion criteria for the review were illness compatible with vertebral infection and / or evidence of spinal involvement on magnetic resonance imaging (MRI). RESULTS: In 56 percutaneous discal biopsy (52% patients) were positive in 28 cases. A single disc was infected in 100 patients. The segments involved were the cervical spine in four, the thoracic spine in 38 and the lumbar spine in 66. One or more comorbid diseases were present in 73 (68%) of 108 patients. Diabetes mellitus was the most common disease. Comorbid disease was rapidly fatal in four patients, ultimately fatal in seven patients, and nonfatal or not present in 97 patients (90 %). CONCLUSION: Early diagnosis is a major challenge. Heightened awareness and the prompt use of MRI are necessary to avoid diagnostic delay. Prolonged antimicrobial therapy and the judicious application of timely surgical intervention are essential for an optimal outcome. PMID- 22215367 TI - Changes of contact pressure and area in patellofemoral joint after different meniscectomies. AB - PURPOSE: We investigated the contact pressure and area of the patellofemoral joint both before and after different meniscectomies to provide a biomechanical basis for selecting meniscectomy and its clinical application for meniscus injuries. METHODS: Six fresh cadaveric knees were used in the study. Using Staubli robots and an ultra-low-min-type pressure-sensitive tablet, changes in contact area and stress in the patellofemoral joint were measured at various flexion angles following different parts and degrees of meniscectomy. RESULTS: The patellofemoral contact area enlarged with the increase of knee flexion angle. From the values obtained from contact areas and average contact pressure of the patellofemoral joint, we found no significant difference between partial meniscectomy and intact knees, but a significant difference was found between total meniscectomy and intact knees. The contact area after lateral meniscectomy was statistically less than that of intact knees. The mean patellofemoral contact pressure after lateral meniscectomy was larger than in intact knees at each angle of flexion. No significant difference in contact area was observed between intact knees and medial meniscectomy. The average patellofemoral contact pressure after medial meniscectomy was larger than in intact knees from 0 degrees ~ 30 degrees of knee flexion, and no significant differences were found between intact knees and medial meniscectomy while knee bending from 60 degrees to 90 degrees . CONCLUSIONS: Different meniscectomies result in high contact pressure or disordered distribution of contact pressure, which may be the cause of postoperative patellofemoral degenerative arthrosis. PMID- 22215368 TI - Thoracoscopic decompression in Pott's spine and its long-term follow-up. AB - PURPOSE: Video-assisted thoracoscopic surgery (VATS) has become an alternative tool for a variety of spinal conditions as this approach minimises much morbidity related to conventional thoracotomy. The purpose of this study was to determine the efficacy of VATS and its long-term results in patients with dorsal spinal tuberculosis. MATERIALS AND METHODS: This retrospective long-term follow-up study of VATS-assisted surgical treatment of dorsal spine tuberculosis included 30 patients with a mean age of 33.5 years (range 15-60). Patients with dorsal spine tuberculosis who were suitable surgical candidates for VATS underwent a three portal thoracoscopy for decompression with/without fusion of the spine along with routine chemotherapy for tuberculosis (TB). Patients were assessed for blood loss, duration of surgery, postoperative incision pain, duration of hospital stay, neurological recovery, and progression of deformity. Patients were observed for a minimum of five years. RESULTS: The mean duration of surgery was 158.8 min (range 90-220 min) with mean blood loss of 296.7 ml (range 200-450 ml). Complications were seen in ten patients. The mean follow-up was 80 months (range 60-90 months) with neurological improvement and return of ambulatory power in all patients at final follow-up. There was an average increase in kyphus angle by 7.5 degrees at final follow-up and 95% of patients achieved an excellent or good subjective outcome. CONCLUSION: VATS-assisted surgical decompression can be a safe and effective technique for anterior debridement and fusion in tuberculosis of the dorsal spine to achieve neurological recovery with reduced morbidity, blood loss, and hospital stay compared to thoracotomy. PMID- 22215369 TI - Risk factors and distribution of symptomatic venous thromboembolism in total hip and knee replacements: prospective study. AB - PURPOSE: Venous thromboembolism (VTE) is a common complication of orthopaedic surgery in the industrialised world; though there may be variability between population groups. This study aims to define the incidence and risk factors for symptomatic VTE following primary elective total hip and knee arthoplasty surgery in a single centre in Eastern Europe. METHODS: This prospective study included 499 adult patients undergoing total hip and knee arthroplasty for symptomatic osteoarthritis over a two-year period at the Clinic of Orthopaedic Surgery and Traumatology, Belgrade. RESULTS: The overall rate of confirmed symptomatic VTE during hospitalisation was 2.6%. According to the univariate logistic regression, an age greater than 75 years (OR = 3.08; 95%CI = 1.01-9.65), a family history of VTE (OR = 6.61; 95% CI = 1.33-32.90), varicose veins (OR = 3.13; 95% CI = 1.03 9.48), and ischemic heart disease (OR = 4.93; 95% CI = 1.61-15.09) were significant risk factors for in-hospital VTE. A family history of VTE and ischemic heart disease were independent risk factors according to multivariate regression analysis. Preoperative initiation of pharmacological thromboprophylaxis (p = 0.03) and a longer duration of thromboprophylaxis (p = 0.001) were protective for postoperative DVT. Though thromboprophylaxis was safe, with very few patients suffering major haemorrhage or heparin-induced thrombocytopenia, there was a general reluctance by our local surgeons to use prolonged thromboprophylaxis. CONCLUSION: VTE is common following hip and knee arthroplasty surgery. Orthopaedic patients with a family history of VTE, heart failure and coronary heart disease are at a considerable risk of thromboembolic complications in the postoperative period. There may be a role for preoperative thromboprophylaxis in addition to prolonged postoperative treatment. PMID- 22215376 TI - Cognitive deficit is associated with phase advance of sleep-wake rhythm, daily napping, and prolonged sleep duration--a cross-sectional study in 2,947 community dwelling older adults. AB - This study aims to examine the phase advance of sleep-wake rhythm, napping habit, nocturnal sleep duration, prolonged sleep latency and insomnia and their relationship with cognitive function. This is a cross-sectional study. Participants in this study are 2,947 community-dwelling adults older than 65 years old. Measurements of mini-mental examination (MMSE) score, go-to-bed time, wake-up time, nocturnal sleep duration, prolonged sleep latency, napping, and insomnia were done. The mean (standard deviation) nocturnal sleep hours was 7.96 (1.39) h. Twenty-one percent and 16.2% of the participants complained of prolonged sleep latency longer than 1 h and insomnia, respectively. Fifty-six percent of the participants napped once or more than once weekly. With advancing age, the participants reported longer sleep duration (p<0.001), went to bed earlier, and woke up earlier, which were significant both before and after adjustment. The participants who had lower MMSE score went to bed earlier and woke up earlier, which were statistically significant both before and after adjustment. An inverted U-shaped relationship was observed between MMSE score and napping frequency, p for tend 0.026.The MMSE score decreased when the sleep duration prolonged from 7 h to ?10 h (p for trend 0.006). No trend was observed from the sleep duration <4 up to 7.9 h (p for trend 0.500). Modest age independent phase advance of the sleep-wake rhythm is associated with lower cognitive function. Whether this is a manifestation of early pre-clinical dementia and whether its recognition with early stabilization can slow cognitive decline remain elusive. PMID- 22215375 TI - Chronic training increases blood oxidative damage but promotes health in elderly men. AB - The objective of the present study was to investigate a large panel of oxidative stress biomarkers in long-term trained elderly men to analyse the effects of chronic training on an aged population. We collected blood samples from two groups of male volunteers older than 65 years who maintain a measure of functional independence: one group of sedentary subjects without a history of regular physical activity and the other of subjects who have sustained training, starting during middle age (mean training time=49 +/- 8 years). We studied morbidity and polypharmacy, as well as haematological parameters including red cell count, haemoglobin concentration, haematocrit, mean corpuscular volume, red cell distribution width and several oxidative biomarkers including protein carbonyl content and lipid peroxidation in plasma and erythrocytes, red blood cell H2O2-induced haemolysis test, plasma total antioxidant activity and the main antioxidant enzymes of erythrocytes: superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase. After adjusting for confounding factors, we observed an increase in all oxidative damage biomarkers in the plasma and erythrocytes of the long-term exercise group. However, we reported a decrease in the number of diseases per subject with statistical differences nearly significant (p=0.061), reduced intake of medications per subject and lower levels of red cell distribution width in the chronic exercise group. These results indicate that chronic exercise from middle age to old age increases oxidative damage; however, chronic exercise appears to be an effective strategy to attenuate the age-related decline in the elderly. PMID- 22215377 TI - Momilactione B inhibits protein kinase A signaling and reduces tyrosinase-related proteins 1 and 2 expression in melanocytes. AB - Momilactone B (MB) is a terpenoid phytoalexin present in rice bran that exhibits several biological activities. MB reduced the melanin content in B16 melanocytes melanin content and inhibited tyrosinase activities. Using transcriptome analysis, the genes involved in protein kinase A (PKA) signaling were found to be markedly altered. B16 cells stimulated with MB had decreased concentrations of cAMP protein kinase A activity, and cAMP-response element-binding protein which is a key transcription factor for microphthalmia-associated transcription factor (MITF) expression. Accordingly, the expression of MITF and its target genes, which are essential for melanogenesis, were reduced. MB thus exhibits anti melanogenic effects by repressing tyrosinase enzyme activity and inhibiting the PKA signaling pathway which, in turn, decreases melanogenic gene expression. PMID- 22215378 TI - Accumulation of pyruvate by changing the redox status in Escherichia coli. AB - Pyruvate was produced from glucose by Escherichia coli BW25113 that contained formate dehydrogenase (FDH) from Mycobacterium vaccae. In aerobic shake-flask culture (K (L) a = 4.9 min(-1)), the recombinant strain produced 6.7 g pyruvate l(-1) after 24 h with 4 g sodium formate l(-1) and a yield of 0.34 g pyruvate g glucose(-1). These values were higher than those of the original strain (0.2 g l( 1) pyruvate and 0.02 g pyruvate g glucose(-1)). Based on the reaction mechanism of FDH, the introduction of FDH into E. coli enhances the accumulation of pyruvate by the regeneration of NADH from NAD(+) since NAD(+) is a shared cosubstrate with the pyruvate dehydrogenase complex, which decarboxylates pyruvate to acetyl-CoA and CO(2). The oxygenation level was enough high to inactivate lactate dehydrogenase, which was of benefit to pyruvate accumulation without lactate as a by-product. PMID- 22215380 TI - Close encounters of the distracting kind: identifying the cause of visual tracking errors. AB - Why can we track only so many objects? We addressed this question by asking when and how tracking errors emerge. To test the hypothesis that many tracking errors are target/nontarget confusions emerging from close encounters, we compared standard multiple-object tracking trials with trials on which a nontarget turned a random color whenever it approached within 4 degrees of a target. This manipulation significantly improved performance by alleviating the correspondence challenge of a close encounter. Two control experiments showed that color change benefits were not merely due to target recovery. Follow-up experiments demonstrated that color change benefits did not accrue monotonically with distance but, instead, seemed to obey a step function; and an additional experiment demonstrated that, without color changes, the frequency of close encounters predicts tracking performance. Taken together, these experiments suggest that uncertainty about target location imposes the primary constraint on tracking, at times causing errors by leading to confusions between targets and nontargets. PMID- 22215379 TI - Expression of functional gamma-aminobutyric acid type A receptors in Schwann-like adult stem cells. AB - gamma-Aminobutyric acid (GABA) receptors are present in peripheral and central glia and modulate important physiological parameters of glial cells. Schwann cells (SC), the peripheral nervous system glial cells, play essential roles in nerve regeneration, but they are unsuitable for bioengineering of nerve repair. Increasing interest has been focused on adult stem cells derived from bone marrow (BM-MSC) or adipose tissue (ASC), which can be differentiated into SC-like phenotype and used as SC replacements. SC-like adult stem cells express GABA-B receptors that can modulate their proliferation. The aim of this study was to investigate GABA-A receptors functional expression in differentiated stem cells. BM-MSC and ASC were found to express GABA-A alpha2 and beta3, but not beta1 mRNA transcripts. Protein expression levels of GABA-A alpha2 and beta3 receptors were upregulated following SC-like differentiation as shown by Western blot studies. GABA-A receptor stimulation with muscimol increased the proliferation rate of SC, differentiated BM-MSC and differentiated ASC. In conclusion, GABA-A alpha2 and beta3 receptor subunits are present in BM-MSC and ASC and upregulated following glial differentiation. GABA-A subunits in differentiated stem cells and SC assemble in functional receptors modulating cell proliferation. Functional GABA-A and GABA-B receptors represent a possible pharmacological target to modulate SC like stem cells physiology. PMID- 22215381 TI - Fluorescence detection methods for microfluidic droplet platforms. AB - The development of microfluidic platforms for performing chemistry and biology has in large part been driven by a range of potential benefits that accompany system miniaturisation. Advantages include the ability to efficiently process nano- to femoto- liter volumes of sample, facile integration of functional components, an intrinsic predisposition towards large-scale multiplexing, enhanced analytical throughput, improved control and reduced instrumental footprints. In recent years much interest has focussed on the development of droplet-based (or segmented flow) microfluidic systems and their potential as platforms in high-throughput experimentation. Here water-in-oil emulsions are made to spontaneously form in microfluidic channels as a result of capillary instabilities between the two immiscible phases. Importantly, microdroplets of precisely defined volumes and compositions can be generated at frequencies of several kHz. Furthermore, by encapsulating reagents of interest within isolated compartments separated by a continuous immiscible phase, both sample cross-talk and dispersion (diffusion- and Taylor-based) can be eliminated, which leads to minimal cross-contamination and the ability to time analytical processes with great accuracy. Additionally, since there is no contact between the contents of the droplets and the channel walls (which are wetted by the continuous phase) absorption and loss of reagents on the channel walls is prevented. Once droplets of this kind have been generated and processed, it is necessary to extract the required analytical information. In this respect the detection method of choice should be rapid, provide high-sensitivity and low limits of detection, be applicable to a range of molecular species, be non-destructive and be able to be integrated with microfluidic devices in a facile manner. To address this need we have developed a suite of experimental tools and protocols that enable the extraction of large amounts of photophysical information from small-volume environments, and are applicable to the analysis of a wide range of physical, chemical and biological parameters. Herein two examples of these methods are presented and applied to the detection of single cells and the mapping of mixing processes inside picoliter-volume droplets. We report the entire experimental process including microfluidic chip fabrication, the optical setup and the process of droplet generation and detection. PMID- 22215383 TI - DPP-4 inhibitors and lipids: systematic review and meta-analysis. AB - INTRODUCTION: Lipid profile is an important determinant of cardiovascular risk in type 2 diabetic patients. Available glucose-lowering agents can affect lipid levels. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to reduce total cholesterol, but results are inconsistent across trials. The present metaanalysis was designed to assess the effect of DPP-4 inhibitors on blood lipids, verifying possible differences across compounds of this class. METHODS: An extensive search of Medline and the Cochrane Library (any date up to December 31, 2010, restricted to randomized clinical trials, published in English) was performed for all trials containing, in any field, the words "sitagliptin," "vildagliptin," "saxagliptin," "alogliptin," "linagliptin," and/or "dutogliptin." Completed but unpublished trials were identified through a search of the ClinicalTrials.gov website, using the same keywords as above. Differences in the endpoint levels and absolute or percent variations of lipids were assessed. A metaregression was performed on the trials specified above to assess the effect of putative moderators on the effect of DPP-4 inhibitors on plasma lipids, considering all drugs together and each one separately. RESULTS: Although the number of trials of appropriate size and duration was high (n=53), only a small fraction of those (n=17) reported data on endpoint total, high-density lipoprotein, and low-density lipoprotein cholesterol, and triglyceride. The difference-in-means for endpoint versus baseline total cholesterol in patients on DPP-4 inhibitors treatment was significantly higher in comparison with controls, meaning that treatment with DPP-4 inhibitors is associated with a significant reduction in total cholesterol (-0.18 [-0.29; -0.06] mmol/L (-7.0 [-11.2; -2.50] mg/dL); P=0.002). CONCLUSIONS: This meta-analysis suggests a possible beneficial effect of DPP-4 inhibitors on cholesterol, which, although small, could contribute to the reduction of cardiovascular risk. PMID- 22215384 TI - Reading strategies in Spanish developmental dyslexics. AB - Cross-linguistic studies suggest that the orthographic system determines the reading performance of dyslexic children. In opaque orthographies, the fundamental feature of developmental dyslexia is difficulty in reading accuracy, whereas slower reading speed is more common in transparent orthographies. The aim of the current study was to examine the extent to which different variables of words affect reaction times and articulation times in developmental dyslexics. A group of 19 developmental dyslexics of different ages and an age-matched group of 19 children without reading disabilities completed a word naming task. The children were asked to read 100 nouns that differed in length, frequency, age of acquisition, imageability, and orthographic neighborhood. The stimuli were presented on a laptop computer, and the responses were recorded using DMDX software. We conducted analyses of mixed-effects models to determine which variables influenced reading times in dyslexic children. We found that word naming skills in dyslexic children are affected predominantly by length, while in non-dyslexics children the principal variable is the age of acquisition, a lexical variable. These findings suggest that Spanish-speaking developmental dyslexics use a sublexical procedure for reading words, which is reflected in slower speed when reading long words. In contrast, normal children use a lexical strategy, which is frequently observed in readers of opaque languages. PMID- 22215385 TI - Primary surgery in rural areas of southern Sudan. AB - BACKGROUND: We report through a retrospective analysis our experience of providing surgical care and on-the-job training through mobile surgical missions in southern Sudan during the post conflict period between 2005 and 2009. METHODS: Three surgical teams conducted 23 missions in 5 primary health care centers sited in remote areas of southern Sudan. King's analytical framework for surgical care in developing countries is adopted to evaluate the appropriateness of services rendered. Exact logistic regression was performed to investigate differences in mortality depending on the level of training of the operators and anesthetists. RESULTS: A total of 1,543 patients were operated on during a 5 year period, of which 9 (0.58%) died. The majority of operations were elective surgery cases (which may help contextualize the exceptionally low mortality rate). Several adaptations to surgical techniques adopted and preoperative and postoperative care were required. There were no statistically significant differences in mortality between operations performed by expatriate specialists and local midlevel providers with lower level training. CONCLUSIONS: This experience in southern Sudan demonstrates that surgical services can be established utilizing simple facilities and equipment and employing local personnel selected and trained on-the-job by teams composed of a consultant surgeon, anesthetist, and scrub nurse. Delegation of tasks relating to anesthesia and surgery to midlevel health providers is an appropriate approach in developing countries facing shortage and maldistribution of more qualified health workers. PMID- 22215386 TI - Obstetric history and mammographic density: a population-based cross-sectional study in Spain (DDM-Spain). AB - High mammographic density (MD) is used as a phenotype risk marker for developing breast cancer. During pregnancy and lactation the breast attains full development, with a cellular-proliferation followed by a lobular-differentiation stage. This study investigates the influence of obstetric factors on MD among pre and post-menopausal women. We enrolled 3,574 women aged 45-68 years who were participating in breast cancer screening programmes in seven screening centers. To measure MD, blind anonymous readings were taken by an experienced radiologist, using craniocaudal mammography and Boyd's semiquantitative scale. Demographic and reproductive data were directly surveyed by purpose-trained staff at the date of screening. The association between MD and obstetric variables was quantified by ordinal logistic regression, with screening centre introduced as a random effect term. We adjusted for age, number of children and body mass index, and stratified by menopausal status. Parity was inversely associated with density, the probability of having high MD decreased by 16% for each new birth (P value < 0.001). Among parous women, a positive association was detected with duration of lactation [>9 months: odds ratio (OR) = 1.33; 95% confidence interval (CI) = 1.02 1.72] and weight of first child (>3,500 g: OR = 1.32; 95% CI = 1.12-1.54). Age at first birth showed a different effect in pre- and post-menopausal women (P value for interaction = 0.030). No association was found among pre-menopausal women. However, in post-menopausal women the probability of having high MD increased in women who had their first child after the age of 30 (OR = 1.53; 95% CI = 1.17 2.00). A higher risk associated with birth of twins was also mainly observed in post-menopausal women (OR = 2.02; 95% CI = 1.18-3.46). Our study shows a greater prevalence of high MD in mothers of advanced age at first birth, those who had twins, those who have breastfed for longer periods, and mothers whose first child had an elevated birth weight. These results suggest the influence of hormones and growth factors over the proliferative activity of the mammary gland. PMID- 22215387 TI - Fruit and vegetables consumption and breast cancer risk: the EPIC Italy study. AB - The role of fruit and vegetables in breast cancer (BC) development has long been debated. A large variety of vegetables and fruit are consumed by Mediterranean populations, a favourable setting for evaluating the effects of these foods. The association between vegetables and fruit consumption, overall and by specific types, and BC risk was studied in the Italian section of the European Prospective Investigation into Cancer and Nutrition study. Over 31,000 women, aged 36-64 years, recruited in five Italian centers between 1993 and 1998, were available for analyses with dietary and lifestyle information and anthropometric measurements. After a median follow-up of 11.25 years, 1,072 invasive and in situ incident BC cases were identified. Cox proportional hazard models (adjusted for education, anthropometry, reproductive history, hormone replacement therapy, physical activity, alcohol consumption and smoking habits) showed an inverse association between consumption of all vegetables and BC risk (highest vs. lowest quintile HR 0.65; 95% CI 0.53-0.81, P for trend = 0.003). According to subtypes of vegetables, an inverse association emerged for increasing consumption of leafy vegetables (highest vs. lowest quintile HR 0.70; 95% CI 0.57-0.86, P for trend = 0.0001) and fruiting vegetables (highest vs. lowest quintile HR 0.75; 95% CI 0.60 0.94, P for trend = 0.01). An inverse association also emerged with increasing consumption of raw tomatoes (P for trend = 0.03). In contrast, no association of fruit, overall or by subtypes, with BC risk was found. In this Mediterranean population, a clear protective role of increasing vegetables consumption, mainly leafy and fruiting vegetables, on BC risk emerged. PMID- 22215388 TI - [175 years of the National Library of Medicine, of the United States of America: a scientific and cultural treasure worthy of admiration]. AB - The National Library of Medicine (NLM) of the United States of America, celebrates in 2011 its 175th anniversary. This Library, the largest biomedical library in the world, has a proud and rich history serving the health community and the public, especially since its transfer to the National Institutes of Health in Bethesda, Maryland, in 1968. It holds 17 million publications in 150 languages, and has an important collection of ancient and modern historical books as well as original publications of Vesalius and other founders of biomedicine. Its modern document collections illustrate the progress of medical sciences. These collections include laboratory notes from many scientists whose work forms the foundations of contemporary life sciences. The Library also provides several services for health research and for the public, including databases and services such as MedLine and BLAST. The NLM constantly strives to fulfill the information needs of its customers, whether scientists or the public at large. For example, as the Hispanic population of the Unites States has increased in recent years, the NLM has made larger and larger amounts of data available in Spanish to fulfill the health information needs of this population. NLM programs train professionals in library science and biomedical informatics and link biomedical libraries of 18 academic centers throughout the United States. The NLM funds competitive grants for training at the Library, organizing short instruction courses about library science and informatics, and writing books on health related matters including the history of medicine and public health. The NLM is managed and maintained by an outstanding and farsighted group of professionals and dedicated support staff. Their focus on serving and reaching both the biomedical community and the public at large has been crucial to its development into a world icon of biomedical sciences, information technology and the humanities. PMID- 22215389 TI - [Thrombolysis for acute ischemic stroke with recombinant tissue plasminogen activator in a Chilean public hospital]. AB - BACKGROUND: The only accepted treatment for acute ischemic stroke is thrombolysis with recombinant tissue plasminogen activator (t-PA). It was implemented in Chile in 1996, although its use was mainly restricted in Chile to private clinics. Recently, at year 2009, we have implemented this treatment in a public hospital. AIM: To describe the results of treatment of acute ischemic stroke with t-PA in a public hospital in Chile. MATERIAL AND METHODS: Prospective analysis of all eligible patients with acute ischemic stroke that were admitted within 4 hours of its onset and had no contraindications for thrombolysis. RESULTS: In an eight months period, a total of 19 intravenous thrombolyses were performed in 12 males and seven females aged 28 to 79 years old. The mean lapse between onset of symptoms and onset of thrombolysis was 190 +/- 57 min. Results were favorable, according to Rankin and National Institute of Health Stroke scales. Ninety days after treatment, 63% of patients had minimal or absent disability, 26% had moderate disability and only one (5%) had severe disability. One patient had a clinically not significant intracranial hemorrhage and one patient died six days after thrombolysis. CONCLUSIONS: These results indicate that thrombolysis can be successfully implemented in Chilean public hospitals. The limitations for its use in this setting are mostly administrative. PMID- 22215390 TI - [Itraconazole 800 mg for the prophylaxis of fungal infections in patients with acute leukemia and severe neutropenia]. AB - BACKGROUND: Systemic fungal infections and specifically invasive aspergillosis (IA) are associated with a high morbi-mortality rate in patients with hematologic malignancies. Itraconazole kinetic studies show that plasma levels are not satisfactory, even though there is a reduction of the severity in clinical cases. AIM: To evaluate the results of oral prophylaxis with high dose itraconazole, 400 mg bid, among patients with adult acute leukemia. MATERIAL AND METHODS: Prospective analysis of 93 high risk febrile episodes (with an absolute neutrophil count of less than 500 x mm3 for more 10 days), that occurred in 76 patients. RESULTS: Seventy five percent of episodes occurred in patients with acute myeloid leukemia and 25% in patients with acute lymphoblastic leukemia. Fifty two percent occurred during the induction of chemotherapy. Median duration of severe neutropenia was 21 days (range 10-48). Median duration of itraconazole prophylaxis was 17 days (range 6-34). A low frequency of invasive fungal infections was observed (17%). According to diagnostic criteria, 5% of episodes corresponded to persistent fever , 1% and 11% of episodes, to probable or possible IA, respectively. No confirmed or proven IA was observed. Mortality of IA was 18%. No serious adverse events due to itraconazole were observed. CONCLUSIONS: The use of high dose itraconazole prophylaxis in adult patients with acute leukemia and severe neutropenia was associated to low incidence and mortality of invasive mycoses. PMID- 22215391 TI - [Results of treatment of acute lymphoblastic leukemia in two cohorts of Mexican patients]. AB - BACKGROUND: GIMEMA ALL 0288 trial was designed to evaluate the impact of a 7-day prednisone (PDN) pretreatment on complete remission of acute lymphoblastic leukemia. We adopted this trial in 2007. AIM: To evaluate the results of treatment in two cohorts of patients with acute lymphoblastic leukemia, treated from 2007 to January 2009 and from February to December 2009. MATERIAL AND METHODS: We studied 99 patients treated in the first period (58 males) and 54 patients treated in the second period (33 males) The age of patients ranged from 16 to 60 years and 70% of patients were of high risk. BCR/ABL fusion transcript was present in 12% of patients. RESULTS: Remission rates were 61 and 51% for patients of the first and second group of treatment, respectively. The main cause of death were infections during the induction period. There were 49 relapses, mainly detected in the blood marrow. Global and event free 34 months survival were 32 and 30% respectively. Multivariate analysis disclosed risk stratification and central nervous system infiltration as risk factors for mortality. CONCLUSIONS: The main obstacles for the treatment of acute lymphoblastic leukemia in these cohorts of patients were the high incidence of infections and the lack of use of growth stimulating factors. PMID- 22215392 TI - [Resistance phenotypes and genotypes of Streptococcus pyogenes clinical isolates in Chile over a 10-year period]. AB - BACKGROUND: Macrolide and lincosamide resistance in Streptococcus pyogenes is due to the acquisition of mef, ermB and ermA genes, which confer different resistance phenotypes, namely M, MLSBconstitutive and MLSBinducible respectively. The last report of resistance in Chile was done in the period 1990-1998, in which resistance to macrolides was 5.4%, with M phenotype as the predominant one. AIM: To characterize the evolution of erythromycin and clindamycin resistance and their associated genes in S. pyogenes strains isolated from patients with invasive and non-invasive infections in the period 1996 to 2005. MATERIAL AND METHODS: Resistance to erythromycin and clindamycin was determined in 1,282 clinical isolates using the disk diffusion test. Resistant isolates were analyzed by polymerase chain reaction (PCR) for the presence of the above mentioned resistance genes. RESULTS: Global resistance to erythromycin and clindamycin was 3.5 and 0.7% respectively. Eighty percent of the resistant strains possessed the M. phenotype. CONCLUSIONS: Resistance levels of S. pyogenes have decreased in Chile in the last years. Most resistant strains have M phenotype in contrast to many countries in which the MLSB constitutive phenotype is the predominant one. PMID- 22215393 TI - [Logistic and production process in a regional blood center: modeling and analysis]. AB - BACKGROUND: The blood supply chain is a complex system that considers different interconnected elements that have to be synchronized correctly to satisfy in quality and quantity the final patient requirements. AIM: To determine the blood center maximum production capacity, as well as the determination of the necessary changes for a future production capacity expansion. MATERIAL AND METHODS: This work was developed in the Blood Center of Concepcion, Chile, operations management tools were applied to model it and to propose improvement alternatives for the production process. The use of simulation is highlighted, which permitted the replication of the center behavior and the evaluation of expansion alternatives. RESULTS: It is possible to absorb a 100% increment in blood demand, without making major changes or investments in the production process. Also it was possible to determine the subsequent steps in terms of investments in equipment and human resources for a future expansion of the center coverage. CONCLUSIONS: The techniques used to model the production process of the blood center of Concepcion, Chile, allowed us to analyze how it operates, to detect "bottle necks", and to support the decision making process for a future expansion of its capacity. PMID- 22215394 TI - [Transesophageal echocardiography to monitor fluid administration during the perioperative period]. AB - BACKGROUND: During the perioperative period an adequate intravascular volume must be maintained. Current recommendations overestimate perioperative volume requirements. AIM: To compare perioperative volume administration using standard monitoring methods or guided by left ventricular filling parameters. MATERIAL AND METHODS: Twenty-four patients subjected to colon resection were randomized to monitoring by electrocardiography, blood and central venous pressure, or by transesophageal echocardiography. In the latter, volume administration was adjusted to maintain basal values of left ventricular end diastolic volume and cardiac index. RESULTS: Patients with the standard monitoring system and transesophageal echocardiographic monitoring received 21.1 +/- 12 and 6.3 +/- 2 ml/kg/h of fluids during the perioperative period, respectively (p < 0.01). CONCLUSIONS: The use of transesophageal echocardiography significantly reduced the perioperative fluid administration. PMID- 22215395 TI - [Assessment of the impact of event scale revised for post traumatic stress disorder in Chilean subjects]. AB - BACKGROUND: Impact of Event Scale Revised (IES-R), that evaluates the subjective perception of stress, is used to assess post traumatic stress disorder simptoms. AIM: To adapt and validate IES-R to the Chilean population. MATERIAL AND METHODS: Two hundred seventy eight subjects exposed to stressful life events of varying magnitude were assessed using the IES-R, the Beck Depression Inventory, the anxiety and somatoform subscales of the Depressive, Anxiety and Somatoform Disorders Scale and the AUDIT Questionnaire. RESULTS: IES-R had adequate psychometric properties in terms of internal consistency, test-retest reliability, convergent and discriminating validity. It identified a principal factor, explaining 67% of the variance. CONCLUSIONS: The IES-R can be used in the Chilean population to assess the degree of suffering produced by a traumatic event. PMID- 22215396 TI - [Development of a virtual model of fibro-bronchoscopy]. AB - A virtual model of fibro-bronchoscopy is reported. The virtual model represents in 3D the trachea and the bronchi creating a virtual world of the bronchial tree. The bronchoscope is modeled to look over the bronchial tree imitating the displacement and rotation of the real bronchoscope. The parameters of the virtual model were gradually adjusted according to expert opinion and allowed the training of specialists with a virtual bronchoscope of great realism. The virtual bronchial tree provides clues of reality regarding the movement of the bronchoscope, creating the illusion that the virtual instrument is behaving as the real one with all the benefits in costs that this means. PMID- 22215397 TI - [Prevalence of chronic kidney disease in subjects consulting in urban primary care clinics]. AB - BACKGROUND: Chronic kidney disease (CKD) is a major worldwide public health problem and is associated with increased risk of cardiovascular disease and death. AIM: To assess CKD prevalence in urban Primary Care Services (PCS) of Concepcion, Chile. MATERIAL AND METHODS: The clinical records of 27.894 adults aged 55 +/- 18 years (66% females), consulting in outpatient clinics and in whom serum creatinine was measured, with or without assessment of urine albumin levels, were reviewed. The glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease (MDRD)-4 equation. CKD was defined as an eGFR < 60 ml/min/1.73 m2 and classified according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NFK-KDOQI) guidelines. RESULTS: Mean eGFR was 77.1 +/- 16.3 ml/min/1.73 m2. Twelve percent of subjects had CKD (women, 14.5% and men 7,4%, p < 0,05). The prevalence of stages 3, 4 and 5 of CKD were 11.6, 0.3 and 0.2 % respectively. eGFR was negatively correlated with age ( r = -0,54, p < 0,05). Among patients with an eGFR < 60 ml/min/1.73 m2, 96.3% had eGFR 30-59, 2.3% 15-29 and 1.4 % < of 15. Seventy nine percent were women. 75.1% were aged 65 years or more, 26.8% had a serum creatinine equal or less than 1.0 mg/dL and 40.5% had microalbuminuria. Only 1% of outpatients ascribed to Cardiovascular or Diabetes Programs had the diagnosis of CKD registered. Independent risk predictors of CKD were age > 60 years, female sex and microalbuminuria. CONCLUSIONS: This study showed a high prevalence of CKD in ambulatory patients, mainly among women and older people. The low level of diagnosis of CKD in cardiovascular and diabetes programs is of concern. PMID- 22215398 TI - [Psychophysiological distress among health care professionals working in Chilean public hospitals]. AB - BACKGROUND: The public health reform in Chile resulted in changes in working conditions and organization of health centers. AIM: To examine the presence of psychophysiological symptoms in professionals of public hospitals in the Metropolitan Region and their association with current working conditions. MATERIAL AND METHODS: A questionnaire of quality of working life was applied to a sample of 80 physicians and 110 nurses. The questionnaire considers scales and open questions. RESULTS: Nurses had a higher level of discomfort than physicians (p < 0.01) and had significantly higher scores for emotional distress, physical fatigue, digestive disorders, headache, insomnia, back pain and muscle tension (p < 0.01). There were statistically significant negative correlations between psychophysiological distress and working conditions (r = -0.418), social climate (r = -0.395), satisfaction with the organization (r = -0.337) and psychosocial well-being (r = -0.267). A regression model showed that 21% of the variance in psychophysiological distress was explained by working conditions, psychosocial well-being and adaptation to the organization. CONCLUSIONS: There is a relationship between the high prevalence of psychophysiological symptoms and bad working conditions of public health professionals. PMID- 22215399 TI - [Sub capsular splenic hematoma in a sickle cell trait carrier. Case report]. AB - Drepanocytic anemia is an uncommon hereditary disease in Chile. The heterozygous state of drepanocytic anemia or "sickle trait" has a frequency of 8% among Afro Americans. A small number of patients carrying hemoglobin S are homozygous, with clinical manifestations of hemolytic anemia and thrombotic disease. Sickle trait is usually asymptomatic. We report a 59-year-old male who presented an acute abdominal pain and dyspnea while staying at high altitude. Six days later, an angio CAT scan showed the presence of a subcapsular splenic hematoma that was managed conservatively. Sickle cell induction with sodium metabisulphite was positive. Hemoglobin electrophoresis confirmed the sickle trait. PMID- 22215400 TI - [Addisonian crisis caused by metastatic lung cancer. Report of one case]. AB - Addisonian crisis as a first manifestation of metastatic disease secondary to cancer is uncommon. We report a 63-year-old man with a history of one year of fatigue, weakness, weight loss and repeated symptomatic hypoglycemia. The cortisol stimulation test with ACTH confirmed primary adrenal insufficiency. While receiving adequate treatment with oral hydrocortisone, he presented an adrenal crisis that was treated properly. A CT scan of the lung demonstrated a nodule in the upper right lobe and bilateral adrenal tumors. The biopsy of the lesion revealed a lung adenocarcinoma. The staging with positron emission tomography using 18 fluoroglucose (PET/CT18F- FDG) showed hypermetabolic uptake in the primary lung tumor and in both adrenal glands, suggesting metastatic implants. PMID- 22215401 TI - [Venous thrombosis secondary to catheter insertion for hypothermia after cardiac arrest. Report of one case]. AB - To improve survival and reduce neurological injury, the use of mild hypothermia following cardiac arrest has been recommended. We report a 65 years old woman who presented an out-of-hospital ventricular fibrillation and cardiac arrest. The patient was comatose following initial resuscitation and was admitted into the ICU, where cooling was initiated using an intravascular catheter. After 48 hours, rewarming was initiated. Although no neurological impairment was observed, physical examination of the right inguinal area and echo-Doppler examination revealed an extensive catheter-related thrombophlebitis with right ileocaval vein occlusion., with high risk of massive and life threatening pulmonary embolism. We report a clinical case and review the literature to point out the need for a high index of diagnostic suspicion of deep venous thrombosis in these specific setting. PMID- 22215402 TI - [Tungiasis. Report of one case]. AB - We report a 54-year-old male that, after working in a rural zone of Rio de Janeiro, Brazil, presented with an itching cutaneous lesion in the wrist with a black small central zone. The patient extracted from the lesion a on of 0.5 mm diameter. The pathological study of the insect recognized its body segments. The epidemiological background and the characteristics of the lesion led to the diagnosis of tungiasis. PMID- 22215403 TI - [Strategies for the prophylaxis of thromboembolic disease among medical patients]. AB - Thromboembolic disease is the main preventable cause of in-hospital death. Approximately 10% of nosocomial deaths are attributable to pulmonary embolism and in most cases, the diagnosis is not suspected before the autopsy. There are cost effective measures to decrease the incidence of thromboembolic disease. Pharmacological prophylaxis decreases the incidence of deep venous thrombosis by 65% and the incidence of pulmonary embolism by 35 to 55%. Despite this data and the presence of clinical guidelines, prophylaxis of thromboembolic disease is used only in 40% of medical patients and in 65% of surgical patients with recommended indications. We review the evidence that supports the use of thromboprophylaxis and the different strategies that may increase the compliance of physicians with its use. A protocol implemented in our institution is also proposed. PMID- 22215404 TI - [Bronchiolar disorders: clinical-radiological assessment and classification]. AB - Bronchiolar disorders are generally difficult to diagnose. A detailed clinical history may point toward a specific diagnosis. Pertinent clinical questions include history of smoking, collagen vascular disease, inhalation injury, medication use and organ transplantation. It is important also to evaluate possible systemic and pulmonary signs of infection, evidence of air trapping, and high-pitched expiratory wheezing, which may suggest small airways involvement. Pulmonary function tests and plain chest radiography may demonstrate abnormalities; however, they rarely prove sufficiently specific to obviate bronchoscopic or surgical biopsy. High-resolution CT (HRCT) scanning of the chest is often an important diagnostic tool to guide diagnosis in these difficult cases, because different subtypes of bronchiolar disorders may present with characteristic image findings. Some histopathologic patterns of bronchiolar disease may be relatively unique to a specific clinical context but others are nonspecific with respect to either etiology or pathogenesis. Primary bronchiolar disorders include acute bronchiolitis, respiratory bronchiolitis, follicular bronchiolitis, mineral dust airway disease, constrictive bronchiolitis, diffuse panbronchiolitis, and other rare variants. Prominent bronchiolar involvement may be seen in several interstitial lung diseases, including hypersensitivity pneumonitis, collagen vascular disease, respiratory bronchiolitis-associated interstitial lung disease, cryptogenic organizing pneumonia, and pulmonary Langerhans' cell histiocytosis. Large airway diseases that commonly involve bronchioles include bronchiectasis, asthma, and chronic obstructive pulmonary disease. The clinical and prognostic significance of a bronchiolar lesion is best determined by identifying the etiology, underlying histopathologic pattern and assessing the correlative clinic-physiologic-radiologic context. PMID- 22215405 TI - [Should we hydrate terminally ill patients?]. AB - Terminally ill patients frequently have difficulties with fluid and food intake. The indication of artificial hydration in these patients has been subject of intense debate in the past years and the clinical practice widely varies, mostly based on anecdotal data and not on clinical evidence about risks and benefits associated to artificial hydration in terminal patients. There are not only technical questions concerning benefits and risks associated to artificial hydration, but also questions related to the ethical principles and values involved. Several topics, such as the effect of artificial hydration alleviating symptoms or reversing neurological alterations as delirium, its life prolonging effect or if it promotes unnecessary suffering, are discussed. In this review we will analyze clinical benefits and risks associated to artificial hydration in terminal patients, making reference to some ethical principles involved. PMID- 22215406 TI - [Scientific ethics of the abortion with anencephalic fetus]. AB - author proposes, from the perspective of the Scientific Ethics, to assimilate anencephalic fetuses to non-human fetuses because they have a large deficiency of the brain that is the organ for human specificity. This proposal comes after considering arguments and facts from ontogeny, phylogeny, from the situation of loss of the brain in the adult life and from the organic specificity of the human condition given by the brain. If anencephalic fetuses are not human, the interruption of their pregnancy cannot be considered as abortion, regardless the pregnancy stage. PMID- 22215407 TI - [Clinical decisions in primary health care]. PMID- 22215408 TI - [Trans rectal biopsies and radical prostatectomy]. PMID- 22215409 TI - Insulin glargine: a reevaluation of rodent carcinogenicity findings. AB - The 1995 to 1997 lifetime carcinogenicity studies of insulin glargine in rats and mice were reanalyzed and reassessed for their validity according to current guidelines. In 2-year studies, 50 animals per sex and per group were used. Survival rates between weeks 80 and 90 in female mice and rats were greater than 20 animals in all groups, fulfilling current Food and Drug Administration requirements that enough animals lived long enough to provide adequate exposure to glargine and to be at risk of forming late-developing tumors. Exposure to 5 or 12.5 IU/kg glargine was similar to or 2 to 3 times greater than 5 IU/kg neutral protamine Hagedorn insulin, respectively. Using statistical methods recommended by current guidelines, no significant effect of glargine on mammary gland neoplastic lesions in female rodents was found, confirming earlier results. Thus, both studies can be considered valid according to contemporary standards. Insulin glargine does not present a carcinogenic risk. PMID- 22215410 TI - Correlation between in silico physicochemical characteristics of drugs and their mean residence time in human and dog. AB - The correlation between 52 physicochemical parameters and mean residence time (MRT) for 27 drugs used in human and dog were investigated. The physicochemical parameter values calculated provided a basis for deriving a series of arithmetic expressions, which were used to build a mathematical model describing the relationship between them and the MRT values. From the entire set of analyzed parameters, a subset of 14 was identified that contributed to the derivation of an arithmetic expression: Log(PSA - WPSA + ACID) x [XlogP - (LogKp - EAxLn(Caco2 + AMINE + SAF))] + (AMIDE + IP - FG) - Ln(MW + PISA) the value of which is highly correlated with the MRT value in dogs (P < .001) and allowed prediction of the MRT predicted (MRT(pred)). In humans, no correlation was found that allowed the calculation of MRT(pred). These results indicate that predicting the pharmacokinetics of any specific drug for humans based on pharmacokinetic data obtained in the dog should be undertaken with knowledge of the inherent limitations. PMID- 22215411 TI - Sanguinarine induces apoptosis of HT-29 human colon cancer cells via the regulation of Bax/Bcl-2 ratio and caspase-9-dependent pathway. AB - Sanguinarine is an alkaloid obtained from the bloodroot plant Sanguinaria canadensis and has beneficial effects on oxidative stress and inflammatory disorders. Previous reports have demonstrated that sanguinarine also exhibit anticancer properties. In the current study, we investigated the effects of sanguinarine on HT-29 human colon cancer cells. It was observed that sanguinarine treatment induces a dose-dependent increase in apoptosis of human colon cancer cells. We also investigated the effects of sanguinarine on the expression of apoptosis-associated proteins, and the results revealed that there was an increase in Bax and a decrease in B-cell lymphoma 2 (Bcl-2) protein levels. Moreover, sanguinarine treatment significantly increases the activation of caspases 3 and 9 that are the key executioners in apoptosis. Our results suggest that sanguinarine induces apoptosis of HT-29 human colon cancer cells and may have a potential therapeutic use in the treatment of human colon cancer. PMID- 22215412 TI - Automatic detection and classification of nasopharyngeal carcinoma on PET/CT with support vector machine. AB - PURPOSE: Positron emission tomography/computed tomography (PET/CT) has established values for imaging of head and neck cancers, including the nasopharyngeal carcinoma (NPC), utilizing both morphologic and functional information. In this paper, we introduce a computerized system for automatic detection of NPC, targeting both the primary tumor and regional nodal metastasis, on PET/CT. METHODS: Candidate lesions were extracted based on the features from both PET and CT images and a priori knowledge of anatomical features and subsequently classified by a support vector machine algorithm. The system was validated with 25 PET/CT examinations from 10 patients suffering from NPC. Lesions manually contoured by experienced radiologists were used as the gold standard. RESULTS: Results showed that the system successfully identified all 53 hypermetabolic lesions larger than 1 cm in size and excluded normal physiological uptake in brown fat, muscles, bone marrow, brain, and salivary glands. CONCLUSION: The system combined both imaging features and a priori clinical knowledge for classification between pathological and physiological uptake. Preliminary results showed that the system was highly accurate and promising for adoption in clinical use. PMID- 22215413 TI - Varied but not necessarily random: human performance under variability contingencies is affected by instructions. AB - The goal of the present study was to evaluate the role of verbal stimuli in the production of response variability in humans. College students were distributed into three groups and asked to type three-digit sequences. Participants in the systematic group were instructed to produce sequences according to a rule of their choice; those in the random group were instructed to produce sequences according to chance; and those in the control group were not instructed about how to produce sequences. The experiment employed an ABA design. During the A phases, low-frequent sequences were reinforced (variability contingency), whereas during the B phase, reinforcement was withdrawn (extinction). The results indicated the following: (1) The instructions were efficient at producing systematic and random like patterns for the systematic and random groups, respectively; in the absence of instructions, a mix of both patterns was observed. (2) Behavior was sensitive to extinction independently of the instructions provided. (3) Systematic patterns favored a more equiprobable distribution of sequences across trials. (4) Reaction times were longer for responding in a systematic than in a random-like fashion. The present findings suggest that individual differences in meeting variability contingencies may be due, at least partially, to instructional control. PMID- 22215414 TI - Human papillomavirus-16 (HPV-16) infection association with CIAP-2 expression in head and neck cancer. AB - Human papillomavirus (HPV-16) E6 proteins inhibit apoptosis in both p53-dependent and p53-independent manners. So it was relevant to assess the impact of such infection on head and neck cancers and its relation to the inhibitors of apoptosis (IAPs). CIAP2 is one of these IAPs that is postulated to upregulated by E6 proteins of HPV-16 by amplification of the locus bearing it in many tissues. In this study, we aimed to search for the amplification of the locus bearing CIAP 2 and its relation to HPV-16 in head and neck cancer that may have prognostic and therapeutic impacts on these patients. Total 30 patients diagnosed as head and neck cancer (2 tissue samples were taken from each patient: from the tumor and from the safety margin). All samples were subjected to qualitative polymerase chain reaction analysis for HPV-16 and qualitative and semiquantitative reverse transcription polymerase chain reaction of CIAP-2. There was a significant association between HPV-16 and CIAP2 positivity and head and neck tumors (P=0.01). CIAP-2 expression in malignant tissues was highly associated with HPV 16 infection with 73.9% sensitivity and absolute specificity. PMID- 22215415 TI - Identification of novel serological tumor markers for human prostate cancer using integrative transcriptome and proteome analysis. AB - The aim of this study was to identify novel serological tumor markers for human prostate cancer (PCa). We compared the gene expression profile of PCa tissues to adjacent benign tissues of prostate using gene expression microarray. 1207 genes that were consistently different from adjacent benign tissues of prostate (paired t test, P<0.05) were selected as differentially expressed genes (DEGs). Among them, 652 DEGs were upregulated in PCa, whereas 555 DEGs were downregulated in PCa. In addition, two-dimensional fluorescence difference gel electrophoresis (2D DIGE) coupled with MS was performed to screen for candidate markers in the proteome of PCa and adjacent benign tissues of prostate. A total of 89 spots were significantly up-regulated (ratio>=2, P<0.01) in PCa samples, whereas 66 spots were down-regulated (ratio<=-2, P<0.01). Sixty gene products were identified among these spots. Moreover, 14 potential candidate markers, which were identified as differentially expressed molecules by both gene expression microarray and 2D-DIGE, were chosen for validation and analysis by ELISA. The serum levels of three proteins correlated well with the 2D-DIGE results. Furthermore, the increased serum level of Inosine monophosphate dehydrogenase II (IMPDH2) was significantly associated with the clinicopathological features of the patients with PCa, suggesting its potential as a serological tumor marker. These results demonstrated that integrative transcriptome and proteome analysis could be a powerful tool for marker discovery in PCa. We suggest IMPDH2 as a novel serological tumor marker for detection of early PCa and evaluation of tumor progression. PMID- 22215417 TI - The eye in sexually transmitted infections: a review of the ocular complications of venereal diseases. AB - Ocular complications of sexually transmitted diseases are frequently encountered by ophthalmologists and sexual health physicians in everyday practice. Ocular findings may be the first sign of many of the known sexually transmitted diseases. Thus, a high index of suspicion for ocular involvement in patients at risk of sexually transmitted diseases should be borne in mind and these patients should be referred to a specialist in a timely manner. This review focuses on the more significant ocular manifestations of the most common sexually transmitted diseases with which both ophthalmologists and sexual health physicians need to be familiar. In addition, it provides the most recent statistics on these conditions. PMID- 22215418 TI - Bilateral methicillin-resistant Staphylococcus aureus keratitis following hyperopic photorefractive surgery. AB - To report clinical manifestations of a female patient with bilateral bacterial keratitis following photorefractive keratectomy (PRK). Bilateral PRK was performed for moderate hyperopia. Bandage contact lenses were fitted at the conclusion of the surgery. Bilateral infectious keratitis with hypopion was diagnosed within 4 days after surgery. Smear and culture were obtained and showed the presence of methicillin-resistant Staphylococcus aureus (MRSA). The patient was treated with systemic prednisone and topical antibiotics (vancomycin, tobramycin and netylmicin) and betamethasone. After 1 month corneal leukoma was still present and remained unchanged during the following 7 months. Infectious keratitis is a rare complication of PRK that appears early in the postoperative period. MRSA keratitis may determine long-term visual impairment despite prompt therapeutic intervention. PMID- 22215419 TI - New tools for quantifying HIV-1 reservoirs: plasma RNA single copy assays and beyond. AB - Quantification of plasma HIV-1 RNA below the limit of FDA-approved assays by a single copy quantitative PCR assays (SCA) has provided significant insights into HIV-1 persistence despite potent antiretroviral therapy as well as a means to assess the impact of therapeutic strategies, such as treatment intensification, on residual viremia. In this review, we discuss insights gained from plasma HIV-1 RNA SCA and highlight the need for additional assays to characterize better the cellular and tissue reservoirs of HIV-1. Accurate, reproducible, and sensitive assays to quantify HIV-1 reservoirs, before and after therapeutic interventions, are essential tools in the quest for a cure of HIV-1 infection. PMID- 22215420 TI - Direct-to-consumer genetic testing services: what are the medical benefits? PMID- 22215421 TI - Prospective comparison of family medical history with personal genome screening for risk assessment of common cancers. AB - Family history-based risk assessment (FHRA) is a genetic tool for identifying those at risk of disease. Genome-wide association studies have shown that single nucleotide polymorphisms (SNP) are statistically associated with low- to moderate level risks of diseases. There has been limited study of complementarity for these two assessment methods. We sought to compare cancer risk categorizations from FHRA and from Navigenics Personal Genome Screening (PGS). We compared FHRA with PGS for breast (22 females), prostate (22 males), and colon cancer (44 males and females) assessed by kappa (kappa) statistic. We also assessed each participant's hereditary risk based on clinical criteria and/or gene-test results. Both FHRA and PGS placed 59%, 68% and 44% of participants into the same risk categories for breast, prostate, and colon cancer, respectively. Overall, however, there was little concordance in FHRA versus PGS for all three cancer risks (kappa<0.2). FHRA assigned 22 with hereditary risk compared with PGS, which identified one as high risk (P<0.0001). We assessed nine with hereditary colorectal cancer risk, five with germline mutations, but none were classified as PGS high risk (P=0.0001). FHRA and PGS may be complementary tools for cancer risk assessment. However, evaluation of family history remains the standard to evaluate an individual's cancer risk until further research. PMID- 22215428 TI - Virtuous medicine. PMID- 22215422 TI - HIV-1 infection alters CD4+ memory T-cell phenotype at the site of disease in extrapulmonary tuberculosis. AB - HIV-1-infected people have an increased risk of developing extrapulmonary tuberculosis (TB), the immunopathogenesis of which is poorly understood. Here, we conducted a detailed immunological analysis of human pericardial TB, to determine the effect of HIV-1 co-infection on the phenotype of Mycobacterium tuberculosis (MTB)-specific memory T cells and the role of polyfunctional T cells at the disease site, using cells from pericardial fluid and blood of 74 patients with (n = 50) and without (n = 24) HIV-1 co-infection. The MTB antigen-induced IFN-gamma response was elevated at the disease site, irrespective of HIV-1 status or antigenic stimulant. However, the IFN-gamma ELISpot showed no clear evidence of increased numbers of antigen-specific cells at the disease site except for ESAT-6 in HIV-1 uninfected individuals (p = 0.009). Flow cytometric analysis showed that CD4+ memory T cells in the pericardial fluid of HIV-1-infected patients were of a less differentiated phenotype, with the presence of polyfunctional CD4+ T cells expressing TNF, IL-2 and IFN-gamma. These results indicate that HIV-1 infection results in altered phenotype and function of MTB-specific CD4+ T cells at the disease site, which may contribute to the increased risk of developing TB at all stages of HIV-1 infection. PMID- 22215429 TI - Computed tomography and magnetic resonance angiography in the evaluation of aberrant origin of the external carotid artery branches. AB - Aim of our study was to evaluate the prevalence of aberrant origin of the branches of the external carotid artery (ECA) in 97 patients by computed tomography (CTA) and magnetic resonance angiography (MRA) and to compare the accuracy of these two techniques in the visualization of the ECA system. All patients underwent CTA and MRA examination of the head and neck. Multiplanar and volumetric reformations were obtained in all cases. For each set of images, the presence of aberrant origin of the branches of the external carotid artery was investigated. MRA and CTA images of each patient were compared to define their information content. Anatomical anomalies were found in 88 heminecks, with a prevalence of 53.3%. In the 61 patients in whom the CTA was performed before the MRA, the latter method showed only 92% of abnormalities detected at the first examination; in the 36 patients in whom MRA was performed first, CTA identified all of the anomalies highlighted by the former, adding 12 new. Knowledge of the anomalies of origin of the ECA branches is essential for the head and neck surgeon; the high prevalence of anomalies found in our series as in the previous studies indicates the opportunity to perform a CTA or a MRA of the head and neck before any surgical or interventional procedure. CTA is the method of choice in the evaluation of anomalies of origin of the branches of the ECA and in the definition of their course. PMID- 22215430 TI - Persistent trigeminal artery arising from the arterial ring/fenestration of the cavernous segment of the internal carotid artery. AB - A persistent trigeminal artery (PTA) is the most common carotid-vertebrobasilar anastomosis, usually arising from the cavernous or precavernous segment of the internal carotid artery (ICA) and connecting to the distal basilar artery. There are two types of PTA, lateral and medial. We present the first case of a lateral type PTA arising from the large arterial ring/fenestration of the cavernous segment of the left ICA with findings from both magnetic resonance angiography and selective catheter angiography. PMID- 22215431 TI - Does hormone replacement therapy and use of oral contraceptives increase the risk of non-melanoma skin cancer? AB - OBJECTIVE: We aimed to examine whether use of hormone replacement therapy (HRT) and oral contraceptives (OC) affect the risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in women. METHODS: Using data from 29,875 women enrolled in the prospective "Diet, Cancer, and Health" study between 1993 and 1997, women with available information on HRT and OC use at baseline were identified. Statistical analyses were based on the Cox's proportional hazards model. RESULTS: The mean age at enrollment in the study was 56.7 years, whereas the mean age at the end of follow-up was 67.5 years. 1,175 cases of BCC and 76 cases of SCC were identified in the cohort during follow-up through 2007. The BCC incidence rate ratio was 1.15 (95% CI: 1.07-1.37) for ever users of HRT at baseline compared to never users, whereas risk of BCC was unaffected by duration of HRT use. Ever use of HRT was not associated with SCC risk but a significantly increased risk of 1.35 (95% CI: 1.05-1.72) associated with every 5 years of HRT use was observed. No convincing associations between OC use and BCC or SCC risk were observed. CONCLUSION: The findings indicated that HRT but not OC may increase the risk of NMSC. However, further studies are warranted as risk estimates for SCC had relatively low precision due to a limited number of SCC cases. PMID- 22215432 TI - ISSR and RAPD based evaluation of genetic stability of encapsulated micro shoots of Glycyrrhiza glabra following 6 months of storage. AB - In vitro grown axillary micro shoots of Glycyrrhiza glabra were encapsulated in alginate beads. Following 6 months of normal storage at 25 +/- 2 degrees C the re growth of encapsulated G. glabra micro shoots, reached 98% within 30 days of incubation on MS medium supplemented with 0.1 mg/l IAA. Re growth was characterized by the development of both shoot and root from single encapsulated micro shoot. Healthy plants were established to glass house with 95% survival. The genetic fidelity of plants obtained after conversion of alginate beads was ascertained through 10 RAPD and 13 ISSR primers. Of the 10 RAPD primers tested, 6 of them produced 14 clear and reproducible amplicons with an average of 2.3 bands per primer out of which 28.57% were polymorphic generated by only two primers. Eight ISSR primers produced total 37 bands ranging between 300 and 3,500 bp length. Number of scorable bands for each primer varied from 3 to 8 with an average of 4.6 bands per primer. Cluster analysis from ISSR and RAPD showed that all the tested plants including the mother plant distributed in two major groups with similarity coefficient ranging from 0.91 to 0.96 for RAPD and 0.89 to 0.97 for ISSR. PMID- 22215433 TI - Preventing CVD in women: the NP's role. AB - Cardiovascular disease is the number one killer of women in the United States, but a woman's risk can be decreased with preventative measures. This article focuses on the new American Heart Association guidelines for preventing cardiovascular disease in women and the nurse practitioner's role in implementing them. PMID- 22215434 TI - Annual drug update: 2011 in review. AB - Many new medications were approved throughout 2011. This article will cover a variety of drugs that will be useful in nurse practitioner practice. PMID- 22215436 TI - Exploring the social impact of being a typical peer model for included children with autism spectrum disorder. AB - This study examined the social impact of being a typical peer model as part of a social skills intervention for children with autism spectrum disorder (ASD). Participants were drawn from a randomized-controlled-treatment trial that examined the effects of targeted interventions on the social networks of 60 elementary-aged children with ASD. Results demonstrated that typical peer models had higher social network centrality, received friendships, friendship quality, and less loneliness than non-peer models. Peer models were also more likely to be connected with children with ASD than non-peer models at baseline and exit. These results suggest that typical peers can be socially connected to children with ASD, as well as other classmates, and maintain a strong and positive role within the classroom. PMID- 22215435 TI - Autonomic arousal to direct gaze correlates with social impairments among children with ASD. AB - The present study investigated whether autonomic arousal to direct gaze is related to social impairments among children with autism spectrum disorder (ASD). Arousal was measured through skin conductance responses (SCR) while the participants (15 children with ASD and 16 control children) viewed a live face of another person. Impairments in social skills was assessed with the Developmental, Dimensional and Diagnostic Interview. The level of arousal enhancement to direct gaze in comparison to arousal to faces with averted gaze or closed eyes was positively associated with impairments in social skills (use of language and other social communication skills and use of gesture and non-verbal play) among children with ASD. There was no similar association among children without ASD. The role of arousal-related factors in influencing eye contact behaviour in ASD is discussed. PMID- 22215437 TI - Individual differences in the mixture ratio of rotation and nonrotation trials during rotated mirror/normal letter discriminations. AB - Mental rotation is thought to underlie the increase in response times (RTs) for deciding whether rotated letters are normal or mirrored versions. However, mental rotation predicts a linear increase in RTs, whereas the mirror/normal letter discrimination task typically produces a curved function. Recently, Kung and Hamm suggested that this curved function results from a mixture of trials in which mental rotation is employed and trials in which it is not. The mixture ratio may vary between individuals, with some individuals relying more on mental rotation than others. There is no factor in the Kung and Hamm model that reflects such individual differences. In the present study, we suggest that a possible exponent parameter could be added to the Kung and Hamm model to capture individual differences in the mixture ratio. This exponent parameter appears to capture an individual characteristic since the value obtained correlates between the mirror/normal letter task and a left/right object facing task. The development of a quantity that represents the mixture ratio will aid further testing of processes involved in the visual imagery system. PMID- 22215439 TI - Activity monitoring of functional OprM using a biomimetic microfluidic device. AB - This paper describes the fabrication and use of a biomimetic microfluidic device for the monitoring of a functional porin reconstituted within a miniaturized suspended artificial bilayer lipid membrane (BLM). Such a microfluidic device allows for (1) fluidic and electrical access to both sides of the BLM and (2) reproducible membrane protein insertion and long-term electrical monitoring of its conductance (G(i)), thanks to the miniaturization of the BLM. We demonstrate here for the first time the feasibility to insert a large trans-membrane protein through its beta-barrel, and monitor its functional activity for more than 1 hour (limited by buffer evaporation). In this paper, we specifically used our device for the monitoring of OprM, a bacterial efflux channel involved in the multidrug resistance of the bacteria Pseudomonas aeruginosa. Sub-steps of the OprM channel conductance were detected during the electrical recordings within our device, which might be due to oscillations between several structural conformations (sub states) adopted by the protein, as part of its opening mechanism. This work is a first step towards the establishment of a genuine platform dedicated to the investigation of bacterial proteins under reconstituted conditions, a very promising tool for the screening of new inhibitors against bacterial channels involved in drug resistance. PMID- 22215440 TI - Defective glucocorticoid hormone receptor signaling leads to increased stress and anxiety in a mouse model of Angelman syndrome. AB - Angelman syndrome (AS) is a neurodevelopmental disorder caused due to deletions or loss-of-function mutations in maternally inherited UBE3A. Ube3a functions as an ubiquitin ligase as well as a transcriptional coactivator of steroid hormone receptors. However, the mechanisms by which maternal Ube3a deficiency gives rise to phenotypic features of AS are not clear. We report here that Ube3a regulates glucocorticoid receptor (GR) transactivation and GR signaling pathway is disrupted in Ube3a-maternal-deficient mice brain. The expression of several GR dependent genes is down-regulated in multiple brain regions of Ube3a-maternal deficient mice. AS mice show significantly higher level of blood corticosterone, selective loss of GR and reduced number of parvalbumin-positive inhibitory interneurons in their hippocampus that could ultimately lead to increased stress. These mice also exhibit increased anxiety-like behavior, which could be due to chronic stress. Altogether, our findings suggest that chronic stress due to altered GR signaling might lead to anxiety-like behavior in a mouse of model of AS. PMID- 22215441 TI - Impaired parkin-mediated mitochondrial targeting to autophagosomes differentially contributes to tissue pathology in lysosomal storage diseases. AB - Dysfunctional mitochondria are a well-known disease hallmark. The accumulation of aberrant mitochondria can alter cell homeostasis, thus resulting in tissue degeneration. Lysosomal storage disorders (LSDs) are a group of inherited diseases characterized by the buildup of undegraded material inside the lysosomes that leads to autophagic-lysosomal dysfunction. In LSDs, autophagic stress has been associated to mitochondrial accumulation and dysfunction. However, the mechanisms underlying mitochondrial aberrations and how these are involved in tissue pathogenesis remain largely unexplored. In normal conditions, mitochondrial clearance occurs by mitophagy, a selective form of autophagy, which relies on a parkin-mediated mitochondrial priming and subsequent sequestration by autophagosomes. Here, we performed a detailed analysis of key steps of mitophagy in a mouse model of multiple sulfatase deficiency (MSD), a severe type of LSD characterized by both neurological and systemic involvement. We demonstrated that in MSD liver reduced parkin levels resulted in inefficient mitochondrial priming, thus contributing to the accumulation of giant mitochondria that are located outside autophagic vesicles ultimately leading to cytochrome c release and apoptotic cell death. Morphological and functional changes were also observed in mitochondria from MSD brain but these were not directly associated with neuronal cell loss, suggesting a secondary contribution of mitochondria to neurodegeneration. Together, these data shed new light on the mechanisms underlying mitochondrial dysfunction in LSDs and on their tissue-specific differential contribution to the pathogenesis of this group of metabolic disorders. PMID- 22215442 TI - parkin-induced defects in neurophysiology and locomotion are generated by metabolic dysfunction and not oxidative stress. AB - Parkinson's disease (PD) is characterized by movement disorders, including bradykinesia. Analysis of inherited, juvenile PD, identified several genes linked via a common pathway to mitochondrial dysfunction. In this study, we demonstrate that the larva of the Drosophila parkin mutant faithfully models the locomotory and metabolic defects of PD and is an excellent system for investigating their inter-relationship. parkin larvae displayed a marked bradykinesia that was caused by a reduction in both the frequency of peristalsis and speed of muscle contractions. Rescue experiments confirmed that this phenotype was due to a defect in the nervous system and not in the muscle. Furthermore, recordings of motoneuron activity in parkin larvae revealed reduced bursting and a striking reduction in evoked and miniature excitatory junction potentials, suggesting a neuronal deficit. This was supported by our observations in parkin larvae that the resting potential was depolarized, oxygen consumption and ATP concentration were drastically reduced while lactate was increased. These findings suggest that neuronal mitochondrial respiration is severely compromised and there is a compensatory switch to glycolysis for energy production. parkin mutants also possessed overgrown neuromuscular synapses, indicative of oxidative stress, which could be rescued by overexpression of parkin or scavengers of reactive oxygen species (ROS). Surprisingly, scavengers of ROS did not rescue the resting membrane potential and locomotory phenotypes. We therefore propose that mitochondrial dysfunction in parkin mutants induces Parkinsonian bradykinesia via a neuronal energy deficit and resulting synaptic failure, rather than as a consequence of downstream oxidative stress. PMID- 22215443 TI - Diphenyl diselenide-modulation of macrophage activation: down-regulation of classical and alternative activation markers. AB - Diphenyl diselenide (PhSe)(2), a simple organoselenium compound, possesses interesting pharmacological properties that are under extensive research. As macrophages respond to microenvironmental stimuli and can display activities engaged in the initiation and the resolution of inflammation, in the present report we describe the ability of (PhSe)(2) to modulate the macrophage activation. Our data indicate that (PhSe)(2) could inhibit the NO production in a dose-dependent fashion in peritoneal macrophages activated by LPS or treated with vehicle alone. We could demonstrate that this effect correlated with a reduction in the expression of the inducible NO synthase in (PhSe)(2)-treated cells. Furthermore, (PhSe)(2) suppressed the production of reactive oxygen species, diminished the activity of the arginase enzyme, and the accumulation of nitrotyrosine modified proteins in LPS-stimulated macrophages. This compound also diminished the antigen presentation capacity of classically activated macrophages, as it reduced MHCII and CD86 expression. In addition, (PhSe)(2) modulated the alternative activation phenotype of macrophages. Dexamethasone activated macrophages presented higher production of IL-10 and CD206, which were both down-regulated by the addition of (PhSe)(2). These results suggest that (PhSe)(2) possesses antioxidant and anti-inflammatory activities in classically activated macrophages. We could demonstrate that (PhSe)(2) can be also utilized to modulate the alternative activation phenotype of macrophages. PMID- 22215444 TI - The birth and early growth of a comprehensive multidisciplinary diabetes center in a community hospital: the Bildirici Center for Diabetes Care and Research at Laniado Hospital. AB - Diabetes is a multisystem disorder. Diabetes care is a multidisciplinary process. The Bildirici Center for Diabetes Care and Research opened its doors to its first patients in August 2007, as the first center in Israel to offer comprehensive integrated multidisciplinary care for people with diabetes. In addition to direct patient care, the Center has organized courses, lectures and workshops for people with diabetes, as well as for professionals caring for people with diabetes and for the general community. The ability of individuals within different departments to develop and implement such a center may have been facilitated by the smallness of our institution and the familiarity they share as a result. We have shown how a community hospital, without ties to a major medical center or academic institution, can establish a multidisciplinary inpatient and outpatient diabetes center, the first of its kind in a country. PMID- 22215445 TI - An update on the evaluation and management of pulmonary hypertension in scleroderma. AB - Pulmonary arterial hypertension associated with scleroderma (SScPAH) is a debilitating, highly lethal condition that responds to an array of therapies. Quality of life and prognosis are substantially improved by treatment, and early diagnosis and treatment are associated with improved outcomes. There are serious limitations to current screening programs. Many more questions need to be addressed. Why is PAH so common in SSc? Why is the tolerance of pulmonary hypertension so poor in scleroderma? What are the best measures of response to therapy in SSc patients with PAH? Should we use different parameters in prognostic scores in SScPAH? Why is postcapillary pulmonary hypertension so common in SSc? How do we reliably differentiate lung disease-associated pulmonary hypertension from PAH? The aim of this review is to summarize the main areas of progress over the past decade and to look to the challenges for the next decade. PMID- 22215447 TI - Ubiquitin-mediated regulation of RhoGTPase signalling: IAPs and HACE1 enter the fray. PMID- 22215449 TI - Clinical evaluation of the NiTiBOND stapes prosthesis, an optimized shape memory alloy design. AB - OBJECTIVE: To prospectively analyze short-term (3 mo) results in patients with otosclerosis who underwent stapedotomy with the newly designed NiTiBOND prosthesis and compare them with patients that underwent SMart piston stapedotomy. We aimed to assess "noninferiority" for the new prosthesis. STUDY DESIGN: Prospective controlled trial. SETTING: Tertiary referral center. PATIENTS: Thirty-eight patients were included in the NiTiBOND group (41 ears), and 74 patients were included in the SMart Piston group (75 ears). INTERVENTION(S): Stapedotomy. MAIN OUTCOME MEASURE(S): Pure-tone audiometry 3 months after surgery, intraoperative prosthesis handling as assessed using a questionnaire, and complications were analyzed. RESULTS: Pure-tone audiometry showed postoperative air-bone gap means (standard deviation) of 8.1 (8.3) and 9.9 (5.4) dB; air-bone gap closure within 10 dB was achieved in 71% and 72% and within 20 dB in 93% and 96% for the NiTiBOND and the SMart piston prosthesis, respectively. Noninferiority was shown at all frequencies and in the pure-tone average. The NiTiBOND prosthesis provides excellent intraoperative handling, and no adverse reactions were reported. CONCLUSION: Preliminary short-term results suggest safety and reliability for the new NiTiBOND stapes prosthesis. PMID- 22215446 TI - The dark sides of capillary morphogenesis gene 2. AB - Capillary morphogenesis gene 2 (CMG2) is a type I membrane protein involved in the homeostasis of the extracellular matrix. While it shares interesting similarities with integrins, its exact molecular role is unknown. The interest and knowledge about CMG2 largely stems from the fact that it is involved in two diseases, one infectious and one genetic. CMG2 is the main receptor of the anthrax toxin, and knocking out this gene in mice renders them insensitive to infection with Bacillus anthracis spores. On the other hand, mutations in CMG2 lead to a rare but severe autosomal recessive disorder in humans called Hyaline Fibromatosis Syndrome (HFS). We will here review what is known about the structure of CMG2 and its ability to mediate anthrax toxin entry into cell. We will then describe the limited knowledge available concerning the physiological role of CMG2. Finally, we will describe HFS and the consequences of HFS associated mutations in CMG2 at the molecular and cellular level. PMID- 22215450 TI - Temporal bone histopathology and immunoglobulin deposition in Sjogren's syndrome. AB - HYPOTHESIS: The histopathology of Sjogren's syndrome (SS) in the human inner ear correlates with mouse models of autoimmune inner ear disease. BACKGROUND: SS is an autoimmune disease in which 25% of patients have sensorineural hearing loss (SNHL). The inner ear histology in a SS mouse model has shown degeneration of the stria vascularis (SV) and immunoglobulin G deposition on the basement membrane of SV blood vessels. Correlation with human temporal bone histopathology has not been addressed. METHODS: The histopathology and immunohistochemistry of the inner ear in 4 patients with SS is described and compared with SS mouse models. RESULTS: The histopathology of the inner ear in 3 patients with SS and SNHL showed severe loss of the intermediate cells of the SV and immunoglobulin G deposition on the basement membrane of SV blood vessels. These results parallel those of known SS mouse models. Additionally, there was shrinkage of the spiral ganglia neurons in 2 patients, whereas vestibular ganglia neurons were preserved. The fourth patient with SS and normal hearing showed only mild SV atrophy. CONCLUSION: This is the first study describing the pathologic changes in the inner ear of 4 patients with SS. The 3 SS specimens with SNHL showed pathologic changes in the SV similar to the mouse model of autoimmune inner ear disease. Additionally, we propose that spiral ganglia neurons may be directly affected by SS pathology. These results highlight the importance of correlating the histopathology of human temporal bones with animal models to better understand inner ear disease in future research. PMID- 22215452 TI - Metastatic breast carcinoma to bilateral internal auditory canals. PMID- 22215451 TI - Spectral and temporal measures in hybrid cochlear implant users: on the mechanism of electroacoustic hearing benefits. AB - OBJECTIVE: Compare auditory performance of Hybrid and standard cochlear implant users with psychoacoustic measures of spectral and temporal sensitivity and correlate with measures of clinical benefit. STUDY DESIGN: Cross-sectional study. SETTING: Tertiary academic medical center. PATIENTS: Hybrid cochlear implant users between 12 and 33 months after implantation. Hybrid recipients had preservation of low-frequency hearing. INTERVENTIONS: Administration of psychoacoustic, music perception, and speech reception in noise tests. MAIN OUTCOME MEASURES: Performance on spectral-ripple discrimination, temporal modulation detection, Schroeder-phase discrimination, Clinical Assessment of Music Perception, and speech reception in steady-state noise tests. RESULTS: Clinical Assessment of Music Perception pitch performance at 262 Hz was significantly better in Hybrid users compared with standard implant controls. There was a near significant difference on speech reception in steady-state noise. Surprisingly, neither Schroeder-phase discrimination at 2 frequencies nor temporal modulation detection thresholds across a range of frequencies revealed any advantage in Hybrid users. This contrasts with spectral-ripple measures that were significantly better in the Hybrid group. The spectral-ripple advantage was preserved even when using only residual hearing. CONCLUSION: These preliminary data confirm existing data demonstrating that residual low-frequency acoustic hearing is advantageous for pitch perception. Results also suggest that clinical benefits enjoyed by Hybrid recipients are due to improved spectral discrimination provided by the residual hearing. No evidence indicated that residual hearing provided temporal information beyond that provided by electric stimulation. PMID- 22215453 TI - Ossicular chain preservation in epitympanic cholesteatoma surgery: the modified Bondy technique. PMID- 22215454 TI - Traumatic pneumolabyrinth: air location and hearing outcome. AB - OBJECTIVE: To describe 3 cases of pneumolabyrinth after penetrating injury to the middle ear and to review previously reported cases, comparing precipitating factors and hearing outcomes. DATA SOURCES: Three cases we encountered and the PubMed and Japan Medical Abstracts Society databases. STUDY SELECTIONS: In addition to our 3 cases, we identified 48 cases from 41 articles regarding pneumolabyrinth. DATA EXTRACTIONS: All articles describing cases of pneumolabyrinth were used for this review. DATA SYNTHESIS: Among the 51 cases, audiologic evaluation was not available in 16 cases. In the remaining 35 cases, hearing outcomes were analyzed focusing on 3 factors: 1) differences in and interval until medical intervention, 2) existence of stapes lesions, and 3) extension of air bubble into the inner ear. We failed to find any significant differences in interventions, although operation less than 2 weeks after injury tended to be associated with a higher rate of hearing recovery (54%) than operation 2 weeks or longer after injury (25%). Furthermore, 11 (48%) of 23 cases with pneumolabyrinth limited to the vestibule or semicircular canals showed improved hearing, whereas none of 6 cases (0%) with pneumolabyrinth extending from the vestibular organs to the cochlea showed hearing recovery. This difference was statistically significant (p < 0.05). CONCLUSION: Assessment of the location and extension of pneumolabyrinth appears important in predicting hearing outcomes and planning the management of middle and inner ear trauma. PMID- 22215455 TI - Correlating the head shake-sensory organizing test with dizziness handicap inventory in compensation after vestibular neuritis. AB - OBJECTIVE: Despite complaints of dizziness, some patients with unilateral compensated vestibular weakness show normal results on Sensory Organization Test (SOT), which is being widely used for the evaluation of vestibular function compensation. The head shake-sensory organization test (HS-SOT) has been suggested to increase the sensitivity of SOT. In HS-SOT, the patient is required to shake head under Conditions 2 and 5 of traditional SOT. However, the sensitivity of HS-SOT remains unelucidated in patients with vestibular neuritis. The aim of this study was to determine the sensitivity of HS-SOT and SOT and compare them with the Dizziness Handicap Inventory (DHI) in detecting balance problems in patients with vestibular neuritis complaining of dizziness. SETTING: Tertiary referral center. PATIENTS: A prospective analysis was conducted on all vestibular neuritis patients between September 2009 and April 2011. Thirty-two patients with uncompensated vestibular neuritis were enrolled in this study. Patients with acute symptoms of dizziness, orthopedic problems, or any other severe underlying conditions were excluded. MAIN OUTCOME MEASURES: Equilibrium and vestibular scores of SOT and equilibrium score ratios of HS-SOT and DHI were obtained from each patient after 1 week and 1, 2, and 6 months of the first attack of vestibular neuritis. RESULTS: HS-SOT is more correlated with the DHI than SOT by periods. One month after vestibular neuritis, the correlation between DHI and SOT, HS-SOT Conditions 2 and 5 were -0.301, -0.385, and -0.625, respectively. Six months after vestibular neuritis, the correlation between DHI and SOT, and HS-SOT Conditions 2 and 5 were -0.053, -0.337, and -0.394, respectively. CONCLUSION: HS-SOT was more sensitive than SOT during the compensation of vestibular neuritis. Specifically, during the compensation of vestibular neuritis, HS-SOT Condition 5 was more correlated with DHI than HS-SOT Condition 2. The results suggest that HS-SOT provides more useful measures for the evaluation of vestibular compensation in vestibular neuritis. PMID- 22215456 TI - Cochlear blood flow and speech perception ability in cochlear implant users. AB - OBJECTIVE: The effect of cochlear blood flow (CBF) on speech perception ability in cochlear implant (CI) users has not been reported. We investigated various factors influencing speech perception including CBF in CI users. PATIENTS: Eighty two patients who received CI surgery at an academic hospital. METHODS: CBF was measured during CI surgery using laser Doppler flowmetry. The speech perception level was measured after a sufficient interval after CI surgery. Multivariate analysis was used to evaluate the influences of age, duration of deafness, sex, cause of deafness, and CBF on the speech perception level. RESULTS: CBF decreased significantly with age but was not related to the speech perception level. In patients with congenital hearing loss, the speech perception level was significantly worse in children who received a CI at 3 years of age than in those who received a CI at 2 years of age or younger. Duration of deafness before CI surgery had deteriorative effects on the speech perception level. CONCLUSION: CBF may be associated with progression of hearing loss. However, measuring CBF during CI surgery is not useful for predicting postoperative speech perception. PMID- 22215457 TI - Idiopathic tinnitus concomitant with eye closure. AB - OBJECTIVE: To describe 2 patients presenting with idiopathic tinnitus concomitant with eye closure. STUDY DESIGN: Clinical capsule report. SETTING: University hospital. PATIENTS: Two patients presented with intermittent tinnitus synchronous with eye closing or blinking. Otoscopic examination revealed inward movement of tympanic membranes concomitantly with eye blinking or eye closure in 1 patient. Neither patient had facial nerve disease or myoclonus. INTERVENTIONS: Compliance in impedance audiometry was recorded. RESULTS: Compliance in impedance audiometry was reduced during eye blinking and eye closure in both cases. The tinnitus was attributed to muscular tinnitus via stapedial muscle contraction during eye closure. CONCLUSION: These are the rare 2 reported patients presenting with idiopathic muscular tinnitus concomitant with eye closure. The reductive change of compliance in impedance audiometry during tinnitus coincident with eye closure is a feature of this form of tinnitus. We suggest evaluation of compliance change in impedance audiometry to be a key examination in patients with stapedial muscular tinnitus concomitant with eye closure. PMID- 22215458 TI - Comorbid benign paroxysmal positional vertigo in idiopathic sudden sensorineural hearing loss: an ominous sign for hearing recovery. AB - OBJECTIVE: To determine characteristics and their prognostic value in idiopathic sudden sensorineural hearing loss (ISSNHL) with comorbid ipsilateral benign paroxysmal positional vertigo (BPPV). STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS: Of the 374 patients with a diagnosis of ISSNHL at Seoul National University Bundang Hospital from January 2004 to December 2009, 32 patients (8.6%) with comorbid BPPV were recruited and compared with matched ISSNHL patients without BPPV. INTERVENTIONS: Otologic and neurotologic examinations, pure-tone audiometry (PTA), vestibular function tests, and brain magnetic resonance imagings. MAIN OUTCOME MEASURES: Comparison of the findings of serial audiograms for 6 months and vestibular function tests in patients with ISSNHL and concurrent BPPV with those in age-matched ISSNHL patients without BPPV. RESULTS: Patients with BPPV showed higher PTA averages than those without BPPV on initial and follow-up audiograms. Moreover, the improvement in PTA was less in the BPPV group than in the control. BPPV most commonly involved the posterior canal (17/32, 53.1%), followed by the horizontal canal (8/32, 25%), both the posterior and horizontal canals (6/32, 18.8%), and the anterior canal (1/32, 3.1%). Thirteen (40.6%) of 32 patients had recurrences of BPPV, 9 within a week and another 2 within 3 months. CONCLUSION: Comorbid BPPV is a negative prognostic indicator of auditory function in ISSNHL. Concurrent BPPV in ISSNHL suggests combined damage to the utricle and may indicate severe and widespread labyrinthine damage, leading to the poor prognosis. PMID- 22215460 TI - Mucosal melanoma of the middle ear cavity and Eustachian tube: a case report, literature review, and focus on surgical technique. AB - OBJECTIVE: To present a case of mucosal melanoma of the Eustachian tube with a focus on surgical technique and to review the literature on treatment of mucosal melanoma of the head and neck, and review cases involving the middle ear and/or Eustachian tube. PATIENT: A 67-year-old man was diagnosed with mucosal melanoma of the middle ear and Eustachian tube. INTERVENTION: The patient underwent primary surgical resection including transtemporal/transpetrosal approach, endoscopic nasopharyngectomy, infratemporal fossa dissection, temporomandibular joint resection, ipsilateral neck dissection (levels II-IV), and superficial parotidectomy. RESULTS: The patient was discharged on postoperative Day 7 with a very good functional status. He did have early dysphagia and dysarthria as a result of the VII to XII anastomosis for facial nerve reconstruction, which did require PEG tube placement. However, at 4 months after surgery, the patient was eating solid foods and returning to normal activities. He received radiation therapy postoperatively. There has been no evidence of tumor recurrence at 8 months after treatment. CONCLUSION: The standard treatment of head and neck mucosal melanoma is primarily surgical. Surgical removal of mucosal melanoma in the Eustachian tube/middle ear can present challenges in achieving microscopically negative margins. However, gross tumor resection with postoperative radiotherapy has been shown to improve locoregional control. PMID- 22215463 TI - Recurrent and founder mutations in the Netherlands: the cardiac phenotype of DES founder mutations p.S13F and p.N342D. AB - BACKGROUND: Desmin-related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene (DES). We describe new families carrying the p.S13F or p.N342D DES mutations, the cardiac phenotype of all carriers, and the founder effects. METHODS: We collected the clinical details of all carriers of p.S13F or p.N342D. The founder effects were studied using genealogy and haplotype analysis. RESULTS: We identified three new index patients carrying the p.S13F mutation and two new families carrying the p.N342D mutation. In total, we summarised the clinical details of 39 p.S13F carriers (eight index patients) and of 21 p.N342D carriers (three index patients). The cardiac phenotype of p.S13F carriers is fully penetrant and severe, characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement. Although muscle weakness is a prominent and presenting symptom in p.N342D carriers, their cardiac phenotype is similar to that of p.S13F carriers. The founder effects of p.S13F and p.N342D were demonstrated by genealogy and haplotype analysis. CONCLUSION: DRM may occur as an apparently isolated cardiological disorder. The cardiac phenotypes of the DES founder mutations p.S13F and p.N342D are characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement. PMID- 22215464 TI - Smaller holistic processing of faces associated with face drawing experience. AB - The type of experience involved with an object category has been regarded as one important factor in shaping of the human object recognition system. Laboratory training studies have shown that different kinds of learning experience with the same set of novel objects resulted in different perceptual and neural changes. Whether this applies to natural real-world objects remains to be seen. We compared two groups of observers who had different learning experiences with faces, using holistic processing as a dependent measure. We found that, while ordinary observers had extensive individuation experience with faces and displayed typical holistic face processing, art students who had acquired additional experience in drawing faces, and thus in attending to parts of a face, showed less holistic processing than did ordinary observers. These results converge with laboratory training studies on the role of type of experience in the development of different perceptual markers for different object categories. It is thus insufficient to categorize expertise simply in terms of object domains (e.g., expertise with faces). Instead, perceptual expertise should be classified in terms of the underlying process or task demand. PMID- 22215465 TI - Semantic picture-word interference is a postperceptual effect. AB - Naming a picture is slower while ignoring a semantically related versus an unrelated distractor word (semantic picture-word interference, or PWI). To locate the PWI effect in the word production processing stream (during perceptual encoding, response selection, or afterward), we used the psychological refractory period paradigm, in which participants identified a tone and then, at varying SOAs, named a picture while ignoring a semantically related or unrelated word (following Dell'Acqua, Job, Peressotti, & Pascali, 2007). As in results from the Stroop paradigm (Fagot & Pashler, 1992), we found equivalent PWI effects at short and long SOAs following tone identification in two experiments, indicating that semantic competition occurs at response selection or later. Our results suggest that it is premature to assume that competitive selection occurs at multiple levels in the word production system (van Maanen, van Rijn, & Borst, 2009) or that the Stroop and semantic PWI effects are fundamentally different (Dell'Acqua et al., 2007). PMID- 22215466 TI - An associative model of adaptive inference for learning word-referent mappings. AB - People can learn word-referent pairs over a short series of individually ambiguous situations containing multiple words and referents (Yu & Smith, 2007, Cognition 106: 1558-1568). Cross-situational statistical learning relies on the repeated co-occurrence of words with their intended referents, but simple co occurrence counts cannot explain the findings. Mutual exclusivity (ME: an assumption of one-to-one mappings) can reduce ambiguity by leveraging prior experience to restrict the number of word-referent pairings considered but can also block learning of non-one-to-one mappings. The present study first trained learners on one-to-one mappings with varying numbers of repetitions. In late training, a new set of word-referent pairs were introduced alongside pretrained pairs; each pretrained pair consistently appeared with a new pair. Results indicate that (1) learners quickly infer new pairs in late training on the basis of their knowledge of pretrained pairs, exhibiting ME; and (2) learners also adaptively relax the ME bias and learn two-to-two mappings involving both pretrained and new words and objects. We present an associative model that accounts for both results using competing familiarity and uncertainty biases. PMID- 22215467 TI - Laughter exaggerates happy and sad faces depending on visual context. AB - Laughter is an auditory stimulus that powerfully conveys positive emotion. We investigated how laughter influenced the visual perception of facial expressions. We presented a sound clip of laughter simultaneously with a happy, a neutral, or a sad schematic face. The emotional face was briefly presented either alone or among a crowd of neutral faces. We used a matching method to determine how laughter influenced the perceived intensity of the happy, neutral, and sad expressions. For a single face, laughter increased the perceived intensity of a happy expression. Surprisingly, for a crowd of faces, laughter produced an opposite effect, increasing the perceived intensity of a sad expression in a crowd. A follow-up experiment revealed that this contrast effect may have occurred because laughter made the neutral distractor faces appear slightly happy, thereby making the deviant sad expression stand out in contrast. A control experiment ruled out semantic mediation of the laughter effects. Our demonstration of the strong context dependence of laughter effects on facial expression perception encourages a reexamination of the previously demonstrated effects of prosody, speech content, and mood on face perception, as they may be similarly context dependent. PMID- 22215468 TI - Does high memory load kick task-irrelevant information out of visual working memory? AB - The limited capacity of visual working memory (VWM) requires the existence of an efficient information selection mechanism. While it has been shown that under low VWM load, an irrelevant simple feature can be processed, its fate under high load (e.g., six objects) remains unclear. We explored this issue by probing the "irrelevant-change distracting effect," in which the change of a stored irrelevant feature affects performance. Simple colored shapes were used as stimuli, with color as the target. Using a whole-probe method (presenting six objects in both the memory and test arrays), in Experiment 1 we found that a change to one of the six shapes led to a significant distracting effect. Using a partial-probe method (presenting the probe either at the screen center or at a location selected from the memory array), in Experiment 2 we showed the distracting effect again. These results suggest that irrelevant simple features can be stored into VWM, regardless of memory load. PMID- 22215469 TI - Sparing from the attentional blink is not spared from structural limitations. AB - When a series of three successive to-be-reported items (targets) is displayed in a rapid serial visual presentation (RSVP) stream of distractors, it has been shown that no attentional blink--a marked impairment in the report of the second of two targets, typically observed when the targets appear within 200-600 ms of one another--occurs in target accuracy. The present study examines three recently introduced computational models that provide different explanations of this protracted sparing effect. Using a standard RSVP design and these models, we provide empirical data and simulations that illustrate that structural limitations affect the processing of successive targets. In addition, we compare the candidate mechanisms that might underlie these limitations. PMID- 22215470 TI - Results of a multi-level intervention to prevent and control childhood obesity among Latino children: the Aventuras Para Ninos Study. AB - BACKGROUND: Community-based interventions are needed to reduce the burden of childhood obesity. PURPOSE: To evaluate the impact of a multi-level promotora based (Community Health Advisor) intervention to promote healthy eating and physical activity and prevent excess weight gain among Latino children. METHODS: Thirteen elementary schools were randomized to one of four intervention conditions: individual/family level (Family-only), school/community level (Community-only), combined (Family + Community), or a measurement-only condition. Participants were 808 Latino parents and their children enrolled in kindergarten through 2(nd) grade. Measures included parent and child body mass index (BMI) and a self-administered parent survey that assessed several parent and child behaviors. RESULTS: There were no significant intervention effects on children's BMI z-score. The family intervention changed several obesity-related child behaviors (e.g., fruit/vegetable consumption) and these were mediated by changes in parenting variables (e.g., parent monitoring). CONCLUSION: A promotora-based behavioral intervention was efficacious at changing parental factors and child obesity-related health behaviors. PMID- 22215472 TI - EMT in carcinoma progression and dissemination: facts, unanswered questions, and clinical considerations. AB - Over the past decade, much effort has been made to understand how cancers metastasize. In deciphering the metastatic process, a vast amount of work has focused on the role of the epithelial to mesenchymal transition (EMT), which, in experimental models, confers tumor cells with invasive and metastatic abilities, resistance to therapies, as well as cancer stem cell phenotype-properties that have a major impact on cancer prognosis. Searching "EMT and cancer" in PubMed retrieves thousands of original research articles, yet, we haven't answered the most basic question in the field: has EMT any relevance in human tumors? PMID- 22215471 TI - Sperm chromosomal aneuploidy and DNA integrity of infertile men with anejaculation. AB - PURPOSE: To explore sperm chromosomal aneuploidy, sperm membrane and DNA integrity in infertile patients with anejaculation. METHODS: Semen samples were collected from 18 infertile men with spinal cord injury (SCI) by penile vibratory stimulation (PVS) and from 14 psychogenic anejaculation (PA) patients by percutaneous vasal sperm aspiration (PVSA). These semen samples as well as samples from 16 donors were analyzed using the hypo-osmotic swelling (HOS) test, the sperm chromatin dispersion (SCD) test and multi-color fluorescence in situ hybridization (FISH) with probes specific for chromosomes 13, 18, 21, X and Y. RESULTS: There were significant differences in the percentages of motile sperm, normal morphologic sperm and sperm DNA fragmentation between the infertile men with SCI and the control group (P < 0.05 and P < 0.01). The sperm motility was significantly greater in the PA-PVSA group than in the SCI-PVS group (P < 0.01). The number of round cells per mL of semen obtained from the 18 SCI patients by PVS was between 1 and 8 million. The rate of sperm DNA fragmentation in the SCI PVS group was higher than that of the PA-PVSA group (P < 0.05). The aneuploidy rates for the SCI patients were 2.4-fold higher for chromosomes 13, 18 and 21 and 2.2-fold higher for chromosomes X and Y than for patients in the control group (P < 0.0001). CONCLUSIONS: The semen quality is poorer, sperm DNA fragmentation and sperm chromosomal aneuploidies are seen at a higher rate for SCI patients compared to healthy, fertile and normospermic men. Whether the difference in yield is due to increased scrotal temperature, genitourinary infection, or other reasons requires further study. PMID- 22215473 TI - Addition of rituximab to reduced-dose CHOP chemotherapy is feasible for elderly patients with diffuse large B-cell lymphoma. AB - PURPOSE: The aim of this study was to evaluate the efficacy and toxicity of reduced-dose (RD) RCHOP (rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy for elderly patients with diffuse large B-cell lymphoma (DLBCL). METHODS: This study comprised 85 patients, aged >= 60 years, who were diagnosed with DLBCL; patients were enrolled at a single center between June 2004 and December 2009. Patients received either 6 or 8 cycles of RD-RCHOP, spaced 3 weeks apart, at the physician's discretion. The RD RCHOP regimen consisted of 375 mg/m(2) rituximab, 600 mg/m(2) cyclophosphamide, 30 mg/m(2) doxorubicin, and 1-mg vincristine on day 1 of each cycle, and 40-mg prednisone on days 1-5. The patients received granulocyte colony-stimulating factor if they experienced grade 4 neutropenia or febrile neutropenia during any cycle. RESULTS: The average relative dose intensity was 97.3% for doxorubicin and 97.4% for cyclophosphamide. The complete remission (CR) and overall response rate were 67.1 and 89.5%, respectively. The 3-year event-free survival and overall survival rates were 71.9% +/- 5.1% and 83.3% +/- 5.1%. By using multivariate analyses, we determined that C-reactive protein levels greater than 1.31 mg/dl and the absence of CR were poor prognostic factors. Grade 3 or 4 neutropenia occurred in 35.3% of patients, and febrile neutropenia occurred in only 3 (3.5%) patients. CONCLUSIONS: RD-RCHOP chemotherapy is well tolerated and effective in elderly patients with DLBCL. PMID- 22215474 TI - Dual-emission quantum dots nanocomposites bearing an internal standard and visual detection for Hg2+. AB - A novel dual-fluorescence quantum dots (QD) nanocomposite with tuning emission wavelength and fluorescence intensity was synthesized, in which CdS and CdTe were the internal standard and probe, respectively. This nanocomposite exhibited good photobleaching and pH stability, and exhibited selective sensing for Hg(2+) with a detection limit (3SD/k) of 5.6 nM. Based on the blue background emitted by the internal standard CdS, a novel visual fluorescence detection method has been established, and can be used for the qualitative and semi-quantitative colorimetric analysis of Hg(2+). PMID- 22215475 TI - Role of intraoperative ultrasonography for pancreatic schwannoma. PMID- 22215476 TI - Minimally invasive total hip arthroplasty using a transpiriformis approach: a preliminary report. AB - BACKGROUND: Continuing efforts have been made to develop minimally invasive surgery techniques for THA. One of the most commonly performed of these techniques is the mini-posterior approach. All reported series using this approach describe surgical detachment of the short external rotators of the hip. In 2008, Penenberg et al. described an innovative surgical technique that preserves the short external rotators. We present the results of a single incision modification of this technique in 135 patients. DESCRIPTION OF TECHNIQUE: This technique is based on preservation of all of the short external rotators of the hip with the exception of the piriformis or conjoined tendon. This single-incision technique required the development of specialized instrumentation for exposure and reaming of the acetabulum. The specialized retractors also successfully minimized trauma to the skin and subcutaneous tissue. METHODS: For the 135 patients undergoing THA with this technique, we analyzed demographic and operative data. We recorded complications, evaluated postoperative clinical function using the Harris hip score, and assessed cup abduction angle, cup anteversion, and stem alignment on radiographs. Minimum followup was 14 months (mean, 22 months; range, 14-33 months). RESULTS: There were no dislocations, no sciatic nerve palsies, no wound complications, and low transfusion rates (8%). The postoperative Harris hip score averaged 96.5 (range, 87-100). Overall acetabular cup abduction angle averaged 41 degrees (range, 21 degrees -49 degrees ) and anteversion averaged 21 degrees (range, 15 degrees -27 degrees ). Four percent and 2% of femoral components were inserted into more than 2 degrees varus and 2 degrees valgus alignment, respectively. CONCLUSIONS: This technique shows promise as an alternative tissue-sparing method for minimally invasive THA. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22215477 TI - 2010 Musculoskeletal Tumor Society: Editorial comment: Journal-Society Synergy in Scholarly Publication. PMID- 22215478 TI - Capacitive coupling reduces instrumentation-related infection in rabbit spines: a pilot study. AB - BACKGROUND: Postoperative spine infections cause considerable morbidity. Patients are subjected to long-term antibiotic regimens and may require further surgery. Delivery of electric current through instrumentation can detach biofilm, allowing better antibiotic penetration and assisting in eradicating infection. QUESTION/PURPOSES: We asked (1) whether capacitive coupling treatment in combination with a single dose of antibiotics would reduce infection rates when compared with antibiotics alone in a rabbit spine infection model, (2) whether it would decrease the overall bacterial burden, and (3) whether there was a time dependent response based on days treated with capacitive coupling. METHODS: Thirty rabbits were subjected to a well-established spine infection model with a single dose of intravenously administered systemic ceftriaxone (20 mg/kg of body weight) prophylaxis. Two noncontiguous rods were implanted inside dead space defects at L3 and L6 challenged with 10(6) colony-forming units of Staphylococcus aureus. Rabbits were randomly treated with a capacitive coupling or control device. Instrumentation and soft tissue bacterial growth were assessed after 7 days. RESULTS: Sites treated with capacitive coupling showed a decrease in the incidence of positive culture: 36% versus 81% in the control group. We observed no difference in the soft tissue's infectious burden. Overall bacterial load was not decreased with capacitive coupling. CONCLUSIONS: Capacitive coupling in conjunction with antibiotics reduced the instrumentation-related infection rate compared with antibiotics alone. CLINICAL RELEVANCE: Capacitive coupling noninvasively delivers an alternating current that may detach biofilm from instrumentation. Treatment of infection may be successful without removal of instrumentation, allowing for improved stability and overall decreased morbidity. PMID- 22215479 TI - What to disclose? Revisiting informed consent. AB - BACKGROUND: The requirement of obtaining informed consent before medical procedures is well established. With patients having greater access to information through information technology and owing to other factors, disclosure that goes beyond the traditional elements of the risks, benefits, and alternatives to an intervention is demanded from physicians. QUESTIONS/PURPOSES: We asked if modern informed consent doctrine encompasses such physician-specific variables like professional experience, health, disability, training, qualifications, disciplinary history, FDA-regulatory status pertaining to a medical device, physician research and financial interests, and statistics related to medical outcomes. METHODS: We searched two major legal databases and identified court opinions and legal reviews that have examined the scope of physician disclosure while obtaining informed consent. From this information, we summarized the prevailing state of informed consent law. RESULTS: Despite the expansion of information available to patients, courts have been hesitant to expand the informed consent doctrine to encompass physician-specific variables. Exceptions involve cases in which such variables directly impacted medical care and the patient could demonstrate their relevance in the informed consent process. CONCLUSIONS: Judicial decisions have subtly expanded the doctrine of informed consent beyond its traditional limits, at least in some cases. As informed consent law continues to develop, physicians should ask if information would be material to a reasonable patient while making medical decisions; if so, such information should be disclosed. PMID- 22215480 TI - Case report: Bone tumor of the scapula in a patient undergoing liver transplantation. AB - BACKGROUND: De novo malignancies are serious complications in the late postoperative period after liver transplantation. The most common de novo tumors are skin malignancies, posttransplantation lymphoproliferative disorder, tumors of the head and neck, and Kaposi's sarcoma. Such posttransplant de novo malignancies are apparently rarely found in bone. CASE DESCRIPTION: We describe a patient with a low-grade, aggressive fibrous histiocytoma of the scapula. The patient had undergone liver transplantation 6 years earlier. En bloc resection of the tumor and limb salvage was performed. At the 2-year followup the patient had no signs of local recurrence or metastatic spread; the patient had a Musculoskeletal Tumor Society (MSTS) score of 87. LITERATURE REVIEW: A literature review suggests the main predisposing factors to such malignancies are immunosuppression and its length of use. According to the literature, tumors apparently are rare in bone after liver transplantation, with no clearly documented cases. However, in the presence of such a finding, our study might be the first clearly documented case study of this kind of bone tumor. CLINICAL RELEVANCE: We describe a patient with a bone tumor after liver transplantation. Our literature review suggests liver transplantation and long-term immunosuppression played a role in this patient's tumor. PMID- 22215481 TI - Weight loss/maintenance as an effective tool for controlling type 2 diabetes: novel methodology to sustain weight reduction. AB - The type 2 diabetes epidemic closely parallels the obesity epidemic. Although weight loss is frequently initiated successfully, most patients regain substantial amounts of weight within the first year after completing a weight loss programme. Several studies have shown success over time with weight loss and type 2 diabetes prevention and/or remission. These include the Diabetes Prevention Program and the Look AHEAD study. Novel approaches to weight management have recently found their way onto the internet. With advances in medicine, there has been more patient success in the weight maintenance field. We review the Weight Management System that permits daily counselling to patients who have been losing or maintaining weight. The Weight Management System is a method that combines four fundamental elements: (1) remote daily weight monitoring by the system and the health professional; (2) daily feedback from the system and, when necessary, the health professional; (3) customized information for the needs and desires of the particular patient; and (4) a proprietary algorithm to detect early signs of weight regain. Recent beta testing of this system has confirmed Dr Rena Wing's statistics and has opened up a novel approach to long-term weight management and diabetes prevention. PMID- 22215482 TI - BVPaP-3, a T7-like lytic phage of Pseudomonas aeruginosa: its isolation and characterisation. AB - The increasing emergence of antibiotic-resistant bacteria has produced a growing interest among scientists in bacteriophages as alternative antimicrobial agents. This article reports a lytic phage against an antibiotic-resistant strain of Pseudomonas aeruginosa. Phage BVPaP-3 is a member of the Podoviridae family and morphologically similar to the T7-like phage gh-1. The phage has a hexagonal head of 58-59 nm in diameter and a short tail of 10 * 8 nm. It is stable at a wide range of pH (6-10) and temperatures (4-40 degrees C). Its optimal growth temperature is 37 degrees C and the adsorption rate constant is 1.19 * 10(-9). Latent and eclipse periods are 20 and 15 min, respectively, and the burst size is 44 after 35 min at 37 degrees C. The phage has a DNA size of 41.31 kb and a proteome of 11 proteins. The major protein is 33 kDa in size. PMID- 22215483 TI - Resistance of cyanobacterial fouling on architectural paint films to cleaning by water jet. AB - Mortar panels painted with three different white acrylic coatings were exposed to the environment in urban (Sao Paulo) and rural (Pirassununga) sites in Brazil for 7 years. After this time, all panels were almost equally discoloured, and paint detachment was observed to only a small degree. The biofilms were composed mainly of cyanobacteria and filamentous fungi, principal genera being Gloeocapsa and Chroococcidiopsis of the cyanobacteria, and Cladosporium and Alternaria of the fungi. Two of the three paints in Pirassununga became covered by a pink film that contained red-encapsulated Gloeocapsa and clay particles. The third, an 800% elastomeric matt formulation, became discoloured with a grey, only slightly pink, film, although the same cyanobacteria were present. The levels of paint detachments from all films in both locations were low, with rating range of 0-1 of a maximum 5 (100% detachment). After high-pressure water jetting, paint detachments increased at both locations, up to 2 in Pirassununga and 3 in Sao Paulo. Discoloration decreased; L*A*B* analysis of surface discoloration showed that DeltaE (alteration in colour from the original paint film) changed from 28 39 before cleaning to 13-16 afterwards. The pink coloration was not entirely removed from Pirassununga samples, suggesting that cyanobacterial cells are difficult to detach, and microscopic analysis of the biofilms confirmed that Gloeocapsa was still present as the principal contaminant on all surfaces, with Chroococcidiopsis being present as the second most common. Almost no fungi were detected after water jet application. PMID- 22215484 TI - Childhood B-cell progenitor acute lymphoblastic leukemia presenting a three-way t(11;12;21)(q14;p13;q22) with a RUNX1 gene signal on chromosome 11. PMID- 22215485 TI - Sox9 gene regulation and the loss of the XY/XX sex-determining mechanism in the mole vole Ellobius lutescens. AB - In most mammals, the Y chromosomal Sry gene initiates testis formation within the bipotential gonad, resulting in male development. SRY is a transcription factor and together with SF1 it directly up-regulates the expression of the pivotal sex determining gene Sox9 via a 1.3-kb cis-regulatory element (TESCO) which contains an evolutionarily conserved region (ECR) of 180 bp. Remarkably, several rodent species appear to determine sex in the absence of Sry and a Y chromosome, including the mole voles Ellobius lutescens and Ellobius tancrei, whereas Ellobius fuscocapillus of the same genus retained Sry. The sex-determining mechanisms in the Sry-negative species remain elusive. We have cloned and sequenced 1.1 kb of E. lutescens TESCO which shares 75% sequence identity with mouse TESCO indicating that testicular Sox9 expression in E. lutescens might still be regulated via TESCO. We have also cloned and sequenced the ECRs of E. tancrei and E. fuscocapillus. While the three Ellobius ECRs are highly similar (94-97% sequence identity), they all display a 14-bp deletion (Delta14) removing a highly conserved SOX/TCF site. Introducing Delta14 into mouse TESCO increased both basal activity and SF1-mediated activation of TESCO in HEK293T cells. We propose a model whereby Delta14 may have triggered up-regulation of Sox9 in XX gonads leading to destabilization of the XY/XX sex-determining mechanism in Ellobius. E. lutescens/E. tancrei and E. fuscocapillus could have independently stabilized their sex determination mechanisms by Sry-independent and Sry dependent approaches, respectively. PMID- 22215487 TI - Posaconazole: the case for therapeutic drug monitoring. AB - Invasive fungal infections are associated with high morbidity and mortality. Antifungal therapeutic options remain relatively limited; therefore, optimization of present regimens is essential. Posaconazole is licensed for prevention of invasive fungal infections and oropharyngeal candidiasis and salvage therapy for invasive aspergillosis. Recent data suggest that therapeutic drug monitoring may be an important tool for patient management. Clinical and laboratory animal data suggest that posaconazole demonstrates clinically relevant exposure-response relationships. Higher systemic drug exposure is associated with improved clinical outcomes. Potentially subtherapeutic concentrations are frequently encountered in critically ill patients. Therapeutic drug monitoring provides a way to optimize the use of posaconazole, and this review summarizes the indications and process by which this can be achieved. PMID- 22215486 TI - Identification of mediator complex 26 (Crsp7) gametologs on platypus X1 and Y5 sex chromosomes: a candidate testis-determining gene in monotremes? AB - The basal lineage of monotremes features an extraordinarily complex sex chromosome system which has provided novel insights into the evolution of mammalian sex chromosomes. Recently, sequence information from autosomes, X chromosomes, and XY-shared pseudoautosomal regions has become available. However, no gene has so far been described on any of the Y chromosome-specific regions. We analyzed sequences derived from Y-specific BAC clones to identify genes with potentially male-specific function. Here, we report the identification and characterization of the mediator complex protein gametologs on platypus Y5 (Crspy). We also identified the X-chromosomal copy which unexpectedly maps to X1 (Crspx). Sequence comparison shows extensive divergence between the X and Y copy, but we found no significant positive selection on either gametolog. Expression analysis shows widespread expression of Crspx. Crspy is expressed exclusively in males with particularly strong expression in testis and kidney. Reporter gene assays to investigate whether Crspx/y can act on the recently discovered mouse Sox9 testis-specific enhancer element did reveal a modest effect together with mouse Sox9 + Sf1, but showed overall no significant upregulation of the reporter gene. This is the first report of a differentiated functional male-specific gene on platypus Y chromosomes, providing new insights into sex chromosome evolution and a candidate gene for male-specific function in monotremes. PMID- 22215488 TI - The role of therapeutic drug monitoring of imatinib in patients with chronic myeloid leukemia and metastatic or unresectable gastrointestinal stromal tumors. AB - Imatinib mesylate is a tyrosine kinase inhibitor used as first-line treatment in Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) and metastatic or unresectable gastrointestinal stromal tumors (GIST). Therapeutic drug monitoring (TDM) for imatinib has been suggested to improve efficacy, assess compliance, and evaluate drug-drug interactions. Imatinib has proven efficacy in improving treatment response and survival in patients with Ph+ CML and GIST. Several analytical methods are available to quantify total plasma imatinib concentrations. A good relationship exists between total imatinib plasma concentrations and pharmacologic response. Clinical evaluation of pharmacologic response to imatinib alone may be insufficient given the long duration of therapy before clinical response in patients with Ph+ CML and GIST. Thus, the authors have used a previously published 9-step decision-making algorithm to evaluate the utility of TDM for imatinib. The suggested trough concentrations for improved complete cytogenetic or major molecular response in patients with Ph+ CML and improved time to progression for patients with GIST are >1000 and >1100 ng/mL, respectively. Imatinib exhibits interindividual pharmacokinetic variability. Increased apparent clearance of imatinib has been observed in chronic phase chronic myeloid leukemia and increased body weight. Decreased apparent clearance has been observed in renal impairment and patients on concomitant medications with potent inhibition of cytochrome P450 3A4. Duration of therapy in patients with Ph+ CML and GIST is lifelong. Based on the available evidence, TDM for imatinib may provide additional information on efficacy, compliance, and safety than clinical evaluation alone. Patients with suboptimal response to treatment, treatment failure, rare adverse events, drug interactions, or suspected nonadherence will attain the greatest benefit from TDM. PMID- 22215489 TI - Serum concentrations of antidepressants in the elderly. AB - BACKGROUND: The elderly is the most rapidly growing subpopulation in many countries, and the use of antidepressant drugs among elderly patients may be increasing as depression is one of the most common comorbid conditions in age related diseases. The aim of the present study was to compare serum concentrations of antidepressants in older versus younger individuals in a naturalistic setting. METHODS: Serum concentrations from patients treated with antidepressant drugs were withdrawn from a routine therapeutic drug monitoring database and stratified into the age groups younger than 40 years, 40-65 years, and older than 65 years. Dose-adjusted serum concentrations (concentration to dose ratios; nanomoles per liter per milligram per day) and absolute serum concentrations were compared between the subgroups using patients younger than 40 years as control. RESULTS: Altogether, 32,126 serum concentration samples from 17,930 patients treated with selective serotonin reuptake inhibitors, tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, or tetracyclic antidepressant drugs were included. Only minor differences in mean concentration to dose ratios and absolute serum concentrations were observed between patients aged 40-65 years and controls. In contrast, for 12 of the 14 drugs included, approximately 1.5- to 2-fold higher mean concentration to dose ratios were observed in patients older than 65 years versus controls (P < 0.01). Significantly higher absolute serum concentrations were also observed in the former compared with the latter subgroup for 8 of these 12 agents (P < 0.01). CONCLUSIONS: Patients older than 65 years had a 1.5- to 2-fold higher exposure of most antidepressant drugs compared with those younger than 40 years when given equal doses. This may indicate an increased risk of concentration-dependent side effects in the elderly. PMID- 22215490 TI - Alpha shock. PMID- 22215491 TI - Indications and surgical outcome following pulmonary metastasectomy: a nationwide study. AB - AIM: The aim of this retrospective nationwide study was to investigate indications and surgical outcome after pulmonary metastasectomy (PM) in a well defined cohort of patients and to calculate the proportion of cancer patients who were operated on. METHODS: Between 1984 and 2008, 81 patients (age 54.8 years, 50.6% men) underwent 100 PMs with curative intent in Iceland. For all patients, information on demographics, number of metastases, type of surgery, and complications were collected. Overall survival was estimated with median follow up of 45 months. For the three most common malignancies, the proportion of patients who underwent PM was calculated using information from the Icelandic Cancer Registry on all cases diagnosed. RESULTS: Of 100 PMs, there were 62 wedge resections, 34 lobectomies, and 4 pneumonectomies. The most common complication was persistent air leakage (>96 hour; 11.1%), and operative mortality was 1.2%. Of the 12 kinds of primary malignancies operated, three were most common: colorectal carcinoma (CRC, n = 27), sarcoma (n = 21), and renal cell carcinoma (RCC, n = 14). The proportion of patients who underwent PM was 1.0% for CRC, 6.5% for sarcoma, and 1.4% for RCC, and their 5-year overall survival was 45.2, 18.6, and 38.5%, respectively (p = 0.11). Survival for all patients was 30.8%. CONCLUSION: The surgical outcome and survival of patients who underwent PM in Iceland are comparable to those in the other studies. Although there was no control group and selection bias cannot be eliminated, the survival of PM patients was better than for the nonoperated patients. However, a relatively small proportion of patients with CRC, RCC, and sarcoma underwent metastasectomy. PMID- 22215492 TI - Late gastric incarceration 20 years after penetrating chest trauma. AB - The diagnosis of diaphragmatic injury in trauma patients is a challenge for surgeons. Misdiagnosis is common and can only be corrected when patients present with symptoms of diaphragmatic hernia. We report a rare case of delayed traumatic diaphragmatic hernia masquerading as empyema 20 years after lower chest penetrating trauma. The herniated stomach was found intraoperatively. Delayed traumatic diaphragmatic hernia should always be suspected in patients with trauma that may have occurred many years ago. PMID- 22215493 TI - Posterior mediastinotomy as an unordinary method of mediastinal drainage in patient with descending necrotizing mediastinitis: a case report. AB - The authors present a case report of severe descending necrotizing mediastinitis (DNM) of posterior mediastinum, etiologically of vertebral osteomyelitis treated by the drainage through the posterior mediastinotomy. Mediastinitis caused by vertebral osteomyelitis is very rare. The most important diagnostic and surveillance tool for descending mediastinitis is a CT scan of chest and neck. Every surgical approach to the mediastinum has its advantages and disadvantages, so each patient has to be treated individually and the most suitable type of drainage must be chosen. The posterior mediastinotomy is an unusual alternative of drainage of pre- and paravertebrally localized DNM in posterior mediastinum but it is not recommended as a routine strategy. PMID- 22215494 TI - Modified repair for huge unruptured aneurysm of the right sinus of valsalva. AB - Unruptured aneurysm of the sinus of Valsalva is a rare abnormality. In the present case, the huge aneurysm of the sinus of Valsalva was only involved in the right coronary sinus with the ostium far from its normal place. We designed a modified repair technique, with a scalloped Intergard woven vascular patch combined with aortic flap, to reconstruct the sinus of Valsalva and avoid the reimplantation of right coronary artery. PMID- 22215495 TI - Does bilateral pulmonary banding in comparison to Norwood procedure improve outcome in neonates with hypoplastic left heart syndrome beyond second-stage palliation? A review of the current literature. AB - Best evidence protocol was applied and the question addressed, whether there is an outcome advantage of a hybrid approach including bilateral pulmonary banding (BPB) and ductal stenting over Norwood procedure (NP) to maintain systemic circulation and to restrict pulmonary blood flow in neonates with hypoplastic left heart syndrome (HLHS). Out of 80 articles published since the original description of BPB in 2002, eight were selected to answer the clinical question. All studies were retrospective case-series after BLB, only three compared results with NP controls, but not in a randomized fashion. Only three chose high-risk patients. Mean follow-up interval was mentioned only in one study. Reported mean hospital, interstage, and stage 2 mortalities after BPB was 17.3, 12.4, and 25.3%, respectively. Estimated transplant-free survival beyond stage 2 palliation ranged from 7 to 80%, with no significant differences to NP controls in three studies. Reintervention rate was high, ranging from 20 to 42% at different sites. Due to study design or inhomogeneity of patient groups, current literature does not show evidence that bilateral pulmonary banding improves outcome with respect to survival beyond second-stage HLHS palliation. PMID- 22215496 TI - Transcatheter aortic valve implantation in aortic coarctation. AB - A 77-year-old male patient was scheduled for transcatheter aortic valve implantation for symptomatic and severe aortic valve stenosis. Severe multidirectional kinking of the aorta based on aortic coarctation did not allow for the transfemoral, but only for the transapical approach. The procedure was complicated because of the technically challenging retrograde passage of the transfemorally inserted pig-tail catheter required for intraoperative angiography of the aortic root. Correct positioning of the pig-tail catheter into the ascending aorta was accomplished by use of a loop snare, which was advanced into the descending aorta via the antegrade route, passing the cardiac apex, the stenotic aortic valve, and the coarctation-associated kinking. The pig-tail catheter tip was manipulated into the loop snare, pulled traverse the coarctation, and released within the proximal ascending aorta. Subsequent procedures were uneventful and followed the standardized protocol. A 29 mm Edwards Lifescience transcatheter Sapien bioprosthesis was successfully implanted. PMID- 22215497 TI - Eisenmenger syndrome complicated by pulmonary artery dissection. AB - This report describes a 40-year-old male patient diagnosed with pulmonary artery dissection involving both the left and right branches. The patient also had Eisenmenger syndrome secondary to an uncorrected patent ductus arteriosus. Diagnosis was facilitated through the use of transthoracic echocardiography and computed tomography. Due to the lack of definite guidelines for the optimal treatment strategy of this condition together with the poor condition of the patient, medical management was elected. Not surprisingly, the patient died suddenly only 7 days after the presentation. PMID- 22215498 TI - Autograft mitral valve replacement: a new technique. AB - We describe a new technique wherein we have used the Ionescu Ross Wooler stent for housing the pulmonary autograft. We believe that this technique is easy and reproducible and offers many advantages over the previously described techniques. PMID- 22215499 TI - Aortic leaflet replacement with fresh autologous pericardium: at 17-year follow up. AB - Fresh autologous pericardium is an alternative aortic valve substitute for children; however, the data were scarce and mixing. We presented a case of a 2 year-old boy who underwent right coronary leaflet replacement with fresh autologous pericardium and ventricular septal defect correction. At 17-year follow-up, the valve was in good condition and the patient remained asymptomatic without any medication. PMID- 22215500 TI - Benign localized fibrous tumor of the pleura: report of 25 new cases. AB - OBJECTIVE: Benign localized fibrous tumors (BLFT) of the pleura are very rare slow-growing neoplasms that generally have a favorable prognosis. The aim of this manuscript is to evaluate the predictors of outcome with the review of the literature in a series of 25 patients with BLFT. METHODS: Between January 1985 and November 2009, 25 patients underwent an operation due to BLFT. Of these patients, 14 (56%) were male; mean age was 41.1 (25 to 64) years. All patients underwent thoracotomy. Left thoracotomy approach was used in 16 patients. The mass lesions were totally excised. The histopathological examinations were performed with hematoxylin-eosin and immunohistochemical staining methods. RESULTS: Of the patients, 18 (72%) were symptomatic. Symptoms were cough in 36%, shortness of breath in 32%, and chest pain in 20% of the patients. One patient (4%) appeared to have some symptoms (pain and swelling of the joints) associated with pulmonary osteoarthropathy. Seven patients (28%) underwent an operation due to mass lesion detected at routine control visits. None of the patients had a history of exposure to asbestos. Radiological investigations revealed 16 (64%) mass lesions in the left. Of the lesions found on exploration, 5 (20%) were intrapulmonary localized lesion without pedicle and 20 were pedicled. Of the pedicled masses, 5 were connected to parietal pleura and 15 to visceral pleura and all were intrathoracic extrapulmonary localized lesions. Eight (32%) lesions connected to left lower lobe. Additionally, three pedicled lesions were located in the lung fissure. Pedicled lesions were totally excised together with their pedicles. Intraparenchymal mass lesions were resected using wedge resection. The diameter of the resected masses was ranging between 3 and 22 cm (mean: 8.7). Macroscopically, all were encapsulated with a homogeneous cut surface. Intraoperative mortality and morbidity was not observed. The average hospitalization duration for all patients was 8.6 days (5 to 12). The mean follow up was 33.6 (9 to 142) months with no recurrence. CONCLUSIONS: Benign localized fibrous tumors are uncommon and treated by surgical means. According to our data obtained from literature review, clinicians should be aware of recurrence possibility even after complete resection of benign localized fibrous tumor and the risk of malign transformation. PMID- 22215501 TI - Daily-Mean-SOFA, a new derivative to increase accuracy of mortality prediction in cardiac surgical intensive care units. AB - BACKGROUND: Sequential organ failure assessment (SOFA) score is widely used in many cardiac surgical intensive care units (ICUs). Its derivatives (mean and maximum values) are known to be more accurate than the original daily values of SOFA itself. However, they were designed for research purposes and could be calculated only after ICU discharge. We aimed to develop a reliable derivative that can be easily calculated daily (Daily-Mean-SOFA) for aiding daily-decision making and resource allocation. METHODS: All consecutive adult cardiac surgical patients from our ICU between January 1, 2007 and December 31, 2008 were included. We obtained Initial-SOFA (on day 1), the Original-Daily-SOFA value from the 1st to the 6th postoperative day, Max-SOFA (highest SOFA value during the whole ICU-stay), Mean-SOFA (sum of all daily SOFA values/the length of ICU-stay), and the new "Daily-Mean-SOFA" from day 2 to 6 (sum of SOFA from day 1 until day n/n). We compared their accuracies at predicting ICU mortality using calibration and discrimination statistics. RESULTS: Total 2801 patients were included. The newly developed "Daily-Mean-SOFA" was significantly more accurate than the corresponding SOFA value of the same day in correctly predicting survival and mortality in the whole study population (OCC: 94.1 to 95.0%) and in accurately identifying the individual patient's risk of mortality (AUC: 0.859 to 0.904). It was better than all other derivatives except the Mean-SOFA which was superior to it (OCC: 96.3%; AUC: 0.913). CONCLUSIONS: The Daily-Mean-SOFA is a reliable derivative for daily risk stratification in cardiac ICUs. Due to its accuracy and daily availability, it may be used for risk-directed therapy in cardiac ICUs. PMID- 22215502 TI - Bilateral tension pneumothoraces leading to cardiac arrest after coronary artery bypass surgery. AB - Bilateral pneumothoraces are a very rare event. In clinical settings, inadvertent incursion into the pleural space resulting from diagnostic or therapeutic medical interventions such as bilateral venipunctures or damage to the lung parenchyma due to high pressure ventilation may be causative. Bilateral pneumothoraces postcardiac surgery are rarely reported. We present the case of bilateral tension pneumothoraces leading up to cardiorespiratory arrest in a 57-year-old male, weighing 130 kg, who underwent without any complications a coronary artery bypass surgery. Thoracic chest tubes (retrosternal and intrapericardial) and a left pleural tube were removed 24 hours prior to the incident. Diffuse sternal pain sensation accompanied by slow progressive respiratory distress and confusion shortly before the incident were all developed over a period of 12 hours. A prompt cardiopulmonary resuscitation and bilateral chest tube insertion had prevented a fatality in the patient. PMID- 22215503 TI - Concealed infective endocarditis associated with subaortic left ventricular aneurysm. AB - We describe a case of subaortic left ventricular aneurysm with concealed infective endocarditis. The patient, who was diagnosed with aortic regurgitation and a subaortic left ventricular aneurysm, did not exhibit any evidence of infective endocarditis preoperatively. However, histopathological examination after an aortic valve replacement revealed neutrophil infiltration in the resected aneurysm. One year postoperatively, the infection recurred and an aortic root replacement was performed. PMID- 22215504 TI - Role of primary bacterial contamination of a pulmonary homograft for Ross operation: report of a case and review of the literature. AB - In a 43-year-old female, Ross operation was performed with annular reinforcement of the autograft and a cryo-fixed homograft that proved to be contaminated with enterobacter cloacae and klebsiella pneumoniae at the time of operation. Clinical course was unremarkable, perhaps due to effective antibiotic prophylaxis and treatment. In the literature, little is known about intraoperative bacterial contamination and early endocarditis. The authors report what they believe is the second reported case. Particular resistibilities of homograft and autograft might make early endocarditis unlikely. PMID- 22215505 TI - Control of cytoplasmic translation in plants. AB - Translational control provides cells with a mechanism to rapidly control gene expression in a reversible manner in response to environmental and developmental cues. It involves the dynamic, coordinated activity of numerous factors that direct the synthesis of proteins with precision in space and time. Translational control is primarily regulated at the level of initiation, and as such, mechanisms that regulate translation most often target the initiation machinery. Translation in plants is fundamentally similar to that of other eukaryotes. However, there are significant differences in translation factor isoforms and their associated proteins, and the types of regulation that can act upon these factors. Regulation of translation in plants can involve protein phosphorylation, variable associations of initiation factor isoforms, RNA sequence element interactions, and small RNAs. The assembly of large mRNA-ribonucleoprotein complexes, called processing bodies and stress granules, also influences the translatability of an mRNA. mRNA-cytoskeleton interactions, as well as subcellular and intercellular transport of mRNAs, also appear to regulate translation in plants. Often working together, these control mechanisms finely tune translational expression within the cell. PMID- 22215506 TI - Differential effects of acute hypoxia on the activation of TRPV1 by capsaicin and acidic pH. AB - Transient receptor potential vanilloid 1 (TRPV1) is a Ca(2+)-permeable cation channel activated by a variety of physicochemical stimuli. The effect of hypoxia (P(O(2)), 3%) on rat TRPV1 overexpressed in HEK293T has been studied. The basal TRPV1 current (I (TRPV1)) was partly activated by hypoxia, whereas capsaicin induced TRPV1 (I (TRPV1,Cap)) was attenuated. Such changes were also suggested from hypoxia- and capsaicin-induced Ca(2+) signals in TRPV1-expressing cells. Regarding plausible changes of reactive oxygen species (ROS) under hypoxia, the effects of antioxidants, vitamin C and tiron, as membrane-impermeable and permeable, respectively, were tested. Both I (TRPV1) and I (TRPV1,Cap) were increased by vitamin C, while only I (TRPV1) was slightly increased by tiron. The hypoxic inhibition of I (TRPV1,Cap) was still persistent under hypoxia/vitamin C. Interestingly, hypoxia/tiron strongly inhibited both I (TRPV1) and I (TRPV1,Cap). Also, with vitamin C applied through a pipette solution, hypoxia inhibited I (TRPV1) and I (TRPV1,Cap). In contrast, hypoxia and hypoxia/tiron had no effect on the I (TRPV1) induced by acid (pH 6.2, I (TRPV1,Acid)). Taken together, hypoxia partly activated TRPV1 while it decreased their sensitivity to capsaicin. Putative changes of ROS under hypoxia might underlie the side-specific effects of ROS on TRPV1: inhibitory at the extracellular and stimulatory at the intracellular side, respectively. The differential effects of hypoxia on I (TRPV1,Cap) and I (TRPV1,Acid) suggested that the intracellular ROS increase might attenuate the pharmacological potency of capsaicin. PMID- 22215507 TI - Family structure transitions and changes in maternal resources and well-being. AB - This article uses data from the Fragile Families and Child Wellbeing Study to examine whether family instability is associated with changes in perceived social support, material hardship, maternal depression, and parenting stress among mothers of young children. In addition to accounting for the number of transitions that a mother experiences during the first five years of her child's life, we pay close attention to the type and timing of these transitions. We find that mothers who transition to cohabitation or marriage with their child's biological father experience declines in material hardship and that those who transition to cohabitation or marriage with another man exhibit modest declines in both material hardship and depression. Mothers who exit cohabiting or marital relationships encounter decreases in perceived social support and increases in material hardship, depression, and parenting stress. Overall, our results suggest that both the type and, to a much lesser degree, the timing of family structure transitions may influence maternal well-being. PMID- 22215508 TI - Updates on the multimodality management of desmoplastic small round cell tumor. AB - Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and an aggressive malignancy with poor outcome. This tumor can co-express epithelial, neural, and mesenchymal markers. The molecular hallmark of DSRCT is the EWS-WT1 fusion protein. Despite the diversities in treatment modality, the best results have been seen with radical surgery and adjuvant or neoadjuvant chemotherapy. PMID- 22215509 TI - Glucose meter inaccuracy and the impact on the care of patients. AB - Blood glucose testing utilizing point-of-care (POC) glucose meters has become increasingly common--in hospital settings, in outpatient areas, and in the self care of patients. It is rightly considered an essential tool for the management of diabetes. But many who rely on these meters are unaware of the pitfalls in their use and do not realize that there are settings where misleading results obtained by POC glucose meters may alter clinical decisions in the care of persons with diabetes and in some cases have caused catastrophic errors in care, even deaths. Their use in critical care settings is of great concern because many of the factors that increase the risk of inaccuracy of the POC glucose meters exist in critical care settings. Unfortunately, many clinicians are still uncritically accepting data from the POC glucose meters, to the potential detriment of the care of the patients. To improve the quality of care of those with diabetes, we need to establish better standards for the evaluation of POC glucose meters, encourage wider use of technologies that have improved the accuracy and precision of the meters, and adopt clear rules, particularly in inpatient settings, as to when to avoid using POC glucose meters and also when to verify their results before accepting the results of the POC glucose measurement. Such strategies are essential if we are to use these meters successfully. PMID- 22215510 TI - Bronchial and bronchiolar fibrosis in rats exposed to 2,3-pentanedione vapors: implications for bronchiolitis obliterans in humans. AB - 2,3-Pentanedione (PD) is a component of artificial butter flavorings. The use of PD is increasing since diacetyl, a major butter flavorant, was associated with bronchiolitis obliterans (BO) in workers and has been removed from many products. Because the toxicity of inhaled PD is unknown, these studies were conducted to characterize the toxicity of inhaled PD across a range of concentrations in rodents. Male and female Wistar-Han rats and B6C3F1 mice were exposed to 0, 50, 100, or 200 ppm PD 6 h/d, 5 d/wk for up to 2 wk. Bronchoalveolar lavage fluid (BALF) was collected after 1, 3, 5, and 10 exposures, and histopathology was evaluated after 12 exposures. MCP-1, MCP-3, CRP, FGF-9, fibrinogen, and OSM were increased 2- to 9-fold in BALF of rats exposed for 5 and 10 days to 200 ppm. In mice, only fibrinogen was increased after 5 exposures to 200 ppm. The epithelium lining the respiratory tract was the site of toxicity in all mice and rats exposed to 200 ppm. Significantly, PD also caused both intraluminal and intramural fibrotic airway lesions in rats. The histopathological and biological changes observed in rats raise concerns that PD inhalation may cause BO in exposed humans. PMID- 22215511 TI - Chronic low-level arsenite exposure through drinking water increases blood pressure and promotes concentric left ventricular hypertrophy in female mice. AB - Cardiovascular disease is the leading cause of death in the United States and worldwide. High incidence of cardiovascular diseases has been linked to populations with elevated arsenic content in their drinking water. Although this correlation has been established in many epidemiological studies, a lack of experimental models to study mechanisms of arsenic-related cardiovascular pathogenesis has limited our understanding of how arsenic exposure predisposes for development of hypertension and increased cardiovascular mortality. Our studies show that mice chronically exposed to drinking water containing 100 parts per billion (ppb) sodium arsenite for 22 weeks show an increase in both systolic and diastolic blood pressure. Echocardiographic analyses as well as histological assessment show concentric left ventricular hypertrophy, a primary cardiac manifestation of chronic hypertension. Live imaging by echocardiography shows a 43% increase in left ventricular mass in arsenic-treated animals. Relative wall thickness (RWT) was calculated showing that all the arsenic-exposed animals show an RWT greater than 0.45, indicating concentric hypertrophy. Importantly, left ventricular hypertrophy, although often associated with chronic hypertension, is an independent risk factor for cardiovascular-related mortalities. These results suggest that chronic low-level arsenite exposure promotes the development of hypertension and the comorbidity of concentric hypertrophy. PMID- 22215513 TI - Ultrastructural analysis in preclinical safety evaluation. AB - The first electron microscopic images of biological specimens were made in the 1940s, and the next 30 years comprised an era of descriptive ultrastructure during which transmission electron microscopy (TEM) was integral to an explosion in cellular and molecular biology. However, when questions could no longer be answered by ultrastructural information alone, the use of TEM in biological research declined. Innovative molecular techniques and newer imaging technologies such as confocal fluorescence microscopy filled the gap, providing faster answers with less rigorous training as a prerequisite to data collection. The use of TEM in toxicologic pathology has paralleled the rise and fall of its popularity in other disciplines. However, TEM remains an essential resource that provides direct and unequivocal data to explain and address safety concerns in preclinical toxicity studies. There is still an important place for TEM in preclinical safety evaluation and mechanistic studies, particularly when visualization of subcellular structures provides a link to other endpoints. This review reinforces the value of TEM in preclinical safety testing and model development and encourages best practices for ultrastructural evaluation. PMID- 22215512 TI - Differentiation of rodent immune and hematopoietic system reactive lesions from neoplasias. AB - The immune and hematopoietic systems play an important role in the normal homeostasis of blood and blood cells and for immune responses to endogenous and exogenous processes and insults. In order to interpret histopathologic changes in the immune and hematopoietic systems, it is important to understand the normal anatomy and histology of the thymus, spleen, lymph nodes, bone marrow, and other tissues. The thymus, spleen, and lymph nodes can be categorized by anatomical compartments, each of which contributes to specific immune functions. Lesions may be diagnosed by interpretive or descriptive (semiquantitative) methods. The interpretation of these tissues by lesion in anatomical compartments should allow for better understanding of these reactions and more definitive pathologic findings. Proliferative lesions may be difficult to differentiate from lymphomas and leukemias. The use of immunohistochemistry, compartmental pathology, and methods for the evaluation of clonality will make interpretation easier. PMID- 22215514 TI - Endometrial stromal polyps in rodents: biology, etiology, and relevance to disease in women. AB - Endometrial stromal polyps (ESP) are a common spontaneous reproductive tract lesion in the female rat. However, there is limited information concerning the etiology, biology, and significance of these polyps as an end point in toxicology and carcinogenicity studies. This paper reviews relevant literature to address these aspects of ESP with respect to potential relevance to human uterine tumors. Endometrial stromal polyps in rodents appear as age-related lesions. There are only a few chemicals tested for carcinogenicity in rat and mouse cancer bioassays associated with increased incidence of ESP with no common characteristics or mechanism of action. Uterine endometrial polyps that occur in women and the uterine stromal polyps that occur in rodents have distinct characteristics, although both types of uterine lesions are common, benign, and noncancerous. Human endometrial polyps develop from both endometrial and stromal components, whereas rodent polyps develop from the stromal component of the uterus. Endometrial polyps in women are hormone sensitive, but there is no scientific or experimental evidence to date that suggests that uterine stromal polyps in rodents are hormone sensitive. Therefore, based on differences in their etiology and biology, endometrial stromal polyps observed in rodent toxicity and carcinogenicity studies appear to have limited relevance to human endometrial polyps occurring in women. PMID- 22215515 TI - Mice deficient in glycerol-3-phosphate acyltransferase-1 have a reduced susceptibility to liver cancer. AB - The risk of hepatocellular carcinoma increases with the persistence of non alcoholic fatty liver disease. Triacylglycerol synthesis is initiated by glycerol 3-phosphate acyltransferase (GPAT). Of four isoforms, GPAT1 contributes 30-50% of total liver GPAT activity, and we hypothesized that it might influence liver susceptibility to tumorigenesis. C57Bl/6 mice deficient in GPAT1 were backcrossed 6 times to C3H mice. After exposure to the carcinogen diethylnitrosamine (DEN) and the tumor promoter phenobarbital, male Gpat1-/- mice, compared with controls (Gpat1+/+), had 93% fewer macroscopically visible nodules per liver at 21 weeks of age and 39% fewer at 34 weeks of age. Microscopically, control mice had increased numbers of foci of altered hepatocytes, particularly the basophilic subtype, as well as more, and malignant, liver neoplasms than did the Gpat1-/- mice. At 21 weeks of age, 50% (4/8) of control mice (50%) had hepatocellular adenomas with an average multiplicity (tumors per tumor-bearing-animal) of 4.3, while none occurred in 8 Gpat1-/- mice. At 34 weeks of age, all 15 control mice (100%) had hepatocellular adenomas with an average multiplicity of 5.2 compared to an incidence of 93% in Gpat1-/- mice and multiplicity of 3.1. HCCs were observed in 13% of control mice and in only 6% of Gpat1-/- mice. These data show that alterations in the formation of complex lipids catalyzed by Gpat1 reduce susceptibility to DEN-induced liver tumorigenesis. PMID- 22215516 TI - Heat-shock protein 60 kDa and atherogenic dyslipidemia in patients with untreated mild periodontitis: a pilot study. AB - Identification of predictors of cardiovascular risk can help in the prevention of pathologic episodes and the management of patients at all stages of illness. Here, we investigated the relationships between serum levels of Hsp60 and dyslipidemia in patients with periodontitis by performing a cross-sectional study of 22 patients with mild periodontitis without any prior treatment for it (i.e., drug naive) and 22 healthy controls, matched for age and body mass index (BMI). All subjects were evaluated for periodontal status, gingival inflammation, and oral hygiene. Levels of circulating Hsp60, C-reactive protein (CRP), and plasma lipids were measured, and small, dense low-density lipoproteins (LDL) were indirectly assessed by determining the triglycerides/high-density lipoproteins (HDL) cholesterol ratio. We also assessed by immunohistochemistry Hsp60 levels in oral mucosa of patients and controls. No difference was found in CRP levels or plasma lipids between the two groups, but subjects with periodontitis showed, in comparison to controls, higher levels of small, dense LDL (p = 0.0355) and circulating Hsp60 concentrations (p < 0.0001). However, levels of mucosal Hsp60 did not change significantly between groups. Correlation analysis revealed that circulating Hsp60 inversely correlated with HDL-cholesterol (r = -0.589, p = 0.0039), and positively with triglycerides (r = +0.877, p < 0.0001), and small, dense LDL (r = +0.925, p < 0.0001). Serum Hsp60 significantly correlated with the degree of periodontal disease (r = +0.403, p = 0.0434). In brief, untreated patients with mild periodontitis had increased small, dense LDL and serum Hsp60 concentrations, in comparison to age- and BMI-matched controls and both parameters showed a strong positive correlation. Our data indicate that atherogenic dyslipidemia and elevated circulating Hsp60 tend to be linked and associated to periodontal pathology. Thus, the road is open to investigate the potential value of elevated levels of circulating Hsp60 as predictor of risk for cardiovascular disease when associated to dyslipidemia in periodontitis patients. PMID- 22215517 TI - Proteotoxic stress and circulating cell stress proteins in the cardiovascular diseases. AB - The cardiovasculature is one of the major body systems and probably the one most exposed to stress. There is clear evidence that increasing levels of cell stress proteins within the heart is cardioprotective. In addition, there is rapidly emerging evidence that secreted cell stress proteins play a role in the function of the cardiovascular tissues. Those secreted proteins have three potential functions: (1) as normal homeostatic cardiovascular signals (e.g. protein disulphide isomerase); (2) as anti-inflammatory molecules, which are able to inhibit cardiovascular pathology (e.g. Hsp27); and (iii) as pro-inflammatory signals that can induce and promote cardiovascular pathology (e.g. Hsp60). As all of these various proteins may be released-at different rates-and in different cardiovascular diseases-we need to consider the cohort of potential secreted cell stress proteins as a dynamic system (network) that can aid and/or damage the equally dynamic cardiovascular system. PMID- 22215518 TI - Divergence of intracellular and extracellular HSP72 in type 2 diabetes: does fat matter? PMID- 22215519 TI - Ca2+/calmodulin-dependent protein kinase II mediates platelet-derived growth factor-induced human hepatic stellate cell proliferation. AB - BACKGROUND AND AIM: Proliferation and activation of myofibroblastic hepatic stellate cells (HSCs) in response to growth factors is essential for the development of liver fibrosis. As one of the most potent factors, platelet derived growth factor (PDGF) activates intracellular signals and contributes to sustained HSCs activation. Growing evidence has suggested that the Ca(2+) signal is involved in PDGF pathways. We showed previously for the first time that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is essential for human HSC proliferation. The inhibition of CaMKII by its specific inhibitor, KN-93, significantly decreased the HSC growth and increased expression of cell cycle suppressive regulators P53 and P21. METHODS: In the present study, we investigated the role of CaMKII in PDGF-induced HSC proliferation and underlying mechanisms. RESULTS: We confirmed that in human HSCs, PDGF significantly increased CaMKII mRNA levels, protein expression, and phosphorylation. The interruption of CaMKII by KN-93, specific inhibitory peptide (AIP), or specific CaMKII knockdown by its siRNA not only attenuated PDGF-induced HSC proliferation but also ERK1/2 phosphorylation. However, CaMKII had no effect on JNK phosphorylation. In addition, inhibitors of ERK1/2 (PD98059) and JNK (SP600125) did not affect CaMKII expression. Interruption of CaMKII-ERK cascade, not JNK signal, inhibited PDGF-induced HSC proliferation. CONCLUSION: We confirmed that CaMKII mediated PDGF-induced human HSC proliferation through ERK1/2 but not the JNK mechanism. Our study shed light on CaMKII as a crucial signal in PDGF activated HSCs and a potential therapeutic point in hepatic fibrosis. PMID- 22215520 TI - Phase precession through acceleration of local theta rhythm: a biophysical model for the interaction between place cells and local inhibitory neurons. AB - Phase precession is one of the most well known examples within the temporal coding hypothesis. Here we present a biophysical spiking model for phase precession in hippocampal CA1 which focuses on the interaction between place cells and local inhibitory interneurons. The model's functional block is composed of a place cell (PC) connected with a local inhibitory cell (IC) which is modulated by the population theta rhythm. Both cells receive excitatory inputs from the entorhinal cortex (EC). These inputs are both theta modulated and space modulated. The dynamics of the two neuron types are described by integrate-and fire models with conductance synapses, and the EC inputs are described using non homogeneous Poisson processes. Phase precession in our model is caused by increased drive to specific PC/IC pairs when the animal is in their place field. The excitation increases the IC's firing rate, and this modulates the PC's firing rate such that both cells precess relative to theta. Our model implies that phase coding in place cells may not be independent from rate coding. The absence of restrictive connectivity constraints in this model predicts the generation of phase precession in any network with similar architecture and subject to a clocking rhythm, independently of the involvement in spatial tasks. PMID- 22215522 TI - Review article: medical education research: an overview of methods. AB - PURPOSE: This article provides clinician-teachers with an overview of the process necessary to move from an initial idea to the conceptualization and implementation of an empirical study in the field of medical education. This article will allow clinician-teachers to become familiar with educational research methodology in order to a) critically appraise education research studies and apply evidence-based education more effectively to their practice and b) initiate or collaborate in medical education research. SOURCE: This review uses relevant articles published in the fields of medicine, education, psychology, and sociology before October 2011. PRINCIPAL FINDINGS: The focus of the majority of research in medical education has been on reporting outcomes related to participants. There has been less assessment of patient care outcomes, resulting in informing evidence-based education to only a limited extent. This article explains the process necessary to develop a focused and relevant education research question and emphasizes the importance of theory in medical education research. It describes a range of methodologies, including quantitative, qualitative, and mixed methods, and concludes with a discussion of dissemination of research findings. A majority of studies currently use quantitative methods. This article highlights how further use of qualitative methods can provide insight into the nuances and complexities of learning and teaching processes. CONCLUSIONS: Research in medical education requires several successive steps, from formulating the correct research question to deciding the method for dissemination. Each approach has advantages and disadvantages and should be chosen according to the question being asked and the specific goal of the study. Well-conducted education research should allow progression towards the important goal of using evidence-based education in our teaching and institutions. PMID- 22215523 TI - Bedside ultrasound assessment of gastric content: an observational study. AB - PURPOSE: There is a growing interest in the use of bedside ultrasonography to assess gastric content and volume. It has been suggested that the gastric antrum in particular can be assessed reliably by sonography. The aim of this observational study was to provide a qualitative description of the sonographic characteristics of the gastric antrum when the stomach is empty and following the ingestion of clear fluid, milk, and solid content. CLINICAL FEATURES: Six healthy volunteers were examined on four different occasions (24 scanning sessions): following a period of eight hours of fast and following ingestion of 200 mL of apple juice, 200 mL of 2% milk, and a standard solid meal (sandwich and apple juice). Examinations were performed following a standardized scanning protocol by two clinical anesthesiologists with previous experience in gastric sonography. For each type of gastric content, the sonographic characteristics of the antrum and its content are described and illustrated with figures. CONCLUSIONS: Bedside sonography can determine the nature of gastric content (nil, clear fluid, thick fluid/solid). This qualitative information by itself may be useful to assess risk of aspiration, particularly in situations when prandial status is unknown or uncertain. PMID- 22215521 TI - The structures of nonprotein-coding RNAs that drive internal ribosome entry site function. AB - Internal ribosome entry sites (IRESs) are RNA sequences that can recruit the translation machinery independent of the 5' end of the messenger RNA. IRESs are found in both viral and cellular RNAs and are important for regulating gene expression. There is great diversity in the mechanisms used by IRESs to recruit the ribosome and this is reflected in a variety of RNA sequences that function as IRESs. The ability of an RNA sequence to function as an IRES is conferred by structures operating at multiple levels from primary sequence through higher order three-dimensional structures within dynamic ribonucleoproteins (RNPs). When these diverse structures are compared, some trends are apparent, but overall it is not possible to find universal rules to describe IRES structure and mechanism. Clearly, many different sequences and structures have evolved to perform the function of recruiting, positioning, and activating a ribosome without using the canonical cap-dependent mechanism. However, as our understanding of the specific sequences, structures, and mechanisms behind IRES function improves, more common features may emerge to link these diverse RNAs. PMID- 22215524 TI - Bilateral interhemispheric subdural hematoma after inadvertent lumbar puncture in a parturient. AB - PURPOSE: Interhemispheric subdural hematomas (ISH) are rare in adults and occur most often after cranial trauma. We describe a parturient who developed bilateral acute ISH after inadvertent dural puncture associated with placement of an epidural catheter for labour analgesia. We discuss the features, pathophysiology, and management of this type of subdural hematoma. CLINICAL FEATURES: A 38-yr-old woman requested epidural analgesia for relief of labour pain. An inadvertent dural puncture occurred during placement of a 17G Tuohy needle. After labour and delivery, the patient developed symptoms of a postdural puncture headache, which responded only partially to an epidural blood patch. The patient's headache subsequently became less position-dependent and was associated with episodes of sharp pain radiating down her legs and paresthesias on the left side of her body. A computed tomography (CT) scan showed right frontal and left parietal acute ISH without an intracranial mass effect. The patient was monitored in the intensive care unit and treated conservatively because of the relatively small size of the ISH and the absence of progressive neurological deficits on serial examinations. Daily CT scans showed gradual decreases in the size of the ISH concomitant with improvement of the headache. CONCLUSIONS: Rupture of bridging veins between the cerebral cortex and the superior sagittal sinus is the usual mechanism by which ISH occur. Nearly one-quarter of patients with ISH do not survive, although those with smaller hematomas have a better outcome. If the hematoma is < 1 cm in thickness, a conservative approach to ISH is recommended in the absence of mental status changes, seizure activity, or focal deficits, but with larger ISH or evidence of progressive neurological deterioration, surgical evacuation is most often required to prevent mortality. PMID- 22215525 TI - Percutaneous embolization of a caroticoazygous fistula with the Amplatzer Vascular Plug 1. AB - We present the case of a five-year-old boy with a caroticoazygous fistula, which is an extremely rare congenital vascular malformation. The patient also had patent ductus arteriosus, a common cause of continuous murmur. The murmur continued despite successful coil embolization of the ductus. Repeated catheter angiography revealed a large caroticoazygous fistula. The fistula was successfully embolized using the Amplatzer((r)) Vascular Plug 1. Transcatheter occlusion of caroticoazygous fistula was performed easily, safely, and efficiently with a vascular plug. PMID- 22215526 TI - Strong YB-1 expression is associated with liver metastasis progression and predicts shorter disease-free survival in advanced gastric cancer. AB - BACKGROUND: The most significant cause of gastric cancer (GC) death is metastasis, although the underlying mechanisms remain obscure. Y-box binding protein-1 (YB-1) is associated with tumor aggressiveness and poor prognosis in various cancers. In this study we investigated the relationship between YB-1 expression and the clinicopathologic features and metastasis-associated epithelial-mesenchymal transition (EMT) phenotype in advanced GC patients. PATIENTS AND METHODS: Immunohistochemistry (IHC) was used to analyze YB-1, E cadherin, and vimentin expression in 98 advanced GC cases. RESULTS: Twenty-nine (29.6%) cases of GC exhibited strong YB-1 immunoreactivity. Strong YB-1 staining occurred more often in patients with intestinal or non-scirrhous cancer, and demonstrated a significant correlation with vascular invasion (VI), liver metastasis, and shorter disease-free survival (DFS). However, we observed no relationship between YB-1 expression and EMT phenotype or overall survival. Logistic regression analysis revealed that strong staining for YB-1 was the only predictive factor for liver metastasis. CONCLUSIONS: Our results indicate that YB 1 plays a role in the process of GC metastasis, and that the immunohistochemical detection of this protein potentially delivers valuable insight regarding the prediction of liver metastasis and shorter DFS in patients undergoing curative resection for advanced GC. PMID- 22215527 TI - Regulation of myocardial matrix metalloproteinase expression and activity by cardiac fibroblasts. AB - Cardiac fibroblasts (CF) play a key role in orchestrating the structural remodeling of the myocardium in response to injury or stress, in part through direct regulation of extracellular matrix (ECM) turnover. The matrix metalloproteinases (MMPs) are a family of over 25 zinc-dependent proteases that together have the capacity to degrade all the protein components of the ECM. Fibroblasts are a major source of several MMPs in the heart, thereby representing a viable therapeutic target for regulating ECM turnover in cardiac pathologies characterized by adverse remodeling, such as myocardial infarction, cardiomyopathy, hypertension and heart failure. This review summarizes current knowledge on the identity and regulation of MMPs expressed by CF and discusses future directions for reducing adverse myocardial remodeling by modulating the expression and/or activity of CF-derived MMPs. PMID- 22215529 TI - How grammatical are 3-year-olds? AB - PURPOSE: This study investigated the level of grammatical accuracy in typically developing 3-year-olds and the types of errors they produce. METHOD: Twenty-two 3 year-olds participated in a picture description task. The percentage of grammatical utterances was computed and error types were analyzed. RESULTS: The mean level of grammatical accuracy in typical 3-year-olds was ~71%, with a wide range of variability. The current study revealed a variety of error types produced by 3-year-olds, most of which were produced by fewer than 5 children. The pattern observed for most of the children was to produce a scattering of errors with no more than a few of any 1 error type. CONCLUSION: The level of grammatical accuracy in 3-year-olds was skewed toward the high end. Although tense marking errors were the most frequent error type, they accounted for only 1/3 of the errors produced by 3-year-olds. A more general measure of grammaticality that considers additional aspects of language might, therefore, be useful in assessing language at this age. PMID- 22215530 TI - Acquiring knowledge of derived nominals and derived adjectives in context. AB - PURPOSE: This research investigated children's ability to acquire semantic and syntactic knowledge of derived nominals and derived adjectives in the context of short passages. The study also investigated the relation of morphological awareness and the ability to acquire knowledge of derived words in context. METHOD: A total of 106 children in Grade 4 were given an author-created evaluation, the Derivational Acquisition in Context Evaluation (DAICE), which consisted of several short passages. Each passage contained two instances of a target base word followed by one instance of a derived form of the base word. A multiple-choice measure was administered to assess the children's knowledge of 12 derived words (6 nominals and 6 adjectives). A measure of morphological awareness was given to assess the children's relational knowledge between root words and their suffixes. RESULTS: No significant differences were found for overall performance on derived nominals and derived adjectives. However, the acquisition of semantic and syntactic knowledge was dependent on target word type. A significant relation was found between performance on the measure of morphological awareness and performance on derived nominals. CONCLUSION: This research provided evidence for fast mapping of derived nominals and derived adjectives within the context of short passages. Future directions of related research are suggested. PMID- 22215531 TI - Overlap in speech-language and reading services for kindergartners and first graders. AB - PURPOSE: Speech-language pathologists (SLPs) and reading professionals provide educational services to children who are at risk for reading difficulties, although these professions do not necessarily coordinate efforts. To date, there is limited evidence regarding the proportion of children who receive services from both professionals. The current study reports the prevalence and overlap of speech-language and reading services provided to kindergartners and first graders in Virginia. METHOD: This study analyzed a population-level database of reading screening scores from 74,730 kindergartners and 75,088 first graders. Information regarding the speech-language services received by these children was obtained. Prevalence rates of speech-language impairment, reading risk, and comorbidity were calculated. The distribution of children receiving speech-language services across categories of reading competence was examined. RESULTS: Findings indicated that ~6% of the children received speech-language services and 11.1% of the kindergartners and 13.7% of the first graders received reading services. One quarter of the children receiving speech-language services also received reading services. Furthermore, children receiving speech-language services received reading services at twice the rate of children who were not receiving speech language services in both kindergarten (23.1% vs. 9.1%) and first grade (25.2% vs. 11.3%). CLINICAL IMPLICATIONS: This study provides empirical support for improving coordination between SLPs and reading professionals. PMID- 22215532 TI - Phase I dose-escalating study of ES-285 given as a three-hour intravenous infusion every three weeks in patients with advanced malignant solid tumors. AB - BACKGROUND: ES-285 (spisulosine) is a novel compound derived from the marine mollusk Spisula polynoma with evidence of preclinical antitumor activity. This phase I clinical trial was designed to identify the maximum tolerated dose (MTD) and the recommended dose for phase II trials (RD), as well as to evaluate the safety profile, pharmacokinetics and preliminary efficacy data of ES-285 in patients with advanced solid tumors. PATIENTS AND METHODS: Sixty-one patients at two medical institutions were treated with a 3-h ES-285 intravenous infusion every 3 weeks. Nine dose levels were evaluated. RESULTS: No dose-limiting toxicities (DLTs) were observed during dose escalation from 4 to 128 mg/m(2). Six patients had seven DLTs at the three highest dose levels tested: 256 mg/m(2) (n = 2), 200 mg/m(2) (n = 3) and 160 mg/m(2) (n = 1). Grade 3/4 transaminase increases (n = 3), grade 3/4 central nervous system disorders [confusion (n = 2) and ataxia (n = 1)], and grade 3 pyrexia (n = 1) were the dose-limiting toxicities found with this ES-285 administration schedule. Pharmacokinetic analysis showed ES-285 dose linearity, wide distribution and a long half-life. One non-confirmed partial response was observed in a patient with metastatic melanoma treated with ES-285 128 mg/m(2), and 18 patients showed stable disease at different dose levels, lasting longer than 3 months in six patients. CONCLUSION: Dose level VIII (200 mg/m(2)) was considered the MTD, and dose level IX (160 mg/m(2)) was defined as the RD. Limited antitumor activity was observed. PMID- 22215535 TI - Association of nonalcoholic fatty liver disease with a single nucleotide polymorphism on the gene encoding leptin receptor. AB - Leptin (Lep), a 16-kDa polypeptide hormone, exerts its action through the leptin receptor (LepRb), a member of the class I cytokine receptor family. Both leptin and LepRb probably have been implicated in pathogenesis of nonalcoholic fatty liver disease (NAFLD). This study was designed to assess the role of soluble leptin and LepRb in NAFLD and to investigate whether leptin receptor gene (LepR) single nucleotide polymorphism (SNP; ID rs6700896) influences NAFLD complicated with or without type 2 diabetes mellitus (T2DM). Blood samples from 90 obese NAFLD cases and 30 lean controls of matched age and sex were recruited in the study. Among the NAFLD patients, 32 were T2DM. Plasma leptin and LepRb levels were measured by enzyme linked immunoassay (ELISA). Lipids profile, glucose metabolic parameters, and insulin concentration were measured for all participants. Body mass index (BMI) and insulin resistance (IR) were calculated as well. Genotyping was done using SNP (rs6700986) for LepR gene. Significant difference was reported between NAFLD with or without T2DM and control regarding biochemical markers and LepR genotype and allele frequencies. Mutant homozygous and heterozygous LepR genotype and mutant allele were significantly higher in mild-severe steatosis and in NAFLD with T2DM when compared with mild steatosis and those without T2DM. Frequencies of mutant LepR polymorphism were significantly associated with IR increment. Elevated leptin level seems to be a feature of steatosis, and it appears to increase as hepatocyte steatosis develops. Moreover, polymorphism of LepR gene contributes to the onset of NAFLD by regulating lipid metabolism and affecting insulin sensitivity. PMID- 22215536 TI - Wnt-Notch signalling: an integrated mechanism regulating transitions between cell states. AB - The activity of Wnt and Notch signalling is central to many cell fate decisions during development and to the maintenance and differentiation of stem cell populations in homeostasis. While classical views refer to these pathways as independent signal transduction devices that co-operate in different systems, recent work has revealed intricate connections between their components. These observations suggest that rather than operating as two separate pathways, elements of Wnt and Notch signalling configure an integrated molecular device whose main function is to regulate transitions between cell states in development and homeostasis. Here, we propose a general framework for the structure and function of the interactions between these signalling systems that is focused on the notion of 'transition states', i.e. intermediates that arise during cell fate decision processes. These intermediates act as checkpoints in cell fate decision processes and are characterised by the mixed molecular identities of the states involved in these processes. PMID- 22215537 TI - Mitochondrial DNA mutations: an overview of clinical and molecular aspects. AB - Mutations that arise in mitochondrial DNA (mtDNA) may be sporadic, maternally inherited, or Mendelian in character and include mtDNA rearrangements such as deletions, inversions or duplications, point mutations, or copy number depletion. Primary mtDNA mutations occur sporadically or exhibit maternal inheritance and arise due in large part to the high mutation rate of mtDNA. mtDNA mutations may also occur because of defects in the biogenesis or maintenance of mtDNA, reflecting the contribution of nuclear-encoded genes to these processes, and in this case exhibit Mendelian inheritance. Whether maternally inherited, sporadic, or Mendelian, mtDNA mutations can exhibit a complex and broad spectrum of disease manifestations due to the central role mitochondria play in a variety of cellular functions. In addition, because there exist hundreds to thousands of copies of mtDNA in each cell, the proportion of mutant mtDNA molecules can have a profound effect on the cellular and clinical phenotype. This chapter reviews the classification of mtDNA mutations and the clinical features that determine the diagnosis of a primary mtDNA disorder. PMID- 22215534 TI - Gestational restraint stress and the developing dopaminergic system: an overview. AB - Prenatal stress exerts a strong impact on fetal brain development in rats impairing adaptation to stressful conditions, subsequent vulnerability to anxiety, altered sexual function, and enhanced propensity to self-administer drugs. Most of these alterations have been attributed to changes in the neurotransmitter dopamine (DA). In humans; dysfunction of dopaminergic system is associated with development of several neurological disorders, such as Parkinson disease, schizophrenia, attention-deficit hyperactivity disorder, and depression. Evidences provided by animal research, as well as retrospective studies in humans, pointed out that exposure to adverse events in early life can alter adult behaviors and neurochemical indicators of midbrain DA activity, suggesting that the development of the DA system is sensitive to disruption by exposure to early stressors. The purpose of this article is to provide a general overview of published studies and our own study related to the effect of prenatal insults on the development of DA metabolism and biology, focusing mainly in articles involving prenatal-restraint stress protocols in rats. We will also attempt to make a correlation between theses alterations and DA-related pathological processes in humans. PMID- 22215538 TI - Nuclear gene defects in mitochondrial disorders. AB - Most mitochondrial cytopathies in infants are caused by mutations in nuclear genes encoding proteins targeted to the mitochondria rather than by primary mutations in the mitochondrial DNA. Over the past few years, the awareness of the number of disease-causing mutations in different nuclear genes has grown exponentially. These genes encode the various subunits of each respiratory chain complex, the ancillary proteins involved in the assembly of these subunits, proteins involved in mitochondrial DNA replication and maintenance, proteins involved in mitochondrial protein synthesis, and proteins involved in mitochondrial dynamics. This increased awareness has added a challenging dimension to the current diagnostic workup of mitochondrial cytopathies. The advent of new technologies such as next-generation sequencing should facilitate the resolution of this dilemma. PMID- 22215539 TI - Diagnostic challenges of mitochondrial disorders: complexities of two genomes. AB - Mitochondrial disorders causing respiratory chain dysfunction comprise a group of genetically and clinically heterogeneous diseases. This heterogeneity reflects both the biochemical complexity of oxidative phosphorylation and the genetic contribution of both the nuclear and mitochondrial genomes to the respiratory chain. Current approaches to diagnose and classify mitochondrial disorders incorporate clinical, biochemical, and histological criteria, as well as DNA based molecular diagnostic testing. While the identification of pathogenic mutations is generally accepted as definitive, the large number of candidate nuclear genes, the involvement of two genomes, and potential heteroplasmy of pathogenic mitochondrial DNA (mtDNA) frequently complicate successful molecular diagnostic confirmation. The strategy for pursuing a diagnosis derives from the integration of family history, clinical findings, biochemical evaluations, histopathological analyses, neuroradiological results, and the availability of different tissues for analyses. Screening for common point mutations and large deletions in mtDNA is usually the first step. Specific subsets of known nuclear disease genes can be screened by direct sequencing for cases of recognizable patterns of respiratory chain deficiencies or clinically identifiable syndromic presentations. Measurement of mtDNA content in affected tissues such as muscle and liver allows screening for mtDNA depletion syndromes. The growing list of known disease-causing genes and the promise of next generation sequencing technologies will undoubtedly improve diagnostic accuracy and genetic counseling for this challenging group of disorders. PMID- 22215540 TI - Biochemical analyses of the electron transport chain complexes by spectrophotometry. AB - In the diagnostic work-up of patients with suspected mitochondrial disease, evaluating the activity of the individual oxidative phosphorylation (OXPHOS) complexes is crucial. Here, we describe spectrophotometric assays for OXPHOS enzymology that can be applied to both tissue samples and cultured cells. These assays are designed to assess the enzymatic activity of the individual OXPHOS complexes I-V, along with the Krebs cycle enzyme citrate synthase as a mitochondrial control. As well, we include an assay for the coupled energy transfer between complexes II and III. Determining the enzymatic activities can be valuable in defining isolated or multicomplex disorders and may be relevant to the design of future molecular investigations. PMID- 22215541 TI - Measurement of mitochondrial oxygen consumption using a Clark electrode. AB - Mitochondria require oxygen to produce ATP in sufficient quantities to drive energy-requiring reactions in eukaryotic organisms. The measurement of oxygen consumption rates from isolated mitochondria in vitro is a useful and valuable technique in the research and evaluation of mitochondrial dysfunction and disease since ADP-dependent oxygen consumption directly reflects coupled respiration or oxidative phosphorylation (OXPHOS). This chapter describes the traditional method of mitochondrial polarography using a Clark electrode for measuring coupled respiration in freshly isolated mitochondria from both mammalian tissues and Drosophila melanogaster. PMID- 22215542 TI - Mitochondrial respiratory chain: biochemical analysis and criterion for deficiency in diagnosis. AB - Spectrophotometric evaluation of mitochondrial respiratory chain (MRC) enzymatic complexes is the main approach to the biochemical investigation and diagnosis in oxidative phosphorylation disorders (also known as mitochondrial cytopathies). Regular dual beam spectrophotometers may be used, but we describe the protocols for double wavelength devices, allowing the analysis of complex activities from a small amount of tissue, with high sensitivity. An important concern is which tissue should be selected for analysis. Accordingly, we present the results obtained with different tissues and control values to be used. There are no standards available for the determinations and no interlaboratory quality control schemes are implemented. Additionally, different laboratories may use different protocols and comparison of results may be difficult. Currently, there is no consensus in literature for defining a criterion of an MRC deficiency to be used in biochemical diagnosis. There is statistical evidence that the most adequate criterion to define an MRC deficiency is below 40% of the mean control value normalized to citrate synthase activity. PMID- 22215543 TI - Assays of pyruvate dehydrogenase complex and pyruvate carboxylase activity. AB - Pyruvate dehydrogenase complex (PDC) and pyruvate carboxylase (PC) are mitochondrial enzymes that provide the initial steps of the two main alternatives for pyruvate metabolism: oxidative decarboxylation vs. anaplerotic carboxylation, gluconeogenesis, and glycerogenesis. Assays of the enzymatic activity of these two enzymes in cells and tissues are described in this chapter, based on evolution or fixation of (14)CO(2). These assays are both suitable for use in crude homogenates of cultured skin fibroblasts, lymphocytes, and frozen muscle (PDC) or liver (PC). Activities of these two enzymes are related to spectrophotometric assays of two other mitochondrial enzymes, dihydrolipoamide dehydrogenase (E3) and citrate synthase (CS), providing initial indices of sample integrity and mitochondrial content. These parameters have proven useful for initial detection of inherited human disorders due to deficiencies of these enzymes, and in combination with available genetic analyses can lead to confirmation of specific diagnoses. PMID- 22215545 TI - Measurement of mitochondrial dNTP pools. AB - Because deoxyribonucleoside triphosphates (dNTPs) are the critical substrates for DNA replication and repair, dNTP pools have been studied in context of multiple basic biochemical processes. Over the last 12 years, interest in dNTPs, and specifically the mitochondrial dNTP pools, has expanded to biomedical science because several mitochondrial diseases have been found to be caused by dysfunctions of several enzymes involved in dNTP catabolism or anabolism. Techniques to reliably measure mitochondrial dNTPs should be sensitive and specific to avoid interference caused by the abundant ribonucleotides. Here, we describe detailed protocols to measure mitochondrial dNTPs from two specific samples, cultured skin fibroblasts and mouse liver. The methods can be easily adapted to other types of samples. The protocol follows a polymerase-based method, which is the most widely used approach to measure dNTP pools. Our description is based on the latest update of the technique, which minimizes the potential interference from ribonucleotides. PMID- 22215544 TI - Assessment of thymidine phosphorylase function: measurement of plasma thymidine (and deoxyuridine) and thymidine phosphorylase activity. AB - We describe detailed methods to measure thymidine (dThd) and deoxyuridine (dUrd) concentrations and thymidine phosphorylase (TP) activity in biological samples. These protocols allow the detection of TP dysfunction in patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Since the identification of mutations in TYMP, the gene encoding TP, as the cause of MNGIE (Nishino et al. Science 283:689-692, 1999), the assessment of TP dysfunction has become the best screening method to rule out or confirm MNGIE in patients. TYMP sequencing, to find the causative mutations, is only needed when TP dysfunction is detected. dThd and dUrd are measured by resolving these compounds with high performance liquid chromatography (HPLC) followed by the spectrophotometric monitoring of the eluate absorbance at 267 nm (HPLC-UV). TP activity can be measured by an endpoint determination of the thymine formed after 1 h incubation of the buffy coat homogenate in the presence of a large excess of its substrate dThd, either spectrophotometrically or by HPLC-UV. PMID- 22215546 TI - Measurement of oxidized and reduced coenzyme Q in biological fluids, cells, and tissues: an HPLC-EC method. AB - Direct measure of coenzyme Q (CoQ) in biological specimens may provide important advantages. Precise and selective high-performance liquid chromatography (HPLC) methods with electrochemical (EC) detection have been developed for the measurement of reduced (ubiquinol) and oxidized (ubiquinone) CoQ in biological fluids, cells, and tissues. EC detection is preferred for measurement of CoQ because of its high sensitivity. Reduced and oxidized CoQ are first extracted from biological specimens using 1-propanol. After centrifugation, the 1-propanol supernatant is directly injected into HPLC and monitored at a dual-electrode. The EC reactions occur at the electrode surface. The first electrode transforms ubiquinone into ubiquinol, and the second electrode measures the current produced by the oxidation of the hydroquinone group of ubiquinol. The methods described provide rapid, precise, and simple procedures for determination of reduced and oxidized CoQ in biological fluids, cells, and tissues. The methods have been successfully adapted to meet regulatory requirements for clinical laboratories, and have been proven reliable for analysis of clinical and research samples for clinical trials and animal studies involving large numbers of specimens. PMID- 22215547 TI - Assay to measure oxidized and reduced forms of CoQ by LC-MS/MS. AB - The redox status of mitochondrial coenzyme Q (CoQ) is an important marker for oxidative stress associated with several disorders such as Parkinson disease and Alzheimer disease. Altered redox status may be present in mitochondrial electron transport complex disorders. Intracellular CoQ levels reflect the functional status of the mitochondrial electron transport complex better than plasma levels. Here, we describe the method to determine the reduced and oxidized form of CoQ in white blood cells using LC-MS/MS. PMID- 22215548 TI - Morphological assessment of mitochondrial respiratory chain function on tissue sections. AB - In recent decades, genetic, biochemical, immunological, and cell biological techniques have been applied not only for better understanding of pathogenesis of known mitochondrial encephalomyopathies but also for exploring the possibility of mitochondrial involvement in other neurological, cardiac, gastrointestinal, and urological diseases. Techniques applied in a coordinated fashion have made it clear that mitochondrial dysfunction plays an important role in a wide range of human diseases including degenerative, toxic, metabolic, and neoplastic disorders. In this chapter, we provide updated protocols of essential histochemical and immunohistochemical methods that, in our opinion, are the most reliable morphological tool to visualize respiratory chain abnormality on tissue sections. PMID- 22215549 TI - Blue native polyacrylamide gel electrophoresis: a powerful diagnostic tool for the detection of assembly defects in the enzyme complexes of oxidative phosphorylation. AB - The bulk of ATP consumed by various cellular processes is normally produced by five multimeric protein complexes embedded within the inner mitochondrial membrane in a process known as oxidative phosphorylation (OXPHOS). Mutations that impair the assembly, and therefore the function, of one or more of these enzyme complexes severely compromise energy homeostasis and are a frequent cause of human disease. Because mitochondrial diseases are a clinically heterogeneous group of genetic disorders, biochemical and molecular diagnostic analyses are often an essential first step in confirming suspected cases and ultimately aid in identifying the genetic basis of disease in affected individuals. Blue native polyacrylamide gel electrophoresis has proven to be particularly invaluable in this regard, providing researchers with a facile approach for analyzing the assembly, total abundance, and residual enzymatic activity of individual OXPHOS complexes. As such, this technique has greatly facilitated the more thorough molecular genetic investigation of diseases that are caused by isolated and combined deficiencies in the enzymes that comprise the OXPHOS system. PMID- 22215550 TI - Radioactive labeling of mitochondrial translation products in cultured cells. AB - The mammalian mitochondrial genome contains 37 genes, 13 of which encode polypeptide subunits in the enzyme complexes of the oxidative phosphorylation system. The other genes encode the rRNAs and tRNAs necessary for their translation. The mitochondrial translation machinery is located in the mitochondrial matrix, and is exclusively dedicated to the synthesis of these 13 enzyme subunits. Mitochondrial disease in humans is often associated with defects in mitochondrial translation. This can manifest as a global decrease in the rate of mitochondrial protein synthesis, a decrease in the synthesis of specific polypeptides, the synthesis of abnormal polypeptides, or in altered stability of specific translation products. All of these changes in the normal pattern of mitochondrial translation can be assessed by a straightforward technique that takes advantage of the insensitivity of the mitochondrial translation machinery to antibiotics that completely inhibit cytoplasmic translation. Thus, specific radioactive labeling of the mitochondrial translation products can be achieved in cultured cells, and the results can be visualized on gradient gels. The analysis of mitochondrial translation in cells cultured from patient biopsies is useful in the study of disease-causing mutations in both the mitochondrial and the nuclear genomes. PMID- 22215551 TI - Transmitochondrial cybrids: tools for functional studies of mutant mitochondria. AB - Mitochondrial functions are controlled by both mitochondrial DNA (mtDNA) and nuclear DNA. Hence, it is difficult to identify whether mitochondrial or nuclear genome is responsible for a particular mitochondrial defect. Cybrid is a useful tool to overcome this difficulty, where we can compare mitochondria from different sources in a defined nuclear background. Cybrids are constructed by fusing enucleated cells harboring wild type or altered mtDNA of interest with rho(0) cells (cells lacking mtDNA) in which the endogenous mtDNA has been depleted. Therefore, cybrids are very useful in studying consequences of mtDNA alterations or other mitochondrial defects at the cellular level by excluding the influence of nuclear DNA mutations. PMID- 22215553 TI - Molecular profiling of mitochondrial dysfunction in Caenorhabditis elegans. AB - Cellular effects of primary mitochondrial dysfunction, as well as potential mitochondrial disease therapies, can be modeled in living animals such as the microscopic nematode, Caenorhabditis elegans. In particular, molecular analyses can provide substantial insight into the mechanism by which genetic and/or pharmacologic manipulations alter mitochondrial function. The relative expression of individual genes across both nuclear and mitochondrial genomes, as well as relative quantitation of mitochondrial DNA content, can be readily performed by quantitative real-time PCR (qRT-PCR) analysis of C. elegans. Additionally, microarray expression profiling offers a powerful tool by which to survey the global genetic consequences of various causes of primary mitochondrial dysfunction and potential therapeutic interventions at both the single gene and integrated pathway level. Here, we describe detailed protocols for RNA and DNA isolation from whole animal populations in C. elegans, qRT-PCR analysis of both nuclear and mitochondrial genes, and global nuclear genome expression profiling using the Affymetrix GeneChip C. elegans Genome Array. PMID- 22215552 TI - Fluorescence-activated cell sorting analysis of mitochondrial content, membrane potential, and matrix oxidant burden in human lymphoblastoid cell lines. AB - Fluorescence-activated cell sorting (FACS) permits specific biologic parameters of cellular populations to be quantified in a high-throughput fashion based on their unique fluorescent properties. Relative quantitation of mitochondrial localized dyes in human cells using FACS analysis allows sensitive analysis of a variety of mitochondrial parameters including mitochondrial content, mitochondrial membrane potential, and matrix oxidant burden. Here, we describe protocols that utilize FACS analysis of human lymphoblastoid cell lines (LCL) for relative quantitation of mitochondrial-localized fluorescent dye intensity. The specific dyes described include MitoTracker Green FM to assess mitochondrial content, tetramethylrhodamine ethyl ester (TMRE) to assess mitochondrial membrane potential, and MitoSOX Red to assess mitochondrial matrix oxidant burden. Representative results of FACS-based mitochondrial analyses demonstrate the variability of these three basic mitochondrial parameters in LCLs from healthy individuals, as well as the sensitivity of applying FACS analysis of LCLs to study the effects of pharmacologic induction and scavenging of oxidant stress. PMID- 22215554 TI - Analysis of common mitochondrial DNA mutations by allele-specific oligonucleotide and Southern blot hybridization. AB - Mitochondrial disorders are clinically and genetically heterogeneous. There are a set of recurrent point mutations in the mitochondrial DNA (mtDNA) that are responsible for common mitochondrial diseases, including MELAS (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes), MERRF (myoclonic epilepsy and ragged red fibers), LHON (Leber's hereditary optic neuropathy), NARP (neuropathy, ataxia, retinitis pigmentosa), and Leigh syndrome. Most of the pathogenic mtDNA point mutations are present in the heteroplasmic state, meaning that the wild-type and mutant-containing mtDNA molecules are coexisting. Clinical heterogeneity may be due to the degree of mutant load (heteroplasmy) and distribution of heteroplasmic mutations in affected tissues. Additionally, Kearns Sayre syndrome and Pearson syndrome are caused by large mtDNA deletions. In this chapter, we describe a multiplex PCR/allele-specific oligonucleotide (ASO) hybridization method for the screening of 13 common point mutations. This method allows the detection of low percentage of mutant heteroplasmy. In addition, a nonradioactive Southern blot hybridization protocol for the analysis of mtDNA large deletions is also described. PMID- 22215555 TI - Sequence analysis of the whole mitochondrial genome and nuclear genes causing mitochondrial disorders. AB - The diagnosis of mitochondrial disorders has increased considerably over the past few years. However, the genetics are complex, as the causative mutations can be in either the mitochondrial or the nuclear genome. Identification of the molecular defects in the causative genes is the key to a definitive diagnosis of the disease. Here, we describe PCR-based sequence analysis of the entire mitochondrial genome and a group of nuclear genes known to cause mitochondrial disorders. PMID- 22215556 TI - Utility of array CGH in molecular diagnosis of mitochondrial disorders. AB - Array comparative genomic hybridization (aCGH) is a powerful clinical diagnostic tool that can be used to evaluate copy number changes in the genome. Targeted aCGH provides a much higher resolution in targeted gene regions to detect copy number changes within single gene or single exon. A custom-designed oligonucleotide aCGH platform (MitoMet((r))) has been developed to provide tiled coverage of the entire 16.6-kb mitochondrial genome and high-density coverage of a set of nuclear genes associated with metabolic and mitochondrial related disorders, for quick evaluation of copy number changes in both genomes (1). The high-density probes in mitochondrial genome on the MitoMet((r)) array allow estimation of mtDNA deletion breakpoints and deletion heteroplasmy (2). This technology is particularly useful as a complementary diagnostic test to detect large deletions in genes related to mitochondrial disorders. PMID- 22215557 TI - Quantification of mtDNA mutation heteroplasmy (ARMS qPCR). AB - Pathogenic mitochondrial DNA (mtDNA) mutations are usually present in heteroplasmic forms that vary in concentration among different tissues. Manifestation of clinical phenotypes depends on the degree of mtDNA mutation heteroplasmy (mutation load) in affected tissues. It is therefore important to quantify the degree of mutation heteroplasmy in various tissues. In this chapter, we outline the design of allele refractory mutation system (ARMS)-based quantitative PCR (qPCR) analysis of common mtDNA point mutations, a cost effective and sensitive single-step method to simultaneously detect and quantify heteroplasmic mtDNA point mutations. PMID- 22215558 TI - Measurement of mitochondrial DNA copy number. AB - Mitochondrial disorders are complex and heterogeneous diseases that may be caused by molecular defects in either the nuclear or mitochondrial genome. The biosynthesis and maintenance of the integrity of the mitochondrial genome is solely dependent on a number of nuclear proteins. Defects in these nuclear genes can lead to mitochondrial DNA (mtDNA) depletion (Spinazzola et al. Biosci Rep 27:39-51, 2007). The mitochondrial DNA (mtDNA) depletion syndromes (MDDSs) are autosomal recessive disorders characterized by a significant reduction in mtDNA content. These genes include POLG, DGUOK, TK2, TYMP, MPV17, SUCLA2, SUCLG1, RRM2B, and C10orf2, all nine genes have mutations reported to cause various forms of MDDSs. In this chapter, we outline the real-time quantitative polymerase chain reaction (qPCR) analysis of mtDNA content in muscle or liver tissues. PMID- 22215559 TI - Determination of the clinical significance of an unclassified variant. AB - After completion of Human Genome Project (HGP) in 2003, as well as the new technology development in genomic research, the most accurate genetics blueprint of human is available. Researchers started to dissect and understand the genetic map of the human species. As a consequence, analyses of novel or unclassified genetic variations become increasingly important in translational medicine. One of the medical specialties in modern medicine is clinical genetics, which is overseen by the American Board of Medical Genetics (ABMG). In 2008, ABMG published a guideline for interpretation of new variants using ACMG Standards and Guidelines (Richards et al. Genet Med 10:294-300, 2008). In this chapter, we provide updated procedures of evaluating different databases, computational tools, and structural analysis methods that we currently utilize to assist in clinical interpretation. PMID- 22215560 TI - The use of cellular diagnostics for identifying sub-lethal stress in reef corals. AB - Coral reefs throughout the world are exhibiting documented declines in coral cover and species diversity, which have been linked to anthropogenic stressors including land-based sources of pollution. Reductions in coastal water and substratum quality are affecting coral survivorship, reproduction and recruitment, and hence, the persistence of coral reefs. One major obstacle in effectively addressing these declines is the lack of tools that can identify cause-and-effect relationships between stressors and specific coral reef losses, while a second problem is the inability to measure the efficacy of mitigation efforts in a timely fashion. We examined corals from six coral reefs on Guam, Mariana Islands, which were being affected by different environmental stressors (e.g. PAH's, pesticides, PCB's and sedimentation). Cellular diagnostic analysis differentiated the cellular-physiological condition of these corals. Examination of protein expression provided insight into their homeostatic responses to chemical and physical stressors in exposed corals prior to outright mortality, providing improved opportunities for developing locally-based management responses. This approach adds critically needed tools for addressing the effects of multiple stressors on corals and will allow researchers to move beyond present assessment and monitoring techniques that simply document the loss of coral abundance and diversity. PMID- 22215561 TI - ROCK1 induces ERK nuclear translocation in PDGF-BB-stimulated migration of rat vascular smooth muscle cells. AB - It has been known that Rho-associated protein kinase (ROCK) signaling regulates the migration of vascular smooth muscle cells (VSMCs). However, the isoform specific roles of ROCK and its underlying mechanism in VSMC migration are not well understood. The current study thus aimed to investigate the roles of ROCK1/2 and their relationship to the MAPK signaling pathway in platelet-derived growth factor (PDGF)-induced rat aorta VSMC migration by manipulating ROCK gene expression. The results revealed that ROCK1 small interfering ribonucleic acid (siRNA) rather than ROCK2 siRNA decreased PDGF-BB-generated VSMC migration, and upregulation of ROCK1 expression via transfection of constructed pEGFP-C1/ROCK1 plasmid further increased the migration of PDGF-BB-treated VSMCs. In PDGF-treated VSMCs, ROCK1 siRNA did not affect the phosphorylation levels of ERK and p38 in the cytoplasm, but decreased the level of ERK phosphorylation in the nucleus. These findings demonstrate that activated ROCK1 can promote VSMC migration through facilitating phosphorylation and nuclear translocation of ERK protein. PMID- 22215562 TI - External validation of the KORA S4/F4 prediction models for the risk of developing type 2 diabetes in older adults: the PREVEND study. AB - Recently, prediction models for type 2 diabetes mellitus (T2DM) in older adults (aged >=55 year) were developed in the KORA S4/F4 study, Augsburg, Germany. We aimed to externally validate the KORA models in a Dutch population. We used data on both older adults (n = 2,050; aged >=55 year) and total non-diabetic population (n = 6,317; aged 28-75 year) for this validation. We assessed performance of base model (model 1: age, sex, BMI, smoking, parental diabetes and hypertension) and two clinical models: model 1 plus fasting glucose (model 2); and model 2 plus uric acid (model 3). For 7-year risk of T2DM, we calculated C statistic, Hosmer-Lemeshow chi(2)-statistic, and integrated discrimination improvement (IDI) as measures of discrimination, calibration and reclassification, respectively. After a median follow-up of 7.7 years, 199 (9.7%) and 374 (5.9%) incident cases of T2DM were ascertained in the older and total population, respectively. In the older adults, C-statistic was 0.66 for model 1. This was improved for model 2 and model 3 (C-statistic = 0.81) with significant IDI. In the total population, these respective C-statistics were 0.77, 0.85 and 0.85. All models showed poor calibration (P < 0.001). After adjustment for the intercept and slope of each model, we observed good calibration for most models in both older and total populations. We validated the KORA clinical models for prediction of T2DM in an older Dutch population, with discrimination similar to the development cohort. However, the models need to be corrected for intercept and slope to acquire good calibration for application in a different setting. PMID- 22215563 TI - The chemical ecology of cecidomyiid midges (Diptera: Cecidomyiidae). AB - The family of cecidomyiid midges (Diptera: Cecidomyiidae) exhibits diversified patterns of life history, behavior, host range, population dynamics and other ecological traits. Those that feed on plants include many important agricultural pests; most cultivated plants are attacked by at least one midge species. Several features of the reproductive biology of cecidomyiid midges point to an important role for chemical communication, with this topic last reviewed comprehensively 12 years ago. Here, we review progress on identification of sex pheromones, chemicals involved in location of host plants, the neurophysiology of reception of volatile chemicals, and application of semiochemicals to management of pest species of cecidomyiid midges that has occurred during the last decade. We hope this review will stimulate and sustain further research in these fields. PMID- 22215564 TI - Safety assessment of transgenic Bacillus thuringiensis rice T1c-19 in Sprague Dawley rats from metabonomics and bacterial profile perspectives. AB - Bacillus thuringiensis rice is facing commercialization as the main food source in the near future. The unintended effects of genetically modified (GM) organisms are the most important barriers to their promotion. We aimed to establish a new in vivo evaluation model for genetically modified foods by using metabonomics and bacterial profile approaches. T1c-19 rice flour or its transgenic parent MH63 was used at 70% wt/wt to produce diets that were fed to rats for ~ 90 days. Urine metabolite changes were detected using (1)H NMR. Denaturing gradient gel electrophoresis and real-time polymerase chain reaction (RT-PCR) were used to detect the bacterial profiles between the two groups. The metabonomics was analyzed for metabolite changes in rat urine, when compared with the non-GM rice group, where rats were fed a GM rice diet. Several metabolites correlated with rat age and sex but not with GM rice diet. Significant biological differences were not identified between the GM rice diet and the non-GM rice diet. The bacteria related to rat urine metabolites were also discussed. The results from metabonomics and bacterial profile analyses were comparable with the results attained using the traditional method. Because metabonomics and bacterial profiling offer noninvasive, dynamic approaches for monitoring food safety, they provide a novel process for assessing the safety of GM foods. PMID- 22215565 TI - Silver nanoparticle-enhanced chemiluminescence method for determining naproxen based on europium(III)-sensitized Ce(IV)-Na2S2O4 reaction. AB - A simple and sensitive chemiluminescence (CL) method coupled with flow-injection technique is proposed to determine naproxen (NAP). The method is based upon the enhancement of the weak CL signal arising from the reaction of Ce(IV) and Na(2)S(2)O(4) with Eu(3+) to form the Eu(3+)-Ce(IV)-Na(2)S(2)O(4) system. The CL intensity was significantly increased by the introduction of NAP into this system in the presence of silver nanoparticles (Ag NPs). Examination of the recorded UV vis spectra and fluorescence spectra indicated that the energy of the intermediate SO(2)*, which originated from the redox reaction of Ce(IV) and Na(2)S(2)O(4), was transferred to Eu(3+) via NAP and that the process was accelerated by Ag NPs due to their catalytic activity. Under the optimum conditions, the CL intensity was increased with increasing NAP concentration and the correlation was linear (r = 0.9992) over the NAP concentration range of 1-420 ng mL(-1). The limit of detection (LOD) was 0.11 ng mL(-1) with a relative standard deviation (RSD) of 1.15% for 5 replicate determinations of 200 ng mL(-1) NAP. The method was successfully applied to determine NAP in pharmaceutical and biological samples. PMID- 22215566 TI - The retrograde approach to coronary artery chronic total occlusions: a practical approach. AB - The retrograde approach has revolutionized the treatment of chronic total occlusions. Several retrograde techniques have recently been described. In this article, we present a practical review with step-by-step instructions on the indications for retrograde interventions, equipment and retrograde channel selection, and techniques for retrograde crossing and treatment of chronic total occlusions. PMID- 22215567 TI - Primary percutaneous coronary intervention for acute myocardial infarction in the elderly aged >=75 years. AB - OBJECTIVES: We aimed to see whether primary percutaneous coronary intervention (PCI) benefits for ST-segment elevation myocardial infarction (STEMI) in the aged could be validated. BACKGROUND: Primary PCI benefits in elderly patients with STEMI remain uncertain. METHODS: We reviewed 947 consecutive patients treated with primary PCI for STEMI: 331 were aged >=75 years (older) and 616 <75 years (younger). RESULTS: The older group had higher percentage of renal insufficiency (7.9% vs. 3.1%, P = 0.0010), prior stroke (9.4% vs. 3.9%, P = 0.0006), 30-day mortality rate (7.6% vs. 3.9%, P = 0.015), and cardiac mortality rate (6.6% vs. 3.7%, P = 0.045). Successful reperfusion rates were similarly high in both groups (90.0% and 92.7%, P = 0.16), despite the higher proportion of patients with door to-balloon time >90 min (15% vs. 8.4%, P = 0.0016) in older patients. Successful compared with unsuccessful PCI significantly decreased 30-day mortality rates in the older group (6.0% vs. 21%, P = 0.0018) and in the younger group (2.8% vs. 18%, P < 0.0001). When reperfusion was successful, cardiac mortality rate in older patients was not significantly greater than in younger patients (5.4% vs. 2.8%, P = 0.057). By multivariate analysis, unsuccessful reperfusion independently predicted 30-day mortality (odds ratio, 4.04; 95% confidence interval, 1.79-9.12; P = 0.0008), whereas age >=75 years (odds ratio, 1.00; 95% confidence interval, 0.41-2.41; P = 0.99) and door-to-balloon time >90 min (odds ratio, 1.78; 95% confidence interval, 0.76-4.20; P = 0.19) did not. CONCLUSIONS: Pre-existing comorbidities characterize older patients developing STEMI. Aggressive PCI in older patients improves prognosis, and short door-to-balloon time is an important parameter conditioning the prognosis. PMID- 22215568 TI - A single chromosome unexpectedly links highly divergent isolates of Toxoplasma gondii. AB - Toxoplasma gondii is an obligate intracellular parasite that can cause disease in all warm-blooded animals studied to date, including humans. Over a billion people have been infected with this parasite worldwide. In Europe and North America, Toxoplasma has a clonal population structure, where only three lineages are highly dominant (strain types I, II, and III). Khan et al. [mBio 2(6): e00228-11, 2011] have carried out phylogenetic analyses on a large number of diverse strains from outside of these lineages and found evidence for a significant split between the clonal North American/European lineages and those in South America. In contrast to most of the genome, nearly all North American/European strains sampled, and the majority of South American strains sampled, harbored at least portions of a monomorphic chromosome Ia (Ia*). In contrast to previous models, these data suggest that the monomorphic haplotype originated in South America and migrated to the North. These authors propose that South American haplotype 12 was a precursor to modern-day type II, while South American haplotypes 6 and 9 crossed with haplotype 12 to give rise to the type I and III lineages, respectively. However, the findings reported by Khan et al. complicate the origin of chromosome Ia, since there are members of haplotypes 9 and 12 with nearly complete versions of Ia* and members of haplotypes 6 and 12 with over 50% of Ia*. This unexpected finding raises exciting new questions about how an entire common chromosome can be found within strains that are highly divergent at most other genomic loci. PMID- 22215569 TI - The KGD motif of Epstein-Barr virus gH/gL is bifunctional, orchestrating infection of B cells and epithelial cells. AB - Epstein-Barr virus (EBV), a member of the herpesvirus family, is the causative agent of common human infections and specific malignancies. EBV entry into target cells, including B cells and epithelial cells, requires the interaction of multiple virus-encoded glycoproteins. Glycoproteins H and L (gH/gL) cooperate with glycoprotein B (gB) to mediate fusion of the viral envelope with target cell membranes. Both the gH/gL complex and gB are required for fusion, whereas glycoprotein 42 (gp42) acts as a tropism switch and is required for B cell infection and inhibits epithelial cell infection. Our previous studies identified a prominent KGD motif located on the surface of gH/gL. In the current study, we found that this motif serves as a bifunctional domain on the surface of gH/gL that directs EBV fusion of B cells and epithelial cells. Mutation of the KGD motif to AAA decreased fusion with both epithelial and B cells and reduced the binding of gH/gL to epithelial cells and to gp42. We also demonstrate that deletion of amino acids 62 to 66 of gp42 selectively reduces binding to wild-type gH/gL, but not the KGD mutant, suggesting that the KGD motif of gH/gL interacts with the N-terminal amino acids 62 to 66 of gp42. PMID- 22215571 TI - Strongly reduced fragmentation and soft emission processes in sputtered ion formation from amino acid films under large Ar(n)+ (n <= 2200) cluster ion bombardment. AB - The analysis of organic and biological substances by secondary-ion mass spectrometry (SIMS) has greatly benefited from the use of cluster ions as primary bombarding species. Thereby, depth profiling and three-dimensional (3D) imaging of such systems became feasible. Large Ar(n)(+) cluster ions may constitute a further improvement in this direction. To explore this option, size-selected Ar(n)(+) cluster ions with 300 <= n <= 2200 (bombarding energies 5.5 and 11 keV) were used to investigate the emission of positive secondary ions from four amino acid specimens (arginine, glycine, phenylalanine, and tyrosine) by time-of-flight SIMS. For all cluster sizes, the protonated molecule of the respective amino acid is observed in the mass spectra. With increasing cluster size the number of fragment ions decreases strongly in relation to the intact molecules, to the extent that the fraction of fragment ions amounts to less than 10% in some cases. Such 'soft' emission processes also lead the ejection of dimers and even multimers of the amino acid molecules. In the case of the phenylalanine, secondary ion species composed of up to at least seven phenylalanine moieties were observed. Tentatively, the ionization probability of the emitted molecules is envisaged to depend on the presence of free protons in the emission zone. Their number can be expected to decrease concurrently with the decreasing amount of fragmentation for large Ar(n)(+) cluster ions (i.e. for low energies per cluster atom). PMID- 22215570 TI - Leukocyte inflammatory responses provoked by pneumococcal sialidase. AB - Cell surface expression of sialic acid has been reported to decrease during immune cell activation, but the significance and regulation of this phenomenon are still being investigated. The major human bacterial pathogen Streptococcus pneumoniae causes pneumonia, sepsis and meningitis, often accompanied by strong inflammatory responses. S. pneumoniae expresses a sialidase (NanA) that contributes to mucosal colonization, platelet clearance, and blood-brain barrier penetration. Using wild-type and isogenic NanA-deficient mutant strains, we showed that S. pneumoniae NanA can desialylate the surface of human THP-1 monocytes, leading to increased ERK phosphorylation, NF-kappaB activation, and proinflammatory cytokine release. S. pneumoniae NanA expression also stimulates interleukin-8 release and extracellular trap formation from human neutrophils. A mechanistic contribution of unmasking of inhibitory Siglec-5 from cis sialic acid interactions to the proinflammatory effect of NanA is suggested by decreased SHP 2 recruitment to the Siglec-5 intracellular domain and RNA interference studies. Finally, NanA increased production of proinflammatory cytokines in a murine intranasal challenge model of S. pneumoniae pneumonia. PMID- 22215572 TI - Stable isotope analysis of organic carbon in small (ug C) samples and dissolved organic matter using a GasBench preparation device. AB - The stable isotopes of organic matter can provide valuable information on carbon cycling dynamics, microbial metabolisms, and past climates. Since bulk measurements may mask dynamic changes to critical portions of the organic pool, researchers are increasingly isolating individual compounds for isotopic analysis. The amount of carbon isolated is frequently small, requiring specialized equipment for its analysis. We present a simple and accurate method to measure the delta(13)C values of ug-amounts of organic compounds and dissolved organic matter in freshwaters using wet oxidation and a GasBench II preparation device. Samples containing 3 ug C can be analyzed with a precision of <0.40/00. For samples containing 1.2 ug C, the precision is <0.80/00. The blank is estimated to be ~0.2 ug C. The accuracy of the method is demonstrated for a wide range of compounds including those that are difficult to oxidize such as humic acid and phthalic acid. The delta(13)C values of DOC from river and riparian ground water determined by this method are comparable with those determined with an elemental analyzer on freeze-dried samples of DOC. The low detection limit and the ease with which it can be combined with isolation techniques such as liquid chromatography make this technique attractive for the off-line analysis of organic compounds, and open new possibilities for the development of methodologies for compound-specific carbon isotope analysis of complex mixtures separated by HPLC. PMID- 22215573 TI - delta13C and delta15N values in scales of Micropterus salmoides largemouth bass as a freshwater environmental indicator. AB - We have investigated the effectiveness of using the Micropterus salmoides largemouth bass, which is a top predator found throughout the world, as the index of a hydrosphere environment and its food chain. To this end, we used stable carbon and nitrogen isotope analysis (SIA). Largemouth bass were collected from eight dam reservoirs and two ponds in Toyama Prefecture, Japan. Toyama is located in central Japan and features a variety of distinct geographical environments, a result of the 3000-m elevation that changes over short distances, and abundant water systems. The mean delta(13)C and delta(15)N values for the lipid-extracted muscle of largemouth bass from all sampling locations showed large variability, but there were only small standard deviations at each sampling location. The isotope ratios for largemouth bass express the characteristics of each investigated hydrosphere environment and food chain. A very high correlation (delta(13)C: Y(scale) = 0.96 X(muscle) + 1.58, R(2) = 0.98, delta(15)N: Y(scale) = 0.92 X(muscle) - 1.15, R(2) = 0.95) of SIA values was found between largemouth bass scales and lipid-extracted muscles, which suggests that the more easily analyzed scales are useful as SIA samples for the monitoring and comparison of hydrosphere environments throughout the world. PMID- 22215574 TI - Chemical and isotopic compositions of bottled waters sold in Korea: chemical enrichment and isotopic fractionation by desalination. AB - A total of 54 Korean bottled waters were investigated to characterize their origins and types using elemental and isotopic composition, as well as to identify elemental and isotopic changes in desalinated marine water that arise due to desalination. The different types of bottled water displayed a wide pH range (3.42 to 7.21). The elemental compositions of still and sparkling waters were quite similar, whereas desalinated marine water was clearly distinguished by its high concentrations of Ca, Mg, B, and Cl. In addition, desalinated marine water had much higher isotope ratios of oxygen and hydrogen (-0.5 and -20/00, respectively) than still and sparkling waters (-8.4 and -570/00). The elemental composition of desalinated marine water was adjusted through post-treatment procedures; in particular, boron was greatly enriched during desalination processes. The carbon isotope compositions of dissolved inorganic carbon (delta(13)C(DIC) values) varied widely according to the origins of the bottled waters (-25.6 to -13.60/00 for still water, -31.2 to -26.70/00 for sparkling water, and -24.1 to -6.30/00 for desalinated marine water). This indicates that carbon isotopes in dissolved inorganic carbon are significantly fractionated by desalination processes and re-modified through post-treatment procedures. The results suggest that combined elemental and stable isotopic tracers are useful for identifying the origin of bottled water, verifying elemental and isotopic modifications during desalination processes, and characterizing various water types of bottled waters. PMID- 22215575 TI - Pressurized laboratory experiments show no stable carbon isotope fractionation of methane during gas hydrate dissolution and dissociation. AB - The stable carbon isotopic ratio of methane (delta(13)C-CH(4)) recovered from marine sediments containing gas hydrate is often used to infer the gas source and associated microbial processes. This is a powerful approach because of distinct isotopic fractionation patterns associated with methane production by biogenic and thermogenic pathways and microbial oxidation. However, isotope fractionations due to physical processes, such as hydrate dissolution, have not been fully evaluated. We have conducted experiments to determine if hydrate dissolution or dissociation (two distinct physical processes) results in isotopic fractionation. In a pressure chamber, hydrate was formed from a methane gas source at 2.5 MPa and 4 degrees C, well within the hydrate stability field. Following formation, the methane source was removed while maintaining the hydrate at the same pressure and temperature which stimulated hydrate dissolution. Over the duration of two dissolution experiments (each ~20-30 days), water and headspace samples were periodically collected and measured for methane concentrations and delta(13)C CH(4) while the hydrate dissolved. For both experiments, the methane concentrations in the pressure chamber water and headspace increased over time, indicating that the hydrate was dissolving, but the delta(13)C-CH(4) values showed no significant trend and remained constant, within 0.50/00. This lack of isotope change over time indicates that there is no fractionation during hydrate dissolution. We also investigated previous findings that little isotopic fractionation occurs when the gas hydrate dissociates into gas bubbles and water due to the release of pressure. Over a 2.5 MPa pressure drop, the difference in the delta(13)C-CH(4) was <0.30/00. We have therefore confirmed that there is no isotope fractionation when the gas hydrate dissociates and demonstrated that there is no fractionation when the hydrate dissolves. Therefore, measured delta(13)C-CH(4) values near gas hydrates are not affected by physical processes, and can thus be interpreted to result from either the gas source or associated microbial processes. PMID- 22215576 TI - High-performance thin-layer chromatography plate blotting for liquid microjunction surface sampling probe mass spectrometric analysis of analytes separated on a wettable phase plate. AB - A blotting method that transfers analytes separated on wettable high-performance thin-layer chromatography (HPTLC) plates to a hydrophobic reversed-phase C8 HPLTC plate suitable for analysis with a liquid microjunction surface sampling probe electrospray ionization mass spectrometry system was described and demonstrated. The simple blotting procedure transfers the analyte from the wettable plate to the topmost surface of a rigidly backed, easy-to-mount hydrophobic substrate that already has been proven viable for analysis by this sampling probe/mass spectrometry system. The utility of the approach was demonstrated by the analysis of a four-component peptide mixture originally separated on a ProteoChrom(r) HPTLC cellulose sheet and then blotted onto the reversed-phase HPTLC plate. PMID- 22215577 TI - A pilot study for the intrinsic labeling of egg proteins with 15N and 13C. AB - The aim of this study was to produce intrinsically and uniformly doubly (15)N (13)C-labeled proteins. These proteins can be used as intrinsic tracers of dietary amino acids, both alpha-amino groups and carbon skeletons, during postprandial metabolic utilization. Two (Rhodes) laying hens were fed for 16 days with a standard poultry diet supplemented with 0, 0.2% or 0.4% of a mixture of 20 doubly (15)N-(13)C-labeled AAs. A third hen was given a non-enriched diet, as the control. The eggs laid were collected over 24 days, from 3 days before to 4 days after supplementation. The (15)N and (13)C enrichments in proteins from white and yolk were measured by EA-IRMS and GC-C-IRMS for enrichment in individual amino acids. After 10 days of supplementation, the (15)N enrichment reached an isotopic plateau at 1500 to 3000 0/00, depending on the supplementation level, in both white and yolk while the (13)C enrichment was 220 to 650 0/00 in white and was 100 to 250 0/00 in yolk. The (15)N enrichment was similar among the amino acids, except for the aromatic ones in which the enrichment was lower. The delta(13)C values were variable among amino acids in both white and yolk, ranging from 77 0/00 for tyrosine to 555 0/00 for proline with the 0.2 % supplementation level. In conclusion, the incorporation of 0.2 % labeled amino acids in the hen diet allowed us to achieve sufficient enrichment for metabolic studies. However, due to the non-homogeneity of the (13)C labeling, adequate (13)C enrichment of individual amino acids must be considered depending on the investigated metabolic pathway. PMID- 22215578 TI - An unusual intramolecular transfer of the fluorobenzyl cation between two remote amidic nitrogen atoms induced by collision in the gas phase. AB - A highly unusual rearrangement in collision-induced dissociation mass spectrometry is reported that involves intramolecular transfer of the fluorobenzyl cation between two remote amidic nitrogen atoms separated by five chemical bonds. The same intramolecular transfer was also observed for two related analogs. It is postulated that the ionic reactions are initiated by protonation of the first amidic nitrogen, resulting in formation of the fluorobenzyl cation and a neutral partner that are maintained together in the gas phase by electrostatic interactions as an intermediate ion-neutral complex. In the ion-neutral complex, the nascent fluorobenzyl cation approaches geometrically to the second amidic nitrogen atom on the neutral partner, and subsequently forms a new C-N bond and an isomeric precursor ion as the charge is retained on the amidic nitrogen. The newly formed isomeric precursor ion eventually undergoes the final fragmentation by amide bond cleavage. Alternatively, the ionic reactions proceed through a direct intramolecular transfer mechanism by which the molecular ion adopts to a ring-like configuration in the gas phase, so that both the donor and recipient nitrogens are geometrically close to each other within a bonding distance to permit a direct transfer between two sites even though they are separated by multiple chemical bonds. PMID- 22215579 TI - Using gas chromatography/isotope ratio mass spectrometry to determine the fractionation factor for H2 production by hydrogenases. AB - Hydrogenases catalyze the reversible formation of H(2), and they are key enzymes in the biological cycling of H(2). H isotopes have the potential to be a very useful tool in quantifying hydrogen ion trafficking in biological H(2) production processes, but there are several obstacles that have thus far limited the application of this tool. Here, we describe a new method that overcomes some of these barriers and is specifically designed to measure isotopic fractionation during enzyme-catalyzed H(2) evolution. A key feature of this technique is that purified hydrogenases are employed, allowing precise control over the reaction conditions and therefore a high level of precision. In addition, a custom designed high-throughput gas chromatograph/isotope ratio mass spectrometer is employed to measure the isotope ratio of the H(2). Using our new approach, we determined that the fractionation factor for H(2) production by the [NiFe] hydrogenase from Desulfovibrio fructosovorans is 0.273 +/- 0.006. This result indicates that, as expected, protons are highly favored over deuterium ions during H(2) evolution. Potential applications of this newly developed method are discussed. PMID- 22215580 TI - Identification of energy consumption and nutritional stress by isotopic and elemental analysis of urine in bonobos (Pan paniscus). AB - A mounting body of evidence suggests that changes in energetic conditions like prolonged starvation can be monitored using stable isotope ratios of tissues such as bone, muscle, hair, and blood. However, it is unclear if urinary stable isotope ratios reflect a variation in energetic condition, especially if these changes in energetic condition are accompanied by shifts in dietary composition. In a feeding experiment conducted on captive bonobos (Pan paniscus), we monitored urinary delta(13)C, delta(15)N, total C (carbon), total N (nitrogen), and C/N ratios and compared these results with glucocorticoid levels under gradually changing energy availability and dietary composition. Measurements of daily collected urine samples over a period of 31 days showed that while shifts in urinary isotope signatures of delta(13)C and delta(15)N as well as total C were best explained by changes in energy consumption, urinary total N excretion as well as the C/N ratios matched the variation in dietary composition. Furthermore, when correcting for fluctuations in dietary composition, the isotope signatures of delta(13)C and delta(15)N as well as total C correlated with urinary glucocorticoid levels; however, the urinary total N and the C/N ratio did not. These results indicate for the first time that it is possible to non-invasively explore specific longitudinal records on animal energetic conditions and dietary compositions with urinary stable isotope ratios and elemental compositions, and this research provides a strong foundation for investigating how ecological factors and social dynamics affect feeding habits in wild animal populations such as primates. PMID- 22215581 TI - Characterization and identification of chemical compositions in the extract of Artemisia rupestris L. by liquid chromatography coupled to quadrupole time-of flight tandem mass spectrometry. AB - Liquid chromatography coupled to negative electrospray ionization (ESI) tandem mass spectrometry (MS/MS) employing a time-of-flight tandem mass spectrometer was used in the structural determination of phenolic compounds and sesquiterpenoids occurring in the extract from Artemisia rupestris L. A total of 91 compounds including chlorogenic acid derivatives, flavonoids (aglycone, O-glycosyl, C glycosyl and C,O-glycosyl), 2-phenoxychromones and guaiane sesquiterpenoids were identified by comparing the retention time and fragmentation behavior with reference standards or according to accurate mass measurement and the characteristic fragmentation at low and high collision energy. Most of these compounds were reported in Artemisia rupestris L. for the first time. Meanwhile, the proposed pathway and the major diagnostic fragmentation of 2-phenoxychromone and rupestonic acid were investigated to trace 2-phenoxychromone and rupestonic acid derivatives in crude plant extracts. According to these rules, we have successfully characterized five potential novel compounds including three 2 phenoxychromones (6-demethoxy-4'-O-methylcapillarisin-O-hexosylglucuronide, 6 demethoxy-4'-O-methylcapillarisin-O-pentosylhexoside and 6-demethoxy-4'-O methylcapillarisin-O-deoxyhexosylhexoside) and two sesquiterpenoids (hexosyl glycurinide-rupestonic acid and hexoside-rupestonic acid). PMID- 22215582 TI - Paleoenvironmental history of the West Baray, Angkor (Cambodia). AB - Angkor (Cambodia) was the seat of the Khmer Empire from the 9th to 15th century AD. The site is noted for its monumental architecture and complex hydro engineering systems, comprised of canals, moats, embankments, and large reservoirs, known as barays. We infer a 1,000-y, (14)C-dated paleoenvironmental record from study of an approximately 2-m sediment core taken in the largest Khmer reservoir, the West Baray. The baray was utilized and managed from the time of construction in the early 11th century, through the 13th century. During that time, the West Baray received relatively high rates of detrital input. In the 14th century, linear sedimentation rates diminished by an order of magnitude, yielding a condensed section that correlates temporally with episodes of regional monsoon failure during the late 14th and early 15th century, recorded in tree ring records from Vietnam. Our results demonstrate that changes in the water management system were associated with the decline of the Angkorian kingdom during that period. By the 17th century, the West Baray again functioned as a limnetic system. Ecologic and sedimentologic changes over the last millennium, detected in the baray deposits, are attributed to shifts in regional-scale Khmer water management, evolving land use practices in the catchment, and regional climate change. PMID- 22215583 TI - Evidence for the extraterrestrial origin of a natural quasicrystal. AB - We present evidence that a rock sample found in the Koryak Mountains in Russia and containing icosahedrite, an icosahedral quasicrystalline phase with composition Al(63)Cu(24)Fe(13), is part of a meteorite, likely formed in the early solar system about 4.5 Gya. The quasicrystal grains are intergrown with diopside, forsterite, stishovite, and additional metallic phases [khatyrkite (CuAl(2)), cupalite (CuAl), and beta-phase (AlCuFe)]. This assemblage, in turn, is enclosed in a white rind consisting of diopside, hedenbergite, spinel (MgAl(2)O(4)), nepheline, and forsterite. Particularly notable is a grain of stishovite (from the interior), a tetragonal polymorph of silica that only occurs at ultrahigh pressures (>= 10 Gpa), that contains an inclusion of quasicrystal. An extraterrestrial origin is inferred from secondary ion mass spectrometry (18)O/(16)O and (17)O/(16)O measurements of the pyroxene and olivine intergrown with the metal that show them to have isotopic compositions unlike any terrestrial minerals and instead overlap those of anhydrous phases in carbonaceous chondrite meteorites. The spinel from the white rind has an isotopic composition suggesting that it was part of a calcium-aluminum-rich inclusion similar to those found in CV3 chondrites. The mechanism that produced this exotic assemblage is not yet understood. The assemblage (metallic copper-aluminum alloy) is extremely reduced, and the close association of aluminum (high temperature refractory lithophile) with copper (low temperature chalcophile) is unexpected. Nevertheless, our evidence indicates that quasicrystals can form naturally under astrophysical conditions and remain stable over cosmic timescales, giving unique insights on their existence in nature and stability. PMID- 22215584 TI - A quantum-quantum Metropolis algorithm. AB - The classical Metropolis sampling method is a cornerstone of many statistical modeling applications that range from physics, chemistry, and biology to economics. This method is particularly suitable for sampling the thermal distributions of classical systems. The challenge of extending this method to the simulation of arbitrary quantum systems is that, in general, eigenstates of quantum Hamiltonians cannot be obtained efficiently with a classical computer. However, this challenge can be overcome by quantum computers. Here, we present a quantum algorithm which fully generalizes the classical Metropolis algorithm to the quantum domain. The meaning of quantum generalization is twofold: The proposed algorithm is not only applicable to both classical and quantum systems, but also offers a quantum speedup relative to the classical counterpart. Furthermore, unlike the classical method of quantum Monte Carlo, this quantum algorithm does not suffer from the negative-sign problem associated with fermionic systems. Applications of this algorithm include the study of low temperature properties of quantum systems, such as the Hubbard model, and preparing the thermal states of sizable molecules to simulate, for example, chemical reactions at an arbitrary temperature. PMID- 22215585 TI - Quantum coherence spectroscopy reveals complex dynamics in bacterial light harvesting complex 2 (LH2). AB - Light-harvesting antenna complexes transfer energy from sunlight to photosynthetic reaction centers where charge separation drives cellular metabolism. The process through which pigments transfer excitation energy involves a complex choreography of coherent and incoherent processes mediated by the surrounding protein and solvent environment. The recent discovery of coherent dynamics in photosynthetic light-harvesting antennae has motivated many theoretical models exploring effects of interference in energy transfer phenomena. In this work, we provide experimental evidence of long-lived quantum coherence between the spectrally separated B800 and B850 rings of the light harvesting complex 2 (LH2) of purple bacteria. Spectrally resolved maps of the detuning, dephasing, and the amplitude of electronic coupling between excitons reveal that different relaxation pathways act in concert for optimal transfer efficiency. Furthermore, maps of the phase of the signal suggest that quantum mechanical interference between different energy transfer pathways may be important even at ambient temperature. Such interference at a product state has already been shown to enhance the quantum efficiency of transfer in theoretical models of closed loop systems such as LH2. PMID- 22215586 TI - Localization of the proteasomal ubiquitin receptors Rpn10 and Rpn13 by electron cryomicroscopy. AB - Two canonical subunits of the 26S proteasome, Rpn10 and Rpn13, function as ubiquitin (Ub) receptors. The mutual arrangement of these subunits--and all other non-ATPase subunits--in the regulatory particle is unknown. Using electron cryomicroscopy, we calculated difference maps between wild-type 26S proteasome from Saccharomyces cerevisiae and deletion mutants (rpn10Delta, rpn13Delta, and rpn10Deltarpn13Delta). These maps allowed us to localize the two Ub receptors unambiguously. Rpn10 and Rpn13 mapped to the apical part of the 26S proteasome, above the N-terminal coiled coils of the AAA-ATPase heterodimers Rpt4/Rpt5 and Rpt1/Rpt2, respectively. On the basis of the mutual positions of Rpn10 and Rpn13, we propose a model for polyubiquitin binding to the 26S proteasome. PMID- 22215587 TI - Atomically precise gold nanocrystal molecules with surface plasmon resonance. AB - Since Faraday's pioneering work on gold colloids, tremendous scientific research on plasmonic gold nanoparticles has been carried out, but no atomically precise Au nanocrystals have been achieved. This work reports the first example of gold nanocrystal molecules. Mass spectrometry analysis has determined its formula to be Au(333)(SR)(79) (R = CH(2)CH(2)Ph). This magic sized nanocrystal molecule exhibits fcc-crystallinity and surface plasmon resonance at approximately 520 nm, hence, a metallic nanomolecule. Simulations have revealed that atomic shell closing largely contributes to the particular robustness of Au(333)(SR)(79), albeit the number of free electrons (i.e., 333 - 79 = 254) is also consistent with electron shell closing based on calculations using a confined free electron model. Guided by the atomic shell closing growth mode, we have also found the next larger size of extraordinarily stability to be Au(~530)(SR)(~100) after a size-focusing selection--which selects the robust size available in the starting polydisperse nanoparticles. This work clearly demonstrates that atomically precise nanocrystal molecules are achievable and that the factor of atomic shell closing contributes to their extraordinary stability compared to other sizes. Overall, this work opens up new opportunities for investigating many fundamental issues of nanocrystals, such as the formation of metallic state, and will have potential impact on condensed matter physics, nanochemistry, and catalysis as well. PMID- 22215588 TI - Bivalent recognition of nucleosomes by the tandem PHD fingers of the CHD4 ATPase is required for CHD4-mediated repression. AB - CHD4 is a catalytic subunit of the NuRD (nucleosome remodeling and deacetylase) complex essential in transcriptional regulation, chromatin assembly and DNA damage repair. CHD4 contains tandem plant homeodomain (PHD) fingers connected by a short linker, the biological function of which remains unclear. Here we explore the combinatorial action of the CHD4 PHD1/2 fingers and detail the molecular basis for their association with chromatin. We found that PHD1/2 targets nucleosomes in a multivalent manner, concomitantly engaging two histone H3 tails. This robust synergistic interaction displaces HP1gamma from pericentric sites, inducing changes in chromatin structure and leading to the dispersion of the heterochromatic mark H3K9me3. We demonstrate that recognition of the histone H3 tails by the PHD fingers is required for repressive activity of the CHD4/NuRD complex. Together, our data elucidate the molecular mechanism of multivalent association of the PHD fingers with chromatin and reveal their critical role in the regulation of CHD4 functions. PMID- 22215589 TI - Spiral chain O4 form of dense oxygen. AB - Oxygen is in many ways a unique element: It is the only known diatomic molecular magnet, and it exhibits an unusual O(8) cluster in its high-pressure solid phase. Pressure-induced molecular dissociation as one of the fundamental problems in physical sciences has been reported from theoretical or experimental studies of diatomic solids H(2), N(2), F(2), Cl(2), Br(2), and I(2) but remains elusive for molecular oxygen. We report here the prediction of the dissociation of molecular oxygen into a polymeric spiral chain O(4) structure (space group I4(1)/acd, theta O(4)) above 1.92-TPa pressure using the particle-swarm search method. The theta O(4) phase has a similar structure as the high-pressure phase III of sulfur. The molecular bonding in the insulating epsilon-O(8) phase or the isostructural superconducting zeta-O(8) phase remains remarkably stable over a large pressure range of 0.008-1.92 TPa. The pressure-induced softening of a transverse acoustic phonon mode at the zone boundary V point of O(8) phase might be the ultimate driving force for the formation of theta-O(4). Stabilization of theta-O(4) turns oxygen from a superconductor into an insulator by opening a wide band gap (approximately 5.9 eV) that originates from the sp(3)-like hybridized orbitals of oxygen and the localization of valence electrons. PMID- 22215590 TI - Silkworms transformed with chimeric silkworm/spider silk genes spin composite silk fibers with improved mechanical properties. AB - The development of a spider silk-manufacturing process is of great interest. However, there are serious problems with natural manufacturing through spider farming, and standard recombinant protein production platforms have provided limited progress due to their inability to assemble spider silk proteins into fibers. Thus, we used piggyBac vectors to create transgenic silkworms encoding chimeric silkworm/spider silk proteins. The silk fibers produced by these animals were composite materials that included chimeric silkworm/spider silk proteins integrated in an extremely stable manner. Furthermore, these composite fibers were, on average, tougher than the parental silkworm silk fibers and as tough as native dragline spider silk fibers. These results demonstrate that silkworms can be engineered to manufacture composite silk fibers containing stably integrated spider silk protein sequences, which significantly improve the overall mechanical properties of the parental silkworm silk fibers. PMID- 22215591 TI - Historical contingency affects signaling strategies and competitive abilities in evolving populations of simulated robots. AB - One of the key innovations during the evolution of life on earth has been the emergence of efficient communication systems, yet little is known about the causes and consequences of the great diversity within and between species. By conducting experimental evolution in 20 independently evolving populations of cooperatively foraging simulated robots, we found that historical contingency in the occurrence order of novel phenotypic traits resulted in the emergence of two distinct communication strategies. The more complex foraging strategy was less efficient than the simpler strategy. However, when the 20 populations were placed in competition with each other, the populations with the more complex strategy outperformed the populations with the less complex strategy. These results demonstrate a tradeoff between communication efficiency and robustness and suggest that stochastic events have important effects on signal evolution and the outcome of competition between distinct populations. PMID- 22215592 TI - Player preferences among new and old violins. AB - Most violinists believe that instruments by Stradivari and Guarneri "del Gesu" are tonally superior to other violins--and to new violins in particular. Many mechanical and acoustical factors have been proposed to account for this superiority; however, the fundamental premise of tonal superiority has not yet been properly investigated. Player's judgments about a Stradivari's sound may be biased by the violin's extraordinary monetary value and historical importance, but no studies designed to preclude such biasing factors have yet been published. We asked 21 experienced violinists to compare violins by Stradivari and Guarneri del Gesu with high-quality new instruments. The resulting preferences were based on the violinists' individual experiences of playing the instruments under double blind conditions in a room with relatively dry acoustics. We found that (i) the most-preferred violin was new; (ii) the least-preferred was by Stradivari; (iii) there was scant correlation between an instrument's age and monetary value and its perceived quality; and (iv) most players seemed unable to tell whether their most-preferred instrument was new or old. These results present a striking challenge to conventional wisdom. Differences in taste among individual players, along with differences in playing qualities among individual instruments, appear more important than any general differences between new and old violins. Rather than searching for the "secret" of Stradivari, future research might best focused on how violinists evaluate instruments, on which specific playing qualities are most important to them, and on how these qualities relate to measurable attributes of the instruments, whether old or new. PMID- 22215593 TI - Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta). AB - People attend not only to their own experiences, but also to the experiences of those around them. Such social awareness profoundly influences human behavior by enabling observational learning, as well as by motivating cooperation, charity, empathy, and spite. Oxytocin (OT), a neurosecretory hormone synthesized by hypothalamic neurons in the mammalian brain, can enhance affiliation or boost exclusion in different species in distinct contexts, belying any simple mechanistic neural model. Here we show that inhaled OT penetrates the CNS and subsequently enhances the sensitivity of rhesus macaques to rewards occurring to others as well as themselves. Roughly 2 h after inhaling OT, monkeys increased the frequency of prosocial choices associated with reward to another monkey when the alternative was to reward no one. OT also increased attention to the recipient monkey as well as the time it took to render such a decision. In contrast, within the first 2 h following inhalation, OT increased selfish choices associated with delivery of reward to self over a reward to the other monkey, without affecting attention or decision latency. Despite the differences in species typical social behavior, exogenous, inhaled OT causally promotes social donation behavior in rhesus monkeys, as it does in more egalitarian and monogamous ones, like prairie voles and humans, when there is no perceived cost to self. These findings potentially implicate shared neural mechanisms. PMID- 22215594 TI - Detecting anthrax in the mail by coherent Raman microspectroscopy. AB - In this report, we show the collection of spatial information through a turbid medium by coherent Raman microspectroscopic imaging. In particular, the technique is capable of identifying anthrax endospores inside a sealed paper envelope. PMID- 22215595 TI - Life motion signals lengthen perceived temporal duration. AB - Point-light biological motions, conveying various different attributes of biological entities, have particular spatiotemporal properties that enable them to be processed with remarkable efficiency in the human visual system. Here we demonstrate that such signals automatically lengthen their perceived temporal duration independent of global configuration and without observers' subjective awareness of their biological nature. By using a duration discrimination paradigm, we showed that an upright biological motion sequence was perceived significantly longer than an inverted but otherwise identical sequence of the same duration. Furthermore, this temporal dilation effect could be extended to spatially scrambled biological motion signals, whose global configurations were completely disrupted, regardless of whether observers were aware of the nature of the stimuli. However, such an effect completely disappeared when critical biological characteristics were removed. Taken together, our findings suggest a special mechanism of time perception tuned to life motion signals and shed new light on the temporal encoding of biological motion. PMID- 22215596 TI - Stabilization of hepatitis C virus RNA by an Ago2-miR-122 complex. AB - MicroRNAs (miRNAs) are small noncoding RNAs that regulate eukaryotic gene expression by binding to regions of imperfect complementarity in mRNAs, typically in the 3' UTR, recruiting an Argonaute (Ago) protein complex that usually results in translational repression or destabilization of the target RNA. The translation and decay of mRNAs are closely linked, competing processes, and whether the miRNA induced silencing complex (RISC) acts primarily to reduce translation or stability of the mRNA remains controversial. miR-122 is an abundant, liver specific miRNA that is an unusual host factor for hepatitis C virus (HCV), an important cause of liver disease in humans. Prior studies show that it binds the 5' UTR of the messenger-sense HCV RNA genome, stimulating translation and promoting genome replication by an unknown mechanism. Here we show that miR-122 binds HCV RNA in association with Ago2 and that this slows decay of the viral genome in infected cells. The stabilizing action of miR-122 does not require the viral RNA to be translationally active nor engaged in replication, and can be functionally substituted by a nonmethylated 5' cap. Our data demonstrate that a RISC-like complex mediates the stability of HCV RNA and suggest that Ago2 and miR 122 act coordinately to protect the viral genome from 5' exonuclease activity of the host mRNA decay machinery. miR-122 thus acts in an unconventional fashion to stabilize HCV RNA and slow its decay, expanding the repertoire of mechanisms by which miRNAs modulate gene expression. PMID- 22215597 TI - Glycosyl transferases in family 61 mediate arabinofuranosyl transfer onto xylan in grasses. AB - Xylan, a hemicellulosic component of the plant cell wall, is one of the most abundant polysaccharides in nature. In contrast to dicots, xylan in grasses is extensively modified by alpha-(1,2)- and alpha-(1,3)-linked arabinofuranose. Despite the importance of grass arabinoxylan in human and animal nutrition and for bioenergy, the enzymes adding the arabinosyl substitutions are unknown. Here we demonstrate that knocking-down glycosyltransferase (GT) 61 expression in wheat endosperm strongly decreases alpha-(1,3)-linked arabinosyl substitution of xylan. Moreover, heterologous expression of wheat and rice GT61s in Arabidopsis leads to arabinosylation of the xylan, and therefore provides gain-of-function evidence for alpha-(1,3)-arabinosyltransferase activity. Thus, GT61 proteins play a key role in arabinoxylan biosynthesis and therefore in the evolutionary divergence of grass cell walls. PMID- 22215598 TI - Estrogen receptor-alpha expression in neuronal cells affects bone mass. AB - It has generally been assumed that bone mass is controlled by endocrine mechanisms and the local bone environment. Recent findings demonstrate that central pathways are involved in the regulation of bone mass. Estrogen is involved in the regulation of bone homeostasis and the CNS is also a target for estrogen actions. The aim of this study was to investigate in vivo the role of central estrogen receptor-alpha (ERalpha) expression for bone mass. Nestin-Cre mice were crossed with ERalpha(flox) mice to generate mice lacking ERalpha expression specifically in nervous tissue (nestin-ERalpha(-/-)). Bone mineral density was increased in both the trabecular and cortical bone compartments in nestin-ERalpha(-/-) mice compared with controls. Femoral bone strength was increased in nestin-ERalpha(-/-) mice, as demonstrated by increased stiffness and maximal load of failure. The high bone mass phenotype in nestin-ERalpha(-/-) mice was mainly caused by increased bone formation. Serum leptin levels were elevated as a result of increased leptin expression in white adipose tissue (WAT) and slightly increased amount of WAT in nestin-ERalpha(-/-) mice. Leptin receptor mRNA levels were reduced in the hypothalamus but not in bone. In conclusion, inactivation of central ERalpha signaling results in increased bone mass, demonstrating that the balance between peripheral stimulatory and central inhibitory ERalpha actions is important for the regulation of bone mass. We propose that the increased bone mass in nestin-ERalpha(-/-) mice is mediated via decreased central leptin sensitivity and thereby increased secretion of leptin from WAT, which, in turn, results in increased peripheral leptin-induced bone formation. PMID- 22215599 TI - Serum amyloid A opposes lipoxin A4 to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) will soon be the third most common cause of death globally. Despite smoking cessation, neutrophilic mucosal inflammation persistently damages the airways and fails to protect from recurrent infections. This maladaptive and excess inflammation is also refractory to glucocorticosteroids (GC). Here, we identify serum amyloid A (SAA) as a candidate mediator of GC refractory inflammation in COPD. Extrahepatic SAA was detected locally in COPD bronchoalveolar lavage fluid, which correlated with IL-8 and neutrophil elastase, consistent with neutrophil recruitment and activation. Immunohistochemistry detected SAA was in close proximity to airway epithelium, and in vitro SAA triggered release of IL-8 and other proinflammatory mediators by airway epithelial cells in an ALX/FPR2 (formyl peptide receptor 2) receptor dependent manner. Lipoxin A(4) (LXA(4)) can also interact with ALX/FPR2 receptors and lead to allosteric inhibition of SAA-initiated epithelial responses (pA(2) 13 nM). During acute exacerbation, peripheral blood SAA levels increased dramatically and were disproportionately increased relative to LXA(4). Human lung macrophages (CD68(+)) colocalized with SAA and GCs markedly increased SAA in vitro (THP-1, pEC(50) 43 nM). To determine its direct actions, SAA was administered into murine lung, leading to induction of CXC chemokine ligand 1/2 and a neutrophilic response that was inhibited by 15-epi-LXA(4) but not dexamethasone. Taken together, these findings identify SAA as a therapeutic target for inhibition and implicate SAA as a mediator of GC-resistant lung inflammation that can overwhelm organ protective signaling by lipoxins at ALX/FPR2 receptors. PMID- 22215600 TI - Lysine methyltransferase G9a methylates the transcription factor MyoD and regulates skeletal muscle differentiation. AB - Skeletal muscle cells have served as a paradigm for understanding mechanisms leading to cellular differentiation. The proliferation and differentiation of muscle precursor cells require the concerted activity of myogenic regulatory factors including MyoD. In addition, chromatin modifiers mediate dynamic modifications of histone tails that are vital to reprogramming cells toward terminal differentiation. Here, we provide evidence for a unique dimension to epigenetic regulation of skeletal myogenesis. We demonstrate that the lysine methyltransferase G9a is dynamically expressed in myoblasts and impedes differentiation in a methyltransferase activity-dependent manner. In addition to mediating histone H3 lysine-9 di-methylation (H3K9me2) on MyoD target promoters, endogenous G9a interacts with MyoD in precursor cells and directly methylates it at lysine 104 (K104) to constrain its transcriptional activity. Mutation of K104 renders MyoD refractory to inhibition by G9a and enhances its myogenic activity. Interestingly, MyoD methylation is critical for G9a-mediated inhibition of myogenesis. These findings provide evidence of an unanticipated role for methyltransferases in cellular differentiation states by direct posttranslational modification of a transcription factor. PMID- 22215601 TI - Attenuation of extrinsic signaling reveals the importance of matrix remodeling on maintenance of embryonic stem cell self-renewal. AB - The role of extrinsic factors in maintaining self-renewal of embryonic stem cells (ESCs) has been extensively studied since the cells' isolation, but the necessity for cell-secreted factors in self-renewal has remained undefined to date. Although it is generally accepted that addition of leukemia inhibitory factor (LIF) together with either serum or bone morphogenetic protein 4 (BMP4) is sufficient to maintain mouse ESCs (mESCs) in a self-renewing state, this does not preclude the possibility that autocrine factors are also required. Here we make use of a microfluidic perfusion device that is able to globally diminish diffusible autocrine signaling by applying continuous media flow to deplete cell secreted factors. We demonstrate mESC culture for several days under continuous microfluidic perfusion and show that cell-secreted factors are removed and can be recovered downstream. We find that perturbing cell-secreted signaling causes mESCs to exit their stable self-renewing state in defined conditions that normally support self-renewal and to exhibit properties characteristic of epiblast cells. This state change is not due to the presence of the known autocrine differentiation inducer fibroblast growth factor 4, but, remarkably, it can be prevented by global remodeling of the extracellular matrix (ECM). We also find that cell-secreted matrix remodeling proteins are removed under perfusion and that inhibition of extracellular matrix remodeling causes mESCs to differentiate. Taken together, our data indicate that LIF and BMP4 are not sufficient to maintain self-renewal and that cell-secreted factors are necessary to continuously remodel the ECM and thereby prevent differentiation, revealing a previously undescribed level of mESC regulation through the use of microfluidic perfusion technology. PMID- 22215602 TI - Proapoptotic protein Bim is differentially required during thymic clonal deletion to ubiquitous versus tissue-restricted antigens. AB - Positive and negative selection of thymocytes in the thymus are critical for the development of a mature and self-tolerant T-cell repertoire. The proapoptotic Bcl 2 family member Bim is important for negative selection by inducing apoptosis in thymocytes receiving a strong signal through their antigen receptor. However, in the case of ubiquitous self-antigens (UbA), Bim is not required for the clonal deletion of self-reactive thymocytes, suggesting the existence of nonapoptotic clonal deletion mechanisms. Unlike UbA, clonal deletion to tissue-restricted antigens (TRAs) requires positive selection and CCR7-mediated migration to the medulla. This led us to hypothesize that Bim is required for the latter. To study the role of Bim in clonal deletion to TRA, we constructed bone marrow (BM) chimeras using OT-I Bim-deficient or -sufficient donor bone marrow and recipients that express membrane bound chicken ovalbumin under control of the rat insulin promoter (Rip-mOVA). We found that clonal deletion to TRA was completely abrogated in the absence of Bim and large numbers of mature OT-I CD8 T cells survived in the periphery. Despite the large numbers of autoreactive T cells, the chimeras did not develop diabetes and OT-I Bim-deficient T cells from these chimeras were functionally impaired. Collectively, these data provide unique evidence of a differential, thymocyte-intrinsic, molecular requirement downstream of the T-cell receptor (TCR) for clonal deletion to UbA versus TRA and highlight the profound ability of other tolerance mechanisms to control T-cell autoreactivity in the absence of thymic clonal deletion. PMID- 22215603 TI - Novelty exposure overcomes foot shock-induced spatial-memory impairment by processes of synaptic-tagging in rats. AB - Novelty processing can transform short-term into long-term memory. We propose that this memory-reinforcing effect of novelty could be explained by mechanisms outlined in the "synaptic tagging hypothesis." Initial short-term memory is sustained by a transient plasticity change at activated synapses and sets synaptic tags. These tags are later able to capture and process the plasticity related proteins (PRPs), which are required to transform a short-term synaptic change into a long-term one. Novelty is involved in inducing the synthesis of PRPs [Moncada D, et al. (2011) Proc Natl Acad Sci USA 108:12937-12936], which are then captured by the tagged synapses, consolidating memory. In contrast to novelty, stress can impair learning, memory, and synaptic plasticity. Here, we address questions as to whether novelty-induced PRPs are able to prevent the loss of memory caused by stress and if the latter would not interact with the tag setting process. We used water-maze (WM) training as a spatial learning paradigm to test our hypothesis. Stress was induced by a strong foot shock (FS; 5 * 1 mA, 2 s) applied 5 min after WM training. Our data show that FS reduced long-term but not short-term memory in the WM paradigm. This negative effect on memory consolidation was time- and training-dependent. Interestingly, novelty exposure prevented the stress-induced memory loss of the spatial task and increased BDNF and Arc expression. This rescuing effect was blocked by anisomycin, suggesting that WM-tagged synapses were not reset by FS and were thus able to capture the novelty-induced PRPs, re-establishing FS-impaired long-term memory. PMID- 22215604 TI - The spread of a transposon insertion in Rec8 is associated with obligate asexuality in Daphnia. AB - Although transitions from sexual to asexual reproduction are thought to have important evolutionary consequences, little is known about the mechanistic underpinnings of these changes. The cyclical parthenogen Daphnia pulex is a powerful model in which to address these issues because female-limited meiosis suppression can be transmitted to sexual individuals via males, providing the opportunity for genetic dissection of the trait. A previous study identified genomic regions differentiating obligately asexual females from their sexual counterparts, and a candidate gene within one such region, encoding the meiotic cohesin Rec8, is the subject of this investigation. The D. pulex genome contains three Rec8 loci, all of which are quite polymorphic. However, at one of the loci, all obligately asexual clones carry an allele containing an identical upstream insertion of a transposable element as well as a frameshift mutation, both of which are completely absent from sexual lineages. The low level of variation within the insertion allele across all asexual lineages suggests that this element may be in the process of spreading through the species, and abrogation or modification of Rec8 function is possibly responsible for converting meiotically reproducing lineages into obligate asexuals. PMID- 22215605 TI - Large-scale, spatially-explicit test of the refuge strategy for delaying insecticide resistance. AB - The refuge strategy is used worldwide to delay the evolution of pest resistance to insecticides that are either sprayed or produced by transgenic Bacillus thuringiensis (Bt) crops. This strategy is based on the idea that refuges of host plants where pests are not exposed to an insecticide promote survival of susceptible pests. Despite widespread adoption of this approach, large-scale tests of the refuge strategy have been problematic. Here we tested the refuge strategy with 8 y of data on refuges and resistance to the insecticide pyriproxyfen in 84 populations of the sweetpotato whitefly (Bemisia tabaci) from cotton fields in central Arizona. We found that spatial variation in resistance to pyriproxyfen within each year was not affected by refuges of melons or alfalfa near cotton fields. However, resistance was negatively associated with the area of cotton refuges and positively associated with the area of cotton treated with pyriproxyfen. A statistical model based on the first 4 y of data, incorporating the spatial distribution of cotton treated and not treated with pyriproxyfen, adequately predicted the spatial variation in resistance observed in the last 4 y of the study, confirming that cotton refuges delayed resistance and treated cotton fields accelerated resistance. By providing a systematic assessment of the effectiveness of refuges and the scale of their effects, the spatially explicit approach applied here could be useful for testing and improving the refuge strategy in other crop-pest systems. PMID- 22215606 TI - Hypothesis: cyclical histogenesis is the basis of circannual timing. AB - Circannual rhythms are innately timed long-term (tau ~ 12 months) cycles of physiology and behavior, crucial for life in habitats ranging from the equator to the Poles. Here the authors propose that circannual rhythm generation depends on tissue-autonomous, reiterated cycles of cell division, functional differentiation, and cell death. They see the feedback control influencing localized stem cell niches as crucial to this cyclical histogenesis hypothesis. Analogous to multi-oscillator circadian organization, circannual rhythm generation occurs in multiple tissues with hypothalamic and pituitary sites serving as central pacemakers. Signals including day length, nutrition, and social factors can synchronize circannual rhythms through hormonal influences, notably via the thyroid and glucocorticoid axes, which have profound effects on histogenesis. The authors offer 4 arguments in support of this hypothesis: (1) Cyclical histogenesis is a prevalent process in seasonal remodeling of physiology. It operates over long time domains and exhibits tissue autonomy in its regulation. (2) Experiments in which selected peripheral endocrine signals are held constant indicate that circannual rhythms are not primarily the product of interacting hormonal feedback loops. (3) Hormones known to control cell proliferation, differentiation, and organogenesis profoundly affect circannual rhythm expression. (4) The convergence point between photoperiodic input pathways and circannual rhythm expression occurs in histogenic regions of the hypothalamus and pituitary. In this review, the authors discuss how testing this hypothesis will depend on the use of cellular/molecular tools and animal models borrowed from developmental biology and neural stem cell research. PMID- 22215607 TI - Seasonal changes in cell proliferation in the adult sheep brain and pars tuberalis. AB - To adapt to seasonal variations in the environment, most mammalian species exhibit seasonal cycles in their physiology and behavior. Seasonal plasticity in the structure and function of the central nervous system contributes to the adaptation of this physiology in seasonal mammals. As part of these plasticity mechanisms, seasonal variations in proliferation rate and neuron production have been extensively studied in songbirds. In this report, we investigated whether this type of brain plasticity also occurs in sheep, a seasonal species, by assessing variations in cell proliferation in the sheep diencephalon. We administered the cell birth marker 5'-bromodeoxyuridine (BrdU) to adult female sheep in July and December, during long and short photoperiod, respectively. The BrdU incorporation was analyzed and quantified in the hypothalamus, a key center for neuroendocrine regulations, as well as in other structures involved in relaying neuroendocrine and sensory information, including the median eminence, the pars tuberalis of the pituitary gland, and the thalamus. In December, 2-fold and 6-fold increases in the number of BrdU+ nuclei were observed in the hypothalamus and thalamus, respectively, when compared with July. This variation is independent of the influence of peripheral gonadal estradiol variations. An inverse seasonal regulation of cell proliferation was observed in the pars tuberalis. In contrast, no seasonal variation in cell proliferation was seen in the subventricular zone of the lateral ventricle. Many of the newborn cells in the adult ovine hypothalamus and thalamus differentiate into neurons and glial cells, as assessed by the expression of neuronal (DCX, NeuN) and glial (GFAP, S100B) fate markers. In summary, we show that the estimated cell proliferation rates in the sheep hypothalamus, thalamus, and pars tuberalis are different between seasons. These variations are independent of the seasonal fluctuations of peripheral estradiol levels, unlike the results described in the brain nuclei involved in song control of avian species. PMID- 22215608 TI - The circadian clock, light, and cryptochrome regulate feeding and metabolism in Drosophila. AB - Recent studies in mammals have demonstrated a central role for the circadian clock in maintaining metabolic homeostasis. In spite of these advances, however, little is known about how these complex pathways are coordinated. Here, we show that fundamental aspects of the circadian control of metabolism are conserved in the fruit fly Drosophila. We assay feeding behavior and basic metabolite levels in individual flies and show that, like mammals, Drosophila display a rapid increase in circulating sugar following a meal, which is subsequently stored in the form of glycogen. These daily rhythms in carbohydrate levels are disrupted in clock mutants, demonstrating a critical role for the circadian clock in the postprandial response to feeding. We also show that basic metabolite levels are coordinated in a clock-dependent manner and that clock function is required to maintain lipid homeostasis. By examining feeding behavior, we show that flies feed primarily during the first 4 hours of the day and that light suppresses a late day feeding bout through the cryptochrome photoreceptor. These studies demonstrate that central aspects of feeding and metabolism are dependent on the circadian clock in Drosophila. Our work also uncovers novel roles for light and cryptochrome on both feeding behavior and metabolism. PMID- 22215609 TI - Light affects the branching pattern of peptidergic circadian pacemaker neurons in the brain of the cockroach Leucophaea maderae. AB - Pigment-dispersing factor-immunoreactive neurons anterior to the accessory medulla (aPDFMes) in the optic lobes of insects are circadian pacemaker neurons in cockroaches and fruit flies. The authors examined whether any of the aPDFMes of the cockroach Leucophaea maderae are sensitive to changes in period and photoperiod of light/dark (LD) cycles as a prerequisite to adapt to changes in external rhythms. Cockroaches were raised in LD cycles of 11:11, 13:13, 12:12, 6:18, or 18:6 h, and the brains of the adults were examined with immunocytochemistry employing antisera against PDF and orcokinin. Indeed, in 11:11 LD cycles, only the number of medium-sized aPDFMes specifically decreased, while it increased in 13:13. In addition, 18:6 LD cycles increased the number of large- and medium-sized aPDFMes, as well as the posterior pPDFMes, while 6:18 LD cycles only decreased the number of medium-sized aPDFMes. Furthermore, PDF immunoreactive fibers in the anterior optic commissure and orcokinin immunoreactive fibers in both the anterior and posterior optic commissures were affected by different lengths of light cycles. Thus, apparently different groups of the PDFMes, most of all the medium-sized aPDFMes, which colocalize orcokinin, respond to changes in period and photoperiod and could possibly allow for the adjustment to different photoperiods. PMID- 22215610 TI - Functional conservation of clock output signaling between flies and intertidal crabs. AB - Intertidal species have both circadian and circatidal clocks. Although the behavioral evidence for these oscillators is more than 5 decades old, virtually nothing is known about their molecular clockwork. Pigment-dispersing hormones (PDHs) were originally described in crustaceans. Their insect homologs, pigment dispersing factors (PDFs), have a prominent role as clock output and synchronizing signals released from clock neurons. We show that gene duplication in crabs has led to two PDH genes (beta-pdh-I and beta-pdh-II). Phylogenetically, beta-pdh-I is more closely related to insect pdf than to beta-pdh-II, and we hypothesized that beta-PDH-I may represent a canonical clock output signal. Accordingly, beta-PDH-I expression in the brain of the intertidal crab Cancer productus is similar to that of PDF in Drosophila melanogaster, and neurons that express PDH-I also show CYCLE-like immunoreactivity. Using D. melanogaster pdf null mutants (pdf(01)) as a heterologous system, we show that beta-pdh-I is indistinguishable from pdf in its ability to rescue the mutant arrhythmic phenotype, but beta-pdh-II fails to restore the wild-type phenotype. Application of the three peptides to explanted brains shows that PDF and beta-PDH-I are equally effective in inducing the signal transduction cascade of the PDF receptor, but beta-PDH-II fails to induce a normal cascade. Our results represent the first functional characterization of a putative molecular clock output in an intertidal species and may provide a critical step towards the characterization of molecular components of biological clocks in intertidal organisms. PMID- 22215611 TI - Genetic interaction of Per1 and Dec1/2 in the regulation of circadian locomotor activity. AB - In mammals, 24-h rhythms are controlled by a hierarchical system of endogenous clocks, with a circadian pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus that synchronizes peripheral oscillators throughout the body. The molecular clock machinery is regulated by interlocked transcriptional translational feedback loops (TTLs). The core TTL includes the transcriptional modulators PER (1-3) and CRY (1/2) that feed back on their own expression by interaction with CLOCK/BMAL1. An accessory loop involving the transcription factors DEC1 and DEC2 has been described that also impinges on CLOCK/BMAL1 mediated transactivation. In Drosophila, the DEC ortholog CWO shows synergistic activity to PER. This prompted the authors to analyze PER1-DEC interaction in the mammalian SCN. They generated Per1/Dec double and triple mutant mice to monitor activity rhythms under entrained and free-running conditions. Furthermore, they analyzed expression of the clock genes Per2, Rev-Erbalpha, and Bmal1 in wild-type and Per1/Dec mutant SCN by in situ hybridization. The experiments reveal a critical role for Per1-Dec interaction in regulating activity phase under entrained conditions. In constant darkness, a synergistic function for Per1 and Dec1/2 in period regulation was found, correlating with disrupted clock gene mRNA levels in the SCN. Luciferase reporter gene assays indicate an activatory function of DECs on Bmal1 expression. Together, the results suggest a partially redundant and bidirectional regulatory function for the 2 Dec genes in the TTL and a conservation of Per-Dec (Cwo) synergism between vertebrate and invertebrate clocks. PMID- 22215612 TI - Valproic acid phase shifts the rhythmic expression of Period2::Luciferase. AB - Valproic acid (VPA) is an anticonvulsant used to treat bipolar disorder, a psychiatric disease associated with disturbances in circadian rhythmicity. Little is known about how VPA affects circadian rhythms. The authors cultured tissues containing the master brain pacemaker for circadian rhythmicity, the suprachiasmatic nuclei (SCN), and skin fibroblasts from transgenic PERIOD2::LUCIFERASE (PER2::LUC) mice and studied the effect of VPA on the circadian PER2::LUC rhythm by measuring bioluminescence. VPA (1 mM) significantly phase advanced the PER2::LUC rhythm when applied at a time point corresponding to the lowest (trough, ~ZT 0) PER2::LUC expression but phase delayed the PER2::LUC rhythm when the drug was administered at the time of highest (peak, ~ZT 12) protein expression. In addition, it significantly increased the overall amplitude of PER2::LUC oscillations at time points at or close to ZT 12 but had no effect on period. Real-time PCR analyses on mouse and human fibroblasts revealed that expressions of other clock genes were increased after 2 h treatment with VPA. Because VPA is known to inhibit histone deacetylation, the authors treated cultures with an established histone deacetylation inhibitor, trichostatin A (TSA; 20 ng/mL), to compare the effect of VPA and TSA on molecular rhythmicity. They found that TSA had similar effects on the PER2::LUC rhythm as VPA. Furthermore, VPA and TSA significantly increased acetylation on histone H3 but in comparison little on histone H4. Lithium is another commonly used treatment for bipolar disorder. Therefore, the authors also studied the impact of lithium chloride (LiCl; 10 mM) on the PER2::LUC rhythm. LiCl delayed the phase, but in contrast to VPA and TSA, LiCl lengthened the PER2::LUC period and had no effect on histone acetylation. These results demonstrate that VPA can delay or advance the phase, as well as increase the amplitude, of the PERIOD2::LUCIFERASE rhythm depending on the circadian time of application. Furthermore, the authors show that LiCl delays the phase and lengthens the period of the PER2::LUC rhythm, confirming previous reports on circadian lithium effects. These different molecular effects may underlie differential chronotherapeutic effects of VPA and lithium. PMID- 22215613 TI - Daily rhythms in olfactory discrimination depend on clock genes but not the suprachiasmatic nucleus. AB - The suprachiasmatic nucleus (SCN) regulates a wide range of daily behaviors and has been described as the master circadian pacemaker. The role of daily rhythmicity in other tissues, however, is unknown. We hypothesized that circadian changes in olfactory discrimination depend on a genetic circadian oscillator outside the SCN. We developed an automated assay to monitor olfactory discrimination in individual mice throughout the day. We found olfactory sensitivity increased approximately 6-fold from a minimum during the day to a peak in the early night. This circadian rhythm was maintained in SCN-lesioned mice and mice deficient for the Npas2 gene but was lost in mice lacking Bmal1 or both Per1 and Per2 genes. We conclude that daily rhythms in olfactory sensitivity depend on the expression of canonical clock genes. Olfaction is, thus, the first circadian behavior that is not based on locomotor activity and does not require the SCN. PMID- 22215615 TI - Promoting patient-centred care through trainee feedback: assessing residents' C-I CARE (ARC) program. AB - AIMS: In recent years, patient satisfaction has been integrated into residency training practices through core competency requirements as set forth by the Accreditation Council of Graduate Medical Education (ACGME). In 2006, the UCLA Health Systems established a program designed to obtain patient feedback and assess the communication abilities of resident physicians with a standard tool through the Assessing Residents' C-I-CARE (ARC) Program. METHODS: This Program utilized a 17-item questionnaire, completed via a facilitator-administered interview, which employed polar, Likert and comment scale questions to assess physician trainees' interpersonal and communication skills. RESULTS: From 2006 to 2010, the ARC Program provided patient feedback data to more than six clinical departments while collecting 5,634 surveys for 323 trainees. Scores for resident recognition and performance increased from the first to second year of activity by an average of 22.5%, while attending recognition scores decreased 19% over the four years. Additionally, residents and attendings in surgical specialties received higher recognition rates than those in non-surgical specialties. CONCLUSIONS: The ARC Program provided a standard tool for attaining patient feedback through a facilitator-administered survey that assisted in the accreditation process of training programs. Furthermore, hospitals, health organizations and medical schools may find the ARC Program valuable in collecting information for quality control as well as providing an opportunity for students to become involved in the healthcare field. PMID- 22215614 TI - The acetyltransferase Clock is dispensable for circadian aftereffects in mice. AB - Recent demonstration of the histone acetyltransferase activity of the Clock gene greatly expanded the regulatory role of circadian clocks in gene transcription. Clock and its partner Bmal1 are responsible for the generation of circadian oscillations that are synchronized (entrained) to the external light cycle. Entraining light often produces long-lasting changes in the endogenous period called aftereffects. Aftereffects are light-dependent alterations in the speed of free-running rhythms that persist for several weeks upon termination of light exposure. How light causes such long-lasting changes is unknown. However, the persistent nature of circadian aftereffects in conjunction with the long-term effects of epigenetic modifications on development and various aspects of brain physiology prompted us to hypothesize that the histone acetyltransferase CLOCK was required for circadian aftereffects. The authors exposed Clock knockout mice to 25-hour light cycles and report that these mice retain the ability to display circadian aftereffects, indicating that Clock is dispensable for this form of circadian plasticity. PMID- 22215616 TI - Angiotensin II induces epithelial-to-mesenchymal transition in renal epithelial cells through reactive oxygen species/Src/caveolin-mediated activation of an epidermal growth factor receptor-extracellular signal-regulated kinase signaling pathway. AB - Chronic activation of the renin-angiotensin system plays a deleterious role in progressive kidney damage, and the renal proximal tubule is known to play an important role in tubulointerstitial fibrosis; however, the underlying molecular mechanism is unclear. Here we report that in the proximal tubule-like LLCPKcl4 cells expressing angiotensin II (Ang II) type 1 receptor, Ang II induced changes in cell morphology and expression of epithelial-to-mesenchymal transition (EMT) markers, which were inhibited by the miotogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK)-activating kinase (MEK) inhibitor PD98059 or the Src kinase inhibitor PP2. Ang II-stimulated phosphorylation of caveolin-1 (Cav) at Y14 and epidermal growth factor receptor (EGFR) at Y845 and induced association of these phosphoproteins in caveolin enriched lipid rafts, thereby leading to prolonged EGFR-ERK signaling that was inhibited by Nox4 small interfering RNA (siRNA) and Src siRNA. Two different antioxidants not only inhibited phosphorylation of Src at Y416 but also blocked the EGFR-ERK signaling. Moreover, erlotinib (the EGFR tyrosine kinase inhibitor), EGFR siRNA, and Cav siRNA all inhibited both prolonged EGFR-ERK signaling and phenotypic changes induced by Ang II. Thus, this report provides the first evidence that reactive oxygen species (ROS)/Src-dependent activation of persistent Cav-EGFR-ERK signaling mediates renal tubular cell dedifferentiation and identifies a novel molecular mechanism that may be involved in progressive renal injury caused by chronic exposure to Ang II. PMID- 22215617 TI - New mutations at the imprinted Gnas cluster show gene dosage effects of Gsalpha in postnatal growth and implicate XLalphas in bone and fat metabolism but not in suckling. AB - The imprinted Gnas cluster is involved in obesity, energy metabolism, feeding behavior, and viability. Relative contribution of paternally expressed proteins XLalphas, XLN1, and ALEX or a double dose of maternally expressed Gsalpha to phenotype has not been established. In this study, we have generated two new mutants (Ex1A-T-CON and Ex1A-T) at the Gnas cluster. Paternal inheritance of Ex1A T-CON leads to loss of imprinting of Gsalpha, resulting in preweaning growth retardation followed by catch-up growth. Paternal inheritance of Ex1A-T leads to loss of imprinting of Gsalpha and loss of expression of XLalphas and XLN1. These mice have severe preweaning growth retardation and incomplete catch-up growth. They are fully viable probably because suckling is unimpaired, unlike mutants in which the expression of all the known paternally expressed Gnasxl proteins (XLalphas, XLN1 and ALEX) is compromised. We suggest that loss of ALEX is most likely responsible for the suckling defects previously observed. In adults, paternal inheritance of Ex1A-T results in an increased metabolic rate and reductions in fat mass, leptin, and bone mineral density attributable to loss of XLalphas. This is, to our knowledge, the first report describing a role for XLalphas in bone metabolism. We propose that XLalphas is involved in the regulation of bone and adipocyte metabolism. PMID- 22215618 TI - Novel roles of the chemorepellent axon guidance molecule RGMa in cell migration and adhesion. AB - The repulsive guidance molecule A (RGMa) is a contact-mediated axon guidance molecule that has significant roles in central nervous system (CNS) development. Here we have examined whether RGMa has novel roles in cell migration and cell adhesion outside the nervous system. RGMa was found to stimulate cell migration from Xenopus animal cap explants in a neogenin-dependent and BMP-independent manner. RGMa also stimulated the adhesion of Xenopus animal cap cells, and this adhesion was dependent on neogenin and independent of calcium. To begin to functionally characterize the role of specific domains in RGMa, we assessed the migratory and adhesive activities of deletion mutants. RGMa lacking the partial von Willebrand factor type D (vWF) domain preferentially perturbed cell adhesion, while mutants lacking the RGD motif affected cell migration. We also revealed that manipulating the levels of RGMa in vivo caused major migration defects during Xenopus gastrulation. We have revealed here novel roles of RGMa in cell migration and adhesion and demonstrated that perturbations to the homeostasis of RGMa expression can severely disrupt major morphogenetic events. These results have implications for understanding the role of RGMa in both health and disease. PMID- 22215620 TI - Heat shock transcription factor Hsf1 is involved in tumor progression via regulation of hypoxia-inducible factor 1 and RNA-binding protein HuR. AB - Previously we demonstrated that the heat shock transcription factor Hsf1 is indispensable for transformation of mammary epithelial cells by the Her2 oncogene. Since Hsf1 affects oncogene-induced senescence (OIS), these findings suggest that Hsf1 affects tumor initiation when OIS plays a role. Indeed, here we report that Hsf1 knockout suppressed mammary hyperplasia in Her2-expressing mice and reduced tumor emergence. On the other hand, Hsf1 expression increases with advanced breast cancer, indicating that there is an additional role of Hsf1 in tumor progression. We studied rare tumors that developed in Hsf1-knockout mice and found that these tumors grew slower than tumors in control animals and showed suppressed angiogenesis. Similarly, in the xenograft model, knockdown of Hsf1 suppressed angiogenesis, which was associated with suppression of the HIF-1 pathway. Suppression of HIF-1 was at the level of translation due to downregulation of the RNA-binding protein HuR. Importantly, besides HIF-1, HuR controls translation of other major regulators of cancer progression, many of which were suppressed in Hsf1-knockdown cells. Therefore, in addition to OIS, Hsf1 regulates the HuR-HIF-1 pathway, thus affecting both cancer initiation and progression. PMID- 22215619 TI - A novel feedback loop regulates the response to endoplasmic reticulum stress via the cooperation of cytoplasmic splicing and mRNA translation. AB - The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers transcriptional and translational reprogramming. This unfolded protein response (UPR) protects cells during transient stress and can lead to apoptosis during prolonged stress. Two key mediators of the UPR are PKR-like ER kinase (PERK), which phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha), resulting in decreased protein synthesis, and the alpha subunit of inositol-requiring enzyme 1 (IRE1alpha), which initiates cytoplasmic splicing of the mRNA encoding the transcription factor X-box binding protein 1 (XBP1). XBP1 induces transcription of genes involved in protein quality control. This report describes cross talk between these two pathways: phosphorylation of eIF2alpha was required for maximal induction of spliced XBP1 (XBP1s) protein levels via a mechanism that involved stabilization of XBP1s mRNA. By using mouse embryo fibroblasts deficient in UPR signaling pathways, we demonstrate that stress-induced stabilization of XBP1s mRNA requires cytoplasmic splicing of the mRNA and inhibition of its translation. Because the XBP1s protein promotes transcription of its own gene, the UPR-induced mRNA stabilization is part of a positive feedback loop that induces XBP1s protein accumulation and transcription of target genes during stress. We propose a model in which eIF2alpha phosphorylation-mediated control of mRNA turnover is a molecular switch that regulates the stress response transcription program and the ER's capacity for protein folding during stress. PMID- 22215621 TI - Epithelial to mesenchymal transition-like and mesenchymal to epithelial transition-like processes might be involved in the pathogenesis of pelvic endometriosis. AB - BACKGROUND: Endometrium is derived from intermediate mesoderm via mesenchymal to epithelial transition (MET) during development of the urogenital system. By retaining some imprint of their mesenchymal origin, endometrial epithelial cells may be particularly prone to return to this state, via epithelial to mesenchymal transition (EMT). We hypothesized that pelvic endometriosis originates from retrograde menstruation of endometrial tissue and that EMT-like and MET-like processes might be involved in the pathogenesis of pelvic endometriosis. METHODS: We investigated commonly used molecular markers for EMT, including cytokeratin, E cadherin, N-cadherin, vimentin, S100A4 and dephosphorylated beta-catenin by immunohistochemistry in different forms of pelvic endometriosis: deep infiltrating endometriosis, ovarian endometriosis and superficial peritoneal endometriosis (red and black lesions), as well as samples of menstrual endometrium, other benign ovarian cysts (mucinous and serous cyst adenoma), and abdominal scar endometriosis for comparison. RESULTS: Epithelial cells of red peritoneal lesions and ovarian endometriosis showed less epithelial marker (cytokeratin, P < 0.0001) expression and more mesenchymal marker (vimentin and/or S100A4, P < 0.0001) expression than those of menstrual endometrium. In contrast, epithelial cells of black peritoneal lesions and deep infiltrating endometriosis showed more epithelial marker (E-cadherin) expression than those of menstrual endometrium (P < 0.03), red peritoneal lesions (P < 0.0001) and ovarian endometriosis (P< 0.0001), but maintained expression of some mesenchymal markers (vimentin, S100A4). In addition, dephosphorylated beta-catenin protein expression was significantly higher in epithelial cells of deep infiltrating endometriosis (P < 0.0001) than in epithelial cells of red and black peritoneal lesions and ovarian endometriosis. CONCLUSIONS: EMT-like and MET-like processes might be involved in the pathogenesis of pelvic endometriosis. PMID- 22215623 TI - Glycoconjugates recognized by peanut agglutinin lectin in the inner acellular layer of the lamina propria of seminiferous tubules in human testes showing impaired spermatogenesis. AB - BACKGROUND: The aim of this study was to evaluate the histochemical characteristics of the thickened inner acellular layer (IL) of the lamina propria specifically present in the human seminiferous tubules of testes showing impaired spermatogenesis. METHODS: Eighteen biopsies for the investigation of infertility and 10 orchiectomies for testicular cancer and cryptorchidism were used. Lectin staining [peanut agglutinin (PNA), Maackia amurensis (MAA), Sambuccus nigra (SNA)], PNA lectin staining with sialidase digestion, immunohistochemistry and binding assay of progesterone were performed and analysed quantitatively. RESULTS: The IL of the thickened lamina propria of the seminiferous tubules in the testes showed PNA lectin affinity and binding affinity for progesterone. Both affinities of MAA and SNA were in the IL of only fairly thickened lamina propria. Furthermore, a positive correlation was present between the thickness of the lamina propria and the accumulation of glycoconjugates showing PNA lectin affinity (r = 0.829, P < 0.001) or progesterone (r = 0.629, P < 0.001) in the IL. However, ILs show no immunoreactivities of progesterone receptor, androgen receptor or human serum albumin. Progesterone inhibited the binding affinity of PNA lectin to the IL (P < 0.001), but not the affinity to the spermatogenic cells. In addition, sialidase digestion increased the PNA affinity not in the IL but in the spermatogenic cells (P < 0.001). CONCLUSIONS: These results indicate that the IL of the thickened lamina propria always consists of glycoconjugates with PNA lectin affinity and possible binding affinity to progesterone. In addition, the glycoconjugates in the IL may be predictors of abnormal spermatogenesis in the testes of infertile patients. PMID- 22215624 TI - Presence of DNA of adeno-associated virus in subfertile couples, but no association with fertility factors. AB - BACKGROUND: Based on previous reports suggesting a role of adeno-associated virus (AAV) in miscarriage, the prevalence of AAV DNA in genital tracts of male and female partners of subfertile couples was determined to assess a potential association of AAV infection with clinically relevant parameters of male and female fertility. METHODS: A prospective study was performed in the outpatient infertility clinic of a university-based hospital. Semen samples and endocervical material obtained from 146 male and 134 female partners of asymptomatic subfertile couples were analyzed for the presence of AAV DNA (using nested PCR). Patients' medical histories and details of clinical examinations were recorded. Semen quality, including sperm functional capacity and the presence of antisperm antibodies (ASA) and seminal white blood cells (WBC), was assessed in aliquots of the same ejaculate. Detailed examinations of the cervical factor and other variables of female subfertility were performed. Both partners were screened for bacterial infection. RESULTS: The presence of AAV DNA in semen was not significantly related to semen quality, including sperm functional capacity or local ASA, nor was it coupled to the presence of AAV in the endocervical material of female partners. The presence of AAV DNA was not associated with the presence of other micro-organisms of the lower genital tract or with seminal WBC in men. AAV DNA in endocervical material was not related to a reduced quality of cervical mucus or to other female infertility factors. CONCLUSIONS: The presence of AAV DNA in semen samples or endocervical swabs showed no significant association with clinically relevant infertility factors. However, longitudinal studies may clarify previous suggestions of an influence of AAV infection on early pregnancy problems. PMID- 22215622 TI - High throughput, cell type-specific analysis of key proteins in human endometrial biopsies of women from fertile and infertile couples. AB - BACKGROUND: Although histological dating of endometrial biopsies provides little help for prediction or diagnosis of infertility, analysis of individual endometrial proteins, proteomic profiling and transcriptome analysis have suggested several biomarkers with altered expression arising from intrinsic abnormalities, inadequate stimulation by or in response to gonadal steroids or altered function due to systemic disorders. The objective of this study was to delineate the developmental dynamics of potentially important proteins in the secretory phase of the menstrual cycle, utilizing a collection of endometrial biopsies from women of fertile (n = 89) and infertile (n = 89) couples. METHODS AND RESULTS: Progesterone receptor-B (PGR-B), leukemia inhibitory factor, glycodelin/progestagen-associated endometrial protein (PAEP), homeobox A10, heparin-binding EGF-like growth factor, calcitonin and chemokine ligand 14 (CXCL14) were measured using a high-throughput, quantitative immunohistochemical method. Significant cyclic and tissue-specific regulation was documented for each protein, as well as their dysregulation in women of infertile couples. Infertile patients demonstrated a delay early in the secretory phase in the decline of PGR B (P < 0.05) and premature mid-secretory increases in PAEP (P < 0.05) and CXCL14 (P < 0.05), suggesting that the implantation interval could be closing early. Correlation analysis identified potential interactions among certain proteins that were disrupted by infertility. CONCLUSIONS: This approach overcomes the limitations of a small sample number. Protein expression and localization provided important insights into the potential roles of these proteins in normal and pathological development of the endometrium that is not attainable from transcriptome analysis, establishing a basis for biomarker, diagnostic and targeted drug development for women with infertility. PMID- 22215625 TI - Psychological adjustment and psychosocial stress among Japanese couples with a history of recurrent pregnancy loss. AB - BACKGROUND: Little is known about the effects of recurrent pregnancy loss (RPL) on the psychological adjustment of couples. The aim of this study was to elucidate psychological adjustment and RPL-associated psychosocial stress affecting Japanese couples with a history of RPL, focusing on gender differences and quality of the marital relationship. METHODS: The study included 76 RPL couples who visited the outpatient clinic of a tertiary hospital. They completed self-administered questionnaires that assessed RPL-associated stress, quality of their marital relationship (Quality Marriage Index, QMI), depression (Beck Depression Index) and anxiety (State-Trait Anxiety Inventory). RESULTS: Women showed significantly higher levels of depression, anxiety and RPL-associated personal and social stress compared with men. Although there were no differences in QMI scores and RPL-associated marital stress between men and women, women with a low perception of marital relationship quality (low QMI) had significantly higher levels of depression and anxiety compared with women with a moderate or high QMI. In contrast, depression and anxiety scores did not differ according to the quality of the marital relationship among men. Of 76 couples, 26 men (34%) and 45 women (59%) who had considered professional mental health consultations regarding their RPL status but had not yet initiated the process were more depressed and anxious than 48 men and 24 women, respectively, who had never considered such consultation. CONCLUSIONS: Women were significantly more distressed than men. Poor quality of the marital relationship was significantly associated with impaired psychological adjustment among women, but not among men. These gender discrepancies may foster a mutual worsening of psychological adjustment and marital relationships in RPL couples. The need to seek help not only in women but also in a substantial portion of men suggests the importance of couple-based psychological care in the management of RPL. PMID- 22215626 TI - Oral tadalafil reduces intra-abdominal adhesion reformation in rats. AB - BACKGROUND: Currently, there is no ideal agent to prevent adhesion formation. We have shown that sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, reduces post operative adhesion formation by vasodilatation and increases fibrinolytic activity. Here, we evaluated whether tadalafil, a long-acting PDE-5 inhibitor, decreases post-operative adhesion reformation in rats. MATERIALS AND METHODS: Standardized lesions were created in Wistar albino rats by cauterization of uterine horns and abrasion of adjacent peritonium. The extent and severity of adhesions were scored on the 14th post-operative day and adhesiolysis was performed at the second laparotomy. Animals were then assigned randomly into two groups. The study group (n = 11) received 10 mg/kg oral tadalafil by gavage 60 min before the second laparotomy and daily for 14 days afterwards. Controls (n = 11) received the same volume of tap water for 14 days by gavage. Animals were killed 15 days after adhesiolysis and adhesions were scored blind during the third laparotomy. RESULTS Basal adhesion scores at the time of the second laparotomy were comparable in the study and control groups. Scores for the extent of adhesion reformation in the study and control groups did not differ [median 1 (range 0-3) versus median 2 (range 1-3); P: 0.81] but tadalafil reduced the respective severity scores [median 0.5 (range 0-1) versus median 1 (range 0.5-1); P: 0.02] and total scores [median 2 (range 0-4) versus median 2.5 (range 1.5-4); P: 0.042]. CONCLUSIONS: Oral administration of tadalafil during the perioperative period reduces intra-abdominal adhesion reformation in rats. PMID- 22215627 TI - Individual serum levels of anti-Mullerian hormone in healthy girls persist through childhood and adolescence: a longitudinal cohort study. AB - BACKGROUND: In adult women, the circulating level of anti-Mullerian hormone (AMH) is a novel marker of ovarian function, as it reflects the number of remaining ovarian follicles. Therefore, AMH has gained widespread attention in fertility clinics, and a low AMH is believed to predict impaired fertility and imminent menopause. However, the natural course of circulating AMH levels during female childhood and adolescence is not known. METHODS: Serum levels of AMH and FSH were measured in girls participating in The COPENHAGEN Puberty Study. Longitudinal part: 85 healthy girls and adolescents were examined, and blood samples were drawn every 6 months for an average of 3 years: median (range) number of samples per girl was 6 (2-10), age at baseline was 9.2 (5.9-12.9) years. Cross-sectional part: 224 prepubertal girls (age 8.3, 5.6-11.7 years) were examined and each girl had one blood sample drawn. RESULTS: The individual mean AMH levels in girls followed longitudinally ranged from 5 to 54 pmol/l (median 18 pmol/l). The mean intra-individual coefficient of variation of AMH was 22% (range 0-54%). Overall, each girl maintained her AMH level throughout childhood and adolescence although minor, but significant, changes occurred during pubertal transition. In prepubertal girls, AMH was negatively correlated with FSH (r = -0.31, P < 0.001). Twelve per cent (10/85) had mean AMH below a cut-off value of 8 pmol/l, indicating that the interpretation of low AMH as a marker of approaching menopause may not apply to pre- and peri-pubertal girls. CONCLUSIONS: Circulating AMH exhibits only minor fluctuations during childhood and adolescence, and a random AMH measurement seems representative for a given girl. The negative AMH FSH correlation in prepubertal girls supports the notion that AMH is a quantitative marker of ovarian follicles even in young girls. PMID- 22215628 TI - Expression pattern of osteopontin and alphavbeta3 integrin during the implantation window in infertile patients with early stages of endometriosis. AB - BACKGROUND: To study endometrial receptivity in terms of osteopontin (OPN) and alphavbeta3 integrin expression and co-expression in infertile women with early stages of endometriosis. METHODS: We investigated the immunohistochemical expression and co-expression of OPN and alphavbeta3 integrin in the endometrium of 20 infertile patients with Stage I or II endometriosis as the only detectable cause of infertility, 20 infertile patients with unexplained infertility and 20 fertile women undergoing tubal sterilization. Two endometrial biopsies were performed during a single menstrual cycle (postovulatory Day +7 to +8 and 4 days later) in each subject. RESULTS: No statistically significant differences regarding OPN and alphavbeta3 integrin expression were found between infertile patients with endometriosis and the two control groups. There was no significant correlation between OPN and alphavbeta3 integrin staining intensity in the mid luteal phase biopsies in any of the groups studied. CONCLUSIONS: Endometrial OPN and alphavbeta3 integrin expression or co-expression is not impaired during the window of implantation in patients with Stage I-II endometriosis. Further studies are needed to determine whether these results imply normal endometrial receptivity in such patients or add to the increasing uncertainty about the clinical value of assessing the endometrium with these markers of implantation. PMID- 22215629 TI - Mitochondrial haplotype does not influence sperm motility in a UK population of men. AB - BACKGROUND: Sperm motility is regulated by mitochondrial enzymes that are partially encoded by mitochondrial DNA (mtDNA). MtDNA has therefore been suggested as a putative genetic marker of male fertility. However, recent studies in different populations have identified both significant and non-significant associations between mtDNA variation and sperm motility. Here, we tested whether mtDNA variation was associated with sperm motility in a large cohort of men from the UK, to test the robustness of previous studies and the reliability of mtDNA as a marker of poor sperm motility. METHODS: A total of 463 men attending for semen analysis as part of infertility investigations were recruited from a UK laboratory. Sperm motility was measured using both computer-assisted sperm analysis and traditional manual measurements. MtDNA haplogroup and haplotype were determined in 357 and 298 men, respectively, using single nucleotide polymorphism (SNP) markers throughout the mtDNA genome, and compared with sperm motility data. The linkage between the SNP markers, and possible associations between individual SNPs and motility, were also investigated. RESULTS: We found no statistical association between haplogroup or haplotype and sperm motility, regardless of how it was measured (P > 0.05 in all cases). Moreover, individual SNPs which were in linkage disequilibrium and dispersed across the mitochondrial genome, and therefore sensitive to mtDNA variation, were not predictive of sperm motility. CONCLUSIONS: Mitochondrial haplotype is unlikely to be a reliable genetic marker of male factor infertility. PMID- 22215630 TI - Influence of prenatal organohalogen levels on infant male sexual development: sex hormone levels, testes volume and penile length. AB - BACKGROUND: Prenatal exposure to endocrine disruptors, like organohalogen compounds (OHCs), might be responsible for the increased aberrations in human male sexual development (hypospadias, cryptorchidism, testicular cancer and fall in sperm count) observed over the past decades. This development is established during fetal life, and reflected in sex hormone levels, testes volume and penile length post-partum. The present study investigates the correlation between prenatal OHC levels and male sexual development outcomes. METHODS AND RESULTS: Levels of eight neutral [2,2'-bis-(4-chlorophenyl)-1,1'-dichloroethene (4,4' DDE), 2,2',4,4',5,5'-hexachlorobiphenyl, 2,2',4,4'-tetrabromodiphenyl ether (BDE) 47, -99, -100, -153, -154 and 1,2,5,6,9,10-hexabromocyclododecane, HBCDD] and four phenolic [(pentachlorophenol (PCP), 4OH-CB-107 (4-hydroxy-2,3,3',4',5 pentachlorobiphenyl), -146 and -187)] OHCs were determined in 55 maternal serum samples taken at 35 weeks of pregnancy. Eight sex development-related hormones [testosterone, free testosterone, sex hormone-binding globulin (SHBG); LH, FSH, estradiol (E(2)), free E(2) (FE(2)) and inhibin B (InhB)] were determined in their sons at 3 months of age, and testes volume and penile length at 3 and 18 months of age. The following prenatal OHC levels correlated significantly with sex hormone levels: PCP with SHBG and InhB (rho = 0.30 and -0.43, respectively), 4OH-CB-107 with testosterone (rho = 0.31) and BDE-154 with FE(2), E(2) and InhB (rho = 0.49, 0.54 and 0.34, respectively). BDE-154 levels correlated positively with testes volume at 18 months of age (rho = 0.34). CONCLUSIONS: Prenatal OHC exposure is correlated with aspects of sexual development outcome in boys up to 18 months of age. PMID- 22215631 TI - Similarly increased congenital anomaly rates after intrauterine insemination and IVF technologies: a retrospective cohort study. AB - BACKGROUND: While intrauterine insemination (IUI), a simple, inexpensive and non invasive technique, is the most used assisted reproduction technology (ART) worldwide, the risk of major birth defects following IUI is paradoxically not well documented. METHODS: Retrospective cohort study performed in Burgundy, France, over a 9-year period which consisted of the cross analysis of two prospective databases, the Burgundy perinatal network database and the database of the assisted conception units in Burgundy. A total of 1348 ART singletons [in vitro fertilization technologies (IVFT): n= 903; IUI: n= 445] matched with 4044 infants conceived naturally, 552 ART twins (IVFT: n= 362; IUI: n= 190) matched with 1656 twins who were conceived naturally. The major birth defects were categorized according to the European Surveillance of Congenital Anomalies classification EUROCAT. RESULTS: Compared with naturally conceived singletons, singletons born after IUI and IVFT had a higher prevalence of major congenital malformations, with adjusted odd ratios (AOR) of 2.0 [95% confidence interval (CI) 1.0-3.8] and 2.0 (CI 1.3-3.1); 3.6 and 4.2% of infants born, respectively. All twins and unlike-sex twins born after IVFT but not IUI, have an increased prevalence of major birth defects compared with naturally conceived twins; AOR of 3.0 (CI 1.6-5.6) and 3.7 (CI 1.1-16.9), respectively. When comparing IUI with IVFT, no differences were observed for singletons (AOR 1.0; CI 0.4-2.2), all twins (AOR 0.4; CI 0.1-1.2) and unlike-sex twins (AOR 0.3; CI 0.1-4.5). CONCLUSIONS: The risk of major birth defects in singletons conceived through IUI was increased over naturally conceived singletons. This risk was no different from that observed after IVFT. PMID- 22215632 TI - Occupational exposure to chemicals and fetal growth: the Generation R Study. AB - BACKGROUND: Developmental diseases, such as birth defects, growth restriction and preterm delivery, account for >25% of infant mortality and morbidity. Several studies have shown that exposure to chemicals during pregnancy is associated with adverse birth outcomes. The aim of this study was to identify whether occupational exposure to various chemicals might adversely influence intrauterine growth patterns and placental weight. METHODS: Associations between maternal occupational exposure to various chemicals and fetal growth were studied in 4680 pregnant women participating in a population-based prospective cohort study from early pregnancy onwards in the Netherlands (2002-2006), the Generation R Study. Mothers who filled out a questionnaire during mid-pregnancy (response: 77% of enrolment) were included if they conducted paid employment during pregnancy and had a spontaneously conceived singleton live born pregnancy (n = 4680). A job exposure matrix was used, linking job titles to expert judgement on exposure to chemicals in the workplace. Fetal growth characteristics were repeatedly measured by ultrasound and were used in combination with measurements at birth. Placental weight was obtained from medical records and hospital registries. Linear regression models for repeated measurements were used to study the associations between maternal occupational exposure to chemicals and intrauterine growth. RESULTS: We observed that maternal occupational exposure to polycyclic aromatic hydrocarbons, phthalates, alkylphenolic compounds and pesticides adversely influenced several domains of fetal growth (fetal weight, fetal head circumference and fetal length). We found a significant association between pesticide and phthalate exposure with a decreased placental weight. CONCLUSIONS: Our results suggest that maternal occupational exposure to several chemicals is associated with impaired fetal growth during pregnancy and a decreased placental weight. Further studies are needed to confirm these findings and to assess post natal consequences. PMID- 22215633 TI - Specificity controls for immunocytochemistry: the antigen preadsorption test can lead to inaccurate assessment of antibody specificity. AB - The biomedical research community relies directly or indirectly on immunocytochemical data. Unfortunately, validation of labeling specificity is difficult. A common specificity test is the preadsorption test. This test was intended for testing crude antisera but is now frequently used to validate monoclonal and affinity purified polyclonal antibodies. Here, the authors assess the power of this test. Nine affinity purified antibodies to different epitopes on 3 proteins (EAAT3, slc1a1; EAAT2, slc1a2; BGT1, slc6a12) were tested on samples (tissue sections and Western blots with or without fixation). The selected antibodies displayed some degree of cross-reactivity as defined by labeling of samples from knockout mice. The authors show that antigen preadsorption blocked all labeling of both wild-type and knockout samples, implying that preadsorption also blocked binding to cross-reactive epitopes. They show how this can give an illusion of specificity and illustrate sensitivity specificity relationships, the importance of good negative controls, that fixation can create new epitopes, and that cross-reacting epitopes present in sections may not be present on Western blots and vice versa. In conclusion, they argue against uncritical use of the preadsorption test and, in doing so, address a number of other issues related to immunocytochemistry specificity testing. PMID- 22215634 TI - Matrilysin (MMP-7) inhibition of BMP-7 induced renal tubular branching morphogenesis suggests a role in the pathogenesis of human renal dysplasia. AB - Congenital renal dysplasia (RD) is a severe form of congenital renal malformation characterized by disruption of normal renal development with cyst formation, reduced or absent nephrons, and impaired renal growth. The authors previously identified that matrilysin (matrix metalloproteinase-7) was overexpressed in a microarray gene expression analysis of human RD compared to normal control kidneys. They now find that active matrilysin gene transcription and protein synthesis occur within dysplastic tubules and epithelial cells lining cysts in human RD by RT-PCR and immunohistochemistry. Similar staining patterns were seen in obstructed kidneys of pouch opossums that show histological features similar to that of human RD. In vitro, matrilysin inhibits formation of branching structures in mIMCD-3 cells stimulated by bone morphogenetic protein-7 (BMP-7) but does not inhibit hepatocyte growth factor-stimulated branching. BMP-7 signaling is essential for normal kidney development, and overexpression of catalytically active matrilysin in human embryonic kidney 293 cells reduces endogenous BMP-7 protein levels and inhibits phosphorylation of BMP-7 SMAD signaling intermediates. These findings suggest that matrilysin expression in RD may be an injury response that disrupts normal nephrogenesis by impairing BMP-7 signaling. PMID- 22215635 TI - Correlated immunohistochemical and cytological assays for the prediction of hematogenous dissemination of breast cancer. AB - Although metastasis is a major cause of death from breast cancer, our ability to predict which tumors will metastasize is limited (American Cancer Society 2010). Proper assessment of metastatic risk and elucidating the underlying mechanisms of metastasis will help personalize therapy and may provide insight into potential therapeutic targets. Traditionally, histologic grading, staging, hormone receptors, HER2/Neu, and proliferation assays have been the gold standard on which oncologists based their treatment decisions. However, all of these are indirect measures of metastatic risk. Recent insights from intravital imaging directly address questions of mechanism and have led to a new way of using histologic and cytologic material to assess metastatic risk. This review describes the tumor microenvironment model of invasion and intravasation, as well as an emerging histopathologic application based on this model. In particular, the authors describe a new immunohistochemical approach to the assessment of metastatic risk based on the density of intravasation microenvironment sites called the tumor microenvironment of metastasis. In addition, they describe an isoform assay for the actin regulatory protein Mena using fine needle aspiration samples and the details about how these 2 assays may be applied in clinical practice in a synergistic way to assess the risk of metastasis. PMID- 22215636 TI - Determining degradation and synthesis rates of arabidopsis proteins using the kinetics of progressive 15N labeling of two-dimensional gel-separated protein spots. AB - The growth and development of plant tissues is associated with an ordered succession of cellular processes that are reflected in the appearance and disappearance of proteins. The control of the kinetics of protein turnover is central to how plants can rapidly and specifically alter protein abundance and thus molecular function in response to environmental or developmental cues. However, the processes of turnover are largely hidden during periods of apparent steady-state protein abundance, and even when proteins accumulate it is unclear whether enhanced synthesis or decreased degradation is responsible. We have used a (15)N labeling strategy with inorganic nitrogen sources coupled to a two dimensional fluorescence difference gel electrophoresis and mass spectrometry analysis of two-dimensional IEF/SDS-PAGE gel spots to define the rate of protein synthesis (K(S)) and degradation (K(D)) of Arabidopsis cell culture proteins. Through analysis of MALDI-TOF/TOF mass spectra from 120 protein spots, we were able to quantify K(S) and K(D) for 84 proteins across six functional groups and observe over 65-fold variation in protein degradation rates. K(S) and K(D) correlate with functional roles of the proteins in the cell and the time in the cell culture cycle. This approach is based on progressive (15)N labeling that is innocuous for the plant cells and, because it can be used to target analysis of proteins through the use of specific gel spots, it has broad applicability. PMID- 22215638 TI - Management of subarachnoid hemorrhage with intracerebral hematoma: clipping and clot evacuation versus coil embolization followed by clot evacuation. AB - BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) with associated intracerebral hemorrhage (ICH) is often treated with concomitant surgical clipping and ICH evacuation. The aim of this study was to determine if aneurysm coiling followed by ICH evacuation is a viable alternative treatment. METHODS: A retrospective review was conducted between July 2000 and March 2009 of patients with aneurysmal SAH plus ICH (>30 ml or with midline shift >5 mm) who underwent aneurysm repair (either coiling or clipping) and craniotomy for ICH evacuation. Demographic and radiographic criteria, time to aneurysm protection, length of stay (LOS), treatment complications, discharge disposition and 3 month functional outcome were compared between groups. RESULTS: Of 18 SAH+ICH patients, 10 underwent aneurysm coiling followed by ICH evacuation and eight underwent clipping with ICH evacuation. Compared with clipped patients, coiled patients had a lower Glasgow Coma Scale score (median 5.5 vs 7.5), higher ICH score (median 3 vs 2), worse modified Fisher score (median 4 vs 3) and higher rate of herniation at presentation (50% vs 25%). Median time to aneurysm protection was shorter in coiled patients (299 vs 885 min, p<0.001). Comparing coiled with clipped patients, rates of death (30% vs 25%), poor outcome (70% vs 50%), median ICU LOS (20 vs 22 days), median hospital LOS (27 vs 29 days) and total median direct costs ($64,537 vs $61,243) were similar, as were complication rates (all p>0.05). CONCLUSIONS: Coiling followed by ICH evacuation is associated with faster time to aneurysm protection and similar outcome, LOS and cost as clipping and evacuation. This may be a viable alternative to clipping and ICH evacuation. PMID- 22215637 TI - Quantitative proteomics reveals dynamic changes in the plasma membrane during Arabidopsis immune signaling. AB - The plant plasma membrane is a crucial mediator of the interaction between plants and microbes. Understanding how the plasma membrane proteome responds to diverse immune signaling events will lead to a greater understanding of plant immunity and uncover novel targets for crop improvement. Here we report the results from a large scale quantitative proteomics study of plasma membrane-enriched fractions upon activation of the Arabidopsis thaliana immune receptor RPS2. More than 2300 proteins were identified in total, with 1353 proteins reproducibly identified across multiple replications. Label-free spectral counting was employed to quantify the relative protein abundance between different treatment samples. Over 20% of up-regulated proteins have known roles in plant immune responses. Significantly changing proteins include those involved in calcium and lipid signaling, membrane transport, primary and secondary metabolism, protein phosphorylation, redox homeostasis, and vesicle trafficking. A subset of differentially regulated proteins was independently validated during bacterial infection. This study presents the largest quantitative proteomics data set of plant immunity to date and provides a framework for understanding global plasma membrane proteome dynamics during plant immune responses. PMID- 22215643 TI - Accuracy and precision of the Prodigy AutoCode blood glucose monitor. AB - OBJECTIVES: To assess the accuracy and precision of the Prodigy AutoCode blood glucose monitor. METHODS: This open-label, prospective equivalence study was conducted at Wilson Community Health Center in Wilson, North Carolina. Accuracy was assessed by comparing finger stick blood glucose values to venipuncture. Precision was assessed by comparing consecutive finger stick blood glucose values from 2 Prodigy AutoCode monitors. Data were analyzed using paired t tests, signed rank tests, regression, and mixed effect models. RESULTS: Fifty-three subjects completed the study. Meter 1 produced 14 (26%) and meter 2 produced 13 (25%) blood glucose readings outside the acceptable error margin of +/-20% set by the International Organization for Standardization (ISO) and the Food and Drug Administration (FDA). Neither meter was accurate compared to venipuncture (P < .001 for both). Consecutive blood glucose results obtained from meters 1 and 2 were precise (meter 1 vs 2, P = .533). CONCLUSIONS: The Prodigy AutoCode demonstrated precision between two different monitors but was inaccurate compared to venipuncture. Less than the required 95% of blood glucose values from each monitor fell within the acceptable 20% error margin relative to venipuncture. All readings outside the acceptable error margin were overestimations, indicating potentially significant safety concerns including untreated or undertreated hypoglycemia. PMID- 22215644 TI - An overview of alcohol testing and interpretation in the 21st century. AB - Ethanol analysis is the most commonly carried out drug testing in a forensic toxicology laboratory. Determination of blood alcohol concentration (BAC) is needed in a multitude of situations, including in postmortem analysis, driving under the influence (DUI) and drug-facilitated sexual assault (DFSA) cases, workplace drug monitoring, and probation investigations. These analyses are carried out by direct measurement of ethanol concentrations as well as of metabolic by-products, such as ethyl glucuronide (EtG) and ethyl sulfate (EtS). This review article will discuss pharmacokinetics, including absorption, distribution, and elimination of ethanol, methods for the detection of ethanol, the effect of ethanol on human performance, the role of alcohol in injuries and fatalities, and information regarding the interactions that may occur between alcohol and other drugs. Finally, an explanation will be given on how to interpret alcohol levels as well as the extrapolation and calculation of blood alcohol levels at times prior to sample collection. PMID- 22215645 TI - Prescriber monitoring for benign prostatic hyperplasia within a family medicine clinic: a comparison of medication classes. AB - PURPOSE: The purpose of this study was to compare prescriber monitoring for safety and efficacy of medication classes used to treat benign prostatic hyperplasia (BPH). METHODS: This was a retrospective chart review of patients diagnosed with BPH who were prescribed medications within a family medicine clinic between January 2008 and August 2010. Patients were divided into those receiving nonselective and uroselective alpha-blockers, 5-alpha reductase inhibitors (5-ARIs), and combination therapy. A chart review was performed with regard to predetermined criteria to monitor how efficacy and adverse effects were assessed by providers in the clinic. RESULTS: A general genitourinary assessment was documented most frequently for patients receiving 5-ARIs and least frequently in patients receiving nonselective alpha-blockers. A digital rectal examination was documented in 11% of patients. Prostate-specific antigen concentrations were assessed evenly across all medication classes and documented in 47% of eligible patients. However, the American Urological Association Symptom Index and quality of-life questions were not performed on any patients, and assessments of adverse effects were not documented. CONCLUSION: Although prescribers in a family medicine clinic recorded a general genitourinary assessment for patients receiving BPH medications, a more standardized approach is needed. PMID- 22215646 TI - Postmortem drug levels: innocent bystander or guilty as charged. AB - Determining the etiology or cause of an event in forensic cases often creates many theories. On piece of additional information which may be helpful in cases involving a drug or medication are concentrations or serum levels. Although many confounders can affect the interpretation of the drug level, it is imperative to also relate the data to the clinical scenario presented. Drug levels can be highly variable, depending on the time drawn, location from where the sample was obtained, and reference/references utilized in its interpretation. Postmortem drugs levels often do not reflect the blood levels before death. A drug level can be elevated exclusively because of postmortem distribution. This may result in a conclusion of a poisoning as the cause of death when in fact the death resulted from nonpharmacologic or nontoxicologic causes. Caution is advised from making any conclusions based solely on the drug level; rather an in-depth review of the clinical scenario, reference literature, and drug characteristics are required. PMID- 22215647 TI - Forensic aspects of drug-induced violence. AB - Violence is unfortunately a part of society. The causes of violence are not completely understood, but it involves sociological, genetic, financial, biological, and environmental factors. Drugs can cause aggression by altering the neurotransmitters dopamine, norepinephrine, gamma-aminobutyric acid (GABA), and serotonin. Specific drugs associated with aggression include alcohol, anabolic steroids, cocaine, amphetamines, sedatives, opiates, and hallucinogens. Aggression can be categorized into impulsive and predatory aggression. Drugs under certain conditions cause impulsive aggression. Sometimes a defense in criminal cases is that the drug caused the violence, that is drug-induced insanity. A case of insanity is more likely to be accepted if the event was unplanned and had no apparent motive. An acceptance of insanity by voluntary intoxication is rarely accepted by the criminal justice system. A more common legal strategy is to seek diminished capacity which aims to obtain a reduction in the severity of the criminal charges. We will discuss some, but not all of the pharmacological and physiological issues relating to drug-induced violence. Then some of the "big picture" forensic issues will be presented. Our goal is to present a primer on the pharmacological and forensic issues relating to drug induced violence. No attempt was made to provide a comprehensive review of all the literature related to drug-induced violence. PMID- 22215648 TI - Nonprescription drug abuse. AB - Nonprescription drug, also referred to as over-the-counter (OTC) abuse, is a serious and growing global health challenge. Drugs from many different therapeutic classes and numerous dosage forms and drug delivery systems are implicated in nonprescription drug abuse. Individuals who commonly abuse certain nonprescription medications are likewise diverse, varying in age, demographics, and overall health status. The clinician is in a unique position to assist in identifying those patients at risk for nonprescription drug abuse and those who are abusers, and may play an important role in intervention, patient care, and in the treatment of nonprescription drug abuse. A concise review of nonprescription drug abuse may be of use to the clinician in this regard. PMID- 22215649 TI - A service-learning project to eliminate barriers to oral care for children with special health care needs. AB - Children with special health care needs face many barriers to oral care and are at high risk for oral disease. School nurses are in a unique position to promote oral wellness in this vulnerable population. Collaboration between school nurses and dental hygiene faculty resulted in the formation of a partnership between a university-based dental hygiene program and two special education districts in rural southern Illinois. Senior dental hygiene students participated in a school based service-learning project that provided dental examinations, preventive services, and education to children with special health care needs. Evidence based behavioral interventions were used to teach children to comply with oral procedures. School nurses mentored dental hygiene students in behavior management of children. Dental exams were provided to 234 children from four special education schools with the majority receiving cleanings and fluoride. PMID- 22215650 TI - 12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response. AB - Central obesity is associated with chronic inflammation, insulin resistance, beta cell dysfunction, and endoplasmic reticulum (ER) stress. The 12/15-lipoxygenase enzyme (12/15-LO) promotes inflammation and insulin resistance in adipose and peripheral tissues. Given that obesity is associated with ER stress and 12/15-LO is expressed in adipose tissue, we determined whether 12/15-LO could mediate ER stress signals. Addition of 12/15-LO lipid products 12(S)-HETE and 12(S)-HPETE to differentiated 3T3-L1 adipocytes induced expression and activation of ER stress markers, including BiP, XBP-1, p-PERK, and p-IRE1alpha. The ER stress inducer, tunicamycin, upregulated ER stress markers in adipocytes with concomitant 12/15 LO activation. Addition of a 12/15-LO inhibitor, CDC, to tunicamycin-treated adipocytes attenuated the ER stress response. Furthermore, 12/15-LO-deficient adipocytes exhibited significantly decreased tunicamycin-induced ER stress. 12/15 LO action involves upregulation of interleukin-12 (IL-12) expression. Tunicamycin significantly upregulated IL-12p40 expression in adipocytes, and IL-12 addition increased ER stress gene expression; conversely, LSF, an IL-12 signaling inhibitor, and an IL-12p40-neutralizing antibody attenuated tunicamycin-induced ER stress. Isolated adipocytes and liver from 12/15-LO-deficient mice fed a high fat diet revealed a decrease in spliced XBP-1 expression compared with wild-type C57BL/6 mice on a high-fat diet. Furthermore, pancreatic islets from 12/15-LO deficient mice showed reduced high-fat diet-induced ER stress genes compared with wild-type mice. These data suggest that 12/15-LO activity participates in ER stress in adipocytes, pancreatic islets, and liver. Therefore, reduction of 12/15 LO activity or expression could provide a new therapeutic target to reduce ER stress and downstream inflammation linked to obesity. PMID- 22215652 TI - Selective PPARgamma modulator INT131 normalizes insulin signaling defects and improves bone mass in diet-induced obese mice. AB - INT131 is a potent non-thiazolidinedione (TZD)-selective peroxisome proliferator activated receptor-gamma modulator being developed for the treatment of type 2 diabetes. In preclinical studies and a phase II clinical trial, INT131 has been shown to lower glucose levels and ameliorate insulin resistance without typical TZD side effects. To determine whether the insulin-sensitizing action of INT131 is mediated by effects on insulin-mediated glucose homeostasis and insulin signaling, high-fat diet-induced obese (DIO) insulin-resistant mice treated with INT131 were studied. INT131's effects on bone density were also investigated. Treatment with INT131 enhanced systemic insulin sensitivity, as revealed by lower insulin levels in the fasted state and an increase in the area above the curve during an insulin tolerance test. These effects were independent of changes in adiposity. Insulin-stimulated PI3K activity in skeletal muscle and adipose tissue of DIO mice was significantly reduced ~50-65%, but this was restored completely by INT131 therapy. The INT131 effects on PI3K activity are most likely due to increased IRS-1 tyrosine phosphorylation. Concurrently, insulin-mediated Akt phosphorylation also increased after INT131 treatment in DIO mice. Importantly, INT131 therapy caused a significant increase in bone mineral density without alteration in circulating osteocalcin in these mice. These data suggest that a newly developed insulin-sensitizing agent, INT131, normalizes obesity-related defects in insulin action on PI3K signaling in insulin target tissues by a mechanism involved in glycemic control. If these data are confirmed in humans, INT131 could be used for treating type 2 diabetes without loss in bone mass. PMID- 22215653 TI - Plasma mannose-binding lectin is stimulated by PPARalpha in humans. AB - The peroxisome proliferator activated receptor-alpha (PPARalpha) is a major transcriptional regulator of lipid metabolism in liver and represents the molecular target for hypolipidemic fibrate drugs. Effects of PPARalpha on lipid metabolism are partially mediated by circulating proteins such as FGF21 and ANGPTL4. The present study was undertaken to screen for and identify circulating proteins produced by human liver that are under the control of PPARalpha. Toward that aim, primary human hepatocytes were treated with the synthetic PPARalpha agonist Wy-14643 and whole genome expression data selected for secreted proteins. Expression of FGF21, ANGPTL4, and mannose-binding lectin (MBL), a soluble mediator of innate immunity and primary component of the lectin branch of the complement system, was markedly upregulated by Wy-14643 in primary human hepatocytes. Mice express two MBL isomers, Mbl1 and Mbl2. Mbl1 mRNA was weakly induced by Wy-14643 in primary mouse hepatocytes and remained unaltered by Wy 14643 in mouse liver. Mbl2 mRNA was unchanged by Wy-14643 in primary mouse hepatocytes and was strongly reduced by Wy-14643 in mouse liver. Remarkably, plasma Mbl1 levels were increased by chronic PPARalpha activation in lean and obese mice. Importantly, in two independent clinical trials, treatment with the PPARalpha agonist fenofibrate at 200 mg/day for 6 wk and 3 mo increased plasma MBL levels by 73 (P = 0.0016) and 86% (P = 0.017), respectively. It is concluded that hepatocyte gene expression and plasma levels of MBL are stimulated by PPARalpha and fenofibrate in humans, linking PPARalpha to regulation of innate immunity and complement activation in humans and suggesting a possible role of MBL in lipid metabolism. PMID- 22215651 TI - Anabolic signaling and protein deposition are enhanced by intermittent compared with continuous feeding in skeletal muscle of neonates. AB - Orogastric tube feeding is indicated for neonates with impaired ability to ingest and can be administered by intermittent bolus or continuous schedule. Our aim was to determine whether feeding modalities affect muscle protein deposition and to identify mechanisms involved. Neonatal pigs were overnight fasted (FAS) or fed the same amount of food continuously (CON) or intermittently (INT; 7 * 4 h meals) for 29 h. For 8 h, between hours 20 and 28, pigs were infused with [(2)H(5)]phenylalanine and [(2)H(2)]tyrosine, and amino acid (AA) net balances were measured across the hindquarters. Insulin, branched-chain AA, phenylalanine, and tyrosine arterial concentrations and whole body phenylalanine and tyrosine fluxes were greater for INT after the meal than for CON or FAS. The activation of signaling proteins leading to initiation of mRNA translation, including eukaryotic initiation factor (eIF)4E.eIF4G complex formation in muscle, was enhanced by INT compared with CON feeding or FAS. Signaling proteins of protein degradation were not affected by feeding modalities except for microtubule associated protein light chain 3-II, which was highest in the FAS. Across the hindquarters, AA net removal increased for INT but not for CON or FAS, with protein deposition greater for INT. This was because protein synthesis increased following feeding for INT but remained unchanged for CON and FAS, whereas there was no change in protein degradation across any dietary treatment. These results suggest that muscle protein accretion in neonates is enhanced with intermittent bolus to a greater extent than continuous feeding, mainly by increased protein synthesis. PMID- 22215654 TI - The role of the stomach in the control of appetite and the secretion of satiation peptides. AB - It is widely accepted that gastric parameters such as gastric distention provide a direct negative feedback signal to inhibit eating; moreover, gastric and intestinal signals have been reported to synergize to promote satiation. However, there are few human data exploring the potential interaction effects of gastric and intestinal signals in the short-term control of appetite and the secretion of satiation peptides. We performed experiments in healthy subjects receiving either a rapid intragastric load or a continuous intraduodenal infusion of glucose or a mixed liquid meal. Intraduodenal infusions (3 kcal/min) were at rates comparable with the duodenal delivery of these nutrients under physiological conditions. Intraduodenal infusions of glucose elicited only weak effects on appetite and the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). In contrast, identical amounts of glucose delivered intragastrically markedly suppressed appetite (P < 0.05) paralleled by greatly increased plasma levels of GLP-1 and PYY (<=3-fold, P < 0.05). Administration of the mixed liquid meal showed a comparable phenomenon. In contrast to GLP-1 and PYY, plasma ghrelin was suppressed to a similar degree with both intragastric and intraduodenal nutrients. Our data confirm that the stomach is an important element in the short term control of appetite and suggest that gastric and intestinal signals interact to mediate early fullness and satiation potentially by increased GLP-1 and PYY secretions. PMID- 22215655 TI - FoxO1 as a double-edged sword in the pancreas: analysis of pancreas- and beta cell-specific FoxO1 knockout mice. AB - Diabetes is characterized by an absolute or relative deficiency of pancreatic beta-cells. New strategies to accelerate beta-cell neogenesis or maintain existing beta-cells are desired for future therapies against diabetes. We previously reported that forkhead box O1 (FoxO1) inhibits beta-cell growth through a Pdx1-mediated mechanism. However, we also reported that FoxO1 protects against beta-cell failure via the induction of NeuroD and MafA. Here, we investigate the physiological roles of FoxO1 in the pancreas by generating the mice with deletion of FoxO1 in the domains of the Pdx1 promoter (P-FoxO1-KO) or the insulin 2 promoter (beta-FoxO1-KO) and analyzing the metabolic parameters and pancreatic morphology under two different conditions of increased metabolic demand: high-fat high-sucrose diet (HFHSD) and db/db background. P-FoxO1-KO, but not beta-FoxO1-KO, showed improved glucose tolerance with HFHSD. Immunohistochemical analysis revealed that P-FoxO1-KO had increased beta-cell mass due to increased islet number rather than islet size, indicating accelerated beta-cell neogenesis. Furthermore, insulin-positive pancreatic duct cells were increased in P-FoxO1-KO but not beta-FoxO1-KO. In contrast, db/db mice crossed with P-FoxO1-KO or beta-FoxO1-KO showed more severe glucose intolerance than control db/db mice due to decreased glucose-responsive insulin secretion. Electron microscope analysis revealed fewer insulin granules in FoxO1 knockout db/db mice. We conclude that FoxO1 functions as a double-edged sword in the pancreas; FoxO1 essentially inhibits beta-cell neogenesis from pancreatic duct cells but is required for the maintenance of insulin secretion under metabolic stress. PMID- 22215656 TI - Influence of bicarbonate/low-GDP peritoneal dialysis fluid (BicaVera) on in vitro and ex vivo epithelial-to-mesenchymal transition of mesothelial cells. AB - BACKGROUND: Peritoneal membrane damage induced by peritoneal dialysis (PD) is largely associated with epithelial-to-mesenchymal transition (EMT) of mesothelial cells (MCs), which is believed to be a result mainly of the glucose degradation products (GDPs) present in PD solutions. OBJECTIVES: This study investigated the impact of bicarbonate-buffered, low-GDP PD solution (BicaVera: Fresenius Medical Care, Bad Homburg, Germany) on EMT of MCs in vitro and ex vivo. METHODS: IN VITRO STUDIES: Omentum-derived MCs were incubated with lactate-buffered standard PD fluid or BicaVera fluid diluted 1:1 with culture medium. Ex vivo studies: From 31 patients randomly distributed to either standard or BicaVera solution and followed for 24 months, effluents were collected every 6 months for determination of EMT markers in effluent MCs. RESULTS: Culturing of MCs with standard fluid in vitro resulted in morphology change to a non-epithelioid shape, with downregulation of E-cadherin (indicative of EMT) and strong induction of vascular endothelial growth factor (VEGF) expression. By contrast, in vitro exposure of MCs to bicarbonate/low-GDP solution had less impact on both EMT parameters. Ex vivo studies partially confirmed the foregoing results. The BicaVera group, with a higher prevalence of the non-epithelioid MC phenotype at baseline (for unknown reasons), showed a clear and significant trend to gain and maintain an epithelioid phenotype at medium- and longer-term and to show fewer fibrogenic characteristics. By contrast, the standard solution group demonstrated a progressive and significantly higher presence of the non-epithelioid phenotype. Compared with effluent MCs having an epithelioid phenotype, MCs with non epithelioid morphology showed significantly lower levels of E-cadherin and greater levels of fibronectin and VEGF. In comparing the BicaVera and standard solution groups, MCs from the standard solution group showed significantly higher secretion of interleukin 8 and lower secretion of collagen I, but no differences in the levels of other EMT-associated molecules, including fibronectin, VEGF, E cadherin, and transforming growth factor beta1. Peritonitis incidence was similar in both groups. Functionally, the use of BicaVera fluid was associated with higher transport of small molecules and lower ultrafiltration capacity. CONCLUSIONS: Effluent MCs grown ex vivo from patients treated with bicarbonate/low-GDP BicaVera fluid showed a trend to acquire an epithelial phenotype, with lower production of proinflammatory cytokines and chemokines (such as interleukin 8) than was seen with MCs from patients treated with a lactate-buffered standard PD solution. PMID- 22215657 TI - Effluent free radicals are associated with residual renal function and predict technique failure in peritoneal dialysis patients. AB - OBJECTIVE: Residual renal function (RRF) is associated with low oxidative stress in peritoneal dialysis (PD). In the present study, we investigated the relationship between the impact of oxidative stress on RRF and patient outcomes during PD. METHODS: Levels of free radicals (FRs) in effluent from the overnight dwell in 45 outpatients were determined by electron spin resonance spectrometry. The FR levels, clinical parameters, and the level of 8-hydroxy-2'-deoxyguanosine were evaluated at study start. The effects of effluent FR level on technique and patient survival were analyzed in a prospective cohort followed for 24 months. RESULTS: Levels of effluent FRs showed significant negative correlations with daily urine volume and residual renal Kt/V, and positive correlations with plasma beta(2)-microglobulin and effluent 8-hydroxy-2'-deoxyguanosine. A highly significant difference in technique survival (p < 0.05), but not patient survival, was observed for patients grouped by effluent FR quartile. The effluent FR level was independently associated with technique failure after adjusting for patient age, history of cardiovascular disease, and presence of diabetes mellitus (p < 0.001). The level of effluent FRs was associated with death-censored technique failure in both univariate (p < 0.001) and multivariate (p < 0.01) hazard models. Compared with patients remaining on PD, those withdrawn from the modality had significantly higher levels of effluent FRs (p < 0.005). CONCLUSIONS: Elevated effluent FRs are associated with RRF and technique failure in stable PD patients. These findings highlight the importance of oxidative stress as an unfavorable prognostic factor in PD and emphasize that steps should be taken to minimize oxidative stress in these patients. PMID- 22215658 TI - Pyrrole-imidazole polyamide targeting transforming growth factor beta1 ameliorates encapsulating peritoneal sclerosis. AB - OBJECTIVE: Encapsulating peritoneal sclerosis (EPS) is a devastating fibrotic complication in patients treated with peritoneal dialysis (PD). Transforming growth factor beta1 (TGF-beta1) is a pivotal factor in the induction of EPS. METHODS: To develop pyrrole-imidazole (PI) polyamide, a novel gene silencer, targeted to the TGF-beta1 promoter (Polyamide) for EPS, we examined the effects of Polyamide on messenger RNA (mRNA) expression of TGF-beta1, vascular endothelial growth factor (VEGF), and extracellular matrix (ECM) in mesothelial cells in vitro, and on the thickness of injured peritoneum evaluated by histology and high-resolution regional elasticity mapping in rats in vivo. RESULTS: Polyamide significantly lowered mRNA expression of TGF-beta1 and ECM in vitro. Polyamide labeled with fluorescein isothiocyanate was taken up into the injured peritoneum and was strongly localized in the nuclei of most cells. Polyamide 1 mg was injected intraperitoneally 1 or 3 times in rats receiving a daily intraperitoneal injection of chlorhexidine gluconate and ethanol (CHX) for 14 days. Polyamide significantly suppressed peritoneal thickening and the abundance of TGF-beta1 and fibronectin mRNA, but did not affect expression of VEGF mRNA in the injured peritoneum. Elasticity distribution mapping showed that average elasticity was significantly lower in Polyamide-treated rats than in rats treated solely with CHX. CONCLUSIONS: Polyamide suppressed the stiffness, ECM formation, and thickening of the injured peritoneum that occurs during EPS pathogenesis. These data suggest that PI polyamide targeted to the TGF-beta1 promoter will be a specific and feasible therapeutic strategy for patients with EPS. PMID- 22215659 TI - Microbiology of peritonitis in peritoneal dialysis patients with multiple episodes. AB - BACKGROUND: Peritoneal dialysis (PD)-associated peritonitis clusters within patients. Patient factors contribute to peritonitis risk, but there is also entrapment of organisms within the biofilm that forms on PD catheters. It is hypothesized that this biofilm may prevent complete eradication of organisms, predisposing to multiple infections with the same organism. METHODS: Using data collected in the Canadian multicenter Baxter POET (Peritonitis, Organism, Exit sites, Tunnel infections) database from 1996 to 2005, we studied incident PD patients with 2 or more peritonitis episodes. We determined the proportion of patients with 2 or more episodes caused by the same organism. In addition, using a multivariate logistic regression model, we tested whether prior peritonitis with a given organism predicted the occurrence of a subsequent episode with the same organism. RESULTS: During their time on PD, 558 patients experienced 2 or more peritonitis episodes. Of those 558 patients, 181 (32%) had at least 2 episodes with the same organism. The organism most commonly causing repeat infection was coagulase-negative Staphylococcus (CNS), accounting for 65.7% of cases. Compared with peritonitis caused by other organisms, a first CNS peritonitis episode was associated with an increased risk of subsequent CNS peritonitis within 1 year (odds ratio: 2.1; 95% confidence interval: 1.5 to 2.8; p < 0.001). Among patients with repeat CNS peritonitis, 48% of repeat episodes occurred within 6 months of the earlier episode. CONCLUSIONS: In contrast to previous data, we did not find a high proportion of patients with multiple peritonitis episodes caused by the same organism. Coagulase-negative Staphylococcus was the organism most likely to cause peritonitis more than once in a given patient, and a prior CNS peritonitis was associated with an increased risk of CNS peritonitis within the subsequent year. PMID- 22215661 TI - Saccharomyces cerevisiae NineTeen complex (NTC)-associated factor Bud31/Ycr063w assembles on precatalytic spliceosomes and improves first and second step pre mRNA splicing efficiency. AB - Pre-mRNA splicing occurs in spliceosomes whose assembly and activation are critical for splice site selection and catalysis. The highly conserved NineTeen complex protein complex stabilizes various snRNA and protein interactions early in the spliceosome assembly pathway. Among several NineTeen complex-associated proteins is the nonessential protein Bud31/Ycr063w, which is also a component of the Cef1p subcomplex. A role for Bud31 in pre-mRNA splicing is implicated by virtue of its association with splicing factors, but its specific functions and spliceosome interactions are uncharacterized. Here, using in vitro splicing assays with extracts from a strain lacking Bud31, we illustrate its role in efficient progression to the first catalytic step and its requirement for the second catalytic step in reactions at higher temperatures. Immunoprecipitation of functional epitope-tagged Bud31 from in vitro reactions showed that its earliest association is with precatalytic B complex and that the interaction continues in catalytically active complexes with stably bound U2, U5, and U6 small nuclear ribonucleoproteins. In complementary experiments, wherein precatalytic spliceosomes are selected from splicing reactions, we detect the occurrence of Bud31. Cross-linking of proteins to pre-mRNAs with a site-specific 4-thio uridine residue at the -3 position of exon 1 was tested in reactions with WT and bud31 null extracts. The data suggest an altered interaction between a ~25-kDa protein and this exonic residue of pre-mRNAs in the arrested bud31 null spliceosomes. These results demonstrate the early spliceosomal association of Bud31 and provide plausible functions for this factor in stabilizing protein interactions with the pre-mRNA. PMID- 22215662 TI - Independent structural domains in paramyxovirus polymerase protein. AB - All enzymatic activities required for genomic replication and transcription of nonsegmented negative strand RNA viruses (or Mononegavirales) are believed to be concentrated in the viral polymerase (L) protein. However, our insight into the organization of these different enzymatic activities into a bioactive tertiary structure remains rudimentary. Fragments of Mononegavirales polymerases analyzed to date cannot restore bioactivity through trans-complementation, unlike the related L proteins of segmented NSVs. We investigated the domain organization of phylogenetically diverse Paramyxovirus L proteins derived from measles virus (MeV), Nipah virus (NiV), and respiratory syncytial virus (RSV). Through a comprehensive in silico and experimental analysis of domain intersections, we defined MeV L position 615 as an interdomain candidate in addition to the previously reported residue 1708. Only position 1708 of MeV and the homologous positions in NiV and RSV L also tolerated the insertion of epitope tags. Splitting of MeV L at residue 1708 created fragments that were unable to physically interact and trans-complement, but strikingly, these activities were reconstituted by the addition of dimerization tags to the fragments. Equivalently split fragments of NiV, RSV, and MeV L oligomerized with comparable efficiency in all homo- and heterotypic combinations, but only the homotypic pairs were able to trans-complement. These results demonstrate that synthesis as a single polypeptide is not required for the Mononegavirales polymerases to adopt a proper tertiary conformation. Paramyxovirus polymerases are composed of at least two truly independent folding domains that lack a traditional interface but require molecular compatibility for bioactivity. The functional probing of the L domain architecture through trans-complementation is anticipated to be applicable to all Mononegavirales polymerases. PMID- 22215664 TI - Acridine yellow G blocks glioblastoma growth via dual inhibition of epidermal growth factor receptor and protein kinase C kinases. AB - Amplification of the epidermal growth factor receptor (EGFR), frequently expressed as a constitutively active deletion mutant (EGFRvIII), occurs commonly in glioblastoma multiformes (GBM). However, blockade of EGFR is therapeutically disappointing for gliomas with PTEN deletion. To search for small molecules treating this aggressive cancer, we have established a cell-based screening and successfully identified acridine yellow G that preferentially blocks cell proliferation of the most malignant U87MG/EGFRvIII cells over the less malignant U87MG/PTEN cells. Oral administration of this compound markedly diminishes the brain tumor volumes in both subcutaneous and intracranial models. It directly inhibits EGFR and PKCs with IC(50) values of ~7.5 and 5 MUM, respectively. It dually inhibits EGFR and PKCs, resulting in a blockade of mammalian target of rapamycin signaling and cell cycle arrest in the G(1) phase, which leads to activation of apoptosis in the tumors. Hence, combinatorial inhibition of EGFR and PKCs might provide proof of concept in developing therapeutic agents for treating malignant glioma and other human cancers. PMID- 22215663 TI - Functional RNA interference (RNAi) screen identifies system A neutral amino acid transporter 2 (SNAT2) as a mediator of arsenic-induced endoplasmic reticulum stress. AB - Exposure to the toxic metalloid arsenic is associated with diabetes and cancer and causes proteotoxicity and endoplasmic reticulum (ER) stress at the cellular level. Adaptive responses to ER stress are implicated in cancer and diabetes; thus, understanding mechanisms of arsenic-induced ER stress may offer insights into pathogenesis. Here, we identify genes required for arsenite-induced ER stress response in a genome-wide RNAi screen. Using an shRNA library targeting ~20,000 human genes, together with an ER stress cell model, we performed flow cytometry-based cell sorting to isolate cells with defective response to arsenite. Our screen discovered several genes modulating arsenite-induced ER stress, including sodium-dependent neutral amino acid transporter, SNAT2. SNAT2 expression and activity are up-regulated by arsenite, in a manner dependent on activating transcription factor 4 (ATF4), an important mediator of the integrated stress response. Inhibition of SNAT2 expression or activity or deprivation of its primary substrate, glutamine, specifically suppressed ER stress induced by arsenite but not tunicamycin. Induction of SNAT2 is coincident with the activation of the nutrient-sensing mammalian target of rapamycin (mTOR) pathway, which is at least partially required for arsenite-induced ER stress. Importantly, inhibition of the SNAT2 or the System L transporter, LAT1, suppressed mTOR activation by arsenite, supporting a role for these transporters in modulating amino acid signaling. These findings reveal SNAT2 as an important and specific mediator of arsenic-induced ER stress, and suggest a role for aberrant mTOR activation in arsenic-related human diseases. Furthermore, this study demonstrates the utility of RNAi screens in elucidating cellular mechanisms of environmental toxins. PMID- 22215665 TI - Luminal and cytosolic pH feedback on proton pump activity and ATP affinity of V type ATPase from Arabidopsis. AB - Proton pumping of the vacuolar-type H(+)-ATPase into the lumen of the central plant organelle generates a proton gradient of often 1-2 pH units or more. Although structural aspects of the V-type ATPase have been studied in great detail, the question of whether and how the proton pump action is controlled by the proton concentration on both sides of the membrane is not understood. Applying the patch clamp technique to isolated vacuoles from Arabidopsis mesophyll cells in the whole-vacuole mode, we studied the response of the V ATPase to protons, voltage, and ATP. Current-voltage relationships at different luminal pH values indicated decreasing coupling ratios with acidification. A detailed study of ATP-dependent H(+)-pump currents at a variety of different pH conditions showed a complex regulation of V-ATPase activity by both cytosolic and vacuolar pH. At cytosolic pH 7.5, vacuolar pH changes had relative little effects. Yet, at cytosolic pH 5.5, a 100-fold increase in vacuolar proton concentration resulted in a 70-fold increase of the affinity for ATP binding on the cytosolic side. Changes in pH on either side of the membrane seem to be transferred by the V-ATPase to the other side. A mathematical model was developed that indicates a feedback of proton concentration on peak H(+) current amplitude (v(max)) and ATP consumption (K(m)) of the V-ATPase. It proposes that for efficient V-ATPase function dissociation of transported protons from the pump protein might become higher with increasing pH. This feature results in an optimization of H(+) pumping by the V-ATPase according to existing H(+) concentrations. PMID- 22215666 TI - Interleukin 33 as a mechanically responsive cytokine secreted by living cells. AB - Interleukin 33 (IL-33), a member of the Interleukin 1 cytokine family, is implicated in numerous human inflammatory diseases such as asthma, atherosclerosis, and rheumatoid arthritis. Despite its pathophysiologic importance, fundamental questions regarding the basic biology of IL-33 remain. Nuclear localization and lack of an export signal sequence are consistent with the view of IL-33 as a nuclear factor with the ability to repress RNA transcription. However, signaling via the transmembrane receptor ST2 and documented caspase-dependent inactivation have suggested IL-33 is liberated during cellular necrosis to effect paracrine signaling. We determined the subcellular localization of IL-33 and tracked its intracellular mobility and extracellular release. In contrast to published data, IL-33 localized simultaneously to nuclear euchromatin and membrane-bound cytoplasmic vesicles. Fluorescent pulse-chase fate-tracking documented dynamic nucleo-cytoplasmic flux, which was dependent on nuclear pore complex function. In murine fibroblasts in vitro and in vivo, mechanical strain induced IL-33 secretion in the absence of cellular necrosis. These data document IL-33 dynamic inter-organelle trafficking and release during biomechanical overload. As such we recharacterize IL-33 as both an inflammatory as well as mechanically responsive cytokine secreted by living cells. PMID- 22215667 TI - Inhibition of antigen trafficking through scavenger receptor A. AB - B cell acquisition and presentation of specific autoantigens (auto-Ags) are thought to play an important and complex role in autoimmunity development. We previously identified scavenger receptor A (SR-A) as an early target in altering B cell-mediated autoimmunity. SR-A is highly expressed on professional antigen presenting cells such as macrophages (MPhis) and dendritic cells (DCs). In this study, we demonstrate that SR-A is responsible for controlling B cell interactions with DCs/MPhis to promote Ag transfer from B cells to DCs/MPhis. We established a high-throughput ELISA-based screen to identify novel SR-A inhibitors, the specificity of which was determined by dose dependence and Biacore surface plasmon resonance testing. We identified small molecule inhibitors (SMIs) able to reduce SR-A-mediated Ag transfer in human cells. In particular, the SMIs prevented SR-A-positive cells from accumulating/loading Ag over time. Furthermore, we determined that one SMI, sennoside B, can reduce SR-A mediated capture of B cells. Finally, SMI-mediated decreases in Ag transfer or accumulation reduced T cell proliferation in vitro and in vivo. These observations demonstrate that B cell-DC/MPhi interactions are conducive to promoting Ag trafficking between these cell types via SR-A. Inhibitors of SR-A may provide a novel therapeutic strategy in ameliorating autoimmune disease development. PMID- 22215668 TI - gammadelta T cell receptors recognize the non-classical major histocompatibility complex (MHC) molecule T22 via conserved anchor residues in a MHC peptide-like fashion. AB - The molecular mechanisms by which gammadelta T cells recognize ligand remain a mystery. The non-classical MHC molecule T22 represents the best characterized ligand for murine gammadelta T cells, with a motif (W ... EGYEL) present in the gammadelta T cell receptor complementary-determining region 3delta (CDR3delta) loop mediating gammadelta T cell recognition of this molecule. Produced through V(D)J recombination, this loop is quite diverse, with different numbers and chemical types of amino acids between Trp and EGYEL, which have unknown functional consequences for T22 recognition. We have investigated the biophysical and structural effects of CDR3delta loop diversity, revealing a range of affinities for T22 but a common thermodynamic pattern. Mutagenesis of these CDR3delta loops defines the key anchor residues involved in T22 recognition as W ... EGYEL, similar to those found for the G8 CDR3delta loop, and demonstrates that spacer residues modulate but are not required for T22 recognition. Comparison of the location of these residues in the T22 interface reveals a striking similarity to peptide anchor residues in classically presented MHC peptides, with the key Trp residue of the CDR3delta motif completing the deficient peptide-binding groove of T22. This suggests that gammadelta T cell recognition of T22 utilizes the conserved ligand-presenting nature of the MHC fold. PMID- 22215669 TI - Calpain-mediated degradation of myocyte enhancer factor 2D contributes to excitotoxicity by activation of extrasynaptic N-methyl-D-aspartate receptors. AB - Synaptic and extrasynaptic NMDA receptors (NMDARs) appear to play opposite roles in neuronal survival and death. Here we report the new findings on the dysregulation of survival factor, myocyte enhancer factor 2D (MEF2D), by extrasynaptic NMDARs. Excitotoxicity led to the NMDAR-dependent degradation of MEF2D protein and inhibition of its transactivation activity in mature cortical neurons. The activation of extrasynaptic NMDARs alone was sufficient for degradation of MEF2D. Calpain directly cleaved MEF2D in vitro and blocking this protease activity greatly attenuated NMDAR signaled degradation of MEF2D in neurons. Consistently, inhibition of calpain protected cortical neurons from NMDA induced excitotoxicity. Furthermore, knockdown of MEF2D sensitized neurons to NMDA-induced excitotoxicity, which was not protected by calpain inhibition. Collectively, these findings suggest that dysregulation of MEF2D by calpain may mediate excitotoxicity via an extrasynaptic NMDAR-dependent manner. PMID- 22215670 TI - Cytochromes P450 CYP94C1 and CYP94B3 catalyze two successive oxidation steps of plant hormone Jasmonoyl-isoleucine for catabolic turnover. AB - The jasmonate hormonal pathway regulates important defensive and developmental processes in plants. Jasmonoyl-isoleucine (JA-Ile) has been identified as a specific ligand binding the COI1-JAZ co-receptor to relieve repression of jasmonate responses. Two JA-Ile derivatives, 12OH-JA-Ile and 12COOH-JA-Ile, accumulate in wounded Arabidopsis leaves in a COI1- and JAR1-dependent manner and reflect catabolic turnover of the hormone. Here we report the biochemical and genetic characterization of two wound-inducible cytochromes P450, CYP94C1 and CYP94B3, that are involved in JA-Ile oxidation. Both enzymes expressed in yeast catalyze two successive oxidation steps of JA-Ile with distinct characteristics. CYP94B3 performed efficiently the initial hydroxylation of JA-Ile to 12OH-JA-Ile, with little conversion to 12COOH-JA-Ile, whereas CYP94C1 catalyzed preferentially carboxy-derivative formation. Metabolic analysis of loss- and gain-of-function plant lines were consistent with in vitro enzymatic properties. cyp94b3 mutants were largely impaired in 12OH-JA-Ile levels upon wounding and to a lesser extent in 12COOH-JA-Ile levels. In contrast, cyp94c1 plants showed wild-type 12OH-JA-Ile accumulation but lost about 60% 12COOH-JA-Ile. cyp94b3cyp94c1 double mutants hyperaccumulated JA-Ile with near abolition of 12COOH-JA-Ile. Distinct JA-Ile oxidation patterns in different plant genotypes were correlated with specific JA responsive transcript profiles, indicating that JA-Ile oxidation status affects signaling. Interestingly, exaggerated JA-Ile levels were associated with JAZ repressor hyperinduction but did not enhance durably defense gene induction, revealing a novel negative feedback signaling loop. Finally, interfering with CYP94 gene expression affected root growth sensitivity to exogenous jasmonic acid. These results identify CYP94B3/C1-mediated oxidation as a major catabolic route for turning over the JA-Ile hormone. PMID- 22215672 TI - Structure of yeast kinetochore Ndc10 DNA-binding domain reveals unexpected evolutionary relationship to tyrosine recombinases. AB - We have solved the x-ray structure of the N-terminal half of the yeast kinetochore protein Ndc10 at 1.9 A resolution. This essential protein is a key constituent of the budding yeast centromere and is essential for the recruitment of the centromeric nucleosome and establishment of the kinetochore. The fold of the protein shows unexpected similarities to the tyrosine recombinase/lambda integrase family of proteins, most notably Cre, with some variation in the relative position of the subdomains. This finding offers new insights into kinetochore evolution and the adaptation of a well studied protein fold to a novel role. By comparison with tyrosine recombinases and mutagenesis studies, we have been able to define some of the key DNA-binding motifs. PMID- 22215671 TI - AMP is an adenosine A1 receptor agonist. AB - Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5'-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5'-monophosphonate, ACP) directly activated the adenosine A(1) receptor (A(1)R). In contrast, AMP only activated the adenosine A(2B) receptor (A(2B)R) after hydrolysis to adenosine by ecto-5'-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A(1)R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A(1)R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6 azophenyl-2',4'-disulfonic acid and suramin) did not block adenosine- or AMP evoked activation. Moreover, mutation of His-251 in the human A(1)R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A(1)R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine. PMID- 22215673 TI - C-terminal di-arginine motif of Cdc42 protein is essential for binding to phosphatidylinositol 4,5-bisphosphate-containing membranes and inducing cellular transformation. AB - Rho GTPases regulate a diverse range of processes that are dependent on their proper cellular localization. The membrane localization of these GTPases is due in large part to their carboxyl-terminal geranylgeranyl moiety. In addition, most of the Rho family members contain a cluster of positively charged residues (i.e. a "polybasic domain"), directly preceding their geranylgeranyl moiety, and it has been suggested that this domain serves to fine-tune their localization among different cellular membrane sites. Here, we have taken a closer look at the role of the polybasic domain of Cdc42 in its ability to bind to membranes and induce the transformation of fibroblasts. A FRET assay for the binding of Cdc42 to liposomes of defined composition showed that Cdc42 associates more strongly with liposomes containing phosphatidylinositol 4,5-bisphosphate (PIP(2)) when compared either with uncharged control membranes or with liposomes containing a charge equivalent amount of phosphatidylserine. The carboxyl-terminal di-arginine motif (Arg-186 and Arg-187) was shown to play an essential role in the binding of Cdc42 to PIP(2)-containing membranes. We further showed that substitutions for the di arginine motif, when introduced within a constitutively active ("fast cycling") Cdc42(F28L) background, had little effect on the ability of the activated Cdc42 mutant to induce microspikes/filopodia in NIH 3T3 cells, whereas they eliminated its ability to transform fibroblasts. Taken together, these findings suggest that the di-arginine motif within the carboxyl terminus of Cdc42 is necessary for this GTPase to bind at membrane sites containing PIP(2), where it can initiate signaling activities that are essential for the oncogenic transformation of cells. PMID- 22215674 TI - Inhibitors of V-ATPase proton transport reveal uncoupling functions of tether linking cytosolic and membrane domains of V0 subunit a (Vph1p). AB - Vacuolar ATPases (V-ATPases) are important for many cellular processes, as they regulate pH by pumping cytosolic protons into intracellular organelles. The cytoplasm is acidified when V-ATPase is inhibited; thus we conducted a high throughput screen of a chemical library to search for compounds that acidify the yeast cytosol in vivo using pHluorin-based flow cytometry. Two inhibitors, alexidine dihydrochloride (EC(50) = 39 MUM) and thonzonium bromide (EC(50) = 69 MUM), prevented ATP-dependent proton transport in purified vacuolar membranes. They acidified the yeast cytosol and caused pH-sensitive growth defects typical of V-ATPase mutants (vma phenotype). At concentrations greater than 10 MUM the inhibitors were cytotoxic, even at the permissive pH (pH 5.0). Membrane fractions treated with alexidine dihydrochloride and thonzonium bromide fully retained concanamycin A-sensitive ATPase activity despite the fact that proton translocation was inhibited by 80-90%, indicating that V-ATPases were uncoupled. Mutant V-ATPase membranes lacking residues 362-407 of the tether of Vph1p subunit a of V(0) were resistant to thonzonium bromide but not to alexidine dihydrochloride, suggesting that this conserved sequence confers uncoupling potential to V(1)V(0) complexes and that alexidine dihydrochloride uncouples the enzyme by a different mechanism. The inhibitors also uncoupled the Candida albicans enzyme and prevented cell growth, showing further specificity for V ATPases. Thus, a new class of V-ATPase inhibitors (uncouplers), which are not simply ionophores, provided new insights into the enzyme mechanism and original evidence supporting the hypothesis that V-ATPases may not be optimally coupled in vivo. The consequences of uncoupling V-ATPases in vivo as potential drug targets are discussed. PMID- 22215675 TI - Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein. AB - WTX is a tumor suppressor protein that is lost or mutated in up to 30% of cases of Wilms tumor. Among its known functions, WTX interacts with the beta-transducin repeat containing family of ubiquitin ligase adaptors and promotes the ubiquitination and degradation of the transcription factor beta-catenin, a key control point in the WNT/beta-catenin signaling pathway. Here, we report that WTX interacts with a second ubiquitin ligase adaptor, KEAP1, which functions to regulate the ubiquitination of the transcription factor NRF2, a key control point in the antioxidant response. Surprisingly, we find that unlike its ability to promote the ubiquitination of beta-catenin, WTX inhibits the ubiquitination of NRF2. WTX and NRF2 compete for binding to KEAP1, and thus loss of WTX leads to rapid ubiquitination and degradation of NRF2 and a reduced response to cytotoxic insult. These results expand our understanding of the molecular mechanisms of WTX and reveal a novel regulatory mechanism governing the antioxidant response. PMID- 22215676 TI - Dimerization and cytoplasmic localization regulate Hippo kinase signaling activity in organ size control. AB - The Hippo (Hpo) signaling pathway controls organ size by regulating the balance between cell proliferation and apoptosis. Although the Hpo function is conserved, little is known about the mechanism of how its kinase activity is regulated. Based on structural information, we performed mutation-function analysis and provided in vitro and in vivo evidence that Hpo activation requires proper dimerization of its N-terminal kinase domain as well as the C-terminal SARAH domain. Hpo carrying point mutation M242E can still dimerize, yet the dimers formed between intermolecular kinase domains were altered in conformation. As a result, autophosphorylation of Hpo at Thr-195 was blocked, and its kinase activity was abolished. In contrast, Hpo carrying I634D, a single mutation introduced in the Hpo C-terminal SARAH domain, disrupted the dimerization of the SARAH domain, leading to reduced Hippo activity. We also find that the Hpo C terminal half contains two nuclear export signals that promote cytoplasmic localization and activity of Hpo. Taken together, our results suggest that dimerization and nucleocytoplasmic translocation of Hpo are crucial for its biological function and indicate that a proper dimer conformation of the kinase domain is essential for Hpo autophosphorylation and kinase activity. PMID- 22215677 TI - Mass spectrometry-assisted study reveals that lysine residues 1967 and 1968 have opposite contribution to stability of activated factor VIII. AB - The A2 domain rapidly dissociates from activated factor VIII (FVIIIa) resulting in a dampening of the activity of the activated factor X-generating complex. The amino acid residues that affect A2 domain dissociation are therefore critical for FVIII cofactor function. We have now employed chemical footprinting in conjunction with mass spectrometry to identify lysine residues that contribute to the stability of activated FVIII. We hypothesized that lysine residues, which are buried in FVIII and surface-exposed in dissociated activated FVIII (dis-FVIIIa), may contribute to interdomain interactions. Mass spectrometry analysis revealed that residues Lys(1967) and Lys(1968) of region Thr(1964)-Tyr(1971) are buried in FVIII and exposed to the surface in dis-FVIIIa. This result, combined with the observation that the FVIII variant K1967I is associated with hemophilia A, suggests that these residues contribute to the stability of activated FVIII. Kinetic analysis revealed that the FVIII variants K1967A and K1967I exhibit an almost normal cofactor activity. However, these variants also showed an increased loss in cofactor activity over time compared with that of FVIII WT. Remarkably, the cofactor activity of a K1968A variant was enhanced and sustained for a prolonged time relative to that of FVIII WT. Surface plasmon resonance analysis demonstrated that A2 domain dissociation from activated FVIII was reduced for K1968A and enhanced for K1967A. In conclusion, mass spectrometry analysis combined with site-directed mutagenesis studies revealed that the lysine couple Lys(1967)-Lys(1968) within region Thr(1964)-Tyr(1971) has an opposite contribution to the stability of FVIIIa. PMID- 22215678 TI - Insights into role of bromodomain, testis-specific (Brdt) in acetylated histone H4-dependent chromatin remodeling in mammalian spermiogenesis. AB - Mammalian spermiogenesis is of considerable biological interest especially due to the unique chromatin remodeling events that take place during spermatid maturation. Here, we have studied the expression of chromatin remodeling factors in different spermatogenic stages and narrowed it down to bromodomain, testis specific (Brdt) as a key molecule participating in chromatin remodeling during rat spermiogenesis. Our immunocytochemistry experiments reveal that Brdt colocalizes with acetylated H4 in elongating spermatids. Remodeling assays showed an acetylation-dependent but ATP-independent chromatin reorganization property of Brdt in haploid round spermatids. Furthermore, Brdt interacts with Smarce1, a member of the SWI/SNF family. We have studied the genomic organization of smarce1 and identified that it has two splice variants expressed during spermatogenesis. The N terminus of Brdt is involved in the recognition of Smarce1 as well as in the reorganization of hyperacetylated round spermatid chromatin. Interestingly, the interaction between Smarce1 and Brdt increases dramatically upon histone hyperacetylation both in vitro and in vivo. Thus, our results indicate this interaction to be a vital step in the chromatin remodeling process during mammalian spermiogenesis. PMID- 22215679 TI - Adaptive evolution of class 5 fimbrial genes in enterotoxigenic Escherichia coli and its functional consequences. AB - Class 5 fimbriae of enterotoxigenic Escherichia coli (ETEC) comprise eight serologically discrete colonization factors that mediate small intestinal adhesion. Their differentiation has been attributed to the pressure imposed by host adaptive immunity. We sequenced the major pilin and minor adhesin subunit genes of a geographically diverse population of ETEC elaborating CFA/I (n = 31), CS17 (n = 20), and CS2 (n = 18) and elucidated the functional effect of microevolutionary processes. Between the fimbrial types, the pairwise nucleotide diversity for the pilin or adhesin genes ranged from 35-43%. Within each fimbrial type, there were 17 non-synonymous and 1 synonymous point mutations among all pilin or adhesin gene copies, implying that each fimbrial type was acquired by ETEC strains very recently, consistent with a recent origin of this E. coli pathotype. The 17 non-synonymous allelic differences occurred in the CFA/I pilin gene cfaB (two changes) and adhesin gene cfaE (three changes), and CS17 adhesin gene csbD (12 changes). All but one amino acid change in the adhesins clustered around the predicted ligand-binding pocket. Functionally, these changes conferred an increase in cell adhesion in a flow chamber assay. In contrast, the two mutations in the non-adhesive CfaB subunit localized to the intersubunit interface and significantly reduced fimbrial adhesion in this assay. In conclusion, naturally occurring mutations in the ETEC adhesive and non-adhesive subunits altered function, were acquired under positive selection, and are predicted to impact bacteria-host interactions. PMID- 22215681 TI - Characterization of CYP76M5-8 indicates metabolic plasticity within a plant biosynthetic gene cluster. AB - Recent reports have revealed genomic clustering of enzymatic genes for particular biosynthetic pathways in plant specialized/secondary metabolism. Rice (Oryza sativa) carries two such clusters for production of antimicrobial diterpenoid phytoalexins, with the cluster on chromosome 2 containing four closely related/homologous members of the cytochrome P450 CYP76M subfamily (CYP76M5-8). Notably, the underlying evolutionary expansion of these CYP appears to have occurred after assembly of the ancestral biosynthetic gene cluster, suggesting separate roles. It has been demonstrated that CYP76M7 catalyzes C11alpha hydroxylation of ent-cassadiene, and presumably mediates an early step in biosynthesis of the derived phytocassane class of phytoalexins. Here we report biochemical characterization of CYP76M5, -6, and -8. Our results indicate that CYP76M8 is a multifunctional/promiscuous hydroxylase, with CYP76M5 and -7 seeming to provide only redundant activity, while CYP76M6 seems to provide both redundant and novel activity, relative to CYP76M8. RNAi-mediated double knockdown of CYP76M7 and -8 suppresses elicitor inducible phytocassane production, indicating a role for these monooxygenases in phytocassane biosynthesis. In addition, our data suggests that CYP76M5, -6, and -8 may play redundant roles in production of the oryzalexin class of phytoalexins as well. Intriguingly, the preceding diterpene synthase for oryzalexin biosynthesis, unlike that for the phytocassanes, is not found in the chromosome 2 diterpenoid biosynthetic gene cluster. Accordingly, our results not only uncover a complex evolutionary history, but also further suggest some intriguing differences between plant biosynthetic gene clusters and the seemingly similar microbial operons. The implications for the underlying metabolic evolution of plants are then discussed. PMID- 22215680 TI - Integrated stress response modulates cellular redox state via induction of cystathionine gamma-lyase: cross-talk between integrated stress response and thiol metabolism. AB - The integrated stress response mediated by eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation maintains cellular homeostasis under endoplasmic reticulum (ER) stress. eIF2alpha phosphorylation induces activating transcription factor 4 (ATF4), a basic leucine zipper transcription factor that regulates the expression of genes responsible for amino acid metabolism, cellular redox state, and anti-stress responses. Cystathionine gamma-lyase (CSE) and cystathionine beta-synthase are critical enzymes in the transsulfuration pathway, which also regulate cellular redox status by modulating glutathione (GSH) levels. To determine the link between the integrated stress response and the transsulfuration pathway, we used homocysteine (Hcy) as an inducer of eIF2alpha phosphorylation and ATF4 gene induction. Mouse embryonic fibroblasts (MEFs) lacking ATF4 (ATF4(-/-)) had reduced GSH levels and increased reactive oxygen species and were susceptible to apoptotic cell death under normal culture conditions. Further, ATF4(-/-) MEFs were more sensitive to Hcy-induced cytotoxicity and showed significantly reduced intracellular GSH levels associated with apoptosis. ATF4(-/-) MEFs could be rescued from l-Hcy-induced apoptosis by beta-mercaptoethanol medium supplementation that increases cysteine levels and restores GSH synthesis. ATF4(-/-) MEFs showed little or no CSE protein but did express cystathionine beta-synthase. Further, ER stress-inducing agents, including tunicamycin and thapsigargin, induced the expression of CSE in ATF4(+/+) MEFs. Consistent with ATF4(-/-) MEFs, CSE(-/-) MEFs showed significantly greater apoptosis when treated with tunicamycin, thapsigargin, and l-Hcy, compared with CSE(+/+) MEFs. Liver and kidney GSH levels were also reduced in CSE(-/-) mice, suggesting that CSE is a critical factor in GSH synthesis and may act to protect the liver and kidney from a variety of conditions that cause ER stress. PMID- 22215683 TI - Toward a better understanding of mouse models of disease. PMID- 22215684 TI - Pathobiology of aging mice and GEM: background strains and experimental design. AB - The use of induced and spontaneous mutant mice and genetically engineered mice (and combinations thereof) to study cancers and other aging phenotypes to advance improved functional human life spans will involve studies of aging mice. Genetic background contributes to pathology phenotypes and to causes of death as well as to longevity. Increased recognition of expected phenotypes, experimental variables that influence phenotypes and research outcomes, and experimental design options and rationales can maximize the utility of genetically engineered mice (GEM) models to translational research on aging. This review aims to provide resources to enhance the design and practice of chronic and longevity studies involving GEM. C57BL6, 129, and FVB/N strains are emphasized because of their widespread use in the generation of knockout, transgenic, and conditional mutant GEM. Resources are included also for pathology of other inbred strain families, including A, AKR, BALB/c, C3H, C57L, C58, CBA, DBA, GR, NOD.scid, SAMP, and SJL/J, and non-inbred mice, including 4WC, AB6F1, Ames dwarf, B6, 129, B6C3F1, BALB/c,129, Het3, nude, SENCAR, and several Swiss stocks. Experimental strategies for long-term cross-sectional and longitudinal studies to assess causes of or contributors to death, disease burden, spectrum of pathology phenotypes, longevity, and functional healthy life spans (health spans) are compared and discussed. PMID- 22215682 TI - Ringo/cyclin-dependent kinase and mitogen-activated protein kinase signaling pathways regulate the activity of the cell fate determinant Musashi to promote cell cycle re-entry in Xenopus oocytes. AB - Cell cycle re-entry during vertebrate oocyte maturation is mediated through translational activation of select target mRNAs, culminating in the activation of mitogen-activated protein kinase and cyclin B/cyclin-dependent kinase (CDK) signaling. The temporal order of targeted mRNA translation is crucial for cell cycle progression and is determined by the timing of activation of distinct mRNA binding proteins. We have previously shown in oocytes from Xenopus laevis that the mRNA-binding protein Musashi targets translational activation of early class mRNAs including the mRNA encoding the Mos proto-oncogene. However, the molecular mechanism by which Musashi function is activated is unknown. We report here that activation of Musashi1 is mediated by Ringo/CDK signaling, revealing a novel role for early Ringo/CDK function. Interestingly, Musashi1 activation is subsequently sustained through mitogen-activated protein kinase signaling, the downstream effector of Mos mRNA translation, thus establishing a positive feedback loop to amplify Musashi function. The identified regulatory sites are present in mammalian Musashi proteins, and our data suggest that phosphorylation may represent an evolutionarily conserved mechanism to control Musashi-dependent target mRNA translation. PMID- 22215685 TI - Aluminum toxicity in neonatal parenteral nutrition: what can we do? AB - Aluminum toxicity has been described in patients of all ages who are receiving a variety of therapies, including dialysis, phosphate-binding medications, and parenteral nutrition (PN). Neonates are at an increased risk of aluminum toxicity because of anatomic, physiologic, and nutrition-related factors not present in other populations. In 2004, the Food and Drug Administration recommended restricting daily aluminum administration to 5 MUg/kg/day and now requires that additives used to compound PN have the maximum aluminum content at expiration listed on the product label. Although the pharmacist can work to decrease aluminum toxicity in this population, it remains difficult to reach this threshold. PMID- 22215686 TI - Belatacept: a new biologic and its role in kidney transplantation. AB - OBJECTIVE: To review the pharmacology, efficacy, safety, and role of belatacept in maintenance immunosuppression in adult kidney transplant recipients (KTR). DATA SOURCES: PubMed, EMBASE, International Pharmaceutical Abstracts, Web of Knowledge (1990-November 2011), and Google were searched using the terms belatacept, kidney or renal, and transplant. STUDY SELECTION AND DATA EXTRACTION: Relevant articles (English language and human subjects) were reviewed. Selected studies included 3 Phase 2 and 2 Phase 3 trials. Data were compared with Food and Drug Administration (FDA) briefing documents and belatacept full prescribing information. DATA SYNTHESIS: Belatacept, a cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin, is the first marketed intravenous maintenance immunosuppressant. It is approved for use in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids to prevent rejection in adult KTR. Belatacept exhibits linear pharmacokinetics and first-order elimination. The less intensive regimen used in Phase 3 trials is approved by the FDA. In low-moderate immunologic risk KTR, short-term patient and allograft survival appear comparable with that seen with cyclosporine, with improved renal function despite more frequent and severe early acute rejection. Preliminary data from Phase 2 corticosteroid-avoidance and conversion trials suggest that better renal function, acceptable rejection rates, and comparable patient and allograft survival may be achieved with belatacept compared with calcineurin inhibitors (CNIs). Common adverse effects of belatacept include anemia, neutropenia, urinary tract infection, headache, and peripheral edema. While a more favorable cardiovascular and metabolic profile and lack of requirement for therapeutic drug monitoring are attractive, a higher frequency of posttransplant lymphoproliferative disorder is concerning. Belatacept drug costs are significantly higher than those of standard CNI- or sirolimus-based regimens. CONCLUSIONS: Belatacept provides a new option for maintenance immunosuppression in adult KTR. Further research is needed to compare its efficacy and safety with standard tacrolimus-based regimens, to evaluate whether increased drug costs are offset by long-term improvements in patient and allograft survival, and to establish its role in the immunosuppression armamentarium. PMID- 22215688 TI - Chemotherapy-induced spontaneous orgasms in a patient with breast cancer. PMID- 22215689 TI - Clinical experience with ranolazine in a veteran population with chronic stable angina. AB - BACKGROUND: Efficacy of ranolazine in the treatment of chronic stable angina (CSA) has been established; however, pivotal trials did not require the optimization of conventional antianginal drug therapy (CADT) prior to use in a veteran population. OBJECTIVE: To determine whether ranolazine, when added to optimized doses of CADT, improves angina in a veteran population with CSA and refractory symptoms. METHODS: In an observational retrospective study, 35 patients prescribed ranolazine and having a baseline Seattle Angina Questionnaire (SAQ) administered at a Veterans Affairs medical center in Gainesville, FL, were evaluated. Patients who were prescribed ranolazine by a provider from outside the institution and did not obtain a baseline SAQ were excluded. The primary outcome measure was the change in SAQ scores from baseline to 1 and 3 months after initiation of ranolazine treatment. Secondary measures included clinically significant QTc interval prolongation (>500 msec or an increase of at least 60 msec from baseline), adverse drug reactions, discontinuation rates, and drug-drug interactions. RESULTS: The addition of ranolazine to optimized CADT was associated with improvement in all dimensions of the SAQ scores at 1 and 3 months compared to baseline scores (p < 0.001 for all dimensions). Mean changes in SAQ dimension scores at 1 and 3 months, respectively, were as follows: physical limitation, +9.86 and +11.94; angina stability, +39.29 and +32.69; angina frequency, +26.79 and +25.38; treatment satisfaction, +11.38 and +10.66; and disease perception, +16.85 and +18.59. Improvments in all dimensions, except treatment satisfaction, were clinically significant as defined by set criteria. Of the 7 patients whose ranolazine dosages were increased to 1000 mg twice daily, only 2 patients were able to maintain treatment at that dosage. CONCLUSIONS: Ranolazine added to optimized doses of CADT demonstrated an improvement in angina symptoms when given to a veteran population with persistent CSA. PMID- 22215692 TI - Targeting the insulin-like growth factor axis for the development of novel therapeutics in oncology. AB - Insulin-like growth factors (IGF) are polypeptide hormones with potent anabolic and mitogenic effects that regulate cell growth and differentiation. Dysregulation of the IGF axis has been well documented in the development and progression of multiple types of cancer. As a result, compounds targeting the IGF axis have become an area of intense preclinical and clinical research for cancer therapeutics. The IGF axis is intimately involved with the insulin-signaling pathway because of their close homologies. This homology may explain hurdles encountered in the clinical development of IGF-targeted therapies, such as less than-expected antitumor efficacy that may arise from compensatory increases in the activity of insulin receptor isoform A (IR-A), in response to IGF-I receptor (IGF-IR) inhibition and perturbations in glucose homeostasis, arising from the inhibition of insulin receptor isoform B (IR-B) activity. In this brief review, we compare differentiating factors that characterize the 3 major classes of IGF targeting compounds: therapeutic antibodies that target IGF-IR, small molecule tyrosine kinase inhibitors that inhibit kinase activities of IGF-IR and IR, and antibodies that target IGF ligands. PMID- 22215696 TI - Systematic selection of screening participants by risk score in a Chlamydia screening programme is feasible and effective. AB - OBJECTIVES: Systematic screening for Chlamydia trachomatis by individual invitation can be optimised by filtering participants on risk profile, excluding people at no or low risk. The authors investigated this technique in a large scale chlamydia screening programme in The Netherlands in one rural region where relatively low prevalence was expected (<2%). METHODS: Invitees were alerted by personal letter to log in to http://www.chlamydiatest.nl and fill in an 8-item questionnaire. Only invitees with sufficient score could proceed to request a test kit. The authors investigated the effect of selection on participation, positivity and acceptability in three screening rounds and on the number needed to invite and the number needed to screen. RESULTS: The selection led to exclusion of 36% of potential participants and a positivity rate of 4.8% among participants, achieving similar number needed to screen values in the rural and urban areas. Higher scores were clearly related to higher positivity rates. Persons who were excluded from participation did not have a lower response in the next round. The acceptability study revealed disappointment about exclusion of 30% of excluded participants but most approved of the screening set-up. CONCLUSIONS: Systematic selection of screening participants by risk score is feasible and successful in realising higher positivity rates. A somewhat stricter selection could be applied in the rural and urban areas of the screening programme. Multiple-item selection with a cut-off total score may work better than, more commonly used, selection by single criteria, especially in low-risk populations. Acceptability of selection is high but could still be improved by better communication on expectations. PMID- 22215693 TI - Opposing effects of pigment epithelium-derived factor on breast cancer cell versus neuronal survival: implication for brain metastasis and metastasis-induced brain damage. AB - Brain metastases are a significant cause of morbidity and mortality for patients with cancer, yet preventative and therapeutic options remain an unmet need. The cytokine pigment epithelium-derived factor (PEDF) is downregulated in resected human brain metastases of breast cancer compared with primary breast tumors, suggesting that restoring its expression might limit metastatic spread. Here, we show that outgrowth of large experimental brain metastases from human 231-BR or murine 4T1-BR breast cancer cells was suppressed by PEDF expression, as supported by in vitro analyses as well as direct intracranial implantation. Notably, the suppressive effects of PEDF were not only rapid but independent of the effects of this factor on angiogenesis. Paralleling its cytotoxic effects on breast cancer cells, PEDF also exerted a prosurvival effect on neurons that shielded the brain from tumor-induced damage, as indicated by a relative 3.5-fold reduction in the number of dying neurons adjacent to tumors expressing PEDF. Our findings establish PEDF as both a metastatic suppressor and a neuroprotectant in the brain, highlighting its role as a double agent in limiting brain metastasis and its local consequences. PMID- 22215695 TI - HPV-related information sharing and factors associated with U.S. men's disclosure of an HPV test result to their female sexual partners. AB - OBJECTIVES: Prevalence of human papillomavirus (HPV) is high in both men and women, yet men have seldom been involved in HPV education/prevention programmes, and their disclosure of known HPV infection has rarely been studied. This analysis sought to determine factors associated with men's HPV test result disclosure and HPV-related information sharing with partners. METHODS: From 2007 to 2010, men enrolled in a psychosocial study of responses to HP testing who reported having a female main sexual partner (N=251) completed surveys including questions about HPV test results, disclosure of HPV test results to partner(s), relationship characteristics and stigma (for those who reported HPV-positive results) approximately 3 weeks after receiving an HPV test result. Logistic regression was conducted to determine factors associated with disclosure of HPV test results in cross-sectional analysis. RESULTS: Most men disclosed their test results to a main partner (82%). Self-reported HPV-negative test result, a high school education and a higher commitment to a sexual partner were significantly associated with increased disclosure in multivariable analysis. Men who disclosed (vs those who did not) were significantly more likely to provide their partners with HPV-related information. Among men who disclosed to their main partner, nearly half reported that partner asked them questions about HPV. CONCLUSIONS: Results from this study highlight the critical role that men who are symptomatic for, who are tested for or who are vaccinated against HPV can play in educating their sexual partners, independent of whether they actually disclose their test results. PMID- 22215697 TI - Social dominance orientation: revisiting the structure and function of a variable predicting social and political attitudes. AB - Social dominance orientation (SDO) is one of the most powerful predictors of intergroup attitudes and behavior. Although SDO works well as a unitary construct, some analyses suggest it might consist of two complementary dimensions -SDO-Dominance (SDO-D), or the preference for some groups to dominate others, and SDO-Egalitarianism (SDO-E), a preference for nonegalitarian intergroup relations. Using seven samples from the United States and Israel, the authors confirm factor analytic evidence and show predictive validity for both dimensions. In the United States, SDO-D was theorized and found to be more related to old-fashioned racism, zero-sum competition, and aggressive intergroup phenomena than SDO-E; SDO-E better predicted more subtle legitimizing ideologies, conservatism, and opposition to redistributive social policies. In a contentious hierarchical intergroup context (the Israeli-Palestinian context), SDO-D better predicted both conservatism and aggressive intergroup attitudes. Fundamentally, these analyses begin to establish the existence of complementary psychological orientations underlying the preference for group-based dominance and inequality. PMID- 22215699 TI - When bias and insecurity promote accuracy: mean-level bias and tracking accuracy in couples' conflict discussions. AB - Heterosexual couples (N = 57) discussed features about each other they wanted to change. During a review of their recorded discussions, for each 30 s of interaction, perceivers provided judgments of their partner's regard, and partners reported their actual regard for the perceiver. The authors simultaneously assessed the extent to which perceivers' over- or underestimated their partner's regard (mean-level bias) and tracked their partner's changing regard across the discussion (tracking accuracy). Perceivers on average tended to underestimate their partner's regard (negative mean-level bias) but exhibited substantial tracking accuracy. Bias and accuracy were related; perceivers that were more negatively biased more accurately tracked changes in their partner's regard. Women who were more insecure about their partner's continued regard demonstrated more negative mean-level bias and greater tracking accuracy, whereas more secure women demonstrated more positive bias and lower accuracy. The results indicate that bias and accuracy are shaped by context-relevant goals and motives. PMID- 22215698 TI - Social roles, basic need satisfaction, and psychological health: the central role of competence. AB - The authors propose that competence need fulfillment within valued role domains (i.e., spouse, parent, worker) will account, in part, for associations between autonomy and relatedness need fulfillment and psychological health. Testing these assertions in cross-sectional and longitudinal surveys of women in two independent community samples, the findings are the first to formally examine whether the satisfaction of competence needs within social roles accounts for associations between other types of need satisfaction and affective outcomes as well as depressive symptomology. Evidence supporting the hypothesis was stronger when examining individuals' affective health as compared to their depressive symptoms. Implications of the findings are discussed with regard to need fulfillment within social roles. PMID- 22215700 TI - More than a feeling: discrete emotions mediate the relationship between relative deprivation and reactions to workplace furloughs. AB - A key insight from investigations of individual relative deprivation (IRD) is that people can experience objective disadvantages differently. In this study, university faculty (N = 953) who reported greater IRD in response to a mandatory furlough (i.e., involuntary pay reductions) were more likely to (a) voice options designed to improve the university (voice), (b) consider leaving their job (exit), and (c) neglect their work responsibilities (neglect), but were (d) less likely to express loyalty to the university (loyalty). Consistent with the emotions literature, (a) anger mediated the relationship between IRD and voice, (b) fear between IRD and exit, (c) sadness between IRD and neglect, and (d) gratitude between IRD and loyalty. IRD was inversely associated with self reported physical and mental health via these different emotional pathways. These results show how discrete emotions can explain responses to IRD and, in turn, contribute to organizational viability and the health of its members. PMID- 22215701 TI - When aggressive individuals see the world more accurately: the case of perceptual sensitivity to subtle facial expressions of anger. AB - Previous research has suggested that aggressive individuals exhibit a bias to perceive nonangry expressions as angry. Another line of thinking, however, posits that aggression is a learned response to hostile environments and should be linked to social-cognitive skills suited to such environments. If so, aggressive individuals may exhibit greater perceptual sensitivity to subtle facial cues of anger. Three studies were conducted to test this proposal. In them, participants' ability to discriminate between subtly different intensities of facial anger was tested. Aggressive participants generally displayed greater perceptual sensitivity to subtle cues of facial anger. This pattern could not be explained in terms of response bias and was specific to angry expressions. The results thus support the idea that aggression is associated with social-cognitive skills rather than bias and ineptitude. PMID- 22215702 TI - The eyes and ears of status: how status colors perceptual judgment. AB - To those with high status, abundance is granted. Moving beyond the multitude of objective benefits, the authors explore how status, once conferred, colors the perceptual world people inhabit. In four experiments, participants' status state influenced their judgments of status-relevant features in their environment. Participants in a state of high status reported hearing applause (Experiment 1) and seeing facial expressions (Experiment 2), in reaction to their performance, as louder and more favorable. In addition, expectations of how others will respond--expectations stemming from one's current status state--accounted for this effect (Experiment 3). Finally, differences in judgments between participants experiencing high versus low status were observed only when the target of the evaluation was the self (Experiment 4). These results advance scholars' understanding of the psychological experience of status and contribute to the growing literature on the dominant influence psychological states have on people's judgments of their social world. PMID- 22215703 TI - Triggering self-presentation efforts outside of people's conscious awareness. AB - Three studies utilized priming techniques to examine whether self-presentations can be activated without conscious awareness. The results across all experiments consistently demonstrated nonconscious self-presentation effects, in that people were unaware that their self-presentations were triggered automatically and that their self-presentations were comparable to participants who were explicitly instructed to self-present. The findings are novel because they are the first to demonstrate that self-presentations can be triggered without conscious awareness in a manner similar to self-presentations that are strategically selected. In addition, the results help undermine the common misconception that self presentation typically involves conscious deliberation, pretense, or outright deception. PMID- 22215704 TI - Prognostic value of the variability in home-measured blood pressure and heart rate: the Finn-Home Study. AB - The objective of the study was to assess the prognostic value of variability in home-measured blood pressure (BP) and heart rate (HR) in a general population. We studied a representative sample of the Finnish adult population with 1866 study subjects aged 45-74 years. BP and HR self-measurements were performed on 7 consecutive days. The variabilities of BP and HR were defined as the SDs of morning minus evening, day-by-day, and first minus second measurements. The primary end point was incidence of a cardiovascular event. The secondary end point was total mortality. During a follow-up of 7.8 years, 179 subjects had experienced a cardiovascular event, and 130 subjects had died. In Cox proportional hazard models adjusted for age, sex, BP/HR, and other cardiovascular risk factors, morning-evening home BP variability (systolic/diastolic relative hazard: 1.04/1.10 [95% CI: 1.01-1.07/1.05-1.15] per 1-mm Hg increase in BP variability) and morning day-by-day home BP variability (relative hazard: 1.04/1.10 [95% CI: 1.00-1.07/1.04-1.16] per 1-mm Hg increase in BP variability) were predictive of cardiovascular events. Morning-evening home HR variability (relative hazard: 1.07 [95% CI: 1.02-1.12] per 1-bpm increase in HR variability) and morning day-by-day home HR variability (relative hazard: 1.11 [95% CI: 1.05 1.17] per 1-bpm increase in HR variability) were also independent predictors of cardiovascular events. Greater variabilities of morning home BP and HR are independent predictors of cardiovascular events. Because the variabilities of home BP and HR are easily acquired in conjunction with home BP and HR level, they should be used as the additive information in the assessment of cardiovascular risk. PMID- 22215705 TI - Angiotensin-(1-7) deficiency and baroreflex impairment precede the antenatal Betamethasone exposure-induced elevation in blood pressure. AB - Betamethasone is administered to accelerate lung development and improve survival of premature infants but may be associated with hypertension later in life. In a sheep model of fetal programming resulting from exposure at day 80 of gestation to Betamethasone (Beta-exposed), adult sheep at 6 to 9 months or 1.8 years of age have elevated mean arterial pressure (MAP) and attenuated spontaneous baroreflex sensitivity (sBRS) for control of heart rate compared to age-matched controls associated with imbalances in angiotensin (Ang) II vs Ang-(1-7) tone. At 6 weeks of age, evoked BRS is already low in the Beta-exposed animals. In this study, we assessed the potential contribution of the renin-angiotensin system to the impaired sBRS. Female lambs (6 weeks old) with Beta exposure in utero had similar MAP to control lambs (78+/-2 vs 77+/-2 mm Hg, n=4-5 per group), but lower sBRS (8+/-1 vs 16+/-3 ms/mm Hg; P<0.05) and impaired heart rate variability. Peripheral AT1 receptor blockade using candesartan lowered MAP in both groups (~10 mm Hg) and improved sBRS and heart rate variability in Beta-exposed lambs to a level similar to control. AT7 receptor blockade by infusion of D-ala Ang-(1-7) (700 ng/kg/min for 45 minutes) reduced sBRS 46%+/-10% in Beta-exposed vs in control lambs (P<0.15) and increased MAP in both groups (~6+/-2 mm Hg). Our data reveal that Beta exposure impairs sBRS and heart rate variability at a time point preceding the elevation in MAP via mechanisms involving an imbalance in the Ang II/Ang-(1-7) ratio consistent with a progressive loss in Ang-(1-7) function. PMID- 22215707 TI - Preface for the Joint Proceedings of the High Blood Pressure Research 2011 Scientific Sessions and the Inter-American Society of Hypertension Meeting. PMID- 22215706 TI - Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia. AB - The cardinal manifestations of the pregnancy-specific disorder preeclampsia, new onset hypertension, and proteinuria that resolve with placental delivery have been linked to an extracellular protein made by the placenta, soluble fms-like tyrosine kinase 1 (sFlt1), that injures the maternal vasculature. However, the mechanisms by which sFlt1, which is heavily matrix bound, gain access to the systemic circulation remain unclear. Here we report that the preeclamptic placenta's outermost layer, the syncytiotrophoblast, forms abundant "knots" that are enriched with sFlt1 protein. These syncytial knots easily detach from the syncytiotrophoblast, resulting in free, multinucleated aggregates (50-150 MUm diameter) that are loaded with sFlt1 protein and mRNA, are metabolically active, and are capable of de novo gene transcription and translation. At least 25% of the measurable sFlt1 in the third-trimester maternal plasma is bound to circulating placental microparticles. We conclude that detachment of syncytial knots from the placenta results in free, transcriptionally active syncytial aggregates that represent an autonomous source of sFlt1 delivery into the maternal circulation. The process of syncytial knot formation, shedding of syncytial aggregates, and appearance of placental microparticles in the maternal circulation appears to be greatly accelerated in preeclampsia and may contribute to the maternal vascular injury that characterizes this disorder. PMID- 22215710 TI - Placenta messages to the mother: not just debris. PMID- 22215708 TI - Role of renal DJ-1 in the pathogenesis of hypertension associated with increased reactive oxygen species production. AB - The D(2) dopamine receptor (D(2)R) is important in the pathogenesis of essential hypertension. We have already reported that systemic deletion of the D(2)R gene in mice results in reactive oxygen species (ROS)-dependent hypertension, suggesting that the D(2)R has antioxidant effects. However, the mechanism of this effect is unknown. DJ-1 is a protein that has antioxidant properties. D(2)R and DJ-1 are expressed in the mouse kidney and colocalize and coimunoprecipitate in mouse renal proximal tubule cells. We hypothesized that D(2)Rs regulate renal ROS production in the kidney through regulation of DJ-1 expression or function. Heterozygous D(2)(+/-) mice have increased blood pressure, urinary 8 isoprostanes, and renal Nox 4 expression, but decreased renal DJ-1 expression. Silencing D(2)R expression in mouse renal proximal tubule cells increases ROS production and decreases the expression of DJ-1. Conversely, treatment of these cells with a D(2)R agonist increases DJ-1 expression and decreases Nox 4 expression and NADPH oxidase activity, effects that are partially blocked by a D(2)R antagonist. Silencing DJ-1 expression in mouse renal proximal tubule cells increases ROS production and Nox 4 expression. Selective renal DJ-1 silencing by the subcapsular infusion of DJ-1 siRNA in mice increases blood pressure, renal Nox4 expression, and NADPH oxidase activity. These results suggest that the inhibitory effects of D(2)R on renal ROS production are at least, in part, mediated by a positive regulation of DJ-1 expression/function and that DJ-1 may have a role in the prevention of hypertension associated with increased ROS production. PMID- 22215709 TI - Agonistic autoantibodies as vasodilators in orthostatic hypotension: a new mechanism. AB - Agonistic autoantibodies to the beta-adrenergic and muscarinic receptors are a novel investigative and therapeutic target for certain orthostatic disorders. We have identified the presence of autoantibodies to beta2-adrenergic and/or M3 muscarinic receptors by ELISA in 75% (15 of 20) of patients with significant orthostatic hypotension. Purified serum IgG from all 20 of the patients and 10 healthy control subjects were examined in a receptor-transfected cell-based cAMP assay for beta2 receptor activation and beta-arrestin assay for M3 receptor activation. There was a significant increase in IgG-induced activation of beta2 and M3 receptors in the patient group compared with controls. A dose response was observed for both IgG activation of beta2 and M3 receptors and inhibition of their activation with the nonselective beta blocker propranolol and muscarinic blocker atropine. The antibody effects on beta2 and/or M3 (via production of NO) receptor-mediated vasodilation were studied in a rat cremaster resistance arteriole assay. Infusion of IgG from patients with documented beta2 and/or M3 receptor agonistic activity produced a dose-dependent vasodilation. Sequential addition of the beta-blocker propranolol and the NO synthase inhibitor N(G)-nitro L-arginine methyl ester partially inhibited IgG-induced vasodilation (percentage of maximal dilatory response: from 57.7+/-10.4 to 35.3+/-4.6 and 24.3+/-5.8, respectively; P<0.01; n=3), indicating that antibody activation of vascular beta2 and/or M3 receptors may contribute to systemic vasodilation. These data support the concept that circulating agonistic autoantibodies serve as vasodilators and may cause or exacerbate orthostatic hypotension. PMID- 22215711 TI - Appropriate time interval to repeat ambulatory blood pressure monitoring in patients with white-coat resistant hypertension. AB - Resistant hypertension is defined as uncontrolled office blood pressure, despite the use of >=3 antihypertensive drugs. Ambulatory blood pressure monitoring (ABPM) is mandatory to diagnose 2 different groups, those with true and white coat resistant hypertension. Patients are found to change categories between controlled/uncontrolled ambulatory pressures without changing their office blood pressures. In this way, ABPM should be periodically repeated. The aim of this study was to evaluate the most appropriate time interval to repeat ABPM to assure sustained blood pressure control in patients with white-coat resistant hypertension. This prospective study enrolled 198 patients (69% women; mean age: 68.9+/-9.9 years) diagnosed as white-coat resistant hypertension on ABPM. Patients were submitted to a second confirmatory examination 3 months later and repeated twice at 6-month intervals. Statistical analyses included Bland-Altman repeatability coefficients and multivariate logistic regression. Mean office blood pressure was 163+/-20/84+/-17 mm Hg, and mean 24-hour blood pressure was 118+/-8/66+/-7 mm Hg. White-coat resistant hypertension diagnosis presented a moderate reproducibility and was confirmed in 144 patients after 3 months. In the third and fourth ABPMs, 74% and 79% of patients sustained the diagnosis. In multivariate regression, a daytime systolic blood pressure <=115 mm Hg in the confirmatory ABPM triplicated the chance of white-coat resistant hypertension status persistence after 1 year. In conclusion, a confirmatory ABPM is necessary after 3 months of the first white-coat-resistant hypertension diagnosis, and the procedure should be repeated at 6-month intervals, except in patients with daytime systolic blood pressure <=115 mm Hg, in whom it may be repeated annually. PMID- 22215712 TI - Tetrahydrobiopterin and endothelial nitric oxide synthase uncoupling. PMID- 22215713 TI - Exercise training prevents the microvascular rarefaction in hypertension balancing angiogenic and apoptotic factors: role of microRNAs-16, -21, and -126. AB - Aerobic exercise training (ET) lowers hypertension and improves patient outcomes in cardiovascular disease. The mechanisms of these effects are largely unknown. We hypothesized that ET modulates microRNAs (miRNAs) involved in vascularization. miRNA-16 regulates the expression of vascular endothelial growth factor and antiapoptotic protein Bcl-2. miRNA-21 targets Bcl-2. miRNA-126 functions by repressing regulators of the vascular endothelial growth factor pathway. We investigated whether miRNA-16, -21 and -126 are modulated in hypertension and by ET. Twelve-week-old male spontaneously hypertensive rats (SHRs; n=14) and Wistar Kyoto (WKY; n=14) rats were assigned to 4 groups: SHRs, trained SHRs (SHR-T), Wistar Kyoto rats, and trained Wistar Kyoto rats. ET consisted of 10 weeks of swimming. ET reduced blood pressure and heart rate in SHR-Ts. ET repaired the slow-to-fast fiber type transition in soleus muscle and the capillary rarefaction in SHR-Ts. Soleus miRNA-16 and -21 levels increased in SHRs paralleled with a decrease of 48% and 25% in vascular endothelial growth factor and Bcl-2 protein levels, respectively. Hypertension increased Bad and decreased Bcl-x and endothelial NO synthase levels and lowered p-Bad(ser112):Bad ratio. ET in SHR-Ts reduced miRNA-16 and -21 levels and elevated vascular endothelial growth factor and Bcl-2 levels. ET restored soleus endothelial NO synthase levels plus proapoptotic and antiapoptotic mediators in SHR-Ts, indicating that the balance between angiogenic and apoptotic factors may prevent microvascular abnormalities in hypertension. miRNA-126 levels were reduced in SHRs with an increase of 51% in phosphoinositol-3 kinase regulatory subunit 2 expression but normalized in SHR Ts. Our data show that ET promoted peripheral revascularization in hypertension, which could be associated with regulation of select miRNAs, suggesting a mechanism for its potential therapeutic application in vascular diseases. PMID- 22215714 TI - Tonic postganglionic sympathetic inhibition induced by afferent renal nerves? AB - Other than efferent sympathetic innervation, the kidney has peptidergic afferent fibers expressing TRPV1 receptors and releasing substance P. We tested the hypothesis that stimulation of afferent renal nerve activity with the TRPV1 agonist capsaicin inhibits efferent renal sympathetic nerve activity tonically by a neurokinin 1 receptor-dependant mechanism. Anesthetized Sprague-Dawley rats were instrumented as follows: (1) arterial and venous catheters for recording of blood pressure and heart rate and drug administration; (2) left-sided renal arterial catheter for selective intrarenal administration of the TRPV1 agonist capsaicin (3.3, 6.6, 10, 33*10(-7) m; 10 MUL; after 15, 30, 45, and 60 minutes, respectively) to stimulate afferent renal nerve activity; (3) right-sided bipolar electrode for continuous renal sympathetic nerve recording; and (4) specialized renal pelvic and renal artery catheters to separate pelvic from intrarenal afferent activity. Before and after intrarenal capsaicin application, increasing intravenous doses of the neurokinin 1 receptor blocker RP67580 were given. Intrarenal capsaicin decreased integrated renal sympathetic activity from 65.4+/ 13.0 mV*s (baseline) to 12.8+/-3.2 mV*s (minimum; P<0.01). This sustained renal sympathetic inhibition reached its minimum within 70 minutes and was not directly linked to the transient electric afferent response to be expected with intrarenal capsaicin. Suppressed renal sympathetic activity transiently but completely recovered after intravenous administration of the neurokinin 1 blocker (maximum: 120.3+/-19.4 mV*s; P<0.01). Intrarenal afferent activity could be unequivocally separated from pelvic afferent activity. For the first time we provide direct evidence that afferent intrarenal nerves provide a tonically acting sympathoinhibitory system, which seems to be rather mediated by neurokinin release acting via neurokinin 1 receptor pathways rather than by electric afferent effects on central sympathetic outflow. PMID- 22215715 TI - Asymmetric dimethylarginine and reactive oxygen species: unwelcome twin visitors to the cardiovascular and kidney disease tables. AB - Plasma levels of asymmetric dimethylarginine or markers of reactive oxygen species are increased in subjects with risk factors for cardiovascular disease or chronic kidney disease. We tested the hypothesis that reactive oxygen species generate cellular asymmetric dimethylarginine that together cause endothelial dysfunction that underlies the risk of subsequent disease. Rat preglomerular vascular smooth muscle cells transfected with p22(phox) had increased NADPH oxidase activity, enhanced activity and expression of protein arginine methyltransferase, and reduced activity and protein expression of dimethylarginine dimethylaminotransferase and of cationic amino acid transferase 1 resulting in increased cellular levels of asymmetric dimethylarginine. Rats infused with angiotensin II had oxidative stress. The endothelial function of their mesenteric arterioles was changed from vasodilatation to vasoconstriction, accompanied by increased vascular asymmetric dimethylarginine. All of these changes were prevented by Tempol. In vivo silencing of dimethylarginine dimethylaminotransferase 1 increased plasma levels of asymmetric dimethylarginine, whereas silencing of dimethylarginine dimethylaminotransferase 2 impaired endothelial function. We suggest that initiation factors, such as angiotensin II, expressed in blood vessels or tissues of subjects with cardiovascular and kidney disease risk factors generate reactive oxygen species from NADPH oxidase that enhances cellular asymmetric dimethylarginine in an amplification loop. This leads to adverse changes in vascular and organ functions, as a consequence of reduced tissue levels of NO and increased reactive oxygen species. Thus, we conclude that reactive oxygen species and asymmetric dimethylarginine form a tightly coupled amplification system that translates cardiovascular/kidney risk into overt disease. PMID- 22215716 TI - Glycogen phosphorylase isoenzyme BB plasma concentration is elevated in pregnancy and preterm preeclampsia. AB - Glycogen phosphorylase is a key enzyme in glycogenolysis. Released with myocardial ischemia, blood concentration of glycogen phosphorylase isoenzyme BB (GPBB) is a marker of acute coronary syndromes. Pregnancy imposes metabolic stress, and preeclampsia is associated with cardiac complications. However, plasma GPBB concentration during pregnancy is unknown. This study was conducted to determine maternal plasma GPBB concentration in normal pregnancy and in preeclampsia. Plasma samples from 6 groups (n=396) were studied: nonpregnant and pregnant women with normal term delivery, term and preterm preeclampsia, and term and preterm small-for-gestational-age neonates. GPBB concentration was measured with a specific immunoassay. Placental tissues (n=45) obtained from pregnant women with preterm and term preeclampsia, spontaneous preterm delivery, and normal term delivery were analyzed for potential GPBB expression by immunoblotting. Median plasma GPBB concentration was higher in pregnant women than in nonpregnant women (38.7 versus 9.2 ng/mL; P<0.001), which remained significant after adjusting for age, race, and parity. Maternal plasma GPBB concentrations did not change throughout gestation. Cases of preterm (but not term) preeclampsia had higher median plasma GPBB concentrations than gestational age-matched normal pregnancy cases (72.6 versus 26.0 ng/mL; P=0.001). Small-for gestational-age neonates did not affect plasma GPBB concentration. GPBB was detected in the placenta and was less abundant in preterm preeclampsia than in preterm delivery cases (P<0.01). There is physiological elevation of plasma GPBB concentration during pregnancy; an increase in maternal plasma GPBB is a novel phenotype of preterm preeclampsia. It is strongly suggested that these changes are attributed to GPBB of placental origin. PMID- 22215717 TI - Direct angiotensin II type 2 receptor stimulation in Nomega-nitro-L-arginine methyl ester-induced hypertension: the effect on pulse wave velocity and aortic remodeling. AB - Pulse wave velocity (PWV), a direct marker of arterial stiffness, is an independent cardiovascular risk factor. Although the angiotensin II type 1 receptor blockade belongs to major antihypertensive and cardioprotective therapies, less is known about the effects of long-term stimulation of the angiotensin II type 2 receptor. Previously, compound 21, a selective nonpeptide angiotensin II type 2 receptor agonist improved the outcome of myocardial infarction in rats along with anti-inflammatory properties. We investigated whether compound 21 alone or in combination with angiotensin II type 1 receptor blockade by olmesartan medoxomil could prevent PWV increase and aortic remodeling in N(omega)-nitro-L-arginine-methyl ester (L-NAME)-induced hypertension. Male adult Wistar rats (n=65) were randomly assigned to control, L-NAME, L NAME+compound-21, L-NAME+olmesartan, and L-NAME+olmesartan+compound-21 groups and treated for 6 weeks. We observed that L-NAME hypertension was accompanied by enhanced PWV, increased wall thickness, and stiffness of the aorta, along with elevated hydroxyproline concentration. Olmesartan completely prevented hypertension, PWV and wall thickness increase, and the increase of aortic stiffness and partly prevented hydroxyproline accumulation. Compound 21 partly prevented all of these alterations, yet without concomitant prevention of blood pressure rise. Although the combination therapy with olmesartan and compound 21 led to blood pressure levels, PWV, and wall thickness comparable to olmesartan alone-treated rats, only in the combination group was complete prevention of increased hydroxyproline deposition achieved, resulting in even more pronounced stiffness reduction. We conclude that chronic angiotensin II type 2 receptor stimulation prevented aortic stiffening and collagen accumulation without preventing hypertension in rats with inhibited NO synthase. These effects were additive to angiotensin II type 1 receptor blockade, yet without additional blood pressure-lowering effect, and they seem to be NO and blood pressure independent. PMID- 22215720 TI - Independent contrasts and PGLS regression estimators are equivalent. AB - We prove that the slope parameter of the ordinary least squares regression of phylogenetically independent contrasts (PICs) conducted through the origin is identical to the slope parameter of the method of generalized least squares (GLSs) regression under a Brownian motion model of evolution. This equivalence has several implications: 1. Understanding the structure of the linear model for GLS regression provides insight into when and why phylogeny is important in comparative studies. 2. The limitations of the PIC regression analysis are the same as the limitations of the GLS model. In particular, phylogenetic covariance applies only to the response variable in the regression and the explanatory variable should be regarded as fixed. Calculation of PICs for explanatory variables should be treated as a mathematical idiosyncrasy of the PIC regression algorithm. 3. Since the GLS estimator is the best linear unbiased estimator (BLUE), the slope parameter estimated using PICs is also BLUE. 4. If the slope is estimated using different branch lengths for the explanatory and response variables in the PIC algorithm, the estimator is no longer the BLUE, so this is not recommended. Finally, we discuss whether or not and how to accommodate phylogenetic covariance in regression analyses, particularly in relation to the problem of phylogenetic uncertainty. This discussion is from both frequentist and Bayesian perspectives. PMID- 22215718 TI - Chronic intrarenal insulin replacement reverses diabetes mellitus-induced natriuresis and diuresis. AB - We showed recently that sustained natriuresis in type 1 diabetic dogs was attributed to the decrease in insulin rather than the hyperglycemia alone. The sodium-retaining action of insulin appeared to require hyperglycemia, and it completely reversed the diabetic natriuresis and diuresis. This study tested whether the sodium-retaining effect was attributed to direct intrarenal actions of insulin. Alloxan-treated dogs (D; n=7) were maintained normoglycemic using 24 h/d IV insulin replacement. After control measurements, IV insulin was decreased to begin a 6-day diabetic period. Blood glucose increased from 84+/-6 mg/dL to an average of 428 mg/dL on days 5 and 6, sodium excretion increased from 74+/-8 to 98+/-7 meq/d over the 6 days, and urine volume increased from 1645+/-83 to 2198+/ 170 mL/d. Dir dogs (n=7) were subjected to the same diabetic regimen, but, in addition, insulin was infused continuously into the renal artery at 0.3 mU/kg per minute during the 6-day period. This did not affect plasma insulin. Blood glucose increased from 94+/-10 mg/dL to an average of 380 mg/dL on days 5 and 6, but sodium excretion averaged 76+/-5 and 69+/-8 meq/d during control and diabetes mellitus, respectively. The diuresis also was prevented. Glomerular filtration rate increased only in Dir dogs, and there was no change in mean arterial pressure in either group. This intrarenal insulin infusion had no effect on sodium or volume excretion in normal dogs. Intrarenal insulin replacement in diabetic dogs caused a sustained increase in tubular reabsorption that completely reversed diabetic natriuresis. Insulin plus glucose may work to prevent salt wasting in uncontrolled type 2 diabetes mellitus. PMID- 22215721 TI - Is recombination a problem for species-tree analyses? PMID- 22215719 TI - Sensitization of slow pressor angiotensin II (Ang II)-initiated hypertension: induction of sensitization by prior Ang II treatment. AB - Sensitization involving the central nervous system has been studied in many conditions but has received little attention in investigation of the pathogenesis of hypertension. Our experiments were initiated to determine whether angiotensin II (Ang II)-induced hypertension can be sensitized by prior Ang II treatment and the role of the brain renin-angiotensin-aldosterone system (RAAS) in this process. To demonstrate Ang II-induced sensitization, we used an experimental design of induction-delay-expression. Male rats were implanted for telemetered blood pressure (BP) recording. During induction (I), low doses of subcutaneous or intracerebroventricular Ang II were delivered for 1 week, and then the rats were rested for 1 week (delay [D]) to ensure that any exogenous Ang II was metabolized. After this, a second higher dose of Ang II was given subcutaneously for 2 weeks (expression [E]). During I and D, the low doses of Ang II had no sustained effects on BP. However, during E, the Ang II-induced BP increase was greater in the groups that had received low doses of Ang II during I in comparison to the group receiving saline during I. Central angiotensin type 1 receptor antagonist delivery blocked this sensitization. Brain tissue collected at the end of D and E showed increased mRNA expression of several RAAS components in key forebrain regions of sensitized rats. Fos-related antigen-like immunoreactivity was also increased at the end of E in the sensitized forebrain. These results indicate that subpressor doses of Ang II act on the brain to sensitize the hypertensive response to subsequent Ang II and that sensitization is associated with altered expression of RAAS components in forebrain cardiovascular control structures. PMID- 22215722 TI - Autophagy as a therapeutic target for ischaemia /reperfusion injury? Concepts, controversies, and challenges. AB - Autophagy is the tightly orchestrated cellular 'housekeeping' process responsible for the degradation and disposal of damaged and dysfunctional organelles and protein aggregates. In addition to its established basal role in the maintenance of normal cellular phenotype and function, there is growing interest in the concept that targeted modulation of autophagy under conditions of stress (most notably, ischaemia/reperfusion) may represent an adaptive mechanism and render the myocardium resistant to ischaemia/reperfusion injury. Our aims in this review are to: (i) provide a balanced overview of the emerging hypothesis that perturbation of autophagy may serve as a novel, intriguing, and powerful cardioprotective treatment strategy and (ii) summarize the controversies and challenges in exploiting autophagy as a therapeutic target for ischaemia/reperfusion injury. PMID- 22215723 TI - Mitochondrial complex II is essential for hypoxia-induced pulmonary vasoconstriction of intra- but not of pre-acinar arteries. AB - AIMS: Alveolar hypoxia acutely elicits contraction of pulmonary arteries, leading to a rise in pulmonary arterial pressure (PAP) and shifting blood to better ventilated areas of the lung. The molecular mechanisms underlying this hypoxic pulmonary vasoconstriction (HPV) are still incompletely understood. Here, we investigated the role of succinate dehydrogenase (SDH; synonymous to mitochondrial complex II) in HPV, with particular emphasis on regional differences along the vascular bed and consequences for PAP and perfusion-to ventilation matching, using mutant mice heterozygous for the SDHD subunit of complex II (SDHD(+/-)). METHODS AND RESULTS: Western blots revealed reduced protein content of complex II subunits SDHA, SDHB, and SDHC in lungs of SDHD(+/-) mice, despite unaffected mRNA content as determined by real-time PCR. Hypoxic pulmonary vasoconstriction of small (20-50 um) intra-acinar and larger (51-100 um) pre-acinar arteries was evaluated by videomorphometric analysis of precision cut lung slices. The hypoxic response was detectable in pre-acinar arteries but absent from intra-acinar arteries of SDHD(+/-) mice. In isolated perfused lungs, basal PAP and its hypoxia-induced increase were indistinguishable between both mouse strains. Arterial oxygenation was measured after provocation of regional ventilatory failure by tracheal fluid instillation in anaesthetized mice, and it declined more in SDHD(+/-) than in wild-type mice. CONCLUSION: SDHD is required for the formation of a stable mitochondrial complex II and it is selectively important for HPV of intra-acinar vessels. This specialized vascular segment participates in perfusion-to-ventilation matching but does not significantly contribute to the acute hypoxic rise in PAP that results from more proximal vasoconstriction. PMID- 22215725 TI - The big four-oh. PMID- 22215724 TI - Activated CD47 promotes pulmonary arterial hypertension through targeting caveolin-1. AB - AIMS: Pulmonary arterial hypertension (PAH) is a progressive lung disease characterized by pulmonary vasoconstriction and vascular remodelling, leading to increased pulmonary vascular resistance and right heart failure. Loss of nitric oxide (NO) signalling and increased endothelial nitric oxide synthase (eNOS) derived oxidative stress are central to the pathogenesis of PAH, yet the mechanisms involved remain incompletely determined. In this study, we investigated the role activated CD47 plays in promoting PAH. METHODS AND RESULTS: We report high-level expression of thrombospondin-1 (TSP1) and CD47 in the lungs of human subjects with PAH and increased expression of TSP1 and activated CD47 in experimental models of PAH, a finding matched in hypoxic human and murine pulmonary endothelial cells. In pulmonary endothelial cells CD47 constitutively associates with caveolin-1 (Cav-1). Conversely, in hypoxic animals and cell cultures activation of CD47 by TSP1 disrupts this constitutive interaction, promoting eNOS-dependent superoxide production, oxidative stress, and PAH. Hypoxic TSP1 null mice developed less right ventricular pressure and hypertrophy and markedly less arteriole muscularization compared with wild-type animals. Further, therapeutic blockade of CD47 activation in hypoxic pulmonary artery endothelial cells upregulated Cav-1, increased Cav-1CD47 co-association, decreased eNOS-derived superoxide, and protected animals from developing PAH. CONCLUSION: Activated CD47 is upregulated in experimental and human PAH and promotes disease by limiting Cav-1 inhibition of dysregulated eNOS. PMID- 22215726 TI - Dermal tissue allograft for the repair of massive irreparable rotator cuff tears. AB - BACKGROUND: Massive irreparable rotator cuff tears in patients without advanced glenohumeral arthritis can pose a challenge to surgeons. Numerous management strategies have been utilized, and studies have shown varied results with regard to shoulder pain, range of motion, strength, and overall function. HYPOTHESIS: Patients undergoing repair of massive irreparable rotator cuff tears through a mini-open approach with the use of human dermal tissue matrix allograft would demonstrate an improvement in pain, range of motion, strength, and subjective functional outcomes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We performed a prospective observational study of 24 patients who underwent interposition repair of massive rotator cuff tears using human dermal allograft. All patients were evaluated preoperatively and postoperatively by the treating surgeon. Data were collected preoperatively and postoperatively for an average 3 year follow-up period (range, 29-40 months). Active range of motion as well as supraspinatus and infraspinatus strength was assessed. Subjective outcome measures included pain level (visual analog scale of 0-10, with 10 = severe pain), American Shoulder and Elbow Score (ASES), and Short-Form 12 (SF-12) score. Imaging evaluation to assess for repair integrity was performed using static and dynamic ultrasonography at final follow-up. RESULTS: Mean pain level decreased from 5.4 to 0.9 (P = .0002). Mean active forward flexion and external rotation motion improved from 111.7 degrees to 157.3 degrees (P = .0002) and from 46.2 degrees to 65.1 degrees (P = .001), respectively. Mean shoulder abduction improved from 105.0 degrees to 151.7 degrees (P = .0001). Supraspinatus and infraspinatus strength improved from 7.2 to 9.4 (P = .0003) and from 7.8 to 9.3 (P = .002), respectively. Mean ASES improved from 66.6 to 88.7 (P = .0003). Mean SF-12 scores improved from 48.8 to 56.8 (P = .03). One partial graft retear occurred because of patient noncompliance during postoperative rehabilitation. However, this patient still demonstrated improvement in pain, motion, and subjective outcomes at final follow-up. Ultrasonography demonstrated "fully intact" repairs in 76% of patients. All remaining patients had "partially intact" repairs. There were no complete tears. CONCLUSION: In our series of carefully selected candidates, all patients demonstrated a significant improvement in pain, range of motion, and strength. Subjective outcome measures, including mean ASES and SF-12 scores, also demonstrated significant improvement at an average 3-year follow-up. PMID- 22215727 TI - Surgical hip dislocation for femoroacetabular impingement. PMID- 22215728 TI - Dyrk1A influences neuronal morphogenesis through regulation of cytoskeletal dynamics in mammalian cortical neurons. AB - Down syndrome (DS) is the most frequent genetic cause of mental retardation. Cognitive dysfunction in these patients is correlated with reduced dendritic branching and complexity, along with fewer spines of abnormal shape that characterize the cortical neuronal profile of DS. DS phenotypes are caused by the disruptive effect of specific trisomic genes. Here, we report that overexpression of dual-specificity tyrosine phosphorylation-regulated kinase 1A, DYRK1A, is sufficient to produce the dendritic alterations observed in DS patients. Engineered changes in Dyrk1A gene dosage in vivo strongly alter the postnatal dendritic arborization processes with a similar progression than in humans. In cultured mammalian cortical neurons, we determined a reduction of neurite outgrowth and synaptogenesis. The mechanism underlying neurite dysgenesia involves changes in the dynamic reorganization of the cytoskeleton. PMID- 22215729 TI - 2011: Signaling breakthroughs of the year. AB - The editors of Science Signaling are pleased to start 2012 with our 10th compilation of the most exciting cell signaling research to emerge in the previous year. The Signaling Breakthroughs list is selected from articles nominated by members of the Science Signaling Editorial Board as providing major advances in cell signaling, particularly those that were unexpected or likely to open up new avenues of research. This edition includes breakthroughs in the structural analysis of signaling proteins, technological advances in imaging, and insights into the mechanisms controlling gene expression, immune function, and the cellular response to stress. PMID- 22215730 TI - Comment on "load-induced modulation of signal transduction networks": reconciling ultrasensitivity with bifunctionality? AB - Jiang et al. (Research Article, 11 October 2011, DOI: 10.1126/scisignal.2002152) used a combined experimental and computational modeling approach to study the dynamic response behavior of covalent modification cycles in the presence of downstream targets ("loads"). Despite remarkable agreement between experiments and model predictions, there exists an apparent discrepancy in their approach because the utilized theoretical model does not reflect the bifunctional nature of the enzyme system used in experiments. Furthermore, a simple extension of the model to the case of bifunctional enzymes yields predictions that are partially at variance with the experimental results. It seems that an appropriate mechanistic model would have to reconcile two apparent contradictory concepts: ultrasensitivity and bifunctionality. PMID- 22215732 TI - Inhibition of PP1 phosphatase activity by HBx: a mechanism for the activation of hepatitis B virus transcription. AB - The regulatory protein HBx is essential for hepatitis B virus (HBV) replication in vivo and for transcription of the episomal HBV genome. We previously reported that in infected cells HBx activates genes targeted by the transcription factor CREB [cyclic adenosine monophosphate (cAMP) response element-binding protein]. cAMP induces phosphorylation and activation of CREB, and CREB inactivation is promoted by protein phosphatase 1 (PP1), which binds to CREB through histone deacetylase 1 (HDAC1). We showed that CREB was recruited to HBV DNA. Phosphorylation induced by cAMP had a longer half-life when CREB was bound to the episomal HBV genome compared to when it was bound to the promoter of a host target gene not regulated by HBx, suggesting that the virus has developed a mechanism to favor its own transcription. This mechanism required HBx, which interacted with and inhibited PP1 to extend the half-life of CREB phosphorylation. Silencing of PP1 rescued replication of an HBx-deficient HBV genome, suggesting that HBx enhances viral transcription in part by neutralizing PP1 activity. Our results illustrate a previously unknown mechanism of HBV transcriptional activation by HBx in which HBx interferes with the inactivation of CREB by the PP1 and HDAC1 complex. PMID- 22215733 TI - Incoherent feedforward control governs adaptation of activated ras in a eukaryotic chemotaxis pathway. AB - Adaptation in signaling systems, during which the output returns to a fixed baseline after a change in the input, often involves negative feedback loops and plays a crucial role in eukaryotic chemotaxis. We determined the dynamical response to a uniform change in chemoattractant concentration of a eukaryotic chemotaxis pathway immediately downstream from G protein-coupled receptors. The response of an activated Ras showed near-perfect adaptation, leading us to attempt to fit the results using mathematical models for the two possible simple network topologies that can provide perfect adaptation. Only the incoherent feedforward network accurately described the experimental results. This analysis revealed that adaptation in this Ras pathway is achieved through the proportional activation of upstream components and not through negative feedback loops. Furthermore, these results are consistent with a local excitation, global inhibition mechanism for gradient sensing, possibly with a Ras guanosine triphosphatase-activating protein acting as a global inhibitor. PMID- 22215734 TI - Smart choices for healthy families: a pilot study for the treatment of childhood obesity in low-income families. AB - This pre-post study used a mixed-methods approach to examine the impact of a family-based weight management program among a low-income population. Smart Choices for Healthy Families was developed through an integrated research practice partnership and piloted with 26 children and parents (50% boys; mean age = 10.5 years; 54% Black) who were referred by their pediatrician. Smart Choices included six biweekly group sessions and six automated telephone-counseling calls over 3 months. Children displayed reduced body mass index z-scores (p < .05), increased lean muscle mass (p < .001), and increased quality of life (p < .0001). Follow-up interviews indicated that physicians valued the lay leaders' ability to provide lifestyle education, whereas lay leaders extended their reach to more community members. Parents wanted to become positive role models and found that the calls maintained focus on goals. Smart Choices shows promise to initiate weight management for children in low-income families. PMID- 22215735 TI - Pneumococcal gene complex involved in resistance to extracellular oxidative stress. AB - Streptococcus pneumoniae is a gram-positive bacterium which is a member of the normal human nasopharyngeal flora but can also cause serious disease such as pneumonia, bacteremia, and meningitis. Throughout its life cycle, S. pneumoniae is exposed to significant oxidative stress derived from endogenously produced hydrogen peroxide (H(2)O(2)) and from the host through the oxidative burst. How S. pneumoniae, an aerotolerant anaerobic bacterium that lacks catalase, protects itself against hydrogen peroxide stress is still unclear. Bioinformatic analysis of its genome identified a hypothetical open reading frame belonging to the thiol specific antioxidant (TlpA/TSA) family, located in an operon consisting of three open reading frames. For all four strains tested, deletion of the gene resulted in an approximately 10-fold reduction in survival when strains were exposed to external peroxide stress. However, no role for this gene in survival of internal superoxide stress was observed. Mutagenesis and complementation analysis demonstrated that all three genes are necessary and sufficient for protection against oxidative stress. Interestingly, in a competitive index mouse pneumonia model, deletion of the operon had no impact shortly after infection but was detrimental during the later stages of disease. Thus, we have identified a gene complex involved in the protection of S. pneumoniae against external oxidative stress, which plays an important role during invasive disease. PMID- 22215736 TI - The Mycobacterium tuberculosis SecA2 system subverts phagosome maturation to promote growth in macrophages. AB - The ability of Mycobacterium tuberculosis to grow in macrophages is critical to the virulence of this important pathogen. One way M. tuberculosis is thought to maintain a hospitable niche in macrophages is by arresting the normal process of phagosomes maturing into acidified phagolysosomes. The process of phagosome maturation arrest by M. tuberculosis is not fully understood, and there has remained a need to firmly establish a requirement for phagosome maturation arrest for M. tuberculosis growth in macrophages. Other intracellular pathogens that control the phagosomal environment use specialized protein export systems to deliver effectors of phagosome trafficking to the host cell. In M. tuberculosis, the accessory SecA2 system is a specialized protein export system that is required for intracellular growth in macrophages. In studying the importance of the SecA2 system in macrophages, we discovered that SecA2 is required for phagosome maturation arrest. Shortly after infection, phagosomes containing a DeltasecA2 mutant of M. tuberculosis were more acidified and showed greater association with markers of late endosomes than phagosomes containing wild-type M. tuberculosis. We further showed that inhibitors of phagosome acidification rescued the intracellular growth defect of the DeltasecA2 mutant, which demonstrated that the phagosome maturation arrest defect of the DeltasecA2 mutant is responsible for the intracellular growth defect. This study demonstrates the importance of phagosome maturation arrest for M. tuberculosis growth in macrophages, and it suggests there are effectors of phagosome maturation that are exported into the host environment by the accessory SecA2 system. PMID- 22215737 TI - Flotillin-1 (Reggie-2) contributes to Chlamydia pneumoniae growth and is associated with bacterial inclusion. AB - Chlamydiae are obligate intracellular pathogens replicating only inside the eukaryotic host. Here, we studied the effect of human flotillin-1 protein on Chlamydia pneumoniae growth in human line (HL) and A549 epithelial cell lines. RNA interference was applied to disrupt flotillin-1-mediated endocytosis. Host associated bacteria were detected by quantitative PCR, and C. pneumoniae growth was evaluated by inclusion counts. C. pneumoniae attachment to host cells was unaffected, but bacterial intracellular growth was attenuated in the flotillin-1 silenced cells. By using confocal microscopy, we detected flotillin-1 colocalized with the inclusion membrane protein A (IncA) in the C. pneumoniae inclusion membranes. In addition, flotillin-1 was associated with IncA in detergent resistant membrane microdomains (DRMs) in biochemical fractioning. These results suggest that flotillin-1 localizes to the C. pneumoniae inclusion membrane and plays an important role for intracellular growth of C. pneumoniae. PMID- 22215738 TI - Role of Francisella lipid A phosphate modification in virulence and long-term protective immune responses. AB - Lipopolysaccharide (LPS) structural modifications have been shown to specifically affect the pathogenesis of many gram-negative pathogens. In Francisella, modification of the lipid A component of LPS resulted in a molecule with no to low endotoxic activity. The role of the terminal lipid A phosphates in host recognition and pathogenesis was determined using a Francisella novicida mutant that lacked the 4' phosphatase enzyme (LpxF). The lipid A of this strain retained the phosphate moiety at the 4' position and the N-linked fatty acid at the 3' position on the diglucosamine backbone. Studies were undertaken to determine the pathogenesis of this mutant strain via the pulmonary and subcutaneous routes of infection. Mice infected with the lpxF-null F. novicida mutant by either route survived primary infection and subsequently developed protective immunity against a lethal wild-type (WT) F. novicida challenge. To determine the mechanism(s) by which the host controlled primary infection by the lpxF-null mutant, the role of innate immune components, including Toll-like receptor 2 (TLR2), TLR4, caspase-1, MyD88, alpha interferon (IFN-alpha), and gamma interferon(IFN-gamma), was examined using knockout mice. Interestingly, only the IFN-gamma knockout mice succumbed to a primary lpxF-null F. novicida mutant infection, highlighting the importance of IFN-gamma production. To determine the role of components of the host adaptive immune system that elicit the long-term protective immune response, T- and B-cell deficient RAG1(-/-) mice were examined. All mice survived primary infection; however, RAG1(-/-) mice did not survive WT challenge, highlighting a role for T and B cells in the protective immune response. PMID- 22215739 TI - Failure to recruit anti-inflammatory CD103+ dendritic cells and a diminished CD4+ Foxp3+ regulatory T cell pool in mice that display excessive lung inflammation and increased susceptibility to Mycobacterium tuberculosis. AB - Susceptibility to Mycobacterium tuberculosis is characterized by excessive lung inflammation, tissue damage, and failure to control bacterial growth. To increase our understanding of mechanisms that may regulate the host immune response in the lungs, we characterized dendritic cells expressing CD103 (alpha(E) integrin) (alphaE-DCs) and CD4(+) Foxp3(+) regulatory T (T(reg)) cells during M. tuberculosis infection. In resistant C57BL/6 and BALB/c mice, the number of lung alphaE-DCs increased dramatically during M. tuberculosis infection. In contrast, highly susceptible DBA/2 mice failed to recruit alphaE-DCs even during chronic infection. Even though tumor necrosis factor alpha (TNF-alpha) is produced by multiple DCs and macrophage subsets and is required for control of bacterial growth, alphaE-DCs remained TNF-alpha negative. Instead, alphaE-DCs contained a high number of transforming growth factor beta-producing cells in infected mice. Further, we show that T(reg) cells in C57BL/6 and DBA/2 mice induce gamma interferon during pulmonary tuberculosis. In contrast to resistant mice, the T(reg) cell population was diminished in the lungs, but not in the draining pulmonary lymph nodes (PLN), of highly susceptible mice during chronic infection. T(reg) cells have been reported to inhibit M. tuberculosis-specific T cell immunity, leading to increased bacterial growth. Still, despite the reduced number of lung T(reg) cells in DBA/2 mice, the bacterial load in the lungs was increased compared to resistant animals. Our results show that alphaE-DCs and T(reg) cells that may regulate the host immune response are increased in M. tuberculosis-infected lungs of resistant mice but diminished in infected lungs of susceptible mice. PMID- 22215740 TI - Conserved and variant epitopes of Plasmodium vivax Duffy binding protein as targets of inhibitory monoclonal antibodies. AB - The Duffy binding protein (DBP) is a vital ligand for Plasmodium vivax blood stage merozoite invasion, making the molecule an attractive vaccine candidate against vivax malaria. Similar to other blood-stage vaccine candidates, DBP allelic variation eliciting a strain-specific immunity may be a major challenge for development of a broadly effective vaccine against vivax malaria. To understand whether conserved epitopes can be the target of neutralizing anti-DBP inhibition, we generated a set of monoclonal antibodies to DBP and functionally analyzed their reactivity to a panel of allelic variants. Quantitative analysis by enzyme-linked immunosorbent assay (ELISA) determined that some monoclonal antibodies reacted strongly with epitopes conserved on all DBP variants tested, while reactivity of others was allele specific. Qualitative analysis characterized by anti-DBP functional inhibition using an in vitro erythrocyte binding inhibition assay indicated that there was no consistent correlation between the endpoint titers and functional inhibition. Some monoclonal antibodies were broadly inhibitory while inhibition of others varied significantly by target allele. These data demonstrate a potential for vaccine-elicited immunization to target conserved epitopes but optimization of DBP epitope target specificity and immunogenicity may be necessary for protection against diverse P. vivax strains. PMID- 22215741 TI - Analysis of global transcriptional profiles of enterotoxigenic Escherichia coli isolate E24377A. AB - Enterotoxigenic Escherichia coli (ETEC) is an important pathogenic variant (pathovar) of E. coli in developing countries from a human health perspective, causing significant morbidity and mortality. Previous studies have examined specific regulatory networks in ETEC, although little is known about the global effects of inter- and intrakingdom signaling on the expression of virulence and colonization factors in ETEC. In this study, an E. coli/Shigella pan-genome microarray, combined with quantitative reverse transcriptase PCR (qRT-PCR) and RNA sequencing (RNA-seq), was used to quantify the expression of ETEC virulence and colonization factors. Biologically relevant chemical signals were combined with ETEC isolate E24377A during growth in either Luria broth (LB) or Dulbecco's modified Eagle medium (DMEM), and transcription was examined during different phases of the growth cycle; chemical signals examined included glucose, bile salts, and preconditioned media from E. coli/Shigella isolates. The results demonstrate that the presence of bile salts, which are found in the intestine and thought to be bactericidal, upregulates the expression of many ETEC virulence factors, including heat-stable (estA) and heat-labile (eltA) enterotoxin genes. In contrast, the ETEC colonization factors CS1 and CS3 were downregulated in the presence of bile, consistent with findings in studies of other enteric pathogens. RNA-seq analysis demonstrated that one of the most differentially expressed genes in the presence of bile is a unique plasmid-encoded AraC-like transcriptional regulator (peaR); other previously unknown genetic elements were found as well. These results provide transcriptional targets and putative mechanisms that should help improve understanding of the global regulatory networks and virulence expression in this important human pathogen. PMID- 22215742 TI - Delivery of large heterologous polypeptides across the cytoplasmic membrane of antigen-presenting cells by the Bordetella RTX hemolysin moiety lacking the adenylyl cyclase domain. AB - The Bordetella adenylate cyclase toxin-hemolysin (CyaA; also called ACT or AC Hly) targets CD11b-expressing phagocytes and translocates into their cytosol an adenylyl cyclase (AC) that hijacks cellular signaling by conversion of ATP to cyclic AMP (cAMP). Intriguingly, insertion of large passenger peptides removes the enzymatic activity but not the cell-invasive capacity of the AC domain. This has repeatedly been exploited for delivery of heterologous antigens into the cytosolic pathway of CD11b-expressing dendritic cells by CyaA/AC(-) toxoids, thus enabling their processing and presentation on major histocompatibility complex (MHC) class I molecules to cytotoxic CD8(+) T lymphocytes (CTLs). We produced a set of toxoids with overlapping deletions within the first 371 residues of CyaA and showed that the structure of the AC enzyme does not contain any sequences indispensable for its translocation across target cell membrane. Moreover, replacement of the AC domain (residues 1 to 371) with heterologous polypeptides of 40, 146, or 203 residues yielded CyaADeltaAC constructs that delivered passenger CTL epitopes into antigen-presenting cells (APCs) and induced strong antigen-specific CD8(+) CTL responses in vivo in mice and ex vivo in human peripheral blood mononuclear cell cultures. This shows that the RTX (repeats in toxin) hemolysin moiety, consisting of residues 374 to 1706 of CyaA, harbors all structural information involved in translocation of the N-terminal AC domain across target cell membranes. These results decipher the extraordinary capacity of the AC domain of CyaA to transport large heterologous cargo polypeptides into the cytosol of CD11b(+) target cells and pave the way for the construction of CyaADeltaAC-based polyvalent immunotherapeutic T cell vaccines. PMID- 22215743 TI - Toward a better dialogue between neuro-oncologists and phase I investigators. PMID- 22215744 TI - Outcomes for radical prostatectomy: is it the singer, the song, or both? PMID- 22215745 TI - Health-related quality of life among 5-year survivors of esophageal cancer surgery: a prospective population-based study. AB - PURPOSE: To clarify whether health-related quality of life (HRQL) can be restored in 5-year survivors of esophageal cancer surgery. PATIENTS AND METHODS: The nationwide Swedish prospective and population-based cohort for this study consisted of patients with esophageal cancer who were treated surgically between 2001 and 2005 and were alive 5 years after surgery. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ C30) and EORTC QLQ-OES18 (the disease site-specific module for esophageal cancer) were used to assess HRQL 6 months, 3 years, and 5 years postoperatively. Paired t tests were used to evaluate changes in HRQL over time. Patients' HRQL was classified as improved, stable, or deteriorated. Multivariable linear regression was used to calculate mean score difference in HRQL with 95% CIs between patients and a background population according to HRQL category. RESULTS: Among 153 eligible patients alive after 5 years, 117 (76%) answered all HRQL assessments. Among a random sample of 6,969 Swedish adults representing the corresponding background population, 4,910 (70.5%) participated. For most patients, HRQL remained stable or improved over time, and their HRQL was comparable to that of the background population. Patients who deteriorated over time reported large and clinically significant mean score differences for all measures. For example, 5 years after surgery, physical function was stable or improved in 86% of patients and their mean score (87) was similar to that of the background population (88), but the 14% who deteriorated had a substantially lower mean score of 56. CONCLUSION: HRQL recovers to a level comparable to that in the background population in most patients who survive 5 years after esophagectomy for cancer, although a subgroup of patients has substantially worse HRQL. PMID- 22215746 TI - Multicentric granular cell tumors with heart involvement: a case report. PMID- 22215747 TI - The American Society of Clinical Oncology's Blueprint for Transforming Clinical and Translational Cancer Research. PMID- 22215748 TI - ROS1 rearrangements define a unique molecular class of lung cancers. AB - PURPOSE: Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in a subset of non-small-cell lung cancers (NSCLCs). Because little is known about these tumors, we examined the clinical characteristics and treatment outcomes of patients with NSCLC with ROS1 rearrangement. PATIENTS AND METHODS: Using a ROS1 fluorescent in situ hybridization (FISH) assay, we screened 1,073 patients with NSCLC and correlated ROS1 rearrangement status with clinical characteristics, overall survival, and when available, ALK rearrangement status. In vitro studies assessed the responsiveness of cells with ROS1 rearrangement to the tyrosine kinase inhibitor crizotinib. The clinical response of one patient with ROS1-rearranged NSCLC to crizotinib was investigated as part of an expanded phase I cohort. RESULTS: Of 1,073 tumors screened, 18 (1.7%) were ROS1 rearranged by FISH, and 31 (2.9%) were ALK rearranged. Compared with the ROS1-negative group, patients with ROS1 rearrangements were significantly younger and more likely to be never-smokers (each P < .001). All of the ROS1-positive tumors were adenocarcinomas, with a tendency toward higher grade. ROS1-positive and -negative groups showed no difference in overall survival. The HCC78 ROS1-rearranged NSCLC cell line and 293 cells transfected with CD74-ROS1 showed evidence of sensitivity to crizotinib. The patient treated with crizotinib showed tumor shrinkage, with a near complete response. CONCLUSION: ROS1 rearrangement defines a molecular subset of NSCLC with distinct clinical characteristics that are similar to those observed in patients with ALK-rearranged NSCLC. Crizotinib shows in vitro activity and early evidence of clinical activity in ROS1-rearranged NSCLC. PMID- 22215749 TI - Asymmetric intense bilateral adrenal uptake on [18F]fluorodeoxyglucose positron emission tomography/computed tomography in a patient with solitary pulmonary nodule. PMID- 22215750 TI - Palifermin in prevention of head and neck cancer radiation-induced mucositis: not yet a definitive word on safety and efficacy profile. PMID- 22215751 TI - Making sense of clinical trial data: is inverse probability of censoring weighted analysis the answer to crossover bias? AB - Ideally, therapeutic interventions are evaluated through randomized clinical trials. These trials are commonly analyzed with an intent-to-treat (ITT) approach, whereby patients are analyzed in their assigned treatment group regardless of actual treatment received. If an interim analysis of such trials demonstrates compelling evidence of a difference in benefit, ethical considerations often dictate that the trial be unblinded and participants be provided access to the more efficacious agent. Because interim analysis may not address longer-term outcomes of interest, important clinical questions such as overall survival benefit-the ultimate test of efficacy to many-may remain unanswered. The ensuing crossover disturbs randomization and may lead to biased longer-term analysis, compromising the utility of clinical data. This has been especially apparent in recent adjuvant and prevention breast cancer trials. We consider four such trials: HERA (Herceptin Adjuvant), NSABP P-1 (National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention P-1), MA.17, and BIG 1-98 (Breast International Group 1-98), the long-term outcomes of which were complicated by unblinding and selective crossover. We also discuss the biases associated with ITT analysis and, alternatively, censoring of follow-up data (ie, dropping out) after selective crossover. Moreover, we discuss how the statistical procedure of inverse probability of censoring weighted (IPCW) analysis may be used to account for selective crossover as an alternative to ITT or censoring analysis, as was recently done for the BIG 1-98 trial. Notably, IPCW analysis may be particularly suited for detecting overall survival benefits that otherwise would not be detected with an ITT approach, as reported for the BIG 1 98 trial. PMID- 22215752 TI - Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non small-cell lung cancer. AB - PURPOSE: Patients with non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations have excellent response to EGFR tyrosine kinase inhibitors (TKIs), but T790M mutation accounts for most TKI drug resistance. This study used highly sensitive methods to detect T790M before and after TKI therapy and investigated the association of T790M and its mutation frequencies with clinical outcome. PATIENTS AND METHODS: Direct sequencing, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and next-generation sequencing (NGS) were used to assess T790M in the following two cohorts of patients with NSCLC: TKI-naive patients (n = 107) and TKI-treated patients (n = 85). Results were correlated with TKI treatment response and survival. RESULTS: MALDI-TOF MS was highly sensitive in detecting and quantifying the frequency of EGFR-activating mutations and T790M (detection limits, 0.4% to 2.2%). MALDI-TOF MS identified more T790M than direct sequencing in TKI-naive patients with NSCLC (27 of 107 patients, 25.2% v three of 107 patients, 2.8%, respectively; P < .001) and in TKI-treated patients (before TKI: 23 of 73 patients, 31.5% v two of 73 patients, 2.7%, respectively; P < .001; and after TKI: 10 of 12 patients, 83.3% v four of 12 patients, 33.3%, respectively; P = .0143). The EGFR mutations and their frequencies were confirmed by NGS. T790M was an independent predictor of decreased progression-free survival (PFS) in patients with NSCLC who received TKI treatment (P < .05, multivariate Cox regression). CONCLUSION: T790M may not be a rare event before or after TKI therapy in patients with NSCLC with EGFR-activating mutations. The pretreatment T790M mutation was associated with shorter PFS with EGFR TKI therapy in patients with NSCLC. PMID- 22215753 TI - Advanced stage, increased lactate dehydrogenase, and primary site, but not adolescent age (>= 15 years), are associated with an increased risk of treatment failure in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB LMB 96 study. AB - PURPOSE: Adolescents (age 15 to 21 years) compared with younger children with mature B-cell non-Hodgkin's lymphoma (NHL) have been historically considered to have an inferior prognosis. We therefore analyzed the impact of age and other diagnostic factors on the risk of treatment failure in children and adolescents treated on the French-American-British Mature B-Cell Lymphoma 96 (FAB LMB 96) trial. PATIENTS AND METHODS: Patients were divided by risk: group A (limited), group B (intermediate), and group C (advanced), as previously described. Prognostic factors analyzed for event-free survival (EFS) included age (< 15 v >= 15 years), stage (I/II v III/IV), primary site, lactate dehydrogenase (LDH), bone marrow/CNS (BM/CNS) involvement, and histology (diffuse large B-cell lymphoma v mediastinal B-cell lymphoma v Burkitt lymphoma or Burkitt-like lymphoma). RESULTS: The 3-year EFS for the whole cohort was 88% +/- 1%. Age was not associated as a risk factor for increased treatment failure in either univariate analysis (P = .15) or multivariate analysis (P = .58). Increased LDH (>= 2 * upper limit of normal [ULN] v < 2 * ULN), primary site, and BM-positive/CNS positive disease were all independent risk factors associated with a significant increase in treatment failure rate (relative risk, 2.0; P < .001, P < .012, and P < .001, respectively). CONCLUSION: LDH level at diagnosis, mediastinal disease, and combined BM-positive/CNS-positive involvement are independent risk factors in children with mature B-cell NHL. Future studies should be developed to identify specific therapeutic strategies (immunotherapy) to overcome these risk factors and to identify the biologic basis associated with these prognostic factors in children with mature B-cell NHL. PMID- 22215754 TI - The 39th David A. Karnofsky Lecture: bench-to-bedside translation of targeted therapies in multiple myeloma. AB - Multiple myeloma (MM) is a remarkable example of rapid bench-to-bedside translation in new drug development. The proteasome inhibitor bortezomib and immunomodulatory drug lenalidomide targeted MM cells in the bone marrow (BM) microenvironment to overcome conventional drug resistance in laboratory and animal models and were rapidly translated into clinical trials demonstrating their efficacy in patients with relapsed and then newly diagnosed MM, with a doubling of the median survival as a direct result. The future is even brighter. First, immune-based therapies are being developed (eg, elotuzumab monoclonal antibody [MoAb]; CD138DM immunotoxin; MM cell-dendritic cell vaccines; CD138, CS 1, and XBP-1 peptide vaccines; anti-17 MoAb; and other treatments to overcome causes of immune dysfunction). Second, promising next-generation agents target the MM cell in its microenvironment (eg, deubiquitinating enzyme inhibitors; chymotryptic [carfilzomib, Onyx 0912, MLN 9708] and broader [NPI-0052] proteasome inhibitors; immunoproteasome inhibitors; and pomalidamide). Moreover, agents targeting bone biology (eg, zoledronic acid, anti-DKK-1 MoAb, anti-B-cell activating factor MoAb and bortezomib, Btk inhibitor) show promise not only in preserving bone integrity but also against MM. Third, rationally based combination therapies, including bortezomib with Akt, mammalian target of rapamycin, or histone deacetylase inhibitors, are active even in bortezomib refractory MM. Finally, genomics is currently being used in the definition of MM heterogeneity, new target discovery, and development of personalized therapy. Myeloma therefore represents a paradigm for targeting the tumor in its microenvironment, which has already markedly improved patient outcome in MM and has great potential in other hematologic malignancies and solid tumors as well. PMID- 22215755 TI - ROS1 rearrangements in lung cancer: a new genomic subset of lung adenocarcinoma. PMID- 22215756 TI - Adverse effects of robotic-assisted laparoscopic versus open retropubic radical prostatectomy among a nationwide random sample of medicare-age men. AB - PURPOSE: Robotic-assisted laparoscopic radical prostatectomy is eclipsing open radical prostatectomy among men with clinically localized prostate cancer. The objective of this study was to compare the risks of problems with continence and sexual function following these procedures among Medicare-age men. PATIENTS AND METHODS: A population-based random sample was drawn from the 20% Medicare claims files for August 1, 2008, through December 31, 2008. Participants had hospital and physician claims for radical prostatectomy and diagnostic codes for prostate cancer and reported undergoing either a robotic or open surgery. They received a mail survey that included self-ratings of problems with continence and sexual function a median of 14 months postoperatively. RESULTS: Completed surveys were obtained from 685 (86%) of 797 eligible participants, and 406 and 220 patients reported having had robotic or open surgery, respectively. Overall, 189 (31.1%; 95% CI, 27.5% to 34.8%) of 607 men reported having a moderate or big problem with continence, and 522 (88.0%; 95% CI, 85.4% to 90.6%) of 593 men reported having a moderate or big problem with sexual function. In logistic regression models predicting the log odds of a moderate or big problem with postoperative continence and adjusting for age and educational level, robotic prostatectomy was associated with a nonsignificant trend toward greater problems with continence (odds ratio [OR] 1.41; 95% CI, 0.97 to 2.05). Robotic prostatectomy was not associated with greater problems with sexual function (OR, 0.87; 95% CI, 0.51 to 1.49). CONCLUSION: Risks of problems with continence and sexual function are high after both procedures. Medicare-age men should not expect fewer adverse effects following robotic prostatectomy. PMID- 22215758 TI - Putting theory into practice: the introduction of obstetric near-miss case reviews in the Republic of Moldova. AB - QUALITY ISSUE: The quality of obstetric services remains a major issue in the Republic of Moldova. Services are well staffed and intensively used but do not deliver the expected outputs. INITIAL ASSESSMENT: Providers have limited experience with clinical audits and perceive them as a way to punish individuals. CHOICE OF SOLUTION: Near-miss case reviews were introduced. Discussing near-miss cases might be less threatening to providers than discussing maternal deaths because the women survived. IMPLEMENTATION: The quality of audits was evaluated against explicit criteria in three pilot maternities. EVALUATION: On average one case was discussed every 5-6 weeks. Information from women's interviews was presented at all meetings, although the quality of the women's interviews was low. The weakest aspect of care was monitoring and follow-up treatment; the majority of proposed actions concerned the availability or compliance to protocols (52-69%). Proposed actions were consistent with prior analysis (95 100%), formulated in a clear and measurable way (58-90%), but the rate of failure to identify important actions was quite high in one facility (33%). Actions were more likely to be implemented when they concerned organization and management, drugs and supplies and least likely when they concerned staff. LESSONS LEARNED: It is relatively easy to build capacity in organizing obstetric 'near-miss' audits, but more difficult to ensure that discussions are transposed into actions. In settings with no tradition of patients' involvement, increased attention should be given to providers' capacity to tackle patient-related factors. PMID- 22215759 TI - Health system responsiveness for delivery care in Southern Thailand. AB - OBJECTIVE: To assess the perception of women who gave birth in a hospital on health system responsiveness and their satisfaction. DESIGN: A cross-sectional study. SETTING: Four district, one regional and one university hospitals in the Songkhla province, Southern Thailand. PARTICIPANTS: All women who delivered in the participating hospitals from November 2007 to December 2008. METHODS: All women were interviewed at 24- or 48-h post partum by well-trained interviewers who worked independently outside the hospital. MAIN OUTCOME MEASURES: Eight components of health system responsiveness were measured. The factors associated with high rate of health responsiveness and its effect on the women's satisfaction was estimated by multiple logistic regression. RESULTS: A total of 2822 women were interviewed and their ages ranged from 12 to 48 years (mean +/- SD: 27.6 +/- 6.3). The components of health system responsiveness, which influenced the women's decision for delivering in a hospital were, in the order of importance, prompt attention, dignity, clear communication, autonomy, basic amenities, confidentiality, choice of provider and social support. The majority of women (>80%) gave high ratings for dignity, clear communication, prompt attention and autonomy. The type of hospital was a significant factor in all components of health responsiveness. Compared with women with universal coverage, women insured with the social security and civil servant medical benefit schemes gave higher ratings of dignity, confidentiality and choice of provider. Women's satisfaction for delivery care was significantly associated with high rates of all health responsiveness components, except choice of health providers. CONCLUSIONS: Prompt attention, dignity, clear communication and autonomy influenced women's decision to deliver in the hospital. High health system responsiveness is important for women's satisfaction. PMID- 22215761 TI - Weight loss strategies for adolescents: a 14-year-old struggling to lose weight. AB - With prevalence approaching 20% in the United States, adolescent obesity has become a common problem for patients, parents, and clinicians. Obese adolescents may experience physical and psychosocial complications, as illustrated by the case of Ms K, a 14-year-old girl with a body mass index of 40. Unfortunately, the effectiveness of pediatric obesity treatment is modest in younger children and declines in older children and adolescents, and few interventions involving adolescents have produced significant long-term weight loss. Nevertheless, novel strategies to alter energy balance have shown preliminary evidence of benefit in clinical trials, including a diet focused on food quality rather than fat restriction and a lifestyle approach to encourage enjoyable physical activity throughout the day rather than intermittent exercise. Parents can have an important influence on weight-related behaviors in adolescents despite typically complicated emotional dynamics at this age, especially through the use of noncoercive methods. A key parenting practice applicable to children of all ages is to create a protective environment in the home, substituting nutritious foods for unhealthful ones and facilitating physical activities instead of sedentary pursuits. Other behaviors that may promote successful long-term weight management include good sleep hygiene, stress reduction, and mindfulness. Ultimately, the obesity epidemic can be attributed to changes in the social environment that hinder healthful lifestyle habits, and prevention will require a comprehensive public health strategy. PMID- 22215760 TI - Changes in clients' care ratings after HIV prevention training of hospital workers in Malawi. AB - OBJECTIVE: To examine the changes in clients' health-care ratings before and after hospital workers received an HIV prevention intervention in Malawi, which increased the workers' personal and work-related HIV prevention knowledge, attitudes and preventive behaviors. DESIGN: Pre- and post-intervention client surveys. SETTING: A large urban referral hospital in Malawi. PARTICIPANTS: Clients at purposefully selected inpatient and outpatient units on designated days (baseline, n = 310 clients; final, n = 683). INTERVENTION: Ten-session peer group intervention for health workers focused on HIV transmission, personal and work-related prevention, treating clients and families respectfully and incorporating HIV-related teaching. MAIN OUTCOME MEASURES: Brief face-to-face clients' interview obtaining ratings of confidentiality of HIV, whether HIV related teaching occurred and ratings of service quality. RESULTS: Compared with baseline, at the final survey, clients reported higher confidence about confidentiality of clients' HIV status (83 vs. 75%, P < 0.01) and more clients reported that a health worker talked to them about HIV and AIDS (37 versus 28%, P < 0.01). More clients rated overall health services as 'very good' (five-item mean rating, 68 versus 59%, P < 0.01) and this was true for both inpatients and outpatients examined separately. However, there was no improvement in ratings of the courtesy of laboratory or pharmacy workers or of the adequacy of treatment instructions in the pharmacy. CONCLUSIONS: HIV prevention training for health workers can have positive effects on clients' ratings of services, including HIV related confidentiality and teaching, and should be scaled-up throughout Malawi and in other similar countries. Hospitals need to improve laboratory and pharmacy services. PMID- 22215763 TI - Reduced antegrade flow in the coronary sinus is a predictor of coronary artery stenosis in hypertensive patients. AB - OBJECTIVES: The purpose of this study was to evaluate the feasibility of assessing blood flow in the coronary sinus by transthoracic Doppler echocardiography for detecting coronary artery stenosis in hypertensive patients. METHODS: Flow in the coronary sinus was studied in 105 participants who all had undergone coronary angiography: 35 nonhypertensive patients, 34 hypertensive patients without coronary artery disease (CAD), and 36 hypertensive patients with CAD. The antegrade phase of flow in the coronary sinus was analyzed and compared among the groups. Multivariate analysis for blood flow and coronary artery stenosis was done. RESULTS: Compared with the nonhypertensive patients, the hypertensive patients without CAD had significantly higher blood flow (9.36 +/- 5.94 vs 5.84 +/- 2.91 mL/stroke and 584.45 +/- 177.32 vs 327.68 +/- 125.48 mL/min, respectively; P < .001) in the coronary sinus. Compared with the hypertensive patients without CAD, those with CAD had significantly lower blood flow (5.18 +/- 0.72 vs 9.36 +/- 5.94 mL/stroke and 352.51 +/- 156.18 vs 584.45 +/ 177.32 mL/min; P < .001) and a lower velocity time integral (13.14 +/- 2.51 vs 19.85 +/- 4.89 cm; P < .01). Stepwise multiple regression analysis indicated that the coronary sinus diameter, velocity time integral, and heart rate significantly correlated with the blood flow per minute in the coronary sinus in each group, and the flow per minute was the independent determinant of the percent stenosis diameter. The sensitivity, specificity, and accuracy for the prediction of severe stenosis (>70%) in the left coronary artery were 91.07%, 87.76%, and 88.49% for blood flow of less than 220 mL/min in the coronary sinus. CONCLUSIONS: Transthoracic Doppler echocardiography can effectively depict blood flow changes in the coronary sinus, and reduced antegrade flow is a sensitive and specific predictor of coronary artery stenosis in hypertensive patients. PMID- 22215762 TI - Intraoperative contrast-enhanced sonography of bowel blood flow: preliminary experience. AB - OBJECTIVES: The potential to predict, and therefore avoid, anastomotic failure has eluded generations of colon and rectal surgeons to date. A reliable, reproducible method of assessing bowel blood flow therefore would be of enormous potential clinical relevance. To our knowledge, intraoperative contrast-enhanced sonography of the bowel has not been performed previously. We present our study assessing the feasibility of using contrast-enhanced sonography to study bowel perfusion intraoperatively. METHODS: We studied 8 patients (4 male and 4 female) with an age range of 52 to 81 years who underwent colorectal surgery (right hemicolectomies, n = 3; Hartmann procedure, n = 1; anterior resections, n = 2; and bowel resections with ileocolic anastomoses, n = 2). A 5-mL bolus of a sulfur hexafluoride contrast agent solution was injected before and after vascular ligation with simultaneous noncompression ultrasound scanning directly over the large bowel. The patients were followed clinically to assess for leaks. Contrast enhanced sonographic time-intensity curves were generated for the time to peak and maximum amplitude. RESULTS: Moderate interobserver agreement was shown for the time to peak (kappa = 0.50) and maximum amplitude (kappa = 0.42), and moderate intraobserver agreement was shown for the time to peak (kappa= 0.53) and maximum amplitude (kappa= 0.53). No significant differences were shown between the time to peak (P = .28) and maximum amplitude (P = .49) for the preligation and postligation scans. CONCLUSIONS: To our knowledge, intraoperative contrast enhanced sonography of the bowel has not been performed previously. We have shown the technique to be feasible with good intraobserver and interobserver agreement. Further work is ongoing to optimize the technique and assess its use in predicting anastomotic breakdown. PMID- 22215764 TI - Use of bedside sonography for diagnosing acute epiglottitis in the emergency department: a preliminary study. AB - OBJECTIVES: The purpose of this study was to investigate the ability of sonography to identify acute epiglottitis in the emergency department. METHODS: Fifteen patients with a final diagnosis of acute epiglottitis from indirect laryngoscopy by an otolaryngologist were enrolled in the study. To compare the normal epiglottis and acute epiglottitis, 15 healthy volunteers were assigned to a control group. The sonographic appearances of the epiglottitis and the pre epiglottic space were recorded. The anteroposterior diameter of the epiglottis at the midpoint and both edges in a transverse view was measured in all participants. RESULTS: A statistically significant difference (P < .001) was observed in the anteroposterior diameter of the epiglottis at the midpoint and both lateral edges between the patients and healthy volunteers. However, there was overlap in the ranges for the midpoint but no overlap in both lateral edges between groups. The upper-limit value for the healthy control group was 3.2 mm at both lateral edges, whereas the cutoff values of the right and left edges were 3.7 and 3.6 mm, respectively, according to the lower-limit value for the epiglottitis group. CONCLUSIONS: The anteroposterior diameter of the epiglottis was significantly different between the patients with epiglottitis and the healthy volunteers. Because of this significant difference in the anteroposterior diameter of the epiglottis, sonography can be used as a rapid, noninvasive, and effective diagnostic tool for identifying cases of epiglottitis in the emergency department. PMID- 22215765 TI - The nerve/tunnel index: a new diagnostic standard for carpal tunnel syndrome using sonography: a pilot study. AB - OBJECTIVES: To define the relationship between body indices of healthy adults and cross-sectional areas of the carpal tunnel and median nerve and to obtain the nerve/tunnel index, which represents a new standard for diagnosing carpal tunnel syndrome using sonography. METHODS: Body indices (height, weight, and body mass index) were analyzed in 60 healthy adults, and electromyography and sonography were also performed. The cross-sectional areas of the proximal and distal median nerve and carpal tunnel were obtained by sonography. The proximal and distal nerve/tunnel indices were obtained by calculating the ratio between the proximal and distal cross-sectional areas of the median nerve to those of the carpal tunnel and multiplying the value by 100. RESULTS: Although the proximal cross sectional areas of the median nerve and body indices showed statistically significant relationships with weak positive correlations, the proximal and distal areas of the carpal tunnel showed relatively stronger correlations with body indices. Between sexes, there were significant differences in the proximal median nerve cross-sectional area (mean +/- SD: male, 10.48 +/- 3.21 mm(2); female, 8.81 +/- 3.21 mm(2); P < .05) and proximal carpal tunnel area (male, 182.50 +/- 21.15 mm(2); female, 151.23 +/- 21.14 mm(2); P < .05). There was no difference in the proximal nerve/tunnel index (male, 5.80% +/- 1.72%; female, 5.91% +/- 1.63%). There was a statistically significant difference in the distal carpal tunnel cross-sectional area (male, 138.90 +/- 20.95 mm(2); female, 121.50 +/- 18.99 mm(2); P < .05) between sexes, but the distal median area (male, 9.99 +/- 3.42 mm(2); female, 8.46 +/- 1.84 mm(2)) and distal nerve/tunnel index (male, 7.15% +/- 2.00%; female, 7.01% +/- 1.38%) showed no significant differences. The proximal index was significantly higher than the distal index (proximal, 5.85% +/ 1.66%; distal, 7.08% +/- 1.71%). CONCLUSIONS: The nerve/tunnel index is unaffected by body indices or sex and thus may be a useful and objective standard for diagnosing carpal tunnel syndrome. PMID- 22215766 TI - Sonographic measurements of subsynovial connective tissue thickness in patients with carpal tunnel syndrome. AB - OBJECTIVES: A major pathologic finding in patients with idiopathic carpal tunnel syndrome is noninflammatory fibrosis and thickening of the subsynovial connective tissue. The objective of this study was to determine the ability of sonography to depict this thickening by comparing subsynovial connective tissue thickness in patients with carpal tunnel syndrome and healthy control participants. METHODS: Longitudinal sonograms of the middle finger superficial flexor tendon and subsynovial connective tissue were obtained at 3 levels: at the wrist crease (proximal tunnel), at the hook of the hamate (mid tunnel), and at the distal edge of the transverse carpal ligament (distal tunnel). The thickness of the subsynovial connective tissue perpendicular to the direction of the tendon and the diameter of the flexor digitorum superficialis tendon at the same level were measured. Then, a thickness ratio was created. RESULTS: At all 3 levels, the subsynovial connective tissue was thicker in patients than in controls (P < .0001) with a thickness ranging from 0.60 to 0.63 mm in patients and 0.46 to 0.50 mm in controls. The thickness ratio was significantly greater in patients at the hamate and distal levels (P = .018 and .013, respectively). CONCLUSIONS: With this study, we have shown that it is possible to measure subsynovial connective tissue thickness with sonography, and the tissue is thicker in patients with carpal tunnel syndrome than in healthy controls. PMID- 22215767 TI - Sonographic evaluation of the greater occipital nerve in unilateral occipital neuralgia. AB - OBJECTIVES: Occipital neuralgia is a headache that may result from greater occipital nerve entrapment. Entrapped peripheral nerves typically have an increase in cross-sectional area. The purpose of this study was to measure the cross-sectional area and circumference of symptomatic and asymptomatic greater occipital nerves in patients with unilateral occipital neuralgia and to correlate the greater occipital nerve cross-sectional area with headache severity, sex, and body mass index. METHODS: Both symptomatic and contralateral asymptomatic greater occipital nerve cross-sectional areas and circumferences were measured by a single examiner using sonography in 17 patients. The Wilcoxon signed rank test and Spearman rank order correlation coefficient were used to analyze the data. RESULTS: Significant differences between the cross-sectional areas and circumferences of the symptomatic and asymptomatic greater occipital nerves were noted (P < .001). No difference existed in cross-sectional area (P = .40) or circumference (P = .10) measurements of the nerves between male and female patients. A significant correlation existed between the body mass index and symptomatic (r = 0.424; P = .045) and asymptomatic (r = 0.443; P = .037) cross sectional areas. There was no correlation shown between the cross-sectional area of the symptomatic nerve and the severity of Headache Impact Test 6 scores (r = 0.342; P = .179). CONCLUSIONS: We report sonographic evidence showing an increased cross-sectional area and circumference of the symptomatic greater occipital nerve in patients with unilateral occipital neuralgia. PMID- 22215768 TI - Quantification of skeletal muscle fibrosis at different healing stages using sonography: a morphologic and histologic study in an animal model. AB - OBJECTIVES: This study attempted to quantify the degree of muscle fibrosis on sonograms of injured gastrocnemius muscles at different healing stages in a rat model. Correlations between the quantifications and histologic assessments of the injured muscles were also determined. METHODS: Sonograms and histologic findings of gastrocnemius muscle fibrosis were obtained during the second, third, and fourth weeks after surgically induced lesions in the right gastrocnemius muscles of 15 Wistar rats. The echo intensity, reflecting the degree of brightness on a sonogram, was divided into 256 gray levels instead of decibels. The mean echo intensity of each pixel in the region of interest was calculated as a summation of the echo intensities in all pixels divided by the pixel numbers in the region. To control individual variations among the rats, we calculated a K value, defined as the difference in the mean echo intensity between normal and affected muscles. RESULTS: Significant correlations (r > 0.7; P < .05) between mean echo intensity and K values and the fibrous tissue percentage were identified. The mean echo intensity in the injured gastrocnemius muscles was significantly (P = .029) greater than that in the normal muscles 3 weeks after injury. In histologic assessments, muscle fibrosis was most prominent 3 weeks after injury. However, the differences in fibrosis at different healing stages were not significant. CONCLUSIONS: Mean echo intensity and K values can reflect the extent of fibrosis in affected muscles and may be valuable for quantifying muscle fibrosis in clinical practice. PMID- 22215769 TI - Normal epiphyseal cartilage measurements in the knee in children: an alternative sonographic approach. AB - OBJECTIVES: The purpose of this study was to validate previously reported distal femoral cartilage measurements in healthy children of different ages using an alternative sonographic imaging plane and patient position than previously reported and to provide preliminary proximal tibial epiphyseal cartilage measurements in healthy children. METHODS: Distal femoral and proximal tibial epiphyseal cartilage thickness was measured using sonography in a cohort of healthy children based on a coronal image at the medial aspect of the femorotibial joint with the knee in 30 degrees of flexion. The average of 3 measurements of femoral and tibial epiphyseal cartilage was obtained and correlated with age and sex. Femoral epiphyseal cartilage measurements were compared to recently reported measurements at the patellofemoral joint. RESULTS: Sixty children (31 boys and 29 girls; newborn to 21 years; mean, 9 years; median, 7 years 11 months) were imaged. Seventy-four percent of distal femoral cartilage epiphyseal measurements fell into the 95% confidence intervals predicted by previously published reports. At age ranges outside those previously reported, there was less concordance between measured cartilage thickness values and those predicted. CONCLUSIONS: Values of distal femoral epiphyseal cartilage thickness measured by sonography of the femorotibial joint are similar to those reported at the patellofemoral joint. We propose that femoral epiphyseal cartilage thickness be measured on the basis of a coronal image at the medial femorotibial joint. This technique requires less knee flexion, which may prove advantageous when evaluating cartilage in patients with joint inflammation and a limited range of motion. It also allows concurrent measurement of tibial epiphyseal cartilage and thus provides another parameter for assessing cartilage loss. PMID- 22215770 TI - Comparative study of color Doppler voiding urosonography without contrast enhancement and direct radionuclide voiding cystography for diagnosis of vesicoureteric reflux in children. AB - OBJECTIVES: Most available studies investigating the diagnostic accuracy of color Doppler voiding urosonography in the detection of vesicoureteric reflux used an echo contrast agent. It is unknown whether echo contrast agents are necessary for diagnosis or follow-up of vesicoureteric reflux. We compared color Doppler voiding urosonography without contrast enhancement and direct radionuclide voiding cystography in the detection and grading of vesicoureteric reflux with respect to the sex and age of patients as well as the severity of reflux. METHODS: In the 66 patients enrolled (56 girls and 10 boys), 132 renoureteral units were investigated. All patients under went Doppler voiding urosonography and direct radionuclide voiding cystography within 3 hours. Direct radionuclide voiding cystography was used as the reference standard. RESULTS: Our results indicate good overall sensitivity (83%) and specificity (77%) for color Doppler voiding urosonography without contrast enhancement in comparison with direct radionuclide voiding cystography. As the age of the patients decreased, the sensitivity of urosonography increased, reaching 100% among patients younger than 1 year. In the comparison of different grades of reflux severity, we found that the sensitivity and specificity were elevated as the grade increased (both parameters reaching 100% in the most severe cases). Severity grading was equal between the two methods. CONCLUSIONS: We have shown that Doppler voiding urosonography without contrast enhancement is a comparably reliable method versus direct radionuclide voiding cystography in the detection and grading of vesicoureteric reflux, especially at higher grades of reflux and in children younger than 1 year. PMID- 22215771 TI - Variations in the Elasticity of Breast Tissue During the Menstrual Cycle Determined by Real-time Sonoelastography. AB - OBJECTIVES: The purpose of this study was to determine the dependence of breast tissue elasticity on the menstrual cycle of healthy volunteers by means of real time sonoelastography. METHODS: Twenty-two healthy volunteers (aged 18-33 years) were examined once weekly during two consecutive menstrual cycles using sonoelastography. Group 1 (n= 10) was not taking hormonal medication; group 2 (n = 12) was taking oral contraceptives. RESULTS: The breast parenchyma appeared softer than the dermis and harder than the adipose tissue, and elasticity varied over the menstrual cycle and between groups. Group 1 (no hormone intake) showed continuously increasing elasticity with relatively soft breast parenchyma in the menstrual and follicular phases and harder parenchyma in the luteal phase (P = .012). Group 2 (oral contraceptives) showed no statistically significant changes in breast parenchymal elasticity according to sonoelastography. The parenchyma was generally softer in group 1 compared with group 2 throughout the menstrual cycle (P = .033). The dermis, the subcutaneous adipose tissue, and the pectoralis major muscle showed no changes in elasticity. Comparison of measurements made during the first and the second menstrual cycles showed similar patterns of elasticity in both groups. CONCLUSIONS: Sonoelastography is a reproducible method that can be used to determine the dependence of breast parenchyma elasticity on the menstrual cycle and on the intake of hormonal contraceptives. PMID- 22215772 TI - Spatiotemporal image correlation with spherical sampling and high-definition flow: new 4-dimensional method for assessment of tissue vascularization changes during the cardiac cycle: reproducibility analysis. AB - OBJECTIVES: To describe and assess the interobserver reproducibility of a new method for evaluation of ovarian vascularization using spatiotemporal image correlation-high definition flow (STIC-HDF). METHODS: Stored 4-dimensional (4D) STIC-HDF volume data from 39 healthy pre-menopausal fertile women (aged <35 years) examined in the follicular part of the menstrual cycle by transvaginal sonography were assessed by two different examiners blinded from each other (one in Spain the other in Poland). Using 1-cm(3) spherical sampling, the vascularization index (VI) from the most vascularized part of the ovarian stroma was calculated at two different moments of the cardiac cycle (systole and diastole). System settings were kept constant for all patients (pulse repetition frequency, 0.6 kHz; gain, 0.2) with a depth of 40 mm. Analysis was performed offline using 4D software on a personal computer. On the basis of VI and vascularization-flow index (VFI) values during systole and diastole, 4 new 4D indices were defined: 4D systolic/diastolic volumetric index (4D-SDVI = VI(syst)/VI(diast)), 4D hemodynamic volumetric index (4D-HVI = [VI(syst) + VI(diast)]/[VI(syst) - VI(diast)]), 4D systolic/diastolic vascularization-flow index (4D-SDVFI = VFI(syst)/VFI(diast)), and 4D hemodynamic vascularization-flow index (4D-HVFI = [VFI(syst) + VFI(diast)]/[VFI(syst)- VFI(diast)]). Reproducibility of measurements was estimated by calculating the intraclass correlation coefficient (ICC). RESULTS: The systolic VI, diastolic VI, 4D-SDVI, 4D-HVI, systolic VFI, diastolic VFI, and 4D-HVFI showed good reproducibility (ICC, 0.992, 0.994, 0.879, 0.915, 0.995, 0.995, and 0.893, respectively). The 4D SDVFI showed moderate reproducibility (ICC, 0.797). CONCLUSIONS: We describe 4 new 4D vascular indices for assessing tissue vascularization using STIC-HDF technology. Assessment of ovarian vascularization using this STIC-HDF spherical sampling is reliable. The calculation of these new indices is reproducible between two different examiners. PMID- 22215773 TI - A study of the cost, accuracy, and benefits of 3-dimensional sonography compared with hysterosalpingography in women with uterine abnormalities. AB - OBJECTIVES: We conducted a prospective blinded study to evaluate the costs, accuracy, risks, and benefits of 3-dimensional (3D) transvaginal sonography compared to hysterosalpingography. METHODS: A total of 101 women aged 26 to 44 years with evidence of uterine anomalies were enrolled. All participants had routine hysterosalpingography as part of their infertility evaluation as well as 3D transvaginal sonography as part of the study. Surgical findings were used as the standard for final diagnosis. RESULTS: A total of 6 normal uteri and 119 uterine anomalies were classified: 30 congenital uterine anomalies (3 arcuate, 1 unicornuate, 4 bicornuate, 2 didelphys, and 20 septate uteri) and 89 acquired anomalies (38 polyps, 30 fibroids, 17 synechiae, and 4 adenomyosis). Congenital anomalies were correctly identified in 30 of 30 cases by 3D sonography but from 10 to 30 of 30 cases by hysterosalpingography. The detection rates for acquired uterine anomalies were lower for both techniques: 44 to 89 of 89 cases for 3D sonography and 22 to 74 of 89 cases for hysterosalpingography. Only 7 of the 20 septi would have been surgically corrected if patients only had hysterosalpingography. On the contrary, 30 of 30 patients with congenital uterine anomalies, 2 of 4 patients with adenomyosis, and all 6 patients with normal uteri were spared from surgery with diagnoses by 3D sonography. No adverse effects were reported after sonography, and only 6 minor ones were reported after hysterosalpingography. CONCLUSIONS: Three-dimensional transvaginal sonography provides visualization and evaluation of the uterine cavity with similar or better accuracy than standard hysterosalpingography in the office setting, with lower cost and morbidity. PMID- 22215774 TI - Sonographic evaluation of the yolk sac. AB - This pictorial essay aims to inform related clinicians by summarizing the normal and abnormal sonographic findings of the yolk sac in the first trimester of pregnancy. An abnormality in the sonographic appearance of a yolk sac can predict subsequent embryonic death or abnormalities. Therefore, the accurate recognition of normal and abnormal sonographic findings concerning the yolk sac can be used to anticipate the course of pregnancy. PMID- 22215775 TI - Common applications of dermatologic sonography. AB - In recent years, there has been growing use of sonography in the dermatologic field. Thus, this review analyzes the most common dermatologic applications of sonography with some technical considerations for performing this type of examination. Moreover, the sonographic findings in common benign and malignant skin tumors, inflammatory dermatologic diseases, and ungual and cosmetic conditions, among others, are considered. Thus, this noninvasive technique may be a potent adjunctive tool in the diagnosis and management of dermatologic conditions in daily practice, delivering critical information otherwise unavailable to the clinical naked eye. PMID- 22215776 TI - Features of testicular epidermoid cysts on contrast-enhanced sonography and real time tissue elastography. AB - A series of 7 testicular epidermoid cysts were imaged by contrast-enhanced sonography to assess internal vascularity and by real-time tissue elastography to grade stiffness by a visual and strain ratio quantification scoring system. No internal vascular enhancement was seen on contrast-enhanced sonography; the 3 largest lesions showed rim enhancement. On the real-time elastographic color display, all lesions were predominantly blue ("hard"), and the lesions analyzed for the strain ratio had a mean value of 43.57. Contrast-enhanced sonography depicts the absence of vascular flow, and real-time elastography shows that the epidermoid cysts are hard. This combination of information will help further characterize these lesions. PMID- 22215777 TI - Lissencephaly with bilateral complete cleft lip and palate: an early second trimester diagnosis. PMID- 22215778 TI - Prenatal diagnosis of a rare gingival granular cell tumor of the fetal mouth. PMID- 22215779 TI - Free-floating right ventricular thrombus as assessed by real-time 3-dimensional transesophageal echocardiography. PMID- 22215780 TI - Sonography of an epidermoid inclusion cyst of the thyroid gland. PMID- 22215781 TI - Will the real optic nerve sheath please stand up? PMID- 22215782 TI - AIUM practice guideline for the performance of an ultrasound examination in the practice of urology. PMID- 22215783 TI - AIUM practice guideline for the performance of an ultrasound examination of the extracranial cerebrovascular system. PMID- 22215784 TI - AIUM practice guideline for the performance of an ultrasound examination of the neonatal spine. PMID- 22215785 TI - AIUM practice guideline for the performance of sonohysterography. PMID- 22215786 TI - AIUM practice guideline for the performance of ultrasound vascular mapping for preoperative planning of dialysis access. PMID- 22215787 TI - Factors associated with social interaction anxiety among Chinese adolescents. AB - OBJECTIVES: To investigate potential risk factors for social anxiety, particularly social interaction anxiety among the Chinese adolescents. METHODS: A cross-sectional health survey was conducted in Guangzhou city of the Guangdong Province where high school students aged 13 to 18 years were recruited. The sample was selected from all high schools in the city using a 2-stage random cluster sampling technique. Social interaction anxiety was assessed using the Social Interaction Anxiety Scale. Information collected in the survey included: demographics, self-perception on school performance, relationship with teachers and peers, satisfaction with self-image, achievements, and parenting style of the mother. The parent-child relationship, specifically the relationship between respondents and their mothers, was assessed using the mother attachment subscale of the Inventory of Parent and Peer Attachment. Self-esteem was assessed using the Rosenberg Self-Esteem Scale. The multiple linear regression technique was applied to investigate associations between selected potential risk factors and social interaction anxiety, with adjustments for cluster sampling. RESULTS: Lower family income, lower self-esteem, and hostility were significantly associated with social interaction anxiety among adolescents. Variables identified as risk factors of anxiety disorder in the literature, such as gender, were not associated with social interaction anxiety in this sample. CONCLUSIONS: These results were consistent with those of other studies conducted mainly in the United States and Europe. Regarding non-significant results related to gender, they need viewing in the context of parenting styles of Chinese mothers. PMID- 22215788 TI - An Indian adaptation of the Involvement Evaluation Questionnaire: similarities and differences in assessment of caregiver burden. AB - OBJECTIVES: The Involvement Evaluation Questionnaire (IEQ) is a comprehensive, conceptually valid and reliable means of assessing caregiver burden. However, its psychometric properties have rarely been examined in non-European settings. The aim of the present study was to evaluate the psychometric properties of an Indian translation of the IEQ (Hindi-IEQ). METHODS: The European Union (English) version of IEQ was translated into Hindi and reviewed by a group of experts and caregivers for translation accuracy, cultural appropriateness, and for relevance and acceptability of items and constructs. The Hindi-IEQ was then administered to 162 primary caregivers of patients with severe mental illnesses. Eighteen caregivers completed both the English and Hindi versions to check the level of agreement between them. Another 27 completed the Hindi-IEQ twice, a week apart, to evaluate its test-retest reliability. Factor structure of the Hindi-IEQ was examined using an exploratory, principal components and factor analysis. RESULTS: Pearson's correlation coefficients were significant for 24 items, while intraclass correlation coefficients were significant for 28 of the 31 items (P < 0.05), indicating a satisfactory level of agreement between the Hindi and English versions. Test-retest reliability for all items of the Hindi-IEQ was adequate, with kappa values ranging from 0.46 to 0.95 and intraclass correlation coefficients from 0.76 to 1.00. Internal consistency (Cronbach's alpha = 0.89) and the split-half reliability (Spearman-Brown coefficient = 0.68) of the Hindi IEQ were also satisfactory. However, several differences were noted in the factor structure and distribution of scores of the Hindi-IEQ, which were quite unlike that of the European Union version. CONCLUSIONS: The similarities and differences between the 2 versions of the IEQ indicated that sociocultural factors could influence assessment of caregiver burden across different cultures. PMID- 22215789 TI - Modulating factors that preserve cognitive function in healthy ageing. AB - OBJECTIVES: Most studies examining factors contributing to cognitive impairments and dementia in late life focused on risks. In this study, we aimed to evaluate factors that might help preserve cognition in healthy Hong Kong elders. METHODS: This was a 2-year prospective study of 476 cognitively healthy community dwellers (aged 60-92 years) recruited in Hong Kong. Participants were assessed with a battery of cognitive tests and questionnaires on their sense of loneliness and leisure activities. RESULTS: A high level of cognitive activity participation (r = 0.13, p = 0.03) and a low level of loneliness (r = -0.15, p = 0.01) were associated with better cognitive test performance. Participants with more years of education (odds ratio = 1.27, P < 0.001) and a higher frequency of drinking (odds ratio = 1.17, p = 0.05) were associated with high cognitive function, while those with a high level of loneliness (odds ratio = 0.79, p = 0.01) were associated with low cognitive function. The correlation with cognitive activity participation remained significant in participants with very good cognitive function (r = 0.20, p = 0.04). CONCLUSIONS: These results suggested that social engagement and moderate drinking may be modulating factors for cognition. Further studies should explore the interactions between lifestyle factors and cognition in older adults with no significant cognitive impairment. PMID- 22215790 TI - Inhalant abuse: a study from a tertiary care de-addiction clinic. AB - OBJECTIVES: Inhalant use has been considered one of the most dangerous forms of substance abuse leading even to serious accidents and death. The current study explored the correlates of inhalant abuse in subjects from a drug de-addiction clinic. METHODS: The study was conducted at a tertiary-level multi-specialty hospital in India, which entailed a chart review of patients with inhalant abuse / dependence presenting to the clinic over a 2-year period. All the treatment records of the de-addiction clinic were reviewed and information gathered regarding these patients. RESULTS: The study involved the records of 36 subjects, with a mean age of 16 years (standard deviation, 4; range, 11-26 years). Most subjects (86%) were adolescents; three-quarters of whom had no family history of substance abuse. The mean (standard deviation) age of initiation of inhalant use was 14 (4) years. The commonest cause of first use reported by the subjects was experimentation (94%), and 97% of them came to know of inhalant from their inhalant-using friends. CONCLUSIONS: These findings provide important information on a relatively under-researched area. PMID- 22215791 TI - Parental psychological symptoms and familial risk factors of children and adolescents who exhibit school refusal. AB - OBJECTIVES: To assess the levels of psychological symptoms in the parents of children with school refusal and determine the familial risk factors in its development. METHODS: This study was performed on 55 pairs of parents who had children exhibiting school refusal and were compared with a control group. A socio-demographic data form, the Beck Depression Inventory, the State-Trait Anxiety Inventory, and the Symptom Checklist-90 revised were applied to these parents. RESULTS: Parents of the school refusal group had higher anxiety and depression scores than the controls. Among the risk factors for school refusal, physical punishment by the parents, a history of organic disease in the parents or children, and a history of psychiatric disorders in the parents or other relatives were found to be significant. CONCLUSIONS: Depending on genetic and environmental factors, parents with psychiatric disorders appeared to be associated with development of psychiatric disorders in their children. Moreover, psychiatric disorders in parents negatively affected the treatment of their children and adolescents who exhibited school refusal. It is therefore vital to treat psychiatric disorders of parents with the children having psychiatric disorders, and thus increase parent participation in their children's therapeutic process. PMID- 22215792 TI - Growth kinetics in a strained crystal film on a wavy patterned substrate. AB - We study the combination of the Asaro-Tiller-Grinfeld morphological instability of a strained film and the organizing effect of an underlying patterned substrate. We use a continuum description of surface diffusion accounting for elasticity, surface energy and wetting interactions. We solve both the mechanical equilibrium and the growth dynamics during annealing at linear order in the film modulation amplitude. We characterize the kinetic phase diagram as a function of time, the film thickness and the ratio between the substrate and the instability wavelengths. We find that the film surface can skip from a configuration in phase with the substrate to either an out-of-phase or a non-ordered configuration, depending on the pattern wavelength and annealing time. PMID- 22215794 TI - Comparative anatomy: Giorgione's Venus, Connoisseur Morelli, and the Reverend Bayes. PMID- 22215795 TI - Editorial: semaphorins: a further chemotropic family expressed in the thymus. PMID- 22215796 TI - Editorial: molecular eavesdropping: phagocytic cells spy on bacterial communication. PMID- 22215798 TI - Space charge characteristics of an insulating thin film negatively charged by a low-energy electron beam. AB - In this study, based on a comprehensive numerical simulation of self-consistent charging, we investigate the formation, evolution and influencing factors of space charge distributions for a grounded insulating thin film of SiO(2) negatively charged by a keV non-penetrating focused electron beam. The simulated space charge presents first positive distributions and then negative ones along both the radial and depth directions because of the difference between electron and hole transports. The variations in distribution occur within a range of the minimum potential acting as a potential barrier for carrier transport. The negative space charge is distributed more widely and deeply, though its peak value in density is usually lower than that of the positive one. Electrons trapped outside the minimum potential range dominate the strength of negative charging. With the increase in potential barrier and the occurrence of leakage current, the space charge eventually reaches equilibrium and exhibits an approximately one-dimensional axial distribution outside the minimum potential range. Distribution features of the space charge density in the equilibrium state correlate with the film and beam parameters via transients of the leakage current. These results and analyses provide new insights into the negative charging effects involved in various electron-beam-based surface microscopic methods, analyses and fabrication techniques. PMID- 22215797 TI - Obesity and altered glucose metabolism impact HDL composition in CETP transgenic mice: a role for ovarian hormones. AB - Mechanisms underlying changes in HDL composition caused by obesity are poorly defined, partly because mice lack expression of cholesteryl ester transfer protein (CETP), which shuttles triglyceride and cholesteryl ester between lipoproteins. Because menopause is associated with weight gain, altered glucose metabolism, and changes in HDL, we tested the effect of feeding a high-fat diet (HFD) and ovariectomy (OVX) on glucose metabolism and HDL composition in CETP transgenic mice. After OVX, female CETP-expressing mice had accelerated weight gain with HFD-feeding and impaired glucose tolerance by hyperglycemic clamp techniques, compared with OVX mice fed a low-fat diet (LFD). Sham-operated mice (SHAM) did not show HFD-induced weight gain and had less glucose intolerance than OVX mice. Using shotgun HDL proteomics, HFD-feeding in OVX mice had a large effect on HDL composition, including increased levels of apoA2, apoA4, apoC2, and apoC3, proteins involved in TG metabolism. These changes were associated with decreased hepatic expression of SR-B1, ABCA1, and LDL receptor, proteins involved in modulating the lipid content of HDL. In SHAM mice, there were minimal changes in HDL composition with HFD feeding. These studies suggest that the absence of ovarian hormones negatively influences the response to high-fat feeding in terms of glucose tolerance and HDL composition. CETP-expressing mice may represent a useful model to define how metabolic changes affect HDL composition and function. PMID- 22215799 TI - Cooling and seizure burden in term neonates: an observational study. AB - OBJECTIVE: To investigate any possible effect of cooling on seizure burden, the authors quantified the recorded electrographic seizure burden based on multichannel video-EEG recordings in term neonates with hypoxic-ischaemic encephalopathy (HIE) who received cooling and in those who did not. STUDY DESIGN: Retrospective observational study. PATIENTS: Neonates >37 weeks gestation born between 2003 and 2010 in two hospitals. METHODS: Off-line analysis of prolonged continuous multichannel video-EEG recordings was performed independently by two experienced encephalographers. Comparison between the recorded electrographic seizure burden in non-cooled and cooled neonates was assessed. Data were treated as non-parametric and expressed as medians with interquartile ranges (IQR). RESULTS: One hundred and seven neonates with HIE underwent prolonged continuous multichannel EEG monitoring. Thirty-seven neonates had electrographic seizures, of whom 31 had EEG recordings that were suitable for the analysis (16 non-cooled and 15 cooled). Compared with non-cooled neonates, multichannel EEG monitoring commenced at an earlier postnatal age in cooled neonates (6 (3-9) vs 15 (5-20) h)and continued for longer (88 (75-101) vs 55 (41-60) h). Despite this increased opportunity to capture seizures in cooled neonates, the recorded electrographic seizure burden in the cooled group was significantly lower than in the non-cooled group (60 (39-224) vs 203 (141-406) min). Further exploratory analysis showed that the recorded electrographic seizure burden was only significantly reduced in cooled neonates with moderate HIE (49 (26-89) vs 162 (97-262) min). CONCLUSIONS: A decreased seizure burden was seen in neonates with moderate HIE who received cooling. This finding may explain some of the therapeutic benefits of cooling seen in term neonates with moderate HIE. PMID- 22215800 TI - Early term and late preterm birth are associated with poorer school performance at age 5 years: a cohort study. AB - OBJECTIVE: To compare school performance at age 5 years in children born at full term (39-41 weeks gestation) with those born at early term (37-38 weeks gestation), late preterm (34-36 weeks gestation), moderately preterm (32-33 weeks gestation) and very preterm (<32 weeks gestation). DESIGN: Population-based cohort (UK Millennium Cohort Study). PARTICIPANTS: Seven thousand six hundred and fifty children born in 2000-2001 and attending school in England in 2006. METHODS: School performance was measured using the foundation stage profile (FSP), a statutory assessment by teachers at the end of the child's first school year. The FSP comprises 13 assessment scales (scored from 1 to 9). Children who achieve an average of 6 points per scale and at least 6 in certain scales are classified as 'reaching a good level of overall achievement'. RESULTS: Fifty-one per cent of full term children had not reached a good level of overall achievement; this proportion increased with prematurity (55% in early term, 59% in late preterm, 63% in moderately preterm and 66% in very preterm children). Compared with full term children, an elevated risk remained after adjustment, even in early term (adjusted RR 1.05, 95% 1.00 to 1.11) and late preterm children (adjusted RR 1.12, 95% CI 1.04 to 1.22). Similar effects were noted for 'not working securely' in mathematical development, physical development and creative development. The effects of late preterm and early term birth were small in comparison with other risk factors. CONCLUSIONS: Late preterm and early term birth are associated with an increased risk of poorer educational achievement at age 5 years. PMID- 22215801 TI - Electrolytes in sick neonates - which sodium is the right answer? AB - INTRODUCTION: Hypoproteinaemia leads to spuriously high-sodium values when measured by indirect ion-selective electrodes (ISE) as used in main laboratory analysers compared with direct ISE employed in point-of-care analysers (POCT). The authors, therefore, investigated the occurrence of hypoalbuminaemia and its effect on measured sodium from POCT and the main laboratory analyser of neonatal intensive-care samples. METHOD: Sodium, in paired retrospective samples, measured by the main laboratory and neonatal unit blood-gas (POCT) analysers were compared. RESULTS: Hypoalbuminaemia (<30 g/l) was present in 1400/2420 paired results. Sodium was higher when measured by laboratory analyser, the difference increased with decreasing albumin; sodium (laboratory - POCT)=7.6 (+/-1.1)-0.22 (+/-0.04)*albumin. A difference >3 mmol/l was present in 31% and consequently underestimated (9.4%) hyponatraemia and overestimated (3.8%) hypernatraemia. CONCLUSION: Hypoalbuminaemia is common in sick neonates and monitoring electrolytes using POCT and laboratory analysers frequently yield significantly different results with consequent misclassification. In these patients, measurement of electrolytes by direct ISE (blood-gas analyser) may be more accurate. PMID- 22215802 TI - National neonatal data to support specialist care and improve infant outcomes. AB - 'Liberating the NHS' and the new Outcomes Framework make information central to the management of the UK National Health Service (NHS). The principles of patient choice and government policy on the transparency of outcomes for public services are key drivers for improving the performance. Specialist neonatal care is able to respond positively to these challenges owing to the development of a well defined dataset and comprehensive national data collection. When combined with analysis, audit and feedback at the national level, this is proving to be an effective means to harness the potential of clinical data. Other key characteristics have been an integrated approach to ensure that data are captured once and serve multiple needs, collaboration between professional organisations, parents, academic institutions, the commercial sector and NHS managers, and responsiveness to changing requirements. The authors discuss these aspects of national neonatal specialist data and point to future developments. PMID- 22215804 TI - A firm grip does not always pay off: a new Phact(r) 4 integrin signaling. AB - beta1 integrin signaling plays crucial roles in enteric nervous system development. Zhang and colleagues (pp. 69-81) discovered that phosphatase and actin regulator 4 (Phactr4) antagonizes beta1 integrin signaling through protein phosphatase 1 (PP1) in focal adhesions of enteric neural crest cells (ENCCs). Loss of Phactr4-PP1 interaction leads to increased beta1 integrin signaling, loss of collective and directional migration, and hindgut hypogangaliosis, indicating that the right adjustment of beta1 integrin signaling is required for the normal migration and organization of ENCCs. PMID- 22215805 TI - The enemy within: intronic miR-26b represses its host gene, ctdsp2, to regulate neurogenesis. AB - Differentiation of multipotent stem cells occurs through the highly coordinated control of gene expression. Repressor element 1 (RE1) silencing transcription factor (REST), a master transcriptional regulator in neuronal stem cells, restricts neuronal gene expression. REST activity is context-dependent and is modified by its cofactors, such as Ctdsp2. In this issue of Genes & Development, Dill and colleagues (pp. 25-30) report on the microRNA-mediated regulation of neural differentiation. Interestingly, this microRNA is post-transcriptionally regulated and modulates expression of its host gene, ctdsp2. PMID- 22215807 TI - Intronic miR-26b controls neuronal differentiation by repressing its host transcript, ctdsp2. AB - Differentiation of neural stem cells (NSCs) to neurons requires the activation of genes controlled by the repressor element 1 (RE1) silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF) protein complex. Important components of REST/NRSF are phosphatases (termed RNA polymerase II C-terminal domain small phosphatases [CTDSPs]) that inhibit RNA polymerase II and suppress neuronal gene expression in NSCs. Activation of genes controlled by CTDSPs is required for neurogenesis, but how this is achieved is not fully understood. Here we show that ctdsp2 is a target of miR-26b, a microRNA that is encoded in an intron of the ctdsp2 primary transcript. This intrinsic negative feedback loop is inactive in NSCs because miR-26b biogenesis is inhibited at the precursor level. Generation of mature miR-26b is activated during neurogenesis, where it suppresses Ctdsp2 protein expression and is required for neuronal cell differentiation in vivo. PMID- 22215806 TI - A decade of 3C technologies: insights into nuclear organization. AB - Over the past 10 years, the development of chromosome conformation capture (3C) technology and the subsequent genomic variants thereof have enabled the analysis of nuclear organization at an unprecedented resolution and throughput. The technology relies on the original and, in hindsight, remarkably simple idea that digestion and religation of fixed chromatin in cells, followed by the quantification of ligation junctions, allows for the determination of DNA contact frequencies and insight into chromosome topology. Here we evaluate and compare the current 3C-based methods (including 4C [chromosome conformation capture-on chip], 5C [chromosome conformation capture carbon copy], HiC, and ChIA-PET), summarize their contribution to our current understanding of genome structure, and discuss how shape influences genome function. PMID- 22215808 TI - Polyploidization of glia in neural development links tissue growth to blood-brain barrier integrity. AB - Proper development requires coordination in growth of the cell types composing an organ. Many plant and animal cells are polyploid, but how these polyploid tissues contribute to organ growth is not well understood. We found the Drosophila melanogaster subperineurial glia (SPG) to be polyploid, and ploidy is coordinated with brain mass. Inhibition of SPG polyploidy caused rupture of the septate junctions necessary for the blood-brain barrier. Thus, the increased SPG cell size resulting from polyploidization is required to maintain the SPG envelope surrounding the growing brain. Polyploidization likely is a conserved strategy to coordinate tissue growth during organogenesis, with potential vertebrate examples. PMID- 22215803 TI - Comparison of gene repertoires and patterns of evolutionary rates in eight aphid species that differ by reproductive mode. AB - In theory, the loss of sexual reproduction is expected to result in the accumulation of deleterious mutations. In aphids, two main types of life cycle, cyclic and obligate parthenogenesis, represent respectively "sexual" and "asexual" reproductive modes. We used the complete pea aphid genome and previously published expressed sequence tags (ESTs) from two other aphid species. In addition, we obtained 100,000 new ESTs from five more species. The final set comprised four sexual and four asexual aphid species and served to test the influence of the reproductive mode on the evolutionary rates of genes. We reconstructed coding sequences from ESTs and annotated these genes, discovering a novel peptide gene family that appears to be among the most highly expressed transcripts from several aphid species. From 203 genes found to be 1:1 orthologs among the eight species considered, we established a species tree that partly conflicted with taxonomy (for Myzus ascalonicus). We then used this topology to evaluate the dynamics of evolutionary rates and mutation accumulation in the four sexual and four asexual taxa. No significant increase of the nonsynonymous to synonymous ratio or of nonsynonymous mutation numbers was found in any of the four branches for asexual taxa. We however found a significant increase of the synonymous rate in the branch leading to the asexual species Rhopalosiphum maidis, which could be due to a change in the mutation rate or to an increased number of generations implied by its change of life cycle. PMID- 22215809 TI - PRC2 directly methylates GATA4 and represses its transcriptional activity. AB - Polycomb-repressive complex 2 (PRC2) promotes tissue-specific differentiation by depositing trimethylated histone H3 Lys 27 (H3K27me3) epigenetic marks to silence ectopic gene expression programs. Here, we show that EZH2, the catalytic subunit of PRC2, is required for cardiac morphogenesis. Both in vitro and in fetal hearts, EZH2 interacted with cardiac transcription factor GATA4 and directly methylated it at Lys 299. PRC2 methylation of GATA4 attenuated its transcriptional activity by reducing its interaction with and acetylation by p300. Our results reveal a new mechanism of PRC2-mediated transcriptional repression in which PRC2 methylates a transcription factor to inhibit its transcriptional activity. PMID- 22215810 TI - Spatial arrangement of an RNA zipcode identifies mRNAs under post-transcriptional control. AB - How RNA-binding proteins recognize specific sets of target mRNAs remains poorly understood because current approaches depend primarily on sequence information. In this study, we demonstrate that specific recognition of messenger RNAs (mRNAs) by RNA-binding proteins requires the correct spatial positioning of these sequences. We characterized both the cis-acting sequence elements and the spatial restraints that define the mode of RNA binding of the zipcode-binding protein 1 (ZBP1/IMP1/IGF2BP1) to the beta-actin zipcode. The third and fourth KH (hnRNP K homology) domains of ZBP1 specifically recognize a bipartite RNA element comprised of a 5' element (CGGAC) followed by a variable 3' element (C/A-CA-C/U) that must be appropriately spaced. Remarkably, the orientation of these elements is interchangeable within target transcripts bound by ZBP1. The spatial relationship of this consensus binding site identified conserved transcripts that were verified to associate with ZBP1 in vivo. The dendritic localization of one of these transcripts, spinophilin, was found to be dependent on both ZBP1 and the RNA elements recognized by ZBP1 KH34. PMID- 22215811 TI - Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. AB - Cell attachment to the extracellular matrix (ECM) is crucial to cell physiology such as polarity, motility, and proliferation. In normal cells, loss of attachment to the ECM induces a specific type of apoptosis, termed anoikis. Resistance to anoikis in cancer cells promotes their survival in circulation and dispersion to distant anatomic sites, leading to tumor metastasis. The Yes associated protein (YAP) transcription coactivator is a human oncogene and a key regulator of organ size. The Hippo tumor suppressor pathway phosphorylates and inhibits YAP. However, little is known about the signals that regulate the Hippo pathway. Here we report that through cytoskeleton reorganization, cell detachment activates the Hippo pathway kinases Lats1/2 and leads to YAP phosphorylation and inhibition. The detachment-induced YAP inactivation is required for anoikis in nontransformed cells, whereas in cancer cells with deregulation of the Hippo pathway, knockdown of YAP and TAZ restores anoikis. Furthermore, we provided evidence that Lats1/2 expression level is indeed significantly down-regulated in metastatic prostate cancer. Our findings provide a novel connection between cell attachment and anoikis through the Hippo pathway and have important implications in cancer therapeutics. PMID- 22215812 TI - Phactr4 regulates directional migration of enteric neural crest through PP1, integrin signaling, and cofilin activity. AB - Hirschsprung disease (HSCR) is caused by a reduction of enteric neural crest cells (ENCCs) in the gut and gastrointestinal blockage. Knowledge of the genetics underlying HSCR is incomplete, particularly genes that control cellular behaviors of ENCC migration. Here we report a novel regulator of ENCC migration in mice. Disruption of the Phactr4 gene causes an embryonic gastrointestinal defect due to colon hypoganglionosis, which resembles human HSCR. Time-lapse imaging of ENCCs within the embryonic gut demonstrates a collective cell migration defect. Mutant ENCCs show undirected cellular protrusions and disrupted directional and chain migration. Phactr4 acts cell-autonomously in ENCCs and colocalizes with integrin and cofilin at cell protrusions. Mechanistically, we show that Phactr4 negatively regulates integrin signaling through the RHO/ROCK pathway and coordinates protein phosphatase 1 (PP1) with cofilin activity to regulate cytoskeletal dynamics. Strikingly, lamellipodia formation and in vivo ENCC chain migration defects are rescued by inhibition of ROCK or integrin function. Our results demonstrate a previously unknown pathway in ENCC collective migration in vivo and provide new candidate genes for human genetic studies of HSCR. PMID- 22215813 TI - Schizosaccharomyces pombe Ccq1 and TER1 bind the 14-3-3-like domain of Est1, which promotes and stabilizes telomerase-telomere association. AB - The telomerase protein Est1 exists in multiple organisms, including Schizosaccharomyces pombe, humans, and Saccharomyces cerevisiae, but its function has only been closely examined in S. cerevisiae, where it is a recruiter/activator of telomerase. Here, we demonstrate that S. pombe Est1 was required for the telomere association of the telomerase holoenzyme, suggesting that it too has a recruitment role. Its association with telomeres was dependent on Trt1, the catalytic subunit, and Ccq1, a telomeric protein. Surprisingly, Est1 telomere binding was only partially dependent on TER1, the telomerase RNA, even though Est1 bound nucleotides 415-507 of TER1. A ter1-Delta415-507 strain had short telomeres and very low Est1 and Trt1 telomere association in late S phase but did not senesce. An unbiased search for mutations that reduced Est1-TER1 interaction identified mutations only in the Est1 14-3-3-like domain, a phosphoserine-binding motif, the first example of a 14-3-3-like domain with RNA binding activity. These mutations also reduced Est1-Ccq1 binding. One such mutant prevented Est1 telomere association and caused telomere loss and slow senescence, similar to ccq1Delta. We propose that the Est1-Ccq1 interaction is critical for telomerase recruitment, while the Est1-TER1 interaction acts downstream from Ccq1 mediated recruitment to stabilize the holoenzyme at the telomere. PMID- 22215815 TI - Evaluation of salivary anti-Salmonella typhi lipopolysaccharide IgA ELISA for serodiagnosis of typhoid fever in children. AB - This observational study was conducted to determine the diagnostic accuracy of ELISA for the detection of anti-Salmonella typhi lipopolysaccharide (LPS) salivary immunoglobulin A (IgA) antibodies in 37 children with culture confirmed typhoid, 30 febrile controls with an alternative diagnosis and 30 healthy controls. The test was positive in 33/37 (89.2%) cases of typhoid, but negative in all patients in the two control groups. Maximum absorbance of anti-LPS IgA was observed during the second and third weeks of typhoid, with a progressive decline thereafter. The sensitivity of ELISA was 71.4%, 100%, 100%, 9.1% and 0%, in first, second, third, fourth and fifth week of illness, respectively. Further large scale studies measuring salivary anti-LPS IgA antibodies are needed to confirm the potential of saliva-based serology in children with suspected typhoid. PMID- 22215814 TI - Structure and operation of the DNA-translocating type I DNA restriction enzymes. AB - Type I DNA restriction/modification (RM) enzymes are molecular machines found in the majority of bacterial species. Their early discovery paved the way for the development of genetic engineering. They control (restrict) the influx of foreign DNA via horizontal gene transfer into the bacterium while maintaining sequence specific methylation (modification) of host DNA. The endonuclease reaction of these enzymes on unmethylated DNA is preceded by bidirectional translocation of thousands of base pairs of DNA toward the enzyme. We present the structures of two type I RM enzymes, EcoKI and EcoR124I, derived using electron microscopy (EM), small-angle scattering (neutron and X-ray), and detailed molecular modeling. DNA binding triggers a large contraction of the open form of the enzyme to a compact form. The path followed by DNA through the complexes is revealed by using a DNA mimic anti-restriction protein. The structures reveal an evolutionary link between type I RM enzymes and type II RM enzymes. PMID- 22215816 TI - Management of difficult infantile haemangiomas. AB - Infantile haemangiomas are common vascular tumours of infancy. They typically present shortly after birth, undergo a period of rapid proliferation, and then slowly involute over many years. Although most patients require no intervention, appropriate investigation and treatment may be necessary in a minority of cases. Identifying which patients require further investigation or intervention can be difficult due to the heterogeneity of clinical presentation. This is compounded by a lack of rigorous randomised controlled trials on haemangioma management. Therefore, the rationale for treatment is not always straightforward. Haemangiomas occur anywhere on the body, have superficial, deep or mixed morphology, and depending on anatomic location, size and subtype, can be associated with underlying structural anomalies and many other potential complications. Generally, the management of difficult haemangiomas is best approached on a case-by-case basis. Over the last few years, there have been several advances in our understanding of haemangiomas, together with some exciting new therapeutic options. In the following review, the authors discuss the various possible complications of infantile haemangiomas, the rationale for treatment and appropriate possible interventions. PMID- 22215817 TI - Paediatric video-telemetry safety survey. PMID- 22215818 TI - Giant hydronephrosis: uncommon presentation of a common disease. PMID- 22215819 TI - Evaluating bacterial gene-finding HMM structures as probabilistic logic programs. AB - MOTIVATION: Probabilistic logic programming offers a powerful way to describe and evaluate structured statistical models. To investigate the practicality of probabilistic logic programming for structure learning in bioinformatics, we undertook a simplified bacterial gene-finding benchmark in PRISM, a probabilistic dialect of Prolog. RESULTS: We evaluate Hidden Markov Model structures for bacterial protein-coding gene potential, including a simple null model structure, three structures based on existing bacterial gene finders and two novel model structures. We test standard versions as well as ADPH length modeling and three state versions of the five model structures. The models are all represented as probabilistic logic programs and evaluated using the PRISM machine learning system in terms of statistical information criteria and gene-finding prediction accuracy, in two bacterial genomes. Neither of our implementations of the two currently most used model structures are best performing in terms of statistical information criteria or prediction performances, suggesting that better-fitting models might be achievable. AVAILABILITY: The source code of all PRISM models, data and additional scripts are freely available for download at: http://github.com/somork/codonhmm. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22215820 TI - Spread the word about the Journal in 2012: from impact factor to plagiarism and image falsification detection software. PMID- 22215821 TI - The importance of sex in pulmonary hypertension. PMID- 22215822 TI - Medical education in the clouds. PMID- 22215823 TI - The future of critical care research: an abstruse agenda seeking clarity (with government assistance!). PMID- 22215824 TI - The past, present, and future of advance directives as a guide to end-of-life decision making. PMID- 22215825 TI - As accessible as a book on a library shelf: the imperative of routine simulation in modern health care. AB - Technology-enhanced patient simulation has emerged as an important new modality for teaching and learning in medicine. In particular, immersive simulation platforms that replicate the clinical environment promise to revolutionize medical education by enabling an enhanced level of safety, standardization, and efficiency across health-care training. Such an experiential approach seems unique in reliably catalyzing a level of emotional engagement that fosters immediate and indelible learning and allows for increasingly reliable levels of performance evaluation-all in a completely risk-free environment. As such, medical simulation is poised to emerge as a critical component of training and certification throughout health care, promising to fundamentally enhance quality and safety across disciplines. To encourage routine simulation-based practice as part of its core quality and safety mission, Massachusetts General Hospital now incorporates simulation resources within its historic medical library (est. 1847), located at the center of the campus. In this new model, learners go to the library not only to read about a patient's illness, but also to take care of their "patient." Such an approach redefines and advances the central role of the library on the campus and ensures that simulation-based practice is centrally available as part of everyday hospital operations. This article describes the reasons for identifying simulation as an institutional priority leading up to the Massachusetts General Hospital Bicentennial Celebration (1811-2011) and for creating a simulation-based learning laboratory within a hospital library. PMID- 22215826 TI - Do CIs give you confidence? AB - This article describes the conceptual basis for the P value and the CI. We show that both are derived from the same underlying concepts and provide useful, but similar information. PMID- 22215827 TI - Multisociety task force for critical care research: key issues and recommendations: executive summary. PMID- 22215828 TI - Multisociety task force for critical care research: key issues and recommendations. AB - BACKGROUND: Research in critical care extends from the bench to the bedside, involving multiple departments, specialties, and funding organizations. Because of this diversity, it has been difficult for all stakeholders to collectively identify challenges and establish priorities. OBJECTIVE: To define a comprehensive agenda for critical care research using input from a broad range of stakeholders to serve as a blueprint for future initiatives. METHODS: The Critical Care Societies Collaborative (CCSC), consisting of the leadership of the American Association of Critical-Care Nurses (AACN), the American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Society of Critical Care Medicine (SCCM), joined the US Critical Illness and Injury Trials Group (USCIITG) in forming a task force to define a comprehensive critical care research agenda. This group of 25 identified experts was divided into subgroups to address basic, translational, clinical, implementation, and educational research. The subgroups met via conference calls, and the entire task force met in person for a 2-day session. The result was a detailed discussion of the research priorities that served as the basis for this report. RESULTS: The task force identified challenges, specific priority areas, and recommendations for process improvements to support critical care research. Additionally, four overarching themes emerged: 1) the traditional "silo-ed" approach to critical care research is counterproductive and should be modified; 2) an approach that more effectively links areas of research (ie, basic and translational research, or clinical research and implementation) should be embraced; 3) future approaches to human research should account for disease complexity and patient heterogeneity; and 4) an enhanced infrastructure for critical care research is essential for future success. CONCLUSIONS: This document contains the themes/recommendations developed by a large, multiprofessional cross section of critical care scientists, clinicians, and educators. It provides a unique framework for future research in critical care medicine. PMID- 22215829 TI - Inflammation in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling of the precapillary pulmonary arteries, with excessive proliferation of vascular cells. Although the exact pathophysiology remains unknown, there is increasing evidence to suggest an important role for inflammation. Firstly, pathologic specimens from patients with PAH reveal an accumulation of perivascular inflammatory cells, including macrophages, dendritic cells, T and B lymphocytes, and mast cells. Secondly, circulating levels of certain cytokines and chemokines are elevated, and these may correlate with a worse clinical outcome. Thirdly, certain inflammatory conditions such as connective tissue diseases are associated with an increased incidence of PAH. Finally, treatment of the underlying inflammatory condition may alleviate the associated PAH. Underlying pathologic mechanisms are likely to be "multihit" and complex. For instance, the inflammatory response may be regulated by bone morphogenetic protein receptor type 2 (BMPR II) status, and, in turn, BMPR II expression can be altered by certain cytokines. Although antiinflammatory therapies have been effective in certain connective-tissue-disease-associated PAH, this approach is untested in idiopathic PAH (iPAH). The potential benefit of antiinflammatory therapies in iPAH is of importance and requires further study. PMID- 22215831 TI - Defining features of advance directives in law and clinical practice. AB - In the > 30 years since the New Jersey Supreme Court's seminal opinion in the case of Karen Ann Quinlan, all 50 states and the District of Columbia have enacted legislation to recognize the legal right of competent adults to write advance directives. The purpose of advance directives is to provide direction for health-care decisions near the end of life, when the ravages of illness, disease, or injury have taken the ability to decide for one's self. This article reviews the defining features of advance directives and the governing law, discusses some common practical concerns regarding the use and effectiveness of advance directives, and identifies several significant ethical-legal challenges for honoring advance directives at the bedside. With a primary focus on the health care proxy, the anatomy of advance directives is analyzed under four general rubrics: formal requirements, decisional capacity and when the directive takes effect, rights and responsibilities of proxies and health-care providers, and the scope and limitations of decisions to forego life-sustaining treatment. There is much common ground among state laws, but particular legal provisions may vary from state to state. Physicians, nurses, social workers, and other health-care professionals should be familiar with the law of their home state. PMID- 22215830 TI - Combined pulmonary fibrosis and emphysema syndrome: a review. AB - There is increasing clinical, radiologic, and pathologic recognition of the coexistence of emphysema and pulmonary fibrosis in the same patient, resulting in a clinical syndrome known as combined pulmonary fibrosis and emphysema (CPFE) that is characterized by dyspnea, upper-lobe emphysema, lower-lobe fibrosis, and abnormalities of gas exchange. This syndrome frequently is complicated by pulmonary hypertension, acute lung injury, and lung cancer. The CPFE syndrome typically occurs in male smokers, and the mortality associated with this condition, especially if pulmonary hypertension is present, is significant. In this review, we explore the current state of the literature and discuss etiologic factors and clinical characteristics of the CPFE syndrome. PMID- 22215832 TI - alpha1-antitrypsin deficiency in fraternal twins born with familial spontaneous pneumothorax. AB - We report a case of spontaneous familial pneumothorax in fraternal twin boys. The twins' family history is remarkable for reactive airway disease and a female sibling also born with spontaneous pneumothorax. The family had no history of connective tissue disorders, renal cancer, or dermatologic diseases. Analysis of the twins' alpha(1)-antitrypsin (AAT) genotype, phenotype, and serum concentration revealed that both were compound heterozygous for rare SERPINA1 alleles. These findings suggest a role for AAT deficiency in spontaneous pneumothorax of the newborn. To our knowledge, these are the first genetic data to support etiology of neonatal spontaneous familial pneumothorax. PMID- 22215833 TI - A giant cardiac lipoma associated with ventricular inversion and ventricular aneurysm: ultrasonography and CT imaging findings. AB - Cardiac lipomas are rare, mostly asymptomatic, and usually found incidentally during noncardiac examinations; however, they also can be symptomatic, depending on their size and location. Here, we report a case of surgically proved pericardial lipoma that was big and for which cardiac structures were substantially altered. The combination of CT imaging and ultrasonography enabled a precise diagnosis in terms of localization, tissue characterization, and complications of the tumor. The origin of the tumor, however, remains undetermined despite a series of postoperative CT scan and ultrasound examinations. PMID- 22215834 TI - Severity scoring in the critically ill: part 1--interpretation and accuracy of outcome prediction scoring systems. AB - This review examines the use of scoring systems to assess ICU performance. APACHE (Acute Physiology and Chronic Health Evaluation), MPM (mortality probability model), and SAPS (simplified acute physiology score) are the three major ICU scoring systems in use today. Central to all three is the use of physiologic data for severity adjustment. Differences in the size, nature, and time horizon of the data set translate into minor differences in accuracy and difficulty of data abstraction. APACHE IV provides ICU and hospital predictions for mortality and length of stay, whereas MPM and SAPS only provide hospital mortality predictions (although new algorithms generated from MPM data elements may predict ICU length of stay adequately). The primary use of scoring systems is for assessing ICU performance, with the ratio of actual-to-predicted outcomes in the study cohort providing performance comparisons to the reference ICUs. The reliability of scoring system predictions depends on the completeness and accuracy of the abstracted data; accordingly, ICUs must implement robust data quality control processes. CIs of the ratios are inversely related to sample size, and care must be taken to avoid overinterpreting changes in outcomes. ICU structural and process issues also can affect scoring system performance measures. Despite good discrimination and calibration, scoring systems are used in only 10% to 15% of US ICUs. Without ICU performance data, there is little hope of improving quality and reducing costs. Current demands for transparency and computerization of documentation are likely to drive future use of ICU scoring systems. PMID- 22215835 TI - An unusual pulmonary mass with mediastinal invasion and multiple intrapulmonary nodules in a 52-year-old man. PMID- 22215836 TI - A 70-year-old woman with acute right ventricular failure and circulatory collapse. PMID- 22215837 TI - A 46-year-old man with seizures, brain lesions, and pulmonary infiltrates. PMID- 22215838 TI - Low incidence of catheter-related complications in patients with advanced pulmonary arterial hypertension undergoing continuous epoprostenol infusion. PMID- 22215839 TI - High correlation between salivary cortisol and free serum cortisol measurements does not mean good agreement. PMID- 22215840 TI - Edict of postoperative fever and atelectasis. PMID- 22215841 TI - Montelukast for bronchiolitis obliterans syndrome after lung transplantation. PMID- 22215842 TI - All that glitters is not gold in pursuing the diagnosis of pulmonary embolism. PMID- 22215843 TI - The endobronchial ultrasound-guided transbronchial needle biopsy learning curve for mediastinal and hilar lymph node diagnosis. PMID- 22215844 TI - Ultrasound-guided peripheral venous access in severely ill patients with suspected difficult vascular puncture. PMID- 22215845 TI - Follow-up recommendations for chest CT scan reports of incidental pulmonary nodules. PMID- 22215846 TI - Current practices for ventilator-associated pneumonia prevention in Japan: a survey study. PMID- 22215847 TI - Notice of retraction: Use of incorrect data set and inability to verify results due to missing data in "Chest tube drainage of transudative pleural effusions hastens liberation from mechanical ventilation" (Chest. 2011;139[3]:519-523). PMID- 22215848 TI - Notice of retraction: Invalid study design and inability to verify results due to missing data in "Pigtail catheter drainage of transudative pleural effusions hastens liberation from mechanical ventilation [abstract]" (Chest. 2007;132[4]:455). PMID- 22215849 TI - Functional nature of electrogram fractionation demonstrated by left atrial high density mapping. AB - BACKGROUND: Complex fractionated atrial electrograms (CFAE) are targets of atrial fibrillation (AF) ablation. Serial high-density maps were evaluated to understand the impact of activation direction and rate on electrogram (EGM) fractionation. METHODS AND RESULTS: Eighteen patients (9 persistent) underwent high-density, 3 dimensional, left-atrial mapping (>400 points/map) during AF, sinus (SR), and CS paced (CSp) rhythms. In SR and CSp, fractionation was defined as an EGM with >=4 deflections, although, in AF, CFE-mean <80 ms was considered as continuous CFAE. The anatomic distribution of CFAE sites was assessed, quantified, and correlated between rhythms. Mechanisms underlying fractionation were investigated by analysis of voltage, activation, and propagation maps. A minority of continuous CFAE sites displayed EGM fractionation in SR (15+/-4%) and CSp (12+/-8%). EGM fractionation did not match between SR and CSp at 70+/-10% sites. Activation maps in SR and CSp showed that wave collision (71%) and regional slow conduction (24%) caused EGM fractionation. EGM voltage during AF (0.59+/-0.58 mV) was lower than during SR and CSp (>1.0 mV) at all sites. During AF, the EGM voltage was higher at continuous CFAE sites than at non-CFAE sites (0.53 mV (Q1, Q3: 0.33 to 0.83) versus 0.30 mV (Q1, Q3: 0.18 to 0.515), P<0.00001). Global LA voltage in AF was lower in patients with persistent AF versus patients with paroxysmal AF (0.6+/ 0.59 mV versus 1.12+/-1.32 mV, P<0.01). CONCLUSIONS: The distribution of fractionated EGMs is highly variable, depending on direction and rate of activation (SR versus CSp versus AF). Fractionation in SR and CSp rhythms mostly resulted from wave collision. All sites with continuous fractionation in AF displayed normal voltage in SR, suggesting absence of structural scar. Thus, many fractionated EGMs are functional in nature, and their sites dynamic. PMID- 22215850 TI - Drug approvals 2011: focus on companion diagnostics. PMID- 22215851 TI - Next steps in clinical trial redesign. PMID- 22215852 TI - Adoptive immunotherapy poised to deliver on decades-old promise. PMID- 22215853 TI - ALK gene amplified in most inflammatory breast cancers. PMID- 22215854 TI - StatBite: Drugs in development by therapeutic area (2010). PMID- 22215855 TI - Unique amino acid signatures that are evolutionarily conserved distinguish simple type, epidermal and hair keratins. AB - Keratins (Ks) consist of central alpha-helical rod domains that are flanked by non-alpha-helical head and tail domains. The cellular abundance of keratins, coupled with their selective cell expression patterns, suggests that they diversified to fulfill tissue-specific functions although the primary structure differences between them have not been comprehensively compared. We analyzed keratin sequences from many species: K1, K2, K5, K9, K10, K14 were studied as representatives of epidermal keratins, and compared with K7, K8, K18, K19, K20 and K31, K35, K81, K85, K86, which represent simple-type (single-layered or glandular) epithelial and hair keratins, respectively. We show that keratin domains have striking differences in their amino acids. There are many cysteines in hair keratins but only a small number in epidermal keratins and rare or none in simple-type keratins. The heads and/or tails of epidermal keratins are glycine and phenylalanine rich but alanine poor, whereas parallel domains of hair keratins are abundant in prolines, and those of simple-type epithelial keratins are enriched in acidic and/or basic residues. The observed differences between simple-type, epidermal and hair keratins are highly conserved throughout evolution. Cysteines and histidines, which are infrequent keratin amino acids, are involved in de novo mutations that are markedly overrepresented in keratins. Hence, keratins have evolutionarily conserved and domain-selectively enriched amino acids including glycine and phenylalanine (epidermal), cysteine and proline (hair), and basic and acidic (simple-type epithelial), which reflect unique functions related to structural flexibility, rigidity and solubility, respectively. Our findings also support the importance of human keratin 'mutation hotspot' residues and their wild-type counterparts. PMID- 22215856 TI - Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. AB - BACKGROUND: There is a modest risk of myocardial infarction (MI) and myocardial ischemic events in patients with atrial fibrillation. METHODS AND RESULTS: Data from the RE-LY study (Randomized Evaluation of Long-Term Anticoagulation Therapy) were used to report rates of MI, unstable angina, cardiac arrest, and cardiac death and the prespecified net clinical benefit and treatment effects of dabigatran versus warfarin. MI occurred at annual rates of 0.82% and 0.81% with dabigatran 110 or 150 mg BID compared with 0.64% with warfarin (hazard ratio [HR] 1.29, 95% confidence interval [CI] 0.96-1.75, P=0.09 for dabigatran 110 mg; HR 1.27, 95% CI 0.94-1.71, P=0.12 for dabigatran 150 mg). Annual rates of a composite of MI, unstable angina, cardiac arrest, and cardiac death were 3.16% per year with dabigatran 110 mg, 3.33% per year with dabigatran 150 mg, and 3.41% per year with warfarin (HR versus warfarin 0.93, 95% CI 0.80-1.06, P=0.28 for dabigatran 110 mg and HR 0.98, 95% CI 0.85-1.12, P=0.77 for dabigatran 150 mg). Events prespecified as "net clinical benefit" (all strokes, systemic embolism, MI, pulmonary embolism, major bleeding, and all-cause death) occurred at a rate of 7.34% per year with dabigatran 110 mg, 7.11% per year with dabigatran 150 mg, and 7.91% per year with warfarin (HR 0.92, 95% CI 0.84-1.01, P=0.09 for dabigatran 110 mg and HR 0.90, 95% CI 0.82-0.99, P=0.02 for dabigatran 150 mg). The relative effects of dabigatran versus warfarin on myocardial ischemic events were consistent in patients with or without a baseline history of MI or coronary artery disease. CONCLUSIONS: There was a nonsignificant increase in MI with dabigatran compared with warfarin, but other myocardial ischemic events were not increased. Treatment effects of dabigatran were consistent in patients at higher and lower risk of myocardial ischemic events. PMID- 22215857 TI - Downregulation of TMEM16A calcium-activated chloride channel contributes to cerebrovascular remodeling during hypertension by promoting basilar smooth muscle cell proliferation. AB - BACKGROUND: The Ca(2+)-activated chloride channel (CaCC) plays an important role in a variety of physiological functions. In vascular smooth muscle cells, CaCC is involved in the regulation of agonist-stimulated contraction and myogenic tone. The physiological functions of CaCC in blood vessels are not fully revealed because of the lack of specific channel blockers and the uncertainty concerning its molecular identity. METHODS AND RESULTS: Whole-cell patch-clamp studies showed that knockdown of TMEM16A but not bestrophin-3 attenuated CaCC currents in rat basilar smooth muscle cells. The activity of CaCC in basilar smooth muscle cells isolated from 2-kidney, 2-clip renohypertensive rats was decreased, and CaCC activity was negatively correlated with blood pressure (n=25; P<0.0001) and medial cross-sectional area (n=24; P<0.0001) in basilar artery during hypertension. Both upregulation of CaMKII activity and downregulation of TMEM16A expression contributed to the reduction of CaCC in the hypertensive basilar artery. Western blot results demonstrated that angiotensin II repressed TMEM16A expression in basilar smooth muscle cells (n=6; P<0.01). Knockdown of TMEM16A facilitated and overexpression of TMEM16A inhibited angiotensin II-induced cell cycle transition and cell proliferation determined by flow cytometry and BrdU incorporation (n=6 in each group; P<0.05). TMEM16A affected cell cycle progression mainly through regulating the expression of cyclin D1 and cyclin E. CONCLUSIONS: TMEM16A CaCC is a negative regulator of cell proliferation. Downregulation of CaCC may play an important role in hypertension-induced cerebrovascular remodeling, suggesting that modification of the activity of CaCC may be a novel therapeutic strategy for hypertension-associated cardiovascular diseases such as stroke. PMID- 22215858 TI - Risk of sudden death in Wolff-Parkinson-White syndrome: how high is the risk? PMID- 22215860 TI - The bicentennial volume of the British Journal of Psychiatry: the winding pathway of mental science. AB - The Asylum Journal, first published in 1853, is now, as the British Journal of Psychiatry, in its 200th volume. It has changed greatly in its breadth and scope, but its core values and concerns--professional respect, removal of stigma, delivery of care, understanding of pathology, and informed treatment--have remained at its heart throughout. We predict some changes for the future, but not dramatic ones, and conclude that the impinging advances of science will elucidate and refine, but not remove, the need for a journal that is proud to represent psychiatry or, in the words of John Bucknill, its first editor, 'to render prominent its characteristics and to stamp it as a specialty'. PMID- 22215861 TI - Bipolar depression and treatment with antidepressants. AB - Treatment of bipolar disorder with antidepressants tested almost exclusively in unipolar cases is common but unsupported by an appropriate body of evidence. This anomaly is highlighted by a large Taiwanese study, which implies that patients with depression difficult to treat with antidepressants are quite likely to be diagnosed subsequently with bipolar disorder. PMID- 22215859 TI - Risk of malignant arrhythmias in initially symptomatic patients with Wolff Parkinson-White syndrome: results of a prospective long-term electrophysiological follow-up study. AB - BACKGROUND: The available amount of detailed long-term data in patients with Wolff-Parkinson-White syndrome is limited, and no prospective electrophysiological studies looking at predictors of malignant arrhythmia are available. METHODS AND RESULTS: Among 8575 symptomatic Wolff-Parkinson-White patients with atrioventricular reentrant tachycardia referred for electrophysiological test, 369 (mean age, 23+/-12.5 years) declined catheter ablation and were followed up. The primary end point of the study was to evaluate over a 5-year follow-up the predictors and characteristics of patients who develop malignant arrhythmias. After a mean follow-up of 42.1+/-10 months, malignant arrhythmias developed in 29 patients (mean age, 13.9+/-5.6 years; 26 male), resulting in presyncope/syncope (25 patients), hemodynamic collapse (3 patients), or cardiac arrest caused by ventricular fibrillation (1 patient). Of the remaining 340 patients, 168 (mean age, 34.2+/-9.0 years) remained asymptomatic up to 5 years, and 172 (mean age, 13.6+/-5.1 years) had benign recurrence, including sustained atrioventricular reentrant tachycardia (132 patients) or atrial fibrillation (40 patients). Compared with the group with no malignant arrhythmias, the group with malignant arrhythmias showed shorter accessory-pathway effective refractory period (P<0.001) and more often exhibited multiple accessory pathways (P<0.001), and atrioventricular reentrant tachycardia triggering sustained pre-excited atrial fibrillation was more frequently inducible (P<0.001). Multivariable analysis demonstrated that short accessory pathway effective refractory period (P<0.001) and atrioventricular reentrant tachycardia triggering sustained pre-excited atrial fibrillation (P<0.001) were independent predictors of malignant arrhythmias. CONCLUSIONS: Symptomatic patients with Wolff-Parkinson-White syndrome generally have a good outcome, and predictors of malignant arrhythmias are similar to those reported for asymptomatic patients with ventricular pre-excitation. PMID- 22215862 TI - Nocturnal enuresis with antipsychotic medication. AB - Nocturnal enuresis can be discomfiting and troublesome. There is increasing evidence that as a side-effect of second-generation antipsychotics, particularly clozapine, it may be underrecognised. Direct but sensitive questioning may be required to elicit this side-effect. We briefly review possible mechanisms of this problem, and management and treatment options. PMID- 22215863 TI - Transcranial stimulation in depression. AB - Transcranial direct current stimulation is coming of age with the large treatment study published in this issue. We review transcranial stimulation methods, their efficacy and the likely impact on National Health Service (NHS) practice. Their use in individuals who do not respond to or cannot tolerate medication should now be explored in large controlled naturalistic studies in the NHS. PMID- 22215864 TI - To meta-analyse or not to meta-analyse: abortion, birth and mental health. AB - Two recent meta-analyses claim that abortion leads to a deterioration in mental health. Previous reviews concluded that the mental health outcomes following an unwanted pregnancy are much the same whether the woman gives birth or terminates the pregnancy, although there is an increased mental health risk with an unwanted pregnancy. Meta-analysis is particularly susceptible to bias in this area. The physical health outcomes for women with an unwanted pregnancy have improved greatly by making abortion legal. To further improve the mental health outcomes associated with an unwanted pregnancy we should focus practice and research on the individual needs of women with an unwanted pregnancy, rather than how the pregnancy is resolved. PMID- 22215865 TI - Efficacy, cost-effectiveness and acceptability of self-help interventions for anxiety disorders: systematic review. AB - BACKGROUND: Self-help interventions for psychiatric disorders represent an increasingly popular alternative to therapist-administered psychological therapies, offering the potential of increased access to cost-effective treatment. AIMS: To determine the efficacy, cost-effectiveness and acceptability of self-help interventions for anxiety disorders. METHOD: Randomised controlled trials (RCTs) of self-help interventions for anxiety disorders were identified by searching nine online databases. Studies were grouped according to disorder and meta-analyses were conducted where sufficient data were available. Overall meta analyses of self-help v. waiting list and therapist-administered treatment were also undertaken. Methodological quality was assessed independently by two researchers according to criteria set out by the Cochrane Collaboration. RESULTS: Thirty-one RCTs met inclusion criteria for the review. Results of the overall meta-analysis comparing self-help with waiting list gave a significant effect size of 0.84 in favour of self-help. Comparison of self-help with therapist administered treatments revealed a significant difference in favour of the latter with an effect size of 0.34. The addition of guidance and the presentation of multimedia or web-based self-help materials improved treatment outcome. CONCLUSIONS: Self-help interventions appear to be an effective way of treating individuals diagnosed with social phobia and panic disorder. Further research is required to evaluate the cost-effectiveness and acceptability of these interventions. PMID- 22215866 TI - Transcranial direct current stimulation for depression: 3-week, randomised, sham controlled trial. AB - BACKGROUND: Preliminary evidence suggests transcranial direct current stimulation (tDCS) has antidepressant efficacy. AIMS: To further investigate the efficacy of tDCS in a double-blind, sham-controlled trial (registered at www.clinicaltrials.gov: NCT00763230). METHOD: Sixty-four participants with current depression received active or sham anodal tDCS to the left prefrontal cortex (2 mA, 15 sessions over 3 weeks), followed by a 3-week open-label active treatment phase. Mood and neuropsychological effects were assessed. RESULTS: There was significantly greater improvement in mood after active than after sham treatment (P<0.05), although no difference in responder rates (13% in both groups). Attention and working memory improved after a single session of active but not sham tDCS (P<0.05). There was no decline in neuropsychological functioning after 3-6 weeks of active stimulation. One participant with bipolar disorder became hypomanic after active tDCS. CONCLUSIONS: Findings confirm earlier reports of the antidepressant efficacy and safety of tDCS. Vigilance for mood switching is advised when administering tDCS to individuals with bipolar disorder. PMID- 22215867 TI - Abortion and mental health: guidelines for proper scientific conduct ignored. PMID- 22215868 TI - Abortion and mental health: guidelines for proper scientific conduct ignored. PMID- 22215869 TI - Abortion and mental health: guidelines for proper scientific conduct ignored. PMID- 22215870 TI - Abortion and mental health: guidelines for proper scientific conduct ignored. PMID- 22215871 TI - Abortion and mental health: guidelines for proper scientific conduct ignored. PMID- 22215872 TI - Abortion and mental health: guidelines for proper scientific conduct ignored. PMID- 22215873 TI - Abortion and mental health: guidelines for proper scientific conduct ignored. PMID- 22215874 TI - Abortion and mental health: guidelines for proper scientific conduct ignored. PMID- 22215876 TI - Legal leverage. PMID- 22215877 TI - Legal leverage. PMID- 22215878 TI - Family psychoeducation for major depression: randomised controlled trial. PMID- 22215879 TI - MRI of the cervical spine with neck extension: is it useful? AB - OBJECTIVES: Standard MRI of the cervical spine is performed in a different anatomical position to that utilised for traditional contrast myelography. Those well practised in myelography are familiar with the considerable changes in configuration of the bony and soft tissues of the cervical spine that may occur with changes in the degree of neck flexion and extension. We set out to compare the findings in a select group of patients with myeloradiculopathy who had undergone myelography and MRI in both standard and neck-extended positions. These findings were correlated with the clinical status. METHODS: 29 patients underwent myelography with CT (CTM) and MRI in neutral and neck-extended positions. The imaging was assessed for the degree of cord compression and neural foraminal narrowing, quantified using a simple grading scheme suitable for routine clinical practice. The degree of neck extension was assessed using an angular measurement. RESULTS: For both CTM and MRI, scanning with the neck extended significantly increases the severity of cord compression compared with the standard supine position, to a degree similar to that shown during conventional prone myelography. The degree of perceived cord compression is related to the degree of neck extension achieved. Correlation of standard MRI findings and the clinical level of radiculopathy is poor. This correlation improves when the neck is extended. CONCLUSIONS: The most appropriate position for routine MRI of the cervical spine in degenerative disease remains unknown, but in selected patients imaging with the neck extended may provide important additional information. PMID- 22215880 TI - Role of diffusion-weighted MRI in diagnosis of acute renal allograft dysfunction: a prospective preliminary study. AB - OBJECTIVE: The aim was to evaluate the effects of diagnostic performance of diffusion-weighted (DW) MRI in the assessment of acute impairment of transplanted kidneys. METHODS: From January 2009 to January 2010, 49 patients with stable renal allograft function (Group 1) and 21 patients with acute graft impairment (Group 2) were included in the study. All patients were evaluated with coronal T(2) weighted (T(2)W) and DW MRI of the kidney. Patients in Group 2 underwent graft biopsy to determine the underlying histopathological aetiology. Apparent diffusion coefficient (ADC) was calculated and the kidneys were studied for any areas of diffusion restriction. Two radiologists, who were blinded to the results of histopathology, independently interpreted the T(2)W and DW images. RESULTS: The histopathological diagnosis of Group 2 (21 patients) was acute cellular rejection (ACR) in 10, acute tubular necrosis (ATN) in 7 and immunosuppressive toxicity in 4 patients. ADC values in Group 1 were significantly higher compared with Group 2 (p<0.001), patients with ACR (p<0.001), patients with ATN (p<0.001) and patients with drug toxicity (p<0.001). Using 2 * 10(-3) mm(2) s(-1) as a cut off, there was no overlap between the ADC values of patients with normal graft function and those with ATN. Both ACR and ATN had a low ADC value, but on the ADC map the kidney in cases of ATN appears heterogeneous with a characteristic mosaic pattern resembling the Tiger skin. There was no significant T(2)W morphological difference between the two groups. CONCLUSION: These results show how DW MRI is a promising new technique for the diagnosis of acute renal transplant dysfunction. PMID- 22215881 TI - Imaging assessment of desmoid tumours in familial adenomatous polyposis: is state of-the-art 1.5 T MRI better than 64-MDCT? AB - OBJECTIVE: Desmoid tumour is a common extraintestinal manifestation of patients with familial adenomatous polyposis (FAP) who have undergone prophylactic colectomy. We aimed to determine whether MRI provides equivalent or better assessment of desmoid tumours than CT, the current first-line investigation. METHODS: Following ethics approval and informed consent, FAP patients with known desmoid tumour underwent contrast-enhanced 64-slice multidetector CT (MDCT) and 1.5 T MRI (incorporating T(1) weighted, T(2) weighted, short tau inversion recovery and T(1) weighted with contrast, axial, sagittal and coronal sequences). The number, site, size, local extent, tumour signal intensity and desmoid-to aorta enhancement ratio were analysed. RESULTS: MRI identified 23 desmoid tumours in 9 patients: 9 intra-abdominal desmoid (IAD) tumours, 10 abdominal wall desmoid (AWD) tumours and 4 extra-abdominal desmoid (EAD) tumours. CT identified only 21 desmoids; 1 EAD and 1 AWD were not identified. The two modalities were equivalent in terms of defining local extent of desmoid. Five IAD tumours involved the bowel, six caused ureteric compression and none compromised the proximal superior mesenteric artery. There was no difference in median desmoid size: 56.7 cm(2) (range 2-215 cm(2)) on MDCT and 56.3 cm(2) (3-215 cm(2)) on MRI (p=0.985). The mean MRI enhancement ratio, at 1.12 (standard deviation 0.43), was greater than the CT enhancement ratio, which was 0.48 (0.16) (p<0.0001). High signal intensity on T(2) MRI was associated with increased MRI enhancement ratio (p=0.006). CONCLUSIONS: MRI is at least equivalent (and may be superior) to MDCT for the detection of desmoid tumours in FAP. Coupled with the advantage of avoiding radiation, it should be considered as the primary imaging modality for young FAP patients. PMID- 22215882 TI - Investigating the relationship between virtual cystoscopy image quality and CT slice thickness. AB - OBJECTIVE: To investigate the effect of reconstruction slice thickness on image quality at CT virtual cystoscopy (VC). METHODS: Pelvic CT examinations in bladder cancer patients were reconstructed at different slice thicknesses (0.6-5 mm) and intervals, and resulting VC images assessed. Quality indicators were ridging, holes, floaters and dimpling artefacts, tumour definition, and an overall score, ranked 1 (best) to 7 (worst). CT number and standard deviation (SD) for bladder contents and bladder wall were recorded. The mean SD was used as a measure of noise, and the contrast-to-noise ratio (CNR) was calculated as the CT number difference between them divided by the average image noise. The mean CNR across the three levels was used for analysis. Each qualitative image quality measure was compared with CT number, noise and CNR measurements. RESULTS: Dimpling artefacts increased with thinner slice reconstruction and correlated with increased noise, often resulting in poor tumour definition. The best overall image quality score was seen for VC images reconstructed at 1.2 mm slice thickness, probably because of the competing effects of spatial resolution and CNR. CONCLUSION: A slice thickness reconstruction <1.2 mm does not provide for better image quality at VC owing to the presence of increased noise. PMID- 22215883 TI - A clinical review of treatment outcomes in glioblastoma multiforme--the validation in a non-trial population of the results of a randomised Phase III clinical trial: has a more radical approach improved survival? AB - OBJECTIVE: Glioblastoma multiforme (GBM) accounts for up to 60% of all malignant primary brain tumours in adults, occurring in 2-3 cases per 100,000 in Europe and North America. In 2005, a Phase III clinical trial demonstrated a significant improvement in survival over 2, and subsequently 5, years with the addition of concurrent and adjuvant temozolomide (TMZ) to radical radiotherapy (RT). The aim of this study was to investigate if the demonstrated improved survival in the literature translated to clinical practice. METHODS: This was a retrospective study including all patients with histologically proven GBM diagnosed from 1999 to 2008 and treated with adjuvant RT at our institution. A total of 273 patients were identified. Statistical analysis was carried out using SPSS(r) v.18 (SPSS, Chicago, IL). RESULTS: The median survival for the whole group (n=273) over the 10-year period was 7.6 months (95% confidence interval 6.7-8.4 months). Overall, the cumulative probability of survival at 1 and 2 years was 31.5% and 9.4%, respectively. In total, 146 patients received radical RT. 103 patients were treated with radical RT and TMZ and 43 patients received radical RT alone. The median survival for patients receiving radical RT with TMZ was 13.4 months (95% CI 10.9-15.8 months) vs 8.8 months for radical RT alone (95% CI 6.9-10.7 months, p=0.006). 2-year survival figures were 21.2% vs 4.7%, respectively. On multivariate analysis, independent predictors of survival included Karnofsky Performance Status, RT dose, TMZ and extent of surgery. The strongest predictors of poorer outcome based on the hazard ratio were palliative RT, followed by not receiving TMZ chemotherapy, then KPS <90 and a biopsy only surgical approach. CONCLUSION: This paper demonstrates improved survival outcomes consistent with those published in the literature for the addition of concurrent and adjuvant TMZ to radical RT for the treatment of GBM. Although 63% of patients seen in the clinic were suitable for a combined modality approach, the prognosis for the lower Radiation Therapy Oncology Group classes still remains poor. PMID- 22215885 TI - Paraspinal volumetric modulated arc therapy. AB - OBJECTIVES: The processes involved in the treatment of paraspinal tumours by volumetric modulated arc therapy (VMAT) are described here by means of an illustrative case. METHODS: Az single anticlockwise arc from gantry angle 179 degrees to 181 degrees was constructed using SmartArc (Philips Radiation Oncology Systems, Fitchburg, WI) with control points spaced at 2 degrees . The dose prescription was 60 Gy in 30 fractions to cover the planning target volume (PTV) as uniformly as possible while sparing the 0.3-cm planning risk volume (PRV) around the spinal cord. The plan was verified before treatment using a diode array phantom and radiochromic film. Treatment delivery was on a Synergy linear accelerator with a beam modulator head (Elekta Ltd, Crawley, UK). RESULTS: Homogeneous dose coverage of the PTV was achieved with a D(2%) of 62.0 Gy and D(98%) of 55.6 Gy. Maximum spinal cord dose was 49.9 Gy to 0.1 cm(3) and maximum dose to the spinal cord PRV was 55.4 Gy to 0.1 cm(3). At pre-treatment verification, the percentage of the high-dose region receiving a dose within 3% and 3 mm of the planned dose was 98.8% with the diode array and 93.4% with film. Delivery time was 2 min 15 s and the course of treatment was successfully completed. CONCLUSIONS: VMAT was successfully planned, verified and delivered for this challenging tumour site. VMAT provides a very suitable method of treating complex paraspinal tumours, offering a high-quality conformal dose distribution with a short delivery time. PMID- 22215884 TI - Thin-section CT findings of patients with acute Streptococcus pneumoniae pneumonia with and without concurrent infection. AB - OBJECTIVES: The aim of this study was to compare the pulmonary thin-section CT findings of patients with acute Streptococcus pneumoniae pneumonia with and without concurrent infection. METHODS: The study group comprised 86 patients with acute S. pneumoniae pneumonia, 36 patients with S. pneumoniae pneumonia combined with Haemophilus influenzae infection, 26 patients with S. pneumoniae pneumonia combined with Pseudomonas aeruginosa infection and 22 patients with S. pneumoniae pneumonia combined with methicillin-susceptible Staphylococcus aureus (MSSA) infection. We compared the thin-section CT findings among the groups. RESULTS: Centrilobular nodules and bronchial wall thickening were significantly more frequent in patients with pneumonia caused by concurrent infection (H. influenzae: p<0.001 and p<0.001, P. aeruginosa: p<0.001 and p<0.001, MSSA: p<0.001 and p<0.001, respectively) than in those infected with S. pneumoniae alone. Cavity and bilateral pleural effusions were significantly more frequent in cases of S. pneumoniae pneumonia with concurrent P. aeruginosa infection than in cases of S. pneumoniae pneumonia alone (p<0.001 and p<0.001, respectively) or with concurrent H. influenzae (p<0.05 and p<0.001, respectively) or MSSA infection (p<0.05 and p<0.05, respectively). CONCLUSIONS: When a patient with S. pneumoniae pneumonia has centrilobular nodules, bronchial wall thickening, cavity or bilateral pleural effusions on CT images, concurrent infection should be considered. PMID- 22215886 TI - MRI of the anatomical structures of the knee: the proton density-weighted fast spin-echo sequence vs the proton density-weighted fast-recovery fast spin-echo sequence. AB - OBJECTIVE: The purpose of this study was to compare the proton-density (PD) weighted fast spin-echo (FSE) and fast-recovery FSE (FRFSE) sequences for the evaluation of the anatomical structures of the knee. METHOD: 24 healthy volunteers who underwent MRI by both sagittal PD-weighted FSE and FRFSE sequences were evaluated. The signal-to-noise ratio, contrast-to-noise ratio (CNR) and anatomical detail visualisation were compared for the two techniques. RESULTS: The mean CNRs and reader ratings for both readers were significantly higher for the PD-weighted FRFSE images than for the PD-weighted FSE images in the cartilages/the femorotibial joint effusion and the cruciate ligaments/the effusion around the cruciate ligaments; however, the mean CNRs and reader ratings for both readers were significantly higher for the PD-weighted FSE sequences than for the PD-weighted FRFSE sequences in the cartilages/the menisci and the cruciate ligaments. CONCLUSIONS: The main advantages of the PD-weighted FRFSE sequence are the increase in contrast between fluid and non-fluid tissues and the time saved by using the procedure. However, in the absence of joint effusion, the PD-weighted FRFSE sequence generates a poorer contrast between the cartilage and meniscus, the cruciate ligaments and fat of the intercondylar fossa. PMID- 22215887 TI - Clinical utility of 18F FDG-PET/CT in the detection of bone marrow disease in Hodgkin's lymphoma. AB - OBJECTIVE: The aim of the study was to evaluate the potential role of fludeoxyglucose (FDG)-positron emission tomography (PET)/CT in the detection of bone/bone marrow disease in patients with Hodgkin's lymphoma (HL). METHODS: We retrospectively reviewed ((18)F)-FDG-PET/CT scans of 122 newly diagnosed, biopsy proven cases of HL performed between November 2009 and June 2010. All the patients were staged before treatment by both PET/CT and bone marrow biopsy (BMB). Patients were subdivided into three groups based on the findings of FDG PET/CT. Group A consisted of patients showing diffuse FDG uptake, Group B consisted of patients showing unifocal FDG uptake and Group C patients showed multifocal FDG-avid foci on PET/CT scans. Bone marrow results were also reviewed and considered positive if lymphomatous involvement was detected on bone marrow trephine biopsy. BMB results were correlated with FDG-PET/CT findings. RESULTS: There were 122 patients in total-81 (66.4%) were male and 41 (33.6%) were female. The age range was from 6 years to 78 years (mean 35.70 years). PET/CT was reported as negative for bone/bone marrow involvement in 85 (69.7%) patients, while the remaining 37 showed abnormal FDG uptake. The sensitivity of FDG-PET/CT was calculated to be 100%, the specificity was 76.57%, the negative predictive value was 76.57%, the positive predictive value was 29.72% and the diagnostic accuracy was 78.62%. CONCLUSION: (18)F-FDG-PET/CT and BMB are complementary in the evaluation of bone marrow disease. PMID- 22215888 TI - IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. AB - Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in most grade 2 and 3 gliomas, secondary glioblastomas, and a subset of acute myelogenous leukemias but have not been detected in other tumor types. The mutations occur at specific arginine residues and result in the acquisition of a novel enzymatic activity that converts 2-oxoglutarate to D-2 hydroxyglutarate. This study reports IDH1 and IDH2 genotyping results from a set of lymphomas, which included a large set of peripheral T-cell lymphomas. IDH2 mutations were identified in approximately 20% of angioimmunoblastic T-cell lymphomas (AITLs), but not in other peripheral T-cell lymphoma entities. These results were confirmed in an independent set of AITL patients, where the IDH2 mutation rate was approximately 45%. This is the second common genetic lesion identified in AITL after TET2 and extends the number of neoplastic diseases where IDH1 and IDH2 mutations may play a role. PMID- 22215890 TI - Newer oral anticoagulants should be used as first-line agents to prevent thromboembolism in patients with atrial fibrillation and risk factors for stroke or thromboembolism. PMID- 22215891 TI - New oral anticoagulants should not be used as first-line agents to prevent thromboembolism in patients with atrial fibrillation. PMID- 22215892 TI - Behavioral strategies for cardiovascular risk reduction in diverse and underserved racial/ethnic groups. PMID- 22215893 TI - Echinococcosis of the heart and ascending aorta. PMID- 22215894 TI - Executive summary: heart disease and stroke statistics--2012 update: a report from the American Heart Association. PMID- 22215895 TI - When side matters: contrast echocardiography with injection from the left antecubital vein to detect a persistent left superior vena cava draining to the left atrium in a patient with cerebral stroke. PMID- 22215897 TI - Letter by Van Laecke and Vanholder regarding article, "Risk of recurrent cardiac events after onset of menopause in women with congenital long-QT syndrome types 1 and 2". PMID- 22215898 TI - Letter to the editor by Kohrmann and Schellinger regarding article, "Current status of endovascular stroke treatment". PMID- 22215899 TI - Letter by Ravensbergen et al regarding article, "long-term recording of cardiac arrhythmias with an implantable cardiac monitor in patients with reduced ejection fraction after acute myocardial infarction: the cardiac arrhythmias and risk stratification after acute myocardial infarction (CARISMA) study". PMID- 22215901 TI - Elusive extranuclear estrogen receptors in breast cancer. AB - Estrogen receptors at the plasma membrane and cytoplasm have been difficult to detect in breast cancer specimens. New imaging approaches are needed to determine the percentage of cancers expressing extranuclear estrogen receptors and their impact on cancer biology and treatment. PMID- 22215902 TI - On drug development, chance, and the prepared mind. PMID- 22215903 TI - Drug development: portals of discovery. AB - A British humorist said, "There is much to be said for failure. It is much more interesting than success." This CCR Focus section is aimed at identifying lessons to be learned from difficulties encountered in recent years during development of anticancer agents. Clearly, we have not found a silver bullet tyrosine kinase inhibitor against solid tumors comparable with imatinib in chronic myelogenous leukemia. Although vemurafenib for B-Raf-mutated melanoma and crizotinib for non small cell lung cancers with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements were developed rapidly and offer hope for individualized targeted therapies, the development of agents targeting a number of other pathways has been slower and less successful. These agents include drugs for blocking the insulin-like growth factor I/insulin receptor pathways, mitotic kinase inhibitors, and Hsp90 antagonists. Several potentially useful, if not groundbreaking, agents have had setbacks in clinical development, including trastuzumab emtansine, gemtuzumab ozogamicin, and satraplatin. From experience, we have learned the following: (i) not every altered protein or pathway is a valid anticancer target; (ii) drugs must effectively engage the target; (iii) the biology of the systems we use must be very well understood; and (iv) clinical trials must be designed to assess whether the drug reached and impaired the target. It is also important that we improve the drug development enterprise to enhance enrollment, streamline clinical trials, reduce financial risk, and encourage the development of agents for niche indications. Such enormous challenges are offset by potentially tremendous gains in our understanding and treatment of cancer. PMID- 22215904 TI - BRAF inhibitors for the treatment of metastatic melanoma: clinical trials and mechanisms of resistance. AB - The efficacy of selective BRAF inhibitors has now been established in the 50% of patients with metastatic melanoma whose tumors harbor activating mutations. However, for the vast majority of patients, responses persist for less than a year. In extensive preclinical investigations, researchers have focused on potential resistance mechanisms with the hope of identifying treatment strategies that can overcome resistance. Preliminary results suggest that reactivation of the mitogen-activated protein kinase (MAPK) pathway by several BRAF-independent mechanisms is the predominant pattern. However, MAPK pathway-independent mechanisms also seem to play a potential role. More definitive cataloging of resistance mechanisms in patients' tumor samples is needed as combination regimens are being readied for clinical evaluation. PMID- 22215905 TI - The insulin receptor/insulin-like growth factor receptor family as a therapeutic target in oncology. AB - Over the past decade, encouraging preclinical and early clinical data concerning the relevance of the insulin receptor/insulin-like growth factor (IGF) receptor family to neoplasia led to ambitious clinical trial programs of more than a dozen drug candidates that target these receptors. These candidates include antireceptor antibodies, antiligand antibodies, receptor-specific tyrosine kinase inhibitors, and agents such as picropodophyllin and metformin that have novel mechanisms of action. Several recently reported phase III clinical trials of anti IGF-I receptor antibodies have been disappointing and are sufficient to disprove the hypothesis that the antibodies tested have large favorable impacts on unselected patients with cancer. However, many of these trials were designed prior to recent insights concerning pathophysiology and predictive biomarkers. Future studies are required, but it will be important to optimize their design rather than simply repeat the approaches taken to date. PMID- 22215906 TI - Inhibitors targeting mitosis: tales of how great drugs against a promising target were brought down by a flawed rationale. AB - Although they have been advocated with an understandable enthusiasm, mitosis specific agents such as inhibitors of mitotic kinases and kinesin spindle protein have not been successful clinically. These drugs were developed as agents that would build on the success of microtubule-targeting agents while avoiding the neurotoxicity that encumbers drugs such as taxanes and vinca alkaloids. The rationale for using mitosis-specific agents was based on the thesis that the clinical efficacy of microtubule-targeting agents could be ascribed to the induction of mitotic arrest. However, the latter concept, which has long been accepted as dogma, is likely important only in cell culture and rapidly growing preclinical models, and irrelevant in patient tumors, where interference with intracellular trafficking on microtubules is likely the principal mechanism of action. Here we review the preclinical and clinical data for a diverse group of inhibitors that target mitosis and identify the reasons why these highly specific, myelosuppressive compounds have failed to deliver on their promise. PMID- 22215908 TI - A CDD polymorphism as predictor of capecitabine-induced hand-foot syndrome- letter. PMID- 22215910 TI - On the nullity of a graph with cut-points. AB - Let G be a simple graph of order n and A(G) be its adjacency matrix. The nullity of a graph G, denoted by eta(G), is the multiplicity of the eigenvalue zero in the spectrum of A(G). Denote by Ck and Lk the set of all connected graphs with k induced cycles and the set of line graphs of all graphs in Ck, respectively. In 1998, Sciriha [I. Sciriha, On singular line graphs of trees, Congr. Numer. 135 (1998) 73-91] show that the order of every tree whose line graph is singular is even. Then Gutman and Sciriha [I. Gutman, I. Sciriha, On the nullity of line graphs of trees, Discrete Math. 232 (2001) 35-45] show that the nullity set of L0 is {0,1}. In this paper, we investigate the nullity of graphs with cut-points and deduce some concise formulas. Then we generalize Scirihas' result, showing that the order of every graph G is even if such a graph G satisfies that G?Ck and eta(L(G))=k+1, and the nullity set of Lk is {0,1,...,k,k+1} for any given k, where L(G) denotes the line graph of the graph G. PMID- 22215907 TI - Hsp90 molecular chaperone inhibitors: are we there yet? AB - Heat shock protein (Hsp) 90 is an ATP-dependent molecular chaperone that is exploited by malignant cells to support activated oncoproteins, including many cancer-associated kinases and transcription factors, and it is essential for oncogenic transformation. Originally viewed with skepticism, Hsp90 inhibitors are now being actively pursued by the pharmaceutical industry, with 17 agents having entered clinical trials. Investigators established Hsp90's druggability using the natural products geldanamycin and radicicol, which mimic the unusual ATP structure adopted in the chaperone's N-terminal nucleotide-binding pocket and cause potent and selective blockade of ATP binding/hydrolysis, inhibit chaperone function, deplete oncogenic clients, and show antitumor activity. Preclinical data obtained with these natural products have heightened interest in Hsp90 as a drug target, and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) has shown clinical activity (as defined by Response Evaluation Criteria in Solid Tumors) in HER2+ breast cancer. Many optimized synthetic, small-molecule Hsp90 inhibitors from diverse chemotypes are now in clinical trials. Here, we review the discovery and development of Hsp90 inhibitors and assess their potential. There has been significant learning from studies of the basic biology of Hsp90, as well as translational drug development involving this chaperone, enhanced by the use of Hsp90 inhibitors as chemical probes. Success will likely lie in treating cancers that are addicted to particular driver oncogene products (e.g., HER2, ALK, EGFR, and BRAF) that are sensitive Hsp90 clients, as well as malignancies (especially multiple myeloma) in which buffering of proteotoxic stress is critical for survival. We discuss approaches for enhancing the effectiveness of Hsp90 inhibitors and highlight new chaperone and stress-response pathway targets, including HSF1 and Hsp70. PMID- 22215911 TI - "REM-related" obstructive sleep apnea: an epiphenomenon or a clinically important entity? PMID- 22215912 TI - Is brain injury in obstructive sleep apnea reversible? PMID- 22215913 TI - What a difference a day makes. PMID- 22215914 TI - Obesity, oxygen desaturation, and the need for a phenotypic classification of sleep disordered breathing. PMID- 22215915 TI - Tired and sick. PMID- 22215916 TI - The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses. AB - The International Classification of Sleep Disorders, Second Edition (ICSD-2) distinguishes 5 subtypes of central sleep apnea syndromes (CSAS) in adults. Review of the literature suggests that there are two basic mechanisms that trigger central respiratory events: (1) post-hyperventilation central apnea, which may be triggered by a variety of clinical conditions, and (2) central apnea secondary to hypoventilation, which has been described with opioid use. The preponderance of evidence on the treatment of CSAS supports the use of continuous positive airway pressure (CPAP). Much of the evidence comes from investigations on CSAS related to congestive heart failure (CHF), but other subtypes of CSAS appear to respond to CPAP as well. Limited evidence is available to support alternative therapies in CSAS subtypes. The recommendations for treatment of CSAS are summarized as follows: CPAP therapy targeted to normalize the apnea-hypopnea index (AHI) is indicated for the initial treatment of CSAS related to CHF. (STANDARD)Nocturnal oxygen therapy is indicated for the treatment of CSAS related to CHF. (STANDARD)Adaptive Servo-Ventilation (ASV) targeted to normalize the apnea-hypopnea index (AHI) is indicated for the treatment of CSAS related to CHF. (STANDARD)BPAP therapy in a spontaneous timed (ST) mode targeted to normalize the apnea-hypopnea index (AHI) may be considered for the treatment of CSAS related to CHF only if there is no response to adequate trials of CPAP, ASV, and oxygen therapies. (OPTION)The following therapies have limited supporting evidence but may be considered for the treatment of CSAS related to CHF after optimization of standard medical therapy, if PAP therapy is not tolerated, and if accompanied by close clinical follow-up: acetazolamide and theophylline. (OPTION)Positive airway pressure therapy may be considered for the treatment of primary CSAS. (OPTION)Acetazolamide has limited supporting evidence but may be considered for the treatment of primary CSAS. (OPTION)The use of zolpidem and triazolam may be considered for the treatment of primary CSAS only if the patient does not have underlying risk factors for respiratory depression. (OPTION)The following possible treatment options for CSAS related to end-stage renal disease may be considered: CPAP, supplemental oxygen, bicarbonate buffer use during dialysis, and nocturnal dialysis. (OPTION) . PMID- 22215917 TI - Magnetic resonance spectroscopy and neurocognitive dysfunction in obstructive sleep apnea before and after CPAP treatment. AB - STUDY OBJECTIVES: To determine whether cerebral metabolite changes may underlie abnormalities of neurocognitive function and respiratory control in OSA. DESIGN: Observational, before and after CPAP treatment. SETTING: Two tertiary hospital research institutes. PARTICIPANTS: 30 untreated severe OSA patients, and 25 age matched healthy controls, all males free of comorbidities, and all having had detailed structural brain analysis using voxel-based morphometry (VBM). MEASUREMENTS AND RESULTS: Single voxel bilateral hippocampal and brainstem, and multivoxel frontal metabolite concentrations were measured using magnetic resonance spectroscopy (MRS) in a high resolution (3T) scanner. Subjects also completed a battery of neurocognitive tests. Patients had repeat testing after 6 months of CPAP. There were significant differences at baseline in frontal N acetylaspartate/choline (NAA/Cho) ratios (patients [mean (SD)] 4.56 [0.41], controls 4.92 [0.44], P = 0.001), and in hippocampal choline/creatine (Cho/Cr) ratios (0.38 [0.04] vs 0.41 [0.04], P = 0.006), (both ANCOVA, with age and premorbid IQ as covariates). No longitudinal changes were seen with treatment (n = 27, paired t tests), however the hippocampal differences were no longer significant at 6 months, and frontal NAA/Cr ratios were now also significantly different (patients 1.55 [0.13] vs control 1.65 [0.18] P = 0.01). No significant correlations were found between spectroscopy results and neurocognitive test results, but significant negative correlations were seen between arousal index and frontal NAA/Cho (r = -0.39, corrected P = 0.033) and between % total sleep time at SpO(2) < 90% and hippocampal Cho/Cr (r = -0.40, corrected P = 0.01). CONCLUSIONS: OSA patients have brain metabolite changes detected by MRS, suggestive of decreased frontal lobe neuronal viability and integrity, and decreased hippocampal membrane turnover. These regions have previously been shown to have no gross structural lesions using VBM. Little change was seen with treatment with CPAP for 6 months. No correlation of metabolite concentrations was seen with results on neurocognitive tests, but there were significant negative correlations with OSA severity as measured by severity of nocturnal hypoxemia. PMID- 22215918 TI - A randomized controlled trial of intensive sleep retraining (ISR): a brief conditioning treatment for chronic insomnia. AB - STUDY OBJECTIVE: To investigate the effectiveness of intensive sleep retraining in comparison and combination with traditional behavioral intervention for chronic primary insomnia. PARTICIPANTS: Seventy-nine volunteers with chronic sleep-onset insomnia (with or without sleep maintenance difficulties) were randomly assigned either to intensive sleep retraining (ISR), stimulus control therapy (SCT), ISR plus SCT, or the control (sleep hygiene) treatment condition. INTERVENTION: ISR treatment consisted of 50 sleep onset trials over a 25-h sleep deprivation period. MEASUREMENTS AND RESULTS: Treatment response was assessed with sleep diary, activity monitoring, and questionnaire measures. The active treatment groups (ISR, SCT, ISR+SCT) all resulted in significant improvements in sleep onset latency and sleep efficiency, with moderate to large effect sizes from pre- to post-treatment. Wake time after sleep onset decreased significantly in the SCT and ISR+SCT groups. Total sleep time increased significantly in the ISR and ISR+SCT treatment groups. Participants receiving ISR (ISR, ISR+SCT) experienced rapidly improved SOL and TST during treatment, suggesting an advantage of rapid improvements in sleep in response to ISR. Although there were few statistically significant differences between groups on individual variables, ISR+SCT resulted in consistently larger effect sizes of change than other treatments, including questionnaire measures of sleep quality, sleep self efficacy, and daytime functioning. The combination treatment group (ISR+SCT) showed trends to outperform other active treatment groups with fewer treatment dropouts, and a greater proportion of treatment responders with 61% reaching "good sleeper" status. Treatment gains achieved at post-treatment in the active treatment groups were largely maintained throughout follow-up periods to 6 months. CONCLUSION: This 25-hour intensive conditioning treatment for chronic insomnia can produce rapid improvements in sleep, daytime functioning, and psychological variables. Adding ISR to traditional interventions seems to result in a superior treatment response. PMID- 22215919 TI - Persistent insomnia: the role of objective short sleep duration and mental health. AB - STUDY OBJECTIVES: Few population-based, longitudinal studies have examined risk factors for persistent insomnia, and the results are inconsistent. Furthermore, none of these studies have examined the role of polysomnographic (PSG) variables such as sleep duration or sleep apnea on the persistence of insomnia. DESIGN: Representative longitudinal study. SETTING: Sleep laboratory. PARTICIPANTS: From a random, general population sample of 1741 individuals of the adult Penn State Cohort, 1395 were followed-up after 7.5 years. MEASUREMENTS: Individuals underwent one-night PSG and full medical evaluation at baseline and a telephone interview at follow-up. PSG sleep duration was analyzed as a continuous variable and as a categorical variable: < 6 h sleep (short sleep duration) and >= 6 h sleep (longer sleep duration). RESULTS: The rates of insomnia persistence, partial remission, and full remission were 44.0%, 30.0%, and 26.0%, respectively. Objective short sleep duration significantly increased the odds of persistent insomnia as compared to normal sleep (OR = 3.19) and to fully remitted insomnia (OR = 4.92). Mental health problems at baseline were strongly associated with persistent insomnia as compared to normal sleep (OR = 9.67) and to a lesser degree compared to fully remitted insomnia (OR = 3.68). Smoking, caffeine, and alcohol consumption and sleep apnea did not predict persistent insomnia. CONCLUSIONS: Objective short sleep duration and mental health problems are the strongest predictors of persistent insomnia. These data further support the validity and clinical utility of objective short sleep duration as a novel marker of the biological severity of insomnia. PMID- 22215920 TI - Density and frequency caudo-rostral gradients of sleep spindles recorded in the human cortex. AB - STUDY OBJECTIVE: This study aims at providing a quantitative description of intrinsic spindle frequency and density (number of spindles/min) in cortical areas using deep intracerebral recordings in humans. PATIENTS OR PARTICIPANTS: Thirteen patients suffering from pharmaco-resistant focal epilepsy and investigated through deep intracortical EEG in frontal, parietal, temporal, occipital, insular, and limbic cortices including the hippocampus were included. METHODS: Spindle waves were detected from the ongoing EEG during slow wave sleep (SWS) by performing a time-frequency analysis on filtered signals (band-pass filter: 10-16 Hz). Then, spindle intrinsic frequency was determined using a fast Fourier transform, and spindle density (number of spindles per minute) was computed. RESULTS: Firstly, we showed that sleep spindles were recorded in all explored cortical areas, except temporal neocortex. In particular, we observed the presence of spindles during SWS in areas such as the insular cortex, medial parietal cortex, occipital cortex, and cingulate gyrus. Secondly, we demonstrated that both spindle frequency and density smoothly change along the caudo-rostral axis, from fast frequent posterior spindles to slower and less frequent anterior spindles. Thirdly, we identified the presence of spindle frequency oscillations in the hippocampus and the entorhinal cortex. CONCLUSIONS: Spindling activity is widespread among cortical areas, which argues for the fundamental role of spindles in cortical functions. Mechanisms of caudo-rostral gradient modulation in spindle frequency and density may result from a complex interplay of intrinsic properties and extrinsic modulation of thalamocortical and corticothalamic neurons. PMID- 22215921 TI - Sleep, glucose, and daytime functioning in youth with type 1 diabetes. AB - STUDY HYPOTHESES: 1) Youth with evidence of SDB (total apnea-hypopnea index [Total-AHI] >= 1.5) would have significantly worse glucose control than those without SDB; 2) Elevated self-reported sleepiness in youth with T1DM would be related to compromised psychosocial functioning; and 3) Youth with T1DM would have significantly less slow wave sleep (SWS) than controls. DESIGN: The study utilized home-based polysomnography, actigraphy, and questionnaires to assess sleep, and continuous glucose monitors and hemoglobin A1C (HbA1C) values to assess glucose control in youth with T1DM. We compared sleep of youth with T1DM to sleep of a matched control sample. SETTING: Diabetic participants were recruited in a pediatric endocrinology clinic. PARTICIPANTS: Participants were youth (10 through 16 years) with T1DM. Controls, matched for sex, age, and BMI percentile, were from the Tucson Children's Assessment of Sleep Apnea study. RESULTS: Participants with a Total-AHI >= 1.5 had higher glucose levels. Sleepiness and/or poor sleep habits correlated with reduced quality of life, depressed mood, lower grades, and lower state standardized reading scores. Diabetic youth spent more time (%) in stage N2 and less time in stage N3. Findings related to sleep architecture included associations between reduced SWS and higher HbA1C, worse quality of life, and sleepiness. More time (%) spent in stage N2 related to higher glucose levels/hyperglycemia, behavioral difficulties, reduced quality of life, lower grades, depression, sleep-wake behavior problems, poor sleep quality, sleepiness, and lower state standardized math scores. PMID- 22215922 TI - Interrelationships between body mass, oxygen desaturation, and apnea-hypopnea indices in a sleep clinic population. AB - STUDY OBJECTIVES: To investigate the relationship between oxygen desaturation index (ODI), body mass index (BMI), and apnea-hypopnea index (AHI) in a large sleep clinic population. DESIGN: Retrospective observational. SETTING: Sleep disorders clinic. PATIENTS OR PARTICIPANTS: 11,448 individuals undergoing diagnostic polysomnography (PSG) at a sleep disorders clinic. MEASUREMENTS AND RESULTS: Polysomnography were scored using Chicago criteria. ODI at 2%, 3%, and 4% threshold levels were derived. The study population was subdivided into BMI categories in steps of 5 kg/m(2). Mean ODI and the accuracy of ODI for detecting an AHI >= 15 (moderate-severe OSA) or >= 30 (severe OSA) were examined by BMI category, using the area under the curve (AUC) of receiver operator characteristic (ROC) curves for the 3 ODI thresholds. Based on AUC, ODI-3% performed best overall, achieving a significantly higher AUC than ODI-2% and ODI 4% for the diagnosis of moderate-severe OSA, and a higher AUC than ODI-2% for the diagnosis of severe OSA. When examining the effect of BMI, ODI-3% achieved a significantly higher AUC than ODI-2% in all BMI categories, and ODI-4% in non obese subjects. The sensitivity of ODI for detecting OSA increased with BMI, while specificity decreased. CONCLUSIONS: ODI-3% performed best overall, and when combined with appropriate clinical assessment, could be considered as an initial diagnostic test for OSA. OSA is more frequently associated with oxygen desaturation in obese subjects. BMI influences the accuracy of ODI for the diagnosis of OSA, and ODI should not be used in isolation as a test for OSA in subjects with a BMI below 25kg/m(2). PMID- 22215923 TI - A prospective study of sleep duration and pneumonia risk in women. AB - STUDY OBJECTIVE: Experimental data suggest sleep deprivation may impair host immunity. We sought to assess the effect of poor sleep on pneumonia risk. DESIGN: Prospective, observational cohort study. PARTICIPANTS: 56,953 female nurses (ages 37 to 57 years old) participating in the Nurses' Health Study II cohort free of cancer, cardiovascular disease, diabetes, and asthma with no prior history of pneumonia. MEASUREMENTS AND RESULTS: At baseline, participants reported their average sleep duration and whether this quantity was adequate for them. Questionnaires ascertaining a new pneumonia diagnosis were mailed every 2 years. Cases required physician diagnosis and chest radiograph confirmation. Cox proportional hazards models were used to assess the relative risk for incident pneumonia over 4 years. Over 217,500 person-years, 977 cases of pneumonia were identified. Relative to 8-h sleepers, both short and long sleep durations were associated with elevated pneumonia risk. The age-adjusted relative risk for pneumonia was 1.70 (95% CI 1.30-2.23) in those sleeping <= 5 h and 1.49 (95% CI 1.12-1.98) in those sleeping >= 9 h. After adjusting for potential confounders, the relative risks were 1.39 (95% CI: 1.06-1.82) in those sleeping <= 5 h and 1.38 (95% CI 1.04-1.84) in those sleeping >= 9 h. Perceived inadequate sleep was also associated with pneumonia with a relative risk of 1.50 (95% CI 1.29-1.74) in multivariate models. CONCLUSIONS: Both reduced and prolonged habitual sleep durations are associated with increased risk of pneumonia. Further research is needed to understand how sleep habits can influence immunity. PMID- 22215924 TI - Effects of GF-015535-00, a novel alpha1 GABA A receptor ligand, on the sleep-wake cycle in mice, with reference to zolpidem. AB - STUDY OBJECTIVES: Novel, safe, and efficient hypnotic compounds capable of enhancing physiological sleep are still in great demand in the therapy of insomnia. This study compares the sleep-wake effects of a new alpha1 GABA(A) receptor subunit ligand, GF-015535-00, with those of zolpidem, the widely utilized hypnotic compound. METHODS: Nine C57Bl6/J male mice were chronically implanted with electrodes for EEG and sleep-wake monitoring. Each mouse received 3 doses of GF-015535-00 and zolpidem. Time spent in sleep-wake states and cortical EEG power spectra were analyzed. RESULTS: Both zolpidem and GF-015535-00 prominently enhanced slow wave sleep and paradoxical sleep in the mouse. However, as compared with zolpidem, GF-015535-00 showed several important differences: (1) a comparable sleep-enhancing effect was obtained with a 10 fold smaller dose; (2) the induced sleep was less fragmented; (3) the risk of subsequent wake rebound was less prominent; and (4) the cortical EEG power ratio between slow wave sleep and wake was similar to that of natural sleep and thus compatible with physiological sleep. CONCLUSION: The characteristics of the sleep-wake effects of GF-015535-00 in mice could be potentially beneficial for its use as a therapeutic compound in the treatment of insomnia. Further investigations are required to assess whether the same characteristics are conserved in other animal models and humans. PMID- 22215925 TI - The effects of stimulus degradation after 48 hours of total sleep deprivation. AB - STUDY OBJECTIVES: To test the hypothesis that total sleep deprivation (TSD) slows stimulus detection and evaluation processes. Towards that end we manipulate degradation of the imperative stimulus, a manipulation well established to affect the processes of interest, in a delayed letter recognition (DLR) task and the psychomotor vigilance task (PVT), and predicted that after TSD the ordinary reaction time (RT) slowing effect of stimulus degradation would be increased. These hypotheses were only partially confirmed (see below). DESIGN: Participants were exposed to 48 h of total sleep loss. The PVT and DLR were administered to the same participants. The PVT was administered 8 times -every 6 h from 12:00 on Day 1. The DLR was administered twice, at 09:00 of Day 1 and 48 h later. SETTING: Participants were continuously monitored in a sleep laboratory. SUBJECTS: 26 healthy young adults enrolled. Due to dropouts and technical failures, the final n's were 20 for the DLR and 21 for the PVT. MEASUREMENTS AND RESULTS: General linear mixed models were employed. In the DLR task there was no interaction between TSD and degradation on any variable. There was, however, a significant interaction between TSD and degradation on mean reaction time in the PVT (P = 0.01). CONCLUSIONS: As in our previous reports, we observe the specificity with which total sleep deprivation affects cognitive processes. One aspect of visual processing, stimulus detection, was affected by total sleep deprivation and made a significant contribution to the performance impairments observed. Another aspect of visual processing, stimulus evaluation, remained unaffected after 2 days and nights of total sleep loss. PMID- 22215926 TI - Relationship between Kleine-Levin syndrome and upper respiratory infection in Taiwan. AB - STUDY OBJECTIVES: In Kleine-Levin Syndrome (KLS), new episodes of hypersomnia are often preceded by an acute flu-like syndrome or upper airway infection 3 to 5 days before onset. This study investigated the relationship between the occurrence of mild upper respiratory tract infections (URIs) in the general population and the occurrence and seasonality and hypersomnic episodes in KLS patients. DESIGN: This investigation was a longitudinal clinical study. Based on data obtained from the National Health Research Institutes between 2006 and 2007, the timing of hypersomnic episodes in 30 KLS patients were compared with calendar reports of URI events, and the results compared with age-matched general Taiwanese population. MEASUREMENTS: Clinical symptoms, physical examination, polysomnographic recording, SPECT study, and laboratory tests affirming KLS during both periods of hypersomnic attack and non-attack were collected. Every symptomatic episode was then followed up. The cross-correlation function (CCF) and bivariate correlations analysis were performed to see the relationship between KLS and URIs. RESULTS: A positive finding of CCF analysis and significant bivariate correlations were found between KLS episodes and URI in the general population (r = 0.456*). In onset of hypersomnia, significant correlations existed among "acute upper respiratory infections" (r = 0.446*), "acute bronchitis and bronchiolitis" (r = 0.462*), and "pharyngitis and nasopharyngitis" (r = 0.548*) subtypes of infections. A positive correlation between higher reports of symptomatic hypersomnia and URI also existed in a given season. A positive nonsignificant trend for "allergic rhinitis" (r = 0.400) was also found. CONCLUSION: The agent behind URI or its consequence (such as fever) is associated with increased incidence of KLS episodes and may explain periodic symptomatic recurrences. PMID- 22215927 TI - Insomnia symptoms and HIV infection among participants in the Women's Interagency HIV Study. AB - OBJECTIVES: This study assessed the prevalence of insomnia symptoms among women with and without HIV-infection and examined factors associated with insomnia. DESIGN: Participants (n = 1682) were enrolled in the Women's Interagency HIV Study (WIHS); 69% were infected with HIV. This was a cross-sectional analysis of data from standardized interviewer-administered instruments and physical/gynecological exams. Analysis focused on sociodemographics, sleep measures, depressive symptoms, drug use, alcohol consumption, medications, and HIV-related clinical variables. Women were classified as having symptoms of insomnia if they reported either difficulty initiating sleep, difficulty maintaining sleep, or early morning awakening >= 3 times a week in the past 2 weeks. RESULTS: Overall, HIV-infected women were 17% more likely to endorse insomnia symptoms than uninfected women (OR = 1.17, 95% CI: 1.04-1.34, P < 0.05). The adjusted prevalence of insomnia symptoms varied by HIV status and age groups. Among women ages 31-40 years, those with HIV infection were 26% more likely to endorse insomnia symptoms than their counterparts (OR = 1.26, 95% CI: 1.01-1.59, P < 0.05). No significant differences were observed in the likelihood of reporting insomnia symptoms based on HIV treatment type. Multivariate-adjusted regression analyses showed that depression was the most consistent and significant independent predictor of the likelihood of reporting insomnia symptoms across all age strata. CONCLUSIONS: Insomnia symptoms are common among both HIV-infected and uninfected women. Prevalence of insomnia did not vary significantly by HIV status, except among younger women. Younger women with HIV infection are at greater risk for experiencing insomnia symptoms. PMID- 22215928 TI - Electrocardiogram-based sleep spectrogram measures of sleep stability and glucose disposal in sleep disordered breathing. AB - STUDY OBJECTIVES: Sleep disordered breathing (SDB) is independently associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Experimental sleep fragmentation has been shown to impair insulin sensitivity. Conventional electroencephalogram (EEG)-based sleep-quality measures have been inconsistently associated with indices of glucose metabolism. This analysis explored associations between glucose metabolism and an EEG-independent measure of sleep quality, the sleep spectrogram, which maps coupled oscillations of heart rate variability and electrocardiogram (ECG)-derived respiration. The method allows improved characterization of the quality of stage 2 non-rapid eye movement (NREM) sleep. DESIGN: Cross-sectional study. SETTING: N/A. PARTICIPANTS: Nondiabetic subjects with and without SDB (n = 118) underwent the frequently sampled intravenous glucose tolerance test (FSIVGTT) and a full-montage polysomnogram. The sleep spectrogram was generated from ECG collected during polysomnography. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Standard polysomnographic stages (stages 1, 2, 3+4, and rapid eye movement [REM]) were not associated with the disposition index (D(I)) derived from the FSIVGTT. In contrast, spectrographic high-frequency coupling (a marker of stable or "effective" sleep) duration was associated with increased, and very-low-frequency coupling (a marker of wake/REM/transitions) associated with reduced D(I). This relationship was noted after adjusting for age, sex, body mass index, slow wave sleep, total sleep time, stage 1, the arousal index, and the apnea-hypopnea index. CONCLUSIONS: ECG-derived sleep-spectrogram measures of sleep quality are associated with alterations in glucose-insulin homeostasis. This alternate mode of estimating sleep quality could improve our understanding of sleep and sleep breathing effects on glucose metabolism. PMID- 22215929 TI - Reliability of a single objective measure in assessing sleepiness. AB - STUDY OBJECTIVES: To evaluate reliability of single objective tests in assessing sleepiness. DESIGN: Subjects who completed polysomnography underwent a 4-nap multiple sleep latency test (MSLT) the following day. Prior to each nap opportunity on MSLT, subjects performed the psychomotor vigilance test (PVT) and divided attention driving task (DADT). Results of single versus multiple test administrations were compared using the intraclass correlation coefficient (ICC) and adjusted for test administration order effects to explore time of day effects. Measures were explored as continuous and binary (i.e., impaired or not impaired). SETTING: Community-based sample evaluated at a tertiary, university based sleep center. PARTICIPANTS: 372 adult commercial vehicle operators oversampled for increased obstructive sleep apnea risk. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: AS CONTINUOUS MEASURES, ICC WERE AS FOLLOWS: MSLT 0.45, PVT median response time 0.69, PVT number of lapses 0.51, 10-min DADT tracking error 0.87, 20-min DADT tracking error 0.90. Based on binary outcomes, ICC were: MSLT 0.63, PVT number of lapses 0.85, 10-min DADT 0.95, 20-min DADT 0.96. Statistically significant time of day effects were seen in both the MSLT and PVT but not the DADT. Correlation between ESS and different objective tests was strongest for MSLT, range [-0.270 to -0.195] and persisted across all time points. CONCLUSIONS: Single DADT and PVT administrations are reliable measures of sleepiness. A single MSLT administration can reasonably discriminate individuals with MSL < 8 minutes. These results support the use of a single administration of some objective tests of sleepiness when performed under controlled conditions in routine clinical care. PMID- 22215930 TI - Direct comparison of two new actigraphs and polysomnography in children and adolescents. AB - STUDY OBJECTIVES: To evaluate the validity and reliability of 2 new models of commercially available actigraphs compared to polysomnography for children and adolescents. DESIGN AND SETTING: Subjects concurrently wore the Ambulatory Monitoring Inc. Motionlogger Sleep Watch (AMI) and the Phillips Respironics Mini Mitter Actiwatch-2 (PRMM) while undergoing overnight polysomnography (PSG) in a pediatric sleep laboratory housed in a tertiary care children's hospital. PARTICIPANTS: 115 youth (59 girls, 56 boys), ages 3-18 years (mean 8.8 years, SD 4.4 years). MEASUREMENTS: Outcome variables were total sleep time (TST), wake after sleep onset (WASO), and sleep efficiency (SE). Epoch-by-epoch comparisons were made between the 2 devices and PSG to determine sensitivity, specificity, and accuracy. Agreement between the 2 devices was determined with t-tests and the Bland-Altman concordance technique. Different algorithms/sensitivities, developmental age groups, and sleep disordered breathing (SDB) status were also examined. RESULTS: For both device brands, sensitivity (0.89-0.97), specificity (0.54-0.77), and accuracy (0.87-0.90) were similar to previous reports. Notably, compared to PSG, both device brands significantly overestimated WASO, while the AMI device also significantly underestimated TST. Inter-device comparison of the 2 brands found poor agreement for TST, WASO, and SE. Agreement with PSG differed depending on the scoring algorithm (AMI) or sensitivity setting (PRMM), as well as across developmental age group and sleep disordered breathing (SDB) status. CONCLUSIONS: Similar to previous reports, both new actigraph brands were found to have good sensitivity (to detect sleep), but poorer specificity (to detect wake). Study results also suggest that researchers should adjust the scoring algorithm/sensitivity depending on a study's design (e.g., young children vs. adolescents, healthy children vs. youth with SDB). Further, inter-device reliability was poor, suggesting the need for caution when comparing results across studies that use different brands of actigraphic devices. PMID- 22215931 TI - Aldosterone and Risk for Insulin Resistance. PMID- 22215932 TI - High-order total variation minimization for interior SPECT. AB - Recently, we developed an approach for solving the computed tomography (CT) interior problem based on the high-order TV (HOT) minimization, assuming that a region-of-interest (ROI) is piecewise polynomial. In this paper, we generalize this finding from the CT field to the single-photon emission computed tomography (SPECT) field, and prove that if an ROI is piecewise polynomial, then the ROI can be uniquely reconstructed from the SPECT projection data associated with the ROI through the HOT minimization. Also, we propose a new formulation of HOT, which has an explicit formula for any n-order piecewise polynomial function, while the original formulation has no explicit formula for n >= 2. Finally, we verify our theoretical results in numerical simulation, and discuss relevant issues. PMID- 22215933 TI - Computer-Mediated Assessment of Intelligibility in Aphasia and Apraxia of Speech. AB - BACKGROUND: Previous work indicates that single word intelligibility tests developed for dysarthria are sensitive to segmental production errors in aphasic individuals with and without apraxia of speech. However, potential listener learning effects and difficulties adapting elicitation procedures to coexisting language impairments limit their applicability to left hemisphere stroke survivors. AIMS: The main purpose of this study was to examine basic psychometric properties for a new monosyllabic intelligibility test developed for individuals with aphasia and/or AOS. A related purpose was to examine clinical feasibility and potential to standardize a computer-mediated administration approach. METHODS #ENTITYSTARTX00026; PROCEDURES: A 600-item monosyllabic single word intelligibility test was constructed by assembling sets of phonetically similar words. Custom software was used to select 50 target words from this test in a pseudo-random fashion and to elicit and record production of these words by 23 speakers with aphasia and 20 neurologically healthy participants. To evaluate test-retest reliability, two identical sets of 50-word lists were elicited by requesting repetition after a live speaker model. To examine the effect of a different word set and auditory model, an additional set of 50 different words was elicited with a pre-recorded model. The recorded words were presented to normal-hearing listeners for identification via orthographic and multiple-choice response formats. To examine construct validity, production accuracy for each speaker was estimated via phonetic transcription and rating of overall articulation. OUTCOMES #ENTITYSTARTX00026; RESULTS: Recording and listening tasks were completed in less than six minutes for all speakers and listeners. Aphasic speakers were significantly less intelligible than neurologically healthy speakers and displayed a wide range of intelligibility scores. Test-retest and inter-listener reliability estimates were strong. No significant difference was found in scores based on recordings from a live model versus a pre-recorded model, but some individual speakers favored the live model. Intelligibility test scores correlated highly with segmental accuracy derived from broad phonetic transcription of the same speech sample and a motor speech evaluation. Scores correlated moderately with rated articulation difficulty. CONCLUSIONS: We describe a computerized, single-word intelligibility test that yields clinically feasible, reliable, and valid measures of segmental speech production in adults with aphasia. This tool can be used in clinical research to facilitate appropriate participant selection and to establish matching across comparison groups. For a majority of speakers, elicitation procedures can be standardized by using a pre-recorded auditory model for repetition. This assessment tool has potential utility for both clinical assessment and outcomes research. PMID- 22215934 TI - Rapid serial naming and reading ability: the role of lexical access. AB - Rapid serial naming tasks are frequently used to explain variance in reading skill. However, the construct being measured by rapid naming is yet undetermined. The Phonological Processing theory suggests that rapid naming relates to reading because of similar demands of access to long-term stored phonological representations of visual stimuli. Some researchers have argued that isolated or discrete-trial naming is a more precise measure of lexical access than serial naming, thus it is likely that any shared variance between these two formats can be attributed to similar lexical access demands. The present study examined whether there remained any variance in reading ability that could be uniquely explained by the rapid naming task while controlling for isolated naming. Structural equation modeling was used to examine these relations within the context of the phonological processing model. Results indicated that serial naming uniquely predicted reading, and the relation was stronger with isolated naming controlled for, suggesting that isolated naming functioned as a suppressor variable in the relation of serial naming with reading. PMID- 22215935 TI - Peripheral ossifying fibroma: A clinical report. AB - The gingiva is often the site of localized growths that are considered to be reactive rather than neoplastic in nature. Many of these lesions are difficult to be identified clinically and can be identified as specific entity only on the basis of typical and consistent histomorphology. Peripheral ossifying fibroma is one such reactive lesion. It has been described with various synonyms and is believed to arise from the periodontal ligament comprising about 9% of all gingival growths. The size of the lesion is usually small, located mainly in the anterior maxilla with a higher predilection for females, and it is more common in the second decade of life. A clinical report of a 12-year-old girl with a large peripheral ossifying fibroma in the posterior maxilla showing significant growth and interference with occlusion is presented. PMID- 22215936 TI - Crouzon's syndrome: A review of literature and case report. AB - Crouzon's syndrome is an autosomal dominant disorder with complete penetrance and variable expressivity. Described by a French neurosurgeon in 1912, it is a rare genetic disorder. Crouzon's syndrome is caused by mutation in the fibroblast growth factor receptor 2 (FGFR2) gene. Normally, the sutures in the human skull fuse after the complete growth of the brain, but if any of these sutures close early then it may interfere with the growth of the brain. The disease is characterized by premature synostosis of coronal and sagittal sutures which begins in the first year of life. Case report of a 7 year old boy is presented with characteristic features of Crouzon's syndrome with mental retardation. The clinical, radiographic features along with the complete oral rehabilitation done under general anesthesia and preventive procedures done are described. PMID- 22215937 TI - In vivo magnetic resonance spectroscopy of liver tumors and metastases. AB - Primary liver cancer is the fifth most common malignancy in men and the eighth in women worldwide. The liver is also the second most common site for metastatic spread of cancer. To assist in the diagnosis of these liver lesions non-invasive advanced imaging techniques are desirable. Magnetic resonance (MR) is commonly used to identify anatomical lesions, but it is a very versatile technique and also can provide specific information on tumor pathophysiology and metabolism, in particular with the application of MR spectroscopy (MRS). This may include data on the type, grade and stage of tumors, and thus assist in further management of the disease. The purpose of this review is to summarize and discuss the available literature on proton, phosphorus and carbon-13-MRS as performed on primary liver tumors and metastases, with human applications as the main perspective. Upcoming MRS approaches with potential applications to liver tumors are also included. Since knowledge of some technical background is indispensable to understand the results, a basic introduction of MRS and some technical issues of MRS as applied to tumors and metastases in the liver are described as well. In vivo MR spectroscopy of tumors in a metabolically active organ such as the liver has been demonstrated to provide important information on tumor metabolism, but it also is challenging as compared to applications on some other tissues, in particular in humans, mostly because of its abdominal location where movement may be a disturbing factor. PMID- 22215938 TI - Utility of co-transplanting mesenchymal stem cells in islet transplantation. AB - Islet transplantation is characterized by the transplantation of isolated islets from donor pancreata into a diabetic recipient. Although it is a viable choice in the treatment of insulin dependent diabetes mellitus, most patients (approximately 90%) require insulin five years after transplantation. Recently, the co-transplantation of mesenchymal stem cells (MSCs) and islets in animal studies has revealed the effectiveness of MSCs co-transplantation for improving islet function. The mechanisms underlying the beneficial impact of MSCs include immunomodulation and the promotion of angiogenesis. In this review, we discuss MSCs and how they support improved graft survival and function. PMID- 22215939 TI - Helicobacter pylori's virulence and infection persistence define pre-eclampsia complicated by fetal growth retardation. AB - AIM: To better understand the pathogenic role of Helicobacter pylori (H. pylori) in pre-eclampsia (PE), and whether it is associated or not with fetal growth retardation (FGR). METHODS: Maternal blood samples were collected from 62 consecutive pregnant women with a diagnosis of PE and/or FGR, and from 49 women with uneventful pregnancies (controls). Serum samples were evaluated by immunoblot assay for presence of specific antibodies against H. pylori antigens [virulence: cytotoxin-associated antigen A (CagA); ureases; heat shock protein B; flagellin A; persistence: vacuolating cytotoxin A (VacA)]. Maternal complete blood count and liver enzymes levels were assessed at delivery by an automated analyzer. RESULTS: A significantly higher percentage of H. pylori seropositive women were found among PE cases (85.7%) compared to controls (42.9%, P < 0.001). There were no differences between pregnancies complicated by FGR without maternal hypertension (46.2%) and controls. Importantly, persistent and virulent infections (VacA/CagA seropositive patients, intermediate leukocyte blood count and aspartate aminotransferase levels) were exclusively associated with pre eclampsia complicated by FGR, while virulent but acute infections (CagA positive/VacA negative patients, highest leukocyte blood count and aspartate aminotransferase levels) specifically correlated with PE without FGR. CONCLUSION: Our data strongly indicate that persistent and virulent H. pylori infections cause or contribute to PE complicated by FGR, but not to PE without feto placental compromise. PMID- 22215940 TI - Infliximab in pediatric inflammatory bowel disease rapidly decreases fecal calprotectin levels. AB - AIM: To study the response to infliximab in pediatric inflammatory bowel disease (IBD), as reflected in fecal calprotectin levels. METHODS: Thirty-six pediatric patients with IBD [23 Crohn's disease (CD), 13 ulcerative colitis (UC); median age 14 years] were treated with infliximab. Fecal calprotectin was measured at baseline, and 2 and 6 wk after therapy, and compared to blood inflammatory markers. Maintenance medication was unaltered until the third infusion but glucocorticoids were tapered off if the patient was doing well. RESULTS: At introduction of infliximab, median fecal calprotectin level was 1150 MUg/g (range 54-6032 MUg/g). By week 2, the fecal calprotectin level had declined to a median 261 MUg/g (P < 0.001). In 37% of the patients, fecal calprotectin was normal (< 100 MUg/g) at 2 wk. By week 6, there was no additional improvement in the fecal calprotectin level (median 345 MUg/g). In 22% of the patients, fecal calprotectin levels increased by week 6 to pretreatment levels or above, suggesting no response (or a loss of early response). Thus, in CD, the proportion of non responsive patients by week 6 seemed lower, because only 9% showed no improvement in their fecal calprotectin level when compared to the respective figure of 46% of the UC patients (P < 0.05). CONCLUSION: When treated with infliximab, fecal calprotectin levels reflecting intestinal inflammation normalized rapidly in one third of pediatric patients suggesting complete mucosal healing. PMID- 22215941 TI - Five methods for detection of Helicobacter pylori in the Turkish population. AB - AIM: To compare culture analysis, Helicobacter pylori (H. pylori) stool antigen (HpSA) test, polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) for H. pylori detection. METHODS: One hundred and thirty-two consecutive adult dyspeptic patients receiving diagnostic endoscopy at the department of gastroenterology were enrolled in this study. Culture and histological examination were performed on biopsy specimens. PCR and FISH tests were applied to histopathological samples. Stool samples that were simultaneously collected were tested for the H. pylori antigen using the HpSA test and bacterial DNA using stool PCR. RESULTS: H. pylori was positively identified by histological examination in 85/132 (64.4%) of the patients, while positive samples were found in 56 (42.4%), 64 (48.5%), 98 (74.2%), 28 (21.2%) and 81 (61.4%) of the patients by culture, HpSA, PCR, stool PCR and FISH methods, respectively. The results of the culture, biopsy PCR, HpSA and FISH tests, with the exception of the stool PCR, were found to correlate with the histological examination as a gold standard. CONCLUSION: The HpSA test is a rapid, simple, and noninvasive test for monitoring therapy. FISH is an accurate, rapid, cost-effective, and easy-to-use test for H. pylori detection. PMID- 22215942 TI - Spectrum of final pathological diagnosis of gastric adenoma after endoscopic resection. AB - AIM: To investigate how many discrepancies occur in patients before and after endoscopic treatment of referred adenoma and the reason for these results. METHODS: We retrospectively reviewed data from 554 cases of 534 patients who were referred from primary care centres for adenoma treatment and treated for endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) at Chungnam National University Hospital, from July 2006 to June 2009. Re-endoscopy was examined in 142 cases and biopsy was performed in 108 cases prior to treatment. Three endoscopists (1, 2 and 3) performed all EMRs or ESDs and three pathologists (1, 2 and 3) diagnosed most of the cases. Transfer notes, medical records and endoscopic pictures of these cases were retrospectively reviewed and analyzed. RESULTS: Adenocarcinoma was 72 (13.0%) cases in total 554 cases after endoscopic treatment of referred adenoma. When the grade of dysplasia was high (55.0%), biopsy number was more than three (22.7%), size was no smaller than 2.0 cm (23.2%), morphologic type was depressed (35.8%) or yamada type IV (100%), and color was red (30.9%) or mixed-or-undetermined (25.0%), it had much more malignancy rate than the others (P < 0.05). All 18 cases diagnosed as adenocarcinoma in the re-endoscopic forceps biopsy were performed by endoscopist 1. There were different malignancy rates according to the pathologist (P = 0.027). CONCLUSION: High grade dysplasia is the most important factor for predicting malignancy as a final pathologic diagnosis before treating the referred gastric adenoma. This discrepancy can occur mainly through inappropriately selecting a biopsy site where cancer cells do not exist, but it also depends on the pathologist to some extent. PMID- 22215943 TI - Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naive patients. AB - AIM: To determine whether adding vitamin D, a potent immunomodulator, improves the hepatitis C virus (HCV) response to antiviral therapy. METHODS: Seventy-two consecutive patients with chronic HCV genotype 1 were randomized into two groups: the treatment group (n = 36, 50% male, mean age 47 +/- 11 years) received Peg alpha-2b interferon (1.5 MUg/kg per week) plus ribavirin (1000-1200 mg/d) together with vitamin D3 (2000 IU/d, target serum level > 32 ng/mL), and the control group (n = 36, 60% male, mean age 49 +/- 7 years) received identical therapy without vitamin D. HCV-RNA was assessed by real-time polymerase chain reaction (sensitivity, 10 IU/mL). The sustained virologic response (SVR) was defined as undetectable HCV-RNA at 24 wk post-treatment. RESULTS: Clinical characteristics were similar in both groups. The treatment group had a higher mean body mass index (27 +/- 4 kg/m2 vs 24 +/- 3 kg/m2; P < 0.01), viral load (50% vs 42%, P < 0.01), and fibrosis score (> F2: 42% vs 19%, P < 0.001) than the controls. At week 4, 16 (44%) treated patients and 6 (17%) controls were HCV-RNA negative (P < 0.001). At week 12, 34 (94%) treated patients and 17 (48%) controls were HCV-RNA negative (P < 0.001). At 24 wk post-treatment (SVR), 31 (86%) treated patients and 15 (42%) controls were HCV-RNA negative (P < 0.001). Viral load, advanced fibrosis and vitamin D supplementation were strongly and independently associated with SVR (multivariate analysis). Adverse events were mild and typical of Peg-alpha-2b/ribavirin. CONCLUSION: Adding vitamin D to conventional Peg-alpha-2b/ribavirin therapy for treatment-naive patients with chronic HCV genotype 1 infection significantly improves the viral response. PMID- 22215944 TI - Posterior lingual lidocaine: a novel method to improve tolerance in upper gastrointestinal endoscopy. AB - AIM: To evaluate the effect of posterior lingual lidocaine swab on patient tolerance to esophagogastroduodenoscopy, the ease of performance of the procedure, and to determine if such use will reduce the need for intravenous sedation. METHODS: Eighty patients undergoing diagnostic esophagogastroduodenoscopy in a tertiary care medical center were randomized to either lidocaine swab or spray. Intravenous meperidine and midazolam were given as needed during the procedure. RESULTS: Patients in the lidocaine swab group (SWG) tolerated the procedure better than those in the spray group (SPG) with a median tolerability score of 2 (1, 4) compared to 4 (2, 5) (P < 0.01). The endoscopists encountered less difficulty performing the procedures in the SWG with lower median difficulty scores of 1 (1, 5) compared to 4 (1, 5) in the SPG (P < 0.01). In addition, the need for intravenous sedation was also lower in the SWG compared to the SPG with fewer patients requiring intravenous sedation (13/40 patients vs 38/40 patients, respectively, P < 0.01). The patients in the SWG were more satisfied with the mode of local anesthesia they received as compared to the SPG. In addition, the endoscopists were happier with the use of lidocaine swab. CONCLUSION: The use of a posterior lingual lidocaine swab in esophagogastroduodenoscopy improves patient comfort and tolerance and endoscopist satisfaction and decreases the need for intravenous sedation. PMID- 22215945 TI - Statin use and the risk of colorectal cancer: a population-based case-control study. AB - AIM: To investigate whether the use of statins is associated with colorectal cancer risk. METHODS: We conducted a population-based case-control study in Taiwan. Data were retrospectively collected from the Taiwan National Health Insurance Research Database. Cases consisted of all patients who were aged 50 years and older and had a first-time diagnosis of colorectal cancer between the period 2005 and 2008. The controls were matched to cases by age, sex, and index date. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multiple logistic regression. RESULTS: We examined 1156 colorectal cancer cases and 4624 controls. The unadjusted ORs for any statin prescription was 1.10 (95% CI = 0.94-1.30) and the adjusted OR was 1.09 (95% CI = 0.91-1.30). When statin use was categorized by cumulative dose, the adjusted ORs were 0.99 (95% CI = 0.78-1.27) for the group with cumulative statin use below 105 defined daily doses (DDDs); 1.07 (95% CI = 0.78-1.49) for the group with cumulative statin use between 106 and 298.66 DDDs; and 1.30 (95% CI = 0.96-1.75) for the group with cumulative statin use of 298.66 DDDs or more compared with nonusers. CONCLUSION: This study does not provide support for a protective effect of statins against colorectal cancer. PMID- 22215947 TI - Meta-analysis of robotic and laparoscopic surgery for treatment of rectal cancer. AB - AIM: To conduct a meta-analysis to determine the relative merits of robotic surgery (RS) and laparoscopic surgery (LS) for rectal cancer. METHODS: A literature search was performed to identify comparative studies reporting perioperative outcomes for RS and LS for rectal cancer. Pooled odds ratios and weighted mean differences (WMDs) with 95% confidence intervals (95% CIs) were calculated using either the fixed effects model or random effects model. RESULTS: Eight studies matched the selection criteria and reported on 661 subjects, of whom 268 underwent RS and 393 underwent LS for rectal cancer. Compared the perioperative outcomes of RS with LS, reports of RS indicated favorable outcomes considering conversion (WMD: 0.25; 95% CI: 0.11-0.58; P = 0.001). Meanwhile, operative time (WMD: 27.92, 95% CI: -13.43 to 69.27; P = 0.19); blood loss (WMD: 32.35, 95% CI: -86.19 to 21.50; P = 0.24); days to passing flatus (WMD: -0.18, 95% CI: -0.96 to 0.60; P = 0.65); length of stay (WMD: -0.04; 95% CI: -2.28 to 2.20; P = 0.97); complications (WMD: 1.05; 95% CI: 0.71-1.55; P = 0.82) and pathological details, including lymph nodes harvested (WMD: 0.41, 95% CI: -0.67 to 1.50; P = 0.46), distal resection margin (WMD: -0.35, 95% CI: -1.27 to 0.58; P = 0.46), and positive circumferential resection margin (WMD: 0.54, 95% CI: 0.12 2.39; P = 0.42) were similar between RS and LS. CONCLUSION: RS for rectal cancer is superior to LS in terms of conversion. RS may be an alternative treatment for rectal cancer. Further studies are required. PMID- 22215946 TI - IkappaB kinase-beta inhibitor attenuates hepatic fibrosis in mice. AB - AIM: To investigate the anti-fibrosis effect of IkappaB kinase-beta inhibitor (IKK2 inhibitor IMD0354) in liver fibrosis. METHODS: Twenty male C57BL6 mice were divided into four groups. Five high-fat fed mice were injected with lipopolysaccharide (LPS, 10 mg/kg) intraperitoneally and five high-fat fed mice were without LPS injection to build models of liver injury, and the intervention group (five mice) was injected intraperitoneally with IKK2 inhibitor (IMD 30 mg/kg for 14 d), while the remaining five mice received a normal diet as controls. Hepatic function, pathological evaluation and liver interleukin-6 (IL 6) expression were examined. Western blotting and real-time polymerase chain reaction were used to detect the expressions of nuclear factor-kappaB (NF kappaB), alpha-smooth muscle actin (alpha-SMA), tumor growth factor-beta1 (TGF beta1), tumor necrosis factor-alpha (TNF-alpha), typeIand type III collagen proteins and mRNA. RESULTS: A mouse model of liver injury was successfully established, and IMD decreased nuclear translocation of NF-kappaB p65 in liver cells. In the IMD-treated group, the levels of alanine aminotransferase (103 +/- 9.77 MU/L vs 62.4 +/- 7.90 MU/L, P < 0.05) and aminotransferase (295.8 +/- 38.56 MU/L vs 212 +/- 25.10 MU/L, P < 0.05) were significantly decreased when compared with the model groups. The histological changes were significantly ameliorated. After treatment, the expressions of IL-6 (681 +/- 45.96 vs 77 +/- 7.79, P < 0.05), TGF-beta1 (Western blotting 5.65% +/- 0.017% vs 2.73% +/- 0.005%, P < 0.05), TNF-alpha (11.58% +/- 0.0063% vs 8.86% +/- 0.0050%, P < 0.05), typeIcollagen (4.49% +/- 0.014% vs 1.90% +/- 0.0006%, P < 0.05) and type III collagen (3.46% +/- 0.008% vs 2.29% +/- 0.0035%, P < 0.05) as well as alpha-SMA (6.19 +/- 0.0036 MU/L vs 2.16 +/- 0.0023 MU/L, P < 0.05) protein and mRNA were downregulated in the IMD group compared to the fibrosis control groups (P < 0.05). CONCLUSION: IKK2 inhibitor IMD markedly improved non-alcoholic fatty liver disease in mice by lowering NF-kappaB activation, which could become a remedial target for liver fibrosis. PMID- 22215948 TI - Therapeutic effects of combined oxaliplatin and S-1 in older patients with advanced gastric cardiac adenocarcinoma. AB - AIM: To evaluate the effects and safety of combination chemotherapy with oxaliplatin (L-OHP) and S-1 (SOX regimen) in older patients with advanced gastric cardiac adenocarcinoma (GCA). METHODS: Seventy patients with advanced GCA were classified according to age into an older group (>= 75 years) and a control group (< 75 years). The SOX regimen was administered to the two groups as follows: S-1 (40 mg/m2 po bid) on days 1 to 14 followed by a 7-d off period, plus L-OHP (65 mg/m2 iv) for 2 h on days 1 and 8 of a 21-d cycle. This regimen was repeated for four to six cycles. Response and swallow statuses were evaluated after two cycles (6 wk). Effects and toxicity were evaluated four weeks after chemotherapy was completed. RESULTS: The response rate was 65.6% (21/32) in the older group and 68.4% (26/38) in the control group (chi2 = 0.062 and P = 0.804). Improvement in swallowing was 78.1% (25/32) in the older group and 76.3% (29/38) in the control group (chi2 = 0.032 and P = 0.857). Efficacy was 68.8% (22/32) in the older group and 65.8% (25/38) in the control group (chi2 = 0.069 and P = 0.793). Toxicities were reversible and similar in both groups (P > 0.05). CONCLUSION: The SOX regimen is an effective, safe and well-tolerated regimen for older patients with advanced GCA. PMID- 22215949 TI - Enterovenous fistulization: a rare complication of Crohn's disease. AB - The presence of hepatic portal venous gas (HPVG) is associated with numerous diseases, and has been regarded as a serious, even catastrophic condition. However, anecdotal reports mention that some patients with inflammatory bowel disease (IBD), who developed HPVG after diagnostic examinations of the colon, were successfully managed with antibiotic therapy and have followed benign courses. In contrast, among IBD patients, the development of HPVG is rarely caused by enterovenous fistula. We describe a 32-year-old man with Crohn's ileocolitis who presented with hypotension and fever associated with HPVG, as well as superior mesenteric vein thrombosis, possibly caused by enterovenous fistula, who was successfully managed by surgery. We also review the literature concerning portal venous gas associated with Crohn's disease. PMID- 22215950 TI - Patient-provider communication data: linking process and outcomes in oncology care. AB - OVERVIEW: Patient-provider communication is vital to quality patient care in oncology settings and impacts health outcomes. Newer communication datasets contain patient symptom reports, real-time audiofiles of visits, coded communication data, and visit outcomes. The purpose of this paper is to: (1) review the complex communication processes during patient-provider interaction during oncology care; (2) describe methods of gathering and coding communication data; (3) suggest logical approaches to analyses; and (4) describe one new dataset that allows linking of patient symptoms and communication processes with visit outcomes. CHALLENGES: Patient-provider communication research is complex due to numerous issues, including human subjects' concerns, methods of data collection, numerous coding schemes, and varying analytic techniques. DATA COLLECTION AND CODING: Coding of communication data is determined by the research question(s) and variables of interest. Subsequent coding and timestamping the behaviors provides categorical data and determines the interval between and patterns of behaviors. ANALYTIC APPROACHES: Sequential analyses move from descriptive statistics to explanatory analyses to direct analyses and conditional probabilities. In the final stage, explanatory modeling is used to predict outcomes from communication elements. Examples of patient and provider communication in the ambulatory oncology setting are provided from the new Electronic Self Report Assessment-Cancer II dataset. SUMMARY: More complex communication data sets provide opportunities to link elements of patient provider communication with visit outcomes. Given more complex datasets, a step wise approach is necessary to analyze and identify predictive variables. Sequential analyses move from descriptive results to predictive models with communication data, creating links between patient symptoms and concerns, real time audiotaped communication, and visit outcomes. The results of these analyses will be useful in developing evidence-based interventions to enhance communication and improve psychosocial outcomes in oncology settings. PMID- 22215951 TI - The Amelogenin Proteins and Enamel Development in Humans and Mice. AB - Before a tooth erupts into the oral cavity, the mineralized enamel and dentin layers begin to develop. During these early stages of enamel formation, an abundant group of proteins known as amelogenins are secreted by ameloblast cells within the developing tooth. These proteins are required for the enamel layer to reach its normal thickness and attain its intricate structure. Human patients with amelogenin gene mutations have a condition referred to as amelogenesis imperfecta, and we have analyzed human gene defects so that we can recreate them in mice. We have generated mice with a null amelogenin mutation where no amelogenin is produced, mice that over-express normal and mutated amelogenins, and over-expressors have been mated to null mice for rescue experiments. Because there are at least 15 messages that are alternatively spliced from a single amelogenin primary RNA transcript, these approaches have begun to reveal the functions of individual amelogenin proteins during enamel development. Finally, amelogenins are processed by carefully regulated proteolytic digestion leading to many additional amelogenin peptides and it is likely that protein function is altered during this developmental process. We have also had some surprises, as one of our mouse models develops odontogenic tumors, and we know now that some of the amelogenins are expressed in other regions of the body outside of the oral cavity, and may have a role in signal transduction. PMID- 22215952 TI - Adaptation and the perception of facial age. AB - We examined how the perceived age of adult faces is affected by adaptation to younger or older adult faces. Observers viewed images of a synthetic male face simulating ageing over a modelled range from 15 to 65 years. Age was varied by changing shape cues or textural cues. Age level was varied in a staircase to find the observer's subjective category boundary between "old" and "young". These boundaries were strongly biased by adaptation to the young or old face, with significant aftereffects induced by either shape or textural cues. A further experiment demonstrated comparable aftereffects for photorealistic images of average older or younger adult faces, and found that aftereffects showed some selectivity for a change in gender but also strongly transferred across gender. This transfer shows that adaptation can adjust to the attribute of age somewhat independently of other facial attributes. These findings suggest that perceived age, like many other natural facial dimensions, is highly susceptible to adaptation, and that this adaptation can be carried by both the structural and textural changes that normally accompany facial ageing. PMID- 22215953 TI - Mutational analysis of xenobiotic metabolizing genes (CYP1A1 and GSTP1) in sporadic head and neck cancer patients. AB - CYP1A1 is the phase I enzyme that detoxifies the carcinogen or converts it into a more electrophilic form, metabolized by phase II enzymes like GSTP1. These detoxifying genes have been extensively studied in association with head and neck cancer (HNC) in different ethnic groups worldwide. The current study was aimed at screening genetic polymorphisms of genes CYP1A1 and GSTP1 in 388 Pakistani HNC patients and 150 cancer-free healthy controls, using PCR-SSCP. No already known variants of either gene were found, however a novel frameshift mutation due to insertion of T (g.2842_2843insT) was observed in the CYP1A1 gene. A statistically significant number (5.4%) of HNC cases, with the mean age of 51.75 (+/-15.7) years, presented this frameshift mutation in the conserved domain of CYP1A1. Another novel substitution mutation in was found in the GSTP1 gene, presenting TA instead of AG. The g.2848A > T polymorphism causes a leucine-to-leucine formation, whereas g.2849G > A causes alanine-to-threonine formation at amino acid positions 166 and 167, respectively. These exonic mutations were found in 9.5% of the HNC patients and in none of the controls. In addition, two intronic deletions of C (g.1074delC and g.1466delC) were also found in 11 patients with a mean age of 46.2 (+/-15.6) years. In conclusion, accumulation of mutations in genes CYP1A1 and GSTP1 appears to be associated with increased risk of developing HNC, suggesting that mutations in these genes may play a role in the etiology of head and neck cancer. PMID- 22215954 TI - Association between Knops blood group polymorphisms and susceptibility to malaria in an endemic area of the Brazilian Amazon. AB - Complement receptor 1 (CR1) gene polymorphisms that are associated with Knops blood group antigens may influence the binding of Plasmodium parasites to erythrocytes, thereby affecting susceptibility to malaria. The aim of this study was to evaluate the genotype and allele and haplotype frequencies of single nucleotide polymorphisms (SNPs) of Knops blood group antigens and examine their association with susceptibility to malaria in an endemic area of Brazil. One hundred and twenty-six individuals from the Brazilian Amazon were studied. The CR1-genomic fragment was amplified by PCR and six SNPs and haplotypes were identified after DNA sequence analysis. Allele and haplotype frequencies revealed that the Kn(b) allele and H8 haplotype were possibly associated with susceptibility to Plasmodium falciparum. The odds ratios were reasonably high, suggesting a potentially important association between two Knops blood antigens (Kn(b) and KAM(+)) that confer susceptibility to P. falciparum in individuals from the Brazilian Amazon. PMID- 22215955 TI - Polymorphisms associated with the risk of lung cancer in a healthy Mexican Mestizo population: Application of the additive model for cancer. AB - Lung cancer is the leading cause of cancer mortality in Mexico and worldwide. In the past decade, there has been an increase in the number of lung cancer cases in young people, which suggests an important role for genetic background in the etiology of this disease. In this study, we genetically characterized 16 polymorphisms in 12 low penetrance genes (AhR, CYP1A1, CYP2E1, EPHX1, GSTM1, GSTT1, GSTPI, XRCC1, ERCC2, MGMT, CCND1 and TP53) in 382 healthy Mexican Mestizos as the first step in elucidating the genetic structure of this population and identifying high risk individuals. All of the genotypes analyzed were in Hardy Weinberg equilibrium, but different degrees of linkage were observed for polymorphisms in the CYP1A1 and EPHX1 genes. The genetic variability of this population was distributed in six clusters that were defined based on their genetic characteristics. The use of a polygenic model to assess the additive effect of low penetrance risk alleles identified combinations of risk genotypes that could be useful in predicting a predisposition to lung cancer. Estimation of the level of genetic susceptibility showed that the individual calculated risk value (iCRV) ranged from 1 to 16, with a higher iCRV indicating a greater genetic susceptibility to lung cancer. PMID- 22215956 TI - Association of GNB3 C825T polymorphism with plasma electrolyte balance and susceptibility to hypertension. AB - The role of G-protein activation in cardiovascular disorders is well-known. G protein beta3 subunit (GNB3) C825T polymorphism is associated with increased intracellular signal transduction. We investigated the role of the variant in plasma sodium and potassium concentrations and association with hypertension. 345 healthy controls and 455 patients with essential hypertension were enrolled. Plasma renin activity and aldosterone concentration were measured. The variant, typed by SNaPshot, was analyzed on an ABI Prism 3100 Genetic Analyzer and GeneScan. The TT genotype and T allele were over-represented in the patients (p < 0.001, p < 0.0001). Multiple-logistic regression disclosed that the risk of hypertension was significantly greater for TT (p < 0.0001, OR = 6.1, CI = 2.9 12.7). One-way ANOVA revealed that hypertensive T-allele carriers (CT+TT), compared to non-carriers (CC), had a greater body mass index (BMI), mean arterial pressure (MAP) and PAC (p = 0.01, p = 0.01, p < 0.0001, respectively); while the patients with 825TT risk genotype showed higher plasma sodium and lower potassium (p < 0.0001, each). The results strongly emphasize, not only the role of C825T polymorphism by the induction of increased G-protein activity and enhancement of Na/h exchangers, but also the association with higher plasma sodium and lower potassium levels, high BMI and susceptibility to hypertension. PMID- 22215957 TI - Chromosome 19p13.3 deletion in a child with Peutz-Jeghers syndrome, congenital heart defect, high myopia, learning difficulties and dysmorphic features: Clinical and molecular characterization of a new contiguous gene syndrome. AB - The Peutz-Jeghers syndrome (PJS) is an autosomal-dominant hamartomatous polyposis syndrome characterized by mucocutaneous pigmentation, gastrointestinal polyps and the increased risk of multiple cancers. The causative point mutation in the STK11 gene of most patients accounts for about 30% of the cases of partial and complete gene deletion. This is a report on a girl with PJS features, learning difficulties, dysmorphic features and cardiac malformation, bearing a de novo 1.1 Mb deletion at 19p13.3. This deletion encompasses at least 47 genes, including STK11. This is the first report on 19p13.3 deletion associated with a PJS phenotype, as well as other atypical manifestations, thereby implying a new contiguous gene syndrome. PMID- 22215958 TI - Cytogenetic analysis of five Hypostomus species (Siluriformes, Loricariidae). AB - In this work, we analyzed the karyotypes of five Hypostomus species. Hypostomus cf. heraldoi, from the Mogi-Guacu River, had 2n = 72 chromosomes, with a nucleolar organizer region (NOR) in one chromosomal pair. Hypostomus regani, from the Mogi-Guacu River had 2n = 72 chromosomes with NORs in two chromosomal pairs. Hypostomus sp., from the Mogi-Guacu River basin, had 2n = 68 chromosomes, with NORs in two chromosomal pairs. Hypostomus aff. agna, from Cavalo Stream, had 2n = 74 chromosomes with NORs in two chromosomal pairs. Hypostomus cf. topavae, from Carrapato Stream, had 2n = 80 chromosomes, with NORs in two chromosomal pairs. Hypostomus species showed marked diversity in the karyotypic formula, which suggested the occurrence of several Robertsonian rearrangements and pericentric inversions during the evolutionary history of this genus. This hypothesis was supported by the occurrence of a large number of uniarmed chromosomes and multiple NORs in a terminal position in most species and may be a derived condition in the Loricariidae. PMID- 22215959 TI - Relative contribution of effects included in contemporary groups for adjusted and actual 120-day and 210-day weights in Nelore cattle in Brazil. AB - The objective of this research was to estimate the relative magnitude of effects included in contemporary groups (CG) and their interactions with adjusted and actual 120 d and 210 d weights in 72,731 male and female Nelore calves born from 1985 to 2005 in 40 herds from PMGRN (Genetic Improvement Program of Nelore). Ten models with different CG structures were compared. The analyses were done using the general linear models (GLM) procedure run in SAS software. All of the effects included in the CG for each model were significant (p < 0.001) for the four traits analyzed. Inclusion of semester or trimester of birth as part of a CG was more appropriate than its use as an independent effect in the model because it accounted for interactions with the other effects in the CG. Calf sex (CS) and dam age at calving (DAC) had similar effects across the models, which suggested independence from other effects in these models. The corresponding age deviation effect had a larger impact on actual weight at 120 d than any other effect in all of the models tested. The use of actual weights in models with no CS effect in CG provides an alternative that would allow better genetic connectedness among CGs and greater accuracy in genetic evaluations. PMID- 22215960 TI - Zero-inflated Poisson regression models for QTL mapping applied to tick resistance in a Gyr * Holstein F2 population. AB - Now a days, an important and interesting alternative in the control of tick infestation in cattle is to select resistant animals, and identify the respective quantitative trait loci (QTLs) and DNA markers, for posterior use in breeding programs. The number of ticks/animal is characterized as a discrete-counting trait, which could potentially follow Poisson distribution. However, in the case of an excess of zeros, due to the occurrence of several noninfected animals, zero inflated Poisson and generalized zero-inflated distribution (GZIP) may provide a better description of the data. Thus, the objective here was to compare through simulation, Poisson and ZIP models (simple and generalized) with classical approaches, for QTL mapping with counting phenotypes under different scenarios, and to apply these approaches to a QTL study of tick resistance in an F2 cattle (Gyr * Holstein) population. It was concluded that, when working with zero inflated data, it is recommendable to use the generalized and simple ZIP model for analysis. On the other hand, when working with data with zeros, but not zero inflated, the Poisson model or a data-transformation-approach, such as square root or Box-Cox transformation, are applicable. PMID- 22215961 TI - Chromosomal localization of the 18S-28S and 5S rRNA genes and (TTAGGG)n sequences of butterfly lizards (Leiolepis belliana belliana and Leiolepis boehmei, Agamidae, Squamata). AB - Chromosomal mapping of the butterfly lizards Leiolepis belliana belliana and L. boehmei was done using the 18S-28S and 5S rRNA genes and telomeric (TTAGGG)n sequences. The karyotype of L. b. belliana was 2n = 36, whereas that of L. boehmei was 2n = 34. The 18S-28S rRNA genes were located at the secondary constriction of the long arm of chromosome 1, while the 5S rRNA genes were found in the pericentromeric region of chromosome 6 in both species. Hybridization signals for the (TTAGGG)n sequence were observed at the telomeric ends of all chromosomes, as well as interstitially at the same position as the 18S-28S rRNA genes in L. boehmei. This finding suggests that in L. boehmei telomere-to telomere fusion probably occurred between chromosome 1 and a microchromosome where the 18S-28S rRNA genes were located or, alternatively, at the secondary constriction of chromosome 1. The absence of telomeric sequence signals in chromosome 1 of L. b. belliana suggested that its chromosomes may have only a few copies of the (TTAGGG)n sequence or that there may have been a gradual loss of the repeat sequences during chromosomal evolution. PMID- 22215962 TI - Comparative analysis of human and bovine protein kinases reveals unique relationship and functional diversity. AB - Reversible protein phosphorylation by protein kinases and phosphatases is a common event in various cellular processes. The eukaryotic protein kinase superfamily, which is one of the largest superfamilies of eukaryotic proteins, plays several roles in cell signaling and diseases. We identified 482 eukaryotic protein kinases and 39 atypical protein kinases in the bovine genome, by searching publicly accessible genetic-sequence databases. Bovines have 512 putative protein kinases, each orthologous to a human kinase. Whereas orthologous kinase pairs are, on an average, 90.6% identical, orthologous kinase catalytic domain pairs are, on an average, 95.9% identical at the amino acid level. This bioinformatic study of bovine protein kinases provides a suitable framework for further characterization of their functional and structural properties. PMID- 22215963 TI - Characterization of PRLR and PPARGC1A genes in buffalo (Bubalus bubalis). AB - More than 40 million households in India depend at least partially on livestock production. Buffaloes are one of the major milk producers in India. The prolactin receptor (PRLR) gene and peroxisome proliferators activated receptor-gamma coactivator 1-alpha (PPARGC1A) gene are reportedly associated with milk protein and milk fat yields in Bos taurus. In this study, we sequenced the PRLR and PPARGC1A genes in the water buffalo Bubalus bubalis. The PRLR and PPARGC1A genes coded for 581 and 819 amino acids, respectively. The B. bubalis PRLR gene differed from the corresponding Bos taurus at 21 positions and four differences with an additional arginine at position 620 in the PPARGC1A gene were found in the amino acid sequence. All of the changes were confirmed by cDNA sequencing. Twelve buffalo-specific single nucleotide polymorphisms (SNPs) were identified in both genes, with five of them being non-synonymous. PMID- 22215964 TI - Genetic diversity analysis of common beans based on molecular markers. AB - A core collection of the common bean (Phaseolus vulgaris L.), representing genetic diversity in the entire Mexican holding, is kept at the INIFAP (Instituto Nacional de Investigaciones Forestales, Agricolas y Pecuarias, Mexico) Germplasm Bank. After evaluation, the genetic structure of this collection (200 accessions) was compared with that of landraces from the states of Oaxaca, Chiapas and Veracruz (10 genotypes from each), as well as a further 10 cultivars, by means of four amplified fragment length polymorphisms (AFLP) +3/+3 primer combinations and seven simple sequence repeats (SSR) loci, in order to define genetic diversity, variability and mutual relationships. Data underwent cluster (UPGMA) and molecular variance (AMOVA) analyses. AFLP analysis produced 530 bands (88.5% polymorphic) while SSR primers amplified 174 alleles, all polymorphic (8.2 alleles per locus). AFLP indicated that the highest genetic diversity was to be found in ten commercial-seed classes from two major groups of accessions from Central Mexico and Chiapas, which seems to be an important center of diversity in the south. A third group included genotypes from Nueva Granada, Mesoamerica, Jalisco and Durango races. Here, SSR analysis indicated a reduced number of shared haplotypes among accessions, whereas the highest genetic components of AMOVA variation were found within accessions. Genetic diversity observed in the common-bean core collection represents an important sample of the total Phaseolus genetic variability at the main Germplasm Bank of INIFAP. Molecular marker strategies could contribute to a better understanding of the genetic structure of the core collection as well as to its improvement and validation. PMID- 22215965 TI - Nucleotide diversity and molecular evolution of the WAG-2 gene in common wheat (Triticum aestivum L) and its relatives. AB - In this work, we examined the genetic diversity and evolution of the WAG-2 gene based on new WAG-2 alleles isolated from wheat and its relatives. Only single nucleotide polymorphisms (SNP) and no insertions and deletions (indels) were found in exon sequences of WAG-2 from different species. More SNPs and indels occurred in introns than in exons. For exons, exons+introns and introns, the nucleotide polymorphism pi decreased from diploid and tetraploid genotypes to hexaploid genotypes. This finding indicated that the diversity of WAG-2 in diploids was greater than in hexaploids because of the strong selection pressure on the latter. All dn/ds ratios were < 1.0, indicating that WAG-2 belongs to a conserved gene affected by negative selection. Thirty-nine of the 57 particular SNPs and eight of the 10 indels were detected in diploid species. The degree of divergence in intron length among WAG-2 clones and phylogenetic tree topology suggested the existence of three homoeologs in the A, B or D genome of common wheat. Wheat AG-like genes were divided into WAG-1 and WAG-2 clades. The latter clade contained WAG-2, OsMADS3 and ZMM2 genes, indicating functional homoeology among them. PMID- 22215966 TI - Combining ability of summer-squash lines with different degrees of parthenocarpy and PRSV-W resistance. AB - The aim was to assess heterosis in a set of 16 summer-squash hybrids, and evaluate the combining capacity of the respective parental lines, which differed as to the degree of parthenocarpy and resistance to PRSV-W (Papaya Ringspot Virus Watermelon strain). The hybrids were obtained using a partial diallel cross design (4 * 4). The lines of parental group I were 1 = ABX-037G-77-03-05-01-01 bulk, 2 = ABX-037G-77-03-05-03-10-bulk, 3 = ABX-037G-77-03-05-01-04-bulk and 4 = ABX-037G-77-03-05-05-01-bulk, and of group II, 1' = ABX-037G-77-03-05-04-08-bulk, 2' = ABX-037G-77-03-05-02-11-bulk, 3' = Clarice and 4' = Caserta. The 16 hybrids and eight parental lines were evaluated for PRSV-W resistance, parthenocarpic expression and yield in randomized complete-block designs, with three replications. Parthenocarpy and the resistance to PRSV-W were rated by means of a scale from 1 to 5, where 1 = non-parthenocarpic or high resistance to PRSV-W, and 5 = parthenocarpic or high susceptibility to PRSV-W. Both additive and non additive gene effects were important in the expression of parthenocarpy and resistance to PRSV-W. Whereas estimates of heterosis in parthenocarpy usually tended towards a higher degree, resistance to PRSV-W was towards higher susceptibility. At least one F(1) hybrid was identified with a satisfactory degree of parthenocarpy, resistance to PRSV-W and high fruit-yield. PMID- 22215967 TI - Genome-wide identification and phylogenetic analysis of the ERF gene family in cucumbers. AB - Members of the ERF transcription-factor family participate in a number of biological processes, viz., responses to hormones, adaptation to biotic and abiotic stress, metabolism regulation, beneficial symbiotic interactions, cell differentiation and developmental processes. So far, no tissue-expression profile of any cucumber ERF protein has been reported in detail. Recent completion of the cucumber full-genome sequence has come to facilitate, not only genome-wide analysis of ERF family members in cucumbers themselves, but also a comparative analysis with those in Arabidopsis and rice. In this study, 103 hypothetical ERF family genes in the cucumber genome were identified, phylogenetic analysis indicating their classification into 10 groups, designated I to X. Motif analysis further indicated that most of the conserved motifs outside the AP2/ERF domain, are selectively distributed among the specific clades in the phylogenetic tree. From chromosomal localization and genome distribution analysis, it appears that tandem-duplication may have contributed to CsERF gene expansion. Intron/exon structure analysis indicated that a few CsERFs still conserved the former intron position patterns existent in the common ancestor of monocots and eudicots. Expression analysis revealed the widespread distribution of the cucumber ERF gene family within plant tissues, thereby implying the probability of their performing various roles therein. Furthermore, members of some groups presented mutually similar expression patterns that might be related to their phylogenetic groups. PMID- 22215968 TI - Transgenic plants of Petunia hybrida harboring the CYP2E1 gene efficiently remove benzene and toluene pollutants and improve resistance to formaldehyde. AB - The CYP2E1 protein belongs to the P450 enzymes family and plays an important role in the metabolism of small molecular and organic pollutants. In this study we generated CYP2E1 transgenic plants of Petunia using Agrobacterium rhizogenes K599. PCR analysis confirmed that the regenerated plants contained the CYP2E1 transgene and the rolB gene of the Ri plasmid. Southern blotting revealed the presence of multiple copies of CYP2E1 in the genome of transgenic plants. Fluorescent quantitative PCR revealed exogenous CYP2E1 gene expression in CYP2E1 transgenic plants at various levels, whereas no like expression was detected in either GUS transgenic plants or wild-types. The absorption of benzene and toluene by transgenic plants was analyzed through quantitative gas chromatography. Transgenic plants with high CYP2E1 expression showed a significant increase in absorption capacity of environmental benzene and toluene, compared to control GUS transgenic and wild type plants. Furthermore, these plants also presented obvious improved resistance to formaldehyde. This study, besides being the first to reveal that the CYP2E1 gene enhances plant resistance to formaldehyde, also furnishes a new method for reducing pollutants, such as benzene, toluene and formaldehyde, by using transgenic flowering horticultural plants. PMID- 22215969 TI - Expressed sequence tag analysis of khat (Catha edulis) provides a putative molecular biochemical basis for the biosynthesis of phenylpropylamino alkaloids. AB - Khat (Catha edulis Forsk.) is a flowering perennial shrub cultivated for its neurostimulant properties resulting mainly from the occurrence of (S)-cathinone in young leaves. The biosynthesis of (S)-cathinone and the related phenylpropylamino alkaloids (1S,2S)-cathine and (1R,2S)-norephedrine is not well characterized in plants. We prepared a cDNA library from young khat leaves and sequenced 4,896 random clones, generating an expressed sequence tag (EST) library of 3,293 unigenes. Putative functions were assigned to > 98% of the ESTs, providing a key resource for gene discovery. Candidates potentially involved at various stages of phenylpropylamino alkaloid biosynthesis from L-phenylalanine to (1S,2S)-cathine were identified. PMID- 22215970 TI - Positive selection, molecular recombination structure and phylogenetic reconstruction of members of the family Tombusviridae: Implication in virus taxonomy. AB - A detailed study of putative recombination events and their evolution frequency in the whole genome of the currently known members of the family Tombusviridae, comprising 79 accessions retrieved from the international databases, was carried out by using the RECCO and RDP version 3.31beta algorithms. The first program allowed the detection of potential recombination sites in seven out of eight virus genera (Aureusvirus, Avenavirus, Carmovirus, Dianthovirus, Necrovirus, Panicovirus, and Tombusvirus), the second program provided the same results except for genus Dianthovirus. On the other hand, both methods failed to detect recombination breakpoints in the genome of members of genus Machlomovirus. Furthermore, based on Fisher's Exact Test of Neutrality, positive selection exerted on protein-coding genes was detected in 17 accession pairs involving 15 different lineages. Except genera Machlomovirus, and Panicovirus along with unclassified Tombusviridae, all the other taxonomical genera and the unassigned Tombusviridae encompassed representatives under positive selection. The evolutionary history of all members of the Tombusviridae family showed that they segregated into eight distinct groups corresponding to the eight genera which constitute this family. The inferred phylogeny reshuffled the classification currently adopted by the International Committee on Taxonomy of Viruses. A reclassification was proposed. PMID- 22215971 TI - Optimizing expression and purification of an ATP-binding gene gsiA from Escherichia coli k-12 by using GFP fusion. AB - The cloning, expression and purification of the glutathione (sulfur) import system ATP-binding protein (gsiA) was carried out. The coding sequence of Escherichia coli gsiA, which encodes the ATP-binding protein of a glutathione importer, was amplified by PCR, and then inserted into a prokaryotic expression vector pWaldo-GFPe harboring green fluorescent protein (GFP) reporter gene. The resulting recombinant plasmid pWaldo-GFP-GsiA was transformed into various E. coli strains, and expression conditions were optimized. The effect of five E. coli expression strains on the production of the recombinant gsiA protein was evaluated. E. coli BL21 (DE3) was found to be the most productive strain for GsiA GFP fusion-protein expression, most of which was insoluble fraction. However, results from in-gel and Western blot analysis suggested that expression of recombinant GsiA in Rosetta (DE3) provides an efficient source in soluble form. By using GFP as reporter, the most suitable host strain was conveniently obtained, whereby optimizing conditions for overexpression and purification of the proteins for further functional and structural studies, became, not only less laborious, but also time-saving. PMID- 22215972 TI - Fusion of the subunits alpha and beta of succinyl-CoA synthetase as a phylogenetic marker for Pezizomycotina fungi. AB - Gene fusions, yielding the formation of multidomain proteins, are evolutionary events that can be utilized as phylogenetic markers. Here we describe a fusion gene comprising the alpha and beta subunits of succinyl-coA synthetase, an enzyme of the TCA cycle, in Pezizomycotina fungi. This fusion is present in all Pezizomycotina with complete genome sequences and absent from all other organisms. Phylogenetic analysis of the alpha and beta subunits of succinyl-CoA synthetase suggests that both subunits were duplicated and retained in Pezizomycotina while one copy was lost from other fungi. One of the duplicated copies was then fused in Pezizomycotina. Our results suggest that the fusion of the alpha and beta subunits of succinyl-CoA synthetase can be used as a molecular marker for membership in the Pezizomycotina subphylum. If a species has the fusion it can be reliably classified as Pezizomycotina, while the absence of the fusion is suggestive that the species is not a member of this subphylum. PMID- 22215973 TI - Isolation of endophytic bacteria from arboreal species of the Amazon and identification by sequencing of the 16S rRNA encoding gene. AB - Endophytic bacteria from three arboreal species native to the Amazon (Carapa guianenses, Ceiba pentandra, and Swietenia macrophylla), were isolated and identified, through partial sequencing of the 16S rRNA encoding gene. From these, 16 isolates were obtained, although, when compared to sequences deposited in GenBank, only seven had produced identifiable fragments. Bacillus, Pantoea and two non-culturable samples were identified. Results obtained through sequence analysis revealed low genetic diversity across the isolates, even when analyzing different species and plant structures. This is the first report concerning the isolation and identification of endophytic bacteria in these plant species. PMID- 22215975 TI - Genotoxicity biomonitoring of sewage in two municipal wastewater treatment plants using the Tradescantia pallida var. purpurea bioassay. AB - The genotoxicity of untreated and treated sewage from two municipal wastewater treatment plants (WTP BN and WTP SJN) in the municipality of Porto Alegre, in the southern Brazilian state of Rio Grande do Sul, was evaluated over a one-year period using the Tradescantia pallida var. purpurea (Trad-MCN) bioassay. Inflorescences of T. pallida var. purpurea were exposed to sewage samples in February (summer), April (autumn), July (winter) and October (spring) 2009, and the micronuclei (MCN) frequencies were estimated in each period. The high genotoxicity of untreated sewage from WTP BN in February and April was not observed in treated sewage, indicating the efficiency of treatment at this WTP. However, untreated and treated sewage samples from WTP SJN had high MCN frequencies, except in October, when rainfall may have been responsible for reducing these frequencies at both WTPs. Physicochemical analyses of sewage from both WTPs indicated elevated concentrations of organic matter that were higher at WTP SJN than at WTP BN. Chromium was detected in untreated and treated sewage from WTP SJN, but not in treated sewage from WTP BN. Lead was found in all untreated sewage samples from WTP SJN, but only in the summer and autumn at WTP BN. These results indicate that the short-term Trad-MCN genotoxicity assay may be useful for regular monitoring of municipal WTPs. PMID- 22215974 TI - Estimates of DNA damage by the comet assay in the direct-developing frog Eleutherodactylus johnstonei (Anura, Eleutherodactylidae). AB - The aim of this study was to use the Comet assay to assess genetic damage in the direct-developing frog Eleutherodactylus johnstonei. A DNA diffusion assay was used to evaluate the effectiveness of alkaline, enzymatic and alkaline/enzymatic treatments for lysing E. johnstonei blood cells and to determine the amount of DNA strand breakage associated with apoptosis and necrosis. Cell sensitivity to the mutagens bleomycin (BLM) and 4-nitro-quinoline-1-oxide (4NQO) was also assessed using the Comet assay, as was the assay reproducibility. Alkaline treatment did not lyse the cytoplasmic and nuclear membranes of E. johnstonei blood cells, whereas enzymatic digestion with proteinase K (40 MUg/mL) yielded naked nuclei. The contribution of apoptosis and necrosis (assessed by the DNA diffusion assay) to DNA damage was estimated to range from 0% to 8%. BLM and 4NQO induced DNA damage in E. johnstonei blood cells at different concentrations and exposure times. Dose-effect curves with both mutagens were highly reproducible and showed consistently low coefficients of variation (CV <= 10%). The results are discussed with regard to the potential use of the modified Comet assay for assessing the exposure of E. johnstonei to herbicides in ecotoxicological studies. PMID- 22215976 TI - Studies of micronuclei and other nuclear abnormalities in red blood cells of Colossoma macropomum exposed to methylmercury. AB - The frequencies of micronuclei (MN) and morphological nuclear abnormalities (NA) in erythrocytes in the peripheral blood of tambaqui (Colossoma macropomum), treated with 2 mg.L(-1) methylmercury (MeHg), were analyzed. Two groups (nine specimens in each) were exposed to MeHg for different periods (group A - 24 h; group B - 120 h). A third group served as negative control (group C, untreated; n = 9). Although, when compared to the control group there were no significant differences in MN frequency in the treated groups, for NA, the differences between the frequencies of group B (treated for 120 h) and the control group were extremely significant (p < 0.02), thus demonstrating the potentially adverse effects of MeHg on C. macropomum erythrocytes after prolonged exposure. PMID- 22215977 TI - Transcript levels of ten caste-related genes in adult diploid males of Melipona quadrifasciata (Hymenoptera, Apidae) - A comparison with haploid males, queens and workers. AB - In Hymenoptera, homozygosity at the sex locus results in the production of diploid males. In social species, these pose a double burden by having low fitness and drawing resources normally spent for increasing the work force of a colony. Yet, diploid males are of academic interest as they can elucidate effects of ploidy (normal males are haploid, whereas the female castes, the queens and workers, are diploid) on morphology and life history. Herein we investigated expression levels of ten caste-related genes in the stingless bee Melipona quadrifasciata, comparing newly emerged and 5-day-old diploid males with haploid males, queens and workers. In diploid males, transcript levels for dunce and paramyosin were increased during the first five days of adult life, while those for diacylglycerol kinase and the transcriptional co-repressor groucho diminished. Two general trends were apparent, (i) gene expression patterns in diploid males were overall more similar to haploid ones and workers than to queens, and (ii) in queens and workers, more genes were up-regulated after emergence until day five, whereas in diploid and especially so in haploid males more genes were down-regulated. This difference between the sexes may be related to longevity, which is much longer in females than in males. PMID- 22215978 TI - Spatiotemporal transcription of the P element and the 412 retrotransposon during embryogenesis of Drosophila melanogaster and D. willistoni. AB - Transposable elements (TEs) are mobile nucleotide sequences which, through changing position in host genomes, partake in important evolutionary processes. The expression patterns of two TEs, P element transposon and 412 retrotransposon, were investigated during Drosophila melanogaster and D. willistoni embryogenesis, by means of embryo hybridization using riboprobes. Spatiotemporal transcription patterns for both TEs were similar to those of developmental genes. Although the two species shared the same P element transcription pattern, this was not so with 412 retrotransposon. These findings suggest that the regulatory sequences involved in the initial development of Drosophila spp are located in the transposable element sequences, and differences, such as in this case of the 412 retrotransposon, lead to losses or changes in their transcription patterns. PMID- 22215979 TI - Genetic diversity and population structure of the Guinea pig (Cavia porcellus, Rodentia, Caviidae) in Colombia. AB - The aim was to establish the genetic diversity and population structure of three guinea pig lines, from seven production zones located in Narino, southwest Colombia. A total of 384 individuals were genotyped with six microsatellite markers. The measurement of intrapopulation diversity revealed allelic richness ranging from 3.0 to 6.56, and observed heterozygosity (Ho) from 0.33 to 0.60, with a deficit in heterozygous individuals. Although statistically significant (p < 0.05), genetic differentiation between population pairs was found to be low. Genetic distance, as well as clustering of guinea-pig lines and populations, coincided with the historical and geographical distribution of the populations. Likewise, high genetic identity between improved and native lines was established. An analysis of group probabilistic assignment revealed that each line should not be considered as a genetically homogeneous group. The findings corroborate the absorption of native genetic material into the improved line introduced into Colombia from Peru. It is necessary to establish conservation programs for native-line individuals in Narino, and control genealogical and production records in order to reduce the inbreeding values in the populations. PMID- 22215980 TI - Exploitation of mitochondrial nad6 as a complementary marker for studying population variability in Lepidoptera. AB - The applicability of mitochondrial nad6 sequences to studies of DNA and population variability in Lepidoptera was tested in four species of economically important moths and one of wild butterflies. The genetic information so obtained was compared to that of cox1 sequences for two species of Lepidoptera. nad6 primers appropriately amplified all the tested DNA targets, the generated data proving to be as informative and suitable in recovering population structures as that of cox1. The proposal is that, to obtain more robust results, this mitochondrial region can be complementarily used with other molecular sequences in studies of low level phylogeny and population genetics in Lepidoptera. PMID- 22215981 TI - Molecular cloning and characterization of Ecdysone oxidase and 3-dehydroecdysone 3alpha-reductase involved in the ecdysone inactivation pathway of silkworm, Bombyx mori. AB - Molting hormone (ecdysteroid) is one of the most important hormones in insects. The synthesis and inactivation of the ecdysteroid regulate the developmental process of insects. A major pathway of ecdysone inactivation is that ecdysone is converted to 3-dehydroecdysone, and then further to 3-epiecdysone in insects. Two enzymes (ecdysone oxidase: EO and 3DE-3alpha-reductase) participate in this pathway. In this study, based on the previously characterized cDNAs in Spodoptera littoralis, we cloned and characterized EO and 3DE-3alpha-reductase genes in the silkworm, Bombyx mori. The heterologously expressed proteins of the two genes in yeast showed the ecdysone oxidase and 3DE-3alpha-reductase activities, respectively. Expression of BmEO was only detected in the midgut at transcriptional and translational levels. We also localized EO within the midgut goblet cell cavities. For Bm3DE-3alpha-reductase gene, RT-PCR and western blot showed that it was expressed in the midgut and the Malpighian tubules. Moreover, we localized 3DE-3alpha-reductase within the midgut goblet cell cavities and the cytosol of principal cells of the Malpighian tubules. These two genes have similar expression profiles during different developmental stages. Both genes were highly expressed at the beginning of the 5th instar, and remained a relative low level during the feeding stage, and then were highly expressed at the wandering stage. All these results showed that the profiles of the two genes were well correlated with the ecdysteroid titer. The functional characterization of the enzymes participating in ecdysone inactivation in the silkworm provides hints for the artificial regulation of the silkworm development and biological control of pests. PMID- 22215982 TI - Specific contributions of ventromedial, anterior cingulate, and lateral prefrontal cortex for attentional selection and stimulus valuation. AB - Attentional control ensures that neuronal processes prioritize the most relevant stimulus in a given environment. Controlling which stimulus is attended thus originates from neurons encoding the relevance of stimuli, i.e. their expected value, in hand with neurons encoding contextual information about stimulus locations, features, and rules that guide the conditional allocation of attention. Here, we examined how these distinct processes are encoded and integrated in macaque prefrontal cortex (PFC) by mapping their functional topographies at the time of attentional stimulus selection. We find confined clusters of neurons in ventromedial PFC (vmPFC) that predominantly convey stimulus valuation information during attention shifts. These valuation signals were topographically largely separated from neurons predicting the stimulus location to which attention covertly shifted, and which were evident across the complete medial-to-lateral extent of the PFC, encompassing anterior cingulate cortex (ACC), and lateral PFC (LPFC). LPFC responses showed particularly early onset selectivity and primarily facilitated attention shifts to contralateral targets. Spatial selectivity within ACC was delayed and heterogeneous, with similar proportions of facilitated and suppressed responses during contralateral attention shifts. The integration of spatial and valuation signals about attentional target stimuli was observed in a confined cluster of neurons at the intersection of vmPFC, ACC, and LPFC. These results suggest that valuation processes reflecting stimulus-specific outcome predictions are recruited during covert attentional control. Value predictions and the spatial identification of attentional targets were conveyed by largely separate neuronal populations, but were integrated locally at the intersection of three major prefrontal areas, which may constitute a functional hub within the larger attentional control network. PMID- 22215983 TI - Mitotic spindle assembly around RCC1-coated beads in Xenopus egg extracts. AB - During cell division the genetic material on chromosomes is distributed to daughter cells by a dynamic microtubule structure called the mitotic spindle. Here we establish a reconstitution system to assess the contribution of individual chromosome proteins to mitotic spindle formation around single 10 um diameter porous glass beads in Xenopus egg extracts. We find that Regulator of Chromosome Condensation 1 (RCC1), the Guanine Nucleotide Exchange Factor (GEF) for the small GTPase Ran, can induce bipolar spindle formation. Remarkably, RCC1 beads oscillate within spindles from pole to pole, a behavior that could be converted to a more typical, stable association by the addition of a kinesin together with RCC1. These results identify two activities sufficient to mimic chromatin-mediated spindle assembly, and establish a foundation for future experiments to reconstitute spindle assembly entirely from purified components. PMID- 22215985 TI - How the brain homes in on valuable objects. PMID- 22215986 TI - Violent crime, epilepsy, and traumatic brain injury. PMID- 22215984 TI - Structural basis of response regulator inhibition by a bacterial anti-activator protein. AB - The complex interplay between the response regulator ComA, the anti-activator RapF, and the signaling peptide PhrF controls competence development in Bacillus subtilis. More specifically, ComA drives the expression of genetic competence genes, while RapF inhibits the interaction of ComA with its target promoters. The signaling peptide PhrF accumulates at high cell density and upregulates genetic competence by antagonizing the interaction of RapF and ComA. How RapF functions mechanistically to inhibit ComA activity and how PhrF in turn antagonizes the RapF-ComA interaction were unknown. Here we present the X-ray crystal structure of RapF in complex with the ComA DNA binding domain. Along with biochemical and genetic studies, the X-ray crystal structure reveals how RapF mechanistically regulates ComA function. Interestingly, we found that a RapF surface mimics DNA to block ComA binding to its target promoters. Furthermore, RapF is a monomer either alone or in complex with PhrF, and it undergoes a conformational change upon binding to PhrF, which likely causes the dissociation of ComA from the RapF ComA complex. Finally, we compare the structure of RapF complexed with the ComA DNA binding domain and the structure of RapH complexed with Spo0F. This comparison reveals that RapF and RapH have strikingly similar overall structures, and that they have evolved different, non-overlapping surfaces to interact with diverse cellular targets. To our knowledge, the data presented here reveal the first atomic level insight into the inhibition of response regulator DNA binding by an anti-activator. Compounds that affect the interaction of Rap and Rap-like proteins with their target domains could serve to regulate medically and commercially important phenotypes in numerous Bacillus species, such as sporulation in B. anthracis and sporulation and the production of Cry protein endotoxin in B. thuringiensis. PMID- 22215987 TI - Disclosure of investigators' recruitment performance in multicenter clinical trials: a further step for research transparency. AB - Rafael Dal-Re and colleagues argue that the recruitment targets and performance of all site investigators in multi-centre clinical trials should be disclosed in trial registration sites before a trial starts, and when it ends. PMID- 22215988 TI - Risk of violent crime in individuals with epilepsy and traumatic brain injury: a 35-year Swedish population study. AB - BACKGROUND: Epilepsy and traumatic brain injury are common neurological conditions, with general population prevalence estimates around 0.5% and 0.3%, respectively. Although both illnesses are associated with various adverse outcomes, and expert opinion has suggested increased criminality, links with violent behaviour remain uncertain. METHODS AND FINDINGS: We combined Swedish population registers from 1973 to 2009, and examined associations of epilepsy (n = 22,947) and traumatic brain injury (n = 22,914) with subsequent violent crime (defined as convictions for homicide, assault, robbery, arson, any sexual offense, or illegal threats or intimidation). Each case was age and gender matched with ten general population controls, and analysed using conditional logistic regression with adjustment for socio-demographic factors. In addition, we compared cases with unaffected siblings. Among the traumatic brain injury cases, 2,011 individuals (8.8%) committed violent crime after diagnosis, which, compared with population controls (n = 229,118), corresponded to a substantially increased risk (adjusted odds ratio [aOR] = 3.3, 95% CI: 3.1-3.5); this risk was attenuated when cases were compared with unaffected siblings (aOR = 2.0, 1.8 2.3). Among individuals with epilepsy, 973 (4.2%) committed a violent offense after diagnosis, corresponding to a significantly increased odds of violent crime compared with 224,006 population controls (aOR = 1.5, 1.4-1.7). However, this association disappeared when individuals with epilepsy were compared with their unaffected siblings (aOR = 1.1, 0.9-1.2). We found heterogeneity in violence risk by age of disease onset, severity, comorbidity with substance abuse, and clinical subgroups. Case ascertainment was restricted to patient registers. CONCLUSIONS: In this longitudinal population-based study, we found that, after adjustment for familial confounding, epilepsy was not associated with increased risk of violent crime, questioning expert opinion that has suggested a causal relationship. In contrast, although there was some attenuation in risk estimates after adjustment for familial factors and substance abuse in individuals with traumatic brain injury, we found a significantly increased risk of violent crime. The implications of these findings will vary for clinical services, the criminal justice system, and patient charities. PMID- 22215989 TI - Cognitive performance in late adolescence and the subsequent risk of subdural hematoma: an observational study of a prospective nationwide cohort. AB - BACKGROUND: There are few identified risk factors for traumatic brain injuries such as subdural hematoma (SDH). The aim of the present study was to investigate whether low cognitive performance in young adulthood is associated with SDH later in life. A second aim was to investigate whether this risk factor was associated with education and physical fitness. METHODS AND FINDINGS: Word recollection, logical, visuospatial, and technical performances were tested at a mean age of 18.5 years in a prospective nation-wide cohort of 440,742 men. An estimate of global intelligence was calculated from these four tests. Associations between cognitive performance, education, physical fitness, and SDH during follow-up were explored using Cox regression analyses. During a median follow-up of 35 years, 863 SDHs were diagnosed in the cohort. Low global intelligence was associated with an increased risk of SDH during follow-up (hazard ratio [HR]: 1.33, per standard deviation decrease, 95% CI = 1.25-1.43). Similar results were obtained for the other measures of cognitive performance (HR: 1.24-1.33, p<0.001 for all). In contrast, a high education (HR: 0.27, comparing more than 2 years of high school and 8 years of elementary school, 95% CI = 0.19-0.39), and a high level of physical fitness (HR: 0.76, per standard deviation increase, 95% CI = 0.70-0.83), was associated with a decreased risk of suffering from a SDH. CONCLUSIONS: The present findings suggest that reduced cognitive function in young adulthood is strongly associated with an increased risk of SDH later in life. In contrast, a higher level of education and a higher physical fitness were associated with a decreased risk of SDH. PMID- 22215990 TI - Poor diet in shift workers: a new occupational health hazard? AB - The PLoS Medicine Editors discuss the link between shift work, diet, and type 2 diabetes, and argue that unhealthy eating should be considered a new form of occupational hazard. PMID- 22215991 TI - Robust signal processing in living cells. AB - Cellular signaling networks have evolved an astonishing ability to function reliably and with high fidelity in uncertain environments. A crucial prerequisite for the high precision exhibited by many signaling circuits is their ability to keep the concentrations of active signaling compounds within tightly defined bounds, despite strong stochastic fluctuations in copy numbers and other detrimental influences. Based on a simple mathematical formalism, we identify topological organizing principles that facilitate such robust control of intracellular concentrations in the face of multifarious perturbations. Our framework allows us to judge whether a multiple-input-multiple-output reaction network is robust against large perturbations of network parameters and enables the predictive design of perfectly robust synthetic network architectures. Utilizing the Escherichia coli chemotaxis pathway as a hallmark example, we provide experimental evidence that our framework indeed allows us to unravel the topological organization of robust signaling. We demonstrate that the specific organization of the pathway allows the system to maintain global concentration robustness of the diffusible response regulator CheY with respect to several dominant perturbations. Our framework provides a counterpoint to the hypothesis that cellular function relies on an extensive machinery to fine-tune or control intracellular parameters. Rather, we suggest that for a large class of perturbations, there exists an appropriate topology that renders the network output invariant to the respective perturbations. PMID- 22215993 TI - Systematic search for recipes to generate induced pluripotent stem cells. AB - Generation of induced pluripotent stem cells (iPSCs) opens a new avenue in regenerative medicine. One of the major hurdles for therapeutic applications is to improve the efficiency of generating iPSCs and also to avoid the tumorigenicity, which requires searching for new reprogramming recipes. We present a systems biology approach to efficiently evaluate a large number of possible recipes and find those that are most effective at generating iPSCs. We not only recovered several experimentally confirmed recipes but we also suggested new ones that may improve reprogramming efficiency and quality. In addition, our approach allows one to estimate the cell-state landscape, monitor the progress of reprogramming, identify important regulatory transition states, and ultimately understand the mechanisms of iPSC generation. PMID- 22215992 TI - Modeling brain resonance phenomena using a neural mass model. AB - Stimulation with rhythmic light flicker (photic driving) plays an important role in the diagnosis of schizophrenia, mood disorder, migraine, and epilepsy. In particular, the adjustment of spontaneous brain rhythms to the stimulus frequency (entrainment) is used to assess the functional flexibility of the brain. We aim to gain deeper understanding of the mechanisms underlying this technique and to predict the effects of stimulus frequency and intensity. For this purpose, a modified Jansen and Rit neural mass model (NMM) of a cortical circuit is used. This mean field model has been designed to strike a balance between mathematical simplicity and biological plausibility. We reproduced the entrainment phenomenon observed in EEG during a photic driving experiment. More generally, we demonstrate that such a single area model can already yield very complex dynamics, including chaos, for biologically plausible parameter ranges. We chart the entire parameter space by means of characteristic Lyapunov spectra and Kaplan Yorke dimension as well as time series and power spectra. Rhythmic and chaotic brain states were found virtually next to each other, such that small parameter changes can give rise to switching from one to another. Strikingly, this characteristic pattern of unpredictability generated by the model was matched to the experimental data with reasonable accuracy. These findings confirm that the NMM is a useful model of brain dynamics during photic driving. In this context, it can be used to study the mechanisms of, for example, perception and epileptic seizure generation. In particular, it enabled us to make predictions regarding the stimulus amplitude in further experiments for improving the entrainment effect. PMID- 22215994 TI - Combinatorial binding in human and mouse embryonic stem cells identifies conserved enhancers active in early embryonic development. AB - Transcription factors are proteins that regulate gene expression by binding to cis-regulatory sequences such as promoters and enhancers. In embryonic stem (ES) cells, binding of the transcription factors OCT4, SOX2 and NANOG is essential to maintain the capacity of the cells to differentiate into any cell type of the developing embryo. It is known that transcription factors interact to regulate gene expression. In this study we show that combinatorial binding is strongly associated with co-localization of the transcriptional co-activator Mediator, H3K27ac and increased expression of nearby genes in embryonic stem cells. We observe that the same loci bound by Oct4, Nanog and Sox2 in ES cells frequently drive expression in early embryonic development. Comparison of mouse and human ES cells shows that less than 5% of individual binding events for OCT4, SOX2 and NANOG are shared between species. In contrast, about 15% of combinatorial binding events and even between 53% and 63% of combinatorial binding events at enhancers active in early development are conserved. Our analysis suggests that the combination of OCT4, SOX2 and NANOG binding is critical for transcription in ES cells and likely plays an important role for embryogenesis by binding at conserved early developmental enhancers. Our data suggests that the fast evolutionary rewiring of regulatory networks mainly affects individual binding events, whereas "gene regulatory hotspots" which are bound by multiple factors and active in multiple tissues throughout early development are under stronger evolutionary constraints. PMID- 22215995 TI - Balanced synaptic input shapes the correlation between neural spike trains. AB - Stimulus properties, attention, and behavioral context influence correlations between the spike times produced by a pair of neurons. However, the biophysical mechanisms that modulate these correlations are poorly understood. With a combined theoretical and experimental approach, we show that the rate of balanced excitatory and inhibitory synaptic input modulates the magnitude and timescale of pairwise spike train correlation. High rate synaptic inputs promote spike time synchrony rather than long timescale spike rate correlations, while low rate synaptic inputs produce opposite results. This correlation shaping is due to a combination of enhanced high frequency input transfer and reduced firing rate gain in the high input rate state compared to the low state. Our study extends neural modulation from single neuron responses to population activity, a necessary step in understanding how the dynamics and processing of neural activity change across distinct brain states. PMID- 22215996 TI - Emergent behaviors from a cellular automaton model for invasive tumor growth in heterogeneous microenvironments. AB - Understanding tumor invasion and metastasis is of crucial importance for both fundamental cancer research and clinical practice. In vitro experiments have established that the invasive growth of malignant tumors is characterized by the dendritic invasive branches composed of chains of tumor cells emanating from the primary tumor mass. The preponderance of previous tumor simulations focused on non-invasive (or proliferative) growth. The formation of the invasive cell chains and their interactions with the primary tumor mass and host microenvironment are not well understood. Here, we present a novel cellular automaton (CA) model that enables one to efficiently simulate invasive tumor growth in a heterogeneous host microenvironment. By taking into account a variety of microscopic-scale tumor host interactions, including the short-range mechanical interactions between tumor cells and tumor stroma, degradation of the extracellular matrix by the invasive cells and oxygen/nutrient gradient driven cell motions, our CA model predicts a rich spectrum of growth dynamics and emergent behaviors of invasive tumors. Besides robustly reproducing the salient features of dendritic invasive growth, such as least-resistance paths of cells and intrabranch homotype attraction, we also predict nontrivial coupling between the growth dynamics of the primary tumor mass and the invasive cells. In addition, we show that the properties of the host microenvironment can significantly affect tumor morphology and growth dynamics, emphasizing the importance of understanding the tumor-host interaction. The capability of our CA model suggests that sophisticated in silico tools could eventually be utilized in clinical situations to predict neoplastic progression and propose individualized optimal treatment strategies. PMID- 22215997 TI - Two birds with one stone? Possible dual-targeting H1N1 inhibitors from traditional Chinese medicine. AB - The H1N1 influenza pandemic of 2009 has claimed over 18,000 lives. During this pandemic, development of drug resistance further complicated efforts to control and treat the widespread illness. This research utilizes traditional Chinese medicine Database@Taiwan (TCM Database@Taiwan) to screen for compounds that simultaneously target H1 and N1 to overcome current difficulties with virus mutations. The top three candidates were de novo derivatives of xylopine and rosmaricine. Bioactivity of the de novo derivatives against N1 were validated by multiple machine learning prediction models. Ability of the de novo compounds to maintain CoMFA/CoMSIA contour and form key interactions implied bioactivity within H1 as well. Addition of a pyridinium fragment was critical to form stable interactions in H1 and N1 as supported by molecular dynamics (MD) simulation. Results from MD, hydrophobic interactions, and torsion angles are consistent and support the findings of docking. Multiple anchors and lack of binding to residues prone to mutation suggest that the TCM de novo derivatives may be resistant to drug resistance and are advantageous over conventional H1N1 treatments such as oseltamivir. These results suggest that the TCM de novo derivatives may be suitable candidates of dual-targeting drugs for influenza. PMID- 22215998 TI - The FGGY carbohydrate kinase family: insights into the evolution of functional specificities. AB - Function diversification in large protein families is a major mechanism driving expansion of cellular networks, providing organisms with new metabolic capabilities and thus adding to their evolutionary success. However, our understanding of the evolutionary mechanisms of functional diversity in such families is very limited, which, among many other reasons, is due to the lack of functionally well-characterized sets of proteins. Here, using the FGGY carbohydrate kinase family as an example, we built a confidently annotated reference set (CARS) of proteins by propagating experimentally verified functional assignments to a limited number of homologous proteins that are supported by their genomic and functional contexts. Then, we analyzed, on both the phylogenetic and the molecular levels, the evolution of different functional specificities in this family. The results show that the different functions (substrate specificities) encoded by FGGY kinases have emerged only once in the evolutionary history following an apparently simple divergent evolutionary model. At the same time, on the molecular level, one isofunctional group (L ribulokinase, AraB) evolved at least two independent solutions that employed distinct specificity-determining residues for the recognition of a same substrate (L-ribulose). Our analysis provides a detailed model of the evolution of the FGGY kinase family. It also shows that only combined molecular and phylogenetic approaches can help reconstruct a full picture of functional diversifications in such diverse families. PMID- 22215999 TI - Genome comparison of human and non-human malaria parasites reveals species subset specific genes potentially linked to human disease. AB - Genes underlying important phenotypic differences between Plasmodium species, the causative agents of malaria, are frequently found in only a subset of species and cluster at dynamically evolving subtelomeric regions of chromosomes. We hypothesized that chromosome-internal regions of Plasmodium genomes harbour additional species subset-specific genes that underlie differences in human pathogenicity, human-to-human transmissibility, and human virulence. We combined sequence similarity searches with synteny block analyses to identify species subset-specific genes in chromosome-internal regions of six published Plasmodium genomes, including Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi, Plasmodium yoelii, Plasmodium berghei, and Plasmodium chabaudi. To improve comparative analysis, we first revised incorrectly annotated gene models using homology-based gene finders and examined putative subset-specific genes within syntenic contexts. Confirmed subset-specific genes were then analyzed for their role in biological pathways and examined for molecular functions using publicly available databases. We identified 16 genes that are well conserved in the three primate parasites but not found in rodent parasites, including three key enzymes of the thiamine (vitamin B1) biosynthesis pathway. Thirteen genes were found to be present in both human parasites but absent in the monkey parasite P. knowlesi, including genes specifically upregulated in sporozoites or gametocytes that could be linked to parasite transmission success between humans. Furthermore, we propose 15 chromosome-internal P. falciparum-specific genes as new candidate genes underlying increased human virulence and detected a currently uncharacterized cluster of P. vivax-specific genes on chromosome 6 likely involved in erythrocyte invasion. In conclusion, Plasmodium species harbour many chromosome-internal differences in the form of protein-coding genes, some of which are potentially linked to human disease and thus promising leads for future laboratory research. PMID- 22216000 TI - Joint ancestry and association testing in admixed individuals. AB - For samples of admixed individuals, it is possible to test for both ancestry effects via admixture mapping and genotype effects via association mapping. Here, we describe a joint test called BMIX that combines admixture and association statistics at single markers. We first perform high-density admixture mapping using local ancestry. We then perform association mapping using stratified regression, wherein for each marker genotypes are stratified by local ancestry. In both stages, we use generalized linear models, providing the advantage that the joint test can be used with any phenotype distribution with an appropriate link function. To define the alternative densities for admixture mapping and association mapping, we describe a method based on autocorrelation to empirically estimate the testing burdens of admixture mapping and association mapping. We then describe a joint test that uses the posterior probabilities from admixture mapping as prior probabilities for association mapping, capitalizing on the reduced testing burden of admixture mapping relative to association mapping. By simulation, we show that BMIX is potentially orders-of-magnitude more powerful than the MIX score, which is currently the most powerful frequentist joint test. We illustrate the gain in power through analysis of fasting plasma glucose among 922 unrelated, non-diabetic, admixed African Americans from the Howard University Family Study. We detected loci at 1q24 and 6q26 as genome-wide significant via admixture mapping; both loci have been independently reported from linkage analysis. Using the association data, we resolved the 1q24 signal into two regions. One region, upstream of the gene FAM78B, contains three binding sites for the transcription factor PPARG and two binding sites for HNF1A, both previously implicated in the pathology of type 2 diabetes. The fact that both loci showed ancestry effects may provide novel insight into the genetic architecture of fasting plasma glucose in individuals of African ancestry. PMID- 22216001 TI - Five questions about non-mevalonate isoprenoid biosynthesis. PMID- 22216002 TI - Prion uptake in the gut: identification of the first uptake and replication sites. AB - After oral exposure, prions are thought to enter Peyer's patches via M cells and accumulate first upon follicular dendritic cells (FDCs) before spreading to the nervous system. How prions are actually initially acquired from the gut lumen is not known. Using high-resolution immunofluorescence and cryo-immunogold electron microscopy, we report the trafficking of the prion protein (PrP) toward Peyer's patches of wild-type and PrP-deficient mice. PrP was transiently detectable at 1 day post feeding (dpf) within large multivesicular LAMP1-positive endosomes of enterocytes in the follicle-associated epithelium (FAE) and at much lower levels within M cells. Subsequently, PrP was detected on vesicles in the late endosomal compartments of macrophages in the subepithelial dome. At 7-21 dpf, increased PrP labelling was observed on the plasma membranes of FDCs in germinal centres of Peyer's patches from wild-type mice only, identifying FDCs as the first sites of PrP conversion and replication. Detection of PrP on extracellular vesicles displaying FAE enterocyte-derived A33 protein implied transport towards FDCs in association with FAE-derived vesicles. By 21 dpf, PrP was observed on the plasma membranes of neurons within neighbouring myenteric plexi. Together, these data identify a novel potential M cell-independent mechanism for prion transport, mediated by FAE enterocytes, which acts to initiate conversion and replication upon FDCs and subsequent infection of enteric nerves. PMID- 22216003 TI - Ce-Duox1/BLI-3 generated reactive oxygen species trigger protective SKN-1 activity via p38 MAPK signaling during infection in C. elegans. AB - Infected animals will produce reactive oxygen species (ROS) and other inflammatory molecules that help fight pathogens, but can inadvertently damage host tissue. Therefore specific responses, which protect and repair against the collateral damage caused by the immune response, are critical for successfully surviving pathogen attack. We previously demonstrated that ROS are generated during infection in the model host Caenorhabditis elegans by the dual oxidase Ce Duox1/BLI-3. Herein, an important connection between ROS generation by Ce Duox1/BLI-3 and upregulation of a protective transcriptional response by SKN-1 is established in the context of infection. SKN-1 is an ortholog of the mammalian Nrf transcription factors and has previously been documented to promote survival, following oxidative stress, by upregulating genes involved in the detoxification of ROS and other reactive compounds. Using qRT-PCR, transcriptional reporter fusions, and a translational fusion, SKN-1 is shown to become highly active in the C. elegans intestine upon exposure to the human bacterial pathogens, Enterococcus faecalis and Pseudomonas aeruginosa. Activation is dependent on the overall pathogenicity of the bacterium, demonstrated by a weakened response observed in attenuated mutants of these pathogens. Previous work demonstrated a role for p38 MAPK signaling both in pathogen resistance and in activating SKN-1 upon exposure to chemically induced oxidative stress. We show that NSY-1, SEK-1 and PMK-1 are also required for SKN-1 activity during infection. Evidence is also presented that the ROS produced by Ce-Duox1/BLI-3 is the source of SKN-1 activation via p38 MAPK signaling during infection. Finally, for the first time, SKN-1 activity is shown to be protective during infection; loss of skn-1 decreases resistance, whereas increasing SKN-1 activity augments resistance to pathogen. Overall, a model is presented in which ROS generation by Ce-Duox1/BLI-3 activates a protective SKN-1 response via p38 MAPK signaling. PMID- 22216004 TI - Helicobacter pylori versus the host: remodeling of the bacterial outer membrane is required for survival in the gastric mucosa. AB - Modification of bacterial surface structures, such as the lipid A portion of lipopolysaccharide (LPS), is used by many pathogenic bacteria to help evade the host innate immune response. Helicobacter pylori, a gram-negative bacterium capable of chronic colonization of the human stomach, modifies its lipid A by removal of phosphate groups from the 1- and 4'-positions of the lipid A backbone. In this study, we identify the enzyme responsible for dephosphorylation of the lipid A 4'-phosphate group in H. pylori, Jhp1487 (LpxF). To ascertain the role these modifications play in the pathogenesis of H. pylori, we created mutants in lpxE (1-phosphatase), lpxF (4'-phosphatase) and a double lpxE/F mutant. Analysis of lipid A isolated from lpxE and lpxF mutants revealed lipid A species with a 1 or 4'-phosphate group, respectively while the double lpxE/F mutant revealed a bis phosphorylated lipid A. Mutants lacking lpxE, lpxF, or lpxE/F show a 16, 360 and 1020 fold increase in sensitivity to the cationic antimicrobial peptide polymyxin B, respectively. Moreover, a similar loss of resistance is seen against a variety of CAMPs found in the human body including LL37, beta-defensin 2, and P-113. Using a fluorescent derivative of polymyxin we demonstrate that, unlike wild type bacteria, polymyxin readily associates with the lpxE/F mutant. Presumably, the increase in the negative charge of H. pylori LPS allows for binding of the peptide to the bacterial surface. Interestingly, the action of LpxE and LpxF was shown to decrease recognition of Helicobacter LPS by the innate immune receptor, Toll-like Receptor 4. Furthermore, lpxE/F mutants were unable to colonize the gastric mucosa of C57BL/6J and C57BL/6J tlr4 -/- mice when compared to wild type H. pylori. Our results demonstrate that dephosphorylation of the lipid A domain of H. pylori LPS by LpxE and LpxF is key to its ability to colonize a mammalian host. PMID- 22216005 TI - Epstein-Barr virus evades CD4+ T cell responses in lytic cycle through BZLF1 mediated downregulation of CD74 and the cooperation of vBcl-2. AB - Evasion of immune T cell responses is crucial for viruses to establish persistence in the infected host. Immune evasion mechanisms of Epstein-Barr virus (EBV) in the context of MHC-I antigen presentation have been well studied. In contrast, viral interference with MHC-II antigen presentation is less well understood, not only for EBV but also for other persistent viruses. Here we show that the EBV encoded BZLF1 can interfere with recognition by immune CD4+ effector T cells. This impaired T cell recognition occurred in the absence of a reduction in the expression of surface MHC-II, but correlated with a marked downregulation of surface CD74 on the target cells. Furthermore, impaired CD4+ T cell recognition was also observed with target cells where CD74 expression was downregulated by shRNA-mediated inhibition. BZLF1 downregulated surface CD74 via a post-transcriptional mechanism distinct from its previously reported effect on the CIITA promoter. In addition to being a chaperone for MHC-II alphabeta dimers, CD74 also functions as a surface receptor for macrophage Migration Inhibitory Factor and enhances cell survival through transcriptional upregulation of Bcl-2 family members. The immune-evasion function of BZLF1 therefore comes at a cost of induced toxicity. However, during EBV lytic cycle induced by BZLF1 expression, this toxicity can be overcome by expression of the vBcl-2, BHRF1, at an early stage of lytic infection. We conclude that by inhibiting apoptosis, the vBcl-2 not only maintains cell viability to allow sufficient time for synthesis and accumulation of infectious virus progeny, but also enables BZLF1 to effect its immune evasion function. PMID- 22216006 TI - Engineered anopheles immunity to Plasmodium infection. AB - A causative agent of human malaria, Plasmodium falciparum, is transmitted by Anopheles mosquitoes. The malaria parasite is under intensive attack from the mosquito's innate immune system during its sporogonic development. We have used genetic engineering to create immune-enhanced Anopheles stephensi mosquitoes through blood meal-inducible expression of a transgene encoding the IMD pathway controlled NF-kB Rel2 transcription factor in the midgut and fat-body tissue. Transgenic mosquitoes showed greater resistance to Plasmodium and microbial infection as a result of timely concerted tissue-specific immune attacks involving multiple effectors. The relatively weak impact of this genetic modification on mosquito fitness under laboratory conditions encourages further investigation of this approach for malaria control. PMID- 22216007 TI - Functional analysis of the kinome of the wheat scab fungus Fusarium graminearum. AB - As in other eukaryotes, protein kinases play major regulatory roles in filamentous fungi. Although the genomes of many plant pathogenic fungi have been sequenced, systematic characterization of their kinomes has not been reported. The wheat scab fungus Fusarium graminearum has 116 protein kinases (PK) genes. Although twenty of them appeared to be essential, we generated deletion mutants for the other 96 PK genes, including 12 orthologs of essential genes in yeast. All of the PK mutants were assayed for changes in 17 phenotypes, including growth, conidiation, pathogenesis, stress responses, and sexual reproduction. Overall, deletion of 64 PK genes resulted in at least one of the phenotypes examined, including three mutants blocked in conidiation and five mutants with increased tolerance to hyperosmotic stress. In total, 42 PK mutants were significantly reduced in virulence or non-pathogenic, including mutants deleted of key components of the cAMP signaling and three MAPK pathways. A number of these PK genes, including Fg03146 and Fg04770 that are unique to filamentous fungi, are dispensable for hyphal growth and likely encode novel fungal virulence factors. Ascospores play a critical role in the initiation of wheat scab. Twenty six PK mutants were blocked in perithecia formation or aborted in ascosporogenesis. Additional 19 mutants were defective in ascospore release or morphology. Interestingly, F. graminearum contains two aurora kinase genes with distinct functions, which has not been reported in fungi. In addition, we used the interlog approach to predict the PK-PK and PK-protein interaction networks of F. graminearum. Several predicted interactions were verified with yeast two hybrid or co-immunoprecipitation assays. To our knowledge, this is the first functional characterization of the kinome in plant pathogenic fungi. Protein kinase genes important for various aspects of growth, developmental, and infection processes in F. graminearum were identified in this study. PMID- 22216008 TI - CNS recruitment of CD8+ T lymphocytes specific for a peripheral virus infection triggers neuropathogenesis during polymicrobial challenge. AB - Although viruses have been implicated in central nervous system (CNS) diseases of unknown etiology, including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such diseases has been largely unsuccessful. Here, we explore the hypothesis that viruses need not replicate in the tissue in which they cause disease; specifically, that a peripheral infection might trigger CNS pathology. To test this idea, we utilized a transgenic mouse model in which we found that immune cells responding to a peripheral infection are recruited to the CNS, where they trigger neurological damage. In this model, mice are infected with both CNS-restricted measles virus (MV) and peripherally restricted lymphocytic choriomeningitis virus (LCMV). While infection with either virus alone resulted in no illness, infection with both viruses caused disease in all mice, with ~50% dying following seizures. Co infection resulted in a 12-fold increase in the number of CD8+ T cells in the brain as compared to MV infection alone. Tetramer analysis revealed that a substantial proportion (>35%) of these infiltrating CD8+ lymphocytes were LCMV specific, despite no detectable LCMV in CNS tissues. Mechanistically, CNS disease was due to edema, induced in a CD8-dependent but perforin-independent manner, and brain herniation, similar to that observed in mice challenged intracerebrally with LCMV. These results indicate that T cell trafficking can be influenced by other ongoing immune challenges, and that CD8+ T cell recruitment to the brain can trigger CNS disease in the apparent absence of cognate antigen. By extrapolation, human CNS diseases of unknown etiology need not be associated with infection with any particular agent; rather, a condition that compromises and activates the blood-brain barrier and adjacent brain parenchyma can render the CNS susceptible to pathogen-independent immune attack. PMID- 22216009 TI - Acute multiple organ failure in adult mice deleted for the developmental regulator Wt1. AB - There is much interest in the mechanisms that regulate adult tissue homeostasis and their relationship to processes governing foetal development. Mice deleted for the Wilms' tumour gene, Wt1, lack kidneys, gonads, and spleen and die at mid gestation due to defective coronary vasculature. Wt1 is vital for maintaining the mesenchymal-epithelial balance in these tissues and is required for the epithelial-to-mesenchyme transition (EMT) that generates coronary vascular progenitors. Although Wt1 is only expressed in rare cell populations in adults including glomerular podocytes, 1% of bone marrow cells, and mesothelium, we hypothesised that this might be important for homeostasis of adult tissues; hence, we deleted the gene ubiquitously in young and adult mice. Within just a few days, the mice suffered glomerulosclerosis, atrophy of the exocrine pancreas and spleen, severe reduction in bone and fat, and failure of erythropoiesis. FACS and culture experiments showed that Wt1 has an intrinsic role in both haematopoietic and mesenchymal stem cell lineages and suggest that defects within these contribute to the phenotypes we observe. We propose that glomerulosclerosis arises in part through down regulation of nephrin, a known Wt1 target gene. Protein profiling in mutant serum showed that there was no systemic inflammatory or nutritional response in the mutant mice. However, there was a dramatic reduction in circulating IGF-1 levels, which is likely to contribute to the bone and fat phenotypes. The reduction of IGF-1 did not result from a decrease in circulating GH, and there is no apparent pathology of the pituitary and adrenal glands. These findings 1) suggest that Wt1 is a major regulator of the homeostasis of some adult tissues, through both local and systemic actions; 2) highlight the differences between foetal and adult tissue regulation; 3) point to the importance of adult mesenchyme in tissue turnover. PMID- 22216010 TI - A complex genomic rearrangement involving the endothelin 3 locus causes dermal hyperpigmentation in the chicken. AB - Dermal hyperpigmentation or Fibromelanosis (FM) is one of the few examples of skin pigmentation phenotypes in the chicken, where most other pigmentation variants influence feather color and patterning. The Silkie chicken is the most widespread and well-studied breed displaying this phenotype. The presence of the dominant FM allele results in extensive pigmentation of the dermal layer of skin and the majority of internal connective tissue. Here we identify the causal mutation of FM as an inverted duplication and junction of two genomic regions separated by more than 400 kb in wild-type individuals. One of these duplicated regions contains endothelin 3 (EDN3), a gene with a known role in promoting melanoblast proliferation. We show that EDN3 expression is increased in the developing Silkie embryo during the time in which melanoblasts are migrating, and elevated levels of expression are maintained in the adult skin tissue. We have examined four different chicken breeds from both Asia and Europe displaying dermal hyperpigmentation and conclude that the same structural variant underlies this phenotype in all chicken breeds. This complex genomic rearrangement causing a specific monogenic trait in the chicken illustrates how novel mutations with major phenotypic effects have been reused during breed formation in domestic animals. PMID- 22216012 TI - Histone H3K9 trimethylase Eggless controls germline stem cell maintenance and differentiation. AB - Epigenetic regulation plays critical roles in the regulation of cell proliferation, fate determination, and survival. It has been shown to control self-renewal and lineage differentiation of embryonic stem cells. However, epigenetic regulation of adult stem cell function remains poorly defined. Drosophila ovarian germline stem cells (GSCs) are a productive adult stem cell system for revealing regulatory mechanisms controlling self-renewal and differentiation. In this study, we show that Eggless (Egg), a H3K9 methyltransferase in Drosophila, is required in GSCs for controlling self-renewal and in escort cells for regulating germ cell differentiation. egg mutant ovaries primarily exhibit germ cell differentiation defects in young females and gradually lose GSCs with time, indicating that Egg regulates both germ cell maintenance and differentiation. Marked mutant egg GSCs lack expression of trimethylated H3K9 (H3k9me3) and are rapidly lost from the niche, but their mutant progeny can still differentiate into 16-cell cysts, indicating that Egg is required intrinsically to control GSC self-renewal but not differentiation. Interestingly, BMP-mediated transcriptional repression of differentiation factor bam in marked egg mutant GSCs remains normal, indicating that Egg is dispensable for BMP signaling in GSCs. Normally, Bam and Bgcn interact with each other to promote GSC differentiation. Interestingly, marked double mutant egg bgcn GSCs are still lost, but their progeny are able to differentiate into 16-cell cysts though bgcn mutant GSCs normally do not differentiate, indicating that Egg intrinsically controls GSC self-renewal through repressing a Bam/Bgcn-independent pathway. Surprisingly, RNAi-mediated egg knockdown in escort cells leads to their gradual loss and a germ cell differentiation defect. The germ cell differentiation defect is at least in part attributed to an increase in BMP signaling in the germ cell differentiation niche. Therefore, this study has revealed the essential roles of histone H3K9 trimethylation in controlling stem cell maintenance and differentiation through distinct mechanisms. PMID- 22216013 TI - Ror2 enhances polarity and directional migration of primordial germ cells. AB - The trafficking of primordial germ cells (PGCs) across multiple embryonic structures to the nascent gonads ensures the transmission of genetic information to the next generation through the gametes, yet our understanding of the mechanisms underlying PGC migration remains incomplete. Here we identify a role for the receptor tyrosine kinase-like protein Ror2 in PGC development. In a Ror2 mouse mutant we isolated in a genetic screen, PGC migration and survival are dysregulated, resulting in a diminished number of PGCs in the embryonic gonad. A similar phenotype in Wnt5a mutants suggests that Wnt5a acts as a ligand to Ror2 in PGCs, although we do not find evidence that WNT5A functions as a PGC chemoattractant. We show that cultured PGCs undergo polarization, elongation, and reorientation in response to the chemotactic factor SCF (secreted KitL), whereas Ror2 PGCs are deficient in these SCF-induced responses. In the embryo, migratory PGCs exhibit a similar elongated geometry, whereas their counterparts in Ror2 mutants are round. The protein distribution of ROR2 within PGCs is asymmetric, both in vitro and in vivo; however, this asymmetry is lost in Ror2 mutants. Together these results indicate that Ror2 acts autonomously to permit the polarized response of PGCs to KitL. We propose a model by which Wnt5a potentiates PGC chemotaxis toward secreted KitL by redistribution of Ror2 within the cell. PMID- 22216011 TI - Candidate gene screen in the red flour beetle Tribolium reveals six3 as ancient regulator of anterior median head and central complex development. AB - Several highly conserved genes play a role in anterior neural plate patterning of vertebrates and in head and brain patterning of insects. However, head involution in Drosophila has impeded a systematic identification of genes required for insect head formation. Therefore, we use the red flour beetle Tribolium castaneum in order to comprehensively test the function of orthologs of vertebrate neural plate patterning genes for a function in insect head development. RNAi analysis reveals that most of these genes are indeed required for insect head capsule patterning, and we also identified several genes that had not been implicated in this process before. Furthermore, we show that Tc-six3/optix acts upstream of Tc wingless, Tc-orthodenticle1, and Tc-eyeless to control anterior median development. Finally, we demonstrate that Tc-six3/optix is the first gene known to be required for the embryonic formation of the central complex, a midline spanning brain part connected to the neuroendocrine pars intercerebralis. These functions are very likely conserved among bilaterians since vertebrate six3 is required for neuroendocrine and median brain development with certain mutations leading to holoprosencephaly. PMID- 22216015 TI - Dynamic Mechanical Response of Biomedical 316L Stainless Steel as Function of Strain Rate and Temperature. AB - A split Hopkinson pressure bar is used to investigate the dynamic mechanical properties of biomedical 316L stainless steel under strain rates ranging from 1 * 10(3) s(-1) to 5 * 10(3) s(-1) and temperatures between 25 degrees C and 800 degrees C. The results indicate that the flow stress, work-hardening rate, strain rate sensitivity, and thermal activation energy are all significantly dependent on the strain, strain rate, and temperature. For a constant temperature, the flow stress, work-hardening rate, and strain rate sensitivity increase with increasing strain rate, while the thermal activation energy decreases. Catastrophic failure occurs only for the specimens deformed at a strain rate of 5 * 10(3) s(-1) and temperatures of 25 degrees C or 200 degrees C. Scanning electron microscopy observations show that the specimens fracture in a ductile shear mode. Optical microscopy analyses reveal that the number of slip bands within the grains increases with an increasing strain rate. Moreover, a dynamic recrystallisation of the deformed microstructure is observed in the specimens tested at the highest temperature of 800 degrees C. PMID- 22216016 TI - DNA Interaction Studies of a New Platinum(II) Complex Containing Different Aromatic Dinitrogen Ligands. AB - A new mononuclear Pt(II) complex, [Pt(DMP)(DIP)]Cl(2).H(2)O, in which DMP is 4,4 dimethyl-2,2-bipyridine and DIP is 4,7-diphenyl-1,10-phenantroline, has been synthesized and characterized by physicochemical and spectroscopic methods. The binding interaction of this complex with calf thymus DNA (CT-DNA) was investigated using fluorimetry, spectrophotometry, circular dichroism, viscosimetry and cyclic voltametry (CV). UV-VIS spectrum showed 4 nm bathochromic shift of the absorption band at 280 nm along with significant hypochromicity for the absorption band of the complex. The intrnisic binding constant (K(b) = 2 * 10(4) M(-1)) is more in keeping with intercalators and suggests this binding mode. The viscosity measurements showed that the complex-DNA interaction can be hydrophobic and confirm intercalation. Moreover, the complex induced detectable changes in the CD spectrum of CT-DNA. The fluorescence studies revealed that the probable quenching mechanism of fluorescence of the complex by CT-DNA is static quenching. The thermodynamic parameters (DeltaH > 0 and DeltaS > 0) showed that main interaction with hydrogenic forces occurred that is intercalation mode. Also, CV results confirm this mode because, with increasing the CT-DNA concentration, shift to higher potential was observed. PMID- 22216017 TI - Metal-based biologically active compounds: synthesis, spectral, and antimicrobial studies of cobalt, nickel, copper, and zinc complexes of triazole-derived schiff bases. AB - A series of cobalt, nickel, copper, and zinc complexes of bidentate Schiff bases derived from the condensation reaction of 4-amino-5-mercapto-3-methyl/ethyl-1,2,4 triazole with 2,4-dichlorobenzaldehyde were synthesized and tested as antimicrobial agents. The synthesized Schiff bases and their metal complexes were characterized with the aid of elemental analyses, magnetic moment measurements, spectroscopic and thermogravimetric techniques. The presence of coordinated water in metal complexes was supported by infrared and thermal gravimetric studies. A square planar geometry was suggested for Cu(II) and octahedral geometry proposed for Co(II), Ni(II), and Zn(II) complexes. The Schiff bases and their metal complexes have been screened for antibacterial (Pseudomonas aeruginosa, Bacillus subtilis) and antifungal activities (Aspergillus niger, A. flavus). The metal complexes exhibited significantly enhanced antibacterial and antifungal activity as compared to their simple Schiff bases. PMID- 22216014 TI - Azospirillum genomes reveal transition of bacteria from aquatic to terrestrial environments. AB - Fossil records indicate that life appeared in marine environments ~3.5 billion years ago (Gyr) and transitioned to terrestrial ecosystems nearly 2.5 Gyr. Sequence analysis suggests that "hydrobacteria" and "terrabacteria" might have diverged as early as 3 Gyr. Bacteria of the genus Azospirillum are associated with roots of terrestrial plants; however, virtually all their close relatives are aquatic. We obtained genome sequences of two Azospirillum species and analyzed their gene origins. While most Azospirillum house-keeping genes have orthologs in its close aquatic relatives, this lineage has obtained nearly half of its genome from terrestrial organisms. The majority of genes encoding functions critical for association with plants are among horizontally transferred genes. Our results show that transition of some aquatic bacteria to terrestrial habitats occurred much later than the suggested initial divergence of hydro- and terrabacterial clades. The birth of the genus Azospirillum approximately coincided with the emergence of vascular plants on land. PMID- 22216018 TI - The pathway of obstructed labour as perceived by communities in south-western Uganda: a grounded theory study. AB - BACKGROUND: Obstructed labour is still a major cause of maternal and perinatal morbidity and mortality in Uganda, where many women give birth at home alone or assisted by non-skilled birth attendants. Little is known of how the community view obstructed labour, and what actions they take in cases where this complication occurs. OBJECTIVE: The objective of the study was to explore community members' understanding of and actions taken in cases of obstructed labour in south-western Uganda. DESIGN: Grounded theory (GT) was used to analyse data from 20 focus group discussions (FGDs), 10 with women and 10 with men, which were conducted in eight rural and two urban communities. RESULTS: A conceptual model based on the community members' understanding of obstructed labour and actions taken in response is presented as a pathway initiated by women's desire to 'protecting own integrity' (core category). The pathway consisted of six other categories closely linked to the core category, namely: (1) 'taking control of own birth process'; (2) 'reaching the limit--failing to give birth' (individual level); (3) 'exhausting traditional options'; (4) 'partner taking charge'; (5) 'facing challenging referral conditions' (community level); and finally (6) 'enduring a non-responsive healthcare system' (healthcare system level). CONCLUSIONS: There is a need to understand and acknowledge women's reluctance to involve others during childbirth. However, the healthcare system should provide acceptable care and a functional referral system closer to the community, thus supporting the community's ability to seek timely care as a response to obstructed labour. Easy access to mobile phones may improve referral systems. Upgrading of infrastructure in the region requires a multi-sectoral approach. Testing of the conceptual model through a quantitative questionnaire is recommended. PMID- 22216019 TI - Impact of maternal obesity and diabetes on long-term health of the offspring. PMID- 22216022 TI - Effects of proton pump inhibitors and h(2) receptor antagonists on the ileum motility. AB - Objectives. To investigate the effects of proton pump inhibitors (PPIs) and H(2) receptor antagonists on ileum motility in rats with peritonitis and compare changes with control group rats. Methods. Peritonitis was induced by cecal ligation and puncture in 8 rats. Another of 8 rats underwent a sham operation and were accepted as controls. Twenty-four hours later after the operation, the rats were killed, and their ileum smooth muscle was excised and placed in circular muscle direction in a 10 mL organ bath. Changes in amplitude and frequency of contractions were analyzed before and after PPIs and H(2) receptor blockers. Results. PPI agents decreased the motility in a dose-dependent manner in ileum in both control and intraabdominal sepsis groups. While famotidine had no significant effect on ileum motility, ranitidine and nizatidine enhanced motility in ileum in both control and intraabdominal sepsis groups. This excitatory effect of H(2) receptor antagonists and inhibitor effects of PPIs were significantly high in control group when compared to the peritonitis group. The inhibitor effect of pantoprazole on ileum motility was significantly higher than the other two PPI agents. Conclusions. It was concluded that H(2) receptor antagonists may be more effective than PPIs for recovering the bowel motility in the intraabdominal sepsis situation. PMID- 22216023 TI - Colitides. PMID- 22216020 TI - ER stress and apoptosis: a new mechanism for retinal cell death. AB - The endoplasmic reticulum (ER) is the primary subcellular organelle where proteins are synthesized and folded. When the homeostasis of the ER is disturbed, unfolded or misfolded proteins accumulate in the ER lumen, resulting in ER stress. In response to ER stress, cells activate a set of tightly controlled regulatory programs, known as the unfolded protein response (UPR), to restore the normal function of the ER. However, if ER stress is sustained and the adaptive UPR fails to eliminate unfolded/misfolded proteins, apoptosis will occur to remove the stressed cells. In recent years, a large body of studies has shown that ER stress-induced apoptosis is implicated in numerous human diseases, such as diabetes and neurogenerative diseases. Moreover, emerging evidence supports a role of ER stress in retinal apoptosis and cell death in blinding disorders such as age-related macular degeneration and diabetic retinopathy. In the present review, we summarize recent progress on ER stress and apoptosis in retinal diseases, focusing on various proapoptotic and antiapoptotic pathways that are activated by the UPR, and discuss how these pathways contribute to ER stress induced apoptosis in retinal cells. PMID- 22216021 TI - Targeting the Cellular Signaling: BRAF Inhibition and Beyond for the Treatment of Metastatic Malignant Melanoma. AB - Although advances in cytotoxic treatments have been obtained in several neoplasias, in metastatic melanoma there was no drug able to significantly change the natural history of the disease in the last 30 years. In the last decade, translational research identified important mechanisms in malignant transformation, invasion, and progression. Signaling pathways can be abnormally activated by oncogenes. The identification of oncogenic mutated kinases implicated in this process provides an opportunity for new target therapies. The melanoma dependence on BRAF-mutated kinase allowed the development of inhibitors that produced major responses in clinical trials. This is the beginning of a novel class of drugs in metastatic melanoma; the identification of the transduction signaling networking and other "druggable" kinases is in active research. In this paper, we discuss the ongoing research on cellular signaling inhibition, resistance mechanisms, and strategies to overcome treatment failure. PMID- 22216024 TI - Liver Regeneration after Partial Hepatectomy Is Not Impaired in Mice with Double Deficiency of Myd88 and IFNAR Genes. AB - Liver regeneration is known to occur in mice lacking one or more Toll-like receptors (TLRs) or the adaptor protein MyD88. Though MyD88 is required for signaling by many TLRs, others signal via MyD88-independent pathways, leading to the induction of type I interferons (IFNs). Here, we assessed liver regeneration after partial hepatectomy (PH) in mice lacking both MyD88 and the type I IFN receptor (Myd88-IFNAR double-KO). Approximately 28% of Myd88-IFNAR double-KO mice had gross liver lesions prior to surgery. In mice without lesions, Myd88-IFNAR deficiency abrogated the increase in circulating IL-6 after PH but did not impair hepatocyte BrdU incorporation, mitotic figure counts, or recovery of liver-to body weight ratios. These results indicate that type I IFNs are not responsible for the preservation of liver regeneration in Myd88-deficient mice, and they also cast doubt on the idea of microbial products being essential triggers of liver regeneration in mice undergoing PH. PMID- 22216025 TI - Oncologic outcomes of surgery in t3 prostate cancer: experience of a single tertiary center. AB - Aim. The aim of this study is to present the oncologic outcomes and to determine the prognostic factors of overall survival (OS), cancer-specific survival (CSS), disease-progression-free survival (DPFS), and biochemical-progression-free survival (BPFS) after surgery for pT3 prostate cancer (PCa). Methods. Between 2002 and 2007, a pT3 stage after radical prostatectomy was detected in 182 patients at our institution. The Kaplan-Meier analysis was used to calculate OS, CSS, DPFS, and BPFS. Cox regression was used to identify predictive factors of survival. Results. pT3a was detected in 126 (69%) and pT3b in 56 (31%) of cases. Five-year OS, CSS, DPFS, and BPFS rates were 90.7%, 94%, 91.8%, and 48.4%, respectively. Survival was significantly different when comparing pT3a to pT3b groups. The 5-year OS, CSS, DPFS, and BPFS were 96% versus 72%, 98% versus 77%, 97.3% versus 79.3%, and 60% versus 24.2%, respectively. Specimen Gleason score was the most significant predictor of OS, CSS, DPFS, and BPFS. The risk of death increased up to 3-fold when a Gleason score 8-10 was present at the final pathology. Conclusions. Radical prostatectomy may offer very good CSS, OS, DPFS, and BPFS rates in pT3a PCa. However, outcomes in patients with pT3b or specimen Gleason >=8 were significantly worse, suggesting the need for multimodality treatment in those cases. PMID- 22216026 TI - Correlation of Gleason scores with diffusion-weighted imaging findings of prostate cancer. AB - The purpose of our study was to compare the apparent diffusion coefficient (ADC) derived from diffusion-weighted imaging (DWI) of prostate cancer (PCa) patients with three classes of pathological Gleason scores (GS). Patients whose GS met these criteria (GS 3 + 3, GS 3 + 4, and GS 4 + 3) were included in this study. The DWI was performed using b values of 0, 50, and 400 s/mm(2) in 44 patients using an endorectal coil on a 1.5T MRI scanner. The apparent diffusion coefficient (ADC) values were calculated from the DWI data of patients with three different Gleason scores. In patients with a high-grade Gleason score (4 + 3), the ADC values were lower in the peripheral gland tissue, pathologically determined as tumor compared to low grade (3 + 3 and 3 + 4). The mean and standard deviation of the ADC values for patients with GS 3 + 3, GS 3 + 4, and GS 4 + 3 were 1.135 +/- 0.119, 0.976 +/- 0.103 and 0.831 +/- 0.087 mm(2)/sec. The ADC values were statistically significant (P < 0.05) between the three different scores with a trend of decreasing ADC values with increasing Gleason scores by one-way ANOVA method. This study shows that the DWI-derived ADC values may help differentiate aggressive from low-grade PCa. PMID- 22216027 TI - Verbal episodic memory and endogenous estradiol: an association in patients with mild cognitive impairment and Alzheimer's disease. AB - In the continuum of patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and normal controls, a possible association of verbal memory and endogenous estradiol (E(2)) levels was investigated. Verbal episodic memory was measured with a german version of the California verbal memory test (CVLT). Results were controlled for apolipoprotein E (ApoE) phenotype. We studied 37 controls, 32 MCIs and 117 ADs. Groups differed in all trials of the CVLT (P < 0.001) and in E(2) levels (P < 0.001). E2 levels differed significantly between groups only among females (P < 0.001). In females correcting for age and ApoE, there was an overall correlation between CVLT delayed recall and level of E(2) (P = 0.025). Stepwise regression analyses found E(2) level to be a significant predictor for CVLT delayed recall (P < 0.001). It may be concluded that lower E(2) levels occur more in the course of the disease than may be considered as a risk factor per se. PMID- 22216028 TI - Relationship between Serum Concentration of Uric Acid and Insulin Secretion among Adults with Type 2 Diabetes Mellitus. AB - To determine the relationship between serum concentrations of uric acid and insulin secretion with hyperglycaemic clamp technique among adults with type 2 diabetes mellitus (DM2) without hyperuricemia, we carried out a cross-sectional study on 45 patients of both gender. We observed correlation between uric acid with male gender r = 0.710 (P = 0.001). Also correlation between uric acid and total insulin secretion was positive r = 0.295 (P = 0.049). As well as a positive correlation adjusted for body mass index was demonstrated for the first, second, and total phases of insulin secretion, respectively, r = 0.438 (P = 0.022), r = 0.433 (P = 0.022), and r = 0.439 (P = 0.024). Serum concentration of uric acid showed a positive relationship with the total phase of insulin secretion; even in states prior to hyperuricemia, uric acid can play an important role in the function of the beta cell in patients with DM2. PMID- 22216029 TI - The involvement of ser1898 of the human L-type calcium channel in evoked secretion. AB - A PKA consensus phosphorylation site S1928 at the alpha(1)1.2 subunit of the rabbit cardiac L-type channel, Ca(V)1.2, is involved in the regulation of Ca(V)1.2 kinetics and affects catecholamine secretion. This mutation does not alter basal Ca(V)1.2 current properties or regulation of Ca(V)1.2 current by PKA and the beta-adrenergic receptor, but abolishes Ca(V)1.2 phosphorylation by PKA. Here, we test the contribution of the corresponding PKA phosphorylation site of the human alpha(1)1.2 subunit S1898, to the regulation of catecholamine secretion in bovine chromaffin cells. Chromaffin cells were infected with a Semliki-Forest viral vector containing either the human wt or a mutated S1898A alpha(1)1.2 subunit. Both subunits harbor a T1036Y mutation conferring nifedipine insensitivity. Secretion evoked by depolarization in the presence of nifedipine was monitored by amperometry. Depolarization-triggered secretion in cells infected with either the wt alpha(1)1.2 or alpha(1)1.2/S1898A mutated subunit was elevated to a similar extent by forskolin. Forskolin, known to directly activate adenylyl-cyclase, increased the rate of secretion in a manner that is largely independent of the presence of S1898. Our results are consistent with the involvement of additional PKA regulatory site(s) at the C-tail of alpha(1)1.2, the pore forming subunit of Ca(V)1.2. PMID- 22216030 TI - Effect of Cavity Design on the Strength of Direct Posterior Composite Restorations: An Empirical and FEM Analysis. AB - The aim of the present study was to verify the hypothesis that cavity design does not affect the strength of direct composite restorations as do material properties. Finite element modeling (FEM) and empirical testing were done for two cavity designs: a box shape (cube) and a concave shape (U). Two microhybrid composites were used to prepare the samples with the help of split stainless steel moulds. Compressive strength was tested. The results were statistically analyzed. Both FEA and empirical testing were complementary to each other in that the concave shape showed a significantly higher strength than box. Material properties affected the values only when box shape was used. The null hypothesis is thus rejected, and it is concluded that design significantly affects the strength of direct composite restorations. PMID- 22216031 TI - A new anatomically based nomenclature for the roots and root canals-part 1: maxillary molars. AB - Numerous terminologies have been employed in the dental literature to describe the roots and root canal systems of maxillary molars. This multiplicity in naming of roots and canals makes the reader susceptible to misinterpretation and confusion. No consensus thus far has been arrived at for defining the names of roots and root canals in maxillary molars, including their various morphological aberrations. The anatomical relation of roots and their root canals were identified and were subsequently named based on definite sets of criteria. A new method for identification and naming of roots and root canal anatomy in maxillary molars, based on their root and canal relationship, was formulated and is presented in this paper. The nomenclature makes certain essential modifications to the traditional approach to accommodate naming of the various aberrations presented in the maxillary molars. A simple, yet extensive, nomenclature system has been proposed that appropriately names the internal and external morphology of maxillary molars. PMID- 22216032 TI - Restoration of noncarious cervical lesions: when, why, and how. AB - At this time, restoration of noncarious cervical lesions (NCCLs) is a common occurrence in clinics nowadays. Some reasons for this are the growth of the elderly population, a smaller rate of tooth loss, and possibly the increase of some etiologic factors. These factors include inadequate brushing techniques in gingival recession cases, corrosive food and drink consumption, and occlusal stress concentrating factors (occlusal interferences, premature contacts, habits of bruxism, and clenching). Unfortunately, Class V restorations also represent one of the less durable types of restorations and have a high index of loss of retention, marginal excess, and secondary caries. Some causes for these problems include difficulties in isolation, insertion, contouring, and finishing and polishing procedures. This work aims to help dentists in choosing the best treatment strategy, which necessarily involves steps of problem identification, diagnosis, etiological factor removal or treatment, and, if necessary, restoration. Finally, appropriate restorative techniques are suggested for each situation. PMID- 22216033 TI - Modulation of Tumor Cell Survival, Proliferation, and Differentiation by the Peptide Derived from Tenascin-C: Implication of beta1-Integrin Activation. AB - Cell adhesion to extracellular matrix (ECM) participates in various biological processes, such as cell survival, proliferation, differentiation, and migration. Since these processes are essential for keeping homeostasis, aberration of these processes leads to a variety of diseases including cancer. Previously, we found that a peptide derived from tenascin- (TN-) C, termed TNIIIA2, stimulates cell adhesion to ECM through activation of beta1-integrin. It has been shown that TNIIIA2 can modulate cell proliferation and differentiation. Interestingly, TNIIIA2 could not only enhance cell proliferation but also induce apoptotic cell death, depending on cellular context. In this review, we show the function of the peptide TNIIIA2 in cell survival, proliferation, and differentiation and refer to the possibility of new strategy for tumor suppression by regulating cell adhesion status using the ECM-derived functional peptides. PMID- 22216035 TI - Neuroendocrine carcinoma of the stomach: a case study. AB - Gastric neuroendocrine carcinomas are rare and have a poor prognosis, and the diagnostic criteria for this disease have recently changed. We herein report a case of sporadic gastric neuroendocrine carcinoma. A 75-year-old man was referred to our hospital with epigastric pain. Endoscopic examination revealed a localized ulcerative lesion (diameter, 4 cm) at the upper stomach. The diagnosis on biopsy was neuroendocrine carcinoma. Total gastrectomy with D2 lymphadenectomy, splenectomy, and cholecystectomy was performed. Pathologically, the tumor infiltrated the subserosal layer, and 6/49 lymph nodes were involved. The tumor was uniform in shape and arranged in a rosette-like structure to form solid nests, with medium-sized, round-to-cuboid-shaped tumor cells and intense mitosis 46/10 HPF. It was positive for synaptophysin and chromogranin A, and the Ki-67 labeling index was 70-80%. The diagnosis of neuroendocrine carcinoma was made according to the WHO 2010 criteria. The patient was followed up for three years without recurrence. PMID- 22216034 TI - Gab adapter proteins as therapeutic targets for hematologic disease. AB - The Grb-2 associated binder (Gab) family of scaffolding/adaptor/docking proteins is a group of three molecules with significant roles in cytokine receptor signaling. Gabs possess structural motifs for phosphorylation-dependent receptor recruitment, Grb2 binding, and activation of downstream signaling pathways through p85 and SHP-2. In addition, Gabs participate in hematopoiesis and regulation of immune response which can be aberrantly activated in cancer and inflammation. The multifunctionality of Gab adapters might suggest that they would be too difficult to consider as candidates for "targeted" therapy. However, the one drug/one target approach is giving way to the concept of one drug/multiple target approach since few cancers are addicted to a single signaling molecule for survival and combination drug therapies can be problematic. In this paper, we cover recent findings on Gab multi-functionality, binding partners, and their role in hematological malignancy and examine the concept of Gab-targeted therapy. PMID- 22216036 TI - Sundown syndrome in persons with dementia: an update. AB - "Sundowning" in demented individuals, as distinct clinical phenomena, is still open to debate in terms of clear definition, etiology, operationalized parameters, validity of clinical construct, and interventions. In general, sundown syndrome is characterized by the emergence or increment of neuropsychiatric symptoms such as agitation, confusion, anxiety, and aggressiveness in late afternoon, in the evening, or at night. Sundowning is highly prevalent among individuals with dementia. It is thought to be associated with impaired circadian rhythmicity, environmental and social factors, and impaired cognition. Neurophysiologically, it appears to be mediated by degeneration of the suprachiasmatic nucleus of the hypothalamus and decreased production of melatonin. A variety of treatment options have been found to be helpful to ameliorate the neuropsychiatric symptoms associated with this phenomenon: bright light therapy, melatonin, acetylcholinesterase inhibitors, N methyl-d-aspartate receptor antagonists, antipsychotics, and behavioral modifications. To decrease the morbidity from this specific condition, improve patient's well being, lessen caregiver burden, and delay institutionalization, further attention needs to be given to development of clinically operational definition of sundown syndrome and investigations on etiology, risk factors, and effective treatment options. PMID- 22216037 TI - Gamma oscillation in schizophrenia. AB - Dysfunctional neural circuitry has been found to be involved in abnormalities of perception and cognition in patients with schizophrenia. Gamma oscillations are essential for integrating information within neural circuits and have therefore been associated with many perceptual and cognitive processes in healthy human subjects and animals. This review presents an overview of the neural basis of gamma oscillations and the abnormalities in the GABAergic interneuronal system thought to be responsible for gamma-range deficits in schizophrenia. We also review studies of gamma activity in sensory and cognitive processes, including auditory steady state response, attention, object representation, and working memory, in animals, healthy humans and patients with schizophrenia. PMID- 22216038 TI - Post-Traumatic Stress Disorder, Depression, and Heart-Rate Variability among North Korean Defectors. AB - OBJECTIVE: This study evaluated the symptoms of post-traumatic stress disorder (PTSD) among North Korean defectors and their level of suicidal ideation and the correlation between these and heart-rate variability (HRV) to explore the possibility of using HRV as an objective neurobiological index of signs of autonomic nervous system disorder. METHODS: A total of 32 North Korean defectors (nine men, 23 women) were selected as subjects, and their HRV was measured after they completed the Minnesota Multiphasic Personality Inventory-PTSD (MMPI-PTSD) scale and the Beck Depression Inventory (BDI). RESULTS: 1) Low-frequency (LF)/high-frequency (HF) ratios in the HRV index and MMPI-PTSD scores were correlated (r=0.419, p<0.05), as were BDI item 9 (suicidal ideation) and MMPI PTSD scores (r=0.600, p<0.01). 2) A regression analysis of LF/HF ratios and MMPI PTSD scores revealed an R-value of 13.8% (Adj. R(2)=0.138, F=4.695, p=0.041), and a regression analysis of BDI item 9 and MMPI-PTSD scores showed an R-value of 32.8% (Adj. R(2)=0.328, F=11.234, p=0.003). In other words, the LF/HF ratio (beta=0.419) and BDI item 9 (beta=0.600) appear to be risk factors in predicting MMPI-PTSD scores. CONCLUSION: The LF/HF ratio, a standard index of autonomic nervous system activity, can be used as an objective neurobiological index to analyze PTSD among North Korean defectors presenting with various mental and physical symptoms, and the approximate level of suicide -ideation can act as a predicting factor for PTSD. PMID- 22216039 TI - Reliability and validity of the korean version of the childhood trauma questionnaire-short form for psychiatric outpatients. AB - OBJECTIVE: The Childhood Trauma Questionnaire (CTQ) is perhaps the most widely used and well-studied retrospective measure of childhood abuse or neglect. This study tested the initial reliability and validity of a Korean translation of the Childhood Trauma Questionnaire (CTQ-K) among non-psychotic psychiatric outpatients. METHODS: The CTQ-K was administered to a total of 163 non-psychotic psychiatric outpatients at a university-affiliated training hospital. Internal consistency, four-week test-retest reliability, and validity were calculated. A portion of the participants (n=65) also completed the Trauma Assessment Questionnaire (TAQ), the Impact of Events Scale-Revised, and the Dissociative Experiences Scale-Taxon. RESULTS: Four-week test-retest reliability was high (r=0.87) and internal consistency was good (Cronbach's alpha=0.88). Each type of childhood trauma was significantly correlated with the corresponding subscale of the TAQ, thus confirming its concurrent validity. In addition, the CTQ-K total score was positively related to post-traumatic symptoms and pathological dissociation, demonstrating the convergent validity of the scale. The CTQ-K was also negatively correlated with the competence and safety subscale of the TAQ, confirming discriminant validity. Additionally, we confirmed the factorial validity by identifying a five-factor structure that explained 64% of the total variance. CONCLUSION: Our study indicates that the CTQ-K is a measure of psychometric soundness that can be used to assess childhood abuse or neglect in Korean patients. It also supports the cross-cultural equivalence of the scale. PMID- 22216040 TI - The Symptom Frequency Characteristics of the Hamilton Depression Rating Scale and Possible Symptom Clusters of Depressive Disorders in Korea: The CRESCEND Study. AB - OBJECTIVE: This study analyzed the symptom frequencies of 17-item Hamilton Depression Rating Scale (HDRS-17) to understand the characteristics of each item and to propose the possible symptoms clusters. METHODS: From psychiatric clinics of 18 Hospitals in Korea, 1,183 patients, diagnosed with major depressive disorder (psychotic or non-psychotic), dysthymia or depressive disorder not otherwise specified. according to DSM-IV criteria, participated in this study from January 2006 to August 2008. The frequencies of each item of HDRS-17 were analyzed according to sex and severity. In addition, we compared this study with a previous study performed in England by Hamilton and with two studies performed in Korea by Kim et al. RESULTS: The frequencies of HDRS-17 items varied widely in this study, ranging from 95.8% in work and activities to 37.4% in loss of weight. But, depressed mood, psychic anxiety and work and activities items exhibited constant and higher frequency or rank regardless of study, the severity of depression or sex. Insomnia early, somatic gastrointestinal, genital symptoms and insight showed relatively constant but lower frequency or rank in disregard of studies or the clinical variables. Other symptoms had variable frequencies or ranks according to the variable clinical situations (culture, time, sex, severity of depression). CONCLUSION: WE PROPOSE THREE CLUSTERS OF SYMPTOMS IN DEPRESSIVE DISORDERS: core symptoms cluster, an associated symptoms, and a situation specific symptoms. We can use these possible symptom clusters of depression in simplifying diagnosis of depression, increasing diagnostic specificity in special situation and indexing disease severity. PMID- 22216041 TI - A Study on Correlation between Anxiety Symptoms and Suicidal Ideation. AB - OBJECTIVE: In South Korea, the number of deaths from suicide has increased in the last two decades, and suicide has become both a social and political problem. In this study, after controlling the variables influencing suicidal ideation, it was expected that it would be determined if anxiety symptoms are independently related to suicidal ideation. METHODS: Data were obtained from 327 psychiatric outpatients accomplished a self-reported questionnaire that included sociodemographic characteristics and clinical variables as well as self-rating scales for measuring the severity of one's anxiety, depression, and suicidal ideation. Logistic-regression analyses were used to determine the correlation between anxiety symptoms and significant suicidal ideation, adjusting for covariates. RESULTS: The patients with significant suicidal ideation were shown to be less educated, unemployed, never married, divorced, or separated by death, or living alone, and were shown to have a lower income, a drinking habit, a higher number of past suicide attempts, and more family members who committed suicide, than the patients without significant suicidal ideation. After adjusting the covariates influencing significant suicidal ideation, anxiety symptoms were associated with significant suicidal ideation. However, after adjusting for depressive symptoms, only the trait anxiety was associated with significant suicidal ideation. CONCLUSION: These findings suggest that anxiety symptoms are an independent risk factor for suicidal ideation. Clinicians may thus use anxiety symptoms for the screening examination when evaluating suicidal ideation and risk, and will have to actively evaluate and treat the anxiety symptoms of patients with suicidal tendencies. PMID- 22216042 TI - Alexithymia and acne vulgaris: a case control study. AB - OBJECTIVE: To assess relationship between alexithymia and acne vulgaris in young people. METHODS: A hundred and eleven subjects between 15 and 25 years of age referred to out-patient clinic of dermatology with acne and 78 subjects applied to family physician for complaints other than acne were included in patient and control groups of the study, respectively. A questionnaire to determine demographic characteristics, an acne classification to determine severity of acne and Toronto Alexithymic Scale (TAS) to assess alexithymia were used. RESULTS: The mean scores of TAS were 52.7+/-10.8 and 51.7+/-10.7 in patient and control groups, respectively. Alexitymia was determined in 23.4% of the subjects in acne group and in 24.4% of control group. No significant differences were found between groups in terms of alexithymia, intermediate alexitymia and three-factors of TAS. CONCLUSION: Alexithymia does not appear to be related to acne vulgaris. PMID- 22216043 TI - Exploratory factor analysis and confirmatory factor analysis of the korean version of hypomania checklist-32. AB - OBJECTIVE: The Hypomania Checklist - 32 (HCL-32) is a self-assessment instrument developed by Angst et al. (2005) to identify bipolarity in the general population, as well as patients with unipolar depression. The principal objective of this study was to assess the factor structure of the Korean version of the HCL 32 for mood disorder patients, via exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). METHODS: The Korean version of HCL-32 were evaluated in a sample of 608 mood disorder patients, including 210 bipolar disorder patients and 398 unipolar disorder patients, all of whom were diagnosed in accordance with either the Structured Clinical Interview of DSM-IV or Mini International Neuropsychiatric Interview They were divided randomly into two groups, and then the EFA was administered to group 1 and the CFA was administered to group 2. RESULTS: A 3-factor structure for the HCL-32 was generated, which explained 44% of the total variance from EFA. Factor 1, comprising 18 items, was designated as 'elated mood/increased energy'; factor 2, comprising 8 items, was designated as 'risk-taking behavior/irritability'; and factor 3, comprising 2 items, was designated as 'increased sexual activity'. Researchers confirmed the 3 factor solution derived from group 1 by the CFA. CONCLUSION: The primary findings of this study were the replication and confirmation of the 3-factor structure in Korean mood disorder patients; our results were consistent with previous EFAs. PMID- 22216044 TI - Early assessment of delirium in elderly patients after hip surgery. AB - OBJECTIVE: This study is intended to identify predictive factors of delirium, including risk factors and prodromal symptoms. METHODS: This study included sixty five patients aged 65 years or older who had undergone hip surgery. Baseline assessments included age; gender; admission type (acute/elective); reason for surgery (fracture/replacement); C-reactive protein (CRP); Acute Physiology, Age, Chronic Health Evaluation (APACHE III); and the Mini-Mental State Examination (MMSE). The Korean version of the Delirium Rating Scale-Revised-98 (K-DRS-98) was used to assess prodromal symptoms daily before the onset of delirium. RESULTS: Almost 28% (n=18) of the 65 patients developed delirium after surgery. Delirium in elderly patients after hip surgery was observed more often in older patients and those with acute admission, hip fracture, higher APACHE III score, lower MMSE score, and higher CRP levels within early days after the operation. Sleep-wake cycle disturbances, thought process abnormalities, orientation, and long-term memory in symptom items of K-DRS-98 were showed significant difference on 4 days before delirium, lability of affect on 3 days before, perceptual disturbances and hallucination, and visuo-spatial ability on 2 days before, and delusion, motor agitation, and short-term memory on the day before the occurrence of delirium. CRP levels within 24 hours and 72 hours after hospitalization were significantly higher in the delirium group. CONCLUSION: Medical professionals must pay attention to behavioral, cognitive changes and risk factors in elderly patients undergoing hip surgery and to the prodromal phase of delirium. K-DRS-98 may help in identifying the prodromal symptoms of delirium in elderly patients after hip surgery. PMID- 22216045 TI - A combination of the korean version of the mini-mental state examination and korean dementia screening questionnaire is a good screening tool for dementia in the elderly. AB - OBJECTIVE: The aim of this study is to investigate whether a combination of the Korean version of the mini-mental state examination (K-MMSE) and the Korean dementia screening questionnaire (KDSQ) is better than the use of test alone when differentiating patients with dementia from those without dementia in Korea. METHODS: The subjects (patients without dementia, 1120; patients with dementia, 908) were recruited from the Clinical Research Center for Dementia of South Korea. K-MMSE and KDSQ were used. Diagnosis of dementia was made according to the Diagnostic and Statistical Manual of Mental Disorders, fourth Edition. The weighted sum rule derived from logistic regression analysis was used for the combination of K-MMSE and KDSQ. RESULTS: On comparing the Area Under the Curve for each test using the method of Hanley and McNeil, the weighted sum was significantly greater than KDSQ or K-MMSE, and K-MMSE was significantly greater than KDSQ. CONCLUSION: This study shows that when differentiating patients with dementia from those without dementia in Korea, a combination of K-MMSE and KDSQ achieved using the weighted sum method is better than either test performed alone. Further epidemiological studies in community-based settings are required before our results can be generalized to nonclinical samples. PMID- 22216046 TI - Multistrategic memory training with the metamemory concept in healthy older adults. AB - OBJECTIVE: According to the increase of older people, the need for effective methods to maintain or improve cognitive functions in the elderly has increased. These cognitive enhancing methods may contribute to the prevention of elderly cognitive decline by aging and dementing illness as well. This study aimed to examine the effectiveness of multistrategic memory training with the metamemory concept on cognitive functions in the normal health elderly in Korea. METHODS: The program used in this study was developed by psychiatrists and psychologists in accordance with Korean situations. We applied the training program to the community-dwelling elderly with subjective memory complaints. Twenty participants were randomly received the intervention with 20 non-treatment controls. This program consisted of 10 sessions and was administered once a week. We examined the effects of this memory training for verbal memory, visuospatial memory, working memory, and verbal fluency ability by repeated ANOVA. RESULTS: There were significant improvements in Word List Short-term Delayed Free and Cued Recall, Word list Long-term Delayed Free and Cued Recall and visuospatial recognition memory. Performance improvements in visuospatial span forwards and the Categorical Fluency Test were also significant. These improvements were still significant after adjusting for depression improvement exact categorical fluency. CONCLUSION: This study shows that multistrategic memory training with the metamemory concept may improve memory ability and other cognitive functions which are not trained and that these improvements may be achieved by pure cognitive training effects. PMID- 22216047 TI - Neutrophils are decreased in obsessive-compulsive disorder: preliminary investigation. AB - OBJECTIVE: There has been no study in the literature evaluating total blood count in obsessive-compulsive disorder (OCD). Therefore, we performed the present study to spesifically measure serum total blood count particularly white blood cells to see whether or not its eventual alterations might have an etiopathogenetic significance in patients with OCD. METHODS: Total blood count was measured in thirty patients and same number of healthy controls. Additionally, all patients were assessed by Yale-Brown Obsession Compulsion Scale (Y-BOCS). RESULTS: Except for neutrophil count, there were no significant differences between the groups regarding any haematological parameter. The mean neutrophil count of the patient group was lower compared to that of the control subjects. CONCLUSION: In conclusion, the present study suggests that neutrophil count is reduced in pure OCD patients and this finding may contribute to the role of immunological factors in the pathogenesis of OCD. PMID- 22216048 TI - Transferrin in korean children with attention deficit hyperactivity disorder. AB - OBJECTIVE: The aim of the present study was to investigate the relationship between iron, ferritin, transferrin, total iron binding capacity (TIBC), hemoglobin, mean corpuscular volume (MCV) mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) in children with ADHD. METHODS: MethodsaaThe sample consisted of 48 ADHD children and sex and age matched control children (a couple of 28 boys, 22 girls; age 6-8 years; mean+/-SD, 6.98+/-0.39). We diagnosed ADHD according to DSM-IV. ADHD symptoms were evaluated subjectively with Conners' Parent Rating Scales, Dupaul Parent ADHD Rating Scales. Subjects with ADHD and control were evaluated the hematology test including the iron, transferrin, MCV etc. Paired t test were used to evaluate the relation of a lot of hematology findings between ADHD and control group. RESULTS: The serum iron, ferritin, transferrin, TIBC, hemoglobin, MCV, MCH, and MCHC of ADHD group were respectively 80.92+/-33.33 ug/dL, 35.81+/-16.59 ng/mL, 248.42+/-44.15 mg/dL, 351.69+/-102.13 ug/dL, 12.78+/-0.71 g/dL, 82.94+/-2.58 fL, 27.18+/-1.12 uug, 32.79+/-1.12%. Otherwise the serum iron, ferritin, transferrin, TIBC, hemoglobin, MCV, MCH, and MCHC of control group were respectively 82.04+/-28.14 ug/dL, 37.05+/-18.28 ng/mL, 266.27+/-25.40 mg/dL, 352.77+/-89.54 ug/dL, 12.77+/-0.70 g/dL, 81.81+/-2.96 fL, 26.69+/-0.99 uug, 32.66+/-0.96%. A significant difference were found in the transferrin(t=2.63, p=0.011), MCV (t=2.19, p=0.034), and MCH (t=2.18, p=0.034). CONCLUSION: These results suggested that lower transferrin levels might be related with ADHD symptoms. PMID- 22216049 TI - Electroencephalographic abnormalities in clozapine-treated patients: a cross sectional study. AB - The objective of our study was to examine the electroencephalogram (EEG) abnormalities associated with clozapine treatment. It was a cross-sectional study on 87 psychiatric patients on clozapine treatment. 32 channel digital EEG was recorded and analysed visually for abnormalities. EEG abnormalities were observed in 63.2% of patients. Both slowing and epileptiform activities were noted in 41.4% of patients. The EEG abnormalities were not associated with dose or duration of clozapine exposure. PMID- 22216050 TI - Use of Lorazepam in drug-assisted interviews: two cases of dissociative amnesia. AB - Drug-assisted interviews are useful for psychiatric diagnosis and treatment. However, amobarbital, a typical medication used for this purpose, is associated with elevated risk of respiratory depression. Benzodiazepines are good substitutes for amobarbital, with similar therapeutic effects and fewer complications. Although drug-assisted interviews are not widely used, they may be beneficial for selected patients who do not respond to conventional treatments such as supportive psychotherapy or psychopharmacotherapy. We report two cases of dissociative amnesia that were treated using lorazepam-assisted interviews. The use of lorazepam in drug-assisted interviews is effective and safe for resolving dissociative amnesia. PMID- 22216051 TI - Completion of chronic hepatitis C virus treatment in interferon-induced major depressive disorder with psychotic features. AB - Interferon (IFN)-associated psychiatric disorders can be managed without interruption to hepatitis C virus (HCV) treatment. The limited number of cases in the literature reporting psychotic depression as an adverse drug reaction to IFN resulted in discontinuation of HCV therapy. The author reports a case of a 49 year-old man with chronic HCV genotype 1a treated with pegylated interferon-alpha and ribavirin developing major depressive disorder with psychotic features. The patient was successfully treated with both an antidepressant and antipsychotic for this suspected IFN-associated adverse drug effect while continuing 12 months of uninterrupted HCV treatment and subsequently achieving sustained hepatitis C virological response. Although IFN can cause distressing psychiatric disturbances, appropriate treatment with psychotropic agents and careful monitoring allows patients to be maintained on a full course of HCV treatment. PMID- 22216052 TI - Human immunodeficiency virus-associated tuberculosis. PMID- 22216053 TI - The trade in medicinal animals in northeastern Brazil. AB - Over the centuries, a significant part of the Brazilian fauna is widely sold, more specifically in retail stores or street markets. The objective was to characterize the sale of medicinal animals in five large northeast cities. Information about the sale of zootherapeutic items was obtained in the cities of Aracaju-SE, Fortaleza-CE, Maceio-AL, Recife-PE, and Salvador-BA. A total of 68 animal species were sold for medicinal purposes in the cities studied; these are the first results on the use and sale of zootherapeutics in the markets of Aracaju, Fortaleza, and Salvador and first recorded on the medicinal use of the Achatina fulica, Trachycardium muricatum, Philodryas olfersii, Desmodus rotundus, and Leptodactylus vastus. Knowledge of the fauna utilized popular medicine is indispensable for conservation, demonstrating that research on this subject is necessary to determine appropriate practices for the management of the fauna. PMID- 22216054 TI - A comparative randomised controlled trial of the effects of brain wave vibration training, iyengar yoga, and mindfulness on mood, well-being, and salivary cortisol. AB - This randomised trial compared the effects of Brain Wave Vibration (BWV) training, which involves rhythmic yoga-like meditative exercises, with Iyengar yoga and Mindfulness. Iyengar provided a contrast for the physical components and mindfulness for the "mental" components of BWV. 35 healthy adults completed 10 75 minute classes of BWV, Iyengar, or Mindfulness over five weeks. Participants were assessed at pre- and postintervention for mood, sleep, mindfulness, absorption, health, memory, and salivary cortisol. Better overall mood and vitality followed both BWV and Iyengar training, while the BWV group alone had improved depression and sleep latency. Mindfulness produced a comparatively greater increase in absorption. All interventions improved stress and mindfulness, while no changes occurred in health, memory, or salivary cortisol. In conclusion, increased well being followed training in all three practices, increased absorption was specific to Mindfulness, while BWV was unique in its benefits to depression and sleep latency, warranting further research. PMID- 22216055 TI - Experimental Assessment of Moringa oleifera Leaf and Fruit for Its Antistress, Antioxidant, and Scavenging Potential Using In Vitro and In Vivo Assays. AB - We have investigated effect of Moringa oleifera leaf and fruit extracts on markers of oxidative stress, its toxicity evaluation, and correlation with antioxidant properties using in vitro and in vitro assays. The aqueous extract of leaf was able to increase the GSH and reduce MDA level in a concentration dependent manner. The ethanolic extract of fruit showed highest phenolic content, strong reducing power and free radical scavenging capacity. The antioxidant capacity of ethanolic extract of both fruit and leaf was higher in the in vitro assay compared to aqueous extract which showed higher potential in vivo. Safety evaluation studies showed no toxicity of the extracts up to a dose of 100 mg/kg body weight. Our results support the potent antioxidant activity of aqueous and ethanolic extract of Moringa oleifera which adds one more positive attribute to its known pharmacological importance. PMID- 22216056 TI - Chinese Medicine's Intervention Effect on Nogo-A/NgR. AB - Cerebral vascular disease is very common in the elderly and is one of the most dangerous diseases which is hazardous to the body's health, and it is the medical specialists' study hot spot not only in the clinical field but also in the medical basic research field. Neural regeneration has been paid more and more attention in recent years. Nogo's function in the process of neural regeneration has become the focal point since it was discovered in the year 2000. Many studies elucidate that Nogo negatively affects the neural regeneration and plasticity. Chinese medicine plays an important role in the prevention and treatment of neural diseases, and recently some researches about the Chinese medicine's intervention effect on Nogo-A/NgR sprang up, so it is necessary to make a review on this aspect. PMID- 22216057 TI - Acupuncture stimulation alleviates corticosterone-induced impairments of spatial memory and cholinergic neurons in rats. AB - The purpose of this study was to examine whether acupuncture improves spatial cognitive impairment induced by repeated corticosterone (CORT) administration in rats. The effect of acupuncture on the acetylcholinergic system was also investigated in the hippocampus. Male rats were subcutaneously injected with CORT (5 mg/kg) once daily for 21 days. Acupuncture stimulation was performed at the HT7 (Sinmun) acupoint for 5 min before CORT injection. HT7 acupoint is located at the end of transverse crease of ulnar wrist of forepaw. In CORT-treated rats, reduced spatial cognitive function was associated with significant increases in plasma CORT level (+36%) and hippocampal CORT level (+204%) compared with saline treated rats. Acupuncture stimulation improved the escape latency for finding the platform in the Morris water maze. Consistently, the acupuncture significantly alleviated memory-associated decreases in cholinergic immunoreactivity and mRNA expression of BDNF and CREB in the hippocampus. These findings demonstrate that stimulation of HT7 acupoint produced significant neuroprotective activity against the neuronal impairment and memory dysfunction. PMID- 22216058 TI - Jaceosidin Induces Apoptosis in U87 Glioblastoma Cells through G2/M Phase Arrest. AB - Artemisia argyi is a widely used medicinal plant in China. The present study was designed to identify the bioactive constituents with antiglioma activity from leaves of Artemesia argyi. A bioactivity guided approach based on MTT assay for cells growth inhibition led to the isolation of a flavonoid, "jaceosidin" from ethanol extract of leaves of Artemesia argyi. The growth inhibitory effect of jaceosidin was explored using flow cytometry and Western blot studies. Our results showed that jaceosidin exerts growth inhibitory effect by arresting the cells at G2/M phase and induction of apoptosis. Furthermore, our study revealed that induction of apoptosis was associated with cell cycle arrest at G2/M phase, upregulation of p53 and Bax, decrease in mitochondrial membrane potential, release of cytochrome c, and activation of caspase 3. This mitochondrial-caspase 3-dependent apoptosis pathway was confirmed by pretreatment with caspase 3 inhibitor, Ac-DEVD-CHO. Our findings suggested that jaceosidin induces mitochondrial-caspase-3-dependent apoptosis in U87 cells by arresting the cell cycle at G2/M phase. PMID- 22216059 TI - Neuroendocrine mechanisms of acupuncture in the treatment of hypertension. AB - Hypertension affects approximately 1 billion individuals worldwide. Pharmacological therapy has not been perfected and often is associated with adverse side effects. Acupuncture is used as an adjunctive treatment for a number of cardiovascular diseases like hypertension. It has long been established that the two major contributors to systemic hypertension are the intrarenal renin angiotensin system and chronic activation of the sympathetic nervous system. Recent evidence indicates that in some models of cardiovascular disease, blockade of AT1 receptors in the rostral ventrolateral medulla (rVLM) reduces sympathetic nerve activity and blood pressure, suggesting that overactivity of the angiotensin system in this nucleus may play a role in the maintenance of hypertension. Our experimental studies have shown that electroacupuncture stimulation activates neurons in the arcuate nucleus, ventrolateral gray, and nucleus raphe to inhibit the neural activity in the rVLM in a model of visceral reflex stimulation-induced hypertension. This paper will discuss current knowledge of the effects of acupuncture on central nervous system and how they contribute to regulation of acupuncture on the endocrine system to provide a perspective on the future of treatment of hypertension with this ancient technique. PMID- 22216060 TI - Layer-by-Layer Assemblies in Nanoporous Templates: Nano-Organized Design and Applications of Soft Nanotechnology. AB - The synergistic combination of layer-by-layer (LbL) assembly and nanoporous membrane templating has greatly facilitated the creation of complex and functional nanotubular structures. The approach takes advantage of both the new properties conferred by assembling diverse LbL building blocks and the tight dimensional control offered by nanotemplating to enable new functionalities that arise from the highly anisotropic "one-dimensional" LbL-nanotube format. In this review, we aim to convey the key developments and provide a current snap-shot of such templated LbL nanoarchitectures. We survey recent developments that have enabled the assembly of polymers, biomolecules and inorganic nanoparticles "a la carte", via electrostatic, covalent and specific (bio)recognition interactions. We also discuss the emerging mechanistic understanding of the LbL assembly process within the nanopore environment. Finally, we present a diverse range of LbL nanotube "devices" to illustrate the versatility of the nanotemplated LbL toolbox for generating functional soft nanotechnology. PMID- 22216061 TI - Resiliency and survival skills among newly homeless adolescents: Implications for future interventions. AB - Recent studies on homeless adolescents suggest that the profiles of homeless adolescents are heterogeneous, and that certain clusters of homeless adolescents demonstrated resiliency and positive coping strategies. This study examined the relationship between HIV-related risk factors and resiliency (survival skills) of homeless adolescents over a 2-year period. Those who did not engage in unprotected sex reported significantly higher survival skills scores. Similarly, those who were monogamous during the study period reported significantly higher survival skills scores. However, there was a significant decline in survival skills scores after 6 months, regardless of the HIV-related risk factors. Findings from this study point to the urgent need to identify and target resilient adolescents early on to provide interventions to facilitate the transition to stable living situations before their resiliency deteriorates. PMID- 22216064 TI - Predictors of attack severity and duration in multiple sclerosis: a prospective study. AB - OBJECTIVE: To evaluate predictors of severity and duration of early Multiple Sclerosis (MS) attacks. METHODS: We analyzed 248 attacks in 95 patients in a prospective study. Severity: the difference between the EDSS score at the day of maximum worsening and the EDSS score before the onset of the attack. DURATION: the time between the date of onset of the first symptom and the date of maximum improvement of the last symptom. RESULTS: The number of involved Functional Systems (FS), FS type (brainstem and pyramidal), and total attack duration were linked to severity. Number of FS involved, FS type (sphincteric and sensory), and severity of the attack were related to duration. Neither severity nor duration were correlated to other predictors: gender, age and season at attack onset, speed of onset, infections in the preceding month, age at first attack, season of birth and first attack, CSF examination, first brain MRI, recovery from the first attack. In the multivariate analysis, the Odds Ratio (OR) and Confidence Intervals (CI) for severe attacks was 3.6, 1.7-7.7 for involvement of pyramidal FS, 2.6, 1.2-6.0 for brainstem and 2.5, 1.2-5.3 for long attack duration. Sphincteric (4.4; 1.7-11.0) and sensory FS (1.8; 1.0-3.2) were the only variables explaining duration. The probability of a second moderate/severe or long attack was not influenced by severity or duration of the first. CONCLUSION: FS are predictive of severity and duration of early MS attacks. Severity and duration of the first attack do not predict severity and duration of the second. PMID- 22216063 TI - Continuous positive airway pressure treatment: effect on serum lipids in patients with obstructive sleep apnoea. AB - Obstructive Sleep Apnoea (OSA) is a common disorder in adults. Its hallmark is repetitive episodes of partial or complete obstruction of the upper airway during sleep associated with increasing respiratory efforts. This leads to oxyhaemoglobin desaturation, sleep fragmentation, and daytime symptoms, mainly excessive sleepiness. Accumulating evidence suggests that intermittent hypoxia and oxyhaemoglobin desaturation may, irrespective of obesity, lead to elevation of serum lipids even in non-dyslipidaemic OSA patients. Continuous Positive Airway Pressure (CPAP) is the treatment of choice for OSA, since it eliminates upper airway collapse during sleep and improves sleep fragmentation, daytime symptoms and quality of life. Moreover, it has been proposed that the amelioration of breathing disturbances during sleep can improve several markers of the lipid profile, such as total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol as well as apolipoproteins A, B and C. Indeed, some studies have reported improvements in these parameters especially in CPAP adherent patients. However, other studies failed to confirm this beneficial effect. The present article reviews the issue whether CPAP treatment exerts a beneficial effect on lipids. PMID- 22216062 TI - Management of dyslipidemia in HIV-infected patients. AB - Antiretroviral therapy has dramatically increased survival for HIV-infected individuals. As this population lives longer, coronary heart disease has become an important comorbid condition. Dyslipidemia in HIV-infected individuals is a complex condition, with multiple contributing factors including the HIV virus itself, individual genetic characteristics and antiretroviral therapy-induced metabolic changes. Effective management of dyslipidemia in this population is essential to reduce cardiovascular risk but presents multiple challenges due to interactions between antiretroviral therapy agents and lipid-lowering medications. PMID- 22216065 TI - Evaluation of the Beliefs of Parents in Iran about How to Care for Children During Dental Visits. AB - Parents play an important role in their children's dental care and in their behavior during dental visits. Separating children from their parents during dental visits has been a challenging subject of debate for many years. Therefore, this study aims to evaluate parents' attitudes about being present during their children's visits to the dentist. The subjects for this cross-sectional study included 340 Iranian parents of five-10-year-old children who had been referred to dental clinics in Kerman, Iran. For this study, the parents of these children completed self-administered questionnaires. Results showed that 218 parents (64.1%) agreed with leaving the practice room during their child's treatment, while 122 (35.9%) did not agree. The main reason expressed by 41.3% of the parents for leaving the practicing room was that the dentist would be better able to control the child if they were alone. Another reason, cited by 16.5% of the parents, was not wanting to see their child suffering, and 42.2% said they believed that their child would be better treated if they were not present. Most parents who were in agreement with leaving the practice room while their child was receiving dental care felt this would lead to a better treatment outcome. PMID- 22216066 TI - Plasma Homocysteine is Not Related to the Severity of Microangiopathy in Secondary Raynaud Phenomenon. AB - INTRODUCTION: The role of elevated homocysteine in primary and secondary Raynaud phenomenon (RP) and in patients with atherosclerosis has been reported controversially. In secondary RP due to connective tissue disease specific alterations of nailfold capillaries might be present. An association between these microvascular changes and homocysteine has been suggested. AIM: The aim of this study was to determine whether homocysteine level differs between patients with primary and secondary RP and to test the hypothesis that homocysteine or other cardiovascular risk factors are associated with specific features of microangiopathy in secondary RP. PATIENTS AND METHODS: Eighty-one consecutive patients with RP referred for vascular assessment were studied by nailfold capillaroscopy. Homocysteine, C-reactive protein and cholesterol were measured and other cardiovascular risk factors and comorbidities assessed. RESULTS: Homocysteine, C-reactive-protein and cholesterol levels did not differ between patients with primary (n=60) and secondary RP (n=21). Likewise, no differences in the prevalence of cardiovascular risk factors and comorbidities were found. In secondary RP no correlation was found between microvascular involvement and homocysteine or C-reactive protein. CONCLUSION: Plasma homocysteine is not different in patients with either primary or secondary RP and is therefore not a marker for the distinction of these diseases. The extent of microvascular involvement in secondary RP does not correlate with plasma homocysteine. PMID- 22216068 TI - Considerations About the Role of the CCR5 Gene in Juvenile Idiopathic Arthritis - Look at the Whole or Put All Parts Together? PMID- 22216067 TI - Crystalline glucosamine sulfate in the treatment of osteoarthritis: evidence of long-term cardiovascular safety from clinical trials. AB - BACKGROUND AND OBJECTIVE: Glucosamine is a safe and common treatment for osteoarthritis. Even so, literature data on the cardiovascular safety of glucosamine are limited. The objective of this paper is to investigate the long term effects of crystalline glucosamine sulfate (CGS) on key measures of cardiovascular risk in patients with osteoarthritis. METHODS: We analyzed safety data from two long-term (6-month and 3-year, respectively) randomized controlled trials of CGS. Mean changes in blood pressure, lipids, and glucose were calculated for all patients randomized to CGS or placebo in either study and for subgroups with abnormally elevated baseline values. Shift tables were used to analyze transitions from normal to abnormal levels, or vice versa. RESULTS: This analysis on 428 osteoarthritis patients includes data from subjects who had, on average, high normal blood pressure or high cholesterol at baseline. There were no significant changes in mean blood pressure after 6 months on CGS (systolic: 5+/-15 mmHg; diastolic: -5+/-10 mmHg) or placebo (systolic: -7+/-14 mmHg; diastolic: -4+/-10 mmHg). Subgroup analysis did not show significant effects in subjects with hypertension. Likewise, blood lipids (total/LDL cholesterol) and blood glucose did not change over 3 years and 6 months of treatment, respectively, even in hypercholesterolemic or hyperglycemic subjects. The proportions of patients whose blood pressure or cholesterol levels shifted from normal to abnormal, or vice versa, were comparable in the CGS and placebo groups. CONCLUSIONS: Long-term use of CGS did not affect blood pressure, lipids, or glucose in patients with osteoarthritis. These findings further support the cardiovascular safety of CGS. PMID- 22216069 TI - Enhanced expression of tissue inhibitor of metalloproteinases-4 gene in human osteoarthritic synovial membranes and its differential regulation by cytokines in chondrocytes. AB - OBJECTIVE: Tissue inhibitors of metalloproteinases (TIMPs) are multi-functional proteins with matrix metalloproteinases-inhibiting activities. We studied expression of anti-inflammatory, TIMP-4 gene in human joint tissues and its regulation by arthritis-associated cytokines. RESULTS: TIMP-4 RNA expression originating from synovial fibroblasts was significantly (2.4 fold; p<0.001) elevated in 8 osteoarthritic (OA) versus 7 non-arthritic synovial membranes. Non arthritic and OA femoral head and knee chondrocytes displayed substantial but variably constitutive expression of the TIMP-4 mRNA. In articular chondrocytes, transforming growth factor beta (TGF-beta1) and oncostatin M (OSM) upregulated TIMP-4 RNA and protein expression while interleukin-1 (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) did not, suggesting differential regulation by arthritis-associated cytokines. Interleukin 17 (IL-17) mildly induced TIMP-4 mRNA. TGF-beta1 induction of TIMP-4 expression was partly inhibited by ERK pathway and Sp1 transcription factor inhibitors. CONCLUSION: Enhanced TIMP-4 gene expression in OA synovial membranes and cartilage may be due to induction by TGF beta1, OSM and IL-17, suggesting its pathophysiological role in tissue remodeling in human joints. TGF-beta1 induction of TIMP-4 expression is mediated partly by ERK pathway and Sp1 transcription factor. PMID- 22216070 TI - Can Behcet's Disease Related Pulmonary Arterial Aneurysms be Completely Resolved? AB - Behcet disease is a systemic disease with diverse clinical symptoms which include, but not limited to, patients having oral and genital ulcers and eye involvement. We here report an 18-year-old male presenting with massive hemoptysis and cardiac arrest, having history of ulcers in the oral cavity and genitalia as well as having recent episode of uveitis. A pulmonary CT angiography revealed bilateral arterial aneurysms of pulmonary vessels. On receiving Immunosuppressive treatment for Behcet disease with prednisone and azathioprine over one year the pulmonary arterial aneurysms were completely resolved and the patient was discharged from the hospital albeit with persistent hypoxic brain injury from cardiac arrest. PMID- 22216071 TI - Prevalence of rheumatoid arthritis in the southern part of denmark. AB - The aim of the present study was to estimate the prevalence of rheumatoid arthritis in the southern part of Denmark. Using a screening questionnaire, telephone interview, register data, and a clinical examination cases were ascertained from a random sample of 4995 individuals over the age of 15. As case definition we used the original and modified 1987 American College of Rheumatology classification criteria. The overall point prevalence was 0.26% (95% confidence interval: 0.13-0.39) in the total sample and 0.35% (95% confidence interval: 0.17-0.52) among the responders; the cumulative prevalence was 0.75% (95% confidence interval: 0.52-0.97) in the total sample and 0.92% (95% confidence interval: 0.62-1.21) among the responders.The cumulative prevalence was higher than in other studies combining the results of a survey with register data. The point prevalence was underestimated due to low participation rate in the clinical examination and remission among the participants. PMID- 22216072 TI - Assessment of triangle tilt surgery in children with obstetric brachial plexus injury using the pediatric outcomes data collection instrument. AB - BACKGROUND: The benefits of triangle tilt surgery in children with OBPI have been previously validated through measurements of statistical improvements in Mallet scores and in glenohumeral congruity. The purpose of the current study was to evaluate the effectiveness of triangle tilt surgery through the application of the Pediatric Outcomes Data Collection Instrument, a well validated questionnaire designed to evaluate function and comfort in children with musculoskeletal disorders. METHODS: OBPI patients between 2 and 10 years of age who came to our institute for routine office visits between May 2009 and October 2009 were considered to participate in the study. Among the patient group, the first 130 completed surveys who met the study criteria were included in the study. The Pediatric Outcomes Data Collection Instrument was completed by the parents of patients who have undergone triangle tilt surgery (Group 1: N=63) or those who were considered candidates for this procedure (Group 2: N=67). The results were compared between the two patient groups and analyzed using the unpaired student's t-test. Later, 23 patients from the group 2, underwent triangle tilt surgery (Group 3). We collected post-op data, compared and analyzed the outcome of the surgery in these patients to their own pre-op PODCI scores, using the paired student's t test. RESULTS: In patients who have undergone triangle tilt surgery, significantly higher PODCI scores were observed in the parameters of upper extremity function (p<0.05), sports/physical function (p<0.05), basic mobility (p<0.0001) and global functioning (p<0.05), when compared to patients who have not undergone triangle tilt surgery. Further, PODCI scores in group 3 patients were significantly higher after surgery in the parameters of upper extremity function (p <0.03), Pain/Comfort (p <0.05), basic mobility (p<0.0002) and global functioning (p<0.03), when compared to before triangle tilt surgery. CONCLUSION: The results of the Pediatric Outcomes Data Collection Instrument demonstrate the functional benefits of triangle tilt surgery in patients with obstetric brachial plexus injury. PMID- 22216073 TI - Characterization of Alternanthera mosaic virus and its Coat Protein. AB - A new isolate of Alternantheramosaic virus (AltMV-MU) was purified from Portulaca grandiflora plants. It has been shown that the AltMV-MU coat protein (CP) can be efficiently reassembled in vitro under different conditions into helical RNA-free virus-like particles (VLPs) antigenically related to native virus. The AltMV-MU and VLPs were examined by atomic force and transmission electron microscopies. The encapsidated AltMV-MU RNA is nontranslatable in vitro. However, it can be translationally activated by CP phosphorylation or by binding to the TGB1protein from the virus-coded movement triple gene block. PMID- 22216074 TI - The Porcine Circovirus Type 2 Nonstructural Protein ORF3 Induces Apoptosis in Porcine Peripheral Blood Mononuclear Cells. AB - Porcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus-associated diseases in pigs. To analyze whether the PCV2 nonstructural protein ORF3 is able to induce apoptosis in nature target cells, transient expression of ORF3 in porcine peripheral blood mononuclear cells (PBMC) was performed, and apoptosis was confirmed by terminal dexoynucleotidyl transferase (TdT)-mediated BrdUTP-nick end labeling (TUNEL) assay. The apoptotic responses induced by the full length or the C-terminal half of ORF3 were significantly higher (p < 0.001) than that of cells transfected with the control plasmid. In contrast, the N-terminal half of ORF3 restrictively localized in the cytoplasm and remarkably reduced its ability to induce apoptosis, the apoptotic activity might be correlated with the nuclear localization of ORF3. Furthermore, two clusters of basic residues on the C-terminal half region at the amino acid residues 53-68 and 85-104 could mediate the nuclear localization of fusion protein, confirming their potential role as a nuclear localization signal. PMID- 22216075 TI - Retinoblastoma presenting in a child with hypomelanosis of Ito. AB - PURPOSE: To describe a case of a child with a known history of pigmentary mosaicism suggestive of Hypomelanosis of Ito presenting with unilateral leukocoria, who was ultimately diagnosed with retinoblastoma. METHODS: A report of a 16-month-old girl with pigmentary mosaicism and unilateral retinoblastoma. RESULTS: A previously healthy 16-month-old girl with a diagnosis of a mosaic hypopigmentation at the age of 6 months based on a linear and whorled pattern of skin hypopigmentation along the lines of Blaschko, presented with unilateral strabismus, leukocoria, retinal detachment, and sub-retinal exudation. Hypomelanosis of Ito and other similar neurocutaneous syndromes are known to be associated with abnormal retinal pigmentation, vascular abnormalities, and retinal detachment. Examination included a fluorescein angiogram, ultrasonography, and an MRI of the brain and orbits that demonstrated features consistent with retinoblastoma. Given these findings and a flat electroretinogram, the eye was enucleated with final pathologic confirmation of retinoblastoma. CONCLUSIONS: Previously unreported presentation of unilateral retinoblastoma in a child with pigmentary mosaicism. PMID- 22216076 TI - Presumed pyogenic granuloma associated with intravitreal anti-vascular endothelial growth factor therapy. AB - To report a case of a presumed pyogenic granuloma at the site of multiple intravitreal anti-Vascular Endothelial Growth Factor (VEGF) injections. Intravitreal anti-VEGF injections can be complicated by a localized reaction of the conjunctiva. PMID- 22216077 TI - Managing deteriorating patients: registered nurses' performance in a simulated setting. AB - AIM: To examine, in a simulated environment, rural nurses' ability to assess and manage patient deterioration using measures of knowledge, situation awareness and skill performance. BACKGROUND: Nurses' ability to manage deterioration and 'failure to rescue' are of significant concern with questions over knowledge and clinical skills. Simulated emergencies may help to identify and develop core skills. METHODS: An exploratory quantitative performance review. Thirty five nurses from a single ward completed a knowledge questionnaire and two video recorded simulated scenarios in a rural hospital setting. Patient actors simulated deteriorating patients with an Acute Myocardial Infarction (AMI) and Chronic Obstructive Pulmonary Disease (COPD) as the primary diagnosis. How aware individuals were of the situation (levels of situation awareness) were measured at the end of each scenario. RESULTS: KNOWLEDGE OF DETERIORATION MANAGEMENT VARIED CONSIDERABLY (RANGE: 27%-91%) with a mean score of 67%. Average situation awareness scores and skill scores across the two scenarios (AMI and COPD) were low (50%) with many important observations and actions missed. Participants did identify that 'patients' were deteriorating but as each patient deteriorated staff performance declined with a reduction in all observational records and actions. In many cases, performance decrements appeared to be related to high anxiety levels. Participants tended to focus on single signs and symptoms and failed to use a systematic approach to patient assessment. CONCLUSION: Knowledge and skills were generally low in this rural hospital sample with notable performance decrements as patients acutely declined. Educational models that incorporate high fidelity simulation and feedback techniques are likely to have a significant positive impact on performance. PMID- 22216078 TI - Physiological MRI. PMID- 22216079 TI - Magnetic resonance characterization of ischemic tissue metabolism. AB - Magnetic resonance imaging (MRI) and spectroscopy (MRS) are versatile diagnostic techniques capable of characterizing the complex stroke pathophysiology, and hold great promise for guiding stroke treatment. Particularly, tissue viability and salvageability are closely associated with its metabolic status. Upon ischemia, ischemic tissue metabolism is disrupted including altered metabolism of glucose and oxygen, elevated lactate production/accumulation, tissue acidification and eventually, adenosine triphosphate (ATP) depletion and energy failure. Whereas metabolism impairment during ischemic stroke is complex, it may be monitored non invasively with magnetic resonance (MR)-based techniques. Our current article provides a concise overview of stroke pathology, conventional and emerging imaging and spectroscopy techniques, and data analysis tools for characterizing ischemic tissue damage. PMID- 22216081 TI - Loss of Coherence of Low Frequency Fluctuations of BOLD FMRI in Visual Cortex of Healthy Aged Subjects. AB - Aging effects on blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) have been studied using task induced hemodynamic responses with controversial findings. The present study systematically investigated the normal aging effect in the visual cortex using 3 indices of low frequency fluctuations of resting state BOLD fMRI, i.e., amplitude of low frequency fluctuations (ALFF), regional homogeneity (ReHo) and functional connectivity (FC). These 3 resting state measurements were compared with task induced BOLD activation in the visual cortex of 2 groups of 10 young and 10 elderly subjects. Our results showed reduced functional connectivity and regional homogeneity of low frequency fluctuations of BOLD fMRI in aged subjects as compared to young subjects. While the mean magnitude of BOLD activation and the mean amplitude of low frequency fluctuations of BOLD fMRI did not vary between the 2 age groups, larger variances were observed in both measures in aged subjects. These data suggest that normal aging may be associated with "loss of coherence" of low frequency fluctuations of resting state BOLD fMRI in the visual cortex, and may affect task induced BOLD response through increased inter- and intra-subject variability. PMID- 22216080 TI - High-field FMRI for human applications: an overview of spatial resolution and signal specificity. AB - In the last decade, dozens of 7 Tesla scanners have been purchased or installed around the world, while 3 Tesla systems have become a standard. This increased interest in higher field strengths is driven by a demonstrated advantage of high fields for available signal-to-noise ratio (SNR) in the magnetic resonance signal. Functional imaging studies have additional advantages of increases in both the contrast and the spatial specificity of the susceptibility based BOLD signal. One use of this resultant increase in the contrast to noise ratio (CNR) for functional MRI studies at high field is increased image resolution. However, there are many factors to consider in predicting exactly what kind of resolution gains might be made at high fields, and what the opportunity costs might be. The first part of this article discusses both hardware and image quality considerations for higher resolution functional imaging. The second part draws distinctions between image resolution, spatial specificity, and functional specificity of the fMRI signals that can be acquired at high fields, suggesting practical limitations for attainable resolutions of fMRI experiments at a given field, given the current state of the art in imaging techniques. Finally, practical resolution limitations and pulse sequence options for studies in human subjects are considered. PMID- 22216082 TI - Sustainability of an HIV PEP Program for Sexual Assault Survivors: "Lessons Learned" from Health Care Providers. AB - This study explored challenges to continuing an HIV post-exposure prophylaxis (PEP) program of care provided to sexual assault survivors in the province of Ontario, Canada. Data were collected as part of an implementation and evaluation of a universal offering of HIV PEP (known as the HIV PEP Program) at 24 of 34 provincial hospital-based sexual assault treatment centres. Experienced health care providers were surveyed (n = 132) and interviewed in four focus groups (n = 26) about their perceptions of what, if any, factors threatened their ability to maintain the HIV PEP Program. All focus groups were audio-recorded and the recordings transcribed. The transcriptions and open-ended survey responses were analyzed using content analysis. Administrator, nurse, physician, social worker, and pharmacist respondents perceived important barriers to sustainability of the HIV PEP Program. Eight constructs were identified within four broad themes: resources (inadequate funds, overworked and unacknowledged staff), expertise (insufficient external supports, insufficiently trained and knowledgeable staff), commitment (lack of institutional support, physician resistance to offering HIV PEP), and accommodation (lack of flexibility in addressing specific client and community needs, inaccessibility and lack of clarity of tools). We discuss the implications of these findings and the actions that were taken to address the challenges. PMID- 22216084 TI - Timelines of past events: Reconstructive retrieval of temporal patterns. AB - Most naturalistic events are temporally and structurally complex in that they comprise a number of elements and that each element may have different onset and offset times within the event. This study examined temporal information processing of complex patterns of partially overlapping stimulus events by using 2 tasks of temporal processing. Specifically, participants observed a pantomime in which 5 actors appeared on the scene for different periods of time. At test, they estimated the duration each actor was present or reconstructed the temporal pattern of the pantomime by drawing a timeline for each actor. Participants made large errors in the time estimation task, but they provided relatively accurate responses by using the timeline as a retrieval support. These findings suggest that temporal processing of complex asynchronous events is a challenging cognitive task, but that reliance on visuo-spatial retrieval support, possibly in combination with other temporal heuristics, may produce functional approximations of complex temporal patterns. PMID- 22216083 TI - Saccadic eye movements are related to turning performance in Parkinson disease. AB - BACKGROUND: Persons with Parkinson disease (PD) experience difficulty turning, leading to freezing of gait and falls. We hypothesized that saccade dysfunction may relate to turning impairments, as turns are normally initiated with a saccade. OBJECTIVE: Determine whether saccades are impaired during turns in PD and if characteristics of the turn-initiating saccade are predictive of ensuing turn performance. METHODS: 23 persons with PD off medication and 19 controls performed 90 and 180 degree in-place turns to the right and left. Body segment rotations were measured using 3-D motion capture and oculomotor data were captured using a head-mounted eye tracking system and electrooculography. Total number of saccades and the amplitude, velocity, and timing of the first saccade were determined. RESULTS: Turn performance (turn duration, number of steps to turn) was impaired in PD (p<0.05). PD performed more saccades, and the velocity and timing of the first saccade was impaired for both turn amplitudes (p<0.05). Amplitude of the first saccade was decreased in PD during 180 degree turns. Turn duration correlated with oculomotor function. Characteristics of the first saccade explained 48% and 58% of the variance in turn duration for 90 and 180 degree turns, respectively. CONCLUSIONS: Turning performance is impaired in PD and may be influenced by saccade dysfunction. An association between saccade function and turning performance may be indicative of the key role of saccades in initiating proper turning kinematics. Future work should focus on improving saccade performance during functional tasks and testing the effects of therapeutic interventions on related outcomes. PMID- 22216085 TI - Activation of lymphocytes induced by bronchial epithelial cells with prolonged RSV infection. AB - Respiratory syncytial virus (RSV) preferentially infects airway epithelial cells,which might be responsible for susceptibility to asthma; however, the underlying mechanism is not clear. This study determined the activation of lymphocytes and drift of helper T (Th) subsets induced by RSV-infected human bronchial epithelial cells (HBECs) in vitro. HBECs had prolonged infection with RSV, and lymphocytes isolated from human peripheral blood were co-cultured with RSV-infected HBECs. Four groups were established, as follows: lymphocytes (group L); lymphocytes infected with RSV (group RL); co-culture of lymphocytes with non infected HBECs (group HL); and co-culture of lymphocytes with infected HBECs (group HRL). After co-culture with HBECs for 24 hours, lymphocytes were collected and the following were determined in the 4 groups: cell cycle status; apoptosis rate; and concentrations of IL-4, IFN-gamma, and IL-17 in the supernatants. Cell cycle analysis for lymphocytes showed a significant increase in S phase cells, a decrease in G1 phase cells, and a higher apoptosis rate in group HRL compared with the other three groups. In group HRL, the levels of IL-4, IFN-gamma, and IL 17 in supernatants were also higher than the other three groups. For further study, lymphocytes were individually treated with supernatants from non-infected and RSV-infected HBECs for 24 h. We showed that supernatants from RSV-infected HBECs induced the differentiation of Th2 and Th17 subsets, and suppressed the differentiation of Treg subsets. Our results showed that HBECs with prolonged RSV infection can induce lymphocyte proliferation and apoptosis, and enhance the release of cytokines by lymphocytes. Moreover, subset drift might be caused by RSV-infected HBECs. PMID- 22216086 TI - Parametric construction of episode networks from pseudoperiodic time series based on mutual information. AB - Recently, the construction of networks from time series data has gained widespread interest. In this paper, we develop this area further by introducing a network construction procedure for pseudoperiodic time series. We call such networks episode networks, in which an episode corresponds to a temporal interval of a time series, and which defines a node in the network. Our model includes a number of features which distinguish it from current methods. First, the proposed construction procedure is a parametric model which allows it to adapt to the characteristics of the data; the length of an episode being the parameter. As a direct consequence, networks of minimal size containing the maximal information about the time series can be obtained. In this paper, we provide an algorithm to determine the optimal value of this parameter. Second, we employ estimates of mutual information values to define the connectivity structure among the nodes in the network to exploit efficiently the nonlinearities in the time series. Finally, we apply our method to data from electroencephalogram (EEG) experiments and demonstrate that the constructed episode networks capture discriminative information from the underlying time series that may be useful for diagnostic purposes. PMID- 22216087 TI - A crucial role of activin A-mediated growth hormone suppression in mouse and human heart failure. AB - Infusion of bone marrow-derived mononuclear cells (BMMNC) has been reported to ameliorate cardiac dysfunction after acute myocardial infarction. In this study, we investigated whether infusion of BMMNC is also effective for non-ischemic heart failure model mice and the underlying mechanisms. Intravenous infusion of BMMNC showed transient cardioprotective effects on animal models with dilated cardiomyopathy (DCM) without their engraftment in heart, suggesting that BMMNC infusion improves cardiac function via humoral factors rather than their differentiation into cardiomyocytes. Using conditioned media from sorted BMMNC, we found that the cardioprotective effects were mediated by growth hormone (GH) secreted from myeloid (Gr-1(+)) cells and the effects was partially mediated by signal transducer and activator of transcription 3 in cardiomyocytes. On the other hand, the GH expression in Gr-1(+) cells was significantly downregulated in DCM mice compared with that in healthy control, suggesting that the environmental cue in heart failure might suppress the Gr-1(+) cells function. Activin A was upregulated in the serum of DCM models and induced downregulation of GH levels in Gr-1(+) cells and serum. Furthermore, humoral factors upregulated in heart failure including angiotensin II upregulated activin A in peripheral blood mononuclear cells (PBMNC) via activation of NFkappaB. Similarly, serum activin A levels were also significantly higher in DCM patients with heart failure than in healthy subjects and the GH levels in conditioned medium from PBMNC of DCM patients were lower than that in healthy subjects. Inhibition of activin A increased serum GH levels and improved cardiac function of DCM model mice. These results suggest that activin A causes heart failure by suppressing GH activity and that inhibition of activin A might become a novel strategy for the treatment of heart failure. PMID- 22216088 TI - Molecular mechanisms of bortezomib resistant adenocarcinoma cells. AB - Bortezomib (VelcadeTM) is a reversible proteasome inhibitor that is approved for the treatment of multiple myeloma (MM). Despite its demonstrated clinical success, some patients are deprived of treatment due to primary refractoriness or development of resistance during therapy. To investigate the role of the duration of proteasome inhibition in the anti-tumor response of bortezomib, we established clonal isolates of HT-29 adenocarcinoma cells adapted to continuous exposure of bortezomib. These cells were ~30-fold resistant to bortezomib. Two novel and distinct mutations in the beta5 subunit, Cys63Phe, located distal to the binding site in a helix critical for drug binding, and Arg24Cys, found in the propeptide region were found in all resistant clones. The latter mutation is a natural variant found to be elevated in frequency in patients with MM. Proteasome activity and levels of both the constitutive and immunoproteasome were increased in resistant cells, which correlated to an increase in subunit gene expression. These changes correlated with a more rapid recovery of proteasome activity following brief exposure to bortezomib. Increased recovery rate was not due to increased proteasome turnover as similar findings were seen in cells co-treated with cycloheximide. When we exposed resistant cells to the irreversible proteasome inhibitor carfilzomib we noted a slower rate of recovery of proteasome activity as compared to bortezomib in both parental and resistant cells. Importantly, carfilzomib maintained its cytotoxic potential in the bortezomib resistant cell lines. Therefore, resistance to bortezomib, can be overcome with irreversible inhibitors, suggesting prolonged proteasome inhibition induces a more potent anti-tumor response. PMID- 22216089 TI - The danger of having all your eggs in one basket--winter crash of the re introduced Przewalski's horses in the Mongolian Gobi. AB - Large mammals re-introduced into harsh and unpredictable environments are vulnerable to stochastic effects, particularly in times of global climate change. The Mongolian Gobi is home to several rare large ungulates such as re-introduced Przewalski's horses (Equus ferus przewalskii) and Asiatic wild asses (Equus hemionus), but also to a millennium-old semi-nomadic livestock herding culture.The Gobi is prone to large inter-annual environmental fluctuations, but the winter 2009/2010 was particularly severe. Millions of livestock died and the Przewalski's horse population in the Gobi crashed. We used spatially explicit livestock loss statistics, ranger survey data and GPS telemetry to provide insight into the effect of a catastrophic climate event on the two sympatric wild equid species and the livestock population in light of their different space use strategies.Herders in and around the Great Gobi B Strictly Protected Area lost on average 67% of their livestock. Snow depth varied locally, resulting in livestock losses following an east-west gradient. Herders had few possibilities for evasion, as competition for available winter camps was high. Przewalski's horses used three different winter ranges, two in the east and one in the west. Losses averaged 60%, but differed hugely between east and west. Space use of Przewalski's horses was extremely conservative, as groups did not attempt to venture beyond their known home ranges. Asiatic wild asses seemed to have suffered few losses by shifting their range westwards.The catastrophic winter 2009/2010 provided a textbook example for how vulnerable small and spatially confined populations are in an environment prone to environmental fluctuations and catastrophes. This highlights the need for disaster planning by local herders, multiple re-introduction sites with spatially dispersed populations for re-introduced Przewalski's horses, and a landscape-level approach beyond protected area boundaries to allow for migratory or nomadic movements in Asiatic wild asses. PMID- 22216090 TI - A higher-order generalized singular value decomposition for comparison of global mRNA expression from multiple organisms. AB - The number of high-dimensional datasets recording multiple aspects of a single phenomenon is increasing in many areas of science, accompanied by a need for mathematical frameworks that can compare multiple large-scale matrices with different row dimensions. The only such framework to date, the generalized singular value decomposition (GSVD), is limited to two matrices. We mathematically define a higher-order GSVD (HO GSVD) for N>=2 matrices D(i)?R(m(i) * n), each with full column rank. Each matrix is exactly factored as D(i)=U(i)Sigma(i)V(T), where V, identical in all factorizations, is obtained from the eigensystem SV=VLambda of the arithmetic mean S of all pairwise quotients A(i)A(j)(-1) of the matrices A(i)=D(i)(T)D(i), i?j. We prove that this decomposition extends to higher orders almost all of the mathematical properties of the GSVD. The matrix S is nondefective with V and Lambda real. Its eigenvalues satisfy lambda(k)>=1. Equality holds if and only if the corresponding eigenvector v(k) is a right basis vector of equal significance in all matrices D(i) and D(j), that is sigma(i,k)/sigma(j,k)=1 for all i and j, and the corresponding left basis vector u(i,k) is orthogonal to all other vectors in U(i) for all i. The eigenvalues lambda(k)=1, therefore, define the "common HO GSVD subspace." We illustrate the HO GSVD with a comparison of genome-scale cell-cycle mRNA expression from S. pombe, S. cerevisiae and human. Unlike existing algorithms, a mapping among the genes of these disparate organisms is not required. We find that the approximately common HO GSVD subspace represents the cell-cycle mRNA expression oscillations, which are similar among the datasets. Simultaneous reconstruction in the common subspace, therefore, removes the experimental artifacts, which are dissimilar, from the datasets. In the simultaneous sequence independent classification of the genes of the three organisms in this common subspace, genes of highly conserved sequences but significantly different cell cycle peak times are correctly classified. PMID- 22216092 TI - Restricting microbial exposure in early life negates the immune benefits associated with gut colonization in environments of high microbial diversity. AB - BACKGROUND: Acquisition of the intestinal microbiota in early life corresponds with the development of the mucosal immune system. Recent work on caesarean delivered infants revealed that early microbial composition is influenced by birthing method and environment. Furthermore, we have confirmed that early-life environment strongly influences both the adult gut microbiota and development of the gut immune system. Here, we address the impact of limiting microbial exposure after initial colonization on the development of adult gut immunity. METHODOLOGY/PRINCIPAL FINDINGS: Piglets were born in indoor or outdoor rearing units, allowing natural colonization in the immediate period after birth, prior to transfer to high-health status isolators. Strikingly, gut closure and morphological development were strongly affected by isolator-rearing, independent of indoor or outdoor origins of piglets. Isolator-reared animals showed extensive vacuolation and disorganization of the gut epithelium, inferring that normal gut closure requires maturation factors present in maternal milk. Although morphological maturation and gut closure were delayed in isolator-reared animals, these hard-wired events occurred later in development. Type I IFN, IL-22, IL-23 and Th17 pathways were increased in indoor-isolator compared to outdoor-isolator animals during early life, indicating greater immune activation in pigs originating from indoor environments reflecting differences in the early microbiota. This difference was less apparent later in development due to enhanced immune activation and convergence of the microbiota in all isolator reared animals. This correlated with elevation of Type I IFN pathways in both groups, although T cell pathways were still more affected in indoor-reared animals. CONCLUSIONS/SIGNIFICANCE: Environmental factors, in particular microbial exposure, influence expression of a large number of immune-related genes. However, the homeostatic effects of microbial colonization in outdoor environments require sustained microbial exposure throughout development. Gut development in high-hygiene environments negatively impacts on normal succession of the gut microbiota and promotes innate immune activation which may impair immune homeostasis. PMID- 22216091 TI - M-CSF induces monocyte survival by activating NF-kappaB p65 phosphorylation at Ser276 via protein kinase C. AB - Macrophage colony-stimulating factor (M-CSF) promotes mononuclear phagocyte survival and proliferation. The transcription factor Nuclear Factor-kappaB (NF kappaB) is a key regulator of genes involved in M-CSF-induced mononuclear phagocyte survival and this study focused at identifying the mechanism of NF kappaB transcriptional activation. Here, we demonstrate that M-CSF stimulated NF kappaB transcriptional activity in human monocyte-derived macrophages (MDMs) and the murine macrophage cell line RAW 264.7. The general protein kinase C (PKC) inhibitor Ro-31-8220, the conventional PKCalpha/beta inhibitor Go-6976, overexpression of dominant negative PKCalpha constructs and PKCalpha siRNA reduced NF-kappaB activity in response to M-CSF. Interestingly, Ro-31-8220 reduced Ser276 phosphorylation of NF-kappaBp65 leading to decreased M-CSF-induced monocyte survival. In this report, we identify conventional PKCs, including PKCalpha as important upstream kinases for M-CSF-induced NF-kappaB transcriptional activation, NF-kappaB-regulated gene expression, NF-kappaB p65 Ser276 phosphorylation, and macrophage survival. Lastly, we find that NF-kappaB p65 Ser276 plays an important role in basal and M-CSF-stimulated NF-kappaB activation in human mononuclear phagocytes. PMID- 22216093 TI - Dental occlusion in a split Amazon indigenous population: genetics prevails over environment. AB - BACKGROUND: Studies examining human and nonhuman primates have supported the hypothesis that the recent increase in the occurrence of misalignment of teeth and/or incorrect relation of dental arches, named dental malocclusion, is mainly attributed to the availability of a more processed diet and the reduced need for powerful masticatory action. For the first time on live human populations, genetic and tooth wear influences on occlusal variation were examined in a split indigenous population. The Arara-Iriri people are descendants of a single couple expelled from a larger village. In the resultant village, expansion occurred through the mating of close relatives, resulting in marked genetic cohesion with substantial genetic differences. METHODOLOGY/PRINCIPAL FINDINGS: Dental malocclusion, tooth wear and inbreeding coefficient were evaluated. The sample examined was composed of 176 individuals from both villages. Prevalence Ratio and descriptive differences in the outcomes frequency for each developmental stage of the dentition were considered. Statistical differences between the villages were examined using the chi-square test or Fisher's exact statistic. Tooth wear and the inbreeding coefficient (F) between the villages was tested with Mann-Whitney statistics. All the statistics were performed using two-tailed distribution at p<=0.05. The coefficient inbreeding (F) confirmed the frequent incestuous unions among the Arara-Iriri indigenous group. Despite the tooth wear similarities, we found a striking difference in occlusal patterns between the two Arara villages. In the original village, dental malocclusion was present in about one third of the population; whilst in the resultant village, the occurrence was almost doubled. Furthermore, the morphological characteristics of malocclusion were strongly different between the groups. CONCLUSIONS/SIGNIFICANCE: Our findings downplay the widespread influence of tooth wear, a direct evidence of what an individual ate in the past, on occlusal variation of living human populations. They also suggest that genetics plays the most important role on dental malocclusion etiology. PMID- 22216094 TI - Double mutation in photosystem II reaction centers and elevated CO2 grant thermotolerance to mesophilic cyanobacterium. AB - Photosynthetic biomass production rapidly declines in mesophilic cyanobacteria grown above their physiological temperatures largely due to the imbalance between degradation and repair of the D1 protein subunit of the heat susceptible Photosystem II reaction centers (PSIIRC). Here we show that simultaneous replacement of two conserved residues in the D1 protein of the mesophilic Synechocystis sp. PCC 6803, by the analogue residues present in the thermophilic Thermosynechococcus elongatus, enables photosynthetic growth, extensive biomass production and markedly enhanced stability and repair rate of PSIIRC for seven days even at 43 degrees C but only at elevated CO(2) (1%). Under the same conditions, the Synechocystis control strain initially presented very slow growth followed by a decline after 3 days. Change in the thylakoid membrane lipids, namely the saturation of the fatty acids is observed upon incubation for the different strains, but only the double mutant shows a concomitant major change of the enthalpy and entropy for the light activated Q(A)(-)->Q(B) electron transfer, rendering them similar to those of the thermophilic strain. Following these findings, computational chemistry and protein dynamics simulations we propose that the D1 double mutation increases the folding stability of the PSIIRC at elevated temperatures. This, together with the decreased impairment of D1 protein repair under increased CO(2) concentrations result in the observed photothermal tolerance of the photosynthetic machinery in the double mutant. PMID- 22216095 TI - Deep-sequencing analysis of the mouse transcriptome response to infection with Brucella melitensis strains of differing virulence. AB - Brucella melitensis is an important zoonotic pathogen that causes brucellosis, a disease that affects sheep, cattle and occasionally humans. B. melitensis strain M5-90, a live attenuated vaccine cultured from B. melitensis strain M28, has been used as an effective tool in the control of brucellosis in goats and sheep in China. However, the molecular changes leading to attenuated virulence and pathogenicity in B. melitensis remain poorly understood. In this study we employed the Illumina Genome Analyzer platform to perform genome-wide digital gene expression (DGE) analysis of mouse peritoneal macrophage responses to B. melitensis infection. Many parallel changes in gene expression profiles were observed in M28- and M5-90-infected macrophages, suggesting that they employ similar survival strategies, notably the induction of anti-inflammatory and antiapoptotic factors. Moreover, 1019 differentially expressed macrophage transcripts were identified 4 h after infection with the different B. melitensis strains, and these differential transcripts notably identified genes involved in the lysosome and mitogen-activated protein kinase (MAPK) pathways. Further analysis employed gene ontology (GO) analysis: high-enrichment GOs identified endocytosis, inflammatory, apoptosis, and transport pathways. Path-Net and Signal Net analysis highlighted the MAPK pathway as the key regulatory pathway. Moreover, the key differentially expressed genes of the significant pathways were apoptosis-related. These findings demonstrate previously unrecognized changes in gene transcription that are associated with B. melitensis infection of macrophages, and the central signaling pathways identified here merit further investigation. Our data provide new insights into the molecular attenuation mechanism of strain M5-90 and will facilitate the generation of new attenuated vaccine strains with enhanced efficacy. PMID- 22216096 TI - Programmed bending reveals dynamic mechanochemical coupling in supported lipid bilayers. AB - In living cells, mechanochemical coupling represents a dynamic means by which membrane components are spatially organized. An extra-ordinary example of such coupling involves curvature-dependent polar localization of chemically-distinct lipid domains at bacterial poles, which also undergo dramatic reequilibration upon subtle changes in their interfacial environment such as during sporulation. Here, we demonstrate that such interfacially-triggered mechanochemical coupling can be recapitulated in vitro by simultaneous, real-time introduction of mechanically-generated periodic curvatures and attendant strain-induced lateral forces in lipid bilayers supported on elastomeric substrates. In particular, we show that real-time wrinkling of the elastomeric substrate prompts a dynamic domain reorganization within the adhering bilayer, producing large, oriented liquid-ordered domains in regions of low curvature. Our results suggest a mechanism in which interfacial forces generated during surface wrinkling and the topographical deformation of the bilayer combine to facilitate dynamic reequilibration prompting the observed domain reorganization. We anticipate this curvature-generating model system will prove to be a simple and versatile tool for a broad range of studies of curvature-dependent dynamic reorganizations in membranes that are constrained by the interfacial elastic and dynamic frameworks such as the cell wall, glycocalyx, and cytoskeleton. PMID- 22216097 TI - Interactions between plasma levels of 25-hydroxyvitamin D, insulin-like growth factor (IGF)-1 and C-peptide with risk of colorectal cancer. AB - BACKGROUND: Vitamin D status and levels of insulin-like growth factor (IGF)-1 and C-peptide have been implicated in colorectal carcinogenesis. However, in contrast to vitamin D IGF-1 is not an easily modifiable risk factor. METHODS: Combining data from the Health Professionals Follow up Study (HPFS) and the Nurses' Health Study cohort (NHS) additive and multiplicative interactions were examined between plasma 25-hydroxyvitamin D (25(OH)D) and IGF-1, IGFBP-3 as well as C-peptide levels in 499 cases and 992 matched controls. For the various analytes, being high or low was based on being either above (or equal) or below the medians, respectively. RESULTS: Compared to participants with high 25(OH)D and low IGF 1/IGFBP-3 ratio (reference group), participants with a high IGF-1/IGFBP-3 ratio were at elevated risk of colorectal cancer when 25(OH)D was low (odds ratio (OR): 2.05 (95% CI: 1.43 to 2.92), but not when 25(OH)D was high (OR:1.20 (95% CI: 0.84 to 1.71, p(interaction): additive =0.06, multiplicative =0.25). Similarly, compared to participants with high 25(OH)D and low molar IGF-1/IGFBP-3 ratio and low C-peptide levels (reference group), participants with a combination of either high IGF-1/IGFBP-3 ratio or high C-peptide were at elevated risk for colorectal cancer when 25(OH)D was low (OR =1.90, 95% CI: 1.22 to 2.94) but not when 25(OH)D was high (OR=1.15, 95% CI: 0.74 to 1.77, p(interaction): additive=0.004; multiplicative=0.04). CONCLUSION: The results from this study suggest that improving vitamin D status may help lower risk of colorectal cancer associated with higher IGF-1/IGFBP-3 ratio or C-peptide levels. PMID- 22216099 TI - Paleogene radiation of a plant pathogenic mushroom. AB - BACKGROUND: The global movement and speciation of fungal plant pathogens is important, especially because of the economic losses they cause and the ease with which they are able to spread across large areas. Understanding the biogeography and origin of these plant pathogens can provide insights regarding their dispersal and current day distribution. We tested the hypothesis of a Gondwanan origin of the plant pathogenic mushroom genus Armillaria and the currently accepted premise that vicariance accounts for the extant distribution of the species. METHODS: The phylogeny of a selection of Armillaria species was reconstructed based on Maximum Parsimony (MP), Maximum Likelihood (ML) and Bayesian Inference (BI). A timeline was then placed on the divergence of lineages using a Bayesian relaxed molecular clock approach. RESULTS: Phylogenetic analyses of sequenced data for three combined nuclear regions provided strong support for three major geographically defined clades: Holarctic, South American-Australasian and African. Molecular dating placed the initial radiation of the genus at 54 million years ago within the Early Paleogene, postdating the tectonic break-up of Gondwana. CONCLUSIONS: The distribution of extant Armillaria species is the result of ancient long-distance dispersal rather than vicariance due to continental drift. As these finding are contrary to most prior vicariance hypotheses for fungi, our results highlight the important role of long-distance dispersal in the radiation of fungal pathogens from the Southern Hemisphere. PMID- 22216098 TI - A deep insight into the sialotranscriptome of the gulf coast tick, Amblyomma maculatum. AB - BACKGROUND: Saliva of blood sucking arthropods contains compounds that antagonize their hosts' hemostasis, which include platelet aggregation, vasoconstriction and blood clotting; saliva of these organisms also has anti-inflammatory and immunomodullatory properties. Perhaps because hosts mount an active immune response against these compounds, the diversity of these compounds is large even among related blood sucking species. Because of these properties, saliva helps blood feeding as well as help the establishment of pathogens that can be transmitted during blood feeding. METHODOLOGY/PRINCIPAL FINDINGS: We have obtained 1,626,969 reads by pyrosequencing a salivary gland cDNA library from adult females Amblyomma maculatum ticks at different times of feeding. Assembly of this data produced 72,441 sequences larger than 149 nucleotides from which 15,914 coding sequences were extracted. Of these, 5,353 had >75% coverage to their best match in the non-redundant database from the National Center for Biotechnology information, allowing for the deposition of 4,850 sequences to GenBank. The annotated data sets are available as hyperlinked spreadsheets. Putative secreted proteins were classified in 133 families, most of which have no known function. CONCLUSIONS/SIGNIFICANCE: This data set of proteins constitutes a mining platform for novel pharmacologically active proteins and for uncovering vaccine targets against A. maculatum and the diseases they carry. PMID- 22216100 TI - Community-based outbreaks in vulnerable populations of invasive infections caused by Streptococcus pneumoniae serotypes 5 and 8 in Calgary, Canada. AB - BACKGROUND: Outbreaks of invasive pneumococcal disease (IPD) typically occur within institutions. Beginning in 2005, we detected an increase in serotype (ST) 5 and ST8 IPD cases, predominantly in homeless persons living in an open community. METHODOLOGY/PRINCIPAL FINDINGS: CASPER (Calgary Area S. pneumoniae Epidemiology Research) surveillance study of all IPD (sterile site isolates) in our region (pop ~1,100,000). Interviews and chart reviews of all cases and all isolates phenotypically analyzed and selected isolated tested by multi-locus sequence typing (MLST). CONCLUSIONS/SIGNIFICANCE: During 2005-2007, 162 cases of ST5 IPD and 45 cases of ST8 IPD were identified. The isolates demonstrated phenotypic and genotypic clonality. The ST5 isolates were sequence type (ST) 289 and demonstrated intermediate susceptibility to TMP-SMX. The ST8 isolates were predominantly ST1268, with a susceptible antimicrobial susceptibility profile. Individuals with ST5 IPD were more likely to be middle aged (OR 2.6), homeless (OR 4.4), using illicit drugs(OR 4.8), and asthmatic(OR 2.6). Those with ST8 were more likely to be male (OR 4.4), homeless (OR 2.6), aboriginal (OR7.3), and a current smoker (OR 2.5). Overlapping outbreaks of ST5 and ST8 IPD occurred in an open community in Calgary, Canada and homelessness was a predominant risk factor. Homelessness represents a unique community in which pneumococcal outbreaks can occur. PMID- 22216101 TI - Gene discovery in the threatened elkhorn coral: 454 sequencing of the Acropora palmata transcriptome. AB - BACKGROUND: Cnidarians, including corals and anemones, offer unique insights into metazoan evolution because they harbor genetic similarities with vertebrates beyond that found in model invertebrates and retain genes known only from non metazoans. Cataloging genes expressed in Acropora palmata, a foundation-species of reefs in the Caribbean and western Atlantic, will advance our understanding of the genetic basis of ecologically important traits in corals and comes at a time when sequencing efforts in other cnidarians allow for multi-species comparisons. RESULTS: A cDNA library from a sample enriched for symbiont free larval tissue was sequenced on the 454 GS-FLX platform. Over 960,000 reads were obtained and assembled into 42,630 contigs. Annotation data was acquired for 57% of the assembled sequences. Analysis of the assembled sequences indicated that 83-100% of all A. palmata transcripts were tagged, and provided a rough estimate of the total number genes expressed in our samples (~18,000-20,000). The coral annotation data contained many of the same molecular components as in the Bilateria, particularly in pathways associated with oxidative stress and DNA damage repair, and provided evidence that homologs of p53, a key player in DNA repair pathways, has experienced selection along the branch separating Cnidaria and Bilateria. Transcriptome wide screens of paralog groups and transition/transversion ratios highlighted genes including: green fluorescent proteins, carbonic anhydrase, and oxidative stress proteins; and functional groups involved in protein and nucleic acid metabolism, and the formation of structural molecules. These results provide a starting point for study of adaptive evolution in corals. CONCLUSIONS: Currently available transcriptome data now make comparative studies of the mechanisms underlying coral's evolutionary success possible. Here we identified candidate genes that enable corals to maintain genomic integrity despite considerable exposure to genotoxic stress over long life spans, and showed conservation of important physiological pathways between corals and bilaterians. PMID- 22216102 TI - Improved culture-based isolation of differentiating endothelial progenitor cells from mouse bone marrow mononuclear cells. AB - Numerous endothelial progenitor cell (EPC)-related investigations have been performed in mouse experiments. However, defined characteristics of mouse cultured EPC have not been examined. We focused on fast versus slow adherent cell population in bone marrow mononuclear cells (BMMNCs) in culture and examined their characteristics. After 24 h-culture of BMMNCs, attached (AT) cells and floating (FL) cells were further cultured in endothelial differentiation medium separately. Immunological and molecular analyses exhibited more endothelial-like and less monocyte/macrophage-like characteristics in FL cells compared with AT cells. FL cells formed thick/stable tube and hypoxia or shear stress overload further enhanced these endothelial-like features with increased angiogenic cytokine/growth factor mRNA expressions. Finally, FL cells exhibited therapeutic potential in a mouse myocardial infarction model showing the specific local recruitment to ischemic border zone and tissue preservation. These findings suggest that slow adherent (FL) but not fast attached (AT) BMMNCs in culture are EPC-rich population in mouse. PMID- 22216103 TI - RegnANN: Reverse Engineering Gene Networks using Artificial Neural Networks. AB - RegnANN is a novel method for reverse engineering gene networks based on an ensemble of multilayer perceptrons. The algorithm builds a regressor for each gene in the network, estimating its neighborhood independently. The overall network is obtained by joining all the neighborhoods. RegnANN makes no assumptions about the nature of the relationships between the variables, potentially capturing high-order and non linear dependencies between expression patterns. The evaluation focuses on synthetic data mimicking plausible submodules of larger networks and on biological data consisting of submodules of Escherichia coli. We consider Barabasi and Erdos-Renyi topologies together with two methods for data generation. We verify the effect of factors such as network size and amount of data to the accuracy of the inference algorithm. The accuracy scores obtained with RegnANN is methodically compared with the performance of three reference algorithms: ARACNE, CLR and KELLER. Our evaluation indicates that RegnANN compares favorably with the inference methods tested. The robustness of RegnANN, its ability to discover second order correlations and the agreement between results obtained with this new methods on both synthetic and biological data are promising and they stimulate its application to a wider range of problems. PMID- 22216104 TI - Comparative phylogeography in a specific and obligate pollination antagonism. AB - In specific and obligate interactions the nature and abundance of a given species can have important effects on the survival and population dynamics of associated organisms. In a phylogeographic framework, we therefore expect that the fates of organisms interacting specifically are also tightly interrelated. Here we investigate such a scenario by analyzing the genetic structures of species interacting in an obligate plant-insect pollination lure-and-trap antagonism, involving Arum maculatum (Araceae) and its specific psychodid (Diptera) visitors Psychoda phalaenoides and Psycha grisescens. Because the interaction is asymmetric (i.e., only the plant depends on the insect), we expect the genetic structure of the plant to be related with the historical pollinator availability, yielding incongruent phylogeographic patterns between the interacting organisms.Using insect mtDNA sequences and plant AFLP genome fingerprinting, we inferred the large-scale phylogeographies of each species and the distribution of genetic diversities throughout the sampled range, and evaluated the congruence in their respective genetic structures using hierarchical analyses of molecular variances (AMOVA). Because the composition of pollinator species varies in Europe, we also examined its association with the spatial genetic structure of the plant.Our findings indicate that while the plant presents a spatially well defined genetic structure, this is not the case in the insects. Patterns of genetic diversities also show dissimilar distributions among the three interacting species. Phylogeographic histories of the plant and its pollinating insects are thus not congruent, a result that would indicate that plant and insect lineages do not share the same glacial and postglacial histories. However, the genetic structure of the plant can, at least partially, be explained by the type of pollinators available at a regional scale. Differences in life-history traits of available pollinators might therefore have influenced the genetic structure of the plant, the dependent organism, in this antagonistic interaction. PMID- 22216105 TI - Control of local intracellular calcium concentration with dynamic-clamp controlled 2-photon uncaging. AB - The variations of the intracellular concentration of calcium ion ([Ca(2+)](i)) are at the heart of intracellular signaling, and their imaging is therefore of enormous interest. However, passive [Ca(2+)](i) imaging provides no control over these variations, meaning that a full exploration of the functional consequences of [Ca(2+)](i) changes is difficult to attain. The tools designed so far to modify [Ca(2+)](i), even qualitatively, suffer drawbacks that undermine their widespread use. Here, we describe an electro-optical technique to quantitatively set [Ca(2+)](i), in real time and with sub-cellular resolution, using two-photon Ca(2+) uncaging and dynamic-clamp. We experimentally demonstrate, on neurons from acute olfactory bulb slices of Long Evans rats, various capabilities of this technique previously difficult to achieve, such as the independent control of the membrane potential and [Ca(2+)](i) variations, the functional knocking-in of user defined virtual voltage-dependent Ca(2+) channels, and the standardization of [Ca(2+)](i) patterns across different cells. Our goal is to lay the groundwork for this technique and establish it as a new and versatile tool for the study of cell signaling. PMID- 22216106 TI - Physical properties of biological entities: an introduction to the ontology of physics for biology. AB - As biomedical investigators strive to integrate data and analyses across spatiotemporal scales and biomedical domains, they have recognized the benefits of formalizing languages and terminologies via computational ontologies. Although ontologies for biological entities-molecules, cells, organs-are well-established, there are no principled ontologies of physical properties-energies, volumes, flow rates-of those entities. In this paper, we introduce the Ontology of Physics for Biology (OPB), a reference ontology of classical physics designed for annotating biophysical content of growing repositories of biomedical datasets and analytical models. The OPB's semantic framework, traceable to James Clerk Maxwell, encompasses modern theories of system dynamics and thermodynamics, and is implemented as a computational ontology that references available upper ontologies. In this paper we focus on the OPB classes that are designed for annotating physical properties encoded in biomedical datasets and computational models, and we discuss how the OPB framework will facilitate biomedical knowledge integration. PMID- 22216107 TI - Reduced light response of neuronal firing activity in the suprachiasmatic nucleus and optic nerve of cryptochrome-deficient mice. AB - To examine roles of the Cryptochromes (Cry1 and Cry2) in mammalian circadian photoreception, we recorded single-unit neuronal firing activity in the suprachiasmatic nucleus (SCN), a primary circadian oscillator, and optic nerve fibers in vivo after retinal illumination in anesthetized Cry1 and Cry2 double knockout (Cry-deficient) mice. In wild-type mice, most SCN neurons increased their firing frequency in response to retinal illumination at night, whereas only 17% of SCN neurons responded during the daytime. However, 40% of SCN neurons responded to light during the daytime, and 31% of SCN neurons responded at night in Cry-deficient mice. The magnitude of the photic response in SCN neurons at night was significantly lower (1.3-fold of spontaneous firing) in Cry-deficient mice than in wild-type mice (4.0-fold of spontaneous firing). In the optic nerve near the SCN, no difference in the proportion of light-responsive fibers was observed between daytime and nighttime in both genotypes. However, the response magnitude in the light-activated fibers (ON fibers) was high during the nighttime and low during the daytime in wild-type mice, whereas this day-night difference was not observed in Cry-deficient mice. In addition, we observed day-night differences in the spontaneous firing rates in the SCN in both genotypes and in the fibers of wild-type, but not Cry-deficient mice. We conclude that the low photo response in the SCN of Cry-deficient mice is caused by a circadian gating defect in the retina, suggesting that Cryptochromes are required for appropriate temporal photoreception in mammals. PMID- 22216108 TI - Assessment of the variability in influenza A(H1N1) vaccine effectiveness estimates dependent on outcome and methodological approach. AB - BACKGROUND: Estimation of Influenza vaccine effectiveness (VE) varies with study design, clinical outcome considered and statistical methodology used. By estimating VE using differing outcomes and statistical methods on the same cohort of individuals the variability in the estimates produced can be better understood. The Pandemic Influenza Primary Care Reporting (PIPeR) cohort of approximately 193,000 individuals was used to estimate pandemic VE in Scotland during season 2009-10. VE results for three outcomes; influenza related consultations, virological confirmed influenza and death were considered. Use of individualised records allowed all models to be adjusted for age, sex, deprivation, risk status relating to chronic illnesses, seasonal vaccination status and a marker of the individual's propensity to consult. For the consultation and death outcomes, VE was calculated by comparing consultation rates in the unvaccinated and vaccinated groups, adjusted for the listed factors, using both Cox and Poisson regression models. For the consultation outcome, the unvaccinated group was split into individuals before vaccination and those never vaccinated to allow for potential differences in the health seeking behaviour of these groups. For the virology outcome estimates were calculated using a generalised additive logistic regression model. All models were adjusted for time. Vaccine effect was demonstrated for the influenza-like illness consultation outcome using the Cox model (VE=49% 95% CI (19%, 67%)) with lower estimates from the model splitting the before and never vaccinated groups (VE=34.2% with 95% CI (-0.5%, 58.9%)). Vaccine effect was also illustrated for overall mortality (VE=40% (95% CI 18%, 56%)) and a virological confirmed subset of symptomatic individuals (VE=60% (95% CI -38%, 89%)). CONCLUSIONS: This study illustrates positive point estimates of Influenza VE across methodology and outcome for a single cohort of individuals during season 2009-10. Understanding of potential differences between approaches aids interpretation of VE results in future seasons. PMID- 22216109 TI - Novel M tuberculosis antigen-specific T-cells are early markers of infection and disease progression. AB - BACKGROUND: Mycobacterium tuberculosis Region-of-Difference-1 gene products present opportunities for specific diagnosis of M. tuberculosis infection, yet immune responses to only two gene-products, Early Secretory Antigenic Target-6 (ESAT-6) and Culture Filtrate Protein-10 (CFP-10), have been comprehensively investigated. METHODS: T-cell responses to Rv3873, Rv3878 and Rv3879c were quantified by IFN-gamma-enzyme-linked-immunospot (ELISpot) in 846 children with recent household tuberculosis exposure and correlated with kinetics of tuberculin skin test (TST) and ESAT-6/CFP-10-ELISpot conversion over six months and clinical outcome over two years. RESULTS: Responses to Rv3873, Rv3878, and Rv3879c were present in 20-25% of contacts at enrolment. Rv3873 and Rv3879c responses were associated with and preceded TST conversion (P=0.02 and P=0.04 respectively), identifying these antigens as early targets of cell-mediated immunity following M. tuberculosis exposure. Responses to Rv3873 were additionally associated with subsequent ESAT-6/CFP-10-ELISpot conversion (P=0.04). Responses to Rv3873 and Rv3878 predicted progression to active disease (adjusted incidence rate ratio [95% CI] 3.06 [1.05,8.95; P=0.04], and 3.32 [1.14,9.71; P=0.03], respectively). Presence of a BCG-vaccination scar was associated with a 67% (P=0.03) relative risk reduction for progression to active tuberculosis. CONCLUSIONS: These RD1 derived antigens are early targets of cellular immunity following tuberculosis exposure and T-cells specific for these antigens predict progression to active tuberculosis suggesting diagnostic and prognostic utility. PMID- 22216110 TI - Quality of maternal and neonatal care in Albania, Turkmenistan and Kazakhstan: a systematic, standard-based, participatory assessment. AB - BACKGROUND: Progress in maternal and neonatal mortality has been slow in many countries despite increasing access to institutional births, suggesting deficiencies in the quality of care. We carried out a systematic assessment of the quality of maternal and newborn care in three CEE/CIS countries, using an innovative approach to identify priority issues and promote action. METHODS: A standard-based tool, covering over 400 items grouped in 13 main areas ranging from support services to case management, was used to assess a sample of ten maternity hospitals in Albania, Kazakhstan and Turkmenistan. Sources of information were visit to services, medical records, observation of cases, and interviews with staff and mothers. A score (range 0 to 3) was attributed to each item and area of care. The assessment was carried out by a multidisciplinary team of international and national professionals. Local managers and staff provided the necessary information and were involved in discussing the findings and the priority actions. RESULTS: Quality of care was found to be substandard in all 13 areas. The lowest scores (between one and two) were obtained by: management of normal labour, delivery, obstetric complications and sick babies; infection prevention; use of guidelines and audits; monitoring and follow-up. Neonatal care as a whole scored better than obstetric care. Interviewed mothers identified lack of information, insufficient support during labour and lack of companionship as main issues. Actions to improve quality of care were identified at facility as well as at central level and framed according to main health system functions. CONCLUSIONS: Quality of care is a key issue to improve maternal and neonatal outcomes, particularly in countries such as CEE/CIS where access to institutional births is nearly universal. Approaches that involve health professionals and managers in comprehensive, action-oriented assessments of quality of care are promising and should be further supported. PMID- 22216111 TI - Alteration of gene expression profile in Niemann-Pick type C mice correlates with tissue damage and oxidative stress. AB - BACKGROUND: Niemann-Pick type C disease (NPC) is a neurovisceral lipid storage disorder mainly characterized by unesterified cholesterol accumulation in lysosomal/late endosomal compartments, although there is also an important storage for several other kind of lipids. The main tissues affected by the disease are the liver and the cerebellum. Oxidative stress has been described in various NPC cells and tissues, such as liver and cerebellum. Although considerable alterations occur in the liver, the pathological mechanisms involved in hepatocyte damage and death have not been clearly defined. Here, we assessed hepatic tissue integrity, biochemical and oxidative stress parameters of wild type control (Npc1(+/+); WT) and homozygous-mutant (Npc1(-/-); NPC) mice. In addition, the mRNA abundance of genes encoding proteins associated with oxidative stress, copper metabolism, fibrosis, inflammation and cholesterol metabolism were analyzed in livers and cerebella of WT and NPC mice. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed various oxidative stress parameters in the liver and hepatic and cerebellum gene expression in 7-week-old NPC1-deficient mice compared with control animals. We found signs of inflammation and fibrosis in NPC livers upon histological examination. These signs were correlated with increased levels of carbonylated proteins, diminished total glutathione content and significantly increased total copper levels in liver tissue. Finally, we analyzed liver and cerebellum gene expression patterns by qPCR and microarray assays. We found a correlation between fibrotic tissue and differential expression of hepatic as well as cerebellar genes associated with oxidative stress, fibrosis and inflammation in NPC mice. CONCLUSIONS/SIGNIFICANCE: In NPC mice, liver disease is characterized by an increase in fibrosis and in markers associated with oxidative stress. NPC is also correlated with altered gene expression, mainly of genes involved in oxidative stress and fibrosis. These findings correlate with similar parameters in cerebellum, as has been previously reported in the NPC mice model. PMID- 22216112 TI - Carbohydrate metabolism is essential for the colonization of Streptococcus thermophilus in the digestive tract of gnotobiotic rats. AB - Streptococcus thermophilus is the archetype of lactose-adapted bacterium and so far, its sugar metabolism has been mainly investigated in vitro. The objective of this work was to study the impact of lactose and lactose permease on S. thermophilus physiology in the gastrointestinal tract (GIT) of gnotobiotic rats. We used rats mono-associated with LMD-9 strain and receiving 4.5% lactose. This model allowed the analysis of colonization curves of LMD-9, its metabolic profile, its production of lactate and its interaction with the colon epithelium. Lactose induced a rapid and high level of S. thermophilus in the GIT, where its activity led to 49 mM of intra-luminal L-lactate that was related to the induction of mono-carboxylic transporter mRNAs (SLC16A1 and SLC5A8) and p27(Kip1) cell cycle arrest protein in epithelial cells. In the presence of a continuous lactose supply, S. thermophilus recruited proteins involved in glycolysis and induced the metabolism of alternative sugars as sucrose, galactose, and glycogen. Moreover, inactivation of the lactose transporter, LacS, delayed S. thermophilus colonization. Our results show i/that lactose constitutes a limiting factor for colonization of S. thermophilus, ii/that activation of enzymes involved in carbohydrate metabolism constitutes the metabolic signature of S. thermophilus in the GIT, iii/that the production of lactate settles the dialogue with colon epithelium. We propose a metabolic model of management of carbohydrate resources by S. thermophilus in the GIT. Our results are in accord with the rationale that nutritional allegation via consumption of yogurt alleviates the symptoms of lactose intolerance. PMID- 22216113 TI - Great apes' risk-taking strategies in a decision making task. AB - We investigate decision-making behaviour in all four non-human great ape species. Apes chose between a safe and a risky option across trials of varying expected values. All species chose the safe option more often with decreasing probability of success. While all species were risk-seeking, orangutans and chimpanzees chose the risky option more often than gorillas and bonobos. Hence all four species' preferences were ordered in a manner consistent with normative dictates of expected value, but varied predictably in their willingness to take risks. PMID- 22216114 TI - Striking a balance: socioeconomic development and conservation in grassland through community-based zoning. AB - The goal of preserving nature is often in conflict with economic development and the aspirations of the rural poor. Nowhere is this more striking than in native grasslands, which have been extensively converted until a mere fraction of their original extent remains. This is not surprising; grasslands flourish in places coveted by humans, primed for agriculture, plantations, and settlements that nearly always trump conservation efforts. The Umgano grassland conservation and poverty reduction project in KwaZulu-Natal Province, South Africa uses community based spatial planning to balance the conversion of its lower-conservation value grasslands to a timber plantation, while conserving higher-value grasslands for heritage purposes and managed livestock grazing. Ten years after project launch, we measured the ecological and socioeconomic impacts of the project using Normalized Differential Vegetation Index remote sensing data and over 500 household interviews, as compared with similar non-conserved areas. Zoned management of the Umgano area had resulted in between 9% and 17% greater average peak production in the grassland areas compared to control sites. There was also a 21% gain in incomes for the roughly one hundred people employed by the forestry efforts, when compared to others in their village. Community-based spatial zoning is an overlooked tool for balancing conservation and development but may require, as we found in Umgano, certain critical factors including strong local leadership, an accountable financial management mechanism to distribute income, outside technical expertise for the zoning design, and community support. PMID- 22216115 TI - FHA-mediated cell-substrate and cell-cell adhesions are critical for Bordetella pertussis biofilm formation on abiotic surfaces and in the mouse nose and the trachea. AB - Bordetella spp. form biofilms in the mouse nasopharynx, thereby providing a potential mechanism for establishing chronic infections in humans and animals. Filamentous hemagglutinin (FHA) is a major virulence factor of B. pertussis, the causative agent of the highly transmissible and infectious disease, pertussis. In this study, we dissected the role of FHA in the distinct biofilm developmental stages of B. pertussis on abiotic substrates and in the respiratory tract by employing a murine model of respiratory biofilms. Our results show that the lack of FHA reduced attachment and decreased accumulation of biofilm biomass on artificial surfaces. FHA contributes to biofilm development by promoting the formation of microcolonies. Absence of FHA from B. pertussis or antibody-mediated blockade of surface-associated FHA impaired the attachment of bacteria to the biofilm community. Exogenous addition of FHA resulted in a dose-dependent inhibitory effect on bacterial association with the biofilms. Furthermore, we show that FHA is important for the structural integrity of biofilms formed on the mouse nose and trachea. Together, these results strongly support the hypothesis that FHA promotes the formation and maintenance of biofilms by mediating cell substrate and inter-bacterial adhesions. These discoveries highlight FHA as a key factor in establishing structured biofilm communities in the respiratory tract. PMID- 22216116 TI - Differential effects of pravastatin and simvastatin on the growth of tumor cells from different organ sites. AB - 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, commonly known as statins, may possess cancer preventive and therapeutic properties. Statins are effective suppressors of cholesterol synthesis with a well established risk-benefit ratio in cardiovascular disease prevention. Mechanistically, targeting HMGCR activity primarily influences cholesterol biosynthesis and prenylation of signaling proteins. Pravastatin is a hydrophilic statin that is selectively taken up by a sodium-independent organic anion transporter protein-1B1 (OATP1B1) exclusively expressed in liver. Simvastatin is a hydrophobic statin that enters cells by other mechanisms. Poorly-differentiated and well-differentiated cancer cell lines were selected from various tissues and examined for their response to these two statins. Simvastatin inhibited the growth of most tumor cell lines more effectively than pravastatin in a dose dependent manner. Poorly-differentiated cancer cells were generally more responsive to simvastatin than well-differentiated cancer cells, and the levels of HMGCR expression did not consistently correlate with response to statin treatment. Pravastatin had a significant effect on normal hepatocytes due to facilitated uptake and a lesser effect on prostate PC3 and colon Caco-2 cancer cells since the OATP1B1 mRNA and protein were only found in the normal liver and hepatocytes. The inhibition of cell growth was accompanied by distinct alterations in mitochondrial networks and dramatic changes in cellular morphology related to cofilin regulation and loss of p-caveolin. Both statins, hydrophilic pravastatin and hypdrophobic simvastatin caused redistribution of OATP1B1 and HMGCR to perinuclear sites. In conclusion, the specific chemical properties of different classes of statins dictate mechanistic properties which may be relevant when evaluating biological responses to statins. PMID- 22216118 TI - Response of a specialist bat to the loss of a critical resource. AB - Human activities have negatively impacted many species, particularly those with unique traits that restrict their use of resources and conditions to specific habitats. Unfortunately, few studies have been able to isolate the individual and combined effects of different threats on population persistence in a natural setting, since not all organisms can be associated with discrete habitat features occurring over limited spatial scales. We present the results of a field study that examines the short-term effects of roost loss in a specialist bat using a conspicuous, easily modified resource. We mimicked roost loss in the natural habitat and monitored individuals before and after the perturbation to determine patterns of resource use, spatial movements, and group stability. Our study focused on the disc-winged bat Thyroptera tricolor, a species highly morphologically specialized for roosting in the developing furled leaves of members of the order Zingiberales. We found that the number of species used for roosting increased, that home range size increased (before: mean 0.14+/-SD 0.08 ha; after: 0.73+/-0.68 ha), and that mean association indices decreased (before: 0.95+/-0.10; after: 0.77+/-0.18) once the roosting habitat was removed. These results demonstrate that the removal of roosting resources is associated with a decrease in roost-site preferences or selectivity, an increase in mobility of individuals, and a decrease in social cohesion. These responses may reduce fitness by potentially increasing energetic expenditure, predator exposure, and a decrease in cooperative interactions. Despite these potential risks, individuals never used roost-sites other than developing furled leaves, suggesting an extreme specialization that could ultimately jeopardize the long-term persistence of this species' local populations. PMID- 22216117 TI - Comparison of quantitative techniques including Xpert MTB/RIF to evaluate mycobacterial burden. AB - INTRODUCTION: Accurate quantification of mycobacterial load is important for the evaluation of patient infectiousness, disease severity and monitoring treatment response in human and in-vitro laboratory models of disease. We hypothesized that newer techniques would perform as well as solid media culture to quantify mycobacterial burden in laboratory specimens. METHODS: We compared the turn around-time, detection-threshold, dynamic range, reproducibility, relative discriminative ability, of 4 mycobacterial load determination techniques: automated liquid culture (BACTEC-MGIT-960), [(3)H]-uracil incorporation assays, luciferase-reporter construct bioluminescence, and quantitative PCR(Xpert MTB/RIF) using serial dilutions of Mycobacterium bovis and Mycobacterium tuberculosis H37RV. Mycobacterial colony-forming-units(CFU) using 7H10 Middlebrook solid media served as the reference standard. RESULTS: All 4 assays correlated well with the reference standard, however, bioluminescence and uracil assays had a detection threshold >=1*10(3) organisms. By contrast, BACTEC-MGIT 960 liquid culture, although only providing results in days, was user-friendly, had the lowest detection threshold (<10 organisms), the greatest discriminative ability (1 vs. 10 organisms; p=0.02), and the best reproducibility (coefficient of variance of 2% vs. 38% compared to uracil incorporation; p=0.02). Xpert MTB/RIF correlated well with mycobacterial load, had a rapid turn-around-time (<2 hours), was user friendly, but had a detection limit of ~100 organisms. CONCLUSIONS: Choosing a technique to quantify mycobacterial burden for laboratory or clinical research depends on availability of resources and the question being addressed. Automated liquid culture has good discriminative ability and low detection threshold but results are only obtained in days. Xpert MTB/RIF provides rapid quantification of mycobacterial burden, but has a poorer discrimination and detection threshold. PMID- 22216119 TI - Protein kinase C delta (PKCdelta) affects proliferation of insulin-secreting cells by promoting nuclear extrusion of the cell cycle inhibitor p21Cip1/WAF1. AB - BACKGROUND: High fat diet-induced hyperglycemia and palmitate-stimulated apoptosis was prevented by specific inhibition of protein kinase C delta (PKCdelta) in beta-cells. To understand the role of PKCdelta in more detail the impact of changes in PKCdelta activity on proliferation and survival of insulin secreting cells was analyzed under stress-free conditions. METHODOLOGY AND PRINCIPAL FINDINGS: Using genetic and pharmacological approaches, the effect of reduced and increased PKCdelta activity on proliferation, apoptosis and cell cycle regulation of insulin secreting cells was examined. Proteins were analyzed by Western blotting and by confocal laser scanning microscopy. Increased expression of wild type PKCdelta (PKCdeltaWT) significantly stimulated proliferation of INS-1E cells with concomitant reduced expression and cytosolic retraction of the cell cycle inhibitor p21(Cip1/WAF1). This nuclear extrusion was mediated by PKCdelta-dependent phosphorylation of p21(Cip1/WAF1) at Ser146. In kinase dead PKCdelta (PKCdeltaKN) overexpressing cells and after inhibition of endogenous PKCdelta activity by rottlerin or RNA interference phosphorylation of p21(Cip1/WAF1) was reduced, which favored its nuclear accumulation and apoptotic cell death of INS-1E cells. Human and mouse islet cells express p21(Cip1/WAF1) with strong nuclear accumulation, while in islet cells of PKCdeltaWT transgenic mice the inhibitor resides cytosolic. CONCLUSIONS AND SIGNIFICANCE: These observations disclose PKCdelta as negative regulator of p21(Cip1/WAF1), which facilitates proliferation of insulin secreting cells under stress-free conditions and suggest that additional stress-induced changes push PKCdelta into its known pro-apoptotic role. PMID- 22216120 TI - Genomic expression analysis reveals strategies of Burkholderia cenocepacia to adapt to cystic fibrosis patients' airways and antimicrobial therapy. AB - Pulmonary colonization of cystic fibrosis (CF) patients with Burkholderia cenocepacia or other bacteria of the Burkholderia cepacia complex (Bcc) is associated with worse prognosis and increased risk of death. During colonization, the bacteria may evolve under the stressing selection pressures exerted in the CF lung, in particular, those resulting from challenges of the host immune defenses, antimicrobial therapy, nutrient availability and oxygen limitation. Understanding the adaptive mechanisms that promote successful colonization and long-term survival of B. cenocepacia in the CF lung is essential for an improved therapeutic outcome of chronic infections. To get mechanistic insights into these adaptive strategies a transcriptomic analysis, based on DNA microarrays, was explored in this study. The genomic expression levels in two clonal variants isolated during long-term colonization of a CF patient who died from the cepacia syndrome were compared. One of the isolates examined, IST439, is the first B. cenocepacia isolate retrieved from the patient and the other isolate, IST4113, was obtained three years later and is more resistant to different classes of antimicrobials. Approximately 1000 genes were found to be differently expressed in the two clonal variants reflecting a marked reprogramming of genomic expression. The up-regulated genes in IST4113 include those involved in translation, iron uptake (in particular, in ornibactin biosynthesis), efflux of drugs and in adhesion to epithelial lung tissue and to mucin. Alterations related with adaptation to the nutritional environment of the CF lung and to an oxygen limited environment are also suggested to be a key feature of transcriptional reprogramming occurring during long-term colonization, antibiotic therapy and the progression of the disease. PMID- 22216121 TI - A common KIF6 polymorphism increases vulnerability to low-density lipoprotein cholesterol: two meta-analyses and a meta-regression analysis. AB - BACKGROUND: We sought to determine if a common polymorphism can influence vulnerability to LDL cholesterol, and thereby influence the clinical benefit derived from therapies that reduce LDL cholesterol. METHODS: We conducted a meta analysis of the association between a common Trp719Arg polymorphism in the kinesin-like protein 6 (KIF6) gene and the risk of cardiovascular disease (CVD), and a meta-regression analysis to measure the effect modification of this polymorphism on the association between LDL cholesterol and the risk of CVD. We used this measure of genetic effect modification to predict the expected difference in clinical benefit among KIF6 719Arg allele carriers and non-carriers in response to therapies that reduce LDL cholesterol. We then conducted a meta analysis of statin trials to compare the expected difference in clinical benefit with the observed difference during treatment with a statin. RESULTS: In a meta analysis involving 144,931 participants, the KIF6 719Arg allele was not associated with the relative risk (RR) of CVD (RR: 1.02, 95%CI: 0.98-1.07, p=0.288). Meta-regression analysis involving 88,535 participants, however, showed that the 719Arg allele appears to influence the effect of LDL cholesterol on the risk of CVD. KIF6 carriers experienced a 13% greater reduction in the risk of CVD per mmol/L decrease in LDL cholesterol than non-carriers. We interpreted this difference as the expected difference in clinical benefit among KIF6 carriers and non-carriers in response to therapies that lower LDL cholesterol. The difference in clinical benefit predicted by the increased vulnerability to LDL cholesterol among KIF6 carriers (ratio of RR: 0.87, 95%CI: 0.80-0.94, p = 0.001) agreed very closely with the observed difference among 50,060 KIF6 carriers and non-carriers enrolled in 8 randomized trials of statin therapy (ratio of RR: 0.87, 95%CI: 0.77 0.99, p=0.038). CONCLUSION: The KIF6 719Arg allele increases vulnerability to LDL cholesterol and thereby influences the expected clinical benefit of therapies that reduce LDL cholesterol. PMID- 22216122 TI - Icariin and its derivative icariside II extend healthspan via insulin/IGF-1 pathway in C. elegans. AB - Compounds that delay aging might also postpone age-related diseases and extend healthspan in humans. Icariin is a flavonol extracted from several plant species of the Epimedium family. The icariin and its metabolic derivatives have been shown to exert wide protective effects in age-related diseases. However, whether icariin and its derivatives have the potency of delaying aging remains unclear. Here, we report that icariin and its derivative icariside II extend C. elegans lifespan. Using HPLC, we found high level of icariside II in the animals treated with icariin, suggesting icariside II is the bioactive form in vivo of icariin. Icariside II also increased the thermo and oxidative stress tolerance, slowed locomotion decline in late adulthood and delayed the onset of paralysis mediated by polyQ and Abeta(1-42) proteotoxicity. The lifespan extension effect of icariside II is dependent on the insulin/IGF-1 signaling (IIS) since the daf 16(mu86) and daf-2(e1370) failed to show any lifespan extension upon icariside II treatment. Consistently, icariside II treatment upregulates the expression of DAF 16 targets in the wild-type. Moreover, our data suggests that the heat shock transcription factor HSF-1 has a role in icariside II-dependent lifespan extension further implicating the IIS pathway. In conclusion, we demonstrate a novel natural compound, icariside II as the bioactive form of icariin, extends the healthspan via IIS pathway in C. elegans. PMID- 22216123 TI - Do porpoises choose their associates? A new method for analyzing social relationships among cetaceans. AB - BACKGROUND: Observing and monitoring the underwater social interactions of cetaceans is challenging. Therefore, previous cetacean studies have monitored these interactions by surface observations. However, because cetaceans spend most of their time underwater, it is important that their underwater behavior is also continuously monitored to better understand their social relationships and social structure. The finless porpoise is small and has no dorsal fin. It is difficult to observe this species in the wild, and little is known of its sociality. METHODOLOGY/PRINCIPAL FINDINGS: The swim depths of 6 free-ranging finless porpoises were simultaneously recorded using a time-synchronized bio-logging system. Synchronous diving was used as an index of association. Two pairs, #27 (an immature female estimated to be 3.5 years old) and #32 (an adult male), #28 (a juvenile male estimated to be 2 years old) and #29 (an adult male), tended to participate in long periods of synchronized diving more frequently than 13 other possible pairs, indicating that the 4 porpoises chose their social partners. The adult males (#32, #29) tended to follow the immature female (#27) and juvenile male (#28), respectively. However, during synchronized diving, the role of an initiator often changed within the pair, and their body movements appeared to be non-agonistic, e.g., rubbing of bodies against one another instead of that on one side, as observed with chasing and escaping behaviors. CONCLUSIONS/SIGNIFICANCE: The present study employed a time-synchronized bio-logging method to observe the social relationships of free-ranging aquatic animals based on swimming depth. The results suggest that certain individuals form associations even if they are not a mother and calf pair. Long synchronized dives occurred when particular members were reunited, and this suggests that the synchronized dives were not a by product of opportunistic aggregation. PMID- 22216124 TI - Low variation in the polymorphic Clock gene poly-Q region despite population genetic structure across barn swallow (Hirundo rustica) populations. AB - Recent studies of several species have reported a latitudinal cline in the circadian clock gene, Clock, which influences rhythms in both physiology and behavior. Latitudinal variation in this gene may hence reflect local adaptation to seasonal variation. In some bird populations, there is also an among individual association between Clock poly-Q genotype and clutch initiation date and incubation period. We examined Clock poly-Q allele variation in the Barn Swallow (Hirundo rustica), a species with a cosmopolitan geographic distribution and considerable variation in life-history traits that may be influenced by the circadian clock. We genotyped Barn Swallows from five populations (from three subspecies) and compared variation at the Clock locus to that at microsatellite loci and mitochondrial DNA (mtDNA). We found very low variation in the Clock poly Q region, as >96% of individuals were homozygous, and the two other alleles at this locus were globally rare. Genetic differentiation based on the Clock poly-Q locus was not correlated with genetic differentiation based on either microsatellite loci or mtDNA sequences. Our results show that high diversity in Clock poly-Q is not general across avian species. The low Clock variation in the background of heterogeneity in microsatellite and mtDNA loci in Barn Swallows may be an outcome of stabilizing selection on the Clock locus. PMID- 22216125 TI - Accounting for population stratification in practice: a comparison of the main strategies dedicated to genome-wide association studies. AB - Genome-Wide Association Studies are powerful tools to detect genetic variants associated with diseases. Their results have, however, been questioned, in part because of the bias induced by population stratification. This is a consequence of systematic differences in allele frequencies due to the difference in sample ancestries that can lead to both false positive or false negative findings. Many strategies are available to account for stratification but their performances differ, for instance according to the type of population structure, the disease susceptibility locus minor allele frequency, the degree of sampling imbalanced, or the sample size. We focus on the type of population structure and propose a comparison of the most commonly used methods to deal with stratification that are the Genomic Control, Principal Component based methods such as implemented in Eigenstrat, adjusted Regressions and Meta-Analyses strategies. Our assessment of the methods is based on a large simulation study, involving several scenarios corresponding to many types of population structures. We focused on both false positive rate and power to determine which methods perform the best. Our analysis showed that if there is no population structure, none of the tests led to a bias nor decreased the power except for the Meta-Analyses. When the population is stratified, adjusted Logistic Regressions and Eigenstrat are the best solutions to account for stratification even though only the Logistic Regressions are able to constantly maintain correct false positive rates. This study provides more details about these methods. Their advantages and limitations in different stratification scenarios are highlighted in order to propose practical guidelines to account for population stratification in Genome-Wide Association Studies. PMID- 22216127 TI - Witnessing violence toward siblings: an understudied but potent form of early adversity. AB - Research on the consequences of witnessing domestic violence has focused on inter adult violence and most specifically on violence toward mothers. The potential consequences of witnessing violence to siblings have been almost entirely overlooked. Based on clinical experience we sought to test the hypothesis that witnessing violence toward siblings would be as consequential as witnessing violence toward mothers. The community sample consisted of unmedicated, right handed, young adults who had siblings (n=1,412; 62.7% female; 21.8+/-2.1 years of age). History of witnessing threats or assaults to mothers, fathers and siblings, exposure to parental and sibling verbal abuse and physical abuse, sexual abuse and sociodemographic factors were assessed by self-report. Symptoms of depression, anxiety, somatization, anger-hostility, dissociation and 'limbic irritability' were assessed by rating scales. Data were analyzed by multiple regression, with techniques to gauge relative importance; logistic regression to assess adjusted odds ratios for clinically-significant ratings; and random forest regression using conditional trees. Subjects reported witnessing violence to siblings slightly more often than witnessing violence to mothers (22% vs 21%), which overlapped by 51-54%. Witnessing violence toward siblings was associated with significant effects on all ratings. Witnessing violence toward mother was not associated with significant effects on any scale in these models. Measures of the relative importance of witnessing violence to siblings were many fold greater than measures of importance for witnessing violence towards mothers or fathers. Mediation and structural equation models showed that effects of witnessing violence toward mothers or fathers were predominantly indirect and mediated by changes in maternal behavior. The effects of witnessing violence toward siblings were more direct. These findings suggest that greater attention be given to the effects of witnessing aggression toward siblings in studies of domestic violence, abuse and early adversity. PMID- 22216126 TI - Hypoxia-induced invadopodia formation involves activation of NHE-1 by the p90 ribosomal S6 kinase (p90RSK). AB - The hypoxic and acidic microenvironments in tumors are strongly associated with malignant progression and metastasis, and have thus become a central issue in tumor physiology and cancer treatment. Despite this, the molecular links between acidic pH- and hypoxia-mediated cell invasion/metastasis remain mostly unresolved. One of the mechanisms that tumor cells use for tissue invasion is the generation of invadopodia, which are actin-rich invasive plasma membrane protrusions that degrade the extracellular matrix. Here, we show that hypoxia stimulates the formation of invadopodia as well as the invasive ability of cancer cells. Inhibition or shRNA-based depletion of the Na(+)/H(+) exchanger NHE-1, along with intracellular pH monitoring by live-cell imaging, revealed that invadopodia formation is associated with alterations in cellular pH homeostasis, an event that involves activation of the Na(+)/H(+) exchange rate by NHE-1. Further characterization indicates that hypoxia triggered the activation of the p90 ribosomal S6 kinase (p90 RSK), which resulted in invadopodia formation and site-specific phosphorylation and activation of NHE-1. This study reveals an unsuspected role of p90RSK in tumor cell invasion and establishes p90RS kinase as a link between hypoxia and the acidic microenvironment of tumors. PMID- 22216128 TI - Directedness of information flow in mobile phone communication networks. AB - Without having direct access to the information that is being exchanged, traces of information flow can be obtained by looking at temporal sequences of user interactions. These sequences can be represented as causality trees whose statistics result from a complex interplay between the topology of the underlying (social) network and the time correlations among the communications. Here, we study causality trees in mobile-phone data, which can be represented as a dynamical directed network. This representation of the data reveals the existence of super-spreaders and super-receivers. We show that the tree statistics, respectively the information spreading process, are extremely sensitive to the in out degree correlation exhibited by the users. We also learn that a given information, e.g., a rumor, would require users to retransmit it for more than 30 hours in order to cover a macroscopic fraction of the system. Our analysis indicates that topological node-node correlations of the underlying social network, while allowing the existence of information loops, they also promote information spreading. Temporal correlations, and therefore causality effects, are only visible as local phenomena and during short time scales. Consequently, the very idea that there is (intentional) information spreading beyond a small vecinity is called into question. These results are obtained through a combination of theory and data analysis techniques. PMID- 22216129 TI - The absence of MIST1 leads to increased ethanol sensitivity and decreased activity of the unfolded protein response in mouse pancreatic acinar cells. AB - BACKGROUND: Alcohol abuse is a leading cause of pancreatitis in humans. However, rodent models suggest that alcohol only sensitizes the pancreas to subsequent insult, indicating that additional factors play a role in alcohol-induced pancreatic injury. The goal of this study was to determine if an absence of MIST1, a transcription factor required for complete differentiation of pancreatic acinar cells in mice, increased the sensitivity to alcohol. METHODS: Two to four month-old mice lacking MIST1 (Mist1(-/-)) or congenic C57 Bl6 mice were placed on a Lieber-DeCarli diet (36% of total kcal from ethanol and fat), a control liquid diet (36% kcal from fat) or a regular breeding chow diet (22% kcal from fat). After six weeks, pancreatic morphology was assessed. Biochemical and immunofluorescent analysis was used to assess mediators of the unfolded protein response (UPR). RESULTS: Ethanol-fed Mist1(-/-) mice developed periductal accumulations of inflammatory cells that did not appear in wild type or control fed Mist1(-/-) mice. Wild type mice fed diets high in ethanol or fat showed enhancement of the UPR based on increased accumulation of peIF2alpha and spliced XBP1. These increases were not observed in Mist1(-/-) pancreatic tissue, which had elevated levels of UPR activity prior to diet exposure. Indeed, exposure to ethanol resulted in a reduction of UPR activity in Mist1(-/-) mice. CONCLUSIONS: Our findings suggest that an absence of MIST1 increases the sensitivity to ethanol that correlated with decreased activity of the UPR. Therefore, events that affect the expression and/or function of MIST1 may be confounding factors in pancreatitis. PMID- 22216130 TI - Molecular cloning and expression analysis of fushi tarazu factor 1 in the brain of air-breathing catfish, Clarias gariepinus. AB - BACKGROUND: Fushi tarazu factor 1 (FTZ-F1) encodes an orphan nuclear receptor belonging to the nuclear receptor family 5A (NR5A) which includes adrenal 4 binding protein or steroidogenic factor-1 (Ad4BP/SF-1) and liver receptor homologue 1 (LRH-1) and plays a pivotal role in the regulation of aromatases. METHODOLOGY/PRINCIPAL FINDINGS: Present study was aimed to understand the importance of FTZ-F1 in relation to brain aromatase (cyp19a1b) during development, recrudescence and after human chorionic gonadotropin (hCG) induction. Initially, we cloned FTZ-F1 from the brain of air-breathing catfish, Clarias gariepinus through degenerate primer RT-PCR and RACE. Its sequence analysis revealed high homology with other NR5A1 group members Ad4BP/SF-1 and LRH 1, and also analogous to the spatial expression pattern of the latter. In order to draw functional correlation of cyp19a1b and FTZ-F1, we analyzed the expression pattern of the latter in brain during gonadal ontogeny, which revealed early expression during gonadal differentiation. The tissue distribution both at transcript and protein levels revealed its prominent expression in brain along with liver, kidney and testis. The expression pattern of brain FTZ-F1 during reproductive cycle and after hCG induction, in vivo was analogous to that of cyp19a1b shown in our earlier study indicating its involvement in recrudescence. CONCLUSIONS/SIGNIFICANCE: Based on our previous results on cyp19a1b and the present data, it is plausible to implicate potential roles for brain FTZ-F1 in ovarian differentiation and recrudescence process probably through regulation of cyp19a1b in teleosts. Nevertheless, these interactions would require primary coordinated response from ovarian aromatase and its related transcription factors. PMID- 22216131 TI - A viral discovery methodology for clinical biopsy samples utilising massively parallel next generation sequencing. AB - Here we describe a virus discovery protocol for a range of different virus genera, that can be applied to biopsy-sized tissue samples. Our viral enrichment procedure, validated using canine and human liver samples, significantly improves viral read copy number and increases the length of viral contigs that can be generated by de novo assembly. This in turn enables the Illumina next generation sequencing (NGS) platform to be used as an effective tool for viral discovery from tissue samples. PMID- 22216132 TI - A carrier for non-covalent delivery of functional beta-galactosidase and antibodies against amyloid plaques and IgM to the brain. AB - BACKGROUND: Therapeutic intervention of numerous brain-associated disorders currently remains unrealized due to serious limitations imposed by the blood brain-barrier (BBB). The BBB generally allows transport of small molecules, typically <600 daltons with high octanol/water partition coefficients, but denies passage to most larger molecules. However, some receptors present on the BBB allow passage of cognate proteins to the brain. Utilizing such receptor-ligand systems, several investigators have developed methods for delivering proteins to the brain, a critical requirement of which involves covalent linking of the target protein to a carrier entity. Such covalent modifications involve extensive preparative and post-preparative chemistry that poses daunting limitations in the context of delivery to any organ. Here, we report creation of a 36-amino acid peptide transporter, which can transport a protein to the brain after routine intravenous injection of the transporter-protein mixture. No covalent linkage of the protein with the transporter is necessary. APPROACH: A peptide transporter comprising sixteen lysine residues and 20 amino acids corresponding to the LDLR binding domain of apolipoprotein E (ApoE) was synthesized. Transport of beta galactosidase, IgG, IgM, and antibodies against amyloid plques to the brain upon iv injection of the protein-transporter mixture was evaluated through staining for enzyme activity or micro single photon emission tomography (micro-SPECT) or immunostaining. Effect of the transporter on the integrity of the BBB was also investigated. PRINCIPAL FINDINGS: The transporter enabled delivery to the mouse brain of functional beta-galactosidase, human IgG and IgM, and two antibodies that labeled brain-associated amyloid beta plaques in a mouse model of Alzheimer's disease. SIGNIFICANCE: The results suggest the transporter is able to transport most or all proteins to the brain without the need for chemically linking the transporter to a protein. Thus, the approach offers an avenue for rapid clinical evaluation of numerous candidate drugs against neurological diseases including cancer. (299 words). PMID- 22216133 TI - EB1 is required for spindle symmetry in mammalian mitosis. AB - Most information about the roles of the adenomatous polyposis coli protein (APC) and its binding partner EB1 in mitotic cells has come from siRNA studies. These suggest functions in chromosomal segregation and spindle positioning whose loss might contribute to tumourigenesis in cancers initiated by APC mutation. However, siRNA-based approaches have drawbacks associated with the time taken to achieve significant expression knockdown and the pleiotropic effects of EB1 and APC gene knockdown. Here we describe the effects of microinjecting APC- or EB1- specific monoclonal antibodies and a dominant-negative EB1 protein fragment into mammalian mitotic cells. The phenotypes observed were consistent with the roles proposed for EB1 and APC in chromosomal segregation in previous work. However, EB1 antibody injection also revealed two novel mitotic phenotypes, anaphase-specific cortical blebbing and asymmetric spindle pole movement. The daughters of microinjected cells displayed inequalities in microtubule content, with the greatest differences seen in the products of mitoses that showed the severest asymmetry in spindle pole movement. Daughters that inherited the least mobile pole contained the fewest microtubules, consistent with a role for EB1 in processes that promote equality of astral microtubule function at both poles in a spindle. We propose that these novel phenotypes represent APC-independent roles for EB1 in spindle pole function and the regulation of cortical contractility in the later stages of mitosis. Our work confirms that EB1 and APC have important mitotic roles, the loss of which could contribute to CIN in colorectal tumour cells. PMID- 22216134 TI - Comparison of IRES and F2A-based locus-specific multicistronic expression in stable mouse lines. AB - Efficient and stoichiometric expression of genes concatenated by bi- or multi cistronic vectors has become an invaluable tool not only in basic biology to track and visualize proteins in vivo, but also for vaccine development and in the clinics for gene therapy. To adequately compare, in vivo, the effectiveness of two of the currently popular co-expression strategies - the internal ribosome entry site (IRES) derived from the picornavirus and the 2A peptide from the foot and-mouth disease virus (FDMV) (F2A), we analyzed two locus-specific knock-in mouse lines co-expressing SRY-box containing gene 9 (Sox9) and enhanced green fluorescent protein (EGFP) linked by the IRES (Sox9(IRES-EGFP)) or the F2A (Sox9(F2A-EGFP)) sequence. Both the constructs expressed Sox9 and EGFP proteins in the appropriate Sox9 expression domains, with the IRES construct expressing reduced levels of EGFP compared to that of the F2A. The latter, on the other hand, produced about 42.2% Sox9-EGFP fusion protein, reflecting an inefficient ribosome 'skipping' mechanism. To investigate if the discrepancy in the 'skipping' process was locus-dependent, we further analyzed the FLAG(3)-Bapx1(F2A EGFP) mouse line and found similar levels of fusion protein being produced. To assess if EGFP was hindering the 'skipping' mechanism, we examined another mouse line co-expressing Bagpipe homeobox gene 1 homolog (Bapx1), Cre recombinase and EGFP (Bapx1(F2A-Cre-F2A-EGFP)). While the 'skipping' was highly efficient between Bapx1 and Cre, the 'skipping' between Cre and EGFP was highly inefficient. We have thus demonstrated in our comparison study that the efficient and close to equivalent expression of genes linked by F2A is achievable in stable mouse lines, but the EGFP reporter may cause undesirable inhibition of the 'skipping' at the F2A sequence. Hence, the use of other reporter genes should be explored when utilizing F2A peptides. PMID- 22216135 TI - Differential trends in the codon usage patterns in HIV-1 genes. AB - Host-pathogen interactions underlie one of the most complex evolutionary phenomena resulting in continual adaptive genetic changes, where pathogens exploit the host's molecular resources for growth and survival, while hosts try to eliminate the pathogen. Deciphering the molecular basis of host-pathogen interactions is useful in understanding the factors governing pathogen evolution and disease propagation. In host-pathogen context, a balance between mutation, selection, and genetic drift is known to maintain codon bias in both organisms. Studies revealing determinants of the bias and its dynamics are central to the understanding of host-pathogen evolution. We considered the Human Immunodeficiency Virus (HIV) type 1 and its human host to search for evolutionary signatures in the viral genome. Positive selection is known to dominate intra host evolution of HIV-1, whereas high genetic variability underlies the belief that neutral processes drive inter-host differences. In this study, we analyze the codon usage patterns of HIV-1 genomes across all subtypes and clades sequenced over a period of 23 years. We show presence of unique temporal correlations in the codon bias of three HIV-1 genes illustrating differential adaptation of the HIV-1 genes towards the host preferred codons. Our results point towards gene-specific translational selection to be an important force driving the evolution of HIV-1 at the population level. PMID- 22216136 TI - The effects of mechanical stress on the growth, differentiation, and paracrine factor production of cardiac stem cells. AB - Stem cell therapies have been clinically employed to repair the injured heart, and cardiac stem cells are thought to be one of the most potent stem cell candidates. The beating heart is characterized by dynamic mechanical stresses, which may have a significant impact on stem cell therapy. The purpose of this study is to investigate how mechanical stress affects the growth and differentiation of cardiac stem cells and their release of paracrine factors. In this study, human cardiac stem cells were seeded in a silicon chamber and mechanical stress was then induced by cyclic stretch stimulation (60 cycles/min with 120% elongation). Cells grown in non-stretched silicon chambers were used as controls. Our result revealed that mechanical stretching significantly reduced the total number of surviving cells, decreased Ki-67-positive cells, and increased TUNEL-positive cells in the stretched group 24 hrs after stretching, as compared to the control group. Interestingly, mechanical stretching significantly increased the release of the inflammatory cytokines IL-6 and IL-1beta as well as the angiogenic growth factors VEGF and bFGF from the cells in 12 hrs. Furthermore, mechanical stretching significantly reduced the percentage of c-kit positive stem cells, but increased the expressions of cardiac troponin-I and smooth muscle actin in cells 3 days after stretching. Using a traditional stretching model, we demonstrated that mechanical stress suppressed the growth and proliferation of cardiac stem cells, enhanced their release of inflammatory cytokines and angiogenic factors, and improved their myogenic differentiation. The development of this in vitro approach may help elucidate the complex mechanisms of stem cell therapy for heart failure. PMID- 22216137 TI - Winning fights induces hyperaggression via the action of the biogenic amine octopamine in crickets. AB - Winning an agonistic interaction against a conspecific is known to heighten aggressiveness, but the underlying events and mechanism are poorly understood. We quantified the effect of experiencing successive wins on aggression in adult male crickets (Gryllus bimaculatus) by staging knockout tournaments and investigated its dependence on biogenic amines by treatment with amine receptor antagonists. For an inter-fight interval of 5 min, fights between winners escalated to higher levels of aggression and lasted significantly longer than the preceding round. This winner effect is transient, and no longer evident for an inter-fight interval of 20 min, indicating that it does not result from selecting individuals that were hyper-aggressive from the outset. A winner effect was also evident in crickets that experienced wins without physical exertion, or that engaged in fights that were interrupted before a win was experienced. Finally, the winner effect was abolished by prior treatment with epinastine, a highly selective octopamine receptor blocker, but not by propranolol, a beta-adrenergic receptor antagonist, nor by yohimbine, an insect tyramine receptor blocker nor by fluphenazine an insect dopamine-receptor blocker. Taken together our study in the cricket indicates that the physical exertion of fighting, together with some rewarding aspect of the actual winning experience, leads to a transient increase in aggressive motivation via activation of the octopaminergic system, the invertebrate equivalent to the adrenergic system of vertebrates. PMID- 22216138 TI - Non-negative matrix factorization for learning alignment-specific models of protein evolution. AB - Models of protein evolution currently come in two flavors: generalist and specialist. Generalist models (e.g. PAM, JTT, WAG) adopt a one-size-fits-all approach, where a single model is estimated from a number of different protein alignments. Specialist models (e.g. mtREV, rtREV, HIVbetween) can be estimated when a large quantity of data are available for a single organism or gene, and are intended for use on that organism or gene only. Unsurprisingly, specialist models outperform generalist models, but in most instances there simply are not enough data available to estimate them. We propose a method for estimating alignment-specific models of protein evolution in which the complexity of the model is adapted to suit the richness of the data. Our method uses non-negative matrix factorization (NNMF) to learn a set of basis matrices from a general dataset containing a large number of alignments of different proteins, thus capturing the dimensions of important variation. It then learns a set of weights that are specific to the organism or gene of interest and for which only a smaller dataset is available. Thus the alignment-specific model is obtained as a weighted sum of the basis matrices. Having been constrained to vary along only as many dimensions as the data justify, the model has far fewer parameters than would be required to estimate a specialist model. We show that our NNMF procedure produces models that outperform existing methods on all but one of 50 test alignments. The basis matrices we obtain confirm the expectation that amino acid properties tend to be conserved, and allow us to quantify, on specific alignments, how the strength of conservation varies across different properties. We also apply our new models to phylogeny inference and show that the resulting phylogenies are different from, and have improved likelihood over, those inferred under standard models. PMID- 22216139 TI - Latitudinal gradients in degradation of marine dissolved organic carbon. AB - Heterotrophic microbial communities cycle nearly half of net primary productivity in the ocean, and play a particularly important role in transformations of dissolved organic carbon (DOC). The specific means by which these communities mediate the transformations of organic carbon are largely unknown, since the vast majority of marine bacteria have not been isolated in culture, and most measurements of DOC degradation rates have focused on uptake and metabolism of either bulk DOC or of simple model compounds (e.g. specific amino acids or sugars). Genomic investigations provide information about the potential capabilities of organisms and communities but not the extent to which such potential is expressed. We tested directly the capabilities of heterotrophic microbial communities in surface ocean waters at 32 stations spanning latitudes from 76 degrees S to 79 degrees N to hydrolyze a range of high molecular weight organic substrates and thereby initiate organic matter degradation. These data demonstrate the existence of a latitudinal gradient in the range of complex substrates available to heterotrophic microbial communities, paralleling the global gradient in bacterial species richness. As changing climate increasingly affects the marine environment, changes in the spectrum of substrates accessible by microbial communities may lead to shifts in the location and rate at which marine DOC is respired. Since the inventory of DOC in the ocean is comparable in magnitude to the atmospheric CO(2) reservoir, such a change could profoundly affect the global carbon cycle. PMID- 22216141 TI - High connectivity in the deepwater snapper Pristipomoides filamentosus (Lutjanidae) across the Indo-Pacific with isolation of the Hawaiian archipelago. AB - In the tropical Indo-Pacific, most phylogeographic studies have focused on the shallow-water taxa that inhabit reefs to approximately 30 m depth. Little is known about the large predatory fishes, primarily snappers (subfamily Etelinae) and groupers (subfamily Epinephelinae) that occur at 100-400 m. These long-lived, slow-growing species support fisheries across the Indo-Pacific, yet no comprehensive genetic surveys within this group have been conducted. Here we contribute the first range-wide survey of a deepwater Indo-Pacific snapper, Pristipomoides filamentosus, with special focus on Hawai'i. We applied mtDNA cytochrome b and 11 microsatellite loci to 26 samples (N=1,222) collected across 17,000 km from Hawai'i to the western Indian Ocean. Results indicate that P. filamentosus is a highly dispersive species with low but significant population structure (mtDNA Phi(ST)=0.029, microsatellite F(ST)=0.029) due entirely to the isolation of Hawai'i. No population structure was detected across 14,000 km of the Indo-Pacific from Tonga in the Central Pacific to the Seychelles in the western Indian Ocean, a pattern rarely observed in reef species. Despite a long pelagic phase (60-180 days), interisland dispersal as adults, and extensive gene flow across the Indo-Pacific, P. filamentosus is unable to maintain population connectivity with Hawai'i. Coalescent analyses indicate that P. filamentosus may have colonized Hawai'i 26 K-52 K y ago against prevailing currents, with dispersal away from Hawai'i dominating migration estimates. P. filamentosus harbors low genetic diversity in Hawai'i, a common pattern in marine fishes, and our data indicate a single archipelago-wide stock. However, like the Hawaiian Grouper, Hyporthodus quernus, this snapper had several significant pairwise comparisons (F(ST)) clustered around the middle of the archipelago (St. Rogatien, Brooks Banks, Gardner) indicating that this region may be isolated or (more likely) receives input from Johnston Atoll to the south. PMID- 22216140 TI - Phenotypic switching of nonpeptidergic cutaneous sensory neurons following peripheral nerve injury. AB - In adult mammals, the phenotype of half of all pain-sensing (nociceptive) sensory neurons is tonically modulated by growth factors in the glial cell line-derived neurotrophic factor (GDNF) family that includes GDNF, artemin (ARTN) and neurturin (NRTN). Each family member binds a distinct GFRalpha family co receptor, such that GDNF, NRTN and ARTN bind GFRalpha1, -alpha2, and -alpha3, respectively. Previous studies revealed transcriptional regulation of all three receptors in following axotomy, possibly in response to changes in growth factor availability. Here, we examined changes in the expression of GFRalpha1-3 in response to injury in vivo and in vitro. We found that after dissociation of adult sensory ganglia, up to 27% of neurons die within 4 days (d) in culture and this can be prevented by nerve growth factor (NGF), GDNF and ARTN, but not NRTN. Moreover, up-regulation of ATF3 (a marker of neuronal injury) in vitro could be prevented by NGF and ARTN, but not by GDNF or NRTN. The lack of NRTN efficacy was correlated with rapid and near-complete loss of GFRalpha2 immunoreactivity. By retrogradely-labeling cutaneous afferents in vivo prior to nerve cut, we demonstrated that GFRalpha2-positive neurons switch phenotype following injury and begin to express GFRalpha3 as well as the capsaicin receptor, transient receptor potential vanilloid 1(TRPV1), an important transducer of noxious stimuli. This switch was correlated with down-regulation of Runt-related transcription factor 1 (Runx1), a transcription factor that controls expression of GFRalpha2 and TRPV1 during development. These studies show that NRTN responsive neurons are unique with respect to their plasticity and response to injury, and suggest that Runx1 plays an ongoing modulatory role in the adult. PMID- 22216142 TI - Identification of surprisingly diverse type IV pili, across a broad range of gram positive bacteria. AB - BACKGROUND: In Gram-negative bacteria, type IV pili (TFP) have long been known to play important roles in such diverse biological phenomena as surface adhesion, motility, and DNA transfer, with significant consequences for pathogenicity. More recently it became apparent that Gram-positive bacteria also express type IV pili; however, little is known about the diversity and abundance of these structures in Gram-positives. Computational tools for automated identification of type IV pilins are not currently available. RESULTS: To assess TFP diversity in Gram-positive bacteria and facilitate pilin identification, we compiled a comprehensive list of putative Gram-positive pilins encoded by operons containing highly conserved pilus biosynthetic genes (pilB, pilC). A surprisingly large number of species were found to contain multiple TFP operons (pil, com and/or tad). The N-terminal sequences of predicted pilins were exploited to develop PilFind, a rule-based algorithm for genome-wide identification of otherwise poorly conserved type IV pilins in any species, regardless of their association with TFP biosynthetic operons (http://signalfind.org). Using PilFind to scan 53 Gram-positive genomes (encoding >187,000 proteins), we identified 286 candidate pilins, including 214 in operons containing TFP biosynthetic genes (TBG+ operons). Although trained on Gram-positive pilins, PilFind identified 55 of 58 manually curated Gram-negative pilins in TBG+ operons, as well as 53 additional pilin candidates in operons lacking biosynthetic genes in ten species (>38,000 proteins), including 27 of 29 experimentally verified pilins. False positive rates appear to be low, as PilFind predicted only four pilin candidates in eleven bacterial species (>13,000 proteins) lacking TFP biosynthetic genes. CONCLUSIONS: We have shown that Gram-positive bacteria contain a highly diverse set of type IV pili. PilFind can be an invaluable tool to study bacterial cellular processes known to involve type IV pilus-like structures. Its use in combination with other currently available computational tools should improve the accuracy of predicting the subcellular localization of bacterial proteins. PMID- 22216143 TI - Zebrafish prox1b mutants develop a lymphatic vasculature, and prox1b does not specifically mark lymphatic endothelial cells. AB - BACKGROUND: The expression of the Prospero homeodomain transcription factor (Prox1) in a subset of cardinal venous cells specifies the lymphatic lineage in mice. Prox1 is also indispensible for the maintenance of lymphatic cell fate, and is therefore considered a master control gene for lymphangiogenesis in mammals. In zebrafish, there are two prox1 paralogues, the previously described prox1 (also known as prox1a) and the newly identified prox1b. PRINCIPAL FINDINGS: To investigate the role of the prox1b gene in zebrafish lymphangiogenesis, we knocked-down prox1b and found that depletion of prox1b mRNA did not cause lymphatic defects. We also generated two different prox1b mutant alleles, and maternal-zygotic homozygous mutant embryos were viable and did not show any lymphatic defects. Furthermore, the expression of prox1b was not restricted to lymphatic vessels during zebrafish development. CONCLUSION: We conclude that Prox1b activity is not essential for embryonic lymphatic development in zebrafish. PMID- 22216145 TI - Identification of new alleles and the determination of alleles and genotypes frequencies at the CYP2D6 gene in Emiratis. AB - CYP2D6 belongs to the cytochrome P450 superfamily of enzymes and plays an important role in the metabolism of 20-25% of clinically used drugs including antidepressants. It displays inter-individual and inter-ethnic variability in activity ranging from complete absence to excessive activity which causes adverse drug reactions and toxicity or therapy failure even at normal drug doses. This variability is due to genetic polymorphisms which form poor, intermediate, extensive or ultrarapid metaboliser phenotypes. This study aimed to determine CYP2D6 alleles and their frequencies in the United Arab Emirates (UAE) local population. CYP2D6 alleles and genotypes were determined by direct DNA sequencing in 151 Emiratis with the majority being psychiatric patients on antidepressants. Several new alleles have been identified and in total we identified seventeen alleles and 49 genotypes. CYP2D6*1 (wild type) and CYP2D6*2 alleles (extensive metaboliser phenotype) were found with frequencies of 39.1% and 12.2%, respectively. CYP2D6*41 (intermediate metaboliser) occurred in 15.2%. Homozygous CYP2D6*4 allele (poor metaboliser) was found with a frequency of 2% while homozygous and heterozygous CYP2D6*4 occurred with a frequency of 9%. CYP2D6*2xn, caused by gene duplication (ultrarapid metaboliser) had a frequency of 4.3%. CYP2D6 gene duplication/multiduplication occurred in 16% but only 11.2% who carried more than 2 active functional alleles were considered ultrarapid metabolisers. CYP2D6 gene deletion in one copy occurred in 7.5% of the study group. In conclusion, CYP2D6 gene locus is heterogeneous in the UAE national population and no significant differences have been identified between the psychiatric patients and controls. PMID- 22216144 TI - Combinatorial polymer electrospun matrices promote physiologically-relevant cardiomyogenic stem cell differentiation. AB - Myocardial infarction results in extensive cardiomyocyte death which can lead to fatal arrhythmias or congestive heart failure. Delivery of stem cells to repopulate damaged cardiac tissue may be an attractive and innovative solution for repairing the damaged heart. Instructive polymer scaffolds with a wide range of properties have been used extensively to direct the differentiation of stem cells. In this study, we have optimized the chemical and mechanical properties of an electrospun polymer mesh for directed differentiation of embryonic stem cells (ESCs) towards a cardiomyogenic lineage. A combinatorial polymer library was prepared by copolymerizing three distinct subunits at varying molar ratios to tune the physicochemical properties of the resulting polymer: hydrophilic polyethylene glycol (PEG), hydrophobic poly(epsilon-caprolactone) (PCL), and negatively-charged, carboxylated PCL (CPCL). Murine ESCs were cultured on electrospun polymeric scaffolds and their differentiation to cardiomyocytes was assessed through measurements of viability, intracellular reactive oxygen species (ROS), alpha-myosin heavy chain expression (alpha-MHC), and intracellular Ca(2+) signaling dynamics. Interestingly, ESCs on the most compliant substrate, 4%PEG 86%PCL-10%CPCL, exhibited the highest alpha-MHC expression as well as the most mature Ca(2+) signaling dynamics. To investigate the role of scaffold modulus in ESC differentiation, the scaffold fiber density was reduced by altering the electrospinning parameters. The reduced modulus was found to enhance alpha-MHC gene expression, and promote maturation of myocyte Ca(2+) handling. These data indicate that ESC-derived cardiomyocyte differentiation and maturation can be promoted by tuning the mechanical and chemical properties of polymer scaffold via copolymerization and electrospinning techniques. PMID- 22216146 TI - Protein kinase A regulates molecular chaperone transcription and protein aggregation. AB - Heat shock factor 1 (HSF1) regulates one of the major pathways of protein quality control and is essential for deterrence of protein-folding disorders, particularly in neuronal cells. However, HSF1 activity declines with age, a change that may open the door to progression of neurodegenerative disorders such as Huntington's disease. We have investigated mechanisms of HSF1 regulation that may become compromised with age. HSF1 binds stably to the catalytic domain of protein kinase A (PKAcalpha) and becomes phosphorylated on at least one regulatory serine residue (S320). We show here that PKA is essential for effective transcription of HSP genes by HSF1. PKA triggers a cascade involving HSF1 binding to the histone acetylase p300 and positive translation elongation factor 1 (p-TEFb) and phosphorylation of the c-terminal domain of RNA polymerase II, a key mechanism in the downstream steps of HSF1-mediated transcription. This cascade appears to play a key role in protein quality control in neuronal cells expressing aggregation-prone proteins with long poly-glutamine (poly-Q) tracts. Such proteins formed inclusion bodies that could be resolved by HSF1 activation during heat shock. Resolution of the inclusions was inhibited by knockdown of HSF1, PKAcalpha, or the pTEFb component CDK9, indicating a key role for the HSF1 PKA cascade in protein quality control. PMID- 22216147 TI - Dynamics of resistance development to imatinib under increasing selection pressure: a combination of mathematical models and in vitro data. AB - In the last decade, cancer research has been a highly active and rapidly evolving scientific area. The ultimate goal of all efforts is a better understanding of the mechanisms that discriminate malignant from normal cell biology in order to allow the design of molecular targeted treatment strategies. In individual cases of malignant model diseases addicted to a specific, ideally single oncogene, e.g. Chronic myeloid leukemia (CML), specific tyrosine kinase inhibitors (TKI) have indeed been able to convert the disease from a ultimately life-threatening into a chronic disease with individual patients staying in remission even without treatment suggestive of operational cure. These developments have been raising hopes to transfer this concept to other cancer types. Unfortunately, cancer cells tend to develop both primary and secondary resistance to targeted drugs in a substantially higher frequency often leading to a failure of treatment clinically. Therefore, a detailed understanding of how cells can bypass targeted inhibition of signaling cascades crucial for malignant growths is necessary. Here, we have performed an in vitro experiment that investigates kinetics and mechanisms underlying resistance development in former drug sensitive cancer cells over time in vitro. We show that the dynamics observed in these experiments can be described by a simple mathematical model. By comparing these experimental data with the mathematical model, important parameters such as mutation rates, cellular fitness and the impact of individual drugs on these processes can be assessed. Excitingly, the experiment and the model suggest two fundamentally different ways of resistance evolution, i.e. acquisition of mutations and phenotype switching, each subject to different parameters. Most importantly, this complementary approach allows to assess the risk of resistance development in the different phases of treatment and thus helps to identify the critical periods where resistance development is most likely to occur. PMID- 22216148 TI - Choriodecidual group B streptococcal inoculation induces fetal lung injury without intra-amniotic infection and preterm labor in Macaca nemestrina. AB - BACKGROUND: Early events leading to intrauterine infection and fetal lung injury remain poorly defined, but may hold the key to preventing neonatal and adult chronic lung disease. Our objective was to establish a nonhuman primate model of an early stage of chorioamnionitis in order to determine the time course and mechanisms of fetal lung injury in utero. METHODOLOGY/PRINCIPAL FINDINGS: Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term=172 days) received one of two treatments: 1) choriodecidual and intra-amniotic saline (n=5), or 2) choriodecidual inoculation of Group B Streptococcus (GBS) 1*10(6) colony forming units (n=5). Cesarean section was performed regardless of labor 4 days after GBS or 7 days after saline infusion to collect fetal and placental tissues. Only two GBS animals developed early labor with no cervical change in the remaining animals. Despite uterine quiescence in most cases, blinded review found histopathological evidence of fetal lung injury in four GBS animals characterized by intra-alveolar neutrophils and interstitial thickening, which was absent in controls. Significant elevations of cytokines in amniotic fluid (TNF-alpha, IL-8, IL-1beta, IL-6) and fetal plasma (IL-8) were detected in GBS animals and correlated with lung injury (p<0.05). Lung injury was not directly caused by GBS, because GBS was undetectable in amniotic fluid (~10 samples tested/animal), maternal and fetal blood by culture and polymerase chain reaction. In only two cases was GBS cultured from the inoculation site in low numbers. Chorioamnionitis occurred in two GBS animals with lung injury, but two others with lung injury had normal placental histology. CONCLUSIONS/SIGNIFICANCE: A transient choriodecidual infection can induce cytokine production, which is associated with fetal lung injury without overt infection of amniotic fluid, chorioamnionitis or preterm labor. Fetal lung injury may, thus, occur silently without symptoms and before the onset of the fetal systemic inflammatory response syndrome. PMID- 22216149 TI - Protection in macaques immunized with HIV-1 candidate vaccines can be predicted using the kinetics of their neutralizing antibodies. AB - BACKGROUND: A vaccine is needed to control the spread of human immunodeficiency virus type 1 (HIV-1). An in vitro assay that can predict the protection induced by a vaccine would facilitate the development of such a vaccine. A potential candidate would be an assay to quantify neutralization of HIV-1. METHODS AND FINDINGS: We have used sera from rhesus macaques that have been immunized with HIV candidate vaccines and subsequently challenged with simian human immunodeficiency virus (SHIV). We compared neutralization assays with different formats. In experiments with the standardized and validated TZMbl assay, neutralizing antibody titers against homologous SHIV(SF162P4) pseudovirus gave a variable correlation with reductions in plasma viremia levels. The target cells used in the assays are not just passive indicators of virus infection but are actively involved in the neutralization process. When replicating virus was used with GHOST cell assays, events during the absorption phase, as well as the incubation phase, determine the level of neutralization. Sera that are associated with protection have properties that are closest to the traditional concept of neutralization: the concentration of antibody present during the absorption phase has no effect on the inactivation rate. In GHOST assays, events during the absorption phase may inactivate a fixed number, rather than a proportion, of virus so that while complete neutralization can be obtained, it can only be found at low doses particularly with isolates that are relatively resistant to neutralization. CONCLUSIONS: Two scenarios have the potential to predict protection by neutralizing antibodies at concentrations that can be induced by vaccination: antibodies that have properties close to the traditional concept of neutralization may protect against a range of challenge doses of neutralization sensitive HIV isolates; a window of opportunity also exists for protection against isolates that are more resistant to neutralization but only at low challenge doses. PMID- 22216151 TI - The inheritance of histone modifications depends upon the location in the chromosome in Saccharomyces cerevisiae. AB - Histone modifications are important epigenetic features of chromatin that must be replicated faithfully. However, the molecular mechanisms required to duplicate and maintain histone modification patterns in chromatin remain to be determined. Here, we show that the introduction of histone modifications into newly deposited nucleosomes depends upon their location in the chromosome. In Saccharomyces cerevisiae, newly deposited nucleosomes consisting of newly synthesized histone H3-H4 tetramers are distributed throughout the entire chromosome. Methylation of lysine 4 on histone H3 (H3-K4), a hallmark of euchromatin, is introduced into these newly deposited nucleosomes, regardless of whether the neighboring preexisting nucleosomes harbor the K4 mutation in histone H3. Furthermore, if the heterochromatin-binding protein Sir3 is unavailable during DNA replication, histone H3-K4 methylation is introduced onto newly deposited nucleosomes in telomeric heterochromatin. Thus, a conservative distribution model most accurately explains the inheritance of histone modifications because the location of histones within euchromatin or heterochromatin determines which histone modifications are introduced. PMID- 22216150 TI - Induction of Bcl-2 expression by hepatitis B virus pre-S2 mutant large surface protein resistance to 5-fluorouracil treatment in Huh-7 cells. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor prognosis due to resistance to conventional chemotherapy and limited efficacy of radiotherapy. Our previous studies have indicated that expression of Hepatitis B virus pre-S2 large mutant surface antigen (HBV pre S2Delta) is associated with a significant risk of developing HCC. However, the relationship between HBV pre-S2Delta protein and the resistance of chemotherapeutic drug treatment is still unclear. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that the expression of HBV pre-S2Delta mutant surface protein in Huh-7 cell significantly promoted cell growth and colony formation. Furthermore, HBV pre-S2Delta protein increased both mRNA (2.7+/-0.5-fold vs. vehicle, p=0.05) and protein (3.2+/-0.3-fold vs. vehicle, p=0.01) levels of Bcl-2 in Huh-7 cells. HBV pre-S2Delta protein also enhances Bcl-2 family, Bcl-xL and Mcl-1, expression in Huh-7 cells. Meanwhile, induction of NF-kappaB p65, ERK, and Akt phosphorylation, and GRP78 expression, an unfolded protein response chaperone, were observed in HBV pre-S2Delta and HBV pre-S-expressing cells. Induction of Bcl 2 expression by HBV pre-S2Delta protein resulted in resistance to 5-fluorouracil treatment in colony formation, caspase-3 assay, and cell apoptosis, and can enhance cell death by co-incubation with Bcl-2 inhibitor. Similarly, transgenic mice showed higher expression of Bcl-2 in liver tissue expressing HBV pre-S2Delta large surface protein in vivo. CONCLUSION/SIGNIFICANCE: Our result demonstrates that HBV pre-S2Delta increased Bcl-2 expression which plays an important role in resistance to 5-fluorouracil-caused cell death. Therefore, these data provide an important chemotherapeutic strategy in HBV pre-S2Delta-associated tumor. PMID- 22216152 TI - Direct observation of defects and increased ion permeability of a membrane induced by structurally disordered Cu/Zn-superoxide dismutase aggregates. AB - Interactions between protein aggregates and a cellular membrane have been strongly implicated in many protein conformational diseases. However, such interactions for the case of Cu/Zn superoxide dismutase (SOD1) protein, which is related to fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS), have not been explored yet. For the first time, we report the direct observation of defect formation and increased ion permeability of a membrane induced by SOD1 aggregates using a supported lipid bilayer and membrane patches of human embryonic kidney cells as model membranes. We observed that aggregated SOD1 significantly induced the formation of defects within lipid membranes and caused the perturbation of membrane permeability, based on surface plasmon resonance spectroscopy, atomic force microscopy and electrophysiology. In the case of apo SOD1 with an unfolded structure, we found that it bound to the lipid membrane surface and slightly perturbed membrane permeability, compared to other folded proteins (holo SOD1 and bovine serum albumin). The changes in membrane integrity and permeability were found to be strongly dependent on the type of proteins and the amount of aggregates present. We expect that the findings presented herein will advance our understanding of the pathway by which structurally disordered SOD1 aggregates exert toxicity in vivo. PMID- 22216153 TI - Tramtrack is genetically upstream of genes controlling tracheal tube size in Drosophila. AB - The Drosophila transcription factor Tramtrack (Ttk) is involved in a wide range of developmental decisions, ranging from early embryonic patterning to differentiation processes in organogenesis. Given the wide spectrum of functions and pleiotropic effects that hinder a comprehensive characterisation, many of the tissue specific functions of this transcription factor are only poorly understood. We recently discovered multiple roles of Ttk in the development of the tracheal system on the morphogenetic level. Here, we sought to identify some of the underlying genetic components that are responsible for the tracheal phenotypes of Ttk mutants. We therefore profiled gene expression changes after Ttk loss- and gain-of-function in whole embryos and cell populations enriched for tracheal cells. The analysis of the transcriptomes revealed widespread changes in gene expression. Interestingly, one of the most prominent gene classes that showed significant opposing responses to loss- and gain-of-function was annotated with functions in chitin metabolism, along with additional genes that are linked to cellular responses, which are impaired in ttk mutants. The expression changes of these genes were validated by quantitative real-time PCR and further functional analysis of these candidate genes and other genes also expected to control tracheal tube size revealed at least a partial explanation of Ttk's role in tube size regulation. The computational analysis of our tissue-specific gene expression data highlighted the sensitivity of the approach and revealed an interesting set of novel putatively tracheal genes. PMID- 22216154 TI - Composition of human skin microbiota affects attractiveness to malaria mosquitoes. AB - The African malaria mosquito Anopheles gambiae sensu stricto continues to play an important role in malaria transmission, which is aggravated by its high degree of anthropophily, making it among the foremost vectors of this disease. In the current study we set out to unravel the strong association between this mosquito species and human beings, as it is determined by odorant cues derived from the human skin. Microbial communities on the skin play key roles in the production of human body odour. We demonstrate that the composition of the skin microbiota affects the degree of attractiveness of human beings to this mosquito species. Bacterial plate counts and 16S rRNA sequencing revealed that individuals that are highly attractive to An. gambiae s.s. have a significantly higher abundance, but lower diversity of bacteria on their skin than individuals that are poorly attractive. Bacterial genera that are correlated with the relative degree of attractiveness to mosquitoes were identified. The discovery of the connection between skin microbial populations and attractiveness to mosquitoes may lead to the development of new mosquito attractants and personalized methods for protection against vectors of malaria and other infectious diseases. PMID- 22216155 TI - The activity of spontaneous action potentials in developing hair cells is regulated by Ca(2+)-dependence of a transient K+ current. AB - Spontaneous action potentials have been described in developing sensory systems. These rhythmic activities may have instructional roles for the functional development of synaptic connections. The importance of spontaneous action potentials in the developing auditory system is underpinned by the stark correlation between the time of auditory system functional maturity, and the cessation of spontaneous action potentials. A prominent K(+) current that regulates patterning of action potentials is I(A). This current undergoes marked changes in expression during chicken hair cell development. Although the properties of I(A) are not normally classified as Ca(2+)-dependent, we demonstrate that throughout the development of chicken hair cells, I(A) is greatly reduced by acute alterations of intracellular Ca(2+). As determinants of spike timing and firing frequency, intracellular Ca(2+) buffers shift the activation and inactivation properties of the current to more positive potentials. Our findings provide evidence to demonstrate that the kinetics and functional expression of I(A) are tightly regulated by intracellular Ca(2+). Such feedback mechanism between the functional expression of I(A) and intracellular Ca(2+) may shape the activity of spontaneous action potentials, thus potentially sculpting synaptic connections in an activity-dependent manner in the developing cochlea. PMID- 22216156 TI - Helicobacter pylori infection of gastrointestinal epithelial cells in vitro induces mesenchymal stem cell migration through an NF-kappaB-dependent pathway. AB - The role of bone marrow-derived mesenchymal stem cells (MSC) in the physiology of the gastrointestinal tract epithelium is currently not well established. These cells can be recruited in response to inflammation due to epithelial damage, home, and participate in tissue repair. In addition, in the case of tissue repair failure, these cells could transform and be at the origin of carcinomas. However, the chemoattractant molecules responsible for MSC recruitment and migration in response to epithelial damage, and particularly to Helicobacter pylori infection, remain unknown although the role of some chemokines has been suggested. This work aimed to get insight into the mechanisms of mouse MSC migration during in vitro infection of mouse gastrointestinal epithelial cells by H. pylori. Using a cell culture insert system, we showed that infection of gastrointestinal epithelial cells by different H. pylori strains is able to stimulate the migration of MSC. This mechanism involves the secretion by infected epithelial cells of multiple cytokines, with a major role of TNFalpha, mainly via a Nuclear Factor-kappa B dependent pathway. This study provides the first evidence of the role of H. pylori infection in MSC migration and paves the way to a better understanding of the role of bone marrow-derived stem cells in gastric pathophysiology and carcinogenesis. PMID- 22216157 TI - Improved resolution of reef-coral endosymbiont (Symbiodinium) species diversity, ecology, and evolution through psbA non-coding region genotyping. AB - Ribosomal DNA sequence data abounds from numerous studies on the dinoflagellate endosymbionts of corals, and yet the multi-copy nature and intragenomic variability of rRNA genes and spacers confound interpretations of symbiont diversity and ecology. Making consistent sense of extensive sequence variation in a meaningful ecological and evolutionary context would benefit from the application of additional genetic markers. Sequences of the non-coding region of the plastid psbA minicircle (psbA(ncr)) were used to independently examine symbiont genotypic and species diversity found within and between colonies of Hawaiian reef corals in the genus Montipora. A single psbA(ncr) haplotype was recovered in most samples through direct sequencing (~80-90%) and members of the same internal transcribed spacer region 2 (ITS2) type were phylogenetically differentiated from other ITS2 types by substantial psbA(ncr) sequence divergence. The repeated sequencing of bacterially-cloned fragments of psbA(ncr) from samples and clonal cultures often recovered a single numerically common haplotype accompanied by rare, highly-similar, sequence variants. When sequence artifacts of cloning and intragenomic variation are factored out, these data indicate that most colonies harbored one dominant Symbiodinium genotype. The cloning and sequencing of ITS2 DNA amplified from these same samples recovered numerically abundant variants (that are diagnostic of distinct Symbiodinium lineages), but also generated a large amount of sequences comprising PCR/cloning artifacts combined with ancestral and/or rare variants that, if incorporated into phylogenetic reconstructions, confound how small sequence differences are interpreted. Finally, psbA(ncr) sequence data from a broad sampling of Symbiodinium diversity obtained from various corals throughout the Indo-Pacific were concordant with ITS lineage membership (defined by denaturing gradient gel electrophoresis screening), yet exhibited substantially greater sequence divergence and revealed strong phylogeographic structure corresponding to major biogeographic provinces. The detailed genetic resolution provided by psbA(ncr) data brings further clarity to the ecology, evolution, and systematics of symbiotic dinoflagellates. PMID- 22216158 TI - Lapatinib induces autophagy, apoptosis and megakaryocytic differentiation in chronic myelogenous leukemia K562 cells. AB - Lapatinib is an oral, small-molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptors (EGFR, or ErbB/Her) in solid tumors. Little is known about the effect of lapatinib on leukemia. Using human chronic myelogenous leukemia (CML) K562 cells as an experimental model, we found that lapatinib simultaneously induced morphological changes resembling apoptosis, autophagy, and megakaryocytic differentiation. Lapatinib-induced apoptosis was accompanied by a decrease in mitochondrial transmembrane potential and was attenuated by the pancaspase inhibitor z-VAD-fmk, indicating a mitochondria-mediated and caspase dependent pathway. Lapatinib-induced autophagic cell death was verified by LC3-II conversion, and upregulation of Beclin-1. Further, autophagy inhibitor 3 methyladenine as well as autophagy-related proteins Beclin-1 (ATG6), ATG7, and ATG5 shRNA knockdown rescued the cells from lapatinib-induced growth inhibition. A moderate number of lapatinib-treated K562 cells exhibited features of megakaryocytic differentiation. In summary, lapatinib inhibited viability and induced multiple cellular events including apoptosis, autophagic cell death, and megakaryocytic differentiation in human CML K562 cells. This distinct activity of lapatinib against CML cells suggests potential for lapatinib as a therapeutic agent for treatment of CML. Further validation of lapatinib activity in vivo is warranted. PMID- 22216159 TI - Optical dissection of neural circuits responsible for Drosophila larval locomotion with halorhodopsin. AB - Halorhodopsin (NpHR), a light-driven microbial chloride pump, enables silencing of neuronal function with superb temporal and spatial resolution. Here, we generated a transgenic line of Drosophila that drives expression of NpHR under control of the Gal4/UAS system. Then, we used it to dissect the functional properties of neural circuits that regulate larval peristalsis, a continuous wave of muscular contraction from posterior to anterior segments. We first demonstrate the effectiveness of NpHR by showing that global and continuous NpHR-mediated optical inhibition of motor neurons or sensory feedback neurons induce the same behavioral responses in crawling larvae to those elicited when the function of these neurons are inhibited by Shibire(ts), namely complete paralyses or slowed locomotion, respectively. We then applied transient and/or focused light stimuli to inhibit the activity of motor neurons in a more temporally and spatially restricted manner and studied the effects of the optical inhibition on peristalsis. When a brief light stimulus (1-10 sec) was applied to a crawling larva, the wave of muscular contraction stopped transiently but resumed from the halted position when the light was turned off. Similarly, when a focused light stimulus was applied to inhibit motor neurons in one or a few segments which were about to be activated in a dissected larva undergoing fictive locomotion, the propagation of muscular constriction paused during the light stimulus but resumed from the halted position when the inhibition (>5 sec) was removed. These results suggest that (1) Firing of motor neurons at the forefront of the wave is required for the wave to proceed to more anterior segments, and (2) The information about the phase of the wave, namely which segment is active at a given time, can be memorized in the neural circuits for several seconds. PMID- 22216160 TI - Intratumoral injection of Propionibacterium acnes suppresses malignant melanoma by enhancing Th1 immune responses. AB - Malignant melanoma (MM) is an aggressive cutaneous malignancy associated with poor prognosis; many putatively therapeutic agents have been administered, but with mostly unsuccessful results. Propionibacterium acnes (P. acnes) is an aerotolerant anaerobic gram-positive bacteria that causes acne and inflammation. After being engulfed and processed by phagocytes, P. acnes induces a strong Th1 type cytokine immune response by producing cytokines such as IL-12, IFN-gamma and TNF-alpha. The characteristic Th2-mediated allergic response can be counteracted by Th1 cytokines induced by P. acnes injection. This inflammatory response induced by P. acnes has been suggested to have antitumor activity, but its effect on MM has not been fully evaluated.We analyzed the anti-tumor activity of P. acnes vaccination in a mouse model of MM. Intratumoral administration of P. acnes successfully protected the host against melanoma progression in vivo by inducing both cutaneous and systemic Th1 type cytokine expression, including TNF-alpha and IFN-gamma, which are associated with subcutaneous granuloma formation. P. acnes treated tumor lesions were infiltrated with TNF-alpha and IFN-gamma positive T cells. In the spleen, TNF-alpha as well as IFN-gamma producing CD8(+)T cells were increased, and interestingly, the number of monocytes was also increased following P. acnes administration. These observations suggest that P. acnes vaccination induces both systemic and local antitumor responses. In conclusion, this study shows that P. acnes vaccination may be a potent therapeutic alternative in MM. PMID- 22216161 TI - Shape variation in Aterian tanged tools and the origins of projectile technology: a morphometric perspective on stone tool function. AB - BACKGROUND: Recent findings suggest that the North African Middle Stone Age technocomplex known as the Aterian is both much older than previously assumed, and certainly associated with fossils exhibiting anatomically modern human morphology and behavior. The Aterian is defined by the presence of 'tanged' or 'stemmed' tools, which have been widely assumed to be among the earliest projectile weapon tips. The present study systematically investigates morphological variation in a large sample of Aterian tools to test the hypothesis that these tools were hafted and/or used as projectile weapons. METHODOLOGY/PRINCIPAL FINDINGS: Both classical morphometrics and Elliptical Fourier Analysis of tool outlines are used to show that the shape variation in the sample exhibits size-dependent patterns consistent with a reduction of the tools from the tip down, with the tang remaining intact. Additionally, the process of reduction led to increasing side-to-side asymmetries as the tools got smaller. Finally, a comparison of shape-change trajectories between Aterian tools and Late Paleolithic arrowheads from the North German site of Stellmoor reveal significant differences in terms of the amount and location of the variation. CONCLUSIONS/SIGNIFICANCE: The patterns of size-dependent shape variation strongly support the functional hypothesis of Aterian tools as hafted knives or scrapers with alternating active edges, rather than as weapon tips. Nevertheless, the same morphological patterns are interpreted as one of the earliest evidences for a hafting modification, and for the successful combination of different raw materials (haft and stone tip) into one implement, in itself an important achievement in the evolution of hominin technologies. PMID- 22216164 TI - Toward an identification of resources influencing habitat use in a multi-specific context. AB - Interactions between animal behaviour and the environment are both shaping observed habitat use. Despite the importance of inter-specific interactions on the habitat use performed by individuals, most previous analyses have focused on case studies of single species. By focusing on two sympatric populations of large herbivores with contrasting body size, we went one step beyond by studying variation in home range size and identifying the factors involved in such variation, to define how habitat features such as resource heterogeneity, resource quality, and openness created by hurricane or forest managers, and constraints may influence habitat use at the individual level. We found a large variability among individual's home range size in both species, particularly in summer. Season appeared as the most important factor accounting for observed variation in home range size. Regarding habitat features, we found that (i) the proportion of area damaged by the hurricane was the only habitat component that inversely influenced roe deer home range size, (ii) this habitat type also influenced both diurnal and nocturnal red deer home range sizes, (iii) home range size of red deer during the day was inversely influenced by the biomass of their preferred plants, as were both diurnal and nocturnal core areas of the red deer home range, and (iv) we do not find any effect of resource heterogeneity on home range size in any case. Our results suggest that a particular habitat type (i.e. areas damaged by hurricane) can be used by individuals of sympatric species because it brings both protected and dietary resources. Thus, it is necessary to maintain the openness of these areas and to keep animal density quite low as observed in these hunted populations to limit competition between these sympatric populations of herbivores. PMID- 22216162 TI - Consequences of non-intervention for infectious disease in African great apes. AB - Infectious disease has recently joined poaching and habitat loss as a major threat to African apes. Both "naturally" occurring pathogens, such as Ebola and Simian Immunodeficiency Virus (SIV), and respiratory pathogens transmitted from humans, have been confirmed as important sources of mortality in wild gorillas and chimpanzees. While awareness of the threat has increased, interventions such as vaccination and treatment remain controversial. Here we explore both the risk of disease to African apes, and the status of potential responses. Through synthesis of published data, we summarize prior disease impact on African apes. We then use a simple demographic model to illustrate the resilience of a well known gorilla population to disease, modeled on prior documented outbreaks. We found that the predicted recovery time for this specific gorilla population from a single outbreak ranged from 5 years for a low mortality (4%) respiratory outbreak, to 131 years for an Ebola outbreak that killed 96% of the population. This shows that mortality rates comparable to those recently reported for disease outbreaks in wild populations are not sustainable. This is particularly troubling given the rising pathogen risk created by increasing habituation of wild apes for tourism, and the growth of human populations surrounding protected areas. We assess potential future disease spillover risk in terms of vaccination rates amongst humans that may come into contact with wild apes, and the availability of vaccines against potentially threatening diseases. We discuss and evaluate non interventionist responses such as limiting tourist access to apes, community health programs, and safety, logistic, and cost issues that constrain the potential of vaccination. PMID- 22216163 TI - In vivo tracking of human neural stem cells with 19F magnetic resonance imaging. AB - BACKGROUND: Magnetic resonance imaging (MRI) is a promising tool for monitoring stem cell-based therapy. Conventionally, cells loaded with ironoxide nanoparticles appear hypointense on MR images. However, the contrast generated by ironoxide labeled cells is neither specific due to ambiguous background nor quantitative. A strategy to overcome these drawbacks is (19)F MRI of cells labeled with perfluorocarbons. We show here for the first time that human neural stem cells (NSCs), a promising candidate for clinical translation of stem cell based therapy of the brain, can be labeled with (19)F as well as detected and quantified in vitro and after brain implantation. METHODOLOGY/PRINCIPAL FINDINGS: Human NSCs were labeled with perfluoropolyether (PFPE). Labeling efficacy was assessed with (19)F MR spectroscopy, influence of the label on cell phenotypes studied by immunocytochemistry. For in vitro MRI, NSCs were suspended in gelatin at varying densities. For in vivo experiments, labeled NSCs were implanted into the striatum of mice. A decrease of cell viability was observed directly after incubation with PFPE, which re-normalized after 7 days in culture of the replated cells. No label-related changes in the numbers of Ki67, nestin, GFAP, or betaIII tubulin+ cells were detected, both in vitro and on histological sections. We found that 1,000 NSCs were needed to accumulate in one image voxel to generate significant signal-to-noise ratio in vitro. A detection limit of ~10,000 cells was found in vivo. The location and density of human cells (hunu+) on histological sections correlated well with observations in the (19)F MR images. CONCLUSION/SIGNIFICANCE: Our results show that NSCs can be efficiently labeled with (19)F with little effects on viability or proliferation and differentiation capacity. We show for the first time that (19)F MRI can be utilized for tracking human NSCs in brain implantation studies, which ultimately aim for restoring loss of function after acute and neurodegenerative disorders. PMID- 22216165 TI - Safety of postoperative administration of human urinary trypsin inhibitor in lung cancer patients with idiopathic pulmonary fibrosis. AB - BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) undergoing pulmonary resection for lung cancer carry risks of acute exacerbations of IPF (AE) postoperatively. Currently, agents which may attenuate AE are actively sought. Urinary trypsin inhibitor, ulinastatin, is a synthetic glycoprotein which may potentially inhibit various inflammatory factors associated with the development and progression of IPF. The present study was done to evaluate the effects of administration of high dose ulinastatin in lung cancer patients with IPF immediately following lung resection. METHODS: Patients with IPFs radiologically diagnosed on high resolution CT, and histologically diagnosed resectable lung cancers, were eligible for the study. The effects of escalating doses of ulinastatin 3*10(5), 6*10(5), and 9*10(5) units/body/day, administered postoperatively for 3 days were evaluated. The endpoints were safety and feasibility. RESULTS: Nine patients were evaluated, in cohorts of 3 patients per dosage. Postoperative follow up ranged from 3 to 12 months (median 9 months). The postoperative courses were uneventful in all patients. No subjective adverse events such as abdominal symptoms or skin rashes, or objective adverse events as per serum laboratory tests, such as liver or kidney dysfunctions potentially attributable to ulinastatin administration were observed. AE was seen in one patient at 3 months after surgery, but since this occurred shortly after administration of chemotherapy, it was considered to be attributable to the chemotherapy rather than surgery. DISCUSSION: Ulinastatin administration after lung resection in lung cancer patients with IPF was considered to be safe and feasible. Further study is planned at the highest dose of this study to evaluate efficacy. TRIAL REGISTRATION: UMIN.ac.jp/ctr/UMIN000002410. PMID- 22216166 TI - Who needs microtubules? Myogenic reorganization of MTOC, Golgi complex and ER exit sites persists despite lack of normal microtubule tracks. AB - A wave of structural reorganization involving centrosomes, microtubules, Golgi complex and ER exit sites takes place early during skeletal muscle differentiation and completely remodels the secretory pathway. The mechanism of these changes and their functional implications are still poorly understood, in large part because all changes occur seemingly simultaneously. In an effort to uncouple the reorganizations, we have used taxol, nocodazole, and the specific GSK3-beta inhibitor DW12, to disrupt the dynamic microtubule network of differentiating cultures of the mouse skeletal muscle cell line C2. Despite strong effects on microtubules, cell shape and cell fusion, none of the treatments prevented early differentiation. Redistribution of centrosomal proteins, conditional on differentiation, was in fact increased by taxol and nocodazole and normal in DW12. Redistributions of Golgi complex and ER exit sites were incomplete but remained tightly linked under all circumstances, and conditional on centrosomal reorganization. We were therefore able to uncouple microtubule reorganization from the other events and to determine that centrosomal proteins lead the reorganization hierarchy. In addition, we have gained new insight into structural and functional aspects of the reorganization of microtubule nucleation during myogenesis. PMID- 22216167 TI - A short caspase-3 isoform inhibits chemotherapy-induced apoptosis by blocking apoptosome assembly. AB - Alternative splicing of caspase-3 produces a short isoform caspase-3s that antagonizes caspase-3 apoptotic activity. However, the mechanism of apoptosis inhibition by caspase-3s remains unknown. Here we show that exogenous caspase-3 sensitizes MCF-7 and HBL100 breast cancers cells to chemotherapeutic treatments such as etoposide and methotrexate whereas co-transfection with caspase-3s strongly inhibits etoposide and methotrexate-induced apoptosis underlying thus the anti-apoptotic role of caspase-3s. In caspase-3 transfected cells, lamin-A and alpha-fodrin were cleaved when caspase-3 was activated by etoposide or methotrexate. When caspase-3s was co-transfected, this cleavage was strongly reduced. Depletion of caspase-3 by RNA interference in HBL100 containing endogenous caspase-3s caused reduction in etoposide and methotrexate-induced apoptosis, whereas the depletion of caspase-3s sensitized cells to chemotherapy. In the presence of caspase-3s, a lack of interaction between caspase-3 and caspase-9 was observed. Immunoprecipitation assays showed that caspase-3s binds the pro-forms of caspase-3. This result suggested that the absence of interaction with caspase-9 when both variants of caspase-3 are present contribute to block the apoptosome assembly and inhibit apoptosis. These data support that caspases 3s negatively interferes with caspase-3 activation and apoptosis in breast cancer, and that it can play key roles in the modulation of response to chemotherapeutic treatments. PMID- 22216168 TI - Common promoter elements in odorant and vomeronasal receptor genes. AB - In mammals, odorants and pheromones are detected by hundreds of odorant receptors (ORs) and vomeronasal receptors (V1Rs and V2Rs) expressed by sensory neurons that are respectively located in the main olfactory epithelium and in the vomeronasal organ. Even though these two olfactory systems are functionally and anatomically separate, their sensory neurons show a common mechanism of receptor gene regulation: each neuron expresses a single receptor gene from a single allele. The mechanisms underlying OR and VR gene expression remain unclear. Here we investigated if OR and V1R genes share common sequences in their promoter regions.We conducted a comparative analysis of promoter regions of 39 mouse V1R genes and found motifs that are common to a large number of promoters. We then searched mouse OR promoter regions for motifs that resemble the ones found in the V1R promoters. We identified motifs that are present in both the V1R and OR promoter regions. Some of these motifs correspond to the known O/E like binding sites while others resemble binding sites for transcriptional repressors. We show that one of these motifs specifically interacts with proteins extracted from both nuclei from olfactory and vomeronasal neurons. Our study is the first to identify motifs that resemble binding sites for repressors in the promoters of OR and V1R genes. Analysis of these motifs and of the proteins that bind to these motifs should reveal important aspects of the mechanisms of OR/V1R gene regulation. PMID- 22216169 TI - Rationale and design of the Leipzig (LIFE) Heart Study: phenotyping and cardiovascular characteristics of patients with coronary artery disease. AB - OBJECTIVE: We established the Leipzig (LIFE) Heart Study, a biobank and database of patients with different stages of coronary artery disease (CAD) for studies of clinical, metabolic, cellular and genetic factors of cardiovascular diseases. DESIGN: The Leipzig (LIFE) Heart Study (NCT00497887) is an ongoing observational angiographic study including subjects with different entities of CAD. Cohort 1, patients undergoing first-time diagnostic coronary angiography due to suspected stable CAD with previously untreated coronary arteries. Cohort 2, patients with acute myocardial infarction (MI) requiring percutaneous revascularization. Cohort 3, patients with known left main coronary artery disease (LMCAD). RESULTS: We present preliminary results of demographics and phenotyping based on a 4-years analysis of a total of 3,165 subjects. Cohort 1 (n=2,274) shows the typical distribution of elective coronary angiography cohorts with 43% cases with obstructive CAD and 37% normal angiograms. Cohorts 2 and 3 consist of 590 and 301 subjects, respectively, adding patients with severe forms of CAD. The suitability of the database and biobank to perform association studies was confirmed by replication of the CAD susceptibility locus on chromosome 9p21 (OR per allele: 1.55 (any CAD), 1.54 (MI), 1.74 (LMCAD), p<10(-6), respectively). A novel finding was that patients with LMCAD had a stronger association with 9p21 than patients with obstructive CAD without LMCAD (OR 1.22, p=0.042). In contrast, 9p21 did not associate with myocardial infarction in excess of stable CAD. CONCLUSION: The Leipzig (LIFE) Heart Study provides a basis to identify molecular targets related to atherogenesis and associated metabolic disorders. The study may contribute to an improvement of individual prediction, prevention, and treatment of CAD. PMID- 22216170 TI - Critical role of VCP/p97 in the pathogenesis and progression of non-small cell lung carcinoma. AB - BACKGROUND: Valosin-containing protein (VCP)/p97 is an AAA ATPase molecular chaperone that regulates vital cellular functions and protein-processing. A recent study indicated that VCP expression levels are correlated with prognosis and progression of non-small cell lung carcinoma (NSCLC). We not only verified these findings but also identified the specific role of VCP in NSCLC pathogenesis and progression. METHODOLOGY/PRINCIPAL FINDINGS: Our results show that VCP is significantly overexpressed in non-small cell lung carcinoma (NSCLC) as compared to normal tissues and cell lines (p<0.001). Moreover, we observed the corresponding accumulation of ubiquitinated-proteins in NSCLC cell lines and tissues as compared to the normal controls. VCP inhibition by si/shRNA or small molecule (Eeyarestatin I, EerI) significantly (p<0.05, p<0.00007) suppressed H1299 proliferation and migration but induced (p<0.00001) apoptosis. Cell cycle analysis by flow cytometry verified this data and shows that VCP inhibition significantly (p<0.001, p<0.003) induced cell cycle arrest in the G0/G1 phases. We also found that VCP directly regulates p53 and NFkappaB protein levels as a potential mechanism to control tumor cell proliferation and progression. Finally, we evaluated the therapeutic potential of VCP inhibition and observed significantly reduced NSCLC tumor growth in both in vitro and xenograft murine (athymic-nude) models after EerI treatment (p<0.05). CONCLUSIONS/SIGNIFICANCE: Thus, targeting VCP in NSCLC may provide a novel strategy to restore p53 and NFkappaB levels and ameliorate the growth and tumorigenicity, leading to improved clinical outcomes. PMID- 22216171 TI - Risk factors for progression from severe maternal morbidity to death: a national cohort study. AB - BACKGROUND: Women continue to die unnecessarily during or after pregnancy in the developed world. The aim of this analysis was to compare women with severe maternal morbidities who survived with those who died, to quantify the risk associated with identified factors to inform policy and practice to improve survival. METHODS AND FINDINGS: We conducted a national cohort analysis using data from two sources obtained between 2003 and 2009: the Centre for Maternal and Child Enquiries maternal deaths database and the United Kingdom Obstetric Surveillance System database. Included women had eclampsia, antenatal pulmonary embolism, amniotic fluid embolism, acute fatty liver of pregnancy or antenatal stroke. These conditions were chosen as major causes of maternal mortality and morbidity about which data were available through both sources, and include 42% of direct maternal deaths over the study period. Rates, risk ratios, crude and adjusted odd ratios were used to investigate risks factors for maternal death. Multiple imputation and sensitivity analysis were used to handle missing data. We identified 476 women who survived and 100 women who died. Maternal death was associated with older age (35+ years aOR 2.36, 95%CI 1.22-4.56), black ethnicity (aOR 2.38, 95%CI 1.15-4.92), and unemployed, routine or manual occupation (aOR 2.19, 95%CI 1.03-4.68). An association was also observed with obesity (BMI>=30 kg/m(2) aOR 2.73, 95%CI 1.15-6.46). CONCLUSIONS: Ongoing high quality national surveillance programmes have an important place in addressing challenges in maternal health and care. There is a place for action to reverse the rising trends in maternal age at childbirth, and to reduce the burden of obesity in pregnancy, as well as ongoing recognition of the impact of older maternal age on the risks of pregnancy. Development and evaluation of services to mitigate the risk of dying associated with black ethnicity and lower socioeconomic status is also essential. PMID- 22216172 TI - Functional induction of the cystine-glutamate exchanger system Xc(-) activity in SH-SY5Y cells by unconjugated bilirubin. AB - We have previously reported that exposure of SH-SY5Y neuroblastoma cells to unconjugated bilirubin (UCB) resulted in a marked up-regulation of the mRNA encoding for the Na(+)-independent cystine?glutamate exchanger System X(c)(-) (SLC7A11 and SLC3A2 genes). In this study we demonstrate that SH-SY5Y cells treated with UCB showed a higher cystine uptake due to a significant and specific increase in the activity of System X(c)(-), without the contribution of the others two cystine transporters (X(AG)(-) and GGT) reported in neurons. The total intracellular glutathione content was 2 folds higher in the cells exposed to bilirubin as compared to controls, suggesting that the internalized cystine is used for gluthathione synthesis. Interestingly, these cells were significantly less sensitive to an oxidative insult induced by hydrogen peroxide. If System X(c)(-) is silenced the protection is lost. In conclusion, these results suggest that bilirubin can modulate the gluthathione levels in neuroblastoma cells through the induction of the System X(c)(-), and this renders the cell less prone to oxidative damage. PMID- 22216173 TI - Interactions among the A and T units of an ECF-type biotin transporter analyzed by site-specific crosslinking. AB - Energy-coupling factor (ECF) transporters are a huge group of micronutrient importers in prokaryotes. They are composed of a substrate-specific transmembrane protein (S component) and a module consisting of a moderately conserved transmembrane protein (T component) and two ABC ATPase domains (A components). Modules of A and T units may be dedicated to a specific S component or shared by many different S units in an organism. The mode of subunit interactions in ECF transporters is largely unknown. BioMNY, the focus of the present study, is a biotin transporter with a dedicated AT module. It consists of the S unit BioY, the A unit BioM and the T unit BioN. Like all T units, BioN contains two three amino-acid signatures with a central Arg residue in a cytoplasmic helical region. Our previous work had demonstrated a central role of the two motifs in T units for stability and function of BioMNY and other ECF transporters. Here we show by site-specific crosslinking of pairs of mono-cysteine variants that the Ala-Arg Ser and Ala-Arg-Gly signatures in BioN are coupling sites to the BioM ATPases. Analysis of 64 BioN-BioM pairs uncovered interactions of both signatures predominantly with a segment of ~13 amino acid residues C-terminal of the Q loop of BioM. Our results further demonstrate that portions of all BioN variants with single Cys residues in the two signatures are crosslinked to homodimers. This finding may point to a dimeric architecture of the T unit in BioMNY complexes. PMID- 22216174 TI - CD9 tetraspanin interacts with CD36 on the surface of macrophages: a possible regulatory influence on uptake of oxidized low density lipoprotein. AB - CD36 is a type 2 scavenger receptor with multiple functions. CD36 binding to oxidized LDL triggers signaling cascades that are required for macrophage foam cell formation, but the mechanisms by which CD36 signals remain incompletely understood. Mass spectrometry analysis of anti-CD36 immuno-precipitates from macrophages identified the tetraspanin CD9 as a CD36 interacting protein. Western blot showed that CD9 was precipitated from mouse macrophages by anti-CD36 monoclonal antibody and CD36 was likewise precipitated by anti-CD9, confirming the mass spectrometry results. Macrophages from cd36 null mice were used to demonstrate specificity. Membrane associations of the two proteins on intact cells was analyzed by confocal immunofluorescence microscopy and by a novel cross linking assay that detects proteins in close proximity (<40 nm). Functional significance was determined by assessing lipid accumulation, foam cell formation and JNK activation in wt, cd9 null and cd36 null macrophages exposed to oxLDL. OxLDL uptake, lipid accumulation, foam cell formation, and JNK phosphorylation were partially impaired in cd9 null macrophages. The present study demonstrates that CD9 associates with CD36 on the macrophage surface and may participate in macrophage signaling in response to oxidized LDL. PMID- 22216175 TI - Phenotype prediction using regularized regression on genetic data in the DREAM5 Systems Genetics B Challenge. AB - A major goal of large-scale genomics projects is to enable the use of data from high-throughput experimental methods to predict complex phenotypes such as disease susceptibility. The DREAM5 Systems Genetics B Challenge solicited algorithms to predict soybean plant resistance to the pathogen Phytophthora sojae from training sets including phenotype, genotype, and gene expression data. The challenge test set was divided into three subcategories, one requiring prediction based on only genotype data, another on only gene expression data, and the third on both genotype and gene expression data. Here we present our approach, primarily using regularized regression, which received the best-performer award for subchallenge B2 (gene expression only). We found that despite the availability of 941 genotype markers and 28,395 gene expression features, optimal models determined by cross-validation experiments typically used fewer than ten predictors, underscoring the importance of strong regularization in noisy datasets with far more features than samples. We also present substantial analysis of the training and test setup of the challenge, identifying high variance in performance on the gold standard test sets. PMID- 22216176 TI - Erythroid-specific expression of beta-globin from Sleeping Beauty-transduced human hematopoietic progenitor cells. AB - Gene therapy for sickle cell disease will require efficient delivery of a tightly regulated and stably expressed gene product to provide an effective therapy. In this study we utilized the non-viral Sleeping Beauty (SB) transposon system using the SB100X hyperactive transposase to transduce human cord blood CD34(+) cells with DsRed and a hybrid IHK-beta-globin transgene. IHK transduced cells were successfully differentiated into multiple lineages which all showed transgene integration. The mature erythroid cells had an increased beta-globin to gamma globin ratio from 0.66+/-0.08 to 1.05+/-0.12 (p=0.05), indicating expression of beta-globin from the integrated SB transgene. IHK-beta-globin mRNA was found in non-erythroid cell types, similar to native beta-globin mRNA that was also expressed at low levels. Additional studies in the hematopoietic K562 cell line confirmed the ability of cHS4 insulator elements to protect DsRed and IHK-beta globin transgenes from silencing in long-term culture studies. Insulated transgenes had statistically significant improvement in the maintenance of long term expression, while preserving transgene regulation. These results support the use of Sleeping Beauty vectors in carrying an insulated IHK-beta-globin transgene for gene therapy of sickle cell disease. PMID- 22216177 TI - Replication, gene expression and particle production by a consensus Merkel Cell Polyomavirus (MCPyV) genome. AB - Merkel Cell Polyomavirus (MCPyV) genomes are clonally integrated in tumor tissues of approximately 85% of all Merkel cell carcinoma (MCC) cases, a highly aggressive tumor of the skin which predominantly afflicts elderly and immunosuppressed patients. All integrated viral genomes recovered from MCC tissue or MCC cell lines harbor signature mutations in the early gene transcript encoding for the large T-Antigen (LT-Ag). These mutations selectively abrogate the ability of LT-Ag to support viral replication while still maintaining its Rb binding activity, suggesting a continuous requirement for LT-Ag mediated cell cycle deregulation during MCC pathogenesis. To gain a better understanding of MCPyV biology, in vitro MCPyV replication systems are required. We have generated a synthetic MCPyV genomic clone (MCVSyn) based on the consensus sequence of MCC derived sequences deposited in the NCBI database. Here, we demonstrate that transfection of recircularized MCVSyn DNA into some human cell lines recapitulates efficient replication of the viral genome, early and late gene expression together with virus particle formation. However, serial transmission of infectious virus was not observed. This in vitro culturing system allows the study of viral replication and will facilitate the molecular dissection of important aspects of the MCPyV lifecycle. PMID- 22216178 TI - The Pseudomonas aeruginosa reference strain PA14 displays increased virulence due to a mutation in ladS. AB - Pseudomonas aeruginosa is a pathogen that causes acute and chronic infections in a variety of hosts. The pathogenic potential of P. aeruginosa is strain dependent. PA14 is a highly virulent strain that causes disease in a wide range of organisms, whereas PAO1 is moderately virulent. Although PA14 carries pathogenicity islands that are absent in PAO1, the presence or absence of specific gene clusters is not predictive of virulence. Here, we show that the virulent strain PA14 has an acquired mutation in the ladS gene. This mutation has a deleterious impact on biofilm, while it results in elevated type III secretion system (T3SS) activity and increased cytotoxicity towards mammalian cells. These phenotypes can be reverted by repairing the ladS mutation on the PA14 genome. The RetS/LadS/GacS signaling cascade is associated with virulence and the switch between acute and chronic infections. RetS is a sensor that down-regulates biofilm formation and up-regulates the T3SS. Mutations in retS are acquired in strains isolated from chronically infected cystic fibrosis patients and lead to hyperbiofilm formation and reduced cytotoxicity. Conversely, the LadS sensor promotes biofilm formation and represses the T3SS. We conclude that the ladS mutation is partly responsible for the high cytotoxicity of PA14, and our findings corroborate the central role of RetS and LadS in the switch between acute and chronic infections. Given the extensive use of the reference strain PA14 in infection and virulence models, the bias caused by the ladS mutation on the observed phenotypes will be crucial to consider in future research. PMID- 22216179 TI - Biased use of the IGHV4 family and evidence for antigen selection in Chlamydophila psittaci-negative ocular adnexal extranodal marginal zone lymphomas. AB - Extranodal marginal zone lymphomas (EMZL) are the most common lymphomas in the ocular adnexa. The etiology and potential role for antigenic stimulation in these lymphomas are still controversial. We have examined IGHV gene usage and mutations in 67 Chlamydophila psittaci-negative ocular adnexal EMZL. Clonal IGHV gene sequences were identified in 43 tumors originating from the orbit (19), conjunctivae (18) and lacrimal gland (6). Forty four potentially functional clonal IGHV gene sequences were detected with overrepresentation of the IGHV4 family and IGHV4-34 gene. All but 3 sequences were mutated with the average percent homology to the germ line of 93.5+/-6.1. Multinomial model and Focused binomial test demonstrated evidence for positive and/or negative antigen selection in 59% of the potentially functional IGHV genes. Intraclonal variation was detected in 8 of 11 tumor specimens. Overall our findings demonstrate that C. psittaci-negative ocular adnexal EMZL exhibit biased usage of IGHV families and genes with evidence for intraclonal heterogeneity and antigen selection in multiple tumors, implicating B-cell receptor-mediated antigen stimulation in the pathogenesis of these lymphomas. PMID- 22216180 TI - The evolution of the multicoloured face of mandrills: insights from the perceptual space of colour vision. AB - Multicomponent signals consist of several traits that are perceived as a whole. Although many animals rely on multicomponent signals to communicate, the selective pressures shaping these signals are still poorly understood. Previous work has mainly investigated the evolution of multicomponent signals by studying each trait individually, which may not accurately reflect the selective pressures exerted by the holistic perception of signal receivers. Here, we study the design of the multicoloured face of an Old World primate, the mandrill (Mandrillus sphinx), in relation to two aspects of signalling that are expected to be selected by receivers: conspicuousness and information. Using reflectance data on the blue and red colours of the faces of 34 males and a new method of hue vectorisation in a perceptual space of colour vision, we show that the blue hue maximises contrasts to both the red hue and the foliage background colouration, thereby increasing the conspicuousness of the whole display. We further show that although blue saturation, red saturation and the contrast between blue and red colours are all correlated with dominance, dominance is most accurately indicated by the blue-red contrast. Taken together our results suggest that the evolution of blue and red facial colours in male mandrills are not independent and are likely driven by the holistic perception of conspecifics. In this view, we propose that the multicoloured face of mandrills acts as a multicomponent signal. Last, we show that information accuracy increases with the conspicuousness of the whole display, indicating that both aspects of signalling can evolve in concert. PMID- 22216182 TI - Periodic active case finding for TB: when to look? AB - OBJECTIVE: To investigate the factors influencing the performance and cost efficacy of periodic rounds of active case finding (ACF) for TB. METHODS: A mathematical model of TB dynamics and periodic ACF (PACF) in the HIV era, simplified by assuming constant prevalence of latent TB infection, is analyzed for features that control intervention outcome, measured as cases averted and cases found. Explanatory variables include baseline TB incidence, interval between PACF rounds, and different routine and PACF case-detection rates among HIV-infected and uninfected TB cases. FINDINGS: PACF can be cost-saving over a 10 year time frame if the cost-per-round is lower than a threshold proportional to initial incidence and cost-per-case-treated. More cases are averted at higher baseline incidence rates, when more potent PACF strategies are used, intervals between PACF rounds are shorter, and when the ratio of HIV-negative to positive TB cases detected is higher. More costly approaches, e.g. radiographic screening, can be as cost-effective as less costly alternatives if PACF case-detection is higher and/or implementation less frequent. CONCLUSION: Periodic ACF can both improve control and save medium-term health care costs in high TB burden settings. Greater costs of highly effective PACF at frequent (e.g. yearly) intervals may be offset by higher numbers of cases averted in populations with high baseline TB incidence, higher prevalence of HIV-uninfected cases, higher costs per-case-treated, and more effective routine case-detection. Less intensive approaches may still be cost-neutral or cost-saving in populations lacking one or more of these key determinants. PMID- 22216181 TI - The pore-forming protein Cry5B elicits the pathogenicity of Bacillus sp. against Caenorhabditis elegans. AB - The soil bacterium Bacillus thuringiensis is a pathogen of insects and nematodes and is very closely related to, if not the same species as, Bacillus cereus and Bacillus anthracis. The defining characteristic of B. thuringiensis that sets it apart from B. cereus and B. anthracis is the production of crystal (Cry) proteins, which are pore-forming toxins or pore-forming proteins (PFPs). Although it is known that PFPs are important virulence factors since their elimination results in reduced virulence of many pathogenic bacteria, the functions by which PFPs promote virulence are incompletely understood. Here we study the effect of Cry proteins in B. thuringiensis pathogenesis of the nematode Caenorhabditis elegans. We find that whereas B. thuringiensis on its own is not able to infect C. elegans, the addition of the PFP Cry protein, Cry5B, results in a robust lethal infection that consumes the nematode host in 1-2 days, leading to a "Bob" or bag-of-bacteria phenotype. Unlike other infections of C. elegans characterized to date, the infection by B. thuringiensis shows dose-dependency based on bacterial inoculum size and based on PFP concentration. Although the infection process takes 1-2 days, the PFP-instigated infection process is irreversibly established within 15 minutes of initial exposure. Remarkably, treatment of C. elegans with Cry5B PFP is able to instigate many other Bacillus species, including B. anthracis and even "non-pathogenic" Bacillus subtilis, to become lethal and infectious agents to C. elegans. Co-culturing of Cry5B-expressing B. thuringiensis with B. anthracis can result in lethal infection of C. elegans by B. anthracis. Our data demonstrate that one potential property of PFPs is to sensitize the host to bacterial infection and further that C. elegans and probably other roundworms can be common hosts for B. cereus-group bacteria, findings with important ecological and research implications. PMID- 22216184 TI - Spatial patterns of parrotfish corallivory in the Caribbean: the importance of coral taxa, density and size. AB - The past few decades have seen an increase in the frequency and intensity of disturbance on coral reefs, resulting in shifts in size and composition of coral populations. These changes have lead to a renewed focus on processes that influence demographic rates in corals, such as corallivory. While previous research indicates selective corallivory among coral taxa, the importance of coral size and the density of coral colonies in influencing corallivory are unknown. We surveyed the size, taxonomy and number of bites by parrotfish per colony of corals and the abundance of three main corallivorous parrotfish (Sparisoma viride, Sparisoma aurofrenatum, Scarus vetula) at multiple spatial scales (reefs within islands: 1-100 km, and between islands: >100 km) within the Bahamas Archipelago. We used a linear mixed model to determine the influence of coral taxa, colony size, colony density, and parrotfish abundance on the intensity of corallivory (bites per m(2) of coral tissue). While the effect of colony density was significant in determining the intensity of corallivory, we found no significant influence of colony size or parrotfish abundance (density, biomass or community structure). Parrotfish bites were most frequently observed on the dominant species of reef building corals (Montastraea annularis, Montastraea faveolata and Porites astreoides), yet our results indicate that when the confounding effects of colony density and size were removed, selective corallivory existed only for the less dominant Porites porites. As changes in disturbance regimes result in the decline of dominant frame-work building corals such as Montastraea spp., the projected success of P. porites on Caribbean reefs through high reproductive output, resistance to disease and rapid growth rates may be attenuated through selective corallivory by parrotfish. PMID- 22216183 TI - Habituation of the C-start response in larval zebrafish exhibits several distinct phases and sensitivity to NMDA receptor blockade. AB - The zebrafish larva has been a valuable model system for genetic and molecular studies of development. More recently, biologists have begun to exploit the surprisingly rich behavioral repertoire of zebrafish larvae to investigate behavior. One prominent behavior exhibited by zebrafish early in development is a rapid escape reflex (the C-start). This reflex is mediated by a relatively simple neural circuit, and is therefore an attractive model behavior for neurobiological investigations of simple forms of learning and memory. Here, we describe two forms of short-lived habituation of the C-start in response to brief pulses of auditory stimuli. A rapid form, persisting for >=1 min but <15 min, was induced by 120 pulses delivered at 0.5-2.0 Hz. A more extended form (termed "short-term habituation" here), which persisted for >=25 min but <1 h, was induced by spaced training. The spaced training consisted of 10 blocks of auditory pulses delivered at 1 Hz (5 min interblock interval, 900 pulses per block). We found that these two temporally distinguishable forms of habituation are mediated by different cellular mechanisms. The short-term form depends on activation of N-methyl-d aspartate receptors (NMDARs), whereas the rapid form does not. PMID- 22216185 TI - Sensitivity of global translation to mTOR inhibition in REN cells depends on the equilibrium between eIF4E and 4E-BP1. AB - Initiation is the rate-limiting phase of protein synthesis, controlled by signaling pathways regulating the phosphorylation of translation factors. Initiation has three steps, 43S, 48S and 80S formation. 43S formation is repressed by eIF2alpha phosphorylation. The subsequent steps, 48S and 80S formation are enabled by growth factors. 48S relies on eIF4E-mediated assembly of eIF4F complex; 4E-BPs competitively displace eIF4E from eIF4F. Two pathways control eIF4F: 1) mTORc1 phosphorylates and inactivates 4E-BPs, leading to eIF4F formation; 2) the Ras-Mnk cascade phosphorylates eIF4E. We show that REN and NCI H28 mesothelioma cells have constitutive activation of both pathways and maximal translation rate, in the absence of exogenous growth factors. Translation is rapidly abrogated by phosphorylation of eIF2alpha. Surprisingly, pharmacological inhibition of mTORc1 leads to the complete dephosphorylation of downstream targets, without changes in methionine incorporation. In addition, the combined administration of mTORc1 and MAPK/Mnk inhibitors has no additive effect. The inhibition of both mTORc1 and mTORc2 does not affect the metabolic rate. In spite of this, mTORc1 inhibition reduces eIF4F complex formation, and depresses translocation of TOP mRNAs on polysomes. Downregulation of eIF4E and overexpression of 4E-BP1 induce rapamycin sensitivity, suggesting that disruption of eIF4F complex, due to eIF4E modulation, competes with its recycling to ribosomes. These data suggest the existence of a dynamic equilibrium in which eIF4F is not essential for all mRNAs and is not displaced from translated mRNAs, before recycling to the next. PMID- 22216186 TI - The P-loop domain of yeast Clp1 mediates interactions between CF IA and CPF factors in pre-mRNA 3' end formation. AB - Cleavage factor IA (CF IA), cleavage and polyadenylation factor (CPF), constitute major protein complexes required for pre-mRNA 3' end formation in yeast. The Clp1 protein associates with Pcf11, Rna15 and Rna14 in CF IA but its functional role remained unclear. Clp1 carries an evolutionarily conserved P-loop motif that was previously shown to bind ATP. Interestingly, human and archaean Clp1 homologues, but not the yeast protein, carry 5' RNA kinase activity. We show that depletion of Clp1 in yeast promoted defective 3' end formation and RNA polymerase II termination; however, cells expressing Clp1 with mutant P-loops displayed only minor defects in gene expression. Similarly, purified and reconstituted mutant CF IA factors that interfered with ATP binding complemented CF IA depleted extracts in coupled in vitro transcription/3' end processing reactions. We found that Clp1 was required to assemble recombinant CF IA and that certain P-loop mutants failed to interact with the CF IA subunit Pcf11. In contrast, mutations in Clp1 enhanced binding to the 3' endonuclease Ysh1 that is a component of CPF. Our results support a structural role for the Clp1 P-loop motif. ATP binding by Clp1 likely contributes to CF IA formation and cross-factor interactions during the dynamic process of 3' end formation. PMID- 22216188 TI - Activation-induced cytidine deaminase expression in CD4+ T cells is associated with a unique IL-10-producing subset that increases with age. AB - Activation-induced cytidine deaminase (AID), produced by the Aicda gene, is essential for the immunoglobulin gene (Ig) alterations that form immune memory. Using a Cre-mediated genetic system, we unexpectedly found CD4(+) T cells that had expressed Aicda (exAID cells) as well as B cells. ExAID cells increased with age, reaching up to 25% of the CD4(+) and B220(+) cell populations. ExAID B cells remained IgM(+), suggesting that class-switched memory B cells do not accumulate in the spleen. In T cells, AID was expressed in a subset that produced IFN-gamma and IL-10 but little IL-4 or IL-17, and showed no evidence of genetic mutation. Interestingly, the endogenous Aicda expression in T cells was enhanced in the absence of B cells, indicating that the process is independent from the germinal center reaction. These results suggest that in addition to its roles in B cells, AID may have previously unappreciated roles in T-cell function or tumorigenesis. PMID- 22216187 TI - Two novel parvoviruses in frugivorous New and Old World bats. AB - Bats, a globally distributed group of mammals with high ecological importance, are increasingly recognized as natural reservoir hosts for viral agents of significance to human and animal health. In the present study, we evaluated pools of blood samples obtained from two phylogenetically distant bat families, in particular from flying foxes (Pteropodidae), Eidolon helvum in West Africa, and from two species of New World leaf-nosed fruit bats (Phyllostomidae), Artibeus jamaicensis and Artibeus lituratus in Central America. A sequence-independent virus discovery technique (VIDISCA) was used in combination with high throughput sequencing to detect two novel parvoviruses: a PARV4-like virus named Eh-BtPV-1 in Eidolon helvum from Ghana and the first member of a putative new genus in Artibeus jamaicensis from Panama (Aj-BtPV-1). Those viruses were circulating in the corresponding bat colony at rates of 7-8%. Aj-BtPV-1 was also found in Artibeus lituratus (5.5%). Both viruses were detected in the blood of infected animals at high concentrations: up to 10E8 and to 10E10 copies/ml for Aj-BtPV-1 and Eh-BtPV-1 respectively. Eh-BtPV-1 was additionally detected in all organs collected from bats (brain, lungs, liver, spleen, kidneys and intestine) and spleen and kidneys were identified as the most likely sites where viral replication takes place. Our study shows that bat parvoviruses share common ancestors with known parvoviruses of humans and livestock. We also provide evidence that a variety of Parvovirinae are able to cause active infection in bats and that they are widely distributed in these animals with different geographic origin, ecologies and climatic ranges. PMID- 22216189 TI - KRAS mutations testing in colorectal carcinoma patients in Italy: from guidelines to external quality assessment. AB - BACKGROUND: Monoclonal antibodies directed against the epidermal growth factor receptor (EGFR) have been approved for the treatment of patients with metastatic colorectal carcinoma (mCRC) that do not carry KRAS mutations. Therefore, KRAS testing has become mandatory to chose the most appropriate therapy for these patients. METHODOLOGY/PRINCIPAL FINDINGS: In order to guarantee the possibility for mCRC patients to receive an high quality KRAS testing in every Italian region, the Italian Association of Medical Oncology (AIOM) and the Italian Society of Pathology and Cytopathology -Italian division of the International Academy of Pathology (SIAPEC-IAP) started a program to improve KRAS testing. AIOM and SIAPEC identified a large panel of Italian medical oncologists, pathologists and molecular biologists that outlined guidelines for KRAS testing in mCRC patients. These guidelines include specific information on the target patient population, the biological material for molecular analysis, the extraction of DNA, and the methods for the mutational analysis that are summarized in this paper. Following the publication of the guidelines, the scientific societies started an external quality assessment scheme for KRAS testing. Five CRC specimens with known KRAS mutation status were sent to the 59 centers that participated to the program. The samples were validated by three referral laboratories. The participating laboratories were allowed to use their own preferred method for DNA extraction and mutational analysis and were asked to report the results within 4 weeks. The limit to pass the quality assessment was set at 100% of true responses. In the first round, only two centers did not pass (3%). The two centers were offered to participate to a second round and both centers failed again to pass. CONCLUSIONS: The results of this first Italian quality assessment for KRAS testing suggest that KRAS mutational analysis is performed with good quality in the majority of Italian centers. PMID- 22216190 TI - Degradation of pheromone and plant volatile components by a same odorant degrading enzyme in the cotton leafworm, Spodoptera littoralis. AB - BACKGROUND: Odorant-Degrading Enzymes (ODEs) are supposed to be involved in the signal inactivation step within the olfactory sensilla of insects by quickly removing odorant molecules from the vicinity of the olfactory receptors. Only three ODEs have been both identified at the molecular level and functionally characterized: two were specialized in the degradation of pheromone compounds and the last one was shown to degrade a plant odorant. METHODOLOGY: Previous work has shown that the antennae of the cotton leafworm Spodoptera littoralis, a worldwide pest of agricultural crops, express numerous candidate ODEs. We focused on an esterase overexpressed in males antennae, namely SlCXE7. We studied its expression patterns and tested its catalytic properties towards three odorants, i.e. the two female sex pheromone components and a green leaf volatile emitted by host plants. CONCLUSION: SlCXE7 expression was concomitant during development with male responsiveness to odorants and during adult scotophase with the period of male most active sexual behaviour. Furthermore, SlCXE7 transcription could be induced by male exposure to the main pheromone component, suggesting a role of Pheromone-Degrading Enzyme. Interestingly, recombinant SlCXE7 was able to efficiently hydrolyze the pheromone compounds but also the plant volatile, with a higher affinity for the pheromone than for the plant compound. In male antennae, SlCXE7 expression was associated with both long and short sensilla, tuned to sex pheromones or plant odours, respectively. Our results thus suggested that a same ODE could have a dual function depending of it sensillar localisation. Within the pheromone-sensitive sensilla, SlCXE7 may play a role in pheromone signal termination and in reduction of odorant background noise, whereas it could be involved in plant odorant inactivation within the short sensilla. PMID- 22216191 TI - Mycobacterium abscessus glycopeptidolipid prevents respiratory epithelial TLR2 signaling as measured by HbetaD2 gene expression and IL-8 release. AB - Mycobacterium abscessus has emerged as an important cause of lung infection, particularly in patients with bronchiectasis. Innate immune responses must be highly effective at preventing infection with M. abscessus because it is a ubiquitous environmental saprophyte and normal hosts are not commonly infected. M. abscessus exists as either a glycopeptidolipid (GPL) expressing variant (smooth phenotype) in which GPL masks underlying bioactive cell wall lipids, or as a variant lacking GPL which is immunostimulatory and invasive in macrophage infection models. Respiratory epithelium has been increasingly recognized as playing an important role in the innate immune response to pulmonary pathogens. Respiratory epithelial cells express toll-like receptors (TLRs) which mediate the innate immune response to pulmonary pathogens. Both interleukin-8 (IL-8) and human beta-defensin 2 (HbetaD2) are expressed by respiratory epithelial cells in response to toll-like receptor 2 (TLR2) receptor stimulation. In this study, we demonstrate that respiratory epithelial cells respond to M. abscessus variants lacking GPL with expression of IL-8 and HbetaD2. Furthermore, we demonstrate that this interaction is mediated through TLR2. Conversely, M. abscessus expressing GPL does not stimulate expression of IL-8 or HbetaD2 by respiratory epithelial cells which is consistent with "masking" of underlying bioactive cell wall lipids by GPL. Because GPL-expressing smooth variants are the predominant phenotype existing in the environment, this provides an explanation whereby initial M. abscessus colonization of abnormal lung airways escapes detection by the innate immune system. PMID- 22216192 TI - Bacterial niche-specific genome expansion is coupled with highly frequent gene disruptions in deep-sea sediments. AB - The complexity and dynamics of microbial metagenomes may be evaluated by genome size, gene duplication and the disruption rate between lineages. In this study, we pyrosequenced the metagenomes of microbes obtained from the brine and sediment of a deep-sea brine pool in the Red Sea to explore the possible genomic adaptations of the microbes in response to environmental changes. The microbes from the brine and sediments (both surface and deep layers) of the Atlantis II Deep brine pool had similar communities whereas the effective genome size varied from 7.4 Mb in the brine to more than 9 Mb in the sediment. This genome expansion in the sediment samples was due to gene duplication as evidenced by enrichment of the homologs. The duplicated genes were highly disrupted, on average by 47.6% and 70% for the surface and deep layers of the Atlantis II Deep sediment samples, respectively. The disruptive effects appeared to be mainly due to point mutations and frameshifts. In contrast, the homologs from the Atlantis II Deep brine sample were highly conserved and they maintained relatively small copy numbers. Likely, the adaptation of the microbes in the sediments was coupled with pseudogenizations and possibly functional diversifications of the paralogs in the expanded genomes. The maintenance of the pseudogenes in the large genomes is discussed. PMID- 22216193 TI - Small-scale heterogeneity in deep-sea nematode communities around biogenic structures. AB - The unexpected high species richness of deep-sea sediments gives rise to the questions, which processes produce and maintain diversity in the deep sea, and at what spatial scales do these processes operate? The idea of a small-scale habitat structure at the deep-sea floor provides the background for this study. At small scales biogenic structures create a heterogeneous environment that influences the structure of the surrounding communities and the dynamics of the meiobenthic populations. As an example for biogenic structures, small deep-sea sponges (Tentorium semisuberites Schmidt 1870) and their sedimentary environment were investigated for small-scale distribution patterns of benthic deep-sea nematodes. Sampling was carried out with the remotely operated vehicle Victor 6000 at the Arctic deep-sea observatory HAUSGARTEN. In order to investigate nematode community patterns sediment cores around three small sponges and corresponding control cores were analysed. A total of approx. 5800 nematodes were identified. The comparison of the nematode communities from sponge and control samples indicated an influence of the biogenic structure "sponge" on diversity patterns and habitat heterogeneity. The increased number of nematode species and functional groups found in the sediments around the sponges suggest that on a small scale the sponge acts as a gradient and creates a more divers habitat structure. The nematode community from the sponge sediments shows a greater taxonomic variance and species richness together with lower relative abundances of the species compared to those from control sediments. Obviously, the more homogeneous habitat conditions of the control sediments offer less micro-habitats than the sediments around the sponges. This seems to reduce the number of functional groups and species coexisting in the control sediments. PMID- 22216194 TI - Thiopurine methyltransferase predicts the extent of cytotoxicty and DNA damage in astroglial cells after thioguanine exposure. AB - Thiopurine methyltransferase (Tpmt) is the primary enzyme responsible for deactivating thiopurine drugs. Thiopurine drugs (i.e., thioguanine [TG], mercaptopurine, azathioprine) are commonly used for the treatment of cancer, organ transplant, and autoimmune disorders. Chronic thiopurine therapy has been linked to the development of brain cancer (most commonly astrocytomas), and Tpmt status has been associated with this risk. Therefore, we investigated whether the level of Tpmt protein activity could predict TG-associated cytotoxicity and DNA damage in astrocytic cells. We found that TG induced cytotoxicity in a dose dependent manner in Tpmt(+/+), Tpmt(+/-) and Tpmt(-/-) primary mouse astrocytes and that a low Tpmt phenotype predicted significantly higher sensitivity to TG than did a high Tpmt phenotype. We also found that TG exposure induced significantly more DNA damage in the form of single strand breaks (SSBs) and double strand breaks (DSBs) in primary astrocytes with low Tpmt versus high Tpmt. More interestingly, we found that Tpmt(+/-) astrocytes had the highest degree of cytotoxicity and genotoxicity (i.e., IC(50), SSBs and DSBs) after TG exposure. We then used human glioma cell lines as model astroglial cells to represent high (T98) and low (A172) Tpmt expressers and found that A172 had the highest degree of cytoxicity and SSBs after TG exposure. When we over-expressed Tpmt in the A172 cell line, we found that TG IC(50) was significantly higher and SSB's were significantly lower as compared to mock transfected cells. This study shows that low Tpmt can lead to greater sensitivity to thiopurine therapy in astroglial cells. When Tpmt deactivation at the germ-line is considered, this study also suggests that heterozygosity may be subject to the greatest genotoxic effects of thiopurine therapy. PMID- 22216195 TI - Gene regulatory network reconstruction using Bayesian networks, the Dantzig Selector, the Lasso and their meta-analysis. AB - Modern technologies and especially next generation sequencing facilities are giving a cheaper access to genotype and genomic data measured on the same sample at once. This creates an ideal situation for multifactorial experiments designed to infer gene regulatory networks. The fifth "Dialogue for Reverse Engineering Assessments and Methods" (DREAM5) challenges are aimed at assessing methods and associated algorithms devoted to the inference of biological networks. Challenge 3 on "Systems Genetics" proposed to infer causal gene regulatory networks from different genetical genomics data sets. We investigated a wide panel of methods ranging from Bayesian networks to penalised linear regressions to analyse such data, and proposed a simple yet very powerful meta-analysis, which combines these inference methods. We present results of the Challenge as well as more in-depth analysis of predicted networks in terms of structure and reliability. The developed meta-analysis was ranked first among the 16 teams participating in Challenge 3A. It paves the way for future extensions of our inference method and more accurate gene network estimates in the context of genetical genomics. PMID- 22216196 TI - Beta-cell specific deletion of Dicer1 leads to defective insulin secretion and diabetes mellitus. AB - Mature microRNAs (miRNAs), derived through cleavage of pre-miRNAs by the Dicer1 enzyme, regulate protein expression in many cell-types including cells in the pancreatic islets of Langerhans. To investigate the importance of miRNAs in mouse insulin secreting beta-cells, we have generated mice with a beta-cells specific disruption of the Dicer1 gene using the Cre-lox system controlled by the rat insulin promoter (RIP). In contrast to their normoglycaemic control littermates (RIP-Cre(+/-) Dicer1(Delta/wt)), RIP-Cre(+/-)Dicer1(flox/flox) mice (RIP-Cre Dicer1(Delta/Delta)) developed progressive hyperglycaemia and full-blown diabetes mellitus in adulthood that recapitulated the natural history of the spontaneous disease in mice. Reduced insulin gene expression and concomitant reduced insulin secretion preceded the hyperglycaemic state and diabetes development. Immunohistochemical, flow cytometric and ultrastructural analyses revealed altered islet morphology, marked decreased beta-cell mass, reduced numbers of granules within the beta-cells and reduced granule docking in adult RIP-Cre Dicer1(Delta/Delta) mice. beta-cell specific Dicer1 deletion did not appear to disrupt fetal and neonatal beta-cell development as 2-week old RIP-Cre Dicer1(Delta/Delta) mice showed ultrastructurally normal beta-cells and intact insulin secretion. In conclusion, we have demonstrated that a beta-cell specific disruption of the miRNAs network, although allowing for apparently normal beta cell development, leads to progressive impairment of insulin secretion, glucose homeostasis and diabetes development. PMID- 22216197 TI - The Nrf1 CNC-bZIP protein is regulated by the proteasome and activated by hypoxia. AB - BACKGROUND: Nrf1 (nuclear factor-erythroid 2 p45 subunit-related factor 1) is a transcription factor mediating cellular responses to xenobiotic and pro-oxidant stress. Nrf1 regulates the transcription of many stress-related genes through the electrophile response elements (EpREs) located in their promoter regions. Despite its potential importance in human health, the mechanisms controlling Nrf1 have not been addressed fully. PRINCIPAL FINDINGS: We found that proteasomal inhibitors MG-132 and clasto-lactacystin-beta-lactone stabilized the protein expression of full-length Nrf1 in both COS7 and WFF2002 cells. Concomitantly, proteasomal inhibition decreased the expression of a smaller, N-terminal Nrf1 fragment, with an approximate molecular weight of 23 kDa. The EpRE-luciferase reporter assays revealed that proteasomal inhibition markedly inhibited the Nrf1 transactivational activity. These results support earlier hypotheses that the 26 S proteasome processes Nrf1 into its active form by removing its inhibitory N terminal domain anchoring Nrf1 to the endoplasmic reticulum. Immunoprecipitation demonstrated that Nrf1 is ubiquitinated and that proteasomal inhibition increased the degree of Nrf1 ubiquitination. Furthermore, Nrf1 protein had a half-life of approximately 5 hours in COS7 cells. In contrast, hypoxia (1% O(2)) significantly increased the luciferase reporter activity of exogenous Nrf1 protein, while decreasing the protein expression of p65, a shorter form of Nrf1, known to act as a repressor of EpRE-controlled gene expression. Finally, the protein phosphatase inhibitor okadaic acid activated Nrf1 reporter activity, while the latter was repressed by the PKC inhibitor staurosporine. CONCLUSIONS: Collectively, our data suggests that Nrf1 is controlled by several post-translational mechanisms, including ubiquitination, proteolytic processing and proteasomal-mediated degradation as well as by its phosphorylation status. PMID- 22216198 TI - A genome-wide association study of the Protein C anticoagulant pathway. AB - The Protein C anticoagulant pathway regulates blood coagulation by preventing the inadequate formation of thrombi. It has two main plasma components: protein C and protein S. Individuals with protein C or protein S deficiency present a dramatically increased incidence of thromboembolic disorders. Here, we present the results of a genome-wide association study (GWAS) for protein C and protein S plasma levels in a set of extended pedigrees from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project. A total number of 397 individuals from 21 families were typed for 307,984 SNPs using the Infinium(r) 317 k Beadchip (Illumina). Protein C and protein S (free, functional and total) plasma levels were determined with biochemical assays for all participants. Association with phenotypes was investigated through variance component analysis. After correcting for multiple testing, two SNPs for protein C plasma levels (rs867186 and rs8119351) and another two for free protein S plasma levels (rs1413885 and rs1570868) remained significant on a genome-wide level, located in and around the PROCR and the DNAJC6 genomic regions respectively. No SNPs were significantly associated with functional or total protein S plasma levels, although rs1413885 from DNAJC6 showed suggestive association with the functional protein S phenotype, possibly indicating that this locus plays an important role in protein S metabolism. Our results provide evidence that PROCR and DNAJC6 might play a role in protein C and free protein S plasma levels in the population studied, warranting further investigation on the role of these loci in the etiology of venous thromboembolism and other thrombotic diseases. PMID- 22216199 TI - Synergistic effects of apigenin and paclitaxel on apoptosis of cancer cells. AB - BACKGROUND: It was well known that the clinical use of chemotherapeutic drugs is restricted by severe adverse reactions and drug resistances. Thus it is necessary to figure out a strategy to increase the specific anti-tumor efficiency of chemotherapeutic drugs. Apigenin, a kind of flavonoids, has been reported to possess anticancer activities with very low cytotoxicity to normal tissue. METHODOLOGY/PRINCIPAL FINDINGS: Our results from cell viability assay, western blots and TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay demonstrated the synergistic pro-apoptotic effects of a low dose of apigenin and paclitaxel in human cancer cell lines. To analyze the underlying mechanism, we examined reactive oxygen species (ROS) staining after cells were treated with a combination of apigenin and paclitaxel, or each of them alone. Data from flow cytometry showed that superoxides but not reduction of peroxides accumulated in HeLa cells treated with apigenin or a combination of apigenin and paclitaxel. Apigenin and paclitaxel-induced HeLa cell apoptosis was related to the level of ROS in cells. We further evaluated activity and protein level of superoxide dismutase (SOD). Apigenin significantly inhibited SOD activity but did not alter the SOD protein level suggesting that apigenin promoted ROS accumulation through suppressing enzyme activity of SOD. Addition of Zn(2+), Cu(2+) and Mn(2+) to cell lysates inhibited apigenin's effects on SOD activity. At the same time, data from caspase-2 over-expression and knocked-down experiments demonstrated that caspase 2 participated in apigenin and paclitaxel-induced HeLa cell apoptosis. CONCLUSIONS/SIGNIFICANCE: Taken together, our study demonstrated that apigenin can sensitize cancer cells to paclitaxel induced apoptosis through suppressing SOD activity, which then led to accumulation of ROS and cleavage of caspase-2, suggesting that the combined use of apigenin and paclitaxel was an effective way to decrease the dose of paclitaxel taken. PMID- 22216200 TI - Prostate cancer cell lines under hypoxia exhibit greater stem-like properties. AB - Hypoxia is an important environmental change in many cancers. Hypoxic niches can be occupied by cancer stem/progenitor-like cells that are associated with tumor progression and resistance to radiotherapy and chemotherapy. However, it has not yet been fully elucidated how hypoxia influences the stem-like properties of prostate cancer cells. In this report, we investigated the effects of hypoxia on human prostate cancer cell lines, PC-3 and DU145. In comparison to normoxia (20% O(2)), 7% O(2) induced higher expressions of HIF-1alpha and HIF-2alpha, which were associated with upregulation of Oct3/4 and Nanog; 1% O(2) induced even greater levels of these factors. The upregulated NANOG mRNA expression in hypoxia was confirmed to be predominantly retrogene NANOGP8. Similar growth rates were observed for cells cultivated under hypoxic and normoxic conditions for 48 hours; however, the colony formation assay revealed that 48 hours of hypoxic pretreatment resulted in the formation of more colonies. Treatment with 1% O(2) also extended the G(0)/G(1) stage, resulting in more side population cells, and induced CD44 and ABCG2 expressions. Hypoxia also increased the number of cells positive for ABCG2 expression, which were predominantly found to be CD44(bright) cells. Correspondingly, the sorted CD44(bright) cells expressed higher levels of ABCG2, Oct3/4, and Nanog than CD44(dim) cells, and hypoxic pretreatment significantly increased the expressions of these factors. CD44(bright) cells under normoxia formed significantly more colonies and spheres compared with the CD44(dim) cells, and hypoxic pretreatment even increased this effect. Our data indicate that prostate cancer cells under hypoxia possess greater stem-like properties. PMID- 22216201 TI - Lateral gene expression in Drosophila early embryos is supported by Grainyhead mediated activation and tiers of dorsally-localized repression. AB - The general consensus in the field is that limiting amounts of the transcription factor Dorsal establish dorsal boundaries of genes expressed along the dorsal ventral (DV) axis of early Drosophila embryos, while repressors establish ventral boundaries. Yet recent studies have provided evidence that repressors act to specify the dorsal boundary of intermediate neuroblasts defective (ind), a gene expressed in a stripe along the DV axis in lateral regions of the embryo. Here we show that a short 12 base pair sequence ("the A-box") present twice within the ind CRM is both necessary and sufficient to support transcriptional repression in dorsal regions of embryos. To identify binding factors, we conducted affinity chromatography using the A-box element and found a number of DNA-binding proteins and chromatin-associated factors using mass spectroscopy. Only Grainyhead (Grh), a CP2 transcription factor with a unique DNA-binding domain, was found to bind the A-box sequence. Our results suggest that Grh acts as an activator to support expression of ind, which was surprising as we identified this factor using an element that mediates dorsally-localized repression. Grh and Dorsal both contribute to ind transcriptional activation. However, another recent study found that the repressor Capicua (Cic) also binds to the A-box sequence. While Cic was not identified through our A-box affinity chromatography, utilization of the same site, the A-box, by both factors Grh (activator) and Cic (repressor) may also support a "switch-like" response that helps to sharpen the ind dorsal boundary. Furthermore, our results also demonstrate that TGF-beta signaling acts to refine ind CRM expression in an A-box independent manner in dorsal-most regions, suggesting that tiers of repression act in dorsal regions of the embryo. PMID- 22216202 TI - Special agents can promote cooperation in the population. AB - Cooperation is ubiquitous in our real life but everyone would like to maximize her own profits. How does cooperation occur in the group of self-interested agents without centralized control? Furthermore, in a hostile scenario, for example, cooperation is unlikely to emerge. Is there any mechanism to promote cooperation if populations are given and play rules are not allowed to change? In this paper, numerical experiments show that complete population interaction is unfriendly to cooperation in the finite but end-unknown Repeated Prisoner's Dilemma (RPD). Then a mechanism called soft control is proposed to promote cooperation. According to the basic idea of soft control, a number of special agents are introduced to intervene in the evolution of cooperation. They comply with play rules in the original group so that they are always treated as normal agents. For our purpose, these special agents have their own strategies and share knowledge. The capability of the mechanism is studied under different settings. We find that soft control can promote cooperation and is robust to noise. Meanwhile simulation results demonstrate the applicability of the mechanism in other scenarios. Besides, the analytical proof also illustrates the effectiveness of soft control and validates simulation results. As a way of intervention in collective behaviors, soft control provides a possible direction for the study of reciprocal behaviors. PMID- 22216203 TI - Liver-specific Commd1 knockout mice are susceptible to hepatic copper accumulation. AB - Canine copper toxicosis is an autosomal recessive disorder characterized by hepatic copper accumulation resulting in liver fibrosis and eventually cirrhosis. We have identified COMMD1 as the gene underlying copper toxicosis in Bedlington terriers. Although recent studies suggest that COMMD1 regulates hepatic copper export via an interaction with the Wilson disease protein ATP7B, its importance in hepatic copper homeostasis is ill-defined. In this study, we aimed to assess the effect of Commd1 deficiency on hepatic copper metabolism in mice. Liver specific Commd1 knockout mice (Commd1(Deltahep)) were generated and fed either a standard or a copper-enriched diet. Copper homeostasis and liver function were determined in Commd1(Deltahep) mice by biochemical and histological analyses, and compared to wild-type littermates. Commd1(Deltahep) mice were viable and did not develop an overt phenotype. At six weeks, the liver copper contents was increased up to a 3-fold upon Commd1 deficiency, but declined with age to concentrations similar to those seen in controls. Interestingly, Commd1(Deltahep) mice fed a copper-enriched diet progressively accumulated copper in the liver up to a 20 fold increase compared to controls. These copper levels did not result in significant induction of the copper-responsive genes metallothionein I and II, neither was there evidence of biochemical liver injury nor overt liver pathology. The biosynthesis of ceruloplasmin was clearly augmented with age in Commd1(Deltahep) mice. Although COMMD1 expression is associated with changes in ATP7B protein stability, no clear correlation between Atp7b levels and copper accumulation in Commd1(Deltahep) mice could be detected. Despite the absence of hepatocellular toxicity in Commd1(Deltahep) mice, the changes in liver copper displayed several parallels with copper toxicosis in Bedlington terriers. Thus, these results provide the first genetic evidence for COMMD1 to play an essential role in hepatic copper homeostasis and present a valuable mouse model for further understanding of the molecular mechanisms underlying hepatic copper homeostasis. PMID- 22216204 TI - Ethnic inequalities in mortality: the case of Arab-Americans. AB - BACKGROUND: Although nearly 112 million residents of the United States belong to a non-white ethnic group, the literature about differences in health indicators across ethnic groups is limited almost exclusively to Hispanics. Features of the social experience of many ethnic groups including immigration, discrimination, and acculturation may plausibly influence mortality risk. We explored life expectancy and age-adjusted mortality risk of Arab-Americans (AAs), relative to non-Arab and non-Hispanic Whites in Michigan, the state with the largest per capita population of AAs in the US. METHODOLOGY/PRINCIPAL FINDINGS: Data were collected about all deaths to AAs and non-Arab and non-Hispanic Whites in Michigan between 1990 and 2007, and year 2000 census data were collected for population denominators. We calculated life expectancy, age-adjusted all-cause, cause-specific, and age-specific mortality rates stratified by ethnicity and gender among AAs and non-Arab and non-Hispanic Whites. Among AAs, life expectancies among men and women were 2.0 and 1.4 years lower than among non-Arab and non-Hispanic White men and women, respectively. AA men had higher mortality than non-Arab and non-Hispanic White men due to infectious diseases, chronic diseases, and homicide. AA women had higher mortality than non-Arab and non Hispanic White women due to chronic diseases. CONCLUSIONS/SIGNIFICANCE: Despite better education and higher income, AAs have higher age-adjusted mortality risk than non-Arab and non-Hispanic Whites, particularly due to chronic diseases. Features specific to AA culture may explain some of these findings. PMID- 22216206 TI - Development of an antibody to bovine IL-2 reveals multifunctional CD4 T(EM) cells in cattle naturally infected with bovine tuberculosis. AB - Gaining a better understanding of the T cell mechanisms underlying natural immunity to bovine tuberculosis would help to identify immune correlates of disease progression and facilitate the rational design of improved vaccine and diagnostic strategies. CD4 T cells play an established central role in immunity to TB, and recent interest has focussed on the potential role of multifunctional CD4 T cells expressing IFN-gamma, IL-2 and TNF-alpha. Until now, it has not been possible to assess the contribution of these multifunctional CD4 T cells in cattle due to the lack of reagents to detect bovine IL-2 (bIL-2). Using recombinant phage display technology, we have identified an antibody that recognises biologically active bIL-2. Using this antibody, we have developed a polychromatic flow cytometric staining panel that has allowed the investigation of multifunctional CD4 T-cells responses in cattle naturally infected with M. bovis. Assessment of the frequency of antigen specific CD4 T cell subsets reveals a dominant IFN-gamma(+)IL-2(+)TNF-alpha(+) and IFN-gamma(+) TNF-alpha(+) response in naturally infected cattle. These multifunctional CD4 T cells express a CD44(hi)CD45RO(+)CD62L(lo) T-effector memory (T(EM)) phenotype and display higher cytokine median fluorescence intensities than single cytokine producers, consistent with an enhanced 'quality of response' as reported for multifunctional cells in human and murine systems. Through our development of these novel immunological bovine tools, we provide the first description of multifunctional T(EM) cells in cattle. Application of these tools will improve our understanding of protective immunity in bovine TB and allow more direct comparisons of the complex T cell mediated immune responses between murine models, human clinical studies and bovine TB models in the future. PMID- 22216205 TI - Heterologous expression of membrane proteins: choosing the appropriate host. AB - BACKGROUND: Membrane proteins are the targets of 50% of drugs, although they only represent 1% of total cellular proteins. The first major bottleneck on the route to their functional and structural characterisation is their overexpression; and simply choosing the right system can involve many months of trial and error. This work is intended as a guide to where to start when faced with heterologous expression of a membrane protein. METHODOLOGY/PRINCIPAL FINDINGS: The expression of 20 membrane proteins, both peripheral and integral, in three prokaryotic (E. coli, L. lactis, R. sphaeroides) and three eukaryotic (A. thaliana, N. benthamiana, Sf9 insect cells) hosts was tested. The proteins tested were of various origins (bacteria, plants and mammals), functions (transporters, receptors, enzymes) and topologies (between 0 and 13 transmembrane segments). The Gateway system was used to clone all 20 genes into appropriate vectors for the hosts to be tested. Culture conditions were optimised for each host, and specific strategies were tested, such as the use of Mistic fusions in E. coli. 17 of the 20 proteins were produced at adequate yields for functional and, in some cases, structural studies. We have formulated general recommendations to assist with choosing an appropriate system based on our observations of protein behaviour in the different hosts. CONCLUSIONS/SIGNIFICANCE: Most of the methods presented here can be quite easily implemented in other laboratories. The results highlight certain factors that should be considered when selecting an expression host. The decision aide provided should help both newcomers and old-hands to select the best system for their favourite membrane protein. PMID- 22216207 TI - Parent-offspring correlations in pedometer-assessed physical activity. AB - BACKGROUND: Physical activity is a major component of a healthy lifestyle in youth and adults. To identify determinants of this complex behavior is an important research objective in the process of designing interventions to promote physical activity at population level. In addition to individual determinants, there is evidence documenting familial influences on physical activity. However, the few studies that have addressed this issue with objective measures did not provide data on parent-offspring physical activity relationships throughout childhood and adolescence. The purpose of this study was to assess familial correlations in pedometer-assessed physical activity. METHODS: We measured ambulatory activity in 286 French nuclear families (283 mothers, 237 fathers, and 631 children aged 8-18 years) by pedometer recordings (Yamax Digiwalker DW 450) over a week. Correlations were computed with their 95% confidence intervals (CI) for spouse pairs, siblings, mother-offspring, and father-offspring. Data were expressed as steps per day and computed both for the full recording period and separately for weekdays and weekends. RESULTS: The correlations were the highest between siblings (r=0.28, 95%CI: 0.17-0.38). Parent-offspring correlations were significant in mothers (r=0.21, 95%CI: 0.12-0.30), especially between mothers and daughters (r=0.24, 95%CI: 0.12-0.36 vs. r=0.18, 95%CI: 0.05-0.31 for sons), but were almost nonexistent in fathers. Correlations were generally higher on weekend days compared to weekdays. Mother-offspring correlations did not decrease with increasing age of children (r=0.17, 95%CI: 0.00-0.34 in 8-11-year-olds, r=0.20, 95%CI: 0.07-0.33 in 12-15-year-olds, and r=0.25, 95%CI: 0.07-0.39 in >=16-year olds). Finally, between-spouse correlations were significant only during weekend days (r=0.14, 95%CI: 0.01-0.27). CONCLUSION: Ambulatory activity correlated within families, with a possible mother effect. Mother-offspring correlations remained significant through the transition from childhood to adolescence. Further studies are required to better understand the respective influences of shared activities, parental modeling and support as well as genetic factors on the familial aggregation of physical activity. PMID- 22216208 TI - An immunoassay for dibutyl phthalate based on direct hapten linkage to the polystyrene surface of microtiter plates. AB - BACKGROUND: Dibutyl phthalate (DBP) is predominantly used as a plasticizer inplastics to make them flexible. Extensive use of phthalates in both industrial processes and other consumer products has resulted in the ubiquitous presence of phthalates in the environment. In order to better determine the level of pollution in the environment and evaluate the potential adverse effects of exposure to DBP, immunoassay for DBP was developed. METHODOLOGY/PRINCIPAL FINDINGS: A monoclonal antibody specific to DBP was produced from a stable hybridoma cell line generated by lymphocyte hybridoma technique. An indirect competitive enzyme-linked immunosorbent assay (icELISA) employing direct coating of hapten on polystyrene microtiter plates was established for the detection of DBP. Polystyrene surface was first oxidized by permanganate in dilute sulfuric acid to generate carboxyl groups. Then dibutyl 4-aminophthalate, which is an analogue of DBP, was covalently linked to the carboxyl groups of polystyrene surface with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC). Compared with conjugate coated format (IC(50)=106 ng/mL), the direct hapten coated format (IC(50)=14.6 ng/mL) improved assay sensitivity after careful optimization of assay conditions. The average recovery of DBP from spiked water sample was 104.4% and the average coefficient of variation was 9.95%. Good agreement of the results obtained by the hapten coated icELISA and gas chromatography-mass spectrometry further confirmed the reliability and accuracy of the icELISA for the detection of DBP in certain plastic and cosmetic samples. CONCLUSIONS/SIGNIFICANCE: The stable and efficient hybridoma cell line obtained is an unlimited source of sensitive and specific antibody to DBP. The hapten coated format is proposed as generally applicable because the carboxyl groups on modified microtiter plate surface enables stable immobilization of aminated or hydroxylated hapten with EDC. The developed hapten coated icELISA can be used as a convenient quantitative tool for the sensitive and accurate monitoring DBP in water, plastic and cosmetic samples. PMID- 22216209 TI - Sexual transmission of a plant pathogenic bacterium, Candidatus Liberibacter asiaticus, between conspecific insect vectors during mating. AB - Candidatus Liberibacter asiaticus is a fastidious, phloem-inhabiting, gram negative bacterium transmitted by Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Psyllidae). The bacterium is the presumed causal agent of huanglongbing (HLB), one of the most destructive and economically important diseases of citrus. We investigated whether Las is transmitted between infected and uninfected D. citri adults during courtship. Our results indicate that Las was sexually transmitted from Las-infected male D. citri to uninfected females at a low rate (<4%) during mating. Sexual transmission was not observed following mating of infected females and uninfected males or among adult pairs of the same sex. Las was detected in genitalia of both sexes and also in eggs of infected females. A latent period of 7 days or more was required to detect the bacterium in recipient females. Rod shaped as well as spherical structures resembling Las were observed in ovaries of Las-infected females with transmission electron microscopy, but were absent in ovaries from uninfected D. citri females. The size of the rod shaped structures varied from 0.39 to 0.67 um in length and 0.19 to 0.39 um in width. The spherical structures measured from 0.61 to 0.80 um in diameter. This investigation provides convincing evidence that a plant pathogenic bacterium is sexually transmitted from male to female insects during courtship and established evidence that bacteria persist in reproductive organs. Moreover, these findings provide an alternative sexually horizontal mechanism for the spread of Las within populations of D. citri, even in the absence of infected host trees. PMID- 22216210 TI - Bifunctional anti-huntingtin proteasome-directed intrabodies mediate efficient degradation of mutant huntingtin exon 1 protein fragments. AB - Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by a trinucleotide (CAG)(n) repeat expansion in the coding sequence of the huntingtin gene, and an expanded polyglutamine (>37Q) tract in the protein. This results in misfolding and accumulation of huntingtin protein (htt), formation of neuronal intranuclear and cytoplasmic inclusions, and neuronal dysfunction/degeneration. Single-chain Fv antibodies (scFvs), expressed as intrabodies that bind htt and prevent aggregation, show promise as immunotherapeutics for HD. Intrastriatal delivery of anti-N-terminal htt scFv-C4 using an adeno-associated virus vector (AAV2/1) significantly reduces the size and number of aggregates in HDR6/1 transgenic mice; however, this protective effect diminishes with age and time after injection. We therefore explored enhancing intrabody efficacy via fusions to heterologous functional domains. Proteins containing a PEST motif are often targeted for proteasomal degradation and generally have a short half life. In ST14A cells, fusion of the C-terminal PEST region of mouse ornithine decarboxylase (mODC) to scFv-C4 reduces htt exon 1 protein fragments with 72 glutamine repeats (httex1-72Q) by ~80-90% when compared to scFv-C4 alone. Proteasomal targeting was verified by either scrambling the mODC-PEST motif, or via proteasomal inhibition with epoxomicin. For these constructs, the proteasomal degradation of the scFv intrabody proteins themselves was reduced<25% by the addition of the mODC-PEST motif, with or without antigens. The remaining intrabody levels were amply sufficient to target N-terminal httex1 72Q protein fragment turnover. Critically, scFv-C4-PEST prevents aggregation and toxicity of httex1-72Q fragments at significantly lower doses than scFv-C4. Fusion of the mODC-PEST motif to intrabodies is a valuable general approach to specifically target toxic antigens to the proteasome for degradation. PMID- 22216211 TI - Enrichment of variations in KIR3DL1/S1 and KIR2DL2/L3 among H1N1/09 ICU patients: an exploratory study. AB - BACKGROUND: Infection by the pandemic influenza A (H1N1/09) virus resulted in significant pathology among specific ethnic groups worldwide. Natural Killer (NK) cells are important in early innate immune responses to viral infections. Activation of NK cells, in part, depend on killer-cell immunoglobulin-like receptors (KIR) and HLA class I ligand interactions. To study factors involved in NK cell dysfunction in overactive immune responses to H1N1 infection, KIR3DL1/S1 and KIR2DL2/L3 allotypes and cognate HLA ligands of H1N1/09 intensive-care unit (ICU) patients were determined. METHODOLOGY AND FINDINGS: KIR3DL1/S1, KIR2DL2/L3, and HLA -B and -C of 51 H1N1/09 ICU patients and 105 H1N1-negative subjects (St. Theresa Point, Manitoba) were characterized. We detected an increase of 3DL1 ligand-negative pairs (3DL1/S1(+) Bw6(+) Bw4(-)), and a lack of 2DL1 HLA-C2 ligands, among ICU patients. They were also significantly enriched for 2DL2/L3 ligand-positive pairs (P<0.001, Pc<0.001; Odds Ratio:6.3158, CI95%:2.481-16.078). Relative to St. Theresa aboriginals (STh) and Venezuelan Amerindians (VA), allotypes enriched among aboriginal ICU patients (Ab) were: 2DL3 (Ab>VA, P=0.024, Pc=0.047; Odds Ratio:2.563, CI95%:1.109-5.923), 3DL1*00101 (Ab>VA, P<0.001, Pc<0.001), 3DL1*01502 (Ab>STh, P=0.034, Pc=0.268), and 3DL1*029 (Ab>STh, P=0.039, Pc=0.301). Aboriginal patients ligand-positive for 3DL1/S1 and 2DL1 had the lowest probabilities of death (R(d)) (R(d)=28%), compared to patients that were 3DL1/S1 ligand-negative (R(d)=52%) or carried 3DL1*029 (R(d)=52%). Relative to Caucasoids (CA), two allotypes were enriched among non-aboriginal ICU patients (NAb): 3DL1*00401 (NAb>CA, P<0.001, Pc<0.001) and 3DL1*01502 (CA3 um) found in the choroid were quantified. The number of lipofuscin granules significantly increased in ZD-LE as compared to control rats. Infiltrated cells bigger than 3 um were only detected in the choroid of ZD-LE animals. Moreover, the thickness of the Bruch's membrane of ZD-LE rats varied between 0.4-3 um and thin, rangy ED1 positive macrophages were found attached at these sites of Bruch's membrane or even inside it. CONCLUSIONS/SIGNIFICANCE: In pigmented rats, zinc deficiency yielded an accumulation of lipofuscin in the RPE and of large pigmented macrophages in the choroids as well as the appearance of thin, rangy macrophages at Bruch's membrane. Moreover, we showed that a zinc diet reduced the zinc mole fraction of melanosomes in the RPE and modulated the thickness of the Bruch's membrane. PMID- 22216223 TI - Sexual selection halts the relaxation of protamine 2 among rodents. AB - Sexual selection has been proposed as the driving force promoting the rapid evolutionary changes observed in some reproductive genes including protamines. We test this hypothesis in a group of rodents which show marked differences in the intensity of sexual selection. Levels of sperm competition were not associated with the evolutionary rates of protamine 1 but, contrary to expectations, were negatively related to the evolutionary rate of cleaved- and mature-protamine 2. Since both domains were found to be under relaxation, our findings reveal an unforeseen role of sexual selection: to halt the degree of degeneration that proteins within families may experience due to functional redundancy. The degree of relaxation of protamine 2 in this group of rodents is such that in some species it has become dysfunctional and it is not expressed in mature spermatozoa. In contrast, protamine 1 is functionally conserved but shows directed positive selection on specific sites which are functionally relevant such as DNA-anchoring domains and phosphorylation sites. We conclude that in rodents protamine 2 is under relaxation and that sexual selection removes deleterious mutations among species with high levels of sperm competition to maintain the protein functional and the spermatozoa competitive. PMID- 22216225 TI - Divergence in sex steroid hormone signaling between sympatric species of Japanese threespine stickleback. AB - Sex steroids mediate the expression of sexually dimorphic or sex-specific traits that are important both for mate choice within species and for behavioral isolation between species. We investigated divergence in sex steroid signaling between two sympatric species of threespine stickleback (Gasterosteus aculeatus): the Japan Sea form and the Pacific Ocean form. These sympatric forms diverge in both male display traits and female mate choice behaviors, which together contribute to asymmetric behavioral isolation in sympatry. Here, we found that plasma levels of testosterone and 17beta-estradiol differed between spawning females of the two sympatric forms. Transcript levels of follicle-stimulating hormone-beta (FSHbeta) gene were also higher in the pituitary gland of spawning Japan Sea females than in the pituitary gland of spawning Pacific Ocean females. By contrast, none of the sex steroids examined were significantly different between nesting males of the two forms. However, combining the plasma sex steroid data with testis transcriptome data suggested that the efficiency of the conversion of testosterone into 11-ketotestosterone has likely diverged between forms. Within forms, plasma testosterone levels in males were significantly correlated with male body size, a trait important for female mate choice in the two sympatric species. These results demonstrate that substantial divergence in sex steroid signaling can occur between incipient sympatric species. We suggest that investigation of the genetic and ecological mechanisms underlying divergence in hormonal signaling between incipient sympatric species will provide a better understanding of the mechanisms of speciation in animals. PMID- 22216227 TI - A human development framework for CO2 reductions. AB - Although developing countries are called to participate in CO(2) emission reduction efforts to avoid dangerous climate change, the implications of proposed reduction schemes in human development standards of developing countries remain a matter of debate. We show the existence of a positive and time-dependent correlation between the Human Development Index (HDI) and per capita CO(2) emissions from fossil fuel combustion. Employing this empirical relation, extrapolating the HDI, and using three population scenarios, the cumulative CO(2) emissions necessary for developing countries to achieve particular HDI thresholds are assessed following a Development As Usual approach (DAU). If current demographic and development trends are maintained, we estimate that by 2050 around 85% of the world's population will live in countries with high HDI (above 0.8). In particular, 300 Gt of cumulative CO(2) emissions between 2000 and 2050 are estimated to be necessary for the development of 104 developing countries in the year 2000. This value represents between 20 % to 30 % of previously calculated CO(2) budgets limiting global warming to 2 degrees C. These constraints and results are incorporated into a CO(2) reduction framework involving four domains of climate action for individual countries. The framework reserves a fair emission path for developing countries to proceed with their development by indexing country-dependent reduction rates proportional to the HDI in order to preserve the 2 degrees C target after a particular development threshold is reached. For example, in each time step of five years, countries with an HDI of 0.85 would need to reduce their per capita emissions by approx. 17% and countries with an HDI of 0.9 by 33 %. Under this approach, global cumulative emissions by 2050 are estimated to range from 850 up to 1100 Gt of CO(2). These values are within the uncertainty range of emissions to limit global temperatures to 2 degrees C. PMID- 22216226 TI - Identification and functional characterization of novel phosphorylation sites in TAK1-binding protein (TAB) 1. AB - TAB1 was defined as a regulatory subunit of the protein kinase TAK1, which functions upstream in the pathways activated by interleukin (IL)-1, tumor necrosis factor (TNF), toll-like receptors (TLRs) and stressors. However, TAB1 also functions in the p38 MAPK pathway downstream of TAK1. We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro. Serines 452/453 and 456/457 were phosphorylated upon phosphatase blockade by calyculin A, or in response to IL-1 or translational stressors such as anisomycin and sorbitol. Deletion or phospho-mimetic mutations of aa 452-457 of TAB1 retain TAB1 and p38 MAPK in the cytoplasm. The TAB1 mutant lacking aa 452-457 decreases TAB1 dependent phosphorylation of p38 MAPK. It also enhances TAB1-dependent CCL5 secretion in response to IL-1 and increases activity of a post-transcriptional reporter gene, which contains the CCL5 3' untranslated region. These data suggest a complex role of aa 452-457 of TAB1 in controlling p38 MAPK activity and subcellular localization and implicate these residues in TAK1- or p38 MAPK dependent post-transcriptional control of gene expression. PMID- 22216224 TI - Influenza vaccination for immunocompromised patients: systematic review and meta analysis from a public health policy perspective. AB - BACKGROUND: Immunocompromised patients are vulnerable to severe or complicated influenza infection. Vaccination is widely recommended for this group. This systematic review and meta-analysis assesses influenza vaccination for immunocompromised patients in terms of preventing influenza-like illness and laboratory confirmed influenza, serological response and adverse events. METHODOLOGY/PRINCIPAL FINDINGS: Electronic databases and grey literature were searched and records were screened against eligibility criteria. Data extraction and risk of bias assessments were performed in duplicate. Results were synthesised narratively and meta-analyses were conducted where feasible. Heterogeneity was assessed using I(2) and publication bias was assessed using Begg's funnel plot and Egger's regression test. Many of the 209 eligible studies included an unclear or high risk of bias. Meta-analyses showed a significant effect of preventing influenza-like illness (odds ratio [OR]=0.23; 95% confidence interval [CI]=0.16-0.34; p<0.001) and laboratory confirmed influenza infection (OR=0.15; 95% CI=0.03-0.63; p=0.01) through vaccinating immunocompromised patie nts compared to placebo or unvaccinated controls. We found no difference in the odds of influenza-like illness compared to vaccinated immunocompetent controls. The pooled odds of seroconversion were lower in vaccinated patients compared to immunocompetent controls for seasonal influenza A(H1N1), A(H3N2) and B. A similar trend was identified for seroprotection. Meta-analyses of seroconversion showed higher odds in vaccinated patients compared to placebo or unvaccinated controls, although this reached significance for influenza B only. Publication bias was not detected and narrative synthesis supported our findings. No consistent evidence of safety concerns was identified. CONCLUSIONS/SIGNIFICANCE: Infection prevention and control strategies should recommend vaccinating immunocompromised patients. Potential for bias and confounding and the presence of heterogeneity mean the evidence reviewed is generally weak, although the directions of effects are consistent. Areas for further research are identified. PMID- 22216228 TI - Low pitched voices are perceived as masculine and attractive but do they predict semen quality in men? AB - Women find masculinity in men's faces, bodies, and voices attractive, and women's preferences for men's masculine features are thought to be biological adaptations for finding a high quality mate. Fertility is an important aspect of mate quality. Here we test the phenotype-linked fertility hypothesis, which proposes that male secondary sexual characters are positively related to semen quality, allowing females to obtain direct benefits from mate choice. Specifically, we examined women's preferences for men's voice pitch, and its relationship with men's semen quality. Consistent with previous voice research, women judged lower pitched voices as more masculine and more attractive. However men with lower pitched voices did not have better semen quality. On the contrary, men whose voices were rated as more attractive tended to have lower concentrations of sperm in their ejaculate. These data are more consistent with a trade off between sperm production and male investment in competing for and attracting females, than with the phenotype-linked fertility hypothesis. PMID- 22216229 TI - An empirical comparison of information-theoretic criteria in estimating the number of independent components of fMRI data. AB - BACKGROUND: Independent Component Analysis (ICA) has been widely applied to the analysis of fMRI data. Accurate estimation of the number of independent components of fMRI data is critical to reduce over/under fitting. Although various methods based on Information Theoretic Criteria (ITC) have been used to estimate the intrinsic dimension of fMRI data, the relative performance of different ITC in the context of the ICA model hasn't been fully investigated, especially considering the properties of fMRI data. The present study explores and evaluates the performance of various ITC for the fMRI data with varied white noise levels, colored noise levels, temporal data sizes and spatial smoothness degrees. METHODOLOGY: Both simulated data and real fMRI data with varied Gaussian white noise levels, first-order auto-regressive (AR(1)) noise levels, temporal data sizes and spatial smoothness degrees were carried out to deeply explore and evaluate the performance of different traditional ITC. PRINCIPAL FINDINGS: Results indicate that the performance of ITCs depends on the noise level, temporal data size and spatial smoothness of fMRI data. 1) High white noise levels may lead to underestimation of all criteria and MDL/BIC has the severest underestimation at the higher Gaussian white noise level. 2) Colored noise may result in overestimation that can be intensified by the increase of AR(1) coefficient rather than the SD of AR(1) noise and MDL/BIC shows the least overestimation. 3) Larger temporal data size will be better for estimation for the model of white noise but tends to cause severer overestimation for the model of AR(1) noise. 4) Spatial smoothing will result in overestimation in both noise models. CONCLUSIONS: 1) None of ITC is perfect for all fMRI data due to its complicated noise structure. 2) If there is only white noise in data, AIC is preferred when the noise level is high and otherwise, Laplace approximation is a better choice. 3) When colored noise exists in data, MDL/BIC outperforms the other criteria. PMID- 22216230 TI - Sucrose monoester micelles size determined by Fluorescence Correlation Spectroscopy (FCS). AB - One of the several uses of sucrose detergents, as well as other micelle forming detergents, is the solubilization of different membrane proteins. Accurate knowledge of the micelle properties, including size and shape, are needed to optimize the surfactant conditions for protein purification and membrane characterization. We synthesized sucrose esters having different numbers of methylene subunits on the substituent to correlate the number of methylene groups with the size of the corresponding micelles. We used Fluorescence Correlation Spectroscopy (FCS) and two photon excitation to determine the translational D of the micelles and calculate their corresponding hydrodynamic radius, R(h). As a fluorescent probe we used LAURDAN (6-dodecanoyl-2-dimethylaminonaphthalene), a dye highly fluorescent when integrated in the micelle and non-fluorescent in aqueous media. We found a linear correlation between the size of the tail and the hydrodynamic radius of the micelle for the series of detergents measured. PMID- 22216231 TI - Catechol-O-methyltransferase Val158Met polymorphism associates with individual differences in sleep physiologic responses to chronic sleep loss. AB - BACKGROUND: The COMT Val158Met polymorphism modulates cortical dopaminergic catabolism, and predicts individual differences in prefrontal executive functioning in healthy adults and schizophrenic patients, and associates with EEG differences during sleep loss. We assessed whether the COMT Val158Met polymorphism was a novel marker in healthy adults of differential vulnerability to chronic partial sleep deprivation (PSD), a condition distinct from total sleep loss and one experienced by millions on a daily and persistent basis. METHODOLOGY/PRINCIPAL FINDINGS: 20 Met/Met, 64 Val/Met, and 45 Val/Val subjects participated in a protocol of two baseline 10h time in bed (TIB) nights followed by five consecutive 4 h TIB nights. Met/Met subjects showed differentially steeper declines in non-REM EEG slow-wave energy (SWE)-the putative homeostatic marker of sleep drive-during PSD, despite comparable baseline SWE declines. Val/Val subjects showed differentially smaller increases in slow-wave sleep and smaller reductions in stage 2 sleep during PSD, and had more stage 1 sleep across nights and a shorter baseline REM sleep latency. The genotypes, however, did not differ in performance across various executive function and cognitive tasks and showed comparable increases in subjective and physiological sleepiness in response to chronic sleep loss. Met/Met genotypic and Met allelic frequencies were higher in whites than African Americans. CONCLUSIONS/SIGNIFICANCE: The COMT Val158Met polymorphism may be a genetic biomarker for predicting individual differences in sleep physiology-but not in cognitive and executive functioning resulting from sleep loss in a healthy, racially-diverse adult population of men and women. Beyond healthy sleepers, our results may also provide insight for predicting sleep loss responses in patients with schizophrenia and other psychiatric disorders, since these groups repeatedly experience chronically curtailed sleep and demonstrate COMT-related treatment responses and risk factors for symptom exacerbation. PMID- 22216232 TI - A network-based approach on elucidating the multi-faceted nature of chronological aging in S. cerevisiae. AB - BACKGROUND: Cellular mechanisms leading to aging and therefore increasing susceptibility to age-related diseases are a central topic of research since aging is the ultimate, yet not understood mechanism of the fate of a cell. Studies with model organisms have been conducted to ellucidate these mechanisms, and chronological aging of yeast has been extensively used as a model for oxidative stress and aging of postmitotic tissues in higher eukaryotes. METHODOLOGY/PRINCIPAL FINDINGS: The chronological aging network of yeast was reconstructed by integrating protein-protein interaction data with gene ontology terms. The reconstructed network was then statistically "tuned" based on the betweenness centrality values of the nodes to compensate for the computer automated method. Both the originally reconstructed and tuned networks were subjected to topological and modular analyses. Finally, an ultimate "heart" network was obtained via pooling the step specific key proteins, which resulted from the decomposition of the linear paths depicting several signaling routes in the tuned network. CONCLUSIONS/SIGNIFICANCE: The reconstructed networks are of scale-free and hierarchical nature, following a power law model with gamma = 1.49. The results of modular and topological analyses verified that the tuning method was successful. The significantly enriched gene ontology terms of the modular analysis confirmed also that the multifactorial nature of chronological aging was captured by the tuned network. The interplay between various signaling pathways such as TOR, Akt/PKB and cAMP/Protein kinase A was summarized in the "heart" network originated from linear path analysis. The deletion of four genes, TCB3, SNA3, PST2 and YGR130C, was found to increase the chronological life span of yeast. The reconstructed networks can also give insight about the effect of other cellular machineries on chronological aging by targeting different signaling pathways in the linear path analysis, along with unraveling of novel proteins playing part in these pathways. PMID- 22216233 TI - Dissociable effects of valence and arousal in adaptive executive control. AB - BACKGROUND: Based on introspectionist, semantic, and psychophysiological experimental frameworks, it has long been assumed that all affective states derive from two independent basic dimensions, valence and arousal. However, until now, no study has investigated whether valence and arousal are also dissociable at the level of affect-related changes in cognitive processing. METHODOLOGY/PRINCIPAL FINDINGS: We examined how changes in both valence (negative vs. positive) and arousal (low vs. high) influence performance in tasks requiring executive control because recent research indicates that two dissociable cognitive components are involved in the regulation of task performance: amount of current control (i.e., strength of filtering goal-irrelevant signals) and control adaptation (i.e., strength of maintaining current goals over time). Using a visual pop-out distractor task, we found that control is exclusively modulated by arousal because interference by goal-irrelevant signals was largest in high arousal states, independently of valence. By contrast, control adaptation is exclusively modulated by valence because the increase in control after trials in which goal-irrelevant signals were present was largest in negative states, independent of arousal. A Monte Carlo simulation revealed that differential effects of two experimental factors on control and control adaptation can be dissociated if there is no correlation between empirical interference and conflict-driven modulation of interference, which was the case in the present data. Consequently, the observed effects of valence and arousal on adaptive executive control are indeed dissociable. CONCLUSIONS/SIGNIFICANCE: These findings indicate that affective influences on cognitive processes can be driven by independent effects of variations in valence and arousal, which may resolve several heterogeneous findings observed in previous studies on affect-cognition interactions. PMID- 22216234 TI - Aberrant hippocampal subregion networks associated with the classifications of aMCI subjects: a longitudinal resting-state study. AB - BACKGROUND: Altered hippocampal structure and function is a valuable indicator of possible conversion from amnestic type mild cognitive impairment (aMCI) to Alzheimer's disease (AD). However, little is known about the disrupted functional connectivity of hippocampus subregional networks in aMCI subjects. METHODOLOGY/PRINCIPAL FINDINGS: aMCI group-1 (n=26) and controls group-1 (n=18) underwent baseline and after approximately 20 months follow up resting-state fMRI scans. Integrity of distributed functional connectivity networks incorporating six hippocampal subregions (i.e. cornu ammonis, dentate gyrus and subicular complex, bilaterally) was then explored over time and comparisons made between groups. The ability of these extent longitudinal changes to separate unrelated groups of 30 subjects (aMCI-converters, n=6; aMCI group-2, n=12; controls group 2, n=12) were further assessed. Six longitudinal hippocampus subregional functional connectivity networks showed similar changes in aMCI subjects over time, which were mainly associated with medial frontal gyrus, lateral temporal cortex, insula, posterior cingulate cortex (PCC) and cerebellum. However, the disconnection of hippocampal subregions and PCC may be a key factor of impaired episodic memory in aMCI, and the functional index of these longitudinal changes allowed well classifying independent samples of aMCI converters from non converters (sensitivity was 83.3%, specificity was 83.3%) and controls (sensitivity was 83.3%, specificity was 91.7%). CONCLUSIONS/SIGNIFICANCE: It demonstrated that the functional changes in resting-state hippocampus subregional networks could be an important and early indicator for dysfunction that may be particularly relevant to early stage changes and progression of aMCI subjects. PMID- 22216235 TI - A novel 'gene insertion/marker out' (GIMO) method for transgene expression and gene complementation in rodent malaria parasites. AB - Research on the biology of malaria parasites has greatly benefited from the application of reverse genetic technologies, in particular through the analysis of gene deletion mutants and studies on transgenic parasites that express heterologous or mutated proteins. However, transfection in Plasmodium is limited by the paucity of drug-selectable markers that hampers subsequent genetic modification of the same mutant. We report the development of a novel 'gene insertion/marker out' (GIMO) method for two rodent malaria parasites, which uses negative selection to rapidly generate transgenic mutants ready for subsequent modifications. We have created reference mother lines for both P. berghei ANKA and P. yoelii 17XNL that serve as recipient parasites for GIMO-transfection. Compared to existing protocols GIMO-transfection greatly simplifies and speeds up the generation of mutants expressing heterologous proteins, free of drug resistance genes, and requires far fewer laboratory animals. In addition we demonstrate that GIMO-transfection is also a simple and fast method for genetic complementation of mutants with a gene deletion or mutation. The implementation of GIMO-transfection procedures should greatly enhance Plasmodium reverse-genetic research. PMID- 22216236 TI - Earthworm-mycorrhiza interactions can affect the diversity, structure and functioning of establishing model grassland communities. AB - Both earthworms and arbuscular mycorrhizal fungi (AMF) are important ecosystem engineers co-occurring in temperate grasslands. However, their combined impacts during grassland establishment are poorly understood and have never been studied. We used large mesocosms to study the effects of different functional groups of earthworms (i.e., vertically burrowing anecics vs. horizontally burrowing endogeics) and a mix of four AMF taxa on the establishment, diversity and productivity of plant communities after a simulated seed rain of 18 grassland species comprising grasses, non-leguminous forbs and legumes. Moreover, effects of earthworms and/or AMF on water infiltration and leaching of ammonium, nitrate and phosphate were determined after a simulated extreme rainfall event (40 l m( 2)). AMF colonisation of all three plant functional groups was altered by earthworms. Seedling emergence and diversity was reduced by anecic earthworms, however only when AMF were present. Plant density was decreased in AMF-free mesocosms when both anecic and endogeic earthworms were active; with AMF also anecics reduced plant density. Plant shoot and root biomass was only affected by earthworms in AMF-free mesocosms: shoot biomass increased due to the activity of either anecics or endogeics; root biomass increased only when anecics were active. Water infiltration increased when earthworms were present in the mesocosms but remained unaffected by AMF. Ammonium leaching was increased only when anecics or a mixed earthworm community was active but was unaffected by AMF; nitrate and phosphate leaching was neither affected by earthworms nor AMF. Ammonium leaching decreased with increasing plant density, nitrate leaching decreased with increasing plant diversity and density. In order to understand the underlying processes of these interactions further investigations possibly under field conditions using more diverse belowground communities are required. Nevertheless, this study demonstrates that belowground-aboveground linkages involving earthworms and AMF are important mediators of the diversity, structure and functioning of plant communities. PMID- 22216237 TI - Risk factors for pre-treatment mortality among HIV-infected children in rural Zambia: a cohort study. AB - BACKGROUND: Many HIV-infected children in sub-Saharan Africa enter care at a late stage of disease. As preparation of the child and family for antiretroviral therapy (ART) can take several clinic visits, some children die prior to ART initiation. This study was undertaken to determine mortality rates and clinical predictors of mortality during the period prior to ART initiation. METHODS: A prospective cohort study of HIV-infected treatment-naive children was conducted between September 2007 and September 2010 at the HIV clinic at Macha Hospital in rural Southern Province, Zambia. HIV-infected children younger than 16 years of age who were treatment-naive at study enrollment were eligible for analysis. Mortality rates prior to ART initiation were calculated and risk factors for mortality were evaluated. RESULTS: 351 children were included in the study, of whom 210 (59.8%) were eligible for ART at study enrollment. Among children ineligible for ART at enrollment, 6 children died (mortality rate: 0.33; 95% CI:0.15, 0.74). Among children eligible at enrollment, 21 children died before initiation of ART and their mortality rate (2.73 per 100 person-years; 95% CI:1.78, 4.18) was significantly higher than among children ineligible for ART (incidence rate ratio: 8.20; 95% CI:3.20, 24.83). In both groups, mortality was highest in the first three months of follow-up. Factors associated with mortality included younger age, anemia and lower weight-for-age z-score at study enrollment. CONCLUSIONS: These results underscore the need to increase efforts to identify HIV-infected children at an earlier age and stage of disease progression so they can enroll in HIV care and treatment programs prior to becoming eligible for ART and these deaths can be prevented. PMID- 22216238 TI - Multi-scale stochastic simulation of diffusion-coupled agents and its application to cell culture simulation. AB - Many biological systems consist of multiple cells that interact by secretion and binding of diffusing molecules, thus coordinating responses across cells. Techniques for simulating systems coupling extracellular and intracellular processes are very limited. Here we present an efficient method to stochastically simulate diffusion processes, which at the same time allows synchronization between internal and external cellular conditions through a modification of Gillespie's chemical reaction algorithm. Individual cells are simulated as independent agents, and each cell accurately reacts to changes in its local environment affected by diffusing molecules. Such a simulation provides time scale separation between the intra-cellular and extra-cellular processes. We use our methodology to study how human monocyte-derived dendritic cells alert neighboring cells about viral infection using diffusing interferon molecules. A subpopulation of the infected cells reacts early to the infection and secretes interferon into the extra-cellular medium, which helps activate other cells. Findings predicted by our simulation and confirmed by experimental results suggest that the early activation is largely independent of the fraction of infected cells and is thus both sensitive and robust. The concordance with the experimental results supports the value of our method for overcoming the challenges of accurately simulating multiscale biological signaling systems. PMID- 22216239 TI - Oxygen sensitivity of anammox and coupled N-cycle processes in oxygen minimum zones. AB - Nutrient measurements indicate that 30-50% of the total nitrogen (N) loss in the ocean occurs in oxygen minimum zones (OMZs). This pelagic N-removal takes place within only ~0.1% of the ocean volume, hence moderate variations in the extent of OMZs due to global warming may have a large impact on the global N-cycle. We examined the effect of oxygen (O(2)) on anammox, NH(3) oxidation and NO(3)(-) reduction in (15)N-labeling experiments with varying O(2) concentrations (0-25 umol L(-1)) in the Namibian and Peruvian OMZs. Our results show that O(2) is a major controlling factor for anammox activity in OMZ waters. Based on our O(2) assays we estimate the upper limit for anammox to be ~20 umol L(-1). In contrast, NH(3) oxidation to NO(2)(-) and NO(3)(-) reduction to NO(2)(-) as the main NH(4)(+) and NO(2)(-) sources for anammox were only moderately affected by changing O(2) concentrations. Intriguingly, aerobic NH(3) oxidation was active at non-detectable concentrations of O(2), while anaerobic NO(3)(-) reduction was fully active up to at least 25 umol L(-1) O(2). Hence, aerobic and anaerobic N cycle pathways in OMZs can co-occur over a larger range of O(2) concentrations than previously assumed. The zone where N-loss can occur is primarily controlled by the O(2)-sensitivity of anammox itself, and not by any effects of O(2) on the tightly coupled pathways of aerobic NH(3) oxidation and NO(3)(-) reduction. With anammox bacteria in the marine environment being active at O(2) levels ~20 times higher than those known to inhibit their cultured counterparts, the oceanic volume potentially acting as a N-sink increases tenfold. The predicted expansion of OMZs may enlarge this volume even further. Our study provides the first robust estimates of O(2) sensitivities for processes directly and indirectly connected with N-loss. These are essential to assess the effects of ocean de-oxygenation on oceanic N-cycling. PMID- 22216240 TI - Expression of Trichoderma reesei beta-mannanase in tobacco chloroplasts and its utilization in lignocellulosic woody biomass hydrolysis. AB - Lignocellulosic ethanol offers a promising alternative to conventional fossil fuels. One among the major limitations in the lignocellulosic biomass hydrolysis is unavailability of efficient and environmentally biomass degrading technologies. Plant-based production of these enzymes on large scale offers a cost-effective solution. Cellulases, hemicellulases including mannanases and other accessory enzymes are required for conversion of lignocellulosic biomass into fermentable sugars. beta-mannanase catalyzes endo-hydrolysis of the mannan backbone, a major constituent of woody biomass. In this study, the man1 gene encoding beta-mannanase was isolated from Trichoderma reesei and expressed via the chloroplast genome. PCR and Southern hybridization analysis confirmed site specific transgene integration into the tobacco chloroplast genomes and homoplasmy. Transplastomic plants were fertile and set viable seeds. Germination of seeds in the selection medium showed inheritance of transgenes into the progeny without any Mendelian segregation. Expression of endo-beta-mannanase for the first time in plants facilitated its characterization for use in enhanced lignocellulosic biomass hydrolysis. Gel diffusion assay for endo-beta-mannanase showed the zone of clearance confirming functionality of chloroplast-derived mannanase. Endo-beta-mannanase expression levels reached up to 25 units per gram of leaf (fresh weight). Chloroplast-derived mannanase had higher temperature stability (40 degrees C to 70 degrees C) and wider pH optima (pH 3.0 to 7.0) than E.coli enzyme extracts. Plant crude extracts showed 6-7 fold higher enzyme activity than E.coli extracts due to the formation of disulfide bonds in chloroplasts, thereby facilitating their direct utilization in enzyme cocktails without any purification. Chloroplast-derived mannanase when added to the enzyme cocktail containing a combination of different plant-derived enzymes yielded 20% more glucose equivalents from pinewood than the cocktail without mannanase. Our results demonstrate that chloroplast-derived mannanase is an important component of enzymatic cocktail for woody biomass hydrolysis and should provide a cost effective solution for its diverse applications in the biofuel, paper, oil, pharmaceutical, coffee and detergent industries. PMID- 22216241 TI - hElp3 directly modulates the expression of HSP70 gene in HeLa cells via HAT activity. AB - Human Elongator complex, which plays a key role in transcript elongation in vitro assay, is incredibly similar in either components or function to its yeast counterpart. However, there are only a few studies focusing on its target gene characterization in vivo. We studied the effect of down-regulation of the human elongation protein 3 (hELP3) on the expression of HSP70 through antisense strategy. Transfecting antisense plasmid p1107 into HeLa cells highly suppressed hELP3 expression, and substantially reduced expression of HSP70 mRNA and protein. Furthermore, chromatin immunoprecipitation assay (ChIP Assay) revealed that hElp3 participates in the transcription elongation of HSPA1A in HeLa cells. Finally, complementation and ChIP Assay in yeast showed that hElp3 can not only complement the growth and slow activation of HSP70 (SSA3) gene transcription, but also directly regulates the transcription of SSA3. On the contrary, these functions are lost when the HAT domain is deleted from hElp3. These data suggest that hElp3 can regulate the transcription of HSP70 gene, and the HAT domain of hElp3 is essential for this function. These findings now provide novel insights and evidence of the functions of hELP3 in human cells. PMID- 22216242 TI - Soluble CD44 interacts with intermediate filament protein vimentin on endothelial cell surface. AB - CD44 is a cell surface glycoprotein that functions as hyaluronan receptor. Mouse and human serum contain substantial amounts of soluble CD44, generated either by shedding or alternative splicing. During inflammation and in cancer patients serum levels of soluble CD44 are significantly increased. Experimentally, soluble CD44 overexpression blocks cancer cell adhesion to HA. We have previously found that recombinant CD44 hyaluronan binding domain (CD44HABD) and its non-HA-binding mutant inhibited tumor xenograft growth, angiogenesis, and endothelial cell proliferation. These data suggested an additional target other than HA for CD44HABD. By using non-HA-binding CD44HABD Arg41Ala, Arg78Ser, and Tyr79Ser triple mutant (CD443MUT) we have identified intermediate filament protein vimentin as a novel interaction partner of CD44. We found that vimentin is expressed on the cell surface of human umbilical vein endothelial cells (HUVEC). Endogenous CD44 and vimentin coprecipitate from HUVECs, and when overexpressed in vimentin-negative MCF-7 cells. By using deletion mutants, we found that CD44HABD and CD443MUT bind vimentin N-terminal head domain. CD443MUT binds vimentin in solution with a Kd in range of 12-37 nM, and immobilised vimentin with Kd of 74 nM. CD443MUT binds to HUVEC and recombinant vimentin displaces CD443MUT from its binding sites. CD44HABD and CD443MUT were internalized by wild-type endothelial cells, but not by lung endothelial cells isolated from vimentin knock-out mice. Together, these data suggest that vimentin provides a specific binding site for soluble CD44 on endothelial cells. PMID- 22216243 TI - Y-Chromosome variation in hominids: intraspecific variation is limited to the polygamous chimpanzee. AB - BACKGROUND: We have previously demonstrated that the Y-specific ampliconic fertility genes DAZ (deleted in azoospermia) and CDY (chromodomain protein Y) varied with respect to copy number and position among chimpanzees (Pan troglodytes). In comparison, seven Y-chromosomal lineages of the bonobo (Pan paniscus), the chimpanzee's closest living relative, showed no variation. We extend our earlier comparative investigation to include an analysis of the intraspecific variation of these genes in gorillas (Gorilla gorilla) and orangutans (Pongo pygmaeus), and examine the resulting patterns in the light of the species' markedly different social and mating behaviors. METHODOLOGY/PRINCIPAL FINDINGS: Fluorescence in situ hybridization analysis (FISH) of DAZ and CDY in 12 Y-chromosomal lineages of western lowland gorilla (G. gorilla gorilla) and a single lineage of the eastern lowland gorilla (G. beringei graueri) showed no variation among lineages. Similar findings were noted for the 10 Y-chromosomal lineages examined in the Bornean orangutan (Pongo pygmaeus), and 11 Y-chromosomal lineages of the Sumatran orangutan (P. abelii). We validated the contrasting DAZ and CDY patterns using quantitative real-time polymerase chain reaction (qPCR) in chimpanzee and bonobo. CONCLUSION/SIGNIFICANCE: High intraspecific variation in copy number and position of the DAZ and CDY genes is seen only in the chimpanzee. We hypothesize that this is best explained by sperm competition that results in the variant DAZ and CDY haplotypes detected in this species. In contrast, bonobos, gorillas and orangutans-species that are not subject to sperm competition-showed no intraspecific variation in DAZ and CDY suggesting that monoandry in gorillas, and preferential female mate choice in bonobos and orangutans, probably permitted the fixation of a single Y variant in each taxon. These data support the notion that the evolutionary history of a primate Y chromosome is not simply encrypted in its DNA sequences, but is also shaped by the social and behavioral circumstances under which the specific species has evolved. PMID- 22216244 TI - High antipredatory efficiency of insular lizards: a warning signal of excessive specimen collection? AB - We live-captured lizards on islands in the Gulf of California and the Baja California peninsula mainland, and compared their ability to escape predation. Contrary to expectations, endemic lizard species from uninhabited islands fled from humans earlier and more efficiently than those from peninsular mainland areas. In fact, 58.2% (n=146) of the lizards we tried to capture on the various islands escaped successfully, while this percentage was only 14.4% (n=160) on the peninsular mainland. Separate evidence (e.g., proportion of regenerated tails, low human population at the collection areas, etc.) challenges several potential explanations for the higher antipredatory efficiency of insular lizards (e.g., more predation pressure on islands, habituation to humans on the peninsula, etc.). Instead, we suggest that the ability of insular lizards to avoid predators may be related to harvesting by humans, perhaps due to the value of endemic species as rare taxonomic entities. If this hypothesis is correct, predation related behavioral changes in rare species could provide early warning signals of their over-exploitation, thus encouraging the adoption of conservation measures. PMID- 22216245 TI - The promigratory activity of the matricellular protein galectin-3 depends on the activation of PI-3 kinase. AB - Expression of galectin-3 is associated with sarcoma progression, invasion and metastasis. Here we determined the role of extracellular galectin-3 on migration of sarcoma cells on laminin-111. Cell lines from methylcholanthrene-induced sarcomas from both wild type and galectin-3(-/-) mice were established. Despite the presence of similar levels of laminin-binding integrins on the cell surface, galectin-3(-/-) sarcoma cells were more adherent and less migratory than galectin 3(+/+) sarcoma cells on laminin-111. When galectin-3 was transiently expressed in galectin-3(-/-) sarcoma cells, it inhibited cell adhesion and stimulated the migratory response to laminin in a carbohydrate-dependent manner. Extracellular galectin-3 led to the recruitment of SHP-2 phosphatase to focal adhesion plaques, followed by a decrease in the amount of phosphorylated FAK and phospho-paxillin in the lamellipodia of migrating cells. The promigratory activity of extracellular galectin-3 was inhibitable by wortmannin, implicating the activation of a PI-3 kinase dependent pathway in the galectin-3 triggered disruption of adhesion plaques, leading to sarcoma cell migration on laminin-111. PMID- 22216246 TI - Preservation of ranking order in the expression of human Housekeeping genes. AB - Housekeeping (HK) genes fulfill the basic needs for a cell to survive and function properly. Their ubiquitous expression, originally thought to be constant, can vary from tissue to tissue, but this variation remains largely uncharacterized and it could not be explained by previously identified properties of HK genes such as short gene length and high GC content. By analyzing microarray expression data for human genes, we uncovered a previously unnoted characteristic of HK gene expression, namely that the ranking order of their expression levels tends to be preserved from one tissue to another. Further analysis by tensor product decomposition and pathway stratification identified three main factors of the observed ranking preservation, namely that, compared to those of non-HK (NHK) genes, the expression levels of HK genes show a greater degree of dispersion (less overlap), stableness (a smaller variation in expression between tissues), and correlation of expression. Our results shed light on regulatory mechanisms of HK gene expression that are probably different for different HK genes or pathways, but are consistent and coordinated in different tissues. PMID- 22216247 TI - Impaired release of antimicrobial peptides into nasal fluid of hyper-IgE and CVID patients. AB - BACKGROUND: Patients with primary immunodeficiency (PID) often suffer from frequent respiratory tract infections. Despite standard treatment with IgG substitution and antibiotics many patients do not improve significantly. Therefore, we hypothesized that additional immune deficits may be present among these patients. OBJECTIVE: To investigate if PID patients exhibit impaired production of antimicrobial peptides (AMPs) in nasal fluid and a possible link between AMP-expression and Th17-cells. METHODS: Nasal fluid, nasopharyngeal swabs and peripheral blood mononuclear cells (PBMCs) were collected from patients and healthy controls. AMP levels were measured in nasal fluid by Western blotting. Nasal swabs were cultured for bacteria. PBMCs were stimulated with antigen and the supernatants were assessed for IL-17A release by ELISA. RESULTS: In healthy controls and most patients, AMP levels in nasal fluid were increased in response to pathogenic bacteria. However, this increase was absent in patients with common variable immunodeficiency (CVID) and Hyper-IgE syndrome (HIES), despite the presence of pathogenic bacteria. Furthermore, stimulation of PBMCs revealed that both HIES and CVID patients exhibited an impaired production of IL-17A. CONCLUSION: CVID and HIES patients appear to have a dysregulated AMP response to pathogenic bacteria in the upper respiratory tract, which could be linked to an aberrant Th17 cell response. PMID- 22216248 TI - Gaining greater insight into HCV emergence in HIV-infected men who have sex with men: the HEPAIG Study. AB - OBJECTIVES: The HEPAIG study was conducted to better understand Hepatitis C virus (HCV) transmission among human immuno-deficiency (HIV)-infected men who have sex with men (MSM) and assess incidence of HCV infection among this population in France. METHODS AND RESULTS: Acute HCV infection defined by anti-HCV or HCV ribonucleic acid (RNA) positivity within one year of documented anti-HCV negativity was notified among HIV-infected MSM followed up in HIV/AIDS clinics from a nationwide sampling frame. HIV and HCV infection characteristics, HCV potential exposures and sexual behaviour were collected by the physicians and via self-administered questionnaires. Phylogenetic analysis of the HCV-NS5B region was conducted. HCV incidence was 48/10 000 [95% Confidence Interval (CI):43-54] and 36/10 000 [95% CI: 30-42] in 2006 and 2007, respectively. Among the 80 men enrolled (median age: 40 years), 55% were HIV-diagnosed before 2000, 56% had at least one sexually transmitted infection in the year before HCV diagnosis; 55% were HCV-infected with genotype 4 (15 men in one 4d-cluster), 32.5% with genotype 1 (three 1a-clusters); five men were HCV re-infected; in the six-month preceding HCV diagnosis, 92% reported having casual sexual partners sought online (75.5%) and at sex venues (79%), unprotected anal sex (90%) and fisting (65%); using recreational drugs (62%) and bleeding during sex (55%). CONCLUSIONS: This study emphasizes the role of multiple unprotected sexual practices and recreational drugs use during sex in the HCV emergence in HIV-infected MSM. It becomes essential to adapt prevention strategies and inform HIV-infected MSM with recent acute HCV infection on risk of re-infection and on risk-reduction strategies. PMID- 22216249 TI - Differential gene expression from microarray analysis distinguishes woven and lamellar bone formation in the rat ulna following mechanical loading. AB - Formation of woven and lamellar bone in the adult skeleton can be induced through mechanical loading. Although much is known about the morphological appearance and structural properties of the newly formed bone, the molecular responses to loading are still not well understood. The objective of our study was to use a microarray to distinguish the molecular responses between woven and lamellar bone formation induced through mechanical loading. Rat forelimb loading was completed in a single bout to induce the formation of woven bone (WBF loading) or lamellar bone (LBF loading). A set of normal (non-loaded) rats were used as controls. Microarrays were performed at three timepoints after loading: 1 hr, 1 day and 3 days. Confirmation of microarray results was done for a select group of genes using quantitative real-time PCR (qRT-PCR). The micorarray identified numerous genes and pathways that were differentially regulated for woven, but not lamellar bone formation. Few changes in gene expression were evident comparing lamellar bone formation to normal controls. A total of 395 genes were differentially expressed between formation of woven and lamellar bone 1 hr after loading, while 5883 and 5974 genes were differentially expressed on days 1 and 3, respectively. Results suggest that not only are the levels of expression different for each type of bone formation, but that distinct pathways are activated only for woven bone formation. A strong early inflammatory response preceded an increase in angiogenic and osteogenic gene expression for woven bone formation. Furthermore, at later timepoints there was evidence of bone resorption after WBF loading. In summary, the vast coverage of the microarray offers a comprehensive characterization of the early differences in expression between woven and lamellar bone formation. PMID- 22216250 TI - Predictors of health-related quality of life in patients at risk for cardiovascular disease in European primary care. AB - BACKGROUND: Cardiovascular risk management plays an important role in primary care. In patients at high risk for cardiovascular diseases (CVD) lifestyle and, where appropriate, medical interventions are recommended in guidelines. Health related quality of life (HRQoL) is an important outcome in clinical practice. This study aimed to assess the HRQoL of this patient group and to investigate the impact of both patients' characteristics and practice quality scores on their assessments of HRQoL. METHODS AND FINDINGS: An observational study in 218 general practices from 8 European countries was conducted. 2142 patients at risk for CVD (33.5% female) with a mean age of 66.3 (SD 9.1) years completed a questionnaire including the EQ-5D instrument and provided data from medical record. Validated quality indicators of general practices were assessed using practice questionnaires and face-to-face interviews. A hierarchical multilevel analysis was performed to identify predictors of EQ-5D scores at patient and practice level. The mean EQ-5D score was 0.78 (SD 0.19). Female gender (r=-0.03, p<0.0016), age (r=-0.01, p=0.0387) and lower educational level (r=-0.03, p<0.0001) were correlated negatively with EQ-5D scores. Clinically more important was the correlation of HRQoL with the frequency of practice contacts (r=-0.12, p<0.0001) and the number of uncontrolled risk factors (r= -0.01, p<0.0039). Medication adherence (r=0.032, p<0.0001), and physical activity (r=0.02, p<0.0001) were identified as positive predictors of HRQoL. The EUPROPEP-score category 'organization' (r=0.02, p<0.0001) was positively related to EQ-5D scores, whereas other practice scores were not correlated to EQ-5D-scores. CONCLUSIONS: In patients at risk for CVD, good medication adherence, regular physical activity, controlling of biomedical risk factor levels and patient centered practice organization have been shown to be positively correlated to HRQoL and should therefore be targeted in interventions not only to reduce morbidity but also to sustain or even to ameliorate HRQoL. PMID- 22216251 TI - Genome-wide identification of transcriptional start sites in the plant pathogen Pseudomonas syringae pv. tomato str. DC3000. AB - RNA-Seq has provided valuable insights into global gene expression in a wide variety of organisms. Using a modified RNA-Seq approach and Illumina's high throughput sequencing technology, we globally identified 5'-ends of transcripts for the plant pathogen Pseudomonas syringae pv. tomato str. DC3000. A substantial fraction of 5'-ends obtained by this method were consistent with results obtained using global RNA-Seq and 5'RACE. As expected, many 5'-ends were positioned a short distance upstream of annotated genes. We also captured 5'-ends within intergenic regions, providing evidence for the expression of un-annotated genes and non-coding RNAs, and detected numerous examples of antisense transcription, suggesting additional levels of complexity in gene regulation in DC3000. Importantly, targeted searches for sequence patterns in the vicinity of 5'-ends revealed over 1200 putative promoters and other regulatory motifs, establishing a broad foundation for future investigations of regulation at the genomic and single gene levels. PMID- 22216252 TI - Statistical epistasis and functional brain imaging support a role of voltage gated potassium channels in human memory. AB - Despite the current progress in high-throughput, dense genome scans, a major portion of complex traits' heritability still remains unexplained, a phenomenon commonly termed "missing heritability." The negligence of analytical approaches accounting for gene-gene interaction effects, such as statistical epistasis, is probably central to this phenomenon. Here we performed a comprehensive two-way SNP interaction analysis of human episodic memory, which is a heritable complex trait, and focused on 120 genes known to show differential, memory-related expression patterns in rat hippocampus. Functional magnetic resonance imaging was also used to capture genotype-dependent differences in memory-related brain activity. A significant, episodic memory-related interaction between two markers located in potassium channel genes (KCNB2 and KCNH5) was observed (P(nominal combined)=0.000001). The epistatic interaction was robust, as it was significant in a screening (P(nominal)=0.0000012) and in a replication sample (P(nominal)=0.01). Finally, we found genotype-dependent activity differences in the parahippocampal gyrus (P(nominal)=0.001) supporting the behavioral genetics finding. Our results demonstrate the importance of analytical approaches that go beyond single marker statistics of complex traits. PMID- 22216253 TI - Role of palladin phosphorylation by extracellular signal-regulated kinase in cell migration. AB - Phosphorylation of actin-binding proteins plays a pivotal role in the remodeling of the actin cytoskeleton to regulate cell migration. Palladin is an actin binding protein that is phosphorylated by growth factor stimulation; however, the identity of the involved protein kinases remains elusive. In this study, we report that palladin is a novel substrate of extracellular signal-regulated kinase (ERK). Suppression of ERK activation by a chemical inhibitor reduced palladin phosphorylation, and expression of active MEK alone was sufficient for phosphorylation. In addition, an in vitro kinase assay demonstrated direct palladin phosphorylation by ERK. We found that Ser77 and Ser197 are essential residues for phosphorylation. Although the phosphorylation of these residues was not required for actin cytoskeletal organization, we found that expression of non phosphorylated palladin enhanced cell migration. Finally, we show that phosphorylation inhibits the palladin association with Abl tyrosine kinase. Taken together, our results indicate that palladin phosphorylation by ERK has an anti migratory function, possibly by modulating interactions with molecules that regulate cell migration. PMID- 22216254 TI - Apc mutation enhances PyMT-induced mammary tumorigenesis. AB - The Adenomatous Polyposis Coli (APC) tumor suppressor gene is silenced by hypermethylation or mutated in up to 70% of human breast cancers. In mouse models, Apc mutation disrupts normal mammary development and predisposes to mammary tumor formation; however, the cooperation between APC and other mutations in breast tumorigenesis has not been studied. To test the hypothesis that loss of one copy of APC promotes oncogene-mediated mammary tumorigenesis, Apc(Min/+) mice were crossed with the mouse mammary tumor virus (MMTV)-Polyoma virus middle T antigen (PyMT) or MMTV-c-Neu transgenic mice. In the PyMT tumor model, the Apc(Min/+) mutation significantly decreased survival and tumor latency, promoted a squamous adenocarcinoma phenotype, and enhanced tumor cell proliferation. In tumor-derived cell lines, the proliferative advantage was a result of increased FAK, Src and JNK signaling. These effects were specific to the PyMT model, as no changes were observed in MMTV-c-Neu mice carrying the Apc(Min/+) mutation. Our data indicate that heterozygosity of Apc enhances tumor development in an oncogene-specific manner, providing evidence that APC-dependent pathways may be valuable therapeutic targets in breast cancer. Moreover, these preclinical model systems offer a platform for dissection of the molecular mechanisms by which APC mutation enhances breast carcinogenesis, such as altered FAK/Src/JNK signaling. PMID- 22216255 TI - Long-term care facilities: important participants of the acute care facility social network? AB - BACKGROUND: Acute care facilities are connected via patient sharing, forming a network. However, patient sharing extends beyond this immediate network to include sharing with long-term care facilities. The extent of long-term care facility patient sharing on the acute care facility network is unknown. The objective of this study was to characterize and determine the extent and pattern of patient transfers to, from, and between long-term care facilities on the network of acute care facilities in a large metropolitan county. METHODS/PRINCIPAL FINDINGS: We applied social network constructs principles, measures, and frameworks to all 2007 annual adult and pediatric patient transfers among the healthcare facilities in Orange County, California, using data from surveys and several datasets. We evaluated general network and centrality measures as well as individual ego measures and further constructed sociograms. Our results show that over the course of a year, 66 of 72 long-term care facilities directly sent and 67 directly received patients from other long-term care facilities. Long-term care facilities added 1,524 ties between the acute care facilities when ties represented at least one patient transfer. Geodesic distance did not closely correlate with the geographic distance among facilities. CONCLUSIONS/SIGNIFICANCE: This study demonstrates the extent to which long-term care facilities are connected to the acute care facility patient sharing network. Many long-term care facilities were connected by patient transfers and further added many connections to the acute care facility network. This suggests that policy-makers and health officials should account for patient sharing with and among long-term care facilities as well as those among acute care facilities when evaluating policies and interventions. PMID- 22216256 TI - Jaw laterality and related handedness in the hunting behavior of a scale-eating characin, Exodon paradoxus. AB - BACKGROUND: Asymmetry in animal bodies and behavior has evolved several times, but our knowledge of their linkage is limited. Tanganyikan scale-eating cichlids have well-known antisymmetry in their bodies and behavior; individuals open their mouths leftward (righty) or rightward (lefty), and righties always attack the right flank of the prey, whereas lefties attack the left. This study analyzed the morphological asymmetry in a scale-eating characiform, Exodon paradoxus, and its behavioral handedness. METHODOLOGY/PRINCIPAL FINDINGS: Each eight E. paradoxus was observed for 1-h with a prey goldfish in an aquarium to detect the behavioral handedness. Following the experiment, the lateral differences in the mandibles and head-inclination of these eight and ten additional specimens were analyzed. Both measurements on the morphology showed a bimodal distribution, and the laterality identified by these two methods was always consistent within a given individual, indicating that the characin has morphological antisymmetry. Furthermore, this laterality significantly corresponded to behavioral handedness; that is, lefties more often rasped scales from the right flank of the prey and vice versa. However, the correlation between laterality and handedness is the opposite of that in the cichlids. This is due to differences in the feeding apparatus and technique. The characin has cuspids pointing forward on the external side of the premaxilla, and it thrusts its dominant body side outward from its body axis on the flank of the prey to tear off scales. By contrast, the cichlids draw their dominant body side inward toward the axis or rotate it to scrape or wrench off scales with the teeth lined in the opened mouth. CONCLUSIONS/SIGNIFICANCE: This study demonstrated that the antisymmetry in external morphology and the corresponding behavioral handedness have evolved in two lineages of scale-eating fishes independently, and these fishes adopt different utilization of their body asymmetry to tear off scales. PMID- 22216257 TI - Vitamin D3 deficiency differentially affects functional and disease outcomes in the G93A mouse model of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by motor neuron death in the central nervous system. Vitamin D supplementation increases antioxidant activity, reduces inflammation and improves motor neuron survival. We have previously demonstrated that vitamin D(3) supplementation at 10* the adequate intake improves functional outcomes in a mouse model of ALS. OBJECTIVE: To determine whether vitamin D deficiency influences functional and disease outcomes in a mouse model of ALS. METHODS: At age 25 d, 102 G93A mice (56 M, 46 F) were divided into two vitamin D(3) groups: 1) adequate (AI; 1 IU D(3)/g feed) and 2) deficient (DEF; 0.025 IU D(3)/g feed). At age 113 d, tibialis anterior (TA), quadriceps (quads) and brain were harvested from 42 mice (22 M and 20 F), whereas the remaining 60 mice (34 M and 26 F) were followed to endpoint. RESULTS: During disease progression, DEF mice had 25% (P=0.022) lower paw grip endurance AUC and 19% (P=0.017) lower motor performance AUC vs. AI mice. Prior to disease onset (CS 2), DEF mice had 36% (P=0.016) lower clinical score (CS) vs. AI mice. DEF mice reached CS 2 six days later vs. AI mice (P=0.004), confirmed by a logrank test which revealed that DEF mice reached CS 2 at a 43% slower rate vs. AI mice (HR= .57; 95% CI: 0.38, 1.74; P=0.002). Body weight-adjusted TA (AI: r=0.662, P=0.001; DEF: r=0.622, P=0.006) and quads (AI: r=0.661, P=0.001; DEF: r=0.768; P<0.001) weights were strongly correlated with age at CS 2. CONCLUSION: Vitamin D(3) deficiency improves early disease severity and delays disease onset, but reduces performance in functional outcomes following disease onset, in the high-copy G93A mouse. PMID- 22216258 TI - Metabolomic assessment of induced and activated chemical defence in the invasive red alga Gracilaria vermiculophylla. AB - In comparison with terrestrial plants the mechanistic knowledge of chemical defences is poor for marine macroalgae. This restricts our understanding in the chemically mediated interactions that take place between algae and other organisms. Technical advances such as metabolomics, however, enable new approaches towards the characterisation of the chemically mediated interactions of organisms with their environment. We address defence responses in the red alga Gracilaria vermiculophylla using mass spectrometry based metabolomics in combination with bioassays. Being invasive in the north Atlantic this alga is likely to possess chemical defences according to the prediction that well defended exotics are most likely to become successful invaders in systems dominated by generalist grazers, such as marine macroalgal communities. We investigated the effect of intense herbivore feeding and simulated herbivory by mechanical wounding of the algae. Both processes led to similar changes in the metabolic profile. Feeding experiments with the generalist isopod grazer Idotea baltica showed that mechanical wounding caused a significant increase in grazer resistance. Structure elucidation of the metabolites of which some were up regulated more than 100 times in the wounded tissue, revealed known and novel eicosanoids as major components. Among these were prostaglandins, hydroxylated fatty acids and arachidonic acid derived conjugated lactones. Bioassays with pure metabolites showed that these eicosanoids are part of the innate defence system of macroalgae, similarly to animal systems. In accordance with an induced defence mechanism application of extracts from wounded tissue caused a significant increase in grazer resistance and the up-regulation of other pathways than in the activated defence. Thus, this study suggests that G. vermiculophylla chemically deters herbivory by two lines of defence, a rapid wound-activated process followed by a slower inducible defence. By unravelling involved pathways using metabolomics this work contributes significantly to the understanding of activated and inducible defences for marine macroalgae. PMID- 22216259 TI - Adults' awareness of faces follows newborns' looking preferences. AB - From the first days of life, humans preferentially orient towards upright faces, likely reflecting innate subcortical mechanisms. Here, we show that binocular rivalry can reveal face detection mechanisms in adults that are surprisingly similar to inborn face detection mechanism. We used continuous flash suppression (CFS), a variant of binocular rivalry, to render stimuli invisible at the beginning of each trial and measured the time upright and inverted stimuli needed to overcome such interocular suppression. Critically, specific stimulus properties previously shown to modulate looking preferences in neonates similarly modulated adults' awareness of faces presented during CFS. First, the advantage of upright faces in overcoming CFS was strongly modulated by contrast polarity and direction of illumination. Second, schematic patterns consisting of three dark blobs were suppressed for shorter durations when the arrangement of these blobs respected the face-like configuration of the eyes and the mouth, and this effect was modulated by contrast polarity. No such effects were obtained in a binocular control experiment not involving CFS, suggesting a crucial role for face-sensitive mechanisms operating outside of conscious awareness. These findings indicate that visual awareness of faces in adults is governed by perceptual mechanisms that are sensitive to similar stimulus properties as those modulating newborns' face preferences. PMID- 22216260 TI - Domain analysis reveals that a deubiquitinating enzyme USP13 performs non activating catalysis for Lys63-linked polyubiquitin. AB - Deubiquitination is a reverse process of cellular ubiquitination important for many biological events. Ubiquitin (Ub)-specific protease 13 (USP13) is an ortholog of USP5 implicated in catalyzing hydrolysis of various Ub chains, but its enzymatic properties and catalytic regulation remain to be explored. Here we report studies of the roles of the Ub-binding domains of USP13 in regulatory catalysis by biochemical and NMR structural approaches. Our data demonstrate that USP13, distinct from USP5, exhibits a weak deubiquitinating activity preferring to Lys63-linked polyubiquitin (K63-polyUb) in a non-activation manner. The zinc finger (ZnF) domain of USP13 shares a similar fold with that of USP5, but it cannot bind with Ub, so that USP13 has lost its ability to be activated by free Ub. Substitution of the ZnF domain with that of USP5 confers USP13 the property of catalytic activation. The tandem Ub-associated (UBA) domains of USP13 can bind with different types of diUb but preferentially with K63-linked, providing a possible explanation for the weak activity preferring to K63-polyUb. USP13 can also regulate the protein level of CD3delta in cells, probably depending on its weak deubiquitinating activity and the Ub-binding properties of the UBA domains. Thus, the non-activating catalysis of USP13 for K63-polyUb chains implies that it may function differently from USP5 in cellular deubiquitination processes. PMID- 22216261 TI - Association of a deletion of GSTT2B with an altered risk of oesophageal squamous cell carcinoma in a South African population: a case-control study. AB - BACKGROUND: Polymorphisms in the Glutathione S-transferase genes are associated with altered risks in many cancers, but their role in oesophageal cancer is unclear. Recently a 37-kb deletion polymorphism of GSTT2B that reduces expression of GSTT2 has been described. We evaluated the influence of the GSTT1 and GSTT2B deletion polymorphisms, and the GSTP1 Ile105Val polymorphism (rs1695) on susceptibility to oesophageal squamous cell carcinoma (OSCC) in the Black and Mixed Ancestry populations of South Africa. METHODS AND RESULTS: The GSTT1, GSTT2B and GSTP1 variants were genotyped in 562 OSCC cases and 907 controls, and tested for association with OSCC and for interaction with smoking and alcohol consumption. Linkage disequilibrium (LD) between the deletions at GSTT1 and GSTT2B was determined, and the haplotypes tested for association with OSCC. Neither the GSTT1 deletion nor the GSTP1 Ile105Val polymorphism was associated with OSCC risk in the Black or Mixed Ancestry populations. The GSTT2B deletion was not associated with OSCC risk in the Black population, but was associated with reduced risk of OSCC in the Mixed Ancestry population (OR=0.71; 95% CI 0.57 0.90, p=0.004). Case-only analysis showed no interaction between the GST polymorphisms and smoking or alcohol consumption. LD between the neighboring GSTT1 and GSTT2B deletions was low in both populations (r(2)(Black)=0.04; r(2)(MxA)=0.07), thus these deletions should be assessed independently for effects on disease risk. CONCLUSIONS: Although there was no association between the GSTT1 deletion polymorphism or the GSTP1 Ile105Val polymorphism with OSCC, our results suggest that the presence of the recently described GSTT2B deletion may have a protective effect on the risk of OSCC in the Mixed Ancestry South African population. This is the first report of the contribution of the GSTT2B deletion to cancer risk. PMID- 22216262 TI - Granulysin-expressing CD4+ T cells as candidate immune marker for tuberculosis during childhood and adolescence. AB - BACKGROUND: Granulysin produced by cytolytic T cells directly contributes to immune defense against tuberculosis (TB). We investigated granulysin as a candidate immune marker for childhood and adolescent TB. METHODS: Peripheral blood mononuclear cells (PBMC) from children and adolescents (1-17 years) with active TB, latent TB infection (LTBI), nontuberculous mycobacteria (NTM) infection and from uninfected controls were isolated and restimulated in a 7-day restimulation assay. Intracellular staining was then performed to analyze antigen specific induction of activation markers and cytotoxic proteins, notably, granulysin in CD4(+) CD45RO(+) memory T cells. RESULTS: CD4(+) CD45RO(+) T cells co-expressing granulysin with specificity for Mycobacterium tuberculosis (Mtb) were present in high frequency in TB-experienced children and adolescents. Proliferating memory T cells (CFSE(low)CD4(+)CD45RO(+)) were identified as main source of granulysin and these cells expressed both central and effector memory phenotype. PBMC from study participants after TB drug therapy revealed that granulysin-expressing CD4(+) T cells are long-lived, and express several activation and cytotoxicity markers with a proportion of cells being interferon gamma-positive. In addition, granulysin-expressing T cell lines showed cytolytic activity against Mtb-infected target cells. CONCLUSIONS: Our data suggest granulysin expression by CD4(+) memory T cells as candidate immune marker for TB infection, notably, in childhood and adolescence. PMID- 22216263 TI - The contribution of vegetation and landscape configuration for predicting environmental change impacts on Iberian birds. AB - Although climate is known to be one of the key factors determining animal species distributions amongst others, projections of global change impacts on their distributions often rely on bioclimatic envelope models. Vegetation structure and landscape configuration are also key determinants of distributions, but they are rarely considered in such assessments. We explore the consequences of using simulated vegetation structure and composition as well as its associated landscape configuration in models projecting global change effects on Iberian bird species distributions. Both present-day and future distributions were modelled for 168 bird species using two ensemble forecasting methods: Random Forests (RF) and Boosted Regression Trees (BRT). For each species, several models were created, differing in the predictor variables used (climate, vegetation, and landscape configuration). Discrimination ability of each model in the present-day was then tested with four commonly used evaluation methods (AUC, TSS, specificity and sensitivity). The different sets of predictor variables yielded similar spatial patterns for well-modelled species, but the future projections diverged for poorly-modelled species. Models using all predictor variables were not significantly better than models fitted with climate variables alone for ca. 50% of the cases. Moreover, models fitted with climate data were always better than models fitted with landscape configuration variables, and vegetation variables were found to correlate with bird species distributions in 26-40% of the cases with BRT, and in 1-18% of the cases with RF. We conclude that improvements from including vegetation and its landscape configuration variables in comparison with climate only variables might not always be as great as expected for future projections of Iberian bird species. PMID- 22216264 TI - Translational regulation of utrophin by miRNAs. AB - BACKGROUND: Utrophin is the autosomal homolog of dystrophin, the product of the Duchenne Muscular Dystrophy (DMD) locus. Its regulation is of therapeutic interest as its overexpression can compensate for dystrophin's absence in animal models of DMD. The tissue distribution and transcriptional regulation of utrophin have been characterized extensively, and more recently translational control mechanisms that may underlie its complex expression patterns have begun to be identified. METHODOLOGY/PRINCIPAL FINDINGS: Using a variety of bioinformatic, molecular and cell biology techniques, we show that the muscle isoform utrophin-A is predominantly suppressed at the translational level in C2C12 myoblasts. The extent of translational inhibition is estimated to be ~99% in C2C12 cells and is mediated by both the 5'- and 3'-UTRs of the utrophin-A mRNA. In this study we identify five miRNAs (let-7c, miR-150, miR-196b, miR-296-5p, miR-133b) that mediate the repression, and confirm repression by the previously identified miR 206. We demonstrate that this translational repression can be overcome by blocking the actions of miRNAs, resulting in an increased level of utrophin protein in C2C12 cells. CONCLUSIONS/SIGNIFICANCE: The present study has identified key inhibitory mechanisms featuring miRNAs that regulate utrophin expression, and demonstrated that these mechanisms can be targeted to increase endogenous utrophin expression in cultured muscle cells. We suggest that miRNA mediated inhibitory mechanisms could be targeted by methods similar to those described here as a novel strategy to increase utrophin expression as a therapy for DMD. PMID- 22216266 TI - Pax3 stimulates p53 ubiquitination and degradation independent of transcription. AB - BACKGROUND: Pax3 is a developmental transcription factor that is required for neural tube and neural crest development. We previously showed that inactivating the p53 tumor suppressor protein prevents neural tube and cardiac neural crest defects in Pax3-mutant mouse embryos. This demonstrates that Pax3 regulates these processes by blocking p53 function. Here we investigated the mechanism by which Pax3 blocks p53 function. METHODOLOGY/PRINCIPAL FINDINGS: We employed murine embryonic stem cell (ESC)-derived neuronal precursors as a cell culture model of embryonic neuroepithelium or neural crest. Pax3 reduced p53 protein stability, but had no effect on p53 mRNA levels or the rate of p53 synthesis. Full length Pax3 as well as fragments that contained either the DNA-binding paired box or the homeodomain, expressed as GST or FLAG fusion proteins, physically associated with p53 and Mdm2 both in vitro and in vivo. In contrast, Splotch Pax3, which causes neural tube and neural crest defects in homozygous embryos, bound weakly, or not at all, to p53 or Mdm2. The paired domain and homeodomain each stimulated Mdm2 mediated ubiquitination of p53 and p53 degradation in the absence of the Pax3 transcription regulatory domains, whereas Splotch Pax3 did not stimulate p53 ubiquitination or degradation. CONCLUSIONS/SIGNIFICANCE: Pax3 inactivates p53 function by stimulating its ubiquitination and degradation. This process utilizes the Pax3 paired domain and homeodomain but is independent of DNA-binding and transcription regulation. Because inactivating p53 is the only required Pax3 function during neural tube closure and cardiac neural crest development, and inactivating p53 does not require Pax3-dependent transcription regulation, this indicates that Pax3 is not required to function as a transcription factor during neural tube closure and cardiac neural crest development. These findings further suggest novel explanations for PAX3 functions in human diseases, such as in neural crest-derived cancers and Waardenburg syndrome types 1 and 3. PMID- 22216265 TI - General anesthetics inhibit erythropoietin induction under hypoxic conditions in the mouse brain. AB - BACKGROUND: Erythropoietin (EPO), originally identified as a hematopoietic growth factor produced in the kidney and fetal liver, is also endogenously expressed in the central nervous system (CNS). EPO in the CNS, mainly produced in astrocytes, is induced under hypoxic conditions in a hypoxia-inducible factor (HIF)-dependent manner and plays a dominant role in neuroprotection and neurogenesis. We investigated the effect of general anesthetics on EPO expression in the mouse brain and primary cultured astrocytes. METHODOLOGY/PRINCIPAL FINDINGS: BALB/c mice were exposed to 10% oxygen with isoflurane at various concentrations (0.10 1.0%). Expression of EPO mRNA in the brain was studied, and the effects of sevoflurane, halothane, nitrous oxide, pentobarbital, ketamine, and propofol were investigated. In addition, expression of HIF-2alpha protein was studied by immunoblotting. Hypoxia-induced EPO mRNA expression in the brain was significantly suppressed by isoflurane in a concentration-dependent manner. A similar effect was confirmed for all other general anesthetics. Hypoxia-inducible expression of HIF-2alpha protein was also significantly suppressed with isoflurane. In the experiments using primary cultured astrocytes, isoflurane, pentobarbital, and ketamine suppressed hypoxia-inducible expression of HIF-2alpha protein and EPO mRNA. CONCLUSIONS/SIGNIFICANCE: Taken together, our results indicate that general anesthetics suppress activation of HIF-2 and inhibit hypoxia-induced EPO upregulation in the mouse brain through a direct effect on astrocytes. PMID- 22216267 TI - A naturally associated rhizobacterium of Arabidopsis thaliana induces a starvation-like transcriptional response while promoting growth. AB - Plant growth promotion by rhizobacteria is a known phenomenon but the underlying mechanisms are poorly understood. We searched for plant growth-promoting rhizobacteria that are naturally associated with Arabidopsis thaliana to investigate the molecular mechanisms that are involved in plant growth-promotion. We isolated a Pseudomonas bacterium (Pseudomonas sp. G62) from roots of field grown Arabidopsis plants that has not been described previously and analyzed its effect on plant growth, gene expression and the level of sugars and amino acids in the host plant. Inoculation with Pseudomonas sp. G62 promoted plant growth under various growth conditions. Microarray analysis revealed rapid changes in transcript levels of genes annotated to energy-, sugar- and cell wall metabolism in plants 6 h after root inoculation with P. sp. G62. The expression of several of these genes remained stable over weeks, but appeared differentially regulated in roots and shoots. The global gene expression profile observed after inoculation with P. sp. G62 showed a striking resemblance with previously described carbohydrate starvation experiments, although plants were not depleted from soluble sugars, and even showed a slight increase of the sucrose level in roots 5 weeks after inoculation. We suggest that the starvation-like transcriptional phenotype - while steady state sucrose levels are not reduced - is induced by a yet unknown signal from the bacterium that simulates sugar starvation. We discuss the potential effects of the sugar starvation signal on plant growth promotion. PMID- 22216268 TI - Adult body weight is programmed by a redox-regulated and energy-dependent process during the pronuclear stage in mouse. AB - In mammals fertilization triggers a series of Ca(2+) oscillations that not only are essential for events of egg activation but also stimulate oxidative phosphorylation. Little is known, however, about the relationship between quantitative changes in egg metabolism and specific long-term effects in offspring. This study assessed whether post-natal growth is modulated by early transient changes in NAD(P)H and FAD(2+) in zygotes. We report that experimentally manipulating the redox potential of fertilized eggs during the pronuclear (PN) stage affects post-natal body weight. Exogenous pyruvate induces NAD(P)H oxidation and stimulates mitochondrial activity with resulting offspring that are persistently and significantly smaller than controls. Exogenous lactate stimulates NAD(+) reduction and impairs mitochondrial activity, and produces offspring that are smaller than controls at weaning but catch up after weaning. Cytosolic alkalization increases NAD(P)(+) reduction and offspring of normal birth-weight become significantly and persistently larger than controls. These results constitute the first report that post-natal growth rate is ultimately linked to modulation of NAD(P)H and FAD(2+) concentration as early as the PN stage. PMID- 22216269 TI - Identification of domains and amino acids essential to the collagen galactosyltransferase activity of GLT25D1. AB - Collagen is modified by hydroxylation and glycosylation of hydroxylysine residues. This glycosylation is initiated by the beta1,O galactosyltransferases GLT25D1 and GLT25D2. The structurally similar protein cerebral endothelial cell adhesion molecule CEECAM1 was previously reported to be inactive when assayed for collagen glycosyltransferase activity. To address the cause of the absent galactosyltransferase activity, we have generated several chimeric constructs between the active human GLT25D1 and inactive human CEECAM1 proteins. The assay of these chimeric constructs pointed to a short central region and a large C terminal region of CEECAM1 leading to the loss of collagen galactosyltransferase activity. Examination of the three DXD motifs of the active GLT25D1 by site directed mutagenesis confirmed the importance of the first (amino acids 166-168) and second motif (amino acids 461-463) for enzymatic activity, whereas the third one was dispensable. Since the second DXD motif is incomplete in CEECAM1, we have restored the motif by introducing the substitution S461D. This change did not restore the activity of the C-terminal region, thereby showing that additional amino acids were required in this C-terminal region to confer enzymatic activity. Finally, we have introduced the substitution Q471R-V472M-N473Q-P474V in the CEECAM1-C-terminal construct, which is found in most animal GLT25D1 and GLT25D2 isoforms but not in CEECAM1. This substitution was shown to partially restore collagen galactosyltransferase activity, underlining its importance for catalytic activity in the C-terminal domain. Because multiple mutations in different regions of CEECAM1 contribute to the lack of galactosyltransferase activity, we deduced that CEECAM1 is functionally different from the related GLT25D1 protein. PMID- 22216270 TI - Acid solution is a suitable medium for introducing QX-314 into nociceptors through TRPV1 channels to produce sensory-specific analgesic effects. AB - BACKGROUND: Previous studies have demonstrated that QX-314, an intracellular sodium channel blocker, can enter into nociceptors through capsaicin-activated TRPV1 or permeation of the membrane by chemical enhancers to produce a sensory selective blockade. However, the obvious side effects of these combinations limit the application of QX-314. A new strategy for targeting delivery of QX-314 into nociceptors needs further investigation. The aim of this study is to test whether acidic QX-314, when dissolves in acidic solution directly, can enter into nociceptors through acid-activated TRPV1 and block sodium channels from the intracellular side to produce a sensory-specific analgesic effect. METHODOLOGY/PRINCIPAL FINDINGS: Acidic solution or noradrenaline was injected intraplantarly to induce acute pain behavior in mice. A chronic constrictive injury model was performed to induce chronic neuropathic pain. A sciatic nerve blockade model was used to evaluate the sensory-specific analgesic effects of acidic QX-314. Thermal and mechanical hyperalgesia were measured by using radiant heat and electronic von Frey filaments test. Spinal Fos protein expression was determined by immunohistochemistry. The expression of p-ERK was detected by western blot assay. Whole cell clamp recording was performed to measure action potentials and total sodium current in rats DRG neurons. We found that pH 5.0 PBS solution induced behavioral hyperalgesia accompanied with the increased expression of spinal Fos protein and p-ERK. Pretreatment with pH 5.0 QX-314, and not pH 7.4 QX-314, alleviated pain behavior, inhibited the increased spinal Fos protein and p-ERK expression induced by pH 5.0 PBS or norepinephrine, blocked sodium currents and abolished the production of action potentials evoked by current injection. The above effects were prevented by TRPV1 channel inhibitor SB366791, but not by ASIC channel inhibitor amiloride. Furthermore, acidic QX-314 employed adjacent to the sciatic nerve selectively blocked the sensory but not the motor functions in naive and CCI mice. CONCLUSIONS/SIGNIFICANCE: Acid solution is a suitable medium for introducing QX-314 into nociceptors through TRPV1 channels to produce a sensory-specific analgesic effect. PMID- 22216271 TI - Long-term alterations of cytokines and growth factors expression in irradiated tissues and relation with histological severity scoring. AB - PURPOSE: Beside its efficacy in cancer treatment, radiotherapy induces degeneration of healthy tissues within the irradiated area. The aim of this study was to analyze the variations of proinflammatory (IL-1alpha, IL-2, IL-6, TNF alpha, IFN-gamma), profibrotic (TGF-beta1), proangiogneic (VEGF) and stem cell mobilizing (GM-CSF) cytokines and growth factors in an animal model of radiation induced tissue degeneration. MATERIALS AND METHODS: 24 rats were irradiated unilaterally on the hindlimb at a monodose of 30 Gy. Six weeks (n=8), 6 months (n=8) and 1 year (n=8) after irradiation the mediators expression in skin and muscle were analyzed using Western blot and the Bio-Plex(r) protein array (BPA) technology. Additional histological severity for fibrosis, inflammation, vascularity and cellularity alterations scoring was defined from histology and immnunohistochemistry analyses. RESULTS: A significant increase of histological severity scoring was found in irradiated tissue. Skin tissues were more radio sensitive than muscle. A high level of TGF-beta1 expression was found throughout the study and a significant relation was evidenced between TGF-beta1 expression and fibrosis scoring. Irradiated tissue showed a chronic inflammation (IL-2 and TNF-alpha significantly increased). Moreover a persistent expression of GM-CSF and VEGF was found in all irradiated tissues. The vascular score was related to TGF-beta1 expression and the cellular alterations score was significantly related with the level of IL-2, VEGF and GM-CSF. CONCLUSION: The results achieved in the present study underline the complexity and multiplicity of radio-induced alterations of cytokine network. It offers many perspectives of development, for the comprehension of the mechanisms of late injuries or for the histological and molecular evaluation of the mode of action and the efficacy of rehabilitation techniques. PMID- 22216272 TI - Reduced food intake and body weight in mice deficient for the G protein-coupled receptor GPR82. AB - G protein-coupled receptors (GPCR) are involved in the regulation of numerous physiological functions. Therefore, GPCR variants may have conferred important selective advantages during periods of human evolution. Indeed, several genomic loci with signatures of recent selection in humans contain GPCR genes among them the X-chromosomally located gene for GPR82. This gene encodes a so-called orphan GPCR with unknown function. To address the functional relevance of GPR82 gene deficient mice were characterized. GPR82-deficient mice were viable, reproduced normally, and showed no gross anatomical abnormalities. However, GPR82-deficient mice have a reduced body weight and body fat content associated with a lower food intake. Moreover, GPR82-deficient mice showed decreased serum triacylglyceride levels, increased insulin sensitivity and glucose tolerance, most pronounced under Western diet. Because there were no differences in respiratory and metabolic rates between wild-type and GPR82-deficient mice our data suggest that GPR82 function influences food intake and, therefore, energy and body weight balance. GPR82 may represent a thrifty gene most probably representing an advantage during human expansion into new environments. PMID- 22216273 TI - Nitric oxide-sensitive guanylyl cyclase is differentially regulated by nuclear and non-nuclear estrogen pathways in anterior pituitary gland. AB - 17beta-estradiol (E2) regulates hormonal release as well as proliferation and cell death in the pituitary. The main nitric oxide receptor, nitric oxide sensitive- or soluble guanylyl cyclase (sGC), is a heterodimer composed of two subunits, alpha and beta, that catalyses cGMP formation. alpha1beta1 is the most abundant and widely expressed heterodimer, showing the greater activity. Previously we have shown that E2 decreased sGC activity but exerts opposite effects on sGC subunits increasing alpha1 and decreasing beta1 mRNA and protein levels. In the present work we investigate the mechanisms by which E2 differentially regulates sGC subunits' expression on rat anterior pituitary gland. Experiments were performed on primary cultures of anterior pituitary cells from adult female Wistar rats at random stages of estrous cycle. After 6 h of E2 treatment, alpha1 mRNA and protein expression is increased while beta1 levels are down-regulated. E2 effects on sGC expression are partially dependent on de novo transcription while de novo translation is fully required. E2 treatment decreased HuR mRNA stabilization factor and increased AUF1 p37 mRNA destabilization factor. E2-elicited beta1 mRNA decrease correlates with a mRNA destabilization environment in the anterior pituitary gland. On the other hand, after 6 h of treatment, E2-BSA (1 nM) and E2-dendrimer conjugate (EDC, 1 nM) were unable to modify alpha1 or beta1 mRNA levels, showing that nuclear receptor is involved in E2 actions. However, at earlier times (3 h), 1 nM EDC causes a transient decrease of alpha1 in a PI3k-dependent fashion. Our results show for the first time that E2 is able to exert opposite actions in the anterior pituitary gland, depending on the activation of classical or non-classical pathways. Thus, E2 can also modify sGC expression through membrane-initiated signals bringing to light a new point of regulation in NO/sGC pathway. PMID- 22216274 TI - Age-related neural dedifferentiation in the motor system. AB - Recent neuroimaging studies using multi-voxel pattern analysis (MVPA) show that distributed patterns of brain activation elicited by different visual stimuli are less distinctive in older adults than in young adults. However, less is known about the effects of aging on the neural representation of movement. The present study used MVPA to compare the distinctiveness of motor representations in young and older adults. We also investigated the contributions of brain structure to age differences in the distinctiveness of motor representations. We found that neural distinctiveness was reduced in older adults throughout the motor control network. Although aging was also associated with decreased gray matter volume in these regions, age differences in motor distinctiveness remained significant after controlling for gray matter volume. Our results suggest that age-related neural dedifferentiation is not restricted to sensory perception and is instead a more general feature of the aging brain. PMID- 22216275 TI - Temporal recalibration in vocalization induced by adaptation of delayed auditory feedback. AB - BACKGROUND: We ordinarily perceive our voice sound as occurring simultaneously with vocal production, but the sense of simultaneity in vocalization can be easily interrupted by delayed auditory feedback (DAF). DAF causes normal people to have difficulty speaking fluently but helps people with stuttering to improve speech fluency. However, the underlying temporal mechanism for integrating the motor production of voice and the auditory perception of vocal sound remains unclear. In this study, we investigated the temporal tuning mechanism integrating vocal sensory and voice sounds under DAF with an adaptation technique. METHODS AND FINDINGS: Participants produced a single voice sound repeatedly with specific delay times of DAF (0, 66, 133 ms) during three minutes to induce 'Lag Adaptation'. They then judged the simultaneity between motor sensation and vocal sound given feedback. We found that lag adaptation induced a shift in simultaneity responses toward the adapted auditory delays. This indicates that the temporal tuning mechanism in vocalization can be temporally recalibrated after prolonged exposure to delayed vocal sounds. Furthermore, we found that the temporal recalibration in vocalization can be affected by averaging delay times in the adaptation phase. CONCLUSIONS: These findings suggest vocalization is finely tuned by the temporal recalibration mechanism, which acutely monitors the integration of temporal delays between motor sensation and vocal sound. PMID- 22216276 TI - Interfacing external quantum devices to a universal quantum computer. AB - We present a scheme to use external quantum devices using the universal quantum computer previously constructed. We thereby show how the universal quantum computer can utilize networked quantum information resources to carry out local computations. Such information may come from specialized quantum devices or even from remote universal quantum computers. We show how to accomplish this by devising universal quantum computer programs that implement well known oracle based quantum algorithms, namely the Deutsch, Deutsch-Jozsa, and the Grover algorithms using external black-box quantum oracle devices. In the process, we demonstrate a method to map existing quantum algorithms onto the universal quantum computer. PMID- 22216278 TI - Large scale association analysis identifies three susceptibility loci for coronary artery disease. AB - Genome wide association studies (GWAS) and their replications that have associated DNA variants with myocardial infarction (MI) and/or coronary artery disease (CAD) are predominantly based on populations of European or Eastern Asian descent. Replication of the most significantly associated polymorphisms in multiple populations with distinctive genetic backgrounds and lifestyles is crucial to the understanding of the pathophysiology of a multifactorial disease like CAD. We have used our Lebanese cohort to perform a replication study of nine previously identified CAD/MI susceptibility loci (LTA, CDKN2A-CDKN2B, CELSR2 PSRC1-SORT1, CXCL12, MTHFD1L, WDR12, PCSK9, SH2B3, and SLC22A3), and 88 genes in related phenotypes. The study was conducted on 2,002 patients with detailed demographic, clinical characteristics, and cardiac catheterization results. One marker, rs6922269, in MTHFD1L was significantly protective against MI (OR=0.68, p=0.0035), while the variant rs4977574 in CDKN2A-CDKN2B was significantly associated with MI (OR=1.33, p=0.0086). Associations were detected after adjustment for family history of CAD, gender, hypertension, hyperlipidemia, diabetes, and smoking. The parallel study of 88 previously published genes in related phenotypes encompassed 20,225 markers, three quarters of which with imputed genotypes The study was based on our genome-wide genotype data set, with imputation across the whole genome to HapMap II release 22 using HapMap CEU population as a reference. Analysis was conducted on both the genotyped and imputed variants in the 88 regions covering selected genes. This approach replicated HNRNPA3P1-CXCL12 association with CAD and identified new significant associations of CDKAL1, ST6GAL1, and PTPRD with CAD. Our study provides evidence for the importance of the multifactorial aspect of CAD/MI and describes genes predisposing to their etiology. PMID- 22216277 TI - Activity-induced remodeling of olfactory bulb microcircuits revealed by monosynaptic tracing. AB - The continued addition of new neurons to mature olfactory circuits represents a remarkable mode of cellular and structural brain plasticity. However, the anatomical configuration of newly established circuits, the types and numbers of neurons that form new synaptic connections, and the effect of sensory experience on synaptic connectivity in the olfactory bulb remain poorly understood. Using in vivo electroporation and monosynaptic tracing, we show that postnatal-born granule cells form synaptic connections with centrifugal inputs and mitral/tufted cells in the mouse olfactory bulb. In addition, newly born granule cells receive extensive input from local inhibitory short axon cells, a poorly understood cell population. The connectivity of short axon cells shows clustered organization, and their synaptic input onto newborn granule cells dramatically and selectively expands with odor stimulation. Our findings suggest that sensory experience promotes the synaptic integration of new neurons into cell type-specific olfactory circuits. PMID- 22216280 TI - Dengue virus activates polyreactive, natural IgG B cells after primary and secondary infection. AB - BACKGROUND: Dengue virus is transmitted by mosquitoes and has four serotypes. Cross-protection to other serotypes lasting for a few months is observed following infection with one serotype. There is evidence that low-affinity T and/or B cells from primary infections contribute to the severe syndromes often associated with secondary dengue infections. such pronounced immune-mediated enhancement suggests a dengue-specific pattern of immune cell activation. This study investigates the acute and early convalescent B cell response leading to the generation of cross-reactive and neutralizing antibodies following dengue infection. METHODOLOGY/PRINCIPAL FINDINGS: We assayed blood samples taken from dengue patients with primary or secondary infection during acute disease and convalescence and compared them to samples from patients presenting with non dengue related fever. Dengue induced massive early plasmablast formation, which correlated with the appearance of polyclonal, cross-reactive IgG for both primary and secondary infection. Surprisingly, the contribution of IgG to the neutralizing titer 4-7 days after fever onset was more than 50% even after primary infection. CONCLUSIONS/SIGNIFICANCE: Poly-reactive and virus serotype cross-reactive IgG are an important component of the innate response in humans during both primary and secondary dengue infection, and "innate specificities" seem to constitute part of the adaptive response in dengue. While of potential importance for protection during secondary infection, cross-reactive B cells will also compete with highly neutralizing B cells and possibly interfere with their development. PMID- 22216279 TI - A viral vectored prime-boost immunization regime targeting the malaria Pfs25 antigen induces transmission-blocking activity. AB - The ookinete surface protein Pfs25 is a macrogamete-to-ookinete/ookinete stage antigen of Plasmodium falciparum, capable of exerting high-level anti-malarial transmission-blocking activity following immunization with recombinant protein-in adjuvant formulations. Here, this antigen was expressed in recombinant chimpanzee adenovirus 63 (ChAd63), human adenovirus serotype 5 (AdHu5) and modified vaccinia virus Ankara (MVA) viral vectored vaccines. Two immunizations were administered to mice in a heterologous prime-boost regime. Immunization of mice with AdHu5 Pfs25 at week 0 and MVA Pfs25 at week 10 (Ad-MVA Pfs25) resulted in high anti Pfs25 IgG titers, consisting of predominantly isotypes IgG1 and IgG2a. A single priming immunization with ChAd63 Pfs25 was as effective as AdHu5 Pfs25 with respect to ELISA titers at 8 weeks post-immunization. Sera from Ad-MVA Pfs25 immunized mice inhibited the transmission of P. falciparum to the mosquito both ex vivo and in vivo. In a standard membrane-feeding assay using NF54 strain P. falciparum, oocyst intensity in Anopheles stephensi mosquitoes was significantly reduced in an IgG concentration-dependent manner when compared to control feeds (96% reduction of intensity, 78% reduction in prevalence at a 1 in 5 dilution of sera). In addition, an in vivo transmission-blocking effect was also demonstrated by direct feeding of immunized mice infected with Pfs25DR3, a chimeric P. berghei line expressing Pfs25 in place of endogenous Pbs25. In this assay the density of Pfs25DR3 oocysts was significantly reduced when mosquitoes were fed on vaccinated as compared to control mice (67% reduction of intensity, 28% reduction in prevalence) and specific IgG titer correlated with efficacy. These data confirm the utility of the adenovirus-MVA vaccine platform for the induction of antibodies with transmission-blocking activity, and support the continued development of this alternative approach to transmission-blocking malaria subunit vaccines. PMID- 22216281 TI - The HIV-1 transactivator factor (Tat) induces enterocyte apoptosis through a redox-mediated mechanism. AB - The intestinal mucosa is an important target of human immunodeficiency virus (HIV) infection. HIV virus induces CD4+ T cell loss and epithelial damage which results in increased intestinal permeability. The mechanisms involved in nutrient malabsorption and alterations of intestinal mucosal architecture are unknown. We previously demonstrated that HIV-1 transactivator factor (Tat) induces an enterotoxic effect on intestinal epithelial cells that could be responsible for HIV-associated diarrhea. Since oxidative stress is implicated in the pathogenesis and morbidity of HIV infection, we evaluated whether Tat induces apoptosis of human enterocytes through oxidative stress, and whether the antioxidant N acetylcysteine (NAC) could prevent it. Caco-2 and HT29 cells or human intestinal mucosa specimens were exposed to Tat alone or combined with NAC. In an in-vitro cell model, Tat increased the generation of reactive oxygen species and decreased antioxidant defenses as judged by a reduction in catalase activity and a reduced (GSH)/oxidized (GSSG) glutathione ratio. Tat also induced cytochrome c release from mitochondria to cytosol, and caspase-3 activation. Rectal dialysis samples from HIV-infected patients were positive for the oxidative stress marker 8 hydroxy-2'-deoxyguanosine. GSH/GSSG imbalance and apoptosis occurred in jejunal specimens from HIV-positive patients at baseline and from HIV-negative specimens exposed to Tat. Experiments with neutralizing anti-Tat antibodies showed that these effects were direct and specific. Pre-treatment with NAC prevented Tat induced apoptosis and restored the glutathione balance in both the in-vitro and the ex-vivo model. These findings indicate that oxidative stress is one of the mechanism involved in HIV-intestinal disease. PMID- 22216282 TI - Global analysis of DNA methylation by Methyl-Capture sequencing reveals epigenetic control of cisplatin resistance in ovarian cancer cell. AB - Cisplatin resistance is one of the major reasons leading to the high death rate of ovarian cancer. Methyl-Capture sequencing (MethylCap-seq), which combines precipitation of methylated DNA by recombinant methyl-CpG binding domain of MBD2 protein with NGS, global and unbiased analysis of global DNA methylation patterns. We applied MethylCap-seq to analyze genome-wide DNA methylation profile of cisplatin sensitive ovarian cancer cell line A2780 and its isogenic derivative resistant line A2780CP. We obtained 21,763,035 raw reads for the drug resistant cell line A2780CP and 18,821,061reads for the sensitive cell line A2780. We identified 1224 hyper-methylated and 1216 hypomethylated DMRs (differentially methylated region) in A2780CP compared to A2780. Our MethylCap-seq data on this ovarian cancer cisplatin resistant model provided a good resource for the research community. We also found that A2780CP, compared to A2780, has lower observed to expected methylated CpG ratios, suggesting a lower global CpG methylation in A2780CP cells. Methylation specific PCR and bisulfite sequencing confirmed hypermethylation of PTK6, PRKCE and BCL2L1 in A2780 compared with A2780CP. Furthermore, treatment with the demethylation reagent 5-aza-dC in A2780 cells demethylated the promoters and restored the expression of PTK6, PRKCE and BCL2L1. PMID- 22216284 TI - The AAA-ATPase VPS4 regulates extracellular secretion and lysosomal targeting of alpha-synuclein. AB - Many neurodegenerative diseases share a common pathological feature: the deposition of amyloid-like fibrils composed of misfolded proteins. Emerging evidence suggests that these proteins may spread from cell-to-cell and encourage the propagation of neurodegeneration in a prion-like manner. Here, we demonstrated that alpha-synuclein (alphaSYN), a principal culprit for Lewy pathology in Parkinson's disease (PD), was present in endosomal compartments and detectably secreted into the extracellular milieu. Unlike prion protein, extracellular alphaSYN was mainly recovered in the supernatant fraction rather than in exosome-containing pellets from the neuronal culture medium and cerebrospinal fluid. Surprisingly, impaired biogenesis of multivesicular body (MVB), an organelle from which exosomes are derived, by dominant-negative mutant vacuolar protein sorting 4 (VPS4) not only interfered with lysosomal targeting of alphaSYN but facilitated alphaSYN secretion. The hypersecretion of alphaSYN in VPS4-defective cells was efficiently restored by the functional disruption of recycling endosome regulator Rab11a. Furthermore, both brainstem and cortical Lewy bodies in PD were found to be immunoreactive for VPS4. Thus, VPS4, a master regulator of MVB sorting, may serve as a determinant of lysosomal targeting or extracellular secretion of alphaSYN and thereby contribute to the intercellular propagation of Lewy pathology in PD. PMID- 22216285 TI - Morpholino gene knockdown in adult Fundulus heteroclitus: role of SGK1 in seawater acclimation. AB - The Atlantic killifish (Fundulus heteroclitus) is an environmental sentinel organism used extensively for studies on environmental toxicants and salt (NaCl) homeostasis. Previous research in our laboratory has shown that rapid acclimation of killifish to seawater is mediated by trafficking of CFTR chloride channels from intracellular vesicles to the plasma membrane in the opercular membrane within the first hour in seawater, which enhances chloride secretion into seawater, thereby contributing to salt homeostasis. Acute transition to seawater is also marked by an increase in both mRNA and protein levels of serum glucocorticoid kinase 1 (SGK1) within 15 minutes of transfer. Although the rise in SGK1 in gill and its functional analog, the opercular membrane, after seawater transfer precedes the increase in membrane CFTR, a direct role of SGK1 in elevating membrane CFTR has not been established in vivo. To test the hypothesis that SGK1 mediates the increase in plasma membrane CFTR we designed two functionally different vivo-morpholinos to knock down SGK1 in gill, and developed and validated a vivo-morpholino knock down technique for adult killifish. Injection (intraperitoneal, IP) of the splice blocking SGK1 vivo-morpholino reduced SGK1 mRNA in the gill after transition from fresh to seawater by 66%. The IP injection of the translational blocking and splice blocking vivo-morpholinos reduced gill SGK1 protein abundance in fish transferred from fresh to seawater by 64% and 53%, respectively. Moreover, knock down of SGK1 completely eliminated the seawater induced rise in plasma membrane CFTR, demonstrating that the increase in SGK1 protein is required for the trafficking of CFTR from intracellular vesicles in mitochondrion rich cells to the plasma membrane in the gill during acclimation to seawater. This is the first report of the use of vivo-morpholinos in adult killifish and demonstrates that vivo-morpholinos are a valuable genetic tool for this environmentally relevant model organism. PMID- 22216286 TI - Polymorphisms in the RNASE3 gene are associated with susceptibility to cerebral malaria in Ghanaian children. AB - BACKGROUND: Cerebral malaria (CM) is the most severe outcome of Plasmodium falciparum infection and a major cause of death in children from 2 to 4 years of age. A hospital based study in Ghana showed that P. falciparum induces eosinophilia and found a significantly higher serum level of eosinophil cationic protein (ECP) in CM patients than in uncomplicated malaria (UM) and severe malaria anemia (SA) patients. Single nucleotide polymorphisms (SNPs) have been described in the ECP encoding-gene (RNASE3) of which the c.371G>C polymorphism (rs2073342) results in an arginine to threonine amino acid substitution p.R124T in the polypeptide and abolishes the cytotoxicity of ECP. The present study aimed to investigate the potential association between polymorphisms in RNASE3 and CM. METHODOLOGY/PRINCIPAL FINDINGS: The RNASE3 gene and flanking regions were sequenced in 206 Ghanaian children enrolled in a hospital based malaria study. An association study was carried out to assess the significance of five SNPs in CM (n=45) and SA (n=56) cases, respectively. The two severe case groups (CM and SA) were compared with the non-severe control group comprising children suffering from UM (n=105). The 371G allele was significantly associated with CM (p=0.00945, OR=2.29, 95% CI=1.22-4.32) but not with SA. Linkage disequilibrium analysis demonstrated significant linkage between three SNPs and the haplotype combination 371G/*16G/*94A was strongly associated with susceptibility to CM (p=0.000913, OR=4.14, 95% CI=1.79-9.56), thus, defining a risk haplotype. The RNASE3 371GG genotype was found to be under frequency-dependent selection. CONCLUSIONS/SIGNIFICANCE: The 371G allele of RNASE3 is associated with susceptibility to CM and forms part of a risk associated haplotype GGA defined by the markers: rs2073342 (G-allele), rs2233860 (G-allele) and rs8019343 (A-allele) respectively. Collectively, these results suggest a hitherto unrecognized role for eosinophils in CM pathogenesis. PMID- 22216283 TI - Pathway-based analysis of a melanoma genome-wide association study: analysis of genes related to tumour-immunosuppression. AB - Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (p(emp)=0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (p(emp)=0.006) and secretion of suppressive factors (p(emp)=0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges. PMID- 22216287 TI - Estrogen-mediated upregulation of Noxa is associated with cell cycle progression in estrogen receptor-positive breast cancer cells. AB - Noxa is a Bcl-2-homology domain (BH3)-only protein reported to be a proapoptotic member of the Bcl-2 family. Estrogen has been well documented to stimulate cell growth and inhibit apoptosis in estrogen receptor (ER)-positive breast cancer cells. Intriguingly, recent reports have shown that 17beta-estradiol (E2) induces Noxa expression, although the mechanisms underlying E2-mediated induction of Noxa and its functional significance are unknown. Using MCF7 human breast cancer cells as an experimental model, we show that Noxa is upregulated by E2 via p53 independent processes that involve c-Myc and ERalpha. Experiments using small interfering ribonucleic acids (siRNA) to specifically knock down p53, c-Myc, and ERalpha demonstrated that c-Myc and ERalpha, but not p53, are involved in the transcriptional upregulation of Noxa following E2 treatment. Furthermore, while E2 promoted the recruitment of c-Myc and ERalpha to the NOXA promoter in chromatin immunoprecipitation (ChIP) assays, E2 did not induce p53 recruitment. Interestingly, E2-mediated upregulation of Noxa was not associated with apoptosis. However, siRNA-mediated knockdown of Noxa resulted in cell cycle arrest in G(0)/G(1)-phase and significantly delayed the G(1)-to-S-phase transition following E2 treatment, indicating that Noxa expression is required for cell cycle progression in ER-positive breast cancer cells. PMID- 22216289 TI - Circular DNA intermediate in the duplication of Nile tilapia vasa genes. AB - vasa is a highly conserved RNA helicase involved in animal germ cell development. Among vertebrate species, it is typically present as a single copy per genome. Here we report the isolation and sequencing of BAC clones for Nile tilapia vasa genes. Contrary to a previous report that Nile tilapia have a single copy of the vasa gene, we find evidence for at least three vasa gene loci. The vasa gene locus was duplicated from the original site and integrated into two distant novel sites. For one of these insertions we find evidence that the duplication was mediated by a circular DNA intermediate. This mechanism of gene duplication may explain the origin of isolated gene duplicates during the evolution of fish genomes. These data provide a foundation for studying the role of multiple vasa genes in the development of tilapia gonads, and will contribute to investigations of the molecular mechanisms of sex determination and evolution in cichlid fishes. PMID- 22216288 TI - Extent of height variability explained by known height-associated genetic variants in an isolated population of the Adriatic coast of Croatia. AB - BACKGROUND: Human height is a classical example of a polygenic quantitative trait. Recent large-scale genome-wide association studies (GWAS) have identified more than 200 height-associated loci, though these variants explain only 2~10% of overall variability of normal height. The objective of this study was to investigate the variance explained by these loci in a relatively isolated population of European descent with limited admixture and homogeneous genetic background from the Adriatic coast of Croatia. METHODOLOGY/PRINCIPAL FINDINGS: In a sample of 1304 individuals from the island population of Hvar, Croatia, we performed genome-wide SNP typing and assessed the variance explained by genetic scores constructed from different panels of height-associated SNPs extracted from five published studies. The combined information of the 180 SNPs reported by Lango Allen el al. explained 7.94% of phenotypic variation in our sample. Genetic scores based on 20~50 SNPs reported by the remaining individual GWA studies explained 3~5% of height variance. These percentages of variance explained were within ranges comparable to the original studies and heterogeneity tests did not detect significant differences in effect size estimates between our study and the original reports, if the estimates were obtained from populations of European descent. CONCLUSIONS/SIGNIFICANCE: We have evaluated the portability of height associated loci and the overall fitting of estimated effect sizes reported in large cohorts to an isolated population. We found proportions of explained height variability were comparable to multiple reference GWAS in cohorts of European descent. These results indicate similar genetic architecture and comparable effect sizes of height loci among populations of European descent. PMID- 22216290 TI - Attitudes toward and uptake of H1N1 vaccine among health care workers during the 2009 H1N1 pandemic. AB - BACKGROUND: Though recommended by many and mandated by some, influenza vaccination rates among health care workers, even in pandemics, remain below optimal levels. The objective of this study was to assess vaccination uptake, attitudes, and distinguishing characteristics (including doctor-nurse differences) of health care workers who did and did not receive the pandemic H1N1 influenza vaccine in late 2009. METHODOLOGY/PRINCIPAL FINDINGS: In early 2010 we mailed a self-administered survey to 800 physicians and 800 nurses currently licensed and practicing in Minnesota. 1,073 individuals responded (cooperation rate: 69%). 85% and 62% of Minnesota physicians and nurses, respectively, reported being vaccinated. Accurately estimating the risk of vaccine side effects (OR 2.0; 95% CI 1.5-2.7), agreeing with a professional obligation to be vaccinated (OR 10.1; 95% CI 7.1-14.2), an ethical obligation to follow public health authorities' recommendations (OR 9.9; 95% CI 6.6-14.9), and laws mandating pandemic vaccination (OR 3.1; 95% CI 2.3-4.1) were all independently associated with receiving the H1N1 influenza vaccine. CONCLUSIONS/SIGNIFICANCE: While a majority of health care workers in one midwestern state reported receiving the pandemic H1N1 vaccine, physicians and nurses differed significantly in vaccination uptake. Several key attitudes and perceptions may influence health care workers' decisions regarding vaccination. These data inform how states might optimally enlist health care workers' support in achieving vaccination goals during a pandemic. PMID- 22216291 TI - Association between IgM anti-herpes simplex virus and plasma amyloid-beta levels. AB - OBJECTIVE: Herpes simplex virus (HSV) reactivation has been identified as a possible risk factor for Alzheimer's disease (AD) and plasma amyloid-beta (Abeta) levels might be considered as possible biomarkers of the risk of AD. The aim of our study was to investigate the association between anti-HSV antibodies and plasma Abeta levels. METHODS: The study sample consisted of 1222 subjects (73.9 y in mean) from the Three-City cohort. IgM and IgG anti-HSV antibodies were quantified using an ELISA kit, and plasma levels of Abeta(1-40) and Abeta(1-42) were measured using an xMAP-based assay technology. Cross-sectional analyses of the associations between anti-HSV antibodies and plasma Abeta levels were performed by multi-linear regression. RESULTS: After adjustment for study center, age, sex, education, and apolipoprotein E-e4 polymorphism, plasma Abeta(1-42) and Abeta(1-40) levels were specifically inversely associated with anti-HSV IgM levels (beta = -20.7, P=0.001 and beta = -92.4, P=0.007, respectively). In a sub sample with information on CLU- and CR1-linked SNPs genotyping (n=754), additional adjustment for CR1 or CLU markers did not modify these associations (adjustment for CR1 rs6656401, beta = -25.6, P=0.002 for Abeta(1-42) and beta = 132.7, P=0.002 for Abeta(1-40;) adjustment for CLU rs2279590, beta = -25.6, P=0.002 for Abeta(1-42) and beta = -134.8, P=0.002 for Abeta(1-40)). No association between the plasma Abeta(1-42)-to-Abeta(1-40) ratio and anti-HSV IgM or IgG were evidenced. CONCLUSION: High anti-HSV IgM levels, markers of HSV reactivation, are associated with lower plasma Abeta(1-40) and Abeta(1-42) levels, which suggest a possible involvement of the virus in the alterations of the APP processing and potentially in the pathogenesis of AD in human. PMID- 22216292 TI - Characterization of fluorescent eye markers for mammalian transgenic studies. AB - Genotyping mice by DNA based methods is both laborious and costly. As an alternative, we systematically examined fluorescent proteins expressed in the lens as transgenic markers for mice. A set of eye markers has been selected such that double and triple transgenic animals can be visually identified and that fluorescence intensity in the eyes can be used to distinguish heterozygous from homozygous mice. Taken together, these eye markers dramatically reduce the time and cost of genotyping transgenics and empower analysis of genetic interaction. PMID- 22216293 TI - Selection against accumulating mutations in niche-preference genes can drive speciation. AB - Our current understanding of sympatric speciation is that it occurs primarily through disruptive selection on ecological genes driven by competition, followed by reproductive isolation through reinforcement-like selection against inferior intermediates/heterozygotes. Our evolutionary model of selection on resource recognition and preference traits suggests a new mechanism for sympatric speciation. We find speciation can occur in three phases. First a polymorphism of functionally different phenotypes is established through evolution of specialization. On the gene level, regulatory functions have evolved in which some alleles are conditionally switched off (i.e. are silent). These alleles accumulate harmful mutations that potentially may be expressed in offspring through recombination. Second mating associated with resource preference invades because harmful mutations in parents are not expressed in the offspring when mating assortatively, thereby dividing the population into two pre-zygotically isolated resource-specialist lineages. Third, silent alleles that evolved in phase one now accumulate deleterious mutations over the following generations in a Bateson-Dobzhansky-Muller fashion, establishing a post-zygotic barrier to hybridization. PMID- 22216294 TI - Extremely high Tp53 mutation load in esophageal squamous cell carcinoma in Golestan Province, Iran. AB - BACKGROUND: Golestan Province in northeastern Iran has one of the highest incidences of esophageal squamous cell carcinoma (ESCC) in the world with rates over 50 per 100,000 person-years in both sexes. We have analyzed TP53 mutation patterns in tumors from this high-risk geographic area in search of clues to the mutagenic processes involved in causing ESCC. METHODOLOGY/PRINCIPAL FINDINGS: Biopsies of 119 confirmed ESCC tumor tissue from subjects enrolled in a case control study conducted in Golestan Province were analyzed by direct sequencing of TP53 exons 2 through 11. Immunohistochemical staining for p53 was carried out using two monoclonal antibodies, DO7 and 1801. A total of 120 TP53 mutations were detected in 107/119 cases (89.9%), including 11 patients with double or triple mutations. The mutation pattern was heterogeneous with infrequent mutations at common TP53 "hotspots" but frequent transversions potentially attributable to environmental carcinogens forming bulky DNA adducts, including 40% at bases known as site of mutagenesis by polycyclic aromatic hydrocarbons (PAHs). Mutations showed different patterns according to the reported temperature of tea consumption, but no variation was observed in relation to ethnicity, tobacco or opium use, and alcoholic beverage consumption or urban versus rural residence. CONCLUSION/SIGNIFICANCE: ESCC tumors in people from Golestan Province show the highest rate of TP53 mutations ever reported in any cancer anywhere. The heterogeneous mutation pattern is highly suggestive of a causative role for multiple environmental carcinogens, including PAHs. The temperature and composition of tea may also influence mutagenesis. PMID- 22216295 TI - A-6G and A-20C polymorphisms in the angiotensinogen promoter and hypertension risk in Chinese: a meta-analysis. AB - BACKGROUND: Numerous studies in Chinese populations have evaluated the association between the A-6G and A-20C polymorphisms in the promoter region of angiotensinogen gene and hypertension. However, the results remain conflicting. We carried out a meta-analysis for these associations. METHODS AND RESULTS: Case control studies in Chinese and English publications were identified by searching the MEDLINE, EMBASE, CNKI, Wanfang, CBM, and VIP databases. The random-effects model was applied for dichotomous outcomes to combine the results of the individual studies. We finally selected 24 studies containing 5932 hypertensive patients and 5231 normotensive controls. Overall, we found significant association between the A-6G polymorphism and the decreased risk of hypertension in the dominant genetic model (AA+AG vs. GG: P=0.001, OR=0.71, 95%CI 0.57-0.87, P(heterogeneity)=0.96). The A-20C polymorphism was significantly associated with the increased risk for hypertension in the allele comparison (C vs. A: P=0.03, OR=1.14, 95%CI 1.02-1.27, P(heterogeneity)=0.92) and recessive genetic model (CC vs. CA+AA: P=0.005, OR=1.71, 95%CI 1.18-2.48, P(heterogeneity)=0.99). In the subgroup analysis by ethnicity, significant association was also found among Han Chinese for both A-6G and A-20C polymorphisms. A borderline significantly decreased risk of hypertension between A-6G and Chinese Mongolian was seen in the allele comparison (A vs. G: P=0.05, OR=0.79, 95%CI 0.62-1.00, P(heterogeneity)=0.84). CONCLUSION: Our meta-analysis indicated significant association between angiotensinogen promoter polymorphisms and hypertension in the Chinese populations, especially in Han Chinese. PMID- 22216296 TI - Phosphorylation of vasodilator-stimulated phosphoprotein (VASP) dampens hepatic ischemia-reperfusion injury. AB - Recent work has demonstrated that the formation of platelet neutrophil complexes (PNCs) affects inflammatory tissue injury. Vasodilator-stimulated phosphoprotein (VASP) is crucially involved into the control of PNC formation and myocardial reperfusion injury. Given the clinical importance of hepatic IR injury we pursued the role of VASP during hepatic ischemia followed by reperfusion. We report here that VASP(-/-) animals demonstrate reduced hepatic IR injury compared to wildtype (WT) controls. This correlated with serum levels of lactate dehydrogenase (LDH), aspartate (AST) and alanine (ALT) aminotransferase and the presence of PNCs within ischemic hepatic tissue and could be confirmed using repression of VASP through siRNA. In studies employing bone marrow chimeric mice we identified hematopoietic VASP to be of crucial importance for the extent of hepatic injury. Phosphorylation of VASP on Ser(153) through Prostaglandin E1 or on Ser(235) through atrial natriuretic peptide resulted in a significant reduction of hepatic IR injury. This was associated with a reduced presence of PNCs in ischemic hepatic tissue. Taken together, these studies identified VASP and VASP phosphorylation as crucial target for future hepatoprotective strategies. PMID- 22216297 TI - Identification of sequence variants in genetic disease-causing genes using targeted next-generation sequencing. AB - BACKGROUND: Identification of gene variants plays an important role in research on and diagnosis of genetic diseases. A combination of enrichment of targeted genes and next-generation sequencing (targeted DNA-HiSeq) results in both high efficiency and low cost for targeted sequencing of genes of interest. METHODOLOGY/PRINCIPAL FINDINGS: To identify mutations associated with genetic diseases, we designed an array-based gene chip to capture all of the exons of 193 genes involved in 103 genetic diseases. To evaluate this technology, we selected 7 samples from seven patients with six different genetic diseases resulting from six disease-causing genes and 100 samples from normal human adults as controls. The data obtained showed that on average, 99.14% of 3,382 exons with more than 30 fold coverage were successfully detected using Targeted DNA-HiSeq technology, and we found six known variants in four disease-causing genes and two novel mutations in two other disease-causing genes (the STS gene for XLI and the FBN1 gene for MFS) as well as one exon deletion mutation in the DMD gene. These results were confirmed in their entirety using either the Sanger sequencing method or real time PCR. CONCLUSIONS/SIGNIFICANCE: Targeted DNA-HiSeq combines next-generation sequencing with the capture of sequences from a relevant subset of high-interest genes. This method was tested by capturing sequences from a DNA library through hybridization to oligonucleotide probes specific for genetic disorder-related genes and was found to show high selectivity, improve the detection of mutations, enabling the discovery of novel variants, and provide additional indel data. Thus, targeted DNA-HiSeq can be used to analyze the gene variant profiles of monogenic diseases with high sensitivity, fidelity, throughput and speed. PMID- 22216298 TI - Novel patient cell-based HTS assay for identification of small molecules for a lysosomal storage disease. AB - Small molecules have been identified as potential therapeutic agents for lysosomal storage diseases (LSDs), inherited metabolic disorders caused by defects in proteins that result in lysosome dysfunctional. Some small molecules function assisting the folding of mutant misfolded lysosomal enzymes that are otherwise degraded in ER-associated degradation. The ultimate result is the enhancement of the residual enzymatic activity of the deficient enzyme. Most of the high throughput screening (HTS) assays developed to identify these molecules are single-target biochemical assays. Here we describe a cell-based assay using patient cell lines to identify small molecules that enhance the residual arylsulfatase A (ASA) activity found in patients with metachromatic leukodystrophy (MLD), a progressive neurodegenerative LSD. In order to generate sufficient cell lines for a large scale HTS, primary cultured fibroblasts from MLD patients were transformed using SV40 large T antigen. These SV40 transformed (SV40t) cells showed to conserve biochemical characteristics of the primary cells. Using a specific colorimetric substrate para-nitrocatechol sulfate (pNCS), detectable ASA residual activity were observed in primary and SV40t fibroblasts from a MLD patient (ASA-I179S) cultured in multi-well plates. A robust fluorescence ASA assay was developed in high-density 1,536-well plates using the traditional colorimetric pNCS substrate, whose product (pNC) acts as "plate fluorescence quencher" in white solid-bottom plates. The quantitative cell-based HTS assay for ASA generated strong statistical parameters when tested against a diverse small molecule collection. This cell-based assay approach can be used for several other LSDs and genetic disorders, especially those that rely on colorimetric substrates which traditionally present low sensitivity for assay miniaturization. In addition, the quantitative cell-based HTS assay here developed using patient cells creates an opportunity to identify therapeutic small molecules in a disease-cellular environment where potentially disrupted pathways are exposed and available as targets. PMID- 22216299 TI - Development of shuttle vectors for transformation of diverse Rickettsia species. AB - Plasmids have been identified in most species of Rickettsia examined, with some species maintaining multiple different plasmids. Three distinct plasmids were demonstrated in Rickettsia amblyommii AaR/SC by Southern analysis using plasmid specific probes. Copy numbers of pRAM18, pRAM23 and pRAM32 per chromosome in AaR/SC were estimated by real-time PCR to be 2.0, 1.9 and 1.3 respectively. Cloning and sequencing of R. amblyommii AaR/SC plasmids provided an opportunity to develop shuttle vectors for transformation of rickettsiae. A selection cassette encoding rifampin resistance and a fluorescent marker was inserted into pRAM18 yielding a 27.6 kbp recombinant plasmid, pRAM18/Rif/GFPuv. Electroporation of Rickettsia parkeri and Rickettsia bellii with pRAM18/Rif/GFPuv yielded GFPuv expressing rickettsiae within 2 weeks. Smaller vectors, pRAM18dRG, pRAM18dRGA and pRAM32dRGA each bearing the same selection cassette, were made by moving the parA and dnaA-like genes from pRAM18 or pRAM32 into a vector backbone. R. bellii maintained the highest numbers of pRAM18dRGA (13.3 - 28.1 copies), and R. parkeri, Rickettsia monacensis and Rickettsia montanensis contained 9.9, 5.5 and 7.5 copies respectively. The same species transformed with pRAM32dRGA maintained 2.6, 2.5, 3.2 and 3.6 copies. pRM, the plasmid native to R. monacensis, was still present in shuttle vector transformed R. monacensis at a level similar to that found in wild type R. monacensis after 15 subcultures. Stable transformation of diverse rickettsiae was achieved with a shuttle vector system based on R. amblyommii plasmids pRAM18 and pRAM32, providing a new research tool that will greatly facilitate genetic and biological studies of rickettsiae. PMID- 22216300 TI - Role of zebrafish lbx2 in embryonic lateral line development. AB - BACKGROUND: The zebrafish ladybird homeobox homologous gene 2 (lbx2) has been suggested to play a key role in the regulation of hypaxial myogenic precursor cell migration. Unlike their lbx counterparts in mammals, the function of teleost lbx genes beyond myogenesis during embryonic development remains unexplored. PRINCIPAL FINDINGS: Abrogation of lbx2 function using a specific independent morpholino oligonucleotide (MO) or truncated lbx2 mRNA with an engrailed domain deletion (lbx2(eh-)) resulted in defective formation of the zebrafish posterior lateral line (PLL). Migration of the PLL primordium was altered and accompanied by increased cell death in the primordium of lbx2-MO-injected embryos. A decreased number of muscle pioneer cells and impaired expression pattern of sdf1a in the horizontal myoseptum was observed in lbx2 morphants. SIGNIFICANCE: Injection of lbx2 MO or lbx2(eh-) mRNA resulted in defective PPL formation and altered sdf1a expression, confirming an important function for lbx2 in sdf1a dependent migration. In addition, the disassociation of PPL nerve extension with PLL primordial migration in some lbx2 morphants suggests that pathfinding of the PLL primordium and the lateral line nerve may be regulated independently. PMID- 22216301 TI - Polysialic acid is required for dopamine D2 receptor-mediated plasticity involving inhibitory circuits of the rat medial prefrontal cortex. AB - Decreased expression of dopamine D2 receptors (D2R), dysfunction of inhibitory neurotransmission and impairments in the structure and connectivity of neurons in the medial prefrontal cortex (mPFC) are involved in the pathogenesis of schizophrenia and major depression, but the relationship between these changes remains unclear. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a plasticity-related molecule, may serve as a link. This molecule is expressed in cortical interneurons and dopamine, via D2R, modulates its expression in parallel to that of proteins related to synapses and inhibitory neurotransmission, suggesting that D2R-targeted antipsychotics/antidepressants may act by affecting the plasticity of mPFC inhibitory circuits. To understand the role of PSA-NCAM in this plasticity, rats were chronically treated with a D2R agonist (PPHT) after cortical PSA depletion. PPHT-induced increases in GAD67 and synaptophysin (SYN) neuropil expression were blocked when PSA was previously removed, indicating a role for PSA-NCAM in this plasticity. The number of PSA NCAM expressing interneuron somata also increased after PPHT treatment, but the percentages of these cells belonging to different interneuronal subpopulations did not change. Cortical pyramidal neurons did not express PSA-NCAM, but puncta co-expressing this molecule and parvalbumin could be found surrounding their somata. PPHT treatment increased the number of PSA-NCAM and parvalbumin expressing perisomatic puncta, but decreased the percentage of parvalbumin puncta that co-expressed SYN. PSA depletion did not block these effects on the perisomatic region, but increased further the number of parvalbumin expressing puncta and increased the percentage of puncta co-expressing SYN and parvalbumin, suggesting that the polysialylation of NCAM may regulate perisomatic inhibition of mPFC principal neurons. Summarizing, the present results indicate that dopamine acting on D2R influences structural plasticity of mPFC interneurons and point to PSA-NCAM as a key player in this remodeling. PMID- 22216302 TI - Multiple polymorphisms affect expression and function of the neuropeptide S receptor (NPSR1). AB - BACKGROUND: neuropeptide S (NPS) and its receptor NPSR1 act along the hypothalamic-pituitary-adrenal axis to modulate anxiety, fear responses, nociception and inflammation. The importance of the NPS-NPSR1 signaling pathway is highlighted by the observation that, in humans, NPSR1 polymorphism associates with asthma, inflammatory bowel disease, rheumatoid arthritis, panic disorders, and intermediate phenotypes of functional gastrointestinal disorders. Because of the genetic complexity at the NPSR1 locus, however, true causative variations remain to be identified, together with their specific effects on receptor expression or function. To gain insight into the mechanisms leading to NPSR1 disease-predisposing effects, we performed a thorough functional characterization of all NPSR1 promoter and coding SNPs commonly occurring in Caucasians (minor allele frequency >0.02). PRINCIPAL FINDINGS: we identified one promoter SNP (rs2530547 [-103]) that significantly affects luciferase expression in gene reporter assays and NPSR1 mRNA levels in human leukocytes. We also detected quantitative differences in NPS-induced genome-wide transcriptional profiles and CRE-dependent luciferase activities associated with three NPSR1 non-synonymous SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]), with a coding variant exhibiting a loss-of-function phenotype (197Phe). Potential mechanistic explanations were sought with molecular modelling and bioinformatics, and a pilot study of 2230 IBD cases and controls provided initial support to the hypothesis that different cis-combinations of these functional SNPs variably affect disease risk. SIGNIFICANCE: these findings represent a first step to decipher NPSR1 locus complexity and its impact on several human conditions NPS antagonists have been recently described, and our results are of potential pharmacogenetic relevance. PMID- 22216303 TI - Functional polymorphism of IL-1 alpha and its potential role in obesity in humans and mice. AB - Proinflammatory cytokines secreted from adipose tissue contribute to the morbidity associated with obesity. IL-1alpha is one of the proinflammatory cytokines; however, it has not been clarified whether IL-1alpha may also cause obesity. In this study, we investigated whether polymorphisms in IL-1alpha contribute to human obesity. A total of 260 obese subjects were genotyped for IL 1alpha C-889T (rs1800587) and IL-1alpha G+4845T (rs17561). Analyses of genotype distributions revealed that both IL-1alpha polymorphisms C-889T (rs1800587) and G+4845T (rs17561) were associated with an increase in body mass index in obese healthy women. In addition, the effect of rs1800587 on the transcriptional activity of IL-1alpha was explored in pre-adipocyte 3T3-L1 cells. Significant difference was found between the rs1800587 polymorphism in the regulatory region of the IL-1alpha gene and transcriptional activity. We extended these observations in vivo to a high-fat diet-induced obese mouse model and in vitro to pre-adipocyte 3T3-L1 cells. IL-1alpha levels were dramatically augmented in obese mice, and triglyceride was increased 12 hours after IL-1alpha injection. Taken together, IL-1alpha treatment regulated the differentiation of preadipocytes. IL 1alpha C-889T (rs1800587) is a functional polymorphism of IL-1alpha associated with obesity. IL-1alpha may have a critical function in the development of obesity. PMID- 22216304 TI - Aminoacyl-tRNA-charged eukaryotic elongation factor 1A is the bona fide substrate for Legionella pneumophila effector glucosyltransferases. AB - Legionella pneumophila, which is the causative organism of Legionnaires disease, translocates numerous effector proteins into the host cell cytosol by a type IV secretion system during infection. Among the most potent effector proteins of Legionella are glucosyltransferases (lgt's), which selectively modify eukaryotic elongation factor (eEF) 1A at Ser-53 in the GTP binding domain. Glucosylation results in inhibition of protein synthesis. Here we show that in vitro glucosylation of yeast and mouse eEF1A by Lgt3 in the presence of the factors Phe tRNA(Phe) and GTP was enhanced 150 and 590-fold, respectively. The glucosylation of eEF1A catalyzed by Lgt1 and 2 was increased about 70-fold. By comparison of uncharged tRNA with two distinct aminoacyl-tRNAs (His-tRNA(His) and Phe tRNA(Phe)) we could show that aminoacylation is crucial for Lgt-catalyzed glucosylation. Aminoacyl-tRNA had no effect on the enzymatic properties of lgt's and did not enhance the glucosylation rate of eEF1A truncation mutants, consisting of the GTPase domain only or of a 5 kDa peptide covering Ser-53 of eEF1A. Furthermore, binding of aminoacyl-tRNA to eEF1A was not altered by glucosylation. Taken together, our data suggest that the ternary complex, consisting of eEF1A, aminoacyl-tRNA and GTP, is the bona fide substrate for lgt's. PMID- 22216305 TI - Psychophysiological correlates of sexually and non-sexually motivated attention to film clips in a workload task. AB - Some authors have speculated that the cognitive component (P3) of the Event Related Potential (ERP) can function as a psychophysiological measure of sexual interest. The aim of this study was to determine if the P3 ERP component in a workload task can be used as a specific and objective measure of sexual motivation by comparing the neurophysiologic response to stimuli of motivational relevance with different levels of valence and arousal. A total of 30 healthy volunteers watched different films clips with erotic, horror, social-positive and social-negative content, while answering an auditory oddball paradigm. Erotic film clips resulted in larger interference when compared to both the social positive and auditory alone conditions. Horror film clips resulted in the highest levels of interference with smaller P3 amplitudes than erotic and also than social-positive, social-negative and auditory alone condition. No gender differences were found. Both horror and erotic film clips significantly decreased heart rate (HR) when compared to both social-positive and social-negative films. The erotic film clips significantly increased the skin conductance level (SCL) compared to the social-negative films. The horror film clips significantly increased the SCL compared to both social-positive and social-negative films. Both the highly arousing erotic and non-erotic (horror) movies produced the largest decrease in the P3 amplitude, a decrease in the HR and an increase in the SCL. These data support the notion that this workload task is very sensitive to the attentional resources allocated to the film clip, although they do not act as a specific index of sexual interest. Therefore, the use of this methodology seems to be of questionable utility as a specific measure of sexual interest or as an objective measure of the severity of Hypoactive Sexual Desire Disorder. PMID- 22216306 TI - Comprehensive serum profiling for the discovery of epithelial ovarian cancer biomarkers. AB - FDA-cleared ovarian cancer biomarkers are limited to CA-125 and HE4 for monitoring and recurrence and OVA1, a multivariate panel consisting of CA-125 and four additional biomarkers, for referring patients to a specialist. Due to relatively poor performance of these tests, more accurate and broadly applicable biomarkers are needed. We evaluated the dysregulation of 259 candidate cancer markers in serum samples from 499 patients. Sera were collected prospectively at 11 monitored sites under a single well-defined protocol. All stages of ovarian cancer and common benign gynecological conditions were represented. To ensure consistency and comparability of biomarker comparisons, all measurements were performed on a single platform, at a single site, using a panel of rigorously calibrated, qualified, high-throughput, multiplexed immunoassays and all analyses were conducted using the same software. Each marker was evaluated independently for its ability to differentiate ovarian cancer from benign conditions. A total of 175 markers were dysregulated in the cancer samples. HE4 (AUC=0.933) and CA 125 (AUC=0.907) were the most informative biomarkers, followed by IL-2 receptor alpha, alpha1-antitrypsin, C-reactive protein, YKL-40, cellular fibronectin, CA 72-4 and prostasin (AUC>0.800). To improve the discrimination between cancer and benign conditions, a simple multivariate combination of markers was explored using logistic regression. When combined into a single panel, the nine most informative individual biomarkers yielded an AUC value of 0.950, significantly higher than obtained when combining the markers in the OVA1 panel (AUC 0.912). Additionally, at a threshold sensitivity of 90%, the combination of the top 9 markers gave 88.9% specificity compared to 63.4% specificity for the OVA1 markers. Although a blinded validation study has not yet been performed, these results indicate that alternative biomarker combinations might lead to significant improvements in the detection of ovarian cancer. PMID- 22216307 TI - A connection between colony biomass and death in Caribbean reef-building corals. AB - Increased sea-surface temperatures linked to warming climate threaten coral reef ecosystems globally. To better understand how corals and their endosymbiotic dinoflagellates (Symbiodinium spp.) respond to environmental change, tissue biomass and Symbiodinium density of seven coral species were measured on various reefs approximately every four months for up to thirteen years in the Upper Florida Keys, United States (1994-2007), eleven years in the Exuma Cays, Bahamas (1995-2006), and four years in Puerto Morelos, Mexico (2003-2007). For six out of seven coral species, tissue biomass correlated with Symbiodinium density. Within a particular coral species, tissue biomasses and Symbiodinium densities varied regionally according to the following trends: Mexico>=Florida Keys>=Bahamas. Average tissue biomasses and symbiont cell densities were generally higher in shallow habitats (1-4 m) compared to deeper-dwelling conspecifics (12-15 m). Most colonies that were sampled displayed seasonal fluctuations in biomass and endosymbiont density related to annual temperature variations. During the bleaching episodes of 1998 and 2005, five out of seven species that were exposed to unusually high temperatures exhibited significant decreases in symbiotic algae that, in certain cases, preceded further decreases in tissue biomass. Following bleaching, Montastraea spp. colonies with low relative biomass levels died, whereas colonies with higher biomass levels survived. Bleaching- or disease associated mortality was also observed in Acropora cervicornis colonies; compared to A. palmata, all A. cervicornis colonies experienced low biomass values. Such patterns suggest that Montastraea spp. and possibly other coral species with relatively low biomass experience increased susceptibility to death following bleaching or other stressors than do conspecifics with higher tissue biomass levels. PMID- 22216308 TI - Nanotube action between human mesothelial cells reveals novel aspects of inflammatory responses. AB - A well-known role of human peritoneal mesothelial cells (HPMCs), the resident cells of the peritoneal cavity, is the generation of an immune response during peritonitis by activation of T-cells via antigen presentation. Recent findings have shown that intercellular nanotubes (NTs) mediate functional connectivity between various cell types including immune cells - such as T-cells, natural killer (NK) cells or macrophages - by facilitating a spectrum of long range cell cell interactions. Although of medical interest, the relevance of NT-related findings for human medical conditions and treatment, e.g. in relation to inflammatory processes, remains elusive, particularly due to a lack of appropriate in vivo data. Here, we show for the first time that primary cultures of patient derived HPMCs are functionally connected via membranous nanotubes. NT formation appears to be actin cytoskeleton dependent, mediated by the action of filopodia. Importantly, significant variances in NT numbers between different donors as a consequence of pathophysiological alterations were observable. Furthermore, we show that TNF-alpha induces nanotube formation and demonstrate a strong correlation of NT connectivity in accordance with the cellular cholesterol level and distribution, pointing to a complex involvement of NTs in inflammatory processes with potential impact for clinical treatment. PMID- 22216310 TI - Visceral artery aneurysms in liver transplant candidates and in patients after liver transplantation. AB - There are only few reviews concerning visceral aneurysms in cirrhotics, and a small number of papers on visceral aneurysms in liver transplant patients. The present paper investigates this condition in both groups of patients in a 10-year retrospective study. PMID- 22216309 TI - The cytokine release inhibitory drug CRID3 targets ASC oligomerisation in the NLRP3 and AIM2 inflammasomes. AB - BACKGROUND: The Inflammasomes are multi-protein complexes that regulate caspase-1 activation and the production of the pro-inflammatory cytokine IL-1beta. Previous studies identified a class of diarylsulfonylurea containing compounds called Cytokine Release Inhibitory Drugs (CRIDs) that inhibited the post-translational processing of IL-1beta. Further work identified Glutathione S-Transferase Omega 1 (GSTO1) as a possible target of these CRIDs. This study aimed to investigate the mechanism of the inhibitory activity of the CRID CP-456,773 (termed CRID3) in light of recent advances in the area of inflammasome activation, and to clarify the potential role of GSTO1 in the regulation of IL-1beta production. METHODOLOGY AND RESULTS: In murine bone marrow derived macrophages, CRID3 inhibited IL-1beta secretion and caspase 1 processing in response to stimulation of NLRP3 and AIM2 but not NLRC4. CRID3 also prevented AIM2 dependent pyroptosis in contrast to the NLRP3 inhibitors glyburide and parthenolide, which do not inhibit AIM2 activation. Confocal microscopy and Western blotting assays indicated that CRID3 inhibited the formation of ASC complexes or 'specks' in response to NLRP3 and AIM2 stimulation. Co-immunoprecipitation assays show that GSTO1 interacted with ASC. SIGNIFICANCE: These results identify CRID3 as a novel inhibitor of the NLRP3 and AIM2 inflammasomes and provide an insight into the mechanism of action of this small molecule. In addition GSTO1 may be a component of the inflammasome that is required for ASC complex formation. PMID- 22216311 TI - Seropositivity and risk factors associated with Toxoplasma gondii infection in wild birds from Spain. AB - Toxoplasma gondii is a zoonotic intracellular protozoan parasite of worldwide distribution that infects many species of warm-blooded animals, including birds. To date, there is scant information about the seropositivity of T. gondii and the risk factors associated with T. gondii infection in wild bird populations. In the present study, T. gondii infection was evaluated on sera obtained from 1079 wild birds belonging to 56 species (including Falconiformes (n=610), Strigiformes (n=260), Ciconiiformes (n=156), Gruiformes (n=21), and other orders (n=32), from different areas of Spain. Antibodies to T. gondii (modified agglutination test, MAT titer >=1:25) were found in 282 (26.1%, IC(95%:)23.5-28.7) of the 1079 birds. This study constitute the first extensive survey in wild birds species in Spain and reports for the first time T. gondii antibodies in the griffon vulture (Gyps fulvus), short-toed snake-eagle (Circaetus gallicus), Bonelli's eagle (Aquila fasciata), golden eagle (Aquila chrysaetos), bearded vulture (Gypaetus barbatus), osprey (Pandion haliaetus), Montagu's harrier (Circus pygargus), Western marsh harrier (Circus aeruginosus), peregrine falcon (Falco peregrinus), long-eared owl (Asio otus), common scops owl (Otus scops), Eurasian spoonbill (Platalea leucorodia), white stork (Ciconia ciconia), grey heron (Ardea cinerea), common moorhen (Gallinula chloropus); in the International Union for Conservation of Nature (IUCN) "vulnerable" Spanish imperial eagle (Aquila adalberti), lesser kestrel (Falco naumanni) and great bustard (Otis tarda); and in the IUCN "near threatened" red kite (Milvus milvus). The highest seropositivity by species was observed in the Eurasian eagle owl (Bubo bubo) (68.1%, 98 of 144). The main risk factors associated with T. gondii seropositivity in wild birds were age and diet, with the highest exposure in older animals and in carnivorous wild birds. The results showed that T. gondii infection is widespread and can be at a high level in many wild birds in Spain, most likely related to their feeding behaviour. PMID- 22216312 TI - Intranasal immunization of the combined lipooligosaccharide conjugates protects mice from the challenges with three serotypes of Moraxella catarrhalis. AB - BACKGROUND: There are no licensed vaccines available against Moraxella catarrhalis, a significant human respiratory pathogen. Lipooligosaccharide (LOS) based conjugate vaccines derived from individual serotype M. catarrhalis only showed partial protection coverage. A vaccine combining LOS conjugates of two or three serotypes might provide a broader protection. METHODS: Mice were immunized intranasally with the combined conjugates consisting of LOS from serotype A and B or serotype A, B, and C followed by challenge with different M. catarrhalis strains of three serotypes. Mouse lungs, nasal washes, and sera were collected after each challenge for bacterial counts, histological evaluation, cytokine profiles, antibody level and binding activity determinations. RESULTS: Intranasal administration of the combined LOS conjugates not only enhanced pulmonary bacterial clearance of all three serotypes of M. catarrhalis strains in vaccinated mice, but also elevated serotype-specific anti-LOS immunoglobulin (Ig)A and IgG titers in nasal wash and serum respectively. Mice vaccinated with the combined LOS conjugates also showed increased interferon (IFN)-gamma, interleukin (IL)-12, and IL-4 in the lungs after challenges. Compared to the control group, mice immunized with the combined LOS conjugates also showed reduced lung inflammation after M. catarrhalis infections. The hyperimmune sera induced by the combined conjugates exhibited a broad cross-reactivity toward all three serotypes of M. catarrhalis under transmission electron microscopy. CONCLUSIONS: The combined vaccine of serotype A and B LOS conjugates provides protection against most M. catarrhalis strains by eliciting humoral and cellular immune responses. PMID- 22216313 TI - Recent emergence of dengue virus serotype 4 in French Polynesia results from multiple introductions from other South Pacific Islands. AB - BACKGROUND: Infection by dengue virus (DENV) is a major public health concern in hundreds of tropical and subtropical countries. French Polynesia (FP) regularly experiences epidemics that initiate, or are consecutive to, DENV circulation in other South Pacific Island Countries (SPICs). In January 2009, after a decade of serotype 1 (DENV-1) circulation, the first cases of DENV-4 infection were reported in FP. Two months later a new epidemic emerged, occurring about 20 years after the previous circulation of DENV-4 in FP. In this study, we investigated the epidemiological and molecular characteristics of the introduction, spread and genetic microevolution of DENV-4 in FP. METHODOLOGY/PRINCIPAL FINDINGS: Epidemiological data suggested that recent transmission of DENV-4 in FP started in the Leeward Islands and this serotype quickly displaced DENV-1 throughout FP. Phylogenetic analyses of the nucleotide sequences of the envelope (E) gene of 64 DENV-4 strains collected in FP in the 1980s and in 2009-2010, and some additional strains from other SPICs showed that DENV-4 strains from the SPICs were distributed into genotypes IIa and IIb. Recent FP strains were distributed into two clusters, each comprising viruses from other but distinct SPICs, suggesting that emergence of DENV-4 in FP in 2009 resulted from multiple introductions. Otherwise, we observed that almost all strains collected in the SPICs in the 1980s exhibit an amino acid (aa) substitution V287I within domain I of the E protein, and all recent South Pacific strains exhibit a T365I substitution within domain III. CONCLUSIONS/SIGNIFICANCE: This study confirmed the cyclic re emergence and displacement of DENV serotypes in FP. Otherwise, our results showed that specific aa substitutions on the E protein were present on all DENV-4 strains circulating in SPICs. These substitutions probably acquired and subsequently conserved could reflect a founder effect to be associated with epidemiological, geographical, eco-biological and social specificities in SPICs. PMID- 22216314 TI - Prediction of high-grade vesicoureteral reflux after pediatric urinary tract infection: external validation study of procalcitonin-based decision rule. AB - BACKGROUND: Predicting vesico-ureteral reflux (VUR) >=3 at the time of the first urinary tract infection (UTI) would make it possible to restrict cystography to high-risk children. We previously derived the following clinical decision rule for that purpose: cystography should be performed in cases with ureteral dilation and a serum procalcitonin level >=0.17 ng/mL, or without ureteral dilatation when the serum procalcitonin level >=0.63 ng/mL. The rule yielded a 86% sensitivity with a 46% specificity. We aimed to test its reproducibility. STUDY DESIGN: A secondary analysis of prospective series of children with a first UTI. The rule was applied, and predictive ability was calculated. RESULTS: The study included 413 patients (157 boys, VUR >=3 in 11%) from eight centers in five countries. The rule offered a 46% specificity (95% CI, 41-52), not different from the one in the derivation study. However, the sensitivity significantly decreased to 64% (95%CI, 50-76), leading to a difference of 20% (95%CI, 17-36). In all, 16 (34%) patients among the 47 with VUR >=3 were misdiagnosed by the rule. This lack of reproducibility might result primarily from a difference between derivation and validation populations regarding inflammatory parameters (CRP, PCT); the validation set samples may have been collected earlier than for the derivation one. CONCLUSIONS: The rule built to predict VUR >=3 had a stable specificity (ie. 46%), but a decreased sensitivity (ie. 64%) because of the time variability of PCT measurement. Some refinement may be warranted. PMID- 22216315 TI - Oxygen: a fundamental property regulating pelagic ecosystem structure in the coastal southeastern tropical Pacific. AB - BACKGROUND: In the southeastern tropical Pacific anchovy (Engraulis ringens) and sardine (Sardinops sagax) abundance have recently fluctuated on multidecadal scales and food and temperature have been proposed as the key parameters explaining these changes. However, ecological and paleoecological studies, and the fact that anchovies and sardines are favored differently in other regions, raise questions about the role of temperature. Here we investigate the role of oxygen in structuring fish populations in the Peruvian upwelling ecosystem that has evolved over anoxic conditions and is one of the world's most productive ecosystems in terms of forage fish. This study is particularly relevant given that the distribution of oxygen in the ocean is changing with uncertain consequences. METHODOLOGY/PRINCIPAL FINDINGS: A comprehensive data set is used to show how oxygen concentration and oxycline depth affect the abundance and distribution of pelagic fish. We show that the effects of oxygen on anchovy and sardine are opposite. Anchovy flourishes under relatively low oxygen conditions while sardine avoid periods/areas with low oxygen concentration and restricted habitat. Oxygen consumption, trophic structure and habitat compression play a fundamental role in fish dynamics in this important ecosystem. CONCLUSIONS/SIGNIFICANCE: For the ocean off Peru we suggest that a key process, the need to breathe, has been neglected previously. Inclusion of this missing piece allows the development of a comprehensive conceptual model of pelagic fish populations and change in an ocean ecosystem impacted by low oxygen. Should current trends in oxygen in the ocean continue similar effects may be evident in other coastal upwelling ecosystems. PMID- 22216316 TI - Risk of tuberculosis in dialysis patients: a nationwide cohort study. AB - BACKGROUND: The ability to identify individuals at increased risk of developing tuberculosis (TB) has important implications for public health policy and patient care. We conducted a general population historical cohort study in all Australian States and Territories to establish the risk of TB arising in people on chronic hemo- or peritoneal dialysis. METHODOLOGY/PRINCIPAL FINDINGS: Cases of TB disease in patients receiving chronic dialysis were identified by record linkage using the Australia & New Zealand Dialysis and Transplant Registry (ANZDATA) and State and Territory TB notification databases 2001 to 2006. Main outcome measure was the relative risk of TB in people on dialysis, adjusted for TB incidence in country of birth, sex, age and indigenous status. A total of 6,276 cases of active TB were reported among 19,855,283 people living in Australia between 2001 and 2006. Among 14,506 patients on dialysis, 37 had a notification for TB disease after commencing dialysis, of whom 28 were culture positive. The incidence of TB was 66.8/100,000/year (95% CI 47.7 to 93.2) among people on dialysis and 5.7/100,000/year (95% CI 5.5 to 5.8) in the general population. The adjusted relative risk (aRR) of TB in people on dialysis was 7.8 (95% CI 3.3 to 18.7), and the aRR of culture positive TB was 8.6 (95% CI 3.9 to 19.3). CONCLUSIONS/SIGNIFICANCE: Patients on dialysis are at increased risk of TB. The final decision to screen for, and to treat, LTBI in individual dialysis patients will be influenced by a cumulative assessment of the risk of reactivation of TB and by assessment of risk factors for adverse effects of treatment. PMID- 22216317 TI - The Mycobacterium tuberculosis FAS-II dehydratases and methyltransferases define the specificity of the mycolic acid elongation complexes. AB - BACKGROUND: The human pathogen Mycobacterium tuberculosis (Mtb) has the originality of possessing a multifunctional mega-enzyme FAS-I (Fatty Acid Synthase-I), together with a multi-protein FAS-II system, to carry out the biosynthesis of common and of specific long chain fatty acids: the mycolic acids (MA). MA are the main constituents of the external mycomembrane that represents a tight permeability barrier involved in the pathogenicity of Mtb. The MA biosynthesis pathway is essential and contains targets for efficient antibiotics. We have demonstrated previously that proteins of FAS-II interact specifically to form specialized and interconnected complexes. This finding suggested that the organization of FAS-II resemble to the architecture of multifunctional mega enzyme like the mammalian mFAS-I, which is devoted to the fatty acid biosynthesis. PRINCIPAL FINDINGS: Based on conventional and reliable studies using yeast-two hybrid, yeast-three-hybrid and in vitro Co-immunoprecipitation, we completed here the analysis of the composition and architecture of the interactome between the known components of the Mtb FAS-II complexes. We showed that the recently identified dehydratases HadAB and HadBC are part of the FAS-II elongation complexes and may represent a specific link between the core of FAS-II and the condensing enzymes of the system. By testing four additional methyltransferases involved in the biosynthesis of mycolic acids, we demonstrated that they display specific interactions with each type of complexes suggesting their coordinated action during MA elongation. SIGNIFICANCE: These results provide a global update of the architecture and organization of a FAS-II system. The FAS-II system of Mtb is organized in specialized interconnected complexes and the specificity of each elongation complex is given by preferential interactions between condensing enzymes and dehydratase heterodimers. This study will probably allow defining essential and specific interactions that correspond to promising targets for Mtb FAS-II inhibitors. PMID- 22216318 TI - Phosphorylation state-dependent interactions of hepadnavirus core protein with host factors. AB - Dynamic phosphorylation and dephosphorylation of the hepadnavirus core protein C terminal domain (CTD) are required for multiple steps of the viral life cycle. It remains unknown how the CTD phosphorylation state may modulate core protein functions but phosphorylation state-dependent viral or host interactions may play a role. In an attempt to identify host factors that may interact differentially with the core protein depending on its CTD phosphorylation state, pulldown assays were performed using the CTD of the duck hepatitis B virus (DHBV) and human hepatitis B virus (HBV) core protein, either with wild type (WT) sequences or with alanine or aspartic acid substitutions at the phosphorylation sites. Two host proteins, B23 and I2PP2A, were found to interact preferentially with the alanine-substituted CTD. Furthermore, the WT CTD became competent to interact with the host proteins upon dephosphorylation. Intriguingly, the binding site on the DHBV CTD for both B23 and I2PP2A was mapped to a region upstream of the phosphorylation sites even though B23 or I2PP2A binding to this site was clearly modulated by the phosphorylation state of the downstream and non-overlapping sequences. Together, these results demonstrate a novel mode of phosphorylation regulated protein-protein interaction and provide new insights into virus-host interactions. PMID- 22216319 TI - Epithelial cells derived from swine bone marrow express stem cell markers and support influenza virus replication in vitro. AB - The bone marrow contains heterogeneous population of cells that are involved in the regeneration and repair of diseased organs, including the lungs. In this study, we isolated and characterized progenitor epithelial cells from the bone marrow of 4- to 5-week old germ-free pigs. Microscopically, the cultured cells showed epithelial-like morphology. Phenotypically, these cells expressed the stem cell markers octamer-binding transcription factor (Oct4) and stage-specific embryonic antigen-1 (SSEA-1), the alveolar stem cell marker Clara cell secretory protein (Ccsp), and the epithelial cell markers pan-cytokeratin (Pan-K), cytokeratin-18 (K-18), and occludin. When cultured in epithelial cell growth medium, the progenitor epithelial cells expressed type I and type II pneumocyte markers. Next, we examined the susceptibility of these cells to influenza virus. Progenitor epithelial cells expressed sialic acid receptors utilized by avian and mammalian influenza viruses and were targets for influenza virus replication. Additionally, differentiated type II but not type I pneumocytes supported the replication of influenza virus. Our data indicate that we have identified a unique population of progenitor epithelial cells in the bone marrow that might have airway reconstitution potential and may be a useful model for cell-based therapies for infectious and non-infectious lung diseases. PMID- 22216320 TI - Translocated LPS might cause endotoxin tolerance in circulating monocytes of cystic fibrosis patients. AB - Cystic Fibrosis (CF) is an inherited pleiotropic disease that results from abnormalities in the gene codes of a chloride channel. The lungs of CF patients are chronically infected by several pathogens but bacteraemia have rarely been reported in this pathology. Besides that, circulating monocytes in CF patients exhibit a patent Endotoxin Tolerance (ET) state since they show a significant reduction of the inflammatory response to bacterial stimulus. Despite a previous description of this phenomenon, the direct cause of ET in CF patients remains unknown. In this study we have researched the possible role of microbial/endotoxin translocation from a localized infection to the bloodstream as a potential cause of ET induction in CF patients. Plasma analysis of fourteen CF patients revealed high levels of LPS compared to healthy volunteers and patients who suffer from Chronic Obstructive Pulmonary Disease. Experiments in vitro showed that endotoxin concentrations found in plasma of CF patients were enough to induce an ET phenotype in monocytes from healthy controls. In agreement with clinical data, we failed to detect bacterial DNA in CF plasma. Our results suggest that soluble endotoxin present in bloodstream of CF patients causes endotoxin tolerance in their circulating monocytes. PMID- 22216321 TI - Design and implementation of degenerate microsatellite primers for the mammalian clade. AB - Microsatellites are popular genetic markers in molecular ecology, genetic mapping and forensics. Unfortunately, despite recent advances, the isolation of de novo polymorphic microsatellite loci often requires expensive and intensive groundwork. Primers developed for a focal species are commonly tested in a related, non-focal species of interest for the amplification of orthologous polymorphic loci; when successful, this approach significantly reduces cost and time of microsatellite development. However, transferability of polymorphic microsatellite loci decreases rapidly with increasing evolutionary distance, and this approach has shown its limits. Whole genome sequences represent an under exploited resource to develop cross-species primers for microsatellites. Here we describe a three-step method that combines a novel in silico pipeline that we use to (1) identify conserved microsatellite loci from a multiple genome alignments, (2) design degenerate primer pairs, with (3) a simple PCR protocol used to implement these primers across species. Using this approach we developed a set of primers for the mammalian clade. We found 126,306 human microsatellites conserved in mammalian aligned sequences, and isolated 5,596 loci using criteria based on wide conservation. From a random subset of ~1000 dinucleotide repeats, we designed degenerate primer pairs for 19 loci, of which five produced polymorphic fragments in up to 18 mammalian species, including the distinctly related marsupials and monotremes, groups that diverged from other mammals 120-160 million years ago. Using our method, many more cross-clade microsatellite loci can be harvested from the currently available genomic data, and this ability is set to improve exponentially as further genomes are sequenced. PMID- 22216322 TI - Effects of 3,4-methylenedioxymethamphetamine administration on retinal physiology in the rat. AB - 3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is known to produce euphoric states, but may also cause adverse consequences in humans, such as hyperthermia and neurocognitive deficits. Although MDMA consumption has been associated with visual problems, the effects of this recreational drug in retinal physiology have not been addressed hitherto. In this work, we evaluated the effect of a single MDMA administration in the rat electroretinogram (ERG). Wistar rats were administered MDMA (15 mg/kg) or saline and ERGs were recorded before (Baseline ERG), and 3 h, 24 h, and 7 days after treatment. A high temperature (HT) saline treated control group was also included. Overall, significantly augmented and shorter latency ERG responses were found in MDMA and HT groups 3 h after treatment when compared to Baseline. Twenty-four hours after treatment some of the alterations found at 3 h, mainly characterized by shorter latency, tended to return to Baseline values. However, MDMA-treated animals still presented increased scotopic a-wave and b-wave amplitudes compared to Baseline ERGs, which were independent of temperature elevation though the latter might underlie the acute ERG alterations observed 3 h after MDMA administration. Seven days after MDMA administration recovery from these effects had occurred. The effects seem to stem from specific changes observed at the a-wave level, which indicates that MDMA affects subacutely (at 24 h) retinal physiology at the outer retinal (photoreceptor/bipolar) layers. In conclusion, we have found direct evidence that MDMA causes subacute enhancement of the outer retinal responses (most prominent in the a-wave), though ERG alterations resume within one week. These changes in photoreceptor/bipolar cell physiology may have implications for the understanding of the subacute visual manifestations induced by MDMA in humans. PMID- 22216323 TI - Oligomerization of ZFYVE27 (Protrudin) is necessary to promote neurite extension. AB - ZFYVE27 (Protrudin) was originally identified as an interacting partner of spastin, which is most frequently mutated in hereditary spastic paraplegia. ZFYVE27 is a novel member of FYVE family, which is implicated in the formation of neurite extensions by promoting directional membrane trafficking in neurons. Now, through a yeast two-hybrid screen, we have identified that ZFYVE27 interacts with itself and the core interaction region resides within the third hydrophobic region (HR3) of the protein. We confirmed the ZFYVE27's self-interaction in the mammalian cells by co-immunoprecipitation and co-localization studies. To decipher the oligomeric nature of ZFYVE27, we performed sucrose gradient centrifugation and showed that ZFYVE27 oligomerizes into dimer/tetramer forms. Sub-cellular fractionation and Triton X-114 membrane phase separation analysis indicated that ZFYVE27 is a peripheral membrane protein. Furthermore, ZFYVE27 also binds to phosphatidylinositol 3-phosphate lipid moiety. Interestingly, cells expressing ZFYVE27(DeltaHR3) failed to produce protrusions instead caused swelling of cell soma. When ZFYVE27(DeltaHR3) was co-expressed with wild-type ZFYVE27 (ZFYVE27(WT)), it exerted a dominant negative effect on ZFYVE27(WT) as the cells co-expressing both proteins were also unable to induce protrusions and showed cytoplasmic swelling. Altogether, it is evident that a functionally active form of oligomer is crucial for ZFYVE27 ability to promote neurite extensions. PMID- 22216324 TI - Gender inequitable masculinity and sexual entitlement in rape perpetration South Africa: findings of a cross-sectional study. AB - OBJECTIVE: To describe the prevalence and patterns of rape perpetration in a randomly selected sample of men from the general adult population, to explore factors associated with rape and to describe how men explained their acts of rape. DESIGN: Cross-sectional household study with a two- stage randomly selected sample of men. METHODS: 1737 South African men aged 18-49 completed a questionnaire administered using an Audio-enhanced Personal Digital Assistant. Multivariable logistic regression models were built to identify factors associated with rape perpetration. RESULTS: In all 27.6% (466/1686) of men had raped a woman, whether an intimate partner, stranger or acquaintance, and whether perpetrated alone or with accomplices, and 4.7% had raped in the last 12 months. First rapes for 75% were perpetrated before age 20, and 53.9% (251) of those raping, did so on multiple occasions. The logistic regression model showed that having raped was associated with greater adversity in childhood, having been raped by a man and higher maternal education. It was associated with less equitable views on gender relations, having had more partners, and many more gender inequitable practices including transactional sex and physical partner violence. Also drug use, gang membership and a higher score on the dimensions of psychopathic personality, namely blame externalisation and Machiavellian egocentricity. Asked about why they did it, the most common motivations stemmed from ideas of sexual entitlement. CONCLUSIONS: Perpetration of rape is so prevalent that population-based measures of prevention are essential to complement criminal justice system responses. Our findings show the importance of measures to build gender equity and change dominant ideas of masculinity and gender relations as part of rape prevention. Reducing men's exposure to trauma in childhood is also critically important. PMID- 22216326 TI - Increase in diarrheal disease associated with arsenic mitigation in Bangladesh. AB - BACKGROUND: Millions of households throughout Bangladesh have been exposed to high levels of arsenic (As) causing various deadly diseases by drinking groundwater from shallow tubewells for the past 30 years. Well testing has been the most effective form of mitigation because it has induced massive switching from tubewells that are high (>50 ug/L) in As to neighboring wells that are low in As. A recent study has shown, however, that shallow low-As wells are more likely to be contaminated with the fecal indicator E. coli than shallow high-As wells, suggesting that well switching might lead to an increase in diarrheal disease. METHODS: Approximately 60,000 episodes of childhood diarrhea were collected monthly by community health workers between 2000 and 2006 in 142 villages of Matlab, Bangladesh. In this cross-sectional study, associations between childhood diarrhea and As levels in tubewell water were evaluated using logistic regression models. RESULTS: Adjusting for wealth, population density, and flood control by multivariate logistic regression, the model indicates an 11% (95% confidence intervals (CIs) of 4-19%) increase in the likelihood of diarrhea in children drinking from shallow wells with 10-50 ug/L As compared to shallow wells with >50 ug/L As. The same model indicates a 26% (95%CI: 9-42%) increase in diarrhea for children drinking from shallow wells with <=10 ug/L As compared to shallow wells with >50 ug/L As. CONCLUSION: Children drinking water from shallow low As wells had a higher prevalence of diarrhea than children drinking water from high As wells. This suggests that the health benefits of reducing As exposure may to some extent be countered by an increase in childhood diarrhea. PMID- 22216325 TI - Increased renal methylglyoxal formation with down-regulation of PGC-1alpha-FBPase pathway in cystathionine gamma-lyase knockout mice. AB - We have previously reported that hydrogen sulfide (H(2)S), a gasotransmitter and vasodilator has cytoprotective properties against methylglyoxal (MG), a reactive glucose metabolite associated with diabetes and hypertension. Recently, H(2)S was shown to up-regulate peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha, a key gluconeogenic regulator that enhances the gene expression of the rate-limiting gluconeogenic enzyme, fructose-1,6-bisphosphatase (FBPase). Thus, we sought to determine whether MG levels and gluconeogenic enzymes are altered in kidneys of 6-22 week-old cystathionine gamma-lyase knockout (CSE(-/-); H(2)S-producing enzyme) male mice. MG levels were determined by HPLC. Plasma glucose levels were measured by an assay kit. Q-PCR was used to measure mRNA levels of PGC-1alpha and FBPase-1 and -2. Coupled-enzymatic assays were used to determine FBPase activity, or triosephosphate levels. Experimental controls were either age-matched wild type mice or untreated rat A-10 cells. Interestingly, we observed a significant decrease in plasma glucose levels along with a significant increase in plasma MG levels in all three age groups (6-8, 14-16, and 20-22 week old) of the CSE(-/-) mice. Indeed, renal MG and triosephosphates were increased, whereas renal FBPase activity, along with its mRNA levels, were decreased in the CSE(-/-) mice. The decreased FBPase activity was accompanied by lower levels of its product, fructose-6-phosphate, and higher levels of its substrate, fructose 1,6-bisphosphate in renal extracts from the CSE(-/-) mice. In agreement, PGC 1alpha mRNA levels were also significantly down-regulated in 6-22 week-old CSE(-/ ) mice. Furthermore, FBPase-1 and -2 mRNA levels were reduced in aorta tissues from CSE(-/-) mice. Administration of NaHS, a H(2)S donor, increased the gene expression of PGC-1alpha and FBPase-1 and -2 in cultured rat A-10 cells. In conclusion, overproduction of MG in CSE(-/-) mice is due to a H(2)S-mediated down regulation of the PGC-1alpha-FBPase pathway, further suggesting the important role of H(2)S in the regulation of glucose metabolism and MG generation. PMID- 22216327 TI - Heregulin beta-1 induces loss of cell-cell contact and enhances expression of MUC1 at the cell surface in HCC2998 and MKN45-1 cells. AB - Signal transduction and cell responses after stimulation with heregulin beta-1 (HRG) are examined in HCC2998 and MKN45-1 cells, which have been used for a model system to study the formation of signet ring carcinomas, one of poorly differentiated adenocarcinomas. HRG stimulation causes rounding of the cells, responding to HRG. The adherens junction, which is present in the control cells, is disrupted and cell-cell interaction is lost after stimulation. Inhibition of phosphatidylinositol (PI)-3 kinase or p38 MAP kinase blocked this reaction, which indicates that the PI-3 kinase-p38 MAP kinase pathway is required for this reaction. Inhibition of the p38 MAP kinase pathway resulted in immediate restoration of cell-cell interaction. This result indicates that signaling for adherent molecules is strictly regulated by growth factor signaling. Expression of MUC1 at the cell surface is also observed and found to be expressed only after HRG stimulation. The total amount of MUC1 remains unchanged, suggesting that this amount is not due to induction of gene expression but to translocation of MUC1 from the inner membrane to the plasma membrane. This reaction is independent of the cytohesin pathway but dependent on PI-3 kinase activity. In addition to these reactions, HRG stimulates cell growth of both HCC2998 and MKN45-1 cells, depending on the ERK pathway given that the MEK inhibitor abolishes this effect. Therefore, HRG induces various reactions in HCC2998 and MKN45-1 cells by different pathways. These reactions are all related to characteristics of tumors, which implicates that HRG signaling can contribute to the formation of tumors. PMID- 22216328 TI - Trans fatty acids induce vascular inflammation and reduce vascular nitric oxide production in endothelial cells. AB - Intake of trans fatty acids (TFA), which are consumed by eating foods made from partially hydrogenated vegetable oils, is associated with a higher risk of cardiovascular disease. This relation can be explained by many factors including TFA's negative effect on endothelial function and reduced nitric oxide (NO) bioavailability. In this study we investigated the effects of three different TFA (2 common isomers of C18 found in partially hydrogenated vegetable oil and a C18 isomer found from ruminant-derived-dairy products and meat) on endothelial NF kappaB activation and nitric oxide (NO) production. Human endothelial cells were treated with increasing concentrations of Elaidic (trans-C18:1 (9 trans)), Linoelaidic (trans-C18:2 (9 trans, 12 trans)), and Transvaccenic (trans-C18:1 (11 trans)) for 3 h. Both Elaidic and Linoelaidic acids were associated with increasing NF-kappaB activation as measured by IL-6 levels and phosphorylation of IkappaBalpha, and impairment of endothelial insulin signaling and NO production, whereas Transvaccenic acid was not associated with these responses. We also measured superoxide production, which has been hypothesized to be necessary in fatty acid-dependent activation of NF-kappaB. Both Elaidic acid and Linoelaidic acid are associated with increased superoxide production, whereas Transvaccenic acid (which did not induce inflammatory responses) did not increase superoxide production. We observed differential activation of endothelial superoxide production, NF-kappaB activation, and reduction in NO production by different C18 isomers suggesting that the location and number of trans double bonds effect endothelial NF-kappaB activation. PMID- 22216329 TI - Haplotype analysis improved evidence for candidate genes for intramuscular fat percentage from a genome wide association study of cattle. AB - In genome wide association studies (GWAS), haplotype analyses of SNP data are neglected in favour of single point analysis of associations. In a recent GWAS, we found that none of the known candidate genes for intramuscular fat (IMF) had been identified. In this study, data from the GWAS for these candidate genes were re-analysed as haplotypes. First, we confirmed that the methodology would find evidence for association between haplotypes in candidate genes of the calpain calpastatin complex and musculus longissimus lumborum peak force (LLPF), because these genes had been confirmed through single point analysis in the GWAS. Then, for intramuscular fat percent (IMF), we found significant partial haplotype substitution effects for the genes ADIPOQ and CXCR4, as well as suggestive associations to the genes CEBPA, FASN, and CAPN1. Haplotypes for these genes explained 80% more of the phenotypic variance compared to the best single SNP. For some genes the analyses suggested that there was more than one causative mutation in some genes, or confirmed that some causative mutations are limited to particular subgroups of a species. Fitting the SNPs and their interactions simultaneously explained a similar amount of the phenotypic variance compared to haplotype analyses. Haplotype analysis is a neglected part of the suite of tools used to analyse GWAS data, would be a useful method to extract more information from these data sets, and may contribute to reducing the missing heritability problem. PMID- 22216330 TI - Molecular insights into the pathogenesis of Alzheimer's disease and its relationship to normal aging. AB - Alzheimer's disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression. PMID- 22216331 TI - Assessing implicit odor localization in humans using a cross-modal spatial cueing paradigm. AB - BACKGROUND: Navigation based on chemosensory information is one of the most important skills in the animal kingdom. Studies on odor localization suggest that humans have lost this ability. However, the experimental approaches used so far were limited to explicit judgements, which might ignore a residual ability for directional smelling on an implicit level without conscious appraisal. METHODS: A novel cueing paradigm was developed in order to determine whether an implicit ability for directional smelling exists. Participants performed a visual two alternative forced choice task in which the target was preceded either by a side congruent or a side-incongruent olfactory spatial cue. An explicit odor localization task was implemented in a second experiment. RESULTS: No effect of cue congruency on mean reaction times could be found. However, a time by condition interaction emerged, with significantly slower responses to congruently compared to incongruently cued targets at the beginning of the experiment. This cueing effect gradually disappeared throughout the course of the experiment. In addition, participants performed at chance level in the explicit odor localization task, thus confirming the results of previous research. CONCLUSION: The implicit cueing task suggests the existence of spatial information processing in the olfactory system. Response slowing after a side-congruent olfactory cue is interpreted as a cross-modal attentional interference effect. In addition, habituation might have led to a gradual disappearance of the cueing effect. It is concluded that under immobile conditions with passive monorhinal stimulation, humans are unable to explicitly determine the location of a pure odorant. Implicitly, however, odor localization seems to exert an influence on human behaviour. To our knowledge, these data are the first to show implicit effects of odor localization on overt human behaviour and thus support the hypothesis of residual directional smelling in humans. PMID- 22216332 TI - Substance-related health problems during rave parties in The Netherlands (1997 2008). AB - The objective of this study was to describe a 12-year (1997-2008) observation of substance-related incidents occurring at rave parties in the Netherlands, including length of visits to first-aid stations, substances used, and severity of the incidents. During rave parties, specifically trained medical and paramedical personnel staffed first aid stations. Visitors were diagnosed and treated, and their data were recorded using standardized methods. During the 12 year period with 249 rave parties involving about 3,800,000 visitors, 27,897 people visited a first aid station, of whom 10,100 reported having a substance related problem. The mean age of these people was 22.3+/-5.4 years; 52.4% of them were male. Most (66.7%) substance-related problems were associated with ecstasy or alcohol use or both. Among 10,100 substance-related cases, 515 required professional medical care, and 16 of these cases were life threatening. People with a substance-related problem stayed 20 min at the first aid station, which was significantly longer than the 5 min that those without a substance-related health problem stayed. These unique data from the Netherlands identify a variety of acute health problems related to the use of alcohol, amphetamines, cannabis, cocaine, ecstasy, and GHB. Although most problems were minor, people using GHB more often required professional medical care those using the other substances. We recommended adherence to harm and risk reduction policy, and the use of first aid stations with specially trained staff for both minor and serious incidents. PMID- 22216334 TI - Association of pre-treatment nutritional status with change in CD4 count after antiretroviral therapy at 6, 12, and 24 months in Rwandan women. AB - BACKGROUND: Body mass index (BMI) independently predicts mortality in studies of HIV infected patients initiating antiretroviral therapy (ART). We hypothesized that poorer nutritional status would be associated with smaller gains in CD4 count in Rwandan women initiating ART. METHODS AND FINDINGS: The Rwandan Women's Interassociation Study and Assessment, enrolled 710 ART-naive HIV-positive and 226 HIV-negative women in 2005 with follow-up every 6 months. The outcome assessed in this study was change in CD4 count at 6, 12, and 24 months after ART initiation. Nutritional status measures taken prior to ART initiation were BMI; height adjusted fat free mass (FFMI); height adjusted fat mass (FMI), and sum of skinfold measurements. 475 women initiated ART. Mean (within 6 months) pre-ART CD4 count was 216 cells/uL. Prior to ART initiation, the mean (+/-SD) BMI was 21.6 (+/-3.78) kg/m(2) (18.3% malnourished with BMI<18.5); and among women for whom the following were measured, mean FFMI was 17.10 (+/-1.76) kg/m(2); FMI 4.7 (+/-3.5) kg/m(2) and sum of skinfold measurements 4.9 (+/-2.7) cm. FFMI was significantly associated with a smaller change in CD4 count at 6 months in univariate analysis (-6.7 cells/uL per kg/m(2), p=0.03) only. In multivariate analysis after adjustment for covariates, no nutritional variable was associated with change in CD4 count at any follow up visit. CONCLUSION: In this cohort of African women initiating ART, no measure of malnutrition prior to ART was consistently associated with change in CD4 count at 6, 12, and 24 months of follow up, suggesting that poorer pre-treatment nutritional status does not prevent an excellent response to ART. PMID- 22216333 TI - Duffy antigen receptor for chemokines mediates chemokine endocytosis through a macropinocytosis-like process in endothelial cells. AB - BACKGROUND: The Duffy antigen receptor for chemokines (DARC) shows high affinity binding to multiple inflammatory CC and CXC chemokines and is expressed by erythrocytes and endothelial cells. Recent evidence suggests that endothelial DARC facilitates chemokine transcytosis to promote neutrophil recruitment. However, the mechanism of chemokine endocytosis by DARC remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the role of several endocytic pathways in DARC-mediated ligand internalization. Here we report that, although DARC co-localizes with caveolin-1 in endothelial cells, caveolin-1 is dispensable for DARC-mediated (125)I-CXCL1 endocytosis as knockdown of caveolin-1 failed to inhibit ligand internalization. (125)I-CXCL1 endocytosis by DARC was also independent of clathrin and flotillin-1 but required cholesterol and was, in part, inhibited by silencing Dynamin II expression.(125)I-CXCL1 endocytosis was inhibited by amiloride, cytochalasin D, and the PKC inhibitor Go6976 whereas Platelet Derived Growth Factor (PDGF) enhanced ligand internalization through DARC. The majority of DARC-ligand interactions occurred on the endothelial surface, with DARC identified along plasma membrane extensions with the appearance of ruffles, supporting the concept that DARC provides a high affinity scaffolding function for surface retention of chemokines on endothelial cells. CONCLUSIONS/SIGNIFICANCE: These results show DARC-mediated chemokine endocytosis occurs through a macropinocytosis-like process in endothelial cells and caveolin 1 is dispensable for CXCL1 internalization. PMID- 22216335 TI - Rapid processing of both reward probability and reward uncertainty in the human anterior cingulate cortex. AB - Reward probability and uncertainty are two fundamental parameters of decision making. Whereas reward probability indicates the prospect of winning, reward uncertainty, measured as the variance of probability, indicates the degree of risk. Several lines of evidence have suggested that the anterior cingulate cortex (ACC) plays an important role in reward processing. What is lacking is a quantitative analysis of the encoding of reward probability and uncertainty in the human ACC. In this study, we addressed this issue by analyzing the feedback related negativity (FRN), an event-related potential (ERP) component that reflects the ACC activity, in a simple gambling task in which reward probability and uncertainty were parametrically manipulated through predicting cues. Results showed that at the outcome evaluation phase, while both win and loss-related FRN amplitudes increased as the probability of win or loss decreased, only the win related FRN was modulated by reward uncertainty. This study demonstrates the rapid encoding of reward probability and uncertainty in the human ACC and offers new insights into the functions of the ACC. PMID- 22216336 TI - Common and unique network dynamics in football games. AB - The sport of football is played between two teams of eleven players each using a spherical ball. Each team strives to score by driving the ball into the opposing goal as the result of skillful interactions among players. Football can be regarded from the network perspective as a competitive relationship between two cooperative networks with a dynamic network topology and dynamic network node. Many complex large-scale networks have been shown to have topological properties in common, based on a small-world network and scale-free network models. However, the human dynamic movement pattern of this network has never been investigated in a real-world setting. Here, we show that the power law in degree distribution emerged in the passing behavior in the 2006 FIFA World Cup Final and an international "A" match in Japan, by describing players as vertices connected by links representing passes. The exponent values gamma ~ 3.1 are similar to the typical values that occur in many real-world networks, which are in the range of 2DPA->24:5n-3. The second reaction DPA >24:5n-3 appeared to be saturated at substrate concentrations not saturating for the first reaction EPA->DPA. ALA dose-dependently inhibited Fads2 conversion of 24:5n-3 to 24:6n-3. CONCLUSIONS: The competition between ALA and 24:5n-3 for Fads2 may explain the decrease in DHA levels observed after certain intakes of dietary ALA have been exceeded. In addition, the apparent saturation of the second Elovl2 reaction, DPA->24:5n-3, provides further explanations for the accumulation of DPA when ALA, SDA or EPA is provided in the diet. This study suggests that Elovl2 will be critical in understanding if DHA synthesis can be increased by dietary means. PMID- 22216342 TI - The prognostic significance of apoptosis-related biological markers in Chinese gastric cancer patients. AB - BACKGROUND AND OBJECTIVE: The prognosis varied among the patients with the same stage, therefore there was a need for new prognostic and predictive factors. The aim of this study was to evaluate the relationship of apoptosis-related biological markers such as p53, bcl-2, bax, and c-myc, and clinicopathological features and their prognostic value. METHODS: From 1996 to 2007, 4426 patients had undergone curative D2 gastrectomy for gastric cancer at Fudan University Shanghai Cancer Center. Among 501 patients, the expression levels of p53, bcl-2, bax, and c-myc were examined by immunohistochemistry. The prognostic value of biological markers and the correlation between biological markers and other clinicopathological factors were investigated. RESULTS: There were 339 males and 162 females with a mean age of 57. The percentages of positive expression of p53, bcl-2, bax, and c-myc were 65%, 22%, 43%, and 58%, respectively. There was a strong correlation between p53, bax, and c-myc expression (P=0.00). There was significant association between bcl-2, and bax expression (P<0.05). p53 expression correlated with histological grade (P=0.01); bcl-2 expression with pathological stage (P=0.00); bax expression with male (P=0.02), histological grade (P=0.01), Borrmann type (P=0.01), tumor location (P=0.00), lymph node metastasis (P=0.03), and pathological stage (P=0.03); c-myc expression with Borrmann type (P=0.00). bcl-2 expression was related with good survival in univariate analysis (P=0.01). Multivariate analysis showed that bcl-2 expression and pathological stage were defined as independent prognostic factors. There were significant differences of overall 5-year survival rates according to bcl-2 expression or not in stage IIB (P=0.03). CONCLUSION: The expression of bcl-2 was an independent prognostic factor for patients with gastric cancer; it might be a candidate for the gastric cancer staging system. PMID- 22216343 TI - Reduced cortical thickness in mental retardation. AB - Mental retardation is a developmental disorder associated with impaired cognitive functioning and deficits in adaptive behaviors. Many studies have addressed white matter abnormalities in patients with mental retardation, while the changes of the cerebral cortex have been studied to a lesser extent. Quantitative analysis of cortical integrity using cortical thickness measurement may provide new insights into the gray matter pathology. In this study, cortical thickness was compared between 13 patients with mental retardation and 26 demographically matched healthy controls. We found that patients with mental retardation had significantly reduced cortical thickness in multiple brain regions compared with healthy controls. These regions include the bilateral lingual gyrus, the bilateral fusiform gyrus, the bilateral parahippocampal gyrus, the bilateral temporal pole, the left inferior temporal gyrus, the right lateral orbitofrontal cortex and the right precentral gyrus. The observed cortical thickness reductions might be the anatomical substrates for the impaired cognitive functioning and deficits in adaptive behaviors in patients with mental retardation. Cortical thickness measurement might provide a sensitive prospective surrogate marker for clinical trials of neuroprotective medications. PMID- 22216344 TI - Chronic deficiency of nitric oxide affects hypoxia inducible factor-1alpha (HIF 1alpha) stability and migration in human endothelial cells. AB - BACKGROUND: Endothelial dysfunction in widely diffuse disorders, such as atherosclerosis, hypertension, diabetes and senescence, is associated with nitric oxide (NO) deficiency. Here, the behavioural and molecular consequences deriving from NO deficiency in human umbilical vein endothelial cells (HUVECs) were investigated. RESULTS: Endothelial nitric oxide synthase (eNOS) was chronically inhibited either by N(G)-Nitro-L-arginine methyl ester (L-NAME) treatment or its expression was down-regulated by RNA interference. After long-term L-NAME treatment, HUVECs displayed a higher migratory capability accompanied by an increased Vascular Endothelial Growth Factor (VEGF) and VEGF receptor-2 (kinase insert domain receptor, KDR) expression. Moreover, both pharmacological and genetic inhibition of eNOS induced a state of pseudohypoxia, revealed by the stabilization of hypoxia-inducible factor-1alpha (HIF-1alpha). Furthermore, NO loss induced a significant decrease in mitochondrial mass and energy production accompanied by a lower O(2) consumption. Notably, very low doses of chronically administered DETA/NO reverted the HIF-1alpha accumulation, the increased VEGF expression and the stimulated migratory behaviour detected in NO deficient cells. CONCLUSION: Based on our results, we propose that basal release of NO may act as a negative controller of HIF-1alpha levels with important consequences for endothelial cell physiology. Moreover, we suggest that our experimental model where eNOS activity was impaired by pharmacological and genetic inhibition may represent a good in vitro system to study endothelial dysfunction. PMID- 22216345 TI - Thymidine kinase 2 deficiency-induced mitochondrial DNA depletion causes abnormal development of adipose tissues and adipokine levels in mice. AB - Mammal adipose tissues require mitochondrial activity for proper development and differentiation. The components of the mitochondrial respiratory chain/oxidative phosphorylation system (OXPHOS) are encoded by both mitochondrial and nuclear genomes. The maintenance of mitochondrial DNA (mtDNA) is a key element for a functional mitochondrial oxidative activity in mammalian cells. To ascertain the role of mtDNA levels in adipose tissue, we have analyzed the alterations in white (WAT) and brown (BAT) adipose tissues in thymidine kinase 2 (Tk2) H126N knockin mice, a model of TK2 deficiency-induced mtDNA depletion. We observed respectively severe and moderate mtDNA depletion in TK2-deficient BAT and WAT, showing both tissues moderate hypotrophy and reduced fat accumulation. Electron microscopy revealed altered mitochondrial morphology in brown but not in white adipocytes from TK2-deficient mice. Although significant reduction in mtDNA-encoded transcripts was observed both in WAT and BAT, protein levels from distinct OXPHOS complexes were significantly reduced only in TK2-deficient BAT. Accordingly, the activity of cytochrome c oxidase was significantly lowered only in BAT from TK2 deficient mice. The analysis of transcripts encoding up to fourteen components of specific adipose tissue functions revealed that, in both TK2-deficient WAT and BAT, there was a consistent reduction of thermogenesis related gene expression and a severe reduction in leptin mRNA. Reduced levels of resistin mRNA were found in BAT from TK2-deficient mice. Analysis of serum indicated a dramatic reduction in circulating levels of leptin and resistin. In summary, our present study establishes that mtDNA depletion leads to a moderate impairment in mitochondrial respiratory function, especially in BAT, causes substantial alterations in WAT and BAT development, and has a profound impact in the endocrine properties of adipose tissues. PMID- 22216346 TI - Cardiovascular agents affect the tone of pulmonary arteries and veins in precision-cut lung slices. AB - INTRODUCTION: Cardiovascular agents are pivotal in the therapy of heart failure. Apart from their action on ventricular contractility and systemic afterload, they affect pulmonary arteries and veins. Although these effects are crucial in heart failure with coexisting pulmonary hypertension or lung oedema, they are poorly defined, especially in pulmonary veins. Therefore, we investigated the pulmonary vascular effects of adrenoceptor agonists, vasopressin and angiotensin II in the model of precision-cut lung slices that allows simultaneous studies of pulmonary arteries and veins. MATERIALS AND METHODS: Precision-cut lung slices were prepared from guinea pigs and imaged by videomicroscopy. Concentration-response curves of cardiovascular drugs were analysed in pulmonary arteries and veins. RESULTS: Pulmonary veins responded stronger than arteries to alpha(1)-agonists (contraction) and beta(2)-agonists (relaxation). Notably, inhibition of beta(2) adrenoceptors unmasked the alpha(1)-mimetic effect of norepinephrine and epinephrine in pulmonary veins. Vasopressin and angiotensin II contracted pulmonary veins via V(1a) and AT(1) receptors, respectively, without affecting pulmonary arteries. DISCUSSION: Vasopressin and (nor)epinephrine in combination with beta(2)-inhibition caused pulmonary venoconstriction. If applicable in humans, these treatments would enhance capillary hydrostatic pressures and lung oedema, suggesting their cautious use in left heart failure. Vice versa, the prevention of pulmonary venoconstriction by AT(1) receptor antagonists might contribute to their beneficial effects seen in left heart failure. Further, alpha(1)-mimetic agents might exacerbate pulmonary hypertension and right ventricular failure by contracting pulmonary arteries, whereas vasopressin might not. PMID- 22216348 TI - Energetic conditions promoting top-down control of prey by predators. AB - Humans remove large amounts of biomass from natural ecosystems, and large bodied high trophic level animals are especially sensitive and vulnerable to exploitation. The effects of removing top-predators on food webs are often difficult to predict because of limited information on species interaction strengths. Here we used a three species predator-prey model to explore relationships between energetic properties of trophodynamic linkages and interaction strengths to provide heuristic rules that indicate observable energetic conditions that are most likely to lead to stable and strong top-down control of prey by predator species. We found that strong top-down interaction strengths resulted from low levels of energy flow from prey to predators. Strong interactions are more stable when they are a consequence of low per capita predation and when predators are subsidized by recruitment. Diet composition also affects stability, but the relationship depends on the form of the functional response. Our results imply that for generalist satiating predators, strong top down control on prey is most likely for prey items that occupy a small portion of the diet and when density dependent recruitment is moderately high. PMID- 22216347 TI - Promoting long-term survival of insulin-producing cell grafts that differentiate from adipose tissue-derived stem cells to cure type 1 diabetes. AB - BACKGROUND: Insulin-producing cell clusters (IPCCs) have recently been generated in vitro from adipose tissue-derived stem cells (ASCs) to circumvent islet shortage. However, it is unknown how long they can survive upon transplantation, whether they are eventually rejected by recipients, and how their long-term survival can be induced to permanently cure type 1 diabetes. IPCC graft survival is critical for their clinical application and this issue must be systematically addressed prior to their in-depth clinical trials. METHODOLOGY/PRINCIPAL FINDINGS: Here we found that IPCC grafts that differentiated from murine ASCs in vitro, unlike their freshly isolated islet counterparts, did not survive long term in syngeneic mice, suggesting that ASC-derived IPCCs have intrinsic survival disadvantage over freshly isolated islets. Indeed, beta cells retrieved from IPCC syngrafts underwent faster apoptosis than their islet counterparts. However, blocking both Fas and TNF receptor death pathways inhibited their apoptosis and restored their long-term survival in syngeneic recipients. Furthermore, blocking CD40-CD154 costimulation and Fas/TNF signaling induced long-term IPCC allograft survival in overwhelming majority of recipients. Importantly, Fas-deficient IPCC allografts exhibited certain immune privilege and enjoyed long-term survival in diabetic NOD mice in the presence of CD28/CD40 joint blockade while their islet counterparts failed to do so. CONCLUSIONS/SIGNIFICANCE: Long-term survival of ASC derived IPCC syngeneic grafts requires blocking Fas and TNF death pathways, whereas blocking both death pathways and CD28/CD40 costimulation is needed for long-term IPCC allograft survival in diabetic NOD mice. Our studies have important clinical implications for treating type 1 diabetes via ASC-derived IPCC transplantation. PMID- 22216349 TI - Gene flow in genetically modified wheat. AB - Understanding gene flow in genetically modified (GM) crops is critical to answering questions regarding risk-assessment and the coexistence of GM and non GM crops. In two field experiments, we tested whether rates of cross-pollination differed between GM and non-GM lines of the predominantly self-pollinating wheat Triticum aestivum. In the first experiment, outcrossing was studied within the field by planting "phytometers" of one line into stands of another line. In the second experiment, outcrossing was studied over distances of 0.5-2.5 m from a central patch of pollen donors to adjacent patches of pollen recipients. Cross pollination and outcrossing was detected when offspring of a pollen recipient without a particular transgene contained this transgene in heterozygous condition. The GM lines had been produced from the varieties Bobwhite or Frisal and contained Pm3b or chitinase/glucanase transgenes, respectively, in homozygous condition. These transgenes increase plant resistance against pathogenic fungi. Although the overall outcrossing rate in the first experiment was only 3.4%, Bobwhite GM lines containing the Pm3b transgene were six times more likely than non-GM control lines to produce outcrossed offspring. There was additional variation in outcrossing rate among the four GM-lines, presumably due to the different transgene insertion events. Among the pollen donors, the Frisal GM line expressing a chitinase transgene caused more outcrossing than the GM line expressing both a chitinase and a glucanase transgene. In the second experiment, outcrossing after cross-pollination declined from 0.7-0.03% over the test distances of 0.5-2.5 m. Our results suggest that pollen-mediated gene flow between GM and non-GM wheat might only be a concern if it occurs within fields, e.g. due to seed contamination. Methodologically our study demonstrates that outcrossing rates between transgenic and other lines within crops can be assessed using a phytometer approach and that gene-flow distances can be efficiently estimated with population-level PCR analyses. PMID- 22216351 TI - Neighbours' breeding success and the sex ratio of their offspring affect the mate preferences of female zebra finches. AB - Several hypotheses on divorce predict that monogamous pairs should split up more frequently after a breeding failure. Yet, deviations from the expected pattern "success-stay, failure-leave" have been reported in several species. One possible explanation for these deviations would be that individuals do not use only their own breeding performance (i.e., private information) but also that of others (i.e., public information) to decide whether or not to divorce. To test this hypothesis, we investigated the relative importance of private and public information for mate choice decisions in female zebra finches (Taeniopygia guttata).We manipulated the reproductive performance of breeding pairs and measured females' preferences for their mate and the neighbouring male first following pair formation and then seven weeks later when all females had laid eggs and the young were independent. Although all females reduced their preference for their mate after a breeding failure, the decrease was significant only when the neighbouring pair had reproduced successfully. Furthermore, there was no evidence that females biased the sex ratio of their offspring according to their mate's attractiveness. On the other hand, after reproduction, both successful and unsuccessful females increased their preferences for males who had produced a larger proportion of sons. Despite the fact that other mechanisms may have also contributed to our findings, we suggest that females changed their mate preferences based on the proportion of sons produced by successful males, because offspring sex ratio reflects the male's testosterone level at the moment of fertilization and hence is an indicator of his immune condition. PMID- 22216350 TI - Profiling insulin like factor 3 (INSL3) signaling in human osteoblasts. AB - BACKGROUND: Young men with mutations in the gene for the INSL3 receptor (Relaxin family peptide 2, RXFP2) are at risk of reduced bone mass and osteoporosis. Consistent with the human phenotype, bone analyses of Rxfp2(-/-) mice showed decreased bone volume, alterations of the trabecular bone, reduced mineralizing surface, bone formation, and osteoclast surface. The aim of this study was to elucidate the INSL3/RXFP2 signaling pathways and targets in human osteoblasts. METHODOLOGY/PRINCIPAL FINDINGS: Alkaline phosphatase (ALP) production, protein phosphorylation, intracellular calcium, gene expression, and mineralization studies have been performed. INSL3 induced a significant increase in ALP production, and Western blot and ELISA analyses of multiple intracellular signaling pathway molecules and their phosphorylation status revealed that the MAPK was the major pathway influenced by INSL3, whereas it does not modify intracellular calcium concentration. Quantitative Real Time PCR and Western blotting showed that INSL3 regulates the expression of different osteoblast markers. Alizarin red-S staining confirmed that INSL3-stimulated osteoblasts are fully differentiated and able to mineralize the extracellular matrix. CONCLUSIONS/SIGNIFICANCE: Together with previous findings, this study demonstrates that the INSL3/RXFP2 system is involved in bone metabolism by acting on the MAPK cascade and stimulating transcription of important genes of osteoblast maturation/differentiation and osteoclastogenesis. PMID- 22216352 TI - The aging of biomedical research in the United States. AB - In the past 30 years, the average age of biomedical researchers has steadily increased. The average age of an investigator at the National Institutes of Health (NIH) rose from 39 to 51 between 1980 and 2008. The aging of the biomedical workforce was even more apparent when looking at first-time NIH grantees. The average age of a new investigator was 42 in 2008, compared to 36 in 1980. To determine if the rising barriers at NIH for entry in biomedical research might impact innovative ideas and research, we analyzed the research and publications of Nobel Prize winners from 1980 to 2010 to assess the age at which their pioneering research occurred. We established that in the 30-year period, 96 scientists won the Nobel Prize in medicine or chemistry for work related to biomedicine, and that their groundbreaking research was conducted at an average age of 41-one year younger than the average age of a new investigator at NIH. Furthermore, 78% of the Nobel Prize winners conducted their research before the age of 51, the average age of an NIH principal investigator. This suggested that limited access to NIH might inhibit research potential and novel projects, and could impact biomedicine and the next generation scientists in the United States. PMID- 22216353 TI - Infection of the central nervous system, sepsis and amyotrophic lateral sclerosis. AB - BACKGROUND: Severe infections may lead to chronic inflammation in the central nervous system (CNS) which may in turn play a role in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). The relentless progression and invasive supportive treatments of ALS may on the other hand induce severe infections among ALS patients. METHODOLOGY AND PRINCIPAL FINDINGS: The present study included 4,004 ALS patients identified from the Swedish Patient Register during 1991-2007 and 20,020 age and sex matched general population controls. Conditional logistic regression was used to estimate the odds ratios (ORs) of ALS given a previous hospitalization for CNS infection or sepsis. Cox models were used to estimate the hazard ratios (HRs) of hospitalization for CNS infection or sepsis after ALS diagnosis. Overall, previous CNS infection (OR: 1.3, 95% confidence interval [CI]: 0.8, 2.4) or sepsis (OR: 1.2, 95% CI: 0.9, 1.6) was not associated with ALS risk. However, compared to ALS free individuals, ALS cases were more likely to be hospitalized for sepsis after diagnosis (HR: 2.6, 95% CI: 1.9, 3.5). We did not observe a higher risk of CNS infection after ALS diagnosis. CONCLUSIONS/SIGNIFICANCE: Our results suggest that acute and severe infections unlikely contribute to the development of ALS; however, ALS patients are at a higher risk of sepsis after diagnosis, compared to ALS free individuals. PMID- 22216354 TI - Diseases and causes of death in European bats: dynamics in disease susceptibility and infection rates. AB - BACKGROUND: Bats receive increasing attention in infectious disease studies, because of their well recognized status as reservoir species for various infectious agents. This is even more important, as bats with their capability of long distance dispersal and complex social structures are unique in the way microbes could be spread by these mammalian species. Nevertheless, infection studies in bats are predominantly limited to the identification of specific pathogens presenting a potential health threat to humans. But the impact of infectious agents on the individual host and their importance on bat mortality is largely unknown and has been neglected in most studies published to date. METHODOLOGY/PRINCIPAL FINDINGS: Between 2002 and 2009, 486 deceased bats of 19 European species (family Vespertilionidae) were collected in different geographic regions in Germany. Most animals represented individual cases that have been incidentally found close to roosting sites or near human habitation in urban and urban-like environments. The bat carcasses were subjected to a post-mortem examination and investigated histo-pathologically, bacteriologically and virologically. Trauma and disease represented the most important causes of death in these bats. Comparative analysis of pathological findings and microbiological results show that microbial agents indeed have an impact on bats succumbing to infectious diseases, with fatal bacterial, viral and parasitic infections found in at least 12% of the bats investigated. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate the importance of diseases and infectious agents as cause of death in European bat species. The clear seasonal and individual variations in disease prevalence and infection rates indicate that maternity colonies are more susceptible to infectious agents, underlining the possible important role of host physiology, immunity and roosting behavior as risk factors for infection of bats. PMID- 22216355 TI - Effect of the Salmonella pathogenicity island 2 type III secretion system on Salmonella survival in activated chicken macrophage-like HD11 cells. AB - In order to better identify the role of the Salmonella pathogenicity island 2 (SPI-2) type III secretion system (T3SS) in chickens, we used the well-known gentamicin protection assay with activated HD11 cells. HD11 cells are a macrophage-like chicken cell line that can be stimulated with phorbol 12 myristate 13-acetate (PMA) to exhibit more macrophage-like morphology and greater production of reactive oxygen species (ROS). Activated HD11 cells were infected with a wild-type Salmonella enterica subspecies enterica serovar Typhimurium (S. Typhimurium) strain, a SPI-2 mutant S. Typhimurium strain, a wild-type Salmonella enterica subspecies enterica serovar Enteritidis (S. Enteritidis) strain, a SPI-2 mutant S. Enteritidis strain, or a non-pathogenic Escherichia coli (E. coli) strain. SPI-2 mutant strains were found to survive as well as their parent strain at all time points post-uptake (PU) by the HD11 cells, up to 24 h PU, while the E. coli strain was no longer recoverable by 3 h PU. We can conclude from these observations that the SPI-2 T3SS of S. Typhimurium and S. Enteritidis is not important for survival of Salmonella in the activated macrophage-like HD11 cell line, and that Salmonella must employ other mechanisms for survival in this environment, as E. coli is effectively eliminated. PMID- 22216356 TI - Novel cytochrome P450, cyp6a17, is required for temperature preference behavior in Drosophila. AB - Perception of temperature is an important brain function for organisms to survive. Evidence suggests that temperature preference behavior (TPB) in Drosophila melanogaster, one of poikilothermal animals, is regulated by cAMP dependent protein kinase (PKA) signaling in mushroom bodies of the brain. However, downstream targets for the PKA signaling in this behavior have not been identified. From a genome-wide search for the genes regulated by PKA activity in the mushroom bodies, we identified the cyp6a17 Cytochrome P450 gene as a new target for PKA. Our detailed analysis of mutants by genetic, molecular and behavioral assays shows that cyp6a17 is essential for temperature preference behavior. cyp6a17 expression is enriched in the mushroom bodies of the adult brain. Tissue-specific knockdown and rescue experiments demonstrate that cyp6a17 is required in the mushroom bodies for normal temperature preference behavior. This is the first study, to our knowledge, to show PKA-dependent expression of a cytochrome P450 gene in the mushroom bodies and its role as a key factor for temperature preference behavior. Taken together, this study reveals a new PKA Cytochrome P450 pathway that regulates the temperature preference behavior. PMID- 22216357 TI - Circadian clocks in mouse and human CD4+ T cells. AB - Though it has been shown that immunological functions of CD4+ T cells are time of day-dependent, the underlying molecular mechanisms remain largely obscure. To address the question whether T cells themselves harbor a functional clock driving circadian rhythms of immune function, we analyzed clock gene expression by qPCR in unstimulated CD4+ T cells and immune responses of PMA/ionomycin stimulated CD4+ T cells by FACS analysis purified from blood of healthy subjects at different time points throughout the day. Molecular clock as well as immune function was further analyzed in unstimulated T cells which were cultured in serum-free medium with circadian clock reporter systems. We found robust rhythms of clock gene expression as well as, after stimulation, IL-2, IL-4, IFN-gamma production and CD40L expression in freshly isolated CD4+ T cells. Further analysis of IFN-gamma and CD40L in cultivated T cells revealed that these parameters remain rhythmic in vitro. Moreover, circadian luciferase reporter activity in CD4+ T cells and in thymic sections from PER2::LUCIFERASE reporter mice suggest that endogenous T cell clock rhythms are self-sustained under constant culture conditions. Microarray analysis of stimulated CD4+ T cell cultures revealed regulation of the NF-kappaB pathway as a candidate mechanism mediating circadian immune responses. Collectively, these data demonstrate for the first time that CD4+ T cell responses are regulated by an intrinsic cellular circadian oscillator capable of driving rhythmic CD4+ T cell immune responses. PMID- 22216358 TI - Functional relationship between skull form and feeding mechanics in Sphenodon, and implications for diapsid skull development. AB - The vertebrate skull evolved to protect the brain and sense organs, but with the appearance of jaws and associated forces there was a remarkable structural diversification. This suggests that the evolution of skull form may be linked to these forces, but an important area of debate is whether bone in the skull is minimised with respect to these forces, or whether skulls are mechanically "over designed" and constrained by phylogeny and development. Mechanical analysis of diapsid reptile skulls could shed light on this longstanding debate. Compared to those of mammals, the skulls of many extant and extinct diapsids comprise an open framework of fenestrae (window-like openings) separated by bony struts (e.g., lizards, tuatara, dinosaurs and crocodiles), a cranial form thought to be strongly linked to feeding forces. We investigated this link by utilising the powerful engineering approach of multibody dynamics analysis to predict the physiological forces acting on the skull of the diapsid reptile Sphenodon. We then ran a series of structural finite element analyses to assess the correlation between bone strain and skull form. With comprehensive loading we found that the distribution of peak von Mises strains was particularly uniform throughout the skull, although specific regions were dominated by tensile strains while others were dominated by compressive strains. Our analyses suggest that the frame-like skulls of diapsid reptiles are probably optimally formed (mechanically ideal: sufficient strength with the minimal amount of bone) with respect to functional forces; they are efficient in terms of having minimal bone volume, minimal weight, and also minimal energy demands in maintenance. PMID- 22216360 TI - Generalized serpiginous eruption during immunosuppressive treatment for leprosy reactive neuritis. PMID- 22216359 TI - The use of artemether-lumefantrine for the treatment of uncomplicated Plasmodium vivax malaria. AB - The long-standing dearth of knowledge surrounding Plasmodium vivax, the most widely distributed of the malaria species, merits urgent attention. A growing awareness of the true burden of this parasite and its potential to cause severe disease, and the identification of increasing parasite resistance in many areas of the world to chloroquine, the mainstay of vivax treatment, underscores the need to identify new and effective treatment strategies. Artemisinin-based combination therapies (ACTs) have been widely adopted as first-line treatment for P. falciparum malaria and would offer logistic benefits in areas of co endemicity. However, while ACTs show high and similar efficacy against the blood stages of P. vivax, neither ACTs nor chloroquine are active against vivax hypnozoites and must be complemented with a full course of primaquine to eradicate dormant vivax hypnozoites and prevent relapses. Artemether-lumefantrine (AL), the most commonly deployed ACT, has shown rapid clearance of P. vivax parasitemia and fever. The relatively short half-life of lumefantrine would appear beneficial in terms of reducing risk of resistance when compared to other ACTs. However, it has a shorter capability to suppress vivax relapses or prevent de novo infections, which generally translates into comparatively lower in vivo short-term measures of efficacy (e.g., day 28 or day 42 uncorrected cure rates). Assuming that the different artemisinin derivatives have equivalent efficacy against vivax, differences between AL and other ACTs may be restricted to the duration of plasma therapeutic levels of the partner drug, a variable of limited clinical relevance, particularly in regions with low vivax transmission rates or in cases where primaquine is added to the regimen to prevent relapses. More rigorous assessment of the use of ACTs in general, and AL in particular, for the treatment of P. vivax infections, either alone or in combination with primaquine, is merited. In the meantime, AL treatment of vivax malaria may be a pragmatic choice for areas with chloroquine-resistant P. vivax, and in co-endemic areas where AL is already used routinely against P. falciparum and parasitological differentiation is not routinely performed or only clinical diagnosis is used. PMID- 22216361 TI - The emerging story of disability associated with lymphatic filariasis: a critical review. AB - Globally, 40 million people live with the chronic effects of lymphatic filariasis (LF), making it the second leading cause of disability in the world. Despite this, there is limited research into the experiences of people living with the disease. This review summarises the research on the experiences of people living with LF disability. The review highlights the widespread social stigma and oppressive psychological issues that face most people living with LF-related disability. Physical manifestations of LF make daily activities and participation in community life difficult. The findings confirm the need for the Global Programme to Eliminate Lymphatic Filariasis (GPELF) to support morbidity management activities that address the complex biopsychosocial issues that people living with LF-related disability face. PMID- 22216362 TI - Effect of a control project on clinical profiles and outcomes in buruli ulcer: a before/after study in Bas-Congo, Democratic Republic of Congo. AB - BACKGROUND: Buruli ulcer (BU) is a necrotizing bacterial infection of skin, subcutaneous tissue and bone caused by Mycobacterium ulcerans. Although the functional impairment caused by BU results in severe suffering and in socio economic problems, the disease remains largely neglected in Africa. The province of Bas-Congo in Democratic Republic of Congo contains one of the most important BU foci of the country, i.e. the Songololo Territory in the District of Cataractes. This study aims to assess the impact of a BU control project launched in 2004 in the Songololo Territory. METHODS: We used a comparative non-randomized study design, comparing clinical profiles and outcomes of the group of patients admitted at the General Reference Hospital (GRH) of the "Institut Medical Evangelique" (IME) of Kimpese 3 years before the start of the project (2002-2004) with those admitted during the 3 years after the start of the project (2005 2007). RESULTS: The BU control project was associated with a strong increase in the number of admitted BU cases at the GRH of IME/Kimpese and a fundamental change in the profile of those patients; more female patients presented with BU, the proportion of relapse cases amongst all admissions reduced, the proportion of early lesions and simple ulcerative forms increased, more patients healed without complications and the case fatality rate decreased substantially. The median duration since the onset of first symptoms however remained high, as well as the proportion of patients with osteomyelitis or limitations of joint movement, suggesting that the diagnostic delay remains substantial. CONCLUSION: Implementing a specialized program for BU may be effective in improving clinical profiles and outcomes in BU. Despite these encouraging results, our study highlights the need of considering new strategies to better improve BU control in a low resources setting. PMID- 22216363 TI - Single dose novel Salmonella vaccine enhances resistance against visceralizing L. major and L. donovani infection in susceptible BALB/c mice. AB - Visceral leishmaniasis is a major neglected tropical disease, with an estimated 500,000 new cases and more than 50,000 deaths attributable to this disease every year. Drug therapy is available but costly and resistance against several drug classes has evolved. Despite all efforts, no commercial, let alone affordable, vaccine is available to date. Thus, the development of cost effective, needle independent vaccines is a high priority. Here, we have continued efforts to develop live vaccine carriers based on recombinant Salmonella. We used an in silico approach to select novel Leishmania parasite antigens from proteomic data sets, with selection criteria based on protein abundance, conservation across Leishmania species and low homology to host species. Five chosen antigens were differentially expressed on the surface or in the cytosol of Salmonella typhimurium SL3261. A two-step procedure was developed to select optimal Salmonella vaccine strains for each antigen, based on bacterial fitness and antigen expression levels. We show that vaccine strains of Salmonella expressing the novel Leishmania antigens LinJ08.1190 and LinJ23.0410 significantly reduced visceralisation of L. major and enhanced systemic resistance against L. donovani in susceptible BALB/c mice. The results show that Salmonella are valid vaccine carriers for inducing resistance against visceral leishmaniasis but that their use may not be suitable for all antigens. PMID- 22216364 TI - Individuals with Le(a+b-) blood group have increased susceptibility to symptomatic vibrio cholerae O1 infection. AB - BACKGROUND: Human genetic factors such as blood group antigens may affect the severity of infectious diseases. Presence of specific ABO and Lewis blood group antigens has been shown previously to be associated with the risk of different enteric infections. The aim of this study was to determine the relationship of the Lewis blood group antigens with susceptibility to cholera, as well as severity of disease and immune responses to infection. METHODOLOGY: We determined Lewis and ABO blood groups of a cohort of patients infected by Vibrio cholerae O1, their household contacts, and healthy controls, and analyzed the risk of symptomatic infection, severity of disease if infected and immune response following infection. PRINCIPAL FINDINGS: We found that more individuals with cholera expressed the Le(a+b-) phenotype than the asymptomatic household contacts (OR 1.91, 95% CI 1.03-3.56) or healthy controls (OR 1.90, 95% CI 1.13-3.21), as has been seen previously for the risk of symptomatic ETEC infection. Le(a-b+) individuals were less susceptible to cholera and if infected, required less intravenous fluid replacement in hospital, suggesting that this blood group may be associated with protection against V. cholerae O1. Individuals with Le(a-b-) blood group phenotype who had symptomatic cholera had a longer duration of diarrhea and required higher volumes of intravenous fluid replacement. In addition, individuals with Le(a-b-) phenotype also had lessened plasma IgA responses to V. cholerae O1 lipopolysaccharide on day 7 after infection compared to individuals in the other two Lewis blood group phenotypes. CONCLUSION: Individuals with Lewis blood type Le(a+b-) are more susceptible and Le(a-b+) are less susceptible to V. cholerae O1 associated symptomatic disease. Presence of this histo-blood group antigen may be included in evaluating the risk for cholera in a population, as well as in vaccine efficacy studies, as is currently being done for the ABO blood group antigens. PMID- 22216365 TI - Dengue virus type 4 phylogenetics in Brazil 2011: looking beyond the veil. AB - Dengue Fever and Dengue Hemorrhagic Fever are diseases affecting approximately 100 million people/year and are a major concern in developing countries. In the present study, the phylogenetic relationship of six strains of the first autochthonous cases of DENV-4 infection occurred in Sao Paulo State, Parana State and Rio Grande do Sul State, Brazil, 2011 were studied. Nucleotide sequences of the envelope gene were determined and compared with sequences representative of the genotypes I, II, III and Sylvatic for DEN4 retrieved from GenBank. We employed a Bayesian phylogenetic approach to reconstruct the phylogenetic relationships of Brazilian DENV-4 and we estimated evolutionary rates and dates of divergence for DENV-4 found in Brazil in 2011. All samples sequenced in this study were located in Genotype II. The studied strains are monophyletic and our data suggest that they have been evolving separately for at least 4 to 6 years. Our data suggest that the virus might have been present in the region for some time, without being noticed by Health Surveillance Services due to a low level of circulation and a higher prevalence of DENV-1 and DENV- 2. PMID- 22216366 TI - In vitro and in vivo efficacy of Monepantel (AAD 1566) against laboratory models of human intestinal nematode infections. AB - BACKGROUND: Few effective drugs are available for soil-transmitted helminthiases and drug resistance is of concern. In the present work, we tested the efficacy of the veterinary drug monepantel, a potential drug development candidate compared to standard drugs in vitro and in parasite-rodent models of relevance to human soil-transmitted helminthiases. METHODOLOGY: A motility assay was used to assess the efficacy of monepantel, albendazole, levamisole, and pyrantel pamoate in vitro on third-stage larvae (L3) and adult worms of Ancylostoma ceylanicum, Necator americanus and Trichuris muris. Ancylostoma ceylanicum- or N. americanus infected hamsters, T. muris- or Ascaris suum-infected mice, and Strongyloides ratti-infected rats were treated with single oral doses of monepantel or with one of the reference drugs. PRINCIPAL FINDINGS: Monepantel showed excellent activity on A. ceylanicum adults (IC(50) = 1.7 ug/ml), a moderate effect on T. muris L3 (IC(50) = 78.7 ug/ml), whereas no effect was observed on A. ceylanicum L3, T. muris adults, and both stages of N. americanus. Of the standard drugs, levamisole showed the highest potency in vitro (IC(50) = 1.6 and 33.1 ug/ml on A. ceylanicum and T. muris L3, respectively). Complete elimination of worms was observed with monepantel (10 mg/kg) and albendazole (2.5 mg/kg) in A. ceylanicum-infected hamsters. In the N. americanus hamster model single 10 mg/kg oral doses of monepantel and albendazole resulted in worm burden reductions of 58.3% and 100%, respectively. Trichuris muris, S. ratti and A. suum were not affected by treatment with monepantel in vivo (following doses of 600 mg/kg, 32 mg/kg and 600 mg/kg, respectively). In contrast, worm burden reductions of 95.9% and 76.6% were observed following treatment of T. muris- and A. suum infected mice with levamisole (200 mg/kg) and albendazole (600 mg/kg), respectively. CONCLUSIONS/SIGNIFICANCE: Monepantel reveals low or no activities against N. americanus, T. muris, S. ratti and A. suum in vivo, hence does not qualify as drug development candidate for human soil-transmitted helminthiases. PMID- 22216368 TI - Hepatitis E: Epidemiology and prevention. AB - Hepatitis E is caused by the hepatitis E virus (HEV), the major etiologic agent of enterically transmitted non-A hepatitis worldwide. HEV is responsible for major outbreaks of acute hepatitis in developing countries, especially in many parts of Africa and Asia. The HEV is a spherical, non-enveloped, single-stranded, positive sense RNA virus that is approximately 32 nm to 34 nm in diameter and is the only member in the family Hepeviridae and genus Hepevirus. There are four distinct genotypes of HEV (genotypes 1-4). While genotype 1 is predominantly associated with large epidemics in developing countries, genotype 3 has recently emerged as a significant pathogen in developed countries. The clinical manifestations and the laboratory abnormalities of hepatitis E are not distinguishable from that caused by other hepatitis viruses. However, high mortality among pregnant women particularly during the third trimester distinguishes HEV from other causes of acute viral hepatitis. Specific etiologic diagnosis among infected cases can be made by serological testing or detection of viral nucleic acid by reverse transcription polymerase chain reaction. Although there are vaccine candidates that had been shown to be safe and efficacious in clinical trials, none are approved currently for use. There is no specific therapy for acute hepatitis E as treatment remains supportive. PMID- 22216367 TI - Genetic engineering of Trypanosoma (Dutonella) vivax and in vitro differentiation under axenic conditions. AB - Trypanosoma vivax is one of the most common parasites responsible for animal trypanosomosis, and although this disease is widespread in Africa and Latin America, very few studies have been conducted on the parasite's biology. This is in part due to the fact that no reproducible experimental methods had been developed to maintain the different evolutive forms of this trypanosome under laboratory conditions. Appropriate protocols were developed in the 1990s for the axenic maintenance of three major animal Trypanosoma species: T. b. brucei, T. congolense and T. vivax. These pioneer studies rapidly led to the successful genetic manipulation of T. b. brucei and T. congolense. Advances were made in the understanding of these parasites' biology and virulence, and new drug targets were identified. By contrast, challenging in vitro conditions have been developed for T. vivax in the past, and this per se has contributed to defer both its genetic manipulation and subsequent gene function studies. Here we report on the optimization of non-infective T. vivax epimastigote axenic cultures and on the process of parasite in vitro differentiation into metacyclic infective forms. We have also constructed the first T. vivax specific expression vector that drives constitutive expression of the luciferase reporter gene. This vector was then used to establish and optimize epimastigote transfection. We then developed highly reproducible conditions that can be used to obtain and select stably transfected mutants that continue metacyclogenesis and are infectious in immunocompetent rodents. PMID- 22216369 TI - Management of hepatitis B in developing countries. AB - Hepatitis B is one of the leading causes of chronic hepatitis in developing countries, with 5% to 15% of the population carrying virus. The high prevalence is due to failure to adopt appropriate measure to confine the spread of infection. Most hepatitis B patients present with advanced diseases. Although perinatal transmission is believed to be an important mode, most infections in the developing world occur in childhood and early adulthood. Factors in developing countries associated with the progression of chronic hepatitis B (CHB) include co-infections with human immunodeficiency virus, delta hepatitis virus, hepatitis C virus, alcohol intake and aflatoxin. Treatment protocols extrapolated from developed countries may need modifications according to the resources available. There is some controversy as to when to start treatment, with what medication and for how long? There is now enough evidence to support that hepatitis B patients should be considered for treatment if they show persistently elevated abnormal aminotransferase levels in the last 6 mo, checked on at least three separate occasions, and a serum hepatitis B virus DNA level of > 2000 IU/mL. Therapeutic agents that were approved by Pure Food and Drug Administration are now available in many developing countries. These include standard interferon (INF)-alpha, pegylated INF-alpha, lamivudine, adefovir, entecavir and telbivudine. Drug resistance has emerged as a major challenge in the management of patients with CHB. The role of the universal vaccination program for effective control of hepatitis B cannot be emphasized enough. PMID- 22216370 TI - Hepatic osteodystrophy: An important matter for consideration in chronic liver disease. AB - Hepatic osteodystrophy (HO) is the generic term defining the group of alterations in bone mineral metabolism found in patients with chronic liver disease. This paper is a global review of HO and its main pathophysiological, epidemiological and therapeutic aspects. Studies examining the most relevant information concerning the prevalence, etiological factors, diagnostic and therapeutic aspects involved in HO were identified by a systematic literature search of the PubMed database. HO generically defines overall alterations in bone mineral density (BMD) (osteoporosis or osteopenia) which appear as a possible complication of chronic liver disease. The origin of HO is multifactorial and its etiology and severity vary in accordance with the underlying liver disease. Its exact prevalence is unknown, but different studies estimate that it could affect from 20% to 50% of patients. The reported mean prevalence of osteoporosis ranges from 13%-60% in chronic cholestasis to 20% in chronic viral hepatitis and 55% in viral cirrhosis. Alcoholic liver disease is not always related to osteopenia. HO has been commonly studied in chronic cholestatic disease (primary biliary cirrhosis and primary sclerosing cholangitis). Several risk factors and pathogenic mechanisms have been associated with the loss of BMD in patients with chronic liver disease. However, little information has been discovered in relationship to most of these mechanisms. Screening for osteopenia and osteoporosis is recommended in advanced chronic liver disease. There is a lack of randomized studies assessing specific management for HO. PMID- 22216371 TI - Regulation of heme oxygenase expression by alcohol, hypoxia and oxidative stress. AB - AIM: To study the effect of both acute and chronic alcohol exposure on heme oxygenases (HOs) in the brain, liver and duodenum. METHODS: Wild-type C57BL/6 mice, heterozygous Sod2 knockout mice, which exhibit attenuated manganese superoxide dismutase activity, and liver-specific ARNT knockout mice were used to investigate the role of alcohol-induced oxidative stress and hypoxia. For acute alcohol exposure, ethanol was administered in the drinking water for 1 wk. Mice were pair-fed with regular or ethanol-containing Lieber De Carli liquid diets for 4 wk for chronic alcohol studies. HO expression was analyzed by real-time quantitative polymerase chain reaction and Western blotting. RESULTS: Chronic alcohol exposure downregulated HO-1 expression in the brain but upregulated it in the duodenum of wild-type mice. It did not alter liver HO-1 expression, nor HO-2 expression in the brain, liver or duodenum. In contrast, acute alcohol exposure decreased both liver HO-1 and HO-2 expression, and HO-2 expression in the duodenum of wild-type mice. The decrease in liver HO-1 expression was abolished in ARNT(+/-) mice. Sod2(+/-) mice with acute alcohol exposure did not exhibit any changes in liver HO-1 and HO-2 expression or in brain HO-2 expression. However, alcohol inhibited brain HO-1 and duodenal HO-2 but increased duodenal HO-1 expression in Sod2(+/-) mice. Collectively, these findings indicate that acute and chronic alcohol exposure regulates HO expression in a tissue-specific manner. Chronic alcohol exposure alters brain and duodenal, but not liver HO expression. However, acute alcohol exposure inhibits liver HO-1 and HO-2, and also duodenal HO-2 expression. CONCLUSION: The inhibition of liver HO expression by acute alcohol-induced hypoxia may play a role in the early phases of alcoholic liver disease progression. PMID- 22216372 TI - An early proof-of-concept of cardiac resynchronization therapy. AB - Almost 50 years ago, we published detailed hemodynamic findings in a patient with heart failure and intermittent left bundle branch block. Delayed intraventricular conduction was consistently accompanied by an increased duration of left ventricular (LV) isometric contraction, a drop in systolic blood pressure, a rise in heart rate, and a drop in cardiac output. To our knowledge, this observation provided the first ever evidence that delayed mechanical LV contraction was associated with deterioration, and return to a normal pre-ejection phase with improvement in LV function. PMID- 22216373 TI - Near-infrared spectroscopy for evaluation of global and skeletal muscle tissue oxygenation. AB - Non-invasive clinical examination has well-recognized limitations in detecting compensated and uncompensated low flow states and their severity. This paper describes the principles of near-infrared absorption spectroscopy (NIRS) and the basis for its proposed use in heart failure/cardiogenic and septic shock to assess global and regional tissue oxygenation. The vascular occlusion test is explained. Limitations of NIRS, current controversies, and what is necessary in the future to make this technology a part of the initial and ongoing assessment of a patient are also discussed. The ultimate goal of such techniques is to prevent miss-assessment and inadequate resuscitation of patients, two major factors in the development of multisystem organ failure and death. PMID- 22216374 TI - Cardiovascular disease research in Latin America: a comparative bibliometric analysis. AB - AIM: To investigate the number of publications in cardiovascular disease (CVD) in Latin America and the Caribbean over the last decade. METHODS: We performed a bibliometric analysis in PubMed from 2001 to 2010 for Latin America and the Caribbean, the United States, Canada, Europe, China, and India. RESULTS: Latin America published 4% of articles compared with 26% from the United States/Canada and 42% from Europe. In CVD, Latin America published 4% of articles vs 23% from the United States/Canada and 40% from Europe. The number of publications in CVD in Latin America increased from 41 in 2001 to 726 in 2010. CONCLUSION: Latin America, while publishing more articles than previously, lags behind developed countries. Further advances in research infrastructure are necessary to develop prevention strategies for this region. PMID- 22216375 TI - 25- hydroxyvitamin d: explosion in clinical interest and laboratory requests. PMID- 22216376 TI - Nanomedicine: promising tiny machine for the healthcare in future-a review. AB - One of the 21st century's most promising technologies is nanotechnology. Nanomedicine, an offshoot of nanotechnology, refers to highly specific medical intervention at the molecular scale for curing disease or repairing damaged tissues, such as bone, muscle, or nerve. Nanotechnology is a collective term referring to technological developments on the nanometer scale, usually 0.1-100 nm. A nanometer is one-billionth of a meter, too small to be seen with a conventional laboratory microscope. It is at this size scale - about 100 nanometers or less - that biological molecules and structures inside living cells operate. Therefore, nanotechnology is engineering and manufacturing at the molecular scale.Utilities of nanotechnology to biomedical sciences imply creation of materials and devices designed to interact with the body at sub-cellular scales with a high degree of specificity. This could be potentially translated into targeted cellular and tissue-specific clinical applications aimed at maximal therapeutic effects with very limited adverse-effects. Nanomedicine can offer impressive resolutions for various life threatening diseases. Disease areas which can be expected to benefit most from nanotechnology within the next few years are cancer, diseases of the cardiovascular system, the lungs, blood, neurological (especially neurodegenerative) diseases, diabetes, inflammatory/infectious diseases, Parkinson's or Alzheimer's disease and orthopaedic problems. In the first half of the 21st century, nanomedicine should eliminate virtually all common diseases of the 20th century, and virtually all medical pain. This article presents an overview of some of the applications of nanotechnology in nanomedicine. PMID- 22216377 TI - Preferral Antibiotic Treatment Policy to be adopted in the 'Integrated Management of Childhood Illness Strategy in all ?the Developing Countries? AB - OBJECTIVES: To review the rationale and practice for the use of single dose antibiotics in 'children below five years' as pre-referral treatment in the emergency triage and treatment protocol of IMCI in the developing countries and also, to assess the available evidence on the suitability of adopting the use of pre-referral antibiotic treatment as a standard strategy of Emergency Triage and Treatment (ETAT) in "Integrated Management of Childhood Illnesses" (IMCI) for all developing countries. METHODS: Scientific, reliable information from the international articles (published and unpublished) were collected. A series of Medline search with key words were performed. Opinions of epidemiologists, public health officers and researchers University Alumni and senior health officials of some developing countries were included in this review. RESULTS: Indirect evidence regarding for or against adopting pre-referral antibiotic treatment were found in developing countries where IMCI was implemented. It was also noted that the efficiency ranking based on the health system performance correlated negatively with the per capita income (r=-0.7, p=<0.001) and the per capita health expenditure. (r=-0.6, p=0.001). The gap between mortality rates of the '<1' and '1 to 4' years age groups was narrower in countries such as Oman and Argentina compared to the other developing countries. While the doctor population ratio was higher in countries with better efficiency rankings, (r=-0.66, p=0.01). CONCLUSION: The differences found within the developing world indicate that the use of pre-referral antibiotic is certainly open to modification depending on the resources and health system performance. PMID- 22216378 TI - Intestinal injury from blunt abdominal trauma: a study of 47 cases. AB - OBJECTIVES: To determine the cause, presentation, anatomical distribution, diagnostic method, management and outcome of intestinal injuries from blunt abdominal trauma. METHODS: The study included 47 patients who underwent laparotomy for intestinal injuries from blunt abdominal trauma over a period of 4 years. A retrospective study was conducted and the patients were analyzed with respect to the cause, presentation, anatomical distribution, diagnostic methods, associated injuries, treatment and mortality. RESULTS: 47 patients with 62 major injuries to the bowel and mesentery due to blunt abdominal trauma were reviewed. The male to female ratio was 8.4: 1 and the average age was 34.98 years. There were 44 injuries to the small intestine including 1 duodenal injury, 11 colonic injuries and 7 injuries to the mesentry. 26 patients were injured in road traffic accidents. Out of 29 patients with intestinal perforation, free peritoneal air was present on plain abdominal and chest radiography in 23 patients. 18 patients underwent laparotomy on the basis of clinical findings alone. The commonest injury was a perforation at the antimesentric border of the small bowel. Treatment consisted of simple closure of the perforation, resection and anastomosis and repair followed by protective colostomy for colonic perforations. 3 (6.38%) deaths were recorded, while 8 (17.02%) patients developed major complications. CONCLUSION: Although early recognition of intestinal injuries from blunt abdominal trauma is difficult, it is very important due to its tremendous infectious potential. Intestinal perforations are often associated with severe injuries which are probably be the determining factors in survival. PMID- 22216379 TI - The Trends of DMARDS prescribed in Rheumatoid Arthritis Patients in Malaysia. AB - OBJECTIVES: To evaluate the trends of disease-modifying anti-rheumatic drugs (DMARDs) used in the treatment of rheumatoid arthritis (RA). METHODS: Patients who fulfilled the ACR criteria for RA from 1995 to 2006 and who attended the Rheumatology clinic at Ipoh Hospital were selected and their records were evaluated to determine the changing trends in the use of DMARDs. RESULTS: 128 patients with RA were identified. The most commonly prescribed DMARD as monotherapy was sulphasalazine (47.7%), followed by methotrexate (35.9%) and hydroxychloroquine. Methotrexate and sulphasalazine were the most frequently prescribed DMARDs, of which the use of methotrexate has increased 6 folds from 1997 to 2007 and the use of sulphasalazine remains around 30% to 50%. The combination of methotrexate with leflunomide has significantly increased in usage by 4 folds during the study period whilst methotrexate with sulphasalazine combination usage had slightly declined. CONCLUSION: DMARDs are still the cornerstone in the treatment of RA. Changes in the trend and aggressive use of DMARDs has been markedly influenced by the patient's awareness of early treatment, the incapacitating damage, availability of recently introduced leflunomide and the advancement of current recommended treatment protocol. PMID- 22216380 TI - Alterations in TSH and Thyroid Hormones following Mobile Phone Use. AB - OBJECTIVES: In recent years, the widespread use of mobile phones has lead to a public debate about possible detrimental effects on human health. In spite of years of research, there is still a great controversy regarding the possibility of induction of any significant physiological effects in humans by microwave radiations emitted by mobile phones. This study aims to investigate the effects of electromagnetic fields induced by the Global System for Mobile communications (GSM) mobile phones on the Thyroid Stimulating Hormone (TSH) and thyroid hormones in humans. METHODS: 77 healthy university students participated in this study. The levels of T3, T4 and TSH were measured by using appropriate enzyme-linked immunosorbent assay (ELISA) kits (Human, Germany). RESULTS: The average levels of T3, T4 and TSH in students who moderately used mobile phones were 1.25+/-0.27 ng/ml, 7.76+/-1.73 ug/dl and 4.25+/-2.12 uu/l respectively. The levels in the students who severely used mobile phones were 1.18+/-0.30, 7.75+/-1.14 and 3.75+/ 2.05 respectively. In non-users, the levels were 1.15+/-0.27, 8.42+/-2.72 and 2.70+/-1.75, respectively. The difference among the levels of TSH in these 3 groups was statistically significant (P<0.05). CONCLUSION: As far as the study is concerned, this is the first human study to assess the associations between mobile phone use and alterations in the levels of TSH and thyroid hormones. Based on the findings, a higher than normal TSH level, low mean T4 and normal T3 concentrations in mobile users were observed. It seems that minor degrees of thyroid dysfunction with a compensatory rise in TSH may occur following excessive use of mobile phones. It may be concluded that possible deleterious effects of mobile microwaves on hypothalamic-pituitary-thyroid axis affects the levels of these hormones. PMID- 22216381 TI - Medical Specialties in Oman: Scaling Up through National Action. AB - OBJECTIVES: To analyze the situation of medical specialists in the Sultanate of Oman, in terms of its past and current size and future needs. METHODS: Data of Oman Medical Specialty Board (OMSB) and Ministry of Health (MoH) on medical specialists in Oman and the current Omanization levels in various specialties were reviewed and analyzed. Projections of the need for medical specialists by the End-2020 and in 2032 were calculated based on three different scenarios. RESULTS: Data on the number of medical specialists in Oman revealed a steady increase over the years, starting from only 52 specialists in 1975 to 2,162 in 2008; 25.1% of them were Omanis. The ratios of Omanization showed some inconsistency over the years in certain categories of specialization and were considerably low in some important specialties, e.g. Anesthesiology (5.7%) and Obstetrics & Gynecology (18.5%). By the End-2020, the total workforce of medical specialists in Oman is expected to reach 2,228; 408 of them would be Omanis. Otherwise, to achieve 100% Omanization, the number of Omani specialists required would be 1,772. According to three different scenarios, the number of medical specialists in Oman would range from 2,785-4,569 by 2032; of them 1,859-3,646 would be Omanis. CONCLUSION: In order to rapidly increase the number of medical specialists in Oman to satisfy the country's needs, OMSB has to adopt a visionary long-term strategy, through which it wouldbeta be able to gather all stakeholders resources within a national framework and direct a significant investment of funds towards scaling up medical specialists production. PMID- 22216382 TI - Prevalence of bacterial vaginosis and impact of genital hygiene practices in non pregnant women in zanjan, iran. AB - OBJECTIVES: Bacterial vaginosis is one of the most common causes of reproductive tract infection (RTI), it's prevalence is influenced by many factors. The aim of this study is to determine the prevalence of bacterial vaginosis and impact of sexual and genital hygienie practices and socio-demographic characteristics in non pregnant women of Zanjan province in Iran. METHODS: 500 non-pregnant, married women were randomly selected for this study. This is a descriptive-analytic study conducted among non-pregnant referred to primry healthcare centres in Zanjan between May to August 2006. Following gynecological examination and vaginal sample collection by physicians, bacterial vaginosis was confirmed by Nugent criteria, tricomoniasis by direct microscopy and candidiasis by direct microscopic observation and evaluation of presenting clinical signs of vulvovaginitis. RESULTS: The prevalence of RTI was 27.6%. Out of which 16.2% was devoted to bacterial vaginosis (BV), 6.6% to trichomoniasis and 4.8% to Vulvovaginal candidiasis (VVC). In contrast to coital hygiene, there was a significant correlation between menstrual and individual vaginal hygiene and BV (p<0.01 and p<0.001) respectively. There was a significant correlation between BV and education (p<0.025), number of pregnancy (p<0.05) and method of contraception (p<0.005). No significant correlation was observed between age, age of marriage and abortion. CONCLUSION: The data obtained suggests that the prevalence rate of BV is relatively high and could be affected by hygiene behaviors and certain socio-demographic characteristics, which indicate the need for comprehensive, scheduled programs of healthcare educations, aimed at reducing BV prevalence. PMID- 22216383 TI - Endometriosis at caesarian section scar. AB - Endometriosis is a common gynecological condition which is sometimes presented to general surgeons as a lump in the abdomen. It can pose a diagnostic dilemma and should be in the differential diagnosis of lumps in the abdomen in females. Diagnosis is usually made following histological examination. This is a case report of abdominal wall endometriosis following caesarian section. This report discusses and evaluates the incidence, pathophysiology, course, diagnosis, treatment and prevention of this condition. PMID- 22216384 TI - Soft tissue chondroma: a case report and literature review. AB - Extra skeletal soft tissue chondroma is a very rare, slow progressing, benign tumor. It has a specific tendency for hands and feet. It can sometimes be misdiagnosed as a synovial cyst or a more serious condition such as synovial sarcoma. Moreover, it can exhibit worrying radiologic and histological features mimicking chondrosarcomas. This study presents a very rare case of soft tissue chondroma of the foot. PMID- 22216385 TI - A rare presentation of primary antiphospholipid syndrome. AB - This case presents a young patient with myocardial infarction, in-situ thrombosis of left anterior descending coronary artery and right common-iliac artery due to primary antiphospholipid syndrome. This report discusses the relationship between antiphospholipid antibodies and coronary artery disease along with management of this rare condition. PMID- 22216386 TI - Calcified ventricular aneurysm. PMID- 22216387 TI - A huge oral ranula. PMID- 22216388 TI - Chest Pain in A/E with ST Elevation. PMID- 22216389 TI - Prevalence of Bacterial Pathogens in Aseer Region, Kingdom of Saudi Arabia: Emphasis on Antimicrobial Susceptibility of Staphylococcus aureus. AB - OBJECTIVES: This short study aims to determine the prevalence of various bacterial pathogens causing infections in the Aseer regions, and to also assess the distribution of Staphylococcus aureus in relation to different body sites as well as their in vitro antimicrobial susceptibility profile. METHODS: Clinical specimens (n=9831) from various infections diagnosed at Aseer Central Hospital (ACH) and Abha General Hospital (AGH), were analyzed bacteriologically. Confirmed S. aureus isolates (n=210) were tested against 44 antibacterial agents as per standard methods. RESULTS: Bacterial pathogens were recovered from 24.9% of the samples. The results revealed that Escherichia coli, Klebsiella pneumoniae, Enterococcus spp. and S. aureus to be the main etiological agents, while purulent exudates of wounds and abscesses were the main source of S. aureus. Out of the 210 S. aureus isolates; 77 (38.5%) were recovered from purulent exudates of wounds and abscesses of the examined patients and 53 (26.5%) were from high vaginal discharges, while other body sites exhibited different rates of S. aureus. On the other hand, 45% of the 210 S. aureus isolates were found to be multidrug resistant S. aureus (MRSA). CONCLUSION: The results from this study revealed that Escherichia coli and staphylococci were the main etiological agents, while purulent exudates of wounds and abscesses were the main source of S. aureus. Also, a higher rate of MRSA was detected. PMID- 22216390 TI - Urinary tract infection in postmenopausal women. AB - Urinary tract infection (UTI) is the most common bacterial infection in women in general and in postmenopausal women in particular. Two groups of elderly women with recurrent UTI should be differentiated regarding age and general status: healthy, young postmenopausal women aged 50 to 70 years who are neither institutionalized or catheterized and elderly institutionalized women with or without a catheter. Bacteriuria occurs more often in elderly functionally impaired women, but in general it is asymptomatic. However, the risk factors associated with recurrent UTI in elderly women are not widely described. In a multivariate analysis it was found that urinary incontinence, a history of UTI before menopause, and nonsecretor status were strongly associated with recurrent UTI in young postmenopausal women. Another study described the incidence and risk factors of acute cystitis among nondiabetic and diabetic postmenopausal women. Independent predictors of infection included insulin-treated patients and a lifetime history of urinary infection. Borderline associations included a history of vaginal estrogen cream use in the past month, kidney stones, and asymptomatic bacteriuria at baseline. Another important factor in postmenopausal women is the potential role that estrogen deficiency plays in the development of bacteriuria. There are at least two studies showing a beneficial effect of estrogen in the management of recurrent bacteriuria in elderly women. One of these studies showed that vaginal estrogen cream reduced vaginal pH from 5.5+/-0.7 to 3.6+/-1.0, restored lactobacillus, and decreased new episodes of UTI. Another study reported similar results using an estriol vaginal ring. However, contradictory results are found in the literature. For example, additional studies found that the use of estriol-containing vaginal pessaries was less effective than oral nitrofurantoin macrocrystals in preventing UTI in postmenopausal women. Two other studies also did not find any benefit in the reduction of UTI by oral estrogen therapy. Unfortunately, the use of estrogen in preventing UTI in postmenopausal women remains questionable. New strategies have been researched for reducing the use of antibiotics in the prevention and treatment of UTI. Two of them are probiotics and cranberry juice or capsules. Although several studies regarding probiotics and cranberry juice or capsules have reported a reduction of episodes of UTI, there is no conclusive evidence that they are useful in the prevention of UTI in postmenopausal women. As for the optimal drug, dosage, and length of treatment for UTI in the elderly, there are no studies comparing these data with the treatment for young women. PMID- 22216391 TI - Prostate-Specific Antigen Density as a Powerful Predictor of Extracapsular Extension and Positive Surgical Margin in Radical Prostatectomy Patients with Prostate-Specific Antigen Levels of Less than 10 ng/ml. AB - PURPOSE: To assess the ability of preoperative variables to predict extracapsular extension (ECE) and positive surgical margin (PSM) in radical prostatectomy patients with prostate-specific antigen (PSA) levels of less than 10 ng/ml. MATERIALS AND METHODS: From January 2008 to December 2009, 121 patients with prostate cancer with PSA levels lower than 10 ng/ml who underwent radical prostatectomy were enrolled in the study. The differences in clinical factors (age, PSA, PSA density [PSAD], digital rectal examination [DRE] positivity, positive magnetic resonance imaging [MRI], Gleason sum, positive core number, and positive biopsy core percentage) with ECE and the presence of positive margins were determined and their independent predictive significances were analyzed. RESULTS: The ECE-positive patients had higher PSA, PSAD, and MRI-positive percentages, and PSM patients had higher PSA, PSAD, MRI-positive percentages, Gleason sum, and positive biopsy core percentages for prostate cancer. In the multivariate analysis, PSAD and MRI positivity were the best independent predictors for ECE, and PSA and PSAD were the best independent predictors of PSM. By receiver operating characteristic curve analysis, PSAD had better discriminative area under the curve value than did PSA for ECE (0.765 vs 0.661) and PSM (0.780 vs 0.624). The best predictive PSAD value was 0.29 ng/ml/cc for ECE and 0.27 ng/ml/cc for PSM. CONCLUSIONS: PSAD has relevance to ECE (plus MRI findings) and PSM (plus PSA). PSAD might be a powerful predictor of ECE and PSM preoperatively in patients undergoing a radical prostatectomy with PSA levels of less than 10 ng/ml. PMID- 22216392 TI - Pilot study of the clinical significance of serum and urinary her-2/neu protein in bladder cancer patients. AB - PURPOSE: HER-2/neu overexpression is documented in some bladder cancers. To our knowledge, there are no current studies evaluating urine HER-2/neu levels. Therefore, we examined the clinical significance of serum and urine HER-2/neu protein in bladder cancer. MATERIALS AND METHODS: Urothelial bladder carcinoma patients (n=38, including 31 men and 7 women) and healthy controls (n=25, including 20 men and 5 women) were included in the study. Urine cytology and serum and urine HER-2/neu levels were measured before the transurethral resection of bladder tumor procedure. Prognostic factors including tumor stage, histologic grade, tumor size, multiplicity, and preoperative urine cytology and their association with urinary HER-2/neu were analyzed by simple and multiple regression analyses. RESULTS: There was no significant difference in serum HER 2/neu between the two groups (p=0.489). The mean urinary HER-2/neu was 7,586.82 relative luminescence unit (RLU) in bladder cancer patients and 4,245.84 RLU in healthy controls. The mean RLU values of urinary HER-2/neu in the bladder cancer patient group were significantly higher than in healthy controls (p=0.012). An receiver operating characteristic curve was generated, and using the cutoff value of >=4,800 RLU of urinary HER-2/neu, 71.1% sensitivity and 84.0% specificity were obtained. Among the clinical factors, only positive preoperative urine cytology samples were associated with urinary HER-2/neu levels by both simple and multiple regression analyses. CONCLUSIONS: Bladder cancer patients demonstrated significantly higher urinary HER-2/neu than did healthy controls. These findings suggest that urinary HER-2/neu may be valuable as a new urinary marker. The application of urinary HER-2/neu needs additional investigation. PMID- 22216393 TI - Are men who undergo radical prostatectomy with lower urinary tract symptoms at an increased risk for aggressive prostate cancer? AB - PURPOSE: We aimed to determine whether prediagnostic lower urinary tract symptoms (LUTS) are associated with the aggressiveness of nonmetastatic prostate cancer (PCa) and compared the clinicopathologic features of PCa patients with and without preexisting LUTS. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 295 prostate cancer patients who underwent a radical prostatectomy (RP) by a single surgeon from 2006 to 2010. A total of 205 patients were assigned to two groups according to whether they showed preoperative LUTS (International Prostate Symptom Score [IPSS]>=8). Clinical, operative, pathologic, and postoperative functional data were collected. RESULTS: The mean age at RP was 62.7 years in the no LUTS group (group A, n=108) and 64.7 in the LUTS group (group B, n=97). The baseline mean IPSS score was 6.1 in group A and 14.6 in group B (p=0.029). The incidence of pathologic T3a stage or above was significantly higher in group B than in group A (p=0.036). The mean postoperative follow-up period was 16.8 months (range, 4 to 38 months). The mean time to biochemical recurrence was 16.9 and 18.2 months in groups A and B, respectively (p=0.148). The median time to recovery of urinary incontinence was 3.6 and 3.3 months in groups A and B, respectively. CONCLUSIONS: PCa patients without baseline LUTS had a favorable result of pathologic T stage even though there were no significant differences in biochemical recurrence or recovery of postoperative incontinence compared with patients with baseline LUTS. PMID- 22216394 TI - 120 W Greenlight HPS Laser Photoselective Vaporization of the Prostate for Treatment of Benign Prostatic Hyperplasia in Men with Detrusor Underactivity. AB - PURPOSE: Most men with benign prostatic hyperplasia (BPH) have bothersome lower urinary tract symptoms (LUTS). This study aimed to investigate the safety and efficacy of high-performance system (HPS) laser photoselective vaporization of the prostate (PVP) for the treatment of BPH in men with detrusor underactivity (DU). MATERIALS AND METHODS: From March 2009, 371 patients with BPH were divided into 2 groups according to the findings of preoperative urodynamic study: 239 (64.4%) patients with bladder outlet obstruction (BOO) and 132 (35.6%) patients with bladder outlet obstruction with detrusor underactivity (BOO+DU). 120 W HPS laser PVP was performed to resolve the BOO. The perioperative data and postoperative results at 1 month and 12 months, including the International Prostate Symptom Score (IPSS), maximum urinary flow (Qmax), and postvoid residual urine (PVR) values, were evaluated. RESULTS: Compared with the preoperative parameters, significant improvements in IPSS, Qmax, and PVR were observed in each group at 1 and 12 months after the operation. In addition, IPSS, Qmax, and PVR were not significantly different between the BOO and BOO+DU groups at 1 and 12 months after the operation. CONCLUSIONS: Surgery to relieve BOO in the patients with BPH seems to be an appropriate treatment modality regardless of the existence of DU. PMID- 22216395 TI - Outcomes of transurethral removal of intravesical or intraurethral mesh following midurethral sling surgery. AB - PURPOSE: To present outcomes of transurethral removal (TUR) of intravesical or intraurethral mesh after midurethral slings. MATERIALS AND METHODS: This was a retrospective chart review of 23 consecutive women: 20 with intravesical mesh and 3 with intraurethral mesh. RESULTS: To remove the mesh, transurethral resection with an electrode loop (TUR-E) was used in 16 women and transurethral resection with a holmium laser (TUR-H) was used in 7. The median follow-up was 2.1 months. Twenty-six percent of the women (6/23) had a mesh remnant: 6.2% (1/16) of the women treated with TUR-E and 71.4% (5/7) of the women treated with TUR-H. Of the 5 women treated with TUR-H, 3 underwent concomitant transvaginal removal. On the follow-up cystoscopic exam, a mesh remnant was observed in 3 women (1 treated with TUR-E and 2 treated with TUR-H). Vesico-vaginal fistulas were found in 2 women during and after TUR-E, respectively. Stress urinary incontinence recurred in 1 woman. CONCLUSIONS: TUR-E has a high success rate but carries a risk of bladder perforation. Complete resection using TUR-H depends on the location of the mesh and the range of motion of the instrument. PMID- 22216396 TI - Early sequential changes in bladder function after partial bladder outlet obstruction in awake sprague-dawley rats: focus on the decompensated bladder. AB - PURPOSE: We investigated bladder function, with special focus on initial functional changes, by objective report of decompensated bladder according to the percentage of residual urine volume to bladder capacity in awake, obstructed rats. MATERIALS AND METHODS: Thirty rats were randomly subjected to sham operations (n=10) or partial bladder outlet obstruction (BOO, n=20). Cystometric investigations were performed without anesthesia 1 or 2 weeks after BOO surgery. To reduce the influence of confounding factors in awake cystometry, we used simultaneous recordings of intravesical and intraabdominal pressures. Decompensated bladder was defined as the bladder with more than 20% of residual volume compared with bladder capacity. RESULTS: Compared with that in sham animals, basal pressure was elevated in both BOO groups. Threshold pressure was higher in the 2 week BOO (p<0.01) group. Compliance was decreased in the 1 week BOO group (p<0.01) and increased in the 2 week BOO group (p<0.001). Bladder capacity was not increased in the 1 week BOO group, but was increased in the 2 week BOO group (p<0.01). Decompensation was found in 62.5% of the 1 week BOO group and in 33.3% of the 2 week BOO group. CONCLUSIONS: From the earlier phase, the bladders exhibited serial changes in pressure and volume parameters, and decompensated bladders defined by the percentage of residual volume to bladder capacity could be seen. During the later phase, there was an increasing tendency of compensated bladders, accompanied by the bladders being enlarged and more compliant. PMID- 22216397 TI - Initial experience with retroperitoneal laparoendoscopic single-site surgery for upper urinary tract surgery. AB - PURPOSE: To report our initial clinical experience and perioperative outcomes of retroperitoneal laparoendoscopic single-site surgery (RLESS) for upper urinary tract surgery. MATERIALS AND METHODS: Between June 2009 and October 2010, we performed RLESS in 23 patients for various indications including radical nephrectomy (n=4), nephroureterectomy (n=2), simple nephrectomy (n=10), and renal cyst ablation (n=7). RLESS was performed with a homemade single-port device with a conventional rigid laparoscopic instrument and laparoscope. The parameters analyzed were age, body mass index, operative time, estimated blood loss, transfusion, time of oral intake, visual analogue pain scale score (VAPS), length of hospital stay, and complications. RESULTS: One case of simple nephrectomy was converted to open nephrectomy because of severe adhesion and inadequate surgical exposure. RLESS was completed in 23 patients. Mean operative time was 168.7+/ 29.2, 227.5+/-50.0, 230.0+/-56.5, and 70.5+/-8.9 minutes for simple nephrectomy, radical nephrectomy, nephroureterectomy, and renal cyst ablation, respectively. Estimated blood loss was 113.0+/-149.8, 170.0+/-156.8, 400.0+/-141.4, and 22.8+/ 16.0 ml. The time to oral intake after surgery was 1.4+/-0.5, 1.2+/-0.5, 1.5+/ 0.7, and 1.1+/-0.3 days. The mean VAPS score was 1.1+/-0.2, 2.1+/-0.5, 2.0+/-0.5, and 1.0+/-0.0 of 10 (range, 0.8 to 2.6). The hospital stay was 4.6+/-1.5, 3.7+/ 0.5, 6.0+/-1.4, and 3.2+/-1.7 days. No major perioperative complications were observed. CONCLUSIONS: The initial outcomes of our experience suggest that RLESS is a technically feasible and safe procedure for upper urinary tract surgery. Prospective comparative studies with conventional retroperitoneal laparoscopic surgery are needed to confirm the potential benefits of RLESS. PMID- 22216398 TI - Expectant Management of Ureter Stones: Outcome and Clinical Factors of Spontaneous Passage in a Single Institution's Experience. AB - PURPOSE: The aim of this study was to evaluate the outcome of ureter stones with expectant management and the clinical factors associated with stone passage in Koreans. MATERIALS AND METHODS: We reviewed the charts of patients who visited the emergency room or urological office of our institution with acute renal colic between 2001 and 2008. A total of 656 ureter stone formers were enrolled in this study who had decided to be treated by expectant management. Clinical data such as gender, age, size and location of the stone, body mass index, and previous stone history were analyzed to find the factors related to spontaneous passage of ureter stones. RESULTS: Of the 656 ureter stones, 566 stones (86.3%) were spontaneously expelled. Mean duration of follow-up was 17.5 days (range, 1 to 100 days). Mean time to stone passage was 6.8 days for stones less than 2 mm in size, 12.6 days for stones 2 to 4 mm, 14.8 days for stones 4 to 6 mm, and 21.8 days for stones 6 to 8 mm (p<0.001). The cumulative spontaneous passage rate was 55.3% in 7 days, 73.7% in 14 days, 88.5% in 28 days, and 97.7% in 60 days after the first attack. A total of 90 patients (13.7%) required interventions because of symptom relapse or renal deterioration that was related to the location and size of the stone (each, p<0.001). The more proximal the location and the larger the stone was than 6 mm, the less the chance of spontaneous passage (each, p<0.001). CONCLUSIONS: Size and location of ureter stones are the most important factors for predicting the spontaneous passage of the stone. If a patient has a distal ureter stone of less than 6 mm in size, it is acceptable for the urologist to observe for spontaneous passage for 2 months. PMID- 22216399 TI - Comparison of human muscle-derived stem cells and human adipose-derived stem cells in neurogenic trans-differentiation. AB - PURPOSE: Erectile dysfunction (ED) remains a major complication from cavernous nerve injury during radical prostatectomy. Recently, stem cell treatment for ED has been widely reported. This study was conducted to investigate the availability, differentiation into functional cells, and potential of human muscle-derived stem cells (hMDSCs) and human adipose-derived stem cells (hADSCs) for ED treatment. MATERIALS AND METHODS: We compared the neural differentiation of hMDSCs and hADSCs. Human muscle and adipose tissues were digested with collagenase, followed by filtering and centrifugation. For neural induction, isolated hMDSCs and hADSCs were incubated in neurobasal media containing forskolin, laminin, basic-fibroblast growth factor, and epidermal growth factor for 5 days. Following neural induction, hMDSCs and hADSCs were differentiated into neural cells, including neurons and glia, in vitro. RESULTS: In neural differentiated hMDSCs (d-hMDSCs) and differentiated hADSCs (d-hADSCs), neural stem cell marker (nestin) showed a significant decrease by immunocytochemistry, and neuronal marker (beta-tubulin III) and glial marker (GFAP) showed a significant increase, compared with primary hMDSCs and hADSCs. Real-time chain reaction analysis and Western blotting demonstrated significantly elevated levels of mRNA and protein of beta-tubulin III and GFAP in d-hADSCs compared with d hMDSCs. CONCLUSIONS: We demonstrated that hMDSCs and hADSCs can be induced to undergo phenotypic and molecular changes consistent with neurons. The neural differentiation capacity of hADSCs was better than that of hMDSCs. PMID- 22216400 TI - A study assessing the quality of life related to voiding symptoms and sexual functions in menopausal women. AB - PURPOSE: To investigate the impact of menopause on the quality of life (QoL) of middle-aged and older women, including their general well-being, voiding-related symptoms, and sexual distress. MATERIALS AND METHODS: To assess QoL, we administered a questionnaire that included questions about voiding-related symptoms and female sexual distress and part of the Women's Health Questionnaire. The self-administered questionnaires were completed by 1,679 women in the Korea. Data for 1,262 women were available for analysis, including premenopausal (n=307), perimenopausal (n=240), and postmenopausal (n=715) groups. RESULTS: Voiding-related discomfort increased significantly in perimenopausal and postmenopausal women compared with premenopausal women (p<0.001). General well being worsened as menopause progressed (p<0.001). Menopausal women who were older (p=0.014), had a hysterectomy (p=0.005), or had urinary incontinence (p=0.001) had more voiding-related symptoms. Hypertension (p=0.026), cardiac disease (p=0.013), and arthritis (p=0.001) resulted in significantly decreased general well-being. Women with a hysterectomy (p=0.017) and those with arthritis (p=0.004) had high sexual distress. In the menopausal group, employed women had better general well-being than did unemployed women. CONCLUSIONS: Menopause negatively affected the QoL of middle-aged and older women because of decreased general well-being and increased voiding-related symptoms. General health, even in menopausal women, was important to maintain a better QoL. To preserve the QoL of women undergoing menopause, control of menopause and underlying disease should be considered. PMID- 22216401 TI - Spontaneously ruptured renal cell carcinoma during hemodialysis in two patients with end-stage renal disease. AB - Spontaneously ruptured renal cell carcinoma (RCC) in end-stage kidney disease is very rare. Preoperative diagnosis is difficult because of the relatively small tumor size, associated hematoma, and surrounding acquired cysts. Two middle-aged men who were maintained on hemodialysis (HD) for over 10 years suddenly developed flank pain during HD. Computed tomography scans revealed an enhancing ruptured renal mass in one patient, and no obvious tumor lesion except for a hematoma in the other, both of which were later confirmed as RCCs by pathologic specimens. PMID- 22216402 TI - Xanthogranulomatous cystitis arising from the posterior wall of the bladder. AB - Xanthogranulomatous cystitis is a rare, benign chronic inflammatory disease of unknown etiology. Herein we report a case of a 41-year-old man who presented with painless hematuria and a bladder mass on imaging studies. PMID- 22216403 TI - Enantioselective Carbon-Sulfur Bond Formation: gamma Additions of Aryl Thiols to Allenoates Catalyzed by a Chiral Phosphepine. AB - An effective phosphine-catalyzed method has been developed for the enantioselective addition of aryl thiols to the gamma position of allenoates, thereby furnishing ready access to aryl alkyl sulfides in very good ee. An array of mechanistic data are consistent with addition of the chiral phosphine to the allenoate being the turnover-limiting step of the catalytic cycle. The optimized reaction conditions, as well as the mechanistic observations, differ markedly from an earlier report on asymmetric additions of alkyl thiols to allenoates, which highlights the potential for divergent behavior between alkyl and aryl thiols when serving as nucleophiles. PMID- 22216404 TI - Depression, strokes and dementia: new biological insights into an unfortunate pathway. AB - The literature emphasizes the risk of depression after a stroke. Less well known is the fact that depression may be as big a risk factor for strokes as hypertension, particularly in the older age group. This article reviews the risk for stroke and cognitive impairment consequent to depression, and describes the cardiovascular and immunological mechanisms that would appear to link depression to its cerebrovascular consequences. As well, the article refers to the brain imaging signatures that may allow prediction of impending brain injury. Finally, some questions that might be explored by future research are suggested, and some practical means to identify and help those at risk for the development of depression-associated vascular disease of the brain are suggested. PMID- 22216405 TI - Differing pattern of ambulatory blood pressure in very elderly men expresses dynamics in atherosclerotic load in the senescence. AB - To assess an impact of vascular risk factors on ambulatory blood pressure measurement (ABPM) in the elderly, we followed up a population-based cohort of men from 68 until 82 years, when 104 survivors underwent ABPM. Results. At age 68, hypertension and high clinic blood pressure (CBP) did not predict ABPM level. Smoking and low ankle-brachial index (ABI) predicted higher ABPM variability and pulse pressure (PP), but not absolute ABPM values. At age 82, hypertension, high or increasing CBP, strongly positively correlated with all variables of ABPM. Carotid stenosis, low or declining ABI during followup, correlated with higher nocturnal ABPM and PP. Concluding. Hypertension and vascular risk factors in a cohort of 68-year-old men do not result in higher ABPM at age 82, possibly due to inflection point in their pressure development. Higher ABPM reflects instead an increasing CBP and aggravating atherosclerosis during the preceding decade in that part of the cohort with previously favorable risk factor status. PMID- 22216406 TI - Enzymes in biofuels production. PMID- 22216407 TI - Aetiology, clinical presentation, and outcome of meningitis in patients coinfected with human immunodeficiency virus and tuberculosis. AB - We conducted a retrospective review of confirmed HIV-TB coinfected patients previously enrolled as part of the SAPiT study in Durban, South Africa. Patients with suspected meningitis were included in this case series. From 642 individuals, 14 episodes of meningitis in 10 patients were identified. For 8 patients, this episode of meningitis was the AIDS defining illness, with cryptococcus (9/14 episodes) and tuberculosis (3/14 episodes) as the commonest aetiological agents. The combination of headache and neck stiffness (78.6%) was the most frequent clinical presentation. Relapsing cryptococcal meningitis occurred in 3/7 patients. Mortality was 70% (7/10), with 4 deaths directly due to meningitis. In an HIV TB endemic region we identified cryptococcus followed by tuberculosis as the leading causes of meningitis. We highlight the occurrence of tuberculous meningitis in patients already receiving antituberculous therapy. The development of meningitis heralded poor outcomes, high mortality, and relapsing meningitis despite ART. PMID- 22216408 TI - Prevention of sepsis in children: a new paradigm for public policy. AB - Sepsis is one of the leading causes of death worldwide. While the management of critically ill patients with sepsis is certainly better now compared to 20 years ago, sepsis-associated mortality remains unacceptably high. Annual deaths from sepsis in both children and adults far surpass the number of deaths from acute myocardial infarction (AMI), stroke, or cancer. Given the substantial toll that sepsis takes worldwide, prevention of sepsis remains a global priority. Multiple effective prevention strategies exist. Antibiotic prophylaxis, immunizations, and healthcare quality improvement initiatives are important means through which we may reduce the morbidity and mortality from sepsis around the world. Inclusion of these strategies in a coordinated and thoughtful campaign to reduce the global burden of sepsis is necessary for the improvement of pediatric health worldwide. PMID- 22216409 TI - Integrative structural biomechanical concepts of ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is not fully explained by inflammatory processes. Clinical, epidemiological, genetic, and course of disease features indicate additional host-related risk processes and predispositions. Collectively, the pattern of predisposition to onset in adolescent and young adult ages, male preponderance, and widely varied severity of AS is unique among rheumatic diseases. However, this pattern could reflect biomechanical and structural differences between the sexes, naturally occurring musculoskeletal changes over life cycles, and a population polymorphism. During juvenile development, the body is more flexible and weaker than during adolescent maturation and young adulthood, when strengthening and stiffening considerably increase. During middle and later ages, the musculoskeletal system again weakens. The novel concept of an innate axial myofascial hypertonicity reflects basic mechanobiological principles in human function, tissue reactivity, and pathology. However, these processes have been little studied and require critical testing. The proposed physical mechanisms likely interact with recognized immunobiological pathways. The structural biomechanical processes and tissue reactions might possibly precede initiation of other AS-related pathways. Research in the combined structural mechanobiology and immunobiology processes promises to improve understanding of the initiation and perpetuation of AS than prevailing concepts. The combined processes might better explain characteristic enthesopathic and inflammatory processes in AS. PMID- 22216410 TI - Dynamic Contrast Enhanced MRI Can Monitor the Very Early Inflammatory Treatment Response upon Intra-Articular Steroid Injection in the Knee Joint: A Case Report with Review of the Literature. AB - Dynamic contrast-enhanced MRI in inflammatory arthritis, especially in conjunction with computer-aided analysis using appropriate dedicated software, seems to be a highly sensitive tool for monitoring the early inflammatory treatment response in patients with rheumatoid arthritis. This paper gives a review of the current knowledge of the emerging technique. The potential of the technique is demonstrated and discussed in the context of a case report following the early effect of an intra-articular steroid injection in a patient with rheumatoid arthritis flare in the knee. PMID- 22216411 TI - Age-related health hazards in old patients with first-time referral to a rheumatologist: a descriptive study. AB - Objective. To study the prevalence of generic age-related health hazards in elderly patient referred to a rheumatologist. Methods. Patients aged 75 or older referred to a specialized gerontorheumatological outpatient service over a period of 2 years were studied prospectively to determine the prevalence of comorbidities, a history of falls, inactivity, cognitive dysfunction, loneliness, and depression in this patient group. Results. A group of 154 patients were included in the study. Comorbidities were observed in 88% of the patients. At least one fall was reported in the last year by 44% of the patients; 44% of the patients reported low levels of health-enhancing physical activity. Depressed mood and loneliness were elevated in 30% and 31% of the patients, respectively. Mild or moderate cognitive impairment was observed in 13% of the patients. Conclusion. Patients in this study were characterized by poor physical ability, high levels of pain, and high prevalence of age-related health hazards. PMID- 22216412 TI - Association between Human Plasma Chondroitin Sulfate Isomers and Carotid Atherosclerotic Plaques. AB - Several studies have evidenced variations in plasma glycosaminoglycans content in physiological and pathological conditions. In normal human plasma GAGs are present mainly as undersulfated chondroitin sulfate (CS). The aim of the present study was to evaluate possible correlations between plasma CS level/structure and the presence/typology of carotid atherosclerotic lesion. Plasma CS was purified from 46 control subjects and 47 patients undergoing carotid endarterectomy showing either a soft or a hard plaque. The concentration and structural characteristics of plasma CS were assessed by capillary electrophoresis of constituent unsaturated fluorophore-labeled disaccharides. Results showed that the concentration of total CS isomers was increased by 21.4% (P < 0.01) in plasma of patients, due to a significant increase of undersulfated CS. Consequently, in patients the plasma CS charge density was significantly reduced with respect to that of controls. After sorting for plaque typology, we found that patients with soft plaques and those with hard ones differently contribute to the observed changes. In plasma from patients with soft plaques, the increase in CS content was not associated with modifications of its sulfation pattern. On the contrary, the presence of hard plaques was associated with CS sulfation pattern modifications in presence of quite normal total CS isomers levels. These results suggest that the plasma CS content and structure could be related to the presence and the typology of atherosclerotic plaque and could provide a useful diagnostic tool, as well as information on the molecular mechanisms responsible for plaque instability. PMID- 22216415 TI - Copper status in Alzheimer's disease and other neurodegenerative disorders: genetics, mechanisms, neurophysiology, and therapies. PMID- 22216414 TI - Depressive symptoms in a general population: associations with obesity, inflammation, and blood pressure. AB - To determine whether obesity, inflammation, or conventional risk factors are related to depressive symptoms (DeprSy) in the general population. Responses to 3 questions served to assess sense of depression. Body mass index (BMI), C-reactive protein (CRP), and other epidemiologic data of participants were available. In 1940, individuals who consulted a psychiatrist in the preceding year, or felt depressed (together DeprSy), 248 were female. Logistic regressions for adjusted associations of BMI with DeprSy were not significant as was serum CRP level. Diabetes and, in men, fasting glucose concentrations were associated with DeprSy. Systolic blood pressure (SBP) was robustly inversely associated with DeprSy in diverse models at ORs of 0.74 (95%CI 0.63; 0.89) independent of confounders, including antihypertensive and lipid-lowering medication. The use of antidepressants could not explain the reduced BP. Women are predisposed to depression with which, not BMI and CRP, but SBP is inversely associated. Anti inflammatory substances produced in depressed persons might explain the slightly lower BP. PMID- 22216413 TI - Chain gangs: new aspects of hyaluronan metabolism. AB - Hyaluronan is a matrix polymer prominent in tissues undergoing rapid growth, development, and repair, in embryology and during malignant progression. It reaches 10(7) Daltons in size but also exists in fragmented forms with size specific actions. It has intracellular forms whose functions are less well known. Hyaluronan occurs in all vertebrate tissues with 50% present in skin. Hyaluronan provides a scaffold on which sulfated proteoglycans and matrix proteins are organized. These supramolecular structures are able to entrap water and ions to provide tissues with hydration and turgor. Hyaluronan is recognized by membrane receptors that trigger intracellular signaling pathways regulating proliferation, migration, and differentiation. Cell responses are often dependent on polymer size. Catabolic turnover occurs by hyaluronidases and by free radicals, though proportions between these have not been determined. New aspects of hyaluronan biology have recently become realized: involvement in autophagy, in the pathology of diabetes., the ability to modulate immune responses through effects on T regulatory cells and, in its fragmented forms, by being able to engage several toll-like receptors. It is also apparent that hyaluronan synthases and hyaluronidases are regulated at many more levels than previously realized, and that the several hyaluronidases have functions in addition to their enzymatic activities. PMID- 22216416 TI - New acetylcholinesterase inhibitors for Alzheimer's disease. AB - Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD) because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI) continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds. PMID- 22216417 TI - Enteropathogenic bacteria contamination of unchlorinated drinking water in Korea, 2010. AB - OBJECTIVES: The purpose of this study was to assess the microbiological quality of unchlorinated drinking water in Korea, 2010. One hundred and eighty unchlorinated drinking water samples were collected from various sites in Seoul and Gyeonggi province. METHODS: To investigate bacterial presence, the pour plate method was used with cultures grown on selective media for total bacteria, total coliforms, and Staphylococcus spp., respectively. RESULTS: In the 180 total bacteria investigation, 72 samples from Seoul and 33 samples from Gyeonggi province were of an unacceptable quality (>10(2) CFU/mL). Of all the samples tested, total coliforms were detected in 28 samples (15.6%) and Staphylococcus spp. in 12 samples (6.7%). Most of the coliform isolates exhibited high-level resistance to cefazolin (88.2%), cefonicid (64.7%) and ceftazidime (20.6%). In addition, Staphylococcus spp. isolates exhibited high-level resistance to mupirocin (42%). Species of Pseudomonas, Acinetobacter, Cupriavidus, Hafnia, Rahnella, Serratia, and Yersinia were isolated from the water samples. CONCLUSIONS: The results of this study suggest that consumption of unchlorinated drinking water could represent a notable risk to the health of consumers. As such, there is need for continuous monitoring of these water sources and to establish standards. PMID- 22216418 TI - Mesoporous silica nanoparticles in biomedical applications. AB - This tutorial review provides an outlook on nanomaterials that are currently being used for theranostic purposes, with a special focus on mesoporous silica nanoparticle (MSNP) based materials. MSNPs with large surface area and pore volume can serve as efficient carriers for various therapeutic agents. The functionalization of MSNPs with molecular, supramolecular or polymer moieties, provides the material with great versatility while performing drug delivery tasks, which makes the delivery process highly controllable. This emerging area at the interface of chemistry and the life sciences offers a broad palette of opportunities for researchers with interests ranging from sol-gel science, the fabrication of nanomaterials, supramolecular chemistry, controllable drug delivery and targeted theranostics in biology and medicine. PMID- 22216419 TI - Luminescent cyanometallates based on phenylpyridine-Ir(III) units: solvatochromism, metallochromism, and energy-transfer in Ir/Ln and Ir/Re complexes. AB - [Ir(ppy)(2)(CN)(2)](-) (ppy = anion of 2-phenylpyridine) and some substituted derivatives have been investigated for their ability to interact with additional metal cations, both in solution and the solid state, via the externally-directed cyanide lone pairs, and to act as energy-donors in the resulting assemblies. [Ir(ppy)(2)(CN)(2)](-) is slightly solvatochromic, showing a blue-shift of the lowest energy absorption manifold in water compared to organic solvents, and the solubilised (t)Bu-substituted analogue [Ir((t)Buppy)(2)(CN)(2)](-) [(t)Buppy = anion of 2-(4-(t)Bu-phenyl)pyridine] is also metallochromic with coordination of the cyanide lone pairs to two M(II) cations in MeCN (M = Ba, Zn) resulting in blue-shifts of the lowest-energy absorption and emission maxima. These effects are however modest because of (i) the presence of only two cyanide groups, and (ii) the fact that the lowest-energy excited state has a substantial (3)LC component and is therefore not purely charge-transfer in nature. Crystallisation of [Ir(ppy)(2)(CN)(2)](-) as its (PPN)(+) salt in the presence of excess of lanthanide(III) salts leads to formation of assemblies based on Ir-CN-Ln bonds, which generate in the solid state either Ir(2)Ln(2)(MU-CN)(4) square assemblies or linear trinuclear species with Ir-CN-Ln-NC-Ir cores. In the Ir(2)Eu(2)(MU CN)(4) and Ir(2)Nd(2)(MU-CN)(4) complexes the Ir-based emission is substantially quenched due to energy-transfer to lower-lying f-f states of these lanthanide ions. In addition reaction of [Ir(F(2)ppy)(2)(CN)(2)](-) [F(2)ppy = cyclometallating anion of 2-(2,4-difluorophenyl)pyridine] with [Re(phen)(CO)(3)(MeCN)][PF(6)] in solution affords dinuclear IrRe and trinuclear IrRe(2) species in which {Re(phen)(CO)(3)} units are attached to the N-donor termini of one or both of the cyanide groups; these complexes have been structurally characterised and display quantitative Ir->Re energy-transfer, showing luminescence only from the Re(I) terminus on excitation of the Ir(III) unit. PMID- 22216420 TI - Coordination versatility of tridentate pyridyl aroylhydrazones towards iron: tracking down the elusive aroylhydrazono-based ferric spin-crossover molecular materials. AB - The two potentially tridentate and monoprotic Schiff bases acetylpyridine benzoylhydrazone (HL(1)) and acetylpyridine 4-tert-butylbenzoylhydrazone (HL(2)) demonstrate remarkable coordination versatility towards iron on account of their propensity to undergo tautomeric transformations as imposed by the metal centre. Each of the pyridyl aroylhydrazone ligands complexes with the ferrous or ferric ion under strictly controlled reaction conditions to afford three six-coordinate mononuclear compounds [Fe(II)(HL)(2)](ClO(4))(2), [Fe(II)L(2)] and [Fe(III)L(2)]ClO(4) (HL = HL(1) or HL(2)) displaying distinct colours congruent with their intense CT visible absorptions. The synthetic manoeuvres rely crucially on the stoichiometry of the reactants, the basicities of the reaction mixtures and the choice of solvent. Electrochemically, each of these iron compounds exhibits a reversible metal-centred redox process. By all appearances, [Fe(III)(L(1))(2)]ClO(4) is one of only two examples of a crystallographically elucidated iron(III) bis-chelate compound of a pyridyl aroylhydrazone. Several pertinent physical measurements have established that each of the Schiff bases stabilises multiple spin states of iron; the enolate form of these ligands exhibits greater field strength than does the corresponding neutral keto tautomer. To the best of our knowledge, [Fe(III)(L(1))(2)]ClO(4) and [Fe(III)(L(2))(2)]ClO(4) are the first examples of ferric spin crossovers of aroylhydrazones. Whereas in the former the spin crossover (SCO) is an intricate gradual process, in the latter the (6)A(1)<->(2)T(2) transition curve is sigmoidal with T(1/2)~280 K and the SCO is virtually complete. As regards [Fe(III)(L(1))(2)]ClO(4), Mossbauer and EPR spectroscopic techniques have revealed remarkable dependence of the spin transition on sample type and extent of solvation. In frozen MeOH solution at liquid nitrogen temperature, both iron(III) compounds exist wholly in the doublet ground state. PMID- 22216424 TI - Forced disappearance in an era of globalization: biopolitics, shadow networks, and imagined worlds. AB - In this article, I argue that the practice of forced disappearance of persons on the part of paramilitary groups has become linked to specific processes of globalization. Global flows related to biopolitics, global crime networks, and dehumanizing imaginations reproduced by mass media together constitute a driving force behind forced disappearances. Drawing on ethnographic fieldwork in the Colombian city of Medellin, I analyze how these global flows interact with local armed actors, helping create a climate conducive to forced disappearance. These mechanisms in Colombia show similarities to those in some African and Asian countries. Gaining insight into the mechanisms behind forced disappearance may help prevent it from occurring in the future. Enhancing social inclusion of residents, unraveling the transnational crime networks in which perpetrators are involved, and disseminating rehumanizing images of victims all contribute to curbing the practice of forced disappearance. PMID- 22216422 TI - Dunbar's number: group size and brain physiology in humans reexamined. AB - Popular academic ideas linking physiological adaptations to social behaviors are spreading disconcertingly into wider societal contexts. In this article, we note our skepticism with one particularly popular-in our view, problematic-supposed causal correlation between neocortex size and social group size. The resulting Dunbar's Number, as it has come to be called, has been statistically tested against observed group size in different primate species. Although there may be reason to doubt the Dunbar's Number hypothesis among nonhuman primate species, we restrict ourselves here to the application of such an explanatory hypothesis to human, culture-manipulating populations. Human information process management, we argue, cannot be understood as a simple product of brain physiology. Cross cultural comparison of not only group size but also relationship-reckoning systems like kinship terminologies suggests that although neocortices are undoubtedly crucial to human behavior, they cannot be given such primacy in explaining complex group composition, formation, or management. PMID- 22216425 TI - Scents of place: the dysplacement of a First Nations community in Canada. AB - Here I explore how the experience of place at a First Nations reserve in Ontario, located in the middle of Canada's "Chemical Valley," is disrupted by the extraordinary levels of pollution found there. In so doing, I give special attention to air pollution and residents' responses to associated odors - that is, to the sense of smell. Focusing on a unique feature of smell - that it operates primarily through indexicality - I draw on C. S. Peirce's semiotic framework to highlight ways in which perception of odors entails embodiment of the perceived substance, thus connecting self and surroundings in profound and transformative ways. Ultimately, I argue that the local smellscape, while having reinforced a sense of positive emplacement on the reserve in the past, is now, because of the constant presence of toxic fumes, instilling in residents a profound sense of alienation from the ancestral landscape - a condition I call "dysplacement." PMID- 22216428 TI - CE and CEC innovations. PMID- 22216427 TI - Abstracts of the 49th Annual Meeting of the ISCEV (International Society for Clinical Electrophysiology of Vision). September 18-23, 2011. Lac-Beauport, Quebec, Canada. PMID- 22216426 TI - Ethnographic empathy and the social context of rights: "rescuing" Maasai girls from early marriage. AB - Esther is one of many young Maasai girls in Kenya "rescued" from early marriage. Her story is conventionally portrayed (trans)nationally and locally as a struggle between conservative pastoral patriarchs and the individual right of young girls to an education. I offer an ethnographic contextualization of the underlying factors giving rise to practices of early marriage, among the Maasai in Enkop, highlighting the contemporary predicaments of pastoralism in the face of population growth, climactic instability, and land-tenure reform and the insecurities and challenges around formal education. Through the intimate portrayal of Esther's case, early marriage is situated not as a relic of tradition and malicious patriarchy but, rather, as a contemporary adaptation to livelihood insecurity. I illustrate how prevailing concepts of "tradition," "culture," "victimhood," and "collective rights" in human rights theory obscure important structural factors that give rise to early marriage and deflect attention from effective policy initiatives. PMID- 22216429 TI - An automated capillary electrophoresis system for high-speed separation of DNA fragments based on a short capillary. AB - A high-speed DNA fragment separation system was developed based on a short capillary and a slotted-vial array automated sample introduction system. The injection process of DNA sample in a short capillary was investigated systematically with three injection techniques including constant-field-strength, low-field-strength and translational spontaneous injections. Under the optimized conditions, picoliter-scale sample plugs (corresponding to ca. 20-MUm plug length) were obtained, which ensure the high-speed and high-efficiency separation for DNA fragments with a short effective separation length. Other separation conditions including the sieving matrix concentration, separation field strength and effective separation length were also optimized. The present system was applied in the separation of PhiX174-Hae III digest DNA marker. With an effective separation length of 2.5 cm, the separation could be achieved in <100 s with plate heights ranging from 0.21 to 0.74 MUm (corresponding to plate numbers from 4.86 * 10(6) to 1.36 * 10(6)/m). The repeatabilities for the migration time of the eleven fragments were between 0.4 and 1.1% RSD (n=8). By using the automated continuous injection method, the separation for four different DNA samples could be achieved within 250 s. The present system was further applied in the fast sizing of real DNA samples of PCR products. PMID- 22216430 TI - A novel, neutral hydroxylated octadecyl acrylate monolith with fast electroosmotic flow velocity and its application to the separation of various solutes including peptides and proteins in the absence of electrostatic interactions. AB - A neutral hydroxylated octadecyl monolith (ODM-OH) for reversed-phase capillary electrochromatography has been developed. The ODM-OH was prepared by the in situ polymerization of octadecyl acrylate and pentaerythritol triacrylate (PETA) in a ternary porogenic solvent. Pentaerythritol triacrylate possesses a hydroxyl functional group, which imparts the monolith with a hydrophilic group, thus the acronym ODM-OH. The ODM-OH column exhibited cathodal EOF over a wide range of pH and ACN concentration in the mobile phase despite the fact that it was devoid of any fixed charges. This ODM-OH monolith exhibited stronger EOF than its counterpart the ODM made from the in situ polymerization of octadecyl acrylate and trimethylolpropane trimethacrylate. Similar to ODM, it is believed that the EOF was due to the adsorption of ions from the mobile phase onto the surface of the monolith thus imparting the neutral monolithic column the zeta potential necessary to support the EOF. The higher EOF exhibited by ODM-OH was due to the presence of polar OH groups on its surface, which would favor stronger adsorption of ions from the mobile phase. The wide applications of the neutral ODM-OH column were demonstrated in the separation of a wide range of small and large solutes. As a typical result, the ODM-OH was able to separate proteins quite rapidly yielding 200,000 plates/m. PMID- 22216431 TI - Naphthyl methacrylate-phenylene diacrylate-based monolithic column for reversed phase capillary electrochromatography via hydrophobic and pi interactions. AB - A neutral naphthyl methacrylate-phenylene diacrylate-based monolith (NPM) was introduced for RP-CEC of various neutral and charged solute probes via hydrophobic and pi interactions. The NPM column was prepared by the in situ polymerization of naphthyl methacrylate as the functional monomer and 1,4 phenylene diacrylate (PDA) as the crosslinker in a ternary porogenic solvent containing cyclohexanol, dodecanol and water. The NPM column exhibited cathodal EOF despite the fact that it was devoid of any fixed charges. NPM exhibited stronger EOF than its counterpart naphthyl methacrylate monolith (NMM) made from the in situ polymerization of naphthyl methacrylate and trimethylolpropane trimethacrylate (TRIM). As for NMM, it is believed that the EOF arises from the adsorption of mobile phase ions onto the monolith surface. The higher EOF exhibited by NPM may be attributed to the acrylate nature of PDA as compared to the methacrylate nature of TRIM, and therefore PDA has a higher binding capacity for mobile phase ions due to its higher polarity than TRIM. The adsorption of mobile phase ions together with the additional pi interactions offered by the aromatic rings of the NPM matrix modulated solute retention and separation selectivity. The applications of NPM were demonstrated by the separation of a wide range of small and large solutes including peptides, tryptic peptide maps and proteins. PMID- 22216432 TI - Comparative enantioseparations of pharmaceuticals in capillary electrochromatography on polysaccharide-based chiral stationary phases containing selectors with or without chlorinated derivatives. AB - The screening conditions of an existing chiral strategy in CEC were tested for their applicability on four chlorine-containing polysaccharide-based stationary phases. The selectors of these phases are cellulose tris(3-chloro-4 methylphenylcarbamate), amylose tris(5-chloro-2-methylphenylcarbamate), cellulose tris(4-chloro-3-methylphenylcarbamate) and cellulose tris(3,5 dichlorophenylcarbamate). The enantioselectivity of these phases was compared with those of the four phases without chlorine (Chiralpak(r) AD-RH, Chiralcel(r) OD-RH, Chiralpak(r) AS-RH and Chiralcel(r) OJ-RH) used in the earlier defined strategy. A test set of 48 structurally diverse drug compounds was analyzed using the screening conditions of the strategy. These results led to possibilities to upgrade the current screening strategy so that improved success rates are obtained. The chlorine-containing chiral stationary phases demonstrated an added value to the screening process since they showed enantioresolution for compounds not resolved by the chiral stationary phases not containing chlorine in their structure. PMID- 22216433 TI - Multi-walled carbon nanotube composites with polyacrylate prepared for open tubular capillary electrochromatography. AB - A new phase containing immobilized carbon nanotubes (CNTs) was synthesized by in situ polymerization of acid-treated multi-walled CNTs using butylmethacrylate (BMA) as the monomer and ethylene dimethacrylate as the crosslinker on a silanized capillary, forming a porous-layered open-tubular column for CEC. Incorporation of CNT nanomaterials into a polymer matrix could increase the phase ratio and take advantage of the easy preparation of an OT-CEC column. The completed BMA-CNT column was characterized by SEM, ATR-IR, and EOF measurements, varying the pH and the added volume organic modifier. In the multi-walled CNTs structure, carboxylate groups were the major ionizable ligands on the phase surface exerting the EOF having electroosmotic mobility, 4.0 * 10(4) cm2 V(-1)1 S(-1)1, in the phosphate buffer at pH 2.8 and RSD values (n=5), 3.2, 4.1, and 4.3%, for three replicate capillaries at pH 7.6. Application of the BMA-CNT column in CEC separations of various samples, including nucleobases, nucleosides, flavonoids, and phenolic acids, proved satisfactory upon optimization of the running buffers. Their optima were found in the borate buffers at pH 9.0/50 mM, pH 9.5/10 mM/50% v/v ACN, and pH 9.5/30 mM/10% v/v methanol, respectively. The separations could also be used to assess the relative contributions of electrophoresis and chromatography to the CEC mechanism by calculating the corresponding velocity and retention factors. Discussions about interactions between the probe solutes and the bonded phase included the pi-pi interactions, electrostatic repulsion, and hydrogen bonding. Furthermore, a reversed-phase mode was discovered to be involved in the chromatographic retention. PMID- 22216434 TI - Abstracts of the ASTS (American Society of Transplant Surgeons) 12th Annual State of the Art Winter Symposium. January 12-15, 2012. Miami, Florida, USA. PMID- 22216435 TI - NrF2 /Keap1 as gatekeepers of redox homeostasis - do they prevent or cause cancer? PMID- 22216436 TI - Assay of vitamin B in urine by capillary electrochromatography with methacrylate based monolithic column. AB - A novel and simple method for the separation of major vitamin B analytes, such as thiamine, riboflavin, nicotinamide, vitamin B4, pyridoxine, has been developed by CEC using the monolithic column. It has been found that the baseline separation of the five analytes could be achieved with 5.0 mM phosphate buffer at pH 4.0. Compared with the open-tubular capillary and the bared capillary columns, the poly(butylmethacrylate-co-ethylene glycol dimethacrylate) monolithic capillary could exhibit the best resolution in the analysis. Then the method was validated and the linear calibration ranges were obtained with correlation coefficients more than 0.997. The precision and the recovery were also investigated and showed a good result. Furthermore, the proposed method was successfully applied to assay the concentration of vitamin B analytes and the metabolic situation in human urine samples. PMID- 22216437 TI - Microphthalmia-associated transcription factor, melanoma, and renal carcinoma: the small ubiquitin-like modifier connection. PMID- 22216438 TI - Detrapping particles in gel electrophoresis: a numerical study of different pulsed field sequences. AB - Large particles tend to get trapped in dead-ends more often than small particles when electrophoresed in random cross-linked gels. It is known that pulsed electric fields can be used to free particles from these traps, leading to an increase in velocity and improved size separation. Although numerical and theoretical models have been proposed for the mobility of smaller particles in the so-called Ogston sieving limit, the effect of pulsed fields on trapping has not been previously modeled. We present a numerical study of detrapping and we compare our results with those of To and Boyde (To, K.-Y., Boyde, T. R., Electrophoresis 1993, 14, 597). We use an exact numerical method to examine detrapping in various two-dimensional systems of obstacles. We also propose and investigate new ways to optimize the pulse sequence in order to separate particles of different sizes. PMID- 22216439 TI - Preliminary studies of a novel multifunctional wide-bore electrophoresis system. AB - This paper presents the results obtained from a novel multifunctional analysis platform established on the basis of wide-bore electrophoresis (WBE) and CE. The WBE-CE system integrated various analytical steps including separation, transfer, reaction, detection, and storage into a single system. During the WBE-CE process, a distinct three-electrode format was adopted to continuously separate and transfer samples between WBE and CE without the interruption of switching on-and off the power suppliers. This continuous mode of operation also helped to eliminate the need for exactly timing the transfer of specific samples zone from WBE to CE and avoided the danger of missing specific samples. Samples representing mixtures of acids, bases, or proteins were analyzed on this system for evaluating its feasibility and applicability. The results indicated that the resolution achieved on this WBE-CE system was better than either the WBE or the CE alone. Further, samples transferred out of the WBE system could participate in online reaction, such as enzymatic reaction in the CE. Alternatively, samples from the WBE system could be transferred out and stored offline in a vial for post-transfer reaction. The results demonstrated that this WBE-CE system has the potential to be a multifunctional platform for a range of applications. PMID- 22216440 TI - On-line drug metabolites generation and their subsequent target analysis by capillary zone electrophoresis with UV-absorption detection. AB - This study presents the in-capillary enzymatic biotransformation of dextromethorphan, an antitusive drug and opioid receptor antagonist, and subsequent electrophoretic separation of its products. The study includes the optimization of separation parameters to fulfill the requirements of an online microreaction. The analyses were performed in a bare fused-silica capillary using 100 mM sodium tetraborate (pH 10.0) mixed with linear polyacrylamide (20%, v/v) and 2-propanol (10%, v/v). This BGE was suitable for monitoring both off-line and in-capillary incubations. The partial filling technique enabled the enzymatic reaction to be carried out in its optimal environment (20 mM sodium phosphate, pH 7.4). Finally, in-capillary microreaction in the presence of cytochrome P450 3A4 gave satisfactory outcomes. PMID- 22216441 TI - A new mutation with staggering effects. PMID- 22216442 TI - Glutamate receptors: emerging players in melanomagenesis. PMID- 22216443 TI - An integrated on-chip sirtuin assay. AB - A microchip-based assay to monitor the conversion of peptide substrates by human recombinant sirtuin 1 (hSIRT1) is presented. For this purpose a fused silica microchip consisting of a microfluidic separation structure with an integrated serpentine micromixer has been used. As substrate for the assay, we used a 9 fluorenylmethoxycarbonyl (Fmoc)-labeled tetrapeptide derived from the amino acid sequence of p53, a known substrate of hSIRT1. The Fmoc group at the N-terminus resulting from solid-phase peptide synthesis enabled deep UV laser-induced fluorescence detection with excitation at 266 nm. The enzymatic reaction of 0.1 U/MUL hSIRT1 was carried out within the serpentine micromixer using a 400 MUM solution of the peptide in buffer. In order to reduce protein adsorption, the reaction channel was dynamically coated with hydroxypropylmethyl cellulose. The substrate and the deacetylated product were separated by microchip electrophoresis on the same chip. The approach was successfully utilized to screen various SIRT inhibitors. PMID- 22216444 TI - Is proteomics starting to deliver on biomarkers discovery. PMID- 22216445 TI - Evaluation of enantioselective binding of fluoxetine to human serum albumin by ultrafiltration and CE--experimental design and quality considerations. AB - Several pharmacokinetic processes are affected by enantioselectivity (ES). At the level of distribution, protein binding (PB) is one of the most important. The enantioselective binding of fluoxetine (FLX) to HSA has been evaluated in this work by ultrafiltration of FLX-HSA mixtures and chiral analysis of unbound fractions by EKC-CD. PB, affinity constants (K) and ES were obtained for both enantiomers of FLX. In order to improve the consistency of the estimations, the evaluation of affinity constants of each enantiomer was performed using two designs, one keeping constant the total concentration of protein and varying the total concentration of the enantiomers, and the other in the opposite way, in both cases via an unusual short-concentration interval strategy to assure model validity. Different mathematical approaches were compared and characterised and some of them, judged as the most consistent under the experimental conditions used, were selected to provide final estimates. Quality considerations include criteria for three critical aspects: (i) detecting/eliminating outliers, (ii) checking the number of binding sites in the protein and (iii) evaluating the robustness of each approach. The differences on estimates from the selected approaches were used as an uncertainty source to delimit the reported values. The ES of HSA for FLX enantiomers was approximate. Estimates include the assumptions of independent and competitive models. In the last case, a SIMPLEX function was designed capable of simultaneously optimizing the non-linear binding models for both enantiomers, thus improving the consistence of results. PMID- 22216446 TI - Identification of poliovirions and subviral particles by capillary electrophoresis. AB - Poliovirions, purified from infected cell extracts with anion-exchange chromatography, can be analyzed and identified by CE in untreated fused silica capillaries using UV detection. Other subviral particles can be eluted as well from the same infected cell extract using a higher salt concentration buffer on the ion-exchange chromatography. Virions can be identified because of their conversion into empty capsids upon heating at 56 degrees C. As a result of heating, the viral genome is released from the capsid. Here, we show that during this incubation some intermediate particles were found. The latter were identified by enzymatic peak shift analysis. The high salt concentration eluate subviral particles were analyzed with preincubation affinity CE together with their sensitivity for RNase and proteinase K treatment. Electropherograms of the higher salt concentration eluate display a mixture of at least four different subviral particles. One particle proved to have an [N1, H] antigenicity and was resistant to RNase and proteinase K digestion. The remaining particles were all sensitive to proteinase K treatment. This CE method proved to be valuable in the detection, identification and analysis of poliovirions and poliovirus particles offering an alternative powerful, cheap, fast and easy analysis method. PMID- 22216447 TI - NaDDBS as a dispersion agent for multiwalled carbon nanotubes in capillary EKC separation of nucleotides. AB - A novel pseudostationary phase (PSP) of multiwalled carbon nanotubes (MWCNTs) dispersed with sodium dodecylbenzenesulfonate (NaDDBS) was used for the EKC separation of nucleotides. NaDDBS has a long hydrophobic chain and a benzylsulfonate group. It suspends more MWCNTs (about 100-fold) than SDS, and the pi-pi interaction between the benzene ring of NaDDBS and MWCNTs prolongs the slurry suspension time. Using NaDDBS as a surfactant can reduce the required amount of MWCNTs and decrease the baseline noise. To produce a stable suspension, the optimum ratio (w/w) of MWCNTs to NaDDBS was investigated with turbidimetry. In this context, several parameters affecting EKC separation were studied, including buffer pH, composition, concentration, and the organic modifier. Use of NaDDBS (8 mg/L)/MWCNTs (0.8 mg/L) as the PSP in a phosphate buffer (30 mM, pH 8) yielded complete resolution of seven geometric isomers of a nucleoside monophosphate. In stacking mode, with 10% MeOH in the sample plug, the mixture of nucleoside mono-, di-, and tri-phosphates was satisfactorily separated in phosphate buffer (50 mM, pH 9). The results indicate that nucleotides with bases containing more electron-withdrawing groups interact more strongly with MWCNTs. The system has been used to separate oligonucleotides, and to analyze nucleotides in a complex matrix sample. PMID- 22216448 TI - Dual CD system-modified MEEKC method for the determination of clemastine and its impurities. AB - A dual system of CDs was used for the first time in MEEKC with the aim of determining clemastine and its three main related impurities in both drug substances and tablets. The addition of methyl-beta-cyclodextrin and heptakis(2,6 di-O-methyl)-beta-cyclodextrin to the microemulsion pseudo-stationary phase was essential to increase the resolving power of the system to obtain a baseline separation among the compounds. The best microemulsion composition was identified by mixture design and the effects of the factors concentrations of CDs and voltage were investigated by a response surface study applying a Central Composite Design. In both cases, Derringer's desirability function made it possible to find the global optimum, which corresponded to the following combination: microemulsion, 89.8% 10 mM borate buffer pH 9.2, 1.5% n-heptane and 8.7% of SDS/n-butanol in 1:2 ratio; 18 mM methyl-beta-cyclodextrin, 38 mM heptakis(2,6-di-O-methyl)-beta-cyclodextrin, 17 kV. By applying these conditions, the separation was completed in about 5.5 min. The method was validated following International Conference on Harmonisation guidelines and was applied to a real sample of clemastine tablets. PMID- 22216449 TI - Statistical evaluation of CZE-UV and CZE-ESI-MS data of intact alpha-1-acid glycoprotein isoforms for their use as potential biomarkers in bladder cancer. AB - alpha-1-acid glycoprotein (AGP) is a highly heterogeneous protein that presents a vast number of isoforms (molecules of the protein differing in its peptidic and/or glycosidic moieties). In the last years, several authors have studied the potential use of AGP as a cancer biomarker. These studies focus on the correlation of different features of AGP structure (i.e. fucosylation, antennarity) with cancer or on the total protein blood concentration. In this study, the potential of CZE-UV and CZE-ESI-MS analysis of intact AGP isoforms to study the correlation of this protein with bladder cancer is shown. Samples from 16 individuals (eight healthy, eight bladder cancer) were analyzed and characterized in great detail including data on intact protein isoforms and on released glycans. The analytical data were evaluated employing different statistical techniques (ANOVA; principal component analysis, PCA; linear discriminant analysis; and partial least squares-discriminant analysis). Statistical differences between the two groups of study were observed. The best results were obtained by linear discriminant analysis of the CZE-ESI-MS data for intact AGP isoforms (93.75% of correct classification). Due to MS characterization, it can be observed that differences between the samples are mainly due to higher abundance of AGP isoforms containing tri- and tetra antennary fucosylated oligosaccharides in cancer patients. The results show the great potential of CE-MS in combination with advanced data processing for the use of intact protein isoforms as disease biomarkers. PMID- 22216450 TI - Use of organic solvent to prevent protein adsorption in CE-MS experiments. AB - Protein adsorption onto capillary wall often hampers CE separations, particularly in the CZE mode. Electrostatic interactions are not the only factors affecting adsorption, as hydrophobic interactions and/or protein conformational changes are also involved in the adsorption phenomenon. Numerous methods can be used to reduce or avoid adsorption, such as (i) addition of low molecular weight molecules in the BGE, (ii) use of surfactants, or (iii) capillary coatings. However, most of these methods are not MS-compatible. In this study, we evaluated the addition of organic solvent as an alternative MS-compatible method to decrease protein adsorption. The effect of the solvent addition was emphasized using classical methods for estimating reversible and irreversible adsorption. In many cases, organic solvents were effective at decreasing adsorption. However, the influence of the organic solvent on protein adsorption should be evaluated case-by-case in CE method development. PMID- 22216451 TI - P-REX1, a Rac guanine exchange factor, links melanocyte development and melanoma progression. PMID- 22216453 TI - Capillary electrophoresis of the proteolytic activity of the stratum corneum obtained by tape stripping. AB - Serine proteases and some cathepsins are present in the stratum corneum. They are known to play a significant role in the pathophysiological mechanism of several dermatological conditions (e.g. atopic dermatitis) and in the induction of itch. Tape stripping of skin is a simple technique used in the investigation of skin barrier function and in the penetration of topically applied drugs. Herein, we show that CE, under stacking conditions, is a well-suited technique to measure the proteolytic activity of enzymes in the stratum corneum. Disks of about 6 mm (id) were cut from adhered tapes and submerged directly in a buffer containing the appropriate peptide substrate. After incubation, the split peptides were separated and detected directly by CE at 214 nm in a borate buffer. The esterase activity on N-benzoyl-tyrosine ethyl ester and the amidase activity on succinyl Ala-Ala-Pro-Phe-p-nitroanilide and the splitting of hemoglobin were detected by CE. The esterase activity was the highest when compared to the proteolytic activities. Skin scratching increased the enzymatic activity adhered to the tapes. The CE offered over the traditional end-point colorimetric methods the ability to measure the low enzymatic activity and the ability to detect the released peptides directly. This technique is simple, non-invasive, easy to perform and uses non-expensive substrates. It can be useful in quantifying cathepsins and serine proteases in the skin. PMID- 22216452 TI - Highly sensitive trivalent copper chelate-H2O2 system for CE-chemiluminescent detection of luminol-type compounds. AB - Luminol-type compounds can be used as chemiluminescent (CL) derivatization reagents for amines, carboxylic acids and protein. Copper chelate diperiodatocuprate(III) (K5[Cu(HIO6)2], DPC) was synthesized by complexation of copper at trivalent oxidation state and periodate in a strong basic medium. It was found that DPC can greatly enhance the reaction between luminol-type compounds and H2O2 to produce very strong CL emission. Based on this fact, a rapid CE method combined with high-sensitive end-column CL detection was established to simultaneously analyze luminol and N-(4-aminobutyl)-N ethylisoluminol (ABEI) with wide concentration range of 3.0-300 nmol/L in 5 min. The RSDs of the signal intensity and the migration time were less than 3.9 and 7.0% for a standard sample containing 100 nmol/L luminol and ABEI (n=5), respectively. The investigation implies that DPC is a promising sensitizer for CE CL detection of a great variety of biomolecules and drugs in biological samples after derivatization using luminol derivatives. PMID- 22216454 TI - A rapid and sensitive CE method with field-enhanced sample injection and in capillary derivatization for selenomethionine metabolism catalyzed by flavin containing monooxygenases. AB - A rapid and sensitive electrophoretically mediated microanalysis method with field-enhanced sample injection (FESI) for in-capillary derivatization was developed to determine selenomethionine (SeMet) and selenomethionine selenoxide (SeOMet). Phthalic anhydride (PA) was selected as the derivatization reagent due to the fast reaction at room temperature and the stability of derivatives. The in capillary derivatization was accomplished by electrophoretically mixing PA and sample plugs. PA reagent was introduced hydrodynamically into the capillary, whereas the sample solution was injected electrokinetically, thus allowing a selective preconcentration of the analytes by FESI. For FESI, the optimum sample solvent was 2 mM borate solution. The borate buffer was suitable for both in capillary derivatization and separation of the derivatives. The combination of electrophoretically mediated microanalysis with FESI for in-capillary derivatization was successfully achieved with about 800-fold concentration sensitivity enhancement compared to direct CE-UV detection in the same setup. The present method is miniaturized and fully automated, which ensures the on-line derivatization, stacking, separation and detection in 10 min. Finally, the developed method was successfully applied to measure enzyme activities by analyzing the reaction mixtures of SeMet with human flavin-containing monooxygenases (FMO). The results showed that both FMO1 and FMO3, but not FMO5 could catalyze the Se-oxygenation of SeMet. PMID- 22216455 TI - Practical hints on meaningful use. PMID- 22216456 TI - A practical guide to prescribing daily disposables. PMID- 22216457 TI - The advantages of an incorporated practice. PMID- 22216458 TI - It's all in a name--or is it? PMID- 22216459 TI - Abstracts of the Asian Pacific Monothematic Meeting on Helicobacter Pylori 2012. January 13-15, 2012. Kuala Lumpur, Malaysia. PMID- 22216460 TI - An appreciation of Ralph Marvin Steinman (1943-2011). AB - Ralph Steinman, an editor at the Journal of Experimental Medicine since 1978, shared the 2011 Nobel Prize in Physiology or Medicine for his discovery of dendritic cells (DCs) and their role in immunity. Ralph never knew. He died of pancreatic cancer on September 30, 3 days before the Nobel announcement. Unaware of his death at the time of their announcement, the Nobel Committee made the unprecedented decision that his award would stand. Ralph was the consummate physician-scientist to the end. After his diagnosis, he actively participated in his 4.5 years of treatments, creating experimental therapies using his own DCs in conjunction with the therapies devised by his physicians, all the while traveling, lecturing, and most of all pursuing new investigations in his laboratory. For 38 years-from his discovery of DCs to his Nobel Prize-Ralph pioneered the criteria and methods used to identify, isolate, grow, and study DCs. He and his colleagues demonstrated that DCs are initiators of immunity and regulators of tolerance. In his most recent studies, Ralph was harnessing the specialized features of DCs to design improved vaccines. The following synopsis describes some of his seminal discoveries. PMID- 22216461 TI - Remembering Ralph Steinman. PMID- 22216463 TI - Abstracts of the 23rd European Congress of Pathology. August 27-September 1, 2011. Helsinki, Finland. PMID- 22216462 TI - Tryptophan auxotroph mutants suppress the superroot2 phenotypes, modulating IAA biosynthesis in arabidopsis. AB - Plant phytohormone, Indole-3-acetic acid (IAA ), is synthesized by tryptophan (trp) dependent and independent pathway. Here we report that tryptophan auxotroph mutants completely suppressed the abnormalities of auxin over production mutant, superroot2. SUR2 is considered to modulate Trp dependent pathway, resulting IAA accumulation in Arabidopsis. Tryptophan auxotroph mutants showed hyper sensitivity to the auxin polar transport inhibitor, NPA, on the phenotype of reduced gravitropism. These results together with the results of histochemical analyses, tryptophan auxotroph mutants seem to have a complete defect in Trp dependent IAA biosynthesis pathway, and it is also suggested that the Trp dependent pathway is responsible for the normal root gravitropism. PMID- 22216464 TI - Ethnic differences in spirituality in a sample of men and women in diverse substance abuse treatment settings: implications for practitioners. AB - There has been a growing recognition of the need to understand the role of spirituality in ethnically diverse populations in social work and other helping professions. Although researchers are increasingly examining ethnic variations in prevalence rates, treatment utilization, and treatment outcomes for individuals with substance abuse problems, limited research attention has been focused on the relationship between spirituality and ethnicity in the substance abuse field. The current study addressed this gap in the literature by comparing three ethnically diverse groups in terms of multiple aspects of spirituality. Findings showed that African Americans scored significantly higher in spiritual well-being, religiousness, and cognitive orientation toward spirituality compared to Whites, whereas Whites scored significantly higher in existential well-being compared to African Americans. Hispanics scored significantly lower in experiential/phenomenological dimension of spirituality compared to Whites and African Americans. Implications for practitioners are discussed. PMID- 22216466 TI - Good-bye pyramid, hello food plate. USDA scraps food pyramid in favor of easier model. PMID- 22216465 TI - Combining niacin with statins: does it help heart health? PMID- 22216467 TI - A one-two punch to ward off migraines. PMID- 22216468 TI - A major advance in treating hepatitis C. PMID- 22216469 TI - Intense activity may help lower your stroke risk. PMID- 22216470 TI - Is it OK to eat or drink grapefruit products when I'm taking a statin? PMID- 22216471 TI - My doctor has prescribed antibiotics in the past to help prevent traveler's diarrhea, but your recent article on the subject says not to use them for prevention. Why not? PMID- 22216472 TI - National and local vulnerability to climate-related disasters in Latin America: the role of social asset-based adaptation. AB - The Latin American region is particularly prone to climate-related natural hazards. However, this article argues that natural hazards are only partly to blame for the region's vulnerability to natural disasters with quantitative evidence suggesting instead that income per capita and inequality are main determinants of natural disaster mortality in Latin America. Locally, the region's poor are particularly susceptible to climate-related natural hazards. As a result of their limited access to capital, adaptation based on social assets constitutes an effective coping strategy. Evidence from Bolivia and Belize illustrates the importance of social assets in protecting the most vulnerable against natural disasters. PMID- 22216473 TI - The representation of the female body in the multimedia works of Regina Jose Galindo. AB - The female body is central to the performance art, poetry and blog site interventions of Guatemalan Regina Jose Galindo. While Galindo is best known for her performance work, this article compares the hereto overlooked, distinctive and often shocking representations of the female body across her multimedia outputs. We first consider the ways in which, in all three media, Galindo presents an 'excessive', carnivalised, grotesque and abject female body. Second, we analyse representations of the female body that has been subjected to violence at a private and public level. In so doing, we show how Galindo not only contests hegemonic visions of gender and (national) identity but also challenges the viewer/reader to engage with, rather than look away from, the violence to which women are subjected in patriarchal society. PMID- 22216474 TI - Shifting subjects of health-care: placing "medical tourism" in the context of Malaysian domestic health-care reform. AB - "Medical tourism" has frequently been held to unsettle naturalised relationships between the state and its citizenry. Yet in casting "medical tourism" as either an outside "innovation" or "invasion," scholars have often ignored the role that the neoliberal retrenchment of social welfare structures has played in shaping the domestic health-care systems of the "developing" countries recognised as international medical travel destinations. While there is little doubt that "medical tourism" impacts destinations' health-care systems, it remains essential to contextualise them. This paper offers a reading of the emergence of "medical tourism" from within the context of ongoing health-care privatisation reform in one of today's most prominent destinations: Malaysia. It argues that "medical tourism" to Malaysia has been mobilised politically both to advance domestic health-care reform and to cast off the country's "underdeveloped" image not only among foreign patient-consumers but also among its own nationals, who are themselves increasingly envisioned by the Malaysian state as prospective health care consumers. PMID- 22216475 TI - A new inequality? Privatisation, urban bias, migration and medical tourism. AB - Access to health care in developing countries, the main destinations of medical tourists, is notoriously uneven, and often becoming more so. Medical tourism, urban bias and privatisation have combined to exacerbate this trend. This is exemplified in both Thailand and India, where regional areas have been disadvantaged by the migration of health-care workers to hospitals focusing on medical tourism, neo-liberal national financial provision for medical tourism (and related tourism campaigns) and evidence of trickle-down gains is lacking. Medical tourism challenges rather than complements local health care providers, distorts national health care systems, and raises critical national economic, ethical and social questions. PMID- 22216476 TI - The tyranny of taste: the case of organic rice in Cambodia. AB - Fair-trade and organic products are often sold at price premiums justified by smaller production volumes that are associated with greater social and environmental responsibility. The consumption of these products confers on the consumer a greater sense of morality - and usually a claim to better taste. This paper tells the story of attempts to promote organic/fair-trade rice production by de facto organic Cambodian farmers for export to North American and European markets in order to assist poor farmers to trade their way out of poverty. It demonstrates that instead of promoting sustainable agriculture and fair trade between developed and developing markets, organic/fair-trade projects may impose First World consumer ideals and tastes that are out of step with the larger realities of agrarian transition in Cambodia and the wider region of developing Southeast Asia. PMID- 22216477 TI - Occupational health and safety of merchant seafarers from Kiribati and Tuvalu. AB - Intensifying international competition in the shipping industry in response to global pressures makes seafarers' jobs increasingly difficult. Challenging conditions in ship employment are problematic, particularly in a development context where home communities' dependence on seafarers' income is high and social protection is low. Qualitative fieldwork revealed that seafarers from Kiribati and Tuvalu endure exceptionally lengthy work periods at sea to remain competitive. Absence from home while working in constrained and mobile spaces with multinational crews, frequent security controls and speedy turnarounds impacting on sleep deprivation and decreased shore time have implications for physical and emotional health and can become safety matters. Hence, there is a growing need to address mechanisms to protect seafarers from the physical and emotional effects of global demands in the shipping industry. PMID- 22216478 TI - [Indigenous settlement and territoriality in the 16th-century Maule region]. PMID- 22216479 TI - Risks of online advertisement of direct-to-consumer thermography for breast cancer screening. AB - Direct-to-consumer online advertising for thermography as a sole agent with which to diagnose breast cancer is misleading and exploits women who are seeking preventive health care for breast cancer. Regulatory action should be taken against companies who continue to mislead the public to ensure patient safety and evidence-based public health information. PMID- 22216480 TI - Geospatial health: the first five years. AB - Geospatial Health is an international, peer-reviewed scientific journal produced by the Global Network for Geospatial Health (GnosisGIS). This network was founded in 2000 and the inaugural issue of its official journal was published in November 2006 with the aim to cover all aspects of geographical information system (GIS) applications, remote sensing and other spatial analytic tools focusing on human and veterinary health. The University of Naples Federico II is the publisher, producing two issues per year, both as hard copy and an open-access online version. The journal is referenced in major databases, including CABI, ISI Web of Knowledge and PubMed. In 2008, it was assigned its first impact factor (1.47), which has now reached 1.71. Geospatial Health is managed by an editor-in-chief and two associate editors, supported by five regional editors and a 23-member strong editorial board. This overview takes stock of the first five years of publishing: 133 contributions have been published so far, primarily original research (79.7%), followed by reviews (7.5%), announcements (6.0%), editorials and meeting reports (3.0% each) and a preface in the first issue. A content analysis of all the original research articles and reviews reveals that three quarters of the publications focus on human health with the remainder dealing with veterinary health. Two thirds of the papers come from Africa, Asia and Europe with similar numbers of contributions from each continent. Studies of more than 35 different diseases, injuries and risk factors have been presented. Malaria and schistosomiasis were identified as the two most important diseases (11.2% each). Almost half the contributions were based on GIS, one third on spatial analysis, often using advanced Bayesian geostatistics (13.8%), and one quarter on remote sensing. The 120 original research articles, reviews and editorials were produced by 505 authors based at institutions and universities in 52 countries. Importantly, a considerable proportion of the authors come from countries with a low or medium human development index (29.3%). In view of the increasing number of submissions, we are considering to publish more than two issues per year in the future. Finally, our vision is to open-up a new section predominantly based on visual presentations, including brief video clips, as discussed in a symposium at the 60th annual meeting of the American Society of Tropical Medicine and Hygiene in December 2011. PMID- 22216481 TI - [Aspects of the private life of the upper classes of Valparaiso: the house, family, and household, 1830-80]. PMID- 22216482 TI - [Overseeing justice, building the state, and controlling crime in the 19th century: the birth and development of judicial statistics in Belgium, 1795 1901]. PMID- 22216483 TI - [Unsuccessful initiatives toward the establishment of disciplinary, punitive, and correctional institutions and workhouses in Mechelen during the 17th and 18th centuries]. PMID- 22216484 TI - Feeding Low Countries towns: the grain trade in the fifteenth century. PMID- 22216485 TI - [Food provisioning of the Army Group Southern Ukraine in April-August 1944 within the Romanian-German alliance]. PMID- 22216486 TI - Science, an ally of feminism? Isabelle Gatti de Gamond on women and science. PMID- 22216487 TI - [Health service research (14): Support extended to care-givers and health service research]. PMID- 22216488 TI - [Public health for scientific study of society and health (10). Basic knowledge on biological intellectual properties--improvement of public health through cooperation between industry and academia]. PMID- 22216489 TI - Performance and impaired performance. PMID- 22216490 TI - An electroencephalographic investigation of short-term effects of three hypothalamic hormones (TRH, LH/FSH-RH, GH-RIH) in normal subjects. AB - Three hypothalamic regulatory hormones, thyrotrophin-releasing hormone (TRH), luteinizing hormone/follicle-stimulating hormone-releasing hormone (LH/FSH-RH) and growth hormone-release inhibiting hormone (GH-RIH) given intravenously had no effect on the electroencephalographic response known as the contingent negative variation (CNV) in normal subjects. TRH was given as a 10 ml infusion of 600 microg over 8 min to six subjects. This produced subjective sensations and a rise in heart rate but no significant alteration of CNV magnitude. LH/FSH-RH was given in a dose of 200 microg in 10 ml over 2 min to six subjects. This had no effect on CNV magnitude or heart rate and produced no subjective effects. GH-RIH was given as a 10 ml infusion of 250 microg over 10 min to six subjects. Again there was no alteration in the magnitude of the CNV; the heart rate was slowed. PMID- 22216491 TI - Effect of diazepam and fosazepam (a soluble derivative of diazepam) on sleep in man. AB - The effect of diazepam (5 mg and 10 mg), and fosazepam (60 mg and 80 mg), a soluble derivative of diazepam, on sleep was studied in six healthy adult males using electroencephalography for sleep measures, and analogue scales for subjective assessments of well-being and sleep quality. The effect of diazepam was limited to the night of ingestion, but the effect of fosazepam was carried over to the next night and so modified sleep for about 30 h after ingestion. Effects on total sleep time were limited to the night of ingestion. There were increases with diazepam (10 mg) (P = 0.05), and with fosazepam (60 mg and 80 mg) (P = 0.001). For the night of ingestion sleep onset latencies were shortened, and awakenings were reduced by both drugs. The latency to stage 3 was shortened by fosazepam (60 mg and 80 mg) (P = 0.05). The low and high dose of each drug reduced the duration (min) of stage 0 sleep (P = 0.01), but fosazepam also reduced the duration (min) of stage 1 sleep (P = 0.001), and there was an increase in stage 2 sleep (P = 0.01). With fosazepam there were carry over effects to the next night with reduction of stage 1 sleep (P = 0.05). There were no effects on the duration of stage 3, but there was evidence that stage 4 activity was reduced during the recovery night after ingestion of fosazepam (80 mg). No effects were observed on REM sleep. Subjects reported an improved sense of well-being during the day after ingestion of diazepam and fosazepam, and with fosazepam they reported improved sleep. Correlations were calculated for sleep measures and subjective assessments. PMID- 22216492 TI - Effect of a metabolite of diazepam, 3-hydroxydiazepam (temazepam), on sleep in man. AB - The effect of 3-hydroxydiazepam (temazepam, 10 mg and 20 mg) on sleep was studied in six healthy adult males using electroencephalography for sleep measures, and analogue scales for subjective assessments of well-being and sleep quality. The effects were compared with diazepam (5 mg and 10 mg). Effect on total sleep time was restricted to the night of ingestion. There was no change in total sleep time after temazepam (10 mg), but with 20 mg total sleep time was increased (P = 0.01). Sleep onset latencies and awakenings were markedly reduced. Temazepam reduced the duration (min) of stage 0 (P = 0.05) and stage 1 (P = 0.01) sleep, and the effect on stage 1 was seen during each two hourly interval of sleep (P = 0.05). No effects were observed with stage 3, 3+4 and REM sleep, except that the appearance of the first REM period was delayed with temazepam (20 mg) (P = 0.001). The subjects, as a group, reported improved sleep, but subjective assessments of well-being were not altered. Correlations were calculated for sleep measures and subjective assessments. PMID- 22216493 TI - A comparison of some physiological and psychological effects of propranolol and diazepam in normal subjects. AB - Some central and peripheral effects of orally administered propranolol (60 mg), diazepam (5 mg) and placebo were compared in normal subjects. The central effects measured were changes in magnitude of the contingent negative variation (CNV) and subjective anxiety ratings; the peripheral effects were changes in heart rate, blood pressure, galvanic skin response and hand steadiness. After diazepam there was a decrease in CNV magnitude and in the level of subjective anxiety; there was a slight fall in blood pressure but little change in heart rate. After propranolol, on the other hand, there was no significant change in CNV magnitude or anxiety rating, but a significant fall in heart rate and systolic blood pressure. It is concluded that, at the dosage used, propranolol, unlike diazepam, does not affect the central mechanisms determining CNV magnitude or subjective anxiety. The relationship of this finding to the use of beta-adrenergic receptor blockers in clinical anxiety states is discussed. PMID- 22216494 TI - The radioimmunoassay of tricyclic antidepressants. AB - An antiserum to nortriptyline has been produced in a sheep against a nortriptyline-bovine serum albumin conjugate. The conjugate was prepared using the reagent N-(4-bromobutyl) phthalimide followed by a carbodiimide reaction to link the hapten to the carrier protein. The antibodies produced were shown to be specific for the tricyclic group of drugs. The sensitivity of the radioimmunoassay developed is currently limited by the lack of a high specific activity label. The possibilities of developing a radioimmunoassay for nortriptyline in plasma are discussed. PMID- 22216495 TI - A therapeutic audit at autopsy. AB - A survey of one hundred patients submitted to autopsy has been carried out to assess the contribution of investigational procedures, surgery and drug therapy to death. In nineteen patients drug therapy, usually appropriate and necessary therapy, was thought to have contributed to death. In five patients failure to continue therapy properly contributed to death. The survey was not representative either of patients dying in hospital or in the community, but it suggests that a larger and more comprehensive survey should be undertaken. PMID- 22216496 TI - The cardiovascular effects of bromocriptine in Parkinsonism. AB - The cardiovascular effects of bromocriptine, a dopamine receptor agonist, were investigated in twenty-eight Parkinsonian patients. Bromocriptine caused a significant impairment of postural compensation with a fall in systolic pressure and an absence of the rise in diastolic pressure after standing for 1 min when patients taking active drug were compared to the same patients on placebo. The hypotensive effect persisted for at least 6 weeks of treatment. There was also a significant reduction in supine heart rate. One patient had marked falls in supine and erect blood pressure after a single oral dose of bromocriptine (2.5 mg) and a further patient developed paroxysmal atrial tachyarrhythmias. Both blood pressure and heart rate changes reversed spontaneously after stopping bromocriptine. It is proposed that dopaminergic mechanisms either in the central nervous system or the periphery contribute to cardiovascular regulation in man. PMID- 22216497 TI - CSF concentrations and serum protein binding of carbamazepine and carbamazepine 10,11-epoxide in epileptic patients. AB - Serum and CSF samples of patients receiving chronic carbamazepine treatment were analysed. Daily fluctuations in serum levels of carbamazepine and carbamazepine 10,11-epoxide did not appear to be related to the dosage schedule, but some patients tended to have lower fluctuations when the carbamazepine was given more frequently. The epoxide/carbamazepine serum ratios varied greatly from patient to patient, and also fluctuated during the day for the same patient. Carbamazepine and carbamazepine-10,11-epoxide were present in CSF in concentrations ranging from 19 to 34% and 26 to 71% of the serum concentrations, respectively. There was a significant relationship between the free fraction of both drugs evaluated in vivo and the CSF/serum ratios. The need for a careful evaluation of the possible clinical effect of the epoxide is stressed. PMID- 22216498 TI - Absorption of drugs by the lung. AB - Ten patients undergoing diagnostic bronchoscopy had radioisotopically labelled drugs put directly into their bronchi; two received sodium cromoglycate, two salbutamol, three salmefamol and three rimiterol. All four drugs were rapidly absorbed but higher peak plasma levels per unit dose were seen with sodium cromoglycate and salbutamol than with the other two drugs. It is suggested that the lung metabolizes salmefamol and rimiterol but does not metabolize salbutamol or sodium cromoglycate. PMID- 22216499 TI - Comparison of oral theophylline and salbutamol by inhalation in asthmatic patients. AB - The bronchodilator effects of 375 mg theophylline orally and 200 microg salbutamol by pressurized aerosol were compared in a randomized, cross-over, double-blind trial in fourteen asthmatic patients. The mean peak percentage FEV1 increase from control was 43.7% at 60 min after salbutamol and 30.3% at 180 min after theophylline. Salbutamol produced significantly greater bronchodilatation than theophylline for the initial 30 min (P < 0.01). Theophylline demonstrated a longer duration of action than salbutamol, with a significantly greater FEV1 response at 360 min (P < 0.02). There was no significant difference between the total effect of each drug for the 360 min period, as calculated by the areas under the respective FEV1 response curves. PMID- 22216500 TI - Effects of oral salbutamol and pirbuterol on FEV1, heart rate and blood pressure in asthmatics. AB - In a double-blind trial the effects on ventilatory function (FEV1), heart rate and blood pressure of oral pirbuterol and oral salbutamol in various single doses were studied in ten patients with chronic asthma. Pirbuterol (15 mg) and salbutamol (4 mg) produced equal peak levels of bronchodilatation. There was no significant difference in the mean rise in heart rates caused by the two drugs, and no other significant side-effects were noted. PMID- 22216501 TI - Alpha-adrenoceptor blocking drugs in asthma. AB - The effect of alpha-adrenoceptor blocking drug, thymoxamine alone and in combination with isoprenaline, was studied on the specific airways conductance (SGaw) in ten patients with extrinsic asthma. Thymoxamine when given together with isoprenaline produced significantly greater increase in SGaw as compared to improvement achieved with isoprenaline alone. It is suggested that the potentiation of isoprenaline induced bronchodilatation by thymoxamine is mediated by increased cyclic AMP formation in the bronchial smooth muscle. PMID- 22216502 TI - Canrenone--the principal active metabolite of spironolactone? AB - The properties of the aldosterone antagonists spironolactone and potassium canrenoate in tablet formulations were examined in two studies in healthy subjects, the first study comparing levels of their common major metabolite, canrenone, in plasma and the second study comparing the pharmacological activity of the two drugs in reversing the renal effects of the synthetic mineralocorticoid fludrocortisone. At equal dosage by weight potassium canrenoate yielded peak levels and areas under the curve for canrenone in plasma which were significantly lower than those for spironolactone, and the peak level of canrenone was reached significantly later. Comparison with published work suggests that the experimental formulation of potassium canrenoate had low bioavailability. Spironolactone produced statistically valid log dose-response curves against fludrocortisone as regards sodium excretion, potassium retention and increased urine sodium to potassium ratio. There was no significant log dose reponse after potassium canrenoate, and a statistically valid estimate of relative potency could not be obtained. The results of the two studies seem inconsistent with the view that canrenone alone is responsible for the pharmacological activity of both drugs, and suggest that a significant part of the activity of spironolactone may be attributable to metabolites other than canrenone. PMID- 22216503 TI - A comparison of the effect of frusemide and bumetanide on the diuretic response and fibrinolytic mechanism in man. AB - A double-blind, crossover trial has compared the diuretic response of ten normal male subjects to the oral administration of frusemide (40 mg) and bumetanide (1 mg). Both drugs gave a similar profile, with acute onset and cessation of response, and a marked peak effect. There was no significant difference between the times taken for each drug to produce its peak diuretic effect. The peak rate of diuretic response, and the total response for six hours after drug ingestion, were significantly greater after bumetanide, with respect to urinary volume and sodium excretion. The peak rate of magnesium excretion was greater after bumetanide. There was no difference between the drugs with respect to potassium, calcium or creatinine excretion or the urinary Na/K ratio. Following peak diuresis, potassium excretion did not show a linear return to its control value. At the time of peak diuresis, both drugs caused a significant reduction of euglobulin lysis time; levels of available plasmin were significantly lowered after frusemide, and levels of active plasmin were significantly raised after bumetanide. The significance of these findings in relation to the fibrinolytic mechanism is discussed. Estimations of plasma viscosity, serum total protein and magnesium concentrations showed that maximal haemoconcentration occurred several hours after diuresis. PMID- 22216504 TI - Controlled trial of frusemide as an antiepileptic drug in focal epilepsy. AB - The antiepileptic activity of oral frusemide (120 mg daily) was compared with that of an identical placebo in a double-blind crossover trial in fourteen patients with severe focal epilepsy who were receiving long-term therapy with established antiepileptic drugs. A statistically significant reduction in the frequency of focal fits was seen with the active drug. Marked drowsiness occurred in three patients during frusemide therapy, causing their withdrawal from the trial. A slight, but significant, rise in serum phenobarbitone concentrations was observed during frusemide therapy, but no change was seen in serum primidone or phenytoin concentrations. Frusemide significantly lowered plasma sodium and potassium concentrations, and increased plasma bicarbonate. PMID- 22216506 TI - Phenelzine in urine: assay and relation to acetylator status. AB - Phenelzine cannot be extracted as such from biological fluids. Formation of the acetonide derivative prior to extraction allows phenelzine to be extracted and assayed by gas chromatography at levels down to 0.5 microg/ml. At this sensitivity the drug can be detected in urine but not in plasma, after therapeutic doses. Persons typed as slow acetylators of sulphadimidine excreted approximately twice as much unmetabolized phenelzine in urine compared to fast acetylators. PMID- 22216505 TI - Factors influencing the absorption and disposition of mecillinam and pivmecillinam in man. AB - In a pharmacokinetic study in six volunteers peak serum mecillinam concentrations were proportional to the oral dose of pivmecillinam at two dose levels of 200 and 400 mg. Effects of bed rest, probenecid and a 6 day course of treatment with pivmecillinam on serum mecillinam concentrations after an oral dose of pivmecillinam (two 200 mg capsules) have been investigated. Resting subjects had lower peak serum levels and a decreased rate of clearance than moderately active subjects, changes which are similar to those previously reported for benzylpenicillin. Pretreatment with probenecid produced significantly higher serum mecillinam levels, a longer serum antibiotic half-life and a decreased rate of drug clearance which suggests that mecillinam is actively excreted by kidney tubules. Plasma mecillinam level profiles obtained after the first dose of a 6 day treatment period were not significantly different from corresponding values after the first dose on the seventh day which indicates that each dose of mecillinam is eliminated in healthy young adults before succeeding doses are taken. PMID- 22216507 TI - Digoxin therapy: textbooks, theory and practice. AB - Recommendations for correct therapy with digoxin from twenty-five sources are reviewed. Some recommendations may be unsuitable for use with high bioavailability tablets; some are accompanied by insufficient data relating to factors affecting both the response to digoxin and its handling by the body. Guidelines based on pharmacokinetic and pharmacodynamic principles are suggested to help decide optimal digoxin treatment schedules in the presence and absence of non-cardiac disease. PMID- 22216508 TI - Increased platelet aggregation in patients receiving chlorpromazine: responses to 5-hydroxytryptamine, dopamine and N-dimethyl dopamine. AB - Platelet aggregation responses to 5-HT, dopamine, N-dimethyl dopamine and adenosine diphosphate were compared in normal subjects and patients treated with chlorpromazine (CPZ) for longer than 6 months. We confirmed our previous finding that 5-HT induced aggregation is enhanced in CPZ treated patients. Increased aggregation responses were also observed with dopamine and N-dimethyl dopamine. Quantitative comparisons of aggregation rates and total changes in optical density of platelet rich plasma relative to adenosine diphosphate showed significant increases with 5-HT, dopamine and N-dimethyl dopamine. Implication of dopaminergic mechanisms in the central effects of phenothiazines suggests that changes in dopamine induced aggregation responses may be useful in attempting correlations of clinical and pharmacological effects. PMID- 22216509 TI - A controlled study on the antihypertensive effect of a new beta-adrenergic receptor blocking drug, metoprolol, in combination with chlorthalidone. AB - A double-blind crossover evaluation of the antihypertensive effect of metoprolol v. placebo was carried out in a series of twenty-three patients with mild or moderate essential hypertension who were receiving chlorthalidone (25 mg daily) as their basic treatment. An individually titrated metoprolol dosage (75-300 mg) was used. The double-blind crossover study consisted of two 3-month periods during which the patients received either metoprolol or placebo in addition to chlorthalidone. Metoprolol, as compared with placebo, produced a statistically significant reduction of blood pressure, both in supine and standing positions. Normotension was achieved during metoprolol-chlorthalidone treatment in twenty two of the twenty-three patients, but during placebo-chlorthalidone treatment in only twelve of the twenty-three patients. During the double-blind crossover study mild side-effects occurred during metoprolol-chlorthalidone treatment in fourteen patients during first month, in twelve patients during second month and seven patients during third month. During placebo-chlorthalidone treatment side effects occurred in seven, six and seven patients, respectively. In conclusion, metoprolol caused a significant fall in blood pressure when given to patients already receiving chlorthalidone. Metoprolol in combination with chlorthalidone appears to be an effective and well-tolerated treatment for mild and moderate hypertension in those patients not responding to chlorthalidone alone. PMID- 22216510 TI - Effect of beta-adrenoceptor blocking drugs on EEG. PMID- 22216511 TI - Correlation of pupil reactivity to tyramine or hydroxyamphetamine and tyramine pressor responses in patients treated with amitriptyline or mianserin. PMID- 22216512 TI - The assessment of interactions in man between tyramine and viloxazine hydrochloride, an antidepressant drug. PMID- 22216513 TI - Has pharmacology a place in today's medical schools? PMID- 22216514 TI - The influence of pH on the buccal absorption and renal excretion of disopyramide in man. PMID- 22216515 TI - Salivary digoxin concentrations. PMID- 22216516 TI - Serum digoxin concentrations. PMID- 22216517 TI - Drugs for the Third World. PMID- 22216518 TI - Bromocriptine and dopamine receptor stimulation. AB - The response to different doses of bromocriptine (12.5, 25, 50 and 100 mg) has been established in six patients with Parkinson's disease. Bromocriptine, like levodopa, causes improved mobility in patients with Parkinsonism, emesis, hallucinations, a fall in supine and erect blood pressure, increase of plasma growth hormone and suppression of prolactin concentration. Bromocriptine (50 or 100 mg) has as great an anti-Parkinsonian effect as average therapeutic doses of levodopa, and a longer duration of action, 6-10 hours. In the dose range studied, bromocriptine appears to be a complete dopamine agonist, although 100 mg was less effective than 50 mg in two patients. The different actions of bromocriptine and other dopamine agonist drugs may result from stimulation of different types of dopamine receptor. PMID- 22216519 TI - Plasma dopa concentrations after different preparations of levodopa in normal subjects. AB - The concurrent administration of levodopa with a decarboxylase inhibitor produced a plasma concentration/time curve comparable with 1/4 to 1/5 of the dose of levodopa given alone. There was no evidence to suggest that the decarboxylase inhibitor slowed the rate of elimination of levodopa from plasma. Metoclopramide (Maxolon) increased the rate of levodopa absorption. Higher plasma concentrations of levodopa during the first 2 h after dosing were followed by lower plasma concentrations during the third and fourth hours. The amount of levodopa absorbed after Larodopa as indicated by the AUC was not altered by adding metoclopramide. None of the current preparations of levodopa produced sustained plasma concentrations. In vitro testing confirmed that Brocadopa Temtabs tablets disintegrate and dissolve slowly. In vivo, Brocadopa Temtabs behaved as a slow release preparation but it did not produce sustained plasma concentrations of levodopa. PMID- 22216520 TI - Intrinsic heart rate on exercise and the measurement of beta-adrenoceptor blockade. AB - Methods of expressing the effects of beta-adrenoceptor blocking drugs on exercise heart rate have been evaluated using a standardised exercise test. In six normal subjects given atropine (0.04 mg/kg) on two separate occasions, the mean +/- s.e. mean exercise heart rate rose by 10.3 +/- 1.8 beats/min and by 11.0 +/- 1.6 beats/min respectively. This increase was designated the 'vagal effect and was not significantly different in the two studies. After atropinsation, propranolol (0.2 mg/kg) reduced mean +/- s.e. mean exercise heart rate by 45.3 +/- 2.6 beats/min and 0.4 mg/kg by 50.8 +/- 4.5 beats/min. This mean sympathetic blockade was not altered significantly by increasing the dose of propranolol but, in four of the six subjects, the larger dose produced an increased effect of 4, 6, 12 and 16 beats/min, suggesting that maximum sympathetic blockade may not have been produced by 0.2 mg/kg. Knowledge of the vagal effect in each subject with standardised exercise enabled prediction to be made of the exercise heart rate after propranolol (0.4 mg/kg) without previous atropinisation. Propranolol (0.4 mg/kg) was then given intravenously to each subject and the actual exercise heart rate measured. There was no significant difference between the predicted and observed exercise heart rates. Propranolol (0.6 mg/kg) without atropine was then given to the four subjects who had shown increased effect with (0.4 mg/kg) and the sympathetic blockade was measured. In one subject, a further increase in sympathetic blockade of 10 beats/min was found. The intrinsic heart rate at rest and on exercise was measured for propranolol (0.2 and 0.4 mg/kg) and, for propranolol (0.6 mg/kg), the intrinsic heart rate on exercise was calculated. At rest, although no significant difference was found between the two dose levels, three subjects did not appear to have maximum autonomic blockade at 0.2 mg/kg. Similarly, several subjects had lower intrinsic heart rates on exercise after 0.4 or 0.6 mg/kg than after 0.2 mg/kg. The intrinsic heart rate on exercise was significantly greater than that obtained at rest. Using the maximum sympathetic blockade obtained in each subject as the sympathetic component of exercise, the effects of increasing oral doses of practolol on exercise heart were measured as percentage blockade of sympathetic effect and this was compared with other conventional methods of measuring beta-adrenoceptor blockade. It was found that percentage blockade of sympathetic effect correlated most closely with both percentage and absolute reduction of exercise heart rate. Correlations with exercise heart rate after drug and percentage inhibition of tachycardia, whilst also significant, did not appear as good. When the effects of practolol were expressed in terms of the potential blockade, a plateau occurred between 70 and 80% of 'maximum' sympathetic blockade. The failure to achieve higher levels with practolol may be the result of its partial agonist or intrinsic sympathomimetic activity. PMID- 22216522 TI - The effect of metoprolol and practolol on lung function and blood pressure in hypertensive asthmatics. AB - The effect of metoprolol, a new beta1-adrenoceptor blocking agent, was compared to practolol in the treatment of hypertension in seventeen asthmatics during concurrent optimum bronchodilator therapy with a selective beta2-adrenoceptor stimulant. The two beta-adrenoceptor antagonists were given at two dose levels, practolol (200 mg and 400 mg) daily, and metoprolol (100 mg and 200 mg) daily, in a twice-daily dosage schedule, at 12 h intervals, for 17 days. The comparison was made double-blind and a crossover design was used. The drugs were given in randomized order. The study started with a run-in placebo period and there was a washout period on placebo between the treatment periods. Spirometry, blood pressures and heart rates were recorded in a standardized manner. At the lower dose levels no influence on FEV1 was noted, and no difference was found between the two active drugs. At the higher dose level FEV1 was reduced by both beta adrenoceptor-blocking drugs. Four out of twelve patients given the higher dose experienced exacerbation of their asthma. The heart rate fell with both drugs and at both dose levels. During the placebo period a marked increase of heart rate was noted. The blood pressure fell at both dose levels compared to placebo, no difference being recorded between the two drugs. Metoprolol and practolol are equally effective beta1-adrenoceptor blocking drugs. In this study it was found that metoprolol could be used in asthmatics who had indications for beta adrenoceptor blockade, provided that the total daily dose did not exceed 100 mg. Optimal bronchodilator treatment with a bronchoselective beta-adrenoceptor agonist is an absolute prerequisite in order to avoid the risk of aggravation of asthma. PMID- 22216521 TI - Adrenoceptor responsiveness in bronchial asthma: effect of isoprenaline inhalation on plasma cyclic 3',5'-AMP levels. AB - The effect of isoprenaline inhalation on plasma levels of cyclic AMP has been studied in a group of normal subjects and compared to a group of asthmatics. The normal subjects had a prompt rise in their plasma cyclic AMP level, and when compared to the asthmatic group, had a significantly greater percentage rise in plasma cyclic AMP from the basal levels. The markedly attenuated response to isoprenaline inhalation in the asthmatic group is consistent with the concept that asthmatics have a relative impairment of beta-adrenoceptor function. These results support the in vitro studies demonstrating that lymphocytes from asthmatic subjects incubated with isoprenaline produce less cyclic AMP than those from normal subjects. PMID- 22216523 TI - The influence of thiethylperazine on the absorption of effervescent aspirin in migraine. AB - The absorption of effervescent aspirin was studied in three groups of patients during attacks of migraine. The first group received intramuscular thiethylperazine 10 min before effervescent aspirin; the second group received intramuscular metoclopramide 10 min before effervescent aspirin; and the third group received effervescent aspirin alone. Where possible each patient was retested when headache-free but under conditions which were otherwise as similar as possible to those during the acute attack. Intramuscular metoclopramide corrected the impairment of drug absorption that occurred during a migraine attack, whereas thiethylperazine did not. In the group of patients treated with thiethylperazine and aspirin, the impairment of absorption did not correlate with the duration of the symptoms, nor with the severity of the headache and nausea. Patients treated with thiethylperazine and aspirin tended to take longer to recover than those patients treated with metoclopramide and aspirin. However, in the thiethylperazine treated group, the time to recover did not correlate with the salicylate level achieved. PMID- 22216524 TI - Acetylator phenotype and the clinical pharmacology of slow-release procainamide. AB - Slow-release procainamide given 8-hourly is shown to produce plasma levels generally accepted as giving effective prophylaxis against ventricular dysrhythmias occurring after recent myocardial infarction. Patients can be classified into 'slow' and 'fast' acetylators of procainamide. Knowledge of acetylator status is helpful in determining the dose of procainamide necessary to attain effective steady-state plasma levels while avoiding toxic ones. Acetylator status cannot be assessed accurately using sulphadimidine when the patients are also taking procainamide. PMID- 22216525 TI - Drug interactions and long-term antidiabetic therapy. AB - A study has been carried out on a representative sample (709 patients) of the Aberdeen Diabetic Clinic. The aims were to measure the occurrence and attempt to assess the clinical significance of drug interactions involving antidiabetic agents. In the month before interview, 63% of the patients were taking between one and nine additional prescribed medicines. Fifty-one per cent of the patients had been exposed to one to five drugs with a potential to interact with their anti-diabetic therapy. Only 22% of the patients had taken no drugs other than their anti-diabetic medication. The degree of control of diabetes, based on arbitrary criteria on data from seven consecutive out-patient visits, was significantly worse for sulphonylurea-treated patients exposed to drugs with the potential to interact compared to patients not taking such drugs. In particular, control was adversely affected in older patients taking concurrent barbiturate or diuretic therapy. No such influence of interacting drugs on control was evident in patients on insulin or biguanide therapy. A system designed to prevent the unintentional initiation of drug interactions in patients on hypoglycaemic agents is described. PMID- 22216526 TI - Biotransformation and excretion of lorazepam in patients with chronic renal failure. AB - To evaluate the effect of end-stage renal insufficiency and haemodialysis on the elimination of lorazepam, single oral doses of the drug (2.5 mg) were administered to normal subjects and patients with chronic renal failure (CC(r) : less than 2 ml/min) in the interdialysis period and during haemodialysis. The concentration of lorazepam and its major metabolite, lorazepam-glucuronide, were assayed using electron capture g.l.c. Plasma half-life (T1/2) of unchanged lorazepam in the patient group (11.3 +/- 0.6 h) was not different from that obtained in normals (11.1 +/- 0.9 h). Only minor quantities of the unchanged drug could be recovered in the 24 h urine in both groups: 0.3% of the ingested dose in normals and trace amounts in the patient group. No unchanged lorazepam could be detected in the ultrafiltrate from the coil kidney. Since the lower sensitivity of the method is about 5 ng/ml, this would indicate the in vivo binding of the active drug to plasma proteins to be at least 70%. The effect of haemodialysis on lorazepam plasma T1/2 was also insignificant (9.4 +/- 1.0 h). Urinary excretion of lorazepam-glucuronide was found to be considerably decreased in chronic renal failure associated with accumulation of high concentrations of this conjugate in plasma during days after a single oral dose. The plasma T1/2 of this conjugate in normals was 20.7 +/- 2.1 h. Roughly 35% of this main metabolite's concentration in plasma was detected in the ultrafiltrate from the coil kidney indicating the dialyzability of this conjugate and that the extent of plasma protein binding of lorazepam-glucuronide in vivo was approximately 65%. The above results indicate that after a single oral dose (2.5 mg) the biotransformation of lorazepam to its glucuronide conjugate remains unaltered and that high concentrations of this metabolite accumulate in plasma in the presence of severe renal function impairment. PMID- 22216527 TI - Effect of phenytoin therapy on thyroid function. AB - Serum total and free fraction of thyroxine and triiodothyronine and urinary losses of unconjugated hormones in normal subjects and in patients treated long term with therapeutic doses of phenytoin have been measured. Decreases in serum total hormone concentrations with increased free fractions and resultant significant increase in the concentration of free thyroxine but not triiodothyronine were apparent in phenytoin-treated subjects. However, serum free hormone concentrations remained within the euthyroid range. These changes in serum free hormone concentration were reflected by an increased urinary loss of unconjugated thyroxine, but normal excretion of unconjugated triiodothyronine. Phenytoin in therapeutic doses displaces thyroxine and to a lesser extent, triiodothyronine from binding proteins in serum and thus increases peripheral clearance of thyroid hormones. PMID- 22216528 TI - Altered distribution of digoxin in renal failure--a cause of digoxin toxicity? AB - Three cases are described in which renal failure was accompanied by a lowered apparent volume of distribution of digoxin. In two cases this resulted in frank digoxin toxicity and in one equivocal toxicity. In all three cases digoxin plasma levels were greater than 2 ng/ml. The possible causes of the abnormal distribution of digoxin in renal failure are discussed. Recommendations are outlined for the use of digoxin in patients with renal failure aimed at circumventing the problem raised by a lowered apparent volume of distribution of the drug. PMID- 22216529 TI - Digoxin concentrations in serum and saliva: relationship to ECG changes and dosage in healthy volunteers. AB - After 1 week of baseline observations increasing oral doses of digoxin were administered to four healthy volunteers over a 6-7 week period. A dose-response relationship exists with regards to PTQ-changes (a quantitative measure of ECG changes). PTQ-changes were related linearly to both serum and salivary digoxin levels. PTQ-changes appear to be useful as a non-invasive measure for studying various aspects of digoxin pharmacodynamics. Serial salivary digoxin levels might be a better index of the effect of cardiac glycosides than individual or serial serum levels. PMID- 22216530 TI - Drug advertising in medical journals. AB - One hundred different drug advertisements from each of seven leading medical journals have been assessed. Information about drug interactions, adverse reactions, mode of action, absorption, distribution, metabolism, excretion and cost was seldom provided in UK journals. A requirement should exist that drug advertisements include such clinically important information. Only a few pharmaceutical companies are attempting to educate doctors through their marketing and promotional material in advertisements in medical journals. PMID- 22216531 TI - Improved fluorimetric assay of plasma propranolol. PMID- 22216532 TI - A rapid method for the determination of diphenhydramine in plasma. PMID- 22216533 TI - Bioavailability of beta-adrenoceptor blocking drugs. PMID- 22216534 TI - ANA works to get APRNs counted as primary care providers. PMID- 22216535 TI - Treating nurses "fairly". PMID- 22216536 TI - All payer claims database. PMID- 22216537 TI - Lessons from the Mediator scandal. PMID- 22216538 TI - Collagenase Clostridium histolyticum. Short-term benefit in Dupuytren's contracture, unknown long-term risks. AB - Dupuytren's contracture is due to fibroblast overgrowth in the aponeuroses of the hand and fingers, leading to excessive collagen production. This can cause functional impairment due to retraction of one or several fingers.The standard treatment is surgery, but relapses are frequent. A product containing collagenolytic bacterial enzymes (collagenases) is now marketed for local treatment of these retractions. Two double-blind placebo-controlled trials in 308 and 66 patients show that 1 to 3 local injections at one-month intervals lead to near-total reduction in finger retraction in about 50% of cases, versus about 5% of cases after placebo injections. A non-comparative follow-up of 830 successfully treated patients, lasting an average of 7.4 months, showed a relapse rate of 4%. The Most patients experience local reactions such as swelling, bruising, bleeding and pain. These reactions were rarely severe in clinical trials (1% of patients), but cases of tendon rupture have been described. Nearly all treated patients develop anticollagenase antibodies. The only known consequence of this immune reaction is pruritus, reported by about 11% of patients participating in clinical trials. The possible impact of these antibodies on the efficacy of subsequent injections is not known. A certain antigenic kinship between the bacterial collagenases and certain human enzymes raises the possibility of long-term autoimmune reactions. In practice, the limitations of surgical management and the simplicity of local collagenase injections make it a valid option for the treatment of Dupuytren's contracture. Uncertainties concerning the long-term harm-benefit balance mean that this treatment should only be considered when surgery is not an option. PMID- 22216539 TI - Botulinum toxin type A for migraine. First, do no harm. AB - Headache prevention in adults with chronic migraine is based first on oral drug therapy, preferably with propranolol, and on tapering off possible analgesic overuse. Botulinum toxin type A injections in head and neck muscles is now authorised for this purpose in the United Kingdom. It has been used off label for several years. Clinical evaluation in this indication is based on two placebo controlled double-blind trials with identical designs. A total of 1384 patients underwent two sessions of intramuscular injections of botulinum toxin type A or placebo, 3 months apart, into at least 31 specific sites in the head and neck. Compared to baseline, patients who received botulinum toxin in one trial (but not in the other) experienced a statistically significant reduction in headache frequency at the end of the study, but the results are undermined by methodological issues. Botulinum toxin type A has not been compared with preventive oral therapy. An inherently unreliable indirect comparison suggests that botulinum toxin type A is clearly less effective than oral propranolol. In its other approved indications, botulinum toxin type A has been linked to deaths and muscle paralysis distant from the injection site, leading to swallowing difficulties and respiratory disorders. Some patients enrolled in clinical trials of botulinum toxin type A experienced transient worsening of their migraine and headache (9.3%, versus 5.8% of patients receiving placebo injections), exaggerated paralytic effects, and muscle pain and stiffness. In practice, given its uncertain efficacy, at best only modest, botulinum toxin type A is simply too risky a treatment for migraine. It is better to focus on fine tuning of standard prophylaxis. PMID- 22216540 TI - Bending the rules. PMID- 22216541 TI - Bleomycin in malignant pleural effusion. Choose talc pleurodesis. AB - Not more effective than talc in preventing recurrent pleural effusions, based on a review with meta-analysis of 7 trials in 256 patients. Bleomycin carries a risk of systemic adverse effects and treatment errors. PMID- 22216542 TI - Dienogest. Endometriosis: still no progress. AB - No more effective for relief of pelvic pain than a GnRH agonist alone (without hormone replacement therapy). PMID- 22216543 TI - Drug-induced gingival hyperplasia. AB - Gingival hyperplasia refers to an overgrowth of gum tissue. It starts in the anterior interdental tissues and then extends posteriorly. The gums can sometimes enlarge to cover almost all the teeth. The hyperplastic tissue appears to be fibrous. The consequences are mainly cosmetic. Gingival hyperplasia can be caused by a number of drugs, generally during long-term use. PMID- 22216544 TI - Dronedarone trial stopped due to excess mortality. PMID- 22216545 TI - Proper management of lithium therapy. AB - Lithium is the standard drug used to treat bipolar disorder. Most of its adverse effects are dose-dependent, and there is only a small margin between therapeutic and toxic blood concentrations. A review of 567 reports by the UK National Patient Safety Agency (NPSA) showed that the adverse effects of lithium were mainly due to dosing errors, irregular blood lithium assay, poor monitoring of renal or thyroid function, and inadequate patient information. An audit of 436 British medical teams recovered follow-up data on 2976 patients treated with lithium. Patient monitoring, studied during the previous year, was usually inadequate. In practice, regular lithium assay, regular renal and thyroid monitoring, and provision of verbal and written information to patients and their families are essential in preventing adverse effects. PMID- 22216546 TI - Sorafenib: muscle wasting. AB - Sorafenib inhibits multiple kinases involved in angiogenesis and tumour growth. It is used for second-line treatment of advanced kidney cancer and some forms of liver cancer. A placebo-controlled trial in 80 patients with metastatic kidney cancer showed a statistically significant increase in muscle loss during sorafenib therapy. Skeletal muscle mass fell by about 5% after 6 months of treatment and by 8% after one year. In practice, patients treated with sorafenib should be assessed for muscle wasting. The clinical consequences of muscle wasting--loss of autonomy and walking difficulties--should be considered when weighing the benefits and harms of sorafenib therapy. PMID- 22216547 TI - Advising or referring patients on the basis of an interview. Diagnostic competence. AB - In many situations (in community pharmacies, on the telephone, etc.), healthcare professionals have to make decisions based on information obtained by interviewing the patient or a third party, without recourse to a physical examination or investigations. Several studies have shown that the interview plays an important role in healthcare decision-making. The provisional diagnosis reached just after taking the patient's history in an interview often matches the final diagnosis. When analysing the information obtained through an interview, it is helpful to take into account the incidence of the condition, to be on the alert for signs of serious situations, and to consider the patient's point of view. In order to obtain more background information, a number of questions should be systematically included in the interview: relevant details about the patient, the history of the complaint, any actions taken, and any past or present drug treatment. PMID- 22216548 TI - Interviewing patients in primary care: a few pointers. PMID- 22216549 TI - Warning signs of high-risk situations. PMID- 22216550 TI - Women with diabetes: control blood glucose before conception. AB - Maternal pregestational diabetes increases the risks of fetal malformations, miscarriage and perinatal death. The risk increases with the HbA1c level. For women known to have diabetes, optimal glycaemic control before conception and at the start of pregnancy probably reduces these risks. PMID- 22216551 TI - Chlamydia trachomatis and pregnancy. AB - Chlamydia trachomatis infection seems to have little impact on the outcome of pregnancy. If transmitted to the newborn during delivery, this pathogen can cause conjunctivitis or, occasionally, neonatal pneumonia. Amoxicillin (a 7-day course) is the antibiotic of choice for pregnant women with C. trachomatis cervicitis or urethritis. There is no evidence that other antibiotics are safer or more effective. Doxycycline and fluoroquinolones are contraindicated during pregnancy. The possible benefits of treating asymptomatic C. trachomatis infection in pregnant women are uncertain. PMID- 22216552 TI - The proven, often unconscious, influence of small gifts. AB - Many studies have shown that even small gifts influence the recipient. Gifts work as a marketing tool by exploiting psychological and social responses that have been well described by the social sciences. Social science explains why, counterintuitively, a small gift has the potential to influence the recipient more than a large one, specifically because the recipient is unaware of its influence. Exposure to promotional items (pens, logos) also influences attitudes. Understanding marketing techniques and their psychological basis helps us resist being influenced. The regulations in force do not take sufficient account of the potential of corporate gifts to influence healthcare professionals. PMID- 22216553 TI - Drug companies and patient groups: the influence of funding. AB - Patients should be able to rely on advocacy groups to push their interests, not those of pharmaceutical companies. PMID- 22216554 TI - Contextually relevant resources in speech-language therapy and audiology in South Africa--are there any? AB - In this editorial introduction we aim to explore the notion of contextually relevant resources. We argue that it is the responsibility of speech-language therapists (SLTs) and audiologists (As) working in South Africa to develop contextually relevant resources, and not to rely on the countries or cultures where the professions originated to do so. Language is often cited as the main barrier to contextually relevant resources: most SLTs and As are aware of the need for more resources in the local languages. However, the issue is not as straightforward as translating resources from English into other languages. The challenges related to culture, e.g. formal education and familiarity with the test situation, have to be considered, as well as the population on which norms were obtained and the nature of vocabulary or picture items. This paper introduces four original research papers that follow in this edition of the journal, and showcases them as examples of innovative development in our field. At the same time we call for the further development of assessment materials, intervention resources, and contributions to the evidence base in our context. We emphasise the importance of local knowledge to drive the development of these resources in innovative and perhaps unexpected ways, and suggest that all clinicians have an important role to play in this process. PMID- 22216555 TI - The translation of the Vertigo Symptom Scale into Afrikaans: a pilot study. AB - Dizziness is a common clinical problem that is challenging to diagnose and treat. One of a subset of symptoms that fall under the encompassing term of dizziness is vertigo, which is the subjective experience of hallucination of movement, often associated with vestibular disorders. While dizziness has a broad range of causes, the association between vestibular disturbance, and its attendant vertigo, and anxiety is well established. The Vertigo Symptom Scale (VSS) is a questionnaire that assesses aspects of vertigo and vertigo-related anxiety. The aim of this study was twofold. In phase 1, a translation of the VSS into Afrikaans was evaluated using the Delphi consensus technique and two panels of participants. Panel 1 comprised first-language Afrikaans speakers who commented on the language, grammar and vocabulary of the items. Panel 2 were bilingual health care practitioners with either a psychology background or a special interest in vertigo. After two rounds of consultation, consensus was achieved and the final translation of the Afrikaans Vertigo Symptom Scale (AVSS) was agreed upon, as well as a list of Afrikaans words descriptive of vertigo. Phase 2 used a descriptive, correlational design. The aim was to pilot the AVSS with a sample of vertiginous and control participants to establish its ability to differentiate between the two groups and to explore experiences of vertigo and anxiety within the two embedded subscales. The results of the pilot study yielded significant statistical differences (p < 0.001) between the groups on both subscales of the tool. Preliminary results suggest that the AVSS is able to identify patients with vertiginous disturbance and anxiety. The AVSS presents with good sensitivity and specificity as measured by the receiver-operating characteristic (ROC) curve. Afrikaans is the home language of almost 6 million people in South Africa. The translation of the VSS into Afrikaans presents health care professionals with a tool with which to assess vertigo and vertigo-related anxiety in this population. PMID- 22216556 TI - The development of a neonatal communication intervention tool. AB - Neonatal communication intervention is important in South Africa, which has an increased prevalence of infants born with risks for disabilities and where the majority of infants live in poverty. Local literature showed a dearth of information on the current service delivery and roles of speech-language therapists (SLTs) and audiologists in neonatal nurseries in the South African context. SLTs have the opportunity to provide the earliest intervention, provided that intervention is well-timed in the neonatal nursery context. The aim of the research was to compile a locally relevant neonatal communication intervention instrument/tool for use by SLTs in neonatal nurseries of public hospitals. The study entailed descriptive, exploratory research. During phase 1, a survey was received from 39 SLTs and 2 audiologists in six provinces. The data revealed that participants performed different roles in neonatal nurseries, which depended on the environment, tools, materials and instrumentation available to them. Many participants were inexperienced, but resourceful in their attempts to adapt tools/materials. Participants expressed needs for culturally appropriate and user friendly instruments for parent guidance and staff/team training on the topic of developmental care. During phase 2, a tool for parent guidance titled Neonatal communication intervention programme for parents was compiled in English and isiZulu. The programme was piloted by three participants. Suggestions for enhancements of the programme were made, such as providing a glossary of terms, adapting the programme's language and terminology, and providing more illustrations. SLTs and audiologists must contribute to neonatal care of high risk infants to facilitate development and to support families. PMID- 22216557 TI - Development of a music perception test for adult hearing-aid users. AB - The purpose of this research was twofold: firstly, to develop a music perception test (MPT) for hearing-aid users, and secondly, to evaluate the influence of non linear frequency compression (NFC) on music perception with the use of the self compiled test. This article focuses on the description of the development and validation of the MPT. To date, the main direction in frequency-lowering hearing aid studies has been in relation to speech perception abilities. As hearing-aid technology has improved, interest has grown in musical perception as a dimension that could improve hearing-aid users' quality of life. The MPT was designed to evaluate different aspects of rhythm, timbre, pitch and melody. The development of the MPT could be described as design-based. Phase 1 of the study included test development and recording, while phase 2 entailed presentation of stimuli to normal hearing listeners (n = 15) and hearing-aid users (n = 4). Based on the findings of phase 2, item analysis was performed to eliminate or change stimuli that resulted in high error rates. During phase 3 the adapted version of the test was performed on a smaller group of normal hearing listeners (n = 4) and 20 hearing-aid users. Results proved that adults with normal hearing as well as adults using hearing aids were able to complete all the sub-tests of the MPT, although hearing-aid users scored lower on the various sub-tests than normal hearing listeners. For the rhythm section of the MPT normal hearing listeners scored on average 93.8% versus 75.5% of hearing-aid users; for the timbre section the scores were 83% versus 62.3% respectively. Normal hearing listeners obtained an average score of 86.3% for the pitch section and 88.2% for the melody section, compared with the 70.8% and 61.9% respectively obtained by hearing-aid users. This implies that the MPT can be used successfully for assessment of music perception in hearing-aid users within the South African context and may therefore result in more effective hearing-aid fittings taking place. The test can be used as a counselling tool to assist audiologists and patients in understanding the problems they experience regarding music perception, and might be used for future musical training in areas where participants experience problems in customising individual fittings. PMID- 22216558 TI - Communication after mild traumatic brain injury--a spouse's perspective. AB - Individuals with mild traumatic brain injury (MTBI) often perform within normal limits on linguistic and cognitive assessments. However, they may present with debilitating communicative difficulties in daily life. A multifaceted approach to MTBI with a focus on everyday communication in natural settings is required. Significant others who interact with the individual with MTBI in a variety of settings may be sensitive to communicative difficulties experienced by the individual with MTBI. This article examines communication after MTBI from the perspective of the spouse. A case study design was implemented. The spouses of two individuals with MTBI served as the participants for this study. Semi structured interviews were held, during which each participant was requested to describe the communication of their spouse with MTBI. The content obtained from the interviews was subjected to a discourse analysis. The results show that both participants perceived changes in the communication of their spouse following the MTBI. The results further show that MTBI affected communication of the two individuals in different ways. The value of a 'significant other' in providing information regarding communication in natural settings is highlighted. The implications of these findings for the assessment and management of the communication difficulties associated with MTBI are discussed. PMID- 22216559 TI - "Dem bones, dem bones, dem dry bones". PMID- 22216560 TI - The 2011 Gold Medal for Distinguished Service--Dr. S. Jerry Long. PMID- 22216561 TI - Distraction osteogenesis for craniomaxillofacial problems. AB - Distraction osteogenesis (DO) is a biological process involving the formation of new bone between viable bone segments that are gradually separated by incremental traction. This technology has proved useful in several craniomaxillofacial applications where conventional techniques were previously used. This article describes DO and demonstrates three disparate uses for this technology. PMID- 22216562 TI - Management of invasive cervical resorption: observations from three private practices and a report of three cases. AB - Invasive cervical resorption (ICR) is a type of external resorption that is not well understood or well known in the dental community. It is often misdiagnosed, leading to improper treatment or unnecessary loss of the tooth. Treatment may involve the periodontium as well as the tooth and pulp, and management can be complex. Early diagnosis and appropriate treatment are the keys to a successful outcome. This article discusses the decision-making process and management of ICR, with emphasis on the restorative aspects of treatment. Three treatment cases are presented that include nonsurgical and surgical approaches, with recalls of 4, 8, and 9.5 years. PMID- 22216564 TI - Guide for the mentoring dentist: the admissions office perspective. AB - There is no better way to give back to dentistry--which has given us so much as dentists--than to mentor a young person into the profession. With the size of the applicant pool dramatically increasing over the past 10 years (73.6 percent), the challenge of the admissions process has increased as well. To put it simply, the "line" of those desiring dentistry as a profession has become quite long. In 2010, based upon data from the Texas Medical and Dental Schools Application Service, the ratio of dental applicants to positions exceeded the ratio of applicants to medical school positions! We haven't seen ratios like this since the late 1970's. This guide will aid mentoring dentists in the process of helping their mentees to be successful as applicants, dental students and, ultimately, dental practitioners. PMID- 22216563 TI - Gluma versus dentin bonding agents to treat dentin hypersensitivity (UT CAT #824). PMID- 22216565 TI - The direct Class IV restoration. PMID- 22216566 TI - Oral and maxillofacial pathology case of the month. Mucous extravasation phenomenon (mucocele). PMID- 22216567 TI - Physical safety from violence in the dental practice. PMID- 22216568 TI - Hotting up: public sector pensions. PMID- 22216569 TI - Confessions of a doubter: the '4200'. PMID- 22216570 TI - Immunisations--updated information, paracetamol and consent. PMID- 22216571 TI - Concerns over practice education ratios. PMID- 22216572 TI - Beyond FNP. PMID- 22216573 TI - A review of images of sleeping infants in UK magazines and on the internet. AB - This paper reports on findings of a survey of women's magazines and the internet looking at the extent to which images of babies reinforce or undermine safe infant care advice to reduce the risk of cot death. All images of babies printed in all issues of nine magazines over an eight-month period during 2009 to 2010 were reviewed. The review also included the first 20 pages of a Google search of UK sleeping babies conducted on one day in 2011. In total, 559 images were reviewed. A substantial proportion of images depicted unsafe situations, in particular side and prone sleeping and sleeping indoors with the head covered by a hat or other covering. There was a dearth of images of babies sleeping in the feet-to-foot position or with a dummy, both of which are included in FSID/Department of Health guidelines on reducing the risk of cot death. The findings are discussed in the context of health visitors' and other community practitioners' work and current government cuts in resources, and suggestions are made to respond to the situation. PMID- 22216574 TI - Health visitors' and nurses' role in the 65-year follow-up of an early post-war birth cohort. AB - This paper describes a national birth cohort study of influences on health, development and ageing processes throughout life, so far to age 65 years. It began as an early post-war study of maternity in England, Wales and Scotland two years before the NHS began, and continued as a follow-up study of a large sample (5362) of those births. The study has influenced scientific and policy thinking by showing the relationships of children's physical and mental development and home background with many aspects of health and life chances throughout their life, including the processes of physical and mental ageing. Health visitors and research nurses have been closely involved in the study's work throughout. Four comparable cohort follow-up studies have since been started in Britain, and a sixth is soon to begin. These national cohort studies provide the opportunity to compare development and health in succeeding generations. Health visitors and nurses have also been involved in these subsequent studies. PMID- 22216575 TI - Enabling practice development and research through partnerships with higher education. AB - This paper reports on a study that aimed to review a Practice Development and Research Partnership (PDRP) that was formed between an NHS community trust and a higher education institute (HEI) in 2008. Specific objectives were to focus on exploring stakeholders' views and experiences of the PDRP and to identify opportunities, barriers or challenges that were encountered. The ultimate goal of the PDRP was to promote partnership working between practitioners and academics in creating a culture of research and innovation in improving patient care, experiences and services. A qualitative research design was employed. Five lead practitioners, six academics and five senior managers from the PDRP steering group participated in semi-structured interviews. All were recorded and transcribed verbatim and a thematic approach to data analysis adopted. The PDRP provided opportunities for professional development for practitioners and academics, enhanced partnership working and recognised the need for a dedicated partnership coordinator. The evaluation recognised ambiguity with regard to roles, responsibilities and expectations. PDRPs can provide a vehicle for local NHS services to work collaboratively with HEls in developing a productive research environment that addresses local gaps in service and education in improving the quality of the patient experience. PMID- 22216576 TI - Being a part of it. PMID- 22216577 TI - NHS pensions update. PMID- 22216578 TI - Breastfeeding in public: Australia and the UK. PMID- 22216579 TI - NICE updates guidance on caesareans. PMID- 22216580 TI - Infantile vesicular rash. AB - Neonatal rashes are common but can cause significant anxiety and concern to parents and health professionals. Most often these rashes are benign and parents need to be reassured. It is important to be aware of the uncommon but potentially serious rashe seen in the neonatal period such as neonatal herpes, inconentia pigmentii. Neonatal herpes is one of the most serious perinatal infections and is commonly caused by infected maternal genital secretions at the time of birth. The outcome of an untreated herpes infection can be devastating as high incidence of mortality is recorded in disseminated herpes and herpes encephalitis infections. Midwifery staff can help in the detection of asymptomatic herpes cases in pregnant women by taking a detailed history of previous herpes infections, as viral shredding is known to occur in such cases. Presented here is a case of neonatal herpes skin, eye and mucosa syndrome which, at times, can cause a diagnostic challenge and delay as was seen in this case.. PMID- 22216581 TI - A fight for the right to life. AB - This paper describes the experience of 'Pamela*, mother of a child with spina bifida, diagnosed prenatally. It was disclosed during a research project exploring 'Family Centred Care' (FCC) with disabled children, and a very challenging ethical dilemma arose. This mother felt unsupported in her decision to go ahead with having her baby with spina bifida; this was in contrast to the support she received for her disabled child, once born. The discussion will focus around the challenge of supporting parents in decision making in midwifery and health care practice. PMID- 22216582 TI - Magnesium sulphate for pre-eclampsia: care of the neonate. AB - Whilst the care of women requiring magnesium sulphate for pre-eclampsia and eclampsia is well documented, there is considerably less guidance on the identification and treatment of magnesium toxicity in women and neonates within midwifery literature, particularly in relation to neonatal care. Given the potential risk of magnesium toxicity in the neonate and the ensuing problems that may occur, it is essential that all midwives are knowledgeable about the care and observations required for the fetus and neonate. This paper provides a background to the neonatal anatomy and physiology, recognition of neonatal magnesium toxicity and implications for midwifery practice. PMID- 22216583 TI - Prenatal exposure to anti-epileptic drugs: the need for preconception counselling. AB - There is accumulating evidence that prenatal exposure to antiepileptic drugs (AEDs) poses an increased risk to the fetus. There is robust evidence surrounding the incidence of major congenital malformations following exposure to some commonly prescribed AEDs, and growing evidence that prenatal exposure to certain AEDs is also associated with a reduction in cognitive functioning and an increase in neurodevelopmental disorders in childhood. This article discusses some of the findings in regards to pregnancy outcome after exposure to AEDs, the possible implications for the child and, given recent findings, the need for preconception counselling for women with epilepsy of childbearing potential. PMID- 22216584 TI - At home in early labour: what fathers do and how they feel--part 2. AB - This is the second in a series of three articles which present data from a 2010 survey completed by 263 fathers on their experience of being at home with their partner in early labour. Fathers' state of mind during early labour is explored. Anxiety levels are found to be high, particularly in regard to the wellbeing of their partners and babies. Attending antenatal classes does not appear to diminish anxiety and nor does speaking to a midwife in early labour. These results require cautious interpretation but also suggest that men need better preparation for their role in supporting mothers during labour. PMID- 22216585 TI - Reducing 'swine flu': the midwife's role. AB - With 70 per cent of pregnant women remaining unvaccinated in January 2011, the Department of Health (DOH) and the Royal College of Obstetricians and Gynaecologists (RCOG) provided further updated advice for providers of maternity services in February 2011, stressing that pregnant women should be included in the 'at risk' groups for GPs' seasonal flu vaccine, which would also reduce the incidence of H1N1 virus in newborns (DOH and RCOG 2011). The launch of the 'NHS Flu Fighter' this autumn is expected to increase the uptake of NHS staff being vaccinated, further reducing transmission to this vulnerable group. PMID- 22216587 TI - Human milk: medicine for premature babies. AB - Following years of research there have been some significant developments in the understanding and subsequent support being offered to Neonatal Intensive Care Unit (NICU) families. In addition, ground breaking advances in the treatment of premature infants, with specific interest in the role of human milk, are now available. New information was presented by leading international researcher, Professor Meier, at an international symposium earlier this year. This article seeks to share this insightful information and provide support to those working in or around the NICU. PMID- 22216586 TI - Perilous periodontitis: a clinical study. AB - The aim of this study is to determine whether periodontitis in pregnant women could be a risk factor for pre term low birth weight. The oral hygiene status, periodontal status and periodontal treatment needs of mothers who birthed infants with normal birth weight and normal gestation period (group A) and mothers who birthed pre term low birth weight infants (group B) were assessed and compared. The clinical parameters used were Oral Hygiene Index--simplified (OHI-S), gingival bleeding index (GBI), probing pocket depth and Community Periodontal Index of Treatment Needs (CPITN). This article presents the study and its findings and draws conclusions as to the relationship between poor periodontal condition and pre term low birth weight. PMID- 22216588 TI - Use of technology in childbirth. 3. Assisted conception. PMID- 22216589 TI - The limerick lullaby project: an intervention to relieve prenatal stress. PMID- 22216590 TI - The challenge of early births. PMID- 22216591 TI - Use of a diode laser to restore skin scarred by cosmetic tattooing on the mouth. PMID- 22216592 TI - Incisive canal cyst. PMID- 22216593 TI - Stigma. PMID- 22216594 TI - A debate on cultural competence in mental health is urgently needed. PMID- 22216595 TI - Disclosure dilemma. PMID- 22216596 TI - Getting connected. PMID- 22216598 TI - Recovery heroes: who needs them? PMID- 22216597 TI - Out of Africa. PMID- 22216599 TI - A festive offering. PMID- 22216600 TI - Conferences across Europe. PMID- 22216601 TI - The draft plan for payment by results. PMID- 22216602 TI - A child in mind. PMID- 22216603 TI - Delivering a service for people with a personality disorder is complex but it can be achieved. PMID- 22216604 TI - Doctor's orders. PMID- 22216605 TI - Perspectives. PMID- 22216607 TI - Our survey said. PMID- 22216606 TI - Tuning in: a story by a patient and a therapist about making sense of voices. PMID- 22216608 TI - On the record: looking at ordinary people's tales of living with their mental illness. Interview by Alita Buttress. PMID- 22216609 TI - Voting is not enough. PMID- 22216610 TI - Publishing a cathartic experience. PMID- 22216611 TI - More debate on 12-hour shifts needed. PMID- 22216612 TI - Another tale of bad nursing care. PMID- 22216613 TI - Health care assistants could do more. PMID- 22216614 TI - Christian values lacking. PMID- 22216615 TI - Grateful for caregiving experience. PMID- 22216616 TI - Antibiotic sprays threaten health. PMID- 22216617 TI - Caring for carers in critical care. PMID- 22216618 TI - Critical care nursing--looking back to learn about the present. PMID- 22216619 TI - Building foundations for the future. PMID- 22216620 TI - A service to support bereaved families. PMID- 22216621 TI - Hitting the target and missing the point. PMID- 22216622 TI - Oxygen therapy for heart attacks. PMID- 22216623 TI - From India to New Zealand--a challenging but rewarding passage. PMID- 22216624 TI - Cholesterol: the good, the bad and the ugly. PMID- 22216625 TI - Beyond 2020: a vision for nursing. PMID- 22216626 TI - Communication lies at the heart of safe patient care. PMID- 22216627 TI - [A time for reflection and progress]. PMID- 22216628 TI - [Cooperation with physicians just needs to start]. PMID- 22216629 TI - [Transporting patients presents a serious infringement risk to law and order]. PMID- 22216630 TI - [Handicap, pain and suffering]. PMID- 22216631 TI - [Seasonal influenza vaccination, a campaign just until January 31, 2012]. PMID- 22216632 TI - [Chronic obstructive pulmonary disease, 64 million people world-wide]. PMID- 22216633 TI - [Training for public health through the study of the social environment]. AB - By studying the environment, future social services assistants are introduced to a global social reality approach, between research and action. The work of a social services assistant is based on a humanist approach to the concept of health. Well-being is dependent on an individual's environment. The social services assistant studies people in terms of their singularity and of the interweaving of their relationships with others. PMID- 22216634 TI - [Local application of strong opioids and wound-related pain]. AB - The local application of strong opioids seems to offer relief for the patient suffering from eschars, tumorous wounds or ulcers thanks to peripheral opioid receptors. Morphine mixed with a hydrogel is the most commonly used method. PMID- 22216635 TI - [Dietary care, an essential support for colon cancer treatments]. AB - Dietetics is currently playing an increasingly important role in the treatment of cancers. Saint-Antoine hospital in Paris offers nutritional support on medical prescription to every patient undergoing treatment for colon cancer. In both digestive surgery and oncology departments, the dietician supports and monitors patients throughout their hospitalisation. PMID- 22216636 TI - [Allergies and the environment. Cause and effect]. PMID- 22216637 TI - [Allergy and atopic disease, understanding to provide better care]. AB - Allergies have become more widespread on the medical landscape of developed countries over recent years. Left untreated, or poorly treated, they are responsible for a high level of morbidity and underestimated social prejudice. Screening, treatment and monitoring are essential. PMID- 22216638 TI - [Allergies and health surveillance networks]. AB - Allergies are evidence of an immune conflict between individuals and their environment. Health surveillance in this area monitors the evolution of these allergies and their causes and studies the link between changes to the environment in terms of the air, food, medicines or cosmetics. PMID- 22216639 TI - [Dermatological allergies]. AB - The skin is an organ which is particularly susceptible to the development of allergic reactions. Each skin allergy corresponds to a specific physiopathological mechanism. Skin tests can identify, in the vast majority of cases, the allergen responsible. PMID- 22216640 TI - [Respiratory allergies]. AB - A respiratory allergy corresponds to an inflammation of the airways linked to an immunological reaction of an allergic origin. Asthma is a common manifestation of such an allergy. A global approach involving the patient, and taking into account the allergen and the environment determines the effectiveness of the care. PMID- 22216641 TI - [Food allergies in children]. AB - A food allergy is often the first manifestation of an allergy in a child. Early diagnosis, the identification of the food responsible and the therapeutic education of the parents and the child improve its evolution. PMID- 22216642 TI - [Food allergy in children, an account of a pathway to a cure]. PMID- 22216644 TI - [Psychosomatic approach to allergies]. AB - Allergies are a physical manifestation which can be approached positively. Localising the allergy enables the link with the person's history to be identified and helps to give meaning to the symptoms. Kinesiology and Chinese medicine can complement the western approach to the illness. PMID- 22216643 TI - [The role of the nurse in the therapeutic education of patients at high risk of anaphylaxis]. AB - Allergies are common discases which affect 20 to 25% of the French population. The major risks are anaphylactic shock, laryngeal oedema and acute severe asthma. A process of therapeutic education helps to limit these risks for the patient. PMID- 22216645 TI - [Medical counselors on the indoor environment]. PMID- 22216646 TI - [The intrauterine environment in childhood allergy]. PMID- 22216647 TI - [Bibliography - allergies]. PMID- 22216648 TI - [The critical reading of scientific articles, an easy-to-use method]. AB - Faced with the abundance of available literature, clinicians must follow a method in order to carry out a critical reading of scientific articles. This enables them to decide how relevant the selected article is to the issues specific to their area of work and to choose whether to undertake a basic critical reading or to embark on an active reading. PMID- 22216649 TI - [Organizational stress]. PMID- 22216650 TI - A dentifrice with multiple benefits. PMID- 22216651 TI - A multi-tasking dentifrice for the 21st century. PMID- 22216652 TI - Anti-hypersensitivity mechanism of action for a dentifrice containing 0.3% triclosan, 2.0% PVM/MA copolymer, 0.243% NaF and specially-designed silica. AB - PURPOSE: To evaluate the laboratory dentin occlusion efficacy and effects on dentin permeability of a new multi-benefit dentifrice in order to gain insight into the mechanism of action of a novel technology for dentin hypersensitivity relief based on a specially-designed silica and copolymer system. METHODS: Acid etched human dentin was evaluated with confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM) after treatment with one of the following: (1) a dentifrice containing 0.3% triclosan, 2.0% PVM/MA copolymer, 0.243% sodium fluoride with specially designed silica (Test Dentifrice 1); (2) a dentifrice containing 0.3% triclosan and the same overall silica loading as Test Dentifrice 1 but without copolymer and the specially-designed silica (Placebo Dentifrice); (3) a commercially-available dentifrice containing 0.454% stannous fluoride in a silica base with sodium hexametaphosphate and zinc lactate (Test Dentifrice 2); and (4) a commercially-available non-sensitive dentifrice containing 0.243% sodium fluoride in a silica base (Negative Control Dentifrice). The composition of dentin treated with either Test Dentifrice 1 or Negative Control Dentifrice was analyzed using energy dispersive x-ray (EDX) and electron spectroscopy for chemical analysis (ESCA). To highlight dentin occluding efficacy of the specially designed silica, dentin was treated with Test Dentifrice 1 formulated with fluorescently-tagged specially-designed silica and resulting occlusion followed with CLSM. The dentin occluding abilities of Test Dentifrices 1 and 2 were compared with the Negative Control dentifrice using CLSM after a 4-day cycling model consisting of twice daily dentifrice treatment and four acid challenges. Effects of treatment with Test Dentifrices 1 or 2 on dentin permeability and subsequent resistance of occluding deposits to acid dissolution and dislodgement by pulpal pressure were assessed using hydraulic conductance. RESULTS: Dentin specimens treated with Test Dentifrices 1 and 2 were significantly occluded compared to Placebo Dentifrice and Negative Control Dentifrice when visualized with CLSM. The level of occlusion remaining after challenge with cola was highest for dentin treated with Test Dentifrice 1 in CLSM xz views. Test Dentifrice 1 produced dentin surface deposits and tubule plugs containing silicon in addition to calcium and phosphorus as indicated by ESCA and EDX. CLSM visualization of fluorescently-tagged material confirmed occlusion by the specially-designed silica which was localized at the dentin tubule openings. Imaging of dentin by CLSM after the 4-day cycling model revealed a significantly higher amount of occluded tubules for dentin treated with Test Dentifrice 1 compared to the Negative Control Dentifrice or Test Dentifrice 2. Etched dentin treated with the Test Dentifrice 1 was significantly less permeable compared to that treated with the Negative Control Dentifrice, exhibiting over 80% reduction in dentin permeability. The occlusion provided by the Test Dentifrice 1 was maintained and provided significantly better reduction in permeability after extended pulpal pressure and acid challenge compared to dentin treated with Test Dentifrice 2. PMID- 22216653 TI - Assessment of hypersensitivity reduction of a dentifrice containing 0.3% triclosan, 2.0% PVM/MA copolymer, 0.243% NaF and specially-designed silica as compared to a dentifrice containing 0.454% stannous fluoride, sodium hexametaphosphate and zinc lactate and to a dentifrice containing 0.243% NaF on dentin hypersensitivity reduction: an 8-week study. AB - PURPOSE: To evaluate the 8-week dentin hypersensitivity efficacy of three toothpastes: (1) a dentifrice containing 0.3% triclosan, 2.0% PVM/MA copolymer, 0.243% sodium fluoride and specially-designed silica (Test Dentifrice 1); (2) a commercially-available dentifrice containing 0.454% stannous fluoride in a silica base with sodium hexametaphosphate and zinc lactate (Test Dentifrice 2); and (3) a commercially-available non-sensitive dentifrice containing 0.243% sodium fluoride in a silica base (Negative Control Dentifrice). METHODS: For this 8-week randomized controlled clinical study, qualifying subjects had to have at least two hypersensitive teeth with a tactile hypersensitivity score (Yeaple Probe) between 10 and 50 grams of force, and air blast hypersensitivity score of 2 or 3 (Schiff Cold Air Sensitivity Scale). Subjects brushed twice daily for 1 minute, using the assigned toothpaste and toothbrush. Dentin hypersensitivity assessments, as well as examinations of oral hard and soft tissues, were conducted at the baseline examination and after 4 and 8 weeks of brushing. RESULTS: 118 subjects complied with the protocol, and completed the 8-week study. At baseline, the mean tactile sensitivity scores for toothpastes (1), (2) and (3) were 13.6, 14.1 and 13.1; at 4 weeks 28.75, 20.13, and 20.00; and after 8 weeks 33.1, 24.0 and 20.5, respectively. The mean air blast scores for toothpastes (1), (2), and (3) at baseline were 2.5, 2.5, and 2.4; at 4 weeks 1.25, 1.50 and 1.85; and after 8 weeks 0.99, 1.36 and 1.5, respectively. At all time points after the baseline examination, for both tactile and air blast sensitivity scores, the differences between Test Dentifrice 1 and the Negative Control Dentifrice were statistically significant (P < 0.05). The differences between Test Dentifrice 1 and Test Dentifrice 2 were statistically significant (P < 0.05) at 4 and 8 weeks after baseline examination for tactile sensitivity scores and at 8 weeks after baseline examination for air blast sensitivity scores. PMID- 22216654 TI - Comparative investigation of a dentifrice containing triclosan/copolymer/sodium fluoride and specially-designed silica and a dentifrice containing 0.243% sodium fluoride in a silica base for the control of established supra-gingival plaque and gingivitis: a 6-month clinical study. AB - PURPOSE: To investigate the efficacy of a dentifrice containing 0.3% triclosan, 2.0% PVM/MA copolymer, 0.243% sodium fluoride, and specially-designed silica in controlling established dental plaque and gingivitis. METHODS: Qualifying adult male and female subjects from the West Palm Beach, Florida area were randomly assigned into one of two treatment groups: (1) a dentifrice containing 0.3% triclosan, 2.0% PVM/MA copolymer, 0.243% sodium fluoride, and specially-designed silica (Test Dentifrice); and (2) a dentifrice containing 0.243% sodium fluoride in a silica base (Negative Control Dentifrice). All subjects received an oral soft and hard tissue examination, baseline plaque and gingivitis were assessed, and subjects were dispensed their assigned dentifrice product along with a soft bristled adult toothbrush for home use. Subjects were instructed to brush their teeth for 1 minute, twice daily (morning and evening), using only the dentifrice provided. Examinations for plaque and gingivitis, and oral soft and hard tissue assessments were repeated after 3 and 6 months of product use. RESULTS: 115 subjects complied with the protocol, and completed the 6-month examination. After 6 months of product use, subjects assigned to the Test Dentifrice group exhibited statistically significant reductions from baseline with respect to Plaque Index, Plaque Severity Index, Gingival Index, and Gingivitis Severity Index scores; and subjects assigned to the Negative Control Dentifrice group exhibited statistically significant reductions from baseline with respect to Gingival Index scores only. Relative to the Negative Control Dentifrice group, the Test Dentifrice group exhibited an 18.8% reduction in Plaque Index; a 50% reduction in Plaque Severity Index; a 19.6% reduction in Gingival Index; and a 60% reduction in Gingivitis Severity Index after 6 months, all of which were statistically significant. PMID- 22216655 TI - Extrinsic stain removal efficacy of a new dentifrice containing 0.3% triclosan, 2.0% PVM/MA copolymer, 0.243% NaF and specially-designed silica for sensitivity relief and whitening benefits as compared to a dentifrice containing 0.3% triclosan, 2% PVM/MA copolymer, 0.243% NaF and to a negative control dentifrice containing 0.243% NaF: a 6-week study. AB - PURPOSE: This single-center, double-blind, randomized, parallel-group clinical study was designed to investigate the extrinsic stain removal efficacy of a new antisensitivity dentifrice containing 0.3% triclosan, 2% polyvinylmethyl ether/maleic acid copolymer (PVM/MA copolymer), 0.243% NaF and a new silica specially-designed to occlude dentin tubules, relative to a Positive Control dentifrice and a Negative Control dentifrice. METHODS: 117 qualifying adults were stratified by baseline Lobene Stain Index scores and randomly assigned to brush twice daily using a soft-bristled toothbrush and one of three dentifrices: (1) the Test Dentifrice; (2) a previously clinically proven dentifrice variant containing 0.3% triclosan, 2% PVM/MA copolymer, 0.243% NaF in a high cleaning silica base (Positive Control); and (3) a dentifrice containing 0.243% NaF in a silica base (Negative Control). Extrinsic stain area and stain intensity examinations were repeated after 3 and 6 weeks of product use. RESULTS: Relative to the Negative Control group, the Test group and the Positive Control group exhibited statistically significant improvements in mean Lobene composite stain scores after 3 weeks of product use (39.8% and 40.7% respectively) and after 6 weeks of product use (58.8% and 61.8% respectively). There were no statistically significant differences observed between the stain removal performance of the Test Dentifrice and the Positive Control Dentifrice after 3 and 6 weeks of product use. PMID- 22216656 TI - Defence of pensions is a wholly just cause. PMID- 22216658 TI - Midwifery roles are being filled by nurses as a cost-cutting tactic. PMID- 22216657 TI - NMC will look at ethnic make up of staff in fitness to practise hearings. PMID- 22216659 TI - Trust is close to eradicating its 34 million pounds sterling agency staffing bill. PMID- 22216661 TI - Lansley says the government's pensions offer is a fair deal. PMID- 22216660 TI - Hundreds of thousands expected to join strike action over pensions. PMID- 22216662 TI - 'Holding off on ballot is in nurses' interests'. PMID- 22216663 TI - Reputation on the line. AB - As part of our Care campaign, we look at whether a string of exposes and investigations are threatening to undermine confidence in nursing. PMID- 22216664 TI - A century of support. AB - Macmillan Cancer Support is aiming to offer increasingly holistic and community based care for the growing number of people who are living with and surviving cancer. PMID- 22216665 TI - Psychological needs of patients with functional bowel disorder. AB - Psychological processes have an important role in functional bowel disorder (FBD), with a high incidence of psychological distress experienced by this patient group. One way of conceptualising illness, particularly chronic conditions such as FBD, is within a biopsychosocial framework, where the interaction between biological, behavioural and cognitive processes and the social and physical environment define the illness experience. Therefore, in addition to medical treatment, patients with FBD and concomitant psychological difficulties should be offered psychological intervention. This article describes several psychological approaches and discusses how these might be delivered in practice. PMID- 22216666 TI - An electronic resource to support staff providing end of life care. AB - The Department of Health's End of Life Care Strategy provided the opportunity to develop effective care, regardless of the setting. However, providing end of life care is challenging for all healthcare practitioners, with each care setting experiencing unique challenges. Within one acute NHS trust, the challenges of identifying and diagnosing dying were identified. An electronic resource tool was developed to aid prognostication and provide a single point of reference to assist healthcare practitioners in improving end of life care for patients in an acute hospital setting. PMID- 22216667 TI - An overview of triage in the emergency department. AB - Emergency care services in the UK are receiving increasing numbers of patients presenting with a wide range of problems, from life-threatening conditions to minor injury or illness. All patients seeking emergency care need to be assessed and classified to prioritise those who have the most urgent problems and are in need of immediate care. This article provides an overview of triage within an emergency care setting. It explores the development of triage and describes the nationally recognised Manchester Triage System. The professional and legal responsibilities of the triage nurse are also discussed. PMID- 22216668 TI - Postnatal depression. PMID- 22216669 TI - Try an unconventional shift. PMID- 22216670 TI - Checkout these services. PMID- 22216671 TI - Decisions close to home. PMID- 22216672 TI - Cardiac involvement with amyloidosis: mechanisms of disease, diagnosis and management. AB - The amyloidoses represent a group of clinical disorders of diverse etiologies that have as a common pathophysiologic denominator the deposition of misfolded protein based amyloid fibrils in the interstitial space of various organs. They are uncommon diseases with protean clinical presentations. Cardiac involvement is the determining factor for a patient's prognosis. Clinicians have to maintain a high index of suspicion and actively search for signs and symptoms of cardiac involvement in patients with preexisting conditions known to be associated with the development of amyloidosis. Early diagnosis and accurate fibril typing are the first steps in managing the disease. Judicious use of various diagnostic modalities such as serum markers and imaging studies, and good communication among all the physicians involved in the care of these sick and frail patients, are keys to a better outcome. PMID- 22216673 TI - Aortic root motion: a marker of left ventricular diastolic dysfunction using M mode echocardiography? An observational study. AB - Echocardiography remains the best non invasive tool for identifying patients who may have impaired filling of the left ventricle or diastolic dysfunction. The most accurate echocardiographic modality that reveals normal and abnormal diastolic function is doppler tissue imaging (DTI), and more recently, strain imaging. The complex and user intense DTI modality traces the motion of the mitral annulus during left ventricular filling revealing diastolic impairment. The aortic annulus with its attached aortic root moves simultaneously with the rigidly attached mitral annulus. M-mode traced motion of the aortic root in diastole mimics the motion of the mitral annulus and thus should depict left ventricular diastolic function. Hypertensive patients and normal subjects were screened for left ventricular diastolic dysfunction (LVDD) with DTI, mitral inflow velocities (MIF) and M-mode aortic root motion (M-MARM). The easily obtained and less complex M-MARM was as accurate as DTI in detecting and ruling out regional PMID- 22216674 TI - Bone marrow metastasis as first recurrence of gastric cancer: a case report. AB - We report a case of a 71-year-old male with resected stage IIIA signet ring cell adenocarcinoma of the stomach treated with adjuvant chemo-radiation therapy who presented with metastatic disease confined to the bone marrow. Pancytopenia was the sole presentation of metastasis and bone marrow was the only site of tumor recurrence. There were no documented bone lesions. The tumor was extremely aggressive and the patient expired seventeen days after diagnosis of tumor recurrence. PMID- 22216675 TI - Septic shock from Pasturella multocida following a cat bite: case report and review of literature. AB - Pasteurella multocida is a gram-negative organism categorized morphologically as a coccobacillus. P. multocida is a natural inhabitant found in the nasopharynx and oropharynx of numerous animal hosts, but serves as an opportunistic pathogen in humans. Pasturella multocida has multiple subspecies; when identified as the cause of infection they are broadly termed pasturelloses. Infections involving P. multocida are typically reported to occur in immune-compromised patients. Few cases in the literature identify pasturellosis as the causative agent of septic shock, especially in cirrhotic patients. Our patient's underlying cirrhosis and past splenectomy place her in the higher risk category for developing invasive Pasturella infection. We report a patient who presented with septic shock that was initially thought to be related to a urinary tract infection. It was later revealed that the patient's condition was caused by a recent cat bite leading to Pasturella bacteremia compounded by hepatic cirrhosis and previous splenectomy. PMID- 22216676 TI - A case of idiopathic retroperitoneal fibrosis. AB - Retroperitoneal fibrosis is the presence of a fibrotic plaque in the prelumbar or presacral area. It can occur as a result of certain medications, fluid collections, inflammatory disease of various intra-abdominal organs, previous surgery or radiation therapy and various metastatic neoplasms. Most cases of retroperitoneal fibrosis are considered idiopathic. We report an interesting case of idiopathic retroperitoneal fibrosis with the emphasis on the importance of pathology to establish the diagnosis. PMID- 22216677 TI - Inhaled amphotericin B as fungal prophylaxis in heart transplant recipients. PMID- 22216678 TI - Sustaining Medicare's promise. AB - Medicare is projected to face shortfalls by 2024. Structural changes of the program have been discussed, but current healthcare reform proposals have not included modifications that are certain to reduce expenditures. One idea that is gaining political traction is to advance the age of beneficiaries to match that of Social Security (ie, 67). This article reviews the rationale and savings associated with this proposal. PMID- 22216679 TI - A history of the Department of Gynecology and Obstetrics at the 200th anniversary of Yale medical school. PMID- 22216680 TI - Foreword. 1961. PMID- 22216681 TI - The past is prologue to the future. PMID- 22216682 TI - Address of the new President. PMID- 22216683 TI - If accountable care is to succeed. PMID- 22216684 TI - Address of the Executive Vice President. PMID- 22216685 TI - "Dean Winternitz: Yale medical school's passionate humanist". PMID- 22216686 TI - One of the "side effects" of the House of Delegates annual meeting. PMID- 22216687 TI - Re: Intracranial hemorrhage from undetected aneurysmal rupture complicating transphenoidal pituitary adenoma resection. PMID- 22216688 TI - "I can't stand needles!". PMID- 22216689 TI - National Institute of Nursing research has widened the blue highway of translation research. PMID- 22216690 TI - Using the Appraisal of Guidelines for Research and Evaluation II to assess clinical practice guidelines. PMID- 22216692 TI - Measuring patient satisfaction with postpartum teaching methods used by nurses within the interaction model of client health behavior. AB - The purpose of this study was to determine the relationship between new mothers' interaction with nurses using different teaching methods to provide postpartum discharge teaching and their satisfaction with nursing care. Cox's Interaction Model of Client Health Behavior (IMCHB) provided the framework for this study. This study used a quasi-experimental posttest design with two groups to examine patient satisfaction with different teaching methods used by nurses to provide postpartum education. The Modified Client Satisfaction Tool measured satisfaction with discharge teaching. Data were analyzed with descriptive statistics, chi square, Kendall's tau, and Mann-Whitney U tests. The data showed high satisfaction scores for new mothers receiving both methods of discharge teaching, indicating that new mothers who received the traditional method of discharge instruction provided by nurses were just as satisfied as those who received the demonstration/return demonstration method of discharge instructions provided by nurses. Providing individualized care, based on the expressed needs of the patient, was demonstrated in this study to result in high satisfaction with nursing care using both methods of providing postpartum discharge teaching. PMID- 22216693 TI - Comparative effectiveness research: using systematic reviews and meta-analyses to synthesize empirical evidence. AB - The increased demand for evidence-based health care practices calls for comparative effectiveness research (CER), namely the generation and synthesis of research evidence to compare the benefits and harms of alternative methods of care. A significant contribution of CER is the systematic identification and synthesis of available research studies on a specific topic. The purpose of this article is to provide an overview of methodological issues pertaining to systematic reviews and meta-analyses to be used by investigators with the purpose of conducting CER. A systematic review or meta-analysis is guided by a research protocol, which includes (a) the research question, (b) inclusion and exclusion criteria with respect to the target population and studies, (c) guidelines for obtaining relevant studies, (d) methods for data extraction and coding, (e) methods for data synthesis, and (f) guidelines for reporting results and assessing for bias. This article presents an algorithm for generating evidence based knowledge by systematically identifying, retrieving, and synthesizing large bodies of research studies. Recommendations for evaluating the strength of evidence, interpreting findings, and discussing clinical applicability are offered. PMID- 22216691 TI - No more fighting and biting during mouth care: applying the theoretical constructs of threat perception to clinical practice. AB - The purpose of this article is to describe how the neurobiological principles of threat perception and fear response can support clinical approaches to prevent and reduce care-resistant behaviors during mouth care. Nursing home residents who exhibit care-resistant behavior are at risk for poor oral health because daily oral hygiene may not be consistently provided. Poor oral health predisposes these older people to systemic problems such as pneumonia, cerebral vascular accidents, and hyperglycemia. Care-resistant behavior is a fear-evoked response to nurses' unintentionally threatening behavior during mouth care. Nurses can safely and effectively provide mouth care to persons with dementia who resist care by using personalized combinations of 15 threat reduction strategies. PMID- 22216694 TI - Double whammy for a new breed of foreign-educated nurses: lived experiences of Filipino physician-turned nurses in the United States. AB - This phenomenological study examined the lived experiences of eight self identified Filipino physician-turned nurses working in Las Vegas in the United States. Participants were interviewed, and audiotaped interviews were transcribed verbatim. Meanings of significant statements and clusters of themes and subthemes were then generated using the Colaizzi's (1978) method. In addition, van Manen's (1990) existentials of lived world was adopted to interpret the collected data. The results of the study revealed that the experiences of these Filipino physician-turned nurses involved multidimensional challenges captured in three themes in context of cross-national and transprofessional migration. As a result, they faced a "double whammy" adjustment to a new cultural and work environment common to all foreign nurses (cultural adaptation) and unique identity/role change from physician to nurse (transprofessional adaptation)--that made their transition especially challenging, resulting in short-lived nursing careers at the bedside. Tailored transition programs for physician-turned foreign nurses are needed to address their transprofessional adaptation. In addition, costs and benefits of recruiting and employing physician-turned foreign nurses as direct caregivers need to be reconsidered in light of this study's findings. PMID- 22216695 TI - Esophageal bypass using a gastric tube for a malignant tracheoesophageal/bronchoesophageal fistula: a report of 4 cases. AB - Tracheoesophageal/bronchoesophageal fistulas are often caused by locally advanced esophageal cancer and lung cancer, and result in life-threatening conditions such as severe cough and dyspnea due to pneumonia. We herein report the clinical characteristics of 4 patients with tracheoesophageal/bronchoesophageal fistulas. All patients were men, and ranged in age from 40-69 years. Three patients had esophageal cancer and 1 had lung cancer. All 4 underwent esophageal bypass using a gastric tube with tube drainage of the distal side of the esophagus. Three patients died at 3, 4, and 5 months after surgery. However, these patients were allowed to enjoy food orally up until the last few days of life. One patient who underwent esophageal bypass and chemoradiotherapy has remained well for 5 years without any evidence of recurrence. This bypass procedure is therefore considered to be a feasible treatment choice for patients with tracheoesophageal/bronchoesophageal fistulas. PMID- 22216696 TI - Minilaparotomy for perforated duodenal ulcer. AB - The usefulness of the minilaparotomy approach for perforated duodenal ulcer repair was retrospectively evaluated in 37 patients (26 men; mean age, 56.5 years). Simple closure with an omental patch by minilaparotomy (skin incision, < or = 7 cm) was successful in 86.5% of the cases, with an operative mortality of 2.7%. Compared with the results in historic control patients who underwent conventional open surgery (n = 27), a shorter operative time (P < 0.01), lower frequency of analgesic use (P = 0.03), earlier passage of flatus (P < 0.01), and shorter hospital stay (P = 0.04) were obtained in the patients undergoing minilapartomoy. The postoperative morbidity was identical between the two groups (16.2% versus 33.3%, P = 0.40). On multivariate analysis, a large amount of intraabdominal fluid was the only significant risk factor for extension of the minilaparotomy wound (P = 0.012). The minilaparotomy approach appears to be a feasible, safe, and less invasive approach compared with the conventional open approach and could be a useful alternative to the laparoscopic approach in selected patients with perforated duodenal ulcer. PMID- 22216697 TI - Postoperative defecatory function of an ileal pouch-anal anastomosis after a restorative proctocolectomy for ulcerative colitis: evaluation using fecoflowmetry. AB - An ileal pouch is usually reconstructed as an alternative to a neorectum after a total proctocolectomy for ulcerative colitis (UC). However, the real defecatory function of an ileal pouch is uncertain. This study was designed to analyze the functional and clinical outcomes after a proctocolectomy and ileal pouch-anal anastomosis (IPAA) for UC using fecoflowmetry (FFM). Sixteen patients who underwent IPAA for UC between 1990 and 2005 were studied. They were evaluated by FFM, together with Kelly's clinical score (KCS), and anorectal manometric assessments were also performed. FFM showed that the fecoflow pattern (FFP) of 14 patients (87%) was the block type and of 2 patients (13%) was the segmental type. The clinical score and tolerance volume showed no improvement 1 year or more after IPAA. However, the value of the maximum fecal stream flow rate (Fmax) improved with time. FFM shows that the defecatory function improved after IPAA, and it may therefore contribute to a good long-term outcome after the surgery. PMID- 22216698 TI - Gene expression of mesenchyme forkhead 1 (FOXC2) significantly correlates with the degree of lymph node metastasis in colorectal cancer. AB - In stage III colorectal cancer, patients with N1 stage tumors show poorer outcome than patients with N2 stage tumors. Our objective was to identify genes that are predictive for the presence of lymph node metastasis, and to characterize the aggressiveness of lymph node metastases. Gene expression profiles of colorectal cancer were determined by microarray in training (n = 116) and test (n = 25) sets of patients. We identified 40 discriminating probes in patients with and without lymph node metastases. Using these probes, we could predict the presence of lymph node metastasis with an accuracy of 87.1% (training set) and 76.0% (test set). Among discriminating probes, FOXC2 expression was significantly correlated with the degree of lymph node metastasis. FOXC2 was expressed significantly and disparately in patients with N1 and N2 stage tumors as analyzed by real-time reverse transcriptase-polymerase chain reaction. FOXC2 appears to be involved in determining the aggressiveness of lymph node metastasis in colorectal cancer. PMID- 22216699 TI - Intestinal pneumatosis in which CT colonography was of significant diagnostic value: case report. AB - Intestinal pneumatosis refers to the presence of gas in the gastrointestinal wall. It is often difficult to clinically differentiate this condition from gastrointestinal perforation, sometimes resulting in emergency surgery. Imaging studies are important to establish the differential diagnosis. However, there have been few studies showing the efficacy of computed tomography (CT) colonography in diagnosing pneumatosis. We report a case of intestinal pneumatosis in which CT colonography was of significant diagnostic value. A 43 year-old man was referred to our hospital for a detailed investigation of multiple submucosal tumor-like lesions associated with multiple pneumatosis from the cecum to the ascending colon. These lesions were revealed by colonoscopy performed in another hospital on May 21, 2008. Abdominal 3-dimensional CT showed multiple pneumatic lesions from the cecum to the ascending colon, and the patient was diagnosed as having intestinal pneumatosis. The patient is being followed conservatively because he is asymptomatic. PMID- 22216700 TI - Complications after pancreaticoduodenectomy for pancreatic cancer: a retrospective study. AB - Postoperative complications, such as pancreatic fistulae, after pancreaticoduodenectomy for pancreatic cancers are associated with surgical outcomes of patients with pancreatic cancers. A total of 160 patients with pancreatic cancers undergoing pancreaticoduodenectomy were retrospectively analyzed. Patients were grouped into a fistulae group (n = 34) and a nonfistulae group (n = 126). The fistulae group had a significantly higher morbidity rate than the nonfistulae group (P < 0.0001), but hospital mortality was not different in both groups (P = 0.481). There was a higher incidence of intra-abdominal hemorrhage in patients with pancreatic fistulae than in those without fistulae. Two patients in fistulae group underwent reoperation. Patients with pancreatic fistulae had significantly longer hospital stay than those without fistulae. Pancreatic duct diameter, smoking, years of tobaccos consumption, preoperative jaundice, and surgical hours were associated with risk of fistulae on univariate analysis. In a multivariate analysis, diameter of pancreatic duct, surgical hours, and preoperative jaundice were independent risk factors of pancreatic fistulae. Incidence of pancreatic fistulae after pancreaticoduodenectomy is significantly influenced by the size of pancreatic duct diameter, surgical time, and preoperative jaundice. Early postoperative hemorrhage could be cautiously prevented. The survival is not significantly impacted by pancreatic fistulae. PMID- 22216701 TI - Mirizzi syndrome--two case reports and a short review of the literature. AB - The authors have analyzed the problem of Mirizzi syndrome (MS) and found in the literature that it was reported in 0.3% to 3% of patients undergoing cholecystectomy. Anatomic disorder, especially the presence of cholecystocholedochal fistula, increases the risk of bile duct injury during cholecystectomy, albeit more often during laparoscopic than laparotomic cholecystectomy. A comparative study was performed regarding the incidence of MS in two groups of patients: 332 patients in Zrenjanin in the year 2009, and 531 patients in Belgrade in the year 2005, with an incidence of MS found in 2 patients in Zrenjanin (0.63%) and 4 patients in Belgrade (0.75%). The incidence rate was 6% in Zrenjanin and 7.5% in Belgrade, but there was no statistically significant difference between the two groups. All patients with MS were diagnosed during the operative period using operative cholangiography. During preoperative diagnosis, patients underwent laboratory ultrasound examination, and those who were suspected of having an anatomic disorder underwent operative cholangiography, although patients today more often undergo choledochoscopy then cholangiography. MS according to classification by Csendes was found in all 6 patients undergoing operation. PMID- 22216703 TI - Incarcerated diaphragmatic hernia with intrathoracic bowel obstruction after right liver donation. AB - Liver transplantation has become an acceptable surgical procedure with the advancement of the technical and rejection considerations involved. Initially nonliving donors were used for transplantation procedures. However, with improved techniques, living donor procedures have become much more frequent. With this, complications involving the transplant organ donor may occur. We present 2 patients with intrathoracic bowel obstruction due to herniation of the small intestine and colon through a defect in the dome of the diaphragm with development of chest pain and gastrointestinal symptoms. Both patients were diagnosed by computerized tomography scan and had a right thoracotomy with lysis of the adhesions, reduction of the hernia, repair of the diaphragm, and mesh reinforcement of the diaphragm. Neither patient had a prior diaphragm defect. These patients, on review of the literature, represent the first 2 such reported cases and suggest the need to be aware of any potential diaphragm defects before closure of the abdomen after resection of the donor liver or if they develop appropriate symptomatology. PMID- 22216702 TI - Comparison of Lichtenstein and laparoscopic transabdominal preperitoneal repair of recurrent inguinal hernias. AB - The aim of our study was the comparative analysis of the results of two surgical methods: tension-free repair by the Lichtenstein technique and laparoscopic transabdominal preperitoneal (TAPP) repair. In total 52 patients with recurrent inguinal hernia were randomly assigned to the two groups: Lichtenstein (28 patients) and TAPP (24 patients). Comparisons between these groups were done by several preoperative, intraoperative, and postoperative factors. For postoperative factors both short-term and long-term results were considered. Average operation time for Lichtenstein group was 59.6 +/- 9.9 minutes, compared with 64.4 +/- 8.4 minutes for TAPP patients (P = 0.068). In TAPP patients there was less pain in the postoperative period (P = 0.002) and fewer sick-leave days (13.4 +/- 1.7 versus 17.5 +/- 2.6 days; P < 0.001) and, correspondingly, faster recovery. In the Lichtenstein group a total of 4 postoperative complications (infection, hematoma, seroma, urinary retention) were observed, compared with 8 in the TAPP group (P = 0.19). Statistically significant difference was only by urinary retention (0 for Lichtenstein, 4 for TAPP; P = 0.039). There were no cases of hernia recurrence observed during the followup. Chronic pain developed in 5 patients from the Lichtenstein group (17.9%) and 2 patients from the TAPP group (8.3%; P = 0.28) more than 1 year after the operation; 4 Lichtenstein patients (14.3%) and 1 TAPP patient (4.2%; P = 0.23) more than 2 years after the operation; and 3 Lichtenstein patients (10.7%) and 1 TAPP patient (4.2%; P = 0.36) more than 3 years after the operation. For the treatment of recurrent inguinal hernias, which are developed after use of conventional (nonmesh) methods, the first choice should be given to the laparoscopic method, especially for young, physically active, nonobese patients, and if there are any contraindications for the laparoscopy, the Lichtenstein approach should be recommended. PMID- 22216704 TI - Cyclin E low-molecular-weight isoform as a predictor of breast cancer in Japanese women. AB - Overexpression of low-molecular-weight isoforms (LMWI) of cyclin E in breast cancer cells is associated with poor prognosis and could serve a novel role in breast cancer progression. LMWI originate from proteolytic processing of cyclin E, which is deregulated and hyperactive. In this study, levels of full-form/LMWI cyclin E were determined with the use of Western blot analysis in 69 Japanese breast cancer patients. LMWI cyclin E levels were significantly correlated with known parameters such as tumor grade and estrogen/progesterone receptor expression. In multivariate analysis, patient survival was significantly correlated with tumor grade but not with either form of cyclin E. LMWI was not as strong a predictor as tumor grade in this study, whereas some cases of early relapse with LMWI overexpression and lower tumor grade were reported. Thus, LMWI might be a good complementary factor to other predictors for early relapse of breast cancer. PMID- 22216705 TI - A high level of carcinoembryonic antigen as initial manifestation of medullary thyroid carcinoma in a patient with subclinical hyperthyroidism. AB - Carcinoembryonic antigen (CEA), a tumor marker with a glycoprotein structure, is frequently used in follow-up gastrointestinal malignancies. CEA levels may also increase in neuroendocrine tumors, including medullary thyroid carcinoma (MTC), and in some benign diseases. Patients whose blood tests show high CEA levels should have additional tests regarding MTC. Although MTC comprises only 3%-11% of all thyroid cancers, it should be tested because it has a poor prognosis and may accompany multiple endocrine neoplasia. We present the case of a 76-year-old man with subclinical hyperthyroidism with sporadic MTC who presented with initial high serum CEA levels. He underwent total thyroidectomy and left modified neck dissection. Pathologic specimens stained strongly for CEA. The patient's blood was analyzed for mutations in exons 10, 11, 13, 14, 15, and 16, but the RET proto oncogene revealed no mutations. The patient was regularly followed by measurement of serum CEA levels and performance of positron emission tomography-computed tomography. Seventeen months after surgery, the patient has remained well and showed no signs of tumor recurrence. PMID- 22216706 TI - Ectopic bone formation and extramedullary hematopoiesis in the thyroid gland: report of a case and literature review. AB - This purpose of this article is to document ectopic bone formation (EBF) and extramedullary hematopoiesis (EMH) in thyroidectomy specimens. We present a case of multinodular goiter with EMH and EBF, as well as a literature review of studies published in the English language on EMH and/or bone formation in the thyroid gland, accessed through PubMed and Google Scholar databases. Thirteen published cases of EMH and/or EBF in the thyroid gland were evaluated, and a case of multinodular goiter with histopathologically proven EMH and EBF in a 54-year old woman is herein presented. In the reviewed literature, 12 patients were women, and 1 was a man (age range, 28-82 years; median, 56.46 +/- 18 years). EMH was histopathologically detected in 8 patients, EMH and EBF were detected in 4 patients, and only bone formation was detected in 1 patient. Although a solitary nodule was detected in 7 patients, multinodular goiter was detected in 6 patients. Fine needle aspiration cytology was used in the preoperative period to arrive at a diagnosis in 6 of the 13 patients, but it was not possible to obtain proper biopsy material in the remaining patients. Although no previously known hematologic disease was detected in 11 patients, 2 were known to have myelofibrosis in the preoperative period. When EMH is pathologically detected in the thyroid, the question of whether there is an underlying hematologic disease in the patient must be investigated. In addition, it must be kept in mind during fine needle aspiration cytology and frozen section examinations that EMH maybe among the differential diagnoses for anaplastic thyroid cancers. PMID- 22216707 TI - Aortoenteric fistulae: present-day management. AB - An aortoenteric fistula (AEF) is a communication between the aorta and an adjacent loop of the bowel. The three most useful diagnostic modalities for detecting AEF are abdominal computed tomography scan with intravenous contrast, esophagogastroduodenoscopy, and arteriography. The treatment of AEFs has improved in recent years, but despite the multiple surgical techniques reported, many of the patients do not survive or are left debilitated after treatment. Endovascular repair is an efficient and safe method to stabilize patients with life threatening AEFs. The aim of this study is to provide a comprehensive and synthetic review of the latest advantages on the diagnosis and management of primary and secondary AEF. PMID- 22216709 TI - Effects of full-stream carbon filtration on the development of head and lateral line erosion syndrome (HLLES) in ocean surgeon. AB - Head and lateral line erosion syndrome (HLLES) is a common but very poorly understood disease of marine aquarium fish. One suspected etiology is the use of granulated activated carbon (GAC) to filter the water. Seventy-two ocean surgeons Acanthurus bahianus were distributed among three carbon-negative control systems and three GAC-treated systems such that each tank contained approximately the same total body mass. Each replicate system was made up of two 250-L circular tanks with a common filtration system (6 fish per tank, 12 fish per replicate system). The GAC-treated tanks were exposed to full-stream, extruded coconut shell activated carbon, which produced a mean total organic carbon content of 0.4 mg/L. The results of this study indicate that extruded coconut shell activated carbon filtering at full-stream rates can cause HLLES-type lesions in ocean surgeons. The HLLES developed exponentially over 15 d, beginning in the chin region. This was followed by pitting in the cheek region, which expanded until erosions coalesced. Once the carbon was discontinued, the processes reversed in a mean time of 49 d. As the lesions healed, they reverted from the coalesced to the pitted stage and then darkened before returning to normal. PMID- 22216708 TI - A novel technique for three-dimensional reconstruction for surgical simulation around the craniocervical junction region. AB - Performing surgeries on the craniocervical junction presents a technical challenge for operating surgeons. Three-dimensional (3D) reconstruction and surgical simulation have improved the efficacy and success rate of surgeries. The aim of this study was to create a 3D, digitized visible model of the craniocervical junction region to help realize accurate simulation of craniocervical surgery on a graphic workstation. Transverse sectional anatomy data for the study were chosen from the first Chinese visible human. Manual axial segmentation of the skull base, cervical spine, cerebellum, vertebral artery, internal carotid artery, sigmoid sinus, internal jugular vein, brain stem, and spinal cord were carried out by using Photoshop software. The segmented structures were reconstructed in 3 dimensions with surface and volume rendering to accurately display 3D models spatially. In contrast to conventional 3D reconstruction techniques that are based on computed tomography and magnetic resonance imaging Digital Imaging and Communications in Medicine (DICOM) inputs and provide mostly osseous details, this technique can help to illustrate the surrounding soft tissue structure and provide a realistic surgical simulation. The reconstructed 3D model was successfully used in simulating complex procedures in the virtual environment, including the transoral approach, bone drillings, and clivus resection. PMID- 22216710 TI - Metacercarial distribution of Centrocestus formosanus among fish hosts in the Guadalupe River drainage of Texas. AB - We examined the gills of wild fish collected from central Texas for Centrocestus formosanus metacercariae to determine whether this temperature-restricted parasite had invaded the thermally dynamic Guadalupe River via an introduced population in its thermally stable tributary, the Comal River. We collected fish from three sites in the Guadalupe River near its confluence with the Comal River (upstream, at, and downstream) and one site in the Comal River. Centrocestus formosanus infected 14 of the 25 species examined (56.0%) and 171 of the individual fish (27.1%). Several of the infected fish represent new host records for the parasite, and two are listed as species of special concern by the state of Texas. Mean metacercarial intensities varied from 8 to 616 among species, and the highest recorded intensity was greater than 800 in two Guadalupe roundnose minnow Dionda nigrotaeniata. Among the 24 species examined from the Guadalupe River, 11 (45.8%) were infected with C. formosanus. Thorough surveys at the study sites yielded no living specimens of the first obligate intermediate snail host (red-rim melania Melanoides tuberculatus), which must be present to perpetuate the parasite. Thus, the infections were probably due to drifting cercariae that had been shed into the water column upstream of the study area in the Comal River. We therefore investigated spatial patterns in cercarial acquisition using caged fish to determine whether drifting cercariae were present in the water column at the study sites. Of 57 uninfected blacktail shiners Cyprinella venusta exposed to Guadalupe River water downstream from and at the confluence, 52 (91.2%) became infected with C. Formosanus metacercariae at a mean rate of 4 metacercariae/d. This finding extends the known geographic range of this invasive exotic parasite and is the first report of the life cycle being advanced in the fish assemblage of a thermally variable temperate stream in the USA. PMID- 22216711 TI - Regulatory factors and structure of a component population of the spionid Polydora bioccipitalis infesting the surf clam Mesodesma donacium. AB - Spionidae, particularly polydorids, are common polychaete parasites of edible mollusks around the world. However, our understanding of the regulatory factors and population structure of these parasites is scant. In this study involving Polydora bioccipitalis and the surf clam Mesodesma donacium we evaluated (1) the environmental correlates of the prevalence and mean intensity of the infestation, (2) the relationship between the number of egg capsules and juvenile and adult parasites and the time elapsed since infestation, and (3) the spatial patterns of juveniles and adults within the host. Environmental factors showed no significant correlations with prevalence and mean intensity, suggesting that these factors do not act directly as regulators. Rather, storm surges seemingly induced clam stranding, which in turn affected both the prevalence and intensity of the infestation. The numbers of juveniles and egg capsules in blisters were significantly related to the time since infestation, suggesting mechanisms of use and expansion of the space within the host. Juvenile worms showed an aggregated distribution that was probably related to the episodic nature of infestation events, whereas adults exhibited uniform distributions that probably reflect territorial behavior and reproductive strategies. PMID- 22216712 TI - Carbonic anhydrase activities from the rainbow trout lens correspond to the development of acute gas bubble disease. AB - Dissolved gas supersaturation is hazardous to fish and can result in gas bubble disease (GBD). Signs of GBD typically include bubbles in the eyes, fins, skin, lateral line, and gill filaments. Ocular abnormalities in diseased salmonids typically occur after aberrant gas production in the eyes. In this study, freshwater rainbow trout Oncorhynchus mykiss were exposed experimentally to percent total gas pressure (TGP%) levels of 104% (control) and 115%. No mortalities occurred during the 7-d experimental period. Effects of GBD were observed externally as a darkened skin, exophthalmia, localized hemorrhage in the eye, and gas bubbles on the operculum. Additional signs included increased swimming activity and, more frequently, panic episodes. Carbonic anhydrase (CA) enzyme activities from the lens and retina were determined at days 0, 1, 3, 5, and 7 of the study. Venous blood gases were also measured on day 7. Retinal pH did not differ between normal and affected fish, but blood characteristics such as the partial pressure of O2, partial pressure of CO2, carboxyhemoglobin level, and bicarbonate ion concentration were significantly elevated in affected fish relative to normal fish. Venous blood pH and oxyhemoglobin levels were not significantly different between affected and normal fish. Patterns of response to total dissolved gas levels differed between the lens and the retina. Mean CA activities in the lenses of fish exposed to a TGP% level of 115% were significantly below those of control fish. However, retinal CA activities did not significantly differ between the two groups over the course of the experiment. These findings show that dissolved gas supersaturation reduces CA activity in the rainbow trout lens. PMID- 22216713 TI - Passive immunization of Pacific herring against viral hemorrhagic septicemia. AB - The plasma of Pacific herring Clupea pallasii that survived laboratory-induced viral hemorrhagic septicemia (VHS) epizootics contained humoral substances that, when injected into naive animals, conferred passive immunity against the disease. Among groups exposed to viral hemorrhagic septicemia virus (VHSV), injection of donor plasma from VHS survivors resulted in significantly greater survival (50%) and significantly lower tissue titers (1.5 x 10(5) plaque-forming units [PFU]/g) than the injection of plasma from VHSV-naive donors (6% survival; 3.7 x 10(6) PFU/g). Additionally, the magnitude of the protective immune response increased during the postexposure period; plasma that was collected from survivors at 123 d postexposure (931 degree-days) provided greater protection than plasma collected from survivors at 60 d postexposure (409 degree-days). These results provide proof of concept that the VHSV exposure history of Pacific herring populations can be determined post hoc; furthermore, the results can be used as the foundation for developing additional high-throughput diagnostic techniques that may be effective at quantifying herd immunity and forecasting the potential for future VHS epizootics in populations of wild Pacific herring. PMID- 22216714 TI - Quantitative polymerase chain reaction (PCR) for detection of aquatic animal pathogens in a diagnostic laboratory setting. AB - Real-time, or quantitative, polymerase chain reaction (qPCR) is quickly supplanting other molecular methods for detecting the nucleic acids of human and other animal pathogens owing to the speed and robustness of the technology. As the aquatic animal health community moves toward implementing national diagnostic testing schemes, it will need to evaluate how qPCR technology should be employed. This review outlines the basic principles of qPCR technology, considerations for assay development, standards and controls, assay performance, diagnostic validation, implementation in the diagnostic laboratory, and quality assurance and control measures. These factors are fundamental for ensuring the validity of qPCR assay results obtained in the diagnostic laboratory setting. PMID- 22216715 TI - The effect of high total ammonia concentration on the survival of channel catfish experimentally infected with Flavobacterium columnare. AB - Ammonia concentrations in water can affect the severity of Flavobacterium columnare infections in fish. Two trials lasting 7 d each were conducted to determine the effect of a single immersion flush treatment of total ammonia nitrogen (TAN; 15 mg/L) on the survival of channel catfish Ictalurus punctatus infected with E columnare; the chemical was added while the water flowed continuously through the tanks. Both trials consisted of four treatments: (1) no ammonia exposure and no bacterial challenge (control), (2) ammonia exposure only, (3) bacterial challenge only, and (4) both ammonia exposure and bacterial challenge. Two hours after exposure to ammonia, the highest un-ionized ammonia level was 0.43 mg/L. The percent un-ionized ammonia is based on TAN, temperature, and pH. Caudal fins from three fish in each treatment were sampled at 24 h posttreatment to be analyzed by quantitative real-time polymerase chain reaction (qPCR). No significant difference in survival (mean +/- SE) was noted between the channel catfish in treatment 1 (95.2 +/- 1.2%) and those in treatment 2 (95.6 +/- 1.0%); however, survival in both treatments 1 and 2 differed significantly from that in treatments 3 (8.5 + 4.5%) and 4 (41.8 +/- 12.7%). Treatment 4 catfish had significantly higher survival than treatment 3 catfish. Quantitative PCR data showed that treatment 4 fish had significantly less F. columnare (7.6 x 10(5)) than did treatment 3 fish (1.2 x 10(7)), and treatment 2 fish (8.5 x 10(3)) had significantly less bacteria than did treatment 1 fish (6.9 x 10(4)), indicating that ammonia limited the F. columnare infection. The highest mean concentration of the bacteria (3.9 x 10(7)) was found on moribund fish. The ammonia concentrations tested did not negatively influence fish survival but interfered with the infection process. An in vitro assay was also conducted to evaluate the direct effects of ammonia on F columnare. PMID- 22216716 TI - Reference intervals for intraocular pressure measured by rebound tonometry in ten raptor species and factors affecting the intraocular pressure. AB - Intraocular pressure (IOP) was measured with the TonoVet rebound tonometer in 10 raptor species, and possible factors affecting IOP were investigated. A complete ophthalmic examination was performed, and IOP was assessed in 2 positions, upright and dorsal recumbency, in 237 birds belonging to the families Accipitridae, Falconidae, Strigidae, and Tytonidae. Mean IOP values of healthy eyes were calculated for each species, and differences between families, species, age, sex, left and right eye, as well as the 2 body positions were evaluated. Physiologic fluctuations of IOP were assessed by measuring IOP serially for 5 days at the same time of day in 15 birds of 3 species. Results showed IOP values varied by family and species, with the following mean IOP values (mm Hg +/- SD) determined: white-tailed sea eagle (Haliaeetus albicilla), 26.9 +/- 5.8; red kite (Milvus milvus), 13.0 +/- 5.5; northern goshawk (Accipiter gentilis), 18.3 +/- 3.8; Eurasian sparrowhawk (Accipiter nisus), 15.5 +/- 2.5; common buzzard (Buteo buteo), 26.9 +/- 7.0; common kestrel (Falco tinnunculus), 9.8 +/- 2.5; peregrine falcon, (Falco peregrinus), 12.7 +/- 5.8; tawny owl (Strix aluco), 9.4 +/- 4.1; long-eared owl (Asio otus), 7.8 +/- 3.2; and barn owl (Tyto alba), 10.8 +/- 3.8. No significant differences were found between sexes or between left and right eyes. In goshawks, common buzzards, and common kestrels, mean IOP was significantly lower in juvenile birds than it was in adult birds. Mean IOP differed significantly by body position in tawny owls (P = .01) and common buzzards (P = .04). By measuring IOP over several days, mean physiologic variations of +/- 2 mm Hg were detected. Differences in IOP between species and age groups should be considered when interpreting tonometric results. Physiologic fluctuations of IOP may occur and should not be misinterpreted. These results show that rebound tonometry is a useful diagnostic tool in measuring IOP in birds of prey because it provides rapid results and is well tolerated by birds. PMID- 22216717 TI - Clinicopathologic, gross necropsy, and histologic findings after intramuscular injection of carprofen in a pigeon (Columba livia) model. AB - To evaluate the pathologic effects of carprofen in a pigeon model (Columba livia), 52 young adult pigeons were used in a randomized control study design. Sixteen pigeons were randomly assigned to 1 of 3 treatment groups and received carprofen by intramuscular injection at dosages of either 2, 5, or 10 mg/kg once daily for 7 days. Four pigeons served as saline-injected controls. Four pigeons from each group and 1 control pigeon were randomly selected on days 2, 4, 6, and 8 to obtain blood samples and then were euthanatized and submitted for necropsy. Histologic lesions in pectoral muscle, liver, kidney, and digestive tract tissue samples were ranked in severity as 0, normal/not present; 1, minimal; 2, mild; 3, mild to moderate; 4, moderate; 5, moderate to marked; and 6, marked pathologic changes. Two-way analysis of variance (day x dose) and pairwise t tests revealed significant (P < or = .05) mild decreases in total protein and glucose concentrations and marked increases in aspartate aminotransferase and alanine aminotransferase enzyme activities after carprofen treatments. Gross lesions in carprofen-treated pigeons were pale injection sites (23/48 [47.9%]), mottled yellow livers (9/48 [18.8%]), and congestion of small intestines (7/48 [14.6%]). Liver, kidney, and muscle injection sites had significantly increased (P < or = .05) severity of histologic lesions. In pigeons, intramuscular administration of carprofen is associated with increased aspartate aminotransferase and alanine aminotransferase enzyme concentrations, gross lesions in muscle injection sites and liver, and histologic lesions in liver and muscle. PMID- 22216718 TI - Pharmacokinetics of butorphanol after intravenous, intramuscular, and oral administration in Hispaniolan Amazon parrots (Amazona ventralis). AB - Previous studies have validated the clinical use of opioids with kaap-receptor affinities for pain management in birds. Butorphanol, a kappa opioid receptor agonist and a mu opioid receptor antagonist, is currently considered by many clinicians to be the opioid of choice for this use. However, despite studies reporting the analgesic properties of butorphanol in psittacine birds, dosing intervals have not been established for any psittacine species. The goals of this study in the Hispaniolan Amazon parrot (Amazona ventralis) were to evaluate the pharmacokinetics of butorphanol tartrate after intravenous (IV), intramuscular (IM), and oral (PO) administration and to determine the bioavailability of butorphanol tartrate after oral administration. Twelve Hispaniolan Amazon parrots were used in the study, with a complete-crossover experimental design and a 3 month period separating each part of the study. The birds were randomly assigned to 3 groups (n = 4) for each stage. Butorphanol tartrate was administered once at a dose of 5 mg/kg in the basilic vein or pectoral muscles or as an oral solution delivered via feeding tube into the crop for the IV, IM, and PO studies, respectively. After butorphanol administration, blood samples were collected at 1, 5, 15, 30, 60, 90, 120, 180, and 240 minutes for the IV and IM studies and at 5, 15, 30, 60, 90, 120, 180, 240, and 300 minutes for the PO study. Because of the size limitation of the birds, naive pooling of datum points was used to generate a mean plasma butorphanol concentration at each time point. For each study, birds in each group (n = 4) were bled 3 times after dosing. Plasma butorphanol concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry, and pharmacokinetic parameters were calculated. Butorphanol tartrate was found to have high bioavailability and rapid elimination following IM administration. In contrast, oral administration resulted in low bioavailability (< 10%), thus precluding the use of this route of administration for clinical purposes. Based on these results, in Hispaniolan Amazon parrots, butorphanol tartrate dosed at 5 mg/kg IV or IM would have to be administered every 2 and 3 hours, respectively, to maintain plasma concentrations consistent with published therapeutic levels. To our knowledge, this is the first published study presenting the pharmacokinetic analysis of butorphanol tartrate in a psittacine species as well as the first study presenting pharmacokinetic analysis of butorphanol after oral administration in any avian species. PMID- 22216719 TI - Hematologic parameters in raptor species in a rehabilitation setting before release. AB - To be considered for release, raptors undergoing rehabilitation must have recovered from their initial injury in addition to being clinically healthy. For that purpose, a good understanding of reference hematologic values is important in determining release criteria for raptors in a rehabilitation setting. In this study, retrospective data were tabulated from clinically normal birds within 10 days of release from a rehabilitation facility. Hematologic values were compiled from 71 red-tailed hawks (Buteo jamaicensis), 54 Eastern screech owls (Megascops asio), 31 Cooper's hawks (Accipiter cooperii), 30 great-horned owls (Bubo virginianus), 28 barred owls (Strix varia), 16 bald eagles (Haliaeetus leucocephalus), and 12 broad-winged hawks (Buteo platypterus). Parameters collected included a white blood cell count and differential, hematocrit, and total protein concentration. Comparisons were made among species and among previously published reports of reference hematologic values in free-ranging birds or permanently captive birds. This is the first published report of reference values for Eastern screech owls, barred owls, and broad-winged hawks; and the first prerelease reference values for all species undergoing rehabilitation. These data can be used as a reference when developing release criteria for rehabilitated raptors. PMID- 22216720 TI - Proventricular dilatation disease in cockatiels (Nymphicus hollandicus) after infection with a genotype 2 avian bornavirus. AB - An isolate of genotype 2 avian bornavirus (ABV) was recovered from a cockatiel (Nymphicus hollandicus) that was euthanatized for an unrelated lesion and showing no clinical evidence of proventricular dilatation disease (PDD). On histopathologic examination, mild inflammatory lesions were present in the heart and brain, but gastrointestinal lesions characteristic of classic PDD were not observed. To investigate if this ABV2 isolate had reduced virulence, the virus was propagated in duck embryo fibroblasts and inoculated into 2 adult cockatiels by the oral and intramuscular routes. One bird developed clinical signs on day 33 and was euthanatized on day 36. The second challenged bird developed clinical signs on day 41 and was euthanatized on day 45. At necropsy, the proventriculus of both birds was slightly enlarged. Histopathologic examination showed lesions typical of PDD in the brain, spinal cord, heart, adrenal gland, and intestine. A control, uninoculated cockatiel was apparently healthy when euthanatized on day 50. These results show that ABV2 is now the second ABV genotype to be formally shown to cause PDD. PMID- 22216721 TI - Granulomatous myocarditis caused by Candida albicans in a canary (Serinus canaria). AB - Candida albicans is among the major agents of mucous membrane mycosis in humans and animals, with systemic and deep infections observed in immunocompromised hosts. We describe a case of fatal granulomatous myocarditis caused by C albicans in a 20-day-old canary (Serinus canaria). The etiologic diagnosis was confirmed by identifying characteristic morphologic features of the organism, combined with histochemical staining, and followed by the use of ad hoc biomolecular analysis. PMID- 22216722 TI - Successful management of simple fractures of the femoral neck with femoral head and neck excision arthroplasty in two free-living avian species. AB - A red-tailed hawk (Buteo jamaicensis) and a Canada goose (Branta canadensis) were evaluated for unilateral pelvic limb lameness. Physical examination findings and results of diagnostic imaging revealed femoral neck fractures in both birds. Both birds were treated with a femoral head and neck excision arthroplasty. The affected legs were not immobilized, and the birds were encouraged to use the legs immediately after surgery to encourage formation of a pseudoarthrosis. Within 2 weeks, both birds were using the affected limb well enough to be either successfully released or transferred to a wildlife rehabilitation facility. Femoral head and neck excision arthroplasty without immobilization of the limb is recommended for managing avian femoral neck fractures, especially in free-ranging species in which a rapid and complete or near complete return to function is vital for survival in the wild. PMID- 22216723 TI - Hydrocephalus in a yellow-headed Amazon parrot (Amazona ochrocephala oratrix). AB - A 37-year-old female yellow-headed Amazon parrot (Amazona ochrocephala oratrix) was presented after a 4-month-period behavior change and intermittent episodes of obtunded mentation. Clinical findings on physical examination included ataxia, a weak grasp, and reluctance to move. Results of magnetic resonance imaging were consistent with severe hydrocephalus without evidence of cerebrospinal fluid obstruction. The bird was treated with tapering dosages of prednisolone over a 4 month period, during which time the episodes did not occur. Discontinuation of treatment was attempted several times but resulted in relapse. After 3.5 years of maintenance treatment with prednisolone, the bird was presented subsequent to a 5 hour episode of obtunded mentation and worsening neurologic signs. Despite increasing the dose of prednisolone and providing additional supportive care, the bird's condition worsened, and euthanasia was elected. Necropsy findings included severe hydrocephalus with significant loss of right cerebral parenchyma and no evidence of cerebrospinal fluid obstruction. Histologic examination of the remaining cerebral parenchyma revealed a moderate, multifocal, cellular infiltrate; encephalomalacia; fibrosis; and hemosiderosis in tissue adjacent to the distended ventricles. Other findings included hepatic vacuolar degeneration. Diagnostic imaging and postmortem findings were consistent with a diagnosis of hydrocephalus ex vacuo. To our knowledge, this is the first report of hydrocephalus in an Amazon parrot as well as the first report of hydrocephalus in any avian species associated with long-term follow-up and prolonged corticosteroid treatment. PMID- 22216724 TI - The role of veterinarians in the conservation of avian species. PMID- 22216725 TI - What is your diagnosis? Lymphosarcoma. PMID- 22216726 TI - [The image of the month. A snake at large. (A thrombus in the foramen ovale)]. PMID- 22216727 TI - [Endoleak, a specific complication of the endovascular treatment of aortic aneurysms]. AB - Endoleaks represent the most common complication of endovascular aortic aneurysm repair. With the increasing use of endovascular techniques for aortic aneurysm repair, the prevalence of endoleaks has risen. While maintaining pressurization of the aneurysm sac, endoleaks expose to persistent risks of an evolution towards rupture. Long-term surveillance with imaging studies is necessary to reduce the incidence of these specific complications that may require intervention. The objective of this article is to draw the attention to the possible occurrence of these complications and to report the elements of diagnosis and treatment. PMID- 22216728 TI - [A right supradiaphragmatic mass varying over 6 years]. AB - A pleuro-pericardial cyst represents an uncommon form of congenital disease. We relate the case of an initially symptomless female patient presenting with a voluminous mediastinal mass. The fortuitous discovery of an asymptomatic mediastinal mass should always prompt consideration, among others, of the diagnosis of a pleuro-pericardial cyst. PMID- 22216729 TI - [Cyberknife and benign pathologies]. AB - Conventional radiotherapy is known to be an effective treatment approach even for "benign" pathologies. However, this kind of treatment yields a high potential for side effects. The Cyberknife, a robotic stereotactic radiotherapy device, enables to offset a large proportion of the disadvantages encountered with conventional radiotherapy essentially through the high precision of dose administration and sparing of healthy tissues. Therefore, it seems to be a treatment of choice in the approach of some benign intracranial diseases. We review published data on indications and outcome of Cyberknife for intracranial "non-malignant" disease. PMID- 22216730 TI - [Post-dural puncture headache: treatment and prevention]. AB - Post-dural puncture headache (PDPH) is a common iatrogenic and incapacitating complication. Dural puncture can be intentional (spinal block, myelography,...) or accidental (epidural block). Risk factors are well described and the obstetric patient is at high risk for PDPH. The treatment of PDPH is not standardised. Many options have been proposed, but only the epidural blood patch has apparent benefits. A few measures have been suggested to prevent PDPH after unintentional dural puncture, but none has been shown to work with certainty. PMID- 22216732 TI - [Fungi, pets and their owners]. AB - Some parasitic or pathogen fungi for pet skin are possibly transmitted to humans in whom they are responsible for superficial mycozoonoses. Cats, dogs and some small rodents are commonly involved. The lesions correspond to glabrous skin dermatophytoses and to microsporic tinea of the scalp. These disorders represent the vast majority of the prevalent mycozoonoses in Wallonia. Microsporum canis and Trichophyton mentagrophytes are the two fungi that are commonly involved. PMID- 22216731 TI - [The usefulness of combined gynecologic and endocrinologic consultation in pediatrics: a retrospective study of the reasons for consultation and the practical approach]. AB - The gynaecological issues encountered in children and teenagers lay at the intersection of paediatric endocrinology and gynaecology. More than ten years ago, an outpatient clinic in paediatric endocrinology and gynaecology has been created. Here, we review the last 6 years. 214 girls were included, considering only the first visit for each patient. Collected data are initial concern for this consultation, age at first consultation and confirmed or suspected diagnosis. A classification is done according to the initial concern of patients in six categories. Principal queries concern pubertal development, precocious pilosity or abnormalities in menstrual cycles. Vulvovaginitis and morphologic abnormalities are also frequently encountered. This consultation suggests a paediatric approach with a child feeling confident and a gynaecological examination with a specialist knowing the anatomy particularities and the development of the children. This article focuses on the importance of specific gynaecological examination in children and reviews the main diseases encountered. PMID- 22216735 TI - The fatigue pictogram: psychometric evaluation of a new clinical tool. AB - Fatigue is one of the most prevalent side effects of cancer, yet clinicians may not focus on it during busy clinic appointments. The purpose of this project was to evaluate the psychometric properties of a new two-item instrument designed to quickly identify patients experiencing difficulties with fatigue. The evaluation was conducted with 190 lung cancer patients attending ambulatory clinics. The Fatigue Pictogram had good reliability for test-retest over a 24-hour period (Weighted Kappa 0.71 for Question 1 and 0.72 for Question 2) and for equivalence of method (in person versus phone) (Weighted Kappa 0.64 for Question 1 and 0.65 for Question 2). Validity was assessed by comparing results of the new tool against the Multidimensional Fatigue Inventory and the SF-36. Overall, patients who indicated high fatigue levels did so on all respective scales. The new Fatigue Pictogram was easy to administer and score in a busy clinical setting. It provides a standardized reliable and valid instrument to identify patients experiencing difficulty with fatigue. PMID- 22216734 TI - Reciprocity, qualitative research and vulnerable cancer populations: an opinion piece. PMID- 22216733 TI - [Facial nerve palsy. Not always that easy!]. AB - We report the case of a 45 years old woman who experienced two episodes of facial palsy, first on the left side, then on the other. This particular case allows us to discuss the diagnostic process and clinical reasoning to follow in front of this symptomatology -using a didactic questioning- and to briefly review the anatomy of the seventh cranial nerve. Treatment and possible complications are also discussed. PMID- 22216736 TI - Intervention patterns of pivot nurses in oncology. AB - The Pivot Nurse in Oncology (PNO) is a health care professional dedicated to providing patients with cancer and their families with continuing and consistent supportive care throughout the care trajectory. The purpose of this paper is to describe the variation and frequency of nursing interventions delivered by 12 PNOs at our health centre. An administrative analysis over a three-year period revealed a total of 43,906 interventions that were grouped into 10 categories. This analysis provided a description of the intervention frequency and these interventions were further collapsed into the four role functions of the PNO. Coordination/continuity of care and the assessment of needs and symptoms were identified as the dominant practice domains of the PNO in the professional cancer navigator role. PMID- 22216737 TI - The sexuality of Quebec women with cervical cancer: looking for love despite radiotherapy's trauma to their sexual body. AB - The purpose of this phenomenological study was to describe the experience of sexuality of middle-aged Quebec women living with cervical cancer. Ten women accepted to take part in the study. The findings reveal a new outlook on sexuality, as these women refocus their positions on their lives, their conjugal relationships and the adverse effects of therapies. The participants expressed the will to combine feelings of love with sexual pleasures. They all felt the need to talk about the embarrassing and traumatizing effects of treatment on their sexuality. These findings raise the need for nurses to recognize these women's sexual concerns and to further research in this area. PMID- 22216739 TI - Report from Director at Large--professional practice. PMID- 22216738 TI - Report from DAL--Education. What collaborative work was accomplished by the DAL- Education this year? PMID- 22216740 TI - Palliative care nurses fuel the flame of learning. PMID- 22216741 TI - Stannylenes: structures, electron affinities, ionization energies, and singlet triplet gaps of SnX2/SnXY and XSnR/SnR2/RSnR' species (X; Y = H, F, Cl, Br, I, and R; R' = CH3, SiH3, GeH3, SnH3). AB - Systematic computational studies of stannylene derivatives SnX(2)/SnXY and XSnR/SnR(2)/RSnR' were carried out using density functional theory. The basis sets used for H, F, Cl, Br, C, Si, and Ge atoms are of double-zeta plus polarization quality with additional s- and p-type diffuse functions, denoted DZP++. For the iodine and tin atoms, the Stuttgart-Dresden basis sets, with relativistic small-core effective core potentials (ECP), are used. All geometries are fully optimized with three functionals (BHLYP, BLYP, and B3LYP). Harmonic vibrational wavenumber analyses are performed to evaluate zero-point energy corrections and to determine the nature of the stationary points located. Predicted are four types of neutral-anion separations, plus adiabatic ionization energies (E(IE)) and singlet-triplet energy gaps (DeltaE(S-T)). The dependence of all three energetic properties upon choice of substituent is remarkably strong. The EA(ad(ZPVE)) values (eV) obtained with the B3LYP functional range from 0.70 eV [Sn(CH(3))(2)] to 2.36 eV [SnI(2)]. The computed E(IE) values lie between 7.33 eV [Sn(SnH(3))(2)] and 11.15 eV [SnF(2)], while the singlet-triplet splittings range from 0.60 eV [Sn(SnH(3))(2)] to 3.40 eV [SnF(2)]. The geometries and energetics compare satisfactorily with the few available experiments, while most of these species are investigated for the first time. Some unusual structures are encountered for the SnXI(+) (X = F, Cl, and Br) cations. The structural parameters and energetics are discussed and compared with the carbene, silylene, and germylene analogues. PMID- 22216744 TI - Protein and nanoparticle adsorption on orthogonal, charge-density-versus-net charge surface-chemical gradients. AB - An orthogonal, charge-density-versus-net-charge, surface-chemical gradient, composed of ternary mixed self-assembled monolayers, has been prepared from three hydrophilic components: positively chargeable amine-terminated, negatively chargeable carboxylic-acid-terminated, and hydroxyl-terminated alkanethiols, with the latter bearing a slight negative charge in electrolytes. The chemical composition and its distribution have been monitored by X-ray photoelectron spectroscopy. The adsorption behavior of negatively charged SiO(2) nanoparticles and positively charged amine-modified SiO(2) nanoparticles has been studied. Additionally, negatively charged proteins (bovine serum albumin and fibrinogen) and positively charged proteins (lysozyme) were adsorbed on the gradients. Negatively charged nanoparticles and proteins adsorb mainly in the positively charged region and vice versa, illustrating that the adsorption behavior is mainly influenced by electrostatic interactions, and showing the potential of the gradient for sorting applications. Despite literature reports to the contrary, no area was found that was completely resistant to protein adsorption. PMID- 22216747 TI - Research note: adolescents' perception of psychosis risk following cannabis consumption. AB - Cannabis consumption during adolescence has been associated with the onset of psychosis. In 2010, we examined adolescents' perception of this association. Adolescents (N = 583) from four Romanian urban high schools filled in psychosis proneness scales according to the risk they assigned to hypothetical adolescents described in vignettes. Target adolescent's frequency and age of first consumption were manipulated. Analysis of variance indicated a main effect of target's consumption frequency, but no effect of age of first consumption on psychosis risk perception. Participants' own consumption status acted as moderator. Results highlight the discrepancy between clinical research results and adolescents' perception of psychosis risk. The study's limitations are noted. PMID- 22216745 TI - Biologically relevant oxidants cause bound proteins to readily oxidatively cross link at Guanine. AB - Oxidative DNA-protein cross-links have received less attention than other types of DNA damage and remain as one of the least understood types of oxidative lesion. A model system using ribonuclease A and a 27-nucleotide DNA was used to determine the propensity of oxidative cross-linking to occur in the presence of oxidants. Cross-link formation was examined using four different oxidation systems that generate singlet oxygen, superoxide, and metal-based Fenton reactions. It is shown that oxidative cross-linking occurs in yields ranging from 14% to a maximal yield of 61% in all oxidative systems when equivalent concentrations of DNA and protein are present. Because singlet oxygen is the most efficient oxidation system in generating DNA-protein cross-links, it was chosen for further analyses. Cross-linking occurred with single-stranded DNA binding protein and not with bovine serum albumin. Addition of salt lowered nonspecific binding affinity and lowered cross-link yield by up to 59%. The yield of cross linking increased with increased ratios of protein compared with DNA. Cross linking was highly dependent on the number of guanines in a DNA sequence. Loss of guanine content on the 27-nucleotide DNA led to nearly complete loss in cross linking, while primer extension studies showed cross-links to predominantly occur at guanine base on a 100-nucleotide DNA. The chemical species generated were examined using two peptides derived from the ribonuclease A sequence, N-acetyl AAAKF and N-acetyl-AYKTT, which were cross-linked to 2'-deoxyguanosine. The cross link products were spiroiminodihydantoin, guanidinohydantoin, and tyrosyl-based adducts. Formation of tyrosine-based adducts may be competitive with the more well-studied lysine-based cross-links. We conclude that oxidative cross-links may be present at high levels in cells since the propensity to oxidatively cross-link is high and so much of the genomic DNA is coated with protein. PMID- 22216748 TI - Infection patterns of Paradollfusnema amphisbaenia (Nematoda: Cosmocercidae) in a population of Amphisbaena wuchereri (Squamata: Amphisbaenidae) from Minas Gerais state, south-eastern Brazil, and its relations with host size, sex and fat body mass. AB - Specimens (n= 41) of the amphisbaenid Amphisbaena wuchereri taken from a population in Minas Gerais state, south-eastern Brazil, were examined for gastrointestinal parasites. A single nematode species was found, Paradollfusnema amphisbaenia. This was a new host record for this nematode species. This parasite was encountered in the large intestine (prevalence of 100%), in the stomach (prevalence of 2%) and in the small intestine (prevalence of 7.3%). The intensity of infection ranged from 1 to 457 individual parasites per host and was positively correlated with body size of both male and female amphisbaenians. The discrepancy index (D) indicated that P. amphisbaenia tended to an even distribution in this host population. The nematode, which did not affect fat body mass, induced inflammatory infiltrations in the small intestine, indicating that the parasites might injure the host's organs. PMID- 22216749 TI - Cost savings in inpatient oncology through an integrative medicine approach. AB - OBJECTIVES: To evaluate the cost impact of an integrative medicine intervention on an inpatient oncology service. STUDY DESIGN: This study used nonrandomized, nonequivalent groups. A baseline sample of inpatient oncology patients at Beth Israel Medical Center admitted to the medical oncology unit before implementation of the Urban Zen Initiative were compared with patients admitted after the Urban Zen Initiative was in place. METHODS: The Urban Zen Initiative incorporated yoga therapy, holistic nursing techniques, and a "healing environment" into routine inpatient oncology care. Length of stay and medication use data were extracted from Beth Israel's decision support electronic database. We compared length of stay, total medication costs, and costs of as-needed medications for both groups: the baseline sample of inpatient oncology patients and patients exposed to the Urban Zen healing environment initiative. RESULTS: We had complete cost data on 85 patients in our baseline group and 72 in our intervention group. We found no difference in length of stay between the 2 groups. We found a significant decrease in use of antiemetic, anxiolytic, and hypnotic medication costs as well as a decrease in total medication costs in the Urban Zen sample compared with the baseline group. CONCLUSIONS: An integrative medicine approach including yoga therapy, holistic nursing, and a healing environment in the inpatient setting can decrease use of medications, resulting in substantial cost savings for hospitals in the care of oncology patients. PMID- 22216750 TI - Adjunctive aripiprazole for depression: predictive value of early assessment. AB - OBJECTIVES: To determine whether early symptom improvement with adjunctive aripiprazole in major depressive disorder (MDD) predicts overall symptom remission. STUDY DESIGN: Post hoc pooled analysis of 3 randomized, double-blind studies evaluating efficacy, safety, and tolerability of adjunctive aripiprazole or placebo with standard antidepressant therapy (ADT) in inadequate responders to a prospective 8-week ADT and at least 1 historical ADT. METHODS: A multivariate logistic regression model was developed to determine factors predicting remission most strongly at the end point. Remission was defined as a Montgomery-Asberg Depression Rating Scale (MADRS) total score of 10 or less at end point. RESULTS: Early improvement in depression symptoms was the most significant predictor of remission. In adjunctive aripiprazole and placebo groups, improvement of 20% or more in MADRS total score (week 2) was a significant predictor of remission. At week 2, high sensitivity and high negative predictive values (NPVs) were reported for remission in both treatment arms. In the adjunctive aripiprazole arm, early improvement predicted later MADRS remission with high sensitivity (88.0%) and a high NPV (91.5%). Positive predictive value was moderate in both the adjunctive aripiprazole (45.4%) and placebo (37.5%) arms; specificity was 55.0% with adjunctive aripiprazole and 71.5% with placebo. CONCLUSIONS: Week 2 was a clinically meaningful time point to identify early improvers, and lack of improvement early in treatment was a highly significant predictor of lack of later remission. Early assessment of changes in symptoms could prove useful in clinical practice and more appropriately target healthcare costs. PMID- 22216751 TI - Costs of providing antiplatelet medication for percutaneous coronary intervention patients. AB - OBJECTIVES: To propose a model in which insurers work with hospitals to provide a discharge supply of antiplatelet medication to patients receiving stents and to examine the cost implications of this strategy. STUDY DESIGN: A decision tree was modeled using data from previously published research. The study adopts an insurer's perspective. METHODS: Data on patient delays in filling antiplatelet prescriptions and rates of associated adverse events were taken from published research. The costs of adverse events (death or acute myocardial infarction [AMI]) are taken from Healthcare Cost and Utilization Project estimates of hospital costs for diagnosis-related groups associated with AMI. RESULTS: In the base case, expected costs totaled $1782 when stent implantation patients were provided with a discharge supply of medication and $1857 under the current standard of care, a difference of $75. Insurers can supply up to 60 days of medication without increasing total costs. The strategy of offering a discharge supply of medication is cost saving under a range of estimated rehospitalization costs and medication costs. However, this result is dependent on the ability of a discharge supply of medication to reduce rates of death or AMI. CONCLUSIONS: Providing discharge supplies of antiplatelet medication resulted in lower overall costs for insurers in most of the cases modeled. PMID- 22216752 TI - Effect of market competition on hospital performance for heart failure. AB - OBJECTIVES: To investigate whether market competition is a potential driver of hospital performance on the key evidence-based Joint Commission heart-failure (HF) quality indicators of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker prescribed, left ventricular function assessment, smoking cessation counseling, and discharge instructions. STUDY DESIGN: Retrospective multivariate analysis. METHODS: Hospital performance data for HF was obtained from The Joint Commission's ORYX program from 2003 to 2006. The performance data were linked with hospital characteristics from the American Hospital Association Annual Survey and area-level sociodemographic information from the Area Resource File. Healthcare markets were defined as hospital referral regions (HRRs) and market competition intensity was defined by the Herfindahl-Hirschman Index. Hospital-level and HRR-level ordinary least squares fixed effects regression models were used to estimate the relationship between market competition and performance. RESULTS: A paired comparison indicated that there was a significant change in the mean hospital-level performance over time on all of the HF quality indicators. From the multivariate analyses, hospitals in the least competitive markets (Quintile 5) performed slightly better (2.9%) than the most competitive markets (Quintile 1) for left ventricular function assessment (P <.01). At the HRR level, however, the least competitive markets (Quintile 5) performed moderately worse (5.1%) on the discharge-instructions quality indicator compared with the most competitive markets (Quintile 1) (P = .05). CONCLUSIONS: Market competition intensity was associated with only small differences in hospital performance. The level of market competitiveness may produce only marginal incremental benefits to inpatient HF care. PMID- 22216754 TI - Haplosporidium raabei n. sp. (Haplosporidia): a parasite of zebra mussels, Dreissena polymorpha (Pallas, 1771). AB - Extensive connective tissue lysis is a common outcome of haplosporidian infection. Although such infections in marine invertebrates are well documented, they are relatively rarely observed in freshwater invertebrates. Herein, we report a field study using a comprehensive series of methodologies (histology, dissection, electron microscopy, gene sequence analysis, and molecular phylogenetics) to investigate the morphology, taxonomy, systematics, geographical distribution, pathogenicity, and seasonal and annual prevalence of a haplosporidian observed in zebra mussels, Dreissena polymorpha. Based on its genetic sequence, morphology, and host, we describe Haplosporidium raabei n. sp. from D. polymorpha - the first haplosporidian species from a freshwater bivalve. Haplosporidium raabei is rare as we observed it in histological sections in only 0.7% of the zebra mussels collected from 43 water bodies across 11 European countries and in none that were collected from 10 water bodies in the United States. In contrast to its low prevalences, disease intensities were quite high with 79.5% of infections advanced to sporogenesis. PMID- 22216753 TI - 'Omic approaches to preventing or managing metastatic breast cancer. AB - Early detection of metastasis-prone breast cancers and characterization of residual metastatic cancers are important in efforts to improve management of breast cancer. Applications of genome-scale molecular analysis technologies are making these complementary approaches possible by revealing molecular features uniquely associated with metastatic disease. Assays that reveal these molecular features will facilitate development of anatomic, histological and blood-based strategies that may enable detection prior to metastatic spread. Knowledge of these features also will guide development of therapeutic strategies that can be applied when metastatic disease burden is low, thereby increasing the probability of a curative response. PMID- 22216755 TI - beta2-adrenoceptor transfection enhances contractile reserve of isolated rat ventricular myocytes exposed to chronic isoprenaline stimulation by improving beta1-adrenoceptor responsiveness. AB - CONTEXT: Heart failure (HF) is a progressive deterioration in heart function associated with overactivity of the sympathetic nervous system. Elevated sympathetic nervous system activity down regulates the beta-adrenergic signal system, suppressing beta-adrenoceptors (beta-ARs)-mediated contractile support in the failing heart. OBJECTIVE: We investigated the effects of beta(2)-AR gene transfer on shortening amplitude of isolated ventricular myocytes under chronic exposure to isoprenaline (ISO), and further determine the contributions of beta(1)-AR and beta(2)-AR to the contraction. MATERIALS AND METHODS: Cardiomyocytes were isolated from adult rat hearts and then transfected with beta(2)-AR gene using an adenovirus vector. Four hours after the infection, cardiomyocytes were treated with ISO for another 24 hours to imitate high levels of circulating catecholamines in HF. Western blotting was performed to measure myocardial protein expression of beta(2)-AR. Video-based edge-detection system was used to evaluate basal and ISO-stimulated shortening amplitudes of cardiomyocytes. RESULTS: beta(2)-AR gene transfer increased beta(2)-AR protein content. Chronic ISO stimulation produced a negative inotropic response, whereas acute ISO stimulation showed a positive inotropic response. beta(2)-AR gene transfer had no significant effects on shortening amplitude of cardiomyocytes under normal conditions, but enhanced the blunted contraction of cardiomyocytes under pathological conditions induced by chronic ISO stimulation, and the effect was inhibited by beta(1)-AR antagonist, CGP 20712A, instead of beta(2)-AR antagonist, ICI 118,551. DISCUSSION AND CONCLUSIONS: We conclude that beta(2)-AR gene transfer in isolated ventricular myocytes under chronic ISO stimulation improves cellular contraction, and the beneficial effects might be mediated by improving beta(1)-adrenoceptor responsiveness. PMID- 22216756 TI - iGLASS: an improvement to the GLASS method for estimating species trees from gene trees. AB - Several methods have been designed to infer species trees from gene trees while taking into account gene tree/species tree discordance. Although some of these methods provide consistent species tree topology estimates under a standard model, most either do not estimate branch lengths or are computationally slow. An exception, the GLASS method of Mossel and Roch, is consistent for the species tree topology, estimates branch lengths, and is computationally fast. However, GLASS systematically overestimates divergence times, leading to biased estimates of species tree branch lengths. By assuming a multispecies coalescent model in which multiple lineages are sampled from each of two taxa at L independent loci, we derive the distribution of the waiting time until the first interspecific coalescence occurs between the two taxa, considering all loci and measuring from the divergence time. We then use the mean of this distribution to derive a correction to the GLASS estimator of pairwise divergence times. We show that our improved estimator, which we call iGLASS, consistently estimates the divergence time between a pair of taxa as the number of loci approaches infinity, and that it is an unbiased estimator of divergence times when one lineage is sampled per taxon. We also show that many commonly used clustering methods can be combined with the iGLASS estimator of pairwise divergence times to produce a consistent estimator of the species tree topology. Through simulations, we show that iGLASS can greatly reduce the bias and mean squared error in obtaining estimates of divergence times in a species tree. PMID- 22216757 TI - Pilot study of palliative care consultation in patients with advanced heart failure referred for cardiac transplantation. AB - BACKGROUND: Heart failure (HF) in its chronic form is an irreversible and progressive disease. Palliative care (PC) interventions have traditionally been focused on patients with advanced cancer. We performed a pilot study to assess the feasibility of implementing the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for early PC intervention in patients with advanced HF who were seeking or received potentially curative therapies. METHODS: Twenty consecutive patients with advanced HF referred to PC from the heart transplant service with stage D, New York Heart Association (NYHA) class III-IV symptoms were analyzed retrospectively in a tertiary care setting. Data were reviewed to assess the clinical impact of PC intervention. Feedback was obtained to assess satisfaction of the patients, their families, and the health care professionals. An independent assessment of the impact of the PC service in the care of each patient was performed by a cardiologist and PC physician by use of a scoring system. RESULTS: Twenty consecutive patients with HF were analyzed. PC consult was obtained for a variety of reasons. All patients complained of a high symptom burden. PC consultation resulted in a decrease in the use of opioids and increased patient satisfaction. Patients and their family members generally reported improved holistic care, continuity of care, more focused goals of care, and improved planning of treatment courses. The nonstandardized scoring system used to determine the impact of the PC service showed an average of moderate to significant impact when assessed by both a cardiologist and a PC physician. CONCLUSION: PC consultation appears to be beneficial in the treatment and quality of life of advanced HF patients, independent of their prognosis. This pilot study demonstrated feasibility and sufficient evidence of clinical benefit to warrant a larger randomized clinical trial assessing the benefit of standard involvement by PC in patients with advanced HF, independent of the patient's prognosis or treatment goals. PMID- 22216760 TI - The 1.8 A crystal structure of ACTIBIND suggests a mode of action for T2 ribonucleases as antitumorigenic agents. AB - ACTIBIND and its human homologue RNASET2 are T2 ribonucleases (RNases). RNases are ubiquitous and efficient enzymes that hydrolyze RNA to 3' mononucleotides and also possess antitumorigenic and antiangiogenic activities. Previously, we have shown that ACTIBIND and RNASET2 bind actin and interfere with the cytoskeletal network structure, thereby inhibiting cell motility and invasiveness in cancer and in endothelial cells. We also showed that ACTIBIND binds actin in a molar ratio of 1:2. Here, we further characterize ACTIBIND and determine its crystal structure at 1.8 A resolution, which enables us to propose two structural elements that create binding sites to actin. We suggest that each of these binding sites is composed of one cysteine residue and one conserved amino acid region. These binding sites possibly interfere with the cytoskeleton network structure and as such may be responsible for the antitumorigenic and antiangiogenic activities of ACTIBIND and its human analogue RNASET2. PMID- 22216761 TI - Emergency incisional hernia repair: a difficult problem waiting for a solution. AB - BACKGROUND: Emergency repair of incarcerated incisional hernia with associated bowel obstruction in potentially or contaminated field is technically challenging due to edematous, inflamed and friable tissues with occasional need for concurrent bowel resection and carries high rates of post-operative infectious complications. The aim of this study was to retrospectively assess the wound related morbidity of use of permanent prosthetic mesh in emergency repair of incarcerated incisional hernia with associated bowel obstruction. We also describe a new technique of leaving the mesh exposed to heal by secondary intention with granulation tissue. METHODS: Between 2000 and 2010 a total of 60 patients underwent emergency surgery for incarcerated incisional hernia with associated bowel obstruction with placement of permanent prosthetic mesh. The wound was closed after hernia repair in 55 patients while it was left open to granulate in 5 patients. RESULTS: In the group of patients with primary wound closure, 11 patients developed superficial surgical site infection, 5 developed deep wound infection and one patient had cellulitis. These patients were treated with wound debridement and antibiotics. Mesh removal was required in one patient. There were no infections in the group of patients who had their surgical wounds left open. One patient in this group died on the fifth postoperative day from septicemia. CONCLUSION: Use of permanent prosthetic mesh in emergency repair of incarcerated incisional hernia with associated bowel obstruction. in contaminated field is associated with high risk of wound infection. PMID- 22216763 TI - Predictive and prognostic value of circulating nucleosomes and serum biomarkers in patients with metastasized colorectal cancer undergoing Selective Internal Radiation Therapy. AB - BACKGROUND: Selective Internal Radiation Therapy (SIRT) is a new and effective locoregional anticancer therapy for colorectal cancer patients with liver metastases. Markers for prediction of therapy response and prognosis are needed for the individual management of those patients undergoing SIRT. METHODS: Blood samples were prospectively and consecutively taken from 49 colorectal cancer patients with extensive hepatic metastases before, three, six, 24 and 48 h after SIRT to analyze the concentrations of nucleosomes and further laboratory parameters, and to compare them with the response to therapy regularly determined 3 months after therapy and with overall survival. RESULTS: Circulating nucleosomes, cytokeratin-19 fragments (CYFRA 21-1), carcinoembryonic antigen (CEA), C-reactive protein (CRP) and various liver markers increased already 24 h after SIRT. Pretherapeutical levels of CYFRA 21-1, CEA, cancer antigen 19-9 (CA 19-9), asparate-aminotransferase (AST) and lactate dehydrogenase (LDH) as well as 24 h values of nucleosomes were significantly higher in patients suffering from disease progression (N = 35) than in non-progressive patients (N = 14). Concerning overall survival, CEA, CA 19-9, CYFRA 21-1, CRP, LDH, AST, choline esterase (CHE), gamma-glutamyl-transferase, alkaline phosphatase, and amylase (all 0 h, 24 h) and nucleosomes (24 h) were found to be prognostic relevant markers in univariate analyses. In multivariate Cox-Regression analysis, the best prognostic model was obtained for the combination of CRP and AST. When 24 h values were additionally included, nucleosomes (24 h) further improved the existing model. CONCLUSION: Panels of biochemical markers are helpful to stratify pretherapeutically colorectal cancer patients for SIR-therapy and to early estimate the response to SIR-therapy. PMID- 22216762 TI - Systems-wide RNAi analysis of CASP8AP2/FLASH shows transcriptional deregulation of the replication-dependent histone genes and extensive effects on the transcriptome of colorectal cancer cells. AB - BACKGROUND: Colorectal carcinomas (CRC) carry massive genetic and transcriptional alterations that influence multiple cellular pathways. The study of proteins whose loss-of-function (LOF) alters the growth of CRC cells can be used to further understand the cellular processes cancer cells depend upon for survival. RESULTS: A small-scale RNAi screen of ~400 genes conducted in SW480 CRC cells identified several candidate genes as required for the viability of CRC cells, most prominently CASP8AP2/FLASH. To understand the function of this gene in maintaining the viability of CRC cells in an unbiased manner, we generated gene specific expression profiles following RNAi. Silencing of CASP8AP2/FLASH resulted in altered expression of over 2500 genes enriched for genes associated with cellular growth and proliferation. Loss of CASP8AP2/FLASH function was significantly associated with altered transcription of the genes encoding the replication-dependent histone proteins as a result of the expression of the non canonical polyA variants of these transcripts. Silencing of CASP8AP2/FLASH also mediated enrichment of changes in the expression of targets of the NFkappaB and MYC transcription factors. These findings were confirmed by whole transcriptome analysis of CASP8AP2/FLASH silenced cells at multiple time points. Finally, we identified and validated that CASP8AP2/FLASH LOF increases the expression of neurofilament heavy polypeptide (NEFH), a protein recently linked to regulation of the AKT1/beta-catenin pathway. CONCLUSIONS: We have used unbiased RNAi based approaches to identify and characterize the function of CASP8AP2/FLASH, a protein not previously reported as required for cell survival. This study further defines the role CASP8AP2/FLASH plays in the regulating expression of the replication dependent histones and shows that its LOF results in broad and reproducible effects on the transcriptome of colorectal cancer cells including the induction of expression of the recently described tumor suppressor gene NEFH. PMID- 22216764 TI - Repeat expansion in C9ORF72 in Alzheimer's disease. PMID- 22216765 TI - Preseasonal prophylactic treatment with antihistamines suppresses IL-5 but not IL 33 mRNA expression in the nasal mucosa of patients with seasonal allergic rhinitis caused by Japanese cedar pollen. AB - CONCLUSIONS: These findings suggest that the down-regulation of interleukin (IL) 5 gene expression in collaboration with the suppression of histamine H(1) receptor (H1R) gene expression in the nasal mucosa provides the basis for better therapeutic effects of preseasonal prophylactic treatment with antihistamines in patients with seasonal allergic rhinitis caused by Japanese cedar pollen. OBJECTIVES: The effects of prophylactic administration of antihistamines on the expression of IL-5 and IL-33 mRNA in the nasal mucosa of the patients with pollinosis were investigated. METHODS: Eight patients had already visited the hospital before the peak pollen period and started preseasonal prophylactic treatment with antihistamines. Seventeen patients who first visited the hospital during the peak pollen period were designated as the no treatment group. After local anesthesia, nasal mucosa was obtained by scraping the inferior concha with a small spatula during the peak pollen period. RESULTS: During the peak pollen period, the expression of IL-5 mRNA, but not that of IL-33 mRNA, in the nasal mucosa of patients receiving preseasonal prophylactic treatment with antihistamines was significantly lower in comparison with that of patients without treatment. Moreover, there was a significant correlation between the expression of IL-5 mRNA and the nasal symptoms or the expression of H1R mRNA. PMID- 22216767 TI - Deep tissue optical and optoacoustic molecular imaging technologies for pre clinical research and drug discovery. AB - For centuries, biological discoveries were based on optical imaging, in particular microscopy but also several chromophoric assays and photographic approaches. With the recent emergence of methods appropriate for bio-marker in vivo staining, such as bioluminescence, fluorescent molecular probes and proteins, as well as nanoparticle-based targeted agents, significant attention has been shifted toward in vivo interrogations of different dynamic biological processes at the molecular level. This progress has been largely supported by the development of advanced tomographic imaging technologies suitable for obtaining volumetric visualization of bio-marker distributions in small animals at a whole body or whole-organ scale, an imaging frontier that is not accessible by the existing tissue-sectioning microscopic techniques due to intensive light scattering beyond the depth of a few hundred microns. Major examples of such recently developed optical imaging modalities are reviewed here, including bioluminescence tomography (BLT), fluorescence molecular tomography (FMT), and optical projection tomography (OPT). The pharmaceutical imaging community has quickly appropriated itself of these novel forms of optical imaging, since they come with very compelling advantages, such as quantitative three-dimensional capabilities, direct correlation to the biological cultures, easiness and cost effectiveness of use, and the use of safe non-ionizing radiation. Some multi modality approaches, combining light with other imaging modalities such as X-Ray CT or MRI, giving the ability to acquire both an optical contrast reconstruction along with a hi-fidelity anatomical images, are also reviewed. A separate section is devoted to the hybrid imaging techniques based on the optoacoustic phenomenon, such as multispectral optoacoustic tomography (MSOT), which are poised to leverage the traditional contrast and specificity advantages of optical spectrum by delivering an ever powerful set of capabilities, including real-time operation and high spatial resolution, not affected by the scattering nature of biological tissues. PMID- 22216768 TI - Technology-driven intervention to improve hypertension outcomes in community health centers. AB - OBJECTIVES: To assess the impact of an electronic medical record (EMR) with clinical decision support (CDS) and performance feedback on provider adherence to guideline-recommended care and blood pressure (BP) control compared with a standard EMR alone. STUDY DESIGN: Quasi-experimental with repeated measures. METHODS: The study was conducted in a 4-site, federally qualified health center, Open Door Family Medical Centers, located in New York. The research team, Open Door leadership, providers, and staff developed and implemented a tailored multicomponent CDS system, which included a BP alert, a hypertension (HTN) order set, an HTN template, and clinical reminders. We extracted patient-level data for each encounter 17 months prior to implementation of the intervention (June 2007 October 2008) and 15 months post-intervention (April 2009-June 2010), from the EMR's data tables for all adult nonobstetric patients with a diagnosis of HTN (N = 3636). RESULTS: Rates of HTN control were significantly greater in the post intervention period compared with the baseline period (50.9% vs 60.8%; P <.001). Process measures, derived from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Guidelines, also improved significantly. Logistic regression with generalized estimating equations showed that patients were 1.5 times more likely to have controlled BP post-intervention than pre-intervention. Correlates of poor BP control were black race, higher body mass index, diabetes, female gender, income, and a greater number of prescribed antihypertensive medications. CONCLUSIONS: Our findings suggest that health information technology that is implemented as part of a multicomponent quality improvement initiative can lead to improvements in HTN care and outcomes. PMID- 22216769 TI - Public attitudes toward health information exchange: perceived benefits and concerns. AB - OBJECTIVES: To characterize consumers' attitudes regarding the perceived benefits of electronic health information exchange (HIE), potential HIE privacy and security concerns, and to analyze the intersection of these concerns with perceived benefits. STUDY DESIGN: A cross-sectional study. METHODS: A random digit-dial telephone survey of English-speaking adults was conducted in 2010. Multivariate logistic regression models examined the association between consumer characteristics and concerns related to the security of electronic health records (EHRs) and HIE. RESULTS: A majority of the 1847 respondents reported they were either "very" or "somewhat" concerned about privacy of HIE (70%), security of HIE (75%), or security of EHRs (82%). Concerns were significantly higher (P <.05) among employed individuals 40 to 64 years old and minorities. Many believed that HIE would confer benefits such as improved coordination of care (89%). Overall, 75% agreed that the benefits of EHRs outweighed risks to privacy and security, and 60% would permit HIE for treatment purposes even if the physician might not be able to protect their privacy all of the time. Over half (52%) wanted to choose which providers access and share their data. CONCLUSIONS: Greater participation by consumers in determining how HIE takes place could engender a higher degree of trust among all demographic groups, regardless of their varying levels of privacy and security concerns. Addressing the specific privacy and security concerns of minorities, individuals 40 to 64 years old, and employed individuals will be critical to ensuring widespread consumer participation in HIE. PMID- 22216770 TI - Progress toward meaningful use: hospitals' adoption of electronic health records. AB - OBJECTIVES: To update the status of electronic health record (EHR) adoption in US hospitals and assess their readiness for "Meaningful Use" (MU). STUDY DESIGN: We used data from the 2010 American Hospital Association Annual Information Technology Survey. The survey was first conducted in 2007 and is made available both online and through the mail to all non-federal acute-care hospitals in the United States. METHODS: We measure the percentages of applicable hospitals that have adopted "basic" and "comprehensive" EHRs as defined in previous literature. Additionally, we report the percentage of hospitals planning to apply for MU in the near term, and assess hospitals' readiness for the program and how readiness varies by key characteristics. RESULTS: We received responses from 2902 hospitals (64% of all non-federal acute-care hospitals). More than 15% have adopted at least a "basic" EHR, representing nearly 75% growth since 2008. Approximately two thirds plan to apply for MU before 2013; however, only 4.4% had implemented each of the "core" MU functionalities we measured. Hospitals closer to achieving MU are more likely to be larger non-profits (P <.001) and vary by other key characteristics. Certain functionalities included in MU, such as computerized provider order entry, electronic generation of quality measures, and electronic access to records for patients are proving more challenging to implement for all hospitals. CONCLUSIONS: Broad enthusiasm exists among hospitals for participation in MU. However, adoption will have to accelerate above its current pace for readiness to match intention. Gaps in adoption show bringing all hospitals along is the key policy challenge. PMID- 22216771 TI - Meaningful use of health information technology: evidence suggests benefits and challenges lie ahead. AB - Less than 3 years into the passage of the Health Information Technology for Economic and Clinical Health (HITECH) provisions of the American Recovery and Reinvestment Act of 2009, measurable results are emerging. For example, in the first 11 months during which healthcare providers ("eligible professionals") and acute care hospitals ("eligible hospitals") had the opportunity to demonstrate stage 1 "Meaningful Use" of Healthcare Information Technology (HIT), more than 20,000 "eligible professionals" and 750 "eligible hospitals" have done so. In the current issue of The American Journal of Managed Care, we showcase examples of HITECH's potential impact, as well as illustrate the opportunities and challenges ahead. Two studies in this issue illustrate how HIT can improve the capacity of our healthcare system to manage chronic illnesses. The study by Vollmer et al describes how an interactive voice recognition system can improve adherence to inhaled corticosteroids among individuals with asthma in a large health maintenance organization. Shelley's study shows that the combination of electronic medical records, clinical decision support, and performance feedback can improve the rate of blood pressure control in patients with hypertension who receive care in community health centers. Together, these studies provide hope that the nation's investment in HIT could one day yield clinical dividends. Three other studies in this issue suggest that success for HIT will require attention to both technological and sociological factors. The study by Millery et al attributes the success of an HIT-based intervention to a multi-faceted approach that involves a combination of decision support tools, systematic provider feedback, implementation support, and leadership. Results from Abramson's study suggest that the full error-reduction potential of e-prescribing may only be reached with the combination of on-line clinical decision support and support for clinicians. The study by Dimitropoulos et al further illustrates that a broad spectrum of healthcare consumers needs to be engaged to allay their privacy and security concerns about Health Information Exchange. To be sure, the challenges that lie ahead remain formidable. The survey results reported by Jha et al warn us that in spite of the broad-based enthusiasm for the HITECH program among US hospitals, certain required functionalities remain challenging to implement. Attainment of the HITECH objectives is by no means certain. The HITECH legislation represents a once-in-a-generation opportunity to deploy tools that could address many of the problems underlying the US healthcare system. While the healthcare community appears to be making good progress toward making these tools available to clinicians, these tools will mean little unless we leverage them to redesign healthcare to be safe, effective, patient-centered, timely, efficient, and equitable. PMID- 22216772 TI - Use of health information technology to improve medication adherence. AB - OBJECTIVES: To evaluate the effectiveness of an intervention based on health information technology (HIT) that used speech recognition software to promote adherence to inhaled corticosteroids (ICS) among individuals with asthma who were members of a large health maintenance organization. STUDY DESIGN: Pragmatic randomized clinical trial. METHODS: Adults with asthma enrolled in a large managed care organization (N = 8517) were randomized to receive either usual care or an interactive voice recognition (IVR) intervention designed to prompt medication refills and improve ICS adherence. The primary outcome was ICS adherence as measured by modified medication possession ratio calculated from the electronic medical record (EMR). Secondary measures included survey- and EMR based measures of asthma morbidity. RESULTS: Our primary analyses found that ICS adherence increased modestly but significantly for participants in the intervention group relative to those in the usual care group ( Delta= 0.02, 95% confidence interval 0.01-0.03), with a baseline adherence of 0.42 in both groups. No difference was observed in asthma morbidity measures. In post hoc analyses of participants receiving 2 or more direct IVR contacts or detailed messages, the intervention effect was more marked. The overall effect was triple that observed in the primary analyses (0.06 vs 0.02), and significant differences were observed between groups in asthma control. CONCLUSIONS: An HIT-based adherence intervention shows potential for supporting medication adherence in patients with chronic diseases such as asthma. However, additional research is needed to determine how best to enhance the reach and effectiveness of such interventions. PMID- 22216773 TI - The comparative effectiveness of 2 electronic prescribing systems. AB - OBJECTIVES: The increasingly widespread adoption of electronic health records (EHRs) is substantially changing the American healthcare delivery system. Differences in the actual effectiveness of EHRs and their component applications, including electronic prescribing (e-prescribing), is not well understood. We compared the effects of 2 types of e-prescribing systems on medication safety as an example of how comparative effectiveness research (CER) can be applied to the study of healthcare delivery. STUDY DESIGN AND METHODS: We previously conducted 2 non-randomized, prospective studies with pre-post controls comparing prescribing errors among: (1) providers who adopted a standalone e-prescribing system with robust technical and clinical decision support (CDS) and (2) providers who adopted an EHR with integrated e-prescribing with less robust available CDS and technical support. Both studies evaluated small groups of ambulatory care providers in the same New York community using identical methodology including prescription and chart reviews. We undertook this comparative effectiveness study to directly compare prescribing error rates among the 2 groups of e-prescribing adopters. RESULTS: The stand-alone system reduced error rates from 42.5 to 6.6 errors per 100 prescriptions (P <.001). The integrated system reduced error rates from 26.0 to 16.0 per 100 prescriptions (P= .07). After adjusting for baseline differences, stand-alone users had a 4-fold lower rate of errors at 1 year (P <.001). CONCLUSIONS: Despite improved work flow integration, the integrated e prescribing application performed less well, likely due to differences in available CDS and technical resources. Results from this small study highlight the importance of CER that directly compares components of healthcare delivery. PMID- 22216774 TI - Qualitative evaluation to explain success of multifaceted technology-driven hypertension intervention. AB - OBJECTIVES: This study sought to examine the implementation of an electronic health record-based intervention to improve quality of hypertension care in community health centers. The primary goal was to use qualitative analysis to explain how different components of the intervention contributed to positive patient-level outcomes. STUDY DESIGN: Qualitative process evaluation. METHODS: The intervention included alerts, order sets, templates, clinical reminder algorithms, and provider performance feedback. Semi-structured interviews were conducted with primary care providers before (n = 16) and after (n = 16) intervention, and with key staff and leadership involved in the implementation (n = 6). The research team applied an iterative systematic qualitative coding process to identify salient themes. Several constructs from IT implementation theories guided the analysis. RESULTS: The analysis focused on: (1) satisfaction and perceived usefulness of intervention components, (2) perceived proximal changes resulting from intervention, and (3) perceived facilitators of change. Different participants found different components useful. Proximal impact manifested in multiple ways (eg, more aggressive follow-up appointments and prescribing) and in increased overall attention to hypertension. Facilitators of success included leadership, organizational culture, provider engagement, rigorous implementation process, framing of intervention as quality improvement (QI), and health center capacity to process data. CONCLUSIONS: We attribute the success of the intervention to a multifaceted approach where the combination of multiple intervention components resulted in across the-board change in hypertension care practices. In contrast with research that attempts to isolate the impact of circumscribed health information technology (HIT) tools, our experience suggests that HIT can achieve success in patient outcomes when rigorously implemented as a multifaceted intervention and framed as QI activity. PMID- 22216775 TI - The influence of adult worm age and definitive host on the transmission of Echinostoma caproni: egg hatchability and miracidial infectivity. AB - We analysed the influence of different ages of Echinostoma caproni adult worms reared in different definitive host-species on egg hatchability and miracidial infectivity. Eggs obtained from 2-, 4- and 6-week-old adult worms collected from rats, hamsters and mice, hatched miracidia that were used to infect laboratory reared specimens of Biomphalaria glabrata. Highest egg hatchability was obtained with eggs derived from hamsters and mice. Egg hatchability did not seem to be affected by the age of E. caproni adult worms. Miracidial infectivity was not affected by the definitive host species. However, miracidial infectivity was affected by the age of adult worms when they developed in the mice intestine. The long period of miracidial infectivity in hamsters revealed this definitive host as the most suitable for experimental development of the life cycle and parasite transmission. PMID- 22216776 TI - Adrenomedullin: exciting new horizons. AB - Adrenomedullin is a peptide initially isolated from pheochromocytoma. It has a wide distribution and has multiple actions in many systems including the cardiovascular, renal, endocrine, reproductive, immune, nervous and musculoskeletal systems. This is reflected in the patents. These cover the use of adrenomedullin in diagnosis and as a biomarker for prognosis, especially in cardiovascular diseases and diabetes. It has also been proposed as a therapeutic agent, as a method to promote regeneration and repair, such as in ischaemic conditions and bone fractures. Conversely, its antagonists or antibodies binding it are claimed to have potential use in blocking angiogenesis in cancers. PMID- 22216777 TI - Emerging therapies for dyslipidemia: known knowns and known unknowns of MTP inhibitors. AB - Last decade had witnessed enormous efforts to develop therapies to treat one or more components of metabolic syndrome, a cluster of diseases including diabetes, obesity and dyslipidemia. Several newer targets are identified and evaluated to treat these metabolic disorders. Microsomal triglyceride transfer protein (MTP) has been identified as one of the promising target for the treatment of dyslipidemia. MTP plays crucial role in the assembly of triglyceride rich chylomicrones in enterocytes and VLDL in hepatocytes and several lines of evidence suggested that MTP inhibitors can be instrumental in combating familial hypercholesterolemia. Several first generation compounds are currently being evaluated in clinic and fatty liver is found to be the main adverse effect of these agents. Recently development of enterocyte specific inhibitor of MTP is emphasized in order to deal with fatty liver issue. In this review, we have dealt with important mechanistic aspects of MTP inhibition, patent scenario and clinical trial outcomes and some of the recent patents related to newly discover chemical scaffolds. PMID- 22216778 TI - Targeting BLyS in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic disabling autoimmune disease that significantly impacts the quality of life of patients, and can associate with several complications including end-stage renal disease and shortened lifespan. A central component in the pathogenesis of SLE is the B-cell production of autoantibodies to multiple self-antigens. Since, B lymphocyte stimulator (BLyS) plays a key role in the selection, differentiation and survival of most B cells, it has been studied as a therapeutic target in SLE. After a gap of more than fifty years without new drugs being approved for this disease, the human neutralizing anti-BLyS monoclonal antibody belimumab has recently been approved by the FDA for SLE therapy. This review provides an overview on the targeting of BLyS in lupus animal models, the use of belimumab in human SLE, and relevant patents. PMID- 22216780 TI - Exercise addiction: symptoms, diagnosis, epidemiology, and etiology. AB - Regular physical activity plays a crucial role in health maintenance and disease prevention. However, excessive exercise has the potential to have adverse effects on both physical and mental health. The scholastic and empirical discussion of excessive physical activity focuses on obsessive and compulsive exercising, and uses several labels. However, in this review, we argue that the most appropriate term for this phenomenon is exercise addiction, emphasizing that excessive physical exercise fits the typical and most common characteristics of behavioral addictions. The aim of this review is to synthesize the current knowledge on symptomology, diagnosis, epidemiology, and etiology of exercise addiction. PMID- 22216781 TI - Anticancer drug discovery from the marine environment. AB - Discovery, isolation, biochemical/pharmacological characterization, pre-clinical and clinical trials of drugs derived from the marine environment are continuously developing and increasing. One of the most promising area is cancer therapy. Currently, there are two drugs approved by the Food and Drug Administration (FDA) and European Agency for the Evaluation of Medicinal Products (EMA) in cancer treatment, namely Cytarabine (Cytosar-U1(r)) and Eribulin (E7389 or Halaven(r)). Trabectedin (ET-743 or Yondelis1(r)), approved by EMA, is completing key Phase III studies in the U.S. for final approval. It was estimated that 118 marine natural products (MNPs) are currently in preclinical trials, 22 MNPs in clinical trials and 3 MNPs on the market. The characteristics and selectivity profiles of new drugs for cancer therapy, as well as drugs disclosed in related patent applications, will be the focus of this review, providing a brief and ready to use reference. PMID- 22216782 TI - Effectiveness of a pediatric palliative home care team as experienced by parents and health care professionals. AB - OBJECTIVES: Little data are available on palliative home care for children. The objective of this study was to evaluate the effectiveness of a specialized pediatric palliative home care team (PPHCT) as experienced by parents and health care professionals (HCPs). METHODS: Parents and HCPs involved in the care of terminally ill children who died and whom the PPHCT was in charge of were surveyed with questionnaires focusing on satisfaction with the PPHCT, satisfaction with the course of the dying phase, and the development of anxiety, depression, and prolonged grief disorder. RESULTS: Forty-three parent dyads participated (return rate, 88%). Satisfaction with the PPHCT scored a median of 10 (numeric rating scale, 0-10). The child's death was predominantly experienced as very peaceful (median, 9); 71% died at home. According to parents, involvement of the PPHCT led to highly significant (p<0.001) improvements in the children's symptoms and quality of life, as well as in aspects of communication and administrative barrier reduction. Anxiety was detected in 25% of parents, depression in 19%, and prolonged grief disorder in 13%. HCPs (return rate, 83%) evaluated all investigated care domains (particularly cooperation/communication/family support) as being significantly improved (p<0.001). Thirty-five percent of HCPs felt uncertain concerning pediatric palliative care; 79% would welcome specific training opportunities. CONCLUSIONS: Involvement of a PPHCT is experienced as a substantial improvement of care by parents and HCPs. Coordination of palliative care during the last phase of life appears to be an important quality factor for the home care of dying children and their families. PMID- 22216784 TI - Application of advanced data collection and quality assurance methods in open prospective study - a case study of PONS project. AB - INTRODUCTION: Large-scale epidemiologic studies can assess health indicators differentiating social groups and important health outcomes of the incidence and mortality of cancer, cardiovascular disease, and others, to establish a solid knowledgebase for the prevention management of premature morbidity and mortality causes. This study presents new advanced methods of data collection and data management systems with current data quality control and security to ensure high quality data assessment of health indicators in the large epidemiologic PONS study (The Polish-Norwegian Study). MATERIAL AND METHODS: The material for experiment is the data management design of the large-scale population study in Poland (PONS) and the managed processes are applied into establishing a high quality and solid knowledge. RESULTS: The functional requirements of the PONS study data collection, supported by the advanced IT web-based methods, resulted in medical data of a high quality, data security, with quality data assessment, control process and evolution monitoring are fulfilled and shared by the IT system. Data from disparate and deployed sources of information are integrated into databases via software interfaces, and archived by a multi task secure server. CONCLUSIONS: The practical and implemented solution of modern advanced database technologies and remote software/hardware structure successfully supports the research of the big PONS study project. Development and implementation of follow-up control of the consistency and quality of data analysis and the processes of the PONS sub-databases have excellent measurement properties of data consistency of more than 99%. The project itself, by tailored hardware/software application, shows the positive impact of Quality Assurance (QA) on the quality of outcomes analysis results, effective data management within a shorter time. This efficiency ensures the quality of the epidemiological data and indicators of health by the elimination of common errors of research questionnaires and medical measurements. PMID- 22216783 TI - Intestinal growth and pathology of Giardia duodenalis assemblage subtype A(I), A(II), B and E in the gerbil model. AB - This study investigated the significance of the genetic differences between assemblages A, B and E on intestinal growth and virulence. Intestinal growth and virulence were studied in 2 laboratory (A(I): WB and B: GS/M-83-H7) and 6 field isolates of assemblage subtype A(I), A(II), B and E(III). Intestinal trophozoite burdens, body weight and faecal consistency were monitored until day 29 post infection (p.i.), morphological (mucosal architecture and inflammation) and functional (disaccharidase and alkaline phosphatase enzyme activity) damage to the small intestine were evaluated on days 7 and 18 p.i. The assemblage subtypes A(I) and B were more infectious and produced higher trophozoite loads for a longer period compared to the subtypes A(II) and E(III). The body weight of infected gerbils was significantly reduced compared to uninfected controls, but did not differ between the assemblage subtypes. Consistent softening of the faeces was only observed with assemblage B. Assemblage B next to assemblage subtype A(I) elicited relatively higher pathogenicity, characterized by more extensive damage to mucosal architecture, decreased brush-border enzyme function and infiltration of inflammatory cells. Assemblage E(III) and A(II) isolates showed relatively low virulence. The Giardia assemblage subtypes exhibit different levels of growth and virulence in the gerbil model. PMID- 22216785 TI - Cigarette smoking among a sample of PONS study subjects: preliminary assessment. AB - AIM: To evaluate the prevalence, socio-demographic patterns and behavioural characteristics of tobacco smoking in a pilot group of PONS respondents. MATERIALS AND METHODS: Open-ended prospective cohort study conducted in Swietokrzyskie Province. A pilot group of subjects aged 45-64 years was examined. Data on smoking were collected with the use of the Health State Questionnaire administered by the CAPI method. RESULTS: 62.6% of males and 45.5% of females participating in the PONS study were ever smokers. In the male population, the percentage of current and former smokers were 19.8% and 42.8%. In females, these percentages were at the lower level of 15.3% and 30.3%, respectively. Self reported data on smoking prevalence seem to be consistent with objective assessment of exposure to tobacco smoke (measured by carbon monoxide level in exhaled lung air), especially for non-smokers. CONCLUSIONS: The analysis found substantial differences in the level of current and former smoking between PONS study and nation-wide surveys conducted in the adult Polish population. Percentages of current smokers in the PONS study are two or even more times lower, and the prevalence of former smoking is almost two times higher than among adult Poles. The above differences may result from social characteristics of the fi rst group of PONS subjects and their health behaviours. PONS subjects who decided to take pat in the fi rst phase of the study are proportionally better educated than a comparable age group of the adult Polish population, and therefore may be more health-oriented than respondents from the general population. Therefore, it is recommended that the next phase of the PONS study should promote and focus on the less educated inhabitants of the study areas, especially males. PMID- 22216786 TI - Alcohol drinking patterns and habits among a sample of PONS study subjects: preliminary assessment. AB - INTRODUCTION: Alcohol drinking is a major contributing factor to death, disease, injury and social problems such as violence or child neglect and abuse, especially in Eastern Europe. OBJECTIVES: To preliminary evaluate the prevalence and social and behavioural patterns of alcohol drinking in a pilot group of the Polish-Norwegian Study (PONS study) subjects. MATERIAL AND METHODS: Open-ended prospective cohort study conducted in Swietokrzyskie province. A pilot group of subjects aged 45-64 years has been examined. Data on alcohol drinking were collected for 3,845 respondents with the use of the Health State Questionnaire administered by the CAPI method. RESULTS: In males, 72.3% drank alcohol currently, 22.7% were former drinkers, and only 5% never drinkers. Among females, the percentage of current alcohol drinkers was significantly lower than in males, while the percentages of former and never drinkers was higher (50.3%, 35.4% and 14.6%, respectively). 7.4% of males and 0.8% of females drank alcohol daily or almost daily, and weekly alcohol drinking was respectively at level of 32.2% and 15.7%. Males drank mainly vodka (or other spirits) and beer, females grape wine and vodka. CONCLUSIONS: PONS study includes interesting dataset for assessing prevalence and patterns of alcohol drinking at population level. Alcohol drinking seems to be common among PONS subjects. Comparison with nation-wide surveys shows on higher number of alcohol abstainers and lower number of binge drinkers among PONS study subjects. On the other hand, frequency and social patterns of alcohol drinking seem to be consistent with data found in national studies. PMID- 22216787 TI - Assessment of dietary intake in a sample of Polish population - baseline assessment from the prospective cohort 'PONS' study. AB - OBJECTIVE: The aim of this study was to assess the dietary intake of participants in the Polish-Norwegian Study (PONS). METHODS: The presented study comprised 3,862 inhabitants of Swietokrzyskie Province aged 45-64 (2,572 females and 1,290 males). Daily intakes of energy, protein, carbohydrate, fat and fatty acid were estimated using the Food Frequency Questionnaire (FFQ). RESULTS: Energy intake was significantly higher in males than females (1,461.4 vs 1,320.7 kcal/day), and in participants aged 45-54 than in those aged 55-64 (1,409.5 vs 1,338.5 kcal/day). The percentage of energy from saturated fatty acids was higher than dietary recommendations. Protein, fat and carbohydrate intakes were significantly higher in males compared to females, and in younger than in older group. Daily cholesterol intake was significantly higher in males compared to females and in younger than in older group. People with a higher level of education had a higher energy, protein and fat intake. CONCLUSION: Under-reporting of energy intake was observed in a significant percentage of participants, especially in males. Gender, age and education status had statistically significant impact on dietary intake. Increase in the intake of dietary fibre, mono- and polyunsaturated fatty acids with diet by the studied participants will make the diets more healthy. PMID- 22216788 TI - Evaluation of mineral and vitamin intake in the diet of a sample of Polish population - baseline assessment from the prospective cohort 'PONS' study. AB - OBJECTIVE: The aim of this cohort study was to evaluate selected mineral and vitamin intake of the Polish-Norwegian Study (PONS) participants. METHODS: Daily mineral and vitamin intake of PONS study participants was estimated using Food Frequency Questionnaire (FFQ). Overall, 3,862 inhabitants of Swietokrzyskie Province aged 45-64 (2,572 females and 1,290 males) enrolled in the study. RESULTS: Mean calcium, iron, magnesium, phosphorus, potassium, and sodium intake were, in males: 660.6 mg/day, 15.4 mg/day, 218.5 mg/day, 889.3 mg/day, 2,453.4 mg/day and 2,571.5 mg/day, and in females: 703.6 mg/day, 13.9 mg/day, 220.8 mg/day, 916.3 mg/day, 2,497.3 mg/day and 2,301.8 mg/day, respectively. Iron and sodium intake was significantly higher in males compared to females. Calcium intake was lower in males than in females and in participants aged 55-64 then those aged 45-54. Estimated daily sodium intake was similar among individuals with and without hypertension. Mean vitamin C, thiamin, riboflavin, vitamin B6, A and E were, in males: 80.1 mg/day, 1.3 mg/day, 1.5 mg/day, 1.6 mg/day, 8,454.0 IU/day and 5.4 mg/day and in females: 83.7 mg/day, 1.1 mg/day, 1.6 mg/day, 1.6 mg/day, 9,494.6 IU/day and 4.9 mg/day, respectively. Females had a higher intake of vitamin C and A , while males had higher thiamin and vitamin E intakes. Higher daily vitamin C intake was observed in the younger than in the older group, and in participants with higher education than those with a lower level of education. CONCLUSION: Significant differences were observed in daily intake of some vitamins and minerals by gender, age, level of education, and place of residence. Some participants had a lower intake of some minerals and vitamins than Polish recommendations. PMID- 22216789 TI - Patterns of leisure time physical activity and its determinants among a sample of adults from Kielce region, Poland - the 'PONS' study. AB - The aim of the study was to evaluate the prevalence, socio-demographic patterns and behavioural characteristics of leisure time physical activity in a pilot group of respondents of the Polish-Norwegian Study (PONS). MATERIALS AND METHODS: PONS is an open-ended prospective study set in Swietokrzyski Province with study cohort consisting of adults aged 45-64 years. The physical activity section of the questionnaire was based on the International Physical Activity Questionnaire. RESULTS: 43% of the respondents had not walked for at least 10 minutes in their leisure time during the last week. The majority did not engage in any moderate or vigorous physical activity (PA). Being physically active was more prevalent among residents of urban areas and among respondents with a higher level of education. Performing PA was also positively associated with higher net income per household member. On average, respondents had spent 47 hours in a sedentary position during last week. The majority of subjects reported watching TV for 6-20 hours per week. Not having enough time and lack of willingness were given as the main reasons for being inactive. CONCLUSIONS: A significant proportion of participants were inactive in their leisure time, even activity less than 10 minutes during the last 7 days was common. Walking was the most popular form of PA in this domain. Urban residence, higher level of education and better financial situation were strongly associated with higher levels of PA. PMID- 22216790 TI - Prevalence of obesity - baseline assessment in the prospective cohort 'PONS' study. AB - OBJECTIVE: The aim of the study was to evaluate the prevalence of overweight and obesity in the population of Swietokrzyskie Province in Poland. METHODS: Body mass index (BMI), waist to hip ratio (WHR) and waist circumference (WC) in the Polish-Norwegian Study (PONS) was measured in 2,567 females and 1,287 males. Anthropometric measurements included fat mass, height, weight, waist and hip circumference. BMI and WHR were calculated. RESULTS: Data showed that 52% of males and 42% of females were overweight (25.0 <= BMI<30.0 kg/m2), and the prevalence of obesity (BMI >= 30.0 kg/m2) was 35% in both genders. The average BMI was higher in males (28.5 kg/m2) than in females (28.2 kg/m2). Analysis of WC showed that 36% of males and 45% of females had abdominal obesity, whereas measurements of WHR showed abdominal obesity in 64% of males and 79% of females. Generally, the prevalence of obesity was higher in the older age group (55-64 years) and in rural inhabitants. The prevalence of overweight increased with educational level, but the prevalence of obesity decreased with level of education in both males and females. CONCLUSIONS: Almost 80% of the PONS population were either overweight or obese; therefore, the PONS population is at increased risk of developing obesity-related diseases. PMID- 22216791 TI - Cancer risk factors in Poland: the PONS Study. AB - INTRODUCTION: The burden of cancer in Eastern Europe is expected to increase, and in 2006, Polish males were ranked second in lifetime risk of lung cancer. The Polish-Norwegian Study (PONS) is a population study in the Kielce District, and the presented study describes the distribution of preventable causes of cancer according to gender, age, education, and urban/rural status. METHODS: PONS comprises individuals 45-64 years of age at baseline. A structured lifestyle interview was conducted, and the following risk factors were recorded: smoking, alcohol consumption and obesity. Binomial regression analysis was used to estimate age and gender adjusted prevalence ratios (PR) for the associated factors. RESULTS: A total of 3,862 adults were included in the analysis. Approximately 17% reported current tobacco smoking on a daily basis, 34% were former smokers, and 49% were non- smokers. Current smoking was more prevalent in males (20%) than females (15%), but there was no clear association with educational level or urban/rural status. Females also reported a lower frequency of alcohol consumption than males. Among males, 15% reported drinking alcohol more than once a week, as compared to 2% of the females. There was no clear association with urban/rural status, or with level of education. The total prevalence of obesity (BMI >= 30) was 30%; the prevalence of obesity class 2 (BMI >= 35) and class 3 (BMI >= 40) was 8% and 1.7%, respectively. Obesity increased by age, especially in females, and was less frequent among people with high education and people with urban residence. CONCLUSIONS: The Kielce region of Poland is experiencing a significant burden of cancer risk factors, including obesity and tobacco smoking, but smoking may be a decreasing habit. It is necessary to increase the awareness of the population to the harmful eff ects of smoking and obesity to prevent cancer and other lifestyle related diseases. PMID- 22216792 TI - A cross-sectional study of cardiovascular disease and associated factors. AB - OBJECTIVE: Cardiovascular diseases (CVD) are a major cause of mortality and morbidity in Poland. Data on risk factors of CVD in this country are limited. The presented study investigated risk factors of self-reported CVD within the Polish- Norwegian Study (PONS). METHODS: PONS is an ongoing prospective study in Poland. The data used was provided by 3,853 participants, aged 45-64, during baseline interviews. RESULTS: Prevalence of chronic diseases among participants was as follows: hypertension, 38.4%; diabetes, 5.9%; and CVD, 11.0%. There was no association between CVD and gender and place of residence. CVD was associated with ever-smoking (OR= 1.25; 95% CI: 1.00-1.55), whereas there was an inverse association with alcohol drinking in the year preceding enrolment in the study (OR= 0.50; 95% CI: 0.39-0.63). CVD was associated with body mass index (BMI), as well as with measures of abdominal adiposity, in the following order: waist to height ratio>waist circumference>waist to hip ratio; however, none of these measures showed a stronger association with CVD than BMI. Both hypertension (OR= 1.33; 95% CI: 1.05-1.68) and diabetes (OR= 1.33; 95% CI: 1.05-1.68) were associated with CVD in adjusted models. CONCLUSIONS: This study shows the association between several risk factors and prevalence of self-reported CVD and provides information about distribution of those factors among an adult population in Poland. The results of the ongoing PONS study in a prospective setting will provide more accurate risk estimates for the observed associations, as well as risk estimates for other risk factors of CVD, including dietary factors, and attributable risks for various factors. PMID- 22216793 TI - Prevalence of hypertension in a sample of Polish population - baseline assessment from the prospective cohort 'PONS' study. AB - OBJECTIVE: The aim of this cohort study was to evaluate the prevalence of hypertension and cardiovascular risk factors in the studied population. METHODS: Presented results are a part of the Polish-Norwegian Study (PONS) project. The study group consisted of 3,862 inhabitants of Swietokrzyskie Province aged 45-64 years (2,572 females and 1,290 males). RESULTS: Prevalence, awareness and control of hypertension was evaluated in the studied population of 3,854 urban and rural inhabitants. Mean blood pressure in the whole studied population was 139.6/81.9 mmHg; of the studied population 61.7% were hypertensive. Hypertension was more prevalent in the studied males (70.63%) than in the females (57.24%). In both males and females, the older subgroups (55-64 y.o.) had significantly higher blood pressure than the younger subgroups (45-54). Education had a significant impact on the prevalence of hypertension, and the highest prevalence of hypertension was observed in the middle level educated groups of females and males. No significant difference was observed between rural and urban inhabitants. In both females and males, the prevalence of hypertension significantly decreased with level of education. Hypertension was well-controlled in only 13.8% of the subjects. More studied females than males achieved good control of blood pressure (14.09 vs. 12.7%), and better control of blood pressure was significantly more frequent in better those who were better educated. Hypertension was not diagnosed in 23.2% of studied population. Significantly, more males than females had undiagnosed hypertension (30.4 vs. 19.5%). No significant difference between rural and urban populations was observed. Interestingly, both in females and males, the better educated groups had more undiagnosed hypertension than those who were well-educated. CONCLUSIONS: The studied group had a high prevalence of hypertension (61.7%), which was less frequent and better controlled in the studied females than in the males. No significant difference was observed between the urban and rural populations. Level of education had significant impact on the prevalence of hypertension. PMID- 22216794 TI - Prevalence of diabetes mellitus and IFG in the prospective cohort 'PONS' study - baseline assessment. AB - OBJECTIVE: The aim of this cross-sectional study was to assess the prevalence of diabetes mellitus and impaired fasting glucose (IFG) in the Polish-Norwegian Study (PONS) population in Poland. METHODS: The presented results are part of the PONS project, and cover information from 3,854 people aged 45-64 (2,567 females and 1,287 males) who are inhabitants of Swietokrzyski Province. RESULTS: In the study group there were 62.8% participants with normoglycaemia, 28.9% participants with IFG and 8.4% participants with diabetes. In those with diabetes, there were 95 participants (2.5%) whose diabetes was unknown prior to this study. Among 5.9% patients with known diabetes 52.9% of the participants had a fasting blood glucose level of >= 126 mg%. There were 46.8% males and 70.8% females with normoglycaemia, 41.0% males and 22.8% females with IFG, and 12.2% males and 6.4% females with diabetes. The prevalence of diabetes was higher in participants in the older age group (55-64) compared to younger participants (45-54). The prevalence of diabetes decreased with increasing education and was higher among overweight or obese participants compared to normal weight participants. CONCLUSION: The prevalence of diabetes mellitus in study population was generally high, but especially high in males, and the awareness of diabetes in the population was generally low. Among participants with known diabetes more than half was not well controlled. PMID- 22216795 TI - Metabolic syndrome in Poland - the PONS Study. AB - INTRODUCTION: In Central and Eastern European countries, cardiovascular disorders (CVD) in middle age are much more common than in Western Europe, and it is imperative to understand the causes underlying this excess disease burden. The metabolic syndrome comprises a constellation of metabolic abnormalities that increase the risk of cardiovascular disease. METHODS: Data were obtained by structured interview, and by measurements of anthropometric factors and blood analyses among 3,862 individuals. Metabolic syndrome was defined according the International Diabetes Federation Task Force on Epidemiology and Prevention, as the presence of at least 3 of 5 abnormalities: 1) abdominal obesity, 2) glucose intolerance, 3) high triglycerides, 4) low HDL cholesterol, 5) high blood pressure. RESULTS: Overall, 1,518 participants (39.5%) had metabolic syndrome. The prevalence among females was 34.3% (877 females) vs. 49.9% (641 males) among males, and increased with age in both genders. Abdominal obesity was the most common abnormality (2,897 participants, 75.1%), followed by high blood pressure (2,741 participants, 71%), glucose intolerance (1,437 participants, 37.3%), elevated triglycerides (817 participants, 21.2%) and low HDL (615 participants, 15.9%). CONCLUSION: The prevalence of metabolic syndrome and metabolic abnormalities is high and represents strong risk factors for CVD morbidity and mortality. However, these factors are all potentially preventable by lifestyle modification and/or by pharmacological treatment. There is an urgent need for the health service to act, and to increase public awareness of metabolic syndrome. PMID- 22216796 TI - Depressive episodes and depressive tendencies among a sample of adults in Kielce, south-eastern Poland. AB - INTRODUCTION AND OBJECTIVES: Previous community research has shown differences in depression and depressive symptoms across different socioeconomic and demographic groups. However, very few population-based studies on depression have been conducted in Poland. The purpose of the present study is to assess depressive episodes and depressive tendencies, and associations of the latter with selected socio-economic and demographic predictors among a sample of adults from Poland. MATERIALS AND METHODS: Data stem from a community health survey carried out as part of a large prospective study among people aged 45-64 in the Kielce province of south-eastern Poland (n=3,862). Self-reported depressive episodes, depressive tendencies (7 items) and use of antidepressants were measured. Depressive tendencies were modelled as a latent variable and analyzed against selected demographic and socioeconomic predictors. RESULTS: The prevalence of depressive episodes was higher among females (25.0%) than among males (14.7%). When depressive tendencies were modelled as a latent variable, the following predictors were associated with high scores: age (females only), living in rural districts, being a pensioner (not including old age pension), and being unemployed (males only). Scores on depressive tendencies were negatively associated with high education, being self-employed (borderline significance only) and high personal income. CONCLUSIONS: Depressive episodes were prevalent among the sample. If the associations between depressive tendencies and demographic variables shown in this study are confirmed by future studies, it suggests that action should be taken to offer improved preventive action and improved mental health services - such as early treatment - to females, people living in rural areas, and selected low status segments of the population in particular. PMID- 22216797 TI - Case of the PONS study. PMID- 22216799 TI - Internal and external validity of cohort studies. PMID- 22216798 TI - Improving health in central and eastern europe. PMID- 22216800 TI - POlish-Norwegian Study (PONS). PMID- 22216801 TI - Biological agents as occupational hazards - selected issues. AB - There are two main groups of biological agents regarded as occupational hazards: allergenic and/or toxic agents forming bioaerosols, and agents causing zoonoses and other infectious diseases. Bioaerosols occurring in the agricultural work environments comprise: bacteria, fungi, high molecular polymers produced by bacteria (endotoxin) or by fungi (beta-glucans), low molecular secondary metabolites of fungi (mycotoxins, volatile organic compounds) and various particles of plant and animal origin. All these agents could be a cause of allergic and/or immunotoxic occupational diseases of respiratory organ (airways inflammation, rhinitis, toxic pneumonitis, hypersensitivity pneumonitis and asthma), conjunctivitis and dermatitis in exposed workers. Very important among zoonotic agents causing occupational diseases are those causing tick-borne diseases: Lyme borreliosis, anaplasmosis, babesiosis, bartonellosis. Agricultural workers in tropical zones are exposed to mosquito bites causing malaria, the most prevalent vector-borne disease in the world. The group of agents causing other, basically not vector-borne zoonoses, comprises those evoking emerging or re emerging diseases of global concern, such as: hantaviral diseases, avian and swine influenza, Q fever, leptospiroses, staphylococcal diseases caused by the methicillin-resistant Staphylococcus aureus (MRSA) strains, and diseases caused by parasitic protozoa. Among other infectious, non-zoonotic agents, the greatest hazard for health care workers pose the blood-borne human hepatitis and immunodeficiency viruses (HBV, HCV, HIV). Of interest are also bacteria causing legionellosis in people occupationally exposed to droplet aerosols, mainly from warm water. PMID- 22216802 TI - Biomonitoring and biomarkers of organophosphate pesticides exposure - state of the art. AB - Human biomonitoring provides an efficient and cost-effective way to identify and quantify exposure to chemical substances, including those having deleterious eff ects on human organisms. Once the risk of hazardous exposure has been identified and the mechanism of toxic eff ects has been elucidated, an ultimate decision about how to reduce exposure can be made. A particularly high risk of exposure to hazardous chemicals is associated with the use of pesticides in agriculture, especially the use of organophosphorous pesticides (OP), which are the most widely and commonly used insecticides worldwide. There is some strong evidence that chronic exposure to these compounds may have adverse eff ects on health. Exposure to pesticides has been associated with an increase in the incidence of non-Hodgkin's lymphoma, multiple myeloma, soft tissue sarcoma, lung sarcoma, and cancer of the pancreas, stomach, liver, bladder and gall bladder, Parkinson disease, Alzheimer disease, and reproductive outcomes. In view of these findings, the detection of populations at risk constitutes a very important topic. The biomonitoring studies on individuals exposed to pesticides have shown an elevated level of indicators of DNA damage, such as chromosomal aberrations (CA), sister chromatid exchanges (SCE), micronuclei (MN), and recently, single cell gel electrophoresis (SCGE). The cytogenetic markers of DNA damage have become very popular and useful in providing an analytical data for risk assessment, such as internal exposure doses and early biological eff ects of both occupational and environmental exposure to pesticides. The article describes the usefulness and the limitations of these biomarkers in biomonitoring studies of populations exposed to pesticides, with regard to the main routes of uptake and different matrices, which can be used to monitor risk assessment in occupational settings. The article also summarizes the latest reports about biomarkers of susceptibility, and mentions other biomarkers widely used in biomonitoring studies, such as pesticide or its metabolites level. PMID- 22216803 TI - Legal highs - legal aspects and legislative solutions. AB - In recent years the attention of society, the media and politicians has focused on the negative phenomenon of the occurrence of an enormous amount of new psychoactive substances flooding the European market. In Poland and in Europe they are known under the name 'legal highs' or 'smart drugs'. In many countries these compounds present a serious social and health problem. The core of the problem is the fact that in the light of the law these substances are legal, while actually they imitate the eff ect of illegal narcotics. Smart drugs are sold allegedly as 'products not intended for human consumption', under the cover of 'collector's commodities', 'incense sticks' or 'bath salts'. Efforts undertaken by many countries, including Poland, are biased towards gaining control over this pathological phenomenon by placing the subsequent substances on the list of prohibited agents. However, the resilient chemical and pharmaceutical industry still remains one step ahead by introducing new derivatives of already banned products, practically identical in action. The presented article is an attempt to bring closer the problem of smart drugs in Poland, from the occurrence of this alarming phenomenon, through the spread of sales in shops all over Poland, to a series of changes in the Polish anti-narcotic law, drastic actions of closing the shops throughout the entire country, and transferring the sale of smart drugs to the internet. PMID- 22216804 TI - Chronic obstructive pulmonary disease in farmers and agricultural workers - an overview. AB - Chronic obstructive pulmonary disease (COPD) is a common inflammatory disease of the airways characterized by airflow obstruction that is not fully reversible. It is most often caused by smoking, but other factors including exposure to biological agents can play a significant role in its development. It is one of the leading causes of morbidity and mortality among the adult population worldwide. In Poland, symptoms of chronic impairment of airflow are present in 8.5% of males and 4.9% of females. Livestock farmers have an increased risk of chronic bronchitis, COPD, and reduced forced expiratory volume (FEV1). COPD in farmers working inside confinement buildings is related to organic dust exposure and may become severe. The management of COPD is aimed at improving the patient's quality of life and functional status. Currently, apart from lung transplantation, there is no treatment that would significantly improve lung function and decrease mortality. This led us to the conclusion that we should study the problem further, and cautiously monitor patients to help efforts aimed at the prevention of respiratory diseases among farmers and agricultural workers. PMID- 22216805 TI - Diabetic foot - the need for comprehensive multidisciplinary approach. AB - Diabetes mellitus is considered to be civilization disease development of which is influenced by environmental changes. Diabetic foot (ulceration, infection, gangrene) is one of the most disabling complication of diabetes mellitus. It contributes to the increased mortality and cardiovascular death. It also frequently leads to depression, social exclusion and physical impairment. Risk factors of diabetic foot are as follows: age, race, sex, duration of diabetes, biomechanical factors, level of glycemia, smoking habits. According to international standards diabetic foot can be successfully treated only by the multidisciplinary team which can provide more comprehensive and integrated care as compared to ordinary medical team or single specialist. Multidisciplinary team consists of: diabetologist, shoemaker, orthopedist, psychologist, surgeons both vascular and general, podologists, radiologists, educators, nurses and rehabilitation team. Such coordinated attitude to a patient may be the future solution for any civilization and environment-related disease requiring treatment which cannot be successfully provided by any ordinary medical team. PMID- 22216806 TI - Diabetes and depression: a combination of civilization and life-style diseases is more than simple problem adding - literature review. AB - The article presents a review of current medical and psychological literature published between 2000 - 2010, with the use of the PubMed database, concerning the occurrence of anxiety and depression in diabetic patients, with particular consideration of those affected by complications. Anxiety and fear are the most frequent emotional disorders among diabetic patients. Depression occurs in approximately 30% of patients with diabetes. Both diabetes and depression belong to so called 'life style' or 'civilization diseases'. Numerous studies have confirmed that the course of depression in patients with diabetes is more severe, and the relapses of depression episodes are more frequent. The studies show that diabetic patients experience various types of psychosocial and emotional problems due to which the monitoring of own state of health is not the priority in life. In the process of treatment of both sole diabetes and concomitant anxiety and depression it is important to adjust and motivate patients to apply widely understood therapeutic recommendations. The treatment of depression syndrome in the course of diabetes does not have to lead to improvement in glycaemic control. The following factors influencing the therapeutic eff ect should be mentioned: duration of diabetes, presence of complications, and the eff ect of the drugs applied on body weight, or possibly initial diabetes management. It seems, therefore, that the patient education model based on the provision of knowledge concerning diabetes and its complications, methods of treatment, principles of nutrition and health-promoting life style, may be insufficient, at least for patients with depression. The results of a review of reports shows that an optimum treatment of diabetes, in accordance with the current state of knowledge, requires from physicians a special consideration of psychological and psychiatric knowledge for the 2 following reasons: 1) effectiveness of therapy to a high degree depends on the proper behaviour of a patient; 2) considerably more frequent, compared to the total population, occurrence of the symptoms of emotional disorders negatively affect the course of diabetes. PMID- 22216807 TI - Bioaerosol assessment in naturally ventilated historical library building with restricted personnel access. AB - The aim of this study was to check the degree and identify the sources of microbial contamination of the Jasna Gora (Bright Hill) monastery library 10 years after disinfection of the incunabula collection. The registered maximum viable indoor microbial concentrations were 1,875 and 7,100 cfu/m3 for stationary and personal measurements, whereas respective total concentrations were 71,000 and 100,000 counts/m3. There was no statistically significant difference between the concentrations of viable microorganisms measured in the stationary using Andersen, GSP, and Button samplers. Moreover, GSP and Button samplers can be interchangeably applied when viable or total microbial levels are stationary or personally measured. The culturable microorganisms constituted 0.5 - 3.9% of the total microflora only. Filamentous fungi were the most prevalent outdoors, whereas Gram-positive cocci and endospore forming Gram-positive rods dominated indoors in the air and settled dust, respectively. Hence, an unrestrained infiltration of ambient air through the draughtiness of the building envelope is probably the main process responsible for indoor fungal pollution, whereas bacterial contaminants have their major sources in the indoor environment. Moreover, even a chemically cleansed library collection, having a restricted personnel access, but under the influence of ambient air, can undergo microbial contamination and becomes an important microbial emission source. PMID- 22216808 TI - Co-existence of Legionella and other Gram-negative bacteria in potable water from various rural and urban sources. AB - A total of 320 potable water samples were collected from various rural and urban sources located in the Lublin region of eastern Poland. They comprised: 55 samples of treated (chlorinated) tap water from rural dwellings distributed by the municipal water supply system (MWSS), 111 samples of treated tap water from urban dwellings distributed by the MWSS, 45 samples of untreated well water from household wells and 109 samples from private water supply systems (PWSS) distributing untreated well water. Water samples were examined for the presence and species composition of Legionella, Yersinia, Gram-negative bacteria belonging to family Enterobacteriaceae (GNB-E) and Gram-negative bacteria not belonging to the family Enterobacteriaceae (GNB-NE), by filtering through cellulose filters and culture on respectively GVPC, CIN, EMB and tryptic soya agar media. The occurrence of Legionella in the samples taken from the outlets of the urban MWSS was high (77.5%), and significantly greater compared to frequencies noted in rural MWSS (7.3%), and samples of well water from household wells (28.9%) and PWSS (13.8%) (p<0.001). Strains L. pneumophila serogroups 2-14, L. pneumophila serogroup 1 and Legionella spp. (species other than L. pneumophila) formed respectively 64.3%, 17.5%, and 18.2% of total isolates from urban MWSS, 100%, 0, and 0 of those from rural MWSS, 69.2%, 7.7%, and 23.1% of those from household wells, and 66.7%, 0, and 33.3% of those from PWSS. The concentration of Legionella strains in the positive samples from urban MWSS exceeded the threshold limit value of 100 cfu/100 ml in 86.1%, while in the other sources this value was not exceeded. No Yersinia strains were isolated from the examined water samples. Altogether 8 species or genera of Gram-negative bacteria belonging to Enterobacteriaceae family (GNB-E) and 10 species or genera of Gram-negative bacteria not belonging to the Enterobacteriaceae family (GNB-NE) were found in the examined samples. In the MWSS samples, an inverse relationship was found between Legionella and GNB-E and the numbers of Enterobacter spp. and Serratia spp. strains were significantly more common in the samples without Legionella. By contrast, in the PWSS samples, the numbers of Enterobacter spp., Klebsiella spp. and Salmonella spp. were distinctly and significantly greater (p<0.01-p<0.001) in the samples containing Legionella. Among GNB-NE, Pseudomonas aeruginosa strains occurred significantly more frequently in samples containing Legionella (for MWSS and well water separately p<0.05, for total samples p<0.001). Similarly, strains of Flavobacterium breve and Xanthomonas spp. occurred significantly more often in the samples with Legionella, while the numbers of Aeromonas spp. and Vibrio spp. strains were significantly greater in the samples not containing Legionella. In conclusion, a health risk could be associated with exposure to the water from urban MWSS because of the high prevalence and concentration of Legionella, and with exposure to well water from PWSS because of the correlation of occurrence of Legionella and potentially pathogenic Enterobacteriaceae strains, and the possibility of synergistic eff ects. The adverse eff ects could be also due to the significant correlation of Legionella and Pseudomonas aeruginosa that occured in water from various sources. PMID- 22216809 TI - Preliminary assessment of usefulness of cELISA test for screening pig and cattle populations for presence of antibodies against Toxoplasma gondii. AB - Serology testing is an appropriate method for the detection of slaughter animals infected with Toxoplasma, which remain one of the main reservoirs of this parasite in the environment. Competitive ELISA (cELISA) in indirect modification was worked out and optimized for detecting antibodies to Toxoplasma gondii in pigs and cattle. Preliminary validation process showed that the sensitivity and specificity of cELISA obtained in pigs was better than in cattle (88.1% and 94.5% vs. 76.9% and 93.4%, respectively). Sera of 861 pigs and 865 cattle were examined with newly worked out cELISA test and modified agglutination test (MAT) (Toxo Screen DA, bioMerieux, France). In the total of 1,726 examined animal sera, seropositive results were obtained in 15.0% by cELISA (15.4% in pigs and 14.6% in catttle), and in 13.6% by MAT (14.3% in pigs and 12.8% in cattle). Significant differences in percentages of positive results among populations of the studied animals from various areas of Poland were noted. Obtained results showed the usefulness of cELISA for examining sera of slaughter animals (especially pigs). The considerable rates of infection of slaughter animals with T. gondii in the area of research indicate a potential threat to human health. PMID- 22216810 TI - Abundance and seasonal activity of adult Dermacentor reticulatus (Acari: Amblyommidae) in eastern Poland in relation to meteorological conditions and the photoperiod. AB - Investigations of the abundance and seasonal activity of adult D. reticulatus in relation to the eff ect of climatic conditions (temperature, humidity) and the photoperiod on host-seeking behaviour were conducted in eastern Poland (51 degrees 25'N) in 1999-2000. D. reticulatus host-seeking activity was observed between the end of March at 5 degrees C temperature and 89% humidity, and the beginning of December at 6 degrees C temperature and 92% humidity. The peak autumn activity found between September - November was more than 2-fold higher than the spring peak, which occurred between April - May. The activity of females, males, and the total number of adult ticks was correlated with the temperature (p<0.01) and photoperiod (p<0.01); additionally, no dependency was found between adult tick activity and humidity of the environment (p>0.05). Females predominated throughout almost the entire activity period, but the ratios between females and males varied in the particular seasons. Males predominated only after the activity of adult ticks ceased between June - second decade of August, which was related to the reproductive processes. The investigations demonstrated that the activity dynamics in D. reticulatus from eastern Poland is similar to that in the southern European population, but different from that in the north-eastern Polish, Russian and West European populations. This indicates a need to monitor the threats of diseases transmitted by D. reticulatus within different regions of its range of geographic distribution. PMID- 22216811 TI - Selected environmental aspects of the introduction into the polish market of exotic wood species on the example of caviuna (Machaerium scleroxylon Tul.). AB - The chemical and elemental composition of caviuna wood was determined. The elemental composition of the examined wood was similar to the elemental composition of the deciduous tree species of the temperate zone except that it did not contain sulphur. The examined wood was found to comprise a very high content of extractive substances which could contain toxic substances, as well as a considerably higher proportion than in other palisander species mineral compounds determining tool dulling. Numerous cases of diseases were recorded among people who came into contact with the examined wood. An elevated level of eosinophils was found in these people. It was confirmed that Caviuna wood, following its introduction into the trade turnover of exotic wood species, posed many threats in the working environment. PMID- 22216812 TI - Conditioning of participation of disabled males and females from eastern regions of Poland in tourism and recreation. AB - Disability is a serious social, cultural and economic problem, the solving of which requires both legal regulations and coordinated activities by the State. A constantly increasing number of the disabled is an important premise for undertaking actions aimed at complex rehabilitation of this population group, and their engagement in social and economic life. Creating possibilities for spending free time in an attractive way, in accordance with ones interests and needs, is an essential area of rehabilitation activities. In 2005, the Institute of Tourism and Recreation at the State Higher Vocational School in Bial Podlaska launched representative, complex studies concerning the social conditioning of involvement of the disabled from the regions of Eastern Poland in tourism and mobile recreation. The presented material is an excerpt from this study report. It concerns barriers which limit or make it impossible for disabled males and females to participate in tourism and mobile recreation in the regions of Lublin, Rzeszow, and Bialstok. Among barriers, which to the highest degree limit the participation of the disabled in tourism and recreation, the respondents indicated their poor material standard. Other important barriers were inconveniences associated with transport, lack of up-to-date information, and type of disability. The barriers limiting motor activity were also analyzed according to gender. Statistically significant differences were observed between males and females with respect to the following characteristics: transport, lack of adequate information, lack of off er of activities, and lack of assistance. It is noteworthy that males more strongly than females emphasized such barriers as lack of information, off er of assistance, while females indicated the problems with transport. PMID- 22216813 TI - Application of the hypothesis of Developmental Origin of Health and Diseases (DOHaD) in epidemiological studies of women at reproductive age and pregnant women in Poland. AB - Epidemiological population studies indicate that the nutrition of women at reproductive age and during pregnancy exerts an eff ect not only on the term of delivery, development of the foetus and birth weight, but also on the susceptibility of off spring to civilization diseases in adulthood, according to the hypothesis of Developmental Origin of Heath and Diseases (DOHaD). The author analyses the results of epidemiological studies conducted in 2011 in a randomly selected representative population of 6,000 Polish adolescents aged 14-24 (of the total of adolescents, a population of females was selected for analysis), and the results of foetal period health monitoring of mother and child (PRAMS) which has been conducted in Poland since 2009 in the population of mothers and their newborn babies staying after delivery in all hospitals in Poland. Analysis of these two population studies indicates that a high percentage of Polish women at reproductive age are dieting. At the same time, confirmation of the fact of becoming pregnant occurs between weeks 5-8 after conception. This shows that until that time, the foetuses of women on the Apple weight loss diet develop conditions of nutritional deficits which, according to the DOHaD hypothesis, may result in epigenetic changes which increase the susceptibility of off spring in adulthood to civilization diseases: cardiovascular disorders, type 2 diabetes or metabolic syndrome. This hypothesis is confirmed by the high percentages of newborns in Poland born with low birth weight or prematurely born, as well as the fact that the percentage of anemia in pregnant Polish women is twice as high as in other developed countries. Simultaneously, a large number of babies are born with excessive birth weight (macrosomia). The author considers that in the countries of East-Central Europe the phenomenon observed is characteristic at present of the developing countries of the Third World, called the 'double burden of malnutrition'. This situation creates risk of the occurrence of an epidemics of civilization diseases in our part of Europe of a greater intensity than in other developed countries. The author postulates that the educational actions in the area of health promotion in the control of overweight and obesity should be differentiated according to gender and age. The activities to-date in the field of overweight and obesity control in Poland has led to an increase in the number of girls and young women suffering from nutritional disorders as a result of too drastic methods of losing weight. According to the DOHaD hypothesis applied, this may have tragic results for their off spring and for future generations. PMID- 22216814 TI - Physical activity among women at reproductive age and during pregnancy (Youth Behavioural Polish Survey - YBPS and Pregnancy-related Assessment Monitoring Survay - PrAMS) - epidemiological population studies in Poland during the period 2010-2011. AB - Physical activity is among the basic human needs and is the key precondition for the maintenance and enhancement of health throughout all periods of life. Physical inactivity is now identified as the fourth leading risk factor for global mortality. Physical inactivity levels are rising in many countries, with major implications for the prevalence of non-communicable diseases and the general health of the population worldwide. An adequate level of physical activity among young women at reproductive age is especially important because it is one of the preconditions affecting their capability for procreation which, to a great extent, aff ects their activity during pregnancy and conditions the course of pregnancy and labour. Unfortunately, many scientific reports indicate a decrease in physical activity among adolescents, especially girls. The primary cause of this alarming phenomenon are changes in behaviours, including an increasingly greater amount of time devoted to so-called sedentary activities. Such negative health behaviours of women may have negative health eff ects on the functioning of their organism and, in the future, on the development of their off spring. The objective of the presented study was analysis of the level of physical activity among women at reproductive age (prior to conception), and pregnant women in Poland. The study group covered 3,940 women, (730 girls aged up to 15, and 3,210 women aged over 15), and 6,252 pregnant women. The survey was conducted among schoolchildren and students during the last quarter of 2011, while the survey among pregnant women was carried out twice: in the second quarter of 2010, and in the third quarter of 2011. The results of the study revealed a relatively low level of physical activity among young women and pregnant women. The analysis showed an alarming downward tendency in the physical activity of women related to age. Such a decrease in physical activity among girls already during the period of puberty may be of key importance during the period of maturity, especially when they become pregnant. It is highly recommended, therefore, that effective actions should be taken in the area of public health; this would enhance the social awareness, especially among females, concerning the importance of physical activity for the normal development of the organism and an adequate course of pregnancy and labour. PMID- 22216815 TI - Universal screening as a recommendation for thyroid tests in pregnant women. AB - According to recent recommendations, thyroid tests in pregnancy should be performed only in women in risk groups. However, detailed studies indicate that such an approach results in missing hypothyroidism in 30% and hyperthyroidism in 69% of pregnant women. The aim of this study was to compare the effectiveness of diagnosing hypothyroidism in pregnant women by applying universal screening tests, and assessing risk factors. The study was carried out on 270 non-selected women in single pregnancy who underwent screening for hypothyroidism (diagnostic criteria: TSH >2.5 mIU/L) during their fi rst prenatal visit between the 6th - 10th week of gestation. After excluding the patients with pre-gestational hypothyroidism, risk factors for this disorder were assessed in the remaining subjects. A group of 28 patients (10.4% of all subjects) with hypothyroidism was selected for further thyroid tests, while the remaining 242 pregnant women (TSH <2.5 mIU/L) aged 26.3+/-3.59 formed the control group. Twenty subjects (71.4%) were thyroid antibodies-positive, while 8 patients were thyroid antibodies negative. When analyzing hypothyroidism risk factors, one was found in 10 subjects (35.7%), 2 in 5 subjects (17.8%), whereas, in 13 subjects (46.4%) none were present. Symptoms suggesting thyroid dysfunction were discovered in 8 patients (53.3%), goitre in 5 patients (33.3%), another 5 patients (33.3%) had a positive gynaecological history, and only 2 patients had a positive family history of autoimmune thyroid diseases. During the analysis, it was found that TSH positively correlated with the age of the subjects. In the whole study group, a significant correlation was found between log TSH and hypothyroidism risk factors. Hypothyroidism (TSH >2.5 mlU/L) was diagnosed in 10.4% of the patients. The primary cause of this pathology was thyroiditis which was diagnosed in 71.4% of the subjects. Hypothyroidism risk factors were present in 53.6% of the patients, while in 46.4% there were none, which indicates the necessity of carrying out screening tests in all pregnant women as a method of choice, regardless of the presence of thyroid disease risk factors. A positive correlation between the frequency of thyroid diseases risk factors, TSH, and the age of the patients in the presented study serves as an additional argument for the necessity of universal screening. PMID- 22216816 TI - Haematological parameters in postpartum women and their babies in Poland - comparison of urban and rural areas. AB - Anaemia is a serious health problem in the contemporary world which aff ects 24.8% of the total human population. It is especially frequent among pregnant women and children. Anaemia is considered as a risk factor of an unfavourable outcome of pregnancy. More than a half of the cases of anaemia, especially among pregnant women, are caused by iron deficiency. The prevalence of anaemia worldwide is especially high among the rural population. It is estimated that the incidence of anaemia after delivery is 4-27%. Anaemia occurring in pregnant women is the cause of anaemia in newborns after birth. The objective of the study was analysis of the haematological parameters of postpartum women and newborns, with particular consideration of the comparison between urban and rural areas. The studies were conducted with the use of questionnaire forms based on the project undertaken in the USA: Pregnancy Risk Assessment Monitoring System (PRAMS). The survey was carried out on a single day, during the period 9-13 August 2010, in all hospitals in Poland where mothers were hospitalized with their newborns. The presented study was based on the replies concerning the results of whole blood count tests in mothers and their babies. The results of the study did not confirm any significant differences between Hct, Hb and RBC values between urban and rural mothers. In both cases, the Hct levels were at the lower limit of normal. Also, no differences with respect to the above-mentioned values were noted among the newborns, although the babies of urban mothers had a higher Hb level. The results of the studies indicate the lack of differences in the health of mothers and their newborn babies with respect to the urban or rural place of residence. Despite this, anaemia is associated with complications which are life-threatening for the mother and the baby; therefore, efforts should be undertaken in order to minimize this problem. PMID- 22216818 TI - Eating habits of children and adolescents from rural regions depending on gender, education, and economic status of parents. AB - The proper lifestyle of a child, including proper eating habits, should be monitored to ensure proper physical and psychological development. This applies particularly to rural areas which are economically, socially and educationally backward. The study included 1,341 rural schoolchildren and adolescents aged 9-13 years (734 females, 607 males). The representative survey research was conducted in 2008, making use of an original survey questionnaire. The results showed that the majority of respondents eat improperly. 83.2% of them have regular breakfast, and 62.6% have regular light lunch. Most respondents do not eat more than 4 meals a day (usually 3-4). It is worrying that the consumption of sweets is high (34.9% of the surveyed group eat them regularly), whereas fruit and vegetable consumption is low. In this study, relationships between types of diet and such descriptive variables as gender, parents' educational status, and economic situation of the households are described. In families where the parents have a higher education and the household situation is good, the eating habits are much better. The list of poor dietary habits of pupils from rural schools includes skipping breakfast and/or light lunch, high consumption of sweets and low consumption of fruit and vegetables. There are correlations between improper dietary habits and gender of the children and adolescents, educational status of parents, economic situation of households, and housing conditions. PMID- 22216817 TI - Child labour for the benefit of the family in rural Poland. AB - Employing children to work in a family household or on a farm is a widespread phenomena in many countries worldwide. This paper presents the results of an investigation of the phenomenon of the involvement of children aged 11-14 years in work on family farms and in rural households in central and eastern Poland, a typical agricultural region. The data obtained are characterized by high reliability due to utilization of various research techniques: surveys and observations based on records of daily routines. Material collected by questionnaire survey is significant because of the relatively large group of respondents - 1,536 people, selected by stratified sampling. Records of the daily routines of 332 people randomly selected from the general sample of 1,536 people, were conducted over a total period of 2 months through all the seasons - 2 weeks in each season - provided reliable data. Analysis of the collected material allowed characterization of the phenomenon of children's engagement in the work in a family household and on a farm belonging to their parents or relatives, and an indication of the life and health hazards of children involved in work for a benefit of the family. PMID- 22216819 TI - Estimation of physical activity and prevalence of excessive body mass in rural and urban Polish adolescents. AB - Excessive body mass and sedentary lifestyle are well-known factors for cardiovascular risk, which when present in the young population may have significant health consequences, both in the short- and long-term. The aim of the study was to evaluate the prevalence of overweight, obesity, and sedentary lifestyle in two teenage populations living in an urban or rural area. An additional aim was to compare their physical activity. The study was designed and conducted in 2009. The study population consisted of 116 students aged 15-17 years - 61 males (52.7%) and 55 females (47.3%), randomly selected from public junior grammar schools and secondary schools in the Poznan Region. There were 61 respondents from a rural area - 32 males (52.5%) and 29 females (47.5%), whereas 55 teenagers lived in an urban area - 29 males (47.5%) and 26 females (47.3%). Students were asked to complete a questionnaire, which was especially prepared for the study and contained questions concerning health and lifestyle. A basic physical examination was carried out in all 116 students, including measurements of the anthropometric features. Calculations were performed using the statistical package STATISTICA (data analysis software system), Version. 8.0. When comparing these two populations, no statistically significant differences were detected in the ratio of weight-growth, with the exception of the fact that the urban youths had a larger hip circumference (97.1 v. 94.3 cm, p<0.05). In the group of urban students there were also significantly more subjects with excessive body weight (27.3% v. 24.6%, p<0.05), with a predominant proportion of obese students (60%). There were significantly more male obese individuals (66.7%). In the population of rural teenagers, obesity rate did not differ statistically significantly from the percentage of overweight (11.5% v. 13.1%, p>0.05), the problem of excessive weight affected both sexes in a similar proportion (25% boys and 24.1% girls, p>0.05). In this paper it is shown that there were differences concerning physical activity of teenagers living in urban and rural areas. Urban students much more often declared an active lifestyle (72.7% v.42.6%, p<0.05), used a variety of additional forms of activity (not counting compulsory physical education classes). PMID- 22216820 TI - Engagement in risky behaviours by 15-19-year-olds from Polish urban and rural areas. AB - INTRODUCTION: Anti-health behaviours pose a threat to the health status of the adolescent population in Poland. Among other things, the use and abuse of tobacco, alcohol and psychoactive substances are very dangerous as they may give rise to further health inequalities in young people. The aim of the research was to compare scopes of anti-health behaviours of adolescents in rural and urban areas in Poland. MATERIAL AND METHODS: The study consisted of 1,580 adolescents (aged 15-19 years) - 596 from urban areas and 984 from rural areas of the Zachodniopomorskie Province in Poland. RESULTS: 25.61% of 15-19-year-old city dwellers and 30.57% of their rural peers are active tobacco smokers. The smoking habit is more popular among female adolescents than among their male peers. 4.64% of rural 15-19-year-olds, and 4.52% of their city peers, are addicted to narcotics, 11.16% of the surveyed rural adolescents and 6.7% of their peers living in urban areas are addicted to alcohol. More than 50% of adolescents drink alcohol occasionally. CONCLUSIONS: A significant number of young people in both rural and urban areas are engaged in risky health behaviours. The frequency of such behaviours depends on the age, gender and place of residence. These disproportions may contribute to future health inequalities in rural and urban areas. PMID- 22216821 TI - Differences in deformity and bracing-related stress between rural and urban area patients with adolescent idiopathic scoliosis treated with a Cheneau brace. AB - The aim of the study was to compare the difference in stress levels between adolescent female groups of patients from urban and rural areas who were treated conservatively with an idiopathic scoliosis. The study comprised 2 groups of patients, 34 from an urban and 30 from a rural area, with a minimum application of a Cheneau brace for 12 hours a day, for a minimum of 1 month. Two study groups completed the Polish version of both Bad Sobernheim Stress Questionnaire Deformity and Bad Sobernheim Stress Questionnaire-Brace. Both groups of patients felt moderate stress connected with conservative treatment and low stress related to trunk deformation. No difference was observed in stress level related to body disfigurement and conservative treatment between the 2 groups of patients. In the rural group of patients, a correlation between the apical translation and stress related to deformity was observed. No significant differences were stated in stress levels and coping mechanisms between patients from rural and urban areas, treated conservatively due to idiopathic scoliosis. A difference was observed, however, regarding the correlation connected with the apical translation and stress level. PMID- 22216822 TI - Smoking and the level of nicotine addiction in relation to the state of hard dental tissues in young adults. AB - Nowadays, smoking is considered to be one of the unhealthiest human behaviours. The aim of this study was to evaluate the potential influence of smoking, as well as the degree of the addiction, on the health status of hard dental tissues in young adults. The study involved 148 randomly selected young adults. Mean age of the study subjects was 20 years +/- 4 months. Questionnaire survey (6-grade Fagerstrom Nicotine Tolerance Questionnaire) and clinical examination were performed and the obtained results statistically analyzed. The mean value of 6 grade Fagerstrom Nicotine Tolerance Questionnaire was 2.298 +/- 1.992. Of the studied population, 88.06% had no features of biological dependency. Mean DMF and DMFs Indexes were 11.31 +/- 5.06 and 16.91 +/- 10.65, respectively. It was established that in the study population, over 45% of the subjects smoked. However, there was no correlation found between smoking and gender, and no cause eff ect relationship between smoking and hard dental tissues status as defined by DMF, DMFs values and their components. It was observed that in the case of people who began smoking at an earlier age, the degree of nicotine dependency was higher. None of the study subjects demonstrated features of heavy or pharmacological nicotine dependency. PMID- 22216823 TI - Consequences of smoke inhalation in the 'Epidemiology of Allergic Diseases in Poland' project (ECAP). AB - This paper presents a risk assessment of individuals with respiratory allergies who are exposed to active and passive tobacco smoke (environmental tobacco smoke or ETS). Smoking tobacco and ETS is a serious environmental hazard known to be harmful to human health. This analysis is based on the results of the Epidemiology of Allergic Diseases in Poland (ECAP) study, which was conducted from 2006-2008 on a sample of approximately 22,500 respondents in 9 areas of Poland, both urban and rural. Data collection was based on individual interviews and a questionnaire employing Computer Assisted Personal Interviewing technology (CAPI). 46.8% of respondents declared themselves as smokers, defined as those who smoke and have done so for at least one year. In this group, 41.5% of respondents were female and 54.3% were male. While differences between various areas of Poland were demonstrated, they did not necessarily correlate with urbanization. Rural Zamosc reported 41.4% of smokers while metropolitan Poznan had 41.9% of smokers. These statistics can be contrasted against other urban areas such as Katowice and Gdansk, which had 51.8% and 52.3% of smokers, respectively (n = 9376). 29.6% of rural women reported smoking, while this percentage was higher among urban women, ranging from 36.3% in Poznan to 49.5% in Gdansk. However, the highest percentage of smokers was among males in Zamosc at 56.1%. This percentage was higher than the overall average in this study. The largest percentages of active smoking occurred among laborers, craftsmen, miners, drivers, farmers and fishermen, the self-employed and gardeners. This quantitative assessment of the prevalence of smoking underlines the importance of the consequences of this habit as they relate to asthma and respiratory allergies. The findings demonstrate smoking as a serious social problem associated with allergic diseases, and a habit that differs between place of residence and work environment. PMID- 22216824 TI - Quality of life and rural place of residence in Polish women - population based study. AB - OBJECTIVE: The purpose of this population-based study was to analyse the association between the health-related quality of life and rural residence among Polish females, including variables related to social environment and clinical characteristics. METHODS: The snowball recruitment method was used to invite 1,560 women aged 45-60 to participate in the study. Participants received a questionnaire about demographic characteristics, environmental and work stress, use of anxiolytichypnotic medications and self-reported quality of life based on the SF-36 form. Univariate and multivariate analysis was carried out by means of a logistic regression model. RESULTS: We found worse physical health and better mental health among women living in rural areas compared to those from urban settings. The rural residence was an independent predictor for poor physical health (below 25 percentile) odds ratio [OR] 1.6 95%, confidence interval [CI] 1.17-2.2). Living in rural areas was also associated at the borderline level of statistical significance, with reduction of risk of low quality of life in mental health (OR = 0.75; 95% CI = 0.55-1.02). According to other results from multivariate analysis, being retired, receiving social pension, long duration of illness symptoms, and consulting a medical specialist were the risk factors of reported bad physical health. Higher education and access to medical specialist protects against having a bad quality of life related to mental health. Being given the sack, stress at work, feeling anger, and long duration of symptoms are the risk factors of poor mental health. CONCLUSION: The rural residence is strongly associated with environmental and psychosocial factors in women aged 40 65. PMID- 22216825 TI - In vivo investigations of neurotensin receptors in adipocytes, hepatocytes and enterocytes of rat. AB - INTRODUCTION: Atherosclerotic vascular disease is currently the biggest threat and the highest cause of death worldwide, approaching almost 60%.The development of atherosclerosis is affected by ecological factors associated with industry and pollution of the environment. Neurotensin (NT) is a peptide acting via 3 kinds of neurotensin receptors (NTR) localized in target tissues. In several studies, the presence of its receptors has been shown in chicken liver, and the influence of NT on the metabolism of this organ was confirmed (glycogenolysis stimulation through sympathetic nervous system, enterohepatic circulation of bile acids, metabolism of lipoproteins). MATERIALS AND METHODS: Healthy male WISTAR rats weighing 300}30 grams, were used for the experiments. The animals were divided into 4 groups: 1) control group, to which 0.9% NaCl was administrated (i.p.); 2) the second group was given levocabastine 1mg/kg i.p.; 3) the third group received SR 48692 0.4 mg/; 4) the fourth group was given NT analog [D-Trp 11]-neurotensin 15 nM/kg. Plasmatic membranes of liver, small intestine and adipose tissue were prepared according to the method of Havrankova. Analysis of results obtained in the investigation of NT receptors was performed using the Scatchard method from LIGAND-Pc, v. 3.1 software. RESULTS: The investigation of antigenity of I125NT showed proper antigen-antibody reaction. No binding of the I125NT with plasmatic membranes of adipocytes or enterocytes was observed. Unspecific binding of I125NT with 10 MUmol/L of free NT was observed in the plasmatic membranes of hepatocytes. CONCLUSION: The presence of NT receptors only in the membranes of hepatocytes may suggest their role in the regulation of lipid metabolism via receptor - ligand way. PMID- 22216826 TI - The role of age, environmental and occupational factors on semen density. AB - The problem of effect of the environment on human reproduction has been in the focus of researchers' interest for many years. OBJECTIVE: To examine the relationship between semen density in males with reproduction problems, and their age, living and working conditions. MATERIAL AND METHOD: The study covered 224 males with reproduction problems. The study had a prospective character and was conducted in three stages - the first stage was carried out using the questionnaire devised by the authors; the second and the third stages consisted in the examination and evaluation of male semen density. Statistical analysis was used to search for the relationship between these groups and variables adopted in the study, i.e. age, occupation performed, place of residence, self-reported housing conditions and material standard, reporting by the males in the study of arduousness of work or health hazards perceived by the males examined, and duration of employment in such conditions. RESULTS: The males in the study were divided into three groups according to their semen density. Group I (20 * 10(6) mln/ml or more) included 62 (27.7%) respondents, Group II (below 20 * 10(6) mln/ml) covered 121 males (54.0%), while Group III (only single spermatozoa or none) - 41 males (18.3%). Male semen density are significantly correlated with men's ages and jobs as well as the general evaluations of the jobs held by the men (p<0.05). No significant relationship is observed between living conditions, arduous work conditions and occupational hazards as perceived by males, or duration of employment in such conditions, and male semen density (p>0.05). CONCLUSIONS: The results obtained encourage continuation of the studies and cover a larger group of males with reproduction problems. PMID- 22216827 TI - Psychosocial conditioning of depressive disorders in post-menopausal women. AB - Studies confirm that the period prior to, during, and some time after menopause are the times of increase risk of the development of depressive disorders. It is indicated that the level of depression at this stage of a woman's life depends on the time which had elapsed since the onset of menopause and a number of demographic and psychosocial factors. The objective of the study was evaluation of selected psychosocial factors determining the level of depression in postmenopausal women. The study was conducted in 2011, among 364 rural and 382 urban women living in the south-eastern areas of Poland. Women aged 52-60, who had stopped menstruating within the last three years, and had delivered at least one child, were selected for the study. Analysis of the results of the studies shows that the psychosocial situation of Polish women at postmenopausal age varies. Rural postmenopausal women more often had a poorer material standard than urban women, and also had a significantly higher statistically level of depression. The level of depression among rural and urban women in the study differed and was related with education level, family, and occupational situation, as well as the level of satisfaction with social and sex life. The presents study shows that women living in the rural areas are to a greater extent exposed to the occurrence of depressive symptoms. Due to the scale of the phenomenon, at this stage, these women should receive support not only from a psychiatrist, to whom they still too rarely report in Poland, but primarily to a family physician or a gynecologist PMID- 22216829 TI - Acute collective gas poisoning at work in a manure storage tank. AB - Cases of deaths in manure or septic tanks are rare in legal-medical practice, more frequently as unfortunate occupational accidents. Poisoning with toxic gases, especially with hydrogen sulfide, is reported as the cause of death, while the exhaustion of oxygen in the air is omitted with the simultaneous excess of carbon dioxide. In such cases, determination of the direct cause of death constitutes a big problem because post-mortem examination does not reveal the specific changes. A case of acute collective poisoning by gases in a manure storage tank is presented of 5 agricultural workers, 2 of whom died. While explaining the cause of poisoning and deaths, toxicological blood tests were performed in the victims of the accident, as well as gases inside the manure storage tank. The post-mortem examinations and toxicological blood tests performed did not allow determination of the direct cause of death. Toxicological tests of gases from inside the manure tank showed a very low concentration of oxygen, with a simultaneous very high concentration of carbon dioxide, and a considerable level of hydrogen sulfide. The cause of fainting of three and deaths of two workers was not the poisoning with hydrogen sulfide, but oxygen deficiency in the air of the tank. PMID- 22216828 TI - Hantavirus RNA not detected in Ixodes ricinus ticks. AB - A total of 174 unfed Ixodes ricinus ticks (104 nymphs, 36 males, and 34 females) collected in the Roztocze National Park in eastern Poland were examined by the PCR and nested PCR methods for the presence of hantavirus RNA. None of the examined Ixodes ricinus specimens showed the presence of the hantavirus-specific RNA, in spite of using 2 genetic markers and the clearly positive results obtained with the positive control. Thus, a hypothesis about the possible participation of ticks in the transmission of hantaviruses, has so far not been confirmed. PMID- 22216830 TI - Considerations on Directive 98/8 of the European Commission - the biocide directive. AB - Nowadays, versatile human activity requires the development of technologies in the chemical and biological industries that ultimately enable an increase in human activity, and help create the living conditions in the domain of human civilization. Increasing this activity very frequently requires the implementation of new technologies concerning the active elimination of numerous threats and obstacles which are found in the human and natural environment. The concept of so-called biocidal products has been introduced into the European legislation as long as ten years ago, defining them as various types of 'chemical substances or microorganisms which can deter, render harmless, or exert a controlling eff ect on any harmful organism, by chemical or biological means'. They can be added to other materials (typically liquids) to protect them against biological infestation and growth. Biocidal products - due to their specificity, toxicity and composition - create a serious risk for human and animal life and health, as well as for the natural environment, it is therefore fully justified to have legal regulations concerning such biocides. Because biocidal products are intended to kill living organisms, and as such, many biocidal products pose a significant risk to human health and welfare, and have significant adverse eff ects on the natural environment. Great care is required when handling biocides and appropriate protective clothing and equipment should be used. Currently, Directive 98/8/EC is a comprehensive set of legal regulations concerning biocidal products, their specificity, principles relating to their placing on the market, and guidelines for their control. It is worth emphasizing that Directive 98/8/EC implements the clampdown on poisoning cases with biocides, the duty of which was passed to the so-called Centres of Consultation and Toxicological Information. These centres provide round-the-clock (24-hour) medical consultation and assistance in cases of poisonings with these products. The presented study constitutes an in-depth presentation and analysis of the European law concerning biocides and the current regulations applying to them. PMID- 22216831 TI - Genomic design of strong direct-gap optical transition in Si/Ge core/multishell nanowires. AB - Finding a Si-based material with strong optical activity at the band-edge remains a challenge despite decades of research. The interest lies in combining optical and electronic functions on the same wafer, while retaining the extraordinary know-how developed for Si. However, Si is an indirect-gap material. The conservation of crystal momentum mandates that optical activity at the band-edge includes a phonon, on top of an electron-hole pair, and hence photon absorption and emission remain fairly unlikely events requiring optically rather thick samples. A promising avenue to convert Si-based materials to a strong light absorber/emitter is to combine the effects on the band-structure of both nanostructuring and alloying. The number of possible configurations, however, shows a combinatorial explosion. Furthermore, whereas it is possible to readily identify the configurations that are formally direct in the momentum space (due to band-folding) yet do not have a dipole-allowed transition at threshold, the problem becomes not just calculation of band structure but also calculation of absorption strength. Using a combination of a genetic algorithm and a semiempirical pseudopotential Hamiltonian for describing the electronic structures, we have explored hundreds of thousands of possible coaxial core/multishell Si/Ge nanowires with the orientation of [001], [110], and [111], discovering some "magic sequences" of core followed by specific Si/Ge multishells, which can offer both a direct bandgap and a strong oscillator strength. The search has revealed a few simple design principles: (i) the Ge core is superior to the Si core in producing strong bandgap transition; (ii) [001] and [110] orientations have direct bandgap, whereas the [111] orientation does not; (iii) multishell nanowires can allow for greater optical activity by as much as an order of magnitude over plain nanowires; (iv) the main motif of the winning configurations giving direct allowed transitions involves rather thin Si shell embedded within wide Ge shells. We discuss the physical origin of the enhanced optical activity, as well as the effect of possible experimental structural imperfections on optical activity in our candidate core/multishell nanowires. PMID- 22216832 TI - Combining colloidal probe atomic force and reflection interference contrast microscopy to study the compressive mechanics of hyaluronan brushes. AB - We describe a method that combines colloidal probe atomic force microscopy (AFM) and reflection interference contrast microscopy (RICM) to characterize the mechanical properties of thin and solvated polymer films. When analyzing polymer films, a fundamental problem in colloidal probe AFM experiments is to determine the distance at closest approach between the probe and the substrate on which the film is deposited. By combining AFM and RICM in situ, forces and absolute distances can be measured simultaneously. Using the combined setup, we quantify the compressive mechanics of films of the polysaccharide hyaluronan that is end grafted to a supported lipid bilayer. The experimental data, and comparison with polymer theory, show that hyaluronan films are well-described as elastic, very soft and highly solvated polymer brushes. The data on these well-defined films should be a useful reference for the investigation of the more complex hyaluronan rich coats that surround many living cells. PMID- 22216833 TI - Chromosome 15q24 microdeletion syndrome. AB - Chromosome 15q24 microdeletion syndrome is a recently described rare microdeletion syndrome that has been reported in 19 individuals. It is characterized by growth retardation, intellectual disability, and distinct facial features including long face with high anterior hairline, hypertelorism, epicanthal folds, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, small mouth, long smooth philtrum, and full lower lip. Other common findings include skeletal and digital abnormalities, genital abnormalities in males, hypotonia, behavior problems, recurrent infections, and eye problems. Other less frequent findings include hearing loss, growth hormone deficiency, hernias, and obesity. Congenital malformations, while rare, can be severe and include structural brain anomalies, cardiovascular malformations, congenital diaphragmatic hernia, intestinal atresia, imperforate anus, and myelomeningocele. Karyotypes are typically normal, and the deletions were detected in these individuals by array comparative genomic hybridization (aCGH). The deletions range in size from 1.7-6.1 Mb and usually result from nonallelic homologous recombination (NAHR) between paralogous low copy repeats (LCRs). The majority of 15q24 deletions have breakpoints that localize to one of five LCR clusters labeled LCR15q24A, -B, -C, -D, and -E. The smallest region of overlap (SRO) spans a 1.2 Mb region between LCR15q24B to LCR15q24C. There are several candidate genes within the SRO, including CYP11A1, SEMA7A, CPLX3, ARID3B, STRA6, SIN3A and CSK, that may predispose to many of the clinical features observed in individuals with 15q24 deletion syndrome. The deletion occurred as a de novo event in all of the individuals when parents were available for testing. Parental aCGH and/or FISH studies are recommended to provide accurate genetic counseling and guidance regarding prognosis, recurrence risk, and reproductive options. Management involves a multi-disciplinary approach to care with the primary care physician and clinical geneticist playing a crucial role in providing appropriate screening, surveillance, and care for individuals with this syndrome. At the time of diagnosis, individuals should receive baseline echocardiograms, audiologic, ophthalmologic, and developmental assessments. Growth and feeding should be closely monitored. Other specialists that may be involved in the care of individuals with 15q24 deletion syndrome include immunology, endocrine, orthopedics, neurology, and urology. Chromosome 15q24 microdeletion syndrome should be differentiated from other genetic syndromes, particularly velo-cardio-facial syndrome (22q11.2 deletion syndrome), Prader Willi syndrome, and Noonan syndrome. These conditions share some phenotypic similarity to 15q24 deletion syndrome yet have characteristic features specific to each of them that allows the clinician to distinguish between them. Molecular genetic testing and/or aCGH will be able to diagnose these conditions in the majority of individuals. DISEASE NAME AND SYNONYMS: Chromosome 15q24 deletion syndrome. 15q24 deletion syndrome. 15q24 microdeletion syndrome. PMID- 22216834 TI - Linker-based hemisuccinate derivatives of artemisinin: synthesis and antimalarial assessment against multidrug-resistant Plasmodium yoelii nigeriensis in mice. AB - Artesunic acid 5, the hemisuccinate derivative of dihydroartemisinin 2, is the only clinically useful water-soluble derivative of artemisinin 1. However, being a lactol ester, it is rapidly hydrolyzed back to dihydroartemisinin in aqueous alkaline solution, a reaction that seriously limits its utility. A new series of potentially more stable linker-based hemisuccinate derivatives 12a-i and 14a-c have been prepared. The process involved acid-catalyzed reaction of dihydroartemisinin with various diols and polyethylene glycols to give hydroxy functionalized ethers 7a-i and 10a-c and their further derivatization to hemisuccinate esters 12a-i and 14a-c. Both the hydroxy-functionalized ethers 7a-i and 10a-c and their hemisuccinate derivatives 12a-i and 14a-c have been assessed for antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice. Several of these hemisuccinate derivatives have shown very promising activity. Hemisuccinate derivatives 12f and 12i, the two most active compounds of the series, provided 100% protection to malaria-infected mice at 24 mg/kg * 4 days and therefore are twice as potent as artesunic acid, which provides a similar level of protection at 48 mg/kg * 4 days. PMID- 22216835 TI - A novel PbS hierarchical superstructure guided by the balance between thermodynamic and kinetic control via a single-source precursor route. AB - In this work, a novel lead sulfide (PbS) hierarchical superstructure, denoted as octapodal dendrites with a cubic center, has been synthesized employing a simple single-source precursor route. Our experimental results demonstrate that the novel hierarchical superstructure was generated through the delicate balance between the kinetic growth and thermodynamic growth regimes. Moreover, the morphology of PbS crystals can be controlled by adjusting the solvent under a thermodynamically or kinetically controlled growth regime. It is highly expected that these findings will be useful in understanding the formation of PbS nanocrystals with different morphologies, which are also applicable to other face centered cubic nanocrystals. PMID- 22216837 TI - Systematic review: conservative treatments for secondary lymphedema. AB - BACKGROUND: Several conservative (i.e., nonpharmacologic, nonsurgical) treatments exist for secondary lymphedema. The optimal treatment is unknown. We examined the effectiveness of conservative treatments for secondary lymphedema, as well as harms related to these treatments. METHODS: We searched MEDLINE(r), EMBASE(r), Cochrane Central Register of Controlled Trials(r), AMED, and CINAHL from 1990 to January 19, 2010. We obtained English- and non-English-language randomized controlled trials or observational studies (with comparison groups) that reported primary effectiveness data on conservative treatments for secondary lymphedema. For English-language studies, we extracted data in tabular form and summarized the tables descriptively. For non-English-language studies, we summarized the results descriptively and discussed similarities with the English-language studies. RESULTS: Thirty-six English-language and eight non-English-language studies were included in the review. Most of these studies involved upper-limb lymphedema secondary to breast cancer. Despite lymphedema's chronicity, lengths of follow-up in most studies were under 6 months. Many trial reports contained inadequate descriptions of randomization, blinding, and methods to assess harms. Most observational studies did not control for confounding. Many studies showed that active treatments reduced the size of lymphatic limbs, although extensive between-study heterogeneity in areas such as treatment comparisons and protocols, and outcome measures, prevented us from assessing whether any one treatment was superior. This heterogeneity also precluded us from statistically pooling results. Harms were rare (< 1% incidence) and mostly minor (e.g., headache, arm pain). CONCLUSIONS: The literature contains no evidence to suggest the most effective treatment for secondary lymphedema. Harms are few and unlikely to cause major clinical problems. PMID- 22216839 TI - A reader's guide to 200 years of the New England Journal of Medicine. PMID- 22216838 TI - Bench-to-bedside review: Damage-associated molecular patterns in the onset of ventilator-induced lung injury. AB - Mechanical ventilation (MV) has the potential to worsen pre-existing lung injury or even to initiate lung injury. Moreover, it is thought that injurious MV contributes to the overwhelming inflammatory response seen in patients with acute lung injury or acute respiratory distress syndrome. Ventilator-induced lung injury (VILI) is characterized by increased endothelial and epithelial permeability and pulmonary inflammation, in which the innate immune system plays a key role. A growing body of evidence indicates that endogenous danger molecules, also termed damage-associated molecular patterns (DAMPs), are released upon tissue injury and modulate the inflammatory response. DAMPs activate pattern recognition receptors, may induce the release of proinflammatory cytokines and chemokines, and have been shown to initiate or propagate inflammation in non infectious conditions. Experimental and clinical studies demonstrate the presence of DAMPs in bronchoalveolar lavage fluid in patients with VILI and the upregulation of pattern recognition receptors in lung tissue by MV. The objective of the present article is to review research in the area of DAMPs, their recognition by the innate immune system, their role in VILI, and the potential utility of blocking DAMP signaling pathways to reduce VILI in the critically ill. PMID- 22216840 TI - Efficacy results of a trial of a herpes simplex vaccine. AB - BACKGROUND: Two previous studies of a herpes simplex virus type 2 (HSV-2) subunit vaccine containing glycoprotein D in HSV-discordant couples revealed 73% and 74% efficacy against genital disease in women who were negative for both HSV type 1 (HSV-1) and HSV-2 antibodies. Efficacy was not observed in men or HSV-1 seropositive women. METHODS: We conducted a randomized, double-blind efficacy field trial involving 8323 women 18 to 30 years of age who were negative for antibodies to HSV-1 and HSV-2. At months 0, 1, and 6, some subjects received the investigational vaccine, consisting of 20 MUg of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant; control subjects received the hepatitis A vaccine, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units. The primary end point was occurrence of genital herpes disease due to either HSV-1 or HSV-2 from month 2 (1 month after dose 2) through month 20. RESULTS: The HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], -29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (-8%; 95% CI, -59 to 26). CONCLUSIONS: In a study population that was representative of the general population of HSV-1- and HSV-2-seronegative women, the investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection. (Funded by the National Institute of Allergy and Infectious Diseases and GlaxoSmithKline; ClinicalTrials.gov number, NCT00057330.). PMID- 22216841 TI - TFAP2E-DKK4 and chemoresistance in colorectal cancer. AB - BACKGROUND: Chemotherapy for advanced colorectal cancer leads to improved survival; however, predictors of response to systemic treatment are not available. Genomic and epigenetic alterations of the gene encoding transcription factor AP-2 epsilon (TFAP2E) are common in human cancers. The gene encoding dickkopf homolog 4 protein (DKK4) is a potential downstream target of TFAP2E and has been implicated in chemotherapy resistance. We aimed to further evaluate the role of TFAP2E and DKK4 as predictors of the response of colorectal cancer to chemotherapy. METHODS: We analyzed the expression, methylation, and function of TFAP2E in colorectal-cancer cell lines in vitro and in patients with colorectal cancer. We examined an initial cohort of 74 patients, followed by four cohorts of patients (total, 220) undergoing chemotherapy or chemoradiation. RESULTS: TFAP2E was hypermethylated in 38 of 74 patients (51%) in the initial cohort. Hypermethylation was associated with decreased expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines. Colorectal-cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin. In the four other patient cohorts, TFAP2E hypermethylation was significantly associated with nonresponse to chemotherapy (P<0.001). Conversely, the probability of response among patients with hypomethylation was approximately six times that in the entire population (overall estimated risk ratio, 5.74; 95% confidence interval, 3.36 to 9.79). Epigenetic alterations of TFAP2E were independent of mutations in key regulatory cancer genes, microsatellite instability, and other genes that affect fluorouracil metabolism. CONCLUSIONS: TFAP2E hypermethylation is associated with clinical nonresponsiveness to chemotherapy in colorectal cancer. Functional assays confirm that TFAP2E-dependent resistance is mediated through DKK4. In patients who have colorectal cancer with TFAP2E hypermethylation, targeting of DKK4 may be an option to overcome TFAP2E-mediated drug resistance. (Funded by Deutsche Forschungsgemeinschaft and others.). PMID- 22216842 TI - A tale of coronary artery disease and myocardial infarction. PMID- 22216843 TI - Genomics and perinatal care. PMID- 22216844 TI - Images in clinical medicine. Lung herniation after cough-induced rupture of intercostal muscle. PMID- 22216845 TI - Clinical problem-solving. Breathless. PMID- 22216846 TI - NEJM@200--two centuries at the Journal. PMID- 22216849 TI - Apixaban versus warfarin in atrial fibrillation. PMID- 22216850 TI - Apixaban versus warfarin in atrial fibrillation. PMID- 22216852 TI - Oral acyclovir suppression after neonatal herpes. PMID- 22216854 TI - Treatment of neonatal sepsis with immune globulin. PMID- 22216856 TI - Hepatocellular carcinoma. PMID- 22216857 TI - Hepatocellular carcinoma. PMID- 22216859 TI - Case 26-2011: A boy with a complex kidney cyst. PMID- 22216860 TI - Case 26-2011: A boy with a complex kidney cyst. PMID- 22216861 TI - TET2 and DNMT3A mutations in human T-cell lymphoma. PMID- 22216862 TI - Images in clinical medicine. Madura foot. PMID- 22216863 TI - Timeline: 200 years of the New England Journal of Medicine. PMID- 22216865 TI - Constructing logical models of gene regulatory networks by integrating transcription factor-DNA interactions with expression data: an entropy-based approach. AB - Models of gene regulatory networks (GRNs) attempt to explain the complex processes that determine cells' behavior, such as differentiation, metabolism, and the cell cycle. The advent of high-throughput data generation technologies has allowed researchers to fit theoretical models to experimental data on gene expression profiles. GRNs are often represented using logical models. These models require that real-valued measurements be converted to discrete levels, such as on/off, but the discretization often introduces inconsistencies into the data. Dimitrova et al. posed the problem of efficiently finding a parsimonious resolution of the introduced inconsistencies. We show that reconstruction of a logical GRN that minimizes the errors is NP-complete, so that an efficient exact algorithm for the problem is not likely to exist. We present a probabilistic formulation of the problem that circumvents discretization of expression data. We phrase the problem of error reduction as a minimum entropy problem, develop a heuristic algorithm for it, and evaluate its performance on mouse embryonic stem cell data. The constructed model displays high consistency with prior biological knowledge. Despite the oversimplification of a discrete model, we show that it is superior to raw experimental measurements and demonstrates a highly significant level of identical regulatory logic among co-regulated genes. A software implementing the method is freely available at: http://acgt.cs.tau.ac.il/modent. PMID- 22216867 TI - Impact of migration on explanatory models of illness and addiction severity in patients with drug dependence in a Paris suburb. AB - Objectives of this study were to assess explanatory models (considering illness experience and meaning), addiction severity among patients with drug dependence, and the role of migration. Adapted Explanatory Model Interview Catalogue interviews were conducted with 70 outpatients in a Paris suburb. Among them, 42 were either first- or second-generation immigrants, most from North Africa. Explanatory models were analyzed qualitatively and quantitatively according to migration status, assessing potential confounders with multivariate linear models. Explanatory models were heterogeneous. Compared with nonmigrants, migrants reported fewer somatic and violence-related symptoms. They attributed the causes of their addiction more frequently to social and magico-religious factors and less to psychological factors. Conversely, no difference in addiction severity was found between migrants and nonmigrants. Considering local patterns of illness experience and meaning of drug dependence is a critical component of culturally sensitive clinical care. PMID- 22216869 TI - Toward a business case for performance improvement. PMID- 22216870 TI - Physician prescribing behavior and its impact on patient-level outcomes. AB - OBJECTIVES: Concerns over rising drug costs, pharmaceutical advertising, and potential conflicts of interest have focused attention on physician prescribing behavior. We examine how broadly physicians prescribe within the 10 most prevalent therapeutic classes, the factors affecting their choices, and the impact of their prescribing behavior on patient-level outcomes. STUDY DESIGN: Retrospective study from 2005 to 2007 examining prescribers with at least 5 initial prescriptions within a class from 2005 to 2007. Medical and pharmacy claims are linked to prescriber information from 146 different health plans, reflecting 1975 to 8923 unique providers per drug class. METHODS: Primary outcomes are the number of distinct drugs in a class initially prescribed by a physician over 1- and 3-year periods, medication possession ratio, and out-of pocket costs. RESULTS: In 8 of 10 therapeutic classes, the median physician prescribes at least 3 different drugs and fewer than 1 in 6 physicians prescribe only brand drugs. Physicians prescribing only 1 or 2 drugs in a class are more likely to prescribe the most advertised drug. Physicians who prescribe fewer drugs are less likely to see patients with other comorbid conditions and varied formulary designs. Prescribing fewer drugs is associated with lower rates of medication adherence and higher out-ofpocket costs for drugs, but the effects are small and inconsistent across classes. CONCLUSIONS: Physicians prescribe more broadly than commonly perceived. Though narrow prescribers are more likely to prescribe highly advertised drugs, few physicians prescribe these drugs exclusively. Narrow prescribing has modest effects on medication adherence and out-of-pocket costs in some classes. PMID- 22216871 TI - Self-reported health and functional status information improves prediction of inpatient admissions and costs. AB - OBJECTIVES: To determine whether adding selfreported health and functional status data to a diagnostic risk-score model explains additional variance in predicting inpatient admissions and costs. STUDY DESIGN: Retrospective observational analysis. METHODS: We used data from a Health Status Questionnaire (HSQ), completed by 6407 Kaiser Permanente Northwest Medicare patients between December 2006 and October 2008. We used answers from 3 items on the HSQ: (1) General Self rated Health score, (2) needing help with 1 or more activities of daily living, and (3) having a bothersome health condition. We calculated a DxCG relative risk score from utilization information in the year prior to the survey, using electronic medical records. We compared: (1) DxCG as the sole independent variable and (2) DxCG plus the 3 items as independent variables. We estimated area under the curve (AUC) for each model. Any inpatient admission (yes/no) and being in the top 10% of costs (in the year after survey) were the dependent variables for the first and second logistic regression models, respectively. RESULTS: The 3 items explained an additional 2.8% and 4.0% of variance for inpatient admissions and top 10% of costs,respectively, in addition to the variance explained by the DxCG score alone. For DxCG alone, the AUC was 0.686 (95% confidence interval [CI] 0.663-0.710) and 0.741 (95% CI 0.719- 0.764), respectively, for inpatient admissions and top 10% of costs and improved to 0.709 (95% CI 0.687-0.730) and 0.770 (95% CI 0.749-0.790) when the 3 self-reported items were added. CONCLUSIONS: Using self-reported health information improved the predictive power of a DxCG model to forecast inpatient admissions and patient cost-tier. PMID- 22216872 TI - Collection of language data and services provided by health plans. AB - OBJECTIVES: Key stakeholders agree better data on patients' language are needed to effectively address language-related barriers to timely, highquality healthcare. Our objective was to describe health plan efforts to collect language data from its members, provide language services, and improve the provision of culturally and linguistically appropriate services (CLAS). STUDY DESIGN: National surveys in 2003, 2006, and 2008. METHODS: Surveys were administered to health plans offering commercial, Medicaid, and/or Medicare Advantage products. RESULTS: 123 health plans responded to the 2008 survey (50% response rate), including 65 commercial (50%), 46 Medicaid (53%), and 12 Medicare plans (44%), representing a total enrollment of 133.8 million Americans. In 2008, 74.0% of health plans collected language data (commercial 60.0%, Medicaid 89.1%, Medicare 91.7%), which is an increase for each plan type since 2003. Health plans used direct and indirect collection methods. Nearly all health plans reported offering language services, the most common being telephonic interpreting, multilingual member materials, and access to bilingual providers. A variety of strategies for improving CLAS were cited by health plans, including improving health plan communication materials, health literacy initiatives for members, and targeted training for providers and staff. CONCLUSIONS: Health plans have made substantial progress in the collection of language data and many are offering options for language services. With the rapid growth in Medicaid participation and newly insured individuals anticipated under the Affordable Care Act, health plans may be uniquely positioned to implement and test interventions that aim to improve appropriate utilization of language services by providers and patients. PMID- 22216873 TI - Comparing variation in Medicare and private insurance spending in Texas. AB - OBJECTIVES: A great deal of research has documented the wide variation in Medicare spending across different geographic regions in the United States. However, little research has been done on spending variation in the commercial sector. The objectives of this paper are (1) to compare variations in spending and inpatient utilization in the Blue Cross Blue Shield of Texas (BCBSTX) population and the Medicare population across 32 Texas regions and (2) to investigate if the pattern of widely varying Medicare spending but similar BCBSTX spending found in a previous analysis of El Paso and Hidalgo/McAllen exists across the state. STUDY DESIGN: Retrospective study using 2008 BCBSTX and Medicare data. We used total spending per member/enrollee per month and inpatient admissions per 1000 members/enrollees. METHODS: After adjusting BCBSTX and Medicare spending for price and adjusting BCBSTX spending and utilization for age and gender, we computed coefficients of variation, standard deviations from the Texas means, and kernel density estimates for standard deviations from the mean to compare variation in BCBSTX and Medicare spending and inpatient utilization. RESULTS: Results indicated that variations across Texas in total spending and inpatient utilization are similar in BCBSTX and Medicare both in level and in direction, as the correlations between Medicare and commercial spending and inpatient utilization are positive after excluding the Hidalgo/McAllen regions. CONCLUSIONS: Over the state of Texas, regions of high Medicare spending also tend to be regions of high private insurance spending. McAllen appears to be an outlier for Medicare spending, but not for BCBSTX spending. PMID- 22216874 TI - Jugular bulb diverticulum dehiscence towards the vestibular aqueduct in a patient with otosclerosis. AB - OBJECTIVES: To demonstrate the need for computed tomography imaging of the temporal bone before considering revision stapes surgery in patients with recurrent or residual conductive hearing loss. CASE REPORT: We report the case of a high-riding jugular bulb with an associated jugular bulb diverticulum, which was dehiscent towards the vestibular aqueduct, in a patient with confirmed otosclerosis who did not experience hearing improvement after stapedotomy. CONCLUSION: This case demonstrates the usefulness of temporal bone computed tomography in the evaluation of patients with otosclerosis in whom stapedotomy has not improved hearing. In such patients, revision surgery to address residual hearing loss would eventually prove unnecessary and avoidable. PMID- 22216875 TI - Importance of neutropenia for development of invasive infections at various phases of treatment for hemato-oncological diseases in children. AB - INTRODUCTION: Prolonged neutropenia in patients with acute myeloid leukemia (AML), relapsed acute lymphoblastic leukemia (r-ALL), myelodysplastic syndrome (MDS), and those receiving hematopoietic stem cell transplantation (HSCT), is a well-known risk factor for infectious complications. Few data are available about the incidence and etiology of infectious episodes during the total treatment period associated with a decreased immunity. METHODS: Between January 2000 and December 2005 children diagnosed with AML, r-ALL, and MDS, and post-HSCT patients were included in the study. A retrospective review based on microbiological data was performed to describe the incidence and etiology of the infectious complications during the total treatment period. RESULTS: One hundred and thirty disease-specific patient episodes were included. Forty-two percent of 184 microbiologically proven infectious episodes were diagnosed in patients receiving chemotherapy, and 58% occurred in HSCT patients. During neutropenia, 123 (67%) infectious episodes were diagnosed; of the isolated species 83% were bacterial, 6% fungal, and 11% viral. In the period without neutropenia, 61 (33%) infectious episodes were diagnosed, with 38% bacterial, 3% fungal, and 59% viral species isolated. Of the infectious episodes diagnosed in patients treated with an HSCT, 52% (n = 55) occurred in the post-engraftment period. In contrast, in patients treated with chemotherapy, 92% of the infectious episodes were diagnosed during neutropenia. CONCLUSION: The number of proven infectious episodes in post-HSCT patients was not influenced by the presence of neutropenia, while in patients receiving chemotherapy significantly lower numbers of proven infectious episodes were diagnosed outside the neutropenic period. PMID- 22216878 TI - Surgical treatment of eosinophilic granuloma of the infratemporal fossa: a successful treatment option. AB - The patient was a 16-year-old girl complaining about progressive swelling on the right side of her face, right headache, and right orbital proptosis. A CT scan revealed a lytic mass centered in the greater wing of the right sphenoid bone with extension into the orbit, middle cranial fossa, and infratemporal fossa. The patient underwent a subtemporal-preauricular infratemporal fossa approach, which allowed complete resection of the tumor, with a low morbidity. The pathological diagnosis was eosinophilic granuloma. At 36 months after the initial treatment the patient is free of disease. We conclude that lesions of this complex anatomic area are a challenge to biopsy and treat and they could be treated only with radical surgery with low morbidity, at centers with expertise in skull base surgery. PMID- 22216879 TI - Defining the molecular role of gp91phox in the immune manifestation of acute allergic asthma using a preclinical murine model. AB - OBJECTIVE: The phenomena manifested during inflammation require interplay between circulating effector cells, local resident cells, soluble mediators and genetic host factors to establish, develop and maintain itself. Of the molecues involed in the initiation and perpetuation of acute allergic inflammation in asthma, the involvement of effector cells in redox reactions for producing O2- (superoxide anion) through the mediation of NADPH oxidase is a critical step. Prior data suggest that reactive oxygen species (ROS) produced by NADPH oxidase homologues in non-phagocytic cells play an important role in the regulation of signal transduction, while macrophages use a membrane-associated NADPH oxidase to generate an array of oxidizing intermediates which inactivate MMPs on or near them. MATERIALS AND METHODS AND TREATMENT: To clarify the role of gp91phox subunit of NADPH oxidase in the development and progression of an acute allergic asthma phenotype, we induced allergen dependent inflammation in a gp91phox-/- single knockout and a gp91phox-/-MMP-12-/- double knockout mouse models. RESULTS: In the knockout mice, both inflammation and airway hyperreactivity were more extensive than in wildtype mice post-OVA. Although OVA-specific IgE in plasma were comparable in wildtype and knockout mice, enhanced inflammatory cell recruitment from circulation and cytokine release in lung and BALf, accompanied by higher airway resistance as well as Penh in response to methacholine, indicate a regulatory role for NADPH oxidase in development of allergic asthma. While T cell mediated functions like Th2 cytokine secretion, and proliferation to OVA were upregulated synchronous with the overall robustness of the asthma phenotype, macrophage upregulation in functions such as proliferation, and mixed lymphocyte reaction indicate a regulatory role for gp91phox and an overall non-involvement or synergistic involvement of MMP12 in the response pathway (comparing data from gp91phox-/- and gp91phox-/-MMP-12-/- mice). PMID- 22216881 TI - Synthesis of nestlike ZnO hierarchically porous structures and analysis of their gas sensing properties. AB - Nestlike 3D ZnO porous structures with size of 1.0-3.0 MUm have been synthesized through annealing the zinc hydroxide carbonate precursor, which was obtained by a one-pot hydrothermal process with the assistance of glycine, Na(2)SO(4), and polyvinyl pyrrolidone (PVP). The nestlike 3D ZnO structures are built of 2D nanoflakes with the thickness of ca. 20 nm, which exhibit the nanoporous wormhole like characteristic. The measured surface area is 36.4 m(2)g(-1) and the pore size is ca. 3-40 nm. The unique nestlike 3D ZnO porous structures provided large contacting surface area for electrons, oxygen and target gas molecules, and abundant channels for gas diffusion and mass transport. Gas sensing tests showed that the nestlike 3D ZnO porous structures exhibit excellent gas sensing performances such as high sensitivity and fast response and recovery speed, suggesting the potential applications as advanced gas sensing materials. PMID- 22216882 TI - Reversible dewetting of a molecularly thin fluid water film in a soft graphene mica slit pore. AB - The behavior of water and other molecular liquids confined to the nanoscale is of fundamental importance, e.g., in biology, material science, nanofluidics, and tribology. Direct microscopic imaging of wetting dynamics in subnanometer pores is however challenging. We will show in the following that a molecularly thin water film confined between mica and graphene is fluid. Ambient humidity allows to control the wetting and dewetting of the film. We follow these processes in space and time using scanning force microscopy imaging of the graphene conforming to the film. At sufficiently high humidity a continuous molecularly thin water film wets the interface between the graphene and mica. At lower humidities the film dewets with fractal depressions exhibiting dimensions around 1.7 and depths comparable to the size of a water molecule. The soft graphene cover offers a previously unexplored semihydrophilic slit pore of self-adjustable size, which enables high-resolution imaging of confined molecularly thin fluid films, and bears the potential for the fabrication of novel nanofluidic devices. PMID- 22216880 TI - The Q43L mutant of neuregulin 2beta is a pan-ErbB receptor antagonist. AB - The ErbB4 receptor tyrosine kinase possesses both tumour suppressor and oncogenic activities. Thus pharmacological agents are needed to help elucidate ErbB4 functions. However, limitations of existing ErbB4 agonists and antagonists have led us to seek novel ErbB4 antagonists. The Q43L mutant of the ErbB4 agonist NRG2beta (neuregulin 2beta) stimulates ErbB4 tyrosine phosphorylation, yet fails to stimulate ErbB4 coupling to cell proliferation. Thus in the present paper we hypothesize that NRG2beta/Q43L may be an ErbB4 antagonist. NRG2beta/Q43L competitively antagonizes agonist stimulation of ErbB4 coupling to cell proliferation. NRG2beta/Q43L stimulates less ErbB4 tyrosine phosphorylation than does NRG2beta. In addition, NRG2beta stimulation of cell proliferation requires PI3K (phosphoinositide 3-kinase) activity and NRG2beta stimulates greater Akt phosphorylation than does NRG2beta/Q43L. Moreover, EGFR [EGF (epidermal growth factor) receptor] kinase activity (but not that of ErbB4) is critical for coupling ErbB4 to proliferation. Experiments utilizing ErbB4 splicing isoforms and mutants suggest that NRG2beta and NRG2beta/Q43L may differentially stimulate ErbB4 coupling to the transcriptional co-regulator YAP (Yes-associated protein). Finally, NRG2beta/Q43L competitively antagonizes agonist stimulation of EGFR and ErbB2/ErbB3, indicating that NRG2beta/Q43L is a pan-ErbB antagonist. Thus we postulate that NRG2beta/Q43L and other antagonistic ligands stimulate ErbB tyrosine phosphorylation on a set of residues distinct from that stimulated by agonists, thus suggesting a novel mechanism of ErbB receptor regulation. Moreover, NRG2beta/Q43L and related ligand-based antagonists establish a paradigm for the discovery of anti-ErbB therapeutics. PMID- 22216884 TI - Fundamental changes to EPA's research enterprise: the path forward. AB - Environmental protection in the United States has reached a critical juncture. It has become clear that to address the complex and interrelated environmental challenges we face, we must augment our traditional approaches. The scientific community must build upon its deep understanding of risk assessment, risk management, and reductionism with tools, technologies, insights and approaches to pursue sustainability. The U.S. Environmental Protection Agency (EPA) has recognized this need for systemic change by implementing a new research paradigm called "The Path Forward." This paper outlines the principles of the Path Forward and the actions taken since 2010 to align EPA's research efforts with the goal of sustainability. PMID- 22216886 TI - Gastric lactobezoar - a rare disorder? AB - Gastric lactobezoar, a pathological conglomeration of milk and mucus in the stomach of milk-fed infants often causing gastric outlet obstruction, is a rarely reported disorder (96 cases since its first description in 1959). While most patients were described 1975-1985 only 26 children have been published since 1986. Clinically, gastric lactobezoars frequently manifest as acute abdomen with abdominal distension (61.0% of 96 patients), vomiting (54.2%), diarrhea (21.9%), and/or a palpable abdominal mass (19.8%). Respiratory (23.0%) and cardiocirculatory (16.7%) symptoms are not uncommon. The pathogenesis of lactobezoar formation is multifactorial: exogenous influences such as high casein content (54.2%), medium chain triglycerides (54.2%) or enhanced caloric density (65.6%) of infant milk as well as endogenous factors including immature gastrointestinal functions (66.0%), dehydration (27.5%) and many other mechanisms have been suggested. Diagnosis is easy if the potential presence of a gastric lactobezoar is thought of, and is based on a history of inappropriate milk feeding, signs of acute abdomen and characteristic features of diagnostic imaging. Previously, plain and/or air-, clear fluid- or opaque contrast medium radiography techniques were used to demonstrate a mass free-floating in the lumen of the stomach. This feature differentiates a gastric lactobezoar from intussusception or an abdominal neoplasm. Currently, abdominal ultrasound, showing highly echogenic intrabezoaric air trapping, is the diagnostic method of choice. However, identifying a gastric lactobezoar requires an investigator experienced in gastrointestinal problems of infancy as can be appreciated from the results of our review which show that in not even a single patient gastric lactobezoar was initially considered as a possible differential diagnosis. Furthermore, in over 30% of plain radiographs reported, diagnosis was initially missed although a lactobezoar was clearly demonstrable on repeat evaluation of the same X-ray films. Enhanced diagnostic sensitivity would be most rewarding since management consisting of cessation of oral feedings combined with administration of intravenous fluids and gastric lavage is easy and resolves over 85% of gastric lactobezoars. In conclusion, gastric lactobezoar is a disorder of unknown prevalence and is nowadays very rarely published, possibly because of inadequate diagnostic sensitivity and/or not yet identified but beneficial modifications of patient management. PMID- 22216887 TI - Oral and anal sex practices among high school youth in Addis Ababa, Ethiopia. AB - BACKGROUND: Understanding the full range of sexual behaviors of young people is crucial in developing appropriate interventions to prevent and control sexually transmitted infections including HIV. However, such information is meager in developing countries. The objective of this study was to describe oral and anal sex practices and identify associated factors among high school youth. METHODS: A cross-sectional study was conducted among high school youth in Addis Ababa, Ethiopia. A multi-stage sampling procedure was followed to select a representative sample of school youth. The total sample size for this study was 3840. Data were collected using a self-administered questionnaire. Data analysis was guided by the ecological framework. RESULTS: The overall proportion of people who reported ever having oral sex was 5.4% (190) and that of anal sex was 4.3% (154). Of these 51.6% (98) had oral sex and 57.1% (87) had anal sex in the past 12 months. Multiple partnerships were reported by 61.2% of the respondents who had oral sex and 51.1% of students practicing anal sex. Consistent condom use was reported by 12.2% of those practicing oral sex and 26.1% of anal sex. Reasons for oral and anal sex included prevention of pregnancy, preserving virginity, and reduction of HIV and STIs transmission. Oral sex practice was strongly and significantly associated with perception of best friends engagement in oral sex (AOR = 5.7; 95% CI 3.6-11.2) and having illiterate mothers (AOR = 11.5; 95%CI 6.4 18.5). Similarly, anal sex practice was strongly and significantly associated with favorable attitude towards anal sex (AOR = 6.2; 95%CI 3.8-12.4), and perceived best friends engagement in anal sex (AOR = 9.7; 95%CI 5.4-17.7). CONCLUSION: Considerable proportion of adolescents had engaged in oral and anal sex practices. Multiple sexual partnerships were common while consistent condom use was low. Sexual health education and behavior change communication strategies need to cover a full range of sexual practices. PMID- 22216888 TI - Adsorption of plutonium oxide nanoparticles. AB - Adsorption of monodisperse cubic plutonium oxide nanoparticles ("Pu-NP", [Pu(38)O(56)Cl(x)(H(2)O)(y)]((40-x)+), with a fluorite-related lattice, approximately 1 nm in edge size) to the muscovite (001) basal plane from aqueous solutions was observed in situ (in 100 mM NaCl background electrolyte at pH 2.6). Uptake capacity of the surface quantified by alpha-spectrometry was 0.92 MUg Pu/cm(2), corresponding to 10.8 Pu per unit cell area (A(UC)). This amount is significantly larger than that of Pu(4+) needed for satisfying the negative surface charge (0.25 Pu(4+) for 1 e(-)/A(UC)). The adsorbed Pu-NPs cover 17% of the surface area, determined by X-ray reflectivity (XR). This correlates to one Pu-NP for every 14 unit cells of muscovite, suggesting that each particle compensates the charge of the unit cells onto which it adsorbs as well as those in its direct proximity. Structural investigation by resonant anomalous X-ray reflectivity distinguished two different sorption states of Pu-NPs on the surface at two different regimes of distance from the surface. A fraction of Pu is distributed within 11 A from the surface. The distribution width matches the Pu NP size, indicating that this species represents Pu-NPs adsorbed directly on the surface. Beyond the first layer, an additional fraction of sorbed Pu was observed to extend more broadly up to more than 100 A from the surface. This distribution is interpreted as resulting from "stacking" or aggregation of the nanoparticles driven by sorption and accumulation of Pu-NPs at the interface although these Pu NPs do not aggregate in the solution. These results are the first in situ observation of the interaction of nanoparticles with a charged mineral-water interface yielding information important to understanding the environmental transport of Pu and other nanophase inorganic species. PMID- 22216889 TI - Complexes of Ge(IV)- and Sn(IV)-fluorides with cyclic and acyclic carbenes: bis(dialkylamino)-difluoromethylenes as carbene sources. AB - Carbene complexes of Ge(IV)- and Sn(IV)-fluorides have been synthesized by oxidative addition of 2,2-difluoro-1,3-dimethylimidazolidine and bis(dimethylamino)difluoromethane to GeCl(2)*dioxane and SnF(2). Chloride analogs of the Ge(IV) complexes were also isolated. All compounds were characterized in the solid state by single-crystal X-ray diffraction. PMID- 22216890 TI - Early or late parenteral nutrition: ASPEN vs. ESPEN. PMID- 22216891 TI - Study of Trypanosoma cruzi epimastigote cell death by NMR-visible mobile lipid analysis. AB - Cell death mechanisms in Trypanosoma cruzi have not been disclosed in detail though different conventional techniques have been used in the classification of parasite-cell death type. Nuclear magnetic resonance (NMR) has successfully been used as a tool to evaluate the onset of apoptosis in a number of higher eukaryote cell models analysing the ratio of CH(2)/CH(3) integration from the visible mobile lipids (VML). Surprisingly, this versatile non-invasive spectroscopy technique has never been employed with this purpose in T. cruzi. In the present study it is shown that under different parasite death-conditions the ratio CH(2)/CH(3) varied drastically. Thus, T. cruzi epimastigotes in apoptotic conditions increase significantly this ratio while in necrotic as well as in autophagic situations the parasites maintain the VML, CH(2)/CH(3) ratio, in normal values. Additionally, other VML markers commonly used in these studies, such as the change in the region of methyl-choline moiety, -N(+)(CH(3))(3), exhibited different particular patterns according to the type of cell death. Our results suggest that the (1)H NMR-VML technique is an adequate tool to discriminate different T. cruzi death pathways. PMID- 22216892 TI - The bivalent ligand approach leads to highly potent and selective acylguanidine type histamine H2 receptor agonists. AB - Bivalent histamine H(2) receptor (H(2)R) agonists were synthesized by connecting pharmacophoric 3-(2-amino-4-methylthiazol-5-yl)-, 3-(2-aminothiazol-5-yl)-, 3 (imidazol-4-yl)-, or 3-(1,2,4-triazol-5-yl)propylguanidine moieties by N(G) acylation with alkanedioic acids of various chain lengths. The compounds were investigated for H(2)R agonism in GTPase and [(35)S]GTPgammaS binding assays at guinea pig (gp) and human (h) H(2)R-Gsalpha(S) fusion proteins including various H(2)R mutants, at the isolated gp right atrium, and in GTPase assays for activity on recombinant H(1), H(3), and H(4) receptors. The bivalent ligands are H(2)R partial or full agonists, up to 2 orders of magnitude more potent than monovalent acylguanidines and, with octanedioyl or decanedioyl spacers, up to 4000 times more potent than histamine at the gpH(2)R. In contrast to their imidazole analogues, the aminothiazoles are highly selective for H(2)R vs other HR subtypes. Compounds with (theoretically) sufficient spacer length (20 CH(2) groups) to simultaneously occupy two orthosteric binding sites in H(2)R dimers are nearly inactive, whereas the highest potency resides in compounds with considerably shorter spacers. Thus, there is no evidence for interaction with H(2)R dimers. The high agonistic potency may result from interaction with an accessory binding site at the same receptor protomer. PMID- 22216894 TI - Combination therapy with insulin glargine and exenatide: real-world outcomes in patients with type 2 diabetes. AB - OBJECTIVE: To investigate the real-world use of combination insulin glargine/exenatide therapy for type 2 diabetes mellitus (T2DM) and associated treatment persistence and glycemic control. METHODS: In this retrospective study, data were extracted from a national US insurance claims database for patients with T2DM for whom insulin glargine and exenatide were co-prescribed in differing order: insulin glargine added after exenatide (EXE+); exenatide added after insulin glargine (GLA+); glargine and exenatide initiated together (GLA + EXE). Patients had continuous health plan coverage for 6 months pre- (baseline) and 1 year post-index (follow-up). RESULTS: A total of 453 patients were eligible for analysis: 141 patients were included in the EXE+ cohort, 281 in the GLA+ cohort, and 31 in the GLA + EXE cohort. There were significant differences between the groups at baseline, including a significantly lower A1C in the GLA+ versus the EXE+ cohort (p = 0.0023). Around one third of patients stayed on both drugs up until the end of the follow-up period (GLA+: 30.2%; EXE+: 29.0%; GLA + EXE: 29.0%). However, more patients stayed on insulin glargine than on exenatide in each cohort. Significant A1C reductions were observed in each of the cohorts at follow-up: GLA+: -0.4%; EXE+: -0.9%; GLA + EXE: -1.2%; p < 0.01, and were significantly higher in the GLA + EXE and EXE+ cohorts than in the GLA+ cohort (p = 0.03 and p = 0.002, respectively). The mean number of hypoglycemic events increased slightly from baseline but remained low in each of the cohorts (GLA+: 0.12 to 1.42; EXE+: 0.09 to 1.04; GLA + EXE: 0.23 to 1.87 per patient, all p > 0.1). CONCLUSIONS: Combined therapy with insulin glargine and exenatide resulted in A1C reductions in T2DM patients with poor glycemic control without a significantly increased risk of hypoglycemia irrespective of treatment order. Limitations of this study are the between-cohort differences at baseline, lack of a comparator group, and small n number, particularly in the GLA + EXE cohort. PMID- 22216895 TI - Graphene quantum dots derived from carbon fibers. AB - Graphene quantum dots (GQDs), which are edge-bound nanometer-size graphene pieces, have fascinating optical and electronic properties. These have been synthesized either by nanolithography or from starting materials such as graphene oxide (GO) by the chemical breakdown of their extended planar structure, both of which are multistep tedious processes. Here, we report that during the acid treatment and chemical exfoliation of traditional pitch-based carbon fibers, that are both cheap and commercially available, the stacked graphitic submicrometer domains of the fibers are easily broken down, leading to the creation of GQDs with different size distribution in scalable amounts. The as-produced GQDs, in the size range of 1-4 nm, show two-dimensional morphology, most of which present zigzag edge structure, and are 1-3 atomic layers thick. The photoluminescence of the GQDs can be tailored through varying the size of the GQDs by changing process parameters. Due to the luminescence stability, nanosecond lifetime, biocompatibility, low toxicity, and high water solubility, these GQDs are demonstrated to be excellent probes for high contrast bioimaging and biosensing applications. PMID- 22216897 TI - Controlling the microadsorption structure of porphyrin dye assembly on clay surfaces using the "size-matching rule" for constructing an efficient energy transfer system. AB - The microadsorption structure of two kinds of porphyrin molecules on an anionic clay surface was investigated by photochemical energy transfer reaction. Three procedures were examined for the preparation of the clay/porphyrin complexes: (i) coadsorption (CA) method, (ii) sequential adsorption (SA) method, and (iii) independent adsorption (IA) method as described in the text. Efficient and moderate energy transfer reactions were observed in the CA and SA complexes, respectively. On the contrary, the energy transfer did not occur in the IA complex. These results indicate that the microadsorption structure of the two kinds of porphyrin on the clay mineral surface resulting from the sample preparation methods, affects the energy transfer efficiency. As a result, it was revealed that (i) the adsorbed porphyrins can move on the clay mineral surface but cannot move from one clay surface to another clay sheet, and (ii) the integration structure of two kinds of porphyrin is more stable than the segregation structure in the present system. This unusual structure originated from an extremely strong electrostatic interaction between the porphyrin and the clay mineral as a result of a "size-matching rule". These unique strongly fixed dye assemblies on the clay mineral surface, in which the aggregation and segregation of dyes are suppressed, is very promising and attractive for constructing efficient photochemical reaction systems. PMID- 22216896 TI - Racial disparities in perinatal outcomes among women with gestational diabetes. AB - BACKGROUND: We sought to evaluate perinatal outcomes by race/ethnicity among women with gestational diabetes mellitus (GDM). METHODS: We conducted a 14-year retrospective cohort study of women with GDM. Selected perinatal outcomes were examined. Unadjusted and adjusted prevalence ratios (PR, aPR) of perinatal outcomes, comparing Hispanic and African American women with Caucasian women, were calculated. RESULTS: Hispanics comprised 54% of the 1018 woman cohort. Half received medical management of GDM (52%), more than African Americans (45%) or Caucasians (39%)(p<0.05). Compared with Caucasians, Hispanics had fewer deliveries <37 weeks (aPR 0.58, 95% confidence interval [CI] 0.42-0.81), less gestational hypertension (aPR 0.43, 95% CI 0.22-0.83), larger median birth weight infants (3453 g vs 3291 g, p<0.05), and greater risk of shoulder dystocia (aPR 3.52, 95% CI 1.30-9.50). Hispanic women had fewer adverse outcomes overall compared with Caucasian or African American women. CONCLUSIONS: We report differences between Hispanic and Caucasian women with GDM. Treatment to achieve glycemic control and reduce adverse outcomes may differ by race/ethnicity. PMID- 22216898 TI - Endoscopic sinus surgery for fungal ball rhinosinusitis in South China: long-term results and analysis of prognostic factors. AB - CONCLUSION: Endoscopic sinus surgery (ESS) treatment has achieved good long-term results in patients in South China with fungal ball rhinosinusitis. Gender (female), age (young), nasal polyps, allergy, high Lund-Mackay scores, prior sinus surgery and diabetes mellitus affect patients' outcomes. OBJECTIVE: To evaluate objective testing and quality of life (QOL) outcomes of patients with fungal ball rhinosinusitis before and after ESS in South China and to determine preoperative factors that predict surgical outcomes. METHODS: We retrospectively analyzed the outcomes for 330 patients with fungal ball rhinosinusitis after ESS. QOL was assessed using Sinonasal Outcome Test-20 (SNOT-20), Short Form-36 (SF-36) questionnaires and visual analogue scale (VAS). Objective testing was evaluated by Lund-Kennedy endoscopic scoring system. Prognostic factors were determined based on the QOL scores and Lund-Kennedy scores after ESS using a multivariate linear regression. RESULTS: ESS significantly improved the objective testing and QOL outcomes in patients with fungal ball rhinosinusitis (p < 0.05). Objective outcome: postoperative Lund-Kennedy scores were significantly worse in patients with nasal polyps, allergy and high Lund-Mackay scores (p < 0.05). QOL outcomes: postoperative SF-36 scores were adversely affected by gender (female), age (young), nasal polyps, allergy and prior sinus surgery (p < 0.05); postoperative VAS scores were adversely affected by gender (female), nasal polyps, allergy and diabetes mellitus (p < 0.05). PMID- 22216900 TI - Phagocyte-specific S100 proteins in the local response to the Echinococcus granulosus larva. AB - Infection by larval Echinococcus granulosus is usually characterized by tight inflammatory control. However, various degrees of chronic granulomatous inflammation are also observed, reaching a high point in infection of cattle by the most prevalent parasite strain worldwide, which is not well adapted to this host species. In this context, epithelioid and multinucleated giant macrophages surround the parasite, and the secreted products of these cells often associate with the larval wall. The phagocyte-specific S100 proteins, S100A8, S100A9 and S100A12, are important non-conventionally secreted amplifiers of inflammatory responses. We have analysed by proteomics and immunohistochemistry the presence of these proteins at the E. granulosus larva-host interface. We found that, in the context of inflammatory control as observed in human infections, the S100 proteins are not abundant, but S100A9 and S100A8 can be expressed by eosinophils distal to the parasite. In the granulomatous inflammation context as observed in cattle infections, we found that S100A12 is one of the most abundant host derived, parasite-associated proteins, while S100A9 and S100A8 are not present at similarly high levels. As expected, S100A12 derives mostly from the epithelioid and multinucleated giant cells. S100A12, as well as cathepsin K and matrix metalloproteinase-9, also expressed by E. granulosus-elicited epithelioid cells, are connected to the Th17 arm of immunity, which may therefore be involved in this granulomatous response. PMID- 22216901 TI - Preventing intimal thickening of vein grafts in vein artery bypass using STAT-3 siRNA. AB - BACKGROUND: Proliferation and migration of vascular smooth muscle cells (VSMCs) play a key role in neointimal formation which leads to restenosis of vein graft in venous bypass. STAT-3 is a transcription factor associated with cell proliferation. We hypothesized that silencing of STAT-3 by siRNA will inhibit proliferation of VSMCs and attenuate intimal thickening. METHODS: Rat VSMCs were isolated and cultured in vitro by applying tissue piece inoculation methods. VSMCs were transfected with STAT 3 siRNA using lipofectamine 2000. In vitro proliferation of VSMC was quantified by the MTT assay, while in vivo assessment was performed in a venous transplantation model. In vivo delivery of STAT-3 siRNA plasmid or scramble plasmid was performed by admixing with liposomes 2000 and transfected into the vein graft by bioprotein gel applied onto the adventitia. Rat jugular vein-carotid artery bypass was performed. On day 3 and7 after grafting, the vein grafts were extracted, and analyzed morphologically by haematoxylin eosin (H&E), and assessed by immunohistochemistry for expression of Ki-67 and proliferating cell nuclear antigen (PCNA). Western-blot and reverse transcriptase polymerase chain reaction (RT-PCR) were used to detect the protein and mRNA expression in vivo and in vitro. Cell apoptosis in vein grafts was detected by TUNEL assay. RESULTS: MTT assay shows that the proliferation of VSMCs in the STAT-3 siRNA treated group was inhibited. On day 7 after operation, a reduced number of Ki-67 and PCNA positive cells were observed in the neointima of the vein graft in the STAT-3 siRNA treated group as compared to the scramble control. The PCNA index in the control group (31.3 +/- 4.7) was higher than that in the STAT-3 siRNA treated group (23.3 +/- 2.8) (P < 0.05) on 7d. The neointima in the experimental group(0.45 +/- 0.04 MUm) was thinner than that in the control group(0.86 +/- 0.05 MUm) (P < 0.05).Compared with the control group, the protein and mRNA levels in the experimental group in vivo and in vitro decreased significantly. Down regulation of STAT-3 with siRNA resulted in a reduced expression of Bcl-2 and cyclin D1. However, apoptotic cells were not obviously found in all grafts on day 3 and 7 post surgery. CONCLUSIONS: The STAT-3 siRNA can inhibit the proliferation of VSMCs in vivo and in vitro and attenuate neointimal formation. PMID- 22216904 TI - The adaptor protein p62/SQSTM1 in osteoclast signaling pathways. AB - Paget's disease of bone (PDB) is a skeletal disorder characterized by focal and disorganized increases in bone turnover and overactive osteoclasts. The discovery of mutations in the SQSTM1/p62 gene in numerous patients has identified protein p62 as an important modulator of bone turnover. In both precursors and mature osteoclasts, the interaction between receptor activator of NF-kappaB ligand (RANKL) and its receptor RANK results in signaling cascades that ultimately activate transcription factors, particularly NF-kappaB and NFATc1, promoting and regulating the osteoclast differentiation, activity, and survival. As a scaffold with multiple protein-protein interaction motifs, p62 is involved in virtually all the RANKL-activated osteoclast signaling pathways, along with being implicated in numerous other cellular processes. The p62 adaptor protein is one of the functional links reported between RANKL and TRAF6-mediated NF-kappaB activation, and also plays a major role as a shuttling factor that targets polyubiquitinated proteins for degradation by either the autophagy or proteasome pathways. The dysregulated expression and/or activity of p62 in bone disease up regulates osteoclast functions. This review aims to outline and summarize the role of p62 in RANKL-induced signaling pathways and in ubiquitin-mediated signaling in osteoclasts, and the impact of PDB-associated p62 mutations on these processes. PMID- 22216903 TI - Identification of autophosphorylation sites in eukaryotic elongation factor-2 kinase. AB - eEF2K [eEF2 (eukaryotic elongation factor 2) kinase] phosphorylates and inactivates the translation elongation factor eEF2. eEF2K is not a member of the main eukaryotic protein kinase superfamily, but instead belongs to a small group of so-called alpha-kinases. The activity of eEF2K is normally dependent upon Ca(2+) and calmodulin. eEF2K has previously been shown to undergo autophosphorylation, the stoichiometry of which suggested the existence of multiple sites. In the present study we have identified several autophosphorylation sites, including Thr(348), Thr(353), Ser(366) and Ser(445), all of which are highly conserved among vertebrate eEF2Ks. We also identified a number of other sites, including Ser(78), a known site of phosphorylation, and others, some of which are less well conserved. None of the sites lies in the catalytic domain, but three affect eEF2K activity. Mutation of Ser(78), Thr(348) and Ser(366) to a non-phosphorylatable alanine residue decreased eEF2K activity. Phosphorylation of Thr(348) was detected by immunoblotting after transfecting wild-type eEF2K into HEK (human embryonic kidney)-293 cells, but not after transfection with a kinase-inactive construct, confirming that this is indeed a site of autophosphorylation. Thr(348) appears to be constitutively autophosphorylated in vitro. Interestingly, other recent data suggest that the corresponding residue in other alpha-kinases is also autophosphorylated and contributes to the activation of these enzymes [Crawley, Gharaei, Ye, Yang, Raveh, London, Schueler-Furman, Jia and Cote (2011) J. Biol. Chem. 286, 2607 2616]. Ser(366) phosphorylation was also detected in intact cells, but was still observed in the kinase-inactive construct, demonstrating that this site is phosphorylated not only autocatalytically but also in trans by other kinases. PMID- 22216905 TI - A single-blind randomised controlled trial of the effects of a web-based decision aid on self-testing for cholesterol and diabetes. Study protocol. AB - BACKGROUND: Self-tests, tests on body materials to detect medical conditions, are widely available to the general public. Self-testing does have advantages as well as disadvantages, and the debate on whether self-testing should be encouraged or rather discouraged is still ongoing. One of the concerns is whether consumers have sufficient knowledge to perform the test and interpret the results. An online decision aid (DA) with information on self-testing in general, and test specific information on cholesterol and diabetes self-testing was developed. The DA aims to provide objective information on these self-tests as well as a decision support tool to weigh the pros and cons of self-testing. The aim of this study is to evaluate the effect of the online decision aid on knowledge on self testing, informed choice, ambivalence and psychosocial determinants. METHODS/DESIGN: A single blind randomised controlled trial in which the online decision aid 'zelftestwijzer' is compared to short, non-interactive information on self-testing in general. The entire trial will be conducted online. Participants will be selected from an existing Internet panel. Consumers who are considering doing a cholesterol or diabetes self-test in the future will be included. Outcome measures will be assessed directly after participants have viewed either the DA or the control condition. Weblog files will be used to record participants' use of the decision aid. DISCUSSION: Self-testing does have important pros and cons, and it is important that consumers base their decision whether they want to do a self-test or not on knowledge and personal values. This study is the first to evaluate the effect of an online decision aid for self testing. TRIAL REGISTRATION: Dutch Trial Register: NTR3149. PMID- 22216906 TI - Validity of the self-reported drug use section of the Addiction Severity Index and associated factors used under naturalistic conditions. AB - The study examined the validity of 1848 self-reported uses of drugs determined within an Addiction Severity Index interview in comparison with urinalysis results among drug-dependent subjects undergoing treatment in outpatient clinics (Aquitaine area, southwest France, 1994-2005). Agreement and kappa statistics were calculated for each substance. Factors associated with agreement were defined using a multivariate analysis. The conditional kappa coefficients were excellent for all substances assessed. The accuracy between self-reports and urinalysis results was influenced by factors that only slightly affected conditional kappa coefficients. Clients did not underreport their substance use in naturalistic clinical assessment conditions. PMID- 22216907 TI - Police perceptions of supervised consumption sites (SCSs): a qualitative study. AB - Police are key stakeholders in cities considering supervised consumption site (SCS) implementation. We examine police perceptions of SCSs using data collected between 2008 and 2010. Data from interviews and focus groups conducted with police officers of varied ranks (n = 18) in Ottawa and Toronto, Canada, were analyzed using thematic analyses. Participants opposed SCS implementation in their respective cities. The police views we heard invoke values and perspectives on evidence that differ from those used in research. Whether these divergent frameworks are reconcilable is a question for future research. Study limitations are noted. The Ontario HIV Treatment Network funded the study. PMID- 22216911 TI - New insights into the adsorption of 3-(trimethoxysilyl)propylmethacrylate on hydroxylated ZnO nanopowders. AB - Functionalization of zinc oxide (ZnO) nano-objects by silane grafting is an attractive method to provide nanostructured materials with a variety of surface properties. Active hydroxyl groups on the oxide surface are one of the causes governing the interfacial bond strength in nanohybrid particles. Here, "as prepared" and commercially available zinc oxide nanopowders with a wide range of surface hydroxyl density were functionalized by a well-known polymerizable silane coupling agent, i.e., 3-(trimethoxysilyl)propylmethacrylate (MPS). Fourier transform infrared (FTIR) and solid-state (13)C and (29)Si nuclear magnetic resonance (NMR) spectroscopic investigations demonstrated that the silane coupling agent was fully hydrolyzed and linked to the hydroxyl groups already present on the particle surface through covalent and hydrogen bonds. Due to a basic catalyzed condensation of MPS with water, a siloxane layer was shown to be anchored to the nanoparticles through mono- and tridentate structures. Quantitative investigations were performed by thermogravimetric (TGA) and elemental analyses. The amount of silane linked to ZnO particles was shown to be affected by the amount of isolated hydroxyl groups available to react on the particle surface. For as-prepared ZnO nanoparticles, the number of isolated and available hydroxyl groups per square nanometer was up to 3 times higher than the one found on commercially available ZnO nanoparticles, leading to higher amounts of polymerizable silane agent linked to the surface. The MPS molecules were shown to be mainly oriented perpendicular to the oxide surface for all the as-prepared ZnO nanoparticles, whereas a parallel orientation was found for the preheated commercially ZnO nanopowders. In addition, ZnO nanoparticles were shown to be hydrophobized by the MPS treatment with water contact angles higher than 60 degrees . PMID- 22216912 TI - Evidence for a complex relationship between antibiotics and antibiotic-resistant Escherichia coli: from medical center patients to a receiving environment. AB - The aim of this study was to investigate the relationship between antibiotics and antibiotic-resistant fecal bacteria (E. coli) in water along a medical center wastewater treatment plant-river continuum (4 km). A multiresidue chemical analysis methodology, using solid phase extraction coupled with liquid chromatography tandem mass spectrometry, was performed to detect whether low levels of contamination by 34 antibiotics were related to antibiotic resistance of E. coli and antibiotic use. The contamination of water by antibiotics and antibiotic-resistant E. coli decreased along the continuum. Although amoxicillin was predominantly prescribed, only ofloxacin (1 ng.L(-1)) and sulfamethoxazole (4 ng.L(-1)) persisted in the river. At the retirement home, in the medical center, even though no tetracycline and sulfamethoxazole were consumed, the highest occurrences of antibiotic resistance were in classes of quinolones (42.0%), sulfonamides (24.0%), tetracyclines (38.0%), and penicillins (38.0%), mainly due to the presence of multiple antibiotic-resistance genes on class 1 integrons. Along the continuum, the occurrence of E. coli resistant to antibiotics and those carrying class 1 integrons decreased in water samples (p-value <0.001). Interestingly, in the river, only persistent antibiotic compounds (ofloxacin, sulfamethoxazole) were found, but they did not correspond to the major resistances (tetracycline, amoxicillin) of E. coli. PMID- 22216917 TI - Causality between polyhexamethyleneguanidine occurrence in unrecorded alcohol and cholestatic hepatitis outbreak in Russia. PMID- 22216918 TI - Structural mass spectrometry: rapid methods for separation and analysis of peptide natural products. AB - A significant challenge in natural product discovery is the initial discrimination of discrete secondary metabolites alongside functionally similar primary metabolic cellular components within complex biological samples. A property that has yet to be fully exploited for natural product identification and characterization is the gas-phase collision cross section, or, more generally, the mobility-mass correlation. Peptide natural products possess many of the properties that distinguish natural products, as they are frequently characterized by a high degree of intramolecular bonding and possess extended and compact conformations among other structural modifications. This report describes a rapid structural mass spectrometry technique based on ion mobility-mass spectrometry for the comparison of peptide natural products to their primary metabolic congeners using mobility-mass correlation. This property is empirically determined using ion mobility-mass spectrometry, applied to the analysis of linear versus modified peptides, and used to discriminate peptide natural products in a crude microbial extract. Complementary computational approaches are utilized to understand the structural basis for the separation of primary metabolism derived linear peptides from secondary metabolite cyclic and modified cyclic species. These findings provide a platform for enhancing the identification of secondary metabolic peptides with distinct mobility-mass ratios within complex biological samples. PMID- 22216919 TI - Effects of ultraviolet radiation on the transmission process of an intertidal trematode parasite. AB - The transmission of parasites takes place under exposure to a range of fluctuating environmental factors, one being the changing levels of solar ultraviolet radiation (UVR). Here, we investigated the effects of ecologically relevant levels of UVR on the transmission of the intertidal trematode Maritrema novaezealandensis from its first intermediate snail host (Zeacumantus subcarinatus) to its second intermediate amphipod host (Paracalliope novizealandiae). We assessed the output of parasite transmission stages (cercariae) from infected snail hosts, the survival and infectivity of cercariae, the susceptibility of amphipod hosts to infection (laboratory experiments) and the survival of infected and uninfected amphipod hosts (outdoor experiment) when exposed to photo-synthetically active radiation only (PAR, 400-700 nm; no UV), PAR+UVA (320-700 nm) or PAR+UVA+UVB (280-700 nm). Survival of cercariae and susceptibility of amphipods to infection were the only two steps significantly affected by UVR. Survival of cercariae decreased strongly in a dose-dependent manner, while susceptibility of amphipods increased after exposure to UVR for a prolonged period. Exposure to UVR thus negatively affects both the parasite and its amphipod host, and should therefore be considered an influential component in parasite transmission and host-parasite interactions in intertidal ecosystems. PMID- 22216920 TI - Cancers that U.S. physicians believe the HPV vaccine prevents: findings from a physician survey, 2009. AB - BACKGROUND: There is strong scientific evidence that human papillomavirus (HPV) vaccines, which protect against two oncogenic HPV types (16 and 18), can prevent cervical, vaginal, and vulvar cancers in women. In addition, recent research has established that the HPV vaccine can prevent anal cancer and has implied that it may also prevent oropharyngeal cancers. METHODS: A 2009 web-based survey of 1500 physicians from four specialties (pediatricians, family practitioners, internists, and obstetrician-gynecologists) explored knowledge about which female cancers the HPV vaccine was effective in preventing. Physician characteristics associated with the belief that the HPV vaccine prevents cervical, vaginal, vulvar, anal, and other cancers were examined using logistic regression models. RESULTS: Nearly all respondents (97.8%) identified cervical cancer as being prevented by the HPV vaccine; however, lower awareness that the vaccine prevents vaginal (23.8%), vulvar (27.8%), and anal cancer (28.4%) was found. Physician specialty was the most significant covariate identified, with obstetrician gynecologists being more likely than other physicians to report that the HPV vaccine protected against vaginal (p<0.001), vulvar (p<0.001), and anal (p<0.001) cancers. CONCLUSIONS: Physicians may benefit from educational efforts clarifying which noncervical cancers can be prevented by the HPV vaccine. Education is needed across all medical specialties, but it is particularly important for pediatricians and family practitioners, the physicians most likely to administer the HPV vaccine to young adolescents. PMID- 22216921 TI - Highly fluorescent fluoride-responsive hydrogels embedded with CdTe quantum dots. AB - Functionalized CdTe quantum dots (QDs) synthesized via ion exchange demonstrated a selective response toward fluoride in aqueous solutions based on a rapid sol gel transition that was visible to the naked eye. The fluoride-induced hydrogel exhibited excellent fluorescent performance because of the incorporation of QDs. As a result, this highly fluorescent fluoride-induced hydrogel may pave a new way to sense fluoride using a visible sol-gel transition. PMID- 22216922 TI - Celiac disease and sensorineural hearing loss in children. AB - CONCLUSION: Sensorineural hearing loss (SNHL) is a neurological situation and celiac disease (CD) may be seen coincidentally. Children with clinical signs of hearing deficiency of unknown etiology should be assessed for CD. OBJECTIVE: CD is a chronic inflammatory gluten-dependent intestinal disease and has extraintestinal findings. The aim of this study was to determine the incidence of CD and SNHL in our pediatric patients. METHODS: A total of 25 pediatric patients (50 ears) with biopsy-proven CD were diagnosed in the pediatric gastroenterology department; 25 healthy control subjects (50 ears) were also included in the study. All subjects underwent pure tone audiometry at frequencies of 250-8000 Hz and tympanometry. RESULTS: In the patients and controls, normal peak compliance, gradient, peak pressure, ear canal volume, and acoustic reflexes were obtained by tympanometry. There was no air-bone gap in any of the participants. There was a statistically significant difference between the audiometric results in the CD and control groups (right ear and left ear) (p < 0.05). PMID- 22216923 TI - Active living neighborhoods: is neighborhood walkability a key element for Belgian adolescents? AB - BACKGROUND: In adult research, neighborhood walkability has been acknowledged as an important construct among the built environmental correlates of physical activity. Research into this association has only recently been extended to adolescents and the current empirical evidence is not consistent. This study investigated whether neighborhood walkability and neighborhood socioeconomic status (SES) are associated with physical activity among Belgian adolescents and whether the association between neighborhood walkability and physical activity is moderated by neighborhood SES and gender. METHODS: In Ghent (Belgium), 32 neighborhoods were selected based on GIS-based walkability and SES derived from census data. In total, 637 adolescents (aged 13-15 year, 49.6% male) participated in the study. Physical activity was assessed using accelerometers and the Flemish Physical Activity Questionnaire. To analyze the associations between neighborhood walkability, neighborhood SES and individual physical activity, multivariate multi-level regression analyses were conducted. RESULTS: Only in low-SES neighborhoods, neighborhood walkability was positively associated with accelerometer-based moderate to vigorous physical activity and the average activity level expressed in counts/minute. For active transport to and from school, cycling for transport during leisure time and sport during leisure time no association with neighborhood walkability nor, with neighborhood SES was found. For walking for transport during leisure time a negative association with neighborhood SES was found. Gender did not moderate the associations of neighborhood walkability and SES with adolescent physical activity. CONCLUSIONS: Neighborhood walkability was related to accelerometer-based physical activity only among adolescent boys and girls living in low-SES neighborhoods. The relation of built environment to adolescent physical activity may depend on the context. PMID- 22216925 TI - NTPDase activity in lymphocytes of rats infected by Trypanosoma evansi. AB - Trypanosoma evansi is the aetiological agent of trypanosomosis in domestic animals. In this pathology, an inflammatory response can be observed and, as a consequence, the increase of extracellular adenine nucleotides such as ATP. These nucleotide concentrations are regulated by ectoenzymes such as NTPDase (EC 3.6.1.5, CD39), which catalyses the hydrolysis of ATP and ADP into AMP. In this study, the activity of NTPDase in lymphocytes of rats experimentally infected with T. evansi was evaluated. The animals were inoculated with the parasite and monitored by blood smear on a daily basis. The animals were then were divided into 4 groups according to the degree of parasitaemia and period of infection. The blood collections for enzyme analysis and lymphocyte count were performed on the 3rd (beginning of infection), 5th (acute infection) and 15th (chronic infection) days post-infection (p.i.). The control group was composed of non infected animals. In the infected group a decrease in ATP hydrolysis (36%) was observed on the 3rd day p.i. and a decrease in ADP hydrolysis (62%) was observed on the 5th day p.i. when compared to the control. On the 15th day p.i., an increase in ATP (94%) and ADP (50%) hydrolysis was observed in the infected group. Considering these data it is suggested that NTPDase activity is altered on the surface of lymphocytes of rats infected with T. evansi at different time points of infection. PMID- 22216926 TI - Activated plasma coagulation beta-Factor XII-induced vasoconstriction in rats. AB - By inducing BK (bradykinin)-stimulated adrenomedullary catecholamine release, bolus injection of the beta-fragment of activated plasma coagulation Factor XII (beta-FXIIa) transiently elevates BP (blood pressure) and HR (heart rate) of anaesthetized, vagotomized, ganglion-blocked, captopril-treated bioassay rats. We hypothesized that intravenous infusion of beta-FXIIa into intact untreated rats would elicit a qualitatively similar vasoconstrictor response. BN (Brown Norway) rats received for 60 min either: (i) saline (control; n=10); (ii) beta-FXIIa (85 ng/min per kg of body weight; n=9); or (iii) beta-FXIIa after 2ADX (bilateral adrenalectomy; n=9). LV (left ventricular) volume and aortic BP were recorded before (30 min baseline), during (60 min) and after (30 min recovery) the infusion. TPR (total peripheral resistance) was derived from MAP (mean arterial pressure), SV (stroke volume) and HR. Saline had no haemodynamic effects. beta FXIIa infusion increased its plasma concentration 3-fold in both groups. In adrenally intact rats, beta-FXIIa infusion increased MAP by 6% (5+/-2 mmHg) and TPR by 45% (0.50+/-0.12 mmHg/ml per min), despite falls in SV (-38+/-8 MUl) and HR [-18+/-5 b.p.m. (beats/min)] (all P<0.05). In 2ADX rats, beta-FXIIa had no HR effect, but decreased SV (-89+/-9 MUl) and MAP (-4+/-1 mmHg), and increased TPR by 66% (0.59+/-0.15 mmHg/ml per min) (all P<0.05). After infusion, adrenally intact rats exhibited persistent vasoconstriction (MAP, 10+/-1 mmHg; TPR, 0.55+/ 0.07 mmHg/ml per min; both P<0.05), whereas in 2ADX rats, MAP remained 5+/-1 mmHg below baseline (P<0.05) and TPR returned to baseline. End-study arterial adrenaline (epinephrine) concentrations in the three groups were 1.9+/-0.6, 9.8+/ 4.1 and 0.6+/-0.2 nmol/l respectively. Thus, in neurally intact lightly anaesthetized untreated rats, beta-FXIIa infusion induces both adrenal catecholamine-mediated and adrenally independent increases in peripheral resistance. PMID- 22216927 TI - Paracetamol serum concentrations in preterm infants treated with paracetamol intravenously: a case series. AB - INTRODUCTION: Until now, studies on paracetamol given intravenously have mainly been performed with the pro-drug propacetamol or with paracetamol in preterm babies above 32 weeks of gestation. Studies in these babies indicate that intravenous paracetamol is tolerated well, however studies on the efficacy of intravenous paracetamol are lacking. There are no pharmacokinetic data on the administration of multiple doses of paracetamol in preterm babies with a gestational age below 32 weeks. CASE PRESENTATION: We present a case series of nine Caucasian preterm babies, six boys and three girls, with a mean gestational age of 28.6 weeks (range 25.9 to 31.6 weeks). Case one, a girl with a gestational age of 25 weeks and six days, presented with necrotizing enterocolitis. In the second case, a female baby with a gestational age of 26 weeks and two days presented with hematoma. In case three, a female baby with a gestation of 26 weeks and one day developed intraventricular hemorrhage. In case four, a male baby with a gestational age of 31 weeks and four days presented with pain after vacuum delivery. Case five, a female baby born after a gestation of 29 weeks and six days presented with hematoma. In case six, a male baby with a gestation of 30 weeks and six days presented with hematoma. In case seven, a male baby, born with a gestational age of 30 weeks and six days, presented with caput succedaneum and hematoma. In case eight, a male baby, born after a gestation of 28 weeks and four days, developed abdominal distention. Case nine, a female baby, born with a gestational age of 27 weeks and three days presented with hematoma. These babies were treated with intravenous paracetamol 15 mg/kg every six hours. Serum concentrations and aspartate transaminase were determined after prolonged administration. Pain scores were assessed using the Premature Infant Pain Profile. CONCLUSION: Paracetamol serum concentrations ranged from 8 to 64 mg/L after eight to 12 doses of intravenous paracetamol. Adequate analgesia was obtained in seven babies. During paracetamol therapy the median serum level of aspartate transaminase was 20 U/L (range 12 to 186 U/L). This case series indicates that prolonged intravenous administration of paracetamol in preterm babies with a gestational age of less than 32 weeks is tolerated well in the first days after birth. However, in the absence of proper pharmacokinetic data in this age group we cannot advocate the use of paracetamol intravenously. PMID- 22216929 TI - Host specificity and temporal and seasonal shifts in host preference of a web spider parasitoid Zatypota percontatoria. AB - Current knowledge about polysphinctine parasite wasps' interactions with their spider hosts is very fragmented and incomplete. This study presents the host specificity of Zatypota percontatoria (Muller) (Hymenoptera: Ichneumonidae) and its adaptation to varying host availability. Two years of field observations show that Z. percontatoria is a stenophagous parasitoid that parasitizes only five closely related web-building spiders of the family Theridiidae (Araneae). Within the Theridiidae it attacks only species belonging to a small group of species, here called the "Theridion" group. These hosts have a similar biology, but are available at different levels of abundance and at different sizes over the season. Laboratory experiments showed that this wasp species ignores linyphiid, araneid or dictynid spiders and accepts only theridiid spiders of the "Theridion" group. In the field study, wasp females preferred older juvenile and sub-adult female spider instars with intermediate body size. Only 5% of the parasitized spiders were males. Parasitism in the natural population of theridiid spiders was on average 1.3%. Parasitism was most frequent on two species, Theridion varians Hahn in 2007 and Neottiura bimaculata Linnaeus in 2008. The parasitization rate was positively correlated with spider abundance. The wasp responded adaptively to seasonal changes in host abundance and host body size and shifted host preference according to the availability of suitable hosts during, as well as between, seasons. In spring and summer the highest percentage of parasitism was on T. varians and in autumn it was on N. bimaculata. PMID- 22216931 TI - Reaction of cobalt(III) with sodium salicylate in aqueous perchloric acid. PMID- 22216930 TI - Effects of phorbol myristate acetate and sivelestat on the lung injury caused by fat embolism in isolated lungs. AB - BACKGROUND: Fat embolism syndrome (FES) associated with acute lung injury (ALI) is a clinical condition following long bone fracture. We have reported 14 victims due to ALI with FES. Our laboratory has developed an animal model that produced fat emboli (FE). The major purpose of this study was to test whether neutrophil activation with phorbol myristate acetate (PMA) and inhibition with sivelestat (SVT) exert protection on the lung. METHODS: The lungs of Sprague-Dawley rats were isolated and perfused. FE was produced by addition of corn oil micelles into the lung perfusate. PMA and SVT were given simultaneously with FE. Parameters such as lung weight/body weight ratio, LW gain, exhaled nitric oxide (NO), protein concentration in bronchoalveolar lavage relating to ALI were measured. The neutrophil elastase (NE), myeloperoxidase, malondialdehyde and phopholipase A2 activity were determined. We also measured the nitrate/nitrite, methyl guanidine (MG), and cytokines. Pulmonary arterial pressure and microvascular permeability were assessed. Lung pathology was examined and scored. The inducible and endothelial NO synthase (iNOS and eNOS) were detected. RESULTS: FE caused ALI and increased biochemical factors. The challenge also resulted in pulmonary hypertension and increased microvascular permeability. The NE appeared to be the first to reach its peak at 1 hr, followed by other factors. Coadministration with PMA exacerbated the FE-induced changes, while SVT attenuated the effects of FE. CONCLUSIONS: The FE-induced lung changes were enhanced by PMA, while SVT had the opposite effect. Sivelestat, a neutrophil inhibitor may be a therapeutic choice for patients with acute respiratory distress syndrome (ARDS) following fat embolism. PMID- 22216932 TI - Assessing the in vitro and in vivo toxicity of superparamagnetic iron oxide nanoparticles. PMID- 22216933 TI - Burr-hole drainage for the treatment of acute epidural hematoma in coagulopathic patients: a report of eight cases. AB - Craniotomy has been accepted as the treatment of choice for the management of acute epidural hematomas (AEDH). However, in practice, it seems possible to evacuate AEDH via a single burr hole instead of the traditional craniotomy in certain circumstances. Among 160 patients with AEDH meeting criteria for evacuation admitted to the emergency and accident division of our center between 2006 and 2009, we found 8 cases of hematoma appearing isodense to brain parenchyma on computed tomography (CT), who had concomitant coagulopathy. These patients were managed by burr-hole drainage for treatment of the liquefied AEDH. A closed drainage system was then kept in the epidural space for 3 days. In all 8 patients, AEDH was evacuated successfully via burr-hole placement over the site of hematoma. The level of consciousness and other symptoms improved within the first day, and no patient required an additional routine craniotomy. For patients with slowly-developing AEDH in the context of impaired coagulation, burr-hole evacuation and drainage might be a less invasive method of treatment compared to conventional craniotomy. PMID- 22216934 TI - Compositional differences between size classes of dissolved organic matter from freshwater and seawater revealed by an HPLC-FTIR system. AB - The molecular complexity of dissolved organic matter (DOM) hinders its characterization. New approaches are thus needed for a better understanding of DOM reactivity and fate in aquatic systems. In this study, high-performance liquid chromatography (HPLC), using size-exclusion separation, was coupled with Fourier transform infrared spectroscopy (FTIR). A solvent-elimination interface was used to deposit DOM fractions onto a germanium disk that were then analyzed by FTIR. Samples included ultrafiltered DOM (UDOM) and fulvic acids from the St. Lawrence Estuary and its tributaries. Results showed significant compositional changes with molecular size and origin, especially in UDOM. Larger fractions of UDOM contained more carbohydrates, amides, aromatics/alkenes and aliphatics, while smaller fractions contained more carboxylate and OH groups. Small marine molecules (500-900 Da) were also enriched in sulfate groups that appeared bound to UDOM. Large marine molecules were the most amide-rich fractions. Fulvic acids were enriched in carboxylate and OH groups, showed little changes in composition, and appeared similar to small terrigenous (riverine) UDOM even in marine water. This work shows that an HPLC-FTIR system is a powerful and complementary tool in the characterization of DOM. The compositional changes observed may explain the reported contrasting reactivity and fate of DOM having different size and origin. PMID- 22216935 TI - Hamamelitannin from witch hazel (Hamamelis virginiana) displays specific cytotoxic activity against colon cancer cells. AB - Hamamelis virginiana (witch hazel) bark is a rich source of condensed and hydrolyzable tannins reported to exert a protective action against colon cancer. The present study characterizes different witch hazel tannins as selective cytotoxic agents against colon cancer. To cover the structural diversity of the tannins that occur in H. virginiana bark, the hydrolyzable tannins, hamamelitannin and pentagalloylglucose, together with a proanthocyanidin-rich fraction (F800H4) were selected for the study. Treatment with these compounds reduced tumor viability and induced apoptosis, necrosis, and S-phase arrest in the cell cycle of HT29 cells, with hamamelitannin being the most efficient. Owing to polyphenol-mediated H(2)O(2) formation in the incubation media, the antiproliferative effect was determined in the presence and absence of catalase to rule out any such interference. The presence of catalase significantly changed the IC(50) only for F800H4. Furthermore, at concentrations that inhibit the growth of HT29 cells by 50%, hamamelitannin had no harmful effects on NCM460 normal colonocytes, whereas pentagalloylglucose inhibited both cancerous and normal cell growth. Using the TNPTM assay, we identified a highly reactive phenolic position in hamamelitannin, which may explain its efficacy at inhibiting colon cancer growth. PMID- 22216936 TI - Boosting a teen substance use prevention program with motivational interviewing. AB - A brief motivational interviewing (MI) intervention may be a viable adjunct to school-based substance abuse prevention programs. This article describes the development and implementation of a brief MI intervention with 573 adolescents (mean age 16.8; 40.3% female, 68% Latino) enrolled in eight continuation high schools in Southern California. Study participants were assigned to the MI condition in a randomized controlled trial of Project Toward No Drug Abuse. Data are provided on dosage, topics discussed, and quality of MI determined with the Motivational Interviewing Skill Code (MISC). Results suggest that the protocol was feasible and implemented with adequate fidelity. The study's limitations are noted. PMID- 22216937 TI - A comprehensive comparative review of adenosine diphosphate receptor antagonists. AB - INTRODUCTION: Thrombosis risk necessitates dual antiplatelet therapy with aspirin and an adenosine diphosphate (ADP) receptor antagonist, in patients who have acute coronary syndrome. Current guidelines emphasize the critical role of dual antiplatelet therapy in both medical management and invasive strategy, especially in patients undergoing percutaneous coronary intervention. With the availability of multiple ADP-receptor antagonists, it is crucial to select the most appropriate agent for each patient. AREAS COVERED: The pertinent trials were identified through a MEDLINE search, in addition to a manual search from the articles retrieved. This review examines the differences between clopidogrel, prasugrel and ticagrelor in terms of their pharmacological/pharmacokinetic properties, clinical efficacy, drug interactions and safety parameters. EXPERT OPINION: Prasugrel and ticagrelor exhibit greater platelet inhibition and superior efficacy compared with clopidogrel, at the expense of higher bleeding risk. Prasugrel and ticagrelor should be preferred over clopidogrel in patients who are at a high risk of thrombotic events with low risk of bleeding. Additionally, these two agents may offer advantage over clopidogrel in those patients who might have risk for drug resistance due to CYP2C19 polymorphism. In selecting the ideal agent for patients, clinicians should tailor the antiplatelet regimen by considering individual risk factors and medication characteristics. PMID- 22216941 TI - A recipe for designing molecules with ever-increasing electron affinities. AB - Halogens possess among the highest electron affinities of elements in the periodic table. Superhalogen molecules with electron affinities higher than those of halogen atoms have been known to form when a metal atom is surrounded with halogen atoms. Recently, it was discovered that a new class of molecules called hyperhalogens with electron affinities higher than those of superhalogens can form when the latter serve as the building block. By use of density functional theory and B3LYP hybrid exchange-correlation functional we show that molecules with electron affinities even higher can be formed by using hyperhalogens as building blocks. We demonstrate this by using Na and Li as metal atoms and F, BF(4), and Na(BF(4))(2) as halogen, superhalogen, and hyperhalogen building blocks. The predicted electron affinities of Na[Na(BF(4))(2)](2) and Li[Li(BF(4))(2)](2) are 9.18 and 9.01 eV, which are, respectively, 0.85 and 0.5 eV higher than those of their hyperhalogen [Na(BF(4))(2) and Li(BF(4))(2)] counterparts. PMID- 22216939 TI - In situ ATR-FTIR studies on MgCl2-diisobutyl phthalate interactions in thin film Ziegler-Natta catalysts. AB - To study the surface structure of MgCl(2) support and its interaction with other active components in Ziegler-Natta catalyst, such as electron donors, we prepared a thin film analogue for Ziegler-Natta ethylene polymerization catalyst support by spin-coating a solution of MgCl(2) in ethanol, optionally containing a diester internal donor (diisobutyl-ortho-phthalate, DIBP) on a flat Si crystal surface. The donor content of these films was quantified by applying attenuated total internal reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and X-ray photoelectron spectroscopy (XPS). Changes in the interaction of DIBP with MgCl(2) at various temperatures were monitored by in situ ATR-FTIR. Upon increasing the temperature, a shift in the (C?O) band toward lower wavenumbers was observed together with the depletion of (O-H) stretching band due to the desorption of residual ethanol. We assign this shift to gradual redistribution of adsorbed DIBP from adsorption sites on the MgCl(2) (104) surface toward the more acidic MgCl(2) (110) surface. The morphologies of MgCl(2) and MgCl(2)/DIBP films were studied by transmission electron microscopy (TEM) revealing a preferential orientation of ClMgCl layers (001) parallel to the lateral film dimensions. This orientation becomes more pronounced upon annealing. In the absence of donor, the MgCl(2) grow in to large crystals aligned in large domains upon annealing. Both crystal growth and alignment is impeded by the presence of donor. PMID- 22216942 TI - Sequential C-N and C-O bond formation in a single pot: synthesis of 2H benzo[b][1,4]oxazines from 2,5-dihydroxybenzaldehyde and amino acid precursors. AB - Functionalized beta-aryl alanine ester derivatives were found to undergo rapid C N and C-O bond formation with quinol carbonyl compounds to afford 2H benzo[b][1,4]oxazines in good to excellent yields. This unprecedented finding reported herein offers a straightforward, highly efficient, and rapid method for the synthesis of 2H-benzo[b][1,4]oxazines. PMID- 22216938 TI - Oncolytic virotherapy in veterinary medicine: current status and future prospects for canine patients. AB - Oncolytic viruses refer to those that are able to eliminate malignancies by direct targeting and lysis of cancer cells, leaving non-cancerous tissues unharmed. Several oncolytic viruses including adenovirus strains, canine distemper virus and vaccinia virus strains have been used for canine cancer therapy in preclinical studies. However, in contrast to human studies, clinical trials with oncolytic viruses for canine cancer patients have not been reported. An 'ideal' virus has yet to be identified. This review is focused on the prospective use of oncolytic viruses in the treatment of canine tumors - a knowledge that will undoubtedly contribute to the development of oncolytic viral agents for canine cancer therapy in the future. PMID- 22216943 TI - Delusions and metacognition in patients with schizophrenia. AB - INTRODUCTION: The aim of the present study was to explore the basis of the strong feeling of conviction and the high resistance to change characteristic of delusions and to test whether patients with schizophrenia suffering from delusions have specific metacognitive impairments when compared to both patients without delusions and healthy controls. METHODS: 14 actively delusional patients with schizophrenia, 14 nondelusional patients, and 14 healthy subjects were administered two measures assessing different aspects of metacognition: an emotional metacognitive version of the WCST adapted from Koren et al. (2004) and the Beck Cognitive Insight Scale. RESULTS: Relative to both healthy controls and nondelusional patients, delusional participants were specifically impaired on metacognitive measures of free choice improvement and global monitoring. This was correlated with high self-certainty on the BCIS relative to nondelusional patients. CONCLUSIONS: Our results suggest that metacognitive impairments play an important role in the maintenance of delusional beliefs. It may therefore be important to adapt remediation strategies to the metacognitive profiles of patients. PMID- 22216944 TI - Theory of Mind as a potential trait marker of schizophrenia: a family study. AB - INTRODUCTION: Although there is some evidence that Theory of Mind (ToM) deficits may be trait markers of schizophrenia it is not clear yet if ToM deficits are primary deficits, that is, to be independent of deficits in general intellectual abilities and executive function. The aim was to examine if ToM deficits may be trait markers of the illness and the effect of cognitive inhibition, general intellectual abilities and depression on ToM abilities of patients with schizophrenia and their unaffected parents. METHODS: We assessed ToM abilities (first-order and second-order ToM stories, The Revised Eyes Test), cognitive inhibition (Stroop Task), general intellectual ability (Standard Progressive Matrices Test Plus) in patients with schizophrenia (N=21) and their unaffected fathers (N=21) and mothers (N=21) in comparison with healthy control families (healthy control males, N=21, healthy control fathers, N=21, healthy control mothers, N=21) RESULTS: Patients showed deficits in first-order ToM tasks but some of these deficits were mediated by general intellectual abilities. Impairments in cognitive inhibition mediated only patients' performance in The Revised Eyes Test. Patients showed deficits in second-order ToM stories independently of deficits in general intellectual abilities and cognitive inhibition. Unaffected parents did not show deficits in first-order ToM tasks, whereas they showed deficits in second-order ToM stories. However, the deficits that unaffected parents showed in second-order ToM stories were mediated by their deficits in general intellectual abilities, and there was an effect of remitted depression on the unaffected mothers' performance. CONCLUSIONS: The results suggest that intact neurocognitive and general intellectual abilities are necessary in order patients and their unaffected parents to pass successfully ToM tasks. Patients and their unaffected parents show ToM deficits but these deficits are not similar. Patients show ToM deficits but these deficits seem to be a component of the pathophysiology of the illness (e.g., deficits in executive function, general intellectual abilities). PMID- 22216946 TI - Effects of interaction of ionic and nonionic surfactants on self-assembly of PEO PPO-PEO triblock copolymer in aqueous solution. AB - We study the effects of interaction of surfactants on the self-assembly of a triblock copolymer in aqueous solution by measuring percolation transition temperature (T(p)), micellar size, zeta potential, and rheological properties. We use PEO-PPO-PEO triblock copolymer (Pluronics-F108) with anionic sodium dodecyl sulfate (SDS), cationic cetyltrimethylammonium bromide (CTAB), and nonionic nonylphenolethoxylate (NP9) for our investigations. The addition of SDS in pluronics solution leads to a dramatic reduction in the viscoelastic properties, while it remains almost unaffected with CTAB and NP9. The 2 orders of magnitude decrease in the elastic modulus in the presence of SDS indicates a soft solid like microstructure formed by aggregating self-assembled triblock polymers. Our results indicate a strong electrostatic barrier imparted by the headgroup of SDS at the core-corona interface that inhibits the formation of hexagonally packed layers of micelles and the packing order. The analysis of autocorrelation function at high concentrations of ionic surfactant indicates that pure surfactant micelles coexist with large intermicellar structures. With increasing surfactant concentration, the zeta potential of the pluronic micelle is found to decrease. These results suggest that the microstructure and elastic properties of block copolymer micelles can be tuned by varying the concentrations of ionic surfactant that enhances their potential in applications as nanocarriers for drug delivery systems. PMID- 22216948 TI - Differences between children and adolescents who commit suicide and their peers: A psychological autopsy of suicide victims compared to accident victims and a community sample. AB - BACKGROUND: The purpose of this study was to gain knowledge about the circumstances related to suicide among children and adolescents 15 years and younger. METHODS: We conducted a psychological autopsy, collecting information from parents, hospital records and police reports on persons below the age of 16 who had committed suicide in Norway during a 12-year period (1993-2004) (n = 41). Those who committed suicide were compared with children and adolescents who were killed in accidents during the same time period (n = 43) and with a community sample. RESULTS: Among the suicides 25% met the criteria for a psychiatric diagnosis and 30% had depressive symptoms at the time of death. Furthermore, 60% of the parents of the suicide victims reported the child experienced some kind of stressful conflict prior to death, whereas only 12% of the parents of the accident victims reported such conflicts. CONCLUSION: One in four suicide victims fulfilled the criteria for a psychiatric diagnosis. The level of sub-threshold depression and of stressful conflict experienced by youths who committed suicide did not appear to differ substantially from that of their peers, and therefore did not raise sufficient concern for referral to professional help. PMID- 22216947 TI - Living with diabetes: rationale, study design and baseline characteristics for an Australian prospective cohort study. AB - BACKGROUND: Diabetes mellitus is a major global public health threat. In Australia, as elsewhere, it is responsible for a sizeable portion of the overall burden of disease, and significant costs. The psychological and social impact of diabetes on individuals with the disease can be severe, and if not adequately addressed, can lead to the worsening of the overall disease picture. The Living With Diabetes Study aims to contribute to a holistic understanding of the psychological and social aspects of diabetes mellitus. METHODS/DESIGN: The Living With Diabetes Study is a 5-year prospective cohort study, based in Queensland, Australia. The first wave of data, which was collected via a mailed self-report survey, was gathered in 2008, with annual collections thereafter. Measurements include: demographic, lifestyle, health and disease characteristics; quality of life (EQ-5D, ADDQoL); emotional well-being (CES-D, LOT-R, ESSI); disease self management (PAM); and health-care utilisation and patient-assessed quality of care (PACIC). 29% of the 14,439 adults who were invited to participate in the study agreed to do so, yielding a sample size of 3,951 people. DISCUSSION: The data collected by the Living With Diabetes Study provides a good representation of Australians with diabetes to follow over time in order to better understand the natural course of the illness. The study has potential to further illuminate, and give a comprehensive picture of the psychosocial implications of living with diabetes. Data collection is ongoing. PMID- 22216949 TI - Predictors of asthma self-management education among children and adults--2006 2007 behavioral risk factor surveillance system asthma call-back survey. AB - BACKGROUND: Patient self-management, besides expert care, is necessary to improve health outcomes among persons with asthma. Our objective was to describe the characteristics of persons with asthma likely to receive asthma self-management education. METHODS: The 2006 and 2007 Behavioral Risk Factor Surveillance System (BRFSS) Child and Adult Asthma Call-back Survey (ACBS) data were analyzed. Binary and multinomial response logistic regression models were used to examine the association between asthma self-management education and explanatory variables. RESULTS: Of the 31,278 persons who ever had asthma, 3953 of the children (75.8%) and 19,723 of the adults (72.8%) were classified as having active asthma. For both children and adults, the three most commonly reported asthma education components were being taught how to use an inhaler (78.6% and 89.8%, respectively); being taught what to do during an asthma episode (86.3% and 74.6%); and to recognize early signs or symptoms of an asthma episode (82.0% and 64.4%). Children and adults who reported routine care visits, hospitalization, and asthma episodes in the past 12 months because of asthma were more likely to report several asthma education components and higher asthma education scores. Children aged 12-17 years were more likely to report having instruction in peak flow meter use (1.3; 1.1-1.6) and inhaler use (1.3; 1.2-1.4), whereas older adults (aged 54-64 years or 65+ years), adults who were not high school (HS) graduates, and smokers were less likely to report having asthma management education than the corresponding comparison groups. CONCLUSIONS: Having a routine care visit, being hospitalized, and having an asthma episode were significantly associated with reporting multiple asthma education components, whereas being an older adult, having less than a HS degree, and being a smoker were associated with reporting fewer asthma education components. Asthma control programs should continue to monitor asthma self-management education and promote asthma education to all persons with asthma, especially for older adults, persons with less education, and smokers. PMID- 22216952 TI - Considering RNAi experimental design in parasitic helminths. AB - Almost a decade has passed since the first report of RNA interference (RNAi) in a parasitic helminth. Whilst much progress has been made with RNAi informing gene function studies in disparate nematode and flatworm parasites, substantial and seemingly prohibitive difficulties have been encountered in some species, hindering progress. An appraisal of current practices, trends and ideals of RNAi experimental design in parasitic helminths is both timely and necessary for a number of reasons: firstly, the increasing availability of parasitic helminth genome/transcriptome resources means there is a growing need for gene function tools such as RNAi; secondly, fundamental differences and unique challenges exist for parasite species which do not apply to model organisms; thirdly, the inherent variation in experimental design, and reported difficulties with reproducibility undermine confidence. Ideally, RNAi studies of gene function should adopt standardised experimental design to aid reproducibility, interpretation and comparative analyses. Although the huge variations in parasite biology and experimental endpoints make RNAi experimental design standardization difficult or impractical, we must strive to validate RNAi experimentation in helminth parasites. To aid this process we identify multiple approaches to RNAi experimental validation and highlight those which we deem to be critical for gene function studies in helminth parasites. PMID- 22216951 TI - Defining the concept of 'tick repellency' in veterinary medicine. AB - Although widely used, the term repellency needs to be employed with care when applied to ticks and other periodic or permanent ectoparasites. Repellency has classically been used to describe the effects of a substance that causes a flying arthropod to make oriented movements away from its source. However, for crawling arthropods such as ticks, the term commonly subsumes a range of effects that include arthropod irritation and consequent avoiding or leaving the host, failing to attach, to bite, or to feed. The objective of the present article is to highlight the need for clarity, to propose consensus descriptions and methods for the evaluation of various effects on ticks caused by chemical substances. PMID- 22216955 TI - Letter to the editor. Diffuse unilateral subacute neuroretinitis (DUSN). AB - PURPOSE: To show that diffuse unilateral subacute neuroretinitis (DUSN) may masquerade as multiple evanescent white dot syndrome, and to describe structural and functional recovery following treatment in DUSN. DESIGN: Case report. METHODS: Baseline and serial optical coherence tomography (OCT) and perimetry following photocoagulation of nematode. RESULTS: After laser treatment, the inner segment-outer segment (IS-OS) junction was restored and the visual field was improved. CONCLUSIONS: DUSN, early on, can be mistaken for other inflammatory white dot syndromes. OCT and perimetry, in combination, provide strong support for success of treatment with photocoagulation. PMID- 22216957 TI - Clinical application of stem cell therapy in Parkinson's disease. AB - Cell replacement therapies in Parkinson's disease (PD) aim to provide long lasting relief of patients' symptoms. Previous clinical trials using transplantation of human fetal ventral mesencephalic (hfVM) tissue in the striata of PD patients have provided proof-of-principle that such grafts can restore striatal dopaminergic (DA-ergic) function. The transplants survive, reinnervate the striatum, and generate adequate symptomatic relief in some patients for more than a decade following operation. However, the initial clinical trials lacked homogeneity of outcomes and were hindered by the development of troublesome graft induced dyskinesias in a subgroup of patients. Although recent knowledge has provided insights for overcoming these obstacles, it is unlikely that transplantation of hfVM tissue will become routine treatment for PD owing to problems with tissue availability and standardization of the grafts. The main focus now is on producing DA-ergic neuroblasts for transplantation from stem cells (SCs). There is a range of emerging sources of SCs for generating a DA ergic fate in vitro. However, the translation of these efforts in vivo currently lacks efficacy and sustainability. A successful, clinically competitive SC therapy in PD needs to produce long-lasting symptomatic relief without side effects while counteracting PD progression. PMID- 22216959 TI - A latent class analysis of alcohol abuse and dependence symptoms among Puerto Rican youth. AB - The study aim was to classify youths into homogenous groups based on their symptoms of Alcohol Abuse and Dependence. An NIDA-funded cross-sectional survey was administered to 622 middle and high school students in San Juan, Puerto Rico in 2000. Latent class analysis (LCA) examined the Alcohol Abuse and Dependence symptoms. Three distinct classes of drinkers were found: low (86.0% of sample), moderate (11.7% of sample), and high (2.3% of sample) severity classes which were distinguished by differing estimated probabilities of symptom reporting. The study has implications for the diagnosis of Alcohol Abuse and Dependence among Puerto Rican youths. Limitations are also noted. PMID- 22216960 TI - Modulating cell behaviors on chiral polymer brush films with different hydrophobic side groups. AB - Chirality is one of the significant biochemical signatures of life. Nearly all biological polymers are homochiral as they usually show high preference toward one specific enantiomer. This phenomenon inspires us to design biomaterials with chiral units and study their interactions with cells and other biological entities. In this article, through adopting three pairs of aliphatic amino acids with different hydrophobic side groups as chiral species, and using two adhesive cell lines as examples, we show that the chirality of polymer brushes can trigger differential cell behaviors on the enantiomorphous surfaces, and more interestingly, such chiral effect on cellular behaviors can be modulated in a certain extent by varying the hydrophobic side groups of the chiral moieties composing the polymers. This work not only proves the versatility of the chiral effect at the cell level but also demonstrates a method to bridge the gap between organic signal molecules and biomaterials. It thus points out a promising approach for designing novel biomaterials based on the chiral effect, which will be an important complement for conventional strategies in the study of biomaterials. PMID- 22216962 TI - Fabrication of CaO-based sorbents for CO2 capture by a mixing method. AB - Three types of sorbent were fabricated using various calcium and support precursors via a simple mixing method, in order to develop highly effective, durable, and cheap CaO-based sorbents suitable for CO(2) capture. The sorption performance and morphology of the sorbents were measured in a thermogravimetric analyzer and a scanning electron microscopy, respectively. The experimental results indicate that cement is a promising low-cost support precursor for contributing to the enhancement of cyclic CO(2) sorption capacity, especially when organometallic calcium precursors were used. A sorbent (with 75% CaO content) made from calcium l-lactate hydrate and cement showed the highest CO(2) sorption capacity of 0.36 g of CO(2)/g of sorbent and its capacity decreased only slightly after 70 cycles of carbonation and calcination. PMID- 22216963 TI - Personalizing treatment in type 2 diabetes: a self-monitoring of blood glucose inclusive innovative approach. AB - A strong correlation exists between improved blood glucose control, obtained from the earliest stages of diabetes, and the prevention of complications. However, tight glycometabolic control does not always translate into an advantage for every patient. Because the characteristics of individual patients play an important role in diabetes care, there is a need to develop personalized action plans. This article suggests tailored therapeutic algorithms for some of the commonest type 2 diabetes phenotypes, taking into consideration age, body mass index, presence of micro- and macrovascular complications, hypoglycemia risk, and the co-existence of chronic renal failure. Particular emphasis is placed on exploiting information supplied through the rational use of self-monitoring of blood glucose as a tool for optimizing diabetes management, according to the prevalence of fasting/preprandial or postprandial hyperglycemia. PMID- 22216967 TI - Terminal alkyne addition to diazodicarboxylates: synthesis of hydrazide linked alkynes (ynehydrazides). AB - A new route to form C(sp)-N bonds has been developed via addition of in situ generated lithium acetylides to sterically hindered diazodicarboxylates. The reaction provides straightforward access to a previously unexplored ynehydrazide class of stable N-linked alkynes directly from commercially available precursors. Preliminary results show that alkynyl hydrazides are useful reagents for the selective installation of nitrogen functional groups and as precursors to pharmaceutically relevant heterocycles using metal catalyzed cycloadditions and condensations. PMID- 22216965 TI - Diversity in parasitic nematode genomes: the microRNAs of Brugia pahangi and Haemonchus contortus are largely novel. AB - BACKGROUND: MicroRNAs (miRNAs) play key roles in regulating post-transcriptional gene expression and are essential for development in the free-living nematode Caenorhabditis elegans and in higher organisms. Whether microRNAs are involved in regulating developmental programs of parasitic nematodes is currently unknown. Here we describe the the miRNA repertoire of two important parasitic nematodes as an essential first step in addressing this question. RESULTS: The small RNAs from larval and adult stages of two parasitic species, Brugia pahangi and Haemonchus contortus, were identified using deep-sequencing and bioinformatic approaches. Comparative analysis to known miRNA sequences reveals that the majority of these miRNAs are novel. Some novel miRNAs are abundantly expressed and display developmental regulation, suggesting important functional roles. Despite the lack of conservation in the miRNA repertoire, genomic positioning of certain miRNAs within or close to specific coding genes is remarkably conserved across diverse species, indicating selection for these associations. Endogenous small interfering RNAs and Piwi-interacting (pi)RNAs, which regulate gene and transposon expression, were also identified. piRNAs are expressed in adult stage H. contortus, supporting a conserved role in germline maintenance in some parasitic nematodes. CONCLUSIONS: This in-depth comparative analysis of nematode miRNAs reveals the high level of divergence across species and identifies novel sequences potentially involved in development. Expression of novel miRNAs may reflect adaptations to different environments and lifestyles. Our findings provide a detailed foundation for further study of the evolution and function of miRNAs within nematodes and for identifying potential targets for intervention. PMID- 22216966 TI - Releasable SNAP-tag probes for studying endocytosis and recycling. AB - Site-specific labeling of cellular proteins with chemical probes is a powerful tool for live cell imaging of biological processes. One popular system, known as the SNAP-tag, is based on an engineered variant of the 20-kDa DNA repair protein O(6)-alkylguanine-DNA-alkyltransferase (AGT) that covalently reacts with O(6) benzylguanine (BG) and can be derivatized with a number of reporter groups. For studying the endocytosis and recycling of cell surface proteins, the covalent nature of BG binding to the SNAP-tag is problematic, since removing excess noninternalized probe from the cell surface is not feasible. Here we describe a modification of the SNAP-tag technology that permits the rapid release of fluorescently labeled probes from the cell surface without affecting the population of labeled molecules sequestered within endosomes. This simple yet effective approach allows quantitative measurements of endocytosis and recycling in both imaging and biochemical assays and is especially useful when studying endosomal dynamics in live cells. PMID- 22216968 TI - Transmesenteric approach for left transperitoneal renal surgery: technique and experience. AB - INTRODUCTION: In the last few years laparoscopic surgery has become the gold standard for the treatment of several urological diseases such as renal cancer and ureteropelvic junction obstruction (UPJO). A transmesenteric approach for left laparoscopic pyeloplasty has been recently described in order to avoid bowel manipulation and the potentially related complications. The aim of the present study is to describe the surgical technique and the advantages of the transmesenteric approach for laparoscopic pyeloplasty, pyelolithotomy, and simple nephrectomy in our experience. SUBJECTS AND METHODS: From December 2007 to May 2010, 12 laparoscopic procedures for left renal diseases were performed using a transmesenteric approach. The indications were left UPJO in 9 cases, left pelvic ureteral stones in 2 cases, and left end-stage kidney disease in one case. RESULTS: No conversions or intraoperative complications were observed. No blood transfusions were required. Resumption of oral intake and canalization occurred in all cases within 48 hours of the procedure. All patients had an uneventful postoperative course. CONCLUSIONS: The laparoscopic transmesenteric approach represents an interesting and advantageous technical improvement of minimally invasive surgery for the treatment of left renal diseases. PMID- 22216969 TI - Selective renal parenchymal clamping in retroperitoneal partial nephrectomy. AB - OBJECTIVE: Herein, we report our experience with retroperitoneoscopic partial nephrectomy (RPN) without hilar occlusion by the use of a laparoscopic clamp to induce selective regional ischemia. METHODS: A 48-year-old woman was referred for a left upper polar renal mass, which was suspected to be malignant. The contralateral kidney revealed severe atrophy, and she was scheduled to undergo RPN using a laparoscopic clamp to induce selective regional ischemia. At first, the kidney is fully mobilized within the retroperitoneal space. Thereafter, the laparoscopic clamp is applied directly to the kidney, about 1 cm below the resection line. When closed, the renal parenchyma is compressed, so that blood supply to the tumor is interrupted. The preserved portion of the kidney is perfused normally, and it is possible to remove the tumor in a bloodless field without involving warm ischemia. RESULTS: Renal hilar clamping was avoided, with minimal estimated blood loss. There was no perioperative complication, and the final pathology revealed a hemorrhagic renal cyst. The radioisotope absorption of the enucleated kidney was well maintained, except for the marginal area of the enucleated site. The renogram pattern was found to be equivocal when compared with the preoperative renogram. CONCLUSION: Regional renal parenchymal clamping during RPN can be safely and effectively used to create a bloodless operative field. Moreover, our preliminary experience demonstrates that this technique facilitates maximal nephron-sparing surgery for patients with an anatomically or functionally solitary kidney, without involving warm ischemia. PMID- 22216970 TI - Salting effects on protein components in aqueous NaCl and urea solutions: toward understanding of urea-induced protein denaturation. AB - The mechanism of urea-induced protein denaturation is explored through studying the salting effect of urea on 14 amino acid side chain analogues, and N methylacetamide (NMA) which mimics the protein backbone. The solvation free energies of the 15 molecules were calculated in pure water, aqueous urea, and NaCl solutions. Our results show that NaCl displays strong capability to salt out all 15 molecules, while urea facilitates the solvation (salting-in) of all the 15 molecules on the other hand. The salting effect is found to be largely enthalpy driven for both NaCl and urea. Our observations can explain the higher stability of protein's secondary and tertiary structures in typical salt solutions than that in pure water. Meanwhile, urea's capability to better solvate protein backbone and side-chain components can be extrapolated to explain protein's denaturation in aqueous urea solution. Urea salts in molecules through direct binding to solute surface, and the strength is linearly dependent on the number of heavy atoms of solute molecules. The van der Waals interactions are found to be the dominant force, which challenges a hydrogen-bonding-driven mechanism proposed previously. PMID- 22216971 TI - Prereactive complexes in chlorination of benzene, triazine, and tetrazine: a quantum chemical study. AB - In order to perform a complete search for prereactive complexes between arenes and chlorine, the stochastic search method was employed. Stationary points are optimized at B3LYP, M05-2X, and MP2 levels, while improved energetics are calculated using the B2PLYP-D method, which includes corrections important for accurate description of dispersion forces. New intermediates were located and their mechanistic relevance has been discussed. It has been suggested that, at least in the gas-phase, the T-shaped complex precedes the formation of classical benzene/chlorine pi-complex. No sigma-complex is found on the energy surface, unless explicit counterions are included in calculations. Neither pi- nor sigma complexes were located on the reactant side of chlorination of triazine, but only linear and T-shaped complexes were identified as stable minima. These structures represent important prereactive complexes for chlorination of triazine. In the case of tetrazine, which is unlikely to undergo direct chlorination, only two complexes (resting and T-shaped) were located. PMID- 22216973 TI - Transcriptional changes in Teladorsagia circumcincta upon encountering host tissue of differing immune status. AB - The aim of this study was to elucidate transcriptional changes in the parasitic nematode Teladorsagia circumcincta upon encountering either naive or immune ovine hosts. Pools of 100 000 exsheathed 3rd- stage T. circumcincta larvae were exposed in vitro to either an immune or naive ovine abomasal environment, RNA was extracted from the larvae and sequenced using the Roche 454 platform. Each sample produced approximately 82 000 reads that assembled to give approximately 5500 Isotigs (contigs). The two sequence datasets were clustered together to give a total of 6969 clusters of which 18 were differentially expressed (P<0.001) between the two groups. Clusters with a predominance of reads in larvae exposed to the immune abomasal environment encoded homologues of peptidyl-glycine alpha amidating monooxygenase, heat shock-protein 16-2 and IDA-1, a tyrosine phosphatase-like receptor protein. Clusters with a predominance of reads in the naive environment encoded homologues of cytochrome b, EGg Laying defective family member 21 and NADH dehydrogenase subunit 5. Gene ontology analyses indicated that larvae exposed to the immune environment showed an increase in expression of genes involved in 'carbon utilization', 'response to stimulus' and 'developmental process'. These data suggest that T. circumcincta modulates gene expression in response to the immune status of the host. PMID- 22216974 TI - Cost analysis of two anaesthetic machines: "Primus(r)" and "Zeus(r)". AB - BACKGROUND: Two anaesthetic machines, the "Primus(r)" and the "Zeus(r)" (Draeger AG, Lubeck, Germany), were subjected to a cost analysis by evaluating the various expenses that go into using each machine. METHODS: These expenses included the acquisition, maintenance, training and device-specific accessory costs. In addition, oxygen, medical air and volatile anaesthetic consumption were determined for each machine. RESULTS: Anaesthesia duration was 278 +/- 140 and 208 +/- 112 minutes in the Primus(r) and the Zeus(r), respectively. The purchase cost was ?3.28 and ?4.58 per hour of operation in the Primus(r) and the Zeus(r), respectively. The maintenance cost was ?0.90 and ?1.20 per hour of operation in the Primus(r) and the Zeus(r), respectively. We found that the O2 cost was ?0.015 +/- 0.013 and ?0.056 +/- 0.121 per hour of operation in the Primus(r) and the Zeus(r), respectively. The medical air cost was ?0.005 +/- 0.003 and ?0.016 +/- 0.027 per hour of operation in the Primus(r) and the Zeus(r), respectively. The volatile anaesthetic cost was ?2.40 +/- 2.40 and ?4.80 +/- 4.80 per hour of operation in the Primus(r) and the Zeus(r), respectively. CONCLUSION: This study showed that the "Zeus(r)" generates a higher cost per hour of operation compared to the "Primus(r)". PMID- 22216976 TI - Excerpts from the occupational and environmental meeting Tel Aviv November 2010. PMID- 22216975 TI - Expression of apoptosis-regulating genes in the rat prostate following botulinum toxin type A injection. AB - BACKGROUND: Onabotulinumtoxin A (OnabotA) injection has been investigated as a novel treatment for benign prostatic enlargement caused by benign prostatic hyperplasia. An OnabotA-induced volume reduction caused by sympathetic fibers impairment has been proposed as a potential mechanism of action. Our aim was to investigate the expression of apoptosis-regulating proteins in the rat prostate following OnabotA intraprostatic injection. METHODS: Adult Wistar rats were injected in the ventral lobes of the prostate with 10 U of OnabotA or saline. A set of OnabotA-injected animals was further treated with 0.5 mg/kg of phenylephrine (PHE) subcutaneously daily. All animals were sacrificed after 1 week and had their prostates harvested. Immunohistochemical staining was performed for Bax, Bcl-xL and caspase-3 proteins and visualized by the avidin biotin method. The optical density of the glandular cells was also determined, with measurement of differences between average optical densities for each group. RESULTS: Saline-treated animals showed intense epithelial staining for Bcl-xL and a faint labelling for both Bax and Caspase-3. OnabotA-treated rats showed a reduced epithelial staining of Bcl-xL and a consistently increased Bax and Caspase-3 staining when compared with saline-treated animals. PHE-treated animals showed a stronger Bcl-xL staining and reduced staining of both Bax and Caspase-3 when compared to the OnabotA group. Mean signal intensity measurements for each immunoreaction confirmed a significant decrease of the signal intensity for Bcl xL and a significant increase of the signal intensity for Bax and Caspase 3 in OnabotA-injected animals when compared with the control group. In OnabotA+PHE treated animals mean signal intensity for Bcl-xL, Bax and Caspase 3 immunoreactions was identical to that of the control animals. CONCLUSIONS: These results support the hypothesis that OnabotA activates apoptotic pathways in the rat prostate through a mechanism that involves sympathetic outflow impairment. PMID- 22216977 TI - Endotoxin-induced cytokine and chemokine expression in the HIV-1 transgenic rat. AB - BACKGROUND: Repeated exposure to a low dose of a bacterial endotoxin such as lipopolysaccharide (LPS) causes immune cells to become refractory to a subsequent endotoxin challenge, a phenomenon known as endotoxin tolerance (ET). During ET, there is an imbalance in pro- and anti-inflammatory cytokine and chemokine production, leading to a dysregulated immune response. HIV-1 viral proteins are known to have an adverse effect on the immune system. However, the effects of HIV 1 viral proteins during ET have not been investigated. METHODS: In this study, HIV-1 transgenic (HIV-1Tg) rats and control F344 rats (n = 12 ea) were randomly treated with 2 non-pyrogenic doses of LPS (LL) to induce ET, or saline (SS), followed by a high challenge dose of LPS (LL+L, SS+L) or saline (LL+S, SS+S). The gene expression of 84 cytokines, chemokines, and their receptors in the brain and spleen was examined by relative quantitative PCR using a PCR array, and protein levels in the brain, spleen, and serum of 7 of these 84 genes was determined using an electrochemiluminescent assay. RESULTS: In the spleen, there was an increase in key pro-inflammatory (IL1alpha, IL-1beta, IFN-gamma) and anti inflammatory (IL-10) cytokines, and inflammatory chemokines (Ccl2, Ccl7, and Ccl9,) in response to LPS in the SS+L and LL+L (ET) groups of both the HIV-1Tg and F344 rats, but was greater in the HIV-1Tg rats than in the F344. In the ET HIV-1Tg and F344 (LL+L) rats in the spleen, the LPS-induced increase in pro inflammatory cytokines was diminished and that of the anti-inflammatory cytokine was enhanced compared to the SS+L group rats. In the brain, IL-1beta, as well as the Ccl2, Ccl3, and Ccl7 chemokines were increased to a greater extent in the HIV 1Tg rats compared to the F344; whereas Cxcl1, Cxcl10, and Cxcl11 were increased to a greater extent in the F344 rats compared to the HIV-1Tg rats in the LL+L and SS+L groups. CONCLUSION: Our data indicate that the continuous presence of HIV-1 viral proteins can have tissue-dependent effects on endotoxin-induced cytokine and chemokine expression in the ET state. PMID- 22216979 TI - Investigation of alpha-naphthyl acetate esterase and acid phosphatase in the peripheral blood leukocytes of greyhounds. AB - The purpose of our study was to determine the percentages of alpha-naphthyl acetate esterase (ANAE)- and acid phosphatase (ACP)-positive peripheral blood lymphocytes (PBL), the presence of the ANAE and ACP enzymes in leukocytes, and the proportion of PBL in greyhounds. Peripheral blood samples were collected from the cephalic antebrachial vein of 14 (7 animals of each sex) healthy 1-2-year-old greyhounds. Mean percentages of ANAE-positive PBL were found to be 73.29 +/- 0.95% in female and 74.29 +/- 2.21% in male dogs. The difference between mean values of the genders was not statistically significant. The ACP values were 36.00 +/- 2.94% for females and 33.57 +/- 2.15% for males. No significant differences were found with regard to gender. For both enzymes, although monocytes and eosinophilic granulocytes displayed a positive reaction, neutrophils gave negative reactions. The proportion of PBL was 36.29 +/- 5.31% and 33.00 +/- 2.38 % in female and male dogs, respectively. The differences were not significant. PMID- 22216980 TI - Exosomes and immune surveillance of neoplastic lesions: a review. AB - The immune system has been reported to suppress the development and progression of neoplastic lesions; however, the exact mechanisms by which neoplastic lesions and the immune system interact are not well understood. Within the last decade, tiny membrane bound particles, approximately 30-100 nm in diameter, have been observed in the blood and other body fluids. These particles, currently called exosomes, are released from many types of tissues including tumors, and they contain and carry many proteins, and mRNAs and microRNA species. We review here how tumors suppress the immune system, especially by the formation of exosomes. Exosomes released from tumors are carried in part by the vascular system to distant cells, which phagocytose them. Depending on the proteins, mRNAs or microRNAs in the exosomes and the cell type, phagocytosis of exosomes may provide a modulating signal to the cell. In the case of exosomes from tumors, uptake of the exosomes by cells of the immune system has been reported to have three main effects: 1) suppression of the number and activity of natural killer cells, 2) suppression of the activity of T cells and 3) suppression of the number and maturation of mature dendritic cells. PMID- 22216981 TI - Cytotoxicity induced by engineered silver nanocrystallites is dependent on surface coatings and cell types. AB - Due to their unique antimicrobial properties silver nanocrystallites have garnered substantial attention and are used extensively for biomedical applications as an additive to wound dressings, surgical instruments and bone substitute materials. They are also released into unintended locations such as the environment or biosphere. Therefore it is imperative to understand the potential interactions, fate and transport of nanoparticles with environmental biotic systems. Numerous factors including the composition, size, shape, surface charge, and capping molecule of nanoparticles are known to influence cell cytotoxicity. Our results demonstrate that the physical/chemical properties of the silver nanoparticles including surface charge, differential binding and aggregation potential, which are influenced by the surface coatings, are a major determining factor in eliciting cytotoxicity and in dictating potential cellular interactions. In the present investigation, silver nanocrystallites with nearly uniform size and shape distribution but with different surface coatings, imparting overall high negativity to high positivity, were synthesized. These nanoparticles included poly(diallyldimethylammonium) chloride-Ag, biogenic-Ag, colloidal-Ag (uncoated), and oleate-Ag with zeta potentials +45 +/- 5, -12 +/- 2, -42 +/- 5, and -45 +/- 5 mV, respectively; the particles were purified and thoroughly characterized so as to avoid false cytotoxicity interpretations. A systematic investigation on the cytotoxic effects, cellular response, and membrane damage caused by these four different silver nanoparticles was carried out using multiple toxicity measurements on mouse macrophage (RAW-264.7) and lung epithelial (C-10) cell lines. Our results clearly indicate that the cytotoxicity was dependent on various factors such as surface charge and coating materials used in the synthesis, particle aggregation, and the cell-type for the different silver nanoparticles that were investigated. Poly(diallyldimethylammonium)-coated Ag nanoparticles were found to be the most toxic, followed by biogenic-Ag and oleate-Ag nanoparticles, whereas uncoated or colloidal silver nanoparticles were found to be the least toxic to both macrophage and lung epithelial cells. Also, based on our cytotoxicity interpretations, lung epithelial cells were found to be more resistant to the silver nanoparticles than the macrophage cells, regardless of the surface coating. PMID- 22216982 TI - Nestling development and the timing of tick attachments. AB - Parasites exposed to fast-developing hosts experience a variety of conditions over a short time period. Only few studies in vertebrate-ectoparasite systems have integrated the timing of ectoparasite infestations in the host's development into the search for factors explaining ectoparasite burden. In this study we examined the temporal pattern of attachment in a nidicolous tick (Ixodes arboricola) throughout the development of a songbird (Parus major). In the first experiment, we exposed bird clutches at hatching to a mix of the 3 tick instars (larvae, nymphs and adults), and monitored the ticks that attached in relation to the average broods' age. In a complementary experiment we focused on the attachment in adult female ticks--the largest and most significant instar for the species' reproduction--after releasing them at different moments in the nestlings' development. Our observations revealed a positive association between the size of the attached instar and the broods' age. Particularly, adult females were less likely to be found attached to recently hatched nestlings, which contrasts with the smaller-sized larvae and nymphs. These differences suggest either an infestation strategy that is adapted to host physiology and development, or a result of selection by the hosts' anti-tick resistance mechanisms. We discuss the implications of our results in terms of tick life history strategies. PMID- 22216983 TI - Identification of the p. R116H mutation in a Chinese family with novel variable cataract phenotype: evidence for a mutational hot spot in alphaA-crystallin gene. AB - PURPOSE: To report the recurrent p.R116H mutation in the alphaA-crystallin gene (CRYAA) which causes a novel variable cataract phenotype, and to determine whether this mutation represents a mutational hot spot. METHODS: Family history and clinical data were recorded. The genomic DNA was extracted from peripheral blood leukocytes. Microsatellite markers at loci considered to be associated with autosomal dominant cataracts were selected and genotyped for two-point linkage analysis. Direct sequencing was performed to identify the disease-causing mutation. Haplotype analysis was constructed to compare the affected haplotype in this family and in another Chinese family previously reported by us. RESULTS: Clinical features of cataract in this family were asymmetric in two eyes of some affected subjects. Evidence of linkage was obtained with marker D21S1411 (logarithm of odds [LOD] score [Z] = 2.42, recombination fraction [theta] = 0.0). Sequencing of the candidate CRYAA gene revealed a single base alteration c.347 G > A in exon 3, which resulted in the substitution of highly conserved arginine by histidine at codon 116 (p.R116H). This mutation co-segregated with all affected individuals and was not observed in unaffected family members or 100 normal unrelated individuals. The comparative haplotype analysis showed that the affected haplotypes in the two families were different. CONCLUSIONS: This study identified a novel cataract-microcornea phenotype caused by the recurrent mutation p.R116H in CRYAA, and suggested that this mutation site is not likely the consequence of a founder effect, but probably a result of a mutational hot spot. PMID- 22216984 TI - High-dose intravenous glucocorticoid therapy for Graves' ophthalmopathy: where are we now? PMID- 22216985 TI - Changes in the incidence of thyroid cancer between 1991 and 2005 in Italy: a geographical analysis. AB - BACKGROUND: The incidence of thyroid cancer (TC) has been increasing over the last 30 years in several countries, with some of the worldwide highest TC incidence rates (IRs) reported in Italy. The objectives of this study were to evaluate by histological subtypes the geographical heterogeneity of the incidence of TC in Italy and to analyze recent time trends for papillary thyroid carcinoma (PTC) in different cancer registries (CRs). METHODS: The study included cases of TC (<85 years of age) reported to 25 Italian CRs between 1991 and 2005. Age standardized IRs were computed for all histological subtypes of TC according to CRs. Estimated annual percent change and joinpoint regression analysis were used for analysis of PTC. RESULTS: In women, IRs of PTC ranged between 3.5/100,000 in Latina and 8.5/100,000 in Sassari for the period 1991-1995 (a 2.4-fold difference) and between 7.3/100,000 in Alto Adige and 37.5/100,000 in Ferrara for 2001-2005 (a 5.1-fold difference). In men, IRs ranged between 0.7/100,000 in Latina and 3.4/100,000 in Sassari for the period 1991-1995 (a 4.9-fold difference) and between 2.0/100,000 (Alto Adige, Trento) and 10.6/100,000 in Ferrara for 2001-2005 (a 5.3-fold difference). In both sexes, IRs significantly higher than the pooled estimates emerged for the most recent period in the majority of CRs located within the Po River plain and in Latina, but they were lower in the Alpine belt. For women, CRs reported higher IRs than pool estimates showed, between 1991 to 2005, a significantly more marked annual percent change (+12%) than other CRs (+7%). For men the corresponding estimates were +11% and +8%. CONCLUSIONS: The distribution of PTC does not lend support to a role of environmental radiation exposure due to the Chernobyl fallout, iodine deficiency, or (volcanic) soils. Between 1991 and 2005, wide geographic variations in the incidence of PTC and heterogeneous upward trends emerged, suggesting that the heterogeneity was a relatively recent phenomenon; this appeared to be mainly explained by variations, at a local level, in medical surveillance. PMID- 22216988 TI - Salt stress-induced transcription of sigmaB- and CtsR-regulated genes in persistent and non-persistent Listeria monocytogenes strains from food processing plants. AB - Listeria monocytogenes is a foodborne pathogen that can persist in food processing environments. Six persistent and six non-persistent strains from fish processing plants and one persistent strain from a meat plant were selected to determine if expression of genes in the regulons of two stress response regulators, sigma(B) and CtsR, under salt stress conditions is associated with the ability of L. monocytogenes to persist in food processing environments. Subtype data were also used to categorize the strains into genetic lineages I or II. Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to measure transcript levels for two sigma(B)-regulated genes, inlA and gadD3, and two CtsR-regulated genes, lmo1138 and clpB, before and after (t=10 min) salt shock (i.e., exposure of exponential phase cells to BHI+6% NaCl for 10 min at 37 degrees C). Exposure to salt stress induced higher transcript levels relative to levels under non-stress conditions for all four stress and virulence genes across all wildtype strains tested. Analysis of variance (ANOVA) of induction data revealed that transcript levels for one gene (clpB) were induced at significantly higher levels in non-persistent strains compared to persistent strains (p=0.020; two-way ANOVA). Significantly higher transcript levels of gadD3 (p=0.024; two-way ANOVA) and clpB (p=0.053; two-way ANOVA) were observed after salt shock in lineage I strains compared to lineage II strains. No clear association between stress gene transcript levels and persistence was detected. Our data are consistent with an emerging model that proposes that establishment of L. monocytogenes persistence in a specific environment occurs as a random, stochastic event, rather than as a consequence of specific bacterial strain characteristics. PMID- 22216989 TI - Isolation, molecular characterization, and antibiotic susceptibility of Vibrio parahaemolyticus in Korean seafood. AB - The principal objective of this study was to investigate the incidence, risk assessment, antibiotic resistance, and genotyping of Vibrio parahaemolyticus in Korean seafood. The incidence of V. parahaemolyticus in seafood obtained from several fish markets in Korea was investigated from May to December of 2009, except between July and September. Two selective mediums (TCBS [thiosulfate, citrate, bile salts, and sucrose] agar and CHROMagarTM Vibrio) were used, and the V. parahaemolyticus strains were identified via polymerase chain reaction (PCR) amplification (Vp. flaE, tl, and toxR). 16S rRNA gene sequencing and their virulence were analyzed via the detection of tdh, trh, ORF8, toxRS/old, and toxRS/new genes. We collected 24 strains of V. parahaemolyticus: 19 seafood isolates, three environmental isolates, and two clinical (human) isolates. Among these strains, two tdh+ strains, two ORF8+ strains, 16 toxRS/old+ strains, and one toxRS/new+ strain were isolated. Twenty-two commercial antibiotics were used to assess the antibiotic susceptibility of isolates, and all the strains evidenced resistance to more than four antibiotics. The strains harboring antibiotic-resistant genes such as TetA (25%) and strB (4.16%) were detected via PCR. Repetitive extragenic palindromic sequence (REP)-PCR analysis revealed differences in the V. parahaemolyticus strains from other species and intraspecific strains. PMID- 22216991 TI - "We as drug addicts need that program": Insight from rural African American cocaine users on designing a sexual risk reduction intervention for their community. AB - This focused ethnographic study examines data collected in 2007 from four gender- and age-specific focus groups (FGs) (N = 31) to inform the development of a sexual risk reduction intervention for African American cocaine users in rural Arkansas. A semi-structured protocol was used to guide audio-recorded FGs. Data were entered into Ethnograph and analyzed using constant comparison and content analysis. Four codes with accompanying factors emerged from the data and revealed recommendations for sexual risk reduction interventions with similar populations. Intervention design implications and challenges, study limitations, and future research are discussed. The study was supported by funds from the National Institute of Nursing Research (P20 NR009006-01) and the National Institute on Drug Abuse (1R01DA024575-01 and F31 DA026286-01). PMID- 22216992 TI - A pilot training program for a motivational enhancement approach to hepatitis C virus treatment among individuals in Israeli methadone treatment centers. AB - Although hepatitis C virus (HCV) can be cleared, very few infected persons complete the treatment, resulting in disease progression and transmission. Motivational interventions effectively address health and substance-use-related conditions in many cultures. The research team piloted an HCV treatment motivational enhancement training and supervision for four counselors treating four patients in one (of 11) large methadone programs in Israel between 2007 and 2008. The counselors received a 3-day training followed by seven supervision sessions. Training included cultural and language adaptation from the original United States version to practice in Israel. Feasibility was assessed and demonstrated through training field notes and questionnaire feedback, review of taped intervention sessions for counselor proficiency and patient engagement, and patient completion of intervention sessions and piloted measures. While positive feasibility outcomes were noted, future studies should employ larger numbers of counselors and patients to assess the effectiveness of motivational enhancement in promoting HCV treatment in methadone patients. PMID- 22216993 TI - Use and misuse of opioid replacement therapies: a Queensland study. AB - Buprenorphine/naloxone has recently been introduced in Australia and is available for unsupervised dosing within Queensland. A retrospective observational study of data collected during 2000-2007 for clients obtaining injecting equipment from the Brisbane Harm Reduction Centre in Queensland is presented. The numbers of service occasions and needles and syringes were used as surrogate drug use measures. Buprenorphine and naloxone were misused at lower rates when compared with buprenorphine and methadone. Furthermore, the misuse of opioid replacement therapies represented less than 5% of all illicit opioid injections. Implications and study limitations are discussed. PMID- 22216994 TI - Everyone says it's ok: adolescents' perceptions of peer, parent, and community alcohol norms, alcohol consumption, and alcohol-related consequences. AB - An adolescent's perception of norms is related to her or his engagement in alcohol-related behaviors. Norms have different sources, such as parents, peers, and community. We explored how norms from different sources were simultaneously related to different alcohol-related behaviors (current drinking, drunkenness, heavy episodic drinking, driving under the influence or riding with a impaired driver, and alcohol-related nonviolent consequences) using data collected in 2004 from 6,958 adolescents from 68 communities in five states. Results revealed that parent, friend, and community norms were related to adolescents' alcohol-related behavior, but the strength of these impacts varied across behaviors. The pattern of results varied when the analysis relied on all adolescents or just those who had consumed alcohol in the last year. PMID- 22216997 TI - Effects of surface heterogeneity on the adsorption of CO2 in microporous carbons. AB - Carbon capture combined with utilization and storage has the potential to serve as a near-term option for CO(2) emissions reduction. CO(2) capture by carbon based sorbents and CO(2) storage in geologic formations such as coal and shale both require a thorough understanding of the CO(2) adsorption properties in microporous carbon-based materials. Complex pore structures for natural organic materials, such as coal and gas shale, in addition to general carbon-based porous materials are modeled as a collection of independent, noninterconnected, functionalized graphitic slit pores with surface heterogeneities. Electronic structure calculations coupled with van der Waals-inclusive corrections have been performed to investigate the electronic properties of functionalized graphitic surfaces. With Bader charge analysis, electronic structure calculations can provide the initial framework comprising both the geometry and corresponding charge information required to carry out statistical modeling. Grand canonical Monte Carlo simulations were carried out to determine the adsorption isotherms for a given adsorbent-adsorbate interaction at temperature/pressure conditions relevant to carbon capture applications to focus on the effect of the surface functionalities. On the basis of the current work, oxygen-containing functional groups were predicted to enhance CO(2) adsorption in microporous carbon materials in the absence of water vapor, and the hydrated graphite was found to hinder CO(2) adsorption. PMID- 22216998 TI - Large-size linear and star-shaped dihydropyrazine fused pyrazinacenes. AB - Linear and star-shaped pyrazinacenes 1a-b and 2 were synthesized via condensation between a new building block 11 and pyrene tetraones or cyclohexaone. Compound 2 represents the largest star-shaped dihydropyrazine fused pyrazinacene reported so far. These largely expanded pyrazinacenes show good solubility and have a strong tendency to aggregate in both solution and thin films, indicating their potential applications for organic electronic devices. PMID- 22217001 TI - Photodissociation studies of the electronic and vibrational spectroscopy of Ni(+)(H2O). AB - The electronic spectrum of Ni+(H2O) has been measured from 16200 to 18000 cm-1 using photofragment spectroscopy. Transitions to two excited electronic states are observed; they are sufficiently long-lived that the spectrum is vibrationally and partially rotationally resolved. An extended progression in the metal-ligand stretch is observed, and the absolute vibrational quantum numbering is assigned by comparing isotopic shifts between 58Ni+(H2O) and 60Ni+(H2O). Time-dependent density functional calculations aid in assigning the spectrum. Two electronic transitions are observed, from the 2A1 ground state (which correlates to the 2D, 3d9 ground state of Ni+) to the 32A1 and 22A2 excited states. These states are nearly degenerate and correlate to the 2F, 3d84s excited state of Ni+. Both transitions are quite weak, but surprisingly, the transition to the 2A2 state is stronger, although it is symmetry-forbidden. The 3d84s states of Ni+ interact less strongly with water than does the ground state; therefore, the excited states observed are less tightly bound and have a longer metal-ligand bond than the ground state. Calculations at the CCSD(T)/aug-cc-pVTZ level predict that binding to Ni+ increases the H-O-H angle in water from 104.2 to 107.5 degrees as the metal removes electron density from the oxygen lone pairs. The photodissociation spectrum shows well-resolved rotational structure due to rotation about the Ni-O axis. This permits determination of the spin rotation constants epsilon(alphaalpha)'' = -12 cm-1 and epsilon(alphaalpha)' = -3 cm-1 and the excited state rotational constant A' = 14.5 cm-1. This implies a H-O-H angle of 104 +/- 1 degrees in the 22A2 excited state. The O-H stretching frequencies of the ground state of Ni+(H2O) were measured by combining IR excitation with visible photodissociation in a double resonance experiment. The O-H symmetric stretch is nu1'' = 3616.5 cm-1; the antisymmetric stretch is nu5'' = 3688 cm-1. These values are 40 and 68 cm-1 lower, respectively, than those in bare H2O. PMID- 22217000 TI - Atomic force microscopy and MD simulations reveal pore-like structures of all-D enantiomer of Alzheimer's beta-amyloid peptide: relevance to the ion channel mechanism of AD pathology. AB - Alzheimer's disease (AD) is a protein misfolding disease characterized by a buildup of beta-amyloid (Abeta) peptide as senile plaques, uncontrolled neurodegeneration, and memory loss. AD pathology is linked to the destabilization of cellular ionic homeostasis and involves Abeta peptide-plasma membrane interactions. In principle, there are two possible ways through which disturbance of the ionic homeostasis can take place: directly, where the Abeta peptide either inserts into the membrane and creates ion-conductive pores or destabilizes the membrane organization, or, indirectly, where the Abeta peptide interacts with existing cell membrane receptors. To distinguish between these two possible types of Abeta-membrane interactions, we took advantage of the biochemical tenet that ligand-receptor interactions are stereospecific; L-amino acid peptides, but not their D-counterparts, bind to cell membrane receptors. However, with respect to the ion channel-mediated mechanism, like L-amino acids, D-amino acid peptides will also form ion channel-like structures. Using atomic force microscopy (AFM), we imaged the structures of both D- and L-enantiomers of the full length Abeta(1 42) when reconstituted in lipid bilayers. AFM imaging shows that both L- and D Abeta isomers form similar channel-like structures. Molecular dynamics (MD) simulations support the AFM imaged 3D structures. Previously, we have shown that D-Abeta(1-42) channels conduct ions similarly to their L- counterparts. Taken together, our results support the direct mechanism of Abeta ion channel-mediated destabilization of ionic homeostasis rather than the indirect mechanism through Abeta interaction with membrane receptors. PMID- 22217002 TI - Immunological characterization of Neospora caninum cyclophilin. AB - Neospora caninum is an intracellular parasite that poses a unique ability to infect a variety of cell types by causing host cell migration. Although previous studies demonstrated that parasite-derived proteins could trigger host cell migration, the related molecules have yet to be determined. Our study aimed to investigate the relationship between Neospora-derived molecules and host cell migration using recombinant protein of N. caninum cyclophilin (NcCyp). Indirect fluorescent antibody test revealed that NcCyp was expressed in the tachyzoite cytosol. Furthermore, NcCyp release from extracellular parasites was detected by sandwich enzyme-linked immunosorbent assay in a time-dependent manner. Recombinant NcCyp caused the cysteine-cysteine chemokine receptor 5-dependent migration of murine and bovine cells. Furthermore, immunohistochemistry indicated that NcCyp was consistently detected in tachyzoites distributed within or around the brain lesions. In conclusion, N. caninum-derived cyclophilin appears to contribute to host cell migration, thereby maintaining parasite/host interactions. PMID- 22217003 TI - Detection of Hepatitis B virus in serum and liver of chickens. AB - Hepatitis B virus (HBV) is one of the most important human pathogens. Its existence in food animals could present a significant threat to public health. The objective of this study was to determine if HBV is present in serum and liver of chickens. A total of 129 serum samples from broiler chickens were collected for the detection of HBV antigens and antibodies, and 193 liver samples were tested for HBV DNA sequence by PCR and for the existence of HBV antigens by immunohistochemistry. The overall prevalence of HBsAg, anti-HBs, anti-HBc was 28.68%, 53.49%, 17.05%, respectively, whereas HBeAg, anti-HBe were barely detectable. Three serum samples were found to be positive for both HBsAg and HBeAg. Further analysis of these samples with transmission electron microscopy (TEM) revealed two morphologic particles with 20 nm and 40 nm in diameter, which were similar to small spherical and Danes particles of HBV. The viral DNA sequence identified in two of the chicken livers shared 92.2% of one known HBV strain and 97.9% nucleotide sequence of another HBV strain. Our results showed the existence of HBV in chickens. This would present a significant risk to people who work with live chickens or chicken products if HBV found in chicken could be confirmed to be the same as human HBV. PMID- 22217004 TI - Laparoscopic repair of indirect inguinal hernia in children: does partial resection of the sac make any impact on outcome? AB - PURPOSE: To test the hypothesis that during laparoscopic hernia repair, partial resection of the distal sac along with suture ligation of the neck is better than simple transection and ligation. METHODS: The following two techniques of laparoscopic hernia repair were compared: Group I, circumferential incision of peritoneum at the deep ring and partial resection of the distal sac and suture ligation at the neck; versus Group II, circumferential incision of the peritoneum at the deep ring and suture ligation at the neck. Twenty-five cases of inguinal hernia were randomly selected in each group between the age group of 6 months to 12 years. The outcome measures were recurrence, intra- or postoperative complications, and time taken for surgery. RESULTS: There were no recurrences in either group. Other parameters for comparison were also not statistically different between the two groups. There was no conversion. CONCLUSIONS: Although partial resection of the sac has been an essential step in open hernia repair over five decades, its value has been questioned by our study, because omitting this step during laparoscopic repair has not adversely affected the outcomes. Partial resection of the sac is not a necessary component of hernia repair. It is a technical necessity of the open approach. Therefore, omitting this step in laparoscopic repair does not adversely affect the outcome. PMID- 22217005 TI - Short-term outcomes from a multicenter retrospective study in China comparing laparoscopic and open surgery for the treatment of infected pancreatic necrosis. AB - BACKGROUND: Laparoscopic surgery for confirmed infected pancreatic necrosis (IPN) represents a relatively new solution. There are no studies comparing the outcomes of laparoscopic and open surgery for patients with IPN. The aims of this study were to investigate the feasibility of laparoscopic management for patients with IPN and to compare the outcomes of laparoscopic and open surgery. METHODS: Seventy-six patients with IPN who underwent open surgery (Open-group) or laparoscopic surgery (Lap-group) were retrospectively reviewed. Demographic data, white blood cell count, and APACHE II score upon admission, operative findings, major complications, and mortality were compared between the Open-group and the Lap-group. The Lap-group was further divided into two subgroups (early and late), and the operative difficulty was compared between the two subgroups. RESULTS: There were no significant differences between the Open-group and the Lap-group with respect to demographic data, white blood cell count, and APACHE II score. Although the mean operative time was significantly shorter in the Open-group than in the Lap-group, the estimated blood loss was significantly greater in the Open group than in the Lap-group, as was the rate of complications. The mean postoperative hospital stay in the Open-group was significant longer than in the Lap-group, too. In the Lap-group, the mean operating time, estimated blood loss, and conversion rate in the early subgroup were significantly lower than in the late subgroup. CONCLUSION: Laparoscopic necrosectomy and the placement of an intermittent irrigation and continuous suction drainage system for IPN is feasible, effective, and of minimal invasiveness. The late laparoscopic necrosectomy is relatively difficult. PMID- 22217006 TI - Single/low-copy integration of transgenes in Caenorhabditis elegans using an ultraviolet trimethylpsoralen method. AB - BACKGROUND: Transgenic strains of Caenorhabditis elegans are typically generated by injecting DNA into the germline to form multi-copy extrachromosomal arrays. These transgenes are semi-stable and their expression is silenced in the germline. Mos1 transposon or microparticle bombardment methods have been developed to create single- or low-copy chromosomal integrated lines. Here we report an alternative method using ultraviolet trimethylpsoralen (UV/TMP) to generate single/low-copy gene integrations. RESULTS: We successfully integrated low-copy transgenes from extrachromosomal arrays using positive selection based on temperature sensitivity with a vps-45 rescue fragment and negative selection based on benzimidazole sensitivity with a ben-1 rescue fragment. We confirmed that the integrants express transgenes in the germline. Quantitative PCR revealed that strains generated by this method contain single- or low-copy transgenes. Moreover, positive selection marker genes flanked by LoxP sites were excised by Cre recombinase mRNA microinjection, demonstrating Cre-mediated chromosomal excision for the first time in C. elegans. CONCLUSION: Our UV/TMP integration method, based on familiar extrachromosomal transgenics, provides a useful approach for generating single/low-copy gene integrations. PMID- 22217007 TI - Effect of strain rate on the mechanical properties of Staphylococcus epidermidis biofilms. AB - The quantification of biofilm mechanical properties can serve as a basis for understanding biofilm resilience and for developing biofilm control strategies. One aspect of tensile testing that is likely to be important for a viscoelastic material such as bacterial biofilm, but unfortunately is often overlooked (i.e., not controlled or reported), is the strain rate used during testing. Thus, we performed tensile testing on intact S. epidermidis biofilms using the microcantilever method at 12 strain rate values ranging over approximately 3 orders of magnitude (0.013-9.07 s(-1)). Ultimate or cohesive strength, elastic modulus, and toughness increased with increasing strain rate and approached a plateau at approximately 1.3 s(-1). Failure strain, on the other hand, did not exhibit any trend with strain rate. Given that the mean values of some parameters increased by as much as 1 order of magnitude over the strain rate range used in this work, we suggest that the strain rate during tensile testing should be carefully controlled and reported to facilitate comparisons among different studies. Furthermore, the quantitative expressions developed in this work that relate mechanical property values with strain rate may be useful for modeling the deformation of bacterial biofilms under applied loads. PMID- 22217008 TI - Controversies in modern evolutionary biology: the imperative for error detection and quality control. AB - BACKGROUND: The data from high throughput genomics technologies provide unique opportunities for studies of complex biological systems, but also pose many new challenges. The shift to the genome scale in evolutionary biology, for example, has led to many interesting, but often controversial studies. It has been suggested that part of the conflict may be due to errors in the initial sequences. Most gene sequences are predicted by bioinformatics programs and a number of quality issues have been raised, concerning DNA sequencing errors or badly predicted coding regions, particularly in eukaryotes. RESULTS: We investigated the impact of these errors on evolutionary studies and specifically on the identification of important genetic events. We focused on the detection of asymmetric evolution after duplication, which has been the subject of controversy recently. Using the human genome as a reference, we established a reliable set of 688 duplicated genes in 13 complete vertebrate genomes, where significantly different evolutionary rates are observed. We estimated the rates at which protein sequence errors occur and are accumulated in the higher-level analyses. We showed that the majority of the detected events (57%) are in fact artifacts due to the putative erroneous sequences and that these artifacts are sufficient to mask the true functional significance of the events. CONCLUSIONS: Initial errors are accumulated throughout the evolutionary analysis, generating artificially high rates of event predictions and leading to substantial uncertainty in the conclusions. This study emphasizes the urgent need for error detection and quality control strategies in order to efficiently extract knowledge from the new genome data. PMID- 22217009 TI - Hepatitis E virus in Norway rats (Rattus norvegicus) captured around a pig farm. AB - BACKGROUND: Hepatitis E virus (HEV) transmitted via the oral route through the consumption of contaminated water or uncooked or undercooked contaminated meat has been implicated in major outbreaks. Rats may play a critical role in HEV outbreaks, considering their negative effects on environmental hygiene and food sanitation. Although the serological evidence of HEV infection in wild rodents has been reported worldwide, the infectivity and propagation of HEV in wild rats remain unknown. To investigate if rats are a possible carrier of HEV, we studied wild Norway rats (Rattus norvegicus) that were caught near a pig farm, where HEV was prevalent among the pigs. METHODS: We examined 56 Norway rats for HEV. RNA from internal organs was examined for RT-PCR and positive samples were sequenced. Positive tissue samples were incubated with A549 cell line to isolate HEV. Anti HEV antibodies were detected by ELISA. RESULTS: Sixteen rats were seropositive, and the HEV RNA was detected in 10 of the 56 rats. Sequencing of the partial ORF1 gene from 7 samples resulted in partially sequenced HEV, belonging to genotype 3, which was genetically identical to the HEV prevalent in the swine from the source farm. The infectious HEVs were isolated from the Norway rats by using the human A549 cell line. CONCLUSIONS: There was a relatively high prevalence (17.9%) of the HEV genome in wild Norway rats. The virus was mainly detected in the liver and spleen. The results indicate that these animals might be possible carrier of swine HEV in endemic regions. The HEV contamination risk due to rats needs to be examined in human habitats. PMID- 22217010 TI - Fatty acid modulation of autoinducer (AI-2) influenced growth and macrophage invasion by Salmonella Typhimurium. AB - Autoinducer-2 (AI-2) is a small molecule that is involved in bacterial cell-to cell signaling whose precursor formation is mediated by luxS. A luxS mutant of Salmonella Typhimurium PJ002 (DeltaluxS) was grown in glucose-containing M-9 minimal medium supplemented with varying concentrations (1*, 10*, and 100*) of long-chain fatty acids (linoleic acid, oleic acid, palmitic acid, and stearic acid) to study the influence of fatty acids on growth rate and macrophage invasion. Additionally, in vitro synthesized AI-2 was added to this medium to identify the influence of AI-2 on S. Typhimurium PJ002 (DeltaluxS) growth rate and macrophage invasion. The growth rate constant (k) for each experimental treatment was determined based on OD600 values recorded during 12 h of incubation. There was a significant (p=0.01) increase in the growth rate of S. Typhimurium PJ002 (DeltaluxS) in the presence of AI-2 when compared to the phosphate-buffered saline (PBS) control. However, fatty acids either singly or in a mixture were unable to influence AI-2's effect on growth rate. The presence of AI-2 significantly (p=0.02) decreased the invasiveness of S. Typhimurium PJ002 (DeltaluxS) towards the murine macrophage cell line, RAW 264.7. However, the fatty acid mixture was able to reverse this reduction and restore invasiveness to background levels. These results suggest that, while AI-2 may enhance the growth rate and reduce macrophage invasion by the luxS mutant S. Typhimurium PJ002 (DeltaluxS), fatty acids may influence the virulence in S. Typhimurium (PJ002) by modulating AI-2 activity. PMID- 22217011 TI - Prevalence and characteristics of methicillin-resistant Staphylococcus aureus in pigs and pig workers in Tenerife, Spain. AB - Methicillin-resistant Staphylococcus aureus (MRSA) strains belonging to sequence type (ST) 398 are being reported with increasing frequency in Europe and other countries. This MRSA type has been isolated from colonized and infected animals and humans. The aim of this study was to determine the prevalence of nasal MRSA carriage in pigs and pig workers. A total of 300 pigs from 15 different farms were sampled in the slaughterhouse of Tenerife. A total of 54 pig workers were screened for MRSA: 20 belonged to farms whose pigs had been sampled and 34 to the slaughterhouse. The percentage of positive samples of MRSA in pigs was 85.7%. The overall prevalence of nasal MRSA carriage in pig workers was 9.3%. All MRSA isolates from pigs and humans belonged to one clonal group showing multilocus sequence type (MLST) 398. Two types of Staphylococcal Chromosome Cassette (SCCmec) were found, IV and V. In conclusion, the prevalence of MRSA in nasal samples from pigs and pig workers in Tenerife was high. We therefore consider it essential to deepen epidemiological study of this strain of animal origin, as well as to increase surveillance and control measures at all stages of the food chain. PMID- 22217012 TI - Yersinia enterocolitica: a brief review of the issues relating to the zoonotic pathogen, public health challenges, and the pork production chain. AB - Yersinia enterocolitica is a zoonotic agent that causes gastrointestinal disease in humans, as well as reactive arthritis and erythema nodosum. Enteropathogenic Yersinia are the etiological agents for yersiniosis, which can be acquired through the consumption of contaminated foods. As porcine animals are the main carriers of Y. enterocolitica, food safety measures to minimize human infection are of increasing interest to the scientific and medical community. In this review, we examine why it is imperative that information on the reservoirs, prevalence, virulence, and ability of this pathogen to survive in different environments is further investigated to provide rational measures to prevent or decrease associated disease risks. PMID- 22217013 TI - Low-temperature survival of Salmonella spp. in a model food system with natural microflora. AB - The United States Department of Agriculture requires chilled poultry carcass temperature to be below 4 degrees C (40 degrees F) to inhibit the growth of Salmonella and improve shelf life. Post-process temperature abuse of chicken leads to proliferation of existing bacteria, including Salmonella, which can lead to the increased risk of human infections. While models predicting Salmonella growth at abusive temperatures are developed using sterile media or chicken slurry, there are limited studies of Salmonella growth in the presence of background microflora at 4-10 degrees C. Experiments in this study were conducted to determine the growth of Salmonella Typhimurium and Heidelberg at 4-10 degrees C in brain heart infusion broth (BHI) and non-sterile chicken slurry (CS). Nalidixic acid-resistant Salmonella Typhimurium and S. Heidelberg (3 log CFU/mL) were inoculated separately in CS and sterile BHI in a 12-well microtiter plate and incubated at 4 degrees C, 7 degrees C, and 10 degrees C, following which samples were taken every 24 h for up to 6 days. Samples from each well (n=5) were spread plated on XLT4 agar+nalidixic acid and incubated at 37 degrees C for 24 h. Bacterial populations were reported as CFU/mL. No significant differences (p>0.05) were observed in the survival of both strains in CS and BHI over the period of 6 days at all temperatures except S. Heidelberg at 7 degrees C. Survival populations of both strains at 4 degrees C were significantly different (p <= 0.05) than at 7 degrees C and 10 degrees C in both media types. S. Heidelberg showed a maximum growth of 2 logs in BHI at 10 degrees C among all the treatments. Growth patterns and survival of Salmonella at near refrigeration temperatures during carcass chilling can be useful to develop models to predict Salmonella growth post-processing and during storage, hence assisting processors in improving process controls. PMID- 22217016 TI - Clinical heterogeneity in systematic reviews and health technology assessments: synthesis of guidance documents and the literature. AB - OBJECTIVES: The aim of this study was to synthesize best practices for addressing clinical heterogeneity in systematic reviews and health technology assessments (HTAs). METHODS: We abstracted information from guidance documents and methods manuals made available by international organizations that develop systematic reviews and HTAs. We searched PubMed(r) to identify studies on clinical heterogeneity and subgroup analysis. Two authors independently abstracted and assessed relevant information. RESULTS: Methods manuals offer various definitions of clinical heterogeneity. In essence, clinical heterogeneity is considered variability in study population characteristics, interventions, and outcomes across studies. It can lead to effect-measure modification or statistical heterogeneity, which is defined as variability in estimated treatment effects beyond what would be expected by random error alone. Clinical and statistical heterogeneity are closely intertwined but they do not have a one-to-one relationship. The presence of statistical heterogeneity does not necessarily indicate that clinical heterogeneity is the causal factor. Methodological heterogeneity, biases, and random error can also cause statistical heterogeneity, alone or in combination with clinical heterogeneity. CONCLUSIONS: Identifying potential modifiers of treatment effects (i.e., effect-measure modifiers) is important for researchers conducting systematic reviews and HTAs. Recognizing clinical heterogeneity and clarifying its implications helps decision makers to identify patients and patient populations who benefit the most, who benefit the least, and who are at greatest risk of experiencing adverse outcomes from a particular intervention. PMID- 22217014 TI - Inhibitors of aminoglycoside resistance activated in cells. AB - The most common mechanism of resistance to aminoglycoside antibiotics entails bacterial expression of drug-metabolizing enzymes, such as the clinically widespread aminoglycoside N-6'-acetyltransferase (AAC(6')). Aminoglycoside-CoA bisubstrates are highly potent AAC(6') inhibitors; however, their inability to penetrate cells precludes in vivo studies. Some truncated bisubstrates are known to cross cell membranes, yet their activities against AAC(6') are in the micromolar range at best. We report here the synthesis and biological activity of aminoglycoside-pantetheine derivatives that, although devoid of AAC(6') inhibitory activity, can potentiate the antibacterial activity of kanamycin A against an aminoglycoside-resistant strain of Enterococcus faecium. Biological studies demonstrate that these molecules are potentially extended to their corresponding full-length bisubstrates by enzymes of the coenzyme A biosynthetic pathway. This work provides a proof-of-concept for the utility of prodrug compounds activated by enzymes of the coenzyme A biosynthetic pathway, to resensitize resistant strains of bacteria to aminoglycoside antibiotics. PMID- 22217018 TI - Spreading the one-health concept. PMID- 22217019 TI - Ovariohysterectomy versus ovariectomy. PMID- 22217020 TI - What is your diagnosis? A subchondral bone cyst-like lesion of the third metacarpal condyle and osteoarthritis. PMID- 22217021 TI - Theriogenology question of the month. Endometrioma. PMID- 22217022 TI - Pathology in practice. Mycoplasma pulmonis infection. PMID- 22217023 TI - Pathology in practice. Cytauxzoon felis infection. PMID- 22217025 TI - Evaluation of plasma N-terminal pro-B-type natriuretic peptide concentrations in dogs with and without cardiac disease. AB - OBJECTIVE: To evaluate plasma N-terminal pro-B-type natriuretic peptide (NT proBNP) concentrations in a large, diverse population of dogs with and without cardiac disease and to define the upper reference limit for the biomarker in this species. DESIGN: Cross-sectional single center study. ANIMALS: 1,134 dogs. PROCEDURES: Dogs underwent blood sample collection, physical examination, ECG, and echocardiographic and thoracic radiographic evaluations. Cardiac status was graded by use of a 9-grade cardiac disease classification system and a simplified 4-stage cardiac scoring system. Vertebral heart score (VHS) was assessed in 280 dogs. Associations of plasma NT-proBNP concentrations with multiple variables were evaluated via univariate and multivariate linear regression analysis. Sensitivity and specificity of NT-proBNP concentrations and of VHS to discriminate between dogs with and without clinical signs of cardiac disease were evaluated via receiver-operating characteristic curve analysis. RESULTS: 974 dogs had cardiac disease, 37 had noncardiac-related disease, and 123 were healthy. Plasma NT-proBNP concentrations correlated with cardiac grade and stage; VHS was also associated with cardiac grade. At a cutoff of 874 pmol/L, sensitivity and specificity of NT-proBNP concentration to detect clinical signs of cardiac disease were 70% and 83%, respectively; for VHS, sensitivity and specificity were 56% and 85%, respectively, at a cutoff of 11.5. Mean NT-proBNP concentration was significantly increased in dogs with cardiac-related dyspnea or coughing, compared with dogs in which these signs were noncardiac related. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that 900 pmol/L is the upper reference limit of plasma NT-proBNP concentration in dogs. This biomarker may be a useful tool for staging of cardiac disease and identifying cardiac-related coughing or dyspnea in this species. PMID- 22217024 TI - National surveillance for human and pet contact with oral rabies vaccine baits, 2001-2009. AB - OBJECTIVE: To determine the rate and absolute number of human and pet exposures to oral rabies vaccine (ORV) bait containing liquid vaccinia rabies glycoprotein recombinant vaccine and to evaluate factors that might affect human contact with bait to modify the program and reduce human exposure to the vaccine. DESIGN: Retrospective analysis of surveillance data (2001 to 2009). SAMPLE: Reports on human and pet contact with ORV baits in states with ORV surveillance programs. PROCEDURES: Data were collected from passive, multistate ORV surveillance systems in Alabama, Arizona, Florida, Georgia, Maine, Maryland, Massachusetts, New Hampshire, New Jersey, New York, North Carolina, Ohio, Pennsylvania, Tennessee, Texas, Vermont, Virginia, and West Virginia. Data collected included the nature of human or pet contact with bait and vaccine, the caller's knowledge of the ORV bait program, local human population density, and other relevant demographic data. RESULTS: All 18 states participated in the surveillance program for at least 1 year, for a combined 68 years of observation. One thousand four hundred thirty-six calls were reported, representing 3,076 found baits (6.89/100,000 baits dropped); 296 (20%) calls were related to human contact with ruptured bait, and 550 (38%) involved pet contact with the bait. Six adverse events in humans were reported, one of which required hospitalization. Fifty-nine adverse events in pets were noted, all of which were nonserious. CONCLUSIONS AND CLINICAL RELEVANCE: Findings from surveillance activities have been used to improve baiting strategies and minimize human and pet contact with ORV baits. Overall, human and pet contact with ORV baits was infrequent. Surveillance has led to early identification of persons exposed to ORV and rapid intervention. PMID- 22217026 TI - Safety and efficacy of laparoscopic hepatic biopsy in dogs: 80 cases (2004-2009). AB - OBJECTIVE: To evaluate the safety and efficacy of laparoscopic hepatic biopsy in dogs. DESIGN: Retrospective case series. ANIMALS: 80 client-owned dogs. PROCEDURES: Medical records of dogs that underwent laparoscopic hepatic biopsy between 2004 and 2009 because of suspected hepatic disease were reviewed to obtain information on signalment, intraoperative and postoperative complications, and histologic diagnosis. Follow-up information was obtained through medical records and telephone conversations with owners. RESULTS: 76 of the 80 (95%) dogs survived to hospital discharge. Three (4%) dogs required conversion to laparotomy, but in none of the dogs was conversion to laparotomy needed to control hemorrhage associated with the laparoscopic biopsy procedure. Another 3 (4%) dogs required a blood transfusion; all 3 had been anemic prior to surgery. All laparoscopic biopsy samples were considered to be of sufficient size and to contain a sufficient number of portal triads to obtain a histologic diagnosis. However, disagreements in histologic diagnoses were identified for 7 of the 49 (14%) dogs for which multiple slides were available for review. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that laparoscopic hepatic biopsy is a safe procedure in dogs, with low morbidity and mortality rates, that typically yields sufficient samples for histologic examination. However, because of the possibility of disagreement among histologic diagnoses, multiple samples should be obtained. PMID- 22217027 TI - Long-term results of surgery for atresia ani with or without anogenital malformations in puppies and a kitten: 12 cases (1983-2010). AB - OBJECTIVE: To evaluate signalment, clinical findings, surgical treatment, and long-term outcomes in puppies and kittens after surgical repair of various types of atresia ani (AA) with or without concomitant anogenital or rectogenital malformations. DESIGN: Retrospective case series. ANIMALS: 11 puppies and 1 kitten. PROCEDURES: Medical records of 2 veterinary teaching hospitals were reviewed for puppies and kittens that underwent surgical treatment for AA. Information regarding signalment, diagnosis, surgical procedures, follow-up time, and outcome was recorded. A previously described classification scheme was used to classify AA as type I, II, III, or IV. Follow-up times and outcomes were evaluated. RESULTS: AA was classified as type I in 3 animals, type II in 6, and type III in 3. Nine of 12 patients had anogenital or rectogenital malformations; 8 of these had rectovaginal fistulas. Eleven animals underwent in situ anoplasty, and 1 underwent surgery in which the rectovaginal fistula was used for anal reconstruction. Six also underwent balloon dilation for treatment of anal stenosis, and revision anoplasty was performed in 5. All patients with type I or II AA survived >= 1 year. Two puppies with type III AA were euthanized 3 and 40 days after surgery. Follow-up time for the remaining 10 patients ranged from 12 to 92 months, and 3 had fecal incontinence. CONCLUSIONS AND CLINICAL RELEVANCE: Surgical repair of type I or II AA resulted in long-term survival and fecal continence in most cases. Although numbers were small, patients with type III AA had poorer outcomes than did those with type I or II AA. PMID- 22217028 TI - Comparison of surgical site infection rates in clean and clean-contaminated wounds in dogs and cats after minimally invasive versus open surgery: 179 cases (2007-2008). AB - OBJECTIVE: To report and compare the surgical site infection (SSI) rates for clean and clean-contaminated procedures performed by either a minimally invasive surgical or open surgical approach in a large population of dogs and cats. DESIGN: Prospective case series. ANIMALS: 179 patients (dogs and cats) undergoing minimally invasive abdominal or thoracic surgery. PROCEDURES: Case information from all animals that underwent minimally invasive abdominal or thoracic surgery was prospectively collected and compared with an existing database of the same information collected from 379 patients undergoing laparotomy or thoracotomy via an open surgical approach. For both groups, an SSI was defined as any surgical wound in which purulent discharge was observed within 14 days after the procedure. Follow-up for all patients was obtained by direct examination or telephone interviews. RESULTS: Overall SSI rate in the minimally invasive surgery (MIS) group was 1.7% and in the open surgery (OS) group was 5.5%. On univariate analysis, there was a significantly lower SSI rate in the MIS group, compared with the SSI rate for the OS group. On multivariable logistic regression analysis, this difference appeared to be a result of the fact that surgery times were longer (median, 105 vs 75 minutes) and hair was clipped >= 4 hours prior to surgery for more animals (23% vs 11 %) in the OS group, compared with the MIS group. CONCLUSIONS AND CLINICAL RELEVANCE: MIS may be associated with a lower SSI rate, compared with OS, but confounding factors such as differences in surgery time and preoperative preparation contributed in part to this finding. As such, surgical approach cannot be categorized as an independent risk factor for SSIs in small animals until further studies are performed. PMID- 22217029 TI - Alcohol-facilitated ankylosis of the distal intertarsal and tarsometatarsal joints in horses with osteoarthritis. AB - OBJECTIVE: To assess the safety and efficacy of alcohol-facilitated ankylosis of the distal intertarsal (DIT) and tarsometatarsal (TMT) joints in horses with osteoarthritis (bone spavin). DESIGN: Prospective clinical trial. ANIMALS: 21 horses with DIT or TMT joint-associated hind limb lameness and 5 nonlame horses. PROCEDURES: 11 horses (group 1) underwent lameness, force-plate, and radiographic examinations; following intra-articular analgesia, lameness and force-plate examinations were repeated. Nonlame horses were used for force-plate data acquisition only. Following localization of lameness to the DIT and TMT joints, contrast arthrographic evaluation was performed; when communication with the tibiotarsal joint was not evident or suspected, 70% ethyl alcohol (3 mL) was injected. Group 1 horses underwent lameness, force-plate, and radiographic examinations every 3 months for 1 year. Ten other horses (group 2) underwent lameness and radiographic examinations followed by joint injection with alcohol; follow-up information was obtained from owners or via clinical examination. RESULTS: Significant postinjection reduction in lameness (after 3 days to 3 months) was evident for all treated horses. Twelve months after injection, 10 of 11 group 1 horses were not lame; lameness grade was 0.5 in 1 horse. Follow-up information was available for 9 of 10 group 2 horses; 7 were not lame, and 2 remained mildly lame (1 had a concurrent problem in the injected limb, and the other had DIT joint collapse that precluded needle entry). CONCLUSIONS AND CLINICAL RELEVANCE: Intra-articular alcohol injection in horses with bone spavin resulted in a rapid (usually within 3 months) reduction in lameness and joint space collapse. PMID- 22217030 TI - Echocardiographic evaluation of changes in left ventricular size and valvular regurgitation associated with physical training during and after maturity in Standardbred trotters. AB - OBJECTIVE: To assess whether physical training induces cardiac hypertrophy and valvular regurgitation in maturing Standardbred trotters and to establish a prediction model for the size of the left ventricle. DESIGN: Longitudinal observational study. ANIMALS: 53 Standardbred trotters. PROCEDURES: Each horse underwent 2-D, M-mode, and color flow Doppler echocardiography at 5.5 years of age; previously, each horse had been examined at 2, 2.5, 3, and 3.5 (time of maturity) years of age. Horses were or were not in training or racing for variable periods during the entire assessment period; data for a given horse were assigned to 1 of 2 groups on the basis of the horse's status at the fifth examination (racing [n = 40] or not racing [13]). At each examination, left ventricular (LV) internal diameter in diastole (LVIDd), LV mass, and mean and relative LV wall thicknesses were measured. Prevalence and severity of tricuspid, pulmonary, mitral, and aortic valve regurgitation were determined. RESULTS: During the assessment period, LVIDd, LV mass, and mean LV wall thickness increased; body weight was significantly associated with those variables. Prediction of LV mass was possible when sex and weight were included in the model. Prevalence of valvular regurgitation increased for all valves. An increased risk of development of tricuspid and pulmonary valve regurgitation for horses in racing was observed. CONCLUSIONS AND CLINICAL RELEVANCE: The LV mass and prevalence of valvular regurgitation increased (indicative of development of exercise-induced cardiac hypertrophy and valvular regurgitation) in young horses, even during the latter part of the assessment period, when maturity was attained. PMID- 22217031 TI - Association of p.P347L in the rhodopsin gene with early-onset cystoid macular edema in patients with retinitis pigmentosa. AB - PURPOSE: To describe early-onset cystoid macular edema (CME) in a family with retinitis pigmentosa (RP) due to the p.P347L in the rhodopsin gene (RHO). METHODS: All affected family members, including a 44-year-old mother and four children in their teens (two daughters, 17 and 15 years old, and two sons, 13 and 11 years old), have a mutation of p.P347L in RHO. Funduscopy, Goldmann perimetry, spectral domain optical coherence tomography (SD-OCT) and electroretinogram (ERG) were performed in all affected members to assess the retinal anatomy and function. RESULTS: The mother had very poor visual acuity of light perception in both eyes, and marked foveal atrophy was observed via SD-OCT. Although the macular appearance in the funduscopy looked unremarkable in the four children, SD OCT revealed bilateral CME in all the children. The rod response in ERG was extinguished and the cone response was decreased in all children. CONCLUSION: The results present the possibility that CME in RP patients may be associated with a specific genotype such as the p.P347L in RHO. We speculate that the severe visual prognosis of this mutation may be related to early-onset CME, as shown in this family. However, further investigation in more RP patients with this mutation and CME will be needed. PMID- 22217036 TI - Editorial. training needs. PMID- 22217037 TI - Letters. Three R's. PMID- 22217034 TI - Catalytic diastereoselective reduction of alpha,beta-epoxy and alpha,beta aziridinyl ynones. AB - The Noyori transfer hydrogenation of alpha,beta-epoxy and alpha,beta-aziridinyl ynones leads to the corresponding alpha,beta-epoxy or alpha,beta-aziridinyl propargylic alcohols with high reagent-controlled diastereoselectivity. PMID- 22217039 TI - Letters. Three R's. PMID- 22217038 TI - Letters. Shipping wastes. PMID- 22217040 TI - Letters. Three R's. PMID- 22217041 TI - Currents. PMID- 22217042 TI - International. Environmental protection in Norway. PMID- 22217044 TI - Outlook. PMID- 22217043 TI - PAT Report: Energy recovery from pulping wastes. PMID- 22217045 TI - ERDA's fossil energy activities. PMID- 22217046 TI - How the Army does a bang-up job of treating effluents. PMID- 22217047 TI - National environmental policy: coordination or confusion? PMID- 22217048 TI - Trace organic components as fingerprints in gas chromatographic identification of spilled asphalts. PMID- 22217049 TI - Internal diffusion and reaction in biological films. PMID- 22217050 TI - Chlorinated hydrocarbon pesticides in western North Atlantic Ocean. PMID- 22217051 TI - Lead and cadmium in dusts and soils in a small urban community. PMID- 22217052 TI - Infrared spectra of petroleum weathered naturally and under simulated conditions. PMID- 22217053 TI - Associations of chlorinated hydrocarbons with fine particles and humic substances in nearshore surficial sediments. PMID- 22217054 TI - Long-path infrared spectroscopic investigation at ambient concentrations of the 2% neutral buffered potassium iodide method for determination of ozone. PMID- 22217055 TI - Corrected south coast air basin oxidant data: some conclusions and implications. PMID- 22217056 TI - Investigation of solubilization of plutonium and americium in soil by natural humic compounds. PMID- 22217057 TI - Efficient collection of polycyclic organic compounds from combustion effluents. PMID- 22217058 TI - Detection of vinyl chloride and related compounds by a gas chromatographic, chemiluminescence technique. PMID- 22217059 TI - Feasibility of oil slick removal from sea water using power lasers. PMID- 22217060 TI - Preparation of homogeneous dust sample for comparison of analytical results of atmospheric samples. PMID- 22217061 TI - Industry trends. PMID- 22217063 TI - New literature. PMID- 22217065 TI - Music and substance use. PMID- 22217066 TI - Booze, drugs, and pop music: trends in substance portrayals in the billboard top 100-1968-2008. AB - This paper presents the results of a content analysis of alcohol and drug portrayals in the top 100 Billboard songs from each of the years 1968, 1978, 1988, 1998, and 2008, thus allowing both a characterization of substance portrayals in music generally and an analysis of changes over time. Of the final sample of 496 songs, 10.3% contained a reference to alcohol and 5.7% contained a reference to drugs. A substantial increase was found over the decades, and in particular over the last two: in 1988, 12% of songs referred to either or both classes of substance, compared to 30% in 2008. Marijuana was by far the most frequently mentioned drug. Both alcohol and drugs were much more likely to be portrayed positively than negatively, especially in recent decades. The results are discussed in terms of relevant theories of media processing and impact. PMID- 22217067 TI - Dance is the new metal: adolescent music preferences and substance use across Europe. AB - This study examined relationships between music preferences and substance use (tobacco, alcohol, cannabis) among 18,103 fifteen-year-olds from 10 European countries. In 2005-2006, across Europe, preferences for mainstream Pop (pop chart music) and Highbrow (classical music and jazz) were negatively associated with substance use, while preferences for Dance (house/trance and techno/hardhouse) were associated positively with substance use. In three countries, links were identified between liking Rock (rock, heavy metal punk/hardcore, and gothic) and substance use; associations between Urban (hip-hop and R&B) and substance use were mixed. No substantial gender differences emerged in these patterns, and controlling for relevant covariates did not attenuate the predictive value of substance use. The findings are consistent with the conclusion that music is a robust marker of adolescent substance use. PMID- 22217068 TI - To hell and back: excessive drug use, addiction, and the process of recovery in mainstream rock autobiographies. AB - Rock autobiographies have become increasingly popular since the 1990s. This article analyzes 31 mainstream rock autobiographies describing a wide variety of legal and illegal substances used and reckless behavior. Narrative analysis shows that books concentrate on recovering from addiction. The majority of writers have participated in some kind of treatment. Rock autobiographies use therapeutic vocabulary and borrow discursive elements from culturally familiar Alcoholics Anonymous texts recounting recovery stories. The analysis shows that drugs and alcohol are not associated with rebellion and authenticity as they once were in rock music. Surviving addiction has become a key theme of rock culture. PMID- 22217069 TI - Music video viewing as a marker of driving after the consumption of alcohol. AB - This study has two main objectives. First, it is examined whether the frequent exposure to music video viewing is associated with driving after the consumption of alcohol. Second, it is examined which theoretical framework, a combination of Cultivation Theory and the Theory of Planned Behavior or the Problem Behavior Theory, is suited best to explain this relationship. Participants were 426 Flemish adolescents who took part in a two-wave panel survey (2006-2008) about media use, risk-taking attitudes, intentions, and behaviors. In line with Cultivation Theory and the Theory of Planned Behavior, the results showed that adolescents' music video viewing is a significant marker of later risky driving behavior and that this relationship is mediated through their attitudes and intentions. No support was found for the hypothesis that music video viewing is part of a cluster of problem behaviors (Problem Behavior Theory). Thus, the results of this study seem to indicate that a combination of Cultivation Theory and the Theory of Planned Behavior provides a more useful framework for explaining the relationship between music video viewing and driving after the consumption of alcohol. The implications for prevention and the study's limitations are discussed. PMID- 22217070 TI - Can fantasizing while listening to music play a protective role against the influences of sensation seeking and peers on adolescents' substance use? AB - "The combination of music and drugs proved to be potent, and scientific research has yet to explain it" (Levitin, 2008, p. 74; The World in Six Songs). This study examined if fantasizing while listening to music could represent a potential protective factor against adolescent substance use (cigarette, alcohol, and cannabis). The first hypothesis was that fantasizing while listening to music would moderate (buffer) the link between sensation-seeking and substance use. The second hypothesis was that fantasizing while listening to music would also moderate (buffer) the link between peer substance use and individual substance use. The sample comprised 429 adolescent boys and girls who answered a self report questionnaire in 2003. They were regular students attending a public high school in Montreal, Canada. The results revealed that fantasizing while listening to music came short of buffering the link between sensation-seeking and substance use among highly musically involved adolescents. Still, fantasizing while listening to music significantly attenuated the relationship between peer substance use and individual substance use (thereby, showing a protective effect) among highly musically involved adolescents. Fantasizing while listening to music did not buffer the relation between either risk factor (sensation-seeking or peer substance use) and substance use among moderately musically involved adolescents. PMID- 22217071 TI - The effects of music genre on young people's alcohol consumption: an experimental observational study. AB - The aim of this study was to test whether exposure to specific music genres in a social drinking setting leads to differences in drinking levels. An observational experimental design was used in which we invited peer groups of young adults into a bar lab, a lab which is furnished like an ordinary, small pub. Between two tasks, people had a break of 50 minutes in which they could order nonalcoholic and alcoholic beverages. During the break, participants were exposed to a specific music genre: popular, hard rock, rap, or classical music. Those groups who were exposed to classical music drank significantly more alcohol than those who were exposed to other music genres. This pattern is quite robust and does not depend on participants' sex or age, drinking habits, own music preference, and relative importance of music in participant's lives. The study's limitations are mentioned. PMID- 22217075 TI - Flash photolysis study of complexes between salicylic acid and lanthanide ions in water. AB - In the natural environment humic substances (HS) represent a major factor determining the speciation of metal ions, e.g., in the context of radionuclide migration. Here, due to their intrinsic sensitivity and selectivity, spectroscopic methods are often applied, requiring a fundamental understanding of the photophysical processes present in such HS-metal complexes. Complexes with different metal ions were studied using 2-hydroxybenzoic acid (2HB) as a model compound representing an important part of the chelating substructures in HS. In flash photolysis experiments under direct excitation of 2HB in the absence and the presence of different lanthanide ions, the generation and the decay of the 2HB triplet state, of the phenoxy radical, and of the solvated electron were monitored. Depending on the lanthanide ion different intracomplex processes were observed for these transient species including energy migration to and photoreduction of the lanthanide ion. The complexity of the intracomplex photophysical processes even for small molecules such as 2HB underlines the necessity to step-by-step approach the photochemical reactivity of HS by using suitable model compounds. PMID- 22217076 TI - Charge transfer through modified peptide nucleic acids. AB - We studied the charge transfer properties of bipyridine-modified peptide nucleic acid (PNA) in the absence and presence of Zn(II). Characterization of the PNA in solution showed that Zn(II) interacts with the bipyridine ligands, but the stability of the duplexes was not affected significantly by the binding of Zn(II). The charge transfer properties of these molecules were examined by electrochemistry for self-assembled monolayers of ferrocene-terminated PNAs and by conductive probe atomic force microscopy for cysteine-terminated PNAs. Both electrochemical and single molecular studies showed that the bipyridine modification and Zn(II) binding do not affect significantly the charge transfer of the PNA duplexes. PMID- 22217078 TI - Naphthenic acids degradation and toxicity mitigation in tailings wastewater systems and aquatic environments: a review. AB - Naphthenic acids, NAs (classical formula C(n)H(2n+z)O(2), where n is the carbon numbers, z represents zero or negative even integers), found in oil sands process waters (OSPWs), are toxic to aquatic environments depending upon several factors such as pH, salinity, molecular size and chemical structure of NAs. Among various available methods, biodegradation seems to be generally the most cost-effective method for decreasing concentrations of NAs (n <= 21) and reducing their associated toxicity in OSPW, however the mechanism by which the biodegradation of NAs occurs are poorly understood. Ozonation is superior over biodegradation in decreasing higher molecular weight alkyl branched NAs (preferentially, n >= 22, 6 >= z >= -12) as well as enabling accelerated biodegradation and reducing toxicity. Photolysis (UV at 254 nm) is effective in cleaving higher molecular weight NAs into smaller fragments that will be easier for microorganisms to degrade, whereas photocatalysis can metabolize selective NAs (0 >= z >= -6) efficiently and minimize their associated toxicity. Phytoremediation is applicable for metabolizing specific NAs (O(2), O(3), O(4), and O(5) species) and minimizing their associated toxicities. Petroleum coke (PC) adsorption is effective in reducing the more structurally complex NAs (preferentially 12 >= n >= 18 and z = -10, -12) and their toxicity in OSPWs, depending upon the PC content, pH and temperature. Several factors have influence on the degradation of NAs in OSPWs and aquatic environments, which include molecular mass and chemical structure of NAs, sediment structure, temperature, pH, dissolved oxygen, nutrients, and bacteria types. PMID- 22217079 TI - Treatment of soft drink process wastewater by ozonation, ozonation-H2O2 and ozonation-coagulation processes. AB - In this research, we studied the treatment of wastewater from the soft drink process using oxidation with ozone. A scheme composed of sequential ozonation peroxide, ozonation-coagulation and coagulation-ozonation treatments to reduce the organic matter from the soft drink process was also used. The samples were taken from the conventional activated sludge treatment of the soft drink process, and the experiments using chemical oxidation with ozone were performed in a laboratory using a reactor through a porous plate glass diffuser with air as a feedstock for the generation of ozone. Once the sample was ozonated, the treatments were evaluated by considering the contact time, leading to greater efficiency in removing colour, turbidity and chemical oxygen demand (COD). The effect of ozonation and coagulant coupled with treatment efficiency was assessed under optimal conditions, and substantial colour and turbidity removal were found (90.52% and 93.33%, respectively). This was accompanied by a 16.78% reduction in COD (initial COD was 3410 mg/L). The absorbance spectra of the oxidised products were compared using UV-VIS spectroscopy to indicate the level of oxidation of the wastewater. We also determined the kinetics of decolouration and the removal of turbidity with the best treatment. The same treatment was applied to the sample taken from the final effluent of the activated sludge system, and a COD removal efficiency of 100% during the first minute of the reaction with ozone was achieved. As a general conclusion, we believe that the coagulant polyaluminum chloride - ozone (PAC- ozone) treatment of wastewater from the manufacturing of soft drinks is the most efficient for removing turbidity and colour and represents an advantageous option to remove these contaminants because their removal was performed in minutes compared to the duration of traditional physical, chemical and biological processes that require hours or days. PMID- 22217077 TI - Surveillance in Eastern India (2007-2009) revealed reassortment event involving NS and PB1-F2 gene segments among co-circulating influenza A subtypes. AB - BACKGROUND: Influenza A virus encodes for eleven proteins, of which HA, NA, NS1 and PB1-F2 have been implicated in viral pathogenicity and virulence. Thus, in addition to the HA and NA gene segments, monitoring diversity of NS1 and PB1-F2 is also important. METHODS: 55 out of 166 circulating influenza A strains (31 H1N1 and 24 H3N2) were randomly picked during 2007-2009 and NS and PB1-F2 genes were sequenced. Phylogenetic analysis was carried out with reference to the prototype strains, concurrent vaccine strains and other reference strains isolated world wide. RESULTS: Comparative analysis of both nucleotide and deduced amino acid sequences, revealed presence of NS gene with A/PR/8/34(H1N1)-like mutations (H4N, Q21R, A22V, K44R, N53D, C59R, V60A, F103S and M106I) in both RNA binding and effector domain of NS1 protein, and G63E, the HPAI-H5N1-like mutation in NEP/NS2 of five A/H1N1 strains of 2007 and 2009. NS1 of other A/H1N1 strains clustered with concurrent A/H1N1 vaccine strains. Of 31 A/H1N1 strains, five had PB1-F2 similar to the H3N2 strains; six had non-functional PB1-F2 protein (11 amino acids) similar to the 2009 pandemic H1N1 strains and rest 20 strains had 57 amino acids PB1-F2 protein, similar to concurrent A/H1N1 vaccine strain. Interestingly, three A/H1N1 strains with H3N2-like PB1-F2 protein carried primitive PR8-like NS gene. Full gene sequencing of PB1 gene confirmed presence of H3N2-like PB1 gene in these A/H1N1 strains. CONCLUSION: Overall the study highlights reassortment event involving gene segments other than HA and NA in the co-circulating A/H1N1 and A/H3N2 strains and their importance in complexity of influenza virus genetics. In contrast, NS and PB1-F2 genes of all A/H3N2 eastern India strains were highly conserved and homologous to the concurrent A/H3N2 vaccine strains suggesting that these gene segments of H3N2 viruses are evolutionarily more stable compared to H1N1 viruses. PMID- 22217080 TI - Statistical modeling of air pollution. AB - The present communication deals with the application of several chemometric methods (principal components analysis, source apportioning on absolute principal components scores, chemical mass balance, self-organizing maps) to various aerosol data collections from different regions in Europe. It is shown that different latent factors explaining over 75 % of the total variance are responsible for the data structure and could be reliable identified and interpreted. Further, the contribution of each identified source to the formation of the particle total mass and chemical compounds total concentration is calculated. Thus, a reliable assessment of the air quality in the respective region is done. Classification by self-organizing maps makes it possible to better understand the role of different discriminating tracers in the air pollution. The use of chemical mass balance approach ensures a sound modeling of the pollution sources. The requirements of the sustainability concept for ecological indicators in this case is easily transformed to a multivariate statistical problem taking into account not separate indicators but the specific multivariate nature of the aerosol pollution. PMID- 22217081 TI - Functions of effective microorganisms in bioremediation of the contaminated harbor sediments. AB - The aim of this study was to apply loess balls containing effective microorganisms (EM) to the remediation of contaminated harbor sediments, and to thereby elucidate the functions of EM in remediation. Changes in physicochemical, biochemical, and microbiological parameters were measured to monitor the remediation process at a laboratory scale. Treatment with high concentrations of EM stock culture and EM loess balls (4%), and a low concentration of EM loess balls (0.1%) that contained molasses (0.05%) contributed to more rapid removal of malodor. Acetic acid, propionic acid, valeric acid, caponic acid, and lactic acid were rapidly removed in the presence of molasses (0.05% w/w) as a carbon nutrient source, indicating enhanced EM activity by amendment with molasses. Fermentation of molasses by EM showed that more acetic acid was produced compared with other organic acids, and that the majority of organic acids were eventually converted to acetate via intermediate metabolites. Sediment bioremediation tests showed there was no significant difference in eubacterial density with the control and the treatments. However, the density of a Lactobacillus sp. in sediments treated with 0.1% and 4.0% EM loess balls was significantly higher than the control, which indicated the bioaugmentation effect of EM loess balls in the polluted sediments. Treatment with EM loess balls and an appropriate amount of molasses, or other nutrients, will facilitate the remediation of polluted marine sediments by malodor removal, via EM degradation or utilization of offensive organic acids. To our knowledge, this is the first study to remediate contaminated marine (harbor) sediments using EM loess balls and to understand EM function during the bioaugmentation process, both in terms of organic acid metabolism and the dynamics of the engineered microbial community. PMID- 22217082 TI - Efficiency of a biological aerated filter for the treatment of leachate produced at a landfill receiving non-recyclable waste. AB - The feasibility of a biological aerated filter for the treatment of a partially stabilized leachate from a landfill receiving non-recyclable wastes was assessed in laboratory-scale experiments. Maximum COD, BOD(5) and TSS removal efficiencies achievable by the biofilter as well as the optimal hydraulic and organic loading rates were determined by laboratory-scale tests in batch and continuous mode. Experiments in batch mode which lasted for 7 days showed that COD and BOD(5) removal efficiencies were stabilized after the second day of operation and kept at around 56-60% and 83-97%, respectively, for the rest of the period studied. The remaining fraction (approximately 40% of the COD) was found to be composed of recalcitrant or not easily biodegradable compounds. The COD and BOD(5) removal efficiencies decreased with increasing hydraulic loading rates. The plant worked under optimal conditions at hydraulic loading rates of 0.71 and 1.41 m(3)/m(2)d (hydraulic retention times of 15.95 and 7.97 h, respectively) and at COD loading rates below 14 kg COD/m(3), where COD removal efficiencies were around 60%. TSS removal efficiencies were not significantly influenced by the hydraulic loading rate. The results obtained demonstrated the feasibility of a biological aerated filter for the removal of the biodegradable fraction of the organic matter contained in the leachate. However, a physicochemical process was found to be necessary as pre- or post-treatment for the removal of the recalcitrant fraction. PMID- 22217083 TI - Integrated acid mine drainage management using fly ash. AB - Fly Ash (FA) from a power station in South Africa was investigated to neutralise and remove contaminants from Acid Mine Drainage (AMD). After this primary treatment the insoluble FA residue namely solid residue (SR) was investigated as a suitable mine backfill material by means of strength testing. Moreover, SR was used to synthesise zeolite-P using a two-step synthesis procedure. Furthermore, the zeolite-P was investigated to polish process water from the primary FA-AMD reaction. The main objective of this series of investigations is to achieve zero waste and to propose an integrated AMD management using FA. Fly Ash was mixed with AMD at various predetermined FA-AMD ratios until the mixtures achieved circumneutral pH or higher. The supernatants were then analyzed using Inductively Coupled Plasma Mass Spectrometry (ICP-MS) and Ion Chromatography (IC) for cations and anions respectively. The physical strength testing of SR was carried out by mixing it with 3% Ordinary Portland Cement (OPC) and curing for 410 days. Synthesis of zeolite-P using SR was carried out by two step synthesis procedure: ageing for 24 hours followed by a mild hydrothermal synthesis at 100 degrees C for 4 days. The polishing of process water from primary AMD treatment using FA was ascertained by mixing the process water with zeolite at a liquid to solid ratio of 100:1 for 1 hour. The results indicated that FA can be successfully used to ameliorate AMD. High removal of major AMD contaminants Fe, Al, Mg, Mn and sulphate was achieved with the ash treatment and trace elements such as Zn, Ni, Cu and Pb were also removed by the FA. Strength testing over 410 days indicated that the material gained strength over the testing period. The maximum unconfined compressive strength and elastic modulus was observed to be approximately 0.3 MPa and 150 Mpa respectively. The X-ray diffraction (XRD) analysis of the synthesized product indicated that SR was successfully converted into zeolite-P with some mullite phase remaining as a result of incomplete conversion of the feedstock SR. The zeolite-P was used as an ion exchange material to remove selective elements from the process water. Elements such as Ca, Sr, Ba and V were successfully removed from the process water with the zeolite-P. Only marginal removal of Mo was observed during the experiments. It was also observed that Na was exchanged into the solution. This study successfully demonstrated zero waste concepts and an integrated AMD management scheme using FA was developed in this study. The implementation of this technology will address FA storage problem as well as costs associated with AMD treatment. PMID- 22217084 TI - Isolation of nitrobenzene degrading strain Pseudomonas NB001 and application in the bioremediation of polluted water body. AB - A bacterium using nitrobenzene (NB) as a sole source of carbon, nitrogen and energy was isolated from NB-contaminated water body by the enrichment technology. It was identified as Pseudomonas NB001 by the phylogenetic analysis based on 16S rDNA sequence and the biochemical and physiological characteristics. Degradation of NB by strain NB001 was concomitant with the release of nitrite. Activities of catechol2,3-dioxygenase in strain NB001 cells grown in the culture fluid were higher than that in cells under any other conditions (P < 0.05). Under the pure culture conditions, 98.4% of NB at initial concentration of 50 mg L(-1) was removed in 136 hours. Glucose at starting concentration of 100 mg L(-1) delayed the onset of the exponential phase of NB degradation and weakened the degradation ability of per cell in the pure culture systems. In the river water, 89.5% of NB was degraded in 8 days. Suspended matter obviously increased the degradation rate of NB in the early stages, but decreased in the final stages. Cd(2+) and Hg(2+) significantly weakened the ability of the strain to degrade NB at initial concentrations of 10.0 mg L(-1) and 5.0 mg L(-1), respectively. The results would offer useful information for the application of strain NB001 in the bioremediation or the control of NB-contaminated environment. PMID- 22217085 TI - Mercury in hares organs (Lepus europaeus Pallas) in the vicinity of the mercury contaminated natural gas treatment plant in Croatia. AB - In the last two decades (1990-2008), as part of a comprehensive monitoring of the eco-system, hares were collected in the vicinity of the mercury contaminated natural gas production and treatment plant Molve, Croatia. Their organs (muscle, liver, kidney and brain) were analyzed for total mercury concentration by cold vapor AAS. The range of the median mercury concentration values (wet weight) in hares organs were 0.001-0.005, 0.007-0.045, 0.022-0.126 and 0.0006-0.015 MUg/g for muscle, liver, kidney and brain, respectively. The results of mercury measurements in hares organs during the period of last twenty years demonstrate a small but constant decline in concentration values. Comparing the results obtained in this study with results published in available data and literature on mercury concentration in hare's tissue it can be concluded that area investigated in this research belongs to low mercury contaminated region. Nevertheless, further eco-monitoring and mercury measurements in various hares organs are valuable and necessary and will be continued. PMID- 22217086 TI - Anaerobic digestion of different organic wastes for biogas production and its operational control performed by the modified ADM1. AB - Anaerobic digestion (AD) of different organic wastes for biogas production under variable operating conditions was simulated with a steady-state implementation of the modified IWA Anaerobic Digestion Model No. 1 (ADM1), and an input-output feedback control system using the model as a test platform was developed. The main aim of this study was to compare the characteristics of organic wastes in the AD processes and manage to keep the processes stable based on the results of simulation. The two important operating factors, solid retention time (SRT) and organic loading rate (OLR) (or the ratio of input flows for co-digestion), were investigated. Anaerobic digestion of biowaste was characterized with lower biogas production and instability of the processes, especially at OLR 2.5 kgCOD/m(3).d or more, although longer SRT could increase the biogas production. Moreover, the co-substrate composed of biowaste and corn silage would lead to instability of the processes and much lower biogas production. Biowaste was, however, preferable to be co-digested with manures of living stock or sewage sludge. Manure could contribute to the stability of the AD processes, and its co-substrates with organic wastes rich in carbohydrates such as biowaste and corn silage would improve the biogas production and the proportion of methane. Longer SRTs would improve the biogas production from manure as well as its co-substrates except the co-substrate with biowaste as the production was not distinctly raised. The test of the developed input-output feedback control system showed that the control system could reject a realistic set of random disturbances and keep the AD processes stable under the desired operational conditions with a minimal use of measurement facilities. PMID- 22217087 TI - Trace metal partitioning in caustic calcined magnesia produced from natural magnesite. AB - Caustic calcined magnesia from natural magnesite has been widely employed as a source of magnesium. This mineral, depending on the origin, may contain heavy metals and metalloids that can exceed the regulatory limits in some applications. In most cases, heavy metals and metalloids form solid solutions with the mineral phases of the main impurities, or even magnesium oxide itself, replacing other ions in the crystal lattice. Compared with magnesium oxide, most of these impurities such as silica and silicates are much more chemically stable even in concentrated mineral acids under normal temperature and pressure conditions. In this study, the partitioning of the trace metals was monitored using a sequential extraction procedure (SEP), and their potential solubility was determined using the pH-static leaching test. Only a small fraction of magnesium oxide derived from heavily calcined magnesia is soluble in slightly acidic media. The release of the trace metals and metalloids contained in the soluble fractions was less than 40% as determined by total digestion. It can be concluded that SEP is more accurate than total chemical digestion for setting the maximum limits of the undesirable trace metals. PMID- 22217088 TI - Optimization of suitable ethanol blend ratio for motorcycle engine using response surface method. AB - In view of energy shortage and air pollution, ethanol-gasoline blended fuel used for motorcycle engine was studied in this work. The emissions of carbon monoxide (CO), nitrogen oxides (NO(X)) and engine performance of a 125 cc four-stroke motorcycle engine with original carburetor using ethanol-gasoline fuels were investigated. The model of three-variable Box Behnken design (BBD) was used for experimental design, the ethanol blend ratios were prepared at 0, 10, 20 vol%; the speeds of motorcycle were selected as 30, 45, 60 km/h; and the throttle positions were set at 30, 60, 90 %. Both engine performance and air pollutant emissions were then analyzed by response surface method (RSM) to yield optimum operation parameters for tolerable pollutant emissions and maximum engine performance. The RSM optimization analysis indicated that the most suitable ethanol-gasoline blended ratio was found at the range of 3.92-4.12 vol% to yield a comparable fuel conversion efficiency, while considerable reductions of exhaust pollutant emissions of CO (-29 %) and NO(X) (-12 %) when compared to pure gasoline fuel. This study demonstrated low ethanol-gasoline blended fuels could be used in motorcycle carburetor engines without any modification to keep engine power while reducing exhaust pollutants. PMID- 22217089 TI - Assessment of arsenic and mercury contamination in the Tisa River sediments and industrial canal sediments (Danube alluvial formation), Serbia. AB - The purpose of this study was to examine the levels of As and Hg and mobility of these contaminants in the sediments of the River Tisa and canal sediments (alluvial formation of the Danube River, Serbia), in order to determine the degree to which the ecosystem is harmed by these pollutants. The sequential extraction procedure (modified Tessier method) was used to extract the metals from the sediments. Arsenic is extracted in the second, third and fifth fraction, with dominant extraction in the second fraction. This distribution indicates that As is significantly present in the form of carbonates, whereas the part of As is present in the form of oxides. The most important extraction of Hg is in the fifth stage (extraction with 6M HCl), with over 80 % of extracted element in both types of sediment, indicating a strong association between Hg and Fe crystalline oxides as well as presence of Hg in the form of sulfides. Based on arsenic and mercury content in sediments and results of sequential extraction it can be concluded that on the studied localities there is no significant As and Hg contamination. PMID- 22217090 TI - The removal of 1,4-dioxane from polyester manufacturing process wastewater using an up-flow Biological Aerated Filter (UBAF) packed with tire chips. AB - 1,4-Dioxane is one of the by-products from the polyester manufacturing process, which has been carelessly discharged into water bodies and is a weak human carcinogen. In this study, a laboratory-scale, up-flow biological aerated filter (UBAF), packed with tire chips, was investigated for the treatment of 1,4 dioxane. The UBAF was fed with effluent, containing an average of 31 mg/L of 1,4 dioxane, discharged from an anaerobic treatment unit at H Co. in the Gumi Industrial Complex, South Korea. In the batch, a maximum of 99.5 % 1,4-dioxane was removed from an influent containing 25.6 mg/L. In the continuous mode, the optimal empty bed contact time (EBCT) and air to liquid flow rate (A:L) were 8.5 hours and 30:1, respectively. It was also found that the removal efficiency of 1,4-dioxane increased with increasing loading rate within the range 0.04 to 0.31 kg 1,4-dioxane/m(3).day. However, as the COD:1,4-dioxane ratio was increased within the range 3 to 46 (mg/L COD)/(mg/L 1,4-dioxane), the removal efficiency unexpectedly decreased. PMID- 22217091 TI - Chemically and biologically modified activated carbon sorbents for the removal of lead ions from aqueous media. AB - A method is described for hybridization of the adsorption and biosorption characteristics of chemically treated commercial activated carbon and baker's yeast, respectively, for the formation of environmental friendly multifunctional sorbents. Activated carbon was loaded with baker's yeast after acid-base treatment. Scanning Electron Microscopy (SEM) and Fourier Transform Infrared (FTIR) Spectroscopy were used to characterize these sorbents. Moreover, the sorption capabilities for lead (II) ions were evaluated. A value of 90 MUmol g( 1) was identified as the maximum sorption capacity of activated carbon. Acid-base treatment of activated carbon was found to double the sorption capacity (140-180 MUmol g(-1)). Immobilization of baker's yeast on the surface of activated carbon sorbents was found to further improve the sorption capacity efficiency of lead to 360, 510 and 560 MUmol g(-1), respectively. Several important factors such as pH, contact time, sorbent dose, lead concentration and interfering ions were examined. Lead sorption process was studied and evaluated by several adsorption isotherms and found to follow the Langmuir and BET models. The potential applications of various chemically and biologically modified sorbents and biosorbents for removal of lead from real water matrices were also investigated via multistage micro-column technique and the results referred to excellent recovery values of lead (95.0-99.0 +/- 3.0-5.0 %). PMID- 22217092 TI - Transport and removal of coliphage PRD1 in constructed wetlands. AB - The Convection Dispersion Equation (CDE) was used to calculate PRD1 and Br(-) transport parameters in a subsurface flow constructed wetland. Transport parameters from Br(-) displacement were applied into the CDE to estimate a 0.96 day(-1) first order decay coefficient (k). The PRD1 breakthrough curves were also simulated to obtain effective cross-sectional area (Ac), longitudinal dispersion coefficient (D), convective velocity (v), and k. There was practically no difference between Ac and D for both tracers. However, the estimated convective velocity was higher for PRD1 than for Br(-). Further simulations were conducted by taking experimental concentrations from prior research on surface and subsurface flow constructed wetlands. Dispersion number (d) was estimated to be between 0.17 and 0.029 by using PRD1 and Br(-) transport parameters. These parameters were also used to calculate wetland dimensionless removal (K). An analytical solution for the zero moment of the observed breakthrough curves was applied to estimate PRD1 fraction recoveries in the wetland by using d and K. The results of the present study suggest that this analytical solution may be an alternative design tool for pathogen removal estimation in subsurface flow constructed wetlands. PMID- 22217093 TI - Improved RP-HPLC separation of Hg2+ and CH3Hg+ using a mixture of thiol-based mobile phase additives. AB - Hg(2+) and CH(3)Hg(+) are frequently encountered in the environment either as free ions or complexed with organic matter, such as humic acids. The majority of the reported HPLC-based separations of environmental mercury species, however, separate Hg(2+) from CH(3)Hg(+) in which the former species elutes close to the void volume. To detect mercury-species in environmental waters that may have so far escaped detection, a separation method is needed that sufficiently retains both Hg(2+) and CH(3)Hg(+). One way to develop such a method is to increase the retention of Hg(2+) and CH(3)Hg(+) using existing HPLC separations. We here report on the improvement of a previously reported RP-HPLC-based separation of Hg(2+) and CH(3)Hg(+) that employed a 100 % aqueous mobile phase [10 mM L cysteine (Cys) in 50 mM phosphate buffer (pH 7.5)]. To increase the retention of Hg(2+), Cys was replaced by the comparatively more hydrophobic N-acetylcysteine (N-Cys). To achieve a compromise between an increased retention of Hg(2+) and its baseline separation from CH(3)Hg(+) in the shortest possible analysis time, the retention behavior of both mercurials was investigated on two RP-HPLC columns with mobile phases that contained mixtures of Cys and N-Cys in which the overall thiol concentration was maintained at 10 mM. An optimal separation of both mercurials could be achieved in ~540 s using a Gemini C(18) HPLC column (150 * 4.6 mm I.D.) and a mobile phase comprised of 7.5 mM N-Cys and 2.5 Cys in 50 mM phosphate buffer (pH 7.4). Coupling the developed HPLC separation with an inductively coupled plasma mass spectrometer should allow one to detect mercury species other than Hg(2+) and CH(3)Hg(+) in environmental waters. The detection of such species is critical to better understand the mobilization of mercury species from natural and anthropogenic pollution sources. PMID- 22217094 TI - Diastereoselective preparation of (R)- and (S)-2-methoxy-2-phenylpent-3-ynoic acids and their use as reliable chiral derivatizing agents. AB - Benzoyl-S,O-acetals 1a and 1b were used as chiral auxiliaries to achieve the diastereoselective preparation of both enantiomers of 2-methoxy-2-phenylpent-3 ynoic acids (MPPAs). The latter were condensed with several chiral secondary alcohols and some primary amines to evaluate their potential as chiral derivatizing agents (CDAs). The (1)H NMR spectra of the corresponding esters and amides showed strong consistency with the absolute configuration of the carbinol and amine moieties, whose observed DeltadeltaL(1) and DeltadeltaL(2) values were in the ranges of 0.1-0.4 and 0.02-0.12 ppm, respectively. PMID- 22217095 TI - Epidemiological evidence for the bimodal chronotype using the Composite Scale of Morningness. PMID- 22217096 TI - Effects of aging on the molecular circadian oscillations in Drosophila. AB - Circadian clocks maintain temporal homeostasis by generating daily output rhythms in molecular, cellular, and physiological functions. Output rhythms, such as sleep/wake cycles and hormonal fluctuations, tend to deteriorate during aging in humans, rodents, and fruit flies. However, it is not clear whether this decay is caused by defects in the core transcriptional clock, or weakening of the clock output pathways, or both. The authors monitored age-related changes in behavioral and molecular rhythms in Drosophila melanogaster. Aging was associated with disrupted rest/activity patterns and lengthening of the free-running period of the circadian locomotor activity rhythm. The expression of core clock genes was measured in heads and bodies of young, middle-aged, and old flies. Transcriptional oscillations of four clock genes, period, timeless, Par domain protein 1epsilon, and vrille, were significantly reduced in heads, but not in bodies, of aging flies. It was determined that reduced transcription of these genes was not caused by the deficient expression of their activators, encoded by Clock and cycle genes. Interestingly, transcriptional activation by CLOCK-CYCLE complexes was impaired despite reduced levels of the PERIOD repressor protein in old flies. These data suggest that aging alters the properties of the core transcriptional clock in flies such that both the positive and the negative limbs of the clock are attenuated. PMID- 22217097 TI - Food availability affects circadian clock-controlled activity and Zugunruhe in the night migratory male blackheaded bunting (Emberiza melanocephala). AB - This study investigated the functional linkage between food availability and activity behavior in the Palaearctic Indian night migratory blackheaded bunting (Emberiza melanocephala) subjected to artificial light-dark (LD) cycles. Two experiments were performed on photosensitive birds. In the first one, birds were exposed to short days (LD 10/14; Experiment 1A), long days (LD 13/11; Experiment 1B), or increasing daylengths (8 to 13 h light/d; Experiment 1C) and presented with food either for the whole or a restricted duration of the light period. In Experiments 1A and 1B, illumination of the light and dark periods or of the dark period, alone, was changed to assess the influence of the light environment on direct and circadian responses to food cycles. In the second experiment, birds were exposed to LD 12/12 or LD 8/16 with food availability overlapping with the light (light and food presence in phase) or dark period (light and food presence in antiphase). Also, birds were subjected to constant dim light (LL(dim)) to examine the phase of the activity rhythms under synchronizing influence of the food cycles. Similarly, the presentation of food ad libitum (free food; FF) during an experiment examined the effects of the food-restriction regimes on activity rhythms. A continuous measurement of the activity-rest pattern was done to examine both the circadian and direct effects of the food and LD cycles. Measurement of activity at night enabled assessment of the migratory phenotype, premigratory restlessness, or Zugunruhe. The results show that (i) light masked the food effects if they were present together; (ii) birds had a higher anticipatory activity and food intake during restricted feeding conditions; and (iii) food at night alone reduced both the duration and amount of Zugunruhe as compared to food during the day alone. This suggests that food affects both the daily activity and seasonal Zugunruhe, and food cycles act as a synchronizer of circadian rhythms in the absence of dominant natural environmental synchronizers, such as the light-dark cycle. PMID- 22217098 TI - Dim light at night increases immune function in Nile grass rats, a diurnal rodent. AB - With the widespread adoption of electrical lighting during the 20th century, human and nonhuman animals became exposed to high levels of light at night for the first time in evolutionary history. This divergence from the natural environment may have significant implications for certain ecological niches because of the important influence light exerts on the circadian system. For example, circadian disruption and nighttime light exposure are linked to changes in immune function. The majority of studies investigating the effects of light exposure and circadian disruption on the immune system use nocturnal rodents. In diurnal species, many hormones and immune parameters vary with secretion patterns 180 degrees out of phase to those of nocturnal rodents. Thus, the authors investigated the effects of nighttime light exposure on immunocompetence in diurnal Nile grass rats (Arvicanthis niloticus). Rats were housed in either standard 14-h light (L):10-h dark (D) cycles with L ~150 lux and D 0 lux or dim light at night (dLAN) cycles of LD 14:10 with L ~150 lux and D 5 lux for 3 wks, then tested for plasma bactericidal capacity, as well as humoral and cell mediated immune responses. Rats exposed to dLAN showed increased delayed-type hypersensitivity pinna swelling, which is consistent with enhanced cell-mediated immune function. dLAN rats similarly showed increased antibody production following inoculation with keyhole lymphocyte hemocyanin (KLH) and increased bactericidal capacity. Daytime corticosterone concentrations were elevated in grass rats exposed to nighttime dim light, which may have influenced immunological measures. Overall, these results indicate nighttime light affects immune parameters in a diurnal rodent. PMID- 22217099 TI - Dim light melatonin onset in alcohol-dependent men and women compared with healthy controls. AB - Sleep disturbances in alcohol-dependent (AD) individuals may persist despite abstinence from alcohol and can influence the course of the disorder. Although the mechanisms of sleep disturbances of AD are not well understood and some evidence suggests dysregulation of circadian rhythms, dim light melatonin onset (DLMO) has not previously been assessed in AD versus healthy control (HC) individuals in a sample that varied by sex and race. The authors assessed 52 AD participants (mean +/- SD age: 36.0 +/- 11.0 yrs of age, 10 women) who were 3-12 wks since their last drink (abstinence: 57.9 +/- 19.3 d) and 19 age- and sex matched HCs (34.4 +/- 10.6 yrs, 5 women). Following a 23:00-06:00 h at-home sleep schedule for at least 5 d and screening/baseline nights in the sleep laboratory, participants underwent a 3-h extension of wakefulness (02:00 h bedtime) during which salivary melatonin samples were collected every 30 min beginning at 19:30 h. The time of DLMO was the primary measure of circadian physiology and was assessed with two commonly used methodologies. There was a slower rate of rise and lower maximal amplitude of the melatonin rhythm in the AD group. DLMO varied by the method used to derive it. Using 3 pg/mL as threshold, no significant differences were found between the AD and HC groups. Using 2 standard deviations above the mean of the first three samples, the DLMO in AD occurred significantly later, 21:02 +/- 00:41 h, than in HC, 20:44 +/- 00:21 h (t = -2.4, p = .02). Although melatonin in the AD group appears to have a slower rate of rise, using well-established criteria to assess the salivary DLMO did not reveal differences between AD and HC participants. Only when capturing melatonin when it is already rising was DLMO found to be significantly delayed by a mean 18 min in AD participants. Future circadian analyses on alcoholics should account for these methodological caveats. PMID- 22217100 TI - Gambling when sleep deprived: don't bet on stimulants. AB - Recent evidence suggests that sleep deprivation leads to suboptimal decision making on the Iowa Gambling Task (IGT), a pattern that appears to be unaffected by moderate doses of caffeine. It is not known whether impaired decision-making could be reversed by higher doses of caffeine or by other stimulant countermeasures, such as dextroamphetamine or modafinil. Fifty-four diurnally active healthy subjects completed alternate versions of the IGT at rested baseline, at 23 and 46 h awake, and following a night of recovery sleep. After 44 h awake, participants received a double-blind dose of caffeine (600 mg), dextroamphetamine (20 mg), modafinil (400 mg), or placebo. At baseline, participants showed a normal pattern of advantageous performance, whereas both sleep-deprived sessions were associated with suboptimal decision-making on the IGT. Following stimulant administration on the second night of sleep deprivation, groups receiving caffeine, dextroamphetamine, or modafinil showed significant reduction in subjective sleepiness and improvement in psychomotor vigilance, but decision-making on the IGT remained impaired for all stimulants and did not differ from placebo. Decision-making returned to normal following recovery sleep. These findings are consistent with prior research showing that sleep deprivation leads to suboptimal decision-making on some types of tasks, particularly those that rely heavily on emotion processing regions of the brain, such as the ventromedial prefrontal cortex. Moreover, the deficits in decision-making were not reversed by commonly used stimulant countermeasures, despite restoration of psychomotor vigilance and alertness. These three stimulants may restore some, but not all, aspects of cognitive functioning during sleep deprivation. PMID- 22217101 TI - Effects of sleep loss and circadian rhythm on executive inhibitory control in the Stroop and Simon tasks. AB - This study assessed the influence of sleep loss and circadian rhythm on executive inhibitory control (i.e., the ability to inhibit conflicting response tendencies due to irrelevant information). Twelve ordinarily diurnally active, healthy young male participants performed the Stroop and the Simon task every 3 h in a 40-h constant routine protocol that comprised constant wakefulness under controlled behavioral and environmental conditions. In both tasks, overall performance showed clear circadian rhythm and sleep-loss effects. However, both Stroop and Simon interference remained unchanged across the 40 h of wakefulness, suggesting that neither cumulative sleep loss nor the circadian clock affects executive inhibitory control. The present findings challenge the widely held view that executive functions are especially vulnerable to the influence of sleep loss and circadian rhythm. PMID- 22217102 TI - Lack of nocturnal blood pressure fall in elderly bedridden hypertensive patients with cerebrovascular disease. AB - To prevent recurrence of cerebrovascular disease (CVD), adequate control of blood pressure (BP) is extremely important for the treatment of hypertensive CVD patients. As absence of the nocturnal fall of BP by the expected 10-20% from daytime levels is reported to exaggerate target organ injury, 24-h ambulatory blood pressure monitoring (ABPM) was conducted, especially to obtain data during nighttime sleep. Forty-eight elderly bedridden chronic phase CVD hypertensive patients (assessed 1-3 mo after CVD accident) participated. As a group, nocturnal BP was higher than diurnal BP, whereas nocturnal pulse rate was lower than diurnal pulse rate. The nocturnal BP fall was blunted in most (~90%) of the patients. These results suggest that to perform a rational drug treatment, it is essential to do 24-h ABPM before initiation of antihypertensive therapy in elderly bedridden hypertensive CVD patients. PMID- 22217103 TI - Comparison of beta-adrenergic and glucocorticoid signaling on clock gene and osteoblast-related gene expressions in human osteoblast. AB - Most living organisms exhibit circadian rhythms that are generated by endogenous circadian clocks, the master one being present in the suprachiasmatic nuclei (SCN). Output signals from the SCN are believed to transmit standard circadian time to peripheral tissue through sympathetic nervous system and humoral routes. Therefore, the authors examined the expression of clock genes following treatment with the beta-adrenergic receptor agonist, isoprenaline, or the synthetic glucocorticoid, dexamethasone, in cultured human osteoblast SaM-1 cells. Cells were treated with 10(-6) M isoprenaline or 10(-7) M dexamethasone for 2 h and gene expressions were determined using real-time polymerase chain reaction (PCR) analysis. Treatment with isoprenaline or dexamethasone induced the circadian expression of clock genes human period 1 (hPer1), hPer2, hPer3, and human brain and muscle Arnt-like protein 1 (hBMAL1). Isoprenaline or dexamethasone treatment immediately increased hPer1 and hPer2 and caused circadian oscillation of hPer1 and hPer2 with three peaks within 48 h. hPer3 expression had one peak after isoprenaline or dexamethasone treatment. hBMAL expression had two peaks after isoprenaline or dexamethasone treatment, the temporal pattern being in antiphase to that of the other clock genes. Dexamethasone treatment delayed the oscillation of all clock genes for 2-6 h compared with isoprenaline treatment. The authors also examined the expression of osteoblast-related genes halpha-1 type I collagen (hCol1a1), halkaline phosphatase (hALP), and hosteocalcin (hOC). Isoprenaline induced oscillation of hCol1a1, but not hALP and hOC. On the other hand, dexamethasone induced oscillation of hCol1a1 and hALP, but not hOC. Isoprenaline up-regulated hCol1a1 expression, but dexamethasone down-regulated hCol1a1 and hALP expression in the first phase. PMID- 22217104 TI - Larval ethanol exposure alters adult circadian free-running locomotor activity rhythm in Drosophila melanogaster. AB - Alcohol consumption causes disruptions in a variety of daily rhythms, including the sleep-wake cycle. Few studies have explored the effect of alcohol exposure only during developmental stages preceding maturation of the adult circadian clock, and none have examined the effects of alcohol on clock function in Drosophila. This study investigates developmental and behavioral correlates between larval ethanol exposure and the adult circadian clock in Drosophila melanogaster, a well-established model for studying circadian rhythms and effects of ethanol exposure. We reared Drosophila larvae on 0%, 10%, or 20% ethanol supplemented food and assessed effects upon eclosion and the free-running period of the circadian rhythm of locomotor activity. We observed a dose-dependent effect of ethanol on period, with higher doses resulting in shorter periods. We also identified the third larval instar stage as a critical time for the developmental effects of 10% ethanol on circadian period. These results demonstrate that developmental ethanol exposure causes sustainable shortening of the adult free-running period in Drosophila melanogaster, even after adult exposure to ethanol is terminated, and suggests that the third instar is a sensitive time for this effect. PMID- 22217105 TI - Mice show circadian rhythms of blood pressure during each wake-sleep state. AB - A daily rhythm of blood pressure (BP), with maximum values in the activity period, carries important prognostic information. The extent to which this rhythm depends on behavioral factors remains debated. Mice are the species of choice for functional genomics. In mice, episodes of wakefulness and sleep are not restricted to particular daily periods, allowing BP in each wake-sleep state to be measured at each time of day. The aim of this study was to investigate whether a circadian rhythm of BP is manifest in each wake-sleep state in mice. Mice with B6 genetic background (n = 26) were implanted with a telemetric BP transducer and electrodes to discriminate wake-sleep states and recorded while housed under a 12:12 h light-dark period. For each mouse, 8 values of BP were obtained in each wake-sleep state (wakefulness, non-rapid-eye-movement sleep, and rapid-eye movement sleep) by averaging over successive 3-h time bins. Analysis of variance evidenced a significant time effect in each wake-sleep state as well as a significant wake-sleep state * time interaction effect. In an additional group of mice (n = 3) recorded in constant darkness, the Lomb-Scargle periodogram also revealed a significant circadian rhythm of BP in each wake-sleep state. These findings demonstrate that during each wake-sleep state, mice show daily and circadian rhythms of BP in conditions of entrainment to the light-dark cycle and in free-running conditions of constant darkness, respectively. PMID- 22217106 TI - Window illumination should be expected to poorly correlate with satellite brightness measurements. PMID- 22217108 TI - Bacteriological quality of raw milk used for production of a Brazilian farmstead raw milk cheese. AB - The objective of this study was to evaluate the bacteriological quality of raw cow's milk utilized for the production of Traditional Minas Serro cheese, a Brazilian farmstead raw milk cheese. Raw milk samples were collected from six farmstead cheese operations manufacturing raw milk cheese from cow's milk. Coliform count (CC) and Escherichia coli counts were determined using PetrifilmTM EC plates, and Staphylococcus aureus counts were determined using PetrifilmTM Staph Express count plates. The standard plate count (SPC) was determined using plate count agar. The somatic cell count (SCC) was determined with a DeLaval cell counter. The detection of Listeria monocytogenes was based in the ISO 11290-1 protocol. A total of 165 samples were analyzed, and the SPC was 1.85-7.88 log CFU/mL. Coliform were detected in 140 (84.8%) of the 165 samples, with counts of 1-6.39 log CFU/mL. E. coli was detected in 17 (10.3%) samples, with counts of 1 2.18 log CFU/mL. The SCC in raw milk was 10,000-1,390,000 cells per mL, with mean and geometric mean values of 247,000 and 162,181, respectively. The SCC did not differ significantly between the seasons (p>0.05), but differed between different farms (p<0.05). None of the 155 samples were positive for the presence of Listeria monocytogenes. S. aureus was isolated in 145 (94.1%) of the 154 samples, and the count was 1.47-5.03 log CFU/mL. The median of SPC, CC, and S. aureus counts differed significantly between seasons and between farms (p<0.05). Our results indicate that raw milk for production of farmstead raw milk cheese has a low incidence of L. monocytogenes and a high incidence of S. aureus, and suggest that measurements (such as SCC or SPC) may not serve as a predictor of other bacterial (including pathogenic) presence. PMID- 22217109 TI - The potential capability of social media as a component of food safety and food terrorism surveillance systems. AB - Social media (i.e., internet applications and platforms that allow users to create and share content) are a potentially rich data source for foodborne disease surveillance. This commentary qualitatively evaluates social media as a foodborne disease surveillance system component and discusses novel ways that social media may facilitate the detection of intentional and unintentional food contamination. PMID- 22217110 TI - Volume 27: statistics and thanks. PMID- 22217111 TI - Acute sleep deprivation has no lasting effects on the human antibody titer response following a novel influenza A H1N1 virus vaccination. AB - BACKGROUND: Experimental studies in humans have yielded evidence that adaptive immune function, including the production of antigen-specific antibodies, is distinctly impaired when sleep is deprived at the time of first antigen exposure. Here we examined the effects of a regular 24-hour sleep-wake cycle (including 8 hours of nocturnal sleep) and a 24-hour period of continuous wakefulness on the 7 week antibody production in 11 males and 13 females in response to the H1N1 (swine flu) virus vaccination. The specific antibody titer in serum was assayed by the hemagglutination inhibition test on the days 5, 10, 17, and 52 following vaccination. RESULTS: In comparison to the sleep group, sleep-deprived males but not females had reduced serum concentration of H1N1-specific antibodies five days after vaccination, whereas antibody titers at later time points did not differ between the conditions. CONCLUSIONS: These findings concur with the notion that sleep is a supportive influence in the very early stage of an adaptive immune response to a viral antigen. However, our results do not support the view that acute sleep deprivation has lasting effects on the human antibody titer response to influenza vaccination. PMID- 22217113 TI - Crystalloid body, refractile body and virus-like particles in Apicomplexa: what is in there? AB - The phylum of Apicomplexa comprises parasitic protozoa that share distinctive features such as the apical complex, the apicoplast, specialized cytoskeletal components and secretory organelles. Other unique cytoplasmic inclusions sharing similar features have been described in some representatives of Apicomplexa, although under different denominations. These are the crystalloid body, present for example in Cryptosporidium, Plasmodium and Cystoisospora; the refractile body in Eimeria and Lankesterella; and virus-like particles, also present in Eimeria and Cryptosporidium. Yet, the specific role of these cytoplasmic inclusions in the cell cycle of these protozoa is still unknown. Here, we discuss their morphology, possible inter-relatedness and speculate upon their function to bring these organelles back to the attention of the scientific community and promote new interest towards original research on these elusive structures. PMID- 22217114 TI - Mechanism of drug resistance of hemagglutinin of influenza virus and potent scaffolds inhibiting its function. AB - Highly pathogenic influenza viruses have become a global threat to humans. It is important to select an effective therapeutic option suitable for the subtypes in an epidemic or pandemic. To increase the options, the development of novel antiviral agents acting on targets different from those of the currently approved drugs is required. In this study, we performed molecular dynamics simulations on a spike protein on the viral envelop, hemagglutinin, for the wild-type and three kinds of mutants using a model system consisting of a trimeric hemagglutinin complex, viral lipid membrane, solvation waters, and ions. A natural product, stachyflin, which shows a high level of antiviral activity specific to some subtypes of influenza viruses, was examined on binding to the wild-type hemagglutinin by docking simulation. The compound potency of stachyflin is, however, easily lost due to resistant mutations. From a comparison of simulation results between the wild-type and the resistant mutants, the reason for the drug resistance of hemagglutinin was clarified. Next, 8 compounds were selected from a chemical database by in silico screening, considering the findings from the simulations. Inhibitory activities to suppress the proliferation of influenza virus were measured by cell-based antiviral assays, and two chemical scaffolds were found to be potent for an inhibitor. More than 30 derivatives bearing either of these two chemical scaffolds were synthesized, and cell culture assays were carried out to evaluate the compound potency. Several derivatives displayed a high compound potency, and 50% effective concentrations of two synthesized compounds were below 1 MUM. PMID- 22217115 TI - Remarkable stereoselectivity in intramolecular Borono-Mannich reactions: synthesis of conduramines. AB - An unprecedented intramolecular Petasis condensation provides a novel approach to biologically important conduramines. The compounds are produced with an exclusive anti stereoselectivity for the newly created beta-amino alcohol motif. The stereochemical outcome of the reaction is opposite to the one usually observed in the intermolecular reaction. PMID- 22217112 TI - Stray dogs as indicators of Toxoplasma gondii distributed in the environment: the first report across an urban-rural gradient in China. AB - BACKGROUND: Toxoplasmosis is an important parasitic zoonosis caused by the protozoan Toxoplasma gondii that is distributed world-wide and infects a variety of hosts. However, the prevalence of T. gondii in the environment (such as soil, water and food) is largely unknown. Due to the technical difficulty in oocyst counting directly, an alternative assay using the serologic status of T. gondii in free-living animals, such as stray or free-living dogs, as an indicator, can be used to evaluate environmental contamination indirectly, as they are exposed to the same risk of infection as humans and other animals. RESULTS: In the present study, 231 stray or free-living dogs across an urban-rural gradient were examined to assess the frequency of T. gondii in the environment. Specific antibodies to T. gondii were found in 93 dogs (40.3%) by enzyme-linked immunosorbent assay (ELISA), and no statistically significant differences were observed in seroprevalences of T. gondii between urban dogs (38.7%) and rural dogs (41%) (p > 0.05). CONCLUSIONS: A high seroprevalence of T. gondii in stray or free-living dogs in the present study indicates that there would be a wide distribution and a constant infection pressure of T. gondii across an urban-rural gradient, and the oocysts of T. gondii in the environment would be an important source of infection for humans and other animals both in urban and rural areas in China. PMID- 22217116 TI - Health communication grows in significance--the 100th issue. PMID- 22217117 TI - A look back: the Journal of Health Communication celebrates 100 issues. PMID- 22217122 TI - Mindfulness and substance use intervention. PMID- 22217118 TI - Build it, and will they come? Unexpected findings from a study on a Web-based intervention to improve colorectal cancer screening. AB - Given the extensive use of the Internet for health information, Web-based health promotion interventions are widely perceived as an effective communication channel. The authors conducted this study to determine use of a Web-based intervention intended to improve colorectal cancer screening in a population of women who are at average risk and noncompliant to current screening recommendations. The study was a randomized controlled trial designed to compare the effectiveness of colorectal cancer screening educational materials delivered using the Internet versus a printed format. In 3 years, 391 women seen for routine obstetrics/gynecology follow-up at 2 academic centers provided relevant survey information. Of these, 130 were randomized to the Web intervention. Participants received voluntary access to a password-protected, study-specific Web site that provided information about colorectal cancer and colorectal cancer screening options. The main outcome measures were self-reported and actual Web site use. Only 24.6% of women logged onto the Web site. Age was the only variable that differentiated users from nonusers (p = .03). In contrast, 16% of participants self-reported Web use. There was significant discordance between the veracity of actual and self-reported use (p = .004). Among true users, most (81%) logged on once only. These findings raise questions about how to increase use of important health communication interventions. PMID- 22217121 TI - Adoption of telemedicine: from pilot stage to routine delivery. AB - BACKGROUND: Today there is much debate about why telemedicine has stalled. Teleradiology is the only widespread telemedicine application. Other telemedicine applications appear to be promising candidates for widespread use, but they remain in the early adoption stage. The objective of this debate paper is to achieve a better understanding of the adoption of telemedicine, to assist those trying to move applications from pilot stage to routine delivery. DISCUSSION: We have investigated the reasons why telemedicine has stalled by focusing on two, high-level topics: 1) the process of adoption of telemedicine in comparison with other technologies; and 2) the factors involved in the widespread adoption of telemedicine. For each topic, we have formulated hypotheses. First, the advantages for users are the crucial determinant of the speed of adoption of technology in healthcare. Second, the adoption of telemedicine is similar to that of other health technologies and follows an S-shaped logistic growth curve. Third, evidence of cost-effectiveness is a necessary but not sufficient condition for the widespread adoption of telemedicine. Fourth, personal incentives for the health professionals involved in service provision are needed before the widespread adoption of telemedicine will occur. SUMMARY: The widespread adoption of telemedicine is a major -- and still underdeveloped -- challenge that needs to be strengthened through new research directions. We have formulated four hypotheses, which are all susceptible to experimental verification. In particular, we believe that data about the adoption of telemedicine should be collected from applications implemented on a large-scale, to test the assumption that the adoption of telemedicine follows an S-shaped growth curve. This will lead to a better understanding of the process, which will in turn accelerate the adoption of new telemedicine applications in future. Research is also required to identify suitable financial and professional incentives for potential telemedicine users and understand their importance for widespread adoption. PMID- 22217123 TI - U.S. mortality from liver cirrhosis and alcoholic liver disease in 1999-2004: regional and state variation in relation to per capita alcohol consumption. AB - Apparent per-capita alcohol consumption in 2001 in four U.S. regions (West, Northeast, South, and Midwest), and in 50 states was examined in relation to mortality rates (1999-2004) from liver cirrhosis and for the subcategory alcoholic liver disease. Alcohol consumption and mortality rates were highest in the west. The alcoholic liver disease mortality rate by state was strongly correlated with alcohol consumption, but several outlier or mismatch states were identified. Per-capita alcohol consumption should be useful for US public health policy, as suggested for Europe and Canada, but outlier states require further study. PMID- 22217124 TI - The impact of human rights violations and perceptions of discrimination on health service utilization among injection drug users in Delhi, India. AB - The study was conducted from August to December 2007, in two urban, poor neighborhoods in Delhi. A respondent-driven sampling was used to recruit 343 injection drug users who were interviewed with a survey questionnaire that included items of human rights abuses, health service utilization, and sociodemographic characteristics. Multivariate logistic regression with backward selection of variables was conducted with the three outcome variables-service utilization in general care sector, harm reduction, and drug user treatment. Findings suggest advocating for human rights and securing standards of care in improving health care use and future research on documenting human rights abuses occur in health care settings. The study's limitations are noted. PMID- 22217125 TI - The relationship between community structural characteristics, the context of crack use, and HIV risk behaviors in San Salvador, El Salvador. AB - This paper explores community structural factors in different low-income communities in the San Salvador, El Salvador, that account for differences in the social context in which crack is used and HIV risk behaviors among crack users. Results suggest that both more distal (type of low-income community, level of violent crime, and poverty) and proximate structural factors (type of site where drugs are used, and whether drugs are used within or outside of community of residence) influence HIV risk behaviors among drug users. Additionally, our results suggest that community structural factors influence the historical and geographic variation in drug use sites. PMID- 22217126 TI - Heavy episodic drinking among university students: drinking status and perceived normative comparisons. AB - The present study tests the perceived norms hypothesis in relation to different levels of heavy episodic drinking (HED) among university students. In 2007, 303 students from residence halls and the School of Psychology at the University of Wollongong, Australia, completed a questionnaire about their alcohol consumption and associated attitudes and behaviors. Between-groups analyses of variance (ANOVAs) revealed significantly higher AUDIT (Alcohol Use Disorders Identification Test) scores among students in higher-frequency HED groups. Students who engaged in HED tended to underestimate their own drinking when comparing themselves with others. Improving the accuracy of perceptions about one's own drinking in relation to others (normative information) may help reduce levels of HED among students. PMID- 22217127 TI - A pilot study of the nutritional status of opiate-using pregnant women on methadone maintenance therapy. AB - Pregnant women in methadone maintenance therapy may have poor nutrition during pregnancy. In 2006-2008, methadone-treated pregnant women (n = 22) were recruited at an urban academic medical center and compared with nondrug-using pregnant women (n = 119) at 20-35 weeks' gestation. We measured adiposity using prepregnancy body mass index (BMI), dietary intake using a food frequency questionnaire, and micronutrient and essential fatty acid status using biomarkers. Methadone-treated women had lower BMI, consumed more calories, had lower serum carotenoid concentrations, and higher plasma homocysteine concentrations than controls. The study's limitations and implications for future research are discussed. PMID- 22217128 TI - Population, professional, and client support for different models of managing addictive behaviors. AB - This study, funded by the Academy of Finland, explores how different stakeholder groups in Finland attribute responsibility for various addictions. A random general population survey and surveys with addiction treatment professionals and clients (n = 1,338) were conducted in 2007-2008. The data were analyzed with analyses of variance and logistic regression analysis. Individual responsibility was emphasized by all groups. The Moral model dominated in behavioral and the Enlightenment model in hard drug addictions, views on other substance addictions varied more. Some signs of the actor-observer asymmetry were observed. Personal addiction experiences and sex were the major predictors of the average response tendencies. The heavy emphasis on individual responsibility may prevent help seeking. PMID- 22217129 TI - Vulnerability and the intention to anabolic steroids use among Iranian gym users: an application of the theory of planned behavior. AB - This correlational study explored the psychological antecedents of 253 Iranian gym users' intentions to use the anabolic-androgenic steroids (AAS), based on the Theory of Planned Behavior (TPB). The three predictor variables of (1) attitude, (2) subjective norms, and (3) perceived behavioral control accounted for 63% of the variation in the outcome measure of the intention to use the AAS. There is some support to use the TPB to design and implement interventions to modify and/or improve individuals' beliefs that athletic goals are achievable without the use of the AAS. PMID- 22217131 TI - Otosclerosis: a perilabyrinthine threshold phenomenon. AB - This paper is a review of our most recent findings concerning the osteo-dynamics of the bony otic capsule and pathogenesis of otosclerosis. By exploring the spatial relationship between normal perilabyrinthine bone remodeling, the viability and spatial distribution of labyrinthine osteocytes, and the location of otosclerosis, a unique spatial pattern emerged. Bone remodeling is highly inhibited around the inner ear space. Most likely, inner ear anti-resorptive signals enter the bony otic capsule through the lacuno-canalicular porosity. The patency of this signaling pathway depends on the viability of individual osteocytes. In the young otic capsule the density of viable osteocytes is high and centripetally distributed. This arrangement may sustain a life-long osseus pathway for anti-resorptive signals even within a bone where a considerable loss of viable osteocytes must be expected, as demonstrated by a centripetal accumulation of dead osteocytes with age. The spatial distribution of dead osteocytes follows the same general pattern as otosclerosis. We suggest that clustering of dead osteocytes may impede the transmission of anti-resorptive signals locally, leaving such ghost regions susceptible to focal bone remodeling as in human otosclerosis. The preserved network of viable osteocytes around the depleted ghost regions may contain the process and distort the structure of bone remodeling into an abnormal otosclerotic pattern. PMID- 22217132 TI - 2010-2011 National Health Law Moot Court Competition. PMID- 22217133 TI - 2010-2011 National Health Law Moot Court Competition: best brief. PMID- 22217134 TI - Jacobson revisited. PMID- 22217135 TI - Death investigation liability of medical examiners and coroners. PMID- 22217136 TI - High school athletes and concussions. PMID- 22217137 TI - Would you like a side of statin with that? PMID- 22217141 TI - Circadian activity of the hypothalamic-pituitary-adrenal axis is differentially affected in the rat chronic mild stress model of depression. AB - The altered activity of the hypothalamic-pituitary-adrenal (HPA) axis is often observed in stress-related disorders. According to the literature, about 60% of patients with major depressive disorder elicit high levels of cortisol. It is still unclear why high cortisol levels are not observed in all patients. In this study, we used the chronic mild stress (CMS) rat model of depression, which is based on continuous exposure to unpredictable stressors, to track longitudinal changes in HPA function using fecal corticosterone metabolites (FCM) as a read out. The dexamethasone suppression test was used to assess negative feedback inhibition of the HPA axis. Our results show (1) a disturbance in diurnal corticosterone rhythm measured as fluctuations of the diurnal FCM peak, (2) differences in corticosterone levels between stress-susceptible and stress resilient animals, (3) recovery of diurnal corticosterone rhythm after 8 weeks of CMS, and (4) alterations in sensitivity to dexamethasone in negative feedback regulation of corticosterone secretion during the time course of CMS. Thus, a disruption of HPA axis circadian rhythmicity coincides with the initial state in the development of depression-like behavior. This chronobiological abnormality, as well as the hypersecretion of corticosterone, is state, rather than trait, dependent. PMID- 22217142 TI - Eleven-year surveillance of antibiotic resistance in Streptococcus pneumoniae in Casablanca (Morocco). AB - OBJECTIVE: To analyze trends of antibiotic resistance rates in Streptococcus pneumoniae from 1998 to 2008 in Casablanca (Morocco). METHODS: The antibiotic resistance levels of 955 consecutive nonduplicate isolates were studied using E test and disc diffusion methods. Results were interpreted following Clinical and Laboratory Standards Institute guidelines (2005). Analysis was done according to three periods (1998-2001; 2002-2005; 2006-2008), age, and site of infection. RESULTS: Penicillin nonsusceptibility (PNS) increased significantly over time (15.6%, 17.8%, and 24.8%; p=0.003). Levels of PNS have changed as well: in 2006 2008, 9.1% of the isolates had an MIC >=2 MUg/ml versus 7.7% in 2002-2005 and 3.4% in 1998-2001. The PNS increase was particularly marked in pediatric isolates (21.4%, 25.5%, and 43.3%; p=0.001). There was no significant difference between the rates of PNS in invasive and noninvasive isolates from children, whereas in adults noninvasive isolates were more penicillin nonsusceptible. Amoxicillin and ceftriaxone nonsusceptible isolates were very rare. An increase of resistance rates was also noticed for erythromycin (9.4%, 12.2%, and 14.4%), tetracycline (20%, 18.6%, and 30.5%), and chloramphenicol (5.6%, 5.6%, and 8.1%). Trimethoprim sulfamethoxazole resistance rates remained stable (22.8%, 20%, and 23.8%). Proportions of dual nonsusceptibility to penicillin and erythromycin, increased from 5.6% to 8.9%. Multiple drug resistance (resistance to 3 or more antibiotic classes) was found in 0%, 2.4%, and 7.7% of all isolates, respectively. CONCLUSION: The results reported here maybe useful for guiding update of treatment recommendations and suggest the need for continuous surveillance. Increase of antibiotic resistance correlated with antibiotic consumption, stressing the need for elaboration of antibiotic policy in Morocco. PMID- 22217144 TI - Chemical-state analysis of organic semiconductors using soft X-ray absorption spectroscopy combined with first-principles calculation. AB - The chemical states of organic semiconductors were investigated by total-electron yield soft X-ray absorption spectroscopy (TEY-XAS) and first-principles calculations. The organic semiconductors, pentacene (C(22)H(14)) and pentacenequinone (C(22)H(12)O(2)), were subjected to TEY-XAS and the experimental spectra obtained were compared with the 1s core-level excited spectra of C and O atoms, calculated by a first-principles planewave pseudopotential method. Excellent agreement between the measured and the calculated spectra were obtained for both materials. Using this methodology, we examined the chemical states of the aged pentacene, and confirmed that both C-OH and C?O chemical bonds are generated by exposure to air. This result implies that not only oxygen but also humidity causes pentacene oxidation. PMID- 22217143 TI - Micropatterning topology on soft substrates affects myoblast proliferation and differentiation. AB - Micropatterning techniques and substrate engineering are becoming useful tools to investigate several aspects of cell-cell interaction biology. In this work, we rationally study how different micropatterning geometries can affect myoblast behavior in the early stage of in vitro myogenesis. Soft hydrogels with physiological elastic modulus (E = 15 kPa) were micropatterned in parallel lanes (100, 300, and 500 MUm width) resulting in different local and global myoblast densities. Proliferation and differentiation into multinucleated myotubes were evaluated for murine and human myoblasts. Wider lanes showed a decrease in murine myoblast proliferation: (69 +/- 8)% in 100 MUm wide lanes compared to (39 +/- 7)% in 500 MUm lanes. Conversely, fusion index increased in wider lanes: from (46 +/- 7)% to (66 +/- 7)% for murine myoblasts, and from (15 +/- 3)% to (36 +/- 2)% for human primary myoblasts, using a patterning width of 100 and 500 MUm, respectively. These results are consistent with both computational modeling data and conditioned medium experiments, which demonstrated that wider lanes favor the accumulation of endogenous secreted factors. Interestingly, human primary myoblast proliferation is not affected by patterning width, which may be because the high serum content of their culture medium overrides the effect of secreted factors. These data highlight the role of micropatterning in shaping the cellular niche through secreted factor accumulation, and are of paramount importance in rationally understanding myogenesis in vitro for the correct design of in vitro skeletal muscle models. PMID- 22217145 TI - Four- and six-year-olds use pragmatic competence to guide word learning. AB - The present study investigates whether four- and six-year-old children use pragmatic competence as a criterion for learning from someone else. Specifically, we ask whether children use others' adherence to Gricean maxims to determine whether they will offer valid labels for novel objects. Six-year-olds recognized adherence to the maxims of quality and relation and subsequently trusted the labels provided by a maxim adherer. Four-year-olds displayed this pattern when judging adherence to quality but not relation. A linear regression revealed that children's ability to identify maxim adherers predicted their ability to choose the correct object during word-learning trials. This research demonstrates that children use others' pragmatic history when judging the reliability of the information they offer. PMID- 22217146 TI - De novo translocation t(5;9)(q11.2;p22) associated with hydrops fetalis and cystic hygroma. AB - We report on a case of a prenatally diagnosed non-immune hydrops fetalis and cystic hygroma associated with the balanced translocation t(5;9)(q11.2;p22), an association that to our knowledge has not been reported previously. Both parents had normal karyotypes. The infant was born prematurely at 33 and 3/7 weeks gestation and expired 12 h after delivery. PMID- 22217149 TI - gamma-Tocotrienol does not substantially protect DS neurons from hydrogen peroxide-induced oxidative injury. AB - BACKGROUND: Down syndrome (DS) neurons are more susceptible to oxidative stress and previous studies have shown that vitamin E was able to reduce oxidative stress and improve DS neurons' viability. Therefore, this study was done to investigate the protective role of gamma-tocotrienol (gammaT3) in DS neurons from hydrogen peroxide (H2O2) -induced oxidative stress. The pro-apoptosis tendency of gammaT3 was compared to alpha-tocopherol (alphaT) in non-stress condition as well. METHODS: Primary culture of DS and euploid neurons were divided into six groups of treatment: control, H2O2, gammaT3 pre-treatment with H2O2, gammaT3 only, alphaT pre-treatment with H2O2 and alphaT only. The treatments were assessed by MTS assay and apoptosis assay by single-stranded DNA (ssDNA) apoptosis ELISA assay, Hoechst and Neu-N immunofluorescence staining. The cellular uptake of gammaT3 and alphaT was determined by HPLC while protein expressions were determined by Western blot. Comparison between groups was made by the Student's t test, one-way ANOVA and Bonferroni adjustment as well as two way ANOVA for multiple comparisons. RESULTS: One day incubation of gammaT3 was able to reduced apoptosis of DS neurons by 10%, however gammaT3 was cytotoxic at longer incubation period (14 days) and at concentrations >= 100 MUM. Pre treatment of alphaT and gammaT3 only attenuate apoptosis and increase cell viability in H2O2-treated DS and euploid neurons by 10% in which the effects were minimal to maintain most of the DS cells' morphology. gammaT3 act as a free radical scavenger by reducing ROS generated by H2O2. In untreated controls, DS neurons showed lower Bcl-2/Bax ratio and p53 expression compared to normal neurons, while cPKC and PKC-delta expressions were higher in DS neurons. On the other hand, pre-treatment of gammaT3 in H2O2-treated DS neurons have reduced Bcl 2/Bax ratio, which was not shown in euploid neurons. This suggests that pre treatment of gammaT3 did not promote DS cell survival. Meanwhile gammaT3 and alphaT treatments without H2O2 as well as pre-treatment of gammaT3 and alphaT induced changes in cPKC and PKC-delta expression in DS neurons suggesting interaction of gammaT3 and alphaT with PKC activity. CONCLUSION: Our study suggests that gammaT3 pre-treatment are not sufficient to protect DS neurons from H2O2-induced oxidative assault, instead induced the apoptosis process. PMID- 22217151 TI - Relevance of the POS-1 orthotopic model as an "imaging model" for in vivo and simultaneous monitoring of tumor proliferation and bone remodeling in osteosarcoma. AB - INTRODUCTION: Osteosarcoma (OS) management requires a better understanding of tumor/bone interactions in vivo during disease progression. Using [(18)F]-FDG and [(99m)Tc]-HMDP imaging, we assessed a methodology for an in vivo quantitative characterization of an orthotopic model of osteolytic OS on the basis of (1) tumor proliferation, (2) tumor and bone metabolic activities, and (3) bone remodeling. METHODS: POS-1 tumor bearing mice were monitored in vivo over a 26 day period, with tumor and bone metabolic volumes (TMV and BMV, respectively) being determined from [(18)F]-FDG, bone remodeling from [(99m)Tc]-HMDP, and tumoral volume from micro- computed tomography scans. RESULTS: From day 10, [(18)F]-FDG strongly accumulated within POS-1 tumor, with a tumor/muscle ratio of 3.7 +/- 0.8. TMV and BMV increased as pathology progressed: TMV increased at early stage of pathology (from 56%) whereas BMV strongly increased (from 113%) during late stage. From [(99m)Tc]-HMDP imaging, bone remodeling features were evidenced within the distal region of tibia bearing the tumor, with a mean scintigraphic ratio of 1.36 +/- 0.11 at day 12, that reached value of 2.53 +/- 0.19 at day 26. CONCLUSIONS: Our results validated the POS-1 orthotopic model as "OS imaging model," that could serve for evaluating in vivo therapies targeting tumor proliferation and/or bone remodeling in OS. PMID- 22217148 TI - Identification of the role of C/EBP in neurite regeneration following microarray analysis of a L. stagnalis CNS injury model. AB - BACKGROUND: Neuronal regeneration in the adult mammalian central nervous system (CNS) is severely compromised due to the presence of extrinsic inhibitory signals and a reduced intrinsic regenerative capacity. In contrast, the CNS of adult Lymnaea stagnalis (L. stagnalis), a freshwater pond snail, is capable of spontaneous regeneration following neuronal injury. Thus, L. stagnalis has served as an animal model to study the cellular mechanisms underlying neuronal regeneration. However, the usage of this model has been limited due to insufficient molecular tools. We have recently conducted a partial neuronal transcriptome sequencing project and reported over 10,000 EST sequences which allowed us to develop and perform a large-scale high throughput microarray analysis. RESULTS: To identify genes that are involved in the robust regenerative capacity observed in L. stagnalis, we designed the first gene chip covering ~15, 000 L. stagnalis CNS EST sequences. We conducted microarray analysis to compare the gene expression profiles of sham-operated (control) and crush-operated (regenerative model) central ganglia of adult L. stagnalis. The expression levels of 348 genes were found to be significantly altered (p < 0.05) following nerve injury. From this pool, 67 sequences showed a greater than 2-fold change: 42 of which were up-regulated and 25 down-regulated. Our qPCR analysis confirmed that CCAAT enhancer binding protein (C/EBP) was up-regulated following nerve injury in a time-dependent manner. In order to test the role of C/EBP in regeneration, C/EBP siRNA was applied following axotomy of cultured Lymnaea PeA neurons. Knockdown of C/EBP following axotomy prevented extension of the distal, proximal and intact neurites. In vivo knockdown of C/EBP postponed recovery of locomotory activity following nerve crush. Taken together, our data suggest both somatic and local effects of C/EBP are involved in neuronal regeneration. CONCLUSIONS: This is the first high-throughput microarray study in L. stagnalis, a model of axonal regeneration following CNS injury. We reported that 348 genes were regulated following central nerve injury in adult L. stagnalis and provided the first evidence for the involvement of local C/EBP in neuronal regeneration. Our study demonstrates the usefulness of the large-scale gene profiling approach in this invertebrate model to study the molecular mechanisms underlying the intrinsic regenerative capacity of adult CNS neurons. PMID- 22217152 TI - NMDA receptor activation stimulates transcription-independent rapid wnt5a protein synthesis via the MAPK signaling pathway. AB - Wnt proteins are emerging key regulators of the plasticity and functions of adult brains. However, the mechanisms by which the expression of Wnt proteins is regulated in neurons are unclear. Using cortical primary cultures, we show here that activation of NMDA receptors (NMDARs) induces rapid Wnt5a protein synthesis and secretion. This NMDAR-regulated Wnt5a synthesis does not require transcription and is a result of activity-dependent translation. We also show that NMDAR-regulated Wnt5a translation depends on MAPK signaling but not mTOR signaling. Our findings suggest that the synaptic activity of CNS neurons activates NMDARs, which in turn stimulate translation from stored Wnt5a mRNA via the MAPK signaling pathway. PMID- 22217153 TI - A processive carbohydrate polymerase that mediates bifunctional catalysis using a single active site. AB - Even in the absence of a template, glycosyltransferases can catalyze the synthesis of carbohydrate polymers of specific sequence. The paradigm has been that one enzyme catalyzes the formation of one type of glycosidic linkage, yet certain glycosyltransferases generate polysaccharide sequences composed of two distinct linkage types. In principle, bifunctional glycosyltransferases can possess separate active sites for each catalytic activity or one active site with dual activities. We encountered the fundamental question of one or two distinct active sites in our investigation of the galactosyltransferase GlfT2. GlfT2 catalyzes the formation of mycobacterial galactan, a critical cell-wall polymer composed of galactofuranose residues connected with alternating, regioisomeric linkages. We found that GlfT2 mediates galactan polymerization using only one active site that manifests dual regioselectivity. Structural modeling of the bifunctional glycosyltransferases hyaluronan synthase and cellulose synthase suggests that these enzymes also generate multiple glycosidic linkages using a single active site. These results highlight the versatility of glycosyltransferases for generating polysaccharides of specific sequence. We postulate that a hallmark of processive elongation of a carbohydrate polymer by a bifunctional enzyme is that one active site can give rise to two separate types of glycosidic bonds. PMID- 22217154 TI - A pilot study assessing the prognostic value of CK18 and nDNA biomarkers in severe sepsis patients. AB - BACKGROUND AND OBJECTIVES: Severe sepsis and septic shock have posed significant treatment challenges for many years. Recently, a number of circulating apoptosis biomarkers have emerged, such as full-length and caspase-cleaved cytokeratin 18 (CK18) and nucleosomal DNA (nDNA), that may be predictive of likely outcome. This non-interventional study aimed to assess the ability of enzyme-linked immunosorbent assays (ELISAs) for these biomarkers to provide clinically useful information to guide the management of sepsis. METHODS: This study was conducted in patients admitted to the intensive care unit with severe sepsis at five US centres. Blood samples for assessment of plasma levels of full-length CK18 (measured by the M65(r) ELISA) and caspase-cleaved CK18 (measured by the M30 Apoptosense(r) ELISA) and nDNA (measured by ELISA) were collected from patients within 2 hours of consent (baseline) and on days 2, 4 and 8. Blood samples from 17 healthy volunteers acted as controls. Levels of each biomarker were presented descriptively. RESULTS: A total of 22 patients (mean age 60 [range, 24-83] years; 50% male) were included in the study. The mean APACHE II score was 24.4 (range 7 50). One-third of patients had three organ system failures and over one-half had septic shock. Three patients died during the study. Full-length and caspase cleaved CK18 levels decreased within 48 hours following initiation of treatment of sepsis in patients who survived, whereas increases were observed in the same timeframe in patients who died within 28 days of admission. Baseline nDNA and total soluble CK18 levels (caspase-cleaved and total intact) were significantly (p <= 0.05) higher in patients who required renal support than those who did not. CONCLUSIONS: Despite the small numbers of subjects assessed in the current study, these results confirm that measurement of apoptosis biomarkers may help to provide clinically useful information to manage sepsis and expedite development of novel therapeutics. However, further investigations to fully assess their prognostic value are required. PMID- 22217155 TI - Carbon-fiber microelectrode amperometry reveals sickle-cell-induced inflammation and chronic morphine effects on single mast cells. AB - Sickle cell disease, caused by a mutation of hemoglobin, is characterized by a complex pathophysiology including an important inflammatory component. Mast cells are tissue-resident leukocytes known to influence a range of immune functions in a variety of different ways, largely through the secretion of biologically active mediators from preformed granules. However, it is not understood how mast cells influence the inflammatory environment in sickle cell disease. A notable consequence of sickle cell disease is severe pain. Therefore, morphine is often used to treat this disease. Because mast cells express opioid receptors, it is pertinent to understand how chronic morphine exposure influences mast cell function and inflammation in sickle cell disease. Herein, carbon-fiber microelectrode amperometry (CFMA) was used to monitor the secretion of immunoactive mediators from single mast cells. CFMA enabled the detection and quantification of discrete exocytotic events from single mast cells. Mast cells from two transgenic mouse models expressing human sickle hemoglobin (hBERK1 and BERK) and a control mouse expressing normal human hemoglobin (HbA-BERK) were monitored using CFMA to explore the impact of sickle-cell-induced inflammation and chronic morphine exposure on mast cell function. This work, utilizing the unique mechanistic perspective provided by CFMA, describes how mast cell function is significantly altered in hBERK1 and BERK mice, including decreased serotonin released compared to HbA-BERK controls. Furthermore, morphine was shown to significantly increase the serotonin released from HbA-BERK mast cells and demonstrated the capacity to reverse the observed sickle-cell-induced changes in mast cell function. PMID- 22217156 TI - BuildSummary: using a group-based approach to improve the sensitivity of peptide/protein identification in shotgun proteomics. AB - The target-decoy database search strategy is widely accepted as a standard method for estimating the false discovery rate (FDR) of peptide identification, based on which peptide-spectrum matches (PSMs) from the target database are filtered. To improve the sensitivity of protein identification given a fixed accuracy (frequently defined by a protein FDR threshold), a postprocessing procedure is often used that integrates results from different peptide search engines that had assayed the same data set. In this work, we show that PSMs that are grouped by the precursor charge, the number of missed internal cleavage sites, the modification state, and the numbers of protease termini and that the proteins grouped by their unique peptide count should be filtered separately according to the given FDR. We also develop an iterative procedure to filter the PSMs and proteins simultaneously, according to the given FDR. Finally, we present a general framework to integrate the results from different peptide search engines using the same FDR threshold. Our method was tested with several shotgun proteomics data sets that were acquired by multiple LC/MS instruments from two different biological samples. The results showed a satisfactory performance. We implemented the method in a user-friendly software package called BuildSummary, which can be downloaded for free from http://www.proteomics.ac.cn/software/proteomicstools/index.htm as part of the software suite ProteomicsTools. PMID- 22217158 TI - Gastrointestinal helminths of pipistrelle bats (Pipistrellus pipistrellus/Pipistrellus pygmaeus) (Chiroptera: Vespertilionidae) of England. AB - Although bats are one of the most successful and diverse of mammalian orders, studies that focus upon bat endoparasites are limited. To further knowledge of bat parasitology, pipistrelle bats (Pipistrellus pipistrellus and P. pygmaeus) were acquired from across the Greater Manchester and Lancashire region of England and examined for gastrointestinal helminths using morphological and molecular analyses. Sixty-eight of 90 adult/juvenile bats (76% prevalence) were infected with at least 1 species of helminth and mean helminth abundance was 48.2 (+/ 7.0). All helminths were digenean trematodes and the following species were identified in 51 P. pipistrellus specimens (prevalence in parentheses): Lecithodendrium linstowi (80.4%), L. spathulatum (19.6%), Prosthodendrium sp. (35.3%), Plagiorchis koreanus (29.4%) and Pycnoporus heteroporus (9.8%). Statistical analyses, incorporating multifactorial models, showed that male bats exhibited a significantly more aggregated helminth distribution and lower abundance than females. Positive associations were observed between L. linstowi and L. spathulatum, Prosthodendrium sp. and P. heteroporus and between L. spathulatum and P. koreanus. A revised phylogeny of bat-associated Lecithodendriidae, incorporating novel L. spathulatum and Prosthodendrium sp. 28S rRNA sequences, separated the controversial clade formed by L. linstowi and P. hurkovaae. Further studies are likely to assist the understanding of bat parasite/pathogen relationships, helminth infracommunity structures and phylogenetics. PMID- 22217159 TI - Probing influence of mesophasic transformation on performance of self-emulsifying system: effect of ion. AB - Self-emulsifying systems are mixtures of oils and surfactants, ideally isotropic, sometimes including cosolvents, which emulsify under conditions of gentle agitation, similar to those which would be encountered in the gastrointestinal tract. The process of self-emulsification has remained the center of attraction for most researchers. Controlled hydration of self-emulsifying systems shows formation of an intermediate gel phase which upon rupture forms an emulsion. Current work was undertaken to understand and explore the microstructural properties of intermediate gel phase which are believed to influence the performance (droplet size) of the final formulation. The effect of additives on microstructural properties of intermediate gel phase has also been investigated. Microstructural elucidation of hydrated samples of intermediate regimes was done by using techniques such as small angle X-ray scattering, differential scanning calorimetry and rheology. Samples from intermediate regimes showed formation of local lamellar structure which swelled with hydration. In the present work, the effect of addition of salt form of naproxen (sodium and potassium) and naproxen (base) on microstructural properties of intermediate regimes was investigated. Systems containing naproxen salts formed larger droplets whereas naproxen base formed smaller ones. Microstructural properties of intermediate lamellar structures were well correlated with performance of the final formulation. The current studies indicate that by controlling the properties of intermediate regimes optimized formulations with desired performance can be tailor-made. PMID- 22217160 TI - Gender and age effects interact in preschoolers' help-seeking: evidence for differential responses to changes in task difficulty. AB - This study explored preschool age and gender differences in help-seeking within the theoretical framework of scaffolded problem-solving and self-regulation (Bruner, 1986; Rogoff, 1990; Vygotsky, 1978; 1986). Within-subject analyses tracked changes in help-seeking among 62 preschoolers (34 boys, 28 girls, mean age 4.22 years) solving a challenging puzzle with an adult. The goal was to document whether age and gender interact with fluctuating difficulty to affect children's spontaneous help-seeking. ANOVAs indicated that girls used more help seeking during difficult segments of the task, despite performance equal to the boys. This pattern was strongest among older girls, who outperformed all other children and used the most help-seeking. Partial correlations, controlling for solving time, indicated that age predicted children's help-seeking during the most difficult segments of the task, but only among girls. Gender differences in social-linguistic maturation and cognitive development are discussed within the framework of Vygotskian theory and related educational practice. PMID- 22217161 TI - Stress-induced facilitation of host response to bacterial challenge in F344 rats is dependent on extracellular heat shock protein 72 and independent of alpha beta T cells. AB - Activation of the in vivo stress response can facilitate antibacterial host defenses. One possible mechanism for this effect is stress-induced release of heat shock protein 72 (Hsp72) into the extracellular environment. Hsp72 is a ubiquitous cellular protein that is up-regulated in response to cellular stress, and modulates various aspects of immune function including macrophage inflammatory/bactericidal responses and T-cell function when found in the extracellular environment. The current study tested the hypothesis that in vivo extracellular Hsp72 (eHsp72) at the site of inflammation contributes to stress induced restricted development of bacteria, and facilitated recovery from bacteria-induced inflammation, and that this effect is independent of alpha beta (alphabeta) T cells. Male F344 rats were exposed to either inescapable electrical tail-shocks or no stress, and subcutaneously injected with Escherichia coli (ATCC 15746). The role of eHsp72 was investigated by Hsp72-immunoneutralization at the inflammatory site. The potential contribution of T cells was examined by testing male athymic (rnu/rnu) nude rats lacking mature alphabeta T cells and heterozygous thymic intact control (rnu/+) rats. The results were that stressor exposure increased plasma concentrations of eHsp72 and facilitated recovery from bacterial inflammation. Immunoneutralization of eHsp72 at the inflammatory site attenuated this effect. Stressor exposure impacted bacterial inflammation and eHsp72 equally in both athymic and intact control rats. These results support the hypothesis that eHsp72 at the site of inflammation, and not alphabeta T cells, contributes to the effect of stressor exposure on subcutaneous bacterial inflammation. PMID- 22217162 TI - A diagnostic algorithm to serologically differentiate West Nile virus from Japanese encephalitis virus infections and its validation in field surveillance of poultry and horses. AB - The detection of West Nile virus (WNV) in areas endemic for Japanese encephalitis virus (JEV) is complicated by the extensive serological cross-reactivity between the two viruses. A testing algorithm was developed and employed for the detection of anti-WNV antibody in areas endemic for JEV. Using this differentiation algorithm, a serological survey of poultry (2004 through 2009) and horses (2007 through 2009) was performed. Among 2681 poultry sera, 125 samples were interpreted as being positive for antibodies against JEV, and 14 were suspected to be positive for antibodies against undetermined flaviviruses other than WNV and JEV. Of the 2601 horse sera tested, a total of 1914 (73.6%) were positive to the initial screening test. Of these positive sera, 132 sera (5.1%) had been collected from horses that had been imported from the United States, where WNV is endemic. These horses had WNV vaccination records, and no significant pattern of increasing titer was observed in paired sera tests. Of the remaining 1782 positive sera 1468 sera (56.4%) were also found to contain anti-JEV antibodies, and were interpreted to be JEV-specific antibodies by the differentiation algorithm developed in this study. The remaining 314 horses (12.1%) for which a fourfold difference in neutralizing antibody titer could not be demonstrated, were determined to contain an antibody against an unknown (unidentified or undetermined) flavivirus. No evidence of WNV infections were found during the period of this study. PMID- 22217163 TI - Re-emergence of visceral and cutaneous leishmaniasis in the Greek Island of Crete. AB - Leishmaniases are vector-borne diseases transmitted by phlebotomine sand flies. Three species of Leishmania are found in the Mediterranean basin: Leishmania infantum, the most common species responsible for both visceral (VL) and cutaneous leishmaniasis (CL); Leishmania major, found in North Africa and Middle East causing CL; Leishmania tropica with a limited presence in Europe, causing CL. During the last 25 years, Crete has become an endemic zone for L. infantum with a high number of infected dogs and an increasing number of human cases every year; in the last 4 years, the incidence has reached an average of seven VL patients per year in a population of 600,000. At the same time, CL has re-emerged in Crete due to L. tropica, with an average of three CL cases per year in the last 4 years. Isolates were typed as L. infantum MON-1 and MON-98 and L. tropica MON-300, a zymodeme not reported before. Both VL and CL have spread to the whole of the island during the last 25 years, primarily in semi-urban and urban areas with altitudes of 0-50 m. The prevailing Phlebotomus species were Phlebotomus neglectus (proven vector of L. infantum) and Phlebotomus similis (suspected vector of L. tropica). PMID- 22217164 TI - Crimean-Congo hemorrhagic fever in Tajikistan. AB - Crimean-Congo hemorrhagic fever (CCHF) is a pathogenic tick-borne disease caused by a single-stranded negative-sense RNA virus classified within the Nairovirus genus of the family Bunyaviridae. Cases of CCHF have been registered in Tajikistan since the disease was first brought to medical attention in 1944. However, historical Tajik manuscripts describe the features of hemorrhagic fever associated with ticks, indicating that the disease might have been known in this region for many years before it was officially characterized. Here we review the historical context of CCHF in Tajikistan, much of which has been described over several decades in the Russian literature, and include reports of recent outbreaks in Tajikistan. PMID- 22217165 TI - Cystic echinococcosis in Arad County, Romania. AB - Cystic echinococcosis (CE) is a major parasitosis in Romania, a country where in the past at least one person from 45.5% of its localities underwent surgery for this disease. This survey aimed to provide new epidemiological and clinical data regarding human cases of CE in a western Romanian county. We have retrospectively investigated the medical records of the patients with CE hospitalized during the period of 2004-2010 in the surgical sections of Arad County. A total of 79 patients aged 5-88 years (mean age: 35.9+/-20.1 years) were diagnosed with CE during the study period. The average yearly incidence was 2.4 cases per 100,000 inhabitants, and the majority of the patients (29.1%) were aged 0-19 years. Most of the adult cases (>=18 years) were people with limited formal education (laborers) (45.6%). The analysis for trend showed an overall decrease in the affected persons over the study period (R(2)=0.66, p=0.026). Hepatic localizations of the hydatid cysts predominated within the study group (73.4%). Only 21.5% of the diseased presented complications and the mean length of hospital stay was 16.2+/-10.9 days. Eosinophilia of at least 10% of the leukocyte value occurred in 14% of cases and leukocytosis was noticed in 24.1% of patients. Although the rates of CE cases have decreased in Arad County (Romania), this parasitic disease continues to be a concern for public health services and requires the implementation of more stringent prophylactic measures. PMID- 22217166 TI - A parasitological survey of natural water springs and inhabitants of a tourist city in southeastern Brazil. AB - The goals of this study were to investigate the occurrence of Cryptosporidium oocysts and Giardia cysts in main springs of Campos do Jordao, an important tourist city, in Brazil and to gather the largest amount of parasitological data from autochthonous population that live in rural areas of this city. The membrane filtration technique followed by direct immunofluorescence assay was employed for concentration and visualization of waterborne protozoa. In the period between June 2003 and May 2004, the presence of at least one pathogenic protozoa was detected in 25.0% (3/12) of the springs studied, with mean concentrations ranging from 0.2 to 0.3 Cryptosporidium sp. oocysts and 0.07 to 0.1 Giardia sp. cysts/L. The coproparasitological investigation conducted in dwellers from two rural communities from this city revealed that 49.2% (91/185) of people had intestinal parasites. Among pathogenic protozoa, Cryptosporidium was the most prevalent species (8.1%) followed by Giardia duodenalis (5.9%), Entamoeba histolytica/Entamoeba dispar (2.7%), and Blastocystis hominis (2.2%). The most prevalent geohelminths were Ascaris lumbricoides (14.9%) and Trichuris trichiura (9.7%). This study demonstrated the contamination and the distribution of intestinal parasites, especially Cryptosporidium and Giardia species, in different springs of an important tourist city in Brazil, highlighting the need of monitoring natural water sources. The high prevalence of intestinal parasitosis detected in some specific populations of this city may function as a link of transmission of different intestinal parasitosis due to soil and water contamination, contributing to the maintenance of parasite life cycles. Therefore, the inclusion of consistent public health interventions with measures that include the protection of springs, the installation of minimum health infrastructure, and primary education of the population are widely necessary, aiming the control and prevention of parasite infections. PMID- 22217167 TI - Serological evaluation of Crimean-Congo hemorrhagic fever in humans with high risk professions living in enzootic regions of Isfahan province of Iran and genetic analysis of circulating strains. AB - Crimean-Congo hemorrhagic fever (CCHF) is a zoonotic viral disease that is asymptomatic in infected livestock, but causes a serious threat to humans with a mortality rate up to 50%. Although the CCHF virus (CCHFV) is often transmitted by ticks, livestock-to-human and human-to-human transmission also occurs. In the current study, we focused on CCHF in the province of Isfahan, located in the center of Iran and deemed to be the second most infected province. Human and livestock sera and resident ticks in the livestock are collected from different regions of the province and analyzed with specific IgG ELISA and RT-PCR tests. Overall, 12% and 12.7% of studied human and livestock populations were IgG positive, respectively. The genome of CCHFV was detected in 9% of ticks resident in livestock involved in this survey. The CCHFV isolates from infected ticks were genetically examined. Nucleotide sequence of the S-segment revealed that the different isolates were closely related to each other, with nucleotide sequence identities higher than 98%. Phylogenetic analysis demonstrated that a variant isolate clustered with the Iraq strain. This high proportion of IgG-positive sera and nearly high proportion of infected ticks increases the risk of CCHF outbreaks in the province and probably posits a great danger to other provinces. PMID- 22217168 TI - Differentiation of West Nile virus-infected animals from vaccinated animals by competitive ELISA using monoclonal antibodies against non-structural protein 1. AB - Antibodies against non-structural protein 1 (NS1) are considered to be the most reliable indicator of a present or past infection by West Nile virus (WNV) in animals. In this study, an in-house competitive enzyme-linked immunosorbent assay (NS1-cELISA) utilizing baculovirus-expressed NS1 and monoclonal antibodies against NS1 was established for the detection of antibody responses to NS1 in WNV infected animals. The assay was validated by the simultaneous detection of early antibody responses to NS1 and the structural envelope protein in animals infected with WNV, or inoculated with inactivated WNV. NS1-cELISA detected WNV antibodies at 6 days post-infection (dpi) in a WNV-infected rabbit (percent inhibition [PI] value of 84.0), and at 10 dpi in a WNV-infected chicken (PI value of 67.0). The NS1-cELISA was able to detect WNV antibodies in sera from all WNV-infected rabbits at 10 dpi (PI value of 79.2+/-18.0), and from three of four WNV-infected chickens at 14 dpi (PI value of 73.7+/-22.8). The results of this study demonstrate that the antibody response to NS1 is similar to that against envelope protein in WNV-infected rabbits and chickens, whereas animals inoculated with inactivated WNV develop antibody responses only to the envelope protein but not to NS1. The NS1-cELISA developed here has the potential to be a useful tool for monitoring WNV circulation (i.e., the prevalence of specific antibodies against WNV NS1), by assaying serum samples from regions in which an inactivated vaccine control strategy has been implemented. PMID- 22217169 TI - Optimization of peptide-based ELISA for serological diagnostics: a retrospective study of human monkeypox infection. AB - Although smallpox has been eradicated, other diseases caused by virulent orthopoxviruses such as monkeypox virus (MPV) remain endemic in remote areas of western and central sub-Saharan Africa, and represent a potential biothreat due to international travel and/or inadvertent exposure. Unfortunately, extensive antigenic cross-reactivity among orthopoxviruses presents a challenge to serological diagnosis. We previously reported a 20mer peptide-based ELISA that identified recent MPV infection with >90% sensitivity and >90% specificity. However, the sensitivity of this approach was not determined with samples obtained at later time points after antibody titers had declined from their peak levels. To improve assay sensitivity for detecting MPV-specific antibodies at later time points, we compared diagnostic 20mer peptides to 30mer peptides. In addition, optimal 30mer peptides were tested in combination or after conjugating selected peptides to a carrier protein (bovine serum albumin) to further improve assay performance. An optimized combination of four unconjugated 30mer peptides provided 100% sensitivity for detecting MPV infection at 2-6 months post infection, 45% sensitivity for detecting MPV infection at >2 years post infection, and 99% specificity. However, an optimized combination of two peptide conjugates provided 100% sensitivity for detecting MPV infection at 2-6 months post-infection, 90% sensitivity for detecting MPV infection at >2 years post infection, and 97% specificity. Peptide-based ELISA tests provide a relatively simple approach for serological detection of MPV infection. Moreover, the systematic approach used here to optimize diagnostic peptide reagents is applicable to developing improved diagnostics to a broad range of other viruses, and may be particularly useful for distinguishing between closely-related viruses within the same genus or family. PMID- 22217170 TI - Multiple co-infections of rodents with hantaviruses, Leptospira, and Babesia in Croatia. AB - Hantaviruses, Leptospira spp., and Babesia spp. are rodent-borne pathogens present worldwide. We studied multiple co-infections of small rodents in Croatia with all three pathogens. Twenty-eight Apodemus flavicollis and 16 Myodes glareolus were tested for the presence of hantavirus RNA by real-time RT-PCR, Leptospira strains by renoculture method and Babesia DNA by PCR. Anti-hantavirus antibodies and anti-Leptospira antibodies were detected by serological methods. Very high infection rates with each pathogen were found in A. flavicollis: 20 of 28 rodents (71%) were infected with Dobrava virus, 13 rodents (46%) were infected with Leptospira, and 5 rodents (18%) were infected with Babesia. Multiple co infections with all three pathogens were found in 3 of 28 (11%) A. flavicollis animals, suggesting that the same rodent host can be infected with several pathogens at the same time. Dual infections with both hantaviruses and Leptospira were found in 7 of 44 rodents (16%), with hantaviruses and Babesia in 2 rodents (5%), and double infection with both Leptospira and Babesia were found in 1 rodent (2%). Since hantaviruses, Leptospira, and Babesia have similar geographical distributions, it is to be expected that in other parts of the world multiple co-infections, representing a serious threat to public health, can be found. PMID- 22217171 TI - Do wild ungulates allow improved monitoring of flavivirus circulation in Spain? AB - As a response to the need for improved and cost-efficient West Nile virus (WNV) and other flavivirus surveillance tools, we tested 887 juvenile free-living red deer, 742 free-living juvenile wild boar, and 327 farmed deer, to detect temporal variability in exposure to these viruses. Thirty of 742 wild boar samples (4%; 95% CI 2.8,5.7) yielded a positive ELISA result. Antibody-positive individuals had been sampled between 2003 and 2011 in localities from central and southern Spain. No wild boar from the northern half of Spain (n=120) tested positive. Regarding juvenile wild red deer, only two out of 887 samples yielded a positive ELISA result (0.2%; 95% CI 0.1,0.8). These two samples came from the same site and sampling year. The likelihood of detecting contact with WNV or cross-reacting flaviviruses was 18 times higher among juvenile wild boar than among juvenile red deer. ELISA positivity among farmed deer increased 10-fold after local flavivirus outbreaks recorded in the summer and autumn of 2010. This survey demonstrated the potential usefulness of juvenile wild ungulates, particularly wild boar, as suitable flavivirus sentinels in southwestern Europe, and that systematic serum banking of samples from hunter-harvested wildlife or from individual farmed ungulates provides valuable material for retrospective epidemiological surveys and future disease monitoring. PMID- 22217172 TI - Genotypic diversity of an emergent population of Borrelia burgdorferi at a coastal Maine island recently colonized by Ixodes scapularis. AB - The recent range expansion of Ixodes scapularis has been accompanied by the emergence of Borrelia burgdorferi. The development of genetic diversity in B. burgdorferi at these sites of emergence and its relationship to range expansion is poorly understood. We followed colonization of I. scapularis on a coastal Maine island over a 17-year period. B. burgdorferi's emergence was documented, as was expansion of ospC strain diversity. Ticks collected from rodents and vegetation were examined for the presence of B. burgdorferi. Sequencing and reverse line blot were used to detect B. burgdorferi ospC major groups (oMG). No I. scapularis were found until year four of the study, after which time they increased in abundance. No B. burgdorferi was detected by darkfield microscopy in I. scapularis until 10 years into the study, when 4% of adult ticks were infected. Seven years later, 43% of adult ticks were infected. In 2003, one oMG accounted for 91% of B. burgdorferi strains. This "founder" strain persisted in 2005, but by 2007 was a minority of the 7 oMGs present. Given the island's isolation, gene flow by avian introduction of multiple strains is suggested in the development of B. burgdorferi oMG diversity. PMID- 22217173 TI - Ixodes ricinus is not an epidemiologically relevant vector of Bartonella species in the wood mouse (Apodemus sylvaticus). AB - Bartonella are hemoparasites exploiting a range of mammals as reservoir hosts. Several species are zoonotic pathogens. Fleas, lice, and other arthropods, such as ticks, have been implicated as vectors. While the competence of ticks as vectors of Bartonella species has recently been demonstrated, the epidemiological significance of ticks as vectors of Bartonella species in wildlife populations remains unknown. We used the presence of deer at study sites to control the presence of Ixodes ricinus ticks, and used this system to determine whether I. ricinus contributes to the epidemiology of Bartonella species infections in small mammals. Ticks were present at all sites with deer, but were absent from all sites without deer; however, the abundance of ticks on small mammals did not affect the probability of wood mice being infected with Bartonella species. Data presented here indicate that I. ricinus is not involved in the transmission of Bartonella in woodland rodents. PMID- 22217174 TI - Possible drivers of Crimean-Congo hemorrhagic fever virus transmission in Kosova. AB - Crimean-Congo hemorrhagic fever (CCHF) has long been a disease of concern in Kosova; however, little is known about the enzootic cycles of the virus in this country. Since the first documented case in 1954, sporadic cases and occasional outbreaks have been recorded with cases more consistently reported following the conflict in 1999. CCHF virus exists in enzootic cycles between wild animal species and ticks. The infection rates within ticks and hence the exposure to humans is determined by both the biology and seasonal dynamics of ticks, and the population dynamics and structure of the wild animals. These, in turn, are affected by complex interactions between climatic variables, changes in agricultural practices, land management, and wild animal density. If we are to understand the spatial and temporal occurrence of human disease, we must understand the ecology of the virus in nature. This article discusses the possible ecological, societal, political, and economic drivers that may impact the enzootic cycle of the virus and contribute to an increase in virus amplification and/or human exposure to infected ticks in Kosova. PMID- 22217175 TI - Development of a real-time RT-PCR assay for the detection of Crimean-Congo hemorrhagic fever virus. AB - Crimean-Congo hemorrhagic fever (CCHF) is a virulent tick-borne disease with a case fatality rate ranging from 10-50% for tick-borne transmission, and up to 80% for nosocomial transmission. Human cases have been reported in over 30 countries across Europe, Asia, and Africa. It appears to be spreading to new areas with several countries reporting their first human cases of CCHF disease within the past 10 years. We report a novel real-time RT-PCR assay designed to amplify a conserved region of the CCHF virus S segment. It is capable of detecting strains from all 7 groups of CCHF, including the AP92 strain that until recently represented a lineage of strains that were not associated with human disease. The limit of detection of the assay is 5 copies of target RNA, and the assay shows no cross-reactivity with other viruses from within the same genus, or with viruses causing similar human disease. PMID- 22217176 TI - Detection of Usutu-virus-specific IgG in blood donors from northern Italy. AB - We developed a novel enzyme-linked immunosorbent assay to detect the specific IgG response to Usutu virus (USUV) in humans, by evaluating 359 blood donors who were living in northeastern Italy. Our results demonstrate the presence of an anti USUV response in 4 subjects with no history of other flavivirus infection. PMID- 22217177 TI - Epidemiology and control of human granulocytic anaplasmosis: a systematic review. AB - Granulocytic anaplasmosis caused by Anaplasma phagocytophilum is an emerging tick borne zoonosis worldwide. The obligate intracellular pathogen is transmitted by Ixodes ticks and infects neutrophils in humans and animals, resulting in clinical symptoms ranging from asymptomatic seroconversion to mild, severe, or fatal disease. Since the initial description of human granulocytic anaplasmosis (HGA) in the United States in 1990, HGA has been increasingly recognized in America, Europe, and Asia. This review describes the epidemiology, diagnosis, and treatment of HGA and provides background information on the potential vectors and reservoirs of A. phagocytophilum. PMID- 22217178 TI - Seroepidemiology of Bartonella infection in gray foxes from Texas. AB - Gray foxes (Urocyon cinereoargenteus) were shown to be naturally infected with Bartonella rochalimae, a Bartonella species similar to Bartonella clarridgeiae (B.c.), and Bartonella vinsonii subspecies berkhoffii (B.v.berkhoffii) in northern California. A serological survey was performed to investigate the presence of Bartonella infection in 132 gray foxes from West/Central Texas. Using an immunofluorescence antibody test directed against B.v.berkhoffii and B.c., the antibody prevalence was 50% (66/132), with 22 (33.3%) individuals seropositive for B.c. only, 8 (12.2%) for B.v.berkhoffii, and 36 (54.5%) seroreactive for both B.c. and B.v.berkhoffii. The foxes had 3.63 more odds (95% confidence interval [CI]=1.38, 10.25) to be seropositive for B.c. than for B.v.berkhoffii. Female foxes were more likely to be seropositive for B.c. (odds ratio [OR]=2.90, 95% CI=1.33, 6.36) and also for both antigens (OR=2.50, 95% CI=1.06, 5.90) than males. PMID- 22217179 TI - Prevalence of sand flies and Leishmania donovani infection in a natural population of female Phlebotomus argentipes in Bihar State, India. AB - Leishmaniasis is a vector-borne disease, and in the Indian subcontinent the female Phlebotomus argentipes is the vector for Leishmania donovani. However, data on the extent of sand fly infection rates in natural settings using molecular methods have not been extensively reported in India. In this study a PCR technique was applied targeting the 18S rRNA encoding region to determine the prevalence of Leishmania infection in female P. argentipes captured in the field. For this study, sand flies were collected from 897 houses selected from 50 villages endemic for visceral leishmaniasis (VL) in Muzaffarpur district, Bihar state, using CDC miniature light traps and mouth aspirators. A total of 14,585 sand flies were collected of which 449 were female P. argentipes divided into 132 pools. Molecular detection using PCR targeting the 18S rRNA gene was carried out for the identification of P. argentipes and Leishmania. The overall prevalence of infection was 4.90-17.37% for L. donovani in female P. argentipes in endemic regions of Bihar state. In this study no correlation was found between the presence of infected sand flies and the occurrence of clinical VL. This study provides the first report evaluating the prevalence of Leishmania infection in sand flies in a region endemic for VL in India. Sergentomyia species are the most common species of sand fly. Knowledge of the infection rate in female P. argentipes may help in predicting severity of disease and in vector elimination programs. PMID- 22217180 TI - Zoonotic infections in native communities of James Bay, Canada. AB - The Cree communities of James Bay might be at risk of contracting zoonoses from their contacts with wildlife. Evidence of exposure to seven zoonotic infections, namely Trichinella spp., Toxoplasma gondii, Toxocara canis, Echinococcus granulosus, Leptospira spp., Coxiella burnetii, and Francisella tularensis, was sought in sera from 267 residents of Chisasibi (166) and Waskaganish (101). Study participants responded to questionnaires documenting socio-demographic characteristics and hunting and trapping activities. Associations were assessed by univariable and multivariable logistic regression analysis. High seroprevalence rates were documented for Leptospira spp. (23%), Francisella tularensis (18%), and Toxoplasma gondii (9%). Seroprevalence rates of less than 5% were observed for Coxiella burnetii, Echinococcus granulosus, and Toxocara canis. No subject exhibited serological proof of Trichinella spp. exposure in either community. Serological evidence of exposure to Leptospira spp. and T. gondii was greater in Chisasibi than in Waskaganish, while the T. canis seroprevalence rate was higher in Waskaganish than in Chisasibi. Handling of rabbits was associated with seropositivity for Leptospira spp. Statistical trends were also detected between the handling of ducks and exposure to Toxoplasma gondii, and between both handling animals without gloves and springtime hunting activities and Leptospira spp. seropositivity in Chisasibi and Waskaganish, respectively. A review of the medical records revealed few clinical events potentially related to zoonotic exposures. However, public health authorities and health care workers in these communities should be alert to the risk of these zoonoses. PMID- 22217181 TI - Assessing the risks of West Nile virus-infected mosquitoes from transatlantic aircraft: implications for disease emergence in the United Kingdom. AB - The number of West Nile virus (WNV)-infected mosquitoes aboard aircraft from the United States that arrive in the United Kingdom each summer was determined using a quantitative risk assessment. In the worst-case scenario, when WNV levels in mosquitoes are high (at epidemic levels) the probability of at least one WNV infected mosquito being introduced into the United Kingdom was predicted to be 0.99. During these periods, a mean of 5.2 infected mosquitoes were estimated to be aboard flights from the United States to the United Kingdom during May to October, with 90% certainty that the exact value lies between one and ten mosquitoes. Heathrow airport was predicted to receive the majority of the infected mosquitoes (72.1%). Spatial analysis revealed the region surrounding Heathrow satisfies the criteria for potential WNV exposure as both WNV-competent mosquitoes and susceptible wild bird species are present. This region is, therefore, recommended for targeted, risk-based surveillance of WNV-infected mosquitoes in addition to an increased awareness of the risks to horses, birds and humans. PMID- 22217182 TI - Molecular detection of spotted fever group rickettsiae associated with ixodid ticks in Egypt. AB - Tick-borne diseases comprise a complex epidemiological and ecological network that connects the vectors, pathogens, and a group of host species. The aim of this study was to identify bacteria from the genus Rickettsia associated with ixodid ticks infesting camels and cows in Egypt. Ticks were collected from 6 different localities: Qina, Giza, Qalet El Nakhl, New Valley, El Arish, and Minufia, from July to October 2008. Species were identified using PCR, followed by sequencing. The gltA and rOmpA genes were used for the initial detection of Rickettsia spp. Further characterization of positive samples utilized primers targeting rOmpB, sca4, and intergenic spacers (mppA-purC, dksA-xerC, and rpmE tRNA(fMet)). Cows were infested with Hyalomma anatolicum excavatum and Boophilus annulatus. Camels were infested with Hyalomma dromedarii, H. impeltatum, and H. marginatum marginatum. Approximately 57.1% of H. dromedarii ticks collected from Qalet El Nakhl were infected with Rickettsia africae, exhibiting 99.1-100% identity to reference strains. Within H. impeltatum, 26.7% and 73.3% of ticks from El Arish were infected with R. africae and R. aeschlimannii, with 98.3-100% and 97.9-100% identity, respectively. Furthermore, 33.3% of H. marginatum marginatum ticks in Qalet El Nakhl were infected with the same two species as H. impeltatum, demonstrating 99.1-100% and 99.3-100% identity, respectively. By comparing percent identities and phylogenetic relationships, R. africae is identified for the first time in Egypt, in addition to R. aeschlimannii, which exhibits 100% identity with the Stavropol strain in GenBank. In conclusion, the obtained data underscore the medical and veterinary importance of tick-borne rickettsioses, which necessitate further investigation by authorities in Egypt. Moreover, additional characterization of these rickettsial isolates should be performed to designate their strains, using a polyphasic strategy combining genotypic and phenotypic tests, to facilitate their deposition in the rickettsial collection of the WHO and/or ATCC. PMID- 22217183 TI - Altered networks in bothersome tinnitus: a functional connectivity study. AB - BACKGROUND: The objective was to examine functional connectivity linked to the auditory system in patients with bothersome tinnitus. Activity was low frequency (< 0.1 Hz), spontaneous blood oxygenation level-dependent (BOLD) responses at rest. The question was whether the experience of chronic bothersome tinnitus induced changes in synaptic efficacy between co-activated components. Functional connectivity for seed regions in auditory, visual, attention, and control networks was computed across all 2 mm(3) brain volumes in 17 patients with moderate-severe bothersome tinnitus (Tinnitus Handicap Index: average 53.5 +/- 3.6 (range 38-76)) and 17 age-matched controls. RESULTS: In bothersome tinnitus, negative correlations reciprocally characterized functional connectivity between auditory and occipital/visual cortex. Negative correlations indicate that when BOLD response magnitudes increased in auditory or visual cortex they decreased in the linked visual or auditory cortex, suggesting reciprocally phase reversed activity between functionally connected locations in tinnitus. Both groups showed similar connectivity with positive correlations within the auditory network. Connectivity for primary visual cortex in tinnitus included extensive negative correlations in the ventral attention temporoparietal junction and in the inferior frontal gyrus and rostral insula - executive control network components. Rostral insula and inferior frontal gyrus connectivity in tinnitus also showed greater negative correlations in occipital cortex. CONCLUSIONS: These results imply that in bothersome tinnitus there is dissociation between activity in auditory cortex and visual, attention and control networks. The reciprocal negative correlations in connectivity between these networks might be maladaptive or reflect adaptations to reduce phantom noise salience and conflict with attention to non-auditory tasks. PMID- 22217185 TI - Hearing outcome of recurrent sudden deafness: ipsilateral versus contralateral types. AB - CONCLUSION: Patients with recurrent sudden deafness demonstrating normal vestibular-evoked myogenic potentials (VEMPs) in the lesion ear of the second episode may indicate a good hearing outcome. OBJECTIVE: This study retrospectively reviewed our experience of patients with recurrent sudden deafness during the past 20 years. METHODS: Sixteen (1.4 %) of 1156 patients with sudden deafness were diagnosed as having a recurrent episode, including ipsilateral type in 7 and contralateral type in 9. All patients underwent an audiovestibular test battery and blood and MRI examinations. After 2000, nine patients underwent the VEMP test. RESULTS: In the ipsilateral type, the mean interval between two episodes was 2 +/- 2 years, which did not differ significantly from 3 +/- 3 years in the contralateral type. There were no significant differences in relation to age at onset of the second episode, inter episode interval, gender, presence of vertigo, and abnormal caloric results. However, abnormal rate of VEMP test in the contralateral type (five of five patients) was significantly higher than that in the ipsilateral type (none of four patients). At the second episode, all four patients with normal VEMPs on the lesion ear had improved hearing, while four of five patients with absent or delayed VEMPs showed unchanged hearing. Altogether, the hearing improvement rate in both types of recurrent sudden deafness was 50%. PMID- 22217184 TI - Improved production of biohydrogen in light-powered Escherichia coli by co expression of proteorhodopsin and heterologous hydrogenase. AB - BACKGROUND: Solar energy is the ultimate energy source on the Earth. The conversion of solar energy into fuels and energy sources can be an ideal solution to address energy problems. The recent discovery of proteorhodopsin in uncultured marine gamma-proteobacteria has made it possible to construct recombinant Escherichia coli with the function of light-driven proton pumps. Protons that translocate across membranes by proteorhodopsin generate a proton motive force for ATP synthesis by ATPase. Excess protons can also be substrates for hydrogen (H(2)) production by hydrogenase in the periplasmic space. In the present work, we investigated the effect of the co-expression of proteorhodopsin and hydrogenase on H(2) production yield under light conditions. RESULTS: Recombinant E. coli BL21(DE3) co-expressing proteorhodopsin and [NiFe]-hydrogenase from Hydrogenovibrio marinus produced ~1.3-fold more H(2) in the presence of exogenous retinal than in the absence of retinal under light conditions (70 MUmole photon/(m2.s)). We also observed the synergistic effect of proteorhodopsin with endogenous retinal on H(2) production (~1.3-fold more) with a dual plasmid system compared to the strain with a single plasmid for the sole expression of hydrogenase. The increase of light intensity from 70 to 130 MUmole photon/(m(2).s) led to an increase (~1.8-fold) in H(2) production from 287.3 to 525.7 mL H(2)/L-culture in the culture of recombinant E. coli co-expressing hydrogenase and proteorhodopsin in conjunction with endogenous retinal. The conversion efficiency of light energy to H(2) achieved in this study was ~3.4%. CONCLUSION: Here, we report for the first time the potential application of proteorhodopsin for the production of biohydrogen, a promising alternative fuel. We showed that H(2) production was enhanced by the co-expression of proteorhodopsin and [NiFe]-hydrogenase in recombinant E. coli BL21(DE3) in a light intensity-dependent manner. These results demonstrate that E. coli can be applied as light-powered cell factories for biohydrogen production by introducing proteorhodopsin. PMID- 22217187 TI - Photochemistry of riboflavin derivatives in methanolic solutions. AB - Light-induced degradation of the riboflavin derivatives is reported, including 5 deaza-riboflavin, iso-6,7-riboflavin, 3-methyl-tetra-acetyl-riboflavin (3MeTARF), and 3-benzyl-lumiflavin. The studied compounds undergo photolytic processes with considerable quantum yields in methanolic solutions (phi ~ 10(-3)-10(-4) mol einst(-1)). Photolysis in anaerobic conditions is more efficient than that in the presence of oxygen. Experiments show that triplet excited state of flavin molecules is involved in the reactions. The main photoproducts are the respective alloxazinic and isoalloxazinic derivatives of the substrates. 3MeTARF reveals higher photostability than riboflavin. The values of photodegradation quantum yields were estimated for the four studied derivatives. PMID- 22217186 TI - Hyperleptinemia and hypoadiponectinemia in extreme pediatric obesity. AB - BACKGROUND: Adiponectin and leptin, adipokines associated with metabolic syndrome, type 2 diabetes, and cardiovascular disease, have not been well characterized in extreme pediatric obesity. Therefore, levels were compared in youth that were extremely obese (EO) to normal weight (NW), overweight (OW), and obese (OB) youth. METHODS: Leptin, adiponectin, body mass index (BMI), blood pressure, fasting glucose, insulin, and lipids were obtained in 277 children and adolescents (age 13.4+/-2.6 years; 152 boys). Participants were classified into four BMI groups (NW, OW, OB, EO). Variables were compared across groups using analysis of covariance (ANCOVA) adjusted for gender, age, and race. RESULTS: Risk factors generally worsened across BMI groups. EO had significantly higher levels of leptin than OB (P<0.0001), OW (P<0.0001), and NW (P<0.0001). Leptin was higher in OB compared to OW (P<0.005) and NW (P<0.0001) and higher in OW compared to NW (P<0.0001). Adiponectin levels in EO did not significantly differ from OB or OW but were significantly lower than NW (P<0.0001). Adiponectin was not significantly different among the OB, OW, and NW groups. CONCLUSIONS: Leptin was markedly elevated in EO children and adolescents, suggesting that this subset of obese youth may be at particularly high risk of future weight gain and potentially reduced response to weight-loss interventions. PMID- 22217188 TI - Polycystic ovary syndrome: infertility, cardiovascular, metabolic and obstetrical risks, laboratory and clinical outcomes -- the PICOLO Study. AB - OBJECTIVES: The primary objective of this multicenter study is to evaluate the relative impact of insulin resistance (IR) and body mass index (BMI) in women with polycystic ovary syndrome (PCOS) on (1) Key hemodynamic/thrombogenic variables, (2) Oocyte quality and early embryo development, (3) Fetal growth, placental function and adverse obstetric outcome. SECONDARY OBJECTIVE: To establish a PCOS database and biobank facilitating future basic and interventional research related to PCOS. DESIGN: A cross-sectional and longitudinal cohort study at four University Hospitals in Denmark. POPULATION INCLUSION: About 200 women fulfilling the Rotterdam Criteria and 100 women without PCOS recruited from 2010 to 2012. METHODS: The impact of PCOS, as well as the impact of IR and BMI on the hormonal, metabolic and hemostatic key variables will be analyzed combining conventional, molecular techniques and selected gene analysis. Oocytes will be characterized by gene expression of granulosa and cumulus cells and the early embryo development will be followed by time lapse microscopy. Fetal growth will be assessed by repeated ultrasound measurements, and the pregnancy outcome compared to maternal and fetal biochemical markers of growth and inflammation and clinical pregnancy complications. MAIN OUTCOME MEASURES: Metabolic and hemostatic risk-biomarkers, oocyte and embryo quality, adverse pregnancy outcome, fetal growth and placental function in women with PCOS. PMID- 22217189 TI - Abnormal end-tidal carbon dioxide levels on emergency department arrival in adult and pediatric intubated patients. AB - BACKGROUND: The utility of prehospital intubation is controversial, as uncontrolled studies in trauma patients suggest adverse outcomes with prehospital intubation, perhaps secondary to inappropriate ventilation once intubation is accomplished. OBJECTIVES: The objectives were 1) to establish, immediately upon arrival to the emergency department (ED), the prevalence of abnormal end-tidal carbon dioxide (ETCO(2)) levels in patients with prehospital intubation and 2) to describe the relationship between abnormal ETCO(2) levels on ED arrival and mortality. METHODS: This was a prospective, observational cohort study of patients with prehospital intubation. Patients were excluded if they underwent prehospital cardiopulmonary resuscitation (CPR). On ED arrival, the initial ETCO(2) measurement from the patient's endotracheal tube was immediately obtained prior to purposeful intervention in the patient's ventilation by using an Oridion Surestream Sure VentLine H Set with a Welch Allyn Propaq CS monitor. For each patient, the treating physician documented the ETCO(2) measurement, patient demographics, and details of the transport. The primary outcome was an abnormal ETCO(2) value (<30 mmHg or >45 mmHg). The secondary outcome was mortality. RESULTS: One hundred eligible patients were enrolled, with a median age of 30 years (interquartile range [IQR] 15, 48 years). Esophageal intubations were identified in four cases, and those cases were excluded from further analysis. Mechanisms included trauma, 74; medical, 12; and burn, 10. The median ETCO(2) value was 32 mmHg (IQR 27, 38 mmHg), range 18-80 mmHg. Forty-six of 96 (48%, 95% confidence interval [CI] 38%, 58%) patients had abnormal ETCO(2) values, including 37 (39%, 95% CI 29%, 49%) with low ETCO(2) levels and nine (9%, 95% CI 4%, 17%) with high ETCO(2) levels. Death was higher in those trauma patients with abnormal ETCO(2) levels (10/33, 30%, 95% CI 16%, 49%) than in those with normal ETCO(2) levels (2/41, 5%, 95% CI 0.6%, 17%), relative risk = 6.2 (95% CI 1.5, 26.4), p = 0.004. CONCLUSION: Nearly half of all patients transported by prehospital providers had abnormal ETCO(2) measurements on initial ED presentation, suggesting an area for potential improvement. Trauma patients with abnormal initial ETCO(2) levels were more likely to die. PMID- 22217191 TI - Representational change and strategy use in children's number line estimation during the first years of primary school. AB - BACKGROUND: The objective of this study was to scrutinize number line estimation behaviors displayed by children in mathematics classrooms during the first three years of schooling. We extend existing research by not only mapping potential logarithmic-linear shifts but also provide a new perspective by studying in detail the estimation strategies of individual target digits within a number range familiar to children. METHODS: Typically developing children (n = 67) from Years 1-3 completed a number-to-position numerical estimation task (0-20 number line). Estimation behaviors were first analyzed via logarithmic and linear regression modeling. Subsequently, using an analysis of variance we compared the estimation accuracy of each digit, thus identifying target digits that were estimated with the assistance of arithmetic strategy. RESULTS: Our results further confirm a developmental logarithmic-linear shift when utilizing regression modeling; however, uniquely we have identified that children employ variable strategies when completing numerical estimation, with levels of strategy advancing with development. CONCLUSION: In terms of the existing cognitive research, this strategy factor highlights the limitations of any regression modeling approach, or alternatively, it could underpin the developmental time course of the logarithmic-linear shift. Future studies need to systematically investigate this relationship and also consider the implications for educational practice. PMID- 22217192 TI - Evaluation of the dose-response relationship of amlodipine and losartan combination in patients with essential hypertension: an 8-week, randomized, double-blind, factorial, phase II, multicenter study. AB - BACKGROUND: Despite recommendations for more intensive treatment and the availability of several effective treatments, hypertension remains uncontrolled in many patients. OBJECTIVE: The aim of this study was to determine the dose response relationship and assess the efficacy and safety of amlodipine or losartan monotherapy and amlodipine camsylate/losartan combination therapy in patients with essential hypertension. METHODS: This was an 8-week, randomized, double-blind, factorial design, phase II, multicenter study conducted in outpatient hospital clinics among adult patients aged 18-75 years with essential hypertension. At screening, patients received placebo for 2-4 weeks. Eligible patients (n=320) were randomized to one of eight treatment groups: amlodipine 5 mg or 10 mg, losartan 50 mg or 100 mg, amlodipine camsylate/losartan 5 mg/50 mg, 5 mg/100 mg, 10 mg/50 mg, or 10 mg/100 mg. MAIN OUTCOME MEASURES: The assumption of strict superiority was estimated using the mean change in sitting diastolic blood pressure (DBP) at 8 weeks. Safety was monitored through physical examinations, vital signs, laboratory test results, ECG, and adverse events. RESULTS: The reduction in DBP at 8 weeks was significantly greater in patients treated with the combination therapies compared with the respective monotherapies for all specified comparisons except amlodipine camsylate/losartan 10 mg/100 mg versus amlodipine 10 mg. The incidence of adverse events in the group of patients treated with the amlodipine camsylate/losartan 10 mg/50 mg combination tended to be higher than for any other group (27.9%, 12/43); however, the effect was not statistically significant. CONCLUSION: Combination amlodipine camsylate/losartan (5 mg/50 mg, 5 mg/100 mg and 10 mg/50 mg) resulted in significantly greater BP lowering compared with amlodipine or losartan monotherapy, and was determined to be generally safe and tolerable in patients with essential hypertension. CLINICAL TRIAL REGISTRATION: Registered at clinicaltrials.gov: NCT00942344. PMID- 22217193 TI - Pharmacologic prevention of microvascular and macrovascular complications in diabetes mellitus: implications of the results of recent clinical trials in type 2 diabetes. AB - Observational epidemiologic data indicate that lower blood glucose levels, blood pressure (BP), and lipid parameters are associated with a lower incidence of micro- and macrovascular complications in people with diabetes. While no threshold for this effect is discernible in these observational studies, intervention studies do not mirror this finding. The earliest glycemia target study in type 2 diabetes mellitus, UKPDS, demonstrated unequivocal benefits of tight glucose control on microvascular complications, but needed a prolonged follow-up to demonstrate a benefit on macrovascular outcomes and mortality. Recently, three major studies, ACCORD, ADVANCE, and VADT, evaluated the impact of attaining euglycemia (ACCORD) or near-euglycemia (ADVANCE, VADT) in older patients with diabetes and high cardiovascular (CV) risk. None of these studies, either individually or on pooled analysis, demonstrated any reduction in all cause or CV mortality, although the meta-analyses revealed 15-17% reductions in the incidence of non-fatal myocardial infarction in those exposed to tight glucose control. A higher mortality was observed in the intensive glucose control arm of ACCORD, resulting in the premature termination of the glucose-lowering component of this study. Also, the occurrence of hypoglycemic episodes (total and major) was significantly higher in the intensive glucose control arm. ADVANCE and ACCORD also had BP-lowering components. While data from ADVANCE demonstrated a benefit of routine use of a combination of perindopril and indapamide, with a decline in all-cause mortality, CV mortality, and new-onset microalbuminuria, reducing systolic BP to <120 mmHg in ACCORD did not result in any incremental benefits over a systolic BP<140 mmHg. A residual CV risk observed in people with diabetes even after low-density lipoprotein (LDL) cholesterol lowering has led to trials evaluating additional therapy with fibric acid derivatives to reduce triglyceride levels. The lipid-lowering arm of ACCORD failed to demonstrate any benefit of add-on therapy with fibric acid derivatives to LDL-lowering treatment with HMG-CoA reductase inhibitors (statins) on vascular outcomes in patients with diabetes. However, data from earlier studies, and also from the subgroup analysis of ACCORD, indicate a probable benefit of adding treatment with fibric acid derivatives to individuals with persistently elevated triglyceride levels despite statin therapy. The most compelling evidence comes from studies assessing the impact of multiple risk factors - glucose, BP, and cholesterol. Studies like the Steno study unequivocally demonstrate the benefit of aggressive control of all three parameters on vascular outcomes in patients with diabetes. In conclusion, attempts to achieve euglycemia in older patients with type 2 diabetes with co morbidities are not associated with any survival benefit, but may reduce the occurrence of non-fatal CV events. There is a significant risk of major hypoglycemia with this approach, thereby probably limiting its utility to younger patients with new-onset disease. Similarly, lowering systolic BP below 120 mmHg in high CV risk people with diabetes is associated with significant excess adverse events, limiting the utility of such an intervention. However, a clear benefit, which is also cost effective, is observed with strategies for multiple risk-factor control, which should be universally adopted in clinical practice. PMID- 22217196 TI - Effect of body mass index on treatment of complicated intra-abdominal infections in hospitalized adults: comparison of ertapenem with piperacillin-tazobactam. AB - BACKGROUND: Complicated intra-abdominal infections (cIAI) are a common problem in surgical practice. The effect of body mass index (BMI) on the outcome is poorly understood. We compared the association of BMI and type of antibiotic therapy for cIAI described in a previously published trial of ertapenem vs. piperacillin tazobactam (Namias N, Solomkin JS, Jensen EH, et al. Randomized, multicenter, double-blind study of efficacy, safety, and tolerability of intravenous ertapenem versus piperacillin/tazobactam in treatment of complicated intra-abdominal infections in hospitalized adults. Surg Infect 2007;8:15-28). METHODS: A post-hoc analysis was performed using data obtained from the published study. The effect of BMI and type of antibiotic used for therapy were calculated for clinically favorable outcomes at early follow-up assessment (EFA). RESULTS: The 231 patients who were microbiologically evaluable at EFA were stratified by BMI (<30 or >=30 kg/m(2)). Twelve patients were excluded because of missing BMI data, leaving 219 patients for analysis. There were some differences in baseline characteristics between patients with a BMI <30 kg/m(2), including the source of intra-abdominal infection (more appendicitis in BMI <30 group; p=0.01) and gender (more men in the BMI <30 group; p=0.03). There was no difference in cure rates between the groups (82.9% for BMI <30 kg/m(2) vs. 74.5% for those with BMI >=30 kg/m(2); 8% difference in proportions, 95% confidence interval [CI] -5%, 25%). There was an 80% favorable clinical response to ertapenem in the BMI <30 group compared with an 81% favorable rate in the BMI >=30 group (-1% difference in proportions; 95% CI -22%, 19%). This compared with an 86% favorable response rate to piperacillin tazobactam in the BMI <30 group vs. a 65% favorable clinical response rate in the BMI >=30 group (21% difference in proportions; 95% CI -1%, 47%). CONCLUSIONS: There was no difference in the cure rate of patients with cIAI in the BMI <30 and BMI >=30 kg/m(2) groups. There were no statistically significant differences in the likelihood of response to an antibiotic regimen. However, there was a nominally 21% lower cure rate in the high BMI group receiving piperacillin tazobactam (86% vs. 65%; 21% difference in proportions; 95% CI -1%, 47%), whereas there was only a 1% difference in the cure rate between BMI groups in the patients receiving ertapenem. This difference may be related to gender and etiology of infection. Although limited by the small number of high BMI patients and post-hoc methodology, these results merit consideration of the design of future prospective antibiotic trials to include stratification for BMI and consideration of the effect of BMI on pharmacokinetics and pharmacodynamics. PMID- 22217197 TI - Development of intergeneric and intrageneric somatic cell nuclear transfer (SCNT) cat embryos and the determination of telomere length in cloned offspring. AB - Somatic cell nuclear transfer (SCNT) holds potential as a useful tool for agricultural and biomedical applications. In vitro development of marbled cat intergeneric SCNT reconstructed into domestic cat cytoplast revealed that cloned, marbled cat embryo development was blocked at the morula stage. No pregnancies resulted from the transfer of one- to eight-cell stage embryos into domestic cat surrogate mothers. This suggested that abnormalities occurred in the cloned marbled cat embryos, which may be associated with incomplete reprogramming during early embryo development. Two pregnancies were established in surrogate mothers that received cloned domestic cat embryos, but SCNT offspring developed abnormally. Some specific phenotypes that were observed included incomplete abdominal wall disclosure, improper fetal development. In addition, some of the fetuses were mummified or stillbirths. The two live births died within 5 days. Telomere lengths of cloned kittens as determined by qualtitative polymerase chain reaction (qPCR) were inconclusive: some were found to be shorter, longer, or the same as donor control cells. Our findings support the hypothesis that telomere lengths do not govern the health of these cloned animals. A lack of complete reprogramming may lead to developmental failure and the abnormalities observed in cloned offspring. PMID- 22217195 TI - Immature oxidative stress management as a unifying principle in the pathogenesis of necrotizing enterocolitis: insights from an agent-based model. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a complex disease involving prematurity, enteral feeding, and bacterial effects. We propose that the underlying initial condition in its pathogenesis is reduced ability of the neonatal gut epithelial cells (NGECs) to clear oxidative stress (OS), and that when such a NGEC population is exposed to enteral feeding, the increased metabolic OS tips the population toward apoptosis, inflammation, bacterial activation, and eventual necrosis. The multi-factorial complexity of NEC requires characterization with computational modeling, and herein, we used an agent-based model (ABM) to instantiate and examine our unifying hypothesis of the pathogenesis of NEC. METHODS: An ABM of the neonatal gut was created with NGEC computational agents incorporating rules for pathways for OS, p53, tight junctions, Toll-like receptor (TLR)-4, nitric oxide, and nuclear factor-kappa beta (NF-kappaB). The modeled bacteria activated TLR-4 on contact with NGECs. Simulations included parameter sweeps of OS response, response to feeding, addition of bacteria, and alterations in gut mucus production. RESULTS: The ABM reproduced baseline cellular respiration and clearance of OS. Reduction in OS clearance consistent with clinical NEC led to senescence, apoptosis, or inflammation, with disruption of tight junctions, but rarely to NGEC necrosis. An additional "hit" of bacteria activating TLR-4 potentiated a shift to NGEC necrosis across the entire population. The mucus layer was modeled to limit bacterial-NGEC interactions and reduce this effect, but concomitant apoptosis in the goblet cell population reduced the efficacy of the mucus layer and limited its protective effect in simulated experiments. This finding suggests a means by which increased apoptosis at the cellular population level can lead to a transition to the necrosis outcome. CONCLUSIONS: Our ABM incorporates known components of NEC and demonstrates that impaired OS management can lead to apoptosis and inflammation of NGECs, rendering the system susceptible to an additional insult involving regionalized mucus barrier failure and TLR-4 activation, which potentiates the necrosis outcome. This type of integrative dynamic knowledge representation can be a useful adjunct to help guide and contextualize research. PMID- 22217198 TI - Slight improvement in full-term development of mouse somatic cell nuclear transferred embryos by cotransfer of fertilized embryos. AB - In our previous study (Tsuji et al., 2010 ), administration of hCG to recipients around the timing of implantation significantly increased the in vivo development of mouse embryos after somatic cell nuclear transfer (SCNT) until day 10.5, but did not increase the development to full term. The present study was undertaken to examine whether cotransfer of fertilized embryos or parthenogenetic embryos prevents the embryonic loss of SCNT embryos after day 10.5, allowing them to develop to full term. We found that compared with SCNT embryo transfer alone, full-term development of SCNT embryos slightly, but not significantly, increased by cotransfer of mouse hybrid blastocysts derived from BDF1 (C57BL/6*DBA) female*ICR male into the oviducts of recipients administered hCG (2.0% vs. 5.5%). This was not the case with the cotransfer of blastocysts from an ICR female*ICR male (2.5% vs. 2.2%) or parthenogenetic blastocysts from BDF1 female (3.0% vs. 2.0%). Furthernore, when SCNT blastocysts were transferred into the uteri of recipients, full-term development did not increase even with the cotransfer of hybrid blastocysts. The mechanisms of the effect of cotransfer of fertilized and parthenogenetic embryos on the full-term development of SCNT mouse embryos are discussed. PMID- 22217199 TI - Ovine-induced pluripotent stem cells can contribute to chimeric lambs. AB - Pluripotential stem cells from livestock offer an exciting prospect for the biotechnology industry. Applying strategies established for the derivation of murine induced pluripotential stem cells (iPSCs), we have isolated ovine iPSCs that can give rise to cells characteristic of all three germ cell layers both in vitro from embryoid bodies and in teratomas in vivo. Furthermore, although at a low level, these ovine iPS cells can contribute to live-born chimeric lambs. Colonies derived from ovine embryonic fibroblasts transfected with murine cMyc, Klf4, Oct4, and Sox2 displayed smooth domes with sharp edges when grown in human embryonic stem cell (ESC) medium but not in mouse ESC medium. These ovine iPSCs were alkaline phosphatase positive, expressed Nanog, and had a normal karyotype. These cells represent an important step in the understanding of mechanistic nature of pluripotency in ungulates. PMID- 22217200 TI - Size-dependent fracture of silicon nanoparticles during lithiation. AB - Lithiation of individual silicon nanoparticles was studied in real time with in situ transmission electron microscopy. A strong size dependence of fracture was discovered; that is, there exists a critical particle diameter of ~150 nm, below which the particles neither cracked nor fractured upon first lithiation, and above which the particles initially formed surface cracks and then fractured due to lithiation-induced swelling. The unexpected surface cracking arose owing to the buildup of large tensile hoop stress, which reversed the initial compression, in the surface layer. The stress reversal was attributed to the unique mechanism of lithiation in crystalline Si, taking place by movement of a two-phase boundary between the inner core of pristine Si and the outer shell of amorphous Li-Si alloy. While the resulting hoop tension tended to initiate surface cracks, the small-sized nanoparticles nevertheless averted fracture. This is because the stored strain energy from electrochemical reactions was insufficient to drive crack propagation, as dictated by the interplay between the two length scales, that is, particle diameter and crack size, that control the fracture. These results are diametrically opposite to those obtained previously from single-phase modeling, which predicted only compressive hoop stress in the surface layer and thus crack initiation from the center in lithiated Si particles and wires. Our work provides direct evidence of the mechanical robustness of small Si nanoparticles for applications in lithium ion batteries. PMID- 22217202 TI - Effect of ulinastatin on growth inhibition, apoptosis of breast carcinoma cells is related to a decrease in signal conduction of JNk-2 and NF-kappaB. AB - OBJECTIVE: This study aims to investigate the in vitro effects of Ulinastatin (UTI) and Taxotere (TXT) on cell proliferation; cell apoptosis; xenografted tumor growth; and expression of insulin-like growth factor receptor 1 (IGF-1R), platelet-derived growth factor A (PDGFA), nerve growth factor (NGF), c-Jun N terminal kinase 2 (JNk-2), and NF-kappaB in a human primary breast cancer cells and breast cancer cell line MDA-MB-231. METHODS: The cell lines cultured were divided into four groups: 1) control group, 2) UTI group, 3) TXT group, and 4) UTI+TXT group. The method of MTT essay, flow cytometry, and RT-PCR were used to detect cell proliferation, cell apoptosis, and expression of IGF-1R, PDGFA, NGF, NF-kappaB, JNk-2, respectively. The growth of xenografted tumor in nude mice was used to calculate the anti-tumor rate. Immunohistochemistry staining (SP) was used to detect the expression of IGF-1R, PDGFA, NGF, ki-67, caspase-3, JNk-2, and NF-kappaB. RESULTS: Proliferation of human breast cancer cells and MDA-MB-231 cell lines, and growth rate of xenografted tumor decreased in order of UTI+TXT > TXT > UTI > control, apoptosis increased in the order control < UTI < TXT < UTI+TXT. The gene expression and protein expression of IGF-1R, PDGFA, NGF, NF kappaB and JNk-2 in breast cancer cells was inhibited by UTI and TXT. CONCLUSIONS: UTI 1) inhibits the proliferation of human breast cancer cells and the growth of xenografted tumors, 2) induces cancer cell apoptosis, and 3) enhances the anti-tumor effect of TXT. This mechanism might be related to decreasing signal transduction of JNk-2 and NF-kappaB, and then expression of IGF 1R, PDGFA, NGF. PMID- 22217204 TI - PDGF receptor blocker for pulmonary hypertension: a new agent in therapeutic arsenal. PMID- 22217203 TI - Pre-steady-state kinetic characterization of thiolate anion formation in human leukotriene C4 synthase. AB - Human leukotriene C4 synthase (hLTC4S) is an integral membrane protein that catalyzes the committed step in the biosynthesis of cysteinyl-leukotrienes, i.e., formation of leukotriene C4 (LTC4). This molecule, together with its metabolites LTD4 and LTE4, induces inflammatory responses, particularly in asthma, and thus, the enzyme is an attractive drug target. During the catalytic cycle, glutathione (GSH) is activated by hLTC4S that forms a nucleophilic thiolate anion that will attack LTA4, presumably according to an S(N)2 reaction to form LTC4. We observed that GSH thiolate anion formation is rapid and occurs at all three monomers of the homotrimer and is concomitant with stoichiometric release of protons to the medium. The pK(a) (5.9) for enzyme-bound GSH thiol and the rate of thiolate formation were determined (k(obs) = 200 s-1). Taking advantage of a strong competitive inhibitor, glutathionesulfonic acid, shown here by crystallography to bind in the same location as GSH, we determined the overall dissociation constant (K(d((GS) = 14.3 MUM). The release of the thiolate was assessed using a GSH release experiment (1.3 s-1). Taken together, these data establish that thiolate anion formation in hLTC4S is not the rate-limiting step for the overall reaction of LTC4 production (k(cat) = 26 s-1), and compared to the related microsomal glutathione transferase 1, which displays very slow GSH thiolate anion formation and one-third of the sites reactivity, hLTC4S has evolved a different catalytic mechanism. PMID- 22217205 TI - Mesoporous silica nanoparticles for increasing the oral bioavailability and permeation of poorly water soluble drugs. AB - We investigate the effects of spherical mesoporous silica nanoparticles (MSNs) as an oral drug delivery system to improve the oral bioavailability of the model drug telmisartan (TEL) and examine their cellular uptake and cytotoxicity. Further, we explore the mechanisms behind the improved oral absorption of poorly soluble drugs promoted by MSNs. An investigation of intestinal epithelial cellular binding, association and uptake was carried out by laser scanning confocal microscopy, transmission electron microscopy and fluorescence activated cell sorting. The results show that the cellular uptake is highly time-, concentration- and size-dependent. The model drug permeability studies in the human colon carcinoma (Caco-2) cell lines indicated that MSNs could significantly enhance TEL permeability and reduce rate of drug efflux. After loading TEL into MSNs, its oral bioavailability was compared with that of the marketed product Micardis and TEL-loaded ordered mesoporous silica microparticles (MSMs) in beagle dogs. The relative bioavailability of TEL-loaded MSN formulation and TEL-loaded MSM formulation was 154.4 +/- 28.4% and 129.1 +/- 15.6%, respectively. MSNs offer the potential to achieve enhanced oral bioavailability of poorly soluble drugs via improved drug dissolution rate and enhanced drug permeability. PMID- 22217207 TI - Learning foreign labels from a foreign speaker: the role of (limited) exposure to a second language. AB - Three- and four-year-olds (N = 144) were introduced to novel labels by an English speaker and a foreign speaker (of Nordish, a made-up language), and were asked to endorse one of the speaker's labels. Monolingual English-speaking children were compared to bilingual children and English-speaking children who were regularly exposed to a language other than English. All children tended to endorse the English speaker's labels when asked 'What do you call this?', but when asked 'What do you call this in Nordish?', children with exposure to a second language were more likely to endorse the foreign label than monolingual and bilingual children. The findings suggest that, at this age, exposure to, but not necessarily immersion in, more than one language may promote the ability to learn foreign words from a foreign speaker. PMID- 22217206 TI - Modifications in basal and stress-induced hypothalamic AMP-activated protein kinase (AMPK) activity in rats chronically treated with an angiotensin II receptor blocker. AB - 5' adenosine monophosphate-activated protein kinase (AMPK) plays a prominent role as a metabolic stress sensor. The role of hypothalamic AMPK in response to restraint and surgical stress has not been previously investigated. It has been recently suggested that the renin-angiotensin system, in addition to its role in stress regulation, may play a significant role in regulating metabolic pathways including the regulation of the AMPK system. This study was thus aimed to evaluate the effects of candesartan, an angiotensin II AT1 receptor blocker drug, on hypothalamic AMPK activity under basal conditions and after restraint in conscious rats or after surgical stress under general anesthesia. Male Wistar rats were treated with 5 mg/kg/day candesartan in the drinking water for 2 weeks. The hypothalamic AMPK activity was determined under basal and stress conditions, using a kinase activity assay. Chronic administration of candesartan significantly increased hypothalamic AMPK activity. Hypothalamic AMPK activity was also increased by restraint stress whereas no change was observed during surgical stress under anesthesia. The high levels of hypothalamic AMPK activation observed in candesartan-treated rats were not changed by restraint stress but were reduced to control levels by anesthesia and surgery. In conclusion, chronic candesartan treatment and restraint stress in conscious rats stimulate the hypothalamic AMPK activity, whereas surgical stress under anesthesia inhibits pathways regulating the AMPK activity even in candesartan-treated rats. PMID- 22217208 TI - Pepitome: evaluating improved spectral library search for identification complementarity and quality assessment. AB - Spectral libraries have emerged as a viable alternative to protein sequence databases for peptide identification. These libraries contain previously detected peptide sequences and their corresponding tandem mass spectra (MS/MS). Search engines can then identify peptides by comparing experimental MS/MS scans to those in the library. Many of these algorithms employ the dot product score for measuring the quality of a spectrum-spectrum match (SSM). This scoring system does not offer a clear statistical interpretation and ignores fragment ion m/z discrepancies in the scoring. We developed a new spectral library search engine, Pepitome, which employs statistical systems for scoring SSMs. Pepitome outperformed the leading library search tool, SpectraST, when analyzing data sets acquired on three different mass spectrometry platforms. We characterized the reliability of spectral library searches by confirming shotgun proteomics identifications through RNA-Seq data. Applying spectral library and database searches on the same sample revealed their complementary nature. Pepitome identifications enabled the automation of quality analysis and quality control (QA/QC) for shotgun proteomics data acquisition pipelines. PMID- 22217210 TI - The relevance of the migration inhibitory factor (MIF) for peripheral tissue response in murine sublethal systemic Aspergillus fumigatus infection. AB - We recently demonstrated that macrophage migration inhibitory factor deficient (MIF (- / -)) mice exhibited a higher susceptibility to lethal systemic Aspergillus fumigatus infections than genetically matched, wild-type (WT) C57BL/6 mice, and displayed altered cytokine profiles in the spleen when challenged by sublethal infections. In this report we focused on the potential involvement of MIF in the response of mice to sublethal systemic A. fumigatus infections in tissues other than spleen. Impaired fungal clearance from lungs, kidneys, liver and brain in MIF (- / -) mice was noted and was associated with histologically evident differences in signs of inflammation in these organs. Higher values of some indicators of pathologic changes in urine parameters (increases in bilirubin, glucose and ketones), as well as a greater degree of brain tissue damage, pointed to multiple organs being affected in MIF (- / -) mice. Analysis of the lung response revealed differences in the composition of infiltrated cells between MIF-sufficient and MIF-deficient mice. MPO activity and reactive oxygen species production were impaired, as well as production of IL-17 and IFN-gamma in MIF (- / -) mice as compared to WT counterparts. Lower systemic IL-1beta and IL-6 levels in infected MIF (- / -) mice coincided with reduced blood neutrophil counts and organ infiltration. Collectively, this study identifies MIF as a resistance factor that orchestrates events in several non-lymphoid areas which provide a milieu that accomplishes anti-fungal A. fumigatus defense. PMID- 22217209 TI - Volumetric associations between uncinate fasciculus, amygdala, and trait anxiety. AB - BACKGROUND: Recent investigations of white matter (WM) connectivity suggest an important role of the uncinate fasciculus (UF), connecting anterior temporal areas including the amygdala with prefrontal-/orbitofrontal cortices, for anxiety related processes. Volume of the UF, however, has rarely been investigated, but may be an important measure of structural connectivity underlying limbic neuronal circuits associated with anxiety. Since UF volumetric measures are newly applied measures, it is necessary to cross-validate them using further neural and behavioral indicators of anxiety. RESULTS: In a group of 32 subjects not reporting any history of psychiatric disorders, we identified a negative correlation between left UF volume and trait anxiety, a finding that is in line with previous results. On the other hand, volume of the left amygdala, which is strongly connected with the UF, was positively correlated with trait anxiety. In addition, volumes of the left UF and left amygdala were inversely associated. CONCLUSIONS: The present study emphasizes the role of the left UF as candidate WM fiber bundle associated with anxiety-related processes and suggests that fiber bundle volume is a WM measure of particular interest. Moreover, these results substantiate the structural relatedness of UF and amygdala by a non-invasive imaging method. The UF-amygdala complex may be pivotal for the control of trait anxiety. PMID- 22217211 TI - Microarray technology for yeast identification directly from positive blood cultures. A multicenter Italian experience. AB - The authors evaluated the performance of the MycArrayTM Yeast ID (Myconostica Ltd, UK) assay in the identification of a total of 88 yeast isolates recovered in culture as compared to that obtained through routine methods. The turn-around time for species identification directly from cultures by the MycArray was 6 hours, much quicker than classical methods and all yeasts were correctly identified. In two cases a double identification including Saccharomyces cerevisiae was noted, but it was not confirmed by culture. The results show that MycArray Yeast ID can be a potential tool for rapid detection and identification of Candida species. PMID- 22217212 TI - Phaeohyphomycosis due to Exophiala xenobiotica as a cause of fungal arthritis in an HIV-infected patient. AB - Black yeasts including Exophiala species are increasingly recognized as agents of human disease. In recent years, progress in molecular phylogeny and taxonomy of the genus Exophiala has led to the description of numerous novel species. The 'classical' but highly variable species Exophiala jeanselmei was split into a number of morphological siblings, which, however, were phylogenetically and clinically remote from each other. E. jeanselmei was restricted to an uncommon species causing subcutaneous infections. Hence only limited information is available on the segregants, among which is E. xenobiotica. We describe a case of an HIV-patient presenting with fungal arthritis and subcutaneous nodules caused by the latter species, which was identified by means of phenotypic and molecular methods. PMID- 22217213 TI - Compositional and phylogenetic dissimilarity of host communities drives dissimilarity of ectoparasite assemblages: geographical variation and scale dependence. AB - We tested the hypothesis that compositional and/or phylogenetic dissimilarity of host assemblages affect compositional and/or phylogenetic dissimilarity of parasite assemblages, to different extents depending on scale, using regional surveys of fleas parasitic on small mammals from 4 biogeographical realms. Using phylogenetic community dissimilarity metric, we calculated the compositional and phylogenetic dissimilarity components between all pairs of host and parasite communities within realms and hemispheres. We then quantified the effect of compositional or phylogenetic dissimilarity in host regional assemblages, and geographical distance between assemblages, on the compositional or phylogenetic dissimilarity of flea regional assemblages within a realm, respectively. The compositional dissimilarity in host assemblages strongly affected compositional dissimilarity in flea assemblages within all realms and within both hemispheres. However, the effect of phylogenetic dissimilarity of host assemblages on that of flea assemblages was mostly confined to the Neotropics and Nearctic, but was detected in both the Old and New World at the higher scale, possibly because of phylogenetic heterogeneity in flea and host faunas between realms. The clearer effect of the compositional rather than the phylogenetic component of host community dissimilarity on flea community dissimilarity suggests important roles for host switching and ecological fitting during the assembly history of flea communities. PMID- 22217214 TI - Clindamycin plus quinine for treating uncomplicated falciparum malaria: a systematic review and meta-analysis. AB - BACKGROUND: Artemisinin-based combinations are recommended for treatment of uncomplicated falciparum malaria, but are costly and in limited supply. Clindamycin plus quinine is an alternative non-artemisinin-based combination recommended by World Health Organization. The efficacy and safety of clindamycin plus quinine is not known. This systematic review aims to assess the efficacy of clindamycin plus quinine versus other anti-malarial drugs in the treatment of uncomplicated falciparum malaria. METHODS: All randomized controlled trials comparing clindamycin plus quinine with other anti-malarial drugs in treating uncomplicated malaria were included in this systematic review. Databases searched included: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and LILACS. Two authors independently assessed study eligibility, extracted data and assessed methodological quality. The primary outcome measure was treatment failure by day 28. Dichotomous data was compared using risk ratio (RR), in a fixed effects model. RESULTS: Seven trials with 929 participants were included. Clindamycin plus quinine significantly reduced the risk of day 28 treatment failure compared with quinine (RR 0.14 [95% CI 0.07 to 0.29]), quinine plus sulphadoxine-pyrimethamine (RR 0.17 [95% CI 0.06 to 0.44]), amodiaquine (RR 0.11 [95% CI 0.04 to 0.27]), or chloroquine (RR 0.11 [95% CI 0.04 to 0.29]), but had similar efficacy compared with quinine plus tetracycline (RR 0.33 [95% CI 0.01 to 8.04]), quinine plus doxycycline (RR 1.00 [95% CI 0.21 to 4.66]), artesunate plus clindamycin (RR 0.57 [95% CI 0.26 to 1.24]), or chloroquine plus clindamycin (RR 0.38 [95% CI 0.13 to 1.10]). Adverse events were similar across treatment groups but were poorly reported. CONCLUSION: The evidence on the efficacy of clindamycin plus quinine as an alternative treatment for uncomplicated malaria is inconclusive. Adequately powered trials are urgently required to compare this combination with artemisinin-based combinations. PMID- 22217215 TI - Anomalous conformational change in 1-butyl-3-methylimidazolium tetrafluoroborate D2O mixtures. AB - We have investigated the effect of deuterated water on the conformational equilibrium between the gauche and trans conformers of the [bmim] cation in mixtures of water and 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF(4)]), an ionic liquid, at room temperature. A comparison of the results obtained from solutions made with H(2)O and with D(2)O highlights an anomalous conformational change in the D(2)O solution showing an extended N shaped behavior. The gauche conformer of the [bmim] cation in D(2)O increased up to x = ~50 (D(2)O mol %); however, it decreased up to higher water concentrations of x = ~85 before again increasing drastically toward x = ~100. We provide spectroscopic evidence that the anomalous conformational dynamics of the [bmim] cation in D(2)O is directly related to the H/D exchange reaction of the C-H group at position 2 of the imidazolium ring. PMID- 22217216 TI - Clustering in surgical trials--database of intracluster correlations. AB - BACKGROUND: Randomised trials evaluation of surgical interventions are often designed and analysed as if the outcome of individual patients is independent of the surgeon providing the intervention. There is reason to expect outcomes for patients treated by the same surgeon tend to be more similar than those under the care of another surgeon due to previous experience, individual practice, training, and infrastructure. Such a phenomenon is referred to as the clustering effect and potentially impacts on the design and analysis adopted and thereby the required sample size. The aim of this work was to inform trial design by quantifying clustering effects (at both centre and surgeon level) for various outcomes using a database of surgical trials. METHODS: Intracluster correlation coefficients (ICCs) were calculated for outcomes from a set of 10 multicentre surgical trials for a range of outcomes and different time points for clustering at both the centre and surgeon level. RESULTS: ICCs were calculated for 198 outcomes across the 10 trials at both centre and surgeon cluster levels. The number of cases varied from 138 to 1370 across the trials. The median (range) average cluster size was 32 (9 to 51) and 6 (3 to 30) for centre and surgeon levels respectively. ICC estimates varied substantially between outcome type though uncertainty around individual ICC estimates was substantial, which was reflected in generally wide confidence intervals. CONCLUSIONS: This database of surgical trials provides trialists with valuable information on how to design surgical trials. Our data suggests clustering of outcome is more of an issue than has been previously acknowledged. We anticipate that over time the addition of ICCs from further surgical trial datasets to our database will further inform the design of surgical trials. PMID- 22217217 TI - Meniere's disease in children aged 4-7 years. AB - This is a retrospective review of clinical data and audiovestibular test results from four children in whom symptoms suggesting Meniere's disease started at 4-7 years of age. The four patients all had spontaneous recurrent attacks of (spinning) vertigo and fluctuating low frequency sensorineural hearing loss from an early age, suggesting a diagnosis of definite Meniere's disease. Presumably, due to age-related inability to communicate auditory symptoms, the children did not initially meet requirements for a diagnosis of Meniere's disease. However, by 8 years of age, all four children reported tinnitus and/or fullness in the affected ear and, thus, met the AAO criteria for Meniere's disease. Even if information on subjective auditory symptoms is missing, it is reasonable to consider young children with idiopathic spontaneous recurrent attacks of vertigo in whom audiograms reveals fluctuating low frequency hearing loss to have Meniere's disease. This report is a reminder that Meniere's disease may also occur in young children. PMID- 22217218 TI - Identification of a novel mutation in the beta-globin gene 3' untranslated region [+1,506 (A>C)] in a Japanese male with a heterozygous beta-thalassemia phenotype. AB - beta-Thalassemia (beta-thal) is characterized by the absent or reduced production of beta-globin chains. The precise molecular lesion that causes decreased beta globin synthesis in beta(+)-thal is difficult to predict when mutations occur in the locus control region (LCR), the promoter, the introns or 3' untranslated regions (3'UTRs). Among them, the role of the 3'UTR of beta-globin gene in mRNA stability is poorly understood, mainly due to very few cases that have mutations in this region. So far, only three mutations have been reported in the 3'UTR of beta-globin gene. Although, it is speculated that some of these reported mutations could be associated with mRNA stability, the precise molecular basis still remains unclear. We report here a novel mutation in the beta-globin gene 3'UTR [+1,506 (A>C)] in a 31-year-old Japanese male with hematological parameters suggestive of heterozygous beta-thal. Further functional studies on this novel mutation reported here, may help in understanding of the regulation and expression of the beta-globin gene and its products. PMID- 22217220 TI - Short-Term Psychodynamic Psychotherapy for personality disorders: a critical review of randomized controlled trials. AB - The research evidence for Short-Term Psychodynamic Psychotherapy (STPP) in the treatment of personality disorders (PD) was examined through consideration of studies utilizing randomized controlled designs. An extensive literature search revealed eight published Randomized Controlled Trials (RCT) of moderate study quality. A critical review of this literature is offered to provide an evidence based guidance for clinicians and implications for treatments are discussed. Preliminary conclusions suggest STPP may be considered an efficacious empirically supported treatment option for a range of PDs, producing significant and medium to long-term improvements for a large percentage of patients. Further research is recommended to allow comparisons with alternative evidence-based approaches. PMID- 22217221 TI - Self-administered acupuncture as an alternative to deliberate self-harm: a feasibility study. AB - The aim of this mixed methods feasibility study was to demonstrate the acceptability, practicality, and safety of training patients who regularly use deliberate self harm (DSH) to self-administer acupuncture as an alternative coping skill for emotional distress. Ten adult patients with a diagnosis of emotionally unstable personality disorder who regularly self-harmed were recruited to the study following baseline assessment by a psychiatrist. An acupuncturist taught participants to self-acupuncture. During the 6-week intervention participants recorded their emotional distress, coping behaviors, thoughts, and feelings in a diary. Face-to-face interviews were used to explore participants' motives for DSH and their experience of acupuncture. Framework analysis was conducted on interview transcripts and diary entries to identify common themes. Mood at baseline and six weeks was measured using the BDI and changes in the use of coping behaviors and acupuncture were measured using diary entries. Subjects used acupuncture regularly through the six-week intervention and over this period there was a reduction in the frequency of DSH. Qualitative analysis identified two broad themes relating to the process and the effects of acupuncture. There was wide variation in the effects experienced by subjects which broadly mapped onto to the wide range of motives behind DSH. BDI scores showed a near significant reduction (p = 0.055) from 44.4. to 34.4 over the 6 week intervention. Patients presenting with deliberate self harm can be safely trained to self-administer acupuncture as an alternative coping skill. Acceptability and effectiveness may vary between patients depending on the complex motives underlying their self-harming behavior. While the pilot study was designed to explore the feasibility of the intervention, results from this limited sample suggest that use of self-administered acupuncture may reduce the frequency of self harming behavior and reduce emotional distress as measured using the BDI. PMID- 22217222 TI - Affect regulation and Depressive Personality Disorder. AB - Depressive Personality Disorder (DPD) has been under consideration for inclusion in the Diagnostic and Statistical Manual of Mental Disorders since 1994; yet, few studies have been published that test whether those with DPD have affective experiences that are characterized exclusively by depression and negative affect. One hundred ninety-seven undergraduate students were interviewed for DPD and Borderline Personality Disorder with the Personality Disorder Interview for DSM IV (Widiger, Mangine, Corbitt, Ellis, & Thomas, 1995), in order to control for frequently co-occurring BPD which is characterized by affective lability. Participants also were administered measures of affective lability, affective intensity, anxious and depressive states, and more trait-like manifestations of depression, anxiety, and anger. Results indicate that those with DPD may be described as having a mood state characterized by transitions from a baseline neutral mood to one of anxiety, with their experiences being more prominently depressed and dysphoric. They also have tendencies toward angry hostility, though they may not report frequent shifts from a baseline neutral mood to anger. Those with DPD also report intense, frequent experiences of depression and dysphoria, with many shifts between depression and anxiety. PMID- 22217223 TI - Late adolescent nonsuicidal self-injury: the roles of coping style, self-esteem, and personality pathology. AB - This study examined the relationship between late adolescent nonsuicidal self injury (NSSI) and coping style, self-esteem, and personality pathology. Participants were 302 late adolescent (18-19-year-old) college students who completed questionnaires on self-esteem, coping style, personality disorder symptoms, and NSSI. Participants who engaged in NSSI reported more personality pathology, more maladaptive coping styles, less rational coping, and lower self esteem than did non self-harming participants. As hypothesized, total NSSI correlated with several personality disorders, emotional coping style, and inversely related to self-esteem and adaptive coping styles. Regression equations tested several mediation models to determine whether self-esteem or coping style mediates the relationship between personality disorder symptoms and NSSI. Emotional coping and self-esteem each fully mediated the relationship between various personality disorders and NSSI in the anticipated direction. Results also indicate self-esteem, rational, detached, and emotional coping partially mediate the relationship between several personality disorders and NSSI. PMID- 22217224 TI - The relationship between borderline personality disorder and number of sexual partners. AB - In this study, we examined the number of self-reported lifetime sexual partners between those with and without borderline personality disorder (BPD). Our hypothesis was that, due to the nature of the disorder, those with BPD would exhibit a greater number of lifetime sexual partners. Using a survey methodology in a consecutive sample of internal medicine outpatients (N = 354), we administered two self-report measures for BPD (the borderline personality scale of the Personality Diagnostic Questionnaire-4 and the Self-Harm Inventory), and queried participants, "How many sexual partners have you had in your lifetime?" Correlation coefficients and one-way ANOVAs were conducted to determine the relationship between BPD and the number of sexual partners. According to BPD status with the borderline personality scale of the Personality Diagnostic Questionnaire-4, we found that the mean number of sexual partners among BPD positive participants was nearly double (p < .001) that of BPD-negative participants; according to BPD status with the Self-Harm Inventory, the mean number of sexual partners among BPD-positive participants was more than double (p < .001) that of BPD-negative participants. Compared to internal medicine outpatients without BPD, those with BPD exhibit a statistically significantly greater number of sexual partners. PMID- 22217225 TI - Attachment, borderline personality, and romantic relationship dysfunction. AB - Previous studies have implicated attachment and disturbances in romantic relationships as important indicators for Borderline Personality Disorder (BPD). The current research extends our current knowledge by examining the specific associations among attachment, romantic relationship dysfunction, and BPD, above and beyond the contribution of emotional distress and nonromantic interpersonal functioning in two distinct samples. Study 1 comprised a community sample of women (N = 58) aged 25-36. Study 2 consisted of a psychiatric sample (N = 138) aged 21-60. Results from both Study 1 and Study 2 demonstrated that (1) attachment was specifically related to BPD symptoms and romantic dysfunction, (2) BPD symptoms were specifically associated with romantic dysfunction, and (3) the association between attachment and romantic dysfunction was statistically mediated by BPD symptoms. The findings support specific associations among attachment, BPD symptoms, and romantic dysfunction. PMID- 22217226 TI - Can negative attitudes toward patients with borderline personality disorder be changed? The effect of attending a STEPPS workshop. AB - We sought to determine whether negative attitudes toward patients with borderline personality disorder (BPD) can be modified through education. Mental health clinicians attended a 1-day workshop on the Systems Training for Emotional Predictability and Problem Solving (STEPPS) group treatment program for BPD. A questionnaire to assess attitudes towards BPD was given to 271 clinicians before and after the workshop. Following the workshop, clinicians endorsed having significantly greater empathy toward patients with BPD, and having greater awareness of the distress and low self-esteem associated with the disorder. Significant improvement was seen in the clinicians' attitudes toward patients with BPD and their desire to work with them. Clinicians were significantly less likely to express dislike for BPD patients. They also reported feeling more competent in their ability to treat these patients. The study offers preliminary evidence that negative attitudes toward patients with BPD can be modified through education. PMID- 22217227 TI - The Spanish version of the Wisconsin Personality Disorders Inventory-IV (WISPI IV): tests of validity and reliability. AB - Personality disorders (PD) are a prevalent class of mental disorders that interfere with functioning and cause subjective distress while increasing the intensity and duration of Axis I clinical syndromes, and therefore assessing PD is important even when PDs are not the focus of treatment. The purpose of these studies was to develop and test a new Spanish version of a self-report measure of PD, the Wisconsin Personality Inventory-IV (WISPI-IV) that would be psychometrically equivalent to the English version while also maintaining the same interpersonal content, which is based on Benjamin's analysis of the PD criteria using her Structural Analysis of Social Behavior (SASB) model (1974). Study 1 participants completed the WISPI-IV twice over a two-week interval. For Study 2, participants from two sites in Spain and one site in Argentina completed Spanish versions of the WISPI-IV and other personality measures. SASB-analysis of the translated items showed high correspondence between the interpersonal content of the English version and the Spanish version demonstrating theoretical validation in relation to other PD measures. The Spanish WISPI-IV showed satisfactory reliability based on test-retest correlations and alphas for internal consistency. Study 2 showed the Spanish WISPI-IV had good convergent validity with the Spanish versions of the IIP and SCID-II and performed similarly to the English versions of these measures. Our goal in translating the WISPI-IV was to extend this measure to Spanish-speakers in language that would be understood by different Hispanic sub-groups, however research team members and subjects had a variety of suggestions for changes in item wording. This reflects the difficulty with creating a "neutral" Spanish version of any assessment given regional differences. PMID- 22217228 TI - Validity of the Personality Diagnostic Questionnaire-4 (PDQ-4+) among mentally ill prison inmates in Singapore. AB - We examined the validity of the Personality Diagnostic Questionnaire--4+ (PDQ-4+) as a screening instrument for personality disorders among mentally ill prison inmates in Singapore. A total of 313 prison inmates completed the PDQ-4+ and the Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II). The subjects were 303 (96.8%) males and 10 (3.2%) females with a mean (SD) age of 40.7 (8.8) years. Kappa agreement between PDQ-4+ and SCID-II for the presence at least one personality disorder was moderate with high sensitivity and low specificity. For specific personality disorders and clusters, we found that the PDQ-4+ diagnosed more subjects as having each of the personality disorders than SCID-II with high negative predictive values. The area under the curve indicated moderate discriminatory capabilities. Our results suggest that the PDQ-4+ could be used as a potential screening instrument for personality disorders in prison inmates. PMID- 22217229 TI - Prevalence and comorbidity of axis I and axis II disorders among treatment refractory adolescents admitted for specialized psychotherapy. AB - Research shows that approximately half of the adolescents in a clinical setting suffer from a personality disorder (PD). This finding has not yet been replicated in Europe. To test whether this finding also applies to Europe, structured diagnostic interviews for both Axis I and Axis II disorders were used in 257 adolescents who were admitted to a highly specialized mental health setting in The Netherlands. In this study we found that 40.5% of the adolescents were diagnosed with at least one personality disorder. Most adolescents with a personality disorder (78.9%) also suffered from one or more Axis I disorders. These results are comparable to rates found in previous prevalence studies of personality disorders in both adolescents and adults. Our results provide further evidence to support the cross-national generalizability of the diagnosis of PD in adolescents. PMID- 22217230 TI - Positive affective and cognitive states in borderline personality disorder. AB - The aim of the current study was to compliment previous studies identifying negative states present in borderline personality disorder (BPD) by investigating the presence of positive affective and cognitive states. Ninety-six patients with criteria-defined borderline personality disorder and 24 axis II comparison participants completed the Positive Affect Scale, a 50-item self-report measure designed to assess positive states thought to be characteristic of and discriminating for BPD. Seventeen positive states (4 affective, 10 cognitive, and 3 mixed) were found to be significantly more common among axis II comparison participants than borderline patients. Twelve of these states were common to both borderline patients and axis II comparison participants. Furthermore, four positive states, when co-occurring together, were particularly strongly associated with borderline personality disorder (three negatively and one positively): (a) Fond of myself, (b) That things around me are real, (c) That I've forgiven others, and (d) Assertive. Finally, the overall mean score on the PAS significantly distinguished patients with borderline personality disorder from axis II comparison participants. Taken together, these results suggest that borderline patients are far less likely to report experiencing positive states of an affective, cognitive, and mixed nature than axis II comparison participants. They also suggest that being assertive is a positive state particularly discriminating for borderline personality disorder. PMID- 22217232 TI - Leclercia adecarboxylata bacteremia in a trauma patient: case report and review of the literature. AB - BACKGROUND: Leclercia adecarboxylata is a rarely described gram-negative pathogen. Since the advent of rapid molecular typing techniques, L. adecarboxylata has been described in 23 case reports, often associated with polymicrobial infections or in immunosuppressed hosts. METHODS: A case is described and previous cases of L. adecarboxylata infection are reviewed. CASE REPORT: A 55-year old male victim of trauma developed septic shock several days after presentation to the emergency department. Blood and central vein catheter cultures grew L. adecarboxylata; Haemophilus influenzae and Streptococcus pneumoniae were present in bronchoalveolar lavage samples. With aggressive hemodynamic and ventilator support in addition to antibiotic therapy, the patient cleared the catheter-related blood stream infection. After a challenging intensive care unit stay, the patient eventually was discharged to an inpatient rehabilitation unit. CONCLUSION: An L. adecarboxylata catheter-related blood stream infection developed in the setting of both underlying immunosuppression and polymicrobial infection. As molecular typing techniques continue to improve, L. adecarboxylata is likely to be an increasingly recognized gram-negative pathogen. Interactions between L. adecarboxylata infection, immunosuppression, and polymicrobial infections remain to be elucidated. PMID- 22217234 TI - Quantitative structure-activity relationships of mosquito larvicidal chalcone derivatives. AB - The mosquito larvicidal activities of a series of chalcones and some derivatives were subjected to a quantitative structure-activity relationship (QSAR) study, using more than a thousand constitutional, topological, geometrical, and electronic molecular descriptors calculated with Dragon software. The larvicidal activity values for 28 active compounds of the series were predicted, showing in general a good approximation to the experimental values found in the literature. Chalcones having one or both electron-rich rings showed high toxicity. However, the activity of chalcones was reduced by electron-withdrawing groups, and this was roughly diminished by derivatization of the carbonyl group. A set of six chalcones being structurally similar to some of the active ones, with a still unknown larvicidal activity, were prepared. Their activity values were predicted by applying the developed QSAR models, showing that two chalcones of such set, both 32 and 34, were expected to be highly active. PMID- 22217233 TI - Tiotropium bromide inhalation powder: a review of its use in the management of chronic obstructive pulmonary disease. AB - The anticholinergic agent tiotropium bromide (Spiriva(r)) is a long-acting bronchodilator that is indicated for the treatment of chronic obstructive pulmonary disease (COPD). This article reviews the clinical efficacy and tolerability of tiotropium bromide inhalation powder, administered using the HandiHaler(r) device, in patients with COPD, as well as reviewing its pharmacological properties and the results of pharmacoeconomic analyses. Shorter term placebo-controlled trials in patients with COPD demonstrated significantly higher trough forced expiratory volume in 1 second (FEV(1)) responses with tiotropium bromide than with placebo, confirming it has a duration of action of >=24 hours and is suitable for once-daily administration. Lung function improved to a greater extent with tiotropium bromide than with ipratropium bromide or, in most instances, salmeterol. Indacaterol was shown to be noninferior to tiotropium bromide in terms of the trough FEV(1) response. The large, 4-year UPLIFT(r) trial did not show a significant reduction in the annual rate of decline in FEV(1) with tiotropium bromide versus placebo in patients with COPD, although subgroup analyses demonstrated a significantly lower rate of decline with tiotropium bromide than with placebo in some patient groups (e.g. patients with moderate COPD, patients aged >=50 years, patients not receiving maintenance therapy at baseline). Tiotropium bromide prevented exacerbations in patients with COPD, with a significantly lower exacerbation rate and a significantly longer time to first exacerbation seen with tiotropium bromide than with placebo or salmeterol. Exacerbation rates did not significantly differ between patients receiving tiotropium bromide and those receiving salmeterol/fluticasone propionate. Tiotropium bromide also had beneficial effects on health-related quality of life (HR-QOL) and other endpoints, such as dyspnoea and rescue medication use. Combination therapy with tiotropium bromide plus formoterol with or without budesonide improved lung function to a significantly greater extent than tiotropium bromide alone in patients with COPD. In addition, exacerbation rates were lower and HR-QOL was improved with tiotropium bromide plus budesonide/formoterol versus tiotropium bromide alone. Although the addition of salmeterol/fluticasone propionate to tiotropium bromide did not reduce the COPD exacerbation rate, it did improve lung function and HR-QOL. Tiotropium bromide inhalation powder is generally well tolerated in patients with COPD, with anticholinergic adverse events (e.g. dry mouth, constipation, gastrointestinal obstruction, dysuria) among the most commonly reported adverse events. The UPLIFT(r) trial showed no significant difference between tiotropium bromide and placebo recipients in the risk of stroke, and the risk of serious cardiac adverse events (including congestive heart failure and myocardial infarction) was significantly lower with tiotropium bromide than with placebo. The absence of a detrimental effect on cardiovascular outcomes was supported by the results of a meta-analysis and pooled analyses. In addition, on-treatment mortality was lower with tiotropium bromide than with placebo in the UPLIFT(r) trial. Pooled analyses showed significantly lower cardiovascular mortality with tiotropium bromide than with placebo, with a meta-analysis demonstrating no significant difference between patients receiving tiotropium bromide and controls in cardiovascular mortality. Results of modelled pharmacoeconomic analyses conducted from a healthcare payer perspective in several developed countries suggest that tiotropium bromide is a cost-effective option in patients with COPD. In conclusion, tiotropium bromide inhalation powder is a useful option for the maintenance treatment of patients with COPD. PMID- 22217235 TI - Influence of gender and estrous cycle on plasma and renal catecholamine levels in rats. AB - Several studies have demonstrated that gonadal hormones show significant effects on the brain and signaling pathways of effector organs/cells that respond to neurotransmitters. Since little information is available concerning the impact of male and female gonadal hormones on the renal and peripheral sympathetic system, the objective of this study was to further assess whether and how the renal content and plasma concentration of catecholamines are influenced by gender and the estrous cycle in rats. To achieve this, males Wistar rats were divided into 4 groups: (i) sham (i.e., control), (ii) gonadectomized, (iii) gonadectomized and nandrolone decanoate replacement at physiological levels or (iv) gonadectomized and nandrolone decanoate replacement at high levels. Female Wistar rats were divided into 6 groups: (i) ovariectomized (OVX), (ii) estrogen replacement at physiological levels and (iii) estrogen replacement at at high levels, (iv) progesterone replacement at physiological levels and (v) progesterone replacement at at high levels, and (vi) sham. The sham group was subdivided into four subgroups: (i) proestrus, (ii) estrus, (iii) metaestrus, and (iv) diestrus. Ten days after surgery, the animals were sacrificed and their plasma and renal catecholamine levels measured for intergroup comparisons. Gonadectomy led to an increase in the plasma catecholamine concentration in females, as well as in the renal catecholamine content of both male and female rats. Gonadectomized males also showed a lower level of plasma catecholamine than the controls. The urinary flow, and the fractional excretion of sodium and chloride were significantly increased in gonadectomized males and in the OVX group when compared with their respective sham groups. PMID- 22217238 TI - [An infant without nails]. AB - A 2-week-old boy, born after an uncomplicated pregnancy of consanguineous parents, was seen with congenital absence of all nails on fingers and toes. After 6 weeks marginal nail growth was seen. Because there were no other congenital abnormalities, this was considered to be anonychia congenita; probably caused by a recessive defect of the R-spondin 4-coding gene. PMID- 22217239 TI - [Absent liver dullness due to left-sided liver]. AB - BACKGROUND: Abnormal organ sites may impede the interpretation of physical findings. CASE DESCRIPTION: A 75-year-old man with hypertension had constipation and variable abdominal pain symptoms for a long time. He had no fever or abdominal pain at that time. Physical examination of the abdomen revealed high pitched bowel sounds and hypertympanic percussion with absent liver dullness. An abdominal CT scan revealed coincidentally a left-sided liver, gallbladder and portal system. This was an explanation for the absent liver dullness. CONCLUSION: Rare abnormalities in the anatomical position of organs (such as situs inversus or situs ambiguus) may confuse clinicians in the interpretation of the physical examination. It may lead to an atypical presentation of typical disease pictures, as well as to unfounded alarm symptoms. As far as we know an isolated left-sided liver has not been described before. PMID- 22217240 TI - [Two travellers suffering from typhus]. AB - BACKGROUND: Endemic typhus, caused by Rickettsia typhi, belongs to the typhus group of the rickettsioses. The disease is prevalent worldwide and is probably an underestimated cause of illness accompanied by fever in travellers, due to its frequently mild presentation and resemblance to diseases like typhoid- or dengue fever. Broad-spectrum antibiotics are not effective in the treatment of endemic typhus, but the disease is responsive to doxycycline. CASE DESCRIPTION: A 57-year old man and a 36-year-old woman, who had returned from Indonesia and Nepal and Tibet, respectively, both presented with fever, malaise, headache and arthromyalgia, and both developed a skin rash. A diagnosis of typhoid- or dengue fever was suspected at first. The first patient improved after empirical treatment with doxycycline, the second recovered following treatment with azithromycin. Blood cultures and viral serology remained negative. Additional serology showed evidence of infection with R. typhi. Both patients made a complete recovery. CONCLUSION: Endemic typhus should be included in the differential diagnosis of illness accompanied by fever in travellers, especially if blood cultures remain negative and no improvement is seen with broad-spectrum antibiotics. PMID- 22217241 TI - [Gaubius and medical chemistry]. AB - Hieronymus David Gaub (1705-1780) was the son of a protestant cloth merchant in Heidelberg. Disliking a pietistic boarding school in Halle, Germany, he came to stay with a paternal uncle who was a physician in Amsterdam. Hieronymus studied medicine in Harderwijk and in Leiden, under the guidance of Herman Boerhaave (1668-1738). In 1731 he was appointed reader (and in 1734 professor) in chemistry at the Leiden medical faculty. After Boerhaave's death he also taught medicine, but without access to hospital beds. Gaubius correctly envisaged that chemistry would become an important discipline in medicine, but was limited by the technical constraints of his time. In his textbook of general pathology (1758) he attributed disease to disturbances of not only fluids, but also solid parts, although symptoms remained the basis of his classification. The book would remain influential for several decades, until the advent of pathological anatomy. PMID- 22217242 TI - [Pruritus in liver disease. Pathogenesis and treatment]. AB - Pruritus is a severe symptom in patients with cholestatic hepatobiliary disease; it can greatly reduce the quality of life. Cholestatic itching often peaks in the evening and early night. It mainly occurs on the palms of the hands and soles of the feet but can also occur more generalised. The pathogenesis of cholestatic pruritus has not yet been completely clarified. Possible contributors are bile salts, histamine, progesterone metabolites and opioids. A relationship between these elements and the intensity of the itch has not, however, been demonstrated. Autotaxin, an enzyme that produces lysophosphatidic acid, has recently been identified as a possible pruritogen caused by cholestasis. Treatment is aimed at eliminating pruritogens with bile acid sequestrants (cholestyramine), managing the metabolism of pruritogens (rifampicin), and influencing the perception of itch by the central nervous system with u-opioid antagonists or SSRIs. In cases of unbearable, treatment-resistant itching, consideration may be given to experimental therapies such as UV light therapy or nasobiliary drainage. PMID- 22217243 TI - [Practice guideline 'Brain metastases' (revision)]. AB - Improved survival of cancer patients results in an increase in the incidence of brain metastases. In addition, asymptomatic brain metastases are more often detected as a consequence of active screening. In patients with cancer and new neurological symptoms, MRI of the brain is indicated to assess the presence and number of brain metastases. Decisions concerning treatment of brain metastases should take place within a multidisciplinary team. Treatment is in the first instance focused on improvement or preservation of neurological functioning. The main treatment options for patients with brain metastases are whole brain radiotherapy, stereotactic radiosurgery/radiotherapy, and neurosurgical resection. The choice of treatment depends on the number and the location of the brain metastases, the general and neurological condition of the patient, the extent of extracranial tumour activity, and the expected results of treatment. The revised guideline supports the policy of whole brain radiotherapy not being the standard treatment following stereotactic radiosurgery or radiotherapy. In the case of complete resection, confirmed using early postoperative MRI, whole brain radiotherapy does not add to survival benefit, while patients may suffer from radiation-induced toxicity. PMID- 22217244 TI - [Meniere and his disease]. AB - Prosper Meniere (1799-1862) was born in Angers, where his father was a merchant. He finished his medical studies in Paris and subsequently became an assistant at the Hotel Dieu, first to the surgeon Dupuytren and later to the internist Chomel. Meanwhile he helped to combat an epidemic of cholera in the south of France, and he was personal physician to the imprisoned Duchess de Berry, who had returned from exile to reclaim the throne for the Bourbon dynasty. In 1838 he specialised in otology after he had been made head of the Institute for Deaf Mutes in Paris. In 1861 he described a group of patients who suffered recurrent attacks of vertigo as well as abnormal sounds and whose hearing deteriorated over the years. He attributed this condition to a disorder of the inner ear; this went against the prevailing opinion, which attributed most vertiginous attacks to cerebral congestion. PMID- 22217246 TI - Drugs in preclinical and early-stage clinical development for pancreatic cancer. AB - INTRODUCTION: Pancreatic cancer (PC) is the fourth leading cause of cancer related deaths in the US and Europe, and the lethality of this cancer is demonstrated by the fact that the annual incidences are approximately equal to the annual deaths. Current therapy for PC is multimodal, involving surgery and chemotherapy. Clinical symptoms are unspecific, and consequently about 85% of patients with PC are diagnosed at advanced tumor stages without any surgical therapy options. Since the therapeutic rates for PC are so dismal, it is essential to review the clinical targets for diagnosis and treatment of this lethal cancer. AREAS COVERED: In this review, we discuss potential treatment options for PC by identifying molecular targets including those involved in cell proliferation, survival, migration, invasion and angiogenesis. Targeting these molecules in combination with surgery could improve the clinical outcome for PC patients. EXPERT OPINION: For a decade, gemcitabine has remained the single first line chemotherapeutic agent for advanced adenocarcinoma of the pancreas; however, less than 25% of patients benefit from gemcitabine. The reason for frequent reoccurrence of PC after conventional methods such as surgery, radiation and/or chemotherapy is due to the lack of understanding of the basic underlying metabolic cause of the cancer and thus consequently remains uncorrected. Our understanding of drug resistance in PC is still not clear and may be answered by focusing on new useful biomarkers and their role in chemo- and radioresistance. PMID- 22217247 TI - Global analysis of tomato gene expression during Potato spindle tuber viroid infection reveals a complex array of changes affecting hormone signaling. AB - Viroids like Potato spindle tuber viroid (PSTVd) are the smallest known agents of infectious disease-small, highly structured, circular RNA molecules that lack detectable messenger RNA activity, yet are able to replicate autonomously in susceptible plant species. To better understand the possible role of RNA silencing in disease induction, a combination of microarray analysis and large scale RNA sequence analysis was used to compare changes in tomato gene expression and microRNA levels associated with PSTVd infection in two tomato cultivars plus a third transformed line expressing small PSTVd small interfering RNAs in the absence of viroid replication. Changes in messenger (m)RNA levels for the sensitive cultivar 'Rutgers' were extensive, involving more than half of the approximately 10,000 genes present on the array. Chloroplast biogenesis was down regulated in both sensitive and tolerant cultivars, and effects on mRNAs encoding enzymes involved in the biosynthesis of gibberellin and other hormones were accompanied by numerous changes affecting their respective signaling pathways. In the dwarf cultivar 'MicroTom', a marked upregulation of genes involved in response to stress and other stimuli was observed only when exogenous brassinosteroid was applied to infected plants, thereby providing the first evidence for the involvement of brassinosteroid-mediated signaling in viroid disease induction. PMID- 22217248 TI - A systems approach for identifying resistance factors to Rice stripe virus. AB - Rice stripe virus (RSV) causes disease that can severely affect the productivity of rice (Oryza sativa). Several RSV-resistant cultivars have been developed. However, host factors conferring RSV resistance in these cultivars are still elusive. Here, we present a systems approach for identifying potential rice resistance factors. We developed two near-isogenic lines (NIL), RSV-resistant NIL22 and RSV-susceptible NIL37, and performed gene expression profiling of the two lines in RSV-infected and RSV-uninfected conditions. We identified 237 differentially expressed genes (DEG) between NIL22 and NIL37. By integrating with known quantitative trait loci (QTL), we selected 11 DEG located within the RSV resistance QTL as RSV resistance factor candidates. Furthermore, we identified 417 DEG between RSV-infected and RSV-uninfected conditions. Using an interaction network-based method, we selected 20 DEG highly interacting with the two sets of DEG as RSV resistance factor candidates. Among the 31 candidates, we selected the final set of 21 potential RSV resistance factors whose differential expression was confirmed in the independent samples using real-time reverse-transcription polymerase chain reaction. Finally, we reconstructed a network model delineating potential association of the 21 selected factors with resistance-related processes. In summary, our approach, based on gene expression profiling, revealed potential host resistance factors and a network model describing their relationships with resistance-related processes, which can be further validated in detailed experiments. PMID- 22217245 TI - Proteomic analysis of Sulfolobus solfataricus during Sulfolobus Turreted Icosahedral Virus infection. AB - Where there is life, there are viruses. The impact of viruses on evolution, global nutrient cycling, and disease has driven research on their cellular and molecular biology. Knowledge exists for a wide range of viruses; however, a major exception are viruses with archaeal hosts. Archaeal virus-host systems are of great interest because they have similarities to both eukaryotic and bacterial systems and often live in extreme environments. Here we report the first proteomics-based experiments on archaeal host response to viral infection. Sulfolobus Turreted Icosahedral Virus (STIV) infection of Sulfolobus solfataricus P2 was studied using 1D and 2D differential gel electrophoresis (DIGE) to measure abundance and redox changes. Cysteine reactivity was measured using novel fluorescent zwitterionic chemical probes that, together with abundance changes, suggest that virus and host are both vying for control of redox status in the cells. Proteins from nearly 50% of the predicted viral open reading frames were found along with a new STIV protein with a homologue in STIV2. This study provides insight to features of viral replication novel to the archaea, makes strong connections to well-described mechanisms used by eukaryotic viruses such as ESCRT-III mediated transport, and emphasizes the complementary nature of different omics approaches. PMID- 22217249 TI - Cost-effectiveness analysis of disease modifiying drugs (interferons and glatiramer acetate) as first line treatments in remitting-relapsing multiple sclerosis patients. AB - Abstract Objective: The aim of this study was to assess cost-effectiveness of the different Disease Modifying Drugs (DMD) used as first-line treatments (interferons IM IFNbeta-1a, SC IFNbeta-1a, SC IFNbeta-1b, and glatiramer acetate, GA) in Remitting-Relapsing Multiple Sclerosis (RRMS) in Spain. METHODS: A Markov model was developed to simulate the progression of a cohort of patients with RRMS, during a period of 10 years. Seven health states, defined by the Expanded Disability Status Scale (EDSS), were considered in the model. Patients with an EDSS score less than 6.0 were assumed to be treated with one of the DMD. In addition, all patients were assumed to receive symptomatic treatment. The monthly transition probabilities of the model were obtained from the literature. The analysis was performed from the societal perspective, in which both direct and indirect (losses in productivity) healthcare costs (?, 2010) were included. A discount rate of 3% was applied to both costs and efficacy results. RESULTS: GA was the less costly strategy (?322,510), followed by IM IFNbeta-1a (?329,595), SC IFNbeta-1b (? 333,925), and SC IFNbeta-1a (?348,208). IM IFNbeta-1a has shown the best efficacy results, with 4.176 quality-adjusted life years (QALY), followed by SC IFNbeta-1a (4.158 QALY), SC IFNbeta-1b (4.157 QALY), and GA (4.117 QALY). Incremental costs per QALY gained with IM IFNbeta-1a were ?-1,005,194/QALY, ? 223,397/QALY, and ?117,914/QALY in comparison to SC IFNbeta-1a, SC IFNbeta-1b, and GA, respectively. CONCLUSIONS: First-line treatment with GA is the less costly strategy for the treatment of patients with RRMS. Treatment with IM IFNbeta-1a is a dominant strategy (lower cost and higher QALY) compared with SC IFNbeta-1a and SC IFNbeta-1b. However, IM IFNbeta-1a is not a cost-effective strategy vs GA, because incremental cost per QALY gained with IM IFNbeta-1a exceeds the ?30,000 per QALY threshold commonly used in Spain. LIMITATIONS: The highly-restrictive inclusion criteria of clinical trials limits generalization of the results on efficacy to all patients with multiple sclerosis. Availability of data for head-to-head comparisons is associated with the use of information from clinical trials. PMID- 22217250 TI - Quantum finite-size effects in graphene plasmons. AB - Graphene plasmons are emerging as an alternative solution to noble metal plasmons, adding the advantages of tunability via electrostatic doping and long lifetimes. These excitations have been so far described using classical electrodynamics, with the carbon layer represented by a local conductivity. However, the question remains, how accurately is such a classical description representing graphene? What is the minimum size for which nonlocal and quantum finite-size effects can be ignored in the plasmons of small graphene structures? Here, we provide a clear answer to these questions by performing first-principles calculations of the optical response of doped nanostructured graphene obtained from a tight-binding model for the electronic structure and the random-phase approximation for the dielectric response. The resulting plasmon energies are in good agreement with classical local electromagnetic theory down to ~10 nm sizes, below which plasmons split into several resonances that emphasize the molecular character of the carbon structures and the quantum nature of their optical excitations. Additionally, finite-size effects produce substantial plasmon broadening compared to homogeneous graphene up to sizes well above 20 nm in nanodisks and 10 nm in nanoribbons. The atomic structure of edge terminations is shown to be critical, with zigzag edges contributing to plasmon broadening significantly more than armchair edges. This study demonstrates the ability of graphene nanostructures to host well-defined plasmons down to sizes below 10 nm, and it delineates a roadmap for understanding their main characteristics, including the role of finite size and nonlocality, thus providing a solid background for the emerging field of graphene nanoplasmonics. PMID- 22217252 TI - Inter-and intraspecific variation in fern mating systems after long-distance colonization: the importance of selfing. AB - BACKGROUND: Previous studies on the reproductive biology of ferns showed that mating strategies vary among species, and that polyploid species often show higher capacity for self-fertilization than diploid species. However, the amount of intraspecific variation in mating strategy and selfing capacity has only been assessed for a few species. Yet, such variation may have important consequences during colonization, as the establishment of any selfing genotypes may be favoured after long-distance dispersal (an idea known as Baker's law). RESULTS: We examined intra-and interspecific variation in potential for self-fertilization among four rare fern species, of which two were diploids and two were tetraploids: Asplenium scolopendrium (2n), Asplenium trichomanes subsp. quadrivalens (4n), Polystichum setiferum (2n) and Polystichum aculeatum (4n). Sporophyte production was tested at different levels of inbreeding, by culturing gametophytes in isolation, as well as in paired cultures with a genetically different gametophyte. We tested gametophytes derived from various genetically different sporophytes from populations in a recently planted forest colonized through long-distance dispersal (Kuinderbos, the Netherlands), as well as from older, less disjunct populations.Sporophyte production in isolation was high for Kuinderbos genotypes of all four species. Selfing capacity did not differ significantly between diploids and polyploids, nor between species in general. Rather selfing capacity differed between genotypes within species. Intraspecific variation in mating system was found in all four species. In two species one genotype from the Kuinderbos showed enhanced sporophyte production in paired cultures. For the other species, including a renowned out crosser, selfing capacity was consistently high. CONCLUSIONS: Our results for four different species suggest that intraspecific variation in mating system may be common, at least among temperate calcicole ferns, and that genotypes with high selfing capacity may be present among polyploid as well as diploid ferns. The surprisingly high selfing capacity of all genotypes obtained from the Kuinderbos populations might be due to the isolated position of these populations. These populations may have established through single-spore colonization, which is only possible for genotypes capable of self-fertilization. Our results therewith support the idea that selection for selfing genotypes may occur during long distance colonization, even in normally outcrossing, diploid ferns. PMID- 22217254 TI - Brain activation patterns in major depressive disorder and work stress-related long-term sick leave among Swedish females. AB - Deficits in executive functioning and working memory associated with frontal lobe dysfunction are prominent in depression and work-related long-term sick leave (LTSL). This study used functional magnetic resonance imaging (fMRI) to investigate potential differences in brain activation patterns in these conditions. In addition, the function of the hypothalamic-pituitary-adrenal (HPA) axis was examined and compared between groups. Since there is a clear overrepresentation of women in these diagnostic groups, and to ensure a more homogenous sample population, only women were included. To examine the neural correlates of relevant cognitive processes in patients on sick leave >90 days due to work-related LTSL, recently diagnosed patients with major depression Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV criteria, untreated), and healthy controls (n = 10, each group), a 2-back working memory task and a visual long-term memory task were administered during fMRI scanning. HPA axis functioning was investigated using a diurnal curve of saliva cortisol and a dexamethasone suppression test. Task performance was comparable among the three groups. Multivariate image analysis revealed that both memory tasks engaged a similar brain network in all three groups, including the prefrontal and parietal cortex. During the 2-back task, LTSL patients had significant frontal hypoactivation compared to controls and patients with depression. Saliva cortisol measurements showed a flattening of the diurnal rythmicity in LTSL patients compared to patients with depression and healthy contols. Taken together, these findings indicate that work stress-related LTSL and major depression are dissociable in terms of frontal activation and diurnal cortisol rhythmicity. PMID- 22217253 TI - Outpatient treatment of acute poisonings in Oslo: poisoning pattern, factors associated with hospitalization, and mortality. AB - BACKGROUND: Most patients with acute poisoning are treated as outpatients worldwide. In Oslo, these patients are treated in a physician-led outpatient clinic with limited diagnostic and treatment resources, which reduces both the costs and emergency department overcrowding. We describe the poisoning patterns, treatment, mortality, factors associated with hospitalization and follow-up at this Emergency Medical Agency (EMA, "Oslo Legevakt"), and we evaluate the safety of this current practice. METHODS: All acute poisonings in adults (> or = 16 years) treated at the EMA during one year (April 2008 to April 2009) were included consecutively in an observational study design. The treating physicians completed a standardized form comprising information needed to address the study's aims. Multivariate logistic regression analysis was used to identify the factors associated with hospitalization. RESULTS: There were 2348 contacts for 1856 individuals; 1157 (62%) were male, and the median age was 34 years. The most frequent main toxic agents were ethanol (43%), opioids (22%) and CO or fire smoke (10%). The physicians classified 73% as accidental overdoses with substances of abuse taken for recreational purposes, 15% as other accidents (self-inflicted or other) and 11% as suicide attempts. Most (91%) patients were treated with observation only. The median observation time until discharge was 3.8 hours. No patient developed sequelae or died at the EMA. Seventeen per cent were hospitalized. Gamma-hydroxybutyric acid, respiratory depression, paracetamol, reduced consciousness and suicidal intention were factors associated with hospitalization. Forty-eight per cent were discharged without referral to follow up. The one-month mortality was 0.6%. Of the nine deaths, five were by new accidental overdose with substances of abuse. CONCLUSIONS: More than twice as many patients were treated at the EMA compared with all hospitals in Oslo. Despite more than a doubling of the annual number of poisoned patients treated at the EMA since 2003, there was no mortality or sequelae, indicating that the current practice is safe. Thus, most low- to intermediate-acuity poisonings can be treated safely without the need to access hospital resources. Although the short-term mortality was low, more follow-up of patients with substance abuse should be encouraged. PMID- 22217255 TI - A review of nosocomial norovirus outbreaks: infection control interventions found effective. AB - The purpose of this study was to review documented outbreaks of enteric illness associated with nosocomial norovirus infections and to identify modes of transmission, morbidity and mortality patterns, and recommendations for control. Searches of electronic databases, public health publications, and federal, state/provincial public health websites were completed for 1 January 2000 to 31 December 2010. Computer-aided searches of literature databases and systematic searches of government websites identified 54 relevant outbreak reports. Transmission routes included person-to-person (18.5%), foodborne (3.7%) and in the majority (77.8%) the route was unknown. Actions taken during the outbreak to control infection included restricting the movements of patients and staff (22.5%), enhanced environmental cleaning (13.6%) and hand hygiene (10.3%). Rapid identification of norovirus outbreaks in hospitals is vital for the immediate implementation of infection control measures and isolation of infected individuals in this mainly immunocompromised population. Studies that statistically evaluate infection control measures are needed. PMID- 22217256 TI - Host switch and infestation by Ligula intestinalis L. in a silver bream (Blicca bjoerkna L.) population. AB - Sampling of the fish community was carried out for 20 years in the Mirgenbach reservoir, in North-Eastern France. The prevalence and the mean intensity of Ligula intestinalis (Cestoda) were analysed in roach (Rutilus rutilus) and silver bream (Blicca bjoerkna) populations, the main two infected species. The aim of this study was to investigate the host switch from roach to silver bream and the consequences of L. intestinalis infestation in silver bream, which is an unusual host for this parasite as Ligula parasitism in silver bream appears to be rare. We analysed in detail the relationships between parasitism index (PI), gonadosomatic index (GSI), perivisceral fat abundance (PFA) and condition index (CI) in the silver bream population. In 1998, prevalence of L. intestinalis highlighted a clear host switch from roach to silver bream. In the silver bream population, young fish were the most severely infected and the impact of plerocercoids appeared to be different depending on the host sex. In male silver bream, plerocercoids drew energy from fat reserves even if GSI was also slightly impacted. On the contrary, in females energy was diverted from gonad maturation rather than from perivisceral fat reserves. No significant difference was observed in terms of CI in either sex. PMID- 22217257 TI - Laser dentistry, current advantages, and limits. PMID- 22217258 TI - Effects of Gyejibongnyeong-hwan on dysmenorrhea caused by blood stagnation: study protocol for a randomized controlled trial. AB - BACKGROUND: Gyejibongnyeong-hwan (GJBNH) is one of the most popular Korean medicine formulas for menstrual pain of dysmenorrhea. The concept of blood stagnation in Korean medicine is considered the main factor of causing abdominal pain, or cramps, during menstrual periods. To treat the symptoms, GJBNH is used to fluidify the stagnated blood and induce the blood flow to be smooth, reducing pain as the result. The purpose of this trial is to identify the efficacy of GJBNH in dysmenorrhea caused by blood stagnation. METHODS: This study is a multi centre, randomised, double-blind, controlled trial with two parallel arms: the group taking GJBNH and the group taking placebo. 100 patients (women from age 18 to 35) will be enrolled to the trial. Through randomization 50 patients will be in experiment arm, and the other 50 patients will be in control arm. At the second visit (baseline), all participants who were already screened that they fulfil both the inclusion and the exclusion criteria will be randomised into two groups. Each group will take the intervention three times per day during two menstrual cycles. After the treatment for two cycles, each patient will be followed up during their 3rd, 4th and 5th menstrual cycles. From the screening (Visit 1) through the second follow-up (Visit 6) the entire process will take 25 weeks. DISCUSSION: This trial will provide evidence for the effectiveness of GJBNH in treating periodical pain due to dysmenorrhea that is caused by blood stagnation. The primary outcome between the two groups will be measured by changes in the Visual Analogue Score (VAS) of pain. The secondary outcome will be measured by the Blood Stagnation Scale, the Short-form McGill questionnaire and the COX menstrual symptom scale. Analysis of covariance (ANCOVA) and repeated measured ANOVA will be used to analyze the data analysis. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN30426947. PMID- 22217259 TI - A new beta chain hemoglobin variant with increased oxygen affinity: Hb Santa Giusta Sardegna [beta93(F9)Cys->Trp; HBB c.282T>G]. AB - During a screening program for the identification of beta-thalassemia (beta-thal) carriers in Sardinia, Italy, we identified two subjects with increased hemoglobin (Hb) levels and an abnormal Hb variant. The same variant was detected in a family member. DNA sequencing revealed a TGT > TGG mutation at codon 93 of the beta globin gene. Structural analysis demonstrated that the cystine residue at position 93 of the beta chain was substituted by tryptophan. Since this amino acid substitution had not yet been reported, we designated this variant Hb Santa Giusta Sardegna for the place of birth of the subjects. This amino acid substitution occurs at the tyrosine pocket of the beta chain as well as at the alpha1beta2/alpha2beta1 contact of the quaternary structure of the molecule. The presence of this Hb in the hemolysate causes an increased oxygen affinity, a slightly reduced Bohr effect and a reduced heme-heme interaction (n(50), Hill's constant) in comparison with those of Hb A. PMID- 22217261 TI - Retrolabyrinthine approach for surgical placement of auditory brainstem implants in children. AB - CONCLUSION: The extended retrolabyrinthine approach (RLA) is a safe and reliable approach for auditory brainstem placement in children. The surgical landmarks to reach cochlear nucleus are adequately exposed by this approach. OBJECTIVE: To describe a new approach option for auditory brainstem implants (ABIs) in children, highlighting the anatomical landmarks to appropriately expose the foramen of Luschka. METHODS: Three prelingually deafened children consecutively operated for ABIs via the RLA. RESULTS: ABI placement via the RLA was successfully performed in all children without any further complications except multidirectional nystagmus in one child. The RLA we employed differed from that used for vestibular schwannoma only in the removal of the posterior semicircular canal. The lateral and superior semicircular canals and the vestibule remained intact, and there was no need to expose the dura of the internal auditory meatus. The jugular bulb was completely exposed to allow adequate visualization of the ninth cranial nerve and cerebellar flocculus. PMID- 22217262 TI - Absorption spectra and photolysis of methyl peroxide in liquid and frozen water. AB - Methyl peroxide (CH(3)OOH) is commonly found in atmospheric waters and ices in significant concentrations. It is the simplest organic peroxide and an important precursor to hydroxyl radical. Many studies have examined the photochemical behavior of gaseous CH(3)OOH; however, the photochemistry of liquid and frozen water solutions is poorly understood. We present a series of experiments and theoretical calculations designed to elucidate the photochemical behavior of CH(3)OOH dissolved in liquid water and ice over a range of temperatures. The molar extinction coefficients of aqueous CH(3)OOH are different from the gas phase, and they do not change upon freezing. Between -12 and 43 degrees C, the quantum yield of CH(3)OOH photolysis is described by the following equation: Phi(T) = exp((-2175 +/- 448)1/T) + 7.66 +/- 1.56). We use on-the-fly ab initio molecular dynamics simulations to model structures and absorption spectra of a bare CH(3)OOH molecule and a CH(3)OOH molecule immersed inside 20 water molecules at 50, 200, and 220 K. The simulations predict large sensitivity in the absorption spectrum of CH(3)OOH to temperature, with the spectrum narrowing and shifting to the blue under cryogenic conditions because of constrained dihedral motion around the O-O bond. The shift in the absorption spectrum is not observed in the experiment when the CH(3)OOH solution is frozen suggesting that CH(3)OOH remains in a liquid layer between the ice grains. Using the extinction coefficients and photolysis quantum yields obtained in this work, we show that under conditions with low temperatures, in the presence of clouds with a high liquid-water content and large solar zenith angles, the loss of CH(3)OOH by aqueous photolysis is responsible for up to 20% of the total loss of CH(3)OOH due to photolysis. Gas phase photolysis of CH(3)OOH dominates under all other conditions. PMID- 22217263 TI - Burden of a multiple sclerosis relapse: the patient's perspective. AB - BACKGROUND: Relapses are a common feature of relapsing-remitting multiple sclerosis (RRMS) and increasing severity has been shown to be associated with higher healthcare costs, and to result in transient increases in disability. Increasing disability likely impacts work and leisure productivity, and lowers quality of life. OBJECTIVE: The objective of this study was to characterize from the patient's perspective the impact of a multiple sclerosis (MS) relapse in terms of the economic cost, work and leisure productivity, functional ability, and health-related quality of life (HR-QOL), for a sample of patients with RRMS in the US treated with immunomodulatory agents. METHODS: A cross-sectional, web based, self-report survey was conducted among members of MSWatch.com, a patient support website now known as Copaxone.com. Qualified respondents in the US had been diagnosed with RRMS and were using an immunomodulatory agent. The survey captured costs of RRMS with questions about healthcare resource utilization, use of community services, and purchased alterations and assistive items related to MS. The Work and Leisure Impairment instrument and the EQ-5D were used to measure productivity losses and HR-QOL (health utility), respectively. The Goodin MS neurological impairment questionnaire was used to measure functional disability; questions were added about relapses in the past year. RESULTS: Of 711 qualified respondents, 67% reported having at least one relapse during the last year, with a mean of 2.2 +/- 2.3 relapses/year. Respondents who experienced at least one relapse had significantly higher mean annual direct and indirect costs compared with those who did not experience a relapse ($US38 458 vs $US28 669; p = 0.0004) [year 2009 values]. Direct health-related costs accounted for the majority of the increased cost ($US5201; 53%) and were mainly due to increases in hospitalizations, medications, and ambulatory care. Indirect costs, including informal care and productivity loss, accounted for the additional 47% of increased cost ($US4588). Accounting for the mean number of relapses associated with these increased costs, the total economic cost of one relapse episode could be estimated at about $US4449, exclusive of intangible costs. The mean self reported Expanded Disability Status Scale (EDSS) score, derived from the Goodin MS questionnaire, was significantly higher with relapse than with a clinically stable state (EDSS 4.3 vs 3.7; p < 0.0001), while the mean health utility score was significantly lower with relapse compared with a clinically stable state (0.66 vs 0.75; p = 0.0001). The value of these intangible costs of relapse can be estimated at $US5400. The overall burden (direct, indirect, and intangible costs) of one relapse in patients treated with immunomodulatory agents is therefore estimated conservatively at $US9849. CONCLUSIONS: This study shows that from a patient's perspective an MS relapse is associated with a significant increase in the economic costs as well as a decline in HR-QOL and functional ability. PMID- 22217264 TI - Re-engineering the post-discharge appointment process for general medicine patients. AB - BACKGROUND: Patients are vulnerable to issues that emerge after discharge from the hospital, and this susceptibility is compounded as patients attempt to navigate complex healthcare organizations. Post-discharge clinic appointments may provide the opportunity to mitigate risks posed to patients during this vulnerable time. OBJECTIVE: Our aim was to determine whether actively engaging patients in scheduling post-discharge appointments before leaving the hospital affects the rate of patients seeing an ambulatory care physician. METHODS: This was a prospective cohort pilot study from May to July 2007 with a historical convenience control from 2003. The setting was an inpatient academic tertiary care referral center in the US. Study participants had been discharged from a general medicine hospitalist service during the study time period. Patients, or their designated caregivers, were contacted in hospital rooms to schedule a post discharge appointment before discharge. The primary outcome was rate of attendance at post-discharge appointments, determined a priori. RESULTS: Eighty three patients with 115 scheduled appointments in the intervention group were compared with 306 patients with 398 appointments in the historical control group. The attendance rate was 59.5% in the control group versus 78.3% in the study group (p < 0.0001). Patients received 1.3 discharge appointments per discharge in both the historical and study group. In a limited evaluation, the study group had a trend towards a lower return rate to the emergency department within 3 days of discharge (1.2% vs 3.8%, nonsignificant), and a lower readmission rate within 14 days of discharge (10.8% vs 11.8%, nonsignificant). CONCLUSION: Our patient centered process for helping patients arrange their post-discharge appointments before discharge improved the attendance rate at those appointments. PMID- 22217265 TI - Effects of bed net use, female size, and plant abundance on the first meal choice (blood vs sugar) of the malaria mosquito Anopheles gambiae. AB - BACKGROUND: The purpose of this study was to determine whether the sugar-or-blood meal choice of Anopheles gambiae females one day after emergence is influenced by blood-host presence and accessibility, nectariferous plant abundance, and female size. This tested the hypothesis that the initial meal of female An. gambiae is sugar, even when a blood host is available throughout the night, and, if not, whether the use of a bed net diverts mosquitoes to sugar sources. METHODS: Females and males <1-day post-emergence were released in a mesocosm. Overnight they had access to either one or six Senna didymobotrya plants. Simultaneously they had access to a human blood host, either for 8 h or for only 30 min at dusk and dawn (the remainder of the night being excluded by an untreated bed net). In a third situation, the blood host was not present. All mosquitoes were collected in the morning. Their wing lengths, an indicator of pre-meal energetic state, were measured, and their meal choice was determined by the presence of midgut blood and of fructose. RESULTS: Female sugar feeding after emergence was facultative. When a blood host was accessible for 8 h per night, 92% contained blood, and only 3.7% contained sugar. Even with the use of a bed net, 78% managed to obtain a blood meal during the 30 min of accessibility at dusk or dawn, but 14% of females were now fructose-positive. In the absence of a blood host, and when either one or six plants were available, a total of 21.7% and 23.6% of females and 30.8% and 43.5% of males contained fructose, respectively. Feeding on both sugar and blood was more likely with bed net use and with greater plant abundance. Further, mosquitoes that fed on both resources were more often small and had taken a sugar meal earlier than the blood meal. The abundance of sugar hosts also affected the probability of sugar feeding by males and the amount of fructose obtained by both males and females. CONCLUSION: Even in an abundance of potential sugar sources, female An. gambiae appear to prefer a nearby human source of blood. However, the decision to take sugar was more likely if energy reserves were low. Results probably would differ if sugar hosts were more attractive or yielded larger sugar meals. The diversion of energetically deprived mosquitoes to sugar sources suggests a possible synergy between bed nets and sugar-based control methods. PMID- 22217266 TI - Losartan inhibits STAT1 activation and protects human glomerular mesangial cells from angiotensin II induced premature senescence. AB - Human glomerular mesangial cells (HMCs) have a finite lifespan, and eventually enter irreversible growth arrest known as cellular senescence, which is thought to contribute to kidney ageing and age-related kidney disorders, such as chronic kidney disease. The signal transducer and activator of transcription 1 (STAT1) is a latent transcription factor involved in a variety of signal transduction pathways, including cell proliferation, apoptosis, and differentiation, but whether it could regulate HMC senescence still remains to be explored. In our study, the induction of angiotensin II (Ang II)-accelerated HMC senescence, as judged by increased senescence-associated beta-galactosidase (SA-beta-gal) positive staining cells, morphological changes, and G0/G1 cell cycle arrest. STAT1 activity and the expression of p53 and p21(Cip1) were increased after Ang II treatment. STAT1 knockdown using RNA interference significantly inhibited the progression of HMC senescence and decreased the elevated expression of p53 and p21(Cip1). Pretreating HMCs with Ang II receptor blocker losartan also inhibited the progression of HMC senescence and STAT1 activity. Our results indicate that STAT1 is implicated in the mediation of Ang II-induced HMC senescence through p53/ p21(Cip1) pathway, and that losartan could attenuate HMC senescence by regulating STAT1. The antioxidant N-acetyl-L-cysteine reduced ROS production and STAT1 activity induced by Ang II, indicating that Ang II uses ROS as a second messenger to regulate STAT1 activity. PMID- 22217267 TI - Q fever: baseline monitoring of a sheep and a goat flock associated with human infections. AB - Animal losses due to abortion and weak offspring during a lambing period amounted up to 25% in a goat flock and up to 18% in a sheep flock kept at an experimental station on the Swabian Alb, Germany. Fifteen out of 23 employees and residents on the farm tested positive for Coxiella burnetii antibodies by enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence assay. Ninety-four per cent of the goats and 47% of the sheep were seropositive for C. burnetii by ELISA. Blood samples of 8% of goats and 3% of sheep were PCR positive. C. burnetii was shed by all tested animals through vaginal mucus, by 97% of the goats and 78% of the sheep through milk, and by all investigated sheep through faeces (PCR testing). In this outbreak human and animal infection were temporally related suggesting that one was caused by the other. PMID- 22217269 TI - Modification and characterization of biodegradable methylcellulose films with trimethylolpropane trimethacrylate (TMPTMA) by gamma radiation: effect of nanocrystalline cellulose. AB - Methylcellulose (MC)-based films were prepared by solution casting from its 1% aqueous suspension containing 0.25% glycerol. Trimethylolpropane trimethacrylate (TMPTMA) monomer (0.1-2% by wt) along with the glycerol was added to the MC suspension. The films were cast and irradiated from a radiation dose varied from 0.1 to 10 kGy. Then the mechanical properties such as tensile strength (TS), tensile modulus (TM), and elongation at break (Eb) and barrier properties of the films were evaluated. The highest TS (47.88 PMa) and TM (1791.50 MPa) of the films were found by using 0.1% monomer at 5 kGy dose. The lowest water vapor permeability (WVP) of the films was found to be 5.57 g.mm/m(2).day.kPa (at 0.1% monomer and 5 kGy dose), which is 12.14% lower than control MC-based films. Molecular interactions due to incorporation of TMPTMA were supported by FTIR spectroscopy. A band at 1720 cm(-1) was observed due to the addition of TMPTMA in MC-based films, which indicated the typical (C?O) carbonyl stretching. For the further improvement of the mechanical and barrier properties of the film, 0.025 1% nanocrystalline cellulose (NCC) was added to the MC-based suspension containing 1% TMPTMA. Addition of NCC led to a significant improvement in the mechanical and barrier properties. The novelty of this investigation was to graft insoluble monomer using gamma radiation with MC-based films and use of biodegradable NCC as the reinforcing agent. PMID- 22217270 TI - The influence of oracin on reduction and toxicity of doxorubicin in hepatocytes and mammary epithelial cells MCF-10A. AB - The ways, how to increase effectiveness of doxorubicin (DOX) in cancer cells and decrease its toxicity in normal cells, have been intensively studied. In breast cancer cells MCF-7, isoquinoline derivative oracin (ORC) inhibited DOX reduction and increased DOX antiproliferative effect. The aim of this study was to test the influence of ORC on the reduction of DOX and its toxicity in hepatocytes and non tumourous breast cells. The kinetics of DOX reduction was measured in cytosols from rat liver, human liver and human mammary epithelial cells MCF-10A. Activity and expression of carbonyl reductase 1 (CBR1) were assayed using menadione as a substrate and western blot analysis. End-point tests of viability served for study of cytotoxicity of DOX, ORC and DOX+ORC combinations in rat hepatocytes and MCF-10A cells. The inhibitory effect of ORC on DOX reductases was almost none in MCF-10A cells and mild in liver. CBR1 expression and activity was lower in non tumourous MCF-10A cells than in cancer MCF-7 cells. Cytotoxicity tests showed that DOX+ORC combinations had significantly lower toxicity than DOX alone in MCF 10A cells as well as in hepatocytes. ORC significantly decreases DOX toxicity in MCF-10A and in hepatocytes. Therefore, concomitant use of ORC and DOX may protect normal cells against DOX toxicity. PMID- 22217273 TI - Editorial. Keeping the air cleanup front. PMID- 22217274 TI - Letters. Incineration or pyrolysis. PMID- 22217271 TI - Hepatitis C virus replication-specific inhibition of microRNA activity with self cleavable allosteric ribozyme. AB - Functional sequestration of microRNA 122 (miR-122) by treatment with an oligonucleotide complementary to the miRNA results in long-lasting suppression of hepatitis C virus (HCV) viremia in primates. However, the safety of the constitutive miR-122 silencing approach to HCV inhibition is unclear, since miR 122 can modulate the expression of many host genes. In this study, a regulation system capable of specifically inhibiting miR-122 activity only upon HCV infection was developed. To this end, an allosteric self-cleavable ribozyme capable of releasing antisense sequence to miR-122 only in the presence of HCV nonstructural protein 5B was developed using in vitro selection method. The activity of the reporter construct with miR-122 target sequences at its 3' untranslated region and the expression of endogenous miR-122 target proteins were specifically stimulated through sequestration of miR-122 only in HCV replicon Huh 7 cells, but not in naive Huh-7 cells, when transfected with expression vector encoding the specific allosteric ribozyme. These findings indicate that miR-122 function can be specifically inhibited by the allosteric ribozyme only in HCV replicating cells. Importantly, HCV replicon replication was efficiently inhibited by the allosteric ribozyme. This ribozyme could be useful for the specific, safe, and efficacious anti-HCV modulation. PMID- 22217275 TI - Letters. Waste incineration. PMID- 22217276 TI - Environmental currents. PMID- 22217278 TI - Outlook. PMID- 22217277 TI - Interview. ES speaks with Joseph Lawler. PMID- 22217279 TI - Odor controls for rendering plants. PMID- 22217280 TI - Conserving energy with heat storage wells. PMID- 22217281 TI - Measurement of ultraviolet radiation intensity in photochemical smog studies. PMID- 22217282 TI - Selective electrode measurement of ammonia in water and wastes. PMID- 22217283 TI - Collection and determination of sulfur dioxide incorporating permeation and West Gaeke procedure. PMID- 22217284 TI - Capacity of ferric oxide particles to oxidize sulfur dioxide in air. PMID- 22217285 TI - Stimulated biodegradation of oil slicks using oleophilic fertilizers. PMID- 22217286 TI - Determination of alkylbenzenesulfonate (ABS) in bottom sediment. PMID- 22217287 TI - Permeation of sulfur dioxide through polymeric stack sampling interfaces. PMID- 22217288 TI - Chemiluminescent reactions of peroxyacetyl nitrate and ozone with triethylamine. Possible atmospheric monitor for peroxyacetyl nitrate. PMID- 22217289 TI - Removal of mercury from aqueous solutions by nitrogen-containing chemically modified cotton. PMID- 22217290 TI - Identifying sources of lead contamination by stable isotope techniques. Comments. PMID- 22217291 TI - Identifying sources of lead contamination by stable isotope techniques. Reply to comments. PMID- 22217294 TI - New literature. PMID- 22217292 TI - Industry trends. PMID- 22217296 TI - Molecular spur gears comprising triptycene rotators and bibenzimidazole-based stators. AB - Dynamic gearing of molecular spur gears, the most common type of mechanical gear, is elucidated. Molecular design and conformational analysis show that derivatives of 4,4-bis(triptycen-9-ylethynyl)bibenzimidazole represent suitable constructs to investigate gearing behavior of collateral triptycene (Tp) groups. To test this design, DFT calculations (B97-D/Def2-TZVP) were employed and the results suggest that these molecules undergo geared rotation preferentially to gear slippage. Synthesis of derivatives was carried out, providing a series of molecular spur gears, including the first desymmetrized spur gear molecules, which were subsequently subjected to stereochemical analysis. PMID- 22217297 TI - Dual diagnosis and suicide risk in a Spanish outpatient sample. AB - The present study compares dual-diagnosis patients with other groups of psychiatric patients to determine the differential characteristics in suicide risk and other clinical variables between them. During 2008 in Madrid, 837 outpatients were evaluated in addiction and mental health services. Three comparison groups were created according to current diagnosis: (i) dual patients, (ii) patients with substance use disorders but no other mental disorders, and (iii) patients with mental disorders but no substance use disorders. A multinomial logistic regression model was built to explore the risk associated with dual diagnosis. Criteria for dual diagnosis were met at the time of the study by 440 patients (52.6%). Dual patients showed several demographic and clinical differences and a higher risk for suicide than the other two comparison groups. Further research is needed to define suicide preventive strategies for dual patients. PMID- 22217298 TI - New agents for acute myeloid leukemia: is it time for targeted therapies? AB - INTRODUCTION: The prognosis of acute myeloid leukemia (AML) is improved in the last two decades, even though induction and consolidation chemotherapy has not involved new drugs. The more effective use of well-known agents as well as refinement of supportive care during the inevitable phase of severe pancytopenia following intensive chemotherapy accounts for the reduction of treatment-related death rate. In addition, mortality due to allogeneic and autologous stem cell transplantation has also been reduced, due to adoption of more effective therapies for graft versus host disease and other transplant-related complications. AREAS COVERED: The multitude of chromosomal and molecular abnormalities makes the treatment of AML a challenging prospect. In addition, genetic aberrations are not mutually exclusive and coexist in the leukemic cells. As a consequence, the clinical development of new biologic agents proceeds slowly. Data for this review were identified from PubMed and references from relevant articles published in English from 2000 to 2011. EXPERT OPINION: In Phase II studies, different new agents have been found to be active in AML and are currently under investigation in Phase III trials also in combination with conventional chemotherapy. In the near future, we would have more information about the possibility of introducing new drugs into daily practice. PMID- 22217299 TI - Diagnostic value of progesterone receptor and p53 expression in uterine smooth muscle tumors. AB - BACKGROUND: The diagnosis of uterine smooth muscle tumors depends on a combination of microscopic features. However, a small number of these tumors still pose difficult diagnostic challenges. AIM: To investigate progesterone receptor (PR) and p53 expression in leiomyomas (LMs), atypical leiomyomas (ALMs), smooth muscle tumors of uncertain malignant potential (STUMP), and leiomyosarcomas (LMSs) and to evaluate the potential utility of the selected immunohistochemical markers in differentiating these tumors. MATERIALS AND METHODS: Immunohistochemical expression of PR and p53 was investigated in 41 uterine smooth muscle tumors comprising: 15 LMS, 4 STUMP, 6 ALM and 16 LM. Quantitative evaluation of PR and p53 expression was graded on a scale from 0 to 3+. RESULTS: Leiomyosarcomas showed reduced PR expression. All LMs as well as ALMs and STUMP were stained intensely for PR. Conversely, LMS was strongly stained with p53, while the three non-sarcomatous groups (STUMP, ALM, LM) were either entirely negative or weakly stained for p53. Regarding both PR and p53 expression, the difference between the LMS group and the three non-sarcomatous groups was highly significant (p < 0.001). Combined high PR - low p53 expression was seen in all the 26 examined cases of the non-sarcomatous group including the STUMP cases and none of the LMS cases. Therefore, it represents a "benign" profile with 100% specificity in diagnosis of a non-sarcomatous tumor. CONCLUSION: Immunohistochemistry for PR and p53 is valuable as an adjunct tool to morphological assessment of problematic uterine smooth muscle tumors. PMID- 22217300 TI - Impact of the ABCDE triage in primary care emergency department on the number of patient visits to different parts of the health care system in Espoo City. AB - BACKGROUND: Many Finnish emergency departments (ED) serve both primary and secondary health care patients and are therefore referred to as combined emergency departments. Primary care doctors are responsible for the initial assessment and treatment. They, thereby, also regulate referral and access to secondary care. Primary health care EDs are easy for the public to access, leading to non-acute patient visits to the emergency department. This has caused increased queues and unnecessary difficulties in providing immediate treatment for urgent patients. The primary aim of this study was to assess whether the flow of patients was changed by implementing the ABCDE-triage system in the EDs of Espoo City, Finland. METHODS: The numbers of monthly visits to doctors were recorded before and after intervention in Espoo primary care EDs. To study if the implementation of the triage system redirects patients to other health services, the numbers of monthly visits to doctors were also scored in the private health care, the public sector health services of Espoo primary care during office hours and local secondary health care ED (Jorvi hospital). A face-to-face triage system was applied in the primary care EDs as an attempt to provide immediate treatment for the most acute patients. It is based on the letters A (patient sent directly to secondary care), B (to be examined within 10 min), C (to be examined within 1 h), D (to be examined within 2 h) and E (no need for immediate treatment) for assessing the urgency of patients' treatment needs. The first step was an initial patient assessment by a health care professional (triage nurse). The introduction of this triage system was combined with information to the public on the "correct" use of emergency services. RESULTS: After implementation of the ABCDE triage system the number of patient visits to a primary care doctor decreased by up to 24% (962 visits/month) as compared to the three previous years in the EDs. The Number of visits to public sector GPs during office hours did not alter. Implementation of ABCDE-triage combined with public guidance was associated with decreased total number of doctor visits in public health care. During same period, the number of patient visits in the private health care increased. Simultaneously, the number of doctor visits in secondary health care ED did not alter. CONCLUSIONS: The present ABCDE-triage system combined with public guidance may reduce patient visits to primary health care EDs but not to the secondary health care EDs. Limiting the access of less urgent patients to ED may redirect the demands of patients to private sector rather than office hours GP services. PMID- 22217301 TI - Effectiveness of water treatment for the removal of Cryptosporidium and Giardia spp. AB - Cryptosporidium and Giardia are intestinal parasites of humans and of many other species of animals. Water constitutes an important route of transmission for human infections in both developed and developing countries. In Poland, contamination of water sources with oocysts/cysts is not routinely monitored and scientific research in this field is scarce. Our aim was to compare the contamination of surface and treated water and thus the success of water treatment processes. Water samples (n=94) of between 30 l (surface water) to over 1000 l for tap water, were taken in the period of 2008-2009 using specially constructed equipment with cartridge filtration (Filta-Max; IDEXX, USA). Immunofluorescent assay, and nested polymerase chain reaction were used for the detection of parasites. Cryptosporidium oocysts were found in 85% of surface water and in 59% of raw (intake) water samples. Oocysts were also detected in treated water (16%) but were absent in samples of swimming pool water. The highest mean number of Cryptosporidium oocysts [geometric mean (GM)=61/10 l] was found in samples of rinsing water. Giardia cysts were observed in 61% of surface water samples, in 6% of raw water and in 19% of treated water, with the highest number of cysts noted in rinsing water samples (GM=70 cysts/10 l). Our study highlights the frequent occurrence of parasites in surface waters in Poland and the effectiveness of water treatment for the removal of parasites from drinking water. PMID- 22217302 TI - RNA interference in plant parasitic nematodes: a summary of the current status. AB - SUMMARYRNA interference (RNAi) has emerged as an invaluable gene-silencing tool for functional analysis in a wide variety of organisms, particularly the free living model nematode Caenorhabditis elegans. An increasing number of studies have now described its application to plant parasitic nematodes. Genes expressed in a range of cell types are silenced when nematodes take up double stranded RNA (dsRNA) or short interfering RNAs (siRNAs) that elicit a systemic RNAi response. Despite many successful reports, there is still poor understanding of the range of factors that influence optimal gene silencing. Recent in vitro studies have highlighted significant variations in the RNAi phenotype that can occur with different dsRNA concentrations, construct size and duration of soaking. Discrepancies in methodology thwart efforts to reliably compare the efficacy of RNAi between different nematodes or target tissues. Nevertheless, RNAi has become an established experimental tool for plant parasitic nematodes and also offers the prospect of being developed into a novel control strategy when delivered from transgenic plants. PMID- 22217303 TI - Macrophage immunomodulating and antitumor activities of polysaccharides isolated from Agaricus bisporus white button mushrooms. AB - Agaricus bisporus white button mushroom (WBM) is widely consumed in most countries for its culinary properties. Recently, its dietary intake has been shown to protect against breast cancer. Mushroom polysaccharides are known for their immunomodulating and antitumor properties; however, little is known regarding the properties of A. bisporus polysaccharides. Using size-exclusion chromatography to fractionate the crude extract of A. bisporus, two polysaccharide fractions (designated as ABP-1 and ABP-2) were obtained. The estimated molecular masses of ABP-1 and ABP-2 were 2,000 kDa and 40-70 kDa, respectively, and their sugar compositions consisted mainly of glucose, mannose, xylose, and fructose. Analysis of the effects of the polysaccharides on murine macrophages demonstrated that both fractions stimulated the production of nitric oxide, interleukin-6, and tumor necrosis factor-alpha. Modulation of macrophage function by A. bisporus polysaccharides was mediated in part through activation of nuclear factor-kappaB with the production p50/105 heterodimers. Both ABP-1 and ABP-2 had the ability to inhibit the growth of human breast cancer MCF-7 cells but had little effect on the growth of human colon, prostate, gastric cancer, and murine Sarcoma 180 cells as assessed by a tetrazolium dye [3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide]-based assay. However, when murine Sarcoma 180 cells exposed to ABP-1 or ABP-2 were implanted subcutaneously into mice, a reduction in tumor growth was observed compared with that observed in control mice. Taken together, our data provide a molecular basis to explain in part the reported beneficial therapeutic effects of A. bisporus WBM intake and suggest that macrophages likely contribute to the antitumor effects of Agaricus polysaccharides. PMID- 22217304 TI - [Approaches to vitamin B12 deficiency]. AB - A 28-year-old female vegetarian was referred to a specialist in internal medicine with persistent iron deficiency. Laboratory analysis revealed microcytic anaemia with low ferritin levels but normal total vitamin B12 levels. The red blood cell distribution width, however, showed a very wide variation in red blood cell sizes, indicating a coexisting vitamin B12 deficiency, which was confirmed by the low concentration of active vitamin B12. Another patient, a 69-year-old woman with a history of previous gastric surgery and renal insufficiency as a complication of diabetes mellitus, was suspected to be deficient in vitamin B12, as she had low total vitamin B12 levels and an accumulation of methylmalonic acid and homocysteine in her blood. Testing the total concentration of vitamin B12 alone has insufficient diagnostic accuracy and no accepted gold standard is available for diagnosing vitamin B12 deficiency. With the development of newer tests, such as measuring holotranscobalamin II (concentration of active vitamin B12), atypical and subclinical deficiency states can be recognized. A new approach to diagnosing vitamin B12 deficiency is presented, based upon these 2 case descriptions. PMID- 22217305 TI - [An infant with meningitis caused by resistant pneumococcus: infection despite vaccination]. AB - BACKGROUND: Following the introduction of a heptavalent pneumococcal conjugate vaccine (PCV7) in the Netherlands in 2006, the incidence of invasive pneumococcal disease (IPD) declined significantly. Since then a shift towards non-vaccine serotype IPD has been noted. CASE DESCRIPTION: We present the case of multidrug resistant non-vaccine serotype 19A pneumococcal meningitis in a 5-month-old boy. He was admitted to our Paediatric Intensive Care Unit (PICU) with seizures and septic shock. A barbiturate-induced coma was eventually required to control the seizures; shock was combated with intravenous fluids and inotropes. He received a 6-week course of ceftriaxone and vancomycin. At follow-up, one year after discharge, he had unilateral deafness and minor developmental delay. CONCLUSION: Worldwide, pneumococcal serotype 19A is now the most common cause of IPD in children, with an increasing incidence of multidrug resistant strains. This trend has not yet been observed in the Netherlands. This case demonstrates that even following the introduction of PCV7 pneumococcal meningitis can still occur. Prompt recognition of the symptoms is still essential. PMID- 22217306 TI - [A woman with skin lesions in a tattoo]. AB - A healthy 32-year-old woman presented with red papules in tattoos on the right upper arm and right ankle as well as on non-tattooed skin of the right knee, existing since 3 months. Histopathological examination of skin biopsies showed granulomatous inflammation, suggestive for sarcoidosis. An X-ray and CT-scan of the thorax showed hilar lymphadenopathy suggestive of sarcoidosis. Skin lesions in tattoos can be the first symptom of systemic sarcoidosis. Further investigation in these cases is recommended. PMID- 22217307 TI - [An infant with sternal swelling]. AB - BACKGROUND: Sternal tumours in childhood are rare and alarming. These can be differentiated into benign and malignant tumours. This differentiation is important for the prevention of unnecessary diagnostic testing. CASE REPORT: An 11-month-old girl was seen at the Emergency Department for an acute sternal swelling without obvious trauma or fever. There were no other symptoms or abnormalities found on physical examination. An ultrasound revealed a typical 'dumb bell' sign. This finding, in combination with the clinical picture, indicated a 'self-limiting sternal tumour of childhood' (SELSTOC). Because of this diagnosis, the continuation of further examinations and treatment was abandoned and an expectative course was followed. The swelling completely disappeared within a few weeks. CONCLUSION: SELSTOC is a benign swelling on the sternum occurring in childhood, probably caused by aseptic inflammation. Its acute presentation is alarming and leads to over-diagnosing. However, the combination of the typical clinical presentation and the characteristic ultrasonographic dumb-bell sign justifies an expectative course. The abnormality resolves spontaneously within 6 months. PMID- 22217308 TI - [Drug-promoting advertisements in the Dutch Journal of Medicine and Pharmaceutical Weekly: not always evidence based]. AB - OBJECTIVE: To determine and compare the foundation of claims in drug-promoting advertisements in a Dutch journal for physicians and a Dutch journal for pharmacists. DESIGN: A cross-sectional study. METHOD: We included all the drug promoting advertisements referring to a randomized controlled trial (RCT) we could find on Medline from 2 volumes of the Dutch Journal of Medicine (Nederlands Tijdschrift voor Geneeskunde; NTvG) and the (also Dutch) Pharmaceutical Weekly (Pharmaceutisch Weekblad; PW). The validity of the advertisements (n = 54) and the methodological quality of the referenced RCTs (n = 150) were independently scored by 250 medical students using 2 standardised questionnaires. The advertisements' sources were concealed from the students. Per journal, the percentage of drug-promoting advertisements having a valid claim and the percentage of high-quality RCT references were determined. Average scores on quality and validity were compared between the 2 journals. RESULTS: On a scale of 0-18 points, the mean quality scores of the RCTs differed 0.3 (95% CI: -0.1-0.7) between the NTvG (score: 14.8; SD: 2.2) and the PW (score: 14.5; SD: 2.6). The difference between the validity scores of drug-promoting advertisements in the NTvG (score: 5.8; SD: 3.3) and the PW (score: 5.6; SD: 3.6) was 0.3 (95% CI: -0.3 0.9) on a scale of 0-10 points. For both journals, an average of 15% of drug promoting advertisements was valid (defined as a validity score of > 8 points); 35% of the RCTs referred to was of good methodological quality (defined as a quality score of > 16 points). CONCLUSION: The substantiation of many claims in drug-promoting advertisements in the NTvG and the PW was mediocre. There was no difference between the 2 journals. PMID- 22217309 TI - [Comprehensive geriatric assessment: unfeasible and undesirable]. AB - The new clinical practice guideline on Comprehensive Geriatric Assessment (CGA) issued by the Dutch Geriatrics Society aims to optimise the diagnostic strategy in secondary care geriatric patients in order to achieve a treatment plan that will retain self-reliance and quality of life of these patients for as long as possible. An extensive listing of all somatic, psychological and social factors that could affect the health and welfare of all frail patients forms the basis of this guideline. This is actually an essential goal for any patient, regardless of age and condition. Knowledge of the optimal diagnostic tests and therapy for elderly patients, and a financial evaluation of such assessments are still lacking. Moreover, it remains to be seen if such a thorough assessment by a medical specialist is feasible and desired. The authors suggest using the proposed CGA as a starting point for a broad discussion between geriatric specialists, other medical specialists and general practitioners before implementing this as a general guideline. PMID- 22217310 TI - [Syncope in childhood: not always vasovagal in origin]. AB - Two healthy children, a 10-year-old boy and a 13-year-old girl, both presented with a history of collapse. The boy had had multiple episodes of syncope over a 7 year period. He was diagnosed with reflex syncope on the basis of case history and diagnostic tests. The girl collapsed at school while resting. She was diagnosed with long QT syndrome and was treated with beta-blockers. After DNA testing both her mother (who had, in retrospect, been wrongly diagnosed with epilepsy), and her brother were also diagnosed with long QT syndrome. Syncope is a common complaint in children and adolescents. In most cases the cause is a benign reflex syncope, but potentially life threatening syncope caused by rare cardiac conditions does occur and needs to be recognized in both the patient and their family members (who may be asymptomatic). Benign reflex syncope and cardiac syncope can be distinguished by performing a thorough medical and family history, physical examination and ECG. PMID- 22217311 TI - [Virginia Apgar and her scale]. AB - Virginia Apgar (1909-1974), born in New Jersey, managed to continue medical school despite the financial crisis of 1929, continued for a brief time in surgery and subsequently became one of the first specialists in anaesthesiology. In 1949 she was appointed to a professorship, the first woman to reach this rank at Columbia University in New York. She then dedicated herself to obstetric anaesthesiology and devised the well known scale for the initial assessment of newborn babies, according to 5 criteria. From 1959 she worked for the National Foundation for Infantile Paralysis (now March of Dimes), to expand its activities from prevention of poliomyelitis to other aspects of preventive child care, such as rubella vaccination and testing for rhesus antagonism. She remained single; in her private life she enjoyed fly fishing, took lessons in aviation and was an accomplished violinist. PMID- 22217312 TI - [Chemoprevention of breast cancer: exemestane ready to be tested in study setting]. AB - Prevention of breast cancer is difficult, as most risk factors are difficult to control. Therefore, we have not been able to stop breast cancer incidence rates from rising over past decades. Chemoprevention using aromatase inhibitors, such as exemestane, may change this situation. Aromatase inhibitors are very effective and safe in preventing recurrent disease in postmenopausal breast cancer. A recent randomised placebo-controlled trial showed that in healthy women at moderately increased risk of breast cancer, use of exemestane over a 3-year period reduced the risk of breast cancer by 65%. The reduction was from 0.55% to 0.19% per year, with no adverse events or measurable effect on quality of life. If confirmed by larger studies with longer duration of follow-up, preventive use of exemestane may turn out to be the first acceptable alternative for women at increased risk of developing breast cancer. On a population level, implementation of prevention using aromatase inhibitors has the potential to reduce the incidence of breast cancer. However, currently in the Dutch population, 140 women would need to use exemestane for three years in order to prevent one invasive breast tumour. Therefore, large-scale implementation of exemestane is not advised, but the evidence is sufficient to start studies with exemestane. PMID- 22217313 TI - [Lyre and lancet: doctors as writers]. AB - Many medical doctors have become famous writers or poets. The two professions do have similarities: both have a professional preference for people in a crisis situation, both need to come close to their subject while maintaining a certain distance, the relationship between the individual and the general plays a central role in the practice of medicine and writing, writing and healing are similar in many ways and stories play an important role for both doctors and writers. We discuss these similarities in this article. PMID- 22217314 TI - A case report of a male patient with Hb Hammersmith [beta42(CD1)Phe->Ser, TTT>TCT]. AB - All Hb Hammersmith [beta42(CD1)Phe->Ser, TTT>TCT] patients reported so far have been female, suggesting that this condition may occur as a negative, fatal intrauterine selection against males. In this case report, we describe a male case of Hb Hammersmith. A 6-month-old male patient, born from ovum donation, presented with hemolytic anemia and cyanosis. Hemoglobin (Hb) electrophoresis revealed decreased Hb A (54.0%) and Hb A(2) (0.3%) and markedly increased Hb F (45.7%) levels. Direct sequencing revealed a missense mutation in the HBB gene, c.128T>C (p.Phe42Ser), which is known as Hb Hammersmith. This mutation was not identified in any of this patient's family members. This is the first case of Hb Hammersmith in a male patient, and this study demonstrates that Hb Hammersmith is likely a non fatal condition for males during the intrauterine period. PMID- 22217315 TI - An endogenous factor enhances ferulic acid decarboxylation catalyzed by phenolic acid decarboxylase from Candida guilliermondii. AB - The gene for a eukaryotic phenolic acid decarboxylase of Candida guilliermondii was cloned, sequenced, and expressed in Escherichia coli for the first time. The structural gene contained an open reading frame of 504 bp, corresponding to 168 amino acids with a calculated molecular mass of 19,828 Da. The deduced amino sequence exhibited low similarity to those of functional phenolic acid decarboxylases previously reported from bacteria with 25-39% identity and to those of PAD1 and FDC1 proteins from Saccharomyces cerevisiae with less than 14% identity. The C. guilliermondii phenolic acid decarboxylase converted the main substrates ferulic acid and p-coumaric acid to the respective corresponding products. Surprisingly, the ultrafiltrate (Mr 10,000-cut-off) of the cell-free extract of C. guilliermondii remarkably activated the ferulic acid decarboxylation by the purified enzyme, whereas it was almost without effect on the p-coumaric acid decarboxylation. Gel-filtration chromatography of the ultrafiltrate suggested that an endogenous amino thiol-like compound with a molecular weight greater than Mr 1,400 was responsible for the activation. PMID- 22217316 TI - The mental representation of the magnitude of symbolic and nonsymbolic ratios in adults. AB - This study mainly investigated the specificity of the processing of fraction magnitudes. Adults performed a magnitude-estimation task on fractions, the ratios of collections of dots, and the ratios of surface areas. Their performance on fractions was directly compared with that on nonsymbolic ratios. At odds with the hypothesis that the symbolic notation impedes the processing of the ratio magnitudes, the estimates were less variable and more accurate for fractions than for nonsymbolic ratios. This indicates that the symbolic notation activated a more precise mental representation than did the nonsymbolic ratios. This study also showed, for both fractions and the ratios of dot collections, that the larger the components the less precise the mental representation of the magnitude of the ratio. This effect suggests that the mental representation of the magnitude of the ratio was activated from the mental representation of the magnitude of the components and the processing of their numerical relation (indirect access). Finally, because most previous studies of fractions have used a numerical comparison task, we tested whether the mental representation of magnitude activated in the fraction-estimation task could also underlie performance in the fraction-comparison task. The subjective distance between the fractions to be compared was computed from the mean and the variability of the estimates. This distance was the best predictor of the time taken to compare the fractions, suggesting that the same approximate mental representation of the magnitude was activated in both tasks. PMID- 22217318 TI - Analysis of electron correlation effects and contributions of NMR J-couplings from occupied localized molecular orbitals. AB - NMR J-coupling calculations at the second-order of polarization propagator approach, SOPPA, are among the most reliable. They include a high percentage of the total electron correlation effects in saturated and unsaturated molecular systems. Furthermore, J-couplings are quite sensitive to the whole electronic molecular framework. We present in this article the first study of all three response mechanisms, Fermi contact, FC, spin-dipolar, SD and paramagnetic spin orbital, PSO, for J-couplings with occupied localized molecular orbitals at the SOPPA level of approach. Even though SOPPA results are not invariant under unitary transformations, the difference between results obtained with canonical and localized molecular orbitals, LMOs, are small enough to permit its application with confidence. The following small-size saturated and unsaturated compounds were analyzed: CH(4), CH(3)F, C(2)H(6), NH(3), C(2)H(4), CH(2)NH, H(2)C?CHF, and FHC?CHF. The local character of the FC mechanism that appears in J couplings of these molecular models is shown through the analysis of contributions from LMOs. The importance of including the electron correlation on the engaged bonding orbitals for one-bond couplings is emphasized. Almost all electron correlation effects are included in such orbitals. Interesting findings were the large contributions by s-type LMOs to the C-H and C-C J-couplings; they are responsible for the variation of (1)J(C-C) when going from ethane to ethene and to 1,2-difluoroethene. The previously proposed hyperconjugative transfer mechanism has been tested. Among other tests we found the difference anti-syn of one-bond (1)J(C-H) in imine as due to both the corresponding sigma(C-H) and the lone-pair, LP, contribution. Geminal and vicinal J-couplings were also analyzed. Our findings are in accord with a previous work by Pople and Bothner-by, who considered results taken from calculations or empirical data. For all geminal couplings the pattern of J-couplings, like the change of sign, is originated in the main bondings that participate in the coupling pathways. The finding of asymmetric contributions of LP to vicinal H-H couplings in imine is highlighted. The analysis of J-couplings by contributions from LMOs to the noncontact mechanisms, SD and PSO, show that the pi electronic framework makes both terms grow in the specific case of the model compounds studied here. The PSO mechanism is more efficient when a sigma bond is vicinal to a pi bond. We found in this way an efficient and powerful scheme to get a deeper insight on the electronic molecular framework on which J-couplings are transmitted. PMID- 22217319 TI - Negative electromagnetic plane-wave force in gain media. AB - It is shown that a uniform electromagnetic plane wave can exert a negative force on a homogeneous medium with gain when there is no component of the electric field in that direction. A physical interpretation for this force is given, along with an estimate of the strength achievable in an experiment. PMID- 22217320 TI - Mastoidectomy reconstruction of the posterior wall and obliteration (MAPRO): preliminary results. AB - CONCLUSIONS: Our preliminary results indicate that mastoidectomy by reconstruction of the posterior wall and obliteration (MAPRO) avoided the disadvantages of a canal-wall-down mastoidectomy. MAPRO effectively prevented cholesteatoma recurrence, provided an excellent basis for hearing restoration, and was generally water-safe. OBJECTIVE: To evaluate the authors' experience with the MAPRO technique for eradication of cholesteatomas requiring canal-wall-down mastoidectomy. METHODS: The medical files of all the patients who underwent MAPRO for cholesteatoma between 2008 and 2011 at the Sheba Medical Center were retrospectively reviewed. RESULTS: This series included 49 patients (31 children and 18 adults). The index operation was the first procedure for 30 patients and repeat surgery for 19 patients. Eight patients underwent ossiculoplasty. The mean postoperative follow-up was 28 months. Water tolerance and absence of inflammation were achieved in 93.3% of the first-time group and in 73.7% of the repeat group. (Recurrent cholesteatoma was found on the postoperative non-echo planar base diffusion-weighted magnetic resonance imaging in six (12.2%) patients: three (10%) in the first-time group and three (15.8%) in the repeat group). PMID- 22217321 TI - Association between C-reactive protein and cognitive deficits in elderly men and women: a meta-analysis. AB - BACKGROUND: Certain risk factors for cognitive decline appear modifiable. A potentially modifiable marker of inflammation, C-reactive protein may be associated with cognitive deficits, although not all studies have found a relationship between C-reactive protein and cognitive ability. Further, few research papers have examined whether gender may affect any association between C reactive protein and cognitive deficit. METHODS: To better understand the association between C-reactive protein, cognitive deficit, and gender in elderly people, we meta-analyzed cross-sectional studies that reported cognitive ability assessed by the Mini-Mental State Examination or an equivalent measure, C reactive protein concentrations, and gender. RESULTS: While we identified no studies containing only male subjects, the two identified studies containing both female and male subjects (n = 2,525) showed an effect size for cognition of 0.1809 (95% confidence interval, -0.2652 to -0.0967, p = 0.000025) between high and low C-reactive-protein groups. In contrast, the two identified studies containing only female subjects (n = 1,754) showed an effect size for cognition of 0.0345 (95% confidence interval, -0.0594 to 0.1285, not significant). CONCLUSIONS: In the context of a small number of source studies and lack of an all-male group, these results suggest that any association between C-reactive protein and cognitive deficits may be stronger in elderly men than in elderly women. PMID- 22217322 TI - Scale-up of community-based malaria control can be achieved without degrading community health workers' service quality: the Village Malaria Worker project in Cambodia. AB - BACKGROUND: Malaria control has been scaled up in many developing countries in their efforts to achieve the Millennium Development Goals. Cambodia recently scaled up their Village Malaria Worker (VMW) project by substantially increasing the number of VMWs and expanding the project's health services to include treatment of fever, diarrhoea, and Acute Respiratory Infections (ARI) in children under five. This study examined if the scale-up interfered with VMWs' service quality, actions, and knowledge of malaria control, and analysed VMWs' overall achievements and perceptions of the newly added health services. METHODS: Structured interviews were conducted pre scale-up in February-March 2008 with 251 VMWs and post scale-up in July-August 2010 with 252 VMWs. Comparing the pre and post scale-up survey results (n = 195), changes were examined in terms of VMWs' 1) service quality, 2) malaria prevention and vector control actions, and 3) knowledge of malaria epidemiology and vector ecology. In addition, VMWs' newly added health services were descriptively analysed based on the post scale-up survey (n = 252). RESULTS: VMWs' service quality and actions significantly improved overall during the scale-up of the VMW project (mean index score: +0.805, p < 0.001; +2.923, p < 0.001; respectively). Although most of knowledge areas also showed significant improvement (between +0.256 and +0.499, p < 0.001), less than half (10.3%-47.7%) of the VMWs correctly answered a set of questions on malaria epidemiology and vector ecology, even in the post scale-up survey. About 70% of the respondents reported that their health services to control malaria remained the same or that they were more active after the scale-up. Two-thirds (66.3%) had become more enthusiastic about serving as a VMW since the scale-up, and all but one respondent reported being willing to continue the new services. CONCLUSIONS: The Cambodian experience clearly demonstrated that a nationwide scale-up of community-based malaria control can be achieved without degrading community health workers' service quality. The government's strategy to expand VMWs' health services, while providing sufficient training to maintain the quality of their original malaria control services, could have contributed to the improvement of VMW's service quality, actions, and knowledge in spite of the rapid scale-up of the project. PMID- 22217323 TI - New examination of the performance of the MetaMax I metabolic analyser with the Douglas-bag technique. AB - PURPOSE: To examine the performance of the MetaMax(r) I metabolic analyser of Cortex Biophysik, running a recent version of the software (MetaSoft v. 1.11.05), using the Douglas-bag method as reference. EXPERIMENTS: First, 182 measurements of the maximal O(2) uptake on school children were analysed both by a former version of the software (MetaMax Analysis) and by a recent version (MetaSoft). In further experiments, seven grown-up subjects of different fitness levels cycled for 5 min at constant powers between 50 and 350 W while the O(2) uptake was measured simultaneously by the MetaMax I and the Douglas-bag method during the last minute of altogether 39 exercises. RESULTS: The calculated maximal O(2) uptake of the 182 school children was on average 3% lower when the data were reanalysed by MetaSoft than when analysed by the former version of the software. There was in addition a 2% variation. In further experiments on grown-up subjects the O(2) uptake reported by the MetaMax I did not differ from that reported by the Douglas-bag system when data for all subjects were pooled, and the random error was 4%. However, the relationships differed slightly between the subjects (p = 0.005), and consequently the random error within each subject was 2-3%. The respiratory exchange ratio (R-value) reported by the MetaMax I differed systematically from that of the control method. However, a reliable R-value could be calculated from the instrument's raw data. CONCLUSIONS: Our data suggest that the MetaMax I running MetaSoft reports unbiased values of the O(2) uptake and with moderate random error. PMID- 22217325 TI - Sensitive chemiluminescent imaging for chemoselective analysis of glycan expression on living cells using a multifunctional nanoprobe. AB - A novel sensitive chemiluminescent (CL) imaging method was developed for in situ monitoring of cell surface glycan expression through chemoselective labeling of carbohydrate motifs and then binding to a multifunctional nanoprobe. The nanoprobe was fabricated by assembling biotin-DNA and a large amount of horseradish peroxidase (HRP) on gold nanoparticles (AuNPs). The chemoselective labeling was performed by selective oxidization of the hydroxyl sites of sialyl and galactosyl groups on cell surfaces into aldehydes by periodate and galactose oxidase, respectively, and then aniline-catalyzed hydrazone ligation with biotin hydrazide for specific recognition to avidin. With the biotin-avidin system, the multifunctional nanoprobe could conveniently be bound to the glycan sites on the cell surface. The DNA chain presenting between the AuNPs and biotin assembled on the nanoprobe could obviate the steric effect, and HRP acted to trigger the CL emission of the luminal-H(2)O(2) system. Therefore the expression of both sialyl and galactosyl groups could be selectively monitored by CL imaging with high sensitivity due to the high amount of HRP. Using human liver cancer HCCC-9810 cells as a model, this CL imaging strategy could detect HCCC cells ranging from 6 * 10(2) to 1 * 10(7) cells mL(-1) with a detection limit down to 12 cells. More importantly, this method could be used for distinguishing cancer cells from normal cells and monitoring of dynamic carbohydrate expression on living cells, providing promising application in clinical diagnosis and treatment of cancer. PMID- 22217324 TI - Local delivery of chitosan/VEGF siRNA nanoplexes reduces angiogenesis and growth of breast cancer in vivo. AB - Vascular endothelial growth factor (VEGF) is the important angiogenic factor associated with tumor growth and metastasis in a wide variety of solid tumors. The aim of this study is to investigate the tumor suppressive effect of chitosan/small interfering RNA (siRNA)-VEGF nanoplexes in the rat breast cancer model. Chitosan/siRNA nanoplexes (siVEGF-A, siVEGFR-1, siVEGFR-2) and NRP-1 were prepared in a 15 to1 ratio and injected (intratumorally) into the breast-tumor bearing Sprague-Dawley rats. Tumor volumes were measured during 21 days. To investigate the effect of chitosan/siRNA nanoplexes on VEGF expression in tumors, VEGF was analyzed with immunohistochemistry and western blotting. The mRNA levels of VEGF in tumor samples were determined with real-time PCR (RT-PCR). After siRNA treatment, a marked reduction in tumor volumes was measured in complex-injected rats (97%). Free siRNA injection showed lower tumor inhibition. Reduction of VEGF protein was also shown with western blotting and immunohistochemistry. Similar results were obtained with RT-PCR also. These results indicate that the chitosan/siRNA targeting to VEGF nanoplexes have a remarkably suppressive effect on VEGF expression and tumor volume in breast cancer model of rats. PMID- 22217328 TI - Mycobacterium massiliense outbreak after intramuscular injection, South Korea. AB - SUMMARY We conducted an epidemic investigation to discover the route of transmission and the host factors of an outbreak of post-injection abscesses. Of the 2984 patients who visited a single clinic, 77 cases were identified and 208 age- and sex-matched controls were selected for analysis. Injected medications per se were not found to be responsible, and a deviation from safe injection practice suggested the likelihood of diluent contamination. Therefore the injected medications were classified according to whether there was a need for a diluent, and two medications showed a statistically significant association, i.e. injection with pheniramine [adjusted odds ratios (aOR) 5.93, 95% confidence interval (CI) 2.97-11.87] and ribostamycin (aOR 47.95, 95% CI 11.08-207.53). However, when considered concurrently, pheniramine lost statistical significance (aOR 8.71, 95% CI 0.44-171.61) suggesting that normal saline was the causative agent of this outbreak. Epidemiological evidence strongly suggested that this post-injection outbreak was caused by saline contaminated with Mycobacterium massiliense without direct microbiological evidence. PMID- 22217329 TI - Magnetic resonance imaging, computed tomography, and 68Ga-DOTATOC positron emission tomography for imaging skull base meningiomas with infracranial extension treated with stereotactic radiotherapy--a case series. AB - INTRODUCTION: Magnetic resonance imaging (MRI) and computed tomography (CT) with (68)Ga-DOTATOC positron emission tomography ((68)Ga-DOTATOC-PET) were compared retrospectively for their ability to delineate infracranial extension of skull base (SB) meningiomas treated with fractionated stereotactic radiotherapy. METHODS: Fifty patients with 56 meningiomas of the SB underwent MRI, CT, and (68)Ga-DOTATOC PET/CT prior to fractionated stereotactic radiotherapy. The study group consisted of 16 patients who had infracranial meningioma extension, visible on MRI +/- CT (MRI/CT) or PET, and were evaluated further. The respective findings were reviewed independently, analyzed with respect to correlations, and compared with each other. RESULTS: Within the study group, SB transgression was associated with bony changes visible by CT in 14 patients (81%). Tumorous changes of the foramen ovale and rotundum were evident in 13 and 8 cases, respectively, which were accompanied by skeletal muscular invasion in 8 lesions. We analysed six designated anatomical sites of the SB in each of the 16 patients. Of the 96 sites, 42 had infiltration that was delineable by MRI/CT and PET in 35 cases and by PET only in 7 cases. The mean infracranial volume that was delineable in PET was 10.1 +/- 10.6 cm(3), which was somewhat larger than the volume detectable in MRI/CT (8.4 +/- 7.9 cm(3)). CONCLUSIONS: (68)Ga-DOTATOC-PET allows detection and assessment of the extent of infracranial meningioma invasion. This method seems to be useful for planning fractionated stereotactic radiation when used in addition to conventional imaging modalities that are often inconclusive in the SB region. PMID- 22217330 TI - Photoinduced enhancement in the luminescence of hydrophilic quantum dots coated with photocleavable ligands. AB - In search of strategies to photoactivate the luminescence of semiconductor quantum dots, we devised a synthetic approach to attach photocleavable 2 nitrobenzyl groups to CdSe-ZnS core-shell quantum dots coated with hydrophilic polymeric ligands. The emission intensity of the resulting nanostructured constructs increases by more than 60% with the photolysis of the 2-nitrobenzyl appendages. Indeed, the photoinduced separation of the organic chromophores from the inorganic nanoparticles suppresses an electron-transfer pathway from the latter to the former and is mostly responsible for the luminescence enhancement. However, the thiol groups anchoring the polymeric envelope to the ZnS shell also contribute to the photoinduced emission increase. Presumably, their photooxidation eliminates defects on the nanoparticle surface and promotes the radiative deactivation of the excited quantum dots. This effect is fully reversible but its magnitude is only a fraction of the change caused by the photocleavage of the 2-nitrobenzyl groups. In addition, these particular quantum dots can cross the membrane of model cells and their luminescence increases by ~80% after the intracellular photocleavage of the 2-nitrobenzyl quenchers. Thus, photoswitchable luminescent constructs with biocompatible character can be assembled combining the established photochemistry of the 2-nitrobenzyl photocage with the outstanding photophysical properties of semiconductor quantum dots and the hydrophilic character of appropriate polymeric ligands. PMID- 22217331 TI - Epigenetic modulation of BRCA1 and BRCA2 gene expression by equol in breast cancer cell lines. AB - S-Equol is a metabolite resulting from the conversion of daidzein, a soya phyto oestrogen, by the gut microflora. The potential protective effects of equol in breast cancer are still under debate. Consequently, we investigated the effects of equol on DNA methylation of breast cancer susceptibility genes (BRCA1 and BRCA2) and oncosuppressors in breast cancer cell lines (MDA-MB-231 and MCF-7) and in a dystrophic breast cell line (MCF-10a) following exposure to S-equol (2 MUm) for 3 weeks. We demonstrated by quantitative analysis of methylated alleles a significant decrease in the methylation of the cytosine phosphate guanine (CpG) islands in the promoters of BRCA1 and BRCA2 after the S-equol treatment in MCF-7 and MDA-MB-231 cells and a trend in MCF-10a cells. We also showed that S-equol increases BRCA1 and BRCA2 protein expression in the nuclei and the cytoplasm in MCF-7, MDA-MB-231 and MCF-10a cell lines by immunohistochemistry. The increase in BRCA1 and BRCA2 proteins was also found after Western blotting in the studied cell lines. In summary, we demonstrated the demethylating effect of S-equol on the CpG islands inside the promoters of BRCA1 and BRCA2 genes, resulting in an increase in the level of expressed oncosuppressors in breast cancer cell lines. PMID- 22217332 TI - Possible role of EMID2 on nasal polyps pathogenesis in Korean asthma patients. AB - BACKGROUND: Since subepithelial fibrosis and protruded extracellular matrix are among the histological characteristics of polyps, the emilin/multimerin domain containing protein 2 (EMID2) gene is speculated to be involved in the presence of nasal polyps in asthma and aspirin-hypersensitive patients. METHODS: To investigate the association between EMID2 and nasal polyposis, 49 single nucleotide polymorphisms (SNPs) were genotyped in 467 asthmatics of Korean ancestry who were stratified further into 114 aspirin exacerbated respiratory disease (AERD) and 353 aspirin-tolerant asthma (ATA) subgroups. From pairwise comparison of the genotyped polymorphisms, 14 major haplotypes (frequency > 0.05) were inferred and selected for association analysis. Differences in the frequency distribution of EMID2 variations between polyp-positive cases and polyp-negative controls were determined using logistic analyses. RESULTS: Initially, 13 EMID2 variants were significantly associated with the presence of nasal polyps in the overall asthma group (P = 0.0008-0.05, OR = 0.54-1.32 using various modes of genetic inheritance). Although association signals from 12 variants disappeared after multiple testing corrections, the relationship between EMID2_BL1_ht2 and nasal polyposis remained significant via a codominant mechanism (P corr = 0.03). On the other hand, the nominal associations observed between the genetic variants tested for the presence of nasal polyps in AERD (P = 0.003-0.05, OR = 0.25-1.82) and ATA (P = 0.01-0.04, OR = 0.46-10.96) subgroups disappeared after multiple comparisons, suggesting lack of associations. CONCLUSIONS: These preliminary findings suggest that EMID2_BL1_ht2 may be a susceptibility marker of inflammation of the nasal passages among Korean asthma patients. PMID- 22217333 TI - Host-parasite associations and host-specificity in haemoparasites of reed bed passerines. AB - The host specificity and host sharing of avian haemoparasites (genera Haemoproteus and Plasmodium) is still poorly known, although they infect a large proportion of several studied bird populations. This study used molecular techniques to detect haemoparasites in marsh warblers and in other passerines that feed in reed beds, at 4 sites in Portugal. The host-specificity of the parasite lineages was analysed and compared with other cases described in the literature to assess whether apparent host specificity changes according to the studied system. Nine lineages of Haemoproteus and 15 of Plasmodium were found, of which only 10 Plasmodium were proven to have local transmission. Each lineage was confined to a distinct set of host species. The distribution of parasites in the host species was non-nested, meaning that specialist lineages did not always share hosts with generalists. The most prevalent lineages were those with a wider host range, indicating that the ability to infect more hosts will enhance a parasite's prevalence in its entire host range. We also found that in our areas, a specialist parasite (H. MW1) appears to have a more generalist character than described in the literature, suggesting that a parasite's apparent specialization can depend on the type of host species sampled. PMID- 22217335 TI - Editorial: US students' alcohol consumption: a downward trend, but increased concerns. PMID- 22217334 TI - The most critical unresolved issues associated with race, ethnicity, culture, and substance use. AB - This paper discusses the limitations of previous research on race, ethnicity, culture, and substance use. The study offers the following recommendations for future research in this area: (1) move beyond simple comparisons of mutually exclusive groups, (2) focus on the meaning of an ethnic label to the individual, (3) consider the complex interactions between an individual's cultural identity and the cultural context, (4) understand and acknowledge the researcher's inherent biases, and (5) translate research findings into practice and policy change. PMID- 22217336 TI - The neural substrates of social emotion perception and regulation are modulated by adult attachment style. AB - Adult attachment style (AAS) refers to individual differences in the way people experience and regulate their social relationships and corresponding emotions. Based on developmental and psychological research, it has been hypothesized that avoidant attachment style (AV) entails deactivating strategies in social contexts, whereas anxious attachment style (AX) involves hyper vigilance and up regulation mechanisms. However, the neural substrates of differences in social emotion regulation associated with AAS have not been systematically investigated. Here we used fMRI in 19 healthy adults to investigate the effect of AAS on the processing of pleasant or unpleasant social and nonsocial scenes. Participants were asked either to naturally attend (NAT), cognitively reappraise (REAP), or behaviorally suppress (ESUP) their emotional responses. Avoidantly attached participants showed increased prefrontal and anterior cingulate activation to social negative scenes when making spontaneous emotion judgments. They also exhibited persistent increases in dorsolateral prefrontal cortex and left amygdala activity for the same stimuli during reappraisal, as well as additional activation in supplementary motor area and ventral caudate during the suppression of social positive emotions. These results suggest that AV may imply less efficient reappraisal strategies to regulate social negative emotions, and lead to higher conflict or effortful control when suppression cannot be employed. In contrast, anxiously attached participants showed differential increases in the right amygdala and left parahippocampal cortex for social negative and positive stimuli, respectively, but only when making spontaneous emotion judgments. No effect of AX was found during down-regulation conditions. This suggests heightened arousal to negative information without difficulty in down-regulating emotions through cognitive re-evaluation or suppression. Taken together, these findings reveal for the first time the neural underpinnings of attachment-related differences in social emotion regulation. PMID- 22217338 TI - Secondary erythrocytosis due to compound homozygosity, but not compound heterozygosity, for Hb Luton and alpha-thalassemia: a family study. AB - We describe the hematological and clinical features of homozygous Hb Luton (OMIM 141800.0172), a high affinity alpha-globin variant that has not been previously described in the homozygous state. The proband was found to have a high hemoglobin (Hb) concentration following a routine blood count prior to a planned appendectomy at the age of 16 years. Investigation showed that she was homozygous for both Hb Luton [alpha89(FG1)His->Leu (CAC>CTC), a high oxygen affinity Hb)] and homozygous for alpha(+)-thalassemia (alpha(+)-thal), while her mother, maternal aunt and half-brother were heterozygous for these conditions. Further investigation showed that she also had Gilbert's disease and Raynaud's syndrome. As far as we are aware, this is also the first reported family with a subject homozygous for both Hb Luton and alpha-thal so that the proband has no nomal alpha-globin. The parents of the proband are first cousins and originate from Pakistan. PMID- 22217337 TI - Rapid release of retinal from a cone visual pigment following photoactivation. AB - As part of the visual cycle, the retinal chromophore in both rod and cone visual pigments undergoes reversible Schiff base hydrolysis and dissociation following photobleaching. We characterized light-activated release of retinal from a short wavelength-sensitive cone pigment (VCOP) in 0.1% dodecyl maltoside using fluorescence spectroscopy. The half-time (t(1/2)) of release of retinal from VCOP was 7.1 s, 250-fold faster than that of rhodopsin. VCOP exhibited pH-dependent release kinetics, with the t(1/2) decreasing from 23 to 4 s with the pH decreasing from 4.1 to 8, respectively. However, the Arrhenius activation energy (E(a)) for VCOP derived from kinetic measurements between 4 and 20 degrees C was 17.4 kcal/mol, similar to the value of 18.5 kcal/mol for rhodopsin. There was a small kinetic isotope (D(2)O) effect in VCOP, but this effect was smaller than that observed in rhodopsin. Mutation of the primary Schiff base counterion (VCOP(D108A)) produced a pigment with an unprotonated chromophore (lambda(max) = 360 nm) and dramatically slowed (t(1/2) ~ 6.8 min) light-dependent retinal release. Using homology modeling, a VCOP mutant with two substitutions (S85D and D108A) was designed to move the counterion one alpha-helical turn into the transmembrane region from the native position. This double mutant had a UV visible absorption spectrum consistent with a protonated Schiff base (lambda(max) = 420 nm). Moreover, the VCOP(S85D/D108A) mutant had retinal release kinetics (t(1/2) = 7 s) and an E(a) (18 kcal/mol) similar to those of the native pigment exhibiting no pH dependence. By contrast, the single mutant VCOP(S85D) had an ~3 fold decreased retinal release rate compared to that of the native pigment. Photoactivated VCOP(D108A) had kinetics comparable to those of a rhodopsin counterion mutant, Rho(E113Q), both requiring hydroxylamine to fully release retinal. These results demonstrate that the primary counterion of cone visual pigments is necessary for efficient Schiff base hydrolysis. We discuss how the large differences in retinal release rates between rod and cone visual pigments arise, not from inherent differences in the rate of Schiff base hydrolysis but rather from differences in the properties of noncovalent binding of the retinal chromophore to the protein. PMID- 22217339 TI - A systematic review of adverse events in the placebo arm of donepezil trials: the role of cognitive impairment. AB - BACKGROUND: In randomized clinical trials, adverse events (AEs) are reported for the drug under evaluation and compared with the placebo group. Patients who receive placebo treatment report a high frequency of AEs, but little is understood about the nature of these. No study has yet analyzed the level of cognitive impairment as a crucial aspect for the AEs reported by patients. METHODS: The rates of AEs reported by patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) in the placebo arms of donepezil trials were compared using a systematic review approach. PubMed was searched with the terms "MCI and donepezil" as well as "AD and donepezil" from January 1989 to December 2010. Nineteen studies fulfilled the selection criteria (3 MCI, n = 783; 16 AD, n = 2,059). RESULTS: An overall comparison of 81 categories of AEs in the placebo arm of MCI versus AD trials showed that patients in AD trials experienced a significantly higher number of AEs than patients in MCI trials (p < 0.001). CONCLUSIONS: This is the first study showing that AD patients may be at a greater risk of developing AEs than MCI patients. This may be related to a greater presence of somatic comorbidity predisposing them to express emotional distress as physical symptoms and/or to AD patients being frailer and therefore more susceptible to AEs. The phenomena we observed may be interpreted in terms of the "nocebo effect". PMID- 22217340 TI - Astragaloside IV inhibits apoptotic cell death in the guinea pig cochlea exposed to impulse noise. AB - CONCLUSION: The results suggest that the beneficial effect of astragaloside IV on impulse noise-induced hearing loss may be due to its ability to inhibit reactive oxygen species (ROS) and prevent apoptosis. OBJECTIVE: Astragaloside IV is the major active constituent of Astragalus membranaceus, which has been widely used for the treatment of diseases in China for its antioxidant properties. ROS and apoptosis are involved in damage induced by impulse noise trauma. We aimed to investigate if the beneficial effects of astragaloside IV on cochlea exposed to impulse noise are associated with the inhibition of ROS and the decrease in apoptosis. METHODS: 4-Hydroxynonenal (HNE) was used as the marker of ROS. Active caspase-3 (cas-3) served as a marker for apoptosis. 4HNE and cas-3 were determined immunohistochemically. Guinea pigs in the experimental group were administered astragaloside IV intragastrically. Auditory thresholds were assessed by sound-evoked auditory brainstem response (ABR) 72 h before and after exposure to impulse noise. RESULTS: The results showed that astragaloside IV significantly reduced ABR deficits, and decreased the expression of ROS and cas-3. PMID- 22217343 TI - Measuring irritable bowel syndrome severity--what for and how? PMID- 22217342 TI - HIF-1 activation induces doxorubicin resistance in MCF7 3-D spheroids via P glycoprotein expression: a potential model of the chemo-resistance of invasive micropapillary carcinoma of the breast. AB - BACKGROUND: Invasive micropapillary carcinoma (IMPC) of the breast is a distinct and aggressive variant of luminal type B breast cancer that does not respond to neoadjuvant chemotherapy. It is characterized by small pseudopapillary clusters of cancer cells with inverted cell polarity. To investigate whether hypoxia inducible factor-1 (HIF-1) activation may be related to the drug resistance described in this tumor, we used MCF7 cancer cells cultured as 3-D spheroids, which morphologically simulate IMPC cell clusters. METHODS: HIF-1 activation was measured by EMSA and ELISA in MCF7 3-D spheroids and MCF7 monolayers. Binding of HIF-1alpha to MDR-1 gene promoter and modulation of P-glycoprotein (Pgp) expression was evaluated by ChIP assay and FACS analysis, respectively. Intracellular doxorubicin retention was measured by spectrofluorimetric assay and drug cytotoxicity by annexin V-FITC measurement and caspase activity assay. RESULTS: In MCF7 3-D spheroids HIF-1 was activated and recruited to participate to the transcriptional activity of MDR-1 gene, coding for Pgp. In addition, Pgp expression on the surface of cells obtained from 3-D spheroids was increased. MCF7 3-D spheroids accumulate less doxorubicin and are less sensitive to its cytotoxic effects than MCF7 cells cultured as monolayer. Finally, HIF-1alpha inhibition either by incubating cells with 3-(5'-hydroxymethyl-2'-furyl)-1 benzylindazole (a widely used HIF-1alpha inhibitor) or by transfecting cells with specific siRNA for HIF-1alpha significantly decreased the expression of Pgp on the surface of cells and increased the intracellular doxorubicin accumulation in MCF7 3-D spheroids. CONCLUSIONS: MCF7 breast cancer cells cultured as 3-D spheroids are resistant to doxorubicin and this resistance is associated with an increased Pgp expression in the plasma membrane via activation of HIF-1. The same mechanism may be suggested for IMPC drug resistance. PMID- 22217344 TI - Translation, cultural adaptation and validation of a Spanish version of the Irritable Bowel Syndrome Severity Score. AB - BACKGROUND: the Irritable Bowel Syndrome Severity Score (IBSSS) is a questionnaire only available in English that classifies IBS patients according to the severity of their symptoms and can be used to guide and monitor the treatment. AIMS: to adapt and validate into Spanish the English version of the IBSSS questionnaire. METHODS: the Spanish version of the questionnaire was obtained through a process of translation-evaluation of the comprehensibility and back translation. In a later phase we evaluated the applicability(n = 15), reproducibility (n = 31) and sensitivity to change (n = 40) of the Spanish version of the questionnaire. Finally we evaluated an alternative version of the ISBSS using a numerical scoring system instead of the original analog visual scale (n = 40). RESULTS: the Spanish version of the IBSSS showed an excellent reproducibility (r = 0.81 for global score) and an adequate sensitivity to change: a decrease of 45 points or more identified worsening of IBS with a 70.6% sensitivity and 87.5% specificity; an increase of 45 points or more identified improvement of IBS with a 85.7% sensitivity and 87.5% specificity. The severity score was practically the same regardless of the scoring system used (r = 0.96). CONCLUSIONS: the Spanish version of the IBSSS is a reproducible tool that is able to identify relevant changes over the course of the disease. The use of a numerical scoring system is a valid alternative to the visual scale that improves the applicability of the questionnaire to situations when the written communication is limited or not possible. PMID- 22217345 TI - Thalidomide with peginterferon alfa-2b and ribavirin in the treatment of non responders genotype 1 chronic hepatitis C patients: proof of concept. AB - BACKGROUND: fewer than half of patients infected with hepatitis C virus (HCV) achieve sustained viral clearance after peginterferon alfa/ribavirin (Peg IFN/RBV) therapy. AIMS: thalidomide posses anti-inflammatory and immunomodulatory properties through inhibition of tumor necrosis factor and costimulatory effect on human CD8+ T cells. METHODS: we started a prospective, open label trial of retreatment of very-difficult-to-treat genotype 1 chronic hepatitis C patients (CHC) patients, who had failed to respond to the (Peg-IFN/RBV), with a triple therapy consisting in these same antivirals plus thalidomide 200 mg/day (the TRITAL study). RESULTS: none of the eleven patients fulfilling the inclusion criteria and included in the trial reached complete early virological response or sustained virological response. Viral load decline after 12 weeks of triple therapy thalidomide-based retreatment did not differ from viral dynamics during the first course. The triple therapy was well tolerated and only one patient developed mild bilateral neuropathy. CONCLUSIONS: thalidomide addition to standard therapy is tolerated and did not increase the SVR rate in very-difficult to-treat genotype 1 CHC patients. Different schedules are warranted to improve attempting retreatment of non responder CHC patients. PMID- 22217346 TI - Standard criteria versus Rosemont classification for EUS-diagnosis of chronic pancreatitis. AB - AIM: to study the possible differences in the final diagnosis of chronic pancreatitis by using standard classification described by Wiersema et al. and the new classification proposed recently by Rosemont. MATERIAL AND METHODS: forty seven patients with the diagnosis of chronic pancreatitis were included in this study. The parenchymal and ductal criteria were studied, the patients were divided in two groups for Wiersema criteria: < 4 criteria, non-diagnostic for chronic pancreatitis and >= 4 criteria, diagnosis of chronic pancreatitis. The same patients were divided in four groups according to Rosemont classification: normal pancreas, indeterminate, suggestive and consistent with chronic pancreatitis. We analyzed these data with Chisquare test reported with 95% confidence intervals (CI). RESULTS: in patients with chronic pancreatitis the most frequent criteria observed were lobularity in 66% of cases and pancreatic duct dilatation and calcifications in 57.4% of cases each. We found a significant statistical association between the results of both classifications (p < 0.05). The highest association is found in patients with more than 4 standard criteria and definitive diagnostic of chronic pancreatitis according to Rosemont classification. In patients who have less than 4 standard criteria the diagnosis is suggestive of chronic pancreatitis by using the Rosemont classification in 27.66% (p < 0.05). CONCLUSION: these results show that no significant statistical differences are found for patients with > 4 criteria diagnosis by standard criteria. But 27.66% patients with less than 4 standard criteria would be suggestive according to Rosemont classification (p < 0.05). Hence, the new classification would be useful in patients with high suspicion of chronic pancreatitis with < 4 standard criteria but with more significance such as parenchymal lithiasis, lobularity or ductal calcifications. PMID- 22217347 TI - Epidermal growth factor receptor overexpression/amplification in adenocarcinomas arising in the gastrointestinal tract. AB - INTRODUCTION: it has been suggested that EGFR might be valuable to select patients for immunotherapy for various types of cancers. AIMS: we investigated: a) the gene/proteins alterations in gastrointestinal cancers using immunohistochemistry (IHC) (gene overexpression) and fluorescence in situ hybridisation (FISH) (gene amplification); and b) the associations between EGFR overexpression and amplification and chromosome 7 aneusomy (CEP7) in these cancers. METHODS: 64 tumor specimens were evaluated by IHC and FISH: 17 adenocarcinoma arising in Barrett's esophagus, 21 stomach cancers, 17 colon cancers, and 9 liver metastasis of colon carcinoma. IHC for EGFR was scored at 4 levels of intensity of membrane staining. EGFR gene in FISH was considered as amplified or not and chromosome 7 (where EGFR is located) as polysomic or disomic. The ratio between EGFR gene and chromosome 7 was performed by FISH and classified the case as gene amplification when the ratio was > 2. Polisomy was identified when the copies of chromosome 7 were > 2 in more than 8% malignant cells. RESULTS: no difference was found between EGFR gene amplification/protein overexpression according to cancer site. Concerning IHC, most cases were positive for EGFR intensity (84.4%), while only 50% of cases were positive considering a cut-off of 10%. EGFR FISH amplification was found in 4 cases only (6.2%) and FISH CEP7aneusomy in 40.6%. A statistically significant association was found between EGFR protein positivity (IHC) in term of intensity and EGFR gene amplification by FISH (p = 0.003), and between the EGFR protein positivity (IHC) and chromosome 7 aneusomy (FISH) (p = 0.004). CONCLUSIONS: EGFR amplification assessed by FISH was found in only 4 cases (6.2%) while chromosome 7 aneusomy was identified in 26 (40.6%) cases. IHC proved that EGFR protein overexpression in gastrointestinal cancers is common but FISH assessment showed that EGFR gene amplification is rare. An association was observed between EGFR gene amplification and EGFR protein overexpression in a low number of cases (p = 0.003). A statistically significant association was found between EGFR protein overexpression and chromosome 7 polysomy (p = 0.004). PMID- 22217348 TI - Defining functional dyspepsia. AB - Dyspepsia and functional dyspepsia represent a highly significant public health issue. A good definition of dyspepsia is key for helping us to better approach symptoms, decision making, and therapy indications.During the last few years many attempts were made at establishing a definition of dyspepsia. Results were little successful on most occasions, and clear discrepancies arose on whether symptoms should be associated with digestion, which types of symptoms were to be included, which anatomic location should symptoms have, etc.The Rome III Committee defined dyspepsia as "a symptom or set of symptoms that most physicians consider to originate from the gastroduodenal area", including the following: postprandial heaviness, early satiety, and epigastric pain or burning. Two new entities were defined: a) food-induced dyspeptic symptoms (postprandial distress syndrome); and b) epigastric pain (epigastric pain syndrome). These and other definitions have shown both strengths and weaknesses. At times they have been much too complex, at times much too simple; furthermore, they have commonly erred on the side of being inaccurate and impractical. On the other hand, some (the most recent ones) are difficult to translate into the Spanish language. In a meeting of gastroenterologists with a special interest in digestive functional disorders, the various aspects of dyspepsia definition were discussed and put to the vote, and the following conclusions were arrived at: dyspepsia is defined as a set of symptoms, either related or unrelated to food ingestion, localized on the upper half of the abdomen. They include: a) epigastric discomfort (as a category of severity) or pain; b) postprandial heaviness; and c) early satiety. Associated complaints include: nausea, belching, bloating, and epigastric burn (heartburn). All these must be scored according to severity and frequency. Furthermore, psychological factors may be involved in the origin of functional dyspepsia. On the other hand, it has proven very difficult to establish a clear correlation between symptoms and pathophysiological mechanisms. PMID- 22217349 TI - Iatrogenic esophageal perforation sealed by means of a self-expanding metal stent. PMID- 22217350 TI - Successfully endovascular resolution of iatrogenic right hepatic artery pseudoaneurysm. PMID- 22217351 TI - Cavitating mesenteric lymph node syndrome: a rare complication of celiac disease. AB - Among the many complications of celiac disease, mesenteric lymph node syndrome cavitated is considered one of the rarest, there is few case series published in the literature. The etiology and pathophysiology are unknown but because of its high mortality rate, estimated to be around 50%, it should recognize at an early stage in order to institute appropriate therapy as soon as possible. PMID- 22217352 TI - [Autoinmune pancreatitis]. PMID- 22217353 TI - Gallbladder volvulus: clinical presentation mimicking acute appendicitis of the elderly. PMID- 22217354 TI - Well differentiated giant retroperitoneal liposarcoma during the pregnancy. PMID- 22217355 TI - Liver abscess mimicking colon cancer. PMID- 22217357 TI - Primary intestinal lymphoma associated with Crohn's disease. PMID- 22217356 TI - Gastric metastasis from renal cancer six years after nephrectomy. PMID- 22217358 TI - Treatment of achalasia with botulinum toxin injection guided by endoscopic ultrasonography in a patient with esophageal varices. PMID- 22217359 TI - Tumor necrosis factor alpha release in peripheral blood mononuclear cells of cutaneous lupus and dermatomyositis patients. AB - INTRODUCTION: Several studies have reported that TNFalpha is substantially increased within skin lesions of patients with discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE) and dermatomyositis (DM) compared to controls. Elevated TNFalpha has been reported in the sera of some patients with systemic lupus erythematosus, DLE and SCLE, but not in the sera of patients with DM. Because of the key pathogenic role of autoimmunity in these diseases, in this study we sought to evaluate TNFalpha production by a readily available source of immune cells (namely, peripheral blood mononuclear cells (PBMCs)) taken from controls and from patients with cutaneous lupus or DM. METHODS: Freshly isolated PBMCs were cultured overnight, and TNFalpha protein accumulation in conditioned medium was determined. In addition, flow cytometry using cell-type specific markers was performed to determine the sources of TNFalpha. One-way analysis of variance and Dunnett's multiple comparisons test were performed for statistical comparisons. RESULTS: Accumulation of TNFalpha protein in conditioned medium containing PBMCs from DLE patients, but not from SCLE, TLE or DM patients, was significantly greater (19-fold) than that from controls (P < 0.001). In DLE PBMCs, increased TNFalpha was produced by circulating monocytes and myeloid dendritic cells (mDCs). The mean TNFalpha fluorescence intensity, but not the total number, of both monocytes and mDCs (P < 0.01) from DLE patients was significantly greater (2.3-fold) than that of controls. There were significantly more (13.3-fold) mDCs with intracellular TNFalpha in blood from DLE patients (P < 0.001) and DM patients (P < 0.001) compared to controls. Most importantly, a positive correlation was seen in DLE patients between their disease activity measured using the Cutaneous Lupus Erythematosus Disease Area and Severity Index and TNFalpha protein secretion (r = 0.61, P < 0.08). CONCLUSIONS: TNFalpha protein production by PBMCs is greater in DLE patients than in patients with other cutaneous forms of lupus and DM or in controls. Flow cytometric studies demonstrated that circulating monocytes and mDCs contributed to this increased TNFalpha production. Monocytes and mDCs are present in lesional skin, and the increased TNFalpha production by these cells and other PBMCs likely increase the number of inflammatory cells seen in DLE skin relative to other subsets of cutaneous lupus erythematosus and DM. These results provide a possible biological explanation for the denser infiltrate seen in DLE relative to DM. PMID- 22217360 TI - Effect of pre-weaning concentrate supplementation on peripheral distribution of leukocytes, functional activity of neutrophils, acute phase protein and behavioural responses of abruptly weaned and housed beef calves. AB - BACKGROUND: The effect of pre-weaning concentrate supplementation on peripheral distribution of leukocytes, functional activity of neutrophils, acute phase protein response, metabolic and behavioural response, and performance of abruptly weaned and housed beef calves was investigated. Calves were grazed with their dams until the end of the grazing season when they were weaned and housed (day (d) 0) in a concrete slatted floor shed, and offered grass silage ad libitum plus supplementary concentrates. Twenty-six days prior to weaning and housing, 20 singled suckled, pure-bred Simmental male (non-castrated), (n = 10, m) and female (n = 10, f) calves were assigned to one of two treatments (i) concentrate supplement (CS: n = 10 (5 m and 5 f), mean age (s.d.) 201 (12.8) d, mean weight (s.d.) 258 (20.2) kg) or (ii) no concentrate supplement (controls) (NCS: n = 10, (5 m and 5 f), mean age (s.d.) 201 (13.4) d, mean weight (s.d.) 257 (19.6) kg) pre-weaning. RESULTS: There was a treatment * sampling time interaction (P < 0.05) for percentage CD4+ and WC1+ (gammadelta T cells) lymphocytes and concentration of plasma globulin. On d 2, percentage CD4+ lymphocytes decreased (P < 0.001) in both treatments. Subsequently on d 7, percentage of CD4+ lymphocytes increased (P < 0.01) in CS compared with d 0, whereas percentage of CD4+ lymphocytes in NCS did not differ (P > 0.05) from d 0. On d 2, WC1+ lymphocytes decreased (P < 0.05) in both treatments but the decrease was greater (P <0.05) in NCS than CS. Subsequently, percentages did not differ (P > 0.05) from pre-weaning baseline. On d 2, the increase in concentration of globulin was greater (P < 0.05) in CS compared with NCS, and subsequently there was no difference between treatments. Pre-weaning ADG was 1.07 (s.e.m.) (0.26) kg and 0.99 (s.e.m.) (0.26) kg for CS and NCS, respectively. Post-weaning, CS calves spent more time lying compared with NCS calves. CONCLUSIONS: Calves supplemented with concentrate prior to weaning had a lesser reduction in WC1+ lymphocytes, increased percentage CD4+ lymphocytes and concentration of total protein, and spent more time lying post-weaning, compared with non-supplemented calves. PMID- 22217361 TI - Structure and physical properties of starch/poly vinyl alcohol/laponite RD nanocomposite films. AB - Nanocomposites of starch, poly vinyl alcohol (PVOH), and laponite RD (LRD) were produced by solution mixing and cast into films. In general, an increase in LRD content (0-20%) enhanced tensile strength and decreased water vapor permeability, irrespective of the relative humidity (50% and 75% RH). Tensile strength (TS) of starch/PVOH/LRD films ranged from 6.51 to 13.3 MPa. At 75% RH, TS was up to 65% higher as compared to films with sodium montmorillonite as filler. The most striking results were obtained with respect to elongation at break (E%), which ranged from 144% to 312%. Contrary to other polymer/clay nanocomposites, E% increased on addition of 5-20% LRD and was up to 175% higher than the control without clay. Nanocomposite structure and interactions were investigated using X ray diffraction, transmission electron microscopy, and differential scanning calorimetry. Results indicated that LRD was a compatibilizer and cross-linking agent between polymers, and has the potential for use in biodegradable packaging films with good mechanical performance even in high humidity conditions. PMID- 22217364 TI - Association of methylentetraydrofolate reductase (MTHFR) 677 C > T gene polymorphism and homocysteine levels in psoriasis vulgaris patients from Malaysia: a case-control study. AB - BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) enzyme catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and methyl donors. The methyl donors are required for the conversion of homocysteine to methionine. Mutation of MTHFR 677 C > T disrupts its thermostability therefore leads to defective enzyme activities and dysregulation of homocysteine levels. METHODS: This case-control study (n = 367) was conducted to investigate the correlation of the MTHFR gene polymorphism [NM_005957] and psoriasis vulgaris amongst the Malaysian population. Overnight fasting blood samples were collected from a subgroup of consented psoriasis vulgaris patients and matched controls (n = 84) for the quantification of homocysteine, vitamin B12 and folic acid levels. RESULTS: There was no significant increase of the MTHFR 677 C > T mutation in patients with psoriasis vulgaris compared with controls (chi(2) = 0.733, p = 0.392). No significant association between homocysteine levels and MTHFR gene polymorphism in cases and controls were observed (F = 0.91, df = 3, 80, p = 0.44). However, homocysteine levels in cases were negatively correlated with vitamin B12 (r = -0.173) and folic acid (r = -0.345) levels. Vitamin B12 and folic acid levels in cases were also negatively correlated (r = -0.164). CONCLUSIONS: Our results indicate that there was no significant association between the MTHFR gene polymorphism and psoriasis vulgaris in the Malaysian population. There was no significant increase of the plasma homocysteine level in the psoriasis patients compared to the controls. PMID- 22217365 TI - Optimized electrocardiographic criteria for prior inferior and anterior myocardial infarction. AB - BACKGROUND AND PURPOSE: The first purpose of the study was to optimize empirically the detection of prior inferior myocardial infarction (IMI) and prior anterior myocardial infarction (AMI) by electrocardiogram (ECG). The second purpose was to compare the diagnostic performances of the new criteria with those of 3 widely used commercial diagnostic ECG algorithms. MATERIALS AND METHODS: We analyzed the digital ECG data from 1138 subjects with suspected coronary artery disease in whom the presence or absence of prior IMI or AMI was documented by coronary angiography and left ventriculography. We used receiver operating characteristic curves to develop the new criteria for prior IMI and AMI using a training set of 562 subjects and then tested their diagnostic performances using a separate test set of 576 subjects. In both the training and test sets, we used chi(2) test to compare the performances of the new criteria with those of 3 commercial computerized diagnostic algorithms. RESULTS: The best criterion for prior IMI was the algebraic sum of the Q and T amplitudes in leads III and aVF. Its sensitivities/specificities were 71%/98% and 74%/98% in the training and test sets, respectively. The best criterion for prior AMI was the algebraic sum of the Q, R, and T amplitudes minus the Q duration in leads V(2), V(3), and V(4). Its sensitivities/specificities were 68%/98% and 65%/98% in the training and test sets, respectively. In both the training and test sets, these diagnostic performances were generally superior to those of the 3 commercial algorithms. CONCLUSIONS: Using digital ECG data, we developed and tested new criteria for prior IMI and AMI whose diagnostic performances are generally superior to each of 3 widely used commercial ECG diagnostic algorithms. PMID- 22217366 TI - Prognostic value of high sensitive C-reactive protein in subjects with silent myocardial ischemia. AB - OBJECTIVES: The aim of this study was to evaluate the prognostic value of high sensitive C-reactive protein (CRP) in subjects with silent myocardial ischemia (SMI). DESIGN: In total, 678 healthy men and women aged 55 to 75 years with no history of cardiovascular disease or stroke were included. High-sensitive CRP and 48-hour ambulatory ECG monitoring were performed. The primary endpoint was the combined endpoint of death and myocardial infarction. RESULTS: The median follow up time was 76 months. Seventy-seven subjects (11.4%) had SMI. The combined endpoint occurred in 26% of the subjects with SMI and 14% of the subjects without SMI (P = .005). SMI had a poor prognosis in the group with an elevated CRP >= 3.0 MUg/mL (hazard ratio, 3.46; 95% confidence interval, 1.67-7.16; P = .001) compared with the group of subjects with SMI and a low CRP <3.0 MUg/mL (hazard ratio, 1.37; 95% confidence interval, 0.63-2.98; P = .54). CONCLUSIONS: In apparently healthy subjects, a low level of CRP <3.0 MUg/mL selects a low-risk subgroup, despite the presence of SMI. PMID- 22217367 TI - Acute myocardial infarction with isolated conus branch occlusion. AB - There are few reports of acute myocardial infarction (AMI) relating to the occlusion of the conus branch, most of which are iatrogenic in nature. So far as we are concerned, this is the first case of spontaneous AMI with isolated conus branch occlusion. Electrocardiogram (ECG) showed mild elevation of ST segment in leads V(1) through V(3). Cardiac makers of myocardial infarction were positive. Right coronary angiography revealed an isolated occlusion of the conus branch. Penetration of the guidewire in the occluded lesion was attempted, and recanalization was successfully achieved. The patient was discharged without any adverse events. PMID- 22217369 TI - Laboratory-based surveillance of Campylobacter and Salmonella infection and the importance of denominator data. AB - Laboratory data are the cornerstone in surveillance of infectious disease. We investigated whether changes in reported incidence of Campylobacter and Salmonella infection might be explained by changes in stool sampling rates. Data were extracted from a national database on 585 843 patient stool samples tested by microbiology laboratories in Wales between 1998 and 2008. Salmonella incidence fell from 43 to 19 episodes/100 000 population but Campylobacter incidence after declining from 111/100 000 in 1998 to 84/100 000 in 2003 rose to 119/100 000 in 2008. The proportion of the population sampled rose from 2.0% in 1998 to 2.8% in 2008, mostly due to increases in samples from hospital patients and older adults. The proportion of positive samples declined for both Salmonella and Campylobacter from 3.1% to 1.1% and from 8.9% to 7.5%, respectively. The decline in Salmonella incidence is so substantial that it is not masked even by increased stool sampling, but the recent rise in Campylobacter incidence may be a surveillance artefact largely due to the increase in stool sampling in older people. PMID- 22217370 TI - Thyroid resurgery. PMID- 22217371 TI - Recurrent varicose veins of the lower limbs after surgery. Role of surgical technique (stripping vs. CHIVA) and surgeon's experience. AB - BACKGROUND: Surgical treatment of varicose veins of the lower limbs resolves symptoms and improves quality of life. However, the high recurrence (20-80%) is a costly and complex issue. PATIENTS AND METHODS: This is a retrospective review of 1489 patients with varicose vein of the lower limbs seen at our hospital between January 1980 and December 2005. The aim is to evaluate the effect of surgical technique (stripping vs. CHIVA) and surgeon's experience in reducing recurrences. RESULTS: With experienced surgeons, CHIVA appears to be more effective than stripping in reducing the recurrence rate (p <0.05). However, when performed by an inexperienced surgeon the results are far worse than those achieved with stripping. CONCLUSION: There was a clear reduction in recurrences at 5-10 years with CHIVA than with conventional stripping. However, if performed incorrectly, results are far worse with CHIVA. In fact, good results are far more difficult to achieve with CHIVA than with stripping, which is repeatable and easy to perform. PMID- 22217372 TI - Transmyocardial laser revascularization. Personal experience. AB - BACKGROUND: Indirect revascularization is a therapeutic approach in case of severe angina not suitable for percutaneous or surgical revascularization. Transmyocardial revascularization (TMR) is one of the techniques used for indirect revascularization and it allows to create transmyocardial channels by a laser energy bundle delivered on left ventricular epicardial surface. Benefits of the procedure are related mainly to the angiogenesis caused by inflammation and secondly to the destruction of the nervous fibers of the heart. PATIENTS AND METHOD: From September 1996 up to July 1997, 14 patients (9 males - 66.7%, mean age 64.8+/-7.9 years) underwent TMR. All patients referred angina at rest; Canadian Angina Class was IV in 7 patients (58.3%), III in 5 (41.7%). Before the enrollment, coronarography was routinely performed to find out the feasibility of Coronary Artery Bypass Graft (CABG): 13 patients (91,6%) had coronary arteries lesions not suitable for direct revascularization; this condition was limited only to postero-lateral area in one patient submitted to combined TMR + CABG procedures. RESULTS: Mean discharge time was 3,2+/-1,3 days after surgery. All patients were discharged in good clinical conditions. Perfusion thallium scintigraphy was performed in 7 patients at a mean follow-up of 4+/-2 months, showing in all but one an improvement of perfusion defects. Moreover an exercise treadmill improvement was observed in the same patients and all of them are in good clinical conditions, with significantly reduced use of active drugs. CONCLUSION; Our experience confirms that TMR is a safe and feasible procedure and it offers a therapeutic solution in case of untreatable angina. Moreover, it could be a hybrid approach for patients undergoing CABGs in case of absence of vessels suitable for surgical approach in limited areas of the heart. PMID- 22217373 TI - Unusual case of abdominal pain following liver transplant: causality or casualty? AB - This is an unusual case of chronic abdominal pain following two liver transplants with at least three potential causes: traumatic neuroma, intussusception of the small bowel of the Roux loop and biliary cast. Surgical removal of the latter two factors led to resolution of the pain. The management of the clinical case is discussed. PMID- 22217374 TI - Spontaneous rupture of a giant hepatic hemangioma. Sequential treatment with preoperative transcatheter arterial embolization and conservative hepatectomy. AB - Hemangioma is the most common benign tumor of the liver and it is often asymptomatic. Spontaneous rupture of liver hemangiomas is a rare but potentially lethal complication. Emergent hepatic resection has been the treatment of choice but carries high operative morbidity and mortality. Recently, preoperative transcatheter arterial embolization (TAE) has been used successfully for the management of bleeding ruptured liver tumors and non-operative treatment of symptomatic giant liver hemangiomas. We report a case of spontaneous rupture of a giant hepatic hemangioma that presented with thoracic and abdominal pain and shock due to hemoperitoneum. Once proper diagnosis was made the patient was successfully managed by TAE, followed by conservative hepatic resection. PMID- 22217375 TI - Pneumothorax in the Emergency Room: personal caseload. AB - The aim of this study was to collect information on the incidence, pathophysiology, treatment and mortality of pneumothorax in the Emergency Room. Pneumothorax is classified as spontaneous (primary, secondary or catamenial) or traumatic (iatrogenic or secondary to a blunt or penetrating chest injury). Between January 2007 and December 2009, 102 patients with pneumothorax were seen in our Emergency Room. Their records were examined and their data collected retrospectively. The type and side of the pneumothorax and age, sex, incidence and mortality were analyzed. The cases, involving 93 males and 9 females, broke down as follows: 68 spontaneous (66.7%), 33 traumatic (32.3%) and one iatrogenic (0.98%). The mean age was 47.3 (range 12-99); the incidence was 0.10%. There were no deaths due to pneumothorax in the Emergency Room. Traumatic pneumothorax was associated with blunt chest trauma, pleural effusion, hemothorax, cranial trauma, fractured collarbone, upper and lower limb fracture, pelvic fracture, vertebral and spinal trauma, sternum fracture and abdominal trauma. Pneumothorax is a common clinical problem. A multidisciplinary approach is essential to reduce the risk of morbidity and mortality. The incidence of pneumothorax in the Emergency Room was similar to that reported in the literature, while mortality data cannot be compared due to the lack of published studies. PMID- 22217376 TI - "Syndrome in syndrome": Wernicke syndrome due to afferent loop syndrome. Case report and review of the literature. AB - Wernicke syndrome is a rare neurological pathology due to a deficit in vitamin B1. The syndrome is common among alcohol abusers, patients with malignant tumor or gastrointestinal diseases, those who undergo hemodialysis or long-term peritoneal dialysis, pregnant women with hyperemesis, women who breast-feed, patients with hyperthyroidism or anorexia nervosa or gastric or jejunal-ileal bypass surgery for obesity, patients submitted to gastric surgery or prolonged total parenteral nutrition or prolonged intravenous therapy. We report a case of Wernicke syndrome due to afferent loop syndrome characterized by incoercible vomiting. PMID- 22217377 TI - Multicystic nephroma in an elderly man. Case report. AB - Multicystic nephroma is a relatively rare tumor of the kidney presenting unclear histological origin. Abdominal mass is a common onset sign in children while abdominal flank pain or abdominal discomfort, hematuria and recurrent urinary tract infections usually affect adults. Preoperative diagnosis is impossible especially in the adult variant of the tumor where clear cells carcinoma with cystic degeneration must always be suspected. We herein report a case of a 77 year old man complaining of flank abdominal pain and recurrent episodes of urinary tract infection due to a right-sided multicystic nephroma successfully treated with nephrectomy. PMID- 22217378 TI - Mucocele of the appendix. Two case reports. AB - The authors present two cases of mucocele of the appendix and discuss them in relation to the literature and the clinical features of this disease. They clarify the definition of mucocele as an intraluminal accumulation of mucus in the appendix, and concentrate on the observable pathological processes, agreeing on the higher frequency of mucinous cystadenoma and the possibility that mucocele can develop into peritoneal pseudomyxoma or degenerate into cystadenocarcinoma. They also note that most diagnoses are made intra-operatively during appendectomy, and that, in cases suspected preoperatively, thorough investigation with imaging techniques is very important in order to plan the best treatment. PMID- 22217379 TI - Intestinal obstruction by giant Meckel's diverticulum. Case report. AB - Most cases of Meckel's diverticulum (MD) are asymptomatic and discovered by chance. Management of MD is controversial. The authors describe an exceptional case of intestinal obstruction caused by a giant MD in a patient who had previously undergone appendectomy. A review of the contradictory literature on this subject leads to the conclusion that careful consideration of clinical and morphological data (patient's age, ASA score, the surgical procedure to be performed, morphology and position of the MD, any fibrotic bands) is required before deciding whether or not to resect an asymptomatic MD. PMID- 22217380 TI - Dynamic self-regulating prosthesis in inguinal hernia repair. AB - Inguinal hernia repair is one of the most common surgical procedure performed in Western countries and it consumes a lot of healthcare resources. Several types of different mesh are now disposable and tension-free techniques represent the "golden standard". In our study, fifty male patients were operated on for inguinal hernia and a PAD (i.e., dynamic self-regulating prosthesis) used for the repair of the inguinal defect: this technique demonstrated to be safe, effective and easy to perform. PMID- 22217381 TI - Surgical technique to avoid bladder flap formation during cesarean section. AB - Cesarean section (CS) is now the most common major surgical procedure performed on women worldwide. A CS can be performed by either suturing or not suturing of the visceral peritoneum. Creation of the bladder flap is an integral step of the standard cesarean section. The bladder flap is made by superficially incising and dissecting the peritoneal lining to separate the urinary bladder from the lower uterine segment. It's still debated whether the formation of bladder flap is advantageous or not. If the uterine incision is made slightly above the vesicouterine peritoneal fold, the loose connective tissue between the uterus and the urinary bladder allows spontaneous descent of the bladder. Evidence on the role of the bladder flap in cesarean section is very limited. At present, it remains to be established whether there is any advantage in dissecting the bladder from the lower uterine segment during cesarean section. PMID- 22217383 TI - Dietary L-arginine supplementation improves the intestinal development through increasing mucosal Akt and mammalian target of rapamycin signals in intra-uterine growth retarded piglets. AB - Intra-uterine growth retardation (IUGR) impairs postnatal growth and development of the small intestine (SI) in neonatal pigs and infants. L-Arginine (Arg), a critical amino acid involved in promoting growth and metabolism in young mammals, is more deficient in IUGR fetuses. However, little is known whether dietary Arg supplementation would accelerate the impaired development of the SI induced by IUGR in piglets. In the present study, a total of six litters of newborn piglets were used. In each litter, one normal and two IUGR littermates were obtained. Piglets were fed milk-based diets supplemented with 0 (Normal), 0 (IUGR) and 0.60% Arg (IUGR+Arg) from 7 to 14 d of age, respectively. Compared with Normal piglets at 14 d of age, IUGR decreased (P < 0.05) the growth performance, entire SI weight, and villus height in the jejunum and ileum. IUGR piglets had lower (P < 0.05) mucosal concentrations of Arg, insulin, insulin growth factor 1, as well as phosphorylated Akt, mammalian target of rapamycin (mTOR) and p70 S6 kinase but higher (P < 0.05) enterocyte apoptosis index (AI). After Arg treatment in IUGR piglets, the growth performance, weight of entire SI and mucosa, and villus height in the jejunum and ileum were increased (P < 0.05). Diet supplemented with Arg also increased (P < 0.05) the levels of Arg, insulin, phosphorylated Akt and mTOR in SI mucosa of IUGR piglets, and decreased (P < 0.05) the AI and caspase-3 activity. In conclusion, Arg has a beneficiary effect in improving the impaired SI development in IUGR piglets via regulating cell apoptosis and activating Akt and mTOR signals in SI mucosa. PMID- 22217385 TI - Linguistic rhythm guides parsing decisions in written sentence comprehension. AB - Various recent studies attest that reading involves creating an implicit prosodic representation of the written text which may systematically affect the resolution of syntactic ambiguities in sentence comprehension. Research up to now suggests that implicit prosody itself depends on a partial syntactic analysis of the text, raising the question of whether implicit prosody contributes to the parsing process, or whether it merely interprets the syntactic analysis. The present reading experiments examine the influence of stress-based linguistic rhythm on the resolution of local lexical-syntactic ambiguities in German. Both speech production data from unprepared oral reading and eye-tracking results from silent reading demonstrate that readers favor syntactic analyses that allow for a prosodic representation in which stressed and unstressed syllables alternate rhythmically. The findings contribute evidence confirming immediate and guiding effects of linguistic rhythm on the earliest stages of syntactic parsing in reading. PMID- 22217384 TI - Placebo-related effects in clinical trials in schizophrenia: what is driving this phenomenon and what can be done to minimize it? AB - The effect of placebo observed in schizophrenia clinical trials represents a growing problem that interferes with signal detection for treatments, increases costs of development, discourages investment in schizophrenia research and delays the introduction of new treatments. This paper seeks to clarify key issues related to this problem and identify potential solutions to them. Differences between placebo effect and response are characterized. Recent insights into the central nervous system mechanisms of placebo effect are described. This is followed by a description of protocol/study design and study conduct issues that are contributing to a growing placebo effect in clinical trials. Potential solutions to these problems are provided. PMID- 22217386 TI - Mental visualization of objects from cross-sectional images. AB - We extended the classic anorthoscopic viewing procedure to test a model of visualization of 3D structures from 2D cross-sections. Four experiments were conducted to examine key processes described in the model, localizing cross sections within a common frame of reference and spatiotemporal integration of cross sections into a hierarchical object representation. Participants used a hand-held device to reveal a hidden object as a sequence of cross-sectional images. The process of localization was manipulated by contrasting two displays, in situ vs. ex situ, which differed in whether cross sections were presented at their source locations or displaced to a remote screen. The process of integration was manipulated by varying the structural complexity of target objects and their components. Experiments 1 and 2 demonstrated visualization of 2D and 3D line-segment objects and verified predictions about display and complexity effects. In Experiments 3 and 4, the visualized forms were familiar letters and numbers. Errors and orientation effects showed that displacing cross sectional images to a remote display (ex situ viewing) impeded the ability to determine spatial relationships among pattern components, a failure of integration at the object level. PMID- 22217387 TI - Do the level of energy reserves, hydration status and Borrelia infection influence walking by Ixodes ricinus (Acari: Ixodidae) ticks? AB - Ixodes ricinus horizontal movement within a humidity gradient and the influence of infection by Borrelia burgdorferi sensu lato (s.l.) on tick walking were investigated. Nymphs were placed within an arena containing a humidity gradient ranging from 45 to 95% relative humidity (RH). After 1 h of acclimation at 70% RH ticks were released so that they could either stay, or walk towards either the wet or the dry end. Their position was recorded 2 h post-release. Fat content was quantified and Borrelia infection was detected using real-time PCR and PCR followed by Reverse Line Blotting. Among the 1500 ticks tested, 29.85% were infected. More low-fat nymphs walked inside the arena than high-fat individuals. When nymphs walked, more low-fat ticks walked towards wetter than drier air, whereas more high-fat individuals walked towards drier than wetter air. Among high-fat nymphs, a lower proportion of Borrelia-infected ticks walked inside the arena compared to uninfected individuals, as though spirochetes manipulated their arthropod vector to stay. However, Borrelia infection had no effect on walking direction towards the dry or the wet end. Hence, it appears that I. ricinus nymphs walk horizontally over short distances within a humidity gradient depending on both energy resources and Borrelia infection. PMID- 22217388 TI - Structure determination of a membrane protein in proteoliposomes. AB - An NMR method for determining the three-dimensional structures of membrane proteins in proteoliposomes is demonstrated by determining the structure of MerFt, the 60-residue helix-loop-helix integral membrane core of the 81-residue mercury transporter MerF. The method merges elements of oriented sample (OS) solid-state NMR and magic angle spinning (MAS) solid-state NMR techniques to measure orientation restraints relative to a single external axis (the bilayer normal) from individual residues in a uniformly (13)C/(15)N labeled protein in unoriented liquid crystalline phospholipid bilayers. The method relies on the fast (>10(5) Hz) rotational diffusion of membrane proteins in bilayers to average the static chemical shift anisotropy and heteronuclear dipole-dipole coupling powder patterns to axially symmetric powder patterns with reduced frequency spans. The frequency associated with the parallel edge of such motionally averaged powder patterns is exactly the same as that measured from the single line resonance in the spectrum of a stationary sample that is macroscopically aligned parallel to the direction of the applied magnetic field. All data are collected on unoriented samples undergoing MAS. Averaging of the homonuclear (13)C/(13)C dipolar couplings, by MAS of the sample, enables the use of uniformly (13)C/(15)N labeled proteins, which provides enhanced sensitivity through direct (13)C detection as well as the use of multidimensional MAS solid-state NMR methods for resolving and assigning resonances. The unique feature of this method is the measurement of orientation restraints that enable the protein structure and orientation to be determined in unoriented proteoliposomes. PMID- 22217390 TI - Effects of a long-acting ophthalmic formulation of carteolol containing alginic acid on the corneal epithelial barrier function and water retentive effect. AB - PURPOSE: Effects of a long-acting ophthalmic formulation of carteolol containing alginic acid on the corneal epithelial barrier function and its water retentive effect were investigated. METHODS: Using 10 healthy adult subjects, 2% Mikelan Ophthalmic Solution((r)) (MK) was instilled in the eye once daily for 7 days (MK group) and then after a washout period of at least 28 days, 2% Mikelan LA Ophthalmic Solution((r)) (MKLA) was instilled in the eye once daily for 7 days (LA group). As an index of the corneal epithelial barrier function, the fluorescein uptake was measured using Kowa FL-500. A Schirmer test was conducted to evaluate the tear dynamics. In another 10 subjects, 0.5% Timoptol((r)) (TM) was instilled in the eye unilaterally twice daily for 7 days (TM group), and the tests were conducted in the same manner. RESULTS: Concerning the fluorescein uptake before and after initiation of instillation, the levels before and at 7 days after initiation of instillation were 20.7 and 26.5 ng/mL, respectively, in the LA group and 20.6 and 26.4 ng/mL, respectively, in the MK group, showing no significant difference between levels before and after initiation of instillation in either group. In the TM group, the levels were 21.4 and 65.5 ng/mL, respectively, showing a significant increase after initiation of instillation. In the Schirmer test, the values before and after initiation of instillation were 16.8 and 20.7 mm, respectively, in the LA group and 13.7 and 12.7 mm, respectively, in the MK group, showing a trend toward increase in the LA group. CONCLUSIONS: The findings suggest that the long-acting ophthalmic formulation of carteolol containing alginic acid does not affect the corneal epithelial barrier function and that it may possess a water retentive action. PMID- 22217391 TI - Characterization of beta papillomavirus E4 expression in tumours from Epidermodysplasia Verruciformis patients and in experimental models. AB - This study provides a first characterisation of beta-HPV life-cycle events in tumours abscised from EV patients (the human model of beta-HPV-induced skin cancer), and shows how changes in E4 expression patterns relate to disease severity. beta-HPV life-cycle has also been reconstructed in organotypic raft cultures created using EV-derived keratinocytes. In EV lesions and raft cultures, abundant cytoplasmic E4 expression was detectable in differentiating cells along with viral genome amplification as reported for other HPV types. E4 expression was also seen in PCNA-positive basal cells in some EV skin cancers as well as in tumours from HPV8CER (Complete Early Region) transgenic mice. In these lesions, E4 staining extended throughout the full thickness of the epithelium and was apparent in the markedly atypical cells. The loss of such staining at the tumour border suggests a distinct type of E4 dysregulation that may be exploited as a marker of viral expression during beta-HPV-associated skin cancer progression. PMID- 22217392 TI - Frontal assessment battery and brain perfusion imaging in Alzheimer's disease. AB - BACKGROUND: The frontal assessment battery (FAB) is reported to be a useful tool for assessing frontal dysfunction. However, the neural substrates involved in patients with Alzheimer's disease (AD) remain to be elucidated. The aim of the present study was to identify the regional perfusion patterns of the brain associated with performance scores on the FAB of patients with AD using brain perfusion assessed by single photon emission computed tomography (SPECT). METHODS: Twenty-four AD patients with high scores and 24 age- and sex-matched AD patients with low scores on the FAB were selected from 470 consecutive Japanese patients of the Memory Clinic of Okayama University Hospital. All 48 participants underwent brain SPECT with 99mTc-ethylcysteinate dimer, and the SPECT images were analyzed by statistical parametric mapping. RESULTS: No significant differences were found between high and low FAB scoring groups with respect to Addenbrooke's Cognitive Examination scores, Mini-Mental State Examination scores, or the depression score of the Neuropsychiatric Inventory subscale. Compared with patients with high scores on the FAB, AD patients with low scores showed significant hypoperfusion in the left middle frontal gyrus (MFG) and the right superior frontal gyrus (SFG) extending to the left SFG. CONCLUSION: Our results suggest that functional activity of the SFG and MFG is closely related to the FAB score. The FAB might be a promising strategy to detect early stages of AD with low SFG and MFG function. PMID- 22217393 TI - Association of maternal interaction with emotional regulation in 4- and 9-month infants during the Still Face Paradigm. AB - This study used the Still Face Paradigm to investigate the relationship of maternal interaction on infants' emotion regulation responses. Seventy infant mother dyads were seen at 4 months and 25 of these same dyads were re-evaluated at 9 months. Maternal interactions were coded for attention seeking and contingent responding. Emotional regulation was described by infant stress reaction and overall positive affect. Results indicated that at both 4 and 9 months mothers who used more contingent responding interactions had infants who showed more positive affect. In contrast, mothers who used more attention seeking play had infants who showed less positive affect after the Still Face Paradigm. Patterns of stress reaction were reversed, as mothers who used more attention seeking play had infants with less negative affect. Implications for intervention and emotional regulation patterns over time are discussed. PMID- 22217395 TI - Allergen NCE Inc.'s Fifth Annual Research Conference: Innovation from Cell to Society Quebec City, QC, Canada. 7-9 February 2010. Abstracts. PMID- 22217394 TI - Involvement of Spanish pulmonology centers in patient care, postgraduate education and research in asthma: the results of the ATENEA survey. AB - Although asthma is one of the most prevalent chronic respiratory diseases, the participation of Spanish pulmonology units in the management of asthma may have room for improvement. OBJECTIVE: To determine the degree of involvement of the Spanish pulmonology services in the patient care, education and research related with asthma disease and especially in difficult-to-control asthma. METHODS: A survey made up of 75 questions was sent to the heads of several pulmonology departments. The survey asked questions pertaining to respiratory disease care in general, and in asthma in particular, as well as the educational activities and research in asthma during the previous five years. RESULTS: Out of the 107 surveys sent, 69 (645%) centers filled them out and returned them. Forty-seven (681%) met the criteria for an important level of health-care activity in asthma. However, only 29 (42%) had a monographic consultation for difficult-to-control asthma and 37 (536%) used an education program. As for postgraduate education, only 31 (449%) provided their resident physicians with specific asthma training. And in the research field, 12 (174%) reported having projects funded by SEPAR and 25 (362%) had published studies in journals with an impact factor. CONCLUSIONS: Although the majority of the pulmonology centers interviewed report a notable activity in asthma patient care, their involvement in the specialized approach for difficult-to-control asthma is insufficient. Likewise, participation in educational activities and research related with the disease is inconsistent and limited to few centers. PMID- 22217396 TI - Upper airway symptoms in primary snoring and in sleep apnea. AB - CONCLUSIONS: Upper airway symptoms were common in subjects referred for sleep study. In particular, nasal stuffiness and airway dryness already seemed to bother snorers before development of obstructive sleep apnea syndrome (OSAS). Mouth dryness increased with severity of obstructive sleep apnea (OSA). OBJECTIVES: Upper airway symptoms are common in patients with OSAS. However, prevalence of these symptoms is unknown in primary snoring and mild OSA. We evaluated frequency of upper airway symptoms in a large group of patients referred for diagnostic sleep studies. METHODS: We examined 524 consecutive subjects (69% men, mean +/- SD age 51 +/- 12 years, apnea-hypopnea index (AHI) 15 +/- 21, body mass index 31 +/- 6) by a questionnaire-based survey. The subjects filled in a questionnaire enquiring about current upper airway symptoms and history of nasal and pharyngeal disorders before the sleep study. RESULTS: Frequent upper airway symptoms among study subjects were common: 56% of the patients reported throat dryness, 55% mouth dryness, 54% nasal stuffiness, 52% nose dryness, 33% sneezing, 33% postnasal drip, and 24% rhinorrhea. The patients with moderate or severe OSAS (AHI >=15 and Epworth sleepiness score >=10) suffered from mouth dryness more often (71% vs 40%, p < 0.01) than those with mild or no OSAS. PMID- 22217397 TI - Risk modification by CYP1A1 and GSTM1 polymorphisms in the association of cigarette smoking and systemic lupus erythematosus in a Japanese population. AB - OBJECTIVES: Exposure to reactive oxygen species (ROS) through cigarette smoking is thought to contribute to the development of systemic lupus erythematosus (SLE). Metabolic enzymes are involved in ROS production. The aim of this study was to evaluate the modifying effect of metabolic polymorphisms on the association of cigarette smoking with SLE risk in a Japanese population. METHODS: We investigated the relationship of the cytochrome P450 (CYP) 1A1 rs4646903 and glutathione S-transferase (GST) M1 deletion polymorphisms to SLE risk with attention to interaction with cigarette smoking among 151 SLE cases and 421 controls in female Japanese subjects. Unconditional logistic regression was used to compute the odds ratios (ORs) and their 95% confidence intervals (CIs), with adjustments for several covariates. RESULTS: Smokers with the CC genotype of CYP1A1 rs4646903 were significantly associated with increased risk of SLE (OR 9.72, 95% CI 2.73-34.6). Similarly, smokers with the combined CYP1A1 rs4646903/GSTM1 'at-risk' genotype were significantly associated with increased risk of SLE (OR 17.5, 95% CI 3.20-95.9). More than 60% of the excess risk for SLE in smokers with the CC genotype and smokers with the combined 'at-risk' genotype was due to an additive interaction. A lack of association of the GSTM1 genotypes with smoking was observed. CONCLUSIONS: Our results suggest that a combination of smoking and either the CYP1A1 rs4646903 genotype or the combined metabolic genotype plays an important role in SLE susceptibility in our Japanese population. Additional studies are warranted to confirm the metabolic polymorphism-smoking interaction suggested in the present study. PMID- 22217399 TI - Digenean metacercariae of fishes from the lagoon flats of Palmyra Atoll, Eastern Indo-Pacific. AB - Although many studies on the taxonomy of digenean trematodes of marine fishes have been completed in the Eastern Indo-Pacific (EIP) marine ecoregion, only a few have considered metacercarial stages. Here, the results are presented of a taxonomic survey of the digenean metacercariae of fishes from Palmyra Atoll, a remote and relatively pristine US National Wildlife Refuge located 1680 km SSW of Hawaii. Up to 425 individual fish were collected, comprising 42 fish species, from the sand flats bordering the lagoon of the atoll. Quantitative parasitological examinations of each fish were performed. Morphological descriptions of the encountered digenean metacercariae are provided, together with their prevalence, mean intensities, host and tissue-use. Up to 33,964 individuals were recovered representing 19 digenean metacercaria species from eight families. The species composition of digeneans in lagoon fishes at Palmyra Atoll is a subset of what has previously been reported for the EIP. Further, the large diversity and abundance of metacercariae reported in this study highlight the utility of including this group in future ecological research in the EIP marine ecoregion. PMID- 22217398 TI - Luminal-B breast cancer and novel therapeutic targets. AB - Gene expression profiling has led to a new molecular classification of breast cancer characterized by four intrinsic subtypes: basal-like, HER2-positive, luminal A, and luminal B. Despite expressing estrogen receptor, the luminal-B subtype confers increased risk of early relapse with endocrine therapy compared with the luminal-A subtype. Although luminal-B definitions vary, the hallmark appears to be increased expression of proliferation-related genes. Several biological pathways are identified as possible contributors to the poor outcomes, and novel agents targeting these pathways are being developed with aims to improve survival. We review the definition of luminal-B breast cancer, its pathological and clinical features, and potential targets for treatment. PMID- 22217401 TI - Periprosthetic humeral fractures after shoulder and elbow arthroplasty. AB - Due to rapidly increasing numbers of arthroplasty surgeries of the upper extremity, periprosthetic humeral fractures after shoulder and elbow arthroplasty, formerly described as rare, may hence increase in the near future. Therefore the aim of the present work was to give an overview of the existing literature including possible classifications as well as an update on treatment concepts and experiences with own cases. After a literature research have been done, existing prevalence, classifications and treatment options, mostly described in case series, were processed to create an overview of the existing state of knowledge. Additionally 7 own cases are described in detail to show the different treatment options used at the authors department. The currently used classification systems take fracture location, angulation and rotation and fixation of the implant into account. Possible solutions for periposthetic fractures of the humerus include conservative management, open reduction and internal fixation for stable prosthesis and long stemmed implants for lose implants as well as the use of additional allo- or autogeneous bone grafting and reverse shoulder arthroplasty in revision cases with rotator cuff dysfunction. After all treatment of periprosthetic humeral fractures after shoulder and elbow arthroplasty remain a challenging problem. PMID- 22217400 TI - Neurobehavioural activation during peripheral immunosuppression. AB - Like other physiological responses, immune functions are the subject of behavioural conditioning. Conditioned immunosuppression can be induced by contingently pairing a novel taste with an injection of the immunosuppressant cyclosporine A (CsA) in an associative learning paradigm. This learned immunosuppression is centrally mediated by the insular cortex and the amygdala. However, the afferent mechanisms by which the brain detects CsA are not understood. In this study we analysed whether CsA is sensed via the chemosensitive vagus nerve or whether CsA directly acts on the brain. Our experiments revealed that a single peripheral administration of CsA increases neuronal activity in the insular cortex and the amygdala as evident from increased electric activity, c-Fos expression and amygdaloid noradrenaline release. However, this increased neuronal activity was not affected by prior vagal deafferentation but rather seems to partially be induced by direct action of CsA on cortico-amygdaloid structures and the chemosensitive brainstem regions area postrema and nucleus of the solitary tract. Together, these data indicate that CsA as an unconditioned stimulus may directly act on the brain by a still unknown transduction mechanism. PMID- 22217402 TI - The many faces of chondrosarcoma of bone, own cases and review of the literature with an emphasis on radiology, pathology and treatment. AB - Chondrosarcoma is the third most frequent primary malignant tumor of bone, constituting up to 16% of the malignant osseous neoplasms. Up to date several genetic alterations and markers were described concerning the pathogenesis and the progression of the chondrosarcoma, which represents actually a heterogeneous group of different types including conventional intramedullary, clear cell, myxoid, mesenchymal, and dedifferentiated chondrosarcoma. The pathologic appearance varies, however, in general they grow with a lobulated pattern. Histologically the hyaline cartilage demonstrates high water content and typically enchondral ossification is apparent. Imaging reflect this while radiographic findings suggest the diagnosis when the typical "ring-and-arc" chondroid matrix mineralization, endosteal scalloping and soft-tissue extension were apparent. The CT is used for detecting the mineralization of the matrix, especially when it is subtle or when the lesion is located in complex areas. MRT is the method of choice to detect the high water content of these lesions with a high signal intensity with T2-weighting and its bone marrow extend. Surgical resection is the primary and preferred treatment modality for most individuals with localized disease. In selected cases of the Grad I conventional chondrosarcoma curettage should be discussed. Systemic chemotherapy may be considered in variant forms such as mesenchymal or dedifferentiated chondrosarcomas. In knowledge of the "many faces" of the primary chondrosarcoma individualized patient assessment and optimal clinical management is possible. PMID- 22217403 TI - [Preoperative diagnosis of prosthetic joint infection]. AB - Making pre-operative diagnosis of intermediate and low-grade infections of prosthetic joint infection (PJI) is demanding and requires both clinical experience and good knowledge of diagnostic test performance. It is also necessary to know the rules of working with diagnostic tests based on the expected change in pre-test probability of PJI or the diagnostic odds ratio. This also requires a multi-modal approach with a rational combination of relevant tests because none of them can have both 100% sensitivity and 100% specificity. Suspicion of a developing PJI should be aroused by relevant information present in the patient s medical history and confirmed by clinical examination. Patients with an increased starting PJI probability, i.e. after taking the medical history and clinical examination, should be examined for the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels (screening tests). When both of these tests are positive and no other alternative explanation for their increase is plausible, then the post-test probability of PJI is significantly increased (up to 70%). Under such conditions the diagnosis is made definitive by positive results of synovial fluid analysis (leukocyte count, percentage of neutrophils and lymphocytes, IL-1, IL-6) or an increased IL-6 serum levels. On the other hand, when both ESR and CRP are negative, the post-test probability of PJI is significantly decreased and no further examination for the presence of infection is usually necessary. In case of inconsistent results of ESR and CRP or if there is a high suspicion of joint infection regardless of these test results, joint fluid aspiration (cytology, IL-1, IL-6) and IL-6 serum levels should be assessed. In this situation scintigraphy imaging (three-phase bone scan combined with labelled leukocytes or anti-granulocyte antibodies) can also support or exclude the diagnosis. In low-grade infections or after previous administration of antibiotics it is recommended to repeat the above-mentioned laboratory tests and joint aspiration after at least a two-week interval without antibiotics. Key words: Total joint arthroplasty, prosthetic joint infection, preoperative diagnosis, pre-test probability, post-test probability, algorithm. PMID- 22217404 TI - Surgical treatment of supracondylar humerus fractures in children. AB - PURPOSE OF THE STUDY: Surgical techniques for the treatment of supracondylar fractures in children are repeatedly the subject of discussion. The aim of the present study was to compare experience with the technique of crossed Kirschner wires at our own hospital with current literature. PATIENTS AND METHODS: In the period from 2000-2006 a total of 86 children aged 1.7 to 12.7 years were treated by means of crossed K-wire osteosynthesis. Follow up was conducted at an average of 32 months. Outcomes were evaluated based on von Laer's criteria. RESULTS: Reported complications were migration of the K-wires in 7% of cases and secondary dislocation and re-operation in 4% of cases. Lesion of the radial nerve was diagnosed postoperatively in two cases. Hospital stay was 1.5 days on average. Postoperative immobilization in an upper arm splint and implant removal after 6 weeks on average. 57% of the children received physiotherapy during the course of treatment. Slight varization was found in 11% of children and an unsatisfactory range of motion in 13%. Satisfactory outcomes were recorded for 83% of patients. CONCLUSION: K-wire osteosynthesis is associated with a low complication rate and continues to be a safe standard procedure for the stabilization of supracondylar humerus fractures. Key words: supracondylar humerus fracture, Kirschner wires, paediatric fractures. PMID- 22217405 TI - [Long-term results of the SVL total knee arthroplasty]. AB - PURPOSE OF THE STUDY: The aim of the study was to evaluate the long-term results of the total knee replacement Beznoska SVL implanted at the 1st Department of Orthopaedic Surgery, 1st Faculty of Medicine, Charles University and Motol University Hospital Prague, in the 1997/2009 period. MATERIAL AND METHODS: The SVL implant is a non-constrained knee replacement, anatomically similar to the bone it replaces, which preserves the posterior cruciate ligament. A total of 1101 knee joint replacements were evaluated in 973 patients, of whom 128 underwent bilateral arthroplasty. Kaplan-Meier curves were used to estimate the cumulative survival of implants. Clinical outcomes were assessed using the Knee Society clinical rating system (KS score) and radiographic data evaluation was also included. RESULTS: Using KS scores, the results were excellent in 997, good in 75, satisfactory in 19 and poor in 10 knees. The average range of motion was 0.16 to 106.31 degrees. The complications included flexion contracture, as the most frequent problem (13 knees), 10 knees were infected, aseptic loosening due to polyethylene granuloma was found in eight knees and anterior knee pain was experienced in six cases. At follow-up of 12.5 years implant survivorship was 98 %, as evaluated by the Kaplan-Meier analysis. DISCUSSION: A comparison of SVL implant survivorship with other knee replacement designs is discussed. It should be emphasized that the clinical outcome depends not only on implant quality, but also on the operative technique used and the surgeon's experience and skills. It is the SVL system that allows for the balancing of knee joint stability and thus enables even less experienced surgeons to make use of a more sophisticated implantation technique. CONCLUSIONS: Total knee replacement using the SVL Beznoska implant is a safe, reliable and economic treatment with excellent clinical outcomes. PMID- 22217406 TI - [Treatment of a bone bridge by transplantation of mesenchymal stem cells and chondrocytes in a composite scaffold in pigs: experimental study]. AB - PURPOSE OF THE STUDY: The presented experimental study describes the results of using a combination of allogeneic mesenchymal cells (MSCs) with chondrocytes (CHCs) and a novel scaffold based on type I collagen and chitosan fibres. This biocomposite was transplanted into a defect produced by excision of a bone bridge to induce new cartilaginous tissue formation. The left femur was treated by transplantation into a defect of distal epiphysis; the right femur with implantation of the scaffold only served as control. A better therapeutic result was therefore expected in the left femur - the reduction of growth and angular deformities, and the histological finding of a tissue similar to the cartilage excised from the left femur.. MATERIAL AND METHODS: The miniature pig was selected as an experimental model and 10 pigs were used. Mesenchymal stem cells derived from femoral bone marrow and chondrocytes derived from a sample harvested from the non-weight-bearing articular surface of the distal end of the femur were cultured in medium. The novel scaffold was based on collagen containing chitosan nanofibres. To make manipulation during implantation easier, the cilindrical scaffolds after lyophilisation were again placed in 96-well plates for seeding. The scaffolds before implantation were seeded with 2x106 allogeneic MSCs and 1x106 allogeneic CHCs. The outcomes of treatment were assessed by measuring the length of bone and the degree of distal femoral valgus deformity, and by the histological findings obtained (properties and maturity of the newly-formed tissue, detection of type II collagen, PAS reaction). RESULTS: The right and left legs were examined for longitudinal bone growth and the valgus angle and compared. The treated left leg showed a higher average value for longitudinal growth than the untreated right leg (p = 0.004). The average degree of angular deformity was lower in the left leg than in the right leg (p = 0.008). The microscopic findings showed that a tissue similar to hyaline cartilage was more frequently present in the femoral bone defect of the left leg, as compared with that of the right leg. Type II collagen was detected more frequently and at higher amounts on the left than the right side (p = 0.033). The PAS reaction was positive in all left limbs, with a high degree of positivity in 80 % of them, while this was not achieved in any of the right limbs (p = 0.001). DISCUSSION: The use of stem cells in the indication reported here has only been the matter of time since the information on encouraging results in neurology and cardiology was published. First studies with positive results have soon been reported. The initial hydrogel scaffolds were based on tissue adhesives. However, they were not stable enough and were difficult to handle during surgery. In further studies, therefore, the use was made of a three-dimensional scaffold with a self supporting structure of collagen fibres. This structure also facilitated its hydrodynamic seeding with MSCs and CHCs, which is an effective and sparing procedure for the transplanted cells. Studies concerned with MSCs and/or CHCs transplantation for re - pair of a physeal defect following bone bridge excision, i.e. for bone bridge treatment, in a broader experimental design, however, are still missing. CONCLUSION: Transplantation of a composite scaffold seeded with mesenchymal stem cells and chondrocytes into a physeal defect following bone bridge excision prevented growth disturbance and angular deformity development in the distal femoral epi - physis. In comparison with the control group, it resulted in a more frequent production of a tissue similar to hyaline cartilage, with a cell formation reminiscent of a typical columnar arrangement of the growth plate. Key words: mesenchymal stem cells, growth plate, bone bridge, scaffold. PMID- 22217407 TI - [Xenogeneic protein free cultivation of mesenchymal multipotent stromal cells]. AB - PURPOSE OF THE STUDY: The aim of this study was to compare the standard laboratory method of cultivation of mesenchymal multipotent stromal cells (MSC) and a novel technique of rapid MSC expansion focused on simple clinical use. MATERIAL AND METHODS: Bone marrow mononuclear cells of donors were cultured for 14 days by the standard and the new cultivation method. The standard method (STD) was based on an alpha MEM medium supplemented with foetal calf serum (FCS). The new animal protein-free method (CLI) was based on the clinical grade medium CellgroTM, pooled human serum and human recombinant growth factors (EGF, PDGF-BB, M-CSF, FGF-2) supplemented with dexamethasone, insulin and ascorbic acid. The cell product was analyzed by flow cytometry. Furthermore, the cell products of STD and CLI methods were differentiated in vitro, and histochemical and immunohistochemical analyses, electron microscopy and elemental analysis were performed. Some cells were seeded on biodegradable scaffolds, in vivo implanted into immunodeficient mice for 6 weeks and evaluated by histological methods. RESULTS: Yields of the CLI method after 14 days of cultivation were 40-fold higher than those obtained by the STD technique (p<0.05). Cell products of both STD and CLI methods fulfilled the criteria of MSC in terms of antigen expression assessed by flow cytometry, as well as osteogenic, chondrogenic and adipogenic in vitro differentiation assays. Moreover, these cells seeded on three-dimensional scaffolds cultured in osteogenic medium produced mineral deposits and a fibrillar extracellular matrix seen with the electron microscope. Deposits examined by element analysis contained calcium and phosphorus at a ratio of 5 to 3, which corresponded to hydroxyapatite. The cell product seeded on biodegradable scaffolds and implanted into immunodeficient mice was able to form a bone-like calcified tissue with blood supply of mouse origin. DISCUSSION: The currently used methods of cultivation have certain disadvantages compared to the CLI technique, such as a longer cultivation period, need of primary expansion and reseeding and use of FCS with all its potential risks. High yields of cells obtained by the CLI method in a very short time make the use of cultured cells potentially suitable for an acute trauma management. Other therapeutic non orthotopic applications of CLI-cultured cells have to be further investigated. CONCLUSIONS: The CLI method is unique, rapid, simple and lacking the addition of animal proteins. CLI-cultured cells fulfil the criteria of MSC. The CLI method potentially allows for closed system cultivation in good manufacturing practice (GMP) conditions. It seems to be easily transferable to good clinical practice compared to other protocols and should extend the possibilities of cell therapy and tissue engineering of cartilage and bone. The new method is protected by Czech patent 301 148 and by Europian patent EP 1999250 according to Czech and international laws. PMID- 22217408 TI - [Tricalcium phosphate mixed with autologous bone marrow in the treatment of benign cystic bone lesions in children]. AB - PURPOSE OF THE STUDY: To test the hypothesis that the application of tricalcium phosphate (TCP) mixed with autologous bone marrow can achieve better and faster healing of benign bone lesions than the application of tricalcium phosphate granules alone. MATERIAL AND METHODS: The prospective study included two groups, each consisting of 10 patients, treated for benign cystic bone lesions at the Department of Paediatric Surgery, Orthopaedics and Trauma Surgery from July 1, 2008 to June 30, 2010. The bone cysts involved non-ossifying fibroma, enchodroma, fibrous dysplasia, aneurysmal bone cyst and juvenile bone cyst. One group was treated using ChronOS(TM) Beta-Tricalcium Phosphate (Synthes GmbH, Switzerland) granules mixed with autologous bone marrow harvested during surgery (BM group). The other (CH group) received treatment with ChronOS granules alone. Relevant clinical data were obtained from all 20 patients treated for one of the bone cyst forms mentioned above. The patients were followed up till the end of 2010. RESULTS: TCP application was a one-step procedure in both groups. In the BM group, bone regeneration ad integrum (Neer 1) was achieved, with only an occasional very small residue of the cyst seen on radiographs (Neer 2). None of the patients reported any problems, not even at 6 months after surgery. In the CH group, two patients required further surgical treatment because of insufficient bone healing (Neer 3) and two other patients reported pain persisting at the site of the lesion at 6 months post-operatively. In these patients TCP was used to fill a defect after excochleation of an aneurysmal bone cyst or fibrous dysplasia. The rest of the patients showed satisfactory healing. DISCUSSION: The main objective of the use of synthetic biocompatible materials in surgical treatment of benign bone cysts requiring filling of the lesion is to reduce the post-operative stress of paediatric patients as much as possible. Although our first results were not statistically significant to give unambiguous support to our hypothesis that lesions would heal better with the use of synthetic tricalcium phosphate mixed with autologous bone marrow, there is plenty of evidence that further development of cell technologies will result in a more exact definition of bone substitute materials in both their components, i.e., well-defined cells and non-biological scaffolds close in structure to inorganic compounds of bone, i.e., biodegradable osteoinductive materials. CONCLUSIONS: The patients with benign bone lesions treated by TCP mixed with autologous bone marrow showed neither recurrent disease nor complications. The group treated with TCP alone had recurrent lesions in two and persisting pain also in two patients. Other complications were not recorded. PMID- 22217409 TI - Impact of kyphoplasty treatment for vertebral compression fractures on pain and function in 105 patients. AB - PURPOSE OF THE STUDY: Vertebral compression fractures are very common. Symptomatic relief with conservative therapy is often difficult to achieve. Balloon kyphoplasty is a relatively new technique which stabilises the vertebral body and restores spinal alignment in recent fractures, it achieves significant pain relief and improved functional outcome is reported. The aim of this prospective study was to determine the level of pain relief and functional outcome in patients who were initially treated conservatively for 4-6 weeks and if symptoms did not have tendency to resolve, then had kyphoplasty surgery. MATERIAL AND METHODS: 105 patients underwent balloon kyphoplasty between April 2006 and August 2010 and had 1 year follow up. Total 170 levels were augmented, 65% (n=68) of patients were female and the average age was 74 years. Pain relief was assessed using visual analogue score (VAS) and functional outcome using Oswestry Disability Index (ODI). RESULTS: Results showed decrease of the average pre-operative VAS from 8.2 to 4.4 in the immediate postoperative period (p=0.000). This dramatic improvement remained and was 4.1 at 6 weeks, 3.3 at 6 months and 3.6 at 1 year. The average pre-operative ODI was 58. This improved to 47 in the immediate post-operative period (p=0.002). At 6 weeks this had improved further to 40 and further improvements were seen at 6 months (ODI 37) and 1 year (ODI 38). The average screening time was 2 minutes and 20 seconds. The average volume of cement used per level was 5.5 cm3. Radiographic measurements were performed by independent radiologist. The average pre-operative vertebral angle was 11.6 degrees and 10.9 degrees postoperatively. This was maintained throughout the follow up. This represented a negligible 6% improvement in vertebral body angle. We did not experience any clinically significant complications, we have encountered 11 minor complications which did not require any additional measures (cement leaks, penetration of the vertebral body margins by balloons or K wires and rib fractures). DISCUSSION: Pain relief and improvement of functional outcome was sustained after one year. Limited number of patients who had 2 year follow up showed trend of minimal deterioration of both parameters (VAS and ODI). This can be explained by incidence of few adjacent segment fractures and progressive overall osteoarthritic changes in this aging population. Radiological evaluation showed maintenance of achieved alignment which did not deteriorate over time. Complication rate was low and did not require any further surgical interventions and did not have any effect on final good clinical outcome. CONCLUSION: Balloon kyphoplasty proved to be safe surgical technique and should be considered in patients with ongoing pain following an acute vertebral compression fracture that does not improve with initial conservative treatment. It significantly improves pain and functional status in elderly patients. PMID- 22217410 TI - [Identification of the lumbosacral nerve plexus during the extreme lateral interbody fusion procedure]. AB - PURPOSE OF THE STUDY: The aim of this clinical observation study was to determine the extent to which muscle relaxation induced by anesthesia must be intra operatively reversed for a reliable identification, by intra-operative monitoring, of the lumbosacral (LS) nerve roots during extreme lateral interbody fusion (XLIF). MATERAL AND METHODS: General anesthesia (midazolam, propofol, sufentanil, oxygen/air/sevofluran - rocuronium) was administrated to all pa - tients. Train-of-four (TOF) stimulation of the ulnar nerve at 10-second intervals and an electromyographic response of the adductor pollicis muscle were used, and the duration of neuromuscular block was measured by the value of the TOF-ratio. When the level of recovery from neuromuscular block was TOF-count = 2, reversion to normal function was still accelerated by sugammadex administration at a dose of 2 mg.kg-1. Subsequently, it was determined at which level of muscle relaxation subsidence the first responses to LS nerve root stimulation were evident. Intra operative neurophysiologial monitoring (IOM) with use of the NIM - Neuro(r) 3.0 device allowed for assessment of a triggered electromyographic reaction (tEMG) of LS roots to stimulation during surgery. The neuromuscular reactions were evaluated in 11 patients, five men and six women. The results were analysed by descriptive statistics and presented as median and interquartile-range values. RESULTS: In all patients a reliable monitoring of the depth of muscle relaxation was established. The value of supramaximal impulse was 46 mA (38 to 64 mA). The period from rocuronium administration to a spontaneous recovery of the TOF-count = 2 took 33 min (29 to 35 min). Duration from sugammadex administration to a TOF ratio of . 0.70 was 90 seconds (50 to 140) and to a TOF ratio of . 0.90 was 190 seconds (100 to 220 s). A reliable tEMG response of LS nerve roots to electric stimulation at 10 mA intensity was recorded at a TOF ratio of 0.68 (0.56 to 0.77) and at a 5 mA intensity it was reliable at a TOF ratio of 0.86 (0.75 to 0.90).. None of the patients reported radicular symptoms after surgery. DISCUSSION: From the anatomy of the greater psoas muscle and varied patterns of its LS plexus it is obvious that none of the zones is absolutely safe. In XLIF procedures it is therefore recommended to disect the psoas muscle under both visual and IOM control. Intra-operative checking of the depth of muscle relaxation then will provide information that conditions not affected by rocuronium administration and necessary for the detection of LS roots have been provided. CONCLUSIONS: 1. For a reliable intra-operative identification of LS nerve roots by electric stimulation at a 10 mA intensity it is recommended to achieve the value of TOF ratio equal to at least 0.70. When stimulation at a lower intensity (5 mA) is used, a TOF ratio of . 0.90 is necessary. 2. Administration of sugammadex to reverse an action of the muscle relaxant rocuronium is an effective and quick method to achieve the values required. PMID- 22217411 TI - [Anterior interbody fusion of the cervical spine with a zero-p spacer: radiographic results with a minimum follow-up of one year in a prospective study]. AB - PURPOSE OF THE STUDY: The aim of this study was to compare the efficacy of anterior cervical microdiscectomy and fusion carried out using a newly designed interbody spacer with that of a standard cage plate construct in patients with symptomatic cervical spine spodylosis. The comparison was based on radiographic results and fusion rates. MATERIAL: A total number of 113 consecutive patients were enrolled in this prospective study between October 2008 and July 2009. Mono- or bisegmental spondylosis was diagnosed in the patients in whom conservative treatment of cervicobrachial symptoms had had no effect. Patients with myelopathy were not included.. METHODS: All patients underwent standard anterior microdiscectomy (at one or two levels). The novel anchored spacer Zero-P was used in 61 patients (group 1) and, in 52 patients, stabilisation was done using the interbody spacer Cornerstone and dynamic plate Premier (group 2). Lateral radiographic views of the cervical spine were obtained before surgery and at 6 weeks, and then at 3, 6 and 12 months after surgery. During follow-up, the cervical spine sagittal alignment (CobbC), segmental angle of the treated levels (CobbS), amount of segmental collapse and fusion rates were measured. RESULTS: There was no significant difference in CobbC between the two groups during follow up (p < 0.051). A significant difference in the first two values of CobbS was found (p < 0.001), but next changes in CobbS were without any difference in either group. The mean degree of interspace collapse was without any significant difference between the groups. The fusion rate was significantly higher in group 1 than group 2 nine months after surgery (p = 0.032), but was the same in both groups at 12 months after surgery (p = 1.0). CONCLUSIONS: The anchored spacer Zero-P provides biomechanical stability for the cervical spine similar to the cage and dynamic plate construct. Efforts to improve the cervical stand-alone anterior fusion device and to eliminate disadvantages of plate systems should be studied in larger patient groups with longer follow-ups. Key words: cervical spine, interbody fusion, fusion rate, radiology, stand-alone implant, Zero-P. PMID- 22217412 TI - [Single cannulated screws for stabilisation of pelvic ring and acetabular fractures]. AB - PURPOSE OF THE STUDY: Current trends in minimally invasive surgery together with advances in computed tomography and fluoroscopic guidance allow us to perform close reduction and percutaneous fixation also in non-displaced or minimally displaced fractures of the pelvic ring and acetabulum. Authors report the method of percutaneous screw fixation. MATERIAL AND METHODS: During the period from 1998 to 2010, a total of 568 patients were surgically treated for fractures of the pelvic ring and acetabulum. The patient series included 132 men and 46 women with an average age of 41.6 years (from 15 to 88 years). In this cohort, 225 single screws were placed at various sites of the pelvis. Of the screws, 197 were applied percutaneously and 28 in open procedures. A definition of six screw categories is proposed as well as the list of indications for their use. A detailed description of the techniques for screw placement, including the associated risks, is also presented. A novel method of minimally invasive stabilisation of the ruptured symphysis by means of two pubic screws and a two hole plate is reported. A total of 157 patients were followed for the average period of 11.9 months (from 3 to 144 months). The navigation methods used in pelvic fracture stabilisation are described. RESULTS: It is difficult to provide an overall evaluation of the results in such a heterogeneous group of patients and therefore the outcome was assessed according to the placement of single screws. The types of injury with the use of appropriate screws are described in detail. Complications and the final graphical and clinical outcomes are reported. As the pelvic ring and acetabular injuries vary too much, it was not easy to assess the clinical outcome for each screw category. DISCUSSION: Percutaneous screw fixation is indicated in non-displaced fractures having a potential for displacement as well as in minimally displaced fractures that can be fixed with precisely placed screws. Dislocated fractures have to be reduced before surgery. Percutaneous screw placement can be performed as a single surgical procedure and this technique can also be part of a limited open approach. Percutaneous or open placement of cannulated screws facilitates stabilisation of individual fragments and allows for low surgical invasivity. This type of screw fixation in pelvic surgery provides all benefits of minimally invasive procedures. In this respect, some authors' view that the advantages outweigh a less successful result of fracture reduction can be accepted. A relatively high risk of iatrogenic complications is a disadvantage of this technique. The correct placement of screws has the highest priority because all percutaneous pelvic screws described here are inserted into the sites known as "narrow safe zones". CONCLUSIONS: In specific localisations, the percutaneous fixation of pelvic ring and acetabular fractures using single screws presents a new surgical technique for which the indications have not been exactly defined yet. The procedure should be performed by an experienced surgeon ready to convert surgery from a minimally invasive procedure to an open one, if the navigation technique used does not provide a reliable guidance or when the fracture reduction or stabilisation fails. PMID- 22217413 TI - [Total knee arthroplasty in severe valgus deformity in a patient with achondroplasia]. AB - The authors present the results of total knee replacement in a 66-year-old woman with achondroplasia. The condition was diagnosed on the basis of clinical and radiographic findings; molecular genetic examination confirmed that the patient was heterozygous for the G1138A mutation responsible for substitution of an arginine for a glycine residue at position 380 (G380R). The patient presented with an unusual finding of severe fixed 20-degree valgus deformity, so far not published, which did not conform with the clinical features of achondroplasia. The authors presumed that the deformity had developed due to asymmetric growth of the distal femoral diaphysis resulting in a hypoplastic lateral femoral condyle and, consequently, valgus deformity. They put emphasis on thorough pre-operative radiography in order to define the size of components according to the templates, and on measurement of the valgus angle and femoral mechanical axis. They also drew attention to the problem of an extra-articular tibial alignment guide and recommended the use of its alternative or computer navigation. The surgery restored the mechanical axis, range of motion and stability of the knee, relieved pain and improved walking, which afforded a better quality of life for the patient. PMID- 22217414 TI - [Osteochondroma of the iliac crest: case report]. AB - The authors present the case of a 16-year-old boy with osteochondroma of the iliac crest which gradually resulted in gluteal muscle atrophy, developing curvature of the spine and compression of the external iliac artery. Osteochondroma excision prevented the development of circulatory disorders in the ipsilateral lower extremity, and effective physical therapy enabled the well cooperating patient to restore fully his gluteal muscle strength and normal gait pattern. PMID- 22217415 TI - Impact of aging and diet restriction on retinal function during and after acute intraocular pressure injury. AB - Advancing age is a major risk factor for many neurodegenerative diseases but the underlying pathophysiology is not clear. We hypothesize that aging impairs the ability of neurons in the central nervous system to recover functionally after injury. To test this in retinal ganglion cells in vivo, we developed an optic nerve "stress test" which monitors the functional capacity of the optic nerve and retina, during and after a subischemic injury induced by intraocular pressure elevation. We report that older (18-month) C57BL/6J mice suffered greater loss of inner retinal function compared with younger adult mice following intraocular pressure (IOP) challenge. To investigate whether age-related vulnerability to IOP challenge can be modified, we subjected 12-month-old mice to dietary restriction (DR) (alternate-day fasting) for 6 months. Compared with age-matched ad libitum fed controls, DR mice showed greater recovery in inner retinal function following IOP challenge. DR was associated with reduced oxidative stress level following injury and improved mitochondrial oxidative phosphorylation enzyme activity compared with ad libitum controls. Taken together, this study provides in vivo evidence that DR improves functional recovery of the retina following injury and points to the potential benefits of therapies that target mitochondria for the protection of the aging retina and optic nerve against injury. PMID- 22217416 TI - Selective inhibition of the membrane attack complex of complement by low molecular weight components of the aurin tricarboxylic acid synthetic complex. AB - Complement plays a vital role in both the innate and adaptive immune systems. It recognizes a target, opsonizes it, generates anaphylatoxins, and directly kills cells through the membrane attack complex (MAC). This final function, which assembles C5b-9(n) on viable cell surfaces, can kill host cells through bystander lysis. Here we identify for the first time compounds that can inhibit bystander lysis while not interfering with the other essential functions of complement. We show that aurin tricarboxylic acid (ATA), aurin quadracarboxylic acid (AQA), and aurin hexacarboxylic acid (AHA), block the addition of C9 to C5b-8 so that the MAC cannot form. These molecules inhibit hemolysis of human, rat, and mouse red cells with a half maximal inhibitory concentration (IC(50)) in the nanomolar range. When given orally to Alzheimer disease type B6SJL-Tg mice, they inhibit MAC formation in serum and improve memory retention. On autopsy, they show no evidence of harm to any organ. Aurin tricarboxylic acid, aurin quadracarboxylic acid, and aurin hexacarboxylic acid may be effective therapeutic agents in Alzheimer disease and other degenerative disorders where self damage from the MAC occurs. PMID- 22217417 TI - Vascular predictors of cognitive decline in patients with mild cognitive impairment. AB - Our aim in this study was to assess the relationship between the state of cerebral vessels and the risk of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). We included 117 MCI patients. They underwent an ultrasonographic assessment of common carotid arteries intima-media thickness (IMT) and carotid plaque index. Cerebrovascular reactivity to hypercapnia in the middle cerebral arteries was calculated with the Breath-Holding Index (BHI). After a 12-month follow-up period, neuropsychological examinations demonstrated a progression to dementia in 21 patients. Pathological values of BHI and IMT significantly increased the risk of conversion (BHI: odds ratio, 5.80; 95% confidence interval, 1.83-18.37, p < 0.05; IMT: odds ratio, 3.08; 95% confidence interval, 1.02-9.33; p < 0.05, multinomial logistic regression analysis). Comparison between patients with all normal values and those with the simultaneous alteration of the 2 vascular indexes showed an increase in the risk of conversion from 9% to 33% (ordinal regression analysis). Our findings show that alterations of cerebral vessel functional and anatomic status increase the risk of conversion from MCI to dementia. PMID- 22217419 TI - Vitamin D rejuvenates aging eyes by reducing inflammation, clearing amyloid beta and improving visual function. AB - Vitamin D(3) plays a key role in immune regulation and may protect against the aging process. A focal point for age-related changes is the outer retina of the eye where there is high metabolic demand resulting in a gradual increase in extracellular deposition, inflammation, and cell loss giving rise to visual decline. Here, we demonstrate that vitamin D(3) administration for only 6 weeks in aged mice significantly impacts on this aging process. Treated mice showed significant reductions in retinal inflammation and levels of amyloid beta (Abeta) accumulation, which is a hallmark of aging. They also had significant reductions in retinal macrophage numbers and marked shifts in their morphology. These changes were reflected in a significant improvement in visual function, revealing that vitamin D(3) is a route to avoiding the pace of age-related visual decline. Excess amyloid beta deposition and inflammation are risk factors leading to age related macular degeneration (AMD), the largest cause of blindness in those older than 50 years in developed countries. Recently, vitamin D(3) has been linked epidemiologically to protection against age-related macular degeneration. Hence, vitamin D(3) enrichment is likely to represent a beneficial route for those at risk. PMID- 22217418 TI - Age-associated learning and memory deficits in two mouse versions of the Stone T maze. AB - We have previously reported that a modified Stone T-maze (STM), using escape from water as motivation, was effective in evaluating learning and memory ability in young C57/BL6 mice. Here we report on the effectiveness and sensitivity of the STM in the assessment of age-related learning and memory deficits in mice using either escape from foot shock or water as the motivational manipulations. C57BL/6Nia mice 7-, 12-, 20- and 24-months old received 15 massed trials in the escape from foot shock motivated STM while C57BL/6Nia mice 5-, 12-, and 25-months old were tested in the escape from water STM. Analysis of errors, the main performance variable, revealed similar results in both versions of the task with younger mice making fewer errors. Notably, mice of all ages in the water motivated version moved quickly through the maze, while all ages of mice in the shock-motivated version tended to wait for shock to be initiated to move forward. Overall, both versions of the STM appear to be sensitive to age-related changes in learning and memory and provide an alternative to other testing paradigms such as the Morris water maze which are susceptible to performance confounds which can lead to uninterpretable results. PMID- 22217420 TI - Self-assembled pullulan-silica oxygen barrier hybrid coatings for food packaging applications. AB - The scope of this study encompassed the evaluation of pullulan as a suitable biopolymer for the development of oxygen barrier coatings to be applied on poly(ethylene terephthalate) (PET), especially for food packaging applications. To enhance the oxygen barrier properties of the organic phase (pullulan) even at high relative humidity values, an inorganic phase (silica), obtained through in situ polymerization, was also utilized to obtain hybrid coatings via the sol-gel technique. Transmission electron microscopy (TEM) images and Fourier transform infrared (FT-IR) spectra showed that mixing the two phases yielded a three dimensional hybrid network formed by self-assembly and mediated by the occurrence of new hydrogen-bond interactions at the intermolecular level, although the formation of new covalent bonds could not be excluded. The deposition of the hybrid coatings decreased the oxygen transmission rate (OTR) of the plastic substrate by up to 2 orders of magnitude under dry conditions. The best performance throughout the scanned humidity range (0%-80% relative humidity) was obtained for the formulation with the lowest amount of silica (that is, an organic/inorganic ratio equal to 3). PMID- 22217421 TI - Regulation of the mouse gene encoding TAFI by TNFalpha: role of NFkappaB binding site. AB - Thrombin-activable fibrinolysis inhibitor (TAFI) is a plasma pro carboxypeptidase, encoded by the gene CPB2, with roles in both inhibition of fibrinolysis and inflammation. In mice, plasma TAFI levels and hepatic CPB2 mRNA expression were found to increase within 24h after intra-peritoneal lipopolysaccharide (LPS) injection. On the other hand, plasma TAFI in humans decrease in experimental endotoxemia and sepsis and we have previously demonstrated that CPB2 mRNA abundance in human hepatoma cells is decreased by inflammatory cytokines. Here, we have evaluated the effects of TNFalpha on mouse CPB2 expression. Treatment of primary mouse hepatocytes or the mouse hepatic cell line FL83B with TNFalpha for 12-48h resulted in increases in CPB2 mRNA abundance of up to 2-fold; mouse TAFI protein levels secreted from FL83B cells increased 2.7-fold after 48h treatment with TNFalpha. When FL83B cells were transfected with reporter plasmids containing the mouse CPB2 5'-flanking region, treatment with TNFalpha for 24 and 48h resulted in a 1.5-fold increased mouse CPB2 promoter activity. Mutation of a putative NFkappaB site not conserved in the human gene ablated the increased promoter activity observed following TNFalpha treatment. This site binds NFkappaB as assessed by gel mobility shift assays, and TNFalpha treatment increases the translocation of NFkappaB from the cytoplasm to the nucleus of mouse hepatocytes. These results demonstrate that the unique NFkappaB site in the mouse CPB2 promoter is functional and mediates the upregulation of mouse CPB2 expression by TNFalpha via increase in NFkappaB translocation to the nucleus. PMID- 22217422 TI - Blistering insights into the pathogenesis of bullous pemphigoid. PMID- 22217423 TI - Dissolving the tenacity of obsessional doubt: implications for treatment outcome. AB - BACKGROUND AND OBJECTIVES: Previous research has found that a high impact of possibility based information during reasoning prevents the resolution of doubt among those with Obsessive-Compulsive Disorder (OCD). It was expected that the ability of those with OCD to resolve obsessional doubt would improve following Inference Based Treatment (IBT). METHODS: The ability to resolve doubt, including the relative impact of reality and possibility based information, was measured before and after treatment with the Inference Processes Task in a group of 35 participants diagnosed with OCD. RESULTS: Results confirmed that IBT improved the participants' ability to resolve obsessional doubt. Those who improved their ability to resolve doubt showed a significantly better treatment outcome. Improvements appeared mostly due to a lowered impact of possibility based information following treatment. LIMITATIONS: The study did not include a control condition although results clearly indicate that the ability to resolve obsessional is closely linked to the most relevant quantifiers of treatment outcome. In addition, relatively small sample sizes prevented more powerful multiple comparisons between groups. CONCLUSIONS: Results suggest treatment implications and the relevance of dissolving the tenacity of obsessional doubt in OCD. PMID- 22217424 TI - Cyclodextrin-surfactant coassembly depends on the cyclodextrin ability to crystallize. AB - Full equilibrium phase diagrams are presented for two ternary systems composed of the cationic surfactant dodecyltrimethylammonium bromide (DTAB), water (D(2)O), and a cyclodextrin, either beta-cyclodextrin (beta-CD) or (2-hydroypropyl)-beta cyclodextrin (2HPbetaCD). (2)H NMR, SAXS, WAXS, and visual examination were used to determine the phase boundaries and characterize the nature of the phases formed. Additionally, diffusion (1)H NMR was used to investigate parts of the diagrams. The water solubility of 2HPbetaCD is 80% (w/w), whereas it is only 1.85% (w/w) for beta-CD. Solubility increases for both species upon complexation with DTAB; while the increase is minute for 2HPbetaCD, it is dramatic for beta CD. Both systems displayed an isotropic liquid solution (L(1)) one-phase region, the extension of which differs extensively between the two systems. Additionally, the DTAB:2HPbetaCD:water system also comprised a normal hexagonal (H(1)) area, which was not found for the DTAB:beta-CD:water system. In the DTAB:beta-CD:water system, on the other hand, we found cocrystallization of DTAB and beta-CD. From this work we conclude that DTAB and CD molecules form 1:1 inclusion complexes with high affinities. Moreover, we observed indications of an association of 2HPbetaCD to DTAB micelles in the isotropic solution phase, which was not the case for beta-CD and DTAB micelles. This is, to our knowledge, the first complete phase diagrams of surfactant-CD mixtures; as a novel feature it includes the observation of cocrystallization at high concentrations. PMID- 22217427 TI - Gender (in)equality among employees in elder care: implications for health. AB - INTRODUCTION: Gendered practices of working life create gender inequalities through horizontal and vertical gender segregation in work, which may lead to inequalities in health between women and men. Gender equality could therefore be a key element of health equity in working life. Our aim was to analyze what gender (in)equality means for the employees at a woman-dominated workplace and discuss possible implications for health experiences. METHODS: All caregiving staff at two workplaces in elder care within a municipality in the north of Sweden were invited to participate in the study. Forty-five employees participated, 38 women and 7 men. Seven focus group discussions were performed and led by a moderator. Qualitative content analysis was used to analyze the focus groups. RESULTS: We identified two themes. "Advocating gender equality in principle" showed how gender (in)equality was seen as a structural issue not connected to the individual health experiences. "Justifying inequality with individualism" showed how the caregivers focused on personalities and interests as a justification of gender inequalities in work division. The justification of gender inequality resulted in a gendered work division which may be related to health inequalities between women and men. Gender inequalities in work division were primarily understood in terms of personality and interests and not in terms of gender. CONCLUSION: The health experience of the participants was affected by gender (in)equality in terms of a gendered work division. However, the participants did not see the gendered work division as a gender equality issue. Gender perspectives are needed to improve the health of the employees at the workplaces through shifting from individual to structural solutions. A healthy setting approach considering gender relations is needed to achieve gender equality and fairness in health status between women and men. PMID- 22217426 TI - Translation and localization of SNOMED CT in China: a pilot study. PMID- 22217428 TI - Early cognitive development in children with infantile Pompe disease. AB - This report describes the cognitive development of 17 children with infantile Pompe disease who participated in a 52-week clinical trial of enzyme replacement therapy (ERT) via biweekly infusion of Myozyme(r) (alglucosidase alfa). Subjects were six months of age or younger (adjusted for gestational age) upon initiation of ERT. The Mental Scale of the Bayley Scales of Infant Development-Second Edition (BSID-II) was administered to obtain a Mental Development Index (MDI) at baseline and weeks 12, 26, 38, and 52 of ERT to assess cognitive development in this treated cohort. Data regarding motor development were also obtained at the same visits and these were used to determine correlations between cognitive and motor development. Over the course of the study, two subgroups of subjects emerged: high responders who were sitting independently and/or ambulating by week 52 (n=13) and limited responders who showed minimal motor gains throughout the first year of ERT (n=4). In the high responder group, MDI scores on the BSID-II remained stable throughout the study and were within normal limits. Positive correlations between cognitive and motor development were also present. These data suggest that the cognitive function of infants up to 18 months of age with Pompe disease is unaffected by the possible presence of glycogen in the central nervous system. Continued investigation of the cognitive development of older survivors is warranted. PMID- 22217430 TI - Eco-physiological adaptations that favour freshwater cyanobacteria in a changing climate. AB - Climate change scenarios predict that rivers, lakes, and reservoirs will experience increased temperatures, more intense and longer periods of thermal stratification, modified hydrology, and altered nutrient loading. These environmental drivers will have substantial effects on freshwater phytoplankton species composition and biomass, potentially favouring cyanobacteria over other phytoplankton. In this Review, we examine how several cyanobacterial eco physiological traits, specifically, the ability to grow in warmer temperatures; buoyancy; high affinity for, and ability to store, phosphorus; nitrogen-fixation; akinete production; and efficient light harvesting, vary amongst cyanobacteria genera and may enable them to dominate in future climate scenarios. We predict that spatial variation in climate change will interact with physiological variation in cyanobacteria to create differences in the dominant cyanobacterial taxa among regions. Finally, we suggest that physiological traits specific to different cyanobacterial taxa may favour certain taxa over others in different regions, but overall, cyanobacteria as a group are likely to increase in most regions in the future. PMID- 22217429 TI - Diet in phenylketonuria: a snapshot of special dietary costs and reimbursement systems in 10 international centers. AB - BACKGROUND AND AIMS: To gather exploratory data on the costs and reimbursement of special dietary foods used in the management of phenylketonuria (PKU) from ten international specialist PKU centers. METHODS: Experts from each center provided data on retail costs of the three most frequently used phenylalanine-free protein substitutes and low-protein foods at their center; reimbursement of protein substitutes and low-protein foods; and state monetary benefits provided to PKU patients. RESULTS: The mean annual cost of protein substitutes across 4 age groups (2 y, 8 y, 15 y and adults) ranged from ?4273 to ?21,590 per patient. The cost of low-protein products also differed; the mean cost of low-protein bread varied from ?0.04 to ?1.60 per 100 kcal. All protein substitutes were either fully reimbursed or covered by health insurance. However, reimbursement for low protein products varied and state benefits differed between centers. CONCLUSIONS: The variation in the cost and reimbursement of diet therapy and the level of additional state benefits for PKU patients demonstrates the large difference in expenditure on and access to PKU dietary products. This highlights the inequality between healthcare systems and access to special dietary products for people with PKU, ultimately leading to patients in some countries receiving better care than others. PMID- 22217431 TI - Instrumental activities of daily living performance in healthy and cognitively intact seniors from a Brazilian sample and its relation to age and other socio demographic variables. AB - BACKGROUND: Studies on functional capacity in community-dwelling older people have shown associations between declines in instrumental activities of daily living (IADL) and several factors. Among these, age has been the most consistently related to functional capacity independent of other variables. We aimed at evaluating the performance of a sample of healthy and cognitively intact Brazilian older people on activities of daily living and to analyze its relation to social-demographic variables. METHODS: We conducted a secondary analysis of data collected for previous epidemiological studies with community-dwelling subjects aged 60 years or more. We selected subjects who did not have dementia or depression, and with no history of neurological diseases, heart attack, HIV, hepatitis or arthritis (n = 1,111). Functional capacity was assessed using the Brazilian version of the Older American Resources and Services Questionnaire (BOMFAQ). ADL performance was analyzed according to age, gender, education, and marital status (Pearson's chi2, logistic regression). RESULTS: IADL difficulties were present in our sample, especially in subjects aged 80 years or more, with lower levels of education, or widowed. The logistic regression analysis results indicated that "higher age" and "lower education" (p <= 0.001) remained significantly associated with IADL difficulty. CONCLUSIONS: Functional decline was present in older subjects even in the absence of medical conditions and cognitive impairment. Clinicians and researchers could benefit from knowing what to expect from older people regarding IADL performance in the absence of medical conditions. PMID- 22217432 TI - High-frequency rTMS treatment increases white matter FA in the left middle frontal gyrus in young patients with treatment-resistant depression. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for treatment-resistant depression (TRD), but its therapeutic mechanisms are unclear. White matter abnormalities are thought to cause network dysfunction underlying TRD. Diffusion tensor imaging (DTI) is an ideal tool for examining neural connections and the integrity of white matter. Few studies have used DTI to investigate the impact of rTMS on alterations of whiter matter in TRD. METHOD: 30 young treatment-resistant unipolar depression patients (19 males and 11 females) were enrolled in a double-blind, randomized high-frequency (15 Hz) rTMS treatment study. Seventeen patients were treated with real stimulation, and 13 were treated with sham stimulation. White-matter fractional anisotropy (FA) was evaluated using voxel-based analysis (VBA) of FA maps derived from DTI before and after treatment. Twenty-five age- and gender-matched subjects were examined as a control group. RESULTS: In an exploratory VBA method, clusters of fifty voxels or greater that survived a family-wise error (FWE)-corrected threshold of p<0.05 were considered significant. The results revealed significantly reduced FA in the left middle frontal gyrus, with peak coordinates [-18 46 -14] in TRD patients. This reduced FA was significantly improved after active rTMS treatment, but not sham stimulation. FA increases were correlated with decreased depressive symptoms. LIMITATIONS: This study requires replication and further clarification in a larger patient population, and optimization of stimulation locations and methods. CONCLUSIONS: These results suggest that the efficacy of rTMS on TRD is related to increased white-matter FA in the left middle frontal gyrus. PMID- 22217433 TI - Prosorhynchoides borealis Bartoli, Gibson & Bray, 2006 (Digenea: Bucephalidae) cercariae from Abra prismatica (Mollusca: Bivalvia) in Icelandic waters. AB - This paper reports the adult stage of Prosorhynchoides borealis (Digenea) from Lophius piscatorius in Icelandic waters and infections with the larval stages (sporocysts and cercariae) found for the first time in the bivalve Abra prismatica (Semelidae). The previously known first intermediate host was Abra alba (Semelidae). Ribosomal DNA sequencing studies on all three life stages of the parasite (cercariae, metacercariae, adults) were performed to confirm their identites. Morphometric measurements confirmed that the adult worms belong to the newly described species P. borealis. Prosorhynchoides borealis sporocysts filled with cercariae were found in 16% of A. prismatica bivalves sampled at depths between 34 and 93 m off South Iceland. Prevalence ranged from 0 to 44% between different localities. The parasite was found only in the larger bivalves. Extensive sporocyst infection in the haemocoel of the foot caused mechanical muscle damage with subsequent degeneration and necrosis. Other tissues, including the digestive gland, nephridia, gills and intestine, were less heavily infected. Only focal necrosis was observed in the digestive gland, nephridia and gills, and local atrophy in the intestine. Cercariae were also observed in the lumen of both the stomach and intestine. This is the first report of A. prismatica as an alternative first intermediate host for P. borealis. Ribosomal DNA sequence data reveals 100% homology in the data between cercariae, metacercariae and adult digeneans, supporting the morphological data suggesting that all stages belong to the same species. PMID- 22217434 TI - Treatment of mixed bipolar states. AB - Mixed bipolar states are associated with more severe symptoms and outcome. Our aim is to review the literature examining their treatment. We conducted a literature search of randomized clinical studies and post-hoc analyses on mixed bipolar states' treatment. Remarkably, there is only one double-blind, placebo controlled trial, recruiting a mixed episode cohort, and one post-hoc analysis of this trial, while most data come from post-hoc analyses of trials including both manic and mixed patients. Improvement of manic symptoms in mixed episodes is similar to that seen in pure manic episodes and independent of baseline depressive features. The magnitude of response to manic symptoms' treatment probably exceeds that of depressive symptoms, which appear to resolve later. Valproate and carbamazepine are effective in acute mixed episodes, but the efficacy of lithium appears questionable. Atypical antipsychotic monotherapy improves both manic and depressive symptoms. Mood-stabilizer-atypical antipsychotic combination increases this effect. Atypical antipsychotic antidepressant combination against acute mixed depression does not increase the risk for mania, although its superior efficacy vs. atypical antipsychotic monotherapy cannot be supported by current data. As regards prophylaxis, atypical antipsychotic monotherapy is associated with a lower incidence of and a longer time to relapse of any kind. The augmentation of lithium or divalproex with atypical antipsychotics increases prophylactic efficacy. Lithium or divalproex monotherapy have not been associated with significant prophylactic benefits following mixed mania. New, randomized prospective trials involving homogeneous cohorts of mixed bipolar patients are needed in order to delineate the appropriate pharmacological treatment of mixed states. PMID- 22217435 TI - Recent advances in treatments for schizophrenia. PMID- 22217436 TI - Antipsychotics in the treatment of schizophrenia: an overview. AB - Schizophrenia is characterized by positive, negative, cognitive, disorganization, and mood symptoms. Antipsychotics are the mainstay in the pharmacologic treatment of schizophrenia. Findings concerning efficacy for positive symptoms and disorganization suggest no consistent differences among available antipsychotics, with the exception of clozapine's superior efficacy for treatment-resistant schizophrenia. Efficacy for negative, depressive, and cognitive symptoms appears to be determined by (1) the extent to which reduction in positive symptoms brings about improvement in these other domains and (2) the extent to which extrapyramidal side effects (EPS) and anticholinergic effects (of the antipsychotic and of agents used to treat EPS) exacerbate them. Thus, the ability of antipsychotics to produce a potent antipsychotic effect without EPS and need for concomitant anticholinergic therapy yields multiple therapeutic benefits. In contrast to their broadly similar efficacy, antipsychotics differ markedly in their propensity to cause various adverse effects. Although second-generation antipsychotics (SGAs) have generally been believed to be associated with a lower risk of EPS but a higher risk of metabolic adverse effects than first-generation agents (FGAs), the substantial variation in these and other side effects among agents within both classes indicates that it is not clinically useful to make a categorical distinction between FGAs and SGAs. Choice of antipsychotic medication should be based on individual preference, prior treatment response and side effect experience, medical history and risk factors, and adherence history, with side effect profile a major determinant of antipsychotic choice. PMID- 22217437 TI - What are we looking for in new antipsychotics? AB - Antipsychotics are the cornerstone of treatment for psychotic and some nonpsychotic disorders. However, despite pharmacologic advances, considerable areas of need remain. This article reviews desirable properties for future antipsychotics and considers how far current agents have come in achieving those objectives. Preferably, new antipsychotics should have a "balanced" pharmacodynamic profile that addresses the need for efficacy without compromising psychiatric or physical well-being; a safe, fast, and convenient pharmacokinetic profile; a definable therapeutic window, and availability in multiple formulations. Compared with available agents, new antipsychotics should ideally have at least similar efficacy for positive symptoms, agitation, and aggression and better efficacy for negative or cognitive symptoms, relapse prevention, treatment-resistant illness, and associated problems such as depression, anxiety, and substance abuse. Improved tolerability and subjective acceptability to patients are also important in promoting adherence and continued treatment. Finally, they should have improved effectiveness in facilitating functioning, subjective well-being, quality of life, and, ultimately, recovery. Given the complexity of schizophrenia, its unknown etiology and pathophysiology, and challenges in clinical trial design and conduct, it is not surprising that it has remained difficult to develop antipsychotics with novel mechanisms. To achieve true breakthroughs, we need greater insight into the pathophysiology underlying specific disease processes and therapeutic and adverse responses. It is hoped that research on drug-specific biomarkers that can predict response in specific patient groups will advance personalized psychiatric care and improve patient outcomes. PMID- 22217438 TI - Asenapine: a clinical overview. AB - Asenapine is a new, second-generation (atypical) antipsychotic medication with demonstrated efficacy for the acute and maintenance treatment of schizophrenia. It is administered as sublingual tablets in doses of 5 or 10 mg bid. It is well tolerated, with a dropout rate for adverse events similar to that of placebo. Asenapine is associated with a mean weight gain of less than 1 kg over a year and a relatively neutral effect on lipid and glucose levels. It can cause sedation and mild extrapyramidal side effects. Asenapine has a broad receptor affinity profile for most serotonergic, dopaminergic, and adrenergic receptors, with no appreciable affinity for muscarinic receptors. Asenapine may be a helpful treatment option for patients with schizophrenia when weight gain, dyslipidemia, and endocrine abnormalities are a concern. PMID- 22217439 TI - Iloperidone: a clinical overview. AB - Iloperidone is a new second-generation (atypical) antipsychotic medication approved for the treatment of schizophrenia in adults. The target dose of 6 mg bid can be achieved in 4 days, with titration recommended to minimize postural hypotension. The maximum recommended dose is 12 mg bid. The tolerability profile of iloperidone is noteworthy in terms of modest weight gain, no medically important changes in lipid and glucose levels, little in the way of prolactin elevation, and absence of extrapyramidal side effects, including akathisia. However, iloperidone can prolong the QTc interval on electrocardiogram. Iloperidone may be best suited for patients who are sensitive to akathisia or who are unable to tolerate the sedation and weight gain that can occur more frequently with other antipsychotics. PMID- 22217440 TI - Lurasidone: a clinical overview. AB - Lurasidone is a new second-generation (atypical) antipsychotic approved for the treatment of schizophrenia in adults. The recommended dose is 40-80 mg given once daily, with no titration needed. Lurasidone should be taken with food. The tolerability profile of lurasidone is noteworthy in terms of a good weight and metabolic profile and no cardiovascular adverse effects such as orthostatic hypotension or prolongation of the QTc interval. Lurasidone is associated with some somnolence, akathisia, nausea, and parkinsonism, especially early in treatment. Its preclinical profile suggested it might be helpful for cognitive or depressive symptoms; early findings have shown some benefit in these areas, but additional studies are needed. Lurasidone may be particularly helpful for patients with schizophrenia who are overweight or have endocrine problems (diabetes, dyslipidemia) or comorbid cardiovascular conditions. PMID- 22217441 TI - Repetitive treatment with diluted bee venom reduces neuropathic pain via potentiation of locus coeruleus noradrenergic neuronal activity and modulation of spinal NR1 phosphorylation in rats. AB - We previously demonstrated that a single injection of diluted bee venom (DBV) temporarily alleviates thermal hyperalgesia, but not mechanical allodynia, in neuropathic rats. The present study was designed to determine whether repetitive injection of DBV produces more potent analgesic effects on neuropathy-induced nociception and whether those effects are associated with increased neuronal activity in the locus coeruleus (LC) and with the suppression of spinal NMDA receptor NR1 subunit phosphorylation (pNR1). DBV (.25 mg/kg) was administered subcutaneously twice a day for 2 weeks beginning on day 15 post-chronic constrictive injury surgery. Pain responses were examined and potential changes in LC Fos expression and spinal pNR1 expression were determined. Repetitive DBV administration significantly reduced mechanical allodynia, as well as thermal hyperalgesia. The activity of LC noradrenergic neurons was increased and spinal pNR1 expression was significantly suppressed by repetitive DBV as compared with those of vehicle or single DBV injection. These suppressive effects of repetitive DBV on neuropathic pain and spinal pNR1 were prevented by intrathecal pretreatment of idazoxan, an alpha-2 adrenoceptor antagonist. These results indicate that repetitive DBV produces potent analgesic effects on neuropathic pain and this is associated with the activation of the LC noradrenergic system and with a reduction in spinal pNR1. PERSPECTIVE: The results of current study demonstrate that repetitive administration of DBV significantly suppresses neuropathic pain. Furthermore, this study provides mechanistic information that repetitive treatment of DBV can produce more potent analgesic effect than single DBV treatment, indicating a potential novel strategy for the management of chronic pain. PMID- 22217442 TI - Identification in lupin seed of a serine-endopeptidase activity cleaving between twin arginine pairs and causing limited proteolysis of seed storage proteins. AB - The occurrence of twin-arginine motifs (-R-R-) in the amino acid sequences of animal pro-proteins frequently defines the cleavage site(s) for their structural/functional maturation. No information is available on the presence and possible biological meaning of these motifs in the seed storage proteins. In this work, a novel endopeptidase activity with cleavage specificity to twin-arginine pairs has been detected in mature dry Lupinus albus seeds. The endopeptidase was tested with a number of endogenous and exogenous protein substrates, which were selected according to the presence of one or more twin-arginine residue motifs in their amino acid sequences. The observed hydrolysis patterns were limited and highly specific. Partial proteolysis led to stable polypeptide fragments that were characterized by 1- and 2-D electrophoresis. Selected polypeptides were submitted to N-terminal amino acid sequencing and mass spectrometry analyses. These approaches, supported by bioinformatic analysis of the available sequences, allowed the conclusion that the polypeptide cleavage events had occurred at the peptide bonds comprised between twin-arginine residue pairs with all tested protein substrates. The endopeptidase activity was inhibited by 4-(2 AminoEthyl)Benzene-Sulphonyl Fluoride hydrochloride (AEBSF), leupeptin, and serine proteinase protein inhibitors, while it was not affected by pepstatin, trans-Epoxysuccinyl-L-leucylamido(4-guanidino)butane (E64), and ethylenediaminetetraacetic acid (EDTA), thus qualifying the Arg-Arg cleaving enzyme as a serine endopeptidase. The structural features of storage proteins from lupin and other legume seeds strongly support the hypothesis that the occurrence of an endopeptidase activity cleaving -R-R- bonds may be functional to facilitate their degradation at germination and possibly generate polypeptide fragments with specific biological activity. PMID- 22217443 TI - BaVS3 probed by V L edge x-ray absorption spectroscopy. AB - Polarization dependent vanadium L edge x-ray absorption spectra of BaVS(3) single crystals are measured in the four phases of the compound. The difference between signals with the polarizations E perpendicular to c and E is parallel to c (linear dichroism) changes with temperature. Besides increasing the intensity of one of the maxima, a new structure appears in the pre-edge region below the metal insulator transition. More careful examination brings to light that the changes start already with pretransitional charge density wave fluctuations. Simple symmetry analysis suggests that the effect is related to rearrangements in the E(g) and A(1g) states, and is compatible with the formation of four inequivalent V-sites along the V-S chain. PMID- 22217444 TI - Iterative reconstruction methods in two different MDCT scanners: physical metrics and 4-alternative forced-choice detectability experiments--a phantom approach. AB - This paper characterizes and evaluates the potential of three commercial CT iterative reconstruction methods (ASIRTM, VEOTM and iDose4(TM)) for dose reduction and image quality improvement. We measured CT number accuracy, standard deviation (SD), noise power spectrum (NPS) and modulation transfer function (MTF) metrics on Catphan phantom images while five human observers performed four alternative forced-choice (4AFC) experiments to assess the detectability of low- and high-contrast objects embedded in two pediatric phantoms. Results show that 40% and 100% ASIR as well as iDose4 levels 3 and 6 do not affect CT number and strongly decrease image noise with relative SD constant in a large range of dose. However, while ASIR produces a shift of the NPS curve apex, less change is observed with iDose4 with respect to FBP methods. With second-generation iterative reconstruction VEO, physical metrics are even further improved: SD decreased to 70.4% at 0.5 mGy and spatial resolution improved to 37% (MTF(50%)). 4AFC experiments show that few improvements in detection task performance are obtained with ASIR and iDose4, whereas VEO makes excellent detections possible even at an ultra-low-dose (0.3 mGy), leading to a potential dose reduction of a factor 3 to 7 (67%-86%). In spite of its longer reconstruction time and the fact that clinical studies are still required to complete these results, VEO clearly confirms the tremendous potential of iterative reconstructions for dose reduction in CT and appears to be an important tool for patient follow-up, especially for pediatric patients where cumulative lifetime dose still remains high. PMID- 22217445 TI - Staff training using STAR: a pilot study in UK care homes. AB - BACKGROUND: Symptoms such as depression, anxiety, and behavioral problems are very common in people with dementia living in care homes. Staff training has been identified as a promising psychosocial intervention. This pilot study investigated the feasibility of implementing the Staff Training in Assisted Living Residences (STAR) program in UK care homes. METHODS: The eight-week STAR program was delivered in two care homes. Twenty-five care staff attended the training. Thirty-two residents, with dementia and clinically significant anxiety, depression, or behavioral problems, were included in the study. Residents and staff were assessed at baseline and eight-week follow-up. RESULTS: Residents demonstrated significantly reduced symptoms of depression and behavioral problems following the implementation of the program, although resident-rated quality of life and anxiety symptoms did not improve significantly. Staff sense of hopefulness towards people with dementia also improved significantly and staff rated themselves as significantly more competent at forming relationships with residents. CONCLUSION: Delivering the STAR program to care staff can have an impact on the behavioral and psychological symptoms of dementia displayed by care home residents. The program was feasible to implement and was rated highly by care staff. A large-scale randomized controlled trial is now required to evaluate the effectiveness of this training intervention. PMID- 22217446 TI - Toll-like receptor 4 on islet beta cells senses expression changes in high mobility group box 1 and contributes to the initiation of type 1 diabetes. AB - Type 1 diabetes mellitus is caused by the autoimmune destruction of beta cells within the islets. In recent years, innate immunity has been proposed to play a key role in this process. High-mobility group box 1 (HMGB1), an inflammatory trigger in a number of autoimmune diseases, activates proinflammatory responses following its release from necrotic cells. Our aim was to determine the significance of HMGB1 in the natural history of diabetes in non-obese diabetic (NOD) mice. We observed that the rate of HMGB1 expression in the cytoplasm of islets was much greater in diabetic mice compared with non-diabetic mice. The majority of cells positively stained for toll-like receptor 4 (TLR4) were beta cells; few alpha cells were stained for TLR4. Thus, we examined the effects of anti-TLR4 antibodies on HMGB1 cell surface binding, which confirmed that HMGB1 interacts with TLR4 in isolated islets. Expression changes in HMGB1 and TLR4 were detected throughout the course of diabetes. Our findings indicate that TLR4 is the main receptor on beta cells and that HMGB1 may signal via TLR4 to selectively damage beta cells rather than alpha cells during the development of type 1 diabetes mellitus. PMID- 22217447 TI - CpG methylation at GATA elements in the regulatory region of CCR3 positively correlates with CCR3 transcription. AB - DNA methylation may regulate gene expression by restricting the access of transcription factors. We have previously demonstrated that GATA-1 regulates the transcription of the CCR3 gene by dynamically interacting with both positively and negatively acting GATA elements of high affinity binding in the proximal promoter region including exon 1. Exon 1 has three CpG sites, two of which are positioned at the negatively acting GATA elements. We hypothesized that the methylation of these two CpGs sites might preclude GATA-1 binding to the negatively acting GATA elements and, as a result, increase the availability of GATA-1 to the positively acting GATA element, thereby contributing to an increase in GATA-1-mediated transcription of the gene. To this end, we determined the methylation of the three CpG sites by bisulfate pyrosequencing in peripheral blood eosinophils, cord blood (CB)-derived eosinophils, PBMCs, and cell lines that vary in CCR3 mRNA expression. Our results demonstrated that methylation of CpG sites at the negatively acting GATA elements severely reduced GATA-1 binding and augmented transcription activity in vitro. In agreement, methylation of these CpG sites positively correlated with CCR3 mRNA expression in the primary cells and cell lines examined. Interestingly, methylation patterns of these three CpG sites in CB-derived eosinophils mostly resembled those in peripheral blood eosinophils. These results suggest that methylation of CpG sites at the GATA elements in the regulatory regions fine-tunes CCR3 transcription. PMID- 22217448 TI - Role of placenta growth factor in cancer and inflammation. AB - Accumulating evidences have documented that angiogenesis is closely linked to inflammation and regulators of angiogenesis play key roles in various inflammatory conditions. PlGF is an angiogenic protein belonging to the VEGF family and is upregulated mainly in pathologic conditions. Recently, PlGF was discovered having a proinflammatory role in inflammatory arthritis and its serum level drew attention not only as a useful surrogate biomarker but also a potential therapeutic target in atherosclerosis and various cancers. Particularly, PlGF has attractive clinical values because endogenous PlGF is redundant for vascular development and physiological vessel maintenance in healthy adults. However, there have been conflicting results about the efficacy of PlGF inhibition depending on the experimental and clinical settings. Further close investigations for resolving the puzzle of PlGF biology are required. PMID- 22217450 TI - TiNS Special Issue: neuropsychiatric disorders. PMID- 22217449 TI - Effect of extracts from Phyllanthus watsonii Airy Shaw on cell apoptosis in cultured human breast cancer MCF-7 cells. AB - Species of Phyllanthus have traditionally been used for hundreds of years for treating many ailments including diabetes, anemia, bronchitis and hepatitis. The present study aims to investigate the cytotoxic and apoptotic effects of methanol (PWM), hexane (PWH) and ethyl acetate (PWE) extracts from the leaves of the endemic plant Phyllanthus watsonii Airy Shaw (Phyllanthaceae) on MCF-7 human breast cancer cells. We observed that the PWM, PWH and PWE extracts were cytotoxic and selectively inhibited the growth and proliferation of MCF-7 cells compared to untreated control in a dose dependent manner with an IC(50) of 12.7 +/- 4.65, 7.9 +/- 0.60 and 7.7 +/- 0.29 MUg/ml, respectively. However, the extracts were not toxic at these concentrations to normal human lung fibroblast MRC-5 cells. Cell death induced by PWM, PWH and PWE extracts were mainly due to apoptosis which was characterized by apoptotic morphological changes and a nuclear DNA fragmentation. Caspase-3 activation following P. watsonii extracts treatment was also evident for apoptotic cell death which was preceded by an S phase cell cycle perturbation. The results suggested that the cytotoxic activity of P. watsonii extracts was related to an early event of cell cycle perturbation and a later event of apoptosis. Hence, P. watsonii displays potential to be further exploited in the discovery and development of new anticancer agents. PMID- 22217451 TI - Mood-stabilizing drugs: mechanisms of action. AB - Mood-stabilizing drugs are the most widely prescribed pharmacological treatments for bipolar disorder, a disease characterized by recurrent episodes of mania and depression. Despite extensive clinical utilization, significant questions concerning their mechanisms of action remain. In recent years, a diverse set of molecular and cellular targets of these drugs has been identified. Based on these findings, downstream effects on neural and synaptic plasticity within key circuits have been proposed. Here, we discuss recent data, identify current challenges impeding progress and define areas for future investigation. Further understanding of the primary targets and downstream levels of convergence of mood stabilizing drugs will guide development of novel therapeutic strategies and help translate discoveries into more effective treatments with less burdensome adverse effect profiles. PMID- 22217453 TI - The Spanish version of the health-related quality of life questionnaire for children and adolescents with heart disease (PedsQL(TM)). AB - INTRODUCTION AND OBJECTIVES: To adapt the Pediatric Quality of Life Inventory (PedsQL(TM)) (General Module and Cardiac Module, 3.0 version) into Spanish. METHODS: Forward and back translation methodology. Cognitive interviewing was used to check the pre-test version. Psychometric properties were computed for the PedsQL(TM) Cardiac Module Scales. Cross-informant variance between children and parents was assessed. RESULTS: The Spanish version has some format changes to make it easier to read and to clarify response choices (version for 5-7 years age group). Some semantically complex terms were replaced with synonyms and others illustrated with examples. Some "out of context" problems were identified with respect to some items (version for children 2-4 and 5-7 years). The percentage of missing item responses ranged from 0% to 5.9%. A high ceiling effect was found, especially in the Cardiac Module, which ranged from 19% to 48.6%. Internal consistency was higher than 0.7, except for Physical Appearance Scale and School Functioning in children. Agreement between information given by children and parents was generally very high. A decreasing trend in scores on all scales was observed in relation to the severity of heart disease, but the differences were only statistically significant in some dimensions. CONCLUSIONS: The Spanish version of the PedsQL(TM) differs somewhat from the original version, particularly on the School Functioning and Physical Appearance Scales, as observed in cognitive interviews. Predictive validity was not demonstrated. PMID- 22217454 TI - Biodegradation of tribenuron methyl that is mediated by microbial acidohydrolysis at cell-soil interface. AB - Tribenuron methyl (TBM) is a member of the sulfonylurea herbicide family and is widely used in weed control. Due to its phytotoxicity to rotating-crops, concerns on TBM-pollution to soil have been raised. In this study, experimental results indicated that microbial activity played a key role in TBM removal from polluted soil. Twenty-six bacterial strains were isolated and their degradation of TBM was evaluated. Serratia sp. strain BW30 was selected and subjected to further investigation on its degradative mechanism. TBM degradation by strain BW30 was dependent on glucose that was converted into lactic or oxalic acids. HPLC-MS analysis revealed two end-products from TBM degradation, and they were identical to the products from TBM acidohydrolysis. Based on this observation, it is proposed that microbe-mediated acidohydrolysis of TBM was involved in TBM degradation in soil, and possible application of this observation in bioremediation of TBM-polluted soil is discussed. PMID- 22217452 TI - Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. AB - Basic and clinical studies demonstrate that stress and depression are associated with atrophy and loss of neurons and glia, which contribute to the decreased size and function of limbic brain regions that control mood and depression, including the prefrontal cortex and hippocampus. Here, we review findings that suggest that opposing effects of stress and/or depression and antidepressants on neurotrophic factor expression and signaling partly explain these effects. We also discuss recent reports that suggest a possible role for glycogen synthase kinase 3 and upstream wingless (Wnt)-frizzled (Fz) signaling pathways in mood disorders. New studies also demonstrate that the rapid antidepressant actions of NMDA receptor antagonists are associated with activation of glutamate transmission and induction of synaptogenesis, providing novel targets for a new generation of fast acting, more efficacious therapeutic agents. PMID- 22217455 TI - Influence of chloride and carbonates on the reactivity of activated persulfate. AB - Chloride and carbonates have the potential to impact pathway, kinetics, and efficiency of oxidation reactions, both as radical scavengers and as metal complexing agents. Traditionally, it is assumed that they have an overall negative impact on the activated persulfate performance. This study investigated the influence of carbonates and chloride on the reactivity of persulfate for three different activation techniques to produce reactive free sulfate radicals; heat, alkaline and iron activation. By using p-nitrosodimethylaniline as model target compound, it was demonstrated that iron activation at neutral pH was not affected by Cl(-) or HCO(3)(-), alkaline activation was enhanced by Cl(-) and even more by CO(3)(2-), and heat activation was enhanced by Cl(-), and no effect from HCO(3)(-) was observed. At pH 2 destruction of perchloroethylene by iron activated persulfate was significantly affected by chloride. Reaction rates decreased, but the overall oxidation efficiency was unaffected up to 28 mM Cl(-). The effect of chloride and carbonates is caused by direct attack of produced reactive chlorine, or carbonate species or by catalysis of the propagation reactions resulting in more sulfate radicals. These results show that carbonate and chloride might play an important role in activated persulfate applications and should not strictly be considered as scavengers. PMID- 22217457 TI - Prediction of enzymatic infarct size in ST-segment elevation myocardial infarction. AB - OBJECTIVES: Predictors of adverse outcomes following myocardial infarction (MI) are well established; however, little is known about what predicts enzymatically estimated infarct size in patients with acute ST-elevation MI. The Complement And Reduction of INfarct size after Angioplasty or Lytics trials of pexelizumab used creatine kinase (CK)-MB area under the curve to determine infarct size in patients treated with primary percutaneous coronary intervention (PCI) or fibrinolysis. METHODS: Prediction of infarct size was carried out by measuring CK MB area under the curve in patients with ST-segment elevation MI treated with reperfusion therapy from January 2000 to April 2002. Infarct size was calculated in 1622 patients (PCI=817; fibrinolysis=805). Logistic regression was used to examine the relationship between baseline demographics, total ST-segment elevation, index angiographic findings (PCI group), and binary outcome of CK-MB area under the curve greater than 3000 ng/ml. RESULTS: Large infarcts occurred in 63% (515) of the PCI group and 69% (554) of the fibrinolysis group. Independent predictors of large infarcts differed depending on mode of reperfusion. In PCI, male sex, no prior coronary revascularization and diabetes, decreased systolic blood pressure, sum of ST-segment elevation, total (angiographic) occlusion, and nonright coronary artery culprit artery were independent predictors of larger infarcts (C index=0.73). In fibrinolysis, younger age, decreased heart rate, white race, no history of arrhythmia, increased time to fibrinolytic therapy in patients treated up to 2 h after symptom onset, and sum of ST-segment elevation were independently associated with a larger infarct size (C index=0.68). CONCLUSION: Clinical and patient data can be used to predict larger infarcts on the basis of CK-MB quantification. These models may be helpful in designing future trials and in guiding the use of novel pharmacotherapies aimed at limiting infarct size in clinical practice. PMID- 22217456 TI - Idiopathic intracranial hypertension: relation between obesity and visual outcomes. AB - BACKGROUND: Increased body mass index (BMI) has been associated with increased risk of idiopathic intracranial hypertension (IIH), but the relationship of BMI to visual outcomes in IIH is unclear. METHODS: A retrospective chart review of all adult cases of IIH satisfying the modified Dandy criteria seen at our institution between 1989 and 2010 was performed. Demographics, diagnostic evaluations, baseline visit and last follow-up examination data, treatment, and visual outcome data were collected in a standardized fashion. Groups were compared, and logistic regression was used to evaluate the relationship of BMI to severe visual loss, evaluating for interaction and controlling for potential confounders. RESULTS: Among 414 consecutive IIH patients, 158 had BMI >=40 (World Health Organization Obese Class III) and 172 had BMI 30-39.9. Patients with BMI >=40 were more likely to have severe papilledema at first neuro-ophthalmology encounter than those with a lower BMI (P = 0.02). There was a trend toward more severe visual loss in 1 or both eyes at last follow-up among those patients with BMI >=40 (18% vs 11%, P = 0.067). Logistic regression modeling found that 10-unit (kilogram per square meter) increases in BMI increased the odds of severe visual loss by 1.4 times (95% confidence interval, 1.03-1.91, P = 0.03) after controlling for sex, race, diagnosed hypertension, and diagnosed sleep apnea. CONCLUSION: Our finding of a trend for severe papilledema and visual loss associated with increasing BMI suggests that very obese IIH patients should be closely monitored for progression of visual field loss. PMID- 22217458 TI - Active behaviours produced by antidepressants and opioids in the mouse tail suspension test. AB - Most classical preclinical tests to predict antidepressant activity were initially developed to detect compounds that influenced noradrenergic and/or serotonergic activity, in accordance with the monoaminergic hypothesis of depression. However, central opioid systems are also known to influence the pathophysiology of depression. While the tail suspension test (TST) is very sensitive to several types of antidepressant, the traditional form of scoring the TST does not distinguish between different modes of action. The present study was designed to compare the behavioural effects of classical noradrenergic and/or serotonergic antidepressants in the TST with those of opioids. We developed a sampling technique to differentiate between behaviours in the TST, namely, curling, swinging and immobility. Antidepressants that inhibit noradrenaline and/or serotonin re-uptake (imipramine, venlafaxine, duloxetine, desipramine and citalopram) decreased the immobility of mice, increasing their swinging but with no effect on their curling behaviour. No differences were observed between antidepressants that act on noradrenergic or serotoninergic transmission. While opioid compounds also decreased the immobility of the mice [morphine, codeine, levorphanol, (-)-methadone, (+/-)-tramadol and (+)-tramadol], they selectively increased curling behaviour. Blocking opioid receptors with naloxone prevented the antidepressant-like effect of codeine, and MU-opioid receptor knockout decreased normal curling behaviour and blocked (+/-)-tramadol-induced curling, further demonstrating the reliability and validity of this approach. These results show that at least two behaviourally distinct processes occur in the TST, highlighting the antidepressant-like effects of opioids evident in this test. Furthermore, our data suggest that swinging and curling behaviours are mediated by enhanced monoamine and opioid neurotransmission, respectively. PMID- 22217459 TI - Can geriatricians improve inpatient heart failure care? Time for a heart to heart. PMID- 22217460 TI - Why do geriatric outpatients have so many moderate and severe vertebral fractures? Exploring prevalence and risk factors. AB - OBJECTIVES: to determine the prevalence of vertebral fractures and their risk factors in geriatric patients. DESIGN: prospective cohort study. SETTING: teaching hospital in Amsterdam, The Netherlands. SUBJECTS: three hundred and three geriatric patients, who had their first visit at a diagnostic day hospital between April and August 2007. MEASUREMENTS: lateral X-rays of the lumbar spine and chest were performed; vertebral fractures were scored according to the semi quantitative method of Genant by trained observers and compared with the official report of radiologists. Co-morbidity, reported falls, mobility and cognitive function were scored. RESULTS: vertebral fractures were observed in 51% (156/303) of geriatric patients. Sixty-nine per cent (107/156) of these fractures were moderate to severe. In 21% (33/156) of the patients with a fracture, vertebral fractures were diagnosed on the lumbar spine X-ray alone. Patients with vertebral fractures had more previous non-vertebral fractures (odds ratio: 2.40 95% CI: 1.40-4.10), had lower serum albumin levels (OR: 0.92 95% CI: 0.87-0.97) and more current prednisone use (OR: 8.94 95% CI: 1.12-71.45). Co-morbidity and cognitive decline were not identified as risk factors. Radiologists reported vertebral fractures in 53% (82/156) of the cases. CONCLUSION: this study showed a very high prevalence of vertebral fractures in geriatric patients; particularly the high prevalence of moderate and severe fractures is remarkable. Because of this high prevalence, the routinely performed lateral X-ray of the chest should be used to look for vertebral fractures. An additional X-ray of the lumbar spine might be useful in patients without vertebral fractures on the chest X-ray. PMID- 22217462 TI - The predictive validity of the Tilburg Frailty Indicator: disability, health care utilization, and quality of life in a population at risk. AB - PURPOSE: To assess the predictive validity of frailty and its domains (physical, psychological, and social), as measured by the Tilburg Frailty Indicator (TFI), for the adverse outcomes disability, health care utilization, and quality of life. DESIGN AND METHODS: The predictive validity of the TFI was tested in a representative sample of 484 community-dwelling persons aged 75 years and older in 2008 (response rate 42%). A subset of all respondents participated 1 year later (N = 336, 69%) and again 2 years later (N = 266, 55%). We used the TFI, the Groningen Activity Restriction Scale assessing disability, seven indicators of health care utilization, and a brief version of the World Health Organization Quality of Life questionnaire (WHOQOL-BREF). The WHOQOL-BREF was assessed in 2008 and 2010; all others were assessed in 2008, 2009, and 2010. RESULTS: The predictive validity of the TFI assessed in 2008 for disability, health care utilization, and quality of life was corroborated by (a) medium to very large associations of frailty with adverse outcomes 1 or 2 years later; (b) mostly good to excellent area under the curve of total frailty; and (c) an increase in predictive accuracy of most adverse outcomes, even after controlling for that same adverse outcome in 2008, and life-course determinants and multimorbidity. Physical frailty was mostly responsible for the predictive validity of the TFI. IMPLICATIONS: This study showed that the TFI is a valid instrument to predict disability, many indicators of health care utilization, and quality of life of older people, 1 and 2 years later. PMID- 22217461 TI - [ECAIS study: inadvertent cardiovascular adverse events in sepsis]. AB - OBJECTIVE: To describe the incidence of cardiovascular adverse events in patients with sepsis in its various stages. DESIGN: A longitudinal, descriptive, observational study was carried out. SETTING: Intensive care units of two university hospitals in Bogota (Colombia). PATIENTS: A number of patients consecutively admitted to the adult ICU with a diagnosis of sepsis, and no evidence of previous ischemic myocardial injury. INTERVENTIONS: Forty-eight hours of electrocardiographic record using Holter technology. MAIN VARIABLES: Ischemia, cardiac arrhythmia, heart rate variability. RESULTS: A total of 100 patients were analyzed, 62% being staged as presenting septic shock. Three percent suffered ischemic events detected by Holter and unnoticed through conventional monitoring. Forty-six percent suffered an arrhythmic event detected by Holter, compared with only 6% as detected by conventional monitoring. Mortality was 40%. All patients showed loss of heart rate variability. CONCLUSION: In this study patients with sepsis showed a low incidence of cardiovascular ischemic events. In contrast, arrhythmic events showed a high incidence. Conventional monitoring failed to detect any of the ischemic events and most arrhythmic events. In this study, cardiovascular events generated by adrenergic discharge had no impact upon mortality. PMID- 22217463 TI - Workforce implications of injury among home health workers: evidence from the National Home Health Aide Survey. AB - PURPOSE OF STUDY: The direct care workforce continues to rank as one of the most frequently injured employee groups in North America. Occupational health and safety studies have shown that workplace injuries translate into negative outcomes for workers and their employers. The National Institute for Occupational Safety and Health (NIOSH) Organization of Work and Occupational Safety and Health framework is used to examine (a) relationships between injuries and work outcomes as reported by home health aides (HHAs) and (b) the likely efficacy of employee training and supervisor support in reducing worker risk for injury. DESIGN AND METHODS: Data for this analysis were drawn from the 2007 National Home Health Aide Survey, a nationally representative survey. Ordinary least squares regression and multinomial logistic regression were used to examine relationships between worker injury and (a) worker outcomes and (b) organizational outcomes and to examine ratings of training and supervisory support relative to risk of injury. RESULTS: Injured aides had lower job satisfaction, higher turnover intent, and poor employment and care quality perceptions. HHA perceptions of poor training and poor supervisory support were significantly related to higher risk for workplace injuries. IMPLICATIONS: The current study suggests that workplace training has an important role in helping reduce direct care worker injuries, thereby decreasing organizational expenses related to injury, such as workers' compensation, sick time, and turnover. The NIOSH Organization of Work and Occupational Safety and Health framework offers a mechanism by which occupational health and safety interventions may be derived to reduce incidents of injury. PMID- 22217464 TI - Gene expression profiling of systems involved in the metabolism and the disposition of xenobiotics: comparison between human intestinal biopsy samples and colon cell lines. AB - Intestinal cell lines are used as in vitro models for pharmacological and toxicological studies. However, a general report of the gene expression spectrum of proteins that are involved in the metabolism and the disposition of xenobiotics in these in vitro systems is not currently available. To fill this information gap, we systematically characterized the expression profile of 377 genes encoding xenobiotic-metabolizing enzymes, transporters, and nuclear receptors and transcription factors in intestinal mucosa (ileum, ascending colon, transverse colon, descending colon, and rectum) from five healthy subjects and in five commonly used intestinal cell lines (Caco-2, C2BBe1, HT29, T84, and FHC). For this, we performed a quantitative real-time reverse transcription-polymerase chain reaction analysis using TaqMan low-density arrays and analyzed the results by different statistical approaches: Spearman correlation coefficients, hierarchical clustering, and principal component analysis (PCA). A large variation in gene expression spectra was observed between intestinal cell lines and intestinal tissues. Both hierarchical clustering and PCA showed that two distinct clusters are visible, of which one corresponds to all cultured cell lines and the other to all intestinal biopsies. The best agreement between human tissue and the representative cell line was observed for human colonic tissues and HT29 and T84 cell lines. Altogether, these data demonstrated that gene expression profiling represents a new valuable tool for investigating in vitro and in vivo expression level correlation. This study has pointed out interesting expression profiles for various colon cell lines, which will be useful for choosing the appropriate in vitro model for pharmacological and toxicological studies. PMID- 22217465 TI - In vitro metabolism of BIIB021, an inhibitor of heat shock protein 90, in liver microsomes and hepatocytes of rats, dogs, and humans and recombinant human cytochrome P450 isoforms. AB - Inhibition of heat shock protein 90 (HSP90) results in the degradation of oncoproteins that drive malignant progression and induce cell death, thus making HSP90 a potential target of cancer therapy. 6-Chloro-9-(4-methoxy-3, 5-dimethyl pyridin-2-ylmethyl)-9H-purin-2-ylamine (BIIB021), a synthetic HSP90 inhibitor, exhibited promising antitumor activity in preclinical models. It is currently in phase II clinical trials for the oral treatment of breast cancer. The objective of this study was to obtain both quantitative and qualitative metabolic profiles of [(14)C]BIIB021 in rat, dog, and human liver microsomes and hepatocytes to provide support for in vivo safety and clinical studies. The metabolites of [(14)C]BIIB021 were identified using liquid chromatography-tandem mass spectrometry coupled with radiometric detection. BIIB021 was extensively metabolized in both liver microsomes and hepatocytes. The major oxidative metabolic pathways identified for all species were due to hydroxylation (M7) and O-demethylation (M2) of the methoxy-dimethylpyridine moiety. The majority of M7 in dog hepatocytes was further conjugated to form the glucuronide (M4). Oxidative dechlorination (M6), monooxygenation (M10), and oxidative N-dealkylation of the methoxy-dimethylpyridine moiety (M11 and M12) were observed as the minor metabolic pathways in hepatocytes of all three species. A glutathione conjugate (M18) was also identified in all species. Its formation was catalyzed, in part, by soluble glutathione transferase via direct displacement of the chlorine on the amino-chloropurine moiety. Subsequent minor secondary metabolites M13, M14, M15, and M17 were observed in human, dog, and rat hepatocytes. Results from incubations of BIIB021 with human recombinant cytochrome P450 (P450) isoforms and a P450 antibody inhibition study in human liver microsomes suggested that the formation of M7 is mainly catalyzed by CYP2C19 and CYP3A4, whereas the formation of minor metabolite M2 in human liver microsomes probably could be attributed to CYP3A4. PMID- 22217466 TI - A driving cessation program to identify and improve transport and lifestyle issues of older retired and retiring drivers. AB - BACKGROUND: This study explored the transport and lifestyle issues of older retired and retiring drivers participating in the University of Queensland Driver Retirement Initiative (UQDRIVE), a group program to promote adjustment to driving cessation for retired and retiring older drivers. METHODS: A mixed method research design explored the impact of UQDRIVE on the transport and lifestyle issues of 55 participants who were of mean age 77.9 years and predominantly female (n = 40). The participants included retired (n = 32) and retiring (n = 23) drivers. Transport and lifestyle issues were identified using the Canadian Occupational Performance Measure and rated pre- and post-intervention. RESULTS: Paired t-tests demonstrated a statistically significant improvement in performance (t = 10.5, p < 0.001) and satisfaction (t = 9.9, p < 0.001) scores of individual issues. Qualitative content analysis identified three categories of issues including: protecting my lifestyle; a better understanding of transport options; and being prepared and feeling okay. CONCLUSIONS: Participation in UQDRIVE had a positive and significant effect on the issues of the participants. The results highlight that although all participants stated issues related predominantly to practical concerns, there were trends in the issues identified by the drivers and retired drivers that were consistent with their current phase of the driving cessation process. PMID- 22217467 TI - An intervention to increase high school students' compliance with carrying auto injectable epinephrine: a MASNRN study. AB - Adolescents with life-threatening allergies are at a greater risk for a fatal anaphylactic event since only about half of them carry unexpired epinephrine available for emergency use. The aim of this study was to test the effectiveness of school nurse interventions that consisted of either routine or periodic checks during the school year for the availability of unexpired auto-injectable epinephrine. Seventy-seven students from 11 Massachusetts high schools participated in this study. Descriptive and chi-square (chi2) statistics as well as the Fisher's exact test were used to analyze data. Findings suggest that while periodic checks for the availability of epinephrine throughout the school year do not increase the likelihood that students will have epinephrine available, those students who do carry their epinephrine are more likely to have unexpired medication with periodic reminders during the school year. PMID- 22217468 TI - Parent and teacher perceptions of the impact of school nurse interventions on children's self-management of diabetes. AB - Diabetes is a common chronic illness among school-age children. The school nurse collaborates with the student, parents, and teachers to help the child manage their diabetes effectively. Very little is known about the relationship between school nurse interventions and parent/teacher perceptions of the child's self management. We examined this relationship in a sample of 69 school-age children who received case management from school nurses. Our findings suggest that teachers and parents do not always agree on how well a child manages their illness. When school nurses provide more education and counseling, parents are more likely to perceive an improvement in their child's self-management. Teachers are more likely to perceive an improvement when the nurse provides more classroom visits and includes the physical education teacher and guidance counselor. These findings suggest that the roles of educator, counselor, and collaborator are important for school nurses who provide care to school-age children with diabetes. PMID- 22217469 TI - Phenotypes and genotypes of erythromycin-resistant Streptococcus pyogenes strains isolated from invasive and non-invasive infections from Mexico and the USA during 1999-2010. AB - OBJECTIVE: To compare the prevalence, phenotypes, and genes responsible for erythromycin resistance among Streptococcus pyogenes isolates from Mexico and the USA. METHODS: Eighty-nine invasive and 378 non-invasive isolates from Mexico, plus 148 invasive, 21 non-invasive, and five unclassified isolates from the USA were studied. Susceptibilities to penicillin, erythromycin, clindamycin, ceftriaxone, and vancomycin were evaluated according to Clinical and Laboratory Standards Institute (CLSI) standards. Phenotypes of erythromycin resistance were identified by triple disk test, and screening for mefA, ermTR, and ermB genes was carried out by PCR. RESULTS: All isolates were susceptible to penicillin, ceftriaxone, and vancomycin. Erythromycin resistance was found in 4.9% of Mexican strains and 5.2% of USA strains. Phenotypes in Mexican strains were 95% M and 5% cMLS; in strains from the USA, phenotypes were 33.3% iMLS, 33.3% iMLS-D, and 33.3% M. Erythromycin resistance genes in strains from Mexico were mefA (95%) and ermB (5%); USA strains harbored ermTR (56%), mefA (33%), and none (11%). In Mexico, all erythromycin-resistant strains were non-invasive, whereas 89% of strains from the USA were invasive. CONCLUSIONS: Erythromycin resistance continues to exist at low levels in both Mexico and the USA, although the genetic mechanisms responsible differ between the two nations. These genetic differences may be related to the invasive character of the S. pyogenes isolated. PMID- 22217470 TI - Mini-Nutritional-Assessment (MNA) without body mass index (BMI) predicts functional disability in elderly Taiwanese. AB - Nutritional status and functional ability are mutually dependent especially in the elderly. This study examined the functional status-predictive ability of the MNA in a cross-sectional study. We analyzed the dataset of the "Survey of Health and Living Status of the Elderly in Taiwan" (SHLSET). Subjects were 2948>=65 year old persons who were rated with the long-form (LF) and short-form (SF) MNA with or without BMI for the risk of malnutrition, and with the Activities of Daily Living (ADL) and the Instrument Activities of Daily Living (IADL) for functional status. The ADL and IADL scores were calculated according to rated nutritional status. Receiver Operating Characteristic (ROC) curves were generated for ADL and IADL status predicted by the MNA. Logistic regression was performed to evaluate the association of rated MNA scores with ADL or IADL status. Results showed that both SF and LF of MNA-T1 and T2 were able to predict ADL and IADL disabilities. Those who were rated malnourished or at risk of malnutrition had drastically higher risk of ADL or IADL dependency compared to those who were rated normal. The SF versions performed well in rating nutritional status and predicting ADL and IADL status. Overall, MNA-T2-SF performed at least equally well as MNA-T1-SF in rating functional decline. These results suggest the MNA is able to predict functional decline of the elderly. MNA-T2, especially the SF, a version without BMI should be particularly useful in clinical, long-term care and community settings. PMID- 22217471 TI - Health-related quality of life in adolescents with or at risk for type 2 diabetes mellitus. AB - OBJECTIVE: To evaluate how adolescents with or at risk for type 2 diabetes mellitus (T2DM) and their parent/guardians (parents) perceive adolescents' health related quality of life. STUDY DESIGN: We interviewed overweight/obese, 12- to 18 year-old youth with T2DM, prediabetes, or insulin resistance and one parent from 5 US sites. Assessments included Pediatric Quality of Life Inventory (PedsQL), Health Utilities Index, family conflict, and diabetes burden. RESULTS: In 108 adolescents, diagnoses included 40.7% with T2DM, 25.0% with prediabetes, and 34.3% with insulin resistance. PedsQL summary score (SS) was higher in adolescents than parents (P=.02). Parents rated physical functioning lower than adolescents (P<.0001), but there were no differences in psychosocial health. Adolescent PedsQL SS did not differ with diagnosis, but was inversely associated with adolescent body mass index z-score (P=.0004) and family conflict (P<.0001) and associated with race/ethnicity (P<.0001). Number of adolescent co-morbidities (P=.007) and burden of diabetes care (P<.05) were inversely associated with parent PedsQL SS. There were no differences in the Health Utilities Index-Mark 3 multi-attribute utility score. CONCLUSIONS: Parents perceive their adolescents' physical functioning as more impaired than adolescents themselves. Contextual factors including severity of obesity, race/ethnicity, family conflict, and burden of diabetes care influence health-related quality of life. Family-based approaches to treatment and prevention of T2DM may benefit from increased attention to the biopsychosocial context. PMID- 22217472 TI - Fasting non-high-density lipoprotein cholesterol and low-density lipoprotein particle size. PMID- 22217474 TI - Synaptopodin and the spine apparatus organelle-regulators of different forms of synaptic plasticity? AB - Synaptopodin (SP) is an actin-binding molecule, which is closely linked with the spine apparatus organelle (SA). Recent experimental evidence suggests that SP containing spines differ in their functional and structural properties from neighboring spines, which do not contain SP. These studies revealed for the first time that SP clusters colocalize with a functional internal source of calcium, which affects synaptic plasticity. Strikingly, SP-cluster associated calcium surges were shown to control synaptic strength in two ways: a ryanodine receptor (RyR) dependent potentiation of synaptic strength was reported, as well as inositol-triphosphate-receptor (IP3R) dependent depression. These results suggested that the SA is an important component of the molecular machinery controlling the calcium-dependent accumulation of AMPA-receptors (AMPA-R) at excitatory synapses. They raise the intriguing possibility that SP/SA could play a role in different forms of synaptic plasticity. PMID- 22217477 TI - Human epithelial growth factor receptor 2 (HER2) status in primary and metastatic esophagogastric junction adenocarcinomas. AB - Differences in human epithelial growth factor receptor 2 dysregulation in primary solid tumors and metastases may (at least partially) explain human epithelial growth factor receptor 2-targeted therapeutic inconsistencies. Human epithelial growth factor receptor 2 status was tested in a series of 47 radically treated consecutive esophagogastric junction adenocarcinomas (male/female, 38/9; mean age, 67.9 years) in both primary cancers and paired synchronous nodal metastases. None of the patients received neoadjuvant therapy. For each case, 2 nonadjacent tissue samples from primary esophagogastric junction adenocarcinoma and 2 different metastatic nodes were considered (188 tissue samples in all). Human epithelial growth factor receptor 2 status was assessed by immunohistochemistry (PATHWAY-HER2/neu [4B5]; Ventana Medical Systems, Milan, Italy) and dual chromogenic in situ hybridization (duoCISH; DAKO, Glostrup, Denmark). Immunohistochemistry staining scores were nil in 22 tumors (47%), 1 (21%) in 10, 2 (13%) in 6, and 3 (19%) in 9. Human epithelial growth factor receptor 2 gene amplification (25.5%) was associated with more differentiated phenotype (Fisher exact test, P = .039) and advanced tumor stage (Fisher exact test, P = .015). Significant agreement was observed between human epithelial growth factor receptor 2 protein expression (immunohistochemistry) and human epithelial growth factor receptor 2 gene's amplification (chromogenic in situ hybridization) (kappa = 0.84, P < .001). Both immunohistochemistry and chromogenic in situ hybridization documented an excellent intratumor agreement in human epithelial growth factor receptor 2 status (kappa = 0.75, P < .001; kappa = 0.88, P < .001, respectively). Human epithelial growth factor receptor 2 status was comparable in primary versus metastatic nodal cancers by both immunohistochemistry and chromogenic in situ hybridization (Cohen Phi, both P < .001). In esophagogastric junction adenocarcinomas, human epithelial growth factor receptor 2 status (as assessed by immunohistochemistry and/or chromogenic in situ hybridization) is virtually unaffected by intratumor variability; it is consistent with findings in nodal metastases, and it reliably identifies patients with esophagogastric junction adenocarcinoma eligible for anti-human epithelial growth factor receptor 2 therapy. PMID- 22217478 TI - Resonant photoemission at the L3 absorption edge of Mn and Ti and the electronic structure of 1T-Mn0.2TiSe2. AB - Resonant valence band x-ray photoelectron spectra (ResPES) excited near the 2p(3/2) core level energies, 2p x-ray photoelectron spectra (XPS) and L(3,2) x ray absorption spectra (XAS) of Ti and Mn in single crystals of 1T-Mn(0.2)TiSe(2) were studied for the first time. The ionic-covalent character of the bonds formed by the Mn atoms with the neighboring Se atoms in the octahedral coordination is established. From the XPS and XAS measurements compared with the results of atomic multiplet calculations of Ti and Mn L(3,2) XAS, it is found that the Ti atoms are in the ionic state of 4 + and the Mn atoms are in the state of 2 +. In ResPES of Mn(0.2)TiSe(2) excited near the Ti 2p(3/2) and Mn 2p(3/2) absorption edges the Ti 3d and Mn 3d bands at binding energies just below the Fermi level are observed. According to theoretical calculations of E(k) the Ti 3d states are localized in the vicinity of the Gamma point and the Mn 3d states are localized along the direction K-Gamma-M in the Brillouin zone of the crystal. PMID- 22217481 TI - Tackling myocardial metabolism: one year evaluation of free fatty acids, norephinephrine and NT-proBNP in ventricular fibrillation during STEMI. PMID- 22217482 TI - A novel fully automated method for mitral regurgitant orifice area quantification. AB - BACKGROUND: Effective regurgitant orifice area (EROA) in mitral regurgitation (MR) is difficult to quantify. Clinically it is measured using the proximal isovelocity surface area (PISA) method, which is intrinsically not automatable, because it requires the operator to manually identify the mitral valve orifice. We introduce a new fully automated algorithm, ("AQURO"), which calculates EROA directly from echocardiographic colour M-mode data, without requiring operator input. METHODS: Multiple PISA measurements were compared to multiple AQURO measurements in twenty patients with MR. For PISA analysis, three mutually blinded observers measured EROA from the four stored video loops. For AQURO analysis, the software automatically processed the colour M-mode datasets and analysed the velocity field in the flow-convergence zone to extract EROA directly without any requirement for manual radius measurement. RESULTS: Reproducibility, measured by intraclass correlation (ICC), for PISA was 0.80, 0.83 and 0.83 (for 3 observers respectively). Reproducibility for AQURO was 0.97. Agreement between replicate measurements calculated using Bland-Altman standard deviation of difference (SDD) was 21,17 and 17mm(2)for the three respective observers viewing independent video loops using PISA. Agreement between replicate measurements for AQURO was 6, 5 and 7mm(2)for automated analysis of the three pairs of datasets. CONCLUSIONS: By eliminating the need to identify the orifice location, AQURO avoids an important source of measurement variability. Compared with PISA, it also reduces the analysis time allowing analysis and averaging of data from significantly more beats, improving the consistency of EROA quantification. AQURO, being fully automated, is a simple, effective enhancement for EROA quantification using standard echocardiographic equipment. PMID- 22217483 TI - Association of a bicuspid aortic valve with an abnormally elongated rudimentary chordae tendinae protruding into the left venticular outflow tract. PMID- 22217479 TI - Disruption of component processes of spatial working memory by electroconvulsive shock but not magnetic seizure therapy. AB - Self-ordered spatial working memory measures provide important information regarding underlying cognitive strategies, such as stereotypy. This strategy is based on repetitive sequential selection of a spatial pattern once a correct sequence has been identified. We previously reported that electroconvulsive shock (ECS) but not magnetic seizure therapy (MST) impaired performance on a spatial working memory task in a preclinical model. Here we tested the hypothesis that ECS disrupted stereotyped patterns in the selection of spatial stimuli. In a within-subject study design, we assessed the effects of ECS, MST, and sham on stereotypy and reaction time in a preclinical model. Stereotypy was assessed by the correlation of actual and predicted response patterns of spatial stimuli. Predicted patterns were based on performance during baseline sessions. ECS resulted in lower correlations between predicted and actual responses to spatial stimuli in two of the three subjects, and it also disrupted stereotypy. For one subject, there was change in the predictability of the spatial locus of responses between experimental conditions. For all three subjects, reaction time was significantly longer in ECS, relative to MST and sham. This is the first study to examine the effect of ECS, and to contrast the effects of ECS and MST, on spatial working memory component processes. Our preliminary findings show that ECS, but not MST decreased stereotypy and increased reaction time. This line of investigation may have significant implications in our understanding cognitive component processes of memory function and impairment. PMID- 22217484 TI - Avoiding bias in measuring "hemisphere radius" in echocardiographic mitral regurgitation quantification: Mona Lisa PISA. PMID- 22217485 TI - The novel DPP-4 inhibitors linagliptin and BI 14361 reduce infarct size after myocardial ischemia/reperfusion in rats. AB - BACKGROUND: Dipeptidylpeptidase-4 inhibition is reported to have beneficial effects on myocardial ischemia. Mechanisms might include a reduced degradation of stromal cell-derived factor-1 alpha with subsequent increased recruitment of circulating stem cells and/or incretin receptor-dependent pathways. This study evaluated the novel xanthine-based dipeptidylpeptidase-4 inhibitors linagliptin (BI 1356) and BI 14361 in cardiac ischemia. METHODS: Male Wistar rats were pretreated with linagliptin or BI 14361 and subjected to ligation of the left anterior descending coronary artery for 30 min. RESULTS: Dipeptidylpeptidase-4 inhibition significantly reduced the infarct size after 7 days (-27.7%, p<0.05) and 8 weeks (-18.0%, p<0.05). There was a significantly improved maximum rate of left ventricular pressure decline (dP/dt min) in linagliptin-treated animals 8 weeks after ischemia/reperfusion. Apart from that, treatment did not improve cardiac function as determined by echocardiography and cardiac catheterization. Immunohistological staining revealed an increased number of cells positive for stromal cell-derived factor-1 alpha, CXCR-4 and CD34 within and around the infarcted area of BI 14361-treated animals. CONCLUSIONS: Linagliptin and BI 14361 are able to reduce infarct size after myocardial ischemia. The immunohistological findings support the hypothesis that dipeptidylpeptidase-4 inhibition via reduced cleavage of stromal cell-derived factor-1 alpha might lead to an enhanced recruitment of CXCR-4+ circulating progenitor cells. PMID- 22217486 TI - The public cost of 3 statins for primary prevention of cardiovascular events in 7 Middle East countries: not all of them can afford it. PMID- 22217487 TI - Gemcitabine with or without docetaxel and resection for recurrent osteosarcoma: the experience at Children's Memorial Hospital. AB - It remains unclear how to optimally incorporate gemcitabine and docetaxel into the management of patients with recurrent osteosarcoma. We describe 4 pediatric patients with recurrent osteosarcoma who were treated with gemcitabine +/- docetaxel and resection. One patient had a partial response and 2 had stable disease. Two patients subsequently underwent surgical resections. Median duration of response was 8 months and was longer for patients who underwent resection. One patient remains disease-free 57 months from recurrence. Our limited series provides additional support for the use of gemcitabine +/- docetaxel for recurrent osteosarcoma and suggests benefit of concurrent local control measures if possible. PMID- 22217488 TI - Childhood osteosarcoma of greater wing of sphenoid: case report and review of literature. AB - Primary osteosarcoma of skull base is extremely rare. We present a case of primary osteosarcoma arising in greater wing of sphenoid in a child. Our patient had an incomplete excision after which he received adjuvant chemotherapy and radiotherapy. There was good response to adjuvant chemoradiotherapy and the patient is disease free at a follow-up of 18 months. Treatment of skull base osteosarcomas is difficult, as complete excision is often not possible. To the best of our knowledge, this is the first case of sphenoid wing osteosarcoma in childhood to be reported in literature. PMID- 22217489 TI - Undifferentiated sarcoma of the liver: a single institution experience using a uniform treatment approach. AB - Undifferentiated (embryonal) sarcoma of the liver is a rare malignant tumor, most commonly seen in children aged 6 to 10 years. Previously believed to carry a poor prognosis, more recent reports indicate that treatment regimens combining surgical resection and adjuvant chemotherapy can yield long-term, disease-free survival. In this study, we review 5 pediatric patients with undifferentiated sarcoma of the liver treated with a uniform approach of resection followed by adjuvant chemotherapy and radiation when indicated. All 5 patients are disease free in their first remission at a median of 53 months. PMID- 22217490 TI - Recurrent congenital fibrosarcoma with heart metastases. AB - Congenital fibrosarcomas are malignant tumors that arise in soft tissues. In infants this unique tumor does not commonly metastasize, even though there may be local recurrences. We report here a boy who had congenital fibrosarcoma in his right foot, which was completely excised at the age of 3 days. Four months later, a solitary encapsulated metastasis emerged in thoracic chest wall, which was operated. During adjuvant chemotherapy he developed histologically confirmed fibrosarcoma metastases in the heart. After extended treatment with cyclophosphamide/topotecan and gemcitabine/docetaxel, the heart tumors disappeared and he has been in complete remission for 3 years. PMID- 22217491 TI - Acute monoblastic leukemia that switched lineage at relapse to acute lymphoblastic leukemia: a case report. AB - We herein present the case of an acute monoblastic leukemia infant who relapsed with acute lymphoblastic leukemia (ALL). Complete remission was achieved after an acute myeloblastic leukemia-directed chemotherapy, but the patient relapsed with pro-B ALL. As he did not respond to acute myeloblastic leukemia-type reinduction therapy, he was switched to ALL-type chemotherapy, and a complete remission was achieved. Unrelated cord blood stem cell transplantation was performed, but he relapsed with pro-B ALL again. After he received ALL-type chemotherapy, he underwent another bone marrow transplant from his human leukocyte antigen mismatch mother, and has been free from recurrence for over 8 months. PMID- 22217492 TI - Extensive gingival and respiratory tract Kaposi sarcoma in a child after allogenic hematopoietic stem cell transplantation. AB - An 8-year-old, human immune virus-negative boy received full human leukocyte antigen-matched related allogenic hematopoietic stem cell transplantation (HSCT) for relapsed acute myeloid leukemia. While on cyclosporine A and prednisolone therapy for graft versus host disease, he developed extensive gingival, cutaneous, and respiratory tract human herpes virus-8-associated Kaposi sarcoma (KS). Withdrawal of cyclosporine, tapering of prednisolone, recovery of lymphocyte count, and local supportive measures resulted in resolution of his gingival and respiratory tract lesions. To our knowledge this is the first case of gingival and extensive respiratory tract KS to be reported in a child post HSCT. PMID- 22217493 TI - Juvenile xanthogranuloma with clonal proliferation in the bone marrow. AB - The triple association between juvenile xanthogranuloma (JXG), juvenile myelomonocytic leukemia and neurofibromatosis was described in literature in about 20 cases. In this paper, the case of an 11-month-old infant boy with a disseminated JXG with unusual cytogenetic representation in the bone marrow was reported. Neurofibromatosis and juvenile myelomonocytic leukemia were excluded, just the same as other leukemias. Bone marrow and peripheral blood cytogenetic analysis revealed a karyotype with many rearrangements 46,XY, 6,der(12)t(6;12)(p21;p13),del(7)(p13p22),+9 once described in the literature as a B-acute lymphoblastic leukemia case. On the contrary, in our patient immunologic testing demonstrated a high activity of T lymphocytes, however, inflammation was excluded. To the best of our knowledge this is the first described case of systemic JXG with determined karyotype representing unusual chromosomal aberrations. PMID- 22217494 TI - Acute lymphoblastic leukemia in a patient with constitutional chromosome 1pter p36.31 duplication and 1q43-qter deletion. AB - Chromosome 1 is the largest of all human chromosomes, containing 3141 genes. It is linked to 890 known genetic diseases including congenital hypothyroidism, hemochromatosis, and prostate cancer. Recognized deletion and duplication syndromes have been described. Deletions in the short arm (p) of the chromosome have been identified in tumors of the brain and kidneys. Duplications in the long (q) arm of the chromosome are reported in myelodysplastic syndromes. Solitary 1p36 deletion or 1q42 duplication are rarely reported entities and their associations with malignancy have not been characterized. We report a case of a child with constitutional 1pter-p36.31 duplication and 1q43-qter deletion who developed acute lymphoblastic leukemia (ALL). The patient's oncologic presentation and subsequent clinical course raise the question of the association of the underlying genetic abnormality and its malignant potential, specifically in relation to ALL. Acquired chromosome 1 deletions and duplications have been well described in other malignant diseases. Constitutional chromosome 1p duplication and 1q deletions have not been described with ALL. PMID- 22217495 TI - RT-PCR screening for ETV6-RUNX1-positive clones in cord blood from newborns in the Danish National Birth Cohort. AB - BACKGROUND: Several large biobanks comprising umbilical cord blood samples have been established allowing efforts to characterize the prevalence and risk factors for preleukemic cell clones in healthy newborns. This study explores the feasibility of demonstrating translocation ETV6-RUNX1 transcripts by reverse transcription polymerase chain reaction in newborns enrolled in a large Danish National Birth Cohort. CONCLUSIONS: The study emphasizes the necessity of either storing viable cord blood cells or preparation of the RNA within 1 to 2 days of birth, in large scale studies of the natural history of childhood acute lymphoblastic leukemia. Finally, the estimated frequency of translocation ETV6 RUNX1-positive cells was below 10. PMID- 22217496 TI - Sleep desaturation and its relationship to lung function, exercise and quality of life in LAM. AB - BACKGROUND: Lymphangioleiomyomatosis (LAM) is characterised by progressive airway obstruction and hypoxaemia in young women. Although sleep may trigger hypoxaemia in patients with airway obstruction, it has not been previously investigated in patients with LAM. METHODS: Consecutive women with lung biopsy proven LAM and absence of hypoxaemia while awake were evaluated with pulmonary function test, echocardiography, 6-min walk test, overnight full polysomnography, and Short Form 36 health-related quality-of-life questionnaire. RESULTS: Twenty-five patients with (mean+/-SD) age 45+/-10 years, SpO(2) awake 95%+/-2, forced expiratory volume in the first second (median-interquartile) FEV(1)(% predicted) 77 (47-90) and carbonic monoxide diffusion capacity, DL(CO) (%) 55 (34-74) were evaluated. Six-minute walk test distance and minimum SpO(2) (median-interquartile) were, respectively, 447m (411-503) and 90% (82-94). Median-interquartile apnoea hypopnoea index was in the normal range 2 (1-5). Fourteen patients (56%) had nocturnal hypoxaemia (10% total sleep time with SpO(2) <90%), and the median sleep time spent with SpO(2) <90% was 136 (13-201)min. Sleep time spent with SpO(2) <90% correlated with the residual volume/total lung capacity ratio (r(s)=0.5, p: 0.02), DL(CO) (r(s)=-0.7, p: 0.001), FEV(1) (r(s)=-0.6, p: 0.002). Multivariate linear regression model showed that RV/TLC ratio was the most important functional variable related to sleep hypoxaemia. CONCLUSION: Significant hypoxaemia during sleep is common in LAM patients with normal SpO(2) while awake, especially among those with some degree of hyperinflation in lung function tests. PMID- 22217497 TI - Sino-American employer perspective about behavioral-driven health conditions: predictive analyses. AB - OBJECTIVE: A large-scale quantitative study was conducted by stratified representative samples from Chicago (prototype of the United States; N = 293), Beijing (prototype of urbanized China; N = 302), and Hong Kong (prototype of East meets-West culture; N = 284) to explore factors that might lead to their stigmatizing attitudes towards hiring individuals with (mental illness, alcohol abuse, drug abuse, and HIV/AIDS) and without (bone cancer) behavioral-driven health conditions. METHODS: Consented employers completed the Employer Survey pertaining to their attitudes towards specific health conditions, previous hiring experiences, resources, assets of applicants, and hiring concerns. RESULTS: The findings suggested that employers in Hong Kong and Beijing were more willing to hire individuals with alcohol abuse, whereas employers in Chicago were more willing to hire those with HIV/AIDS or bone cancer. Logistic regression suggested that the type of health conditions, assets of applicants, and perceived level of dangerousness of applicants were significant predictors that contributed to employers' hiring preference. CONCLUSION: Employers express different hiring preference towards individuals with or without behavioral-driven health conditions. Their hiring preference towards specific type of health conditions is discussed. PMID- 22217498 TI - Synthesis of wide band gap nanocrystalline NiO powder via a sonochemical method. AB - A sonochemistry-based synthesis method was used to produce nanocrystalline nickel oxide powder with ~ 20 nm average crystallite diameter from Ni(OH)(2) precursor. Ultrasound waves were applied to the primary solution to intensify the Ni(OH)(2) precipitation. Dried precipitates were calcined at 320 degrees C to form nanocrystalline NiO particles. The morphology of the produced powder was characterized by transmission electron microscopy. Using sonochemical waves resulted in lowering of the size of the nickel oxide crystallites. FT-IR spectroscopy and X-ray diffraction revealed high purity well-crystallized structure of the synthesized powder. Photoluminescence spectroscopy confirmed production of a wide band-gap structure. PMID- 22217499 TI - Lower-extremity endovascular interventions for Medicare beneficiaries: comparative effectiveness as a function of provider specialty. AB - PURPOSE: Lower-extremity endovascular interventions are increasingly being performed by vascular surgeons (VSs) and interventional cardiologists (ICs) in addition to interventional radiologists (IRs). Regardless of specialty, well trained, experienced, and dedicated operators are expected to offer the best outcomes. To examine specialty-specific trends, outcomes of percutaneous lower extremity revascularizations in Medicare beneficiaries were compared according to physician specialty types providing the service. MATERIALS AND METHODS: Medicare Standard Analytical Files that contain longitudinal data of all services (physician, inpatient, outpatient) provided to a 5% sample of Medicare beneficiaries were studied. All claims for percutaneous angioplasty, atherectomy, and stent implantation of lower-extremity arteries during the years 2005-2007 were extracted, and the following outcomes were assessed: mortality, transfusion, intensive care unit (ICU) use, length of stay, and subsequent revascularization or amputation. Outcomes were compared by using regression models adjusted for age, sex, race, emergency department admission, and comorbid conditions. RESULTS: Most outcomes were significantly worse if the service was provided by vascular surgeons compared with other vascular specialists. The in-hospital mortality rate for procedures performed by VSs was 19% higher than for those performed by others, but this difference was not significant (P =.351). Adjusted average 1 year procedure costs were significantly lower for IRs ($17,640) than for VSs ($19,012) or ICs ($19,096). CONCLUSIONS: Medicare data show that endovascular lower-extremity revascularization by vascular surgeons results in more transfusion and ICU use, longer hospital stay, more repeat revascularization procedures or amputations, and higher costs compared with procedures performed by interventional radiologists. PMID- 22217500 TI - South Australia's older persons mental health services' model of service: a country perspective. PMID- 22217501 TI - Is elective neck dissection necessary for the surgical management of T2N0 glottic carcinoma? AB - OBJECTIVE: Evaluation of neck metastasis incidence in surgically treated T2N0M0 glottic carcinoma patients and discussion the necessity of elective neck dissection in this subset of larynx carcinomas. MATERIALS AND METHODS: The patients who were staged clinically and radiologically as T2N0M0 glottic carcinoma having surgical intervention for their primary tumor and elective neck dissection between March 1996 and July 2009 with at least 2 years of follow up were included in the study. The recordings of patients were evaluated retrospectively for primary tumor location, vocal cord mobility, type of laryngectomy and neck dissection, results of histopathological examination, number of dissected lymph nodes for each specimen and for local and regional failure during the follow up. RESULTS: In the 13-year study period, 24 consecutive patients with a mean age of 56.4 were treated surgically with 20 frontolateral, three vertical laryngectomies and one cricohyoido-epiglottopexy; 19 lateral and 5 functional neck dissections were performed for the necks. Histopathological examinations of the neck dissection specimens revealed an average of 32 lymph nodes (8-65) and there was no metastasis in any of these specimens. After an average 58 months of follow-up, only one patient had local failure and no patients had regional failure. CONCLUSION: As occult metastasis was not detected in any of the neck dissection specimens in cT2N0M0 patients and no regional failure was experienced during the follow-up period, it was concluded that the neck could be followed up without performing elective neck dissection in the surgical management of cT2N0M0 glottic carcinoma patients. PMID- 22217503 TI - Regulatory T cells are converts in simian immunodeficiency virus infection. PMID- 22217505 TI - Pharmacokinetic concerns related to the AIDS Clinical Trial Group (ACTG) A5262 trial. PMID- 22217502 TI - Teleost fish (Solea solea): a novel model for ecotoxicological assay of contaminated sediments. AB - Chemical analysis of sediment is not indicative of the downstream biological effects on aquatic organisms. In this study, the biological effects of sediment were examined using: Teleost fish (Solea solea), Artemia and rotifers. Although chemicals levels were below the limits permissible by Italian law, S. solea juveniles exposed to sediment (0.3%, w/v) for 96 h, revealed significant induction in the expression levels of HSP70, ERalpha, TRalpha, RXRalpha, PPARalpha, PPARbeta, CYP4501A1 and CYP3A mRNAs, suggesting the utility of this species as a novel biosensor. The bio-toxicity of the sediment was further validated by exposing Artemia and rotifers to concentrations of elutriate (derived from the sediment) from 10 to 100% (v/v) (with a 50% mortality rate). These results suggest that sediment defined as moderately contaminated, solely on the basis of the chemical profile, may in fact cause harmful effects to aquatic organisms. This study highlights the need for biological approaches in the establishment of sediment toxicity levels. PMID- 22217506 TI - Epstein-Barr virus associated colitis in an HIV-infected patient. PMID- 22217507 TI - Low-dose albumin in the treatment of spontaneous bacterial peritonitis: should we change the standard treatment? PMID- 22217508 TI - Heat shock proteins (HSP): dermatological implications and perspectives. AB - In recent years, several studies have demonstrated the protective effect of Heat Shock Proteins (HSP) on different organs and tissues under stressful conditions. However, most research explores the performance of those molecular chaperones during immune responses or pathological conditions like cancer, whereas the number of studies related to the performance of HSPs in the skin during diverse natural or physiopathological conditions is very low. Therefore, the aim of this article was to summarize the main concepts concerning the expression and performance of HSPs, from analysis of current medicine and cosmetics publications, as well as exploring the importance of these proteins in the dermatological area in physiological events such as cutaneous aging, skin cancer and wound healing and to present final considerations related to biotechnology performance in this area. PMID- 22217510 TI - A microarray study on the effect of four hormone therapy regimens on gene transcription in whole blood from healthy postmenopausal women. AB - BACKGROUND: Postmenopausal hormone therapy is associated with many diseases and conditions, e.g., cardiovascular diseases and asthma, but the underlying molecular mechanisms are incompletely understood. The aim of the current study was to investigate the effect of four different postmenopausal hormone therapy regimens on gene transcription. MATERIALS AND METHODS: Twenty-four healthy postmenopausal women (six women in four groups) were randomly allocated to conventional-dose 17beta-estradiol/norethisterone acetate (NETA), low-dose 17beta estradiol/NETA, tibolone, or raloxifene hydrochloride. RNA was isolated from whole blood before and after 6weeks of treatment. The changes in mRNA were assessed with a microarray chip. RESULTS: The genes FKBP5, IL13RA1, TPST1, and TLR2 were up-regulated and among the most significantly changed genes in the groups treated with conventional-dose 17beta-estradiol/NETA and tibolone. Up regulation of TPST1 was associated with reduction of tissue factor pathway inhibitor in plasma. Nine biological pathways were associated with conventional dose 17beta-estradiol/NETA, most significantly the pathways for asthma, toll-like receptor signaling, cell adhesion molecules, and MAPK signaling. Transcriptional changes with false discovery rate below 0.10 were found in 10 genes in the conventional-dose 17beta-estradiol/NETA group, 7 genes in the tibolone group, and zero genes in the women on low-dose 17beta-estradiol/NETA. No genes or pathways were associated with raloxifene treatment. CONCLUSIONS: The difference between low-dose and conventional-dose17beta-estradiol/NETA indicates an effect of dose on transcriptional response. Several genes and pathways related to cell adhesion molecules and immunity related cell surface receptors were influenced by conventional-dose 17beta-estradiol/NETA. PMID- 22217511 TI - Using care profiles to commission end-of-life services. AB - AIM: In early 2010, Liverpool Primary Care Trust (PCT) undertook a project to establish whether a care profiles methodology could be used to commission end-of life (EoL) services. The Department of Health (DH) originally used them for a variety of services in the 1990s. The project sought to adapt the original care profiles structure for commissioning purposes, and produce a series of care profiles that would cover the full EoL care pathway. BACKGROUND: The DH required PCTs in England to undertake local reviews of EoL services ahead of its publication of the National EoL Strategy in 2008. Related cross-sector work in Liverpool highlighted the need for a means of specifically commissioning EoL services. It was contended that care profiles offered the opportunity to set service requirements in respect of skill mix, delivery, quality and outcomes for each stage of the EoL pathway, which could be costed subsequently. METHODS: An iterative approach was adopted involving workshops and consensus, based on action learning events, which incorporated and adapted past approaches for developing care profiles. Four half-day workshops were held, each targeting one EoL stage, with the outputs evaluated by an external reference group. A full cross-section of commissioning, provider and service user interests were involved. FINDINGS: The project was successful, with its recommendations subsequently used to commission EoL services across Liverpool. It was concluded that the basic service requirements for EoL care are the same, irrespective of the related disease. The strength of care profiles is their simplicity and flexibility. They complement and augment integrated care pathways, and by requiring the recording of outcomes throughout the care process, they aid quality and audit processes. They should be transferable to other conditions, with benchmarking enabling improved efficiency. They represent the type of clinically relevant and detailed vehicle essential for clinical commissioning groups. PMID- 22217512 TI - Epithelial-mesenchymal transition in the pathophysiology of airway remodelling in asthma. AB - PURPOSE OF REVIEW: We currently understand little about the mechanisms that lead to airway remodeling in asthma. The origin of the mesenchymal cells that contribute to fibrosis of the airway is poorly understood. However, emerging evidence suggests that the airway epithelium could contribute to airway remodeling through the process of epithelial-mesenchymal transition (EMT) following environmental challenge. In this review, we will discuss the mechanistic features of EMT and highlight recent descriptions of EMT in the airway to further define the role of the airway epithelium in the pathogenesis of asthma. RECENT FINDINGS: Growth factors, inflammatory mediators, and matricellular proteins expressed following exposure to environmental insults are known to induce downregulation of epithelial cell-cell adhesions and promote mesenchymal gene expression programs both in vitro and in vivo. These results demonstrate that the plastic and dynamic airway epithelium may contribute to airway remodeling via EMT in asthma. SUMMARY: It is becoming increasingly clear that the airway epithelium orchestrates inflammatory and remodeling responses of the airway. Understanding the regulatory mechanisms involved in epithelial plasticity will be crucial to determine effective therapies to halt the progression of airway remodeling in asthma. PMID- 22217513 TI - Current world literature. PMID- 22217515 TI - Computational analysis of the flow of bile in human cystic duct. AB - Computational fluid dynamic (CFD) simulations of the three-dimensional flow structures in realistic cystic ducts have been performed to obtain quantitative readings of the flow parameters to compare with clinical measurements. Resin casts of real patients' cystic ducts lumen that possess representative anatomical features were scanned to obtain three-dimensional flow domains that were used in the numerical analysis. The convoluting nature of the studied cystic ducts resulted in strong secondary flow that contributed towards a dimensionless pressure drop that is four times higher than those of a straight circular tube of an equivalent length and average diameter. The numerical pressure drop results across the cystic duct compared very well with those obtained from clinical observations which indicate that CFD is an appropriate tool to investigate the flow and functions of the biliary system. From the hydrodynamic point of view, the cystic duct lumen seems to serve as a passive resistor that strives to provide a constant amount of resistance to control the flow of bile out of the gallbladder. This is mainly achieved by the coupling of the secondary flow effects and bile rheology to provide flow resistance. PMID- 22217516 TI - Soy peptide-induced stem cell proliferation: involvement of ERK and TGF-beta1. AB - This study was conducted to investigate the proliferative effect of vegetable soy peptides on adult stem cells (ASCs) in the absence of serum and their possible mechanisms of action. The proliferation of human adipose tissue-derived mesenchymal stem cells (ADSCs) and cord blood-derived mesenchymal stem cells (CB MSCs) treated with soy peptides was found to increase significantly upon 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Click-iT 5-ethynyl-2' deoxyuridine flow cytometry assay. In addition, soy peptides led to stepwise phosphorylation of the p44/42 MAPK (ERK), mammalian target of rapamycin (mTOR), p70 S6 kinase, S6 ribosomal protein (S6RP) and eukaryotic initiation factor 4E (eIF4E) in ADSCs. Furthermore, quantitative analysis of the cytokines revealed that the production of transforming growth factor-beta1 (TGF-beta1), vascular endothelial growth factor and interleukin-6 increased significantly in response to treatment with soy peptides in both ADSCs and CB-MSCs. Similarly, soy peptide induced phosphorylation of the ERK/mTOR/S6RP/eIF4E pathway was blocked in response to pretreatment with PD98059, a specific ERK inhibitor. Moreover, inhibition of TGF-beta1 through PD98059 pretreatment and a consecutive decrease in ADSC proliferation revealed that TGF-beta1 induces the phosphorylation of mTOR/S6RP/eIF4E. Collectively, the results of this study indicate that ERK dependent production of TGF-beta1 plays a crucial role in the soy peptide-induced proliferation of ADSCs under serum-free conditions. PMID- 22217517 TI - HuR-mediated posttranscriptional regulation of p21 is involved in the effect of Glycyrrhiza uralensis licorice aqueous extract on polyamine-depleted intestinal crypt cells proliferation. AB - Glycyrrhiza uralensis licorice has long been used worldwide as a food additive and herbal medicine. It possesses a remarkable healing action on gastrointestinal ulcers. The present study was carried out to assess the effect of licorice on intestinal crypt cell proliferation and to investigate the corresponding molecular mechanism. Considering the role of crypt stem cells in intestinal mucosa repair, a well-established cytostatic cellular model, polyamine-depleted IEC-6 cells, was utilized to evaluate the effect of aqueous licorice on the proliferation of intestinal crypt cells. The growth inhibition of IEC-6 cells caused by alpha-difluoromethylornithine could be significantly reversed by concomitant treatment with 40 MUg/ml and 80 MUg/ml licorice aqueous extract. In particular, the restoration of cell cycle progression was accompanied by a decrease in p21 mRNA level and cytoplasmic accumulation of the RNA-binding protein HuR, which was shown to be involved in the destabilization of p21 mRNA. Using a biotin pull-down assay and a luciferase assay, it was found that licorice modulated p21 mRNA expression was achieved by HuR-targeted AU-rich and U-rich elements that resided in the 3' untranslated region of p21 mRNA. These results demonstrate that licorice can exert its action on stimulating the growth of intestinal crypt cells by regulating p21 mRNA level at the posttranscriptional level by HuR. PMID- 22217518 TI - Down-regulation of vascular HMGB1 and RAGE expression by n-3 polyunsaturated fatty acids is accompanied by amelioration of chronic vasculopathy of small bowel allografts. AB - Chronic allograft rejection, which is manifested as chronic allograft vasculopathy (CAV), continues to refrain the long-term success of small bowel transplantation (SBTx). The pathway mediated by the receptor for advanced glycation end products (RAGE) and its ligand, high mobility group box-1 (HMGB1), may contribute to the pathogenesis of CAV, given that they were involved in the process of allograft rejection. n-3 polyunsaturated fatty acids (PUFAs), which have been discovered to attenuate CAV, may have potential impacts on this pathway. The present study investigated whether n-3 PUFAs attenuated CAV via the regulation of the HMGB1-RAGE pathway in a chronic rejection model of rat SBTx. We revealed that the expression of HMGB1 and RAGE was increased in CAV-bearing vessels as well as endothelial cells isolated from these vessels. Oral administration of fish oil with high levels of n-3 PUFAs following SBTx significantly reduced the HMGB1 and RAGE expression, which coincided with the amelioration of CAV. In contrast, feeding of corn oil that contained low levels of n-3 PUFAs had no favorable effects on CAV development and failed to decrease the HMGB1 and RAGE expression. These results indicate that protective effects of n-3 PUFAs on allograft vessels exist via down-regulation of the HMGB1-RAGE pathway. PMID- 22217519 TI - Agenesis of posterior inferior cerebellar arteries in an asymptomatic adult with Dandy-Walker malformation. PMID- 22217520 TI - Links between headaches and epilepsy: current knowledge and terminology. AB - INTRODUCTION AND OBJECTIVES: Headaches (including migraines) and epilepsy have a high level of comorbidity and may be confused during diagnosis. Although physicians have known for centuries that these two conditions are somehow linked, their relationship remains poorly understood. Herein we describe the known associations between them, their underlying physiopathologic and genetic mechanisms, and the treatments recommended for them. METHOD: We have reviewed the most relevant publication of headache/migraine and epilepsy by using the PubMed data base. DESCRIPTION: An individual can suffer both from headaches (either migraine and/or other type of headache) and epilepsy, either by chance or because of a common underlying pathology. In these cases, the headache usually occurs at a different moment than the seizure ("interictal headache"). However, headaches sometimes occur simultaneously with, or very close in time to, the seizure: one that occurs at the same time as an epileptic seizure is known as an "ictal epileptic headache" or as "hemicrania epileptica"; one that precedes a seizure is known as a "pre-ictal headache"; and one that follows a seizure is known as a "post-ictal headache". There is a particular type of pre-ictal headache, known as "migralepsy", which occurs during or just after a migraine aura. CONCLUSIONS: The terminology and concepts employed to describe possible associations between headaches (mainly migraines) and epilepsy have evolved over time with increasing clinical and physiopathogenic knowledge. Some researchers have suggested eliminating the term migralepsy and using the terms ictal epileptic headache and hemicrania epileptica exclusively and uniformly in all classification systems. PMID- 22217521 TI - Painful polyneuropathy secondary to prolonged treatment with linezolid: presentation of a case. PMID- 22217522 TI - [Expression of NMDA receptor subunits in rat prefrontal cortex with CCL4-induced hepatic damage after a treatment with Rosmarinus officinalis L]. AB - INTRODUCTION: In cirrhosis some toxic substances accumulate in brain and modify the expression of several neuronal receptors. Thus, the use of medicinal plants such as Rosmarinus officinalis L. has been proposed in several pathologies due to its hepatoprotective, antioxidant and neuroprotective activity. In this study we evaluated the expression of the subunits NR1, NR2A and NR2B of the glutamate receptor in rat prefrontal cortex in a model of hepatic damage induced with carbon tetrachloride after a treatment with Rosmarinus officinalis L. METHODS: We used a total of 24 male Wistar rats weighing 80-90 g. body weight. We formed three study groups: control group (C) without a treatment, carbon tetrachloride group (CC14), and CC14 group plus Rosmarinus officinalis L (CCl4+ROM; 1.5 g/kg of extract orally). RESULTS: The expression of the NR1, NR2A and NR2B subunits in cirrhotic animals increased compared to the control group, however treatment with Rosmarinus officinalis L. was able to reduce this expression to normal levels compared with CC14 and CCl4+ROM groups. These results could be due to an improvement in hepatic function. CONCLUSION: Treatment with extract of Rosmarinus officinalis L. in cirrhotic animals modifies the expression of subunits of the NMDA receptor due to an improvement in hepatocellular function in the presence of antioxidant compounds and flavonoids. PMID- 22217523 TI - [Selective immunoglobulin A deficiency is exceptionally associated with multiple sclerosis]. PMID- 22217524 TI - Long standing polyneuropathy as a form of presentation of primary systemic amyloidosis. PMID- 22217525 TI - Guillain-Barre syndrome as first presentation of non-Hodgkin lymphoma. PMID- 22217526 TI - Focal cortical dysplasia. Clinical-radiological-pathological associations. AB - INTRODUCTION: The term focal cortical dysplasia (FCD) describes a particular migration disorder with a symptomatology mainly characterised by drug-resistant epileptic seizures, typical neuroradiological images, and histological characteristics, as well as a very positive response to surgical treatment in the majority of cases. MATERIAL AND METHODS: A total of 7 patients were studied, comprising 6 children with a mean age of 34.3 months and one 25-year-old male with very persistent focal seizures and MRI images that showed FCD. RESULTS: Three of the patients (all girls) were operated on while very young, with extirpation of the FCD and the surrounding area; with the histopathology study showed agreement between the MRI images and the macroscopic study of the slices. The histology study showed findings typical of a Taylor-type FCD (poor differentiation between the cortical grey matter and the subcortical white matter, and balloon cells). Three years after the FCD extirpation, the same 3 patients remained seizure-free with no anti-epilepsy medication. Two others have seizure control with medication, another (the adult) is on the surgical waiting list, and the remaining patient refused the operation. CONCLUSION: Taylor-type FCD is associated with a high percentage of all drug-resistant focal seizures, and it needs to be identified and extirpated as soon as possible. Well planned and well-performed surgery that leaves no remains of dysplasia can cure the disease it in many cases. PMID- 22217527 TI - [Structure and function of NMDA-type glutamate receptor subunits]. AB - INTRODUCTION: To review the physiology of the glutamate receptor subunits such as N-methyl-D-aspartate (NMDA). DEVELOPMENT: Glutamic acid (Glu) is the major excitatory neurotransmitter in the central nervous system which interacts with two types classified into two types: metabotropic and ionotropic. Ionotropic receptors are classified according to the affinity of their specific agonists: N methyl-D-aspartate (NMDA), alpha-amino acid-3-hydroxy-5-methyl-4-isoxazole (AMPA) and kainic acid (KA). NMDA receptors are macromolecular structures that are formed by different combinations of subunits, NMDAR1 (NR1), NMDAR2 (NR2) and NMDAR3 (NR3) CONCLUSIONS: The study of this receptor has been of great interest due to its role in synaptic plasticity, but mainly due to the permeability it has to Ca(++) ion. This review examines the molecular composition of NMDA receptor and the variants of NR1 subunit edition in association with NR2 subunit dimer, the main form of this receptor. The composition, structure and function and their distinct expression patterns in both time and space, has shown the versatility and diversity of functionally different isoforms of the NR1 subunit and various pharmacological properties of the NR2 subunit. PMID- 22217528 TI - Ethical issues raised in addressing the needs of people with serious mental disorders in complex emergencies. AB - Recent manmade and natural disasters highlight weaknesses in the public health systems designed to protect populations from harm and minimize disruption of the social and built environments. Emergency planning and response efforts have, as a result, focused largely on ensuring populations' physical well-being during and after a disaster. Many public health authorities, including the World Health Organization, have recognized the importance of addressing both mental and physical health concerns in emergency plans. Individuals with mental disorders represent a notable proportion of the overall population, and anticipating their needs is critical to comprehensive emergency planning and response efforts. Because people with serious mental disorders historically have been stigmatized, and many individuals with mental disorders may be unable to care for themselves, ethical guidance may be of assistance to those engaged in emergency planning and response. This article considers several broad categories of ethical issues that arise during emergencies for people with serious mental disorders and offers recommendations for ways in which emergency planners and other stakeholders can begin to address these ethical challenges. PMID- 22217529 TI - Oxygenated kidney preservation techniques. AB - Improving preservation techniques to minimize injury is of particular importance in organs from marginal donors. Since the introduction of transplantation and routine use of hypothermic temperatures for kidney preservation, there has been much debate on whether it is necessary to add oxygen to support the low level of metabolism under these conditions. Supplementing the kidney with oxygen during hypothermic preservation is not common practice. However, there is evidence to support its application. Oxygen can be added by various techniques such as retrograde persufflation whereby filtered and humidified oxygen is bubbled through the vasculature; under hyperbaric conditions using specialized pressurized chambers; during hypothermic machine perfusion; with the addition of oxygen carriers; and under normothermic conditions. Evidence suggests that oxygenation is particularly beneficial in restoring cellular levels of adenosine triphosphate after kidneys have been subjected to warm or cold ischemic injury. However, under normal conditions, the benefits are less convincing, but the evidence is insufficient to draw any conclusions. This overview explores the ways in which oxygen can be administered during preservation in experimental and clinical models of kidney transplantation. PMID- 22217530 TI - Low serum IGF-1 is a risk factor for cardiac allograft vasculopathy in cardiac transplant recipients. AB - BACKGROUND: Cardiac allograft vasculopathy (CAV) has an incidence of 43% at 8 years after heart transplantation with extremely limited treatment options and unclear pathogenesis. CAV constitutes a significant complication that limits the long-term survival of heart recipients. Insulin-like growth factor-1 (IGF-1) is associated with different cardiovascular diseases; however, its role in CAV pathogenesis remains unknown. METHODS: Serum samples of 10 matched recipients with CAV and 10 with no-CAV were initially screened with a protein array. Subsequently, IGF-1- and IGF-binding protein-3 (IGFBP-3) were analyzed using enzyme-linked immunosorbent assay in 44 randomly selected CAV and 50 no-CAV patients at two time points. RESULTS: The initial screening showed that IGF-1 and IGFBP-3 are differentially expressed in CAV compared with no-CAV patients (P=0.037 and P<0.0001, respectively). Subsequent enzyme-linked immunosorbent assay analyses indicated that serum IGF-1 protein concentrations were significantly lower in CAV patients (159.7+/-114 ng/mL) as compared with no-CAV patients (234.1+/-136 ng/mL; P=0.02). Serum IGFBP-3 protein concentrations were significantly lower in CAV (0.46+/-0.37 mg/L) as compared with no-CAV patients (1.03+/-0.73 mg/L; P=0.04). Multivariate logistic regression analyses showed that IGF-1 (odds ratio, 0.89; P=0.04) and IGFBP-3 (odds ratio, 0.09; P=0.03) are independent risk factors for CAV. CONCLUSION: Low IGF-1 and IGFPB-3 serum concentrations are associated with CAV. The assessment of serum IGF-1 and IGFPB-3 might be beneficial in identifying cardiac allograft recipients who are prone to develop CAV. Moreover, IGF-1 might be a useful therapy that could protect cardiac allografts against CAV. PMID- 22217531 TI - Ibandronate and calcitriol reduces fracture risk, reverses bone loss, and normalizes bone turnover after LTX. AB - BACKGROUND: Osteoporosis is a common complication in long-term survivors after liver transplantation (LTX). This study investigates the influence of a combination therapy of low dose parenteral ibandronate (IBN) and calcitriol on top of calcium and vitamin D supplementation in such patients. METHODS: For 3 years, 30 osteoporotic patients after LTX (28+/-6 months) were treated with quarterly 2 mg IBN intravenously and daily calcitriol (0.25-1.0 MUg) on top of 1000 mg calcium and 800 IU vitamin D. Recipients with normal bone density (n=24) were enrolled as controls. Laboratory analysis and dual energy X-ray absorptiometry were performed at baseline and every 12 months. Primary endpoints were changes in bone mineral density and fracture incidence. RESULTS: IBN patients showed a significant increase of bone mineral density at the femoral neck and the trochanteric region (13% and 15%, respectively, both P=0.001) as compared with baseline whereas the control group revealed a small but significant loss of -5.0% in the trochanteric and -4.9% in the neck region (P<0.05) over the same time period. Fracture incidence was low among IBN patients (7%); however, 23% of the control patients sustained at least one vertebral fracture. The relative fracture risk was 3.21 for IBN patients (95% confidence interval, 0.6 20.9, P=0.03) resulting in an absolute risk reduction for a new vertebral fracture of 14%. CONCLUSION: In LTX recipients with osteoporosis combination therapy with low dose IBN and calcitriol on top of calcium and vitamin D supplementation is an effective treatment option. PMID- 22217532 TI - Chronic kidney disease after nonrenal solid organ transplantation: a histological assessment and utility of chronic allograft damage index scoring. AB - BACKGROUND: It is proposed that chronic calcineurin inhibitor (CNI) nephrotoxicity has a central role in chronic kidney disease after nonrenal solid organ transplantation (NRSOT), although there are little data on renal histology in this setting. The aim of this study was to assess the histological features and renal outcomes of a cohort of patients with chronic kidney disease after NRSOT. METHODS: Renal biopsies of 62 NRSOT recipients were evaluated for histological diagnoses. Biopsies were graded for chronic allograft damage index parameters and for arteriolar hyalinosis. The sum of all chronic allograft damage index parameters and arteriolar hyalinosis scores was called chronic damage index. RESULTS: The biopsies were performed at a median of 4 (range: 0.3-15.9) years after NRSOT and at serum creatinine of 318+/-17.7 MUmol/L (mean+/-standard deviation). Twenty-two (35.5%) biopsies showed predominant features of chronic CNI nephrotoxicity, 27 (43.5%) predominant features of hypertensive nephropathy, and 12 (19.3%) an alternative primary renal pathology. Twenty-four (38.7%) patients had progression to end-stage renal disease, at a median of 1.5 (0-10.1) years after biopsy and 6.9 (0.3-19.2) years after NRSOT. The risk of renal progression was associated with in situ damage measured by chronic damage index. CONCLUSIONS: Although CNI nephrotoxicity is an important cause of renal failure after NRSOT, many patients do not have overt histological evidence of CNI toxicity. Quantitative parameters of chronic damage can stratify renal prognosis. PMID- 22217533 TI - Effects of preexistent hypertension on blood pressure and residual renal function after donor nephrectomy. AB - BACKGROUND: Living kidney donor selection has become more liberal with acceptation of hypertensive donors. Here, we evaluate short-term and 1- and 5 year renal outcome of living kidney donors with preexistent hypertension. METHODS: We compared outcome of hypertensive donors by gender, age, and body mass index with matched control donors. Hypertension was defined as predonation antihypertensive drug use. All donors had glomerular filtration rate (I iothalamate) and effective renal plasma flow (I-hippuran) measured 4 months before and 2 months after donation. A subset of donors had serum creatinine measured 1 year after donation or a renal function measurement 5 years after donation. RESULTS: Included were 47 hypertensive donors and 94 control donors (both 53% male; mean age, 57+/-7 years; and body mass index, 28+/-4 kg/m). Pre- and early postdonation, systolic blood pressure, and mean arterial pressure were significantly higher in hypertensive donors. Control donors showed a rise in diastolic blood pressure after donation, and thus the predonation difference was lost postdonation. Both at 1 year (29 hypertensive donors, 58 controls) and 5 years after donation (13 hypertensive donors and 26 controls) blood pressure was similar. Renal function was similar at all time points. DISCUSSION: In summary, hypertensive living kidney donors have similar outcome in terms of blood pressure and renal function as control donors, early and 1 and 5 years after donation. PMID- 22217534 TI - Cognitive behavioural therapy for Japanese children and adolescents with anxiety disorders: a pilot study. AB - BACKGROUND: Thirty-three Japanese children and adolescents diagnosed with an anxiety disorder participated in individual or group Cognitive Behaviour Therapy (CBT) that was modelled after evidence-based intervention programs developed in Western countries. METHOD: The treatment consisted of: (a) building rapport and education; (b) identifying emotions and recognizing cognitive self-talk; (c) challenging anxious self-talk; (d) developing an anxiety hierarchy and in vivo exposures; and (e) planning for future challenges. RESULTS: Three months following treatment, 20 of the 33 children and adolescents (60.91%) no longer met criteria for their principal anxiety disorders and 16 (48.48%) were free from all anxiety disorders. Self-reported anxiety, depression, and cognitive errors also decreased significantly from pre- to post-treatment and these gains were maintained at 3-month follow-up. For the most part, similar outcomes were found in both the group and individual formats of CBT. CONCLUSIONS: This study provides preliminary support for the transportability of CBT in both an individual and group format to Japan. PMID- 22217535 TI - Impact of the 2008-2010 economic recession on local health departments. AB - We measured the impact of the 2008-2010 economic recession on local health departments (LHDs) across the United States. Between 2008 and 2010, we conducted 3 Web-based, cross-sectional surveys of a nationally representative sample of LHDs to assess cuts to budgets, workforce, and programs. By early 2010, more than half of the LHDs (53%) were experiencing cuts to their core funding. In excess of 23 000 LHDs jobs were lost in 2008-2009. All programmatic areas were affected by cuts, and more than half of the LHDs had to reduce or eliminate at least 1 programmatic area. The capacity of LHDs to provide core public health services was undermined by the economic recession. PMID- 22217536 TI - Assessing the validity and reliability of the MUST and MST nutrition screening tools in renal inpatients. AB - OBJECTIVE: The aim of this study was to determine the validity and reliability of the Malnutrition Universal Screening Tool (MUST) and the Malnutrition Screening Tool (MST) in hospital inpatients with renal disease. DESIGN: A cross-sectional and longitudinal study. SETTING: The study took place on 3 renal inpatient wards in a tertiary hospital in south London. PATIENTS: A total of 276 participants were recruited. INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: Concurrent validity was assessed by comparing the MUST and MST tools completed by nursing staff with the subjective global assessment tool completed by dietetic staff. Predictive validity was evaluated by assessing the association between malnutrition and length of hospital stay. Mid-upper arm circumference and bioelectrical impedance spectroscopy were used to assess construct validity. In the reliability study, the MUST and MST tools were repeated on the same day by nursing staff. OBJECTIVE: MUST had a sensitivity of 53.8% (95% confidence interval [CI], 46.6% to 60.0%) and a specificity of 78.3% (95% CI, 70.1% to 85.2%), and MST had a sensitivity of 48.7% (95% CI, 41.7% to 54.0%) and a specificity of 85.5% (95% CI, 77.9 to 91.3) when compared with subjective global assessment. Risk of malnutrition as identified by MUST but not the MST tools had a significantly longer length of hospital stay (P = .038 and .061). Both MUST and MST tools identified patients at risk of malnutrition had a significantly lower mid-upper arm circumference (P = .005 and P = .029, respectively) and percent fat mass (P = .023 and P = .052, respectively). Reliability assessed by kappa was 0.58 for MUST (95% CI, 0.20 to 0.80) and 0.33 for MST (95% CI, -0.03 to 0.54). CONCLUSIONS: The MUST and MST nutrition tools are not sensitive enough to identify all of the malnourished renal inpatients, despite being fairly reliable and related to other nutrition status markers. PMID- 22217537 TI - Effect of Brazil nut supplementation on plasma levels of selenium in hemodialysis patients: 12 months of follow-up. AB - BACKGROUND: Large amounts of reactive oxygen species are produced in hemodialysis (HD) patients, and, at higher concentrations, reactive oxygen species are thought to be involved in the pathogenesis of cardiovascular disease. It has been proposed that selenium (Se) may exert an antiatherogenic influence by reducing oxidative stress. The richest known food source of Se is the Brazil nut (Bertholletia excelsa, family Lecythidaceae), found in the Amazon region. OBJECTIVE: The objective of this work was to determine if Se plasma levels in HD patients submitted to a program of supplementation during 3 months with 1 Brazil nut by day could be sustained after 12 months. METHODS: A total of 21 HD patients (54.2 +/- 15.2 years old; average time on dialysis, 82.3 +/- 51.6 months; body mass index, 24.4 +/- 3.8 kg/m(2)) from the RenalCor Clinic in Rio de Janeiro, Brazil, were followed up 12 months after the supplementation study ended. The Se plasma levels were determined by atomic absorption spectrophotometry with hydride generation. RESULTS: The Se Plasma levels (17.3 +/- 19.9 MUg/L) were below the normal range (60 to 120 MUg/L) before nut supplementation, and after 3 months of supplementation, the levels increased to 106.8 +/- 50.3 MUg/L (P < .0001). Twelve months after supplementation, the plasma Se levels decreased to 31.9 +/- 14.8 MUg/L (P < .0001). CONCLUSIONS: The data showed that these patients were Se deficient and that the consumption of Brazil nut was effective to increase the Se parameters of nutritional status. Se levels 12 months after the supplementation period were not as low as presupplementation levels but yet significantly lower, and we needed to motivate patients to adopt different dietary intake patterns. PMID- 22217538 TI - Have renal dietitians successfully implemented evidence-based guidelines into practice? A survey of dietitians across Australia and New Zealand. AB - OBJECTIVE: Successful implementation of evidence-based practice (EBP) guidelines has been shown to improve the nutrition status of dialysis patients. This study aimed to establish use of EBP guidelines and implementation of key recommendations for nutrition assessment of dialysis patients, as well as to identify barriers and enablers associated with EBP guideline adherence. DESIGN: A survey of nutrition assessment practices and barriers to implementation of EBP guidelines was developed and piloted. The survey measured implementation of guidelines regarding frequency of nutrition assessment and use of the subjective global assessment (SGA) to diagnose malnutrition. Barriers to guideline implementation were measured using agreement with statements rated on a Likert scale. Data were summarized as counts and percentages and analyzed using chi squared tests of association, with P < .05 indicating statistical significance. SETTING: The survey targeted specialist renal dietitians across Australian and New Zealand. PARTICIPANTS: Sixty-five renal dietitians from Australia and New Zealand responded to the survey. Most were females (89%, n = 58 of 65), aged <35 years (72%, n = 47 of 65), with one-third (n = 22 of 65) working in renal dietetics for longer than 4 years. RESULTS: Nearly all participants (n = 62 of 65) reported routinely using EBP guidelines; however, only 55% and 66% indicated they had successfully implemented the guidelines regarding minimum 6-monthly nutrition assessment of dialysis patients (n = 36 of 65) and use of the SGA (n = 43 of 65), respectively. Barriers related to time, skills/self-efficacy, and an inefficient referral system were related to lower rates of guideline implementation. CONCLUSION: These findings indicate an evidence-practice gap in the nutritional management of dialysis patients. A standardized approach to EBP guideline implementation including structured 6-monthly nutrition assessment of dialysis patients and group training for use of the SGA tool may assist in closing this evidence-practice gap. PMID- 22217543 TI - Re: Rustom P. Manecksha, Ivor M. Cullen, Sarfraz Ahmad, et al. Prospective randomised controlled trial comparing trigone-sparing versus trigone-including intradetrusor injection of abobotulinumtoxina for refractory idiopathic detrusor overactivity. Eur Urol 2012;61:928-35. PMID- 22217539 TI - Associations of socioeconomic status and processed food intake with serum phosphorus concentration in community-living adults: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - OBJECTIVE: Higher serum phosphorus concentrations are associated with cardiovascular disease events and mortality. Low socioeconomic status is linked with higher serum phosphorus concentration, but the reasons are unclear. Poor individuals disproportionately consume inexpensive processed foods commonly enriched with phosphorus-based food preservatives. Accordingly, we hypothesized that excess intake of these foods accounts for a relationship between lower socioeconomic status and higher serum phosphorus concentration. DESIGN: Cross sectional analysis. SETTING AND PARTICIPANTS: We examined a random cohort of 2,664 participants with available phosphorus measurements in the Multi-Ethnic Study of Atherosclerosis, a community-based sample of individuals free of clinically apparent cardiovascular disease from across the United States. PREDICTOR VARIABLES: Socioeconomic status, the intake of foods commonly enriched with phosphorus-based food additives (processed meats, sodas), and frequency of fast-food consumption. OUTCOMES: Fasting morning serum phosphorus concentrations. RESULTS: In unadjusted analyses, lower income and lower educational achievement categories were associated with modestly higher serum phosphorus concentration (by 0.02 to 0.10 mg/dL, P < .05 for all). These associations were attenuated in models adjusted for demographic and clinical factors, almost entirely due to adjustment for female gender. In multivariable-adjusted analyses, there were no statistically significant associations of processed meat intake or frequency of fast-food consumption with serum phosphorus. In contrast, each serving per day higher soda intake was associated with 0.02 mg/dL lower serum phosphorus concentration (95% confidence interval, -0.04, -0.01). CONCLUSIONS: Greater intake of foods commonly enriched with phosphorus additives was not associated with higher serum phosphorus concentration in a community-living sample with largely preserved kidney function. These results suggest that excess intake of processed and fast foods may not impact fasting serum phosphorus concentrations among individuals without kidney disease. PMID- 22217545 TI - HDACs and their inhibitors in immunology: teaching anticancer drugs new tricks. PMID- 22217540 TI - The interaction of PKN3 with RhoC promotes malignant growth. AB - PKN3 is an AGC-family protein kinase implicated in growth of metastatic prostate cancer cells with phosphoinositide 3-kinase pathway deregulation. The molecular mechanism, however, by which PKN3 contributes to malignant growth and tumorigenesis is not well understood. Using orthotopic mouse tumor models, we now show that inducible knockdown of PKN3 protein not only blocks metastasis, but also impairs primary prostate and breast tumor growth. Correspondingly, overexpression of exogenous PKN3 in breast cancer cells further increases their malignant behavior and invasiveness in-vitro. Mechanistically, we demonstrate that PKN3 physically interacts with Rho-family GTPases, and preferentially with RhoC, a known mediator of tumor invasion and metastasis in epithelial cancers. Likewise, RhoC predominantly associates with PKN3 compared to its closely related PKN family members. Unlike the majority of Rho GTPases and PKN molecules, which are ubiquitously expressed, both PKN3 and RhoC show limited expression in normal tissues and become upregulated in late-stage malignancies. Since PKN3 catalytic activity is increased in the presence of Rho GTPases, the co-expression and preferential interaction of PKN3 and RhoC in tumor cells are functionally relevant. Our findings provide novel insight into the regulation and function of PKN3 and suggest that the PKN3-RhoC complex represents an attractive therapeutic target in late-stage malignancies. PMID- 22217546 TI - Women's cardiovascular health in India. AB - Cardiovascular diseases (CVDs) are the leading cause of death among adult women in many parts of India and a major cause of morbidity. In some parts of the world, gender inequities have been observed in cardiovascular healthcare and cardiovascular outcomes. The authors discuss the data for potential disparities in cardiovascular healthcare for women in India. Data on cardiovascular healthcare provision and CVD outcomes among women in India are generally lacking. The little available data suggest that women in rural areas, younger women and girl children with CVD are less likely to receive appropriate management than men, with this disparity most apparent in those of lower socioeconomic status and education. However, there is a particular lack of information about the prevention and management of atherosclerotic heart disease in women from a range of communities that comprise the extremely diverse population of India. PMID- 22217547 TI - Using comparative anatomy in the axotomy model to identify distinct roles for microglia and astrocytes in synaptic stripping. AB - The synaptic terminals' withdrawal from the somata and proximal dendrites of injured motoneuron by the processes of glial cells following facial nerve axotomy has been the subject of research for many years. This phenomenon is referred to as synaptic stripping, which is assumed to help survival and regeneration of neurons via reduction of synaptic inputs. Because there is no disruption of the blood-brain barrier or infiltration of macrophages, the axotomy paradigm has the advantage of being able to selectively investigate the roles of resident glial cells in the brain. Although there have been numerous studies of synaptic stripping, the detailed mechanisms are still under debate. Here we suggest that the species and strain differences that are often present in previous work might be related to the current controversies of axotomy studies. For instance, the survival ratios of axotomized neurons were generally found to be higher in rats than in mice. However, some studies have used the axotomy paradigm to follow the glial reactions and did not assess variations in neuronal viability. In the first part of this article, we summarize and discuss the current knowledge on species and strain differences in neuronal survival, glial augmentation and synaptic stripping. In the second part, we focus on our recent findings, which show the differential involvement of microglia and astrocytes in synaptic stripping and neuronal survival. This article suggests that the comparative study of the axotomy paradigm across various species and strains may provide many important and unexpected discoveries on the multifaceted roles of microglia and astrocytes in injury and repair. PMID- 22217548 TI - Similar DNA methylation pattern in lung tumours from smokers and never-smokers with second-hand tobacco smoke exposure. AB - Tobacco smoke causes lung cancer in smokers and in never-smokers exposed to second-hand tobacco smoke (SHS). Nonetheless, molecular mechanisms of lung cancer in SHS-exposed never-smokers are still elusive. We studied lung cancers from current smokers (n = 109), former smokers (n = 56) and never-smokers (n = 47) for promoter hypermethylation of five tumour suppressor genes--p16, RARB, RASSF1, MGMT and DAPK1--using methylation-specific polymerase chain reaction. Lung tumours from ever-smokers suggested an increased risk of p16 hypermethylation as compared to never-smokers (P = 0.073), with former smokers having the highest frequency of p16 hypermethylation (P = 0.044 versus current smokers and P = 0.009 versus never-smokers). In the never-smoking group, p16 hypermethylation was seen in lung tumours from SHS-exposed individuals (4/33; 12%) but in none of the non exposed individuals (0/9). The overall occurrence of hypermethylation (measured both as methylation index and as number of genes affected) was similar in those ever exposed to tobacco smoke (smokers, SHS-exposed never-smokers) and differed from non-exposed never-smokers. In multivariate analysis, p16 hypermethylation was more prevalent in lung tumours from male than female patients (P = 0.018) and in squamous cell carcinomas than in adenocarcinomas (P = 0.025). Occurrence of TP53 mutation in the tumour was associated with hypermethylation of at least one gene (P = 0.027). In all, our data suggest that promoter hypermethylation pattern in SHS-exposed never-smokers resembles that observed in smokers. Association between TP53 mutation, a hallmark of smokers' lung cancer, and methylation of one or more of the lung cancer-related genes studied, provides further evidence for common tobacco smoke-related origin for both types of molecular alterations. PMID- 22217549 TI - Cycle arrest and aneuploidy induced by zidovudine in murine embryonic stem cells. AB - Zidovudine (3'-azido-3'-deoxythymidine; AZT) is a nucleoside analogue widely used for the treatment of acquired immune deficiency syndrome (AIDS). Medical guidelines recommend the use of AZT by pregnant women in order to reduce risk of HIV vertical transmission. Although it is efficacious, little is known about the side effects of AZT on embryonic development. In this sense, we used murine embryonic stem (mES) cells as a model to investigate the consequences of AZT exposure for embryogenesis. Firstly, mES colonies were incubated with AZT (50 or 100 MUM) and cell cycle profile was evaluated. While 27.7 +/- 5.43% of untreated mES cells were in G2/M phase, this percentage raised to 45.96 +/- 4.18% after AZT exposure (100 MUM). To identify whether accumulation of cells in G2/M phase could be related to chromosome missegregation with consequent cell cycle arrest, aneuploidy rate was evaluated after AZT treatment. Untreated colonies presented 39.6 +/- 8.4% of cells aneuploid, while after AZT 100 MUM treatment, the proportion of aneuploid cells raised to 67.8 +/- 3.4% with prevalence of chromosome loss. This event was accompanied by micronuclei formation as AZT 100 MUM treated mES cells presented a 2-fold increase compared to untreated ones. These data suggest that AZT exerts genotoxic effects and increases chromosome instability at early stages of embryonic development. PMID- 22217550 TI - Haemodialysis-induced pseudoporphyria successfully treated with glutathione. PMID- 22217551 TI - Clinical evaluation of an autofluorescence diagnostic device for oral cancer detection: a prospective randomized diagnostic study. AB - The prognosis for patients with oral squamous cell carcinoma remains poor despite advances in multimodal treatment concepts. Early diagnosis and treatment is the key to improved patient survival. A device (VELscope) that uses autofluorescence technology, allowing direct fluorescence visualization of the oral cavity, might be a useful tool for oral cancer detection or as an adjunct to standard clinical examination. A total of 289 patients with oral premalignant lesions were randomly divided into two groups for clinical examination of precancerous oral lesions. In group 1, 166 patients were examined conventionally with white light, and in group 2, 123 patients were examined with the autofluorescence visualization device (VELscope) in addition to the white light examination. Biopsies were obtained from all suspicious areas identified in both examination groups (n=52). In the first step, baseline characteristics of the two groups (only white light vs. white light and VELscope) were compared to exclude selection bias. In the second step, for the group examined with white light and VELscope (123 patients), the diagnostic strategies were compared with regard to sensitivity and specificity using biopsy as the gold standard. The results showed that using the VELscope leads to higher sensitivity (100% instead of 17%), but to lower specificity (74% instead of 97%). Thus, we can conclude that the VELscope is a useful new diagnostic device for detection of oral cancer diseases. PMID- 22217552 TI - Chemical and biological extraction of metals present in E waste: A hybrid technology. AB - Management of metal pollution associated with E-waste is widespread across the globe. Currently used techniques for the extraction of metals from E-waste by using either chemical or biological leaching have their own limitations. Chemical leaching is much rapid and efficient but has its own environmental consequences, even the future prospects of associated nanoremediation are also uncertain. Biological leaching on the other hand is comparatively a cost effective technique but at the same moment it is time consuming and the complete recovery of the metal, alone by biological leaching is not possible in most of the cases. The current review addresses the individual issues related to chemical and biological extraction techniques and proposes a hybrid-methodology which incorporates both, along with safer chemicals and compatible microbes for better and efficient extraction of metals from the E-waste. PMID- 22217553 TI - Variations of antioxidant characteristics and mineral contents in pulp and peel of different apple (Malus domestica Borkh.) cultivars from Pakistan. AB - Variations of phenolics, antioxidant activity, and mineral contents in peel and pulp of five apple (Malus domestica Borkh.) cultivars from Pakistan, namely Red Delicious, Golden Delicious, Kashmiri Amri, Kala Kulu and Sky Spur were appraised. The mean extract yield of antioxidant components obtained with 80:20 methanol-water (v/v), was found to be 22.1 g/100 g for peel and 14.2 g/100 g for pulp on a dry weight basis. The amounts of total phenolics and total flavonoids in peel and pulp of different cultivars of apple ranged from 1,907.5-2,587.9 mg gallic acid equivalent/100 g DW and 1,214.3-1,816.4 mg catechin equivalent/100 g DW and 1,185.2-1,475.5 mg GAE/100 g DW and 711.8-999.3 mg CE/100 g DW, respectively. The inhibition of linoleic acid peroxidation and DPPH scavenging activity of the extracts varied from 71.7-84.9 and 66.6-80.8% in peel, and 43.9 52.8 and 42.9-51.1% in pulp, respectively. Reducing power of the tested fruit part extracts at concentration 12.5 mg/mL ranged from 2.54-2.89 and 1.37-1.73, respectively. With regard to minerals analysis, both fruit parts showed the amount of K to be the highest, followed by Mg, Ca, Fe, Na and Zn. The results revealed that peel of the tested apple cultivars in this study had superior antioxidant capacity and mineral concentration than the pulp, indicating significant variations between the parts tested. Thus, consumption of apple fruits along with peel might be recommended to gaining better nutritive benefits. PMID- 22217554 TI - Extraction equilibrium of indium(III) from nitric acid solutions by di(2 ethylhexyl)phosphoric acid dissolved in kerosene. AB - The extraction equilibrium of indium(III) from a nitric acid solution using di(2 ethylhexyl) phosphoric acid (D2EHPA) as an acidic extractant of organophosphorus compounds dissolved in kerosene was studied. By graphical and numerical analysis, the compositions of indium-D2EHPA complexes in organic phase and stoichiometry of the extraction reaction were examined. Nitric acid solutions with various indium concentrations at 25 degrees C were used to obtain the equilibrium constant of InR3 in the organic phase. The experimental results showed that the extraction distribution ratios of indium(III) between the organic phase and the aqueous solution increased when either the pH value of the aqueous solution and/or the concentration of the organic phase extractant increased. Finally, the recovery efficiency of indium(III) in nitric acid was measured. PMID- 22217555 TI - Metabolite profiling of four major flavonoids of Herba Epimedii in zebrafish. AB - The zebrafish model organism was applied first in a metabolic study of icariin, baohuoside I, epimedin A and epimedin C, which are flavonoids in Herba Epimedii. Metabolites of these compounds in zebrafish after exposure for 24 h were identified by HPLC-ESI-MS, whereby the separation was performed with a Zorbax C 18 column using a gradient elution of 0.05% formic acid acetonitrile-0.05% formic acid water. The quasi-molecular ions of compounds were detected in simultaneous negative and positive ionization modes. Metabolic products of icariin and epimedin C via cleavage of glucose residue instead of rhamnose residues were found, which coincided with the results using regular metabolic analysis methods. In addition, the zebrafish model was used to predict the metabolism of the trace component epimedin A, whose metabolic mechanisms haven't been clearly elucidated with the current metabolism model. The metabolic pathway of epimedin A in zebrafish was similar to those of its homologue icariin and epimedin C. Our study demonstrated that the zebrafish model can successfully imitate the current models in elucidating metabolic pathways of model flavonoids, which has advantages of lower cost, far less amount of compound needed, easy set up and high performance. This novel model can also be applied in quickly predicting the metabolism of Chinese herb components, especially trace compounds. PMID- 22217556 TI - Synthesis of stable and soluble one-handed helical homopoly(substituted acetylene)s without the coexistence of any other chiral moieties via two-step polymer reactions in membrane state: molecular design of the starting monomer. AB - A soluble and stable one-handed helical poly(substituted phenylacetylene) without the coexistence of any other chiral moieties was successfully synthesized by asymmetric-induced polymerization of a chiral monomer followed by two-step polymer reactions in membrane state: (1) removing the chiral groups (desubstitution); and (2) introduction of achiral long alkyl groups at the same position as the desubstitution to enhance the solubility of the resulting one handed helical polymer (resubstitution). The starting chiral monomer should have four characteristic substituents: (i) a chiral group bonded to an easily hydrolyzed spacer group; (ii) two hydroxyl groups; (iii) a long rigid hydrophobic spacer between the chiral group and the polymerizing group; (iv) a long achiral group near the chiral group. As spacer group a carbonate ester was selected. The two hydroxyl groups formed intramolecular hydrogen bonds stabilizing a one-handed helical structure in solution before and after the two-step polymer reactions in membrane state. The rigid long hydrophobic spacer, a phenylethynylphenyl group, enhanced the solubility of the starting polymer, and realized effective chiral induction from the chiral side groups to the main chain in the asymmetric-induced polymerization. The long alkyl group near the chiral group avoided shrinkage of the membrane and kept the reactivity of resubstitution in membrane state after removing the chiral groups. The g value (g = ([theta]/3,300)/epsilon) for the CD signal assigned to the main chain in the obtained final polymer was almost the same as that of the starting polymer in spite of the absence of any other chiral moieties. Moreover, since the one-handed helical structure was maintained by the intramolecular hydrogen bonds in a solution, direct observation of the one-handed helicity of the final homopolymer has been realized in CD for the solution for the first time. PMID- 22217557 TI - A biosorption isotherm model for the removal of reactive azo dyes by inactivated mycelia of Cunninghamella elegans UCP542. AB - The biosorption of three reactive azo dyes (red, black and orange II) found in textile effluents by inactive mycelium of Cunninghamella elegans has been investigated. It was found that after 120 hours of contact the adsorption led to 70%, 85%, 93% and 88% removal of reactive orange II, reactive black, reactive red and a mixture of them, respectively. The mycelium surface was found to be selective towards the azo dyes in the following order: reactive red > reactive black > orange II. Dye removal from a mixture solution resulted in 48.4 mg/g retention by mycelium and indicated a competition amongst the dyes for the cellular surface. A Freundlich adsorption isotherm model exhibited a better fit, thus suggesting the presence of heterogeneous binding sites. Electrondense deposits observed on the mycelium ultrastructure suggest that the dyes are mainly retained under the cellular surface of the inactive biomass of C. elegans. PMID- 22217558 TI - Essential tremor: beyond the motor features. AB - There is a growing evidence to suggest that apart from motor features, patients with Essential Tremor (ET) may have significant non-motor features. This review critically analyzes the available evidence of the various non-motor symptoms in patients with ET. Apart from tremor, patients with ET have been reported to have: (i) cognitive abnormalities characterized by mild frontal dysfunction that may have a functional impact, (ii) an association with dementia (both prevalent and incident) among those with late onset of tremor (>65 years), (iii) a higher prevalence of anxiety and an anxious and worrisome personality type, (iv) depressive symptomatology and may even have depression as a premotor symptom, (v) poor sleep quality and (vi) subjective hearing impairment. It is controversial whether olfactory dysfunction occurs in ET and its utility as a diagnostic aid. The biological basis for each of these observations requires further clarification and some findings need confirmation in population-based studies. However the available evidence is sufficient to support the notion that ET can no longer be considered as a pure motor disorder and further studies of these non motor aspects will go a long way in understanding and comprehensively treating ET. PMID- 22217559 TI - Exercise training post-MI favorably modifies heart extracellular matrix in the rat. AB - PURPOSE: In order to assess the effect of daily exercise on extracellular matrix remodeling in the heart after myocardial infarction (MI), we measured collagen concentration (%COL) and nonreducible collagen cross-linking (hydroxylysylpyridinoline, HP) in the right ventricle (RV), and regionally within the infarcted (INF) and viable left ventricular free wall (LVF) and septum (LVS), using a rodent MI training model. METHODS: Infarcts (19%-24% of LV) were surgically induced in adult rats that were assigned to either trained (MI-TR) or sedentary (MI-SED) groups and compared to sham-surgery sedentary controls (SHAM). RESULTS: In LVF, 10 wk of treadmill running had no effect on the increase (P < 0.001) in %COL seen with MI (MI-SED = 7.14% +/- 0.15%, MI-TR = 7.61% +/- 0.19%, SHAM = 3.55% +/- 0.19%). However, it normalized the increase (P < 0.05) in HP cross-linking (MI-SED = 0.43 +/- 0.02, MI-TR = 0.27 +/- 0.03, SHAM = 0.30 +/- 0.04 mol HP.mol(-1) collagen). The INF scar in MI-SED rats showed a sevenfold increase in %COL (P < 0.001) compared to SHAM LVF myocardium, an increase that was attenuated by training (MI-SED = 26% +/- 1% vs MI-TR = 21% +/- 2%; P < 0.05). However, training had no effect on MI-induced increases in cross-linking in the INF scar (1.01 +/- 0.22 vs 0.84 +/- 0.14 mol HP.mol(-1) collagen). In LVS, although a small but significant increase in %COL was seen in both MI groups, HP cross-linking was unaltered compared to SHAM rats. Training also normalized the increase observed in cross-linking in RV after MI. CONCLUSIONS: Because increased HP cross-linking in the heart is associated with decreased chamber compliance, these findings may help to explain the improved heart function seen after daily exercise in cardiac rehabilitation patients. PMID- 22217560 TI - Seasonal and annual variation in young children's physical activity. AB - INTRODUCTION: It is well established that regular physical activity (PA) contributes to lower levels of morbidity and mortality. However, little is known about the stability of very young children's PA habits across seasons and years. The aims of this study were to 1) examine the influence of season and increasing age on objectively assessed PA in preschool children and 2) examine the stability of young children's PA rankings during 1 yr. METHODS: The PA levels of preschool (3- and 4-yr-old) children were measured, using 6-d pedometer step counts, during winter and spring (n = 85, 52 boys). PA levels were measured again 1 yr after the spring data collection when the children had entered primary school (n = 37, 22 boys). Parents completed questionnaires to assess attitudes toward PA, PA habits, and demographic information in the winter of the first year and the spring of the second year. RESULTS: Young children take approximately 2000 (20%) fewer steps per day in winter than in spring with a rank order stability between the two measures of r = 0.04 (P < 0.01). A modest degree of the observed intrachild or seasonal variation was related to the amount of time fathers played with their children (P < 0.05) and the availability of a safe place for children to play (P < 0.05). Children took approximately 2300 (20%) more steps per day at age 5 compared with age 4 (P < 0.01). The rank order stability of young children's PA during this period was low with correlations ranging from 0.01 to 0.15. CONCLUSIONS: Results suggest that a one-off assessment of PA is unlikely to be representative of a young child's activity during 1 yr and that PA tracks poorly from age 4 to 5. PMID- 22217561 TI - Foot strike and injury rates in endurance runners: a retrospective study. AB - PURPOSE: This retrospective study tests if runners who habitually forefoot strike have different rates of injury than runners who habitually rearfoot strike. METHODS: We measured the strike characteristics of middle- and long-distance runners from a collegiate cross-country team and quantified their history of injury, including the incidence and rate of specific injuries, the severity of each injury, and the rate of mild, moderate, and severe injuries per mile run. RESULTS: Of the 52 runners studied, 36 (69%) primarily used a rearfoot strike and 16 (31%) primarily used a forefoot strike. Approximately 74% of runners experienced a moderate or severe injury each year, but those who habitually rearfoot strike had approximately twice the rate of repetitive stress injuries than individuals who habitually forefoot strike. Traumatic injury rates were not significantly different between the two groups. A generalized linear model showed that strike type, sex, race distance, and average miles per week each correlate significantly (P < 0.01) with repetitive injury rates. CONCLUSIONS: Competitive cross-country runners on a college team incur high injury rates, but runners who habitually rearfoot strike have significantly higher rates of repetitive stress injury than those who mostly forefoot strike. This study does not test the causal bases for this general difference. One hypothesis, which requires further research, is that the absence of a marked impact peak in the ground reaction force during a forefoot strike compared with a rearfoot strike may contribute to lower rates of injuries in habitual forefoot strikers. PMID- 22217562 TI - Lower physical activity is associated with skeletal muscle fat content in girls. AB - Fat contained within skeletal muscle is strongly associated with obesity, type 2 diabetes mellitus, and metabolic syndrome. Physical inactivity may be a risk factor for greater fat infiltration within skeletal muscle during growth. PURPOSE: We sought to examine the relationship between physical activity and skeletal muscle fat content of the calf and thigh in girls. METHODS: Data from 464 girls, age 8-13 yr, were used to examine the relationship between physical activity and skeletal muscle fat content of the calf and thigh. Calf and thigh muscle density (mg.cm(-3)), an index of skeletal muscle fat content, was assessed at the 66% tibia and 20% femur sites relative to the respective distal growth plates of the nondominant limb using peripheral quantitative computed tomography. Physical activity level was classified by past-year physical activity questionnaire score. RESULTS: Muscle densities of the calf and thigh were inversely correlated with percent total body fat (r = -0.37 and -0.48, P values < 0.001) and total body fat mass (r = -0.33 and -0.40, P values < 0.001). Multiple linear regression with physical activity, ethnicity, maturity offset, and muscle cross-sectional area as independent variables showed that physical activity was independently associated with muscle densities of the calf (beta = 0.14, P = 0.002) and thigh (beta = 0.15, P < 0.001). Thus, lower physical activity was associated with higher skeletal muscle fat content. CONCLUSIONS: Our results suggest that a lower level of physical activity may lead to excess skeletal muscle fat content of the calf and thigh in girls. PMID- 22217563 TI - Exercise frequency is related to psychopathology but not neurocognitive function. AB - INTRODUCTION: In this study, we measured neurocognitive function, perceived stress, quality of life (QOL), and psychopathology in community-dwelling adults, with data contrasted across tertiles of exercise frequency. METHODS: A group of 998 adults (age 18-85 yr) was measured for neurocognitive function using a computerized neuropsychological test from CNS Vital Signs (Morrisville, NC). They also completed the Brief Symptom Inventory (BSI), which measures psychopathology, as well as the World Health Organization QOL questionnaire and the Perceived Stress Scale. General linear modeling was used to examine relationships between exercise frequency and neurocognitive function, BSI, QOL, and the Perceived Stress Scale. Backward selection in the GLMSELECT procedure in SAS (version 9.1.3; SAS Institute, Inc., Cary, NC) was used to identify confounding variables including age, gender, body mass index, marital status, education level, stress level, alcohol, smoking, and chronic disease. A contrast to test linear trend was performed after adjusting for confounders. Pairwise comparisons were performed across exercise frequency tertiles using the Tukey-Kramer method. RESULTS: P values for trend tests and pairwise comparisons were nonsignificant for all five cognition function domains across exercise frequency tertiles after adjustment for confounders. Age and education level emerged as the best correlates of neurocognitive function. P values for trend were significant for all BSI domains and indices, QOL, and perceived stress, across exercise frequency tertiles. CONCLUSIONS: In conclusion, nine BSI psychopathology domains, perceived stress, and QOL but not five neurocognitive function domains were modestly but significantly associated with aerobic exercise frequency in a heterogeneous group of community-dwelling adults after adjustment for demographic and lifestyle factors. PMID- 22217564 TI - Genetic influences on physical activity in young adults: a twin study. AB - PURPOSE: The aim of this study was to investigate genetic and environmental influences on different aspects of physical activity in young adult twins. METHODS: We studied 1274 Finnish twins with a mean age of 22.4 yr, from the population-based FinnTwin12 study. Physical activity was assessed with the Baecke Questionnaire, yielding four indexes: the sport index, leisure time activity index, work index, and total score. Quantitative genetic analyses based on linear structural equations were used to estimate the contribution of genetic and environmental factors on these physical activity traits. RESULTS: The overall heritability estimates were 64% (95% confidence interval (CI) = 0.56%-0.70%) for sports activity, 41% (95% CI = 0.31%-0.51%) for leisure time activity excluding sports, 56% (95% CI = 0.48%-0.63%) for physical activity at work, and 54% (95% CI = 0.45%-0.62%) for total physical activity. Unique environmental factors accounted for the rest of the trait variances. We did not find evidence for common environmental or dominant genetic influences. The heritability estimates did not differ between men and women, and no sex-specific genetic factors were found. Sports activity and leisure time activity excluding sports were associated (r = 0.27), and additive genetic factors explained 57% of their association. CONCLUSIONS: Our results suggest that genetic factors contribute significantly to physical activity levels in young adults and that sports activity is under stronger genetic influence than leisure time physical activity excluding sports. We also concluded that physical activity at work does not seem to be associated with sports activities or other leisure time physical activity at this age. PMID- 22217565 TI - Effects of footwear and strike type on running economy. AB - PURPOSE: This study tests if running economy differs in minimal shoes versus standard running shoes with cushioned elevated heels and arch supports and in forefoot versus rearfoot strike gaits. METHODS: We measured the cost of transport (mL O(2).kg(-1).m(-1)) in subjects who habitually run in minimal shoes or barefoot while they were running at 3.0 m.s(-1) on a treadmill during forefoot and rearfoot striking while wearing minimal and standard shoes, controlling for shoe mass and stride frequency. Force and kinematic data were collected when subjects were shod and barefoot to quantify differences in knee flexion, arch strain, plantar flexor force production, and Achilles tendon-triceps surae strain. RESULTS: After controlling for stride frequency and shoe mass, runners were 2.41% more economical in the minimal-shoe condition when forefoot striking and 3.32% more economical in the minimal-shoe condition when rearfoot striking (P < 0.05). In contrast, forefoot and rearfoot striking did not differ significantly in cost for either minimal- or standard-shoe running. Arch strain was not measured in the shod condition but was significantly greater during forefoot than rearfoot striking when barefoot. Plantar flexor force output was significantly higher in forefoot than in rearfoot striking and in barefoot than in shod running. Achilles tendon-triceps surae strain and knee flexion were also lower in barefoot than in standard-shoe running. CONCLUSIONS: Minimally shod runners are modestly but significantly more economical than traditionally shod runners regardless of strike type, after controlling for shoe mass and stride frequency. The likely cause of this difference is more elastic energy storage and release in the lower extremity during minimal-shoe running. PMID- 22217566 TI - Regular maternal exercise dose and fetal heart outcome. AB - PURPOSE: Our previous research found lower fetal HR and increased HR variability (HRV) in women who exercised during pregnancy. This finding is similar to the adult heart training response at rest due to aerobic exercise. Dose-response associations have been found between physical activity and cardiorespiratory fitness in adults. Therefore, our objective was to determine whether there is a dose-response relationship between maternal physical activity and fetal HR, HRV, and sympathovagal balance. METHODS: Pregnant women completed a physical activity questionnaire and magnetocardiogram (magnetic correlate to ECG) recordings at 36 wk gestational age. Women reported the duration, intensity, and frequency of each activity for each month of pregnancy as well as 3 months before pregnancy. These values were used to calculate maternal physical activity measures for each participant. Relationships between fetal HR, HRV, and sympathovagal balance at 36 wk gestational age and maternal physical activity (n = 50 pairs) during the third trimester were assessed by Spearman correlations. Regression analysis was performed to further examine these relationships after controlling for maternal and fetal covariates (maternal age, maternal resting HR, maternal weight gain, prepregnancy body mass index (BMI), and fetal activity state). RESULTS: The regression analyses showed that maternal physical activity intensity (kcal.min( 1)) was negatively associated with HR in the active fetal state (P < 0.05), and physical activity duration (minutes during the third trimester) was positively associated with fetal HRV (P < 0.05). There were no statistically significant relationships with maternal physical activity on measures of fetal sympathovagal balance. CONCLUSIONS: Maternal physical activity dose during the third trimester is associated with resting fetal heart effects similar to a trained response. Future studies on the health benefits of this fetal response are highly warranted. PMID- 22217567 TI - Screen-based sedentary behavior and cardiorespiratory fitness from age 11 to 13. AB - PURPOSE: The study's purpose was to determine whether time spent in screen-based sedentary behavior is associated with change in cardiorespiratory fitness (CRF) levels in children from age 11 to 13, adjusting for vigorous physical activity (VPA). METHODS: Participants were children (n = 2097) enrolled in the control arm of the HEALTHY Study, who performed 20-m shuttle run tests at ages 11 and 13. Self-reported screen time was used as a measure of sedentary behavior. Longitudinal quantile regression was used to model the influence of predictors on changes at the 10th, 25th, 50th, 75th, and 90th shuttle run lap percentiles. Screen time (h.d(-1)) was the main predictor, and adjustment was also made for VPA, body mass index, and household education. RESULTS: In boys, more screen time was associated with fewer shuttle run laps completed from age 11 to 13 at the 25th, 50th, and 75th shuttle run lap percentiles; the strongest association was at the 75th shuttle run percentile (-0.57, 95% confidence interval = -0.93 to 0.21). In girls, more screen time was associated with fewer shuttle run laps completed from age 11 to 13 at the 50th, 75th, and 90th shuttle run lap percentiles; the strongest association was at the 90th shuttle run percentile ( 0.65, -1.01 to -0.30). Borderline negative associations were found between screen time and shuttle run laps at the 10th shuttle run percentile in boys and girls ( 0.28, -0.57 to 0.01, and -0.17, -0.41 to 0.06, respectively). CONCLUSIONS: More screen time was associated with lower CRF from age 11 to 13, independent of VPA. However, the association was weakest at the lower tail of the CRF distribution. PMID- 22217568 TI - Destination and route attributes associated with adults' walking: a review. AB - BACKGROUND: Increasing adults' physical activity through environmental initiatives that promote walking as a public health priority. To this end, evidence relevant to the urban planning and transport sectors is required. This review synthesized findings on destination and route attributes associated with utilitarian and recreational walking. METHODS: A literature search was conducted in April 2011 using Web of Science, PubMed, Transport Research Information Services, GEOBASE, and SPORTDiscus. Environmental attributes were classified into the domains of utilitarian and recreational destinations (presence, proximity, quality) and route (sidewalks, connectivity, aesthetics, traffic, safety). Forty six studies examining associations of these attributes with utilitarian and/or recreational walking were identified. Specific destination and route attributes associated with each type of walking were summarized. RESULTS: Adults' utilitarian walking was consistently associated with presence and proximity of retail and service destinations (in 80% of the studies reviewed). It was also associated with functional aspects of routes (sidewalks and street connectivity) in 50% of studies. Recreational walking was associated with presence, proximity, and quality of recreational destinations (35% of studies) and route aesthetic (35% of studies). Both types of walking were found unrelated to route safety and traffic in most studies. CONCLUSIONS: There is consistent evidence that better access to relevant neighborhood destinations (e.g., local stores, services, transit stops) can be conducive to adults' utilitarian walking. Some evidence also suggests that availability of sidewalks and well-connected streets can facilitate utilitarian walking. To better inform initiatives to promote adults' walking in the planning and transport sectors, future studies need to examine how accessible such destinations should be, as well as the effect of the quality of recreational destinations. PMID- 22217569 TI - Arterial stress hormones during scuba diving with different breathing gases. AB - PURPOSE: The purpose of the study was to determine whether the conditions during scuba diving without exercise (e.g., submersion, restricted breathing) stimulate the activities of the sympathoadrenergic system and the hypothalamic-pituitary adrenal axis. This might facilitate panic reactions in dangerous situations. METHODS: Fifteen experienced rescue divers participated in three experiments with two submersions each in a diving tower where ambient pressure could be varied. During submersion (duration = 15 min), they were breathing either pure oxygen (ambient pressure = 1.1 bar) or air (1.1 and 5.3 bar) or Heliox21 (21% O(2) and 79% He, 1.1 and 5.3 bar). The subjects stayed upright immediately below the water surface holding one hand with a cannulated radial artery out in the air. Noradrenaline, adrenaline, and dopamine concentrations in arterial blood and heart rate (HR) variability as indicators of sympathoadrenergic activity and cortisol and adrenocorticotropic hormone concentrations as strain indicators were measured. RESULTS: [Noradrenaline] and [adrenaline] (initial values (mean +/- SE) = 1616 +/- 93 and 426 +/- 38 pmol.L(-1)) decreased significantly by up to 30% and 50%, respectively, after 11 min of submersion, independent of pressure and inspired gas. HR variability showed roughly corresponding changes and also indications for parasympathetic stimulation, but artifacts by interference among HR monitors reduced the number of usable measurements. The other hormone concentrations did not change significantly. CONCLUSIONS: There was no increase of stress hormone concentrations in experienced subjects. The reduction of [noradrenaline] and [adrenaline] during scuba diving seems to be a reaction to orthostatic relief caused by external hydrostatic pressure on peripheral vasculature. The activity of the vegetative nervous system might be estimated from HR variability if interference among pulse watches can be avoided. PMID- 22217570 TI - Reconsidering the effects of respiratory constraints on the optimal running speed. AB - INTRODUCTION: Although both humans and quadrupeds frequently coordinate breathing and limb movement during running, early studies in humans focused on how increased breathing flexibility in humans allowed for relaxed or even transient coordination during locomotion. This difference was used to explain why quadrupeds had an optimal running speed whereas humans did not. Recent research, however, has clearly demonstrated that humans, like quadrupeds, have an optimal running speed. Because these findings are new, it remains unclear why this is true: whether because entrainment in humans was more important than initially predicted or because another restraint is acting. Here, we try to explain the observed minimum cost of transport (CoT) by analyzing metabolic cost with respect to entrainment and a standard set of anthropometrics. METHODS: We measured the energetic cost of human running at five different speeds and calculated individual CoT curves for each participant (N = 9). Simultaneously, entrainment was determined by the degree to which a poststimulus histogram (breaths per 0.05 s bin after a footfall) differed from a uniform plot. RESULTS: We compared the degree of entrainment to each participant's optimal running speed and found that although all of our subjects clearly entrained at some speeds, entrainment was not a function of CoT (P = 0.897). Because entrainment was also not correlated with speed (P = 0.304), it seems that bipedalism removed the respiratory constraints associated with quadrupedalism as originally suggested. CONCLUSIONS: Unlike quadrupeds, for whom respiratory constraints remain implicated in the speed dependence of CoT, constraints that lead to a minimum CoT for people must involve other mechanisms of efficiency such as the storage and release of energy in the lower limbs. PMID- 22217571 TI - Physical activity is related to pain sensitivity in healthy women. AB - There are many benefits associated with meeting current physical activity recommendations. At present, it is unknown whether a reduced sensitivity to pain is included among these benefits. PURPOSE: The study's purpose was to assess the relationship between pain sensitivity and physical activity and sedentary behaviors in a sample of healthy women. METHODS: Self-reported and accelerometer measures of physical activity and sedentary behavior were collected and compared with pain intensity and unpleasantness ratings to noxious thermal stimuli in a sample of 21 healthy women (age = 30.0 +/- 5.8 yr). On the basis of accelerometer data, participants were classified into two groups: meets recommendations (n = 12) and insufficiently active (n = 9). Independent-samples t-tests were conducted to compare pain ratings and physical activity behaviors between groups, and correlation coefficients (Spearman rho) were calculated between average minutes per day spent in moderate, vigorous, and sedentary behaviors, and average intensity and unpleasantness ratings. RESULTS: Participants meeting physical activity recommendations had significantly lower unpleasantness ratings than their insufficiently active peers. Correlational analyses demonstrated a significant relationship between minutes spent in vigorous physical activity and both pain intensity and pain unpleasantness ratings. Relationships were not significant for moderate activity or sedentary behavior. CONCLUSIONS: These results provide preliminary evidence that meeting current physical activity recommendations may be beneficial for pain in women. Moreover, participation in vigorous activity seems to account for the decreased pain sensitivity. In our sample, sedentary behavior did not seem to have a deleterious effect on pain. Results from this study have many potential applications including aiding our understanding of why exercise functions as a treatment for those with chronic pain conditions and providing a rationale for including physical activity assessment in pain research. PMID- 22217572 TI - Parthenogenesis in non-rodent species: developmental competence and differentiation plasticity. AB - An oocyte can activate its developmental process without the intervention of the male counterpart. This form of reproduction, known as parthenogenesis, occurs spontaneously in a variety of lower organisms, but not in mammals. However, it must be noted that mammalian oocytes can be activated in vitro, mimicking the intracellular calcium wave induced by the spermatozoon at fertilization, which triggers cleavage divisions and embryonic development. The resultant parthenotes are not capable of developing to term and arrest their growth at different stages, depending on the species. It is believed that this arrest is due to genomic imprinting, which causes the repression of genes normally expressed by the paternal allele. Human parthenogenetic embryos have recently been proposed as an alternative, less controversial source of embryonic stem cell lines, based on their inherent inability to form a new individual. However many aspects related to the biology of parthenogenetic embryos and parthenogenetically derived cell lines still need to be elucidated. Limited information is available in particular on the consequences of the lack of centrioles and on the parthenote's ability to assemble a new embryonic centrosome in the absence of the sperm centriole. Indeed, in lower species, successful parthenogenesis largely depends upon the oocyte's ability to regenerate complete and functional centrosomes in the absence of the material supplied by a male gamete, while the control of this event appears to be less stringent in mammalian cells. In an attempt to better elucidate some of these aspects, parthenogenetic cell lines, recently derived in our laboratory, have been characterized for their pluripotency. In vitro and in vivo differentiation plasticity have been assessed, demonstrating the ability of these cells to differentiate into cell types derived from the three germ layers. These results confirmed common features between uni- and bi-parental embryonic stem cells. However data obtained with parthenogenetic cells indicate the presence of an intrinsic deregulation of the mechanisms controlling proliferation vs. differentiation and suggest their uni-parental origin as a possible cause. PMID- 22217573 TI - Exploring the application of high-throughput genomics technologies in the field of maternal-embryo communication. AB - Deciphering the complex molecular dialogue between the maternal tract and embryo is crucial to increasing our understanding of pregnancy failure, infertility problems and in the modulation of embryo development, which has consequences through adulthood. High-throughput genomic technologies have been applied to look for a holistic view of the molecular interactions occurring during this dialogue. Among these technologies, microarrays have been widely used, being one of the most popular tools in maternal-embryo communication. Today, next generation sequencing technologies are dwarfing the capabilities of microarrays. The application of these new technologies has broadened to almost all areas of genomics research, because of their massive sequencing capacity. We review the current status of high-throughput genomic technologies and their application to maternal-embryo communication research. We also survey next generation technologies and their huge potential in many research areas. Given the diversity of unanswered questions in the field of maternal-embryo communication and the wide range of possibilities that these technologies offer, here we discuss future perspectives on the use of these technologies to enhance maternal-embryo research. PMID- 22217574 TI - Using computational modeling to investigate sperm navigation and behavior in the female reproductive tract. AB - The processes by which individual sperm cells navigate the length and complexity of the female reproductive tract and then reach and fertilize the oocyte is fascinating. Numerous complex processes potentially influence the transport of spermatozoa within the tract, resulting in a regulated supply of spermatozoa to the oocytes at the site of fertilization. Despite significant differences between species, breeds, and individuals, these processes converge to ensure that a sufficient number of high quality spermatozoa reach the oocytes, resulting in successful fertilization without a significant risk of polyspermy. Different factors, such as the physical complexity of the oviductal environment, changing swimming patterns, capacitation, chemotactic and thermotactic attraction, attachment and detachment from the oviductal epithelium, interactions with local oviductal secretions, individual variations in spermatozoa and subpopulations, peristaltic contractions, and the movement of fluid have all been theorized to influence the transport of spermatozoa to the site of fertilization. However, the predominance of each factor is not fully understood. Computational modeling provides a useful method for combining knowledge about the individual processes in complex systems to help understand the relative significance of each factor. The process of constructing and validating an agent-based computational model of sperm movement and transport within the oviductal environment is described in this report. Spermatozoa are modeled as individual cells with a set of behavioral rules defining how they interact with their local environment and regulate their internal state. The inclusion or potential exclusion of each factor is discussed, along with problems identifying parameters and defining behavioral rules from available literature. Finally, the benefits and limitations of the model are described. PMID- 22217576 TI - Fifth Joint Meeting of J-CaP and CaPSURE: advancing the global understanding of prostate cancer and its management. AB - This report summarizes the presentations and discussions that took place at the Fifth Joint Meeting of J-CaP and CaPSURE held in Tokyo, Japan, in July 2011. The J-CaP and CaPSURE Joint Initiative was established in 2007 with the objective of analyzing, reviewing, comparing and contrasting data on prostate cancer patients from Japan and the USA within the two important large-scale, longitudinal, observational databases-J-CaP and CaPSURE. Since its inception, the initiative has reviewed a wide range of topics and generated valuable data on the patterns of prostate cancer treatment and patient outcomes in the two geographical regions. The objectives of this 5th Joint Meeting were to provide an update on the current status of the J-CaP and CaPSURE databases, and also to discuss perspectives from a range of other Asian countries-Japan, China, Indonesia and Korea-on the use of androgen deprivation therapy for prostate cancer. The collaborators recognize that large databases, such as J-CaP and CaPSURE, provide valuable 'real-world' information, to complement data from clinical trials, which can help to advance the clinical management of prostate cancer patients worldwide. It is anticipated that in the near future, the Joint Initiative will expand globally to include patient registries from other countries so that best practice can be shared and regional differences in patients, treatments and outcomes can be explored. PMID- 22217575 TI - Down-regulation of Nedd4L is associated with the aggressive progression and worse prognosis of malignant glioma. AB - OBJECTIVE: Human neural precursor cell-expressed developmentally down-regulated 4 like (Nedd4L), a ubiquitin protein ligase, is expressed by various cancer cells and might have an oncogenic property. Its expression pattern in glioma tissues is unknown. Therefore, the aim of this study was to investigate whether Nedd4L is present in glioma and to evaluate the correlation of Nedd4L expression with the progression and prognosis of the disease. METHODS: Immunohistochemistry and western blot were used to investigate the expression of Nedd4L protein in 128 patients with gliomas. RESULTS: Immunohistochemistry showed a strong-to-weak range of Nedd4L staining with increasing pathologic grade of glioma (P < 0.001), which was in line with the results from western blot analysis. In addition, a non parametric analysis revealed that the attenuated Nedd4L expression was significantly correlated with a large tumor diameter (P = 0.02), low Karnofsky performance score (P = 0.008), frequent intra-tumor necrosis (P = 0.01) and worse overall survival (P = 0.009). Furthermore, multivariate analysis showed that Nedd4L expression (P = 0.02) and intra-tumor necrosis (P = 0.03) were two important independent prognostic factors identified by the Cox proportional hazards model. CONCLUSIONS: Our results provide convincing evidence for the first time that the expression of Nedd4L is down-regulated in human gliomas. The glioma patients with lower Nedd4L expression have a worse prognosis. PMID- 22217577 TI - Breast ultrasonographic and histopathological characteristics without any mammographic abnormalities. AB - OBJECTIVE: We evaluated ultrasonographic findings and the corresponding histopathological characteristics of breast cancer patients with Breast Imaging Reporting and Data System (BI-RADS) category 1 mammogram. METHODS: We retrospectively reviewed the ultrasonographic findings and the corresponding histopathological features of 45 breast cancer patients with BI-RADS category 1 mammogram and 537 controls with mammographic abnormalities. We evaluated the ultrasonographic findings including mass shape, periphery, internal and posterior echo pattern, interruption of mammary borders and the distribution of low-echoic lesions, and the corresponding histopathological characteristics including histological classification, hormone receptor and human epidermal growth factor receptor 2 status of invasive ductal carcinoma and ductal carcinoma in situ, histological grade, mitotic counts and lymphovascular invasion in individual cases of BI-RADS category 1 mammograms and compared with those of the control group. RESULTS: The ultrasonographic characteristics of the BI-RADS category 1 group were characterized by a higher ratio of round shape (P< 0.001), non spiculated periphery (P= 0.021), non-interruption of mammary borders (P< 0.001) and non-attenuation (P= 0.011) compared with the control group. A total of 52.6% of low-echoic lesions were associated with spotted distribution in the BI-RADS 1 group, whereas 25.8% of low-echoic lesions were associated with spotted distribution in the control group (P= 0.012). As for histopathological characteristics, there was a statistically higher ratio of triple-negative subtype (P= 0.021), and this particular tendency was detected in histological grade 3 in the BI-RADS category 1 group (P= 0.094). CONCLUSION: We evaluated ultrasonographic findings and the corresponding histopathological characteristics for BI-RADS category 1 mammograms and noted significant differences among these findings in this study. Evaluation of these ultrasonographic and histopathological characteristics may provide a more accurate ultrasonographic screening system for breast cancer in Japanese women. PMID- 22217578 TI - [Necrotizing diabetic foot infection: a limb-threatening emergency]. PMID- 22217579 TI - Magnesium intake and prevalence of metabolic syndrome in adults: Tehran Lipid and Glucose Study. AB - OBJECTIVE: We examined the association of metabolic syndrome (MetS) and its components with dietary intakes of Mg in Tehran adults. DESIGN: In a cross sectional study, dietary intakes were assessed using a valid and reliable FFQ. MetS was defined according to the modified guidelines of the National Cholesterol Education Program Adult Treatment Panel III. Waist circumference (WC) was coded according to the newly introduced cut-off points for Iranian adults (>=95 cm for both genders). SETTING: Participants of the Tehran Lipid and Glucose Study (2006 2008). SUBJECTS: Adults (n 2504; 1120 men and 1384 women) aged 18-74 years. RESULTS: The mean age of participants was 40.8 (SD 14.6) years and 38.2 (SD 13.5) years for men and women, respectively. The reported mean intake of Mg was 349 (SD 109) mg/d. After adjustment for confounding factors, dietary Mg intake was inversely associated with fasting blood glucose (beta = -0.08, P = 0.006), TAG (beta = -0.058, P = 0.009) and WC (beta = -0.013, P = 0.006); however, there were no associations between dietary Mg and diastolic blood pressure, systolic blood pressure or HDL cholesterol. An association was observed between MetS Z-score and Mg intake (crude beta = -0.017, P = 0.001), independent of age, gender, smoking, physical activity and BMI; this association was attenuated following further adjustment for dietary factors and menopausal status (beta = -0.034, P = 0.061). CONCLUSIONS: Our findings suggest a significant inverse association between dietary Mg, MetS and its components. PMID- 22217581 TI - Whose problem is it anyway? PMID- 22217580 TI - Glutamate receptors: the cause or cure in perinatal white matter injury? AB - Glutamate toxicity from hypoxia-ischaemia during the perinatal period causes white matter injury that can result in long-term motor and intellectual disability. Blocking ionotropic glutamate receptors (GluRs) has been shown to inhibit oligodendrocyte injury in vitro, but GluR antagonists have not yet proven helpful in clinical studies. The opposite approach of activating GluRs on developing oligodendrocytes shows promise in experimental studies on rodents as reported by Jartzie et al., in this issue. Group I metabotropic glutamate receptors (mGluRs) are expressed transiently on developing oligodendrocytes in humans during the perinatal period, and the blood-brain-barrier permeable agonist of group I mGluRs, 1-aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD), reduces white matter damage significantly in a rat model of perinatal hypoxia ischaemia. The results suggest drugs activating this class of GluRs could provide a new therapeutic approach for preventing cerebral palsy and other neurological consequences of diffuse white matter injury in premature infants. PMID- 22217582 TI - Temporal evolution of remission following multiple sclerosis relapse and predictors of outcome. AB - BACKGROUND: Relapse is a characteristic clinical feature of multiple sclerosis (MS) and is commonly employed as a measure of efficacy following therapeutic intervention. However, less is known about the temporal evolution of subsequent disability or factors predicting recovery. OBJECTIVES: The objective of this study was to assess the pattern of recovery following relapse and identify factors which predict recovery and residual disability following relapse. METHODS: A total of 226 relapses were studied prospectively in a cohort of 144 patients with standardised clinical assessments of physical disability including Expanded Disability Status Scale (EDSS), 10-m timed walk, 9-hole peg test and Multiple Sclerosis Impact Scale (MSIS-29) at 0, 2, 6 and 12 months. A total of 82 patients completed 12 months of follow up without further relapse. RESULTS: Thirty per cent of relapses were severe (change in EDSS >2.0) of which 11% failed to recover. All measures showed significant improvement at 2 months but additional improvement was also observed in 9-hole peg test and MSIS-29 up to 12 months following initial assessment. Mean time to second relapse was 382 days. The only predictor of relapse severity in the model tested was younger age; however, increasing age and initial relapse severity were also predictors of poor outcome. CONCLUSIONS: This study shows that the majority of improvement in physical disability following relapse occurs by 2 months but that more subtle recovery can take place over 12 months in a small sub-group of patients. These data will aid in patient counselling and will also inform the timing of therapeutic intervention and physical support. PMID- 22217583 TI - Changes at the nodal and perinodal axonal domains: a basis for multiple sclerosis pathology? AB - How axonal damage, a major prognostic factor of multiple sclerosis disability progression, is induced, is likely to be multifactorial. Whereas axonal injury has been identified as a consequence of myelin loss, the possibility of an additional direct damage is also suggested. In this context, recent data have highlighted the nodal and perinodal axonal domains of the myelinated neurons as potential targets of the disease process, opening new perspectives in multiple sclerosis pathophysiology. PMID- 22217584 TI - Analyzing spatial and temporal (222)Rn trends in Maine. AB - Prolonged radon exposure has been linked to lung cancer. Cancer registry data indicates excess risk for age-adjusted lung cancer in Maine. Maine's mean residential radon activity exceeds the EPA maximum contaminant level (MCL). This paper describes the application of spatial autocorrelation methods to retrospective data as a means of analyzing radon activity in Maine. Retrospective air and well water radon activity data, sampled throughout Maine between 1993 and 2008, are standardized and geocoded for analysis. Three spatial autocorrelation algorithms-local Getis-Ord, local Moran, and spatial scan statistic-are used to identify spatial, temporal, and spatiotemporal radon activity clusters and/or outliers. Spatial clusters of high air- and well water-Rn activity are associated with Maine's Lucerne and Sebago granitic formations. Spatial clusters of low air- and well water-Rn activity are associated with Biddeford Granite and the metamorphic bedrock formation Silurian Ordovician Vassalboro. Space-time analysis indicates that most spatial clusters persist over the period of sampling. No significant temporal clusters are identified. Persistent spatial variations in radon may help to better understand and predict radon-related health risks associated with Maine residences. PMID- 22217585 TI - Biokinetics of embedded surrogate radiological dispersal device material. AB - The terrorist use of a radiological dispersal device (RDD) has been described as "not if, but when" (). Exposures from such an event could occur by a number of routes including inhalation, wound contamination, or embedded fragments. Several of the radionuclides thought to be potential RDD components are metals or ceramic material. The use of such material would increase the potential for wounds from embedded fragments of radioactive material. To date, most research in this area has focused on inhalation exposures, while the consequence of embedded fragment exposure has not been investigated. This study modified a previously used rodent model in order to determine the biokinetics of intramuscularly implanted nonradioactive surrogate RDD material. Cobalt, iridium, or strontium titanate was embedded into the gastrocnemius muscle of Sprague Dawley rats. The rats were euthanized at 1, 3, or 6 mo post-implantation. Tissue metal analysis showed that iridium did not solubilize from the implanted pellet, while cobalt and strontium did so rapidly. Cobalt was found in all tissues analyzed, but it was localized mainly to kidney and liver as well as being excreted in the urine. Strontium was found in lung, liver, and spleen, as well as being deposited in bone. However, the greatest strontium concentrations were found in the popliteal lymph nodes, the lymph nodes responsible for draining the area of the gastrocnemius. These results indicate that, depending upon the material, a variety of treatment strategies will be needed when dealing with embedded fragment wounds from a radiological dispersal device event. PMID- 22217586 TI - Dental staff doses with handheld dental intraoral x-ray units. AB - A handheld portable dental intraoral x-ray system is available in the United States and elsewhere. The system is designed to minimize the user's radiation dose. It includes specially designed shielding of the x-ray tube housing and an integral radiation shield to minimize backscatter. Personnel radiation dose records were obtained from 18 dental facilities using both the handheld system and a wall mounted dental x-ray system, providing 661 individual dose measurements. Dental staff doses were also compared for the handheld and conventional systems using both film and digital imaging for the same facilities and staff members. The results indicate that the doses for the handheld systems are significantly less than for wall-mounted systems. The average monthly dose for the handheld systems was 0.28 MUSv vs. 7.86 MUSv (deep dose equivalent) for the wall-mounted systems, a difference that is statistically significant at the p = 0.01 level. Consequently, there should be no concern about the use of this handheld dental intraoral x-ray system. Additional shielding efforts, (e.g., wearing a lead apron) will not provide significant benefit nor reduce staff radiation dose. PMID- 22217587 TI - Validation of QuickScan dicentric chromosome analysis for high throughput radiation biological dosimetry. AB - Currently, the dicentric chromosome assay (DCA) is used to estimate radiation doses to individuals following accidental radiological and nuclear overexposures when traditional dosimetry methods are not available. While being an exceptionally sensitive method for estimating doses by radiation, conventional DCA is time-intensive and requires highly trained expertise for analysis. For this reason, in a mass casualty situation, triage-quality conventional DCA struggles to provide dose estimations in a timely manner for triage purposes. In Canada, a new scoring technique, termed DCA QuickScan, has been devised to increase the throughput of this assay. DCA QuickScan uses traditional DCA sample preparation methods while adapting a rapid scoring approach. In this study, both conventional and QuickScan methods of scoring the DCA assay were compared for accuracy and sensitivity. Dose response curves were completed on four different donors based on the analysis of 1,000 metaphases or 200 events at eight to nine dose points by eight different scorers across two laboratories. Statistical analysis was performed on the data to compare the two methods within and across the laboratories and to test their respective sensitivities for dose estimation. This study demonstrated that QuickScan is statistically similar to conventional DCA analysis and is capable of producing dose estimates as low as 0.1 Gy but up to six times faster. Therefore, DCA QuickScan analysis can be used as a sensitive and accurate method for scoring samples for radiological biodosimetry in mass casualty situations or where faster dose assessment is required. PMID- 22217588 TI - Isotope ratios of (235)U/(238)U and (137)Cs/(235)U in black rain streaks on plaster wall caused by fallout of the Hiroshima atomic bomb. AB - Radiological investigations of fallout from the atomic bomb detonated over Hiroshima city on 6 August 1945 are important to estimate doses for inhabitants. The authors have analyzed the concentrations of (137)Cs, (235)U, and (238)U in streaks of black rain caused by the atomic bomb using gamma-ray spectroscopy and the ICP-QMS method. The black rain streaks were deposited on a plaster wall of a house located 3.7 km west of the hypocenter that has been kept in the same condition as after the rainfall. Cesium-137 ((137)Cs) was detected from black streak samples. Concentration of (137)Cs in the black rain streaks is twice as high as fallout deposition on the ground in this area. A (235)U/(238)U atom ratio of 0.00887 was found, which is higher than the natural ratio, reflecting the fact that the atomic bomb "Little Boy" used enriched uranium as fuel. The ratio (137)Cs/(235)U was determined to be 0.0091, which is about eight times higher than the estimated ratio of 0.00113 based on the fission yield. PMID- 22217589 TI - Assessment of RF exposures from emerging wireless communication technologies in different environments. AB - In situ electromagnetic (EM) radio frequency (RF) exposure to base stations of emerging wireless technologies is assessed at 311 locations, 68 indoor and 243 outdoor, spread over 35 areas in three European countries (Belgium, The Netherlands, and Sweden) by performing narrowband spectrum analyzer measurements. The locations are selected to characterize six different environmental categories (rural, residential, urban, suburban, office, and industrial). The maximal total field value was measured in a residential environment and equal to 3.9 V m(-1), mainly due to GSM900 signals. Exposure ratios for maximal electric field values, with respect to ICNIRP reference levels, range from 0.5% (WiMAX) to 9.3% (GSM900) for the 311 measurement locations. Exposure ratios for total field values vary from 3.1% for rural environments to 9.4% for residential environments. Exposures are lognormally distributed and are the lowest in rural environments and the highest in urban environments. Highest median exposures were obtained in urban environments (0.74 V m(-1)), followed by office (0.51 V m(-1)), industrial (0.49 V m(-1)), suburban (0.46 V m(-1)), residential (0.40 V m(-1)), and rural (0.09 V m(-1)) environments. The average contribution to the total electric field is more than 60% for GSM. Except for the rural environment, average contributions of UMTS HSPA are more than 3%. Contributions of the emerging technologies LTE and WiMAX are on average less than 1%. The dominating outdoor source is GSM900 (95 percentile of 1.9 V m(-1)), indoor DECT dominates (95 percentile of 1.5 V m(-1)). PMID- 22217590 TI - Cancer and non-cancer mortality among Inhabitants in the high background radiation area of Yangjiang, China (1979-1998). AB - The present study aimed to evaluate the effects of high background radiation (HBR) on mortality. A cohort of 31,604 men and women aged 30-74 y living in the study area in Guangdong Province, China, was followed during the period 1979 1998. The information on deaths and migrations of cohort members was collected by visiting study areas every 3-4 y. Cumulative external radiation dose, lagged by 2 y for leukemia and 10 y for cancer excluding leukemia, was estimated for each individual based on hamlet-specific indoor and outdoor doses, and gender- and age specific house occupancy factors. The follow-up study accumulated 736,942 person years at risk and ascertained 6,005 deaths, including 956 cancer deaths and 4,525 non-cancer disease deaths. Mean cumulative radiation doses from natural radiation in the HBR and control area residents were 84.8 mGy and 21.6 mGy, respectively. Mortality due to leukemia (15 deaths) or cancer excluding leukemia (941 deaths) was not related to cumulative radiation dose. The excess relative risk (ERR) Gy of cancer excluding leukemia was estimated to be -1.01 (95% CI: -2.53, 0.95). In site-specific analysis, liver-cancer mortality was inversely related to the cumulative dose (p=0.002). Note, however, that liver cancer is well known for its difficulty in accurate diagnosis. The ERR Gy of cancer excluding leukemia and liver cancer was 0.19 (95% CI: -1.87, 3.04). Non-cancer disease mortality was not related to cumulative radiation dose either. The cumulative HBR dose was not related to the mortality due to cancer or all non-cancer diseases among residents in Yangjiang HBR areas. PMID- 22217591 TI - Direct and indirect tasks on assessment of dose and time distributions and thresholds of acute radiation exposure. AB - Mathematical methods were developed to construct dose and time distributions and their associated risks and threshold values for lethal and non-lethal effects of acute radiation exposure to include mortality and incidence, prodromal vomiting, and agranulocytosis. A new distribution (T-model) was obtained to describe time parameters of acute radiation syndrome such as the latency period, time to onset of vomiting, and time to initiation of agranulocytosis. Based on the dose and time distributions, the parameter translation method was defined using an orthogonal regression, which allows one to solve for these distributions in the case of acute radiation exposure. The assessment of threshold doses was performed for some effects of acute radiation syndrome: for the latency period, ~6-8 Gy absorbed dose and ~0.7-0.9 h time to onset of vomiting; and for incidence (agranulocytosis), ~2-3 Gy absorbed dose and ~2-3 h time to onset of vomiting. The obtained new formula for assessment of radiation risk is applicable to the time parameters of acute radiation syndrome. PMID- 22217592 TI - Locating radiation hazards and sources within contaminated areas by implementing a reverse ray tracing technique in the RadBallTM technology. AB - RadBallTM is a novel technology that can locate unknown radioactive hazards within contaminated areas, hot cells, and gloveboxes. The device consists of a colander-like outer tungsten collimator that houses a radiation-sensitive polymer semisphere. The collimator has a number of small holes; as a result, specific areas of the polymer are exposed to radiation, becoming increasingly more opaque in proportion to the absorbed dose. The polymer semisphere is imaged in an optical computed tomography scanner that produces a high resolution three dimensional map of optical attenuation coefficients. A subsequent analysis of the optical attenuation data, using a reverse ray tracing technique, provides information on the spatial distribution of gamma-ray sources in a given area, forming a three-dimensional characterization of the area of interest. The RadBallTM technology and its reverse ray tracing technique were investigated using known radiation sources at the Savannah River Site's Health Physics Instrument Calibration Laboratory and unknown sources at the Savannah River National Laboratory's Shielded Cells facility. PMID- 22217593 TI - Averted doses to Norwegian Sami reindeer herders after the Chernobyl accident. AB - The Chernobyl fallout is an enduring challenge to reindeer husbandry in Norway, and South Sami reindeer herders in central and southern Norway are as contaminated by (137)Cs as inhabitants close to Chernobyl. Therefore, Norwegian authorities continuously recommend to these reindeer herders the use of countermeasures to reduce their intake of (137)Cs. In this study, the authors have applied data on contamination levels in reindeer, results of dietary surveys, and whole body monitoring data in low and high contaminated areas to estimate the effectiveness of countermeasures and resulting averted doses to the reindeer herders. In the most contaminated area, the various countermeasures applied reduced radiocesium ingestion doses during 1986-2009 by about 73%, to an integrated dose of about 17 mSv. However, to comply with the recommended (137)Cs ingestion dose limit of 1 mSv y(-1), the study indicates that reindeer herders in the most contaminated areas will need to carry on with their countermeasures for another 10-15 y. Furthermore, the study indicates that whole body monitoring is an important tool to assess individual doses and countermeasure effectiveness in long-term management of a contamination situation and that such monitoring may be required to reach long-term reference levels. PMID- 22217594 TI - Radiation dose to the fetus from [(18)F]-FDG administration during the second trimester of pregnancy. AB - The authors estimated the fetal radiation dose from [(18)F]-FDG in a rare case of a woman who underwent a PET/CT scan during the second trimester of pregnancy. The patient, a 27-y-old female with a paraganglioma, received 181.3 MBq [(18)F]-FDG. From the concentrations of radioactivity measured on the images, the time integrated activity coefficients of the fetus and the placenta were derived. The time-integrated activity coefficients of the mother's organs were taken from the standard values of ICRP publication 106. The final fetal dose was calculated using the 6-mo pregnant model of the OLINDA/EXM software. The fetus showed an overall low and homogeneous [(18)F]-FDG uptake, with an average concentration of 2.41 kBq cm(-3). The uptake in the placenta was generally higher (average concentration = 3.69 kBq cm(-3)). The estimated time-integrated activity coefficients were 0.0130 and 0.0058 Bq h Bq(-1) for the fetus and the placenta, respectively. The final average dose to the fetus was 1.97 * 10(-2) mGy MBq(-1) (3.6 mGy in this patient who received 181.3 MBq). Therefore, the dose to the fetus from [(18)F]-FDG administration during the second trimester of pregnancy is low. When medically indicated, pregnancy should not be a categorical basis for withholding [(18)F]-FDG PET scans. PMID- 22217595 TI - The European Radiobiological Archives: online access to data from radiobiological experiments is available now. AB - The European Radiobiological Archive can be accessed at no cost at https://era.bfs.de. The necessary ID and password can be obtained from the curators at era@bfs.de. PMID- 22217596 TI - Voxel2MCNP: software for handling voxel models for Monte Carlo radiation transport calculations. AB - Voxel2MCNP is a program that sets up radiation protection scenarios with voxel models and generates corresponding input files for the Monte Carlo code MCNPX. Its technology is based on object-oriented programming, and the development is platform-independent. It has a user-friendly graphical interface including a two- and three-dimensional viewer. A row of equipment models is implemented in the program. Various voxel model file formats are supported. Applications include calculation of counting efficiency of in vivo measurement scenarios and calculation of dose coefficients for internal and external radiation scenarios. Moreover, anthropometric parameters of voxel models, for instance chest wall thickness, can be determined. Voxel2MCNP offers several methods for voxel model manipulations including image registration techniques. The authors demonstrate the validity of the program results and provide references for previous successful implementations. The authors illustrate the reliability of calculated dose conversion factors and specific absorbed fractions. Voxel2MCNP is used on a regular basis to generate virtual radiation protection scenarios at Karlsruhe Institute of Technology while further improvements and developments are ongoing. PMID- 22217600 TI - MCScanX: a toolkit for detection and evolutionary analysis of gene synteny and collinearity. AB - MCScan is an algorithm able to scan multiple genomes or subgenomes in order to identify putative homologous chromosomal regions, and align these regions using genes as anchors. The MCScanX toolkit implements an adjusted MCScan algorithm for detection of synteny and collinearity that extends the original software by incorporating 14 utility programs for visualization of results and additional downstream analyses. Applications of MCScanX to several sequenced plant genomes and gene families are shown as examples. MCScanX can be used to effectively analyze chromosome structural changes, and reveal the history of gene family expansions that might contribute to the adaptation of lineages and taxa. An integrated view of various modes of gene duplication can supplement the traditional gene tree analysis in specific families. The source code and documentation of MCScanX are freely available at http://chibba.pgml.uga.edu/mcscan2/. PMID- 22217601 TI - Lichen planus-type chronic graft-versus-host disease complicated by mucous membrane pemphigoid with positive anti-BP180/230 and scleroderma-related autoantibodies followed by reduced regulatory T cell frequency. PMID- 22217602 TI - Relations between anthropometric parameters and sexual activity of Hungarian men. AB - In the last decades, there were visible achievements in the evaluation of sexuality-related problems and issues regarding sexual life. However, there are limited reliable and comparable data on the average values of sexual activity and its relation to anthropometric parameters in different populations and age cohorts. This study tries to examine the association between anthropometric parameters and male sexual activity. A clinical population of 1146 male patients between 25 and 45 years of age attending an outpatient clinic of andrology in Budapest (Hungary) was examined and questioned in a medical setting. Age, body height, weight, body mass index (BMI) and self-reported sexual activity were the main outcome measures. The patients were allotted into age groups (25-29, 30-39 and 40-45 years), the youngest group showing the highest coital activity. Although obesity and overweight were present in 61% of the study population, no connections between BMI and sexual activity were apparent. Comparing less active persons with those reporting at least two intercourses per week, significant difference was found between body height groups. Men below 170 cm reported higher activity than men over 180 cm. Despite the fact that the prevalence of obesity among younger generations is increasing, it has had no visible influence on the sexual activity of this age cohort as yet. Our data suggest that sexual activity was not clearly related to other anthropometric parameters, and depends mainly on the characteristics of the population examined. There is a great need for large scale studies worldwide on larger representative samples, using similar methods, to acquire reliable data from other nations and different age groups. PMID- 22217603 TI - Total heart volume as a function of clinical and anthropometric parameters in a population of external beam radiation therapy patients. AB - The aim of this paper was to determine anthropometric parameters leading to the least uncertain estimate of heart size when connecting a computational phantom to an external beam radiation therapy (EBRT) patient. From computed tomography images, we segmented the heart and calculated its total volume (THV) in a population of 270 EBRT patients of both sexes, aged 0.7-83 years. Our data were fitted using logistic growth functions. The patient age, height, weight, body mass index and body surface area (BSA)were used as explanatory variables. For both genders, good fits were obtained with both weight (R2 = 0.89 formales and 0.83 for females) and BSA (R2=0.90 formales and 0.84 for females). These results demonstrate that, among anthropometric parameters, weight plays an important role in predicting THV. These findings should be taken into account when assigning a computational phantom to a patient. PMID- 22217604 TI - The homogeneous fluorescence anisotropic sensing of salivary lysozyme using the 6 carboxyfluorescein-labeled DNA aptamer. AB - A simple and sensitive fluorescence anisotropy method was developed for lysozyme, employing the coupling of fluorophore, 6-carboxyfluorescein (FAM), with lysozyme upon recognition between the target molecule and its DNA aptamer. It was found in this study that the rotational dynamic of the detecting system is crucial to obtain a high anisotropy signal that cannot always be achieved by simply increasing the molecular volume, because molecular volume increase may not be able to efficiently retard the rotational movement of the fluorophore. FAM was selected as the label of the ssDNA aptamer to effectively facilitate the change of the fluorophore from a primarily independent segmental movement to slow global rotation. The time-resolved measurements, including lifetime and dynamic fluorescence anisotropy, were conducted to study the recognition interaction and to better understand the methodology. The proposed method had a wide linear dynamic range of 12.5-300 nM and a high sensitivity with the limit of detection of 4.9 nM (3S/N). This proposed method was successfully applied to assay of human salivary lysozyme. The results based on the standard addition recovery and comparison with enzyme-linked immunosorbent assay (ELISA) demonstrated the feasibility of this method for biological samples. Using coupling between the fluorophore and the analyte can be one of the approaches working toward expanding the application of fluorescence anisotropy based on aptamer-target and antibody antigen recognitions. PMID- 22217605 TI - Monitoring influenza hemagglutinin and glycan interactions using surface plasmon resonance. AB - Hemagglutinin (HA) is a trimeric glycoprotein expressed on the influenza virus membrane. HA of influenza viruses binds to the host's cell surface complex glycans via a terminal sialic acid (Sia), as the first key step in the process of infection, transmission and virulence of influenza viruses. It is important to monitor and evaluate the receptor (glycan) binding preferences of the HAs derived from influenza A viruses, especially those originating from birds and swine, to understand their potential ability for interspecies transmission. From this viewpoint, in the present study, we have developed a protocol for analyzing the glycan-HA interactions efficiently and kinetically, based on surface plasmon resonance (SPR). Our results showed that glycan-HA binding analyses can be performed reliably and efficiently on Biacore-chips in the SPR system, using chemically synthesized biotinylated multivalent-glycans. Using the CAP-chip, we were able to regenerate the surface for multiple analyses, allowing us to derive, for the first time, the precise kinetic parameters for different HA-glycan complexes of newly emerging influenza viruses. These studies suggested that this SPR-based method is suitable for influenza surveillance to define the pandemic scenario as well as to screen of synthetic glycans and other compounds that may interfere with glycan-HA interactions. PMID- 22217606 TI - Strength and fracture origins of a feldspathic porcelain. AB - OBJECTIVES: To identify the strength limiting flaws in in vitro test specimens of a fine-grained feldspathic dental porcelain. METHODS: Four-point flexural strengths were measured for 26 test specimens. The fracture origin site of every test specimen was studied using stereoptical and scanning electron microscopy. A fractographically labeled Weibull strength distribution graph was prepared. RESULTS: The complex microstructure of the feldspathic dental porcelain included a variety of feldspars, tridymite, and a feldspathoid as well as pores/bubbles and residual glass. The relatively high flexural strength is due in part to the fine grain size. Fractography revealed five flaw types that controlled strength: baseline microstructural flaws, pores/bubbles, side wall grinding damage, corner machining damage, and inclusions. The baseline microstructural flaws probably were clusters of particular crystalline phases. SIGNIFICANCE: Each flaw type probably has a different severity and size distribution, and hence has a different strength distribution. The Weibull strength distribution graph blended the strength distributions of the five flaw types and the apparent good fit of the combined data to a unimodal strength distribution was misleading. Polishing failed to eliminate deeper transverse grinding cracks and corner damage from earlier preparation steps in many of the test pieces. Bend bars should be prepared carefully with longitudinal surface grinding whenever possible and edge chamfers should be carefully applied. If the grinding and preparation flaws were eliminated, the Weibull modulus for this feldspathic porcelain would be greater than 30. Pores/bubbles sometimes controlled strength, but only if they touched each other or an exposed surface. Isolated interior bubble/pores were harmless. PMID- 22217607 TI - New insight into the "depth of cure" of dimethacrylate-based dental composites. AB - OBJECTIVES: To demonstrate that determination of the depth of cure of resin-based composites needs to take into account the depth at which the transition between glassy and rubbery states of the resin matrix occurs. METHODS: A commercially available nano-hybrid composite (Grandio) in a thick layer was light cured from one side for 10 or 40 s. Samples were analyzed by Vickers indentation, Raman spectroscopy, atomic force microscopy, electron paramagnetic imaging and differential scanning calorimetry to measure the evolution of the following properties with depth: microhardness, degree of conversion, elastic modulus of the resin matrix, trapped free radical concentration and glass transition temperature. These measurements were compared to the composite thickness remaining after scraping off the uncured, soft composite. RESULTS: There was a progressive decrease in the degree of conversion and microhardness with depth as both properties still exhibited 80% of their upper surface values at 4 and 3.8 mm, respectively, for 10 s samples, and 5.6 and 4.8 mm, respectively, for 40 s samples. In contrast, there was a rapid decrease in elastic modulus at around 2.4 mm for the 10 s samples and 3.0 mm for the 40 s samples. A similar decrease was observed for concentrations of propagating radicals at 2 mm, but not for concentrations of allylic radicals, which decreased progressively. Whereas the upper composite layers presented a glass transition temperature - for 10 s, 55 degrees C (+/-4) at 1 mm, 56.3 degrees C (+/-2.3) at 2 mm; for 40 s, 62.3 degrees C (+/-0.6) at 1 mm, 62 degrees C (+/-1) at 2 mm, 62 degrees C (+/-1.7) at 3 mm - the deeper layers did not display any glass transition. The thickness remaining after scraping off the soft composite was 7.01 (+/-0.07 mm) for 10 s samples and 9.48 (+/-0.22 mm) for 40 s samples. SIGNIFICANCE: Appropriate methods show that the organic matrix of resin-based composite shifts from a glassy to a gel state at a certain depth. Hence, we propose a new definition for the "depth of cure" as the depth at which the resin matrix switches from a glassy to a rubbery state. Properties currently used to evaluate depth of cure (microhardness, degree of conversion or scraping methods) fail to detect this transition, which results in overestimation of the depth of cure. PMID- 22217608 TI - Evaluation of the effect of Uncaria tomentosa extracts on the size and shape of human erythrocytes (in vitro). AB - In this study, we continued our investigations concerning the interaction of Uncaria tomentosa extracts with the human erythrocytes. The analysis of the size and shape of the erythrocytes by means of flow cytometry and phase contrast microscopy was performed. We executed our experiments using ethanolic and aqueous extracts from the leaves and bark of U. tomentosa. Disturbances were observed in the size and shape of the erythrocytes incubated with ethanolic and aqueous extracts at the concentrations of 100 MUg/mL and 250 MUg/mL, respectively. The observed changes were probably related to the entry of polyphenolic compounds contained in U. tomentosa extracts into erythrocyte membrane. Externalization of phosphatidylserine on the erythrocytic surfaces was also noticed during incubation with extracts at concentration of 250 MUg/mL. We concluded that all of the extracts examined induced changes in the erythrocyte membrane properties, whereas ethanolic extracts from bark induced the most significant changes. The possible binding of polyphenols to the erythrocyte surface may have accounted for the protective properties of extracts against haemolysis of RBCs, which was observed in our previous study (Bors et al., 2011), but considerable incorporation of polyphenols into cell membranes can result in disturbance of phosphatidylserine transport and changes in erythrocyte shape. Nevertheless the results of the investigations showed that considerable morphological changes appear only as a result of erythrocyte exposure to high concentrations (50 ppm and 100 ppm) of the extracts studied, thus they should not lead to clinical erythrocytic damage if recommended doses of U. tomentosa preparations are administrated. PMID- 22217609 TI - Nonmotor manifestations in Parkinson disease. AB - BACKGROUND: Although the diagnosis of Parkinson disease (PD) still relies mainly on the appearance of its classical motor features of resting tremor, rigidity, bradykinesia, and postural instability, nonmotor manifestations in PD are now recognized as an integral component of this multisystem disorder. REVIEW SUMMARY: Nonmotor complications in PD occur commonly. The current understanding of cognitive dysfunction; neuropsychiatric manifestations including psychosis, impulsive control, and compulsive disorders, depression, anxiety and apathy; autonomic complications such as hypotension, erectile dysfunction, and urinary complications; sleep disorders and other nonmotor manifestations are summarized in this review. CONCLUSION: Nonmotor complications often carry a greater impact than motor features in PD. Therefore, heightened awareness and proper recognition of these features are critical in improving a Parkinson patient's quality of life. PMID- 22217610 TI - Cerebrovascular complications of neurocysticercosis. AB - BACKGROUND: It is well established that several infectious diseases can directly lead to ischemic or hemorrhagic stroke. Neurocysticercosis (NCC), caused by infection of the human central nervous system with the parasite Taenia solium, is recognized as an important public health problem in developing countries. The clinical manifestations of NCC are nonspecific and varied depending on the number and topography of lesions. Cerebrovascular disease is a relatively common but underrecognized complication of NCC; published data indicate that the incidence of stroke is between 4% and 12% in patients with NCC, depicting a clear relationship among these 2 pathologies. REVIEW SUMMARY: We review the cerebrovascular complications of NCC including the possible role of NCC as a cerebrovascular risk factor, including epidemiology, pathogenesis, diagnosis, and management of the cerebrovascular complications derived from cysticercal infarction and those associated with the use of anticysticercal drugs. Common and uncommon clinical manifestations, localization of stroke, and associated syndromes are discussed along with their prognostic significance. CONCLUSIONS: Although an underrecognized cause of stroke, present preponderantly in undeveloped countries, NCC still causes significant incapacity and even death in young patients suffering from stroke in the absence of cerebrovascular risk factors; hence, neurologists should become familiar with this potential complication. PMID- 22217611 TI - Early diagnosis, monitoring, and treatment of optic neuritis. AB - BACKGROUND: About half of multiple sclerosis patients present with optic neuritis (ON) as a clinically isolated syndrome (CIS). In the Optic Neuritis Treatment Trial study, 28% of patients with ON and an abnormal brain magnetic resonance imaging (MRI) did not have a relapse at the end of 15 years. It is still difficult to predict which CIS patients will go on to develop clinically definite multiple sclerosis and which will have a benign course. REVIEW SUMMARY: This review focuses on more advanced methods of detecting and quantifying ON in multiple sclerosis that have been developed in the past 15 years, especially on recent developments in optical coherence tomography measurement of the retinal nerve fiber layer and its role in monitoring axonal loss in the course of the disease. New clinical trial methods of measuring visual acuity include high contrast visual acuity testing with the Early Treatment Diabetic Retinopathy Study charts, low-contrast letter acuity, and contrast sensitivity testing. More advanced neuroimaging techniques include magnetization transfer imaging and diffusion tensor imaging to quantify visual pathway lesions. Other tests of visual function, such as multifocal visual-evoked potentials and functional MRI, have been shown to be more sensitive than conventional visual-evoked potentials or MRI in detecting early, subtle visual impairment in ON and early recovery of visual function related to cortical plasticity. Newer agents are currently being investigated for CIS in ongoing clinical trials. CONCLUSIONS: Better methods are being developed for the earlier diagnosis, monitoring, and treatment of ON. In the future, CIS patients may be stratified according to their risk of development of clinically definite multiple sclerosis and therefore, receive the appropriate treatment. PMID- 22217612 TI - Successful treatment of leptomeningeal gliomatosis of pilomyxoid astrocytoma after failed frontline chemotherapy. AB - INTRODUCTION: Pilomyxoid astrocytoma (PMA) is a rare variant of pilocytic astrocytoma. Compared with pilocytic astrocytoma, PMA is more aggressive, has a higher rate of local recurrence, and often disseminates to the leptomeninges. Leptomeningeal gliomatosis is another rare but often intractable neoplasm. PMA presenting as leptomeningeal gliomatosis can be a therapeutic challenge, particularly in young children for whom many pediatric oncologists consider radiation therapy only as a back-up treatment. However, chemotherapy, usually considered a frontline treatment for low-grade tumors such as PMA, has little impact on leptomeningeal gliomatosis. CASE REPORT: We report on a 5-year-old boy with an approximately 2-month history of progressively worsening loss of vision. Radiographic studies with contrast revealed an enhanced mass within the optic nerve, an enhanced lesion in the leptomeninges, and diffusely scattered nonenhanced white matter lesions in the craniospinal axis. The patient was treated with a 10-week carboplatin and vincristine regimen without a biopsy. After completing induction and 1 maintenance cycle, however, the patient developed coma caused by hydrocephalus. External ventricular drainage was performed and a biopsy was taken through ventriculoscopy, revealing PMA. The patient was then treated with craniospinal irradiation and concomitant temozolomide, a regimen to which he had a complete response. Two years after initial presentation the patient was free of disease. CONCLUSIONS: This report documents a rare, intractable tumor and provides evidence that radiation therapy, given as craniospinal irradiation, can be effective for leptomeningeal gliomatosis. PMID- 22217613 TI - Posttraumatic dystonia and hemiplegic migraine: different expressions of neuronal hyperexcitability? AB - The development of focal hand dystonia after a traumatic injury of the central or the peripheral nervous system is a rare condition with multifactorial predisposing factors. We report on a patient who developed focal dystonia of the left hand after a cervical whiplash injury. Magnetic resonance imaging did not show cerebral or spinal lesions, whereas a brain F-FDG PET scan revealed hypometabolism of the right primary sensory-motor cortex extending to the inferior and superior parietal lobule. The patient had a history of recurrent migraine attacks. Four months before the whiplash injury, she had transient dystonic posture of the left hand during a hemiplegic migraine attack. Brain magnetic resonance imaging scan and neurovascular investigations were negative. Among the predisposing factors to the development of trauma-induced dystonia, a putative role of neuronal hyperexcitability, shared by migraine and dystonia, is discussed. PMID- 22217614 TI - Valproic acid-induced eosinophilic pleural effusion: a case report and review of the literature. AB - We present a case of eosinophilic pleural effusion due to valproic acid (VPA), a rare adverse event that has been reported previously. A 30-year-old male patient presented with respiratory symptoms and right-sided pleuritic pain, within days of initiation of VPA treatment for a generalized seizure. Chest radiography revealed a moderate-sized right-sided pleural effusion, which was an exudate with a pH of 7.54 and 48% eosinophils. Symptoms resolved soon after discontinuation of the drug, as did the effusion in a repeat radiograph 3 weeks later. The likelihood that VPA was the cause of the effusion is examined. PMID- 22217615 TI - A case of spontaneous spinal epidural hematoma mimicking a stroke. AB - INTRODUCTION: For intravenous (IV) thrombolytic therapies to be effective, a correct diagnosis of acute ischemic stroke must be made within 3 hours from the onset of symptoms, a relatively short window period. However, obtaining a diagnosis in the time frame is not easy; a wide variety of conditions mimic a stroke, including seizures, migraine, and even a spinal mass, and often these are diagnosed as acute ischemic stroke and receive thrombolytic therapy. CASE REPORT: A patient presented suffering progressive and fluctuating painful triparesis coupled with acute onset dissociated sensory loss. The patient complained of dysarthria and transient altered mentality at the onset of symptoms; therefore, we suspected an ischemic infarction of the brainstem and spinal cord accompanied by vertebral artery dissection. As the time at diagnosis was 2 hours 30 minutes after symptom onset, we started IV thrombolytic treatment using recombinant tissue plasminogen activator. Magnetic resonance imaging during the recombinant tissue plasminogen activator infusion revealed a spontaneous spinal epidural hematoma (SSEH) of the cervical and thoracic spine, leading the patient to undergo an emergency surgery. CONCLUSIONS: SSEH is an uncommon clinical condition, and a manifestation of SSEH with anterior spinal artery syndrome is also rare. Furthermore, an emergency operation after IV thrombolytic treatment is an extraordinary situation. PMID- 22217616 TI - Thrombolytic therapy for ischemic stroke secondary to paradoxical embolism in pregnancy: a case report and literature review. AB - INTRODUCTION: Thrombolysis for acute ischemic stroke has been rarely administrated during pregnancy. Paradoxical embolism through a patent foramen ovale (PFO) or pulmonary arteriovenous malformation (AVM) is an identified risk factor for ischemic stroke. CASE REPORT: We report a 24-year-old woman at 11 weeks gestation who developed a sudden onset of dysarthria, hemiparesis, and hemisensory loss. She was diagnosed as having an ischemic stroke in the left middle cerebral artery (MCA) territory. She was treated with intra-arterial recombinant tissue plasminogen activator with subsequent resolution of her neurological deficits. Further workup revealed the presence of a PFO with a large right-to-left shunt. After being put on antithrombotic therapy, she presented again at 13 gestational weeks with a new ischemic infarction in the vertebrobasilar territory. Her PFO was closed percutaneously under ultrasonic guidance but the right-to-left shunt persisted. After a normal delivery, she was found to have a large pulmonary AVM which was successfully resected without complication. CONCLUSIONS: This report describes the successful usage of intra arterial tissue plasminogen activator for acute ischemic stroke during early pregnancy. In patients with presumed paradoxical embolism, careful attention should be paid to rule out a coexistence of PFO and pulmonary AVM. PMID- 22217617 TI - Unusual case of intra-arterial doxorubicin chemoembolization-associated posterior reversible encephalopathy syndrome. AB - A 63-year-old white female with a history of metastatic breast cancer to the liver developed acute-onset nausea, vomiting, mental status change, and generalized seizures following transarterial chemoembolization using doxorubicin. The patient was hospitalized with the above symptoms immediately following transarterial chemoembolization using drug eluting bead doxorubicin into the right hepatic artery. The patient developed intractable nausea, vomiting, and abdominal pain and had a generalized tonic-clonic seizure lasting for 40 seconds, approximately 24 hours after the procedure. The patient was confused and lethargic for 2 days with progressive improvement in her mental status. Her neurological examination showed encephalopathy with disorientation to time, place or person, and she also had a glassy look. Cranial nerves were normal other than lack of response to threat stimulus bilaterally; motor and sensory examination was unremarkable. Initial blood pressure was 130/90 mm Hg and routine chemistry and complete blood count on admission were within normal limits. The cerebrospinal fluid analysis showed clear and colorless fluid with glucose of 56 mg/dL, protein of 42 mg/dL, white blood cells of 2/MUL, and red blood cells of 10/MUL and did not show any evidence of infectious or toxic etiology on encephalopathy. Continuous electro encephalography showed diffuse slowing but no epileptiform discharges. The magnetic resonance imaging (MRI) revealed increased signal intensity in the bilateral parieto-occipital area, right more than the left, on fluid-attenuated inversion recovery, apparent diffusion coefficient, and T2-weighted imaging, with no increased signal on diffusion weighted image consistent with vasogenic edema. The patient's symptoms and MRI findings were consistent with diagnosis of posterior reversible encephalopathy syndrome. Resolution of the MRI changes is noted on the follow-up imaging 8 weeks later. Posterior reversible encephalopathy syndrome in this case is most likely related to intra-arterial doxorubicin infusion because of the temporal association between administration, symptom onset, and MRI changes. PMID- 22217618 TI - Is donepezil effective for multiple sclerosis-related cognitive dysfunction? A critically appraised topic. AB - BACKGROUND: Cognitive dysfunction affects approximately half of the patients with multiple sclerosis (MS). Cholinesterase inhibitor drugs are approved to treat cognitive dysfunction associated with degenerative dementia. OBJECTIVE: To critically assess current evidence regarding the efficacy of the cholinesterase inhibitor, donepezil in the treatment of MS-associated cognitive impairment. METHODS: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario, structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the fields of behavioral neurology and MS. RESULTS: A randomized control trial was selected for critical appraisal. This trial randomized MS patients to receive donepezil 10 mg daily or placebo for treatment of MS-related cognitive dysfunction. There was no significant treatment effect found between the 2 groups on either the primary outcome of memory or any of the secondary cognitive measures. Post hoc analyses suggested a trend favoring donepezil in subjects with greater baseline cognitive dysfunction. CONCLUSIONS: Donepezil 10 mg daily for 24 weeks is not superior to placebo in improving MS related cognitive dysfunction. PMID- 22217619 TI - Morphological, biological and molecular characterization of three strains of Trypanosoma cruzi Chagas, 1909 (Kinetoplastida, Trypanosomatidae) isolated from Triatoma sordida (Stal) 1859 (Hemiptera, Reduviidae) and a domestic cat. AB - A study was conducted of the biological, morphological and molecular characters of 3 strains of Trypanosoma cruzi (SI(5), SI(8) and SIGR(3)) isolated from specimens of Triatoma sordida collected in Santo Inacio and a domestic cat. In order to carry out the study, the following parameters were evaluated: pre-patent period, parasitaemia curves, morphology of the parasites, mortality rates, histopathological lesions and molecular typing. The strains presented variable pre-patent periods, low parasitaemia and no animal mortality. The morphological study of trypomastigotes showed a predominance of intermediate-width and short length forms, as well as low nuclear index. Epimastigotes presented a low nuclear index, intermediate-width forms in strains SI(5) and SI(8), and large-width forms in SIGR(3). A shorter length could be noted in strains SI(8) and SIGR3, whereas SI(5) displayed an intermediate length. The histopathological study did not detect amastigote nests in tissues. The amplification of the divergent domain of 24Salpha rRNA, HSP60 and GPI genes of strains SI(5), SI(8) and SIGR(3) classified the 3 strains into Group II. Biological parameters made it possible to classify the strains isolated in Santo Inacio (BA) into Biodeme III, Zymodeme 1 and Group II of T. cruzi. PMID- 22217620 TI - Exposure of small mammals to ticks and rickettsiae in Atlantic Forest patches in the metropolitan area of Recife, North-eastern Brazil. AB - Between December 2007 and March 2009, small mammals were captured in 6 Atlantic Forest patches in Brazil. We assessed tick-host associations and whether they differ among forest strata, sites, seasons, and host age classes or between sexes. Moreover, we assessed the exposure of animals to Rickettsia spp. In total, 432 animals were captured and 808 ticks were found on 32.9% of them. Significant differences were found among host species, collection sites, and forest strata; microhabitat preference was a strong risk factor for tick infestation. The highest tick density rates were recorded in forest fragments settled in rural areas; 91.3% of the ticks were collected from animals trapped in these forest fragments. A high prevalence (68.8%) of antibodies to Rickettsia spp. was detected among animals. This study suggests that disturbed Atlantic Forest fragments provide an environment for ticks and small mammals, which are highly exposed to rickettsiae. It also indicates that forest patches settled in rural areas are usually associated with higher small mammal diversity as well as with higher tick density rates. PMID- 22217621 TI - Severe influenza among children and young adults with neurologic and neurodevelopmental conditions - Ohio, 2011. AB - Children with neurologic and neurodevelopmental conditions are at increased risk for severe outcomes from influenza, including death. In April 2011, the Ohio Department of Health and CDC investigated an influenza outbreak that began in February 2011 in a residential facility for 130 children and young adults with neurologic and neurodevelopmental conditions. This report summarizes the characteristics and clinical courses of 13 severely ill residents with suspected or confirmed influenza; 10 were hospitalized, and seven died. Diagnosis is challenging in this population, and clinicians should consider influenza in patients with neurologic and neurodevelopmental conditions who have respiratory illness or a decline in baseline medical status when influenza is circulating in the community. Prompt testing, early and aggressive antiviral treatment, and antiviral chemoprophylaxis are important for these patients. When influenza is suspected, antiviral treatment should be given as soon as possible after symptom onset, ideally within 48 hours. Treatment should not wait for laboratory confirmation of influenza. During outbreaks, antiviral chemoprophylaxis should be provided to all residents of institutional facilities (e.g., nursing homes and long-term- care facilities), regardless of vaccination status. Residential facilities for patients with neurologic and neurodevelopmental conditions are encouraged to vaccinate all eligible residents and staff members against influenza. PMID- 22217622 TI - Imported human rabies -New Jersey, 2011. AB - On July 8, 2011, the New Jersey Department of Health and Senior Services (NJDHSS) contacted CDC about possible rabies in a hospitalized Haitian woman aged 73 years. Rabies was included in the differential diagnosis because she had acute, progressive encephalitis of unknown etiology. No history of animal exposure had been reported at the time of hospitalization. On July 18, CDC confirmed rabies virus infection, later identified as a canine rabies virus variant present in Haiti. The patient's neurologic status continued to deteriorate, leading to her death on July 20. This report summarizes the patient's clinical course and the associated public health investigation. This is the third report of human rabies in the United States acquired in Haiti since 2000 and highlights the importance of obtaining a detailed history for patients who have traveled from a rabies endemic country and the value of consultation with medical and public health professionals regarding any animal bites. PMID- 22217623 TI - Receipt of A(H1N1)pdm09 vaccine by prisons and jails - United States, 2009-10 influenza season. AB - Approximately 2.3 million inmates were confined to U.S. prisons and jails on any given day in 2009. However, over the course of a year, approximately 10 million persons spend time in a correctional facility. To determine to what extent correctional facility populations were included in the national vaccine response to the influenza A (H1N1)pdm09 pandemic, staff members at the Emory University Preparedness and Emergency Response Research Center, aided by the National Commission on Correctional Health Care (NCCHC), conducted a survey to document whether jails and prisons received A(H1N1)pdm09 vaccine during the 2009-10 pandemic period. This report summarizes the results of that survey, which found that 55% of jails did not receive A(H1N1)pdm09 vaccine during the pandemic period, whereas only 14% of federal prisons and 11% of state prisons did not receive the vaccine. Greater inclusion of correctional facilities, especially smaller facilities, in pandemic preparedness planning might better protect correctional facility populations and the community as a whole in the event of future influenza pandemics. PMID- 22217624 TI - Update: Influenza A (H3N2)v transmission and guidelines - five states, 2011. AB - From August 17 to December 23, 2011, CDC received reports of 12 human infections with influenza A (H3N2)v viruses that have the matrix (M) gene from the influenza A (H1N1)pdm09 virus (formerly called swine-origin influenza A [H3N2] and pandemic influenza A [H1N1] 2009 viruses, respectively). The 12 cases occurred in five states (Indiana, Iowa, Maine, Pennsylvania, and West Virginia), and 11 were in children. Six of the 12 patients had no identified recent exposure to swine. Three of the 12 patients were hospitalized, and all have recovered fully. PMID- 22217625 TI - Notes from the field: Escherichia coli O157:H7 gastroenteritis associated with a State Fair - North Carolina, 2011. AB - On October 24, 2011, the North Carolina Division of Public Health (NCDPH) was notified of four Shiga toxin-producing Escherichia coli (STEC) infections among persons who had attended the 2011 North Carolina State Fair, held October 13-23 in Raleigh. Approximately 1 million visitors had attended the fair. PMID- 22217626 TI - Lessons learned from a family-focused weight management intervention for obese and overweight children. AB - OBJECTIVE: Treatment for childhood obesity is characterised by high attrition rates and failure to achieve weight maintenance. It is therefore important to develop more effective programmes. The aim of the present qualitative study was to explore the views of parents, children and health trainers to identify issues which can inform the development of more effective programmes. DESIGN: A qualitative study combining in-depth interviews and focus groups. Participants were selected purposively from current and past attendees. SETTING: WATCH-IT, a UK-based community child weight management programme. SUBJECTS: Twenty-three families who had previously attended (or were currently attending) WATCH-IT were interviewed. Focus groups with ten trainers explored their views of the intervention. RESULTS: Parents and children had different goals for involvement, with parents focusing on psychological benefits, while children concentrated on goals relating to weight loss and physical fitness. Parents were found to struggle to provide consistent support to their children and this was exacerbated by family dynamics. The child's commitment to lose weight, support from their family and a good relationship between the child and their trainer were viewed as important keys to successful weight management. CONCLUSIONS: The study will guide the design of existing and future programmes by providing insights into issues that challenge successful engagement. It highlights the possible value of exploring the therapeutic relationship between trainers and participants. PMID- 22217629 TI - The Dadaab camps - Mitigating the effects of drought in the Horn (perspective). AB - Since mid 2011 the tragedy unfolding across the Horn of Africa following prolonged drought in the region has been a major focus for international relief operations and emergency aid. However, the most effective strategies for mitigating the effects of the drought have not been given sufficient media coverage or discussed critically enough in the public arena. Instead, while important and necessary, the focus has largely remained on emotive pleas for increased aid. This unfortunately, detracts from a considered discourse on the most effective interventions in the current circumstances and reduces scrutiny on performance of the primary agencies and bodies responsible for coordinating the relief effort. The authors present a personal perspective having recently returned from the Dadaab refugee camps where much of the relief effort has focused. PMID- 22217632 TI - Antihypertensives in octogenarians. PMID- 22217630 TI - Identifying women with suspected ovarian cancer in primary care: derivation and validation of algorithm. AB - OBJECTIVE: To derive and validate an algorithm to estimate the absolute risk of having ovarian cancer in women with and without symptoms. DESIGN: Cohort study with data from 375 UK QResearch general practices for development and 189 for validation. PARTICIPANTS: Women aged 30-84 without a diagnosis of ovarian cancer at baseline and without appetite loss, weight loss, abdominal pain, abdominal distension, rectal bleeding, or postmenopausal bleeding recorded in previous 12 months. Main outcome The primary outcome was incident diagnosis of ovarian cancer recorded in the next two years. METHODS: Risk factors examined included age, family history of ovarian cancer, previous cancers other than ovarian, body mass index (BMI), smoking, alcohol, deprivation, loss of appetite, weight loss, abdominal pain, abdominal distension, rectal bleeding, postmenopausal bleeding, urinary frequency, diarrhoea, constipation, tiredness, and anaemia. Cox proportional hazards models were used to develop the risk equation. Measures of calibration and discrimination assessed performance in the validation cohort. RESULTS: In the derivation cohort there were 976 incident cases of ovarian cancer from 2.03 million person years. Independent predictors were age, family history of ovarian cancer (9.8-fold higher risk), anaemia (2.3-fold higher), abdominal pain (sevenfold higher), abdominal distension (23-fold higher), rectal bleeding (twofold higher), postmenopausal bleeding (6.6-fold higher), appetite loss (5.2 fold higher), and weight loss (twofold higher). On validation, the algorithm explained 57.6% of the variation. The receiver operating characteristics curve (ROC) statistic was 0.84, and the D statistic was 2.38. The 10% of women with the highest predicted risks contained 63% of all ovarian cancers diagnosed over the next two years. CONCLUSION: The algorithm has good discrimination and calibration and, after independent validation in an external cohort, could potentially be used to identify those at highest risk of ovarian cancer to facilitate early referral and investigation. Further research is needed to assess how best to implement the algorithm, its cost effectiveness, and whether, on implementation, it has any impact on health outcomes. PMID- 22217633 TI - Computer assisted diagnosis of ovarian cancer in primary care. PMID- 22217634 TI - MSF reconsiders Somali operations after fatal attack. PMID- 22217635 TI - US citizens score poorly on ratings of cardiovascular risk factors. PMID- 22217636 TI - Uganda is left with fewer than 5000 doctors and no strategic plan to retain them. PMID- 22217637 TI - WHO wades into row over sharing of H5N1 flu research. PMID- 22217638 TI - Prediction of coracoid thickness using a glenoid width-based model: implications for bone reconstruction procedures in chronic anterior shoulder instability. AB - BACKGROUND: Chronic anterior shoulder instability with glenoid bone loss can be a very challenging clinical problem. Significant bone loss is commonly managed with the Latarjet procedure. However, in some cases with severe glenoid bone loss, iliac crest bone grafting is required to obtain a graft of adequate size. Iliac crest bone graft is associated with high rates of donor-site complications. Whereas glenoid dimensions can be determined by use of 3-dimensional computed tomography reconstructions, the thickness of the coracoid cannot be easily measured. This study aims to define a ratio between glenoid width and coracoid thickness that can be used in preoperative planning to determine whether coracoid transfer will yield adequate bone graft to restore glenoid contour or whether iliac crest bone graft must be taken. METHODS: We studied 100 paired cadaveric scapulae (50 male and 50 female scapulae). The bony dimensions of the coracoid and glenoid were measured for each specimen. RESULTS: Coracoid and glenoid dimensions are provided. The mean thickness of the male coracoid was 35.4% of the width of the glenoid. The mean female coracoid thickness was 34.4% of the glenoid width. DISCUSSION: A new biomorphologic model is presented to predict coracoid thickness and the ability of the Latarjet procedure to restore stability to a given bone-deficient glenoid. This model may aid the shoulder surgeon in preoperative planning and help promote successful outcomes in glenoid reconstruction surgery by determining whether a Latarjet procedure or iliac crest bone graft is the most appropriate procedure given the predicted amount of coracoid bone graft available. PMID- 22217639 TI - Acute traumatic brachialis rupture in a young rugby player: a case report. PMID- 22217640 TI - Operative treatment of isolated teres major ruptures. PMID- 22217641 TI - Chronic incarceration of the medial epicondyle: a case report. PMID- 22217642 TI - Improved strength of early versus late supraspinatus tendon repair: a study in the rabbit. AB - HYPOTHESIS: The optimal timing for surgical repair of the supraspinatus (SSP) tendon after full-substance tear has not been established. The objectives of this prospective investigation of SSP tendon repair delayed by 1, 2, or 3 months followed by a 3-month postoperative course were to (1) determine the site of failure, (2) measure the tensile strength and stiffness, and (3) assess the ability of computed tomography to predict mechanical strength. MATERIALS AND METHODS: We transected 1 SSP tendon in 36 rabbits and then repaired it with transosseous sutures after a delay of 1, 2, or 3 months. We compared the results with 36 intact shoulders from 18 age-matched control rabbits. RESULTS: Experimental specimens failed at the tendon (n = 26) more often than at the enthesis (n = 10) (P < .05). The mean peak loads to failure 3 months after repair delayed by 1 month and delayed by 2 months were significantly greater than their respective control values (P < .05 for both); there was no difference after a delay of 3 months. There was no association between the presence of hypoattenuation on computed tomography and repair strength (P > .05). CONCLUSIONS: Our findings indicate better mechanical results with earlier repair (1 or 2 months) after SSP tendon than after a delay of 3 months. Early surgical repair may lower the risk of tendon retear. PMID- 22217643 TI - Shoulder internal rotation elbow flexion test for diagnosing cubital tunnel syndrome. AB - BACKGROUND: Shoulder internal rotation enhances symptom provocation attributed to cubital tunnel syndrome. We present a modified elbow flexion test--the shoulder internal rotation elbow flexion test--for diagnosing cubital tunnel syndrome. METHODS: Fifty-five ulnar nerves in cubital tunnel syndrome patients and 123 ulnar nerves in controls were examined with 5 seconds each of elbow flexion, shoulder internal rotation, and shoulder internal rotation elbow flexion tests before and after treatment (surgery in 18; conservative in others). For the shoulder internal rotation elbow flexion test position, 90 degrees abduction, maximum internal rotation, and 10 degrees flexion of the shoulder were combined with the elbow flexion test position. The test was considered positive if any symptom for cubital tunnel syndrome developed <5 seconds. Influence of the shoulder internal rotation elbow flexion test was evaluated by nerve conduction studies in 10 cubital tunnel syndrome nerves and 7 control nerves. RESULTS: The sensitivities/specificities of the 5-second elbow flexion, shoulder internal rotation, and shoulder internal rotation elbow flexion tests were 25%/100%, 58%/100%, and 87%/98%, respectively. Sensitivity differences between the shoulder internal rotation elbow flexion test and the other two tests were significant. Shoulder internal rotation elbow flexion test results and cubital tunnel syndrome symptoms were significantly correlated. Influence of the shoulder internal rotation elbow flexion test on the ulnar nerve was seen in 8 of 10 cubital tunnel syndrome nerves but not in controls. CONCLUSIONS: The 5-second shoulder internal rotation elbow flexion test is specific, easy and quick provocative test for diagnosing cubital tunnel syndrome. PMID- 22217645 TI - Muscle releases to improve passive motion and relieve pain in patients with spastic hemiplegia and elbow flexion contractures. AB - INTRODUCTION: Patients with spastic hemiplegia after upper motor neuron (UMN) injury can develop elbow contractures. This study evaluated outcomes of elbow releases in treating spastic elbow flexion contractures in hemiplegic patients. METHODS: Adults with spastic hemiplegia due to UMN injury who underwent elbow releases (brachialis, brachioradialis, and biceps muscles) were included. Nonoperative treatment was unsuccessful in all patients. Patients complained of difficulty with passive functions. Passive range of motion (ROM), pain relief, Modified Ashworth spasticity score, and complications were evaluated preoperatively and postoperatively. RESULTS: There were 8 men and 21 women with an average age of 52.4 years (range, 24.1-81.4 years). Seventeen patients had pain preoperatively. Postoperative follow-up was a mean of 1.7 years (range, 1 4.5 years). Preoperatively, patients lacked a mean of 78 degrees of passive elbow extension compared with 17 degrees postoperatively (P < .001). The Modified Ashworth spasticity score improved from 3.3 to 1.4 (P = .001). All patients with preoperative pain had improved pain relief, and 16 (94%) were pain free. There were 3 wound complications that resolved nonsurgically and 1 recurrence. Age, sex, etiology, and chronicity of UMN injury were not associated with improvement in motion or pain relief (P > .05). CONCLUSION: Releases of the brachialis, brachioradialis, and biceps muscles can be an effective means of pain relief, improved passive ROM, and decreased spasticity in patients with elbow flexion deformity after UMN injury. PMID- 22217644 TI - Relationship of radiographic acromial characteristics and rotator cuff disease: a prospective investigation of clinical, radiographic, and sonographic findings. AB - BACKGROUND: Many studies have attempted to correlate radiographic acromial characteristics with rotator cuff tears, but the results have not been conclusive. Therefore, the purpose of this study was to determine the relationship between rotator cuff disease and the development of symptoms with different radiographic acromial characteristics, including shape, index, and presence of a spur. MATERIALS AND METHODS: The records of 216 patients enrolled in an ongoing prospective, longitudinal study investigating asymptomatic rotator cuff tears were reviewed. All patients underwent standardized radiographic evaluation, clinical evaluation, and shoulder ultrasonography at regularly scheduled surveillance visits. Three blinded observers reviewed all radiographs to determine the acromial morphology, presence, and size of an acromial spur, as well as the acromial index. These findings were analyzed to determine an association with the presence of a full-thickness rotator cuff tear. RESULTS: The 3 observers demonstrated poor agreement for acromial morphology (kappa = 0.41), substantial agreement for the presence of an acromial spur (kappa = 0.65), and excellent agreement for the acromial index (kappa = 0.86). The presence of an acromial spur was highly associated with the presence of a full-thickness rotator cuff tear (P = .003), even after adjusting for age. No association was found between the acromial index and rotator cuff disease (P = .92). CONCLUSION: The presence of an acromial spur is highly associated with the presence of a full thickness rotator cuff tear in symptomatic and asymptomatic patients. The acromial morphology classification system is an unreliable method to assess the acromion. The acromial index shows no association with the presence of rotator cuff disease. PMID- 22217646 TI - A commentary on Association of adiponectin polymorphism with cord blood adiponectin concentrations and intrauterine growth. PMID- 22217648 TI - Spectra of BRCA1 and BRCA2 mutations in Korean patients with breast cancer: the importance of whole-gene sequencing. AB - The frequencies and spectra of germline mutations in the BRCA1 and BRCA2 genes vary among populations. In the present study, the mutation spectra of the BRCA1/BRCA2 genes in Korean breast cancer patients were investigated using whole gene sequencing method. A total of 134 unrelated Korean breast cancer patients who were identified as being at high risk of carrying BRCA1/BRCA2 mutations were included. PCR amplification and direct sequencing were performed covering all exons and flanking intronic sequences of the BRCA1/BRCA2 genes. A total of 26 mutations were detected in 31 of 134 patients (23.1%). The mutation detection rate in the present study is higher than those of previous studies using screening methods (2.5-11.3%) and similar to that of a recent study, which used whole-gene sequencing (21.2%). The BRCA2: c.7480C>T mutation, which has been suggested to be a founder mutation in Koreans, was detected in only one patient. Five mutations were recurrent but observed in no more than two patients. Given that the mutation detection rates using whole-gene sequencing were much higher than for screening methods and that there were no consistent observations of founder mutations, whole-gene sequencing of both BRCA1 and BRCA2 genes should be the method of choice to identify mutations in high-risk Korean patients. PMID- 22217647 TI - Hypomethylation of the KCNQ1OT1 imprinting center of chromosome 11 associated to Sotos-like features. PMID- 22217649 TI - Chemotherapy-induced infiltrative pneumonitis cases in breast cancer patients. AB - A number of chemotherapy drugs are well known to cause various histopathologic patterns of lung injury. The incidence of chemotherapy-induced infiltrative pneumonitis is rare and the diagnosis is difficult due to the nonspecific clinical and radiological presentations. However, it can cause significant morbidity and mortality in cancer patients. There is no consensus on the treatment of this adverse event, but prompt diagnosis and intervention is important as fatal outcomes have been reported. We present five cases of chemotherapy-induced infiltrative pneumonitis in breast cancer patients involving docetaxel, paclitaxel, gemcitabine and cyclophosphamide. PMID- 22217650 TI - Turkish adaptation of Spinal Cord Independence Measure--version III. AB - Various rating scales have been used to assess ability in individuals with spinal cord injury. There is no specific functional assessment scale for Turkish patients with spinal cord injury. The Spinal Cord Independence Measure (SCIM) is a specific test, which has become popular in the last decade. A study was conducted to validate and evaluate the Turkish adaptation of the SCIM III (T-SCIM III). The SCIM III was translated into Turkish. Reliability, (internal consistency, interrater reliability, and test-retest reliability), validity (with Functional Independence Measurement), and sensitivity (changes in 8-week exercise program) were studied. Internal consistency for total score was sufficient (Cronbach alpha=0.79). The interrater reliability was moderate to high (Cohen kappa between 0.72 and 1). Convergent validity was high (r=0.89, P<0.01). The T SCIM III was found to be more sensitive than the Functional Independence Measurement to changes in function. Hence, we recommend the use of T-SCIM III in clinical practice as a reliable, valid, and easy-to-use tool. PMID- 22217651 TI - Editor's workshop. PMID- 22217652 TI - Body dissatisfaction on top of depressive mood among adolescents with severe dysmenorrhea. AB - OBJECTIVES: This study aims to determine whether adolescent girls with severe dysmenorrhea (SD) have different psychological characteristics from their peers. STUDY DESIGN: Cross-sectional survey (SMASH 02). SETTINGS: Nationally representative sample of adolescents attending post-mandatory education. PARTICIPANTS: N = 7548, of whom 3340 were females, aged 16-20 years. INTERVENTION: Self-administered, anonymous survey consisted of 565 items on 4 main topics: sociodemographic determinants of health, health status, health behaviors, and health care use. OUTCOMES: Body image variables, mental health, and associated variables like sexual abuse and health perceptions. Bivariate analysis and binomial logistic regression controlling for explanatory variables were performed. RESULTS: 12.4% (95% confidence interval [CI]: 11.0-14) declared SD. Compared to their peers, subjects with SD were more likely to report depressive symptoms (adjusted odds ratio [AOR]: 1.73; 95% CI: 1.38-2.15), have a higher gynecological age (AOR: 1.13; 95% CI: 1.05-1.20), and attend vocational school (AOR: 1.33; 95% CI: 1.00-1.76). Moreover, the proportion of those reporting dissatisfaction with their body appearance was higher (AOR: 1.50; 95% CI: 1.02-2.22). CONCLUSION: Patients with SD not only show a different profile from their peers in terms of their mental health academic track and gynecological age, but they are also more dissatisfied with their body appearance. Clinicians should pay particular attention to patients with SD and offer them a global evaluation, bearing in mind what factors can be associated with SD. PMID- 22217653 TI - Characterization of a flat-panel detector for ion beam spot measurements. AB - Dynamic beam delivery techniques are being increasingly used for cancer therapy. Scanning ion beams require extensive and time-demanding quality assurance procedures and beam tuning. Accordingly, fast measurement techniques improving the efficiency of the procedures and accommodating the safety requirements are highly desirable. Major requirements for a detector used for beam-shape measurements are high spatial resolution in two dimensions, reusability, online readout and easy handling. At the Heidelberg Ion Beam Therapy Facility (Germany), we examined the performance of the RID 256 L flat-panel detector for beam spot measurements. The two-dimensional beam profiles of proton and carbon ion beams measured were compared to measurements with radiographic films at intermediate energies using the index. The difference to the beam width measured with radiographic films of less than 3% demonstrates sufficient accuracy of ion beam width measurements possible with this detector for both proton and carbon ion beams. The beam shapes were also measured at different beam intensities. At both the highest and lowest energies available at the HIT, no beam spot-shape deformation was found with increasing beam intensities, as long as the boundary of the dynamic range was not exceeded. The signal leak along the readout direction was identified as an undesirable effect. However, due to small amplitudes and static beams, this effect is of minor importance for beam spot measurements. Distortion of results due to detector radiation damage was monitored. No detector radiation damage was observed over the experiments. Moreover, the observed short-time detector response stability (within +/-0.1%) as well as medium term stability (within 0.5% in 15 months) was excellent. This flat panel detector is compact and easy to use. Together with its low weight, this helps to speed up measurement procedures substantially. All these properties make this an ideal detector for the fast, high-resolution imaging of static ion beam spots needed for constancy measurements in daily beam quality assurance and for accelerator tuning. For daily use, radiation damage has to be monitored continuously and corrected for if necessary. PMID- 22217654 TI - Application of phenotypic microarrays to environmental microbiology. AB - Environmental organisms are extremely diverse and only a small fraction has been successfully cultured in the laboratory. Culture in micro wells provides a method for rapid screening of a wide variety of growth conditions and commercially available plates contain a large number of substrates, nutrient sources, and inhibitors, which can provide an assessment of the phenotype of an organism. This review describes applications of phenotype arrays to anaerobic and thermophilic microorganisms, use of the plates in stress response studies, in development of culture media for newly discovered strains, and for assessment of phenotype of environmental communities. Also discussed are considerations and challenges in data interpretation and visualization, including data normalization, statistics, and curve fitting. PMID- 22217656 TI - Plant development--a snapshot in 2012. PMID- 22217657 TI - Travel health: safety and preparation strategies for clinicians. AB - Travel health has become a popular and widely accepted component of the medical community. With the increase in medical travel, NPs must be aware of the guidelines pertaining to health issues and diseases that arise in underdeveloped countries. PMID- 22217655 TI - MicroRNA-195 plays a tumor-suppressor role in human glioblastoma cells by targeting signaling pathways involved in cellular proliferation and invasion. AB - Accumulating evidence has implicated the deregluation of miRNAs in tumorigenesis. Previous studies have reported that microRNA-195 (miR-195) is markedly down regulated in human glioblastoma cells, compared with normal brain tissue, but the biological role of miR-195 in glioblastoma development is currently unknown. In this study, we define a tumor-suppressor role for miR-195 in human glioblastoma cells. Over-expression of miR-195 in glioblastoma cell lines robustly arrested cell cycle progression and significantly repressed cellular invasion. We identified E2F3 and CCND3 as functional downstream targets of miR-195 in glioblastoma cells. Through knockdown studies, we demonstrated that E2F3 was the dominant effector of miR-195-mediated cell cycle arrest and that CCND3 was a key mediator of miR-195-induced inhibition of glioblastoma cell invasion. Furthermore, we showed that p27(Kip1) was an important regulator downstream of CCND3 and that the accumulation of p27(Kip1) in the cytoplasm might be responsible for the miR-195-mediated cell invasion inhibition in glioblastoma cells. This work provides evidence for the initial mechanism by which miR-195 negatively regulates both the proliferation and invasion of glioblastoma cells, suggesting that the down-regulation of miR-195 might contribute to the malignant transformation of glioblastoma cells and could be a molecular signature associated with glioblastoma progression. PMID- 22217659 TI - Minimizing tracheobronchial aspiration in the tube-fed patient, part 2. PMID- 22217660 TI - Tinea versicolor: understanding effective treatment options. PMID- 22217662 TI - APRN consensus model implementation and planning. AB - The Annual Legislative Update describes the legislative issues that have the most impact on nurse practitioners and other advanced practice nurses across the country. PMID- 22217663 TI - Can treating depression improve diabetic management? AB - Diabetes with comorbid depression increases healthcare use, expenditures, and risk for complications. This study investigated current practice patterns for diabetic management as measured by HbA1C (A1C). Results indicated significant increases in Patient Health Questionnaire (PHQ)-9 and HbA1C scores among patients with diabetes who take antidepressant drugs. PMID- 22217664 TI - Diabetes. PMID- 22217666 TI - IDH1/2 mutations in WHO grade II astrocytomas associated with localization and seizure as the initial symptom. AB - INTRODUCTION: Seizures are the most common initial symptom in patients with low grade glioma and their occurrence strongly depends on the tumor location. The majority of low-grade gliomas reveal mutations in the genes encoding isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2). These mutations are associated with metabolic changes that are potentially epileptogenic. We investigated the correlation between IDH1/2 mutations and tumor localization and seizure as the initial symptom. MATERIALS AND METHODS: This retrospective study included patients with a diagnosis of WHO grade II astrocytoma and cortical infiltration and in whom initial symptoms were documented and biopsy tissue was available for IDH1/2 analysis. IDH1/2 mutation analysis was performed by direct sequencing or by immunohistochemistry with an antibody which detects mutated protein IDH1 R132H. Sequencing was carried out if immunohistochemistry was negative. IDH1/2 status was defined as mutated if either of these investigations were positive. RESULTS: Seventy-nine patients were included. IDH1 or IDH2 mutation was present in 63 (80%) patients who on average were younger than patients without IDH1/2 mutation (40 vs. 47 years, p=0.0331, t-test). IDH1/2 mutations were associated with frontal tumor location (p=0.0202). All 12 tumors in the insula revealed IDH1/2 mutations. Seizure as the initial symptom was recorded in 57 (72%) patients and was associated with IDH1 or IDH2 mutation by multivariate analysis (OR 22.563, p=0.0019). CONCLUSION: In WHO grade II astrocytomas, IDH1/2 mutations mostly occur in tumors infiltrating the frontal lobe. Seizure as the initial symptom is associated with IDH1 or IDH2 mutation. PMID- 22217667 TI - Guidelines for safe work practices in human and animal medical diagnostic laboratories. Recommendations of a CDC-convened, Biosafety Blue Ribbon Panel. AB - Prevention of injuries and occupational infections in U.S. laboratories has been a concern for many years. CDC and the National Institutes of Health addressed the topic in their publication Biosafety in Microbiological and Biomedical Laboratories, now in its 5th edition (BMBL-5). BMBL-5, however, was not designed to address the day-to-day operations of diagnostic laboratories in human and animal medicine. In 2008, CDC convened a Blue Ribbon Panel of laboratory representatives from a variety of agencies, laboratory organizations, and facilities to review laboratory biosafety in diagnostic laboratories. The members of this panel recommended that biosafety guidelines be developed to address the unique operational needs of the diagnostic laboratory community and that they be science based and made available broadly. These guidelines promote a culture of safety and include recommendations that supplement BMBL-5 by addressing the unique needs of the diagnostic laboratory. They are not requirements but recommendations that represent current science and sound judgment that can foster a safe working environment for all laboratorians. Throughout these guidelines, quality laboratory science is reinforced by a common-sense approach to biosafety in day-to-day activities. Because many of the same diagnostic techniques are used in human and animal diagnostic laboratories, the text is presented with this in mind. All functions of the human and animal diagnostic laboratory--microbiology, chemistry, hematology, and pathology with autopsy and necropsy guidance--are addressed. A specific section for veterinary diagnostic laboratories addresses the veterinary issues not shared by other human laboratory departments. Recommendations for all laboratories include use of Class IIA2 biological safety cabinets that are inspected annually; frequent hand washing; use of appropriate disinfectants, including 1:10 dilutions of household bleach; dependence on risk assessments for many activities; development of written safety protocols that address the risks of chemicals in the laboratory; the need for negative airflow into the laboratory; areas of the laboratory in which use of gloves is optional or is recommended; and the national need for a central site for surveillance and nonpunitive reporting of laboratory incidents/exposures, injuries, and infections. PMID- 22217668 TI - Verruciform xanthoma is another condition associated with pseudoepitheliomatous hyperplasia. PMID- 22217669 TI - Spatial distribution of the risk for metabolic complications: an application in south-east Brazil, 2006-2007. AB - OBJECTIVE: To identify spatial variation in the risk for metabolic complications (RMC) by means of a semi-parametric approach for multinomial data. DESIGN: Cross sectional study. SETTING: We visited 730 households selected in the first of a two-stage sample in South health district in Campinas, Sao Paulo, Brazil, 2006 2007. SUBJECTS: We interviewed 651 individuals and obtained their respective anthropometric measures and geographical coordinates of their house location. They were classified according to a combination of BMI and abdominal circumference as having no risk, increased, high or very high RMC. RESULTS: Gender, age and schooling were associated with RMC. Crude spatial risk for the three levels of RMC in relation to the absence of risk suggested different patterns in each level. Adjusted spatial risk for the RMC showed smaller significant areas, but the pattern remained similar to crude risk. CONCLUSIONS: Spatial point analysis with a multinomial approach improves the understanding of differences in RMC found, as we could identify specific areas in which to intervene. The public health significance of these findings may lie in the additional evidence provided that spatial location and its features can influence patterns of RMC. PMID- 22217670 TI - In vitro development of nuclear transfer embryos derived from porcine embryonic germ cells and their descendent neural precursor cells. AB - Undifferentiated stem cells may support a greater development of cloned embryos compared with differentiated cell types due to their ease of reprogramming during the nuclear transfer (NT) process. Hence, stem cells may be more suitable as nuclear donor cells for NT procedures than are somatic cells. Embryonic germ (EG) cells are undifferentiated stem cells that are isolated from cultured primordial germ cells (PGC) and can differentiate into several cell types. In this study, the in vitro development of NT embryos using porcine EG cells and their derivative neural precursor (NP) cells was investigated, thus eliminating any variation in genetic differences. The rates of fusion did not differ between NT embryos from EG and NP cells; however, the rate of cleavage in NT embryos derived from EG cells was significantly higher (p < 0.05) than that from NP cells (141/247 [57.1%] vs. 105/228 [46.1%]). Similarly, the rate of blastocyst development was significantly higher (P < 0.05) in NT using EG cells than the rate using NP cells (43/247 [17.4%] vs. 18/228 [7.9%]). The results obtained from the present study in pigs demonstrate a reduced capability for nuclear donor cells to be reprogrammed following the differentiation of porcine EG cells. Undifferentiated EG cells may be more amenable to reprogramming after reconstruction compared with differentiated somatic cells. PMID- 22217671 TI - Endocardial fibroelastosis of the heart. PMID- 22217672 TI - [Acute renal failure due to malaria in children]. PMID- 22217673 TI - Thymosin beta 4 ameliorates hyperglycemia and improves insulin resistance of KK Cg-Ay/J mouse. AB - OBJECT: To evaluate the efficacy of thymosin beta 4 (Tbeta(4)) on hyperglycemia and insulin sensitivity in a mouse model of type 2 diabetes mellitus (T2DM). METHODS: KK mice were divided into the following groups: KK control group, with saline treatment; KK Tbeta(4) group, with daily Tbeta(4) 100ng/10g body weight intraperitoneal injection for 12 weeks. Non-diabetic C57BL mice were used as normal control. OGTT, plasma insulin, HbA1c, serum adiponectin, Tbeta(4), cholesterol, and triglyceride were measured before and after Tbeta(4) treatment. The phosphorylated AKT and total AKT protein levels of skeletal muscle from all groups were determined. RESULTS: After Tbeta(4) treatment, repeat OGTT showed a significant decrease in glucose profiles in the KK Tbeta(4) group compared with the KK control group. The KK-Tbeta(4) group had reduced mean HbA1c and triglyceride levels, and increased adiponectin compared with KK control group. C57BL mice showed normal glucose homeostasis. The phosphorylated AKT levels of skeletal muscle were significantly increased in KK Tbeta(4) group compared with KK control group after glucose stimulation. C57BL mice showed no changes in phosphorylated AKT levels after Tbeta(4) treatment. CONCLUSIONS: Tbeta(4) improved glucose intolerance and ameliorated insulin resistance in KK mouse. Tbeta(4) may be a potential alternative insulin sensitizer for treatment of T2DM. PMID- 22217674 TI - High normal blood pressure is an independent risk factor for cardiovascular disease among middle-aged but not in elderly populations: 9-year results of a population-based study. AB - Data are conflicting and sparse regarding the impact of high normal blood pressure (BP) (systolic BP (SBP) of 130-139 mm Hg or diastolic BP (DBP) of 85-89 mm Hg) on incident cardiovascular disease (CVD) among middle-aged vs elderly population. We examined the risk of BP categories among 6273 participants >= 30 years, free of CVD at baseline, during more than 9.3 years follow-up. Cox regression analysis was used to estimate the hazard ratio (HR) of CVD for normal BP group (SBP between 120-129 mmHg or DBP between 80-85 mmHg), high normal BP group and hypertension group (SBP >= 140 mm Hg or DBP >= 90 mmHg or taking antihypertensive drugs), considering those with optimal BP (SBP<120 mmHg and DBP<80 mmHg) as reference. During follow-up, 512 CVD events occurred. There was significant interaction between age and BP categories (P=0.028) in prediction of CVD. In multivariate analysis, HRs (95% CIs) of CVD were 1.62 (1.11-2.37) and 2.20 (1.57-3.09) for middle aged with high normal and hypertensive BP groups, respectively. Among elderly (>= 60 years), HR was 2.09 (1.36-3.21) only for hypertensive ones. High normal BP is a risk factor for incident of CVD only among middle-aged population. Furthermore, the effect of hypertension on incident CVD was stronger among younger population. PMID- 22217675 TI - Association between daily cigarette consumption and hypertension moderated by CYP2A6 genotypes in Chinese male current smokers. AB - The purpose of this study was to assess whether cytochrome P450 enzyme 2A6 (CYP2A6) genotypes moderate the association between smoking and hypertension. In this study, 954 Chinese male current smokers from a community-based chronic disease screening project in Guangzhou were interviewed with a structured questionnaire about socio-demographic status, smoking and other health-related behaviors. Blood was collected for DNA extraction and CYP2A6 genotyping. Hypertension was defined according to 2007 ESH-ESC Practice Guidelines. A multivariate logistic regression was performed to examine the interaction between smoking quantity and CYP2A6 genotypes on hypertension after adjusting for age, education level and other potential confounders. Multivariate analyses indicated that smoking more than 15 cigarettes per day significantly increased the risk of hypertension (odds ratio (OR)=1.59, 95% confidence interval (CI)=1.21-2.10) compared with smoking 1-15 cigarettes per day, and further suggested that smoking interacted with normal CYP2A6 metabolizer genotype to increase the risk of hypertension. Smokers consuming more than 15 cigarettes per day with normal CYP2A6 metabolizer genotypes had the highest risk of hypertension (OR=2.04, 95% CI=1.11-3.75) compared with those consuming 1-15 cigarettes per day with slower CYP2A6 metabolizer genotypes. These findings demonstrated that smoking quantity was positively associated with hypertension and that CYP2A6 genotypes may moderate this relationship. PMID- 22217677 TI - A 2 amino acid shift in position leads to a substantial difference in the pattern of processing of 2 HIV-1 epitopes. AB - BACKGROUND: The sequence diversity that exists between HIV-1 strains presents a major obstacle to the design of a vaccine that will be effective on a global scale. Focusing on highly conserved cytotoxic T-lymphocyte epitopes as vaccine targets has been called into question by evidence that variation within epitope flanking regions can affect processing and presentation. METHODS: Using epitope specific T-cell clones tested for recognition of HLA-matched target cells infected with vaccinia viruses expressing HIV-1 nef genes derived from different HIV-1 clades, we examined the efficiency of presentation of an HLA-B*40 restricted HIV-1 nef epitope compared to that of an HLA-B*08 restricted epitope with which it overlaps by 6 amino acides. RESULTS: This small shift in epitope position substantially changed the patter or epitope processing and led either to an increase or decrease in antigen generation dependent on the viral sequences present. CONCLUSIONS: These data demonstrate the complexity of the antigen presentation pathway and the difficulties associated with selecting CTL epitopes as targets for an HIV-1 vaccine that will be effective in many populations and against several viral strains. PMID- 22217676 TI - Low cerebrospinal fluid concentrations of the nucleotide HIV reverse transcriptase inhibitor, tenofovir. AB - BACKGROUND: Tenofovir is a nucleotide HIV reverse transcriptase inhibitor whose chemical properties suggest that it may not penetrate into the central nervous system in therapeutic concentrations. The study's objective was to determine tenofovir's penetration into cerebrospinal fluid (CSF). METHODS: CNS HIV Antiretroviral Therapy Effects Research is a multicenter observational study to determine the effects of antiretroviral therapy on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within an hour of each other from subjects taking tenofovir between October 2003 and March 2007. All samples were assayed by mass spectrometry with a detection limit of 0.9 ng/mL. RESULTS: One hundred eighty-three participants (age 44 +/- 8 years; 83 +/- 32 kg; 33 females; CSF protein 44 +/- 16 mg/dL) had plasma and CSF samples drawn 12.2 +/ 6.9 and 11 +/- 7.8 hours post dose, respectively. Median plasma and CSF tenofovir concentrations were 96 ng/mL [interquartile range (IQR) 47-153 ng/mL] and 5.5 ng/mL (IQR 2.7-11.3 ng/mL), respectively. Thirty-four of 231 plasma (14.7%) and 9 of 77 CSF samples (11.7%) were below detection. CSF to plasma concentration ratio from paired samples was 0.057 (IQR 0.03-0.1; n = 38). Median CSF to wild-type 50% inhibitory concentration ratio was 0.48 (IQR 0.24-0.98). Seventy-seven percent of CSF concentrations were below the tenofovir wild-type 50% inhibitory concentration. More subjects had detectable CSF HIV with lower (<= 7 ng/mL) versus higher (>7 ng/mL) CSF tenofovir concentrations (29% versus 9%; P = 0.05). CONCLUSIONS: Tenofovir concentrations in the CSF are only 5% of plasma concentrations, suggesting limited transfer into the CSF, and possibly active transport out of the CSF. CSF tenofovir concentrations may not effectively inhibit viral replication in the CSF. PMID- 22217678 TI - Kinetics of nevirapine and its impact on HIV-1 RNA levels in maternal plasma and breast milk over time after perinatal single-dose nevirapine. AB - OBJECTIVE: To determine kinetics after single-dose nevirapine and the impact on HIV RNA [viral load (VL)] in maternal plasma and breast milk (BM). METHODS: Cohort of 120 HIV-1-infected pregnant Ugandan women received perinatal single dose nevirapine alone and followed up with their infants through 24 weeks postdelivery. We assessed the relationship of nevirapine concentration (tandem mass spectroscopy) and HIV-1 VL (Roche AMPLICOR HIV-1 Kit, version 1.5) in maternal plasma and BM over time. RESULTS: At week 1 postpartum, NVP (>=10 ng/mL) was detected in all 53 plasma and 47 of 51 (92.2%) BM samples with median (interquartile ranges) of, respectively, 171 (78-214) ng/mL and 112 (64-158) ng/mL, P = 0.075, which decreased subsequently with traces persisting through week 4 in plasma. Plasma and BM VL dropped by week 1 and were highly correlated at delivery (R = 0.71, P < 0.001) and week 1 (R = 0.69, P < 0.001) but not thereafter. At week 1, VL correlated inversely with NVP concentration in plasma (R = 0.39, P = 0.004) and BM (R = 0.48, P = 0.013). There was a VL rebound in both compartments, which peaked at week 4 to levels greater than those at week 1 [significantly in plasma (P < 0.001) but not in BM] and remained stable thereafter. Median VL was consistently greater (11- to 50-fold) in plasma than BM at all time points (all P < 0.001). CONCLUSIONS: After single-dose nevirapine, NVP concentration was comparably high through week 1, accompanied by suppression of plasma and BM VL. A longer "tail" (>1 week) of potent postnatal antiretroviral drugs is warranted to minimize the observed VL rebound and potential for NVP resistance as a result of persistent NVP traces. PMID- 22217679 TI - Improved estimation of the distribution of suppressed plasma HIV-1 RNA in men receiving effective antiretroviral therapy. AB - Plasma HIV-1 RNA was measured in 306 samples, collected from 273 highly active antiretroviral therapy-experienced men, using both the Roche COBAS TaqMan (limit of detection = 20 copies per milliliter) and Roche Amplicor (limit of detection = 50 copies per milliliter) assays. Mixtures of Gaussian distributions incorporating left-censored data were used in analyses. The more sensitive TaqMan assay estimated that 23% and 0.0003% of HIV-1 RNA values would be below 1 copy per milliliter and 1 copy per 3 L, respectively. This is in sharp contrast to the overestimation provided by the less sensitive Amplicor assay, whereby the corresponding predicted percentages were 51% and 1%. Both assays appropriately characterized suboptimal virologic response as the rightmost peaks of both distributions provided an excellent fit to the observed data. Our results based on a widely available 20 copies per milliliter sensitive assay reproduce those obtained using customized assays that quantified HIV-1 RNA values as low as 1 copy per milliliter. PMID- 22217680 TI - Socioeconomic support reduces nonretention in a comprehensive, community-based antiretroviral therapy program in Uganda. AB - OBJECTIVES: We evaluated the benefit of socioeconomic support (S-E support), comprising various financial and nonfinancial services that are available based on assessment of need, in reducing mortality and lost to follow-up (LTFU) at Reach Out Mbuya, a community-based, antiretroviral therapy program in Uganda. DESIGN: Retrospective observational cohort data from adult patients enrolled between May 31, 2001, and May 31, 2010, were examined. METHODS: Patients were categorized into none, 1, and 2 or more S-E support based on the number of different S-E support services they received. Using Cox proportional hazards regression, we modeled the association between S-E support and mortality or LTFU. Kaplan-Meier curves were fitted to examine retention functions stratified by S-E support. RESULTS: In total, 6654 patients were evaluated. After 10 years, 2700 (41%) were retained. Of the 3954 not retained, 2933 (74%) were LTFU and 1021 (26%) had died. After 1, 2, 5, and 10 years, the risks of LTFU or mortality in patients who received no S-E support were significantly higher than those who received some S-E support. In adjusted hazards ratios, patients who received no S E support were 1.5-fold (1.39-1.64) and 6.7-fold (5.56-7.69) more likely to get LTFU compared with those who received 1 or >= 2 S-E support, respectively. Likewise, patients who received no S-E support were 1.5-fold (confidence interval: 1.16 to 1.89) and 4.3-fold (confidence interval: 2.94 to 6.25) more likely to die compared with those who received 1 or 2+ S-E support, respectively. CONCLUSIONS: Provision of S-E support reduced LTFU and mortality, suggesting the value of incorporating such strategies for promoting continuity of care. PMID- 22217683 TI - [The Guest Editor's commentary]. PMID- 22217682 TI - Comparison of whole-body phantom designs to estimate organ equivalent neutron doses for secondary cancer risk assessment in proton therapy. AB - Secondary neutron fluence created during proton therapy can be a significant source of radiation exposure in organs distant from the treatment site, especially in pediatric patients. Various published studies have used computational phantoms to estimate neutron equivalent doses in proton therapy. In these simulations, whole-body patient representations were applied considering either generic whole-body phantoms or generic age- and gender-dependent phantoms. No studies to date have reported using patient-specific geometry information. The purpose of this study was to estimate the effects of patient-phantom matching when using computational pediatric phantoms. To achieve this goal, three sets of phantoms, including different ages and genders, were compared to the patients' whole-body CT. These sets consisted of pediatric age specific reference, age adjusted reference and anatomically sculpted phantoms. The neutron equivalent dose for a subset of out-of-field organs was calculated using the GEANT4 Monte Carlo toolkit, where proton fields were used to irradiate the cranium and the spine of all phantoms and the CT-segmented patient models. The maximum neutron equivalent dose per treatment absorbed dose was calculated and found to be on the order of 0 to 5 mSv Gy(-1). The relative dose difference between each phantom and their respective CT-segmented patient model for most organs showed a dependence on how close the phantom and patient heights were matched. The weight matching was found to have much smaller impact on the dose accuracy except for very heavy patients. Analysis of relative dose difference with respect to height difference suggested that phantom sculpting has a positive effect in terms of dose accuracy as long as the patient is close to the 50th percentile height and weight. Otherwise, the benefit of sculpting was masked by inherent uncertainties, i.e. variations in organ shapes, sizes and locations.Other sources of uncertainty included errors associated with beam positioning, neutron weighting factor definition and organ segmentation. This work demonstrated the importance of hybrid phantom height matching for more accurate organ dose calculation in proton therapy and the potential limitations of reference phantoms released by regulatory bodies for radiation therapy applications. PMID- 22217681 TI - Operational research to improve HIV prevention in the United States. AB - The HIV/AIDS epidemic in the United States continues despite several recent noteworthy advances in HIV prevention. Contemporary approaches to HIV prevention involve implementing combinations of biomedical, behavioral, and structural interventions in novel ways to achieve high levels of impact on the epidemic. Methods are needed to develop optimal combinations of approaches for improving efficiency, effectiveness, and scalability. This article argues that operational research offers promise as a valuable tool for addressing these issues. We define operational research relative to domestic HIV prevention, identify and illustrate how operational research can improve HIV prevention, and pose a series of questions to guide future operational research. Operational research can help achieve national HIV prevention goals of reducing new infections, improving access to care and optimization of health outcomes of people living with HIV, and reducing HIV-related health disparities. PMID- 22217684 TI - [Modern radiotherapy after breast-conserving surgery]. AB - In the last four decades breast-conserving surgery followed by whole breast irradiation has become the standard of care for the treatment of early-stage (0-I II) breast carcinoma. With the advent of breast-screening, incidence of breast carcinomas with more favorable prognostic characteristics has increased significantly. This change in the prognostic profile of newly diagnosed breast cancers opened a new horizon for clinical research seeking for individual risk adapted protocols of breast cancer radiotherapy. Several groups have been tested the efficacy of accelerated (partial or whole) breast irradiation, which has become the new treatment paradigm in the radiotherapy of early-stage breast cancers. Furthermore, others have attempted to identify subgroups of patients for whom radiotherapy after breast-conserving surgery could be safely omitted. Recently molecular gene expression assays have emerged as promising prognostic and predictive markers for local recurrence. This article reviews the results of these studies focusing on individual risk-adapted radiotherapy after breast conserving surgery for patients with early-stage breast carcinoma. PMID- 22217685 TI - [Modern pharmacological therapy of breast cancer]. AB - Healthy lifestyle, population-based screening mammography and modern medical oncological treatment in specialized breast cancer centers are the basic elements of the fight against breast cancer mortality. Treatment plan for the individual patient should be recommended by multidisciplinary oncoteam before initiating definitive therapy. Strategy of the medical-oncological therapy of breast cancer is determined by the biological features and stage of the tumor. The most important biological features are endocrine sensitivity, Human Epidermal Growth Factor Receptor 2 status and proliferative capability of the tumor. In this review the strategy of medical-oncological treatment (chemotherapy, endocrine therapy, targeted biological therapy) of breast cancer is presented, based on receptor status and proliferative capability of the tumor in various stages of the disease. PMID- 22217686 TI - [Novel oral anticancer drugs: a review of adverse drug reactions, interactions and patient adherence]. AB - Each aspect of oncological care is widely affected by the spread of oral anticancer agents, which raises several questions in terms of safe medication use and patient adherence. Over the past decade targeted therapies have appeared in clinical practice and revolutionized the pharmacological treatment of malignancies. Regular patient - doctor visits and proper patient education is crucial in order to comply with the therapy previously agreed upon with the oncologist, to increase patient adherence, to detect and to treat adverse effects in early stages. Since the information on the new medicines in Hungarian language is sparse it is the intention of the authors to give an overview of the basic knowledge, patient safety issues, adverse effects and interactions. Official drug information summaries and data on pharmacokinetics, interactions and adverse effects from the literature are reviewed as the basis for this overview. PMID- 22217688 TI - Is personality greater than education? PMID- 22217689 TI - Self-scheduling: help or hindrance? PMID- 22217690 TI - An EZ pass to hospital admissions. PMID- 22217691 TI - Overcoming the pitfalls of medication reconciliation. PMID- 22217692 TI - Nursing's role in IT projects. PMID- 22217694 TI - Visionary leader 2011. PMID- 22217695 TI - Round with purpose. PMID- 22217696 TI - Bedside reporting: dynamic dialogue. PMID- 22217697 TI - Human capital and process improvement. PMID- 22217698 TI - Position title: off-shift supervisor. PMID- 22217699 TI - Advancing your education. PMID- 22217701 TI - Targeted (and chemotherapeutic) agents as maintenance treatment in patients with metastatic non-small-cell lung cancer: current status and future challenges. AB - Maintenance treatment has been intensively investigated in the field of advanced/metastatic non-small lung cancer in order to improve outcomes in this devastating disease. Two different approaches have been evaluated; the so-called continuation maintenance when the maintenance agent was part of initial therapy and is continued in the absence of disease progression ("maintained") or switch maintenance when a third agent is initiated after a defined number of cycles chemotherapy in the absence of disease progression. Several phase III trials with both chemotherapeutic and targeted agents have demonstrated either PFS prolongation (continuation maintenance) or both PFS and OS benefit (switch maintenance). Currently, erlotinib and pemetrexed are registered as maintenance treatment in patients with NSCLC not progressing after four cycles of standard platinum-based doublet chemotherapy. However, the development of maintenance treatment has raised a series of questions such as the role of treatment-free intervals, the timing of second-line treatment, selection of patients for maintenance treatment and selection of the most proper agent, and trial design issues such as optimal end-points. The purpose of this paper is to present and discuss the current trials investigating the main treatment paradigms and argue on the above mentioned questions. PMID- 22217700 TI - Regulation of AMPA receptor trafficking and synaptic plasticity. AB - AMPA receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the brain. Dynamic changes in neuronal synaptic efficacy, termed synaptic plasticity, are thought to underlie information coding and storage in learning and memory. One major mechanism that regulates synaptic strength involves the tightly regulated trafficking of AMPARs into and out of synapses. The life cycle of AMPARs from their biosynthesis, membrane trafficking, and synaptic targeting to their degradation are controlled by a series of orchestrated interactions with numerous intracellular regulatory proteins. Here we review recent progress made toward the understanding the regulation of AMPAR trafficking, focusing on the roles of several key intracellular AMPAR interacting proteins. PMID- 22217702 TI - Separate and simultaneous binding effects through a non-cooperative behavior between cyclophosphamide hydrochloride and fluoxymesterone upon interaction with human serum albumin: multi-spectroscopic and molecular modeling approaches. AB - This study was designed to examine the interaction of two anti-breast cancer drugs, i.e., fluoxymesterone (FLU) and cyclophosphamide (CYC), with human serum albumin (HSA) using different kinds of spectroscopic, zeta potential and molecular modeling techniques under imitated physiological conditions. The RLS technique was utilized to investigate the effect of the two anticancer drugs on changes of the protein conformation, both separately and simultaneously. Our study suggested that the enhancement in RLS intensity was attributed to the formation of a new complex between the two drugs and the protein. Both drugs demonstrated a powerful ability to quench the fluorescence of HSA, and the fluorescence quenching action was much stronger when the two drugs coexisted. The quenching mechanism was suggested to be static as confirmed by time-resolved fluorescence spectroscopy results. The effect of both drugs on the conformation of HSA was analyzed using synchronous fluorescence spectroscopy. Our results revealed that the fluorescence quenching of HSA originated from the Trp and Tyr residues, and demonstrated a conformational change of HSA with the addition of both drugs. The binding distances between HSA and the drugs were estimated by the Forster theory, and it was revealed that nonradiative energy transfer from HSA to both drugs occurred with a high probability. According to CD measurements, the influence of both drugs on the secondary structure of HSA in aqueous solutions was also investigated and illustrated that the alpha-helix content of HSA decreased with increasing drug concentration in both systems. Moreover, the zeta potential experiments revealed that both drugs induced conformational changes on HSA. Docking studies were also performed and demonstrated that a reduction of the binding affinity between the drugs and HSA occurred in the presence of both drugs. PMID- 22217703 TI - Repeated isolation of Pseudomonas aeruginosa isolates resistant to both polymyxins and carbapenems from 1 patient. AB - Emergence of polymyxin resistance in carbapenem-resistant isolates is a great concern in clinical settings because it may mean the end of treatment options against Gram-negative bacterial infections. Polymyxin-nonsusceptible and susceptible Pseudomonas aeruginosa isolates resistant to carbapenems and harboring bla(IMP-6) were alternatively isolated from a patient. In vitro antimicrobial susceptibility testing, multilocus sequence typing, and pulsed field gel electrophoresis were performed. Metallo-beta-lactamase genes such as bla(IMP), bla(VIM), bla(SPM), bla(GIM), and bla(SIM) and bla(OXA-50) were detected by polymerase chain reaction. Sequences of 2-component systems, PmrAB and PhoPQ, were also determined. All showed ST235 and the same pulsotype. Amino acid substitutions were identified in PmrB and PhoP from polymyxin-nonsusceptible isolates. Colistin exposure might be associated with the recovery of polymyxin nonsusceptible isolates in this patient. PMID- 22217704 TI - Convenient and rapid removal of detergent from glycolipids in detergent-resistant membrane microdomains. AB - Although detergents are often essential in protocols, they are usually incompatible with further biochemical analysis. There are several methods for detergent removal, but the procedures are complicated or suffer from sample loss. Here, we describe a convenient and rapid method for detergent removal from sialic acid-containing glycosphingolipids (gangliosides) and neutral glycolipids in detergent-resistant membrane (DRM) microdomain. It is based on selective detergent extraction, in which the sample is dried on a glass tube, followed by washing with organic solvent. We investigated 18 organic solvents and used high performance thin-layer chromatography (HPTLC) and matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight mass spectrometry (MALDI QIT-TOF MS) to confirm that dichloroethane (DCE) was the most suitable solvent and completely removed the nonionic detergent Triton X-100. Furthermore, DCE extraction effectively removed interference caused by other nonionic, zwitterionic, or ionic detergents in MALDI-QIT-TOF MS analysis. PMID- 22217705 TI - Lysophosphatidic acids are new substrates for the phosphatase domain of soluble epoxide hydrolase. AB - Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that has a C-terminus epoxide hydrolase domain and an N-terminus phosphatase domain. The endogenous substrates of epoxide hydrolase are known to be epoxyeicosatrienoic acids, but the endogenous substrates of the phosphatase activity are not well understood. In this study, to explore the substrates of sEH, we investigated the inhibition of the phosphatase activity of sEH toward 4-methylumbelliferyl phosphate by using lecithin and its hydrolyzed products. Although lecithin itself did not inhibit the phosphatase activity, the hydrolyzed lecithin significantly inhibited it, suggesting that lysophospholipid or fatty acid can inhibit it. Next, we investigated the inhibition of phosphatase activity by lysophosphatidyl choline, palmitoyl lysophosphatidic acid, monopalmitoyl glycerol, and palmitic acid. Palmitoyl lysophosphatidic acid and fatty acid efficiently inhibited phosphatase activity, suggesting that lysophosphatidic acids (LPAs) are substrates for the phosphatase activity of sEH. As expected, palmitoyl, stearoyl, oleoyl, and arachidonoyl LPAs were efficiently dephosphorylated by sEH (Km, 3-7 MUM; Vmax, 150-193 nmol/min/mg). These results suggest that LPAs are substrates of sEH, which may regulate physiological functions of cells via their metabolism. PMID- 22217706 TI - The continued presence of stem cells and oogonia in the adult mammalian ovary. PMID- 22217707 TI - Mobile genetic elements and cancer. From mutations to gene therapy. AB - In the present review, an association between cancer and the activity of the non LTR retroelements L1, Alu, and SVA, as well as endogenous retroviruses, in the human genome, is analyzed. Data suggesting that transposons have been involved in embryogenesis and malignization processes, are presented. Events that lead to the activation of mobile elements in mammalian somatic cells, as well as the use of mobile elements in genetic screening and cancer gene therapy, are reviewed. PMID- 22217708 TI - Differential expression of PKD1 and PKD2 in gastric cancer and analysis of PKD1 and PKD2 function in the model system. AB - AIM: To study the differential expression of PKD1 and PKD2 in primary gastric cancer samples and to examine the role of PKD1 and PKD2 protein kinases in regulation of gastric tumor cell biology in the model system. METHODS: Tumor samples of different histological variants of primary gastric cancer were analyzed. PKD1 and PKD2 expression levels in tumor samples were accessed by Western blot analysis and quantitative polymerase chain reaction (Q-PCR). As a model system we have used gastric adenocarcinoma sell line AGS sublines constitutively transfected by pcDNA3.1 coding PKD1 or PKD2, or empty pcDNA3.1 vector. These cell lines were analyzed by Western blot, Q-PCR, MTT and proliferation assays, in vitro scratch and Transwell assays, clonogenic assay. RESULTS: It was found that primary gastric tumors possess different levels of PKD1 and PKD2 expression on mRNA and protein levels. Low level of PKD1 expression on protein and mRNA level was detected in low differentiated adenocarcinoma and ring cell gastric cancer - disorders with poor clinical prognosis. The high level of PKD2 expression was also found in gastric tumors with poor prognosis: low differentiated adenocarcinoma and adenogen cancer. To find out whether differential expression of PKD1 and PKD2 could affect biology of gastric tumor cells in vitro, we used a model system based on AGS cell line that constitutively expressed PKD1 or overexpressed PKD2. PKD1 transfection led to the inhibition of cell proliferation, migration and colony formation, in the meanwhile, the PKD2 overexpression enhanced proliferation, migration and colony formation capacities of AGS cells. CONCLUSIONS: Our data suggest that both downregulation of PKD1 or upregulation of PKD2 expression may determine the behavior of gastric tumor cells, which promotes invasive phenotype and could result in general poor prognosis. PMID- 22217709 TI - Nutrient mixture inhibits in vitro and in vivo growth of human acute promyelocytic leukemia HL-60 cells. AB - AIM: Untreated acute promyelocytic leukemia is the most malignant form of acute leukemias, with median survival of less than one month. We investigated in vitro and in vivo synergistic effects of a nutrient mixture (NM) containing ascorbic acid, lysine, proline, and green tea extract, on acute promyelocytic leukemia HL 60 cells. METHODS: In vitro, the HL-60 cells were cultured and exposed to NM at doses 0-1000 MUg/ml. Cell viability was assessed by Trypan blue dye exclusion test, matrix metalloproteinases (MMP) expression by gelatinase zymography, invasion through Matrigel and apoptosis by live green Poly Caspase Detection Kit. In vivo studies were carried out in athymic nude mice subcutaneously inoculated with HL-60 cells. RESULTS: In vitro, NM exhibited a dose dependent reduction in cells viability. Zymography revealed matrix MMP-2 and phorbol 12-myristate 13 acetate induced MMP-9 expression. NM inhibited expression of both MMP in a dose dependent manner. Similar step-wise reduction in the Matrigel invasion by HL-60 cells was also observed by this combination with incremental doses. Gradually increasing doses of NM induced significant apoptosis in HL-60 cells. In vivo, NM inhibited tumor growth by 50%. CONCLUSION: The results indicate that NM significantly suppresses tumor growth, decreases cell viability, inhibits MMP expression, Matrigel invasion and induces apoptosis in HL-60 cells. PMID- 22217710 TI - The influence of sodium dichloroacetate on the oxidative processes in sarcoma 37. AB - AIM: to study the activity of antioxidant enzymes and to evaluate an intensity of prooxidant processes in sarcoma 37 (S37) cells during tumor development and under influence of sodium dichloroacetate (SDA). METHODS: Activity of total superoxide dismutase (SOD), SOD isoforms, catalase (Cat), glutathione peroxidase (GP), and glutathione reductase (GR), as well as content of reduced glutathione (GSH) and lipid peroxidation (LP) secondary byproducts were determined in S37 homogenated tissues of untreated mice and animals treated with SDA at daily dose of 86 mg/kg. RESULTS: SDA treatment of S37-bearing mice resulted in the reduced activities of total SOD, SOD isoforms (especially Mn-SOD), Cat, GP and significantly decreased GSH content on the background of LP intensification in tumor tissue. CONCLUSION: The observed changes of oxidative homeostasis in S37-bearing animals treated with SDA could be considered as an element of antitumor action of SDA. PMID- 22217711 TI - Depressive-like psychoemotional state versus acute stresses enhances Lewis lung carcinoma metastasis in C57BL/6J mice. AB - AIM: The effect of a depression-like status formed by chronic stress on the development of Lewis lung carcinoma metastases in C57Bl/6J mice was investigated. Two types of acute stress (restraint and social stress) were used for comparison. METHODS: The depression-like status was induced by eight-week exposure to repeated but unpredictable stressors (chronic mild stress model) and was assessed in the forced swim test. Tumor cells were inoculated an hour after the onset of social stressor or immediately after physical or chronic stressor impacts. The number of metastases was counted 17 days after the inoculation. RESULTS: Chronic mild stress provokes the development of a depression-like state in mice and causes a twofold increase in the number of metastases in the lungs, while both types of acute stress have no such effects. CONCLUSION: Depressive-like psychoemotional state of animals enhances the metastasis of Lewis lung carcinoma. PMID- 22217712 TI - Ascorbate depletion increases growth and metastasis of melanoma cells in vitamin C deficient mice. AB - AIM: Our main objective was to determine the effect of ascorbate supplementation in mice unable to synthesize ascorbic acid (gulo KO) when challenged with murine B16FO cancer cells. METHODS: Gulo KO female mice 36-40 weeks of age were deprived of or maintained on ascorbate in food and water for 4 weeks prior to subcutaneous injection of 2.5*10(6) B16FO murine melanoma cells in the right flank of mice. A control group of wild type mice were also injected with the melanoma cells and maintained on a regular murine diet. Mice were continued on their respective diets for another 2 weeks after injection. The mice were then sacrificed, blood was drawn and their tumors were measured, excised and processed for histology. RESULTS: Mean weight of animals decreased significantly (30%, p < 0.0001) in the ascorbate-restricted group but increased slightly, but insignificantly, in the ascorbate-supplemented group. The mean tumor weight in ascorbate supplemented mice was significantly reduced (by 64%, p = 0.004) compared to tumor weight in ascorbate-deprived gulo mice. The mean tumor weight of wild type mice did not differ significantly from the ascorbate-supplemented mice. Gulo KO mice supplemented with ascorbate developed smaller tumors with more collagen encapsulation and fibrous capsule interdigitation, while gulo KO mice deprived of ascorbate hosted large tumors with poorly defined borders, showing more necrosis and mitosis. Ascorbate supplementation of gulo KO mice resulted in profoundly decreased serum inflammatory cytokine IL-6 (90% decrease, p = 0.04) and IL-1beta (62% decrease) compared to the levels in gulo KO mice deprived of ascorbate. CONCLUSION: Ascorbate supplementation modulated tumor growth and inflammatory cytokine secretion as well as enhanced encapsulation of tumors in scorbutic mice. PMID- 22217714 TI - Analysis of relative telomere length and apoptosis in humans exposed to ionising radiation. AB - BACKGROUND: Ionizing radiation could modify lymphocyte function via oxidative damage, DNA breaks, and resulting changes of proliferation, apoptosis and cellular senescence, where telomeres may play a critical role. AIM: To study the effect of low-dose irradiation on the telomere length and apoptosis rates in peripheral blood lymphocytes of irradiated persons. PATIENTS AND METHODS: A study was performed on 83 peripheral blood samples from the Chornobyl clean-up workers, radiation workers exposed under the professional limits at construction works at the "Shelter" object and healthy controls. Bone marrow leukocyte telomere length was estimated in 15 patients with myelodysplastic syndrome secondary to low-dose radiation exposure and 12 age-standardized healthy donors. Relative telomere length was studied by the combination of a fluorescence hybridization in situ with PNA probe and flow cytometry, apoptosis - by Annexin-V test. RESULTS: A significant relative telomere length decrease has been demonstrated in Chornobyl clean-up workers compared to healthy donors (13.2 +/- 0.69 and 18.6 +/- 0.73 respectively, p < 0.05), and a tendency (p < 0.1) in radiation workers. At doses over professional limits an inverse dependency is demonstrated between the relative telomere length and a number of lymphocytes in early stage of apoptosis. In MDS group a tendency of telomere elongation was demonstrated in bone marrow granulocytes in RAEB-t and RAEB as comparing with RA. CONCLUSION: This study shows telomere shortening after low-dose irradiation and preservation of these changes even 20 years after exposure. Apoptosis induction is possible by the telomere region changes at least in individuals with shorter telomeres. Apoptosis decrease in MDS clonal transformation is associated with a substantially longer telomeres. PMID- 22217713 TI - Cooperative antitumor effect of endothelial-monocyte activating polypeptide II and flutamide on human prostate cancer xenografts. AB - Recombinant cytokine-like endothelial monocyte-activating polypeptide II (EMAP II) and antiandrogen flutamide target different mechanisms of growth of androgen dependent prostate cancer (PC). The aim of this study was to clarify whether combined treatment with EMAP II and flutamide is more effective than monotherapy with regard to retardation of PC progression. MATERIALS AND METHODS: Antitumor effects of EMAP II (10 ug/kg b.w./d, s.c., 3d), or flutamide (10 mg/kg b.w./d, per os, 3d), or their combination were studied in CBA male mice bearing human androgen-dependent PC xenografts for 7 days. Androgen-dependent phenotype of the tumors was verified in preliminary castrated mice. The xenografts were weighed and underwent a histopathologic examination. The results were compared with those of non-treated mice. RESULTS: EMAP II and flutamide used separately inhibited growth of the xenografts by 74% and 53% respectively. Both drugs caused destructive changes in malignant epithelial cells along with leukocyte infiltration of the tumor. Combined treatment inhibited tumor growth by 85%, and was more effective than monotherapy with regard to morphological changes. CONCLUSIONS: This study demonstrates cooperative inhibitory effect of EMAP II and flutamide on growth and morphology of human PC xenografts that could represent a new modality of palliative treatment of this disease. PMID- 22217715 TI - Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient. AB - Progressive multifocal leukoencephalopathy (PML) is a neurological disease caused by infection of the central nervous system (CNS) with the JC polyomavirus (JCV). JCV is endemic and infects a large proportion (70-90%) of healthy individuals worldwide, but infection is latent. JCV reactivation may occur, if the immune function is compromised. AIM: To present a PML case in a CLL patient after a long course of disease and treatment with fludarabine. JCV virus infection in this patient was proven both in brain biopsy material and blood. METHODS: Patient with a nine-year history of CLL was hospitalized with the weakness in the right leg and left hand, tremors, speech difficulties. An MRI diagnosed infiltrative glial tumor of the left hemisphere, proliferating predominantly in the frontal lobe, more in the gyrus frontalis superior region. CNS tumor biopsy performed. RESULTS: Morphology and immunoprofile of the lesion consistent with progressive multifocal leukoencephalopathy. The material from biopsy was diagnosed as positive for JCV DNA. JCV and HHV-7 genomic sequences were found in patient's PBL DNA sample. In a plasma DNA sample, only genomic sequences were detected. CONCLUSION: The present case draws attention to the fact that the use of fludarabine and its combinations in CLL therapy increases the risk of JCV infection reactivation and development of serious complications like PML. PMID- 22217716 TI - Kikuchi--Fujimoto disease: cervical lymphadenopathy suggestive of relapsing lymphoma in patient with lymphoblastic lymphoma. AB - AIM: Kikuchi - Fujimoto disease (KFD) or histiocytic necrotizing lymphadenitis is a rare disorder and often confused with lymphoma. PATIENT: There is presented a case of 28-year-old patient with cervical lymphadenopathy, who had history of lymphoma. RESULTS: On immunohistopathologic examination diagnosis of KFD was made and patient followed without any treatment. CONCLUSION: Patient's lymphadenopathy had almost resolved and he was completely asymptomatic after three months. In patient with cervical lymphadenopathy KFD should be considered in the differential diagnosis. PMID- 22217717 TI - Frequency-dependent payoffs and sequential decision-making favour consistent tactic use. AB - Although natural selection should have favoured individuals capable of adjusting the weight they give to personal and social information according to circumstances, individuals generally differ consistently in their individual weighting of both types of information. Such individual differences are correlated with personality traits, suggesting that personality could directly affect individuals' ability to collect personal or social information. Alternatively, the link between personality and information use could simply emerge as a by-product of the sequential decision-making process in a frequency dependent context. Indeed, when the gains associated with behavioural options depend on the choices of others, an individual's sequence of arrival could constrain its choice of options leading to the emergence of correlated behaviours. Any factor such as personality that affects decision order could thus be correlated with information use. To test this new explanation, we developed an individual-based model that simulates a group of animals engaged in a game of sequential frequency-dependent decision: a producer-scrounger game. Our results confirm that the sequence of decision, in this case enforced by the order in which animals enter a foraging area, consistently influences their mean tactic use and their individual plasticity, an outcome reminiscent of the correlation reported between personality and social information use. PMID- 22217718 TI - On a collision course: competition and dispersal differences create no-analogue communities and cause extinctions during climate change. AB - Most climate change predictions omit species interactions and interspecific variation in dispersal. Here, we develop a model of multiple competing species along a warming climatic gradient that includes temperature-dependent competition, differences in niche breadth and interspecific differences in dispersal ability. Competition and dispersal differences decreased diversity and produced so-called 'no-analogue' communities, defined as a novel combination of species that does not currently co-occur. Climate change altered community richness the most when species had narrow niches, when mean community-wide dispersal rates were low and when species differed in dispersal abilities. With high interspecific dispersal variance, the best dispersers tracked climate change, out-competed slower dispersers and caused their extinction. Overall, competition slowed the advance of colonists into newly suitable habitats, creating lags in climate tracking. We predict that climate change will most threaten communities of species that have narrow niches (e.g. tropics), vary in dispersal (most communities) and compete strongly. Current forecasts probably underestimate climate change impacts on biodiversity by neglecting competition and dispersal differences. PMID- 22217719 TI - The sound of one-hand clapping: handedness and perisylvian neural correlates of a communicative gesture in chimpanzees. AB - Whether lateralization of communicative signalling in non-human primates might constitute prerequisites of hemispheric specialization for language is unclear. In the present study, we examined (i) hand preference for a communicative gesture (clapping in 94 captive chimpanzees from two research facilities) and (ii) the in vivo magnetic resonance imaging brain scans of 40 of these individuals. The preferred hand for clapping was defined as the one in the upper position when the two hands came together. Using computer manual tracing of regions of interest, we measured the neuroanatomical asymmetries for the homologues of key language areas, including the inferior frontal gyrus (IFG) and planum temporale (PT). When considering the entire sample, there was a predominance of right-handedness for clapping and the distribution of right- and left-handed individuals did not differ between the two facilities. The direction of hand preference (right- versus left-handed subjects) for clapping explained a significant portion of variability in asymmetries of the PT and IFG. The results are consistent with the view that gestural communication in the common ancestor may have been a precursor of language and its cerebral substrates in modern humans. PMID- 22217720 TI - Diversification and the adaptive radiation of the vangas of Madagascar. AB - The vangas of Madagascar exhibit extreme diversity in morphology and ecology. Recent studies have shown that several other Malagasy species also are part of this endemic radiation, even as the monophyly of the clade remains in question. Using DNA sequences from 13 genes and representatives of all 15 vanga genera, we find strong support for the monophyly of the Malagasy vangids and their inclusion in a family along with six aberrant genera of shrike-like corvoids distributed in Asia and Africa. Biogeographic reconstructions of these lineages include both Asia and Africa as possible dispersal routes to Madagascar. To study patterns of speciation through time, we introduce a method that can accommodate phylogenetically non-random patterns of incomplete taxon sampling in diversification studies. We demonstrate that speciation rates in vangas decreased dramatically through time following the colonization of Madagascar. Foraging strategies of these birds show remarkable congruence with phylogenetic relationships, indicating that adaptations to feeding specializations played a role in the diversification of these birds. Vangas fit the model of an 'adaptive radiation' in that they show an explosive burst of speciation soon after colonization, increased diversification into novel niches and extraordinary ecomorphological diversity. PMID- 22217721 TI - Critical thresholds in sea lice epidemics: evidence, sensitivity and subcritical estimation. AB - Host density thresholds are a fundamental component of the population dynamics of pathogens, but empirical evidence and estimates are lacking. We studied host density thresholds in the dynamics of ectoparasitic sea lice (Lepeophtheirus salmonis) on salmon farms. Empirical examples include a 1994 epidemic in Atlantic Canada and a 2001 epidemic in Pacific Canada. A mathematical model suggests dynamics of lice are governed by a stable endemic equilibrium until the critical host density threshold drops owing to environmental change, or is exceeded by stocking, causing epidemics that require rapid harvest or treatment. Sensitivity analysis of the critical threshold suggests variation in dependence on biotic parameters and high sensitivity to temperature and salinity. We provide a method for estimating the critical threshold from parasite abundances at subcritical host densities and estimate the critical threshold and transmission coefficient for the two epidemics. Host density thresholds may be a fundamental component of disease dynamics in coastal seas where salmon farming occurs. PMID- 22217722 TI - Crows cross-modally recognize group members but not non-group members. AB - Recognizing other individuals by integrating different sensory modalities is a crucial ability of social animals, including humans. Although cross-modal individual recognition has been demonstrated in mammals, the extent of its use by birds remains unknown. Herein, we report the first evidence of cross-modal recognition of group members by a highly social bird, the large-billed crow (Corvus macrorhynchos). A cross-modal expectancy violation paradigm was used to test whether crows were sensitive to identity congruence between visual presentation of a group member and the subsequent playback of a contact call. Crows looked more rapidly and for a longer duration when the visual and auditory stimuli were incongruent than when congruent. Moreover, these responses were not observed with non-group member stimuli. These results indicate that crows spontaneously associate visual and auditory information of group members but not of non-group members, which is a demonstration of cross-modal audiovisual recognition of group members in birds. PMID- 22217723 TI - The role of robustness in phenotypic adaptation and innovation. AB - Phenotypes that vary in response to DNA mutations are essential for evolutionary adaptation and innovation. Therefore, it seems that robustness, a lack of phenotypic variability, must hinder adaptation. The main purpose of this review is to show why this is not necessarily correct. There are two reasons. The first is that robustness causes the existence of genotype networks--large connected sets of genotypes with the same phenotype. I discuss why genotype networks facilitate phenotypic variability. The second reason emerges from the evolutionary dynamics of evolving populations on genotype networks. I discuss how these dynamics can render highly robust phenotypes more variable, using examples from protein and RNA macromolecules. In addition, robustness can help avoid an important evolutionary conflict between the interests of individuals and populations-a conflict that can impede evolutionary adaptation. PMID- 22217724 TI - How do communication systems emerge? AB - Communication involves a pair of behaviours--a signal and a response--that are functionally interdependent. Consequently, the emergence of communication involves a chicken-and-egg problem: if signals and responses are dependent on one another, then how does such a relationship emerge in the first place? The empirical literature suggests two solutions to this problem: ritualization and sensory manipulation; and instances of ritualization appear to be more common. However, it is not clear from a theoretical perspective why this should be the case, nor if there are any other routes to communication. Here, we develop an analytical model to examine how communication can emerge. We show that: (i) a state of non-interaction is evolutionarily stable, and so communication will not necessarily emerge even when it is in both parties' interest; (ii) the conditions for sensory manipulation are more stringent than for ritualization, and hence ritualization is likely to be more common; and (iii) communication can arise by a third route, when the intention to communicate can itself be communicated, but this may be limited to humans. More generally, our results demonstrate the utility of a functional approach to communication. PMID- 22217725 TI - Genetic consequences of climate change for northern plants. AB - Climate change will lead to loss of range for many species, and thus to loss of genetic diversity crucial for their long-term persistence. We analysed range-wide genetic diversity (amplified fragment length polymorphisms) in 9581 samples from 1200 populations of 27 northern plant species, to assess genetic consequences of range reduction and potential association with species traits. We used species distribution modelling (SDM, eight techniques, two global circulation models and two emission scenarios) to predict loss of range and genetic diversity by 2080. Loss of genetic diversity varied considerably among species, and this variation could be explained by dispersal adaptation (up to 57%) and by genetic differentiation among populations (F(ST); up to 61%). Herbs lacking adaptations for long-distance dispersal were estimated to lose genetic diversity at higher rate than dwarf shrubs adapted to long-distance dispersal. The expected range reduction in these 27 northern species was larger than reported for temperate plants, and all were predicted to lose genetic diversity according to at least one scenario. SDM combined with F(ST) estimates and/or with species trait information thus allows the prediction of species' vulnerability to climate change, aiding rational prioritization of conservation efforts. PMID- 22217727 TI - How to finance your dreams of further education. PMID- 22217726 TI - Lateralization of face processing in the human brain. AB - Are visual face processing mechanisms the same in the left and right cerebral hemispheres? The possibility of such 'duplicated processing' seems puzzling in terms of neural resource usage, and we currently lack a precise characterization of the lateral differences in face processing. To address this need, we have undertaken a three-pronged approach. Using functional magnetic resonance imaging, we assessed cortical sensitivity to facial semblance, the modulatory effects of context and temporal response dynamics. Results on all three fronts revealed systematic hemispheric differences. We found that: (i) activation patterns in the left fusiform gyrus correlate with image-level face-semblance, while those in the right correlate with categorical face/non-face judgements. (ii) Context exerts significant excitatory/inhibitory influence in the left, but has limited effect on the right. (iii) Face-selectivity persists in the right even after activity on the left has returned to baseline. These results provide important clues regarding the functional architecture of face processing, suggesting that the left hemisphere is involved in processing 'low-level' face semblance, and perhaps is a precursor to categorical 'deep' analyses on the right. PMID- 22217728 TI - Nutrition in Colombian pregnant women. AB - OBJECTIVE: The present study aimed to evaluate the nutritional status of pregnant women in Colombia and the associations between gestational BMI and sociodemographic and gestational characteristics. DESIGN: Cross-sectional study. A secondary analysis was made of data from the 2005 Demographic and Health Survey of Colombia. SETTING: Bogota, Colombia. SUBJECTS: Pregnant adolescents aged 13-19 years (n 430) and pregnant women aged 20-49 years (n 1272). RESULTS: The gestational BMI and sociodemographic characteristics of the adolescents differed from those of the pregnant adult women. Thirty-one per cent of the adolescents were underweight for gestational age, compared with 14.5 % of the adult women. Eighteen per cent of adolescents were overweight for gestational age, in contrast to 37.3 % of adult women. The overall prevalence of anaemia was 44.7 % and the prevalence of low serum ferritin was 38.8 %. Women within the high quintiles of the wealth index (prevalence odds ratio (POR) = 0.56; 95 % CI 0.34, 0.91, P < 0.02) had lower odds of being underweight. Women who received prenatal care (POR = 2.17; 95 % CI 1.48, 3.09, P < 0.001) and were multiparous (POR = 2.10; 95 % CI 1.43, 3.15, P < 0.0 0 1) had higher odds of being overweight. Women in extended families (POR = 0.63; 95 % CI 0.50, 0.95, P < 0.025) had lower odds of being overweight. CONCLUSIONS: Underweight in pregnant adolescents and overweight in adult women coexist as a double burden in Colombia. Factors associated with malnutrition among pregnant women and adolescents should be considered for future interventions in countries experiencing nutritional transition. PMID- 22217729 TI - Recovery of silver from wastewater coupled with power generation using a microbial fuel cell. AB - A cost-effective microbial fuel cell (MFC) system was developed in order to recover silver metal from silver ion containing wastewaters. After 8h reaction, silver metal recovery efficiencies as high as 99.91 +/- 0.00%-98.26 +/- 0.01% were achieved. The initial concentrations were from 50 ppm to 200 ppm with a load resistor of 1000 Omega. In the batch-fed cathode and continuous-fed anode system with an initial silver concentration of 200 ppm, discharge curves display the production of both silver metal and electric energy at a rate of 69.9 kg silver per KWh energy output. The maximum power of about 4.25 W/m(2), maximum voltage of 0.749 V, maximum current density of 5.67 A/m(2), and a fill factor of 0.626 were achieved at 1000 ppm initial silver ion concentration. PMID- 22217730 TI - Biosorption and bio-kinetic studies of halobacterial strains against Ni2+, Al3+ and Hg2+ metal ions. AB - The present study is an attempt to find out the promising metal (Ni(2+), Al(3+), and Hg(2+)) biosorbant halobacterial strains from saltern pan and to study their biokinetic parameters for metal recovery. Of the selected 65 isolates, Natronobacterium magadii, Natronococcus occultus and Halobacterium sodomense shows the maximum metal resistance activity against Ni(2+) (250 ppm), Al(3+) (600 ppm) and Hg(2+) (25 ppm) metals. Biokinetic parameters such as maximum specific growth rate (MU(max)), substrate removable [S] rate, half velocity constant (K(s)), endogenous or decay co-efficient (k(d)), yield co-efficient rate (Yd(-1)) are also analyzed for the selected metals. Further the results of the SEM-EDS analysis confirms the metals uptake of Ni(2+) and Al(3+) in higher concentration and Hg(2+) in lower concentration. It is concluded from the present study that, the biosorption of heavy metals by solar saltern halobacteria can be used as a potential source for the bioremediation of metals. PMID- 22217732 TI - Production of fumaric acid by simultaneous saccharification and fermentation of starchy materials with 2-deoxyglucose-resistant mutant strains of Rhizopus oryzae. AB - A mutant strain with high glucoamylase activity and insensitive to catabolite repression was developed to produce fumaric acid by simultaneous saccharification and fermentation (SSF) of starch without additional commercial glucoamylase supplementation. A series of mutant strains resistant to the non-metabolizable and toxic glucose analog 2-deoxyglucose (2-DG) were obtained by implanting nitrogen ion (N(+)) into Rhizopus oryzae ME-F12. Among them, the best mutant strain DG-3 produced 39.80 g/L fumaric acid, which is 1.28-fold of that produced by ME-F12, and exhibited higher glucoamylase activity during SSF. Higher fumaric acid production (44.10 g/L) was achieved when the initial total sugar concentration of cornstarch was 100g/L. During SSF of cheap, raw bioresource degermed corn powder (100g/L total sugar) by DG-3, the maximum fumaric acid concentration and productivity were 32.18 g/L and 0.44 g/(Lh), respectively. PMID- 22217733 TI - Naphthalene degradation by bacterial consortium (DV-AL) developed from Alang Sosiya ship breaking yard, Gujarat, India. AB - Naphthalene degrading bacterial consortium (DV-AL) was developed by enrichment culture technique from sediment collected from the Alang-Sosiya ship breaking yard, Gujarat, India. The 16S rRNA gene based molecular analyzes revealed that the bacterial consortium (DV-AL) consisted of four strains namely, Achromobacter sp. BAB239, Pseudomonas sp. DV-AL2, Enterobacter sp. BAB240 and Pseudomonas sp. BAB241. Consortium DV-AL was able to degrade 1000 ppm of naphthalene in Bushnell Haas medium (BHM) containing peptone (0.1%) as co-substrate with an initial pH of 8.0 at 37 degrees C under shaking conditions (150 rpm) within 24h. Maximum growth rate and naphthalene degradation rate were found to be 0.0389 h(-1) and 80 mg h( 1), respectively. Consortium DV-AL was able to utilize other aromatic and aliphatic hydrocarbons such as benzene, phenol, carbazole, petroleum oil, diesel fuel, and phenanthrene and 2-methyl naphthalene as sole carbon source. Consortium DV-AL was also efficient to degrade naphthalene in the presence of other pollutants such as petroleum hydrocarbons and heavy metals. PMID- 22217734 TI - Ferrate treatment for inactivation of bacterial community in municipal secondary effluent. AB - This paper demonstrates the effect of ferrate [Fe(VI)-compound], an environmental friendly multi-purpose reagent, in municipal secondary effluent treatment. The purpose was to study the inactivation capability of ferrate and for the first time to compare the effect and efficiency of Fe(VI) with the widely used disinfectant, chlorine gas on the indigenous bacterial community in the case of secondary effluents. The most probable number technique (MPN) was applied for the determination of cultivable heterotrophic bacterial abundance and terminal restriction fragment length polymorphism (T-RFLP) analysis for comparing bacterial communities. The study demonstrated that (i) ferrate and chlorine had different effect on the total bacterial community of secondary effluents, (ii) low ferrate dose [5 mg L(-1) Fe(VI)] was sufficient for >99.9% reduction of indigenous bacteria, and (iii) a similar dosage was also effective in the inactivation of chlorine-resistant bacteria. PMID- 22217735 TI - A free database of radionuclide voxel S values for the dosimetry of nonuniform activity distributions. AB - The increasing availability of SPECT/CT devices with advanced technology offers the opportunity for the accurate assessment of the radiation dose to the biological target volume during radionuclide therapy. Voxel dosimetry can be performed employing direct Monte Carlo radiation transport simulations, based on both morphological and functional images of the patient. On the other hand, for voxel dosimetry calculations the voxel S value method can be considered an easier approach than patient-specific Monte Carlo simulations, ensuring a good dosimetric accuracy at least for anatomic regions which are characterized by uniform density tissue. However, this approach has been limited because of the lack of tabulated S values for different voxel dimensions and radionuclides. The aim of this work is to provide a free dataset of values which can be used for voxel dosimetry in targeted radionuclide studies. Seven different radionuclides (89Sr, 90Y, 131I, 153Sm, 177Lu, 186Re, 188Re), and 13 different voxel sizes (2.21, 2.33, 2.4, 3, 3.59, 3.9, 4, 4.42, 4.8, 5, 6, 6.8 and 9.28 mm) are considered. Voxel S values are calculated performing simulations of monochromatic photon and electron sources in two different homogeneous tissues (soft tissue and bone) with DOSXYZnrc code, and weighting the contributions on the basis of the radionuclide emission spectra. The outcomes are validated by comparison with Monte Carlo simulations obtained with other codes (PENELOPE and MCNP4c) performing direct simulation of the radionuclide emission spectra. The differences among the different Monte Carlo codes are of the order of a few per cent when considering the source voxel and the bremsstrahlung tail, whereas the highest differences are observed at a distance close to the maximum continuous slowing down approximation range of electrons. These discrepancies would negligibly affect dosimetric assessments. The dataset of voxel S values can be freely downloaded from the website www.medphys.it. PMID- 22217736 TI - Shining a light on xeroderma pigmentosum. AB - Xeroderma pigmentosum (XP) is a rare, autosomal recessive disorder of DNA repair characterized by sun sensitivity and UV radiation-induced skin and mucous membrane cancers. Initially described in 1874 by Moriz Kaposi in Vienna, nearly 100 years later, James Cleaver in San Francisco reported defective DNA repair in XP cells. This eventually provided the basis for a mechanistic link between sun exposure, DNA damage, somatic mutations, and skin cancer. XP cells were found to have defects in seven of the proteins of the nucleotide excision repair pathway and in DNA polymerase eta. XP cells are hypersensitive to killing by UV radiation, and XP cancers have characteristic "UV signature" mutations. Clinical studies at the National Institutes of Health found a nearly 10,000-fold increase in skin cancer in XP patients under the age of 20 years, demonstrating the substantial importance of DNA repair in cancer prevention in the general population. Approximately 25% of XP patients have progressive neurological degeneration with progressive loss of neurons, probably from DNA damage induced by oxidative metabolism, which kills nondividing cells in the nervous system. Interestingly, patients with another disorder, trichothiodystrophy, have defects in some of the same genes as XP, but they have primary developmental abnormalities without an increase in skin cancer. PMID- 22217731 TI - Transcriptome analysis of an oil-rich race B strain of Botryococcus braunii (BOT 70) by de novo assembly of 5'-end sequences of full-length cDNA clones. AB - Here the transcriptome of an oil-rich race B strain of Botryococcus braunii (BOT 70) was analyzed to mine genetic information useful in biofuel development. A full-length-enriched cDNA library was constructed via the oligo-capping method and the 5' ends of 11,904 randomly chosen cDNA clones were sequenced. Homology search using BLASTX identified candidate BOT-70 genes for majority of the reactions required for biosynthesis of botryococcenes through the mevalonate independent pathway. The sequence retrieval from the transcriptome dataset implicated that an alternative entry route into the mevalonate-independent pathway via xylulose-5-phosphate, rather than the conventional entry route via 1 deoxy-d-xylulose-5-phosphate, is predominantly active. Analysis of N-terminal sequences of the retrieved genes indicated that the final reactions of botryococcene biosynthesis are likely to take place outside of chloroplasts. The transcriptome dataset has been deposited in the GenBank/EMBL/DDBJ database. PMID- 22217737 TI - Skin barrier disruption: a requirement for allergen sensitization? AB - For at least half a century, noninvasive techniques have been available to quantify skin barrier function, and these have shown that a number of human skin conditions and disorders are associated with defects in skin permeability. In the past decade, several genes responsible for skin barrier defects observed in both monogenetic and complex polygenic disorders have been elucidated and functionally characterized. This has led to an explosion of work in the past 6 years that has identified pathways connecting epidermal barrier disruption and antigen uptake, as well as the quality and/or magnitude of the antigen-specific adaptive immune response. This review will introduce the notion that diseases arise from the dynamic crosstalk that occurs between skin barrier and the immune system using atopic dermatitis or eczema as the disease prototype. Nevertheless, the concepts put forth are highly relevant to a number of antigen-driven disorders for which skin barrier is at least transiently compromised, such as psoriasis, allergic contact dermatitis, and blistering disorders. PMID- 22217739 TI - Melanoma: new insights and new therapies. AB - Metastatic melanoma has historically been considered as one of the most therapeutically challenging malignancies. However, for the first time after decades of basic research and clinical investigation, new drugs have produced major clinical responses. The discovery of BRAF mutations in melanoma created the first opportunity to develop oncogene-directed therapy in this disease and led to the development of compounds that inhibit aberrant BRAF activity. A decade later, vemurafenib, an orally available and well-tolerated selective BRAF inhibitor, ushered in a new era of molecular treatments for advanced disease. Additional targets have been identified, and novel agents that impact on various signaling pathways or modulate the immune system hold the promise of a whole new therapeutic landscape for patients with metastatic melanoma. One of the major thrusts in melanoma therapy is now focused on understanding and targeting the network of signal transduction pathways and on attacking elements that underlie the tumor's propensity for growth and chemoresistance. In this article, we review the novel targeted anticancer approaches that are under consideration in melanoma treatment. PMID- 22217741 TI - Changing views of the role of Langerhans cells. AB - Langerhans cells (LCs) have long been considered to be the major sensitizing cells in the skin by initiating productive immunity in naive resting T cells. This picture has changed over the past decade. We now know (i) that the skin also harbors other types of dendritic antigen-presenting cells and (ii) that the genetically driven removal of the LC population results in increased T-cell immunity against haptens and infectious agents. It is not clear at present whether the situation in genetically modified mice is in any way indicative of the actual in vivo function of LCs. Exciting and challenging years lie ahead of the LC research community. PMID- 22217740 TI - Evaluation of reliability, validity, and responsiveness of the CDASI and the CAT BM. AB - To properly evaluate therapies for cutaneous dermatomyositis (DM), it is essential to administer an outcome instrument that is reliable, valid, and responsive to clinical change, particularly when measuring disease activity. The purpose of this study was to compare two skin severity DM outcome measures, the Cutaneous Disease and Activity Severity Index (CDASI) and the Cutaneous Assessment Tool-Binary Method (CAT-BM), with the Physician Global Assessment (PGA) as the "gold standard". Ten dermatologists evaluated 14 patients with DM using the CDASI, CAT-BM, and PGA scales. Inter- and intra-rater reliability, validity, responsiveness, and completion time were compared for each outcome instrument. Responsiveness was assessed from a different study population, where one physician evaluated 35 patients with 110 visits. The CDASI was found to have a higher inter- and intra-rater reliability. Regarding construct validity, both the CDASI and the CAT-BM were significant predictors of the PGA scales. The CDASI had the best responsiveness among the three outcome instruments examined. The CDASI had a statistically longer completion time than the CAT-BM by about 1.5 minutes. The small patient population may limit the external validity of the findings observed. The CDASI is a better clinical tool to assess skin severity in DM. PMID- 22217738 TI - Applications of nanotechnology in dermatology. AB - What are nanoparticles and why are they important in dermatology? These questions are addressed by highlighting recent developments in the nanotechnology field that have increased the potential for intentional and unintentional nanoparticle skin exposure. The role of environmental factors in the interaction of nanoparticles with skin and the potential mechanisms by which nanoparticles may influence skin response to environmental factors are discussed. Trends emerging from recent literature suggest that the positive benefit of engineered nanoparticles for use in cosmetics and as tools for understanding skin biology and curing skin disease outweigh potential toxicity concerns. Discoveries reported in this journal are highlighted. This review begins with a general introduction to the field of nanotechnology and nanomedicine. This is followed by a discussion of the current state of understanding of nanoparticle skin penetration and their use in three therapeutic applications. Challenges that must be overcome to derive clinical benefit from the application of nanotechnology to skin are discussed last, providing perspective on the significant opportunity that exists for future studies in investigative dermatology. PMID- 22217742 TI - The epidermis as an adjuvant. AB - It is now clear that the epidermis has an active role in local immune responses in the skin. Keratinocytes are involved early in inflammation by providing first line innate mechanisms and, in addition, can contribute to adaptive immune responses that may be associated with clinical disease. Moreover, keratinocytes are capable of enhancing and shaping the outcome of inflammation in response to stimuli and promoting particular types of immune bias. Through understanding the underlying mechanisms, the role of keratinocytes in disease pathogenesis will be further defined, which is likely to lead to the identification of potential targets for prophylactic or therapeutic intervention. PMID- 22217744 TI - Chronology of metastasis in cutaneous melanoma: growth rate model. AB - In humans, it is not possible to obtain experimental evidence of when a cancer begins to metastasize. The purpose of this study was to estimate the time of onset of metastatic dissemination in cutaneous melanoma using a model based on its growth rate (GR). The critical time of onset of metastatic dissemination below which no cases of fatal melanomas were seen may be described with a potential function in which this time is inversely proportional to the GR. The critical time of development beyond which a melanoma may metastasize presents great variation. This time was just 1 month for those melanomas with a fast GR, whereas it was over 5 years for those with a very slow GR. Quantitatively, the fastest-growing melanomas began metastasizing with a greater thickness than the slowest-growing melanomas. A correlation exists between the critical time of onset of metastatic potential and the GR of the melanoma. These results may well have relevance to the understanding of mechanisms of tumor dissemination and for the design of future studies on melanomas, irrespective of whether they are basic studies on biomolecular mechamisms or clinical studies. PMID- 22217743 TI - Ionizing radiation: the good, the bad, and the ugly. AB - Skin changes caused by ionizing radiation have been scientifically documented since 1902. Ionizing radiation is a widely accepted form of treatment for various types of cancer. Despite the technological advances, radiation skin injury remains a significant problem. This injury, often referred to as radiation dermatitis, occurs in about 95% of patients receiving radiation therapy for cancer, and ranges in severity from mild erythema to moist desquamation and ulceration. Ionizing radiation is not only a concern for cancer patients, but also a public health concern because of the potential for and reality of a nuclear and/or radiological event. Recently, the United States has increased efforts to develop medical countermeasures to protect against radiation toxicities from acts of bioterrorism, as well as cancer treatment. Management of radiation dermatitis would improve the therapeutic benefit of radiation therapy for cancer and potentially the mortality expected in any "dirty bomb" attack. Currently, there is no effective treatment to prevent or mitigate radiation skin injury. This review summarizes "the good, the bad, and the ugly" of current and evolving knowledge regarding mechanisms of and treatments for radiation skin injury. PMID- 22217745 TI - Steroidal glycoalkaloids in Solanum chacoense. AB - Potato (Solanum tuberosum L.), a domesticated species that is the fourth most important world agricultural commodity, requires significant management to minimize the effects of herbivore and pathogen damage on crop yield. A wild relative, Solanum chacoense Bitt., has been of interest to plant breeders because it produces an abundance of novel steroidal glycoalkaloid compounds, leptines and leptinines, which are particularly effective deterrents of herbivory by the Colorado potato beetle (Leptinotarsa decemlineata Say). Biochemical approaches were used in this study to investigate the formation and accumulation of SGAs in S. chacoense. SGA contents were determined in various organs at different stages of organ maturity during a time course of plant development. Leptines and leptinines were the main contributors to the increased levels in SGA concentration measured in the aerial versus the subterranean organs of S. chacoense accession 8380-1. Leptines were not detected in aboveground stolons until the stage where shoots had formed mature chlorophyllous leaves. To gain insights into SGA biosynthesis, the abundance of SGAs and steady-state transcripts of genes coding for enzymes of the central terpene and SGA-specific pathways in various plant organs at anthesis were compared. For two genes of primary terpene metabolism, transcript and SGA abundances were correlated, although with some discrepancies. For genes associated with SGA biosynthesis, transcripts were not detected in some tissues containing SGAs; however these transcripts were detected in the progenitor tissues, indicating the possibility that under our standard growth conditions, SGA biosynthesis is largely limited to highly proliferative tissues such as shoot, root and floral meristems. PMID- 22217746 TI - Irreplaceable mortality: is it? PMID- 22217748 TI - The prevalence of 'Candidatus Arsenophonus phytopathogenicus' infecting the planthopper Pentastiridius leporinus (Hemiptera: Cixiidae) increase nonlinearly with the population abundance in sugar beet fields. AB - The planthopper Pentastiridius leporinus (L.) (Hemiptera: Cixiidae) has been identified as the main vector of 'Candidatus Arsenophonus phytopathogenicus', a plant pathogenic bacterium associated to a sugar beet disease in eastern France called syndrome 'basses richesses'. In a 2-yr survey (2006-07), we quantified the abundance of P. leporinus populations migrating into 29 sugar beet fields in eastern France. Sticky traps posted in these fields were monitored on a twice weekly (2006) or weekly (2007) basis. Subsets of the captured planthoppers were tested for the presence of Ca. A. phytopathogenicus through polymerase chain reaction (PCR). Our results showed that planthoppers colonized sugar beet fields in June and July of each year, following temporal patterns of migration that were fitted to logistic functions. The number of planthoppers migrating into sugar beet fields greatly varied among the fields and the years surveyed, averaging from a few (2-10) to over 400 planthoppers per trap. Interestingly, the prevalence of planthoppers infected by Ca. A. phytopathogenicus increased nonlinearly with the abundance of planthoppers captured on the traps. The proportion of infection for Ca. A. phytopathogenicus ranged from ?0.07-1 (total infection) in small (2-10 planthoppers per trap) and large (400 planthoppers per trap) populations, respectively. We hypothesize that the outbreaks of P. leporinus in sugar beet fields, and the consequent increased rates of planthoppers infected by the Ca. A. phytopathogenicus, are key factors leading to the emergence of the sugar beet disease in eastern France. PMID- 22217749 TI - Differences in body size and egg loads of Rhagoletis indifferens (Diptera: Tephritidae) from introduced and native cherries. AB - The western cherry fruit fly, Rhagoletis indifferens Curran, infests introduced, domesticated sweet [Prunus avium (L.) L.], and tart cherries (Prunus cerasus L.) as well as native bitter cherry, Prunus emarginata (Douglas) Eaton. Bitter cherries are smaller than sweet and tart cherries and this could affect various life history traits of flies. The objectives of the current study were to determine 1) if body size and egg loads of flies infesting sweet, tart, and bitter cherries differ from one another; and 2) if any observed body size differences are genetically based or caused by the host fruit environment. Pupae and adults of both sexes reared from larval-infested sweet and tart cherries collected in Washington and Montana were larger than those reared from bitter cherries. In addition, flies of both sexes caught on traps in sweet and tart cherry trees were larger than those caught in bitter cherry trees and females trapped from sweet and tart cherry trees had 54.0-98.8% more eggs. The progeny of flies from naturally-infested sweet and bitter cherries reared for one generation in the laboratory on sweet cherry did not differ in size. The same also was true for progeny of sweet and bitter cherry flies reared in the field on bitter cherry. The results suggest that the larger body sizes of flies from sweet and tart cherries than bitter cherries in the field are caused by host fruit and not genetic factors. PMID- 22217750 TI - Attack pattern of Platypus koryoensis (Coleoptera: Curculionidae: Platypodinae) in relation to crown dieback of Mongolian oak in Korea. AB - The ambrosia beetle, Platypus koryoensis (Murayama), vectors the Korean oak wilt (KOW) pathogen, Raffaelea quercus-mongolicae K.H. Kim, Y.J. Choi, & H.D. Shin, in Korea, which is highly lethal to Mongolian oak, Quercus mongolica Fisch., and is considered a major threat to forest ecosystem health. We characterized the attack pattern of P. koryoensis along the lower trunk of 240 Mongolian oaks in relation to tree decline symptoms on Mt. Uam in Gyeonggi-Do Province, Korea during June-July 2009. For each tree, we recorded diameter at breast height (dbh) (DBH) and P. koryoensis entrance hole density at two heights along the lower trunk (near groundline and at 1.5 m above groundline) and on opposite sides (downslope side and upslope side). Trees were assigned to one of three dieback classes: 1) apparently healthy, no or practically no wilted foliage, and no obvious platypodine frass near the base of the tree; 2) no or only partial wilting with obvious frass near the base of the tree; and 3) apparently recently killed by KOW with all foliage wilted and mostly retained with obvious frass near the base of the tree. As dieback class increased from 1 to 3, P. koryoensis entrance hole density increased at all four trunk locations. Attack density was highest on the downslope side of the trunk near groundline, and principal component analysis indicated that this trunk location was the best indicator of tree dieback. In addition, DBH tended to increase with dieback class suggesting that larger trees were infested first. PMID- 22217751 TI - Abundance, age structure, and voltinism of light brown apple moth populations in California. AB - The light brown apple moth, Epiphyas postvittana (Walker), is native to Australia and first was detected in California in 2006. In this study, we regularly sampled populations on Leptospermum laevigatum (Gaertn.) F.Muell. at two sites in San Francisco and on Arctostaphylos densiflora M.S. Baker at two sites in Santa Cruz over a 2-yr period to monitor the abundance, age structure, and voltinism of this potential pest in relation to degree-days. Our results showed that larval abundance declined at two sites, cycled with peaks in midsummer at one site, and remained steady at one site. Generations overlapped at all four sites with the full range of larval instars being present for most of the year, although populations during the winter were predominantly mid to late instars. Accumulated degree-days predict an average of 3.27 and 4.58 generations per year in San Francisco and Santa Cruz, respectively, which matched our observed peaks of late instar larvae in the field remarkably well. This new information on light brown apple moth phenology in coastal California will be invaluable for the development of effective monitoring and management strategies for this new invader in the studied region. PMID- 22217752 TI - Arboreal spiders in eastern hemlock. AB - Eastern hemlock [Tsuga canadensis (L.) Carriere] is a foundation species in forests of eastern North America that plays a key role in ecosystem function. It is highly susceptible to the exotic invasive hemlock woolly adelgid (Adelges tsugae Annand), which is causing widespread hemlock mortality. We surveyed the spider communities of eastern hemlock and deciduous canopies over 2 yr, collecting over 4,000 spiders from 21 families. We found that eastern hemlock canopies harbored a more abundant, rich, and diverse spider community than did deciduous canopies. Five spider families were present in our hemlock collections that were absent from the deciduous collections, including Mysmenidae, Theridiosomatidae, Mimetidae, Lycosidae, and Agelenidae. In hemlock canopies there were 4* the number of web builders, consisting primarily of the Tetragnathidae and Araneidae, than active hunters, consisting primarily of the Anyphaenidae and the Salticidae. Ours is the first in depth study of the spider community in eastern hemlock. Spider abundance in hemlock canopies suggest that they may play a role regulating herbivore populations, and could possibly affect the invasive hemlock woolly adelgid, either through direct consumption of the adelgids themselves or through interactions with classical biological control agents. PMID- 22217753 TI - Consequences of habitat fragmentation for the prairie-endemic weevil Haplorhynchites aeneus. AB - Widespread destruction of tallgrass prairies in the midwestern United States has fragmented plant communities with the result that populations of endemic animal species have become geographically isolated from one another. The goal of the research summarized here was to evaluate the potential for conserving endemic prairie species of herbivorous insects by managing their host plants. Our study species was the weevil Haplorhynchites aeneus (Boehman), adults of which feed on pollen of plants in the genus Silphium (Asteraceae: Heliantheae). The female weevils clip the peduncles of flower heads and oviposit into the heads, where the larvae feed on the ovules. The research was conducted in 12 prairie sites in eastern Illinois. An allozyme analysis revealed that most populations of H. aeneus at the various prairie sites were genetically differentiated from one another, but the degree of differentiation was not associated with geographic distance between sites. Adult H. aeneus fed and oviposited on the plant species Silphium laciniatum L., S. integrifolium Michx., and S. terebinthinaceum Jacq, which differ in bloom phenology. There was no evidence of genetic differentiation of weevil populations with respect to host plant species, and adult weevils strongly preferred S. terebinthinaceum. We conclude that the oligophagous nature of the weevil assures its survival in small prairie remnants even where some of the host plant species are absent. Although H. aeneus can have a significant impact on reproduction of host plants by clipping flower heads, the perennial nature of Silphium species prevents their local extinction. PMID- 22217754 TI - Influences on the structure of suburban ant (Hymenoptera: Formicidae) communities and the abundance of Tapinoma sessile. AB - Urbanization can alter the organization of ant communities and affect populations of urban pest ants. In this study, we sampled ant communities in urban and suburban yards to understand the habitat factors that shape these communities and influence the abundance of a common pest species, Tapinoma sessile (Say). We used pitfall traps to sample ant communities and a combination of pitfall traps and baiting to collect T. sessile at 24 sites in Knoxville, TN. In total, we collected 46 ant species. Ant species richness ranged from seven to 24 species per yard. Ant species richness tended to be lowest near houses, whereas T. sessile abundance was highest near houses. The best predictors of ant species richness in yards were canopy cover and presence of leaf litter: ant species richness peaked at mid-levels of canopy cover and was negatively correlated with the presence of leaf litter. Tapinoma sessile abundance increased with presence of logs, boards, or landscaping timbers and leaf litter in yards. Our results indicate that ant communities and the abundance of particular pest species in these urban and suburban landscapes are shaped by many of the same factors that structure ant communities in less anthropogenically disturbed environments. PMID- 22217755 TI - Bacteria associated with gut lumen of Camponotus japonicus Mayr. AB - Camponotus ants harbor the obligate intracellular endosymbiont Blochmannia in their midgut bacteriocytes, but little is known about intestinal bacteria living in the gut lumen. In this paper we reported the results of a survey of the intestinal microflora of Camponotus japonicus Mayr based on small-subunit rRNA genes (16S rRNAs) polymerase chain reaction (PCR)-restriction fragment-length polymorphism analysis of worker guts. From 107 clones, 11 different restriction fragment-length polymorphism profiles were identified, and sequences blasting analysis found these represent four types of bacteria. Most (91.6%) of the clones were "Candidatus Blochmannia", the obligate endosymbionts of Camponotus ants, and 6.5% of the clones were "Candidatus Serratia symbiotica", a secondary endosymbiont of aphids; the remaining 2% clones were Fructobacillus fructosus and uncultured Burkholderiales bacterium, respectively. These results show that the diversity of gut bacteria in C. japonicus was low. "Candidatus Serratia symbiotica" was identified from Camponotus ants for the first time, an interesting result because Blochmannia's closest bacterial relative is also in the genus Serratia. This discovery supports the scenario that consumption of aphid honeydew or tissue provides an initial step in the evolution of an advanced symbiosis, and suggests that Camponotus ant could acquire other secondary endosymbionts from Hemiptera host through their diet. In addition, Burkholderiales bacterium also was identified from the gut of C. japonicus for the first time, and whether it is a nitrogen-recycling endosymbiont in Camponotus ants needs to be investigated further. PMID- 22217756 TI - Prey suitability and phenology of Leucopis spp. (Diptera: Chamaemyiidae) associated with hemlock woolly adelgid (Hemiptera: Adelgidae) in the Pacific Northwest. AB - Leucopis spp. (Diptera: Chamaemyiidae) from the Pacific Northwest previously were identified as potential biological control agents for the hemlock woolly adelgid, Adelges tsugae Annand (Hemiptera: Adelgidae), in the eastern United States. We collected Leucopis spp. larvae from A. tsugae infested western hemlocks in Oregon and Washington and reared them on an unidentified Pineus spp., Pineus strobi (Hartig), Adelges cooleyi (Gillette), Adelges piceae (Ratzeburg), and A. tsugae in three no-choice tests. Leucopis spp. survival on A. tsugae was significantly higher than on A. piceae during the 2010 progrediens generation test and significantly higher than on P. strobi and A. cooleyi during the 2010 sistens generation test. However, across all three tests, some larvae completed development to adult on all four of the alternative adelgid species. Larvae that survived to the adult stage were identified as Leucopis argenticollis Zetterstedt and Leucopis piniperda Malloch. These results suggest that populations of L. argenticollis and L. piniperda in the Pacific Northwest may not be specific to A. tsugae. We also studied the phenology of Leucopis spp. on fourteen A. tsugae infested western hemlock trees in Oregon and Washington over a period of 14 mo. Leucopis spp. larvae were collected year-round, but highest densities coincided with the presence of progrediens and sistens eggs and adults of A. tsugae. There was a positive correlation between Leucopis spp. and A. tsugae abundance. PMID- 22217757 TI - The effect of seston on mortality of Simulium vittatum (Diptera: Simuliidae) from insecticidal proteins produced by Bacillus thuringiensis subsp. israelensis. AB - Water was collected from a site on the Susquehanna River in eastern Pennsylvania, where less-than-optimal black fly larval mortality had been occasionally observed after treatment with Bacillus thuringiensis subsp. israelensis de Barjac insecticidal crystalline proteins (Bti ICPs). A series of experiments was conducted with Simulium vittatum Zetterstedt larvae to determine the water related factors responsible for the impaired response to Bti ICPs (Vectobac 12S, strain AM 65-52). Seston in the water impaired the effectiveness of the ICPs, whereas the dissolved substances had no impact on larval mortality. Individual components of the seston then were exposed to the larvae followed by exposure to Bti ICPs. Exposure of larvae to selected minerals and nutritive organic material before ICP exposure resulted in no significant decrease in mortality. Exposure of larvae to silicon dioxide, cellulose, viable diatoms, and purified diatom frustules before Bti ICP exposure resulted in significant reductions in mortality. Exposure of larvae to purified diatom frustules from Cyclotella meneghiniana Kutzing resulted in the most severe impairment of mortality after Bti ICP exposure. It is postulated that frustule-induced impairment of feeding behavior is responsible for the impairment of larval mortality. PMID- 22217758 TI - Evaluation of host range and larval feeding impact of Chrysolina aurichalcea asclepiadis (Villa): considerations for biological control of Vincetoxicum in North America. AB - A biological control program has been initiated against European swallow-worts Vincetoxicum nigrum (L.) Moench. and V. rossicum (Kleopow) Barbar., which are invasive in North America. A population of the leaf beetle Chrysolina aurichalcea asclepiadis (Villa) originating from the western Alps has been under evaluation as a part of this program. The preliminary host range of C. a. asclepiadis was determined among 37 potential host plants. In addition, a prerelease impact study was conducted to determine the effect of larval feeding on the performance of V. nigrum. Under no-choice conditions beetle larvae completed development on nine plant species within the genera Artemisia and Tanacetum (Asteraceae) and Asclepias and Vincetoxicum (Apocynaceae). The host range of adults is broader than larvae (13 plant species within five genera received sustained feeding). Three of the six nontarget species supporting larval development are native to North America, however in separate oviposition tests, female beetles failed to produce eggs when confined to these hosts. In multiple-choice tests, neither larvae nor adults preferred Vincetoxicum spp. to nontarget species. Larval damage by C. a. asclepiadis at densities at and above five larvae per plant substantially reduced growth, biomass, and delayed reproduction of V. nigrum. However, this population of C. a. asclepiadis is polyphagous and unsuitable for biological control of Vincetoxicum because of potential risk of attack to Asclepias tuberosa L. and native North American Asteraceae, particularly Artemisia. PMID- 22217759 TI - Differential performance of tropical soda apple and its biological control agent Gratiana boliviana (Coleoptera: Chrysomelidae) in open and shaded habitats. AB - The leaf feeding beetle Gratiana boliviana Spaeth has been released since 2003 in the southeastern United States for biological control of tropical soda apple, Solanum viarum Dunal. In Florida, G. boliviana can be found on tropical soda apple growing in open pastures as well as in shady wooded areas. The objectives of this study were to determine the effect of light intensity on the performance of tropical soda apple and G. boliviana under greenhouse conditions, and to determine the abundance and mortality of G. boliviana in open and shaded habitats. Leaves growing in the shade were less tough, had higher water and nitrogen content, lower soluble sugars, and less dense and smaller glandular trichomes compared with leaves growing in the open. Plants grew slightly taller and wider under shaded conditions but total biomass was significantly reduced compared with plants grown in the open. In the greenhouse, G. boliviana had higher immature survival, greater folivory, larger adult size, and higher fecundity when reared on shaded plants compared with open plants. Sampling of field populations revealed that the overall abundance of G. boliviana was lower but leaf feeding damage was higher in shaded habitats compared with the open habitats. The percentage of eggs surviving to adult was greater in shaded compared with open habitats. The abundance of predators was higher in the open pasture and was positively correlated with the abundance of G. boliviana. These results indicate that not only plant quality but also habitat structure are important to the performance of weed biological control agents. PMID- 22217760 TI - Limited field establishment of a weed biocontrol agent, Floracarus perrepae (Acariformes: Eriophyidae), against Old World climbing fern in Florida--a possible role of mite resistant plant genotypes. AB - The leaflet galling mite Floracarus perrepae Knihinicki & Boczek was released on Lygodium microphyllum (Cav.) in 63 plots in Florida from 2008 to 2009. Mites transferred onto field plants in 34 plots, but failed to establish populations in the majority of plots. Leaflet galls were observed in only six plots, and in only two plots did mite populations persist for >12 mo. Rates of mite transfer onto field plants were similar for methods using direct transfer of galls versus approaches using passive transfer of mites from infested plants. Often leaflets on some L. microphyllum plants were heavily galled by F. perrepae, whereas leaflets on intertwined stems of other L. microphyllum plants were ungalled but exhibited a characteristic browning and scorching of the leaflet tips. Living mites were consistently present on the undersurface of scorched leaflet tips on ungalled plants, suggesting that this damage might be caused by mite feeding on L. microphyllum genotypes that did not support induction of leaflet galls. Plant nutritional status did not account for differences in galling response, because there were no differences in leaflet nitrogen between galled and ungalled stems. We review those factors known to affect the colonization of biological control agents, and discuss how they may have contributed to the lower than expected rate of F. perrepae establishment. PMID- 22217761 TI - Host plant suitability and feeding preferences of the grapevine pest Abagrotis orbis (Lepidoptera: Noctuidae). AB - Thirteen plant species were tested for their suitability as hosts for Abagrotis orbis (Grote), a climbing cutworm pest of grapevines in British Columbia. Choice tests were also conducted to investigate larval feeding preferences for the Brassicaceae species joi choi, Brassica rapa variety. Chinensis L., spring draba; Draba verna L.; and shepherd's purse, Capsella bursa-pastoris (L.) Medik; compared with postdormant buds of grape, Vitis vinifera L. (Vitaceae), and leaves of nine other plant species from several families. Results showed that tah tsai, Brassica rapa L. variety rosularis (M. Tsen & S. H. Lee) Hanelt (Brassicaceae), is a superior host for A. orbis based on shorter time to adult eclosion, heavier pupae, and higher rates of survival. Later-instar larvae died when fed draba, whereas those reared on shepherd's purse did not survive beyond the third instar. White clover, Trifolium repens L. (Fabaceae), and grape leaves were unsuitable hosts throughout development. Fifth-instar A. orbis preferred plants of the Brassicaceae family, dandelion, Taraxacum officinale Weber (Asteraceae), and strawberry, Fragaria sp. L. (Rosaceae), compared with postdormant grape buds. The results of this study suggest that the winter annual mustards draba and shepherd's purse that often grow abundantly in vine rows might help reduce climbing cutworm damage to the buds of grapevines. PMID- 22217762 TI - Lesser peachtree borer (Lepidoptera: Sesiidae) oviposition on Prunus germplasm. AB - The lesser peachtree borer, Synanthedon pictipes (Grote and Robinson) (Lepidoptera: Sesiidae), is a serious pest of peach, Prunus persica (L.) Batsch, across the southeastern United States. We examined oviposition by S. pictipes on field-grown Prunus scion and rootstock cultivars and two endemic Prunus spp. when sawn limbs, not roots, were assayed in the laboratory. A choice test compared oviposition on the peach scion 'Harvester', peach rootstock 'Guardian', plum*peach hybrid rootstock 'MP-29', and the plum hybrid rootstock 'Sharpe'. A significantly lower percentage of eggs occurred on limbs of Sharpe rootstock than other choices. A choice test using two endemic hosts, black cherry (P. serotina Ehrh.) and Chickasaw plum (P. angustifolia Marsh.), along with Sharpe rootstock, found a lower percentage of eggs on limbs of Sharpe than either endemic host. However, when only limbs of Sharpe and a decoy were used, almost all eggs were laid on Sharpe. Interestingly, when Harvester and Sharpe limbs were paired side by side, a higher percentage of eggs were recovered from the Harvester limb than from the Sharpe limb. An analysis of volatiles from Sharpe may identify why fewer eggs were laid on it. Because S. pictipes attacks host trees above ground and Sharpe rootstock on grafted trees grows below ground, this rootstock might be a management option against the congeneric, root-attacking peachtree borer, S. exitiosa (Say). Our results suggest that high budding a peach scion onto Sharpe rootstock, thus allowing the rootstock to serve as the trunk, warrants further investigation against S. exitiosa under orchard conditions. PMID- 22217763 TI - Host finding and acceptance preference of the yellowmargined leaf beetle, Microtheca ochroloma (Coleoptera: Chrysomelidae), on cruciferous crops. AB - The yellowmargined leaf beetle, Microtheca ochroloma Stal (Coleoptera: Chrysomelidae), is an introduced pest of cruciferous crops in the southern United States, and arguably the most damaging pest of organic crucifer vegetable production in the region. Studies were conducted in the greenhouse and laboratory to investigate host finding and acceptance preference of M. ochroloma on four commonly grown cruciferous crops: cabbage (Brassica oleracea L. variety capitata), collards (B. oleracea L. variety acephala), napa cabbage [B. pekinensis (Lour.)], and turnip (B. rapa L.) First, adult beetles were allowed to choose among the four plants in a multiple-choice greenhouse cage experiment and host preference was evaluated by using three parameters: number of beetles on each plant, number of larvae on each plant, and plant damage ratings. The results showed that M. ochroloma adults actively discriminated among the four host plants, with significantly higher numbers recorded on turnip and napa cabbage than on cabbage or collards. Significantly higher numbers of larvae also were recorded on turnip and napa cabbage starting on day 10. Similarly, higher damage ratings were recorded on turnip and napa cabbage than on the remaining two hosts. Results of four-choice olfactometer experiments, which compared attraction of M. ochroloma to headspace volatiles of the four host plants, demonstrated that host preference is mediated primarily by plant volatiles. Both sexes were significantly more attracted to napa cabbage than to the remaining treatments, with turnip being the second most attractive plant. These results confirm that turnip and napa cabbage are two preferred host plants of M. ochroloma, and may support the development of a trap crop system and attractant-based strategies for managing M. ochroloma in crucifer production. PMID- 22217764 TI - Field observations of oviposition by a specialist herbivore on plant parts and plant species unsuitable as larval food. AB - Where a female places her eggs can have a major impact on the fitness of her offspring, especially for insects in which the winged adults are far more mobile than the neonates. Larvae of Heliothis subflexa (Guenee) (Lepidoptera: Noctuidae), a specialist moth phylogenetically nested within a generalist clade, feed only on fruit of some Physalis species. Field observations of the oviposition behavior of H. subflexa revealed that 1) females laid most of their eggs on leaves of the Physalis plant, despite the larvae's frugivorous diet, and 2) females laid nearly 20% of the eggs on nonhost plant species. Most eggs oviposited on nonhosts were placed close to the host plant-88% were within 15 cm of the Physalis plant. However, in a study of neonate movement, we found that a distance of 2 cm from the hatch site to the host plant significantly decreased the ability of neonates to establish on the host plant. The estimated fitness cost, quantified as reduced neonate survival, for females ovipositing on nonhosts is 8-17%. Many ecological and evolutionary factors could result in oviposition on less suitable host parts and on nonhosts. One possibility is that specialization on Physalis has recently evolved in H. subflexa, and females have not fully optimized their oviposition behavior. However, the fitness cost of oviposition on nonhosts may be balanced by fitness benefits of such behavior, such as faster decision-making and reduced predation. PMID- 22217765 TI - Host selection and colonization strategies with evidence for a female-produced oviposition attractant in a longhorn beetle. AB - In longhorn beetles and many other internally feeding insects, oviposition choice by females is critical to the survival of their offspring because their larvae are incapable of moving between hosts. Here we report on the complex host selection and colonization strategies of a longhorn beetle, Glenea cantor (F.) (Coleoptera: Cerambycidae), which is an important pest of kapok trees [Bombax ceiba L.=Gossampinus malabaricus (DC.) Merr.] in southern Asia. It attacks weakened trees, eventually killing them. The typical oviposition behavioral sequence in the laboratory includes the following: oviposition site search and recognition using antennae and palpi, oviposition slit preparation with mandibles, turning body direction 180 degrees , egg deposition with the ovipositor, and oviposition wound covering with a jelly-like material from the ovipositor. Bark moisture content significantly increases from the upper to lower sections in kapok trees. In accordance with this variation female adults select the upper section of trees first for oviposition. As infestation continues and the host becomes more weakened, ovipositing females move further down the tree for oviposition. Consequently, the larvae kill the hosts from the top down. We show that the jelly-like material or eggs or both have an olfactory role in attracting females to oviposit nearby. Our findings are important in terms of increasing our understanding of host selection and colonization mechanisms of internally feeding insects, particularly cerambycids, and the development of environmentally friendly pest management measures. PMID- 22217766 TI - Multimodal cues drive host-plant assessment in Asian citrus psyllid (Diaphorina citri). AB - Asian citrus psyllid (Diaphorina citri) transmits the causal agent of Huanglongbing, a devastating disease of citrus trees. In this study we measured behavioral responses of D. citri to combinations of visual, olfactory, and gustatory stimuli in test arenas. Stimuli were presented to the psyllids in droplets or lines of an emulsified wax formulation in two different arena types in no-choice tests. First, when placed on a colored ring situated halfway between the center and perimeter of a petri dish, D. citri spent more time on yellow versus gray rings; however, this response disappeared when either gray or yellow wax droplets were applied. When the psyllids were presented with droplets scented with terpenes, the response to both scent and color was increased. The addition of a dilute (?0.1 M) sucrose solution to the wax droplets increased the magnitude of D. citri responses. Next, groups of D. citri were placed on plastic laboratory film covering a sucrose solution, to mimic a leaf surface. Test stimuli were presented via two 'midribs' made from lines of emulsified wax formulation. Probing levels were measured as a function of color saturation and scent composition, and concentration. The test scents were based on qualitatively major volatiles emitted by Murraya paniculata (L.) Jack, Citrus aurantifolia (Christm.) Swingle, and C. sinensis (L.) Osbeck. The highest probing response was observed on the middle concentration (20-MUl scent/10 ml wax formulation) of the C. aurantifolia-scented wax lines. Results indicate that there are interactive effects between the different sensory modalities in directing host-plant assessment behavior. PMID- 22217767 TI - Three homopteran pests of citrus as prey for the convergent lady beetle: suitability and preference. AB - The convergent lady beetle, Hippodamia convergens Guerin-Meneville (Coleoptera: Coccinellidae), is an important predator of soft-bodied insect pests in many regions of the United States, but generally uncommon in Florida citrus. Certain citrus producers in Florida recently initiated releases of commercially available H. convergens from California against the Asian citrus psyllid Diaphorina citri Kuwayama, vector of Huanglongbing or citrus greening disease. However, there is little information on potential efficacy of this predator against the psyllid or other pests of citrus. Preference, development, and reproduction by H. convergens was evaluated on freshly collected nymphs of D. citri, brown citrus aphid Toxoptera citricida Kirkaldy, green citrus aphid Aphis spiraecola Patch, and frozen eggs of the flour moth Ephestia kuehniella Zeller. Larvae preferred D. citri over T. citricida in two-way choice tests and consumed more D. citri or A. spiraecola than T. citricida in no-choice tests. Adults consumed equal numbers of all three species in both tests. Development times of larvae at 25.5+/-0.05 degrees C on A. spiraecola were longer than on the other three diets. Larval survival and pupation times did not differ among diets. Females lived longer than males irrespective of diet, and longevity of both genders was greatly increased on E. kuehniella compared with D. citri and A. spiraecola. Life table analysis indicated that H. convergens should increase on all three species, with a greater potential on psyllids than aphids. Further studies are warranted to assess establishment and persistence of this potential biological control agent in the Florida citrus environment. PMID- 22217769 TI - Shuffling leaf litter samples produces more accurate and precise snapshots of terrestrial arthropod community composition. AB - Understanding the accuracy of sampling techniques is critical to accurate interpretation of local and global ecological patterns. Over the past 20 yr, Winkler leaf litter extractors have become one of the most common techniques used to collect terrestrial arthropods. Although the original description of this technique recommends the use of disturbance during extraction to increase extraction efficiency, most published studies do not follow this recommendation. Here we test experimentally how disturbing, or "shuffling" leaf litter during extraction affects collection efficiency for four groups of arthropods: ants, micro-Hymenoptera, beetles, and spiders. Our results show that extraction efficiency for abundance and richness of ants is increased with disturbance. Disturbance also improves extraction efficiency for beetle abundance, but does not affect micro-Hymenoptera and spider abundance or richness. Significantly, our results also demonstrate that shuffling litter can greatly reduce the variability of extraction efficiency between different sites. Because of this greater efficiency, we recommend use of the shuffling technique, when sampling leaf litter via Winkler extractors to maximize the collection of ants and beetles, especially for studies that compare abundance and richness across multiple sites. PMID- 22217768 TI - Monitoring grape berry moth (Paralobesia viteana: Lepidoptera) in commercial vineyards using a host plant based synthetic lure. AB - For some Lepidopteran pests, such as the grape berry moth Paralobesia viteana (Clemens), poor correlation between males captured in traps baited with sex pheromone and oviposition activities of female moths has called into question the value of pheromone-based monitoring for these species. As an alternative, we compared the capture of female and male grape berry moth in panel traps baited with synthetic host volatiles with captures of males in pheromone-baited wing traps over two growing seasons in two blocks of grapes in a commercial vineyard in central New York. Lures formulated in hexane to release either 7-component or 13-component host volatile blends captured significantly more male and female grape berry moth on panel traps compared with the numbers captured on panel traps with hexane-only lures. For both sexes over both years, the same or more moths were captured in panel traps along the forest edge compared with the vineyard edge early in the season but this pattern was reversed by mid-season. Male moths captured in pheromone-baited wing traps also displayed this temporal shift in location. There was a significant positive correlation between captured males and females on panel traps although not between females captured on panel traps and males captured in pheromone-baited traps for both years suggesting pheromone traps do not accurately reflect either female or male activity. Male moths captured in pheromone traps indicated a large peak early in each season corresponding to first flight followed by lower and variable numbers that did not clearly indicate second and third flights. Panel trap data, combining males and females, indicated three distinct flights, with some overlap between the second and third flights. Peak numbers of moths captured on panel traps matched well with predictions of a temperature-based phenology model, especially in 2008. Although effective, panel traps baited with synthetic host lures were time consuming to deploy and maintain and captured relatively few moths making them impractical, in the current design, for commercial purposes. PMID- 22217770 TI - Disruptive selection maintains variable pheromone blends in the bark beetle Ips pini. AB - The presence of heritable variation is a prerequisite for evolution, but natural selection typically reduces genetic variation. Variation can be maintained in traits under selection through spatial or temporal variation in fitness surfaces, frequency-dependent selection, or disruptive selection. We evaluated the maintenance of variation in the enantiomeric blend of pheromones employed by the bark beetle Ips pini (Say). In natural populations, we quantified fitness surfaces for mating success and progeny production. We investigated the effects of paternal pheromone blend on offspring survival by comparing the spatial scales at which pheromone blends and larval mortality agents vary. Males with extreme pheromone blends obtained up to 1.8 times as many mates who each laid equivalent numbers of eggs, producing strong disruptive selection on male pheromone blend. In combination with imperfect assortative mating that continually produces intermediate genotypes, this fitness surface is sufficient to maintain variation in a heritable trait that is strongly linked to fitness. The ultimate explanation for female preference is unknown but could be because of selection for reduced mortality from specialist predators that prefer common prey pheromone blends. Selection is most likely occurring at the scale of small resource patches within pine stands. Selection at coarser scales (pine stands) is unlikely because pheromone blends did not vary among pine stands. Selection at finer scales (within logs) is unlikely because males of similar enantiomeric blends were not aggregated on logs, and male pheromone blend did not affect the spacing to neighboring galleries. This study documents a rare case of diversifying selection in natural populations. PMID- 22217771 TI - Thermal requirements and effect of temperature and prey on the development of the predator Harmonia axyridis. AB - Thermal requirements (lower temperature threshold and thermal constant) for the development of each developmental stage of the predator Harmonia axyridis (Pallas) were studied on Aphis fabae Scopoli and Dysaphis crataegi (Kaltenbach) under controlled laboratory conditions. The effect of temperature (15, 20, 25, and 30 degrees C) and prey species was examined on pre-imaginal developmental duration and life cycle (pre-oviposition period included) of the predator. Our results suggest comparable thermal requirements for the development of H. axyridis on the particular prey and when compared with other aphid species. The total preimaginal development of H. axyridis, at 15, 20, and 30 degrees C, and its life cycle, at 15 and 30 degrees C, are shorter on D. crataegi than on A. fabae. PMID- 22217772 TI - Cold tolerance and supercooling capacity in overwintering adults of elm leaf beetle Xanthogaleruca luteola (Coleoptera: Chrysomelidae). AB - Elm leaf beetle, Xanthogaleruca luteola (Muller) is one of the key pests of elm trees all over the world, and survives winter in reproductive diapause in sheltered locations. Seasonal variation of whole body supercooling points (SCPs), LT50 (temperature at which 50% of the test individuals die) and survival rate after exposure to subzero temperatures were determined in field collected adults during October 2008 to May 2009 and October 2009 to May 2010. The SCP of adults decreased significantly from October (median=-13.8 degrees C) to January (median= 20.7 degrees C) in first year, relatively similar results was observed in the second year. The lowest LT50 was observed in overwintering adults collected in January (-16.81 degrees C) in the first year and December (-15.59 degrees C) in the second year. Mortality at -15 degrees C for 24 h was >70% in early autumn in both years whereas it decreased to lower than 45% in early winter, the highest mortality (100%) was observed in adults collected in May in both years. Cold acclimated adults (30 d, 5 degrees C) in November 2008 exhibited significantly higher SCP (-12.21+/-0.64 degrees C) than nonacclimated adults (-15.57+/-1.35 degrees C). A 30-d exposure to 5 degrees C caused >20% mortality in November, while <9% mortality was observed in adults collected in December and January 2008. Overwintering adults died upon freezing and the lower lethal temperatures were within the range of SCP, indicating that X. luteola is a freeze intolerant insect. PMID- 22217773 TI - Mate preference and disease risk in Zootermopsis angusticollis (Isoptera: Termopsidae). AB - Termites face significant and chronic intranidal selection pressures from parasites and pathogens that colonize their nests. They also encounter microbes outside their nest while foraging and during dispersal of winged primary reproductives to establish new colonies. The latter run the additional risk of becoming infected by a mating partner. Indeed, death of reproductives because of disease is a major cause of incipient colony failure and may favor prescreening prospective mates for signs of illness. To determine the role of disease on mate preference in termites, female primary reproductives of the Pacific dampwood termite Zootermopsis angusticollis (Hagen) simultaneously were presented with reproductive males that were either healthy or exhibiting a progression of symptoms associated with infection by the entomopathogenic fungus Metarhizium anisopliae (Metchnikoff Sorokin). We compared duration and frequency of female visits to healthy and infected males. In addition, we determined the physiological consequences for females exposed to fungal conidia, either directly or indirectly through their mate. Females showed no preference for healthy rather than infected males. Moreover, only directly-exposed females experienced negative physiological effects, having a reduced chance of survival, gaining less weight, developing fewer functional ovarioles, and producing significantly fewer vitellogenic oocytes than controls. Although there are important fitness-related costs of direct exposure, the lack of mate selection based on disease risk suggests that more imminent ecological pressures (e.g., predators, desiccation) override the need for a careful and time-consuming assessment of a potential mate's health. PMID- 22217774 TI - Variations in fuel use in the flight muscles of wing-dimorphic Gryllus firmus and implications for morph-specific dispersal. AB - Although a considerable amount of information is available on tradeoffs in wing polymorphic insects, only limited data are available on the relationship between flight and biochemical variation within species. In the current study, we compared the biochemical basis in the dorsolongitudinal flight muscle of the wing-dimorphic sand cricket, Gryllus firmus Scudder, with respect to tradeoffs in energy resources related to morph-specific flight, including glycogen, trehalose, and triglycerides. Our results show that levels of glycogen and trehalose in long winged adults (LW[f]) were significantly higher before dispersal, on days 5 and 7. Considering that this is the period during which long-winged adults are flight capable, these results suggest that both glycogen and trehalose are important to flight. However, levels of triglycerides in short-winged crickets (SW) were higher than in long-winged crickets, suggesting that triglycerides are not directly related to initial flight. In SW adults, triglyceride content on days 5 and 7 was significantly higher just before lights off than at the same time on day 1 or at any other time after lights on all other days. This suggests that triglycerides are probably related to reproductive behaviors, such as mating and oviposition, in the SW morph. In addition, flight muscle water content was significantly lower in the LW(f) morph than in the SW morph. PMID- 22217775 TI - Condensed tannins inhibit house fly (Diptera: Muscidae) development in livestock manure. AB - Reducing chemical use for suppressing internal and external parasites of livestock is essential for protecting environmental health. Although plant condensed tannins are known to suppress gastro-intestinal parasites in small ruminants, no research on the effects of tannins on external arthropod populations such as the house fly, Musca domestica L., have been conducted. We examined the impact of plant material containing condensed tannins on house fly development. Prairie acacia (Acacia angustissima (Mill.), Kuntze variety hirta (Nutt.) B.L. Rob.) herbage, panicled tick-clover (Desmodium paniculatum (L.) DC.) herbage, and quebracho (Shinopsis balansae Engl.) extracts were introduced at rates of 1, 3 or 5% condensed tannins/kg beef cattle, dairy cattle, and goat manure, respectively. In a second experiment, we also introduce purified catechin at 1 or 3% of dairy manure dry matter and measured its impact on house fly development. For the house flies used in these experiments, the following was recorded: percent fly emergence (PFE), average daily gain (ADG), and average fly weight (AFW). No effects (P>0.05) in house fly development were measured in the caprine manure. Prairie acacia (20.9% condensed tannins) had no effect on house flies developing in either bovine manures. Tick clover (4.9% condensed tannins) had a negative effect on all three quantifiable variables of house fly development in the bovine manures, whereas quebracho extract (64.0% condensed tannins) at the 3 and 5% rate reduced fly emergence in beef manure and average daily gain in dairy manure. The application of purified catechin at 3%, but not 1%, reduced fly PFE, ADG, and AFW. PMID- 22217776 TI - Temperature and diet effects on immature development of predatory mite Typhlodromus athenas Swirski and Ragusa (Acari: Phyotseiidae). AB - Temperature and food quality both can influence growth rates and developmental time of herbivorous insects and mites. Typhlodromus athenas Swirski and Ragusa is an indigenous mite in the Mediterranean region and data on its temperature dependent development are lacking. In the current study, temperature-dependent development and survival of T. athenas immature stages were evaluated on eggs and all stages of Tetranychus urticae Koch, as well as on almond (Prunus amygdalis Batsch) pollen, under seven constant temperatures ranging from 15 to 35 degrees C, 65% RH, and a photoperiod of 16:8 (L:D) h. On both diets survival was considerably high at all temperatures. The longest developmental period of immature stages was recorded at 15 degrees C, whereas the shortest was at 30 degrees C. Female immatures on almond pollen had shorter developmental time compared to that on twospotted spider mites. Food had a significant effect on female total developmental time at temperatures lower than 25 degrees C. The lower developmental thresholds, estimated by a linear model, for egg-to-adult of females and males fed on pollen were 8.60 and 8.77 degrees C, respectively, whereas on T. urticae they were 10.15 and 10.62 degrees C, respectively. Higher values of tmin for total development were estimated by a nonlinear model (Lactin 2), and ranged from 10.21 degrees C for both females and males on almond, to 11.07 for females and 10.78 degrees C for males on prey. Moreover, this model estimated optimal and lethal temperatures accurately. The results of this study indicate that T. athenas appears better adapted to higher temperatures that occur in the Mediterranean region and may be a useful biological control agent. PMID- 22217777 TI - Mating success and spermatophore composition in Western corn rootworm (Coleoptera: Chrysomelidae). AB - Western corn rootworm (Diabrotica virgifera virgifera LeConte) resistance management for transgenic (or Bt) corn hinges on understanding the mating behavior and biology of this adaptable insect pest. During mating, the male transfers sperm and additional, previously uncharacterized material, to the female in the form of a spermatophore. We investigated the composition of rootworm spermatophores. Proteins were found to be a major component, and the stable isotope (15)N was used to assess the fate of spermatophore nitrogen in mated female beetles and their eggs. We also performed longevity studies on mated and virgin females under three different diet treatments and investigated the relationships between morphometric characteristics and spermatophore volume of mating pairs of beetles. The stable isotope analysis determined that nitrogen provided to the female in the spermatophore was incorporated into the eggs. We found that virgin female beetles on a corn diet lived significantly longer than mated female beetles on the same diet. There were significant positive relationships between male size parameters (head capsule width, pronotum width, and elytral length) and spermatophore volume, and ampulla and spermatophylax volume. PMID- 22217778 TI - Development of a multiplex PCR for identification of vineyard mealybugs. AB - A simple molecular tool was developed and tested to identify seven mealybug species found in North American vineyards: Pseudococcus maritimus Ehrhorn, Pseudococcus viburni (Signoret), Pseudococcus longispinus (Targioni-Tozzeti), Pseudococcus calceolariae (Maskell), Planococcus ficus (Signoret), Planococcus citri (Risso), and Ferrisia gilli Gullan. The developed multiplex PCR is based on the mitochondrial cytochrome c oxidase subunit one gene. In tests, this single step multiplex PCR correctly identified 95 of 95 mealybug samples, representing all seven species and collected from diverse geographic regions. To test the sensitivity, single specimen samples with different Pl. ficus developmental stages (egg to adult female and adult male) were processed PCR and the resulting output provided consistent positive identification. To test the utility of this protocol for adult males caught in sex baited pheromone traps, Pl. ficus adult males were placed in pheromone traps, aged at a constant temperature of 26+/-2 degrees C, and processed with the multiplex each day thereafter for 8 d. Results showed consistent positive identification for up to 6 d (range, 6-8 d). Results are discussed with respect to the usefulness of this molecular tool for the identification of mealybugs in pest management programs and biosecurity of invasive mealybugs. PMID- 22217779 TI - Distribution and mechanism of alpha-amanitin tolerance in mycophagous Drosophila (Diptera: Drosophilidae). AB - Many mycophagous species of Drosophila can tolerate the mushroom poison alpha amanitin in wild mushrooms and in artificial diet. We conducted feeding assays with sixteen Drosophila species and alpha-amanitin in artificial diet to better determine the phylogenetic distribution of this tolerance. For eight tolerant and one related susceptible species, we sequenced the gene encoding the large subunit of RNA Polymerase II, which is the target site of alpha-amanitin. We found no differences in the gene that could account for differences in susceptibility to the toxin. We also conducted feeding assays in which alpha amanitin was combined with chemical inhibitors of cytochrome P450s or glutathione S-transferases (GSTs) in artificial diet to determine if either of these enzyme families is involved in tolerance to alpha-amanitin. We found that an inhibitor of GSTs did not reduce tolerance to alpha-amanitin, but that an inhibitor of cytochrome P450s reduced tolerance in several species. It is possible that the same cytochrome P450 activity that produces tolerance of alpha-amanitin might produce tolerance of other mushroom toxins as well. If so, a general detoxification mechanism based on cytochrome P450s might answer the question of how tolerance to alpha-amanitin arose in mycophagous Drosophila when this toxin is found in relatively few mushrooms. PMID- 22217780 TI - Development and survival of Orius insidiosus (Say) nymphs on encapsulated bee pollen-based diet in a Tier-I toxicity assay. AB - The insidious flower bug, Orius insidiosus (Say) (Heteroptera: Anthocoridae) is an important surrogate species for assessing potential effects of plant incorporated protectants (PIPs) on nontarget heterotrophic predators. In this study, a continuous dietary exposure system was optimized by assessing the effect of diet composition and age on the survival and development of nymphs of O. insidiosus. Greater than 85% control survival and an acceptable rate of development from nymph hatching to adult was achieved using 5-d-old nymphs at test initiation and a bee pollen-based diet supplemented with 25% Ephestia eggs. There was an unacceptable level of mortality (>40%) and/or a significantly prolonged development time when nymphs were <5 d old at test initiation. When 5-d old nymphs were fed a bee pollen diet containing 25% Ephestia eggs and 100 MUg/g potassium arsenate, time-dependent mortality was observed with a median lethal time (LT50) of 4.4 d and 100% mortality was observed after 10 d of feeding, indicating the effectiveness of the test system to detect adverse effects by dietary exposure. It is recommended that well-defined 5-d-old nymphs and an encapsulated bee pollen-based diet containing 25% ground Ephestia eggs be used in a Tier-I dietary feeding exposure assay for detecting potential effects of PIPs on O. insidiosus nymphs. PMID- 22217781 TI - Enhanced beta-ionone emission in Arabidopsis over-expressing AtCCD1 reduces feeding damage in vivo by the crucifer flea beetle. AB - Plant carotenoid derived beta-ionone has been shown to have diverse biological effects on some insect herbivores and herbivore parasitoids. In this study, Arabidopsis transgenic plants over-expressing a carotenoid cleavage dioxygenase1 gene (AtCCD1) were generated to test whether beta-ionone emissions could be enhanced and used to control feeding by the crucifer flea beetle (Phyllotreta cruciferae Goeze). The transgenic plants exhibited a morphological phenotype indistinguishable from the wild type (WT) control over their complete life cycle. Gas chromatography and mass spectrometry analyses of headspace volatiles collected from 6-wk-old intact flowering plants revealed substantially enhanced beta-ionone emission from transgenic plants compared with WT, but no beta-ionone enhancement occurred at a young vegetative stage (4-wk-old seedlings). Bioassays in an enclosed environment showed that AtCCD1 over-expression resulted in ?50% less leaf area damage by flea beetles on transgenic plants compared with WT plants. The mean number of damaged transgenic leaves per plant also was significantly lower in transgenic plants (P<0.05). Our results indicate that AtCCD1 over-expression and induced beta-ionone emission might find application in the control of pests for Brassica crops grown in greenhouse operations. Potentially, beta-ionone also could be used on crops grown in open-air ecosystems if this allomone is released in sufficient quantities to discourage herbivore foragers. PMID- 22217800 TI - Internet use by the public to search for health-related information. AB - BACKGROUND: The use of the Internet to search for health-related information (HRI) has become a common practice worldwide. Our literature review failed to find any evidence of previous studies on this topic from Saudi Arabia. OBJECTIVE: To determine the public use of the Internet in Saudi Arabia to search for HRI and to evaluate patients' perceptions of the quality of the information available on the Internet compared to that provided by their health care providers. METHODS: A self-administered questionnaire about Internet use to search for HRI was distributed randomly to male and female outpatients and visitors attending a public University Hospital in Riyadh, Saudi Arabia from January to May 2010. A Chi-squared test was used to assess the association between different categorical variables. Multiple logistic regression was used to relate the use of the Internet to search for HRI with various socio-demographic variables. RESULTS: The questionnaire response was 80.1%, with completion of 801 of the 1000 distributed questionnaires; 50% (400/801) of respondents were males. The mean age of respondents was 32+/-11 years. The majority of respondents used the Internet in general (87.8%), and 58.4% of them (363/622) used the Internet to search for HRI. The majority stated a doctor was their primary source of HRI (89.3%, 654/732). This practice was considered useful by 84.2%, and the main reason behind it was sheer curiosity (92.7%, 418/451). Other reasons included not getting enough information from their doctor (58.5%, 227/413) and not trusting the information given by their doctor (28.2%, 101/443). Forty-four percent (205/466) searched for HRI before coming to the clinic; 72.5% of those discussed the information with their doctors and 71.7% (119/166) of those who did so believed that this positively affected their relationship with their doctor. Searching the Internet for health information was observed more frequently among the 30-39 year age group (OR=2.0, 95% CI 1.1-3.7), females (OR=3.8, 95% CI 2.3-6.4), individuals with university or higher education (OR=1.7, 95% CI 1.1-2.8), employed individuals (OR=2.7, 95% CI 1.4-4.9) and high income groups (OR=2.8, 95% CI 1.5 5.1). CONCLUSIONS: A proportion of the public searches the Internet to obtain HRI for various reasons, which could have consequences on their health and relationship with their doctors. Therefore, doctors should be aware of the health information available online to help guide patients to reliable websites. Health authorities should also be aware of the issue to offer regulations and solutions. PMID- 22217782 TI - Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents--second edition. PMID- 22217801 TI - Structured electronic operative reporting: comparison with dictation in kidney cancer surgery. AB - PURPOSE: The purpose of this study was to evaluate the functionality of eKidney as a structured reporting tool in operative note generation. To do this, we compared completeness and timeliness of eKidney template-generated nephrectomy OR notes with standard narrative dictation. METHODS: A group of academic uro oncologists and medical informaticians at the University Health Network designed and adopted an electronic online, point-of-care clinical documentation tool, eCancerCare(Kidney) (eKidney) for kidney cancer patient care. The optimal components of clinic and operative note templates, including those for nephrectomy, were agreed upon by expert consensus of the uro-oncologists. Clinician nephrectomy OR reports were analyzed for completeness, comparing those generated in eKidney with conventionally dictated notes. Patterns of missing information from both dictated and eKidney-generated reports were analyzed. The procedure, note completion and transcription dates were recorded which generated time intervals between these events. The records of 189 procedures were included in the analysis. RESULTS: Comparison of clinicians who used both note generation modalities, revealed a mean completion rate of 92% for eKidney/structured notes and 68% for dictated notes (p<0.0001). There was no significant difference in completion rates between attending staff and trainees (residents and fellows) (p=0.131). Most notes were dictated/entered on the day of surgery. Dictated notes were transcribed to EPR a median of 2 days after dictation, however roughly 30% of dictated notes took 5 days or more to get transcribed. All notes generated using eKidney were uploaded to the EPR immediately. LIMITATIONS: Our study has three significant limitations. Firstly, our study was not randomized: physicians could elect to dictate or use eKidney. Secondly, we did not identify data from dictated notes that were not captured by eKidney. Third, we did not compare the time it took physicians to complete the fields in eKidney with the time it takes to dictate a note. CONCLUSIONS: We have demonstrated that the use of structured reporting improves the completeness and timeliness of documentation in kidney cancer surgery. eKidney is an example of the power of templates in ensuring that important details of a procedure are recorded. Future studies looking at user satisfaction, and research and educational potential of eKidney would be valuable. PMID- 22217802 TI - The effects of EMR deployment on doctors' work practices: a qualitative study in the emergency department of a teaching hospital. AB - OBJECTIVE: The goal of this study was to examine the effects of medical notes (MD) in an electronic medical records (EMR) system on doctors' work practices at an Emergency Department (ED). METHODS: We conducted a six-month qualitative study, including in situ field observations and semi-structured interviews, in an ED affiliated with a large teaching hospital during the time periods of before, after, and during the paper-to-electronic transition of the rollout of an EMR system. Data were analyzed using open coding method and various visual representations of workflow diagrams. RESULTS: The use of the EMR in the ED resulted in both direct and indirect effects on ED doctors' work practices. It directly influenced the ED doctors' documentation process: (i) increasing documentation time four to five fold, which in turn significantly increased the number of incomplete charts, (ii) obscuring the distinction between residents' charting inputs and those of attendings, shifting more documentation responsibilities to the residents, and (iii) leading to the use of paper notes as documentation aids to transfer information from the patient bedside to the charting room. EMR use also had indirect consequences: it increased the cognitive burden of doctors, since they had to remember multiple patients' data; it aggravated doctors' multi-tasking due to flexibility in the system use allowing more interruptions; and it caused ED doctors' work to become largely stationary in the charting room, which further contributed to reducing doctors' time with patients and their interaction with nurses. DISCUSSION: We suggest three guidelines for designing future EMR systems to be used in teaching hospitals. First, the design of documentation tools in EMR needs to take into account what we called "note-intensive tasks" to support the collaborative nature of medical work. Second, it should clearly define roles and responsibilities. Lastly, the system should provide a balance between flexibility and interruption to better manage the complex nature of medical work and to facilitate necessary interactions among ED staff and patients in the work environment. PMID- 22217803 TI - Differential expression and processing of secretogranin II in relation to the status of pheochromocytoma: implications for the production of the tumoral marker EM66. AB - We have previously demonstrated that measurement of tissue concentrations of the secretogranin II (SgII or SCG2 as listed in the HUGO database)-derived peptide EM66 may help to discriminate between benign and malignant pheochromocytomas and that EM66 represents a sensitive plasma marker of pheochromocytomas. Here, we investigated the gene expression and protein production of SgII in 13 normal adrenal glands, and 35 benign and 16 malignant pheochromocytomas with the goal to examine the molecular mechanisms leading to the marked variations in the expression of EM66 in tumoral chromaffin tissue. EM66 peptide levels were 16-fold higher in benign than in malignant pheochromocytomas and had an area under the receiver-operating characteristic curve of 0.95 for the distinction of benign and malignant tumors. Q-PCR experiments indicated that the SgII gene was significantly underexpressed in malignant tumors compared with benign tumors. Western blot analysis using antisera directed against SgII and SgII-derived fragments revealed lower SgII protein and SgII-processing products in malignant tumors. Western blot also showed that low p-cAMP-responsive element-binding (CREB) concentrations seemed to be associated with the malignant status. In addition, the prohormone convertase PC1 and PC2 genes and proteins were overexpressed in benign pheochromocytomas compared with malignant pheochromocytomas. Low concentrations of EM66 found in malignant tumors are associated with reduced expression and production of SgII and SgII-derived peptides that could be ascribed to a decrease in SgII gene transcription, probably linked to p-CREB down-regulation, and to lower PC levels. These findings highlight the mechanisms leading to lower concentrations of EM66 in malignant pheochromocytoma and strengthen the notion that this peptide is a suitable marker of this neuroendocrine tumor. PMID- 22217805 TI - Isolation of the multipotent MSC subpopulation from human gingival fibroblasts by culturing on chitosan membranes. AB - Literature has different opinions regarding the percentage of mesenchymal stem cell (MSC)-like population in human gingival tissue. Isolation of these cells is thus important for clinical applications. In this study, two typical but distinct types of gingival fibroblasts (GF), GF-A and GF-B, were grown from human gingival biopsies. They were characterized for surface markers by flow cytometry as well as the expressions of stemness and neural crest marker genes by RT-PCR. The two types of GF were slightly different in their surface markers; however, they had dramatic difference in the expression levels of stemness marker genes and neural crest marker genes. They also demonstrated distinct differentiation capacity. Upon the appropriate induction, GF-A were capable of osteogenic, adipogenic, chondrogenic, and neurogenic differentiation while GF-B only underwent osteogenic differentiation. By culturing either type of GF on chitosan membranes for 24 h, we were able to isolate two distinct subpopulations in each type of GF, i.e. cells with spheroid-forming ability (GF-AS and GF-BS) or those remained flat and attached (GF-AN and GF-BN). We further characterized these cells, and determined the common properties shared by the spheroid-forming subpopulation "S", as well as those shared by the non-spheroid-forming subpopulation "N". The subpopulation "S" was capable of the multilineage differentiation, while the subpopulation "N" was only efficient in osteogenic differentiation. GF-A and GF-B had different proportions of subpopulations. Chitosan as the cell culture substratum up regulated the N-cadherin expression of the "S" but not "N" subpopulation, which may account for the cell sorting effect. This study showed that chitosan membranes could be used for isolation of the spheroid forming subpopulation in human GF that contained multipotent adult stem cells of which the number varied among donors and sites. PMID- 22217804 TI - Hydrogel delivery of erythropoietin to the brain for endogenous stem cell stimulation after stroke injury. AB - Drug delivery to the brain is challenging because systemic delivery requires high doses to achieve diffusion across the blood-brain barrier and often results in systemic toxicity. Intracerebroventricular implantation of a minipump/catheter system provides local delivery, yet results in brain tissue damage and can be prone to infection. An alternate local delivery strategy, epi-cortical delivery, releases the biomolecule directly to the brain while causing minimal tissue disruption. We pursued this strategy with a hyaluronan/methyl cellulose (HAMC) hydrogel for the local release of erythropoietin to induce endogenous neural stem and progenitor cells of the subventricular zone to promote repair after stroke injury in the mouse brain. Erythropoeitin promotes neurogenesis when delivered intraventricularly, thereby making it an ideal biomolecule with which to test this new epi-cortical delivery strategy. We investigated HAMC in terms of the host tissue response and the diffusion of erythropoeitin therefrom in the stroke injured brain for neural repair. Erythropoietin delivered from HAMC at 4 and 11 days post-stroke resulted in attenuated inflammatory response, reduced stroke cavity size, increased number of both neurons in the peri-infarct region and migratory neuroblasts in the subventricular zone, and decreased apoptosis in both the subventricular zone and the injured cortex. We demonstrate that HAMC-mediated epi-cortical administration is promising for minimally invasive delivery of erythropoeitin to the brain. PMID- 22217806 TI - The potential of human fetal mesenchymal stem cells for off-the-shelf bone tissue engineering application. AB - Mesenchymal stem cells (MSCs) have become one of the most promising cell sources for bone tissue engineering (BTE) applications. In this review, we first highlight recent progress in the understanding of MSC biology, their in vivo niche, multi-faceted contribution to fracture healing and bone re-modelling, and their role in BTE. A literature review from clinicaltrials.gov and Pubmed on clinical usage of MSC for both orthopedic and non-orthopedic indications suggests that translational use of MSC for BTE indications is likely to bear fruit in the ensuing decade. Last, we disscuss the profound influence of ontological and antomical origins of MSC on their proliferation and osteogenesis and demonstrated human fetal MSC (hfMSC) as a superior cellular candidate for off-the-shelf BTE applications. This relates to their superior proliferation capacity, more robust osteogenic potential and lower immunogenecity, as compared to MSC from perinatal and postnatal sources. Furthermore, we discuss our experience in developing a hfMSC based BTE strategy with the integrated use of bioreactor-based dynamic priming within macroporous scaffolds, now ready for evaluation in clinical trials. In conclusion, hfMSC is likely the most promising cell source for allogeneic based BTE application, with proven advantages compared to other MSC based ones. PMID- 22217807 TI - Malnutrition and cognitive impairment among people aged 60 years and above living in regular housing or in special housing in Sweden: a population-based cohort study. PMID- 22217808 TI - Are antiemetics still contraindicated for gastroenteritis in children? Solid evidence now supports the safe use of ondansetron. PMID- 22217809 TI - Nurses trained in the use of the ROSIER tool can assess signs and symptoms of stroke with comparable accuracy to doctors performing standard neurological assessment. PMID- 22217810 TI - Age, comorbidity and functional status influence end-of-life decisions in critical illness, while nationality, ethnicity and clinician experience influence the agressiveness of medical care. PMID- 22217811 TI - Perinatal depression. PMID- 22217812 TI - [CADASIL: Case report and literature review]. AB - CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leuko encephalo - pathy, is a rare hereditary disease characterized by recurrent transient ischemic attacks (TIA), strokes, and vascular dementia. It was first described in 1991 by Tourmier-Lasserve. The causative factor of CADASIL is mutations of the Notch3 gene located on chromosome 19. About 400 families have been diagnosed so far. Its clinical manifestations appear for the first time between 30 and 50 years of age and include attacks of migraine with aura, recurrent ischemic subcortical events, subcortical dementia and psychiatric disturbances varying from anxiety to severe depression, even psychotic disorders. Due to the rare incidence of CADASIL, many cases are still misdiagnosed or undiagnosed and are treated as ordinary psychiatric patients. The existing evidence implies that psychiatric disturbances and CADASIL co-occur so the possibility of a patient suffering from CADASIL should be considered in any individual having mental illness and a suggestive family history. This parer describes the psychiatric approach on a patient presenting anxiety, depression and a family history of CADASIL, who faces the dilemma of being diagnosed with CADASIL. PMID- 22217813 TI - [Renal failure: Biological and Psychosocial consequences]. AB - One of the most challenging patient groups that the psychiatrist of consultation liaison psychiatry is called to work with, are the patients with Renal Failure, since this disease is related to complicated and multidimensional physical and psychosocial problems. In this review, a holistic approach is attempted, considering the biological, psychological and psychosocial factors related to the disease and to specific therapeutical programs as well. The interaction of these factors and their impact not only on the course of the disease, but also on the quality of life are discussed. Finally, a brief report on psychosocial and pharmaceutical interventions indicated for this group of patients is made, especially concerning the psychological and psychosocial consequences of renal failure. PMID- 22217814 TI - [A questionnaire on Satisfaction from psychiatric Training]. AB - In the context of the psychiatric reform, as well as of the lifelong education, a Questionnaire for the evaluation of "Satisfaction from Psychiatric Training" has been constructed. It consists of 4 subscales (Satisfaction from Materials, Trainers, Program Organization, and General Satisfaction) and a total of 19 closed-ended items, evaluated in 5-point Likert scales, and an open-ended question for general remarks. One hundred and seventy six subjects, who participated in 8 consecutive training programs in psychiatry, organized by the Vocational Training Center of the Psychiatric Hospital of Petra Olympus, Greece, completed the questionnaire anonymously. The sample was divided into two groups: group A (N=112, from the first 5 programs), for the evaluation of the questionnaire's properties, and group B (N=65, from the next 3 programs) for the validation of the results. Principal component analysis in group A showed the existence of 4 factors corresponding to the 4 subscales and accounted for 67.4% of the questionnaire's variability, which were also confirmed in group B. Internal consistency was high in both groups for the overall questionnaire (Cronbach alpha>0.92) and for each subscale. Test-retest reliability of every subscale was also high (Pearson's r>0.90). The answers in the open-ended remark question were graded by two independent judges in a 5-point Likert scale, in relation to the satisfaction they revealed, which was highly correlated with all questionnaire subscales but one. For the total sample, the questionnaire subscales showed moderately high correlation with one another (r from 0.629 to 0.706) and even higher with the overall score (from 0.820 to 0.892). The questionnaire's sensitivity was demonstrated by the statistically significant differences observed in the satisfaction experienced from the various programs. None of the subscales was significantly correlated with age (r<0.134), with years in work (r<0.059) or was differentiated by gender. In general, this is a brief and easy to use satisfaction questionnaire for psychiatric training programs, with very satisfactory psychometric properties and relatively independent from demographic variables. It covers the four most important satisfaction components, independently from the specific characteristics of trainees or programs. Thus, it can be used as the main axis of satisfaction evaluation in a variety of programs. PMID- 22217815 TI - [Neuro-endocrinology of stress and immune mediated inflammation]. AB - The close interaction among factors stemming from the organic and the psychic spheres, in the formulation of the pathogenetic mechanism, underlying the initial signs and contributing to the course of a disease, is getting more obvious than ever. The theoretical background concerning participation of parameters from the psychic sphere and subsequent activation of cerebral systems-centres of stress, in the formulation of an organic basis of a disease, has been enriched with novel findings. The same happens with the study of the organic basis of psychiatric diseases. The development of scientific fields such as neuroendocrinology and psychoimmunology, that enlighten the relation of the psychomental status and stressful life events with the pathophysiology of organic systems, contributes towards this procedure. In this article, new findings concerning neuroendocrine mechanisms of stress are reviewed and implications of immune character are discussed. PMID- 22217816 TI - [Internet addiction disorder]. AB - According to recent epidemiological data, 18.9% of the world population are internet users (www. internetworldstats.com). Tauhis article attempts to determine the phenomenon of internet addiction disorder and to analyse the concepts of addiction and compulsiveness. The symptoms of internet addiction will be presented; the prevalence and demographic characteristics of internet addicts will be shown. Diagnostic tools developed for internet addiction, most susceptible populations, type of their personalities and integration of internet addiction disorder into the DSM-IV will be investigated in the present article. During the last decade, mental health specialists' research studies on internet addiction have not reached a consensus concerning the name, diagnostic criteria, diagnostic tools or introduction into the DSM-IV system. Nowadays, new technologies have penetrated into everyday life, while their influence is considerably growing, as the number of internet users is increasing. Therefore, it seems important for clinicians to include in their diagnostic interviews with patients questions investigating their relationship with the new technologies, as well as to recognize their impact in their patients' way of living. PMID- 22217817 TI - [Disorders of sweating in psychiatry]. AB - During the past few years psychiatric research has focused its interest on the disorders of sweating: hyperidrosis and hypoidrosis/anhidrosis. Hyperhydrosis is the most commonly encountered in practice. In this situation, the total amount of sweat produced is greater than needed for thermoregulation. The disorders of sweating receive the research attention of many medical specialties. This trend is attributed to their high prevalence, their relation with many psychiatric disorders, their effects on the quality of life of patients, but also of the new therapeutic approaches that have been developed (the use of botulinum toxin, surgical methods, etc). Balancing among different suggestions for the treatment of hyperhidrosis, the psychiatrist must be thoughtful for the therapeutic approach. The cases of hypohidrosis and anhidrosis are less frequently mentioned, for which patients hardly ever complain. They are characterized by reduced sweating below the amount needed to cool down an elevated body temperature, or even absent sweating. They may constitute an urgent medical situation leading to hyperthermia and death. Overall, disorders in sweating may be caused by pharmaceutical or hormonal causes. Many pharmaceutical and psychotherapeutic methods have been used for treatment. Therefore, we believe it is useful for the clinical psychiatrist to keep in mind the psychiatric and psychological aspects of the disorders of sweating, and their impact on patient diagnosis, course and treatment. PMID- 22217818 TI - [Non verbal communication. The body as a medium for expression in withdrawal attempt]. AB - Development is a continuous procedure of innate and extraneous factors. Any behavior, adaptation or experience can be expressed by the human body. During communication, the biggest part is carried out by non verbal communication. The human body plays the most important role to conscious of the relationship between movement and expression ability during communication. Drug addicted people assign themselves, psychologically and biologically to "substance". So, every withdrawal attempt should work not only with the psychical part of the addiction, but with the physical dimension, too. Then, it can be thought as completed. The purpose of this study is to present "body awareness groups", which work out in an alternative "therapy" program to deal with addiction to drug. The purpose of these groups is to help drug addicted people to realize that their body can be a medium for expressing emotions and communication. Member's participation and behavior compares and assesses with their general function to the rest of the "therapeutic groups". The result of this assessment refers to the total psychological and biological withdrawal attempt. PMID- 22217819 TI - A simple method of maintaining chilled saline in the prehospital setting. AB - OBJECTIVE: Mild therapeutic hypothermia has been shown to improve neurologic outcomes after sudden cardiac arrest. Therapeutic hypothermia should be started as soon as return of spontaneous circulation occurs. However, saline is difficult to keep chilled in the prehospital environment. We sought to determine whether a cooler and ice packs could keep saline cold under prehospital conditions. METHODS: In phase 1 of the experiment, two 1000-mL bags of prechilled 0.9% normal saline were placed in a cooler with 3 ice packs. An additional bag of 1000-mL 0.9% normal saline remained outside the cooler as a control. Over 9 consecutive days, we measured the ambient air temperature and the temperature of each bag of saline every 4 hours. In phase 2 of the experiment, the cooler was kept sealed, and the temperature of the saline was measured after 24 hours. RESULTS: The mean temperatures over 24 hours ranged as follows: ambient temperature, 24 degrees C to 27.2 degrees C; bottom bag, 0.6 degrees C to 3.5 degrees C; top bag, 1.4 degrees C to 5.7 degrees C; and control bag, 9.8 degrees C to 26.8 degrees C. A t test was used to compare the chilled saline against the control bag. Statistical significance (P < .05) was achieved at all times. In phase 2 of the experiment, after 24 hours, 100% of the bottom bags and 93% of the top bags were less than 6 degrees C. CONCLUSIONS: Our data demonstrate that saline can be kept chilled in ambulances for 24 hours using ice packs and coolers. The estimated cost is less than $50.00 per ambulance. Using coolers and ice packs is an inexpensive way for emergency medical service agencies to initiate prehospital hypothermia. PMID- 22217820 TI - Small-bore catheter versus chest tube drainage for pneumothorax. AB - STUDY OBJECTIVE: The aim of the study was to compare the effectiveness of drainage via a single-lumen (5F catheter) central venous catheter (CVC) to a conventional (14-20 F catheter) chest tube (CT) for the management of pneumothoraces, including primary spontaneous pneumothorax (PSP), secondary spontaneous pneumothorax (SSP), and traumatic and iatrogenic pneumothoraces. PATIENTS: All consecutive patients admitted to the intermediate intensive care unit of a university hospital for pneumothorax were retrospectively screened over an 8-year period. Patients were preferentially treated using CT from 2003 to 2007 and using CVC from 2008 to 2010. Drainage failure was defined as the need for a second drainage procedure or for surgery. RESULTS: Of 212 patients included, 117 (55%) had PSP, 28 (13%) had SSP associated with chronic obstructive pulmonary disease, 19 (9%) had traumatic pneumothorax, and 48 (23%) had iatrogenic pneumothorax. The failure rate was 23% in PSP, 36% in SSP, 16% in traumatic pneumothorax, and only 2% in iatrogenic pneumothorax. After adjustment, iatrogenic pneumothorax was the only factor that had an influence on drainage failure. The failure rate was similar between the 112 patients treated using CVC and the 100 patients treated using CT (18% vs 21%, P = .60). However, the durations of drainage (3.3 +/- 1.9 vs 4.6 +/- 2.6 days, P < .01) and of hospital stay were significantly shorter in patients treated using CVC as compared with CT. CONCLUSION: Our findings suggest that drainage via a catheter or via a CT is similarly effective in the management of pneumothorax. We recommend considering drainage via a small-bore catheter as a first-line treatment in patients with pneumothorax, whatever its cause. PMID- 22217821 TI - Current research on steroid metabolism: transition from biochemistry to molecular cell biology. PMID- 22217822 TI - Regulation of cholesterol movement to mitochondrial cytochrome P450scc in steroid hormone synthesis. AB - Transfer of cholesterol to cytochrome P450scc is generally the rate-limiting step in steroid synthesis. Depending on the steroidogenic cell, cholesterol is supplied from low or high density lipoproteins (LDL or HDL) or de novo synthesis. ACTH and gonadotropins stimulate this cholesterol transfer prior to activation of gene transcription, both through increasing the availability of cytosolic free cholesterol and through enhanced cholesterol transfer between the outer and inner mitochondrial membranes. Cytosolic free cholesterol from LDL or HDL is primarily increased through enhanced cholesterol ester hydrolysis and suppressed esterification, but increased de novo synthesis can be significant. Elements of the cytoskeleton, probably in conjunction with sterol carrier protein(2) (SCP(2)), mediate cholesterol transfer to the mitochondrial outer membranes. Several factors contribute to the transfer of cholesterol between mitochondrial membranes; steroidogenesis activator peptide acts synergistically with GTP and is supplemented by SCP(2). 5-Hydroperoxyeicosatrienoic acid, endozepine (at peripheral benzodiazepine receptors), and rapid changes in outer membrane phospholipid content may also contribute stimulatory effects at this step. It is suggested that hormonal activation, through these factors, alters membrane structure around mitochondrial intermembrane contact sites, which also function to transfer ADP, phospholipids, and proteins to the inner mitochondria. Cholesterol transfer may occur following a labile fusion of inner and outer membranes, stimulated through involvement of cardiolipin and phosphatidylethanolamine in hexagonal phase membrane domains. Ligand binding to benzodiazepine receptors and the mitochondrial uptake of 37 kDa phosphoproteins that uniquely characterize steroidogenic mitochondria could possibly facilitate these changes. ACTH activation of rat adrenals increases the susceptibility of mitochondrial outer membranes to digitonin solubilization, suggesting increased cholesterol availability. Proteins associated with contact sites were not solubilized, indicating that this part of the outer membrane is resistant to this treatment. Two pools of reactive cholesterol within adrenal mitochondria have been distinguished by different isocitrate- and succinate-supported metabolism. These pools appear to be differentially affected in vitro by the above stimulatory factors. PMID- 22217823 TI - The role of the cytoskeleton in the regulation of steroidogenesis. AB - The slow step in steroid synthesis involves the transport of cholesterol from lipid droplets in the cytoplasm to the first enzyme in the pathway-the cytochrome P450 that converts cholesterol to pregnenolone (P450scc) which is located in the inner mitochondrial membrane. ACTH stimulates this intracellular transport of cholesterol in adrenal cells (Y-1 mouse adrenal tumour cells and cultured bovine fasciculata cells) and this effect of the trophic hormone is inhibited by cytochalasins, by anti-actin antibodies and DNase I suggesting that the response to ACTH requires a pool of monomeric (G-) actin that can be polymerized to F actin. Recent studies have shown that lipid droplets and mitochondria of adrenal cells are both attached to intermediate filaments. Moreover ACTH reorganizes the cytoskeleton and changes the shape of the cell. These observations suggest a mechanism for transport of cholesterol that involves reorganization and contraction of actin microfilaments which may, in turn, cause movement of droplets and mitochondria together through their common attachment to intermediate filaments. PMID- 22217824 TI - Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis. AB - In the pathways of steroid hormone biosynthesis there are two major types of enzymes: cytochromes P450 and other steroid oxidoreductases. This review presents an overview of the function and expression of both types of enzymes with emphasis on steroidogenic P450s. The final part of the review on regulation of steroidogenesis includes a description of the normal physiological fluctuations in the steroid output of adrenal cortex and gonads, and provides an analysis of the relative role of enzyme levels in the determination of these fluctuations. The repertoire of enzymes expressed in a steroidogenic cell matches the cell's capacity for the biosynthesis of specific steroids. Thus, steroidogenic capacity is regulated mainly by tissue and cell specific expression of enzymes, and not by selective activation or inhibition of enzymes from a larger repertoire. The quantitative capacity of steroidogenic cells for the biosynthesis of specific steroids is determined by the levels of steroidogenic enzymes. The major physiological variations in enzyme levels, are generally associated with parallel changes in gene expression. The level of expression of each steroidogenic enzyme varies in three characteristics: (a) tissue- and cell-specific expression, determined during tissue and cell differentiation; (b) basal expression, in the absence of trophic hormonal stimulation; and (c) hormonal signal regulated expression. Each of these three types of expression probably represent the functioning of distinct gene regulatory elements. In adult steroidogenic tissues, the levels of most of the cell- and tissue-specific steroidogenic enzymes depend mainly on trophic hormonal stimulation mediated by a complex network of signal transduction systems. PMID- 22217825 TI - Structure, function and tissue-specific gene expression of 3beta-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase enzymes in classical and peripheral intracrine steroidogenic tissues. AB - The membrane-bound enzyme 3beta-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase (3beta-HSD) catalyses an essential step in the transformation of all 5 pregnen-3beta-ol and 5-androsten-3beta-ol steroids into the corresponding 3-keto 4-ene-steroids, namely progesterone as well as all the precursors of androgens, estrogens, glucocorticoids and mineralocorticoids. We have recently characterized two types of human 3beta-HSD cDNA clones and the corresponding genes which encode type I and II 3beta-HSD isoenzymes of 372 and 371 amino acids, respectively, and share 93.5% homology. The human 3beta-HSD genes containing 4 exons were assigned by in situ hybridization to the p11-p13 region of the short arm of chromosome 1. Human type I 3beta-HSD is the almost exclusive mRNA species present in the placenta and skin while the human type II is the predominant mRNA species in the adrenals, ovaries and testes. The type I protein possesses higher 3beta-HSD activity than type II. We elucidated the structures of three types of rat 3beta HSD cDNAs as well that of one type of 3beta-HSD from bovine and macaque ovary lambdagt11 cDNA libraries, which all encode a 372 amino acid protein. The rat type I and II 3beta-HSD proteins expressed in the adrenals, gonads and adipose tissue share 93.8% homology. Transient expression of human type I and II as well as rat type I and II 3beta-HSD cDNAs in HeLa human cervical carcinoma cells reveals that 3beta-ol dehydrogenase and 5-ene-4-ene isomerase activities reside within a single protein. These expressed 3beta-HSD proteins convert 3beta-hydroxy 5-ene-steroids into 3-keto-4-ene derivatives and catalyze the interconversion of 3beta-hydroxy and 3-keto-5alpha-androstane steroids. By site-directed mutagenesis, we demonstrated that the lower activity of expressed rat type II compared to rat type I 3beta-HSD is due to a change of four residues probably involved in a membrane-spanning domain. When homogenates from cells transfected with a plasmid vector containing rat type I 3beta-HSD is incubated in the presence of dihydrotestosterone (DHT) using NAD+ as co-factor, 5alpha androstanedione was formed (A-dione), indicating an intrinsic androgenic 17beta hydroxysteroid dehydrogenase (17beta-HSD) activity of this 3beta-HSD. We cloned a third type of rat cDNA encoding a predicted type III 3beta-HSD specifically expressed in the rat liver, which shares 80% similarity with the two other isoenzymes. Transient expression in human HeLa cells reveals that the type III isoenzyme does not display oxidative activity for the classical substrates of 3beta-HSD. However, in common with the type I enzyme, it converts A-dione and DHT to the corresponding 3beta-hydroxysteroids, thus showing an exclusive 3 ketosteroid reductase activity. When NADPH is used as co-factor, the affinity for DHT of the type III enzyme becomes 10-fold higher than that of the type I. Rat type III mRNA was below the detection limit in intact female liver. Following hypophysectomy, its concentration increased to 55% of the values measured in intact or hypophysectomized male rats, an increase which can be blocked by administration of ovine prolactin (oPRL). Treatment with oPRL for 10 days starting 15 days after hypophysectomy markedly decreased ovarian 3beta-HSD mRNA accumulation accompanied by a similar decrease in 3beta-HSD activity and protein levels. Treatment with the gonadotropin hCG reversed the potent inhibitory effect of oPRL on these parameters and stimulated 3beta-HSD mRNA levels in ovarian interstitial cells. These data indicate that the presence of multiple 3beta-HSD isoenzymes offers the possibility of tissue-specific expression and regulation of this enzymatic activity that plays an essential role in the biosynthesis of all hormonal steroids in classical as well as peripheral intracrine steroidogenic tissues. PMID- 22217826 TI - Molecular biology of 11beta-hydroxylase and 11beta-hydroxysteroid dehydrogenase enzymes. AB - There are two steroid 11beta-hydroxylase isozymes encoded by the CYP11B1 and CYP11B2 genes on human chromosome 8q. The first is expressed at high levels in the normal adrenal gland, has 11beta-hydroxylase activity and is regulated by ACTH. Mutations in the corresponding gene cause congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency; thus, this isozyme is required for cortisol biosynthesis. The second isozyme is expressed at low levels in the normal adrenal gland but at higher levels in aldosterone-secreting tumors, and has 11beta hydroxylase, 18-hydroxylase and 18-oxidase activities. The corresponding gene is regulated by angiotensin II, and mutations in this gene are found in persons who are unable to synthesize aldosterone due to corticosterone methyloxidase II deficiency. Thus, this isozyme is required for aldosterone biosynthesis. Cortisol and aldosterone are both effective ligands of the "mineralocorticoid" receptor in vitro, but only aldosterone is a potent mineralocorticoid in vivo. This apparent specificity occurs because 11beta-hydroxysteroid dehydrogenase in the kidney converts cortisol to cortisone, which is not a ligand for the receptor. This enzyme is a "short-chain" dehydrogenase which is encoded by a single gene on human chromosome 1. It is possible that mutations in this gene cause a form of childhood hypertension called apparent mineralocorticoid excess, in which the mineralocorticoid receptor is not protected from high concentrations of cortisol. PMID- 22217827 TI - In vivo regulation of gene expression of enzymes controlling aldosterone synthesis in rat adrenal. AB - We studied the effect of alterations in the intake of sodium and potassium as well as changes in circulating adrenocorticotropin (ACTH) on the expression of the two rate-limiting systems of aldosterone formation in the rat. Low sodium and high potassium intake promoted time-dependent increases in the zona glomerulosa cytochrome P450scc (P450scc) and cytochrome P450c11 (P450c11) protein and mRNA levels, but no changes were found in the zona fasciculata-reticularis. In addition, these responses were associated with markedly elevated transcriptional activities. To further define the contribution of P450c11 and P450c18 (aldosterone synthase) in response to these differing intakes, we evaluated their mRNA levels using gene-specific oligonucleotide probes. P450c18 mRNA was restricted to the zona glomerulosa, whereas P450c11 mRNA was detected in both zona glomerulosa and zona fasciculata-reticularis. Furthermore, only P450c18 mRNA was induced by both low sodium or high potassium intake, as P450c11 mRNA levels remained unchanged. Captopril, an inhibitor of angiotensin-I converting enzyme, abolished the enhancing effects of the low sodium regimen on P450scc and P450c18 mRNA levels. Captopril also suppressed the augmentation of P450c18 mRNA observed with potassium supplementation but had no effect on P450scc mRNA levels. When the hypocholesterolemic drug 4-aminopyrazolopyrimidine (4-APP) was administered to rats for 3 consecurive days, both the level of plasma ACTH and the adrenal content of mRNA encoding P450scc increased 24 h post final injection. The coadministration of dexamethasone with 4-APP prevented these increases. In contrast, the mRNA content of P450c11 remained at control levels. In conclusion, this work demonstrates that variations in the intake of sodium and potassium act on the expression of the CYP11B2 gene, but not on that of the CYP11B1 gene. Moreover angiotensin-II (A-II) is an important factor in this mechanism of action. Both ions also enhance the expression of the CYP11A1 gene. A-II appears to participate in the mechanism of action of the low sodium intake at this level. Another mechanism is postulated for the action of potassium supplementation since captopril did not prevent the increased expression of the CYP11A1 gene. In addition, the fact that 4-APP enhanced the mRNA level of P450scc but not that of P450c, also demonstrates different regulation of the P450s involved at the early and final steps of aldosteroone formation in the rat adrenal zona glomerulosa in vivo. PMID- 22217828 TI - Angiotensin-II-directed glomerulosa cell function in fetal adrenal cells. AB - These studies were undertaken to examine the role of angiotensin II (A-II) in the regulation of adrenal glomerulosa cell differentiation. We were interested particularly in the ability of A-II to support aldosterone production in fetal adrenal cells. Many in vitro studies on acute A-II stimulation of aldosterone synthesis in adrenocortical cells have been documented. However, it is the long term modification of steroid-metabolizing enzyme expression that leads to the formation and release of specific adrenal steroids. Herein, we used primary cultures of fetal bovine adrenal (FBA) cells to examine the effects of A-II on aldosterone production and the expression of aldosterone synthase cytochrome P450 (P450c18). A-II treatment caused the primary cultures to maintain glomerulosa cell functions. Cells treated for 3 days with A-II increased aldosterone production by 10-fold. A-II stimulation of aldosterone production occurred rapidly (within 30 min) and in a dose-dependent manner. In addition, A-II enhanced the activity of P450c18, the enzyme responsible for conversion of corticosterone to aldosterone. A-II also suppressed ACTH-promoted cortisol production, while increasing ACTH-stimulated release of aldosterone. It appears that these effects of chronic treatment with A-II were mediated through an A-II type 1 (AT(1)) receptor since the AT(1) receptor antagonist, Dup753, blocked aldosterone production and the increased P450c18 activity. Receptor binding studies suggest that FBA cells possess approx. 110,000 AT(1) binding sites/cell with K(d) = 1.8 * 10(-9) M. Via AT(1) receptors, A-II was able to stimulate both inositol phosphates and cAMP production. The stimulation of cAMP production, however, was much less than seen following ACTH treatment. These data give support to the hypothesis that A-II is involved in the differentiation of fetal adrenal cells into glomerulosa cells. This process appears to be mediated through regulation of steroid-metabolizing enzyme expression and the activation of steroid production. PMID- 22217829 TI - Steroidogenesis in guinea pig adrenal cortex: effects of ACTH on steroid secretion and steroidogenic enzyme activities and expression. AB - In this study, we investigated guinea pig adrenal steroidogenesis, specially, C19 steroid production. Analysis of adrenal steroids by high performance liquid chromatography and gas chromatography indicated the presence of androstenedione and 11beta-hydroxyandrostenedione. Adrenal androstenedione and 11beta hydroxyandrostenedione levels were stimulated by ACTH administration while only 11beta-hydroxyandrostenedione was increased in plasma. In vitro studies using adrenal cortex cells in primary culture confirmed that 11beta hydroxyandrostenedione is the major C19 steroid secreted. The chronic treatment of guinea pig with ACTH stimulated all adrenal post-pregnenolone enzyme activities and decreased P 450c17 mRNA levels while P 450scc, 3beta hydroxysteroid dehydrogenase and P450c11 mRNAs remained unaffected. Treatment of adrenal cells in primary culture with ACTH for 72 h changed the distribution of steroids secreted and decreased 21-hydroxylase activity while 17alpha-hydroxylase and 17,20-lyase activities were increased favoring C19 steroid production. In ACTH-treated cells, the mRNA levels for P450c21 and P450c17 increased and reached a peak at 18 h. Our data indicate that treatment with ACTH stimulates adrenal steroidogenic capacity by increasing steroid secretion and causes transcriptional and post-transcriptional effects on steroidogenic enzymes gene expression. Finally, the direct action of steroids on steroid production by adrenal cells in primary culture was investigated. Our data indicate that steroids themselves increase C19 steroid synthesis and inhibit glucocorticoid production without affecting gene expression for steroidogenic enzymes. PMID- 22217830 TI - Cytochrome P450s in the guinea pig adrenal that are immunologically similar to liver forms: estrogen suppression explains male-female differences. AB - Several cytochrome P450s have been identified in guinea pig adrenal microsomes which are distinct from the known steroidogenic P450s, c17 and c21, and are immunochemically related to cytochrome P450s found in liver. One, a 52 K protein related to P450 I (CYP1), occurs almost exclusively in males, is localized to the inner zone, and is suppressed by ACTH. Its levels correlate with microsomal capacity for xenobiotic metabolism. The others, related to P450s II and III (CYP2 and 3), are more predominant in males, but not exclusive to them, are found in both the inner and outer zones, and are not suppressed by ACTH. Their functions remain to be elucidated. The male predominance of the CYP1-related protein has recently been shown to be due to suppression of the protein in females by estrogen. To determine if estrogen is also involved in the regulation of the CYP2 related proteins, ovariectomized and sham-operated animals were treated with a long-acting estrogen, estradiol valerate, or with the vehicle alone. These P450s reached male levels in ovariectomized females treated only with the vehicle. Their enhanced levels were suppressed by treatment with estrogen. Estrogen treatment also suppressed the levels of the P450s seen in sham-operated females. Endogenous estrogen produced similar effects. In hemi-ovariectomized females the contralateral ovary hypertrophied, a state in which estrogen levels would be maintained or increased. In these females no increase occurred in the immunodetectable P450s. In normal females, estrogen levels are low in prepubertal animals, rise at the time of puberty and drop again after ovarian cycling is completed. The CYP2-related proteins were present in adrenal microsomes of prepubertal females, but were suppressed after puberty. On the other hand, post estrous females, in whom estrogen levels would be low, acquired male levels of these proteins in their adrenal microsomes. P450c17 and P450c21, as well as 3beta hydroxysteroid dehydrogenase, were not affected by surgery or estrogen. Taken together, these experiments indicate that suppression by estrogen in females can account, in large part, for the predominance of several immunochemical homologs of liver P450s in adult male guinea pig adrenals. PMID- 22217831 TI - P450scc regulation in pig granulosa cells: investigation into the mechanism of induction. AB - P450scc catalyses the first and rate-limiting reaction in steroidogenesis and is hormonally regulated. By Northern analysis, using a bovine cDNA probe, we have studied the regulation of P450scc mRNA in pig granulosa cells cultivated in vitro. Using transcription and translation inhibitors, we show that the gonadotropin-induced accumulation of P450scc mRNA mainly results from increased transcription, and that this stimulation, at least in part, is protein synthesis dependent. Although transcriptional regulation of P450scc gene expression is found in other steroidogenic cells, cycloheximide-sensitivity of this regulation is not widespread. Pig granulosa cells thus would constitute a useful model to study this mechanism of regulation. PMID- 22217832 TI - Oncogene-transformed granulosa cells as a model system for the study of steroidogenic processes. AB - Highly steroidogenic granulosa cell lines were established by transfection of primary granulosa cells from preovulatory follicles with SV40 DNA and Ha-ras oncogene. Progesterone production in these cells was enhanced to levels comparable to normal steroidogenic cells, by prolonged (> 12 h) stimulation with 8-Br-cAMP, forskolin and cholera toxin, which elevate intracellular cAMP. The steroidogenic capacity of individual lines correlated with the expression of the ras oncogene product (p21) and the morphology of the cells. Formation of the steroid hormones was associated with de novo synthesis of the mitochondrial cytochrome P450scc system proteins. Since cholesterol import into mitochondria is essential for steroidogenesis, the expression of the peripheral benzodiazepine receptor (PBR) and the sterol carrier protein 2 was characterized in these cells. The induction of the expression of the genes coding for both proteins appeared to be mediated, at least in part, by cAMP. Stimulation of the PBR by specific agonists enhanced progesterone production in these cells. The phorbol ester 12-O tetradecanoyl-phorbol 13-acetate (TPA) dramatically suppressed the cAMP-induced steroidogenesis, in spite of enhanced intracellular cAMP levels, suggesting that TPA can modify the effects of cAMP. cAMP stimulation suppressed growth of transformed cells concomitantly with induction of steroidogenesis. The transformed cells lacked receptors for the native stimulants, the gonadotropic hormones. After transfection of the cells with a lutropin (LH) receptor expression plasmid, the LH and hCG response was reconstituted. In these newly established cell lines gonadotropins were able to stimulate the formation of cAMP and progesterone in a dose-dependent manner with an ED50 characteristic of the native receptor. High doses caused desensitization to gonadotropins as observed in normal cells. These newly established oncogene-transformed granulosa cell lines can serve as a useful model to study inducible steroidogenesis and the effect of oncogene expression on this process. PMID- 22217833 TI - Adrenergic influence on progesterone metabolism and cyclicity in the rat ovary: autotransplantation and chemical sympathectomy. AB - Elimination of adrenergic nerve endings by chemical sympathectomy with 6 hydroxydopamine of normally cycling rats produced no differences in the weights of body, uterus, ovaries or adrenals, but suppressed significantly proestrus/estrus stages. Unilateral fully denervated (autotransplanted) ovaries showed the following changes in [14C]progesterone metabolism: the formation of 20alpha-hydroxy-4-pregnen-3-one increased, whereas 5alpha-pregnane-3alpha,20alpha and 3beta,20alpha-diol, 3alpha- and 3beta-hydroxy-5alpha-pregnan-20-one, 20alpha hydroxy-5alpha-pregnan-3-one, an unidentified metabolite Y and a group of hydrophobic metabolites decreased dramatically. Enzyme activities could not be restored with epinephrine. Sympathectomy changed the spectrum of [14C] progesterone metabolites in the same direction, but only at diestrus and metestrus. Autotransplantation suppressed 5alpha-reductase, 3alpha- and 3beta hydroxysteroid dehydrogenase activities (-HSD) measured by the sum of all 5alpha , 3alpha, and 3beta-metabolites, respectively. Sympathectomy suppressed significantly 5alpha-reductase and 3alpha-HSD at metestrus. 20alpha-HSD was not changed in any experiment. These studies provide evidence that 5alpha-reductase depends on adrenergic input in ovaries of rats at metestrus, a stage of nadir of gonadotropins. During the estrous cycle 5alpha-reductase may be a regulatory enzyme for progesterone metabolism and also influence estradiol biosynthesis. PMID- 22217835 TI - The role of cytokines in the regulation of Leydig cell P450c17 gene expression. AB - Cytokines produced by immune-activated testicular interstitial macrophages (TIMs) may play a fundamental role in the local control mechanisms of testosterone biosynthesis in Leydig cells. We investigated whether in vivo immune-activation of TIMs can modulate Leydig cell steroidogenesis. To immune activate TIMs in vivo, mice were injected intraperitoneally (i.p.) with lipopolysaccharide (LPS, 6 mg/kg). TIMs and Leydig cells were purified for RNA analysis. LPS treatment resulted in a 47-fold increase in interleukin-1beta (IL-1beta) mRNA in TIMs. P450c17 mRNA levels in the Leydig cells from the same animals, decreased to less than 10% compared to control. The effect of LPS on IL-1beta and P450c17 mRNA levels was reversible on both TIMs and Leydig cells, respectively. To determine if the effect of LPS on P450c17 was mediated by a possible decrease in pituitary LH secretion, mice were co-injected with LPS and hCG. Treatment with hCG did not change the effect observed with LPS alone, in TIMs or in Leydig cells. In vitro, LPS treatment of TIMs resulted in marked induction of IL-1beta mRNA expression. In parallel, in vitro treatment of Leydig cells with recombinant IL-1 resulted in a dose-dependent inhibition of P450c17 mRNA expression and testosterone production. These data demonstrate that LPS treatment, in vivo and in vitro, induced IL-1 gene expression in TIMs, and that IL-1 inhibits P450c17 mRNA in vitro. Therefore, we suggest that immune-activation of TIMs might have caused the observed inhibition of P450c17 gene expression in Leydig cells in vivo. PMID- 22217834 TI - Hormonal regulation of steroidogenic enzyme gene expression in Leydig cells. AB - In normal mouse Leydig cells, steady state levels of mRNA of CYP11A, 3beta hydroxysteroid dehydrogenase Delta5- >Delta4-isomerase (3betaHSD), and CYP17 are differentially regulated. There is high basal expression of 3betaHSD and CYP11A mRNA, while expression of CYP17 mRNA is absolutely dependent on cAMP stimulation. cAMP is required for maximal expression of all three enzymes. The expression of CYP11A in normal mouse Leydig cells is repressed by glucocorticoids. Glucocorticoids also repress both basal and cAMP-induced expression of 3betaHSD mRNA, but do not repress the synthesis or mRNA levels of CYP17. cAMP induction of 3betaHSD mRNA can be observed only when aminoglutethimide (AG), an inhibitor of cholesterol metabolism, is added to the Leydig cell cultures. The addition of AG also markedly increases cAMP induction of CYP17 mRNA levels. Addition of testosterone or the androgen agonist, mibolerone, to cAMP plus AG treated cultures reduced 3betaHSD and CYP17 mRNA levels to levels comparable to those observed when cells were treated with cAMP only. These data indicate that testosterone acting via the androgen receptor represses expression of both CYP17 and 3betaHSD. The role of protein synthesis in mediating the cAMP induction of 3betaHSD, CYP17 and CYP11A was examined. The addition of cycloheximide, an inhibitor of protein synthesis, to cAMP treated cultures for 24 h completely suppressed both constitutive and cAMP-induced 3betaHSD mRNA levels. Cycloheximide also repressed cAMP-induced levels of CYP17 to 12% of levels observed in the absence of cycloheximide. In sharp contrast, treatment for 24 h with cycloheximide did not suppress cAMP induction of CYP11A mRNA, but reduced basal levels by approx. 50%. These data indicate that newly synthesized protein(s) are required for cAMP induction of CYP17 and 3betaHSD mRNA levels, but not for CYP11A mRNA. A mouse Cyp17 genomic clone containing the entire coding region plus 10 kb of 5' flanking region has been isolated. Fragments of 5' flanking sequences were subcloned into vectors containing the CAT reporter gene and transfected into MA 10 Leydig cells. Transfected cells were treated with cAMP and expression was determined by measuring CAT activity. A cAMP responsive element was identified in a region between -245 and -346 bp relative to the transcription initiation site of Cyp17. Cotransfection into MA-10 Leydig cells of constructs containing 4.5 kb of Cyp17 5' flanking sequences together with a mouse androgen receptor expression vector demonstrate a dose dependent repression of cAMP-induced Cyp17 transcription by the androgen receptor. Studies with the mouse Cyp11a gene demonstrate that the 5' flanking region of the gene contains sequences between 2.5 and 5 kb that are necessary for expression of mouse Cyp11a in Leydig cells but not in adrenal cells. PMID- 22217836 TI - Regulation of expression of 3beta-hydroxysteroid dehydrogenase is mediated by cAMP in rat Leydig cells and H540 rat Leydig tumor cells. AB - Leydig cells isolated from testes of adult rats have a relatively high level of expression of 3beta-hydroxysteroid dehydrogenase/Delta(5->4)isomerase (3betaHSD) in primary culture. Agents which increase the intracellular levels of cAMP such as forskolin, dibutyryl cAMP, and LH can positively regulate the expression of 3betaHSD in Leydig cells in vitro. The effects of these agents are manifest at several levels and include increases in (1) 3betaHSD activity, (2) the cellular levels of immunoreactive 3betaHSD, (3) the rate of synthesis of 3betaHSD, and (4) the cellular levels of 3betaHSD mRNA which can be readily translated into 3betaHSD in vitro. Two rat Leydig tumor cell lines which are steroidogenically active, H540 and R2C cells, also have a relatively high level of expression of 3betaHSD. Forskolin can positively regulate the expression of 3betaHSD in H540 Leydig tumor cells in which steroidogenesis is responsive to increases in intracellular cAMP, but it has no effect on 3betaHSD in R2C Leydig tumor cells in which steroidogenesis is unresponsive to increases in intracellular cAMP. These results clearly support the hypothesis that cAMP mediates transcriptional regulation of 3betaHSD in Leydig cells. The implication of these in vitro studies is that, in vivo, LH is required to maintain optimal levels of expression of the gene encoding testicular 3betaHSD. PMID- 22217837 TI - Regulation of human aromatase cytochrome P450 gene expression. AB - In the human, estrogen biosynthesis occurs in several tissue sites, including ovary, placenta, adipose, and brain. Recent work from our laboratory has indicated that tissue-specific expression of aromatase cytochrome P450 (P450arom), the enzyme responsible for estrogen biosynthesis, is determined, in part, by the use of tissue-specific promoters. Thus the expression of P450arom in human ovary appears to utilize a promoter proximal to the translation start-site. This promoter is not utilized in placenta but instead, the promoter used to drive aromatase expression in placenta is at least 40 kb upstream from the translational start-site. In addition, there is a minor promoter used in the expression of a small proportion of placental transcripts which is 9 kb upstream from the start of translation. Transcripts from these promoters are also expressed in other fetal tissues including placenta-related cells such as JEG-3 choricarcinoma cells, hydatidiform moles, and other fetal tissues such as fetal liver. On the other hand, in adipose tissue expression of P450arom may be achieved by yet another, adipose-specific promoter. The various 5'-untranslated exons unique for expression driven by each of these promoters are spliced into a common intron/exon boundary upstream from the translational start-site. This means that the protein expressed in each of the various tissue-specific sites of estrogen biosynthesis is identical. PMID- 22217838 TI - Comparison of cAMP-responsive DNA sequences and their binding proteins associated with expression of the bovine CYP17 and CYP11A and human CYP21B genes. AB - Maintenance of optimal steriodogenic capacity in the adrenal cortex requires the action of the peptide hormone ACTH. Upon binding to its cell surface receptor ACTH activates adenylate cyclase leading to elevated levels of intracellular cAMP which in turn enhances transcription of the genes encoding the enzymes involved in the conversion of cholesterol to the steroid hormones. By deletion analysis of their upstream regions, the genes encoding the steroid hydroxylases P450c17, P450c21 and P450scc (CYP17, CYP21B and CYP11A, respectively) were found to contain unique cAMP-responsive sequences (CRSs). These sequences are unique in the sense that they have not previously been described to be associated with other genes whose transcription is regulated by cAMP. Furthermore they appear to bind unique nuclear proteins or transcription factors not previously associated with cAMP-dependent transcription. This review summarizes the relatedness of these CRSs in the bovine CYP17 and CYP11A genes and the human CYP12B gene and provides an up-to-date summary of the properties of their nuclear DNA-binding proteins. PMID- 22217840 TI - Changes in gene expression during senescence of adrenocortical cells in culture. AB - Bovine adrenocortical cells undergo a process in which expression of steroid hydroxylases is lost progressively as a function of population doubling level (PDL) in culture. Each cytochrome P450 shows a characteristic rate of loss of expression as a function of PDL (in order of rates of loss: CYP11B >CYP21 >CYP17 >CYP11A). CYP11B and CYP21 require insulin-like growth factor I as well as cyclic AMP; these are the only factors required for induction in the primary culture. Middle- and later passage cells do not express CYP11B and CYP21 under the same conditions, but will do so when cells are grown in extracellular matrix Matrigel. In late-passage cells neither CYP17, CYP21, nor CYP11B are expressed, even in the presence of Matrigel; only CYP11A is expressed in late-passage cultures. When the different environmental factors required for induction of CYP11B and CYP21 are taken into account, induction of these genes disappears with the same kinetics as previously shown for CYP17 as a function of PDL. The primary cause of the loss of expression of these genes is likely to be a phenotypic switching event similar to that previously demonstrated for CYP17 by in situ hybridization. The mechanism of phenotypic switching is unknown. However, one HpaII site at -2.3 kb of CYP17 was methylated in the bovine adrenal cortex in vivo but showed rapid and complete demethylation when adrenocortical cells were placed in culture. This indicates a unique, reproducible, environmentally determined change in methylation, with as yet undetermined consequences. However, data from reporter constructs suggest that phenotypic switching does not result from a simple loss of regulatory factors that act within 2.5 kb of the promoter. Previous data suggested that SV40 T antigen may affect phenotypic switching, and thus that SV40 may be useful for the derivation of functional adrenocortical cell lines. Adaptation of methods previously used for bovine cells to human adrenocortical cells to produce SV40 T antigen-transfected clones yielded data indicating preservation of essential aspects of the human adrenocortical cell differentiated phenotype. PMID- 22217839 TI - Promoter elements of the mouse 21-hydroxylase (Cyp-21) gene involved in cell selective and cAMP-dependent gene expression. AB - Cyp-21 (the mouse steroid 21-hydroxylase gene) is expressed exclusively in cells of the adrenal cortex, is induced by ACTH and cAMP, and is required for corticosteroid synthesis. This review examines the molecular basis for the regulated expression of Cyp-21 in the ACTH-responsive, mouse adrenocortical tumor cell line, Y1. We demonstrate that 330 bp of 5'-flanking DNA from the Cyp-21 gene are sufficient for cell-selective and ACTH-induced expression of Cyp-21, and that this promoter region comprises multiple, closely spaced enhancer elements each of which is required for promoter function. Within this promoter, we define three related elements that contain variations of an AGGTCA motif and that contribute to the cell-selective expression of Cyp-21. Variations of these same AGGTCA bearing elements are also involved in the expression of Cyp 11a and Cyp 11b in Y1 adrenocortical cells. These elements interact with the same or closely related nuclear proteins found only in steroidogenic cell lines. Taken together, these results suggest that shared elements contribute to the adrenal cell-selective expression of at least three steroidogenic cytochrome P450 genes. The element at 170 and the related elements at -65, -140 and -210 in the Cyp-21 promoter are not active as enhancers in the mutant Y1 cell line, Kin-8. Kin-8 cells contain a mutation in the regulatory subunit of the type 1 cAMP-dependent protein kinase that renders the enzyme resistant to activation by cAMP. Therefore, these elements appear to be selectively dependent upon an intact cAMP-dependent protein kinase for enhancer function. Individually, none of these elements confer cAMP dependence to a reporter gene driven by a heterologous promoter. On the basis of these observations, we suggest that ACTH- and cAMP-dependent expression of Cyp-21 requires the combined actions of the element at -170, and the related elements at -140, -210 and -65. PMID- 22217842 TI - Molecular basis of 17alpha-hydroxylase/17,20-lyase deficiency. AB - 17alpha-Hydroxylase deficiency is characterized by a defect in either or both of 17alpha-hydroxylase and 17,20-lyase activities, based on the fact that a single polypeptide P450c17 can catalyze both reactions. The clinical manifestations of 17alpha-hydroxylase/17,20-lyase deficiency seem to be more heterogeneous than expected, varying from the classical type to less symptomatic forms as also observed in 21-hydroxylase deficiency. We have sequenced all eight exons of the CYP17 (P450c17) gene in DNA from several patients, reconstructed the mutations in a human P450c17 cDNA and expressed the mutant P450c17 in COS 1 cells to characterize the kinetic properties of 17alpha-hydroxylase and 17,20-lyase activities. The molecular bases of cases clinically reported as 17alpha hydroxylase deficiency have turned out to be complete or partial combined deficiencies of 17alpha-hydroxylase/17,20-lyase. The elucidation of the molecular basis generally explains the patient's clinical profiles including the sexual phenotype of the external genitalia. In one case clinically reported as isolated 17,20-lyase deficiency, the molecular basis was found to be partial combined deficiency of both activities, somewhat discordant with the patient's clinical profile. Based on the results obtained so far we can predict that those 17alpha hydroxylase deficient individuals having a homozygous stop codon in the CYP17 gene positioned at the amino terminal side of the P450c17 heme-binding cysteine (442) will all have the same phenotype. However those individuals having homozygous missense mutations or those who are compound heterozygotes having a missense mutation in at least one CYP17 allele will display their own unique phenotype which clinically will be subtly different from all others. PMID- 22217841 TI - Analysis of the duplicated human C4/P450c21/X gene cluster. AB - Gene duplications, deletions and rearrangements occur with an unusually high frequency in the region of the P450c21 genes encoding 21-hydroxylase. In the human genome, the locus contains at least 6 genes, oriented 5' C4A, P450c21A, XA, C4B, P450c21B, XB 3'. Sequence analysis of the XA gene, of the 5' flanking DNA of the C4A gene, and of part of the XB gene revealed that this gene cluster was duplicated by nonhomologous recombination at a CAAG tetranucleotide. The location of this duplication suggests that it may have occurred after mammalian speciation. The XA gene is abundantly expressed in the human adrenal as a stable 2.6 kb RNA, but it is not known if that RNA serves a biological function. Knowledge of the anatomy of the XA gene facilitates genetic analysis of disease causing lesions in the P450c21B gene. Southern blotting data show that about 76% of disordered P450c21B alleles bear gene microconversions that resemble point mutations; the remaining alleles are equally distributed between gene deletions and large gene conversions. PMID- 22217843 TI - Molecular genetic studies on the biosynthesis of aldosterone in humans. AB - Corticosterone methyl oxidase Type I (CMO I) and II (CMO II) have been postulated to be the enzymes involved in the final two steps of aldosterone biosynthesis in humans. We have isolated human cDNAs for P450c11 and P450c18 as well as the corresponding genes, CYP11B1 and CYP11B2. Both protein products of these two genes as expressed in COS-7 cells exhibit steroid 11beta-hydroxylase activity, but only P450c18, a product of CYP11B2, carried steroid 18-hydroxylase activity to form aldosterone. These results indicate that CYP11B2 encodes CMO, the actual catalytic function of which is retained by P450c18, a multifunctional enzyme. This conclusion is further supported by the finding that the P450c18 gene, CYP11B2, is mutated at several different loci in patients deficient in CMO I or II. PMID- 22217844 TI - Steroid 17beta-hydroxysteroid dehydrogenase deficiency in man: an inherited form of male pseudohermaphroditism. AB - Sixty-eight males with testicular 17beta-hydroxysteroid dehydrogenase deficiency (17beta-HSD) were identified among a highly inbred Arab population in Israel, and 45 studied over the last 15 years. The founders of this defect originated in the mountainous region of present Lebanon and Syria, but most of the families now live in Jerusalem, Hebron, the Tel-Aviv area, and in particular Gaza, where the frequency of affected males is estimated at 1 in 100 to 150. Affected individuals (46,XY) are born with ambiguity of the genitalia and reared as females until puberty. Thereafter marked virilization occurs, leading in many cases to the spontaneous adoption of a male gender role. Adults develop a male habitus with abundant body hair and beard, and the phallus and testes enlarge to adult proportions. Gender reassignment was possible only when enough erectile tissue was present at birth and developed into a normal size penis with systemic testosterone. male genitoplasty was performed in 15 children and 8 post-pubertal patients, and female genitoplasty in 2 children and 4 post-pubertal patients. In adults the defect is characterized by markedly increased concentrations of 4 androstendione (4-A) with borderline low to normal testosterone (T) levels, and a high 4-A/T ratio. Dihydrotestosterone (DHT) concentrations were either moderately decreased, normal, or high, and dehydroepiandrosterone levels were high. The estrogen pathway was also impaired, even though both estrone and estradiol-17beta levels were elevated. Children had low basal levels of all androgens, but the defect could be demonstrated after prolonged stimulation with human chorionic gonadotropin. LH and FSH levels were very high after puberty, and normal in childhood. However, an over-response to gonadotropin-releasing hormone was found at all ages. Studies in testicular tissue revealed various abnormalities in steroid metabolism. Tissue from pre-pubertal patients metabolized progesterone (P) only to 4-A, while tissue from post-pubertal patients metabolized P to 16alpha- and 16beta-hydroxyprogesterone (5.4- to 10.3-fold greater production), 17alpha-hydroxyprogesterone (5.4- to 8-fold smaller production), 4-A and T. 4-A was also metabolized to T, indicating that 17beta-HSD was no longer deficient. Flow studies with equimolar concentrations of [14C]P and [3H]pregnenolone showed that the 5-ene pathway was the preferential one for androgen biosynthesis. Both in vivo and in vitro studies indicate that the severity of testicular 17beta-HSD deficiency changes with age. Whereas the enzyme activity is absent in childhood, there is a progressive restoration after puberty. Androgen production increases progressively to normal so that T and DHT concentrations are sufficiently high to gradually induce somatic and genital virilization, thus enabling an adequate male gender function. PMID- 22217845 TI - Inhibitors of P450-dependent steroid biosynthesis: from research to medical treatment. AB - A number of cytochrome P450-dependent enzymes are major targets for both steroidal and nonsteroidal compounds that may be of use in the treatment of a number of androgen-independent, androgen-, estrogen- and other steroid-dependent diseases. Compounds of interest are for example aminoglutethimide and derivatives; esters of 4-pyridineacetic acid; imidazole derivatives, such as ketoconazole, liarozole, fadrozole, CGS 18320 B; bis-chlorophenyl-pyrimidine analogues; triazole derivatives vorozole and CGS 20267, and steroidal aromatase inhibitors such as 4-hydroxyandrostenedione. Some of them (e.g. ketoconazole) triggered studies to find new possibilities in medical treatment. Others are of use clinically or under clinical evaluation to provide a palliative treatment and/or cure to patients with for example prostatic carcinoma, breast cancer, hypercortisolism and benign prostatic hyperplasia. PMID- 22217846 TI - Steroid metabolism by constitutive cytochromes P450. AB - In rat liver endoplasmic reticulum some 16 different cytochromes P450 have been identified as constitutive, sequenced from recombinant DNA, and shown to be distinct gene products. These forms are "multipurpose", i.e. functional in xenobiotic metabolism as well as endogenous substrate metabolism. In the latter case, these forms metabolize steroids, fatty acids, prostaglandins and even ketone bodies, indicating an involvement in homeostasis. In steroid metabolism, in contrast to "biosynthetic" forms of P450 which generally yield one product, the multipurpose forms exhibit broad, overlapping metabolite profiles, with isomeric and epimeric specificity and different mechanisms of product formation. The nature of the substrate docking region is of much interest and attempts have been made to rationalize the manner in which multiple metabolites are produced from a single substrate. Brain, with a very low level of P450 relative to liver also catalyzes steroid metabolism. The nature of the forms involved are not yet known. PMID- 22217847 TI - Alteration of the substrate specificity of mouse 2A P450s by the identity of residue-209: steroid-binding site and orientation. AB - Mouse steroid 7alpha- and 15alpha-hydroxylases (P450c7 and P450c15) and coumarin 7-hydroxylase (P450coh) are structurally similar. To study the structural basis of the substrate specificities of these enzymes, we constructed a series of the mutant P450s, expressed in COS-1 and yeast cells, and studied them spectroscopically as well as enzyme-kinetically. A single amino acid mutation of residue-209 is sufficient to alter the substrate specificity of the P450s from xenobiotics to steroids and subsequently, from testosterone to corticosterone. Moreover, residue-209, when it is asparagine, appears to bind directly to the 11beta-hydroxyl of corticosterone. The mutations also after the spin equilibrium of P450 depending on the hydrophobicity and size of residue-209. We conclude, therefore, that residue-209 resides close to the 6th ligand of heme in the mouse 2A subfamily and is located at a critical site of the substrate-binding pocket. As a result, the identity of the residue-209 plays a key role in determining the substrate specificity. PMID- 22217848 TI - Chimeric cDNA expression and site directed mutagenesis studies of cytochrome P450s CYP2A1 and CYP2A2. AB - Construction of chimeras and site directed mutagenesis were used to study the regioselectivity and kinetics of testosterone hydroxylation by the cytochrome P450s CYP2A1 and CYP2A2. Although these enzymes exhibit 88% sequence similarity, they catalyze very different regioselective hydroxylations of testosterone. Active chimeras inwhich the first 355 amino acids do not correspond to a single enzyme show broad radioselectivity, whereas the specificity of the parent enzyme is obtained if the first 355 amino acids are unchanged. Therefore, the region between amino acids 275 and 355 is important in maintaining regioselectivity. Single point mutants were constructed for the 13 amino acid differences in this region. For 26 single point and 2 double mutants all active mutants have the same regioselectivity as the parent enzymes. However, kinetic analysis of the CYP2A1 mutants showed that 4 single point mutants and 1 double mutant had kinetic parameters very different from the parent enzyme. All of these substitutions are associated with the conserved dioxygen binding region of the putative I helix predicted from the crystal structure of P450(cam). Deuterium isotope effects were used to determine any changes in the rate of reduction and to estimate the relative amount of excess water formation. Changes in reduction rates are not sufficient to account for the differences in V(max) values. Therefore, it is likely that the amount of hydrogen peroxide formed is a primary determinant of V(max). PMID- 22217849 TI - The role and mechanism of growth hormone in the regulation of sexually dimorphic P450 enzymes in rat liver. AB - The determination of sexually dimorphic hepatic steroid metabolism in rat liver has been shown to involve growth hormone. However, the mechanisms by which growth hormone controls the cytochrome P450 enzymes responsible for this dimorphic steroid metabolism is largely unknown. In this review we discuss different levels of growth hormone signal transduction, including receptor binding, signal transduction and activation of target genes by growth hormone. PMID- 22217850 TI - Regulation of liver-specific steroid metabolizing cytochromes P450: cholesterol 7alpha-hydroxylase, bile acid 6beta-hydroxylase, and growth hormone-responsive steroid hormone hydroxylases. AB - The hydroxylation of cholesterol, bile acids, and steroid hormones by liver cytochrome P450 (CYP) enzymes proceeds with a high degree of regiospecificity, and contributes to both biosynthetic and catabolic pathways of sterol metabolism. CYP 7-catalyzed cholesterol 7alpha-hydroxylation, a key control point of bile acid biosynthesis, is regulated at a pretranslational step, probably transcription initiation, by multiple factors, including liver bile acid and cholesterol levels, thyroid hormone status, and diurnal rhythm. Hydrophobic bile acids, such as lithocholic acid, are converted to less cholestatic derivatives by 6beta-hydroxylation carried out by CYP 3A P450s, which also catalyze steroid hormone 6beta-hydroxylation reactions. Complex, gender-dependent developmental patterns characterize the expression of steroid 5alpha-reductase and several rat liver steroid hydroxylase CYPs. Multiple pituitary-dependent factors regulate the expression of these enzymes; of greatest importance are the gonadal steroids and the sex-dependent secretory patterns of growth hormone (GH) that they impart. The continuous presence of GH in circulation, a characteristic of adult female rats, positively regulates expression of the female-specific steroid disulfate 15beta hydroxylase CYP 2C12, while expression of the male-specific steroid 16alpha- and 2alpha-hydroxylase CYP 2C11 is stimulated by the intermittent pituitary secretion of GH that occurs in adult male rats. Intermittent GH can stimulate CYP 2C11 gene expression even when the hormone presents to the hepatocyte at a non physiological pulse amplitude, duration, and frequency, provided that an interpulse interval of no GH (obligatory recovery period) is maintained for at least 2.5 h. GH regulates the expression of the CYP 2C11 and CYP 2C12 genes at the level of transcription initiation. This process is probably mediated by sex dependent and GH-regulated protein-DNA interactions, such as those observed in the 5'-flank of the CYP 2C12 gene. Thyroid hormone is a second major regulator of liver steroid hydroxylase P450 activity. It regulates these enzymes directly, at a pretranslational step, and indirectly, through its stimulation of pituitary GH secretion and by its positive effects on the expression of the flavoenzyme NADPH P450 reductase, which catalyzes electron transfer that is obligatory for all microsomal steroid hydroxylation reactions. PMID- 22217851 TI - Characterization and regulation of the vitamin D hydroxylases. AB - The metabolism of vitamin D is regulated by three major cytochrome P450 containing h hydroxylases-the hepatic 25-hydroxylase, the renal 1alpha hydroxylase, and the renal and intestinal 24-hydroxylase. In the liver, the 25 hydroxylation reaction is catalyzed by microsomal and mitochondrial cytochrome P450cc25. The microsomal P450 accepts electrons from the NADPH-cytochrome P450 reductase, and the mitochondrial P450 accepts electrons from NADPH-ferredoxin reductase and ferredoxin. In the kidney, the 1alpha- and 24-hydroxylation reactions are catalyzed by mitochondrial cytochromes P450cc1alpha and P450cc24, respectively. The 24-hydroxylase is also found in vitamin D target tissues such as the intestine. The rat hepatic mitochondrial P450cc25 and the rat renal mitochondrial P450cc24 have been purified, and their cDNAs have been cloned and sequenced. 1,25-Dihydroxyvitamin D, the active metabolite of vitamin D, markedly stimulates renal P450cc24 mRNA and 24-hydroxylase activity in the intact animal and in renal cell lines. This stimulation occurs via a receptor-mediated mechanism requiring new protein synthesis. Despite the availability of a clone, no studies have yet been reported of the regulation of hepatic P450cc25 at the mRNA level. The study of one of the most important enzymes in vitamin D metabolism, the renal 1alpha-hydroxylase which produces the active metabolite, awaits the definitive cloning of the cDNA for the P450cc1alpha. PMID- 22217852 TI - Molecular cloning of rat liver 3alpha-hydroxysteroid dehydrogenase and identification of structurally related proteins from rat lung and kidney. AB - 3alpha-Hydroxysteroid dehydrogenase and related enzymes play important roles in the metabolism of endogenous compounds including androgens, corticosteroid, prostaglandins and bile acids, as well as drugs and xenobiotics such as benzo(a)pyrene. Complementary DNA clones encoding 3alpha-hydroxysteroid dehydrogenase were isolated from a rat liver cDNA lambda gt11 expression library using monoclonal antibodies as probes. A full-length cDNA clone of 1286 base pairs contained an open reading frame encoding a protein of 322 amino acids with an estimated M(w) of 37 kD. When expressed in E. coli, the encoded protein migrated to the same position on SDS-polycrylamide gels as the enzyme in rat liver cytosols. The protein expressed in bacteria was highly active in androsterone oxidation in the presence of NAD as cofactor and this activity was inhibited by indomethacin, a potent inhibitor of 3alpha-hydroxysteroid dehydrogenase. The predicted amino acid sequence of 3alpha-hydroxysteroid d dehydrogenase was related to sequences of several other aldo-keto reductases such as bovine prostaglandin F synthase, human chlordecone reductase, human aldose reductase, human aldehyde reductase and frog lens epsilon-crystallin, suggesting that these proteins belong to the same gene family. Recently, we have found that monoclonal antibodies against 3alpha-hydroxysteroid dehydrogenase also recognized multiple antigenically related proteins in rat lung, kidney and testis. Further screening of liver, lung and kidney cDNA libraries using these monoclonal antibodies as probes resulted in the isolation of additional five different cDNAs encoding proteins with high degree of structural homology to rat liver 3alpha hydroxysteroid dehydrogenase. PMID- 22217853 TI - The membrane-bound 17beta-estradiol dehydrogenase of porcine endometrial cells: purification, characterization and subcellular localization. AB - The membrane-bound 17beta-estradiol dehydrogenase of porcine endometrial cells was purified to homogeneity as judged by SDS-PAGE and silver staining of a single 32 kD band. A second, more hydrophobic product of the purification protocol contained additional bands at 45 and 80 kD. The 17beta-estradiol dehydrogenase activities of both products exceeded those for 17-one reduction by more than 260 fold. Activities of 3alpha-, 3beta- and 20alpha-dehydrogenases were absent in either fraction. Polyclonal and monoclonal antibodies raised against the 32 kD protein and the more hydrophobic product precipitated the enzymatic activity and reacted with the 32 and 80 kD bands, but not with the 45 kD band in Western blots. The subcellular localization of the enzyme was studied in sections of intact cells and of isolated organelles using gold sol coated with F(ab')2 fragments of monoclonal antibody F1. Gold particles were found exclusively over cytoplasmic vesicles of 120-150 nm diameter with electron-dense contents. PMID- 22217854 TI - Extraglandular hormonal steroidogenesis in aged rats. AB - We have examined the metabolism in vitro of [4-14C]pregnenolone by the following organs of 2.4-year-old rats: submandibular gland, stomach, duodenum, liver, lung, heart, spleen, kidney, skin, prostate, testis and adrenal. All tissues converted pregnenolone to progesterone, the highest yields being observed with adrenal, testis and skin. Androgen formation was intense in the testis and absent in the adrenal. Moreover, 17alpha-hydroxylation of pregnenolone occurred moderately in kidney, skin and submandibular gland and markedly in duodenum and stomach, which also produced high amounts of dehydroepiandrosterone and/or 5-androstene 3beta,17beta-diol. Extratesticular synthesis of androstenedione and testosterone was very low. A significant formation of 20alpha-dihydropregnenolone was observed in all tissues but stomach, duodenum and steroidogenic endocrines. Corticosteroids were not synthesized extraadrenally, except a small amount of 11 deoxycorticosterone in the testis. These results indicate that key steroid biosynthetic enzymes, such as 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase, 17beta- and 20alpha-hydroxysteroid dehydrogenases and steroid 17alpha monooxygenase/17,20-lyase are also expressed extraglandularly in the rat. PMID- 22217855 TI - Steroid UDP glucuronosyltransferases. AB - The glucuronidation of steroids is a major process necessary for their elimination in the bile and urine. In general, steroid glucuronides are biologically less reactive than their parent steroids. However, in some cases often associated with disease and steroid therapy, more reactive or toxic glucuronides may be formed. The concentrations of specific steroid glucuronides in the blood may also indicate hormonal imbalances and may funnction as diagnostic markers of genetic defects in steroid synthesis and metabolism. In this review, the forms of UDP glucuronosyltransferase involved in steroid glucuronidation are described in terms of their specificities, functional domains and regulation. The available evidence suggests that steroid glucuronidation is mainly carried out by members of the UGT2B subfamily which are encoded by genes containing 6 exons. Members of this subfamily exhibit a regioselectively in their glucuronidation of steroids that is mediated by domains in the amino-terminal half on the protein encoded by exons 1 and 2. Although much of this review will describe studies in the rat, preliminary evidence indicates that a similar situation may exist in humans. PMID- 22217856 TI - Cytochrome P450 lanosterol 14alpha-demethylase (CYP51): insights from molecular genetic analysis of the ERG11 gene in Saccharomyces cerevisiae. AB - Eukaryotes characteristically express a cytochrome P450-catalyzed sterol 14alpha methyl demethylase as an essential step in the production of membrane sterols. Lanosterol 14alpha-demethylase of Saccharomyces cerevisiae is the best characterized representative of these enzymes among fungi and provides a model system for the molecular genetic analysis of the reaction. The gene for this P450 and the gene for the S. cerevisiae NADPH-cytochrome P450 reductase have been examined by mutational inactivation and for their regulation of expression. Our results have contributed to a better understanding of sterol biosynthesis in relation to mechanisms of resistance to fungicidal demethylase inhibitors, and promote the rationale for using S. cerevisiae in the further characterization of structure function relationships among sterol 14alpha-demethylases. PMID- 22217857 TI - Steroid 11beta-hydroxylation by a fungal microsomal cytochrome P450. AB - The steroid 11beta-hydroxylase activity of the fungus Cochliobolus lunatus was increased about 100-fold by cultivation of mycelia for 4-5 h with 20 hydroxymethyl-1,4-pregnadien-3-one. Cell-free extracts revealed a maximum activity of 45 nmol 11beta-hydroxyprogesterone/h.mg protein in the 100,000 g pellet fraction. The 11beta-hydroxylation was dependent on NADPH. The formation of 11beta-hydroxyprogesterone correlated linearly with the cytochrome P450 concentration. The fungal 11beta-hydroxylase transformed both 21-methyl and 21 hydroxymethyl steroids. The enzyme showed a broader substrate specificity and lower regioselectivity as compared with the adrenal cytochrome P45011beta system. The fungal cytochrome P450 was partially purified to a specific content of 700 pmol P450/mg protein. Western blots showed that polyclonal antibodies against cytochrome P45011alpha from Rhizopus nigricans cross-react with a 60 kD protein of partially purified fractions. The NADPH-cytochrome c reductase was enriched up to a specific activity of 20 U/mg protein. Polyclonal antibodies against NADPH cytochrome P450 reductases from Candida maltosa and rat liver cross-reacted with the fungal reductase. It is concluded that the 11beta-hydroxylase of Cochliobolus lunatus represents a microsomal two-component monooxygenase system which is composed of a cytochrome P450 (M(r) 60 kD) and a NADPH-cytochrome P450 reductase (M(r) 79 kD). PMID- 22217858 TI - Evaluation of cancer stem cell migration using compartmentalizing microfluidic devices and live cell imaging. AB - In the last 40 years, the United States invested over 200 billion dollars on cancer research, resulting in only a 5% decrease in death rate. A major obstacle for improving patient outcomes is the poor understanding of mechanisms underlying cellular migration associated with aggressive cancer cell invasion, metastasis and therapeutic resistance. Glioblastoma Multiforme (GBM), the most prevalent primary malignant adult brain tumor, exemplifies this difficulty. Despite standard surgery, radiation and chemotherapies, patient median survival is only fifteen months, due to aggressive GBM infiltration into adjacent brain and rapid cancer recurrence. The interactions of aberrant cell migratory mechanisms and the tumor microenvironment likely differentiate cancer from normal cells. Therefore, improving therapeutic approaches for GBM require a better understanding of cancer cell migration mechanisms. Recent work suggests that a small subpopulation of cells within GBM, the brain tumor stem cell (BTSC), may be responsible for therapeutic resistance and recurrence. Mechanisms underlying BTSC migratory capacity are only starting to be characterized. Due to a limitation in visual inspection and geometrical manipulation, conventional migration assays are restricted to quantifying overall cell populations. In contrast, microfluidic devices permit single cell analysis because of compatibility with modern microscopy and control over micro-environment. We present a method for detailed characterization of BTSC migration using compartmentalizing microfluidic devices. These PDMS-made devices cast the tissue culture environment into three connected compartments: seeding chamber, receiving chamber and bridging microchannels. We tailored the device such that both chambers hold sufficient media to support viable BTSC for 4-5 days without media exchange. Highly mobile BTSCs initially introduced into the seeding chamber are isolated after migration though bridging microchannels to the parallel receiving chamber. This migration simulates cancer cellular spread through the interstitial spaces of the brain. The phase live images of cell morphology during migration are recorded over several days. Highly migratory BTSC can therefore be isolated, recultured, and analyzed further. Compartmentalizing microfluidics can be a versatile platform to study the migratory behavior of BTSCs and other cancer stem cells. By combining gradient generators, fluid handling, micro-electrodes and other microfluidic modules, these devices can also be used for drug screening and disease diagnosis. Isolation of an aggressive subpopulation of migratory cells will enable studies of underlying molecular mechanisms. PMID- 22217859 TI - Pivoting distraction osteogenesis in hemifacial microsomia. PMID- 22217861 TI - Perceptions and patterns of use of generic drugs among Italian family pediatricians: first round results of a web survey. AB - Prescription of generic medicines represents an efficacious healthcare cost containment strategy. In some European countries and in the US, generic medicines are largely prescribed. In Italy, generic drugs prescription rate is lower. General Practitioners and Family Pediatricians may be less confident in prescribing generic equivalents instead of "branded" medicines. There are currently no data about Italian Family Pediatricians' perceptions and patterns of use of generic drugs. This is a first nationwide web survey conducted with the aim to evaluate generic medicines knowledge and prescribing habits of Italian Family Pediatricians. 303 Family Pediatricians completed the online questionnaire. 37.2% and 32.6% of them declared to have a sufficient or fairly good knowledge of generic medicines, respectively, and the majority of them believed that efficacy of generic medicines was sufficient (33.6%) or good (45.2%). Nevertheless, Italian Family Pediatricians are still prone to prescribe trade medicines more frequently, since only 13.5% of them declared that more than a half of their patients were treated with generic medicines. Major issues related with generic medicines prescriptions by Italian Family Pediatricians seem to be represented by diffuse scepticism about reliability of bioequivalence tests and safety of switchability from branded to generic equivalents. More information about generic drugs and more research in the field of pediatric pharmacology are needed for increasing generic medicines prescription rate among Italian Family Pediatricians. PMID- 22217862 TI - Crossing borders: a critical review of the role of the European Court of Justice in EU health policy. AB - Over the last two decades, the European Union (EU) has steadily increased its involvement in the health policies of its member states, with considerable support from the European Court of Justice (ECJ). However, much of the literature examining the Court's role has focused upon the intersection between internal market law and the health services sector; the majority of studies have failed to examine the potential role for the Court in public health policy. Observers such as Greer have seen the development of healthcare as a clear case of neofunctional spillover, a view supported but qualified by Wasserfallen and others, who present a more detailed account of the mechanics of the process. Alternative analyses have focused upon the new modes of governance, soft law and other factors - this article reviews the current state of research in the field and the extent to which it should concern health policy actors and non-specialists in EU policy alike. It concludes that the Court has played and continues to play a crucial role in the development of EU public health policy, as well as in health services and broader social policy, where its influence has already been well documented. PMID- 22217860 TI - Delayed diagnosis and underreporting of congenital anomalies associated with oral clefts in the Netherlands: a national validation study. AB - OBJECTIVE: Since 1997, the 15 Dutch cleft palate teams have reported their patients with oral clefts to the national oral cleft registry (NVSCA). During the first visit of the patient to the team - which is usually within the first year of life - the oral cleft and associated congenital anomalies are recorded through a unique recording form by a plastic surgeon/orthodontist/paediatrician. In this study, we evaluated the quality of data on congenital anomalies associated with clefts. METHODS: We drew a random sample of 250 cases registered in the national database with oral clefts from 1997 through 2003; of these, 13 were excluded. Using two independent reregisters derived from two-phased medical data review, we analysed whether associated anomalies were correctly diagnosed and recorded. RESULTS: The agreement on associated anomalies between the NVSCA and medical data ranged from moderate to poor (kappa 0.59 to 0). Seventy-seven percent of the craniofacial anomalies were underreported in the NVSCA: 30% due to delayed diagnosis and 47% due to deficient recording. Additionally, 80% of the associated anomalies of other organ systems were underreported: 52% due to delayed diagnosis and 28% due to deficient recording. The reporting of final diagnoses was somewhat better; however, 54% were still underreported (24% delayed diagnosis and 30% deficient recording). The rate of overreporting was 1.6% or lower. CONCLUSION: Congenital anomalies associated with clefts are underreported in the NVSCA because they are under diagnosed and deficiently recorded during the first consultations with the cleft palate teams. Our results emphasise the need for routine and thorough examination of patients with clefts. Team members should be more focussed on co-occurring anomalies, and early genetic counselling seems warranted in most cases. Additionally, our findings underline the need for postnatal follow-up and ongoing registration of associated anomalies; reregistration in the NVSCA at a later age is recommended. PMID- 22217863 TI - Giving to receive? The right to donate in umbilical cord blood banking for stem cell therapies. AB - OBJECTIVES: To explore the views of lay and professional stakeholders about the donation of cord blood to public banks in England and the policies surrounding it. METHODS: Qualitative in-depth interviews were undertaken between April 2009 and August 2010 with 62 participants based in England who play a key role in cord blood banking and therapy. All interviews were recorded, transcribed in full, and coded and analysed thematically. RESULTS: Participants claimed pregnant women had a right to know of the value of cord blood. This highlighted the flaws of the existing donation infrastructure, which was portrayed as playing a significant role in determining public health. Participants called for a right to donate cord blood to readdress the inequity in healthcare services for pregnant women and transplant recipients. Donors maintained a sense of right over their donation when they discussed cord blood donation as potentially benefiting their family as well as society. CONCLUSION: In order to keep receiving donated body parts, tissue and blood, there is a need to take into account the way in which donation operates within a prevalent 'rights' discourse. PMID- 22217864 TI - Policies to improve the health and well-being of Roma people: the European experience. AB - The Roma constitute the largest ethnic minority in the European Region. The many policy initiatives designed over the past two decades to tackle their adverse social conditions in Central and South Eastern Europe, where the Roma population is concentrated, have had limited success. This paper reviews what is being done to improve the health and social situation of Roma communities in the Region and identifies factors that may limit the effectiveness of these policy initiatives. Strong political commitment, measures to overcome prejudices against Roma, inter sectoral policy coordination, adequate budgets, evidence-based policies, and Roma involvement can be identified as key preconditions for improved health outcomes and well-being. However, developing a sound evidence-based approach to Roma inclusion requires removing obstacles to the collection of reliable data and improving analytical and evaluation capacity. Health policies seeking to reduce health inequalities for Roma people need to be aligned with education, economic, labour market, housing, environmental and territorial development policies and form part of comprehensive policy frameworks allowing for effective integration. PMID- 22217865 TI - Bicaval versus standard technique in orthotopic heart transplant: assessment of atrial performance at magnetic resonance and transthoracic echocardiography. AB - Despite a more physiological morphology of atrial anastomosis in the bicaval technique with respect to standard biatrial anastomosis in orthotopic heart transplantation (OHT), the impact on the long-term outcome is still not clear. In this retrospective study, we sought to investigate the morphology and function of the atria through magnetic resonance imaging (MRI) and transthoracic echocardiography (TTE). Moreover, we aimed to analyse the accuracy of TTE with respect to MRI. Cox regression analysis of 216 consecutive patients receiving OHT between August 1987 and January 2010 identified only recipient age at the time of transplant to be an independent predictor of mortality (P = 0.048, odds ratio = 1.04). After a mean follow-up of 96.6 +/- 77.7 months, 108 patients were alive, of which 35 were found to be eligible for MRI assessment. In this analysis, left and right atrial volumes were found to be significantly larger in the standard group in comparison with the bicaval group (P = 0.001), and no significant difference between the two techniques was observed in left and right atrio ventricular output. Moreover, a significantly reduced accuracy was observed (CCC < 0.3) when TTE results were compared with MRI assessment in evaluating atrial dimensions. Although left and right atrial volumes are significantly larger in the standard group in comparison with the bicaval group, we concluded that no significant difference in the atrial output and survival between the two techniques could be demonstrated. PMID- 22217866 TI - Synthesis and bioevaluation of novel 3,4,5-trimethoxybenzylbenzimidazole derivatives that inhibit Helicobacter pylori-induced pathogenesis in human gastric epithelial cells. AB - Helicobacter pylori infection is associated with gastritis, peptic ulcer, and even gastric malignancy. H. pylori's antibiotic resistance is the major obstacle preventing its eradication. A series of 3,4,5-trimethoxybenzylbenzimidazole derivatives were synthesized and evaluated for their anti-H. pylori activity. The compound, 2-fluorophenyl-5-methyl-1-(3,4,5-trimethoxybenzyl)benzimidazole (FMTMB), was determined as the most potent in the inhibition of H. pylori growth and pathogenesis of host cells. An in vitro H. pylori infection model revealed that FMTMB inhibited H. pylori adhesion and invasion of gastric epithelial cells. Results from this study provide evidence that FMTMB is a potent therapeutic agent that exhibits both anti-H. pylori growth properties and anti-H. pylori-induced pathogenesis of cells. PMID- 22217867 TI - Synthesis and anti-protozoal activity of novel dihydropyrrolo[3,4 d][1,2,3]triazoles. AB - 1,2,4-Oxadiazole and 1,2,3-triazole containing heterocyclic compounds continue to gain interest in synthesis of chemical entities and exhibit various biological activities as anti-protozoal and anti-cancer agents. By using the principle of bioisosterism, a series of novel oxadiazolyl pyrrolo triazole diones; namely, (3aS,6aR)-1-((3-(4-substituted phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5-phenyl-1,6a dihydropyrrolo[3,4-d][1,2,3] triazole-4,6(3aH,5H)-diones (5a-k) was designed and synthesized by the 1,3-dipolar cycloaddition reaction of novel 5-azidomethyl 3 aryl substituted 1,2,4-oxadiazoles (4a-k) with N-phenyl maleimide. The structures of all the cycloadducts were elucidated by means of spectroscopic methods and physical characteristics. The in vitro anti-protozoal and cytotoxic activities of these novel heterocyclic compounds were investigated. PMID- 22217868 TI - Montmorillonite K-10 mediated green synthesis of cyano pyridines: Their evaluation as potential inhibitors of PDE4. AB - An efficient and green synthesis of functionalized cyano pyridines has been achieved via montmorillonite K-10 mediated multi-component reaction in a chemo- and regioselective manner. The four-component reaction of beta-keto ester, arylaldehyde, malononitrile and an alcohol provided a variety of pyridine derivatives and montmorillonite K-10 was found to be a reusable catalyst. The potential of this operationally simple methodology has been demonstrated in further structure elaboration of a compound synthesized via C-C bond forming reactions under Suzuki, Sonogashira and Heck conditions. Some of the cyano pyridines synthesized showed PDE4B inhibitory properties in vitro and good interactions with PDE4B protein in silico suggesting cyano pyridine scaffold as a potential template for the discovery of novel PDE4 inhibitors. PMID- 22217869 TI - Diamidinium and iminium aromatics as new aggregators of the bacterial signaling molecule, c-di-GMP. AB - C-di-GMP has emerged as an important bacterial signaling molecule that is involved in biofilm formation. Small molecules that can form biologically inactive complexes with c-di-GMP have the potential to be used as anti-biofilm agents. Herein, we report that water-soluble diamidinium/iminium aromatics (such as berenil), which are traditionally considered as minor groove binders of nucleic acids, are capable of aggregating c-di-GMP into G-quadruplexes via pi stacking interactions. PMID- 22217870 TI - Amides of xanthurenic acid as zinc-dependent inhibitors of Lp-PLA(2). AB - AX10185, the phenyl amide of xanthurenic acid, was found to be a sub-100nM inhibitor of Lp-PLA(2). However, in the presence of EDTA the inhibitory activity of AX10185 was extinguished while the enzymatic activity of Lp-PLA(2) did not change. Subsequent metal screening experiments determined the inhibition to be Zn(2+) dependent. Structure-activity relationship studies indicated the presence of the 4-hydroxy group to be critical and selected substituted phenyl, polycyclic, and cycloaliphatic amides of xanthurenic acid to be well tolerated. PMID- 22217871 TI - Enzymatic transformation of caffeic acid with enhanced cyclooxygenase-2 inhibitory activity. AB - Convenient enzymatic transformation of the phenylpropanoid caffeic acid (1) with polyphenol oxidase originating from pear afforded three new oxidized metabolites, caffeoxynic acid (2), caffeicinic acid (3), and isocaffeicinic acid (4), along with, 7,8-erythro-caffeicin (5) and phellinsin A (6). The structures of the three new caffeic acid oxidation products were elucidated on the basis of spectroscopic methods. The new products 2 and 3 exhibited significantly enhanced inhibitory activity against cyclooxygenase-2 (COX-2) when compared to parent caffeic acid. PMID- 22217872 TI - Structure-activity relationship of naphthaldehydethiosemicarbazones in melanogenesis inhibition. AB - 2-(Naphthalen-1-ylmethylene)hydrazinecarbothioamide (14, IC(50)=1.1MUM) was discovered as a highly potent inhibitor of melanogenesis. To define the role of hydrogens (at N1 and N3) and sulfur in 14, a series of analogs 15a-p were synthesized and evaluated for anti-melanogenic activity using melanoma B16 cells under the stimulus of alpha-MSH. It was observed that replacement of either of these hydrogens at N1 or N3 by substituents increases the activity significantly. Conversely, concomitant substitutions decrease the inhibitory potency. In addition, the presence of sulfur in thiosemicarbazone is essential for the activity. PMID- 22217873 TI - Synthesis of new praziquantel analogues: potential candidates for the treatment of schistosomiasis. AB - An efficient synthesis of antischistosomal drug praziquantel and analogues was achieved and the synthetic route designed was to afford structurally diverse analogues for better structure-activity relationship understanding. Total of nineteen PZQ analogues with structural variations at amide, piperazine and aromatic moieties have been synthesized and fully characterized. Among all the new analogues tested for antischistosomal activity, one dimethoxy tetrahydroisoquinoline analogue and two tetrahydro-beta-carboline analogues exhibited moderate activity against adult Schistosoma mansoni. Tetrahydro-beta carboline analogues showed moderate activity whereas the presence of p trifluoromethylbenzoyl and p-toluenesulphonyl moieties resulted in complete suppression of antischistosomal activity. PMID- 22217874 TI - Design and synthesis of potent carboxylic acid DGAT1 inhibitors with high cell permeability. AB - A series of potent carboxylic acid DGAT1 inhibitors with high permeability were developed from a virtual screening hit. Strategies were employed to reduce Pgp substrate recognition and increase passive permeability, resulting in the discovery of a series showing good inhibition of cellular triglyceride synthesis. The mutagenic potential of prospective metabolites was evaluated in the Ames assay, and one aniline was shown to be devoid of mutagenicity. PMID- 22217876 TI - AMG 837: a potent, orally bioavailable GPR40 agonist. AB - The discovery that certain long chain fatty acids potentiate glucose stimulated insulin secretion through the previously orphan receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents. Optimization of a series of beta-substituted phenylpropanoic acids led to the identification of (S)-3-(4-((4' (trifluoromethyl)biphenyl-3-yl)methoxy)phenyl)hex-4-ynoic acid (AMG 837) as a potent GPR40 agonist with a superior pharmacokinetic profile and robust glucose dependent stimulation of insulin secretion in rodents. PMID- 22217875 TI - N-Amino acid linoleoyl conjugates: anti-inflammatory activities. AB - Several N-linked amino acid-linoleic acid conjugates were studied for their potential as anti inflammatory agents. The parent molecule, N-linoleoylglycine was tested in an in vivo model, the mouse peritonitis assay where it showed activity in reducing leukocyte migration at doses as low as 0.3mg/kg when administered by mouth in safflower oil. Harvested peritoneal cells produced elevated levels of the inflammation-resolving eicosanoid 15-deoxy-Delta(13,14) PGJ(2). These results are similar to those obtained in earlier studies with N arachidonoylglycine. An in vitro model using mouse macrophage RAW cells was used to evaluate a small group of structural analogs for their ability to stimulate 15 deoxy-Delta(13,14)-PGJ(2) production. The d-alanine derivative was the most active while the d-phenylalanine showed almost no response. A high degree of stereo specificity was observed comparing the d and l alanine isomers; the latter being the less active. It was concluded that linoleic acid conjugates could provide suitable templates in a drug discovery program leading to novel agents for promoting the resolution of chronic inflammation. PMID- 22217877 TI - Design, synthesis, and in vitro antiproliferative activity of novel Dasatinib derivatives. AB - Two series of novel Dasatinib derivatives have been designed and synthesized, with their in vitro cytostatic effect screened on human chronic myeloid leukemia cell line K562 and human myeloid leukemia cell line U937. Some target compounds demonstrated significant inhibitory activities against both cell lines. Compared to the contrast drug Dasatinib, 1b, 1c, 1d, 1e and 1f were found to demonstrate more potent antitumor activities. The structures of all the newly synthesized compounds were determined by (1)H NMR and (13)C NMR. PMID- 22217878 TI - Is the Mediterranean diet adequate to satisfy zinc requirements during adolescence? AB - OBJECTIVE: To evaluate Zn utilization and status among a sample of Spanish boys consuming a diet based on Mediterranean patterns. DESIGN: Dietary Zn balance was assessed by means of Zn intake in food and Zn output in faeces and urine as measured by flame atomic absorption spectrophotometry. In addition, biomarkers of Zn status were analysed. SETTING: Province of Granada, Spain. SUBJECTS: Twenty healthy male adolescents aged 11-14 years, selected based on medical questionnaire, physical examination and nutritional survey of food habits and lifestyle. RESULTS: Mean Zn intake was 11.36 (se 0.31) mg/d, 76% of the recommended value for Spanish adolescents. Zn absorption (2.53 (se 0.55) mg/d) was close to the value of 3.0 mg/d required for the growth spurt. Zn status biomarkers and growth parameters were within the normal values for this age group. CONCLUSIONS: Although a diet based on Mediterranean patterns is associated with factors which can affect Zn absorption, such as high consumption of phytate, its consumption in adequate amounts allows Zn status to be maintained during adolescence. Due to the importance of Zn in preventing growth and behavioural disorders among adolescents, long-term intervention trials to investigate the suitability of the Mediterranean diet with respect to Zn requirements at this time of life are needed. PMID- 22217879 TI - Blood pressure stability in hemodialysis patients confers a survival advantage: results from a large retrospective cohort study. AB - The association between changes in systolic and diastolic blood pressure, and the use of cardioprotective drugs on survival of incident hemodialysis patients, was examined in this retrospective cohort study. Pre-hemodialysis systolic and diastolic blood pressures were averaged over the first month of hemodialysis. Slopes, reflecting temporal changes, were computed by linear regression of systolic blood pressures and Cox regression was used for survival analyses. Patients were initially stratified into four cohorts (below 120, 120 to 150, 151 to 180, and above 180 mm Hg) and further subdivided into groups with stable (no more than a 1-mm Hg change per month), increasing (over 1-mm Hg per month), and decreasing (less than 1-mm Hg per month) slopes during the first year. Analyses were repeated for patients who were treated with cardioprotective drugs for 1 month or more in the second year. In 10,245 patients (59% prescribed cardioprotective drugs), both increases and decreases in all ranges of blood pressure were associated with worse outcomes, whereas stable blood pressure had a survival advantage at all levels of systolic and diastolic pressures. Use of cardioprotective drugs attenuated changes and improved survival. Validation and sensitivity analyses confirmed the primary findings. Therefore, previous temporal trends need to be considered in patient care, and the use of cardioprotective agents is associated with enhanced survival at all blood pressure levels. PMID- 22217881 TI - Aspirin inhibits the production of reactive oxygen species by downregulating Nox4 and inducible nitric oxide synthase in human endothelial cells exposed to oxidized low-density lipoprotein. AB - Aspirin has antithrombotic activity and is commonly used to protect patients from cardiovascular disease attacks. The present study investigated whether aspirin reduces reactive oxygen species and proinflammatory proteins in oxidized low density lipoprotein (ox-LDL)-stimulated human umbilical vein endothelial cells. The results showed that aspirin attenuated reactive oxygen species generation induced by ox-LDL and downregulated Nox4 and inducible nitric oxide synthase expression. Redox-sensitive transcription factor nuclear factor kappa B was inactivated by aspirin, significantly preventing nuclear factor kappa B p65 subunit translocation into the nucleus. The expression of the monocyte/macrophage chemotactic protein 1 also decreased, but endothelial nitric oxide synthase expression increased in aspirin-treated cells. Aspirin ameliorated oxidative stress by downregulating Nox4 and inducible nitric oxide synthase and improved endothelial cell function by increasing endothelial nitric oxide synthase expression. Thus, aspirin may possess protective effects against ox-LDL-induced endothelial cell injury. PMID- 22217880 TI - Decreased renal alpha-Klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion. AB - Hypercalciuria is one of the early manifestations of diabetic nephropathy. We explored here the role of alpha-Klotho, a protein expressed predominantly in distal convoluted tubules that has a role in calcium reabsorption. We studied 31 patients with early diabetic nephropathy and compared them with 31 patients with IgA nephropathy and 7 with minimal change disease. Renal alpha-Klotho expression was significantly lower and urinary calcium excretion (UCa/UCr) significantly higher in diabetic nephropathy than in IgA nephropathy or minimal change disease. Multiple regression analyses indicated that alpha-Klotho mRNA was inversely correlated with calcium excretion. We next measured these parameters in a mouse model of streptozotocin (STZ)-induced diabetic nephropathy, characterized by glomerular hyperfiltration, as seen in early diabetic nephropathy. We also confirmed a reduction of renal alpha-Klotho mRNA down to almost 50% and enhanced calcium excretion in mice with STZ-induced diabetic nephropathy in comparison with nondiabetic mice. Hypercalciuria was exacerbated in heterozygous alpha Klotho knockout mice in comparison with wild-type mice, each with STZ-induced diabetic nephropathy. Thus, alpha-Klotho expression was decreased in distal convoluted tubules in diabetic nephropathy in humans and mice. Renal loss of alpha-Klotho may affect urinary calcium excretion in early diabetic nephropathy. PMID- 22217882 TI - The contribution of d-tubocurarine-sensitive and apamin-sensitive K-channels to EDHF-mediated relaxation of mesenteric arteries from eNOS-/- mice. AB - The nature of the potassium channels involved in determining endothelium-derived hyperpolarizing factor-mediated relaxation was investigated in first-order small mesenteric arteries from male endothelial nitric oxide synthase (eNOS-/-) knockout and control (+/+) mice. Acetylcholine-induced endothelium-dependent relaxation of small mesenteric arteries of eNOS-/- was resistant to N-nitro-L arginine and indomethacin and the guanylyl cyclase inhibitor, 1H-(1,2,4) oxadiazolo (4,3-a) quinoxalin-1-one. Apamin and the combination of apamin and iberiotoxin or apamin and charybdotoxin induced a transient endothelium-dependent contraction of small mesenteric arteries from both eNOS-/- and +/+ mice. Acetylcholine-induced relaxation in eNOS-/- mice was unaffected by charybdotoxin or apamin alone but significantly inhibited by the combination of these agents. However, the combination of scyllatoxin and iberiotoxin did not mimic the inhibitory effect of the apamin/charybdotoxin combination. Tubocurarine alone completely blocked acetylcholine-induced relaxation in eNOS-/- mice. Single channel analysis of myocytes from small mesenteric arterioles revealed a large conductance calcium-activated potassium channel that was sensitive to iberiotoxin, charybdotoxin, and tetraethylammonium. Tubocurarine blocked this channel from the cytosolic side but not when applied extracellularly. Solutions of nitric oxide (NO) gas also relaxed small mesenteric arteries that had been contracted with cirazoline in a concentration-dependent manner, and the sensitivity to NO was reduced by iberiotoxin and the combination of apamin, scyllatoxin, or tubocurarine with charybdotoxin but not by apamin, charybdotoxin, scyllatoxin, or tubocurarine alone. These data indicate that acetylcholine induced endothelium-derived hyperpolarizing factor-mediated relaxation in small mesenteric arteries from eNOS-/- involved the activation of tubocurarine and apamin-/charybdotoxin-sensitive K-channels. In eNOS+/+ mice, the acetylcholine induced response was primarily mediated by NO and was sensitive to iberiotoxin and the combination of apamin and charybdotoxin. PMID- 22217883 TI - Protective effect of theaflavins on homocysteine-induced injury in HUVEC cells in vitro. AB - A model of homocysteine-induced injury in vascular endothelial cells was established to evaluate the protective role of theaflavins on homocysteine injured human vascular endothelial cells (HUVECs). The cells were co-incubated with 3 concentrations of theaflavins (5, 10, or 20 mg/L) and 0.5 mM homocysteine for 24 hours. The morphology and viability of the cells were determined, and the DNA damage was detected by a comet assay. Superoxide dismutase, malondialdehyde, glutathione peroxidase, nitric oxide, nitric oxide synthase, and endothelin-1 were measured. The results showed that theaflavins can reduce the changes in and damage of homocysteine-injured HUVECs, increase the viability of homocysteine injured HUVECs, and alleviate DNA damage induced by homocysteine. These results indicate that theaflavins can inhibit homocysteine-induced injury of HUVECs. Further studies showed that theaflavins may reduce the production of homocysteine induced reactive oxygen species and partly modulate the secretory dysfunction of vascular endothelial cells caused by homocysteine. This finding indicates that the mechanism by which theaflavins inhibit homocysteine-induced injury may relate to their antioxidant activity and the regulation of the secretion of endothelium derived factors. These findings suggest that theaflavins may be beneficial in the prevention of atherosclerosis and cardiovascular disease. PMID- 22217885 TI - Intraosseous infusion is unreliable for adenosine delivery in the treatment of supraventricular tachycardia. AB - Supraventricular tachycardia (SVT) is a common tachyarrhythmia in the pediatric population that can necessitate immediate treatment. Adenosine has been well studied as a mainstay treatment, but the methods of adenosine administration have not been very well delineated. The intraosseous technique has presented itself as a possible method of administration. We describe 2 cases in which adenosine was administered through bone marrow infusion to convert SVT without success. The cases we describe show that intraosseous is not a reliable method of administering adenosine to stop SVT. Both patients presented with SVT refractory to vagal maneuvers and difficult intravenous placement. Intraosseous access was achieved, but administration of adenosine at increasing doses was unable to successfully convert the arrhythmia. PMID- 22217884 TI - Adenosine A2A and A3 receptors are involved in the human endothelial progenitor cells migration. AB - Human endothelial progenitor cells (hEPC) are recruited to sites of neovascularization where they differentiate into endothelial cells. The signals/factors responsible for hEPC migration and adhesion to sites of injury are not well understood. Elevated levels of adenosine are known to increase mature endothelial cell migration in response to tissue injury. However, the understanding of the role of adenosine in the physiology of hEPC is very limited. Using quantitative polymerase chain reaction and western blot analyses, we detected the expression of the adenosine receptors A2A, A2B, and A3 in hEPC. Stimulation of adenosine receptors using adenosine or the nonselective agonist adenosine-5'-N-ethylcarboxamide (NECA) increased hEPC migration in 1.4-fold and 2.1-fold (P < 0.01), respectively. Stimulation of hEPC using the A2A-specific agonist CGS-21680 resembled the effect observed in migration when using adenosine or NECA. Consequently, NECA and CGS-21680-stimulated migration of hEPC were reverted using the A2A receptor antagonist ZM-241385. NECA-stimulated migration was inhibited in dose-dependent manner using MRS-1523 (Ki of 147 +/- 0.016 nM), MRS-1754 (Ki of 1900 +/- 0.02 nM), or ZM-241385 (Ki of 0.2 +/- 0.01 nM). In conclusion, adenosine stimulates hEPC migration by activating A2A and A3 but not A2B receptors and provides evidence to support a role of adenosine in modulating angiogenic capacity of hEPC. PMID- 22217886 TI - A case of penetrating neck trauma in a child. AB - Penetrating injuries to the neck are potentially devastating, and recommendations concerning their evaluation have generated extensive discussion over the years. In this article, we present the case of a 9-year-old girl who narrowly missed a serious vascular injury when she fell on a pencil. We also discuss the most current recommendations concerning management of zone II injuries to the neck of a pediatric patient. PMID- 22217888 TI - Cefixime-induced oculogyric crisis. AB - Oculogyric crisis is a neurologic adverse event characterized by bilateral dystonic, usually upward, conjugate eye deviations. Cefixime is a third generation cephalosporin and is widely used in clinical practice in childhood. Confusion, encephalopathy, coma, myoclonus, nonconvulsive status epilepticus, and seizures have been described with the use of cephalosporins. We presented a cefixime-induced oculogyric crisis in a 7-year-old boy during the treatment of urinary tract infection, and this is the first case of cefixime-induced oculogyric crisis whose ocular symptoms gradually disappeared within 48 hours after the drug was discontinued. PMID- 22217887 TI - Craniofacial injuries from television tip-over. AB - BACKGROUND: Craniofacial injuries caused by television (TV) sets falling on small children are becoming a frequent event seen in emergency departments. Injuries occur primarily to the head and neck regions and range from contusions to intracerebral hemorrhage, which at times can be fatal. OBJECTIVES: Epidemiology and potential complications from TV tip-over injuries are presented. CASE: Three cases of craniofacial injuries are described from blunt trauma incurred from TV tip-over events. CONCLUSIONS: It is important to teach parents about the dangers of the new large slim TV sets and the occurrence of injuries when these are not secured properly or placed away from the reach of the child. PMID- 22217889 TI - Deadly drop--cholinergic syndrome from wearing a laundered uniform. AB - Unintentional organophosphate compound poisoning, although known, contamination of organophosphate compound through laundered uniform and subsequent transcutaneous absorption, in 30 children is reported herewith for its rarity. Emergency physicians have to recognize such entities clinically, confirm by laboratory means wherever possible, and intervene with appropriate measures. PMID- 22217890 TI - Inability to walk, disequilibrium, incoherent speech, disorientation following the instillation of 1% cyclopentolate eyedrops: case report. AB - A 4-year-old boy, who had no prior history of convulsions, presented with inability to walk, disequilibrium, dysarthria (incoherent speech), and impaired cognition (disorientation) following the instillation of 1% cyclopentolate, a commonly used mydriatic in pediatric practice. This case demonstrates the uncommon, although serious, atropine-like adverse effect of cyclopentolate eyedrops in usual dosage in child. PMID- 22217891 TI - Nonaccidental trauma presenting with respiratory distress and pleural effusion. AB - Nonaccidental trauma (NAT) is common and presents with varied symptoms. Pleural effusion as a complication of physical abuse has not been described in the past. We report the case of a 10-week-old infant who presented with multiple nonspecific complaints that included respiratory distress, refusal to feed, constipation, and lethargy. Sepsis was the working diagnosis on admission, but a massive pleural effusion and rib fractures seen on chest imaging ultimately led to the diagnosis of nonaccidental trauma. This interesting case highlights the importance of maintaining a high index of suspicion for abuse irrespective of atypical presenting signs. PMID- 22217892 TI - Ischemic electrocardiographic changes and elevated troponin from severe heatstroke in an adolescent. AB - BACKGROUND: Heatstroke can result in significant diffuse tissue derangement, which can result in multiple organ system dysfunction. The heart can equally be affected and ischemia and infarction may occur. OBJECTIVE: This study aimed to present the potential complications from heatstroke to the myocardium. CASE: A case of a 15-year-old adolescent boy who collapsed after playing football in a hot summer day was found to be hyperthermic and poorly perfused. He had ischemic electrocardiographic changes and elevated cardiac enzymes but with normal coronary arteries. CONCLUSIONS: Heatstroke can lead to morbidity and mortality. Tissue damage during heatstroke is believed to result from uncoupling during oxidative phosphorylation. It is important to realize that heart damage can occur from heatstroke and that appropriate diagnostic and therapeutic measures are required for a good outcome. PMID- 22217893 TI - Cholelithiasis and its complications in children and adolescents: update and case discussion. AB - In recent years, gallbladder disease, primarily in the form of cholelithiasis, has been on the rise among infants and children. Although pediatric gallbladder disease is still less prevalent than adult gallbladder disease, physicians and other clinicians who care for children need to be aware of this underappreciated problem and understand the manifestations of biliary disease in the pediatric population. In this article, case discussions will serve as a platform for discussing the clinical spectrum of cholelithiasis and its complications in children as well as discussing the latest evidence related to diagnosis and treatment. PMID- 22217895 TI - Torsion of the testicle: it is time to stop tossing the dice. AB - In this review, long-held myths and misperceptions about the evaluation and management of testicular torsion are discussed, and recommendations for the management of patients who present with acute scrotal pain are presented. PMID- 22217896 TI - Malrotation with midgut volvulus. PMID- 22217897 TI - Emergency ultrasound diagnosis of deep venous thrombosis in the pediatric emergency department: a case series. AB - The diagnosis of deep venous thrombosis (DVT) in patients presenting to the emergency department (ED) has traditionally been limited to examinations by radiologists and ultrasound technicians. Although contrast venography is considered the criterion standard for diagnosis of DVT, time, personnel, cost, exposure to radiation, and the invasive nature of the study (need for venous access) potentially limit the ability to perform the study in an emergent setting. Ultrasonography is an alternative method for thrombus detection and is widely preferred. However, in many health care settings, consultative ultrasound services may not be available immediately, especially after hours and on weekends. Based on recent studies demonstrating accuracy in adult patients, emergency sonographic evaluation of DVT by emergency physicians is considered a core emergency ultrasound application and is recently recommended as standard training to all emergency medicine residents. The diagnosis of DVT in children by emergency ultrasound in the pediatric ED has not been previously described. We present 3 cases of DVT in adolescents identified by emergency ultrasound evaluation in the pediatric ED. PMID- 22217899 TI - Commentary on "Unintentional fatal phosphine gas poisoning of a family". PMID- 22217898 TI - ECGs in the ED. PMID- 22217900 TI - Phylogenetic analysis of human metapneumovirus from New York State patients during February through April 2010. AB - BACKGROUND: Human metapneumovirus (hMPV) is the second leading cause of lower respiratory infection (LRI) in children around the world and has been linked to LRI in multiple studies. Currently, hMPV is classified into 2 major subtypes (A and B), each with 2 subgroups (1 and 2). OBJECTIVE: To determine which hMPV genotypes were present in NYS patients with influenza-like illness (ILI) from February through April 2010, during a period of unusually heightened activity. STUDY DESIGN: Specimens were collected from February through April of 2010 from patients presenting with ILI who were previously confirmed as positive for hMPV by real-time RT-PCR. A 700 base pair region of the hMPV fusion (F) gene was amplified, sequenced and resulting sequences aligned. A phylogenic tree was constructed based on prototype strains, and the partial F gene sequences obtained in this study. RESULTS: Bi-directional sequence was obtained from 30 patient samples and included in the phylogenic analysis. Specimen sequences grouped into hMPV genotype A2a (16), A2b (9), B2 (4) and B1 (1). No A1 genotypes were found. CONCLUSION: Previously, reports have demonstrated that genotypes A1, A2, B1 and B2 circulate every season, usually with one dominant strain. In contrast, late in the 2009-2010 respiratory season, 4 of the 5 recognized genotypes of hMPV were isolated from NYS ILI patients, and by sequencing a larger portion of the fusion gene, we were able to identify the A2a and A2b genotypes. PMID- 22217906 TI - Single-channel blind estimation of arterial input function and tissue impulse response in DCE-MRI. AB - Multipass dynamic MRI and pharmacokinetic modeling are used to estimate perfusion parameters of leaky capillaries. Curve fitting and nonblind deconvolution are the established methods to derive the perfusion estimates from the observed arterial input function (AIF) and tissue tracer concentration function. These nonblind methods are sensitive to errors in the AIF, measured in some nearby artery or estimated by multichannel blind deconvolution. Here, a single-channel blind deconvolution algorithm is presented, which only uses a single tissue tracer concentration function to estimate the corresponding AIF and tissue impulse response function. That way, many errors affecting these functions are reduced. The validity of the algorithm is supported by simulations and tests on real data from mouse. The corresponding nonblind and multichannel methods are also presented. PMID- 22217907 TI - Improving survival following surgery for pancreatic ductal adenocarcinoma--a ten year experience. AB - OBJECTIVE: Report results following pancreatic surgery at a tertiary referral hospital in Norway, and our experience with the effects of preoperative use of common bile duct stents, the prophylactic efficacy of octreotide, and explore significant survival factors. MATERIAL AND METHODS: Prospective observational study of 275 patients during the years 1999-2009. RESULTS: Ninety-two ductal adenocarcinomas were operated, and 183 cases were inoperable. Pylorus preserving pancreatico-duodenectomy (PPPD) was performed in 42 cases, a classic Whipple procedure (WP) in 38, distal resection in 6 and total pancreatectomy in 6 patients. Median size of the tumours was 3 cm R(0) resection was obtained in 54 patients. Lymph node metastases were found in 64 patients. 20% experienced postoperative intra-abdominal complications, and 30 days postoperative mortality was 4%. A routine use of somatostatine analogues postoperatively did not reduce the frequency of leakage. Two years survival was 34.6% and 5 years 11.8%, respectively. CONCLUSIONS: Patients with ductal adenocarcinomas can be offered potential curative resections with acceptable rates of complication and mortality. Preoperative biliary stenting is still controversial and prophylactic octreotide should be used whenever the anastomosis is considered challenged and in cases of a soft pancreatic remnant. Five years all over survival has improved over the last decade from <5% to >11%. PMID- 22217908 TI - Molecular epidemiology of Mycobacterium avium subsp. paratuberculosis at a regional scale in Germany. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is the causal agent of Johne's disease in dairy cattle. Genotyping of MAP is useful to gain a better understanding of the origin of infection, to evaluate regional control programs, to improve diagnostics, and to develop vaccines. In this study 91 MAP isolates mainly from symptomatic dairy cattle in Rhineland-Palatinate (RP, Germany), its neighbor federal states, and Luxembourg were genotyped using Mycobacterial Interspersed Repetitive Units-Variable Number Tandem Repeat (MIRU-VNTR) and Multilocus Short Sequence Repeats (MLSSR). MIRU-VNTR and MLSSR produced 11 and 6 different genotypes among the 91 isolates, respectively. The combined analysis of both methods produced 25 genotypes with an index of discrimination (D) of 0.93 (95% CI: 0.91-0.95). The results revealed the genetic diversity of MAP and the dominance of two MAP genotypes commonly found in Europe, showed the usefulness of MAP genotyping in studies at a regional scale, and provided useful information for control initiatives in RP. PMID- 22217909 TI - Nephron segment identification in the normal canine kidney by using lectin histochemistry. AB - Lectin-binding patterns in normal canine kidneys were histochemically investigated using eight lectins. WGA, ConA, and RCA-I showed positive signals in glomerular capillary walls, with signals for RCA-I being detected heterogeneously. In tubular segments, signals for WGA, s-WGA, ConA, and RCA-I were distributed widely from proximal tubules to collecting ducts, whereas those for SBA, PNA, DBA, and UEA-I were localized in thin limbs of the loop of Henle, thick ascending limbs, distal tubules, or collecting ducts. Apart from PNA and UEA-I, lectins showed heterogeneous bindings in collecting ducts with the heterogeneity. UEA-I-positive reactions were restricted to those parts of the distal tubules in close proximity to the glomeruli, and in these parts, signals in the macula densa were markedly stronger than in other regions. Based on the present findings, lectin probes, singly or in combination, could be utilized to identify the affected nephron segment in canine renal pathology. PMID- 22217910 TI - Variety in placental shape: when does it originate? AB - OBJECTIVES: Observational and empirical evidence suggest that the average placental shape is round with a centrally inserted umbilical cord. Yet variability of shape is common. When in pregnancy do shape and cord insertion variations originate? MATERIALS AND METHODS: Placental measures from published datasets obtained ultrasonographically at 11-14 weeks and/or at term were correlated. RESULTS: Significant correlations were found between the normalized distance of cord insertion to the margin at 11-14 weeks with the same quantity at delivery (r = 0.509, p < 0.0001). First trimester cord marginality was not correlated with two measures of roundness of the delivered placenta (p = 0.448, and p = 0.812). There was a strong correlation between delivered placental thickness and first trimester cord marginality (r = -0.368, p = 0.009). There was a significant relationship between the cord marginality at 11-14 weeks and the mean chorionic vascular density at delivery (r = -0.287, p = 0.015). Placental position in the uterine cavity influences cord marginality at delivery. Modeling suggests that placental growth in the first trimester is non-round. Placental shape at 11-14 weeks is found to be irregular. This irregularity is not correlated with the roundness of the delivered placenta. Both empirically, and in the context of IVF pregnancies, deformation of the vasculogenic zone yields a bi lobate placental shape. CONCLUSIONS: Our findings strongly support the hypothesis that abnormal cord insertion and a multi-lobate shape result from early influences on the placental growth, such as the shape of the vasculogenic zone, or placental position in the uterus, rather than trophotropism later in pregnancy. PMID- 22217911 TI - Review: Does size matter? Placental debris and the pathophysiology of pre eclampsia. AB - A variety of 'debris' is shed from the syncytial surface of the human placenta ranging from large deported multinuclear fragments to sub-cellular components. It is increasingly clear that at least some of this material has signalling functions. Many categories of circulating debris are increased in pre-eclampsia, and exhibit proteins that are pro-inflammatory and could contribute to the systemic inflammatory response in normal pregnancy, which is exaggerated in pre eclampsia. It is now evident that there is a large 'hidden' population of microvesicles and nanovesicles (including exosomes) which are hard to investigate because of their size. We have used a new technology, nanoparticle tracking analysis, to measure the size and concentration of syncytiotrophoblast vesicles prepared by placental perfusion. The vesicles range in size from 50 nm to 1 MUm with the majority being <500 nm (which includes both exosomes and microvesicles). We speculate whether changes not only in the numbers, but also in the size (beneficial syncytiotrophoblast exosomes and harmful microvesicles) might be important in the maternal syndrome of pre-eclampsia. PMID- 22217912 TI - Management and outcomes of chronic otitis media in patients who received solid organ transplantation. AB - OBJECTIVES: Control of perioperative infection can increase the success rate of organ transplant. The incidence, clinical features, and optimal management of chronic otitis media (COM) in solid organ transplant recipients have not been adequately evaluated. We therefore assessed the incidence and clinical course of COM in solid-organ transplant recipients. DESIGN: Case series with chart review. SETTING: Tertiary referral center. SUBJECTS AND METHODS: We reviewed the medical records of 3278 patients who underwent solid organ transplantations between February 1995 and December 2007 to identify those diagnosed with COM before and after transplant. We analyzed the long-term clinical course and management of COM in these patients. RESULTS: Of 3278 solid organ transplant recipients, 65 (2.0%) were diagnosed with pretransplant COM with a perforated ear drum, including 31 liver, 28 renal, and 6 heart transplant recipients. The primary symptom was otorrhea, followed by hearing disturbance, otalgia, and tinnitus. Middle ear swab culture showed bacterial growth in 17 of the 40 patients (42.5%) with suppurative COM. Of these 40 patients, 14 underwent tympanomastoid surgery (operation group) and 26 were prescribed antibiotics (medication group). The remaining 25 patients, with dry perforated ear drums and well-pneumatized mastoids, were observed without treatment (observation group). After transplantation, the incidence of otorrhea was significantly lower in the operation group (11.1%) than in either the medication (26.9%) or observation (26.7%) group (P = .040, .048, respectively). CONCLUSIONS: Precise diagnosis and proper surgical intervention for COM may reduce the rate of otorrhea and exacerbation of COM in solid organ transplant recipients. PMID- 22217913 TI - A small effect of adding antiviral agents in treating patients with severe Bell palsy. AB - In this evidence-based case report, the authors studied the following clinical question: What is the effect of adding antiviral agents to corticosteroids in the treatment of patients with severe or complete Bell palsy? The search yielded 250 original research articles. The 6 randomized trials of these that could be used all reported low-quality data for answering the clinical question; apart from apparent flaws, they did not primarily include patients with severe or complete Bell palsy. Complete functional facial nerve recovery was seen in 75% of the patients receiving prednisolone only and in 83% with additional antiviral treatment. The pooled risk difference of 7% (95% confidence interval, -1% to 15%) results in a number needed to treat of 14 (ie, slightly favors adding an antiviral agent). The authors conclude that although a strong recommendation for adding antiviral agents to corticosteroids to further improve the recovery of patients with severe Bell palsy is precluded by the lack of robust evidence, it should be discussed with the patient. PMID- 22217914 TI - Thyroidectomy-related malpractice claims. AB - OBJECTIVE: Little information is available regarding the frequency of thyroidectomy-related malpractice claims. Previous studies have not assessed claims that were settled or dropped before trial, providing only a limited view of the medical-legal environment. We sought to determine the frequency of thyroid surgery-related malpractice claims, their causes, and outcomes. STUDY DESIGN: Database assessment. SETTING: Academic medical center. SUBJECTS AND METHODS: The database of the Physician Insurers Association of America was reviewed. These data are estimated to represent 25% of medical malpractice claims in the United States. Claims from 1985 to 2008 with thyroid-related procedure codes were evaluated for claimant information, insured's specialty, loss description, causation, and claim outcomes. RESULTS: During the 24-year period reviewed, 380 claims related to thyroid surgery were reported. 128 claims (33.7% of total claims) resulted in an indemnity payment either due to settlement or a finding against the defendant. The average indemnity payment was $185,366 (range, $363 to $2,000,000). Among cases in which a specific outcome was reported, 55 were related to laryngeal nerve injury or voice disturbance. No substantial change occurred in the incidence of claims across the study period. During this time, approximately 2,585,000 thyroidectomies were performed. Extrapolating from the Physician Insurers Association of America data, this represents an estimated 5.9 claims per 10,000 cases. CONCLUSION: Malpractice claims related to thyroid surgery are surprisingly infrequent. While the rates of thyroid surgery have risen steadily, there has not been a corresponding increase in the rate of related malpractice claims. PMID- 22217915 TI - Margin photocoagulation in laser surgery for early glottic cancer: impact on disease local control. AB - OBJECTIVE: Assess the impact of surgical margin CO2 laser photocoagulation (LPC) on disease local control in patients submitted to endoscopic surgery for early glottic cancer in comparison with subjects treated with laser cordectomy without borders LPC. STUDY DESIGN: Historical cohort study. SETTING: Regional referral cancer center. SUBJECTS AND METHODS: A total 281 patients with early glottic cancer (T1a, T1b, T2) were treated with endoscopic laser cordectomy according to the European Laryngological Society Classification between 1999 and 2006. Among the patients, 123 (treated between 2003 and 2006) were submitted to postresection LPC of surgical margins (group 1), whereas 158 (operated between 1999 and 2002) underwent laser cordectomy without margin LPC (group 2). Median follow-up was 51 months (range, 36-101 months). RESULTS: Local recurrence was found in 43 of 281 (15.30%) subjects (18 with T1a, 13 with T1b, 12 with T2). A significant difference in recurrence rate was found among patients treated with margin LPC in comparison with group 2 (P = .022). In particular, a lower recurrence rate in LPC patients was noticed in case of close (<= 1 mm), nondefinable, and positive margins with infiltration of the superficial border. No significant difference was noticed in the case of negative edges (>1 mm) or involvement of either deep margin or both superficial and deep edges. CONCLUSIONS: Surgical margin LPC increases disease local control in the case of close and superficial margin positivity. In such cases, no further treatment (surgical revision or radiotherapy) seems to be required in LPC patients. In case of deep border involvement, surgical revision or radiotherapy should be performed. PMID- 22217917 TI - Toward semantic interoperability of electronic health records. AB - Although the goal of achieving semantic interoperability of electronic health records (EHRs) is pursued by many researchers, it has not been accomplished yet. In this paper, we present a proposal that smoothes out the way toward the achievement of that goal. In particular, our study focuses on medical diagnoses statements. In summary, the main contributions of our ontology-based proposal are the following: first, it includes a canonical ontology whose EHR-related terms focus on semantic aspects. As a result, their descriptions are independent of languages and technology aspects used in different organizations to represent EHRs. Moreover, those terms are related to their corresponding codes in well known medical terminologies. Second, it deals with modules that allow obtaining rich ontological representations of EHR information managed by proprietary models of health information systems. The features of one specific module are shown as reference. Third, it considers the necessary mapping axioms between ontological terms enhanced with so-called path mappings. This feature smoothes out structural differences between heterogeneous EHR representations, allowing proper alignment of information. PMID- 22217916 TI - MR-guided pulsed high intensity focused ultrasound enhancement of docetaxel combined with radiotherapy for prostate cancer treatment. AB - The purpose of this study is to evaluate the efficacy of the enhancement of docetaxel by pulsed focused ultrasound (pFUS) in combination with radiotherapy (RT) for treatment of prostate cancer in vivo. LNCaP cells were grown in the prostates of male nude mice. When the tumors reached a designated volume by MRI, tumor bearing mice were randomly divided into seven groups (n = 5): (1) pFUS alone; (2) RT alone; (3) docetaxel alone; (4) docetaxel + pFUS; (5) docetaxel + RT; (6) docetaxel + pFUS + RT, and (7) control. MR-guided pFUS treatment was performed using a focused ultrasound treatment system (InSightec ExAblate 2000) with a 1.5T GE MR scanner. Animals were treated once with pFUS, docetaxel, RT or their combinations. Docetaxel was given by i.v. injection at 5 mg kg(-1) before pFUS. RT was given 2 Gy after pFUS. Animals were euthanized 4 weeks after treatment. Tumor volumes were measured on MRI at 1 and 4 weeks post-treatment. Results showed that triple combination therapies of docetaxel, pFUS and RT provided the most significant tumor growth inhibition among all groups, which may have potential for the treatment of prostate cancer due to an improved therapeutic ratio. PMID- 22217918 TI - Facioscapulohumeral muscular dystrophy: new insights from compound heterozygotes and implication for prenatal genetic counselling. AB - Background Facioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disease with a prevalence of 1 in 20 000. Almost all patients with FSHD carry deletions of integral copies of tandem 3.3 kb repeats (D4Z4) located on chromosome 4q35. However, FSHD families have been reported in which individuals carrying a D4Z4-reduced allele remain asymptomatic. Recently, it has been proposed that the D4Z4-reduced allele is pathogenic only in association with the permissive haplotype, 4APAS. Methods and results Through the Italian National Registry for FSHD (INRF), genotype-phenotype correlations were extensively studied in 11 non-consanguineous families in which two D4Z4-reduced alleles segregate. Overall, 68 subjects carrying D4Z4-reduced alleles were examined, including 15 compound heterozygotes. It was found that in four families the only FSHD-affected subject was the compound heterozygote for the D4Z4-reduced allele, and 52.6% of subjects carrying a single D4Z4-reduced 4A161PAS haplotype were non-penetrant carriers; moreover, the population frequency of the 4A161PAS haplotype associated with a D4Z4-reduced allele was found to be as high as 1.2%. Conclusions This study reveals a high frequency of compound heterozygotes in the Italian population and the presence of D4Z4-reduced alleles with the 4A161PAS pathogenic haplotype in the majority of non-penetrant subjects in FSHD families with compound heterozygosity. These data suggest that carriers of FSHD-sized alleles with 4A161PAS haplotype are more common in the general population than expected on the basis of FSHD prevalence. These findings challenge the notion that FSHD is a fully penetrant autosomal dominant disorder uniquely associated with the 4A161PAS haplotype, with relevant repercussions for genetic counselling and prenatal diagnosis. PMID- 22217920 TI - Numerical analysis of coronary artery bypass grafts: an over view. AB - Arterial bypass grafts tend to fail after some years due to the development of intimal thickening (restenosis). Non-uniform hemodynamics following a bypass operation contributes to restenosis and bypass failure can occur due to the focal development of anastomotic intimal hyperplasia. Additionally, surgical injury aggravated by compliance mismatch between the graft and artery has been suggested as an initiating factor for progress of wall thickening along the suture line Vascular grafts that are small in diameter tend to occlude rapidly. Computational fluid dynamics (CFD) methods have been effectively used to simulate the physical and geometrical parameters characterizing the hemodynamics of various arteries and bypass configurations. The effects of such changes on the pressure and flow characteristics as well as the wall shear stress during a cardiac cycle can be simulated. Recently, utilization of fluid and structure interactions have been used to determine fluid flow parameters and structure forces including stress and strains relationships under steady and transient conditions. In parallel to this, experimental diagnostics techniques such as Laser Doppler Anemometry, Particle Image Velocimetry, Doppler Guide wire and Magnetic Resonance Imaging have been used to provide essential information and to validate the numerical results. Moreover, clinical imaging techniques such as magnetic resonance or computed tomography have assisted considerably in gaining a detailed patient-specific picture of the blood flow and structure dynamics. This paper gives a review of recent numerical investigations of various configurations of coronary artery bypass grafts (CABG). In addition, the paper ends with a summary of the findings and the future directions. PMID- 22217919 TI - Very young adolescents and alcohol: evidence of a unique susceptibility to peer alcohol use. AB - AIM: The aim of this study is to examine the susceptibility of very young adolescents (10-12 years of age) to peer alcohol-related influences, compared to older adolescents (13-14 years of age). METHODS: The analysis sample consisted of 7064 adolescents in grade 6 (modal age 11) or grade 8 (modal age 13) from 231 schools in 30 communities across three Australian States. Key measures were adolescent reports of alcohol use (past 30 days) and the number of peers who consume alcohol without their parent's awareness. Control variables included parent alcohol use, family relationship quality, pubertal advancement, school connectedness, sensation seeking, depression, length of time in high school, as well as age, gender, father/mother education, and language spoken at home. A multi-level model of alcohol use was used to account for school-level clustering on the dependent variable. RESULTS: For both groups, the number of peers who consumed alcohol was associated with alcohol use, but Grade 6 students showed a unique susceptibility to peripheral involvement with peer drinking networks (having one friend who consumed alcohol). CONCLUSION: The results point to the importance of monitoring and responding to comparatively minor shifts in the proportion of peers who use alcohol, particularly among very young adolescents. PMID- 22217921 TI - Anticancer attributes of desert plants: a review. AB - The ever-increasing emergence of the resistance of mammalian tumor cells to chemotherapy and its severe side effects reduces the clinical efficacy of a large variety of anticancer agents that are currently in use. Thus, despite the significant progress in cancer therapeutics in the last decades, the need to discover and to develop new, alternative, or synergistic anticancer agents remains. Cancer prevention or chemotherapy based on bioactive fractions or pure components derived from desert plants with known cancer-inhibiting properties suggests promising alternatives to current cancer therapy. Plants growing on low nutrient soils and/or under harsh climatic conditions, such as extreme temperatures, intense solar radiation, and water scarcity, are particularly susceptible to attack from reactive oxygen species and have evolved efficient antioxidation defense systems. The many examples of desert plants displaying anticancer effects as presented here indicates that the same defensive secondary metabolites protecting them against the harsh environment may also play a protective or a curative role against cancer, as they also do against diabetes, neurodegenerative, and other acute and chronic diseases. The present review highlights a plethora of studies focused on the antineoplastic properties of desert plants and their prinicipal phytochemicals, such as saponins, flavonoids, tannins, and terpenes. Although many desert plants have been investigated for their antitumor properties, there are many that still remain to be explored - a challenge for the prospective cancer therapy of the future. PMID- 22217922 TI - [MYH9 syndrome and auto-immune haemolytic anaemia: an unrelated association?]. AB - INTRODUCTION: The MYH9 syndrome is a group of rare autosomal dominant platelet disorders associating in most of the cases a macrothrombocytopenia and characteristic leukocyte inclusions. Clinical features may include renal, visual, or hearing impairment. The bleeding tendency is usually moderate. CASE REPORT: We report a 28-year-old-man, with an auto-immune haemolytic anaemia associated with a MYH9 syndrome. CONCLUSION: To our knowledge, this is the first report of such an association. PMID- 22217923 TI - [Management of orbital inflammation in internal medicine: a retrospective case series of 29 patients]. AB - PURPOSE: To describe a case series of patients investigated in internal medicine for an inflammation of the orbit and to clarify the clinical and pathological features of patients with idiopathic orbital inflammatory syndrome (IOIS). PATIENTS AND METHODS: Forty patients were consecutively referred by a specialized center where an orbital biopsy was performed in case of accessible lesion. Eleven patients were excluded because of missing data or diagnosis of lymphomas, periorbital xanthogranulomas, or Graves' disease. Patients with systemic disease (SD) or auto-immune disorder (AID) that validated the international criteria, or those having an IOIS in the absence of local or systemic etiology, were included. The clinicopathologic and immunologic characteristics of IOIS patients, their treatment and their evolutionary profiles are reported according to the histological types described by Mombaerts. RESULTS: Of the 29 patients enrolled, eight had a dacryoadenitis revealing a SD/AID, mainly a necrotizing vasculitis, seven patients had a presumed IOIS and 14 an IOIS histologically documented. The presentation of IOIS was dominated by a diffuse involvement of the orbit. Corticosteroids were administered alone or with an immunosuppressant in 57 and 24% of IOIS patients, respectively. The incidence of relapse/resistance was higher than that of remission, particularly in case of presumed IOIS or in its classical form. All four patients with a stage III-IV of Chisholm were relapsing or resistant. CONCLUSION: A dacryoadenitis may reveal some types of SD/AID. Unlike the severe sialadenitis, the form of sclerosing IOIS may not be a factor associated with relapse or resistance. PMID- 22217924 TI - [Cochlear implant in adults]. AB - Cochlear implant in adults is a procedure, dedicated to rehabilitate severe to profound hearing loss. Because of technological progresses and their applications for signal strategies, new devices can improve hearing, even in noise conditions. Binaural stimulation, cochlear implant and hearing aid or bilateral cochlear implants are the best opportunities to access to better level of comprehension in all conditions and space localisation. By now minimally invasive surgery is possible to preserve residual hearing and use a double stimulation modality for the same ear: electrical for high frequencies and acoustic for low frequencies. In several conditions, cochlear implant is not possible due to cochlear nerve tumour or major malformations of the inner ear. In these cases, a brainstem implantation can be considered. Clinical data demonstrate that improvement in daily communication, for both cochlear and brainstem implants, is correlated with cerebral activation of auditory cortex. PMID- 22217925 TI - Isolating LacZ-expressing cells from mouse inner ear tissues using flow cytometry. AB - Isolation of specific cell types allows one to analyze rare cell populations such as stem/progenitor cells. Such an approach to studying inner ear tissues presents a unique challenge because of the paucity of cells of interest and few transgenic reporter mouse models. Here, we describe a protocol using fluorescence-conjugated probes to selectively label LacZ-positive cells from the neonatal cochleae. The most common underlying pathology of sensorineural hearing loss is the irreversible damage and loss of cochlear sensory hair cells, which are required to transduce sound waves to neural impulses. Recent evidence suggests that the murine auditory and vestibular organs harbor stem/progenitor cells that may have regenerative potential. These findings warrant further investigation, including identifying specific cell types with stem/progenitor cell characteristics. The Wnt signaling pathway has been demonstrated to play a critical role in maintaining stem/progenitor cell populations in several organ systems. We have recently identified Wnt-responsive Axin2-expressing cells in the neonatal cochlea, but their function is largely unknown. To better understand the behavior of these Wnt-responsive cells in vitro, we have developed a method of isolating Axin2-expressing cells from cochleae of Axin2-LacZ reporter mice. Using flow cytometry to isolate Axin2-LacZ positive cells from the neonatal cochleae, we could in turn execute a variety of experiments on live cells to interrogate their behavior as stem/progenitor cells. Here, we describe in detail the steps for the microdissection of neonatal cochlea, dissociation of these tissues, labeling of the LacZ-positive cells using a fluorogenic substrate, and cell sorting. Techniques for dissociating cochleae into single cells and isolating cochlear cells via flow cytometry have been described. We have made modifications to these techniques to establish a novel protocol to isolate LacZ-expressing cells from the neonatal cochlea. PMID- 22217926 TI - Uranium microdistribution in renal cortex of rats after chronic exposure: a study by secondary ion mass spectrometry microscopy. AB - For a few years, the biological effects on ecosystems and the public of the bioaccumulation of radionuclides in situations of chronic exposures have been studied. This work, in keeping with the ENVIRHOM French research program, presents the uranium microdistribution by secondary ion mass spectrometry (SIMS) technique in the renal cortex of rats following chronic exposure to this low level element in the drinking water (40 mg/L) as a function to exposure duration (6, 9, 12, and 18 months). The SIMS mass spectra and 238U+ ion images produced with a SIMS CAMECA 4F-E7 show the kinetic of uranium accumulation in the different structures of the kidney. For the rats contaminated up to 12 months, the radioelement is mainly fixed in the proximal tubules; then after 18 exposure months, uranium is detected in all the segments of the nephron. This work has also shown that ion microscopy is an analytical method to detect trace elements and give elemental cartography at the micrometer scale. PMID- 22217927 TI - Comparison of first and second generation antipsychotics: An update. PMID- 22217928 TI - [A study of irritability in menopausal women]. AB - Despite the fact that irritability is frequently the main presenting complaint of perimenopausal and postmenopausal women, studies specifically researching irritability in this population are scant. One hundred sixty three (163) peri- and postmenopausal women non-HT users, attending a menopause clinic, were included in this cross-sectional study. The investigation focused on whether the occurrence of inward and outward irritability in menopause is associated with various menopausal parameters, such as vasomotor symptoms, insomnia, menopausal status, hormone levels, and with the presence of chronic disease. Furthermore, we examined the possible association of inward and outward irritability with measures of anxiety and depression. Outward and inward irritability of peri- and postmenopausal women seem to be related to chronic disease, a factor that may be partially influenced by the older age of menopausal women. Outwardly directed irritability is found to be related to FSH and LH levels, independently of specific menopausal symptoms, such as vasomotor symptoms or insomnia. Outward irritability was found to be positively correlated with depressive symptomatology, whereas inward irritability correlated with both anxiety and higher depressive symptomatology. PMID- 22217929 TI - [Psychological and psychiatric problems in cancer patients in the general hospital]. AB - Cancer is the most common cause of death after heart disease. The patient diagnosed with cancer confronts high levels of emotional distress, while he has to make crucial decisions about his treatment. As a life threatening illness, it is a traumatic stressor which triggers overwhelming feelings and affects the patient's functioning. There is a variety of psychological responses. Anger, fear, anxiety, hopelessness attend the diagnosis of cancer. Fifty percent of affected individuals develop psychiatric disorders, such as Stress Response Syndromes like Acute Response Syndromes, Post-traumatic Stress Disorder, Major Depression, Adjustment Disorders, and Delirium. The members of consultation liaison psychiatry intervene in a wide spectrum of psychiatric complications of cancer. Also, there are patients with major psychiatric disorders such as schizophrenia who develop cancer and the psychiatrist has to give them an understanding of the illness and to facilitate their active participation in the medical treatment. The main purpose is co-operation between consultation liaison psychiatrists and physicians. Psychiatrists make efforts to promote a better understanding of schizophrenia among physicians and to fight the stigma attached to the disease. The risk of suicide is higher in cancer patients, than in general population and the identification of patients at increased risk of suicide among affected individuals such as those with major depression, alcohol abusers, uncontrolled pain, advanced illness is a very important step in suicide prevention. When the end of life is approaching, psychiatrists have to face physical problems, psychological symptoms and issues of existence, which pose special challenges for the patient. The psychiatrist has to help him to reduce the psychological pain and to encourage his family to listen to his wishes. The consultationliaison psychiatrists intervene at every stage of cancer from the prevention and the preclinical cancer, to palliative care and end-of life, with diagnosis and effective therapy. PMID- 22217930 TI - [The concept of time and its relation to the psychoanalytic-psychotherapeutic setting]. AB - Psychoanalysis is fundamentally related to time because it is an ef for t to understand how disturbances in the present are determined by events in the past. This paper represents an attempt to delineate the developmental line of time sense from birth to object constancy, concentrating on those maturational and environmental factors which determine psychotemporal adaptation in infancy and early childhood until the age of adolescence. Patients' distortions of time can frequently and readily be observed in clinical psychoanalysis reflecting both their psychopathology and their reactions to the temporal aspects of the psychoanalytic setting. PMID- 22217931 TI - [The PLACEBO effect: Definition, theories of action, ethical considerations]. AB - The placebo effect (from latin placere=to please), i.e. the nonspecific psychological therapeutic effects of a substance or procedure, remains one of the biggest challenges encountered by modern medicine, as a therapeutic means with unquestionable and yet unappreciated, global and yet uncontrollable, efficacy. The history of medicine largely intersects the history of placebo effect, as the first scientifically proven non-placebo drug only appeared in the 17th century. Today, placebos have themselves become an object of investigations aiming to clarify the mechanisms of mind-body interactions. Moreover, placebos occupy an important place as methodological tools in modern medical research; randomized double-blind, placebo-controlled studies have been established as the golden standard in the evaluation of new therapies. However, the use of placebos raises a number of important ethical issues, as it comes in contrast to the two most basic principles of medicine, beneficence and autonomy. Therefore, the use of placebos in clinical research should always include measures that ensure minimization of any risk associated with delay of active treatment, as well as preser vation of the patients' interests. In clinical practice, physicians should be aware of psychological dimensions of treatment, of the meaning that the patient ascribes to it, as well as of the influence of the doctor-patient relationship, so that they can use these beneficial nonspecific (i.e. placebo) effects of treatment in the best interest of their patients. PMID- 22217932 TI - [An individualized behavioral approach in psychosocial rehabilitation]. AB - The deinstitutionalization of chronic mental health patients and the simultaneous growth of community mental health structures were elected as central objectives of interventions, based on the concept of psychosocial rehabilitation. The main axes of this ef fort were maximization of the individual's potential and minimization of the long-term hospitalizations' negative consequences. The individualized approach via the application of an individual therapeutic program and the simultaneous evaluation of patients' needs and course during their stay in community residential home structures of psychiatric care constitute the basic condition for the achievement of therapeutic goals of rehabilitation, guarantee of the quality of services provided and continuity of care. The article is completed with the quotation of thoughts and proposals in connection with current approaches concerning the sector of social psychiatry, which everybody has to take into careful consideration in order to do the individual therapeutic program more effective being a powerful tool that helps therapists to draw satisfaction and pleasure from their work and helps patients to become active members of a democratic society. PMID- 22217933 TI - STAT6 phosphorylation inhibitors block eotaxin-3 secretion in bronchial epithelial cells. AB - The STAT6 (signal transducer and activator of transcription 6) protein facilitates T-helper cell 2 (Th2) mediated responses that control IgE-mediated atopic diseases such as asthma. We have identified compounds that bind to STAT6 and inhibit STAT6 tyrosine phosphorylation induced by IL-4. In the bronchial epithelial cell line BEAS-2B, compound (R)-84 inhibits the secretion of eotaxin 3, a chemokine eliciting eosinophil infiltration. (R)-84 appears to prevent STAT6 from assuming the active dimer configuration by directly binding the protein and inhibiting tyrosine phosphorylation. PMID- 22217934 TI - [Intussusception in an adult secondary to metastasis of cutaneous melanoma]. PMID- 22217935 TI - Allergic contact dermatitis to plants: understanding the chemistry will help our diagnostic approach. AB - Allergic contact dermatitis due to plants is common. Potentially allergenic plants and plant products are found in many everyday environments, such as the home, the garden, the workplace, and recreational settings. By improving our knowledge of allergenic plant-derived chemical compounds, we will be better positioned to identify novel allergens. We review the most relevant chemical allergens that contribute to plant allergic contact dermatitis and propose a clinical classification system based on 5 major families of chemical sensitizers: alpha-methylene-gamma-butyrolactones, quinones, phenol derivatives, terpenes, and miscellaneous structures (disulfides, isothiocyanates, and polyacetylenic derivates). We also describe the different clinical pictures of plant allergic contact dermatitis and review currently available patch test materials. A better understanding of the specific allergens involved in plant allergic contact dermatitis will help to predict cross-reactivity between different plant species or families. PMID- 22217936 TI - Adenosine following pulmonary vein isolation to target dormant conduction elimination (ADVICE): methods and rationale. AB - BACKGROUND: Pulmonary vein (PV) isolation (PVI) has emerged as an effective therapy for paroxysmal atrial fibrillation (AF). However, AF recurs in up to 50% of patients, generally because of recovery of PV conduction. Adenosine given during the initial procedure may reveal dormant PV conduction, thereby identifying the need for additional ablation, leading to improved outcomes. The Adenosine Following Pulmonary Vein Isolation to Target Dormant Conduction Elimination (ADVICE) study is a prospective multicentre randomized trial assessing the impact of adenosine-guided PVI in preventing AF recurrences. METHODS: Patients undergoing a first PVI procedure for paroxysmal AF will be recruited. After standard PVI is completed, all patients will receive intravenous adenosine in an attempt to unmask dormant conduction. If dormant conduction is elicited, patients will be randomized to no further ablation (control group) or additional adenosine-guided ablation until dormant conduction is abolished. If no dormant conduction is revealed, randomly selected patients will be followed in a registry. The primary outcome is time to first documented symptomatic AF recurrence. Assuming that dormant conduction is present in 50% of patients post PVI and symptomatic AF recurs in 45% of controls, 244 patients with dormant conduction will be required to obtain > 90% power to detect a difference of 20%. Thus, a total of 488 patients will be enrolled and followed for 12 months. CONCLUSION: The ADVICE trial will assess whether a PVI strategy incorporating elimination of dormant conduction unmasked by intravenous adenosine will decrease the rate of recurrent symptomatic AF compared with standard PVI. PMID- 22217939 TI - Biomechanics: Leaping lizards and dinosaurs. PMID- 22217937 TI - Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. AB - Oestrogen receptor-alpha (ER) is the defining and driving transcription factor in the majority of breast cancers and its target genes dictate cell growth and endocrine response, yet genomic understanding of ER function has been restricted to model systems. Here we map genome-wide ER-binding events, by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), in primary breast cancers from patients with different clinical outcomes and in distant ER positive metastases. We find that drug-resistant cancers still recruit ER to the chromatin, but that ER binding is a dynamic process, with the acquisition of unique ER-binding regions in tumours from patients that are likely to relapse. The acquired ER regulatory regions associated with poor clinical outcome observed in primary tumours reveal gene signatures that predict clinical outcome in ER positive disease exclusively. We find that the differential ER-binding programme observed in tumours from patients with poor outcome is not due to the selection of a rare subpopulation of cells, but is due to the FOXA1-mediated reprogramming of ER binding on a rapid timescale. The parallel redistribution of ER and FOXA1 binding events in drug-resistant cellular contexts is supported by histological co-expression of ER and FOXA1 in metastatic samples. By establishing transcription-factor mapping in primary tumour material, we show that there is plasticity in ER-binding capacity, with distinct combinations of cis-regulatory elements linked with the different clinical outcomes. PMID- 22217938 TI - Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys. AB - Preclinical studies of human immunodeficiency virus type 1 (HIV-1) vaccine candidates have typically shown post-infection virological control, but protection against acquisition of infection has previously only been reported against neutralization-sensitive virus challenges. Here we demonstrate vaccine protection against acquisition of fully heterologous, neutralization-resistant simian immunodeficiency virus (SIV) challenges in rhesus monkeys. Adenovirus/poxvirus and adenovirus/adenovirus-vector-based vaccines expressing SIV(SME543) Gag, Pol and Env antigens resulted in an 80% or greater reduction in the per-exposure probability of infection against repetitive, intrarectal SIV(MAC251) challenges in rhesus monkeys. Protection against acquisition of infection showed distinct immunological correlates compared with post-infection virological control and required the inclusion of Env in the vaccine regimen. These data demonstrate the proof-of-concept that optimized HIV-1 vaccine candidates can block acquisition of stringent, heterologous, neutralization resistant virus challenges in rhesus monkeys. PMID- 22217940 TI - Materials science: A fresh twist for self-assembly. PMID- 22217941 TI - Reconfigurable self-assembly through chiral control of interfacial tension. AB - From determining the optical properties of simple molecular crystals to establishing the preferred handedness in highly complex vertebrates, molecular chirality profoundly influences the structural, mechanical and optical properties of both synthetic and biological matter on macroscopic length scales. In soft materials such as amphiphilic lipids and liquid crystals, the competition between local chiral interactions and global constraints imposed by the geometry of the self-assembled structures leads to frustration and the assembly of unique materials. An example of particular interest is smectic liquid crystals, where the two-dimensional layered geometry cannot support twist and chirality is consequently expelled to the edges in a manner analogous to the expulsion of a magnetic field from superconductors. Here we demonstrate a consequence of this geometric frustration that leads to a new design principle for the assembly of chiral molecules. Using a model system of colloidal membranes, we show that molecular chirality can control the interfacial tension, an important property of multi-component mixtures. This suggests an analogy between chiral twist, which is expelled to the edges of two-dimensional membranes, and amphiphilic surfactants, which are expelled to oil-water interfaces. As with surfactants, chiral control of interfacial tension drives the formation of many polymorphic assemblages such as twisted ribbons with linear and circular topologies, starfish membranes, and double and triple helices. Tuning molecular chirality in situ allows dynamical control of line tension, which powers polymorphic transitions between various chiral structures. These findings outline a general strategy for the assembly of reconfigurable chiral materials that can easily be moved, stretched, attached to one another and transformed between multiple conformational states, thus allowing precise assembly and nanosculpting of highly dynamical and designable materials with complex topologies. PMID- 22217942 TI - Tail-assisted pitch control in lizards, robots and dinosaurs. AB - In 1969, a palaeontologist proposed that theropod dinosaurs used their tails as dynamic stabilizers during rapid or irregular movements, contributing to their depiction as active and agile predators. Since then the inertia of swinging appendages has been implicated in stabilizing human walking, aiding acrobatic manoeuvres by primates and rodents, and enabling cats to balance on branches. Recent studies on geckos suggest that active tail stabilization occurs during climbing, righting and gliding. By contrast, studies on the effect of lizard tail loss show evidence of a decrease, an increase or no change in performance. Application of a control-theoretic framework could advance our general understanding of inertial appendage use in locomotion. Here we report that lizards control the swing of their tails in a measured manner to redirect angular momentum from their bodies to their tails, stabilizing body attitude in the sagittal plane. We video-recorded Red-Headed Agama lizards (Agama agama) leaping towards a vertical surface by first vaulting onto an obstacle with variable traction to induce a range of perturbations in body angular momentum. To examine a known controlled tail response, we built a lizard-sized robot with an active tail that used sensory feedback to stabilize pitch as it drove off a ramp. Our dynamics model revealed that a body swinging its tail experienced less rotation than a body with a rigid tail, a passively compliant tail or no tail. To compare a range of tails, we calculated tail effectiveness as the amount of tailless body rotation a tail could stabilize. A model Velociraptor mongoliensis supported the initial tail stabilization hypothesis, showing as it did a greater tail effectiveness than the Agama lizards. Leaping lizards show that inertial control of body attitude can advance our understanding of appendage evolution and provide biological inspiration for the next generation of manoeuvrable search-and-rescue robots. PMID- 22217944 TI - Acute renal failure after paliperidone overdose: a case report. PMID- 22217943 TI - Pregabalin-associated increase of clozapine serum levels. PMID- 22217945 TI - Peripheral edema associated with risperidone oral solution: a case report and a review of the literature. PMID- 22217946 TI - Olanzapine-related life-threatening hyperosmolar hyperglycemic syndrome: a case report. PMID- 22217947 TI - Valproic Acid-related anticonvulsant hypersensitivity syndrome and subsequent olanzapine-related neutropenia and thrombocytopenia: a case report. PMID- 22217948 TI - Quetiapine- and valproate-associated neutropenia and thrombocytopenia after lamotrigine-induced Steven-Johnson syndrome. PMID- 22217950 TI - Treatment of indiscriminate, inappropriate sexual behavior in frontotemporal dementia with carbamazepine. PMID- 22217949 TI - COMT Val158Met, BDNF Val66Met, and OPRM1 Asn40Asp and methamphetamine dependence treatment response: preliminary investigation. PMID- 22217951 TI - Sex subgroup analysis of treatment response to lisdexamfetamine dimesylate in children aged 6 to 12 years with attention-deficit/hyperactivity disorder. PMID- 22217952 TI - Tourette syndrome with comorbid bipolar disorder and migraine: can lamotrigine monotherapy help? PMID- 22217953 TI - Parkinsonism and rabbit syndrome after discontinuation of low-dose ziprasidone and concomitant initiation of sertraline. PMID- 22217954 TI - Treatment of night eating syndrome with topiramate: dawn of a new day. PMID- 22217955 TI - Topiramate for the treatment of polydipsia-hyponatremia syndrome. PMID- 22217956 TI - Response to nimodipine in ultradian bipolar cycling after amygdalohippocampectomy. PMID- 22217958 TI - Angular cheilitis after paroxetine treatment. PMID- 22217957 TI - Ammonemia in bipolar patients on maintenance treatment with valproic acid. PMID- 22217959 TI - Cross-frequency decomposition: a novel technique for studying interactions between neuronal oscillations with different frequencies. AB - OBJECTIVE: We present a novel method for the extraction of neuronal components showing cross-frequency phase synchronization. METHODS: In general the method can be applied for the detection of phase interactions between components with frequencies f1 and f2, where f2 ~ rf1 and r is some integer. We refer to the method as cross-frequency decomposition (CFD), which consists of the following steps: (a) extraction of f1-oscillations with the spatio-spectral decomposition algorithm (SSD); (b) frequency modification of the f1-oscillations obtained with SSD; and (c) finding f2-oscillations synchronous with f1-oscillations using least squares estimation. RESULTS: Our simulations showed that CFD was capable of recovering interacting components even when the signal-to-noise ratio was as low as 0.01. An application of CFD to the real EEG data demonstrated that cross frequency phase synchronization between alpha and beta oscillations can originate from the same or remote neuronal populations. CONCLUSIONS: CFD allows a compact representation of the sets of interacting components. The application of CFD to EEG data allows differentiating cross-frequency synchronization arising due to genuine neurophysiological interactions from interactions occurring due to quasi sinusoidal waveform of neuronal oscillations. SIGNIFICANCE: CFD is a method capable of extracting cross-frequency coupled neuronal oscillations even in the presence of strong noise. PMID- 22217960 TI - Emotional anticipation rather than processing is altered in patients with vasovagal syncope. AB - OBJECTIVE: To investigate whether the electrocortical activity underlying the anticipation and processing of emotional stimuli is enhanced in individuals with recurrent episodes of vasovagal syncope (VVS). METHODS: Fifteen fainters and 15 age-matched healthy controls were presented a S1-S2 task, where the content of high-arousal pleasant and unpleasant, and neutral pictures (S2) was forecasted by word cues (S1). Stimulus Preceding Negativity (SPN) amplitude during the S1-S2 interval was computed as a measure of affective anticipation. The event-related potentials (ERPs) to S1 and S2 were measured to assess the processing of emotional warning stimuli and pictures. RESULTS: Relative to controls, fainters showed smaller P300 to warning cues anticipating emotional (and, particularly, unpleasant) pictures, and smaller SPN during anticipation of unpleasant pictures. No differences between groups were found with regard to ERP amplitudes during picture processing. CONCLUSIONS: These results suggest that the anticipation, rather than the processing, of aversive stimuli is altered in syncopal patients. SIGNIFICANCE: The reduced cortical anticipation in fainters might reflect the use of non-adaptive emotion regulation strategies for reducing the impact of upcoming highly arousing (and, particularly, of unpleasant) events. PMID- 22217961 TI - Quantitative assessment of nerve echogenicity: comparison of methods for evaluating nerve echogenicity in ulnar neuropathy at the elbow. AB - OBJECTIVE: The objective is to evaluate different methods to assess nerve echogenicity in a quantitative way by comparing a group of patients with ulnar neuropathy at the elbow (UNE) and a healthy control group, subsequently selecting the best tests for quantitative assessment of nerve echogenicity. METHODS: We included 56 patients with UNE and 37 healthy controls. High-resolution ultrasonography images of the ulnar nerve at the level of the medial epicondyle were saved in JPEG, TIFF or DICOM format, with a 19 pixels/mm resolution. Hypoechoic fraction was calculated by using 1 manual and 16 automatic thresholding methods. RESULTS: A significant difference in mean hypoechoic fraction between patients and controls was found using the following automatic thresholding methods: MaxEntropy 82% versus 74% (p < 0.001), RenyiEntropy 80% versus 69% (p < 0.001), Shanbhag 76% versus 68% (p = 0.002), Triangle 45% versus 58% (p = 0.036) and Yen 79% versus 67% (p < 0.001). Of these five tests a significant correlation between hypoechoic fraction and the cross-sectional area was found for: MaxEntropy 0.542 (p < 0.001), RenyiEntropy 0.558 (p < 0.001), Shanbhag 0.219 (p = 0.035) and Yen 0.513 (p < 0.001). The manual thresholding method did not detect a significant difference in hypoechoic fraction between patients and controls, and inter-rater agreement in hypoechoic fraction for manual thresholding was poor. CONCLUSION: Quantitative nerve echogenicity assessment can be successfully used to distinguish between a group of patients with UNE and a healthy control group, preferably by using the MaxEntropy, RenyiEntropy or Yen methods. SIGNIFICANCE: Automatic thresholding techniques using the MaxEntropy, RenyiEntropy or Yen methods are the best quantitative tests, and these quantitative measures can probably be used in further studies evaluating echogenicity in mono- and polyneuropathies. PMID- 22217963 TI - Selection of high-potential embryos by culture in poly(dimethylsiloxane) microwells and time-lapse imaging. AB - OBJECTIVE: To assess the developmental kinetics of human embryos and their ability to develop to morphologically normal blastocysts. DESIGN: Experimental study on human embryos donated for research using a time-lapse imaging system based on individual embryo culture in poly(dimethylsiloxane) microwells and monitored using a microscope inside the incubator. SETTING: Private fertility clinic. PATIENT(S): Surplus embryos donated by couples after undergoing fertility treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Blastocyst score and times required from beginning to completion of the second and third mitotic divisions. RESULT(S): The time required for completion of the second division (the three- to four-cell stage) was shorter in embryos that developed to high scoring blastocysts (0.7 hours, n = 17) than in those forming low-scoring blastocysts (3.7 hours, n = 24). Similarly, the mean time required to completion of the third division (five- to eight-cell stage) was also significantly shorter in embryos forming high-scoring blastocysts (5.7 hours) than among those forming low-scoring blastocysts (16.9 hours). CONCLUSION(S): Individual embryos with the potential to develop to high-scoring blastocysts could be selected at 2-3 days of culture using this system by examining the times required to complete the second and third mitotic divisions. PMID- 22217962 TI - Phospholipase C-zeta-induced Ca2+ oscillations cause coincident cytoplasmic movements in human oocytes that failed to fertilize after intracytoplasmic sperm injection. AB - OBJECTIVE: To evaluate the imaging of cytoplasmic movements in human oocytes as a potential method to monitor the pattern of Ca(2+) oscillations during activation. DESIGN: Test of a laboratory technique. SETTING: University medical school research laboratory. PATIENT(S): Donated unfertilized human oocytes from intracytoplasmic sperm injection (ICSI) cycles. INTERVENTION(S): Microinjection of oocytes with phospholipase C (PLC) zeta (zeta) cRNA and a Ca(2+)-sensitive fluorescent dye. MAIN OUTCOME MEASURE(S): Simultaneous detection of oocyte cytoplasmic movements using particle image velocimetry (PIV) and of Ca(2+) oscillations using a Ca(2+)-sensitive fluorescent dye. RESULT(S): Microinjection of PLCzeta cRNA into human oocytes that had failed to fertilize after ICSI resulted in the appearance of prolonged Ca(2+) oscillations. Each transient Ca(2+) concentration change was accompanied by a small coordinated movement of the cytoplasm that could be detected using PIV analysis. CONCLUSION(S): The occurrence and frequency of cytoplasmic Ca(2+) oscillations, a critical parameter in activating human zygotes, can be monitored by PIV analysis of cytoplasmic movements. This simple method provides a novel, noninvasive approach to determine in real time the occurrence and frequency of Ca(2+) oscillations in human zygotes. PMID- 22217964 TI - LHX1 mutation screening in 96 patients with mullerian duct abnormalities. AB - OBJECTIVE: To investigate whether LHX1 gene mutations exist in Han Chinese patients with mullerian duct abnormalities (MDAs). DESIGN: Mutation screening. SETTING: University hospital. PATIENT(S): Ninety-six MDA patients and 105 control subjects from a Han Chinese population. The parents of the patients carrying the genetic variation were also screened. INTERVENTION(S): Gene sequencing. MAIN OUTCOME MEASURE(S): Karyotype, LHX1 gene sequencing. RESULT(S): We found no significant mutation in coding regions of LHX1. However, there is a new rare polymorphism of LHX1 gene, c.1070-1081del, found in 1 out of 77 incomplete mullerian fusion patients and 1 out of 105 control individuals in the Han Chinese population (thus affecting ~1% of Han Chinese). CONCLUSION(S): No causative perturbation was identified in the LHX1 gene. Mutations in the coding regions of LHX1 may not be a common genetic etiologic factor involved in Han Chinese MDA patients. PMID- 22217965 TI - Lifestyle behaviors in women undergoing in vitro fertilization: a prospective study. AB - OBJECTIVE: To determine the lifestyle behaviors of women before and during an IVF cycle. DESIGN: Prospective survey. SETTING: Private academically affiliated infertility center. PATIENT(S): One hundred eighteen women, ages 18-44, scheduled to undergo an assisted reproductive technology (ART) cycle using their own eggs. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Lifestyle history and daily habit survey. RESULT(S): In the month before their IVF cycle, 92% exercised, 3% smoked, 73% drank alcohol, 76% drank caffeinated beverages, 14% took herbs, and 30% underwent acupuncture. During their ART cycle, 100% exercised, 2% smoked, 49% drank alcohol, 77% drank caffeine, 12% took herbs, and 47% underwent acupuncture. CONCLUSION(S): This is the first prospective assessment of numerous lifestyle habits during an ART cycle. A number of surprising observations were made. Despite physician recommendation against it, some ART patients took herbs while cycling. Patients continue to exercise regularly and drink caffeine daily, and almost half continued to drink alcohol. Lifestyle behavior counseling should be considered for patients pursuing ART. CLINICAL TRIAL REGISTRATION NUMBER: NCT01119391. PMID- 22217966 TI - Effect of spinal and general anesthesia on serum concentration of pro inflammatory and anti-inflammatory cytokines. AB - BACKGROUND: Surgery induces release of neuroendocrine hormones, cytokines and acute phase proteins. The aim of this study was to assess the effect of spinal and general anesthesia on serum concentration of pro-inflammatory and anti inflammatory cytokines, and cytokines which are secreted by Th1 helper lymphocytes. METHODS: 30 patients with American Society of Anesthesiologists status I and II who were scheduled for TURP (Transurethral Resection of the Prostata) were anesthetized in regional (spinal) or general anesthesia. Peripheral venous blood samples were collected 2 h before surgery on the first, third and fifth postoperative days. We measured pro-inflammatory cytokines, anti inflammatory cytokines and cytokines which are secreted by Th1 helper lymphocytes in order to establish differences in patients before and after surgery. RESULTS: Statistically significant differences were found in serum levels of interleukin-2 (IL-2) between general and spinal anesthesia (p=0.043). The concentration of IL-2 was continuously elevated in general anesthesia, but not in spinal anesthesia. It is important to note that the preoperative serum IL-2 concentration in general anesthesia group was significantly higher in comparison to spinal anesthesia group (p=0.028). There was also statistically significant increase of interleukin 6 (IL-6) in spinal (p=0.043) and general anesthesia (p=0.03) in comparison to preoperative value. CONCLUSION: Surgery-related postoperative release of the pro inflammatory cytokine IL-6 was increased in patients after spinal and general anesthesia. In our study, increased levels of the typical Th1 cytokine IL-2 were found in patients anesthetized by general anesthesia compared to spinal anesthesia. Serum concentrations of other pro-inflammatory cytokines, anti inflammatory cytokines and cytokines which are secreted by Th1 helper lymphocytes showed no statistical difference before and after surgery under general and spinal anesthesia. PMID- 22217967 TI - Total lymphocyte count as a surrogate marker to predict CD4 count in human immunodeficiency virus-infected children: a retrospective evaluation. AB - A retrospective study was conducted, and 576 human immunodeficiency virus infected children with total lymphocyte count (TLC) and CD4 count were recruited from China. Spearman rank order correlation and receiver-operating characteristic were used. An overall positive correlation was noted between TLC and CD4 count (prehighly active antiretroviral therapy [pre-HAART], r = 0.789, 6 months of HAART, r = 0.642, 12 months of HAART, r = 0.691, P = 0.001). TLC <= 2600 cells/mm(3) predicted a CD4 count of <= 350 cells/mm(3) with 82.9% sensitivity, 79.6% specificity pre-HAART. Meanwhile, the optimum prediction for CD4 count of <= 350 cells/mm(3) was a TLC of <= 2400 cells/mm at 6 months (73.6% sensitivity and 74.1% specificity) and 12 months (81.7% sensitivity and 76.5% specificity) of HAART. TLC can be used as a surrogate marker for predicting CD4 count of human immunodeficiency virus-infected children before and during HAART in resource limited countries. PMID- 22217968 TI - Pertussis: what the pediatric infectious disease specialist should know. AB - Pertussis is a bacterial disease that is transmitted very efficiently from human to human by droplets. It occurs at any age, is endemic in any population, and can cause outbreaks in highly variable frequencies. Hallmark of the disease is cough with or without paroxysms, whoop, and vomiting. Diagnosis relies on clinical suspicion followed by laboratory confirmation (PCR, Serology) and should be followed by prompt antibiotic treatment to stop spread of the bacteria to contact persons. Control of pertussis by acellular vaccines is possible to some extent if immunization coverage is high and booster doses are given lifelong. However new vaccines with higher efficacy rates are warranted. PMID- 22217969 TI - Thrombocytosis and infections in childhood. PMID- 22217970 TI - Biased measurement of neuropsychiatric adverse effects of pediatric mefloquine treatment. PMID- 22217972 TI - Acute liver failure as the initial manifestation of Wilson disease triggered by human parvovirus b19 infection. PMID- 22217973 TI - Pathergy as a cause of false-positive tuberculin skin test. PMID- 22217974 TI - Shewanella algae bacteremia in a preterm newborn. PMID- 22217975 TI - Kingella endocarditis after closure of ventricular septal defect with a transcatheter device. PMID- 22217976 TI - Postexposure infant prophylaxis in high-risk situations of human immunodeficiency virus type 1 transmission. PMID- 22217978 TI - Detection and management of mood disorders in the maternity setting: the Australian Clinical Practice Guidelines. AB - BACKGROUND: Mood disorders arising in the perinatal period (conception to the first postnatal year), occur in up to 13% of women. The adverse impact of mood disorders on mother, infant and family with potential long-term consequences are well documented. There is a need for clear, evidence-based, guidelines for midwives and other maternity care providers. AIM: To describe the process undertaken to develop the Australian Clinical Practice Guidelines for Depression and Related Disorders in the Perinatal Period and to highlight the key recommendations and their implications for the maternity sector. METHOD: Using NHMRC criteria, a rigorous systematic literature review was undertaken synthesising the evidence used to formulate graded guideline recommendations. Where there was insufficient evidence for recommendations, Good Practice Points were formulated. These are based on lower quality evidence and/or expert consensus. FINDINGS: The quality of the evidence was good in regards to the use of the Edinburgh Postnatal Depression Scale and psychological interventions, but limited as regards medication use and safety perinatally. Recommendations were made for staff training in psychosocial assessment; universal screening for depression across the perinatal period; and the use of evidence based psychological interventions for mild to moderate depression postnatally. Good Practice Points addressed the use of comprehensive psychosocial assessment- including risk to mother and infant, and consideration of the mother-infant interaction--and gave advice around the use and safety of psychotropic medications in pregnancy and breastfeeding. In contrast to their international counterparts, the Australian guidelines emphasize a more holistic, woman and family centred approach to the management of mental health and mood disorders in the perinatal setting. CONCLUSION: The development of these Guidelines is a first step in translating evidence into practice and providing Australian midwives and other maternity care providers with clear guidance on the psychosocial management of women and families. PMID- 22217979 TI - Acoustic, mechanical and near-infrared profiling of osteoarthritic progression in bovine joints. AB - Early-stage treatments for osteoarthritis are attracting considerable interest as a means to delay, or avoid altogether, the pain and lack of mobility associated with late-stage disease, and the considerable burden that it places on the community. With the development of these treatments comes a need to assess the tissue to which they are applied, both in trialling of new treatments and as an aid to clinical decision making. Here, we measure a range of mechanical indentation, ultrasound and near-infrared spectroscopy parameters in normal and osteoarthritic bovine joints in vitro to describe the role of different physical phenomena in disease progression, using this as a basis to investigate the potential value of the techniques as clinical tools. Based on 72 samples we found that mechanical and ultrasound parameters showed differences between fibrillated tissue, macroscopically normal tissue in osteoarthritic joints, and normal tissue, yet did were unable to differentiate degradation beyond that which was visible to the naked eye. Near-infrared spectroscopy showed a clear progression of degradation across the visibly normal osteoarthritic joint surface and as such, was the only technique considered useful for clinical application. PMID- 22217980 TI - The effect of lipid droplet size on satiety and peptide secretion is intestinal site-specific. AB - BACKGROUND & AIMS: : Infusion of fat into the small intestine induces satiety. Reducing fat droplet size accelerates fat digestion, but the effect on satiety after ileal fat infusion is not known. The aim of the study was to compare the effects of fat emulsions differing in droplet size (fine, coarse) infused in either duodenum or ileum on satiety, gastric emptying and peptide secretion. METHODS: In a randomized single-blind crossover study 15 healthy volunteers received, after intubation with a nasoileal tube, 4 different treatments on 4 consecutive days. After consumption of a liquid meal, 6 g of fine or coarse fat emulsion was infused into duodenum or ileum. Study parameters were satiety, gastric emptying and gut peptides. These parameters were statistically evaluated using ANCOVA. RESULTS: In the duodenum, Fine emulsion significantly reduced hunger, increased fullness, delayed gastric emptying, but did not affect peptide secretion versus Coarse. In the ileum, Fine emulsion did not affect hunger, fullness, or gastric emptying, but significantly increased peptide secretion versus Coarse. CONCLUSIONS: Compared to larger fat droplets, smaller droplets significantly affect satiety, gastric emptying and gut peptide release, but with the effect being dependent on the intestinal location of fat delivery. DUTCH TRIALREGISTER: NTR1515. PMID- 22217981 TI - Morphology and ultrastructure of the hindgut fermentation chamber of a melolonthine beetle Holotrichia parallela (Coleoptera: Scarabaeidae) during larval development. AB - The morphology and ultrastructure of the hindgut fermentation chamber of a melolonthine beetle, Holotrichia parallela, were examined using light and electron microscopy. The results showed that the anterior portion of the hindgut expanded into a characteristic lobe-like structure described as a fermentation chamber. Hematoxylin-eosin staining revealed that the wall of the fermentation chamber was composed of three main layers: the longitudinal muscle layer, the circular muscle layer, and the columnar epithelial cells. Scanning electron microscopy showed that the ultrastructure of the inner surface of the fermentation chamber was subjected to significant changes during larval development. Only some folds and a few cocci attached to the folds were found in the first-instar larvae. In the fermentation chambers of the second-instar larvae, a cuticular intima began to emerge, and the bacteria multiplied to form bacterial groups attached to the intima. A special lobe-like structure was formed in the third-instar larvae, constituted by bacteria and the bacteria-covered cuticular intima. Transmission electron microscopy revealed that the lobe-like structure held large numbers of rod-shaped bacteria. These data suggest that the hindgut fermentation chamber may have an important role in the symbiotic relationship between microbes and their insect hosts. PMID- 22217982 TI - Cytokine modulation by endothelin-1 and possible therapeutic implications in systemic sclerosis. AB - Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune disorder characterized by a progressive fibrosis which involves skin and internal organs, caused by microvascular damage. The earliest clinical sign of the disease is Raynauds Phenomenon, a vasospastic response to cold or stress stimuli, followed by the skin and organ involvement over time. This kind of vascular manifestation originates from the microvascular structural alteration, characterized by an abnormal myocyte cell proliferation, intima cell proliferation and adventitia fibrosis. The microvascular damage seems to be the consequence of the autoimmune attack to the endothelium, followed by inflammatory cascade and massive deposition of collagen. From the beginning of the disorder, serum Endothelin-1 (ET- 1) is found in very high concentration: this protein, today, is considered one of the most important mediators of scleroderma vascular alterations. Furthermore, many recent studies have shown that ET-1 is involved in the inflammatory and fibrotic processes, increasing the concentration of pro-fibrotic and pro-inflammatory cytokines. The aim of this review is to clarify the ET-1 role in SSc, in particular the relationship between ET-1 and cytokine expression, adding another element to the understanding of scleroderma disease. PMID- 22217983 TI - Cyclosporine in transplantation - a history of converging timelines. AB - Discovery and pharmacological development of cyclosporine was conducted by Jean Borel and colleagues in the 1970s. Cyclosporine is the first compound to inhibit the lymphocytes specifically and reversibly, and represents the prototype of a new generation of immunosuppressive drugs: the calcineurine inhibitors. Historical chronology of successes in clinical application of cyclosporine and development of solid-organ transplantation are retraced here, underscoring the converging timelines of this drug and these interventions. In 1978-79 the first successful results of the use of cyclosporine in kidney were reported. Cyclosporine was the first single drug able to control rejection. In 1982-83 first trials demonstrated the benefit from treatment with cyclosporine in kidney recipients compared to azathioprine and steroids. In the 1980s solid-organ transplantation entered the cyclosporine era with unhoped-for results in heart transplantation. The present review focuses also on cyclosporine-based regimen of immunosuppression, adverse side effects and safety in pregnancy in subjects under treatment with cyclosporine. PMID- 22217985 TI - Effects of 5-azacytidine and trichostatin A on dendritic cell maturation. AB - Maturation of dendritic cells (DC) towards functional antigen-presenting cells is a complex process, the regulation of which may also involve epigenetic mechanisms. Thus, it is of interest to investigate how gene expression changes during DC maturation can be influenced with epigenetic agents, such as DNA methyltransferase or histone deacetylase inhibitors. Here, we document the effects of DNA methyltransferase inhibitor 5-azacytidine (5AC) and histone deacetylase inhibitor trichostatin A (TSA) on the murine bone marrow-derived, as well as on the human monocyte-derived DC maturation. The major impact of 5AC and TSA on the DC maturation process consisted in the inhibition of unmethylated CpG oligodeoxynucleotide (CpG ODN) 1826 or LPS-induced activation of pro- and anti inflammatory cytokine gene expression activation. In the in vitro studies, TSA but not 5AC significantly reduced the capacity of the peptide-pulsed DC to induce total spleen as well as CD8(+) or CD4(+) cell proliferation. IFNgamma production by the specific CD4(+) spleen cells co-cultured with TSA- but not with 5AC treated DC was lower, as compared to the cytokine production after co-cultivation with untreated mature DC. Collectively, these results demonstrate the potential of epigenetic agents, which are under intensive investigation as promising anti tumour agents, to hamper the immune response induction through their inhibitory effects on DC. PMID- 22217984 TI - Cholesterol and vitamins: revisited study. AB - The link between low density lipoprotein and coronary heart disease has been widely studied. Oxidized LDL damages the artery wall, and a diet rich in vitamins and low in saturated fat and cholesterol may reduce this risk. Not only hypercholesterolemia but also low levels of high density lipoprotein cholesterol are critical risk factors for atherosclerosis and related diseases. It has been reported that high doses of B complex vitamin may be useful in lowering blood cholesterol and triglyceride levels in the body, however the use of this compound has been limited by an annoying flush and concern for toxicity. Niacin is a B complex vitamin with anti-atherosclerotic properties and is an effective medication for raising high density lipoprotein. The combination of niacin with other lipid-lowering drugs, such as statins, reduces the dynamic of atherosclerosis disease. In addition, vitamin E is one of the most important lipid soluble anti-oxidants in humans, and reduces atherosclerosis plaque, coronary artery diseases and myocardial infarction. Vitamin E protects the integrity of membranes by inhibiting lipid peroxidation. In this study we revisited the interrelationship between cholesterol, low density lipoproteins and vitamins. PMID- 22217986 TI - Decreased expression of the melatonin receptor 1 in human colorectal adenocarcinomas. AB - Melatonin exerts anti-proliferative and pro-apoptotic effects in various cancer cell lines. Furthermore, there is evidence for impaired melatonin secretion in human breast and colorectal cancer. Additionally, several studies revealed a modulated expression of the melatonin receptor 1 (MT1), in human breast cancer specimens. Since melatonin binding sites were already identified in the human intestine, our aim is to identify the expression and to characterize the localization of the MT1 receptor in the human colon and in particular to compare MT1 expression levels between non-malignant and malignant colonic tissue. We assessed MT1 transcript levels with real time RT-PCR in colon adenocarcinomas and the adjacent normal colonic mucosa of 39 patients and observed a significant decrease of MT1 mRNA expression in colorectal cancer compared with the healthy adjacent mucosa tissue (0.67 mean difference, P < 0.0001). The results were confirmed at the protein level by Western blot analysis and by immunohistochemistry. MT1 was localized mainly supranuclear in colonic epithelial cells lining the crypts. We also evaluated mRNA expression of different clock genes in the colon samples and found a significant correlation between MT1 and Cryptochrome 1 (Cry1) expression (P < 0.01 for normal and P < 0.05 for tumour tissue). In conclusion, the decreased expression of MT1 in human colorectal cancer could point to a role of melatonin in this disease. PMID- 22217987 TI - Protective effect of an oral natural phytonutrient in recurrent vulvovaginal candidiasis: a 12-month study. AB - The aim of the present study is to assess the clinical efficacy of a phytocompound with antimicotic properties (K-712, with the following 100 mg composition: 10 mg of oleoresin from Pseudowintera colorata at 30 percent concentration in Polygodial together with trace amounts of Olea europea) in recurrent vulvo-vaginal candidiasis (RVVC) as compared to an azole drug during a 12-month period: 6 months of treatment followed by 6 months of observation. This prospective randomized study involved 82 women (19-61 years) with complaints of abnormal vaginal discharge and with a history of at least four proven episodes of RVVC in the previous 12 months. Patients were divided into two groups of treatment of 41 patients each and were given: A) Itraconazole 200 mg orally daily for 4 days, then 200 mg once weekly for 6 months or B) 1 tablet twice a day of a K-712 for 4 weeks and then for the first 2 weeks of each month for a total of 6 months. Both groups were then followed-up for further 6 months. Each treatment schedule was well tolerated with only 4 patients in the azole group complaining of transient mild symptoms (nausea, abdominal discomfort, unpleasant taste). Itraconazole reached an earlier symptomatic relief during the first two weeks of observation as compared with K-712 (p<0.05) but both treatments enabled a comparable benefit during the entire treatment study period, afterwards with comparable symptom/sign score (itraconazole vs K-712: 9 vs 11). At 6-month observation, mycological cure was reached by 83 percent in the itraconazole group and in 78 percent of the K-712-treated patients. During the further 6-month observation period without treatment, the itraconazole group showed significantly more relapses (65.7 vs 34.2 in K-712, p<0.05) and at the end of the whole 12 month study period the mycological cure was significantly higher in the K-712 treated patients (65.8 vs 34.3 percent, p<0.05). There was a non- significant trend increase of less drug-susceptible species in the itraconazole group. From these preliminary data it would appear that a natural antifungal phytocompound proves to be as good as itraconazole in the maintenance treatment of RVVC. Moreover, this approach seems to maintain a higher mycological success rate afterwards by reducing the number of relapses and probably of the growth of azole resistant species. PMID- 22217989 TI - Arterial endothelial dysfunction and idiopathic deep venous thrombosis. AB - Recent epidemiological studies have highlighted higher risk of subsequent development of atherosclerotic disease in patients with deep venous thrombosis (DVT). We evaluated the Flow Mediated Dilation (FMD) looking for arterial endothelial dysfunction, predictive for future ischaemic cardiovascular events, in patients with idiopathic DVT. FMD was measured in the brachial artery in 60 subjects with idiopathic DVT (age 60.1+/-17.4) and in 60 subjects without idiopathic DVT (age 61.2+/-15.1), with a similar cardiovascular risk factor profile. DVT patients showed lower FMD (6.78%+/-5.53% vs 10.88+/-3.31%, p<0.001). Univariate linear models showed that obesity (p=0.010), dyslipidemia (p=0.004), arterial hypertension (p=0.046), use of platelet anti-aggregating agents (p=0.018) and DVT (p<0.001) were associated to lower levels of FMD. In multivariate linear model, only DVT (p<0.001) remained an independent predictor of lower levels of FMD. Furthermore, an 8.5% cut-off value of FMD was chosen in a ROC curve analysis. Values of FMD <= 8.5% were more frequent in DVT patients (71.67% vs 41.67%, p<0.001). Univariate logistic regression models showed that dyslipidemia (p=0.008), use of platelet anti-aggregating agents (p=0.004) and DVT (p<0.001) were associated to a higher risk of having FMD <= 8.5%. Multivariate logistic regression model showed that DVT was the unique independent predictor for FMD <= 8.5% (p<0.001). In conclusion, DVT patients more frequently have impaired FMD, recognized as an indicator of arterial endothelial dysfunction and a marker for increased cardiovascular risk. PMID- 22217988 TI - Role(s) of formyl-peptide receptors expressed in nasal epithelial cells. AB - Chronic rhinosinusitis is one of the most frequent chronic diseases in humans. Little is known about stimuli initiating tissue remodeling process that determines the morphological expression of the disease. N-formyl peptide receptors (FPRs) are innate immunity receptors important in tissue remodeling of gastric and intestinal epithelium. The expression and functions of FPRs in nasal epithelial cells were examined to evaluate whether they could be important in the remodeling of nasal mucosa. The aim of this study is to examine FPR expression in a nasal epithelial cell line (RPMI-2650) at mRNA and protein levels. To determine whether FPRs were functional, chemotaxis experiments were carried out. In addition the effects of FPRs agonists on the expression (PCR and ELISA) of VEGF-A and TGF-beta, two key mediators of tissue remodelling, were examined. Here we demonstrate that RPMI-2650 express FPR and FPRL2, but not FPRL1. fMLP, a bacterial product active on FPR, and uPAR(84-95), an inflammatory mediator agonist for FPRL2, stimulated migration of nasal epithelial cells. fMLP and uPAR(84-95) induce expression and secretion of VEGF-A and TGF-beta. Our results suggest a possible mechanisms initiating tissue remodeling observed during chronic rhinosinusitis. This study provides further evidence that FPRs play a more complex role in human pathophysiology than bacterial recognition. PMID- 22217990 TI - Evaluation of in vitro cytotoxicity of oxaliplatin and 5-fluorouracil in human colon cancer cell lines: combination versus sequential exposure. AB - Adjuvant therapy has evolved to become the standard care of colon cancer, but the tumor capability of activating effective mechanisms of defence against both chemical and physical cytotoxic agents represents a serious obstacle to the successful therapy. Furthermore, the possibility to have an assay useful to measure the drug sensitivity of tumor cells could be of a great importance. As primary human colon cancer cultures from fresh tumor are technically difficult to obtain, experiments with human cancer cell lines remain essential to explore new adjuvant chemotherapy drugs, to investigate the individual responsiveness to the known agents, and particularly to clarify how these chemotherapeutic agents could be used in maximizing outcomes. In the present study we evaluate the cytotoxic effects of 5-fluorouracil (5-FU) and oxaliplatin (OHP) and of their pharmacological interaction in three human colon cancer cell lines (WiDr, HT-29 and SW620), by using an ATP luminescence assay (ATPlite; Perkin Elmer), displaying high sensitivity, linearity and reproducibility. Cell cycle, apoptosis and CD44 expression were investigated with flow cytometry. Our results show that the drug combinations inhibited the cell growth more than each drug alone in all colorectal cancer cell lines. Interestingly, the sequential exposure of OHP and 5 FU resulted in the most cytotoxic effect in all colon cancer cell lines, when compared to the simultaneous one. Our results focus on the powerful cytotoxic effect of 5-FU-OHP combination, when used in sequential exposure, suggesting interesting implications for a rational use of 5-FU, OHP combination in colon rectal cancer therapy. PMID- 22217991 TI - Zinc opposes genotoxicity of cadmium and vanadium but not of lead. AB - Protection by essential metals against the genotoxic effects of toxic elements is an open question. Here, human Hs27 dermal fibroblasts and B-mel melanoblasts were exposed for 10 days to (1 MUM) zinc (Zn) or copper (Cu) or selenium (+ 4, Sei; + 6, Sea). Afterwards, cells were exposed for 3 days to subtoxic concentrations of lead (Pb, 100 MUM) or vanadium (+ 5, V, 2 MUM) or cadmium (Cd, 3 MUM), slightly reducing, by themselves, cell proliferation and unaffecting cell viability and apoptosis. Genotoxic damage was evaluated by cytokinesis-block micronucleus assay (CBMN) and single cell gel electrophoresis (Comet assay, CA). CBMN and CA were preliminarly assessed following 3, 10 and 30 days of exposure to the above concentrations of Pb, V and Cd: Pb induced micronuclei (MN) formation in both Hs27 and B-mel cells, without determining direct DNA damage (as shown by CA); V did not reveal genotoxic effects on fibroblasts (as shown by CBMN and CA) but increased the frequency of MN and comets in melanoblasts; Cd induced a great number of MN and comets in fibroblasts but not in melanoblasts; all these effects did not differ after 3, 10 or 30 days of exposure to such elements so that Hs27 and B-mel cells were exposed to Pb,V and Cd for 3 days following pretreatment with (1 MUM) Zn, Cu, Sei or Sea. By itself, the 10 day-exposure to (1 MUM) Zn, Cu, Sei or Sea did not affect cell proliferation, viability, apoptosis and formation of MN or comets in either Hs27 or B-mel cells. Only Zn significantly reduced the Cd- and V-induced MN and comet formation in fibroblasts and melanoblasts, respectively; in these cells, however, Zn did not affect the Pb induced MN formation. These results emphasize the role of Zn, in respect to other essential metals, in opposing the genotoxic effects of cancerogenic (Cd) or potentially cancerogenic elements (V). PMID- 22217992 TI - Effect of low-level laser irradiation on osteoblast proliferation and bone formation. AB - Applications of laser therapy in biostimulation and healing injured tissues are widely described in medical literature. The present study focuses on the effects of laser irradiation on the growth rate and differentiation of human osteoblast like cells seeded on titanium or zirconia surfaces. Cells were laser irradiated with low therapeutical doses at different intervals and the effects of irradiation were evaluated at each time-point. After 3 hours lasered cells showed an enhanced mitogen activity compared to non-lasered control cells and a higher alkaline phosphatase activity, marker of bone formation. At the same time, the mRNA of RUNX2 and OSTERIX, two genes involved in osteoblast differentiation, showed a clear decrease in lasered cells. This reached the lowest value 6 to 12 hours after irradiation, after which the transcripts started to increase, indicating that the laser treatment did promote the osteogenic potential of growth-induced cells. These results indicate that Low Level Laser Treatment (LLLT) stimulates osteogenic cell proliferation. PMID- 22217993 TI - SOS1 over-expression in genital skin fibroblasts from hirsute women: a putative role of the SOS1/RAS pathway in the pathogenesis of hirsutism. AB - Hirsutism is the development of androgen-dependent terminal body hair in women in places in which terminal hair are normally not found. It is often associated with hyperandrogenemia and/or polycystic ovary syndrome (PCOS), but the existence of uncommom hirsutism forms that are not related to altered androgen plasma levels lead also to the definition of - idiopathic hirsutism. Although the pathophysiology of hirsutism has been linked to increasing 5-alpha reductase (SRD5A) activity and to an alteration of the androgen receptor (AR) transcriptional machinery, many aspects remain unclear. In particular, the relationships between androgens and local factors are poorly understood. In the present paper, we selected for a genital skin biopsy, 8 women affected with severe hirsutism (Ferriman-Gallway score greater than 25) but with normal plasma androgen levels, with the exception of slightly higher serum 3alpha-diol glucuronide levels, and 6 healthy controls and analyzed their androgen- and insulin-specific transcriptional profile using a specific custom low density microarray (AndroChip 2, GPL9164). We identified the over-expression of the Son of Sevenless-1 (SOS1) gene in all of the hirsute skin fibroblast primary cell cultures compared to control healthy women. Since SOS1 is a guanine nucleotide exchange factor that couples receptor tyrosine kinases to the RAS signaling pathway that controls cell proliferation and differentiation, we further analyzed SOS1 expression, protein level and RAS signaling activation pathway in an in vitro model (NHDF, normal human dermal fibroblast cell line). NHDF treated for 24 h with different concentrations of DHT and T showed an increase in SOS1 levels (both mRNA and protein) and also an activation of the RAS pathway. Our in vivo and in vitro data represent a novel preliminary observation that factors activating SOS1 could act as local proliferative modulators linked to the androgen pathway in the pilosebaceous unit. SOS1 over-expression may play a role in the regulation of the RAS/mitogen-activated protein kinase pathway in the skin, in the hair follicle proliferation and cell cycle, suggesting new perspectives in understanding the pathogenesis of idiopathic hirsutism. PMID- 22217994 TI - Immune response to sublingual immunotherapy in children allergic to mites. AB - Allergic rhinitis (AR) is characterized by Th2 polarized immune response. Specific immunotherapy modifies this arrangement restoring a physiologic Th1 profile. Sublingual immunotherapy (SLIT) is widely prescribed, but there is no early marker of response. The aim of this study is to investigate possible marker of SLIT effectiveness. Thirty children with mite allergy were studied: 15 were treated with drugs alone, 15 with SLIT and drugs on demand. The study lasted 2 years. Visual analogue scale (VAS) for symptoms and medication score were evaluated. Serum cytokines (IL-2, IL-4, IL-6, IL-8, IL-10, IFN-gamma, MCP-1, and TNF-alpha) were assessed by ELISA before and after 1 and 2 year SLIT. SLIT treated children obtained a significant improvement of symptoms and a reduction of drug use, whereas children treated with a drug alone did not obtained any change. IL-10 significantly increased, whereas Th2-dependent and pro-inflammatory cytokines significantly decreased. In conclusion, the present study demonstrates that 2-year SLIT is capable of inducing immunologic hyporeactivity to mites. PMID- 22217995 TI - Cellular and molecular responses of human skeletal muscle exposed to hypoxic environment. AB - The effects of a hypobaric, hypoxic environment and exercise performed under extreme conditions, such as at high altitudes, are intriguing physiological aspects that need to be investigated directly on human climbers. Their skeletal muscle is one of the main tissues that can suffer from hypoxia and physical challenges, which will both define the muscle adaptation and the molecular signature of regenerative capacity. We investigated the muscle regenerative capacity characterizing satellite cells. Our study shows that satellite cells are altered by hypobaric, hypoxic environments and exercise performed at high altitudes. Of note, in human skeletal muscle after this 5,000 m a.s.l. expedition, SCs showed a significantly lower ability to regenerate skeletal muscle, in respect to before this high-altitude expedition. This impairment appears to be due to reduced satellite cell activity, consistent with their decreased myogenicity and fusion ability. Furthermore, at the transcriptional level several pathways, such as cell cycle, myogenesis, oxidative metabolism, proteolysis and sarcomeric protein synthesis, were found dysregulated. PMID- 22217996 TI - Analysis of extracellular superoxide dismutase in fibroblasts from patients with systemic sclerosis. AB - Systemic sclerosis (SSc) is a chronic disease of connective tissue characterized by vascular damage, autoantibody production and extensive fibrosis of skin, skeletal muscles, vessels and visceral organs. Fibrosis is a biological process involving inflammatory response and reactive oxygen species (ROS) accumulation leading to fibroblast activation. Extracellular superoxide dismutase (SOD3), a copper and zinc superoxide dismutase, which is expressed in selected tissues, is secreted into the extracellular space and catalyzes the dismutation of superoxide radical to hydrogen peroxide and molecular oxygen. Moreover, SOD3 is associated to inflammatory responses in some experimental models. In this paper we analysed, by RT-PCR and immunofluorescence, SOD3 expression and intracellular localization in dermal fibroblasts from both healthy donors and patients affected by diffuse form of SSc. Moreover, we determined SOD3 enzymatic activity in fibroblast culture medium with the xanthine/xanthine oxidase method. Increased expression of SOD3 mRNA was detected in systemic sclerosis fibroblasts (SScF), as compared to control healthy fibroblasts (HF), and SOD3 immunofluorescence staining displayed a characteristic pattern of secretory proteins in both HF and SScF. Superoxide dismutase assay demonstrated that SOD3 enzymatic activity in SScF culture medium is four times more than in HF culture medium. These data suggest that an alteration in SOD3 expression and activity could be associated to SSc fibrosis. PMID- 22217997 TI - 3,5-diiodo-L-thyronine increases resting metabolic rate and reduces body weight without undesirable side effects. AB - Recently, it was demonstrated that 3,5-diiodo-L-thyronine (T2) stimulates the resting metabolic rate (RMR), and reduces body-weight gain of rats receiving a high-fat diet. The aim of this study is to examine the effects of chronic T2 administration on basal metabolic rate and body weight in humans. Two euthyroid subjects volunteered to undergo T2 administration. Body weight, body mass index, blood pressure, heart rate, electrocardiogram, thyroid and liver ultrasonography, glycemia, total cholesterol, triglycerides, free T3 (FT3), free T4 (FT4), T2, thyroid stimulating hormone (TSH) and RMR were evaluated at baseline and at the end of treatment. RMR increased significantly in each subject. After continuing the T2 treatment for a further 3 weeks (at 300 mcg/day), body weight was reduced significantly (p<0.05) (about 4 percent), while the serum levels of FT3, FT4 and TSH, were unchanged. No side effects were observed at the cardiac level in either subject. No significant change was observed in the same subjects taking placebo. PMID- 22217998 TI - Recurrent infections in children with nickel allergic contact dermatitis. AB - Some patients with nickel (Ni) allergic contact dermatitis (ACD) suffer from systemic symptoms after ingestion of Ni-rich foods, a condition termed Systemic Nickel Allergy Syndrome (SNAS). The aim of this study is to investigate in children the relationship between Ni ACD and lymphocyte subsets or susceptibility to infections. Nineteen children with Ni ACD and 18 controls matched for sex and age were enrolled. All participants underwent patch test, skin prick test and clinical assessment. Serum immunoglobulins and flow cytometry for lymphocyte subset study were also evaluated. In children with Ni ACD a higher incidence of recurrent upper respiratory tract infections and recurrent otitis media were detected. Serum levels of immunoglobulins and lymphocyte subsets did not show significant changes (p>0.05) between the two groups studied. We can hypothesize that in children with Ni ACD the risk of recurrent infections is increased. Although the clinical manifestations of SNAS are still controversial, we can suppose that recurrent infections may be considered a clinical symptom of this syndrome. PMID- 22217999 TI - Subcutaneous immunoglobulin therapy in a patient with myopathic dropped head syndrome and common variable immunodeficiency. AB - Prominent neck extension weakness is an uncommon clinical entity, also termed dropped-head syndrome, that may be part of a generalized neuromuscular disorder. We report here the case of a woman with dropped-head syndrome and pulmonary arterial hypertension secondary to systemic sclerosis. Subsequently, she developed common variable immunodeficiency and subcutaneous immunoglobulin therapy was started. After two months from the start of therapy we did not observe any improvement in the degree of flexion of the head, although the clinical examination shows an improvement in neck extensor muscle strength. Subcutaneous immunoglobulin therapy could be a possible therapeutic option for the treatment of myopathic neck extensor weakness. PMID- 22218000 TI - Antimicrobial resistance pattern of methicillin-resistant Staphylococcus aureus in the food industry. AB - There is increasing concern about the impact on public health of methicillin resistant Staphylococcus aureus (MRSA) associated with animal food products. MRSA remains a serious problem because of the high incidence and multidrug resistance of the strains, even for strains isolated from foods, food environments and food handlers. The objectives of this study are: (i) to evaluate the susceptibility of S. aureus strains isolated from food, food handlers and food-processing environments to 14 antibiotics currently used in veterinary and human therapy; (ii) to assess the presence of the mecA gene. A total of 1007 samples were collected from food, food handlers, and environments and were analyzed for the presence of S. aureus. S. aureus was present in 165 of the 1007 samples. A total of 157 isolates were methicillin-susceptible S. aureus (MSSA) and 8 isolates were MRSA. In particular, out of 8 MRSA strains detected, 4 strains harboured the mecA gene. All MRSA strains were resistant to at least one of the tested antibiotics and 6 strains demonstrated multi-resistance. Considering the high level of resistances in S. aureus and the isolation of MRSA strains, the surveillance of antimicrobial resistance and the spreading of this pathogen is of crucial importance in the food production chain. These data are useful in improving background data on antimicrobial resistance of S. aureus isolated from food, processing environments and food handlers, supporting the prudent use of antibiotics and the development of international control programs. PMID- 22218001 TI - Left ventricular noncompaction cardiomyopathy. AB - Isolated left ventricular noncompaction (ILVNC) is a congenital abnormality in the structure of ventricular tissue due to amorphogenetic defect during embryogenesis. This rare entity can be easily diagnosed by the characteristic appearance of prominent trabeculations and deep inter-trabecular spaces. Clinical manifestations of this disease include benign and malignant ventricular arrhythmia, congestive heart failure signs, cardio-embolic events (stroke), mitral and pulmonary valve incompetence, and reduced global ventricular systolic function. We present the case report of a 58-year-old man with ILVNC. PMID- 22218003 TI - Mental health, care and management of the mentally ill. PMID- 22218002 TI - Investigation of new vehicles to patch test corticosteroids: our experience with ethoxydiglycol to detect contact allergy to hydrocortisone butyrate. AB - Topical corticosteroids (CS) are widely used in dermatology because of their anti inflammatory, anti-proliferative and immuno-suppressive properties. On the other hand, the prolonged application of corticosteroids may induce adverse reactions such as allergic contact dermatitis (ACD). Patch testing CS often poses methodological issues correlated to their drug properties that may hide the manifestations of a positive reaction. Furthermore, the ideal concentration to patch test corticosteroid is still a matter of study and some vehicles have some well-known limitations. This article is divided into two parts: the first one investigated vehicles that may efficiently dissolve the corticosteroids, according to the polarity of the latter; the second part compared the results of the patch tests with hydrocortistone-17-butyrate using two different vehicles: ethanol, which is the standard one, and another vehicle selected as suitable from our CS solubility test. PMID- 22218004 TI - [Schizoaffective disorder: An arguable diagnostic entity]. AB - Seventy-five years ago, J. Kasanin introduced the term "schizoaffective disorder" to refer to a disorder with symptoms of both schizophrenia and affective disorders. Since then, schizoaffective disorder has raised a considerable amount of discussion about its definition and position as a variant of schizophrenia, a variant of mood disorder or as an entity in between. This ambiguity is reflected on the definition of diagnostic criteria of the disorder in the taxonomic systems, which are practically too complex. Furthermore, there are essential differences between DSM-IV and ICD-10 regarding schizoaffective definition. Finally, the disorder has a very low inter-rater reliability and a very low longitudinal diagnostic stability. All the above have even led to proposals of elimination of schizoaffective disorder as a separate diagnostic entity. The prevalence of the disorder varies between 0.3% and 0.8%. Schizoaf fective disorder is more common in women than in men, a dif ference that is mostly attributed to increased incidence among women of the depressive type. The bipolar type of the disorder is more often found in young adults, whereas the depressive type is commoner in older adults. With regards to other variables such as educational level, marital status, prognosis, occupational level and social adjustment, schizoaffective disorder has more favourable characteristics than schizophrenia and less favourable than mood disorders. Age at onset is earlier than mood disorders and later than schizophrenia. The above epidemiologic and clinical data, as well as data from family, twin, genetic and neuroimaging studies, indicate that schizoaffective disorder can be best viewed as a mid point on a continuum between schizophrenia and mood disorders and represents the most prominent paradigm challenging the so-called "Kraepelinian dichotomy" of major psychiatric disorders. Though schizoaffective disorder is a nosological nuisance, it is also a clinical reality and it is not advisable to abandon it as a separate diagnosis. PMID- 22218005 TI - [Habits and problems of sleep in adolescent students]. AB - The evaluation of sleep habits and sleep related problems in high school adolescent students in the Athens area and the assessment of these problems' relation to demographic and other variables was investigated by the Athens Insomnia Scale - 5 item version (AIS-5), which was administered to 713 adolescent Senior High School students in the Greater Athens Area. Data such as age, sex, school records, and time spent per week in school-related and extracurricular activities were collected. The sample's mean sleep duration was 7,5 hours, mean bedtime 12:20 am and wake-up time 7:15 am. Total sleep time was not affected by gender, but was influenced by time spent in various activities. Sleep complaints were related to delayed sleep, onset latency and insufficient total duration of sleep. Girls complained more than boys, while correlations showed that students with lower academic per formance and those in second grade were more likely to have higher AIS-5 scores. The results show that sleep time of high school students is dependent on practical matters such as school schedule and other activities, while sleep complaints are related to female gender, bad school performance as well as to the second grade. The difference between actual sleep time and sleep complaints should be considered when studying the sleep of adolescents. PMID- 22218006 TI - [Attitudes of medical and nursing personnel on suicide]. AB - This paper investigates the attitudes towards suicide among nursing and medical personnel of Rethimno General Hospital and the Community Health Centers of the county of Rethimno. The Suicide Behavior Attitudes Questionnaire (SBAQ) comprises of 21 visual analoque scale items and three subscales: i.e feelings when caring for a suicidal patient, professional capacity and right to suicide. Tauhe study sample consisted of 104 members of the personnel, (48 doctors and 56 nurses). Nursing personnel tended to be more sympathetic towards the patient than doctors. More sympathetic attitudes were also expressed by women compared to men. Religious individuals expressed a more condemnatory attitude towards suicide, and a more sympathetic attitude towards the patient, compared to non religious ones. 26% of the total sample expressed the belief that suicide is not associated with a psychiatric disease. The need for training of the personnel is emphasized in order to give professional care to the difficult group of suicide attempters or patients with suicidal ideation. PMID- 22218007 TI - [Observations on the assertiveness and its relation to empathy in Greek students]. AB - The aim of the present study is to determine the level of assertiveness in a sample of male Greek students and in addition to compare the level of assertiveness with the various factors of empathy. The data of a sample of 104 Greek students were collected by using the Rathus Assertiveness questionnaire which evaluates assertiveness. The questionnaire used in a randomized sample of students, it was anonymous, voluntary and the students were asked to answer it in their personal time. In order to obtain reliable results the questionnaire was translated into the Greek language by two independent translators. The scores obtained were compared with various social factors such as: age, educational status of parents, and whether the students lived with their family or not. The results of the statistical analysis of our data revealed that: (a) There is no significant difference in the level of assertiveness between groups of students living alone or with their parents. (b) The assertiveness of students seems to be related with the educational level of their mothers. (c) In the whole of the students sample there is a statistically significant negative correlation between assertiveness and empathic concern, as well as between assertiveness and personal distress. (d) As regards the social status of the students, assertiveness is positively correlated with personal distress in students who live alone. (e) In contrast, assertiveness in students living with their parents seems to be negatively correlated with cognitive empathy, as well as empathic concern. The results of this study provide evidence that assertiveness has a strong relationship with empathy and the above results are discussed in relation to the pertinent literature examining the content of assertiveness. PMID- 22218008 TI - [Neuroleptic Malignant Syndrome after whithdrawal of anticholinergic agents]. AB - Neuroleptic Malignant Syndrome (NMS) is a rare but a potential lethal condition therefore it always represents a neurological emergency. Although NMS is considered mainly as idiosyncratic complication of antipsychotic medication, isolated reports show that the syndrome can rarely occur due to other causes such as, after abrupt withdrawal of anticholinergics and this was the case that is presented here. The syndrome continious to carry a high mortality rate and its basic management remains risk reduction, early diagnosis and supportive care. Thus, familiarity and vigilance to all known risk factors is considered essential for early diagnosis and intervention, and concequently for the reduction of morbidity and mortality of NMS. PMID- 22218009 TI - [Psychotherapy training in specialist child and adolescent psychiatry]. AB - This paper presents the guidelines for psychotherapy training as part of specialist child and adolescent psychiatry training, as approved by the Section of Child and Adolescent Psychiatry and Psychotherapy (CAPP) of the European Union of Medical Specialties (UEMS). The goal of psychotherapy training as part of specialist CAPP training is to raise the trainees' awareness as regards the requirements in force in each EU country, for one or all the main psychotherapeutic modes. That is: psychoanalytic/psychodynamic individual psychotherapy, cognitive behavioral psychotherapy, or family psychotherapy. Psychotherapy training consists of three elements described in detail for each psychotherapeutic mode: (a) familiarity with theoretical models, (b) personal skills and knowledge of techniques, and (c) awareness of own life experience. The guidelines also include the following: (a) Tauhe volume of training for each mode, while stressing the need for individual and group supervision of the trainees by a qualified child and adolescent therapist, (b) Tauhe competence level and what is included in each psychotherapeutic mode, (c) Tauhe evaluation of the training process. It should be noted that the situation in the field of psychotherapy training, as well as the educational resources and potential, vary from one European country to another. PMID- 22218010 TI - [Necessity and conditions of individual psychotherapy application in a child psychiatric / psychiatric inpatient unit]. AB - Psychiatric care, and especially child psychiatry, is influenced by the modern rational way of economic thinking and the quality of its services is threatened by the demand for greater "productivity". This way of thinking leads to the phenomenon of the continuously increasing neglect of psychotherapeutic interventions. In this particular study we compare the possibilities and the effectiveness between pharmaceutical and psychotherapeutic treatment of mental diseases and emphasize the therapeutic value of interpersonal relation between therapist and patient in any case. We try even to describe and compare three psychiatric approaches (biological/neurological, descriptive and psychoanalytic/psychodynamic) in an attempt to understand and treat mental diseases. Finally, we mark out the necessity of the existence of a psychotherapeutic culture and the application of psychotherapeutic interventions in every psychiatric unit. PMID- 22218012 TI - Nilotinib-mediated increase in fasting glucose level is reversible, does not convert to type 2 diabetes and is likely correlated with increased body mass index. PMID- 22218013 TI - Effects on cognitive performance of eating compared with omitting breakfast in elementary schoolchildren. AB - OBJECTIVE: The objective of this laboratory-based pilot study was to test the effects of consuming, compared with omitting, breakfast across 6 cognitive domains and on levels of perceived energy and well-being. METHODS: In a crossover design, 21 boys and girls, 8 to 10 years of age, were assessed once a week for 2 weeks. On each test day, subjects performed a series of 8 computerized cognitive performance tasks using the CogState software program throughout the morning, but they either consumed or did not consume breakfast. In addition, subjects repeatedly rated their perceived energy level, fatigue, overall well-being, and cheerfulness using a 100-mm Visual Analog Scale. RESULTS: Results showed no significant main effect of breakfast condition (p > .17) or breakfast condition by-time interaction (p > .09) for any of the cognitive performance tasks. On the day when children consumed breakfast, they felt significantly more cheerful (p = .02) and indicated to have more energy (p = .04) than on the day when they skipped breakfast. CONCLUSION: Among children who regularly consume breakfast, skipping breakfast once significantly decreased their perceived level of energy and cheerfulness, but it did not affect their cognitive performance throughout the morning. More experimental studies are needed to assess the effects of different types of breakfast on cognitive performance in children over a prolonged period of time while controlling for familial factors that may affect cognitive performance in children. PMID- 22218011 TI - A spectrometer designed for 6.7 and 14.1 T DNP-enhanced solid-state MAS NMR using quasi-optical microwave transmission. AB - A Dynamic Nuclear Polarisation (DNP) enhanced solid-state Magic Angle Spinning (MAS) NMR spectrometer operating at 6.7 T is described and demonstrated. The 187 GHz TE(13) fundamental mode of the FU CW VII gyrotron is used as the microwave source for this magnetic field strength and 284 MHz (1)H DNP-NMR. The spectrometer is designed for use with microwave frequencies up to 395 GHz (the TE(16) second-harmonic mode of the gyrotron) for DNP at 14.1T (600 MHz (1)H NMR). The pulsed microwave output from the gyrotron is converted to a quasi-optical Gaussian beam using a Vlasov antenna and transmitted to the NMR probe via an optical bench, with beam splitters for monitoring and adjusting the microwave power, a ferrite rotator to isolate the gyrotron from the reflected power and a Martin-Puplett interferometer for adjusting the polarisation. The Gaussian beam is reflected by curved mirrors inside the DNP-MAS-NMR probe to be incident at the sample along the MAS rotation axis. The beam is focussed to a ~1 mm waist at the top of the rotor and then gradually diverges to give much more efficient coupling throughout the sample than designs using direct waveguide irradiation. The probe can be used in triple channel HXY mode for 600 MHz (1)H and double channel HX mode for 284 MHz (1)H, with MAS sample temperatures >=85 K. Initial data at 6.7 T and ~1 W pulsed microwave power are presented with (13)C enhancements of 60 for a frozen urea solution ((1)H-(13)C CP), 16 for bacteriorhodopsin in purple membrane ((1)H-(13)C CP) and 22 for (15)N in a frozen glycine solution ((1)H-(15)N CP) being obtained. In comparison with designs which irradiate perpendicular to the rotation axis the approach used here provides a highly efficient use of the incident microwave beam and an NMR-optimised coil design. PMID- 22218014 TI - Mental health conditions among school-aged children: geographic and sociodemographic patterns in prevalence and treatment. AB - OBJECTIVE: To explore geographic differences in diagnosed emotional and behavioral mental health conditions and receipt of treatment. METHODS: Data are from the 2007 National Survey of Children's Health, a nationally representative, parent-reported, cross-sectional survey. Pediatric mental health conditions were identified using parents' responses to 3 questions regarding whether a health care provider had ever told them that their child had depression, anxiety problems, or behavioral or conduct problems. Parents also reported on past-year treatment or counseling by a mental health professional. State-level differences in condition prevalence were identified using unadjusted and adjusted prevalence estimates. Multivariate logistic regression assessed the odds of not receiving treatment by state and diagnoses. RESULTS: Nearly 8% of children aged 6 to 17 years have ever been diagnosed with depression or anxiety, and 5.4% have ever been diagnosed with behavioral or conduct problems. State-level estimates of parent-reported depression or anxiety varied from 4.8% in Georgia to 14.4% in Vermont, while prevalence of behavioral problems ranged from 3.2% in California to 9.2% in Louisiana. Nearly 10% of all school-aged children and 53.1% of those ever diagnosed with either condition type received past-year treatment. The odds of receiving past-year parent-reported treatment did not differ by state of residence with the exception of Louisiana and Nevada: children ever diagnosed had approximately 2.5 times the odds of not receiving past-year treatment in these states. CONCLUSION: The prevalence of parent-reported mental health disorders among children varies by geographic and sociodemographic factors, while receipt of treatment is generally dependent on sociodemographic and health-related factors. PMID- 22218015 TI - Atypical fetal response to the mother's voice in diabetic compared with overweight pregnancies. AB - OBJECTIVE: To characterize fetal spontaneous heart rate changes and movements and auditory-elicited heart rate changes in fetuses in diabetic pregnancies compared with those in uneventful, overweight pregnancies. METHODS: Spontaneous heart rate and movements and maternal voice-elicited heart rate changes were observed in 46 mother-fetal pairs (n = 14 gestational diabetic and n = 32 overweight prepregnancy) at 36 (+/-1) weeks gestational age. Fetal heart rate changes, body movements, and breathing movements were observed for 20 minutes while the mother was at rest. Subsequently, each fetus was presented with a 2-minute audio recording of the mother's voice using the following 6-minute procedure: 2 minutes no-voice baseline, 2 minutes voice presentation, and 2 minutes no-voice postvoice period; heart rate was recorded continuously. RESULTS: There were no differences in spontaneous heart rate changes, body movements, or breathing movements between the 2 groups. Fetuses in the overweight group showed an increase in the heart rate during the playing of their mother's voice, whereas fetuses in the diabetic group showed no response. CONCLUSIONS: Fetuses in overweight pregnancies responded to the mother's voice with an increase in the heart rate as has been reported previously in uneventful pregnancies. The lack of response to the mother's voice in fetuses in diabetic pregnancies may represent immature neural or auditory system development, an increased sensorineural threshold, and thyroid or iron deficiency. PMID- 22218016 TI - National surveys of child mental health: a measure of children's services or service vagaries? PMID- 22218017 TI - The new attention deficit hyperactivity disorder clinical practice guidelines published by the American Academy of Pediatrics. PMID- 22218018 TI - The Developmental-Behavioral Pediatrics Research Network: another step in the development of the field. AB - Developmental-behavioral pediatrics was formally recognized as a subspecialty of pediatrics in 1999 with one of the goals being to promote research in the field. However, research has generally been a small component of most developmental behavioral pediatricians' activities. In an effort to expand research in the field, the Developmental-Behavioral Pediatrics Research Network (DBPNet) was funded through a cooperative agreement with the Health Resources and Services Administration, Maternal Child Health Bureau. This funding supports the development of an infrastructure to support multisite research that aims to optimize the health and functional status of children with developmental and behavioral concerns and disorders. This article describes the need for a developmental-behavioral pediatrics research network, the development of the infrastructure for DBPNet, and the mechanisms for investigators to collaborate with the Network. PMID- 22218019 TI - Attached to a diagnosis: the quandary of social deficits and reactive attachment disorder. AB - CASE: : Alex is a 9-year-old boy brought to you, his primary care provider, for a "fifth opinion." You have cared for Alex since he was adopted from a Romanian orphanage at 3 years of age. He has been physically healthy with normal growth parameters and no evidence of fetal alcohol syndrome. Alex has long-standing history of social difficulties, impulsivity, lying, controlling, manipulative behaviors, violent outbursts at home with subsequent lack of remorse, and excessive chatter. You referred Alex to an interdisciplinary child development clinic 2 years ago, where he was diagnosed with reactive attachment disorder (RAD) and attention deficit hyperactivity disorder (ADHD). He was noted to have normal cognitive and language skills. Attachment therapy, stimulant therapy, and school accommodations for ADHD were recommended.Alex received some individual counseling with the school psychologist for a year after the first evaluation, with little improvement in core behaviors. The following year, Alex established care with a psychiatrist and a private counselor. The psychiatrist prescribed a succession of stimulants, each of which worked for only a short time and then had waning effect. The counselor worked with Alex and his parents on managing Alex's behavior, which the family reports has been somewhat helpful.Alex's parents express great frustration and sadness that parenting Alex has been such an ongoing struggle since he was adopted. They note that Alex is superficially friendly, chatty, and charming, with everyone he encounters, including strangers, but he never progresses past such superficial interaction, even with his adoptive parents. The parents express that they are deeply wounded that Alex is not more loving and is not more appreciative of the fact that they rescued him from the orphanage.His parents asked his pediatric clinician about Autism as they observe Alex's lack of real affection and social connection with parents or peers. They also note that Alex has difficulty verbalizing his feelings and that he lies frequently, chatters tangentially, and he can watch the Discovery channel for hours. A neurologist, to whom Alex was referred to evaluate staring spells, reassured the family that the spells did not seem to be epilepsy and also diagnosed Alex with "Asperger's syndrome." The school psychologist, after 2 years of equivocation, recently made Alex eligible for autism spectrum services.During the interview and examination, Alex is funny, friendly, and a bit silly. He uses normal eye contact, seems to enjoy the neuromotor examination, and is eager to show you his cool, new handshake. He engages in easy banter, using normal vernacular and prosody. After the visit, you call the therapist to express your opinion that the RAD diagnosis is valid after all and to ask whether the family is engaged in attachment therapy. The therapist refutes the RAD diagnosis, endorsing Asperger's syndrome (AS) instead and notes that Alex is making good progress in school and in therapy, where he is learning pragmatic skills and basic social skills with the use of social stories.Where do you head next? PMID- 22218024 TI - Mechanisms of reflux perception in gastroesophageal reflux disease: a review. AB - Patients with reflux symptoms often do not have excessive esophageal acid exposure, and patients with severe gastroesophageal reflux often do not have reflux symptoms. Understanding why different types of reflux induce symptoms in different patients is vital for addressing therapeutic gaps in the treatment of gastroesophageal reflux disease (GERD). Here we review studies providing insight into how gastroesophageal reflux is perceived, with a focus on comparing reflux characteristics and esophageal sensitivity among subgroups of patients with GERD. The available studies indicate that patients with nonerosive reflux disease have fewer acid reflux episodes and thus less esophageal acid exposure than patients with reflux esophagitis but perceive less intense stimuli because of greater esophageal sensitivity. Reflux characteristics other than acidity, such as the presence of bile, pepsin, liquid, or gas in reflux, and the proximal extent or volume of reflux, may also contribute to symptom perception. Factors contributing to greater esophageal sensitivity may include impaired mucosal barrier function, peripherally mediated esophageal sensitivity (enhanced esophageal receptor signaling), and centrally mediated esophageal sensitivity (physiological stressors, sensitization of spinal sensory neurons). Further insight into mechanisms of reflux perception may require a shift toward studies aimed at understanding predisposing cellular, molecular, and genetic factors. PMID- 22218025 TI - Image of the month: primary culture of normal human colonic epithelial cells. PMID- 22218030 TI - Editorial: hepatocellular carcinoma in type 2 diabetes: more than meets the eye. AB - Hepatocellular carcinoma (HCC), a disease with poor survival rates unless recognized and treated early, ranks as the fifth most common cancer worldwide and has a rising incidence in the United States. Recent data indicate that the growing epidemic of type 2 diabetes mellitus may contribute to this alarming trend. In this issue, Lai et al. utilize a large Taiwanese insurance claims database to demonstrate that diabetes is associated with an increased risk of HCC. Moreover, this risk escalates if diabetes coincides with chronic hepatitis C and cirrhosis. Lai et al. also show that treatment with metformin or thiazolidinediones may reduce the risk of HCC. The findings may prompt risk stratification for HCC surveillance and improved disease control in diabetes as measures of cancer prevention. PMID- 22218031 TI - Editorial: not so nosocomial anymore: the growing threat of community-acquired Clostridium difficile. AB - Clostridium difficile infection is widely accepted to be the leading cause of nosocomial infection-related morbidity and mortality, outpacing both antibiotic resistant staphylococcus and enterococcus. The existence and prevalence of community-acquired Clostridium difficile infection, on the other hand, is much less well appreciated. Growing evidence now suggests that community-acquired Clostridium difficile infection may account for more than a third of Clostridium difficile-associated diarrhea overall. Similar to nosocomial Clostridium difficile infection, community-acquired cases appear to be increasing in incidence, and although associated mortality is lower than in nosocomial cases, morbidity including hospitalization and recurrence are high. Further, traditional risk factors for Clostridium difficile infection including antibiotic exposure appear to be less important in community-acquired cases and common routes of exposure and infection in the community are yet to be elucidated. In this issue of the American Journal of Gastroenterology, Khanna et al. provide important epidemiological data on the growing threat of community-acquired Clostridium difficile infection. PMID- 22218032 TI - Editorial: taking FIT to the people: out of the office and into the mail. AB - Colorectal cancer (CRC) screening is most commonly performed in the United States using an opportunistic approach: patients coming to a physician's office for other unrelated reasons are offered screening with either fecal occult blood tests or, more commonly, a referral for colonoscopy. This approach has been effective to a point. CRC screening rates are increasing, but are still suboptimal and vary across different regions of the United States. Mailed fecal immunochemical test (FIT) outreach has the potential to allow more consistent CRC screening, by moving beyond opportunistic, office visit-based screening, to an organized approach. The study by van Roon et al. in this issue of the American Journal of Gastroenterology demonstrates that mailing FIT collection devices will not result in decreased sensitivity for 10-14 days following the specimen collection. PMID- 22218034 TI - Re: screening colonoscopy for the underserved. PMID- 22218036 TI - Altered bile acid pool using IBAT inhibitors for constipation: a potentially increased risk of malignancy. PMID- 22218037 TI - Vaccinations while on thiopurines: some protection is better than none. PMID- 22218038 TI - Chronic right lower abdominal pain due to lumbar ossification of the posterior longitudinal ligament. PMID- 22218039 TI - Change in malpractice claims in Japanese gastroenterological practice. PMID- 22218040 TI - Advanced-stage syphilis unmasking after immunomodulator therapy in a patient with ulcerative colitis. PMID- 22218041 TI - Helicobacter pylori vacA intermediate region genotyping and progression of gastric preneoplastic lesions. PMID- 22218045 TI - Rights and basic health care. PMID- 22218046 TI - PSD95 gene specific siRNAs attenuate neuropathic pain through modulating neuron sensibility and postsynaptic CaMKIIalpha phosphorylation. AB - OBJECTIVE: To observe the effects of PSD95 gene specific siRNAs on neuropathic pain relief, neuron viability, and postsynaptic calcium/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha) phosphorylation in vitro and in vivo. METHODS: Gene-specific siRNAs of rat PSD95 were synthesized chemically for transfection. Adult male Sprague-Dawley (SD) rats were randomly divided into 3 groups: naive group (n=6), sham group (n=6), and sciatic nerve chronic constriction injury (CCI) group (n=24). The CCI group was further divided into 4 groups (n=6 in each group), which were pretreated with normal saline, transfection vehicle, negative control siRNAs, and PSD95 gene specific siRNAs respectively. All the subgroups received corresponding agents intrathecally for 3 days, started one day before the CCI of sciatic nerve. Both mechanical allodynia and thermal hyperalgesia were measured on post-operative day 3 and 7. PSD95 gene silenced NG108-15 cells were further stimulated by glutamate, with the cell viability and the expression/phosphorylation of CaMKIIalpha measured by MTT cell proliferation assay and Western blot, respectively. RESULTS: The siRNAs decreased PSD95 mRNA level significantly both in vivo and in vitro. Neuropathic pain rats pretreated with PSD95 gene specific siRNAs exhibited significant elevation in the mechanical withdrawal threshold and paw withdrawal thermal latency, without affecting the baseline nociception. PSD95 gene silencing enhanced neuronal tolerance against the glutamate excitotoxicity, meanwhile the phosphorylation of CaMKIIalpha Thr286 was attenuated. CONCLUSION: Pre-emptive administration of PSD95 gene specific siRNAs may attenuate the central sensitization CaMKIIalpha related signaling cascades, leading to the relief of neuropathic pain. PMID- 22218047 TI - Quantitative assessment of hepatic fibrosis by contrast-enhanced ultrasonography. AB - OBJECTIVE: To explore the contrast-enhanced ultrasonographic features for quantitative assessment of hepatic fibrosis. METHODS: 86 patients with chronic viral hepatitis B were enrolled in this study from March 2007 to August 2009. The patients were classified into 5 groups (S(0)-S(4)) according to fibrosis stage evaluated with ultrasound guided liver biopsy. New contrast-enhanced ultrasonography (CEUS) features including area under the time-intensity curve (TIC) of portal venous phase/hepatic arterial phase (Qp/Qa) and intensity of portal venous phase/hepatic arterial phase (Ip/Ia) were used to detect the blood supply ratio (portal vein/hepatic artery) in each group. Arrival time of portal vein trunk (Tp) and decreasing rate of TIC (beta) were also analyzed. RESULTS: Qp/Qa and Ip/Ia decreased from S(0) to S(4), while Tp and beta increased. These 4 features were significantly correlated with the degree of fibrosis (P<0.001) and were significantly different among the five groups (P<0.001). Sensitivity and specificity of Ip/Ia were 80% and 86% for groups >=S(1), 75% and 86% for groups >= S(2), 71% and 84% for groups >= S(3), and 76% and 80% for group S(4), respectively. Sensitivity and specificity of Qp/Qa were 70% and 88% for groups >= S(1), 80% and 76% for groups >= S(2), 74% and 70% for groups >= S(3), and 81% and 95% for group S(4), respectively. CONCLUSION: Ip/Ia and Qp/Qa could be adopted as reliable, non-invasive features for quantitative assessment of hepatic fibrosis. PMID- 22218048 TI - Contrary regulation of TIMP-1 and MMP-9 by hepatocyte growth factor antibody after lung injury. AB - OBJECTIVE: To study the influence of hepatocyte growth factor (HGF) antibody on the lung expression level of matrix metalloproteinases-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). METHODS: Thirty male Wistar rats were randomly divided into 3 groups: control group, model group, and intervention group. Endotoxin was intratracheally infused in the model and intervention groups. HGF antibody was injected in the rats of the intervention group from day 1 to day 14, while the same volume of saline was injected in the control group. The rats were sacrificed on day 28 after endotoxin treatment. The amounts of MMP 9 mRNA and TIMP-1 mRNA were measured by reverse transcription-polymerase chain reaction, and protein expression levels of MMP-9 and TIMP-1 were measured by immunohistochemistry. RESULTS: In the model group, both mRNA and protein expression levels of TIMP-1 were significantly increased, the same as MMP-9. In the intervention group, the increase of TIMP-1 was remarkably reduced compared with the model group, while the mRNA and protein expression levels of MMP-9 were still increased. CONCLUSION: HGF activity may accelerate the repair of lung injury through contrary regulating the expression levels of TIMP-1 and MMP-9. PMID- 22218049 TI - Efficacy and safety of low molecular weight heparin prophylaxis for venous thromboembolism following lumbar decompression surgery. AB - OBJECTIVE: To evaluate the efficacy and safety of low molecular weight heparin (LMWH) prophylaxis for venous thromboembolism (VTE) after lumbar decompression surgery. METHODS: Patients at high or the highest risk of VTE who underwent lumbar spine surgery in Peking Union Medical College Hospital from January 2004 to April 2011 were included in the present study. All the patients received a half dose of LMWH 6 hours after surgery followed by a full dose LMWH once per day until discharge. We recorded incidences of deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding complications, and medication side effects. RESULTS: Seventy-eight consecutive patients were eligible and enrolled in this study. The mean hospital stat was 8.5+/-4.5 days. No symptomatic DVT, PE, or major bleeding events were observed. One patient developed wound ecchymosis, another developed wound bleeding, four had mild hepatic aminotransferase level elevation, and one developed a suspicious allergic reaction. CONCLUSION: LMWH may be applied as an effective and safe prophylaxis for VTE in high-risk patients undergoing lumbar decompression surgery. PMID- 22218050 TI - Neurological manifestations of Takayasu arteritis. AB - OBJECTIVE: To investigate the clinical neurological manifestations of Takayasu arteritis (TA). METHODS: A retrospective study was conducted with 63 consecutive TA cases admitted to Peking Union Medical College Hospital from January 2009 to May 2010. All the patients fulfilled the diagnostic criteria of TA by the American College of Rheumatology. Among the 63 TA patients, 27 with neurological manifestations were included in the present study. All the patients were evaluated using standardized neurological examination, sonography, computed tomography (CT) angiography, and cerebral CT or magnetic resonance imaging. RESULTS: Dizziness and visual disturbance were the most common symptoms, which occurred in 20 (74.1%) and 16 (59.3%) patients respectively. Another common symptom was headache, observed in 15 (55.6%) patients. Six (22.2%) patients had suffered from ischemic stroke; 7 (25.9%) patients had epileptic seizures. Two (7.4%) patients were diagnosed as reversible posterior encephalopathy syndrome (RPES) based on typical clinical and imaging manifestations. CONCLUSIONS: Neurological manifestations are common symptoms in TA patients in the chronic phase, including dizziness, visual disturbance, headache, ischemic stroke, seizures, and some unusual ones such as RPES. We suggested RPES be included into the differential diagnosis of acute neurological changes in TA. PMID- 22218051 TI - Diagnosis and treatment of uveal effusion syndrome: a case series and literature review. AB - OBJECTIVE: To explore the diagnosis, classification, and management of uveal effusion syndrome (UES). METHODS: The clinical data of 10 patients diagnosed with UES in our hospital between 1990-2010 were extracted from hospital records and analyzed, including ophthalmologic examination, ophthalmologic ultrasonography, ultrasound biomicroscopy (UBM), fundus fluorescence angiography (FFA), indocyanine green (ICG) angiography, surgical procedures, and outcomes. RESULTS: The fundus examination of all impacted eyes showed bullous retinal detachment shifting with head position, confirmed by ultrasonography revealing retinal and choroidal detachment. UBM showed annular peripheral ciliochoroidal detachment in all cases. FFA was performed in 5 patients and revealed leopard spots without leakage from choroid into subretinal space. ICG angiograpy was performed in 3 patients and demonstrated diffused granular marked hyperfluorescence in the choroidal fluorescence in the very early phase, which increased with time and persisted until the late phase. Four eyes of 2 patients underwent full-thickness sclerectomies and 1 eye of 1 patient underwent subscleral sclerectomy, all of whom achieved reattachment of the retina without recurrence during 1-year follow up. CONCLUSIONS: Comprehensive preoperative evaluation, including ophthalmologic ultrasonography, computed tomography, and magnetic resonance imaging, is crucial for accurate classification of UES and selection of proper management strategy. Surgical treatment can achieve optimal clinical outcomes for type 1 and type 2 UES. PMID- 22218052 TI - Surgical resection of sternal tumors and reconstruction with titanium mesh. AB - OBJECTIVE: To evaluate the use of titanium mesh reconstruction after sternal tumor resection. METHODS: From January 2007 to January 2011, 14 patients with sternal tumors were admitted into Peking Union Medical Hospital. The clinical characteristics, surgical resection, and technique of reconstruction were reviewed. RESULTS: Of the 14 patients, 3 had a metastatic sternal tumor, the primary sites of which were as follows: hepatic carcinoma in one case (metastasis 19 years after operation), breast carcinoma in another case (metastasis 5 years after operation), and renal carcinoma in the other case (found simultaneously). Two patients showed local involvement of the sternum: 1 had thymic carcinoma, and the other had myofibrosarcoma. The remaining 9 patients had primary tumors: 4 were osteochondroma, 3 chondrosarcoma, 1 eosinophilic granuloma, 1 non-Hodgekin's lymphoma. En bloc resection of the sternal tumor was performed in all the 14 patients. The defect was repaired with the titanium mesh adjusted to the shape of the defect and fixed with the stainless steel wire. Eleven patients were followed up for a period from 2 months to 4 years, during which no translocation or broken of the titanium mesh was observed. CONCLUSIONS: Radical en bloc excision remains the treatment of choice for sternal tumors. Sternum defect reconstruction using titanium mesh as a rigid replacement proves appropriate and effective. PMID- 22218053 TI - Efficacy of surgical therapy for carotid body tumors. AB - OBJECTIVE: To evaluate the efficacy of surgical therapy for carotid body tumors. METHODS: A retrospective analysis was conducted, covering the diagnosis, surgical procedure, postoperative complications, and prognosis of 120 cases of carotid body tumors in Peking Union Medical College Hospital from 1949 to May, 2011. RESULTS: Surgical excision was successfully performed in 111 cases with 117 tumors. In all those cases, 50 underwent simple tumor resection, 42 underwent resection of tumors and ligation of the external carotid arteries, 7 underwent co resection of tumors and common carotid arteries, internal carotid arteries, as well as external arteries without vascular reconstruction, and the other 12 cases experienced tumor resection and vascular reconstruction as internal carotid arteries were involved. After operation, 3 cases developed cerebral infarction, 30 cases showed cranial nerve palsy, including 15 cases of hypoglossal nerve damage, 10 cases of vagus paralysis, and 5 cases of Horner's syndrome. CONCLUSION: It is essential to make a proper surgical strategy, which can reduce postoperative complications. PMID- 22218054 TI - Lack of response in severe pneumocystis pneumonia to combined caspofungin and clindamycin treatment: a case report. AB - Pneumocystis pneumonia (PCP) is among the most common opportunistic infections in patients with acquired immune deficiency syndrome (AIDS). Although trimethoprim sulfamethoxazole (TMP-SMX) is the first line therapy for that condition given its efficacy, approximately one third of patients experienced dose-limiting toxicity. For cases of severe to moderate PCP, if TMP-SMX treatment fails or is contraindicated, primaquine combined with clindamycin or intravenous pentamidine is recommended as second line therapy. However, both primaquine and pentamidine are associated with severe adverse reactions and often unavailable at hospitals in China.As a result, other treatment options have been explored. Caspofungin, an echinocandin, has broad antifungal activity against a wide range of fungi including Candida and Aspergillus species. Cases of PCP patients treated with caspofungin have been reported, although conflicting conclusions have been arrived at. In addition, the use of caspofungin and clindamycin as the first line therapy for severe PCP in AIDS patients has not been reported yet. This article described an AIDS case with severe PCP, treated with the combination of caspofungin and clindamycin. PMID- 22218055 TI - Open partial nephrectomy in solitary kidney with multiple renal cell carcinoma: a case report. AB - Renal cell carcinoma (RCC) in a solitary kidney presents a unique clinical challenge to urological surgeons. Partial nephrectomy (PN) or nephron-sparing surgery in this condition provides good oncological and renal functional outcomes with an acceptable complication rate. Long-term renal function remains stable in most patients with solitary kidneys after a reduction of more than 50% in renal mass.PN is a surgical procedure reserved for patients with a tumor in a solitary kidney, bilateral renal tumors, or renal function impairment. The challenge of preserving renal parenchyma is significantly complicated with the discovery of multiple masses in a solitary kidney because any subsequent complications may result in a significant decline in quality of life. Particularly in the case of postoperative renal failure, dialysis becomes necessary. PMID- 22218056 TI - Surgical removal of a giant vegetation on permanent endocavitary pacemaker wire and lead. AB - Pacemaker lead infections are rare. There are only about 0.4%-1.1% of the patients who have been implanted permanent pacemakers suffering from serious infections which lead to endocarditis. Generally, removal of the infected pacemaker wire and lead, long-term anti-infection therapy, and implantation of a new pacemaker to another anatomic site are accepted approaches for these patients. PMID- 22218057 TI - Atypical chronic myeloid leukaemia with trisomy 13: a case report. AB - A typical chronic myeloid leukaemia (aCML), which shows both myeloproliferative and myelodysplastic features, is a type of myeloproliferative/myelodysplastic disease as defined by the World Health Organisation (WHO) classification of the myeloid neoplasms. Because of the presence of neutrophilic leukocytosis, aCML may resemble chronic myelogenous leukemia (CML). However, in contrast with CML, aCML does not have the Philadelphia chromosome or the bcr/abl fusion gene. With the continuous karotype analysis of aCML, several changes in the karyotype of aCML have been detected. However, few are recurring and no specific cytogenetic changes have been associated with aCML. Nonspecific cytogenetic abnormalities can be observed in 56%~82% of aCML cases. Although the most frequent abnormalities include trisomy 8 and del (20q), abnormalities involving other chromosomes such as 12, 13, 14, 17, and 19 have also been described. In this report we describe a case of aCML with trisomy 13. PMID- 22218058 TI - Modified approach for establishing filament-induced permanent middle cerebral artery occlusion rats and mice models. PMID- 22218059 TI - Determination of the ribosome-binding sequence and spacer length between binding site and initiation codon for efficient protein expression in Bifidobacterium longum 105-A. AB - The frequency of the ribosome-binding site (RBS) and spacer length between binding site and initiation codon were analyzed using informatics, and compared the activities of various synthetic RBSs and spacers in Bifidobacterium longum 105-A. As the result, AAGGAG and a 5 nt spacer length produced the most efficient protein expression. PMID- 22218060 TI - Our silver anniversary. PMID- 22218061 TI - Addressing the educational needs of wound care professionals. PMID- 22218065 TI - Deja vu: skin and dermal substitute codes changed again. PMID- 22218066 TI - Eradication of methicillin-resistant Staphylococcus aureus in pressure ulcers comparing a polyhexanide-containing cellulose dressing with polyhexanide swabs in a prospective randomized study. AB - OBJECTIVE: The study evaluated eradication of methicillin-resistant Staphylococcus aureus (MRSA) from pressure ulcers comparing swabs containing polyhexanide with a cellulose dressing + polyhexanide. After receiving approval from the ethics committee and informed consent, patients from the centers were recruited. DESIGN: Prospective randomized study. Thirty patients (n = 15/n = 15), not responding to wound disinfection after a washout period of 2 weeks, were included in the intention-to-treat analysis. SETTING: This study was performed on hospital patients. PATIENTS: Patients had pressure ulcers containing MRSA. INTERVENTIONS: For the control group, cleansing was performed with polyhexanide swabs (20 minutes), after which a foam dressing was applied. The study group received a polyhexanide-containing cellulose dressing. For bacterial analysis, semiquantitative swab cultures (Robert Koch Institute recommendations) were taken on days 0, 7, and 14 and during 3 consecutive days. RESULTS: The groups were comparable at baseline. At day 7, in the control group, 6 of 15 (40%) MRSA eradication. For the study group, there were 13 of 15 (86.67%) who showed MRSA eradication. At day 14, in the control group, there were 10 of 15 (66.67%) who had MRSA eradication, compared with the study group, where 15 of 15 (100%; P < .05) had the MRSA eradicated. CONCLUSIONS: Wound disinfection with polyhexanide was shown to be successful in both groups, showing superior results for the study group. PMID- 22218067 TI - Systematic review and meta-analysis on the use of honey to protect from the effects of radiation-induced oral mucositis. AB - Recently, 4 separate human controlled trials reported that honey appeared to protect from the effects of radiation-induced oral mucositis formation, a complication of radiation therapy that is responsible for pain and overall reduction in quality of life. In this systematic review and meta-analysis, the authors examined 3 of these controlled trials (n = 120) that met the inclusion and exclusion criteria to determine whether honey had protective effects against radiation-induced oral mucositis. The meta-analysis demonstrated an overall relative risk reduction of 80% in the honey treatment group compared with the control. Although favorable, the data must be approached with caution because of lack of description of the method of randomization and potential bias in all 3 of the individual studies included in the meta-analysis. The results are promising, and further studies are needed to strengthen the current evidence prior to a firm clinical recommendation being given. PMID- 22218068 TI - Estimates of evaporation rates from wounds for various dressing/support surface combinations. AB - The management of exudate is an essential aspect of wound care. The wound bed must remain moist to promote healing, but care must be taken to remove excess fluid to avoid maceration and subsequent breakdown of the periwound site, which could serve as a possible portal to infection. Excess fluid is typically absorbed into and/or evaporates through the wound dressing or may be managed by a powered vacuum-assisted closure device. Although the moisture vapor permeability has been studied for dressings, the rate of evaporation associated with wound's immediate treatment environment, or dressing/treatment surface interface, has not been addressed to date. It is essential for caregivers to have an understanding of how these 2 interventions work together in order to provide optimal care to the wound patient. The purpose of this study was to provide estimates of evaporative withdrawal rates for various wound dressings and therapeutic support surfaces. PMID- 22218069 TI - Exploring the effects of pain and stress on wound healing. AB - Wound-related pain is complex, involving a multitude of physiological and psychological factors, such as emotional state, culture, personality, meanings, and expectations. The impact of pain on the individual can contribute to stress and compromise quality of life. The purpose of this article is to review the relationships among pain, stress, and wound healing. PMID- 22218071 TI - Mapping documentation to support your work performed: part 3. PMID- 22218072 TI - Applications of imaging biomarkers in the early clinical development of central nervous system therapeutic agents. AB - The early clinical drug development process increasingly utilizes imaging biomarkers to provide key information in response to a sequential series of questions about potential therapeutic agents. We present several examples of how imaging can answer some of these questions pertaining to the central nervous system (CNS) during the early phases of development of drugs to treat diseases involving the CNS. We also present an overview of the challenges and the potential of using and further qualifying imaging biomarkers for clinical trials. PMID- 22218073 TI - Cyclin-dependent kinase inhibition with roscovitine: neuroprotection in acute ischemic stroke. AB - Stroke is the third most common cause of mortality and the leading cause of disability in industrialized country. According to population based-studies, ischemic stroke accounts for 67-80% of all strokes. Thrombolysis is used during the acute phase in only 2-5% of ischemic patients. Clinical trials of candidate neuroprotective agents have failed to identify viable therapies for ischemic stroke in humans. There is therefore a great need for new therapeutic strategies, considering that not all brain cells die immediately after ischemic stroke. PMID- 22218074 TI - Neuroimaging markers of cellular function in major depressive disorder: implications for therapeutics, personalized medicine, and prevention. AB - It is estimated that 15% of all individuals will experience a major depressive episode (MDE) during their lifetime and that treatment response is inadequate in 40% of these cases. To address this, neuroimaging is being used to identify MDE subtypes and mechanisms of onset as well as to optimize target occupancy of novel treatments. Neuroimaging of monoamine oxidase-A (MAO-A) binding; glutamate levels; indexes of 5-HT(2A), 5-HTT, 5-HT(1A), and 5-HT(1B) receptors; levels of dopamine transporters D(1) and D(2); and hippocampal volume are described here. Three themes emerge. First, symptoms such as pessimism, motor retardation, anxiety disorder, and verbal memory deficits best indicate the subtype of depression. Second, measures related to mechanisms of monoamine loss, particularly elevated MAO-A binding in prefrontal and anterior cingulate cortex, are present in MDE and in high-risk states for MDE. Third, clinical trials show a consistent 80% 5-HTT occupancy of selective serotonin reuptake inhibitors at doses sufficient to distinguish from placebo in clinical trials (although in vitro affinities vary 100-fold), thereby supporting the need for further occupancy studies to accelerate therapeutic development. PMID- 22218076 TI - Medicine, psychiatry and professionalism. PMID- 22218075 TI - Improving the performance of computer-aided detection of subtle breast masses using an adaptive cueing method. AB - Current computer-aided detection (CAD) schemes for detecting mammographic masses have several limitations including high correlation with radiologists' detection and cueing most subtle masses only on one view. To increase CAD sensitivity in cueing more subtle masses that are likely missed and/or overlooked by radiologists without increasing false-positive rates, we investigated a new case dependent cueing method by combining the original CAD-generated detection scores with a computed bilateral mammographic density asymmetry index. Using the new method, we adaptively raise the CAD-generated scores of the regions detected on 'high-risk' cases to cue more subtle mass regions and reduce the CAD scores of the regions detected on 'low-risk' cases to discard more false-positive regions. A testing dataset involving 78 positive and 338 negative cases was used to test this adaptive cueing method. Each positive case involves two sequential examinations in which the mass was detected in 'current' examination and missed in 'prior' examination but detected in a retrospective review by radiologists. Applying to this dataset, a pre-optimized CAD scheme yielded 75% case-based and 55% region-based sensitivity on 'current' examinations at a false-positive rate of 0.25 per image. CAD sensitivity was reduced to 42% (case based) and 27% (region based) on 'prior' examinations. Using the new cueing method, case-based and region-based sensitivity could maximally increase 9% and 33% on the 'prior' examinations, respectively. The percentages of the masses cued on two views also increased from 27% to 65%. The study demonstrated that using this adaptive cueing method enabled us to help CAD cue more subtle cancers without increasing the false-positive cueing rate. PMID- 22218077 TI - A novel, metaphor-based description of the structural and functional aspects of cognitions for the clinical setting. AB - In view of the continuous theoretical and clinical expansion of cognitive therapy, the traditional, information processing-based description of cognitions into products, processes and schemata displays certain, mainly clinical, limitations. The authors try to refine and expand this "tripartite" conceptualization by employing a new, clinically relevant metaphor to describe cognitions and offer new ideas of potential theoretical and practical utility. Indeed, the dispositional (structural) and functional (state-dependent) aspects of cognitions may be seen as reflecting an underlying theme that could be labeled "the mind as a parliament". Conceptualized as such, the various types of cognitions may then be metaphorically described as members of a parliament, who when confronted by environmental constrains, confer, discourse and decide to give meaning to one's experience and direction to one's behavior. This paper provides a general overview of this metaphor-driven model and a detailed description of its various components. The potential applications of this model as a clinical and educational tool and its limitations are also discussed. PMID- 22218078 TI - Smoking in patients with psychiatric disorders: Effects on their psychopathology and quality of life. AB - We are living in an era of implementing complete smoking cessation in all closed areas, following the example of the USA and other countries in the European Union. We appear more tolerant in our mentally ill in-patients, especially the ones suffering from long-term schizophrenia, where smoking is accepted and even encouraged. We tried to investigate the effect of smoking in these patients. We performed an in depth literature research of medical databases and web search engines containing relevant articles, opinions and arguments. It has been shown from a lot of different studies that the proportion of persons with mental health problems who smoke is considerably higher compared to the general population. 51% of individuals with diagnosis of schizophrenia and 50% of those with bipolar affective disorder smoke more than 20 cigarettes per day against 8% of the general population who smoke the same amount. In another study from the USA , it was calculated that 45% of all cigarettes smoked in one month, were consumed by individuals with diagnosis of mental disorder or substance abuse. Smokers that suffer from schizophrenia present more positive symptoms, although clinical observation and research confirmed data show a positive effect in extrapyramidal symptoms and other side effects of medication. For other parameters such as attention, cognitive function and impulsivity, research is non conclusive and with contradictory results. Rates of premature death are higher for persons with mental illnesses compared with the general population, even if we don't include suicides. Much of these deaths are attributed to cardiovascular and respiratory problems and smoking is considered to be a major contributor to these illnesses. Substances found in cigarette's tar act as enhancers of P450 liver enzymes, increasing the metabolism of certain of antipsychotic medication, including clozapine, fluphenazine, haloperidol and olanzapine. This leads to higher required doses of medication. Smoking adds a big economical burden upon the smoker, who, as an individual with mental illness, is likely to have low income and should be directed to cover other real life necessities that could improve the overall quality of life. People who are heavy smokers find difficult to participate in certain activities or attend places where smoking is not allowed. This contributes further to their social exclusion. This habit should be treated as an addiction. Currently a lot of different treatments both pharmacological and non-pharmacological are available, which can be combined with promising results. PMID- 22218079 TI - Male depression: Discrete differences between the two sexes. AB - Recent research indicates that subtle differences may exist in the symptom profile of male and female depression. The aim of this review is to examine male/female differences in depressive psychopathology in light of the latest research findings and discuss whether these differences might suggest the need for gender specific treatments. Multiple searches using Medline (1985-2008) were carried out. Additional searches were made using the reference lists of published papers and chapters from books. Differences exist in the clinical profile and comorbidity of male and female individuals with depression. Subtle genetic differences, the role of hormones, the role of preexisting anxiety, and personality differences are some of the factors responsible for these findings. These differences imply that different treatment options should be available for males and females suffering from depression. The available data suggest that clinically relevant differences in depressive symptom profile and the underlying pathophysiology between genders in depression do exist. The identification of distinct endophenotypes for major depression, will not only improve our understanding of the disease, but will also contribute to more specific treatment strategies. PMID- 22218080 TI - Deinstitutionalization in Greece: Ethical problems. AB - The following paper is based on a Concerted Action which focused on the "Ethical aspects of deistinstutionalisation in mental health care" in 2001. It investigates the development and the ethical dilemmas posed by deinstitutionalization in Greece. This movement has recently undergone a very active phase but the transition from the traditional model of psychiatric care to the community based system unavoidably creates many ethical problems related to the professionals' attitude towards individual liberties, dignity and other fundamental rights of mentally ill persons. These problems exist not only in the level of the therapist-patient relationship but in the level of policy making as well as its implementation. Moreover, the paper deals with specific ethical problems such as stigmatisation and isolation in the community context, as well as the role of the family. PMID- 22218081 TI - The notion of "Sisyphus task" in medicine: A reconstruction. AB - In medicine, along with the other domains of our life, the myth of Sisyphus is frequently evoked upon confronting a task conceived as laborious, endless and for some futile or even purposeless and meaningless. In this paper, we explore the origin of the myth of Sisyphus so that its connotations and symbolizations will hopefully emerge clearer. It is suggested that the natural background of the myth might be related to the seismologic history of Greece, and Corinth in particular, a city ruined and rebuilt several times. The natural component might symbolically echo in the personified myth of Sisyphus, Corinth's founder and might explain the peculiar labor he was condemned to execute eternally, as well as the meanings the myth carries. Like his own city, Sisyphus also suffered the same "ups and downs" of fate, either as a public figure -patron of several big achievements- or as a punished hero condemned to role a stone in the underworld. His persistent efforts led to temporary successes, even though he could not find permanent solutions to the labors he undertook alive or dead. Thus, the myth of Sisyphus is related to human efforts and its limitations, the feasible and infeasible the two main poles between which the myth functions. Conceptualizing with Sisyphean terms their function, physicians can celebrate their transient victories, and by realizing their limitations, reconstruct their aspirations without decreasing their efforts. PMID- 22218082 TI - Public opinions about mental illness in a Greek area: The influence of socio demographic factors. AB - The importance of certain socio-demographic factors, which influence the attitudes and ideas regarding the mentally ill, were investigated in a resident population of a Greek region. An urban and a rural sample of 1,975 inhabitants were selected with an age range between 18 and 65 years. The Greek version of the Opinions about Mental Illness Questionnaire (OMIQ) was used for measuring the attitudes of social discrimination, social restriction, social care, social integration towards the mentally ill and the beliefs for the aetiology of the mental illness. The collected data were statistically analysed with stepwise multiple regression analysis and for the coding of the variables the method of dummy or indicator variables was followed. Educational level, age and place of residence are the main socio-demographic variables on which the OMIQ score depend. The results of this study could lead to the identification of target groups for the organisation of prevention programs aiming at changing public beliefs towards the mentally ill. PMID- 22218083 TI - Mental and physical health-A holistic approach. AB - The promotion and the protection of physical and, recently, mental health is a globally recognized priority. This is not true though with regard for their interrelationship which has received little attention from both medical branches. It is well known that physical healthproblems or disabilities are accompanied by or combined with mental health symptoms or disorders and vice versa. The advantages of a holistic, individualized approach, which covers not only the subjective complains of the patient but also the interaction between physical and mental health are well established based upon credible scientific data. PMID- 22218084 TI - Quetiapine monotherapy in bipolar disorder: Two years maintenance treatment in an elderly woman. AB - Queatiapine has been used in bipolar mania and most recently in bipolar depression with good results. However its use in maintenance treatment has not been established yet. A case of an elderly woman suffering from bipolar disorder and diabetes mellitus (type II) is presented. The use of quetiapine as a monotherapy (300 mg/day) was efficient and safe and proved to be a good treatment in mood stabilization for two years. PMID- 22218085 TI - The cariogenic characters of xylitol-resistant and xylitol-sensitive Streptococcus mutans in biofilm formation with salivary bacteria. AB - Streptococcus mutans metabolize carbohydrates, such as glucose and sucrose, to produce acid and enhance biofilm formation with the early colonizing bacteria to induce dental caries. Xylitol has been used as a reliable substitute for carbohydrate to inhibit the acid production of S. mutans. However, long-term xylitol consumption leads to the emergence of xylitol-resistance in S. mutans. The aim of this study was to investigate the cariogenic trait of Xylitol resistant (X(R)) S. mutans using biofilm formation and coaggregation of xylitol sensitive (X(S)) and X(R) S. mutans with salivary bacteria and their glucosyltransferases expression. When X(S) or X(R) S. mutans were incubated in brain heart infusion broth with bacteria from human saliva, X(R)S. mutans exhibited reduction in biofilm formation in comparison to X(S) S. mutans. The coaggregation between X(R) S. mutans and S, gordonii, S. mitis, S. oralis or S. sanguinis was less pronounced than that of X(S) S. mutans in the presence of sucrose. However, there was no difference in the coaggregation between X(R) and X(S) S. mutans in the sucrose-free condition. The level of gtfB and gtfC mRNA expression of X(R) S. mutans was lower than that of X(S) S. mutans, whilst the level of gtfD mRNA expression did not differ between the two strains. The reduction of biofilm formation in X(S) S. mutans due to decrease in glucosyltransferases expression suggests that X(R) S. mutans may be less cariogenic than X(S) S. mutans. PMID- 22218086 TI - Time-course changes in fungal elicitor-induced lignan synthesis and expression of the relevant genes in cell cultures of Linum album. AB - Linum album has been shown to accumulate anti-tumor podophyllotoxin (PTOX) and its related lignans. In the present study, we examined the effects of five fungal extracts on the production of lignans in L. album cell cultures. Fusarium graminearum extract induced the highest increase of PTOX [140MUgg(-1) dry weight (DW) of the L. album cell culture] which is seven-fold greater than the untreated control, while Rhizopus stolonifer extract enhanced the accumulation of lariciresinol, instead of PTOX, up to 365MUgg(-1) DW, which was 8.8-fold greater than the control. Quantitative PCR analyses showed that expression of the enzyme genes responsible for the PTOX biosynthesis cascade, such as pinoresinol lariciresinol reductase (PLR), phenylalanine ammonia-lyase (PAL), cinnamoyl-CoA reductase (CCR) and cinnamyl-alcohol dehydrogenase (CAD) genes, were also up regulated in a fungal extract-selective fashion. These results provide evidence that the fungal extracts used in this study differentially increase the production of PTOX or larisiresinol via the up-regulation of the genes in lignan biosynthesis in L. album cell cultures, and suggest that such selective actions of fungal elicitors on the lignan synthesis will lead to more efficient metabolic engineering-based production of PTOX and other beneficial lignans using L. album cell cultures. PMID- 22218087 TI - Symptomatic management of fever by Swiss board-certified pediatricians: results from a cross-sectional, Web-based survey. AB - BACKGROUND: Symptomatic management is often all that is recommended in children with fever. To date, only 2 nationwide surveys of pediatricians regarding their attitudes toward fever have been published. OBJECTIVE: The aim of this study was to describe the management of children with fever by pediatricians in Switzerland. METHODS: For this survey, an initial close-ended questionnaire was tested and subsequently corrected. Between June 2010 and March 2011, an invitation was sent via electronic mail containing a link to the final version of the questionnaire. The survey was not commercially sponsored. RESULTS: The questionnaire was sent to 900 pediatricians, of whom 322 (36%) responded. A total of 96% of respondents identified >=38.5 degrees C as the rectal temperature threshold for fever treatment, and 64% indicated that they prescribe antipyretics for the treatment of general discomfort. A total of 95% of respondents indicated that they prescribe paracetamol (acetaminophen) as the first choice of antipyretic drug, and 91% indicated that they often prescribe ibuprofen as well. An alternating regimen of 2 drugs and physical antipyresis were indicated as common practice by 77% and 65% of pediatricians, respectively. Homeopathic remedies are rarely prescribed (<10% of respondents). The most commonly prescribed routes of administration in children aged 18 months, 5 years, and 10 years were rectal (78%), oral (87%), and oral (99%), respectively. Ninety-two percent of respondents indicated that they believe that an exaggerated fear of fever is common among parents, but 81% stated that they do not lower the temperature threshold for initiating pharmacologic treatment exclusively to calm parents. Most respondents (95%) indicated a belief that it is possible to educate families about the fear of fever. CONCLUSIONS: Based on the findings from the present survey, antipyretics are often prescribed to treat the general discomfort that accompanies fever. Nonetheless, a gap exists between available evidence and clinical practice. Guidelines should take this fact into account. PMID- 22218088 TI - Central neuropeptide Y modulates binge-like ethanol drinking in C57BL/6J mice via Y1 and Y2 receptors. AB - Frequent binge drinking has been linked to heart disease, high blood pressure, type 2 diabetes, and the development of ethanol dependence. Thus, identifying pharmaceutical targets to treat binge drinking is of paramount importance. Here we employed a mouse model of binge-like ethanol drinking to study the role of neuropeptide Y (NPY). To this end, the present set of studies utilized pharmacological manipulation of NPY signaling, immunoreactivity (IR) mapping of NPY and NPY receptors, and electrophysiological recordings from slice preparations of the amygdala. The results indicated that central infusion of NPY, a NPY Y1 receptor (Y1R) agonist, and a Y2R antagonist significantly blunted binge like ethanol drinking in C57BL/6J mice (that achieved blood ethanol levels >80 mg/dl in control conditions). Binge-like ethanol drinking reduced NPY and Y1R IR in the central nucleus of the amygdala (CeA), and 24 h of ethanol abstinence after a history of binge-like drinking promoted increases of Y1R and Y2R IR. Electrophysiological recordings of slice preparations from the CeA showed that binge-like ethanol drinking augmented the ability of NPY to inhibit GABAergic transmission. Thus, binge-like ethanol drinking in C57BL/6J mice promoted alterations of NPY signaling in the CeA, and administration of exogenous NPY compounds protected against binge-like drinking. The current data suggest that Y1R agonists and Y2R antagonists may be useful for curbing and/or preventing binge drinking, protecting vulnerable individuals from progressing to the point of ethanol dependence. PMID- 22218089 TI - Increased Kv1 channel expression may contribute to decreased sIPSC frequency following chronic inhibition of NR2B-containing NMDAR. AB - Numerous studies have documented the effects of chronic N-methyl-D-aspartate receptor (NMDAR) blockade on excitatory circuits, but the effects on inhibitory circuitry are not well studied. NR2A- and NR2B-containing NMDARs play differential roles in physiological processes, but the consequences of chronic NR2A- or NR2B-containing NMDAR inhibition on glutamatergic and GABAergic neurotransmission are unknown. We investigated altered GABAergic neurotransmission in dentate granule cells and interneurons following chronic treatment with the NR2B-selective antagonist, Ro25,6981, the NR2A-prefering antagonist, NVP-AAM077, or the non-subunit-selective NMDAR antagonist, D-APV, in organotypic hippocampal slice cultures. Electrophysiological recordings revealed large reductions in spontaneous inhibitory postsynaptic current (sIPSC) frequency in both granule cells and interneurons following chronic Ro25,6981 treatment, which was associated with minimally altered sIPSC amplitude, miniature inhibitory postsynaptic current (mIPSC) frequency, and mIPSC amplitude, suggesting diminished action potential-dependent GABA release. Chronic NVP-AAM077 or D-APV treatment had little effect on these measures. Reduced sIPSC frequency did not arise from downregulated GABA(A)R, altered excitatory or inhibitory drive to interneurons, altered interneuron membrane properties, increased failure rate, decreased action potential-dependent release probability, or mGluR/GABA(B) receptor modulation of GABA release. However, chronic Ro25,6981-mediated reductions in sIPSC frequency were occluded by the K+ channel blockers, dendrotoxin, margatoxin, and agitoxin, but not dendrotoxin-K or XE991. Immunohistochemistry also showed increased Kv1.2, Kv1.3, and Kv1.6 in the dentate molecular layer following chronic Ro25,6981 treatment. Our findings suggest that increased Kv1 channel expression/function contributed to diminished action potential-dependent GABA release following chronic NR2B-containing NMDAR inhibition and that these Kv1 channels may be heteromeric complexes containing Kv1.2, Kv1.3, and Kv1.6. PMID- 22218090 TI - RSK2 signaling in medial habenula contributes to acute morphine analgesia. AB - It has been established that mu opioid receptors activate the ERK1/2 signaling cascade both in vitro and in vivo. The Ser/Thr kinase RSK2 is a direct downstream effector of ERK1/2 and has a role in cellular signaling, cell survival growth, and differentiation; however, its role in biological processes in vivo is less well known. Here we determined whether RSK2 contributes to mu-mediated signaling in vivo. Knockout mice for the rsk2 gene were tested for main morphine effects, including analgesia, tolerance to analgesia, locomotor activation, and sensitization to this effect, as well as morphine withdrawal. The deletion of RSK2 reduced acute morphine analgesia in the tail immersion test, indicating a role for this kinase in mu receptor-mediated nociceptive processing. All other morphine effects and adaptations to chronic morphine were unchanged. Because the mu opioid receptor and RSK2 both show high density in the habenula, we specifically downregulated RSK2 in this brain metastructure using an adeno associated-virally mediated shRNA approach. Remarkably, morphine analgesia was significantly reduced, as observed in the total knockout animals. Together, these data indicate that RSK2 has a role in nociception, and strongly suggest that a mu opioid receptor-RSK2 signaling mechanism contributes to morphine analgesia at the level of habenula. This study opens novel perspectives for both our understanding of opioid analgesia, and the identification of signaling pathways operating in the habenular complex. PMID- 22218091 TI - Delay- and dose-dependent effects of Delta9-tetrahydrocannabinol administration on spatial and object working memory tasks in adolescent rhesus monkeys. AB - Among adolescents, the perception that cannabis can cause harm has decreased and use has increased. However, in rodents, cannabinoid administration during adolescence induces working memory (WM) deficits that are more severe than if the same exposure occurs during adulthood. As both object and spatial WM mature in a protracted manner, although apparently along different trajectories, adolescent cannabis users may be more susceptible to impairments in one type of WM. Here, we evaluate the acute effects of a range of doses (30-240 MUg/kg) of intravenous Delta9-tetrahydrocannabinol (THC) administration on the performance of spatial and object WM tasks in adolescent rhesus monkeys. Accuracy on the object WM task was not significantly affected by any dose of THC. In contrast, THC administration impaired accuracy on the spatial WM task in a delay- and dose dependent manner. Importantly, the THC-induced spatial WM deficits were not because of motor or motivational impairments. These data support the idea that immature cognitive functions are more sensitive to the acute effects of THC. PMID- 22218092 TI - Dopamine-glutamate interplay in the ventral striatum modulates spatial learning in a receptor subtype-dependent manner. AB - The ventral striatum (VS) is characterized by a distinctive neural architecture in which multiple corticolimbic glutamatergic (GLUergic) and mesolimbic dopaminergic (DAergic) afferents converge on the same output cell type (the medium-sized spiny neuron, MSN). However, despite the gateway function attributed to VS and its involvement in action selection and spatial navigation, as well as the evidence of physical and functional receptor-receptor interaction between different members of ionotropic GLUergic and DAergic receptors, there is no available knowledge that such reciprocal interaction may be critical in shaping the ability to learn novel spatial and non-spatial arrangement of stimuli. In this study, it was evaluated whether intra-VS bilateral infusion of either N methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-selective antagonists may suppress the ability to detect spatial or non-spatial novelty in a non-associative behavioral task. In a second set of experiments, we further examined the hypothesis that VS-mediated spatial information processing may be subserved by some preferential receptor-receptor interactions among specific GLUergic and DAergic receptor subtypes. This was assessed by concomitant intra-VS infusion of the combination between subthreshold doses of either NMDA or AMPA receptor antagonists with individual D1 or D2 receptor blockade. The results of this study highlighted the fact that NMDA or AMPA receptors are differentially involved in processing of spatial and non spatial novelty, and showed for the first time that preferential NMDA/D1 and AMPA/D2 receptor-receptor functional communication, but not NMDA/D2 and AMPA/D1, is required for enabling learning of novel spatial information in the VS. PMID- 22218093 TI - Impaired sensorimotor gating in unmedicated adults with obsessive-compulsive disorder. AB - Functional and structural imaging studies suggest that obsessive-compulsive disorder (OCD) symptoms arise from dysfunction in cortico-striato-thalamo cortical circuits. It has therefore been hypothesized that neurophysiological tasks subserved by these circuits should be abnormal in OCD patients. One neurocognitive probe associated with this circuitry is prepulse inhibition (PPI) of the acoustic startle response. PPI deficits are thought to reflect abnormalities in processing and integration of sensory and motor information. Two prior studies found that OCD patients had PPI deficits at single prepulse (PP) intensities. However, most patients in these studies were taking psychotropic medications at the time of PPI testing, and preclinical studies have demonstrated effects of psychotropic medications on PPI. We examined PPI in 22 unmedicated OCD patients and 22 matched healthy controls at three different PP intensities (74, 78, and 86 dB). OCD patients had significantly less PPI across all three PP intensities compared with controls. Exploratory analyses indicated that OCD patients with a history of tics had lower levels of PPI. Our results demonstrate that unmedicated OCD patients have impaired sensorimotor gating as measured by PPI. This indicates that PPI deficits are present in OCD patients and are not the result of medication effects. Our findings also suggest that OCD patients with a history of tics may have greater impairment in sensorimotor gating than the general OCD population. Future studies should be designed to examine whether PPI deficits characterize tic-related OCD. PMID- 22218096 TI - The landscape of blogging in palliative care. AB - We present the case of a 30-year-old patient with pontine glioblastoma multiforme, World Health Organisation grade IV (WHO IV). This case is of particular interest in terms of the patient's use of social media as a medium of expression. This popular form of communication raises important clinical, ethical and social issues relating to confidentiality and the nature of the physician patient relationship in a unique context. PMID- 22218095 TI - Haplotype polymorphism in the alpha-2B-adrenergic receptor gene influences response inhibition in a large Chinese sample. AB - Response inhibition refers to the suppression of inappropriate or irrelevant responses. It has a central role in executive functions, and has been linked to a wide spectrum of prevalent neuropsychiatric disorders. Increasing evidence from neuropharmacological studies has suggested that gene variants in the norepinephrine neurotransmission system make specific contributions to response inhibition. This study genotyped five tag single-nucleotide polymorphisms covering the whole alpha-2B-adrenergic receptor (ADRA2B) gene and investigated their associations with response inhibition in a relatively large healthy Chinese sample (N=421). The results revealed significant genetic effects of the ADRA2B conserved haplotype polymorphisms on response inhibition as measured by stop signal reaction time (SSRT) (F(2, 418)=5.938, p=0.003). Individuals with the AAGG/AAGG genotype (n=89; mean SSRT=170.2 ms) had significantly shorter SSRTs than did those with either the CCAC/AAGG genotype (n=216; mean SSRT=182.4 ms; uncorrected p=0.03; corrected p=0.09) or the CCAC/CCAC genotype (n=116; mean SSRT=195.8 ms; corrected p<0.002, Cohen's d=0.51). This finding provides the first evidence from association research in support of a critical role of the norepinephrine neurotransmission system in response inhibition. A better understanding of the genetic basis of response inhibition would allow us to develop more effective diagnosis, treatment, and prevention of deficient or underdeveloped response inhibition as well as its related prevalent neuropsychiatric disorders. PMID- 22218094 TI - BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity. AB - Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRI-induced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild type (BDNF(Val/Val)) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF(Met/Met)). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF(Met/Met) mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF(Met/Met) mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment. PMID- 22218097 TI - The effect of policy on end-of-life care practice within nursing care homes: a systematic review. AB - BACKGROUND: The number of older people in the UK is increasing. A significant proportion of end of life care for this population is currently provided and will increasingly be provided within nursing care homes. AIM: To identify the impact of implementing end of life care policy with regard to the use of the Gold Standards Framework in Care Homes programme, the Liverpool Care Pathway (or an Integrated Care Pathway) and educational/training interventions to support the provision of end of life care within nursing care homes within the UK. DESIGN: Systematic literature review of published literature and reports. DATA SOURCES: An electronic search was undertaken of five databases-Medline, CINAHL, EMBASE, Web of Science and the Cochrane library and websites of government and palliative care organisations for papers and reports published between 2000 to June 2010. The reference lists of studies that were retrieved for the detailed evaluation were hand-searched for any additional relevant citations.. Only studies that included comparative outcome data were eligible for inclusion. RESULTS: Eight papers/reports, incorporating information from three studies were identified. Two studies reported on the implementation of the Gold Standards Framework in Care Homes programme and one the implementation of an Integrated Care Pathway for the last days of life. Improvements occurred in resident outcomes and in relation to staff recognising, managing and meeting residents needs for end of life care. CONCLUSIONS: The studies provided limited evidence on improved outcomes following the implementation of these interventions. Further research is needed, both within the UK and internationally, that measures the process and impact of implementing these initiatives. PMID- 22218099 TI - The Sugar Bureau. PMID- 22218100 TI - Forget sponsorship and free trips--welcome to Pharmacare. PMID- 22218101 TI - Lessons from America. PMID- 22218102 TI - Investigating beneficial drug reactions. PMID- 22218103 TI - Research misconduct in the UK. PMID- 22218104 TI - Slovakian doctors promise further action to secure affordable healthcare. PMID- 22218105 TI - Treating boar sperm with cholesterol-loaded cyclodextrins widens the sperm osmotic tolerance limits and enhances the in vitro sperm fertilising ability. AB - Treating sperm with cholesterol-loaded cyclodextrins (CLC) improves the cryosurvival of the sperm of different cold-shock sensitive species. However, the response of boar sperm to this treatment is not fully understood. The aim of this study was to determine how CLC and methyl-beta-cyclodextrin (MbetaCD, not loaded with cholesterol) affect the parameters for boar sperm functionality, including sperm osmotic resistance, and the ability of the sperm to capacitate and to penetrate the sow's immature oocytes in vitro. Samples treated with CLC or MbetaCD prior to freezing exhibited similar percentages of motile sperm, live sperm and sperm with intact acrosomes as the control samples (P>0.05). In addition, these treatments did not alter the response of the boar sperm to capacitating conditions. However, when compared to the controls and the MbetaCD treated samples, the CLC-treated sperm maintained greater percentages of motile sperm and live sperm in a wide range of osmotic solutions including hypo- (50, 75 and 150 mOsm/kg) and hyper-osmotic (600, 800 mOsm/kg) conditions (P<0.05). In addition, the CLC-treated sperm exhibited greater oocyte penetration ability than the control and the MbetaCD-treated sperm (P<0.0001). In conclusion, the pre freezing treatment of boar sperm with CLC does not alter the ability of the sperm to respond to capacitating conditions. Despite not increasing the cryosurvival of the sperm, this treatment widens the sperm osmotic tolerance limits and enhances the in vitro sperm fertilising ability. PMID- 22218098 TI - Immediate and late benefits of treating very elderly people with hypertension: results from active treatment extension to Hypertension in the Very Elderly randomised controlled trial. AB - OBJECTIVE: To assess if very elderly people with hypertension obtain early benefit from antihypertensive treatment. DESIGN: One year open label active treatment extension of randomised controlled trial (Hypertension in the Very Elderly Trial (HYVET)). SETTING: Hospital and general practice based centres mainly in eastern and western Europe, China, and Tunisia. PARTICIPANTS: People on double blind treatment at the end of HYVET were eligible to enter the extension. INTERVENTIONS: Participants on active blood pressure lowering treatment continued taking active drug; those on placebo were given active blood pressure lowering treatment. The treatment regimen was as used in the main trial-indapamide SR 1.5 mg (plus perindopril 2-4 mg if required)-with the same target blood pressure of less than 150/80 mm Hg. MAIN OUTCOME MEASURES: The primary outcome was all stroke; other outcomes included total mortality, cardiovascular mortality, and cardiovascular events. RESULTS: Of 1882 people eligible for entry to the extension, 1712 (91%) agreed to participate. During the extension period, 1682 patient years were accrued. By six months, the difference in blood pressure between the two groups was 1.2/0.7 mm Hg. Comparing people previously treated with active drug and those previously on placebo, no significant differences were seen for stroke (n = 13; hazard ratio 1.92, 95% confidence interval 0.59 to 6.22) or cardiovascular events (n = 25; 0.78, 0.36 to 1.72). Differences were seen for total mortality (47 deaths; hazard ratio 0.48, 0.26 to 0.87; P = 0.02) and cardiovascular mortality (11 deaths; 0.19, 0.04 to 0.87; P = 0.03). CONCLUSION: Very elderly patients with hypertension may gain immediate benefit from treatment. Sustained differences in reductions of total mortality and cardiovascular mortality reinforce the benefits and support the need for early and long term treatment. Trial registration Clinical trials NCT00122811. PMID- 22218106 TI - Urinary pyrethroid metabolites among pregnant women in an agricultural area of the Province of Jiangsu, China. AB - Pyrethroid pesticides are widely used throughout the world in agriculture to protect crops and in public health to control diseases. Of particular concern is exposure of pregnant women and their fetuses because little is known about the potential developmental hazards of such exposure. Several studies have detected internal pyrethroid exposure in urine both in adults and children, but few published data are available on metabolites in pregnant women. The present paper provides data on pyrethroid pesticides exposure based on questionnaire items and measurement of maternal urinary metabolite levels among 1149 pregnant women living in agricultural area of Jiangsu Province, China in 2009-2010, none of which reported occupational exposure to pyrethroid insecticides during pregnancy. To assess exposure to pyrethroid pesticides, urine specimens were analyzed for three main metabolites of 3-phenoxybenzoic acid (3-PBA), cis-and-trans-3-(2,2 dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (cis-DCCA and trans DCCA) using a gas chromatography-mass spectrometry method. The limits of detection for three pyrethroid metabolites were 0.1MUg/L. All pyrethroid metabolites were found in more than 94.0% of the urine samples. Median unadjusted and creatinine-adjusted values for urinary pyrethroid metabolites in these females were 1.01MUg/L and 1.55MUg/g Cre for 3-PBA, 0.44MUg/L and 0.69MUg/g Cre for cis-DCCA, 1.17MUg/L and 1.86MUg/g Cre for trans-DCCA, respectively. About half (45.5%) of women reported that they or family members had applied commercially available indoor insecticides during pregnancy. Both the questionnaire and laboratory data revealed that exposure to pyrethroid pesticides was considerably widespread in our subjects. The median values of urinary metabolites in the present study were about 4-10 times higher as those of general population from the developed countries. Interestingly, we found there was a temporal season variation tendency in different months. Especially, the levels of urinary metabolites in summer were significant higher than those in winter. These data indicated the need to assess the potential adverse effects of pyrethroid pesticides exposure on fetuses and infants in order to take adequate measures to protect pregnant women from pesticide exposures during pregnancy. PMID- 22218107 TI - Human biomonitoring in Israel: past, present, future. AB - The first human biomonitoring (HBM) studies in Israel in the 1970s and 80s focused on measuring exposure to polychlorinated biphenyls (PCBs) and organochlorine insecticides in the general population and organophosphate pesticides in agricultural workers. In the late 1990 s, a regional human biomonitoring study found differences in blood lead levels in children from Israel, Jordan, and the Palestinian Authority. Taken together with data on time trends in lead emissions in Israel, the study indicated the benefits from phasing out of leaded gasoline. More recently, a pilot study in pregnant women in Jerusalem, conducted in collaboration with the US-CDC, found widespread exposure to phthalates, organophosphate pesticides, and the carbamate bendiocarb. Creatinine-adjusted total dimethyl (DM) metabolite concentrations were between 4 and 6 times higher than populations of pregnant women in the United States. The Israel Ministry of Health is currently collaborating with the Hebrew University of Jerusalem and Al Quds University to study exposures to phthalates and organophosphates in pregnant women in Israel and the Palestinian Authority. The Israel Ministry of Health has also begun the first National Biomonitoring Study to measure exposures to bisphenol A, phthalates, organophosphates, polyaromatic hydrocarbons, the phytoestrogens genistein and daidzein, and cotinine in the Israeli adult population. This study is being carried out in collaboration with the University of Erlangen-Nuremberg in Germany. Until recently, HBM programs in Israel were targeted at selected occupational groups (workers potentially exposed to metals, volatile organic compounds (VOCs), and cholinesterase inhibitors) and naval divers potentially exposed to environmental contaminants. The future of HBM in Israel lies in extending such programs to measuring exposures in representative samples of the general population, increasing international collaboration in this field, developing analytical capacity and expertise, and increasing use of human biomonitoring studies in forming and evaluating environmental health policy. PMID- 22218108 TI - A special issue on cell signaling, disease, and stem cells. PMID- 22218110 TI - Immunolocalization of estrogen receptor alpha in Neomysis japonica oocytes and follicle cells during ovarian development. AB - Estrogen induces oocytes development and vitellogenesis in crustacean by interacting with estrogen receptor (ER) subtypes. In the present study, we detect for the first time the ERalpha in oocytes and follicle cells and hepatopancreas cells of mysis by immunohistochemistry using a specific ERalpha antibody. ERalpha was mainly localized in the nuclei of oocytes and follicle cells, while mainly detected in nuclei of oogonia (OG), previtellogenic oocyte (PR) and endogenous vitellogenic oocyte (EN) at previtellogenic and early vitellogenic stage (I-early III). Follicle cells in all stages of ovary (all vitellogenic stages) showed strong ERalpha positive reaction, and they were able to gradually move to oocytes during the development of oocytes. In addition, ERalpha was also localized in the nuclei and cytoplasm of four hepatopancreas cells (including E-, R-, F- and B cell) in all ovary stages. These findings suggest, for the first time to our knowledge, that there could be a close link between oogenesis, follicle cells, hepatopancreas cells and endocrine regulation, and estrogens might be involved in the regulation of oocytes at early ovarian stage in mysis. PMID- 22218111 TI - Cellular and molecular aspects of Goodpasture syndrome. AB - Goodpasture syndrome, a rare human autoimmune disorder, is characterized by the presence of pathogenic autoantibodies that react with the components of the glomerular basement membrane. The clinical condition of the Goodpasture syndrome is characterized by an acute necrotizing glomerulonephritis, often with accompanying pulmonary hemorrhage. Notably, the Goodpasture antigen has been localized to the noncollagenous domain of the alpha3 chain of type IV collagen. Additionally, human leukocyte antigen-DR2, and to a lesser extent human leukocyte antigen-DR4, have been identified as important restriction elements. The role of T cells in Goodpasture syndrome is indicated by the highly restricted specificity of the antibody response and the strong major histocompatibility complex class II association. In this review article, we briefly describe the latest views on the molecular and cellular themes of Goodpasture syndrome. PMID- 22218112 TI - Risk factors profile and cardiovascular events in solid organ transplant recipients. AB - By advances in surgical techniques, success in prevention and treatment of transplant-related infections, and introduction of new immunosuppressive drugs, the patient and graft survival rates in solid organ transplant recipients has steadily and remarkably improved. It has been shown that the longer the transplant patients survival rate, the more saturation with cardiovascular risk factors and the greater risk of cardiovascular mortality. Currently, cardiovascular disease is the primary cause of death after kidney transplantation and is among the three most common causes of death after heart and liver transplantation. Over the past decades, because of risk factor reduction, mortality from coronary artery disease has substantially decreased in the general population. Recent studies suggest that risk factors reduction also significantly decreases cardiovascular events and deaths in solid organ transplant recipients. PMID- 22218113 TI - Seroprevalence of human herpesvirus 8 in kidney transplant recipients in a single center study from Tunisia. AB - Human herpesvirus 8 (HHV8) is a herpesvirus that is always associated with Kaposi sarcoma. An enzyme-linked immunoenzymatic assay was used to detect antibodies to the latent nuclear antigen of HHV8 in kidney transplant patients and kidney transplant candidates from Tunisia. A significantly high HHV8 seroprevalence was documented; 17% of kidney transplant patients and 23% in kidney transplant candidates were seropositive. This is a first report of HHV8 in Tunisia. PMID- 22218114 TI - Left-sided inferior vena cava in horseshoe kidney: an unusual anomaly. PMID- 22218115 TI - Prevalence and outcome of focal segmental glomerulosclerosis in Iranian children with nephrotic syndrome. AB - INTRODUCTION: Some evidence suggest an increase in the prevalence of focal segmental glomerular sclerosis (FSGS) in children. To date, there has been no study of the outcome in children with FSGS and its frequency over several decades in Iran. We aimed to report the changing trend of FSGS incidence and its outcome in a sample of Iranian children. MATERIALS AND METHODS: Between 1982 and 2008, all 716 kidney biopsies performed in children referred to Ali Asghar Children Hospital were recorded and confirmed cases with FSGS lesions were further evaluated. Baseline and clinical characteristics of all FSGS patients were assessed and the therapies and outcomes were reviewed. RESULTS: The incidence rate of FSGS was 10.1% between 1982 and 1990, which was significantly increased to as high as 20.5% after the year 2000 (P = .001). Among 64 children with FSGS, 20 progressed to end-stage renal disease with a mean survival time of 11.45 years (standard error of mean, 1.34 years). Kidney survival rates were 90.4%, 69%, and 47% at 1, 5 and 10 years of follow-up. CONCLUSIONS: Our study demonstrates an increasing trend in FSGS incidence in Iranian children. However, kidney survival rates of our patients were similar to those reported by others in different countries. PMID- 22218116 TI - Inhibitory effect of olive leaf extract on gentamicin-induced nephrotoxicity in rats. AB - INTRODUCTION: Gentamicin sulphate nephrotoxicity seems to be attributed to the generation of reactive oxygen species. Olive leaf extract (OLE) has been demonstrated to have antioxidant and anti-inflammatory effects. The aim of this study was to evaluate the inhibitory effect of OLE on gentamicin-induced nephrotoxicity in rats. MATERIALS AND METHODS: Thirty-five Sprague-dawley rats were divided into 5 groups to receive saline; gentamicin, 100 mg/kg/d; and gentamicin plus OLE in 3 different doses (25 mg/kg/d, 50 mg/kg/d, and 100 mg/kg/d, once daily for 12 days. Serum and renal malondialdehyde were assessed, and tubular necrosis was studied semiquantitatively. Glomerular volume and volume density of the proximal convoluted tubules were estimated stereologically from paraffin sections. Serum creatinine and renal antioxidant enzymes activity were measured. RESULTS: Gentamicin significantly increased serum creatinine, malondialdehyde, and tubular necrosis, and decreased creatinine clearance, volume density of the proximal convoluted tubules, renal glutathione, glutathione peroxidase, catalase, and superoxide dismutase compared with the control group. Cotreatment of gentamicin and OLE significantly decreased serum creatinine, malondialdehyde, tubular necrosis, and renal malondialdehyde, and increased renal glutathione, catalase, superoxide dismutase, volume density of proximal convoluted tubules, and creatinine clearance in comparison with gentamicin-only treated group. Serum malondialdehyde, serum creatinine, tubular necrosis, and volume density of proximal convoluted tubules were maintained at the same level as that of the control group by cotreatment of gentamicin and OLE. CONCLUSIONS: Olive leaf extract ameliorates gentamicin nephrotoxicity via antioxidant activity, increase of renal glutathione content, and increase of renal antioxidant enzymes activity, except for glutathione peroxidase. PMID- 22218117 TI - Effect of Ramadan fasting on urinary risk factors for calculus formation. AB - INTRODUCTION: Even though dehydration could aggravate formation of urinary calculi, the effects of fluid and food restriction on calculus formation is not thoroughly defined. The purpose of this study is to evaluate the effects of fluid and food restriction in Ramadan fasting on urinary factors in kidney and urinary calculus formation. MATERIALS AND METHODS: Fifty-seven men aged 30 to 55 years old, including 37 recurrent calcium calculus formers and 20 with no history of kidney calculi were evaluated for blood tests, ultrasonography investigations, urinalysis, urine culture, and also 24-hour urine collection test. Metabolites including calcium, oxalate, citrate, uric acid, magnesium, phosphate, potassium, sodium, and creatinine were measured before and during Ramadan fasting. The values of calculus-precipitating solutes as well as inhibitory factors were documented thoroughly. RESULTS: Total excretion of calcium, phosphate, and magnesium in 24-hour urine and also urine volume during fasting were significantly lower than those in the nonfasting period. Urine concentration of calcium during fasting was significantly lower than nonfasting (P < .001). Urine concentrations of uric acid, citrate, phosphate, sodium, and potassium during fasting were significantly higher than nonfasting. Uric acid supersaturation was accentuated, and calcium phosphate supersaturation was decreased significantly during fasting. There was no significant increase in calcium oxalate supersaturation during the fasting period. CONCLUSIONS: Fasting during Ramadan has different effects on total excretion and concentrations of urinary precipitate and inhibitory factors contributing to calculus formation. We did not find enough evidence in favor of increased risks of calculus formation during Ramadan fasting. PMID- 22218118 TI - Angiotensin receptor blocker and N-acetyl cysteine for reduction of proteinuria in patients with type 2 diabetes mellitus. AB - INTRODUCTION: Proteinuria and albuminuria are established risk factors for progressive renal damage. Albuminuria can be effectively controlled by antihypertensive drugs that interrupt the renin-angiotensin-aldosterone system. However, the efficiency of N-acetyl cysteine (NAC) in preventing diabetic nephropathy is uncertain. Renoprotective effects of angiotensin receptor blockers and NAC in preventing or reducing of proteinuria in patients with diabetic nephropathy was studied. MATERIALS AND METHODS: In a randomized controlled trial, 70 patients with type 2 diabetic nephropathy (proteinuria and renal insufficiency) were studied. The patients were randomly divided into two groups and were treated with losartan, 25 mg, twice per day, with and without NAC, 600 mg twice daily (study and control groups, respectively; 35 patients in each group). Urine protein was checked before treatment and after 2 months of treatment. RESULTS: The two groups were comparable regarding gender, age, serum creatinine, and urine protein excretion levels. Proteinuria improved in both groups. The mean proteinuria level decreased more in patients with losartan and NAC; however, comparison of proteinuria between the two groups showed no significant difference after 2 months. CONCLUSIONS: Angiotensin receptor blockers reduced proteinuria due to diabetic nephropathy, and this study failed to detect additional effect when NAC was combined with these medications. PMID- 22218120 TI - Hyperlipidemia after kidney transplantation: long-term graft outcome. AB - INTRODUCTION: Metabolic complications are common after kidney transplantation and can cause considerable morbidity and even threaten graft function. This study aimed to investigate the prevalence of hyperlipidemia and its impact on graft function in 10 years of follow-up of patients undergoing kidney transplantation. MATERIALS AND METHODS: This prospective study was conducted on 73 patients who underwent kidney transplantation between April 1996 and April 1998 to evaluate their lipid profile and graft function as well as the effect of hyperlipidemia in long-term kidney allograft function. Kidney allograft dysfunction was defined as a serum creatinine level greater than 1.8 mg/dL. RESULTS: The mean serum triglyceride level was higher at 1, 3, 5, and 10 years, but not 7 years, among patients with graft dysfunction in comparison with patients with normal graft function. However, these differences were not significant. The mean serum total cholesterol level was significantly higher in patients with graft dysfunction at 1 year (P = .03). Of the patients with graft dysfunction, 94.7% developed hypercholesterolemia at the first year visit, as compared to 70.4% of patients with normal graft function (P = .03). The frequency of hypercholesterolemia was higher among those with a serum creatinine greater than 1.8 mg/dL at all other visits, but without significant difference. CONCLUSIONS: Hyperlipidemia is common after kidney transplantation, especially in the first year after transplantation. Higher serum total cholesterol levels might be related to graft dysfunction. PMID- 22218119 TI - Effect of erythropoietin on kidney allograft survival: early use after transplantation. AB - INTRODUCTION: Erythropoietin is administered for treatment of anemia in chronic kidney disease and kidney transplantation. Erythropoietin improves oxygenation of organs and prevents them against apoptosis. The aim of this study was evaluation of erythropoietin's effect on graft survival in the early phase after transplantation. MATERIALS AND METHODS: Forty kidney transplant candidates with a hemoglobin level of 8 g/dL to 10 g/dL were randomized to receive either erythropoietin (PD-Poietin) or placebo for the first posttransplant week. They were followed up for 6 months and serum creatinine levels, glomerular filtration rate (GFR), allograft rejection episodes, and graft loss were compared between the two groups. RESULTS: The mean creatinine level and GFR were 1.16 +/- 0.03 mg/mL and 85.1 +/- 18.3 mL/min in the erythropoietin group and 1.2 +/- 0.2 mg/dL and 83.3 +/- 21.1 mL/min in the control group at baseline. After 6 months of follow-up, the mean of creatinine level and GFR reached to 1.11 +/- 0.23 mg/dL and 86.6 +/- 10.3 mL/min in the erythropoietin group and 1.31 +/- 0.35 mg/dL and 79.7 +/- 12.5 mL/min in the control group, respectively (P = .04 and P = .02). None of the patients lost their grafts and no death was reported. There were no adverse effects in the erythropoietin group. CONCLUSIONS: Our findings suggest that erythropoietin may have beneficial effects on graft function if administered early after transplantation. Erythropoietin can be used for all kidney transplant recipients for protecting the allograft due to its effects on tissue oxygenation. PMID- 22218121 TI - Chemokine receptor 2-V64I and chemokine receptor 5-Delta32 polymorphisms and clinical risk factors of delayed graft function and acute rejection in kidney transplantation. AB - INTRODUCTION: Chemokines and chemokine receptors have a pivotal role in immunity and inflammation. We aimed to evaluate their role in kidney transplant rejection. MATERIALS AND METHODS: The association of chemokine (C-C motif) receptor 2 (CCR2) V64I and CCR5-Delta32 gene polymorphisms with acute rejection (AR) and delayed graft function (DGF) were examined in 100 donor-recipient pairs. The CCR2-V64I and CCR5-Delta32 alleles were determined using polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism, respectively. RESULTS: No associations were found between donors or recipients' CCR2-V64I and CCR5-Delta32 gene polymorphisms and AR or DGF. Of the characteristics of the donors, recipients, and transplantation, glomerulonephritis as a cause of kidney failure in the recipients was weakly associated with AR (relative risk, 6.1; 95% confidence interval, 0.8 to 46.0; P = .07). Transplantation of kidney from females to males was weakly associated with DGF (relative risk, 5.5; 95% confidence interval, 0.9 to 33.0; P = .06). There was a significant association between AR, but not DGF, and graft loss in the patients (relative risk, 28.6; 95% confidence interval, 1.7 to 487.0; P = .03). CONCLUSIONS: Our study failed to suggest CCR2-V64I or CCR5-Delta32 gene polymorphisms as risk factors for AR and DGF in kidney transplantation. Sex-matching between donors and recipients should be considered for living donor kidney transplantation. PMID- 22218123 TI - Multiple myeloma presenting as acute tubulointerstitial nephritis and normal serum protein electrophoresis. AB - Multiple myeloma is uncommon in individuals younger than 40 years. Renal involvement is common in this disease, but acute tubulointerstitial nephritis is very rare. In 20% of patients, only the light chain is produced and serum protein electrophoresis is normal; however, in urine protein electrophoresis of these patients, the M spike is present. We reported a case of multiple myeloma in a 39 year-old man with acute tubulointerstitial nephritis. Serum protein electrophoresis was normal and there was no bone lytic lesion. Remission of multiple myeloma was achieved after treatment with thalidomide and dexamethasone; however, kidney failure was not improved and the patient was maintained on hemodialysis. PMID- 22218122 TI - Prophylactic effect of mycophenolate mofetil on early outcomes of living donor kidney transplantation. AB - INTRODUCTION: Living donor transplantation allows a priori scheduling and the recipient can receive immunosuppressive prophylaxis several days before surgery, which is preoperative induction therapy with oral agents. We evaluated the impact of preoperative mycophenolate mofetil on the outcomes of living donor kidney transplantations. MATERIALS AND METHODS: In a randomized controlled trial was from November 2008 to November 2010, 99 patients receiving their first living donor kidney transplantation were divided into the mycophenolate mofetil (500 mg) and placebo groups, and received 2 tablets per day for 5 days before transplantation. RESULTS: Forty-nine patients received mycophenolate mofetil and 48 received placebo. The mean serum creatinine on discharge day and hospitalization period were significantly less with mycophenolate mofetil compared to placebo (1.62 +/- 1.00 mg/dL versus 1.22 +/- 0.24 mg/dL, P = 0.03 and 20.8 +/- 11.2 days versus 13.5 +/- 4.4 days, P < .001, respectively). No delayed graft function was observed. Slow graft function was 2-fold higher in the placebo group (14.6% versus 8.2%, P = .32). Acute rejection was seen in 12.2% of the patients with mycophenolate mofetil and in 29.2% of the controls (P = .04). Serum creatinine levels at discharge were significantly lower in the mycophenolate mofetil group compared with that in the placebo group (P = .03). CONCLUSIONS: Prophylactic administration of mycophenolate mofetil before living donor kidney transplantation reduced hospitalization period, improved early graft function, and decreased the risk of acute rejection in the first month posttransplant. PMID- 22218124 TI - Massive proteinuria and autosomal dominant polycystic kidney disease: a rare coincidence. AB - Autosomal dominant polycystic kidney disease (ADPKD) with nephrotic syndrome is a rare coincidence. Among 19 reported cases since 1972, focal glomerulosclerosis is the dominant reported pathology. Here, we report the 6th case of focal segmental glomerulosclerosis with ADPKD. A 29-year-old man with a history of APCDK presented with massive proteinuria. He had a history of concurrent leptospirosis and brucellosis, and trace proteinuria and mild hypertension had been diagnosed 4 years earlier. Urine study showed proteinuria (21 g/d) and hematuria. Kidney biopsy report was compatible with focal and segmental sclerosis. The patient received prednisolone and cyclosporine. After 4 months, proteinuria decreased to 600 mg/d. Patients with ADPKD who show massive proteinuria should undergo kidney biopsy. It is possible that different mutations in these patients could clarify the nature of this coincidence. PMID- 22218125 TI - Low-dose or high-dose hydrochlorothiazide in idiopathic hypercalciuria among children? Re: role of high-dose hydrochlorothiazide in idiopathic hypercalciuric urolithiasis of childhood. PMID- 22218127 TI - Evaluation of secondary glaucoma associated with subluxated lens misdiagnosed as acute primary angle-closure glaucoma. AB - PURPOSE: To evaluate the causes of misdiagnosis in patients with acute angle closure glaucoma secondary to subluxated lens, and postoperative outcomes. DESIGN: Retrospective clinical study. METHODS: Five hundred twenty-six cases of acute angle-closure glaucoma were consecutively recruited from Zhongshan Ophthalmic Center between March 2003 and March 2009. Zonular dialysis, anterior chamber angle, and anterior chamber depth were examined by ultrasound biomicroscopy. Surgical therapy was performed according to the degree of zonular dialysis and angle closure. RESULTS: Thirty-one eyes (5.89%) with acute angle closure glaucoma secondary to lens subluxation were misdiagnosed as acute primary angle-closure glaucoma. In these cases, the anterior chamber depth of the affected eyes was significantly shallower than the fellow eyes (1.34+/-0.45 vs. 2.27+/-0.44, P<0.05). The best-corrected visual acuity was significantly improved 3 months after surgery, and intraocular pressure was well controlled in all eyes. Mean intraocular pressure was 12.09+/-4.41 mm Hg without any medication at the final visit. CONCLUSIONS: The causes of misdiagnosis in patients with acute angle closure glaucoma secondary to subluxated lens include neglected history and/or signs of ocular trauma. Lens extraction surgery was an effective therapy for these cases. PMID- 22218128 TI - Longitudinal course of cognitive deficits in schizophrenia. PMID- 22218129 TI - [Anorexia nervosa: Diagnostically a labyrinth and therapeutically a riddle?]. AB - A hundred and fifty years since first described, Anorexia Nervosa continues to problematize scientists regarding its etiology and diagnosis but -primary- its treatment or prevention. The cases of patients characterized as having an "Atypical" Eating Disorder are raised and the present diagnostic criteria are faced with skepticism by many psychiatrists. The etiology of Anorexia Nervosa is considered to be so multifactorial that none of the existing theories (biological, cognitive, systemic and psychodynamic) can satisfactorily explain totally the clinical manifestations of the disorder. Social component seems to play -among others- an important role. Nevertheless, recently there is in process a remarkable effort in order to standardize a clear therapeutic plan totally adjusted in the severity of the clinical features in the course of the disorder. Some treatments seem to be more efficacious than others but generally the results in treating Anorexia Nervosa are not satisfactory. PMID- 22218130 TI - [A review of the effects of lithium on cognitive functions: Effects on the neuropsychiatrically challenged CNS]. AB - Recent data attribute neuroprotective and neurotrophic actions to lithium, leading to expectations of cognitive enhancement action. This hypothesis is at odds with the predominant view of clinical psychiatr y which, on the basis of older clinical data as well as on subjective reports of lithiumtreated patients, associates lithium with cognitive blurring and specific memory deficits. Review of the older data and their integration with more recent clinical and experimental work on the primary effects of lithium on cognitive functioning led us to two central conclusions: (a) Data on the primary cognitive effects of lithium, considered in their entirety, do not support a picture of serious or long-lasting cognitive decline. On the contrary, recent evidence suggests cognitive enhancement under certain conditions. (b) The conditions which appear to promote the emergence of cognitive enhancement under lithium are conditions of challenge to the cognitive systems, such as increased task difficulty resulting in deterioration in the performance of untreated controls. We are suggesting that alternative challenges to cognitive functioning, which therefore would facilitate the emergence of lithium's cognitive enhancement action, include biological insults to the central nervous system (CNS). This second part of our review of the cognitive effects of lithium therefore focuses on studies of its action on cognitive dysfunction associated with functional or biological challenge to the CNS, such as stress, trauma, neurodegenerative and psychiatric disorders. PMID- 22218131 TI - [Change of atmosphere in patients' family after attending rehabilitation programs]. AB - Contemporary research had confirmed the opinion that an unstable familial environment, with expressed negative affects of healthy members, contributes to negative prognosis of patients. Rehabilitation Programs can contribute to reverse this negative atmosphere in families of mentally ill patients. In own research have participated 48 patients and their carers from different settings in the Athens area. We used validated scales (Family Atmosphere Scale, Family Burden Scale and Family Rituals Scale). The measurement took place before and after the participation in the rehabilitation program. We had a 90% follow up rate. Family's climate, measured with all three scales, showed a statistically significant improvement after the end of the rehabilitation program. The burden was the same for mothers and fathers. The diagnosis and the previous therapeutic methods had an influence on the outcome. Current research verifies the positive outcome of rehabilitation programs in the overall improvement of family's atmosphere. Early or simultaneous provision of systemic therapy has a positive affect. Other variables like sex, age, education, profession, socioeconomic status, years of illness, hadn't any significant influence. PMID- 22218132 TI - [Suicide attempts in the General Hospital and warning signs]. AB - Suicide represents a major public health issue and much research is focusing on the prevention and management of suicidal behavior. The present study aims at the assessment of Warning Signs of Suicide. For this purpose, 100 patients admitted for attempted suicide in Sotiria General Hospital have been included in the study. All patients have been examined through a semi-structured psychiatric interview, the somministration of Beck Depression Inventory (BDI) and the assessment of the following Warning Signs: Internalization, Feeling gloomy, Presence of recent trauma in the patient's history, Change of behavior, Fear, Giving gifts, Depression and Aggression. The results showed that 80% of the sample presented at least two warning signs whereas only 10% of the patients had no warning signs. Moreover, a strong correlation was observed between the total score of depression as assessed with the BDI Scale and the number of Warning Signs. Warning Signs are present with a high percentage in patients who attempt suicide and many authors suggest that they should be included in suicide prevention. Therefore, it is important for all mental health clinicians to integrate the assessment of Warning Signs into their practices and to educate both patients and family members to recognize them. PMID- 22218133 TI - [Security rules in acute inpatient wards in psychiatric hospitals in the greater area of Athens]. AB - This research concerns the recording of safety measures in acute mental health wards of psychiatric hospitals in the greater area of Athens. The practices of control and testing on patients performed by nurses are also reported. The total sample consists of 14 acute inpatient psychiatric wards. The results indicated that important differences were noticed in the controls and prohibitions. Moreover, the main characteristic was the lack of protocols and measures of safety, a situation that burdened nursing practice. The lack of rules and strategies that would promote the safety of patient, professionals and therapeutic milieu, were brought into light by nurses' quotes. PMID- 22218134 TI - Development and deployment of an underway radioactive cesium monitor off the Japanese coast near Fukushima Dai-ichi. AB - A custom radiation monitoring system was developed by Oregon State University at the request of the Woods Hole Oceanographic Institute to measure radioactive cesium contaminants in the ocean waters near Fukushima Dai-ichi Nuclear Power Plant. The system was to be used on board the R/V Ka'imikai-O-Kanaloa during a 15 d research cruise to provide real-time approximations of radionuclide concentration and alert researchers to the possible occurrence of highly elevated radionuclide concentrations. A NaI(Tl) scintillation detector was coupled to a custom-built compact digital spectroscopy system and suspended within a sealed tank of continuously flowing seawater. A series of counts were acquired within an energy region corresponding to the main photopeak of (137)Cs. The system was calibrated using known quantities of radioactive (134)Cs and (137)Cs in a ratio equating to that present at the reactors' ocean outlet. The response between net count rate and concentration of (137)Cs was then used to generate temporal and geographic plots of (137)Cs concentration throughout the research cruise in Japanese coastal waters. The concentration of (137)Cs was low but detectable, reaching a peak of 3.8 +/- 0.2 Bq/L. PMID- 22218135 TI - The inactivation of phages MS2, PhiX174 and PR772 using UV and solar photocatalysis. AB - The photolytic and photocatalytic disinfection of three bacteriophages (MS2, PhiX174 and PR772) under both artificial UV irradiation and natural sunlight was studied. A large variation was seen in the relative responses of phages to the two light sources, while solar photocatalysis showed promising disinfection capabilities for all three phages. Under artificial UV, the resistance of phages to both photolytic and artificial treatment was found to decrease in the following order: PR772>PhiX174>MS2. Indeed, 3-log inactivation of PR772 was not achieved after 25 h of illumination in either the absence or presence of catalyst. Under solar treatment, PR772 was inactivated far more readily, 3-log inactivation being achieved within an hour in the presence of catalyst in two trials. It is thought that the variation in solar intensity during the trials had a major effect on disinfection rates, as kinetics for phages varied considerably under different weather conditions. PMID- 22218136 TI - Relationship between obesity and falls by middle-aged and older women. AB - It has been suggested that obesity increases fall risk, based on diminished static balance and increased fall-related injury risk. However, these findings only indirectly relate obesity and falls. The purpose of this study was to use existing data to directly explore the relationship between obesity and falls by community-dwelling women aged 55 years and older. Eighty-six subjects (42 obese) reported falls occurring during the previous year (retrospective falls), and over the following year responded to biweekly communications inquiring whether they fell or stumbled (prospective falls/stumbles). Because trips represent the largest fall cause by community-dwelling adults, we also analyzed outcomes and recovery strategies of 25 women (13 obese) after laboratory-induced trips. Obese and healthy weight women retrospectively reported similar fall rates (40.9% vs 40.5%; P=.97). Similar percentages of healthy weight and obese women prospectively fell (64.7% vs 64.3%; P=.98) and stumbled (38.9% vs 14.3%; P=.24). After laboratory-induced trips, 46.2% of obese verse 25.0% of healthy weight women fell (P=.44). Unlike healthy weight fallers, most obese fallers failed to initiate or complete the recovery step before full-body harness support. Obesity does not appear to increase overall fall risk; although, fall rates after laboratory-induced trips were notably higher, potentially due to altered recovery responses. An incomplete recovery step could increase impact force with the ground, predisposing obese individuals to injury. The fact that there is concurrence between 4 independent outcomes strengthens the findings, suggesting that further, large-scale studies are warranted to inform future clinical practice regarding fall-risk assessment for obese older adults. PMID- 22218137 TI - Sound induced vertigo: superior canal dehiscence resulting from blast exposure. AB - Barotrauma is common in modern warfare. We present the first description of sound induced vertigo caused by superior canal dehiscence (SCD) precipitated by blast exposure. Patients who complain of balance or visual changes after military or terrorist blast exposure should be evaluated for SCD. PMID- 22218138 TI - Radial nerve mobilization decreases pain sensitivity and improves motor performance in patients with thumb carpometacarpal osteoarthritis: a randomized controlled trial. AB - OBJECTIVE: To examine the effects of radial nerve mobilization on pain sensitivity and motor performance in subjects with secondary thumb carpometacarpal osteoarthritis. DESIGN: Randomized controlled trial. Treatment and placebo were given for 4 weeks. Measurements were taken before intervention, after 1 month (first follow-up), and after 2 months (second follow-up). SETTING: Patients from the Department of Physical Therapy, Azienda Sanitaria Locale 3, Collegno (Italy). PARTICIPANTS: Participants (N=60; age range, 70-90y) with right dominant hand secondary thumb carpometacarpal osteoarthritis without other motor related pathology. All patients completed the study. No patients were withdrawn from the study. INTERVENTIONS: Sliding mobilization of the proximal-distal radial nerve or intermittent ultrasound therapy, used as placebo. MAIN OUTCOME MEASURES: We hypothesized that radial nerve mobilization induces hypoalgesia and increases strength in secondary thumb carpometacarpal osteoarthritis. We measured pressure pain threshold (PPT) at the trapeziometacarpal joint, the tubercle of the scaphoid bone, and the unciform apophysis of the hamate bone by algometry. Tip pinch strength and tripod pinch strength were measured by a mechanical pinch gauge. RESULTS: Treatment increased PPT by 3.33+/-.24 kg/cm(2) (P<.001) in the trapeziometacarpal joint and was maintained until first follow-up and second follow-up. Also, PPT in the scaphoid bone and hamate bone was increased (P<.001 and P<.02, respectively). Variables in the placebo group remained unchanged. Tip pinch strength increased by 2.22+/-.22 kg (P<.04) and tripod pinch strength by 2.83+/-.24 kg (P<.019). CONCLUSIONS: Radial nerve mobilization decreases pain sensitivity in the trapeziometacarpal joint and increases tip pinch strength. PMID- 22218140 TI - Quality of nonmydriatic digital fundus photography obtained by nurse practitioners in the emergency department: the FOTO-ED study. AB - OBJECTIVE: Nonmydriatic fundus photography by non-ophthalmic-trained personnel has recently been shown to be a potential alternative to direct ophthalmoscopy in the emergency department (ED). We evaluated the reliability of a novel quality rating scale and applied this scale to nonmydriatic fundus photographs taken during routine ED patient encounters to determine factors associated with diminished photograph quality. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: We included 350 patients enrolled in the Fundus photography versus Ophthalmoscopy Trials Outcomes in the Emergency Department study who were photographed by nurse practitioners after <30 minutes of training followed by supervision. METHODS: Photographs of both eyes were graded for quality on 2 occasions by 2 neuro-ophthalmologists. Four regions were independently evaluated for quality: Optic disc, macula, and superior and inferior vascular arcades. Quality as a function of the number of photographs taken was evaluated by Kaplan Meier analysis. Mixed effects ordinal logistic regression was used to evaluate for predictors of image quality while accounting for the repeated measures design. MAIN OUTCOME MEASURES: Overall photographic quality (1-5 scale; 5 best). RESULTS: We evaluated 1734 photographs. Inter- and intraobserver agreements between neuro-ophthalmologists were very good (weighted kappa, 0.84-0.87). Quality of the optic disc area was better than those of other retinal areas (P<0.002). Kaplan-Meier analysis showed that if a high-quality photograph of an eye was not obtained by the third attempt, it was unlikely that one would be obtained at all. A 10-second increase in the interphotograph interval before a total of 40 seconds increased the odds of a 1-unit higher quality rating by 1.81 times (95% confidence interval [CI], 1.68-1.98), and a 10-year increase in age decreased the odds by 0.76 times (95% CI, 0.69-0.85). Black patients had 0.42 times (95% CI, 0.28-0.63) the odds of a 1-unit higher quality rating compared with whites. CONCLUSIONS: Our 5-point scale is a reliable measure of nonmydriatic photograph quality. The region of interest, interphotograph interval, and patient age and race are significant predictors of image quality for nonmydriatic photographs taken by nurse practitioners in the ED. Addressing these factors may have a direct impact on the successful implementation of nonmydriatic fundus photography into the ED. PMID- 22218141 TI - Ophthalmology Residency Match outcomes for 2011. AB - PURPOSE: To determine the match rate and predictors of matching into an ophthalmology residency. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: All 746 candidates who submitted an application for the 2011 ophthalmology residency match. METHODS: The Ophthalmology Residency Matching Program applicant database was reviewed to determine applicant characteristics and match outcomes. For US seniors, multivariate regression analysis was performed to determine predictors of matching. MAIN OUTCOME MEASURES: Match rate and predictors of US seniors matching. RESULTS: Rank lists were submitted by 622 applicants, among whom 458 (74%) matched. The match rate was higher for US seniors (83%) than for independent applicants (41%; P < 0.001). US seniors who matched were more likely to be Alpha Omega Alpha medical honor society members (odds ratio [OR], 2.94; 95% confidence interval [CI], 1.16-7.29), to attend medical schools ranked in the top 40 according to National Institutes of Health funding (OR, 2.25; CI, 1.14-4.43), and to have ranked more programs (OR, 1.44; CI, 1.29-1.60). Those ranking 6 to 10 programs had an 80% to 90% chance of matching, and those ranking more than 10 programs had a greater than 90% chance of matching. No clear benefit was observed by ranking additional programs once 11 had already been ranked. Average US Medical Licensing Examination Step 1 scores were 239 +/- 14 and 223 +/- 18 for applicants who were matched and unmatched, respectively; this difference was significant by univariate analysis (P < 0.001) but not by multivariate regression (P = 0.163). CONCLUSIONS: Ophthalmology ranks among the most competitive specialties in medicine. Those most likely to match were US seniors who maintained academic excellence beginning in their preclinical years. A finite relationship exists between ranking a greater number of programs and having a greater chance of matching. PMID- 22218142 TI - Vitrectomy without laser treatment or gas tamponade for macular detachment associated with an optic disc pit. AB - PURPOSE: To evaluate the clinical outcomes after vitrectomy, without gas tamponade or laser photocoagulation to the margin of the optic nerve, for the treatment of macular detachment associated with optic disc pits and to characterize retinal manifestations during treatment of optic pit maculopathy using optical coherence tomography (OCT). DESIGN: Noncomparative, retrospective, interventional case series. PARTICIPANTS: Eight consecutive patients (8 to 56 years of age) with unilateral macular detachment associated with optic disc pit. INTERVENTION: Pars plana vitrectomy with induction of a posterior vitreous detachment (PVD) was performed in all eyes. No laser or gas injection was performed in any eye during the original surgery. Patients were followed up for 10 to 46 months (mean, 26 months) after surgery. MAIN OUTCOME MEASURES: Anatomic outcome as determined by OCT and postoperative visual acuities were the main outcome parameters. Fundus autofluorescence (FAF) images were obtained in 4 eyes to document anatomic changes in the macula. RESULTS: Although complete retinal reattachment was achieved in 7 of 8 eyes, up to about 1 year was necessary for the retinal detachment to resolve fully. The 1 eye in which macular detachment failed to resolve completely underwent revision of vitrectomy with a gas tamponade and laser photocoagulation in the peripapillary area. In the early postoperative period, despite persistent macular detachment, the visual acuities improved in 7 eyes. These improved acuities corresponded with remodeling of the photoreceptor outer segments on OCT and the appearance of granular hyperfluorescence on FAF imaging. CONCLUSIONS: Vitrectomy with induction of a PVD at the optic disc without gas tamponade or laser photocoagulation seems to be an effective method of managing macular detachment resulting from optic disc pits. The OCT scanning before and after surgery suggests that peripapillary vitreous traction with the passage of fluid into the retina through the pit is the cause of the schisis-like separation seen in optic disc pit maculopathy. PMID- 22218143 TI - Risk of corneal transplant rejection significantly reduced with Descemet's membrane endothelial keratoplasty. AB - PURPOSE: To evaluate the relative risk of immunologic rejection episode in patients who underwent Descemet's membrane endothelial keratoplasty (DMEK), Descemet's stripping endothelial keratoplasty (DSEK), and penetrating keratoplasty (PK). DESIGN: Comparative case series. PARTICIPANTS: One hundred forty-one eyes treated with DMEK at Price Vision Group, Indianapolis, Indiana. METHODS: The patients in the DMEK group were compared retrospectively with cohorts of DSEK (n = 598) and PK (n = 30) patients treated at the same center, with similar demographics, follow-up duration, and indications for surgery. The postoperative steroid regimen and rejection criteria were identical in the 3 groups. Kaplan-Meier survival analysis, which takes varying length of follow-up into consideration, was performed to determine the cumulative probability of a rejection episode 1 and 2 years after surgery. Proportional hazards analysis was used to determine the relative risk of rejection episodes between the 3 groups. P<0.05 was considered significant and calculated using the log-rank test. MAIN OUTCOME MEASURES: Rejection-free survival and cumulative probability of a rejection episode. RESULTS: The mean recipient age was 66 years (56% females and 94% Caucasian) and median follow-up duration was 13 months (range, 3-40) in the DMEK group. Fuchs' dystrophy was the most common indication for surgery (n = 127; 90%) followed by pseudophakic bullous keratopathy (n = 4; 4%) and regrafts (n = 9; 6.4%). Only 1 patient (0.7%) had a documented rejection episode in the DMEK group compared with 54 (9%) in the DSEK and 5 (17%) in the PK group. The Kaplan Meier cumulative probability of a rejection episode at 1 and 2 years was 1% and 1%, respectively, for DMEK; 8% and 12%, respectively, for DSEK; and 14% and 18%, respectively, for PK. This was a highly significant difference (P = 0.004). The DMEK eyes had a 15 times lesser risk of experiencing a rejection episode than DSEK eyes (95% confidence limit [CL], 2.0-111; P = 0.008) and 20 times lower risk than PK eyes (95% CL, 2.4-166; P = 0.006). CONCLUSIONS: Patients undergoing DMEK had a significantly reduced risk of experiencing a rejection episode within 2 years after surgery compared with DSEK and PK performed for similar indications using the same corticosteroid regimen. PMID- 22218144 TI - Correlation between clinical features, magnetic resonance imaging, and histopathologic findings in retinoblastoma: a prospective study. AB - OBJECTIVE: To correlate clinical features with histopathology findings in advanced intraocular retinoblastoma and to determine the diagnostic accuracy of magnetic resonance imaging (MRI) in detecting tumor invasion. DESIGN: Prospective, nonrandomized case series. PARTICIPANTS: We included 75 patients with group E retinoblastoma. METHODS: Demographic and clinical features were recorded at presentation. Contrast-enhanced MRI was performed to study tumor characteristics and extent of invasion. Primary enucleation was performed and histopathologic features noted. Statistical analysis was done using the Kruskal Wallis test to determine correlation between clinical features and histopathology. Sensitivity, specificity, and accuracy of MRI in detecting tumor invasion were determined. MAIN OUTCOME MEASURES: Significant associations between clinical findings at presentation and high-risk histopathology, and correlation between MRI results and histopathologic evidence of tumor invasion. RESULTS: A significant association was found between iris neovascularization and choroidal invasion (P = 0.032), intraocular pressure and optic nerve invasion (P = 0.034), and shallow anterior chamber and iris invasion (P = 0.021). Corneal diameter did not show any significant correlation with high-risk histopathology. On MRI, tumor volume showed a significant association with optic nerve invasion (P = 0.023). The accuracy of MRI in detecting choroidal invasion was 68% (sensitivity, 60%; specificity, 80%). Prelaminar invasion was correctly identified in 9 out of 15 eyes (accuracy, 84%; sensitivity, 60%; specificity, 90%), whereas the accuracy of MRI in detecting postlaminar invasion was 76% (sensitivity, 61.9%; specificity, 81.5%). Ciliary body invasion was correctly identified in 5 out of 7 eyes (accuracy, 93.3%; specificity, 95.6%) and scleral invasion in 5 out of 6 eyes (accuracy, 98.7%; specificity, 100%). CONCLUSIONS: As far as we are aware, this is the first prospective study on the correlation of clinical features and MRI findings with histopathologic risk factors in eyes primarily enucleated for retinoblastoma. Neovascularization of iris, intraocular pressure, shallow anterior chamber, and tumor volume correlated well with high-risk histopathology. Because MRI has limitations in reliably predicting microscopic infiltration of the choroid and optic nerve, decision in favor of neoadjuvant chemotherapy on the basis of suspected postlaminar invasion on MRI is not justified in the absence of histopathologic evidence of disease. PMID- 22218145 TI - An outbreak of acute post-cataract surgery Pseudomonas sp. endophthalmitis caused by contaminated hydrophilic intraocular lens solution. AB - OBJECTIVE: To report the investigation for the source of infection and the clinical course and treatment response of 11 cases of acute post-cataract surgery endophthalmitis that developed during an outbreak. DESIGN: Retrospective, consecutive, interventional case series. PARTICIPANTS: Eleven patients who developed acute postoperative endophthalmitis after an uneventful cataract surgery with intraocular lens implantation from September 6 to 29, 2010, at a tertiary eye care center in South India. METHODS: Aqueous aspirates, vitreous aspirates, and environmental surveillance specimens were sampled. All specimens were subjected to smear and culture. Positive cultures were subjected to antibiotic susceptibility. Genotypic diversity was determined by polymerase chain reaction (PCR) with enterobacterial repetitive intergenic consensus (ERIC) primers of each strain and was used to establish the clonal relationship between clinical and environmental isolates. The clinical patterns were analyzed. MAIN OUTCOME MEASURES: Positive microbiology, molecular diagnostic similarity among the culture positive endophthalmitis cases, and surveillance specimens. RESULTS: Aqueous and vitreous samples showed gram-negative bacilli in the smears of 8 of 11 eyes, and cultures grew Pseudomonas aeruginosa in 5 of 11 eyes. Among the samples from various surveillance specimens cultured, only the hydrophilic acrylic intraocular lenses and their solution grew P. aeruginosa, with antibiotic susceptibility pattern identical to the clinical isolates. The isolates from the patients and the intraocular lens solution revealed matching patterns similar to an American Type Culture Collection (ATCC) strain of P. aeruginosa on ERIC-PCR. The intraocular lenses of the same make were discontinued at our hospital, and the endophthalmitis did not recur. The final visual acuity improved to >= 20/50 in 8 of 11 patients (72.7%). One patient developed retinal detachment, but was treated successfully, and 2 other patients progressed to phthisis bulbi. CONCLUSIONS: Positive microbiology and the ERIC-PCR results proved that contamination of hydrophilic intraocular lenses and the preservative solution was the source of infection in this outbreak. Early detection and a planned approach during the outbreak helped us to achieve good visual and anatomic outcomes, even though the offending organism was identified as P. aeruginosa. PMID- 22218146 TI - Trends in use of ancillary glaucoma tests for patients with open-angle glaucoma from 2001 to 2009. AB - PURPOSE: To assess trends in the use of ancillary diagnostic tests in the evaluation of patients with open-angle glaucoma (OAG) and glaucoma suspects over the past decade. DESIGN: Retrospective, longitudinal cohort analysis. PARTICIPANTS: A total of 169 917 individuals with OAG and 395 721 individuals with suspected glaucoma aged >=40 years enrolled in a national United States managed care network between 2001 and 2009. METHODS: Claims data were analyzed to assess trends in visual field (VF) testing, fundus photography (FP), and other ocular imaging (OOI) testing for patients with OAG or suspected glaucoma between 2001 and 2009. Repeated-measures logistic regression was performed to identify differences in the odds of undergoing these procedures in 2001, 2005, and 2009 and whether differences exist for patients under the exclusive care of optometrists versus ophthalmologists. MAIN OUTCOME MEASURES: Odds and annual probabilities of undergoing VF testing, FP, and OOI for OAG from 2001 to 2009. RESULTS: For patients with OAG, the odds of undergoing VF testing decreased by 36% from 2001 to 2005, by 12% from 2005 to 2009, and by 44% from 2001 to 2009. By comparison, the odds of having OOI increased by 100% from 2001 to 2005, by 24% from 2005 to 2009, and by 147% from 2001 to 2009. Probabilities of undergoing FP were relatively low (13%-25%) for both provider types and remained fairly steady over the decade. For patients cared for exclusively by optometrists, the probability of VF testing decreased from 66% in 2001 to 44% in 2009. Among those seen exclusively by ophthalmologists, the probability of VF testing decreased from 65% in 2001 to 51% in 2009. The probability of undergoing OOI increased from 26% in 2001 to 47% in 2009 for patients of optometrists and from 30% in 2001 to 46% in 2009 for patients of ophthalmologists. By 2008, patients with OAG receiving care exclusively by optometrists had a higher probability of undergoing OOI than VF testing. CONCLUSIONS: From 2001 to 2009, OOI increased dramatically whereas VF testing declined considerably. Because OOI has not been shown to be as effective at detecting OAG or disease progression compared with VF testing, increased reliance on OOI technology, in lieu of VF testing, may be detrimental to patient care. PMID- 22218148 TI - Combined reduced fluence photodynamic therapy and intravitreal ranibizumab for polypoidal choroidal vasculopathy. AB - PURPOSE: We performed a prospective noncomparative study to report the results of reduced fluence photodynamic therapy (PDT) combined with intravitreal ranibizumab in patients with polypoidal choroidal vasculopathy with active exudation and hemorrhage. METHODS: Seventeen polypoidal choroidal vasculopathy eyes were treated, and follow-up for all patients was 12 months. Photodynamic therapy was administered with reduced fluence (exposure time of 70'') and followed (48 hours later) by intravitreal ranibizumab (0.5 mg in 50 MUL). Intravitreal ranibizumab, with or without reduced fluence PDT, was repeated as indicated by clinical and angiographic findings. RESULTS: During the follow-up, the mean best-corrected visual acuity significantly improved from 0.45 +/- 0.29 logarithm of the minimum angle of resolution at baseline to 0.29 +/- 0.28 logarithm of the minimum angle of resolution at 12 months. The mean total macular volume (documented by optical coherence tomography retinal map examination) decreased from 7.5 +/- 1.18 mm to 6.7 +/- 0.8 mm. In 95% of the cases, best-corrected visual acuity remained stable or improved. CONCLUSION: Reduced fluence PDT limits laser exposure, minimizing the risks of PDT-induced adverse effects. Intravitreal injections of ranibizumab 0.5 mg reduced bleeding and leakage in polypoidal choroidal vasculopathy eyes and interfere with rebound upregulation of vascular endothelial growth factor because of PDT-induced choroidal hypoperfusion. Combined treatment may improve treatment outcomes in polypoidal choroidal vasculopathy while minimizing ocular and systemic complications of treatment. PMID- 22218147 TI - Comparison of a new refractive multifocal intraocular lens with an inferior segmental near add and a diffractive multifocal intraocular lens. AB - PURPOSE: To compare the visual acuity outcomes and ocular optical performance of eyes implanted with a multifocal refractive intraocular lens (IOL) with an inferior segmental near add or a diffractive multifocal IOL. DESIGN: Prospective, comparative, nonrandomized, consecutive case series. PARTICIPANTS: Eighty-three consecutive eyes of 45 patients (age range, 36-82 years) with cataract were divided into 2 groups: group A, 45 eyes implanted with Lentis Mplus LS-312 (Oculentis GmbH, Berlin, Germany); group B, 38 eyes implanted with diffractive IOL Acri.Lisa 366D (Zeiss, Oberkochen, Germany). METHODS: All patients underwent phacoemulsification followed by IOL implantation in the capsular bag. Distance corrected, intermediate, and near with the distance correction visual acuity outcomes and contrast sensitivity, intraocular aberrations, and defocus curve were evaluated postoperatively during a 3-month follow-up. MAIN OUTCOME MEASURES: Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), uncorrected near visual acuity (UNVA), corrected distance near and intermediate visual acuity (CDNVA), contrast sensitivity, intraocular aberrations, and defocus curve. RESULTS: A significant improvement in UDVA, CDVA, and UNVA was observed in both groups after surgery (P <= 0.04). Significantly better values of UNVA (P<0.01) and CDNVA (P<0.04) were found in group B. In the defocus curve, significantly better visual acuities were present in eyes in group A for intermediate vision levels of defocus (P <= 0.04). Significantly higher amounts of postoperative intraocular primary coma and spherical aberrations were found in group A (P<0.01). In addition, significantly better values were observed in photopic contrast sensitivity for high spatial frequencies in group A (P <= 0.04). CONCLUSIONS: The Lentis Mplus LS-312 and Acri.Lisa 366D IOLs are able to successfully restore visual function after cataract surgery. The Lentis Mplus LS 312 provided better intermediate vision and contrast sensitivity outcomes than the Acri.Lisa 366D. However, the Acri.Lisa design provided better distance and near visual outcomes and intraocular optical performance parameters. PMID- 22218149 TI - Hyperautofluorescent ring in autoimmune retinopathy. AB - PURPOSE: To report the presence of a hyperautofluorescent ring and corresponding spectral-domain optical coherence tomography (SD-OCT) features seen in patients with autoimmune retinopathy. METHODS: All eyes were evaluated by funduscopic examination, full-field electroretinography, fundus autofluorescence, and SD-OCT. Further confirmation of the diagnosis was obtained with immunoblot and immunohistochemistry testing of the patient's serum. Humphrey visual fields and microperimetry were also performed. RESULTS: Funduscopic examination showed atrophic retinal pigment epithelium (RPE) associated with retinal artery narrowing but without pigment deposits. The scotopic and photopic full-field electroretinograms were nondetectable in three patients and showed a cone-rod pattern of dysfunction in one patient. Fundus autofluorescence revealed a hyperautofluorescent ring in the parafoveal region, and the corresponding SD-OCT demonstrated loss of the photoreceptor inner segment-outer segment junction with thinning of the outer nuclear layer from the region of the hyperautofluorescent ring toward the retinal periphery. The retinal layers were generally intact within the hyperautofluorescent ring, although the inner segment-outer segment junction was disrupted, and the outer nuclear layer and photoreceptor outer segment layer were thinned. CONCLUSION: This case series revealed the structure of the hyperautofluorescent ring in autoimmune retinopathy using SD-OCT. Fundus autofluorescence and SD-OCT may aid in the diagnosis of autoimmune retinopathy and may serve as a tool to monitor its progression. PMID- 22218150 TI - Acquired vitelliform lesion associated with large drusen. AB - PURPOSE: The purpose of this study was to describe the association of acquired vitelliform lesion (AVL) and large drusen in patients with non-neovascular age related macular degeneration. METHODS: A retrospective review of clinical examination and multimodal imaging data of patients with AVL and large drusen seen over a 12-month period was performed. Acquired vitelliform lesion was defined as subretinal accretion of hyperautofluorescent yellowish material within the macular region not due to vitelliform macular dystrophy. Large drusen were diagnosed by the presence of mounded deposits in the subretinal pigment epithelial space between the retinal pigment epithelium and the Bruch membrane using multimodal imaging analysis (color photography, autofluorescence, and spectral domain optical coherence tomography). RESULTS: Thirteen eyes of 9 white patients with a mean age of 74 years were observed to have AVL associated with large drusen. The median visual acuity was 20/60. All AVLs were hyperautofluorescent and were located in the subretinal space between the retinal pigment epithelium and the photoreceptor inner segment/outer segment junction. The AVL in this series had similar color, autofluorescence, and optical coherence tomographic findings as the AVL seen in association with cuticular drusen and subretinal drusenoid deposits. CONCLUSION: Acquired vitelliform lesions, which have previously been related to cuticular drusen and subretinal drusenoid deposits, can occur in association with large drusen. Abnormalities leading to drusen formation or processes that function in parallel to these may be causative in AVL formation. PMID- 22218152 TI - Inactivating PTP1B upon ER stress. PMID- 22218151 TI - Delayed lymph node metastases after elective neck dissection in patients with oral and oropharyngeal cancer and pN0 neck. AB - PURPOSE: Patients with surgically treated head and neck cancer and clinical N0 neck with high risk of occult lymph node metastasis undergo elective neck dissection (ND). Late lymph node metastasis may appear in those patients with pN0 neck. The aim of the present study was to analyze the incidence and clinical relevance of late lymph node metastasis in patients with head and neck cancer. MATERIALS AND METHODS: The clinical data of 61 patients with head and neck cancer who had undergone elective ND with pN0 neck were retrospectively analyzed. Only patients without local failure, second primary, or radiochemotherapy were included in the study. RESULTS: Late lymph node metastasis could be observed in 4 (6.5%) cases at the margin or outside the initially dissected lymph node levels. In those patients, the primary tumor was localized in the oral cavity (n = 3) or oropharynx (n = 1) and was classified in all cases as T1 or T2. Lymph node metastasis could be found in levels I (n = 2), II (n = 1), and IV (n = 1), respectively. CONCLUSION: Even in the case of pN0 neck after an elective ND, the appearance of late lymph node metastases must be expected. The low proportion of patients with late lymph node metastases after a selective ND in clinical and histologic N0 does not justify an extended form of neck surgery. PMID- 22218153 TI - Associations between n-3 PUFA concentrations and cognitive function after recovery from late-life depression. AB - BACKGROUND: Lower concentrations of n-3 PUFAs have been reported to be associated with cognitive impairment and dementia, but also with depression-itself a potential risk factor for cognitive decline. OBJECTIVE: The aims of this study were to investigate associations between n-3 PUFA concentrations in erythrocyte membrane or plasma and cognitive function in an at-risk sample of older people with previous major depression and to explore specificity with respect to cognitive domains. DESIGN: A cross-sectional sample of 132 eligible participants who had recovered from major depression (mean +/- SD age: 67.8 +/- 6.6 y) were enrolled from outpatient psychiatric services. A series of cognitive tests and a structured questionnaire were administered. Fasting blood samples were collected for n-3 PUFA measurements. RESULTS: Higher EPA and total n-3 PUFA concentrations and a lower ratio of arachidonic acid to EPA in erythrocyte membranes were associated with a higher cognitive composite score: independent of age and sex, but no longer significant after adjustment for education. No associations were found with plasma concentrations of any fatty acid. Considering individual cognitive tests, the strongest and most consistent correlations were found between immediate recall and concentrations of total n-3 PUFAs and alpha linolenic acid (ALA) in erythrocytes, which were observed only in participants with recurrent depression. CONCLUSIONS: Total erythrocyte n-3 PUFA concentrations are positively associated with cognitive function, particularly immediate recall, in older people with previous depression. Lower concentrations of n-3 PUFAs or ALA in erythrocyte membranes may be good predictors for cognitive impairment in older people with previous recurrent depression. PMID- 22218155 TI - Magnesium for cardiovascular health: time for intervention. PMID- 22218154 TI - Less frequent eating predicts greater BMI and waist circumference in female adolescents. AB - BACKGROUND: Little is known about the effect of eating frequency on adiposity. OBJECTIVE: The study aim was to assess the prospective relation of an objective measure of eating frequency with adiposity in girls from ages 9-10 to 19-20 y. DESIGN: By using data from 3-d diet records collected from 2372 girls in the National Heart, Lung, and Blood Institute Growth and Health Study, meal, snack, and total eating frequencies aggregated over the first 2 study years were examined in relation to 10-y change in BMI and waist circumference (WC). RESULTS: Eating frequency was lower in black and older girls than in white and younger girls (P < 0.0001). In whites, lower initial snack and total eating frequencies were related to greater 10-y increases in BMI (P = 0.023 and 0.012, respectively) and WC (P = 0.030 and 0.015, respectively). In blacks, lower initial meal and snack frequencies were related to greater increases in BMI (P = 0.004 and 0.022, respectively) and WC (P = 0.052 and 0.005, respectively). Also, in blacks, lower initial total eating frequency was related to greater increases in WC (P = 0.010). After adjustment for baseline adiposity measure, race, parental education, physical activity, television and video viewing, total energy intake, and dieting for weight loss, lower initial total eating frequency remained related to greater 10-y increases in BMI (P = 0.013) and WC (P = 0.036). CONCLUSIONS: A lower eating frequency predicts a greater gain in adiposity in adolescent females. Intervention trials are needed to test if changing the frequency of eating can affect obesity risk. PMID- 22218156 TI - Fish-oil supplementation enhances the effects of strength training in elderly women. AB - BACKGROUND: Muscle force and functional capacity generally decrease with aging in the older population, although this effect can be reversed, attenuated, or both through strength training. Fish oil (FO), which is rich in n-3 (omega-3) PUFAs, has been shown to play a role in the plasma membrane and cell function of muscles, which may enhance the benefits of training. The effect of strength training and FO supplementation on the neuromuscular system of the elderly has not been investigated. OBJECTIVE: The objective was to investigate the chronic effect of FO supplementation and strength training on the neuromuscular system (muscle strength and functional capacity) of older women. DESIGN: Forty-five women (aged 64 +/- 1.4 y) were randomly assigned to 3 groups. One group performed strength training only (ST group) for 90 d, whereas the others performed the same strength-training program and received FO supplementation (2 g/d) for 90 d (ST90 group) or for 150 d (ST150 group; supplemented 60 d before training). Muscle strength and functional capacity were assessed before and after the training period. RESULTS: No differences in the pretraining period were found between groups for any of the variables. The peak torque and rate of torque development for all muscles (knee flexor and extensor, plantar and dorsiflexor) increased from pre- to posttraining in all groups. However, the effect was greater in the ST90 and ST150 groups than in the ST group. The activation level and electromechanical delay of the muscles changed from pre- to posttraining only for the ST90 and ST150 groups. Chair-rising performance in the FO groups was higher than in the ST group. CONCLUSIONS: Strength training increased muscle strength in elderly women. The inclusion of FO supplementation caused greater improvements in muscle strength and functional capacity. PMID- 22218157 TI - Dietary intake of folate and alcohol, MTHFR C677T polymorphism, and colorectal cancer risk in Korea. AB - BACKGROUND: The incidence of colorectal cancer (CRC) is increasing sharply in Korea, and evidence has suggested the role of dietary methyl supply and related polymorphisms on colorectal carcinogenesis. OBJECTIVE: We investigated the association between folate and alcohol intake, methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, and CRC risk in Koreans. DESIGN: A total of 787 cases and 656 controls were recruited from 2 university hospitals. Multiple logistic regression models were used to estimate ORs and corresponding 95% CIs. RESULTS: MTHFR 677T homozygotes were at a lower risk of CRC (OR: 0.60; 95% CI: 0.46, 0.78 for TT compared with CC/CT). High folate intake was associated with reduced CRC risk (OR: 0.64; 95% CI: 0.49, 0.84 for high compared with low intake), and high alcohol consumption was associated with increased risk of CRC (OR: 1.76; 95% CI: 1.26, 2.46 for high compared with low intake). When data were stratified by the amount of dietary methyl (combined intake of folate and alcohol), those with low-methyl diets had higher risk of CRC (OR: 2.32; 95% CI: 1.18, 4.56) than did those with high-methyl diets among CC/CT carriers, whereas the amount of dietary methyl did not affect the CRC risk among carriers with the TT homozygous variant. This association was stronger in patients with colon cancer than in patients with rectal cancer. CONCLUSION: We found that the effect of dietary methyl supply on colorectal carcinogenesis may differ according to MTHFR C677T genotype and the subsite of origin in a Korean population. PMID- 22218158 TI - A prospective study of prepregnancy dietary fat intake and risk of gestational diabetes. AB - BACKGROUND: Fatty acids play a vital role in glucose homeostasis; however, studies on habitual dietary fat intakes and gestational diabetes mellitus (GDM) risk are limited and provide conflicting findings. OBJECTIVE: We determined whether the total amount and the type and source of prepregnancy dietary fats are related to risk of GDM. DESIGN: A prospective study was conducted in 13,475 women who reported a singleton pregnancy between 1991 and 2001 in the Nurses' Health Study II. In these women, 860 incident GDM cases were reported. The adjusted RR of GDM was estimated for quintiles of total fat, specific fat, and the source of fat intakes by pooled logistic regression. RESULTS: Higher animal fat and cholesterol intakes were significantly associated with increased GDM risk. Across increasing quintiles of animal fat, RRs (95% CIs) for GDM were 1.00 (reference), 1.55 (1.20, 1.98), 1.43 (1.09, 1.88), 1.40 (1.04, 1.89), and 1.88 (1.36, 2.60) (P trend = 0.05). Corresponding RRs (95% CIs) for dietary cholesterol were 1.00 (reference), 1.08 (0.84, 1.32), 1.02 (0.78, 1.29), 1.20 (0.93, 1.55), and 1.45 (1.11, 1.89) (P-trend = 0.04). The substitution of 5% of energy from animal fat for an equal percentage of energy from carbohydrates was associated with significantly increased risk of GDM [RR (95% CI): 1.13 (1.08, 1.18); P < 0.0001]. No significant associations were observed between dietary polyunsaturated fat, monounsaturated fat, or trans fat intakes and GDM risk. CONCLUSION: Higher prepregnancy intakes of animal fat and cholesterol were associated with elevated GDM risk. PMID- 22218159 TI - Amount of time spent in sedentary behaviors and cause-specific mortality in US adults. AB - BACKGROUND: Sedentary behaviors predominate modern life, yet we do not fully understand the adverse effects of these behaviors on mortality after considering the benefits of moderate-vigorous physical activity (MVPA). OBJECTIVE: We tested the hypotheses that higher amounts of overall sitting time and television viewing are positively associated with mortality and described the independent and combined effects of these sedentary behaviors and MVPA on mortality. DESIGN: In the NIH-AARP Diet and Health Study, we examined 240,819 adults (aged 50-71 y) who did not report any cancer, cardiovascular disease, or respiratory disease at baseline. Mortality was ascertained over 8.5 y. RESULTS: Sedentary behaviors were positively associated with mortality after adjustment for age, sex, education, smoking, diet, race, and MVPA. Participants who reported the most television viewing (>=7 h compared with <1 h/d) were at greater risk of all-cause (HR: 1.61; 95% CI: 1.47, 1.76), cardiovascular (HR: 1.85; 95% CI: 1.56, 2.20), and cancer (HR: 1.22; 95% CI: 1.06, 1.40) mortality after adjustment for MVPA. Overall sitting was associated with all-cause mortality. Even among adults reporting high levels of MVPA (>7 h/wk), high amounts of television viewing (>=7 h/d) remained associated with increased risk of all-cause (HR: 1.47; 95% CI: 1.20, 1.79) and cardiovascular (HR: 2.00; 95% CI: 1.33, 3.00) mortality compared with those reporting the least television viewing (<1 h/d). CONCLUSIONS: Time spent in sedentary behaviors was positively associated with mortality, and participation in high levels of MVPA did not fully mitigate health risks associated with prolonged time watching television. Adults should be encouraged to reduce time spent in sedentary behaviors, when possible, and to participate in MVPA at recommended levels. The NIH-AARP Diet and Health Study was registered at clinicaltrials.gov as NCT00340015. PMID- 22218160 TI - Increased intake of oily fish in pregnancy: effects on neonatal immune responses and on clinical outcomes in infants at 6 mo. AB - BACKGROUND: Long-chain n-3 PUFAs found in oily fish may have a role in lowering the risk of allergic disease. OBJECTIVE: The objective was to assess whether an increased intake of oily fish in pregnancy modifies neonatal immune responses and early markers of atopy. DESIGN: Women (n = 123) were randomly assigned to continue their habitual diet, which was low in oily fish, or to consume 2 portions of salmon per week (providing 3.45 g EPA plus DHA) from 20 wk gestation until delivery. In umbilical cord blood samples (n = 101), we measured n-3 fatty acids, IgE concentrations, and immunologic responses. Infants were clinically evaluated at age 6 mo (n = 86). RESULTS: Cord blood mononuclear cell (CBMC) production of interleukin (IL)-2, IL-4, IL-5, IL-10, and tumor necrosis factor alpha in response to phytohemagglutinin (PHA) and of IL-2 in response to Dermatophagoides pteronyssinus allergen 1 (Derp1) was lower in the salmon group (all P <= 0.03). In the subgroup of CBMCs in which an allergic phenotype was confirmed in the mother or father, IL-10 production in response to Toll-like receptor 2, 3, and 4 agonists, ovalbumin, salmon parvalbumin, or Derp1 and prostaglandin E(2) production in response to lipopolysaccharide or PHA was lower in the salmon group (all P <= 0.045). Total IgE at birth and total IgE, incidence and severity of atopic dermatitis, and skin-prick-test positivity at 6 mo of age were not different between the 2 groups. CONCLUSION: Oily fish intervention in pregnancy modifies neonatal immune responses but may not affect markers of infant atopy assessed at 6 mo of age. This trial is registered at clinicaltrials.gov as NCT00801502. PMID- 22218161 TI - Alcohol consumption and the risk of colon cancer by family history of colorectal cancer. AB - BACKGROUND: Individuals with a family history of colorectal cancer may be more susceptible to adverse effects of alcohol consumption. OBJECTIVE: We investigated whether the association between alcohol consumption and colon cancer risk differed by family history of colorectal cancer. DESIGN: We conducted prospective studies in women and men in the Nurses' Health Study and Health Professionals Follow-Up Study, respectively. Alcohol consumption was first assessed in 1980 in women and in 1986 in men. RESULTS: During a follow-up of 26 y among 87,861 women and 20 y among 47,290 men, we documented 1801 cases of colon cancer (1094 women and 707 men). Higher alcohol consumption was associated with an elevated risk of colon cancer, although the association was significant only for the highest intake category of >=30 g/d, with no significant linear trend. The association between alcohol consumption and colon cancer risk differed by family history of colorectal cancer; in comparison with nondrinkers, the pooled multivariate RRs for alcohol consumption of >=30 g/d were 1.23 (95% CI: 0.96, 1.57; NS) among those with no family history and 2.02 (95% CI: 1.30, 3.13) among those with a family history of colorectal cancer (P value test for difference = 0.05). In comparison with nondrinkers with no family history, the RR for colon cancer was 2.80 (95% CI: 2.00, 3.91) for individuals who consumed >=30 g/d and who had a family history of colorectal cancer. CONCLUSION: Reducing alcohol consumption may decrease the incidence of colon cancer, especially among those with a family history of colorectal cancer. PMID- 22218163 TI - Mycobacterium tuberculosis--heterogeneity revealed through whole genome sequencing. AB - The emergence of whole genome sequencing (WGS) technologies as primary research tools has allowed for the detection of genetic diversity in Mycobacterium tuberculosis (Mtb) with unprecedented resolution. WGS has been used to address a broad range of topics, including the dynamics of evolution, transmission and treatment. Here, we have analyzed 55 publically available genomes to reconstruct the phylogeny of Mtb, and we have addressed complications that arise during the analysis of publically available WGS data. Additionally, we have reviewed the application of WGS to the study of Mtb and discuss those areas still to be addressed, moving from global (phylogeography), to local (transmission chains and circulating strain diversity), to the single patient (clonal heterogeneity) and to the bacterium itself (evolutionary studies). Finally, we discuss the current WGS approaches, their strengths and limitations. PMID- 22218162 TI - Flavonoid intake and cardiovascular disease mortality in a prospective cohort of US adults. AB - BACKGROUND: Flavonoids are plant-based phytochemicals with cardiovascular protective properties. Few studies have comprehensively examined flavonoid classes in relation to cardiovascular disease mortality. OBJECTIVE: We examined the association between flavonoid intake and cardiovascular disease (CVD) mortality among participants in a large, prospective US cohort. DESIGN: In 1999, a total of 38,180 men and 60,289 women in the Cancer Prevention Study II Nutrition Cohort with a mean age of 70 and 69 y, respectively, completed questionnaires on medical history and lifestyle behaviors, including a 152-item food-frequency questionnaire. Cox proportional hazards modeling was used to calculate multivariate-adjusted hazard RRs and 95% CIs for associations between total flavonoids, 7 flavonoid classes, and CVD mortality. RESULTS: During 7 y of follow-up, 1589 CVD deaths in men and 1182 CVD deaths in women occurred. Men and women with total flavonoid intakes in the top (compared with the bottom) quintile had a lower risk of fatal CVD (RR: 0.82; 95% CI: 0.73, 0.92; P-trend = 0.01). Five flavonoid classes-anthocyanidins, flavan-3-ols, flavones, flavonols, and proanthocyanidins-were individually associated with lower risk of fatal CVD (all P-trend < 0.05). In men, total flavonoid intakes were more strongly associated with stroke mortality (RR: 0.63; 95% CI: 0.44, 0.89; P-trend = 0.04) than with ischemic heart disease (RR: 0.90; 95% CI: 0.72, 1.13). Many associations appeared to be nonlinear, with lower risk at intakes above the referent category. CONCLUSIONS: Flavonoid consumption was associated with lower risk of death from CVD. Most inverse associations appeared with intermediate intakes, suggesting that even relatively small amounts of flavonoid-rich foods may be beneficial. PMID- 22218164 TI - Paradoxical cardiovascular effects of implementing adaptive emotion regulation strategies in generalized anxiety disorder. AB - Recent models of generalized anxiety disorder (GAD) have expanded on Borkovec's avoidance theory by delineating emotion regulation deficits associated with the excessive worry characteristic of this disorder (see Behar, DiMarco, Hekler, Mohlman, & Staples, 2009). However, it has been difficult to determine whether emotion regulation is simply a useful heuristic for the avoidant properties of worry or an important extension to conceptualizations of GAD. Some of this difficulty may arise from a focus on purported maladaptive regulation strategies, which may be confounded with symptomatic distress components of the disorder (such as worry). We examined the implementation of adaptive regulation strategies by participants with and without a diagnosis of GAD while watching emotion eliciting film clips. In a between-subjects design, participants were randomly assigned to accept, reappraise, or were not given specific regulation instructions. Implementation of adaptive regulation strategies produced differential effects in the physiological (but not subjective) domain across diagnostic groups. Whereas participants with GAD demonstrated lower cardiac flexibility when implementing adaptive regulation strategies than when not given specific instructions on how to regulate, healthy controls showed the opposite pattern, suggesting they benefited from the use of adaptive regulation strategies. We discuss the implications of these findings for the delineation of emotion regulation deficits in psychopathology. PMID- 22218165 TI - Monolayers of polyethilenimine on flat glass: a versatile platform for cations coordination and nanoparticles grafting in the preparation of antibacterial surfaces. AB - A polyethylenimine (PEI) self-assembled monolayer (SAM) is prepared, capable of complexing silver and copper cations and of anchoring silver nanoparticles, exerting antibacterial activity against Escherichia coli and Staphylococcus aureus. Functionalized glassy surfaces have been fully characterized through spectroscopic techniques (UV-Vis spectroscopy, spectroscopic ellipsometry), atomic force microscopy imaging and quantitative Ag and Cu analysis (ICP optical emission spectroscopy). PMID- 22218168 TI - Development of environmental thresholds for streams in agricultural watersheds. AB - Global increases in consumption of chemical nutrients, application of pesticides, and water withdrawal to enhance agricultural yield have resulted in degraded water quality and reduced water availability. Efforts to safeguard or improve environmental conditions of agroecosystems have usually focused on managing on farm activities to reduce materials loss and conserve habitat. Another management measure for improving environmental quality is adoption of environmental performance standards (also called outcome-based standards). This special collection of six papers presents the results of four years of research to devise scientifically credible approaches for setting environmental performance standards to protect water quantity and quality in Canadian agriculturally dominated watersheds. The research, conducted as part of Canada's National Agri Environmental Standards Initiative, aimed to identify Ideal Performance Standards (the desired environmental state needed to maintain ecosystem health) and Achievable Performance Standards (the environmental conditions achievable using currently available and recommended best available processes and technologies). Overviews of the papers, gaps in knowledge, and future research directions are presented. As humans, livestock, and wildlife (both terrestrial and aquatic) experience greater pressures to share the same limited water resources, innovative research is needed that incorporates a landscape perspective, economics, farm practices, and ecology to advance the development and application of tools for protecting water resources in agricultural watersheds. PMID- 22218169 TI - Development of environmental thresholds for nitrogen and phosphorus in streams. AB - Inputs of nutrients (P and N) to freshwaters can cause excessive aquatic plant growth, depletion of oxygen, and deleterious changes in diversity of aquatic fauna. As part of a "National Agri-Environmental Standards Initiative," the Government of Canada committed to developing environmental thresholds for nutrients to protect ecological condition of agricultural streams. Analysis of data from >200 long-term monitoring stations across Canada and detailed ecological study at ~70 sites showed that agricultural land cover was associated with increased nutrient concentrations in streams and this, in turn, was associated with increased sestonic and benthic algal abundance, loss of sensitive benthic macroinvertebrate taxa, and an increase in benthic diatom taxa indicative of eutrophication. Chemical thresholds for N and P were defined by applying five approaches, employing either a predetermined percentile to a water chemistry data set or a relationship between water chemistry and land cover, to identify boundaries between minimally disturbed and impaired conditions. Comparison of these chemical thresholds with biological thresholds (derived from stressor response relationships) produced an approach for rationalizing these two types of thresholds and deriving nutrient criteria. The resulting criteria were 0.01 to 0.03 mg L(-1) total P and 0.87-1.2 mg L(-1) total N for the Atlantic Maritime, 0.02 mg L(-1) total P and 0.21 mg L(-1) total N for the Montane Cordillera, ~0.03 mg L(-1) total P and ~1.1 mg L(-1) total N for the Mixedwood Plains, and ~0.10 mg L(-1) total P and 0.39-0.98 mg L(-1) total N for the interior prairies of Canada. Adoption of these criteria should result in greater likelihood of good ecological condition with respect to benthic algal abundance, diatom composition, and macroinvertebrate composition. PMID- 22218170 TI - Investigation of an Escherichia coli environmental benchmark for waterborne pathogens in agricultural watersheds in Canada. AB - Canada's National Agri-Environmental Standards Initiative sought to develop an environmental benchmark for low-level waterborne pathogen occurrence in agricultural watersheds. A field study collected 902 water samples from 27 sites in four intensive agricultural watersheds across Canada from 2005 to 2007. Four of the sites were selected as reference sites away from livestock and human fecal pollution sources in each watershed. Water samples were analyzed for Campylobacter spp., Salmonella spp., Escherichia coli O157:H7, Cryptosporidium spp., Giardia spp., and the water quality indicator E. coli. The annual mean number of pathogen species was higher at agricultural sites (1.54 +/- 0.07 species per water sample) than at reference sites (0.75 +/- 0.14 species per water sample). The annual mean concentration of E. coli was also higher at agricultural sites (491 +/- 96 colony-forming units [cfu] 100 mL(-1)) than at reference sites (53 +/- 18 cfu 100 mL(-1)). The feasibility of adopting existing E. coli water quality guideline values as an environmental benchmark was assessed, but waterborne pathogens were detected at agricultural sites in 80% of water samples with low E. coli concentrations (<100 cfu 100 mL(-1)). Instead, an approach was developed based on using the natural background occurrence of pathogens at reference sites in agricultural watersheds to derive provisional environmental benchmarks for pathogens at agricultural sites. The environmental benchmarks that were derived were found to represent E. coli values lower than geometric mean values typically found in recreational water quality guidelines. Additional research is needed to investigate environmental benchmarks for waterborne pathogens within the context of the "One World, One Health" perspective for protecting human, domestic animal, and wildlife health. PMID- 22218171 TI - Physical and ecological thresholds for deposited sediments in streams in agricultural landscapes. AB - Excessive sedimentation in streams and rivers remains a pervasive problem for the protection of aquatic habitat and the sustainability of aquatic communities. Whereas water quality criteria have been determined for suspended sediments in many jurisdictions across North America, comparably little has been done for deposited (also known as bedded) sediments. Through Canada's National Agri Environmental Standards Initiative, assessment techniques and analytical tools were developed for estimating environmental thresholds for deposited sediments in agricultural watersheds in New Brunswick (NB) and Prince Edward Island (PEI) in the Atlantic Maritimes of Canada. Physical thresholds were developed through assessment of geomorphic metrics, which were then analyzed using y-intercept and 25th percentile approaches. For NB, there was strong agreement in physical thresholds for both analytical approaches (e.g., percent fines <2 mm were 7.5 for y-intercept and 6.9 for 25th percentile approaches). In contrast, physical thresholds for PEI differed considerably between approaches (e.g., percent fines <2 mm were 6.1 for y-intercept and 19.6 for 25th percentile approaches), likely due to a narrower range in agricultural land cover. Cross-calibration of our provisional physical thresholds for NB with ecological (i.e., benthic macroinvertebrate) assessments show that ecological thresholds, calculated as change-points in relationships between Ephemeroptera-Plecoptera-Trichoptera relative abundance or Modified Family Biotic Index and geomorphic criteria, were more liberal than physical thresholds. These results suggest that provisional thresholds developed using geomorphic criteria should demarcate change from the least disturbed condition and reduce the risk of sedimentation degrading benthic ecosystems. PMID- 22218172 TI - Establishing standards and assessment criteria for ecological instream flow needs in agricultural regions of Canada. AB - Agricultural land use can place heavy demands on regional water resources, strongly influencing the quantity and timing of water flows needed to sustain natural ecosystems. The effects of agricultural practices on streamflow conditions are multifaceted, as they also contribute to the severity of impacts arising from other stressors within the river ecosystem. Thus, river scientists need to determine the quantity of water required to sustain important aquatic ecosystem components and ecological services, to support wise apportionment of water for agricultural use. It is now apparent that arbitrarily defined minimum flows are inadequate for this task because the complex habitat requirements of the biota, which underpin the structure and function of a river ecosystem, are strongly influenced by predictable temporal variations in flow. We present an alternative framework for establishing a first-level, regional ecological instream flow needs standard based on adoption of the Indicators of Hydrologic Alteration/Range of Variability Approach as a broadly applicable hydrological assessment tool, coupling this to the Canadian Ecological Flow Index which assesses ecological responses to hydrological alteration. By explicitly incorporating a new field-based ecological assessment tool for small agricultural streams, we provide a necessary verification of altered hydrology that is broadly applicable within Canada and essential to ensure the continuous feedback between the application of flow management criteria and ecological condition. PMID- 22218173 TI - A hydrological modeling framework for defining achievable performance standards for pesticides. AB - This paper proposes a hydrological modeling framework to define achievable performance standards (APSs) for pesticides that could be attained after implementation of recommended management actions, agricultural practices, and available technologies (i.e., beneficial management practices [BMPs]). An integrated hydrological modeling system, Gestion Integree des Bassins versants a l'aide d'un Systeme Informatise, was used to quantify APSs for six Canadian watersheds for eight pesticides: atrazine, carbofuran, dicamba, glyphosate, MCPB, MCPA, metolachlor, and 2,4-D. Outputs from simulation runs to predict pesticide concentration under current conditions and in response to implementation of two types of beneficial management practices (reduced pesticide application rate and 1- to 10-m-wide edge-of-field and/or riparian buffer strips, implemented singly or in combination) showed that APS values for scenarios with BMPs were less than those for current conditions. Moreover, APS values at the outlet of watersheds were usually less than ecological thresholds of good condition, when available. Upstream river reaches were at greater risk of having concentrations above a given ecological thresholds because of limited stream flows and overland loads of pesticides. Our integrated approach of "hydrological modeling-APS estimation ecotoxicological significance" provides the most effective interpretation possible, for management and education purposes, of the potential biological impact of predicted pesticide concentrations in rivers. PMID- 22218174 TI - Using the soil and water assessment tool to estimate achievable water quality targets through implementation of beneficial management practices in an agricultural watershed. AB - Runoff from crop production in agricultural watersheds can cause widespread soil loss and degradation of surface water quality. Beneficial management practices (BMPs) for soil conservation are often implemented as remedial measures because BMPs can reduce soil erosion and improve water quality. However, the efficacy of BMPs may be unknown because it can be affected by many factors, such as farming practices, land-use, soil type, topography, and climatic conditions. As such, it is difficult to estimate the impacts of BMPs on water quality through field experiments alone. In this research, the Soil and Water Assessment Tool was used to estimate achievable performance targets of water quality indicators (sediment and soluble P loadings) after implementation of combinations of selected BMPs in the Black Brook Watershed in northwestern New Brunswick, Canada. Four commonly used BMPs (flow diversion terraces [FDTs], fertilizer reductions, tillage methods, and crop rotations), were considered individually and in different combinations. At the watershed level, the best achievable sediment loading was 1.9 t ha(-1) yr(-1) (89% reduction compared with default scenario), with a BMP combination of crop rotation, FDT, and no-till. The best achievable soluble P loading was 0.5 kg ha(-1) yr(-1) (62% reduction), with a BMP combination of crop rotation and FDT and fertilizer reduction. Targets estimated through nonpoint source water quality modeling can be used to evaluate BMP implementation initiatives and provide milestones for the rehabilitation of streams and rivers in agricultural regions. PMID- 22218175 TI - Dairy farm methane emissions using a dispersion model. AB - There is a need to know whole-farm methane (CH(4)) emissions since confined animal facilities such as beef cattle feedlots and dairy farms are emission "hot spots" in the landscape. However, measurements of whole-farm CH(4) emissions can differ between farms because of differences in contributing sources such as manure handling, number of lactating and nonlactating cows, and diet. Such differences may limit the usefulness of whole-farm emissions for national inventories and mitigation purposes unless the variance between farms is taken into account or a large number of farms can be examined. Our study describes the application of a dispersion model used in conjunction with field measurements of CH(4) concentration and stability of the air to calculate whole-farm emissions of CH(4) from three dairy farms in Alberta, Canada, during three sequential campaigns conducted in November 2004 and May and July 2005. The dairy farms ranged in herd size from 208 to 351 cows (102 to 196 lactating cows) and had different manure handling operations. The results indicate that the average CH(4) emission per cow (mixture of lactating and nonlactating) from the three dairy farms was 336 g d(-1), which was reduced to 271 g d(-1) when the emission (estimated) from the manure storage was removed. Further separation of source strength yielded an average CH(4) (enteric) emission of 363 g d(-1) for a lactating cow. The estimated CH(4) emission intensities were approximately 15 g CH(4) kg(-1) dry matter intake and 16.7 L CH(4) L(-1) of milk produced. The approach of understanding the farm-to-farm differences in CH(4) emissions as affected by diet, animal type, and manure management is essential when utilizing whole-farm emission measurements for mitigation and inventory applications. PMID- 22218176 TI - In vitro methane removal by volcanic pumice soil biofilter columns over one year. AB - Soil methane (CH(4)) biofilters, containing CH(4)-oxidizing bacteria (methanotrophs), are a promising technology for mitigating greenhouse gas emissions. However, little is known about long-term biofilter performance. In this study, volcanic pumice topsoils (0-10 cm) and subsoils (10-50 cm) were tested for their ability to oxidize a range of CH(4) fluxes over 1 yr. The soils were sampled from an 8-yr-old and a 2-yr-old grassed landfill cover and from a nearby undisturbed pasture away from the influence of CH(4) generated by the decomposing refuse. Methane was passed through the soils in laboratory chambers with fluxes ranging from 0.5 g to 24 g CH(4) m(-3) h(-1). All topsoils efficiently oxidized CH(4). The undisturbed pasture topsoil exhibited the highest removal efficiency (24 g CH(4) m(-3) h(-1)), indicating rapid activation of the methanotroph population to the high CH(4) fluxes. The subsoils were less efficient at oxidizing CH(4) than the topsoils, achieving a maximum rate oxidation rate of 7 g CH(4) m(-3) h(-1). The topsoils exhibited higher porosities; moisture contents; surface areas; and total C, N, and available-P concentrations than the subsoils, suggesting that these characteristics strongly influence growth and activity of the CH(4)-oxidizing bacteria. Soil pH values and available-P levels gradually declined during the trial, indicating a need to monitor chemical parameters closely so that adjustments can be made when necessary. However, other key soil physicochemical parameters (moisture, total C, total N) increased over the course of the trial. This study showed that the selected topsoils were capable of continually sustaining high CH(4) removal rates over 1 yr, which is encouraging for the development of biofilters as a low maintenance greenhouse gas mitigation technology. PMID- 22218177 TI - Effects of cattle slurry acidification on ammonia and methane evolution during storage. AB - Slurry acidification before storage is known to reduce NH(3) emissions, but recent observations have indicated that CH(4) emissions are also reduced. We investigated the evolution of CH(4) from fresh and aged cattle slurry during 3 mo of storage as influenced by pH adjustment to 5.5 with sulfuric acid. In a third storage experiment, cattle slurry acidified with commercial equipment on two farms was incubated. In the manipulation experiments, effects of acid and sulfate were distinguished by adding hydrochloric acid and potassium sulfate separately or in combination, rather than sulfuric acid. In one experiment sulfur was also added to slurry as the amino acid methionine in separate treatments. In each treatment 20-kg portions of slurry (n = 4) were stored for 95 d. All samples were subsampled nine to 10 times for determination of NH(3) and CH(4) evolution rates using a 2-L flow-through system. In all experiments, the pH of acidified cattle slurry increased gradually to between 6.5 and 7. Acidification of slurry reduced the evolution of CH(4) by 67 to 87%. The greatest reduction was observed with aged cattle slurry, which had a much higher potential for CH(4) production than fresh slurry. Sulfate and methionine amendment to cattle slurry without pH adjustment also significantly inhibited methanogenesis, probably as a result of sulfide production. The study suggests that complex microbial interactions involving sulfur transformations and pH determine the potential for CH(4) emission during storage of cattle slurry, and that slurry acidification may be a cost-effective greenhouse gas mitigation option. PMID- 22218178 TI - Nitrous oxide emission from riparian buffers in relation to vegetation and flood frequency. AB - The nitrate (NO(3)(-)) removal capacity of riparian zones is well documented, but information is lacking with regard to N(2)O emission from riparian ecosystems and factors controlling temporal dynamics of this potent greenhouse gas. We monitored N(2)O fluxes (static chambers) and measured denitrification (C(2)H(2) block using soil cores) at six riparian sites along a fourth-order stretch of the White River (Indiana, USA) to assess the effect of flood regime, vegetation type, and forest maturity on these processes. The study sites included shrub/grass, aggrading (<15 yr-old), and mature (>80 yr) forests that were flooded either frequently (more than four to six times per year), occasionally (two to three times per year), or rarely (every 20 yr). While the effect of forest maturity and vegetation type (0.52 and 0.65 mg N(2)O-m(-2) d(-1) in adjacent grassed and forested sites) was not significant, analysis of variance (ANOVA) revealed a significant effect ( < 0.01) of flood regime on N(2)O emission. Among the mature forests, mean N(2)O flux was in this order: rarely flooded (0.33) < occasionally flooded (0.99) < frequently flooded (1.72). Large pulses of N(2)O emission (up to 80 mg N(2)O-m( 2) d(-1)) occurred after flood events, but the magnitude of the flux enhancement varied with flood event, being higher after short-duration than after long duration floods. This pattern was consistent with the inverse relationship between soil moisture and mole fraction of N(2)O, and instances of N(2)O uptake near the river margin after flood events. These results highlight the complexity of N(2)O dynamics in riparian zones and suggest that detailed flood analysis (frequency and duration) is required to determine the contribution of riparian ecosystems to regional N(2)O budget. PMID- 22218179 TI - Inputs and losses by surface runoff and subsurface leaching for pastures managed by continuous or rotational stocking. AB - Pasture management practices can affect forage quality and production, animal health and production, and surface and groundwater quality. In a 5-yr study conducted at the North Appalachian Experimental Watershed near Coshocton, Ohio, we compared the effects of two contrasting grazing methods on surface and subsurface water quantity and quality. Four pastures, each including a small, instrumented watershed (0.51-1.09 ha) for surface runoff measurements and a developed spring for subsurface flow collection, received 112 kg N ha(-1) yr(-1) and were grazed at similar stocking rates (1.8-1.9 cows ha(-1)). Two pastures were continuously stocked; two were subdivided so that they were grazed with frequent rotational stocking (5-6 times weekly). In the preceding 5 yr, these pastures received 112 kg N ha(-1) yr(-1) after several years of 0 N fertilizer and were grazed with weekly rotational stocking. Surface runoff losses of N were minimal. During these two periods, some years had precipitation up to 50% greater than the long-term average, which increased subsurface flow and NO(3)-N transport. Average annual NO(3)-N transported in subsurface flow from the four watersheds during the two 5-yr periods ranged from 11.3 to 22.7 kg N ha(-1), which was similar to or less than the mineral-N received in precipitation. Flow and transport variations were greater among seasons than among watersheds. Flow weighted seasonal NO(3)-N concentrations in subsurface flow did not exceed 7 mg L(-1). Variations in NO(3)-N leached from pastures were primarily due to variable precipitation rather than the effects of continuous, weekly rotational, or frequent rotational stocking practices. This suggests that there was no difference among these grazing practices in terms of NO(3)-N leaching. PMID- 22218180 TI - Biosolids and distillery effluent amendment to Irish Miscanthus *giganteus plantations: impacts on groundwater and soil. AB - It is necessary to determine the risk of water pollution arising from amendment of organic by-products (OBs) to energy crops under Irish conditions. Therefore, the impact of landspreading two OBs on the quality of groundwater underlying plantations of Miscanthus X giganteus was assessed. Municipal biosolids and distillery effluent (DE) were spread annually (for 4 yr) on six 0.117-ha treatment plots at rates of 100, 50, and 0%. The 100% rate represented a maximum P load of 15 t ha(-1) as per Irish EPA regulation. Groundwater was sampled for 25 mo and tested for pH, electrical conductivity, NO(3)(-), orthophosphate (PO(4)(3 )), total soluble P, K(+), Cu, Cd, Cr, Pb, Ni, and Zn. Assessment of quality was based on comparison with Irish groundwater threshold values (GTVs). The study was limited to within-plot using a "well bottom" approach and did not investigate movement of groundwater plumes or vectors of percolation through the soil profile. Mean groundwater concentrations did not exceed GTVs during the sampling period for any species, with the exception of groundwater PO(4)(3-) in the 100% DE plot, which was almost double the GTV of 0.035 mg L(-1). There was no significant build-up of nutrients or heavy metals in groundwater (or soil) for any plot. Excessive PO(4)(3-) in the 100% DE plot groundwater is likely due to high background soil P, soil characteristics, and the occurrence of macropore/soil pore flow. These factors (particularly background soil P) should be assessed when determining suitable sites for land-spreading OBs. PMID- 22218181 TI - Biochar pyrolyzed at two temperatures affects Escherichia coli transport through a sandy soil. AB - The incorporation of biochar into soils has been proposed as a means to sequester carbon from the atmosphere. An added environmental benefit is that biochar has also been shown to increase soil retention of nutrients, heavy metals, and pesticides. The goal of this study was to evaluate whether biochar amendments affect the transport of Escherichia coli through a water-saturated soil. We looked at the transport of three E. coli isolates through 10-cm columns packed with a fine sandy soil amended with 2 or 10% (w/w) poultry litter biochar pyrolyzed at 350 or 700 degrees C. For all three isolates, mixing the high temperature biochar at a rate of 2% into the soil had no impact on transport behavior. When added at a rate of 10%, a reduction of five orders of magnitude in the amount of E. coli transported through the soil was observed for two of the isolates, and a 60% reduction was observed for the third isolate. Mixing the low temperature biochar into the soil resulted in enhanced transport through the soil for two of the isolates, whereas no significant differences in transport behavior were observed between the low-temperature and high-temperature biochar amendments for one isolate. Our results show that the addition of biochar can affect the retention and transport behavior of E. coli and that biochar application rate, biochar pyrolysis temperature, and bacterial surface characteristics were important factors determining the transport of E. coli through our test soil. PMID- 22218182 TI - Phytoextraction of heavy metals by willows growing in biosolids under field conditions. AB - Biosolids produced by sewage treatment facilities can exceed guideline thresholds for contaminant elements. Phytoextraction is one technique with the potential to reduce these elements allowing reuse of the biosolids as a soil amendment. In this field trial, cuttings of seven species/cultivars of Salix(willows) were planted directly into soil and into biosolids to identify their suitability for decontaminating biosolids. Trees were irrigated and harvested each year for three consecutive years. Harvested biomass was weighed and analyzed for the contaminant elements: As, Cd, Cu, Cr, Hg, Pb, Ni, and Zn. All Salix cultivars, except S. chilensis, growing in soils produced 10 to 20 t ha(-1) of biomass, whereas most Salix cultivars growing in biosolids produced significantly less biomass (<6 t ha(-1)). Salix matsudana (30 t ha(-1)) and S. * reichardtii A. Kerner (18 t ha( 1)) had similar aboveground biomass production in both soil and biosolids. These were also the most successful cultivars in extracting metals from biosolids, driven by superior biomass increases and not high tissue concentrations. The willows were effectual in extracting the most soluble/exchangeable metals (Cd, 0.18; Ni, 0.40; and Zn, 11.66 kg ha(-1)), whereas Cr and Cu were extracted to a lesser degree (0.02 and 0.11 kg ha(-1)). Low bioavailable elements, As, Hg, and Pb, were not detectable in any of the aboveground biomass of the willows. PMID- 22218183 TI - Strontium isotope study of coal utilization by-products interacting with environmental waters. AB - Sequential leaching experiments on coal utilization by-products (CUB) were coupled with chemical and strontium (Sr) isotopic analyses to better understand the influence of coal type and combustion processes on CUB properties and the release of elements during interaction with environmental waters during disposal. Class C fly ash tended to release the highest quantity of minor and trace elements-including alkaline earth elements, sodium, chromium, copper, manganese, lead, titanium, and zinc-during sequential extraction, with bottom ash yielding the lowest. Strontium isotope ratios ((87)Sr/(86)Sr) in bulk-CUB samples (total dissolution of CUB) are generally higher in class F ash than in class C ash. Bulk CUB ratios appear to be controlled by the geologic source of the mineral matter in the feed coal, and by Sr added during desulfurization treatments. Leachates of the CUB generally have Sr isotope ratios that are different than the bulk value, demonstrating that Sr was not isotopically homogenized during combustion. Variations in the Sr isotopic composition of CUB leachates were correlated with mobility of several major and trace elements; the data suggest that arsenic and lead are held in phases that contain the more radiogenic (high-(87)Sr/(86)Sr) component. A changing Sr isotope ratio of CUB-interacting waters in a disposal environment could forecast the release of certain strongly bound elements of environmental concern. This study lays the groundwork for the application of Sr isotopes as an environmental tracer for CUB-water interaction. PMID- 22218184 TI - Groundwater and surface-water exchange and resulting nitrate dynamics in the Bogue Phalia basin in northwestern Mississippi. AB - During April 2007 through September 2008, the USGS collected hydrogeologic and water-quality data from a site on the Bogue Phalia to evaluate the role of groundwater and surface-water interaction on the transport of nitrate to the shallow sand and gravel aquifer underlying the Mississippi Alluvial Plain in northwestern Mississippi. A two-dimensional groundwater/surface-water exchange model was developed using temperature and head data and VS2DH, a variably saturated flow and energy transport model. Results from this model showed that groundwater/surface-water exchange at the site occurred regularly and recharge was laterally extensive into the alluvial aquifer. Nitrate was consistently reported in surface-water samples (n = 52, median concentration = 39.8 MUmol/L) although never detected in samples collected from in-stream piezometers or shallow monitoring wells adjacent to the stream (n = 46). These two facts, consistent detections of nitrate in surface water and no detections of nitrate in groundwater, coupled with model results that indicate large amounts of surface water moving through an anoxic streambed, support the case for denitrification and nitrate loss through the streambed. PMID- 22218185 TI - Role of soil sorption and microbial degradation on dissipation of mesotrione in plant-available soil water. AB - Mesotrione is a carotenoid biosynthesis-inhibiting herbicide labeled for pre emergence and postemergence weed control in corn production. Understanding the factors that influence the dissipation of mesotrione in soil and in the plant available water (PAW) is important for the environmental fate assessment and optimal weed management practices. The present research investigated the role of soil properties and microbial activities on the interrelated sorption and degradation processes of mesotrione in four soils by direct measurements of PAW. We found that mesotrione bound to the soils time dependently, with approximately 14 d to reach equilibrium. The 24-h batch-slurry equilibrium experiments provided the sorption partition coefficient ranging from 0.26 to 3.53 L kg(-1), depending on soil organic carbon and pH. The dissipation of mesotrione in the soil-bound phase was primarily attributed to desorption to the PAW. Degradation in the PAW was rapid and primarily dependent on microbial actions, with half-degradation time (DT(50)) <3 d in all four soils tested. The rapid degradation in the PAW became rate limited by sorption as more available molecules were depleted in the soil pore water, resulting in a more slowed overall process for the total soil water system (DT(50) <26 d). The dissipation of mesotrione in the PAW was due to microbial metabolism and time-dependent sorption to the soils. A coupled kinetics model calibrated with the data from the laboratory centrifugation technique provided an effective approach to investigate the interrelated processes of sorption and degradation in realistic soil moisture conditions. PMID- 22218186 TI - Sorption of 17beta-estradiol to pig slurry separates and soil in the soil-slurry environment. AB - Contamination of freshwater by estrogens from manure applied to agricultural land is of grave concern because of the potentially harmful effects on aquatic life and human health. Recent developments in liquid manure (slurry) management include partial removal of particulate slurry dry matter (PSDM) by separation technologies, which may also remove parts of the estrogens and enhance infiltration of the slurry on field application and hence the interaction between estrogens and the soil matrix. This study investigated how 17beta-estradiol (E2), a natural estrogen commonly found in pig manure, sorbs to agricultural soils, to different size fractions of pig slurry separates, and to soils amended with each size fraction to simulate conditions in the soil-slurry environment. A crude fiber fraction (SS1) was prepared by sieving (<500 MUm) the solids removed by an on-farm separation process. Three other size fractions (SS2 > SS3 > SS4) were prepared from the liquid fraction of the separated slurry by sedimentation and centrifugation. Sorption experiments were conducted in 0.01 mol L(-1) CaCl(2) and in natural pig urine matrix. Sorption in 0.01 mol L(-1) CaCl(2) was higher than that in pig urine for all solids used. Sorption of E2 to soil increased with its organic carbon content for both liquid phases. The solid-liquid partition coefficients of slurry separates were 10 to 30 times higher than those of soils, but the organoic carbon normalized partition coefficient values, reflecting sorption per unit organic carbon, were lower for slurry separates. Mixing slurry separates with soil increased the sorption of E2 to the solid phase significantly in the order: SS1 < SS3 < SS2 for both liquid phases. In contrast, SS4 reduced the sorption of E2 to the solid phase by increasing the sorption to suspended or dissolved organic matter. The study suggested that potentially 50 to 75% of E2 in slurry can be removed from the liquid fraction of slurry by physical separation. PMID- 22218187 TI - H(+)/phenanthrene symporter and aquaglyceroporin are implicated in phenanthrene uptake by wheat (Triticum aestivum L.) roots. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous organic pollutants that are toxic to human and nonhuman organisms. Dietary intake of PAHs is a dominant route of exposure for the general population because food crops are a major source of dietary PAHs. The mechanism for crop root uptake of PAHs remains unclear. Here we reveal that wheat root uptake of PAHs involves active and passive processes. The passive uptake is mercury and glycerol dependent. Mercury and glycerol inhibit uptake, indicating that aquaglyceroporins sensitive to mercury contribute to passive uptake. Active uptake is mediated by a phenanthrene/H symporter. The electrical response of wheat roots triggered by phenanthrene consists of two sequential phases: depolarization followed by repolarization. The depolarization is phenanthrene concentration dependent, with saturation kinetics that have an apparent of K(m) 10.8 MUmol L(-1). As uptake proceeds, external solution pH increase is noticed. Lower pH favors the uptake. Vanadate and 2,4-dinitrophenol suppress the electrical response to phenanthrene and phenanthrene uptake, suggesting that plasma membrane H(+)-ATPase is involved in the establishment of an electrochemical proton gradient acting as a driving force for active uptake. Therefore, it is suggested that aquaglyceroporin and phenanthrene/H symporter are implicated in phenanthrene uptake. Our results provide insight into PAH uptake mechanism in wheat roots that is relevant to strategies for reducing PAH accumulation in wheat for food safety, improving phytoremediation of PAH-contaminated soils or water by agronomic practices and genetic modification to target remedial plants for higher PAH uptake capacity. PMID- 22218188 TI - Lidar quantification of bank erosion in Blue Earth County, Minnesota. AB - Sediment and phosphorus (P) transport from the Minnesota River Basin to Lake Pepin on the upper Mississippi River has garnered much attention in recent years. However, there is lack of data on the extent of sediment and P contributions from riverbanks vis-a-vis uplands and ravines. Using two light detection and ranging (lidar) data sets taken in 2005 and 2009, a study was undertaken to quantify sediment and associated P losses from riverbanks in Blue Earth County, Minnesota. Volume change in river valleys as a result of bank erosion amounted to 1.71 million m over 4 yr. Volume change closely followed the trend: the Blue Earth River > the Minnesota River at the county's northern edge > the Le Sueur River > the Maple River > the Watonwan River > the Big Cobb River > Perch Creek > Little Cobb River. Using fine sediment content (silt + clay) and bulk density of 37 bank samples representing three parent materials, we estimate bank erosion contributions of 48 to 79% of the measured total suspended solids at the mouth of the Blue Earth and the Le Sueur rivers. Corresponding soluble P and total P contributions ranged from 0.13 to 0.20% and 40 to 49%, respectively. Although tall banks (>3 m high) accounted for 33% of the total length and 63% of the total area, they accounted for 75% of the volume change in river valleys. We conclude that multitemporal lidar data sets are useful in estimating bank erosion and associated P contributions over large scales, and for riverbanks that are not readily accessible for conventional surveying equipment. PMID- 22218189 TI - Barium as a potential indicator of phosphorus in agricultural runoff. AB - In many catchments, anthropogenic input of contaminants, and in particular phosphorus (P), into surface water is a mixture of agricultural and sewage runoff. Knowledge about the relative contribution from each of these sources is vital for mitigation of major environmental problems such as eutrophication. In this study, we investigated whether the distribution of trace elements in surface waters can be used to trace the contamination source. Water from three groups of streams was investigated: streams influenced only by agricultural runoff, streams influenced mainly by sewage runoff, and reference streams. Samples were collected at different flow regimes and times of year and analyzed for 62 elements using ICP-MS. Our results show that there are significant differences between the anthropogenic sources affecting the streams in terms of total element composition and individual elements, indicating that the method has the potential to trace anthropogenic impact on surface waters. The elements that show significant differences between sources are strontium (p < 0.001), calcium (p < 0.004), potassium (p < 0.001), magnesium (p < 0.001), boron (p < 0.001), rhodium (p = 0.001), and barium (p < 0.001). According to this study, barium shows the greatest potential as a tracer for an individual source of anthropogenic input to surface waters. We observed a strong relationship between barium and total P in the investigated samples (R(2) = 0.78), which could potentially be used to apportion anthropogenic sources of P and thereby facilitate targeting of mitigation practices. PMID- 22218190 TI - Evaluation of simulated strategies for reducing nitrate-nitrogen losses through subsurface drainage systems. AB - The nitrates (NO(3)-N) lost through subsurface drainage in the Midwest often exceed concentrations that cause deleterious effects on the receiving streams and lead to hypoxic conditions in the northern Gulf of Mexico. The use of drainage and water quality models along with observed data analysis may provide new insight into the water and nutrient balance in drained agricultural lands and enable evaluation of appropriate measures for reducing NO(3)-N losses. DRAINMOD NII, a carbon (C) and nitrogen (N) simulation model, was field tested for the high organic matter Drummer soil in Indiana and used to predict the effects of fertilizer application rate and drainage water management (DWM) on NO-N losses through subsurface drainage. The model was calibrated and validated for continuous corn (Zea mays L.) (CC) and corn-soybean [Glycine max (L.) Merr.] (CS) rotation treatments separately using 7 yr of drain flow and NO(3)-N concentration data. Among the treatments, the Nash-Sutcliffe efficiency of the monthly NO(3)-N loss predictions ranged from 0.30 to 0.86, and the percent error varied from -19 to 9%. The medians of the observed and predicted monthly NO(3)-N losses were not significantly different. When the fertilizer application rate was reduced ~20%, the predicted NO(3)-N losses in drain flow from the CC treatments was reduced 17% (95% confidence interval [CI], 11-25), while losses from the CS treatment were reduced by 10% (95% CI, 1-15). With DWM, the predicted average annual drain flow was reduced by about 56% (95% CI, 49-67), while the average annual NO(3)-N losses through drain flow were reduced by about 46% (95% CI, 32-57) for both tested crop rotations. However, the simulated NO(3)-N losses in surface runoff increased by about 3 to 4 kg ha(-1) with DWM. For the simulated conditions at the study site, implementing DWM along with reduced fertilizer application rates would be the best strategy to achieve the highest NO(3)-N loss reductions to surface water. The suggested best strategies would reduce the NO(3)-N losses to surface water by 38% (95% CI, 29-46) for the CC treatments and by 32% (95% CI, 23-40) for the CS treatments. PMID- 22218191 TI - Water and nutrient transport on a heavy clay soil in a fluvial plain in the Netherlands. AB - In flat areas, transport of dissolved nutrients by water through the soil matrix to groundwater and drains is assumed to be the dominant pathway for nutrient losses to ground- and surface waters. However, long-term data on the losses of nutrients to surface water and the contribution of various pathways is limited. We studied nutrient losses and pathways on a heavy clay soil in a fluvial plain in The Netherlands during a 5-yr period. Average annual nitrogen (N) and phosphorus (P) losses to surface water were 15.1 and 3.0 kg ha(-1) yr(-1), respectively. Losses were dominated by particulate N (50%) and P (70%) forms. Rapid discharge through trenches was the dominant pathway (60-90%) for water and nutrient transport. The contribution of pipe drains to the total discharge of water and nutrients was strongly related to the length of the dry period in the preceding summer. This relationship can be explained by the very low conductivity of the soil matrix and the formation of shrinkage cracks during summer. Losses of dissolved reactive P through pipe drains appear to be dominated by preferential flow based on the low dissolved reactive P concentration in the soil matrix at this depth. Rainfall occurring after manure application played an important role with respect to the annual losses of N and P in spring when heavy rainfall occurred within 2 wk after manure application. PMID- 22218193 TI - Propagation of uncertainties in soil and pesticide properties to pesticide leaching. AB - In the new Dutch decision tree for the evaluation of pesticide leaching to groundwater, spatially distributed soil data are used by the GeoPEARL model to calculate the 90th percentile of the spatial cumulative distribution function of the leaching concentration in the area of potential usage (SP90). Until now it was not known to what extent uncertainties in soil and pesticide properties propagate to spatially aggregated parameters like the SP90. A study was performed to quantify the uncertainties in soil and pesticide properties and to analyze their contribution to the uncertainty in SP90. First, uncertainties in the soil and pesticide properties were quantified. Next, a regular grid sample of points covering the whole of the agricultural area in the Netherlands was randomly selected. At the grid nodes, realizations from the probability distributions of the uncertain inputs were generated and used as input to a Monte Carlo uncertainty propagation analysis. The analysis showed that the uncertainty concerning the SP90 is 10 times smaller than the uncertainty about the leaching concentration at individual point locations. The parameters that contribute most to the uncertainty about the SP90 are, however, the same as the parameters that contribute most to uncertainty about the leaching concentration at individual point locations (e.g., the transformation half-life in soil and the coefficient of sorption on organic matter). Taking uncertainties in soil and pesticide properties into account further leads to a systematic increase of the predicted SP90. The important implication for pesticide regulation is that the leaching concentration is systematically underestimated when these uncertainties are ignored. PMID- 22218192 TI - Spatial and temporal drivers of zoonotic pathogen contamination of an agricultural watershed. AB - In regions where animal agriculture is prominent, such as southern Alberta, higher rates of gastrointestinal illness have been reported when compared with nonagricultural regions. This difference in the rate of illness is thought to be a result of increased zoonotic pathogen exposure through environmental sources such as water. In this study, temporal and spatial factors associated with bacterial pathogen contamination of the Oldman River, which transverses this region, were analyzed using classification and regression tree analysis. Significantly higher levels of fecal indicators; more frequent isolations of Campylobacter spp., Escherichia coli O157:H7, and Salmonella enterica spp.; and higher rates of detection of pig-specific Bacteroides markers occurred at downstream sites than at upstream sites, suggesting additive stream inputs. Fecal indicator densities were also significantly higher when any one of these three bacterial pathogens was present and where there were higher total animal manure units; however, occasionally pathogens were present when fecal indicator levels were low or undetectable. Overall, Salmonella spp., Campylobacter spp., and E. coli O157:H7 presence was associated with season, animal manure units, and total rainfall on the day of sampling and 3 d in advance of sampling. Several of the environmental variables analyzed in this study appear to influence pathogen prevalence and therefore may be useful in predicting water quality and safety and in the improvement of watershed management practices in this and other agricultural regions. PMID- 22218194 TI - Links among nitrification, nitrifier communities, and edaphic properties in contrasting soils receiving dairy slurry. AB - Soil biotic and abiotic factors strongly influence nitrogen (N) availability and increases in nitrification rates associated with the application of manure. In this study, we examine the effects of edaphic properties and a dairy (Bos taurus) slurry amendment on N availability, nitrification rates and nitrifier communities. Soils of variable texture and clay mineralogy were collected from six USDA-ARS research sites and incubated for 28 d with and without dairy slurry applied at a rate of ~300 kg N ha(-1). Periodically, subsamples were removed for analyses of 2 M KCl extractable N and nitrification potential, as well as gene copy numbers of ammonia-oxidizing bacteria (AOB) and archaea (AOA). Spearman coefficients for nitrification potentials and AOB copy number were positively correlated with total soil C, total soil N, cation exchange capacity, and clay mineralogy in treatments with and without slurry application. Our data show that the quantity and type of clay minerals present in a soil affect nitrifier populations, nitrification rates, and the release of inorganic N. Nitrogen mineralization, nitrification potentials, and edaphic properties were positively correlated with AOB gene copy numbers. On average, AOA gene copy numbers were an order of magnitude lower than those of AOB across the six soils and did not increase with slurry application. Our research suggests that the two nitrifier communities overlap but have different optimum environmental conditions for growth and activity that are partly determined by the interaction of manure derived ammonium with soil properties. PMID- 22218195 TI - Ammonia stripping of biologically treated liquid manure. AB - A prerequisite for efficient ammonia removal in air stripping is that the pH of the liquid to be stripped is sufficiently high. Swine manure pH is usually around 7. At pH 7 (at 20 degrees C), only 0.4% of ammonium is in ammonia form, and it is necessary to raise the pH of swine slurry to achieve efficient ammonia removal. Because manure has a very high buffering capacity, large amounts of chemicals are needed to change the slurry pH. The present study showed that efficient air stripping of manure can be achieved with a small amount of chemicals and without strong bases like NaOH. Slurry was subjected to aerobic biological treatment to raise pH before stripping. This facilitated 8 to 32% ammonia removal without chemical treatment. The slurry was further subjected to repeated cycles of stripping with MgO and Ca(OH)(2) additions after the first and second strippings, respectively, to raise slurry pH in between the stripping cycles. After three consecutive stripping cycles, 59 to 86% of the original ammonium had been removed. It was shown that the reduction in buffer capacity of the slurry was due to ammonia and carbonate removal during the stripping cycles. PMID- 22218196 TI - Laboratory-scale investigation of UV treatment of ammonia for livestock and poultry barn exhaust applications. AB - The feasibility of using deep ultraviolet (UV) treatment for abatement of ammonia (NH(3)) in livestock and poultry barn exhaust air was examined in a series of laboratory-scale experiments. These experiments simulated moving exhaust air through an irradiation chamber with variables of UV wavelength and dose, NH(3) concentrations, humidity, and presence of hydrogen sulfide (H(2)S). Ammonia, initially at relevant barn exhaust concentrations in air, was substantially or completely reduced by irradiation with 185 nm light. Reactions were monitored using chemiluminescence detection, gas chromatography with mass spectrometry detection, and Fourier transform infrared spectrometry, of which the latter was found to be the most informative and flexible. Detected nitrogen-containing products included N(2)O, NH(4)NO(3), and HNO(3). It was presumed that atomic oxygen is the primary photochemical product that begins the oxidative cascade. The data show that removal of NH(3) is plausible, but they highlight concerns over pollution swapping due to formation of ozone and N(2)O. PMID- 22218197 TI - Simulating nitrate-nitrogen concentration from a subsurface drainage system in response to nitrogen application rates using RZWQM2. AB - Computer models have been widely used to evaluate the impact of agronomic management on nitrogen (N) dynamics in subsurface drained fields. However, they have not been evaluated as to their ability to capture the variability of nitrate nitrogen (NO(3)-N) concentration in subsurface drainage at a wide range of N application rates due to possible errors in the simulation of other system components. The objective of this study was to evaluate the performance of Root Zone Water Quality Model2 (RZWQM2) in simulating the response of NO(3)-N concentration in subsurface drainage to N application rate. A 16-yr field study conducted in Iowa at nine N rates (0-252 kg N ha(-1)) from 1989 to 2004 was used to evaluate the model, based on a previous calibration with data from 2005 to 2009 at this site. The results showed that the RZWQM2 model performed "satisfactorily" in simulating the response of NO(3)-N concentration in subsurface drainage to N fertilizer rate with 0.76, 0.49, and -3% for the Nash Sutcliffe efficiency, the ratio of the root mean square error to the standard deviation, and percent bias, respectively. The simulation also identified that the N application rate required to achieve the maximum contaminant level for the annual average NO(3)-N concentration was similar to field-observed data. This study supports the use of RZWQM2 to predict NO(3)-N concentration in subsurface drainage at various N application rates once it is calibrated for the local condition. PMID- 22218200 TI - Caregiver reports of subsequent injuries among veterans with traumatic brain injury after discharge from inpatient polytrauma rehabilitation programs. AB - OBJECTIVE: : We examined prevalence of, and potential risk factors for, nonfatal injuries among Veterans with traumatic brain injury (TBI) postdischarge from Veterans Affairs inpatient polytrauma rehabilitation programs. METHODS: : We surveyed caregivers of patients who had military service anytime from 2001 to 2009, sustained polytrauma including TBI, received Veterans Affairs inpatient care from 2001 to 2009, were discharged at least 3 months before the study, and were alive when the study was fielded about caregiver and patient health, including patients' medically treated "accidents/new injuries" since discharge. We examined prevalence and source(s) of subsequent injuries and estimated patients' injury risk in reference to hypothesized risk factors. Odds ratios and 95% confidence intervals were calculated using multivariate logistic regression. RESULTS: : Caregivers reported that nearly one-third (32%) of patients incurred medically treated injuries after discharge; most were associated with falls (49%) and motor vehicles (37%). Odds of subsequent injury were associated with select demographics, initial injury characteristics, and postdischarge health and functioning. Characteristics of caregivers, including physical and mental health, were also associated with patients' odds of subsequent injury. CONCLUSIONS: : A significant number of caregivers reported subsequent nonfatal injuries among patients treated for TBI/polytrauma in inpatient rehabilitation settings. Enhanced injury prevention efforts may be beneficial for this population. PMID- 22218201 TI - A preliminary examination of prolonged exposure therapy with Iraq and Afghanistan veterans with a diagnosis of posttraumatic stress disorder and mild to moderate traumatic brain injury. AB - OBJECTIVE: : Preliminary examination of the effectiveness of prolonged exposure (PE) therapy for the treatment of posttraumatic stress disorder (PTSD) with Operation Enduring Freedom and Operation Iraqi Freedom Veterans who have experienced traumatic brain injury (TBI). PARTICIPANTS: : Ten Veterans with a history of mild to moderate TBI and chronic PTSD. SETTING: : Outpatient Mental Health/PTSD clinics and polytrauma centers at 2 VA medical centers. MEASURES: : Comprehensive evaluation that included clinical interview, neuropsychologic evaluation, and/or neuroimaging; Posttraumatic Stress Disorder Checklist and Beck Depression Inventory-Second Edition. PROCEDURES: : Standard implementation of the PE manual was used in all cases with slight adjustments to account for Veterans' residual cognitive deficits. Veterans completed between 8 and 18 sessions. RESULTS: : Veterans demonstrated significant reductions in total PTSD and depression symptoms from pre- to posttreatment. Within-group effect sizes were large. CONCLUSIONS: : These findings suggest that PE can be safely and effectively implemented with Veterans with PTSD, a history of mild to moderate TBI, and current cognitive impairment. PMID- 22218202 TI - Magnitudes of decline on Automated Neuropsychological Assessment Metrics subtest scores relative to predeployment baseline performance among service members evaluated for traumatic brain injury in Iraq. AB - OBJECTIVE: : Identify the proportion of service members demonstrating declines in Automated Neuropsychological Assessment Metrics (ANAM) scores as part of a traumatic brain injury (TBI) evaluation conducted while deployed to Iraq. BACKGROUND: : Although TBI has been associated with poorer performance on cognitive test in the general population and military combatants, little is known about the proportion of service members demonstrating declines in ANAM scores after TBI. METHODS: : Military personnel (N = 116) referred to a combat support hospital for TBI evaluation in Iraq underwent a standardized intake evaluation including computerized neurocognitive testing, psychological and physical health questionnaires, a clinical interview, and a physical examination by a physician. Predeployment and postinjury cognitive performance among service members with and without a TBI diagnosis was compared. RESULTS: : A significantly larger proportion of patients with TBI demonstrated greater declines in speed across all ANAM subtests compared with patients with no TBI. Differences in accuracy scores among patients with TBI relative to patients without TBI were nonsignificant. Patients with TBI also demonstrated greater than minimal declines on throughput Simple Reaction Time, Procedural Reaction Time, Code Substitution-Learning, and Spatial Memory scores, with no significant differences on Code Substitution Delayed or Mathematical Processing (MATH). A similar pattern was seen among individuals examined within 72 hours of index injury. CONCLUSION: : Assessment of cognitive impairment following TBI in a combat zone may assist providers in making treatment recommendations for service members with mild TBI. PMID- 22218203 TI - A brief overview of the Patient Competency Rating Scale: updates and additions to the COMBI. PMID- 22218204 TI - Postoperative pain assessment should not be solely based on numeric ratings! Commentary on van Dijk et al. (2011). PMID- 22218208 TI - Synaptic plasticity: Ubiquitin activates synaptic plasticity. PMID- 22218206 TI - Computational neuroanatomy of speech production. AB - Speech production has been studied predominantly from within two traditions, psycholinguistics and motor control. These traditions have rarely interacted, and the resulting chasm between these approaches seems to reflect a level of analysis difference: whereas motor control is concerned with lower-level articulatory control, psycholinguistics focuses on higher-level linguistic processing. However, closer examination of both approaches reveals a substantial convergence of ideas. The goal of this article is to integrate psycholinguistic and motor control approaches to speech production. The result of this synthesis is a neuroanatomically grounded, hierarchical state feedback control model of speech production. PMID- 22218210 TI - [Psychotherapeutic approaches of depression]. AB - All schools of psychotherapy have developed specific therapeutic approaches for depression. Common elements exist but still there are differences as well. In this we will review the following approaches, mostly cited in the depression therapy literature: Psychoanalytic, Behavioral, Cognitive and Interpersonal. Recent studies show that psychotherapy is ef fective in depression, even in the elderly and in hospitalized patients. Psychotherapy results are very good in mild to moderate depression. In combination with pharmacotherapy, psychotherapy shows good results in severe depression. It has an important role in preventing new episodes. Recent functional imaging studies show how psychotherapy can affect biological brain structure and function. However, there are still methodological issues that have to be dealt with in psychotherapy research. PMID- 22218209 TI - The future of psychiatric reform in Greece. PMID- 22218211 TI - [Validation of adolescent computer addiction test in a greek sample]. AB - The goal of this study is the validation of a reliable research tool for diagnosing computer addiction in adolescents and the description of its particular psychometric properties. 482 students in the city of Trikala, which is Greece's leading city in Internet provision, and 907 students of the city of Larisa took part in this study which was run during the first trimester of 2006. The samples were obtained through randomized stratified sampling for their respective cities. Those students who reported using a personal computer at the time filled in the ACAT (Adolescent Computer Addiction Test), which was modeled after the 20-question Internet Addiction Test. The psychometric tests applied included test-retest reliability, internal consistency and construct validity. Factor analysis revealed four factors which account for 59.15% of total variability of the scale. The ACAT scale was proven to hold excellent test retest reliability, internal consistency and construct validity. The important role of timely education in new technologies is pointed out. This study is a first attempt in creating and applying a reliable tool in the evaluation of adolescent addiction to personal computers in Greece. PMID- 22218213 TI - [The responsibility schema in obsessive compulsive checking and washing]. AB - According to the theory of cognitive therapy, mental disorders are related to specific dysfunctional schemata, assumptions and automatic thoughts. Various pathogenic schemata have been identified in the context of the cognitive explanation of obsessive compulsive disorder, among which is the responsibily schema, proposed by Salkovskis in 1985. The responsibility schema has been defined as the belief that one possesses pivotal power to provoke or prevent subjective crucial negative outcomes. In order to investigate the relationship between the major obsessive compulsive themes and the cognitive schema of responsibility, the Maudsley Obsessive-Compulsive Inventory and the Responsibility Questionnaire were administered to a non-clinical sample of 366 college students. Two groups, consisting of 15 participants each, were identified having obsessive compulsive manifestations (complaints). The first group manifested obsessive compulsive checking and the second group manifested obsessive compulsive washing. No significant sex differences were found between the groups (x2=0.186, df=1, p>0.005), but significant age differences were observed (t=-2.41, df=19.68, p<0.05). In view of this finding, data were subjected to Analysis of Covariance. The age of the participants was treated as a covariate and the main effects of the obsessive compulsive checking and washing on responsibility were analyzed. The findings seem to verify this relationship for obsessive compulsive checking (F=5.63, df=1.307, p<0.05). The subjects who manifested obsessive-compulsive checking reported an increased sense of responsibility as compared to those who experienced obsessive-compulsive washing or were free of obsessive-compulsive manifestations. The available questionnaires did not allow the investigation of the relationship between other types of obsessive compulsive manifestations and responsibility. The use of a non-clinical sample should also be noted. PMID- 22218214 TI - [A cognitive behavioural group therapy program for the improvement of the cognitive and social abilities of patients with schizophrenia]. AB - Pharmacotherapy is the main therapy for the positive and negative symptoms and for the relapse prevention for patients with schizophrenia. The cognitive and behavioural therapy can be combined with other therapies for schizophrenia. Within this frame of reference the cognitive behavioural therapy for schizophrenia and other psychotic syndromes is the first choice for psychiatrists and psychologists in European countries. The National Institute of Clinical Excellence (NICE) has included the cognitive behavioural therapy as a recommended therapy for schizophrenia. The Cognitive Behavioral Therapy includes interventions for the acute phase in an episode (relapse) as well as for the rehabilitation of patients with schizophrenia. The Integrated Psychological Therapy, which is an effective group therapy for the improvement of cognitive and social abilities of patients with schizophrenia, will be represented in the following article. PMID- 22218207 TI - Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. AB - Mitochondria have a number of essential roles in neuronal function. Their complex mobility patterns within neurons are characterized by frequent changes in direction. Mobile mitochondria can become stationary or pause in regions that have a high metabolic demand and can move again rapidly in response to physiological changes. Defects in mitochondrial transport are implicated in the pathogenesis of several major neurological disorders. Research into the mechanisms that regulate mitochondrial transport is thus an important emerging frontier. PMID- 22218212 TI - [The psychopathology of bilingual children in a sample of a Community Mental Health Center]. AB - Thoughts and views of one's internal self can be materialized via verbal symbols. Therefore literal people can use these verbal symbols as a means of recording their ideas and experiences in order for them to be passed on and read by others. Evidently the abovementioned mental operations can be reflected in speech and language. It is not yet known whether bilingualism is the sum of two monolingual situations or whether they coexist. The way each language is organized is also not known, neither are the psychological operations that may influence the organization of each language, memory and the relationship with each language. During childhood and adolescence, language is a very important tool via which one communicates, materializes emotional behavior and organizes oneself. Linguistic development and identity formation both follow a parallel and connected line in view of the internal psychological organization. However, in the bilingual person, this relationship is influenced both by the two different cultural stimuli and by the two different linguistic stimuli (i.e. language). However, in the case where children grow up in a bilingual environment there are some particularities and special issues affecting these children. Under such circumstances, the accomplishment of the feeling of coherence and stability of the self becomes an even more difficult task for the child. Nowadays, in Greek reality, the phenomenon of bilingualism tends to be associated with economic immigration. In the sample used, five fourths of children consist of children coming from families of economic immigrants. The composition of the student population in Greece is characterized by linguistic and cultural polymorphism. The presence and existence of a large number of immigrants has changed the setting in Greece in many regions of the country and in turn, the composition of the school population. Any public school allover in Greece consists, among others, of children coming from families of economic immigrants, including thus a random number of children speaking different languages. Without doubt, immigration affects the immigrating person as much as it affects the new group. Also, immigration adjustment and formation depends on the pre-existing characteristics of the immigrants as much as it does on the characteristics of the welcoming society. Research dealing with the issues of economic immigrants in Greece are limited and mainly come from schools. The focus of interest is aimed firstly on the psychopathology that can be linked to the phenomenon of immigration and secondly on the social consequences of the phenomenon. The formation of psychopathology is associated with immigration and the importance of psychological trauma and its consequences. However, the association between the creation of psychopathology, which is formulated in childhood/adolescence, and the bilingual environment together with identity formation, is not yet clear. The aim of this paper was to study the effect of the dual language environment on psychopathology formation among children and adolescents as it appears in everyday clinical practice and as it has been recorded at the Child and Adolescent Mental Health Unit of the Community Mental Health Centre of Byron and Kaissariani, Psychiatric Hospital, Athens University. Data deriving from the database of the Community Mental Health Centre were extracted from the files of 62 bilingual children, aged 0 to 18 years, who had visited the CMHC of Byron and Kaissariani in the period 2000 to 2005. The data selected concerned the sex, age, maternal language, diagnosis and the existence of economic immigration. Means deriving from the sample of bilingual children were compared to the means of the rest of the sample. (Pearson chi,2 Fishers exact test) Based on the results, four fifths of the sample was composed of children belonging to families of economic immigrants. The occurrence of Pervasive Developmental Disorders was triple among the sample of bilingual children compared to the sample of monolingual children. Among school-aged children the majority of diagnoses concerned Specific Language, Movement and Learning Disorders. On the contrary, during adolescence, there was a two-fold increase of psychiatric illness among bilingual adolescents compared to monolingual adolescents with conduct disorders being more prominent among males and mood disorders more prominent among females. Based on the extent and importance of the influence of the dual linguistic environment on children and adolescents as well as on the originality of the new situation in Greek society, further exploration of this area is believed to be necessary. PMID- 22218215 TI - [Frame of internal functioning and innovative practices in a Day Center for psychotics]. AB - The Day Center (DC) of EPAPSI (Scientific Association for Regional Development and Mental Health) offers complete psycho-social interventions for the psyhotic patients of the 5th Psychiatric Sector, in order to prevent them from relapsing, helps reduce hospitalisation and also works towards psychological and vocational rehabilitation; always aiming at improving the quality of patients' life. Working towards the continuum of care of its patients, the DC applies innovative practises such as: the creation of a community-based supportive network, the running of social clubs, participation in European Programmes concerning the social and vocational rehabilitation of patients, creation of KoiSPE (Limited Liability Social Co-operatives) in co-operation with the Local Authorities, application of new methods of caring and curing, involving the patients in co-running the "therapeutic contract". The successful application of "community psychiatry" and the continuation of psychiatric reform will be accommodated with the contribution and co-operation of "communal" services and the wider public sector as well as the application of new and pioneering programmes. PMID- 22218216 TI - [Clinical Psychiatry and Forensic Psychiatry: Similarities and differences]. AB - Forensic and clinical psychiatry require very different expertise from mental health specialists who work in each field respectively. Despite the fact that classical psychiatric training provides theoretical knowledge and practical skills relevant to both clinical and forensic psychiatric work, the latter requires a quite different understanding of doctor-patient relationship, ethic development and legally oriented practice to be developed. Almost all researchers or opinion leaders in forensic psychiatry agree that, in this distinguished area, specific principles and characteristics apply: the forensic psychiatrist supports mainly the legal system rather than the patient, he needs to develop new interview techniques and a new database of knowledge in order to deal with the "psycho-legal" questions to be answered, and he also needs to avoid psychiatric jargon and adjust his terminology to terms understandable by the legal profession. At the same time forensic psychiatrists should be ready to confront the examinees with contradictory information they may provide and contact third parties to check the validity of their impressions, keeping in mind the probability of malingering or other reasons behind observed behaviours. Moreover the conclusions presented by the forensic psychiatrist to the courts need to be, to a certain degree, safe results based on his observations, examinations and theoretical scientific knowledge, despite the fact that he is frequently asked to comment on issues concerning the past or the future. Finally confidentiality issues are irrelevant to forensic work and the inevitable distribution of reports to all involved parties may result, in some cases, to questioning of the expert witness's professional opinion and his involvement in disciplinary or penal prosecution. All the above require an appropriate training for psychiatrists involved in forensic work, as well as their familiarization with basic legal knowledge and the ethical code relevant to this exceptional field of work. PMID- 22218217 TI - Trans-mastoid facial nerve localisation for malignant neoplasms confined to the parotid gland. AB - Up to 32% of parotid neoplasms are malignant, and treatment for resectable parotid carcinomas remains primarily surgical. Resection is centred round the identification and preservation (where possible) of the main trunk of the facial nerve. Limited dissection of the temporal bone and identification of the facial nerve proximally in the mastoid portion can facilitate resection for all parotid carcinomas that occur in the preauricular portion of the gland. Dissection in the narrow space between the ear or base of the skull and the tumour reduces the risk of tumour spillage, and the margin for resection is optimised. Intramastoid localisation of the facial nerve allows a posterior approach, and access to the dissection plane lies medial to the nerve. We describe the technique in a series of eight patients undergoing resection for parotid malignancies. In our experience the technique promotes adequate resection margins, reduces the risk of tumour spillage, and allows better access for nerve grafting if the facial nerve has to be sacrificed. PMID- 22218218 TI - Pathogenesis of infertility and recurrent pregnancy loss in thyroid autoimmunity. AB - Thyroid autoimmunity is the most prevalent autoimmune state that affects up to 4% of women during the age of fertility. A growing body of clinical studies links thyroid autoimmunity as a cause of infertility and adverse pregnancy outcomes that includes miscarriage or preterm deliveries. Importantly, these adverse effects are persistent in euthyroid women. In the current review we elaborate on the pathogenesis that underlies infertility and increased pregnancy loss among women with autoimmune thyroid disease. Such mechanisms include thyroid autoantibodies that exert their effect in a TSH-dependent but also in a TSH independent manner. The later includes quantitative and qualitative changes in the profile of endometrial T cells with reduced secretion of IL-4 and IL-10 along with hypersecretion of interferon-gamma. Polyclonal B cells activation is 2-3 time more frequent in thyroid autoimmunity and is associated with increased titers of non-organ specific autoantibodies. Hyperactivity and Increased migration of cytotoxic natural killer cells that alter the immune and hormonal response of the uterus is up to 40% more common in women with thyroid autoimmunity. Lack of vitamin D was suggested as a predisposing factor to autoimmune diseases, and was shown to be reduced in patients with thyroid autoimmunity. In turn, its deficiency is also linked to infertility and pregnancy loss, suggesting a potential interplay with thyroid autoimmunity in the context of infertility. In addition, thyroid autoantibodies were also suggested to alter fertility by targeting zona pellucida, human chorionic gonadotropin receptors and other placental antigens. PMID- 22218220 TI - Morning hypertension in chronic kidney disease is sustained type, but not surge type. AB - OBJECTIVE: We have shown that as renal function deteriorates, the circadian blood pressure (BP) rhythm shifts to a nondipper pattern and the duration until nocturnal BP decline [dipping time (DT)] is prolonged. We investigated whether or not morning hypertension (BP 2 h after awakening >135/85 mmHg) in chronic kidney disease (CKD) was sustained type with a prolonged DT. MATERIALS AND METHODS: Twenty-four-hour BP was monitored in 104 patients with CKD. Fifty-one of 104 participants (group A) did not exhibit morning hypertension. The patients with morning hypertension (group B, n=53) were classified into three groups: group C (n=23), participants who exhibited morning hypertension but did not meet the criteria for the surge or sustained type; group D (n=29), the sustained type (with no night-time BP readings <120/70 mmHg); and group E (n=1), the surge type (systolic BP rises >25 mmHg after awakening). RESULTS: The night/day BP ratio and DT were compared among groups A, C, and D because there was only one participant in group E. Night/day ratio of BP and DT were both significantly higher in group D compared with groups A and C. The prevalence of nondippers tended to be higher in group D compared with the other groups (A, 65%; C, 57%; D, 86%, P=0.09). Creatinine clearance was significantly lower in group D compared with groups A and C. CONCLUSION: Sustained elevation of night-time BP until the early morning and high night/day ratio of BP may contribute to the high frequency of morning hypertension, which is generally the sustained rather than the surge type in CKD. PMID- 22218221 TI - Automated office versus home measurement of blood pressure in the assessment of morning hypertension. AB - OBJECTIVE: To compare the quality and accuracy of morning blood pressure (BP) readings as taken by automated office BP (AOBP) and morning home BP (mHBP) techniques using morning ambulatory BP (mABP) measurements as the gold standard. METHODS: A total of 139 individuals were included, 70 men and 69 women, mean age 53+/-13 years. The average AOBP readings as measured using a Microlife Watch BP office device taking triplicate automated simultaneous readings of both arms were compared with mHBP monitored on 6 routine days, using a validated automated electronic device. Both modalities were also compared with the ambulatory readings of the 3 h of waking (mABP3h). RESULTS: The AOBP values were slightly higher than the mABP3h (mean difference 8.2 mmHg, 95% limits of agreement, -18.8 to 35.2 mmHg for the systolic BP and mean difference 4.3 mmHg, 95% limits of agreement, -15.3 to 23.9 mmHg for the diastolic BP). Systolic and diastolic AOBP readings correlated with mABP3h (r=0.66, P=0.001 and r=0.64, P=0.001, respectively). Agreement was fair between AOBP and mHBP in the detection of morning hypertensive patients (agreement 70%, kappa=0.32) as compared with AOBP and mABP3h (agreement 67%, kappa=0.32) and mHBP and mABP3h (agreement 65%, kappa=0.31). CONCLUSION: The AOBP technique could replace mHBP monitoring in the assessment of morning BP, as it provides comparable data in relation to the awake ambulatory BP. Given the simplicity of this method, it could be more readily applied in a larger number of individuals. PMID- 22218222 TI - Wave localization in two-dimensional porous phononic crystals with one dimensional aperiodicity. AB - The localization properties of in-plane elastic waves propagating in two dimensional porous phononic crystals with one-dimensional aperiodicity are initially analyzed by introducing the concept of the localization factor that is calculated by the plane-wave-based transfer-matrix method in this paper. The band structures characterized by using localization factors are calculated for different phononic crystals by altering matrix material properties and geometric structure parameters. Numerical results show that the effect of matrix material properties on wave localization can be ignored, while the effect of geometric structure parameters is obvious. For comparison, the periodic porous system and Fibonacci system with rigid inclusion are also analyzed. It is found that the band gaps are easily formed in aperiodic porous system, but hard for periodic porous system. Moreover, compared with aperiodic system with rigid inclusion, the wider low-frequency band gaps appear in the aperiodic porous system. PMID- 22218224 TI - Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene. AB - A recent genome-wide association study revealed a variant (rs2431697) in an intergenic region, between the pituitary tumor-transforming 1 (PTTG1) and microRNA (miR-146a) genes, associated with systemic lupus erythematosus (SLE) susceptibility. Here, we analyzed with a case-control design this variant and other candidate polymorphisms in this region together with expression analysis in order to clarify to which gene this association is related. The single-nucleotide polymorphisms (SNPs) rs2431697, rs2910164 and rs2277920 were genotyped by TaqMan assays in 1324 SLE patients and 1453 healthy controls of European ancestry. Genetic association was statistically analyzed using Unphased. Gene expression of PTTG1, the miRNAs miR-3142 and primary and mature forms of miR-146a in peripheral blood mononuclear cells (PBMCs) were assessed by quantitative real-time PCR. Of the three variants analyzed, only rs2431697 was genetically associated with SLE in Europeans. Gene expression analysis revealed that this SNP was not associated with PTTG1 expression levels, but with the microRNA-146a, where the risk allele correlates with lower expression of the miRNA. We replicated the genetic association of rs2341697 with SLE in a case-control study in Europeans and demonstrated that the risk allele of this SNP correlates with a downregulation of the miRNA 146a, potentially important in SLE etiology. PMID- 22218223 TI - CIITA promoter I CARD-deficient mice express functional MHC class II genes in myeloid and lymphoid compartments. AB - Three distinct promoters control the master regulator of major histocompatibility complex (MHC) class II expression, class II transactivator (CIITA), in a cell type-specific manner. Promoter I (pI) CIITA, expressed primarily by dendritic cells (DCs) and macrophages, expresses a unique isoform that contains a caspase recruitment domain (CARD). The activity and function of this isoform are not understood, but are believed to enhance the function of CIITA in antigen presenting cells. To determine whether isoform I of CIITA has specific functions, CIITA mutant mice were created in which isoform I was replaced with isoform III sequences. Mice in which pI and the CARD-encoding exon were deleted were also created. No defect in the formation of CD4 T cells, the ability to respond to a model antigen or bacterial or viral challenge was observed in mice lacking CIITA isoform I. Although CIITA and MHC-II expression was decreased in splenic DCs, pI knockout animals expressed CIITA from downstream promoters, suggesting that control of pI activity is mediated by unknown distal elements that could act at pIII, the B-cell promoter. Thus, no critical function is linked to the CARD domain of CIITA isoform I with respect to basic immune system development, function and challenge. PMID- 22218226 TI - Hepatitis C virus and atherosclerosis in a close and dangerous liaison. PMID- 22218227 TI - Let's dance: Organization studies, medical sociology and health policy. AB - This Special Issue of Social Science & Medicine investigates the potential for positive inter-disciplinary interaction, a 'generative dance', between organization studies (OS), and two of the journal's traditional disciplinary foundations: health policy and medical sociology. This is both necessary and timely because of the extent to which organizations have become a neglected topic within medical sociology and health policy analysis. We argue there is need for further and more sustained theoretical and conceptual synergy between OS, medical sociology and health policy, which provides, on the one-hand a cutting-edge and thought-provoking basis for the analysis of contemporary health reforms, and on the other hand, enables the development and elaboration of theory. We emphasize that sociologists and policy analysts in healthcare have been leading contributors to our understanding of organizations in modern society, that OS enhances our understanding of medical settings, and that organizations remain one of the most influential actors of our time. As a starting point to discussion, we outline the genealogy of OS and its application to healthcare settings. We then consider how medical sociology and health policy converge or diverge with the concerns of OS in the study of healthcare settings. Following this, we focus upon the material environment, specifically the position of business schools, which frames the generative dance between OS, medical sociology and health policy. This sets the context for introducing the thirteen articles that constitute the Special Issue of Social Science & Medicine. PMID- 22218229 TI - Global mental health. PMID- 22218225 TI - Nitric oxide inhibits the expression of AT1 receptors in neurons. AB - We have previously observed an increased of angiotensin II (ANG II) type 1 receptor (AT(1)R) with enhanced AT(1)R-mediated sympathetic outflow and concomitant downregulation of neuronal nitric oxide (NO) synthase (nNOS) with reduced NO-mediated inhibition from the paraventricular nucleus (PVN) in rats with heart failure. To test the hypothesis that NO exerts an inhibitory effect on AT(1)R expression in the PVN, we used primary cultured hypothalamic cells of neonatal rats and neuronal cell line NG108-15 as in vitro models. In hypothalamic primary culture, NO donor sodium nitroprusside (SNP) induced dose-dependent decreases in mRNA and protein of AT(1)R (10(-5) M SNP, AT(1)R protein was 10 +/- 2% of control level) while NOS inhibitor N(G)-monomethyl-l-arginine (l-NMMA) induced dose-dependent increases in mRNA and protein levels of AT(1)R (10(-5) M l NMMA, AT(1)R protein was 148 +/- 8% of control level). Similar effects of SNP and l-NMMA on AT(1)R expression were also observed in NG108-15 cell line (10(-6) M SNP, AT(1)R protein was 30 +/- 4% of control level while at the dose of 10(-6) M l-NMMA, AT(1)R protein was 171 +/- 15% of the control level). Specific inhibition of nNOS, using antisense, caused an increase in AT(1)R expression while overexpression of nNOS, using adenoviral gene transfer (Ad.nNOS), caused an inhibition of AT(1)R expression in NG108 cells. Antisense nNOS transfection augmented the increase while Ad.nNOS infection blunted the increase in intracellular calcium concentration in response to ANG II treatment in NG108 cells. In addition, downregulation of AT(1)R mRNA as well as protein level in neuronal cell line in response to S-nitroso-N-acetyl pencillamine (SNAP) treatment was blocked by protein kinase G (PKG) inhibitor, while the peroxynitrite scavenger deforxamine had no effect. These results suggest that NO acts as an inhibitory regulator of AT(1)R expression and the activation of PKG is the required step in the regulation of AT(1)R gene expression via cGMP-dependent signaling pathway. PMID- 22218230 TI - Association of serum BDNF and val66met polymorphism of the brain-derived neurotrophic factor in a sample of first psychotic episode patients. AB - Polymorphisms in the brain-derived neurotrophic factor (BDNF) gene have been indicated to be associated with schizophrenia. Previous studies have suggested that val66met polymorphism may increase the risk for schizophrenia, although other studies have not confirmed this association. Decreased BDNF levels in the brain and the serum of patients with psychotic disorders have been reported in first episode psychotic (FEP) patients. In our study we investigated the potential genetic association of this polymorphism with schizophrenia in a sample of 38 FEP patients with schizophrenia compared with a sample of 21 normal controls. Furthermore, we assessed serum BDNF levels and investigated whether there was an association between this polymorphism and alterations of serum BDNF levels between the investigated groups. There was a significant difference in genotyped frequencies between cases and controls (p=0.030). The homozygous carriers Met/Met were over-represented in the schizophrenia group (13/31, 41.9%), compared to controls (2/19, 10.5%). The serum BDNF levels in the sample of FEP patients was significantly reduced compared to controls (18.87+/-8.23 ng/mL vs 29.2+/-7.73ng/mL, U=140, p=0.0). No association was found between alterations of serum BDNF levels and Val66Met polymorphism in the group of patients (p=0.198). Negative correlations were shown between serum BDNF levels of the patients and the PANSS Negative subscale scores (p=0.015). There was found no significant difference between genotypes and memory scores in the sample of patients. Our findings indicate that serum BDNF levels at the onset of schizophrenia and BDNF Val66Met variant may be susceptibility risk factors for schizophrenia. PMID- 22218231 TI - Attitudes on euthanasia and physician-assisted suicide among medical students in Athens. AB - Attitudes towards assisted death activities among medical students, the future health gatekeepers, are scarce and controversial. The aims of this study were to explore attitudes on euthanasia and physician-assisted suicide among final year medical students in Athens, to investigate potential differences in attitudes between male and female medical students and to review worldwide attitudes of medical students regarding assisted death activities. A 20- item questionnaire was used. The total number of participants was 251 (mean age 24.7+/-1.8 years). 52.0% and 69.7% of the respondents were for the acceptance of euthanasia and physician-assisted suicide, respectively. Women's attitudes were more often influenced by religious convictions as well as by the fact that there is a risk that physician-assisted suicide might be misused with certain disadvantaged groups. On the other hand, men more often believed that a request for physician assisted suicide from a terminally ill patient is prima-facie evidence of a mental disorder, usually depression. Concerning attitudes towards euthanasia among medical students in various countries there are contradictory results. In USA, the Netherlands, Hungary and Switzerland most of the students supported euthanasia and physician-assisted suicide. However, in many other countries such as Norway, Sweden, Yugoslavia, Italy, Germany, Sudan, Malaysia and Puerto Rico most students expressed negative positions regarding euthanasia and physician assisted suicide. PMID- 22218232 TI - Fatigue and somatic anxiety in patients with major depression. AB - The objective this study aimed to investigate the independent contribution of somatic anxiety to the severity of depression-related fatigue. Seventy-six patients (85.5% female), aged 23-65 years (mean 48.7+/-10.6), diagnosed with major depressive disorder and currently in a major depressive episode (MUIotaNuIota 5.0.0.) with a 17-item Hamilton Depression Rating Scale (HDRS) score >=17, were studied. Forty-nine patients (64.5%) were concurrently suf fering from anxiety disorder(s). Patients with physical diseases or other fatigue-related conditions were excluded. Reported fatigue was measured with the 14-item Fatigue Questionnaire (FQ). Based on HDRS item 11 (somatic anxiety) scores, patients were divided into those with somatic anxiety (HDRS-11>=2) and those without (HDRS-11<=1). Pearson's (r) and Spearman's (rho) correlations between FQ score, age, gender, inpatient status, HDRS score and somatic anxiety status were calculated. A multiple regression analysis was then performed, with FQ as the dependent variable. Fifty-seven patients (75%) were rated as suffering from somatic anxiety (HDRS-11>=2). Patients with somatic anxiety had significantly higher HDRS and FQ scores. The FQ score significantly correlated with the HDRS score (r=0.36, p=0.001) and somatic anxiety status (rho=0.35, p=0.002). The FQ score was independently predicted by HDRS score and somatic anxiety status, with standardised beta coefficients of 0.259 (p=0.028) and 0.255 (p=0.031), respectively. R2 was 0.185. Both the severity of depression and the presence of somatic anxiety independently correlate with the severity of reported fatigue in patients with major depression. This finding has potential implications for the management of depression-related fatigue. PMID- 22218234 TI - Acquired competence in cognitive therapy following a two level course. AB - The objective of this study was to examine the predictive value of trainees' previous experience and performance at an introductory course in Cognitive Therapy for their subsequent success in an advanced course. From 203 completers of an introductory course during seven consecutive years 32 participated in an advanced course. In a linear regression analysis previous clinical and psychotherapeutic experience as well as performance at the introductory course were studied as predictors for trainees' success in the advanced course. Performance at the introductory course was the only significant predictor of trainees' successful completion of the advanced course. An introductory course might help to select those trainees who have the desired qualities to succeed in a formal psychotherapeutic training program. PMID- 22218233 TI - Clinical symptoms and social functioning among immigrant and greek patients with schizophrenia: A comparative study. AB - Migration is considered an important risk factor for schizophrenia. However, studies on the differences in psychotic symptomatology between immigrants and native patients revealed mixed results. This study compared clinical symptoms and social functioning between immigrant and native patients with schizophrenia in Greece in order to examine the influence of social factors on the disorder's manifestation and severity. A structured questionnaire including demographic and clinical information was administered to two groups of patients with schizophrenia; the first one was comprised of 65 immigrant patients (38 men and 27 women) and the second included 58 greek patients (35 men and 23 women). Patients' psychopathology was evaluated by the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia (CDSS) and the Global Assessment of Functioning Scale (GAF). The x2 test and the ANOVA were used for the comparisons of categorical and continuous variables respectively between the two groups of patients. Analysis of eigenvalues and multivariate analysis (MANOVA) were also used. Age and duration of illness were significant greater in the greek group of patients. Lack of insight was the only reason of hospitalization of immigrant patients. The immigrant group of patients had significantly lower scores in the negative syndrome subscale, the general psychopathology subscale and the total PANSS scale while they had significantly higher scores in the GAF scale. No between patients' groups difference was found on CDSS scores. Analysis of eigenvalues and MANOVA revealed that the national group (immigrants vs native) and the reason of admission were the only general variables with significant influence on patients' psychopathological features and functioning. Consistently with previous studies that have shown better prognosis in immigrant compared to the native patients with schizophrenia, immigrant patients in our study had milder negative and total psychotic symptomatology and were less impaired in terms of global functioning than the greek group. Being an immigrant appears to be an important factor related to these differences between our study groups. A possible explanation of our findings could be that immigrant patients with schizophrenia attending to greek mental health services have been 'filtered'because of a 'salmon bias' type phenomenon; the severe ill usually return to their country of birth due to the lack of financial and social support for immigrant patients in Greece. An alternative hypothesis is that the families and the local communities of immigrant patients with schizophrenia, being tied enough, provide support to their ill members that results in better outcome, especially with respect to negative syndrome and social functioning. PMID- 22218235 TI - Doping in sports. AB - Regardless of one's stance on the topic, drugs are an important issue in sports. Sports pages in newspapers around the globe routinely report on athletes at every level ofcompetition using performance enhancing substances to gain an unfair advantage over their competitors. The level of sophistication in beating drug testing, and developing "next-generation" agents continues to raise. The relative paucity of well designed research has been an additional factor impeding attempts to adequately address the problem. Very limited funds are currently available to conduct the necessary research. Without credible data, athletes are more vulnerable to the claims made by those benefiting from the sales of these compounds. Many younger fans and those dreaming of a similar future admire highly successful professional athletes. A strong, consistent statement admonishing drug use is needed. Actions speak louder than words. Every time a successful athlete is caught using PE drugs, every effort to diminish drug use is negatively impacted. The "win at all cost" and "second place is the first loser" mentality needs to be continually challenged by words and actions in youth sports at every level of competition. Finally, the war on drugs in sports needs to be a coordinated, well organized international undertaking as sports play an important role in virtually every culture. If we are to maintain the integrity of competition and protect the health of the athletes, we must dramatically increase our efforts to eliminate performance enhancing drugs as an acceptable option for any athlete. Sports science professionals and sports psychiatrists need to work with coaches, trainers, athletes, and national governing bodies to educating athletes on the effects of performance enhancing drug use. To achieve this important goal everyone involved in sports needs to be knowledgeable on the negative impact this has on all aspects of organized sports. It is a difficult challenge, but one that must be addressed. PMID- 22218236 TI - Psychoanalysis and the public health sector: The Greek experience. AB - The question of whether psychoanalysis -outside the original psychoanalytical setting- can co-exist with the public sector of health services has been substantially answered by the development of relevant psychoanalytic theory and the evolution of novel psychotherapeutic techniques. Psychoanalysis has a non specific and a specific effect on the public sector. The first explores how psychoanalytic concepts formulate a special understanding of mental disorders in everyday clinical practice; both in the organisation of services and a personalised approach of particular circumstances and needs of patients. The second explores how different kinds of psychoanalytic therapies are incorporated in the public sector. The setting is as crucially important here as are the appropriate funding, the recruitment of an adequate number of specialists and psychoanalytic training. Unfortunately psychoanalysis is not considered as cost efficient by the majority of decision makers. In Greece, psychoanalysis has been present since the late 20's, initially as an instrument of perfection of children's understanding and education and also as a specific therapeutic method, appropriate for human psyche's understanding and for the treatment of some mental diseases. In the last 30 years psychoanalysis has been more closely implicated in the development of public health services and, by extension, in the psychiatric reform taking place in the country. Psychoanalytic supervision is mainly implemented in outpatient clinical practice. Brief psychoanalytic psychotherapies are implemented in outpatient and inpatient settings. PMID- 22218237 TI - The apple of our eyes! PMID- 22218238 TI - First international assembly of ocular inflammation societies hosted by Uveitis Society of India. PMID- 22218240 TI - Outcome of optical penetrating keratoplasties at a tertiary care eye institute in Western India. AB - AIM: To study the indications, risk factors, postoperative course, and long-term survival of corneal transplants done for optical purposes. DESIGN: Retrospective case series. MATERIALS AND METHODS: Data were obtained by reviewing the records of 181 patients operated at our institute (H.V. Desai Eye Hospital) between October 2005 and October 2007 for optical penetrating keratoplasty. Patients with less than one year of follow up, pediatric cases, therapeutic, tectonic, and lamellar keratoplasties were excluded. Kaplan Meier survival analysis was used to calculate median survival time of grafts and to see correlation between nine variables viz. age, gender, corneal vascularization, previous failed grafts, previous Herpes Simplex keratitis, post-perforation corneal scars, donor tissue quality, graft size, type of surgery and follow-up. These variables were also used for univariate and multivariate analysis using Cox Proportional Hazard Regression Modeling. RESULTS: Median survival of the cohort was 27 months (95% confidence interval: 20.47-33.52). One- and two-year survival rates were 65% and 52.5%, respectively. Median survival was significantly lower in poor prognosis cases (14 months) than good prognosis cases (27 months, P = 0.0405). Graft survival was lower in vascularized corneas (18.55 months, P = 0.030) and in post perforation corneal scars (17.96 months, P = 0.09, borderline significance). Multivariate analysis showed that the same factors were predictive of graft failure. CONCLUSION: Long-term survival of grafts at our center is different from centers in western world. More high-risk cases, paucity of excellent quality donor corneas, and differences in patient profile could be the contributory factors. PMID- 22218239 TI - Phototherapeutic keratectomy. AB - Phototherapeutic keratectomy (PTK) is done regularly for anterior corneal diseases such as corneal dystrophies, corneal degenerations, scars, and band shaped keratopathy. The various indications include both therapeutic and visual. The aim of this article is to discuss the therapeutic indications for PTK, the specific technique pertaining to a specific etiology, the various other procedures like amniotic membrane graft combined with PTK or PTK being done for recurrences in the grafts, and PTK done before cataract surgery when the anterior corneal pathology coexists with the cataract. Post PTK management such as healing of an epithelial defect, use of steroids in the post PTK period, recurrences of primary disease pathology, and infections, will be discussed. Methods of literature search: A Medline search was carried out for articles in the English language, with the keywords, phototherapeutic keratectomy, band-shaped keratopathy, spheroidal degeneration, scars, bullous keratopathy, and corneal dystrophy. The relevant references are mentioned here. PMID- 22218241 TI - Foldable iris-fixated phakic intraocular lens implantation for the correction of myopia: two years of follow-up. AB - PURPOSE: To evaluate the safety, efficacy and potential risks of Artiflex foldable iris-fixated phakic intraocular lens (pIOL) implantation for the management of myopia. MATERIALS AND METHODS: Seventy-eight eyes of 40 consecutive patients with a mean spherical refraction of -11.70 +/- 3.77 diopters (D; range 5.50 to -17.5 D) were included in this prospective, noncomparative, interventional case series. Main parameters assessed were uncorrected visual acuity (UCVA), best-spectacle corrected visual acuity (BSCVA), corneal topography (Orbscan II, BauchandLomb, Rochester, NY, USA), manifest and cycloplegic refractive errors, endothelial cell density (ECD) and applanation tonometry. RESULTS: After 2 years, BSCVA was 20/40 or better in 82% of the eyes and UCVA was 20/40 or better in 84% of the eyes. After 1 month, 1 year, and 2 years, 51.3% (37 of 72 eyes), 58.9% (46 of 78 eyes) and 76.0% (38 of 50 eyes) of eyes gained 1 line or more of BSCVA, respectively. Compared to preoperative values, the mean endothelial cell loss was 2.6% at 1 month, 4.9% at 1 year and 7.4% at 2 years. Pigmented or non-pigmented precipitates were observed in 17 eyes (21.7%) which were treated with topical corticosteroids. At the second postoperative year, pigmented precipitates persisted in nine eyes. However, this was not associated with a loss of BSCVA. CONCLUSION: The implantation of Artiflex pIOL is an effective surgical option for the management of high myopia. The most common complication observed within 2 years of follow-up was accumulation of pigmented precipitates with no effect on the final BSCVA. PMID- 22218242 TI - Primary 23-gauge sutureless vitrectomy for rhegmatogenous retinal detachment. AB - AIMS: To report a prospective non-comparative consecutive interventional study on the safety and efficacy of 23-Gauge transconjunctival sutureless pars plana vitrectomy for primary rhegmatogenous retinal detachment (RRD). MATERIALS AND METHODS: Fifty eyes of 50 consecutive patients were recruited between June 2007 and January 2008. All surgeries were performed using the one-step 23-Gauge system with angled incisions. The surgical protocol consisted of a minimum of eight clinical visits: baseline, 1 day, 1 week, 1-, 3- and 6- months after the initial surgery. The endpoints were anatomical, functional results and complications arising from the surgery. RESULTS: Anatomical success was achieved in 82% of cases (41 out of 50) with single surgery and rose to 98% (49 out of 50) with additional surgery. Mean visual acuity improved from logMAR 0.48(SD 0.36) to 0.26(SD 0.31), P < 0.001. Two cases with ocular hypotony, defined as an intraocular pressure <= 6mmHg, that were associated with a choroidal detachment were seen. CONCLUSIONS: Acceptable anatomical and functional success rates can be achieved with primary 23-Gauge transconjunctival sutureless vitrectomy for RRD. We found that the approach technique is different from conventional vitrectomy and the complications arising from post surgical hypotony and leakage from sclerotomies are potentially higher compared to 20-Gauge vitrectomy. PMID- 22218243 TI - Corneal endothelium after deep anterior lamellar keratoplasty and penetrating keratoplasty for keratoconus: a four-year comparative study. AB - PURPOSE: To compare the status of corneal endothelium and central corneal thickness within the first four postoperative years after deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PK) in patients with keratoconus. MATERIALS AND METHODS: Thirty-nine eyes (Group A) which had PK and 44 eyes (Group B) which had DALK for the treatment of keratoconus were included in this retrospective study. The endothelial cell density (ECD), the mean endothelial cell area and the coefficient of variation of cell area were assessed with a non-contact specular microscope, and the central corneal thickness (CCT) was measured with an ultrasound pachymeter. RESULTS: Mean ECD loss rate at two years was 36.24% in Group A and 18.12% in Group B (P<0.001). Mean ECD loss rate at four years was 47.82% in Group A and 21.62% in Group B (P<0.001). Mean annual ECD loss rate was calculated 14.12% per year in Group A and 5.78% per year in Group B. In the PK group, increase in mean CCT was 15.60% in two years and 15.03% in four years, while in the DALK group, mean CCT increased by 8.05% in two years and 9.31% in four years. CONCLUSIONS: As the majority of ectatic disorders such as keratoconus occur in young people, long-term endothelial cell survival following treatment with keratoplasty is essential for the long-term visual ability. Our finding that corneal endothelial cell loss in the DALK group occurs at a slower rate than in the PK group suggests DALK as a safer alternative to PK in these selected patients. PMID- 22218245 TI - Comparison of different techniques of cataract surgery in bacterial contamination of the anterior chamber in diabetic and non-diabetic population. AB - AIM: To compare the bacterial contamination of the anterior chamber (AC) between manual small incision cataract surgery (SICS) and phacoemulsification (Phaco). To study the conjunctival flora and bacterial contamination of AC between well controlled diabetics and non-diabetics. MATERIALS AND METHODS: Three hundred and sixty-eight patients were randomized to manual SICS and Phaco. Sixty-eight patients were excluded for not completing follow-up or for intraoperative complications like posterior capsule rupture. One hundred and fifty patients in each group were finally analyzed. Conjunctival swabs were taken on admission, after one day of topical ofloxacin and 15 min after 5% Povidone Iodine (PI) instillation. AC aspirate at the end of the surgery was also cultured. RESULTS: Fifty-six (18.66%) patients had positive conjunctival swab on admission which was reduced to 19 (6.33%) with topical ofloxacin and to five (1.66%) with instillation of 5% PI. AC contamination in both manual SICS and Phaco was 0.66%. The conjunctival flora in diabetics was similar to non-diabetics. None of the diabetics had AC contamination. Statistical analysis was performed by Chi-Square test (with Yates' correction). CONCLUSION: Statistically significant reduction in conjunctival flora was achieved with topical ofloxacin and 5% PI instillation and AC contamination in both manual SICS and Phaco was minimal (0.66%). Well controlled diabetics who underwent cataract surgery in this study had similar conjunctival flora and AC contamination as non-diabetics. PMID- 22218246 TI - Assessing Framingham cardiovascular risk scores in subjects with diabetes and their correlation with diabetic retinopathy. AB - AIM: To study the Framingham cardiovascular risk assessment scores in subjects with diabetes and their association with diabetic retinopathy in subjects with diabetes. MATERIALS AND METHODS: In this population-based prospective study, subjects with diabetes were recruited (n=1248; age >=40 years). The Framingham cardiovascular risk scores were calculated for 1248 subjects with type 2 diabetes. The scores were classified as high risk (>10%), and low risk (<10%). RESULTS: Out of the 1248 subjects, 830 (66.5%) patients had a low risk of developing cardiovascular disease (CVD) in 10 years and 418 (33.5%) had a high risk of developing CVD in 10 years. The risk of developing CVD was more in males than females (56.8% vs. 7%) The prevalence of both diabetic retinopathy and sight threatening retinopathy was more in the high-risk group (21% and 4.5%, respectively). The risk factors for developing diabetic retinopathy were similar in both the groups (low vs. high) - duration of diabetes (OR 1.14 vs. 1.08), higher HbA1c (OR 1.24 vs. 1.22), presence of macro- and microalbuminuria (OR 10.17 vs. 6.12 for macro-albuminuria) and use of insulin (OR 2.06 vs. 4.38). The additional risk factors in the high-risk group were presence of anemia (OR 2.65) and higher serum high density lipoprotein (HDL) cholesterol (OR 1.05). CONCLUSION: Framingham risk scoring, a global risk assessment tool to predict the 10-year risk of developing CVD, can also predict the occurrence and type of diabetic retinopathy. Those patients with high CVD scores should be followed up more frequently and treated adequately. This also warrants good interaction between the treating physician/cardiologist and the ophthalmologist. PMID- 22218248 TI - Morphological and functional changes in spectral domain optical coherence tomography and microperimetry in macular microhole variants: spectral domain optical coherence tomography and microperimetry correlation. AB - PURPOSE: To evaluate the relationship between the morphology and retinal function of macular microhole (MMH) variants. MATERIALS AND METHODS: We evaluated 12 eyes of 11 patients with defects in the IS/OS junction of photoreceptor layer with SD OCT. All patients underwent comprehensive ophthalmic examination including spectral domain optical coherence tomography (SD-OCT) and microperimetry. RESULTS: The mean logMAR visual acuity in the affected eye was 0.15 +/- 0.17 (range 0.00-0.5). Mean horizontal diameter of the MMH was 163 +/- 99 MUm; the mean retinal sensitivity in the area corresponding to the MMH was 13.79 +/- 4.6 dB. Negative correlation was found between the MMH diameter and the retinal sensitivity (r = -0.65, P = 0.02). Three morphological patterns of MMH variants were recognized on SD-OCT, which did not differ in retinal sensitivities. CONCLUSION: We described and classified the MMH variants and made an assessment on the physiological functions using microperimeter. PMID- 22218247 TI - Multifocal electroretinogram in normal emmetropic subjects: correlation with optical coherence tomography. AB - AIM OF THE STUDY: To establish the normative database for multifocal electroretinogram (mfERG) parameters in a normal emmetropic population. To correlate the data so obtained with the central macular thickness obtained using the optical coherence tomography (OCT) scan. MATERIALS AND METHODS: mfERG data were obtained from 222 eyes of 111 emmetropic subjects. The amplitude (nv/deg 2 ) and implicit times (ms) of the first-order kernel mfERG responses (N1, P1, and N2 waves) were obtained and grouped into five rings (Ring 1: Central 2 degrees , Ring 2: 2-5 degrees , Ring 3: 5-10 degrees , Ring 4: 10-15 degrees , Ring 5: >15 degrees ). The central macular thickness (CMT) was obtained using the macular thickness scan protocol of the OCT. RESULTS: The mfERG data obtained were used to create a normative database. The amplitudes of the mfERG waves were maximum in the fovea and progressively decreased with increasing eccentricity (P = 0.0001). The latencies of the P1 and N2 waves were longest in the central ring and progressively shortened with eccentricity (P = 0.0001). No statistically significant correlations were observed between central ring 1 parameters and the CMT. CONCLUSION: This study establishes normative database for mfERG parameters in an emmetropic population. No statistically significant correlation was noted between CMT and mfERG parameters. PMID- 22218249 TI - Possible vitreous involvement in a case with rapidly progressing choroidal neovascularization. AB - A 65-year-old man with subfoveal choroidal neovascularization (CNV) underwent photodynamic therapy (PDT). Despite the sequential treatments, the CNV grew larger and finally penetrated the retina. Vitreous adhesion was observed at the edge of the supraretinal fibrotic tissue. The case highlighted the possible unexpected side-effect of PDT. The upregulation of the vascular endothelial growth factor or the enhanced vitreous traction was considered to be responsible for the event. PMID- 22218250 TI - Descemet membrane endothelial keratoplasty with a stromal rim in the treatment of posterior polymorphous corneal dystrophy. AB - A 20-year-old patient, diagnosed with posterior polymorphous corneal dystrophy, developed corneal edema for which he underwent Descemet membrane endothelial keratoplasty with a stromal rim (DMEK-S) in the right eye. No intra- or postoperative complications were noted. At the last follow-up 2 years and 9 months after the procedure, the best corrected visual acuity was 1.0 and endothelial cell density declined from 3533 cells/mm 2 to 1012 cells/mm 2 . Despite the endothelial cell loss, DMEK-S appears to be a good alternative to other surgical techniques for the treatment of corneal endotheliopathies, and it may be of benefit to young patients. PMID- 22218251 TI - Management of peripheral polypoidal choroidal vasculopathy with intravitreal bevacizumab and indocyanine green angiography-guided laser photocoagulation. AB - A 69-year-old lady presented with complaints of decreased vision in left eye since one month. Best Corrected Visual Acuity (BCVA) was 6/18 in that eye. Fundus examination revealed non-central geographic atrophy and soft drusens at macula in both eyes. Temporal periphery of left eye revealed subretinal exudates with altered sub-RPE hemorrhage mimicking peripheral exudative hemorrhagic chorioretinopathy (PEHCR). Fundus Fluorescein Angiogram showed window defects at macula and blocked fluorescence at temporal periphery in left eye. However, Indocyanine green angiography (ICGA) revealed active peripheral choroidal polyps. The patient was successfully treated with intravitreal bevacizumab and ICGA guided laser photocoagulation. 27 months after laser treatment, BCVA improved to 6/9. Rationale of consecutive anti-vascular endothelial growth factor (VEGF) treatment followed by more definitive laser photocoagulation is that anti-VEGF aids in resolution of subretinal fluid, thus making the polyp more amenable to focal laser photocoagulation which stabilizes the choroidal vasculature and prevents further leakage. PMID- 22218252 TI - Comparison of immersion ultrasonography, ultrasound biomicroscopy and anterior segment optical coherence tomography in the evaluation of traumatic phacoceles. AB - Blunt ocular trauma in the elderly can result in anterior dislocation of the crystalline lens into the subconjunctival space (phacocele). Although rare, this presentation can be missed, especially if the patient presents several days after the injury and if the lid is not everted on examination. While a careful clinical examination is adequate in the diagnosis, imaging techniques can be put to use for the accurate location of the associated sclera rupture. We report three cases of post-traumatic phacocele wherein ultrasound biomicroscopy (UBM) was compared to the anterior segment optical coherence tomography (AS-OCT) and B-scan ultrasonography (B-scan), in order to establish the best imaging tool for this condition. We concluded, based on image quality, that UBM could be the imaging modality of choice to aid in the diagnosis of phacocele. PMID- 22218253 TI - Microperimetry and optical coherence tomography in a case of traumatic macular hole and associated macular detachment with spontaneous resolution. AB - The association of macular detachment with posttraumatic macular hole is a known but rare occurrence. Spontaneously occurring resolution of the detachment and closure of the macular hole has been reported only once in the literature. We describe a similar rare event in a young male, the documentation of which was done serially by microperimetry (MP) and optical coherence tomography (OCT). A 17 year-old male presented with a decrease in vision following a closed globe injury to the left eye. A coexisting macular hole and macular detachment were detected in the affected eye. Serial follow-up with OCT and MP documented complete resolution of the macular hole and the macular detachment within 1 week of presentation. The case highlights that spontaneous resolution of traumatic macular hole and related macular detachment may occur and a waiting period is advisable before undertaking any corrective surgical procedure. The pathophysiologic mechanisms of causation and the resolution of posttraumatic macular hole-related retinal detachment are discussed. PMID- 22218254 TI - Magnetic resonance imaging of intact globe superior subluxation into the intracranium. AB - A 67-year-old man with right-sided blunt ocular trauma is reported here. Despite having received primary medical care, the patient complained of severe headache for 14 days. Initial computed tomography (CT) indicated hematoma in the right frontal lobe. However, magnetic resonance imaging (MRI) indicated that the right globe along with its optic nerve had been intactly dislocated into the intracranium and differentiated from hematoma. In this case, the significance of MRI, in blunt ocular trauma work-up, and also regaining successful ocular function are highlighted. PMID- 22218255 TI - Descemet's membrane detachment managed with perfluro-n-octane liquid. AB - We report the case of a 68-year-old male who developed Descemet's membrane detachment after temporal clear corneal phacoemulsification which did not settle with air or viscoelastic injection. The Descemet's membrane was successfully reattached with restoration of 20/50 vision with the help of perfluro-n-octane liquid. To our knowledge, this is the first such case to be reported. PMID- 22218256 TI - Chikungunya virus iridocyclitis in Fuchs' heterochromic iridocyclitis. PMID- 22218257 TI - Tips in ophthalmic photography. PMID- 22218258 TI - Comparison of patient satisfaction with services of vision centers in rural areas of Andhra Pradesh, India. PMID- 22218259 TI - Subconjunctival dirofilariasis mimicking scleritis: first report from Western India. PMID- 22218260 TI - Transient superior oblique paresis after injection of Botulinum Toxin A for facial rejuvenation. PMID- 22218262 TI - Linking nurse characteristics, team member effectiveness, practice environment, and medication error incidence. AB - Clinical unit nurse characteristics, practice environment, and team member effectiveness are assumed to play a critical role in medication safety. This study used a multimethod approach to examine the association of these factors with medication errors. Findings suggested that older, more experienced registered nurses made less medication errors. Environment and team member effectiveness were not strongly associated with medication error incidence. Numerous system factors limited implementation and outcomes of this safety study and are discussed. PMID- 22218263 TI - Keratocystoma of the parotid gland: a clinicopathological study and literature review. AB - The authors investigated the clinicopathological characteristics of keratocystoma of the parotid gland. Two cases of parotid gland keratocystoma in the files of Nanjing Stomatological Hospital were analysed. These slowly growing parotid gland tumours occurred in two women aged 29 and 49 years. The cut surface showed multilocular cystic lesions filled with keratin materials. Histologically, there were multi-cystic spaces and solid epithelium islands, containing keratinized lamellae. Without cytological atypia, the lining stratified squamous epithelium showed apparent keratinization through an orthokeratotic or parakeratotic pathway. No skin appendage formation was observed. Both cases immunoreactively stained positively for AE1/AE3 and CK5/6 but negatively for CK8/18, S-100 and Calponin. There was no evidence of recurrence 3 or 4 years after superficial parotidectomy. The data from these two cases and cases previously published suggest that keratocystoma of the parotid gland is a benign cystic neoplasm. Surgical resection is apparently sufficient for cure. PMID- 22218264 TI - The use of intra-osseous versus extra-osseous distraction devices in atrophic mandibles. AB - To allow for implant placement in severe atrophic edentulous mandibles, distraction osteogenesis can be used to gain sufficient bone height. The efficacy of extra-osseous and intra-osseous devices is evaluated. In this retrospective study, 45 patients treated with an extra-osseous device (EOD) were compared with 43 patients treated with an intra-osseous device (IOD). From a statistical point of view, both patient groups were comparable for age and sex ratio. The IOD group gained more bone height (9.8 mm) than the EOD group (6.0mm). A significantly higher degree of backward tilting of the device was observed in the EOD group (12.1 degrees ), compared with the IOD group (3.0 degrees ). There were also significantly more fractures of the basal bone segment and sensory disturbances of the chin area in the EOD group than in the IOD group. The IOD group scored significantly better on bone height gained, backward tilting of the device, occurrence of fractures, and postoperative sensory disturbances. Despite the fact that the mean preoperative bone height for the IOD group was substantially higher (18.6mm) than for the EOD group (11.9 mm), it may be concluded that for augmentation procedures of the edentulous mandible, the IOD is more favourable. PMID- 22218265 TI - Response to: S. Richardson, N.A. Agni, Z. Pasha, Modified Turkish delight: morcellized polyethylene dorsal graft for rhinoplasty [Int. J. Oral Maxillofac. Surg. 40 (2011) 979-982]. PMID- 22218266 TI - Growing up our way: the first year of life in remote Aboriginal Australia. AB - In this study, we attempted to explore the experiences and beliefs of Aboriginal families as they cared for their children in the first year of life. We collected family stories concerning child rearing, development, behavior, health, and well being between each infant's birth and first birthday. We found significant differences in parenting behaviors and child-rearing practices between Aboriginal groups and mainstream Australians. Aboriginal parents perceived their children to be autonomous individuals with responsibilities toward a large family group. The children were active agents in determining their own needs, highly prized, and included in all aspects of community life. Concurrent with poverty, neocolonialism, and medical hegemony, child-led parenting styles hamper the effectiveness of health services. Hence, until the planners of Australia's health systems better understand Aboriginal knowledge systems and incorporate them into their planning, we can continue to expect the failure of government and health services among Aboriginal communities. PMID- 22218267 TI - Israeli dietitians' professional stigma attached to obese patients. AB - The aim of this study was to explore and define the different dimensions of professional stigma attached to obese patients by dietitians. Four focus groups were conducted with 23 Israeli dietitians. Findings showed that while treating obese patients, dietitians underwent a stigmatization process involving cognitive, emotional, and behavioral phases. Obese patients with an internal locus of control, who took responsibility for their failure to diet, triggered positive feelings (e.g., pity and empathy), whereas obese patients with an external locus of control, who blamed others for their failure, triggered negative feelings (e.g., anger and frustration). Participants' emotional rejection of obese patients was manifested in three behavioral dimensions: instrumental avoidance (e.g., shorter sessions); professional avoidance (e.g., less energy and effort); and interpersonal avoidance (negative tone and evasive verbal and body language). Continuing education for dietitians is recommended to assist them in dealing with their negative feelings and behaviors toward resistant obese patients. PMID- 22218268 TI - When HIV-positive children grow up: a critical analysis of the transition literature in developed countries. AB - Young people with perinatally acquired HIV are routinely problematized in the research literature as inadequately equipped to manage transition to adolescent sexuality and adult clinical care without comprehensive interventions, partly because of challenges associated with adolescence itself, and partly because of neurocognitive and psychosocial dysfunctions commonly attributed to these children. However, little is actually known about this population, given their recent emergence in the HIV epidemic. Using critical discourse analysis, we argue that several problematic assumptions operate in this literature, hampering the objective of understanding these young people. Our analysis can contribute to a reframing of future research on HIV-positive adolescents, by encouraging greater attunement to the experiences of the adolescents themselves and to the discursive meanings that underpin research agendas, so that different and more productive questions can be asked and answered. PMID- 22218270 TI - Linking MRI to daily life experience: the example of poststroke depression. AB - OBJECTIVE: The state-of-the-art tools of neurology, in particular modern neuroimaging techniques, have yet to benefit from the revolution in mobile technologies that provide new insights into the mechanisms underlying clinical syndromes. This study demonstrates the manner in which mobile technologies may provide information that is complementary to MRI data, using the illustration of poststroke depression. METHODS: MRI examinations were provided to 15 stroke patients, followed by computerized ambulatory monitoring of daily life experiences over 1 week. RESULTS: The occurrence of daily life events was significantly associated with the intensity of positive affect during the ambulatory monitoring period. This emotional reactivity was also significantly associated with functional connectivity in brain regions linked with the risk of depression 3 months following stroke. CONCLUSIONS: Novel mobile technologies provide information that is inaccessible to hospital-based tests, and allow for more complete investigations of disorder expression and etiology. PMID- 22218269 TI - Perceptions of sexual risk compensation following posttrial HIV vaccine uptake among young South Africans. AB - Concerns about the impact of risk compensation on advances in biomedical human immunodeficiency virus (HIV) prevention technologies have been documented. We conducted an exploratory qualitative study using focus group discussions with young South African men and women (aged 18 to 24 years) to explore perceptions of risk compensation with regard to a hypothetical posttrial HIV vaccine. During the discussions, participants expressed their disquiet about the potential for risk compensation and the manner in which this might manifest among young people. Discussions specifically focused on reductions in condom use, an increase in multiple partners, and increased frequency of sex. The discussions also revealed contradictory feelings about HIV vaccines: appreciation for their development tempered by concerns about loss of control and undermining morality. Women were particularly concerned with the possibility of increased partner concurrency and infidelity. We suggest that concerns in HIV vaccine target populations about the impact of possible risk compensation be incorporated into strategies for vaccine introduction once vaccines move from the hypothetical to reality. PMID- 22218272 TI - Comment: Mobile technology in neurology. PMID- 22218271 TI - Shared loci for migraine and epilepsy on chromosomes 14q12-q23 and 12q24.2-q24.3. AB - OBJECTIVES: To describe clinical characteristics and to identify susceptibility loci for epilepsy and migraine in a Finnish family with a complex phenotype. METHODS: Participating family members were interviewed and medical files were reviewed. The seizure classification was made according to International League Against Epilepsy criteria. Migraine diagnosis was made using the validated Finnish Migraine Specific Questionnaire for Family Studies and criteria according to the current International Classification of Headache Disorders-II. DNA samples were obtained from 56 family members and nonparametric genome-wide linkage analyses were performed using 382 polymorphic microsatellite markers. The most promising loci were fine-mapped with additional microsatellite markers. RESULTS: Clinical data were obtained from 60 family members of whom 12 (20%) had idiopathic epileptic seizures. Eight of those 12 (67%) also had migraine. Altogether 33 of the 60 family members (55%) had migraine. Significant evidence of linkage was found between a locus on 14q12-q23 and migraine (p = 0.0001). Suggestive evidence of linkage in this region was also found for epilepsy with generalized tonic-clonic seizures (p = 0.0034). In addition, significant evidence of linkage was found at a locus on 12q24.2-q24.3 (p < 0.001) for migraine alone and for the combined phenotype of migraine and epilepsy. CONCLUSIONS: Our data suggest the occurrence of common susceptibility loci for epilepsy and migraine on chromosomes 14q12-q23 and 12q24.2-q24.3, implicating a shared genetic etiology for these 2 diseases. PMID- 22218273 TI - Understanding risk in asymptomatic carotid stenosis: lessons from patients' preferences. PMID- 22218274 TI - Disruptions of functional connectivity in the default mode network of comatose patients. AB - OBJECTIVE: To evaluate the possible role of the default mode network (DMN) in consciousness and assess the diagnostic or prognostic potential of DMN connectivity measures in the assessment of a patient group lacking cognitive awareness. METHODS: DMN connectivity was established using independent component analysis of resting-state fMRI data in patients with reversible (n = 2) and irreversible (n = 11) coma following cardiac arrest and compared to healthy controls (n = 12). RESULTS: A present and intact DMN was observed in controls and those patients who subsequently regained consciousness, but was disrupted in all patients who failed to regain consciousness. CONCLUSIONS: The results suggest that the DMN is necessary but not sufficient to support consciousness. Clinically, DMN connectivity may serve as an indicator of the extent of cortical disruption and predict reversible impairments in consciousness. PMID- 22218275 TI - Reduced head and brain size for age and disproportionately smaller thalami in child-onset MS. AB - OBJECTIVE: Whole brain and regional volume measurement methods were used to quantify white matter, gray matter, and deep gray matter structure volumes in a population of patients with pediatric-onset multiple sclerosis (MS). METHODS: Subjects included 38 patients (mean age 15.2 +/- 2.4 years) and 33 age- and sex matched healthy control (HC) participants. MRI measures included intracranial volume, normalized brain volume, normalized white and gray matter volume, and volumes of the thalamus, globus pallidus, putamen, and caudate. Because these volumes vary across age and sex in children, we normalized the volume measurements for MS and control groups by computing z scores using normative values obtained from healthy children enrolled in the MRI Study of Normal Brain Development. RESULTS: The intracranial volume z score was significantly lower in the patients with MS (-0.45 +/- 1.16; mean +/- SD) compared with the HC participants (+0.25 +/- 0.98; p = 0.01). Patients with MS also demonstrated significant decreases in normalized brain volume z scores (-1.09 +/- 1.49 vs 0.05 +/- 1.22; p = 0.002). After correction for global brain volume, thalamic volumes in the MS population remained lower than those of HCs (-0.68 +/- 1.72 vs 0.15 +/- 1.35; p = 0.02), indicating an even greater loss of thalamic tissue relative to more global brain measures. Moderate correlations were found between T2-weighted lesion load and normalized thalamic volumes (r = -0.44, p < 0.01) and normalized brain volume (r = -0.47, p < 0.01) and between disease duration and normalized thalamic volume (r = -0.58, p < 0.001) and normalized brain volume (r = -0.46, p < 0.01). CONCLUSIONS: When compared with age- and sex-matched control subjects, the onset of MS during childhood is associated with a smaller overall head size, brain volume, and an even smaller thalamic volume. PMID- 22218276 TI - Long-lasting treatment effect of rituximab in MuSK myasthenia. AB - OBJECTIVE: Rituximab has emerged as an efficacious option for drug-resistant myasthenia gravis (MG). However, reports published only describe the short-term follow-up of patients treated and little is known about their long-term clinical and immunologic evolution. Our objective was to report the clinical and immunologic long-term follow-up of 17 patients (6 MuSK+MG and 11 AChR+MG) and compare the response between AChR+MG and MuSK+MG patients. METHODS: Myasthenia Gravis Foundation America postintervention status and changes in treatment and antibody titers were periodically determined. Lymphocyte subpopulations, total immunoglobulin, immunoglobulin G (IgG) anti-MuSK subclasses, and anti-tetanus toxoid IgG before and after treatment were also studied. RESULTS: After a mean post-treatment period of 31 months, 10 of the AChR+MG patients improved but 6 of them needed reinfusions. In contrast, all MuSK+MG patients achieved a remission (4/6) or minimal manifestations (2/6) status and no reinfusions were needed. Consequently, in the MuSK+MG group, prednisone doses were significantly reduced and concomitant immunosuppressants could be withdrawn. Clinical improvement was associated with a significant decrease in the antibody titers only in the 6 MuSK+MG patients. At last follow-up MuSK antibodies were negative in 3 of these patients and showed a decrease of over 80% in the other 3. CONCLUSION: In view of the long-lasting benefit observed in MuSK+MG patients, we recommend to use rituximab as an early therapeutic option in this group of patients with MG if they do not respond to prednisone. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that IV rituximab improves the clinical and immunologic status of patients with MuSK+MG. PMID- 22218277 TI - A randomized trial of decision-making in asymptomatic carotid stenosis. AB - OBJECTIVE: We sought to evaluate whether different presentation formats, presenter characteristics, and patient characteristics affect decision-making in asymptomatic carotid stenosis. METHODS: Subjects included individuals presenting to a neurology clinic. Participants included those over age 18 without known carotid stenosis. Subjects were randomized to a 30-second video with 1 of 5 presentation formats (absolute risk, absolute event-free survival, annualized absolute risk, relative risk, and a qualitative description) delivered by 1 of 4 presenter physicians (black woman, white woman, black man, white man). Subjects then completed a one-page form regarding background demographics and their decision regarding treatment choice. RESULTS: A total of 409 subjects watched the video and completed the survey. Overall, 48.4% of subjects chose surgery. Presentation format strongly predicted choice of surgery (qualitative [64%], relative risk [63%], absolute risk [43%], absolute event-free survival [37%], and annualized absolute risk [35%], p < 0.001). There was a trend for younger age (mean age 52 vs 55, p = 0.054), male gender (53% vs 45%, p = 0.08), and advanced education (42% for high school education or less vs 52% for more than high school education, p = 0.052) to predict surgery choice. Gender and race of presenter, and race of subject, had no influence on the choice of treatment. CONCLUSIONS: Presentation format (information framing) strongly determines patient decision making in asymptomatic carotid stenosis. Subject age, gender, and education level may also influence the decision. Clinicians should consider the influence of these variables when counseling patients. PMID- 22218278 TI - Postmortem verification of MS cortical lesion detection with 3D DIR. AB - OBJECTIVE: To assess the sensitivity and specificity of 3D double inversion recovery (DIR) MRI for detecting multiple sclerosis (MS) cortical lesions (CLs) using a direct postmortem MRI to histopathology comparison. METHODS: Single-slab 3D DIR and 3D fluid-attenuated inversion recovery (FLAIR) images of 56 matched fresh brain samples from 14 patients with chronic MS were acquired at 1.5 T. The images of both sequences were prospectively scored for CLs in consensus by 3 experienced raters who were blinded to histopathology and clinical data. Next, CLs were identified histopathologically and were scored again on 3D DIR and 3D FLAIR (retrospective scoring). CLs were classified as intracortical or mixed gray matter (GM)-white matter lesions. Deep GM lesions were also scored. False positive scores were noted and, from this, specificity was calculated. RESULTS: We found a sensitivity for 3D DIR to detect MS CLs of 18%, which is 1.6-fold higher than 3D FLAIR (improves to 37% with retrospective scoring; 2.0-fold higher than 3D FLAIR). We detected mixed GM-white matter lesions with a sensitivity of 83% using 3D DIR (65% sensitivity for 3D FLAIR), which improved to 96% upon retrospective scoring (91% for 3D FLAIR). For purely intracortical lesions, 3D DIR detected more than 2-fold more than 3D FLAIR (improved to >3-fold upon retrospective scoring). The specificity of 3D DIR to MS CLs was found to be 90%. CONCLUSIONS: In this postmortem verification study, we have shown that 3D DIR is highly pathologically specific, and more sensitive to CLs than 3D FLAIR in MS. PMID- 22218279 TI - CADASIL mutation and Balo concentric sclerosis: a link between demyelination and ischemia? PMID- 22218280 TI - Comment: ischemia or demyelination--or both? PMID- 22218281 TI - Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Ad Hoc Task Force of the Commission on Therapeutic Strategies of the International League Against Epilepsy. AB - OBJECTIVE: To develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. METHODS: The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. RESULTS AND RECOMMENDATIONS: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of ~50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of ~50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors, as pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C). PMID- 22218282 TI - MS cortical lesions on double inversion recovery MRI: few but true. PMID- 22218283 TI - Posture strategies generated by constrained optimization. AB - For people with motion disorders, posture can impact fatigue, discomfort or deformities in the long term. Orthopedic treatments such as orthoses or orthopedic surgeries which change geometric properties can improve posture in these individuals. In this study, a model has been created to study posture strategies in such situations. A 3D mechanical model consisting of eight rigid segments and 30 muscle groups is used in which varying moment arms along the ranges of motion and biarticular muscles are considered. The method is based on static optimization, both to solve the load sharing in the muscle system and to choose posture strategy. The optimization computes the specific posture with minimal required effort (level of muscle activations), while fulfilling constraints containing subject specific ranges of motion, muscle strength/weakness and external support if present. Anthropometry and strength were scaled to each individual, based on reported pediatric anthropometry and strength values, combined with each individual's physical assessment. A control group of 10 able-bodied subjects as well as three subjects with motion disorders were studied, and simulated posture was compared with experimental data. The simulation showed reasonable to good agreement and ability to predict the effect of motion disorders and of external support. An example of application in parameter studies was also presented wherein ankle orthosis angles were varied. The model allows the user to study muscle activity at the muscle group level, position of center of mass and moments at joints in various situations. PMID- 22218284 TI - Accelerometer counts and raw acceleration output in relation to mechanical loading. AB - The purpose of this study was to assess the relationship of accelerometer output, in counts (ActiGraph GT1M) and as raw accelerations (ActiGraph GT3X+ and GENEA), with ground reaction force (GRF) in adults. Ten participants (age: 29.4 +/- 8.2 yr, mass: 74.3 +/- 9.8 kg, height: 1.76 +/- 0.09 m) performed eight trials each of: slow walking, brisk walking, slow running, faster running and box drops. GRF data were collected for one step per trial (walking and running) using a force plate. Low jumps and higher jumps (one per second) were performed for 20 s each on the force plate. For box drops, participants dropped from a 35 cm box onto the force plate. Throughout, three accelerometers were worn at the hip: GT1M, GT3X+ and GENEA. A further GT3X+ and GENEA were worn on the left and right wrist, respectively. GT1M counts correlated with peak impact force (r = 0.85, p < 0.05), average resultant force (r = 0.73, p < 0.05) and peak loading rate (r = 0.76, p < 0.05). Accelerations from the GT3X+ and GENEA correlated with average resultant force and peak loading rate irrespective of whether monitors were worn at the hip or wrist (r > 0.82, p < 0.05, r > 0.63 p < 0.05, respectively). In conclusion, accelerometer count and raw acceleration output correlate positively with GRF and thus may be appropriate for the quantification of activity beneficial to bone. Wrist-worn monitors show a similar relationship with GRF as hip-worn monitors, suggesting that wrist-worn monitors may be a viable option for future studies looking at bone health. PMID- 22218285 TI - Fear processing and social networking in the absence of a functional amygdala. AB - BACKGROUND: The human amygdala plays a crucial role in processing social signals, such as face expressions, particularly fearful ones, and facilitates responses to them in face-sensitive cortical regions. This contributes to social competence and individual amygdala size correlates with that of social networks. While rare patients with focal bilateral amygdala lesion typically show impaired recognition of fearful faces, this deficit is variable, and an intriguing possibility is that other brain regions can compensate to support fear and social signal processing. METHODS: To investigate the brain's functional compensation of selective bilateral amygdala damage, we performed a series of behavioral, psychophysiological, and functional magnetic resonance imaging experiments in two adult female monozygotic twins (patient 1 and patient 2) with equivalent, extensive bilateral amygdala pathology as a sequela of lipoid proteinosis due to Urbach-Wiethe disease. RESULTS: Patient 1, but not patient 2, showed preserved recognition of fearful faces, intact modulation of acoustic startle responses by fear-eliciting scenes, and a normal-sized social network. Functional magnetic resonance imaging revealed that patient 1 showed potentiated responses to fearful faces in her left premotor cortex face area and bilaterally in the inferior parietal lobule. CONCLUSIONS: The premotor cortex face area and inferior parietal lobule are both implicated in the cortical mirror-neuron system, which mediates learning of observed actions and may thereby promote both imitation and empathy. Taken together, our findings suggest that despite the pre-eminent role of the amygdala in processing social information, the cortical mirror-neuron system may sometimes adaptively compensate for its pathology. PMID- 22218287 TI - Finding the missing links in EGFR. PMID- 22218286 TI - Cumulative adversity and smaller gray matter volume in medial prefrontal, anterior cingulate, and insula regions. AB - BACKGROUND: Cumulative adversity and stress are associated with risk of psychiatric disorders. While basic science studies show repeated and chronic stress effects on prefrontal and limbic neurons, human studies examining cumulative stress and effects on brain morphology are rare. Thus, we assessed whether cumulative adversity is associated with differences in gray matter volume, particularly in regions regulating emotion, self-control, and top-down processing in a community sample. METHODS: One hundred three healthy community participants, aged 18 to 48 and 68% male, completed interview assessment of cumulative adversity and a structural magnetic resonance imaging protocol. Whole brain voxel-based-morphometry analysis was performed adjusting for age, gender, and total intracranial volume. RESULTS: Cumulative adversity was associated with smaller volume in medial prefrontal cortex (PFC), insular cortex, and subgenual anterior cingulate regions (familywise error corrected, p < .001). Recent stressful life events were associated with smaller volume in two clusters: the medial PFC and the right insula. Life trauma was associated with smaller volume in the medial PFC, anterior cingulate, and subgenual regions. The interaction of greater subjective chronic stress and greater cumulative life events was associated with smaller volume in the orbitofrontal cortex, insula, and anterior and subgenual cingulate regions. CONCLUSIONS: Current results demonstrate that increasing cumulative exposure to adverse life events is associated with smaller gray matter volume in key prefrontal and limbic regions involved in stress, emotion and reward regulation, and impulse control. These differences found in community participants may serve to mediate vulnerability to depression, addiction, and other stress-related psychopathology. PMID- 22218288 TI - Claims and counterclaims of X-chromosome compensation. PMID- 22218289 TI - Thresholds of replication stress signaling in cancer development and treatment. PMID- 22218295 TI - Conflicts as aversive signals. AB - Theories of human action control deal with the question of how cognitive control is dynamically adjusted to task demands. The conflict monitoring theory of anterior cingulate (ACC) function suggests that the ACC monitors for response conflicts in the ongoing processing stream thereby triggering the mobilization of cognitive control. Alternatively, the outcome evaluation account of ACC function suggests that the ACC monitors for negative performance outcomes, an information that serves as an aversive learning signal for future action selection. Botvinick (2007) recently suggested that both theories might converge on the detection of aversive signals in general. Here, the authors provide first evidence that conflicts are registered as aversive signals. Congruent and incongruent Stroop color-words served as primes, and positive and negative stimuli as targets in an affective priming paradigm. Negative targets were evaluated faster after incongruent than after congruent Stroop primes, and positive targets were evaluated slower after incongruent than after congruent primes. The finding that conflicts are actually registered as aversive signals bridges the gap between competing theories of ACC function and has broad theoretical and behavioral implications as it makes the conflict monitoring theory applicable to a much wider range of situations and tasks. PMID- 22218294 TI - New approaches for dissecting protease functions to improve probe development and drug discovery. AB - Proteases are well-established targets for pharmaceutical development because of their known enzymatic mechanism and their regulatory roles in many pathologies. However, many potent clinical lead compounds have been unsuccessful either because of a lack of specificity or because of our limited understanding of the biological roles of the targeted protease. In order to successfully develop protease inhibitors as drugs, it is necessary to understand protease functions and to expand the platform of inhibitor development beyond active site-directed design and in vitro optimization. Several newly developed technologies will enhance assessment of drug selectivity in living cells and animal models, allowing researchers to focus on compounds with high specificity and minimal side effects in vivo. In this review, we highlight advances in the development of chemical probes, proteomic methods and screening tools that we feel will help facilitate this paradigm shift in drug discovery. PMID- 22218296 TI - The role of the magnocellular visual pathway in the attentional blink. AB - Visual attention has temporal limitations. In the attentional blink (AB) a stream of stimuli such as letters or digits are presented to a participant on a computer monitor at a rapid rate. Embedded in the stream are two targets that the participant must try to identify. Identification of the second target is severely impaired if it is presented within approximately 500ms of the first target. This is the 'blink' in visual attention. In this study we examined the role of the magnocellular visual pathway in the AB. This fast conducting pathway has high temporal resolution and contrast sensitivity. It is also insensitive to the direction of chromatic contrast, and this attribute was exploited in order to isolate its contributions to temporal attention. Colour defined, luminance noise masked AB streams were compared to AB streams of varying achromatic contrast. The four observers, (2F and 2M) aged between 21 and 35years, had normal visual acuity and colour vision. The colour stimuli produced a similar blink to the moderate contrast achromatic stimuli. This indicates that the magnocellular pathway does not have a privileged role in the attentional blink. We provide an explanation of previous apparently contradictory findings in terms of the role of different types of visual masking in the attentional blink. PMID- 22218298 TI - Reconstruction of the subaxial cervical spine using lateral mass and facet screw instrumentation. AB - STUDY DESIGN: Review article. OBJECTIVE: To review the indications, technical details, and complications of lateral mass and transfacet mass fixation methods. SUMMARY OF BACKGROUND DATA: Potential advantages of rigid fixation in subaxial cervical spine have been defined as early mobilization, faster healing and fusion, and increased fusion rates. Lateral mass screw fixation has been the most popular fixation technique for posterior instrumentation. Transfacet screw fixation, on the other hand, is an alternative method less commonly used. METHODS: Narrative and review of the literature. RESULTS: Several different techniques aiming for the most safe and secure lateral mass screw fixation have been described by several different authors. Lateral mass screws provide rigid fixation and high fusion rates in patients with healthy bone. Complications are rare when patients' anatomy is well documented and proper technique is used. Transfacet screw fixation is another method less commonly used and with better biomechanical stability. CONCLUSION: Lateral mass screw provides excellent 3 dimensional fixations from C3 to C7, and currently it is also the most commonly performed posterior fixation method. PMID- 22218299 TI - Scoliosis in a total population of children with cerebral palsy. AB - STUDY DESIGN: Epidemiological total population study based on a prospective follow-up cerebral palsy (CP) registry. OBJECTIVE: To describe the prevalence of scoliosis in a total population of children with CP, to analyze the relation between scoliosis, gross motor function, and CP subtype, and to describe the age at diagnosis of scoliosis. SUMMARY OF BACKGROUND DATA: Children with CP have an increased risk of developing scoliosis. The reported incidence varies, partly due to different definitions and study groups. Knowledge of the prevalence and characteristics of scoliosis in an unselected group of children with different CP types and levels of function is important for health care planning and for analyzing the risk in an individual child. METHODS: A total population of 666 children with CP, aged 4 to 18 years on January 1, 2008, followed with annual examinations in a health care program was analyzed. Gross Motor Function Classification System (GMFCS) level, CP subtype, age at clinical diagnosis of scoliosis, and the Cobb angle at the first radiographical examination were registered. RESULTS: Of the 666 children, 116 (17%) had mild and another 76 (11%) had moderate or severe scoliosis based on clinical examination. Radiographical examination showed a Cobb angle of more than 10 degrees in 54 (8%) children and a Cobb angle of more than 20 degrees in 45 (7%) children. The risk of developing scoliosis increased with GMFCS level and age. In most children, the scoliosis was diagnosed after 8 years of age. Children in GMFCS level IV or V had a 50% risk of having moderate or severe scoliosis by 18 years of age, whereas children in GMFCS level I or II had almost no risk. CONCLUSION: The incidence of scoliosis increased with GMFCS level and age. Observed variations related to CP subtype were confounded by the GMFCS, reflecting the different distribution of GMFCS levels in the subtypes. Follow-up programs for early detection of scoliosis should be based on the child's GMFCS level and age. PMID- 22218297 TI - Sentence processing in Lewy body spectrum disorder: the role of working memory. AB - Prior work has related sentence processing to executive deficits in non-demented patients with Parkinson's disease (PD). We extended this investigation to patients with dementia with Lewy bodies (DLB) and PD dementia (PDD) by examining grammatical and working memory components of sentence processing in the full range of patients with Lewy body spectrum disorder (LBSD). Thirty-three patients with LBSD were given a two-alternative, forced-choice sentence-picture matching task. Sentence type, working memory, and grammatical structure were systematically manipulated in the sentences. We found that patients with PDD and DLB were significantly impaired relative to non-demented PD patients and healthy controls. The deficit in PDD/DLB was most pronounced for sentences lengthened by the strategic placement of an additional prepositional phrase and for sentences with an additional proposition due to a center-embedded clause. However, there was no effect for subject-relative versus object-relative grammatical structure. An MRI voxel-based morphometry analysis in a subset of patients showed significant gray matter thinning in the frontal lobe bilaterally, and this extended to temporal, parietal and occipital regions. A regression analysis related sentence processing difficulty in LBSD to frontal neocortex, including inferior prefrontal, premotor, and dorsolateral prefrontal regions, as well as right superior temporal cortex. These findings are consistent with the hypothesis that patients with PDD and DLB have difficulty processing sentences with increased working memory demands and that this deficit is related in part to their frontal disease. PMID- 22218301 TI - Targeted lentiviral vectors pseudotyped with the Tupaia paramyxovirus glycoproteins. AB - Lentiviral vectors are vectors of choice for many gene therapy applications. Recently, efficient targeting of lentiviral vectors pseudotyped with the Measles virus (MV) glycoproteins has been reported. However, MV antibodies in patients might limit the clinical use of these vectors. We demonstrate here that lentiviral vectors can also be pseudotyped with the glycoproteins of Tupaia paramyxovirus (TPMV), the hemagglutinin (H) and fusion (F) protein. As this animal paramyxovirus has no known close relatives in humans, we do not expect TPMV antibodies in patients. Because TPMV normally does not infect human cells, 'detargeting' from natural receptors is unnecessary. Similar to the MV system, TPMV glycoproteins can mediate targeted cell entry by displaying different single chain antibodies (scAb) directed against surface molecules on target cells on the viral hemagglutinin. We generated a panel of H and F proteins with truncated cytoplasmic tails and determined the variants that efficiently pseudotyped lentiviral vectors. The B-cell marker CD20 was used as a model antigen, and CD20 targeted TPMV vectors selectively transduced CD20-positive cells, including quiescent primary human B-cells. Lentiviral vectors pseudotyped with targeted TPMV envelope proteins might be a valuable vector choice when systemic application of targeted lentiviral vectors in humans is required. PMID- 22218305 TI - A comparative method for both discrete and continuous characters using the threshold model. AB - The threshold model developed by Sewall Wright in 1934 can be used to model the evolution of two-state discrete characters along a phylogeny. The model assumes that there is a quantitative character, called liability, that is unobserved and that determines the discrete character according to whether the liability exceeds a threshold value. A Markov chain Monte Carlo algorithm is used to infer the evolutionary covariances of the liabilities for discrete characters, sampling liability values consistent with the phylogeny and with the observed data. The same approach can also be used for continuous characters by assuming that the tip species have values that have been observed. In this way, one can make a comparative-methods analysis that combines both discrete and continuous characters. Simulations are presented showing that the covariances of the liabilities are successfully estimated, although precision can be achieved only by using a large number of species, and we must always worry whether the covariances and the model apply throughout the group. An advantage of the threshold model is that the model can be straightforwardly extended to accommodate within-species phenotypic variation and allows an interface with quantitative-genetics models. PMID- 22218306 TI - Population dynamics of plant and pollinator communities: stability reconsidered. AB - Plant-pollinator networks are systems of outstanding ecological and economic importance. A particularly intriguing aspect of these systems is their high diversity. However, earlier studies have concluded that the specific mechanisms of plant-pollinator interactions are destabilizing and should lead to a loss of diversity. Here we present a mechanistic model of plant and pollinator population dynamics with the ability to represent a broad spectrum of interaction structures. Using this model, we examined the influence of pollinators on the stability of a plant community and the relationship between pollinator specialization and stability. In accordance with earlier work, our results show that plant-pollinator interactions may severely destabilize plant coexistence, regardless of the degree of pollinator specialization. However, if plant niche differentiation, a classical stabilizing mechanism, is sufficiently strong to overcome the minority disadvantage with respect to pollination, interactions with pollinators may even increase the stability of a plant community. In addition to plant niche differentiation, the relationship between specialization and stability depends on a number of parameters that affect pollinator growth rates. Our results highlight the complex effects of this particular type of mutualism on community stability and call for further investigations of the mechanisms of diversity maintenance in plant-pollinator systems. PMID- 22218302 TI - Antitumor effects of bladder cancer-specific adenovirus carrying E1A-androgen receptor in bladder cancer. AB - The high frequency of recurrence and poor survival rate of bladder cancer demand exploration of novel strategies. Gene therapy via adenovirus has shown promising potential for the treatment of tumors. We constructed a bladder cancer-specific adenovirus carrying E1A-androgen receptor (AR) under the control of UPII promoter and prostate stem cell antigen enhancer (PSCAE), designated as Ad/PSCAE/UPII/E1A AR, and investigated its antitumor effects in vitro and in vivo. We demonstrated that Ad/PSCAE/UPII/E1A-AR could be selectively replicated in bladder tumor cell lines (5637, BIU87, EJ and T24) when compared with control adenovirus Ad/PSCAE/UPII/Luc. However, there was no evidence of cytotoxicity for normal human bladder cell line SV-HUC-1 and hepatoma cell line SMMC7721. AR agonist R1881 could strengthen the oncolytic effect of Ad/PSCAE/UPII/E1A-AR in bladder cancer cells. In addition, we demonstrated that intratumoral injection of Ad/PSCAE/UPII/E1A-AR into established subcutaneous human EJ tumors in nude mice could significantly regress the growth of tumor and markedly prolong survival for tumor-bearing mice; on the other hand, saline-treated tumors continued to grow rapidly. Our studies indicate that Ad/PSCAE/UPII/E1A-AR could effectively treat bladder cancer in vitro and in vivo. Furthermore, our findings provide a promising therapeutic modality for the treatment of bladder cancer. PMID- 22218307 TI - Rensch's rule in large herbivorous mammals derived from metabolic scaling. AB - Rensch's rule, which states that the magnitude of sexual size dimorphism tends to increase with increasing body size, has evolved independently in three lineages of large herbivorous mammals: bovids (antelopes), cervids (deer), and macropodids (kangaroos). This pattern can be explained by a model that combines allometry, life-history theory, and energetics. The key features are that female group size increases with increasing body size and that males have evolved under sexual selection to grow large enough to control these groups of females. The model predicts relationships among body size and female group size, male and female age at first breeding, death and growth rates, and energy allocation of males to produce body mass and weapons. Model predictions are well supported by data for these megaherbivores. The model suggests hypotheses for why some other sexually dimorphic taxa, such as primates and pinnipeds (seals and sea lions), do or do not conform to Rensh's rule. PMID- 22218308 TI - A framework for elucidating the temperature dependence of fitness. AB - Climate warming is predicted to cause large-scale extinctions, particularly of ectothermic species. A striking difference between tropical and temperate ectotherms is that tropical species experience a mean habitat temperature that is closer to the temperature at which fitness is maximized (T(opt)) and an upper temperature limit for survival (T(max)) that is closer to T(opt) than do temperate species. Thus, even a small increase in environmental temperature could put tropical ectotherms at high risk of extinction, whereas temperate ectotherms have a wider temperature cushion. Although this pattern is widely observed, the mechanisms that produce it are not well understood. Here we develop a mathematical framework to partition the temperature response of fitness into its components (fecundity, mortality, and development) and test model predictions with data for insects. We find that fitness declines at high temperatures because the temperature responses of fecundity and mortality act in opposite ways: fecundity decreases with temperature when temperatures exceed the optimal range, whereas mortality continues to increase. The proximity of T(opt) to T(max) depends on how the temperature response of development mediates the interaction between fecundity and mortality. When development is highly temperature sensitive, mortality exceeds reproduction only after fecundity has started to decline with temperature, which causes fitness to decline rapidly to zero when temperatures exceed T(opt). The model correctly predicts empirically observed fitness-temperature relationships in insects from different latitudes. It also suggests explanations for the widely reported phenological shifts in many ectotherms and the latitudinal differences in fitness responses. PMID- 22218309 TI - Hybridization alters early life-history traits and increases plant colonization success in a novel region. AB - Hybridization is hypothesized to promote invasiveness, but empirical tests comparing the performance of hybrid taxa versus parental taxa in novel regions are lacking. We experimentally compared colonization ability of populations of wild radish (Raphanus raphanistrum) with populations of advanced-generation hybrids between wild radish and cultivated radish (Raphanus sativus) in a southeast Texas pasture, well beyond the known invasive range of hybrid radish. We also manipulated the strength of interspecific competition to better generalize across variable environments. In both competitive environments, hybrid populations produced at least three times more seeds than did wild radish populations, a distinction that was driven by greater hybrid seedling emergence, earlier hybrid emergence, and more hybrid seedlings surviving to flower, rather than by greater individual fecundity. Flowering duration in hybrids was less negatively affected by competition than it was in wild radish, while early emergence was associated with subsequent high seed output in both biotypes. Our data show that hybridization can enhance colonization success in a novel region and, by comparison with previous studies, that the life-history traits enhancing hybrid success can differ across regions, even for lineages originating from the same hybridization event. These results imply a much larger arena for hybrid success than previously appreciated. PMID- 22218310 TI - Evolution of dispersal in a predator-prey metacommunity. AB - Dispersal is crucial to allowing species inhabiting patchy or spatially subdivided habitats to persist globally despite the possibility of frequent local extinctions. Theoretical studies have repeatedly demonstrated that species that exhibit a regional metapopulation structure and are subject to increasing rates of local patch extinctions should experience strong selective pressures to disperse more rapidly despite the costs such increased dispersal would entail in terms of decreased local fitness. We extend these studies to consider how extinctions arising from predator-prey interactions affect the evolution of dispersal for species inhabiting a metacommunity. Specifically, we investigate how increasing a strong extinction-prone interaction between a predator and prey within local patches affects the evolution of each species' dispersal. We found that for the predator, as expected, evolutionarily stable strategy (ESS) dispersal rates increased monotonically in response to increasing local extinctions induced by strong predator top-down effects. Unexpectedly for the prey, however, ESS dispersal rates displayed a nonmonotonic response to increasing predator-induced extinction rates-actually decreasing for a significant range of values. These counterintuitive results arise from how extinctions resulting from trophic interactions play out at different spatial scales: interactions that increase extinction rates of both species locally can, at the same time, decrease the frequency of interaction between the prey and predator at the metacommunity scale. PMID- 22218311 TI - Behavioral types of predator and prey jointly determine prey survival: potential implications for the maintenance of within-species behavioral variation. AB - Recent studies in animal behavior have emphasized the ecological importance of individual variation in behavioral types (e.g., boldness, activity). Such studies have emphasized how variation in one species affects its interaction with other species. But few (if any) studies simultaneously examine variation in multiple interacting species, despite the potential for coevolutionary responses to work to either maintain or eliminate variation in interacting populations. Here, we investigate how individual differences in behavioral types of both predators (ocher sea stars, Pisaster ochraceus) and prey (black turban snails, Chlorostoma funebralis) interact to mediate predation rates. We assessed activity level, degree of predator avoidance behavior, and maximum shell diameter of individual C. funebralis and activity levels of individual P. ochraceus. We then placed 46 individually marked C. funebralis into outdoor mesocosms with a single P. ochraceus and allowed them to interact for 14 days. Overall, predator avoidance behavior and maximum shell diameter were positively associated with survival for C. funebralis. However, the effects of these traits depended on the predator's behavioral type: greater predator avoidance behavior was favored with active P. ochraceus, and low predator avoidance behavior was favored with inactive P. ochraceus. We argue that, even in two-species interactions, trait variation in heterospecifics could be an important factor maintaining trait variation within populations. PMID- 22218312 TI - New insights into virulence evolution in multigroup hosts. AB - Many of the standard predictions in evolutionary epidemiology result from models in which all hosts are equally susceptible to acquiring an infection and equally capable of resisting pathogens once an infection has been established. This contrasts with the empirical reality that natural host populations are typically composed of individuals with various susceptibilities and vulnerabilities to pathogen exploitation that can influence all aspects of a given pathogen's transmission-virulence phenotype. In these structured host settings, host dependent variation in the virulence-transmission trade-off plays an important role in determining pathogen evolution. By deriving some game-theoretic equilibrium expressions that describe pathogen evolution in heterogeneous host populations, the contribution of host heterogeneity to the direction of evolution in host exploitation is made explicit. Within this framework, qualitative departures from predictions derived from theory utilizing a homogeneous host assumption can be seen as a manifestation of Simpson's paradox in an evolutionary setting. By reconsidering some predictions from homogeneous host theory through the lens of this new perspective, it can be seen that many standard predictions are actually special cases that result when homogeneity in immunity parameters is imposed on host populations. PMID- 22218313 TI - Haplodiploidy and the evolution of eusociality: split sex ratios. AB - It is generally accepted that from a theoretical perspective, haplodiploidy should facilitate the evolution of eusociality. However, the "haplodiploidy hypothesis" rests on theoretical arguments that were made before recent advances in our empirical understanding of sex allocation and the route by which eusociality evolved. Here we show that several possible promoters of the haplodiploidy effect would have been unimportant on the route to eusociality, because they involve traits that evolved only after eusociality had become established. We then focus on two biological mechanisms that could have played a role: split sex ratios as a result of either queen virginity or queen replacement. We find that these mechanisms can lead haplodiploidy to facilitating the evolution of helping but that their importance varies from appreciable to negligible, depending on the assumptions. Furthermore, under certain conditions, haplodiploidy can even inhibit the evolution of helping. In contrast, we find that the level of promiscuity has a strong and consistently negative influence on selection for helping. Consequently, from a relatedness perspective, monogamy is likely to have been a more important driver of eusociality than the haplodiploidy effect. PMID- 22218314 TI - Behavioral responses in structured populations pave the way to group optimality. AB - An unresolved controversy regarding social behaviors is exemplified when natural selection might lead to behaviors that maximize fitness at the social-group level but are costly at the individual level. Except for the special case of groups of clones, we do not have a general understanding of how and when group-optimal behaviors evolve, especially when the behaviors in question are flexible. To address this question, we develop a general model that integrates behavioral plasticity in social interactions with the action of natural selection in structured populations. We find that group-optimal behaviors can evolve, even without clonal groups, if individuals exhibit appropriate behavioral responses to each other's actions. The evolution of such behavioral responses, in turn, is predicated on the nature of the proximate behavioral mechanisms. We model a particular class of proximate mechanisms, prosocial preferences, and find that such preferences evolve to sustain maximum group benefit under certain levels of relatedness and certain ecological conditions. Thus, our model demonstrates the fundamental interplay between behavioral responses and relatedness in determining the course of social evolution. We also highlight the crucial role of proximate mechanisms such as prosocial preferences in the evolution of behavioral responses and in facilitating evolutionary transitions in individuality. PMID- 22218315 TI - On the equivalence of host local adaptation and parasite maladaptation: an experimental test. AB - In spatiotemporally varying environments, host-parasite coevolution may lead to either host or parasite local adaptation. Using reciprocal infestations over 11 pairs of plots, we tested local adaptation in the hen flea and its main host, the great tit. Flea reproductive success (number of adults at host fledging) was lower on host individuals from the same plot compared with foreign hosts (from another plot), revealing flea local maladaptation. Host reproductive success (number of fledged young) for nests infested by foreign fleas was lower compared with the reproductive success of controls, with an intermediate success for nests infested by local fleas. This suggests host local adaptation although the absence of local adaptation could not be excluded. However, fledglings were heavier and larger when reared with foreign fleas than when reared with local fleas, which could also indicate host local maladaptation if the fitness gain in offspring size offsets the potential cost in offspring number. Our results therefore challenge the traditional view that parasite local maladaptation is equivalent to host local adaptation. The differences in fledgling morphology between nests infested with local fleas and those with foreign fleas suggest that flea origin affects host resource allocation strategy between nestling growth and defense against parasites. Therefore, determining the mechanisms that underlie these local adaptation patterns requires the identification of the relevant fitness measures and life-history trade-offs in both species. PMID- 22218316 TI - Fungal pathogen species richness: why do some plant species have more pathogens than others? AB - Variation among plant species in the number of associated herbivore and pathogen species is predicted to fit a species-area relationship in which the area or biomass embodied by a plant species is a function of individual size and geographic range size. This hypothesis is tested using published estimates of geographic range, individual size, and species richness of fungal pathogens for 490 plant species occurring in the United States and controlling for sampling intensity and phylogenetic effects. The number of pathogens found on a plant species increases with the metrics of area and/or habitat diversity of plant species, and their effects are similar between gymnosperm and angiosperm lineages. The strength of this pattern across a diverse set of plant lineages suggests that accumulation and persistence of pathogen species on plant species are governed by similar processes among temperate plants. PMID- 22218317 TI - Suppression of social conflict and evolutionary transitions to cooperation. AB - Evolutionary conflict arises at all levels of biological organization and presents a barrier to the evolution of cooperation. This barrier can be overcome by mechanisms that reduce the disparity between the fitness optima of subunits, sometimes called the "battleground" of conflict. An alternative, unstudied possibility is that effort invested in conflict is unprofitable. This possibility has received little attention because most existing models of social conflict assume that fitness depends on the ratio of players' conflict efforts, so that "peaceful" outcomes featuring zero conflict effort are evolutionarily unstable. Here I show that peaceful outcomes are stable where success depends on the difference rather than the ratio of efforts invested in conflict. These difference form models are particularly appropriate to model strategies of suppression or policing. The model suggests that incomplete information and asymmetries in strength can act to eliminate costly conflict within groups, even among unrelated individuals, and thereby facilitate the evolution of cooperation. PMID- 22218318 TI - Biotic interactions, rapid evolution, and the establishment of introduced species. AB - The biotic environment can pose a challenge to introduced species; however, it is not known how rapid evolution in introduced and resident species influences the probability that the introduced species will become established. Here, we analyze the establishment phase of invasion with eco-evolutionary models of introduced species involved in predator-prey, mutualistic, or competitive interactions with a resident species. We find that, depending on the strength of the biotic interaction, establishment is impossible, guaranteed, or, in a narrow range, determined by genetic variation. Over this narrow range, rapid evolution of the introduced species always favors establishment, whereas resident evolution may either inhibit or facilitate establishment, depending on the interaction type. Coevolution can also either increase or decrease the chance of establishment, depending on the initial genotype frequencies as well as the interaction type. Our results suggest that the conditions under which genetic variation influences establishment success are limited, but they highlight the importance of considering the resident community's evolutionary response to introduced species as a component of its invasibility. PMID- 22218319 TI - Evolutionarily labile species interactions and spatial spread of invasive species. AB - Both exotic and native species have been shown to evolve in response to invasions, yet the impacts of rapidly evolving interactions between novel species pairs have been largely ignored in studies of invasive species spread. Here, I use a mathematical model of an interacting invasive predator and its native prey to determine when and how evolutionary lability in one or both species might impact the dynamics of the invader's spatial advance. The model shows that evolutionarily labile invaders continually evolve better adapted phenotypes along the moving invasion front, offering an explanation for accelerating spread and spatial phenotype clines following invasion. I then analytically derive a formula to estimate the relative change in spread rate due to evolution. Using parameter estimates from the literature, this formula shows that moderate heritabilities and selection strengths are sufficient to account for changes in spread rates observed in historical and ongoing invasions. Evolutionarily labile native species can slow invader spread when genes flow from native populations with exposure to the invader into native populations ahead of the invasion front. This outcome is more likely in systems with highly diffuse native dispersal, net directional movement of natives toward the invasion front, or human inoculation of uninvaded native populations. PMID- 22218322 TI - Infected aortic aneurysm and inflammatory aortic aneurysm--in search of an optimal differential diagnosis. AB - Infected aortic aneurysm and inflammatory aortic aneurysm each account for a minor fraction of the total incidence of aortic aneurysm and are associated with periaortic inflammation. Despite the similarity, infected aortic aneurysm generally shows a more rapid change in clinical condition, leading to a fatal outcome; in addition, delayed diagnosis and misuse of corticosteroid or immunosuppressing drugs may lead to uncontrolled growth of microorganisms. Therefore, it is mandatory that detection of aortic aneurysm is followed by accurate differential diagnosis. In general, infected aortic aneurysm appears usually as a saccular form aneurysm with nodularity, irregular configuration; however, the differential diagnosis may not be easy sometimes for the following reasons: (1) symptoms, such as abdominal and/or back pain and fever, and blood test abnormalities, such as elevated C-reactive protein and enhanced erythrocyte sedimentation rate, are common in infected aortic aneurysm, but they are not found infrequently in inflammatory aortic aneurysm; (2) some inflammatory aortic aneurysms are immunoglobulin (Ig) G4-related, but not all of them; (3) the prevalence of IgG4 positivity in infected aortic aneurysm has not been well investigated; (4) enhanced uptake of 18F-fluorodeoxyglucose (FDG) by 18F-FDG positron emission tomography may not distinguish between inflammation mediated by autoimmunity and that mediated by microorganism infection. Here we discuss the characteristics of these two forms of aortic aneurysm and the points of which we have to be aware before reaching a final diagnosis. PMID- 22218323 TI - Serum tenascin-C levels as a prognostic biomarker of heart failure events in patients with hypertrophic cardiomyopathy. AB - BACKGROUND AND PURPOSE: Although serum tenascin-C (TN-C) levels are related to left ventricular (LV) remodeling in patients with myocardial infarction and are useful as a prognostic biomarker of heart failure in patients with dilated cardiomyopathy, the clinical significance of TN-C levels has not yet been studied in patients with hypertrophic cardiomyopathy (HCM). Therefore, the purpose of this study is to elucidate whether serum TN-C levels are a prognostic biomarker for heart failure in patients with HCM. METHODS: The relationship between serum TN-C levels and heart failure events was studied in 36 patients with HCM during follow-up. RESULTS: Levels of serum TN-C were 28+/-13 ng/ml (range 11-80 ng/ml). Although patients with LV systolic impairment showed higher TN-C levels than those with preserved LV systolic function (33+/-11 ng/ml vs. 27+/-14 ng/ml; p=0.16), TN-C levels were not related to any echocardiographic parameters. During the follow-up period of 4.8+/-1.4 years, heart failure events were observed in six patients and TN-C levels in patients with events were higher than those in patients without events. Kaplan-Meier analysis showed that the prognosis was worse in patients with high TN-C levels (>=39.2 ng/ml) than in those with low TN C levels. CONCLUSIONS: Heart failure events were more frequently observed in patients with high serum TN-C levels than in those with low TN-C levels. Serum TN C levels may be a new prognostic biomarker for heart failure in patients with HCM. PMID- 22218320 TI - Increasing temperature, not mean temperature, is a cue for avian timing of reproduction. AB - Timing of reproduction in temperate-zone birds is strongly correlated with spring temperature, with an earlier onset of breeding in warmer years. Females adjust their timing of egg laying between years to be synchronized with local food sources and thereby optimize reproductive output. However, climate change currently disrupts the link between predictive environmental cues and spring phenology. To investigate direct effects of temperature on the decision to lay and its genetic basis, we used pairs of great tits (Parus major) with known ancestry and exposed them to simulated spring scenarios in climate-controlled aviaries. In each of three years, we exposed birds to different patterns of changing temperature. We varied the timing of a temperature change, the daily temperature amplitude, and the onset and speed of a seasonal temperature rise. We show that females fine-tune their laying in response to a seasonal increase in temperature, whereas mean temperature and daily temperature variation alone do not affect laying dates. Luteinizing hormone concentrations and gonadal growth in early spring were not influenced by temperature or temperature rise, possibly posing a constraint to an advancement of breeding. Similarities between sisters in their laying dates indicate genetic variation in cue sensitivity. These results refine our understanding of how changes in spring climate might affect the mismatch in avian timing and thereby population viability. PMID- 22218324 TI - Coronary heart disease diagnosis by artificial neural networks including genetic polymorphisms and clinical parameters. AB - The aim of this study was to develop an artificial neural networks-based (ANNs) diagnostic model for coronary heart disease (CHD) using a complex of traditional and genetic factors of this disease. The original database for ANNs included clinical, laboratory, functional, coronary angiographic, and genetic [single nucleotide polymorphisms (SNPs)] characteristics of 487 patients (327 with CHD caused by coronary atherosclerosis, 160 without CHD). By changing the types of ANN and the number of input factors applied, we created models that demonstrated 64-94% accuracy. The best accuracy was obtained with a neural networks topology of multilayer perceptron with two hidden layers for models included by both genetic and non-genetic CHD risk factors. PMID- 22218325 TI - Altered trans-mitral flow velocity pattern after exercise predicts development of new-onset atrial fibrillation in elderly patients with impaired left ventricular relaxation at rest: prognostic value of diastolic stress echocardiography. AB - OBJECTIVE: This study attempted to determine whether exercise induced left ventricular (LV) diastolic dysfunction estimated by altered trans-mitral flow (TMF) velocity pattern after exercise is associated with increased risk of cardiac events including new-onset atrial fibrillation (AF) in elderly patients with impaired LV relaxation at rest. BACKGROUND: Diastolic stress echocardiography has been applied to evaluate LV diastolic function during and post-exercise. Prognostic importance of exercise-induced diastolic dysfunction remains uncertain. PATIENTS AND METHODS: We studied 126 patients (70+/-5 years; 70 males) who underwent treadmill stress echocardiography. Doppler measurements were done before exercise and immediately after the post-stress image acquisition, and the ratio between early (E) and atrial (A) TMF velocities was measured. Patients with impaired LV relaxation (E/A<1.0) at rest were studied. Altered TMF velocity pattern was present when patients with E/A<1.0 at rest developed E/A>=1.0 after exercise. Primary endpoints for follow-up were combination of major cardiac events and new-onset AF. RESULTS: There were 42 patients with altered TMF velocity pattern after exercise. During the 5-year follow-up period, there were 30 cardiac events including 13 new-onset AF. Kaplan Meier survival plot demonstrated that altered TMF velocity pattern after exercise is associated with increased risk of cardiac events (p<0.0001) including development of new-onset AF (p=0.0003). Cox hazard ratio analysis demonstrated that altered TMF velocity pattern after exercise was the best predictor of cardiac events (hazard ratio 3.939; 95%confidence interval 1.662-9.337; p=0.0018). CONCLUSIONS: Altered TMF velocity pattern after exercise provides significant prognostic information for predicting cardiac events including new onset AF in elderly patients with impaired left ventricular relaxation at rest. PMID- 22218326 TI - Extraction of eight triazine and phenylurea herbicides in yogurt by ionic liquid foaming-based solvent floatation. AB - The ionic liquid foaming-based solvent floatation (ILF-SF) was developed for extracting triazines and phenylureas from yogurt. These analytes were separated and determined by high performance liquid chromatography. Some experimental parameters, such as the pH value of floatation solution, extraction solvent, kind of ionic liquid and floatation time were investigated and optimized. The mixture of n-propyl alcohol and ethyl acetate was used as extraction solvent and 1-hexyl 3-methylimidazolium hexafluorophosphate was used as foaming agent. The precision and recoveries of eight herbicides vary from 0.17 to 6.90% and from 86.5 to 118.7%, respectively. The detection limits for simeton, simazine, chlortoluron, isoproturon, ametryn, propazine, prometryne and prebane are 0.59, 0.44, 0.44, 0.46, 0.32, 1.01, 0.34 and 0.23 MUgL(-1), respectively. The enrichment factors for the solvent floatation range from 11.6 to 18.6 for the eight herbicides. PMID- 22218327 TI - A general strategy for performing temperature-programming in high performance liquid chromatography--further improvements in the accuracy of retention time predictions of segmented temperature gradients. AB - In the present work it is shown that the linear elution strength (LES) model which was adapted from temperature-programming gas chromatography (GC) can also be employed for systematic method development in high-temperature liquid chromatography (HT-HPLC). The ability to predict isothermal retention times based on temperature-gradient as well as isothermal input data was investigated. For a small temperature interval of DeltaT=40 degrees C, both approaches result in very similar predictions. Average relative errors of predicted retention times of 2.7% and 1.9% were observed for simulations based on isothermal and temperature gradient measurements, respectively. Concurrently, it was investigated whether the accuracy of retention time predictions of segmented temperature gradients can be further improved by temperature dependent calculation of the parameter S(T) of the LES relationship. It was found that the accuracy of retention time predictions of multi-step temperature gradients can be improved to around 1.5%, if S(T) was also calculated temperature dependent. The adjusted experimental design making use of four temperature-gradient measurements was applied for systematic method development of selected food additives by high-temperature liquid chromatography. Method development was performed within a temperature interval from 40 degrees C to 180 degrees C using water as mobile phase. Two separation methods were established where selected food additives were baseline separated. In addition, a good agreement between simulation and experiment was observed, because an average relative error of predicted retention times of complex segmented temperature gradients less than 5% was observed. Finally, a schedule of recommendations to assist the practitioner during systematic method development in high-temperature liquid chromatography was established. PMID- 22218328 TI - Aqueous size exclusion chromatography in semimicro and micro-columns by newly synthesized monodisperse macroporous hydrophilic beads as a stationary phase. AB - A new class of monodisperse macroporous beads in the hydrophilic form were synthesized by seeded microsuspension copolymerization of two acrylic crosslinking agents, glycerol dimethacrylate (GDMA) and glycerol-1,3 diglycerolate diacrylate (GDGDA). The monodisperse porous poly(glycerol dimethacrylate-co-glycerol-1,3-diglycerolate diacrylate), poly(GDMA-co-GDGDA) beads were highly hydrophilic in nature due to hydroxyl functionality resulting from both crosslinking agents. The beads with different particle sizes between 4.5 and 6.7 MUm and with different porous properties were obtained by changing the seed latex to monomer ratio. The bead size decreased, the average pore size increased and the specific surface area decreased with increasing seed latex to monomer ratio. Poly(GDMA-co-GDGDA) beads were slurry packed in microbore and semimicro-HPLC columns and successfully used as a stationary phase in aqueous size exclusion chromatography (SEC) mode in a micro-liquid chromatography system. The aqueous SEC runs were performed by using dextran standards in the molecular weight range of 1000-670,000 Da. SEC calibration curves exhibiting linearity in a wider range of molecular weight were obtained with the semi-micro and micro-HPLC columns packed with the poly(GDMA-co-GDGDA) beads synthesized with the seed latex to monomer ratios of 0.038 and 0.058 g/mL. The dextran standards could be eluted in an analysis time shorter than 2 min using micro or semi-micro columns packed with poly(GDMA-co-GDGDA) beads as stationary medium. These packings are suitable for molecular weight determination between 5*10(3) and 5*10(5) Da in the aqueous medium by using mobile phase flow rates in the range of 25-250 MUL/min. The average molecular weight determinations of different water soluble polymers, an ionic polymer, poly(2-dimethylaminoethyl methacrylate), a zwitterionic polymer, poly([2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide), and a non-ionic polymer, poly(vinyl alcohol) were performed on a semimicro-column packed with the poly(GDMA-co-GDGDA) beads. Satisfactory results were obtained in the molecular weight determination of hydrophilic polymers by aqueous SEC. PMID- 22218329 TI - Comparison of quantitative structure-retention relationship models on four stationary phases with different polarity for a diverse set of flavor compounds. AB - A quantitative structure-retention relationship study was performed for 656 flavor compounds with highly structural diversity on four stationary phases of different polarities, using topological, constitutional, quantum chemical and geometrical descriptors. Statistical methods were employed to find an informative subset that can accurately predict the gas chromatographic retention indices (RIs). Multivariable linear regression (MLR) was used to map the descriptors to the RIs. The stability and validity of models have been tested by internal and external validation, and good stability and predictive ability were obtained. The resulting QSRR models were well-correlated, with the square of correlation coefficients for cross validation, Q2, values of 0.9595, 0.9528, 0.9595 and 0.9223 on stationary phase OV101, DB5, OV17 and C20M, respectively. The molecular properties known to be relevant for GC retention index, such as molecular size, branching, electron density distribution and hydrogen bond effect were well covered by generated descriptors. The descriptors used in models on four stationary phases were compared, and some reasonable explanations about gas chromatographic retention mechanism were obtained. The model may be useful for the prediction of flavor compounds while experimental data is unavailable. PMID- 22218330 TI - Pseudomorphic synthesis of monodisperse magnetic mesoporous silica microspheres for selective enrichment of endogenous peptides. AB - In this work, we describe a novel synthetic strategy of magnetic mesoporous silica spheres (Fe3O4@mSiO2) for the selective enrichment of endogenous peptides. Fe3O4 particles were coated with silica shell by a sol-gel method, followed by pseudomorphic synthesis to transform nonporous silica shell into ordered mesoporous silica shell. The core/shell structure and mesostructure were individually fabricated in two steps, which can be expedient to independently optimize the properties of monodispersion, magnetization and mesostructure. Actually, it was confirmed that the produced Fe3O4@mSiO2 particles possess good monodispersion, high magnetization, superparamagnetism, uniform accessible mesopores, and large surface area and pore volume. With these good properties, Fe3O4@mSiO2 spheres were applied to the rapid enrichment of peptides. Based on the size-exclusion mechanism and hydrophobic interaction with siloxane bridge group mainly on the surface of inside pores, Fe3O4@mSiO2 can selectively capture peptides and exclude high-MW proteins and salts. Furthermore, peptides in human plasma were successfully enriched by Fe3O4@mSiO2. PMID- 22218331 TI - Combination of off-line two-dimensional hydrophilic interaction liquid chromatography for polar fraction and two-dimensional hydrophilic interaction liquid chromatography*reversed-phase liquid chromatography for medium-polar fraction in a traditional Chinese medicine. AB - Two-dimensional liquid chromatography (2-D LC) has been widely used for the analysis of complex samples owing to its great improvement in separation selectivity and peak capacity. However, one 2-D LC system may not be enough to meet the separation requirements due to the complexity of certain samples and respective limitations of two separation modes. In this work, water extract of Scutellaria barbata D. Don, a traditional Chinese medicine, was fractionated into polar fraction and medium-polar fraction by means of solid phase extraction (SPE). The fraction preparation made it easy to select the corresponding combination of 2-D LC method from hydrophilic interaction chromatography (HILIC) and reversed-phase liquid chromatography (RP-LC). An off-line 2-D HILIC*HILIC to analyze the polar fraction and an off-line 2-D HILIC*RP-LC to analyze the medium polar fraction were developed, respectively. In total, 749 peaks were detected: 206 peaks from the polar fraction by the 2-D HILIC*HILIC and 543 from the medium polar fraction by the 2-D HILIC*RP-LC. The practical peak capacities obtained in both systems were 2698 and 2879, and the orthogonality reached 63.18% and 90.62%, respectively. The results demonstrated that the two systems were both highly orthogonal, and the peak capacities greatly increased. PMID- 22218332 TI - A label-free electrochemical assay for quantification of gene-specific methylation in a nucleic acid sequence. AB - A label-free electrochemical method is developed for simple and convenient quantification of gene-specific DNA hypermethylation in a DNA sequence without PCR amplification, bisulfite conversion or labeling processes. PMID- 22218335 TI - The catalytic efficiency of lipase in a novel water-in-[Bmim][PF6] microemulsion stabilized by both AOT and Triton X-100. AB - In the water-in-[Bmim][PF(6)] microemulsion stabilized by both AOT and Triton X 100, the lipase-catalyzed hydrolysis of 4-nitrophenyl butyrate (p-NPB) was investigated to evaluate the catalytic efficiency of lipase in this novel microemulsion. The structural parameters of the microemulsion and the conditions of the enzymatic reaction affect the catalytic activity of lipase, especially the concentration of Tris-HCl buffer. Under optimum conditions, the catalytic activity of lipase in the present microemulsion is much higher than that in H(2)O saturated [Bmim][PF(6)]. When the partitioning of the substrate in the microemulsion is taken into account, the catalytic efficiency of lipase in this novel microemulsion is 14.3 times that in H(2)O saturated [Bmim][PF(6)] due to the significant decrease of the Michaelis constant in the microemulsion. Due to the large interface, high water activity, and probably the activating effect of the imidazolium cation in the water pool, the present microemulsion is demonstrated to be a promising medium for the lipase-catalyzed hydrolytic reaction. To demonstrate an important biocatalytic application in the IL-based microemulsion, the lipase-catalyzed synthesis of the flavoring agent benzyl acetate via transesterification of vinyl acetate with benzyl alcohol was also studied in the medium. Due to the high dispersion of lipase, large interface and removal of the byproduct, a maximum yield of 94% was obtained, indicating that the novel microemulsion is really important and useful. PMID- 22218336 TI - Enzymatic activation of cellulose acetate membrane for reducing of protein fouling. AB - In this study, the surface of cellulose acetate (CA) ultrafiltration membrane was activated with serine protease (Savinase) enzyme to reduce protein fouling. Enzyme molecules were covalently immobilized with glutaraldehyde (cross-linking agent) onto the surface of CA membranes. The membrane activation was verified using filtration experiments and morphological analysis. Scanning electron microscopy (SEM) images and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy of the activated membrane when compared with raw membrane were confirmed that the enzyme was immobilized onto the membrane surface. The immobilization efficiencies changed from 13.2 to 41.2% according to the enzyme ratios from 2.5 to 10.0 mg/mL. However, the permeability values decreased from 232+/-6 to 121+/-4 L/m(2) h bar with increasing enzyme concentration from 2.5 to 10.0 mg/mL. In fouling experiments, bovine serum albumin (BSA) was used as the protein model solution and activated sludge was used as the model biological sludge. Enzyme-activated membranes exhibited good filtration performances and protein rejection efficiencies were compared with raw CA membrane. Also the relative flux reduction (RFR) ratios of membranes were calculated as 97% and 88% for raw CA and enzyme-activated membranes (5 mg/mL savinase), respectively. The membrane activated with Savinase enzyme could be proposed as a surface treatment method before filtration to mitigate protein fouling. PMID- 22218337 TI - Role of electrostatic interactions in the toxicity of titanium dioxide nanoparticles toward Escherichia coli. AB - The increasing production and use of titanium dioxide nanoparticles (NP-TiO(2)) has led to concerns about their possible impact on the environment. Bacteria play crucial roles in ecosystem processes and may be subject to the toxicity of these nanoparticles. In this study, we showed that at low ionic strength, the cell viability of Escherichia coli was more severely affected at pH 5.5 than at pH 7.0 and pH 9.5. At pH 5.5, nanoparticles (positively charged) strongly interacted with the bacterial cells (negatively charged) and accumulated on their surfaces. This phenomenon was observed in a much lower degree at pH 7.0 (NP-TiO(2) neutrally charged and cells negatively charged) and pH 9.5 (both NP-TiO(2) and cells negatively charged). It was also shown that the addition of electrolytes (NaCl, CaCl(2), Na(2)SO(4)) resulted in a gradual reduction of the NP-TiO(2) toxicity at pH 5.5 and an increase in this toxicity at pH 9.5, which was closely related to the reduction of the NP-TiO(2) and bacterial cell electrostatic charges. PMID- 22218338 TI - Surface self-segregation, wettability, and adsorption behavior of core-shell and pentablock fluorosilicone acrylate copolymers. AB - The surfaces of films cast from core-shell fluorosilicone acrylate copolymer (BA/MMA/DFHM and BA/MMA/DFHM/MPTMS/D(4)) latexes and linear pentablock fluorosilicone acrylate copolymer (PDMS-b-(PMMA-b-PDFHM)(2)) solutions are intensively investigated and compared by XPS, DCA, AFM, and QCM-D measurements. It is found that the molecular structures and in-solution aggregate structures of these well-defined copolymers have a dramatic influence on the surface structure formation, surface wetting, and adsorption behavior. The PDMS-b-(PMMA-b-PDFHM)(2) film cast from chloroform solution with high concentration of low-density unimers is able to perform as strong surface self-segregation of fluorine-containing groups as core-shell copolymer latex films. The BA/MMA/DFHM/MPTMS/D(4) in the core-shell latex particles exhibits the less pronounced surface self-segregation of silicon-containing groups than PDMS-b-(PMMA-b-PDFHM)(2) due to the occurrence of cross-linking reactions between polysiloxane chains. Indeed, such reactions induce the formation of silica network within the film material, which immobilizes tightly the fluorinated groups on the film surface and thus endows the film with higher surface structural stability for water compared to PDMS-b (PMMA-b-PDFHM)(2) film with similar surface fluorine concentration and even higher silicon concentration. Still, the PDMS-b-(PMMA-b-PDFHM)(2) film definitely demonstrates higher advancing and receding contact angles for water than BA/MMA/DFHM/MPTMS/D(4) latex film in the case of synergism between surface enrichment of fluorine and silicon. PMID- 22218339 TI - Synthesis of zinc oxide-encapsulated poly(methyl methacrylate)-chitosan core shell hybrid particles and their electrochemical property. AB - The synthesis of hybrid materials possessing zinc oxide nanoparticles encapsulated in core-shell polymer particles having poly(methyl methacrylate) core and chitosan shell (PMMA-CS/ZnO) was carried out via an emulsifier-free emulsion polymerization. The ZnO nanoparticles modified by 3 (trimethoxysilyl)propyl methacrylate (TPMZnO) were first prepared before being charged to the polymerization system. The effects of polymerization time (from 2 h to 6 h) and the amount of TPMZnO added (0.018 g, 0.020 g, and 0.030 g) were studied. It was found that the polymerization time of 5 h yielded colloidally stable hybrid latex with% MMA conversion up to 90%. Moreover, the increase in the amount of TPMZnO resulted in a decrease in% MMA conversion from 90% to 80%. It was also found from TGA analysis that the amount of TPMZnO added affected the percentage of TPMZnO encapsulation. PMMA-CS/ZnO particles with the size ranging from 173 to 245 nm were observed by TEM. In addition, the PMMA-CS/ZnO hybrid latexes possessed high positive charges in the range of 40-51 mV. The electrochemical property of the electrodes fabricated from PMMA-CS/ZnO nanoparticles was illustrated by cyclic voltammetry. PMID- 22218341 TI - Analytical investigation and numerical modeling of collisions between a droplet and a fiber. AB - The kinetics of the collisions between droplet and the fiber is being studied in both theoretical and numerical way. During theoretical investigations the balances between the various components of total energy of the droplet have been used. As a result, we have obtained the conditions (expressed in terms of non dimensional parameters characterizing the system) at which the deposition of the droplet on the fiber or the separation of the droplet from the fiber occurs. The results of theoretical computation have been compared with the results of the numerical simulations using the two-color lattice-Boltzmann method. PMID- 22218340 TI - Controlling the density and site of attachment of gold nanoparticles onto the surface of carbon nanotubes. AB - A facile method for controlling the density and site of attachment of gold nanoparticles onto the surface of carbon nanotubes is demonstrated. Nitric acid based oxidation was carried out to create carboxylic groups exclusively at the ends of carbon nanotubes, whereas oxidation using a mixture of nitric and sulfuric acid with varied reaction time was carried out to control the population of carboxylic groups on the side walls of nanotubes. In turn, 4-aminothiophenol modified gold nanoparticles were covalently interfaced to these carboxylated multi-walled carbon nanotubes in the presence of a zero length cross-linker, 1 ethylene-3-(3-dimethylaminopropyl) carbodiimide. Raman spectroscopic results showed increase in height of disorder band with each of these successive steps, indicating the increase in degree of functionalization of the carbon nanotubes. Fourier transformed infrared spectroscopic analysis affirmed the functionalization of nanostructures and the formation of nanohybrid. Transmission electron and field emission scanning electron microscopic analysis ascertained the attachment of gold nanoparticles to the ends and side walls of the multi walled carbon nanotubes. The new hybrid nanostructures may find applications in electronic, optoelectronic, and sensing devices. PMID- 22218343 TI - A general method for the synthesis of monodisperse hollow inorganic-organic hybrid microspheres with interior functionalized poly(methacrylic acid) shells. AB - Hollow inorganic-organic hybrid microspheres, such as silica, titania, and zirconia, with interior poly(methacrylic acid) (PMAA) functionalized shell were synthesized by a general method containing a two-stage reaction. The hollow inorganic shell-layer with interior polymeric component was formed over the PMAA template during the second-stage controlled hydrolysis of inorganic precursors together with disintegration of PMAA cores and adhering to the interior wall of the silica during the drying process due to the capillary force as well as the competitive hydrogen bond interaction. In this process, PMAA microspheres were prepared by distillation precipitation polymerization of methacrylic acid (MAA) in acetonitrile as the first-stage reaction. The present work elaborately investigated the effects of the reaction conditions, including the amount of the tetraethyl orthosilicate (TEOS) precursors and the amount of ammonium hydroxide catalyst on the morphology and structure of the resultant hollow composite microspheres, which were characterized by transmission electron microscopy (TEM), Fourier-transform infrared spectra (FT-IR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), and nitrogen adsorption-desorption. PMID- 22218342 TI - SiO2/graphene composite for highly selective adsorption of Pb(II) ion. AB - SiO(2)/graphene composite was prepared through a simple two-step reaction, including the preparation of SiO(2)/graphene oxide and the reduction of graphene oxide (GO). The composite was characterized by UV-Vis spectroscopy, Fourier transform infrared spectroscopy, scanning electron microscope, and X-ray photoelectron spectroscopy, and what is more, the adsorption behavior of as synthesized SiO(2)/graphene composite was investigated. It was interestingly found that the composite shows high efficiency and high selectivity toward Pb(II) ion. The maximum adsorption capacity of SiO(2)/graphene composite for Pb(II) ion was found to be 113.6 mg g(-1), which was much higher than that of bare SiO(2) nanoparticles. The results indicated that SiO(2)/graphene composite with high adsorption efficiency and fast adsorption equilibrium can be used as a practical adsorbent for Pb(II) ion. PMID- 22218344 TI - Activation energy of the reaction between hexacyanoferrate (SH) and thiosulfate ions catalyzed by platinum nanoparticles confined in nanometer space. AB - Pt nanoparticles (NPs) have been successfully encapsulated in SBA-15 mesoporous silica support. The silica was firstly functionalized by polyaminoamine (PAMAM) dendrimers with various generations and provided different nanometer space for Pt NPs. The growth of Pt NPs is restricted by the double confinement effect of PAMAM dendrimers and SBA-15 mesopores. The Pt NPs can be precisely controlled to localize inter- or intradendrimeric within SBA-15 tunnels. The different pore structures of Gn-PAMAM-SBA-15 (Gn-PS15) support have great influence on the catalytic performance of the encapsulated Pt NPs. The blocking structure of higher generation Gn-PS15 support debased the catalytic performance and increased the activation energy of reaction between Fe(CN)(6)(3-) and S(2)O(3)(2-) in a certain degree. PMID- 22218345 TI - High yield synthesis of intrinsic, doped and composites of nano-zinc oxide using novel combinatorial method. AB - A novel synthesis of the production of luminescent zinc oxide (ZnO), either in its intrinsic, metal, non-metal-doped or composite forms with high yield has been developed by parallel iterative techniques, within a combinatorial library prepared by the reduction of nitroarenes. The reduction of nitroarenes by aluminium/zinc dusts in alkaline medium (pH 10+/-2) forms azoxy compounds, whereas in acidic medium (pH 4.9+/-0.2) forms phenyl hydroxylamine and zinc/aluminium dust gets oxidised into respective hydroxide. Here, we demonstrate the reduction of nitroarenes at neutral pH (7.0+/-0.2), which forms intrinsic as well as doped ZnO at 50+/-5 degrees C using zinc dust alone or mixtures of salts of several transition and non-transition metals in presence of 1:10 ratio of solvent and water. Interestingly, it is observed that the photoluminescence emission could be tuned in a wide range from 390 to 615 nm useful for many display related devices. PMID- 22218346 TI - Convergence analysis and oscillations in the method of fictitious sources applied to dielectric scattering problems. AB - Several wave scattering phenomena in optics are modeled by the method of fictitious sources (MFS). Despite its interesting features, the effectiveness of the MFS and its applicability are restricted by open issues, including the placement of the fictitious sources (FS) and the fields' convergence. Concerning these issues, we investigate here the MFS convergence and study oscillations in its solutions for a representative scattering problem of a dielectric cylinder illuminated by a current filament. It is shown analytically that, when the FS radii lie in the interior and exterior of two disks with certain critical radii, the MFS currents' series diverge while the respective fields converge, as the FS number N tends to infinity. Asymptotic formulas of the divergent currents are established, exhibiting that they increase exponentially with N and oscillate. Numerical simulations are included, demonstrating that (i) the divergent currents oscillate for sufficiently large N, (ii) the oscillating values are fairly approximated by the derived asymptotic expressions, and (iii) these oscillations are inherent in MFS and are not due to ill-conditioning; hence, they cannot be overcome by improving the hardware or software. The possibility of obtaining convergent and correct fields from divergent intermediary currents may lead to a potential significant advance of the applicability of the MFS. PMID- 22218347 TI - Specularity and shadow detection for the multisource photometric reconstruction of a textured surface. AB - Textured surface analysis is essential for many applications. In this paper, we present a three-dimensional (3D) recovery approach for real textured surfaces based on photometric stereo. The aim is to be able to reconstruct the textured surfaces in 3D with a high degree of accuracy. For this, the proposed method uses a sequence of six images and a Lambertian bidirectional reflectance distribution function (BRDF) to recover the surface height map. A hierarchical selection of these images is employed to eliminate the effects of shadows and highlights for all surface facets. To evaluate the performances of our method, we compare it to other traditional photometric stereo methods on real textured surfaces using six or more images. PMID- 22218348 TI - Multiple scattering of electromagnetic waves by an aggregate of uniaxial anisotropic spheres. AB - An exact analytical solution is obtained for the scattering of electromagnetic waves from a plane wave with arbitrary directions of propagation and polarization by an aggregate of interacting homogeneous uniaxial anisotropic spheres with parallel primary optical axes. The expansion coefficients of a plane wave with arbitrary directions of propagation and polarization, for both TM and TE modes, are derived in terms of spherical vector wave functions. The effects of the incident angle alpha and the polarization angle beta on the radar cross sections (RCSs) of several types of collective uniaxial anisotropic spheres are numerically analyzed in detail. The characteristics of the forward and backward RCSs in relation to the incident wavelength are also numerically studied. Selected results on the forward and backward RCSs of several types of square arrays of SiO2 spheres illuminated by a plane wave with different incident angles are described. The accuracy of the expansion coefficients of the incident fields is verified by comparing them with the results obtained from references when the plane wave is degenerated to a z-propagating and x- or y-polarized plane wave. The validity of the theory is also confirmed by comparing the numerical results with those provided by a CST simulation. PMID- 22218350 TI - High-accuracy wave field reconstruction: decoupled inverse imaging with sparse modeling of phase and amplitude. AB - We apply a nonlocal adaptive spectral transform for sparse modeling of phase and amplitude of a coherent wave field. The reconstruction of this wave field from complex-valued Gaussian noisy observations is considered. The problem is formulated as a multiobjective constrained optimization. The developed iterative algorithm decouples the inversion of the forward propagation operator and the filtering of phase and amplitude of the wave field. It is demonstrated by simulations that the performance of the algorithm, both visually and numerically, is the current state of the art. PMID- 22218349 TI - Multipole theory for tight focusing of polarized light, including radially polarized and other special cases. AB - A multipole expansion, based on spherical harmonics, provides an efficient method for calculating the field in the focal region of a lens for radially polarized illumination, or other illumination polarization and phase distributions, including vortex beams. The multipole approach also has the benefit of providing a simple measure of the purity of the longitudinal field mode. The method is also convenient for calculation of fields scattered by particles and calculation of optical trapping forces. PMID- 22218351 TI - Method for estimating the relative contribution of phase and power spectra to the total information in natural-scene patches. AB - A wide variety of recent studies have argued that the human visual system provides an efficient means of processing the information in the natural environment. However, the amount of information (entropy) in the signal can be estimated in a number of ways, and it is has been unclear how much of the information is carried by the different sources of redundancy. The primary difficulty is that there has been no rational way to estimate the entropy of such complex scenes. In this paper, we provide a technique that uses a recent approach to estimating the entropy and dimensionality of natural scenes [D. M. Chandler and D. J. Field, J. Opt. Soc. Am. A 24, 922-941 (2007)] to estimate the amount of information attributable to the power and phase spectra in natural-scene patches. By comparing the entropies of patches that have swapped phase spectra and fixed phase spectra, we demonstrate how to estimate both the amount of information in each type of spectrum and the amount of information that is shared by these spectra (mutual information). We applied this technique to small patches (4*4 and 8*8). From our estimates, we show that the power spectrum of 8*8 patches carries approximately 54% of the total information, the phase spectrum carries 56%, and 10% is mutual information (54%+56%-10%=100%). This technique is currently limited to relatively small image patches, due to the number of patches currently in our collection (on the order of 106). However, the technique can, in theory, be extended to larger images. Even with these relatively small patches, we discuss how these results can provide important insights into both compression techniques and efficient coding techniques that work with relatively small image patches (e.g., JPEG, sparse coding, independent components analysis). PMID- 22218352 TI - Design of a general point focusing crystal geometry for x-ray spectroscopy. AB - A nearly exact general equation for geometrical angular deviations from the Bragg angle over entire curved crystal surfaces is derived using a toroidally curvilinear coordinate system and applied on the nine conventional crystal geometries. Although the derived formula confirms Wittry's results for the first five cases, it shows considerable differences for the more important cases, such as 45 degrees point focusing, general point focusing, and Berreman geometries. The effective scattering areas for the mentioned cases have been derived, plotted, and interpreted. A point-to-point focusing crystal geometry is introduced, and it is shown that it approaches Wittry's and spherical plane spherical Johansson geometries as theta(B) -> 90 degrees and theta(B) -> 0 degrees , respectively. PMID- 22218353 TI - Coherence effects in Mie scattering. AB - The scattering of a partially coherent beam by a deterministic, spherical scatterer is studied. In particular, the Mie scattering by a Gaussian Schell model beam is analyzed. Expressions are derived for (a) the extinguished power, (b) the radiant intensity of the scattered field, and (c) the encircled energy in the far field. It is found that the radiant intensity and the encircled energy in the far field depend on the degree of coherence of the incident beam, whereas the extinguished power does not. PMID- 22218354 TI - Effect of spatial coherence on scattering from optically inhomogeneous media. AB - The properties of light scattered from material systems depend on the characteristics of input optical fields. We study numerically the effect of the state of spatial coherence on the properties of scattered fields. Using a customized coupled dipole technique, we demonstrate that this influence manifests in changes of the statistics of intensities scattered at different angles. PMID- 22218355 TI - Polarization ellipse and Stokes parameters in geometric algebra. AB - In this paper, we use geometric algebra to describe the polarization ellipse and Stokes parameters. We show that a solution to Maxwell's equation is a product of a complex basis vector in Jackson and a linear combination of plane wave functions. We convert both the amplitudes and the wave function arguments from complex scalars to complex vectors. This conversion allows us to separate the electric field vector and the imaginary magnetic field vector, because exponentials of imaginary scalars convert vectors to imaginary vectors and vice versa, while exponentials of imaginary vectors only rotate the vector or imaginary vector they are multiplied to. We convert this expression for polarized light into two other representations: the Cartesian representation and the rotated ellipse representation. We compute the conversion relations among the representation parameters and their corresponding Stokes parameters. And finally, we propose a set of geometric relations between the electric and magnetic fields that satisfy an equation similar to the Poincare sphere equation. PMID- 22218356 TI - Rigorous analysis of whispering gallery mode frequency conversion because of time variation of refractive index in a spherical resonator. AB - We investigate theoretically the switching effects for the whispering gallery modes in a spherical dielectric resonator when its material is subject to abrupt time change in permittivity. A rigorous analytical approach is used to study the transformation process. Details of both the transient response and the steady state regime are described. PMID- 22218357 TI - Phase retrieval via spatial light modulator phase modulation in 4f optical setup: numerical inverse imaging with sparse regularization for phase and amplitude. AB - The 4f optical setup is considered with a wave field modulation by a spatial light modulator located in the focal plane of the first lens. Phase as well as amplitude of the wave field are reconstructed from noisy multiple-intensity observations. The reconstruction is optimal due to a constrained maximum likelihood formulation of the problem. The proposed algorithm is iterative with decoupling of the inverse of the forward propagation of the wave field and the filtering of phase and amplitude. The sparse modeling of phase and amplitude enables the advanced high-accuracy filtering and sharp imaging of the complex valued wave field. Artifacts typical for the conventional algorithms (wiggles, ringing, waves, etc.) and attributed to optical diffraction can be suppressed by the proposed algorithm. PMID- 22218358 TI - Self-consistent optical constants of sputter-deposited B4C thin films. AB - The optical constants of ion-beam-sputtered B4C films have been measured by ellipsometry in the 190-950 nm range. The set of data has been extended toward both shorter and longer wavelengths with data in the literature, along with interpolations and extrapolations, in order to obtain a self-consistent set of data by means of Kramers-Kronig analysis. All data correspond to films that were deposited by sputtering on nonheated substrates, and hence they are expected to be amorphous. The B4C bandgap was calculated as a fitting parameter of Tauc equations for indirect transitions using the present optical constants. Good global accuracy of the data was estimated through the use of various sum rules. The consistent data set includes the visible to the extreme UV (EUV); this large spectrum of characterization will enable the design of multilayer coatings that combine a relatively high reflectance in parts of the EUV with a desired performance at a secondary range, such as the visible. PMID- 22218359 TI - Approaches to achieve broadband optical transformation devices with transmuted singularity. AB - Many optical instruments with dielectric singularities cannot be manufactured directly. Their singularities can be transmuted through optical transformation, and equivalent physical media can be built to perform the same optical behaviors. The transformed physical media are usually anisotropic and inhomogeneous and, therefore, difficult to fabricate. In this work, several mathematical approaches are proposed to produce a transformed lens with all the elements of the material tensors to be no less than unity. This increases the ease of implementation, as natural materials may be used, which substantially widens the bandwidth of the transformed devices. Although we focus on an omnidirectional retroreflection lens as an example, the approaches developed here are universal and applicable to a wide class of devices with dielectric singularities. PMID- 22218360 TI - Spatiotemporal receptive fields of cells in V1 are optimally shaped for stimulus velocity estimation. AB - In recent literature, particularly interesting stimulus velocity-selective behaviors were found in the response properties of neurons belonging to the primary visual cortex (V1). In this work, 93 simple and complex cell receptive fields were obtained from the recordings of different experiments made on cats (DeAngelis, Blanche, Touryan) with reverse correlation and the spike-triggered covariance methods and then fitted with a three-dimensional Gabor model, so that cells are seen as minimizers of the Heisenberg uncertainty principle over both space and time. Analysis of the model parameters' cortical distribution suggests that V1 is spatiotemporally organized to maximize the resolution on the stimulus velocity measure. PMID- 22218361 TI - Reflection and transmission of normally incident full-vector X waves on planar interfaces. AB - The reflection and transmission of full-vector X waves normally incident on planar half-spaces and slabs are studied. For this purpose, X waves are expanded in terms of weighted vector Bessel beams; this new decomposition and reconstruction method offers a more lucid and intuitive interpretation of the physical phenomena observed upon the reflection or transmission of X waves when compared to the conventional plane-wave decomposition technique. Using the Bessel beam expansion approach, we have characterized changes in the field shape and the intensity distribution of the transmitted and reflected full-vector X waves. We have also identified a novel longitudinal shift, which is observed when a full vector X wave is transmitted through a dielectric slab under frustrated total reflection condition. The results of our studies presented here are valuable in understanding the behavior of full-vector X waves when they are utilized in practical applications in electromagnetics, optics, and photonics, such as trap and tweezer setups, optical lithography, and immaterial probing. PMID- 22218363 TI - Re2O(7)-catalyzed three-component synthesis of protected secondary and tertiary homoallylic amines. AB - Three-component synthesis of protected secondary and "for the first time" tertiary homoallylic amines is achieved from carbonyl, carbamate, and allyltrimethylsilanes using a Re(2)O(7)-catalyst under mild and open flask conditions. Excellent chemoselectivities and diastereoselectivities were observed. PMID- 22218362 TI - Strategy of computed tomography sinogram inpainting based on sinusoid-like curve decomposition and eigenvector-guided interpolation. AB - Projection incompleteness in x-ray computed tomography (CT) often relates to sparse sampling or detector gaps and leads to degraded reconstructions with severe streak and ring artifacts. To suppress these artifacts, this study develops a new sinogram inpainting strategy based on sinusoid-like curve decomposition and eigenvector-guided interpolation, where each missing sinogram point is considered located within a group of sinusoid-like curves and estimated from eigenvector-guided interpolation to preserve the sinogram texture continuity. The proposed approach is evaluated on real two-dimensional fan-beam CT data, for which the projection incompleteness, due to sparse sampling and symmetric detector gaps, is simulated. A Compute Unified Device Architecture (CUDA)-based parallelization is applied on the operations of sinusoid fittings and interpolations to accelerate the algorithm. A comparative study is then conducted to evaluate the proposed approach with two other inpainting methods and with a compressed sensing iterative reconstruction. Qualitative and quantitative performances demonstrate that the proposed approach can lead to efficient artifact suppression and less structure blurring. PMID- 22218364 TI - A novel NIR fluorescent turn-on sensor for the detection of pyrophosphate anion in complete water system. AB - A novel fluorescent sensor DCAA-Cu(2+) was developed, showing turn-on fluorescence in NIR region with high selectivity to pyrophosphate anion in 100% aqueous solution. PMID- 22218365 TI - [Treatment of facial lipoatrophy by lipofilling in HIV infected patients: retrospective study on 317 patients on 9 years]. AB - INTRODUCTION: HIV infection and antiretroviral therapy are responsible in 20 to 40% of cases of facial lipoatrophy. This one has an impact in an important way on the quality of life with a major social impact. Several treatments are available to correct facial lipoatrophy. We evaluate the efficiency of autologous fat transfer described by Coleman (Lipostructure(r)). PATIENTS AND METHODS: We recorded HIV-infected patients who had facial lipofilling between May 1999 and April 2008.Then, we estimated the severity of their lipoatrophy and the result of lipofilling after 1 month to 4 years follow-up. RESULTS: We have treated 317 patients by lipofilling. We have injected a mean of 8mL of fat on each side. There were no adverse events. Sixty-three percent had a good result on 1-year evaluation. CONCLUSION: Lipofilling is a safe and stable surgical procedure that makes the reference technique to correct facial lipoatrophy in HIV-infected patients. The use of facial fillers must be limited in case of impossibility to take fat tissue, which was exceptional in our study. PMID- 22218366 TI - Meta-analysis of incidence of rare events. AB - This is a review of methods for the meta-analysis of incidence of rare events using summary-level data. It is motivated and illustrated by the dataset used in a published analysis of cardiovascular safety in rosiglitazone trials. This review compares available methods for binary data, considering risk-difference, relative-risk and odds-ratio scales, fixed-effect and random-effects models, and frequentist and Bayesian approaches. Particular issues in this dataset include low incidence rates, the occurrence of studies with no events under one or all treatments, and discrepancy among results achieved using different statistical methodologies. The common method of adding a correction factor to handle zeroes may introduce bias where the incidence of events is small, as in this case. Alternative analyses on the log-odds scale are shown to give similar results, but the choice between them is less important than the potential sources of bias in any meta-analysis arising from limitations in the underlying dataset. It is important to present results carefully, including numerical and graphical summaries on the natural scale of risk when the analysis is on a statistically appropriate scale such as log-odds: the incidence rates should accompany an estimated ratio (of odds or risk) to put the analysis into the proper context. Beyond the statistical methodologies which are the focus of this paper, this dataset highlights the importance of understanding the limitations of the data being combined. Because the rosiglitazone dataset contains clinically heterogeneous trials with low event rates that were not designed or intended to assess cardiovascular outcomes, the findings of any meta-analysis of such trials should be considered hypothesis-generating. PMID- 22218367 TI - The network meta-analytic-predictive approach to non-inferiority trials. AB - In non-inferiority clinical trials, a test treatment is compared to an active control rather than to placebo. Such designs are considered when placebo is unethical or not feasible. The critical question is whether the test treatment would have been superior to placebo, had placebo been used in the non-inferiority trial. This question can only be addressed indirectly, based on information from relevant historical trials with data on active-control and placebo. The network meta-analytic-predictive approach to non-inferiority trials is based on a network meta-analysis of the data from the historical trials and the non-inferiority trial, and the prediction of the putative test vs. placebo effect in the non inferiority trial. The approach extends previous work by incorporating between trial variability for all relevant parameters and focusing on the parameters in the non-inferiority trial rather than on population means. Two prominent examples with binary outcomes are used to illustrate the approach. PMID- 22218368 TI - Issues in performing a network meta-analysis. AB - The example of the analysis of a collection of trials in diabetes consisting of a sparsely connected network of 10 treatments is used to make some points about approaches to analysis. In particular various graphical and tabular presentations, both of the network and of the results are provided and the connection to the literature of incomplete blocks is made. It is clear from this example that is inappropriate to treat the main effect of trial as random and the implications of this for analysis are discussed. It is also argued that the generalisation from a classic random-effect meta-analysis to one applied to a network usually involves strong assumptions about the variance components involved. Despite this, it is concluded that such an analysis can be a useful way of exploring a set of trials. PMID- 22218370 TI - Exuviotrophic apostome ciliates from freshwater decapods in southern Alabama (USA) and a description of Hyalophysa clampi n. sp. (Ciliophora, Apostomatida). AB - Apostome ciliates from crayfish and freshwater shrimp in southern and central Alabama were surveyed in this study. Hyalophysa bradburyae was found on both crayfish and shrimp from 16 sites in eight drainages. A new species, Hyalophysa clampi n. sp., was found infesting crayfish at one site and simultaneously infesting crayfish with H. bradburyae at two sites. Characteristics of the trophont ciliature of H. clampi n. sp. separate it from other species in the genus. Particularly, the contractile vacuole pore is oriented posterior to the ventral kineties xyz, kineties 1 and 2 are undivided, an apparent second contractile vacuole pore is present between the ventral portions of kineties 1 and 2, the anterior ventral field is tightly arranged, and there is an apical field of kineties between kineties 4 through 6. This report expands the known range and diversity of the genus Hyalophysa in the state of Alabama. PMID- 22218371 TI - The striking influence of SWNT-COOH on self-assembled gelation. AB - A miniscule amount of f-SWNTs remarkably improved (~17-fold) the gelation efficiency of amphiphilic molecules by triggering the formation of interconnecting self-assembled fibrillar networks (SAFIN) in supramolecular gelation. PMID- 22218372 TI - Solid state NMR studies of oligourea foldamers: interaction of 15N-labelled amphiphilic helices with oriented lipid membranes. AB - Synthetic oligomers that are derived from natural polypeptide sequences, albeit with unnatural building blocks, have attracted considerable interest in mimicking bioactive peptides and proteins. Many of those compounds adopt stable folds in aqueous environments that resemble protein structural elements. Here we have chemically prepared aliphatic oligoureas and labeled them at selected positions with (15)N for structural investigations using solid-state NMR spectroscopy. In the first step, the main tensor elements and the molecular alignment of the (15)N chemical shift tensor were analyzed. This was possible by using a two-dimensional heteronuclear chemical shift/dipolar coupling correlation experiment on a model compound that represents the chemical, and thereby also the chemical shift characteristics, of the urea bond. In the next step (15)N labeled versions of an amphipathic oligourea, that exert potent antimicrobial activities and that adopt stable helical structures in aqueous environments, were prepared. These compounds were reconstituted into oriented phospholipid bilayers and the (15)N chemical shift and (1)H-(15)N dipolar couplings of two labeled sites were determined by solid-state NMR spectroscopy. The data are indicative of an alignment of this helix parallel to the membrane surface in excellent agreement with the amphipathic character of the foldamer and consistent with previous models explaining the antimicrobial activities of alpha-peptides. PMID- 22218373 TI - An integrated AFM-Raman instrument for studying heterogeneous catalytic systems: a first showcase. AB - The integration of Atomic Force Microscopy and Raman spectroscopy is tested for use in heterogeneous catalysis research by a preliminary investigation, the photo oxidation of rhodamine-6G. Temperature and atmosphere were varied in an in situ cell to show compatibility with realistic reaction conditions. PMID- 22218374 TI - Primary amino-functionalized N-heterocyclic carbene ligands as support for Au(I)...Au(I) interactions: structural, electrochemical, spectroscopic and computational studies of the dinuclear [Au2(NH2(CH2)2imMe)2][NO3]2. AB - The N-heterocyclic carbene (NHC) precursor, 1-(2-aminoethyl)-3-methylimidazolium nitrate, [NH(2)(CH(2))(2)imMe)]NO(3) ([3][NO(3)]) reacted with Ag(2)CO(3) in dimethyl sulfoxide readily yielding a Ag(I)-(NHC-NH(2)) complex presenting limited stability in solution. The in situ carbene transfer reaction of the latter with [Au(tht)Cl] afforded the first example of a dinuclear gold(I) complex [Au(2)(NH(2)(CH(2))(2)imMe)(2)][NO(3)](2) ([5][NO(3)](2)) bearing a primary amino functionalized NHC ligand. The complex has been characterized by NMR, mass spectrometry, X-ray crystallography and cyclic voltammetry; the electrochemical behaviour and photophysical properties of [5][NO(3)](2) have been also investigated and the experimental data have been compared with density functional theory (DFT) and Time Dependent (TDDFT) calculations. Single-crystal structural studies showed that the Au(I)-carbene compound contains dinuclear (AuL)(2) cations in which pairs of gold(I) centres are linked by a pair of bridging ligands, with a Au...Au aurophilic contact of 3.2332(17) A that is maintained in solution as documented by the DFT calculations. Complex [5][NO(3)](2) is photoluminescent in solution at room temperature and the high energy emission peak at 410 nm is remarkably shifted with respect to the absorption band centered at 260 nm. PMID- 22218375 TI - Stability and change in 2012. PMID- 22218376 TI - Intra-articular injection of hyaluronic acid is not superior to saline solution injection for ankle arthritis: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Intra-articular injections of hyaluronic acid are potentially useful to treat ankle osteoarthritis, yet their effectiveness has not been proven. Both single and multiple-dose treatments for ankle arthritis with use of various hyaluronic acid products have been recommended, but few high-quality studies have been published. The aim of this study was to compare the effectiveness of a single intra-articular injection of hyaluronic acid with a single intra-articular injection of normal saline solution (placebo) for osteoarthritis of the ankle. METHODS: Sixty-four patients with ankle osteoarthritis who met all study criteria were randomly assigned to a single intra-articular injection of 2.5 mL of low molecular-weight, non-cross-linked hyaluronic acid or a single intra-articular injection of 2.5 mL of normal saline solution. The primary outcome measure was the change from baseline in the American Orthopaedic Foot & Ankle Society (AOFAS) clinical rating score at the six-week and twelve-week follow-up examination. Secondary outcome measures included the Ankle Osteoarthritis Scale score and patient-reported pain with use of a visual analog pain scale. RESULTS: Of the sixty-four patients randomized and treated, eight patients withdrew, leaving fifty-six patients who completed the entire study. There was one mild adverse event (1.6%) among the sixty-four patients. At six weeks and twelve weeks, the mean AOFAS scores in the hyaluronic acid group had improved from baseline by 4.9 and 4.9 points, respectively, whereas the mean AOFAS scores in the placebo group initially worsened by 0.4 point at six weeks and then improved by 5.4 points at twelve weeks. While the change at twelve weeks from baseline was substantial for both groups, the between-group differences were not significant. CONCLUSIONS: We found that a single intra-articular injection of low-molecular-weight, non-cross linked hyaluronic acid is not demonstrably superior to a single intra-articular injection of saline solution for the treatment of osteoarthritis of the ankle. PMID- 22218377 TI - Impact of comorbidities on hospitalization costs following hip fracture. AB - BACKGROUND: Hip fractures are common in the elderly, and patients with hip fractures frequently have comorbid illnesses. Little is known about the relationship between comorbid illness and hospital costs or length of stay following the treatment of hip fracture in the United States. We hypothesized that specific individual comorbid illnesses and multiple comorbid illnesses would be directly related to the hospitalization costs and the length of stay for older patients following hip fracture. METHODS: With use of discharge data from the 2007 Nationwide Inpatient Sample, 32,440 patients who were fifty-five years or older with an isolated, closed hip fracture were identified. Using generalized linear models, we estimated the impact of comorbidities on hospitalization costs and length of stay, controlling for patient, hospital, and procedure characteristics. RESULTS: Hypertension, deficiency anemias, and fluid and electrolyte disorders were the most common comorbidities. The patients had a mean of three comorbidities. Only 4.9% of patients presented without comorbidities. The average estimated cost in our reference patient was $13,805. The comorbidity with the largest increased hospitalization cost was weight loss or malnutrition, followed by pulmonary circulation disorders. Most other comorbidities significantly increased the cost of hospitalization. Compared with internal fixation of the hip fracture, hip arthroplasty increased hospitalization costs significantly. CONCLUSIONS: Comorbidities significantly affect the cost of hospitalization and length of stay following hip fracture in older Americans, even while controlling for other variables. PMID- 22218378 TI - Injuries associated with traumatic anterior glenohumeral dislocations. AB - BACKGROUND: A number of shoulder girdle injuries are associated with acute anterior glenohumeral dislocations. In the present study we evaluated the prevalence of neurological deficits, greater tuberosity fractures, and rotator cuff injuries in a population of unselected patients who presented with a traumatic anterior glenohumeral dislocation. METHODS: A prospective trauma database was used to record the demographic details on 3633 consecutive patients (2250 male patients and 1383 female patients with a mean age of 47.6 years) who had sustained a traumatic anterior glenohumeral dislocation between 1995 and 2009. On the basis of these data, we assessed the prevalence of and risk factors for ultrasound-proven rotator cuff tears, tuberosity fractures, and neurological deficits occurring in association with the dislocation. RESULTS: Of the 3633 patients who had a dislocation, 492 patients (13.5%) had a neurological deficit following reduction and 1215 patients (33.4%) had either a rotator cuff tear or a greater tuberosity fracture. A dislocation with a neurological deficit alone was found in 210 patients (5.8%), a dislocation with a rotator cuff tear or a greater tuberosity fracture was found in 933 patients (25.7%), and a combined injury pattern was found in 282 patients (7.8%). Female patients with an age of sixty years or older who were injured in low-energy falls were more likely to have a rotator cuff tear or a greater tuberosity fracture. The likelihood of a neurological deficit after an anterior glenohumeral dislocation was significantly increased for patients who had a rotator cuff tear or a greater tuberosity fracture (relative risk, 1.9 [95% confidence interval, 1.7 to 2.1]; p < 0.001). CONCLUSIONS: The prevalence of rotator cuff tear, greater tuberosity fracture, or neurological deficit following primary anterior glenohumeral dislocation is greater than previously appreciated. These associated injuries may occur alone or in combined patterns. Dislocations associated with axillary nerve palsy have similar demographic features to isolated dislocations. Injuries associated with a rotator cuff tear, greater tuberosity fracture, or complex neurological deficit are more common in patients sixty years of age or older. Careful evaluation of rotator cuff function is required for any patient with a dislocation associated with a neurological deficit, and vice versa. PMID- 22218379 TI - Conflict of interest in the assessment of thromboprophylaxis after total joint arthroplasty: a systematic review. AB - BACKGROUND: The choice of modalities for thromboprophylaxis after total joint arthroplasty is controversial. To address this issue, an evidence-based review of previous studies was performed. The characteristics of the studies selected for review can affect the final conclusion of an evidence-based review. One such characteristic, financial conflict of interest related to medical research, is a widespread concern. The purpose of the present study was to determine what proportion of studies on thromboprophylaxis after total joint arthroplasty were sponsored by industry and whether the assessments of thromboprophylaxis after total joint arthroplasty were associated with industry support. METHODS: We searched PubMed for prospective, original, English-language studies, published from 2004 to 2010, on thromboprophylaxis after total joint arthroplasty. The funding sources of the articles were reviewed, and qualitative conclusions regarding the modality of interest for thromboprophylaxis after total joint arthroplasty were classified as being favorable, neutral, or unfavorable. RESULTS: Seventy-one eligible articles were identified; fifty-two were funded by industry, and fourteen were not. The other five studies did not include information about the funding source. A significant association was observed between the funding source and qualitative conclusions (p = 0.033). Only two (3.8%) of the fifty-two industry-sponsored studies had unfavorable conclusions, whereas three (21.4%) of the fourteen non-industry-sponsored studies indicated that, depending on the clinical scenario, the modality examined was neither effective nor safe. CONCLUSIONS: Most studies on thromboprophylaxis after total joint arthroplasty are sponsored by industry. Moreover, the qualitative conclusions in those studies are favorable to the use of the sponsored prophylactic agent. PMID- 22218380 TI - Pathologic fractures in children with acute Staphylococcus aureus osteomyelitis. AB - BACKGROUND: Osteomyelitis is a common pediatric musculoskeletal infection. This infection can weaken the normal bone structure, resulting in the risk of a pathologic fracture. The purpose of this study was to evaluate the risk factors for pathologic fracture in children with Staphylococcus aureus osteomyelitis. METHODS: Seventeen children who were treated for a pathologic long-bone fracture secondary to Staphylococcus aureus osteomyelitis between January 2001 and January 2009 at a tertiary-care pediatric hospital were identified. These patients were compared with a control group consisting of forty-nine children with Staphylococcus aureus osteomyelitis without a fracture who were matched for age, sex, and methicillin susceptibility. A retrospective review of the clinical records, magnetic resonance imaging (MRI) studies, and microbiologic findings was performed. RESULTS: Patients who developed a fracture presented with osteomyelitis at a mean age of 8.8 years (range, two to seventeen years). Fifteen of the seventeen patients had methicillin-resistant Staphylococcus aureus (MRSA) isolates, and two had methicillin-susceptible Staphylococcus aureus (MSSA). The mean time from disease onset to fracture was 72.1 days (range, twenty to 150 days). The duration of hospitalization, number of surgical procedures, duration of antibiotic treatment, and total number of complications differed significantly between the two groups. MRI studies at the time of admission demonstrated a significantly greater prevalence of subperiosteal abscess and greater circumferential size of such an abscess in the patients with a fracture. A sharp zone of abnormally diminished enhancement of the marrow was also more common in these patients. The USA300-0114 pulsotype was more commonly associated with an elevated likelihood of fracture. CONCLUSIONS: Staphylococcus aureus osteomyelitis is a serious infection that may predispose children to pathologic fractures. Protected weight-bearing and activity restriction are recommended in children with Staphylococcus aureus osteomyelitis who have the risk factors demonstrated in this study. PMID- 22218381 TI - Intermediate to long-term outcomes of the STAR Total Ankle Replacement: the patient perspective. AB - BACKGROUND: The purpose of the present study was to document the patient self reported improvements in quality of life, function, and overall impairment scores, as well as the improvement in the clinically derived outcome scores, following a Scandinavian Total Ankle Replacement (STAR) arthroplasty performed for the treatment of end-stage ankle arthritis. METHODS: All patients who underwent a Scandinavian Total Ankle Replacement arthroplasty from July 1998 through February 2008 were prospectively followed and retrospectively reviewed. All surgical procedures were performed by a single surgeon. Preoperatively and at subsequent follow-up visits, patients were assessed with (1) a visual analog scale (VAS) score for pain, (2) the Short Form-36 (SF-36) quality-of-life scale, (3) the American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot scale and subscales, (4) the Buechel-Pappas pain and function scores, and (5) the ankle range of motion. Additional measures that were recorded included (1) concomitant surgical procedures during the initial ankle replacement, (2) revision surgery during the follow-up period, and (3) any additional surgical procedures. Revision was defined as failure of either the tibial or the talar metallic component that required removal of a metallic implant for any reason. RESULTS: Eighty-two consecutive patients were evaluated. The duration of follow-up ranged from twenty four to 108 months (mean, sixty-one months; median, sixty months). During the follow-up period, three patients died and six patients moved out of the region. The latter six patients were followed by another surgeon group, and their data were included. Eight patients were lost to follow-up after twelve months. There were significant improvements in all outcome categories between the preoperative and postoperative evaluations. The most compelling finding of the present study involved the marked improvement in terms of the self-reported measures of impairments, quality of life, pain, and function. CONCLUSIONS: Total ankle arthroplasty with the Scandinavian Total Ankle Replacement prosthesis was associated with significant improvements in terms of pain, function, and quality of life after intermediate to long-term follow-up. PMID- 22218382 TI - Temporal and spatial vascularization patterns of unions and nonunions: role of vascular endothelial growth factor and bone morphogenetic proteins. AB - BACKGROUND: Failure of fracture-healing with nonunion is a major clinical problem. Angiogenesis is closely linked to bone regeneration, but the role of angiogenesis in nonunion formation remains unclear. Because established nonunions are well vascularized, we hypothesized that lack of vascular endothelial growth factor (VEGF) expression and vascularization during the early time course of fracture-healing determine nonunion formation. METHODS: In seventy-two CD-1 mice, a femoral osteotomy with a gap size of 1.80 mm (nonunion group) or a gap size of 0.25 mm (union group) was created and stabilized by a pin-clip technique. Healing was analyzed after three, seven, fourteen, twenty-one, twenty-eight, and seventy days by micro-computed tomography and histomorphometry. Vascularization was determined in different healing zones by immunohistochemical staining of PECAM-1 (platelet-endothelial cell adhesion molecule). Additional animals were analyzed after seven, fourteen, and twenty-one days with Western blot analysis of VEGF, bone morphogenetic protein (BMP)-2, and BMP-4 expression. RESULTS: Micro-computed tomography and histomorphometry showed complete bone-bridging in the union group, whereas animals in the nonunion group showed atrophic nonunion formation. Vascularization increased from day 3 to day 7 in both groups, with a subsequent decrease after fourteen days. However, overall vascularization did not differ between unions and nonunions over time. It is of interest that vascularization within the endosteal healing zone was even higher in nonunions than in unions after fourteen days. Expression of VEGF was significantly higher in nonunions, while expression of BMP-2 and 4 and proliferating cell nuclear antigen were found significantly reduced compared with unions. CONCLUSIONS: Because vascularization during the early time course of fracture-healing was not impaired despite the failure of bone-healing in nonunions, we rejected our hypothesis and accepted the null hypothesis that nonunion formation is not due to failure of VEGF-mediated angiogenesis. Failure of fracture-healing was associated with a decreased expression of BMP-2 and 4 and a disturbed ratio of angiogenic to osteogenic growth factors, which may be responsible for nonunion. CLINICAL RELEVANCE: Because the intrinsic angiogenic response during nonunion formation was sufficient for adequate vascularization, treatment strategies for nonunions should focus on the stimulation of osteogenesis rather than on the stimulation of angiogenesis. PMID- 22218383 TI - Articularis genus: an anatomic and MRI study in cadavers. AB - BACKGROUND: The articularis genus muscle is closely associated with the anterior aspect of the knee joint and may act to elevate or retract the suprapatellar bursa. Its form and function are poorly understood. The purpose of this study was to define the morphology of the articularis genus and its relationship to the suprapatellar bursa. METHODS: The articularis genus muscle was investigated in twenty-two human lower limbs obtained from eleven donors (six men and five women; mean age at death, eighty-three years). Eighteen of these limbs underwent magnetic resonance imaging (MRI) followed by dissection. The number, length, physiological cross-sectional area, attachment sites, and orientation of individual fascicles, muscle bundles, and whole muscles were recorded. The remaining four limbs underwent immunohistochemical analysis to determine muscle fiber types. RESULTS: The articularis genus comprised multiple layered muscle bundles originating from the anterior, anterolateral, and/or anteromedial surfaces of the distal third of the femur. Distal attachment sites included the proximal and/or posterior wall of the suprapatellar bursa, the deep surface of the distal tendon of the vastus intermedius, and the medial and lateral aspects of the knee joint capsule. On dissection, the muscle was observed to consist of a mean of seven muscle bundles (range, four to ten), but only a mean of four bundles were observed on MRI scans (p < 0.0001). The mean cross-sectional area of the articularis genus (and standard deviation) was 1.5 +/- 0.7 cm2, and its mean fascicular length and bundle physiological cross-sectional area were 5.9 +/- 1.0 cm and 0.2 +/- 0.1 cm2, respectively. The articularis genus displayed a mixed fiber type, with the proportion of type-I fibers varying among specimens (range, 39.9% to 76.4%). CONCLUSIONS: These findings highlight the complex and variable anatomy of the articularis genus, particularly with respect to the number of bundles and the distal attachment sites. Distinguishing the superficial bundles of the articularis genus from the vastus intermedius on MRI can be difficult. CLINICAL RELEVANCE: Given its relationship to the anterior aspect of the knee joint and its association with the suprapatellar bursa, the articularis genus may be a neglected cause of undifferentiated anterior knee pain. PMID- 22218384 TI - Biomechanical comparison of anatomic humeral head resurfacing and hemiarthroplasty in functional glenohumeral positions. AB - BACKGROUND: Resurfacing of the humeral head has gained interest as an alternative to traditional hemiarthroplasty because it preserves bone stock and respects the native geometry of the glenohumeral articulation. The purpose of this study was to compare the biomechanics of the intact glenohumeral joint with those following humeral head resurfacing and following hemiarthroplasty. METHODS: Seven fresh frozen cadaveric shoulders were tested with the rotator cuff, pectoralis major, and latissimus dorsi musculature loaded with 20 N and the deltoid muscle loaded with 40 N in a custom shoulder testing system. Each specimen was tested in 20 degrees , 40 degrees , 60 degrees , and 80 degrees of vertical abduction. The articular surfaces of the humeral head and the glenoid were digitized to calculate the positions of the geometric center and apex of the humeral head relative to the geometric center of the glenoid at each testing position. The contact area and contact pressures were also measured with use of a Tekscan pressure sensor. RESULTS: The geometric center of the humeral head shifted by a mean (and standard error) of 2.2 +/- 0.3 mm following humeral resurfacing and 4.7 +/- 0.3 mm following hemiarthroplasty (p < 0.0002). The apex of the humeral head was shifted superiorly at all abduction angles following hemiarthroplasty (p < 0.03). Both humeral resurfacing and hemiarthroplasty decreased the glenohumeral contact area and increased the peak pressure. CONCLUSIONS: Resurfacing more closely restored the geometric center of the humeral head than hemiarthroplasty did, with less eccentric loading of the glenoid. CLINICAL RELEVANCE: Compared with hemiarthroplasty, humeral resurfacing may limit eccentric glenoid wear and permit better function because the glenohumeral joint biomechanics and the moment arms of the rotator cuff and the deltoid muscle are restored more closely to those of the intact condition. PMID- 22218385 TI - Evaluation of the safety of a novel knee load-bypassing device in a sheep model. AB - BACKGROUND: Unloading treatments for osteoarthritis of the knee, such as valgus braces, have been shown to reduce medial joint-loading and pain. The purpose of this preclinical study was to investigate the tissue response to an extracapsular implantable device (KineSpring System; Moximed, Hayward, California) that is designed to reduce loading across the medial compartment of the knee. METHODS: Eleven sheep were implanted with the KineSpring System, consisting of bases secured to the medial femoral and tibial cortices with bone screws and also consisting of a joint-spanning load-absorber composed of a piston and spring assembly inside a polymeric sheath. In nine sheep, titanium alloy washers with either an uncoated or a plasma-sprayed titanium-hydroxyapatite (TPS-HA) coated undersurface were fixed with screws to the contralateral femur and tibia to investigate the effects of surface treatment on extracortical bone apposition. The functionality of the KineSpring System was assessed by fluoroscopy, tissue response was determined by gross and microscopic histology, and implant fixation was determined by radiography, microradiography, and histomorphometry at four, twelve, twenty-six, and fifty-two weeks. RESULTS: The function of the KineSpring System was confirmed in all sheep. Seventeen of eighteen TPS-HA coated bases and thirty-six of thirty-six washers had stable bone fixation; one coated base was loose with evidence of infection. At four weeks, there was an early, expected inflammatory response, but this response resolved by twelve weeks and a pseudosynovial membrane formed around the sheath. Bone apposition increased over time for the TPS-HA coated bases and for uncoated washers (p < 0.05). There was good apposition of the TPS-HA coated washers even at early time points, with no subsequent increase in apposition over time. CONCLUSIONS: The KineSpring System demonstrated safety in a simulated use model for periods of up to fifty-two weeks. Screws result in stable implant fixation and TPS-HA coating allows for early and long-lasting cortical bone apposition and integration. CLINICAL RELEVANCE: This implant warrants further investigation as a means of reducing medial compartment loading and pain in patients with osteoarthritis of the knee. PMID- 22218386 TI - Pseudotumors associated with total hip arthroplasty. AB - Pseudotumors are a rare but important complication occurring with all types of hip replacements.The true prevalence of pseudotumors is debated.Potential causes of pseudotumors may include foreign-body reaction, hypersensitivity, and wear debris.The conduct of clinical trials on the incidence, causes, and treatments of pseudotumors has been inadequate as few investigators have used a randomized controlled design to compare various implant types. PMID- 22218387 TI - How to treat osteochondritis dissecans of the knee: surgical techniques and new trends: AAOS exhibit selection. AB - BACKGROUND: Osteochondritis dissecans is a relatively common cause of knee pain. The aim of this study was to describe the outcomes of five different surgical techniques in a series of sixty patients with osteochondritis dissecans. METHODS: Sixty patients (age 22.4 +/- 7.4 years, sixty-two knees) with osteochondritis dissecans of a femoral condyle (forty-five medial and seventeen lateral) were treated with osteochondral autologous transplantation, autologous chondrocyte implantation with bone graft, biomimetic nanostructured osteochondral scaffold (MaioRegen) implantation, bone-cartilage paste graft, or a "one-step" bone-marrow derived cell transplantation technique. Preoperative and follow-up evaluation included the International Knee Documentation Committee (IKDC) score, the EuroQol visual analog scale (EQ-VAS) score, radiographs, and magnetic resonance imaging. RESULTS: The global mean IKDC score improved from 40.1 +/- 14.3 preoperatively to 77.2 +/- 21.3 (p < 0.0005) at 5.3 +/- 4.7 years of follow-up, and the EQ-VAS improved from 51.7 +/- 17.0 to 83.5 +/- 18.3 (p < 0.0005). No influence of age, lesion size, duration of follow-up, or previous surgical procedures on the result was found. The only difference among the results of the surgical procedures was a trend toward better results following autologous chondrocyte implantation (p = 0.06). CONCLUSIONS: All of the techniques were effective in achieving good clinical and radiographic results in patients with osteochondritis dissecans, and the effectiveness of autologous chondrocyte implantation was confirmed at a mean follow-up of five years. Newer techniques such as MaioRegen implantation and the "one-step" transplantation technique are based on different rationales; the first relies on the characteristics of the scaffold and the second on the regenerative potential of mesenchymal cells. Both of these newer procedures have the advantage of being minimally invasive and requiring a single operation. PMID- 22218388 TI - The occurrence of wrong-site surgery self-reported by candidates for certification by the American Board of Orthopaedic Surgery. AB - BACKGROUND: The concept of "Sign Your Site" was established in 1997 to prevent wrong-site surgery in the U.S., and this was expanded to the mandated Universal Protocol in 2008. However, the true incidence of wrong-site surgery in the U.S. is not known, nor do we know whether the incidence has changed. The American Board of Orthopaedic Surgery (ABOS) requires that candidates for Board certification provide a list of their cases, including surgical complications, whether wrong-site surgery was performed, and whether they complied with the "Sign Your Site" practice. Each candidate attests to the accuracy of his or her notarized case list. The purpose of this study was to report the incidence and nature of wrong-site surgery self-reported by orthopaedic surgeon candidates for certification between 1999 and 2010 and to assess whether any change was associated with the timeline of implementation of the Universal Protocol. METHODS: The ABOS database was queried for the number of examinees, cases, and wrong-site surgery cases reported; a description of each wrong-site surgery case; whether the site was signed; and the surgeon's subspecialty. RESULTS: From 1999 through 2010, 9255 orthopaedic surgeons submitted 1,291,396 cases, and sixty-one of these surgeons reported performing seventy-six wrong-site surgical procedures. Spine surgeons were the most likely to report wrong-site surgery, most commonly single-level lumbar laminotomy. The rate of wrong-site surgical procedures before and after implementation of the Universal Protocol mandate was not significantly different. Eighteen of the twenty wrong-site surgical procedures performed since ABOS data collection for "Sign Your Site" began had been signed preoperatively. CONCLUSIONS: Keeping patients safe remains an essential goal worthy of enormous effort. This study suggests that additional layers of precautions may yield diminishing returns and that attention should be focused on methods to prevent wrong-level spine surgery. Improving communication among the health-care team and shared responsibility may bring us closer to eliminating wrong-site surgery. PMID- 22218389 TI - Discussing treatment options with a minor: the conflicts related to autonomy, beneficence, and paternalism. AB - A seventeen-year-old male, high-school football player presents to an orthopaedic surgeon because of recurrent right knee pain after having undergone an arthroscopic meniscal repair one year previously. The patient did well initially but now has recurrent medial joint-line pain in the knee, which developed when he planted the right leg to throw a pass during summer training camp. He was evaluated by the team's athletic trainer and by an orthopaedic surgeon, both of whom, on the basis of their physical examination of the boy, believe that he may have sustained a recurrent meniscal tear. A magnetic resonance arthrogram is acquired, which confirms the presence of a large longitudinal tear of the medial meniscus in the "red-red" zone, with no signs of degenerative change, articular cartilage damage, or other ligamentous pathology. The patient had just started summer training camp before his senior year of high-school football, and he is considered to be a potential high-level candidate for a Division-I football scholarship.The orthopaedic surgeon presents the patient and his mother with three treatment options: nonoperative management, arthroscopic partial meniscectomy, and arthroscopic meniscal repair. He also presents the relevant risks and benefits of each choice, including, for meniscectomy, the risk of the future development of osteoarthritis if a large portion of the meniscus were to be excised and, for meniscal repair, the need for an extended (four to six-month) rehabilitation period. Both the patient and his mother are apprised of the limitations of preoperative magnetic resonance imaging (MRI) in determining if a meniscal tear can be repaired1-3. The patient states that, on the basis of his symptoms of pain, intermittent locking, and swelling, he does not believe that he would be able to play football if nonoperative management was chosen. He voices a strong preference for meniscectomy, as this would allow him the most rapid return to play. He states that he is not concerned with the future risk of osteoarthritis but is fearful that missing his senior football season will place his scholarship in jeopardy. His mother states that her son would likely not attend college without a scholarship, considering the family's financial situation. The patient states that he therefore wishes to have a meniscectomy, given the likely quicker recovery and faster return to play.The patient's mother was initially in favor of a meniscal repair, if possible. However, over the course of the patient's visit with the surgeon, she is persuaded by her son to favor a meniscectomy. The surgeon again discusses in detail the risks involved with meniscectomy in an adolescent-primarily the higher risk of future knee osteoarthritis. The patient remains persistent in his choice, mainly due to his desire to avoid the prolonged postoperative course of limited weight-bearing and physical therapy and thus the loss of his final high-school season. The mother, who is the patient's legal guardian for consent, ultimately follows her son's wishes and elects to consent to only an arthroscopic meniscectomy. PMID- 22218390 TI - A firmer base for clinical judgment about hyaluronic acid injection: commentary on an article by Henry DeGroot III, MD, et al.: "Intra-articular injection of hyaluronic acid is not superior to saline solution injection for ankle arthritis. A randomized, double-blind, placebo-controlled study". PMID- 22218391 TI - Full disclosure is only the first step in managing potential conflicts of interest: commentary on an article by Young-Kyun Lee, MD, et al. "Conflict of interest in the assessment of thromboprophylaxis after total joint arthroplasty. A systematic review". PMID- 22218392 TI - Acoustofluidics 4: Piezoelectricity and application in the excitation of acoustic fields for ultrasonic particle manipulation. AB - Piezoelectric materials are widely used in the excitation of MHz frequency vibrations in devices for ultrasonic manipulation. An applied electrical voltage is transformed into mechanical stress, strain and displacement. Piezoelectric elements can be used in either a resonant or non-resonant manner. Depending on the desired motion the piezoelectric longitudinal, transverse or shear effects are exploited. Because of the coupling between electrical and mechanical quantities in the constitutive law the modelling of devices turns out to be quite complex. In this paper, the general equations that need to be used are delineated. For a one-dimensional actuator the underlying physics is described, including the consequences resulting for the characterization of devices. For a practical setup used in ultrasonic manipulation, finite element models are used to model the complete system, including piezoelectric excitation, solid motion and acoustic field. It is shown, how proper tailoring of transducer and electrodes allows selective excitation of desired modes. PMID- 22218394 TI - Synthesis of glycosylated 5-hydroxylysine, an important amino acid present in collagen-like proteins such as adiponectin. AB - The synthesis of naturally occurring glycosylated (2S,5R)-hydroxylysine still remains a challenge. This perspective highlights the importance of this post translationally modified amino acid residue in the observed bioactivity of collagen and related collagen-like proteins such as adiponectin, an important target for the treatment of type II diabetes. Strategies employed to date for the syntheses of (2S,5R)-hydroxylysine and the methods to effect glycosylation of this modified amino acid are also summarized herein. PMID- 22218395 TI - Administration of biotin prevents the development of insulin resistance in the skeletal muscles of Otsuka Long-Evans Tokushima Fatty rats. AB - Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for type 2 diabetes mellitus. In the present study, we investigated whether pharmacologic doses of biotin have the potential to abate insulin resistance in the skeletal muscles of OLETF rats. OLETF rats (34 weeks of age) were divided into 2 groups and given distilled water (OLETF-control group) or distilled water containing 3.3 mg L(-1) of biotin (OLETF-biotin group) for 8 weeks. At the end of experimental period, the OLETF-control rats developed severe hyperglycemia and hyperinsulinemia, whereas the OLETF-biotin rats showed significantly smaller responses to oral glucose tolerance test than the OLETF-control rats. The glucose uptake in the hind limbs of the rats was significantly higher in the OLETF-biotin group than in the OLETF-control group. Biotin administration increased the glucose transporter type 4 (GLUT4) protein content in the total membrane fraction but had little effect on the GLUT4 content in the plasma membrane fraction. These results indicate that administration of a pharmacological dose of biotin prevents the development of insulin resistance in the skeletal muscles of OLETF rats presumably via an increase in GLUT4 protein expression but not via GLUT4 translocation. PMID- 22218393 TI - AAV-mediated gene transfer of human pigment epithelium-derived factor inhibits Lewis lung carcinoma growth in mice. AB - Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis in the mammalian eye, and mechanisms through which PEDF exerts its antitumour activity have recently been defined. The aim of our research was to evaluate the ability of adeno-associated virus (AAV) vector-mediated transfer of human PEDF to inhibit lewis lung carcinoma (LCC) cell growth. Intratumoural injection of AAV-PEDF caused significant reduction of the tumour volume and prolonged the survival time of mice bearing LLC cells, which were associated with decreased microvessel density and increased apoptosis in the tumours. AAV vectors represent a very promising tool for cancer gene therapy. No noticeable toxicity concerning AAV was detected as inferred from monitoring changes in animal body weight as well as basic organ structure and histological morphology, and by analyzing mouse liver and kidney function. Our findings indicate that AAV mediated PEDF gene expression may offer an active approach to inhibit LLC growth and that treatment with AAV-PEDF may provide a promising therapeutic strategy in lung cancer treatment. PMID- 22218398 TI - Luminescent bis-tridentate ruthenium(II) and osmium(II) complexes based on terpyridyl-imidazole ligand: synthesis, structural characterization, photophysical, electrochemical, and solvent dependence studies. AB - Homo- and heteroleptic bis-tridentate ruthenium(II) and osmium(II) complexes of compositions [(tpy-PhCH(3))Ru(tpy-HImzPh(3))](ClO(4))(2) (1), [(H(2)pbbzim)Ru(tpy HImzPh(3))] (ClO(4))(2) (2) and [M(tpy-HImzPh(3))(2)](ClO(4))(2) [M = Ru(II) (3) and Os(II) (4)], where tpy-PhCH(3) = p-methylphenyl terpyridine, H(2)pbbzim = 2,6 bis(benzimidazole-2-yl)pyridine and tpy-HImzPh(3) = 4'-[4-(4,5-diphenyl-1H imidazol-2-yl)-phenyl]-[2,2':6',2'']terpyridine, have been synthesized and characterized by using standard analytical and spectroscopic techniques. These compounds were designed to increase the room temperature excited-state lifetimes of bisterpyridine-type ruthenium(II) and osmium(II) complexes. The X-ray crystal structures of two homoleptic complexes 3 and 4 have been determined and show that both the compounds crystallized in orthorhombic form with space group Fddd. The photophysical and redox properties of the complexes have been thoroughly investigated. All the complexes display moderately strong luminescence at room temperature with lifetimes in the range of 6-35 ns. The complexes are found to undergo one reversible oxidation in the positive potential window (0 to +1.6 V) and one irreversible and two successive quasi-reversible reductions in the negative potential window (0 to -2.0 V). The influence of solvents on the photophysical properties of the complexes has also been investigated in detail. PMID- 22218397 TI - Ni(ClO4)(2)-catalysed regio- and diastereoselective [3+2] cycloaddition of indoles and aryl oxiranyl-dicarboxylates/diketones: a facile access to furo[3,4 b]indoles. AB - Ni(ClO(4))(2).6H(2)O-catalysed regioselective and diastereoselective [3+2] annulations of aryl oxiranyl-dicarboxylates and indoles via selective C-C bond cleavage of oxirane were revealed. The cycloadditions proceed smoothly with high regio- and diastereoselectivity under mild conditions leading to 1H-furo[3,4 b]indoles in good to excellent yields. PMID- 22218396 TI - Human breast carcinoma cells are induced to apoptosis by samsum ant venom through an IGF-1-dependant pathway, PI3K/AKT and ERK signaling. AB - In the present study we evaluated the anti-tumor potential of samsum ant venom (SAV) from Pachycondyla sennaarensis on the human breast carcinoma cell line MCF 7. We found that SAV induced growth arrest of MCF-7 cells without affecting the viability of MCF-10 (non-tumorigenic normal breast epithelial cells) and normal PBMCs. We then analyzed its impact on IGF-1-mediated MCF-7 cell proliferation and its effect on the underlying IGF-1 signaling pathways. Using flow cytometry analysis, we showed that the percentage of apoptotic cells was fourfold higher in SAV-treated cells as compared to untreated cells. More importantly, treatment with SAV induced a marked reduction in actin polymerization and a subsequent marked reduction in IGF-1-mediated cell proliferation. In addition to growth inhibitory and pro-apoptotic effects, significant reductions were also observed in the phosphorylation of AKT and ERK, but not p38MAPK, in SAV-treated cells as compared to untreated cells. Our data reveal unique anti-tumor effects of samsum ant venom. PMID- 22218399 TI - Hybridity and intersubjectivity in the clinical encounter: impact on the cultural formulation. AB - Most case studies of the cultural formulation have focused on encounters with a single clinician. This article examines the assessment of a patient across different settings in which multiple clinicians developed separate understandings of the patient's identity. The formal cultural formulation prepared by the last clinician to work with the patient revealed a vastly different picture than what was previously recognized, reflecting both the impact of the identity of the clinician and the systematic evaluation process on the nature of the patient's responses. This suggests that cultural hybridity can stimulate new modes of inquiry as people integrate disparate cultural references to fashion a new identity. Intersubjectivity can also alter information elicited by clinicians. The conclusion highlights the need for practice guidelines for use of the cultural formulation across treatment settings. PMID- 22218400 TI - Identification of putative cancer genes through data integration and comparative genomics between plants and humans. AB - Coordination of cell division with growth and development is essential for the survival of organisms. Mistakes made during replication of genetic material can result in cell death, growth defects, or cancer. Because of the essential role of the molecular machinery that controls DNA replication and mitosis during development, its high degree of conservation among organisms is not surprising. Mammalian cell cycle genes have orthologues in plants, and vice versa. However, besides the many known and characterized proliferation genes, still undiscovered regulatory genes are expected to exist with conserved functions in plants and humans. Starting from genome-wide Arabidopsis thaliana microarray data, an integrative strategy based on coexpression, functional enrichment analysis, and cis-regulatory element annotation was combined with a comparative genomics approach between plants and humans to detect conserved cell cycle genes involved in DNA replication and/or DNA repair. With this systemic strategy, a set of 339 genes was identified as potentially conserved proliferation genes. Experimental analysis confirmed that 20 out of 40 selected genes had an impact on plant cell proliferation; likewise, an evolutionarily conserved role in cell division was corroborated for two human orthologues. Moreover, association analysis integrating Homo sapiens gene expression data with clinical information revealed that, for 45 genes, altered transcript levels and relapse risk clearly correlated. Our results illustrate how a systematic exploration of the A. thaliana genome can contribute to the experimental identification of new cell cycle regulators that might represent novel oncogenes or/and tumor suppressors. PMID- 22218401 TI - Cigarette sharing and gifting in rural China: a focus group study. AB - OBJECTIVES: To understand the reasons behind gifting and sharing cigarettes in China's rural areas and how these practices contribute to smoking initiation and hamper smoking cessation efforts. METHODS: A convenience sample of 31 current smokers and nonsmokers was selected from a rural farming town in Hunan, China. Participants were divided into 6 focus groups according to gender and smoking status. Focus groups discussed the reasons behind gifting and sharing cigarettes as well as the effect these practices have on tobacco initiation and cessation. RESULTS: In rural China, individual cigarettes are primarily shared as a mechanism to convey respect and intimacy. Packs of cigarettes are given primarily due to their convenience as well as being well liked by both smokers and nonsmokers. Sharing individual cigarettes by both peers and older relations contributed to individuals beginning to smoke. Sharing cigarettes among friends was also a major hindrance to smoking cessation. CONCLUSIONS: Gifting and sharing cigarettes significantly contribute to smoking in rural China. Future tobacco control efforts should discourage both these activities to reduce tobacco usage. Tobacco control measures should also aim to inform adults about the health consequences of giving cigarettes to adolescents. Similarly, more information on the benefits of smoking cessation should be provided to China's rural elderly population. This information could lead to increased community support of cessation efforts and ultimately result in reductions in smoking in rural China. PMID- 22218402 TI - Comparing an immediate cessation versus reduction approach to smokeless tobacco cessation. AB - INTRODUCTION: Relatively few studies have investigated pharmacological or behavioral treatment of smokeless tobacco (ST) users who do not have immediate quit plans. In this study, we compared a reduction treatment approach with an immediate cessation approach in a population of ST users who reported no immediate plans to quit. METHODS: Subjects randomly assigned to the immediate cessation condition set a quit date soon after enrollment and were offered 2 weeks of nicotine patch therapy to help in their cessation efforts. Subjects assigned to the ST reduction group were provided with their choice of either 4 mg nicotine lozenge or ST brand switching to help them reduce their ST use or levels of nicotine exposure, respectively. Quit date was 6 weeks after the onset of treatment. Follow-up was at 12 weeks and 26 weeks postenrollment and 26 weeks postquit. RESULTS: Both 7-day point prevalence abstinence and prolonged abstinence rates following the quit date were significantly higher in the immediate cessation group versus the reduction group at 12 and 26 weeks (all p values <= .04) and for prolonged abstinence at 6 months postquit (p = .002). Significant reductions in ST use among nonquitters were observed for both groups (p < .0001) with no differences between groups. CONCLUSION: Our study demonstrated that immediate cessation with an established quit date resulted in greater cessation success than a gradual reduction approach among ST users who do not have an immediate quit plan but are motivated to quit. PMID- 22218403 TI - Precipitated withdrawal from nicotine reduces reinforcing effects of a visual stimulus for rats. AB - INTRODUCTION: Research has identified at least two positive reinforcement-related effects of nicotine: (a) primary reinforcement and (b) enhancement of reinforcement from concurrently available stimuli. Prior examples of the reinforcement-enhancing effects with rats showed that repeated, intermittent nicotine exposure increased responding for non-nicotine reinforcers, and this effect remained robust over several weeks. However, the effects of continuous nicotine exposure on responding for a non-nicotine reinforcer are unknown, as are the effects of abruptly withdrawing continuous nicotine on behavior maintained by the same reinforcer. METHODS: Lever pressing for a visual reinforcer under a fixed ratio schedule was assessed while rats were maintained on a chronic, continuous infusion of nicotine (3.16 mg/kg/day; osmotic minipump). The effects of precipitated withdrawal on responding, following 16 days of continuous nicotine exposure, were assessed by pre-session subcutaneous injections of mecamylamine (1.0 mg/kg). RESULTS: Continuous nicotine initially increased active responding for the visual reinforcer; however, continued exposure resulted in an attenuation of this effect. Precipitated withdrawal from nicotine resulted in a significant decline in active responding. CONCLUSIONS: The initial increase in responding for the visual reinforcer with chronic nicotine exposure is consistent with prior research showing that intermittent exposure to nicotine acts as a reinforcement enhancer. However, the attenuation of this enhancement following prolonged nicotine exposure is in contrast with the persistent effects previously reported. Finally, the decrease in visual reinforcers below control levels (nicotine-naive animals) following nicotine withdrawal highlights a potential for affective withdrawal, which may serve as a motive for continued nicotine use. PMID- 22218405 TI - Selective capture of phosphopeptides by hierarchical Ti-aluminophosphate-5 molecular sieves. AB - Hierarchical Ti-aluminophosphate-5 molecular sieves templated by glucose have been synthesized and applied as a potential adsorbent for the first time to selectively capture phosphopeptides from complex peptide mixtures prior to MALDI TOF MS analysis. PMID- 22218404 TI - Cue-induced cigarette cravings and smoking cessation: the role of expectancies. AB - INTRODUCTION: Cue-induced cigarette cravings have been oft studied as potentially important predictors of smoking cessation outcomes. The literature on the relationship between cue-induced cravings and cessation, however, remains mixed. One possible explanation for the discrepant results in the literature may be the as-yet untested variability in expectancies of craving. Indeed, as with many interoceptive responses, cravings and their downstream consequences may be influenced by expectancies. To date, no study has examined the influence of expected cravings following smoking cue exposures on actual craving experiences and cessation outcomes. The objective of this study, therefore, was to test the possibility that smokers' expected craving levels in response to smoking cues would be related to actual cravings following cue exposure and that expected cravings would be related to cessation outcomes. METHODS: Nicotine-dependent adult smokers (n = 153) were exposed to sets of neutral and smoking cues and completed questionnaires assessing (a) prior to the exposures, the cigarette craving levels they expected to experience following the cue exposures and (b) following the exposures, their actual craving levels. Participants also reported the duration of their most recent quit attempt and their perceived future quit difficulty. RESULTS: Findings indicated that expected cravings assessed prior to the cue exposures were significantly related to actual cravings following the exposures. In addition, both expected cravings and actual cravings were related to shorter previous quit duration and higher perceived quit difficulty. CONCLUSIONS: Study results highlight the importance of considering both expected and actual cravings in cue-induced craving paradigms. PMID- 22218406 TI - 2-Iodo-imidazolium receptor binds oxoanions via charge-assisted halogen bonding. AB - A detailed (1)H-NMR study of the anion binding properties of the 2-iodo imidazolium receptor 1 in DMSO allows to fully attribute the observed affinities to strong charge-assisted C-I...X(-) halogen bonding (XB). Stronger binding was observed for oxoanions over halides. Phosphate, in particular, binds to 1 with an association constant of ca. 10(3) M(-1), which is particularly high for a single X-bond. A remarkably short C-I...O(-) contact is observed in the structure of the salt 1.H(2)PO(4)(-). PMID- 22218407 TI - Antigen-responsive, microfluidic valves for single use diagnostics. AB - The growing need for medical diagnostics in resource limited settings is driving the development of simple, standalone immunoassay devices. A capillary flow device using polymerization based amplification is capable of blocking a microfluidic channel in response to target biomaterials, enabling multiple modes of detection that require little or no supplemental instrumentation. PMID- 22218408 TI - Three-dimensional gadolinium-enhanced MR venography to evaluate central venous steno-occlusive disease in hemodialysis patients. AB - AIM: To determine the agreement and diagnostic accuracy of three-dimensional gadolinium-enhanced magnetic resonance venography (3D-Gd-MRV) in central venous steno-occlusive disease (CVSD) in haemodialysis patients. MATERIALS AND METHODS: Fourteen consecutive haemodialysis patients underwent interventional procedures to evaluate or treat CVSD. 3D-Gd-MRV was performed before the procedures and the results were compared with digital subtraction angiography (DSA). RESULTS: DSA showed >50% stenosis in all 14 patients, 13 of whom were diagnosed correctly using 3D-Gd-MRV. Moderate stenosis was missed at 3D-Gd-MRV in one case whereby the indwelling dialysis central venous catheter may have caused an artefact on the images and hindered the accuracy of the result. The sensitivity of 3D-Gd-MRV in revealing stenosis was 93% (13/14). No complications caused by contrast agent toxicity occurred in any patient. CONCLUSION: 3D-Gd-MRV employing a non-breath hold technique is highly sensitive in the diagnosis of CVSD and may be an alternative technique to DSA for the visualization of central veins. PMID- 22218409 TI - MRI features of the complete histopathological response of locally advanced rectal cancer to neoadjuvant chemoradiotherapy. AB - AIM: To describe the post-chemoradiotherapy magnetic resonance imaging (MRI) features of locally advanced rectal carcinoma (LARC) in which there has been a complete histopathological response to neoadjuvant chemoradiotherapy (CRT). MATERIALS AND METHODS: This retrospective cohort study was performed between January 2005 and November 2009 at a regional cancer centre. Consecutive patients with LARC and a histopathological complete response to long-course CRT were identified. Pre- and post-treatment MRI images were reviewed using a proforma for predefined features and response criteria. ymrT0 was defined as the absence of residual abnormality on MRI. RESULTS: Twenty patients were included in the study. Seven (35%) ypT0 tumours were ymrT0. All 13 ypT0 tumours not achieving ymrT0 appearances had a good radiological response, with at least 65% tumour reduction. The appearances were heterogeneous: in 11/13 patients the tumour was replaced by a region of at least 50% low signal on MRI, with 8/13 having >=80% low signal, and 3/13 with 100% low signal. CONCLUSION: MRI may be useful in identifying a complete histopathological response. However, the MRI appearances of ypT0 tumours are heterogeneous and conventional MRI complete response criteria will not detect the majority of patients with a complete histopathological response. PMID- 22218410 TI - Prophylactic balloon occlusion of internal iliac arteries in women with placenta accreta: literature review and analysis. AB - AIM: To review the literature on the use of prophylactic balloon occlusion alone and in conjunction with arterial embolization of the internal iliac arteries in women with placenta accreta. MATERIALS AND METHODS: The PubMed, MEDLINE, CINAHL, EMBASE, and Cochrane Library databases were searched for keywords related to this technique and its use in the avoidance of caesarean hysterectomy. The relevant published articles were selected and then searched for further references. RESULTS: The literature search found 15 case reports and five studies for a total of 20 articles. The use of balloon catheters to prevent post-partum haemorrhage in women with placenta accreta is controversial with some investigators reporting reduced blood loss and transfusion requirements while others reporting no benefit. This procedure does not appear to reduce operative time or hospital stay. Some groups have described catheter-related complications, such as maternal thromboembolic events and the need for stent placement and/or arterial bypass. Thus far, there is no reported maternal or foetal mortality related to this procedure. CONCLUSION: Current evidence is based upon case reports and small retrospective studies. Larger studies or randomized controlled trials are essential in order to demonstrate the safety and efficacy of bilateral iliac balloon occlusion. The creation of a data registry would also facilitate the reporting of this technique. PMID- 22218411 TI - Myocardial bridge associated with cardiovascular injuries in bovines adult of Canchim race. AB - BACKGROUND: The influence that myocardial bridge exercises over blood stream in the course of arterial segment under the bridge has been discussed by the scientific community. OBJECTIVE: To compare ultrastructural muscle tissue of myocardial bridge and the ventricular wall; to analyze the degree of injury to the tunica intima of the arterial segments, and look for possible changes that may precede or initiate the process of atherosclerotic lesions. METHODS: Forty Canchim bovine hearts were studied regarding alterations of the tunica intima from coronary arteries on the different myocardial bridge segments. For the microscopic examination, hematoxylin-eosin and fuchsin-resorcin staining following conventional microscope techniques were made. For the electronic microscopic examination, myocardial Bridge segments from twelve Canchim bovine hearts were collected from the ventricle wall and coronary artery and were processed according to conventional techniques. RESULTS: In the light microscopy, a higher frequency of lesions on prepontine and postpontine segments of the tunica intima was observed, compared to the pontine segment. Tunica intima thickenings were followed by a disarrangement on the internal elastic limitant lamina. These cells often presented their cytoplasmas engorged by lipidic drops, making up the so-called foam cells. Electronic microscopy revealed that the muscular fibers of the myocardial bridge are usually joined in a straight and smooth way presenting lateral branches with a greater number of mitochondria in the ventricular muscle than in the bridge. CONCLUSION: There are few differences between the muscle tissues studied; intimae lesions are less frequent in pontine regions compared to pre and post-pontine regions. PMID- 22218412 TI - Ventricular hypertrophy and cardiovascular mortality in hemodialysis patients with low educational level. AB - BACKGROUND: Left ventricular hypertrophy is a strong predictor of mortality in chronic kidney patients. A previous study of our group has shown that chronic kidney patients with low educational level has more severe ventricular hypertrophy. OBJECTIVE: To extend a previous study and to assess whether left ventricular hypertrophy can explain the association between schooling and cardiovascular mortality in hemodialysis patients. METHODS: This study assessed 113 patients from January 2005 to March 2008 and followed them up until October 2010. Survival curves were built to compare all-cause and cardiovascular mortality of patients with up to three years of schooling (median schooling) and those with schooling of four years and over. Cox multiple models were built and adjusted to confounding variables. RESULTS: Association between educational level and ventricular hypertrophy was observed. Statistical difference in all-cause and cardiovascular mortality between the different educational levels was observed at 5.5 years of follow-up. In the Cox model, ventricular hypertrophy and C-reactive protein associated with all-cause and cardiovascular mortality. The etiology of kidney failure associated with all-cause mortality, and creatinine associated with cardiovascular mortality. The association between educational level and mortality lost statistical significance in the adjusted model. CONCLUSION: The results of this study confirm those of a previous study. In addition, they show that the higher cardiovascular mortality observed in patients with low educational level can be explained by risk factors of biochemical and cardiac morphological origin. PMID- 22218413 TI - Emergency service admission time and in-hospital mortality in acute coronary syndrome. AB - BACKGROUND: The relationship between admission time to an emergency service and in-hospital outcomes in acute coronary syndrome (ACS) is controversial. Admission during off-hours would be associated with worse prognosis. OBJECTIVE: To assess the influence of admission time on prolonged hospitalization and mortality for ACS patients, regarding regular hours (7AM-7PM) and off-hours (7PM-7AM). METHODS: The study assessed prospectively 1,104 consecutive ACS patients. In-hospital mortality and length of hospital stay >= 5 days were the outcomes analyzed. RESULTS: Admission during regular hours was greater as compared with that during off-hours (63% vs. 37%; p < 0.001). Unstable angina was more prevalent during regular hours (43% vs. 32%; p < 0.001), while non-ST-segment elevation myocardial infarction (NSTEMI) was during off-hours (33% vs. 43%; p = 0.001). Differences in neither mortality nor length of hospital stay were observed in the time periods studied. Predictive factors for length of hospital stay >= 5 days were as follows: age [OR 1.042 (95%CI: 1.025 - 1.058), p < 0.001]; ejection fraction (EF) [OR 0.977 (95%CI: 0.966 - 0.988), p < 0.001]; NSTEMI [OR 1.699 (95%CI: 1.221 - 2.366), p = 0.001]; and smoking [OR 1.723 (95%CI: 1.113 - 2.668), p = 0.014]. Predictive factors for in-hospital mortality were as follows: age [OR 1.090 (95%CI: 1.047 - 1.134), p < 0.001]; EF [OR 0.936 (95%CI: 0.909 - 0.964), p < 0.001]; and surgical treatment [OR 3.781 (95%CI: 1.374 - 10.409), p = 0.01]. CONCLUSION: Prolonged length of hospital stay and in-hospital mortality in ACS patients do not depend on admission time. PMID- 22218414 TI - Functional limitation and intermittent claudication: impact of blood pressure measurements. AB - BACKGROUND: Arterial hypertension is an important risk factor for Lower-Limb Occlusive Arterial Disease (LLOAD). However, the correlation between blood pressure and pulse pressure (PP) with LLOAD severity and functional impairment resulting from this disease is not well established in the Brazilian population. OBJECTIVE: To verify whether there is a correlation between blood pressure, PP, LLOAD severity and functional capacity in patients with symptomatic LLOAD. METHODS: A total of 65 patients (62.2 + 8.1 years, 56.9% males) were evaluated. They were divided into two groups: normal (A) and high (B) blood pressure. LLOAD severity was assessed using the ankle-brachial index (ABI) and functional capacity by the total and pain-free walking distance at the 6-minute walking test (6MWT). RESULTS: Group A consisted of 17 (26.1%) patients. The systolic (SBP), diastolic blood pressure (DBP), and PP were, respectively, 125.4 +/-11.7, 74.5 +/ 9.1 and 50.9 +/- 10.0 mmHg in group A and 160.7 +/- 19.6, 90.0 +/- 12.2 and 70.7 +/- 20.2 mmHg in group B. The ABI was significantly lower in group B (0.66 +/- 0.12 vs. 0.57 +/- 0.13, p <0.05). SBP and PP correlated with LLOAD severity and the distances walked at the 6MWT. Patients with PP > 40 mmHg walked shorter distances. CONCLUSION: SBP and PP significantly correlated with the distances walked in the 6MWT, suggesting they are clinical markers of functional capacity impairment in patients with symptomatic LLOAD. PMID- 22218415 TI - Cardiac autonomic and ventricular mechanical functions in asymptomatic chronic chagasic cardiomyopathy. AB - BACKGROUND: The association of variably altered cardiac autonomic and ventricular systolic and diastolic functions is still controversial and little explored in chronic Chagas' disease. OBJECTIVE: To evaluate the extent to which cardiac autonomic and mechanical ventricular functions are altered and whether they are associated in asymptomatic chagasic cardiomyopathy. METHODS: A total of 13 patients with asymptomatic chagasic cardiomyopathy and 15 normal subjects (control group) were evaluated and the autonomic modulation of heart rate variability for five minutes, in the temporal and spectral domains, in the supine and orthostatic positions, as well as ventricular function based on morphological functional variables obtained by Doppler echocardiography were correlated. Statistical analysis used the Mann-Whitney test and Spearman's correlation. RESULTS: In both positions, the temporal index (p = 0.0004 to 0.01) and total (p = 0.0007-0.005) and absolute spectral areas, of low and high frequencies (p = 0.0001 to 0.002), were lower in the chagasic group. The vagal-sympathetic balance was similar in both positions (p = 0.43 to 0.89). The echocardiographic variables did not differ between groups (p = 0.13 to 0.82), except the left ventricular end systolic diameter, which was larger (p = 0.04) and correlated directly with reduced rates of global (p = 0.01 to 0.04) and parasympathetic (p = 0.002 to 0.01) autonomic modulation in patients with Chagas disease in the orthostatic position. CONCLUSION: The sympathetic and parasympathetic depressions with preserved balance were associated with only one ventricular dysfunction indicator. This suggests that cardiac autonomic dysfunction may precede and be independently more severe than ventricular dysfunction, with no causal association between both disorders in chronic chagasic cardiomyopathy. PMID- 22218416 TI - Fast and facile dissolution of cellulose with tetrabutylphosphonium hydroxide containing 40 wt% water. AB - Tetrabutylphosphonium hydroxide containing 40 wt% water dissolved 20 wt% cellulose at the final concentration within 5 minutes under mild stirring at 25 degrees C. PMID- 22218417 TI - Individualizing osteoporosis therapy. AB - Guidelines for osteoporosis treatment are available; however, these guidelines suggest when to treat patients, without specific recommendations on what drugs to prescribe in various situations. Choice of osteoporosis therapy should be individualized based on consideration of the efficacy, safety, cost, convenience (i.e., dosing regimen and delivery), and other non-osteoporosis-related benefits associated with each agent. Bisphosphonates, administered orally or intravenously, should be considered first-line therapy, particularly in older patients, owing to their efficacy across multiple skeletal sites; however, there are potential short- and long-term safety concerns. Selective estrogen receptor modulators should be considered for younger postmenopausal women at greater risk for vertebral than hip fractures or as second-line therapy in women who cannot tolerate first-line therapies. Low-dose hormone therapy may be appropriate as prevention in women with menopausal symptoms at lower fracture risk. Calcitonin, with its relatively benign safety profile, may be appropriate for elderly women who may have difficulty following the complex dosing schedules of oral bisphosphonates. Anabolic therapies such as teriparatide should be considered for high-risk patients. Strontium ranelate (approved outside of North America), with both anabolic and antiresorptive properties, may be appropriate for women who cannot tolerate or are unable to take bisphosphonates. Denosumab is a monoclonal antibody appropriate for women at high fracture risk or who have failed other osteoporosis therapies, and may be considered in patients with renal insufficiency. It will be important to incorporate newer agents (e.g., bazedoxifene, tissue selective estrogen complex) into this individualized treatment paradigm to optimize clinical outcomes in patients with osteoporosis. PMID- 22218418 TI - Short-term teriparatide therapy as an adjunctive modality for bisphosphonate related osteonecrosis of the jaws. AB - To review the effect of teriparatide as an adjunctive modality for bisphosphonate related osteonecrosis of the jaws (BRONJ), we describe a series of cases of teriparatide therapy for the treatment of BRONJ and serial changes of serum osteoclacin (s-OC) and serum C-terminal telopeptide cross-link of type I collagen (s-CTX). INTRODUCTION: Management of BRONJ is quite challenging and the currently recommended modalities for BRONJ are still suboptimal. For the improvement of bony remodeling, some clinicians advocated bisphosphonate holiday although validity of this drug holiday has been debated so far. Recently, the use of teriparatide was introduced in several cases, but the number of the publication is limited and mostly anecdotal so far. METHOD: Bisphosphonate was suspended and teriparatide was given to six patients diagnosed with BRONJ by single bone specialist. Medical record review and interviews were carried out. S-CTX and s-OC were measured at the baseline, 2 months and 3 months later teriparatide therapy. The outcome of the treatment and the change of biochemical markers were compared. RESULT: In all six patients, s-OC values were significantly elevated within 2 months after teriparatide treatment and the BRONJ lesions were healed. S-CTX values were also elevated in four patients, whereas those of the rest two patients stayed within minimal change. The change was marginally significant at 3 months. CONCLUSION: In terms of the multifactorial etiology of BRONJ, bone formation suppression was noticed in the patients. Based upon this finding, the short-term use of teriparatide might be beneficial to the resolution of BRONJ lesions by improving suppressed bone remodeling. PMID- 22218419 TI - Cocaine modulates pathways for photic and nonphotic entrainment of the mammalian SCN circadian clock. AB - Cocaine abuse is highly disruptive to circadian physiological and behavioral rhythms. The present study was undertaken to determine whether such effects are manifest through actions on critical photic and nonphotic regulatory pathways in the master circadian clock of the mouse suprachiasmatic nucleus (SCN). Impairment of SCN photic signaling by systemic (intraperitoneal) cocaine injection was evidenced by strong (60%) attenuation of light-induced phase-delay shifts of circadian locomotor activity during the early night. A nonphotic action of cocaine was apparent from its induction of 1-h circadian phase-advance shifts at midday. The serotonin receptor antagonist, metergoline, blocked shifting by 80%, implicating a serotonergic mechanism. Reverse microdialysis perfusion of the SCN with cocaine at midday induced 3.7 h phase-advance shifts. Control perfusions with lidocaine and artificial cerebrospinal fluid had little shifting effect. In complementary in vitro experiments, photic-like phase-delay shifts of the SCN circadian neuronal activity rhythm induced by glutamate application to the SCN were completely blocked by cocaine. Cocaine treatment of SCN slices alone at subjective midday, but not the subjective night, induced 3-h phase-advance shifts. Lidocaine had no shifting effect. Cocaine-induced phase shifts were completely blocked by metergoline, but not by the dopamine receptor antagonist, fluphenazine. Finally, pretreatment of SCN slices for 2 h with a low concentration of serotonin agonist (to block subsequent serotonergic phase resetting) abolished cocaine-induced phase shifts at subjective midday. These results reveal multiple effects of cocaine on adult circadian clock regulation that are registered within the SCN and involve enhanced serotonergic transmission. PMID- 22218420 TI - GABAB receptors in the NTS mediate the inhibitory effect of trigeminal nociceptive inputs on parasympathetic reflex vasodilation in the rat masseter muscle. AB - The present study was designed to examine whether trigeminal nociceptive inputs are involved in the modulation of parasympathetic reflex vasodilation in the jaw muscles. This was accomplished by investigating the effects of noxious stimulation to the orofacial area with capsaicin, and by microinjecting GABA(A) and GABA(B) receptor agonists or antagonists into the nucleus of the solitary tract (NTS), on masseter hemodynamics in urethane-anesthetized rats. Electrical stimulation of the central cut end of the cervical vagus nerve (cVN) in sympathectomized animals bilaterally increased blood flow in the masseter muscle (MBF). Increases in MBF evoked by cVN stimulation were markedly reduced following injection of capsaicin into the anterior tongue in the distribution of the lingual nerve or lower lip, but not when injected into the skin of the dorsum of the foot. Intravenous administration of either phentolamine or propranolol had no effect on the inhibitory effects of capsaicin injection on the increases of MBF evoked by cVN stimulation, which were largely abolished by microinjecting the GABA(B) receptor agonist baclofen into the NTS. Microinjection of the GABA(B) receptor antagonist CGP-35348 into the NTS markedly attenuated the capsaicin induced inhibition of MBF increase evoked by cVN stimulation, while microinjection of the GABA(A) receptor antagonist bicuculline did not. Our results indicate that trigeminal nociceptive inputs inhibit vagal-parasympathetic reflex vasodilation in the masseter muscle and suggest that the activation of GABA(B) rather than GABA(A) receptors underlies the observed inhibition in the NTS. PMID- 22218421 TI - Identification of Zn-nicotianamine and Fe-2'-Deoxymugineic acid in the phloem sap from rice plants (Oryza sativa L.). AB - In higher plants, the supply of metals such as Zn and Fe via phloem is important for the growth and physiology of young organs. However, little information is available on the speciation (chemical forms) of these metals in the phloem fluids. Because the pH of phloem fluids is slightly alkaline and the concentration of phosphate, which may bind to metals, is high, Zn and Fe in phloem fluids could be precipitated if these metals do not form complexes with some ligand compounds. In the present experiment, we examined the chemical forms of Zn and Fe in phloem sap collected from rice (Oryza sativa L.) by separating the phloem sap using size-exclusion and anion-exchange chromatography, and identifying the contents using electrospray ionization time-of-flight mass spectrometry. The low molecular weight chemical forms of Zn and Fe were identified as Zn-nicotianamine and Fe(III)-2'-deoxymugineic acid complexes, respectively. This report is the first to identify metal-chelate complexes in rice phloem sap. PMID- 22218422 TI - Phosphole modified pentathienoacene: synthesis, electronic properties and self assembly. AB - A series of new ladder pi-conjugated materials, phosphole modified pentathienoacene (PO-PTA), are synthesized and characterized. Single-crystal X ray results demonstrate that methyl-disubstituted PO-PTA forms a face-to-face dimer structure driven by pi-pi interactions. The investigations of optical properties showed that the oxidized phosphole moiety in this ladder system can effectively narrow the band gap. PO-PTA is a promising building block in pi conjugated polymers and oligomers for optoelectronic applications. The derivative of PO-PTA, obtained by introducing four long alkyl chains, can self-assemble into one-dimensional (1D) fibers based on intermolecular pi-pi interactions, dipole dipole interactions and van der Waals interactions. Interestingly, the uniform and well-ordered monolayers were also obtained for PO-PTA derivative on a HOPG (highly oriented pyrolytic graphite) surface. PMID- 22218423 TI - Human in vivo longevity is reflected in vitro by differential metabolism as measured by (1)H-NMR profiling of cell culture supernatants. AB - The offspring of nonagenarian siblings suffer less from age related conditions and have a lower risk of mortality compared to their partners. Fibroblast strains derived from such offspring in middle age show different in vitro responses to stress, more stress-induced apoptosis and less senescence when compared to strains of their partners. Aiming to find differences in cellular metabolism in vitro between these fibroblast strains, cell culture supernatants collected at 24 hours and five days were analysed using (1)H nuclear magnetic resonance (NMR) based metabolic footprinting. Between 24 hours and five days of incubation, supernatants of all fibroblast strains showed decreased levels of glucose, pyruvate, alanine-glutamine (ala-gln), valine, leucine, isoleucine, serine and lysine and increased levels of glutamine, alanine, lactate and pyroglutamic acid. Strains from offspring and their partners were compared using a partial least squares-discriminant analysis (PLS-DA) model based on the data of the five-day time point. The ala-gln and glucose consumption were higher for fibroblast strains derived from offspring when compared to strains of their partners. Also, production of glutamine, alanine, lactate and pyroglutamic acid was found to be higher for fibroblast strains derived from offspring. In conclusion, differences in NMR-based metabolic profiles of human cells in vitro reflect the propensity for human longevity of the subjects from whom these were derived. PMID- 22218424 TI - Analysis of the coding sequence and expression of the coiled-coil alpha-helical rod protein 1 gene in normal and neoplastic epithelial cervical cells. AB - The role of the CCHCR1 (coiled-coil alpha-helical rod protein 1) protein in the cell is poorly understood. It is thought to be engaged in processes such as proliferation and differentiation of epithelial cells, tissue-specific gene transcription and steroidogenesis. It is supposed to participate in keratinocyte transformation. It has also been found that this protein interacts with the E2 protein of human papilloma virus type 16 (HPV16). The oncogenic HPV forms, such as HPV16, are known to be necessary but not sufficient agents in the development of cervical carcinoma. In the present study, the CCHCR1 gene coding sequence and its expression was analyzed in normal, precancerous and cervical cancer cells. Changes in the non-coding region were found in 20.3% of the examined probes from women with cervical cancer or precancerous lesions and in 16.67% of the control probes. Most of the detected changes were single nucleotide polymorphisms (SNPs). Changes in the coding region were found in 22.8% of the probes with cervical cancer and in 16.67% of the control probes and all of them were SNPs. The level of CCHCR1 transcripts was determined using the real-time PCR method and the highest gene expression was detected in the H-SIL group and slightly decreased in the cervical carcinoma cells, compared with the control probes. It suggests that CCHCR1 could have a role in the process of cervical epithelial cell transformation, but this suggestion must be confirmed experimentally. PMID- 22218425 TI - Secondhand smoke in cars: assessing children's potential exposure during typical journey conditions. AB - OBJECTIVE: To measure levels of fine particulate matter in the rear passenger area of cars where smoking does and does not take place during typical real-life car journeys. METHODS: Fine particulate matter (PM(2.5)) was used as a marker of secondhand smoke and was measured and logged every minute of each car journey undertaken by smoking and non-smoking study participants. The monitoring instrument was located at breathing zone height in the rear seating area of each car. Participants were asked to carry out their normal driving and smoking behaviours over a 3-day period. RESULTS: 17 subjects (14 smokers) completed a total of 104 journeys (63 smoking journeys). Journeys averaged 27 min (range 5-70 min). PM(2.5) levels averaged 85 and 7.4 MUg/m(3) during smoking and non-smoking car journeys, respectively. During smoking journeys, peak PM(2.5) concentrations averaged 385 MUg/m(3), with one journey measuring over 880 MUg/m(3). PM(2.5) concentrations were strongly linked to rate of smoking (cigarettes per minute). Use of forced ventilation and opening of car windows were very common during smoking journeys, but PM(2.5) concentrations were still found to exceed WHO indoor air quality guidance (25 MUg/m(3)) at some point in the measurement period during all smoking journeys. CONCLUSIONS: PM(2.5) concentrations in cars where smoking takes place are high and greatly exceed international indoor air quality guidance values. Children exposed to these levels of fine particulate are likely to suffer ill-health effects. There are increasing numbers of countries legislating against smoking in cars and such measures may be appropriate to prevent the exposure of children to these high levels of secondhand smoke. PMID- 22218427 TI - The missing link in the coordination chemistry of hydrazines--a hydrazinetriide [N-N(Me)](3-) anion coordinated to five Al atoms. AB - The heptanuclear aluminium-nitrogen cage compound [(AlMe(2))(4)(AlMe)(3)(NHNMe)(3)(N-NMe)(OMe)] contains the unique hydrazinetriide fragment [N-N(Me)](3-) stabilized by coordination to five Al atoms. It was synthesised by thermolysis of the sesqui-hydrazide Al[(MU-NH-NHMe)(2)AlMe(2)](3) in refluxing toluene in the presence of a small quantity of methanol. PMID- 22218426 TI - Patterns of cognitive dissonance-reducing beliefs among smokers: a longitudinal analysis from the International Tobacco Control (ITC) Four Country Survey. AB - OBJECTIVE: The purpose of this paper is to assess whether smokers adjust their beliefs in a pattern that is consistent with Cognitive Dissonance Theory. This is accomplished by examining the longitudinal pattern of belief change among smokers as their smoking behaviours change. METHODS: A telephone survey was conducted of nationally representative samples of adult smokers from Canada, the USA, the UK and Australia from the International Tobacco Control Four Country Survey. Smokers were followed across three waves (October 2002 to December 2004), during which they were asked to report on their smoking-related beliefs and their quitting behaviour. FINDINGS: Smokers with no history of quitting across the three waves exhibited the highest levels of rationalisations for smoking. When smokers quit smoking, they reported having fewer rationalisations for smoking compared with when they had previously been smoking. However, among those who attempted to quit but then relapsed, there was once again a renewed tendency to rationalise their smoking. This rebound in the use of rationalisations was higher for functional beliefs than for risk-minimising beliefs, as predicted by social psychological theory. CONCLUSIONS: Smokers are motivated to rationalise their behaviour through the endorsement of more positive beliefs about smoking, and these beliefs change systematically with changes in smoking status. More work is needed to determine if this cognitive dissonance-reducing function has an inhibiting effect on any subsequent intentions to quit. PMID- 22218428 TI - Modulation of gap junction channels and hemichannels by growth factors. AB - Gap junction hemichannels and cell-cell channels have roles in coordinating numerous cellular processes, due to their permeability to extra and intracellular signaling molecules. Another mechanism of cellular coordination is provided by a vast array of growth factors that interact with relatively selective cell membrane receptors. These receptors can affect cellular transduction pathways, including alteration of intracellular concentration of free Ca(2+) and free radicals and activation of protein kinases or phosphatases. Connexin and pannexin based channels constitute recently described targets of growth factor signal transduction pathways, but little is known regarding the effects of growth factor signaling on pannexin based channels. The effects of growth factors on these two channel types seem to depend on the cell type, cell stage and connexin and pannexin isoform expressed. The functional state of hemichannels and gap junction channels are affected in opposite directions by FGF-1 via protein kinase dependent mechanisms. These changes are largely explained by channels insertion in or withdrawal from the cell membrane, but changes in open probability might also occur due to changes in phosphorylation and redox state of channel subunits. The functional consequence of variation in cell-cell communication via these membrane channels is implicated in disease as well as normal cellular responses. PMID- 22218429 TI - [Pediatric endocrinology 2011]. PMID- 22218430 TI - [Clinical and molecular aspects of congenital isolated hypogonadotropic hypogonadism]. AB - Congenital isolated hypogonadotropic hypogonadism (IHH) is characterized by partial or complete lack of pubertal development due to defects in migration, synthesis, secretion or action of gonadotropin-releasing hormone (GnRH). Laboratory diagnosis is based on the presence of low levels of sex steroids, associated with low or inappropriately normal levels of pituitary gonadotropins (LH and FSH). Secretion of other pituitary hormones is normal, as well magnetic resonance imaging of the hypothalamohypophyseal tract, which shows absence of an anatomical defects. When IHH is associated with olfactory abnormalities (anosmia or hyposmia), it characterizes Kallmann syndrome. A growing list of genes is involved in the etiology of IHH, suggesting the heterogeneity and complexity of the genetic bases of this condition. Defects in olfactory and GnRH neuron migration are the etiopathogenic basis of Kallmann syndrome. Mutations in KAL1, FGFR1/FGF8, PROK2/PROKR2, NELF, CHD7, HS6ST1 and WDR11 are associated with defects in neuronal migration, leading to Kallmann syndrome. Notably, defects in FGFR1, FGF8, PROKR2, CHD7 and WDR11 are also associated with IHH, without olfactory abnormalities (normosmic IHH), although in a lower frequency. Mutations in KISS1R, TAC3/TACR3 and GNRH1/GNRHR are described exclusively in patients with normosmic IHH. In this paper, we reviewed the clinical, hormonal and genetic aspects of IHH. PMID- 22218431 TI - New perspectives in the diagnosis of pediatric male hypogonadism: the importance of AMH as a Sertoli cell marker. AB - Sertoli cells are the most active cell population in the testis during infancy and childhood. In these periods of life, hypogonadism can only be evidenced without stimulation tests, if Sertoli cell function is assessed. AMH is a useful marker of prepubertal Sertoli cell activity and number. Serum AMH is high from fetal life until mid-puberty. Testicular AMH production increases in response to FSH and is potently inhibited by androgens. Serum AMH is undetectable in anorchidic patients. In primary or central hypogonadism affecting the whole gonad and established in fetal life or childhood, serum AMH is low. Conversely, when hypogonadism affects only Leydig cells (e.g. LHbeta mutations, LH/CG receptor or steroidogenic enzyme defects), serum AMH is normal or high. In pubertal males with central hypogonadism, AMH is low for Tanner stage (reflecting lack of FSH stimulus), but high for the age (indicating lack of testosterone inhibitory effect). Treatment with FSH provokes an increase in serum AMH, whereas hCG administration increases testosterone levels, which downregulate AMH. In conclusion, assessment of serum AMH is helpful to evaluate gonadal function, without the need for stimulation tests, and guides etiological diagnosis of pediatric male hypogonadism. Furthermore, serum AMH is an excellent marker of FSH and androgen action on the testis. PMID- 22218432 TI - [Therapeutic update on the treatment of craniopharyngiomas]. AB - Craniopharyngioma is an uncommon benign neoplasm, accounting for 1%-3% of all intracranial tumors, and the most common non-neuroepithelial intracranial neoplasm in childhood. Usually, the tumor is confined to the sellar region and the third ventricle, but due to frequent infiltration and adherence to the central nervous system, it often has an unfavorable clinical behavior. Therefore, it is classified by the World Health Organization (WHO) as a tumor of low or uncertain malignant potential. Endocrine after effects, mainly hypothalamic hypopituitarism, obesity and diabetes insipidus are highlighted due to their important impact on the quality of life of patients, mostly children. Optimal treatment of this tumor is a major challenge for neurosurgeons and endocrinologists. The combination of surgery, radiation, and application of radioisotopes and intratumoral drugs, aims at maximizing the chances of cure with minimal complications. Yet, recurrence is still frequent. Choosing the best treatment modality for craniopharyngiomas is a difficult decision, and it should always be specific for each case. In order to explore the multiple therapeutic options for craniopharyngiomas, we reviewed the literature with emphasis on the therapeutic possibilities and complications inherent to the treatment of this disease. PMID- 22218433 TI - [Current situation of neonatal screening for congenital hypothyroidism: criticisms and perspectives]. AB - Congenital hypothyroidism (CH) is one of the most common treatable causes of mental retardation. Efforts should be done in its early detection and treatment. Delays in diagnosis and treatment will result in impaired neurocognitive outcomes. Neonatal screening changed the natural history of this disease. The cutoff value for TSH is 10 mUI/L. In Brazil, neonatal screening has been done for three decades. Currently, it is performed in all Brazilian States and the Brazilian Federal District. Looking at recent data on the National Program for Neonatal Screening (NPNS) we can see a huge difference in the results among Brazilian States. NPNS involved 81.61% of the newborns. Only in 56.94% of the cases, samples were collected from newborns up to 7 days of life. Mean time of collection to arrival of the specimen in the lab, TSH determination, release of results and summoning the patient are far longer than the ideal times, causing a delay in early treatment to prevent neurological sequelae. Recent studies have suggested that changing TSH cutoff values to 6 mUI/L may reduce false negative results. Strategies should be adopted to achieve the goals established by the NPNS. PMID- 22218434 TI - [Growth of preterm-born children]. AB - Children born prematurely might experience a period of growth restriction just after birth. Catch-up growth begins during the first months of life and can be slow and progressive. These children may remain shorter and thinner throughout infancy and childhood compared to children born at term. In some cases, complete catch-up growth occurs only during adolescence. However, some children do not completely recover growth, and adults born prematurely are at increased risk of short stature. Impaired growth is more frequent in those born preterm and small for gestational age. Factors such as target height, birth weight, gestational age, neonatal morbidities and maternal education interfere in growth potential. Special attention should be given to children born preterm during the whole growth period. PMID- 22218435 TI - [Mutations in insulin-like growth factor receptor 1 gene (IGF1R) resulting in intrauterine and postnatal growth retardation]. AB - Approximately 10% of children born small-for-gestational age (SGA) do not show spontaneous growth catch-up. The causes of this deficit in prenatal growth and its maintenance after birth are not completely known, in most cases. Over the past eight years, several heterozygous inactivating mutations and deletions in IGF1R gene have been reported, indicating the role of defects in the IGFs/IGF1R axis as a cause of growth deficit. It has been hypothesized that at least 2.5% of children born SGA may have IGF1R gene defects. The clinical presentation of these patients is highly variable in the severity of growth retardation and hormonal parameters. In the most evident cases, patients have microcephaly, mild cognitive impairment and high levels of IGF-1, associated with short stature of prenatal onset. This review will describe the clinical, molecular and treatment of short stature with hrGH of children with mutations in the IGF1R gene. PMID- 22218436 TI - Endocrine diseases, perspectives and care in Turner syndrome. AB - Turner syndrome is a frequent chromosome disorder in clinical practice. It is characterized by short stature, gonadal dysgenesia and multisystemic involvement, responsible for a high morbidity and reduced life expectancy. The aim of the present paper is to describe the endocrinopathies and major problems at different ages, and to present suggestion for follow-up care in these patients. PMID- 22218437 TI - Adverse effects of growth hormone replacement therapy in children. AB - Human growth hormone (hGH) replacement therapy has been widely available for clinical purposes for more than fifty years. Starting in 1958, hGH was obtained from cadaveric pituitaries, but in 1985 the association between hGH therapy and Creutzfeldt-Jakob disease was reported. In the same year, the use of recombinant hGH (rhGH) was approved. Side effects of rhGH replacement therapy in children and adolescents include rash and pain at injection site, transient fever, prepubertal gynecomastia, arthralgia, edema, benign intracranial hypertension, insulin resistance, progression of scoliosis, and slipped capital femoral epiphysis. Since GH stimulates cell multiplication, development of neoplasms is a concern. We will review the side effects reported in all rhGH indications. PMID- 22218438 TI - [The vitamin D endocrine system]. AB - The vitamin D endocrine system comprises a group of 7-dehydrocholesterol-derived secosteroid molecules, including its active metabolite 1,25-dihydroxy-vitamin D (1,25(OH)(2)D), its precursors and other metabolites, its binding protein (DBP) and nuclear receptor (VDR), as well as cytochrome P450 complex enzymes participating in activation and inactivation pathways of those molecules. The biologic effects of 1,25(OH)(2)D are mediated by VDR, a ligand-activated transcription factor which is a member of the nuclear receptors family, spread in almost all human cells. In addition to its classic role in the regulation of calcium metabolism and bone health, evidence suggests that 1,25(OH)(2)D directly or indirectly modulates about 3% of the human genome, participating in the regulation of chief functions of systemic homeostasis, such as cell growth, differentiation and apoptosis, regulation of immune, cardiovascular and musculoskeletal systems, and insulin metabolism. Given the critical influence of the vitamin D endocrine system in many processes of systemic metabolic equilibrium, the laboratory assays available for the evaluation of this system have to present high accuracy and reproducibility, enabling the establishment of cutoff points that, beyond being consensually accepted, reliably express the vitamin D status of the organism, and the respective clinical-metabolic impacts on the global health of the individual. PMID- 22218439 TI - [Metabolic syndrome in children and adolescents: doubts about terminology but not about cardiometabolic risks]. AB - Metabolic syndrome (MS) has been a condition involved in considerable controversy, starting with the terminology. Gerald Reaven himself, the author who proposed the term MS, advised against the use of this terminology because the definition implies in at least three metabolic alterations, and it is never clear to which group of alterations we are referring to when we say that a patient has MS. In children, the problem is even more complicated, since there are many different adaptations to the criteria used in adults. On the other hand, independent of the terminology, cardiovascular risks are well-established and it is very clear that even children may present metabolic disturbances which predict future metabolic problems. The role of the pediatric endocrinologist or the general pediatrician is to investigate, especially in overweight/obese children, conditions that if treated early, may prevent future complications that today, unfortunately, are being diagnosed only in adult life. In this review, we discuss problems on the definition, epidemiology, pathophysiology, and complications of MS in children and adolescents. PMID- 22218440 TI - Metabolic syndrome in children born small-for-gestational age. AB - Being born small-for-gestational age and a rapid increase in weight during early childhood and infancy has been strongly linked with chronic diseases, including metabolic syndrome, which has been related to intrauterine life environment and linked to epigenetic fetal programming. Metabolic syndrome includes waist circumference >= 90(th) percentile for age, sex and race, higher levels of blood pressure, triglycerides and fasting glucose, and low levels of HDL-cholesterol. Insulin resistance may be present as early as 1 year of age, and obesity and/or type 2 diabetes are more prevalent in those born SGA than those born AGA. The programming of adaptive responses in children born SGA includes an association with increased blood pressure, changes in endothelial function, arterial properties and coronary disease. Early interventions should be directed to appropriate maternal nutrition, before and during pregnancy, promotion of breast feeding, and prevention of rapid weight gain during infancy, and to promote a healthy lifestyle. PMID- 22218441 TI - A rational approach to the diagnosis of polycystic ovarian syndrome during adolescence. AB - Polycystic ovarian syndrome (PCOS) is a lifelong disorder characterized by hyperandrogenism and ovulatory dysfunction, with a wide spectrum of clinical symptoms and signs. Three different sets of diagnostic criteria have been established in order to define this disease in adult women, but there is controversy regarding the use of these criteria in adolescence. During puberty, the adult criteria for ovulatory dysfunction does not seem applicable, because an irregular menstrual pattern and a decreased ovulatory rate is a physiologic event during this period of life. Also, a higher prevalence of polycystic ovarian morphology (PCOM) may be observed during this period, so PCOM is not a useful criterion to define PCOS in young women. These findings suggest that a key factor to diagnose to PCOS during adolescence is hyperandrogenism. In addition, since PCOM is not clearly associated with hyperandrogenism during this period of life, the term "polycystic ovarian syndrome" during adolescence creates confusion and may be misleading. PMID- 22218442 TI - [Childhood adrenocortical tumors: from a clinical to a molecular approach]. AB - Adrenocortical tumors (ACT) are more frequent during childhood, but they can appear at any age. ACTs can be classified in functioning, nonfunctioning (mainly observed in adults) and mixed. The diagnosis is based on clinical, biochemical findings and imaging. In children, in order to classify ACT as benign or malignant, tumor staging classification is recommended. Regarding molecular markers some studies should be taken into account: besides TP53 mutations, previous studies have also provided evidences of IGF2 involvement in 90% of the malignant ACT. Mutations altering exon 3 of CTNNB1 gene have been found in 6% of childhood ACTs. In addition, microRNAs can act as negative regulators of gene expression by targeting mRNA controlling cell growth, differentiation and apoptosis and have been implicated in adrenal tumorigenesis. High-throughput methods to analyze genome-wide expression have been developed over the last decade and identified a subset of tumors with good or poor prognosis. In the future, these studies can provide the basis of specific drug development, which can treat patients according to specific altered signaling pathway. PMID- 22218444 TI - Update on diagnosis and monitoring of cystic fibrosis-related diabetes mellitus (CFRD). AB - Cystic fibrosis (CF) is the most common recessive autosomal disease among Caucasian. Children with CF have benefitted from advances in medical and nutritional treatments, and this can be gleaned from the improvement in the survival of these patients. The increase in the survival rate brought with it the appearance of co-morbidities related to CF. Nowadays cystic fibrosis-related diabetes (CFRD) is considered the most common complication associated with CF. It can appear as early as infancy or adolescence, and its prevalence can be as high as 50% in adult patients. Because of its high prevalence, difficulties in early detection and the risks involved, in recent years several studies and consensuses have focused on this condition, adding information about the epidemiology, pathophysiology, prognosis and treatment of CFRD. The main aspects of these new concepts, as well as the current recommendations for its diagnosis and follow-up, will be presented in this study. PMID- 22218443 TI - Multifunctional role of steroidogenic factor 1 and disorders of sex development. AB - Disorders of sex development (DSD) involve several conditions that result from abnormalities during gonadal determination and differentiation. Some of these disorders may manifest at birth by ambiguous genitalia; others are diagnosed only at puberty, by the delayed onset of secondary sexual characteristics. Sex determination and differentiation in humans are processes that involve the interaction of several genes such as WT1, NR5A1, NR0B1, SOX9, among others, in the testicular pathway, and WNT4, DAX1, FOXL2 and RSPO1, in the ovarian pathway. One of the major proteins in mammalian gonadal differentiation is the steroidogenic nuclear receptor factor 1 (SF1). This review will cover some of the most recent data on SF1 functional roles and findings related to mutations in its coding gene, NR5A1. PMID- 22218445 TI - Neonatal cholestasis in congenital pituitary hormone deficiency and isolated hypocortisolism: characterization of liver dysfunction and follow-up. AB - INTRODUCTION: Neonatal cholestasis due to endocrine diseases is infrequent and poorly recognized. Referral to the pediatric endocrinologist is delayed. OBJECTIVE: We characterized cholestasis in infants with congenital pituitary hormone deficiencies (CPHD), and its resolution after hormone replacement therapy (HRT). SUBJECTS AND METHODS: Sixteen patients (12 males) were included; eleven with CPHD, and five with isolated central hypocortisolism. RESULTS: Onset of cholestasis occurred at a median age of 18 days of life (range 2-120). Ten and nine patients had elevated transaminases and gammaGT, respectively. Referral to the endocrinologist occurred at 32 days (range 1 - 72). Remission of cholestasis occurred at a median age of 65 days, whereas liver enzymes occurred at 90 days. In our cohort isolated, hypocortisolism was a transient disorder. CONCLUSION: Cholestasis due to hormonal deficiencies completely resolved upon introduction of HRT. Isolated hypocortisolism may be a transient cause of cholestasis that needs to be re-evaluated after remission of cholestasis. PMID- 22218446 TI - TSH neurosecretory dysfunction (TSH-nd) in Down syndrome (DS): low risk of progression to Hashimoto's thyroiditis. AB - INTRODUCTION: Patients with Down syndrome (DS) often have elevated TSH (hypothalamic origin), which is called TSH neurosecretory dysfunction (TSH-nd). In these cases, there is slight elevation in TSH (5-15 uUI/mL), with normal free T4 and negative thyroid antibodies (AB). OBJECTIVE: To recognize the risk of progression to Hashimoto's thyroiditis (HT). SUBJECTS AND METHODS: We retrospectively analyzed 40 DS patients (mean age = 4.5 years), followed up for 6.8 years. RESULTS: HT was diagnosed in 9/40 patients, three early in monitoring, and six during evolution. In 31/40 patients, TSH-nd diagnosis remained unchanged over the years, with maximum TSH values ranging from 5 to 15 uUI/mL. In this group, free T4 also remained normal and AB were negative. There was a significant TSH reduction (p = 0.017), and normal TSH concentrations (< 5.0 uUI/mL) were observed in 29/31 patients, in at least one moment. No patient had TSH > 15 uUI/mL. CONCLUSION: DS patients with TSH-nd present low risk of progression to HT (10% for females and 6% for males). PMID- 22218447 TI - Weight-adjusted neonatal 17OH-progesterone cutoff levels improve the efficiency of newborn screening for congenital adrenal hyperplasia. AB - OBJECTIVE: To evaluate weight-adjusted strategy for levels of neonatal-17OHP in order to improve newborn screening (NBS) efficiency. SUBJECTS AND METHODS: Blood samples collected between 2-7 days of age from 67,640 newborns were evaluated. When N17OHP levels were >= 20 ng/mL, and a second sample was requested. We retrospectively analyzed neonatal-17OHP levels measured by Auto DELFIA- B024-112 assay, grouped according to birth-weight: G1: < 1,500 g, G2: 1,501-2,000 g, G3: 2,000-2,500 g and G4: > 2,500 g. 17OHP cutoff values were determined for each group using the 97.5(th), 99(th), 99.5(th) and 99.8(th) percentiles. RESULTS: 0.5% of newborns presented false-positive results using the cutoff level >= 20 ng/mL for all groups. Neonates of low birthweight made up 69% of this group. Seven full-term newborns presented congenital adrenal hyperplasia (CAH) and, except for one of them, 17OHP levels were > 120 ng/mL. Only the 99.8(th) percentile presented higher predictive positive value (2%), and lower rate of false-positives in all groups. CONCLUSIONS: We suggest the use of 99.8(th) percentile obtained by weight-adjusted N17OHP values of healthy newborns to reduce the rate of false-positive results in NBS. PMID- 22218448 TI - Optimal cutoff points for body mass index, waist circumference and HOMA-IR to identify a cluster of cardiometabolic abnormalities in normal glucose-tolerant Brazilian children and adolescents. AB - OBJECTIVE: The aim of this study was to establish the best cutoff values for waist circumference (WC), body mass index (BMI) and HOMA-IR (HR) to identify a cluster (>= 3) of cardiovascular risk factors (CVRF) in normal glucose-tolerant (NGT) Brazilian children and adolescents. SUBJECTS AND METHODS: Cross-sectional study of 319 individuals (aged 10 to 19y) from a southern Brazilian city. Gender specific receiver-operating characteristics (ROC) curves were constructed to assess cutoffs values of BMI (kg/m(2), WC (cm), and HR. RESULTS: The areas under the ROC curves to detect a cluster of CVRF were 0.92, 0.93 and 0.68 (females), and 0.93, 0.93 and 0.89 (males), for WC, BMI and HR, respectively. The cutoff values were 83.0 and 80.5 cm (WC), 22.7 and 20.4 kg/m(2) (BMI), and 1.65 and 1.95 (HR), for females and males, respectively, to detect the cluster of CVRF. CONCLUSION: These values of BMI, WC-) and (HR) detected a high proportion of NGTt Brazilian children and adolescents with a cluster of CVRF. PMID- 22218449 TI - Metabolic evaluation of young women with congenital adrenal hyperplasia. AB - OBJECTIVE: To evaluate insulin resistance and lipid profile in women with congenital adrenal hyperplasia (CAH) caused by classical 21-hydroxylase deficiency (21OHD), and their association with body mass index (BMI) and corticosteroid dosage. SUBJECTS AND METHODS: We assessed BMI, waist circumference, current glucocorticoid dosage, glucose, insulin and lipid profile in eighteen young women (mean +/- SD, 19.3 +/- 3.0 years) with 21OHD CAH. RESULTS: BMI was normal in 12 patients, 5 of them were overweight, and 1 was obese. Waist circumference was high in 7 patients. Fasting insulin and HOMA-IR were elevated in seven and eight patients, respectively. Total cholesterol and triglycerides were high in only two patients, and HDL-cholesterol was low in four. Insulin resistance was not associated with BMI, waist circumference or glucocorticoid dose. CONCLUSIONS: Young women with 21OHD CAH had infrequent dyslipidemia, but had a higher prevalence of insulin resistance and central obesity, that were independent of BMI or corticosteroid dosage. PMID- 22218450 TI - Early traits of metabolic syndrome in pediatric post-cancer survivors: outcomes in adolescents and young adults treated for childhood medulloblastoma. AB - OBJECTIVE: To analyze traits of metabolic syndrome (MetS) in medulloblastoma survivors. SUBJECTS AND METHODS: Sixteen childhood medulloblastoma survivors aged 18.0 (4.4) years, with history of craniospinal radiation therapy (RT) were compared with nine control subjects matched by age, gender, and body mass index, according to fat distribution, metabolic and cardiovascular variables. RESULTS: Medulloblastoma patients showed increases in waist circumference and its relationships (all p < 0.05), and HOMA1-IR (p = 0.006), which were modified by growth hormone (GH) secretion status. However, these increases were within normal range. CONCLUSIONS: Adolescent and young adult survivors of medulloblastoma showed centripetal fat deposition and decreased insulin sensitivity, associated with GH status. Pediatric brain tumor survivors following RT should be monitored for the diagnosis of MetS traits predisposing to cardiovascular disease. PMID- 22218451 TI - Near-final height in patients with congenital adrenal hyperplasia treated with combined therapy using GH and GnRHa. AB - INTRODUCTION: Intrinsic limitations of glucocorticoid therapy in patients with congenital adrenal hyperplasia (CAH) determine frequent loss in final height. The association of secondary central precocious puberty and early epiphyseal fusion is also frequent. In these conditions, GnRHa treatment alone or in combination with GH has been indicated. OBJECTIVES: This is a retrospective study, describing the estatural findings of CAH patients with significant decrease in height prediction, who were submitted to combined GH plus GnRHa therapy up to near-final height. SUBJECTS AND METHODS: We studied 13 patients, eight females and five males, eight with the classical and five with the nonclassical form of the disorder. Treatment with hydrocortisone (10-20 mg/m(2)/day) or prednisolone (3-6 mg/kg/day) was associated with GnRHa (3.75 mg/months) for 4.0 (1.5) years, and GH (0.05 mg/kg/day) for 3.6 (1.4) years. RESULTS: Stature standard deviation score for bone age improved significantly after GH treatment, becoming similar to target height at the end of the second year of GH treatment. CONCLUSION: We conclude that combined GH plus GnRHa therapy can be useful in a subset of CAH patients with significant reduction of predicted final height associated with poor hormonal control and central precocious puberty. PMID- 22218452 TI - Absolute measurement of androgen receptor mRNA in peripheral blood mononuclear, preputial skin and urethral mucosa cells of control individuals with phimosis using qRT-PCR. AB - INTRODUCTION: Androgen actions are exerted upon the androgen receptor (AR), and complete genital virilization of normal 46,XY individuals depends on adequate function and expression of the AR gene in a tissue-specific manner. OBJECTIVE: Standardization of normal ARmRNA in androgen-sensitive tissues. MATERIALS AND METHODS: In this study, we determined the quantitative amounts of ARmRNA in peripheral blood mononuclear, urethral mucosa and preputial skin cells of control subjects with phimosis by using RT-PCR. RESULTS: The mean (SD) values of AR expression in blood, urethra and prepuce were: 0.01 (0.01); 0.43 (0.32); 0.31 (0.36), respectively. CONCLUSION: The AR expression is low in blood and equivalent in urethral mucosa and preputial skin, which may be useful in the diagnosis of individuals with abnormal external genitalia. PMID- 22218453 TI - Biosimilars. AB - Although common themes permeate the environment across continents and particular divergences as to how to proceed exist between different regulatory agencies, it seems that policies are still in flux. Not all policies will suffice to fit all dissimilar biologics, and these in place or being developed may, in turn, change to accommodate new or unexpected developments. Consideration for accelerated approval for those compounds that do not present complex questions should be considered.The regulatory agencies should be more forthcoming, the industry sector exercise social responsibility, and the public should have realistic expectations. PMID- 22218456 TI - Horizontal gene transfers as metagenomic gene duplications. AB - While it is well accepted that horizontal gene transfer plays an important role in the evolution and the diversification of prokaryotic genomes, many questions remain open regarding its functional mechanisms of action and its interplay with the extant genome. This study addresses the relationship between proteome innovation by horizontal gene transfer and genome content in Proteobacteria. We characterize the transferred genes, focusing on the protein domain compositions and their relationships with the existing protein domain superfamilies in the genome. In agreement with previous observations, we find that the protein domain architectures of horizontally transferred genes are significantly shorter than the genomic average. Furthermore, protein domains that are more common in the total pool of genomes appear to have a proportionally higher chance to be transferred. This suggests that transfer events behave as if they were drawn randomly from a cross-genomic community gene pool, much like gene duplicates are drawn from a genomic gene pool. Finally, horizontally transferred genes carry domains of exogenous families less frequently for larger genomes, although they might do it more than expected by chance. PMID- 22218455 TI - Chemoenzymatic synthesis of a mixed phosphine-phosphine oxide catalyst and its application to asymmetric allylation of aldehydes and hydrogenation of alkenes. AB - The chemoenzymatic synthesis of a Lewis basic phosphine-phosphine oxide organocatalyst from a cis-dihydrodiol metabolite of bromobenzene proceeds via a palladium-catalysed carbon-phosphorus bond coupling and a novel room temperature Arbuzov [2,3]-sigmatropic rearrangement of an allylic diphenylphosphinite. Allylation of aromatic aldehydes were catalysed by the Lewis basic organocatalyst giving homoallylic alcohols in up to 57% ee. This compound also functioned as a ligand for rhodium-catalysed asymmetric hydrogenation of acetamidoacrylate giving reduction products with ee values of up to 84%. PMID- 22218454 TI - Substituted heteroaromatic compounds: effect on nicotine self-administration in rats. AB - RATIONALE: Certain compounds that nonselectively inhibit a prominent human nicotine-metabolizing enzyme (i.e., human cytochrome P-450 2A6, hCYP 2A6) showed inhibition of smoking in humans. However, a comprehensive examination of hCYP 2A6 inhibitors to decrease nicotine self-administration in rats has not been reported. OBJECTIVES: We tested substituted heteroaromatic compounds designed to selectively inhibit hCYP 2A6 in a model system to (a) examine selective hCYP 2A6 inhibitors to decrease cotinine formation in vivo in rats administered with nicotine and (b) examine their efficacy to decrease nicotine self-administration in rats. METHODS: Rats were trained to IV self-administer nicotine in 1-h sessions. Nicotine self-administration was carried out at a unit dose of 0.03 mg/kg/infusion in 0.1 ml/s. Pretreatment with substituted heteroaromatic test compounds (0.5-25 mg/kg, i.p., 30 min prior to nicotine self-administration sessions) resulted in dose-dependent decreases of nicotine self-administration. Using operant conditioning techniques, nicotine- vs. food-reinforced responding was evaluated for compounds 10 and 11. RESULTS: Compounds 10 and 11 selectively decreased nicotine self-administration with estimated ED(50) values 4 and 2.8 mg/kg, respectively. Of the test compounds examined, none showed significant affinity for mammalian alpha4beta2- or alpha7-neuronal nicotinic acetylcholine (nAChR) receptors and none were inhibitors of the human dopamine transporter (hDAT); thus, neither the endogenous nAChRs nor DAT apparently plays a role in decreasing nicotine self-administration for this series of compounds. CONCLUSION: The results indicate that chemical analogs of nicotine can play a role in nicotine self-administration harm reduction but a non-nAChR and a non-hDAT mechanism are likely involved. PMID- 22218457 TI - Highly stereoselective synthesis of cis-beta-enaminones mediated by diethyl azodicarboxylate. AB - Promoted by diethyl azodicarboxylate, a novel and highly stereoselective synthesis of cis-beta-enaminones via oxidative dehydrogenation and hydration of the substituted propargylamines was realized. The possible mechanism was also proposed. PMID- 22218459 TI - Locating spatial variation in the association between wildland fire risk and social vulnerability across six Southern states. AB - Wildland fire in the South commands considerable attention, given the expanding wildland urban interface (WUI) across the region. Much of this growth is propelled by higher income retirees and others desiring natural amenity residential settings. However, population growth in the WUI increases the likelihood of wildfire fire ignition caused by people, as humans account for 93% of all wildfires fires in the South. Coexisting with newly arrived, affluent WUI populations are working class, poor or otherwise socially vulnerable populations. The latter groups typically experience greater losses from environmental disasters such as wildfire because lower income residents are less likely to have established mitigation programs in place to help absorb loss. We use geographically weighted regression to examine spatial variation in the association between social vulnerability (SOVUL) and wildfire risk. In doing so, we identify "hot spots" or geographical clusters where SOVUL varies positively with wildfire risk across six Southern states--Alabama, Arkansas, Florida, Georgia, Mississippi, and South Carolina. These clusters may or may not be located in the WUI. These hot spots are most prevalent in South Carolina and Florida. Identification of these population clusters can aid wildfire managers in deciding which communities to prioritize for mitigation programming. PMID- 22218458 TI - Zirconium phosphate nano-platelets: a novel platform for drug delivery in cancer therapy. AB - Doxorubicin was intercalated into novel zirconium phosphate nano-platelets (ZrP). The obtained doxorubicin intercalated ZrP nano-platelets had an impressive 34.9% (w/w) drug loading. We used this material to deliver doxorubicin to breast cancer cells (MCF-7). Cellular studies with MCF-7 cells showed higher uptake and cytotoxicity of doxorubicin loaded ZrP compared to free doxorubicin. PMID- 22218460 TI - Resolving the conflict between ecosystem protection and land use in protected areas of the Sierra Madre de Chiapas, Mexico. AB - Livelihoods of people living in many protected areas (PAs) around the world are in conflict with biodiversity conservation. In Mexico, the decrees of creation of biosphere reserves state that rural communities with the right to use buffer zones must avoid deforestation and their land uses must become sustainable, a task which is not easily accomplished. The objectives of this paper are: (a) to analyze the conflict between people's livelihoods and ecosystem protection in the PAs of the Sierra Madre de Chiapas (SMC), paying special attention to the rates and causes of deforestation and (b) to review policy options to ensure forest and ecosystem conservation in these PAs, including the existing payments for environmental services system and improvements thereof as well as options for sustainable land management. We found that the three largest PAs in the SMC are still largely forested, and deforestation rates have decreased since 2000. Cases of forest conversion are located in specific zones and are related to agrarian and political conflicts as well as growing economic inequality and population numbers. These problems could cause an increase in forest loss in the near future. Payments for environmental services and access to carbon markets are identified as options to ensure forest permanence but still face problems. Challenges for the future are to integrate these incentive mechanisms with sustainable land management and a stronger involvement of land holders in conservation. PMID- 22218461 TI - NOD1 and NOD2 stimulation triggers innate immune responses of human periodontal ligament cells. AB - Nod-like receptors (NLRs) are cytosolic sensors for microbial molecules. Nuucleotide-binding oligomerization domain (NOD)1 and NOD2 recognize the peptidoglycan derivatives, meso-diaminopimelic acid (meso-DAP) and muramyl dipeptide (MDP), respectively, and trigger host innate immune responses. In the present study, we examined the function of NOD1 and NOD2 on innate immune responses in human periodontal ligament (PDL) cells. The gene expression of NOD1 and NOD2 was examined by RT-PCR. IL-6 and IL-8 production in culture supernatants was measured by ELISA. Western blot analysis was performed to determine the activation of NF-kappaB and MAPK in response to Tri-DAP and MDP. The genes of NOD1 and NOD2 appeared to be expressed in PDL cells. Although the levels of NOD2 expression were weak in intact cells, MDP stimulation increased the gene expression of NOD2 in PDL cells. Tri-DAP and MDP led to the production of IL-6 and IL-8 and the activation of NF-kappaB and MAPK in PDL cells. Toll-like receptor (TLR) stimulation led to increased gene expression of NOD1 and NOD2 in PDL cells. Pam3CSK4 (a TLR2 agonist) and IFN-gamma synergized with Tri-DAP and MDP to produce IL-8 and IL-6 in PDL cells. Our results indicate that NOD1 and NOD2 are functionally expressed in human PDL cells and can trigger innate immune responses. PMID- 22218462 TI - Two high-throughput screening assays for aberrant RNA-protein interactions in myotonic dystrophy type 1. AB - Myotonic dystrophy type 1 (DM1), the most prevalent form of adult muscular dystrophy, is caused by expansion of a CTG repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene. The pathogenic effects of the CTG expansion arise from the deleterious effects of the mutant transcript. RNA with expanded CUG tracts alters the activities of several RNA binding proteins, including muscleblind-like 1 (MBNL1). MBNL1 becomes sequestered in nuclear foci in complex with the expanded CUG-repeat RNA. The resulting loss of MBNL1 activity causes misregulated alternative splicing of multiple genes, leading to symptoms of DM1. The binding interaction between MBNL1 and mutant RNA could be a key step in the pathogenesis of DM1 and serves as a potential target for therapeutic intervention. We have developed two high-throughput screens suitable assays using both homogenous time-resolved fluorescence energy transfer and AlphaScreen technologies to detect the binding of a C-terminally His-tagged MBNL1 and a biotinylated (CUG)(12) RNA. These assays are homogenous and successfully miniaturized to 1,536-well plate format. Both assays were validated and show robust signal-to-basal ratios and Z' factors. PMID- 22218463 TI - Lambda genomic DNA quantification using ultrasonic treatment followed by liquid chromatography-isotope dilution mass spectrometry. AB - Quantification of genomic DNA that is traceable to the SI was performed successfully by measuring the individual nucleotides. Specifically, ultrasound was used to shear lambda genomic DNA into fragments of less than 200 base pairs, followed by deoxyribonuclease Iota and phosphodiesterase Iota digestion and liquid chromatography-isotope dilution mass spectrometry (LC-IDMS) quantification to estimate the mass fraction of the lambda DNA, based on the constituent deoxynucleotide monophosphates (dNMPs) within the molecule. Digital PCR (dPCR) was employed to quantify the same lambda DNA solution to provide independent data for comparing the performance of two quantitative methods. On the basis of the LC IDMS measurement after ultrasonic treatment of the sample, the concentration of lambda DNA was 273.1 +/- 9.8 MUg/g (expanded uncertainty at the 95% confidence interval). This shows good agreement with the data from dPCR. Additionally, the result calculated on the basis of the sum of the concentrations of the four dNMPs is the same as that calculated on the basis of the sequence, which indicates that knowledge of the DNA sequence and length is unnecessary to measure the total DNA concentration when applying ultrasonic treatment-LC-IDMS. PMID- 22218465 TI - How much radiologically isolated syndrome suggestive of multiple sclerosis is multiple sclerosis? PMID- 22218466 TI - Incidental demyelinating inflammatory lesions in asymptomatic patients: a Brazilian cohort with radiologically isolated syndrome and a critical review of current literature. AB - Despite the definition of specific diagnostic criteria to identify radiologically isolated syndrome (RIS) suggestive of multiple sclerosis, its natural history remains incompletely understood. We retrospectively analyzed a Brazilian cohort of 12 patients to clarify their features and to emphasize the role of imaging predictors in clinical conversion. We demonstrated that, although some individuals did not exhibit progression over a lengthy follow-up period (16.7%), most patients will progress clinically or radiologically in the initial years of the follow-up (83.3%). Infratentorial and spinal cord involvement, as well as the total number of lesions, were more relevant predictors of progression than gadolinium enhancement. Further studies remain necessary to define the risk of conversion in males and to clarify the cognitive abilities of RIS patients. This study may provide an improved understanding of the natural course and evolution of incidental magnetic resonance imaging lesions, and further assists with the management of RIS in clinical practice. PMID- 22218467 TI - Clinical predictors of response to immunomodulators for multiple sclerosis. AB - OBJECTIVES: To determine, based on clinical criteria, the proportion of multiple sclerosis (MS) patients responsive to immunomodulators (RI) and nonresponsive to immunomodulators (NRI), and to ascertain whether clinical and epidemiological data differs between RI and NRI patient groups. METHODS: Patients were assessed on rate of exarcerbations per year, for the period before and after commencement of treatment. The RI and NRI groups were compared for several clinical and epidemiological characteristics. DISCUSSION AND CONCLUSION: A total of 31.4% of the patients were nonresponders to the immunomodulatory treatment. The main predictors of immunomodulatory response were early diagnostic and commencement of therapy and high rate of annual exacerbations prior to treatment. Given the arsenal of medication options available for MS management, screening potential candidates for different therapeutic approaches are critical to optimize evolution of patients with the disease. PMID- 22218468 TI - Accuracy of prospective memory tests in mild Alzheimer's disease. AB - OBJECTIVES: To verify the accuracy of prospective memory (ProM) tests in Alzheimer's disease (AD). METHODS: Twenty mild AD patients (CDR 1), and 20 controls underwent Digit Span (DS), Trail Making (TM) A and B, visual perception, Rey Auditory-Verbal Learning tests, and Cornell Scale for Depression. AD diagnosis was based on DSM-IV and NINCDS-ADRDA criteria. ProM was assessed with the appointment and belonging subtests of Rivermead Behavioral Memory Test (RBMT); and with two new tests (the clock and animal tests). RESULTS: AD patients had a worse performance than controls on the majority of tests, except DS forward and TM-A. There was no correlation between RBMT and the new ProM tests. As for accuracy, the only significant difference concerned the higher sensitivity of our animal test versus the RBMT belonging test. CONCLUSIONS: The clock and the animal tests showed similar specificity, but higher sensitivity than the RBMT subtests. PMID- 22218470 TI - Autism spectrum disorder and celiac disease: no evidence for a link. AB - OBJECTIVE: To evaluate the possible association between celiac disease (CD) and/or gluten sensitivity (GS) and autism spectrum disorder (ASD). METHODS: Occurrences of CD were determined in a group of children and adolescents affected by ASD and, conversely, occurrences of ASD were assessed in a group of biopsy proven celiac patients. To detect the possible existence of GS, the levels of antigliadin antibodies in ASD patients were assessed and compared with the levels in a group of non-celiac children. RESULTS: The prevalence of CD or GS in ASD patients was not greater than in groups originating from the same geographical area. Similarly the prevalence of ASD was not greater than in a group of biopsy proven CD patients. CONCLUSION: No statistically demonstrable association was found between CD or GS and ASD. Consequently, routine screening for CD or GS in all patients with ASD is, at this moment, neither justified nor cost-effective. PMID- 22218469 TI - Translation, cultural adaptation and psychometric evaluation of the Leganes cognitive test in a low educated elderly Brazilian population. AB - OBJECTIVE: To validate the Leganes cognitive test (LCT) for cognitive screening in low educated elderly Brazilians. METHODS: The study sample was composed of 59 elderly residents from the city of Santa Cruz, in Brazil, with low schooling levels. Reliability was analyzed with a two-day interval between assessments, and concurrent validity was assessed using the Mini Mental State Examination (MMSE). RESULTS: According to the LCT, the prevalence of dementia was 11.8%. The scale items showed a moderate to strong correlation between domains (p<0.01), and inter rater reliability exhibited ICC=0.81, 95%CI=0.72-0.88. The factor analysis resulted in two factors: memory and orientation. Interscale agreement was considered poor (k=-0.02), supporting the hypothesis of an educational impact on final MMSE scores. CONCLUSION: The results suggest that LCT has acceptable levels of reliability for use in low-educated Brazilian elderly. PMID- 22218471 TI - The impact of EEG in the diagnosis and management of patients with acute impairment of consciousness. AB - OBJECTIVES: To assess the frequency of electroencephalogram (EEG) requests in the emergency room (ER) and intensive care unit (ICU) for patients with impairment of consciousness (IC) and its impact in the diagnosis and management. METHODS: We followed patients who underwent routine EEG from ER and ICU with IC until discharge or death. RESULTS: During the study, 1679 EEGs were performed, with 149 (8.9%) from ER and ICU. We included 65 patients and 94 EEGs to analyze. Epileptiform activity was present in 42 (44.7%). EEG results changed clinical management in 72.2% of patients. The main reason for EEG requisition was unexplained IC, representing 36.3% of all EEGs analyzed. Eleven (33%) of these had epileptiform activity. CONCLUSION: EEG is underused in the acute setting. The frequency of epileptiform activity was high in patients with unexplained IC. EEG was helpful in confirming or ruling out the suspected initial diagnosis and changing medical management in 72% of patients. PMID- 22218473 TI - Morphological abnormalities in mitochondria of the skin of patients with sporadic amyotrophic lateral sclerosis. AB - OBJECTIVES: Mitochondrial dysfunction has been reported in the central nervous system, hepatocytes and peripheral blood lymphocytes from patients with sporadic amyotrophic lateral sclerosis (SALS). However, the status of skin mitochondria has not been reported, in spite of the fact that SALS patients present skin abnormalities. The objective of the present study was to compare mitochondrial ultrastructural parameters in keratinocytes from patients with SALS and healthy controls. METHODS: Our study was based on the analysis of 112 skin mitochondria from 5 SALS patients and 99 organelles from 4 control subjects by electron microscopy. RESULTS: Computerized image analysis showed that mitochondrial major axis length, area and perimeter of the organelle were significantly smaller in SALS respect of healthy control subjects. Morphologically, SALS mitochondria presented cristolysis and breakage of the outer membrane. CONCLUSIONS: Mitochondrial dysfunction in the skin may possibly reflect changes occurring in mitochondria of the central nervous system. The analysis of mitochondrial morphology in this tissue may be of value to follow disease progression and, eventually, the effectiveness of current therapies for SALS. PMID- 22218472 TI - Devising and validating a headache diary in a series of patients with chronic daily headache from Colombia. AB - OBJECTIVE: To devise and test the reliability and validity of a brief headache diary in a series of Colombian patients with chronic daily headache. METHODS: The study was designed in five stages: selection of domains (group of patients and experts); initial devising of the items (writing group); identification of non understandable items (n=20); assessment of internal consistency (n=100); assessment of validity and assessment of sensitivity to change during seven consecutive days (n=25, 175 observations). RESULTS: Five domains were selected: headache presence, severity and length of pain, analgesics intake, and missing workdays. The headache diary is internally consistent (~75% of rotated variance), correlates with the medical interview (Spearman's rho and Kendall's tau over 0.8 for each domain) and it has an adequate and stable sensitivity and specificity (82 to 96%). CONCLUSIONS: This headache diary is a reliable and valid instrument and represents the most important features affecting Colombian patients with chronic daily headache. PMID- 22218474 TI - Cyclosporin safety in a simplified rat brain tumor implantation model. AB - Brain cancer is the second neurological cause of death. A simplified animal brain tumor model using W256 (carcinoma 256, Walker) cell line was developed to permit the testing of novel treatment modalities. Wistar rats had a cell tumor solution inoculated stereotactically in the basal ganglia (right subfrontal caudate). This model yielded tumor growth in 95% of the animals, and showed absence of extracranial metastasis and systemic infection. Survival median was 10 days. Estimated tumor volume was 17.08 +/- 6.7 mm(3) on the 7(th) day and 67.25 +/- 19.8 mm(3) on 9(th) day post-inoculation. Doubling time was 24.25 h. Tumor growth induced cachexia, but no hematological or biochemical alterations. This model behaved as an undifferentiated tumor and can be promising for studying tumor cell migration in the central nervous system. Dexamethasone 3.0 mg/kg/day diminished significantly survival in this model. Cyclosporine 10 mg/kg/day administration was safely tolerated. PMID- 22218475 TI - Treatment of neuromyelitis optica: an evidence based review. AB - Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system characterized by severe optic neuritis and transverse myelitis, usually with a relapsing course. Aquaporin-4 antibody is positive in a high percentage of NMO patients and it is directed against this water channel richly expressed on foot processes of astrocytes. Due to the severity of NMO attacks and the high risk for disability, treatment should be instituted as soon as the diagnosis is confirmed. There is increasing evidence that NMO patients respond differently from patients with multiple sclerosis (MS), and, therefore, treatments for MS may not be suitable for NMO. Acute NMO attacks usually are treated with high dose intravenous corticosteroid pulse and plasmapheresis. Maintenance therapy is also required to avoid further attacks and it is based on low-dose oral corticosteroids and non-specific immunosuppressant drugs, like azathioprine and mycophenolate mofetil. New therapy strategies using monoclonal antibodies like rituximab have been tested in NMO, with positive results in open label studies. However, there is no controlled randomized trial to confirm the safety and efficacy for the drugs currently used in NMO. PMID- 22218476 TI - A rare cause of recurrent peripheral facial palsy. PMID- 22218477 TI - Multiple subcortical strokes caused by mucormycosis in a patient with lymphoma. PMID- 22218478 TI - Cervical myelopathy caused by ligamentum flavum ossification. PMID- 22218479 TI - Facial somatosensorial evaluation in idiopathic trigeminal neuralgia. PMID- 22218480 TI - Meningioma after immunomodulation for multiple sclerosis. PMID- 22218481 TI - Magnetic resonance appearance of recurrent ophthalmoplegic migraine. PMID- 22218482 TI - "Black turbinate sign": a potential predictor of mucormycosis in cavernous sinus thrombophlebitis. PMID- 22218485 TI - Spontaneous spinal epidural hematoma during pregnancy. PMID- 22218487 TI - Global mapping of protein phosphorylation events identifies Ste20, Sch9 and the cell-cycle regulatory kinases Cdc28/Pho85 as mediators of fatty acid starvation responses in Saccharomyces cerevisiae. AB - Synthesis, degradation, and metabolism of fatty acids are strictly coordinated to meet the nutritional and energetic needs of cells and organisms. In the absence of exogenous fatty acids, proliferation and growth of the yeast Saccharomyces cerevisiae depends on endogenous synthesis of fatty acids, which is catalysed by fatty acid synthase. In the present study, we have used quantitative proteomics to examine the cellular response to inhibition of fatty acid synthesis in Saccharomyces cerevisiae. We have identified approximately 2000 phosphorylation sites of which more than 400 have been identified as being regulated in a temporal manner in response to inhibition of fatty acid synthesis by cerulenin. By bioinformatic analysis of these phosphorylation events, we have identified the cell cycle kinases Cdc28 and Pho85, the PAK kinase Ste20 as well as the protein kinase Sch9 as central mediators of the cellular response to inhibition of fatty acid synthesis. PMID- 22218488 TI - Parathyroid hormone measurements, guidelines statements and clinical treatments: a real-world cautionary tale. PMID- 22218489 TI - HbA1c and diagnosis of diabetes. The test has finally come of age. PMID- 22218490 TI - Differential effects of 20 non-dioxin-like PCBs on basal and depolarization evoked intracellular calcium levels in PC12 cells. AB - Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) are environmental pollutants that are well known for their neurotoxic effects. Numerous in vitro studies reported PCB-induced increases in the basal intracellular calcium concentration ([Ca(2+)](i)), and in vivo NDL-PCB neurotoxicity appears at least partly mediated by these disturbances. However, effects of NDL-PCBs on depolarization-evoked calcium influx are poorly investigated, and effects of several congeners, including PCB53, on calcium homeostasis are still unknown. We therefore studied the effects of 20 selected NDL-PCBs on basal and depolarization-evoked [Ca(2+)](i) in fura-2-loaded PC12 cells using single-cell fluorescence microscopy. The results demonstrate that hexa- and heptachlorobiphenyls (with the exception of PCB136) were unable to affect basal and depolarization-evoked [Ca(2+)](i). However, most tri- and tetrachlorinated as well as some pentachlorinated NDL-PCBs (at 1 and 10MUM) increased basal [Ca(2+)](i) during a 15-min exposure. The increase in basal [Ca(2+)](i), which differed in kinetics for the different congeners, depended partly on influx of extracellular calcium and calcium release from the endoplasmic reticulum. Importantly, all tested tri- and tetrachlorinated biphenyls and some pentachlorinated NDL-PCBs (PCB95, PCB100, and PCB104) reduced depolarization-evoked [Ca(2+)](i), with PCB51 and PCB53 being most potent (near complete inhibition at 1MUM). The reduction in depolarization evoked calcium influx depended on the exposure duration but not on the foregoing PCB-induced increase in basal [Ca(2+)](i). The inhibition of voltage-gated calcium channels is a novel and sensitive mode of action for NDL-PCBs that contributes to the disturbances in calcium homeostasis and likely is related to NDL-PCB-induced (developmental) neurotoxicity. PMID- 22218491 TI - Mechanism of inhibition of the ATPase domain of human topoisomerase IIalpha by 1,4-benzoquinone, 1,2-naphthoquinone, 1,4-naphthoquinone, and 9,10 phenanthroquinone. AB - The inhibition of human topoisomerase IIalpha (Hu-TopoIIalpha), a major enzyme involved in maintaining DNA topology, repair, and chromosome condensation/decondensation results in loss of genomic integrity. In the present study, the inhibition of ATPase domain of Hu-TopoIIalpha as a possible mechanism of genotoxicity of 1,4-benzoquinone (BQ), hydroquinone (HQ), naphthoquinone (1,2 NQ and 1,4-NQ), and 9,10-phenanthroquinone (9,10-PQ) was investigated. In silico modeling predicted that 1,4-BQ, 1,2-NQ, 1,4-NQ, and 9,10-PQ could interact with Ser-148, Ser-149, Asn-150, and Asn-91 residues of the ATPase domain of Hu TopoIIalpha. Biochemical inhibition assays with the purified ATPase domain of Hu TopoIIalpha revealed that 1,4-BQ is the most potent inhibitor followed by 1,4-NQ > 1,2-NQ > 9,10-PQ > HQ. Ligand-binding studies using isothermal titration calorimetry revealed that 1,4-BQ, HQ, 1,4-NQ, 1,2-NQ, and 9,10-PQ enter into four sequentially binding site models inside the domain. 1,4-BQ exhibited the strongest binding, followed by 1,4-NQ > 1,2-NQ > 9,10-PQ > HQ, as revealed by their average K(d) values. The cellular fate of such inhibition was further evidenced by an increase in the number of Hu-TopoIIalpha-DNA cleavage complexes in the human lung epithelial cells (BEAS-2B) using trapped in agarose DNA immunostaining (TARDIS) assay, which utilizes antibody specific for Hu TopoIIalpha. Furthermore, the increase in gamma-H2A.X levels quantitated by flow cytometry and visualized by immunofluorescence microscopy illustrated that accumulation of DNA double-strand breaks inside the cells can be attributed to the inhibition of Hu-TopoIIalpha. These findings collectively suggest that 1,4 BQ, 1,2-NQ, 1,4-NQ, and 9,10-PQ inhibit the ATPase domain and potentially result in Hu-TopoIIalpha-mediated clastogenic and leukemogenic events. PMID- 22218493 TI - Inguinal hernia repair under local anaesthesia in patients with cirrhosis. PMID- 22218496 TI - Some cyclization reactions of 1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one: preparation and computational analysis of non symmetrical zwitterionic biscyanines. AB - Regioselective nucleophilic addition of bisnucleophiles 1,2-benzenediamine, 2 amino-benzenethiol, and N-phenyl-1,2-benzenediamine to 1,3 diphenylbenzo[e][1,2,4]triazin-7(1H)-one (1) at C6 followed by intramolecular cyclocondensation at the C7 carbonyl afforded highly coloured tetracenes 1,3 diphenyl-1,6-dihydro-[1,2,4]triazino[5,6-b]phenazin-4-ium 4 methylbenzenesulfonate (12), 1,3-diphenyl-1H-[1,2,4]triazino[6,5-b]phenothiazine (14) and 1,3,11-triphenyl-1,6-dihydro-[1,2,4]triazino[5,6-b]phenazin-11-ium 4 methylbenzenesulfonate (15), respectively. Neutralization of the latter with alkali gave the free base 1,3,11-triphenyl-1H-[1,2,4]triazino[5,6-b]phenazin-11 ium-6-ide (16). Furthermore, the benzotriazinone 1 reacts with dimethyl malonate to give 6-(methoxycarbonyl)-7-oxo-1,3-diphenyl-7H-benzofuro[5,6-e][1,2,4]triazin 1-ium-4-ide (17) in 74% yield, while with S(4)N(4) [5,6-c]-thiadiazolo-7-oxo-1,3 diphenyl-1,2,4-benzotriazine (22) was formed in 15% yield. The free bases 16 and 17 display negative solvatochromism, which supports charge separated ground states similar to those of zwitterionic biscyanines, and DFT calculations at the UB3LYP/6-31G(d) level afford DeltaE(ST) values of -13.6 and -18.7 kcal mol(-1), respectively that strongly favour the singlet ground state. All ring systems described are new and fully characterized. PMID- 22218495 TI - Hepatitis B virus X protein inhibits extracellular IFN-alpha-mediated signal transduction by downregulation of type I IFN receptor. AB - We have previously shown that hepatitis B virus (HBV) protein X (HBX), a regulatory protein of HBV, activates Stat1, leading to type I interferon (IFN) production. Type I IFN secreted from HBX-expressing hepatic cells enforces antiviral signals through its binding to the cognate type I IFN receptor. We therefore investigated how cells handle this detrimental situation. Interestingly, compared to Chang cells stably expressing an empty vector (Chang Vec), Chang cells stably expressing HBX (Chang-HBX) showed lower levels of IFN alpha receptor 1 (IFNAR1) protein, a subunit of type I IFN receptor. The levels of IFNAR1 transcripts detected in Chang-HBX cells were lower than the levels in Chang-Vec cells, indicating that HBX regulates IFNAR1 at the transcriptional level. Moreover, we observed that HBX induced the translocation of IFNAR1 to the cytoplasm. Consistent with these observations, HBX also downregulated Tyk2, which is required for the stable expression of IFNAR1 on the cell surface. Eventually, Chang-HBX cells consistently maintained a lower level of IFNAR1 expression and displayed no proper response to IFN-alpha, while Chang-Vec cells exhibited a proper response to IFN-alpha treatment. Taken together, we propose that HBX downregulates IFNAR1, leading to the avoidance of extracellular IFN-alpha signal transduction. PMID- 22218497 TI - Cascade reactions in crystals through cation-pi-controlled reorientation on exposure to HCl gas. AB - Exposure of 4-azachalcones to HCl gas produced the corresponding HCl salts with a head-to-tail stacked alignment, irradiation of which produced the corresponding syn-HT dimers with high regio- and stereoselectivities, thus showing the effectiveness of the cascade process in crystals. PMID- 22218498 TI - Multiple homogeneous immunoassays based on a quantum dots-gold nanorods FRET nanoplatform. AB - Multi-sized quantum dots (QDs) donors and tailor-made gold nanorods (GNRs) are employed to form a FRET nanoplatform for homogeneous immunoassays developed for analysis of multiple virus antigens. The single GNRs/multiple QDs nanocomposite based nanosensor offers a simple and sensitive approach for multiple analytes detection in a homogeneous format. PMID- 22218499 TI - Asymmetry in grasp force matching and sense of effort. AB - While asymmetries in upper limb force matching have been observed, the mechanisms underlying asymmetry in the sense of effort have not been conceptualized. The aim of this study was to investigate asymmetries in the perception and reproduction of grasp force. Forty-two young adults, 22 right-handed (RH) and 20 left-handed (LH), were, respectively, divided into three groups according to differences between their right and left-hand strength (left stronger than right, right stronger than left and right & left equivalent). A reference force, representing 20% of the maximal voluntary contraction (MVC) produced by the right or left hand, was matched with same hand (Ipsilateral Remembered--IR) or opposite (Contralateral Remembered--CR) hand. The matching relative error was 92% (for RH) and 46% (for LH) greater in the CR than IR condition. Asymmetries in matching were significant for RH participants only in the CR condition and were dependent on right/left differences in hand strength as shown by the constant error (CE). For this RH population, right-hand overshoot of the left-hand reference and left hand undershoot of the right-hand reference were significant when the right hand was stronger than the left. Asymmetry remained significant when CE was normalized (%MVC). Asymmetry was reduced when the strength of each hand was equivalent or when the left hand was stronger than the right. These findings suggest that effort perception is asymmetric in RH but not in LH individuals. The hand x strength interaction indicates that asymmetry in force matching is a consequence of both a difference in the respective cortical representations and motor components, which confer a different "gain" (input-output relationship) to each system. The similarity with position sense asymmetry suggests that the gain concept may be generalized to describe some functional/performance differences between the two hand/hemisphere systems. The more symmetrical performance of the LH than RH group underlines that context specific influence of handedness, hemisphere dominance and hemispheric interactions modulate performance symmetries/asymmetries. PMID- 22218500 TI - Modulation of voltage-gated sodium channels hyperpolarizes the voltage threshold for activation in spinal motoneurones. AB - Previous work has shown that motoneurone excitability is enhanced by a hyperpolarization of the membrane potential at which an action potential is initiated (V(th)) at the onset, and throughout brainstem-evoked fictive locomotion in the adult decerebrate cat and neonatal rat. Modeling work has suggested the modulation of Na(+) conductance as a putative mechanism underlying this state-dependent change in excitability. This study sought to determine whether modulation of voltage-gated sodium channels could induce V(th) hyperpolarization. Whole-cell patch-clamp recordings were made from antidromically identified lumbar spinal motoneurones in an isolated neonatal rat spinal cord preparation. Recordings were made with and without the bath application of veratridine, a plant alkaloid neurotoxin that acts as a sodium channel modulator. As seen in HEK 293 cells expressing Nav1.2 channels, veratridine-modified channels demonstrated a hyperpolarizing shift in their voltage-dependence of activation and a slowing of inactivation that resulted in an enhanced inward current in response to voltage ramp stimulations. In the native rat motoneurones, veratridine-modified sodium channels induced a hyperpolarization of V(th) in all 29 neonatal rat motoneurones examined (mean hyperpolarization: -6.6 +/- 4.3 mV). V(th) hyperpolarization was not due to the effects on Ca(2+) and/or K(+) channels as blockade of these currents did not alter V(th). Veratridine also significantly increased the amplitude of persistent inward currents (PICs; mean increase: 72.5 +/- 98.5 pA) evoked in response to slow depolarizing current ramps. However, the enhancement of the PIC amplitude had a slower time course than the hyperpolarization of V(th), and the PIC onset voltage could be either depolarized or hyperpolarized, suggesting that PIC facilitation did not mediate the V(th) hyperpolarization. We therefore suggest that central neuronal circuitry in mammals could affect V(th) in a mechanism similar to that of veratridine, by inducing a negative shift in the activation voltage of sodium channels. Furthermore, this shift appears to be independent of the enhancement of PICs. PMID- 22218502 TI - Salvage radiotherapy in patients with recurrent esophageal carcinoma. AB - PURPOSE: The feasibility and effectiveness of radiotherapy in the management of recurrent esophageal carcinoma (REC) is reported. PATIENTS AND METHODS: A consecutive cohort of 54 patients with rcT1-4, rcN0-1, or cM0 recurrent esophageal carcinoma (69% squamous cell carcinoma, 31% adenocarcinoma) was treated between 1988 and 2010. The initial treatment for these patients was definitive radiochemotherapy, surgery alone, or neoadjuvant radiochemotherapy + surgical resection in 8 (15%), 33 (61%), and 13 (24%) patients, respectively. The median time to recurrence from initial treatment was 19 months (range 4-79 months). The site of the recurrence was anastomotic or local, nodal, or both in 63%, 30%, and 7% of patients, respectively. Salvage radio(chemo)therapy was carried out with a median dose of 45 Gy (range 30-68 Gy). RESULTS: Median follow up time for surviving patients from the start of R(C)T was 38 months (range 10 105 months). Relief of symptoms was achieved in 19 of 28 symptomatic patients (68%). The median survival time was 12 months (95% confidence interval (CI) 7-17 months) and the median recurrence-free interval was 8 months (95% CI 4-12 months). The survival rates at 1, 2, and 3 years were 55 +/- 7%, 29 +/- 6%, and 19 +/- 5%, respectively. The recurrence-free survival rates at 1, 2, and 3 years were 44 +/- 7%, 22 +/- 6%, and 15 +/- 5%, respectively. A radiation dose >= 45 Gy and conformal RT were associated with a better prognosis. CONCLUSION: RT is feasible and effective in the management of recurrent esophageal carcinoma, especially for relief of symptoms. Toxicity is in an acceptable range. The outcome of REC is poor; however, long-term survival of patients with recurrent esophageal carcinoma after radiochemotherapy might be possible, even with a previous history of radiotherapy in the initial treatment. If re-irradiation of esophageal carcinoma is contemplated, three-dimensional conformal techniques and a minimum total dose of 45 Gy are recommended. PMID- 22218501 TI - Breast cancer and funnel chest. Comparing helical tomotherapy and three dimensional conformal radiotherapy with regard to the shape of pectus excavatum. AB - BACKGROUND AND PURPOSE: Preserving lung, heart, and the contralateral breast from toxicity is a technical challenge in women with funnel chest, who require breast irradiation. The purpose of this study was to determine whether helical tomotherapy (HT) offers an advantage compared to three-dimensional (3D) conformal radiotherapy (CRT) for patients with pectus excavatum with regard to its shape. PATIENTS AND METHODS: Ten breast cancer patients with pectus excavatum were graded into a low or high deformation group using different indices, measured and calculated by using the planning CT. A planning comparison was performed, creating plans for CRT and HT. Target uniformity, target conformity, and exposure to the organs at risk (OARs) were compared. RESULTS: The uniformity and conformity of the target dose distribution and the median/average dose of the planning target volume (PTV) was inferior in CRT compared to HT in both deformation groups. By using tomotherapy, the volume of the lungs, the contralateral breast, and the heart, which received high dose exposure, could be significantly reduced. Tomotherapy plans led to a significantly higher low dose exposure to the lungs and contralateral breast. CONCLUSION: This is the first study which evaluates a group of 10 breast cancer patients with funnel chest. Better uniformity and conformity combined with a significant reduction of high dose exposure to the OARs can be reached using tomotherapy. However, tomotherapy plans have a significantly larger volume of low dose to the lungs and contralateral breast. Therefore, the stochastic risk should be considered after low dose exposure in women with low deformation. PMID- 22218503 TI - [Phase I dose-escalation study of stereotactic body radiation therapy for low- and intermediate-risk prostate cancer]. PMID- 22218504 TI - [RTOG study 0324: Cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small-cell lung cancer]. PMID- 22218505 TI - [Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer]. PMID- 22218507 TI - Hepatitis C therapy in 2011: is less more, is more less? PMID- 22218509 TI - Risk of coronary artery disease in individuals infected with human immunodeficiency virus. AB - Current treatment for human immunodeficiency virus (HIV) infection has improved survival and allowed infected patients to develop atherosclerotic coronary artery disease (CAD). Specific strategies to reduce cardiovascular risk in the infected population have not been developed. It is necessary to know the magnitude of cardiovascular risk in this population. OBJECTIVES: This study aimed to assess cardiovascular risk using a well-known clinical score and to investigate coronary artery calcium scoring (CACS) in this population. METHODS: This was a cross sectional study. Adults with HIV infection were studied. Demographic, clinical and anthropometric data, serum glucose and lipids were obtained. Cardiovascular risk was calculated through Framingham risk score (FRS) and CACS. Categorical variables were compared by Chi-square or Fisher's exact test, and continuous variables were analyzed by Student t test or Mann-Whitney test. An analysis of concordance between FRS and CACS was performed using kappa statistic. RESULTS: Forty patients, aged 45.9 +/- 8.1 years, were studied. Age of risk for CAD were found in 30.0%, hypertension in 55.0%, diabetes in 10.0%, smoking in 35.0%, dyslipidemia in 67.5% and family history of CAD in 57.5%. Altered levels of total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were found in 30.0%, 25.0% and 82.5%, respectively. HDL-cholesterol and triglycerides were altered more frequently among protease inhibitors users. The FRS classified the risk as low for 72.5%, moderate for 25.0%, and high for 2.5%. CACS > 0 was found in 32.5% of the patients, in 67.5% the score was low, in 17.5% moderate, and in 15.0% high. Concordance between FRS and CACS showed a kappa = 0.435. CONCLUSIONS: There is a high prevalence of risk factors for CAD in the studied population, with dyslipidemia being the most frequent. HDL-cholesterol and triglycerides were the most frequently altered factors and were associated with the use of protease inhibitors. Risk assessed by the FRS was low in most cases. CACS > 0 was found in 32.5%, demonstrating the need to re-evaluate the strategies for assessing cardiovascular risk in the HIV-infected population. PMID- 22218508 TI - Antimicrobial activity of doripenem against Gram-negative pathogens: results from INVITA-A-DORI Brazilian study. AB - In vitro activity of doripenem and comparator antimicrobial agents was evaluated against Gram-negative bacilli recently isolated from Brazilian private hospitals that were enrolled in the INVITA-A-DORI Brazilian Study. A total of 805 unique Gram-negative bacilli were collected from patients hospitalized at 18 medical centers between May/08 and March/09. Each hospital was asked to submit 50 single Gram-negative bacilli isolated from blood, lower respiratory tract or intraabdominal secretions. Bacterial identification was confirmed and antimicrobial susceptibility testing was performed using Clinical Laboratory Standards Institute (CLSI) microdilution method at a central laboratory. CLSI M100-S21 (2011) or US-FDA package insert criteria (tigecycline) was used for interpretation of the antimicrobial susceptibility results. Doripenem was as active as meropenem and more active than imipenem against E. coli and K. pneumoniae isolates. A total of 50.0% of Enterobacter spp. isolates were resistant to ceftazidime but 85.7% of them were inhibited at doripenem MICs < 1 ug/mL. Polymyxin B was the only agent to show potent activity against Acinetobacter spp. (MIC50/90, < 0.5/1 ug/mL) and P. aeruginosa (MIC50/90, 1/2 ug/mL). Although high rates of imipenem (53.1%) and meropenem (44.5%) resistance were detected among P. aeruginosa, doripenem showed MIC50 of 16 ug/mL against imipenem-resistant P. aeruginosa and inhibited a greater number of imipenem resistant P. aeruginosa (10.5%) at MIC values of < 4 ug/mL than did meropenem (0.0%). In this study, doripenem showed similar in vitro activity to that of meropenem and retained some activity against imipenem-resistant P. aeruginosa isolated from Brazilian medical centers. PMID- 22218510 TI - Evaluation of the presence of microorganisms in solid-organ preservation solution. AB - OBJECTIVE: To assess the presence of microorganism contamination in the preservation solution for transplant organs (kidney/pancreas). METHOD: Between August 2007 and March 2008, 136 samples of preservation solution were studied prior to graft implantation. Variables related to the donor and to the presence of microorganisms in the preservation solution of organs were evaluated, after which the contamination was evaluated in relation to the "recipient culture" variable. Univariate and multivariate statistical analyses were performed. RESULTS: The contamination rate of the preservation solution was 27.9%. Coagulase negative Staphylococcus was the most frequently isolated microorganism. However, highly virulent agents, such as fungi and enterobacteria, were also isolated. In univariate analysis, the variable "donor antibiotic use" was significantly associated to the contamination of the preservation solution. On the other hand, multivariate analysis found statistical significance in "donor antibiotic use" and "donor's infectious complications" variables. CONCLUSIONS: In this study, 27.9% of the preservation solutions of transplant organs were contaminated. Infectious diseases and non-use of antibiotics by the donor were significantly related to the presence of microorganisms in organ preservation solutions. Contamination in organ preservation solutions was not associated with infection in the recipient. PMID- 22218511 TI - Perinatal morbidity and mortality associated with chlamydial infection: a meta analysis study. AB - OBJECTIVE: To evaluate the effect of Chlamydia trachomatis infection during pregnancy on perinatal morbidity and mortality. METHODS: Systematic review and meta-analysis in an electronic database and manual, combining high sensitivity specific descriptors seeking to answer the research objective. The articles considered to be of high methodological quality (score above 6 on the Newcastle Ottawa Scale) were assessed by meta-analysis. RESULTS: Summary estimates of 12 studies were calculated by means of Mantel-Haenszel test with 95% confidence interval. It was observed that Chlamydia infection during pregnancy increased risk of preterm labor (relative risk (RR) = 1.35 [1.11, 1.63]), low birth weight (RR = 1.52 [1.24, 1.87]) and perinatal mortality (RR = 1.84 [1.15, 2.94]). No evidence of increased risk was associated with Chlamydia infection in regard to premature rupture of membranes (RR = 1.13 [0.95, 1.34]), abortion and postpartum endometritis (RR = 1.20 [0.65, 2.20] and 0.89 [0.49, 1.61] respectively). CONCLUSION: The diagnosis and treatment of Chlamydia cervicitis during pregnancy can reduce perinatal morbidity and mortality associated with this infection. However, clinical trials are needed to confirm these findings. PMID- 22218512 TI - Reading and interpretation of chest X-ray in adults with community-acquired pneumonia. AB - INTRODUCTION: Traditional reading of chest X-rays usually has a low prognostic value and poor agreement. OBJECTIVE: This study aimed to determine the interobserver and intraobserver agreement using two reading formats in patients with community-acquired pneumonia, and to explore their association with etiology and clinical outcomes. METHODS: A pulmonologist and a radiologist, who were blind to clinical data, interpreted 211 radiographs using a traditional analysis format (type and location of pulmonary infiltrates and pleural findings), and a quantitative analysis (pulmonary damage categorized from 0 to 10). For both, the interobserver and intraobserver agreement was estimated (Kappa statistic and intraclass correlation coefficient). The latter was assessed in a subsample of 25 radiographs three months after the initial reading. Finally, the observers made a joint reading to explore its prognostic usefulness via multivariate analysis. RESULTS: Seventy-four chest radiographs were discarded due to poor quality. With the traditional reading, the mean interobserver agreement was moderate (0.43). It was considered good when the presence of pleural effusion, and the location of the infiltrates in the right upper lobe and both lower lobes, were evaluated; moderate for multilobar pneumonia; and poor for the type of infiltrates. The mean intraobserver agreement for each reviewer was 0.71 and 0.5 respectively. The quantitative reading had an agreement between good and excellent (interobserver 0.72, intraobserver 0.85 and 0.61). Radiological findings were neither associated to a specific pathogen nor to mortality. CONCLUSION: In patients with pneumonia, the interpretation of the chest X-ray, especially the smallest of details, depends solely on the reader. PMID- 22218514 TI - Incidence and risk factors of immune reconstitution inflammatory syndrome in HIV TB coinfected patients. AB - Tuberculosis is one of the leading causes of development of Immune reconstitution inflammatory syndrome (IRIS) in HIV patients receiving antiretroviral therapy (ART). OBJECTIVE: To determine the incidence of IRIS in HIV-TB coinfected patients, and to find out the possible risk factors associated with IRIS. MATERIALS AND METHODS: Study commenced with 96 patients adhered to standard antitubercular therapy (ATT) and ART without defaulting, and followed up for six months. RESULT: The mean (+/- SD) CD4 count and CD4 percentage at baseline was 59.16 (+/- 24.63) per mm3 and 4.59% (+/- 1.73) respectively. Only 18.75% developed IRIS after 57.05 (+/- 14.12) days of initiation of ART. Extrapulmonary tuberculosis was the most significant factor associated with IRIS (83.33%) than those without IRIS (44.87%) (p = 0.0032). Specifically, tubercular lymphadenitis (38.88%, p = 0.0364) and disseminated tuberculosis (33.33%, p = 0.0217) were significantly associated with IRIS. The other risk factors associated with appearance of IRIS were higher CD4 count (p = 0.0212) at three months after initiation of ART and increment of CD4 count (p = 0.0063) and CD4 percentage (p = 0.0016) during this period. The major manifestations of IRIS were fever (40%), followed by lymphadenitis (38%). The mortality rate in IRIS was not higher than those without IRIS. CONCLUSION: Patients with extrapulmonary tuberculosis, especially tubercular lymphadenitis, were more likely to develop IRIS and fever was associated in most of them. Higher increment of CD4 count may indicate development of IRIS in presence of new or worsening tuberculosis lesion. PMID- 22218513 TI - Magnetic bead technology for viral RNA extraction from serum in blood bank screening. AB - Nucleic acid amplification testing (NAT) was recently recommended by Brazilian legislation and has been implemented at some blood banks in the city of Sao Paulo, Brazil, in an attempt to reduce blood-born transmission of human immunodeficiency virus (HIV) and hepatitis C virus. OBJECTIVE: Manual magnetic particle-based extraction methods for HIV and HCV viral nucleic acids were evaluated in combination with detection by reverse transcriptase - polymerase chain reaction (RT-PCR) one-step. METHODS: Blood donor samples were collected from January 2010 to September 2010, and minipools of them were submitted to testing. ELISA was used for the analysis of anti-HCV/HIV antibodies. Detection and amplification of viral RNA was performed using real-time PCR. RESULTS: Out of 20.808 samples screened, 53 samples (29 for HCV and 24 for HIV) were confirmed as positive by serological and NAT methods. CONCLUSION: The manual magnetic bead based extraction in combination with real-time PCR detection can be used to routinely screen blood donation for viremic donors to further increase the safety of blood products. PMID- 22218515 TI - Simultaneous detection of hepatitis B virus genotypes and mutations associated with resistance to lamivudine, adefovir, and telbivudine by the polymerase chain reaction-ligase detection reaction. AB - OBJECTIVES: Detection of mutations associated to nucleos(t)ide analogs and hepatitis B virus (HBV) genotyping are essential for monitoring treatment of HBV infection. We developed a multiplex polymerase chain reaction-ligase detection reaction (PCR-LDR) assay for the rapid detection of HBV genotypes and mutations associated with lamivudine, adefovir, and telbivudine resistance in HBV-infected patients. METHODS: HBV templates were amplified by PCR, followed by LDR and electrophoresis on a sequencer. The assay was evaluated using plasmids that contained wild-type or mutant HBV sequences and 216 clinical samples. RESULTS: The PCR-LDR assay and sequencing gave comparable results for 158 of the 216 samples (73.1%) with respect to mutation detection and genotyping. Complete agreement between the two methods was observed for all the samples (100%) at codon 180 and codon 204. Concordant results were observed for 99.4% of the 158 samples at codon 181 and 98.7% at codon 236. The genotyping results were completely concordant between the PCR-LDR assay and sequencing. The PCR-LDR assay could detect a proportion of 1% mutant plasmid in a background of wild-type plasmid. CONCLUSION: The PCR-LDR assay is sensitive and specific for detection of HBV genotypes and drug resistance mutations, and could be helpful for decision making in the treatment of HBV infection. PMID- 22218516 TI - Chlamydia trachomatis as a probable cofactor in human papillomavirus infection in aboriginal women from northeastern Argentina. AB - OBJECTIVES: High-risk types of human papillomavirus (HPV) are strongly associated with cervical cancer (CC), and Chlamydia trachomatis (CT), the most frequent sexually transmitted bacterial infection (STBI) worldwide, seems to be a risk factor for HPV infection and for CC. It is also known that both agents are more prevalent in vulnerable communities where lack of adequate primary health care is a cause for concern. The aim of this work was to determine the impact of CT and HPV infections in women belonging to an isolated aboriginal population (Pilaga community) from a poor region in Northern Argentina (province of Formosa). For this purpose, a cross-sectional study was performed in all sexually active Pilaga women, who attended a local community-based gynecological health screening project. The polymerase chain reaction (PCR) method on a cervical brush specimen was used to detect both agents. RESULTS: A total of 227 women (20% of the total female population of the Pilaga community) were studied and the overall prevalence was 26.4% for CT, 46.7% for HPV and 16.3% for concurrent infection. CT infection was higher in HPV DNA positive (34.2%) than in HPV DNA negative women (19%; OR: 2.22/95% CI = 1.16-4.28 / p = 0.009) and the most prevalent HPV types were HPV-16 (19.4%), 6 and 18 (5.3%), 58 (3.5%) and 33 (3.1%). CONCLUSIONS: The prevalence of CT and HPV observed in Pilaga women are among the worst registered in Latin America. Also, data collected suggest that chlamydial infection may play an important role in the natural history of HPV infection. On this respect, we propose that the association between these two agents seems to be more related to a mutual potentiation than to the fact that they share a common route of transmission. PMID- 22218517 TI - Preventing catheter-associated infections in the Pediatric Intensive Care Unit: impact of an educational program surveying policies for insertion and care of central venous catheters in a Brazilian teaching hospital. AB - OBJECTIVES: To determine the impact of an educational program on the prevention of central venous catheter-related infections in a Brazilian Pediatric Intensive Care Unit. PATIENTS AND METHODS: All patients admitted to the unit between February 2004 and May 2005 were included in the cohort study in a longitudinal assessment. An educational program was developed based on the Centers for Disease Control and Prevention recommendations for prevention of catheter-associated infections and was adapted to local conditions and resources after an initial observational phase. Incidence of catheter-associated infections was measured by means of on-site surveillance. RESULTS: One hundred eighteen nosocomial infections occurred in 253 patients (46.6 infections per 100 admissions) and in 2,954 patient-days (39.9 infections per 1,000 patient-days). The incidence density of catheter infections was 31.1 episodes per 1.000 venous central catheter-days before interventions, and 16.5 episodes per 1,000 venous central catheter-days afterwards (relative risk 0.53 [95% CI 0.28-1.01]). Corresponding rates for exit-site catheter infections were 8.0 and 2.5 episodes per 1,000 venous central catheter-days [0.32 (0.07-1.49)], and the rates for bloodstream infections were 23.1 and 13.9 episodes per 1,000 venous central catheter-days, before and after interventions [0.61 (0.32-1.14)]. CONCLUSION: A prevention strategy targeted at the insertion and maintenance of vascular access can decrease rates of vascular-access infections in pediatric intensive care unit. PMID- 22218518 TI - Prevalence of anxiety, depression and quality of life in HTLV-1 infected patients. AB - The HAM/TSP caused by HTLV-1 infection usually affects patients to disabling states, and sometimes can lead them to paraplegia presenting symptoms of depression and anxiety, impacting on quality of life. OBJECTIVE: The purpose of this study was to evaluate the frequency of depression and anxiety and its impact on quality of life in HTLV-1-infected TSP/HAM patients. MATERIAL AND METHODS: This was a cross-sectional study including 67 asymptomatic (control group) and 63 with TSP/HAM subjects. The instruments used were a demographic questionnaire, scales for anxiety and depression diagnosis (BDI and BAI), questionnaire for the assessment of Quality of Life of the World Health Organization (WHOQOL-Brief) and neurological scale to measure the disability level (Osame's Disability Status Scale). All patients had HTLV-I diagnosis by serological and molecular approaches, monitored at Instituto de Infectologia Emilio Ribas from May 2008 to July 2009. Data were analyzed statistically by frequencies, the Mann-Whitney test and the Spearman correlation test. Data among groups were analyzed and correlated with functional and severity aspects. RESULTS: The results showed that patients with HAM/TSP compared to asymptomatic carriers had higher rates of depression (p < 0.001) and anxiety (p < 0.001), and impairment on quality of life in the areas of: dissatisfaction with health (p < 0.001), physical (p < 0.001) and the environment (p = 0.003). The main factors that correlated with levels of depression and anxiety and the domains of the WHOQOL-brief were: education, family income and social class. CONCLUSION: A well conducted evaluation and counseling may help in treatment, for a better quality of life of these patients. PMID- 22218519 TI - Epstein-Barr virus DNA load and its association with Helicobacter pylori infection in gastroduodenal diseases. AB - Helicobacter pylori and Epstein-Barr virus (EBV) infections are common worldwide. Although H. pylori infection is a major factor in gastroduodenal diseases, its role in association with EBV infection is unknown. OBJECTIVE: To study the association of H. pylori infection and EBV DNA load in patients with gastroduodenal diseases. METHODS: Biopsy samples were collected from 200 adult patients [non-ulcer dyspepsia (NUD) 100, peptic ulcer disease (PUD) 50, gastric carcinoma (GC) 50] undergoing upper gastrointestinal endoscopy. H. pylori infection was diagnosed by rapid urease test, culture, histopathology, PCR and Q PCR. EBV DNA was detected by non-polymorphic Epstein-Barr nuclear antigen-1 (EBNA 1) gene based Q-PCR. RESULTS: In patients with GC and PUD, EBV DNA was detected more often than NUD (GC versus NUD = 90% versus 37%, p < 0.001; PUD versus NUD = 70% versus 37%, p < 0.001). The dual prevalence of H. pylori infection and EBV DNA was significantly higher in patients with GC and PUD than in those with NUD. Median copy number of EBV DNA was considerably higher in GC and PUD than NUD (p < 0.01). The copy number of EBV DNA was significantly higher in H. pylori infected patients (p = 0.015). The number of ureA gene copies was also found to be significantly higher in PUD and NUD with presence of EBV DNA. However, in GC no significant difference was seen between EBV positive and negative status. CONCLUSION: There was a trend for higher EBV DNA load in H. pylori positive individuals suggesting a probable role of H. pylori in modulating the conversion of EBV to its lytic phase. PMID- 22218520 TI - Lessons to learn with the methicillin-resistant Staphylococcus aureus control in Norway. AB - The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in Norway is low, compared to other European and American countries. The health system includes mandatory case reporting and has written guidelines for prevention and control. This communication describes the national public policies related to MRSA obtained from documents and academic experience gained during a doctoral fellowship in Oslo, Norway. The painstaking procedures used for investigating suspected cases, including health professionals, decolonization and case monitoring, could be important tools to be used by countries with a high prevalence of MRSA. PMID- 22218521 TI - Klebsiella ESBL bacteremia-mortality and risk factors. AB - BACKGROUND: Extended spectrum beta-lactamase (ESBL)-producing bacteria have become recognized as a problem in South America. The aim of this study was to evaluate risk factors and mortality rate in bacteremia caused by ESBL-producing Klebsiella pneumoniae in a Brazilian hospital. METHODS: A three-year retrospective cohort study with 104 cases of K. pneumoniae bacteremia (61 ESBL and 43 non-ESBL). Several clinical and laboratory variables were evaluated. The outcome of interest was 30-day mortality. The adequate treatment was evaluated according to antibiotic susceptibility. RESULTS: Multivariable analysis showed that central venous catheter and mechanical ventilation were independent risk factors for ESBL. The duration of hospitalization before the bacteremia was not a risk factor. Mortality was similar in ESBL and non-ESBL and inadequate therapy was not shown to be a risk factor. CONCLUSION: ESBL-producing Klebsiella bacteremia can occur early, suggesting that a carbapenem should be included in the initial empirical therapy for bacteremia in patients under mechanical ventilation and/or central venous catheter in our institution. PMID- 22218522 TI - Penile herpes zoster: an unusual location for a common disease. AB - Herpes zoster is a common dermatological condition which affects up to 20% of the population, most frequently involving the thoracic and facial dermatomes with sacral lesions occurring rarely and only a few reported cases of penile shingles. CASE REPORT: We report two cases of unusual penile clinical presentations of varicella zoster virus infection in immunocompetent men. The patients presented with grouped clusters of vesicles and erythema on the left side of penile shaft and posterior aspect of the left thigh and buttock, involving s2-s4 dermatomes. The lesions resolved quickly upon administration of oral antiviral therapy. CONCLUSION: Penile herpes zoster should not be overlooked in patients with unilateral vesicular rash. PMID- 22218523 TI - Immune reconstitution inflammatory syndrome associated with pulmonary sarcoidosis in an HIV-infected patient: an immunohistochemical study. AB - Sarcoidosis has been rarely described in literature as a cause of interstitial pulmonary disease associated with AIDS. This study reports a case of immune reconstitution inflammatory syndrome associated with pulmonary sarcoidosis in a patient with a history of previous pulmonary tuberculosis concomitant with HIV infection. Results of the immunohistochemical study of samples from the resected right lower lobe are described. Pathological findings suggest a role of Th1, Th2 and Th17 response in IRIS associated sarcoidosis. PMID- 22218524 TI - Two cases of Saint Louis encephalitis in HIV-1 infected patients in Buenos Aires. AB - Saint Louis encephalitis virus (SLE) is a mosquito borne disease. Only a small proportion of cases progress to severe clinical forms. There have been few reports on HIV-infected patients and the relationship between immunodeficiency and the course of the disease remains unclear. Herein we describe two cases of SLE in HIV-1-infected patients in Buenos Aires city. PMID- 22218525 TI - Progressive multifocal leukoencephalopathy restricted to the posterior fossa in a patient with systemic lupus erythematosus. AB - Progressive multifocal leukoencephalopathy is a neurological infectious disease caused by the John Cunningham polyomavirus (JCV), an opportunistic agent with worldwide distribution. This disease is frequently seen in immunosuppressed patients and rarely associated with systemic lupus erythematosus. In the central nervous system PML demyelinating lesions occur in the supratentorial compartment. The authors describe a rare case of PML secondary to SLE treatment with atypical presentation restricted to the posterior fossa. PMID- 22218526 TI - Reemergence of measles in Bulgaria: a large outbreak in Plovdiv, 2010. PMID- 22218528 TI - Pattern of ethionamide susceptibility and its association with isoniazid resistance among previously treated tuberculosis patients from India. PMID- 22218529 TI - The topology design principles that determine the spatiotemporal dynamics of G protein cascades. AB - Small monomeric G-proteins control cellular behavior, cycling between inactive GDP-bound and active GTP-bound states. Activating and deactivating transitions are regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), respectively. G-proteins can control different GEF and GAP activities, thereby creating GTPase signaling cascades. Here, we characterize all 128 different wiring topologies of two-layer cascades, which include feedforward/feedback interactions and an auto-regulatory loop. Exclusion of "mirror" designs leaves 64 topologies, which are classified into eight groups. We demonstrate that eight different cascades in each group generate the same number of steady states and similar spatiotemporal dynamics. Two groups (featuring 16 topologies) can generate three distinct dynamics: (i) bistable switches, (ii) excitable behavior, and (iii) sustained oscillations, giving rise to propagating waves of G-protein activation switches and pulses. Four other groups can produce switch-like, bistable behaviors and trigger waves. The remaining two groups have a single steady state. This first, complete classification of all possible interaction circuitries systematically links topological design to the spatiotemporal dynamics of G-protein cascades, predicting and explaining experimentally observed behavior. PMID- 22218527 TI - Role of antibodies reactive to HspX in discriminating pulmonary tuberculosis contacts with high risk of developing active disease. PMID- 22218530 TI - Low circulating serum levels of second mitochondria-derived activator of caspase (Smac/DIABLO) in patients with bladder cancer. AB - Smac/DIABLO promotes apoptosis by antagonizing inhibitor of apoptosis proteins. The expression of Smac/DIABLO in tissues has been reported in various cancers; however, little is known about circulating levels of Smac/DIABLO. The present study was designed to first determine if Smac/DIABLO can be detected in the serum and then assess whether the circulating levels of Smac/DIABLO are of prognostic significance in patients with bladder cancer. The levels of Smac/DIABLO in the sera of 173 patients with bladder cancer and 36 normal donors were determined by using an enzyme-linked immunosorbent assay. The mean serum level of Smac/DIABLO in patients with bladder cancer was approximately 2-fold lower than that in normal donors. The mean level of serum Smac/DIABLO in patients with muscle invasive bladder cancer was lower than that in patients with non-muscle invasive cancer. In addition, the mean serum Smac/DIABLO level in patients with T4 muscle invasive bladder cancer was lower than that in patients with T2 and T3 cancers. The mean serum level of Smac/DIABLO in patients with Grade 3 bladder cancer was lower than that in patients with Grade 1 and Grade 2 cancers. Analysis by Kaplan Meier revealed that patients with Ta and T1 non-muscle invasive bladder cancer with high level of serum Smac/DIABLO (more than mean value) had a longer post operative tumor-free interval than those with low level (less than mean value) in the 3-year follow-up. Furthermore, patients with T2-T4 muscle-invasive bladder cancer with high serum Smac/DIABLO level (more than mean value) had a higher post operative disease-free rate when compared with patients with low level (less than mean value) in the 5-year follow-up. The present study is the first to analyze circulating levels of Smac/DIABLO in the serum. The findings demonstrate that the mean serum level of Smac/DIABLO was downregulated in patients with bladder cancer compared to control healthy individuals, especially high grade muscle-invasive bladder cancer. Noteworthy, lower serum level of Smac/DIABLO predicted early recurrence in patients with bladder cancer. Overall, the findings suggest that measuring the levels of Smac/DIABLO in the serum may be considered a prognostic parameter in patients with bladder cancer. Furthermore, Smac/DIABLO may be a molecular therapeutic target in bladder cancer. PMID- 22218531 TI - Benzimidazole-based anion receptors: tautomeric switching and selectivity. AB - Tautomeric switching is observed in a series of benzimidazole-based anion receptors upon addition of basic anions. An N-methylbenzimidazole based receptor selectively interacts with dihydrogen phosphate over a variety of other putative anionic guests via a combination of donated and accepted hydrogen bonds. PMID- 22218533 TI - [The promotion of health and integrated prevention of risk factors for cardiovascular diseases]. AB - Cardiovascular diseases are currently the most common causes of morbimortality worldwide. In the context of disease prevention, actions creating favorable health environments and promoting healthy choices prove fundamental. Intervention programs with a community basis have been introduced in different countries since the beginning of the 1970s, aiming to modify cardiovascular risk factors and decrease morbidity and mortality due to cardiovascular diseases. In such experiences, the importance of public policies and cardiovascular risk vigilance systems needs to be stressed, permitting a more accurate assessment of the magnitude of the problem and the development of more cost-effective actions. The scope of this bibliographical study was to describe community-geared experiences in many countries in the campaign against cardiovascular diseases through health promotion and primary prevention of risk factors, as well as to identify in Brazil the vigilance actions of the risk factors of non-transmissible chronic diseases, stressing the strategic challenges facing the Family Health Program in tackling cardiovascular diseases. PMID- 22218534 TI - [Prevention of cardiovascular diseases and the promotion of health]. PMID- 22218535 TI - [The Promotion of Health and the Integrated Prevention of Risk Factors for Cardiovascular Diseases: until when we will be "mopping up the ice"?]. PMID- 22218536 TI - [Morbidity profile and the standard of access to health services for elderly practitioners of physical activities]. AB - The morbidity profile and access to health services of 132 women and 33 men, with average age of 69.1 +/- 6 years--all practitioners of physical activities was- analyzed. A questionnaire for the socio-demographic profile, physical activity involved, self-referred morbidity and access to health services was applied. In the analysis, descriptive and inferencial statistics were used, with a significance level of 5%. Most of the sample was 60-69 years old (55.7%), practicing water aerobics (52.7%) and had high blood pressure (48.4%). The women aged 60 to 69 years (p <0.05) and 70 to 79 years (p <0.05) had at least one chronic disease. The indicators of access to health services were similar between genders (p> 0.05). The younger-aged men went more often to a doctor during the last year than the younger-aged women (p <0.05). In the other age brackets, feminine hegemony was maintained, with significant difference for 70 to 79 year old females (p <0.05). Most of the elderly sought their private doctor (33.3%) or a health center (27.8 %). The main problems of the health services were medication (64.8%) and delays in scheduling consultations (48.4%). It was noted that the elderly are worried about preventive healthcare, which can be linked to the benefits of the practice of physical activity. PMID- 22218537 TI - [Rehabilitation care for victims of accidents and violence: the situation of the municipal districts in Pernambuco, Brazil]. AB - A diagnostic analysis of care was conducted for rehabilitation of victims of accidents and violence in municipal districts of Pernambuco, Brazil, with over 100 thousand inhabitants. A cross-sectional and descriptive study was carried out. The principles of the triangulation method were followed because the study required the input of various informers and used a variety of collection techniques. An interview was conducted with the municipal manager of each district to map out and select the services to be analyzed. Questionnaires were applied to the managers of the services for identification of the unit, characterization of the activities and description of the structure. The results revealed that more than half of the services involved group care, prevention of relapses and neuropsychomotor stimulation. The team numbered 273 health professionals, with physiotherapists being the largest group (34.8%), followed by psychologists (13.5%), and speech therapists (12.8%). Only one municipal district supplied ortheses, prostheses and auxiliary equipment for locomotion. Deficits of some types of services and discrepancies in the distribution of such services were observed in the different areas of the state. PMID- 22218538 TI - [Awareness about Aids among elderly males and young adults: a study of the perception of this disease]. AB - The scope was to compare awareness of elderly males and young adults about aids, taking education into consideration. By means of an epidemiological, descriptive and cross-sectional study, the information of 30 elderly males and 62 young adults about the concept, transmission, prevention, diagnosis and treatment of aids was investigated by structured interviews based on a standardized and validated questionnaire. Frequency distribution, Chi-square test or Fisher's exact test, as well as Student's t test or the Mann-Whitney test were used, with a significance level of 0.05 for contingency and variance analysis. The Mantel Haenszel test with a significance level of 0.05 and Odds Ratio with 95% confidence intervals were used to determine scholarship influence. Individual perception of good health was greater among young adults (61.3% vs 43.3% for elderly) and major sexual activity for elderly males was detected (80% vs 62.9% of young adults). Nevertheless, the elderly males declared adequate knowledge about aids less frequently (26.7% vs 80.6% of young adults); prior HIV test (13.3% vs 24.2% of young adults) and receiving orientation about aids (36.7% vs 98.4% of young adults). Elderly males had insufficient information on HIV/aids, when compared with young adults, highlighting the need to pay closer attention to the elderly population. PMID- 22218539 TI - Oral manifestations in HIV+ children in Mozambique. AB - The scope of this study was to identify the prevalence of oral manifestations in HIV+/AIDS patients at the DIA Pediatric Hospital of Maputo. All 90 patients were included in the research. Data on dental caries (dmft/DMFT index), soft tissues and saliva flow were analyzed. Information on diet and hygienic habits was obtained in a semi-structured questionnaire. The t- student and chi-square tests were used for statistical assessment. The most frequent oral lesion was candidiasis (5.5%) and upon further oral examination the prevalence of parotid enlargement was 23.0%. The mean dmft 2.6 (SD 3.6) was considerably higher in relation to DMFT of 0.6 (SD 1.6), and the differences between them were statistically significant (P<0.05). The occurrence of mucosal lesions was higher in children who did not take antiretroviral therapy (ART) (p = 0.026). The use of ART is associated with reduced prevalence of oral lesions in HIV+ patients; however, rampant caries were highest in this group. Primary dentition of HIV+ patients should be considered high risk for caries. PMID- 22218540 TI - [Profile of mortality by intoxication with medication in Brazil, 1996-2005: portrait of a decade]. AB - The occurrence of deaths caused by intoxication with medication have been considered a worsening public health problem. The study describes the epidemiological profile of medication-related intoxication in the general Brazilian population from 1996 to 2005. A descriptive study was conducted with mortality data obtained from the Mortality Information System of the Brazilian Ministry of Health. Deaths were selected according to the codes of the International Classification of Diseases (ICD-10). A total of 4,403 deaths were found inn males (53.9%), bachelors (53.7%) and the 20 to 39 year-old age bracket (44%). The majority of deaths were caused by intentional self-intoxication using anticonvulsants, sedatives, antiparkinsonians and psychotropics. The standardized mortality rate was higher in the Midwest region and Potential Life-Years Lost increased by 15.5%. The study showed the characteristics and variations in mortality by intoxication with medication in Brazil, which can be a reflex of the medication consumption patterns of the country, indicating the need for enhancement of sanitary vigilance policies. PMID- 22218541 TI - [Epidemiology and organization of health services: diabetes mellitus in a community of the city of Porto Alegre]. AB - This study sought to assess the conditions of processing and results in care for people aged over 20 diagnosed with diabetes mellitus and living in an area covered by the UBS Vila Gaucha, in Porto Alegre. Disease control rate of interviewees with self-reported diabetes was assessed. Definition of this rate was established from arterial pressure values, glycosylated hemoglobin, abdominal circumference, and/or BMI. Of the 753 people aged over 20 years, 37 (4.9%; 95% CI 3.4 6.5) mentioned diabetes mellitus diagnosed by a physician. Disease control rate measurements were performed in 31 (83.8%) people. Results revealed 24 (77.4%) individuals with altered blood pressure levels, 25 (80.6%) with BMI equal to or above 25 kg/m2, 29 (93.5%) with abdominal circumference above normal and 18 (58.1%) with glycosylated hemoglobin equal to or above 8%. Diagrams were used to analyze disease control rate factors. Only one patient was classified as controlled. Diagram interpretation points to the need for policies and actions aiming to reduce body weight in the community, which would include practically all patients with diabetes. PMID- 22218542 TI - [General awareness and use of generic medication among citizens of Tubarao, state of Santa Catarina, Brazil]. AB - Although generic medication has been introduced in the country to offer an accessible alternative to brand-name medication, it represents only 14% of sales in number of units within the pharmaceutical market. The aim of this work was to research the level of awareness and the use of generic products among residents of the municipality of Tubarao, State of Santa Catarina, Brazil. A transversal study was carried out with a sample of 234 interviewees, distributed among municipal areas. With regard to use, the majority of those interviewed had used generic medication, and half of them had at least one such product in their home. To verify awareness of different types of medication, pictures with the generic, brand name and similar packaging for paracetamol and atenolol were shown and 91% were able to identify all products correctly. To be of higher economic standing, already having used generic products, believing that the generic medication has the same effect as the brand name medication, finding generic products in drugstores easily and being accustomed to buy generic products, were factors that were positively associated with the correct identification. PMID- 22218543 TI - [More human than human: halitosis as the hallmark of pathological dental omission]. AB - The theoretical perspective of the analysis conducted is linked to the fact that dental awareness should not be seen as something universal, independent from reality, though participating in its construction. This paper explores the idea symbolized in the colonization of contemporary Dentistry awareness to beyond " the more human than human ". With the example of the increasing pathologization of halitosis, as an objective disorder not only of oral health, but that affects individuals, this work develops an analysis of the (re)invention of pathologies, through visualization technologies in late modernity. It concludes that the veracity of dental awareness, among the main actors, its discourses and its social practices, is never neutral, but always articulated to the interests with which it is permanently involved. The sense of smell moves from knowledge memory and from space to time and certainly from things to beings. Halitosis is, most of the times, unlikely, mixed, singular, and uncertain in time and place. PMID- 22218544 TI - [Risk-taking and HIV/Aids prevention: a biographical approach to sexual behavior in Portugal]. AB - On the basis of a representative survey carried out in 2007 of the Portuguese population aged between 18 and 65, this study investigates the impact of factors during the course of sexual life on risk-taking behavior and perceptions among 3055 heterosexual men and women. A number of sexual biography profiles were identified through cluster analysis of indicators related to the identity, number and sequence of partners throughout life. We discovered different profiles, from systematic occasional partnerships and use of paid sex, more frequent among men, to the single partner profile, which is more prevalent among women. By carrying out several linear regression analyses, we were able to evaluate the predictive impact of biographical factors on condom use and prevention behavior. Our results indicate that sexual biographies are more important in explaining the prevalence of condom use with different sexual partners. On the other hand, fear of infection and information on HIV transmission seem to influence the cognitive mobilization of prevention strategies and change of sexual behavior. However, condom use is still more dependent on sexual life pattern and interaction with sexual partners. PMID- 22218545 TI - [Tuberculosis in day-to-day medical practice and the boomerang effect of neglect]. AB - The scope of this study was to understand the perceptions and feelings of physicians dealing with tuberculosis (TB) in Rio de Janeiro. Eleven physicians working in a large public hospital were interviewed using a semi-structured questionnaire. The interpretation of the interviews was based on hermeneutic dialectic phenomenology. The answers were analyzed in order to identify and understand their live TB-related experiences from their statements. Among the categories that emerged, neglect was chosen as the focus of this article in its four dimensions: respect, responsibility, conditions of care and discomfort. The boomerang effect of neglect was perceived during interviews with physicians: the one who neglects is also neglected. Other reported feelings included lack of motivation, anger, and frustration. The mental health of physicians is a preoccupation because of overwork in inadequate conditions. The question that arises is how health staff working in such environments can adequately care for their patients. We conclude that in order to achieve TB control as well as other health system goals, human resource policies that respond to physicians' job needs should be implemented. PMID- 22218546 TI - [Social determinants of health in the elderly]. AB - Health is affected throughout the course of life by characteristics of social context, which produce inequalities in terms of exposure and vulnerability. These social determinants interfere with the well-being, functional independence and quality of life of the elderly, but are generally overlooked in interventions and policies. Therefore, the aim of this study was to systematize the knowledge of the social determinants of health in the elderly, using the Dahlgren and Whitehead model as a conceptual guide. The effects of demographic changes in the aging process and morbidity profile were approached at the structural level. The conditions of life and work with impact on current and future health and the role of social cohesion were studied at the intermediate level. Lastly, the behavior and lifestyles of major risk were examined at close quarters. It was detected that equity in health requires attention to social determinants during the course of life in order to minimize chronic diseases and deficiencies of the elderly, which reflect their social positions in early life. PMID- 22218547 TI - [Relationship between climate change and determinant factors of mortality among the elderly in the municipality of Sao Carlos (Sao Paulo, Brazil) over a period of ten years]. AB - The aim of this study was to identify the correlation between the number of deaths of elderly people and climate change in the district of Sao Carlos (SP) over a period of 10 years (1997-2006). Records of deaths were obtained from DATASUS for people aged over 60 who died between 1997 and 2006 in Sao Carlos. The average monthly maximum and minimum temperature data and relative air humidity in Sao Carlos were provided by the National Institute of Meteorology. The mortality coefficient of the district was calculated by gender and age and the resulting data were analyzed using t test, one-way ANOVA, the Bonferroni test and the Pearson correlation coefficient test. There were 8,304 deaths which predominantly occurred among males aged over 80, and diseases of the circulatory system were the main cause of death. There was a positive correlation between mortality by infectious disease and minimum humidity, and a negative correlation between mortality by infectious diseases and minimum temperatures, between mortality caused by respiratory disease and minimum humidity, between mortality caused by endocrine disease and minimum and maximum temperature. Thereby, it was possible to conclude that there was a correlation between climate change and mortality among elderly individuals in Sao Carlos. PMID- 22218548 TI - [Team work and interdiciplinarity: challenges facing the implementation of comprehensive outpatient care for people with HIV/Aids in Pernambuco]. AB - The complexity of providing healthcare to people with HIV/Aids requires investment in comprehensive action and care, constituting a challenge for the multidisciplinary work teams to build an interdisciplinary practice. This study sought to analyze comprehensive healthcare in the Specialized Assistance Services for HIV/Aids (SAE-HIV/Aids) in Recife, in the State of Pernambuco, starting with the process and organization of team work. This is a case study developed in three SAE-HIV/Aids units, based on a qualitative approach using different research techniques. The results show that SAE-HIV/Aids have complied with most of the Brazilian Health Ministry recommendations in terms of basic infrastructure, though none of them had a team of appropriate size. These services have shown signs of fragmentation and difficulty in establishing a systematic intersectorial and interdisciplinary practice, with failings in ensuring the reference and counter-reference flow. It was seen that there was little appreciation of the role of the manager as team leader. The need to perceive the user as a whole was identified, as well as for the team to work in a coordinated manner in order to ensure communicative and relational activities. PMID- 22218550 TI - [Reflections on community-based rehabilitation strategy (CBR): the experience of a CBR program in Bolivia]. AB - Community-Based Rehabilitation (CBR) is a strategy for community development endorsed by the World Health Organization (WHO), the International Labor Office (ILO) and the United Nations Educational, Scientific and Cultural Organization (UNESCO). It is designed to promote rehabilitation, equal opportunity and social inclusion of Disabled Persons (DP) in their home communities by fostering cooperation among disabled individuals, their families, and other concerned social actors, it encourages community leadership and full social participation by DP through multi-sector cooperation. This article explores the historical antecedents and basic features of CBR strategy through an analysis of a directed culture change initiative developed by a foundation in the Cochabamba administrative region of Bolivia. Especially in intercultural environments, certain aspects of the socio-cultural context may determine whether CBR programs succeed or fail. PMID- 22218549 TI - [Use of benzodiazepines in local public health services in Coronel Fabriciano in the State of Minas Gerais]. AB - In this study, indications for benzodiazepines in the healthcare services of the city of Coronel Fabriciano (State of Minas Gerais, Brazil) were analyzed in terms of compliance with the indications established in the literature. The study was carried out using all prescriptions for benzodiazepines in municipal healthcare units between September and October 2006, as well as the prescription form filled out by the prescriber and computer files. A total of 1866 prescriptions were analyzed; 59.7% were for diazepam and the rest were for clonazepam. The mean daily dose per 1000 inhabitants/day was 24.69 for diazepam and 3.58 for clonazepam. Approximately 50% of the indications were as a hypnotic or anti anxiety medication; 21.9% were for "chronic use/dependence" and the rest were for other indications. Among the prescriptions that fulfilled the inclusion criteria for the analysis of indication adequacy (1618), approximately 70% were found to be inadequate considering the indication and duration of treatment. It revealed a high percentage of the inadequate use of benzodiazepines, especially due to prolonged use and the treatment of cases considered by the prescribers as chronic use/dependence. Thus, healthcare services bear responsibility for the maintenance of dependence. PMID- 22218551 TI - [Hypertension communicated and hypertension understood: nursing know-how and practices in a Family Health Program in Fortaleza, State of Ceara]. AB - The scope of the study was to examine the communication practices of nurses in consultation of arterial hypertension in the Family Health Program in Fortaleza, Ceara, revealing the elements that cause asymmetry of power between nurses and the hypertensive individuals verbal expression. The theoretical references are Critical Discourse Analysis and Pragmatics. This is an exploratory descriptive and qualitative study, in which participant observation was conducted in a Basic Family Health Unit. The following discourses arose: the nurse as conductor of the interaction with verbal and nonverbal discursive commands; the hypertensive subject as subjugated by the nurse; the nurse as an articulated instrument that communicates a body of social practice; the body of the hypertensive person as a tool that supports an imaginary power load; the interaction between nurse and the hypertensive person in a one-sided situation, obliging the hypertensive individual to obey orders. The relationship between the nurse and the hypertensive person develops asymmetrically, built on symbolic materials of social practices under the legitimacy of the paradigm of current Nursing Consultation in our society. PMID- 22218552 TI - [Evaluation of the System of Sanitary Vigilance of Blood at the federal level, Brazil, 2007]. AB - This study evaluated the Sanitary Vigilance System for Blood at federal government level (VIGISAN). This assessment included the following components: managerial system of registration of hemotherapeutic services; external evaluation program of quality of hemotherapy services; hemovigilance system; standardization and inspection of health services for blood and its components. Besides the description and the calculation of efficiency (cost-effectiveness ratio) of VIGISAN, the assessment consisted of two phases based on three methods. VIGISAN had a poorly defined structure, though it operated smoothly and its utility was acceptable for public health. From a total of four defined indicators to evaluate performance, one obtained a satisfactory result. Three out of the seven evaluation attributes achieved positive assessment in this study. The cost effectiveness ratio was US$ 37,965.16 per activity performed, which resulted in loss of efficiency for the system. This study demonstrates the importance of conducting evaluations of vigilance systems in public health, which should be performed periodically in order to contribute to improvement of the system and thus improve public health in the country. PMID- 22218553 TI - [Building evaluation criteria: experts and user satisfaction with pharmaceutical delivery services for HIV/Aids]. AB - A criterion is a typical tool in the evaluation field that can be defined as a standard-dimension under which the object of an evaluation receives qualitative or quantitative judgments. During an evaluation, several rigorous methodological procedures are involved in development and application of suitable criteria to determine the value of the object being evaluated. This article presents a set of criteria to evaluate user satisfaction with HIV/Aids-related pharmaceutical delivery services. The criteria construction process involved consensus amongst different experts, from academia, NGOs, management, by means of the Delphi technique. This technique prescribes a series of formal steps towards a consensus of experts, based on pre-structured methodology and processes. The findings were systematically organized in a structure under which the resulting satisfaction criteria are hierarchically organized. Results suggest the importance of developing a methodological strategy in evaluation that involves participation of different actors and of enhancing knowledge on user satisfaction and pharmaceutical delivery services for HIV/Aids. PMID- 22218554 TI - [Analysis of Cost-effectiveness of screening for breast cancer with conventional mammography, digital and magnetic resonance imaging]. AB - A cost-effectiveness analysis was conducted in screening for breast cancer. The use of conventional mammography, digital and magnetic resonance imaging were compared with natural disease history as a baseline. A Markov model projected breast cancer in a group of 100,000 women for a 30 year period, with screening every two years. Four distinct scenarios were modeled: (1) the natural history of breast cancer, as a baseline, (2) conventional film mammography, (3) digital mammography and (4) magnetic resonance imaging. The costs of the scenarios modeled ranged from R$ 194.216,68 for natural history, to R$ 48.614.338,31, for screening with magnetic resonance imaging. The difference in effectiveness between the interventions ranged from 300 to 78.000 years of life gained in the cohort. The ratio of incremental cost-effectiveness in terms of cost per life year gains, conventional mammographic screening has produced an extra year for R$ 13.573,07. The ICER of magnetic resonance imaging was R$ 2.904.328,88, compared to no screening. In conclusion, it is more cost-effective to perform the screening with conventional mammography than other technological interventions. PMID- 22218555 TI - [The role of the nurse in the Brazilian Unified Heath System: from community health to the family health strategy]. AB - The scope of this paper is to take a retrospective look at the professional role of the nurse in the Brazilian Unified Health System and understand the meaning of their social practice in this field of discussions and theoretical-practical meanings. The Grounded Theory was used as a methodological reference and interviews were the technique for data collection, conducted between May and December of 2007, with 35 health professionals and others. The codification and data analysis revealed that the Unified Health System and especially the Family Health Strategy, should be considered facilitating and stimulating strategies of the process of expansion and consolidation of nursing care as a social entrepreneurial practice, since they pave the way to a new approach in community intervention, through seeing the human being as a multi-dimensional and singular being, inserted in a real and concrete context. PMID- 22218556 TI - [International experiences and trends in health care models for the elderly]. AB - The profound socio-economic transformation occurring in Brazil is also driven by the demographic changes. Health expenditures will increase due to the aging population and increased use of health services. The National Agency for Supplementary Health published a resolution that encourages the participation of beneficiaries in health insurance programs for active aging, with the possibility of discounts in fees. Thus, the elderly now receive cash benefits to adhere to preventive health programs and early detection of diseases. We assessed the programs in the U.S. and UK, analyzing their successes and failings, which may assist in the formulation of health policies that are more appropriate and more cost-effective for the Brazilian elderly. This Opinion article seeks to demonstrate to Brazilian operators that it is time to change and to elicit discussions about the need for new strategies. A creative focus should be directed to the care of the elderly, who are the ones who suffer the effects of their own weakness and demand more health services. PMID- 22218557 TI - [Diabetes mellitus: reasons for prevalence in different geographic regions of Brazil, 2002 2007]. AB - Awareness of Diabetes Mellitus (DM) as a relevant health problem in Brazil and realizing the importance of estimates of prevalence for public health planning and strategies, gave rise to this work seeking to estimate the reason for the prevalence of Diabetes Mellitus (DM) in different Brazilian states in the periods from 2002 to 2004 and 2005 to 2007. It involves a descriptive study based on Brazilian population data with a diagnosis of DM recorded in the Basic Care Information System (SIAB) of the Brazilian Ministry of Health. The prevalence rates were calculated for the periods from 2002 to 2004 and 2005 to 2007 and the Prevalence Ratios were then estimated per location and per reliability interval of 95% (RI95%). A high prevalence of DM was observed in Brazilian states with a significant increase (R>1; RI95%>1) for the periods in all Brazilian states, especially the Federal District (R=1.9800; RI95%=1.97241.9876) and the state of Maranhao (R=1.5217; RI95%=1.51981.5235). The conclusion drawn was that there was a significant increase in the prevalence of DM in Brazil between 2002 and 2007, highlighting the need for the formulation of strategies for prevention and control of the disease. PMID- 22218558 TI - [Evolution of physical fitness and functional capacity in active elderly women over 50 years of age according to chronological age in Santos city]. AB - The scope of this study was to compare the evolution of physical fitness, functional capacity and bone mineral density in active elderly women over a one year period. The sample consisted of 78 women from 50 to 79 years of age (c:62.4 +/- 7.1) participating in an aerobic program, twice a week, 50 minutes per session during 3.4 years and divided into three age groups: A: 50-59 (n:38); B: 60-69 (n:28); C: 70-79 (n:12). Results were compared using Two Way ANOVA, "post hoc" Bonferroni and delta (D%) variations (*p<.o1). The velocity of rising from a chair and gait speed revealed a significant difference in the three groups ranging from -14.3% to -45.5%; there was a significant improvement in A and B groups in walking speed (-12.1% to -13.9%), and also in maximum gait speed ( 15.4% to -18.5%), elbow flexion in all the groups (18.9% to 24.1%), vertical jump (22.5% to 43.9%) in groups B and C, and rising from a chair in 30 seconds (25.2% to 30.8%) in groups A and B, the flexibility test showed an increase in group A (16.2% to 33.3%) and stationary walking in the three groups of (16,4% 30.0%) and bone mineral density (BMD) presented a significant increase (3.1% to 10.2%). The results indicate the salutary effect of regular physical activity. PMID- 22218559 TI - A review of pesticide exposure and cancer incidence in the agricultural health study cohort. AB - We reviewed epidemiologic evidence related to occupational pesticide exposures and cancer incidence in the Agricultural Health Study (AHS) cohort. Studies were identified from the AHS publication list available on a Medline/PubMed database search in March 2009. Findings related to lifetime-days and/or intensity-weighted lifetime-days of pesticide use are the primary focus of this review, because these measures allow for the evaluation of potential exposure-response relationships. Most of the 32 pesticides examined were not strongly associated with cancer incidence in pesticide applicators. Increased rate ratios and positive exposure-response patterns were reported for 12 pesticides currently registered in Canada and/or the United States. Exposure misclassification is also a concern in the AHS and may limit the analysis of exposure-response patterns. Epidemiologic evidence outside the AHS remains limited with respect to most of the observed associations, but animal toxicity data support the biological plausibility of relationships observed six pesticides. Continued follow-up is needed to clarify associations reported to date. In particular, further evaluation of registered pesticides is warranted. PMID- 22218561 TI - [What kind of doctor we need?]. PMID- 22218563 TI - Failure of teriparatide in treatment of bone complications of adult hypophosphatasia. PMID- 22218562 TI - Resveratrol induces apoptosis via ROS-triggered autophagy in human colon cancer cells. AB - Resveratrol (Res; 3,4',5-trihydroxy-trans-stilbene), which is a polyphenol found in grapes, can block cell proliferation and induce growth arrest and/or cell death in several types of cancer cells. However, the precise mechanisms by which Res exerts anticancer effects remain poorly understood. Res blocked both anchorage-dependent and -independent growth of HT-29 and COLO 201 human colon cancer cells in a dose- and time-dependent manner. Annexin V staining and Western blot analysis revealed that Res induced apoptosis accompanied by an increase in Caspase-8 and Caspase-3 cleavage. In HT-29 cells, Res caused autophagy as characterized by the appearance of autophagic vacuoles by electron microscopy and elevation of microtubule-associated protein 1 light chain 3 (LC3)-II by immunoblotting, which was associated with the punctuate pattern of LC3 detected by fluorescein microscopy. Inhibition of Res-induced autophagy by the autophagy inhibitor 3-methyladenine caused a significant decrease in apoptosis accompanied by decreased cleavage of Casapse-8 and Caspase-3, indicating that Res-induced autophagy was cytotoxic. However, inhibition of Res-induced apoptosis by the pan caspase inhibitor Z-VAD(OMe)-FMK did not decrease autophagy but elevated LC3-II levels. Interestingly, Res increased the intracellular reactive oxygen species (ROS) level, which correlated to the induction of Casapse-8 and Caspase-3 cleavage and the elevation of LC3-II; treatment with ROS scavenger N-acetyl cysteine diminished this effect. Therefore, the effect of Res on the induction of apoptosis via autophagy is mediated through ROS in human colon cancer cells. PMID- 22218564 TI - A structured approach to the study of metabolic control principles in intact and impaired mitochondria. AB - We devised an approach to extract control principles of cellular bioenergetics for intact and impaired mitochondria from ODE-based models and applied it to a recently established bioenergetic model of cancer cells. The approach used two methods for varying ODE model parameters to determine those model components that, either alone or in combination with other components, most decisively regulated bioenergetic state variables. We found that, while polarisation of the mitochondrial membrane potential (DeltaPsi(m)) and, therefore, the protomotive force were critically determined by respiratory complex I activity in healthy mitochondria, complex III activity was dominant for DeltaPsi(m) during conditions of cytochrome-c deficiency. As a further important result, cellular bioenergetics in healthy, ATP-producing mitochondria was regulated by three parameter clusters that describe (1) mitochondrial respiration, (2) ATP production and consumption and (3) coupling of ATP-production and respiration. These parameter clusters resembled metabolic blocks and their intermediaries from top-down control analyses. However, parameter clusters changed significantly when cells changed from low to high ATP levels or when mitochondria were considered to be impaired by loss of cytochrome-c. This change suggests that the assumption of static metabolic blocks by conventional top-down control analyses is not valid under these conditions. Our approach is complementary to both ODE and top-down control analysis approaches and allows a better insight into cellular bioenergetics and its pathological alterations. PMID- 22218565 TI - Asymmetric hydrogenation of alpha- or beta-acyloxy alpha,beta-unsaturated phosphonates catalyzed by a Rh(I) complex of monodentate phosphoramidite. AB - The Rh(I) complex of a monodentate phosphoramidite bearing a primary amine moiety (DpenPhos) has been disclosed to be highly efficient for the asymmetric hydrogenation of a variety of alpha- or beta-acyloxy alpha,beta-unsaturated phosphonates, providing the corresponding biologically important chiral alpha- or beta-hydroxy phosphonic acid derivatives with excellent enantioselectivities (90 >99% ee). PMID- 22218566 TI - [IgA pemphigus of the subcorneal pustular dermatosis type. Successful therapy with a combination of dapsone and acitretin]. AB - IgA pemphigus of the subcorneal pustular dermatosis type is a rare autoimmune blistering disease in the pemphigus spectrum. Patients are clinically characterized by extensive erythemas that primarily affect intertriginous areas. The erythematous macules are covered with numerous vesicles and pustules with occasional hypopyon formation. Histopathology shows subcorneal acantholysis with clefting and numerous neutrophils within the blister as well as in the edematous papillary dermis. IgA autoantibodies bind in vivo to keratinocytes within the upper half of the epidermis. Desmocollin 1, the autoantigen of this disease, is a member of desmosomal cadherins and is only expressed on more differentiated keratinocytes. The demonstration of circulating autoantibodies against desmocollin 1 in routine diagnosis is challenging and requires indirect immunofluorescence staining of desmocollin 1 transfected COS7 cells. We report a patient with a severe course of the disease who only responded to combined therapy with dapsone and acitretin. PMID- 22218569 TI - Evaluation of the use of SCAR markers for screening genetic diversity of Lentinula edodes strains. AB - In this study, three molecular marker systems including sequence related amplified polymorphism (SRAP), random amplified polymorphic DNA (RAPD), and inter simple sequence repeats (ISSR) were screened to select polymorphisms of 24 main commercial strains of Lentinula edodes cultivated widely in China. Twenty-nine sequence characterized amplified region (SCAR) markers were developed to set up a dendrogram using UPMGA based on nucleotide sequences of some SRAP, RAPD, and ISSR polymorphic fragments. The grouping showed that the 24 strains were apparently clustered into five groups at a level of 0.68 similarity coefficient, and those that have similar breeding background clustered preferentially into the same subgroup. Results also revealed that the 24 strains had a low level of genetic diversity, and the breeding source of L. edodes should be broadened by exploiting wild types and introducing exotic strains. In addition, the tested strains of L. edodes could be clearly distinguished and identified from others by using different combinations of SCAR primers. Thus, results of this work demonstrated that SCAR was an excellent genetic marker system to characterize and investigate genetic diversity of L. edodes. Furthermore, this provided an alternative method to identify the genetic relationship of different strains of other fungi. PMID- 22218571 TI - Desulfurization of N,N-dimethylthioformamide by hydrosilane with the help of an iron complex. Isolation and characterization of an iron-carbene complex as an intermediate of C=double bond cleavage. AB - Desulfurization of N,N-dimethylthioformamide (Me(2)NCHS) by hydrosilane has been achieved under photo irradiation in the presence of a methyl iron complex. The reaction sequences have been proposed, in which silyl migration from Fe to S of thioformamide triggers the cleavage of a C=S bond to give a carbene-iron complex. This intermediate was isolated and characterized by X-ray analysis. PMID- 22218570 TI - Co-expression and synergism analysis of Vip3Aa29 and Cyt2Aa3 insecticidal proteins from Bacillus thuringiensis. AB - Vegetative insecticidal protein (Vip3) from Bacillus thuringiensis shows high activity against lepidopteran insects. Cytolytic delta-endotoxin (Cyt) also has high toxicity to dipteran larvae and synergism with other crystal proteins (Cry), but synergism between Cyt and Vip3 proteins has not been tested. We analyzed for synergism between Cyt2Aa3 and Vip3Aa29. Both cyt2Aa3 and vip3Aa29 genes were co expressed in Escherichia coli strain BL21 carried on vector pCOLADuet-1. Vip3Aa29 showed insecticidal activity against Chilo suppressalis and Spodoptera exigua, with 50% lethal concentration (LC(50)) at 24.0 and 36.6 MUg ml(-1), respectively. It could also inhibit Helicoverpa armigera growth, with 50% inhibition concentration at 22.6 MUg ml(-1). While Cyt2Aa3 was toxic to Culex quinquefasciatus (LC(50): 0.53 MUg ml(-1)) and Chironomus tepperi (LC(50): 36 MUg ml(-1)), it did not inhibit C. suppressalis, S. exigua, and H. armigera. However, the co-expression of Cyt2Aa3 and Vip3Aa29 showed synergistic effect on C. suppressalis and S. exigua, and the individual activities were strengthened 3.35- and 4.34-fold, respectively. The co-expression had no synergism against C. tepperi and H. armigera, but exerted some antagonistic effect on Cx. quinquefasciatus. The synergism between Cyt2Aa and Vip3Aa was thus discovered for the first time, which confirmed that Cyt toxin can enhance the toxicity of other toxins against some non-target insects. By synergism analysis, the effectiveness of microbial insecticides can be verified. PMID- 22218572 TI - Research gaps and challenges for malaria control in Brazil. PMID- 22218573 TI - [Severe mental illness in mothers and congenital malformations in newborns: a meta-analysis]. AB - The risk of congenital malformations appears to be higher in infants of mothers with mental disorders as compared to those of mothers with no history of psychiatric illness. This article presents a meta-analysis of studies on the association between maternal mental illness and congenital malformations. The review consisted of an article search in the MEDLINE, ISIWEB, Scopus, and SciELO databases, using the following key words: "mental disorders" OR "mental health" OR "psychotic disorders" OR "schizophrenia" AND "congenital abnormalities" OR "birth defects". A total of 108 studies were identified, and five articles were selected according to the established criteria. These articles were included in a meta-analysis, involving a total of 4,194 children of mothers with mental illness and 249,548 children of mothers with no such disorders. Pooled relative risk showed a significant association between exposure to mental illness in mothers and risk of malformations in newborns (RR = 2.06, 95%CI: 1.46-2.67). The study highlights the relationship between maternal mental health during pregnancy and its effects on the infant's health. PMID- 22218574 TI - [Multiple imputation and complete case analysis in logistic regression models: a practical assessment of the impact of incomplete covariate data]. AB - Researchers in the health field often deal with the problem of incomplete databases. Complete Case Analysis (CCA), which restricts the analysis to subjects with complete data, reduces the sample size and may result in biased estimates. Based on statistical grounds, Multiple Imputation (MI) uses all collected data and is recommended as an alternative to CCA. Data from the study Saude em Beaga, attended by 4,048 adults from two of nine health districts in the city of Belo Horizonte, Minas Gerais State, Brazil, in 2008-2009, were used to evaluate CCA and different MI approaches in the context of logistic models with incomplete covariate data. Peculiarities in some variables in this study allowed analyzing a situation in which the missing covariate data are recovered and thus the results before and after recovery are compared. Based on the analysis, even the more simplistic MI approach performed better than CCA, since it was closer to the post recovery results. PMID- 22218575 TI - [Effectiveness of community participation in Municipal Health Councils in Santa Catarina State, Brazil]. AB - This article presents a model for the evaluation of community participation in municipal (county) health systems. The theoretical basis for this evaluative study was the existing Brazilian legislation on community participation in drafting health strategies and overseeing health policy implementation. The indicators and measures were validated using the expert consensus technique. The proposed model has 26 indicators divided into five evaluative dimensions that reflect the legislation's adequacy for the structure, organization, representativeness, health planning participation, and autonomy of the Municipal Health Councils. Its applicability was tested in 24 municipalities in Santa Catarina State, Brazil. The data analysis indicated the best results for the dimension "planning system in the Unified National Health System" and the worst for "structure" and "autonomy". Only two municipalities showed good results for the final summary indicator. The study demonstrated the feasibility and adequacy of the proposed evaluation model. PMID- 22218576 TI - [Demographic characteristics and mortality among indigenous peoples in Mato Grosso do Sul State, Brazil]. AB - The present study aimed to assess mortality rates and related demographic factors among indigenous peoples in the State of Mato Grosso do Sul, Central-West Brazil, compared to the State's general population. Mortality rates were estimated based on data obtained from the Health Care Database for Indigenous Peoples and monthly patient care records as well as demographic data from the Brazilian Unified National Health System (SUS) and mortality data from the SUS Mortality Database. Compared to the overall population, among indigenous peoples there were proportionally more individuals under 15 years of age and fewer elderly, besides higher mortality rates at early ages and from infectious and parasitic diseases. Indigenous men showed significantly higher mortality rates from external causes and respiratory and infectious diseases, while among women the mortality rates from external causes and infectious diseases were higher. Suicide rates among young indigenous individuals were also particularly alarming. Indigenous people's health conditions are worse than those of the general population in Mato Grosso do Sul. PMID- 22218578 TI - [Dimensional structure of the Brazilian version of the Scale of Satisfaction with Interpersonal Processes of General Medical Care]. AB - The objective of this study was to reassess the dimensional structure of a Brazilian version of the Scale of Satisfaction with Interpersonal Processes of General Medical Care, proposed originally as a one-dimensional instrument. Strict confirmatory factor analysis (CFA) and exploratory factor analysis modeled within a CFA framework (E/CFA) were used to identify the best model. An initial CFA rejected the one-dimensional structure, while an E/CFA suggested a two dimensional structure. The latter structure was followed by a new CFA, which showed that the model without cross-loading was the most parsimonious, with adequate fit indices (CFI = 0.982 and TLI = 0.988), except for RMSEA (0.062). Although the model achieved convergent validity, discriminant validity was questionable, with the square-root of the mean variance extracted from dimension 1 estimates falling below the respective factor correlation. According to these results, there is not sufficient evidence to recommend the immediate use of the instrument, and further studies are needed for a more in-depth analysis of the postulated structures. PMID- 22218577 TI - [Overweight among adults in Pernambuco State, Brazil: prevalence and associated factors]. AB - In order to evaluate the prevalence of overweight and associated factors in Pernambuco State, Brazil, a cross-sectional population-based study was conducted in 2006, including 1,580 adults 25 to 59 years of age. Overweight was defined as body mass index > 25kg/m2. The conceptual model included demographic, socioeconomic, reproductive, and behavioral variables. Prevalence of overweight was 51.1% (95%CI: 48.6-53.6) and was statistically associated with age over 40 years (PR = 1.27; 95%CI: 1.10-1.46), female gender (PR = 1.29; 95%CI: 1.16-1.43), former smoking (PR = 1.42; 95%CI: 1.20-1.69), higher income (PR = 1.49; 95%CI: 1.30-1.71), and history of early pregnancy (< 18 years) (PR = 1.25; 95%CI: 1.11 1.66). There was no association with alcohol consumption, level of physical activity, or specific foods. The high prevalence of overweight is consistent with epidemic levels of this problem elsewhere in world, and the association with several factors supports its multifactor etiology. PMID- 22218579 TI - Racial inequalities in access to women's health care in southern Brazil. AB - The aim of this population-based cross-sectional study was to investigate access by 20 to 60 year-old women--both black and white--to early detection (pap-smear) exams for breast and cervical cancer in two towns--Sao Leopoldo and Pelotas--in Rio Grande do Sul State, southern Brazil. Estimates of the association between race/color and access to Pap-smear and breast exams were adjusted for income, education, economic class and age. Of the 2,030 women interviewed, 16.1% were black and 83.9%, white. Black women were significantly less likely to have had a Pap-smear and/or breast exam than white women. Racial inequalities in access to cancer early detection exams persisted after controlling for age and other socioeconomic factors. Racial differentials in access to early detection (Pap smear) exams for breast and cervical cancers might result from racial and socioeconomic inequalities experienced by black women in access to reproductive health care services and programs. PMID- 22218580 TI - [Death from dengue fever as a sentinel event for evaluation of quality of healthcare: a case study in two municipalities in Northeast Brazil, 2008]. AB - Despite the existing resources for adequate dengue patient care in the Brazilian healthcare system, the case-fatality rate for the disease is still high in the country. In order to identify factors associated with dengue-related death, this study evaluated quality of care according to the degree of implementation of specific measures, the technical and scientific quality of care, and access to health services in two municipalities (counties) in Northeast Brazil. An evaluative study of the implementation analysis type was performed, with death from dengue as the sentinel event for quality of care. To assess the degree of implementation and quality of care, the study scored the interview criteria and patient chart analysis; access was evaluated by thematic analysis. As for structure and process, the health services were found to be partially adequate (70%). No geographic or economic barriers were found to explain the occurrence of deaths. Technical and scientific quality failed to achieve adequate levels in the municipalities (46% and 30%) or in the specific services, and clinical management of dengue by the health services proved insufficient. PMID- 22218581 TI - Adolescent pregnancy and completion of basic education: a study of young people in three state capital cities in Brazil. AB - This study evaluated the association between adolescent pregnancy and the completion of basic education, mediated by macrosocial indicators. A cross sectional household survey was conducted with individuals between the ages of 18 and 24 in three Brazilian cities. For the purposes of this study, individuals between the ages of 20 and 24 were selected from this sample survey that included 4,634 people. A total of 29.6% of the girls declared that they had become pregnant prior to reaching the age of 20, while 21.4% of the boys stated that they had made a girl pregnant in adolescence. Girls from households with a per capita family income of US$70 or less and who became pregnant at least once during adolescence were more likely to have not completed basic education; whereas from households with a per capita family income of US$70 or less, with parents who separated before the adolescent reached the age of 20 and that had made a partner pregnant prior reaching the age of 20 were more likely to have not completed basic education. It is vital that the school system provides girls and boys with guidance on sexuality and contraception and encourages them to remain in education. PMID- 22218582 TI - [Quality of life and burnout among public high school and primary school teachers in Southern Brazil]. AB - In order to investigate quality of life among public schoolteachers in relation to socio-demographic characteristics and work conditions, a cross-sectional study was conducted in a sample of 601 primary and secondary teachers from the State and Municipal public school system in the urban area of Pelotas, Rio Grande do Sul State, Brazil. The study analyzed the following domains from the WHOQOL-BREF scale: physical health, psychological health, social relationships, and environment. The mean indices were: 69.2 (SD = 16.8) for physical health, 70.6 (SD = 14.0) for psychological health, 72.5 (SD = 17.3) for social relationships, and 60.7 (SD = 14.0) for environment. Age, time in the teaching career, and total number of students were not significantly associated with quality of life. Teachers in municipal schools scored higher than their counterparts in the State public schools in the physical health domain (p = 0.026). Men scored higher than women in the physical and psychological health domains. Higher family income was associated with better quality of life. Higher classroom workload was associated with better scores in the physical health and environment domains. PMID- 22218583 TI - [Nutritional status and associated factors among the elderly in Vicosa, Minas Gerais State, Brazil]. AB - This cross-sectional study in 2009 focused on the prevalence of underweight and overweight and associated factors in a sample of 621 elderly individuals in Vicosa, Minas Gerais State, Brazil. Data were obtained through home interviews on nutritional status and socio-demographic and health conditions. Of the total sample, 53.3% were females. Median BMI was 26.40 kg/m2 (range = 15.20-46.82) and was lower for men than for women. Prevalence of overweight was high (45%; 95%CI: 40%-49%), decreased with age, was positively associated with female gender and history of arthritis/arthrosis, and was negatively associated with age 80 years or older and smoking. Prevalence of underweight was high in men (18.2%), increased with age, and was positively associated with worse self-rated health. The findings highlight the importance of health strategies that favor lifestyle changes and healthy eating habits. PMID- 22218584 TI - [Performance analysis of the Rio de Janeiro State Neonatal Screening Program, 2005-2007]. AB - Guidelines emphasize that the appropriate time frame for neonatal screening with the heel stick test is from the 3rd to 7th day of life, in 100% of newborns. Treatment for congenital hypothyroidism and phenylketonuria, when initiated in the first two weeks of life, is capable of preventing the neurological sequelae of these diseases. The Rio de Janeiro State Neonatal Screening Program was accredited for Phase 2 of the National Neonatal Screening Program, with two program models (A and B). A performance analysis was conducted for the Neonatal Screening Program, for the years 2005 to 2007. Coverage increased from 2002 to 2007, reaching 80.4%, with 33.8% of the blood samples drawn in the first 7 days of life. The two models showed similar performance, short of the targets, with 50% of the confirmed cases receiving their diagnosis at more than 48 days of life. The delays accumulated in the various stages of the process can impede the benefits of early detection, the cornerstone of neonatal screening. The deleterious long-term effects transcend the individual sphere, with an impact on the health system and a major social burden. PMID- 22218585 TI - [Association between health risk behaviors in parents and adolescents in a rural area in southern Brazil]. AB - This article aimed to assess the association between health risk behaviors in parents and adolescents in a rural area. The sample included 377 schoolchildren 10 to 18 years of age and 338 parents. The following variables were analyzed: level of leisure-time and commuting physical activity, inadequate eating habits, overweight/obesity, smoking, and alcohol consumption. Prevalence rates for smoking and alcohol consumption by adolescents in the previous 30 days were 6.7% and 27%, respectively. Forty-five percent of adolescents failed to reach the target physical activity score. Adherence to steps to healthy eating was low. Physical activity in adolescents was positively associated with that of parents, and adolescent drinking was associated with maternal alcohol consumption. There was no significant association for other behaviors. In the analysis stratified by gender, level of physical exercise in female adolescents was associated with that of fathers. Parental health risk behaviors were associated with the behaviors in the adolescent children in this rural area. PMID- 22218586 TI - [Self-rated health and associated factors in adults: a population survey in Rio Branco, Acre State, Brazil, 2007-2008]. AB - The subjective concept of health included in the self-rated health process allows identifying factors associated with good self-rated health in populations. This cross-sectional population-based study in 2007-2008 focused on self-rated health and associated factors among adults (n = 1,516) in Rio Branco, Acre State, Brazil. The multivariate analysis used Poisson regression, with fair/poor self rated health as the dependent variable. Differences in gender, age group, level of schooling, and income negatively affected individuals' self-rated health. After adjusting for age, gender, and self-reported illness, the estimated risks for fair/poor health were higher for the unemployed, obese, and those with some self-reported illness. The results suggest that differences in living conditions for adults in Rio Branco are associated with precarious self-rated health. PMID- 22218587 TI - Employment conditions and health inequities: a case study of Brazil. AB - This paper was prepared for the Employment Conditions and Health Inequalities Knowledge Network (EMCONET), part of the WHO Commission on the Social Determinants of Health. We describe the Brazilian context of employment conditions, labor conditions and health, their characteristics and causal relationships. The social, political and economic factors that influence these relationships are also presented with an emphasis on social inequalities, and how they are reproduced within the labor market and thereby affect the health and wellbeing of workers. A literature review was conducted in SciELO, LILACS, Google and Google Scholar, MEDLINE and the CAPES Brazilian thesis database. We observed that there are more workers operating in the informal sector than in the formal sector and these former have no social insurance or any other social benefits. Work conditions and health are poor in both informal and formal enterprises since health and safety labor norms are not effective. The involvement of social movements and labor unions in the elaboration and management of workers' health polices and programs with universal coverage, is a promising initiative that is underway nationwide. PMID- 22218588 TI - [Sandflies in rural localities in northwest Parana State, Brazil]. AB - This study reports the results from sandfly captures at six sites in a rural area of Japura, Parana State, Brazil, showing the vector's presence indoors, outdoors, and in residual forest. Sandfly captures were performed with Falcao traps from 8:00 AM to 3:00 PM. At sites 195, 223, 236, and 527, three captures were performed at different times from December 2007 to January 2009. At sites 175 and 218, captures were performed from January to December 2008. 8,453 sandflies were captured, with an average of 155.40 specimens per hour. Nyssomyia neivai was the predominant species. Most sandflies were captured in domestic animal shelters (75.91 per hour) and in ciliary forest (38.45 per hour) during the hottest and rainiest months, in the outdoor environment with accumulation of organic matter and inadequate disposal of household wastewater. The study emphasizes the need for regular outdoor cleaning around households and building domestic animal shelters far from residences. PMID- 22218589 TI - ["Prisms of Perception": multiple readings of mass media health messages in Northeast Brazil]. AB - This anthropological study from February 2009 to November 2010 revealed the comprehension and cultural critique of three mass media health campaigns in Northeast Brazil. Twenty-four ethnographic interviews were conducted, exploring the iconographic and semantic content of the campaigns in the Dende community in Fortaleza, Ceara State, Brazil. The authors used Content Analysis; Systems of Signs, Significance, and Actions; and Contextualized Semantic Interpretation. There is a gap between the elaboration and reception of messages. Multiple interpretations occur (proximal reading, kaleidoscope of comprehension, and distant reading), depending on the reader's cognitive proximity to (or detachment from) the message. This "perceptual plasticity" arises from the creativity of popular imagination. Health professionals who hear rather than dismiss the "recipient's" subjective voice, which re-signifies authoritative messages, can penetrate the perception of the recipient's "visual world". In the context of poverty, this re-framing is essential for people to comprehend and proactively defend their own health. PMID- 22218590 TI - Exposure of luminal membranes of LLC-PK1 cells to ANG II induces dimerization of AT1/AT2 receptors to activate SERCA and to promote Ca2+ mobilization. AB - ANG II is secreted into the lumens of proximal tubules where it is also synthesized, thus increasing the local concentration of the peptide to levels of potential physiological relevance. In the present work, we studied the effect of ANG II via the luminal membranes of LLC-PK(1) cells on Ca(2+)-ATPase of the sarco(endo)plasmic reticulum (SERCA) and plasma membrane (PMCA). ANG II (at concentrations found in the lumen) stimulated rapid (30 s) and persistent (30 min) SERCA activity by more than 100% and increased Ca(2+) mobilization. Pretreatment with ANG II for 30 min enhanced the ANG II-induced Ca(2+) spark, demonstrating a positively self-sustained stimulus of Ca(2+) mobilization by ANG II. ANG II in the medium facing the luminal side of the cells decreased with time with no formation of metabolites, indicating peptide internalization. ANG II increased heterodimerization of AT(1) and AT(2) receptors by 140%, and either losartan or PD123319 completely blocked the stimulation of SERCA by ANG II. Using the PLC inhibitor U73122, PMA, and calphostin C, it was possible to demonstrate the involvement of a PLC->DAG(PMA)->PKC pathway in the stimulation of SERCA by ANG II with no effect on PMCA. We conclude that ANG II triggers SERCA activation via the luminal membrane, increasing the Ca(2+) stock in the reticulum to ensure a more efficient subsequent mobilization of Ca(2+). This first report on the regulation of SERCA activity by ANG II shows a new mechanism for Ca(2+) homeostasis in renal cells and also for regulation of Ca(2+)-modulated fluid reabsorption in proximal tubules. PMID- 22218591 TI - PKB/Akt partners with Dab2 in albumin endocytosis. AB - Albumin in the glomerular filtrate is normally retrieved by concerted efforts of clathrin, LDL-type receptor megalin- and clathrin-associated sorting proteins. In glomerular diseases, albumin overload triggers a proapoptotic and inflammatory response contributing to tubulointerstitial fibrosis and tubular atrophy. The relationship between albumin overload-induced proximal tubule injury and albumin endocytosis remains to be discovered. We investigated presence of a possible overlap between endocytosis and cell survival. We showed a novel interaction between prosurvival protein, protein kinase B (PKB/Akt), and adaptor protein, disabled 2 (Dab2), with coimmunoprecipitation. Further delineation of this interaction by GST pull-down experiments utilizing different Dab2 constructs identified proline-rich domain as the interacting partner. Expression of Dab2 and PKB/Akt was downregulated at high concentrations of albumin associated with apoptosis. We then examined the physiological relevance of this interaction with functional studies. Overexpression of PKB/Akt increased albumin uptake in human proximal tubule cells. Conversely, inhibition of PKB/Akt with a nonselective Akt/PKB signaling inhibitor-2 and a dominant negative construct of PKB/Akt resulted in a decrease in albumin uptake. Inhibition of Dab2 by silencing RNA abolished PKB/Akt-induced albumin uptake demonstrating the physiological importance of this novel interaction. We concluded that PKB/Akt is part of an endocytic machinery and it mediates albumin uptake through its interaction with Dab2. The role that PKB/Akt plays in the endocytic cascade may dictate its decreased expression in proteinuric states in an attempt to limit albumin endocytosis that may tilt the balance between cell survival and apoptosis toward cell death. PMID- 22218593 TI - Renoprotective effects of long-term oral nicotine in a rat model of spontaneous proteinuria. AB - Many proteinuric renal conditions are accompanied by renal inflammation. Nicotine is known to have anti-inflammatory properties and is used in oral form to help subjects quit smoking. A potential anti-inflammatory role of nicotine in proteinuric renal diseases has not been investigated to date. We therefore evaluated the effects of oral nicotine in a rat model of proteinuria-induced renal inflammation. We used a well-established model of adult (24 wk of age) male Munich-Wistar-Fromter rats. Animals were given three different physiological doses of nicotine in drinking water for 28 wk until 52 wk of age (long term). A group without nicotine served as a parallel control. At 52 wk of age, the control group had a 2.1 times reduction in creatinine clearance, 3.2 times increase in urinary protein excretion, an increased focal glomerulosclerosis (FGS) score, increased glomerular desmin deposition, decreased glomerular podocin, and a higher accumulation of macrophages and myofibroblasts compared with 24-wk-old animals. Oral treatment with nicotine dose dependently preserved renal function and halted proteinuria progression, which were independent of blood pressure reduction. It also reduced FGS, desmin deposition, podocin loss, and density of renal macrophages and myofibroblasts. Nicotine also reduced the level of gene expression of the renal inflammatory markers monocyte chemoattractant protein and vascular cell adhesion molecule-1. In conclusion, long-term oral nicotine preserved kidney function, reduced proteinuria, reduced renal inflammation, and protected progression of renal structural damage in a rat model of proteinuria. We further suggest evaluating nicotine as a potential additional therapeutic option for treating proteinuric kidney diseases. PMID- 22218592 TI - Group VIA phospholipase A2 is a target for vasopressin signaling in the thick ascending limb. AB - Na(+)-K(+)-2Cl(-) cotransporter (NKCC2)-mediated NaCl reabsorption in the thick ascending limb (TAL) is stimulated by AVP via V2 receptor/PKA/cAMP signaling. This process is antagonized by locally produced eicosanoids such as 20-HETE or prostaglandin E(2), which are synthesized in a phospholipase A(2)-dependent reaction cascade. Using microarray-based gene expression analysis, we found evidence for an AVP-dependent downregulation of the calcium-independent isoform of PLA(2), iPLA(2)beta, in the outer medulla of rats. In the present study, we therefore examined the contribution of iPLA(2)beta to NKCC2 regulation. Immunoreactive iPLA(2)beta protein was detected in cultured mTAL cells as well as in the entire TAL of rodents and humans with the exception of the macula densa. Administration of the V2 receptor-selective agonist desmopressin (5 ng/h; 3 days) to AVP-deficient diabetes insipidus rats increased outer medullary phosphorylated NKCC2 (pNKCC2) levels more than twofold in association with a marked reduction in iPLA(2)beta abundance (-65%; P < 0.05), thus confirming microarray results. Inhibition of iPLA(2)beta in Sprague-Dawley rats with FKGK 11 (0.5 MUM) or in mTAL cells with FKGK 11 (10 MUM) or (S)-bromoenol lactone (5 MUM) for 1 h markedly increased pNKCC2 levels without affecting total NKCC2 expression. Collectively, these data indicate that iPLA(2)beta acts as an inhibitory modulator of NKCC2 activity and suggest that downregulation of iPLA(2)beta may be a relevant step in AVP-mediated urine concentration. PMID- 22218595 TI - What about age related decline in renal function? PMID- 22218594 TI - Pien Tze Huang inhibits tumor cell proliferation and promotes apoptosis via suppressing the STAT3 pathway in a colorectal cancer mouse model. AB - Signal transducer and activator of transcription 3 (STAT3) plays a critical role in cell survival and proliferation. Constitutive activation of STAT3 is strongly correlated with pathogenesis of various types of malignant tumors including colorectal cancer (CRC), and therefore is a major focus in the development of anti-cancer agents. Pien Tze Huang (PZH), a well-known traditional Chinese formula prescribed already in the Ming Dynasty, has been demonstrated to be clinically effective in the treatment of CRC. However, the precise mechanism of its anti-cancer activity remains largely unknown. In the present study we evaluated the efficacy of PZH against tumor growth in vivo in the CRC mouse xenograft model, and investigated the underlying molecular mechanisms. We found that administration of PZH reduced tumor volume and tumor weight but had no effect on body weight gain in CRC mice, demonstrating that PZH can inhibit colon cancer growth in vivo without apparent adverse effect. We also observed that PZH treatment inhibited the phosphorylation level of STAT3 in tumor tissues. Consequently, the inhibitory effect of PZH on STAT3 activation resulted in the up regulation of Bax/Bcl-2 ratio as well as down-regulation of Cyclin D1 and CDK4 expression, leading to the induction of apoptosis as well as the inhibition of cell proliferation. These results suggest that promotion of cancer cell apoptosis and inhibition of proliferation via suppression of STAT3 pathway might be one of the mechanisms by which PZH treats colorectal cancer. PMID- 22218596 TI - Shift resources and focus from psychiatric beds to the community. PMID- 22218597 TI - Listen to patients and clinicians before cutting more psychiatric beds. PMID- 22218598 TI - We need a moratorium on further reductions in psychiatric beds till we debate an action plan. PMID- 22218599 TI - Dismissing patients' past healthcare cost seems premature. PMID- 22218600 TI - Use of national tariff makes formula inaccurate. PMID- 22218602 TI - Test for HIV and syphilis too in suspected early dementia. PMID- 22218603 TI - Are limited opening times really to blame for men's underuse of healthcare services? PMID- 22218604 TI - Simply changing the rules on sick notes hasn't worked before. PMID- 22218605 TI - Allowing juniors to train in one hospital would greatly reduce car use. PMID- 22218606 TI - NHS should adopt effective private company policies. PMID- 22218607 TI - Let us avoid Pascal's two excesses in quest for secularism's medical voice. PMID- 22218608 TI - Debate on altruistic kidney donation was too simplistic. PMID- 22218609 TI - Integrated care should be NHS priority, say think tanks. PMID- 22218610 TI - Dithiocarbamates: a new class of carbonic anhydrase inhibitors. Crystallographic and kinetic investigations. AB - The zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) is inhibited by several classes of zinc-binders (sulfonamides, sulfamates, and sulfamides) as well as by compounds which do not interact with the metal ion (phenols, polyamines and coumarins). Here we report a new class of potent CA inhibitors which bind the zinc ion: the dithiocarbamates (DTCs). They coordinate to the zinc ion from the enzyme active site in monodentate manner and establish many favorable interactions with amino acid residues nearby. Several low nanomolar CA I, II and IX inhibitors were detected. PMID- 22218611 TI - Traumatic middle meningeal artery pseudoaneurysms: diagnosis and endovascular treatment of two cases and review of the literature. AB - Intracranial pseudoaneurysms are rare and mostly associated with a history of head trauma. Only little is known about their natural development. They are characterized by an unpredictable course with a possibility of causing secondary intracranial hemorrhage with significant morbidity and mortality. We present two cases of traumatic pseudoaneurysms of the middle meningeal artery (MMA) treated via endovascular coil occlusion and review of literature. Pseudoaneurysms of the middle meningeal artery carry a potential risk of rupture. They can be detected via a computed tomography angiogram (CT-A). An endovascular embolization followed by catheter angiography may represent a safe treatment of traumatic middle meningeal artery pseudoaneurysms. Considering the risk of secondary rupture and the potentially catastrophic consequences, we recommend a CT-A in all patients with skull base fractures and intracranial hemorrhage. PMID- 22218614 TI - Colorimetric tracking of protein structural evolution based on the distance dependent light scattering of embedded gold nanoparticles. AB - In this communication, we describe a new, simplified colorimetric method for in situ tracking of structural evolution of Cu/Zn-superoxide dismutase (SOD1) aggregates, based on changes in plasmonic coupling between gold nanoparticles (GNPs) embedded along the structural backbone of the SOD1 aggregates. PMID- 22218612 TI - Characterization of intersex production in Trichogramma kaykai infected with parthenogenesis-inducing Wolbachia. AB - Sexually aberrant individuals, displaying both male and female characteristics, are rare in occurrence but are documented throughout the animal kingdom. In parasitoid wasps of the genus Trichogramma, such individuals typically appear as a result of rearing Wolbachia-infected thelytokous wasps at high temperatures. Sexually aberrant Trichogramma have been referred to interchangeably in the literature as gynandromorphs, sexual mosaics and intersexes. However, accurately used, the terms "gynandromorph" and "sexual mosaic" describe an individual composed of a mixture of genetically distinct tissues corresponding to the sexual phenotypes observed, while "intersex" refers to an individual having a uniform genetic constitution but with some tissues exhibiting sexual phenotypes conflicting with the associated genotype. Here, we investigate the heat-induced production of sexually aberrant offspring by thelytokous Trichogramma kaykai. Aberrant individuals were rare, but each was characterized as one of 11 morphotypes ranging from very feminine to very masculine. Overall, the production of aberrant individuals increased with time from the onset of maternal oviposition. However, while the production of males also increased with time, the degree of masculinity of aberrant individuals did not; the different morphotypes appeared to be produced haphazardly. We conclude that the aberrant individuals produced by T. kaykai are actually intersexes and not gynandromorphs. The wasp's close association with Wolbachia and the absence of intersexes in uninfected populations allow us to discuss a possible origin of the condition. PMID- 22218615 TI - Answers to common clinical questions. AB - Again, we present a rich issue with great information to address common clinical questions. A common class of drug (proton pump inhibitors) and insufficiently common diet (high fiber content) are related to improved diabetes control. Four good health habits make a huge difference, especially for obese patients. Meaningful use is just not always that meaningful. Computed tomography scans for common chest complaints probably are overused in emergency rooms. Continuous insurance is important to receipt of prevention services, even for those with access to care when they do not have insurance. Practice-based research can be difficult to accomplish, yet can yield some good results--in this case, improved colon cancer screening rates. Consider hyperaldosteronism in patients with resistant hypertension. Reflect on the mistakes other family physicians report; we often learn from others' mistakes. Surgical mesh migration can cause many things, but would you guess it would cause symptoms of irritable bowel syndrome? A nice primer on what is known about chemoprevention of prostate cancer. And, how to influence care outcomes: high-leverage, not just measurable, activities. PMID- 22218616 TI - Guest family physician commentaries. PMID- 22218617 TI - Critical access hospital (CAH) graduate medical education (GME): too little, and maybe too late. PMID- 22218618 TI - Increasing graduate medical education (GME) in critical access hospitals (CAH) could enhance physician recruitment and retention in rural America. AB - Critical Access Hospitals (CAHs) are essential to a functinoning health care safety net and are a potential partner of rural Graduate Medical Education (GME) which is associated with greater likelihood of service in rural and underserved areas. Currently very little Medicare funding supports GME in the CAH setting, highlighting a missed opportunity to improve access to care in rural America. PMID- 22218619 TI - Healthy lifestyle habits and mortality in overweight and obese individuals. AB - BACKGROUND: Though the benefits of healthy lifestyle choices are well-established among the general population, less is known about how developing and adhering to healthy lifestyle habits benefits obese versus normal weight or overweight individuals. The purpose of this study was to determine the association between healthy lifestyle habits (eating 5 or more fruits and vegetables daily, exercising regularly, consuming alcohol in moderation, and not smoking) and mortality in a large, population-based sample stratified by body mass index (BMI). METHODS: We examined the association between healthy lifestyle habits and mortality in a sample of 11,761 men and women from the National Health and Nutrition Examination Survey III; subjects were ages 21 and older and fell at various points along the BMI scale, from normal weight to obese. Subjects were enrolled between October 1988 and October 1994 and were followed for an average of 170 months. RESULTS: After multivariable adjustment for age, sex, race, education, and marital status, the hazard ratios (95% CIs) for all-cause mortality for individuals who adhered to 0, 1, 2, or 3 healthy habits were 3.27 (2.36-4.54), 2.59 (2.06-3.25), 1.74 (1.51-2.02), and 1.29 (1.09-1.53), respectively, relative to individuals who adhered to all 4 healthy habits. When stratified into normal weight, overweight, and obese groups, all groups benefited from the adoption of healthy habits, with the greatest benefit seen within the obese group. CONCLUSIONS: Healthy lifestyle habits are associated with a significant decrease in mortality regardless of baseline body mass index. PMID- 22218620 TI - Dietary fiber for the treatment of type 2 diabetes mellitus: a meta-analysis. AB - BACKGROUND: The evidence of the relationship between fiber intake and control of diabetes is mixed. The purpose of this study was to determine if an increase in dietary fiber affects glycosylated hemoglobin (HbA1c) and fasting blood glucose in patients with type 2 diabetes mellitus. METHODS: Randomized studies published from January 1, 1980, to December 31, 2010, that involved an increase in dietary fiber intake as an intervention, evaluated HbA1c and/or fasting blood glucose as an outcome, and used human participants with known type 2 diabetes mellitus were selected for review. RESULTS: Fifteen studies met inclusion and exclusion criteria. The overall mean difference of fiber versus placebo was a reduction of fasting blood glucose of 0.85 mmol/L (95% CI, 0.46-1.25). Dietary fiber as an intervention also had an effect on HbA1c over placebo, with an overall mean difference of a decrease in HbA1c of 0.26% (95% CI, 0.02-0.51). CONCLUSION: Overall, an intervention involving fiber supplementation for type 2 diabetes mellitus can reduce fasting blood glucose and HbA1c. This suggests that increasing dietary fiber in the diet of patients with type 2 diabetes is beneficial and should be encouraged as a disease management strategy. PMID- 22218621 TI - Early adopters of electronic prescribing struggle to make meaningful use of formulary checks and medication history documentation. AB - INTRODUCTION: Use of electronic prescribing (e-prescribing) can improve safety and reduce costs of care by alerting prescribers to drug-drug interactions, patient nonadherence to therapies, and insurance coverage information. Deriving these benefits will require clinical decision support based on presentation of accurate and complete formulary and benefit (F&B) and medication history (RxH) data to prescribers, but relatively little is known about how this information is used in primary care. METHODS: This is a multimethod comparative case study of 8 practices, which were selected to ensure practice size and physician specialty variation, implementing a stand-alone e-prescribing program. Field researchers observed prescription workflow and interviewed physicians and office staff. RESULTS: Before implementation, few prescribers reported using F&B references when making medication choices; all used paper-based methods for tracking medication history. After implementation, some prescribers reported using F&B data to inform medication choices but missing information reduced confidence in these resources. Low confidence in RxH data led to paper-based workarounds. CONCLUSIONS: Challenges experienced with formulary checks and RxH documentation led to prescriber distrust and unwillingness to rely on e-prescribing-based information. Greater data accuracy and completeness must be assured if e prescribing is to meet meaningful use objectives to improve the efficiency and safety of prescribing in primary care settings. PMID- 22218622 TI - Increased emergency department computed tomography use for common chest symptoms without clear patient benefits. AB - OBJECTIVE: The aim of this study was to examine changes in the utilization of computed tomography (CT) in the evaluation of common chest symptoms and the rate of clinically significant diagnoses in emergency departments after 2004. METHODS: This study analyzed the National Hospital Ambulatory Medical Care Survey, comparing 1997 to 1999 and 2005 to 2007. Set in US emergency departments, individuals older than 14 years old were eligible. The main outcome was proportion of common chest symptom-related visits (n = 17,098) associated with a CT order before 2000 and after 2004. Secondary outcomes were the proportion of these visits associated with a clinically significant diagnosis (pulmonary embolism, acute myocardial infarction, acute coronary syndrome, heart failure, pneumonia, and pleural effusion); an incidental diagnosis such as lung mass; and a clinically nonsignificant diagnosis such as nonspecific chest pain. RESULTS: The proportion of common chest symptom-related visits associated with a CT order increased from 2.1% in 1997 to 1999 to 11.5% in 2005 to 2007 (P < .001), whereas the overall proportion of these visits associated with a clinically significant diagnosis decreased from 23.6% in 1997 to 1999 to 19.1% in 2005 to 2007 (P < .001).The rate of acute myocardial infarction diagnosis decreased from 6.6% to 3.3% (P < .001), whereas the rate of pulmonary embolism diagnosis did not change (0.33% vs. 0.47%; P = .24) from 1997 to 1999 to 2005 to 2007. The rate of incidental diagnoses did not change (0.13% vs. 0.17%; P = .69), whereas the rate of clinically nonsignificant diagnoses increased from 35.6% to 45.8% (P < .001) from 1997 to 1999 to 2005 to 2007. CONCLUSIONS: CT ordering in emergency departments for the evaluation of common chest symptoms has increased dramatically without improving the rate of pulmonary embolism or other clinically significant diagnoses. Overuse of CT exposes patients to radiation and increases health care costs without any apparent diagnostic benefit. PMID- 22218623 TI - Receipt of diabetes preventive care among safety net patients associated with differing levels of insurance coverage. AB - BACKGROUND: Patients receive care in safety net clinics regardless of insurance status; however, receipt of diabetes preventive care might vary among patients with differing levels of insurance continuity. METHODS: In a retrospective cohort study, using electronic health record data from adults with diabetes who were receiving care in 50 safety net clinics in Oregon in 2005 to 2007, we conducted adjusted logistic regressions to model the associations between amount of time with insurance and rates of receipt of lipid screening, influenza vaccination, nephropathy screening (urine microalbumin), and HbA1c (glycohemoglobin) screening. RESULTS: Of 3384 adults with diabetes, 711 were partially insured (covered 1% to 99% of the 3-year study period), 909 had no coverage, and 1764 were continuously insured. In adjusted models, persons with partial or no coverage during the 3-year study period were less likely to receive most preventive services compared with those with continuous coverage. We found no evidence of a dose-response relationship with increasing duration of coverage, nor of a threshold amount of partial coverage, associated with better receipt of care. CONCLUSIONS: Safety net clinic patients need both access to primary care and continuous insurance. All patients with partial coverage, regardless of the extent of time with insurance, had lower odds of receiving preventive care. PMID- 22218624 TI - Proton pump inhibitor therapy associated with lower glycosylated hemoglobin levels in type 2 diabetes. AB - INTRODUCTION: Oral hypoglycemic medications sometimes do not control type 2 diabetes well. Proton pump inhibitors (PPIs) as adjunctive therapy might improve diabetes control through increasing serum gastrin and fasting insulin levels. METHODS: Electronic medical records in a family medicine residency program office practice were reviewed for 73 individuals with type 2 diabetes (not taking insulin), for whom PPIs were prescribed. Values for glycosylated hemoglobin (HbA1c) for periods of time when a PPI had been prescribed were compared with HbA1c levels for periods of time with no record of PPI prescribing or over-the counter PPI use. RESULTS: The mean HbA1c for patients not taking insulin was 7.11 during periods with recorded prescribing or over-the-counter use of PPIs, compared with 7.70 during periods without recorded PPI therapy (P = .001). Mean HbA1c for metformin monotherapy was not significantly different (6.81 with PPI vs. 7.10 without PPI; n = 16; P = .25). Mean HbA1c was significantly different for combination therapy that included metformin and/or sulfonylurea and/or giltazone (7.26 vs. 7.80; n = 27; P = .002). CONCLUSION: The observed association between PPI therapy and lower HbA1c levels suggests that PPIs may be useful as adjunctive therapy for type 2 diabetes. PMID- 22218625 TI - Development and validation of a clinical decision rule for the diagnosis of influenza. AB - INTRODUCTION: A clinical decision rule to improve the accuracy of a diagnosis of influenza could help clinicians avoid unnecessary use of diagnostic tests and treatments. Our objective was to develop and validate a simple clinical decision rule for diagnosis of influenza. METHODS: We combined data from 2 studies of influenza diagnosis in adult outpatients with suspected influenza: one set in California and one in Switzerland. Patients in both studies underwent a structured history and physical examination and had a reference standard test for influenza (polymerase chain reaction or culture). We randomly divided the dataset into derivation and validation groups and then evaluated simple heuristics and decision rules from previous studies and 3 rules based on our own multivariate analysis. Cutpoints for stratification of risk groups in each model were determined using the derivation group before evaluating them in the validation group. For each decision rule, the positive predictive value and likelihood ratio for influenza in low-, moderate-, and high-risk groups, and the percentage of patients allocated to each risk group, were reported. RESULTS: The simple heuristics (fever and cough; fever, cough, and acute onset) were helpful when positive but not when negative. The most useful and accurate clinical rule assigned 2 points for fever plus cough, 2 points for myalgias, and 1 point each for duration <48 hours and chills or sweats. The risk of influenza was 8% for 0 to 2 points, 30% for 3 points, and 59% for 4 to 6 points; the rule performed similarly in derivation and validation groups. Approximately two-thirds of patients fell into the low- or high-risk group and would not require further diagnostic testing. CONCLUSION: A simple, valid clinical rule can be used to guide point-of-care testing and empiric therapy for patients with suspected influenza. PMID- 22218626 TI - A randomized colorectal cancer screening intervention trial in the Iowa Research Network (IRENE): study recruitment methods and baseline results. AB - BACKGROUND: Only about half of eligible Americans are adherent with colorectal cancer (CRC) screening. Because patients generally access CRC screening via their primary care physicians, interventions to improve screening should be tested in the primary care setting. This article describes the recruitment and baseline characteristics of patients from 16 practice-based research network practices for a study to improve CRC screening. METHODS: A total of 8327 invitations were mailed to patients of these practices, and 1685 returned consent forms and baseline surveys. RESULTS: Of those who consented, 942 were up to date with screening, which indicates that office databases were unable to provide information about those who were already screened. The 743 due for screening were younger (mean age, 61 vs. 63 years), less likely to have an immediate family member with CRC (11% vs. 19%), less likely to have Medicare (29% vs. 40%), more likely to have no insurance (5% vs. 1%), and less likely to report a physician/nurse recommendation for CRC screening (63% vs. 92%) for all comparisons. CONCLUSIONS: Our experiences for this practice-based research network randomized clinical intervention trial may be useful to others. Practice and patient recruitment processes were onerous with institutional review board issues, poorly prepared patient databases, and discarding of mail by the US Postal Service. PMID- 22218627 TI - Mailed fecal immunochemical tests plus educational materials to improve colon cancer screening rates in Iowa Research Network (IRENE) practices. AB - INTRODUCTION: Only about half of all eligible Americans have been screened for colorectal cancer (CRC). The objective of this study was to test whether mailed educational materials and a fecal immunochemical test (FIT), with or without a scripted telephone reminder, led to FIT testing. In addition, we compared changes in attitudes toward, readiness for, and barriers to screening from baseline to follow-up after education about screening. METHODS: Subjects due for CRC screening were recruited from 16 Iowa Research Network family physician offices. Half of the subjects were randomized to receive mailed written and DVD educational materials, along with a FIT, either with or without a telephone call designed to encourage screening and address barriers. Subjects completed surveys regarding their attitudes and readiness for CRC screening at baseline and after education about screening. The main outcome was whether the subject completed FIT testing. RESULTS: A total of 373 individuals received educational materials (including a FIT) and 231 (62%) returned a posteducation survey. The mean age was 61.2 years; 52% were women, 99% were white, 39% had a high school education or less, 39% had a total family income of less than $40,000, and 7% had no insurance. The written materials were read by 82%, understood by 91% (of those who read them), and 82% felt their knowledge was increased. The DVD was viewed by 67%, understood by 94% of those who viewed it, and 86% felt the DVD increased their knowledge. Compared with baseline, individuals reported being significantly more likely to bring up CRC screening at their next doctor's visit (P < .0001) and being more likely to be tested for CRC in the next 6 months (P < .0001). Comparing baseline with follow-up, summary attitude scores improved (P < .0001), readiness scores improved (P < .0001), and there were fewer barriers (P = .034, Wilcoxon signed rank). The FIT return rate increased from 0% to 45.2% in the education alone group and from 0% to 48.7% for the group receiving education plus the telephone call (P < .0001 for each group individually and overall when compared with Medicare beneficiaries in Iowa). CONCLUSIONS: Mailing FIT kits with easy-to-understand educational materials improved attitudes toward screening and dramatically increased CRC screening rates among patients who were due for screening in a practice-based research network. A telephone call addressing barriers to screening did not result in increased FIT testing compared with mailed education alone. PMID- 22218628 TI - An assessment of the Hawthorne Effect in practice-based research. AB - BACKGROUND: Practical studies in real-world settings may be particularly vulnerable to unintended effects on intervention outcomes, including what is commonly known as the Hawthorne Effect. This phenomenon suggests that study subjects' behavior or study results are altered by the subjects' awareness that they are being studied or that they received additional attention. This is especially a concern when subjects are not blinded to randomization or when they participate in studies with observational components. As part of a larger practical intervention designed to improve the clinical management of skin and soft tissue infections (SSTIs), we specifically examined the potential for a Hawthorne Effect from the extra attention some clinicians received when completing follow-up case reviews. METHODS: De-identified, electronic data from a larger practical intervention allowed for the comparison of the clinical management of SSTIs among 14 randomly selected clinicians who participated in follow-up case reviews versus 77 clinicians who did not. RESULTS: There were no differences in the management of SSTIs between the 2 groups of clinicians. No evidence of a Hawthorne Effect was observed in this quality-improvement intervention. CONCLUSION: More extensive contact with the research team did not seem to have unintended effects on the outcomes of interest for the management of SSTIs. Further study in practice-based research settings could help to establish whether different types of studies and outcomes are more or less susceptible to the Hawthorne Effect. PMID- 22218629 TI - Diagnostic errors in primary care: lessons learned. AB - BACKGROUND: Diagnostic errors occur more commonly than other kinds of errors, they are more likely to harm patients, and they are more likely to be preventable. Little is known about the presenting complaints, initial (incorrect) diagnoses, and physicians' personal lessons learned related to diagnostic errors. METHODS: In 2009 and 2010, we invited a random sample of 200 family physicians, 200 general internists, and 200 general pediatricians practicing in Iowa to describe an important diagnostic error using a 1-page, mailed questionnaire. The data were analyzed using quantitative and qualitative methods. RESULTS: The response rate was 34% (202 of 600 physicians). Common presenting complaints included abdominal pain (n = 27 of 202 patients, 13%); fever (n = 19; 9%); and fatigue (n = 15, 7%). Common initial (incorrect) diagnoses included benign viral infections (n = 35, 17%); musculoskeletal pain (n = 21, 10%); and chronic obstructive pulmonary disease/asthma (n = 13, 6%). The 202 responding physicians described 254 personal lessons learned, which we used to develop a taxonomy of 24 generic lessons. Three common lessons were: (1) consider diagnosis X in patients presenting with symptom Y (n = 37 lessons, 15%; eg, "Any discomfort above the umbilicus may be coronary artery disease."); (2) look beyond the initial, most obvious diagnosis (n = 26 lessons, 10%); and (3) be alert to atypical presentations of disease (n = 24 lessons, 9%). CONCLUSIONS: In this study, diagnostic errors often were preceded by common symptoms and common, relatively benign initial diagnoses. The lessons learned often involved various aspects of broadening the differential diagnosis. PMID- 22218630 TI - Prevalence of hyperaldosteronism in primary care patients with resistant hypertension. AB - INTRODUCTION: Because hyperaldosteronism is the most common curable reason for secondary hypertension, screening is recommended. However, prevalence among general practice patients and feasibility of screening is still unclear. A design to assess prevalence in general practice and barriers against screening was created. METHODS: This was an open, observational pilot study and focus group. In 2 general practices, all patients with arterial hypertension were included. Those with resistant hypertension (>140/90 mm Hg and taking >=3 antihypertensive drugs) were eligible for screening. The design and feasibility of the study were discussed in a focus group of experienced general practitioners. RESULTS: Of 3107 patients visiting the practices, 564 were diagnosed as having arterial hypertension. Seventy-nine fulfilled criteria for resistant hypertension. Aldosterone:renin ratio (ARR) could be measured in 63 of those patients. Withdrawal of beta-blocker was feasible in 34 of the 63 with measurable ARR. ARR was positive in 15, and in 3 of those 15 with positive ARR, it was caused by elevated aldosterone levels. Focus group discussion revealed barriers and concerns regarding organizational, financial, and practical aspects of a systematic screening. CONCLUSIONS: Screening for hyperaldosteronism in general practice seems possible in selected patients, but not in a systematic way. Barriers against systematic screening were a necessity for beta-blocker cessation as well as structural prerequisites for patient identification. PMID- 22218631 TI - Is insomnia an independent predictor of obstructive sleep apnea? AB - INTRODUCTION: Obstructive sleep apnea (OSA) is a disorder with high prevalence in primary care. However, little research exists on screening for OSA in primary care samples. METHODS: One hundred family medicine patients completed standardized symptom and demographic questionnaires and a structured clinical interview for sleep disorders. Two-step logistic regression was performed to determine the independent predictive value of insomnia for clinical identification of OSA. Additional t tests were computed to examine age and sex patterns of insomnia. RESULTS: A model including body mass index and daytime sleepiness predicted OSA status (chi(2) = 18.63; P < .001) and explained 27% of the variance in OSA clinical diagnosis. Addition of insomnia scores to the model significantly improved predictive utility (chi(2) = 25.79; P < .001) and explained 36% of the variance in OSA. Insomnia scores were higher for women compared with men (P = .033) and women with OSA compared with women without OSA (P = .007). CONCLUSIONS: Inquiry regarding insomnia may improve clinical identification of OSA when screening for OSA in primary care. This finding possibly is unique to the evaluation of OSA in a primary care versus sleep laboratory sample. The predictive utility of insomnia may be specific to women. PMID- 22218632 TI - Chemoprevention of prostate cancer: myths and realities. AB - BACKGROUND: Prostate cancer will affect 15% to 18% of men in North America and will result in death in 3%. Established curative and palliative treatments for prostate cancer are associated with significant morbidity and cost. For these reasons, prostate cancer is an ideal target for prevention. METHODS: Using MEDLINE we performed a systematic review of clinical trials that have investigated pharmaceutical or nutritional interventions for the prevention of prostate cancer. The available evidence was critically evaluated and summarized according to the strength of recommendation taxonomy. RESULTS: Many pharmaceutical and nutritional interventions have been investigated for the prevention of prostate cancer. The strongest evidence exists to support the use of 5 alpha-reductase inhibitors (5-ARIs) for prevention of prostate cancer. However, the evidence is insufficient to recommend that these agents be used routinely among all men. In addition, the optimal timing or duration of 5-ARI use in not known. At present there is no suitable evidence to recommend using any specific nutritional supplement or diet to prevent prostate cancer. CONCLUSIONS: Prostate cancer prevention should not be offered systematically to all men. There may be a role for 5-ARI use among motivated men who wish to take a proactive approach to prostate cancer prevention. PMID- 22218633 TI - Irritable bowel syndrome: a "mesh" of a situation. AB - The diagnosis of irritable bowel syndrome (IBS) frequently is made after the exclusion of a mechanical etiology for a patient's symptoms. This case demonstrates that IBS symptoms can be caused by a rare complication of a common surgery: mesh herniorrhaphy repair. The patient is a 50-year-old woman who underwent periumbilical Marlex mesh herniorrhaphy 13 years before presentation. After her operation, the patient developed constipation (approximately one bowel movement per week) alternating with diarrhea for approximately 10 years. An abdominal radiograph showed large amounts of stool, and after a normal colonoscopy the patient was diagnosed with IBS. The patient was treated with tegaserod (Zelnorm) and polyethylene glycol (MiraLAX), which did not palliate her symptoms. The patient presented with obstructive symptoms and physical findings of an incarcerated umbilical hernia. A computed tomography (CT) scan of the abdomen confirmed an umbilical hernia involving a segment of small bowel with surrounding fecalization of enteric contents. During operative repair, the patient was found to have Marlex mesh fully eroded into the lumen of the small bowel, causing a partial obstruction. The involved section of small bowel was resected, and during serial follow-up the patient had complete resolution of her IBS-like symptoms. A discussion follows regarding the implications of mesh migration, and questions are posed for future research. PMID- 22218634 TI - Target lesions and other paintball injuries. AB - Paintball is a popular combat game, with more than 5 million participants per year. As it has increased in popularity, the incidence of paintball-related injuries also has increased. The most common injuries are classic, benign skin lesions that are easily recognized if one is aware of them. Devastating eye injuries also may occur if participants do not wear face masks. Other reported injuries include musculoskeletal injuries, solid organ injuries, and vascular pseudoaneurysms. Rarely, paintball-related deaths have been reported. This article is the first to review the full spectrum of paintball injuries; in addition, the article emphasizes the importance of encouraging participants to adhere to appropriate safety measures, particularly wearing an appropriate face mask at all times during the game. PMID- 22218635 TI - Prediction of incomplete screening mammograms based on age and race. AB - OBJECTIVE: This study examined the age-associated rate of incomplete mammograms requiring additional testing based on Breast Imaging-Reporting and Data System (BIRADS) score. METHODS: A retrospective, observational study design from a tertiary medical center was used to evaluate which explanatory variables significantly predicted whether a woman had an incomplete mammogram. An incomplete mammogram was defined as a BIRADS score of 0 (requiring further imaging), whereas a benign process was defined as a BIRADS score of 1 or 2. Explanatory variables included traditional clinical factors (age, race, and menopausal state). RESULTS: During the study period, 20,269 subjects were evaluated. The majority of the patients were white (n = 12,955; 64.6%) and had a BIRADS score consistent with a benign finding (n = 17,571; 86.6%). Premenopausal state (odds ratio [OR], 1.38; 95% CI, 1.27-1.50), white race (OR, 1.18; 95% CI, 1.08-1.29), and younger age (OR, 1.38; 95% CI, 1.27-1.50) significantly increased the odds a woman had an incomplete study. CONCLUSIONS: In this cross-sectional, single-institution analysis, premenopausal state and white race are associated with an increased rate for incomplete mammograms. Patients should be counseled appropriately before the initiation of screening. PMID- 22218636 TI - A case of IgG4-related tubulointerstitial nephritis with left hydronephrosis after a remission of urinary tract tuberculosis. AB - IgG4-related systemic disease encompasses multi-organ disorders, including tubulointerstitial nephritis. This disease is accompanied by a high serum IgG4 concentration and IgG4-positive plasma cell infiltration. We herein describe a 63 year-old woman with renal failure and dryness of the eyes and mouth, who had been treated with antituberculosis agents for urinary tract tuberculosis. She had a negative finding for a PCR analysis for Mycobacterium tuberculosis, a positive QuantiFERON-TB test, high serum IgG4 concentrations (2,660 mg/dl), and low serum IgM and IgA concentrations (34 and 82 mg/dl, respectively). Imaging tests revealed swelling in the submandibular glands, pancreas, and right kidney. A renal biopsy showed IgG4-positive plasma cell infiltration in the interstitium and tubular atrophy. This case was diagnosed as IgG4-related systemic disease. Corticosteroid therapy improved renal failure and swelling in the submandibular glands, pancreas, and right kidney. The case suggests that an abnormal reaction to tuberculosis may be associated with a predominance of type-2 helper T-cell immunity, thus resulting in IgG4-related systemic disease. PMID- 22218637 TI - The effect of isometric exercise of the hand on the synovial blood flow in patients with rheumatoid arthritis measured by color Doppler ultrasound. AB - In 90% of patients with rheumatoid arthritis (RA), the joints of the hand are affected. Studies of grip strength training have not indicated a negative effect on disease activity after training. Introduction of ultrasound Doppler (USD) to measure increased blood flow induced by inflammation has made it possible to investigate the direct effect on blood supply in the synovium after training. In this case-control study, 24 patients with RA with USD activity in the wrist joint participated. The USD activity was measured by the color fraction (CF) (CF = colored pixels/total number of pixels in ROI). Twenty-four patients were assigned to an 8-week grip strength training program. At baseline and after 8 weeks of training, an USD examination of the wrist joint was performed. In the training group, we measured grip strength and pain in the wrist joint. Six patients withdrew from the training because of pain or change in medication. Eighteen patients served as control group. There was a modest, not significant, decrease in the CF in response to training (1.86%; P = 0.08). Grip strength increased 8.8% after training (P = 0.055). Pain in motion deceased after training (P = 0.04). No difference in the CF was seen between the training and control groups, neither at baseline nor at follow-up (P = 0.82 and P = 0.48). Patients withdrawing from training had a significantly higher CF than the other patients (P > 0.001). The results in this study might indicate that the flow in the synovium assessed by USD is not affected by grip strength training. PMID- 22218638 TI - Fish skin disease and brittle bones. PMID- 22218639 TI - The effect of hyaluronic acid on osteopontin and CD44 mRNA of fibroblast-like synoviocytes in patients with osteoarthritis of the knee. AB - The aim of this study was to investigate the effect of hyaluronic acid (HA) on the expression of osteopontin (OPN) and CD44 mRNA of fibroblast-like synoviocytes (FLS) in the patients with osteoarthritis (OA) of the knee. FLS were obtained from the knees of 10 patients with OA. Real-time quantitative polymerase chain reaction (Q-PCR) was used to assess the expression of the OPN mRNA and CD44 mRNA. The relative OPN mRNA expression in HA group (6.47 +/- 2.30-fold) was significantly higher than in the control group (P = 0.045, P < 0.05), while in HYL group (0.65 +/- 0.21-fold) it was lower than in the control group (P = 0.037, P < 0.05), and the difference in OPN mRNA expression between HA group and HYL group also showed statistically significant (P = 0.001, P < 0.05); however, there was no significant difference between each group of the relative CD44 mRNA expression (P > 0.05). Our study showed that HA can upregulate OPN mRNA expression in OA fibroblast-like synoviocytes, and the high expression of OPN mRNA in OA may be a result of increased HA level of OA synovitis; however, HA cannot affect the CD44 mRNA expression in OA fibroblast-like synoviocytes, and the high expression of CD44 mRNA in OA may be not a result of increased HA level of OA synovitis. PMID- 22218640 TI - Assessment of sexual functions in female patients with ankylosing spondylitis compared with healthy controls. AB - Healthy human sexuality is integral to a well-lived life. Recent studies reported that sexual problems were common in patients with ankylosing spondylitis (AS) in relation to the consequences of the illness such as pain, stiffness of the spine and depression. Twenty-three female patients with AS and 27 healthy female controls were applied the Female Sexual Function Index (FSFI) to determine the influence of the disease on sexual functions. The rate of low sexual function was 60.9% in female patients with AS and 66.7% in healthy controls (P > 0.05). Ten patients were depressed in our study group according to the Beck Depression Inventory (BDI), while 15 healthy controls were depressed (P > 0.05). No statistically significant differences were found between the female patients and controls in FSFI and BDI scores. There was a significant correlation between BDI and total FSFI, desire and orgasm domains in female patients with AS. Pain, disease activity and functional status of the patients with AS were correlated with FSFI. However, there was no correlation between spinal mobility, laboratory parameters and sexual functions. General health, vitality, emotional role and mental health subscales of Short Form-36 were correlated with total FSFI scores. We did not find any relationship between AS quality of life scale and sexual functions. Sexual dysfunctions are common, but not different in female patients with AS when compared with healthy controls. Sexual problems in female patients with AS seem to be associated with higher depression level, increased disease activity, decreased functionality, higher pain scores and decreased quality of life. PMID- 22218642 TI - Migratory polyarthritis as a paraneoplastic syndrome in childhood leukemia. PMID- 22218641 TI - Home-based exercise therapy in ankylosing spondylitis: short-term prospective study in patients receiving tumor necrosis factor alpha inhibitors. AB - The importance of exercise and regular physiotherapy in patients with ankylosing spondylitis (AS) under treatment with tumor necrosis factor alpha inhibitors (TNFalpha inhibitors) was reported in some studies, but the literature on this topic is still scarce. The aim of this study was to assess the effects of home based exercise therapy on functional capacity, disease activity, spinal mobility, quality of life, emotional state and fatigue in patients with AS receiving TNFalpha inhibitors. Forty-two AS patients were trained on the disease, and home based exercise program was demonstrated to all the patients. At baseline and at the end of 10 week, we evaluated Bath AS Disease Activity Index, Bath AS Functional Index, Bath AS Metrology Index, Multidimensional Assessment of Fatigue Scale, Beck Depression Inventory and Short-Form 36. Patients following home-based exercise program five times a week at least 30 min per session (exercise group) were compared with those exercising less than five times a week (control group). At baseline, exercise and control group had similar demographic features. After 10 weeks, all outcome parameters showed statistically significant improvements in exercise group. There were significant differences in all the parameters except social functioning subscale of Short-Form 36 between groups in favor of exercise group at 10th week (P < 0.05). Home-based exercise program is an effective therapy in increasing functional capacity and joint mobility, decreasing disease activity, improving emotional state, fatigue and quality of life for AS patient receiving TNFalpha inhibitors. We need to find out new ways to provide continuity of AS patients with it. PMID- 22218643 TI - Factors influencing quality of life (QOL) for Korean patients with rheumatoid arthritis (RA). AB - The aim of the study was to identify factors influencing the health-related quality of life (HR-QOL) for Korean RA patients and factors associated with each dimension of the EQ-5D. Two hundred and twenty-five RA patients were recruited from one University Hospital in Seoul, South Korea. Their clinical and socio demographic data were widely collected by means of interviews, self-administered questionnaires, and clinical examinations. Multiple logistic regression analyses were performed to determine the factors influencing QOL and factors associated with each dimension of the EQ-5D. The mean EQ-5D utility observed for Korean RA patients was 0.60 (-0.29 to 1.0). Functional disability measured with Health Assessment Questionnaire (OR = 10.0, CI 2.8-34.5), disease activity score (DAS) 28 (OR = 2.6, CI 1.4-4.9), and pain VAS (OR = 2.2, CI 1.2-4.1) was three main factors influencing on QOL of RA patients. Although the functional disability consistently showed significant associations with all dimensions, various factors were associated with the each five specific dimension of EQ-5D. Pain (OR = 2.5, CI 1.4-4.6), history of hospitalization (OR = 2.1, CI 1.0-4.3), and men (OR = 2.6, CI 1.0-6.8) were associated with lower QOL in mobility. Use of alternative medicine (OR = 2.0, CI 1.1-3.7) and disease activity (OR = 3.1, CI 1.7-5.7) were associated with lower self-care QOL. For the patients with discomfort in usual activity, pain (OR = 4.7, CI 2.4-9.2) and the presence of anemia (OR = 2.3, CI 1.2-4.5) were major influencing factors. Higher disease activity (OR = 4.5, CI 1.0-21.2) and pain (OR = 3.3, CI 1.9-5.8) were associated with the pain/discomfort dimension of EQ-5D, and the pain (OR = 3.3, CI 1.9-5.8) was an independent associating factor of anxiety/depression. The strongest determinants of lower QOL in Korean RA patients were functional disability, higher disease activity, and subjective pain. However, various factors are influencing on the QOL for RA patients according to aspects of QOL. It suggested that clinicians should pay more attention to other factors of RA patients as well as clinical remission to improve their QOL. PMID- 22218646 TI - A polycation-chaperoned in-stem molecular beacon system. AB - In the presence of poly(L-lysine)-graft-dextran, an in-stem molecular beacon involving three perylene-anthraquinone pairs in the stem region had a signal/background ratio of as high as 570. Response speed was also remarkable; equilibrium was attained within 5 minutes after addition of substrate DNA at 20 degrees C. PMID- 22218644 TI - Clinical characteristics of concurrent and sequentially presented lupus-related protein-losing enteropathy: what are their differences? AB - Our objective was to compare patients with concurrent and sequentially presented systemic lupus erythematosus (SLE)-related protein-losing enteropathy (PLE). Patients with history of SLE admitted for PLE were selected and their clinical, laboratory, endoscopic and imaging characteristics, treatment and outcome were analyzed. From 2001 to 2010, 21 and 27 patients had concurrent and sequentially presented SLE-related PLE, respectively, and their clinical characteristics were comparable except the following: the concurrent group had more pleural effusion (P < 0.01), cutaneous (P < 0.03), neurological (P = 0.02) manifestations, higher creatine phosphokinase (127.6 IU/L vs. 105.7 IU/L, P < 0.05) and lactate dehydrogenase (504.0 IU/L vs. 422.2 IU/L, P < 0.05); whereas the sequential group had higher anti-double strand DNA titer (179.8 vs. 100.4, P < 0.05), 24-h urine protein excretion (1.1 g/d vs. 0.6 g/d, P < 0.05) and increased proteinuria after onset of PLE (0.21 g/d vs. 1.1 g/d, P < 0.04). The endoscopic, histological and radiological features were comparable between the two groups. More patients from the sequential group required more potent immunosuppressive therapy for induction (55.6% vs. 14.3%, P = 0.002) and maintenance (48.2% vs. 9.5%, P < 0.01).The concurrent group associated with better treatment outcomes, with requiring shorter mean time (4.5 months vs. 7.9 months, P = 0.03) for normalbuminemia and more individuals (90.5% vs. 63%, P < 0.02) achieving normalbuminemia in first year. The complications were infrequent: two drug-related adverse events from each group, one patient each from the concurrent group developed shingle and SLE nephropathy. PLE associated with concurrent and sequentially presented of SLE are comparable in clinical behavior; and the immunosuppressive therapy is generally well-responded and tolerated. However, the concurrent group is associated with better disease activity control. PMID- 22218647 TI - Edge-decorated graphene nanoribbons by scandium as hydrogen storage media. AB - On the basis of density functional theory calculations, we show that edge decorated graphene nanoribbons (GNRs) by scandium can bind multiple hydrogen molecules in a quasi-molecular fashion. The average adsorption energy of H(2) on Sc ranges from 0.17 to 0.23 eV, ideally suited to hydrogen storage. For the narrowest GNR with either armchair or zigzag edges, the predicted weight percentage of H(2) is >9 wt%, exceeding the gravimetric target value set by the Department of Energy (DOE). The bonding energy between Sc and the GNR is significantly greater than the cohesive energy of bulk Sc so that clustering of Sc will not occur once Sc is bonded with carbon atoms at the edge of GNRs. Moreover, the adsorption energy of H(2) can be modestly tuned (either enhanced or reduced) by applying an external electric field. PMID- 22218648 TI - GQ1b-seronegative Fisher syndrome: clinical features and new serological markers. AB - IgG anti-GQ1b antibodies are a powerful serological marker for the diagnosis of Fisher syndrome (FS), but little is known regarding serological markers in FS patients that do not have the autoantibodies. The authors analyzed IgG antibodies against gangliosides other than GQ1b, ganglioside complexes, and ganglioside-like lipo-oligosaccharide (LOS) of Campylobacter jejuni isolates from FS patients. We identified 24 (12%) patients with GQ1b-seronegative FS among 207 FS patients who had been referred to our laboratory for anti-ganglioside antibody testing. Patients with GQ1b-seronegative FS were male and had a history of antecedent gastrointestinal illness more frequently than FS patients with IgG anti-GQ1b antibodies. Other clinical features during the illness were not distinguishing for GQ1b-seronegative FS. Four (17%) of 24 patients with GQ1b-seronegative FS had IgG antibodies against single gangliosides such as GM1b, GD1a, or GT1a. Antibodies against GM1 and GT1a complex were detected in four GQ1b-seronegative FS patients, three of whom did not have antibodies against single gangliosides. Mass spectrometry analysis showed that C. jejuni isolates from FS patients had GD1c-, GalNAc-GM1b-, or GalNAc-GD1c-like LOS, and not GQ1b-like LOS, highlighting the utility of examining serum antibodies against these ganglioside mimics in GQ1b-seronegative FS patients. Seven (29%) had IgG antibodies against the LOS from C. jejuni strains expressing GD1c-, GalNAc-GM1b-, or GalNAc-GD1c-like LOS. These findings suggest that IgG antibodies against GM1b, GD1c, GalNAc-GM1b, and ganglioside complexes are serological markers for GQ1b-seronegative Fisher syndrome. PMID- 22218650 TI - SOD2 as a potential modifier of X-linked adrenoleukodystrophy clinical phenotypes. AB - X-linked adrenoleukodystrophy (XALD), a neurological disorder caused by mutations in the peroxisomal membrane protein gene ABCD1, presents as a rapidly progressing, inflammatory cerebral demyelination (cerebral cases) or a slowly progressing, distal axonopathy (non-cerebral cases). Specific ABCD1 defects do not explain this significant phenotypic variation. Patients have increased plasma and tissue very long chain fatty acid levels and increased cellular oxidative stress and oxidative damage. Superoxide dismutase 2 (SOD2), at candidate modifier locus 6q25.3, detoxifies superoxide radicals protecting against oxidative stress and damage. We tested an SOD2 variant C47T (Ala16Val) associated with reduced enzymatic activity as a potential modifier gene of cerebral demyelinating disease by comparing 117 cerebral XALD cases with 105 non-cerebral XALD cases. The hypoactive valine allele of the variant was associated with cerebral disease under a dominant model in the full data set (p = 0.04; ORT* = 1.90, 95% CI 1.01 3.56) and the non-childhood cerebral disease subset (p = 0.03; ORT* = 2.47, 95% CI 1.08-5.61). Three tag SNPs were genotyped to test for additional SNP or haplotype associations. A common haplotype, GTAC, which included the SOD2 valine allele, was associated with cerebral disease in the full data set (p = 0.03; OR = 1.75, 95% CI 1.11-2.75) and the non-childhood cerebral disease subset (p = 0.008; OR = 2.20, 95% CI 1.27-3.83). There was no association between childhood cerebral XALD and the C47T variant or the GTAC haplotype. Thus, reduced SOD2 activity may contribute to the development of cerebral demyelination in adolescent and adult XALD patients. PMID- 22218649 TI - Different independent susceptibility markers for first-ever cerebral infarction and myocardial infarction in young patients. AB - Cerebral infarction (CI) and myocardial infarction (MI) share some common features, but there are other differences in risk factors. The aim of our study is to determine whether there are some significantly independent susceptibility markers for them. All consecutive patients between the ages of 18 and 45 years with first-ever CI and MI during 2001-2010 were recruited to participate in the study. Using multivariate logistic regression modeling, we explore many different data, such as age at onset, sex ratio, numbers of patients with history of hypertension, smoking, drinking, and serum lipid, uric acid, prealbumin (PA), and white blood cell (WBC) count levels. Logistic regression analysis adjusted for confounders confirmed the following independent susceptibility markers for young CI patients: hypertension, admission serum PA levels, daily alcohol [odds ratio (OR), 0.251; 95% confidence interval (CI), 0.097-0.648, p = 0.004; OR, 0.994; 95% CI, 0.988-0.999, p = 0.031; OR, 0.150; 95% CI, 0.047-0.473, p = 0.001], and for MI patients: age at onset, current smoking, serum WBC, and glucose levels (OR, 1.293; 95% CI, 1.146-1.457, p = 0.000; OR, 8.914; 95% CI, 3.575-22.231, p = 0.000; OR, 1.344; 95% CI, 1.169-1.544, p = 0.000; OR, 1.149; 95% CI, 1.022-1.291, p = 0.020). We conclude that there are some significantly different independent susceptibility markers for young CI and MI patients. PMID- 22218651 TI - Is there delayed gastric emptying in patients with multiple system atrophy? An analysis using the (13)C-acetate breath test. AB - Autonomic failure is one of the criteria according to the second consensus statement for the diagnosis of multiple system atrophy (MSA). Gastrointestinal symptoms are frequent complaints in patients with MSA and may be associated with reduced gastrointestinal motility due to autonomic nervous system dysfunction. However, there are few reports on gastric emptying in patients with MSA. We investigated gastric emptying in 25 patients with MSA, 20 patients with sporadic adult-onset ataxia of unknown etiology (SAOA), and 20 healthy volunteers using the (13)C-acetate breath test. Gastric emptying function is estimated by this test as the half-emptying time (HET) and peak time of the (13)C-%-dose-excess curve (T (max)), with expirations collected for 4 h after a test meal and determination of (13)CO(2) content using an infrared (IR) spectrophotometer. The HET and T (max) of gastric emptying were significantly delayed in patients with MSA as compared to those in SAOA and controls (p < 0.01). The HET and T (max) were not significantly different between SAOA and controls. No correlation existed between the HET or T (max) and the duration or severity of the disease in MSA patients. These results suggested that gastric emptying was significantly delayed in patients with MSA, and the delay already appeared in the early stage of the disease. Delayed gastric emptying is one of the autonomic failures and may be a clinical marker of MSA. PMID- 22218652 TI - Why did we perform a lumbar puncture in a young patient with ischemic stroke? PMID- 22218653 TI - [Patterns of antiretroviral therapy adoption by the Brazilian public health system]. AB - OBJECTIVE: The aim of the present scientific study is to evaluate the patterns of antiretroviral technology adoption by the Brazilian Public Health System (SUS). METHODS: Based on previous articles published in scientific medical literature, three indicators to assess antiretroviral technology adoption by SUS were proposed: knowledge-adoption interval; critical mass of knowledge; and validation adoption interval. Using the databases from the SUS Department of Information Technology (DATASUS) and from the Brazilian Logistic Center for Medication Control (SICLOM), two pharmaceutical groups were selected (antiretroviral medications and a group of high cost medications). RESULTS: Antiretroviral medications were adopted faster than the high cost medication group when assessed on the basis of "knowledge-adoption" interval and "validation-adoption" interval. Yet, they require a lower "critical mass of knowledge" before adoption. CONCLUSION: Antiretroviral medications have been adopted faster and based on a lower number of scientific medical articles than a selected group of high cost medications. PMID- 22218654 TI - Hepatitis A: seroprevalence and associated factors among schoolchildren of Sao Luis (MA), Brazil. AB - OBJECTIVES: To estimate the prevalence of antibodies to hepatitis A virus (antiVHA-IgG) in children aged 7-14 years from public and private schools, and to identify demographic, socioeconomic and sanitation factors associated with the prevalence of antiVHA-IgG. METHODS: Seroepidemiological study for the detection of IgG antiVHA. It was conducted from April 2002 to April 2004 with 462 elementary school students from Sao Luis, ranging from 7 to 14-years of age. Thirty schools randomly selected took part in the study, with a probability proportional to the number of students enrolled; 23 schools were public and 7 were private. Data was obtained through a structured questionnaire. In order to identify the variables independently associated with IgG antiVHA, the Poisson multiple regression analysis was performed, estimating the adjusted PRs and their 95% confidence intervals. The variables associated with the prevalence of hepatitis A with p < 0 were the only ones that remained in the final model. The level of significance of 0.05 (alpha = 0.05) was adopted. RESULTS: The prevalence of antiVHA-IgG was 64%, 71.5% in public and 36.5% in private schools. After multivariate analysis, age 11 to 14 years, more than one person per bedroom, and less than two bathrooms per household were associated with a higher prevalence of antiVHA-IgG. Higher parental education was associated with lower prevalence of antiVHA-IgG. CONCLUSIONS: Hepatitis A is endemic among schoolchildren in Sao Luis. The prevalence rate was similar to those found in other regions of the country with similar socio-economic and health conditions. Factors historically associated with a higher prevalence of hepatitis A were also identified in this population. PMID- 22218655 TI - [The satisfaction with surgical sterilization provision among the users of the unified health system in a city of Sao Paulo state]. AB - OBJECTIVES: To evaluate the satisfaction with the surgical sterilization performed by Unified Health System (SUS) and to detect factors that can influence the choice between tubal ligation and vasectomy. METHODS: A total of 235 women and 78 men who were sterilized in a five years time period were interviewed. The studied variables included their socio-demographic features, their reason for sterilization, their opinion on the access to the surgery, the counseling, hospital services and the satisfaction with the procedure. RESULTS: Most were married or lived together, had an average of 3.4 living children and a mean of 6.7 years of schooling. They declared that the average monthly per capita income was R$ 212.81. The most of them belonged to the social status C. They were white and Catholics. The most of them found easy to obtain the surgery and the waiting time was appropriate. They become satisfied with the counseling and 99% were satisfied with sterilization. However, one fourth, incorrectly, found that sterilization was easy to reverse. A study on the couples showed important differences on choosing vasectomy or tubal ligation. CONCLUSIONS: The results show that it is necessary for improvement in the information provided to the candidates to sterilization. Although they are satisfied now, they could not be in the future. The evaluation from the perspective of the health service user should take into account not only their opinion, but also their interests. PMID- 22218656 TI - [Investigation in field pharmacoepidemiology: a proposal for the actions of pharmacovigilance in Brazil]. AB - The present article aims to propose and to describe the investigation in field pharmacoepidemiology as having a major role in pharmacovigilance by municipal, state and federal governments to manage drug-related reports, communication and information in the media. First, pharmacovigilance is put into context, by including its concepts, events of interest and main functions. Subsequently, field pharmacoepidemiology investigation oriented to the twelve steps is described. Then, we present a general picture of the investigation in field pharmacoepidemiology conducted in Brazil. Finally, we argue that investigation in field pharmacoepidemiology is an important tool to improve measures in pharmacovigilance and to improve patient safety in the country. PMID- 22218657 TI - Adult mortality from leukemia, brain cancer, amyotrophic lateral sclerosis and magnetic fields from power lines: a case-control study in Brazil. AB - Recent publications renewed interest in assessing potential health risks for subjects living close to transmission lines. This study aimed at evaluating the association of both distance of home address to the nearest overhead transmission line and of the calculated magnetic fields from the power lines and mortality from leukemia, brain cancer, and amyotrophic lateral sclerosis. We carried out a death certificate based case-control study accessing adult mortality in the Metropolitan Region of Sao Paulo, in Brazil. Analysis included 1,857 cases of leukemia, 2,357 of brain cancer, 367 of amyotrophic lateral sclerosis, and 4,706 as controls. An increased risk for mortality from leukemia among adults living at closer distances to transmission lines compared to those living further then 400 m was found. Risk was higher for subjects that lived within 50 m from power lines (OR=1.47; 95% CI=0.99-2.18). Similarly, a small increase in leukemia mortality was observed among adults living in houses with higher calculated magnetic fields (OR=1.61; 95% CI=0.91-2.86 for those exposed to magnetic fields >0.3 uT). No increase was seen for brain tumours or amyotrophic lateral sclerosis. Our findings are suggestive of a higher risk for leukemia among subjects living closer to transmission lines, and for those living at homes with higher calculated magnetic fields, although the risk was limited to lower voltage lines. PMID- 22218658 TI - [Relationship between health care insurance and Papanicolaou exam: a propensity score application using a complex sample inquiry]. AB - Cervical uterine cancer is the second most common malignancy affecting women worldwide. Papanicolaou smear is a simple screening test that can detect the disease at an early and curable stage. Although indicated to every adult woman, Pap smear screening covers less than 70% of Brazilian women. This study aimed to evaluate if private health care insurance coverage was associated with Papanicolaou smear screening. We analyzed data from 6,299 women aged 35 years or older, resident in Rio de Janeiro state, who had been interviewed in the National Household Sample Survey (PNAD) in 2003. In order to minimize the occurrence of biases, we utilized the propensity score matching method, considering all information from sample design in the scores estimation (sample weights, strata and primary sampling units). A sub-sample of 2,348 women was then obtained, with socioeconomic and biological covariates equally distributed between the groups with and without private health insurance coverage (1,174 pairs). Logistic regression model was then used and the results showed that the chance of Papanicolaou smear screening is 26.1% higher (OR=1.261; p=0,096; CI 95%= [0.96;1.66]) for women with health insurance coverage when compared to women without health insurance coverage at 10% of significance. The results indicate the need of extending periodic cervical cancer screening for all women, reducing the inequalities still present nowadays. PMID- 22218659 TI - Pregnancy outcomes in contaminated areas, SP, Brazil. AB - OBJECTIVE: Estimate and compare prevalence of events related to pregnancy (pregnancy, low birth weight, premature delivery, spontaneous abortion, stillbirth, congenital malformation, and multiple births) in populations exposed and non-exposed to environmental contaminants in Santos and Sao Vicente Estuary. METHODS: This study was part of a large project financed by CNPq, which aimed to estimate health effects associated with environmental area, contaminants exposure among individuals of the Baixada Santista region. This cross-sectional study evaluated two neighborhoods of Sao Vicente near a contaminated area, and one neighborhood of Bertioga, the control area. A structured and previously tested questionnaire was applied at 236 households in Sao Vicente and 251 households in Bertioga in order to obtain the data. The chi-square test or Fisher's exact test were used to evaluate associations between area and qualitative variables; Student's t test or two proportion comparison test were used to evaluate differences between variables; and a significance level of 5% adopted. RESULTS: There was significant association between living in Bertioga (p = 0.01) and number of pregnancies in the past five years. In Sao Vicente, 64 (28.3%) childbearing age women became pregnant whereas in Bertioga there where 109 (38.8%). There were no statistical significant associations between living in any area and others pregnancy outcomes evaluated. CONCLUSION: Although no significant association was found, prevalence of low birth weight, preterm delivery and spontaneous abortion and prevalent odds ratio were higher in contaminated area. This study's evidence of a reduced number of pregnancies in contaminated area strengthens the need for additional more in-depth studies in Santos and Sao Vicente Estuary. PMID- 22218660 TI - Sickness-absenteeism, job demand-control model, and social support: a case control study nested in a cohort of hospital workers, Santa Catarina, Brazil. AB - The aim of the study was to identify the Job Demand-Control (JDC) and social support contribution for sickness-absenteeism duration of Health Treatment Licences (HTL) in hospital workers (civil servants) of the Santa Catarina State Department of Health of (SES/SC), Brazil. These health workers have the second highest HTL among civil servants in the state, especially those working in hospitals. This is a case-control study nested in a cohort of hospital workers followed up between 07/01/2008 and 06/30/2009. The workers with HTL in this period were selected as cases and those without HTL were selected as cases matched by sex, age and working sector. The outcome was the duration of HTL and the exposure variables were JDC and supervisor and coworker social support. We used both primary and secondary data, zero-inflated negative binomial regression analysis, and socioeconomic and occupation variables in the adjustments. The data used for analysis included 425 participants (144 cases; 281 controls). Low coworker support added 2,04 (95% confidence interval (CI): 1,05-3,93) HTL days. This effect increased to 2,68 days (95% CI: 1,37-5,27) when combined with low job strain and raised 78% (95% CI: 1,02-3,12) more than JDC with high coworker support combined with high strain (iso-strain). This study uncovered the importance of coworker support for the duration of sickness-absenteeism and suggested its use for the interventions aiming to decrease the duration of HTL. PMID- 22218661 TI - [Ambulatory care utilization in the past 15 years: comparison between two population-based studies]. AB - Profound changes in the Brazilian health system have occurred in the past few decades. Data from two cross-sectional population-based studies carried out in 1992 (n = 1,657) and 2007 (n = 2,706), among individuals from 20-69 years, were compared aiming to describe changes in Pelotas, Brazil. Prevalence of consultations in the past twelve and three months were calculated and stratified by gender. The most recent consultation was analyzed according to place and reason. Utilization in the past year increased from 69.8% to 76.2% (p < 0.001) and in the past three months from 39.5% to 60.6% (p < 0.001). There was an increase in use of authorized services, except for black/brown people who mainly continued using public services (69% in 1992 and 61.8% in 2007). Among men, preventive consultations increased more than ten-fold. In the past fifteen years, most of public demand was absorbed by authorized services. This absorption was not even, black/brown users remained in public services. The greatest increase in preventive consultations by males occurred in the low risk age group (20-39 years). PMID- 22218663 TI - Scheduling delay in suspected cases of oral cancer. AB - The objective of the study was to evaluate scheduling delay of dental exams in the city of Sao Paulo of patients suspected of having oral cancer. A cross sectional study was performed in which telephone conversations simulated clinical situations that represented two types of patients: one presenting symptoms suggestive of oral cancer (CA), and another one suggesting the need for prostheses (PR). The scheduling delay was evaluated by the days until an appointment for care; and among public offices, by type of schedule (emergency or routine). Negative binomial regression was used (95% statistical significance). Five hundred and seventy-five public and private dental offices participated in the study. The mean scheduling delay for the CA group was 2.88 days, and for the PR group, 4.34 days (p = 0.01). The mean scheduling delay was shorter in private dental offices (2.59 days) than in offices that accepted health insurance (2.74 days) (p = 0.01); the delay was shorter when performed by the dentist rather than by the dental assistant, 2.45 versus 4.21 days (p = 0.01). In public services, 69% of patients in the cancer group were sent to the emergency service. Dental services were accessible for scheduling clinical examinations among patients suspected of having oral cancer. PMID- 22218662 TI - [Association between mothers' quality of life and infants' nutritional status]. AB - OBJECTIVE: Determine associations between the quality of life of mothers and the nutritional status of children. METHODS: case-control study involving 152 mothers of children aged zero to five years, living in the coverage area of a basic health unit in the city of Porto Alegre. The calculation of sample size was estimated as 152 mothers - 76 mothers with children at nutritional risk/malnutrition (cases) and 76 mothers with eutrophic children (controls). Information was collected regarding the quality of life of mothers, measured by the instrument of the World Health Organization, and the association between maternal quality of life and nutritional status of children was examined. RESULTS: In relation to the psychiatric realm, for each eutrophic child whose mother has lower quality of life there is a chance of 5.4 children at nutritional risk/malnutrition with mothers in the same condition. In the environmental field, for each eutrophic child whose mother has lower quality of life there is a chance of 2.9 children at nutritional risk/malnutrition with mothers in the same condition. Regarding educational level, for each eutrophic child whose mother has lower quality of life there is a chance of 4.2 children at nutritional risk/malnutrition with mothers in the same condition. CONCLUSIONS: Mothers' low quality of life was associated with an infant in nutritional risk/malnutrition and may be a risk factor for the nutritional status of children. PMID- 22218664 TI - [Incidence of in-hospital adverse events in the State of Rio de Janeiro, Brazil: evaluation of patient medical record]. AB - OBJECTIVE: To evaluate the quality of information obtained from medical records of three teaching hospitals in the State of Rio de Janeiro, Brazil, which participated in a previous study on the incidence of adverse events (AE). METHODS: Descriptive study based on the information collected from medical record review during the incidence study. An evaluation score of completeness, measuring the proportion of absent information was applied, based on the following items: excellent (less than 5%), good (5% - 10%), moderate (11% - 20%), bad (21% - 50%), and very bad (more than 50%). Proportions and 95%confidence intervals were calculated for each variable obtained from medical records. Analysis was developed for the whole group of patients, by hospital groups, and by patients with and without AE. For analyzing the group of variables, means were estimated and the t-student's test was applied for comparisons. The Chi-squared test and Fisher's statistics were applied for comparing patients with and without AE. RESULTS: The quality of information obtained from patient medical records was considered bad in the group of patients as a whole. Variables with the highest proportion of absent information were: "Nurse's first evaluation of the patient" (63.9%) and "Social worker's evaluation" (80%). Hospital 3 had the best results in terms of quality of medical records and hospital 1 had the worst results. The quality of medical records of patients with AE was better than the quality of medical records of patients that had no AE. CONCLUSIONS: Variables considered essential for patient's healthcare were not well documented. Measures to develop quality of medical records are necessary to improve patient's healthcare. PMID- 22218665 TI - [Nutritional and socioeconomic status in adults living in Ribeirao Preto, SP, 2006. OBEDIARP Project]. AB - OBJECTIVE: To estimate overweight and obesity prevalence, and socioeconomic correlates in adults living in Ribeirao Preto city - SP, Brazil, in 2006. METHODS: A cross-sectional population-based epidemiological study was carried out in adults aged 30 years and older using three-stage cluster sampling: 81 census tracts were firstly selected, followed by 1,671 households and 1,205 individuals. The variability introduced in the third sampling fraction (individuals assortment) was corrected, resulting in a weighted sample of 2,197 participants. The nutritional status was classified in three categories (normal, overweight and obesity) according the Body Mass Index (BMI) cut-offs recommended by World Health Organization-2000 criteria. To investigate the nutritional status correlates, prevalence ratios were estimated by points and 95% confidence intervals, using Poisson regression. RESULTS: Overweight prevalence was higher in male (49.7%) than female (33.7%), whereas the obesity prevalence was higher in female (27.5%) than male (19.1%). In the final model, considering "overweight" as the outcome, the following variables were positively associated: the last two strata of age: "50-59" and "60 and older"; the "1st tertile" of income, and living "with partner". Females presented a protective effect compared to males. Considering "obesity", all the "age categories" and "marital status" were positively associated to the outcome. CONCLUSION: Along with the high overweight and obesity prevalences in Ribeirao Preto, the detection of different sets of socioeconomic correlates pointed out the need of specific intervention strategies, focused on health promotion and chronic-degenerative diseases prevention in the population. PMID- 22218666 TI - Comparison of methods to evaluate total body fat and its distribution. AB - OBJECTIVE: To compare two methods for evaluating total body fat and its distribution. METHODS: Cross-sectional, cohort-nested study. Sixty-two women received a nutritional status evaluation which included total body fat (BF) obtained through the sum of skinfolds (SigmaSF) and bioimpedance (BIA). Visceral fat distribution was measured using ultrasonography (USG) (intra-abdominal fat thickness) (IAT) and waist circumference (WC). The concordance correlation coefficient (CCC) and the determination coefficient (r2) were calculated. RESULTS: Mean patient age was 48.19 (8.99) years. Thirty-six women (58.06%) had a very large WC and 42 (67.74%) had high body fat. There was moderate concordance (r2 = 0.42; CCC = 0.59; p < 0.01) between the methods for determining body fat (%) and optimal concordance (r2 = 0.90; CCC = 0.91; p < 0.01) for body fat (kg) determined by BIA and SigmaSF. The comparison between WC and IAT (USG) showed moderate concordance (r2 = 0.49; p < 0.01) between the methods. CONCLUSIONS: Moderate concordance in determining total body fat (%) and optimal concordance in determining body fat (kg) were found between the methods. Moderate concordance was found between the methods for determining body fat distribution. PMID- 22218667 TI - Factors associated with work ability and perception of fatigue among nursing personnel from Amazonia. AB - OBJECTIVE: To analyze factors associated with inadequate work ability and perceived fatigue among nursing professionals. METHODS: A cross-sectional study was conducted involving 272 nursing personnel at an emergency hospital in Rio Branco/State of Acre, Brazil. Data collection was performed using the following instruments: questionnaire on sociodemographic data, working conditions and life styles; the Work Ability Index - WAI, and a questionnaire on perceived fatigue. Bivariate and multiple Poisson regression was used in the analysis of factors associated with work ability and perceived fatigue. RESULTS: The prevalence of inadequate work ability was 40.8% and presented the following associated factors: female sex (RP = 1.84; 95% CI 1.06 - 3.18); refering: other job commitment (RP = 1.71; 1.25 - 2.35); understaffing (RP = 1.96; 1.10 - 3.47); repetitive and monotonous tasks (RP = 1.84; 1.24 - 2.72); reporting three or more clinically undiagnosed morbidities (RP = 1.48; 1.06 - 2.06); excessive reported fatigue (RP = 2.37; 1.81 - 3.12). The prevalence of severe fatigue was 25.7% and the associated factors were: repetitive and monotonous tasks (RP = 1.74; 1.00 - 3.03); reporting three to five clinically-diagnosed morbidities (RP = 1.98; 1.00 3.11) and six or more self-reported morbidities (RP = 3.79; 2.04 - 7.03). CONCLUSIONS: The study revealed that most of the studied population showed reduced work ability and high levels of fatigue. These results point toward the need for interventions on an individual level (such as life conditions) and workplace improvements, looking jointly at the organizational aspects and work environment, particularly organizational aspects. PMID- 22218668 TI - Prevalence and distribution of risk factors for non-communicable chronic diseases among adults from Lages city, south of Brazil, 2007. AB - OBJECTIVE: To describe prevalence and the distribution of risk factors to non communicable chronic diseases among adults from Lages, Santa Catarina, Brazil. METHODS: Probabilistic sample of adult urban population, of both genders and aged from 20 to 59 years old was interviewed (n=2022). The sample process was made through conglomerates. It was applied a structured questionnaire with questions related to demographical, socio-economical, and behavior and self-referred diseases. In this study the following informations, related to the risk/protection factors for non-communicable chronic diseases, were used: gender, age, school background, body mass index, waist circumference, smoking, physical activity, pressure levels, self-referred mellitus diabetes and feeding characteristics. Prevalence for risk/protection factors for non-communicable chronic diseases, in the total population and according to gender and school background, was calculated. RESULTS: The studied population is prone to non communicable chronic diseases, presenting substantial proportions of hypertension (33.78%), overweight individuals (33.46%), obesity (23.46%) and abdominal obesity (43.81%). In relation to feeding characteristics, women presented higher prevalence of behaviors considered as protection factors, relative to men. It was found less than 30.0% of physically inactive individuals and 45.9% of smokers or ex-smokers. CONCLUSION: Descriptive studies such as this could be the basis for the development of public policies specific to the adult population of Lages, in order to guide the organization, planning and quality improvement of health assistance services, aiming the reduction in the occurrence and in the impact of non-communicable chronic diseases. PMID- 22218670 TI - [Evaluation of rabies post-exposure prophylaxis in humans injured by dogs and cats in the municipality of Jaboticabal, SP, from 2000 through 2006]. AB - The present study aimed to evaluate rabies post-exposure prophylaxis (PEP) in humans in the municipality of Jaboticabal, Sao Paulo from 2000 through 2006. A descriptive and retrospective study was conducted by collecting data available in patient records. Vaccination costs were also calculated; 2,493 patients injured by animals received PEP, totaling R$ 179,105.14 and 7,108 doses; 2,184 (71.5%) out of the total reports were caused by dogs and cats clinically healthy at the moment of the attack. These animals remained sound throughout the 10-day observation period. The observation was conducted by the victim or by the owner. Considering animal observation and the epidemiological status of rabies in the municipality, all of these patients could have been dismissed from PEP treatment. Instead, only 464 were dismissed, meaning that 1,720 patients were unnecessarily vaccinated. An estimated 4,590 doses and R$114,420.81 could have been saved. In comparison with rates of other municipalities of the State of Sao Paulo and with the national mean, the number of PEP in Jaboticabal is very high and it became evident that management evaluated neither the health status of the animal nor the epidemiological status of the area for rabies. Permanent awareness and education of public health professionals with respect to rabies epidemiology and the need to perform correct observation of the aggressors are recommended. It is essential that medical and veterinary services be integrated to provide better assessment of cases and safer decisions on the institution of PEP. PMID- 22218669 TI - Fall in homicides in the city of Sao Paulo: an exploratory analysis of possible determinants. AB - Throughout the first decade of the 2000s the homicide mortality rate (HMR) showed a significant reduction in the state and the city of Sao Paulo (MSP). The aim of this study is to describe the trend of HMR, socio-demographic indicators, and the investment in social and public security, and to analyze the correlation between HMR and independent variables in the MSP between 1996 and 2008. An exploratory time series ecological study was conducted. The following variables were included: HMR per 100,000 inhabitants, socio-demographic indicators, and investments in social and public security. The moving-averages for all variables were calculated and trends were analyzed through Simple Linear Regression models. Annual percentage changes, the average annual change and periodic percentage changes were calculated for all variables, and the associations between annual percentage changes were tested by Spearman's correlation analysis. Correlations were found for the proportion of youth in the population (r = 0.69), unemployment rate (r = 0.60), State budget for education and culture (r = 0.87) and health and sanitation (r = 0.56), municipal (r = 0.68) and State (r = 0.53) budget for Public Security, firearms seized (r = 0.69) and the incarceration rate (r = 0.71). The results allow us to support the hypothesis that demographic changes, acceleration of the economy, in particular the fall in unemployment, investment in social policies and changes in public security policies act synergistically to reduce HMR in Sao Paulo. Complex models of analysis, incorporating the joint action of different potential explanatory variables, should be developed. PMID- 22218671 TI - Sleep disturbance in alcoholism: proposal of a simple measurement, and results from a 24-week randomized controlled study of alcohol-dependent patients assessing acamprosate efficacy. AB - AIMS: Sleep disturbance symptom (SDS) is commonly reported in alcoholic patients. Polysomnography studies suggested that acamprosate decreased SDS. We assessed this hypothesis by using data of a randomized controlled trial. As a secondary objective, we suggested and tested the validity of a simple measurement of SDS based on the Hamilton depression and anxiety inventory subset. METHODS: We re analysed a multi-center study evaluating the efficacy of acamprosate compared with placebos on alcohol-dependent patients in concentrating on SDS change in time. The Sleep sum score index (SAEI) was built from check-lists on adverse effects reported at each visit and constituted our main endpoint. We also tested the validity of the short sleep index (SSI) defined by the four sleep items of the Hamilton depression and anxiety scales. Statistical analyses were conducted on an intention to treat basis. RESULTS: A total of 592 patients were included, and 292 completed the 6-month trial. Compared with SAEI considered as our reference, the observed specificity and sensitivity of SSI were 91.6 and 87.6%. From 40.2% of patients experiencing SDS at baseline, this proportion decreased until 26.1% at M6 in the placebo group and 19.5% in the acamprosate group (relative risk placebo/acamprosate = 1.49, 95% confidence interval 1.10, 1.98, P = 0.04). CONCLUSION: Treating alcoholic patients to enhance abstinence has a beneficial effect in reducing SDS, and the duration of abstinence during the treatment constitutes the main positive factor. An additional effect of acamprosate is conjectured from its effect on the glutamatergic tone. The SSI constitutes a simple, reasonably sensitive and specific instrument tool to measure SDS. PMID- 22218672 TI - Thermo-sensitive imprinted polymer coating CdTe quantum dots for target protein specific recognition. AB - A thermo-sensitive imprinted polymer coating CdTe quantum dots was developed to prepare fluorescent thermo-sensitive protein-affinity materials, which exhibited high specific recognition ability towards target proteins. PMID- 22218673 TI - Gene silencing using the recessive rice bacterial blight resistance gene xa13 as a new paradigm in plant breeding. AB - Resistant germplasm resources are valuable for developing resistant varieties in agricultural production. However, recessive resistance genes are usually overlooked in hybrid breeding. Compared with dominant traits, however, they may confer resistance to different pathogenic races or pest biotypes with different mechanisms of action. The recessive rice bacterial blight resistance gene xa13, also involved in pollen development, has been cloned and its resistance mechanism has been recently characterized. This report describes the conversion of bacterial blight resistance mediated by the recessive xa13 gene into a dominant trait to facilitate its use in a breeding program. This was achieved by knockdown of the corresponding dominant allele Xa13 in transgenic rice using recently developed artificial microRNA technology. Tissue-specific promoters were used to exclude most of the expression of artificial microRNA in the anther to ensure that Xa13 functioned normally during pollen development. A battery of highly bacterial blight resistant transgenic plants with normal seed setting rates were acquired, indicating that highly specific gene silencing had been achieved. Our success with xa13 provides a paradigm that can be adapted to other recessive resistance genes. PMID- 22218674 TI - The use of plants for the production of therapeutic human peptides. AB - Peptides have unique properties that make them useful drug candidates for diverse indications, including allergy, infectious disease and cancer. Some peptides are intrinsically bioactive, while others can be used to induce precise immune responses by defining a minimal immunogenic region. The limitations of peptides, such as metabolic instability, short half-life and low immunogenicity, can be addressed by strategies such as multimerization or fusion to carriers, to improve their pharmacological properties. The remaining major drawback is the cost of production using conventional chemical synthesis, which is also difficult to scale-up. Over the last 15 years, plants have been shown to produce bioactive and immunogenic peptides economically and with the potential for large-scale synthesis. The production of peptides in plants is usually achieved by the genetic fusion of the corresponding nucleotide sequence to that of a carrier protein, followed by stable nuclear or plastid transformation or transient expression using bacterial or viral vectors. Chimeric plant viruses or virus-like particles can also be used to display peptide antigens, allowing the production of polyvalent vaccine candidates. Here we review progress in the field of plant derived peptides over the last 5 years, addressing new challenges for diverse pathologies. PMID- 22218677 TI - Seroprevalence of human polyomavirus 9 and cross-reactivity to African green monkey-derived lymphotropic polyomavirus. AB - Human polyomavirus 9 (HPyV9) was discovered recently in immunocompromised patients and shown to be genetically closely related to B-lymphotropic polyomavirus (LPyV). No serological data are available for HPyV9, but human antibodies against LPyV have been reported previously. To investigate the seroepidemiology of HPyV9 and the sero-cross-reactivity between HPyV9 and LPyV, a capsomer-based IgG ELISA was established using the major capsid protein VP1 of HPyV9 and LPyV. VP1 of an avian polyomavirus was used as control. For HPyV9, a seroprevalence of 47 % was determined in healthy adults and adolescents (n = 328) and 20 % in a group of children (n =101). In both groups, the seroreactivities for LPyV were less frequent and the ELISA titres of LPyV were lower. Of the HPyV9 reactive sera, 47 % reacted also with LPyV, and the titres for both PyVs correlated. Sera from African green monkeys, the natural hosts of LPyV, reacted also with both HPyV9 and LPyV, but here the HPyV9 titres were lower. This potential sero-cross-reactivity between HPyV9 and LPyV was confirmed by competition assays, and it was hypothesized that the reactivity of human sera against LPyV may generally be due to cross-reactivity between HPyV9 and LPyV. The HPyV9 seroprevalence of liver transplant recipients and patients with neurological dysfunctions did not differ from that of age-matched controls, but a significantly higher seroprevalence was determined in renal and haematopoietic stem-cell transplant recipients, indicating that certain immunocompromised patient groups may be at a higher risk for primary infection with or for reactivation of HPyV9. PMID- 22218675 TI - OsPFA-DSP1, a rice protein tyrosine phosphatase, negatively regulates drought stress responses in transgenic tobacco and rice plants. AB - Dephosphorylation plays a pivotal role in regulating plant growth, development and abiotic/biotic stress responses. Here, we characterized a plant and fungi atypical dual-specificity phosphatase (PFA-DSP) subfamily member, OsPFA-DSP1, from rice. OsPFA-DSP1 was determined to be a functional protein tyrosine phosphatase (PTP) in vitro using phosphatase activity assays. Quantitative real time PCR and GENEVESTIGATOR analysis showed that OsPFA-DSP1 mRNA was induced by drought stress. Transfection of rice protoplasts showed that OsPFA-DSP1 accumulated in both the cytoplasm and nucleus. Ectopic overexpression of OsPFA DSP1 in tobacco increased sensitivity to drought stress and insensitivity to ABA induced stomatal closure and inhibition of stomatal opening. Furthermore, overexpression of OsPFA-DSP1 in rice also increased sensitivity to drought stress. These results indicated that OsPFA-DSP1 is a functional PTP and may act as a negative regulator in drought stress responses. PMID- 22218676 TI - A microsatellite linkage map for the cultivated strawberry (Fragaria * ananassa) suggests extensive regions of homozygosity in the genome that may have resulted from breeding and selection. AB - The linkage maps of the cultivated strawberry, Fragaria * ananassa (2n = 8x = 56) that have been reported to date have been developed predominantly from AFLPs, along with supplementation with transferrable microsatellite (SSR) markers. For the investigation of the inheritance of morphological characters in the cultivated strawberry and for the development of tools for marker-assisted breeding and selection, it is desirable to populate maps of the genome with an abundance of transferrable molecular markers such as microsatellites (SSRs) and gene-specific markers. Exploiting the recent release of the genome sequence of the diploid F. vesca, and the publication of an extensive number of polymorphic SSR markers for the genus Fragaria, we have extended the linkage map of the 'Redgauntlet' * 'Hapil' (RG * H) mapping population to include a further 330 loci, generated from 160 primer pairs, to create a linkage map for F. * ananassa containing 549 loci, 490 of which are transferrable SSR or gene-specific markers. The map covers 2140.3 cM in the expected 28 linkage groups for an integrated map (where one group is composed of two separate male and female maps), which represents an estimated 91% of the cultivated strawberry genome. Despite the relative saturation of the linkage map on the majority of linkage groups, regions of apparent extensive homozygosity were identified in the genomes of 'Redgauntlet' and 'Hapil' which may be indicative of allele fixation during the breeding and selection of modern F. * ananassa cultivars. The genomes of the octoploid and diploid Fragaria are largely collinear, but through comparison of mapped markers on the RG * H linkage map to their positions on the genome sequence of F. vesca, a number of inversions were identified that may have occurred before the polyploidisation event that led to the evolution of the modern octoploid strawberry species. PMID- 22218678 TI - dsRNA provides sequence-dependent protection against infectious myonecrosis virus in Litopenaeus vannamei. AB - Viral diseases are significant impediments to the sustainability of shrimp aquaculture. In addition to endemic disease, new viral diseases continue to emerge and cause significant impact on the shrimp industry. Disease caused by infectious myonecrosis virus (IMNV) has caused tremendous losses in farmed Pacific white shrimp (Litopenaeus vannamei) since it emerged in Brazil and translocated to Indonesia. There are no existing antiviral interventions, outside of pathogen exclusion, to mitigate disease in commercial shrimp operations. Here, we describe an iterative process of panning the genome of IMNV to discover RNA interference trigger sequences that initiate a robust and long-lasting protective response against IMNV in L. vannamei. Using this process, a single, low dose (0.02 ug) of an 81 or 153 bp fragment, with sequence corresponding to putative cleavage protein 1 in ORF1, protected 100 % of animals from disease and mortality caused by IMNV. Furthermore, animals that were treated with highly efficacious dsRNA survived an initial infection and were resistant to subsequent infections over 50 days later with a 100-fold greater dose of virus. This protection is probably sequence dependent, because targeting the coding regions for the polymerase or structural genes of IMNV conferred lesser or no protection. Interestingly, non-sequence specific dsRNA did not provide any degree of protection to animals as had been described for other shrimp viruses. Our data indicate that the targeted region for dsRNA is a crucial factor in maximizing the degree of protection and lowering the dose required to induce a protective effect against IMNV infection in shrimp. PMID- 22218679 TI - Signatures of natural selection in a primate bitter taste receptor. AB - Bitter taste receptors (TAS2Rs) enable animals to detect and avoid toxins in the environment, including noxious defense compounds produced by plants. This suggests that TAS2Rs are under complex pressures from natural selection. To investigate these pressures, we examined signatures of selection in the primate TAS2R38 gene. Whole-gene (1,002 bp) sequences from 40 species representing all major primate taxa uncovered extensive variation. Nucleotide substitutions occurred at 448 positions, resulting in 201 amino acid changes. Two single nucleotide deletions, one three-nucleotide in-frame deletion, and one premature stop codon were also observed. The rate of non-synonymous substitution (omega = dN/dS), was high in TAS2R38 (omega = 0.60) compared to other genes, but significantly lower than expected under neutrality (P = 4.0 * 10(-9)), indicating that purifying selection has maintained the basic structure of the receptor. However, differences were present among receptor subregions. Non-synonymous rates were significantly lower than expected in transmembrane domains (omega = 0.55, P = 1.18 * 10(-12)) and internal loops (omega = 0.51, P = 7.04 * 10(-5)), but not external loops (omega = 1.16, P = 0.53), and evidence of positive selection was found in external loop 2, which exhibited a high rate (omega = 2.53) consistent with rapid shifts in ligand targeting. These patterns point to a history of rapid yet constrained change in bitter taste responses in the course of primate evolution. PMID- 22218680 TI - Diffusion-controlled sensitization of photocleavage reactions on surfaces. AB - The kinetic rate equation for the photosensitized cleavage reaction of surface bound photolabile chromophores with free diffusion of sensitizer molecules from the bulk of a solution to the surface is derived by determining the stationary solution of a diffusion equation with suitable boundary conditions. The relation between the phenomenological rate constant for the photosensitized reaction at the surface and in the bulk is established. Applying the result to the analysis of an experimental example, the origin of the quasi zeroth-order kinetics of the sensitized reaction is revealed. A theoretical comparison of intramolecular sensitization in photocleavable protecting groups with a molecular antenna and sensitization with the freely diffusing sensitizer shows that in a typical case sensitization with free diffusion is more effective than intramolecular sensitization for sensitizer concentrations higher than 5 mM. PMID- 22218683 TI - Role of MexAB-OprM in intrinsic resistance of Pseudomonas aeruginosa to temocillin and impact on the susceptibility of strains isolated from patients suffering from cystic fibrosis. PMID- 22218684 TI - The blues of P(16)INK(4a): aberrant promoter methylation and association with colorectal cancer in the Kashmir valley. AB - Hypermethylation of the promoter region of the p16INK4a (p16) gene plays a significant role in the development and progression of colorectal cancer (CRC). The aim of the present study was to establish the role of the methylation status of the p16 gene in 114 CRC cases and to correlate it with the various clinicopathological parameters. Analysis of p16 promoter methylation was performed by methylation-specific PCR. Forty-eight (42.1%) of the CRC cases were found to be methylated for the p16 gene in our population. The methylation status was found to be associated with the gender, lymph node status, tumour stage, smoking status and tumour grade of the CRC patients. p16 plays a pivotal role in tumour development and progression to advanced stages. PMID- 22218689 TI - Chimp virus makes a savvy vaccine vector. PMID- 22218690 TI - Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man. AB - Currently, no vaccine exists for hepatitis C virus (HCV), a major pathogen thought to infect 170 million people globally. Many studies suggest that host T cell responses are critical for spontaneous resolution of disease, and preclinical studies have indicated a requirement for T cells in protection against challenge. We aimed to elicit HCV-specific T cells with the potential for protection using a recombinant adenoviral vector strategy in a phase 1 study of healthy human volunteers. Two adenoviral vectors expressing NS proteins from HCV genotype 1B were constructed based on rare serotypes [human adenovirus 6 (Ad6) and chimpanzee adenovirus 3 (ChAd3)]. Both vectors primed T cell responses against HCV proteins; these T cell responses targeted multiple proteins and were capable of recognizing heterologous strains (genotypes 1A and 3A). HCV-specific T cells consisted of both CD4+ and CD8+ T cell subsets; secreted interleukin-2, interferon-gamma, and tumor necrosis factor-alpha; and could be sustained for at least a year after boosting with the heterologous adenoviral vector. Studies using major histocompatibility complex peptide tetramers revealed long-lived central and effector memory pools that retained polyfunctionality and proliferative capacity. These data indicate that an adenoviral vector strategy can induce sustained T cell responses of a magnitude and quality associated with protective immunity and open the way for studies of prophylactic and therapeutic vaccines for HCV. PMID- 22218691 TI - Vaccine vectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species. AB - Replication-defective adenovirus vectors based on human serotype 5 (Ad5) induce protective immune responses against diverse pathogens and cancer in animal models, as well as elicit robust and sustained cellular immunity in humans. However, most humans have neutralizing antibodies to Ad5, which can impair the immunological potency of such vaccines. Here, we show that rare serotypes of human adenoviruses, which should not be neutralized in most humans, are far less potent as vaccine vectors than Ad5 in mice and nonhuman primates, casting doubt on their potential efficacy in humans. To identify novel vaccine carriers suitable for vaccine delivery in humans, we isolated and sequenced more than 1000 adenovirus strains from chimpanzees (ChAd). Replication-defective vectors were generated from a subset of these ChAd serotypes and screened to determine whether they were neutralized by human sera and able to grow in human cell lines. We then ranked these ChAd vectors by immunological potency and found up to a thousandfold variation in potency for CD8+ T cell induction in mice. These ChAd vectors were safe and immunologically potent in phase 1 clinical trials, thereby validating our screening approach. These data suggest that the ChAd vectors developed here represent a large collection of non-cross-reactive, potent vectors that may be exploited for the development of new vaccines. PMID- 22218693 TI - NEW: network-enabled wisdom in biology, medicine, and health care. AB - Complete repertoires of molecular activity in and between tissues provided by new high-dimensional "omics" technologies hold great promise for characterizing human physiology at all levels of biological hierarchies. The combined effects of genetic and environmental perturbations at any level of these hierarchies can lead to vicious cycles of pathology and complex systemic diseases. The challenge lies in extracting all relevant information from the rapidly increasing volumes of omics data and translating this information first into knowledge and ultimately into wisdom that can yield clinically actionable results. Here, we discuss how molecular networks are central to the implementation of this new biology in medicine and translation to preventive and personalized health care. PMID- 22218692 TI - Paracrine signaling through MYCN enhances tumor-vascular interactions in neuroblastoma. AB - Neuroblastoma, a tumor of peripheral neural crest origin, numbers among the most common childhood cancers. Both amplification of the proto-oncogene MYCN and increased neoangiogenesis mark high-risk disease. Because angiogenesis is regulated by phosphatidylinositol 3-kinase (PI3K), we tested a clinical PI3K inhibitor, NVP-BEZ235, in MYCN-dependent neuroblastoma. NVP-BEZ235 decreased angiogenesis and improved survival in both primary human (highly pretreated recurrent MYCN-amplified orthotopic xenograft) and transgenic mouse models for MYCN-driven neuroblastoma. Using both gain- and loss-of-function approaches, we demonstrated that the antiangiogenic efficacy of NVP-BEZ235 depended critically on MYCN in vitro and in vivo. Thus, clinical PI3K/mammalian target of rapamycin inhibitors drove degradation of MYCN in tumor cells, with secondary paracrine blockade of angiogenesis. Our data demonstrated significantly improved survival in treated animals and suggest that NVP-BEZ235 should be tested in children with high-risk, MYCN-amplified neuroblastoma. PMID- 22218697 TI - A neonate with long QT syndrome, refractory ventricular arrhythmias, and lidocaine toxicity. AB - Long QT syndrome is characterized by electrocardiographic appearance of long QT intervals and propensity to polymorphic ventricular tachycardia. Aggressive anticipatory clinical management is required for a good outcome, especially in the symptomatic neonate. We present a neonate with a compound mutation with refractory ventricular tachycardia that necessitated multimodal pharmacotherapy with lidocaine, esmolol, and amiodarone along with ventricular pacing. Despite normal serum lidocaine levels, complex pharmacokinetic interactions resulted in presumed neurotoxicity due to lidocaine. This report discusses the implications and challenges of management of a neonate with compound long mutations. PMID- 22218698 TI - The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes. AB - AIMS/HYPOTHESIS: Diagnosing MODY is difficult. To date, selection for molecular genetic testing for MODY has used discrete cut-offs of limited clinical characteristics with varying sensitivity and specificity. We aimed to use multiple, weighted, clinical criteria to determine an individual's probability of having MODY, as a crucial tool for rational genetic testing. METHODS: We developed prediction models using logistic regression on data from 1,191 patients with MODY (n = 594), type 1 diabetes (n = 278) and type 2 diabetes (n = 319). Model performance was assessed by receiver operating characteristic (ROC) curves, cross-validation and validation in a further 350 patients. RESULTS: The models defined an overall probability of MODY using a weighted combination of the most discriminative characteristics. For MODY, compared with type 1 diabetes, these were: lower HbA(1c), parent with diabetes, female sex and older age at diagnosis. MODY was discriminated from type 2 diabetes by: lower BMI, younger age at diagnosis, female sex, lower HbA(1c), parent with diabetes, and not being treated with oral hypoglycaemic agents or insulin. Both models showed excellent discrimination (c-statistic = 0.95 and 0.98, respectively), low rates of cross validated misclassification (9.2% and 5.3%), and good performance on the external test dataset (c-statistic = 0.95 and 0.94). Using the optimal cut-offs, the probability models improved the sensitivity (91% vs 72%) and specificity (94% vs 91%) for identifying MODY compared with standard criteria of diagnosis <25 years and an affected parent. The models are now available online at www.diabetesgenes.org . CONCLUSIONS/INTERPRETATION: We have developed clinical prediction models that calculate an individual's probability of having MODY. This allows an improved and more rational approach to determine who should have molecular genetic testing. PMID- 22218700 TI - Trace metal impurities in catalysis. AB - Metal-catalysed transformations are a powerful tool in organic chemistry and the enormous progress, which has been made in the last few decades, was one more time honoured by the Nobel Prize in Chemistry in 2010. Many metal-containing compounds have been applied in carbon-carbon and carbon-heteroatom bond formations. However, not every component originally claimed as catalyst turned out to be the active ingredient in the end. Sometimes trace metal impurities were the actual catalytic species. In this tutorial review, we will highlight recent findings in transition metal-catalysed cross-coupling reactions and detail several reports from the past, which illustrate that "trace metal catalysis" is not a newly discovered phenomenon. PMID- 22218701 TI - A quartz nanopillar hemocytometer for high-yield separation and counting of CD4(+) T lymphocytes. AB - We report the development of a novel quartz nanopillar (QNP) array cell separation system capable of selectively capturing and isolating a single cell population including primary CD4(+) T lymphocytes from the whole pool of splenocytes. Integrated with a photolithographically patterned hemocytometer structure, the streptavidin (STR)-functionalized-QNP (STR-QNP) arrays allow for direct quantitation of captured cells using high content imaging. This technology exhibits an excellent separation yield (efficiency) of ~95.3 +/- 1.1% for the CD4(+) T lymphocytes from the mouse splenocyte suspensions and good linear response for quantitating captured CD4(+) T-lymphoblasts, which is comparable to flow cytometry and outperforms any non-nanostructured surface capture techniques, i.e. cell panning. This nanopillar hemocytometer represents a simple, yet efficient cell capture and counting technology and may find immediate applications for diagnosis and immune monitoring in the point-of-care setting. PMID- 22218702 TI - Neural regenerative strategies incorporating biomolecular axon guidance signals. AB - There are currently no acceptable cures for central nervous system injuries, and damage induced large gaps in the peripheral nervous system have been challenging to bridge to restore neural functionality. Innervation by neurons is made possible by the growth cone. This dynamic structure is unique to neurons, and can directly sense physical and chemical activity in its environment, utilizing these cues to propel axons to precisely reach their targets. Guidance can occur through chemoattractive factors such as neurotrophins and netrins, chemorepulsive agents like semaphorins and slits, or contact-mediated molecules such as ephrins and those located in the extracellular matrix. The understanding of biomolecular activity during nervous system development and injury has generated new techniques and tactics for improving and restoring function to the nervous system after injury. This review will focus on the major neuronal guidance molecules and their utility in current tissue engineering and neural regenerative strategies. PMID- 22218703 TI - Masked red-emitting carbopyronine dyes with photosensitive 2-diazo-1-indanone caging group. AB - Caged near-IR emitting fluorescent dyes are in high demand in optical microscopy but up to now were unavailable. We discovered that the combination of a carbopyronine dye core and a photosensitive 2-diazo-1-indanone residue leads to masked near-IR emitting fluorescent dyes. Illumination of these caged dyes with either UV or visible light (lambda < 420 nm) efficiently generates fluorescent compounds with absorption and emission at 635 nm and 660 nm, respectively. A high yielding synthetic route with attractive possibilities for further dye design is described in detail. Good photostability, high contrast, and a large fluorescence quantum yield after uncaging are the most important features of the new compounds for non-invasive imaging in high-resolution optical microscopy. For use in immunolabelling the caged dyes were decorated with a (hydrophilic) linker and an (activated) carboxyl group. PMID- 22218699 TI - Canine models of Duchenne muscular dystrophy and their use in therapeutic strategies. AB - Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which the loss of dystrophin causes progressive degeneration of skeletal and cardiac muscle. Potential therapies that carry substantial risk, such as gene- and cell based approaches, must first be tested in animal models, notably the mdx mouse and several dystrophin-deficient breeds of dogs, including golden retriever muscular dystrophy (GRMD). Affected dogs have a more severe phenotype, in keeping with that of DMD, so may better predict disease pathogenesis and treatment efficacy. Various phenotypic tests have been developed to characterize disease progression in the GRMD model. These biomarkers range from measures of strength and joint contractures to magnetic resonance imaging. Some of these tests are routinely used in clinical veterinary practice, while others require specialized equipment and expertise. By comparing serial measurements from treated and untreated groups, one can document improvement or delayed progression of disease. Potential treatments for DMD may be broadly categorized as molecular, cellular, or pharmacologic. The GRMD model has increasingly been used to assess efficacy of a range of these therapies. A number of these studies have provided largely general proof-of-concept for the treatment under study. Others have demonstrated efficacy using the biomarkers discussed. Importantly, just as symptoms in DMD vary among patients, GRMD dogs display remarkable phenotypic variation. Though confounding statistical analysis in preclinical trials, this variation offers insight regarding the role that modifier genes play in disease pathogenesis. By correlating functional and mRNA profiling results, gene targets for therapy development can be identified. PMID- 22218704 TI - Tailor-made ultrathin manganese oxide nanostripes: 'magic widths' on Pd(1 1 N) terraces. AB - The growth of ultrathin two-dimensional manganese oxide nanostripes on vicinal Pd(1 1 N) surfaces leads to particular stable configurations for certain combinations of oxide stripe and substrate terrace widths. Scanning tunneling microscopy and high-resolution low-energy electron diffraction measurements reveal highly ordered nanostructured surfaces with excellent local and long-range order. Density functional theory calculations provide the physical origin of the stabilization mechanism of 'magic width' stripes in terms of a finite-size effect, caused by the significant relaxations observed at the stripe boundaries. PMID- 22218705 TI - A compact and highly fluorescent orange-emitting polymer dot for specific subcellular imaging. AB - We demonstrate a new compact CN-PPV dot, which emits in the orange wavelength range with high brightness. The small particle size, high brightness, and the ability to highly specifically target subcellular structures make the CN-PPV dots promising probes for biological imaging and bioanalytical applications. PMID- 22218706 TI - Synthesis and structural characterization of two-coordinate low-valent 14-group metal complexes bearing bulky bis(amido)silane ligands. AB - A series of germylene, stannylene and plumbylene complexes [eta(2)(N,N) Me(2)Si(DippN)(2)Ge:] (3a), [eta(2)(N,N)-Ph(2)Si(DippN)(2)Ge:] (3b), [eta(2)(N,N) Me(2)Si(DippN)(2)Sn:] (4), [eta(2)(N,N)-Me(2)Si(DippN)(2)Pb:](2) (5a), and [eta(2)(N,N)-Ph(2)Si(DippN)(2)Pb:] (5b) (Dipp = 2,6-iPr(2)C(6)H(3)) bearing bulky bis(amido)silane ligands were readily prepared either by the transamination of M[N(SiMe(3))(2)](2) (M = Sn, Pb) and [Me(2)Si(DippNH)(2)] or by the metathesis reaction of bislithium bis(amido)silane [eta(1)(N),eta(1)(N)-R(2)Si(DippNLi)(2)] (R = Me, Ph) with the corresponding metal halides GeCl(2)(dioxane), SnCl(2), and PbCl(2), respectively. Preliminary atom-transfer chemistry involving [eta(2)(N,N) Me(2)Si(DippN)(2)Ge:] (3a) with oxygen yielded a dimeric oxo-bridged germanium complex [eta(2)(N,N)-Me(2)Si(DippN)(2)Ge(MU-O)](2) (6). All complexes were characterized by (1)H, (13)C, (119)Sn NMR, IR, and elemental analysis. X-ray single crystal diffraction analysis revealed that the metal centres in 3b, 4, and 5b are sterically protected to prevent interaction between the metal centre and the nitrogen donors of adjacent molecules while complex 5a shows a dimeric feature with a strong intermolecular Pb...N interaction. PMID- 22218707 TI - Depositional history of polychlorinated biphenyls in a dated sediment core from the northwestern Arabian Gulf. AB - The vertical distribution of polychlorinated biphenyls (PCBs) was measured in a dated sediment core from the northwestern Arabian Gulf to reconstruct their depositional history. The downcore profile showed an increase in concentrations from depth to a subsurface maximum of approximately 1,500 pg g(-1) in approximately 1991, followed by an exponential decrease to the sediment-water interface. Current concentrations of SigmaPCBs are similar to levels predating the episodic input of PCBs in sediments dated coincident with the 1991 Arabian Gulf war. The spike in SigmaPCB concentrations during the war may be related to the destruction of PCB-laden transformers during the conflict. The 15-fold decrease in SigmaPCB concentrations from the period of maximum flux to prewar levels suggests that the factors delivering PCBs to sediments at present are similar to those that that existed before the war-related inputs. PMID- 22218708 TI - Atypical teratoid rhabdoid tumor located in the pineal region following prophylactic irradiation for acute lymphoblastic leukemia. AB - Atypical teratoid rhabdoid tumor (AT/RT) is a rare entity. In the central nervous system, AT/RT generally arises from the posterior fossa of infants and behaves aggressively. AT/RT is reported to arise from the infratentorial region (63%) and other sites, such as the suprasellar region, cerebellopontine angle, and spinal cord. The pineal region is rare (6%) as a site of origin. Radiation-induced brain tumors are well known. In this report, we present a case of a pineal region tumor causing acute hydrocephalus that could be pathologically diagnosed as AT/RT following prophylactic cranial irradiation for acute lymphoblastic leukemia. PMID- 22218709 TI - Glioblastoma angiogenesis: VEGF resistance solutions and new strategies based on molecular mechanisms of tumor vessel formation. AB - Glioblastomas are highly vascular tumors. Recent preclinical and clinical investigations have revealed that agents targeting angiogenesis may have efficacy against this type of tumor. Antibodies to vascular endothelial growth factor are being studied in this patient population. Unfortunately, treatment inevitably fails. This review provides an update on recent research on the mechanisms by which tumor cells acquire resistance, and discusses recent preclinical and experimental development of novel new-generation anti-angiogenic agents that overcome this problem, especially those based on the molecular mechanisms of tumor vessel formation. The tumor vasculature not only nourishes glioblastomas, but also provides a specialized microenvironment for tumor stem-like cells and for the brain tumor. The factors, pathways, and interactions described in this review provide information about the cell biology of glioblastomas which may ultimately result in new modes of treatment. PMID- 22218710 TI - Rhegmatogenous retinal detachment after LASIK for myopia of up to -10 diopters: 10 years of follow-up. AB - BACKGROUND: The aim of this work was to characterize rhegmatogenous retinal detachment (RRD) in over 22,000 eyes after laser-assisted in situ keratomileusis (LASIK) for the correction of myopia <= -10.00 diopters (D), its characteristics, and its frequency at 10 years of follow-up. METHODS: This is a retrospective single-center interventional non-comparative case series. A total of 22,296 myopic eyes that underwent surgical correction of myopia <= -10.00 D were included. LASIK for the correction of myopia was performed in all eyes. Patients were followed for 10 years after LASIK. The clinical charts of patients that developed rhegmatogenous retinal detachment (RRD) after LASIK were reviewed. RESULTS: A total of 11,594 (52%) eyes came back for follow-up after LASIK at 10 years. Twenty-two eyes (19 patients) developed a RRD after LASIK at 10 years. Rhegmatogenous retinal detachments occurred between 1 month and 10 years (mean: 31.6 +/- 39.3 months) after LASIK. Eyes that developed a RRD had from -1.50 to 9.75 D of myopia (mean: -4.81 +/- 2.2 D) before LASIK. The frequency of RRD after LASIK determined in our study was 0.05% (11/22,296) at 1 year, 0.15% (18/11,371) at 5 years, and 0.19% (22/11,594) at 10 years. CONCLUSIONS: Rhegmatogenous retinal detachment after LASIK for the correction of myopia <= -10.00 D is infrequent. The risk of RRD after LASIK is very low if you screen patients, and do prophylactic treatment as performed in this study. RRD, if managed promptly, will result in good vision. We recommend that patients scheduled for refractive surgery undergo a very thorough dilated indirect funduscopy with scleral depression and treatment of any retinal lesion predisposing to the development of a RRD before LASIK surgery should be performed. PMID- 22218711 TI - Analysis of agreement of assessment tools of body balance in the elderly. AB - BACKGROUND: The diagnosis of clinical parameters associated with falls in the elderly has become a major challenge for the scientific community. Despite the existence of several tools aiming to assess body balance in the elderly, it is still scarce the number of studies that have investigated and discussed the agreement between different methods. OBJECTIVE: To analyze the correlation between tests used to assess the body balance in the elderly. METHODS: This was a cross-sectional, observational study conducted with 30 healthy female community dwelling elderly volunteers with different levels of physical conditioning. The Functional Reach Test (FRT), the Berg Balance Scale (BBS), the Timed Up and Go (TUG) and the Performance-Oriented Mobility Assessment of Balance (POMA) were used. The data analysis was performed by using the Spearmam's rank correlation coefficient, with a significance level of 5% (p<0.05). RESULTS: There was positive and moderate correlation between the FRT and BBS (r=0.4845, p=0.0067), between FRT and POMA (r=0.4136, p=0.0231), and between BBS and POMA (r=0.6088, p=0.0004). CONCLUSION: The tests are complementary since they showed specific and distinct limitations. It is reasonable, therefore, to use these instruments together to get better assessment of elderly body balance. PMID- 22218712 TI - Impaired functional capacity and exacerbation of pain and exertion during the 6 minute walk test in women with fibromyalgia. AB - BACKGROUND: Fibromyalgia has been association with physical performance limitations. Additionally, activities of daily living have been reported to be directly associated with the exacerbation of pain and perceived exertion in this patient population. OBJECTIVES: To compare the performance of a 6-minute walk (6MWT) test in patients with fibromyalgia and controls and to evaluate the relationship between test performance and quality of life, limitations of activities of daily living and physical activity level. METHODS: The study included 19 women with fibromyalgia (FM) and 20 healthy controls (CG). A 6MWT was conducted and pain intensity and perceived effort (PE) were assessed during the test. In addition, Fibromyalgia Impact Questionnaire (FIQ), Health Assessment Questionnaire (HAQ) and International Physical Activity Questionnaire (IPAQ) were applied. RESULTS: The fibromyalgia group walked significantly shorter distances when compared to the control group (FM: 473.52+/-77.84 m vs. CG: 541.75+/-85.62 m; p=0.02). In the fibromyalgia group, there was a negative correlation between distance in 6MWT and FIQ (r=-0.46; p=0.05), HAQ (r=-0.49; p=0.03) and oxygen consumption (r=0.78; p<0.01). There was also a correlation between HAQ and oxygen consumption (r=0.52; p=0.02). Participants with fibromyalgia had higher pain intensity and perceived effort during the test when compared to the control group. CONCLUSIONS: Women with fibromyalgia had greater impaired of functional capacity, exacerbation of pain and exertion during the 6MWT when compared to healthy women. PMID- 22218713 TI - Perpectives and challenges of the triennium 2010-2012 for the postgraduate programs of the area 21 by CAPES. PMID- 22218715 TI - The JAK2-Akt-glycogen synthase kinase-3beta signaling pathway is involved in toll like receptor 2-induced monocyte chemoattractant protein-1 regulation. AB - Monocyte chemoattractant protein-1 (MCP-1) is an essential cytokine for the migration of monocytes into vessels, and is also involved in the pathogenesis of atherosclerosis. In this study, we investigated the importance of janus kinase 2 (JAK2) and the function of the Akt and glycogen synthase kinase-3beta (GSK3beta) pathway in toll-like receptor (TLR2)-mediated MCP-1 expression. The TLR2 agonist, Pam3CSK4, induced MCP-1 expression in the Raw264.7 cell line. The induction of MCP-1 was seen in the bone marrow-derived macrophages of wild-type mice but not in TLR2 knockout mice. The TLR2-mediated MCP-1 induction was myeloid differentiation primary response gene 88 (MyD88)-independent. By contrast, the inactivation of JAK2 attenuated TLR2-mediated MCP-1 expression. The JAK inhibitor suppressed the phosphorylation of GSK3beta as well as Akt by Pam3CSK4 stimulation. While the inactivation of Akt by LY294002 suppressed TLR2-mediated MCP-1 induction, the inactivation of GSK3beta by LiCl potentiated TLR2-mediated MCP-1 induction. Furthermore, Akt inhibitor suppressed TLR2-mediated phosphorylation of GSK3beta. Taken together, these results suggest that a MyD88 independent pathway exists in TLR2 signaling; the JAK2-Akt-GSK3beta pathway is a novel MyD88-independent pathway for MCP-1 induction. PMID- 22218717 TI - The diagnostic value of Ki-67, P53 and P63 in distinguishing partial Hydatidiform mole from hydropic abortion. AB - BACKGROUND AND AIMS: The aim of the present study was to investigate the expression of Ki-67, P53 and P63 in hydropic abortion and partial mole and to explore possible role of these three parameters in distinguishing partial mole from hydropic. METHODS: The hydropic abortion (n = 13) and partial mole (n = 23) were retrieved from the files of 2002 to 2010 at the Department of Pathology, Peking University People's Hospital and Department of Pathology, Haidian Maternal and Child Health Hospita1. All cases had typical histological features and complete clinical information. All pathologic diagnoses were reviewed by two gynaecologic pathologists and had no conflict. All cases showed P57 negative, which can exclude the diagnosis of CHM. An immunochemical study of the expressions of Ki-67, P53 and P63 was performed. RESULTS: Microscopically, the pathologic characteristics of a HA include villous oedema with minimal to no cistern formation and mild trophoblastic hyperplasia. In contrast, the pathologic features of PHM were characterized by focal trophoblastic hyperplasia and a variable degree of hydropic swelling with central cistern formation. The Ki-67 expression was observed in the nuclear of cytotrophoblastic cell and intermediate trophoblasts population within placental tissue. The Ki-67 expression in HA is less than that in PHM. The p53 expression was observed in the nuclear of cytotrophoblastic cell and intermediate trophoblasts population within placental tissue. There was a significant difference between HA and PHM. Positive staining for P63 was localized in the nuclei of cytotrophoblastic cell population. No significant difference was observed in positive rate of p63 expression between HA and PHM. CONCLUSION: The high Ki-67 labeling index and over-expression of p53, detected by immunohistochemistry, could serve as useful adjuncts to conventional methods of diagnosis in distinguishing PHM from HA. Due to, however, the limited samples, it needs to expand the number of the cases to verify this conclusion. PMID- 22218718 TI - [Diabetes Care Austria 2009: registry for type 2 diabetic patients in general practitioners' ordinations in Austria]. AB - Diabetes Care Austria was a nationwide data acquisition of type 2 diabetes treatment at Austrian general practitioners. A total of 5,385 general practitioners were contacted in the end of 2009; finally, 101 agreed to participate in the data collection. Out of all 9 Austrian provinces, a cross sectional sample of 1.513 type 2 diabetic patients was investigated. Demographic data, diabetes treatment, quality of diabetes control as well as micro- and macrovascular complications were analysed with respect to diabetes duration, categorised into 6 classes. A total of 1.513 type 2 diabetic patients with a mean age of 65.4 +/- 10.7 years and a mean diabetes duration of 8.7 +/- 7.3 years were analysed. Metformin was equally used in more than 50% of patients in all classes of diabetes duration. The use of sulfonylureas was significantly (p < 0.001) increased from 25% in patients with a diabetes duration of less than 3 years to more than 40% in subjects with a disease duration of longer than 15 years. The prescription of glitazones was significantly (p = 0.02) augmented with increasing diabetes duration. DPP-4 inhibitors were used in more than 5% of patients with a maximum of 13% in subjects with a diabetes duration of 4-9 years (p < 0.001). The mean HbA1c was below 7.5% in all classes and was significantly (p < 0.01) the lowest with 7.0 +/- 1.2% in patients with the shortest diabetes duration when compared to all other categories. Diabetes Care Austria yielded representative data for diabetes therapy of type 2 diabetic patients treated by general practitioners. Diabetes treatment was successful, as proven by a mean HbA1c value of 7.2%. An insulin therapy was initialised late, but was nevertheless effective as shown by comparable HbA1c values in patients with a diabetes duration of 4 to more than 15 years. PMID- 22218719 TI - Risk factors for ischaemic heart disease mortality among men with different occupational physical demands. A 30-year prospective cohort study. AB - Objectives Men with high physical work demands have elevated cardiovascular strain, which may lead to enhanced atherosclerosis. Theoretically, the impact of risk factors for ischaemic heart disease (IHD) may thus depend on physical work demands. The authors investigated this hypothesis. Design Prospective 30-year follow-up. Setting The Copenhagen Male Study. Participants 5249 gainfully employed men aged 40-59 years; 311 men with cardiovascular disease/diabetes were excluded. Primary and secondary outcome measures IHD and all-cause mortality. Results 579 men (11.8%) died due to IHD and 2628 (53.7%) from all-cause mortality. Similarities and differences in risk predictors were found between men with low (n=1219), medium (n=2636) and high (n=846) physical work demands. After control for potential confounders, high physical fitness conferred a reduced risk of IHD mortality only among men with high physical work demands (HR: 0.48, 95% CI 0.24 to 0.96), a moderate/high level of leisure-time physical activity was associated with reduced risk of IHD mortality only among men with moderate and high physical work demands. High systolic blood pressure and smoking were risk factors in all groups. Similar, but less pronounced differences in risk factors for all-cause mortality between groups were found. Conclusions The risk factors for IHD and all-cause mortality, low physical fitness and low leisure-time physical activity are not identical for men with different physical work demands. Preventive initiatives for IHD should be tailored to the physical work demands. PMID- 22218720 TI - Developing and validating a scoring tool for identifying people who inject drugs at increased risk of hepatitis C virus infection. AB - Objectives To develop and validate a scoring tool based on demographic and injecting risk behaviours to identify those who require additional, non-routine serological screening for hepatitis C virus (HCV) by assessing their personal risk. Design Cross-sectional and prospective cohorts. Setting People who inject drugs (PWID) and attended Needle and Syringe Programs (NSP) in Australia during the period from 1998 to 2008. Participants Cross-sectional data included 16 127 PWID who attended NSP in Australia. Prospective data included 215 HCV-negative PWID who were recruited through street-based outreach, methadone clinics in Australia. Primary and secondary outcome measures HCV seroprevalence in the cross-sectional and HCV seroconversions in the prospective data sets. Results Current study included 16 127 PWID who attended NSP in Australia. Type of drug last injected, frequency and duration of injecting, sharing needles and syringes or other injecting equipment and imprisonment history were associated with HCV infection in all age groups. Strong relationships between an individual's 'HCV score' and their risk of testing HCV antibody positive were observed. An estimated 78% (95% CI 75% to 81%), 82% (95% CI 80% to 84%), 80% (95% CI 78% to 82%) and 80% (95% CI 77% to 82%) of HCV infections across the age groups (<25, 25 29, 30-39 and >=40 years) would be avoided if participants in the upper four quintiles of HCV scores fell instead into the lowest quintile. Conclusions Knowledge of HCV status has important implications for public health and care and treatment. Risk assessment strategies may assist in alerting PWID who are at increased risk of HCV infection to present for testing. PMID- 22218721 TI - Effect of vitamin A supplementation in women of reproductive age on cause specific early and late infant mortality in rural Ghana: ObaapaVitA double-blind, cluster-randomised, placebo-controlled trial. AB - Objectives To assess the effect of vitamin A supplementation in women of reproductive age in Ghana on cause- and age-specific infant mortality. In addition, because of recently published studies from Guinea Bissau, effects on infant mortality by sex and season were assessed. Design Double-blind, cluster randomised, placebo-controlled trial. Setting 7 contiguous districts in the Brong Ahafo region of Ghana. Participants All women of reproductive age (15-45 years) resident in the study area randomised by cluster of residence. All live born infants from 1 June 2003 to 30 September 2008 followed up through 4-weekly home visits. Intervention Weekly low-dose (25 000 IU) vitamin A. Main outcome measures Early infant mortality (1-5 months); late infant mortality (6-11 months); infection-specific infant mortality (0-11 months). Results 1086 clusters, 62 662 live births, 52 574 infant-years and 3268 deaths yielded HRs (95% CIs) comparing weekly vitamin A with placebo: 1.04 (0.88 to 1.05) early infant mortality; 0.99 (0.84 to 1.18) late infant mortality; 1.03 (0.92 to 1.16) infection-specific infant mortality. There was no evidence of modification of the effect of vitamin A supplementation on infant mortality by sex (Wald statistic =0.07, p=0.80) or season (Wald statistic =0.03, p=0.86). Conclusions This is the largest analysis of cause of infant deaths from Africa to date. Weekly vitamin A supplementation in women of reproductive age has no beneficial or deleterious effect on the causes of infant death to age 6 or 12 months in rural Ghana. Trial registration number http://ClinicalTrials.gov: NCT00211341. PMID- 22218722 TI - High rates of late HIV diagnosis among people who inject drugs compared to men who have sex with men and heterosexual men and women in Australia. AB - We aimed to estimate temporal trends in the proportion of HIV diagnoses which could be characterized as recent infections in Australia for men who have sex with men (MSM), people who inject drugs (PWID), and heterosexual men and women using modified back-projection methodology based on data sources from HIV/AIDS Surveillance database. The proportion of HIV diagnoses among MSM that can be classified as recent infections increased in MSM, heterosexual men and women consistently. However, after initial increases during 1996-2000, the proportion of overall recent infections estimated among PWID declined by 50% in 2007 compared to 2000 (from 23 to 11%). These data suggest that late HIV diagnoses were more common among PWID compared to other groups. Ongoing prevention efforts need to be coupled with targeted testing and treatment efforts to increase the diagnosis of recent infection in PWID and reduce apparent inequities in access to screening. PMID- 22218723 TI - Predictors of late presentation for HIV diagnosis: a literature review and suggested way forward. AB - Early commencement of antiretroviral treatment can be beneficial and economical in the long run. Despite global advances in access to care, a significant proportion of adults presenting at HIV/AIDS care facilities present with advanced HIV disease. Understanding factors associated with late presentation for HIV/AIDS services is critical to the development of effective programs and treatment strategies. Literature on factors associated with late presentation for an HIV diagnosis is reviewed. Highlighted is the current emphasis on socio-demographic factors, the limited exploration of psychosocial correlates, and inconsistencies in the definition of late presentation that make it difficult to compare findings across different studies. Perspectives based on experiences from resource limited settings are underreported. Greater exploration of psychosocial predictors of late HIV diagnosis is advocated for, to guide future intervention research and to inform public policy and practice targeted at 'difficult to reach' populations. PMID- 22218724 TI - Recent advances on the chemistry of transition metal complexes of 2 (arylazo)pyridines and its arylamino derivatives. AB - Recent advancement on the redox properties of a selection of transition metal complexes of the azoaromatic ligands: bidentate L(1) [2-(arylazo)pyridine] and tridentate HL(2) [2-(aminoarylphenylazo)pyridine] are described and compared. Due to the presence of a low lying azo-centered pi*-orbital, these azoaromatic ligands may exist in multiple valent states. The coordination chemistry of the L(1) ligands was thoroughly studied during the 1980s. These complexes undergo facile reduction in solution at low accessible potentials. One electron reduced azo-complexes, though known for a long time to occur in solution, have only recently been isolated in a crystalline state. New synthetic protocols for the synthesis of metal-bound azo-radical complexes have been developed. Low-valent metal complexes such as metal carbonyls have been found to be excellent starting materials for this purpose. In a few selected cases, syntheses of these complexes were also achieved from very high valent metal oxides using triphenylphosphine as both a reducing and oxo-abstracting agent. Issues related to the ambiguities of the electronic structures in the azo-metal complexes have been discussed considering bond parameters, redox and spectral properties. Unusual redox events such as RIET (Redox-Induced Electron Transfer) phenomena in a few systems have been elaborated and compared with the known example. Novel examples of N=N bond cleavage reactions via four-electron reduction and subsequent C-N bond formation in metal-bound coordinated ligands have been noted. PMID- 22218725 TI - Preface: gynecologic urology. PMID- 22218726 TI - Longitudinal predictors of first time depression treatment utilization among adults with depressive disorders. AB - PURPOSE: Depressive disorders are a growing public health concern, however, a substantial number of depressed individuals do not receive treatment. This study examined the longitudinal predictors of receiving depression treatment among adults with persistent depressive disorders and no lifetime history of treatment. METHODS: The sample included respondents to the National Epidemiologic Survey on Alcohol Related Conditions (NESARC), a large population-based survey, who met criteria for a 12-month major depressive disorder (MDD) or dysthymia (DYS) and had no prior depression treatment. Bivariate and multivariate analyses were conducted examining which socio-demographic and clinical predictors among individuals with depressive disorders and no prior treatment at Wave 1 were associated with receiving depression treatment at Wave 2 (N = 337). RESULTS: Only 47.2% of those with MDD or DYS and no prior treatment at Wave 1 had received depression treatment at Wave 2. Females were more likely to have received treatment at Wave 2: those of Hispanic ethnicity, other race, unmarried, 12 years of education, self-rated health of good/very good/excellent and anxiety disorders were less likely to have received treatment at Wave 2. Those with substance use disorders were more likely to have received treatment at Wave 2. CONCLUSIONS: This study highlights individuals who would likely benefit from increased efforts to enhance depression treatment utilization. PMID- 22218727 TI - Development of energetic pharmacophore for the designing of 1,2,3,4 tetrahydropyrimidine derivatives as selective cyclooxygenase-2 inhibitors. AB - We present here the Energetic pharmacophore model representing complementary features of the 1,2,3,4-tetrahydropyrimidine for selective cyclooxygenase-2 (COX 2) inhibition. For the development of pharmacophore hypothesis, a total of 43 previously reported compounds were docked on active site of COX-2 enzyme. The generated pharmacophore features were ranked using energetic terms of Glide XP docking for 1,2,3,4-tetrahydropyrimidine scaffold to optimize its structure requirement for COX-2 inhibition. The thirty new 4,5,6-triphenyl-1,2,3,4 tetrahydropyrimidine derivatives were synthesized and assessed for selective COX 2 inhibitory activity. Two compounds 4B1 and 4B11 were found to be potent and selective COX-2 inhibitors. The molecular docking studies revealed that the newly synthesized compounds can be docked into COX-2 binding site and also provide the molecular basis for their activity. PMID- 22218728 TI - Bifunctional bacterial magnetic nanoparticles for tumor targeting. AB - Bifunctional bacterial magnetic nanoparticles (BBMPs), which present both magnetic drug targeting and tumor bio-targeting properties, have been developed by chemically coupling both doxorubicin and a galactosyl ligand on to the membrane surface of the bacterial magnetic nanoparticles (BMPs). The BBMP product has a high drug load ratio and magnetic respondence, and exhibits a narrow size distribution and is sensitive to pH to enable drug release. In comparison to doxorubicin-coupled BMPs, without modification with a galactosyl ligand, BBMPs present a higher uptake by the target asialoglycoprotein receptor (ASGP-R) expressed by HepG2 cells and display stronger cytotoxicity. PMID- 22218729 TI - Positive correlation between tumor necrosis factor (TNF)-α and cardiorespiratory fitness after six-months of regular aerobic exercise in Peruvian Amerindian women. AB - BACKGROUND: Adipose tissue is a source of inflammatory cytokines which may influence insulin action. AIM: To evaluate exercise effects on plasma (p)-levels of tumor necrosis factor (TNF)-alpha , and interleukin (IL)-6 in Peruvian Amerindian women. MATERIAL AND METHODS: After five years of observation during which p-glucose deteriorated and weight increased, 44 Peruvian Amerindian women aged 20-59 years took part in a 6-month exercise program. Plasma TNF-alpha and IL 6 had been measured 5 years earlier, and were reassessed before and after exercise, using ELISA kits. Cardiorespiratory fitness was derived from the results of the twelve minutes' walk and expressed as maximum oxygen uptake (VO(2max)). RESULTS: After the training program, estimated VO(2max) increased from 18.55 +/- 3.79 to 20.91 +/- 4.61 mL kg(-1) min(-1) (p < 0.01) and p-TNF alpha increased from 3.2 +/- 3.4 to 4.3 +/- 6.6 pg/mL (p = 0.03). There were reductions in p-glucose from 5.19 +/- 1.59 to 4.32 +/- 1.62 mmol/L (p < 0.01) and in waist circumference (p=0.01). Weight, p-insulin, and IL-6 did not change. Levels of p-glucose and p-TNF-alpha observed after the training period were identical to values 5 years earlier. P-TNF-alpha was positively associated with estimated VO(2max), prior to (r = .414, p < 0.01) as well as after (r = .362, p < 0.05) exercise, independently of adiposity. P-IL-alpha was associated with waist circumference but not with estimated VO(2max). CONCLUSIONS: P-TNF-a correlated with estimated VO(2max) independently of adiposity. Beneficial effects of exercise on p-glucose were observed in spite of an increase in p-TNF-alpha. PMID- 22218730 TI - Biomimetic material--poly(N-vinylimidazole)-zinc complex for CO2 separation. AB - A novel material, poly(N-vinylimidazole)-zinc complex, is prepared to simulate the zinc active site of carbonic anhydrase. The obtained complex can separate CO(2) efficiently. PMID- 22218732 TI - Controlling the width of self-assembled dysprosium silicide nanowires on the Si(001) surface. AB - We present STM data that show that it is possible to use a metal induced 2 * 7 reconstruction of Si(001) to narrow the width distribution of Dy silicide nanowires. This behavior is distinct from the effect of the 7 * 7 reconstruction on the Si(111) surface, where the 7 * 7 serves as a static template and the deposited metal avoids the unit cell boundaries on the substrate. In this case, the 2 * 7 is a dynamic template, and the nanowires nucleate at anti-phase boundaries between 2 * 7 reconstruction domains. PMID- 22218731 TI - Detection of human enterovirus 71 and coxsackievirus A16 in children with hand, foot and mouth disease in China. AB - The aims of the present study were to investigate the genetic characteristics of enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) strains in China and to evaluate the relationship between the genotypes of CVA16 and EV71 and their geographical distribution. A total of 399 stool specimens were collected from children with symptoms of hand, foot and mouth disease (HFMD) in Zhejiang Province. The presence of enteroviruses was determined using reverse transcription-semi-nested PCR targeted to the VP1 gene of all human enteroviruses and DNA sequencing. EV71 and CVA16, the major etiological agents of HFMD, were detected in 38.4% (38/99) and 35.4% (35/99) of HEV-A species-positive cases, respectively. Based on the phylogenetic analysis of the VP1 gene, EV71 strains identified in this study belong to subgenotype C4, and CVA16 strains herein were classified into clusters B2a and B2b within the genotype B2. Taking into consideration other published data, we conclude that the genetic characteristics of enteroviruses in China reflect the pattern of the endemic circulation of the subgenotype C4 to EV71 and clusters B2a and B2b within genotype B2 to CVA16, which have been continuously circulating in China since 1997. This observation indicates that the genetic characteristics of enteroviruses in China seem to depend on their special geographical and climatical features allowing them to be sustained with little external effect. PMID- 22218733 TI - Role of thiamine in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia in elderly individuals and is associated with progressive neurodegeneration of the human neocortex. Thiamine levels and the activity of thiamine-dependent enzymes are reduced in the brains and peripheral tissues of patients with AD. Genetic studies have provided the opportunity to determine what proteins link thiamine to AD pathology (ie, transketolase, apolipoprotein E, alpha-1-antitrypsin, pyruvate dehydrogenase complex, p53, glycogen synthetase kinase-3beta, c-Fos gene, the Sp1 promoter gene, and the poly(ADP-ribosyl) polymerase-1 gene). We reviewed the association between histopathogenesis and neurotransmitters to understand the relationship between thiamine and AD pathology. Oral thiamine trials have been shown to improve the cognitive function of patients with AD; however, absorption of thiamine is poor in elderly individuals. In the early stage of thiamine deficient encephalopathy (Wernicke's encephalopathy), however, parental thiamine has been used successfully. Therefore, further studies are needed to determine the benefits of using parental thiamine as a treatment for AD. PMID- 22218734 TI - Atrial fibrillation predicts cognitive impairment in patients with ischemic stroke. AB - BACKGROUND: Atrial fibrillation (AF) is considered as a risk factor for cognitive impairment. METHODS: This retrospective chart review study was conducted in a patient stroke rehabilitation ward of a university-affiliated referral hospital. The participants were 707 patients admitted for a standard rehabilitation course after an ischemic stroke. Cognitive status was assessed by the Mini-Mental State Examination (MMSE), and scores lower than 24 points were considered as suggestive of cognitive impairment. RESULTS: Atrial fibrillation, age, gender, diabetes, and dementia emerged as the only statistically significant parameters differing between those with MMSE score lower than 24 or higher. In a multiple logistic regression analysis, AF (odds ratio 1.6, 95% confidence interval 1.03-2.47, P = .03) was associated with an increased risk of cognitive impairment. CONCLUSIONS: Our findings suggest that atrial fibrillation upon admission is independently associated with lower MMSE scores in patients with ischemic stroke. PMID- 22218735 TI - Expression and distribution of symplekin regulates the assembly and function of the epithelial tight junction. AB - Symplekin is multifunctional protein localized to both the tight junction and the nucleus with known roles in mRNA polyadenylation, proliferation, differentiation and tumorigenesis. Functions of symplekin at tight junctions have not been systematically investigated. In this study, increased expression of symplekin was observed during the formation of tight junctions in cultured HT-29 and HepG2 epithelial cells. Repression of symplekin by RNAi increased the permeability of epithelial monolayers, disrupted cellular polarity, and decreased the expression of the tight junction protein ZO-1. Moreover, symplekin was co-localized with ZO 1 at tight junctions and co-immunoprecipitated with ZO-1, indicating that ZO-1 and symplekin form complexes. In conclusion, symplekin expression regulates the assembly of tight junctions, thus helps to maintain the integrity of the epithelial monolayer and cellular polarity. PMID- 22218736 TI - Red nucleus degeneration in hypertrophic olivary degeneration after pediatric posterior fossa tumor resection: use of susceptibility-weighted imaging (SWI). AB - We report the use of susceptibility-weighted imaging (SWI) in detection of red nucleus (rubral) degeneration and atrophy in children with hypertrophic olivary degeneration (HOD) after posterior fossa tumor resection. The use of this modality for this particular application has not been previously described. Detection of red nucleus changes seems to be facilitated by the contrast mechanism of SWI over conventional MRI sequences. SWI can be considered in the evaluation of these patients and in the future might provide a means for further classification of patients with HOD and related symptomatology. PMID- 22218737 TI - Morphology controllable synthesis of monkshoodvine root-bark like carbon and its biosensing application. AB - Unique monkshoodvine root-bark like morphology carbon materials (MLC) have been successfully synthesized under hydrothermal conditions. Utilizing the merits of high surface area and good electron conductivity of the MLC, a layered biosensor designed by assembling the MLC, hemoglobin (Hb) and gold nanoparticles was further developed. Scanning electron microscope and transmission electron microscope showed that the morphology of carbon materials can be successfully controlled simply by moderating the initiator amount of precursor and reaction temperature. The results indicated that the MLC was formed at the reaction condition of 5 mg Ferrocene + 6 mL CCl(4) at 280 degrees C. Electrochemical methods, such as cyclic voltammetry and electrochemical impedance spectroscopy, were used to characterize the layered biosensor and its application for sensitive detection of hydrogen peroxide (H(2)O(2)). Under optimized experimental condition, the linear range for the determination of H(2)O(2) was 0.06 MUM to 1.6 mM with a detection limit of 0.03 MUM (S/N = 3). Furthermore, the biosensor also showed a fast response (within 2 s) and high stability. PMID- 22218738 TI - Daytime sleepiness and sleep duration in long-term cancer survivors and non cancer controls: results from a registry-based survey study. AB - PURPOSE: Sleep-related complaints are common in cancer survivors. Although daytime sleepiness and sleep duration are associated with poor functional status, quality of life, and mortality in the general population, little is known about these issues in long-term cancer survivors. This study examined differences in daytime sleepiness and sleep duration between long-term cancer survivors and non cancer controls. METHODS: Survey data were analyzed from individuals diagnosed with cancer >=2 years in the past (n = 1,171, mean age = 64.30, 80.8% white, 22.8% male) and spouse/friends controls (n = 250, mean age = 60.78, 88.0% white, 64.8% male). Daytime sleepiness was assessed using the Epworth Sleepiness Scale. Associations between sleep-related variables and history of cancer were estimated with multivariable logistic regression, adjusting for potential confounders. Stratified analyses were conducted to identify subgroups of survivors most at risk for sleep problems. RESULTS: Cancer survivors were more likely than controls to report excessive daytime sleepiness (OR = 1.64, 95% CI: 1.07, 2.50). A cancer diagnosis was associated with longer sleep duration among males (OR = 1.25, 95% CI: 1.02, 1.53), but not in females (OR = 0.87, 95% CI: 0.37, 1.05). All other associations were similar regardless of cancer site, histology, time since diagnosis, treatment history, and history of multiple cancers. CONCLUSIONS: Disturbances in daytime sleepiness and sleep duration persist among long-term cancer survivors and should be monitored in routine survivorship care. More research is needed to identify cancer survivors who are at increased risk for daytime sleepiness and disturbed sleep duration, as well as to identify causal mechanisms for, and interventions to mitigate, persistent differences. PMID- 22218740 TI - Primary percutaneous coronary intervention and intravascular ultrasound imaging for coronary thrombosis after cisplatin-based chemotherapy. AB - Although cisplatin is indispensable for the chemotherapy treatment of many malignancies, cisplatin-associated thrombosis is attracting increasing attention. However, experience of primary percutaneous coronary intervention (PCI) and intravascular ultrasound imaging (IVUS) for coronary thrombosis, possibly due to cisplatin-based chemotherapy, has been limited. Case 1 with postoperative gastric cancer developed acute myocardial infarction (AMI) on the sixth day of the second chemotherapy course with conventional doses of cisplatin and tegafur gimeracil oteracil potassium. Emergency coronary angiography (CAG) showed a filling defect in the proximal left anterior descending coronary artery (LAD) concomitant with no reflow in the distal LAD. Case 2 with advanced lung cancer and brain metastasis suffered AMI on the fifth day of the first chemotherapy course with conventional doses of cisplatin and gemcitabine. Emergency CAG delineated a total occlusion in the proximal right coronary artery. In both cases, thrombectomy using aspiration catheter alone obtained optimal angiographic results and subsequent IVUS revealed no definite atherosclerotic plaque, while slow flow still remained even after selective intra-coronary infusion of vasodilator in the case 1. These cases suggest that primary PCI using thrombus-aspiration catheter might be safe and effective for coronary thrombosis due to cisplatin-based chemotherapy. PMID- 22218742 TI - Influence of precursors chemistry on ALD growth of cobalt-molybdenum oxide films. AB - Cobalt molybdenum compounds are important catalytic materials in many processes, e.g. in splitting of ammonia to form CO free hydrogen fuel. We here report on deposition of such cobalt molybdenum oxides by atomic layer deposition (ALD) using different types of metal precursors CoCp(2) (Cp = cyclopentadienyl), Co(thd)(2) (Hthd = 2,2,6,6-tetramethylheptan-3,5-dione), Mo(CO)(6) and oxygen precursors O(3), H(2)O, and (O(3) + H(2)O). The growth dynamics have been investigated using quartz crystal microbalance (QCM) methods. It is evident that mixing of the different precursor chemistries affect the growth patterns. When water is introduced to the reactions, a surface controlled mechanism takes place which guides the deposited stoichiometry towards the CoMoO(4) phase over a wide range of cobalt rich pulsed compositions. This is a rare example of how surface chemistry can control stoichiometry of depositions in ALD. The deposited films have been investigated by X-ray diffraction, Raman spectroscopy and atomic force microscopy. The catalytic activity of selected films have been characterized by temperature programmed ammonia decomposition, proving the films to be catalytically active and lowering the decomposition temperature by some 200 degrees C. PMID- 22218741 TI - Genotype-phenotype correlation in interstitial 6q deletions: a report of 12 new cases. AB - Interstitial deletions of 6q are associated with variable phenotypes, including growth retardation, dysmorphic features, upper limb malformations, and Prader Willi (PW)-like features. Only a minority of cases in the literature have been characterized with high resolution techniques, making genotype-phenotype correlations difficult. We report 12 individuals with overlapping, 200-kb to 16.4 Mb interstitial deletions within 6q15q22.33 characterized by microarray-based comparative genomic hybridization to better correlate deletion regions with specific phenotypes. Four individuals have a PW-like phenotype, though only two have deletion of SIM1, the candidate gene for this feature. Therefore, other genes on 6q may contribute to this phenotype including multiple genes on 6q16 and our newly proposed candidate, the transcription cofactor gene VGLL2 on 6q22.2. Two individuals present with movement disorders as a major feature, and ataxia is present in a third. The 4.1-Mb 6q22.1q22.2 critical region for movement disorders includes the cerebellar-expressed candidate gene GOPC. Observed brain malformations include thick corpus callosum in two subjects, cerebellar vermal hypoplasia in two subjects, and cerebellar atrophy in one subject. Seven subjects' deletions overlap a ~250-kb cluster of four genes on 6q22.1 including MARCKS, HDAC2, and HS3ST5, which are involved in neural development. Two subjects have only this gene cluster deleted, and one deletion was apparently de novo, suggesting at least one of these genes plays an important role in development. Although the phenotypes associated with 6q deletions can vary, using overlapping deletions to delineate critical regions improves genotype-phenotype correlation for interstitial 6q deletions. PMID- 22218744 TI - Leaching of heavy metals from artificial soils composed of sewage sludge and fly ash. AB - The purpose of this study was to determine the leaching characteristics of heavy metals from artificial soils composed of sewage sludge and fly ash. A leaching experiment was carried out over a period of 90 days. The leachates from artificial soils were collected every 15 days, and the concentrations of cadmium, lead, copper, zinc, chromium, and nickel in leachates were determined. Results showed that pH values of the artificial soils leachate were stable, ranging from 6.71 to 7.62 at the end of the experiment. Except of the cadmium, the concentrations of chromium, nickel, and copper in leachates of the artificial soils reached a stable level at the end of the experiment. The final concentrations of copper in leachates varied from 27.1 to 127.5 MUg L(-1), which was lower than European threshold value for drinking water, (1,000 MUg L(-1)), while final nickel and chromium concentrations in leachates exceeded the European threshold ones. Amorpha fruticosa and Robina pseudoacacia grown in the artificial soils had different effects on cadmium, nickel, chromium, and copper leaching behavior. Amorpha fruticosa resulted in higher Ni and Cu concentrations in leachates, while Robina pseudoacacia enhanced leaching concentration of Cr. PMID- 22218745 TI - Cadmium and lead levels in muscle and edible offal of cow reared in Nigeria. AB - The study assessed the concentration of cadmium and lead in the muscle, liver, kidney, intestine and tripe of cow in Nigeria. Results show that the ranges of detectable values of cadmium in mg/kg were 0.01-0.80 in muscle, <0.004-0.90 in liver, 0.10-1.12 in kidney, 0.01-0.90 in intestine and 0.01-1.10 in tripe while for lead, the ranges were <0.005-0.72 in muscle, 0.08-501.79 in liver, 0.04-44.89 in kidney, 0.01-108.02 in intestine and 0.01-127.90 in tripe. Cadmium was accumulated mostly in kidney while Pb accumulated more in liver and both were above international maximum permissible levels in most samples. PMID- 22218743 TI - The actual role of sodium cromoglycate in the treatment of asthma--a critical review. AB - INTRODUCTION: Despite international consensus and clearly written guidelines urging wider use of corticosteroids or combinations of inhaled short- and long acting beta-agonists (SABA and LABA) and corticosteroids in persistent asthma, prescribing patterns and compliance rates fall far short of recommendations. OBJECTIVES: The failure to use steroids more aggressively is due, in part, to their side effects, even with inhaled forms of the drug. There is a role for expanded use of sodium cromolyn in asthma. Its potent anti-inflammatory effects, lack of side effects, and acceptable dosing and method of delivery, as well as its special role in exercise-induced asthma, make it a very suitable choice in the initial therapy for control of asthma. CONCLUSION: Compared to SABA and LABA, cromoglycates alone are unsuspicious of being used to enhance physical performance. PMID- 22218746 TI - The use of the first order system transfer function in the analysis of proboscis extension learning of honey bees, Apis mellifera L., exposed to pesticides. AB - No attempts have been made to apply a mathematical model to the learning curve in honey bees exposed to pesticides. We applied a standard transfer function in the form Y = B3*exp(- B2 * (X - 1)) + B4 * (1 - exp(- B2 * (X - 1))), where X is the trial number; Y is proportion of correct responses, B2 is the learning rate, B3 is readiness to learn and B4 is ability to learn. Reanalyzing previously published data on the effect of insect growth regulators tebufenozide and diflubenzuron on the classical conditioning of proboscis extension, the model revealed additional effects not detected with standard statistical tests of significance. PMID- 22218748 TI - Leaching of indaziflam applied at two rates under different rainfall situations in Florida Candler soil. AB - Indaziflam {N-[(1R, 2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[(1RS) 1fluoroethyl]-1,3,5-triazine-2,4-diamine} is a new pre-emergence herbicide recently registered for a broad spectrum weed control in Florida citrus. Experiments were conducted to evaluate leaching of indaziflam applied at 73 and 145 g ai ha(-1) in Florida Candler soil under simulated rainfall of 5, 10, and 15 cm ha(-1). Indaziflam leached the least (12.6 +/- 0.6 cm) when applied at 73 g ai ha(-1) under 5 cm ha(-1) rainfall. Indaziflam leached furthest (30.2 +/- 0.9 cm) when applied at 145 g ai ha(-1) under 15 cm ha(-1) rainfall. The visual control ratings of a bio-indicator species ryegrass (Lolium multiflorum L.) was 97% at 15 cm ha(-1) rainfall when indaziflam applied at 145 g ai ha(-1) in the 26 to 30 cm horizon indicating the maximum movement and activity of indaziflam. A dose response experiment was conducted to determine the sensitivity of ryegrass to various doses of indaziflam that confirmed that application of indaziflam at 29.20 g ai ha(-1) was sufficient to prevent germination of ryegrass. There was no mortality of ryegrass plants beyond the 30 cm and the biomass of ryegrass was comparable with untreated control indicating that indaziflam did not leach beyond this distance even under 15 cm ha(-1) rainfall. PMID- 22218747 TI - Determination of trace elements level of pikeperch collected from the Caspian Sea. AB - Toxic and essential elements levels (chromium, copper, iron, manganese, nickel, lead, cadmium, and zinc) have been determined in the brain, heart, liver, gill, gonads, spleen, bile and muscle of S. lucioperca, collected from the Caspian Sea by employing Flame- Atomic absorption spectrometry. Results indicated that nearly all of the toxic metals concentrations (nickel, lead and cadmium) in tissues were higher than limits for fish suggested by Food and Agricultural Organization, World Health Organization and European Union. Lead was higher in spleen than other tissues. Levels of essential metals (iron, copper, zinc and manganese) were below the limits suggested by European Union and Food and Agricultural Organization/World Health Organization and Turkish Food Codex for fish. Iron distribution pattern in tissues was in the following order: heart (88.67 +/- 2.74 MUg g(-1) wet wt) > spleen (70.96 +/- 2.05 MUg g(-1) wet wt) > bile (29.35 +/- 0.94 MUg g(-1) wet wt) > brain (14.29 +/- 0.51 MUg g(-1) wet wt) > liver (8.57 +/ 0.29 MUg g(-1) wet wt) > gill (3.20 +/- 0.14 MUg g(-1) wet wt) > red (2.79 +/- 0.11 MUg g(-1) wet wt) and white muscles (2.79 +/- 0.09 MUg g(-1) wet wt) > gonads (2.57 +/- 0.07 MUg g(-1) wet wt). PMID- 22218749 TI - Polycyclic aromatic hydrocarbons at different crossroads in Zagreb, Croatia. AB - Polycyclic aromatic hydrocarbons (PAHs) were measured in the PM(10) particle fraction collected at two different measuring sites in Zagreb, Croatia. In summer, concentrations of all PAHs at both sites were low. In winter, mass concentrations of all PAHs measured at southern site were much higher than those at north. Contents of all PAHs in the PM(10) particle fraction were much lower in summer than that in the winter period. For example, average content of BaP in PM(10) in summer was 2.26 ng/mg at site A and 4.17 ng/mg at site B, while in winter it was 34.72 and 46.69 ng/mg, respectively. PMID- 22218750 TI - Affective regulation of cognitive-control adjustments in remitted depressive patients after acute tryptophan depletion. AB - Negative affect in healthy populations regulates the appraisal of demanding situations, which tunes subsequent effort mobilization and adjustments in cognitive control. In the present study, we hypothesized that dysphoria in depressed individuals similarly modulates this adaptation, possibly through a neural mechanism involving serotonergic regulation. We tested the effect of dysphoria induced by acute tryptophan depletion (ATD) in remitted depressed patients on conflict adaptation in a Simon task. ATD temporarily lowers the availability of the serotonin precursor L-Tryptophan and is known to increase depressive symptoms in approximately half of remitted depressed participants. We found that depressive symptoms induced by ATD were associated with increased conflict adaptation. Our finding extends recent observations implying an important role of affect in regulating conflict-driven cognitive control. PMID- 22218752 TI - Management of the dialysis patient in general intensive care. AB - The incidence of end-stage renal disease (ESRD) is rising and represents an important group of patients admitted to intensive care units (ICU). ESRD patients have significant co-morbidities and specific medical requirements. Renal replacement therapy (RRT), cardiovascular disease, disorders of electrolytes, drug metabolism, and sepsis are discussed. This review provides a practical approach to problems specific to the ESRD patient and common problems on ICU that require special consideration in ESRD patients. ESRD patients are at risk of hyperkalaemia. I.V. insulin and nebulized salbutamol lower serum potassium until definitive treatment with RRT is instituted. ESRD patients are prone to hypocalcaemia, which requires i.v. replacement if associated with complications. Midazolam has delayed metabolism and elimination in renal impairment and should be avoided. Morphine and its derivatives accumulate in renal failure and shorter acting opiates are preferable. The use of diuretics is limited to patients with residual urine output. When required, therapeutic systemic anticoagulation should be achieved with unfractionated heparin as it is reversible and its metabolism and clearance are independent of renal function. The risk of sepsis is higher among ESRD patients when compared with patients with normal renal function. Empiric treatment should include both Gram-positive and Gram-negative cover, and methicillin-resistant Staphylococcus aureus cover if the patient has a dialysis catheter. Cardiovascular events account for the majority of deaths among ESRD patients. Troponin-I and CK-MB in combination should be used as markers of acute myocardial damage in the appropriate context, whereas B-type natriuretic peptide and troponin-T values are of less value. PMID- 22218753 TI - Catalysis using gold nanoparticles decorated on nanocrystalline cellulose. AB - A novel nanocomposite was prepared by deposition of carbonate-stabilized Au nanoparticles (AuNPs) onto the surface of poly(diallyldimethyl ammonium chloride) (PDDA)-coated carboxylated nanocrystalline cellulose (NCC). The hybrid material possessed AuNPs (1.45% by weight) with an average diameter of 2.95 +/- 0.06 nm. The catalytic activity of AuNP/PDDA/NCC for reducing 4-nitrophenol to 4 aminophenol was compared to other Au-supported composites. An activation energy of 69.2 kJ mol(-1) was obtained for the reaction. Indeed, the reaction rate constant k of (5.1 +/- 0.2) * 10(-3) s(-1) was comparable to the benchmark literature value obtained using AuNPs (<5 nm in diameter) decorated on a network of crystalline cellulose fibers. Our strategy promotes the use of natural resources to prepare reusable hybrid inorganic-organic materials for important reactions with facilitated product isolation/purification. PMID- 22218754 TI - Polymorphisms in the 3'UTR of the human leptin gene and their role in hypertension. AB - Leptin is a protein hormone, mainly synthesized in adipocytes, that regulates the food intake and energy expenditure of the body. Rare mutations in the leptin gene cause obesity. Common polymorphisms of the leptin gene have been associated with obesity, however their association with arterial blood pressure has not been fully elucidated. The aim of the present study was to examine the effect of variants in the 3' flanking region of the leptin gene on blood pressure in hypertensive subjects with high (35.2 +/- 5.12) and low (20.13 +/- 1.3) body mass index (BMI). Microsatellite polymorphisms and the C538T SNP in the 3'UTR of the leptin gene were screened in 362 subjects, and different biochemical and anthropometric parameters were measured. The levels of serum urea, creatinine, glucose, cholesterol, triglyceride, leptin and angiotensin II were determined in all subjects. A strong association of microsatellite polymorphisms with essential hypertension was found in subjects with a high BMI, but this association was only slight in subjects with a normal BMI. The C538T variant was not found in this population. The frequency of the Class I/Class I and Class I/Class II genotype for tetranucleotide polymorphisms was also significantly higher in the hypertensive compared to the normotensive group (p <= 0.0001). In addition, a significant correlation was found between serum leptin and Class I/I and Class I/II genotypes. Linear regression analysis showed an independent correlation of leptinemia with BMI (p=0.019), while a notable correlation was found between serum leptin concentration and angiotensin II. The study confirmed that shorter alleles of microsatellites in the 3' flanking region of leptin are significantly associated with hypertension, however, the underlying mechanism remains unknown. PMID- 22218755 TI - Skin fibroblasts as a tool for identifying the risk of nephropathy in the type 1 diabetic population. AB - Human fibroblasts in culture have been employed as an in vitro system to investigate some pathophysiological mechanisms of diabetes mellitus also associated with the development of diabetic nephropathy. In fact, there is increasing evidence that genetic factors either convey the risk of, or protect from, diabetic nephropathy and that the expression profiles and/or the behaviour of the cultured skin fibroblasts from type 1 diabetic patients could reflect these genetic influences. On the other hand, alterations could be attributable not only to changes in DNA sequence, but also to epigenetic factors. Our aim is to make a critical overview of the studies involving primary cultures of skin fibroblasts as tools to investigate the pathophysiology of diabetic nephropathy performed until now in this area. Cultured skin fibroblasts could be useful not only for the identification of patients at risk of developing diabetic renal disease, but also for a better understanding of the complex multifactorial mechanisms leading to the long-term complications in diabetes. PMID- 22218756 TI - Low expression and secretion of circulating soluble CTLA-4 in peripheral blood mononuclear cells and sera from type 1 diabetic children. AB - BACKGROUND: High levels of soluble cytotoxic T-lymphocyte antigen 4 (soluble CTLA 4), an alternative splice form of the regulatory T-cell (Treg) associated CTLA-4 gene, have been associated with type 1 diabetes (T1D) and other autoimmune diseases, such as Grave's disease and myasthenia gravis. At the same time, studies have shown soluble CTLA-4 to inhibit T-cell activation through B7 binding. This study aimed to investigate the role of soluble CTLA-4 in relation to full-length CTLA-4 and other Treg-associated markers in T1D children and in individuals with high or low risk of developing the disease. METHODS: T1D children were studied at 4 days, 1 and 2 years after diagnosis in comparison to individuals with high or low risk of developing the disease. Isolated peripheral blood mononuclear cells were stimulated with the T1D-associated glutamic acid decarboxylase 65 and phytohaemagglutinin. Subsequently, soluble CTLA-4, full length CTLA-4, FOXP3 and TGF-beta mRNA transcription were quantified and protein concentrations of soluble CTLA-4 were measured in culture supernatant and sera. RESULTS AND CONCLUSIONS: Low protein concentrations of circulating soluble CTLA-4 and a positive correlation between soluble CTLA-4 mRNA and protein were seen in T1D, in parallel with a negative correlation in healthy subjects. Further, low levels of mitogen-induced soluble CTLA-4 were accompanied by low C-peptide levels. Interestingly, low mitogen-induced soluble CTLA-4 mRNA and low TGF-beta mRNA expression were seen in high risk individuals, suggesting an alteration in activation and down-regulating immune mechanisms during the pre-diabetic phase. PMID- 22218757 TI - Strategies for insulin initiation: insights from the French LIGHT observational study. AB - BACKGROUND: The progressive nature of type 2 diabetes necessitates exogenous insulin use for most patients; basal insulin plus oral anti-diabetes drugs (OADs) is a well-validated way to facilitate insulin initiation. The primary aim of this study was to explore insulin initiation strategies and outcomes for patients using insulin detemir or glargine plus oral anti-diabetes drugs. METHODS: LIGHT was a 3-month, longitudinal observational study conducted across 761 French centres in insulin-naive type 2 diabetes patients managed under routine clinical care conditions, in either primary or secondary care. Endpoints included changes in HbA(1c) , fasting plasma glucose (FPG), rate of hypoglycaemia, weight, and adverse events. RESULTS: Most physicians initiated a basal analogue to improve glycaemic control (97%), with many delaying beginning treatment for several months (9 +/- 9.0 months for general practitioners, 10.2 +/- 16.2 months for specialists). Most patients continued oral anti-diabetes drug therapy (95%) and lifestyle measures (92%), with 2-3 blood glucose readings per day and follow-up telephone calls for dose optimization. Mean change in HbA(1c) from baseline was - 1.3%, and - 3.1 mmol/L for fasting plasma glucose (both p < 0.0001). Hypoglycaemia increased from 1.4 to 5.6 events/patient/year (p < 0.0001), and weight decreased on average by 0.5 kg with detemir, with no change in glargine. Most patients (93%) reported being satisfied or very satisfied with their insulin. CONCLUSIONS: Insulin initiation with detemir or glargine can be successfully managed in both primary and secondary care; the benefits of basal analogues (once-daily dosing, low rates of hypoglycaemia compared with neutral protamine Hagedorn) may have contributed to patient acceptance of the regimen. PMID- 22218758 TI - Hospitalizations due to primary care-sensitive cardiovascular conditions in municipalities of Central-West Brazil. AB - OBJECTIVE: To analyze rates of hospitalization due to primary care-sensitive cardiovascular conditions. METHODS: This ecological study on 237 municipalities in the state of Goias, Central-West Brazil, between 2000 and 2008, used data from the Hospital Information System and the Primary Care Information System. The hospitalization rates were calculated as the ratio between the number of hospitalizations due to cardiovascular conditions and the population over the age of 40 years. The data were evaluated over the three-year periods A (2000-2002), B (2003-2005) and C (2006-2008), according to sex, age group, population size, whether the individual belonged to the metropolitan region, healthcare macroregion, distance from the state capital, living conditions index and coverage within the Family Health Strategy. The potential population coverage of the Family Health Strategy was calculated in accordance with Ministry of Health guidelines. The variability of the rates was evaluated using the t test and ANOVA. RESULTS: A total of 253,254 hospitalizations (17.2%) occurred due to primary care-sensitive cardiovascular conditions. The hospitalization rates diminished between the three-year periods: A (213.5, SD = 104.6), B (199.7, SD = 96.3) and C (150.2, SD = 76.1), with differences from A to C and from B to C (p < 0.001). Municipal population size did not influence the behavior of the rates. Municipalities near the state capital and those in the metropolitan area presented higher rates (p < 0.001). At all percentiles of the Life and Health Conditions Index, there were decreases in the rates (p < 0.001), except at percentile 1. Decreases were also observed in all the macroregions except for the northeastern region of the state. The reduction in rates was independent of the Family Health Strategy coverage. CONCLUSION: The rates of hospitalization due to primary care-sensitive cardiovascular conditions decreased in these municipalities, independent of the Family Health Strategy coverage. PMID- 22218759 TI - Social determinants of the use of health services among a public university workers. AB - OBJECTIVE: To analyze the use of health services and socioeconomic status among a public university workers. METHODS: A cross-sectional study with 759 workers at a Brazilian public university who reported health-related restrictions of their usual activities in the previous 14 days, was carried out. Data were supplied by the 2001 cohort of the "Pro-Saude Study" in Rio de Janeiro, Southeastern Brazil. Health services use was assessed with a proxy for "seeking health care" and according to the type of service. The presence of additional variation in morbidity was verified by time restriction. Schooling, income and occupation markers were analyzed, and crude and adjusted proportion ratios of use and types of service were calculated. RESULTS: The occupation level was the indicator of the greatest inequality in health services use. After adjustments for gender, age and the other socioeconomic status markers, the ratio of the proportion of health care use was 1.31 for manual workers (95%CI: 1.11;1.55) and 1.21 for non-manual workers (95%CI: 1.06;1.37) compared to the reference category of professionals. CONCLUSIONS: A pattern of social inequality was identified in health services use. Even after an adjustment for health need, the pattern favored individuals with lower socioeconomic status, particularly for the occupation marker. Remaining differences in individual morbidities do not explain this finding. Rather, occupational factors may exert a greater influence on health services use in this population. PMID- 22218760 TI - Infant mortality and geographic access to childbirth in Brazilian municipalities. AB - OBJECTIVE: To analyze geographic access to hospital childbirth in Brazilian municipalities. METHODS: Information on deaths and births were analyzed in regards to appropriateness for calculating the infant mortality rate during the period 2005 to 2007, for the 5,564 Brazilian municipalities. Indicators of supply and geographic access to health services were calculated to express hospital childbirth access. A multivariate regression model was used to test the association between geographic access to childbirth and the infant mortality rate in municipalities with adequate vital information. RESULTS: Of the municipalities analyzed, 56% had adequate vital information, corresponding to 72% of Brazil's population. The geographic distance between the municipality of residence and municipality of hospitalization was inversely associated to population size, per capita income and the infant mortality rate, even when controlling for demographic and socioeconomic factors. CONCLUSIONS: Although important strategies have been developed in Brazil to improve the quality of care for pregnant women, actions to guarantee equal access to childbirth services are still insufficient. Large geographic distance to childbirth facility was identified as a risk factor for infant mortality, together with unequal supply of quality health services and lack of integration with primary care. PMID- 22218761 TI - Predictors of dental visits for routine check-ups and for the resolution of problems among preschool children. AB - OBJECTIVE: To estimate the prevalence of dental visits among preschool children and determine the factors associated with using dental services. METHODS: A cross sectional study was conducted with 1,129 five-year-old children from the Pelotas Birth Cohort Study in Pelotas (Southern Brazil) 2004, from September 2009 to January 2010. Use of dental services at least once in the child's life and the reason for the child's first dental visit were recorded. The categories assigned for the first dental visit were: routine check-up, resolution of a problem, or never saw a dentist. The oral examinations and interviews were performed in the children's homes. Socioeconomic aspects and independent variables related to the mother and child were analyzed using multivariable logistic regression. RESULTS: The prevalence of dental visits (both categories combined) was 37.0%. The main predictors for a routine visit were higher economic status, mothers with more schooling, and mothers who had received guidance about prevention. Major predictors for a visit because of a problem were having felt pain in the previous six months, mothers with higher education level, and mothers who had received guidance about prevention. Approximately 45.0% of mothers received information about how to prevent cavities, usually from the dentist. Children of mothers who adhered to health programs were more likely to have had a routine dental visit. CONCLUSIONS: The rate of preschool visits to dental services was lower than the rate for medical appointments (childcare). In addition to income and education, maternal behavior plays an important role in routine visits. Pain reported in the last six months and a high number of teeth affected by tooth decay, independent of other factors, were associated with visits for a specific problem. It is important to integrate oral health instruction into maternal and child health programs. PMID- 22218762 TI - Counterfeiting of drugs in Brazil. AB - OBJECTIVE: To identify the main counterfeit drugs seized by the Brazilian Federal Police and the states where seizures have been made. METHODS: A retrospective descriptive study on expert reports produced by criminal investigators of the Federal Police between January 2007 and September 2010, in relation to counterfeit drugs, was carried out. RESULTS: The drugs with greatest numbers of seizures were selective phosphodiesterase-5 inhibitors that are used for treating male erectile dysfunction (Cialis(r) and Viagra(r), mean = 66% ), followed by anabolic steroids (Durateston(r) and Hemogenin(r): 8.9% and 5.7%, respectively). The greatest proportions of the counterfeit drugs were seized in the states of Parana, Santa Catarina (both Southeastern Brazil) and Sao Paulo (Southeastern), and the number of non-authentic drugs sent for investigation increased by more than 200% over the study period. There were increases in seizures of smuggled drugs found together with counterfeit drugs: 67% of the seizures included at least one smuggled drug. CONCLUSIONS: Counterfeiting of drugs is a severe public health problem. Identification of the classes of counterfeit drugs present in Brazil and the main Brazilian states with this problem may facilitate future preventive and suppressive actions by the Brazilian bodies responsible for such actions. PMID- 22218764 TI - Porous salts based on the pamoate ion. AB - A number of porous salts based on the pamoate anion in combination with lutidinium or picolinium cations have been characterised. One salt undergoes single-crystal to single-crystal solvent exchange, while another isostructural series of salts contain channels that can be partly evacuated without collapse of the framework. PMID- 22218763 TI - MicroRNAs: novel regulators of oligodendrocyte differentiation and potential therapeutic targets in demyelination-related diseases. AB - MicroRNAs (miRNAs or miRs) are a class of endogenous small non-coding RNAs that consist of about 22 nucleotides and play critical roles in various biological processes, including cell proliferation, differentiation, apoptosis, and tumorigenesis. In recent years, some specific miRNA, such as miR-219, miR-138, miR-9, miR-23, and miR-19b were found to participate in the regulation of oligodendrocyte (OL) differentiation and myelin maintenance, as well as in the pathogenesis of demyelination-related diseases (e.g., multiple sclerosis, ischemic stroke, and leukodystrophy). These miRNAs control their target mRNA or regulate the protein levels of some signaling pathways, and participate in OL differentiation and the pathogenesis of demyelination-related diseases. During pathologic processes, the expression levels of specific miRNAs are dynamically altered. Therefore, miRNAs act as diagnostic and prognostic indicators of defects in OL differentiation and demyelination-related diseases, and they can provide potential targets for therapeutic drug development. PMID- 22218765 TI - A kinetic modeling for carbon metabolism in sequencing batch reactor under multiple aerobic/anoxic conditions. AB - In order to further investigate activated sludge system for better carbon metabolism and nitrogen removal with less energy consumption, a new kinetic model was established. The detailed description of the proposed model was introduced for understanding the mechanisms involved in the activated sludge system, especially simultaneous substrate storage and biomass growth (SSSG) processes and soluble microbial product generation. The evaluation of the proposed model was demonstrated by a lab-scale sequencing batch reactor (SBR) operated with three different sets, i.e., aeration/non-aeration (set 1), non-aeration/aeration/non aeration (set 2), and alternating aeration/non-aeration (set 3) processes. The purpose was to investigate carbon metabolism under multiple aerobic/anoxic conditions. The calibrated results showed quite an acceptable model fit to the on line measured dissolved oxygen (DO) data for the three SBR sets. Predictions of the calibrated model were successfully confirmed using off-line analyses of soluble chemical oxygen demands (COD) and nitrogen dynamic variations, respectively. The simulated results showed that more SMP was generated under aerobic condition than that under anoxic condition, and more nitrate (S (NO)) consumption resulted in less SMP generation, i.e., approximately 7% and 57% less extra carbon source in sets 2 and 3 were required to remove 8% and 58% of S (NO), respectively, compared with set 1. And the kinetics of SSSG process in the proposed model was indirectly validated by comparisons between experimental DO profiles and simulations. Therefore, the new model provides an effective technique for better optimizing the effluent COD and nitrogen with low energy cost in biological wastewater treatment plants. PMID- 22218766 TI - Improving the performance of an end-point PCR assay commonly used for the detection of Bacteroidales pertaining to cow feces. AB - Bacteroidales are normal gut flora of warm-blooded animals. Since each host species carries a different diversity of Bacteroidales, the detection of host associated gene markers of Bacteroidales has emerged as a promising tool for the tracking of the source of fecal pollution in aquatic ecosystems. To detect cow associated Bacteroidales, a commonly used method has been an end-point PCR assay with the 16S rRNA genes primers CF128F (cow-associated) and Bac708R (all Bacteroidales). The PCR assay has demonstrated high rates of true-positive detection (i.e., high sensitivity) in all previous studies. However, the assay also had high rates of false-positive detection to the samples of non-target hosts in some cases (i.e., low specificity). In opposite to the reason many investigators have proposed, our results suggested that false detection was not necessarily due to the presence of the target sequence of CF128F in the feces of non-target hosts. Instead, we found sequences of non-target hosts having single internal mismatches with CF128F. Those mismatches were well tolerated in PCR, partly due to the universality of Bac708R. To improve the detection performance, we designed a novel primer CF592R (targeting the same clade of sequences as CF128F) to substitute Bac708R. The use of CF529R alleviated false detection and also led to a tenfold reduction in detection limit in the samples tested, compared to the use of Bac708R. Many other end-point PCR assays that detect the 16S rRNA genes in Bacteroidales also use a host-associated primer to couple with Bac708R, and low specificity or sensitivity has been reported. Based on our findings for CF128F, we suggest that the suitability of Bac708R in those PCR assays needs to be revisited. PMID- 22218767 TI - Expression of a library of fungal beta-glucosidases in Saccharomyces cerevisiae for the development of a biomass fermenting strain. AB - Converting cellulosic biomass to ethanol involves the enzymatic hydrolysis of cellulose and the fermentation of the resulting glucose. The yeast Saccharomyces cerevisiae is naturally ethanologenic, but lacks the enzymes necessary to degrade cellulose to glucose. Towards the goal of engineering S. cerevisiae for hydrolysis of and ethanol production from cellulose, 35 fungal beta-glucosidases (BGL) from the BGL1 and BGL5 families were screened for their ability to be functionally expressed and displayed on the cell surface. Activity assays revealed that the BGL families had different substrate specificities, with only the BGL1s displaying activity on their natural substrate, cellobiose. However, growth on cellobiose showed no correlation between the specific growth rates, the final cell titer, and the level of BGL1 activity that was expressed. One of the BGLs that expressed the highest levels of cellobiase activity, Aspergillus niger BGL1 (Anig-Bgl101), was then used for further studies directed at developing an efficient cellobiose-fermenting strain. Expressing Anig-Bgl101 from a plasmid yielded higher ethanol levels when secreted into the medium rather than anchored to the cell surface. In contrast, ethanol yields from anchored and secreted Anig Bgl101 were comparable when integrated on the chromosome. Flow cytometry analysis revealed that chromosomal integration of Anig-Bgl101 resulted in a higher percentage of the cell population that displayed the enzyme but with overall lower expression levels. PMID- 22218768 TI - Metabolic control of Clostridium thermocellum via inhibition of hydrogenase activity and the glucose transport rate. AB - Clostridium thermocellum has the ability to catabolize cellulosic biomass into ethanol, but acetic acid, lactic acid, carbon dioxide, and hydrogen gas (H(2)) are also produced. The effect of hydrogenase inhibitors (H(2), carbon monoxide (CO), and methyl viologen) on product selectivity was investigated. The anticipated effect of these hydrogenase inhibitors was to decrease acetate production. However, shifts to ethanol and lactate production are also observed as a function of cultivation conditions. When the sparge gas of cellobiose limited chemostat cultures was switched from N(2) to H(2), acetate declined, and ethanol production increased 350%. In resting cell suspensions, lactate increased when H(2) or CO was the inhibitor or when the cells were held at elevated hyperbaric pressure (6.8 atm). In contrast, methyl-viologen-treated resting cells produced twice as much ethanol as the other treatments. The relationship of chemostat physiology to methyl viologen inhibition was revealed by glucose transport experiments, in which methyl viologen decreased the rate of glucose transport by 90%. C. thermocellum produces NAD(+) from NADH by H(2), lactate, and ethanol production. When the hydrogenases were inhibited, the latter two products increased. However, excess substrate availability causes fructose 1,6 diphosphate, the glycolytic intermediate that triggers lactate production, to increase. Compensatory ethanol production was observed when the chemostat fluid dilution rate or methyl viologen decreased substrate transport. This research highlights the complex effects of high concentrations of dissolved gases in fermentation, which are increasingly envisioned in microbial applications of H(2) production for the conversion of synthetic gases to chemicals. PMID- 22218770 TI - Microbial and fungal protease inhibitors--current and potential applications. AB - Proteolytic enzymes play essential metabolic and regulatory functions in many biological processes and also offer a wide range of biotechnological applications. Because of their essential roles, their proteolytic activity needs to be tightly regulated. Therefore, small molecules and proteins that inhibit proteases can be versatile tools in the fields of medicine, agriculture and biotechnology. In medicine, protease inhibitors can be used as diagnostic or therapeutic agents for viral, bacterial, fungal and parasitic diseases as well as for treating cancer and immunological, neurodegenerative and cardiovascular diseases. They can be involved in crop protection against plant pathogens and herbivorous pests as well as against abiotic stress such as drought. Furthermore, protease inhibitors are indispensable in protein purification procedures to prevent undesired proteolysis during heterologous expression or protein extraction. They are also valuable tools for simple and effective purification of proteases, using affinity chromatography. Because there are such a large number and diversity of proteases in prokaryotes, yeasts, filamentous fungi and mushrooms, we can expect them to be a rich source of protease inhibitors as well. PMID- 22218769 TI - Expanding the set of rhodococcal Baeyer-Villiger monooxygenases by high throughput cloning, expression and substrate screening. AB - To expand the available set of Baeyer-Villiger monooxygenases (BVMOs), we have created expression constructs for producing 22 Type I BVMOs that are present in the genome of Rhodococcus jostii RHA1. Each BVMO has been probed with a large panel of potential substrates. Except for testing their substrate acceptance, also the enantioselectivity of some selected BVMOs was studied. The results provide insight into the biocatalytic potential of this collection of BVMOs and expand the biocatalytic repertoire known for BVMOs. This study also sheds light on the catalytic capacity of this large set of BVMOs that is present in this specific actinomycete. Furthermore, a comparative sequence analysis revealed a new BVMO-typifying sequence motif. This motif represents a useful tool for effective future genome mining efforts. PMID- 22218772 TI - The impact of dissolved organic carbon on the spatial variability of methanogenic archaea communities in natural wetland ecosystems across China. AB - Significant spatial variation in CH(4) emissions is a well-established feature of natural wetland ecosystems. To understand the key factors affecting CH(4) production, the variation in community structure of methanogenic archaea, in relation to substrate and external environmental influences, was investigated in selected wetlands across China, using denaturing gradient gel electrophoresis. Case study areas were the subtropical Poyang wetland, the warm-temperate Hongze wetland, the cold-temperate Sanjiang marshes, and the alpine Ruoergai peatland on the Qinghai-Tibetan Plateau. The topsoil layer in the Hongze wetland exhibited the highest population of methanogens; the lowest was found in the Poyang wetland. Maximum CH(4) production occurred in the topsoil layer of the Sanjiang Carex lasiocarpa marsh, the minimum was observed in the Ruoergai peatland. CH(4) production potential was significantly correlated with the dissolved organic carbon (DOC) concentration but not with the abundance or diversity indices of methanogenic archaea. Phylogenetic analysis and DOC concentration indicated a shift in the dominant methanogen from the hydrogenotrophic Methanobacteriales in DOC-rich wetlands to Methanosarcinaceae with a low affinity in wetlands with relatively high DOC and then to the acetotrophic methanogen Methanosaetaceae with a high affinity in wetlands with low DOC, or with high DOC but rich sulfate reducing bacteria. Therefore, it is proposed that the dominant methanogen type in wetlands is primarily influenced by available DOC concentration. In turn, the variation in CH(4) production potential in the wetlands of eastern China is attributable to differences in the DOC content and the dominant type of methanogen present. PMID- 22218771 TI - Simultaneous removal of phosphorus and nitrogen in a sequencing batch biofilm reactor with transgenic bacteria expressing polyphosphate kinase. AB - To improve phosphorus removal from wastewater, we constructed a high-phosphate accumulating microorganism, KTPPK, using Pseudomonas putida KT2440 as a host. The expression plasmid was constructed by inserting and expressing polyphosphate kinase gene (ppk) from Microcystis aeruginosa NIES-843 into broad-host-range plasmid, pBBR1MCS-2. KTPPK was then added to a sequencing batch biofilm reactor (SBBFR) using lava as a biological carrier. The results showed that SBBFR with KTPPK not only efficiently removed COD, NH(3)-N, and NO(3)(-)-N but also had a high removal capacity for PO(4)(3-)-P, resulting in a low phosphorus concentration remaining in the outflow of the SBBFR. The biofilm increased by 30 53% on the lava in the SBBFR that contained KTPPK after 11 days when compared with the reactor that contained P. putida KT2440. Real-time quantitative polymerase chain reaction confirmed that the copy of ppk was maintained at about 3.5 * 10(10) copies per MUL general DNA in the biofilm after 20 days. Thus, the transgenic bacteria KTPPK could maintain a high density and promote phosphorus removal in the SBBFR. In summary, this study indicates that the use of SBBFR with transgenic bacteria has the potential to remove phosphorus and nitrogen from wastewater. PMID- 22218774 TI - Quantum-mechanical interference in charge exchange between hydrogen and graphene like surfaces. AB - The neutral to negative charge fluctuation of a hydrogen atom in front of a graphene surface is calculated by using the Anderson model within an infinite intra atomic Coulomb repulsion approximation. We perform an ab initio calculation of the Anderson hybridization function that allows investigation of the effect of quantum-mechanical interference related to the Berry phase inherent to the graphene band structure. We find that consideration of the interaction of hydrogen on top of many C atoms leads to a marked asymmetry of the imaginary part of the hybridization function with respect to the Fermi level. Consequently, Fano factors larger than one and strongly dependent on the energy around the Fermi level are predicted. Moreover, the suppression of the hybridization for energies above the Fermi level can explain the unexpected large negative ion formation measured in the scattering of protons by graphite-like surfaces. PMID- 22218776 TI - Shall we use endoscopic submucosal dissection for every gastric neoplasia? PMID- 22218775 TI - The inflammatory network in the gastrointestinal tumor microenvironment: lessons from mouse models. AB - Accumulating evidence has indicated that inflammatory responses are important for cancer development. Epidemiological studies have shown that regular use of non steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of colon cancer development. Subsequently, mouse genetic studies have shown that cyclooxygenase (COX)-2, one of the target molecules of NSAIDs, and its downstream product, prostaglandin E(2) (PGE(2)), play an important role in gastrointestinal tumorigenesis. Bacterial infection stimulates the Toll-like receptor (TLR)/MyD88 pathway in tumor tissues, which leads to the induction of COX-2 in stromal cells, including macrophages. Induction of the COX-2/PGE(2) pathway in tumor stroma is important for the development and maintenance of an inflammatory microenvironment in gastrointestinal tumors. In such a microenvironment, tumor-associated macrophages express proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and these cytokines, respectively, activate the nuclear factor (NF)-kappaB and Stat3 transcription factors in epithelial cells, as well as in stromal cells. Recent mouse studies have uncovered the role of such an inflammatory network in the promotion of gastrointestinal tumor development. Genetically engineered and chemically induced mouse tumor models which mimic sporadic or inflammation-associated tumorigenesis were used in these studies. In this review article, we focus on mouse genetic studies using these tumor models, which have contributed to the elucidation of the molecular mechanisms associated with the inflammatory network in gastrointestinal tumors, and we also discuss the role of each pathway in cancer development. The involvement of immune cells such as macrophages, mast cells, and regulatory T cells in tumor promotion is also discussed. PMID- 22218777 TI - Paediatric clear cell meningioma with multiple distant recurrences after presumed intra-operative cell spread. PMID- 22218778 TI - Physical activity benefits bone density and bone-related hormones in adult men with cervical spinal cord injury. AB - Severe bone loss is a recognized complication of chronic spinal cord injury (SCI). Physical exercise contributes to bone health; however, its influence on bone mass of cervical SCI individuals has not been investigated. The aim of this study was to investigate the influence of physical activity on bone mass, bone metabolism, and vitamin D status in quadriplegics. Total, lumbar spine (L1-L4), femur and radius bone mineral density (BMD) were assessed in active (n = 15) and sedentary (n = 10) quadriplegic men by dual energy X-ray absorptiometry. Concentrations of 25-hydroxyvitamin D [25(OH)D], PTH, IGF1, osteocalcin and NTx were measured in serum. After adjustments for duration of injury, total body mass, and habitual calcium intake, bone indices were similar between groups, except for L1-L4 BMD Z score that was higher in the sedentary group (P < 0.05). Hours of physical exercise per week correlated positively with 25(OH)D (r = 0.59; P < 0.05) and negatively with PTH (r = -0.50; P < 0.05). Femur BMD was negatively associated with the number of months elapsed between the injury and the onset of physical activity (r = -0.60; P < 0.05). Moreover, in the active subjects, both L1-L4 BMD Z score (r = 0.72; P < 0.01) and radius BMD (r = 0.59; P < 0.05) were positively associated with calcium intake. In this cross-sectional study, both the onset of physical activity after injury and the number of hours dedicated to exercise were able to influence bone density and bone-related hormones in quadriplegic men. Our results also suggest a positive combined effect of exercise and calcium intake on bone health of quadriplegic individuals. PMID- 22218779 TI - Cognitive impairment in antiphospholipid syndrome: evidence from animal models. AB - Although antiphospholipid syndrome (APS) is a multisystem prothrombotic condition, its inflammatory nature has been increasingly recognized in recent years. Stroke and transitory ischemic attacks are the neurological manifestations included in APS criteria, however many other neurological involvements have been attributed to antiphospholipid antibodies (aPL), such as seizures, transverse myelitis, and cognitive impairment. In this article we will review evidence from animal model that explain the role of aPL in cognition. PMID- 22218780 TI - Chronic hyponatremia exacerbates multiple manifestations of senescence in male rats. AB - The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is frequently responsible for chronic hyponatremia in the elderly due to age-related disruption of the inhibitory component of brain osmoregulatory mechanisms. Recent research has indicated that chronic hyponatremia is associated with gait disturbances, increased falls, and bone fragility in humans, and we have found that chronic hyponatremia causes increased bone resorption and reduced bone mineral density in young rats. In this study, we used a model of SIADH to study multi-organ consequences of chronic hyponatremia in aged rats. Sustained hyponatremia for 18 weeks caused progressive reduction of bone mineral density by DXA and decreased bone ash calcium, phosphate and sodium contents at the tibia and lumbar vertebrae. Administration of 10-fold higher vitamin D during the last 8 weeks of the study compensated for the reduction in bone formation and halted bone loss. Hyponatremic rats developed hypogonadism, as indicated by slightly lower serum testosterone and higher serum FSH and LH concentrations, markedly decreased testicular weight, and abnormal testicular histology. Aged hyponatremic rats also manifested decreased body fat, skeletal muscle sarcopenia by densitometry, and cardiomyopathy manifested as increased heart weight and perivascular and interstitial fibrosis by histology. These findings are consistent with recent results in cultured osteoclastic cells, indicating that low extracellular sodium concentrations increased oxidative stress, thereby potentially exacerbating multiple manifestations of senescence. Future prospective studies in patients with SIADH may indicate whether these multi-organ age-related comorbidities may potentially contribute to the observed increased incidence of fractures and mortality in this population. PMID- 22218783 TI - Enclosure size and the use of local and global geometric cues for reorientation. AB - Multiple spatial cues are utilized to orient with respect to the environment, but it remains unclear why feature (i.e., objects in the environment) and geometric (i.e., shape of the environment) cues are differentially influenced by enclosure size, and the extent to which local (i.e., wall lengths and corner angles) and global (i.e., principal axis of space) geometric cues are influenced by enclosure size. In the present study, we investigated the extent to which environmental size influenced the use of corner angle (i.e., a local geometric cue) and the principal axis of space (i.e., a global geometric cue) for reorientation. We developed an orientation task that allowed the manipulation of enclosure size during training and the isolation of the use of the principal axis of space during testing. Participants were trained to respond to a location in either a small or a large trapezoid-shaped enclosure uniquely specified by both local (i.e., wall lengths and corner angles) and global (i.e., principal axis of space) geometric cues. During testing, we presented both groups with a small and large rectangle (to assess the use of principal axis of space) and a small and large parallelogram (to asses relative use of corner angles and the principal axis of space when in conflict). Enclosure size influenced the relative use of corner angles but not of the principal axis of space. Results suggest that corner angles function like features and that changes in the use of feature cues are the source of the relative reliance on feature and geometric cues during changes of enclosure size. PMID- 22218785 TI - Vicarious viewing time: prolonged response latencies for sexually attractive targets as a function of task- or stimulus-specific processing. AB - The amount of time an individual spends gazing at images is longer if the depicted person is sexually appealing. Despite an increasing use of such response latencies as a diagnostic tool in applied forensic settings, the underlying processes that drive the seemingly robust effect of longer response latencies for sexually attractive targets remain unknown. In the current study, two alternative explanations are presented and tested using an adapted viewing time paradigm that disentangled task- and stimulus-specific processes. Heterosexual and homosexual male participants were instructed to rate the sexual attractiveness of target persons differing in sex and sexual maturation from four experimentally assigned perspectives--heterosexual and homosexual perspectives for both sexes. This vicarious viewing time paradigm facilitated the estimation of the independent contributions of task (assigned perspective) and stimuli to viewing time effects. Results showed a large task-based effect as well as a relatively smaller stimulus based effect. This pattern suggests that, when viewing time measures are used for the assessment of sexual interest, it should be taken into consideration that response latency patterns can be biased by judging images from a selected perspective. PMID- 22218782 TI - The negative effect of prolonged somatotrophic/insulin signaling on an adult bone marrow-residing population of pluripotent very small embryonic-like stem cells (VSELs). AB - It is well known that attenuated insulin/insulin-like growth factor signaling (IIS) has a positive effect on longevity in several animal species, including mice. Here, we demonstrate that a population of murine pluripotent very small embryonic-like stem cells (VSELs) that reside in bone marrow (BM) is protected from premature depletion during aging by intrinsic parental gene imprinting mechanisms and the level of circulating insulin-like growth factor-I (IGF-I). Accordingly, an increase in the circulating level of IGF-I, as seen in short lived bovine growth hormone (bGH)-expressing transgenic mice, which age prematurely, as well as in wild-type animals injected for 2 months with bGH, leads to accelerated depletion of VSELs from bone marrow (BM). In contrast, long living GHR-null or Ames dwarf mice, which have very low levels of circulating IGF I, exhibit a significantly higher number of VSELs in BM than their littermates at the same age. However, the number of VSELs in these animals decreases after GH or IGF-I treatment. These changes in the level of plasma-circulating IGF-I corroborate with changes in the genomic imprinting status of crucial genes involved in IIS, such as Igf-2-H19, RasGRF1, and Ig2R. Thus, we propose that a chronic increase in IIS contributes to aging by premature depletion of pluripotent VSELs in adult tissues. PMID- 22218781 TI - Primate aging in the mammalian scheme: the puzzle of extreme variation in brain aging. AB - At later ages, humans have high risk of developing Alzheimer disease (AD) which may afflict up to 50% by 90 years. While prosimians and monkeys show more substantial changes, the great apes brains examined show mild neurodegenerative changes. Compared with rodents, primates develop and reproduce slowly and are long lived. The New World primates contain some of the shortest as well as some of the longest-lived monkey species, while the prosimians develop the most rapidly and are the shortest lived. Great apes have the largest brains, slowest development, and longest lives among the primates. All primates share some level of slowly progressive, age-related neurodegenerative changes. However, no species besides humans has yet shown regular drastic neuron loss or cognitive decline approaching clinical grade AD. Several primates accumulate extensive deposits of diffuse amyloid-beta protein (Abeta) but only a prosimian-the gray mouse lemur regularly develops a tauopathy approaching the neurofibrillary tangles of AD. Compared with monkeys, nonhuman great apes display even milder brain-aging changes, a deeply puzzling observation. The genetic basis for these major species differences in brain aging remains obscure but does not involve the Abeta coding sequence which is identical in nonhuman primates and humans. While chimpanzees merit more study, we note the value of smaller, shorter-lived species such as marmosets and small lemurs for aging studies. A continuing concern for all aging studies employing primates is that relative to laboratory rodents, primate husbandry is in a relatively primitive state, and better husbandry to control infections and obesity is needed for brain aging research. PMID- 22218786 TI - Is pedophilia a sexual orientation? AB - In this article, I address the question of whether pedophilia in men can be construed as a male sexual orientation, and the implications for thinking of it in this way for scientific research, clinical practice, and public policy. I begin by defining pedophilia and sexual orientation, and then compare pedophilia (as a potential sexual orientation with regard to age) to sexual orientations with regard to gender (heterosexuality, bisexuality, and homosexuality), on the bases of age of onset, correlations with sexual and romantic behavior, and stability over time. I conclude with comments about the potential social and legal implications of conceptualizing pedophilia as a type of sexual orientation in males. PMID- 22218788 TI - The debate about paraphilic coercive disorder is mostly ideological and going nowhere. PMID- 22218787 TI - Are HIV-negative men who have sex with men and who bareback concerned about HIV infection? Implications for HIV risk reduction interventions. AB - The emergence of barebacking (intentional unprotected anal intercourse in situations where there is risk of HIV infection) among men who have sex with men (MSM) has been partially attributed to a decrease in HIV-related concerns due to improved anti-retroviral treatment. It is important to understand the level of concern these men have regarding HIV infection because it can affect their interest in risk reduction behaviors as well as their possible engagement in risk reduction interventions. As part of a study on MSM who use the Internet to seek sexual partners, 89 ethnic and racially diverse men who reported never having an HIV-positive test result completed an in-depth qualitative interview and a computer-based quantitative assessment. Of the 82 men who were asked about concerns of HIV infection during the qualitative interviews, 30 expressed "significant concern" about acquiring HIV, 42 expressed "moderate concern," and 10 expressed "minimal concern." Themes that emerged across the different levels of concern were their perceptions of the severity of HIV infection, having friends who were HIV positive, and their own vulnerability to HIV infection. However, these themes differed depending on the level of concern. Among the most frequently mentioned approaches to decrease risk of HIV infection, participants mentioned avoiding HIV-positive sex partners, limiting the number of partners with whom they barebacked, and not allowing partners to ejaculate inside their rectum. Findings suggest that many MSM who bareback would be amenable to HIV prevention efforts that do not depend solely on condom use. PMID- 22218789 TI - DSM-5 paraphilic diagnoses and SVP law. PMID- 22218790 TI - [Breast cancer prevention and the need for a professional approach to its detection and control]. PMID- 22218791 TI - Breast cancer in the world: incidence and mortality. AB - The aim of this paper is to describe the burden of breast cancer in the world, as the now most common cancer in women in the globe. Here a descriptive pattern based on information available in IARC and WHO databases describing estimated age specific incidence is presented, both for incidence and mortality. The newer treatment modalities and screening programs have been developed to alleviate the burden of this disease, but much more needs to be done in the developing countries for the impact to reach outside of the developed nations. PMID- 22218792 TI - [Breast cancer mortality trends in Mexico, 1980-2009]. AB - Breast cancer has become an important health risk for women worldwide.The important growth of breast cancer-related deaths within those caused by malign tumors throughout the globe went past the 460 000 in 2008,becoming the deadliest disease worldwide. Demographic changes and lifestyles have modified the population exposure to risk factors of maladies such as cancer, and since 1980 breast cancer mortality has remained on an upward tendency, surpassing cervical cancer in 2006. After analyzing mortality rates along 30 years in Mexican women 25 or more years old, differences by state and age-groups are apparent. Although this cause of death has been associated with a highest regional development, some changes are taking place,since the number of deaths is also growing among women of less-developed regions in the country,as showed in this work. Mexico faces an evident challenge regarding breast cancer. Our country requires to join efforts and implement programs aimed at teaching self-care of health among the population,promoting healthier lifestyles, and reshaping our diagnostic infrastructure to achieve earlier detection and provide proper treatment. PMID- 22218793 TI - International programs for the detection of breast cancer. AB - The benefit of early breast cancer detection is the foundation for programs around the globe to reduce morbidity and mortality related to breast cancer. These programs range from educational programs targeted to women and health professionals to organized or opportunistic screening programs that target specific age groups of women. Modern mammography programs tend to follow the protocols from the randomized clinical trials, but there is variation in key program elements such as the age groups invited to screening, the screening interval, performance indicators, and the uptake rate. Until recently, the emphasis on early breast cancer detection was limited to mammography, but the steady rise in incidence and mortality in low and medium resource countries, where mammography may be unaffordable, has led to a renewal in emphasizing the incremental value of downsizing palpable tumors through physical exams. There is consensus that programs should be designed based on disease burden and available resources, but that even in low resource countries there are opportunities to reduce breast deaths through earlier diagnosis and effective treatment. Screening programs are most effective when they are organized, and program planners should consider WHO criteria and local input data as a basis for tailoring screening programs to the needs of their population. PMID- 22218794 TI - [Carcinogenesis]. AB - Cell division is controlled by stimulatory and inhibitory systems.The origin of cancer is monoclonal, and in order that a normal cell switches its phenotype and becomes a neoplastic cell, genetic mutations must occur on it.These genetic mutations modify the products that in normal conditions the gene would codify and, finally, cause cancer. Cancer may be hereditary (due to mutations in one or both of germinal cells alleles) or sporadic (due to action of environmental mutagenic agents).The mechanisms that may cause alterations on genes may be genetic or epigenetic. Genetic mechanisms occur when structural alterations of genome are present and the epigenetic processes occur due to enzymatic alterations or alterations on its substrates. Carcinogenesis has three stages: initiation, promotion and progression.The last of these stages, progression, is exclusive of malignant transformation and implies the capacity to invade surrounding or distant tissues. For metastasis to take place, many mechanisms are required: angiogenesis, matrix degradation, cell migration, evasion of host immune response and metastatic colonization. This article presents a partial review of current bibliography about concepts related to carcinogenesis and conveys the minimum necessary information to achieve an understanding of this complex process. PMID- 22218795 TI - Genetics of breast cancer: applications to the Mexican population. AB - Breast cancer research has yielded several important results including the strong susceptibility genes,BRCA1 and BRCA2 and more recently 19 genes and genetic loci that confer a more moderate risk.The pace of discovery is accelerating as genetic technology and computational methods improve. These discoveries will change the way that breast cancer risk is understood in Mexico over the next few decades. PMID- 22218796 TI - [Genetic predisposition for breast cancer: BRCA1 and BRCA2 genes]. AB - The discovery of genes BRCA1 and BRCA2 has led to the introduction of genetic tests more complex every time for the evaluation of the hereditary cancer risk, among others. In the present paper we explore the criteria to decide when to run the testing for the genes, as well as the implications for the treatment of patients who are identified with them. PMID- 22218797 TI - Diet and breast cancer. AB - Both diet and nutrition have been studied in relationship with breast cancer risk, as the great variation among different countries in breast cancer incidence could possibly be explained through the inflammatory and immune response, as well as antioxidant intake, among others. To date, no clear association with diet beyond overweight and weight gain has been found, except for alcohol consumption. Nonetheless, the small number of studies done in middle to low income countries where variability of food intake is wider, is beginning to show interesting results. PMID- 22218798 TI - Alcohol consumption and the risk of breast cancer. AB - Epidemiologic studies addressing the association of alcohol consumption with breast cancer consistently suggest a modest association and a dose-response relationship. The epidemiologic evidence does not point to a single mechanism to explain the association, and several mechanisms have been proposed. Alcohol consumption is shown to increase levels of endogenous estrogens, known risk factors for breast cancer. This hypothesis is further supported by data showing that the alcohol-breast cancer association is limited to women with estrogen receptor positive tumors. Products of alcohol metabolism are known to be toxic and are hypothesized to cause DNA modifications that lead to cancer. Recent research has focused on genes that influence the rate of alcohol metabolism, with genes that raise blood concentrations of acetaldehyde hypothesized to heighten breast cancer risk. Mounting evidence suggests that antioxidant intake(e.g.folate)mayreducealcohol-associatedbreast cancer risk, because it neutralizes reactive oxygen species, a second-stage product of alcohol metabolism. Diets lacking sufficient antioxidant intake, as a result, may further elevate the risk of breast cancer among alcohol consumers. Given that alcohol consumption is increasing worldwide and especially among women in countries of rapid economic growth, a greater understanding of the mechanisms underlying the known alcohol-breast cancer association is warranted. Avoiding overconsumption of alcohol is recommended, especially for women with known risk factors for breast cancer. PMID- 22218804 TI - Synthesis and characterization of a ferrocene-linked bis-fullerene[60] dumbbell. AB - A new [60]fullerene dumbbell consisting of two fulleropyrrolidines connected to a central ferrocene unit by amide linkages has been prepared and fully characterized by elemental analysis, (1)H NMR, UV/Vis, fluorescence and mass spectrometry. The electrochemical properties as determined by cyclic voltammetry show ground state electronic communication between the ferrocene and the fullerene units. In addition, the preparaton of a ferrocene building block for an alternative linking approach is presented. PMID- 22218805 TI - Growing normally in an urban environment: positive deviance among slum children of Vadodara, India. AB - OBJECTIVE: To assess factors contributing to positive deviance among the urban poor of Vadodara city. METHODS: Mothers of sixty 6-18 mo old children- 30 each in positive deviant (PD: normal by weight-age) and negative deviant (ND: grade II by weight-age) groups-were interviewed through home visits using semi-structured questionnaires. RESULTS: Factors contributing significantly to PD (p < 0.01): PD children (vs. ND), were older (12-18 mo vs. 6-11 mo); families were smaller (5-7 vs. >7 members), of lower parity (1-2 vs. 3-4), greater birth interval (>3 y vs. 1-2 y); received colostrum (96% vs. 26%), breastfed at least 8-9 times/d (86% vs. 20%); were started on complementary feeds (CF) at 6-8 mo (53% vs. 23%); given thicker consistency CF (73% vs. 36%); fed actively (40% vs. 23%), fewer had diarrhea episodes in past 15 d (26% vs. 83%). Mean calorie intake (% RDA) from CF among PD was significantly higher than in ND (68% vs.42%). CONCLUSIONS: Factors contributing to PD in urban poor families are similar to those reported in rural India; which implies that ICDS-Health services for both urban and rural poor need to ensure that national IYCF guidelines-healthcare recommendations are followed by communities. Further research relating PD to desirable complementary feeding and hygiene-healthcare practices in rural and urban areas is required. PMID- 22218806 TI - Raised intracranial pressure (ICP): management in emergency department. AB - Raised intracranial pressure is a life threatening condition; unless recognized and treated early, it may progress into herniation syndrome and death. Symptoms and signs are neither sufficiently sensitive nor specific, hence a high index of suspicion and vigilance are needed for early recognition. Immediate goal of management is to prevent / reverse herniation and to maintain good cerebral perfusion pressure. The therapeutic measures include stabilization of airway, breathing and circulation, along with neutral neck position, head end elevation by 30 degrees , adequate sedation and analgesia, minimal stimulation, and hyperosmolar therapy (mannitol or 3% saline). Short-term hyperventilation (to achieve PCO(2) ~ 30 mm Hg) using bag ventilation can be resorted to if signs of impending herniation are present. PMID- 22218807 TI - Hepatitis B virus X protein promotes the growth of hepatocellular carcinoma by modulation of the Notch signaling pathway. AB - Hepatitis B virus X protein (HBx) plays a crucial role in the development of hepatocellular carcinoma (HCC), however, little is known about the mechanism. Here, we investigated the relationship between HBx and Notch signaling in HepG2 cells after they were transfected with the HBx gene. It was found that HBx upregulated the expression of Notch-1, Jagged-1 and Hes-1 at the transcriptional level by binding to the Notch-1 intracellular domain, which is congruent with the observations of enhanced malignant biological activities of HBx-transfected HepG2 cells compared with normal HepG2 cells. However, while Notch signaling was blocked, the HBx-induced abnormalities were partially reversed. These findings suggest that HBx may promote the progression of HCC via the activated Notch pathway. PMID- 22218808 TI - Field profiles of bulk plasmon polariton modes in layered systems containing a metamaterial. AB - Electric and magnetic fields in a one-dimensional layered system that alternates air and a metamaterial are investigated. Special attention is devoted to frequencies of electric and magnetic bulk plasmons. It is shown that plasmon polaritons nearby such frequencies display field profiles concentrated in the metamaterial, where the field component parallel to the stacking direction is essentially uniform and dominates the perpendicular one. PMID- 22218809 TI - Effects of genetic modifications to flax (Linum usitatissimum) on arbuscular mycorrhiza and plant performance. AB - Although arbuscular mycorrhizal fungi (AMF) are known for their positive effect on flax growth, the impact of genetic manipulation in this crop on arbuscular mycorrhiza and plant performance was assessed for the first time. Five types of transgenic flax that were generated to improve fiber quality and resistance to pathogens, through increased levels of either phenylpropanoids (W92.40), glycosyltransferase (GT4, GT5), or PR2 beta-1,3-glucanase (B14) or produce polyhydroxybutyrate (M50), were used. Introduced genetic modifications did not change the degree of mycorrhizal colonization as compared to parent cultivars Linola and Nike. Arbuscules were well developed in each tested transgenic type (except M50). In two lines (W92.40 and B14), a higher abundance of arbuscules was observed when compared to control, untransformed flax plants. However, in some cases (W92.40, GT4, GT5, and B14 Md), the mycorrhizal dependency for biomass production of transgenic plants was slightly lower when compared to the original cultivars. No significant influence of mycorrhiza on the photosynthetic activity of transformed lines was found, but in most cases P concentration in mycorrhizal plants remained higher than in nonmycorrhizal ones. The transformed flax lines meet the demands for better quality of fiber and higher resistance to pathogens, without significantly influencing the interaction with AMF. PMID- 22218810 TI - Human metapneumovirus in bronchoalveolar lavage fluid of critically ill patients with suspected pneumonia. PMID- 22218811 TI - Dendritic morphology of neurons in medial prefrontal cortex and hippocampus in 2VO rats. AB - Cerebral ischemia is the main cause of cognitive impairment. Changes in dendritic morphology and spines have been shown to occur with synaptic plasticity and cognitive function. Bilateral occlusion of the common carotid arteries (2VO) in rats was an effective model of chronic cerebral ischemia. In this experiment, SD rats were divided into model group (2VO) and sham-operated group. At 2, 4, 8 and 16 weeks, rats were tested in Morris water maze to observe learning and memory abilities, and then the brain tissue was stained by Golgi method to investigate the morphology of dendrites of pyramidal neurons under light microscope. Dendritic length and arborization and spine density of pyramidal neurons in medial prefrontal cortex (mPFC) and hippocampal CA1 were analyzed by ImageJ. Progressive learning and memory deficits appeared since 2 weeks. Compared to the sham-operated group, the dendritic length and arborization significantly decreased in the model group at 4, 8 and 16 weeks after 2VO in CA1, while there was no significant difference in mPFC. Dendritic spine density in hippocampal CA1 of the model group significantly decreased after 2 weeks, and it was decreased after 8 weeks in mPFC. The results suggest that under the condition of chronic cerebral ischemia, the alteration of dendritic morphology and spine density underlay cognitive impairment. PMID- 22218812 TI - Multiple myeloma with cauda equina infiltration. AB - We report a case of a 51-year-old man with multiple myeloma who presented with lumbar pain and left limb paresis. Cerebrospinal fluid, brain and spinal cord resonance imaging revealed a diffuse infiltration of the cauda equina without any cranial leptomeningeal enhancement. An infiltration limited to the cauda equina is extremely rare. PMID- 22218813 TI - On the effect of scene motion on color constancy. AB - A series of experiments with human subjects have shown that color constancy improves when an object moves. It has been hypothesized that this effect is due to some kind of influence of high-level motion processing. We have built a computational model for color perception which replicates the results qualitatively which have been obtained with human subjects. We show that input from high-level motion processing is not required. In our model, the dependence is an effect of eye movement in combination with neural processing. Depending on the type of stimulus used, the eye either tracks the object or the background. When the object moves but is tracked by the observer, the background appears to move when considering the stimulus with respect to eye coordinates. Hence, the retinal input is different for the two conditions leading to a difference in color constancy performance. PMID- 22218815 TI - Electron transfer and hydrogen generation from a molecular dyad: platinum(II) alkynyl complex anchored to [FeFe] hydrogenase subsite mimic. AB - A PS-Fe(2)S(2) molecular dyad 1a directly anchoring a platinum(II) alkynyl complex to a Fe(2)S(2) active site of a [FeFe] H(2)ase mimic, and an intermolecular system of its reference complexes 1b and 2, have been successfully constructed. Time-dependence of H(2) evolution shows that PS-Fe(2)S(2)1a as well as complex 2 with 1b can produce H(2) in the presence of a proton source and sacrificial donor under visible light irradiation. Spectroscopic and electrochemical studies on the electron transfer event reveal that the reduced Fe(I)Fe(0) species generated by the first electron transfer from the excited platinum(II) complex to the Fe(2)S(2) active site in PS-Fe(2)S(2)1a and complex 2 with 1b is essential for photochemical H(2) evolution, while the second electron transfer from the excited platinum(II) complex to the protonated Fe(I)Fe(0) species is thermodynamically unfeasible, which might be an obstacle for the relatively small amount of H(2) obtained by PS-Fe(2)S(2) molecular dyads reported so far. PMID- 22218814 TI - Predictors of primary care physicians' self-reported intention to conduct suicide risk assessments. AB - Primary care physicians play a significant role in depression care, suicide assessment, and suicide prevention. However, little is known about what factors relate to and predict quality of depression care (assessment, diagnosis, and treatment), including suicide assessment. The authors explored the extent to which select patient and physician factors increase the probability of one element of quality of care: namely, intention to conduct suicide assessment. Data were collected from 404 randomly selected primary care physicians after their interaction with CD-ROM vignettes of actors portraying major depression with moderate levels of severity. The authors examined which patient factors and physician factors increase the likelihood of physicians' intention to conduct a suicide assessment. Data from the study revealed that physician-participants inquired about suicide 36% of the time. A random effects logistic model indicated that several factors were predictive of physicians' intention to conduct a suicide assessment: patient's comorbidity status (odds ratio (OR) = 0.61; 95% confidence interval (CI) = 0.37-1.00), physicians' age (OR = 0.67; 95% CI = 0.49 0.92), physicians' race (OR = 1.84; 95% CI = 1.08-3.13), and how depressed the physician perceived the virtual patient to be (OR = 0.58; 95% CI = 0.39-0.87). A substantial number of primary care physicians in this study indicated they would not assess for suicide, even though most physicians perceived the virtual patient to be depressed or very depressed. Further study is needed to establish factors that may be modified and targeted to increase the likelihood of physicians' providing one element of quality of care--suicide assessment--for depressed patients. PMID- 22218816 TI - Introduction to special section on health disparities. PMID- 22218817 TI - Comparing single-pool and multiple-pool designs regarding test security in computerized testing. AB - This article compares the use of single- and multiple-item pools with respect to test security against item sharing among some examinees in computerized testing. A simulation study was conducted to make a comparison among different pool designs using the item selection method of maximum item information with the Sympson-Hetter exposure control and content balance. The results from the simulation study indicate that two-pool designs have a better degree of resistance to item sharing than do the single-pool design in terms of measurement precision in ability estimation. This article further characterizes the conditions under which employing a multiple-pool design is better than using a single, whole pool in terms of minimizing the number of compromised items encountered by examinees under a randomized item selection method. Although no current computerized testing program endorses the randomized item selection method, the results derived in this study can shed some light on item pool designs regarding test security for all item selection algorithms, especially those that try to equalize or balance item exposure rates by employing a randomized item selection method locally, such as the a-stratified-with-b blocking method. PMID- 22218818 TI - The Multi-Stimulus Box: an innovative learning device for the comparative study of object perception and recognition with various types of stimuli. AB - In this article, we report the construction of a novel type of automated learning device for exploring a broad range of issues in animal visual cognition. The testing box (Multi-Stimulus Box, or MSB) we describe is an experimental chamber that enables the flexible presentation of various stimulus types while providing control over incidental cues to the greatest possible extent. Among the stimuli that can be presented are photographs, real objects, and even holograms. The MSB allows for comparative research across different stimulus qualities and species, and is thus a promising tool for advancing our understanding of the role of stimulus qualities for animals' perception, discrimination, and categorization of objects. PMID- 22218820 TI - Risk factors for childhood asthma deaths from the UK Eastern Region Confidential Enquiry 2001-2006. AB - BACKGROUND: Confidential enquiries into asthma deaths can identify inadequacies in medical management and factors which contribute to patients' death. AIMS: To identify risk factors for paediatric asthma deaths over a 6-year period. METHODS: Observational case-series study of paediatric asthma deaths between 2001-2006 in the UK Eastern Region. Hospital, primary care and post-mortem data were obtained for every child (<=17 yrs) with asthma recorded on the death certificate, and a detailed questionnaire was completed. Information was obtained on asthma severity, medications, hospital admissions, GP and hospital follow-up, adherence, psychosocial / behavioural factors, allergies, details of the terminal attack and precipitating factors. RESULTS: 20 children (10 male; 8-17 yrs; median: 11.5 yrs) died of asthma between 2001-2006. 9/20 had mild to moderate asthma (BTS/ SIGN criteria), 10/20 had severe asthma and 1 child was not known to have asthma. 13/20 were clinically atopic. Only 3 had undergone allergy assessment. 10/20 died between June and August. 12/20 children had adverse psychosocial and behavioural factors. 7/20 children were on non-combination long-acting beta2-agonist (LABA) treatment without inhaled corticosteroids (ICS). CONCLUSIONS: Almost half the deaths occurred in children with mild/moderate asthma. We recommend that allergic factors and seasonal allergy should be identified early, non-combination LABAs avoided, and speculate that overuse of short-acting beta2-agonists (SABAs) may indicate non-adherence with ICS. Asthma deaths in children can be avoided if risk factors are identified early. PMID- 22218819 TI - Statin use in COPD patients is associated with a reduction in mortality: a national cohort study. AB - AIMS: To assess whether statin use is associated with reduced mortality in patients with chronic obstructive pulmonary disease (COPD). METHODS: Hospitalisation, drug dispensing, and mortality records were linked for New Zealanders aged 50-80 years discharged from hospital with a first admission with COPD in 2006. Patients were classified according to whether or not they were prescribed statins prior to admission. Baseline characteristics were compared and hazard ratios calculated for statin users versus statin non-users for all cause mortality over follow-up of up to 4 years. RESULTS: A total of 1,687 patients (mean age 70.6 years) were followed, including 596 statin users and 1,091 non-users. There were more men in the statin user group (58.4% vs. 48.5%), and statin users were more likely to have a history of cardiovascular disease (58.6% vs. 25.1%), prescription for frusemide as a proxy for heart failure (47.7% vs. 24.5%) or diabetes (35.4% vs.11.6%) than statin non-users (p<0.001). A total of 671 deaths occurred during the follow-up period. After adjustment for age, sex, ethnic group, history of cardiovascular disease, diabetes, and prescription for frusemide, the hazard ratio for statin users vs. statin non users for all-cause mortality was 0.69 (95% CI 0.58 to 0.84). CONCLUSIONS: Statin use is associated with a 30% reduction in all-cause mortality at 3-4 years after first admission for COPD, irrespective of a past history of cardiovascular disease and diabetes. PMID- 22218821 TI - Plug-and-play, infrared, laser-mediated PCR in a microfluidic chip. AB - Microfluidic polymerase chain reaction (PCR) systems have set milestones for small volume (100 nL-5 MUL), amplification speed (100-400 s), and on-chip integration of upstream and downstream sample handling including purification and electrophoretic separation functionality. In practice, the microfluidic chips in these systems require either insertion of thermocouples or calibration prior to every amplification. These factors can offset the speed advantages of microfluidic PCR and have likely hindered commercialization. We present an infrared, laser-mediated, PCR system that features a single calibration, accurate and repeatable precision alignment, and systematic thermal modeling and management for reproducible, open-loop control of PCR in 1 MUL chambers of a polymer microfluidic chip. Total cycle time is less than 12 min: 1 min to fill and seal, 10 min to amplify, and 1 min to recover the sample. We describe the design, basis for its operation, and the precision engineering in the system and microfluidic chip. From a single calibration, we demonstrate PCR amplification of a 500 bp amplicon from lambda-phage DNA in multiple consecutive trials on the same instrument as well as multiple identical instruments. This simple, relatively low-cost plug-and-play design is thus accessible to persons who may not be skilled in assembly and engineering. PMID- 22218822 TI - Enhanced anesthetic propofol biochips by modifying molecularly imprinted nanocavities of biosensors. AB - This paper presents enhanced performance of anesthetic propofol biosensors by modifying molecularly imprinted nanocavities of biosensors. In this work, the relationship between molecularly imprinted nanocavities and performance of molecularly imprinted polymer (MIP) films is investigated. The morphological control of imprinted nanocavities on molecularly imprinted biosensors is done by adjusting polymer composition and polymerization process. The newly developed MIP biosensors are characterized using our developed microfluidic biochips and optical microsystems. Experimental results show that the sizes of molecularly imprinted nanocavities were reduced to 10 to 14 nm from 10 to 25 nm. The roughness of the MIP film surface was reduced to 2.5 nm from 6.6 nm. Smaller imprinted nanocavities have better molecular separation performance. The specificity and linearity of the anesthetic biosensors could be enhanced by adjusting morphology of imprinted nanocavities. The linearity and the sensitivity of the microfluidic biochip with an improved on-chip MIP biosensor have been enhanced from 0.9341 to 49.5 mV/mm2.ml/MUg, respectively, to 0.9782 and 176.9 mV/mm2.ml/MUg. The anesthetic propofol biosensor presented in this study is applicable to numerous fluidic-based disposable biochips. PMID- 22218824 TI - A dual catalyst system provides the shortest pathway for L-menthol synthesis. AB - We have demonstrated that a combination of enantiopure 2-diarylmethylpyrrolidines and heterogeneous Pd/BaSO(4) is an efficient catalytic system for the asymmetric hydrogenation of citral, specifically, a mixture of E-citral and Z-citral in any ratio, and that citronellal is obtained with high enantioselectivity. This dual catalyst system provides a new and more economical route to L-menthol. PMID- 22218825 TI - Positive effects of local therapy with a vaginal lactic acid gel on dysuria and E.coli bacteriuria question our current views on recurrent cystitis. AB - OBJECTIVE: We tested the effect of vaginally applied lactic acid gel on symptoms and bacteriuria in acutely exacerbated recurrent Eschericia coli cystitis. METHODS: Carnoy fixed samples of the morning urine from 20 women with a history of recurrent E.coli cystitis were prospectively investigated for bacteriuria using fluorescence in situ hybridization (FISH). RESULTS: In 11/20 women with acute cystitis, the symptoms and bacteriuria were regressive with lactic acid gel treatment, without the need for antibiotic treatment. The complete regression of symptoms took between 1 week (7 women) and 4 weeks (4 women). In parallel with this regression, the microscopic shape of E.coli bacteria in these women changed from short rods to long curly filaments starting within the first days of therapy. The filamentous transformation affected 100% of the E.coli population in six women and at least 50% of E.coli population in five women and was not observed in urine samples from untreated women or in women without clinical response to lactic acid gel. This could not happen if the bladder was the origin of the infection. CONCLUSIONS: A number of recurrent and probably acute cystitis is a local vagino-urethritis caused by an adhesive invasive E.coli biofilm of the vaginal surface. PMID- 22218826 TI - The potential role of glutamate in the current diabetes epidemic. AB - In the present article, we propose the perspective that abnormal glutamate homeostasis might contribute to diabetes pathogenesis. Previous reports and our recent data indicate that chronically high extracellular glutamate levels exert direct and indirect effects that might participate in the progressive loss of beta-cells occurring in both T1D and T2D. In addition, abnormal glutamate homeostasis may impact all the three accelerators of the "accelerator hypothesis" and could partially explain the rising frequency of T1D and T2D. PMID- 22218827 TI - Effects of graft pretensioning in anterior cruciate ligament reconstruction. AB - PURPOSE: Graft pretensioning is used in anterior cruciate ligament (ACL) reconstruction to prevent secondary slackening. Its effects on collagen fibrillar ultrastructure are not known. In this study, we hypothesized that graft pretensioning in ACL reconstruction creates ultrastructural changes detectable in scanning electron microscopy (SEM). METHODS: A prospective comparative study was carried out on 38 ACL reconstructions using a 4-strand semitendinosus graft. Samples were harvested intra-operatively before and after pretensioning for 30 s, 2 or 5 min. The images produced in SEM were analyzed using an original semi quantitative "CIP" score taking into account collagen cohesion, integrity, and parallelism. Intra- and inter-tester reliability for the CIP score were tested. RESULTS: The CIP scores decreased by 3.5 (1.6) points after pretensioning (P < 0.05). Significant differences were found in the 5, 2 min and 30 s subgroups for the global CIP score. Relative decrease (Delta CIP) was significantly higher in the 2 and 5 min subgroups after pretensioning in comparison with the 30 s subgroups. Intra- and inter-tester reliability for the CIP score were 0.85 and 0.92 (P < 0.05). CONCLUSION: Pretensioning ACL grafts resulted in alteration of the collagen fibrillar ultrastructure, detectable using SEM. These results confirm the existence of collagen ultrastructural changes after pretensioning that may be related to its duration. LEVEL OF EVIDENCE: Prospective comparative study, Level II. PMID- 22218829 TI - Comparison of three non-invasive quantitative measurement systems for the pivot shift test. AB - PURPOSE: The purpose of this study was to evaluate three different non-invasive measuring devices for the pivot shift phenomenon with reference to direct bony movement measured by an electromagnetic device rigidly attached to the tibia and femur. METHODS: A lower body cadaveric specimen was prepared to create a positive pivot shift in both knees. Twelve expert knee surgeons from worldwide performed their preferred pivot shift technique three times in each knee. After watching an instructional video, the examiners used a standardized technique to perform three additional pivot shift maneuvers in each knee. An electromagnetic tracking system, rigidly attached to femur and tibia, was used to provide reference measurements during the pivot shift test. Three different devices were correlated to the reference method and evaluated in this study: (1) Electromagnetic tracking system with skin sensors; (2) Triaxial accelerometer system; (3) Simple image analysis. RESULTS: When results from both pivot shift techniques (preferred and standardized) were combined, the electromagnetic tracking system with skin sensors showed positive correlation with the reference measurement for acceleration and translation parameters (r = 0.88 and r = 0.67, respectively; both P < 0.01); The triaxial accelerometer system demonstrated good correlation with the reference measurement for acceleration (r = 0.75; P < 0.001). The image analysis system was poorly correlated to the translation of the reference measurement (r = 0.24; P < 0.01). CONCLUSION: The electromagnetic tracking system with skin sensors provided the best correlation with the reference method. The triaxial accelerometer showed also a good correlation and the image analysis system showed a positive, but poor correlation with the reference method. More research is needed in order to validate simple and non-invasive devices for clinical application. PMID- 22218828 TI - Pivot shift as an outcome measure for ACL reconstruction: a systematic review. AB - PURPOSE: To identify and evaluate the evidence for the pivot shift test as an outcome measure following ACL reconstruction. Achieving rotatory control of the knee post anterior cruciate ligament (ACL) reconstruction has been shown to increase patient satisfaction, decrease functional instability and potentially delay the development of osteoarthritis. The pivot shift is able to assess this rotatory component of knee laxity and appears to have the potential to become a benchmark in gauging the success of ACL surgery. Multiple confounding factors and discrepancies in performing the maneuver itself however put its usefulness in question. Thus, the literature was reviewed to assess whether the pivot shift was able to correlate with final functional outcomes. METHODS: Two reviewers searched two databases (MEDLINE and EMBASE) for randomized control trials that involved anterior cruciate ligament reconstruction in the last 5 years. All non-clinical studies were excluded. A quality assessment of the included studies was performed using the Jadad scale by a reviewer. The number of studies using the Pivot Shift Test as well as the test's relationship with functional outcome was evaluated. RESULTS: The literature search yielded 274 studies, of which 65 papers were included. The average Jadad quality score for papers reporting pivot shift as an outcome measure was 2.4, with the most frequent score being 3. Forty seven of 65 studies described the Pivot Shift Test as an outcome measure following ACL reconstruction. Of the 47 studies that included pivot shift as an outcome measure, 40 (85%) correlated with the final functional outcomes. CONCLUSION: The pivot shift test is an important test following ACL reconstruction, and it correlates with functional outcomes. PMID- 22218830 TI - Varying fitness cost associated with resistance to fluoroquinolones governs clonal dynamic of methicillin-resistant Staphylococcus aureus. AB - The purpose of this study was to investigate the impact of fluoroquinolone resistance on the existence and dynamic of MRSA clones. Resistance to ciprofloxacin was induced in strains of community-acquired (CA) MRSA from various sequence types and the fitness cost suffered by mutant derivatives measured in a propagation assay. In addition, the fitness of fluoroquinolone resistant health care-associated (HA) MRSA isolates from major clones prevalent in Hungary were compared with each other and with those of the CA-MRSA derivatives. The genetic background of fluoroquinolone resistance and fitness cost in CA-MRSA was investigated. The fitness cost observed in the CA-MRSA derivatives proved diverse; the derivatives of the ST30-MRSA-IV strain suffered significantly greater fitness cost than those of the ST8-MRSA-IV and ST80-MRSA-IV isolates. Strains from the New York-Japan (ST5-MRSA-II), South German (ST228-MRSA-I) and EMRSA-15 (ST22-MRSA-IV) HA-MRSA clones proved more viable than CA-MRSA derivatives with similar MIC values to ciprofloxacin and HA-MRSA strains from the Hungarian/Brazilian clone (ST239-MRSA-III). Our strains from the New York-Japan, South-German and EMRSA-15 clones seem to have a competitive edge over the tested CA-MRSA isolates in the health care setting. The greater fitness observed in our New York-Japan and South-German strains could account for the replacement by them of the Hungarian/Brazilian clone in Hungary about ten years ago. Alterations in relevant genes were detected. The Ser80 -> Phe mutation in the grlA gene may have seriously compromised viability. Surprisingly silent nucleotide substitutions in the grlB gene seemed to impact fitness in derivatives of the ST30-MRSA-IV isolate. PMID- 22218831 TI - Analysis of cyclops lesions after different anterior cruciate ligament reconstructions: a comparison of the single-bundle and remnant bundle preservation techniques. AB - OBJECTIVE: The aim of this work was to compare the prevalence of cyclops lesions after anterior cruciate ligament reconstruction (ACLR) using the single-bundle and remnant bundle preservation techniques. MATERIALS AND METHODS: One hundred consecutive patients, who had undergone postoperative MRI of the knee followed by arthroscopic ACLR with the remnant bundle preservation technique (R) between February 2007 and August 2010, were enrolled in this study. Thirty-six consecutive patients who underwent ACLR using the single-bundle technique (S) were also included in this study as a control group. The MR findings were scored based on the presence of pre-ACL graft lesion as 0, 1, 2, or 3 on the sagittal images. The sixty-one specimens by second-look surgery (20 in S, 41 in R) were pathologically examined. RESULTS: The numbers of patients with scores of 0, 1, 2, and 3 were 1, 18, 14, and 3 in group S and 4, 60, 29, and 7, in group R, respectively. Of the 61 patients who underwent second-look surgery (20 in S, 41 in R), eight had a cyclops lesion (three in group S and five in group R). The prevalence of cyclops lesion was not significantly different in group R and group S (p = 0.761). CONCLUSIONS: The prevalence of a cyclops lesion was similar in both groups. PMID- 22218832 TI - Detection of small tendon lesions by sonoelastographic visualization of strain profile differences: initial experiences. AB - PURPOSE: To assess the capability of a commercial sonoelastography system to detect small tendon lesions by quantitative analysis of elastogram profiles. MATERIALS AND METHODS: Strips of equine digital flexor tendons were used to model small human tendons. Two tendons were examined. From each tendon, six unmodified tendon strips (controls) and six tendon strips with a central defect of the same tendons were compared. The tendon strips were placed under a physiological tensile strain of 5%. Sonoelastographic visualization of the strain profile was performed. Regions of interest (ROI) were defined left and right of the tendon defects. Average tissue strains in these ROI were compared with tissue strain in controls. RESULTS: In the first series of experiments, there was a significant (p = 0.011) difference in the strain profile in regions proximal and distal to the tendon lesions compared with the respective tendon areas in the control tendon strips. In a second series of experiments, similar trends were observed, but the differences were not significant (p = 0.824). CONCLUSION: Even under carefully controlled experimental conditions using computational post-processing of sonoelastograms, tendon lesions could only be partially detected within elastograms from a clinical sonoelastography system. The ability to detect differences in some strain profiles indicates that tensile sonoelastography has the potential to identify small tendon lesions (such as those in the hand), but that substantial improvements with respect to quantitative analysis are required to make such measures diagnostically relevant. PMID- 22218834 TI - Temporal association between federal gun laws and the diversion of guns to criminals in Milwaukee. AB - The practices of licensed gun dealers can threaten the safety of urban residents by facilitating the diversion of guns to criminals. In 2003, changes to federal law shielded gun dealers from the release of gun trace data and provided other protections to gun dealers. The 14-month period during which the dealer did not sell junk guns was associated with a 68% reduction in the diversion of guns to criminals within a year of sale by the dealer and a 43% increase in guns diverted to criminals following sales by other dealers. The laws were associated with a 203% increase in the number of guns diverted to criminals within a year of sale by the gun store, which was the focus of this study. Policies which affect gun dealer accountability appeared to influence the diversion of guns to criminals. PMID- 22218835 TI - Genetic and environmental components of neonatal weight gain in preterm infants. AB - BACKGROUND AND OBJECTIVES: Postnatal nutrition and subsequent weight gain or failure in the neonatal period are likely regulated by both the environment and the genetic background. With the goal of estimating the variability of postnatal weight gain due to genes and environment, comparison between monozygotic (ie, genetically identical) and dizygotic (genetically similar as 2 siblings) twins can be performed. METHODS: This study selected a very homogenous set of monozygotic and dizygotic twins who met the following inclusion criteria: gestational age between 30 and 36 weeks, birth weight between 1250 and 2200 g, and length of stay >12 days. Opposite-gender pairs and pairs that differed >20% in terms of birth weight were excluded from this analysis. The outcome measure of this study was the daily weight gain expressed in grams per kilogram per day during the period between day of birth and day of discharge. The average difference between members of a pair was computed in the 2 groups of twins, and heritability was estimated. RESULTS: The within-pair differences of the outcome measure were lower for monozygotic twins than for dizygotic twins, suggesting a strong genetic component. The total variance of the phenotype under study is explained by 2 sources of variation, additive genetic (87% [95% confidence interval: 67% to 94%]) and unique environment (13% [95% confidence interval: 6% to 33%]) components. CONCLUSIONS: This high heritability estimate could suggest using this set of criteria to identify genes that regulate postnatal weight gain or failure. PMID- 22218836 TI - Cytokine dermatitis and febrile seizure from imiquimod. AB - Cytokine dermatitis is a well-known and common clinical adverse effect of imiquimod 5% cream (Aldara, 3M). Data from initial Phase III clinical trials reveal a minority of study drug patients experience systemic adverse effects, including fever, arthralgia, headache, myalgia, and lymphadenopathy. These adverse effects are caused, presumably, from increased absorption of study drug over the area of dermatitis, leading to systemic cytokine release. Furthermore, the incidence of systemic reactions was rarely statistically increased above control patients. We describe herein a case of severe cytokine dermatitis in a 2 year-old female patient treated with daily imiquimod for molluscum contagiosum who subsequently developed febrile seizure. We believe this to be the first reported case of seizure associated with imiquimod 5% cream (Aldara, 3M) in a pediatric setting. PMID- 22218833 TI - Adipocyte differentiation-specific gene transcriptional response to C18 unsaturated fatty acids plus insulin. AB - Adipocyte differentiation (AD) and AD-specific gene expression was studied in 3T3 L1 cells in response to oleic acid (OA) or linoleic acid (LA) alone and in combination with insulin. This system facilitated the study of key regulators of adipogenesis PPARgamma and C/EBPalpha and other AD-specific genes, in the absence of dexamethasone (DEX) and isobutyl-1-methyl xanthine (IBMX) (components of the traditional AD medium, DMI). Lipid accumulation and expression levels of AD specific genes were enhanced by both OA and LA in the presence of insulin but not by OA or LA alone. Gene expression levels of PPARgamma, C/EBPalpha, FABP4, and SREBP1c induced by OA plus insulin, were comparable to DMI medium, by study day 10. The response to long-chain fatty acids (LCFA) plus insulin in the presence or absence of LY294002 demonstrated that the insulin-induced PI 3-kinase pathway regulates AD and AD-specific gene expression levels. Insulin treatment in the presence or absence of genistein suggested that genistein invoked inhibition of AD and AD-specific gene expression. In contrast when LCFA were also included with insulin, the presence of genistein invoked a pronounced and opposite effect on AD to that in the absence of LCFA. This effect may be modulated via C/EBPalpha as C/EBPalpha but not PPARgamma expression patterns closely reflected the changes in AD. DMI invoked a rapid expression of all genes studied, and LCFA plus insulin invoke more gradual increases in gene expression, to similar levels to those invoked by DMI. The model system is valuable for study of transactivators and response elements of PPARgamma and C/EBPalpha genes. PMID- 22218837 TI - Prevalence, patterns, and persistence of sleep problems in the first 3 years of life. AB - OBJECTIVE: Examine the prevalence, patterns, and persistence of parent-reported sleep problems during the first 3 years of life. METHODS: Three hundred fifty nine mother/child pairs participated in a prospective birth cohort study. Sleep questionnaires were administered to mothers when children were 6, 12, 24, and 36 months old. Sleep variables included parent response to a nonspecific query about the presence/absence of a sleep problem and 8 specific sleep outcome domains: sleep onset latency, sleep maintenance, 24-hour sleep duration, daytime sleep/naps, sleep location, restlessness/vocalization, nightmares/night terrors, and snoring. RESULTS: Prevalence of a parent-reported sleep problem was 10% at all assessment intervals. Night wakings and shorter sleep duration were associated with a parent-reported sleep problem during infancy and early toddlerhood (6-24 months), whereas nightmares and restless sleep emerged as associations with report of a sleep problem in later developmental periods (24-36 months). Prolonged sleep latency was associated with parent report of a sleep problem throughout the study period. In contrast, napping, sleep location, and snoring were not associated with parent-reported sleep problems. Twenty-one percent of children with sleep problems in infancy (compared with 6% of those without) had sleep problems in the third year of life. CONCLUSIONS: Ten percent of children are reported to have a sleep problem at any given point during early childhood, and these problems persist in a significant minority of children throughout early development. Parent response to a single-item nonspecific sleep query may overlook relevant sleep behaviors and symptoms associated with clinical morbidity. PMID- 22218838 TI - Pediatric self-management: a framework for research, practice, and policy. AB - Self-management of chronic pediatric conditions is a formidable challenge for patients, families, and clinicians, with research demonstrating a high prevalence of poor self-management and nonadherence across pediatric conditions. Nevertheless, effective self-management is necessary to maximize treatment efficacy and clinical outcomes and to reduce unnecessary health care utilization and costs. However, this complex behavior is poorly understood as a result of insufficient definitions, reliance on condition-specific and/or adult models of self-management, failure to consider the multitude of factors that influence patient self-management behavior, and lack of synthesis of research, clinical practice, and policy implications. To address this need, we present a comprehensive conceptual model of pediatric self-management that articulates the individual, family, community, and health care system level influences that impact self-management behavior through cognitive, emotional, and social processes. This model further describes the relationship among self-management, adherence, and outcomes at both the patient and system level. Implications for research, clinical practice, and health care policy concerning pediatric chronic care are emphasized with a particular focus on modifiable influences, evidence based targets for intervention, and the role of clinicians in the provision of self-management support. We anticipate that this unified conceptual approach will equip stakeholders in pediatric health care to (1) develop evidence-based interventions to improve self-management, (2) design programs aimed at preventing the development of poor self-management behaviors, and (3) inform health care policy that will ultimately improve the health and psychosocial outcomes of children with chronic conditions. PMID- 22218839 TI - Drinking frequency as a brief screen for adolescent alcohol problems. AB - OBJECTIVE: Routine alcohol screening of adolescents in pediatric settings is recommended, and could be facilitated by a very brief empirically validated alcohol screen based on alcohol consumption. This study used national sample data to test the screening performance of 3 alcohol consumption items (ie, frequency of use in the past year, quantity per occasion, frequency of heavy episodic drinking) in identifying youth with alcohol-related problems. METHODS: Data were from youth aged 12 to 18 participating in the annual National Survey on Drug Use and Health from 2000 to 2007. The screening performance of 3 alcohol consumption items was tested, by age and gender, against 2 outcomes: any Diagnostic and Statistical Manual, Fourth Edition alcohol use disorder symptom ("moderate"-risk outcome), and a diagnosis of Diagnostic and Statistical Manual, Fourth Edition alcohol dependence ("high"-risk outcome). RESULTS: Prevalence of the 2 outcomes increased with age: any alcohol use disorder symptom ranged from 1.4% to 29.2%; alcohol dependence ranged from 0.2% to 5.3%. Frequency of drinking had higher sensitivity and specificity in identifying both outcomes, compared with quantity per occasion and heavy episodic drinking frequency. For both outcomes, results indicate the utility of similar cut points for drinking frequency for males and females at each age. Age-specific frequency cut points, however, are recommended for both moderate- and high-risk outcomes to maximize screening performance. CONCLUSIONS: Drinking frequency provides an empirically supported brief screen to efficiently identify youth with alcohol-related problems. PMID- 22218840 TI - An integrated scientific framework for child survival and early childhood development. AB - Building a strong foundation for healthy development in the early years of life is a prerequisite for individual well-being, economic productivity, and harmonious societies around the world. Growing scientific evidence also demonstrates that social and physical environments that threaten human development (because of scarcity, stress, or instability) can lead to short-term physiologic and psychological adjustments that are necessary for immediate survival and adaptation, but which may come at a significant cost to long-term outcomes in learning, behavior, health, and longevity. Generally speaking, ministries of health prioritize child survival and physical well-being, ministries of education focus on schooling, ministries of finance promote economic development, and ministries of welfare address breakdowns across multiple domains of function. Advances in the biological and social sciences offer a unifying framework for generating significant societal benefits by catalyzing greater synergy across these policy sectors. This synergy could inform more effective and efficient investments both to increase the survival of children born under adverse circumstances and to improve life outcomes for those who live beyond the early childhood period yet face high risks for diminished life prospects. PMID- 22218841 TI - Calculation of expected body weight in adolescents with eating disorders. AB - OBJECTIVE: To examine the agreement between three methods to calculate expected body weight (EBW) for adolescents with eating disorders: (1) BMI percentile, (2) McLaren, and (3) Moore methods. METHODS: The authors conducted a cross-sectional analysis of baseline information from adolescents seeking treatment of disordered eating at The University of Chicago. Adolescents (N = 373) aged 12 to 18 years (mean = 15.84, SD = 1.72), with anorexia nervosa (n = 130), bulimia nervosa (n = 59), or eating disorder not otherwise specified (n = 184). Concurrence between the BMI percentile, McLaren, and Moore methods was assessed for agreement above or below arbitrary cut points used in relation to hospitalization (75%), diagnosis (85%), and healthy weight (100%). Patterns of absolute discrepancies were examined by height, age, gender, and menstrual status. Limitations to some of these methods allowed comparison between all 3 methods in only 204 participants. RESULTS: Moderate agreement was seen between the 3 methods (kappa values, 0.48-0.74), with pairwise total classification accuracy at each cut point ranging from 84% to 98%. The most discrepant calculations were observed among the tallest (>75th percentile) and shortest (<20th percentile) cases and older ages (>16 years). Many of the most discrepant cases fell above and below 85% EBW when comparing the BMI percentile and Moore methods, indicating disagreement on possible diagnosis of anorexia nervosa. CONCLUSIONS: These methods largely agree on percent EBW in terms of clinically significant cut points. However, the McLaren and Moore methods present with limitations, and a commonly agreed-upon method for EBW calculation such as the BMI percentile method is recommended for clinical and research purposes. PMID- 22218842 TI - Societal values and policies may curtail preschool children's physical activity in child care centers. AB - BACKGROUND AND OBJECTIVES: Three-fourths of US preschool-age children are in child care centers. Children are primarily sedentary in these settings, and are not meeting recommended levels of physical activity. Our objective was to identify potential barriers to children's physical activity in child care centers. METHODS: Nine focus groups with 49 child care providers (55% African American) were assembled from 34 centers (inner-city, suburban, Head Start, and Montessori) in Cincinnati, Ohio. Three coders independently analyzed verbatim transcripts for themes. Data analysis and interpretation of findings were verified through triangulation of methods. RESULTS: We identified 3 main barriers to children's physical activity in child care: (1) injury concerns, (2) financial, and (3) a focus on "academics." Stricter licensing codes intended to reduce children's injuries on playgrounds rendered playgrounds less physically challenging and interesting. In addition, some parents concerned about potential injury, requested staff to restrict playground participation for their children. Small operating margins of most child care centers limited their ability to install abundant playground equipment. Child care providers felt pressure from state mandates and parents to focus on academics at the expense of gross motor play. Because children spend long hours in care and many lack a safe place to play near their home, these barriers may limit children's only opportunity to engage in physical activity. CONCLUSIONS: Societal priorities for young children- safety and school readiness--may be hindering children's physical development. In designing environments that optimally promote children's health and development, child advocates should think holistically about potential unintended consequences of policies. PMID- 22218843 TI - RCT of montelukast as prophylaxis for upper respiratory tract infections in children. AB - BACKGROUND: Infections with viruses causing upper respiratory tract infection (URI) are associated with increased leukotriene levels in the upper airways. Montelukast, a selective leukotriene-receptor antagonist, is an effective treatment of asthma and allergic rhinitis. OBJECTIVE: To determine whether prophylactic treatment with montelukast reduces the incidence and severity of URI in children. METHODS: A randomized, double-blind, placebo-controlled study was performed in 3 primary care pediatric ambulatory clinics in Israel. Healthy children aged 1 to 5 years were randomly assigned in a 1:1 ratio to receive 12 week treatment with 4 mg oral montelukast or look-alike placebo. Patients were excluded if they had a previous history of reactive airway disease. A study coordinator contacted the parents by phone once a week to obtain information regarding the occurrence of acute respiratory episodes. The parents received a diary card to record any acute symptoms of URI. The primary outcome measure was the number of URI episodes. RESULTS: Three hundred children were recruited and randomly assigned into montelukast (n = 153) or placebo (n = 147) groups. One hundred thirty-one (85.6%) of the children treated with montelukast and 129 (87.7%) of the children treated with placebo completed 12 weeks of treatment. The number of weeks in which URI was reported was 30.4% in children treated with montelukast and 30.7% in children treated with placebo. There was no significant difference in any of the secondary variables between the groups. CONCLUSIONS: In preschool-aged children, 12-week treatment with montelukast, compared with placebo, did not reduce the incidence of URI. PMID- 22218844 TI - Hip dysplasia and the performing arts: is there a correlation? AB - Dancers frequently present with hip pain. The etiology of this pathology has not been clearly identified from an anatomical perspective. Structural variations including hip dysplasia and dynamic variables from the foot to the pelvis will be discussed. Understanding the etiology as a structural entity, neuromuscular entity or a combination of the two, allows for a successful rehabilitative process and a successful return to dance. This article describes the possible correlation between hip dysplasia and hip pain in the dancer, the relationship of dance postures to the kinematic chain and outlines possible treatment strategies for management. PMID- 22218845 TI - A pool of pairs of related objects (POPORO) for investigating visual semantic integration: behavioral and electrophysiological validation. AB - Semantic processing of verbal and visual stimuli has been investigated in semantic violation or semantic priming paradigms in which a stimulus is either related or unrelated to a previously established semantic context. A hallmark of semantic priming is the N400 event-related potential (ERP)--a deflection of the ERP that is more negative for semantically unrelated target stimuli. The majority of studies investigating the N400 and semantic integration have used verbal material (words or sentences), and standardized stimulus sets with norms for semantic relatedness have been published for verbal but not for visual material. However, semantic processing of visual objects (as opposed to words) is an important issue in research on visual cognition. In this study, we present a set of 800 pairs of semantically related and unrelated visual objects. The images were rated for semantic relatedness by a sample of 132 participants. Furthermore, we analyzed low-level image properties and matched the two semantic categories according to these features. An ERP study confirmed the suitability of this image set for evoking a robust N400 effect of semantic integration. Additionally, using a general linear modeling approach of single-trial data, we also demonstrate that low-level visual image properties and semantic relatedness are in fact only minimally overlapping. The image set is available for download from the authors' website. We expect that the image set will facilitate studies investigating mechanisms of semantic and contextual processing of visual stimuli. PMID- 22218847 TI - Voicing quantification is more relevant than period perturbation in substitution voices: an advanced acoustical study. AB - Quality of substitution voicing-i.e., phonation with a voice that is not generated by the vibration of two vocal folds-cannot be adequately evaluated with routinely used software for acoustic voice analysis that is aimed at 'common' dysphonias and nearly periodic voice signals. The AMPEX analysis program (Van Immerseel and Martens) has been shown previously to be able to detect periodicity in irregular signals with background noise, and to be suited for running speech. The validity of this analysis program is first tested using realistic synthesized voice signals with known levels of cycle-to-cycle perturbations and additive noise. Second, exhaustive acoustic analysis is performed of the voices of 116 patients surgically treated for advanced laryngeal cancer and recorded in seven European academic centers. All of them read out a short phonetically balanced passage. Patients were divided into six groups according to the oscillating structures they used to phonate. Results show that features related to quantification of voicing enable a distinction between the different groups, while the features reporting F(0)-instability fail to do so. Acoustic evaluation of voice quality in substitution voices thus best relies upon voicing quantification. PMID- 22218846 TI - Cine MRI of swallowing in patients with advanced oral or oropharyngeal carcinoma: a feasibility study. AB - Treatment of oral and oropharyngeal cancer may cause dysphagia. Purpose is to examine whether cine magnetic resonance imaging (MRI) yields additional information compared to standard examination in the evaluation of posttreatment dysphagia and mobility of oral and oropharyngeal structures. Thirty-four cine MRIs were made in 23 patients with advanced oral and oropharyngeal cancer, consisting of an MR image every 800 ms during swallowing which is compared to videofluoroscopy and quality of life questionnaires. A scoring system was applied to assess mobility on cine MR and videofluoroscopy leading to a score ranging from 9 to 17. Cine MRI of the swallowing in a midsagittal plane visualized the tumor (if located in the same plane), important anatomic structures and surgical reconstructions. Posttreatment mobility on cine MRI and videofluoroscopy was significantly diminished compared to pretreatment, mean pretreatment cine MRI score was 10.8 and posttreatment 12.4 (p = 0.017). Impaired mobility on cine MRI was significantly correlated to more swallowing problems (Spearman's correlation coefficient 0.73, p = 0.04), on videofluoroscopy not. Cine MRI is a promising new technique as an adjunct to standard examinations for evaluation of swallowing in patients with oral and oropharyngeal cancer. Cine MRI directly visualizes the dynamics of swallowing and allows evaluation of pre- and posttreatment differences. Abnormal findings are significantly correlated with subjective swallowing complaints of patients. PMID- 22218848 TI - Recurrent inflammation of accessory parotid tissue associated with unilateral parotid gland aplasia: diagnostic and therapeutic implications. AB - Aplasia of the major salivary glands is a rare condition due to an alteration in the development of the ectodermal tissue of the oral cavity often related to other craniofacial abnormalities or alteration of structures deriving from the first or second archial branch, in particular the lacrimal glands; it can be total or partial and determine clinical states ranging from an asymptomatic condition to a severe xerostomia. The accessory parotid tissue is similar to normal parotid tissue, completely independent from the main gland and susceptible to the same pathological disorders. We describe a very unusual case of an inflammatory disorder of accessory parotid tissue in a 44-year-old male patient with concomitant, and previously unknown, aplasia of the main ipsilateral parotid gland. We also discuss the role of imaging and conservative therapeutic modalities such as botulinum toxin therapy and, in the future, minimally invasive endoscopic-assisted resection in the management of such salivary disorder. PMID- 22218849 TI - Promontorial cochleostomy in nonhuman primates. Is it atraumatic? AB - The purpose of this study is to determine if surgical approach to the inner ear is feasible without generating a hearing loss in an animal model. Five Macaca fascicularis were used as experimental animals and followed up for 27 months. Mastoidectomy, posterior tympanotomy and promontorial cochleostomy were performed on four specimens and one specimen was kept as control animal. Before and after drilling and exposing the endosteal layer and the membranous labyrinth, otoacustic emissions (dPOAE) and auditory brainstem responses (ABR) were used to test hearing. In vivo experimental studies prove it is reliable to expose the membranous labyrinth without causing hearing loss. dPOAE were present after 3, 6, 12, 24 and 26 months of follow-up. Regarding the ABR results from the four M. fascicularis in which a cochleostomy has been carried out, auditory thresholds are within the 20-30 dB interval at 27 months of follow-up. Experimental studies support clinical experiences indicating it is feasible to surgically approach the membranous labyrinth of the cochlea without damaging its hearing function. PMID- 22218851 TI - Matrix-based yeast two-hybrid screen strategies and comparison of systems. AB - Today, matrix-based screens are used primarily for smaller and medium-size clone collections in combination with automation and cloning techniques that allow for reliable and fast interaction screening. Matrix-based yeast two-hybrid screens are an alternative to library-based screens. However, intermediary forms are possible too and we compare both strategies, including a detailed discussion of matrix-based screens. Recent improvement of matrix screens (also called array screens) uses various pooling strategies as well as novel vectors that increase their efficiency while decreasing false-negative rates and increasing reliability. PMID- 22218850 TI - Genetics of hearing loss: where are we standing now? AB - Hearing loss (HL) is the most common sensory impairment and is caused by a broad range of inherited to environmental causes. Inherited HL consists 50-60% of all HL cases. The inherited form of HL is further classified to different categories. More than 300 syndromes and 40 genes have been identified to result in different levels of HL. Although several diagnostic or screening tests have been developed, yet there are controversies around their use. PMID- 22218852 TI - Array-based yeast two-hybrid screens: a practical guide. AB - Yeast two-hybrid screens are carried out as random library screens or matrix based screens. The latter have the advantage of being better controlled and thus typically give clearer results. In this chapter, we provide detailed protocols for matrix-based Y2H screens and give some helpful instructions how to plan a large-scale interaction screen. We also discuss strategies to identify or avoid false negatives and false positives. PMID- 22218853 TI - High-throughput yeast two-hybrid screening. AB - Charting the interactions among proteins is essential for understanding biological processes. While a number of complementary technologies for detecting protein interactions are available, the yeast two-hybrid system is one of the few that have been successfully scaled up. Two-hybrid screens have been used to construct extensive protein interaction maps for humans and several model organisms, and these maps have proven invaluable for studies on a variety of biological systems. These maps, however, have not come close to covering all proteins or interactions detectable by yeast two-hybrid. This is due in part to the difficulty of using library screening methods to sample all possible binary combinations of proteins. Ideally, every binary pair of proteins would be tested individually to ensure that every detectable interaction is identified. For organisms with large proteomes, however, this is not economically feasible and instead efficient pooling schemes must be implemented. The high-throughput two hybrid screening methods presented here are designed to efficiently maximize coverage for selected sets of proteins or entire proteomes. We present two high throughput screening protocols. Both methods are designed to identify interactors for any number of bait proteins expressed as DNA-binding domain (BD) fusions. The choice of which protocol to use depends largely on the nature of the available library of proteins fused to an activation domain (AD). The first protocol is appropriate for screening a library of AD clones, such as a cDNA library, a domain library, or a large pool of AD clones. By contrast, the second protocol is appropriate for screening a large array of individual sequence-verified AD clones. This protocol screens small pools of AD clones from the array in a two phase scheme. Although the methods presented were developed using the LexA version of the yeast two-hybrid system, we include notes as appropriate to accommodate users of other versions. PMID- 22218854 TI - A stringent yeast two-hybrid matrix screening approach for protein-protein interaction discovery. AB - The yeast two-hybrid (Y2H) system is currently one of the most important techniques for protein-protein interaction (PPI) discovery. Here, we describe a stringent three-step Y2H matrix interaction approach that is suitable for systematic PPI screening on a proteome scale. We start with the identification and elimination of autoactivating strains that would lead to false-positive signals and prevent the identification of interactions. Nonautoactivating strains are used for the primary PPI screen that is carried out in quadruplicate with arrayed preys. Interacting pairs of baits and preys are identified in a pairwise retest step. Only PPI pairs that pass the retest step are regarded as potentially biologically relevant interactions and are considered for further analysis. PMID- 22218855 TI - High-throughput yeast two-hybrid screening of complex cDNA libraries. AB - Yeast two-hybrid screening can be used to find cDNAs encoding proteins which bind to a given bait protein in large, pooled cDNA libraries. Screening of complex, pooled libraries is slower and more laborious than screening of arrayed collections of cDNAs, but has several advantages. First, the complexity of a pooled library can be orders of magnitude larger than the size of a typical arrayed library. Second, as long as available cDNA collections are incomplete and limited to full-length cDNAs, pooled cDNA libraries offer a more complete search space and are often the only way to do screens in organisms other than human and a few model organisms. We have streamlined and optimised the screening of pooled libraries in a format which uses micro-titre plates and produces quantitative signals for the selection of hits. This format has the advantage that automation of the process is straightforward and allows a throughput of up to at least 1,000 screens per year per person. PMID- 22218856 TI - Virus-human cell interactomes. AB - Using global approaches and high-throughput technologies in virology brings a new vision of the infections physiology and allows the identification of cellular factors, mandatory for viral life cycle, that could be targeted by original therapeutic agents. It opens perspectives for the treatment of viral infections by acting on cellular pathways that the virus must use for its own replication. Combining these new molecules with classical antiviral drugs and immunomodulators diversifies and enlarges the antiviral arsenal and contributes to fight drug resistance. Our laboratory and others are constructing virus-human interactomes to propose a comprehensive analysis of viral infection at the cellular level. Studying these infection maps, where the viral infection can be visualized as perturbation of the human protein-protein interaction network, and identifying the biological functions that are impaired by these perturbations may lead to discovery of new therapeutic targets. These virus-human interaction maps are constructed in a stringent yeast two-hybrid system by screening human cDNA libraries with viral proteins as bait and integrating interactions mined from literature and public databases. PMID- 22218857 TI - Interactome mapping in malaria parasites: challenges and opportunities. AB - Nearly two-thirds of the proteins encoded by Plasmodium falciparum, the parasite that causes the most deadly form of malaria, are annotated as "hypothetical." The yeast two-hybrid assay, which requires no prior knowledge about the target protein, has great potential to provide functional information about these uncharacterized proteins. However, P. falciparum yeast two-hybrid screens are hampered by the poor expression of P. falciparum genes in yeast. AU-rich sequences in nascent P. falciparum transcripts resemble the 3' end processing sites in yeast mRNAs, and are prematurely cleaved and polyadenylated. In most cases, these aberrant messages are degraded and yield no protein. To overcome this limitation, we have developed methods to extensively fragment P. falciparum genes. Novel yeast two-hybrid vectors, in which auxotrophic markers are fused to the 3' ends of the cloned inserts, are employed to identify those gene fragments that are expressed in yeast. In this chapter, we provide detailed protocols for fragmenting P. falciparum genes, creating P. falciparum activation domain libraries, and performing P. falciparum yeast two-hybrid screens. Though focused on P. falciparum, the approaches described here are applicable to other organisms and are likely to be especially useful for those with AT-rich genomes, which are also likely to be poorly expressed in yeast. PMID- 22218858 TI - Mapping interactomes with high coverage and efficiency using the shifted transversal design. AB - "Smart-pooling" is a strategy to achieve high efficiency, sensitivity, and specificity in large-scale yeast two-hybrid screening. In smart-pooling, reagents are multiplexed in a highly redundant manner and the positives can be read out on the final selection plates without the requirement of any extra experimental steps. We have shown that the Shifted Transversal Design (STD), a powerful theoretical construction for smart-pooling, can be used in yeast two-hybrid interactome mapping. STD pooling can achieve similar levels of sensitivity and specificity as one-on-one array-based yeast two-hybrid, while the costs and workloads are much lower. This chapter focuses on the construction and usage of STD arrays for large-scale yeast two-hybrid interactome mapping. PMID- 22218859 TI - Assigning confidence scores to protein-protein interactions. AB - Screens for protein-protein interactions using assays like the yeast two-hybrid system have generated volumes of useful data. The protein interactions from these screens have been used to develop a better understanding of the functions of individual proteins, regulatory pathways, molecular machines, and entire biological systems. The value of this data, however, is limited by the inherent frequency of false positives that arise in most protein interaction screens. Appreciable numbers of false positives can crop up in both low-throughput and high-throughput screens, and even in screens that employ stringent criteria for defining a positive. A number of classification systems have been used to help distinguish false positives from biologically relevant true positives. This chapter describes a system for assigning a confidence score to each interaction based on the probability that it is a true positive. Such confidence scores can be used to prioritize interactions for validation. The scores are also useful for network analysis methods that take advantage of probabilistic edge weights. The scoring method does not rely on gold standard datasets of reliable true positives and true negatives, and thus circumvents the challenges associated with obtaining such datasets. Moreover, the scoring method uses data features that are largely assay-independent, making it useful for interactions obtained from a variety of different technologies and screening methods. PMID- 22218860 TI - The integration and annotation of the human interactome in the UniHI Database. AB - In recent years, remarkable progress has been made toward the systematic charting of human protein interactions. The utilization of the generated interaction data remained however challenging for biomedical researchers due to lack of integration of currently available resources. To facilitate the direct access and analysis of the human interactome, we have developed the Unified Human Interactome (UniHI) database. It provides researchers with a user-friendly Web interface and integrates interaction data from 12 major resources in its latest version, establishing one of the largest catalogs for human PPIs worldwide. At present, UniHI houses over 250,000 distinct interactions between 22,300 unique proteins and is publically available at http://www.unihi.org. PMID- 22218861 TI - Gene-centered yeast one-hybrid assays. AB - Transcription is regulated by sequence-specific transcription factors (TFs) that bind to short genomic DNA elements that can be located in promoters, enhancers and other cis-regulatory modules. Determining which TFs bind where requires techniques that enable the ab initio identification of TF-DNA interactions. These techniques can either be "TF-centered" (protein-to-DNA), where regions of DNA bound by a TF of interest are identified, or "gene-centered" (DNA-to-protein), where TFs that bind a DNA sequence of interest are identified. Here, we describe gene-centered yeast one-hybrid (Y1H) assays. Briefly, in Y1H assays, a DNA fragment is cloned upstream of two different reporters, and these reporter constructs are integrated into the genome of a yeast strain. Next, plasmids expressing TFs as hybrid proteins (hence the name of the assay) fused with the strong transcriptional activation domain (AD) of the yeast TF Gal4 are introduced into the yeast strain. When a TF interacts with the DNA fragment of interest, the AD moiety activates reporter expression in yeast regardless of whether the TF is an activator or repressor in vivo. Sequencing the plasmid in the colonies that exhibit reporter activation reveals the identity of the TFs that can bind the DNA fragment. We have shown Y1H to be a robust method for detecting interactions between a variety of DNA elements and multiple families of TFs. PMID- 22218862 TI - One- plus two-hybrid system for the efficient selection of missense mutant alleles defective in protein-protein interactions. AB - In an effort to develop a method for the high-throughput analysis of protein interaction interfaces, we devised a novel yeast genetic screening method, termed the "one- plus two-hybrid system," which efficiently selects specific missense mutations that disrupt known protein-protein interactions. This system modifies the standard yeast two-hybrid system to allow the operation of dual reporter systems within the same cell. The one-hybrid screening system is used first to positively select intact prey proteins, harboring informative missense mutations, from a large library of randomly generated mutant alleles. Next, among the isolated missense mutants of the prey proteins, interaction-defective mutants for a given protein (bait) are selected using the two-hybrid screening system. As a validation of the feasibility of this method, we utilized this technique to rapidly characterize the molecular determinants of the interactions between vitamin D receptor and its transcriptional coactivator protein, thyroid hormone receptor-associated protein 220. This efficient and rapid method should prove useful in the systematic analysis of large numbers of interaction interfaces. PMID- 22218863 TI - Investigation of membrane protein interactions using the split-ubiquitin membrane yeast two-hybrid system. AB - Proteins are generally organized into molecular complexes, in which multiple interaction partners collaborate to carry out cellular processes. Thus, techniques to map protein-protein interactions have become pivotal for biological studies of as yet uncharacterized proteins. Investigation of interaction partners of membrane proteins is of special interest, as they play a major role in cellular processes and are often directly linked to human diseases. Owing to their hydrophobic nature, however, it has proven difficult to study their interaction partners. To circumvent this problem, a yeast-based genetic technology for the in vivo detection of membrane protein interactions, the split ubiquitin membrane yeast two-hybrid (MYTH) system, has been developed. MYTH allows for detection of both stable and transient interactions and can be applied to large- and small-scale screens. It uses the split-ubiquitin approach, in which the reconstitution of two ubiquitin halves is mediated by a specific protein protein interaction. Briefly, the bait membrane protein is fused to the C terminal half of ubiquitin and an artificial transcription factor. The mutated N terminal moiety of ubiquitin is fused to the prey protein. Upon interaction of bait and prey proteins, ubiquitin is reconstituted and further recognized by ubiquitin-specific proteases, which subsequently cleave off the transcription factor, thus resulting in reporter gene activation. To date, MYTH has been successfully applied to study interactions of membrane proteins from various organisms and has only recently been adapted for the identification of interaction partners of mammalian receptor tyrosine kinases. PMID- 22218864 TI - Application of the split-protein sensor Trp1 to protein interaction discovery in the yeast Saccharomyces cerevisiae. AB - Yeast two-hybrid based systems are powerful tools for the detection and characterization of protein-protein interactions (PPIs). However, some important protein classes, e.g., integral membrane proteins and transcription factors, are difficult to study using these technologies. To overcome these limitations, we have employed a novel protein complementation screening platform. Protein interactions are detected by reconstitution of the split-protein sensor TRP1, enabling trp1 cells to grow on medium lacking tryptophan. Since the interaction readout is direct and independent of transcriptional reporter activation the rate of false positives is lowered. Furthermore, the technology allows for detection of protein interactions in their natural setting, e.g., the cytosol, the nucleus, and at cellular or organellar membranes. The protocols used for screening are explained in detail and as an example we describe the isolation of novel binding partners found with APP screened against a human cDNA library. PMID- 22218865 TI - Tetracycline repressor-based mammalian two-hybrid systems. AB - The study of protein-protein interactions is critical for the understanding and regulation of biological systems. To that end, yeast two-hybrid systems have been used to study protein-protein interactions in vivo, but they frequently suffer from a high incidence of false positives when applied to mammalian systems. A novel mammalian two-hybrid system has recently been developed which exhibits lower background and higher sensitivity than earlier mammalian two-hybrid systems. It has successfully detected interactions with dissociation constants ranging from 0.99 nM to 55 MUM. The system was built upon the tetracycline repressor-tetracycline operator interaction and is suitable for use in the study of most, if not all, mammalian protein-protein interactions. PMID- 22218866 TI - The fluorescent two-hybrid (F2H) assay for direct analysis of protein-protein interactions in living cells. AB - Information about protein interactions is crucial for the understanding of cellular processes. Current methods for the investigation of protein-protein interactions (PPIs) require either removal of the proteins from their normal cellular environment, perturbation of the cells or costly instrumentation and advanced technical expertise (Fields and Song, Nature 340:245-246, 1989; Deane et al., Mol Cell Proteomics 1:349-356, 2002; Kerppola, Nat Rev Mol Cell Biol 7:449 456, 2006; Blanchard et al., Mol Cell Proteomics 5:2175-2184, 2006; Miller et al., Mol Cell Proteomics 6:1027-1038, 2007; Miyawaki, Dev Cell 4:295-305, 2003; Parrish et al., Curr Opin Biotechnol 17:387-393, 2006; Sekar and Periasamy, J Cell Biol 160:629-633, 2003). Here, we describe a simple assay to directly visualize and analyze PPIs in single living cells. By adapting a lac operator/repressor system, we generated a stable nuclear interaction platform. A fluorescent bait protein is tethered to the interaction platform and assayed for co-localization of fluorescent prey fusion proteins. This fluorescent two-hybrid (F2H) assay allows the investigation of cell cycle dependent PPIs. With this cell based assay protein interactions even from different subcellular compartments can be visualized in real time (Zolghadr et al., Mol Cell Proteomics 7:2279-2287, 2008). The simple optical readout enables automated imaging systems to segment and analyze the acquired data for high-throughput screening of PPIs in living cells in response to external stimuli and chemical compounds. PMID- 22218867 TI - ArrayMAPPIT: a screening platform for human protein interactome analysis. AB - Mammalian protein-protein interaction trap (MAPPIT) is a two-hybrid technology to identify and characterize interactions of proteins with other proteins or organic molecules in living mammalian (human) cells. The method relies on complementation of a modified cytokine receptor complex. Protein interaction restores the signalling competence of the complex, which is monitored through the activation of a reporter gene. Here, we describe a protocol that has been recently developed to increase the utility of MAPPIT as a tool to identify novel interactions. In the ArrayMAPPIT assay, a collection of prey proteins which is arrayed in high density microtiter plates is efficiently screened for interaction partners using reverse transfection into a bait-expressing cell pool. PMID- 22218868 TI - MAPPIT as a high-throughput screening assay for modulators of protein-protein interactions in HIV and HCV. AB - The discovery of novel antivirals for HIV and HCV has been a focus of intensive research for many years. Where the inhibition of critical viral enzymes by small molecules has proven effective for many viruses, there is considerable merit in pursuing protein-protein interactions (PPIs) as targets for therapeutic intervention. The mammalian protein-protein interaction trap (MAPPIT) is a two hybrid system used for the study of PPIs. The bait and prey proteins are linked to deficient cytokine receptor chimeras, where the bait and prey interaction and subsequent ligand stimulation restores JAK-STAT signaling, resulting in reporter gene expression controlled by a STAT3-responsive promoter. We report the use of MAPPIT as a high-throughput screening assay for the discovery of inhibitors or stimulators of the Vif-APOBEC3G interaction and the reverse transcriptase heterodimerization (RTp66-RTp51) for HIV and the NS4A-NS3 interaction for HCV. PMID- 22218869 TI - Integrated measurement of split TEV and cis-regulatory assays using EXT encoded reporter libraries. AB - Intracellular signaling initiated by extracellular ligands that activate cell surface receptors is a complicated process that involves multiple interconnected biochemical steps. Protein-protein interactions are often regulated by activated kinases via phosphorylation of specific residues. Such transient regulated interactions are central to many signaling cascades. Downstream signaling converges at the level of transcription factors to finally regulate adaptive transcriptional responses. There are powerful methods available to study transcriptional changes even at a global level, however, measuring upstream regulatory mechanisms is still challenging. We designed an experimental approach termed EXTassay that enables the parallel analysis of signaling events upstream of gene expression. We make use of different types of reporter gene assays that are invariably linked to unique expressed oligonucleotide tags (EXTs) serving as quantitative decoders of respective assays. EXT-reporters can be introduced into living cells and analyzed in pools by microarray hybridization or sequencing. PMID- 22218870 TI - Capillary electrophoresis analysis of isoniazid using luminol-periodate potassium chemiluminescence system. AB - A rapid and simple capillary electrophoresis method coupled with chemiluminescent (CL) detection was proposed for analysis of isoniazid (ISO) based on the enhancement effect of ISO to CL emission of luminol-periodate potassium reaction. Under the optimal conditions, ISO can be assayed in the range of 7.0 * 10(-7) to 3.0 * 10(-5) g mL(-1) (R(2) = 0.9990) with a limit of detection of 3.0 * 10(-7) g mL(-1) (signal-to-noise ratio of 3). The whole analysis process can be completed within 2.5 min with a theoretical plate number of 6258. The relative standard deviations of the signal intensity and the migration time were 3.1 and 1.4% for a standard sample at 1.0 * 10(-5) g mL(-1) (n = 5), respectively. The presented novel strategy was successfully applied to the determination of ISO in commercial pharmaceutical preparations and spiked human serum samples. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 22218871 TI - Infected pancreatic necrosis occurring in a jejunal aberrant pancreas: report of a case. AB - Acute pancreatitis occurring in an aberrant pancreas (acute aberrant pancreatitis) is a rare clinical condition. A 67-year-old male was referred to the emergency department complaining of severe epigastralgia. He was evaluated by computed tomography, and the findings suggested jejunal penetration into the mesentery and abscess formation. We performed emergency surgery and found a mass located in the jejunal mesentery. Intraoperatively, we diagnosed it to be a malignant tumor complicated by penetration, and we performed a partial resection of the jejunum to remove the mass. Based on the pathological results, it was evident that this was a case of acute aberrant pancreatitis occurring on a background of chronic pancreatitis. The patient had an uneventful postoperative course. This report is the first presentation describing the possible mechanism that contributes to the process of infected pancreatic necrosis in an aberrant pancreas. PMID- 22218872 TI - Single-incision versus conventional three-incision laparoscopic appendectomy: a single centre experience. AB - PURPOSE: To compare the short-term outcomes of single-incision and conventional three-incision laparoscopic appendectomy (LA) at a single surgical unit. METHODS: We conducted a retrospective study comparing the operative outcomes of two LA techniques between January 2009 and November 2010. RESULTS: LA was performed successfully in 44 patients: through a single incision in 27 patients and through three incisions in 17 patients. The time taken to resume oral intake was slightly less in the single-incision group than in the three-incision group, at 1.1 versus 1.5 days, respectively (P = 0.0419). However, blood loss and hospital stay were not significantly different, at 7.2 versus 6.4 ml (P = 0.6244) and 3.7 versus 3.8 days (P = 0.8565), respectively. The cosmetic result was better in the single incision group, because of the well-concealed scar. CONCLUSION: Both single incision and conventional LA are effective and minimally invasive, and should be performed according to the experience of the surgeon. Single-incision LA results in faster recovery, but larger studies are required to confirm this and to determine if these techniques can be used safely for all indications of appendectomy. PMID- 22218873 TI - Optimal suture materials for contaminated gastrointestinal surgery: does infection influence the decrease of the tensile strength of sutures? AB - PURPOSE: Suture materials are selected based on the following factors: absorbable/non-absorbable, monofilament/multifilament, duration with sufficiently high tensile strength, and the tissue to be sutured. Absorbable sutures are hydrolyzed in tissues. However, little is known about the influence of infection on the hydrolysis and decrease in the tensile strength. METHODS: Four kinds of sutures, i.e., non-absorbable multifilament silk, non-absorbable monofilament polypropylene (Prolene((r))), absorbable multifilament polyglactin 910 (Vicryl((r))), and absorbable monofilament polydioxanone (PDS((r))) were implanted in the back of rats. A suspension of Escherichia coli + Bacteroides fragilis or saline was injected subcutaneously into the contaminated and clean condition groups, respectively. The sutures were removed 1, 2, 4 or 8 weeks after the implantation. RESULTS: There was significantly more severe inflammation macroscopically for the silk sutures under the contaminated conditions (p = 0.03), however, no significant differences were observed among the other three sutures. All 4 kinds of sutures showed a reduction of the tensile strength over time. There were no significant differences in the magnitude of reduction between both the clean and contaminated conditions for any of the sutures. CONCLUSIONS: The reduction of the tensile strength with time did not differ significantly between sutures exposed to contaminated and clean conditions, even for the absorbable sutures. PMID- 22218874 TI - The impact of vitamin D status and tumor size on the intraoperative parathyroid hormone dynamics in patients with symptomatic primary hyperparathyroidism. AB - PURPOSE: The intraoperative parathyroid hormone (IOPTH) monitoring is a useful adjunct for predicting whether a cure has been obtained during parathyroidectomy. We studied the influence of vitamin D status and parathyroid tumor weight on the IOPTH dynamics for predicting a cure in patients with symptomatic primary hyperparathyroidism. METHODS: Fifty-nine primary hyperparathyroidism patients with a single adenoma underwent curative surgery. Patients were grouped according to their serum 25-hydroxy vitamin D levels (deficient, insufficient and sufficient) and tumor weights (small, large and giant). The IOPTH results in patient groups were compared, and the percentage of the IOPTH decrease was examined for a correlation with the serum 25-hydroxy vitamin D level and tumor weight. RESULTS: The sensitivity, specificity and overall accuracy of IOPTH in predicting a cure of hyperparathyroidism were 94.8, 100 and 93.2%, respectively. The percentage decrease in the IOTPH was significantly higher in the vitamin D deficient, compared to the vitamin D sufficient patients (p = 0.012); and in the patients with larger tumors, compared to those with smaller parathyroid tumors (p = 0.02). A statistically significant correlation was found between the percentage decrease in the IOPTH at 10 min post-tumor excision and the serum 25-hydroxy vitamin D level (p = 0.037), but not with the tumor weight (p = 0.208). CONCLUSIONS: The IOPTH can accurately predict a cure in patients with severe primary hyperparathyroidism. The percentage of decrease in the IOPTH is steeper in patients with lower serum 25-hydroxy vitamin D levels and larger parathyroid tumors. PMID- 22218875 TI - Single-incision laparoscopic Heller myotomy and Dor fundoplication for achalasia: report of a case. AB - A 31-year-old man, referred to our hospital for investigation of dysphagia, was found to have a spindle-shaped lower esophagus on a contrasted esophagram. The dysphagia was initially treated conservatively, but after 4 years of unsatisfactory control, he requested surgery. Our surgical team has been performing laparoscopic Heller-Dor fundoplication for achalasia since August, 1994, and 265 patients have undergone this procedure so far. Based on our experience, we decided to perform Heller-Dor fundoplication through a single incision for this patient. The operative time was 236 min with minimal blood loss and there were no perioperative complications. His postoperative course was uneventful and he was discharged on postoperative day 4, completing the clinical pathway used for conventional laparoscopic Heller-Dor fundoplication. PMID- 22218876 TI - Biodistribution, radiation dosimetry and scouting of 90Y-ibritumomab tiuxetan therapy in patients with relapsed B-cell non-Hodgkin's lymphoma using 89Zr ibritumomab tiuxetan and PET. AB - PURPOSE: Positron emission tomography (PET) with (89)Zr-ibritumomab tiuxetan can be used to monitor biodistribution of (90)Y-ibritumomab tiuxetan as shown in mice. The aim of this study was to assess biodistribution and radiation dosimetry of (90)Y-ibritumomab tiuxetan in humans on the basis of (89)Zr-ibritumomab tiuxetan imaging, to evaluate whether co-injection of a therapeutic amount of (90)Y-ibritumomab tiuxetan influences biodistribution of (89)Zr-ibritumomab tiuxetan and whether pre-therapy scout scans with (89)Zr-ibritumomab tiuxetan can be used to predict biodistribution of (90)Y-ibritumomab tiuxetan and the dose limiting organ during therapy. METHODS: Seven patients with relapsed B-cell non Hodgkin's lymphoma scheduled for autologous stem cell transplantation underwent PET scans at 1, 72 and 144 h after injection of ~70 MBq (89)Zr-ibritumomab tiuxetan and again 2 weeks later after co-injection of 15 MBq/kg or 30 MBq/kg (90)Y-ibritumomab tiuxetan. Volumes of interest were drawn over liver, kidneys, lungs, spleen and tumours. Ibritumomab tiuxetan organ absorbed doses were calculated using OLINDA. Red marrow dosimetry was based on blood samples. Absorbed doses to tumours were calculated using exponential fits to the measured data. RESULTS: The highest (90)Y absorbed dose was observed in liver (3.2 +/- 1.8 mGy/MBq) and spleen (2.9 +/- 0.7 mGy/MBq) followed by kidneys and lungs. The red marrow dose was 0.52 +/- 0.04 mGy/MBq, and the effective dose was 0.87 +/- 0.14 mSv/MBq. Tumour absorbed doses ranged from 8.6 to 28.6 mGy/MBq. Correlation between predicted pre-therapy and therapy organ absorbed doses as based on (89)Zr ibritumomab tiuxetan images was high (Pearson correlation coefficient r = 0.97). No significant difference between pre-therapy and therapy tumour absorbed doses was found, but correlation was lower (r = 0.75). CONCLUSION: Biodistribution of (89)Zr-ibritumomab tiuxetan is not influenced by simultaneous therapy with (90)Y ibritumomab tiuxetan, and (89)Zr-ibritumomab tiuxetan scout scans can thus be used to predict biodistribution and dose-limiting organ during therapy. Absorbed doses to spleen were lower than those previously estimated using (111)In ibritumomab tiuxetan. The dose-limiting organ in patients undergoing stem cell transplantation is the liver. PMID- 22218877 TI - Effect of stress testing on left ventricular mechanical synchrony by phase analysis of gated positron emission tomography in patients with normal myocardial perfusion. AB - PURPOSE: There are limited data on whether differences exist in left ventricular (LV) mechanical dyssynchrony indices derived from stress versus rest gated positron emission tomography (PET) in patients with normal myocardial perfusion imaging (MPI). METHODS: Stress/rest (82)Rb gated PET was performed in consecutive patients with normal MPI between 2006 and 2010. Patients were divided into two groups: group 1 [LV ejection fraction (EF) >= 55% and QRS < 120 ms] and group 2 (LVEF <=35%). Images were acquired on a dedicated PET scanner prior to and on a hybrid PET/CT system after November 2008. LV dyssynchrony indices [phase standard deviation (SD) degrees and SD (ms)] were derived from stress and rest gated images. RESULTS: There were 91 patients in group 1 (age 61 +/- 13, LVEF 66 +/- 8%, normal QRS) and 126 in group 2 (age 66 +/- 12, LVEF 25 +/- 7%). The stress derived LVEF were significantly higher than rest for either group (p < 0.0001). Patients with cardiomyopathy had significantly higher dyssynchrony indices compared to those with normal LVEF (rest SD degrees 49.2 +/- 21.5 degrees vs 16.8 +/- 7.8 degrees and stress SD degrees 42.5 +/- 19.4 degrees vs 12.4 +/- 3.7 degrees , respectively, p < 0.0001 for both). The dyssynchrony indices derived from rest gated images were significantly higher than those derived from stress in both groups (p < 0.001 by unpaired and paired t test) and irrespective of the type of PET scanner utilized. Finally, 20/87 (23%) patients with normal LVEF and 27/66 (41%) of those with cardiomyopathy but without dyssynchrony based on stress indices were recategorized as having significant dyssynchrony given their resting indices. CONCLUSION: LV mechanical dyssynchrony indices by phase analysis are smaller when derived from peak stress versus rest gated PET imaging in patients with normal MPI, irrespective of the resting LVEF. PMID- 22218878 TI - Evolving paradigms for successful molecular imaging of medullary thyroid carcinoma. PMID- 22218880 TI - A periodically-forced mathematical model for the seasonal dynamics of malaria in mosquitoes. AB - We describe and analyze a periodically-forced difference equation model for malaria in mosquitoes that captures the effects of seasonality and allows the mosquitoes to feed on a heterogeneous population of hosts. We numerically show the existence of a unique globally asymptotically stable periodic orbit and calculate periodic orbits of field-measurable quantities that measure malaria transmission. We integrate this model with an individual-based stochastic simulation model for malaria in humans to compare the effects of insecticide treated nets (ITNs) and indoor residual spraying (IRS) in reducing malaria transmission, prevalence, and incidence. We show that ITNs are more effective than IRS in reducing transmission and prevalence though IRS would achieve its maximal effects within 2 years while ITNs would need two mass distribution campaigns over several years to do so. Furthermore, the combination of both interventions is more effective than either intervention alone. However, although these interventions reduce transmission and prevalence, they can lead to increased clinical malaria; and all three malaria indicators return to preintervention levels within 3 years after the interventions are withdrawn. PMID- 22218881 TI - The mental number line electrified: brain potentials in a numerical flanker task. AB - It has been suggested that the mental representation of numbers is spatial in nature such that numbers are ordered on a mental number line. In the present investigation we use a variant of the Eriksen flanker task requiring a magnitude decision (smaller or larger than 5) for a central target number by pressing a response button with the right or left hand. The target number is flanked by irrelevant distracters that are either identical to the target, different from the target but biasing the same response, or different from the target and biasing a different response. Response latencies and event-related brain potentials were obtained in a group of healthy adults. Besides the typical response congruency effects on response latency and the N2 component of the ERP, we observed several other effects. First, numerical distance of the target to the standard 5 influenced decision latencies and amplitude and latency of the P3 component with smaller distances leading to longer decision latencies, longer P3 latencies and smaller P3 amplitudes. Second, smaller numerical distance between target and distracters led to faster decisions for response congruent and to slower decisions for response-incongruent trials. For response-incongruent trials P3 amplitude was small/large and P3 latency was long/short for small/large distances. These findings underscore the spatial character of number representation and further show that the relation between targets and distracters, although task irrelevant, is assessed automatically with facilitatory and inhibitory effects driven by spatial distance on the mental number line. PMID- 22218879 TI - Abeta Imaging: feasible, pertinent, and vital to progress in Alzheimer's disease. PMID- 22218882 TI - Myelodysplastic syndromes: revisiting the role of the bone marrow microenvironment in disease pathogenesis. AB - Myelodysplastic syndromes are a heterogeneous group of diseases characterized by ineffective hematopoiesis and the propensity to leukemic transformation. Their pathogenesis is complex and likely depends on interplay between aberrant hematopoietic cells and their microenvironment. How niche cells play a role in disease evolution is poorly defined, but the delineation of the hematopoietic stem cell niche and the ability to interrogate its role in hematopoietic disease in animal models have furthered our insights in recent years. The data support a view in which the microenvironment can play an active role in the evolution of myelodysplasia and myeloproliferative disorders, thus providing further rationale to explore therapeutic targeting of mesenchymal-hematopoietic interactions in these diseases. PMID- 22218883 TI - Combination strategies in myelodysplastic syndromes. AB - The myelodysplastic syndromes (MDS) consist of an array of clonal hematological malignancies resulting from disorders of pluripotent hematopoietic stem cells. MDS is associated with a poor overall prognosis and patients are categorized as higher risk and lower risk on the basis of the International Prognostic Scoring System. Currently, lenalidomide, azacitidine, and decitabine are the only three FDA-approved drugs for MDS. Traditional therapies for MDS involve the administration of single agents providing either supportive measures or disease modifying effects directed to slowing progression to acute myeloid leukemia (AML) and improving survival. Recently, however, there has been increasing evidence suggesting that the combination of drugs with different mechanisms of action offers substantial benefit in the form of diminished side effects, improved overall survival, and delayed progression to AML. Multiple studies indicate that when compared with traditional monotherapies, combining various medications with non-overlapping mechanisms of action and toxicities may result in significant benefit for patients with MDS. A variety of combination therapies with growth factors, DNA methytransferase inhibitors, histone deacetylase inhibitors, and immunosuppressant treatments provide encouraging data indicating that the successful future of MDS treatment rests in the combination of multiple treatments modalities to achieve improved clinical outcomes. PMID- 22218886 TI - US follow-up protocol in concordant benign result after US-guided 14-gauge core needle breast biopsy. AB - To determine the time when follow-up ultrasound (US) should begin for concordant benign lesions after US-guided 14-gauge core needle breast biopsy (CNB). This was an IRB-approved retrospective study, with a waiver of informed consent. Among 3,888 consecutive US-guided CNBs performed between August 2005 and March 2008, 1,492 breast masses in 1,309 women with concordant benign results and follow-up US after CNB were included. Their medical records were reviewed. Statistical comparisons for the result of first follow-up US and malignant rates among 6 month, 12-month, and long-term intervals were performed by using Fisher exact test. Results dichotomized for symptom, lesion size (10 mm), and CNB result (specific or not), were also analyzed. In 1,492 masses, seven malignancies (0.5%) were diagnosed by interval growth at first follow-up US performed at 6-month (n = 3), 12-month (n = 1), and long-term interval (n = 3). No significant difference in results of follow-up US and malignant rates was found among follow-up intervals. At 6-month interval, malignant rate in symptomatic group (1.9%, 3/162) was significantly higher than in asymptomatic group (0%, 0/819) (P = 0.004). The size of malignancy at long-term interval tended to be larger than at shorter interval, and metastasis was developed in one patient with malignancy at long term interval. Concordant benign lesions after US-guided 14-gauge CNB should be recommended to begin US follow-up at least at 12 months to detect early-stage cancers. However, for concordant benign lesion associated with any clinical symptoms, follow-up US should begin earlier, at 6 months after CNB. PMID- 22218885 TI - A dietary pattern derived to correlate with estrogens and risk of postmenopausal breast cancer. AB - Circulating estrogens are an established risk factor for breast cancer and some data suggest that diet may influence estrogen levels. Therefore, using a subsample (n = 550) of women from a large cohort, we applied reduced rank regression to identify a dietary pattern that was correlated with estradiol and estrone sulfate. We then adapted the pattern to be used with the full cohort (n = 67,802) and prospectively assessed its association with postmenopausal breast cancer. The estrogen food pattern, characterized by higher intakes of red meat, legumes, and pizza, but lower intakes of coffee and whole grains, was modestly but significantly correlated with estradiol (r = 0.14) and estrone sulfate (r = 0.20). During 22 years of follow-up, we ascertained 4,596 incident breast cancer, with 2,938 estrogen receptor-positive tumors and 689 estrogen receptor-negative tumors. However, after adjusting for potential confounders, we did not observe any association with overall estrogen receptor-positive or estrogen receptor negative breast cancer. In conclusion, diet pattern appeared to only have modest association with estrogens, and was not associated with postmenopausal breast cancer risk. Although these results were null, it should be repeated in other populations as differences in food intake may yield a dietary pattern with stronger association with estrogens. PMID- 22218884 TI - Gamma-ray-induced mutagen sensitivity and risk of sporadic breast cancer in young women: a case-control study. AB - Hypersensitivity to radiation exposure has been suggested to be a risk factor for the development of breast cancer. In this case-control study of 515 young women (<= 55 years) with newly diagnosed sporadic breast cancer and 402 cancer-free controls, we examined the radiosensitivity as measured by the frequency of chromatid breaks induced by gamma-radiation exposure in the G2 phase of phytohemagglutinin-stimulated and short-term cultured fresh lymphocytes. We found that the average chromatid breaks per cell from 50 well-spread metaphases were statistically significantly higher in 403 non-Hispanic White breast cancer patients (0.52 +/- 0.22) than that in 281 non-Hispanic White controls (0.44 +/- 0.16) (P value < 0.001), and in 60 Mexican American breast cancer patients (0.52 +/- 0.19) than that in 65 Mexican American controls (0.44 +/- 0.16) (P value = 0.021), but the difference was not significant in African Americans (52 cases [0.45 +/- 0.16] versus 56 controls [0.47 +/- 0.16], P = 0.651). The frequency of chromatid breaks per cell above the median of control subjects was associated with two-fold increased risk for breast cancer in non-Hispanic Whites and Mexican Americans. A dose-response relationship was evident between radiosensitivity and risk for breast cancer (P (trend) < 0.001) in these two ethnic groups. We concluded that gamma-ray-induced mutagen sensitivity may play a role in susceptibility to breast cancer in young non-Hispanic White and Mexican American women. PMID- 22218888 TI - Live imaging of Drosophila embryos: quantifying protein numbers and dynamics at subcellular locations. AB - Live imaging is critical for understanding the structure and activities of protein interaction networks in cells. By tagging proteins of interest with fluorescent proteins, such as green fluorescent protein (GFP), their localization in cells can be determined and correlated with cellular activities. This can be extended into developmental systems such as Drosophila to understand the molecular and cellular bases of development. In this chapter, we review sample preparation techniques and basic imaging considerations for Drosophila embryos. We then discuss how these techniques can be extended to count absolute protein numbers at specific subcellular locations, and determine their dynamics using fluorescence recovery after photobleaching (FRAP). These techniques can help reveal the structure and dynamics of protein complexes in live cells. PMID- 22218887 TI - Specialist palliative care is more than drugs: a retrospective study of ILD patients. AB - BACKGROUND: This study aimed to assess the palliative care needs of progressive idiopathic fibrotic interstitial lung disease (PIF-ILD) populations in two London ILD centres. METHODS: Patients' records from Royal Brompton Hospital (RBH) and King's College Hospital (KCH) were extracted to assess palliative care needs, use of palliative treatments, and whether end-of-life preferences were documented and achieved. RESULTS: Forty-five PIF-ILD patients were identified (26 RBH, 19 KCH). Patients at RBH were younger (37-81 years, median = 61 years) and predominantly white British (23/26) compared to KCH's older, more racially diverse population (70-99 years, median = 82 years, 6/19 nonwhite). Seventeen of 45 patients had specialist palliative care team involvement. Nearly all patients (42/45) experienced breathlessness in their last year of life. Additional symptoms included cough, fatigue, depression/anxiety, and chest pain. All patients given opioids (22/45) or benzodiazepines (8/45) had documented benefit. Nonpharmacological treatments were rarely used. Few patients had preferred place of care (8/45) or preferred place of death (6/45) documented. CONCLUSIONS: Despite demographic variation, the patient populations at the two hospitals experienced similar symptoms. There was use of standard pharmacological treatments with symptom benefit. Nonpharmacological interventions were seldom used and documentation of preferred place of care and preferred place of death was poor. PMID- 22218889 TI - Analyzing frizzled signaling using fixed and live imaging of the asymmetric cell division of the Drosophila sensory organ precursor cell. AB - When you look at the dorsal thorax of a fruitfly, you can easily get fascinated by the high degree of alignment of the bristles that show a strong polarization in their surface organization. This organization of cells in the plane of the epithelium is known as planar cell polarity (PCP), and was initially characterized in Drosophila melanogaster. This process is important in a broad variety of morphological cellular asymmetries in various organisms. In Drosophila, genetic studies of PCP mutants showed that the asymmetric division of the sensory organ precursor cell (pI cell) is polarized along the anterior posterior axis by Frizzled receptor signaling. Here, we described two methods to image and analyze the PCP in the pI cell model. PMID- 22218890 TI - Protein-protein interaction techniques: dissect PCP signaling in Xenopus. AB - The planar cell polarity (PCP) pathway is a beta-catenin-independent branch of the Wnt signaling cascade. In vertebrate embryos PCP signaling regulates morphogenetic events including convergent extension (CE) movements during gastrualtion. Xenopus embryo has been established as an excellent model system to dissect PCP signaling in vertebrates because morphogenetic cell behaviors including CE can easily be monitored in vivo. Xenopus Paraxial protocadherin (xPAPC) is a transmembrane protein which serves as a link between patterning factors in the Spemann's organizer and regulators of the morphogenetic movements. xPAPC regulates morphogenesis in part by modulating cell adhesion and PCP signaling. Here two methods, GST pull-down assay and yeast two-hybrid assay, are described for the identification of xPAPC interacting proteins to elucidate the mechanism by which xPAPC regulates PCP signaling. PMID- 22218891 TI - Cuticle refraction microscopy: a rapid and simple method for imaging Drosophila wing topography, an alternative readout of wing planar cell polarity. AB - The polarity of hairs on the adult Drosophila wing provides information about the planar cell polarity (PCP) signaling events that occur during pupal wing development. We have recently shown that PCP signaling also determines the orientation of cuticle ridges that traverse the surface of the adult wing membrane; a feature we call the wing membrane topography. Although hair polarity is uniform across the wild-type wing, ridge orientation differs between the anterior and posterior wing. Consequently, mapping wing topography can provide additional information about PCP signaling, rather than simply confirming observations of wing hair polarity. Wing membrane ridges can be imaged using scanning electron microscopy, however, significant preparation time and operator expertise are required. Here, we describe cuticle refraction microscopy, a rapid and simple light microscopy method for imaging Drosophila wing topography. PMID- 22218892 TI - Analysis of cell shape and polarity during zebrafish gastrulation. AB - Gastrulation is a complex set of cellular rearrangements that establish the overall shape of the body plan during development. In addition to being an essential and fascinating aspect of development, the cells of the gastrulating zebrafish embryo also provide an ideal in vivo system to study the interplay of cell polarity and movement in a native 3D environment. During gastrulation, zebrafish mesodermal cells undergo a series of conversions from initial non polarized amoeboid cell movements to more mesenchymal and finally highly polarized and intercalative cell behaviors. Many of the cellular behavior changes of these cells are under the control of the RhoA pathway, which in turn is regulated by many signals, including non-canonical Wnts. The goal of this chapter is to provide researchers with the necessary protocols to examine changes in cell polarity and movement in the developing zebrafish embryo. PMID- 22218893 TI - Analyzing planar cell polarity during zebrafish gastrulation. AB - Planar cell polarity was first described in invertebrates over 20 years ago and is defined as the polarity of cells (and cell structures) within the plane of a tissue, such as an epithelium. Studies in the last 10 years have identified critical roles for vertebrate homologs of these planar cell polarity proteins during gastrulation cell movements. In zebrafish, the terms convergence and extension are used to describe the collection of morphogenetic movements and cell behaviors that contribute to narrowing and elongation of the embryonic body plan. Disruption of planar cell polarity gene function causes profound defects in convergence and extension creating an embryo that has a shortened anterior posterior axis and is broadened mediolaterally. The zebrafish gastrula-stage embryo is transparent and amenable to live imaging using both Nomarski/differential interference contrast and fluorescence microscopy. This chapter describes methods to analyze convergence and extension movements at the cellular level and thereby connect embryonic phenotypes with underlying planar cell polarity defects in migrating cells. PMID- 22218894 TI - Wnt/planar cell polarity signaling in the regulation of convergent extension movements during Xenopus gastrulation. AB - The Wnt/planar cell polarity (PCP) signaling pathway plays a critical role in wing, eye, neural tube defects, and sensory bristle development of Drosophila and vertebrate development. Recently, the Wnt/PCP pathway has been known to regulate convergent extension (CE) movements that are essential for establishing the three germ layers and body axis during early vertebrate development. Here, we describe detailed practical procedures required for the particular studies in Xenopus CE movements. PMID- 22218895 TI - Using 32-cell stage Xenopus embryos to probe PCP signaling. AB - Use of loss-of function (via antisense Morpholino oligonucleotides (MOs)) or over expression of proteins in epithelial cells during early embryogenesis of Xenopus embryos, can be a powerful tool to understand how signaling molecules can affect developmental events. The techniques described here are useful for examining the roles of proteins in cell-cell adhesion, and planar cell polarity (PCP) signaling in cell movement. We describe how to target specific regions within the embryos by injecting an RNA encoding a tracer molecule along with RNA encoding your protein of interest or an antisense MO to knock-down a particular protein within a specific blastomere of the embryo. Effects on cell-cell adhesion, cell movement, and endogenous or exogenous protein localization can be assessed at later stages in specific targeted tissues using fluorescent microscopy and immunolocalization. PMID- 22218896 TI - Gene loss-of-function and live imaging in chick embryos. AB - Planar cell polarity (PCP) is the coordinate organization of cells within the plane of a tissue. PCP is essential for tissue function, such as for proper hearing in the vertebrate ear or for accurate vision in the Drosophila eye. Using the chick embryo, we have recently shown that during early muscle formation, the first formed muscle fibres utilize the PCP pathway to orient parallel to a WNT11 source present in the medial border of somites. Our results further establish that WNT11 acts as a directional cue to regulate this process. To perform this study, two major techniques have been utilized, the gene loss-of-function using a vector-based shRNAmir expression and confocal videomicroscopy of fluorescent gene reporters targeted in specific cell subpopulations by in vivo electroporation. Here we describe the two techniques. PMID- 22218897 TI - Activation and function of small GTPases Rho, Rac, and Cdc42 during gastrulation. AB - Gastrulation is comprised of a series of cell polarization and directional cell migration events that establish the physical body plan of the embryo. One of the major ligand-based pathways that has emerged to play crucial roles in the regulation of gastrulation is the non-canonical Wnt signaling pathway. This aspect of Wnt signaling is comprised of a number of signaling branches that are subsequently integrated for the regulation of changes to the actin cytoskeleton during cell polarization and cell migration during vertebrate gastrulation. The Rho family of small GTPases are activated and required for non-canonical Wnt signaling during gastrulation, and in this chapter, we describe biochemical assays for the detection of Wnt-mediated activation of Rho, Rac, and Cdc42 in both mammalian cells and Xenopus embryo explants. PMID- 22218898 TI - Convergent extension analysis in mouse whole embryo culture. AB - Mutations have been identified in a non-canonical Wnt signalling cascade (the planar cell polarity pathway) in several mouse genetic models of severe neural tube defects. In each of these models, neurulation fails to be initiated at the 3 4 somite stage, leading to an almost entirely open neural tube (termed craniorachischisis). Studies in whole embryo culture have identified a defect in the morphogenetic process of convergent extension during gastrulation, preceding the onset of neural tube closure. The principal defect is a failure of midline extension, both in the neural plate and axial mesoderm. This leads to an abnormally wide neural plate in which the elevating neural folds are too far apart to achieve closure. In this chapter, we provide details of several experimental methods that can be used to evaluate convergent extension in cultured mouse embryos. We describe analytical methods that can reveal the abnormalities that characterise neurulation-stage embryos with defective planar cell polarity signalling, in particular the loop-tail (Lp; Vangl2) mutant. PMID- 22218899 TI - Analysis of PCP defects in mammalian eye lens. AB - Multicellular tissues and organs often show planar cell polarity (PCP) where the constituent cells align along an axis to form coordinated patterns. Mammalian eye lenses are mainly comprised of epithelial-derived fibre cells, which exhibit highly ordered alignment that is regulated by PCP signaling. Each fibre cell has an apically situated primary cilium and in most cases this is polarized towards the lens anterior pole. Here we describe how to visualize the global cellular alignment of lens fibre cells by examining the suture pattern that is formed by the tips of fibres meeting at the anterior pole. We also describe a method for whole mount preparation, which allows observation of the polarized distribution of primary cilia at the apical surface of lens fibres. Given its relative simplicity, at least in cellular terms, and its requirement for a high degree of precision in cellular alignment and orientation, we predict that the lens will be an excellent model system to help elucidate the role of cilia and PCP components in the development of three-dimensional organization in tissues and organs. PMID- 22218900 TI - Examining planar cell polarity in the mammalian cochlea. AB - The mammalian cochlea offers a unique opportunity to study the effects of planar cell polarity signaling during vertebrate development. First, convergence and extension play a role in outgrowth and cellular patterning within the duct, and second, hair cell stereociliary bundles are uniformly oriented towards the lateral edge of the duct. Defects in convergence and extension are manifested as a shortening of the cochlea duct and/or changes in cellular patterning, which can be quantified following dissection from mouse mutants or observed directly using an in vitro outgrowth assay. Changes in stereociliary bundle orientation can be observed and quantitated using either fluorescent tags or scanning electron microscopy (SEM) to visualize individual bundles. The high degree of regularity in many aspects of cochlear anatomy, including cellular patterning and stereociliary bundle orientation, makes it possible to detect subtle changes in the development of PCP in response to either genetic or molecular perturbations. PMID- 22218901 TI - Role of Prickle1 and Prickle2 in neurite outgrowth in murine neuroblastoma cells. AB - Murine Prickle2 but not Prickle1 gene expression was induced in C1300 neuroblastoma cell line during neurite-like process formation induced by all trans-retinoic acid (RA). Overexpression of Prickle1 or Prickle2 in C1300 cells induced striking neurite-like process formation without RA. Prickle1 and Prickle2 associate with Dishevelled1 (Dvl1) and overexpression of Prickle1 or Prickle2 resulted in the reduction of Dvl1 protein in C1300 cells. Overexpression of Dvl1 in C1300 cells prevented the neurite-like process formation induced by Prickle1 or Prickle2 overexpression. Prickle1 and Prickle2 promote neurite-like process formation of C1300 cells via the Dvl1-dependent mechanism. PMID- 22218902 TI - The planar cell polarity pathway and parietal endoderm cell migration. AB - Parietal endoderm (PE) migration is the first long-range migratory event in the mammalian embryo contributing to the parietal yolk sac. PE migration can be studied in vitro using the F9 teratocarcinoma stem cell model system. We have found that PE migration is directed and modulated via the Planar Cell Polarity (PCP) pathway through Rho/ROCK signaling. Wnt inhibition using sFRP results in a loss of orientation, visualized by Golgi apparatus localization, along with disorganized microtubules and a lack of robust focal adhesions. Small GTPases are downstream of PCP signaling and Rho/ROCK inhibition results in a loss of orientation, whereas inhibition of Rac does not affect PCP. Activation of canonical Wnt signaling combined with Wnt inhibition does not prevent loss of oriented migration. These data support a role for non-canonical Wnt/PCP signaling directing oriented migration of PE. PMID- 22218903 TI - Analysis of Wnt/planar cell polarity pathway in cultured cells. AB - Planar cell polarity (PCP) pathway of Wnt signaling plays a crucial role to establish the polarization of cells during tissue development. Our recent findings using in vitro analyses have revealed that Ror2, a member of the Ror family receptor tyrosine kinases, acts as a receptor or co-receptor for Wnt5a and plays a crucial role for Wnt5a-induced polarized cell migration through activating PCP pathway. Indeed, analyses of both Wnt5a and Ror2 mutant mice have shown that Wnt5a-Ror2 signaling is involved in establishing the PCP in epithelial tissues in vivo, indicating that in vitro analyses of polarized cell migration and PCP signaling induced by Wnt5a can be useful tools to explore putative regulators involved in Wnt/PCP pathway. Here, we introduce in vitro methods using cultured cells to monitor polarized cell migration and PCP signaling induced by Wnt5a. PMID- 22218904 TI - Regulation of focal adhesion dynamics by Wnt5a signaling. AB - Wnt5a is a representative ligand that activates the beta-catenin-independent pathway of Wnt signaling in mammals. This pathway might be related to planar cell polarity signaling in Drosophila. Because reliable biochemical assays to measure Wnt5a pathway activity have not yet been established, we examined whether Wnt5a signaling stimulates focal adhesion turnover in migrating cells using live immunofluorescence imaging and immunocytochemical analysis. These assays demonstrated that the Wnt5a pathway cooperates with integrin signaling to regulate cell migration and adhesion through focal adhesion dynamics. PMID- 22218905 TI - The embryonic mouse gut tube as a model for analysis of epithelial polarity. AB - Recent accumulating data indicate links between planer cell polarity (PCP) and apicobasal (AB) polarity in epithelial cells. PCP regulatory genes have been shown to be involved in the establishment of AB polarity in addition to regulating PCP. We have shown that the gut tube of the mouse embryo is a unique model system for the analysis of epithelial polarities, e.g., oriented cell division and AB polarity, with respect to the PCP pathway. The regulation of epithelial polarity by the PCP pathway might play an essential role in organ morphogenesis relating to physiological function. PMID- 22218906 TI - Assessing PCP in the cochlea of mammalian ciliopathy models. AB - The increased availability of mouse models of human genetic ciliary diseases has led to advances in our understanding of the diverse cellular roles played by cilia. The family of so-called "ciliopathies" includes Alstrom Syndrome, Bardet Biedl Syndrome, Primary Ciliary Dyskinesia, and Polycystic Kidney Disease, among many others. In mouse models of Alstrom Syndrome and Bardet-Biedl Syndrome, we have shown developmental defects in the mechano-sensory stereociliary bundles on the apical surfaces of "hair" cells in the cochlea, the mammalian hearing organ. Stereocilia are specialized actin-based microvilli, whose characteristic patterning is thought to be dependent on the hair cell's primary cilium ("kinocilium"). Ciliopathy-associated proteins are localized to the ciliary axoneme and/or the ciliary basal body, or to the bundle itself. Ciliopathy associated genes functionally interact with genes of the noncanonical Wnt pathway, and so implicate PCP in the control of hair cell development. PMID- 22218907 TI - Morphometric analysis of centrosome position in tissues. AB - Planar cell polarity (PCP) is the polarization of cells within the plane of an epithelial cell layer. PCP is important in many tissues in different processes. In the kidney, it is hypothesized to be important in acquiring and maintaining correct tubular diameter. Aberrant PCP has been shown to be involved in polycystic kidney disease. Therefore, research in this field requires a method to study PCP. As PCP and outward-in signaling via the cilia are interconnected, the position of the centrosome, the base of the cilium can be used as a read-out system for PCP. Here, we provide a method in which the position of the centrosome is measured as read-out for PCP. PMID- 22218908 TI - Clinical impact of c-Met expression and its gene amplification in hepatocellular carcinoma. AB - BACKGROUND: c-Met is an oncogene encoding a receptor for hepatocyte growth factor and, as such, plays a key role in hepatocellular carcinomas (HCC). We evaluated c Met protein expression and its gene amplification in order to assess whether they were related to tumor recurrence and survival rates among patients who had undergone tumor resection. METHODS: We used the polymer-based method to perform an immunohistochemistry analysis of c-Met expression on 59 formalin-fixed, paraffin-embedded sections of surgical specimens. c-Met gene amplification was investigated with fluorescence in-situ hybridization. Kaplan-Meier methods and Cox proportional hazards models were used to investigate relationships between c Met expression, patient characteristics, tumor recurrence, and survival. RESULTS: c-Met expression was associated with portal vein invasion (p = 0.006). Recurrence free survival rates were significantly lower in patients with high levels of c Met expression (p < 0.001). However, c-Met expression levels did not significantly affect overall survival rates (p = 0.12). Only 1 patient was found to have c-Met gene amplification; 22 patients were found to have aneuploidy of chromosome 7, on which the c-Met gene is located. Tumors with chromosome 7 polysomy tended to have higher levels of c-Met expression than those with chromosome 7 monosomy or disomy, but this difference was not statistically significant. CONCLUSION: Although c-Met expression was not significantly associated with c-Met gene amplification, it may be a useful predictive marker of recurrence in resected HCC patients. PMID- 22218909 TI - A phase II study to evaluate the efficacy and toxicity of oxaliplatin in combination with gemcitabine in carcinoma of unknown primary. AB - BACKGROUND: Preclinical and clinical data suggest synergy for gemcitabine and oxaliplatin. These agents were tested in several known cancers that also comprise the common carcinoma of unknown primary (CUP) subtypes; namely, lung and pancreaticobiliary profiles. METHODS: The study enrolled 29 patients of whom 28 patients were eligible for treatment. Gemcitabine was given at 1,000 mg/m(2) as a fixed dose rate infusion and oxaliplatin was infused at 100 mg/m(2) every 2 weeks with restaging performed after 3 cycles at 6 weeks. RESULTS: The study reported one complete response (CR) (4%), 6 patients with a partial response (PR) (25%), and 13 with stable disease (SD) (54%); and 4 patients had progressive disease (PD) (17%) on restaging. Median overall survival (OS) and progression-free survival were 12.8 months (95% confidence interval [CI] 8.5-18.5) and 3.1 months (95% CI 1.7-6), respectively. The 1-year OS was 54%. The most common grade 3 toxicities were nausea (22%), vomiting (15%), and fatigue (11%). There were no grade 4 toxicities. This study was closed early as we moved from an empiric therapy platform to a more individualized approach. CONCLUSIONS: Gemcitabine and oxaliplatin is a well-tolerated regimen in CUP with similar outcomes to previously documented CUP studies. In selected good performance status patients this combination may serve as a first-line doublet chemotherapy option for CUP patients. PMID- 22218910 TI - Seizure outcome with surgical management of epileptogenic ganglioglioma: a study of 55 patients. AB - BACKGROUND: Ganglioglioma is a common seizure-associated tumor, and some factors that may influence the postoperative seizure outcome have not been discussed or are controversial. The goal of this study was to observe the postoperative seizure outcome and the prognostic factors in patients with epileptogenic gangliogliomas. METHODS: In this retrospective study, 55 patients with epileptogenic gangliogliomas underwent surgery. Postoperative seizure outcome during follow-up was recorded, and possible postoperative prognostic factors were analyzed. RESULTS: There were 30 males and 25 females in our study. Twenty patients presented with chronic seizures. The mean age at surgery was 19.39 years, and the mean seizure duration prior to surgery was 4.47 years. Forty-three patients had complex partial seizures, 12 patients had simple partial seizures, and secondary generalization occurred in 18 patients. Brain magnetic resonance imaging (MRI) revealed 32 tumors were located in the temporal lobe and 23 in the extratemporal lobes. Intraoperative electrocorticography (ECoG) and intraoperative ultrasound (IOUS) were used in 42 and 11 patients, respectively. Gross total resection of the tumor was achieved in 42 patients (1 patient underwent reoperation), subtotal resection in 11, and partial resection in 2. Simple lesionectomy and tailored epilepsy surgery were performed in 24 and 31 patients, respectively. After a mean follow-up of 3.27 years, 48 patients, including 1 re-operated patient, were seizure free (Engel class I). None of the factors, including age at surgery, seizure duration prior to surgery, the type of seizures, use of intraoperative ECoG and IOUS, extent of tumor resection, and surgical strategy, proved to be significantly correlated with postoperative seizure outcome. CONCLUSIONS: Surgical treatment is effective and safe for patients with epileptogenic gangliogliomas. Early surgical intervention is necessary for achieving early seizure control. Neither intraoperative ECoG nor IOUS necessarily leads to better seizure control, although the latter can be helpful in achieving complete tumor resection. Simple lesionectomy is sufficient for favorable postoperative seizure outcome. PMID- 22218911 TI - Histopathological analysis of intracerebral hemorrhage: implications for clinical management. AB - BACKGROUND: The clinical impact of routine neuropathologic examination of samples from patients with intracerebral hemorrhage (ICH) is unclear. METHODS: Therefore, we evaluated a consecutive series of 378 surgical specimens from patients with ICH concerning demographic data, localization of hemorrhage, preoperative clinical diagnosis and neuropathological diagnosis. RESULTS: Histological examination revealed the putative origin of ICH in 143 cases (37.8%). Vascular pathologies were detected in 127 patients (33.6%), while tumors were identified in 9 patients (2.4%), infarction in 6 patients (1.6%) and abscess in 1 patient (0.3%). Preoperatively, tumor was considered in 65 patients (17.2%), while vascular malformations were supposed in 94 patients (24.9%), infarction in 18 cases (4.8%) and abscess in 3 cases (0.8%). In 198 patients (52.4%) no specific assumption was made. CONCLUSIONS: Comparing preoperative assumptions and histological diagnoses, tumor, vascular malformations and infarctions were clinically overestimated, while arteriolosclerosis and amyloid angiopathy were underestimated. In conclusion, we found that histological findings potentially affecting clinical management and prognosis were obtained in 37.8% of cases. Our data suggest that histopathological examination of intracerebral hemorrhage provides important information for patient management and should be routinely performed. PMID- 22218912 TI - Resveratrol in human cancer chemoprevention--choosing the 'right' dose. AB - There is now robust preclinical evidence to suggest that resveratrol possesses cancer chemopreventive properties. A series of clinical pilot studies has provided insights into its pharmacokinetics, and data on its human antineoplastic pharmacodynamics start to emerge. It is likely that resveratrol will be developed further in the clinic as a putative cancer chemopreventive agent. The question that remains unresolved is: What is the most suitable dose of resveratrol for effective cancer preventive intervention? Mechanistic studies in cells in vitro have almost invariably used concentrations of resveratrol in the 10(-5) to 10( 4) M range, which is much higher than those which can be achieved in the human biophase after consumption of doses up to 1 g. Many of the preclinical efficacy studies in rodent models of carcinogenesis have employed doses which are dramatically above those which can be ingested with the diet. New experimental paradigms need to be used to obtain information on pharmacological changes elicited by resveratrol when present at very low concentrations or when administered at dietary-relevant doses. PMID- 22218913 TI - Infections in spinal instrumentation. AB - Surgical-site infection (SSI) in the spine is a serious postoperative complication. Factors such as posterior surgical approach, arthrodesis, use of spinal instrumentation, age, obesity, diabetes, tobacco use, operating-room environment and estimated blood loss are well established in the literature to affect the risk of infection. Infection after spine surgery with instrumentation is becoming a common pathology. The reported infection rates range from 0.7% to 11.9%, depending on the diagnosis and complexity of the procedure. Besides operative factors, patient characteristics could also account for increased infection rates. These infections after instrumented spinal fusion are particularly difficult to manage due to the implanted, and possibly infected, instrumentation. Because the medical, economic and social costs of SSI after spinal instrumentation are enormous, any significant reduction in risks will pay dividends. The goal of this literature review was to analyse risk factors, causative organisms, diagnostic elements (both clinical and biological), different treatment options and their efficiency and consequences and the means of SSI prevention. PMID- 22218914 TI - Role of Newman's classification in predicting outcomes in patients with crystal arthritis. AB - PURPOSE: The aim of the study was to evaluate the utility of Newman's classification in predicting outcomes in patients presenting with crystal arthritis. METHODS: Between January and December 2009, all patients who presented to our institution with acute crystal arthritis and were investigated with microbiological assessment of their synovial fluid were included in the study. Patients were divided into two groups depending on the fulfilment of Newman's criteria for culture-negative septic arthritis. Group 1 included patients that fulfilled Newman's B criteria. Group 2 included patients that fulfilled Newman's C criteria. A database looking at the demographics, mode of presentation, investigations, treatment and outcomes was then established and the results compared between the two groups. RESULTS: A total of 58 patients were identified (group 1: n = 13; group 2: n = 45). The average age was 71 years (range 33-96). The joint most commonly involved was the knee followed by the wrist. Clinical findings at presentation were comparable in both groups; however, WBC and C reactive protein (CRP) were more likely to be raised in group 1. Although most patients in group 1 were treated with antibiotics (62%) there was still a higher rate of morbidity, greater use of supportive therapy and a longer hospital stay (22.3 days, SD 17.4) in comparison with group 2, where most patients were treated by observation only (76%, mean hospital stay 3.5 days, SD +/- 4.4). The difference in length of hospital stay was statistically significant (p < 0.0001). CONCLUSIONS: Newman's criteria are a good indicator for prognosis in patients with crystal arthritis. However, the presence of crystals in an acutely inflamed joint does not exclude the need for supportive therapy and long hospital stay even in the absence of positive synovial fluid culture. PMID- 22218915 TI - Treatment given near the end of life in castration-resistant prostate cancer. AB - Chemotherapy treatment options are limited for patients with castration-resistant prostate cancer (CRPC). The purpose of this study is to report treatment use and adverse effects (AEs) within the last three months of life in patients with CRPC. Of the 88 patients identified, 32% received treatment within 3 months of death, and documented AEs occurred in 25% of patients. Of those, neutropenia (18.3%), nausea/vomiting (18.3%), and febrile neutropenia (13.6%) were the most frequent. Results of this study show high treatment utility towards the end-of-life in patients with CRPC, with one fourth of patients experiencing AEs. Attention to health-related quality of life becomes increasingly important as new treatments appear to have small impact on survival, and AEs of those treatments may significantly impact patient quality of life. PMID- 22218916 TI - Antimicrobial use at the end of life among hospitalized patients with advanced cancer. AB - BACKGROUND: We sought to evaluate antimicrobial use among patients with advanced cancer. METHODS: Retrospective review of patients experiencing cancer-related death while hospitalized. RESULTS: Among 145 patients, 126 (86.9%) received antimicrobials for a mean of 12.5 +/- 12.9 days. 88 (69.8%) of 126 had clinical findings suggestive of infection. Sixty-one patients (48.4%) had positive cultures, the remaining were treated empirically. "Comfort care" was ultimately pursued in 99 (78.5%) of 126; 35 (35.4%) of 99 continued to receive antimicrobials after a transition to comfort care for an average of 1.6 +/- 1.1 days. On average, antimicrobials were discontinued <1day prior to death. CONCLUSION: Antimicrobial use was common among patients with advanced cancer. Even after transition to comfort care, more than one third of patients remained on antimicrobials. The risks and burdens of antimicrobials should be carefully examined when comfort is the stated goal. PMID- 22218917 TI - Prelude to death or practice failure? Trombley-Brennan terminal tissue injuries. AB - A group of palliative care nurses wanted to investigate the phenomenon they were witnessing in their end-of-life patients. There was a rapid onset of skin change characterized by bruising on various parts of the body in these patients. Traditionally they were described as pressure ulcers. However, the skin changes did not progress as typical pressure ulcers and warranted more investigation. PMID- 22218918 TI - A national survey of hospice administrator and pharmacist perspectives on pharmacist services and the impact on medication requirements and cost. AB - Symptom management at the end of life relies heavily on medications. For this reason, pharmacists are an ideal addition to the interdisciplinary hospice team (IDT). The aim of this study is to characterize the utilization of pharmacists in hospices from the hospice administrator and pharmacist perspectives and to determine the impact utilization has on per diem medication requirement and costs. Surveys were sent to 2824 hospice administrators and 658 pharmacists to obtain their perceptions on what clinical, administrative, and dispensing services were being performed. Responses were returned by 9.4% of administrators and 12.6% of pharmacists. The majority of administrators and pharmacists reported a mix of clinical, administrative, and dispensing responsibilities. Medication requirements and costs were not significantly impacted as the administrator's perception of pharmacist clinical, administrative, or dispensing time increased from 0% to 100%. PMID- 22218919 TI - ICD's near end of life: risk versus benefit- a review. AB - The number of annual implantable cardioverter defibrillator (ICD) implants has substantially increased over the last 5 years and is expected to grow rapidly. Implantable cardioverter defibrillators have a proven mortality benefit by terminating the life-threatening arrhythmias, even near end of life. In patients with moderate/severe symptomatic heart failure, enough clinical literature representing mortality benefits has been published, but limited numbers of studies have reviewed the dwindling risk-benefit profile near end of life, studying quality of life (QoL)/psychosocial impact. Criteria outlining either continued use or deactivation policy/procedures near end of life have not been clearly defined and/or largely implemented, which in turn requires more focused research using multifactorial approach to determine improved patient-centered outcomes. PMID- 22218921 TI - Synganglion histology in different stages of Rhipicephalus sanguineus ticks (Acari: Ixodidae). AB - The present study performs a morpho-histological description of the central nervous system of Rhipicephalus sanguineus ticks in order to analyze if there are differences in this tissue among larvae, nymphs, and adults. The results showed that the central nervous system in all the life stages of R. sanguineus consists of a mass of fused nerves named synganglion. Externally, this organ does not present segmentation, consisting of a single structure located ventromedially in the third anterior of the body. This organ is externally covered by the neural lamella or neurilemma, a uniform and acellular layer. Below, there is the periganglionic membrane or perineurium, formed by glial cells, which are characterized by their elongated nuclei. The esophagus penetrates the synganglion dividing it in two regions: supraesophageal, which is the smaller of the two and consists of a protocerebrum, a single dorsal ganglion located anteriordorsally to the esophagus; and the subesophageal, which is the largest part of the synganglion, located in the posterior region and ventral to the esophagus. Internally, the synganglion is subdivided in an external cortical region-which contains the cellular body of the nervous cells-and an internal neuropile formed by a set of neural fibers and it is constituted by bilaterally symmetric ganglia, from where nerves emerge towards several parts of the body. The results here obtained showed that there are no differences in the morpho-histology of this tissue in different life stages of R. sanguineus, suggesting that the initial structure is maintained during the whole life cycle of the tick, i.e., from larval to adult stage. PMID- 22218920 TI - Spatiotemporal maps of CaMKII in dendritic spines. AB - The calcium calmodulin dependent kinase (CaMKII) is important for long-term potentiation at dendritic spines. Photo-activatable GFP (PaGFP) - CaMKII fusions were used to map CaMKII movements between and within spines in dissociated hippocampal neurons. Photo-activated PaGFP (GFP*) generated in the shaft spread uniformly, but was retained for about 1 s in spines. The differential localization of GFP*-CaMKII isoforms was visualized with hundred nanometer precision frame to frame using de-noising algorithms. GFP*-CaMKIIalpha localized to the tips of mushroom spines. The spatiotemporal profiles of native and kinase defective GFP*-CaMKIIbeta, differed markedly from GFP*-CaMKIIalpha and mutant GFP*-CaMKIIbeta lacking the association domain. CaMKIIbeta bound to cortical actin in the dendrite and the stable actin network in spine bodies. Glutamate produced a transiently localized GFP*-CaMKIIalpha fraction and a soluble GFP* CaMKIIbeta fraction in spine bodies. Single molecule simulations of the interplay between diffusion and biochemistry of GFP* species were guided by the spatiotemporal maps and set limits on binding parameters. They highlighted the role of spine morphology in modulating bound CaMKII lifetimes. The long residence times of GFP*-CaMKIIbeta relative to GFP*-CaMKIIalpha followed as consequence of more binding sites on the actin cytoskeleton than the post-synaptic density. These factors combined to retain CaMKII for tens of seconds, sufficient to outlast the calcium transients triggered by glutamate, without invoking complex biochemistry. PMID- 22218922 TI - Molecular characterization and immunolocalization of a protein disulfide isomerase from Angiostrongylus cantonensis. AB - Protein disulfide isomerases (PDIs), belonging to the thioredoxin superfamily, are oxidoreductases that catalyze the formation, reduction, and isomerization of disulfide bonds among cysteine residues of proteins. In this study, we report the cloning and characterization of a cDNA encoding a protein disulfide isomerase (AcPDI) from a cDNA library of fourth-stage larvae of Angiostrongylus cantonensis. The deduced amino acid sequence contains two thioredoxin domains and exhibits high identity to the homologues from other species. Quantitative real time PCR (qRT-PCR) was performed at the third-stage larvae, fourth-stage larvae, and adult stage of A. cantonensis, and the results revealed that the AcPDI mRNA, while expressed at all three stages, is expressed at a significantly higher level in female adult worms. Results of immunohistochemical studies indicated that the AcPDI expression was specifically localized in the tegument and uterus wall of female adult worms. Biochemical analysis showed that recombinant AcPDI was biologically active in vitro and exhibited the typical biochemical functions of PDIs: oxidase/isomerase and reductase activities. Collectively, these results implied that AcPDI may be a female-enriched protein and associated with the reproductive development of A. cantonensis. In addition, considering its biochemical properties, AcPDI may be involved in the formation of the cuticle of A. cantonensis. PMID- 22218923 TI - Canine leishmaniosis: in vitro efficacy of miltefosine and marbofloxacin alone or in combination with allopurinol against clinical strains of Leishmania infantum. AB - Despite the availability of different therapeutic options, canine visceral leishmaniosis (CVL) remains a challenging disease to treat. Recently miltefosine has been registered for use in dogs, and different studies have demonstrated its leishmanicidal effect. Moreover, it has been suggested that fluoroquinolones, compared to standard chemotherapeutic agents, could be an effective and pragmatic alternative to treat CVL. The efficacy of miltefosine and marbofloxacin alone or in combination with allopurinol against clinical strains of Leishmania infantum was assessed in vitro by incubating increasing concentrations of the drugs with a standard parasite inoculum. Miltefosine was significantly more efficacious than marbofloxacin (P < 0.05) against the two strains of L. infantum either alone or in combination with allopurinol. Both drugs were significantly (P < 0.05) more efficacious when associated with allopurinol than alone. PMID- 22218924 TI - Anti-Trichomonas vaginalis activity of saponins from Quillaja, Passiflora, and Ilex species. AB - Trichomonas vaginalis is a flagellated protozoan that causes trichomonosis, the most prevalent non-viral STD worldwide. The pathogen has been associated with serious health consequences including predisposition to cervical cancer and adverse pregnancy outcomes and infertility. It also acts as a co-factor in HIV transmission and acquisition. The 5-nitroimidazole drugs are used in the treatment, however, treatment noncompliance is observed, and a growing number of T. vaginalis isolates resistant to the drugs have been related. Saponins are natural products possessing many biological activities such as antiprotozoan activity. The aim of this study was to evaluate the anti-T. vaginalis activity of saponins from Quillaja, Passiflora, and Ilex species. Saponins from Passiflora alata and Quillaja saponaria presented the best anti-T. vaginalis activity (MIC = 0.025%). In addition, all samples induced erythrocyte lysis and LDH release. As far as we know, this is the first report demonstrating the potential anti-T. vaginalis activity of these saponins. PMID- 22218925 TI - The "HER2-PI3K/Akt-FASN Axis" regulated malignant phenotype of colorectal cancer cells. AB - Recent evidence suggests that HER2 (ErbB2; Her-2/neu) and the related PI3K/Akt signaling pathway substantially affect the malignant phenotype of colorectal cancer cells. Moreover, fatty acid synthase (FASN), which mediates de-novo fatty acid synthesis, is crucially important in the carcinogenesis process of a variety of cancers, including colorectal cancer. The purpose of this study was to investigate the malignant phenotype regulation of colorectal cancer cells via the "HER2-PI3K/Akt-FASN axis". Caco-2 cells with high expression of HER2 and FASN and high transfection efficiency were selected for functional characterization. The cells were transfected with either HER2-specific RNAi plasmid or negative control RNAi plasmid, followed by Q-RT-PCR and western blot assays to examine expression of HER2, PI3K, Akt, and FASN. MTT and colony-formation assays were used to assess proliferation. Migration was investigated by use of the transwell assay, and apoptosis and cell cycle were assayed by use of flow cytometry. Expression of HER2, PI3K, Akt, and FASN were downregulated when HER2 was silenced. Proliferation decreased after downregulation of HER2, which was consistent with increased apoptosis. Migration of HER2-silenced cells was also impaired. Loss of HER2 inhibits the activity of the "HER2-PI3K/Akt-FASN axis" of Caco-2 cells, and reduced activity of this axis alters the malignant behavior of Caco-2 cells. PMID- 22218926 TI - Molecular basis underlying the S5-dependent reproductive isolation and compatibility of indica/japonica rice hybrids. AB - The S5 locus regulates spikelet fertility of indica/japonica hybrid rice (Oryza sativa). There are three alleles at the S5 locus, including an indica allele (S5i), a japonica allele (S5j), and a wide-compatibility allele (S5n). This study analyzed the molecular basis for S5-dependent reproductive isolation and compatibility of indica/japonica rice hybrids. Three S5 alleles were expressed at extremely low levels, and only in the ovary. S5n was more similar to S5i in both RNA and protein expression profiles. The S5 locus was not essential for embryo sac development, although deleterious interactions between S5i and S5j resulted in reduced rates of spikelet fertility. The yeast two-hybrid system was used to test direct interactions between S5-encoded proteins. The results indicated that the S5i- and S5j-encoded eukaryotic aspartyl proteases formed both homodimers and heterodimers, whereas the S5n-encoded aspartyl protease was incapable of dimerization. Site-directed mutagenesis revealed that a single amino acid difference between S5i- and S5j-encoded aspartyl proteases (phenylalanine/leucine at residue 273) was primarily responsible for embryo sac abortion. The S5 locus may have promoted the subspeciation of indica and japonica, but it also enables gene flow between them. PMID- 22218927 TI - Accumulation of beta-conglycinin in soybean cotyledon through the formation of disulfide bonds between alpha'- and alpha-subunits. AB - beta-Conglycinin, one of the major soybean (Glycine max) seed storage proteins, is folded and assembled into trimers in the endoplasmic reticulum and accumulated into protein storage vacuoles. Prior experiments have used soybean beta conglycinin extracted using a reducing buffer containing a sulfhydryl reductant such as 2-mercaptoethanol, which reduces both intermolecular and intramolecular disulfide bonds within the proteins. In this study, soybean proteins were extracted from the cotyledons of immature seeds or dry beans under nonreducing conditions to prevent the oxidation of thiol groups and the reduction or exchange of disulfide bonds. We found that approximately half of the alpha'- and alpha subunits of beta-conglycinin were disulfide linked, together or with P34, prior to amino-terminal propeptide processing. Sedimentation velocity experiments, size exclusion chromatography, and two-dimensional polyacrylamide gel electrophoresis (PAGE) analysis, with blue native PAGE followed by sodium dodecyl sulfate-PAGE, indicated that the beta-conglycinin complexes containing the disulfide-linked alpha'/alpha-subunits were complexes of more than 720 kD. The alpha'- and alpha subunits, when disulfide linked with P34, were mostly present in approximately 480-kD complexes (hexamers) at low ionic strength. Our results suggest that disulfide bonds are formed between alpha'/alpha-subunits residing in different beta-conglycinin hexamers, but the binding of P34 to alpha'- and alpha-subunits reduces the linkage between beta-conglycinin hexamers. Finally, a subset of glycinin was shown to exist as noncovalently associated complexes larger than hexamers when beta-conglycinin was expressed under nonreducing conditions. PMID- 22218928 TI - Unraveling the genetic component of systemic sclerosis. AB - Systemic sclerosis (SSc) is a severe connective tissue disorder characterized by extensive fibrosis, vascular damage, and autoimmune events. During the last years, the number of genetic markers convincingly associated with SSc has exponentially increased. In this report, we aim to offer an updated review of the classical and novel genetic associations with SSc, analyzing the firmest and replicated signals within HLA and non-HLA genes, identified by both candidate gene and genome-wide association (GWA) studies. We will also provide an insight into the future perspectives and approaches that might shed more light into the complex genetic background underlying SSc. In spite of the remarkable advance in the field of SSc genetics during the last decade, the use of the new genetic technologies such as next generation sequencing (NGS), as well as the deep phenotyping of the study cohorts, to fully characterize the genetic component of this disease is imperative. PMID- 22218929 TI - Migration of intervertebral disc cells into dense collagen scaffolds intended for functional replacement. AB - Invasion of cells from surrounding tissues is a crucial step for regeneration when using a-cellular scaffolds as a replacement of the nucleus pulposus (NP). The aim of current study was to assess whether NP and surrounding annulus fibrosus (AF) cells are capable of migrating into dense collagen scaffolds. We seeded freshly harvested caprine NP and AF cells onto scaffolds consisting of 1.5 and 3.0% type I collagen matrices, prepared by plastic compression, to assess cell invasion. The migration distance appeared both time and density dependent and was higher for NP (25%) compared to AF (10%) cells after 4 weeks. Migration distance was not enhanced by Hst-2, a peptide derived from saliva known to enhance fibroblast migration, and this was confirmed in a scratch assay. In conclusion, we revealed invasion of cells into dense collagen scaffolds and therewith encouraging first steps towards the use of a-cellular scaffolds for NP replacement. PMID- 22218931 TI - Imaging of seasonal affective disorder and seasonality effects on serotonin and dopamine function in the human brain. AB - According to current knowledge, disturbances in brain monoamine transmission play a major role in many psychiatric disorders, and many of the radioligands used for investigating these disorders bind to targets within the brain monoamine systems. However, a phylogenetically ancient and prevailing function of monoamines is to mediate the adaptation of organisms and cells to rhythmical changes in light conditions, and to other environmental rhythms, such as changes in temperature, or the availability of energy resources throughout the seasons. The physiological systems mediating these changes are highly conserved throughout species, including humans. Here we review the literature on seasonal changes in binding of monoaminergic ligands in the human brain. Moreover, we argue for the importance of considering possible effects of season when investigating brain monoamines in healthy subjects and subjects with psychiatric disorders. PMID- 22218930 TI - Early life stress exacerbates cognitive dysfunction induced by d-amphetamine: amelioration by valproic acid. AB - It has been demonstrated that experiences taking place early in life have a profound influence on brain development, interacting with the genetic background and determining differences in the vulnerability to the onset of bipolar disorder when the individual is exposed to a second adverse event later in life. Here, we investigated the effects of exposure to an early adverse life event (maternal deprivation) and to a later adverse life event [D-amphetamine (AMPH)] on cognition in an animal model of mania. We have previously demonstrated that that repeated AMPH exposure produces severe and persistent cognitive impairment, which was more pronounced when the animals were maternal deprived, suggesting that the early adverse life event could be potentiating the effects of the exposure to the second adverse life event later in life. Here, we show that valproic acid ameliorated the cognitive deficits induced by AMPH, but it was not effective when the animals were exposed to both stressors: maternal deprivation and AMPH treatment. PMID- 22218932 TI - Persistently low intact parathyroid hormone levels predict a progression of aortic arch calcification in incident hemodialysis patients. AB - BACKGROUND: Recent observational studies have found that low intact parathyroid hormone (iPTH) is related with mortality in hemodialysis patients and these findings may be considered to be the result of accelerated cardiovascular calcifications in adynamic bone disease. This study was aimed to determine the relationship between persistently low iPTH and aortic arch calcification (AAC) in incident hemodialysis patients. METHODS: From January 2004 to December 2008, a total of 94 incident hemodialysis patients were enrolled in this study. They were divided into three groups according to the changing patterns of iPTH during the first year of hemodialysis. ACC was scored on posterior-anterior plain chest X rays using a specific scale at the initiation of dialysis and followed till May 2011. RESULTS: The median follow-up periods were 46.9 months. The prevalence of baseline AAC and its progression were the highest in the persistently low iPTH group. Also, all-cause mortality was the highest in this group. Age, baseline calcification score and persistently low iPTH independently contributed to the progression of calcification by multivariate logistic regression analyses (HR 1.083, 95% CI 1.023-1.147, P = 0.006; HR 3.320, 95% CI 1.023-10.789, P = 0.046; HR 5.207, 95% CI 1.027-26.412, P = 0.046, respectively). Also, mortality was relatively higher in calcification progressor compared to non-progressor (39.3, 18.2%, P = 0.030). CONCLUSION: Persistently low iPTH was an independent risk factor for both AAC and mortality in incident hemodialysis patients. PMID- 22218933 TI - A randomized-controlled trial of intensive case management emphasizing the recovery model among patients with severe and enduring mental illness. AB - BACKGROUND: There is increasing interest in the application of recovery principles in mental health services. AIMS: We studied the implementation of a programme of intensive case management (ICM) emphasizing recovery principles in a community mental health service in Ireland. METHODS: Eighty service attenders with severe and enduring illness characterized by significant ongoing disability were randomized into (1) a group receiving a programme of ICM and (2) a group receiving treatment as usual (TAU). Groups were compared before and after the programme for general psychopathology using the Brief Psychiatric Rating Scale (BPRS) (clinician rated) and How are You? scale (self-rated). The Functional Analysis of Care Environments (FACE) scale provided assessment of multiple functional domains. RESULTS: The overall group (mean age 44.5 +/- 13.2 years; 60% male) had mean total Health of the Nation Outcome Scale (HoNOS) scale scores of 10.5 +/- 4.6, with problems in social functioning especially prominent (mean social subscale score 5.0 +/- 2.7). The ICM group were younger (p < 0.01) with higher baseline scores on the HoNOS social subscale and BPRS (p < 0.05). An analysis of covariance, controlling for these baseline differences, indicated greater improvement in BPRS scores (p = 0.001), How are You? scores (p = 0.02) and FACE domains for cognition, symptoms and interpersonal relationships (all p < 0.001) in the ICM group. The ICM group underwent greater changes in structured daily activities that were linked to improved BPRS scores (p = 0.01). CONCLUSIONS: A programme of ICM emphasizing recovery principles resulted in significant improvement across psychopathological and functional domains. Improvements were linked to enhanced engagement with structured daily activities. Recovery-oriented practices can be integrated into existing mental health services and provided alongside traditional models of care. PMID- 22218934 TI - Potential anti-inflammatory, anti-adhesive, anti/estrogenic, and angiotensin converting enzyme inhibitory activities of anthocyanins and their gut metabolites. AB - Epidemiological studies have indicated a positive association between the intake of foods rich in anthocyanins and the protection against cardiovascular diseases. Some authors have shown that anthocyanins are degraded by the gut microflora giving rise to the formation of other breakdown metabolites, which could also contribute to anthocyanin health effects. The objective of this study was to evaluate the effects of anthocyanins and their breakdown metabolites, protocatechuic, syringic, gallic, and vanillic acids, on different parameters involved in atherosclerosis, including inflammation, cell adhesion, chemotaxis, endothelial function, estrogenic/anti-estrogenic activity, and angiotensin converting enzyme (ACE) inhibitory activity. From the assayed metabolites, only protocatechuic acid exhibited a slight inhibitory effect on NO production and TNF alpha secretion in LPS-INF-gamma-induced macrophages. Gallic acid caused a decrease in the secretion of MCP-1, ICAM-1, and VCAM-1 in endothelial cells. All anthocyanins showed an ACE-inhibitory activity. Delphinidin-3-glucoside, pelargonidin-3-glucoside, and gallic acid showed affinity for ERbeta and pelargonidin and peonidin-3-glucosides for ERalpha. The current data suggest that anthocyanins and their breakdown metabolites may partly provide a protective effect against atherosclerosis that is multi-causal and involves different biochemical pathways. However, the concentrations of anthocyanins and their metabolites, as used in the present cell culture and in vitro assays mediating anti-inflammatory, anti-adhesive, anti-estrogenic, and angiotensin-converting enzyme inhibitory activities, were often manifold higher than those physiologically achievable. PMID- 22218936 TI - Longitudinal study of dental caries increment in Malaysian school children: a 5 year cohort study. AB - The aim of this 5-year longitudinal cohort study was to assess the prevalence, severity, and trends in caries increment and impact of the School Dental Incremental Care Programme (SDICP). Data were gathered from school dental records as part of the SDICP. A sample of 1830 children were included and checked for caries experience annually using World Health Organization criteria. In total, 95.4% of the children were caries free in 2004, and caries experience declined to 70.5% in 2009 with an average of 4.9% annually. At baseline, the mean DMFT (confidence interval [CI]) was 0.06 (0.05-0.08) and increased to 0.58 (0.53-0.63) in 2009. Children with active caries were 4.4% in 2004, and figures rose to 9.6% in 2009. The FT component increased most rapidly during these 5 years from 0.2% to 25.1%. Overall caries prevalence and increment was low in this study. Proportions of FT component were higher as compared with DT component with low rate of extractions during the latter years of the study. PMID- 22218935 TI - Are some chromosomes particularly good at sex? Insights from amniotes. AB - Several recent studies have produced comparative maps of genes on amniote sex chromosomes, revealing homology of gene content and arrangement across lineages as divergent as mammals and lizards. For example, the chicken Z chromosome, which shares homology with the sex chromosomes of all birds, monotremes, and a gecko, is a striking example of stability of genome organization and retention, or independent acquisition, of function in sex determination. In other lineages, such as snakes and therian mammals, well conserved but independently evolved sex chromosome systems have arisen. Among lizards, novel sex chromosomes appear frequently, even in congeneric species. Here, we review recent gene mapping data, examine the evolutionary relationships of amniote sex chromosomes and argue that gene content can predispose some chromosomes to a specialized role in sex determination. PMID- 22218937 TI - [Suction-generated noise levels during aural toilet]. AB - BACKGROUND: The use of suction for the removal of foreign bodies or cerumen from the external auditory canal is a common procedure in ENT outpatient centers. Patients' lamentations about high noise levels during microsuction can cause assault charges concerning permanent hearing loss or tinnitus. However, the medical opinion of these cases is difficult because only a small amount of objective data about suction-generated noise is available. MATERIALS AND METHODS: In this study, noise levels of different suction devices were measured under standardized conditions in an artificial model head (HEAD acoustics, Germany). In a second set-up water and lard (instead of cerumen) were suctioned from an artificial external auditory canal, which was coupled with a noise mediator (Mediator 2238, Bruel & Kjaer, Denmark). RESULTS: There was a significant influence of the inner diameter of the sucker on the noise level. A sucker with a diameter of 1.4 mm generated a noise level of more than 100 dB(A). The suctioning of water generated a maximum noise level of more than 130 dB(LAmax), while the suctioning of lard reached nearly 150 dB(LAmax). The time lapse of both noise and frequency level for lard suctioning was characteristic of a bang. CONCLUSION: This study demonstrates objective and reproducible data for suction-generated noise levels and could help to evaluate patients' complaints. PMID- 22218938 TI - Executive function and latent classes of childhood obesity risk. AB - Executive function (EF) is the set of neuro-cognitive processes associated with self-regulation, decision-making, and goal-directed behavior. The goal of this study is to examine cross-sectional relationships between EF and latent classes of youth characterized by patterns of obesity-related health behaviors (i.e., high fat/high sugar intake, fruit and vegetable intake, physical activity, sedentary behavior, and dieting). Participants were 997 4th grade youth in a school-based obesity prevention program. Cross-sectional relationships at study baseline between established latent classes of obesity risk and EF problems were assessed. General linear models demonstrated that EF problems were associated with classification into two unhealthy latent obesity risk classes. One potential implication of study findings is that obesity intervention efforts include EF promotion content tailored for latent classes of youth at different levels of obesity risk. PMID- 22218939 TI - Compartment syndrome of the thigh after blunt trauma: a complication not to be ignored. AB - We report a case of anterior thigh compartment syndrome, which occurred after man's thigh was bruised after flipping repeatedly over his bike and being hit by the frame of the bike nearly at around 6 pm. The next day at 1:30 am, he was admitted to the hospital. The initial presentation was a hematoma, and the patient was kept in bed with local cooling. The compartment syndrome of the thigh (CST) diagnosis was made around 6:00 pm when the level of pain was interpreted as disproportionate to the treated lesion; anterior compartment pressure measure was 84 mmHg. A compartment fasciotomy was performed. It is difficult to diagnose a CST in case of muscular contusion as the latter causes symptoms that are similar to CST. A conservative treatment without fasciotomy was carried out by several authors, especially in sportsmen showing a CST following contusion. This conservative treatment implies close monitoring of intramuscular pressures and adjuvant measures (bed rest, holding the thigh at the heart level and oxygenotherapy). PMID- 22218941 TI - Sporadic rainy events are more critical than increasing of drought intensity for woody species recruitment in a Mediterranean community. AB - The understanding of the impact of extreme climatic events under a global climate change scenario is crucial for the accurate forecast of future plant community dynamics. We have experimentally assessed the effect of drier and wetter summer conditions on the recruitment probabilities and the growth of seedlings from eight woody species representative of the most important functional groups in the community, pioneer shrubs, mid-successional shrubs and trees, across the main habitats in the study area (open habitat, shrubland, and forest). Our hypothesis proposes that wet summer conditions would represent a good opportunity for tree species regeneration, enhancing both forest maintenance and expansion. A drier summer scenario, on the other hand, would limit forest regeneration, and probably hinder the colonization of nearby habitats. We found a habitat effect on the emergence, survival, and final biomass, whereas different climate scenarios affected seedling survival and biomass. A wet summer boosted growth and survival, whereas greater drought reduced survival only in some cases. These results were modulated by the habitat type. Overall, shrub species presented higher survival and growth and were less affected by more severe drought, whereas some tree species proved to be extremely dependent on wet summer conditions. We conclude that the reduction in frequency of wet summers predicted for the coming decades in Mediterranean areas will have greater consequences for species recruitment than will increased drought. The different response of the species from the various functional groups has the potential to alter the composition and dominance of future plant communities. PMID- 22218940 TI - Sin Nombre hantavirus decreases survival of male deer mice. AB - How pathogens affect their hosts is a key question in infectious disease ecology, and it can have important influences on the spread and persistence of the pathogen. Sin Nombre virus (SNV) is the etiological agent of hantavirus pulmonary syndrome (HPS) in humans. A better understanding of SNV in its reservoir host, the deer mouse, could lead to improved predictions of the circulation and persistence of the virus in the mouse reservoir, and could help identify the factors that lead to increased human risk of HPS. Using mark-recapture statistical modeling on longitudinal data collected over 15 years, we found a 13.4% decrease in the survival of male deer mice with antibodies to SNV compared to uninfected mice (both male and female). There was also an additive effect of breeding condition, with a 21.3% decrease in survival for infected mice in breeding condition compared to uninfected, non-breeding mice. The data identified that transmission was consistent with density-dependent transmission, implying that there may be a critical host density below which SNV cannot persist. The notion of a critical host density coupled with the previously overlooked disease induced mortality reported here contribute to a better understanding of why SNV often goes extinct locally and only seems to persist at the metapopulation scale, and why human spillover is episodic and hard to predict. PMID- 22218942 TI - Plant neighborhood influences colonization of Brassicaceae by specialist and generalist aphids. AB - A plant's own characteristics, but also those of its neighbors, might have an impact on its probability of being colonized by herbivorous insects. A plant might be less colonized and experience associational resistance when it grows near repellent neighbors. In contrast, it might be more colonized and experience associational susceptibility near attractive neighbors. To date, mechanisms that drive associational defense are not really understood. In order to gain insights into the occurrence of associational resistance versus associational susceptibility under field conditions, we conducted an experiment to determine the influence of neighboring plants on the colonization of a focal plant by aphids. The focal plant was always Brassica oleracea. The neighbors were B. oleracea (control), B. napus, B. nigra, or Solanum lycopersicum, which represent contrasting levels of physical and chemical defenses. The focal plant, B. oleracea, was more colonized by the specialist aphid Brevicoryne brassicae, and experienced associational susceptibility when it was surrounded by B. nigra or B. napus. In contrast, B. oleracea was less colonized by the generalist aphid Myzus persicae, and experienced associational resistance when it was surrounded by S. lycopersicum, B. nigra or B. napus. Neighboring plants had no significant impact on host plant choice by the generalist aphid Macrosiphum euphorbiae. In conclusion, attraction or repulsion of the specialist aphid B. brassicae and the generalist aphid M. persicae by B. nigra, B. napus, and S. lycopersicum resulted in associational susceptibility or associational resistance for B. oleracea. PMID- 22218943 TI - Ozone exposure causes a decoupling of conductance and photosynthesis: implications for the Ball-Berry stomatal conductance model. AB - Industrialization has significantly altered atmospheric chemistry by increasing concentrations of chemicals such as nitrogen oxides (NO( x )) and volatile organic carbon, which react in the presence of sunlight to produce tropospheric ozone (O(3)). Ozone is a powerful oxidant that causes both visual and physiological damage to plants, impairing the ability of the plant to control processes like photosynthesis and transpiration. Damage to photosynthesis and stomatal conductance does not always occur at the same rate, which generates a problem when using the Ball-Berry model to predict stomatal conductance because the calculations directly rely on photosynthesis rates. The goals of this work were to develop a modeling framework to modify Ball-Berry stomatal conductance predictions independently of photosynthesis and to test the framework using experimental data. After exposure to elevated O(3) in open-top chambers, photosynthesis and stomatal conductance in tulip poplar changed at different rates through time. We were able to accurately model observed photosynthetic and stomatal conductance responses to chronic O(3) exposure in a Ball-Berry framework by adjusting stomatal conductance in addition to photosynthesis. This led to a significant improvement in the modeled ability to predict both photosynthesis and stomatal conductance responses to O(3). PMID- 22218944 TI - Aggregative response in bats: prey abundance versus habitat. AB - In habitats where prey is either rare or difficult to predict spatiotemporally, such as open habitats, predators must be adapted to react effectively to variations in prey abundance. Open-habitat foraging bats have a wing morphology adapted for covering long distances, possibly use information transfer to locate patches of high prey abundance, and would therefore be expected to show an aggregative response at these patches. Here, we examined the effects of prey abundance on foraging activities of open-habitat foragers in comparison to that of edge-habitat foragers and closed-habitat foragers. Bat activity was estimated by counting foraging calls recorded with bat call recorders (38,371 calls). Prey abundance was estimated concurrently at each site using light and pitfall traps. The habitat was characterized by terrestrial laser scanning. Prey abundance increased with vegetation density. As expected, recordings of open-habitat foragers clearly decreased with increasing vegetation density. The foraging activity of edge- and closed-habitat foragers was not significantly affected by the vegetation density, i.e., these guilds were able to forage from open habitats to habitats with dense vegetation. Only open-habitat foragers displayed a significant and proportional aggregative response to increasing prey abundance. Our results suggest that adaptations for effective and low-cost foraging constrains habitat use and excludes the guild of open-habitat foragers from foraging in habitats with high prey abundance, such as dense forest stands. PMID- 22218945 TI - Investigation of the influence of phenosan, ichphan-10, and melafen on red blood cells in vivo by atomic force microscopy. PMID- 22218946 TI - Changes in the content of lipids in the seeds of magnetically-oriented radish types grown in a weak permanent magnetic field. PMID- 22218947 TI - Assessment of composition and toxicity for plants of gases produced during physicochemical processing of human exometabolites as applied to biotechnical life support systems. PMID- 22218948 TI - New mammalian selenium-containing protein V: the search for protein partners. PMID- 22218949 TI - The effect of lipopolysaccharide structure on the synthetic activity of human lymphocytes. PMID- 22218950 TI - Effect of hypoxia on nitric oxide formation in animal heart tissues. PMID- 22218951 TI - Thermoluminescence in the primary processes of photosynthesis. "New" approaches to numerical simulation. PMID- 22218952 TI - Tris-2(hydroxyethyl)ammonium (2-methylphenoxy)acetate as an inhibitor of synthesis of acid cholesterol esterase of platelets and mononuclear cells. PMID- 22218953 TI - Juvenile hormone synthesis is stimulated by activation of dopamine D1-like receptors in Drosophila. PMID- 22218954 TI - Recombinant analogue of spidroin 2 for biomedical materials. PMID- 22218955 TI - Synthesis of heterologous G protein-coupled receptors in the methylotrophic yeast P. pastoris. PMID- 22218956 TI - Plant growth regulators melafen and pirafen prevent dysfunction of mitochondria caused by temporary water deficit. PMID- 22218957 TI - Modification of lipoprotein(a) by natural dicarbonyls induced their following free radical peroxidation. PMID- 22218958 TI - Carotenoid triplet states in vitro and in light-harvesting complexes of the phototrophic bacterium Allochromatium minutissimum. PMID- 22218959 TI - Malonyl-ginsenoside Rb1 in cell suspension culture of Panax japonicus var. repens. PMID- 22218960 TI - Monoclonal antibodies against the propeptide of endopeptidase AlpB of Lysobacter sp. XL1 for studying AlpB-protein interactions in bacterial cells. PMID- 22218962 TI - Genetic characterization of Pseudomonas aeruginosa bacteriophage KPP10. AB - Bacteriophage (phage) KPP10 has been used in experimental phage therapies directed against P. aeruginosa infections. To examine the eligibility of phage KPP10 as a therapeutic phage, its genome was analyzed. The genomic DNA was shown to be 88,322 bp long, with 158 open reading frames (ORFs), and three tRNA genes were predicted. No ORF-encoded pathogenicity or lysogenization factor was predicted. A comparative genomic analysis revealed that phage KPP10, together with phage PAK_P3, can be grouped as a new type of lytic phage infecting P. aeruginosa. Phage KPP10 is considered to be suitable for therapeutic purposes because it is a lytic phage without ORF-encoded pathogenicity or a lysogenization factors. PMID- 22218961 TI - Complete nucleotide sequences and genome organization of a cherry isolate of cherry leaf roll virus. AB - The complete nucleotide sequence of cherry leaf roll virus (CLRV, genus Nepovirus) from a naturally infected cherry tree (Prunus avium cv. Bing) in North America was determined. RNA1 and RNA2 consist of 7,893 and 6,492 nucleotides, respectively, plus a poly-(A) tail. Each RNA encodes a single potential open reading frame. The first 657 nucleotides of RNA1 and RNA2 are 99% identical and include the 5'-UTR and the first 214 deduced amino acids of the polyproteins following the first of two in-frame start codons. Phylogenetic analysis reveals close relationships between CLRV and members of subgroup C of the genus Nepovirus. PMID- 22218963 TI - Autographa californica multiple nucleopolyhedrovirus odv-e25 (Ac94) is required for budded virus infectivity and occlusion-derived virus formation. AB - Autographa californica multiple nucleopolyhedrovirus (AcMNPV) odv-e25 is a core gene found in all lepidopteran baculoviruses, but its function is unknown. In this study, we generated an odv-e25-knockout AcMNPV and investigated the roles of ODV-E25 in the baculovirus life cycle. The odv-e25 knockout was subsequently rescued by reinserting the odv-e25 gene into the same virus genome. Fluorescence microscopy showed that transfection with the odv-e25-null bacmid vAcBac(KO) was insufficient for propagation in cell culture, whereas the 'repair' virus vAcBac(RE) was able to function in a manner similar to that of the control vAcBac. We found that odv-e25 was not essential for the release of budded viruses (BVs) into culture medium, although the absence of odv-e25 resulted in a 100-fold lower viral titer at 24 h post-transfection (p.t.). Analysis of viral DNA replication in the absence of odv-e25 showed that viral DNA replication was unaffected in the first 24 h p.t. Furthermore, electron microscopy revealed that polyhedra were found in the nucleus, while mature occlusion-derived viruses (ODVs) were not found in the nucleus or polyhedra in odv-e25 null transfected cells, which indicated that ODV-E25 was required for the formation of ODV. PMID- 22218964 TI - Further characterization of tomato-infecting begomoviruses in Brazil. AB - Tomato cultivation in Brazil is threatened by a number of tomato-infecting viruses belonging to the genus Begomovirus of the family Geminiviridae. Here, we report the full DNA-A sequences of three Brazilian begomoviruses: a potentially new tomato-infecting viruses, tomato interveinal chlorosis virus (ToICV), and two previously proposed begomoviruses for which only partial DNA-A sequences are available in the databases: tomato mottle leaf curl virus (TMoLCV) and tomato golden vein virus (TGVV). The complete sequences of the DNA-B components of TMoLCV and TGVV and the DNA-A components of a number of tomato severe rugose virus variants are also presented. Collectively, all of the analyzed sequences were phylogenetically clustered within the two major groups of Brazilian tomato infecting begomoviruses. PMID- 22218965 TI - Population genetics of cucumber mosaic virus infecting medicinal, aromatic and ornamental plants from northern Italy. AB - The genetic variation and evolution of cucumber mosaic virus (CMV) from aromatic, medicinal and ornamental plants in northern Italy was studied by sequence analysis of the movement protein gene and comparison with equivalent sequences of isolates from other countries. Comparison of nonsynonymous and synonymous substitutions suggested that 30% of amino acid sites were under negative selection and only one was under positive selection. Phylogenetic, nucleotide diversity and genetic differentiation analyses suggested that long-distance migration plays a role in the evolution and determination of the genetic structure and diversity of CMV in northern Italy and other areas. PMID- 22218966 TI - Pepper necrotic spot virus, a new tospovirus infecting solanaceous crops in Peru. AB - Two virus isolates, T1 and T2, causing necrotic spots on leaves and stems of pepper and tomato, respectively, were isolated in the La Joya valley, Arequipa, Peru, in 2010. These two isolates were inoculated to differential hosts for tospoviruses and showed differential fitness: T1 induced necrotic local lesions in Vigna unguiculata, whereas T2 produced only chlorotic spots. The complete nucleotide sequence of the small (S) RNA from T2 and 1863 bp of the S RNA from T1 were determined. The deduced N protein sequence showed high amino acid identity (97%) between the isolates, indicating that the T1 and T2 are isolates of the same virus. Sequence comparisons indicated that the amino acid sequence of the N protein shared 53.49-87.98% identity with known American tospoviruses. Phylogenetic analysis of both the NSs and N proteins revealed that this new tospovirus belongs to the American group. We conclude that this tospovirus should be considered a member of a new species. The name Pepper necrotic spot virus (PNSV) is proposed. PMID- 22218967 TI - Complete genome sequence of the podoviral bacteriophage PhiCP24R, which is virulent for Clostridium perfringens. AB - Bacteriophage PhiCP24R was isolated from raw sewage from a waste treatment plant, and lytic activity was observed against a type A Clostridium perfringens isolate. Electron microscopy revealed a small virion (44-nm-diameter icosahedral capsid) with a short, non-contractile tail, indicative of a member of the family Podoviridae. The phage had a linear, double-stranded DNA genome of 18,919 base pairs (bp) with 41 bp inverted terminal repeats and a type B DNA polymerase, which are characteristics of members of the subfamily Picovirinae. Out of 22 predicted genes in the genome, ten had significant sequence similarity to proteins of known function. Three distinct genes with lytic domains were identified, including a zinc carboxypeptidase domain that has not been previously reported in viruses. The PhiCP24R genome described herein is only the second Clostridium perfringens podovirus genome reported to date. PMID- 22218968 TI - Sequencing and analysis of the complete genome of Newcastle disease virus isolated from a commercial poultry farm in 2010. AB - Newcastle disease virus (NDV) infects wild and domestic birds but causes contagious and lethal disease in domestic poultry. ND is currently endemic in Pakistan, but no complete genome sequence of a Pakistani NDV isolate has been reported. An NDV strain isolated from a commercial poultry farm was completely sequenced. Phylogenetic analysis revealed that the isolate is closely related to genotype VII and, more specifically, to subgenotype VIIb, yet with substantial enough differences to be regarded as new subgenotype (VIIf). These findings provide insight into the genetic nature of NDV circulating in Pakistan and are useful for both laboratory diagnosis and vaccine development for NDV. PMID- 22218969 TI - Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. AB - BACKGROUND: IgG4-related disease (IgG4-RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4+ plasma cells. Although IgG4-RD is not rare and is clinically important, its clinical diagnostic criteria have not been established. Comprehensive diagnostic criteria for IgG4-RD, including the involvement of various organs, are intended for the practical use of general physicians and nonspecialists. METHODS: Two IgG4-RD study groups, the Umehara and Okazaki teams, were organized by the Ministry of Health, Labor and Welfare Japan. As IgG4-RD comprises a wide variety of diseases, these groups consist of physicians and researchers in various disciplines, including rheumatology, hematology, gastroenterology, nephrology, pulmonology, ophthalmology, odontology, pathology, statistics, and basic and molecular immunology throughout Japan, with 66 and 56 members of the Umehara and Okazaki teams, respectively. Collaborations of the two study groups involved detailed analyses of clinical symptoms, laboratory results, and biopsy specimens of patients with IgG4-RD, resulting in the establishment of comprehensive diagnostic criteria for IgG4-RD. RESULTS: Although many patients with IgG4-RD have lesions in several organs, either synchronously or metachronously, and the pathological features of each organ differ, consensus has been reached on two diagnostic criteria for IgG4RD: (1) serum IgG4 concentration >135 mg/dl, and (2) >40% of IgG+ plasma cells being IgG4+ and >10 cells/high powered field of biopsy sample. Although the comprehensive diagnostic criteria are not sufficiently sensitive for the diagnosis of type 1 IgG4-related autoimmune pancreatitis (IgG4-related AIP), they are adequately sensitive for IgG4-related Mikulicz's disease (MD) and kidney disease (KD). In addition, the comprehensive diagnostic criteria, combined with organ-specific diagnostic criteria, have increased the sensitivity of diagnosis to 100% for IgG4-related MD, KD, and AIP. CONCLUSION: Our comprehensive diagnostic criteria for IgG4-RD are practically useful for general physicians and nonspecialists. PMID- 22218970 TI - An immunoglobulin G4-related disease mimicking postoperative lung cancer recurrence. AB - A postoperative lung cancer patient presented with lymphadenopathy, pleural thickening, and 18F-fluorodeoxyglucose (FDG) uptake on a positron emission tomography-computed tomography (PET-CT) scan. Lung cancer recurrence was initially suspected, but bilateral submandibular masses with 18F-FDG uptake indicated the possibility of a systemic disease, such as Mikulicz's disease. High serum immunoglobulin G4 (IgG4) and IgG4-positive plasma cell infiltration in the submandibular glands led to the diagnosis of IgG4-related disease. After systemic steroid therapy, 18F-FDG uptake decreased in both the submandibular glands and the suspected recurrent lesions. PMID- 22218971 TI - A study of the intrinsic autofluorescence of poly (ethylene glycol)-co-(L-lactic acid) diacrylate. AB - Poly (ethylene glycol)-co-(L-Lactic acid) diacrylate (PEG-PLLA-DA) copolymers have been extensively investigated for a number of applications in medicine. PEG PLLA-DA is biodegradable and the human body can process its degradation products. In this study, we describe the autofluorescence of PEG-PLLA-DA copolymers and compared it to the fluorescence of poly(ethylene glycol) diacrylate (PEG-DA) and the precursor molecules used for their synthesis. In addition, we examined the influence of pH on the fluorescence spectra. We found that PEG-PLLA-DA exhibits higher fluorescence than PEG-DA and all reagents involved in the synthesis of PEG PLLA-DA. The fluorescence of PEG-PLLA-DA was affected by pH with fluorescence decreasing at high pH values. At high pH, PEG-PLLA-DA could not polymerize into hydrogels and exhibited a dramatic decrease in autofluorescence, suggesting that hydrolysis of the ester bond affected its autofluorescence. At low pH, PEG-PLLA DA exhibited higher fluorescence and it was able to form crosslinked hydrogels. The autofluorescence of PEG-PLLA-DA could be exploited to monitor polymer degradation and material structure without the need to introduce exogenous fluorescent probes. The origin of fluorescence is not clear at this point in time but it appears to result from a synergetic effect of both lactate units and diacrylate groups in the PEG-PLLA-DA backbone. The observed autofluorescence of PEG-PLLA-DA persists after reaction of the acrylate groups in the polymerization reaction. This autofluorescence is advantageous because it could assist in the study of polymers used for drug delivery and tissue engineering applications. PMID- 22218972 TI - Development of aptamer beacons for rapid presumptive detection of Bacillus spores. AB - A library of 92 DNA aptamer sequences was developed against Bacillus anthracis (nonpathogenic Sterne strain) spores and anthrose sugar immobilized on magnetic beads. The selected DNA sequences were studied for similarities and potential binding pockets between the B. anthracis spore and anthrose aptamers. Several recurring loop structures were identified and tested for their potential to act as aptamer beacons when labeled with TYE 665 dye on their 5' ends and Iowa Black quencher on their 3' ends. Of these candidate sequences, two beacons designated BAS-6F and BAS-6R emerged which gave strong fluorescence responses at high spore concentrations (greater than 30,000 spores/ml). These aptamer beacons also detect B. cereus and B. thuringiensis spores with greater fluorescence intensity, but do not strongly detect vegetative cells from an array of other bacterial species. BAS-6F and 6R are also not capable of detecting pure anthrose, thereby probably ruling that epitope out as a spore surface target for these particular beacons. While not extremely sensitive, the BAS-6F and 6R aptamer beacons are potentially valuable for rapid presumptive detection of anthrax or Bacillus spores in suspect powders or bioterrorist activity where spore concentrations are anticipated to be high. The sequence similarities of these beacons to other published Bacillus spore aptamers are also discussed. PMID- 22218973 TI - Novel benzanthrone aminoderivatives for membrane studies. AB - The potential of novel benzanthrone aminoderivatives to trace the changes in physicochemical properties of lipid bilayer has been evaluated. Binding of the dyes to the lipid bilayers composed of zwitterionic phospholipid phosphatidylcholine (PC) and its mixtures with anionic phospholipid cardiolipin (CL) and cholesterol (Chol) was followed by significant quantum yield increase with small blue shift of emission maximum. Analysis of partition coefficients of the dyes under study showed that all aminobenzanthrones possess high lipid associating ability. The dyes A8 and AM2 proved to be sensitive to the variations in membrane chemical composition responding to the changes in bilayer hydration induced by CL and Chol. PMID- 22218974 TI - The Three Domains of Disgust Scale: factor structure, psychometric properties, and conceptual limitations. AB - This investigation examined the measurement properties of the Three Domains of Disgust Scale (TDDS). Principal components analysis in Study 1 (n = 206) revealed three factors of Pathogen, Sexual, and Moral Disgust that demonstrated excellent reliability, including test-retest over 12 weeks. Confirmatory factor analyses in Study 2 (n = 406) supported the three factors. Supportive evidence for the validity of the Pathogen and Sexual Disgust subscales was found in Study 1 and Study 2 with strong associations with disgust/contamination and weak associations with negative affect. However, the validity of the Moral Disgust subscale was limited. Study 3 (n = 200) showed that the TDDS subscales differentially related to personality traits. Study 4 (n = 47) provided evidence for the validity of the TDDS subscales in relation to multiple indices of disgust/contamination aversion in a select sample. Study 5 (n = 70) further highlighted limitations of the Moral Disgust subscale given the lack of a theoretically consistent association with moral attitudes. Lastly, Study 6 (n = 178) showed that responses on the Moral Disgust scale were more intense when anger was the response option compared with when disgust was the response option. The implications of these findings for the assessment of disgust are discussed. PMID- 22218975 TI - Ruptured intrameatal aneurysm of the anterior inferior cerebellar artery accompanying an arteriovenous malformation: a case report. AB - The distal anterior inferior cerebellar artery (AICA) aneurysms located inside the internal auditory canal are rare. The association of the distal AICA aneurysms and an arteriovenous malformation (AVM) on the same arterial trunk is exceptional. Eight reports of a total of ten cases have been published and all of the reported aneurysms were located in the meatal or postmeatal segment of the AICA. Herein, we report a case of ruptured aneurysm in the intrameatal portion of the AICA accompanying an AVM fed by the same artery. A 55-year-old man suffering from subarachnoid hemorrhage due to a ruptured intrameatal aneurysm with a small AVM underwent surgical trapping of the meatal loop, resulting in uneventful recovery. Follow-up angiography demonstrated neither aneurysm nor residual AVM nidus. We propose that trapping of the meatal loop could be a safe and feasible alternative to unroofing followed by neck clipping in selected patients with an intrameatal aneurysm of the AICA. We also review here the relevant literature. PMID- 22218976 TI - Analyses of gene expression and physiological changes in Microcystis aeruginosa reveal the phytotoxicities of three environmental pollutants. AB - When the concentrations of ampicillin (Amp), atrazine (Atr) and cadmium chloride (Cd) reach excessive quantities, they become toxic to aquatic organisms. Due to the acceleration of the industrialization and the intensification of human activities, the incidence and concentrations of these types of pollutants in aquatic systems are increasing. The primary purpose of this study was to evaluate the short-term effects of Amp, Atr and Cd on the physiological indices and gene expression levels in Microcystis aeruginosa. These three pollutants significantly induced antioxidant activity but continuously accelerated the cellular oxidative damage in microalgae, which suggests an imbalance between the oxidant and the antioxidant systems. Amp, Atr and Cd also decreased the transcription of psaB, psbD1 and rbcL; the lowest transcription of these genes was only 38.1, 23.7 and 7% of the control, respectively. These three pollutants affected nitrogen (N) and phosphorous (P) uptake by inhibiting the transcription of N or P absorbing and transporting related genes, and they down regulated the transcription of microcystin-related genes, which caused a decrease of microcystin levels; and the lowest level of microcystin was only 42.4% of the control. Our results suggest that these pollutants may cause pleiotropic effects on algal growth and physiological and biochemical reactions, and they may even affect secondary metabolic processes. PMID- 22218977 TI - The preparation of the rice coral Montipora capitata nubbins for application in coral-reef ecotoxicology. AB - Securing adequate and appropriate source material for coral-reef ecotoxicology studies is a significant impediment to conducting various experiments supporting the goal of conserving coral-reef ecosystems. Collecting colonies from wild stocks may be counter to protecting coral reef populations. To address this issue the rice coral Montipora capitata was used to generate sufficient genetically identical nubbins for research purposes. Growth and survival rates of these laboratory-prepared M. capitata nubbins were studied over a period of 90 days. The resulting data support the conclusion that the laboratory-prepared M. capitata nubbins showed successful growth and survival rates and are the best solution to solve the source material issue for lab experimentation. This paper describes the laboratory method used for the preparation and maintenance of these M. capitata nubbins and discusses the benefits and difficulties of using these nubbins in ecotoxicity studies. PMID- 22218978 TI - Acute combined exposure to heavy metals (Zn, Cd) blocks memory formation in a freshwater snail. AB - The effect of heavy metals on species survival is well documented; however, sublethal effects on behaviour and physiology are receiving growing attention. Measurements of changes in activity and respiration are more sensitive to pollutants, and therefore a better early indicator of potentially harmful ecological impacts. We assessed the effect of acute exposure (48 h) to two heavy metals at concentrations below those allowable in municipal drinking water (Zn: 1,100 MUg/l; Cd: 3 MUg/l) on locomotion and respiration using the freshwater snail, Lymnaea stagnalis. In addition we used a novel assessment method, testing the ability of the snail to form memory in the presence of heavy metals in both intact snails, and also snails that had the osphradial nerve severed which connects a chemosensory organ, the osphradium, to the central nervous system. Aerial respiration and locomotion remained unchanged by acute exposure to heavy metals. There was also no effect on memory formation of these metals when administered alone. However, when snails were exposed to these metals in combination memory formation was blocked. Severing the osphradial nerve prevented the memory blocking effect of Zn and Cd, indicating that the snails are sensing these metals in their environment via the osphradium and responding to them as a stressor. Therefore, assessing the ability of this species to form memory is a more sensitive measure of heavy metal pollution than measures of activity, and indicates that the snails' ability to demonstrate behavioural plasticity may be compromised by the presence of these pollutants. PMID- 22218979 TI - [Intraoperative MRI (iMRI) in neurosurgery: a radiological point of view]. PMID- 22218990 TI - [Plausibility tests in radiology. Exceeding the time limits]. PMID- 22218992 TI - Screening of biosurfactant-producing Bacillus strains using glycerol from the biodiesel synthesis as main carbon source. AB - Glycerol, a co-product of biodiesel production, was evaluated as carbon source for biosurfactant production. For this reason, seven non-pathogenic biosurfactant producing Bacillus strains, isolated from the tank of chlorination at the Wastewater Treatment Plant at Federal University of Ceara, were screened. The production of biosurfactant was verified by determining the surface tension value, as well as the emulsifying capacity of the free-cell broth against soy oil, kerosene and N-hexadecane. Best results were achieved when using LAMI005 and LAMI009 strains, whose biosurfactant reduced the surface tension of the broth to 28.8 +/- 0.0 and 27.1 +/- 0.1 mN m(-1), respectively. Additionally, at 72 h of cultivation, 441.06 and 267.56 mg L(-1) of surfactin were produced by LAMI005 and LAMI009, respectively. The biosurfactants were capable of forming stable emulsions with various hydrocarbons, such as soy oil and kerosene. Analyses carried out with high performance liquid chromatography (HPLC) showed that the biosurfactant produced by Bacillus subtilis LAMI009 and LAMI005 was compatible with the commercially available surfactin standard. The values of minimum surface tension and the CMC of the produced biosurfactant indicated that it is feasible to produce biosurfactants from a residual and renewable and low-cost carbon source, such as glycerol. PMID- 22218993 TI - UASB/flash aeration enable complete treatment of municipal wastewater for reuse. AB - A simple, efficient and cost-effective method for municipal wastewater treatment is examined in this paper. The municipal wastewater is treated using an upflow anaerobic sludge bed (UASB) reactor followed by flash aeration (FA) as the post treatment, without implementing aerobic biological processes. The UASB reactor was operated without recycle, at hydraulic retention time (HRT) of 8 h and achieved consistent removal of BOD, COD and TSS of 60-70% for more than 12 months. The effect of FA on UASB effluent post-treatment was studied at different HRT (15, 30 and 60 min) and dissolved oxygen (DO) concentrations (low DO = 1-2 mg/L and high DO = 5-6 mg/L). The optimum conditions for BOD, COD and sulfide removal were 30-60 min HRT and high DO concentration inside the FA tank. The final effluent after clarification was characterized by BOD and COD values of 28 35 and 50-58 mg/L, respectively. Sulfides were removed by more than 80%, but the fecal coliform only by ~2 log. The UASB followed by FA is a simple and efficient process for municipal wastewater treatment, except for fecal coliform, enabling water and nutrients recycling to agriculture. PMID- 22218994 TI - Diffuse reflectance spectroscopy of fibrous proteins. AB - UV-visible diffuse reflectance (DR) spectra of the fibrous proteins wool and feather keratin, silk fibroin and bovine skin collagen are presented. Natural wool contains much higher levels of visible chromophores across the whole visible range (700-400 nm) than the other proteins and only those above 450 nm are effectively removed by bleaching. Both oxidative and reductive bleaching are inefficient for removing yellow chromophores (450-400 nm absorbers) from wool. The DR spectra of the four UV-absorbing amino acids tryptophan, tyrosine, cystine and phenylalanine were recorded as finely ground powders. In contrast to their UV visible spectra in aqueous solution where tryptophan and tyrosine are the major UV absorbing species, surprisingly the disulphide chromophore of solid cystine has the strongest UV absorbance measured using the DR remission function F(R)(infinity). The DR spectra of unpigmented feather and wool keratin appear to be dominated by cystine absorption near 290 nm, whereas silk fibroin appears similar to tyrosine. Because cystine has a flat reflectance spectrum in the visible region from 700 to 400 nm and the powder therefore appears white, cystine absorption does not contribute to the cream colour of wool despite the high concentration of cystine residues near the cuticle surface. The disulphide absorption of solid L: -cystine in the DR spectrum at 290 nm is significantly red shifted by ~40 nm relative to its wavelength in solution, whereas homocystine and lipoic acid showed smaller red shifts of 20 nm. The large red shift observed for cystine and the large difference in intensity of absorption in its UV-visible and DR spectra may be due to differences in the dihedral angle between the crystalline solid and the solvated molecules in solution. PMID- 22218995 TI - Molecular mechanism underlying the cerebral effect of Gly-Pro-Glu tripeptide bound to L-dopa in a Parkinson's animal model. AB - Oxidative stress is a critical contributing factor to neurodegenerative disorders. Therefore, the inhibition of ROS formation, responsible for chronic detrimental neuroinflammation, is an important strategy for preventing the neurodegenerative disease and for neuroprotective therapy. Gly-Pro-Glu (GPE) is the N-terminal tripeptide of insulin-like growth factor-I, which is naturally cleaved in the plasma and brain tissues. GPE has neuroprotective effects since it crosses the blood-CSF and the functional CSF-brain barriers and binds to glial cells. It has been shown that GPE improves motor behaviour in rats after 6-OHDA lesion, although it does not rescue dopaminergic neurons. Thus, we hypothesized that the GPE therapeutic efficacy in a Parkinson model might be improved by combining GPE to L: -dopa. Here, we used an animal model that represents a progressive chronic Parkinson's disease (PD) model, characterized by high levels of oxidative stress and inflammation. We showed that the co-drug, in which L: dopa is covalently linked to the GPE tripeptide, by down-regulating the expression of inflammatory genes, decreases the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced inflammatory response and, by up-regulating tyrosine hydroxylase, reduces MPTP-induced neurotoxicity. Furthermore, by determining the nuclear translocation/activation of Nrf2 and NF-kappaB, we showed that systemic administration of the co-drug activates Nrf2-induced antioxidant response while suppressing NF-kappaB inflammatory pathway. Data suggest that the binding of L: -dopa to GPE tripeptide might represent a promising strategy to supply L: -dopa to parkinsonian patients. PMID- 22218996 TI - A novel mathematical model of bone remodelling cycles for trabecular bone at the cellular level. AB - After an initial phase of growth and development, bone undergoes a continuous cycle of repair, renewal and optimisation by a process called remodelling. This paper describes a novel mathematical model of the trabecular bone remodelling cycle. It is essentially formulated to simulate a remodelling event at a fixed position in the bone, integrating bone removal by osteoclasts and formation by osteoblasts. The model is developed to construct the variation in bone thickness at a particular point during the remodelling event, derived from standard bone histomorphometric analyses. The novelties of the approach are the adoption of a predator-prey model to describe the dynamic interaction between osteoclasts and osteoblasts, using a genetic algorithm-based solution; quantitative reconstruction of the bone remodelling cycle; and the introduction of a feedback mechanism in the bone formation activity to co-regulate bone thickness. The application of the model is first demonstrated by using experimental data recorded for normal (healthy) bone remodelling to predict the temporal variation in the number of osteoblasts and osteoclasts. The simulated histomorphometric data and remodelling cycle characteristics compare well with the specified input data. Sensitivity studies then reveal how variations in the model's parameters affect its output; it is hoped that these parameters can be linked to specific biochemical factors in the future. Two sample pathological conditions, hypothyroidism and primary hyperparathyroidism, are examined to demonstrate how the model could be applied more broadly, and, for the first time, the osteoblast and osteoclast populations are predicted for these conditions. Further data are required to fully validate the model's predictive capacity, but this work shows it has potential, especially in the modelling of pathological conditions and the optimisation of the treatment of those conditions. PMID- 22218997 TI - Ethical modernization: research misconduct and research ethics reforms in Korea following the Hwang affair. AB - The Hwang affair, a dramatic and far reaching instance of scientific fraud, shocked the world. This collective national failure prompted various organizations in Korea, including universities, regulatory agencies, and research associations, to engage in self-criticism and research ethics reforms. This paper aims, first, to document and review research misconduct perpetrated by Hwang and members of his research team, with particular attention to the agencies that failed to regulate and then supervise Hwang's research. The paper then examines the research ethics reforms introduced in the wake of this international scandal. After reviewing American and European research governance structures and policies, policy makers developed a mixed model mindful of its Korean context. The third part of the paper examines how research ethics reform is proactive (a response to shocking scientific misconduct and ensuing external criticism from the press and society) as well as reactive (identification of and adherence to national or international ethics standards). The last part deals with Korean society's response to the Hwang affair, which had the effect of a moral atomic bomb and has led to broad ethical reform in Korean society. We conceptualize this change as ethical modernization, through which the Korean public corrects the failures of a growth-oriented economic model for social progress, and attempts to create a more trustworthy and ethical society. PMID- 22218999 TI - Role of preoperative angiography in colon interposition surgery. AB - PURPOSE: The aim of this study was to evaluate the role of preoperative angiography in patients undergoing colonic interposition. MATERIALS AND METHODS: We searched the electronic database of our radiology department for the term "mesenteric angiography" over a 10-year period from January 1, 2001 to December 31, 2010. RESULTS: We identified 54 patients who had undergone mesenteric angiography before esophageal reconstruction, 16 of whom proceeded to have colonic interposition surgery. One patient (6.3%) developed graft necrosis, two (12.5%) developed an anastomotic leak, and three (18.8%) developed an anastomotic stricture. These complication rates are similar to those reported in the surgical literature for patients who did or did not undergo routine preoperative angiography. CONCLUSION: There is no significant difference in the rates of complications secondary to ischemia (graft necrosis, anastomotic stricture, and anastomotic leak) in patients who undergo routine preoperative angiography as compared with those who do not. PMID- 22218998 TI - Ethical challenges with welfare technology: a review of the literature. AB - Demographical changes in high income counties will increase the need of health care services but reduce the number of people to provide them. Welfare technology is launched as an important measure to meet this challenge. As with all types of technologies we must explore its ethical challenges. A literature review reveals that welfare technology is a generic term for a heterogeneous group of technologies and there are few studies documenting their efficacy, effectiveness and efficiency. Many kinds of welfare technology break with the traditional organization of health care. It introduces technology in new areas, such as in private homes, and it provides new functions, e.g. offering social stimuli and entertainment. At the same time welfare technology is developed for groups that traditionally have not been extensive technology users. This raises a series of ethical questions with regard to the development and use of welfare technologies, which are presented in this review. The main challenges identified are: (1) Alienation when advanced technology is used at home, (2) conflicting goals, as welfare technologies have many stakeholders with several ends, (3) respecting confidentiality and privacy when third-party actors are involved, (4) guaranteeing equal access and just distribution, and (5) handling conflicts between instrumental rationality and care in terms of respecting dignity and vulnerability. Addressing these issues is important for developing and implementing welfare technologies in a morally acceptable manner. PMID- 22219000 TI - Affiliation between the American Society of Pharmacometrics and the Journal of Pharmacokinetics and Pharmacodynamics. PMID- 22219001 TI - The founder Ashkenazi Jewish mutations in the MSH2 and MSH6 genes in Israeli patients with gastric and pancreatic cancer. AB - The genetic basis for gastric and pancreatic cancer is largely undetermined. These cancers are overrepresented in hereditary non polyposis colon cancer (HNPCC), inherited cancer syndrome attributed to germline mutations primarily in the MSH2, MLH1 and MSH6 genes. Among Ashkenazi Jewish HNPCC cases, recurring mutations in the MSH2 (1906G>C; A636P) and MSH6 (c.3984_3987dupGTCA; c.3959_3962delCAAG) genes can be detected. The MSH6*c.3984_3987dupGTCA mutation was recently detected in an Ashkenazi family with inherited gastric cancer. We hypothesized that it may be possible to detect the recurring MSH2 and MSH6 mutations in Jewish individuals with familial and sporadic gastric and pancreatic cancer. To test this notion, we genotyped 143 unrelated Jewish Israeli patients with gastric (n = 23) and pancreatic (n = 120) cancer. The majority of cases (100/143-70%) were Ashkenazi Jews, and 10% (n = 16)--of mixed Ashkenazi-non Ashkenazi Jewish ancestry, and most participants (n = 96-67.1%) had a positive family history of cancer. Genotyping the MSH2*A636P mutation was performed by PCR followed by restriction enzyme digest, and the MSH6*c.3984_3987dupGTCA and c.3959_3962delCAAG mutations were detected by fragment size analysis by capillary electrophoresis and sequencing. None of the participants harbored any of the genotyped MSH2 or MSH6 mutations. We conclude that the recurring Ashkenazi MSH2 and MSH6 mutations contribute little if any to sporadic and familial gastric and pancreatic cases in Israeli patients. PMID- 22219002 TI - Tirofiban versus abciximab: tirofiban is administered at suboptimal dosages when evaluated in an arterial thrombosis model in non-human primates. AB - To prevent thrombosis in high-risk acute coronary syndrome patients undergoing percutaneous coronary intervention for re-vascularisation, concomitant administration of a glycoprotein IIb/IIIa inhibitor, such as abciximab, tirofiban or eptifibatide, is recommended. Abciximab and eptifibatide are mostly preferred over tirofiban, which is less effective in preventing ischaemic events. We compared the efficacy and bleeding potential of escalating doses of tirofiban and abciximab in non-human primates. The efficacy of tirofiban and abciximab in inhibiting cyclic flow reductions (CFRs) was tested in a high shear arterial thrombosis model. Bleeding was evaluated with the template bleeding time and an incision bleeding model. Abciximab completely inhibited arterial thrombosis after injection of its therapeutic bolus dose. With tirofiban, a dose three times higher than the recommended therapeutic dose caused weak inhibition characterised by a return of CFRs after re-injury. At nine times the recommended therapeutic dose, complete inhibition was observed, and the efficacy of tirofiban was comparable to abciximab at its therapeutic bolus dose. Blood loss was less than with abciximab at its effective dose. In this model, tirofiban compared favourably with abciximab, although only at a dose of 3-9 times the therapeutic dose, and caused less bleeding than abciximab. PMID- 22219003 TI - Ventricular arrhythmogenesis following slowed conduction in heptanol-treated, Langendorff-perfused mouse hearts. AB - Arrhythmogenic effects of slowed action potential conduction produced by the gap junction and sodium-channel inhibitor heptanol (0.1-2 mM) were explored in Langendorff-perfused mouse hearts. Monophasic action potential recordings showed that 2 mM heptanol induced ventricular tachycardia in the absence of triggered activity arising from early or after-depolarizations during regular 8 Hz pacing and programmed electrical stimulation (PES). It also increased activation latencies and ventricular effective refractory periods (VERPs), but did not alter action potential duration (APD), thereby reducing local critical intervals for re excitation given by APD(90) - VERP. Bipolar electrogram recordings showed that 2 mM heptanol increased electrogram duration (EGD) and ratios of EGDs obtained at the longest to those obtained at the shortest S1S2 intervals studied during PES, suggesting increased dispersion of conduction velocities. These findings show, for the first time in the mouse heart, that slowed conduction induces reversible arrhythmogenic effects despite repolarization abnormalities expected to reduce arrhythmogenicity. PMID- 22219004 TI - Complications of anterior subcutaneous internal fixation for unstable pelvis fractures: a multicenter study. AB - BACKGROUND: Stabilization after a pelvic fracture can be accomplished with an anterior external fixator. These devices are uncomfortable for patients and are at risk for infection and loosening, especially in obese patients. As an alternative, we recently developed an anterior subcutaneous pelvic internal fixation technique (ASPIF). QUESTIONS/PURPOSES: We asked if the ASPIF (1) allows for definitive anterior pelvic stabilization of unstable pelvic injuries; (2) is well tolerated by patients for mobility and comfort; and (3) has an acceptable complication rate. METHODS: We retrospectively reviewed 91 patients who incurred an unstable pelvic injury treated with an anterior internal fixator and posterior fixation at four Level I trauma centers. We assessed (1) healing by callous formation on radiographs and the ability to weightbear comfortably; (2) patient function by their ability to sit, stand, lie on their sides, and how well they tolerated the implants; and (3) complications during the observation period. The minimum followup was 6 months (mean, 15 months; range, 6-40 months). RESULTS: All 91 patients were able to sit, stand, and lie on their sides. Injuries healed without loss of reduction in 89 of 91 patients. Complications included six early revisions resulting from technical error and three infections. Irritation of the lateral femoral cutaneous nerve was reported in 27 of 91 patients and resolved in all but one. Heterotopic ossification around the implants, which was asymptomatic in all cases, occurred in 32 of 91 patients. CONCLUSIONS: The anterior internal fixator provided high rates of union for the anterior injury in unstable pelvic fractures. Patients were able to sit, stand and ambulate without difficulty. Infections and aseptic loosening were reduced but heterotopic ossification and irritation of the LFCN are common. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22219006 TI - Body temperature evaluation during induced pneumoperitoneum with CO2: an experimental study in pigs. AB - BACKGROUND: In prolonged laparoscopic procedures, hypothermia is frequently observed. The possible influence of the vasodilating action of CO(2), due to its increased levels in the blood during the laparoscopic procedures, has yet to be studied. The objective of this study was, therefore, to evaluate body temperature patterns in pigs subjected to pneumoperitoneum with CO(2). METHODS: Thirty male pigs were allocated into three groups of ten animals each: group I, anesthetic procedure and abdominal puncture only; group II, the same as for group I and insufflation with CO(2); and group III, the same as for group I and insufflation with medical grade compressed air. After anesthetic induction and surgical preparation, rectal and esophageal temperatures were measured every 10 min. Blood was collected during the experiment for the gasometric measurement of pCO(2). Animals were insufflated with no gas loss and were kept anesthetized for 180 min. For statistical analysis, Friedman and Kruskal-Wallis tests were used at a level of significance of 95% (P < 0.05). RESULTS: Animals in groups I and II (P = 0.000) had a statistically significant drop in both esophageal and rectal temperatures during the experiment, but not animals in group III. However, when the groups were compared among themselves, no statistically significant differences were found at any of the times measured. A statistically significant drop in pCO(2) levels was observed for groups I and III, but not for animals in groups II. CONCLUSIONS: The use of CO(2) did not significantly affect body temperature variation in pigs subjected to pneumoperitoneum. However, CO(2) produced a temperature drop pattern different than that of compressed air, indicating that CO(2) may lead to thermoregulatory changes and influence the peripheral temperature drop. PMID- 22219005 TI - Can features of phosphate toxicity appear in normophosphatemia? AB - Phosphate is an indispensable nutrient for the formation of nucleic acids and the cell membrane. Adequate phosphate balance is a prerequisite for basic cellular functions ranging from energy metabolism to cell signaling. More than 85% of body phosphate is present in the bones and teeth. The remaining phosphate is distributed in various soft tissues, including skeletal muscle. A tiny amount, around 1% of total body phosphate, is distributed both in the extracellular fluids and within the cells. Impaired phosphate balance can affect the functionality of almost all human systems, including muscular, skeletal, and vascular systems, leading to an increase in morbidity and mortality of the involved patients. Currently, measuring serum phosphate level is the gold standard to estimate the overall phosphate status of the body. Despite the biological and clinical significance of maintaining delicate phosphate balance, serum levels do not always reflect the amount of phosphate uptake and its distribution. This article briefly discusses the potential that some of the early consequences of phosphate toxicity might not be evident from serum phosphate levels. PMID- 22219007 TI - Plasma soluble vascular adhesion molecule-1 levels are persistently elevated during the first month after colorectal cancer resection. AB - INTRODUCTION: Plasma from the second and third weeks after minimally invasive colorectal resection (MICR) has high levels of the proangiogenic proteins VEGF and angiopoietin 2 and also stimulates, in vitro, endothelial cell (EC) proliferation and migration, which are critical to wound and tumor angiogenesis. Soluble vascular cell adhesion molecule-1 (sVCAM-1) stimulates EC chemotaxis and angiogenesis. The impact of MICR on blood levels of sVCAM-1 is unknown. This study's purpose was to determine plasma sVCAM-1 levels after MICR in colorectal cancer (CRC) patients. METHODS: Blood samples from 90 patients (26% rectal, 74% colon) were obtained preoperatively, on postoperative days (POD) 1 and 3, and at other points during the next 2 months. The late samples were bundled into 7-day time blocks. sVCAM-1 levels were determined in duplicate via ELISA and reported as ng/ml. Student's t test was used for data analysis (significance, P < 0.008 after Bonferroni correction). RESULTS: The mean incision length was 7.3 +/- 3.1 cm, and the conversion rate was 3%. Compared with preoperative (PreOp) levels (811.3 +/- 233.2), the mean plasma sVCAM-1 level was significantly higher on POD 1 (905.7 +/- 292.4, P < 0.001) and POD 3 (977.7 +/- 271.8, P < 0.001). Levels remained significantly elevated for the POD 7-13, POD 14-20, POD 21-27, and POD 28-67 time blocks. CONCLUSIONS: MICR for CRC is associated with a persistent increase in plasma sVCAM-1 levels during the first month. This sustained increase may promote angiogenesis and stimulate the growth of residual tumor cells early after surgery. PMID- 22219008 TI - Laparoscopic surgery for rectal cancer: preoperative radiochemotherapy versus surgery alone. AB - BACKGROUND: A few studies have suggested advantages of laparoscopic surgery for rectal cancer. However, the role of laparoscopy has not been clearly defined specifically in cases after neoadjuvant radiochemotherapy. This study aimed to assess the impact of preoperative radiotherapy on the feasibility of laparoscopic rectal excision with sphincter preservation for rectal cancer. METHODS: From 1999 to 2010, the authors considered all patients treated by laparoscopic rectal excision with sphincter preservation for rectal cancer. Patients treated by long course preoperative radiochemotherapy (45 Gy during 5 weeks) were compared with those treated by surgery alone. The end points of the study were mortality, conversion, and overall and surgical morbidity. RESULTS: Among 422 patients treated by laparoscopic conservative rectal excision, 292 received preoperative radiotherapy, and 130 had surgery alone. The two groups were similar in sex, age, body mass index, and American Society of Anesthesiologists (ASA) score. The mortality rate was 0.3% in the radiotherapy group and 0.8% in the surgical group (P = 0.52). The two groups did not differ in terms of conversion (19 vs. 15%; P = 0.39), overall morbidity (37 vs. 29%; P = 0.14), surgical morbidity (20 vs. 18%; P = 0.60), or anastomotic leakage (13 vs. 11%; P = 0.54). Multivariate analysis showed male gender and synchronous metastasis as independent factors of surgical morbidity. The independent factors of conversion were male gender, obesity, tumor stage, and type of anastomosis. Preoperative radiotherapy influenced neither conversion nor surgical morbidity. CONCLUSION: Long-course radiochemotherapy does not have an impact on the feasibility or short-term outcome of laparoscopic conservative rectal excision for rectal cancer. PMID- 22219009 TI - Evaluation of a knitted polytetrafluoroethylene mesh placed intraperitoneally in a New Zealand white rabbit model. AB - BACKGROUND: The intraperitoneal application of surgical mesh remains a controversial issue because of possible complications, especially adhesion and fistula formation. This study aimed to assess the potential of a knitted polytetrafluoroethylene (PTFE) mesh for intraabdominal implantation. METHODS: Twenty-eight 5 * 5 cm samples of knitted macroporous PTFE mesh and light-weight polypropylene mesh (LW-PP) were implanted intraperitoneally in 14 New Zealand white rabbits in a randomized manner and fixed using eight polypropylene stitches. After 90 days, the adhesion formation, adhesion score, shrinkage, strength of fixation to the abdominal wall, and histologic biocompatibility were assessed. RESULTS: No intraoperative or anesthesia-related complications or mesh infection were recorded. The average area covered by adhesions was 4.7 +/- 7.2% for the PTFE and 36.4 +/- 36.1% for the LW-PP. The median adhesion score was 0 for the PTFE and 8 for the LW-PP. Shrinkage was 36.9 +/- 12.9% for the PTFE mesh and 12.6 +/- 8.72% for the LW-PP. The mesh-to-abdominal wall fixation strength was almost the same for both materials (PTFE 3.6 +/- 1.9 vs. LW-PP 3.6 +/- 2.9). The inflammatory cell count was almost the same for the two groups, with no statistically significant difference. The width of the inner granuloma was equal (PTFE 10.5 +/- 0.9 vs. LW-PP 11.1 +/- 0.9). The outer granuloma was reduced significantly in the PTFE group (PTFE 23.0 +/- 2.1 vs. LW-PP 33.6 +/- 7.9). One of the animals in the PTFE group died on postoperative day 12 because of ileus. The reason was an adhesion of the small intestine to the polypropylene fixation stitch, which caused small intestine strangulation. CONCLUSIONS: The knitted PTFE mesh induces fewer intraperitoneal adhesions of lower density than the light weight polypropylene mesh. The strength of the knitted PTFE mesh fixation to the abdominal wall is comparable with that of the light-weight polypropylene mesh, but the shrinkage is greater. The biocompatibility of the knitted PTFE mesh is comparable with that of the light-weight polypropylene implant. PMID- 22219010 TI - Long-term results of ablation with antireflux surgery for Barrett's esophagus: a clinical and molecular biologic study. AB - BACKGROUND: The initial results from ablation therapy for metaplastic/dysplastic Barrett's esophagus (BE) are promising, but the results of extended follow-up evaluation are seldom reported. METHODS: Neodymium:yttrium-aluminum-garnet laser ablation and successful antireflux surgery for 18 patients with metaplastic BE primarily resulted in the total histologic eradication of BE in 15 patients (83%). After antireflux surgery, the healing of gastroesophageal reflux disease (GERD) was objectively verified in all the patients. At late follow-up evaluation, endoscopy, conventional histology, molecular oxidative stress analyses in comparison with normal control conditions (8-hydroxydeoxyguanosine [8 OHdG], superoxide dismutase [SOD], glutathione [GSH], myeloperoxydase [MP]), and immunohistochemistry (p53, and Cdx2, caudal-related homeobox gene 2, marking intestinal differentiation) of the neosquamous epithelium were performed. RESULTS: At the end of the follow-up period (range, 3-15 years; mean, 8 years), intestinal metaplasia without dysplasia was detected histologically in eight patients (44%). Six patients had macroscopic BE (mean length, 3.5 cm; range 1-10 cm). The neosquamous epithelium was histologically normal, with no underlying columnar tissue. The fundoplication was endoscopically normal in 14 patients (82%). The 8-OHdG level was higher in the neosquamous epithelium than in the control conditions in the distal esophagus (4.3 vs. 0.52; P = 0.0002) and the proximal esophagus (1.8 vs. 0.95; P = 0.006). Likewise, SOD activity was higher in the neosquamous epithelium (0.38 vs. 0.12; P = 0.0005), whereas MP activity and GSH levels remained normal. Three patients showed slight nuclear p53 expression (typical in normal inflammatory reactions), whereas Cdx2 positivity was confined to one case with recurrent intestinal metaplasia. CONCLUSIONS: The neosquamous mucosa, generated by the ablation of BE and the treatment of GERD with fundoplication, was stable during long-term follow-up evaluation in two thirds of the patients with initial eradication. It had normal p53 expression and no Cdx2 protein expression. The oxidative stress of the neosquamous esophagus remained high, although the clinical significance of this is unclear. PMID- 22219011 TI - Long-term outcomes of laparoscopic adjustable gastric banding and laparoscopic Roux-en-Y gastric bypass in the United States. AB - BACKGROUND: Although laparoscopic adjustable gastric banding (LAGB) and laparoscopic Roux-en-Y gastric bypass (LRYGB) are the most common bariatric procedures performed in the past decade, little is known about their long-term (>5 years) outcomes. METHODS: A retrospective outcome study investigated 148 consecutive patients from a single practice who underwent LAGB from November 2000 to March 2002. The group was matched with 175 consecutive patients who underwent LRYGB from June 2000 to March 2005. Follow-up data for 5 years or longer was available for 127 LAGB patients (86%) and 105 LRYGB patients (60%). RESULTS: After an initial 4 years of progressive weight loss, body mass index (BMI) loss stabilized at 5-7 years at approximately 15 kg/m(2) for the LRYGB patients and at about 9 kg/m(2) for the LAGB patients with band in place (P < 0.01). At 7 years, the excess weight loss (EWL) was 58.6% for LRYGB and 46.3% for LAGB with band in place (P < 0.01). By 7 years, 19 LAGB patients (15%) had had their bands removed, bringing the failure rate for LAGB (including patients with less than 25% EWL) to 48.3% versus 10.7% for LRYGB (P < 0.01). By 10 years, 29 (22.8%) of the bands had been removed, bringing the total LAGB failure rate to 51.1%. In 10 years, 67 LAGB (52.8%) and 43 LRYGB (41%) adverse events had occurred. However, over time, the LRYGB group experienced 9 (8.6%) serious, potentially life-threatening complications, whereas the LAGB group had none (P < 0.001). One procedure-related death occurred in the LRYGB group. CONCLUSIONS: Over the long term, LRYGB had an approximate reduction of 15 kg/m(2) BMI and 60% EWL, a significantly better outcome than LAGB patients experienced with band intact. The main issue with LAGB was its 50% failure rate in the long term, as defined by poor weight loss and percentage of band removal. Nevertheless, LAGB had a remarkably safe course, and it may therefore be considered for motivated and informed patients. PMID- 22219012 TI - Pre-bent instruments used in single-port laparoscopic surgery versus conventional laparoscopic surgery: comparative study of performance in a dry lab. AB - BACKGROUND: Different types of single-incision laparoscopic surgery (SILS) have become increasingly popular. Although SILS is technically even more challenging than conventional laparoscopy, published data of first clinical series seem to demonstrate the feasibility of these approaches. Various attempts have been made to overcome restrictions due to loss of triangulation in SILS by specially designed SILS-specific instruments. This study involving novices in a dry lab compared task performances between conventional laparoscopic surgery (CLS) and single-port laparoscopic surgery (SPLS) using newly designed pre-bent instruments. METHODS: In this study, 90 medical students without previous experience in laparoscopic techniques were randomly assigned to undergo one of three procedures: CLS, SPLS using two pre-bent instruments (SPLS-pp), or SPLS using one pre-bent and one straight laparoscopic instrument (SPLS-ps). In the dry lab, the participants performed four typical laparoscopic tasks of increasing difficulty. Evaluation included performance times or number of completed tasks within a given time frame. All performances were videotaped and evaluated for unsuccessful attempts and unwanted interactions of instruments. Using subjective questionnaires, the participants rated difficulties with two-dimensional vision and coordination of instruments. RESULTS: Task performances were significantly better in the CLS group than in either SPLS group. The SPLS-ps group showed a tendency toward better performances than the SPLS-pp group, but the difference was not significant. Video sequences and participants' questionnaires showed instrument interaction as the major problem in the single-incision surgery groups. CONCLUSIONS: Although SILS is feasible, as shown in clinical series published by laparoscopically experienced experts, SILS techniques are demanding due to restrictions that come with the loss of triangulation. These can be compensated only partially by currently available SILS-designed instruments. The future of SILS depends on further improvements in the available equipment or the development of new approaches such as needlescopically assisted or robotically assisted procedures. PMID- 22219013 TI - FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer-subgroup analysis of patients with KRAS: mutated tumours in the randomised German AIO study KRK-0306. AB - BACKGROUND: The AIO KRK-0306 trial compares the efficacy of infusional 5 fluorouracil, folinic acid, irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in first-line treatment of metastatic colorectal cancer (mCRC). In October 2008, an amendment terminated the inclusion of patients with KRAS-mutated tumours. This subgroup of patients is evaluated in the present analysis, while the study is ongoing for patients with KRAS wild-type tumours. METHODS: Patients were randomly assigned to FOLFIRI (Tournigand regimen) every 2 weeks plus cetuximab (400 mg/m2 day 1, followed by 250 mg/m2 weekly=arm A) or bevacizumab (5 mg/kg every 2 weeks=arm B). Among 336 randomised patients, KRAS mutation was demonstrated in 100 assessable patients. The primary study end point was objective response rate (ORR). RESULTS: ORR was 44% [95% confidence interval (CI) 29% to 59%] in arm A versus 48% (95% CI, 33% to 62%) in arm B. Progression-free survival was 7.5 versus 8.9 months (hazard ratio: 1.0) and overall survival was 22.7 versus 18.7 months (hazard ratio: 0.86) in arms A versus B, respectively. CONCLUSIONS: This is the first head to head comparison of cetuximab versus bevacizumab in first-line treatment of mCRC. In the present evaluation of patients with KRAS-mutated tumours, neither strategy demonstrated a clearly superior outcome. PMID- 22219014 TI - Aprepitant quetiapine: a clinically significant drug interaction in a patient treated for head and neck cancer. PMID- 22219015 TI - Multicentric/multifocal breast cancer with a single histotype: is the biological characterization of all individual foci justified? AB - BACKGROUND: Invasive multiple breast cancers with a single histological feature (MBCSH) are routinely assessed for biological parameters to indicate adjuvant treatments only in the largest invasive carcinomas. However, the heterogeneity of individual foci in multiple carcinomas has not been widely studied. We analyzed whether such biological features are differently expressed in different MBCSH foci. PATIENT AND METHODS: One hundred and thirteen invasive MBCSH were tested over a 5-year period. The expression of estrogen (ER) and progesterone (PgR) receptors, Ki-67 proliferative index, expression of HER2 and tumor grading were prospectively determined in each tumor focus, and mismatches among foci were recorded. RESULTS: Mismatches in ER status were present in 5 (4.4%) cases and PgR in 18 (15.9%) cases. Mismatches in tumor grading were present in 21 cases (18.6%), proliferative index (Ki-67) in 17 (15%) cases and HER2 status in 11 (9.7%) cases. CONCLUSIONS: In our experience, invasive MBCSH showed heterogeneity among foci. In our clinical practice, such assessment led to 14 (12.4%) patients receiving different adjuvant treatments compared with what would have been indicated if we had only taken into account the biologic status of the primary tumor. PMID- 22219016 TI - Natural history of bone metastasis in colorectal cancer: final results of a large Italian bone metastases study. AB - BACKGROUND: Data are limited regarding bone metastases from colorectal cancer (CRC). The objective of this study was to survey the natural history of bone metastasis in CRC. PATIENTS AND METHODS: This retrospective, multicenter, observational study of 264 patients with CRC involving bone examined cancer treatments, bone metastases characteristics, skeletal-related event (SRE) type and frequency, zoledronic acid therapy, and disease outcomes. RESULTS: Most patients with bone metastases had pathologic T3/4 disease at CRC diagnosis. The spine was the most common site involved (65%), followed by hip/pelvis (34%), long bones (26%), and other sites (17%). Median time from CRC diagnosis to bone metastases was 11.00 months; median time to first SRE thereafter was 2.00 months. Radiation and pathologic fractures affected 45% and 10% of patients, respectively; 32% of patients had no reported SREs. Patients survived for a median of 7.00 months after bone metastases diagnosis; SREs did not significantly affect survival. Subgroup analyses revealed that zoledronic acid significantly prolonged median time to first SRE (2.00 months versus 1.00 month, respectively, P=0.009) and produced a trend toward improved overall survival versus no zoledronic acid. CONCLUSION: This study illustrates the burden of bone metastases from CRC and supports the use of zoledronic acid in this setting. PMID- 22219017 TI - Bringing geriatrics into oncology or also oncology into geriatrics? PMID- 22219018 TI - Identification and validation of gene expression models that predict clinical outcome in patients with early-stage laryngeal cancer. AB - BACKGROUND: Despite improvement in therapeutic techniques, patients with early stage laryngeal cancer still recur after treatment. Gene expression prognostic models could suggest which of these patients would be more appropriate for testing adjuvant strategies. MATERIALS AND METHODS: Expression profiling using whole-genome DASL arrays was carried out on 56 formalin-fixed paraffin-embedded tumor samples of patients with early-stage laryngeal cancer. We split the samples into a training and a validation set. Using the supervised principal components survival analysis in the first cohort, we identified gene expression profiles that predict the risk of recurrence. These profiles were then validated in an independent cohort. RESULTS: Gene models comprising different number of genes identified a subgroup of patients who were at high risk of recurrence. Of these, the best prognostic model distinguished between a high- and a low-risk group (log rank P<0.005). The prognostic value of this model was reproduced in the validation cohort (median disease-free survival: 38 versus 161 months, log-rank P=0.018), hazard ratio=5.19 (95% confidence interval 1.14-23.57, P<0.05). CONCLUSIONS: We have identified gene expression prognostic models that can refine the estimation of a patient's risk of recurrence. These findings, if further validated, should aid in patient stratification for testing adjuvant treatment strategies. PMID- 22219019 TI - Dilemmas, diagnosis and de-stigmatization: parental perspectives on the diagnosis of autism spectrum disorders. AB - Many children who display autistic behaviours at clinical levels do not receive a formal diagnosis. This study used qualitative methods to examine parental influence in pursuing or avoiding a diagnosis of autism spectrum disorder (ASD). The aim was to explore the function of ASD diagnosis for parents, and examine whether a diagnosis affected how parents perceived ASD. Seventeen parents participated in in-depth semi-structured interviews, which were analyzed using thematic and grounded theory approaches. Data analysis revealed dilemmas faced by parents: whether to act to retain the 'normal' status of the child or to 'normalize' the child through diagnosis and subsequent remediation. Parents who had received an ASD diagnosis for their children became proactive in trying to reduce stigmatization of ASD more widely, and in some cases actively advocating ASD diagnosis to other parents. Thus their actions may make it more likely that others will opt for diagnosis in the future. PMID- 22219020 TI - Measuring temperature using MRI: a powerful and versatile technique. AB - The Larmor frequency of water protons has reliably linear temperature dependence. Since this frequency shift is easily measurable using relatively simple MRI techniques, a remarkable opportunity arises for uniquely non-invasive and accurate temperature evaluation, deep within any water-containing object. Major applications are appearing in the field of image-guided surgery. The cutting-edge papers collected in this Special Issue demonstrate both the versatility and the power of MRI thermometry. PMID- 22219021 TI - Fixation of mesh to the peritoneum using a fibrin glue: investigations with a biomechanical model and an experimental laparoscopic porcine model. AB - BACKGROUND: In recent years, the use of fibrin glue has become an established practice in several areas of surgical treatment. For example, fibrin glue is used increasingly as an alternative method for mesh fixation in hernia surgery, significantly helping to reduce the incidence of chronic pain. The experiments in this study were aimed at elucidating the extent to which tack- or suture-based permanent fixation can be replaced by fixation with fibrin glue for laparoscopic intraperitoneal repair of abdominal wall hernias. METHODS: In an initial series of experiments conducted with a biomechanical model, the strength of the fibrin glue for fixation of lightweight mesh (TiMesh light) to muscle tissue was compared with its strength of fixation to the peritoneum. In a second series of experiments, mesh was laparoscopically implanted in an established porcine model. Fibrin glue was used for mesh fixation in six animals. Laparoscopic exploration and explantation of the meshes were conducted after 4 months. Planimetric analysis was performed to investigate adhesion and shrinkage of the mesh surface. RESULTS: The strength of fibrin glue for fixation of mesh to the peritoneum was significantly less than for its fixation to muscle tissue (11.86 N vs. 47.88 N; p = 0.001). Three of the implanted meshes were not completely integrated, and two of these were dislocated. On the average, adhesions were seen on 16% of the mesh surfaces. The mesh shrinkage rate was 24.2%. CONCLUSION: Mesh fixation alone to the undamaged peritoneum in the intraperitoneal region cannot be recommended because of the risk for dislocation. Additional fixation using sutures, tacks, or both is needed until the mesh material is completely integrated. PMID- 22219023 TI - Auricular acupuncture effectively reduces state anxiety before dental treatment- a randomised controlled trial. AB - OBJECTIVES: The objective of this study was to analyse whether auricular acupuncture, acupuncture at the outer ear, could reduce state anxiety before dental treatment. METHODS: This prospective, randomised patient-blinded study with 182 patients compared anxiety before dental treatment following auricular acupuncture at the relaxation-, tranquillizer- and master cerebral points (auricular acupuncture group) versus acupuncture at sham points (finger-, shoulder- and tonsil points; sham group) and a non-intervention control group. Anxiety was assessed using the Spielberger State Trait Anxiety Inventory (German version) before auricular acupuncture and 20 min thereafter, immediately before dental treatment. RESULTS: Auricular acupuncture reduced state anxiety score more effectively from 54.7 +/- 10.8 to 46.9 +/- 10.4 (mean +/- SD) than sham acupuncture from 51.9 +/- 10.2 to 48.4 +/- 10.0. In contrast, state anxiety in the control group increased from 51.0 +/- 11.7 to 54.0 +/- 11.6 (mean increase +3.0; CI +4.7 to +1.2). The decrease in state anxiety in both intervention groups was statistically significant (p < 0.001) when compared to the non-intervention control group. After correcting for group differences in baseline state anxiety, the reduction in anxiety was -7.3 score points (CI -9.0 to -5.6) in the auricular acupuncture group and -3.7 score points (CI -5.4 to -1.9) in the sham group (p = 0.008). CONCLUSION: Auricular acupuncture, a minimally invasive method, effectively reduces state anxiety before dental treatment. CLINICAL RELEVANCE: Auricular acupuncture could be an option for patients scheduled for dental treatment, who experience an uncomfortable degree of anxiety and request an acute intervention for their anxiety. PMID- 22219024 TI - Effect of radiation dose on the prevalence of apical periodontitis--a dosimetric analysis. AB - OBJECTIVES: The objective of this study is to analyse the effect of the radiation dose of oral radiotherapy for cancer on the presence of apical periodontitis in patients without dental pre-screening or specific preventive measures. MATERIALS AND METHODS: All selected patients had been diagnosed with cancer in the head and neck region and presented in the dental clinic post radiotherapy with side effects (mainly radiation caries). The panoramic radiographs of these patients were examined for several parameters, including tooth decay and apical periodontitis. The total radiation dose per tooth was determined. RESULTS: A total of 36 patient files were included, which accounted for 628 teeth to be scored. Tooth decay was present in 88.2% of teeth. Radiographic signs of apical periodontitis were found in 9.1% of the teeth. Teeth with apical periodontitis had significantly more caries present. The radiation dose was significantly higher for teeth with apical periodontitis (37.2 vs. 24.9 Gy). Binary logistic regression found the radiation dose to be the only explanatory variable in the presence of apical periodontitis. CONCLUSIONS: This study found that in zones with higher radiation dose, inflammation of the jawbone due to bacterial infection of the root canal is more likely to develop. This is probably due to bone changes post radiotherapy. CLINICAL RELEVANCE: An increase of this prevalance of apical periodontitis in irradiated bone found in this study needs to be taken into account in the dental evaluation before the start of radiotherapy. PMID- 22219025 TI - The relationship of PTH Bst BI polymorphism, calciotropic hormone levels, and dental fluorosis of children in China. AB - The aim of this study was to explore the association of parathyroid hormone (PTH) gene Bst BI polymorphism, calciotropic hormone levels, and dental fluorosis of children. A case-control study was conducted in two counties (Kaifeng and Tongxu) in Henan Province, China in 2005-2006. Two hundred and twenty-five children were recruited and divided into three groups including dental fluorosis group (DFG), non-dental fluorosis group (NDFG) from high fluoride areas, and control group (CG). Urine fluoride content was determined using fluoride ion selective electrode; PTH Bst BI were genotyped using PCR-RFLP; osteocalcin (OC) and calcitonin (CT) levels in serum were detected using radioimmunoassay. Genotype distributions were BB 85.3% (58/68), Bb 14.7% (10/68) for DFG; BB 77.6% (52/67), Bb 22.4% (15/67) for NDFG; and BB 73.3% (66/90), Bb 27.7% (24/90) for CG. No significant difference of Bst BI genotypes was observed among three groups (P > 0.05). Serum OC and urine fluoride of children were both significantly higher in DFG and NDFG than in CG (P < 0.05, respectively), while a similar situation was not observed between DFG and NDFG in high fluoride areas (P > 0.05). Serum OC level of children with BB genotype was significantly higher compared to those with Bb genotype in high fluoride areas (P < 0.05). However, no significant difference of serum CT or calcium (Ca) was observed. In conclusion, there is no correlation between dental fluorosis and PTH Bst BI polymorphism. Serum OC might be a more sensitive biomarker for detecting early stages of dental fluorosis, and further studies are needed. PMID- 22219026 TI - Expression and role in glycolysis of human ADP-dependent glucokinase. AB - A novel murine enzyme, ADP-dependent glucokinase (ADPGK), has been shown to catalyse glucose phosphorylation using ADP as phosphoryl donor. The ancestral ADPGK gene appears to have been laterally transferred from Archaea early in metazoan evolution, but its biological role has not been established. Here, we undertake an initial investigation of the functional properties of human ADPGK in human tumour cell lines and specifically test the hypothesis that ADPGK might prime glycolysis using ADP under stress conditions such as hypoxia. Recombinant human ADPGK was confirmed to catalyse ADP-dependent glucose phosphorylation in vitro, with an apparent K (M) for glucose of 0.29 mM. Expression databases and western blotting of surgical samples demonstrated high expression in many human tissues, including tumours. Unlike hexokinase-2 (HK2), RNAi studies with exon arrays showed that ADPGK is not a transcriptional target of hypoxia inducible factor-1. Consistent with this, ADPGK protein was not upregulated by hypoxia or anoxia. Surprisingly, stable fivefold overexpression of ADPGK in H460 or HCT116 cells had no apparent effect on proliferation or glycolysis, and did not rescue clonogenicity or glycolysis when HK2 was suppressed by siRNA. Furthermore, suppression of ADPGK by siRNA did not cause detectable inhibition of glycolysis or cell killing by anoxia, although it did induce a statistically significant decrease in plating efficiency of H460 cells under aerobic conditions. Thus, human ADPGK catalyses ADP-dependent phosphorylation of glucose in vitro, but despite its high expression in human tumour cell lines it appears not to make a quantifiable contribution to glycolysis under the conditions evaluated. PMID- 22219027 TI - Hierarchy of direction-tuned motion adaptation in human visual cortex. AB - Prolonged exposure to a single direction of motion alters perception of subsequent static or dynamic stimuli and induces substantial changes in behaviors of motion-sensitive neurons, but the origin of neural adaptation and neural correlates of perceptual consequences of motion adaptation in human brain remain unclear. Using functional magnetic resonance imaging, we measured motion adaptation tuning curves in a fine scale by probing changes in cortical activity after adaptation for a range of directions relative to the adapted direction. We found a clear dichotomy in tuning curve shape: cortical responses in early-tier visual areas reduced at around both the adapted and opposite direction, resulting in a bidirectional tuning curve, whereas response reduction in high-tier areas occurred only at around the adapted direction, resulting in a unidirectional tuning curve. We also found that the psychophysically measured adaptation tuning curves were unidirectional and best matched the cortical adaptation tuning curves in the middle temporal area (MT) and the medial superior temporal area (MST). Our findings are compatible with, but not limited to, an interpretation in which direct impacts of motion adaptation occur in both unidirectional and bidirectional units in early visual areas, but the perceptual consequences of motion adaptation are manifested in the population activity in MT and MST, which may inherit those direct impacts of adaptation from the directionally selective units. PMID- 22219028 TI - Contribution of axonal orientation to pathway-dependent modulation of excitatory transmission by direct current stimulation in isolated rat hippocampus. AB - Transcranial direct current stimulation (tDCS) is a method for modulating cortical excitability by weak constant electrical current that is applied through scalp electrodes. Although often described in terms of anodal or cathodal stimulation, depending on which scalp electrode pole is proximal to the cortical region of interest, it is the orientation of neuronal structures relative to the direct current (DC) vector that determines the effect of tDCS. To investigate the contribution of neural pathway orientation, we studied DCS-mediated neuromodulation in an in vitro rat hippocampal slice preparation. We examined the contribution of dendritic orientation to the direct current stimulation (DCS) neuromodulatory effect by recording field excitatory postsynaptic potentials (fEPSPs) in apical and basal dendrites of CA1 neurons within a constant DC field. In addition, we assessed the contribution of axonal orientation by recording CA1 and CA3 apical fEPSPs generated by stimulation of oppositely oriented Schaffer collateral and mossy fiber axons, respectively, during DCS. Finally, nonsynaptic excitatory signal propagation was measured along antidromically stimulated CA1 axons at different DCS amplitudes and polarity. We find that modulation of both the fEPSP and population spike depends on axonal orientation relative to the electric field vector. Axonal orientation determines whether the DC field is excitatory or inhibitory and dendritic orientation affects the magnitude, but not the overall direction, of the DC effect. These data suggest that tDCS may oppositely affect neurons in a stimulated cortical volume if these neurons are excited by oppositely orientated axons in a constant electrical field. PMID- 22219029 TI - Midline thalamic paraventricular nucleus neurons display diurnal variation in resting membrane potentials, conductances, and firing patterns in vitro. AB - Neurons in the rodent midline thalamic paraventricular nucleus (PVT) receive inputs from brain stem and hypothalamic sites known to participate in sleep-wake and circadian rhythms. To evaluate possible diurnal changes in their excitability, we used patch-clamp techniques to record and examine the properties of neurons in anterior PVT (aPVT) in coronal rat brain slices prepared at zeitgeber time (ZT) 2-6 vs. ZT 14-18 and recorded at ZT 8.4 +/- 0.2 (day) vs. ZT 21.2 +/- 0.2 (night), the subjective quiet vs. aroused states, respectively. Compared with neurons recorded during the day, neurons from the night period were significantly more depolarized and exhibited a lower membrane conductance that in part reflected loss of a potassium-mediated conductance. Furthermore, these neurons were also significantly more active, with tonic and burst firing patterns. Neurons from each ZT period were assessed for amplitudes of two conductances known to contribute to bursting behavior, i.e., low-threshold activated Ca(2+) currents (I(T)) and hyperpolarization-activated cation currents (I(h)). Data revealed that amplitudes of both I(T) and I(h) were significantly larger during the night period. In addition, biopsy samples from the night period revealed a significant increase in mRNA for Ca(v)3.1 and Ca(v)3.3 low-threshold Ca(2+) channel subtypes. Neurons recorded from the night period also displayed a comparative enhancement in spontaneous bursting at membrane potentials of approximately -60 mV and in burst firing consequent to hyperpolarization-induced low-threshold currents and depolarization-induced current pulses. These novel in vitro observations reveal that midline thalamic neurons undergo diurnal changes in their I(T), I(h), and undefined potassium conductances. The underlying mechanisms remain to be characterized. PMID- 22219030 TI - Sound sensitivity of neurons in rat hippocampus during performance of a sound guided task. AB - To investigate how hippocampal neurons encode sound stimuli, and the conjunction of sound stimuli with the animal's position in space, we recorded from neurons in the CA1 region of hippocampus in rats while they performed a sound discrimination task. Four different sounds were used, two associated with water reward on the right side of the animal and the other two with water reward on the left side. This allowed us to separate neuronal activity related to sound identity from activity related to response direction. To test the effect of spatial context on sound coding, we trained rats to carry out the task on two identical testing platforms at different locations in the same room. Twenty-one percent of the recorded neurons exhibited sensitivity to sound identity, as quantified by the difference in firing rate for the two sounds associated with the same response direction. Sensitivity to sound identity was often observed on only one of the two testing platforms, indicating an effect of spatial context on sensory responses. Forty-three percent of the neurons were sensitive to response direction, and the probability that any one neuron was sensitive to response direction was statistically independent from its sensitivity to sound identity. There was no significant coding for sound identity when the rats heard the same sounds outside the behavioral task. These results suggest that CA1 neurons encode sound stimuli, but only when those sounds are associated with actions. PMID- 22219031 TI - Representation of 3-D surface orientation by velocity and disparity gradient cues in area MT. AB - Neural coding of the three-dimensional (3-D) orientation of planar surface patches may be an important intermediate step in constructing representations of complex 3-D surface structure. Spatial gradients of binocular disparity, image velocity, and texture provide potent cues to the 3-D orientation (tilt and slant) of planar surfaces. Previous studies have described neurons in both dorsal and ventral stream areas that are selective for surface tilt based on one or more of these gradient cues. However, relatively little is known about whether single neurons provide consistent information about surface orientation from multiple gradient cues. Moreover, it is unclear how neural responses to combinations of surface orientation cues are related to responses to the individual cues. We measured responses of middle temporal (MT) neurons to random dot stimuli that simulated planar surfaces at a variety of tilts and slants. Four cue conditions were tested: disparity, velocity, and texture gradients alone, as well as all three gradient cues combined. Many neurons showed robust tuning for surface tilt based on disparity and velocity gradients, with relatively little selectivity for texture gradients. Some neurons showed consistent tilt preferences for disparity and velocity cues, whereas others showed large discrepancies. Responses to the combined stimulus were generally well described as a weighted linear sum of responses to the individual cues, even when disparity and velocity preferences were discrepant. These findings suggest that area MT contains a rudimentary representation of 3-D surface orientation based on multiple cues, with single neurons implementing a simple cue integration rule. PMID- 22219032 TI - Effect of host immunity on metastatic potential in renal cell carcinoma: the assessment of optimal in vivo models to study metastatic behavior of renal cancer cells. AB - There has been little information about metastatic behavior of renal cell carcinoma (RCC) cells because human cancers metastasize only rarely in immunodeficient mice. Moreover, it is difficult to know the effect of host immunity on RCC metastasis due to lack of such RCC cells as transplantable in not only xenograft models but also counterparts with intact immunity. Therefore, we scrutinized in vivo metastasis of RCC cells to seek for the optimal preclinical model to study metastatic behavior. The luciferase-expressing three representative human RCC cell lines (Caki-1, A498, and 786-O) and rat ACI-RCC cell which were established in our laboratory were transplanted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice or immunocompetent ACI rats by intracardiac injection as well as orthotopic inoculation. Metastasis was monitored using a bioluminescent imaging technique. Metastasis was rare in the three human RCC cells even when they were directly disseminated into systemic circulation under the condition least susceptible to host immune attack in NOD/SCID mice. In contrast, ACI-RCC cells spontaneously metastasized to pulmonary tissue from orthotopic tumor sites and systemically spread via intracardiac route. Metastases were more extensive when the cells were inoculated into an immunodeficient host, implying suppressive effect of host immunity on colonization of RCC cells. These results suggest that the representative human RCC cells are not adequate resource to study metastasis but that the luciferase labeled ACI-RCC cell characterized by its luminescent stability, enhanced tumorigenicity, and widespread metastatic potential provides a useful in vivo model for preclinical assessment of cancer progression and potential therapies against RCC. PMID- 22219033 TI - Expression and clinical significance of Notch signaling genes in colorectal cancer. AB - The objective of this study was to explore the expression and clinical significance of Notch signaling genes in colorectal cancer. Colorectal cancer samples were prospectively collected from patients post-surgery at the 3rd Affiliated Hospital, Nanjing University of Traditional Chinese Medicine. Immunohistochemistry of tissue arrays was used to analyze the samples and genes involved in the Notch signaling pathway. Microsatellite instability (MSI) was detected by fluorescence multiplex polymerase chain reaction. A total of 146 colorectal cancer samples were collected, including 84 men (57.7%) and 62 women (42.5%). The average age of the study population was 60.8 +/- 10.5 years. Notch1 and Notch2 gene expression correlated with tumor pathology type and degree of differentiation. In addition, Jagged 1 (JAG1) and hairy enhancer of split 1 gene expression correlated with the degree of tumor differentiation. Delta-like 1 gene expression varied significantly with tumor location. There was a significant difference between gene expression and MSI. Of the 138 patients, 134 (91.8%) participated in on-site visits, and the average follow-up time was 42.3 +/- 13.3 months. During this period, 86 patients (71.6%) were tumor-free. At 1 year post surgery, 93% of patients were alive, 74% of patients lived for 3 years, and 67% of patients lived for 5 years. The log-rank test was used to perform univariate analysis, and the COX proportional hazards model was used for the multivariate analysis. Based on these analyses, tumor prognosis correlated with the TNM stage, pathological type, microsatellite status as well as Notch2 and JAG1 gene expression. Patients expressing high levels of Notch2 and JAG1 presented with a significantly better prognosis compared to patients expressing negative or weak levels of Notch2 and JAG1. The expression levels of genes associated with the Notch signaling pathway correlated with tumor pathology and the degree of differentiation. In addition, Notch2 and JAG1 expression levels correlated with survival; however, the underlying mechanism for these correlations remains unclear. PMID- 22219035 TI - Demographic features of idiopathic macular telangiectasia in Japanese patients. AB - PURPOSE: Idiopathic macular telangiectasia (MacTel) is classified into aneurysmal telangiectasia (type 1), perifoveal telangiectasia (type 2) and occlusive telangiectasia (type 3). Most instances of telangiectasia in Western countries are type 2. This study reports clinical and demographic features of MacTel in Japanese patients. METHODS: Newly diagnosed patients with MacTel were examined retrospectively. All patients underwent fluorescein angiography and optical coherence tomography. RESULTS: Thirty-four eyes of 27 patients with MacTel were included. Twenty eyes of 20 patients (74.1%) had type 1, ten eyes of five patients (18.5%) had type 2, and four eyes of two patients (7.4%) had type 3. Foveal capillary dilatation and microaneurysms were observed in all except for one eye of early stage type 2 MacTel. Optical coherence tomography revealed cystoid macular edema in type 1, temporal foveal thinning and a loss of boundary between the inner and outer segments of photoreceptors in type 2, and thinning of all retinal layers around the fovea in type 3. CONCLUSION: The most frequent among our patients was aneurysmal MacTel, whereas perifoveal MacTel was not common. Although the clinical characteristics were similar, the most common type was different from that in Western countries. PMID- 22219034 TI - Emerging links between epigenetic alterations and dysregulation of noncoding RNAs in cancer. AB - Epigenetic changes, including DNA methylation and histone modification, play key roles in the dysregulation of tumor-related genes, thereby affecting numerous cellular processes, including cell proliferation, cell adhesion, apoptosis, and metastasis. In recent years, numerous studies have shown that noncoding RNAs (ncRNAs) are key players in the initiation and progression of cancer and epigenetic mechanisms are deeply involved in their dysregulation. Indeed, the growing list of microRNA (miRNA) genes aberrantly methylated in cancer suggests that a large number of miRNAs exert tumor-suppressive or oncogenic effects. In addition, it now appears that long ncRNAs may be causally related to epigenetic dysregulation of critical genes in cancer. Dissection of the relationships between ncRNAs and epigenetic alterations may lead to the development of novel approaches to the diagnosis and treatment of cancer. PMID- 22219036 TI - Effects of selective-wavelength block filters on pupillary light reflex under red and blue light stimuli. AB - PURPOSE: To investigate at which wavelength melanopsin-containing retinal ganglion cells (mRGCs) depolarize and how they affect pupillary constriction induced by light stimulation in humans. METHODS: The pupil light reflex was evaluated for 30 normal subjects by use of an infrared pupillometer. Blue light stimulation (470 nm) and red light stimulation (635 nm) of 100 cd/m(2) were selected. Selective-wavelength block filters which can selectively remove the wavelengths 440 and 470 nm were used. Visual tests were also performed to observe the effects of the filters on visual acuity, color vision, and contrast sensitivity. RESULTS: The pupil transiently constricts and then settles toward a steady-state diameter when stimulated with the light. When the 470-nm-block filter was worn, the sustained phase of pupillary constriction, thought to be mediated by the mRGCs, was not stable but there was no effect on the initial phase of pupillary constriction under blue light stimulation. Visual acuity, color vision, and contrast sensitivity were not affected by the 470-nm-block filter. CONCLUSIONS: These results suggest that the mRGC in humans may respond to 470-nm-wavelength light at 100 cd/m(2), and there is a possibility of affecting the sustained phase of the light reflex without changing visual performance. PMID- 22219038 TI - Waking up from coronary bypass surgery and one eye does not move right. AB - INTRODUCTION: Complications of coronary artery bypass graft surgery (CABG) include acute oculomotor nerve palsy secondary to ischemic stroke and pituitary apoplexy. These can present with impairment of extraocular muscle function as well as involvement or sparing of the pupil. CASE REPORT: We report the case of a 58-year-old male admitted for elective CABG surgery for severe coronary artery disease and found to have a pupil-sparing partial oculomotor palsy post procedure. Neurological examination revealed left pupil-sparing isolated medial rectus and levator palpebrae superioris paresis. Magnetic resonance imaging demonstrated acute midbrain infarction. CONCLUSION: Acute pupil-sparing partial oculomotor nerve palsy should be recognized as a neurological complication of cardiac surgery. Pupillary involvement can be helpful in identifying the underlying etiology. PMID- 22219037 TI - Diversity of culturable halophilic archaea isolated from Rambla Salada, Murcia (Spain). AB - We have studied the diversity of culturable halophilic Archaea at Rambla Salada, Murcia (south-eastern Spain). We made 8 samplings at different places in this habitat during the years 2006 and 2007 and isolated a total of 49 strains, which were identified by means of phenotypic tests and the hypervariable V1-V3 region of the 16S rRNA gene sequences (around 500 bp). The ribosomal data showed that the isolates belonged to 12 genera within the Halobacteriaceae family, with Haloferax and Natrinema being the most abundant. Five strains showed less than 97% sequence identity with validly described species and may well represent new taxa. All the strains grew best with around 25% w/v salts, required high concentrations of NaCl and magnesium and produced red to pink colonies. They were facultative anaerobes with both respiratory and fermentative metabolisms. The diversity of the archaeal community was analysed with the MOTHUR package. We identified 14 OTUs at the 3% genetic distance level and found quite high diversity. Rarefaction curves of richness estimators and diversity indices demonstrated that our collection of isolates represented the archaeal community at Rambla Salada that can be isolated under the conditions used in this work. This is the first report to be published on the culturable archaea at Rambla Salada, an area of considerable ecological interest. PMID- 22219039 TI - Ethics of mitigation, adaptation and geoengineering. PMID- 22219040 TI - Meteorological factors and ambient bacterial levels in a subtropical urban environment. AB - We conducted a study to investigate the characteristics and determinants of ambient bacteria in Taipei, Taiwan from August 2004 to March 2005. We monitored ambient culturable bacteria in Shin-Jhuang City, an urban area in the Taipei metropolitan areas, using duplicate Burkard Portable Air Samplers with R2A agar. The average concentration of total bacteria was 1,986 colony-forming units per cubic meter of air (CFU/m(3)) (median = 780 CFU/m(3)) over the study period, with the highest level in autumn. Most bacterial taxa had similar seasonal variation, with higher concentrations in autumn and winter. During the study period, Gram negative rods and cocci were predominant. Multivariate analyses indicated that wind speed and wind direction significantly influenced ambient bacterial distribution. Temperature and relative humidity were also important environmental factors positively associated with ambient bacterial concentrations. We observed statistically significant relationships between ambient bacteria and air pollutants, including sulfur dioxide (SO(2)), ozone, particulate matter (aerodynamic diameter <=10 MUm (PM(10))), methane and total hydrocarbons. The concentrations of methane and total hydrocarbons during the previous day were positively associated with total bacteria and Gram negative rods, respectively. Ozone level on the previous day had a negative relationship with Gram negative cocci. SO(2) level with a 3-day lag was positively correlated with concentrations of both total bacteria and Gram negative cocci. In the future, more longitudinal studies are needed to confirm the relationships and possible mechanisms between ambient bacteria and meteorological factors, as well as to evaluate the ecological and health impacts of ambient bacteria. PMID- 22219041 TI - Genetic variation in a female genital trait evolved by sexual coevolution. AB - Understanding the patterns of genetic variation of traits subject to sexual selection is fundamental for explaining its evolutionary dynamics and potential for sexual coevolution. The signa of female Lepidoptera are sclerotized structures located on the inner surface of the genital receptacle that receives the spermatophore during copulation (the corpus bursae), whose main function is tearing the spermatophore envelope. Comparative data indicate that the evolution of signa has been influenced by sexually antagonistic coevolution with spermatophore envelopes. We looked for additive genetic variation in the size and shape of signa in females of the butterfly Callophrys xami (Lycaenidae) from two localities (BG and FC) in Mexico City. We also looked for genetic variation in female body size and in the size of corpus bursae. There were significant between population differences in female body size, signa width and three signa shape traits. We found significant extranuclear maternal effects in one component of signa shape in the BG population, and in body weight, signa length and in one uniform component of signa shape in the FC population. Extranuclear maternal contributions could permit the evolution of female adaptations even if these reduce male fitness. We found additive genetic variation in signa length and width only in one population (BG); heritability estimates were high: 0.96 and 0.8, respectively. The existence of additive genetic variation in signa size could be, at least in part, a result of relaxed sexually antagonistic selection pressures due to the low level of polyandry exhibited by this species. Our results imply that there is currently potential for further sexual coevolution in this trait. PMID- 22219042 TI - Focus in honor of Bela Paizs, recipient of the 2011 Biemann Medal. PMID- 22219043 TI - Disfavoring macrocycle b fragments by constraining torsional freedom: the "twisted" case of QWFGLM b6. AB - While recent studies have shown that for some peptides, such as oligoglycines and Leu-enkephalin, mid-sized b fragment ions exist as a mixture of oxazolone and macrocycle structures, other primary structure motifs, such as QWFGLM, are shown to exclusively give rise to macrocycle structures. The aim of this study was to determine if certain amino acid residues are capable of suppressing macrocycle formation in the corresponding b fragment. The residues proline and 4 aminomethylbenzoic acid (4AMBz) were chosen because of their intrinsic rigidity, in the expectation that limited torsional flexibility may impede "head-to-tail" macrocycle formation. The presence of oxazolone versus macrocycle b(6) fragment structures was validated by infrared multiple photon dissociation (IRMPD) spectroscopy, using the free electron laser FELIX. It is confirmed that proline disfavors macrocycle formation in the cases of QPWFGLM b(7) and in QPFGLM b(6). The 4AMBz substitution experiments show that merely QWFG(4AMBz)M b(6), with 4AMBz in the fifth position, exhibits a weak oxazolone band. This effect is likely ascribed to a stabilization of the oxazolone structure, due to an extended oxazolone ring-phenyl pi-electron system, not due to the rigidity of the 4AMBz residue. These results show that some primary structures have an intrinsic propensity to form macrocycle structures, which is difficult to disrupt, even using residues with limited torsional flexibility. PMID- 22219044 TI - Investigating the role of adducts in protein supercharging with sulfolane. AB - The supercharging effect of sulfolane on cytochrome c (cyt c) during electrospray ionization mass spectrometry (ESI-MS) in the absence of conformational effects was investigated. The addition of sulfolane on the order of 1 mM or greater to denaturing solutions of cyt c results in supercharging independent of protein concentration over the range of 0.1 to 10 MUM. While supercharging was observed in the positive mode, no change in the charge state distribution was observed in the negative mode, ruling out polarity-independent factors such as conformational changes or surface tension effects. A series of sulfolane adducts observed with increasing intensity concurrent with increasing charge state suggests that a direct interaction between sulfolane and the charged sites of cyt c plays an important role in supercharging. We propose that charge delocalization occurring through large-scale dipole reordering of the highly polar supercharging reagent reduces the electrostatic barrier for proximal charging along the cyt c amino acid chain. Supporting this claim, supercharging was shown to increase with increasing dipole moment for several supercharging reagents structurally related to sulfolane. PMID- 22219045 TI - Stimulation-induced decreases in the diffusion of extra-vascular water in the human visual cortex: a window in time and space on mechanisms of brain water transport and economy. AB - In a human magnetic resonance diffusion-weighted imaging (DWI) investigation at 3 T and high diffusion sensitivity weighting (b = 1,800 s/mm(2)), which emphasizes the contribution of water in the extra-vascular compartment and minimizes that of the vascular compartment, we observed that visual stimulation with a flashing checkerboard at 8 Hz for a period of 600 s in eight subjects resulted in significant increases in DWI signals (mean +2.70%, range +0.51 to 8.54%). The increases in DWI signals in activated areas of the visual cortex indicated that during stimulation, the apparent diffusion coefficient (ADC) of extra-vascular compartment water decreased. In response to continuous stimulation, DWI signals gradually increased from pre-stimulation controls, leveling off after 400-500 s. During recovery from stimulation, DWI signals gradually decreased, approaching control levels in 300-400 s. In this study, we show for the first time that the effects of visual stimulation on DWI signals in the human visual cortex are cumulative over an extended period of time. We propose that these relatively slow stimulation-induced changes in the ADC of water in the extra-vascular compartment are due to transient changes in the ratio of faster diffusing free water to slower diffusing bound water and reflect brain water transport processes between the vascular and extra-vascular compartments at the cellular level. The nature of these processes including possible roles of the putative glucose water import and N-acetylaspartate water export molecular water pumps in brain function are discussed. PMID- 22219046 TI - Signal transducer and activator of transcription 2 (STAT2) metabolism coupling postmitotic outgrowth to visual and sound perception network in human left cerebrum by biocomputation. AB - We constructed the high-expression signal transducer and activator of transcription 2 (STAT2) metabolism coupling postmitotic outgrowth to visual and sound perception network in human left cerebrum compared with low-expression (fold change >=2) chimpanzee left cerebrum in GEO data set by using integration of gene regulatory network inference method with gene ontology (GO) analysis of STAT2-activated up- and downstream network. Our result showed that upstream RECQL, PDIA2, ENOSF1, THBS4, RASGRP1, PER2, PDE8A, ORC2L, DCI, OGG1_2, SMA4, GPD1, etc. activated STAT2, and downstream STAT2-activated GSTM3_1, GOSR1, SH3BGR, OSBPL8, PHYH, SAPS2, C21orf33, PDIA2, TRAPPC6A, ENOSF1, CAMTA1, GTF2I_2, etc. in human left cerebrum. STAT2-activated network enhanced regulation of small GTPase-mediated signal transduction, regulation of transcription, regulation of mitosis, regulation of cell growth, positive regulation of phosphoinositide 3 kinase cascade, positive regulation of fat cell differentiation, negative regulation of DNA replication, negative regulation of progression through cell cycle, cyclic nucleotide metabolism, lipid metabolism, carbohydrate metabolism, vitamin A metabolism, N-acetylglucosamine metabolism, UDP-N-acetylgalactosamine metabolism, fatty acid transport, intracellular protein transport, vesicle mediated transport, lipid transport, retrograde transport, Ras protein signal transduction, Wnt receptor signaling pathway, nervous system development, cell extension, cell adhesion, cell differentiation, circadian rhythm, generation of precursor metabolites and energy, establishment of blood-nerve barrier, visual perception, sensory perception of sound, and poly-N-acetyllactosamine biosynthesis, as a result of inducing metabolism coupling postmitotic outgrowth to visual and sound perception in human left cerebrum. PMID- 22219047 TI - A rare case of cementoblastoma associated with the primary dentition. AB - BACKGROUND: Cementoblastoma is a rare odontogenic tumor with few cases reported in the literature involving deciduous teeth. CASE REPORT: A painful intraoral swelling in a young girl close to a primary mandibular first molar presented as a well-defined radiopaque mass attached to the tooth root. After enucleation and histopathological analysis the final diagnosis was cementoblastoma. DISCUSSION: This case highlights the relevance of cementoblastoma to dentists and maxillofacial surgeons, since this condition may mimic other intra-osseous maxillary lesions and require patient-specific treatment. PMID- 22219048 TI - A distinct regulatory role of Th17 cytokines IL-17A and IL-17F in chemokine secretion from lung microvascular endothelial cells. AB - Th17 cytokines IL-17A and IL-17F play a critical role in the activation and recruitment of neutrophils at airway inflammation mainly through the induction of CXC chemokines in the lungs. Vascular endothelial cells belong to the category of major CXC chemokine-producing cells. However, until now, the precise role of Th17 cytokines in CXC chemokine secretion in lung microvascular endothelial cells (LMVECs) has not been fully elucidated. In this study, we examined the biological effects of Th17 cytokines IL-17A and IL-17F on CXCL1, CXCL5, and CXCL8 release in LMVECs. Both IL-17 receptor A (IL-17RA) and IL-17RC are expressed on the surface of LMVECs. In contrast to IL-17F, IL-17A significantly upregulated CXCL1 mRNA expression and protein release, whereas both IL-17A and IL-17F did not have the ability to induce CXCL5 and CXCL8 secretion in LMVECs. IL-17A and IL-17F displayed positive regulatory effects on IL-1beta-induced CXCL1, CXCL5, and CXCL8 secretion. On the other hand, IL-17A enhanced the upregulating effect of TNF alpha on CXCL1, CXCL5, and CXCL8 release, whereas IL-17F had a negative regulatory effect on TNF-alpha-mediated secretion. Th2 cytokines IL-4 and IL-13 showed an inhibitory effect on IL-1beta plus IL-17A-induced CXCL1, CXCL5, and CXCL8 secretion, but displayed a positive regulatory effect on TNF-alpha plus IL 17A-induced secretion. These results provide evidence that Th17 cytokines IL-17A and IL-17F have a distinct regulatory role in CXCL1, CXCL5, and CXCL8 expression in LMVECs stimulated either with IL-1beta or with TNF-alpha. Our findings also suggest that CXC chemokine secretion in LMVECs may be complicatedly regulated by Th17 cytokines, Th2 cytokines, and macrophage-associated cytokines in pathological conditions such as bronchial asthma. PMID- 22219049 TI - The effects of the combination of sodium ferulate and oxymatrine on lipopolysaccharide-induced acute lung injury in mice. AB - In our previous study, the remarkable analgesic and anti-inflammatory effects of the combination of sodium ferulate (SF) and oxymatrine (OMT) had been found. In this study, we investigated the effect of the combination of SF and OMT on acute lung injury using lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The cell counting and the protein concentration in the bronchoalveolar lavage fluid (BALF) were measured. The animal lung edema degree was evaluated by wet/dry weight (W/D) ratio. The superoxidase dismutase (SOD) activity and myeloperoxidase (MPO) activity was assayed by SOD and MPO kits, respectively. The levels of inflammatory mediators including C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-alpha) were assayed by enzyme-linked immunosorbent assay method. The data showed that treatment with the combination of SF and OMT markedly attenuated inflammatory cell numbers and protein concentration in the BALF and improved SOD activity and inhibited MPO activity compared to LPS group. Moreover, the combination significantly inhibited the production of CRP and TNF alpha in lung homogenate. The histological changes of the lungs were also more significantly improved by the combination. At the same dose, the obvious protective effect was not found in SF or OMT-treated alone group except that the protein concentration slightly decreased in SF group. The results indicated that the combination SF and OMT had a protective effect on LPS-induced ALI in mice, and the effect was much better than that of SF or OMT used alone. PMID- 22219051 TI - International occupational health hazards research. Introduction. PMID- 22219050 TI - The involvement of the CD40-CD40L pathway in activated platelet-induced changes in HUVEC COX-2 and PPARalpha expression. AB - We aim to determine the extent of the CD40-CD40L pathway involvement in activated platelet-induced changes in human umbilical endothelial cells (HUVECs). Activated platelets were co-incubated with HUVECs in the presence or absence of CD40LmAb. HUVECs were also directly stimulated with rhCD40L. HUVEC endothelial cyclooxygenase 2 (COX-2) and peroxisome proliferator-activated receptor alpha (PPARalpha) expression was then assessed. To estimate COX-2 activity, PGE2 concentration was determined. PPARalpha activity was assessed using a nuclear factor activity kit. Co-incubation with activated platelets increased HUVEC COX-2 and PPARalpha mRNA expression (P < 0.01). The addition of CD40L mAb significantly attenuated these increases in mRNA and protein (both P < 0.01). Direct stimulation by rhCD40L increased HUVEC COX-2 mRNA and protein (P < 0.05) but did not significantly change the expression of PPARalpha mRNA and protein. CD40LmAb significantly decreased (P < 0.05) and rhCD40L significantly (P < 0.01) increased COX-2 enzymatic activity, but had almost no effects on PPARalpha binding activity. Activated platelets may increase HUVEC COX-2 expression and activity partly through the CD40-CD40L pathway. PMID- 22219052 TI - Environmental asbestos pollution -- situation in Poland. AB - OBJECTIVES: Environmental exposure of the general population to asbestos in Poland is mainly due to degradation of very popular asbestos-cement products and the resultant release of the elementary asbestos fibres into the ambient air. Assessments of environmental pollution by asbestos were based on the volume of the raw material used, amount of manufactured asbestos products, and measuring the concentration of fibres in the air. MATERIAL AND METHODS: Under the governmental program intended to remove asbestos, measurements of the concentration of asbestos fibres were performed in 2004-2010 in all provinces of Poland. Considering that potential sources of asbestos dust emissions were present in residential areas, 1634 sampling sites were designated. From 2 to 4 air samples were collected at each sampling site. A total of 5962 samples were collected during seven years. A single dose of air collected by 25 mm 0.8 MUm pore Sartorius filter was 1,300 litres. The fibres were counted using optical microscopy with phase contrast (PCM) on a polarizing microscope (PLM) at a total magnification of 600*.; method was adapted to determine the concentration of asbestos fibres in non-occupational environment. RESULTS: Mean concentration of asbestos fibres was 492 f/m(3) (95% CI: 467-518). In 82% of the sampling sites, the mean concentrations did not exceed 800 f/m(3). As much as 25.8% of the samples were found to be below the detection limit of the method. Estimated mean concentrations of fibres in different provinces ranged from 146 (95% CI: 106-203) to 709 f/m(3) (95% CI: 591-851). In the areas affected by former asbestos processing plants, mean concentration was 732 f/m(3) (95% CI: 527-1016) and was significantly higher than levels recorded in other areas of Poland. CONCLUSION: Asbestos consumption per capita and the recorded moderate levels of asbestos fibres concentration in atmospheric air point to a relatively low level of environmental asbestos pollution in Poland. PMID- 22219053 TI - Metabolic syndrome in collection and disposal of solid waste sector. AB - OBJECTIVES: This study aims to assess the frequency and factors relevant to metabolic syndrome in workers employed in the collection and disposal of solid waste sector. MATERIALS AND METHODS: This cross-sectional study was conducted in the major solid waste collecting and disposal company named ISTAC AS (Istanbul Environmental Protection and Waste Processing Corporation) in Istanbul, Turkey. All 715 male employees of the company were included in the study without sampling. The study was completed with 619 subjects. Since it was a small group, female workers were not taken into account in the study. Metabolic syndrome frequency was investigated according to the NCEP-ATP III criteria including the levels of systolic and diastolic blood pressure, waist perimeter, HDL, triglyceride, fasting blood glucose values. RESULTS: Metabolic syndrome was present in 40.9% of participating employees. Metabolic syndrome was more common in those working in the excavation field (54.0%), such as caterpillar operators (56.5%), and less common in employees working in administrative offices, such as office staff or managers, who were under 35 years old and who had been working for less than 10 years (p < 0.05). Employees working in work stations other than administrative offices had a 2.60 times higher risk compared to those working in administrative offices. CONCLUSIONS: Metabolic syndrome may be related to work station, job, age and period worked by the subjects. PMID- 22219054 TI - High incidence of acute leukemia in the proximity of some industrial facilities in El Bierzo, northwestern Spain. AB - OBJECTIVES: To estimate the incidence of acute leukemia (AL) in El Bierzo (BZ) and to carry out a cross-association analysis in order to suggest some etiological clues. MATERIALS AND METHODS: We registered all new AL cases diagnosed 2000-2005. Annual standardized incidence rate (SIR) was calculated by the direct method. A cross-association analysis was performed by non-parametric methods and we checked the potential interaction between putative etiological factors by calculating Chi-square-for-trend. RESULTS: SIR was 5.1 cases per 100 000, surpassing the Spanish, European and world average figures and heterogeneous throughout the region. We detected a negative correlation between acute myeloblastic leukemia (AML) SIR in every municipality and both the air distance to the nearest thermoelectric power plant (TPP) (Rho = -0.409; p = 0.01) and to the point of maximum density of the high-power lines (HPL) network (Rho = -0.329; p = 0.04). Accordingly, SIR was higher in the municipalities situated < 7.5 km away from TPP (9.58 vs. 1.72; p = 0.004) or < 10 km away from HPL (3.90 vs. 3.19; p = 0.045). A positive relation between both factors was observed (Chi-square-for trend = 9.209; p = 0.006). CONCLUSIONS: SIR of AL in BZ is higher than the Spanish average and that of most countries in the world. Residing near TPP or HPL confers a higher risk of AML, with synergistic effect between both factors. PMID- 22219055 TI - Subjective complaints of people living near mobile phone base stations in Poland. AB - OBJECTIVES: The aim of our study was to assess the health conditions and subjective symptoms of the inhabitants living in the base stations vicinity and to analyse the relationship between the complaints and level of exposure to electromagnetic fields (EMF). MATERIALS AND METHODS: Our study was performed in housing estates located in five regions of Lodz. The electric field measurements were performed in the buildings located closest to the azimuth of the antennas. Respondents were selected by trained interviewers using an uniform procedure. The number of the households to be examined was set at a minimum of 420. The questionnaire contained: demographic data, occupational and environmental exposure to EMF, health condition, subjective complaints. Results were adjusted for confounders (age, gender, EMF at the workplace and EMF emitted by household equipment) using multiple regression model. RESULTS: 181 men and 319 women from 500 households were examined. Electric field above 0.8 V/m was recorded in 12% of flats. There was no significant correlation between electric field strength and the distance of examined flats from the base stations. To make possible comparison with relevant literature, we analysed also the frequency of the reported symptoms vs. the distance. Headache was declared by 57% people, most frequently (36.4%) living 100-150 m away from the base station compared to people living at longer distances (p = 0.013). 24.4% subjects, mostly living at a distance above 150 m, declared impaired memory. Difference was statistically significant in comparison with people living at other distances (p = 0.004). CONCLUSIONS: The explanation why we did not find any correlation between the electric field strength and frequency of subjective symptoms but found a correlation between subjective symptoms and distance from base station needs further studies. Maybe new metrics of exposure assessment should be adopted for this purpose. PMID- 22219056 TI - Prevalence, characteristics, and work-related risk factors of low back pain among hospital nurses in Taiwan: a cross-sectional survey. AB - BACKGROUND: Low back pain is a common health problem among hospital nurses. However, the prevalence, characteristics, and work-related risk factors of low back pain have not been widely investigated in Taiwan. MATERIALS AND METHODS: This study used a cross-sectional survey of 217 hospital nurses to gather self reported information on the prevalence of back pain, demographic and pain characteristics, and work-related risk factors from 178 respondents who indicated a past history of back pain. The association between the characteristics of back pain and work-related risk factors was also examined. RESULTS: The lifetime prevalence of back pain was 82.03%, and the point prevalence of back pain was 43.78%. The mean pain score is 41.67. The number of years at work was significantly associated with the pain score for an individual's most recent episode of back pain, the extent of bothersomeness of back pain and leg pain, and the extent to which back pain interfered with normal work. CONCLUSION: Back pain is common among hospital nurses in Taiwan. Years at work are significantly associated with pain severity and disability caused by back pain. PMID- 22219057 TI - Job satisfaction of occupational medicine nurses in Poland. AB - OBJECTIVES: The study aimed at assessment of the Polish occupational medicine service system after over ten years of functioning in the current shape, made by occupational nurses. The article focuses on the job satisfaction level among Polish occupational medicine nurses. MATERIALS AND METHODS: The survey was performed among 600 randomly selected occupational medicine nurses, registered in the regional occupational medicine centers. A questionnaire, designed by the research team, containing several questions concerning different aspects of OMS system assessment, including a part dedicated to job satisfaction assessment, was sent to the selected occupational nurses. The response rate was 33.3% (200 questionnaires). RESULTS: The survey shows a relatively high satisfaction level in case of five out of eleven investigated job aspects, and a very low satisfaction level in case of two of them ("Possibility of professional promotion", "Salary"). 26% of the OMS nurses had considered going abroad to work as a nurse in the general health care system, and 17% in the OHS system. Almost 25% of them would not choose a profession of an occupational nurse once again, including 10% who would not choose a nurse job at all. There is a statistically significant correlation between the general job satisfaction and satisfaction with other aspects of nursing work. A strong correlation was observed in case of "Scope of performed tasks" and "Cooperation with employers (clients of the occupational medicine service units)". There is a statistically significant correlation of average strength between the decision concerning choosing an occupational nurse job in case of taking a decision on professional carrier once again and "General job satisfaction". CONCLUSION: Polish occupational nurses are satisfied with their job, however only 26% are fully satisfied. In their work there is place for improvement. The areas which definitely need attention and improvement are "Possibility of professional promotion" and "Salary". Improvements in cooperation between occupational nurses and physicians can make it close to the best practice. PMID- 22219058 TI - Electronystagmography versus videonystagmography in diagnosis of vertigo. AB - OBJECTIVES: Vertigo is a very common symptom mainly caused by the lesion of vestibular system (peripheral or central) and often accompanied by some work related diseases and occupational intoxications. The aim of this study was to assess the value of electronystagmography (ENG) and videonystagmography (VNG) for diagnosing vertigo of various origin. MATERIALS AND METHODS: The study included four groups, 25 subjects each, of patients suffering from vestibular disorders of peripheral, central and mixed origin versus healthy controls. All were examined by means of ENG and VNG, using the bithermal caloric test with 30 degrees C and 44 degrees C air irrigations of the ears. The findings (frequency of induced nystagmus FRQ, its slow phase velocity SPV, canal paresis CP, directional preponderance DP, vestibular excitability VE) were analysed and compared. RESULTS: In all patients with vertigo due to vestibular neuritis, barotrauma and kinetosis, significant CP, the important sign of peripheral site of vestibular lesion was identified both in ENG and VNG. None of the patients with central origin disorders showed CP in VNG; in the majority of cases DP was observed. However, in ENG we found CP in 5 patients with central origin disorders. There were no essential differences between ENG and VNG in measurements of FRQ and SPV except for higher values in VNG in controls and patients with mixed vertigo. CONCLUSIONS: The results suggest that the VNG should be recommended in preference as the valuable method to assess vertigo and to discriminate between the peripheral and the central vestibular lesions. PMID- 22219059 TI - Determinants of heavy smoking: results from the global adult tobacco survey in Poland (2009-2010). AB - OBJECTIVE: The aim of current analysis was to identify socio-demographic correlates of heavy smoking. MATERIALS AND METHODS: Global Adult Tobacco Survey (GATS), a nationally representative household study was implemented in Poland between 2009 and 2010. We used data on representative sample of 1915 adults, age 25 years and older. The Odds Ratios (OR) and 95% Confidence Intervals (CI) for heavy smoking to the broad number of variables including age, age at smoking onset, education, occupational classification, living conditions, place of residence, place of residence at age about 14 years, awareness of smoking health consequences were tested in logistic regression model. RESULTS: Among daily smokers the rate of heavy smokers was 63% in males and 45% in females (p < 0.001). The present study indicated that three characteristics: age, early age at smoking onset and lack of awareness of smoking health consequences were significantly associated with heavy smoking among both genders. Significantly higher risk of heavy smoking was observed among the 50-59 years of age population compared to the youngest group. The heavy smoking rate was highest among males who started smoking under age 14 years (OR = 3.1; 95% CI: 1.4-6.7; p < 0.001) and females that started smoking at age 14-17 years (OR = 2.3; 95% CI: 1.5-3.5; p < 0.0001) compared to those who started smoking at age 21 years or older. Heavy smoking was significantly correlated to lack of awareness of adverse health consequences of smoking (OR = 1.5; 95% CI: 1.1-2.03; p < 0.01 and OR = 1.5; 95% CI: 1.0-2.2; p < 0.01 for men and women, respectively) compared to aware respondents. CONCLUSIONS: These outcomes should be taken into account while developing tobacco control measures. Among other things, educational interventions to increase knowledge of adverse tobacco health effects should be widely implemented. PMID- 22219060 TI - Effect of a specific exercise program on the strength and resistance levels of lumbar muscles in warehouse workers. AB - OBJECTIVE: The aim of this study was to verify the influence of a specific exercise program on the strength and resistance levels of lumbar flexors and extensors in warehouse workers. MATERIALS AND METHODS: The population used in this randomized controlled trial included 557 warehouse male workers from a food distribution company in Oporto/Portugal. Upon the application of the selection criteria, 98 workers deemed eligible were randomized in two groups: 57 were assigned to the intervention group and 41 to the control group. The intervention included 9 easily-executed exercises to promote stretching and strengthening of the lumbar region, to be executed daily, at the beginning of the working time, at the company facilities and lasting 8'. Trunk muscles' voluntary strength and resistance were measured using an isometric electronic dynamometer (Globus Ergometer, Globus, Codigne, Italy) at baseline and eleven months after implementing the exercise program. The data was analyzed using SPSS(r), version 17.0. RESULTS: After implementation of the exercise program, in the intervention group, all variables increased, significant differences were observed as for the muscle strength and resistance values (p = 0.014 and p = 0.006, respectively), as well as in the ratio extensors/flexors (p = 0.037). In the control group, all variables decreased, with a statistically significant decrease of the trunk flexors strength level (p = 0.009). CONCLUSION: The results of this study suggest that a specific exercise intervention program can increase trunk extensors strength and resistance. PMID- 22219061 TI - Dentist-patient communication as perceived by patients in Riyadh, Saudi Arabia. AB - OBJECTIVES: The aim of this study was to assess patient-dentist communication and to evaluate the factors affecting it among Saudi patients and its effect on satisfaction. MATERIALS AND METHODS: A self-administered questionnaire was designed for this survey with 5-scale Likert-type statements. RESULTS: Patients' main concern was the courtesy followed by information interaction, moral support, explaining the procedure and understanding of the patient's feelings. These were the factors that contributed positively to good communication and satisfaction. CONCLUSION: It could be concluded that Saudi dentist possess a satisfactory ability to communicate with their patients. PMID- 22219062 TI - Menometrorrhagia in magnetic resonance imaging operators with copper intrauterine contraceptive devices (IUDS): a case report. AB - The paper describes the cases of 3 female health operators with implanted copper IUDs, developing menometrorrhagia some months after an increase of the working time in a Magnetic Resonance Imaging (MRI) Unit (1.5 T), that progressively disappeared when the previous organization, involving discontinuous work shifts at MRI, was re-established. No known factors possibly related to menometrorrhagia were evidenced in the 3 operators, supporting the hypothesis of a role of the exposure to the electromagnetic fields (EMF) induced by the MRI system in symptoms induction. The possible mechanism remains unsettled, but menometrorrhagia might be triggered by a phlogistic stimulus caused by EMF, possibly the low-frequency currents induced in the wires of the IUD during the movements of the operator inside the static magnetic field generated by the MRI permanent magnet. Until now, the problem of possible interactions between copper IUDs and EMF induced by MRI has been considered in patients undergoing imaging, but the possible risk in MRI Units operators has been largely neglected. To our knowledge, the occurrence of menometrorrhagia is not routinely checked in health surveillance of MRI operators, so these symptoms can pass unnoticed, especially if they are transitory. Therefore, underreporting is rather possible. The cases described here support the need for further research on this topic, especially considering the progressive diffusion of more powerful MRI scanners (3 T and more), and of the interventional magnetic resonance imaging, both potentially involving higher EMF exposures, and a large number of MRI female operators, possibly using IUDs. The possibility that MRI operators with implanted metallic IUDs can be included in the group of "workers at particular risk" according to the EU Directive 2004/40/EC should be considered. PMID- 22219063 TI - Training a new generation of breast surgeons: are we succeeding? AB - BACKGROUND: Society of Surgical Oncology (SSO)-approved fellowships in Breast Oncology began training fellows in 2004. Here we ascertain methods of evaluating and improving the fellowship experience through fellowship alumni experience. METHODS: We conducted an electronic survey of fellowship graduates to learn perceived successes and weaknesses of their fellowship training, as well as their current practice experiences. Our electronic survey focused on their preparedness for practice, their job opportunities, and their use of image-guided biopsies in practice. RESULTS: Between 2005 and 2009, 142 fellows graduated and received our survey; 85 (60%) responded. Although 98% of graduates though that they were well prepared by their fellowship for performing breast cancer surgery, fewer thought that they were well prepared to perform oncoplastic techniques (53%), ultrasound (39%), and ultrasound-guided biopsies (28%). Nevertheless, many acquired additional training, and 63% were performing ultrasound-guided biopsies in practice. The majority (76%) were performing breast surgery exclusively, with 14% identifying themselves as director of a breast center and only 29% describing themselves as being in private practice-the rest being employed at a hospital or university. Only 8% of respondents were disappointed with the job market, and 67% stated they had received at least three job offers; 82% were satisfied in their current job. CONCLUSIONS: SSO breast oncology fellowships appear to be training confident, well-prepared graduates with good job outlooks, and many are achieving leadership positions. Deficiencies in sonography training, some advanced surgical techniques, and administrative experiences should be addressed by program directors as graduates do perceive the need for such training. PMID- 22219065 TI - Prognostic factors for locoregional recurrences in colon cancer. AB - BACKGROUND: There is increased interest in locoregional recurrences of rectal cancer. Despite comparable locoregional recurrence rates in colon cancer, only a few studies on locoregional recurrences among colon cancer patients have been published. This study was designed to identify prognostic factors for locoregional recurrences among patients with colon cancer in the Netherlands. METHODS: The study population was composed of patients who underwent radical surgical resections for invasive colon carcinoma, diagnosed in three regions of the Netherlands from 2000 to 2003. The Kaplan-Meier method was used to calculate 5-year locoregional recurrence rates (LRR). Conditional hazard rates were estimated by the life-table method. Multivariate Cox regression analyses were performed to identify prognostic factors and to calculate a Locoregional Recurrence Risk Score (LRRS). RESULTS: In total 127 of 2,282 patients developed locoregional recurrences within 5 years (LRR 6.4%). The risk of developing a locoregional recurrence was highest at 0.5-1 year after surgery. Patients with left-sided tumors, T3-T4 tumors, and positive lymph nodes and those who did not receive adjuvant chemotherapy were more likely to develop locoregional recurrences. Four risk groups based on the LRRS were defined. Five-year LRR was 2.5% for the very low-risk group and 25.1% for the high-risk group. CONCLUSIONS: Although the locoregional recurrence rate in this study was relatively low, it remains a considerable problem. Identifying individual patients who might benefit from adjuvant chemotherapy may reduce the locoregional recurrence rate. PMID- 22219064 TI - Combination of haptoglobin and osteopontin could predict colorectal cancer hepatic metastasis. AB - PURPOSE: This study aimed to identify novel molecular markers for the early detection of colorectal cancer liver metastasis. METHODS: Genes related to hepatic metastasis were screened from the Oncomine database. The candidate markers were tested by immunohistochemistry, and their predictive accuracy was assessed by the cross-validation method and an independent test set. RESULTS: We got three datasets containing 2,973 genes that were highly expressed in primary colon cancer tissues compared with non-metastatic colon cancer tissues and identified 7 candidate molecules for immunohistochemical validation. A total of 213 colorectal cancer samples were randomly divided into a training set (113 cases) and a blind testing set (100 cases). In the training set, immunohistochemical analysis showed that HP, OPN, and PTGIS expression were significantly higher in the hepatic metastasis group than in the non-metastasis group. Logistic regression analysis showed that HP and OPN levels in primary tumors and lymph node metastasis status were the only significant (P<0.05) parameters for detecting liver metastasis. The predictive accuracy of markers was assessed by the cross-validation method and an independent test set. In leave-one out cross-validation, the two markers combined with clinicopathologic features resulted in 91.2% sensitivity and 96.4% specificity for hepatic metastasis detection. In an independent test set, the combination achieved 94.5% sensitivity and 88.9% specificity for predicting the hepatic metastasis of colorectal cancer. CONCLUSIONS: Our results suggest that combined HP and OPN expression levels are significantly related to liver metastasis and prognosis, and, if this is validated, they could be used as accurate predictors of liver metastasis in colorectal cancer. PMID- 22219066 TI - Evolution of long-term outcome of liver resection for colorectal metastases: analysis of actual 5-year survival rates over two decades. AB - BACKGROUND: Liver resection (LR) is the only potentially curative treatment of colorectal liver metastases (CRLM). Its outcome over the past 2 decades was studied using actual 5-year survival rates. METHODS: Data of 393 consecutive patients who underwent LR for CRLM at Mauriziano Umberto I (Turin) until June 2005 were analyzed. Excluding R2 resections (n = 4) or incomplete 5-year follow up (n = 13), 376 patients were divided according to LR date into groups A (before 1995: 90 patients), B (1995-2000: 94 patients), C (2001-2005: 192). RESULTS: Group C presented increased multiple and bilobar metastases compared with combined group A and B (C vs AB: 54.7% vs 40.2%, P = 0.005; 28.1% vs 19.0%, P = 0.038, respectively), decreased metastases diameter (C vs AB: 32 vs 40 mm, P = 0.0001). The 5-year overall survival, calculated excluding 4 operative mortalities (group AB), increased over the years (A, 20.5%; B, 32.6%; C, 46.4%; P < 0.0001). Early recurrences (1 year) were not decreased, extrahepatic recurrences even increased (C vs AB: 17.2% vs 8.6%, P = 0.015). Recurrence-free 5 year survival improved (C vs AB: 23.4% vs 13.9%, P = 0.019) linked to decreased liver recurrences (C vs AB: 26.8% vs 37.4%, P = 0.023). Resection rate (59% overall for liver recurrence) increased along with 5-year survival after recurrence (A, 4.0%; B, 14.2%; C, 21.4%; P < 0.0001). Survival improvement was confirmed for multiple (P = 0.003) and synchronous metastases (P = 0.008), N+ tumors (P = 0.005), and in patients without chemotherapy (P = 0.001). CONCLUSIONS: Long-term outcome of LR for CRLM improved over 20 years, even in patients with negative prognostic factors, linked to hepatic recurrences reduction and increased survival after recurrence. PMID- 22219068 TI - Long-term outcome of isolated limb perfusion in advanced soft tissue sarcoma of the extremity. AB - BACKGROUND: Isolated limb perfusion with tumor necrosis factor alpha and melphalan (TM-ILP) has proven to be a successful option in treating advanced soft tissue sarcomas (STS), where amputation otherwise is needed to achieve safe surgical margins. METHODS: From 2000 to 2009, 54 patients with locally advanced STS, who all were candidates for amputation, were treated with totally 57 TM-ILP procedures and then followed prospectively. The median follow-up time was 30 months. Median tumor size was 10 cm, and 94% of the patients had high-grade tumors. RESULTS: The clinical overall response after TM-ILP was 71% (including 21% CR), and 60% of the patients underwent resection of the tumor remnant after a median of 2 months. The histopathologic response rate in the resected specimens was 76%. Local recurrence/progress occurred in 37% of the patients after a median of 7 months. Thirteen patients finally underwent amputation after a median of 11 months, giving a long-term limb salvage of 76%. CONCLUSIONS: TM-ILP of advanced soft tissue sarcoma of the extremities makes limb-sparing surgery possible in a high proportion of patients. PMID- 22219067 TI - UHRF1 promotes cell growth and metastasis through repression of p16(ink4a) in colorectal cancer. AB - PURPOSE: To investigate whether ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) expression is upregulated in colorectal cancer (CRC), whether UHRF1 promotes CRC cell growth and migration and the underlying molecular mechanism. METHODS: UHRF1 protein expression was determined in 144 pairs of primary CRC and their corresponding adjacent nontumor tissues by immunohistochemistry with tissue microarrays. UHRF1 mRNA expression was assessed in 20 pairs of the above tissues and four colon cancer cell lines by quantitative reverse transcriptase-polymerase chain reaction. Associations of UHRF1 expression with demographic and clinicopathologic features were determined. Additionally, the effects of lentiviral-mediated RNA interference (RNAi) of UHRF1 on cell proliferation and migration, cell cycle and apoptosis, and the expression of p16(ink4a) and p21(waf1/cip1) were investigated in CRC cell lines. RESULTS: UHRF1 was overexpressed in CRC tissues and cell lines. UHRF1 protein expression levels correlated with the presence of lymph nodes (P = 0.005), distal metastasis (P = 0.030), poor Dukes staging (P = 0.001), and absence of p16(ink4a) expression (P = 0.002). RNAi of UHRF1 inhibited proliferation and migration, and induced apoptosis and cell cycle arrest at the G0/G1 phase. Furthermore, RNAi of UHRF1 enhanced the expression of p16(ink4a), but not p21(waf1/cip1), in CRC cells. CONCLUSIONS: UHRF1 expression is upregulated in CRC and is associated with the progression of CRC. Moreover, RNAi of UHRF1 decreases proliferation and migration but enhances apoptosis of CRC cells, with increased p16(ink4a) expression. UHRF1 promotes CRC growth and metastasis, likely by repressing p16(ink4a), and thus it may be used as a biomarker or even a therapeutic target for CRC. PMID- 22219069 TI - [Bleeding from the anus]. PMID- 22219071 TI - [Quality control of the rheumatological interdisciplinary pain-consultation]. AB - The Rheumatologic Interdisciplinary pain assessment (RIPA) was evaluated for the time period between February 2002 and December 2005 by Scascighini and Sprott in 2007. The objective behind this quality control (performed for the time period from January 2006 through June 2010) was to analyse differences between employed and unemployed patients. Patients were interviewed in a longitudinal profile with a follow-up of three months after the interdisciplinarian evaluation (including medical, physio/occupational therapy as well as psychological evaluations). Client management for the group of currently unemployed persons was simplified for 63.8% of referring doctors following these consultations hours. With the group of currently employed persons it even facilitated client management for 79.2% of referring doctors, subsequent to consultation hours. 92.5% of these referring doctors would recommend the RIPA to colleagues and interested parties. PMID- 22219072 TI - [Highlights in gastroenterology 2011]. AB - "Gastro-Highlights", an annual symposium dedicated to continuing education, took place at the University Hospital Zurich for the sixteenth time this autumn. In this well-attended event, major new findings in the fields of gastroenterology and hepatology that were published in the past year or recently presented at the "Digestive Disease Week (DDW)" were summarized for practising gastroenterologists and internists. PMID- 22219073 TI - [Therapy of chronic hepatitis B and C virus infections in the clinical practice]. AB - Approximately 550 million people worldwide are chronically infected with hepatitis B (HBV) or hepatitis C (HCV) virus. The clinical course of HBV and HCV infection is variable and can lead to a chronic but mild hepatitis or to liver cirrhosis and hepatocellular carcinoma (HCC)1. Therefore, antiviral therapy should be considered in patients with chronic hepatitis to prevent progression of disease. Here, we review the current indications and guidelines for antiviral therapy in chronic HBV and HCV infection. PMID- 22219075 TI - [Diagnosis of secondary etiologies of osteoporosis]. PMID- 22219074 TI - [Ischemic stroke and TIA]. AB - Ischemic stroke is an important disease with high morbidity and mortality. Systemic fibrinolysis is well studied and has become the accepted international standard of acute therapy. Intraarterial lysis and intravascular mechanical treatment options are becoming increasingly important. The time window for acute therapies is limited to a few hours after the onset of symptoms. A substantial proportion of stroke is preceeded by a transient ischemic attack (TIA). The immediate identification of the cause of such a TIA and initiation of treatment can prevent as much as 80% of subsequent strokes. Recent clinical trials attempt to treat more patients with more individualized strategies. PMID- 22219076 TI - [To start eating again could be dangerous]. AB - A 36-year-old woman with anorexia nervosa and resulting malnutrition decided to change her life and eat properly. One day after the refeeding start, instead of feeling better she felt much worse: fatigue, nausea and leg swelling occurred. She consulted our emergency department. A "refeeding syndrome" has been diagnosed. In this case report we discuss causes, clinical presentation and treatment of this illness. The aim is to make practitians aware about the existing of this disease even with oral refeeding. Warning signs have to be interpreted correctly in order to avoid dramatic consequences. PMID- 22219078 TI - [Caffeine consumption in women may reduce the risk of depression]. PMID- 22219077 TI - [Risk of adenocarcinoma in patients with Barrett esophagus is significantly less than previously assumed]. PMID- 22219083 TI - Oocyte cryopreservation in a patient with sickle cell disease prior to hematopoietic stem cell transplantation: first report. AB - PURPOSE: To report the first occurrence of successful ovarian stimulation, oocyte retrieval and oocyte cryopreservation for fertility preservation in an adolescent with severe sickle cell disease scheduled to undergo a hematopoietic stem cell transplant METHODS: Case report. RESULTS: A 19 year old female with severe sickle cell disease presented for fertility preservation counseling prior to hematopoietic stem cell transplantation. She ultimately underwent ovarian stimulation using a minimal stimulation GnRH antagonist protocol resulting in the successful banking of oocytes prior to transplant. The unique hazards associated with ovarian stimulation in patients with sickle cell disease, such as thrombosis and vaso-occlusive events, are discussed and the methods undertaken to minimize these risks are described. CONCLUSIONS: Controlled ovarian hyperstimulation and oocyte banking for fertility preservation is feasible in young women with sickle cell disease requiring hematopoietic stem cell transplant and deserves further investigation. Given the elevated risk of thrombosis and predisposition to painful vaso-occlusive events, controlled ovarian hyperstimulation in patients with sickle cell disease is not straightforward and requires a multi-disciplinary team approach to adequately address and minimize the risks in this unique patient population. PMID- 22219084 TI - Is there association between handedness and radiosensitivity in breast cancer women? AB - Radiosensitivity is a biological response to radiation. This response depends on many factors such as radiation factors as well as biological system factors. It is shown that identical doses of radiation for the treatment of Cancer patients produce different biological responses that are assumed to be depend on different specifications of the biological systems. However, by elimination of these factors, people may still show different biological responses such as acute and low responses to radiotherapy in similar doses of radiation. Some reports indicate that breast cancer, immune diseases including autoimmune diseases such as lupus, Myasthenia Gravies and even the rate of allergy are more frequent in left-handed compared to right-handed individuals. The main goal of the present study is determination of radiosensitivity in left-handed compared to right handed in breast cancer women by cytogenetic assay. Peripheral venous blood samples (10 ml) of 30 breast cancer women (10 left- and 20 right-handed) were divided into two identical parts. One part is exposed to 2 Gy Co-60 gamma rays, and the second part is considered as non-exposed controls. Lymphocytes were cultured in standard media, and cytokinesis blocked to score micronuclei in bi nucleated cells. The frequency of micronuclei in 1,000 cells in each sample is considered as the rate of radiosensitivity and was compared in left- and right handed breast cancer women by appropriate statistical analysis. Results showed that radiosensitivity index in left-handers is higher than right-handers also mean frequency of MN in exposed group of left-handers compare to right-handers is elevated. It seems that left-handed breast cancer women are more radiosensitive than right-handed. More investigations on right- and left-handed healthy people are ongoing in our laboratory. PMID- 22219085 TI - Assessing population-level variation in the mitochondrial genome of Euphausia superba using 454 next-generation sequencing. AB - The Antarctic krill (Euphausia superba Dana 1852) is widely distributed throughout the Southern Ocean, where it provides a key link between primary producers and upper trophic levels and supports a major commercial fishery. Despite its ecological and commercial importance, genetic population structure of the Antarctic krill remains poorly described. In an attempt to illuminate genetic markers for future population and phylogenetic analysis, five E. superba mitogenomes, from samples collected west of the Antarctic Peninsula, were sequenced using new 454 next-generation sequencing techniques. The sequences, of lengths between 13,310 and 13,326 base pairs, were then analyzed in the context of two previously-published near-complete sequences. Sequences revealed relatively well-conserved partial mitochondrial genomes which included complete sequences for 11 of 13 protein-coding genes, 16 of 23 tRNAs, and the large ribosomal subunit. Partial sequences were also recovered for cox1 and the small ribosomal subunit. Sequence analysis suggested that the cox2, nad5, and nad6 genes would be the best candidates for future population genetics analyses, due to their high number of variable sites. Future work to reveal the noncoding control region remains. PMID- 22219086 TI - Binding and cell intoxication studies of anthrax lethal toxin. AB - Anthrax lethal toxin (LT) is a major virulence factor of Bacillus anthracis. The vast majority of the anthrax toxin-related literature describes the assembly of LT as a cell-dependent process. However, some reports have provided evidence for the existence of a fully assembled LT, either in vitro or in the bloodstream of anthrax-infected animals. To follow up on this work, we present studies on fully assembled LT. We first demonstrate facile and cell-free assembly and purification of LT. We then show that fully assembled LT binds an anthrax toxin receptor with almost 100-fold higher affinity than the protective antigen (PA) alone. Quantitative cell intoxication assays were used to determine the LD(50) (lethal dose 50) for LT. The cell-binding studies revealed that LT binds mammalian cells using a different mode from PA. Even when PA-specific receptors were blocked, fully assembled LT was able to bind the cell surface. Our studies support the existing evidence that LT fully assembles in the blood stream and can bind and intoxicate mammalian cells with very high affinity and efficacy. More importantly, the data presented here invoke the possibility that LT may bind cells in a receptor-independent fashion, or recognize receptors that do not interact with PA. Hence, blood borne LT may emerge as a novel therapeutic target for combating anthrax. PMID- 22219088 TI - Response trajectories reveal conflict phase in image-word mismatch. AB - In the present study, response trajectories were used in a picture-word conflict task to determine the timing of intermediate processing stages that are relatively inaccessible to response time measures. A marker was placed above or below the word ABOVE or BELOW so that its location was congruent or in conflict with the word's meaning. To report either word location(above or below the marker) or word meaning, participants moved a mouse upward toward the appropriate top left or right answer corner on the display screen.Their response trajectories showed a number of distinctive features: First, at about 200 ms after stimulus onset(the "decision moment"), the trajectory abruptly began to arc toward the appropriate answer corner; second,when the word's meaning and position were in conflict,the trajectory showed an interruption that continued until the conflict was resolved. By varying the SOA of the word and marker onsets, we found that the word meaning and word position became available at approximately 325 ms and 251 ms, respectively, after their onsets, and that the delay to resolve conflicts was about 138 ms. The timing of these response trajectory events was more stable than any extracted from the final response times, demonstrating the power of response trajectories to reveal processing stages that are only poorly resolved, if at all, by response time measures [added]. PMID- 22219087 TI - A missense mutation (p.G274R) in gene ASPA causes Canavan disease in a Pakistani family. AB - Canavan disease (OMIM 271900) is an autosomal recessive lethal neurodegenerative disorder characterized by spongy degeneration of the brain. A highly consanguineous Pakistani family with Canavan disease was enrolled on the basis of diagnosis. All the affected individuals have mental retardation, megalocephaly and degradation of motor skills, poor head control, partial vision loss, weakness of the muscles and raised urinary concentration of N-acetyl aspartic acid in the urine. Blood samples were collected from affected as well as normal siblings and processed for DNA purification. Linkage analysis was performed by typing three short tandem repeat markers D17S1583 (7.19 cM), D17S1828 (10.02 cM) and D17S919 (14.69 cM) for an already-reported gene/locus ASPA at chromosome 17p13.2 causing Canavan disease. During linkage analysis, all the affected individuals were homozygous for short tandem repeat markers while the normal siblings were heterozygous showing co-segregation of the disease. Gene ASPA (NM_000049) was undertaken to sequence for mutation analysis. As a result of sequence analysis, we found missense substitution 740A->G (p.G274R) in exon 6 of gene ASPA. To our knowledge, this is the first report about Canavan disease on a Pakistani family. PMID- 22219089 TI - [Editorial]. PMID- 22219090 TI - Percutaneous dilatation of coarctation of the aorta, stenotic pulmonary arteries or homografts, and stenotic superior vena cava using Andrastents XL and XXL. AB - BACKGROUND: Major vessel stenoses are currently successfully treated with stent implantation. Recently, new cobalt-chromium stents (Andrastents XL and XXL, Andramed, Germany) have been introduced into clinical practice. This alloy combines high biocompatibility with radial strength and flexibility. AIM: To present our experience with the use of Andrastents XL and XXL for the dilatation of stenosed pulmonary arteries, coarctation of the aorta (CoA), and a stenosed superior vena cava (SVC). METHODS: The study group included 24 patients treated with 26 Andrastents. In 7 patients aged 23.3 (range 18-27) years, with the mean body weight of 64.7 (range 50-77) kg, prestenting of a calcified pulmonary homograft was performed using 9 Andrastents XL or XXL (length of 30, 39, or 48 mm) before the Melody valve implantation. In one patient with a long and stiff stenosis, 3 stents were necessary. In 12 patients with native CoA aged 30.1 (range 9-55) years, with the mean body weight of 60 (range 25-105) kg, twelve Andrastents XL or XXL (length of 30, 39, or 48 mm) were implanted. In 4 patients with the right or left pulmonary artery stenosis close to the bifurcation (age 8.5 [range 6-10] years, body weight 27.3 [range 17-33] kg), 4 Andrastents 30 XL were implanted. In one child (age 7.5 years, body weight 21.7 kg) with a iatrogenic SVC stenosis (after 2 venous cannulations necessary for 2 surgical corrections of his double-outlet right ventricle), the stenosed site was dilated using Andrastent 21 XL. RESULTS: All procedures were performed successfully. No stent fractures were observed during the follow-up. The mean pressure gradient was reduced from 42.4 to 18 mm Hg (RVOT) in patients who underwent Andrastent and Melody valve implantation, from 54.1 to 13.2 mm Hg in patients with CoA, and from 49 to 21.7 mm Hg in patients with pulmonary artery stenosis. No aneurysm formation, stent migration, or rupture of the treated vessel during stent implantation were observed in any patient. The mean fluoroscopy time during stent implanatation was 6.6 min in CoA, 8.8 min in pulmonary artery stenosis, 24.8 min during implantation of Melody valve (with prestenting of RVOT with Andrastents) and 17.6 min during SVC dilation. Procedural outcomes (evaluated using noninvasive methods) remained favourable during the follow-up (0.5-21 months), with no complications observed. CONCLUSIONS: Implantation of Andrastents XL or XXL is a very good therapeutic option in the treatment of major vessel stenoses. PMID- 22219091 TI - [Comment to article AndraStent - nowy stent obwodowy]. PMID- 22219092 TI - Transformation of conventional T cells into regulatory T cells in children with metabolic syndrome. AB - BACKGROUND: Much research has been done in the recent years to establish an association between obesity, metabolic syndrome and the immune system. Numerous data suggest that the decreased number and/or function of regulatory T cells (Treg cells) can lead to chronic minimal inflammation present in patients with obesity and trigger formation of atherosclerotic plaque. AIM: To generate Treg cells from the peripheral blood in children meeting the diagnostic criteria of metabolic syndrome. METHODS: A total of 25 children with metabolic syndrome and 25 controls were enrolled in the study. Peripheral blood was collected, CD4(+)/CD25(-) cells were separated and cultured for 4 weeks in the presence of a Treg expander (CD3/CD28) and interleukin-2. The expression of the transcription factor FoxP3 as a Treg marker was assessed before and after culture using reverse transcriptase polymerase chain reaction (RT-PCR) and flow cytometry. RESULTS: Before the culture we observed a slightly lower percentage of Treg cells in children with metabolic syndrome vs controls. After the culture we noted a significant increase in mRNA expression and in the percentage of FoxP3-positive cells. We observed no differences in the results between the children with metabolic syndrome and the controls. CONCLUSIONS: Our study shows that it is possible to generate Treg cells from peripheral blood of children with metabolic syndrome. In future, these findings could be used to develop a model of immunotherapeutic intervention for patients at risk of cardiovascular disease. PMID- 22219093 TI - [Comment to article Immunomodulacja w chorobach metabolicznych - terapia na jutro?]. PMID- 22219094 TI - Surgical ablation for atrial fibrillation using the Ex-Maze III procedure on the beating heart in patients undergoing mitral valve surgery. AB - BACKGROUND: The Ex-Maze III procedure is a recently developed surgical method for ablation of atrial fibrillation (AF). The procedure uses epicardial approach and can be performed on the beating heart. AIM: To evaluate the efficacy and safety of Ex-Maze III ablation in patients undergoing mitral valve (MV) surgery. METHODS: The study group consisted of 20 consecutive patients (8 males, mean age 67 years) who underwent MV surgery and had concomitant AF. Eighteen patients were diagnosed with long-standing permanent AF and 2 patients with paroxysmal AF. The mean duration of AF was 9.5 years prior to surgery. All the patients underwent the Ex-Maze III procedure on the beating heart immediately before the MV surgery (MV replacement in 17 patients and MV repair in 3 patients). The patients were followed 1, 3, 6 and 12 months after procedure with ECG and 24-h ambulatory ECG monitoring (at 12 months). RESULTS: There were no serious complications in the study group. All the patients were in AF immediately after the procedure and underwent electrical or pharmacological cardioversion (4 and 16 patients, respectively). The proportion of patients remaining in sinus rhythm was 15 (75%) patients at 1 month, 16 (80%) patients at 3 months, 17 (85%) patients at 6 months and 12 months after procedure. CONCLUSIONS: The Ex-Maze III procedure for ablation of AF on the beating heart is safe and effective in patients with AF undergoing concomitant MV surgery. In order to better evaluate the outcomes of the procedure a prospective randomised multicentre study is needed. PMID- 22219095 TI - [Comment to article Chirurgiczna ablacja - postep trwa]. PMID- 22219096 TI - The effects of intracoronary delivery of mononuclear bone marrow cells in patients with myocardial infarction: a two year follow-up results. AB - BACKGROUND: Transplantation of bone marrow stem cells (BMSC) is a new method of prevention of left ventricular (LV) remodelling in post-infarction patients. Studies published to date point to LV systolic and diastolic function improvement following this therapy however only a few studies assessed the long-term effects of BMSC. AIM: To assess the 2 year prognosis in patients with anterior myocardial infarction (MI) treated with BMSC transplantation in the acute phase. METHODS: The study group consisted of 60 patients with first anterior ST-segment elevation MI (STEMI), treated with primary percutaneous angioplasty, with baseline LV ejection fraction (LVEF) < 40%, who were randomly assigned to undergo BMSC transplantation on day 7 of the STEMI (40 patients, BMSC group) or to receive standard treatment (20 patients, control group). In all the patients echocardiography was performed at baseline and after 1, 3, 6, 12 and 24 months. The composite end-point (death, MI, admission for heart failure or repeat revascularisation) was assessed after 2 years of follow-up. RESULTS: Absolute increase of LVEF compared to baseline values was higher in the BMSC group than in the control group. The LVEF increase in BMSC group at 1 month was 7.1% (95% CI 3.1-11.1%), at 6 months - 9.3% (95% CI 5.3-13.3%), at 12 months - 11.0% (95% CI 6.2-13.3%) and at 24 months - 10% (95% CI 7.2-12.1%). In the control group, LVEF increase was 3.7% (95% CI 2.3-9.7%) at 1 month, 4.7% (95% CI 1.2-10.6%) at 6 months, 4.8% (95% CI 1.5-11.0%) at 12 months and 4.7% (95% CI 1.4-10.7%) at 24 months. The composite end-point occurred significantly more frequently in the control group (55%) than in the BMSC group (23%): OR 2.72; 95% CI 1.06-7.02, p = 0.015. CONCLUSIONS: Treatment with mononuclear bone marrow cells on day 7 of the first anterior MI in patients with significant baseline systolic dysfunction improves 2-year outcome. PMID- 22219097 TI - [Comment to article Terapia komorkowa w zawale serca - perspektywy]. PMID- 22219098 TI - The incidence and prognostic significance of cardiac arrhythmias and conduction abnormalities in patients with acute coronary syndromes and renal dysfunction. AB - BACKGROUND: The incidence of cardiac arrhythmias, including atrial fibrillation (AF) in chronic kidney disease, is unknown, although AF is several times more common in patients with end-stage kidney disease than in the general population. AIM: To assess the incidence, types and management of cardiac arrhythmias and conduction abnormalities in patients with acute coronary syndromes (ACS) and renal dysfunction. We also evaluated the prognostic significance of arrhythmias in this patient group. METHODS: We analysed 86 patients with renal dysfunction (GFR < 60 mL/min) out of 1005 patients hospitalised in our department between 2008 and 2009 for unstable angina and ST-elevation and non-ST-elevation myocardial infarction. RESULTS: Cardiac arrhythmias were observed in 44 (51.1%) patients with AF being the most common (27 patients, 31.4%), predominantly in the paroxysmal form (21.4%). A total of 14 (16.3%) patients had cardiac arrhythmias requiring temporary or permanent pacing. Only 4 (4.6%) patients showed transient conduction abnormalities due to hyperkalaemia in the course of renal failure, while the remaining 10 (11.6%) patients demonstrated conduction abnormalities due to ACS. A total of 3 (3.5%) patients had other arrhythmias (atrial tachycardia, ventricular arrhythmias). During the follow-up period (mean duration: 14.3 months) 7 out of 44 patients (15.9%) with renal dysfunction and arrhythmia and 2 out of 42 patients (4.7%) without arrhythmia died (p < 0.05). CONCLUSIONS: Cardiac arrhythmias occur more often in patients with ACS if renal dysfunction is also present and are associated with poor prognosis. PMID- 22219099 TI - [Comment to article Dysfunkcja nerek pogarsza rokowanie osob z OZW]. PMID- 22219100 TI - Cardiovascular risk factors control in Polish patients with type 2 diabetes within the first two years of diagnosis: results of the ARETAEUS1 study. AB - BACKGROUND: The practice guidelines of cardiological and diabetological societies emphasise that cardiovascular (CV) risk control in diabetic patients is especially important and should be stricter than in subjects without diabetes. There are little data on the frequency of meeting treatment goals in patients with newly diagnosed diabetes mellitus type 2 (DM2). AIM: To characterise Polish patients with DM2 diagnosed within the previous two years and to assess if the treatment targets from the current (2008) guidelines of Diabetes Poland regarding control of CV risk factors are met. METHODS: ARETAEUS1 was a cross-sectional questionnaire-based study conducted in various regions of Poland in 2009 (January April). It involved 1,714 patients of all ages and both genders, who had DM2 treated for less than 24 months. They were recruited by randomly selected physicians. RESULTS: Total cholesterol treatment goal (< 4.5 mmol/L) was met in 22% of all patients, triglycerides treatment goal (< 1.7 mmol/L) in 44%, LDL cholesterol treatment goal (< 2.6 mmol/L) in 20% and HDL cholesterol treatment goal (> 1.0 mmol/L in men and > 1.3 mmol/L in women) in 55%. Only 13% of the overall population met the goal of blood pressure (BP) below 130/80 mm Hg. When a less restrictive BP control threshold (< 140/90 mm Hg) was applied, 48% of patients had their BP below the threshold. In the analysis of subgroups (patients with and without previous CV events; receiving 1-5 or not receiving antihypertensive drugs; receiving and not receiving statins and fibrates) we observed from 0% to 3.3% of patients meeting three (HbA1c, BP and cholesterol) treatment goals. The percentages of patients meeting two out of three treatment goals were between 8% and 33% in different subgroups. The percentages of patients meeting only one out of three treatment goals ranged from 27.8% to 46.7% or at least one - from 39% to 69%. CONCLUSIONS: Most patients with newly diagnosed diabetes are not meeting their treatment goals regarding control of CV risk factors, which indicates relatively low adherence to national guideline recommendations for diabetes control and primary CV prevention in DM2. Difficulties in achieving CV treatment targets in the diabetic population indicate the need for a great deal of effort on the part of clinicians and patients. Practice guidelines developers should consider what treatment targets are achievable at a reasonable expense of effort. PMID- 22219101 TI - [Comment to article Polscy lekarze nie sa mistrzami w terapii cukrzycy]. PMID- 22219102 TI - Impact of MTHFR C677T gene polymorphism and vitamins intake on homocysteine concentration in the Polish adult population. AB - BACKGROUND: Homocysteine (Hcy) levels are modulated by nutritional and genetic factors, among which is the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). AIM: To determine the effects of the MTHTR C677T polymorphism, as well as the intake of folate, vitamins B(6) and B(12) on serum Hcy concentration in the Polish population. METHODS: Within the framework of the National Multicentre Health Survey (WOBASZ), a representative sample of the whole Polish population aged 20-74 was screened in 2003-2005. Vitamins intake, Hcy level and known MTHTR C677T genotype were available for 1,561 men and 1,712 women. RESULTS: In the Polish population, T/T, C/T and C/C genotype frequencies were 10%, 43% and 47%, respectively in men, and 9%, 42% and 49%, respectively in women. The T/T genotype was associated with increased levels of Hcy (13.14 MUmol/L in men, and 9.77 mmol/L in women) compared to the C/C and C/T genotypes (10.18 and 8.77, respectively), after adjustment for age, methionine, coffee and alcohol intake, smoking and drugs used. In a multivariable linear regression model, among subjects with the T/T genotype, the only factor influencing Hcy was age in women. In the case of the other groups (C/C and C/T), there was a relationship between Hcy and age, alcohol consumption, drugs used, folate and vitamin B(6) in men, and age, smoking, coffee consumption, drugs used, folate and vitamin B(12) in women. CONCLUSIONS: The T/T genotype is associated with higher levels of Hcy (29% in men, and 11% in women) compared to other genotypes. Nutritional factors affect Hcy levels only in the C/C and C/T MTHFR genotypes. PMID- 22219103 TI - [Comment to article Znaczenie badan epigenetycznych w kardiologii]. PMID- 22219104 TI - Resolution of exercise oscillatory ventilation with adaptive servoventilation in patients with chronic heart failure and Cheyne-Stokes respiration: preliminary study. AB - BACKGROUND: Exercise oscillatory ventilation (EOV) is a common pattern of breathing in heart failure (HF) patients, and indicates a poor prognosis. AIM: To investigate the effects of adaptive servoventilation (ASV) on ventilatory response during exercise. METHODS: We studied 39 HF patients with left ventricular ejection fraction (LVEF) L 45. Cardiorespiratory polygraphy, cardiopulmonary exercise testing (CPET), echocardiography, and measurement of N terminal pro-brain natriuretic peptide (NT-proBNP) concentration were performed. Twenty patients with Cheyne-Stokes respiration and apnoea-hypopnoea index (AHI) >= 15/h were identified. Of these, 11 patients were successfully titrated on ASV and continued therapy. In the third month of ASV treatment, polygraphy, CPET, echocardiography, and measurement of NT-proBNP concentration were performed again. RESULTS: The EOV was detected at baseline in 12 (31%) HF patients, including eight (67%) who underwent ASV. The EOV was associated with significantly lower LVEF, peak oxygen uptake (VO(2)), and ventilatory anaerobic threshold (VAT), and a significantly higher left ventricular diastolic diameter (LVDD), slope of ventilatory equivalent for carbon dioxide (VE/VCO(2)), AHI, central AHI and NT-proBNP concentration. In seven patients with EOV, reversal of EOV in the third month of ASV therapy was observed; only in one patient did EOV persist (p = 0.0156). CONCLUSIONS: The EOV can be reversed with ASV therapy. The EOV in association with central sleep apnoea and Cheyne- -Stokes respiration (CSA/CSR) is prevalent in HF patients and correlates with severity of the disease. PMID- 22219105 TI - [Comment to article Czy leczyc zaburzenia oddychania w niewydolnosci serca?]. PMID- 22219106 TI - [Therapeutic difficulties in a 3 year-old boy with Kawasaki disease]. AB - A case of a three year-old by with delayed diagnosis of disease is presented. Treatment with immunoglobulins and methylpreduisolone was affective, however, no regression in coronary artery lesions was observed. The diagnosis and treatment of Kawasaki disease are discussed. PMID- 22219107 TI - [Neurogenic stunning of left ventricle following epileptic seizures in a patient with aortic regurgitation and Niemann-Pick disease]. AB - A case of a 19 year-old female with the Niemann-Pick disease and transient left ventricular dysfunction following epileptic seizures is presented. Electrocardiographic features and differentid diagnosis of this condition are presented. PMID- 22219108 TI - [Intraoperative imaging of hybrid procedure for muscular ventricular septal defects closure with Amplatzer Duct Occluder II]. AB - Hybrid approach becomes a promising conception of an alternative treatment for muscular ventricular septal defects (VSD) closure in infants. In this paper we report epicardial echocardiography imaging that enabled successful hybrid procedure performed in premature infant referred for surgical correction of a large perimembraneous VSD with simultaneous perventricular approach for concomitant muscular VSD. PMID- 22219109 TI - [Scimitar syndrome in an adult - partial anomalous pulmonary venosus connection]. AB - Scimitar syndrome is a type of partial anomalous pulmonary venous connections, in which part or even the entire right lung is typically drained by right pulmonary veins that anomalously drain into the inferior vena cava. The affected lung is often hypoplastic. The severity of clinical signs and symptoms depend on the degree of a left-to-right shunt and the presence of pulmonary defects. We present a 60 year-old women who has been asymptomatic for a long time. PMID- 22219110 TI - Sleep-disordered breathing in heart failure. PMID- 22219111 TI - [Familial thoracic aortic aneurysms and dissections (FTAAD)]. PMID- 22219112 TI - [AAI stimulation and nodal rhythm]. AB - We describe the case of a 77 year-old white woman treated by AAI pacing. Nodal rhythm with ventriculo-atrial conduction and retrograde P wave were observed in ECG Holter monitoring. The retrograde P wave was sensed by the pacemaker, which responded correctly. PMID- 22219114 TI - [Acute pulmonary embolism in pregnant women]. AB - A case of a 19 year-old woman in the third trimester of her second pregnancy admitted due to suspected of acute pulmonary embolism (PE) is presented. The diagnosis was confirmed by transthoracic echocardiography (TTE) which revealed an immobile wall-adherent thrombus in the left pulmonary artery. A complete regression of the thrombus was obtained after antithrombotic treatment. We conclude that TTE examination can be useful in diagnosing of PE and may be safely used during pregnancy. PMID- 22219115 TI - [Coronary-cameral fistulae drained into left ventricle causing acute coronary syndrome?]. AB - Coronary-cameral fistulae are rare and predominantly congenital communication between the coronary arterial circulation and the chambers or great vessels of the heart, accounted for less than 0.4% of all congenital heart abnormalities. We presented a case of 47 year-old female with troponin positive acute coronary syndrome admitted to our coronary care unit in whom we diagnosed coronary-cameral fistulae which could cause myocardial ischaemia. PMID- 22219117 TI - Implantation of additional defibrillation lead into the coronary sinus: an effective method of decreasing defibrillation threshold. AB - We report a case of successful implantation of an additional defibrillation lead into the coronary sinus due to high defibrillation threshold (DFT) in a seriously ill patient with a history of extensive myocardial infarction referred for implantable cardioverter- defibrillator implantation after an episode of unstable ventricular tachycardia. All previous attempts to reduce DFT, including subcutaneous electrode implantation, had been unsuccessful. PMID- 22219118 TI - [Comment to article Unikalne rozwiazanie problemu nieskutecznej defibrylacji]. PMID- 22219119 TI - Polish Forum for Prevention Guidelines for screening procedures for cardiovascular diseases. PMID- 22219120 TI - [Summary of the article: Stolarz-Skrzypek K, Kuznetsova T, Thijs L et al. Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion. JAMA, 2011; 305: 1777-1785]. PMID- 22219121 TI - [Comment to article Sol - krzepi czy jednak szkodzi?]. PMID- 22219122 TI - Transcatheter occlusion of a large coronary artery fistula using a patent ductus arteriosus occluder. AB - A large fistula from the left coronary artery to the right ventricle was successfully closed percutaneously in a 40 year-old patient using a patent ductus arteriosus occluder. The device was positioned and deployed via the venous system using a guidewire that had been advanced via the aorta, coronary artery and fistula to the venous circulation (arterio-venous loop creation). No complications were reported at follow-up. PMID- 22219124 TI - [Letter to the editor. Myocardial infarction without coronary arteries stenoses in a patient with Jervell and Lange-Nielsen syndrome--diagnostic dilemmas]. PMID- 22219126 TI - TNF-alpha expression in Schwann cells is induced by LPS and NF-kappaB-dependent pathways. AB - Lipopolysaccharide (LPS) is recognized by Toll-like receptor 4 and activates mitogen-activated protein kinase, which leads to the induction of proinflammatory cytokine gene expression. In vivo, Schwann cells (SCs) at the site of injury may also produce tumor necrosis factor-alpha (TNF-alpha). However, the precise mechanism that regulates TNF-alpha synthesis is still not clear. The nuclear transcription factor-kappaB (NF-kappaB) is an important transcription factor which is involved in the regulation of host immune responses. In the present study, we found that LPS possessed a comparable specific activity for activation of NF-kappaB-dependent gene expression in SCs. We also observed IkappaB alpha/IkappaB-beta degradation and the nuclear translocation of P65 due to LPS treatments. LPS-elicited TNF-alpha production in SCs was also drastically suppressed by SN50 (NF-kappaB inhibitor). PMID- 22219127 TI - Role of a neural cell adhesion molecule found in cerebrospinal fluid as a potential biomarker for epilepsy. AB - The neural cell adhesion molecule (NCAM-1) plays an important role in cell adhesion and synaptic plasticity. We designed this study to evaluate NCAM-1 as a potential biomarker for epilepsy. We performed a quantitative evaluation of the levels of NCAM-1 in cerebrospinal fluid (CSF) and serum and noted differences in patients with epilepsy compared to control subjects. We used sandwich enzyme linked immunosorbent assays to measure NCAM-1 concentrations in CSF and serum samples of 76 epileptic patients (subdivided into the following subgroups: drug refractory epilepsy, DRE; first-diagnosis epilepsy, FDE; and drug-effective epilepsy, DEE) and 44 control subjects. Our results show that cerebrospinal fluid NCAM-1 (CSF-NCAM-1) concentrations and NCAM-1 Indices in the epileptic group were lower than in the control group. Both the CSF-NCAM-1 concentration and the NCAM-1 Indices in the drug-refractory epilepsy group were lower than in the drug effective epilepsy group. These differences were statistically significant (P < 0.05). However, serum-NCAM-1 levels were not statistically different when comparing the epilepsy group to the control group (P > 0.05). Our results indicate that CSF-NCAM-1 is a potential biomarker for drug-effective epilepsy and drug-refractory epilepsy. PMID- 22219128 TI - Neuronal damage using fluoro-jade B histofluorescence and gliosis in the striatum after various durations of transient cerebral ischemia in gerbils. AB - Ischemic damage occurs well in vulnerable regions of the brain, including the hippocampus and striatum. In the present study, we examined neuronal damage/death and glial changes in the striatum 4 days after 5, 10, 15 and 20 min of transient cerebral ischemia using the gerbil. Spontaneous motor activity was increased with the duration time of ischemia-reperfusion (I-R). To examine neuronal damage, we used Fluoro-Jade B (F-J B, a marker for neuronal degeneration) histofluorescence staining. F-J B positive cells were detected only in the 20 min ischemia-group, not in the other groups. In addition, we examined gliosis of astrocytes and microglia using anti-glial fibrillary acidic protein (GFAP) and anti- ionized calcium-binding adapter molecule 1 (Iba-1), respectively. In the 5 min ischemia group, GFAP-immunoreactive astrocytes were distinctively increased in number, and the immunoreactivity was stronger than that in the sham-group. In the 10, 15 and 20 min ischemia-groups, GFAP-immunoreactivity was more increased with the duration of I-R. On the other hand, the immunoreactivity and the number of Iba-1 immunoreactive microglia were distinctively increased in the 5 and 10 min ischemia-groups. In the 15 min ischemia-group, cell bodies of microglia were largest, and the immunoreactivity was highest; however, in the 20 min ischemia group, the immunoreactivity was low compared to the 15 min ischemia-group. The results of western blotting for GFAP and Iba-1 were similar to the immunohistochemical data. In brief, these findings showed that neuronal death could be detected only in the 20 min ischemia-group 4 days after I-R, and the change pattern of astrocytes and microglia were apparently different according to the duration time of I-R. PMID- 22219129 TI - Oxidative modification of cysteine 111 promotes disulfide bond-independent aggregation of SOD1. AB - Converging evidence indicates that SOD1 aggregation is a common feature of mutant SOD1-linked fALS, and seems to be directly related to the gain-of-function toxic property. However, the mechanism inducing the aggregation is not understood. To study the contribution of oxidative modification of cysteine residues in SOD1 aggregation, we systematically examined the redox state of SOD1 cysteine residues in the G37R transgenic mouse model at different stages of the disease and under oxidative stress induced by H2O2. Our data suggest that under normal circumstance, cysteine 111 residue in SOD1 is free; however, under oxidative stress, it is prone to oxidative modification by providing the thiolate anion (S ). With the progression of the disease, increased levels of oxidative insults facilitated the oxidation of thiol groups of cysteine residues; human mutant SOD1 could generate an upper shift band in reducing SDS-PAGE, which turned out to be a Cys111-peroxidized SOD1 species. We also detected the formation of SOD1 multimers at different stages of the disease, and found that accumulated oxidative stress facilitated the formation of aggregates, which were not mediated by disulfide bond. This oxidative modification of cysteine 111 therefore promotes the formation of disulfide bond-independent aggregation of SOD1. PMID- 22219131 TI - Oxidative damage in muscular dystrophy correlates with the severity of the pathology: role of glutathione metabolism. AB - Muscular dystrophies (MDs) such as Duchenne muscular dystrophy (DMD), sarcoglycanopathy (Sgpy) and dysferlinopathy (Dysfy) are recessive genetic neuromuscular diseases that display muscle degeneration. Although these MDs have comparable endpoints of muscle pathology, the onset, severity and the course of these diseases are diverse. Different mechanisms downstream of genetic mutations might underlie the disparity in these pathologies. We surmised that oxidative damage and altered antioxidant function might contribute to these differences. The oxidant and antioxidant markers in the muscle biopsies from patients with DMD (n = 15), Sgpy (n = 15) and Dysfy (n = 15) were compared to controls (n = 10). Protein oxidation and lipid peroxidation was evident in all MDs and correlated with the severity of pathology, with DMD, the most severe dystrophic condition showing maximum damage, followed by Sgpy and Dysfy. Oxidative damage in DMD and Sgpy was attributed to the depletion of glutathione (GSH) and lowered antioxidant activities while loss of GSH peroxidase and GSH-S-transferase activities was observed in Dysfy. Lower GSH level in DMD was due to lowered activity of gamma glutamyl cysteine ligase, the rate limiting enzyme in GSH synthesis. Similar analysis in cardiotoxin (CTX) mouse model of MD showed that the dystrophic muscle pathology correlated with GSH depletion and lipid peroxidation. Depletion of GSH prior to CTX exposure in C2C12 myoblasts exacerbated oxidative damage and myotoxicity. We deduce that the pro and anti-oxidant mechanisms could be correlated to the severity of MD and might influence the dystrophic pathology to a different extent in various MDs. On a therapeutic note, this could help in evolving novel therapies that offer myoprotection in MD. PMID- 22219132 TI - Restraint stress in rats alters gene transcription and protein translation in the hippocampus. AB - Stress is a relatively new and emerging risk factor for Alzheimer's disease (AD). Severe stress can alter brain characteristics such as neuronal plasticity, due to changes in the metabolism of cytoskeletal proteins. In this study, male Wistar rats were exposed to restraint stress (RS) for 5 h daily for different time periods. At the end of the exposure periods, the amounts of beta-actin, cofilin, amyloid precursor protein (APP) and mitogen-activated protein kinase 1 (MAPK-1) RNAs and proteins were investigated. The mRNA expressions of beta-actin, cofilin and MAPK-1 followed U-shaped time course. Acute (3 days) and chronic (21 days) RS caused a fourfold and tenfold increases, respectively, in hippocampal beta-actin mRNA expression. In the case of cofilin mRNA expression, elevations were detected in the hippocampus on days 3, 7 and 21. The APP mRNA level was increased on day 21. On protein level, chronic stress elevated the levels of beta-actin, cofilin and APP in the hippocampus. These results suggest that stress causes the induction of some genes and proteins that are also elevated in AD selectively in the hippocampal region of the rat brain. PMID- 22219133 TI - Ischemia-induced inhibition of mitochondrial complex I in rat brain: effect of permeabilization method and electron acceptor. AB - In this study we have examined the effect of global brain ischemia/reperfusion on biochemical properties of the mitochondrial respiratory complex I (CI) in rat hippocampus and cortex. Since the inner mitochondrial membrane forms the permeability barrier for NADH, the methodology of enzymatic activity determinations employs membrane permeabilization methods. This action affects the basic character of electrostatic and hydrophobic interactions inside the membrane and might influence functional properties of membrane embedded proteins. Therefore we have performed the comparative analysis of two permeabilization methods (sonication, detergent) and their impact on CI enzymatic activities under global brain ischemic-reperfusion conditions. We have observed that ischemia led to significant decrease of CI activities using both permeabilization methods in both brain areas. However, significant differencies in enzymatic activities were registered during reperfusion intervals according to used permeabilization method. We have also tested the effect of electron acceptors (decylubiquinone, potassium ferricyanide, nitrotetrazolium blue) on CI activities during I/R. Based on our results we assume that the critical site where ischemia affects CI activities is electron transfer to electron acceptor. Further, the observed mitochondrial dysfunction was analyzed by means of one and 2-dimensional BN PAGE/SDS PAGE with the focus on 3-nitrotyrosine immunodetection as a marker of oxidative damage to proteins. Add to this, initialization of p53 mitochondrial apoptosis through p53, Bax, Bcl-X(L) proteins and a possible involvement of GRIM 19, the CI structural subunit, in apoptotic processes were also studied. PMID- 22219134 TI - Age-related decline in DNA polymerase beta activity in rat brain and tissues. AB - Fidelity of DNA polymerases is vital for maintaining genomic integrity. Deficient DNA repair leads to age related disorders or cancer. If the age at which the decline in activity of predominant DNA repair enzymes starts is identified, and the deficient proteins supplemented, then the manifestation of these diseases can be delayed promoting healthy aging. DNA polymerase beta (pol beta) is a predominant repair enzyme in brain. DNA pol beta activity declines with age in rat brain/neurons but the exact age during the life time of rat when this decline begins is not known, and comparison of this activity was not made between post mitotic and proliferating tissues therefore the pattern of pol beta with age was studied in rat brain and tissues. The decline in pol beta activity started between 30 and 45 days postnatal in all the tissues. Post mitotic tissues showed pronounced decline than the proliferating tissues. PMID- 22219135 TI - Impact of metabolic syndrome on re-stenosis development: role of drug-eluting stents. AB - Metabolic syndrome (MetS) is defined as a cluster of numerous cardiovascular risk factors, which encompasses obesity, dyslipidaemia, insulin resistance and hypertension. Patients with MetS are more prone to developing cardiovascular events than other patients. To date, several approaches such as physical exercise, dietary control and invasive and non-invasive therapeutic interventions for dyslipidaemia, hypertension and insulin resistance have been used to manage MetS. However, there is a progressive elevation in the incidence of fatal and non fatal cardiovascular events due to the increased prevalence of obesity and diabetes. Percutaneous coronary intervention has emerged over the last few years as an effective revascularisation strategy for those with coronary artery disease, in parallel with the development of effective anti-platelet medications and newer drug-eluting stents. In recent years, considerable research efforts have been undertaken to elucidate the pathophysiology of re-stenosis and develop strategies to prevent re-stenosis following percutaneous transluminal coronary angioplasty and stent implantation. Although the rate of stent re-stenosis and target-lesion revascularisation has been reduced, there is little information in the literature on the outcome of MetS in the pathophysiology of re-stenosis. In this review article, we summarise the recent development and progress on re stenosis and the role of drug-eluting stents, particularly in MetS. PMID- 22219136 TI - Elevated active secretory sphingomyelinase in antineutrophil cytoplasmic antibody associated primary systemic vasculitis. PMID- 22219130 TI - Dysfunctional nucleus tractus solitarius: its crucial role in promoting neuropathogenetic cascade of Alzheimer's dementia--a novel hypothesis. AB - The pathophysiological mechanism(s) underlying Alzheimer's disease (AD) still remain unclear, and no disease-modifying or prophylactic therapies are currently available. Unraveling the fundamental neuropathogenesis of AD is an important challenge. Several studies on AD have suggested lesions in a number of CNS areas including the basal forebrain, hippocampus, entorhinal cortex, amygdale/insula, and the locus coeruleus. However, plausible unifying studies on the upstream factors that involve these heterogeneous regions and herald the onset of AD pathogenesis are not available. The current article presents a novel nucleus tractus solitarius (NTS) vector hypothesis that underpins several disparate biological mechanisms and neural circuits, and identifies relevant hallmarks of major presumptive causative factor(s) linked to the NTS, in older/aging individuals. Aging, obesity, infection, sleep apnea, smoking, neuropsychological states, and hypothermia-all activate inflammatory cytokines and oxidative stress. The synergistic impact of systemic proinflammatory mediators activates microglia and promotes neuroinflammation. Acutely, the innate immune response is protective defending against pathogens/toxins; however, when chronic, it causes neuroinflammation and neuronal dysfunction, particularly in brainstem and neocortex. The NTS in the brainstem is an essential multiple signaling hub, and an extremely important central integration site of baroreceptor, chemoreceptor, and a multitude of sensory afferents from gustatory, gastrointestinal, cardiac, pulmonary, and upper airway systems. Owing to persistent neuroinflammation, the dysfunctional NTS exerts deleterious impact on nucleus ambiguus, dorsal motor nucleus of vagus, hypoglossal, parabrachial, locus coeruleus and many key nuclei in the brainstem, and the hippocampus, entorhinal cortex, prefrontal cortex, amygdala, insula, and basal forebrain in the neocortex. The neuronal and synaptic dysfunction emanating from the inflamed NTS may affect its interconnected pathways impacting almost the entire CNS--which is already primed by neuroinflammation, thus promoting cognitive and neuropsychiatric symptoms. The upstream factors discussed here may underpin the neuropathopgenesis of AD. AD pathology is multifactorial; the current perspective underscores the value of attenuating disparate upstream factors--in conjunction with anticholinesterase, anti-inflammatory, immunosuppressive, and anti-oxidant pharmacotherapy. Amelioration of the NTS pathology may be of central importance in countering the neuropathological cascade of AD. The NTS, therefore, may be a potential target of novel therapeutic strategies. PMID- 22219137 TI - Genetic predisposition of the severity of joint destruction in rheumatoid arthritis: a population-based study. AB - BACKGROUND: The susceptibility to rheumatoid arthritis (RA) is partly heritable, but whether the severity of RA is also influenced by genetics has not been determined. The evaluation of the heritability of the severity of RA is basic to further studies on genetic factors. A study was undertaken to determine whether joint destruction is heritable. METHODS: Iceland has an unique comprehensive genealogy database covering today's population and stretching back to >=1000 years ago, as well as genome-wide single nucleotide polymorphism data for a large part of the population. Hand and feet x-rays of 325 Icelandic patients with RA were scored according to the Sharp-van der Heijde method. The degree of relatedness between patients was estimated in two ways: (1) kinship coefficients (KC) on the genealogical data were expressed; and (2) the identical-by-descent (IBD) was estimated applying long-range phasing of the genetic profile of the patients. The degree of relatedness was tested against the similarity in joint destruction rates by linear regression analysis and the heritability of joint destruction was calculated. RESULTS: Significant associations between degree of relatedness and similarity in joint destruction rates were observed for both methods of determining relatedness (p(KC)=0.018, p(IBD)=0.003). The estimated heritability was 45% using KC and 58% using the estimated IBD data. CONCLUSIONS: The severity of joint destruction in RA is influenced by genetic factors. PMID- 22219139 TI - Clinical applicability of the EULAR Sjogren's syndrome disease activity index: a cumulative ESSDAI score adds in describing disease severity. PMID- 22219138 TI - TNF blockade requires 1,25(OH)2D3 to control human Th17-mediated synovial inflammation. AB - OBJECTIVES: T helper 17 (Th17) cells from patients with early rheumatoid arthritis (RA) induce a proinflammatory feedback loop upon RA synovial fibroblast (RASF) interaction, including autocrine interleukin (IL)-17A production. A major challenge in medicine is how to control the pathogenic Th17 cell activity in human inflammatory autoimmune diseases. The objective of this study was to examine whether tumour necrosis factor (TNF) blockade and/or 1,25 dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) controls Th17-mediated synovial inflammation. METHODS: Peripheral CD4+CD45RO+CCR6+ Th17 cells of patients with early RA, Th17-RASF cocultures and synovial biopsy specimens were cultured with or without 1,25(OH)(2)D(3) and/or TNFalpha blockade. Intracellular cytokine expression was detected by flow cytometry. Cytokine and matrix metalloprotease (MMP) production was determined by ELISA. RESULTS: The authors show that the 1,25(OH)(2)D(3), but not TNFalpha blockade, significantly suppressed autocrine IL 17A production in Th17-RASF and synovial biopsy cultures. Combining 1,25(OH)(2)D(3) and TNFalpha blockade had a significant additive effect compared with single treatment in controlling synovial inflammation, indicated by a further reduction in IL-6, IL-8, MMP-1 and MMP-3 in Th17-RASF cocultures and IL-6 and IL-8 expression in cultures of RA synovial tissue. CONCLUSIONS: These data show that TNF blockade does not suppress IL-17A and IL-22, which can be overcome by 1,25(OH)(2)D(3). The combination of neutralising TNF activity and 1,25(OH)(2)D(3) controls human Th17 activity and additively inhibits synovial inflammation. This indicates more valuable therapeutic potential of activation of Vitamin D receptor signalling over current TNF neutralisation strategies in patients with RA and potentially other Th17-mediated inflammatory diseases. PMID- 22219140 TI - Further genomic testing and histological examinations confirm the diagnosis of rheumatoid arthritis in an Italian mummy from the 16th century. PMID- 22219141 TI - Anakinra treatment of SAPHO syndrome: short-term results of an open study. PMID- 22219142 TI - A population-based study on the association between rheumatoid arthritis and erectile dysfunction. PMID- 22219144 TI - In vitro and biodistribution examinations of Tc-99m-labelled doxorubicin-loaded nanoparticles. AB - BACKGROUND: Nanoparticles represent promising drug carrier systems. In the case of cytostatics such as doxorubicin, carrier colloid systems as human serum albumin (HSA) nanoparticles, may increase their therapeutic efficiency and decrease their side-effects (toxicity) and any potential multidrug resistance. In the present study, doxorubicin, as a widely used antineoplastic agent, was incorporated into the matrix of human serum albumin and three different particle sized doxorubicin-loaded HSA nanoparticles were prepared, using a previously described desolvation method. Our objective was to find out if different particle sizes of colloid carriers can allow regarding the given cytostatic agent. MATERIAL AND METHODS: The three prepared nanoparticles were labelled using technetium (Tc-99m) and were tested for their physicochemical colloidal quality, fluctuations, and radiochemical stability. Biodistribution of different-sized radiolabelled colloids were determined by means of scintigraphic imaging studies in healthy male Wistar rats. Images were taken by gamma camera at several times and organ uptakes were estimated by quantitative ROI analysis. RESULTS: In vitro measurements showed that more than 95% of doxorubicin proportion was permanently adsorbed to human serum albumin. Radiolabelled doxorubicin-loaded particles had high-degree and durable labelling efficiency and particle size stability. Biodistribution results had a close correlation to earlier described results of radiocolloids in similar particle size ranges. In vivo examinations verified that colloid carriers have insignificant size fluctuations after an intravenous application and they show the proper distribution according to their particle size. CONCLUSIONS: Our investigations verified that different and stable particle sizes make drug carrier HSA nanoparticles possible to apply different drug targeting in a potential clinical use. PMID- 22219145 TI - V/P scan in diagnosis and follow-up of pulmonary embolism in 15-25-year-old females in relation to hormonal contraception use. AB - BACKGROUND: An analysis of medical records of young females who were examined in our department during a five-year period (2005-2009) on suspicion of pulmonary embolism (PE) in relation to hormonal contraception (HC). MATERIAL AND METHODS: The patient sample included 86 young females aged 15-25 (mean 21) years who underwent a ventilation/ perfusion scintigraphy (V/P scan). Seventeen of them were examined repeatedly. Altogether, 114 scintigraphic examinations were performed. Lung perfusion scintigraphy was performed using a planar gamma camera (Mediso MB 9200) in 4 projections following 100 MBq 99mTc--MAA i.v. application with 81 mKr ventilation scintigraphy concurrently. RESULTS: 1. Among 57/86 (66%) patients on HC, 24 (42%) had scintigraphic signs of PE. 2. 11/57 (19%) of them had clinical signs of deep venous system thrombosis of the lower limbs that were confirmed by sonography. 3. Leiden mutation was found in 9/24 (37%) patients with PE. 4. Among 29/86 (34%) females not taking HC, PE was detected in only 3 patients (10%). 5. 10/17 (59%) repeatedly examined females had permanent post embolic residual changes of lung perfusion. CONCLUSIONS: In our group of patients who underwent a P/V scan, 42% of those on HC were diagnosed with PE on scintigraphy, compared to 10% of those not taking HC. Among the patients with PE, there were 10/24 (42%) young females with persistent post-embolic changes. Our study indicates that the well-known risk of venous thromboembolism related to the use of HC needs to be considered as a cause of PE even among very young females. In our experience, prevention of these life-threatening conditions in patients with a family history of venous thromboembolism consists of timely examination of their thrombotic profile and selection of appropriate contraception. PMID- 22219146 TI - Can treatment using radiolabelled somatostatin analogue increase the survival rate in patients with non-functioning neuroendocrine pancreatic tumours? AB - BACKGROUND: The aim of the study was to assess the effectiveness of peptide receptor radionuclide therapy (PRRT) in patients with non-functioning neuroendocrine pancreatic tumours (NFPNTs) and to compare survival rates in patients with NFPNTs and in patients with other neuroendocrine tumours (NETs) treated using radiolabelled somatostatin analogue in our Department. We would like to analyze factors potentially determining the effectiveness of the therapy and also to assess the myelo- and nephrotoxicity. MATERIAL AND METHODS: Fourteen patients with disseminated disease and/or inoperable NFPNT were qualified to PRRT based on positive SRS (somatostatin receptor scintigraphy). There were 5 men and 9 women, with Karnofsky's index>70%. RESULTS: In the whole group of patients, partial response was observed in 21.4%, stabilization of the disease in 42.9%, and progression of the disease in 35.7% of patients. Mean observation time was 19+/-13 months, mean time to progression was 12+/-9 months, and mean time to death was 16+/-9 months. Six patients died--four of them due to progression of the disease, two due to myocardial infarction. After PRRT we did not observe clinically significant haemotoxicity and/or nephrotoxicity. CONCLUSIONS: 1. Peptide receptor radionuclide therapy may be a safe and effective treatment option in patients with NFPNTs, leading to stabilization or regression of the disease in the majority of patients. 2. There is no statistically significant difference in survival rate between patients with NFPNTs and NETs of other localization treated with PRRT. PMID- 22219147 TI - The non-conventional use of 99mTc-Tetrofosmine for dynamic hepatobiliary scintigraphy. AB - BACKGROUND: Classic dynamic hepatobiliary scintigraphy (DHBS) is commonly performed with 99mTc-Iminodiacetic Acid (IDA) derivatives and represents a non invasive diagnosis method for biliary dyskinesia, fistulas, surgical anastomosis, etc (1). This study assesses the possibility of performing DHBS with 99mTc Tetrofosmine (TF), a radiopharmaceutical (RF) dedicated to myocardial perfusion scintigraphy (MPS), but being excreted through the liver. The possibility to use 99mTc-TF for DHBS may be important in situations when the standardized RF for this procedure (IDA derivatives) is not available. MATERIAL AND METHODS: We performed DHBS for 30 patients referred for investigation by internal medicine and surgery departments. The patients had been fasting for 12 hours. The dynamic investigation started simultaneously with the intravenous (IV) administration of 37-110 MBq (1-3 mCi) 99mTc-TF. Dynamic images were recorded for 30-45 minutes, one image per minute, followed by static scintigraphy at 1 h, 1.5 h, 2 h, and 3 h after IV injection. RESULTS: The quality of scintigraphic images of the liver and biliary tree obtained at DHBS with 99mTc-TF ensured the correct diagnosis of biliary dyskinesia, stasis, stenosis, and fistulas. CONCLUSIONS: DHBS using 99mTc TF is justified by the image quality and by the good cost/benefits ratio. Because the IDA derivatives are not always available, this finding may be important for medical practice. 99mTc-TF evacuated through the bile duct allows DHBS interpretation, while the necessary dose is approximately 8 to 20 times smaller than that used for myocardial perfusion scintigraphy. PMID- 22219148 TI - Comparison of receptor affinity of natSc-DOTA-TATE versus natGa-DOTA-TATE. AB - BACKGROUND: 44Sc as a positron emitter can be an interesting alternative to 68Ga (T1/2=67.71 min) due to its longer half-life (T1/2=3.97 h). Moreover, the b emitter 47Sc can be used for therapy when attached to the same biomolecule vectors. DOTA as a chelating agent has been proven suitable for the radiolabelling of peptides recognising tumour cell receptors in vivo with M3+ radiometals. DOTA-derivatized peptides have been successfully labelled with 90Y and 177Lu for therapy, and with 68Ga for PET imaging. However, published data on 44Sc-labelled DOTA-biomolecules as potential PET radiotracers are still very limited. The aim of this study was to compare the affinity of natGa- and natSc labelled DOTA-TATE to somatostatin receptors subtype 2 expressed in rat pancreatic cancer cell line AR42J. MATERIAL AND METHODS: The cold complexes of DOTA-TATE with natGa and natSc were synthesized and identified by HPLC and MS analysis and evaluated in vitro for competitive binding to cancer cell line AR42J expressing somatostatin receptors subtype 2 (sstr2). RESULTS: The IC50 values calculated from the displacement curve of {125I-Tyr11}-SST-14 were: 0.20+/-0.18, 0.70+/-0.20, 0.64+/-0.22 and 0.67+/-0.12 for natGa-DOTA-TATE, natSc-DOTA-TATE, DOTA-TATE, and {Tyr11}-SST-14 complexes, respectively, with the affinity lowering in the decreasing order: natGa-DOTA-TATE>DOTA-TATE>Tyr11-SST-14>natSc-DOTA-TATE. CONCLUSIONS: The binding affinity of natGa-DOTA-TATE appeared higher than that of natSc-DOTA-TATE. Further in vitro and in vivo studies are needed to verify the influence of the chelated metal on the affinity and uptake of the respective radiolabelled compounds. This information might be crucial when the in vivo applications of peptides labelled with 68Ga and 44Sc for PET, as well as the use of 47Sc for radiotherapy are considered. PMID- 22219149 TI - Contribution of [64Cu]-ATSM PET in molecular imaging of tumour hypoxia compared to classical [18F]-MISO--a selected review. AB - During the carcinogenesis process, tumour cells often have a more rapid proliferation potential than cells that participate in blood capillary formation by neoangiogenesis. As a consequence of the poorly organized vasculature of various solid tumours, a limited oxygen delivery is observed. This hypoxic mechanism frequently occurs in solid cancers and can lead to therapeutic resistance. The present selected literature review is focused on the comparison of two positron emitting radiopharmaceuticals agents, which are currently leaders in tumour hypoxia imaging by PET. {18F}-fluoromisonidazole (=FMISO) is most commonly used as an investigational PET agent with an investigational new drug exemption from the FDA, while {64Cu}-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) has been presented as an alternative radiopharmaceutical not yet readily available. The comparison of these two radiopharmaceutical agents is particularly focused on isotope properties, radiopharmaceutical labelling process, pharmacological mechanisms, dosimetry data in patients, and clinical results in terms of image contrast. PET imaging has demonstrated a good efficacy in tumour hypoxia imaging with both FMISO and Cu-ATSM, but FMISO has presented too slow an in vivo accumulation and a weak image contrast of the hypoxia area. Despite a less favourable dosimetry, 64Cu-ATSM appears superior in terms of imaging performance, calling for industrial and clinical development of this innovative radiopharmaceutical. PMID- 22219150 TI - Radioisotope therapy of bone metastases. AB - Radionuclide therapy has been an integral part of systemic treatment of patients with advanced and disseminated cancer for 50 years. Specific radioisotopes (b- or a-emitters) with selective concentration at sites of bone cancer damage are used in the treatment. Radioisotopes are an important addition to the armamentarium of clinicians who take care of patients with advanced cancer and painful cancer bone metastases (especially osteoblastic and mixed type). They offer a high degree of efficacy with minimal toxicity and simple administration, fulfilling the fundamental criteria for palliative treatment that should combine minimal patient discomfort and toxicity with maximal clinical effect. PMID- 22219151 TI - Bone metastases diagnosis possibilities in studies with the use of 18F-NaF and 18F-FDG. AB - Scintigraphy of the skeletal system is performed mainly with the use of 99mTc MDP. There are other radiopharmaceuticals showing affinity to bone lesions: 99mTc MIBG, 201Tl, 131I (in the case of papillary or follicular thyroid cancers), and 99mTc (V) DMSA (in the case of medullary cancer). Currently, positron emitted radioisotopes are also used in clinical practice. It seems that 18F-NaF/PET is a highly sensitive and specific modality for detection of metastases and other bone lesions. Certain data concerning the role of 18F-FDG, 18F-choline, or 68Ga DOTATATE can be found. The aim of this article is to review the role of 18F-NaF and 18F-FDG in diagnosis of bone metastases. PMID- 22219152 TI - A false-positive finding in therapeutic evaluation: hypermetabolic axillary lymph node in a lymphoma patient following FDG extravasation. AB - We report a case of a false-positive finding in FDG PET/CT following radiotracer extravasation. A 15-year-old male patient was referred for therapeutic evaluation status post-chemotherapy for a lymphoblastic lymphoma. FDG PET/CT showed discordant findings with a marked decrease in a liver/hepatic hilum uptake, disappearance of a subcutaneous left supraclavicular uptake, and appearance of intense right axillary nodal uptake. Extravasation in the right superior limb was noted. Comparison with the previous scan showed that the axillary nodes were present, measured less than 1 cm in their short axis, had not increased in size, and had a fatty hilum. We concluded that FDG uptake was caused by a migration in lymphatic vessels. PMID- 22219153 TI - The role of gated myocardial perfusion scintigraphy (GMPS) in myocarditis: a case report and review of the literature. AB - Acute myocarditis is one of the most challenging diagnoses and treatments in cardiology. The acute viral myocarditis diagnosis is usually based on high suspicion, history taking, and physical examination. Likewise, the use of chest radiography, electrocardiography (ECG), and echocardiography is helpful in making a final diagnosis, but all are non-specific. In addition, in imaging query, magnetic resonance imaging (MRI) depicts some degree of cardiac inflammation in the course of myocarditis. Myocardial perfusion imaging (MPI) has also been shown to be useful in diagnosis, and this noninvasive technique diminishes the need for myocardial biopsy. The current study presents the diagnostic and prognostic role of MPI in a 25-year-old patientwith suspected myocarditis. The patient underwent gated-technetium- 99m-lablled, methoxyisobutyl isonitrile, single photon emission computed tomography (Gated 99mTc-MIBI SPECT) that showed nonheterogeneous absorption with remarkable decreased radiotracer uptake in the myocardium in both stress and rest phases. In addition, the gated mode demonstrated decreased wall motion and thickening of the myocardium with a sum motion score (SMS) of 28, a sum thickening score (STS) of 15, and a measured LVEF of 34%. The study concludes that 99mTC-MIBI SPECT imaging is a useful modality in the preparation of supplementary diagnostic and prognostic information in viral myocarditis. PMID- 22219154 TI - Detection of splenic tissue by 99mTc-labelled Sn-colloid SPECT/CT scintigraphy. AB - This paper presents a case of an 80-year-old man with idiopathic thrombocytopenic purpura after splenectomy performed many years ago, which normalized platelet count, presented with severe thrombocytopenia with no response to treatment. A SPECT/CT study was performed using 99mTc-labelled Sn-colloid. The histology confirmed the presence of splenic tissue in those foci. Spleen examination (SPECT/CT) using 99mTc-labelled Sn-colloid is able to detect splenic tissue and in our opinion is a simpler and less time-consuming procedure than using 99mTc DRBC. PMID- 22219155 TI - [11C]-choline PET/CT in imaging locally advanced prostate cancer. AB - PET Imaging with [11C]-choline has become a useful tool in the investigation of prostate cancer, with as main application the assessment of previously treated patients presenting with rising PSA and negative conventional imaging procedures. In this case report we describe [11C]-choline PET/CT findings in a patient with a locally advanced cancer, which could be successfully identified thanks to the early image acquisition and the delayed urinary excretion of the carbon-11 labeled tracer. PMID- 22219157 TI - Report from the opening of a new PET-CT-NMR centre in Cracow, Poland, June 10, 2011. PMID- 22219158 TI - Report from the 1st World Congress on Gallium-68 and Peptide Receptor Radio Nuclide Therapy (PRRNT), Bad Berka (Germany), June 23-26, 2011. PMID- 22219161 TI - Letter from the editor. PMID- 22219162 TI - Reducing HPV-associated cancer globally. AB - Human papillomavirus (HPV)-related cancers are a major worldwide public health concern. Virtually all cervical cancer is HPV related, with 70% caused by HPV16 and -18. Variable proportions of certain noncervical cancers (e.g., anal, vulvar, and oropharyngeal) are HPV related; more than 90% of the HPV-related ones are caused by HPV16, -18. The HPV-related cancers are dominated by cervical cancer in the developing world, where cervical cancer screening is limited. In this setting, widespread uptake of current HPV vaccines by adolescent girls could reduce this cancer's incidence and mortality by approximately two-thirds, with cost-effective screening programs of adult women having the potential to reduce mortality more rapidly. In the industrialized world, some noncervical HPV-related cancers, especially oropharyngeal, are rapidly increasing, and now rival the incidence of cervical cancer, whose rates continue to decline thanks to established cervical screening programs. Therefore, reducing HPV-associated noncervical cancers with HPV vaccination has greater importance in the industrialized world, especially because there are no approved screening programs for these cancers. Preventing the substantial number of noncervical HPV cancers in men will require either "herd" immunity through high-vaccination rates in females or male vaccination. Current HPV vaccination can complement cervical screening in protecting against cervical cancer and may permit the safe reduction of screening intensity in industrialized countries. Second-generation HPV vaccines (active against a broader array of cervical cancer-related HPV types) could prevent an even higher proportion of cervical precancer and cancer and might permit further reductions in screening intensity. PMID- 22219163 TI - Preventing cancer with vaccines: progress in the global control of cancer. AB - The cancer control community is largely unaware of great advances in the control of major human cancers with vaccines, including the dramatic control of hepatocellular (liver) cancer with hepatitis B virus (HBV) vaccine, now used routinely in more than 90% of countries. The biotechnology revolution has given us a new generation of highly effective vaccines against major global killers, global funding for immunization is orders of magnitude higher than ever before, and the vaccine delivery infrastructure has improved very significantly even in the poorest countries. Liver cancer is the greatest cause of cancer deaths in men of sub-Saharan Africa and much of Asia. Even in highly endemic countries such as China, the prevalence of HB surface antigen carriers has fallen from 10% to 1%-2% in immunized cohorts of children, and liver cancer has already fallen dramatically in Taiwanese children. The Global Alliance for Vaccines and Immunization (now called the GAVI Alliance) has greatly expedited this success by providing HBV vaccine free for five years in most of the world's 72 poorest countries. HBV vaccination can serve as a model for the global control of human papillomavirus (HPV)-related cervical and other cancers with HPV vaccines. Cervical cancer is the greatest cause of cancer death in women in many developing countries; HPV vaccines are highly effective in preventing HPV infection and precancerous lesions in women, and the quadrivalent vaccine also prevents genital warts in men and women and precancerous anal lesions in men. HPV is causing a growing proportion of oropharyngeal cancers, and HPV-related noncervical cancers (penile, anal, and oropharyngeal) may exceed the incidence of cervical cancer within a decade in industrial countries, where cervical screening is effective, causing reevaluation of male HPV immunization. In developing countries, few women are screened for cervical precancerous lesions, making immunization even more important. Currently, 26 primarily industrial countries routinely immunize girls with HPV vaccine, and GAVI will begin to accept applications in 2012 to fund vaccine in developing countries that can deliver the vaccine and if GAVI can negotiate an acceptable price (one manufacturer has already offered a price of $5 per dose). PMID- 22219164 TI - Strawberry fields forever? AB - On the basis of copious preclinical data supporting the preventive efficacy of small fruits such as berries and grapes, Chen and colleagues conducted a randomized (noncomparative) phase II trial evaluating two doses of strawberry powder (60 g/d or 30 g/d for six months) to prevent esophageal cancer in China (reported in this issue of the journal, beginning on page 41); 60 g/d reduced the histologic grade of dysplastic lesions and reduced localized biomarkers, whereas 30 g/d was not effective. Fundamental questions remain such as the best formulation of strawberry powder, the active components associated with powder, and the actual mechanism of action, and standardized preparations will be required to permit the widespread use of strawberry powder with a predicable outcome. Clearly, however, this work is a good example of proof-of-principle and highlights the important role of diet, nutrition, and natural products in cancer prevention. PMID- 22219165 TI - Assessment of interpersonal skills in obese women with binge eating disorder. AB - Based upon interpersonal theory that suggests an association between binge eating disorder (BED) and interpersonal problems, the present study examined empathy and other social skills of obese women with BED. The findings showed that five social skills were statistically associated with the chance of presenting BED. Obese women with less assertiveness, lower ability to express feelings, lower capacity to deal with strangers, lower ability to understand the perspective of others, and with higher levels of distress in interpersonal situations had a higher probability of presenting the diagnosis of BED. These results highlight an association between social skills deficits and BED. PMID- 22219166 TI - Population pharmacokinetic/pharmacodynamic model for the sedative effects of flibanserin in healthy volunteers. AB - PURPOSE: Flibanserin is being developed for treating hypoactive sexual desire disorder in women; the main side effect is sedation. The analysis objective was to relate flibanserin plasma concentrations with acute sedative effects using a population pharmacokinetic/pharmacodynamic (PK/PD) model. METHODS: The population model was developed with NONMEM based on data from 24 healthy volunteers. "Drowsiness" was serially assessed by a Visual Analogue Scale (VAS) on a baseline day and after morning oral administration of 100 mg flibanserin together with PK sampling. RESULTS: PK was best described by a three-compartment disposition model and transit compartments accounting for the lag time in absorption. VAS "drowsiness" baseline profiles were modeled using linear splines with three breakpoints located at clock times at first and last observation, and at the median of the observation time across subjects. The drug effect followed a sigmoidal E(MAX) model using predicted effect site concentrations (C(e)). The VAS vs. C(e) relationship was very steep and effect site and plasma concentration time profiles were very similar thus suggesting little delay between the occurrence of maximum flibanserin plasma concentrations and drowsiness. CONCLUSIONS: At effect site concentrations lower than ~ 200 ng/mL that are reached approximately 4 h after administration, flibanserin shows hardly any effect on the VAS "drowsiness" scale. PMID- 22219167 TI - Stabilization of a supersaturated solution of mefenamic acid from a solid dispersion with EUDRAGIT((r)) EPO. AB - PURPOSE: The stabilization mechanism of a supersaturated solution of mefenamic acid (MFA) from a solid dispersion with EUDRAGIT((r)) EPO (EPO) was investigated. METHODS: The solid dispersions were prepared by cryogenic grinding method. Powder X-ray diffractometry, in vitro dissolution test, in vivo oral absorption study, infrared spectroscopy, and solid- and solution-state NMR spectroscopies were used to characterize the solid dispersions. RESULTS: Dissolution tests in acetate buffer (pH 5.5) revealed that solid dispersion showed > 200-fold higher concentration of MFA. Supersaturated solution was stable over 1 month and exhibited improved oral bioavailability of MFA in rats, with a 7.8-fold higher area under the plasma concentration-versus-time curve. Solid-state (1)H spin lattice relaxation time (T(1)) measurement showed that MFA was almost monomolecularly dispersed in the EPO polymer matrix. Intermolecular interaction between MFA and EPO was indicated by solid-state infrared and (13)C-T(1) measurements. Solution-state (1)H-NMR measurement demonstrated that MFA existed in monomolecular state in supersaturated solution. (1)H-T(1) and difference nuclear Overhauser effect measurements indicated that cross relaxation occurred between MFA and EPO due to the small distance between them. CONCLUSIONS: The formation and high stability of the supersaturated solution were attributable to the specifically formed intermolecular interactions between MFA and EPO. PMID- 22219168 TI - Barriers to translating diagnostic research in febrile children to clinical practice: a systematic review. AB - BACKGROUND: Although the topic of identifying febrile children at risk of serious infections has been addressed by numerous research groups, identified predictors remain diverse and implementation of results in routine practice has been limited. The aim of this paper is to discuss the problems and challenges in advancing diagnostic research in febrile children. METHODS: The characteristics and results of 35 studies identified from a systematic review on predictors for febrile children were evaluated. RESULTS: Current diagnostic research is mainly performed in subpopulations, defined by age and temperature limits and in paediatric emergency settings, ignoring the role of primary care. It is characterised by a dichotomous approach of outcomes and a wide variability of potential predictors. Validation of results to other settings and impact studies of prediction rules on patient outcomes are scarce. In designing diagnostic studies on children suspected of serious infections focus is needed on all clinically relevant populations within the spectrum of primary care and emergency department settings. Consensus is also needed on the definition of fever, the concept of serious infection and the set of predictors to focus on. The heterogeneity of patients in different settings and countries stress the need for continuous updating of prediction rules in routine practice. Broad validation in different clinical settings and countries and impact analysis in routine care is essential. CONCLUSIONS: Scientists in the field of diagnosis of serious infection in children must agree on core design features to be incorporated in all studies in the area of diagnostic research in febrile children. This will improve evidence from future studies, and their generalisability and implementation in routine practice. PMID- 22219169 TI - DNA methylation does not stably lock gene expression but instead serves as a molecular mark for gene silencing memory. AB - DNA methylation is commonly thought of as a "molecular lock" that leads to permanent gene silencing. To investigate this notion, we tested 24 different histone deacetylase inhibitors (HDACi) on colon cancer cells that harbor a GFP locus stably integrated and silenced by a hypermethylated cytomegalovirus (CMV) promoter. We found that HDACi efficiently reactivated expression of GFP and many other endogenous genes silenced by DNA hypermethylation. After treatment, all promoters were marked with active chromatin, yet DNA hypermethylation did not change. Thus, DNA methylation could not prevent gene reactivation by drug-induced resetting of the chromatin state. In evaluating the relative contribution of DNA methylation and histone modifications to stable gene silencing, we followed expression levels of GFP and other genes silenced by DNA hypermethylation over time after treatment with HDACi or DNA-demethylating drugs. Reactivation of methylated loci by HDACi was detectable for only 2 weeks, whereas DNA demethylating drugs induced permanent epigenetic reprogramming. Therefore, DNA methylation cannot be considered as a lock for gene expression but rather as a memory signal for long-term maintenance of gene silencing. These findings define chromatin as an important druggable target for cancer epigenetic therapy and suggest that removal of DNA methylation signals is required to achieve long-term gene reactivation. PMID- 22219170 TI - Health-related quality of life of Spanish children with cystic fibrosis. AB - PURPOSE: To investigate (1) the contributions of sex, age, nutritional status- and physical-fitness-related variables on health-related quality of life (HRQOL) in Spanish children with cystic fibrosis, and (2) the agreement on HRQOL between children and their parents. METHODS: In 28 children aged 6-17 years, body mass index percentile, percentage body fat, physical activity, pulmonary function, cardiorespiratory fitness, functional mobility, and dynamic muscle strength were determined using objective measures. HRQOL was measured using the revised version of the cystic fibrosis questionnaire. Simple and multiple linear regression analyses were performed to determine the variables associated with HRQOL. To assess the agreement on HRQOL between children and parents, intra-class correlation coefficients (ICCs) were calculated. RESULTS: Girls reported worse emotional functioning, a higher treatment burden, and more respiratory problems than boys. Greater functional mobility appeared associated with a less favourable body image and more eating disturbances. Agreement on HRQOL between children and parents was good to excellent, except for the domain of treatment burden. CONCLUSIONS: Sex and age were stronger predictors of HRQOL than nutritional status- or physical-fitness-related variables. Children reported a lower treatment burden than their parents perceived them to have. PMID- 22219172 TI - Drinking patterns, psychological distress and quality of life in a Norwegian general population-based sample. AB - BACKGROUND: The purpose of this study was to investigate possible relationships between drinking patterns, psychological distress and quality of life (QoL) in a general population-based sample in Norway. METHODS: A random sample of 4,000 Norwegian citizens, aged 18 to 79, was drawn from the National Register held by Statistics Norway. RESULTS: Males consumed significantly more alcohol and reported more drinking-related problems with more negative consequences, compared to females. Psychological distress increased, and all QoL domain scores decreased with increasing alcohol consumption within the group drinking alcohol at all. The excessive drinkers demonstrated the highest level of psychological distress and lowest QoL in the psychological, social relationships and environment domains. Non-drinkers reported to have poorest QoL in the physical health domain, whereas light and moderate drinkers demonstrated lowest psychological distress and best QoL. Psychological distress demonstrated substantial more importance for QoL than socio-demographic variables, alcohol consumption, alcohol dependency and negative consequences of alcohol use did. CONCLUSION: The findings indicate the need for a focus on psychological distress and its negative impact upon all QoL domains. Attention should also be paid to excessive drinkers who have poor QoL (psychological, social relationships and environment domains) and a high level of psychological distress. In addition, non-drinkers reported poor physical health. Further research is needed concerning the relation between alcohol consumption, psychological distress and QoL both in general population studies and in more specific samples. PMID- 22219173 TI - The uncut jade: differing views of the potential of expert users on staff training and rehabilitation programmes for service users in Hong Kong. AB - BACKGROUND: Service user participation in direct service provision and evaluation has been developing in the western world in the past 20 years. However, this recovery-based care model is relatively new in Asia. AIM: To understand the views and perceptions of the service users and of psychiatric nurses about the recruitment of peer specialists in a regional psychiatric unit in Hong Kong. METHOD: A qualitative study using probe questions to understand the above issues in the form of focus group discussion. A total of 13 psychiatric nurses and 16 mental health service users were recruited from a regional psychiatric unit for the study. RESULTS: Content analysis based loosely on grounded theory has identified several important themes. While service users are generally enthusiastic about the potential contribution of peer specialists in a service setting, they are much concerned about rejection and discrimination by the psychiatric staff. Psychiatric nurses are also sceptical about the involvement of peer specialists in the delivery of service, although for an entirely different set of reasons. In view of the divergent views of the service users and the psychiatric nurses, a second round of focus group discussion was conducted seven months later to understand whether the themes distilled were consistent with their views expressed in the first round of focus group discussion. CONCLUSION: It is encouraging is that, for those psychiatric nurses who worked with volunteer service users in the pilot scheme of 'expert user participation', there was a change in view towards positive acceptance about peer specialist involvement in service delivery. The study provides some insight into the potential obstacles to and opportunities in the implementation of peer specialist services in routine psychiatric services in Hong Kong. PMID- 22219174 TI - A description of local pig feeding systems in village smallholder farms of Western Kenya. AB - We used face-to-face interviews to gather data on pig feeding practices in rural Busia District, Kenya. We visited 164 pig farms three times in the course of the study period. The pigs were weighed in kilograms during the visits. Feeds offered to pigs were described during the interviews. The most frequently fed feedstuffs were; ground maize or "ugali" (88%), kitchen leftovers (83%) and dried fish locally called "omena" (78%). Farmers provided pigs with water separately from the feeds. Sweet potatoes, "ugali" and cassava were available and could serve as good sources of energy for pigs in the district. Fruits and vegetables were also available and could potentially act as good sources of vitamins. Sweet potato vines, "omena" fish and slaughter blood were available and could provide pigs with proteins. The average daily gain (ADG) for pigs <= 5 months of age, pigs of 5.1-9.9 months of age and pigs of >= 10 months old was 94.5 (+/- 43), 127 (+/- 49.8) and 99 (+/- 92) g, respectively (p = 0.000). This study has outlined the different local pig feeds available in Busia district. We recommend two things: first, additional research on nutrient composition for the identified local feeds, and second, developing and validating simple local feed combinations that would achieve balanced local pig rations. PMID- 22219175 TI - Racial differences in restless legs symptoms and serum ferritin in an incident dialysis patient cohort. AB - PURPOSE: Restless legs syndrome (RLS), a debilitating sleep disorder that is frequently reported by CKD patients on dialysis, may be more common in whites than in non-whites. Iron deficiency is associated with RLS, and serum ferritin is higher among African Americans compared to Caucasians in the general population. No prior studies have compared restless legs symptoms and serum ferritin levels of African-American and those of the Caucasian patients on dialysis. METHODS: In a multicenter observational study that included in-person interviews and medical chart review, we studied 210 patients who had recently started renal dialysis. Predictors of restless legs symptoms were examined in a multivariable logistic regression model. RESULTS: African Americans had a reduced risk of restless legs complaint compared to Caucasian patients (OR, 0.44 [95% CI 0.21-0.93]; P=0.03). African-American patients were also less likely than Caucasian patients to have low serum ferritin values (<100 ng/ml), and among patients with serum ferritin>=100 ng/ml, the average serum ferritin of African-American patients was higher than that of Caucasian patients. CONCLUSIONS: Further study of racial and iron status relationships could advance the understanding of RLS pathophysiology, and RLS is an important patient outcome to monitor, as revised anemia and iron protocols are implemented in the clinical setting. PMID- 22219176 TI - Time to differentiate 'decreased kidney function' from 'kidney disease': towards improving the definition of chronic kidney disease. AB - Chronic kidney disease (CKD) has become an 'epidemic' worldwide, since the publication of K/DOQI guidelines in 2002. This classification indeed has raised the profile of CKD worldwide. However, despite limitations of the glomerular filtration rate (GFR) estimating equations, the majority of this epidemic is caused by the large number of persons with stage 3 CKD, with many elderly individuals with 'low-normal GFR' being diagnosed with CKD, when, in fact, the majority of those may not have the disease, and a handful of resources being utilized in investigating these relatively 'low-risk patients' with 'decreased eGFR' without CKD. Recently, concerns have been raised by nephrologists about this classification system, and I strongly feel that it is important to differentiate 'decreased kidney function' from 'kidney disease', as the GFR estimating equations predict renal function only and nothing else; therefore, I propose some modifications to improve the current classification, so that limited resources and efforts are effectively focused on managing high-risk patients. PMID- 22219178 TI - MHC class I molecules act as tumor suppressor genes regulating the cell cycle gene expression, invasion and intrinsic tumorigenicity of melanoma cells. AB - The alteration of MHC class I (MHC-I) expression is a frequent event during cancer progression, allowing tumor cells to evade the immune system. We report that the loss of one major histocompatibility complex haplotype in human melanoma cells not only allowed them to evade immunosurveillance but also increased their intrinsic oncogenic potential. A second successive defect in MHC-I expression, MHC-I total downregulation, gave rise to melanoma cells that were more oncogenic per se in vivo and showed a higher proliferation rate and greater migratory and invasive potential in vitro. All these processes were reversed by restoring MHC-I expression via human leukocite antigen-A2 gene transfection. MHC-I cell surface expression was inversely correlated with intrinsic oncogenic potential. Modifications in the expression of various cell cycle genes were correlated with changes in MHC-I expression; the most important differences among the melanoma cell lines were in the transcriptional level of AP2-alpha, cyclin A1 and p21WAF1/CIP1. According to these results, altered MHC-I expression in malignant cells can directly increase their intrinsic oncogenic and invasive potential and modulate the expression of cell cycle genes. These findings suggest that human leukocite antigen class I molecules may act directly as tumor suppressor genes in melanoma. PMID- 22219177 TI - A genome-wide search for loci interacting with known prostate cancer risk associated genetic variants. AB - Genome-wide association studies (GWAS) have identified ~30 single-nucleotide polymorphisms (SNPs) consistently associated with prostate cancer (PCa) risk. To test the hypothesis that other sequence variants in the genome may interact with those 32 known PCa risk-associated SNPs identified from GWAS to affect PCa risk, we performed a systematic evaluation among three existing PCa GWAS populations: CAncer of the Prostate in Sweden population, a Johns Hopkins Hospital population, and the Cancer Genetic Markers of Susceptibility population, with a total sample size of 4723 PCa cases and 4792 control subjects. Meta-analysis of the interaction term between each of those 32 SNPs and SNPs in the genome was performed in three PCa GWAS populations. The most significant interaction detected was between rs12418451 in MYEOV and rs784411 in CEP152, with a P(interaction) of 1.15 * 10(-7) in the meta-analysis. In addition, we emphasized two pairs of interactions with potential biological implication, including an interaction between rs7127900 near insulin-like growth factor-2 (IGF2)/IGF2AS and rs12628051 in TNRC6B, with a P(interaction) of 3.39 * 10(-6) and an interaction between rs7679763 near TET2 and rs290258 in SYK, with a P(interaction) of 1.49 * 10(-6). Those results show statistical evidence for novel loci interacting with known risk-associated SNPs to modify PCa risk. The interacting loci identified provide hints on the underlying molecular mechanism of the associations with PCa risk for the known risk-associated SNPs. Additional studies are warranted to further confirm the interaction effects detected in this study. PMID- 22219179 TI - Repression of mammosphere formation of human breast cancer cells by soy isoflavone genistein and blueberry polyphenolic acids suggests diet-mediated targeting of cancer stem-like/progenitor cells. AB - Mammary stem cells are undifferentiated epithelial cells, which initiate mammary tumors and render them resistant to anticancer therapies, when deregulated. Diets rich in fruits and vegetables are implicated in breast cancer risk reduction, yet underlying mechanisms are poorly understood. Here, we addressed whether dietary factors selectively target mammary epithelial cells that display stem like/progenitor subpopulations with previously recognized tumor-initiating potential. Using estrogen receptor-positive MCF-7 and estrogen receptor-negative MDA-MB-231 human breast cancer cell lines and freshly isolated epithelial cells from MMTV-Wnt-1 transgenic mouse mammary tumors, we demonstrate that sera of adult mice consuming soy isoflavone genistein (GEN) or blueberry (BB) polyphenol containing diets alter the population of stem-like/progenitor cells, as measured by their functional ability to self-renew and form anchorage-independent spheroid cultures in vitro at low frequency (1-2%). Serum effects on mammosphere formation were dose-dependently replicated by GEN (40 nM >2 MUM) and targeted the basal stem-like CD44+/CD24-/ESA+ and the luminal progenitor CD24+ subpopulations in MDA MB-231 and MCF-7 cells. GEN inhibition of mammosphere formation was mimicked by the Akt inhibitor perifosine and was associated with enhanced tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) expression. In contrast, a selected mixture of BB phenolic acids was only active in MDA-MD-231 cells and its CD44+/CD24-/ESA+ subpopulation, and this activity was independent of induction of PTEN expression. These findings delineate a novel and selective function of distinct dietary factors in targeting stem/progenitor cell populations in estrogen receptor-dependent and -independent breast cancers. PMID- 22219180 TI - GATA4 expression is primarily regulated via a miR-26b-dependent post transcriptional mechanism during cardiac hypertrophy. AB - AIMS: GATA4 is a transcription factor that is up-regulated during cardiac hypertrophy and plays a fundamental role in myocyte growth and survival. In this study, we investigate the transcriptional vs. post-transcriptional mechanisms that are involved in regulating GATA4 in the heart during neonatal and pressure overload-induced hypertrophic growth. METHODS AND RESULTS: GATA4 protein is significantly higher during pressure overload-induced (2.9 +/- 0.4-fold) and neonatal (6.8 +/- 1-fold) hypertrophic growth vs. the normal adult mouse heart. Using RNA polymerase II immunoprecipitation combined with deep sequencing, we confirmed that active transcription of the Gata4 gene remained unchanged during hypertrophy, whereas it was two-fold higher in the neonatal vs. adult heart, commensurate with the mRNA levels. These results suggested a post-transcriptional mode of regulation of its expression, which prompted the identification of a conserved sequence in its 3'-untranslated region that was responsible for reduced translation via miR-26b. Overexpression of miR-26b reduced GATA4-dependent transcription, endothelin-induced hypertrophy, and sensitized the cells to apoptotic insults. Additionally, miR-26b targeted phospholipase C-beta1, which, in turn, inhibited miR-26b expression, creating a double-negative feedback loop. Accordingly, overexpression of miR-26b in the heart inhibited up-regulation of its targets and the development of hypertrophy. However, knockdown of miR-26b is not sufficient for inducing hypertrophy. CONCLUSION: Down-regulation of miR-26b in the heart is required for the up-regulation of GATA4 and the induction of pressure-induced cardiac hypertrophy. The results also underscore the functional relevance of miRNAs in regulating gene expression during cardiac hypertrophy. PMID- 22219181 TI - Novel role for non-muscle myosin light chain kinase (MLCK) in hyperoxia-induced recruitment of cytoskeletal proteins, NADPH oxidase activation, and reactive oxygen species generation in lung endothelium. AB - We recently demonstrated that hyperoxia (HO) activates lung endothelial cell NADPH oxidase and generates reactive oxygen species (ROS)/superoxide via Src dependent tyrosine phosphorylation of p47(phox) and cortactin. Here, we demonstrate that the non-muscle ~214-kDa myosin light chain (MLC) kinase (nmMLCK) modulates the interaction between cortactin and p47(phox) that plays a role in the assembly and activation of endothelial NADPH oxidase. Overexpression of FLAG tagged wild type MLCK in human pulmonary artery endothelial cells enhanced interaction and co-localization between cortactin and p47(phox) at the cell periphery and ROS production, whereas abrogation of MLCK using specific siRNA significantly inhibited the above. Furthermore, HO stimulated phosphorylation of MLC and recruitment of phosphorylated and non-phosphorylated cortactin, MLC, Src, and p47(phox) to caveolin-enriched microdomains (CEM), whereas silencing nmMLCK with siRNA blocked recruitment of these components to CEM and ROS generation. Exposure of nmMLCK(-/-) null mice to HO (72 h) reduced ROS production, lung inflammation, and pulmonary leak compared with control mice. These results suggest a novel role for nmMLCK in hyperoxia-induced recruitment of cytoskeletal proteins and NADPH oxidase components to CEM, ROS production, and lung injury. PMID- 22219182 TI - Chromodomain helicase DNA-binding protein 4 (CHD4) regulates homologous recombination DNA repair, and its deficiency sensitizes cells to poly(ADP-ribose) polymerase (PARP) inhibitor treatment. AB - To ensure genome stability, cells have evolved a robust defense mechanism to detect, signal, and repair damaged DNA that is generated by exogenous stressors such as ionizing radiation, endogenous stressors such as free radicals, or normal physiological processes such as DNA replication. Homologous recombination (HR) repair is a critical pathway of repairing DNA double strand breaks, and it plays an essential role in maintaining genomic integrity. Previous studies have shown that BRIT1, also known as MCPH1, is a key regulator of HR repair. Here, we report that chromodomain helicase DNA-binding protein 4 (CHD4) is a novel BRIT1 binding partner that regulates the HR repair process. The BRCA1 C-terminal domains of BRIT1 are required for its interaction with CHD4. Depletion of CHD4 and overexpression of the ATPase-dead form of CHD4 impairs the recruitment of BRIT1 to the DNA damage lesions. As a functional consequence, CHD4 deficiency sensitizes cells to double strand break-inducing agents, reduces the recruitment of HR repair factor BRCA1, and impairs HR repair efficiency. We further demonstrate that CHD4-depleted cells are more sensitive to poly(ADP-ribose) polymerase inhibitor treatment. In response to DNA damage induced by poly(ADP ribose) polymerase inhibitors, CHD4 deficiency impairs the recruitment of DNA repair proteins BRIT1, BRCA1, and replication protein A at early steps of HR repair. Taken together, our findings identify an important role of CHD4 in controlling HR repair to maintain genome stability and establish the potential therapeutic implications of targeting CHD4 deficiency in tumors. PMID- 22219183 TI - C-terminal mutations destabilize SIL1/BAP and can cause Marinesco-Sjogren syndrome. AB - Marinesco-Sjogren syndrome (MSS) is an autosomal recessive, neurodegenerative, multisystem disorder characterized by severe phenotypes developing in infancy. Recently, mutations in the endoplasmic reticulum (ER)-associated co-chaperone SIL1/BAP were identified to be the major cause of MSS. SIL1 acts as a nucleotide exchange factor for BiP, the ER Hsp70 orthologue, which plays an essential role in the folding and assembly of nascent polypeptide chains in the ER. SIL1 facilitates the release of BiP from unfolded protein substrates, enabling the subsequent folding and transport of the protein. Although most mutations leading to MSS result in deletion of the majority of the protein, three separate mutations have been identified that disrupt only the last five or six amino acids of the protein, which were assumed to encode a divergent ER retention motif. This study presents an in depth analysis of two of these mutants and reveals that the phenotype in the affected individuals is not likely to be due to depletion of SIL1 from the ER via secretion. Instead, our analyses show that the mutant proteins are particularly unstable and either form large aggregates in the ER or are rapidly degraded via the proteasome. In agreement with our findings, homology modeling suggests that the very C-terminal residues of SIL1 play a role in its structural integrity rather than its localization. These new insights might be a first step toward a possible pharmacological treatment of certain types of MSS by specifically stabilizing the mutant SIL1 protein. PMID- 22219184 TI - Structural basis for sequence-specific DNA recognition by an Arabidopsis WRKY transcription factor. AB - The WRKY family transcription factors regulate plant-specific reactions that are mostly related to biotic and abiotic stresses. They share the WRKY domain, which recognizes a DNA element (TTGAC(C/T)) termed the W-box, in target genes. Here, we determined the solution structure of the C-terminal WRKY domain of Arabidopsis WRKY4 in complex with the W-box DNA by NMR. A four-stranded beta-sheet enters the major groove of DNA in an atypical mode termed the beta-wedge, where the sheet is nearly perpendicular to the DNA helical axis. Residues in the conserved WRKYGQK motif contact DNA bases mainly through extensive apolar contacts with thymine methyl groups. The importance of these contacts was verified by substituting the relevant T bases with U and by surface plasmon resonance analyses of DNA binding. PMID- 22219185 TI - Four-and-a-half LIM domain proteins inhibit transactivation by hypoxia-inducible factor 1. AB - Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that promotes angiogenesis, metabolic reprogramming, and other critical aspects of cancer biology. The four-and-a-half LIM domain (FHL) proteins are a family of LIM domain only proteins implicated in transcriptional regulation and suppression of tumor growth. Here we describe functional interactions between the FHL proteins and HIF 1. FHL1-3 inhibit HIF-1 transcriptional activity and HIF-1alpha transactivation domain function by oxygen-independent mechanisms. FHL2 directly interacts with HIF-1alpha to repress transcriptional activity. FHL1 binds to the p300/CBP co activators and disrupts binding with HIF-1alpha. FHL3 does not bind to HIF-1alpha or p300, indicating that it regulates transactivation by a novel molecular mechanism. Expression of the FHL proteins increased upon HIF-1alpha induction, suggesting the existence of a feedback loop. These results identify FHL proteins as negative regulators of HIF-1 activity, which may provide a mechanism by which they suppress tumor growth. PMID- 22219186 TI - Selective Oma1 protease-mediated proteolysis of Cox1 subunit of cytochrome oxidase in assembly mutants. AB - Stalled biogenesis of the mitochondrial cytochrome c oxidase (CcO) complex results in degradation of subunits containing redox cofactors. The conserved Oma1 metalloproteinase mediates facile Cox1 degradation in cells lacking the Coa2 assembly factor, but not in a series of other mutants stalled in CcO maturation. Oma1 is activated in coa2Delta cells, but the selective Cox1 degradation does not arise merely from its activation. Oma1 is also active in cells with dysfunctional mitochondria and cox11Delta cells impaired in CcO maturation, but this activation does not result in Oma1-mediated Cox1 degradation. The facile and selective degradation of Cox1 in coa2Delta cells, relative to other CcO assembly mutants, is likely due to impaired hemylation and subsequent misfolding of the subunit. Specific Cox1 proteolysis in coa2Delta cells arises from a combination of Oma1 activation and a susceptible conformation of Cox1. PMID- 22219188 TI - Insights into diterpene cyclization from structure of bifunctional abietadiene synthase from Abies grandis. AB - Abietadiene synthase from Abies grandis (AgAS) is a model system for diterpene synthase activity, catalyzing class I (ionization-initiated) and class II (protonation-initiated) cyclization reactions. Reported here is the crystal structure of AgAS at 2.3 A resolution and molecular dynamics simulations of that structure with and without active site ligands. AgAS has three domains (alpha, beta, and gamma). The class I active site is within the C-terminal alpha domain, and the class II active site is between the N-terminal gamma and beta domains. The domain organization resembles that of monofunctional diterpene synthases and is consistent with proposed evolutionary origins of terpene synthases. Molecular dynamics simulations were carried out to determine the effect of substrate binding on enzymatic structure. Although such studies of the class I active site do lead to an enclosed substrate-Mg(2+) complex similar to that observed in crystal structures of related plant enzymes, it does not enforce a single substrate conformation consistent with the known product stereochemistry. Simulations of the class II active site were more informative, with observation of a well ordered external loop migration. This "loop-in" conformation not only limits solvent access but also greatly increases the number of conformational states accessible to the substrate while destabilizing the nonproductive substrate conformation present in the "loop-out" conformation. Moreover, these conformational changes at the class II active site drive the substrate toward the proposed transition state. Docked substrate complexes were further assessed with regard to the effects of site-directed mutations on class I and II activities. PMID- 22219187 TI - Molecular determinants of enterovirus 71 viral entry: cleft around GLN-172 on VP1 protein interacts with variable region on scavenge receptor B 2. AB - Enterovirus 71 (EV71) is one of the major pathogens that cause hand, foot, and mouth disease outbreaks in young children in the Asia-Pacific region in recent years. Human scavenger receptor class B 2 (SCARB2) is the main cellular receptor for EV71 on target cells. The requirements of the EV71-SCARB2 interaction have not been fully characterized, and it has not been determined whether SCARB2 serves as an uncoating receptor for EV71. Here we compared the efficiency of the receptor from different species including human, horseshoe bat, mouse, and hamster and demonstrated that the residues between 144 and 151 are critical for SCARB2 binding to viral capsid protein VP1 of EV71 and seven residues from the human receptor could convert murine SCARB2, an otherwise inefficient receptor, to an efficient receptor for EV71 viral infection. We also identified that EV71 binds to SCARB2 via a canyon of VP1 around residue Gln-172. Soluble SCARB2 could convert the EV71 virions from 160 S to 135 S particles, indicating that SCARB2 is an uncoating receptor of the virus. The uncoating efficiency of SCARB2 significantly increased in an acidic environment (pH 5.6). These studies elucidated the viral capsid and receptor determinants of enterovirus 71 infection and revealed a possible target for antiviral interventions. PMID- 22219189 TI - Allosteric modulation of Ca2+ flux in ligand-gated cation channel (P2X4) by actions on lateral portals. AB - Human P2X receptors are a family of seven ATP-gated ion channels that transport Na(+), K(+), and Ca(2+) across cell surface membranes. The P2X4 receptor is unique among family members in its sensitivity to the macrocyclic lactone, ivermectin, which allosterically modulates both ion conduction and channel gating. In this paper we show that removing the fixed negative charge of a single acidic amino acid (Glu(51)) in the lateral entrance to the transmembrane pore markedly attenuates the effect of ivermectin on Ca(2+) current and channel gating. Ca(2+) entry through P2X4 receptors is known to trigger downstream signaling pathways in microglia. Our experiments show that the lateral portals could present a novel target for drugs in the treatment of microglia-associated disease including neuropathic pain. PMID- 22219190 TI - Biophysical and mechanistic insights into novel allosteric inhibitor of spleen tyrosine kinase. AB - Extracellular stimulation of the B cell receptor or mast cell FcepsilonRI receptor activates a cascade of protein kinases, ultimately leading to antigenic or inflammation immune responses, respectively. Syk is a soluble kinase responsible for transmission of the receptor activation signal from the membrane to cytosolic targets. Control of Syk function is, therefore, critical to the human antigenic and inflammation immune response, and an inhibitor of Syk could provide therapy for autoimmune or inflammation diseases. We report here a novel allosteric Syk inhibitor, X1, that is noncompetitive against ATP (K(i) 4 +/- 1 MUM) and substrate peptide (K(i) 5 +/- 1 MUM), and competitive against activation of Syk by its upstream regulatory kinase LynB (K(i) 4 +/- 1 MUM). The inhibition mechanism was interrogated using a combination of structural, biophysical, and kinetic methods, which suggest the compound inhibits Syk by reinforcing the natural regulatory interactions between the SH2 and kinase domains. This novel mode of inhibition provides a new opportunity to improve the selectivity profile of Syk inhibitors for the development of safer drug candidates. PMID- 22219191 TI - Induction of COX-2 enzyme and down-regulation of COX-1 expression by lipopolysaccharide (LPS) control prostaglandin E2 production in astrocytes. AB - Pathological conditions and pro-inflammatory stimuli in the brain induce cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism mediating the production of prostanoids that, among other actions, have strong vasoactive properties. Although low basal cerebral COX-2 expression has been reported, COX-2 is strongly induced by pro-inflammatory challenges, whereas COX-1 is constitutively expressed. However, the contribution of these enzymes in prostanoid formation varies depending on the stimuli and cell type. Astrocyte feet surround cerebral microvessels and release molecules that can trigger vascular responses. Here, we investigate the regulation of COX-2 induction and its role in prostanoid generation after a pro-inflammatory challenge with the bacterial lipopolysaccharide (LPS) in astroglia. Intracerebral administration of LPS in rodents induced strong COX-2 expression mainly in astroglia and microglia, whereas COX-1 expression was predominant in microglia and did not increase. In cultured astrocytes, LPS strongly induced COX-2 and microsomal prostaglandin-E(2) (PGE(2)) synthase-1, mediated by the MyD88-dependent NFkappaB pathway and influenced by mitogen-activated protein kinase pathways. Studies in COX-deficient cells and using COX inhibitors demonstrated that COX-2 mediated the high production of PGE(2) and, to a lesser extent, other prostanoids after LPS. In contrast, LPS down-regulated COX-1 in an MyD88-dependent fashion, and COX-1 deficiency increased PGE(2) production after LPS. The results show that astrocytes respond to LPS by a COX-2-dependent production of prostanoids, mainly vasoactive PGE(2), and suggest that the coordinated down-regulation of COX-1 facilitates PGE(2) production after TLR-4 activation. These effects might induce cerebral blood flow responses to brain inflammation. PMID- 22219192 TI - Composition and dynamics of the nucleolinus, a link between the nucleolus and cell division apparatus in surf clam (Spisula) oocytes. AB - The nucleolinus is a little-known cellular structure, discovered over 150 years ago (Agassiz, L. (1857) Contributions to the Natural History of the United States of America, First Monograph, Part IIL, Little, Brown and Co., Boston) and thought by some investigators in the late 19th to mid-20th century to function in the formation of the centrosomes or spindle. A role for the nucleolinus in formation of the cell division apparatus has recently been confirmed in oocytes of the surf clam, Spisula solidissima (Alliegro, M. A., Henry, J. J., and Alliegro, M. C. (2010) Proc. Natl. Acad. Sci. U.S.A. 107, 13718-13723). However, we know so little about the composition and dynamics of this compartment, it is difficult to construct mechanistic hypotheses or even to be sure that prior reports were describing analogous structures in the cells of mammals, amphibians, plants, and other organisms where it was observed. Surf clam oocytes are an attractive model to approach this problem because the nucleolinus is easily visible by light microscopy, making it accessible by laser microsurgery as well as isolation by common cell fractionation techniques. In this report, we analyze the macromolecular composition of isolated Spisula nucleolini and examine the relationship of this structure to the nucleolus and cell division apparatus. Analysis of nucleolinar RNA and protein revealed a set of molecules that overlaps with but is nevertheless distinct from the nucleolus. The proteins identified were primarily ones involved in nucleic acid metabolism and cell cycle regulation. Monoclonal antibodies generated against isolated nucleolini revealed centrosomal forerunners in the oocyte cytoplasm. Finally, induction of damage to the nucleolinus by laser microsurgery altered the trafficking of alpha- and gamma tubulin after fertilization. These observations strongly support a role for the nucleolinus in cell division and represent our first clues regarding mechanism. PMID- 22219193 TI - Regulation of human RNA polymerase III transcription by DNMT1 and DNMT3a DNA methyltransferases. AB - The human small nuclear RNA (snRNA) and small cytoplasmic RNA (scRNA) gene families encode diverse non-coding RNAs that influence cellular growth and division. Many snRNA and scRNA genes are related via their compact and yet powerful promoters that support RNA polymerase III transcription. We have utilized the human U6 snRNA gene family to examine the mechanism for regulated transcription of these potent transcription units. Analysis of nine U6 family members showed enriched CpG density within the promoters of actively transcribed loci relative to inert genes, implying a relationship between gene potency and DNA methylation. Indeed, both pharmacological inhibition of DNA methyltransferase (DNMT) activity and the forced diminution of DNMT-1, DNMT-3a, and DNMT-3b by siRNA targeting resulted in increased U6 levels in asynchronously growing MCF7 adenocarcinoma cells. In vitro transcription assays further showed that template methylation impedes U6 transcription by RNA polymerase III. Both DNMT-1 and DNMT 3a were detected at the U6-1 locus by chromatin immunoprecipitation directly linking these factors to RNA polymerase III regulation. Despite this association, the endogenous U6-1 locus was not substantially methylated in actively growing cells. However, both DNMT occupancy and low frequency methylation were correlated with increased Retinoblastoma tumor suppressor (RB) expression, suggesting that the RB status can influence specific epigenetic marks. PMID- 22219194 TI - Myeloperoxidase targets apolipoprotein A-I, the major high density lipoprotein protein, for site-specific oxidation in human atherosclerotic lesions. AB - Oxidative damage by myeloperoxidase (MPO) has been proposed to deprive HDL of its cardioprotective effects. In vitro studies reveal that MPO chlorinates and nitrates specific tyrosine residues of apoA-I, the major HDL protein. After Tyr 192 is chlorinated, apoA-I is less able to promote cholesterol efflux by the ABCA1 pathway. To investigate the potential role of this pathway in vivo, we used tandem mass spectrometry with selected reaction monitoring to quantify the regiospecific oxidation of apoA-I. This approach demonstrated that Tyr-192 is the major chlorination site in apoA-I in both plasma and lesion HDL of humans. We also found that Tyr-192 is the major nitration site in apoA-I of circulating HDL but that Tyr-18 is the major site in lesion HDL. Levels of 3-nitrotyrosine strongly correlated with levels of 3-chlorotyrosine in lesion HDL, and Tyr-18 of apoA-I was the major nitration site in HDL exposed to MPO in vitro, suggesting that MPO is the major pathway for chlorination and nitration of HDL in human atherosclerotic tissue. These observations may have implications for treating cardiovascular disease, because recombinant apoA-I is under investigation as a therapeutic agent and mutant forms of apoA-I that resist oxidation might be more cardioprotective than the native form. PMID- 22219195 TI - Structural link between gamma-aminobutyric acid type A (GABAA) receptor agonist binding site and inner beta-sheet governs channel activation and allosteric drug modulation. AB - Rapid opening and closing of pentameric ligand-gated ion channels (pLGICs) regulate information flow throughout the brain. For pLGICs, it is postulated that neurotransmitter-induced movements in the extracellular inner beta-sheet trigger channel activation. Homology modeling reveals that the beta4-beta5 linker physically connects the neurotransmitter binding site to the inner beta-sheet. Inserting 1, 2, 4, and 8 glycines in this region of the GABA(A) receptor beta subunit progressively decreases GABA activation and converts the competitive antagonist SR-95531 into a partial agonist, demonstrating that this linker is a key element whose length and flexibility are optimized for efficient signal propagation. Insertions in the alpha- and gamma-subunits have little effect on GABA or SR-95531 actions, suggesting that asymmetric motions in the extracellular domain power pLGIC gating. The effects of insertions on allosteric modulator actions, pentobarbital, and benzodiazepines, have different subunit dependences, indicating that modulator-induced signaling is distinct from agonist gating. PMID- 22219196 TI - Glutathione s-transferase omega 1 activity is sufficient to suppress neurodegeneration in a Drosophila model of Parkinson disease. AB - A loss-of-function mutation in the gene parkin causes a common neurodegenerative disease that may be caused by mitochondrial dysfunction. Glutathione S transferase Omega (GSTO) is involved in cell defense mechanisms, but little is known about the role of GSTO in the progression of Parkinson disease. Here, we report that restoration of Drosophila GSTO1 (DmGSTO1), which is down-regulated in parkin mutants, alleviates some of the parkin pathogenic phenotypes and that the loss of DmGSTO1 function enhances parkin mutant phenotypes. We further identified the ATP synthase beta subunit as a novel in vivo target of DmGSTO1. We found that glutathionylation of the ATP synthase beta subunit is rescued by DmGSTO1 and that the expression of DmGSTO1 partially restores the activity and assembly of the mitochondrial F(1)F(0)-ATP synthase in parkin mutants. Our results suggest a novel mechanism for the protective role of DmGSTO1 in parkin mutants, through the regulation of ATP synthase activity, and provide insight into potential therapies for Parkinson disease neurodegeneration. PMID- 22219197 TI - In channelrhodopsin-2 Glu-90 is crucial for ion selectivity and is deprotonated during the photocycle. AB - The light-activated microbial ion channel channelrhodopsin-2 (ChR2) is a powerful tool to study cellular processes with high spatiotemporal resolution in the emerging field of optogenetics. To customize the channel properties for optogenetic experiments, a detailed understanding of its molecular reaction mechanism is essential. Here, Glu-90, a key residue involved in the gating and selectivity mechanism of the ion channel is characterized in detail. The deprotonation of Glu-90 during the photocycle is elucidated by time-resolved FTIR spectroscopy, which seems to be part of the opening mechanism of the conductive pore. Furthermore, Glu-90 is crucial to ion selectivity as also revealed by mutation of this residue combined with voltage clamp experiments. By dynamic homology modeling, we further hypothesized that the conductive pore is flanked by Glu-90 and located between helices A, B, C, and G. PMID- 22219198 TI - Tannic acid is a natural beta-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice. AB - Amyloid precursor protein (APP) proteolysis is essential for production of amyloid-beta (Abeta) peptides that form beta-amyloid plaques in brains of Alzheimer disease (AD) patients. Recent focus has been directed toward a group of naturally occurring anti-amyloidogenic polyphenols known as flavonoids. We orally administered the flavonoid tannic acid (TA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) and evaluated cognitive function and AD-like pathology. Consumption of TA for 6 months prevented transgene-associated behavioral impairment including hyperactivity, decreased object recognition, and defective spatial reference memory, but did not alter nontransgenic mouse behavior. Accordingly, brain parenchymal and cerebral vascular beta-amyloid deposits and abundance of various Abeta species including oligomers were mitigated in TA-treated PSAPP mice. These effects occurred with decreased cleavage of the beta-carboxyl-terminal APP fragment, lowered soluble APP-beta production, reduced beta-site APP cleaving enzyme 1 protein stability and activity, and attenuated neuroinflammation. As in vitro validation, we treated well characterized mutant human APP-overexpressing murine neuron-like cells with TA and found significantly reduced Abeta production associated with less amyloidogenic APP proteolysis. Taken together, these results raise the possibility that dietary supplementation with TA may be prophylactic for AD by inhibiting beta-secretase activity and neuroinflammation and thereby mitigating AD pathology. PMID- 22219199 TI - The C-terminal helices of heat shock protein 70 are essential for J-domain binding and ATPase activation. AB - The J-domain co-chaperones work together with the heat shock protein 70 (HSP70) chaperone to regulate many cellular events, but the mechanism underlying the J domain-mediated HSP70 function remains elusive. We studied the interaction between human-inducible HSP70 and Homo sapiens J-domain protein (HSJ1a), a J domain and UIM motif-containing co-chaperone. The J domain of HSJ1a shares a conserved structure with other J domains from both eukaryotic and prokaryotic species, and it mediates the interaction with and the ATPase cycle of HSP70. Our in vitro study corroborates that the N terminus of HSP70 including the ATPase domain and the substrate-binding beta-subdomain is not sufficient to bind with the J domain of HSJ1a. The C-terminal helical alpha-subdomain of HSP70, which was considered to function as a lid of the substrate-binding domain, is crucial for binding with the J domain of HSJ1a and stimulating the ATPase activity of HSP70. These fluctuating helices are likely to contribute to a proper conformation of HSP70 for J-domain binding other than directly bind with the J domain. Our findings provide an alternative mechanism of allosteric activation for functional regulation of HSP70 by its J-domain co-chaperones. PMID- 22219200 TI - Kinetic mechanism of protein arginine methyltransferase 6 (PRMT6). AB - The protein arginine methyltransferases (PRMTs) are a family of enzymes that catalyze the mono- and dimethylation of arginine residues in a variety of proteins. Although these enzymes play important roles in a variety of cellular processes, aberrant PRMT activity is associated with several disease states, including heart disease and cancer. In an effort to guide the development of inhibitors targeting individual PRMTs, we initiated studies to characterize the molecular mechanisms of PRMT catalysis. Herein, we report studies on the kinetic mechanism of PRMT6. Initial velocity, product inhibition, and dead-end analog inhibition studies with the AcH4-21 and R1 peptides, as well as their monomethylated versions, indicate, in contrast to a previous report, that PRMT6 utilizes a rapid equilibrium random mechanism with dead-end EAP and EBQ complexes. PMID- 22219201 TI - Tumor necrosis factor (TNF) receptor-associated factor 7 is required for TNFalpha induced Jun NH2-terminal kinase activation and promotes cell death by regulating polyubiquitination and lysosomal degradation of c-FLIP protein. AB - The pro-inflammatory cytokine tumor necrosis factor (TNF) alpha signals both cell survival and death. The biological outcome of TNFalpha treatment is determined by the balance between survival factors and Jun NH(2)-terminal kinase (JNK) signaling, which promotes cell death. Here, we show that TRAF7, the most recently identified member of the TNF receptor-associated factors (TRAFs) family of proteins, is essential for activation of JNK following TNFalpha stimulation. We also show that TRAF6 and TRAF7 promote unconventional polyubiquitination of the anti-apoptotic protein c-FLIP(L) and demonstrate that degradation of c-FLIP(L) also occurs through a lysosomal pathway. RNA interference-mediated depletion of TRAF7 correlates with increased c-FLIP(L) expression level, which, in turn, results in resistance to TNFalpha cytotoxicity. Collectively, our results indicate an important role for TRAF7 in the activation of JNK following TNFalpha stimulation and clearly point to an involvement of this protein in regulating the turnover of c-FLIP and, consequently, cell death. PMID- 22219203 TI - PASSion: a pattern growth algorithm-based pipeline for splice junction detection in paired-end RNA-Seq data. AB - MOTIVATION: RNA-seq is a powerful technology for the study of transcriptome profiles that uses deep-sequencing technologies. Moreover, it may be used for cellular phenotyping and help establishing the etiology of diseases characterized by abnormal splicing patterns. In RNA-Seq, the exact nature of splicing events is buried in the reads that span exon-exon boundaries. The accurate and efficient mapping of these reads to the reference genome is a major challenge. RESULTS: We developed PASSion, a pattern growth algorithm-based pipeline for splice site detection in paired-end RNA-Seq reads. Comparing the performance of PASSion to three existing RNA-Seq analysis pipelines, TopHat, MapSplice and HMMSplicer, revealed that PASSion is competitive with these packages. Moreover, the performance of PASSion is not affected by read length and coverage. It performs better than the other three approaches when detecting junctions in highly abundant transcripts. PASSion has the ability to detect junctions that do not have known splicing motifs, which cannot be found by the other tools. Of the two public RNA-Seq datasets, PASSion predicted ~ 137,000 and 173,000 splicing events, of which on average 82 are known junctions annotated in the Ensembl transcript database and 18% are novel. In addition, our package can discover differential and shared splicing patterns among multiple samples. AVAILABILITY: The code and utilities can be freely downloaded from https://trac.nbic.nl/passion and ftp://ftp.sanger.ac.uk/pub/zn1/passion. PMID- 22219202 TI - Dissociation rate constants of human fibronectin binding to fibronectin-binding proteins on living Staphylococcus aureus isolated from clinical patients. AB - Staphylococcus aureus is part of the indigenous microbiota of humans. Sometimes, S. aureus bacteria enter the bloodstream, where they form infections on implanted cardiovascular devices. A critical, first step in such infections is a bond that forms between fibronectin-binding protein (FnBP) on S. aureus and host proteins, such as fibronectin (Fn), that coat the surface of implants in vivo. In this study, native FnBPs on living S. aureus were shown to form a mechanically strong conformational structure with Fn by atomic force microscopy. The tensile acuity of this bond was probed for 46 bloodstream isolates, each from a patient with a cardiovascular implant. By analyzing the force spectra with the worm-like chain model, we determined that the binding events were consistent with a multivalent, cluster bond consisting of ~10 or ~80 proteins in parallel. The dissociation rate constant (k(off), s(-1)) of each multibond complex was determined by measuring strength as a function of the loading rate, normalized by the number of bonds. The bond lifetime (1/k(off)) was two times longer for bloodstream isolates from patients with an infected device (1.79 or 69.47 s for the 10- or 80-bond clusters, respectively; n = 26 isolates) relative to those from patients with an uninfected device (0.96 or 34.02 s; n = 20 isolates). This distinction could not be explained by different amounts of FnBP, as confirmed by Western blots. Rather, amino acid polymorphisms within the Fn-binding repeats of FnBPA explain, at least partially, the statistically (p < 0.05) longer bond lifetime for isolates associated with an infected cardiovascular device. PMID- 22219204 TI - NetSeed: a network-based reverse-ecology tool for calculating the metabolic interface of an organism with its environment. AB - NetSeed is a web tool and Perl module for analyzing the topology of metabolic networks and calculating the set of exogenously acquired compounds. NetSeed is based on the seed detection algorithm, developed and validated in previous studies. AVAILABILITY: The NetSeed web-based tool, open-source Perl module, examples and documentation are freely available online at: http://depts.washington.edu/elbogs/NetSeed. PMID- 22219205 TI - Automatic selection of reference taxa for protein-protein interaction prediction with phylogenetic profiling. AB - MOTIVATION: Phylogenetic profiling methods can achieve good accuracy in predicting protein-protein interactions, especially in prokaryotes. Recent studies have shown that the choice of reference taxa (RT) is critical for accurate prediction, but with more than 2500 fully sequenced taxa publicly available, identifying the most-informative RT is becoming increasingly difficult. Previous studies on the selection of RT have provided guidelines for manual taxon selection, and for eliminating closely related taxa. However, no general strategy for automatic selection of RT is currently available. RESULTS: We present three novel methods for automating the selection of RT, using machine learning based on known protein-protein interaction networks. One of these methods in particular, Tree-Based Search, yields greatly improved prediction accuracies. We further show that different methods for constituting phylogenetic profiles often require very different RT sets to support high prediction accuracy. PMID- 22219206 TI - Quantifying the white blood cell transcriptome as an accessible window to the multiorgan transcriptome. AB - MOTIVATION: We investigate and quantify the generalizability of the white blood cell (WBC) transcriptome to the general, multiorgan transcriptome. We use data from the NCBI's Gene Expression Omnibus (GEO) public repository to define two datasets for comparison, WBC and OO (Other Organ) sets. RESULTS: Comprehensive pair-wise correlation and expression level profiles are calculated for both datasets (with sizes of 81 and 1463, respectively). We have used mapping and ranking across the Gene Ontology (GO) categories to quantify similarity between the two sets. GO mappings of the most correlated and highly expressed genes from the two datasets tightly match, with the notable exceptions of components of the ribosome, cell adhesion and immune response. That is, 10 877 or 48.8% of all measured genes do not change >10% of rank range between WBC and OO; only 878 (3.9%) change rank >50%. Two trans-tissue gene lists are defined, the most changing and the least changing genes in expression rank. We also provide a general, quantitative measure of the probability of expression rank and correlation profile in the OO system given the expression rank and correlation profile in the WBC dataset. PMID- 22219207 TI - Trajectories of social engagement and mortality in late life. AB - OBJECTIVE: There is a dearth of empirical research examining how patterns of stability and change in social engagement affect mortality. This study uses social integration theory within a life course framework to examine trajectories of social engagement over time and how those patterns relate to mortality. METHOD: Data are drawn from the Americans' Changing Lives survey, a nationally representative panel study, with mortality information spanning from 1986 to 2005. RESULTS: Even after controlling for known predictors of mortality, membership in a trajectory of high and slightly increasing social engagement was related to lower risk of mortality. Sociodemographic, health condition, and health behavior variables mediated the impact of the other social engagement trajectories on mortality. DISCUSSION: Findings suggest the importance of maintaining high levels of social engagement over time for the health of older adults. PMID- 22219208 TI - I want to move, but cannot: characteristics of involuntary stayers and associations with health among Canadian seniors. AB - OBJECTIVES: The purpose of this study was to investigate characteristics of seniors in the Canadian population who are involuntary stayers and to assess associations with health. METHOD: Data come from the 1994 Canadian National Population Health Survey, with the sample restricted to those 65 and older (N = 2,551). RESULTS: Nearly 1 in 10 seniors identified as an involuntary stayer. Seniors with few socioeconomic resources, poor health, greater need for assistance, and low social involvement were more likely to identify as an involuntary stayer. Furthermore, seniors who were involuntary stayers report significantly more distress and greater odds of low self-rated health than other seniors. DISCUSSION: This study brings into visibility an understudied segment of the elderly population: seniors who are unable to move from their present location despite their desire to do so. Further research and policy responses assisting seniors to age in a setting of their own choosing are needed. PMID- 22219209 TI - Openness to experience and mortality in men: analysis of trait and facets. AB - OBJECTIVES: We examined whether specific facets are more robust predictors of mortality risk than overall trait openness in a sample of older men. METHODS: The current investigation used data from 1,349 men from the Veterans Affairs Normative Aging Study. From 1990-1991 to 2008, 547 (41%) had died. We used exploratory factor analysis to extract facets of openness, followed by proportional hazards modeling to examine 18-year mortality risk. RESULTS: Two facets emerged from the openness adjectives: intellect and creativity. In the fully adjusted model, only creativity predicted mortality risk. A 1-SD increase in creativity was associated with a 12% decrease in mortality risk. DISCUSSION: The study demonstrated that consideration of facets allows for a more precise understanding of the personality-health association. Higher levels of creativity predict longer survival in a sample of older men which provides preliminary support of the protective role creativity has on health even at advanced ages. PMID- 22219211 TI - Flow-cytometric isolation and enrichment of teleost type A spermatogonia based on light-scattering properties. AB - The transplantation of germ cells is a powerful tool both for studying their development and for reproductive biotechnology. An intraperitoneal germ cell transplantation system was recently developed for use in several teleost species. Donor germ cells transplanted into the peritoneal cavity of hatchlings migrated toward and were incorporated into the recipient's genital ridges, where they underwent gametogenesis. Among male germ cells, only type A spermatogonia were capable of colonizing the recipient gonads, unlike those at more advanced stages. The enrichment of type A spermatogonia is therefore important to achieve efficient donor-cell incorporation and subsequent donor-derived gametogenesis. Here we established a simple and rapid system of isolation and enrichment for fish type A spermatogonia, using flow cytometry. Type A spermatogonia were found to have distinctive forward and side light scatter properties compared to that with other types of testicular cell. Based on these characteristics, we were able to isolate and enrich type A spermatogonia by using flow cytometry. After intraperitoneal transplantation, the enriched type A spermatogonia could be successfully incorporated into the recipient genital ridges. This flow cytometry approach using forward and side light scatter was also found to be applicable to other salmonid and sciaenid species, suggesting that it could be a powerful tool for isolating and enriching transplantable type A spermatogonia in a wide range of teleosts. We expect this method to contribute significantly to germ cell biology and biotechnology. PMID- 22219210 TI - Molecular and cellular regulatory mechanisms of tongue myogenesis. AB - The tongue exerts crucial functions in our daily life. However, we know very little about the regulatory mechanisms of mammalian tongue development. In this review, we summarize recent findings of the molecular and cellular mechanisms that control tissue-tissue interactions during tongue morphogenesis. Specifically, cranial neural crest cells (CNCC) lead the initiation of tongue bud formation and contribute to the interstitial connective tissue, which ultimately compartmentalizes tongue muscles and serves as their attachments. Occipital somite-derived cells migrate into the tongue primordium and give rise to muscle cells in the tongue. The intimate relationship between CNCC- and mesoderm-derived cells, as well as growth and transcription factors that have been shown to be crucial for tongue myogenesis, clearly indicate that tissue-tissue interactions play an important role in regulating tongue morphogenesis. PMID- 22219213 TI - 17Beta-estradiol signaling and regulation of proliferation and apoptosis of rat Sertoli cells. AB - The aim of the present study was to investigate the intracellular signaling events downstream of the classical estrogen receptors (ESRs) and G protein coupled estrogen receptor 1 (GPER) involved in regulation of proliferation and apoptosis of rat Sertoli cells, in which we have previously described ESR1, ESR2, and GPER. ESRs play a role in Sertoli cell proliferation, and GPER, but not ESRs, plays a role modulating gene expression involved with apoptosis. The present study shows that 17beta-estradiol (E2) and the GPER-selective agonist G-1 rapidly activate phosphatidylinositol 3-kinase (PIK3)/serine threonine protein kinase (AKT) and cyclic AMP response element-binding (CREB) phosphorylation. E2 and the ESR1-selective agonist 4,4',4"-(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol (PPT) increase the expression of cyclin D1 (CCND1), whereas the ESR2-selective agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) and G-1 do not change the expression of this protein, suggesting that ESR1 is the upstream receptor regulating Sertoli cell proliferation. E2- or PPT-ESR1, through activation of epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase 3/1 (MAPK3/1) and PIK3 pathways, induces upregulation of CCND1. KG-501, the compound that disrupts the phospho-CREB/CREB binding protein (CBP) complex, does not change E2- or PPT-ESR1-mediated CCND1 expression, suggesting that phospho CREB/cyclic AMP response element/CBP is not involved in the expression of this protein. E2- or G-1-GPER, through activation of EGFR/MAPK3/1 and PIK3 pathways, may be involved in the upregulation of antiapoptotic proteins BCL2 and BCL2L2. E2 or G-1-GPER/EGFR/MAPK3/1/phospho-CREB decreases BAX expression. Taken together, these results show a differential effect of E2-GPER on the CREB-mediated transcription of proapoptotic and antiapoptotic genes of the same BCL2 gene family. ESR1 and GPER can mediate the rapid E2 actions in the Sertoli cells, which in turn can modulate nuclear transcriptional events important for Sertoli cell function and maintenance of normal testis development and homeostasis. Our findings are important to clarify the role of estrogen in a critical period of testicular development, and to direct further studies, which may contribute to better understanding of the causes of male infertility. PMID- 22219212 TI - The autoimmune regulator prevents premature reproductive senescence in female mice. AB - Loss-of-function mutations in the autoimmune regulator (AIRE) gene are responsible for autoimmune polyglandular syndrome type 1 (APS-1), which commonly manifests as infertility in women. AIRE is a transcriptional regulator that promotes expression of tissue-restricted antigens in the thymus, including antigens specific to the ovary. Thymic expression of ovarian genes under AIRE's control may be critical for preventing ovarian autoimmune disease. Because mice lacking Aire are an important APS-1 model, we examined the reproductive properties of female Aire-deficient (Aire(-/-)) mice. Female Aire(-/-) mice on the BALB/c background were examined for reproductive parameters, including fertility, litter sizes, and ovarian follicular reserves. Although delayed puberty was observed in Aire(-/-) mice, all mice entered puberty and exhibited mating behavior. Only 50% of Aire(-/-) females gave an initial litter, and only 16% were able to produce two litters. Ovarian histopathologic examination revealed that 83% of previously bred females lost all ovarian follicular reserves. Among virgin females, follicular depletion was observed in 25% by 8 wk, and by 20 wk, 50%-60% of mice lost all follicles. This was associated with elevated serum follicle-stimulating hormone level and ovarian infiltration of proliferating CD3+ T lymphocytes. Ovulation rates of 6-wk-old Aire(-/-) mice were reduced by 22%, but this difference was not statistically significant. Finally, transplantation experiments revealed that follicular loss depended on factors extrinsic to the ovary. These results suggest that immune-mediated ovarian follicular depletion is a mechanism of infertility in Aire(-/-) mice. The results have important implications in the pathogenesis of ovarian autoimmune disease in women. PMID- 22219214 TI - Are children who play a sport or a musical instrument better at motor imagery than children who do not? AB - OBJECTIVE: Playing a sport or a musical instrument is presumed to improve motor ability. One would therefore predict that children who play a sport or music are better at motor imagery tasks, which rely on an intact cortical proprioceptive representation and precise motor planning, than children who do not. The authors tested this prediction. METHODS: This study involved an online questionnaire and then a motor imagery task. The task measured the reaction time (RT) and the accuracy for left/right-hand judgements in children aged 5 to 17 years. Forty pictured hands (20 left), held in various positions and rotated zero, 90 degrees , 180 degrees or 270 degrees , were displayed on a screen. Participants indicated whether the displayed hands were left or right by pressing keys on a keyboard. RESULTS: Fifty-seven children (30 boys; mean+/-SD age=10+/-3.3 years) participated. The mean+/-SD RT was 3015.4+/-1330.0 ms and the accuracy was 73.9+/ 16.6%. There was no difference in RT between children who played sport, music, neither or both (four-level one-way analysis of variance, p=0.85). There was no difference in accuracy between groups either (Kruskal-Wallis, p=0.46). In a secondary analysis, participants whose parents rated them as being 'clumsy' were no slower (n.s.) but were about 25% less accurate than those rated coordinated or very coordinated (p<0.05). CONCLUSION: The authors conclude against the intuitively sensible and widely held view that participation in a sport or music is associated with better cortical proprioceptive representation and motor planning. Secondary analyses suggest that parent-rated clumsiness is negatively related to motor imagery performance. PMID- 22219215 TI - Reliability and validity of three pain provocation tests used for the diagnosis of chronic proximal hamstring tendinopathy. AB - BACKGROUND: The clinical assessment of chronic proximal hamstring tendinopathy (PHT) in athletes is a challenge to sports medicine. To be able to compare the results of research and treatments, the methods used to diagnose and evaluate PHT must be clearly defined and reproducible. OBJECTIVE: To assess the reliability and validity of three pain provocation tests used for the diagnosis of PHT. METHODS: Ninety-two athletes with (N=46) and without (N=46) PHT were examined by one physician and two physiotherapists, who were trained in the examination techniques before the study. The examiners were blinded to the symptoms and identity of the athletes. The three pain provocation tests examined were the Puranen-Orava, bent-knee stretch and modified bent-knee stretch tests. Intraclass correlation coefficients (ICCs) based on the repeated measures analysis of variance were used to analyse the intraexaminer and interexaminer reliability, while sensitivity, specificity, predictive values and likelihood ratios were used to determine the validity of the three tests. RESULTS: The ICC values in all three tests revealed a high correlation (range 0.82 to 0.88) for the interexaminer reliability and a high-to-very high correlation (range 0.87 to 0.93) for the intraexaminer reliability. All three tests displayed a moderate-to high validity, with the highest degree of validity being yielded by the modified bent-knee stretch test. CONCLUSION: All three pain provocation tests proved to be of potential value in assessing chronic PHT in athletes. However, we recommend that they be used in conjunction with other objective measures, such as MRI. PMID- 22219216 TI - Physical activity and all-cause mortality in older women and men. AB - BACKGROUND: Regular physical activity is associated with reduced risk of mortality in middle-aged adults; however, associations between physical activity and mortality in older people have been less well studied. The objective of this study was to compare relationships between physical activity and mortality in older women and men. METHODS: The prospective cohort design involved 7080 women aged 70-75 years and 11 668 men aged 65-83 years at baseline, from two Australian cohorts - the Australian Longitudinal Study on Women's Health and the Health in Men Study. Self-reported low, moderate and vigorous intensity physical activity, socio-demographic, behavioural and health characteristics were assessed in relation to all-cause mortality from the National Death Index from 1996 to 2009; the median follow-up of 10.4 (women) and 11.5 (men) years. RESULTS: There were 1807 (25.5%) and 4705 (40.3%) deaths in women and men, respectively. After adjustment for behavioural risk factors, demographic variables and self-reported health at baseline, there was an inverse dose - response relationship between physical activity and all-cause mortality. Compared with women and men who reported no activity, there were statistically significant lower hazard ratios for women who reported any activity and for men who reported activities equivalent to at least 300 metabolic equivalent.min/week. Risk reductions were 30 50% greater in women than in men in every physical activity category. CONCLUSIONS: Physical activity is inversely associated with all-cause mortality in older men and women. The relationship is stronger in women than in men, and there are benefits from even low levels of activity. PMID- 22219217 TI - Lifetime injury prevention: the sport profile model. AB - Participation in sporting activities carries an injury risk. Conversely, the increased awareness that physical inactivity is a major risk factor for disease has led government agencies and the medical community to encourage increased levels of physical activity. Many people will achieve this through participation in sport. Injury inevitably leads to a reduction in participation on a temporary or permanent basis, but the injury experience may also influence the lifelong physical activity behaviour. Few studies adequately examine the possible long term consequences of sport participation after the competitive period has been completed, but by understanding the patterns of injuries in different sports one test can develop strategies to prevent and better manage the conditions that occur and promote lifelong physical activity. There is a need to develop models of understanding of injury risk at different life phases and levels of participation in a specific sport. The risk assessment of sport participation has to be relevant to a particular sport, the level of participation, skill, age and potential future health consequences. This article describes a sport-specific model which will improve guidance for coaches and healthcare professionals. It poses questions for sports physicians, healthcare providers, educators and for governing bodies of sports to address in a systematic fashion. Additionally the governing body, as an employer, will need to meet the requirements for risk assessment for professional sport and its ethical responsibility to the athlete. PMID- 22219218 TI - Sport category is an important determinant of cardiac adaptation: an MRI study. AB - BACKGROUND: Physiological cardiac adaptation in athletes is influenced by body surface area, gender, age, training intensity and sport type. This study assesses the influence of sport category and provides a physiological reference for sport category and gender. METHODS: Three hundred and eighty-one subjects (mean age 25+/-5 years, range 18 to 39 years; 61% men) underwent cardiac MRI and ECG: 114 healthy non-athletes (<=3 training h/week) and 267 healthy elite athletes (mean 17+/-6.6 training h/week). Athletes performed low-dynamic high-static (LD-HS, n=42), high-dynamic low-static (HD-LS, n=144) or high-dynamic high-static sports (HD-HS, n=81). RESULTS: Left ventricular (LV) end-diastolic volume (EDV) index (ml/m(2)) for non-athletes/LD-HS/HD-LS/HD-HS, respectively, was 101/107/122/129 in men and 90/103/106/111 in women. LV end-diastolic mass (EDM) index (g/m(2)) for non-athletes/LD-HS/HD-LS/HD-HS was, respectively, 47/49/57/69 for men and 34/38/42/51 for women. Left or right ventricular EDV ratios were alike in all groups. LV EDV/EDM ratios were similar in non-athletes/LD-HS/HD-LS athletes, and only lower in HD-HS athletes, disproving selective ventricular wall thickening in LD-HS athletes. Multivariate linear regression demonstrated HD-LS and HD-HS sport category coefficients (p<0.01) larger than those of training hours, gender and age (LV EDV/EDM coefficients for sport category LD-HS 6/0.75, HD-LS 16/7, HD-HS 21/17). ECG abnormalities were most frequent in HD-HS athletes and in male subjects. CONCLUSIONS: This study demonstrates a balanced cardiac adaptation with preserved ratios of LV/right ventricular volume (in all sport categories) and LV volume/wall mass (in LD-HS and HD-LS sports). Sport category has a strong impact on cardiac adaptation. HD-HS sports show the largest changes, whereas LD-HS sports show dimensions similar to non-athletes. PMID- 22219219 TI - Gamma-frequency neuronal activity is diminished in adults with attention deficit/hyperactivity disorder: a pharmaco-MEG study. AB - Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder affecting approximately 4-7% of children and persisting in 2-5% of adults. The core symptoms include pervasive inattention and inappropriate levels of hyperactivity-impulsivity. High-frequency gamma activity has been implicated in the temporal binding of stimulus properties across cortical areas, and is known to be crucial for complex information processing and attentional processes in particular. Thus, we evaluated the amplitude of gamma-frequency neural responses in adults with and those without ADHD, and tested whether stimulant medications, the most common treatment for ADHD, modulate gamma activity in affected adults. Participants underwent two sessions (~75 min apart) of auditory stimulation using stimuli known to elicit 40 Hz gamma-band responses as magnetoencephalography data were acquired. Between sessions, the ADHD group (who were in maintenance therapy) were administered their daily stimulant medication and both groups were told to relax. The primary results indicated that gamma activity was weaker in the ADHD group during session one (pre-drug), but not session two (post-drug), and that gamma activity significantly increased following stimulant administration in adults with ADHD. These results suggest that ADHD is associated with reduced cortical gamma activity and that stimulants may ameliorate this abnormality. PMID- 22219220 TI - Efficacy of a dose range of surinabant, a cannabinoid receptor blocker, for smoking cessation: a randomized controlled clinical trial. AB - A hyperactive endocannabinoid signalling system may contribute to addictions. We tested the efficacy and safety of surinabant, a novel selective CB1 cannabinoid receptor antagonist, for smoking cessation. In a randomized, double-blind, placebo-controlled, parallel-group clinical trial, participants were assigned to brief counselling and one of three doses of surinabant, 2.5 mg/day (n = 199), 5 mg/day (n = 204), or 10 mg/day (n = 205) or placebo (n = 202) orally for 8 weeks with 6 weeks of non-drug follow-up. For weeks 5 through 8, the 4-week continuous abstinence rates were 25.2% for placebo vs. 22.6%, 22.1% and 21.5% for 2.5 mg/day, 5 mg/day and 10 mg/day doses of surinabant (p for trend, 0.4). The gain in body weight from baseline was reduced with surinabant 2.5 mg/day, 5 mg/day and 10 mg/day (0.75 kg [SE, 0.13], 0.53 kg [SE, 0.13], and 0.24 kg [SE, 0.13], respectively, versus 1.19 kg [SE, 0.13] for placebo; p for trend, < 0.001). The most common adverse events for participants receiving active drug with a greater incidence than placebo were headache, nausea, insomnia, anxiety, nasopharyngitis, diarrhoea and hyperhidrosis. Surinabant did not improve smoking cessation rates compared with placebo, but had a small effect on reducing post-cessation weight gain. PMID- 22219221 TI - Pharmacokinetics and central nervous system effects of the novel dopamine D3 receptor antagonist GSK598809 and intravenous alcohol infusion at pseudo-steady state. AB - GSK598809 is a novel selective dopamine D(3) receptor antagonist, currently in development for the treatment of substance abuse and addiction. In a blinded, randomized, placebo-controlled study, effects of single oral doses of 175 mg GSK598809 were evaluated in healthy volunteers. Pharmacokinetics, central nervous system (CNS) effects and potential for interactions with alcohol were evaluated, using an alcohol infusion paradigm and analysis of eye movements, adaptive tracking, visual analogue scales, body sway, serum prolactin and verbal visual learning test. Adverse effects of GSK598809 included headache, dizziness and somnolence. Plasma concentration of GSK598809 was maximal 2-3 hours postdose and decreased with a half-life of roughly 20 hours. CNS effects were limited to prolactin elevation and decreased adaptive tracking. Co-administration of GSK598809 and alcohol did not affect alcohol pharmacokinetics, but caused a 9% decrease of C (max) and a 15% increase of AUC of GSK598809. CNS effects of co administration were mainly additive, except a small supra-additive increase in saccadic reaction time and decrease in delayed word recall. In conclusion, GSK598809 causes elevation of serum prolactin and a small decrease in adaptive tracking performance. After co-administration with alcohol, effects of GSK598809 are mainly additive and the combination is well tolerated in healthy volunteers. PMID- 22219222 TI - The selective serotonin reuptake inhibitor, escitalopram, enhances inhibition of prepotent responding and spatial reversal learning. AB - Previous findings indicate treatment with a selective serotonin reuptake inhibitor (SSRI) facilitates behavioral flexibility when conditions require inhibition of a learned response pattern. The present experiment investigated whether acute treatment with the SSRI, escitalopram, affects behavioral flexibility when conditions require inhibition of a naturally biased response pattern (elevated conflict test) and/or reversal of a learned response pattern (spatial reversal learning). An additional experiment was carried out to determine whether escitalopram, at doses that affected behavioral flexibility, also reduced anxiety as tested in the elevated plus-maze. In each experiment, Long-Evans rats received an intraperitoneal injection of either saline or escitalopram (0.03, 0.3 or 1.0 mg/kg) 30 min prior to behavioral testing. Escitalopram, at all doses tested, enhanced acquisition in the elevated conflict test, but did not affect performance in the elevated plus-maze. Escitalopram (0.3 and 1.0 mg/kg) did not alter acquisition of the spatial discrimination, but facilitated reversal learning. In the elevated conflict and spatial reversal learning test, escitalopram enhanced the ability to maintain the relevant strategy after being initially selected. The present findings suggest that enhancing serotonin transmission with an SSRI facilitates inhibitory processes when conditions require a shift away from either a naturally biased response pattern or a learned choice pattern. PMID- 22219223 TI - Selective expansion of polyfunctional pathogen-specific CD4(+) T cells in HIV-1 infected patients with immune reconstitution inflammatory syndrome. AB - Since the introduction of highly active antiretroviral therapies (ART), the prognosis for HIV-1 patients has improved immensely. However, approximately 25% of patients can experience a variety of inflammatory symptoms that are collectively known as immune reconstitution inflammatory syndrome (IRIS). Studying the etiology and immunopathology of IRIS has been hampered by the fact that the symptoms and associated opportunistic infections are highly varied. We hypothesized that there is a common mechanism underlying IRIS pathogenesis and investigated a patient group with IRIS related to different pathogens. Functional and phenotypic characterization of PBMC samples was performed by polychromatic flow cytometry after in vitro stimulation with relevant antigenic preparations. In most patients, IRIS events were characterized by the robust increase of preexisting polyfunctional, highly differentiated effector CD4(+) T-cell responses that specifically targeted the antigens of the underlying co-infection. T-cell responses to HIV-1 or other underlying infections were not affected and did not differ between IRIS and non-IRIS patients. These data suggest that patients with IRIS do not have a generalized T-cell dysfunction; instead, IRIS represents a dysregulated CD4(+) T-cell response against residual opportunistic infection antigen. These studies were registered at www.clinical-trials.gov as NCT00557570 and NCT00286767. PMID- 22219224 TI - A rapid diagnostic test for human regulatory T-cell function to enable regulatory T-cell therapy. AB - Regulatory T cells (CD4(+)CD25(hi)CD127(lo)FOXP3(+) T cells [Tregs]) are a population of lymphocytes involved in the maintenance of self-tolerance. Abnormalities in function or number of Tregs are a feature of autoimmune diseases in humans. The ability to expand functional Tregs ex vivo makes them ideal candidates for autologous cell therapy to treat human autoimmune diseases and to induce tolerance to transplants. Current tests of Treg function typically take up to 120 hours, a kinetic disadvantage as clinical trials of Tregs will be critically dependent on the availability of rapid diagnostic tests before infusion into humans. Here we evaluate a 7-hour flow cytometric assay for assessing Treg function, using suppression of the activation markers CD69 and CD154 on responder T cells (CD4(+)CD25(-) [Tresp]), compared with traditional assays involving inhibition of CFSE dilution and cytokine production. In both freshly isolated and ex vivo expanded Tregs, we describe excellent correlation with gold standard suppressor cell assays. We propose that the kinetic advantage of the new assay may place it as the preferred rapid diagnostic test for the evaluation of Treg function in forthcoming clinical trials of cell therapy, enabling the translation of the large body of preclinical data into potentially useful treatments for human diseases. PMID- 22219225 TI - SIRT1 is dispensable for function of hematopoietic stem cells in adult mice. AB - SIRT1 is an NAD(+)-dependent histone deacetylase implicated in the establishment of the primitive hematopoietic system during mouse embryonic development. However, investigation of the role of SIRT1 in adult hematopoiesis has been complicated by the high perinatal mortality of SIRT1-deficient mice (SIRT1(-/-)). We performed a comprehensive in vivo study of the hematopoietic stem cell (HSC) compartment in adult SIRT1(-/-) mice and show that, apart from anemia and leukocytosis in older mice, the production of mature blood cells, lineage distribution within hematopoietic organs, and frequencies of the most primitive HSC populations are comparable to those of wild-type littermate controls. Furthermore, we show that SIRT1-deficient BM cells confer stable long-term reconstitution in competitive repopulation and serial transplantation experiments. The results of the present study rule out an essential physiologic role for cell-autonomous SIRT1 signaling in the maintenance of the adult HSC compartment in mice. PMID- 22219227 TI - Bugs, pundits, evolution, and the New Year. PMID- 22219226 TI - Influence of single nucleotide polymorphisms in factor VIII and von Willebrand factor genes on plasma factor VIII activity: the ARIC Study. AB - Factor VIII (FVIII) functions as a cofactor for factor IXa in the contact coagulation pathway and circulates in a protective complex with von Willebrand factor (VWF). Plasma FVIII activity is strongly influenced by environmental and genetic factors through VWF-dependent and -independent mechanisms. Single nucleotide polymorphisms (SNPs) of the coding and promoter sequence in the FVIII gene have been extensively studied for effects on FVIII synthesis, secretion, and activity, but impacts of non-disease-causing intronic SNPs remain largely unknown. We analyzed FVIII SNPs and FVIII activity in 10,434 healthy Americans of European (EA) or African (AA) descent in the Atherosclerosis Risk in Communities (ARIC) study. Among covariates, age, race, diabetes, and ABO contributed 2.2%, 3.5%, 4%, and 10.7% to FVIII intersubject variation, respectively. Four intronic FVIII SNPs associated with FVIII activity and 8 with FVIII-VWF ratio in a sex- and race-dependent manner. The FVIII haplotypes AT and GCTTTT also associated with FVIII activity. Seven VWF SNPs were associated with FVIII activity in EA subjects, but no FVIII SNPs were associated with VWF Ag. These data demonstrate that intronic SNPs could directly or indirectly influence intersubject variation of FVIII activity. Further investigation may reveal novel mechanisms of regulating FVIII expression and activity. PMID- 22219228 TI - Cytomegalovirus colitis. PMID- 22219229 TI - Diffuse reticulonodular infiltrates. PMID- 22219230 TI - Q: Should target natriuretic peptide levels be used for outpatient management of chronic heart failure? PMID- 22219231 TI - Updates in the medical management of Parkinson disease. AB - Most, if not all, currently available drugs for Parkinson disease address dopaminergic loss and relieve symptoms. However, their adverse effects can be limiting and they do not address disease progression. Moreover, nonmotor features of Parkinson disease such as depression, dementia, and psychosis are now recognized as important and disabling. A cure remains elusive. However, promising interventions and agents are emerging. As an example, people who exercise regularly are less likely to develop Parkinson disease, and if they develop it, they tend to have slower progression. PMID- 22219232 TI - Is niacin ineffective? Or did AIM-HIGH miss its target? AB - The AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) found, in an interim analysis, no cardiovascular benefit from taking extended-release niacin (Niaspan). In fact, there was a trend toward a greater risk of ischemic stroke, which did not reach statistical significance. But questions remain about this complex trial, which included intensive statin therapy in the active-treatment group and the control group. PMID- 22219233 TI - Addressing disparities in health care. PMID- 22219234 TI - Overcoming barriers to hypertension control in African Americans. AB - Barriers to blood pressure control exist at the patient, physician, and system levels. We review the current evidence for interventions that target patient- and physician-related barriers, such as patient education, home blood pressure monitoring, and computerized decision-support systems for physicians, and we emphasize the need for more studies that address the effectiveness of these interventions in African American patients. PMID- 22219235 TI - Skin and soft-tissue infections: classifying and treating a spectrum. AB - Skin and soft-tissue infections (SSTIs) are a common presenting problem in both inpatients and outpatients. SSTIs have been broadly classified as complicated or uncomplicated, but specific disease processes and patient characteristics are important in guiding clinical management. Early recognition of the extent of infection, close follow-up, and familiarity with local antibiotic susceptibility data are critical to successful treatment. PMID- 22219236 TI - Managing community-acquired pneumonia during flu season. AB - The clinical findings of influenza overlap those of community-acquired bacterial pneumonia (CABP), and influenza infection can be complicated by bacterial infections. Reviewed here are the epidemiology, pathophysiology, diagnosis, and management of community-acquired pneumonia (CAP) with special emphasis on considerations during influenza season. PMID- 22219238 TI - Overview of anesthetic considerations for Cesarean delivery. AB - INTRODUCTION: Physiologic changes of pregnancy uniquely influence anesthesia for Cesarean delivery. Included is a review of current obstetrical anesthesia considerations for Cesarean delivery and recent changes improving maternal care and outcome. SOURCES OF DATA: A literature review was conducted using Pubmed and the Cochrane database. AREAS OF AGREEMENT AND CONTROVERSY: Increased use of neuraxial techniques instead of general anesthesia for Cesarean delivery has improved maternal safety. Recent changes in the prevention of gastric aspiration, hypotension from neuraxial techniques, venous thrombosis and a team approach have improved maternal care. Elective Cesarean deliveries and management of urgent deliveries are areas of discussion. AREAS TIMELY FOR DEVELOPING RESEARCH: Obstetric anesthesia advances have improved maternal outcomes. Current areas of needed obstetric anesthesia research include improved obese patient care, the impact of anticoagulation on neuraxial techniques in pregnancy, long-term neurocognitive effects of neonatal exposure to anesthesia and postoperative pain management. PMID- 22219239 TI - Frozen shoulder. AB - Frozen shoulder is commonly encountered in general orthopaedic practice. It may arise spontaneously without an obvious predisposing cause, or be associated with a variety of local or systemic disorders. Diagnosis is based upon the recognition of the characteristic features of the pain, and selective limitation of passive external rotation. The macroscopic and histological features of the capsular contracture are well-defined, but the underlying pathological processes remain poorly understood. It may cause protracted disability, and imposes a considerable burden on health service resources. Most patients are still managed by physiotherapy in primary care, and only the more refractory cases are referred for specialist intervention. Targeted therapy is not possible and treatment remains predominantly symptomatic. However, over the last ten years, more active interventions that may shorten the clinical course, such as capsular distension arthrography and arthroscopic capsular release, have become more popular. This review describes the clinical and pathological features of frozen shoulder. We also outline the current treatment options, review the published results and present our own treatment algorithm. PMID- 22219240 TI - Current concepts in osteolysis. AB - The most frequent cause of failure after total hip replacement in all reported arthroplasty registries is peri-prosthetic osteolysis. Osteolysis is an active biological process initiated in response to wear debris. The eventual response to this process is the activation of macrophages and loss of bone. Activation of macrophages initiates a complex biological cascade resulting in the final common pathway of an increase in osteolytic activity. The biological initiators, mechanisms for and regulation of this process are beginning to be understood. This article explores current concepts in the causes of, and underlying biological mechanism resulting in peri-prosthetic osteolysis, reviewing the current basic science and clinical literature surrounding the topic. PMID- 22219241 TI - Fragility fractures of the distal humerus: What is the optimal treatment? AB - In light of the growing number of elderly osteopenic patients with distal humeral fractures, we discuss the history of their management and current trends. Under most circumstances operative fixation and early mobilisation is the treatment of choice, as it gives the best results. The relative indications for and results of total elbow replacement versus internal fixation are discussed. PMID- 22219242 TI - Occupational radiation exposure and pregnancy in orthopaedics. AB - Radiological imaging is necessary in a wide variety of trauma and elective orthopaedic operations. The evolving orthopaedic workforce includes an increasing number of pregnant workers. Current legislation in the United Kingdom, Europe and United States allows them to choose their degree of participation, if any, with fluoroscopic procedures. For those who wish to engage in radiation-prone procedures, specific regulations apply to limit the radiation dose to the pregnant worker and unborn child. This paper considers those aspects of radiation protection, the potential effects of exposure to radiation in pregnancy and the dose of radiation from common orthopaedic procedures, which are important for safe clinical practice. PMID- 22219243 TI - Current concepts in the rehabilitation of an acute rupture of the tendo Achillis. AB - Rupture of the tendo Achillis is a common injury with a rising incidence. Traditionally the key question following this injury has been whether or not to operate. However a contemporary Cochrane review highlighted that the method of rehabilitation may also have an important contribution to the outcome. Since this review, various early weight-bearing rehabilitation protocols have been described. Currently evidence points to the use of early functional rehabilitation, regardless of operative or non-operative management. However, there is no consensus on which exact functional rehabilitation protocol should be used. Future research should be directed towards improving our understanding of how the different rehabilitative components interact in the tendo Achillis as it heals. PMID- 22219244 TI - Reliability and validity of measuring version of the acetabular component. AB - A variety of radiological methods of measuring version of the acetabular component after total hip replacement (THR) have been described. The aim of this study was to evaluate the reliability and validity of six methods (those of Lewinnek; Widmer; Hassan et al; Ackland, Bourne and Uhthoff; Liaw et al; and Woo and Morrey) that are currently in use. In 36 consecutive patients who underwent THR, version of the acetabular component was measured by three independent examiners on plain radiographs using these six methods and compared with measurements using CT scans. The intra- and interobserver reliabilities of each measurement were estimated. All measurements on both radiographs and CT scans had excellent intra- and interobserver reliability and the results from each of the six methods correlated well with the CT measurements. However, measurements made using the methods of Widmer and of Ackland, Bourne and Uhthoff were significantly different from the CT measurements (both p < 0.001), whereas measurements made using the remaining four methods were similar to the CT measurements. With regard to reliability and convergent validity, we recommend the use of the methods described by Lewinnek, Hassan et al, Liaw et al and Woo and Morrey for measurement of version of the acetabular component. PMID- 22219245 TI - Alumina-on-alumina hip implants: A wear study of retrieved components. AB - Alumina-alumina bearings are among the most resistant to wear in total hip replacement. Examination of their surfaces is one way of comparing damage caused by wear of hip joints simulated in vitro to that seen in explanted bearings. The aim of this study was to determine whether second-generation ceramic bearings exhibited a better pattern of wear than those reported in the literature for first-generation bearings. We considered both macro- and microscopic findings. We found that long-term alumina wear in association with a loose acetabular component could be categorised into three groups. Of 20 specimens, four had 'low wear', eight 'crescent wear' and eight 'severe wear', which was characterised by a change in the physical shape of the bearing and a loss of volume. This suggests that the wear in alumina-alumina bearings in association with a loose acetabular component may be variable in pattern, and may explain, in part, why the wear of a ceramic head in vivo may be greater than that seen after in vitro testing. PMID- 22219246 TI - A comparison of a less invasive piriformis-sparing approach versus the standard posterior approach to the hip: A randomised controlled trial. AB - We undertook a randomised controlled trial to compare the piriformis-sparing approach with the standard posterior approach used for total hip replacement (THR). We recruited 100 patients awaiting THR and randomly allocated them to either the piriformis-sparing approach or the standard posterior approach. Pre- and post-operative care programmes and rehabilitation regimes were identical for both groups. Observers were blinded to the allocation throughout; patients were blinded until the two-week assessment. Follow-up was at six weeks, three months, one year and two years. In all 11 patients died or were lost to follow-up. There was no significant difference between groups for any of the functional outcomes. However, for patients in the piriformis-sparing group there was a trend towards a better six-minute walk test at two weeks and greater patient satisfaction at six weeks. The acetabular components were less anteverted (p = 0.005) and had a lower mean inclination angle (p = 0.02) in the piriformis-sparing group. However, in both groups the mean component positions were within Lewinnek's safe zone. Surgeons perceived the piriformis-sparing approach to be significantly more difficult than the standard approach (p = 0.03), particularly in obese patients. In conclusion, performing THR through a shorter incision involving sparing piriformis is more difficult and only provides short-term benefits compared with the standard posterior approach. PMID- 22219247 TI - Impaction femoral allografting at revision hip arthroplasty: uncemented versus cemented technique using a Freeman femoral component. AB - We report the long-term results of revision total hip replacement using femoral impaction allografting with both uncemented and cemented Freeman femoral components. A standard design of component was used in both groups, with additional proximal hydroxyapatite coating in the uncemented group. A total of 33 hips in 30 patients received an uncemented component and 31 hips in 30 patients a cemented component. The mean follow-up was 9.8 years (2 to 17) in the uncemented group and 6.2 years (1 to 11) in the cemented group. Revision procedures (for all causes) were required in four patients (four hips) in the uncemented group and in five patients (five hips) in the cemented group. Harris hip scores improved significantly in both groups and were maintained independently of the extent of any migration of the femoral component within the graft or graft-cement mantle. PMID- 22219248 TI - Upsizing the femoral component increases patellofemoral contact force in total knee replacement. AB - In posterior stabilised total knee replacement (TKR) a larger femoral component is sometimes selected to manage the increased flexion gap caused by resection of the posterior cruciate ligament. However, concerns remain regarding the adverse effect of the increased anteroposterior dimensions of the femoral component on the patellofemoral (PF) joint. Meanwhile, the gender-specific femoral component has a narrower and thinner anterior flange and is expected to reduce the PF contact force. PF contact forces were measured at 90 degrees , 120 degrees , 130 degrees and 140 degrees of flexion using the NexGen Legacy Posterior Stabilized (LPS)-Flex Fixed Bearing Knee system using Standard, Upsized and Gender femoral components during TKR. Increasing the size of the femoral component significantly increased mean PF forces at 120 degrees , 130 degrees and 140 degrees of flexion (p = 0.005, p < 0.001 and p < 0.001, respectively). No difference was found in contact force between the Gender and the Standard components. Among the patients who had overhang of the Standard component, mean contact forces with the Gender component were slightly lower than those of the Standard component, but no statistical difference was found at 90 degrees , 120 degrees , 130 degrees or 140 degrees of flexion (p = 0.689, 0.615, 0.253 and 0.248, respectively). Upsized femoral components would increase PF forces in deep knee flexion. Gender specific implants would not reduce PF forces. PMID- 22219249 TI - In vitro phenotypic modulation of chondrocytes from knees of patients with osteochondritis dissecans: implications for chondrocyte implantation procedures. AB - We attempted to characterise the biological quality and regenerative potential of chondrocytes in osteochondritis dissecans (OCD). Dissected fragments from ten patients with OCD of the knee (mean age 27.8 years (16 to 49)) were harvested at arthroscopy. A sample of cartilage from the intercondylar notch was taken from the same joint and from the notch of ten patients with a traumatic cartilage defect (mean age 31.6 years (19 to 52)). Chondrocytes were extracted and subsequently cultured. Collagen types 1, 2, and 10 mRNA were quantified by polymerase chain reaction. Compared with the notch chondrocytes, cells from the dissecate expressed similar levels of collagen types 1 and 2 mRNA. The level of collagen type 10 message was 50 times lower after cell culture, indicating a loss of hypertrophic cells or genes. The high viability, retained capacity to differentiate and metabolic activity of the extracted cells suggests preservation of the intrinsic repair capability of these dissecates. Molecular analysis indicated a phenotypic modulation of the expanded dissecate chondrocytes towards a normal phenotype. Our findings suggest that cartilage taken from the dissecate can be reasonably used as a cell source for chondrocyte implantation procedures. PMID- 22219250 TI - The contribution of each anterior cruciate ligament bundle to the Lachman test: a cadaver investigation. AB - The clinical diagnosis of a partial tear of the anterior cruciate ligament (ACL) is still subject to debate. Little is known about the contribution of each ACL bundle during the Lachman test. We investigated this using six fresh-frozen cadaveric lower limbs. Screws were placed in the femora and tibiae as fixed landmarks for digitisation of the bone positions. The femur was secured horizontally in a clamp. A metal hook was screwed to the tibial tubercle and used to apply a load of 150 N directed anteroposteriorly to the tibia to simulate the Lachman test. The knees then received constant axial compression and 3D knee kinematic data were collected by digitising the screw head positions in 30 degrees flexion under each test condition. Measurements of tibial translation and rotation were made, first with the ACL intact, then after sequential cutting of the ACL bundles, and finally after complete division of the ACL. Two-way analysis of variance analysis was performed. During the Lachman test, in all knees and in all test conditions, lateral tibial translation exceeded that on the medial side. With an intact ACL, both anterior and lateral tibial landmarks translated significantly more than those on the medial side (p < 0.001). With sequential division of the ACL bundles, selective cutting of the posterolateral bundle (PLB) did not increase translation of any landmark compared with when the ACL remained intact. Cutting the anteromedial bundle (AMB) resulted in an increased anterior translation of all landmarks. Compared to the intact ACL, when the ACL was fully transected a significant increase in anterior translation of all landmarks occurred (p < 0.001). However, anterior tibial translation was almost identical after AMB or complete ACL division. We found that the AMB confers its most significant contribution to tibial translation during the Lachman test, whereas the PLB has a negligible effect on anterior translation. Section of the PLB had a greater effect on increasing the internal rotation of the tibia than the AMB. However, its contribution of a mean of 2.8 degrees amplitude remains low. The clinical relevance of our investigation suggests that, based on anterior tibial translation only, one cannot distinguish between a full ACL and an isolated AMB tear. Isolated PLB tears cannot be detected solely by the Lachman test, as this bundle probably contributes more resistance to the pivot shift. PMID- 22219251 TI - Use of the reamer-irrigator-aspirator technique to obtain autograft for ankle and hindfoot arthrodesis. AB - The use of autograft bone is the best option when undertaking a procedure that requires bone graft because it is osteogenic, osteoconductive and osseo inductive. Pain, morbidity and complications associated with harvesting iliac or non-iliac sites occur in between 6% and 30% of cases. An alternative source of graft with possibly a lower morbidity is the intramedullary canal. In this study, 28 patients undergoing 30 arthrodesis procedures on the hindfoot had a mean of 48 cm(3) (43 to 50) of bone harvested locally from the hindfoot or the tibial shaft by antegrade or retrograde reaming. No patient sustained a fracture of the calcaneum, talus or tibia. There was no morbidity except for one complication when the reamer breached the medial tibial cortex. This healed uneventfully. This method of using the reamer-irrigator-aspirator system is an extension of the standard technique of intramedullary reaming of the lower limb: it produces good quality bone graft with viable growth factors consistent with that of the iliac crest, and donor site morbidity is low. This is an efficient method of obtaining autologous bone for use in arthrodesis of the ankle or hindfoot. PMID- 22219253 TI - The contribution of the coronoid and radial head to the stability of the elbow. AB - We undertook this study to determine the minimum amount of coronoid necessary to stabilise an otherwise intact elbow joint. Regan-Morrey types II and III, plus medial and lateral oblique coronoid fractures, collectively termed type IV fractures, were simulated in nine fresh cadavers. An electromagnetic tracking system defined the three-dimensional stability of the ulna relative to the humerus. The coronoid surface area accounts for 59% of the anterior articulation. Alteration in valgus, internal and external rotation occurred only with a type III coronoid fracture, accounting for 68% of the coronoid and 40% of the entire articular surface. A type II fracture removed 42% of the coronoid articulation and 25% of the entire articular surface but was associated with valgus and external rotational changes only when the radial head was removed, thereby removing 67% of the articular surface. We conclude that all type III fractures, as defined here, are unstable, even with intact ligaments and a radial head. However, a type II deficiency is stable unless the radial head is removed. Our study suggests that isolated medial-oblique or lateral-oblique fractures, and even a type II fracture with intact ligaments and a functional radial head, can be clinically stable, which is consistent with clinical observation. PMID- 22219252 TI - Revision of total elbow replacement by exchange cementing. AB - We report the effectiveness of revision of total elbow replacement by re cementing. Between 1982 and 2004, 53 elbows in 52 patients were treated with re cementing of a total elbow replacement into part or all of the existing cement mantle or into the debrided host-bone interface, without the use of structural bone augmentation or a custom prosthesis. The original implant revision was still in situ and functional in 42 of 53 elbows (79%) at a mean of 94.5 months (26 to 266) after surgery. In 31 of these 42 elbows (74%) the Mayo Elbow Performance Score was good or excellent. Overall, of the 53 elbows, 18 (34%) required re operation, ten (19%) for loosening. A classification system was developed to identify those not suitable for revision by this technique, and using this we have showed that successful re-implantation is statistically correlated to properly addressing the bone deficiency for both the humeral (p = 0.005) and the ulnar (p = 0.039) components. PMID- 22219254 TI - The insertional torque of a pedicle screw has a positive correlation with bone mineral density in posterior lumbar pedicle screw fixation. AB - In patients with osteoporosis there is always a strong possibility that pedicle screws will loosen. This makes it difficult to select the appropriate osteoporotic patient for a spinal fusion. The purpose of this study was to determine the correlation between bone mineral density (BMD) and the magnitude of torque required to insert a pedicle screw. To accomplish this, 181 patients with degenerative disease of the lumbar spine were studied prospectively. Each underwent dual-energy x-ray absorptiometry (DEXA) and intra-operative measurement of the torque required to insert each pedicle screw. The levels of torque generated in patients with osteoporosis and osteopenia were significantly lower than those achieved in normal patients. Positive correlations were observed between BMD and T-value at the instrumented lumbar vertebrae, mean BMD and mean T value of the lumbar vertebrae, and mean BMD and mean T-value of the proximal femur. The predictive torque (Nm) generated during pedicle screw insertion was [ 0.127 + 1.62 * (BMD at the corresponding lumbar vertebrae)], as measured by linear regression analysis. The positive correlation between BMD and the maximum torque required to insert a pedicle screw suggests that pre-operative assessment of BMD may be useful in determining the ultimate strength of fixation of a device, as well as the number of levels that need to be fixed with pedicle screws in patients who are suspected of having osteoporosis. PMID- 22219255 TI - Decision-making in lumbar spinal stenosis: A survey on the influence of the morphology of the dural sac. AB - Surgical decision-making in lumbar spinal stenosis involves assessment of clinical parameters and the severity of the radiological stenosis. We suspected that surgeons based surgical decisions more on dural sac cross-sectional area (DSCA) than on the morphology of the dural sac. We carried out a survey among members of three European spine societies. The axial T2-weighted MR images from ten patients with varying degrees of DSCA and morphological grades according to the recently described morphological classification of lumbar spinal stenosis, with DSCA values disclosed in half the assessed images, were used for evaluation. We provided a clinical scenario to accompany the images, which were shown to 142 responding physicians, mainly orthopaedic surgeons but also some neurosurgeons and others directly involved in treating patients with spinal disorders. As the primary outcome we used the number of respondents who would proceed to surgery for a given DSCA or morphological grade. Substantial agreement among the respondents was observed, with severe or extreme stenosis as defined by the morphological grade leading to surgery. This decision was not dependent on the number of years in practice, medical density or specialty. Disclosing the DSCA did not alter operative decision-making. In all, 40 respondents (29%) had prior knowledge of the morphological grading system, but their responses showed no difference from those who had not. This study suggests that the participants were less influenced by DSCA than by the morphological appearance of the dural sac. Classifying lumbar spinal stenosis according to morphology rather than surface measurements appears to be consistent with current clinical practice. PMID- 22219256 TI - Characteristics and outcome in patients sustaining a second contralateral fracture of the hip. AB - We compared 5341 patients with an initial fracture of the hip with 633 patients who sustained a second fracture of the contralateral hip. Patients presenting with a second fracture were more likely to be institutionalised, female, older, and have lower mobility and mental test scores. There was no significant difference between the two groups with regards to the change in the level of mobility or return to their original residence at one year follow-up. However, the mortality rate in the second fracture group was significantly higher at one year (31.6% vs 27.3%, p = 0.024). In two thirds of patients, the second fracture was in the same anatomical location as the first. In an analysis of 293 patients, approximately 70% of second fractures occurred within three years of the first. This is the largest study to investigate the outcome of patients who sustain a second contralateral hip fracture. Despite the higher mortality rate at one year, the outcome for surviving patients is not significantly different from those after initial hip fractures. PMID- 22219257 TI - Early antibiotics and debridement independently reduce infection in an open fracture model. AB - Most animal studies indicate that early irrigation and debridement reduce infection after an open fracture. Unfortunately, these studies often do not involve antibiotics. Clinical studies indicate that the timing of initial debridement does not affect the rate of infection but these studies are observational and fraught with confounding variables. The purpose of this study was to control these variables using an animal model incorporating systemic antibiotics and surgical treatment. We used a rat femur model with a defect which was contaminated with Staphylococcus aureus and treated with a three-day course of systemic cefazolin (5 mg/kg 12-hourly) and debridement and irrigation, both of which were initiated independently at two, six and 24 hour time points. After 14 days the bone and hardware were harvested for separate microbiological analysis. No animal that received antibiotics and surgery two hours after injury had detectable bacteria. When antibiotics were started at two hours, a delay in surgical treatment from two to six hours significantly increased the development of infection (p = 0.047). However, delaying surgery to 24 hours increase the rate of infection, but not significantly (p = 0.054). The timing of antibiotics had a more significant effect on the proportion of positive samples than earlier surgery. Delaying antibiotics to six or 24 hours had a profoundly detrimental effect on the infection rate regardless of the timing of surgery. These findings are consistent with the concept that bacteria progress from a vulnerable planktonic form to a treatment-resistant biofilm. PMID- 22219258 TI - Meta-analysis of cause of death following total joint replacement using different thromboprophylaxis regimens. AB - We performed a meta-analysis of modern total joint replacement (TJR) to determine the post-operative mortality and the cause of death using different thromboprophylactic regimens as follows: 1) no routine chemothromboprophylaxis (NRC); 2) Potent anticoagulation (PA) (unfractionated or low-molecular-weight heparin, ximelagatran, fondaparinux or rivaroxaban); 3) Potent anticoagulation combined (PAC) with regional anaesthesia and/or pneumatic compression devices (PCDs); 4) Warfarin (W); 5) Warfarin combined (WAC) with regional anaesthesia and/or PCD; and 6) Multimodal (MM) prophylaxis, including regional anaesthesia, PCDs and aspirin in low-risk patients. Cause of death was classified as autopsy proven, clinically certain or unknown. Deaths were grouped into cardiopulmonary excluding pulmonary embolism (PE), PE, bleeding-related, gastrointestinal, central nervous system, and others (miscellaneous). Meta-analysis based on fixed effects or random effects models was used for pooling incidence data. In all, 70 studies were included (99 441 patients; 373 deaths). The mortality was lowest in the MM (0.2%) and WC (0.2%) groups. The most frequent cause of death was cardiopulmonary (47.9%), followed by PE (25.4%) and bleeding (8.9%). The proportion of deaths due to PE was not significantly affected by the thromboprophylaxis regimen (PA, 35.5%; PAC, 28%; MM, 23.2%; and NRC, 16.3%). Fatal bleeding was higher in groups relying on the use of anticoagulation (W, 33.8%; PA, 9.4%; PAC, 10.8%) but the differences were not statistically significant. Our study demonstrated that the routine use of PA does not reduce the overall mortality or the proportion of deaths due to PE. PMID- 22219259 TI - The treatment of locally recurrent chondrosarcoma: Is extensive further surgery justified? AB - The aim of this study was to define the treatment criteria for patients with recurrent chondrosarcoma. We reviewed the data of 77 patients to examine the influence of factors such as the intention of treatment (curative/palliative), extent of surgery, resection margins, status of disease at the time of local recurrence and the grade of the tumour. A total of 70 patients underwent surgery for recurrent chondrosarcoma. In seven patients surgery was not a viable option. Metastatic disease occurred in 41 patients, appearing synchronously with the local recurrence in 56% of cases. For patients without metastasis at the time of local recurrence, the overall survival at a mean follow-up after recurrence of 67 months (0 to 289) was 74% (5 of 27) compared with 19% (13 of 50) for patients with metastasis at or before the development of the recurrence. Neither the type/extent of surgery, site of tumour, nor the resection margins for the recurrent tumour significantly influenced the overall survival. With limited survival for patients with metastatic disease at the time of local recurrence (0% for patients with grade III and de-differentiated chondrosarcoma), palliative treatment, including local radiation therapy and debulking procedures, should be discussed with the patients to avoid long hospitalisation and functional deficits. For patients without metastasis at the time of local recurrence, the overall survival of 74% justifies an aggressive approach including wide resection margins and extensive reconstruction. PMID- 22219260 TI - Comparison between upper and lower limb lengthening in patients with achondroplasia: a retrospective study. AB - Lengthening of the humerus is now an established technique. We compared the complications of humeral lengthening with those of femoral lengthening and investigated whether or not the callus formation in the humerus proceeds at a higher rate than that in the femur. A total of 24 humeral and 24 femoral lengthenings were performed on 12 patients with achondroplasia. We measured the pixel value ratio (PVR) of the lengthened area on radiographs and each radiograph was analysed for the shape, type and density of the callus. The quality of life (QOL) of the patients after humeral lengthening was compared with that prior to surgery. The complication rate per segment of humerus and femur was 0.87% and 1.37%, respectively. In the humerus the PVR was significantly higher than that of the femur. Lower limbs were associated with an increased incidence of concave, lateral and central callus shapes. Humeral lengthening had a lower complication rate than lower-limb lengthening, and QOL increased significantly after humeral lengthening. Callus formation in the humerus during the distraction period proceeded at a significantly higher rate than that in the femur. These findings indicate that humeral lengthening has an important role in the management of patients with achondroplasia. PMID- 22219261 TI - Retention of forearm plates: risks and benefits in a paediatric population. AB - Most surgeons favour removing forearm plates in children. There is, however, no long-term data regarding the complications of retaining a plate. We present a prospective case series of 82 paediatric patients who underwent plating of their forearm fracture over an eight-year period with a minimum follow-up of two years. The study institution does not routinely remove forearm plates. A total of 116 plates were used: 79 one-third tubular plates and 37 dynamic compression plates (DCP). There were 12 complications: six plates (7.3%) were removed for pain or stiffness and there were six (7.3%) implant-related fractures. Overall, survival of the plates was 85% at 10 years. Cox regression analysis identified radial plates (odds ratio (OR) 4.4, p = 0.03) and DCP fixation (OR 3.2, p = 0.02) to be independent risk factors of an implant-related fracture. In contrast ulnar plates were more likely to cause pain or irritation necessitating removal (OR 5.6, p = 0.04). The complications associated with retaining a plate are different, but do not occur more frequently than the complications following removal of a plate in children. PMID- 22219264 TI - Structural basis for degeneracy among thermosensory neurons in Caenorhabditis elegans. PMID- 22219262 TI - Treatment of a severe neglected valgus deformity after excision of the distal fibula for Ewing's sarcoma. AB - In distal fibular resection without reconstruction, the stabilising effect of the lateral malleolus is lost. Thus, the ankle may collapse into valgus and may be unstable in varus. Here, we describe a child who underwent successful staged surgical correction of a severe neglected valgus deformity after excision of the distal fibula for a Ewing's sarcoma. PMID- 22219265 TI - Topographic contribution of early visual cortex to short-term memory consolidation: a transcranial magnetic stimulation study. AB - The neural correlates for retention of visual information in visual short-term memory are considered separate from those of sensory encoding. However, recent findings suggest that sensory areas may play a role also in short-term memory. We investigated the functional relevance, spatial specificity, and temporal characteristics of human early visual cortex in the consolidation of capacity limited topographic visual memory using transcranial magnetic stimulation (TMS). Topographically specific TMS pulses were delivered over lateralized occipital cortex at 100, 200, or 400 ms into the retention phase of a modified change detection task with low or high memory loads. For the high but not the low memory load, we found decreased memory performance for memory trials in the visual field contralateral, but not ipsilateral to the side of TMS, when pulses were delivered at 200 ms into the retention interval. A behavioral version of the TMS experiment, in which a distractor stimulus (memory mask) replaced the TMS pulses, further corroborated these findings. Our findings suggest that retinotopic visual cortex contributes to the short-term consolidation of topographic visual memory during early stages of the retention of visual information. Further, TMS-induced interference decreased the strength (amplitude) of the memory representation, which most strongly affected the high memory load trials. PMID- 22219266 TI - Reduced prefrontal-parietal effective connectivity and working memory deficits in schizophrenia. AB - The neural mechanisms behind cognitive deficits in schizophrenia still remain unclear. Functional neuroimaging studies on working memory (WM) yielded inconsistent results, suggesting task performance as a moderating variable of prefrontal activation. Beyond regional specific activation, disordered integration of brain regions was supposed as a critical pathophysiological mechanism of cognitive deficits in schizophrenia. Here, we first hypothesized that prefrontal activation implicated in WM depends primarily on task performance and therefore stratified participants into performance subgroups. Second, in line with the dysconnectivity hypothesis, we asked whether connectivity in the prefrontal-parietal network underlying WM is altered in all patients. We used functional magnetic resonance imaging in human subjects (41 schizophrenia patients, 42 healthy controls) and dynamic causal modeling to examine effective connectivity during a WM task. In line with our first hypothesis, we found that prefrontal activation was differentially modulated by task performance: there was a significant task by group by performance interaction revealing an increase of activation with performance in patients and a decrease with performance in controls. Beyond that, we show for the first time that WM-dependent effective connectivity from prefrontal to parietal cortex is reduced in all schizophrenia patients. This finding was independent of performance. In conclusion, our results are in line with the highly influential hypothesis that the relationship between WM performance and prefrontal activation follows an inverted U-shaped function. Moreover, this study in a large sample of patients reveals a mechanism underlying prefrontal inefficiency and cognitive deficits in schizophrenia, thereby providing direct experimental evidence for the dysconnectivity hypothesis. PMID- 22219267 TI - Transformation-tolerant object recognition in rats revealed by visual priming. AB - Successful use of rodents as models for studying object vision crucially depends on the ability of their visual system to construct representations of visual objects that tolerate (i.e., remain relatively unchanged with respect to) the tremendous changes in object appearance produced, for instance, by size and viewpoint variation. Whether this is the case is still controversial, despite some recent demonstration of transformation-tolerant object recognition in rats. In fact, it remains unknown to what extent such a tolerant recognition has a spontaneous, perceptual basis, or, alternatively, mainly reflects learning of arbitrary associative relations among trained object appearances. In this study, we addressed this question by training rats to categorize a continuum of morph objects resulting from blending two object prototypes. The resulting psychometric curve (reporting the proportion of responses to one prototype along the morph line) served as a reference when, in a second phase of the experiment, either prototype was briefly presented as a prime, immediately before a test morph object. The resulting shift of the psychometric curve showed that recognition became biased toward the identity of the prime. Critically, this bias was observed also when the primes were transformed along a variety of dimensions (i.e., size, position, viewpoint, and their combination) that the animals had never experienced before. These results indicate that rats spontaneously perceive different views/appearances of an object as similar (i.e., as instances of the same object) and argue for the existence of neuronal substrates underlying formation of transformation-tolerant object representations in rats. PMID- 22219268 TI - Comprehensive gene expression profiling in the prefrontal cortex links immune activation and neutrophil infiltration to antinociception. AB - Functional neuroimaging studies have implicated the prefrontal cortex (PFCTX) in descending modulation of pain and the placebo effect. This study was performed to elucidate comprehensive PFCTX gene expression in an animal model of persistent trigeminal pain. Adult male C57BL/6J mice received facial carrageenan injection and showed sustained increase in nociceptive responses. Microarray analyses of differentially expressed genes in the PFCTX at 3 d after injection showed "immune system process" as the dominant ontology term and increased mRNA expression of S100a8, S100a9, Lcn2, Il2rg, Fcgr1, Fcgr2b, C1qb, Ptprc, Ccl12, and Cd52 were verified by RT-PCR. Upregulation of S100A8, S100A9, and lipocalin 2 (LCN2) were confirmed by Western blots, and cells in the PFCTX were double immunolabeled with MPO, indicating they were neutrophils. Analyses of blood of facial carrageenan injected mice also showed increased mRNA expression of these markers, suggesting transmigration of activated neutrophils into the brain. Other immune-related genes, Il2rg, Fcgr2b, C1qb, Ptprc, and Ccl12 were upregulated in the PFCTX but not blood. Approximately 70% of S100A9-positive cells in the PFCTX of carrageenan injected mice were located in capillaries adherent to endothelial cells, whereas 30% were within the brain parenchyma. Carrageenan-injected mice showed significantly reduced nociceptive responses after injection of C terminus of murine S100A9 protein in the lateral ventricles and PFCTX but not somatosensory barrel cortex. Together, these findings demonstrate activation of immune-related genes in the PFCTX during inflammatory pain and highlight an exciting role of neutrophils in linking peripheral inflammation with immune activation of the PFCTX and antinociception. PMID- 22219269 TI - Differentiation and functional incorporation of embryonic stem cell-derived GABAergic interneurons in the dentate gyrus of mice with temporal lobe epilepsy. AB - Cell therapies for neurological disorders require an extensive knowledge of disease-associated neuropathology and procedures for generating neurons for transplantation. In many patients with severe acquired temporal lobe epilepsy (TLE), the dentate gyrus exhibits sclerosis and GABAergic interneuron degeneration. Mounting evidence suggests that therapeutic benefits can be obtained by transplanting fetal GABAergic progenitors into the dentate gyrus in rodents with TLE, but the scarcity of human fetal cells limits applicability in patient populations. In contrast, virtually limitless quantities of neural progenitors can be obtained from embryonic stem (ES) cells. ES cell-based therapies for neurological repair in TLE require evidence that the transplanted neurons integrate functionally and replace cell types that degenerate. To address these issues, we transplanted mouse ES cell-derived neural progenitors (ESNPs) with ventral forebrain identities into the hilus of the dentate gyrus of mice with TLE and evaluated graft differentiation, mossy fiber sprouting, cellular morphology, and electrophysiological properties of the transplanted neurons. In addition, we compared electrophysiological properties of the transplanted neurons with endogenous hilar interneurons in mice without TLE. The majority of transplanted ESNPs differentiated into GABAergic interneuron subtypes expressing calcium-binding proteins parvalbumin, calbindin, or calretinin. Global suppression of mossy fiber sprouting was not observed; however, ESNP-derived neurons formed dense axonal arborizations in the inner molecular layer and throughout the hilus. Whole-cell hippocampal slice electrophysiological recordings and morphological analyses of the transplanted neurons identified five basic types; most with strong after-hyperpolarizations and smooth or sparsely spiny dendritic morphologies resembling endogenous hippocampal interneurons. Moreover, intracellular recordings of spontaneous EPSCs indicated that the new cells functionally integrate into epileptic hippocampal circuitry. PMID- 22219270 TI - GABA is depolarizing in hippocampal dentate granule cells of the adolescent and adult rats. AB - GABAergic signaling in hippocampal pyramidal neurons undergoes a switch from depolarizing to hyperpolarizing during early neuronal development. Whether such a transformation of GABAergic action occurs in dentate granule cells (DGCs), located at the first stage of the hippocampal trisynaptic circuit, is unclear. Here, we use noninvasive extracellular recording to monitor the effect of synaptically released GABA on the DGC population. We find that GABAergic responses in adolescent and adult rat DGCs are still depolarizing from rest. Using a morphologically realistic DGC model, we show that GABAergic action, depending on its precise timing and location, can have either an excitatory or inhibitory role in signal processing in the dentate gyrus. PMID- 22219271 TI - Endogenous Rho-kinase signaling maintains synaptic strength by stabilizing the size of the readily releasable pool of synaptic vesicles. AB - Rho-associated kinase (ROCK) regulates neural cell migration, proliferation and survival, dendritic spine morphology, and axon guidance and regeneration. There is, however, little information about whether ROCK modulates the electrical activity and information processing of neuronal circuits. At neonatal stage, ROCKalpha is expressed in hypoglossal motoneurons (HMNs) and in their afferent inputs, whereas ROCKbeta is found in synaptic terminals on HMNs, but not in their somata. Inhibition of endogenous ROCK activity in neonatal rat brainstem slices failed to modulate intrinsic excitability of HMNs, but strongly attenuated the strength of their glutamatergic and GABAergic synaptic inputs. The mechanism acts presynaptically to reduce evoked neurotransmitter release. ROCK inhibition increased myosin light chain (MLC) phosphorylation, which is known to trigger actomyosin contraction, and reduced the number of synaptic vesicles docked to active zones in excitatory boutons. Functional and ultrastructural changes induced by ROCK inhibition were fully prevented/reverted by MLC kinase (MLCK) inhibition. Furthermore, ROCK inhibition drastically reduced the phosphorylated form of p21-associated kinase (PAK), which directly inhibits MLCK. We conclude that endogenous ROCK activity is necessary for the normal performance of motor output commands, because it maintains afferent synaptic strength, by stabilizing the size of the readily releasable pool of synaptic vesicles. The mechanism of action involves a tonic inhibition of MLCK, presumably through PAK phosphorylation. This mechanism might be present in adults since unilateral microinjection of ROCK or MLCK inhibitors into the hypoglossal nucleus reduced or increased, respectively, whole XIIth nerve activity. PMID- 22219274 TI - Phase-amplitude coupling in human electrocorticography is spatially distributed and phase diverse. AB - Spatially distributed phase-amplitude coupling (PAC) is a possible mechanism for selectively routing information through neuronal networks. If so, two key properties determine its selectivity and flexibility, phase diversity over space, and frequency diversity. To investigate these issues, we analyzed 42 human electrocorticographic recordings from 27 patients performing a working memory task. We demonstrate that (1) spatially distributed PAC occurred at distances >10 cm, (2) involved diverse preferred coupling phases, and (3) involved diverse frequencies. Using a novel technique [N-way decomposition based on the PARAFAC (for Parallel Factor analysis) model], we demonstrate that (4) these diverse phases originated mainly from the phase-providing oscillations. With these properties, PAC can be the backbone of a mechanism that is able to separate spatially distributed networks operating in parallel. PMID- 22219272 TI - Respiration drives network activity and modulates synaptic and circuit processing of lateral inhibition in the olfactory bulb. AB - Respiration produces rhythmic activity in the entire olfactory system, driving neurons in the olfactory epithelium, olfactory bulb (OB), and cortex. The rhythmic nature of this activity is believed to be a critical component of sensory processing. OB projection neurons, mitral and tufted cells exhibit both spiking and subthreshold membrane potential oscillations rhythmically coupled to respiration. However, the network and synaptic mechanisms that produce respiration-coupled activity, and the effects of respiration on lateral inhibition, a major component of sensory processing in OB circuits, are not known. Is respiration-coupled activity in mitral and tufted cells produced by sensory synaptic inputs from nasal airflow alone, cortico-bulbar feedback, or intrinsic membrane properties of the projection neurons? Does respiration facilitate or modulate the activity of inhibitory lateral circuits in the OB? Here, in vivo intracellular recordings from identified mitral and tufted cells in anesthetized rats demonstrate that nasal airflow provides excitatory synaptic inputs to both cell types and drives respiration-coupled spiking. Lateral inhibition, inhibitory postsynaptic potentials evoked by intrabulbar microstimulation, was modulated by respiration. In individual mitral and tufted cells, inhibition was larger at specific respiratory phases. However, lateral inhibition was not uniformly larger during a particular respiratory phase in either cell type. Removing nasal airflow abolished respiration-coupled spiking in both cell types and nearly eliminated spiking in mitral, but not tufted, cells. In the absence of nasal airflow, lateral inhibition was weaker in mitral cells and less modulated in tufted cells. Thus, respiration drives distinct network activities that functionally modulate sensory processing in the OB. PMID- 22219273 TI - Afadin, a Ras/Rap effector that controls cadherin function, promotes spine and excitatory synapse density in the hippocampus. AB - Many molecules regulate synaptogenesis, but intracellular signaling pathways required for their functions are poorly understood. Afadin is a Rap-regulated, actin-binding protein that promotes cadherin complex assembly as well as binding many other cell adhesion molecules and receptors. To examine its role in mediating synaptogenesis, we deleted afadin (mllt1), using a conditional allele, in postmitotic hippocampal neurons. Consistent with its role in promoting cadherin recruitment, afadin deletion resulted in 70% fewer and less intense N cadherin puncta with similar reductions of beta-catenin and alphaN-catenin puncta densities and 35% reduction in EphB2 puncta density. Its absence also resulted in 40% decreases in spine and excitatory synapse densities in the stratum radiatum of CA1, as determined by morphology, apposition of presynaptic and postsynaptic markers, and synaptic transmission. The remaining synapses appeared to function normally. Thus, afadin is a key intracellular signaling molecule for cadherin recruitment and is necessary for spine and synapse formation in vivo. PMID- 22219275 TI - SIRT1 protects against alpha-synuclein aggregation by activating molecular chaperones. AB - alpha-Synuclein is a key molecule in the pathogenesis of synucleinopathy including dementia with Lewy bodies, Parkinson's disease, and multiple system atrophy. Sirtuins are NAD(+)-dependent protein deacetylases that are highly conserved and counter aging in lower organisms. We show that the life span of a mouse model with A53T alpha-synuclein mutation is increased by overexpressing SIRT1 and decreased by knocking out SIRT1 in brain. Furthermore, alpha-synuclein aggregates are reduced in the brains of mice with SIRT1 overexpression and increased by SIRT1 deletion. We show that SIRT1 deacetylates HSF1 (heat shock factor 1) and increases HSP70 RNA and protein levels, but only in the brains of mice with A53T and SIRT1 expression. Thus, SIRT1 responds to alpha-synuclein aggregation-induced stress by activating molecular chaperones to protect against disease. PMID- 22219276 TI - Bone marrow transplantation confers modest benefits in mouse models of Huntington's disease. AB - Huntington's disease (HD) is caused by an expanded polyglutamine tract in the protein huntingtin (htt). Although HD has historically been viewed as a brain specific disease, htt is expressed ubiquitously, and recent studies indicate that mutant htt might cause changes to the immune system that could contribute to pathogenesis. Monocytes from HD patients and mouse models are hyperactive in response to stimulation, and increased levels of inflammatory cytokines and chemokines are found in pre-manifest patients that correlate with pathogenesis. In this study, wild-type (WT) bone marrow cells were transplanted into two lethally irradiated transgenic mouse models of HD that ubiquitously express full length htt (YAC128 and BACHD mice). Bone marrow transplantation partially attenuated hypokinetic and motor deficits in HD mice. Increased levels of synapses in the cortex were found in HD mice that received bone marrow transplants. Importantly, serum levels of interleukin-6, interleukin-10, CXC chemokine ligand 1, and interferon-gamma were significantly higher in HD than WT mice but were normalized in mice that received a bone marrow transplant. These results suggest that immune cell dysfunction might be an important modifier of pathogenesis in HD. PMID- 22219278 TI - Initiation and propagation of action potentials in gonadotropin-releasing hormone neuron dendrites. AB - Gonadotropin-releasing hormone (GnRH) neurons are the final output neurons in a complex neuronal network that regulates fertility. The morphology of GnRH neuron dendrites is very different to other central neurons in that they are very long, thin, and unbranched. To study the function of these dendrites, we have used Na(+) and Ca(2+) imaging in combination with dual soma and dendrite electrical recordings in brain slices from GnRH-GFP mice. Here, we show that GnRH neurons actively propagate Na(+) spikes throughout their dendrites. Multisite dendritic recordings confirmed that these spikes were observed in one of the dendrites before the soma in the great majority of neurons tested. Na(+) imaging experiments revealed that the initial 150 MUm of dendrite has a higher density of functional Na(+) channels than more distal regions, suggesting that this region of dendrite is highly excitable and may be the site of spike initiation. Finally, we show that the depolarization from dendritic spikes opens voltage-gated Ca(2+) channels giving rise to dendritic Ca(2+) transients. Together, these findings suggest that the proximal dendrites of GnRH neurons are highly excitable and are likely to be the site of action potential initiation in these neurons. PMID- 22219277 TI - HIV-1 Tat triggers nuclear localization of ZO-1 via Rho signaling and cAMP response element-binding protein activation. AB - The human immunodeficiency virus (HIV)-specific protein trans-activator of transcription (Tat) can contribute to the dysfunction of brain endothelial cells and HIV trafficking into the brain by disrupting tight junction (TJ) integrity at the blood-brain barrier (BBB) level. Specific TJ proteins, such as zonula occludens (ZO) proteins, localize not only at the cell-cell borders but are also present in the nuclei. The objective of the present study was to evaluate the mechanisms and significance of Tat-induced nuclear localization of ZO-1. Treatment of a brain endothelial cell line (hCMEC/D3 cells) with Tat resulted in a decrease in total levels of ZO-1 but significantly upregulated ZO-1 protein expression in the nuclei. In addition, exposure to Tat stimulated Rho signaling and induced phosphorylation and activity of transcription factor cAMP response element-binding protein (CREB), binding sites that have been identified in the proximal region of the ZO-1 promoter. Interestingly, inhibition of the Rho cascade protected against Tat-induced upregulation of ZO-1 in the nuclei and activation of CREB. Depletion of CREB by infection of cells with specific shRNA lentiviral particles attenuated both Tat-induced Rho signaling and nuclear targeting of ZO-1. A decrease in CREB levels also attenuated Tat-induced endothelial and BBB hyperpermeability as well as transendothelial migration of monocytic cells. The role of CREB in Tat-mediated alterations of ZO-1 was confirmed in brain microvessels in mice with CREB shRNA lentiviral particles injected into the cerebral circulation. The present results indicate the crucial role of Rho signaling and CREB in modulation of nuclear localization of ZO-1 and maintaining the integrity of endothelial monolayers. PMID- 22219279 TI - Eye position encoding in three-dimensional space: integration of version and vergence signals in the medial posterior parietal cortex. AB - Eye position signals are pivotal in the visuomotor transformations performed by the posterior parietal cortex (PPC), but to date there are few studies addressing the influence of vergence angle upon single PPC neurons. In the present study, we investigated the influence on single neurons of the medial PPC area V6A of vergence and version signals. Single-unit activity was recorded from V6A in two Macaca fascicularis fixating real targets in darkness. The fixation targets were placed at eye level and at different vergence and version angles within the peripersonal space. Few neurons were modulated by version or vergence only, while the majority of cells were affected by both signals. We advance here the hypothesis that gaze-modulated V6A cells are able to encode gazed positions in the three-dimensional space. In single cells, version and vergence influenced the discharge with variable time course. In several cases, the two gaze variables influence neural discharges during only a part of the fixation time, but, more often, their influence persisted through large parts of it. Cells discharging for the first 400-500 ms of fixation could signal the arrival of gaze (and/or of spotlight of attention) in a new position in the peripersonal space. Cells showing a more sustained activity during the fixation period could better signal the location in space of the gazed objects. Both signals are critical for the control of upcoming or ongoing arm movements, such as those needed to reach and grasp objects located in the peripersonal space. PMID- 22219280 TI - Constitutive activation of Ca2+/calmodulin-dependent protein kinase II during development impairs central cholinergic transmission in a circuit underlying escape behavior in Drosophila. AB - Development of neural circuitry relies on precise matching between correct synaptic partners and appropriate synaptic strength tuning. Adaptive developmental adjustments may emerge from activity and calcium-dependent mechanisms. Calcium/calmodulin-dependent protein kinase II (CaMKII) has been associated with developmental synaptic plasticity, but its varied roles in different synapses and developmental stages make mechanistic generalizations difficult. In contrast, we focused on synaptic development roles of CaMKII in a defined sensory-motor circuit. Thus, different forms of CaMKII were expressed with UAS-Gal4 in distinct components of the giant fiber system, the escape circuit of Drosophila, consisting of photoreceptors, interneurons, motoneurons, and muscles. The results demonstrate that the constitutively active CaMKII-T287D impairs development of cholinergic synapses in giant fiber dendrites and thoracic motoneurons, preventing light-induced escape behavior. The locus of the defects is postsynaptic as demonstrated by selective expression of transgenes in distinct components of the circuit. Furthermore, defects among these cholinergic synapses varied in severity, while the glutamatergic neuromuscular junctions appeared unaffected, demonstrating differential effects of CaMKII misregulation on distinct synapses of the same circuit. Limiting transgene expression to adult circuits had no effects, supporting the role of misregulated kinase activity in the development of the system rather than in acutely mediating escape responses. Overexpression of wild-type transgenes did not affect circuit development and function, suggesting but not proving that the CaMKII-T287D effects are not due to ectopic expression. Therefore, regulated CaMKII autophosphorylation appears essential in central synapse development, and particular cholinergic synapses are affected differentially, although they operate via the same nicotinic receptor. PMID- 22219281 TI - Transgenic mouse model expressing the caspase 6 fragment of mutant huntingtin. AB - Huntington's disease (HD) is caused by a polyglutamine expansion in the Huntingtin (Htt) protein. Proteolytic cleavage of Htt into toxic N-terminal fragments is believed to be a key aspect of pathogenesis. The best characterized putative cleavage event is at amino acid 586, hypothesized to be mediated by caspase 6. A corollary of the caspase 6 cleavage hypothesis is that the caspase 6 fragment should be a toxic fragment. To test this hypothesis, and further characterize the role of this fragment, we have generated transgenic mice expressing the N-terminal 586 aa of Htt with a polyglutamine repeat length of 82 (N586-82Q), under the control of the prion promoter. N586-82Q mice show a clear progressive rotarod deficit by 4 months of age, and are hyperactive starting at 5 months, later changing to hypoactivity before early mortality. MRI studies reveal widespread brain atrophy, and histologic studies demonstrate an abundance of Htt aggregates, mostly cytoplasmic, which are predominantly composed of the N586-82Q polypeptide. Smaller soluble N-terminal fragments appear to accumulate over time, peaking at 4 months, and are predominantly found in the nuclear fraction. This model appears to have a phenotype more severe than current full-length Htt models, but less severe than HD mouse models expressing shorter Htt fragments. These studies suggest that the caspase 6 fragment may be a transient intermediate, that fragment size is a factor contributing to the rate of disease progression, and that short soluble nuclear fragments may be most relevant to pathogenesis. PMID- 22219282 TI - Stable learning in stochastic network states. AB - The mammalian cerebral cortex is characterized in vivo by irregular spontaneous activity, but how this ongoing dynamics affects signal processing and learning remains unknown. The associative plasticity rules demonstrated in vitro, mostly in silent networks, are based on the detection of correlations between presynaptic and postsynaptic activity and hence are sensitive to spontaneous activity and spurious correlations. Therefore, they cannot operate in realistic network states. Here, we present a new class of spike-timing-dependent plasticity learning rules with local floating plasticity thresholds, the slow dynamics of which account for metaplasticity. This novel algorithm is shown to both correctly predict homeostasis in synaptic weights and solve the problem of asymptotic stable learning in noisy states. It is shown to naturally encompass many other known types of learning rule, unifying them into a single coherent framework. The mixed presynaptic and postsynaptic dependency of the floating plasticity threshold is justified by a cascade of known molecular pathways, which leads to experimentally testable predictions. PMID- 22219283 TI - Echoes of the brain within the posterior cingulate cortex. AB - There is considerable uncertainty about the function of the posterior cingulate cortex (PCC). The PCC is a major node within the default mode network (DMN) and has high metabolic activity and dense structural connectivity to widespread brain regions, which suggests it has a role as a cortical hub. The region appears to be involved in internally directed thought, for example, memory recollection. However, recent nonhuman primate work provides evidence for a more active role in the control of cognition, through signaling an environmental change and the need to alter behavior. For an organism to flexibly react to a changing environment, information processed in functionally distinct brain networks needs to be integrated by such a cortical hub. If the PCC is involved in this process, its brain activity should show a complex and dynamic pattern that partially reflects activity in other brain networks. Using fMRI in humans and a multivariate analysis, we demonstrate that the PCC shows this type of complex functional architecture, where echoes of multiple other brain networks are seen in separable yet overlapping subregions. For example, a predominantly ventral region shows strong functional connectivity to the rest of the DMN, whereas two subregions within the dorsal PCC show high connectivity to frontoparietal networks involved in cognitive control. PCC subregions showed distinct patterns of activity modulation during the performance of an attentionally demanding task, suggesting that parts of the dorsal PCC interact with frontoparietal networks to regulate the balance between internally and externally directed cognition. PMID- 22219286 TI - EEG-guided transcranial magnetic stimulation reveals rapid shifts in motor cortical excitability during the human sleep slow oscillation. AB - Evoked cortical responses do not follow a rigid input-output function but are dynamically shaped by intrinsic neural properties at the time of stimulation. Recent research has emphasized the role of oscillatory activity in determining cortical excitability. Here we employed EEG-guided transcranial magnetic stimulation (TMS) during non-rapid eye movement sleep to examine whether the spontaneous <1 Hz neocortical slow oscillation (SO) is associated with corresponding fluctuations of evoked responses. Whereas the SO's alternating phases of global depolarization (up-state) and hyperpolarization (down-state) are clearly associated with fluctuations in spontaneous neuronal excitation, less is known about state-dependent shifts in neocortical excitability. In 12 human volunteers, single-pulse TMS of the primary motor cortical hand area (M1(HAND)) was triggered online by automatic detection of SO up-states and down-states in the EEG. State-dependent changes in cortical excitability were traced by simultaneously recording motor-evoked potentials (MEPs) and TMS-evoked EEG potentials (TEPs). Compared to wakefulness and regardless of SO state, sleep MEPs were smaller and delayed whereas sleep TEPs were fundamentally altered, closely resembling a spontaneous SO. However, both MEPs and TEPs were consistently larger when evoked during SO up-states than during down-states, and amplitudes within each SO state depended on the actual EEG potential at the time and site of stimulation. These results provide first-time evidence for a rapid state dependent shift in neocortical excitability during a neuronal oscillation in the human brain. We further demonstrate that EEG-guided temporal neuronavigation is a powerful tool to investigate the phase-dependent effects of neuronal oscillations on perception, cognition, and motor control. PMID- 22219284 TI - Slit1b-Robo3 signaling and N-cadherin regulate apical process retraction in developing retinal ganglion cells. AB - When neurons exit the cell cycle after their terminal mitosis, they detach from the apical surface of the neuroepithelium. Despite the fact that this detachment is crucial for further neurogenesis and neuronal migration, the underlying mechanisms are still not understood. Here, taking advantage of the genetics and imaging possibilities of the zebrafish retina as a model system, we show by knockdown experiments that the guidance molecule Slit1b and its receptor Robo3 are required for apical retraction of retinal ganglion cells (RGCs). In contrast, N-cadherin seems to be responsible for maintenance of apical attachment, as expression of dominant-negative N-cadherin causes RGCs to lose apical attachments prematurely and rescues retraction in slit1b morphants. These results suggest that Slit-Robo signaling downregulates N-cadherin activity to allow apical retraction in newly generated RGCs. PMID- 22219287 TI - Micro-positron emission tomography imaging of rat brain metabolism during expression of contextual conditioning. AB - Using (18)F-fluorodeoxyglucose microPET imaging, we investigated the neurocircuitry of contextual anxiety versus control in awake, conditioned rats (n = 7-10 per group). In addition, we imaged a group expressing cued fear. Simultaneous measurements of startle amplitude and freezing time were used to assess conditioning. To the best of our knowledge, no neuroimaging studies in conditioned rats have been conducted thus far, although visualizing and quantifying the metabolism of the intact brain in behaving animals is clearly of interest. In addition, more insight into the neurocircuitry involved in contextual anxiety may stimulate the development of new treatments for anxiety disorders. Our main finding was hypermetabolism in a cluster comprising the bed nucleus of the stria terminalis (BST) in rats expressing contextual anxiety compared with controls. Analysis of a subset of rats showing the best behavioral results (n = 5 per subgroup) confirmed this finding. We also observed hypermetabolism in the same cluster in rats expressing contextual anxiety compared with rats expressing cued fear. Our results provide novel evidence for a role of the BST in the expression of contextual anxiety. PMID- 22219285 TI - Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons. AB - Mutations in Cu,Zn superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (FALS), a rapidly fatal motor neuron disease. Mutant SOD1 has pleiotropic toxic effects on motor neurons, among which mitochondrial dysfunction has been proposed as one of the contributing factors in motor neuron demise. Mitochondria are highly dynamic in neurons; they are constantly reshaped by fusion and move along neurites to localize at sites of high-energy utilization, such as synapses. The finding of abnormal mitochondria accumulation in neuromuscular junctions, where the SOD1-FALS degenerative process is though to initiate, suggests that impaired mitochondrial dynamics in motor neurons may be involved in pathogenesis. We addressed this hypothesis by live imaging microscopy of photo-switchable fluorescent mitoDendra in transgenic rat motor neurons expressing mutant or wild-type human SOD1. We demonstrate that mutant SOD1 motor neurons have impaired mitochondrial fusion in axons and cell bodies. Mitochondria also display selective impairment of retrograde axonal transport, with reduced frequency and velocity of movements. Fusion and transport defects are associated with smaller mitochondrial size, decreased mitochondrial density, and defective mitochondrial membrane potential. Furthermore, mislocalization of mitochondria at synapses among motor neurons, in vitro, correlates with abnormal synaptic number, structure, and function. Dynamics abnormalities are specific to mutant SOD1 motor neuron mitochondria, since they are absent in wild-type SOD1 motor neurons, they do not involve other organelles, and they are not found in cortical neurons. Together, these results suggest that impaired mitochondrial dynamics may contribute to the selective degeneration of motor neurons in SOD1-FALS. PMID- 22219288 TI - Dock3 stimulates axonal outgrowth via GSK-3beta-mediated microtubule assembly. AB - Dock3, a new member of the guanine nucleotide exchange factors, causes cellular morphological changes by activating the small GTPase Rac1. Overexpression of Dock3 in neural cells promotes axonal outgrowth downstream of brain-derived neurotrophic factor (BDNF) signaling. We previously showed that Dock3 forms a complex with Fyn and WASP (Wiskott-Aldrich syndrome protein) family verprolin homologous (WAVE) proteins at the plasma membrane, and subsequent Rac1 activation promotes actin polymerization. Here we show that Dock3 binds to and inactivates glycogen synthase kinase-3beta (GSK-3beta) at the plasma membrane, thereby increasing the nonphosphorylated active form of collapsin response mediator protein-2 (CRMP-2), which promotes axon branching and microtubule assembly. Exogenously applied BDNF induced the phosphorylation of GSK-3beta and dephosphorylation of CRMP-2 in hippocampal neurons. Moreover, increased phosphorylation of GSK-3beta was detected in the regenerating axons of transgenic mice overexpressing Dock3 after optic nerve injury. These results suggest that Dock3 plays important roles downstream of BDNF signaling in the CNS, where it regulates cell polarity and promotes axonal outgrowth by stimulating dual pathways: actin polymerization and microtubule assembly. PMID- 22219289 TI - Brain-speech alignment enhances auditory cortical responses and speech perception. AB - Asymmetry in auditory cortical oscillations could play a role in speech perception by fostering hemispheric triage of information across the two hemispheres. Due to this asymmetry, fast speech temporal modulations relevant for phonemic analysis could be best perceived by the left auditory cortex, while slower modulations conveying vocal and paralinguistic information would be better captured by the right one. It is unclear, however, whether and how early oscillation-based selection influences speech perception. Using a dichotic listening paradigm in human participants, where we provided different parts of the speech envelope to each ear, we show that word recognition is facilitated when the temporal properties of speech match the rhythmic properties of auditory cortices. We further show that the interaction between speech envelope and auditory cortices rhythms translates in their level of neural activity (as measured with fMRI). In the left auditory cortex, the neural activity level related to stimulus-brain rhythm interaction predicts speech perception facilitation. These data demonstrate that speech interacts with auditory cortical rhythms differently in right and left auditory cortex, and that in the latter, the interaction directly impacts speech perception performance. PMID- 22219290 TI - Activation of ezrin/radixin/moesin mediates attractive growth cone guidance through regulation of growth cone actin and adhesion receptors. AB - The development of a functioning neural network relies on responses of axonal growth cones to molecular guidance cues that are encountered en route to their target tissue. Nerve growth factor (NGF) and neurotrophin-3 serve as attractive cues for chick embryo sensory growth cones in vitro and in vivo, but little is known about the actin-binding proteins necessary to mediate this response. The evolutionarily conserved ezrin/radixin/moesin (ERM) family of proteins can tether actin filaments to the cell membrane when phosphorylated at a conserved threonine residue. Here we show that acute neurotrophin stimulation rapidly increases active phospho-ERM levels in chick sensory neuron growth cone filopodia, coincident with an increase in filopodial L1 and beta-integrin. Disrupting ERM function with a dominant-negative construct (DN-ERM) results in smaller and less motile growth cones with disorganized actin filaments. Previously, we found that NGF treatment increases actin-depolymerizing factor (ADF)/cofilin activity and growth cone F-actin (Marsick et al., 2010). Here, we show this F-actin increase, as well as attractive turning to NGF, is blocked when ERM function is disrupted despite normal activation of ADF/cofilin. We further show that DN-ERM expression disrupts leading edge localization of active ADF/cofilin and free F-actin barbed ends. Moreover, filopodial phospho-ERM levels are increased by incorporation of active ADF/cofilin and reduced by knockdown of L1CAM.Together, these data suggest that ERM proteins organize actin filaments in sensory neuron growth cones and are crucial for neurotrophin-induced remodeling of F-actin and redistribution of adhesion receptors. PMID- 22219291 TI - A mammalian retinal bipolar cell uses both graded changes in membrane voltage and all-or-nothing Na+ spikes to encode light. AB - Barlow (1953) studied summation in ganglion cell receptive fields and observed a fine discrimination of spatial information from which he inferred that retinal interneurons use analog signals to process images. Subsequent intracellular recordings confirmed that the interneurons of the outer retina, including photoreceptors, horizontal cells, and bipolar cells, respond to light with slow, graded changes in membrane potential. Analog processing may enable interneurons to discriminate fine gradations in light intensity and spatiotemporal pattern, but at the expense of the speed, temporal precision, and threshold discrimination that are characteristic of all-or-nothing Na(+) spikes. We show that one type of mammalian On bipolar cell, the ground squirrel cb5b, has a large tetrodotoxin (TTX)-sensitive Na(+) current. When recorded from in the perforated patch configuration, cb5b cells can signal the onset of a light step with 1-3 all-or nothing action potentials that attain a peak amplitude of -10 to -20 mV (peak width at half-height equals 2-3 ms). When exposed to a continuous, temporally fluctuating stimulus, cb5b cells generate both graded and spiking responses. Cb5b cells spike with millisecond precision, selecting for stimulus sequences in which transitions to light are preceded by a period of darkness. The axon terminals of cb5b bipolar cells costratify with the dendrites of amacrine and ganglion cells that encode light onset with a short latency burst of spikes. The results support the idea that a spiking On bipolar cell is part of a dedicated retinal pathway for rapidly and reliably signaling dark to light transitions. PMID- 22219292 TI - Strong recurrent networks compute the orientation tuning of surround modulation in the primate primary visual cortex. AB - In macaque primary visual cortex (V1), neuronal responses to stimuli inside the receptive field (RF) are modulated by stimuli in the RF surround. This modulation is orientation specific. Previous studies suggested that, for some cells, this specificity may not be fixed but changes with the stimulus orientation presented to the RF. We demonstrate, in recording studies, that this tuning behavior is instead highly prevalent in V1 and, in theoretical work, that it arises only if V1 operates in a regime of strong local recurrence. Strongest surround suppression occurs when the stimuli in the RF and the surround are iso-oriented, and strongest facilitation when the stimuli are cross-oriented. This is the case even when the RF is suboptimally activated by a stimulus of nonpreferred orientation but only if this stimulus can activate the cell when presented alone. This tuning behavior emerges from the interaction of lateral inhibition (via the surround pathways), which is tuned to the preferred orientation of the RF, with weakly tuned, but strong, local recurrent connections, causing maximal withdrawal of recurrent excitation at the feedforward input orientation. Thus, horizontal and feedback modulation of strong recurrent circuits allows the tuning of contextual effects to change with changing feedforward inputs. PMID- 22219293 TI - Adenosine enhances sweet taste through A2B receptors in the taste bud. AB - Mammalian taste buds use ATP as a neurotransmitter. Taste Receptor (type II) cells secrete ATP via gap junction hemichannels into the narrow extracellular spaces within a taste bud. This ATP excites primary sensory afferent fibers and also stimulates neighboring taste bud cells. Here we show that extracellular ATP is enzymatically degraded to adenosine within mouse vallate taste buds and that this nucleoside acts as an autocrine neuromodulator to selectively enhance sweet taste. In Receptor cells in a lingual slice preparation, Ca(2+) mobilization evoked by focally applied artificial sweeteners was significantly enhanced by adenosine (50 MUM). Adenosine had no effect on bitter or umami taste responses, and the nucleoside did not affect Presynaptic (type III) taste cells. We also used biosensor cells to measure transmitter release from isolated taste buds. Adenosine (5 MUM) enhanced ATP release evoked by sweet but not bitter taste stimuli. Using single-cell reverse transcriptase (RT)-PCR on isolated vallate taste cells, we show that many Receptor cells express the adenosine receptor, Adora2b, while Presynaptic (type III) and Glial-like (type I) cells seldom do. Furthermore, Adora2b receptors are significantly associated with expression of the sweet taste receptor subunit, Tas1r2. Adenosine is generated during taste stimulation mainly by the action of the ecto-5'-nucleotidase, NT5E, and to a lesser extent, prostatic acid phosphatase. Both these ecto-nucleotidases are expressed by Presynaptic cells, as shown by single-cell RT-PCR, enzyme histochemistry, and immunofluorescence. Our findings suggest that ATP released during taste reception is degraded to adenosine to exert positive modulation particularly on sweet taste. PMID- 22219294 TI - GABA signaling promotes synapse elimination and axon pruning in developing cortical inhibitory interneurons. AB - Accumulating evidence indicates that GABA acts beyond inhibitory synaptic transmission and regulates the development of inhibitory synapses in the vertebrate brain, but the underlying cellular mechanism is not well understood. We have combined live imaging of cortical GABAergic axons across time scales from minutes to days with single-cell genetic manipulation of GABA release to examine its role in distinct steps of inhibitory synapse formation in the mouse neocortex. We have shown previously, by genetic knockdown of GABA synthesis in developing interneurons, that GABA signaling promotes the maturation of inhibitory synapses and axons. Here we found that a complete blockade of GABA release in basket interneurons resulted in an opposite effect, a cell-autonomous increase in axon and bouton density with apparently normal synapse structures. These results not only demonstrate that GABA is unnecessary for synapse formation per se but also uncover a novel facet of GABA in regulating synapse elimination and axon pruning. Live imaging revealed that developing GABAergic axons form a large number of transient boutons, but only a subset was stabilized. Release blockade led to significantly increased bouton stability and filopodia density, increased axon branch extension, and decreased branch retraction. Our results suggest that a major component of GABA function in synapse development is transmission-mediated elimination of subsets of nascent contacts. Therefore, GABA may regulate activity-dependent inhibitory synapse formation by coordinately eliminating certain nascent contacts while promoting the maturation of other nascent synapses. PMID- 22219295 TI - Dopaminergic signaling in the cochlea: receptor expression patterns and deletion phenotypes. AB - Pharmacological studies suggest that dopamine release from lateral olivocochlear efferent neurons suppresses spontaneous and sound-evoked activity in cochlear nerve fibers and helps control noise-induced excitotoxicity; however, the literature on cochlear expression and localization of dopamine receptors is contradictory. To better characterize cochlear dopaminergic signaling, we studied receptor localization using immunohistochemistry or reverse transcriptase PCR and assessed histopathology, cochlear responses and olivocochlear function in mice with targeted deletion of each of the five receptor subtypes. In normal ears, D1, D2, and D5 receptors were detected in microdissected immature (postnatal days 10 13) spiral ganglion cells and outer hair cells but not inner hair cells. D4 was detected in spiral ganglion cells only. In whole cochlea samples from adults, transcripts for D1, D2, D4, and D5 were present, whereas D3 mRNA was never detected. D1 and D2 immunolabeling was localized to cochlear nerve fibers, near the first nodes of Ranvier (D2) and in the inner spiral bundle region (D1 and D2) where presynaptic olivocochlear terminals are found. No other receptor labeling was consistent. Cochlear function was normal in D3, D4, and D5 knock-outs. D1 and D2 knock-outs showed slight, but significant enhancement and suppression, respectively, of cochlear responses, both in the neural output [auditory brainstem response (ABR) wave 1] and in outer hair cell function [distortion product otoacoustic emissions (DPOAEs)]. Vulnerability to acoustic injury was significantly increased in D2, D4 and D5 lines: D1 could not be tested, and no differences were seen in D3 mutants, consistent with a lack of receptor expression. The increased vulnerability in D2 knock-outs was seen in DPOAEs, suggesting a role for dopamine in the outer hair cell area. In D4 and D5 knock outs, the increased noise vulnerability was seen only in ABRs, consistent with a role for dopaminergic signaling in minimizing neural damage. PMID- 22219296 TI - The energetics of CNS white matter. AB - The energetics of CNS white matter are poorly understood. We derive a signaling energy budget for the white matter (based on data from the rodent optic nerve and corpus callosum) which can be compared with previous energy budgets for the gray matter regions of the brain, perform a cost-benefit analysis of the energetics of myelination, and assess mechanisms for energy production and glucose supply in myelinated axons. We show that white matter synapses consume <=0.5% of the energy of gray matter synapses and that this, rather than more energy-efficient action potentials, is the main reason why CNS white matter uses less energy than gray matter. Surprisingly, while the energetic cost of building myelin could be repaid within months by the reduced ATP cost of neuronal action potentials, the energetic cost of maintaining the oligodendrocyte resting potential usually outweighs the saving on action potentials. Thus, although it dramatically speeds action potential propagation, myelination need not save energy. Finally, we show that mitochondria in optic nerve axons could sustain measured firing rates with a plausible density of glucose transporters in the nodal membrane, without the need for energy transfer from oligodendrocytes. PMID- 22219297 TI - Switch to glutamate receptor 2-lacking AMPA receptors increases neuronal excitability in hypothalamus and sympathetic drive in hypertension. AB - Glutamatergic synaptic input in the hypothalamic paraventricular nucleus (PVN) plays a critical role in regulating sympathetic outflow in hypertension. GluR2 lacking AMPA receptors (AMPARs) are permeable to Ca(2+), and their currents show unique inward rectification. However, little is known about changes in the AMPAR composition and its functional significance in hypertension. In this study, we found that AMPAR-mediated EPSCs (AMPAR-EPSCs) of retrogradely labeled spinally projecting PVN neurons exhibited a linear current-voltage relationship in Wistar Kyoto (WKY) rats. However, AMPAR-EPSCs of labeled PVN neurons in spontaneously hypertensive rats (SHR) displayed inward rectification at positive holding potentials, which were not altered by lowering blood pressure with celiac ganglionectomy. Blocking GluR2-lacking AMPARs with 1-naphthyl acetyl spermine (NAS) caused a greater reduction in the AMPAR-EPSC amplitude and firing activity of PVN neurons in SHR than in WKY rats. Furthermore, blocking NMDA receptors and inhibition of calpain or calcineurin abolished inward rectification of AMPAR EPSCs of PVN neurons in SHR. The GluR2 protein level was significantly less in the plasma membrane but greater in the cytosolic vesicle fraction in SHR than in WKY rats. In addition, microinjection of NAS into the PVN decreased blood pressure and lumbar sympathetic nerve activity in SHR but not in WKY rats. Our study reveals that increased GluR2-lacking AMPAR activity of PVN neurons results from GluR2 internalization through NMDA receptor-calpain-calcineurin signaling in hypertension. This phenotype switch in synaptic AMPARs contributes to increased excitability of PVN presympathetic neurons and sympathetic vasomotor tone in hypertension. PMID- 22219298 TI - Impairment of catecholamine systems during induction of long-term potentiation at hippocampal CA1 synapses in HPC-1/syntaxin 1A knock-out mice. AB - The membrane protein HPC-1/syntaxin 1A is believed to play a key role in synaptic vesicle exocytosis, and it was recently suggested to be required for synaptic plasticity. Despite evidence for the function of HPC-1/syntaxin 1A in synaptic plasticity, the underlying cellular mechanism is unclear. We found that although fast synaptic transmission and long-term depression were unaffected, HPC 1/syntaxin 1A knock-out (STX1A(-/-)) mice showed impaired long-term potentiation (LTP) in response to theta-burst stimulation in CA1 hippocampal slices. The impairment in LTP was rescued by the application of forskolin, an adenylyl cyclase activator, or more robust stimulation, suggesting that cAMP/protein kinase A signaling was suppressed in these mice. In addition, catecholamine release from the hippocampus was significantly reduced in STX1A(-/-) mice. Because HPC-1/syntaxin 1A regulates exocytosis of dense-core synaptic vesicles, which contain neuromodulatory transmitters such as noradrenaline, dopamine and 5 HT, we examined the effect of neuromodulatory transmitters on LTP induction. Noradrenaline and dopamine enhanced LTP induction in STX1A(-/-) mice, whereas catecholamine depletion reduced LTP induction in wild-type mice. Theses results suggest that HPC-1/syntaxin 1A regulates catecholaminergic systems via exocytosis of dense-core synaptic vesicles, and that deletion of HPC-1/syntaxin 1A causes impairment of LTP induction. PMID- 22219299 TI - Dihydromyricetin as a novel anti-alcohol intoxication medication. AB - Alcohol use disorders (AUDs) constitute the most common form of substance abuse. The development of AUDs involves repeated alcohol use leading to tolerance, alcohol withdrawal syndrome, and physical and psychological dependence, with loss of ability to control excessive drinking. Currently there is no effective therapeutic agent for AUDs without major side effects. Dihydromyricetin (DHM; 1 mg/kg, i.p. injection), a flavonoid component of herbal medicines, counteracted acute alcohol (EtOH) intoxication, and also withdrawal signs in rats including tolerance, increased anxiety, and seizure susceptibility; DHM greatly reduced EtOH consumption in an intermittent voluntary EtOH intake paradigm in rats. GABA(A) receptors (GABA(A)Rs) are major targets of acute and chronic EtOH actions on the brain. At the cellular levels, DHM (1 MUM) antagonized both acute EtOH induced potentiation of GABA(A)Rs and EtOH exposure/withdrawal-induced GABA(A)R plasticity, including alterations in responsiveness of extrasynaptic and postsynaptic GABA(A)Rs to acute EtOH and, most importantly, increases in GABA(A)R alpha4 subunit expression in hippocampus and cultured neurons. DHM anti-alcohol effects on both behavior and CNS neurons were antagonized by flumazenil (10 mg/kg in vivo; 10 MUM in vitro), the benzodiazepine (BZ) antagonist. DHM competitively inhibited BZ-site [(3)H]flunitrazepam binding (IC(50), 4.36 MUM), suggesting DHM interaction with EtOH involves the BZ sites on GABA(A)Rs. In summary, we determined DHM anti-alcoholic effects on animal models and determined a major molecular target and cellular mechanism of DHM for counteracting alcohol intoxication and dependence. We demonstrated pharmacological properties of DHM consistent with those expected to underlie successful medical treatment of AUDs; therefore DHM is a therapeutic candidate. PMID- 22219300 TI - Testosterone exerts antiapoptotic effects against H2O2 in C2C12 skeletal muscle cells through the apoptotic intrinsic pathway. AB - Experimental data indicate that apoptosis is activated in the aged skeletal muscle, contributing to sarcopenia. We have previously demonstrated that testosterone protects against hydrogen peroxide (H(2)O(2))-induced apoptosis in C2C12 muscle cells. Here we identified molecular events involved in the antiapoptotic effect of testosterone. At short times of exposure to H(2)O(2) cells exhibit a defense response but at longer treatment times cells undergo apoptosis. Incubation with testosterone prior to H(2)O(2) induces BAD inactivation, inhibition of poly(ADP-ribose) polymerase cleavage, and a decrease in BAX levels, and impedes the loss of mitochondrial membrane potential, suggesting that the hormone participates in the regulation of the apoptotic intrinsic pathway. Simultaneous treatment with testosterone, H(2)O(2), and the androgen receptor (AR) antagonist, flutamide, reduces the effects of the hormone, pointing to a possible participation of the AR in the antiapoptotic effect. The data presented allow us to begin to elucidate the mechanism by which the hormone prevents apoptosis in skeletal muscle. PMID- 22219301 TI - Glutamine and glutamic acid enhance thyroid-stimulating hormone beta subunit mRNA expression in the rat pars tuberalis. AB - Thyroid-stimulating hormone (TSH)-producing cells of the pars tuberalis (PT) display distinct characteristics that differ from those of the pars distalis (PD). The mRNA expression of TSHbeta and alphaGSU in PT has a circadian rhythm and is inhibited by melatonin via melatonin receptor type 1; however, the detailed regulatory mechanism for TSHbeta expression in the PT remains unclear. To identify the factors that affect PT, a microarray analysis was performed on laser-captured PT tissue to screen for genes coding for receptors that are abundantly expressed in the PT. In the PT, we found high expression of the KA2, which is an ionotropic glutamic acid receptor (iGluR). In addition, the amino acid transporter A2 (ATA2), also known as the glutamine transporter, and glutaminase (GLS), as well as GLS2, were highly expressed in the PT compared to the PD. We examined the effects of glutamine and glutamic acid on TSHbeta expression and alphaGSU expression in PT slice cultures. l-Glutamine and l glutamic acid significantly stimulated TSHbeta expression in PT slices after 2- and 4-h treatments, and the effect of l-glutamic acid was stronger than that of l glutamine. In contrast, treatment with glutamine and glutamic acid did not affect alphaGSU expression in the PT or the expression of TSHbeta or alphaGSU in the PD. These results strongly suggest that glutamine is taken up by PT cells through ATA2 and that glutamic acid locally converted from glutamine by Gls induces TSHbeta expression via the KA2 in an autocrine and/or paracrine manner in the PT. PMID- 22219302 TI - Real-time nucleic acid sequence-based amplification assay for rapid detection and quantification of agr functionality in clinical Staphylococcus aureus isolates. AB - Staphylococcus aureus infections are a significant cause of morbidity and mortality in health care settings. S. aureus clinical isolates vary in the function of the accessory gene regulator (agr), which governs the expression of virulence determinants, including surface and exoproteins, while agr activity has been correlated with patient outcome and treatment efficiency. Here we describe a duplex real-time nucleic acid sequence-based amplification (NASBA) detection and quantification platform for rapid determination of agr functionality in clinical isolates. Using the effector of agr response, RNAIII, as the assay target, and expression of the gyrase gene (gyrB) as a normalizer, we were able to accurately discriminate agr functionality in a single reaction. Time to positivity (TTP) ratios between gyrB and RNAIII showed very good correlation with the ratios of RNAIII versus gyrB RNA standard inputs and were therefore used as a simple readout to evaluate agr functionality. We validated the assay by characterizing 106 clinical S. aureus isolates, including strains with genetically characterized agr mutations. All isolates with dysfunctional agr activity exhibited a TTP ratio (TTP(gyrB)/TTP(RNAIII)) lower than 1.10, whereas agr-positive isolates had a TTP ratio higher than this value. The results showed that the assay was capable of determining target RNA ratios over 8 logs (10(-3) to 10(4)) with high sensitivity and specificity, suggesting the duplex NASBA assay may be useful for rapid determination of agr phenotypes and virulence potential in S. aureus clinical isolates. PMID- 22219304 TI - Pseudo-outbreak of extremely drug-resistant pseudomonas aeruginosa urinary tract infections due to contamination of an automated urine analyzer. AB - By the end of May 2010, an increase in the number of urine specimens that were culture positive for extremely drug-resistant (XDR) Pseudomonas aeruginosa was observed in our 800-bed university hospital. This led to an infection control alert. No epidemiological link between the patients and no increase in the frequency of XDR P. aeruginosa in non-urine samples were observed. Therefore, a pseudo-outbreak due to analytical contamination in the laboratory was rapidly suspected. A prospective and retrospective search of cases was initiated, and the sampling of the automated urine analyzers used in the laboratory was performed. Antibiotypes were determined by disc diffusion, and genotypes were determined by pulsed-field gel electrophoresis (PFGE). From February to July 2010, 17 patients admitted to 12 different departments and 6 outpatients were included. The mixing device of the cytometric analyzer used for the numeration of urinary particles (Sysmex UF1000i) proved to be heavily contaminated. Isolates recovered from 12 patients belonged to the same antibiotype and PFGE type as the isolate recovered from the analyzer. Extensive disinfection with a broad-spectrum disinfectant and the replacement of the entire tubing was necessary to achieve the complete negativity of culture samples taken from the analyzer. A pseudo-outbreak caused by an XDR P. aeruginosa clone was proven to be due to the contamination of the cytometric analyzer for urinary sediment. Users of such analyzers should be aware that contamination can occur and should always perform culture either before the processing of the urine sample on the analyzer or on a distinct sample tube. PMID- 22219303 TI - Serial kinetics of the antibody response against the complete Brucella melitensis ORFeome in focal vertebral brucellosis. AB - Human brucellosis is a common zoonosis worldwide. Here we present a case of focal vertebral brucellosis in a 71-year-old Mexican-American woman who contracted infection from unpasteurized goat milk. Standard agglutination serology was negative; the diagnosis was established by the isolation of Brucella melitensis from abscess fluid. A B. melitensis protein microarray comprised of nearly all proteins encoded by the bacterial genome was used to determine the kinetics of this patient's antibody responses to the complete collection of open reading frames existing in the genome (ORFeome). Three patterns of antibody responses against B. melitensis antigens were seen for serum samples obtained on days 0 (pretreatment), 14, 49, 100, and 180: (i) stable titers over time, (ii) a steady fall in titers, and (iii) an initial rise in titers followed by declining titers. Sera from this patient with chronic brucellosis recognized some of the same B. melitensis proteins as those recognized by sera from acute/subacute, blood culture-positive brucellosis patients but also recognized a distinct set of proteins. This study is the first to determine the kinetics of the human antibody responses to the complete repertoire of proteins encoded by a bacterial genome and demonstrates fundamentally different immunopathogenetic mechanisms between acute human brucellosis and chronic human brucellosis. While an extension of these findings to a larger patient population is necessary, these findings have important clinical and diagnostic implications and lead toward new insights into the fundamental immunopathogenesis of brucellosis. PMID- 22219305 TI - Real-time PCR-based mismatch amplification mutation assay for specific detection of CS6-expressing allelic variants of enterotoxigenic Escherichia coli and its application in assessing diarrheal cases and asymptomatic controls. AB - Enterotoxigenic Escherichia coli (ETEC) expressing the colonization factor CS6 is widespread in many developing countries, including India. The different allelic variants of CS6, caused by point mutations in its structural genes, cssA and cssB, are designated AIBI, AIIBII, AIIIBI, AIBII, and AIIIBII. A simple, reliable, and specific mismatch amplification mutation assay based on real-time quantitative PCR (MAMA-qPCR) was developed for the first time for the detection of CS6-expressing ETEC, along with the identification of allelic variations. The assay was based on mismatched nucleotide incorporation at the penultimate base at the 3' ends of the reverse primers specific for cssA and cssB and was validated using 38 CS6-expressing ETEC isolates. This strategy was effective in detecting all the alleles containing single-nucleotide polymorphisms. Using MAMA-qPCR, we also tested CS6 allelic variants in 145 ETEC isolates from children with acute diarrhea and asymptomatic infections, with the latter serving as controls. We observed that the AIBI and AIIIBI allelic variants were mostly associated with cases rather than controls, whereas the AIIBII variants were detected mostly in controls. In addition, the AIBI and AIIIBI alleles were frequently associated with ETEC harboring the heat-stable toxin gene (est) alone or with the heat labile toxin gene (elt), whereas the AIIBII allele was predominant in ETEC isolates harboring the elt gene. This study may help in understanding the association of allelic variants in CS6-expressing ETEC with the clinical features of diarrhea, as well as in ETEC vaccine studies. PMID- 22219306 TI - Evaluation of a PCR test for detection of treponema pallidum in swabs and blood. AB - Syphilis diagnosis is based on clinical observation, serological analysis, and dark-field microscopy (DFM) detection of Treponema pallidum subsp. pallidum, the etiological agent of syphilis, in skin ulcers. We performed a nested PCR (nPCR) assay specifically amplifying the tpp47 gene of T. pallidum from swab and blood specimens. We studied a cohort of 294 patients with suspected syphilis and 35 healthy volunteers. Eighty-seven of the 294 patients had primary syphilis, 103 had secondary syphilis, 40 had latent syphilis, and 64 were found not to have syphilis. The T. pallidum nPCR results for swab specimens were highly concordant with syphilis diagnosis, with a sensitivity of 82% and a specificity of 95%. Reasonable agreement was observed between the results obtained with the nPCR and DFM methods (kappa = 0.53). No agreement was found between the nPCR detection of T. pallidum in blood and the diagnosis of syphilis, with sensitivities of 29, 18, 14.7, and 24% and specificities of 96, 92, 93, and 97% for peripheral blood mononuclear cell (PBMC), plasma, serum, and whole-blood fractions, respectively. HIV status did not affect the frequency of T. pallidum detection in any of the specimens tested. Swab specimens from mucosal or skin lesions seemed to be more useful than blood for the efficient detection of the T. pallidum genome and, thus, for the diagnosis of syphilis. PMID- 22219308 TI - An alternative method for cultivation of Lawsonia intracellularis. AB - An alternative method for the cultivation of Lawsonia intracellularis, an obligate intracellular bacterium and the causative agent of proliferative enteropathy, was developed using an Original Space Bag inflated with a mixture of gas containing 10% hydrogen, 10% carbon dioxide, and 80% nitrogen. The flexibility of this protocol allows the testing of various environmental conditions for static cultivation of this bacterium and the development of diagnostic techniques. PMID- 22219307 TI - Dominance of serotype Ia among group B Streptococci causing invasive infections in nonpregnant adults in Portugal. AB - The population of group B streptococci (GBS) associated with invasive infections in nonpregnant adults from 2001 to 2008 was analyzed in isolates submitted from 24 hospital laboratories in Portugal (n = 225). The isolates were characterized by antimicrobial susceptibility, pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and surface protein gene profiling. GBS invasive cases were found more frequently among men in all age groups. In addition, serotype Ia was the most frequent in our collection, whereas serotype V is dominant elsewhere. Serotype Ia was represented mainly by a single PFGE cluster defined by sequence type 23 (ST23) and surface protein gene eps and by ST24 and bca, similarly to neonatal invasive infections in Portugal, indicating that the same genetic lineages can be responsible for both vaginal colonization and invasive disease in all age groups. In contrast, the hypervirulent serotype III/ST17 neonatal lineage was responsible for a minority of infections. Serotype V isolates were distributed into two genetic lineages, one defined by ST1 and surface protein gene alp3 and macrolide resistant, and another presenting with ST2 and eps and fully susceptible to all antimicrobials tested. The erm(TR) gene was the most frequently found among erythromycin-resistant isolates, while the bovine-associated tet(O) gene was found in a minority of tetracycline-resistant isolates. Our data emphasize the importance of local identification of the genetic lineages responsible for GBS invasive infections in nonpregnant adults. The dominance of serotype Ia in invasive disease in Portugal highlights the importance of this serotype in GBS pathogenesis. PMID- 22219309 TI - Multisite reproducibility of the broth microdilution method for susceptibility testing of Nocardia species. AB - Antimicrobial susceptibility testing (AST) of clinical isolates of Nocardia is recommended to detect resistance to commonly used antimicrobial agents; such testing is complicated by difficulties in inoculum preparation and test interpretation. In this study, six laboratories performed repetitive broth microdilution testing on single strains of Nocardia brasiliensis, Nocardia cyriacigeorgica, Nocardia farcinica, Nocardia nova, and Nocardia wallacei. For each isolate, a total of 30 microdilution panels from three different lots were tested at most sites. The goal of the study was to determine the inter- and intralaboratory reproducibility of susceptibility testing of this group of isolates. Acceptable agreement (>90% agreement at +/-1 dilution of the MIC mode) was found for amikacin, ciprofloxacin, clarithromycin, and moxifloxacin. After eliminating MIC values from single laboratories whose results showed the greatest deviation from those of the remaining laboratories, acceptable agreement was also found for amoxicillin-clavulanic acid, linezolid, minocycline, and tobramycin. Results showed unsatisfactory reproducibility of broth microdilution testing of ceftriaxone with N. cyriacigeorgica and N. wallacei, tigecycline with N. brasiliensis and N. cyriacigeorgica, and sulfonamides with N. farcinica and N. wallacei. N. nova ATCC BAA-2227 is proposed as a quality control organism for AST of Nocardia sp., and the use of a disk diffusion test for sulfisoxazole is proposed as a check of the adequacy of the inoculum and to confirm sulfonamide MIC results. PMID- 22219310 TI - Decoupling eye and hand movement control: visual short-term memory influences reach planning more than saccade planning. AB - When reaching for objects, humans make saccades to fixate the object at or near the time the hand begins to move. In order to address whether the CNS relies on a common representation of target positions to plan both saccades and hand movements, we quantified the contributions of visual short-term memory (VSTM) to hand and eye movements executed during the same coordinated actions. Subjects performed a sequential movement task in which they picked up one of two objects on the right side of a virtual display (the "weapon"), moved it to the left side of the display (to a "reloading station") and then moved it back to the right side to hit the other object (the target). On some trials, the target was perturbed by 1 degrees of visual angle while subjects moved the weapon to the reloading station. Although subjects did not notice the change, the original position of the target, encoded in VSTM, influenced the motor plans for both the hand and the eye back to the target. Memory influenced motor plans for distant targets more than for near targets, indicating that sensorimotor planning is sensitive to the reliability of available information; however, memory had a larger influence on hand movements than on eye movements. This suggests that spatial planning for coordinated saccades and hand movements are dissociated at the level of processing at which online visual information is integrated with information in short-term memory. PMID- 22219311 TI - Evaluation of a recombinant multiepitope peptide for serodiagnosis of Toxoplasma gondii infection. AB - Detection of Toxoplasma gondii infection with sensitive and specific methods is a key step in the prevention and treatment of toxoplasmosis. Among the available diagnostic tests, serology is commonly used. Although serological tests give satisfactory results, the production of reliable reagents remains laborious and expensive. There is therefore a real need to acquire specific and effective recombinant antigens for the serodiagnosis of T. gondii infection. In this study, a multiepitope peptide was designed and successfully expressed in Escherichia coli, and then IgG and IgM enzyme-linked immunosorbent assays (ELISAs) were developed and evaluated. Our results showed that the new multiepitope antigen is one of the most promising recombinant antigens which could be used in routine screening of human toxoplasmosis. PMID- 22219312 TI - Serum indoleamine 2,3-dioxygenase activity predicts prognosis of pulmonary tuberculosis. AB - Tuberculosis (TB) continues to be a major health problem, and there are few biomarkers for predicting prognosis. Indoleamine 2,3-dioxygenase (IDO), a potent immunoregulatory molecule, catalyzes the rate-limiting step of tryptophan (Trp) degradation in the kynurenine (Kyn) pathway. An increase in IDO activity determined by the serum Trp/Kyn ratio has been shown to be associated with poor prognosis in cancers and bacteremia. In TB, however, there are no studies measuring serum IDO activity to determine its clinical significance. We evaluated serum IDO activity with 174 pulmonary TB (PTB) patients and 85 controls, using liquid chromatography/electrospray ionization tandem mass spectrometry. IDO activity was estimated by calculating the serum Kyn-to-Trp ratio. PTB patients had significantly higher Kyn concentrations and IDO activity and significantly lower Trp concentrations (P < 0.0001, P < 0.0001, and P < 0.0001, respectively) than the controls. Of 174 PTB patients, 39 (22.4%) died. The patients who died had significantly higher concentrations of Kyn and significantly lower Trp concentrations, resulting in significantly higher IDO activity (P < 0.0001, P < 0.0001, and P < 0.0001, respectively). In a receiver operating characteristic (ROC) analysis, serum IDO activity had the highest area under the curve (0.850), and this activity was an independent prognostic factor in multivariate analysis. These results suggest that serum IDO activity can be used as a novel prognostic marker in PTB. PMID- 22219313 TI - Prospective evaluation of commercial antibody-based rapid tests in combination with a loop-mediated isothermal amplification PCR assay for detection of Orientia tsutsugamushi during the acute phase of scrub typhus infection. AB - Samples from 160 prospectively recruited febrile patients with typhus-like illness in an area of Thailand (Chiang Rai, northern Thailand) where scrub typhus is endemic were used to evaluate the diagnostic capabilities of four rapid immunochromatographic tests (ICTs) for the detection of Orientia tsutsugamushi IgM and total antibodies during acute scrub typhus infection. Of the 160 cases, 54 (34%) had been confirmed to have scrub typhus using the reference scrub typhus infection criteria (STIC), i.e., positive cell culture isolation, an admission IgM antibody titer of >=1:12,800, a 4-fold rising IgM antibody titer, and/or positivity for >=2 out of 3 PCR gene targets). The ICTs gave the following sensitivities and specificities: the Panbio IgM ICT, 46% (95% confidence interval [CI], 33 to 60) and 95% (95% CI, 89 to 98), respectively; the Standard Diagnostics IgM ICT, 68% (95% CI, 60 to 75) and 73% (95% CI, 68 to 78), respectively; the AccessBio IgM ICT, 56% (95% CI, 48 to 63) and 90% (95% CI, 87 to 94), respectively; and the AccessBio total antibody ABt ICT, 61% (95% CI, 53 to 68) and 68% (95% CI, 63 to 73), respectively. An isothermal loop amplification (LAMP) PCR assay for scrub typhus demonstrated a sensitivity of 52% (95% CI, 38 to 66) and a specificity of 94% (95% CI, 88 to 98). This study has revealed the diagnostic limitations of antibody-based assays in an acute care setting. However, the combination of ICTs with LAMP usually increased sensitivity with a minimal reduction in specificity. The best combination, the Panbio IgM ICT and LAMP, resulted in a sensitivity of 67% (95% CI, 53 to 79) and a specificity of 91% (95% CI, 83 to 95). The combination of antibody-based assays with DNA- or antigen-based tests shows promise for improved diagnostic sensitivity. PMID- 22219314 TI - Evaluation of three commercially available influenza A type-specific blocking enzyme-linked immunosorbent assays for seroepidemiological studies of influenza A virus infection in pigs. AB - The reverse zoonotic transmission of the pandemic H1N1 2009 influenza virus to swine necessitates enhanced surveillance of swine for influenza virus infection. Using a well-characterized panel of naturally infected swine sera, we evaluated and optimized the performances of three commercially available competitive enzyme linked immunosorbent assays (ELISAs), namely, the IDEXX Influenza A Ab test, IDEXX AI MultiS-Screen Ab test, and IDVet ID Screen influenza A antibody competition ELISA, for detecting influenza A virus-reactive antibodies in swine. Receiver operating characteristic (ROC) analysis suggests that adjustment of the manufacturer-recommended cutoff values optimizes the sensitivity and specificity of these assays, making them applicable for seroepidemiology studies of swine influenza. Using such optimized cutoff levels, the sensitivity and specificity of the IDEXX Influenza A Ab test were 86% and 89%, respectively; those for the IDEXX AI MultiS-Screen Ab test were 91% and 87%, respectively; and those for the IDVet ID Screen influenza A test were 95% and 79%, respectively. PMID- 22219315 TI - A reduced-dose seasonal trivalent influenza vaccine is safe and immunogenic in adult and elderly patients in a randomized controlled trial. AB - With the recent pandemic of influenza A (H1N1) and vaccine shortages, there has been considerable interest in developing influenza vaccines with reduced doses, allowing for increased production capacity. Here we report a prospective, randomized, double-blind, single-center clinical trial of a reduced-dose whole virion inactivated, adjuvanted influenza vaccine in adult and elderly volunteers. A total of 234 subjects, including 120 adults (18 to 60 years of age) and 114 elderly subjects (>60 years of age) were enrolled to receive either 6 MUg or the conventional 15-MUg dose of seasonal trivalent influenza vaccines. The subjects were followed for safety analysis, and serum samples were obtained to assess immunogenicity by hemagglutination inhibition testing. The subjects developed antibody responses against the seasonal influenza A virus H1N1 and H3N2 strains, as well as the seasonal influenza B virus included in the vaccines. Single doses of 6 MUg fulfilled licensing criteria for seasonal influenza vaccines. No significant differences in rates of seroconversion or seroprotection or in geometric mean titers were found between the two dosage levels. All adverse events were rare, mild, and transient. We found that the present reduced-dose vaccine is safe and immunogenic in healthy adult and elderly subjects and triggers immune responses that comply with licensing criteria. PMID- 22219316 TI - A CAM- and starch-deficient mutant of the facultative CAM species Mesembryanthemum crystallinum reconciles sink demands by repartitioning carbon during acclimation to salinity. AB - In the halophytic species Mesembryanthemum crystallinum, the induction of crassulacean acid metabolism (CAM) by salinity requires a substantial investment of resources in storage carbohydrates to provide substrate for nocturnal CO(2) uptake. Acclimation to salinity also requires the synthesis and accumulation of cyclitols as compatible solutes, maintenance of root respiration, and nitrate assimilation. This study assessed the hierarchy and coordination of sinks for carbohydrate in leaves and roots during acclimation to salinity in M. crystallinum. By comparing wild type and a CAM-/starch-deficient mutant of this species, it was sought to determine if other metabolic sinks could compensate for a curtailment in CAM and enable acclimation to salinity. Under salinity, CAM deficiency reduced 24 h photosynthetic carbon gain by >50%. Cyclitols were accumulated to comparable levels in leaves and roots of both the wild type and mutant, but represented only 5% of 24 h carbon balance. Dark respiration of leaves and roots was a stronger sink for carbohydrate in the mutant compared with the wild type and implied higher maintenance costs for the metabolic processes underpinning acclimation to salinity when CAM was curtailed. CAM required the nocturnal mobilization of >70% of primary carbohydrate in the wild type and >85% of carbohydrate in the mutant. The substantial allocation of carbohydrate to CAM limited the export of sugars to roots, and the root:shoot ratio declined under salinity. The data suggest a key role for the vacuole in regulating the supply and demand for carbohydrate over the day/night cycle in the starch-/CAM-deficient mutant. PMID- 22219317 TI - Prospective studies of body mass index with head and neck cancer incidence and mortality. AB - BACKGROUND: Results of a pooled analysis of case-control studies show a higher risk of head and neck cancer (HNC) associated with a low body mass index (BMI) and a lower risk associated with being overweight or obese compared with being normal weight. However, these results are prone to bias due to residual confounding by smoking, a strong risk factor, and possible weight loss prior to diagnosis. Using prospectively collected data from the Cancer Prevention Study-II cohort and the Nutrition cohort, we examined the association of BMI with HNC mortality and incidence, overall and by smoking status. METHODS: Mortality analyses included 1,383 cases among 1,059,153 participants; incidence analyses included 340 cases among 150,262 participants. Multivariable Cox proportional hazard models were used to estimate HRs and 95% confidence intervals (CI) for the association of BMI with HNC incidence and mortality. RESULTS: Overall, compared with the category of BMI 22.5-24.9 kg/m(2), the categories of BMI 25.0-29.9 kg/m(2) and >= 30.0 kg/m(2) were associated with a lower risk of HNC mortality but not incidence. In never smokers, there were no associations of BMI with HNC incidence or mortality. In smokers, BMI < 22.5 kg/m(2) was associated with a higher risk of HNC mortality (HR = 1.42, 95% CI, 1.20-1.67). CONCLUSIONS: In this prospective cohort, there was no association between BMI and HNC incidence, although BMI was inversely associated with HNC mortality in smokers. IMPACT: These suggest that there is no etiologic relationship between BMI and HNC. PMID- 22219318 TI - Trends in colorectal cancer incidence rates in the United States by tumor location and stage, 1992-2008. AB - BACKGROUND: Results from case-control studies outside the United States have been conflicted about the efficacy of colonoscopy for reducing cancer risk in the right colon. To contribute to this discourse from an alternative perspective, we analyzed high-quality surveillance data to report on recent trends in population based colorectal cancer incidence rates by tumor location in the United States. METHODS: Data from cancer registries in the Surveillance, Epidemiology, and End Results Program were analyzed to examine colorectal cancer incidence trends from 1992 through 2008 among individuals aged >= 50 years (n = 267,072). Joinpoint regression analysis was used to quantify annual percent change in age standardized rates by tumor location and disease stage. RESULTS: Incidence rates for right-sided colon tumors decreased annually by 2.6% (95% CI: 2.0-3.2) since 1999 in men and 2.3% (CI: 1.6-3.0) since 2000 in women, after remaining stable during the previous seven/eight years. Incidence rates for left-sided tumors were generally decreasing from 1992 to 2008 in both sexes. Beginning in 1999/2000, substantial, almost identical annual declines occurred for late-stage disease in both the right and left colon: 3.9% (CI: 3.1-4.8) and 4.2% (CI: 3.5-4.9), respectively, in men; and 3.3% (CI: 2.5-4.1) and 3.3% (CI: 2.8-3.8) in women. CONCLUSION: Large declines in the incidence of right-sided colon tumors among individuals 50 years and older began around 2000. IMPACT: Increased colonoscopy utilization during the past decade may have contributed to a reduction in risk for cancers in both the right and left colorectum in the United States. PMID- 22219319 TI - Profile of Daniel G. Nocera. PMID- 22219320 TI - Induction of endothelial nitric oxide synthase expression by IL-17 in human vascular endothelial cells: implications for vascular remodeling in transplant vasculopathy. AB - IL-17 is a signature cytokine of Th17 cells, a recently described subset of effector CD4 T cells implicated in the development of several pathologies. We have examined the role of IL-17 in regulating endothelial NO synthase (eNOS) expression in human vascular endothelial cells (ECs) because of the key role of eNOS in determining the pathological outcome of immune-mediated vascular diseases. In cultured ECs, IL-17 increased expression of eNOS, eNOS phosphorylation at Ser(1177), and NO production. The induction of eNOS expression by IL-17 was prevented by the pharmacological inhibition of NF-kappaB, MEK, and JNK, as well as by small interfering RNA-mediated gene silencing of these signaling pathways. The expression of IL-17 was then examined by immunohistochemistry in human arteries affected by transplant vasculopathy (TV), a vascular condition that is a leading reflection of chronic heart transplant rejection. IL-17 was expressed by infiltrating leukocytes in the intima of arteries with TV, and the majority of IL-17-positive cells were T cells. The number of IL-17-positive cells was not correlated with the intima/media ratio, but was negatively correlated with the amount of luminal occlusion. There was also a significant positive correlation between the number of IL-17-positive cells and the density of eNOS-expressing luminal ECs in arteries with TV. Altogether, these findings show that IL-17 induces the expression of eNOS in human ECs and that this may facilitate outward expansion of arteries afflicted with TV. PMID- 22219321 TI - Difference in Th1 and Th17 lymphocyte adhesion to endothelium. AB - T cell subset-specific migration to inflammatory sites is tightly regulated and involves interaction of the T cells with the endothelium. Th17 cells often appear at different inflammatory sites than Th1 cells, or both subsets appear at the same sites but at different times. Differences in T cell subset adhesion to endothelium may contribute to subset-specific migratory behavior, but this possibility has not been well studied. We examined the adhesion of mouse Th17 cells to endothelial adhesion molecules and endothelium under flow in vitro and to microvessels in vivo and we characterized their migratory phenotype by flow cytometry and quantitative RT-PCR. More Th17 than Th1 cells interacted with E selectin. Fewer Th17 than Th1 cells bound to TNF-alpha-activated E-selectin deficient endothelial cells, and intravital microscopy studies demonstrated that Th17 cells engage in more rolling interactions with TNF-alpha-treated microvessels than Th1 cells in wild-type mice but not in E-selectin-deficient mice. Th17 adhesion to ICAM-1 was dependent on integrin activation by CCL20, the ligand for CCR6, which is highly expressed by Th17 cells. In an air pouch model of inflammation, CCL20 triggered recruitment of Th17 but not Th1 cells. These data provide evidence that E-selectin- and ICAM-1-dependent adhesion of Th17 and Th1 cells with endothelium are quantitatively different. PMID- 22219323 TI - Production of TNF-alpha in macrophages activated by T cells, compared with lipopolysaccharide, uses distinct IL-10-dependent regulatory mechanism. AB - Previously, we demonstrated that spontaneous TNF-alpha production by macrophages in rheumatoid arthritis (RA) synovial tissue is largely driven by contact dependent activation with T cells in that tissue. Whereas abundant IL-10 is present in these RA synovial cultures, it does not adequately control the production of TNF-alpha. In this study, we have compared the mechanisms involved in IL-10-mediated TNF-alpha regulation in LPS-stimulated macrophages with macrophages stimulated with activated T cells. We confirm that in LPS-stimulated macrophages the 3' enhancer region of tnf is essential for tnf transcription, and its regulation by IL-10 is dominated by a STAT3-dependent pathway. However, in contrast, we have found that tnf transcription in macrophages stimulated by activated T cells or by RA synovial T cells does not require the 3' enhancer region of tnf, and that its regulation by IL-10 is subsequently altered and clearly is not mediated by a dominant STAT3 pathway. These observations have very important implications for our understanding as to how IL-10 regulates TNF-alpha production at sites of chronic inflammation, such as the synovial tissue of patients with RA. Furthermore, these distinct IL-10 mechanisms will have bearing upon the identification of potential therapeutic targets in RA synovial macrophages where the activation stimulus is clearly not LPS. PMID- 22219324 TI - Vitamin D receptor gene polymorphisms and HLA DRB1*04 cosegregation in Saudi type 2 diabetes patients. AB - The vitamin D receptor (VDR) gene has been involved in the modulation of susceptibility to inflammatory and autoimmune conditions, and could play a role in the pathogenesis of type 2 diabetes mellitus (T2DM). Susceptibility to T2DM was recently also suggested to associate with HLA alleles. We evaluated possible correlations between VDR polymorphisms, HLA alleles, and risk for development of T2DM by analyzing 627 individuals (368 T2DM patients and 259 healthy control subjects) part of a well-characterized cohort followed in Riyadh, Kingdom of Saudi Arabia. Genomic DNA was genotyped for the VDR gene single nucleotide polymorphisms of Fok-1, Taq-1, ApaI, and Bsm-I. Analyses were run by allelic discrimination real-time PCR. HLA genotyping was performed as well by PCR using sequence-specific primers, whereas cytokine production was evaluated by FACS. Results showed T2DM to be significantly associated with the VDR Taq1 (rs731236 AG) and Bsm-I (rs1544410-CT) genotypes, and the VDR rs1544410-T allele. Cosegregations resulting in significant increases of T2DM odds ratio were detected between Taq1 and Bsm-I VDR polymorphisms and HLA DRB1*04. Notably, the VDR polymorphisms observed to be more frequent in T2DM patients correlated with increased VDR expression and IL-12 production, as well as with metabolic parameters of susceptibility to T2DM, including serum cholesterol and high density lipoprotein levels. VDR polymorphisms are present in T2DM, and correlate with HLA DRB1*04 and with immunologic and metabolic parameters; results from this study add T2DM to the list of diseases that are likely modulated by an HLA/VDR interaction. PMID- 22219322 TI - Local activation of dendritic cells alters the pathogenesis of autoimmune disease in the retina. AB - Interest in the identities, properties, functions, and origins of local APC in CNS tissues is growing. We recently reported that dendritic cells (DC) distinct from microglia were present in quiescent retina and rapidly responded to injured neurons. In this study, the disease-promoting and regulatory contributions of these APC in experimental autoimmune uveoretinitis (EAU) were examined. Local delivery of purified, exogenous DC or monocytes from bone marrow substantially increased the incidence and severity of EAU induced by adoptive transfer of activated, autoreactive CD4 or CD8 T cells that was limited to the manipulated eye. In vitro assays of APC activity of DC from quiescent retina showed that they promoted generation of Foxp3(+) T cells and inhibited activation of naive T cells by splenic DC and Ag. Conversely, in vitro assays of DC purified from injured retina demonstrated an enhanced ability to activate T cells and reduced induction of Foxp3(+) T cells. These findings were supported by the observation that in situ activation of DC before adoptive transfer of beta-galactosidase-specific T cells dramatically increased severity and incidence of EAU. Recruitment of T cells into retina by local delivery of Ag in vivo showed that quiescent retina promoted development of parenchymal Foxp3(+) T cells, but assays of preinjured retina did not. Together, these results demonstrated that local conditions in the retina determined APC function and affected the pathogenesis of EAU by both CD4 and CD8 T cells. PMID- 22219325 TI - Development and function of murine B cells lacking RANK. AB - RANKL-RANK signaling regulates numerous physiologic processes such as bone remodeling, lymph node organogenesis, central thermoregulation, and formation of a lactating mammary gland in pregnancy. Recently, a receptor activator of NF kappaB ligand (RANKL)-blocking Ab has been approved for human use in potentially millions of osteoporosis and cancer patients. However, germline deficiencies in RANKL or receptor activator of NF-kappaB (RANK) also lead to strong B cell defects in mice and human patients, suggesting that RANKL-RANK inhibition could interfere with B cell physiology and thereby trigger immunologic side-effects. To address this key question--that is, whether RANKL-RANK signaling affects B cell physiology directly or the observed defects are secondary because of the severe osteopetrosis--we generated B cell-specific RANK knockout mice. We show that B cells deficient for RANK undergo normal development and do not show any obvious defects in Ab secretion, class switch recombination, or somatic hypermutation. Our data indicate that ablation of the RANKL-RANK pathway has no direct adverse effect on B cell physiology. PMID- 22219326 TI - Th17 cells in multiple sclerosis express higher levels of JAK2, which increases their surface expression of IFN-gammaR2. AB - IFN-beta inhibits the expansion of Th17 cells in active multiple sclerosis (AMS), and this might contribute to improve the clinical symptoms. The effectiveness of this inhibition, however, requires intact IFN-gamma signaling in T cells. In this study, we report that both mRNA and cell surface expression of the signaling chain of the IFN-gamma receptor (IFN-gammaR2) and its cognate tyrosine kinase JAK2 are enhanced in peripheral blood Th17 cells and clones from patients with AMS compared with those with inactive multiple sclerosis (IMS) or healthy subjects (HS). IFN-gamma decreased the frequency of Th17 peripheral cells and proliferation of Th17 clones from AMS patients. Stimulation of PBMCs from HS in Th17-polarizing conditions resulted in the enhancement of JAK2 expression and accumulation of cell surface IFN-gammaR2. The role of JAK2 in the modulation of IFN-gammaR2 was demonstrated as its transduction prevented rapid internalization and degradation of IFN-gammaR2 in JAK2-deficient gamma2A cells. In conclusion, these data identify JAK2 as a critical factor that stabilizes IFN-gammaR2 surface expression in Th17 cells from AMS patients, making them sensitive to IFN-gamma. These data may have clinical implications for a better use of IFNs in multiple sclerosis and possibly other inflammatory diseases. PMID- 22219327 TI - Surfactant protein A integrates activation signal strength to differentially modulate T cell proliferation. AB - Pulmonary surfactant lipoproteins lower the surface tension at the alveolar airway interface of the lung and participate in host defense. Previous studies reported that surfactant protein A (SP-A) inhibits lymphocyte proliferation. We hypothesized that SP-A-mediated modulation of T cell activation depends upon the strength, duration, and type of lymphocyte activating signals. Modulation of T cell signal strength imparted by different activating agents ex vivo and in vivo in different mouse models and in vitro with human T cells shows a strong correlation between strength of signal (SoS) and functional effects of SP-A interactions. T cell proliferation is enhanced in the presence of SP-A at low SoS imparted by exogenous mitogens, specific Abs, APCs, or in homeostatic proliferation. Proliferation is inhibited at higher SoS imparted by different doses of the same T cell mitogens or indirect stimuli such as LPS. Importantly, reconstitution with exogenous SP-A into the lungs of SP-A(-/-) mice stimulated with a strong signal also resulted in suppression of T cell proliferation while elevating baseline proliferation in unstimulated T cells. These signal strength and SP-A-dependent effects are mediated by changes in intracellular Ca(2+) levels over time, involving extrinsic Ca(2+)-activated channels late during activation. These effects are intrinsic to the global T cell population and are manifested in vivo in naive as well as memory phenotype T cells. Thus, SP-A appears to integrate signal thresholds to control T cell proliferation. PMID- 22219328 TI - Cells exposed to sublethal oxidative stress selectively attract monocytes/macrophages via scavenger receptors and MyD88-mediated signaling. AB - The innate immune system responds to endogenous molecules released during cellular stress or those that have undergone modifications normally absent in healthy tissue. These structures are detected by pattern-recognition receptors, alerting the immune system to "danger." In this study, we looked for early signals that direct immune cells to cells undergoing stress before irreversible damage takes place. To avoid detecting signals emanating from apoptotic or necrotic cells we exposed fibroblasts to sublethal oxidative stress. Our results indicate that both nonenzymatic chemical reactions and aldehyde dehydrogenase-2 mediated enzymatic activity released signals from fibroblasts that selectively attracted CD14(+) monocytes but not T, NK, and NKT cells or granulocytes. Splenocytes from MyD88(-/-) mice did not migrate, and treatment with an inhibitory peptide that blocks MyD88 dimerization abrogated human monocyte migration. Monocyte migration was accompanied by downmodulation of CD14 expression and by the phosphorylation of IL-1R-associated kinase 1, a well-known MyD88-dependent signaling molecule. The scavenger receptor inhibitors, dextran sulfate and fucoidan, attenuated monocyte migration toward stressed cells and IL 1R-associated kinase 1 phosphorylation. Surprisingly, although monocyte migration was MyD88 dependent, it was not accompanied by inflammatory cytokine secretion. Taken together, these results establish a novel link between scavenger receptors and MyD88 that together function as sensors of oxidation-associated molecular patterns and induce monocyte motility. Furthermore, the data indicate that MyD88 independently regulates monocyte activation and motility. PMID- 22219329 TI - Acquisition of antigen-presenting functions by neutrophils isolated from mice with chronic colitis. AB - Active episodes of the inflammatory bowel diseases are associated with the infiltration of large numbers of myeloid cells including neutrophils, monocytes, and macrophages. The objective of this study was to systematically characterize and define the different populations of myeloid cells generated in a mouse model of chronic gut inflammation. Using the T cell transfer model of chronic colitis, we found that induction of disease was associated with enhanced production of myelopoietic cytokines (IL-17 and G-CSF), increased production of neutrophils and monocytes, and infiltration of large numbers of myeloid cells into the mesenteric lymph nodes (MLNs) and colon. Detailed characterization of these myeloid cells revealed three major populations including Mac-1(+)Ly6C(high)Gr-1(low/neg) cells (monocytes), Mac-1(+)Ly6C(int)Gr-1(+) cells (neutrophils), and Mac 1(+)Ly6C(low/neg)Gr-1(low/neg) leukocytes (macrophages, dendritic cells, and eosinophils). In addition, we observed enhanced surface expression of MHC class II and CD86 on neutrophils isolated from the inflamed colon when compared with neutrophils obtained from the blood, the MLNs, and the spleen of colitic mice. Furthermore, we found that colonic neutrophils had acquired APC function that enabled these granulocytes to induce proliferation of OVA-specific CD4(+) T cells in an Ag- and MHC class II-dependent manner. Finally, we observed a synergistic increase in proinflammatory cytokine and chemokine production following coculture of T cells with neutrophils in vitro. Taken together, our data suggest that extravasated neutrophils acquire APC function within the inflamed bowel where they may perpetuate chronic gut inflammation by inducing T cell activation and proliferation as well as by enhancing production of proinflammatory mediators. PMID- 22219330 TI - The role of nanometer-scaled ligand patterns in polyvalent binding by large mannan-binding lectin oligomers. AB - Mannan-binding lectin (MBL) is an important protein of the innate immune system and protects the body against infection through opsonization and activation of the complement system on surfaces with an appropriate presentation of carbohydrate ligands. The quaternary structure of human MBL is built from oligomerization of structural units into polydisperse complexes typically with three to eight structural units, each containing three lectin domains. Insight into the connection between the structure and ligand-binding properties of these oligomers has been lacking. In this article, we present an analysis of the binding to neoglycoprotein-coated surfaces by size-fractionated human MBL oligomers studied with small-angle x-ray scattering and surface plasmon resonance spectroscopy. The MBL oligomers bound to these surfaces mainly in two modes, with dissociation constants in the micro to nanomolar order. The binding kinetics were markedly influenced by both the density of ligands and the number of ligand binding domains in the oligomers. These findings demonstrated that the MBL binding kinetics are critically dependent on structural characteristics on the nanometer scale, both with regard to the dimensions of the oligomer, as well as the ligand presentation on surfaces. Therefore, our work suggested that the surface binding of MBL involves recognition of patterns with dimensions on the order of 10-20 nm. The recent understanding that the surfaces of many microbes are organized with structural features on the nanometer scale suggests that these properties of MBL ligand recognition potentially constitute an important part of the pattern-recognition ability of these polyvalent oligomers. PMID- 22219331 TI - Downregulation of PCAF by miR-181a/b provides feedback regulation to TNF-alpha induced transcription of proinflammatory genes in liver epithelial cells. AB - Aberrant cellular responses to proinflammatory cytokines, such as TNF-alpha, are pathogenic features in most chronic inflammatory diseases. A variety of extracellular and intracellular feedback pathways has evolved to prevent an inappropriate cellular reaction to these proinflammatory cytokines. In this study, we report that TNF-alpha treatment of human and mouse cholangiocytes and hepatocytes downregulated expression of p300/CBP-associated factor (PCAF), a coactivator and an acetyltransferase that promotes histone acetylation and gene transcription. Of these upregulated microRNAs in TNF-alpha-treated cells, miR 181a/b (miR-181a and miR-181b) suppressed translation of PCAF mRNA. Functional manipulation of miR-181a/b caused reciprocal alterations in PCAF protein expression in cultured cholangiocytes and hepatocytes. Inhibition of miR-181a/b function with anti-miRs blocked TNF-alpha-induced suppression of PCAF expression. Promoter recruitment of PCAF was shown to be associated with TNF-alpha-induced transcription of inflammatory genes. Intriguingly, pretreatment of cells with TNF alpha inhibited transcription of inflammatory genes in response to subsequent TNF alpha stimulation. Overexpression of PCAF or inhibition of miR-181a/b function with anti-miRs attenuated the inhibitory effects of TNF-alpha pretreatment on epithelial inflammatory response to subsequent TNF-alpha stimulation. Downregulation of PCAF and the inhibitory effects of TNF-alpha pretreatment on liver epithelial inflammatory response were further confirmed in a mouse model of TNF-alpha i.p. injection. These data suggest that PCAF is a target for miR 181a/b, and downregulation of PCAF by TNF-alpha provides negative feedback regulation to inflammatory reactions in liver epithelial cells, a process that may be relevant to the epigenetic fine-tuning of epithelial inflammatory processes in general. PMID- 22219332 TI - Cutting edge: Protective effect of CX3CR1+ dendritic cells in a vaccinia virus pulmonary infection model. AB - The protective host immune response to viral infections requires both effective innate and adaptive immune responses. Cross-talk between the two responses is coordinated by the chemokine network and professional APCs such as dendritic cells (DCs). In mice, subpopulations of myeloid DCs in peripheral tissues such as lungs and in blood express CX3CR1 depending on the inflammation state. We thus examined the host response of mice deficient in the chemokine receptor CX3CR1 to an intranasal vaccinia virus infection. CX3CR1-deficient mice displayed significantly more severe morbidity and mortality compared with control wild-type mice within 10 d following vaccinia virus infection. CX3CR1(-/-) mice had increased viral loads and a reduced T cell response compared with wild-type mice. Finally, an adoptive transfer of CX3CR1(+/+) DCs completely protected CX3CR1(-/-) mice to a previously lethal infection. This study therefore opens up the possibility of novel antiviral therapeutics targeting lung DC recruitment. PMID- 22219333 TI - Regulation of fat intake in the absence of flavour signalling. AB - Animals, including humans, can achieve precise regulation of caloric intake by adjusting consumption in response to covert changes in energy density. It remains unknown, however, whether the presence of flavour cues are required for the ability to maintain constant caloric intake. Also unknown are the brain circuits that may function as the central calorie monitors that control adaptive adjustments in energy intake. Here we show that mice trained to lick a dry spout in order to receive intra-gastric infusions of a fat emulsion maintained constant hourly caloric intake by adjusting the number of dry licks in response to changes in caloric density. Animals also increased dry licking according to hunger levels, and developed conditioned preferences for dry sippers associated with high calorie infusions. Importantly, striatal dopamine levels were closely associated with the amount of calories ingested, rather than with the number of dry licks produced. Dopamine levels in dorsal and ventral striatum also reflected caloric density in mice passively receiving intra-gastric infusions of fat emulsions. Consistent with the above, systemic administration of the dopamine receptor blocker haloperidol markedly increased the production of dry licks needed to obtain high-calorie infusions, as if the caloric density of the infusions had been diluted. Conversely, haloperidol markedly decreased the production of dry licks needed to obtain low-calorie infusions. Taken together, our results support the proposition that brain dopamine circuits function as one central sensor of calorie ingestion, since (1) extracellular striatal dopamine levels fluctuate in proportion to the caloric density of nutrients infused in the gut; and (2) inhibiting dopamine receptor signalling disrupts the animals' ability to maintain constant caloric intake across experimental sessions. PMID- 22219334 TI - Colloid volume loading does not mitigate decreases in central blood volume during simulated haemorrhage while heat stressed. AB - Heat stress results in profound reductions in the capacity to withstand a simulated haemorrhagic challenge; however, this capacity is normalized if the individual is volume loaded prior to the challenge. The present study tested the hypothesis that volume loading during passive heat stress attenuates the reduction in regional blood volumes during a simulated haemorrhagic challenge imposed via lower-body negative pressure (LBNP). Seven subjects underwent 30 mmHg LBNP while normothermic, during passive heat stress (increased internal temperature ~1?C), and while continuing to be heated after intravenous colloid volume loading (11 ml kg-1). Relative changes in torso and regional blood volumes were determined by gamma camera imaging with technetium-99m labelled erythrocytes. Heat stress reduced blood volume in all regions (ranging from 7 to 16%), while subsequent volume loading returned those values to normothermic levels. While normothermic,LBNP reduced blood volume in all regions (torso: 22 +/ 8%; heart: 18 +/- 6%; spleen: 15 +/- 8%). During LBNP while heat stressed, the reductions in blood volume in each region were markedly greater when compared to LBNP while normothermic (torso: 73 +/- 2%; heart: 72 +/- 3%; spleen: 72 +/- 5%, all P<0.001 relative to normothermia). Volume loading during heat stress did not alter the extent of the reduction in these blood volumes to LBNP relative to heat stress alone (torso: 73 +/- 1%; heart: 72 +/- 2%; spleen: 74 +/- 3%, all P>0.05 relative to heat stress alone). These data suggest that blood volume loading during passive heat stress (via 11 ml kg-1 of a colloid solution) normalizes regional blood volumes in the torso, but does not mitigate the reduction in central blood volume during a simulated haemorrhagic challenge combined with heat stress. PMID- 22219335 TI - Acetazolamide improves loop gain but not the other physiological traits causing obstructive sleep apnoea. AB - There is some evidence to suggest that acetazolamide may improve obstructive sleep apnoea (OSA).However, how acetazolamide affects the key traits causing OSA remains uncertain. We aimed to investigate the effect of acetazolamide on the traits contributing to OSA and its severity. Acetazolamide (500 mg twice daily) was administered for 1 week to 13 OSA subjects. Pharyngeal anatomy/collapsibility, loop gain (LG), upper-airway muscle responsiveness (gain) and the arousal threshold were determined using multiple 3 min 'CPAP pressure drops': pharyngeal anatomy/collapsibility was quantified as the ventilation at CPAP=0. LG was defined as the ratio of the ventilatory overshoot to the preceding reduction in ventilation. Upper-airway gain was taken as the ratio of the increase in ventilation to the increase in ventilatory drive across the drop. Arousal threshold was quantified as the level of ventilatory drive associated with arousal. The apnoea-hypopnoea index (AHI)was assessed on separate nights using standard polysomnography. Acetazolamide reduced the median [interquartile range] LG (3.4 [2.4-5.4] versus 2.0 [1.4-3.5]; P <0.05) and NREM AHI (50 [36-57] versus 24 [13-42] events h-1; P <0.05), but did not significantly alter pharyngeal anatomy/collapsibility, upper-airway gain, or arousal threshold. There was a modest correlation between the percentage reduction in LG and the percentage reduction in AHI (r =0.660, P =0.05). Our findings suggest that acetazolamide can improve OSA, probably due to reductions in the sensitivity of the ventilatory control system. Identification of patients who may benefit from reductions in LG alone or in combination with other therapies to alter the remaining traits may facilitate pharmacological resolution of OSA in the future. PMID- 22219336 TI - Determinants of colonic barrier function in inflammatory bowel disease and potential therapeutics. AB - Intestinal barrier dysfunction is a main feature of the inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis. Leak flux diarrhoea and a facilitated uptake of noxious antigens are the two consequences resulting from an impaired epithelial barrier. Barrier perturbations in IBD comprise alterations in epithelial tight junctions (TJ), i.e. a reduced number of horizontal TJ strands and an altered TJ protein expression and subcellular distribution. Moreover, increased incidence of apoptotic events as well as erosions and ulcerations can add to that leakiness. These barrier defects are attributed to enhanced activity of pro-inflammatory cytokines like TNFalpha, INFgamma, IL-1beta and IL-13, which are highly expressed in the chronically inflamed intestine. Although the aetiology of IBD is far from being clear, chronic inflammation is believed to result from an inadequate immune response as a consequence of genetic predisposition as well as changes in, and altered responses to, the intestinal microbiota. On the other hand, an insufficient mucosal response to bacterial stimuli results in an insufficient immune response towards intestinal pathogens. However, detailed characterization of barrier defects offers the opportunity to consider and test therapeutic interventions. Beside cytokine antagonists, different plant compounds and probiotics have been shown to stabilize the barrier function by affecting TJ protein expression and distribution. PMID- 22219337 TI - Cortical basket cell dysfunction in schizophrenia. AB - Schizophrenia, a debilitating illness affecting 0.5-1% of the world's population, is characterized by positive, negative and cognitive symptoms. The latter are the best predictor of functional outcome, though largely untreated by current pharmacotherapy; thus a better understanding of the mechanisms underlying cognitive deficits in schizophrenia is crucial. Higher order cognitive processes, such as working memory, are associated with theta (4-7 Hz) and gamma (30-80 Hz) oscillations in the prefrontal cortex (PFC), and subjects with schizophrenia exhibit working memory impairments and reduced cortical theta and gamma band power. Cortical theta and gamma oscillations are dependent on perisomatic inhibition of pyramidal neurons from basket cells expressing cholecystokinin (CCK(b) cells) and parvalbumin (PV(b) cells), respectively. Thus, alterations in basket cells may underlie the cortical oscillation deficits and working memory impairments in schizophrenia. Recent findings from postmortem studies suggest that schizophrenia is associated with multiple molecular alterations that regulate signalling from CCK(b) and PV(b) cells. These alterations include lower CCK and cannabinoid 1 receptor (CB1R) in CCK(b) cells, and lower glutamic acid decarboxylase 67 (GAD67) and increased MU opioid receptor (MUOR) in PV(b) cells, as well as lower GABA(A) receptor alpha1 subunit in pyramidal neurons postsynaptic to PV(b) cells. These changes are thought to lead to increased and decreased strength, respectively, of CCK(b) and PV(b) cell-mediated inhibition of postsynaptic pyramidal cells. Therefore, a convergence of evidence suggests a substantial shift in the relative strengths of PFC pyramidal cell inhibition from CCK(b) and PV(b) cells that may underlie cortical oscillation deficits and working memory impairments in schizophrenia. PMID- 22219338 TI - Differential modulation of crossed and uncrossed reflex pathways by clonidine in adult cats following complete spinal cord injury. AB - Clonidine, an alpha-noradrenergic agonist, facilitates hindlimb locomotor recovery after complete spinal transection (i.e. spinalization) in adult cats. However, the mechanisms involved in clonidine-induced functional recovery are poorly understood. Sensory feedback from the legs is critical for hindlimb locomotor recovery in spinalized mammals and clonidine could alter how spinal neurons respond to peripheral inputs in adult spinalized cats. To test this hypothesis we evaluated the effect of clonidine on the responses of hindlimb muscles, primarily in the left hindlimb, evoked by stretching the left triceps surae muscles and by stimulating the right tibial and superficial peroneal nerves in eight adult decerebrate cats that were spinalized 1 month before the terminal experiment. Cats were not trained following spinalization. Clonidine had no consistent effect on responses of ipsilateral muscles evoked by triceps surae muscle stretch. However, clonidine consistently potentiated the amplitude and duration of crossed extensor responses. Moreover, following clonidine injection, stretch and tibial nerve stimulation triggered episodes of locomotor-like activity in approximately one-third of trials. Differential effects of clonidine on crossed reflexes and on ipsilateral responses to muscle stretch indicate an action at a pre-motoneuronal site. We conclude that clonidine facilitates hindlimb locomotor recovery following spinalization in untrained cats by enhancing the excitability of central pattern generating spinal neurons that also participate in crossed extensor reflex transmission. PMID- 22219339 TI - The DeltaC splice-variant of TRPM2 is the hypertonicity-induced cation channel in HeLa cells, and the ecto-enzyme CD38 mediates its activation. AB - Hypertonicity-induced cation channels (HICCs) are key-players in proliferation and apoptosis but their molecular correlate remains obscure. Furthermore, the activation profile of HICCs is not well defined yet. We report here that, in HeLa cells, intracellular adenosine diphosphate ribose (ADPr) and cyclic ADPr (cADPr), as supposed activators of TRPM2, elicited cation currents that were virtually identical to the osmotic activation of HICCs. Silencing of the expression of TRPM2 and of the ecto-enzyme CD38 (as a likely source of ADPr and cADPr) inhibited HICC as well as nucleotide-induced currents and, in parallel, the hypertonic volume response of cells (the regulatory volume increase, RVI) was attenuated. Quantification of intracellular cADPr levels and the systematic application of extra- vs. intracellular nucleotides indicate that the outwardly directed gradient rather than the cellular activity of ADPr and cADPr triggers TRPM2 activation, probably along with a simultaneous biotransformation of nucleotides.Cloning of TRPM2 identified the DeltaC-splice variant as the molecular correlate of the HICC, which could be strongly supported by a direct comparison of the respective Ca2+ selectivity. Finally, immunoprecipitation and high-resolution FRET/FLIM imaging revealed the interaction of TRPM2 and CD38 in the native as well as in a heterologous (HEK293T) expression system. We propose transport-related nucleotide export via CD38 as a novel mechanism of TRPM2/HICC activation. With the biotransformation of nucleotides running in parallel, continuous zero trans-conditions are achieved which will render the system infinitely sensitive. PMID- 22219340 TI - Sticking out of the crowd: the molecular identity and development of cholecystokinin-containing basket cells. AB - Certain essential cognitive processes require the precise temporal interplay between glutamatergic (excitatory) pyramidal cells and gamma-aminobutyric acid (GABA)-releasing inhibitory interneurons in the hippocampus. Basket cells, the main class of interneurons, target pyramidal cell somata and proximal dendrites and thus are poised to modify network oscillations. Though only present in limited numbers, the impaired development of basket cells can result in changes in the hippocampal circuitry leading to neurological disorders, such as schizophrenia. The diversity of the spatial origins, neurochemical make-up, cytoarchitecture and network contributions amongst basket cells is a provocative example of interneuron heterogeneity in the hippocampus. This review discusses recent data concerned with the developmental trajectories of one subclass, the cholecystokinin-containing basket cell, and emphasizes the significance of the short-range intercellular guidance cues that have recently emerged to impact the formation and function of their inhibitory synapses. PMID- 22219341 TI - Optogenetic activation of LiGluR-expressing astrocytes evokes anion channel mediated glutamate release. AB - Increases in astrocyte Ca(2+) have been suggested to evoke gliotransmitter release, however, the mechanism of release, the identity of such transmitter(s), and even whether and when such release occurs, are controversial, largely due to the lack of a method for selective and reproducible stimulation of electrically silent astrocytes. Here we show that photoactivation of the light-gated Ca(2+) permeable ionotropic GluR6 glutamate receptor (LiGluR), and to a lesser extent the new Ca(2+)-translocating channelrhodopsin CatCh, evokes more reliable Ca(2+) elevation than the mutant channelrhodopsin 2, ChR2(H134R) in cultured cortical astrocytes. We used evanescent-field excitation for near-membrane Ca(2+) imaging, and epifluorescence to activate and inactivate LiGluR. By alternating activation and inactivation light pulses, the LiGluR-evoked Ca(2+) rises could be graded in amplitude and duration. The optical stimulation of LiGluR-expressing astrocytes evoked probabilistic glutamate-mediated signalling to adjacent LiGluR-non expressing astrocytes. This astrocyte-to-astrocyte signalling was insensitive to the inactivation of vesicular release, hemichannels and glutamate-transporters, and sensitive to anion channel blockers. Our results show that LiGluR is a powerful tool to selectively and reproducibly activate astrocytes. PMID- 22219342 TI - Nitric oxide synthase inhibition prevents activity-induced calcineurin-NFATc1 signalling and fast-to-slow skeletal muscle fibre type conversions. AB - The calcineurin-NFAT (nuclear factor of activated T-cells) signalling pathway is involved in the regulation of activity-dependent skeletal muscle myosin heavy chain (MHC) isoform type expression. Emerging evidence indicates that nitric oxide (NO) may play a critical role in this regulatory pathway. Thus, the purpose of this study was to investigate the role of NO in activity-induced calcineurin NFATc1 signalling leading to skeletal muscle faster-to-slower fibre type transformations in vivo. Endogenous NO production was blocked by administering L NAME (0.75 mg ml(-1)) in drinking water throughout 0, 1, 2, 5 or 10 days of chronic low-frequency stimulation (CLFS; 10 Hz, 12 h day(-1)) of rat fast-twitch muscles (L+Stim; n = 30) and outcomes were compared with control rats receiving only CLFS (Stim; n = 30). Western blot and immunofluorescence analyses revealed that CLFS induced an increase in NFATc1 dephosphorylation and nuclear localisation, sustained by glycogen synthase kinase (GSK)-3beta phosphorylation in Stim, which were all abolished in L+Stim. Moreover, real-time RT-PCR revealed that CLFS induced an increased expression of MHC-I, -IIa and -IId(x) mRNAs in Stim that was abolished in L+Stim. SDS-PAGE and immunohistochemical analyses revealed that CLFS induced faster-to-slower MHC protein and fibre type transformations, respectively, within the fast fibre population of both Stim and L+Stim groups. The final fast type IIA to slow type I transformation, however, was prevented in L+Stim. It is concluded that NO regulates activity-induced MHC based faster-to-slower fibre type transformations at the transcriptional level via inhibitory GSK-3beta-induced facilitation of calcineurin-NFATc1 nuclear accumulation in vivo, whereas transformations within the fast fibre population may also involve translational control mechanisms independent of NO signalling. PMID- 22219344 TI - Rod, M-cone and M/S-cone inputs to hyperpolarizing bipolar cells in the mouse retina. AB - Bipolar cells are the central neurons of the retina that convey visual signals from rod and cone photoreceptors in the outer retina to higher-order neurons in the inner retina and the brain. Early anatomical studies have suggested that there are four types of cone hyperpolarizing (OFF) bipolar cells (HBCs) in the mouse retina, but no light responses have been systematically examined. By analysing light-evoked cation and chloride currents (I(C) and I(Cl)) from over 50 morphologically identified HBCs in the dark-adapted wildtype and connexin36 knockout (Cx36(-/-)) mouse retinas, we identified three types of HBCs, each with distinct light responses and morphological characteristics. The HBC(R/MC)s with axon terminals ramifying between 0% and 30% of the inner plexiform layer (IPL) receive mixed inputs from rods and M-cones, the HBC(MC)s with axon terminals ramifying between 10% and 50% of the IPL receive inputs primarily from M-cones, and the HBC(M/SC)s with axon terminals ramifying between 25% and 50% of IPL receive inputs primarily from cones with mixed M- and S-cone pigments. Moreover, we found that HBC(R/MC)s in the Cx36(-/-) mice exhibit light responses very similar to the wildtype HBC(R/MC)s, suggesting that the mixed rod-cone inputs are not mediated by connexin36-dependent rod-cone coupling, but rather by direct synaptic contacts from rods and M-cones. This study constitutes the first systematic investigation that correlates light response characteristics and axonal morphology of HBCs in dark-adapted mouse retina, and contributes to recently emerging evidence that revises the traditional view that mammalian HBCs only contact cone photoreceptors. PMID- 22219343 TI - Effects of acetazolamide on cerebrovascular function and breathing stability at 5050 m. AB - One of the many actions of the carbonic anhydrase inhibitor, acetazolamide (ACZ), is to accelerate acclimatisation and reduce periodic breathing during sleep. The mechanism(s) by which ACZ may improve breathing stability, especially at high altitude, remain unclear. We tested the hypothesis that acute I.V. ACZ would enhance cerebrovascular reactivity to CO2 at altitude, and thereby lower ventilatory drive and improve breathing stability during wakefulness. We measured arterial blood gases, minute ventilation (VE) and middle cerebral artery blood flow velocity (MCAv) before and 30 min following ACZ administration (I.V. 10 mg kg-1) in 12 healthy participants at sea level and following partial acclimatisation to altitude (5050 m).Measures were made at rest and during changes in end-tidal PCO2 and PO2 (isocapnic hypoxia). At sea level, ACZ increased resting MCAv and its reactivity to both hypocapnia and hypercapnia (P < 0.05), and lowered resting VE, arterial O2 saturation (Sa,O2 ) and arterial PO2 (Pa,O2) (P < 0.05); arterial PCO2 (Pa,CO2 ) was unaltered (P > 0.05). At altitude, ACZ also increased resting MCAv and its reactivity to both hypocapnia and hypercapnia (resting MCAv and hypocapnia reactivity to a greater extent than at sea level). Moreover, ACZ at altitude elevated Pa,CO2 and again lowered resting Pa,O2 and Sa,O2 (P <0.05). Although the VE sensitivity to hypercapnia or isocapnic hypoxia was unaltered following ACZ at both sea level and altitude (P > 0.05), breathing stability at altitude was improved (e.g. lower incidence of ventilatory oscillations and variability of tidal volume; P < 0.05). Our data indicate that I.V. ACZ elevates cerebrovascular reactivity and improves breathing stability at altitude, independent of changes in peripheral or central chemoreflex sensitivities. We speculate that Pa,CO2-mediated elevations in cerebral perfusion and an enhanced cerebrovascular reactivity may partly account for the improved breathing stability following ACZ at high altitude. PMID- 22219346 TI - The prostanoid 15-deoxy-Delta12,14-prostaglandin-j2 reduces lung inflammation and protects mice against lethal influenza infection. AB - BACKGROUND: Growing evidence indicates that influenza pathogenicity relates to altered immune responses and hypercytokinemia. Therefore, dampening the excessive inflammatory response induced after infection might reduce influenza morbidity and mortality. METHODS: Considering this, we investigated the effect of the anti inflammatory molecule 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) in a mouse model of lethal influenza infection. RESULTS: Administration of 15d-PGJ(2) on day 1 after infection, but not on day 0, protected 79% of mice against lethal influenza infection. In addition, this treatment considerably reduced the morbidity associated with severe influenza infection. Our results also showed that treatment with 15d-PGJ(2) decreased influenza-induced lung inflammation, as shown by the diminished gene expression of several proinflammatory cytokines and chemokines. Unexpectedly, 15d-PGJ(2) also markedly reduced the viral load in the lungs of infected mice. This could be attributed to maintained type I interferon gene expression levels after treatment. Interestingly, pretreatment of mice with a peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist before 15d-PGJ(2) administration completely abrogated its protective effect against influenza infection. CONCLUSIONS: Our results demonstrate for the first time that treatment of mice with 15d-PGJ(2) reduces influenza morbidity and mortality through activation of the PPARgamma pathway. PPARgamma agonists could thus represent a potential therapeutic avenue for influenza infections. PMID- 22219345 TI - LC-MS/MS analysis of differentially expressed glioblastoma membrane proteome reveals altered calcium signaling and other protein groups of regulatory functions. AB - Membrane proteins play key roles in the development and progression of cancer. We have studied differentially expressed membrane proteins in glioblastoma multiforme (GBM), the most common and aggressive type of primary brain tumor, by high resolution LC-MS/MS mass spectrometry and quantitation by iTRAQ. A total of 1834 membrane proteins were identified with high confidence, of which 356 proteins were found to be altered by 2-fold change or more (198 up- and 158 down regulated); 56% of them are known membrane proteins associated with major cellular processes. Mass spectrometry results were confirmed for representative proteins on individual specimens by immunohistochemistry. On mapping of the differentially expressed proteins to cellular pathways and functional networks, we notably observed many calcium-binding proteins to be altered, implicating deregulation of calcium signaling and homeostasis in GBM, a pathway also found to be enriched in the report (Dong, H., Luo, L., Hong, S., Siu, H., Xiao, Y., Jin, L., Chen, R., and Xiong, M. (2010) Integrated analysis of mutations, miRNA and mRNA expression in glioblastoma. BMC Syst. Biol. 4, 163) based on The Cancer Genome Atlas analysis of GBMs. Annotations of the 356 proteins identified by us with The Cancer Genome Atlas transcriptome data set indicated overlap with 295 corresponding transcripts, which included 49 potential miRNA targets; many transcripts correlated with proteins in their expression status. Nearly 50% of the differentially expressed proteins could be classified as transmembrane domain or signal sequence-containing proteins (159 of 356) with potential of appearance in cerebrospinal fluid or plasma. Interestingly, 75 of them have been already reported in normal cerebrospinal fluid or plasma along with other proteins. This first, in-depth analysis of the differentially expressed membrane proteome of GBM confirms genes/proteins that have been implicated in earlier studies, as well as reveals novel candidates that are being reported for the first time in GBM or any other cancer that could be investigated further for clinical applications. PMID- 22219347 TI - Homozygosity for the toll-like receptor 2 R753Q single-nucleotide polymorphism is a risk factor for cytomegalovirus disease after liver transplantation. AB - Immunity against cytomegalovirus (CMV) is initiated after its recognition by Toll like receptor 2 (TLR2). We assessed the association between a single-nucleotide polymorphism (SNP) that impairs TLR2 function and CMV disease in a cohort of 737 liver recipients. Ninety-two of 737 patients (7.1%, 10.9%, 12.3%, and 12.5% by 3, 6, 12, and 24 months, respectively) developed CMV disease. Kaplan-Meier estimation demonstrated an association between TLR2 R753Q SNP homozygosity and CMV disease (P = .044), especially tissue-invasive CMV disease (P = .001). A multivariate Cox proportional hazard model that accounted for other significant predictors demonstrated a significant association between TLR2 R753Q SNP homozygosity and tissue-invasive CMV disease (hazard ratio, 3.407; 95% confidence interval, 1.518-7.644; P = .0029). In conclusion, homozygosity for TLR2 R753Q SNP is a marker for CMV disease risk, especially for tissue-invasive disease, after liver transplantation. This observation supports the critical role of TLR2 in the pathogenesis of CMV disease in humans. PMID- 22219349 TI - Cardiac complications in patients with community-acquired pneumonia: incidence, timing, risk factors, and association with short-term mortality. AB - BACKGROUND: Community-acquired pneumonia (CAP) affects >5 million adults each year in the United States. Although incident cardiac complications occur in patients with community-acquired pneumonia, their incidence, timing, risk factors, and associations with short-term mortality are not well understood. METHODS AND RESULTS: A total of 1343 inpatients and 944 outpatients with community-acquired pneumonia were followed up prospectively for 30 days after presentation. Incident cardiac complications (new or worsening heart failure, new or worsening arrhythmias, or myocardial infarction) were diagnosed in 358 inpatients (26.7%) and 20 outpatients (2.1%). Although most events (89.1% in inpatients, 75% in outpatients) were diagnosed within the first week, more than half of them were recognized in the first 24 hours. Factors associated with their diagnosis included older age (odds ratio [OR]=1.03; 95% confidence interval [CI], 1.02-1.04), nursing home residence (OR, 1.8; 95% CI, 1.2-2.9), history of heart failure (OR, 4.3; 95% CI, 3.0-6.3), prior cardiac arrhythmias (OR, 1.8; 95% CI, 1.2-2.7), previously diagnosed coronary artery disease (OR, 1.5; 95% CI, 1.04 2.0), arterial hypertension (OR, 1.5; 95% CI, 1.1-2.1), respiratory rate >=30 breaths per minute (OR, 1.6; 95% CI, 1.1-2.3), blood pH <7.35 (OR, 3.2; 95% CI, 1.8-5.7), blood urea nitrogen >=30 mg/dL (OR, 1.5; 95% CI, 1.1-2.2), serum sodium <130 mmol/L (OR, 1.8; 95% CI, 1.02-3.1), hematocrit <30% (OR, 2.0; 95% CI, 1.3 3.2), pleural effusion on presenting chest x-ray (OR, 1.6; 95% CI, 1.1-2.4), and inpatient care (OR, 4.8; 95% CI, 2.8-8.3). Incident cardiac complications were associated with increased risk of death at 30 days after adjustment for baseline Pneumonia Severity Index score (OR, 1.6; 95% CI, 1.04-2.5). CONCLUSIONS: Incident cardiac complications are common in patients with community-acquired pneumonia and are associated with increased short-term mortality. Older age, nursing home residence, preexisting cardiovascular disease, and pneumonia severity are associated with their occurrence. Further studies are required to test risk stratification and prevention and treatment strategies for cardiac complications in this population. PMID- 22219348 TI - Air pollution and incidence of hypertension and diabetes mellitus in black women living in Los Angeles. AB - BACKGROUND: Evidence suggests that longer-term exposure to air pollutants over years confers higher risks of cardiovascular morbidity and mortality than shorter term exposure. One explanation is that the cumulative adverse effects that develop over longer durations lead to the genesis of chronic disease. Preliminary epidemiological and clinical evidence suggests that air pollution may contribute to the development of hypertension and type 2 diabetes mellitus. METHODS AND RESULTS: We used Cox proportional hazards models to assess incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for incident hypertension and diabetes mellitus associated with exposure to fine particulate matter (PM(2.5)) and nitrogen oxides in a cohort of black women living in Los Angeles. Pollutant levels were estimated at participants' residential addresses with land use regression models (nitrogen oxides) and interpolation from monitoring station measurements (PM(2.5)). Over follow-up from 1995 to 2005, 531 incident cases of hypertension and 183 incident cases of diabetes mellitus occurred. When pollutants were analyzed separately, the IRR for hypertension for a 10-MUg/m(3) increase in PM(2.5) was 1.48 (95% CI, 0.95-2.31), and the IRR for the interquartile range (12.4 parts per billion) of nitrogen oxides was 1.14 (95% CI, 1.03-1.25). The corresponding IRRs for diabetes mellitus were 1.63 (95% CI, 0.78 3.44) and 1.25 (95% CI, 1.07-1.46). When both pollutants were included in the same model, the IRRs for PM(2.5) were attenuated and the IRRs for nitrogen oxides were essentially unchanged for both outcomes. CONCLUSION: Our results suggest that exposure to air pollutants, especially traffic-related pollutants, may increase the risk of type 2 diabetes mellitus and possibly of hypertension. PMID- 22219350 TI - crinkled reveals a new role for Wingless signaling in Drosophila denticle formation. AB - The specification of the body plan in vertebrates and invertebrates is controlled by a variety of cell signaling pathways, but how signaling output is translated into morphogenesis is an ongoing question. Here, we describe genetic interactions between the Wingless (Wg) signaling pathway and a nonmuscle myosin heavy chain, encoded by the crinkled (ck) locus in Drosophila. In a screen for mutations that modify wg loss-of-function phenotypes, we isolated multiple independent alleles of ck. These ck mutations dramatically alter the morphology of the hook-shaped denticles that decorate the ventral surface of the wg mutant larval cuticle. In an otherwise wild-type background, ck mutations do not significantly alter denticle morphology, suggesting a specific interaction with Wg-mediated aspects of epidermal patterning. Here, we show that changing the level of Wg activity changes the structure of actin bundles during denticle formation in ck mutants. We further find that regulation of the Wg target gene, shaven-baby (svb), and of its transcriptional targets, miniature (m) and forked (f), modulates this ck dependent process. We conclude that Ck acts in concert with Wg targets to orchestrate the proper shaping of denticles in the Drosophila embryonic epidermis. PMID- 22219351 TI - Recruitment of 5' Hoxa genes in the allantois is essential for proper extra embryonic function in placental mammals. AB - The Hox gene family is well known for its functions in establishing morphological diversity along the anterior-posterior axis of developing embryos. In mammals, one of these genes, Hoxa13, is crucial for embryonic survival, as its function is required for the proper expansion of the fetal vasculature in the placenta. Thus, it appears that the developmental strategy specific to placental mammals is linked, at least in part, to the recruitment of Hoxa13 function in developing extra-embryonic tissues. Yet, the mechanism underlying this extra-embryonic recruitment is unknown. Here, we provide evidence that this functional novelty is not exclusive to Hoxa13 but is shared with its neighboring Hoxa11 and Hoxa10 genes. We show that the extra-embryonic function of these three Hoxa genes stems from their specific expression in the allantois, an extra-embryonic hallmark of amniote vertebrates. Interestingly, Hoxa10-13 expression in the allantois is conserved in chick embryos, which are non-placental amniotes, suggesting that the extra-embryonic recruitment of Hoxa10, Hoxa11 and Hoxa13 most likely arose in amniotes, i.e. prior to the emergence of placental mammals. Finally, using a series of targeted recombination and transgenic assays, we provide evidence that the regulatory mechanism underlying Hoxa expression in the allantois is extremely complex and relies on several cis-regulatory sequences. PMID- 22219352 TI - Synchronous and symmetric migration of Drosophila caudal visceral mesoderm cells requires dual input by two FGF ligands. AB - Caudal visceral mesoderm (CVM) cells migrate synchronously towards the anterior of the Drosophila embryo as two distinct groups located on each side of the body, in order to specify longitudinal muscles that ensheath the gut. Little is known about the molecular cues that guide cells along this path, the longest migration of embryogenesis, except that they closely associate with trunk visceral mesoderm (TVM). The expression of the fibroblast growth factor receptor (FGFR) heartless and its ligands, pyramus (pyr) and thisbe (ths), within CVM and TVM cells, respectively, suggested FGF signaling may influence CVM cell guidance. In FGF mutants, CVM cells die before reaching the anterior region of the TVM. However, an earlier phenotype observed was that the two cell clusters lose direction and converge at the midline. Live in vivo imaging and tracking analyses identified that the movements of CVM cells were slower and no longer synchronous. Moreover, CVM cells were found to cross over from one group to the other, disrupting bilateral symmetry, whereas such mixing was never observed in wild-type embryos. Ectopic expression of either Pyr or Ths was sufficient to redirect CVM cell movement, but only when the endogenous source of these ligands was absent. Collectively, our results show that FGF signaling regulates directional movement of CVM cells and that native presentation of both FGF ligands together is most effective at attracting cells. This study also has general implications, as it suggests that the activity supported by two FGF ligands in concert differs from their activities in isolation. PMID- 22219353 TI - Bmp signaling regulates a dose-dependent transcriptional program to control facial skeletal development. AB - We performed an in depth analysis of Bmp4, a critical regulator of development, disease, and evolution, in cranial neural crest (CNC). Conditional Bmp4 overexpression, using a tetracycline-regulated Bmp4 gain-of-function allele, resulted in facial skeletal changes that were most dramatic after an E10.5 Bmp4 induction. Expression profiling uncovered a signature of Bmp4-induced genes (BIG) composed predominantly of transcriptional regulators that control self-renewal, osteoblast differentiation and negative Bmp autoregulation. The complimentary experiment, CNC inactivation of Bmp2, Bmp4 and Bmp7, resulted in complete or partial loss of multiple CNC-derived skeletal elements, revealing a crucial requirement for Bmp signaling in membranous bone and cartilage development. Importantly, the BIG signature was reduced in Bmp loss-of-function mutants, indicating Bmp-regulated target genes are modulated by Bmp dose. Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG signature, including Satb2, Smad6, Hand1, Gadd45gamma and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation. These data support the hypothesis that Bmp signaling regulates craniofacial skeletal development by balancing self-renewal and differentiation pathways in CNC progenitors. PMID- 22219354 TI - Drosophila Polycomb complexes restrict neuroblast competence to generate motoneurons. AB - Similar to mammalian neural progenitors, Drosophila neuroblasts progressively lose competence to make early-born neurons. In neuroblast 7-1 (NB7-1), Kruppel (Kr) specifies the third-born U3 motoneuron and Kr misexpression induces ectopic U3 cells. However, competence to generate U3 cells is limited to early divisions, when the Eve(+) U motoneurons are produced, and competence is lost when NB7-1 transitions to making interneurons. We have found that Polycomb repressor complexes (PRCs) are necessary and sufficient to restrict competence in NB7-1. PRC loss of function extends the ability of Kr to induce U3 fates and PRC gain of function causes precocious loss of competence to make motoneurons. PRCs also restrict competence to make HB9(+) Islet(+) motoneurons in another neuroblast that undergoes a motoneuron-to-interneuron transition, NB3-1. In contrast to the regulation of motoneuron competence, PRC activity does not affect the production of Eve(+) interneurons by NB3-3, HB9(+) Islet(+) interneurons by NB7-3, or Dbx(+) interneurons by multiple neuroblasts. These findings support a model in which PRCs establish motoneuron-specific competence windows in neuroblasts that transition from motoneuron to interneuron production. PMID- 22219355 TI - Culture does account for variation in game behavior. PMID- 22219356 TI - Analysis of sirtuin 1 expression reveals a molecular explanation of IL-2-mediated reversal of T-cell tolerance. AB - The type III histone deacetylase sirtuin 1 (Sirt1) is a suppressor of both innate and adoptive immune responses. We have recently found that Sirt1 expression is highly induced in anergic T cells. However, the transcriptional program to regulate Sirt1 expression in T cells remains uncharacterized. Here we report that the early responsive genes 2 and 3, which can be up-regulated by T-cell receptor mediated activation of nuclear factor of activated T-cell transcription factors and are involved in peripheral T-cell tolerance, bind to the sirt1 promoter to transcript sirt1 mRNA. In addition, the forkhead transcription factor, FoxO3a, interacts with early responsive genes 2/3 on the sirt1 promoter to synergistically regulate Sirt1 expression. Interestingly, IL-2, a cytokine that can reverse T-cell anergy, suppresses sirt1 transcription by sequestering FoxO3a to the cytoplasm through activating the PI3K-AKT pathway. Expression of the constitutively active form of FoxO3a blocks IL-2-mediated reversal of T-cell tolerance by retaining sirt1 expression. Our findings here provide a molecular explanation of IL-2-mediated reversion of T-cell anergy. PMID- 22219357 TI - GluN2B subunit deletion reveals key role in acute and chronic ethanol sensitivity of glutamate synapses in bed nucleus of the stria terminalis. AB - The bed nucleus of the stria terminalis (BNST) is a critical region for alcohol/drug-induced negative affect and stress-induced reinstatement. NMDA receptor (NMDAR)-dependent plasticity, such as long-term potentiation (LTP), has been postulated to play key roles in alcohol and drug addiction; yet, to date, little is understood regarding the mechanisms underlying LTP of the BNST, or its regulation by ethanol. Acute and chronic exposure to ethanol modulates glutamate transmission via actions on NMDARs. Despite intense investigation, tests of subunit specificity of ethanol actions on NMDARs using pharmacological approaches have produced mixed results. Thus, we use a conditional GluN2B KO mouse line to assess both basal and ethanol-dependent function of this subunit at glutamate synapses in the BNST. Deletion of GluN2B eliminated LTP, as well as actions of ethanol on NMDAR function. Further, we show that chronic ethanol exposure enhances LTP formation in the BNST. Using KO-validated pharmacological approaches with Ro25-6981 and memantine, we provide evidence suggesting that chronic ethanol exposure enhances LTP in the BNST via paradoxical extrasynaptic NMDAR involvement. These findings demonstrate that GluN2B is a key point of regulation for ethanol's actions and suggest a unique role of extrasynaptic GluN2B containing receptors in facilitating LTP. PMID- 22219358 TI - Behavioral study of whisker-mediated vibration sensation in rats. AB - Rats use their vibrissal sensory system to collect information about the nearby environment. They can accurately and rapidly identify object location, shape, and surface texture. Which features of whisker motion does the sensory system extract to construct sensations? We addressed this question by training rats to make discriminations between sinusoidal vibrations simultaneously presented to the left and right whiskers. One set of rats learned to reliably identify which of two vibrations had higher frequency (f(1) vs. f(2)) when amplitudes were equal. Another set of rats learned to reliably identify which of two vibrations had higher amplitude (A(1) vs. A(2)) when frequencies were equal. Although these results indicate that both elemental features contribute to the rats' sensation, a further test found that the capacity to discriminate A and f was reduced to chance when the difference in one feature was counterbalanced by the difference in the other feature: Rats could not discriminate amplitude or frequency whenever A(1)f(1) = A(2)f(2). Thus, vibrations were sensed as the product Af rather than as separable elemental features, A and f. The product Af is proportional to a physical entity, the mean speed. Analysis of performance revealed that rats extracted more information about differences in Af than predicted by the sum of the information in elemental differences. These behavioral experiments support the predictions of earlier physiological studies by demonstrating that rats are "blind" to the elemental features present in a sinusoidal whisker vibration; instead, they perceive a composite feature, the speed of whisker motion. PMID- 22219359 TI - C3-dependent mechanism of microglial priming relevant to multiple sclerosis. AB - Microglial priming predisposes the brain to neurodegeneration and affects disease progression. The signal to switch from the quiescent to the primed state is unknown. We show that deleting the C3 convertase regulator complement receptor 1 related protein y (Crry) induces microglial priming. Mice that were double knockout for Crry and either C3 or factor B did not show priming, demonstrating dependence on alternative pathway activation. Colocalization of C3b/iC3b and CR3 implicated the CR3/iC3b interaction in priming. Systemic lipopolysaccharide challenge overactivated primed microglia with florid expression of proinflammatory molecules, which were blocked by complement inhibition. Relevance for neurodegenerative disease is exemplified by human multiple sclerosis (MS) and by experimental autoimmune encephalomyelitis (EAE), a model of MS. In human MS, microglial priming was evident in perilesional white matter, in close proximity to C3b/iC3b deposits. EAE was accelerated and exacerbated in Crry-deficient mice, and was dependent on C activation. In summary, C3-dependent microglial priming confers susceptibility to other challenges. Our observations are relevant to progression in MS and other neurological diseases exacerbated by acute insults. PMID- 22219360 TI - Human medial gastrocnemius force-velocity behavior shifts with locomotion speed and gait. AB - Humans walk and run over a wide range of speeds with remarkable efficiency. For steady locomotion, moving at different speeds requires the muscle-tendon units of the leg to modulate the amount of mechanical power the limb absorbs and outputs in each step. How individual muscles adapt their behavior to modulate limb power output has been examined using computer simulation and animal models, but has not been studied in vivo in humans. In this study, we used a combination of ultrasound imaging and motion analysis to examine how medial gastrocnemius (MG) muscle-tendon unit behavior is adjusted to meet the varying mechanical demands of different locomotor speeds during walking and running in humans. The results highlighted key differences in MG fascicle-shortening velocity with both locomotor speed and gait. Fascicle-shortening velocity at the time of peak muscle force production increased with walking speed, impairing the ability of the muscle to produce high peak forces. Switching to a running gait at 2.0 m.s(-1) caused fascicle shortening at the time of peak force production to shift to much slower velocities. This velocity shift facilitated a large increase in peak muscle force and an increase in MG power output. MG fascicle velocity may be a key factor that limits the speeds humans choose to walk at, and may explain the transition from walking to running. This finding is consistent with previous modeling studies. PMID- 22219361 TI - Promiscuous archaeal ATP synthase concurrently coupled to Na+ and H+ translocation. AB - ATP synthases are the primary source of ATP in all living cells. To catalyze ATP synthesis, these membrane-associated complexes use a rotary mechanism powered by the transmembrane diffusion of ions down a concentration gradient. ATP synthases are assumed to be driven either by H(+) or Na(+), reflecting distinct structural motifs in their membrane domains, and distinct metabolisms of the host organisms. Here, we study the methanogenic archaeon Methanosarcina acetivorans using assays of ATP hydrolysis and ion transport in inverted membrane vesicles, and experimentally demonstrate that the rotary mechanism of its ATP synthase is coupled to the concurrent translocation of both H(+) and Na(+) across the membrane under physiological conditions. Using free-energy molecular simulations, we explain this unprecedented observation in terms of the ion selectivity of the binding sites in the membrane rotor, which appears to have been tuned via amino acid substitutions so that ATP synthesis in M. acetivorans can be driven by the H(+) and Na(+) gradients resulting from methanogenesis. We propose that this promiscuity is a molecular mechanism of adaptation to life at the thermodynamic limit. PMID- 22219362 TI - Cullin-3 regulates late endosome maturation. AB - Cullin-3 (Cul3) functions as a scaffolding protein in the Bric-a-brac, Tramtrack, Broad-complex (BTB)-Cul3-Rbx1 ubiquitin E3 ligase complex. Here, we report a previously undescribed role for Cul3 complexes in late endosome (LE) maturation. RNAi-mediated depletion of Cul3 results in a trafficking defect of two cargoes of the endolysosomal pathway, influenza A virus (IAV) and epidermal growth factor receptor (EGFR). IAV is able to reach an acidic endosomal compartment, coinciding with LE/lysosome (LY) markers. However, it remains trapped or the capsid is unable to uncoat after penetration into the cytosol. Similarly, activation and subsequent ubiquitination of EGFR appear normal, whereas downstream EGFR degradation is delayed and its ligand EGF accumulates in LE/LYs. Indeed, Cul3 depleted cells display severe morphological defects in LEs that could account for these trafficking defects; they accumulate acidic LE/LYs, and some cells become highly vacuolated, with enlarged Rab7-positive endosomes. Together, these results suggest a crucial role of Cul3 in regulating late steps in the endolysosomal trafficking pathway. PMID- 22219364 TI - Requirements of transcription factor Smad-dependent and -independent TGF-beta signaling to control discrete T-cell functions. AB - TGF-beta modulates immune response by suppressing non-regulatory T (Treg) function and promoting Treg function. The question of whether TGF-beta achieves distinct effects on non-Treg and Treg cells through discrete signaling pathways remains outstanding. In this study, we investigated the requirements of Smad dependent and -independent TGF-beta signaling for T-cell function. Smad2 and Smad3 double deficiency in T cells led to lethal inflammatory disorder in mice. Non-Treg cells were spontaneously activated and produced effector cytokines in vivo on deletion of both Smad2 and Smad3. In addition, TGF-beta failed to suppress T helper differentiation efficiently and to promote induced Treg generation of non-Treg cells lacking both Smad2 and Smad3, suggesting that Smad dependent signaling is obligatory to mediate TGF-beta function in non-Treg cells. Unexpectedly, however, the development, homeostasis, and function of Treg cells remained intact in the absence of Smad2 and Smad3, suggesting that the Smad independent pathway is important for Treg function. Indeed, Treg-specific deletion of TGF-beta-activated kinase 1 led to failed Treg homeostasis and lethal immune disorder in mice. Therefore, Smad-dependent and -independent TGF-beta signaling discretely controls non-Treg and Treg function to modulate immune tolerance and immune homeostasis. PMID- 22219366 TI - Evolution of patterns on Conus shells. AB - The pigmentation patterns of shells in the genus Conus can be generated by a neural-network model of the mantle. We fit model parameters to the shell pigmentation patterns of 19 living Conus species for which a well resolved phylogeny is available. We infer the evolutionary history of these parameters and use these results to infer the pigmentation patterns of ancestral species. The methods we use allow us to characterize the evolutionary history of a neural network, an organ that cannot be preserved in the fossil record. These results are also notable because the inferred patterns of ancestral species sometimes lie outside the range of patterns of their living descendants, and illustrate how development imposes constraints on the evolution of complex phenotypes. PMID- 22219363 TI - Enhanced HIV-1 neutralization by antibody heteroligation. AB - Passive transfer of broadly neutralizing human antibodies against HIV-1 protects macaques against infection. However, HIV-1 uses several strategies to escape antibody neutralization, including mutation of the gp160 viral surface spike, a glycan shield to block antibody access to the spike, and expression of a limited number of viral surface spikes, which interferes with bivalent antibody binding. The latter is thought to decrease antibody apparent affinity or avidity, thereby interfering with neutralizing activity. To test the idea that increasing apparent affinity might enhance neutralizing activity, we engineered bispecific anti-HIV-1 antibodies (BiAbs) that can bind bivalently by virtue of one scFv arm that binds to gp120 and a second arm to the gp41 subunit of gp160. The individual arms of the BiAbs preserved the binding specificities of the original anti-HIV IgG antibodies and together bound simultaneously to gp120 and gp41. Heterotypic bivalent binding enhanced neutralization compared with the parental antibodies. We conclude that antibody recognition and viral neutralization of HIV can be improved by heteroligation. PMID- 22219365 TI - Tiling genomes of pathogenic viruses identifies potent antiviral shRNAs and reveals a role for secondary structure in shRNA efficacy. AB - shRNAs can trigger effective silencing of gene expression in mammalian cells, thereby providing powerful tools for genetic studies, as well as potential therapeutic strategies. Specific shRNAs can interfere with the replication of pathogenic viruses and are currently being tested as antiviral therapies in clinical trials. However, this effort is hindered by our inability to systematically and accurately identify potent shRNAs for viral genomes. Here we apply a recently developed highly parallel sensor assay to identify potent shRNAs for HIV, hepatitis C virus (HCV), and influenza. We observe known and previously unknown sequence features that dictate shRNAs efficiency. Validation using HIV and HCV cell culture models demonstrates very high potency of the top-scoring shRNAs. Comparing our data with the secondary structure of HIV shows that shRNA efficacy is strongly affected by the secondary structure at the target RNA site. Artificially introducing secondary structure to the target site markedly reduces shRNA silencing. In addition, we observe that HCV has distinct sequence features that bias HCV-targeting shRNAs toward lower efficacy. Our results facilitate further development of shRNA based antiviral therapies and improve our understanding and ability to predict efficient shRNAs. PMID- 22219367 TI - Investigation of polymer electrolyte membrane chemical degradation and degradation mitigation using in situ fluorescence spectroscopy. AB - A fluorescent molecular probe, 6-carboxy fluorescein, was used in conjunction with in situ fluorescence spectroscopy to facilitate real-time monitoring of degradation inducing reactive oxygen species within the polymer electrolyte membrane (PEM) of an operating PEM fuel cell. The key requirements of suitable molecular probes for in situ monitoring of ROS are presented. The utility of using free radical scavengers such as CeO(2) nanoparticles to mitigate reactive oxygen species induced PEM degradation was demonstrated. The addition of CeO(2) to uncatalyzed membranes resulted in close to 100% capture of ROS generated in situ within the PEM for a period of about 7 h and the incorporation of CeO(2) into the catalyzed membrane provided an eightfold reduction in ROS generation rate. PMID- 22219368 TI - Strandwise translocation of a DNA glycosylase on undamaged DNA. AB - Base excision repair of genotoxic nucleobase lesions in the genome is critically dependent upon the ability of DNA glycosylases to locate rare sites of damage embedded in a vast excess of undamaged DNA, using only thermal energy to fuel the search process. Considerable interest surrounds the question of how DNA glycosylases translocate efficiently along DNA while maintaining their vigilance for target damaged sites. Here, we report the observation of strandwise translocation of 8-oxoguanine DNA glycosylase, MutM, along undamaged DNA. In these complexes, the protein is observed to translocate by one nucleotide on one strand while remaining untranslocated on the complementary strand. We further report that alterations of single base-pairs or a single amino acid substitution (R112A) can induce strandwise translocation. Molecular dynamics simulations confirm that MutM can translocate along DNA in a strandwise fashion. These observations reveal a previously unobserved mode of movement for a DNA-binding protein along the surface of DNA. PMID- 22219369 TI - Folding energy landscape of the thiamine pyrophosphate riboswitch aptamer. AB - Riboswitches are motifs in the untranslated regions (UTRs) of RNA transcripts that sense metabolite levels and modulate the expression of the corresponding genes for metabolite import, export, synthesis, or degradation. All riboswitches contain an aptamer: an RNA structure that, upon binding ligand, folds to expose or sequester regulatory elements in the adjacent sequence through alternative nucleotide pairing. The coupling between ligand binding and aptamer folding is central to the regulatory mechanisms of thiamine pyrophosphate (TPP) riboswitches and has not been fully characterized. Here, we show that TPP aptamer folding can be decomposed into ligand-independent and -dependent steps that correspond to the formation of secondary and tertiary structures, respectively. We reconstructed the full energy landscape for folding of the wild-type (WT) aptamer and measured perturbations of this landscape arising from mutations or ligand binding. We show that TPP binding proceeds in two steps, from a weakly to a strongly bound state. Our data imply a hierarchical folding sequence, and provide a framework for understanding molecular mechanism throughout the TPP riboswitch family. PMID- 22219370 TI - Exploring monovalent copper compounds with oxygen and hydrogen. AB - New important applications of copper metal, e.g., in the areas of hydrogen production, fuel cell operation, and spent nuclear fuel disposal, require accurate knowledge of the physical and chemical properties of stable and metastable copper compounds. Among the copper(I) compounds with oxygen and hydrogen, cuprous oxide Cu(2)O is the only one stable and the best studied. Other such compounds are less known (CuH) or totally unknown (CuOH) due to their instability relative to the oxide. Here we combine quantum-mechanical calculations with experimental studies to search for possible compounds of monovalent copper. Cuprous hydride (CuH) and cuprous hydroxide (CuOH) are proved to exist in solid form. We establish the chemical and physical properties of these compounds, thereby filling the existing gaps in our understanding of hydrogen- and oxygen-related phenomena in Cu metal. PMID- 22219372 TI - Splash singularity for water waves. AB - We exhibit smooth initial data for the two-dimensional (2D) water-wave equation for which we prove that smoothness of the interface breaks down in finite time. Moreover, we show a stability result together with numerical evidence that there exist solutions of the 2D water-wave equation that start from a graph, turn over, and collapse in a splash singularity (self-intersecting curve in one point) in finite time. PMID- 22219371 TI - Structural and mechanistic insight into N-glycan processing by endo-alpha mannosidase. AB - N-linked glycans play key roles in protein folding, stability, and function. Biosynthetic modification of N-linked glycans, within the endoplasmic reticulum, features sequential trimming and readornment steps. One unusual enzyme, endo alpha-mannosidase, cleaves mannoside linkages internally within an N-linked glycan chain, short circuiting the classical N-glycan biosynthetic pathway. Here, using two bacterial orthologs, we present the first structural and mechanistic dissection of endo-alpha-mannosidase. Structures solved at resolutions 1.7-2.1 A reveal a (beta/alpha)(8) barrel fold in which the catalytic center is present in a long substrate-binding groove, consistent with cleavage within the N-glycan chain. Enzymatic cleavage of authentic Glc(1/3)Man(9)GlcNAc(2) yields Glc(1/3) Man. Using the bespoke substrate alpha-Glc-1,3-alpha-Man fluoride, the enzyme was shown to act with retention of anomeric configuration. Complexes with the established endo-alpha-mannosidase inhibitor alpha-Glc-1,3-deoxymannonojirimycin and a newly developed inhibitor, alpha-Glc-1,3-isofagomine, and with the reducing end product alpha-1,2-mannobiose structurally define the -2 to +2 subsites of the enzyme. These structural and mechanistic data provide a foundation upon which to develop new enzyme inhibitors targeting the hijacking of N-glycan synthesis in viral disease and cancer. PMID- 22219373 TI - TM9/Phg1 and SadA proteins control surface expression and stability of SibA adhesion molecules in Dictyostelium. AB - TM9 proteins form a family of conserved proteins with nine transmembrane domains essential for cellular adhesion in many biological systems, but their exact role in this process remains unknown. In this study, we found that genetic inactivation of the TM9 protein Phg1A dramatically decreases the surface levels of the SibA adhesion molecule in Dictyostelium amoebae. This is due to a decrease in sibA mRNA levels, in SibA protein stability, and in SibA targeting to the cell surface. A similar phenotype was observed in cells devoid of SadA, a protein that does not belong to the TM9 family but also exhibits nine transmembrane domains and is essential for cellular adhesion. A contact site A (csA)-SibA chimeric protein comprising only the transmembrane and cytosolic domains of SibA and the extracellular domain of the Dictyostelium surface protein csA also showed reduced stability and relocalization to endocytic compartments in phg1A knockout cells. These results indicate that TM9 proteins participate in cell adhesion by controlling the levels of adhesion proteins present at the cell surface. PMID- 22219374 TI - Mammalian Atg2 proteins are essential for autophagosome formation and important for regulation of size and distribution of lipid droplets. AB - Macroautophagy is an intracellular degradation system by which cytoplasmic materials are enclosed by the autophagosome and delivered to the lysosome. Autophagosome formation is considered to take place on the endoplasmic reticulum and involves functions of autophagy-related (Atg) proteins. Here, we report the identification and characterization of mammalian Atg2 homologues Atg2A and Atg2B. Simultaneous silencing of Atg2A and Atg2B causes a block in autophagic flux and accumulation of unclosed autophagic structures containing most Atg proteins. Atg2A localizes on the autophagic membrane, as well as on the surface of lipid droplets. The Atg2A region containing amino acids 1723-1829, which shows relatively high conservation among species, is required for localization to both the autophagic membrane and lipid droplet and is also essential for autophagy. Depletion of both Atg2A and Atg2B causes clustering of enlarged lipid droplets in an autophagy-independent manner. These data suggest that mammalian Atg2 proteins function both in autophagosome formation and regulation of lipid droplet morphology and dispersion. PMID- 22219375 TI - The tumor suppressor Lgl1 regulates NMII-A cellular distribution and focal adhesion morphology to optimize cell migration. AB - The Drosophila tumor suppressor Lethal (2) giant larvae (Lgl) regulates the apical-basal polarity in epithelia and asymmetric cell division. However, little is known about the role of Lgl in cell polarity in migrating cells. In this study we show direct physiological interactions between the mammalian homologue of Lgl (Lgl1) and the nonmuscle myosin II isoform A (NMII-A). We demonstrate that Lgl1 and NMII-A form a complex in vivo and provide data that Lgl1 inhibits NMII-A filament assembly in vitro. Furthermore, depletion of Lgl1 results in the unexpected presence of NMII-A in the cell leading edge, a region that is not usually occupied by this protein, suggesting that Lgl1 regulates the cellular localization of NMII-A. Finally, we show that depletion of Lgl1 affects the size and number of focal adhesions, as well as cell polarity, membrane dynamics, and the rate of migrating cells. Collectively these findings indicate that Lgl1 regulates the polarity of migrating cells by controlling the assembly state of NMII-A, its cellular localization, and focal adhesion assembly. PMID- 22219376 TI - Essential roles of zebrafish bmp2a, fgf10, and fgf24 in the specification of the ventral pancreas. AB - In vertebrates, pancreas and liver arise from bipotential progenitors located in the embryonic gut endoderm. Bone morphogenic protein (BMP) and fibroblast growth factor (FGF) signaling pathways have been shown to induce hepatic specification while repressing pancreatic fate. Here we show that BMP and FGF factors also play crucial function, at slightly later stages, in the specification of the ventral pancreas. By analyzing the pancreatic markers pdx1, ptf1a, and hlxb9la in different zebrafish models of BMP loss of function, we demonstrate that the BMP pathway is required between 20 and 24 h postfertilization to specify the ventral pancreatic bud. Knockdown experiments show that bmp2a, expressed in the lateral plate mesoderm at these stages, is essential for ventral pancreas specification. Bmp2a action is not restricted to the pancreatic domain and is also required for the proper expression of hepatic markers. By contrast, through the analysis of fgf10(-/-); fgf24(-/-) embryos, we reveal the specific role of these two FGF ligands in the induction of the ventral pancreas and in the repression of the hepatic fate. These mutants display ventral pancreas agenesis and ectopic masses of hepatocytes. Overall, these data highlight the dynamic role of BMP and FGF in the patterning of the hepatopancreatic region. PMID- 22219377 TI - Single-molecule imaging of translational output from individual RNA granules in neurons. AB - Dendritic RNAs are localized and translated in RNA granules. Here we use single molecule imaging to count the number of RNA molecules in each granule and to record translation output from each granule using Venus fluorescent protein as a reporter. For RNAs encoding activity-regulated cytoskeletal-associated protein (ARC) or fragile X mental retardation protein (FMRP), translation events are spatially clustered near individual granules, and translational output from individual granules is either sporadic or bursty. The probability of bursty translation is greater for Venus-FMRP RNA than for Venus-ARC RNA and is increased in Fmr1-knockout neurons compared to wild-type neurons. Dihydroxyphenylglycine (DHPG) increases the rate of sporadic translation and decreases bursty translation for Venus-FMRP and Venus-ARC RNAs. Single-molecule imaging of translation in individual granules provides new insight into molecular, spatial, and temporal regulation of translation in granules. PMID- 22219378 TI - EPI64 interacts with Slp1/JFC1 to coordinate Rab8a and Arf6 membrane trafficking. AB - Cell function requires the integration of cytoskeletal organization and membrane trafficking. Small GTP-binding proteins are key regulators of these processes. We find that EPI64, an apical microvillar protein with a Tre-2/Bub2/Cdc16 (TBC) domain that stabilizes active Arf6 and has RabGAP activity, regulates Arf6 dependent membrane trafficking. Expression of EPI64 in HeLa cells induces the accumulation of actin-coated vacuoles, a distinctive phenotype seen in cells expressing constitutively active Arf6. Expression of EPI64 with defective RabGAP activity does not induce vacuole formation. Coexpression of Rab8a suppresses the vacuole phenotype induced by EPI64, and EPI64 expression lowers the level of Rab8 GTP in cells, strongly suggesting that EPI64 has GAP activity toward Rab8a. JFC1, an effector for Rab8a, colocalizes with and binds directly to a C-terminal region of EPI64. Together this region and the N-terminal TBC domain of EPI64 are required for the accumulation of vacuoles. Through analysis of mutants that uncouple JFC1 from either EPI64 or from Rab8-GTP, our data suggest a model in which EPI64 binds JFC1 to recruit Rab8a-GTP for deactivation by the RabGAP activity of EPI64. We propose that EPI64 regulates membrane trafficking both by stabilizing Arf6-GTP and by inhibiting the recycling of membrane through the tubular endosome by decreasing Rab8a-GTP levels. PMID- 22219379 TI - Kar2p availability defines distinct forms of endoplasmic reticulum stress in living cells. AB - Accumulation of misfolded secretory proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) stress pathway. To enhance secretory protein folding and promote adaptation to stress, the UPR upregulates ER chaperone levels, including BiP. Here we describe chromosomal tagging of KAR2, the yeast homologue of BiP, with superfolder green fluorescent protein (sfGFP) to create a multifunctional endogenous reporter of the ER folding environment. Changes in Kar2p-sfGFP fluorescence levels directly correlate with UPR activity and represent a robust reporter for high-throughput analysis. A novel second feature of this reporter is that photobleaching microscopy (fluorescence recovery after photobleaching) of Kar2p-sfGFP mobility reports on the levels of unfolded secretory proteins in individual cells, independent of UPR status. Kar2p-sfGFP mobility decreases upon treatment with tunicamycin or dithiothreitol, consistent with increased levels of unfolded proteins and the incorporation of Kar2p-sfGFP into slower-diffusing complexes. During adaptation, we observe a significant lag between down-regulation of the UPR and resolution of the unfolded protein burden. Finally, we find that Kar2p-sfGFP mobility significantly increases upon inositol withdrawal, which also activates the UPR, apparently independent of unfolded protein levels. Thus Kar2p mobility represents a powerful new tool capable of distinguishing between the different mechanisms leading to UPR activation in living cells. PMID- 22219380 TI - Direct inhibition of myosin II effectively blocks glioma invasion in the presence of multiple motogens. AB - Anaplastic gliomas, the most common and malignant of primary brain tumors, frequently contain activating mutations and amplifications in promigratory signal transduction pathways. However, targeting these pathways with individual signal transduction inhibitors does not appreciably reduce tumor invasion, because these pathways are redundant; blockade of any one pathway can be overcome by stimulation of another. This implies that a more effective approach would be to target a component at which these pathways converge. In this study, we have investigated whether the molecular motor myosin II represents such a target by examining glioma invasion in a series of increasingly complex models that are sensitive to platelet-derived growth factor, epidermal growth factor, or both. Our results lead to two conclusions. First, malignant glioma cells are stimulated to invade brain through the activation of multiple signaling cascades not accounted for in simple in vitro assays. Second, even though there is a high degree of redundancy in promigratory signaling cascades in gliomas, blocking tumor invasion by directly targeting myosin II remains effective. Our results thus support our hypothesis that myosin II represents a point of convergence for signal transduction pathways that drive glioma invasion and that its inhibition cannot be overcome by other motility mechanisms. PMID- 22219381 TI - Choosing orientation: influence of cargo geometry and ActA polarization on actin comet tails. AB - Networks of polymerizing actin filaments can propel intracellular pathogens and drive movement of artificial particles in reconstituted systems. While biochemical mechanisms activating actin network assembly have been well characterized, it remains unclear how particle geometry and large-scale force balance affect emergent properties of movement. We reconstituted actin-based motility using ellipsoidal beads resembling the geometry of Listeria monocytogenes. Beads coated uniformly with the L. monocytogenes ActA protein migrated equally well in either of two distinct orientations, with their long axes parallel or perpendicular to the direction of motion, while intermediate orientations were unstable. When beads were coated with a fluid lipid bilayer rendering ActA laterally mobile, beads predominantly migrated with their long axes parallel to the direction of motion, mimicking the orientation of motile L. monocytogenes. Generating an accurate biophysical model to account for our observations required the combination of elastic-propulsion and tethered-ratchet actin-polymerization theories. Our results indicate that the characteristic orientation of L. monocytogenes must be due to polarized ActA rather than intrinsic actin network forces. Furthermore, viscoelastic stresses, forces, and torques produced by individual actin filaments and lateral movement of molecular complexes must all be incorporated to correctly predict large-scale behavior in the actin-based movement of nonspherical particles. PMID- 22219382 TI - Actin retrograde flow and actomyosin II arc contraction drive receptor cluster dynamics at the immunological synapse in Jurkat T cells. AB - Actin retrograde flow and actomyosin II contraction have both been implicated in the inward movement of T cell receptor (TCR) microclusters and immunological synapse formation, but no study has integrated and quantified their relative contributions. Using Jurkat T cells expressing fluorescent myosin IIA heavy chain and F-tractin-a novel reporter for F-actin-we now provide direct evidence that the distal supramolecular activation cluster (dSMAC) and peripheral supramolecular activation cluster (pSMAC) correspond to lamellipodial (LP) and lamellar (LM) actin networks, respectively, as hypothesized previously. Our images reveal concentric and contracting actomyosin II arcs/rings at the LM/pSMAC. Moreover, the speeds of centripetally moving TCR microclusters correspond very closely to the rates of actin retrograde flow in the LP/dSMAC and actomyosin II arc contraction in the LM/pSMAC. Using cytochalasin D and jasplakinolide to selectively inhibit actin retrograde flow in the LP/dSMAC and blebbistatin to selectively inhibit actomyosin II arc contraction in the LM/pSMAC, we demonstrate that both forces are required for centripetal TCR microcluster transport. Finally, we show that leukocyte function-associated antigen 1 clusters accumulate over time at the inner aspect of the LM/pSMAC and that this accumulation depends on actomyosin II contraction. Thus actin retrograde flow and actomyosin II arc contraction coordinately drive receptor cluster dynamics at the immunological synapse. PMID- 22219383 TI - IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin. AB - Endoplasmic reticulum (ER) is responsible for folding of secreted and membrane proteins in eukaryotic cells. Disruption of ER protein folding leads to ER stress. Chronic ER stress can cause cell death and is proposed to underlie the pathogenesis of many human diseases. Inositol-requiring enzyme 1 (IRE1) directs a key unfolded protein response signaling pathway that controls the fidelity of ER protein folding. IRE1 signaling may be particularly helpful in preventing chronic ER stress and cell injury by alleviating protein misfolding in the ER. To examine this, we used a chemical-genetic approach to selectively activate IRE1 in mammalian cells and tested how artificial IRE1 signaling affected the fate of misfolded P23H rhodopsin linked to photoreceptor cell death. We found that IRE1 signaling robustly promoted the degradation of misfolded P23H rhodopsin without affecting its wild-type counterpart. We also found that IRE1 used both proteasomal and lysosomal degradation pathways to remove P23H rhodopsin. Surprisingly, when one degradation pathway was compromised, IRE1 signaling could still promote misfolded rhodopsin degradation using the remaining pathway. Last, we showed that IRE1 signaling also reduced levels of several other misfolded rhodopsins with lesser effects on misfolded cystic fibrosis transmembrane conductance regulator. Our findings reveal the diversity of proteolytic mechanisms used by IRE1 to eliminate misfolded rhodopsin. PMID- 22219384 TI - Are somatic symptoms of depression better predictors of cardiac events than cognitive symptoms in coronary heart disease? AB - Several recent studies have found that somatic symptoms of depression predict cardiac events in patients with established coronary heart disease but cognitive symptoms of depression do not. However, other studies have not supported this finding, and the research in this area is complicated by methodological differences and inconsistencies in the classification of "cognitive" and "somatic" symptoms. In addition, somatic symptoms are more common than cognitive symptoms in cardiac patients and are often associated with more severe depression. These factors may confound the relationship between somatic symptoms and cardiac outcomes. Some reasons why somatic symptoms may be more common than cognitive symptoms in cardiac patients are considered, as well as whether somatic symptoms are likely to be symptoms of depression or of medical illness. Finally, some directions for future research are proposed. PMID- 22219387 TI - Wunderlich syndrome. PMID- 22219386 TI - Inhibition of the Nedd8 system sensitizes cells to DNA interstrand cross-linking agents. AB - The Fanconi anemia pathway is required for repair of DNA interstrand cross-links (ICL). Fanconi anemia pathway-deficient cells are hypersensitive to DNA ICL inducing drugs such as cisplatin. Conversely, hyperactivation of the Fanconi anemia pathway is a mechanism that may underlie cellular resistance to DNA ICL agents. Modulating FANCD2 monoubiquitination, a key step in the Fanconi anemia pathway, may be an effective therapeutic approach to conferring cellular sensitivity to ICL agents. Here, we show that inhibition of the Nedd8 conjugation system increases cellular sensitivity to DNA ICL-inducing agents. Mechanistically, the Nedd8 inhibition, either by siRNA-mediated knockdown of Nedd8-conjugating enzymes or treatment with a Nedd8-activating enzyme inhibitor MLN4924, suppressed DNA damage-induced FANCD2 monoubiquitination and CHK1 phosphorylation. Our data indicate that inhibition of the Fanconi anemia pathway is largely responsible for the heightened cellular sensitivity to DNA ICLs upon Nedd8 inhibition. These results suggest that a combination of Nedd8 inhibition with ICL-inducing agents may be an effective strategy for sensitizing a subset of drug-resistant cancer cells. PMID- 22219388 TI - Obatoclax and lapatinib interact to induce toxic autophagy through NOXA. AB - Prior studies demonstrated that resistance to the ERBB1/2 inhibitor lapatinib could be overcome by the B cell CLL/lymphoma-2 (BCL-2) family antagonist obatoclax (GX15-070). Coadministration of lapatinib with obatoclax caused synergistic cell killing by eliciting autophagic cell death that was dependent upstream on mitochondrial reactive oxygen species generation and increased p62 levels and downstream on activation of p38 mitogen-activated protein kinase and inactivation of mammalian target of rapamycin. By immunohistochemical analysis, in drug combination-treated cells, microtubule-associated protein light chain 3 (LC3) associated with mitochondrial (cytochrome c oxidase), autophagosome (p62), and autolysosome (lysosomal associated membrane protein 2) proteins. Treatment of cells with 3-methyladenine or knockdown of beclin 1 was protective, whereas chloroquine treatment had no protective effect. Expression of myeloid cell leukemia-1 (MCL-1), compared with that of BCL-2 or BCL-2-related gene long isoform, protected against drug combination lethality. Lapatinib and obatoclax initiated autophagy depended on NOXA-mediated displacement of the prosurvival BCL 2 family member, MCL-1, from beclin 1, which was essential for the initiation of autophagy. Taken together, our data argue that lapatinib and obatoclax-induced toxic autophagy is due to impaired autophagic degradation, and this disturbance of autophagic flux leads to an accumulation of toxic proteins and loss of mitochondrial function. PMID- 22219389 TI - International Society for Wildlife Endocrinology: the future of endocrine measures for reproductive science, animal welfare and conservation biology. AB - Hormone analysis is a precise and widely accepted tool for monitoring reproductive function and responses to stressors. Although hormones are present and can be measured in various biological matrices, non-invasive methods have gained popularity over the past 30 years as a more practical approach for assessing ovarian, testicular and, more recently, adrenocortical activity in intractable wildlife species. Non-invasive hormone monitoring also has been key to understanding biological mechanisms related to observed behaviours of captive and free-ranging animals. Despite the increasing popularity of this research field, wildlife endocrinologists have not had a specific forum for sharing and discussing their latest findings, technical developments and common challenges. To provide such a communication platform, the International Society for Wildlife Endocrinology (ISWE) was established in 2010, followed by an international meeting held on 3-4 November 2011 at the Toronto Zoo, Canada. Over several sessions, keynote speakers and participants discussed recent developments of new and innovative methods for hormone monitoring, as well as the latest advances in basic endocrinology as applied to adrenal function, reproductive physiology, animal health, ecology and evolution. Here, we introduce ISWE to the scientific community and discuss how this new society will serve as a resource for wildlife endocrinologists worldwide. PMID- 22219390 TI - Eavesdropping and signal matching in visual courtship displays of spiders. AB - Eavesdropping on communication is widespread among animals, e.g. bystanders observing male-male contests, female mate choice copying and predator detection of prey cues. Some animals also exhibit signal matching, e.g. overlapping of competitors' acoustic signals in aggressive interactions. Fewer studies have examined male eavesdropping on conspecific courtship, although males could increase mating success by attending to others' behaviour and displaying whenever courtship is detected. In this study, we show that field-experienced male Schizocosa ocreata wolf spiders exhibit eavesdropping and signal matching when exposed to video playback of courting male conspecifics. Male spiders had longer bouts of interaction with a courting male stimulus, and more bouts of courtship signalling during and after the presence of a male on the video screen. Rates of courtship (leg tapping) displayed by individual focal males were correlated with the rates of the video exemplar to which they were exposed. These findings suggest male wolf spiders might gain information by eavesdropping on conspecific courtship and adjust performance to match that of rivals. This represents a novel finding, as these behaviours have previously been seen primarily among vertebrates. PMID- 22219391 TI - Olfactory kin recognition in a songbird. AB - The ability to recognize close relatives in order to cooperate or to avoid inbreeding is widespread across all taxa. One accepted mechanism for kin recognition in birds is associative learning of visual or acoustic cues. However, how could individuals ever learn to recognize unfamiliar kin? Here, we provide the first evidence for a novel mechanism of kin recognition in birds. Zebra finch (Taeniopygia guttata) fledglings are able to distinguish between kin and non-kin based on olfactory cues alone. Since olfactory cues are likely to be genetically based, this finding establishes a neglected mechanism of kin recognition in birds, particularly in songbirds, with potentially far-reaching consequences for both kin selection and inbreeding avoidance. PMID- 22219392 TI - Identification of two voltage-dependent anion channel-like protein sequences conserved in Kinetoplastida. AB - The eukaryotic porin superfamily consists of two families, voltage-dependent anion channel (VDAC) and Tom40, which are both located in the mitochondrial outer membrane. In Trypanosoma brucei, only a single member of the VDAC family has been described. We report the detection of two additional eukaryotic porin-like sequences in T. brucei. By bioinformatic means, we classify both as putative VDAC isoforms. PMID- 22219393 TI - A male-killing Wolbachia carries a feminizing factor and is associated with degradation of the sex-determining system of its host. AB - Endosymbiotic bacteria of the genus Wolbachia induce diverse reproductive alterations in their insect hosts. Wolbachia (wSca) infecting the moth Ostrinia scapulalis causes unusual male killing, in which males (genotype: ZZ) selectively die during embryonic and larval development, whereas females (genotype: ZW), in turn, selectively die when cured of infection. To gain insight into the interaction between wSca and the host, we analysed phenotypic and genetic sexes of the embryos and larvae of normal, wSca-infected, and infected-and-cured O. scapulalis by diagnosing the sex-specifically spliced transcripts of Osdsx-a homologue of the sex-determining gene doublesex-and sex chromatin in interphase nuclei, respectively. It was observed that the female-type Osdsx was expressed in the infected male (ZZ) progenies destined to die, whereas the male-type Osdsx was expressed in the cured female (ZW) progenies destined to die. These findings suggest that (i) wSca, a male killer, carries a genetic factor that feminizes the male host, (ii) the sex-determining system of the host is degraded, and (iii) a mismatch between the genetic and phenotypic sexes underlies the sex-specific death. PMID- 22219394 TI - An antiarch placoderm shows that pelvic girdles arose at the root of jawed vertebrates. AB - Almost all gnathostomes or jawed vertebrates (including osteichthyans, chondrichthyans, 'acanthodians' and most placoderms) possess paired pectoral and pelvic fins. To date, it has generally been believed that antiarch placoderms (extinct armoured jawed fishes from the Silurian-Devonian periods) lacked pelvic fins. The putative absence of pelvic fins is a key character bearing on the monophyly or paraphyly of placoderms. It also has far-reaching implications for studying the sequence of origin of pelvic girdles versus that of movable jaws in the course of vertebrate evolution. Parayunnanolepis xitunensis represents the only example of a primitive antiarch with extensive post-thoracic preservation, and its original description has been cited as confirming the primitive lack of pelvic fins in early antiarchs. Here, we present a revised description of Parayunnanolepis and offer the first unambiguous evidence for the presence of pelvic girdles in antiarchs. As antiarchs are placed at the base of the gnathostome radiation in several recent studies, our finding shows that all jawed vertebrates (including antiarch placoderms) primitively possess both pectoral and pelvic fins and that the pelvic fins did not arise within gnathostomes at a point subsequent to the origin of jaws. PMID- 22219395 TI - Integration of intrinsic muscle properties, feed-forward and feedback signals for generating and stabilizing hopping. AB - It was hypothesized that a tight integration of feed-forward and feedback-driven muscle activation with the characteristic intrinsic muscle properties is a key feature of locomotion in challenging environments. In this simulation study it was investigated whether a combination of feed-forward and feedback signals improves hopping stability compared with those simulations with one individual type of activation. In a reduced one-dimensional hopping model with a Hill-type muscle (one contractile element, neither serial nor parallel elastic elements), the level of detail of the muscle's force-length-velocity relation and the type of activation generation (feed-forward, feedback and combination of both) were varied to test their influence on periodic hopping. The stability of the hopping patterns was evaluated by return map analysis. It was found that the combination of feed-forward and proprioceptive feedback improved hopping stability. Furthermore, the nonlinear Hill-type representation of intrinsic muscle properties led to a faster reduction of perturbations than a linear approximation, independent of the type of activation. The results emphasize the ability of organisms to exploit the stabilizing properties of intrinsic muscle characteristics. PMID- 22219396 TI - Effect of magnetically simulated zero-gravity and enhanced gravity on the walk of the common fruitfly. AB - Understanding the effects of gravity on biological organisms is vital to the success of future space missions. Previous studies in Earth orbit have shown that the common fruitfly (Drosophila melanogaster) walks more quickly and more frequently in microgravity, compared with its motion on Earth. However, flight preparation procedures and forces endured on launch made it difficult to implement on the Earth's surface a control that exposed flies to the same sequence of major physical and environmental changes. To address the uncertainties concerning these behavioural anomalies, we have studied the walking paths of D. melanogaster in a pseudo-weightless environment (0g*) in our Earth based laboratory. We used a strong magnetic field, produced by a superconducting solenoid, to induce a diamagnetic force on the flies that balanced the force of gravity. Simultaneously, two other groups of flies were exposed to a pseudo hypergravity environment (2g*) and a normal gravity environment (1g*) within the spatially varying field. The flies had a larger mean speed in 0g* than in 1g*, and smaller in 2g*. The mean square distance travelled by the flies grew more rapidly with time in 0g* than in 1g*, and slower in 2g*. We observed no other clear effects of the magnetic field, up to 16.5 T, on the walks of the flies. We compare the effect of diamagnetically simulated weightlessness with that of weightlessness in an orbiting spacecraft, and identify the cause of the anomalous behaviour as the altered effective gravity. PMID- 22219397 TI - Small actions, big costs: the behavioural energetics of a commercially important invertebrate. AB - Anthropogenic disturbance of farmed animals can be detrimental by adversely affecting behaviours and metabolic rate, potentially reducing their commercial value. However, relatively little is known about the normal behavioural time budgets and associated metabolism of many such species, particularly for example pectinid bivalves, which use anaerobic metabolism during periods of short-burst activity. In the present study, we used the accelerometry technique to measure scallop overall dynamic body acceleration in combination with respirometry in order to obtain and compare the behavioural time budgets and associated metabolism of 10 scallops, Pecten maximus, in an aquaculture hatchery and 10 in the wild. Scallops in the wild typically spent only 0.1 per cent of the time moving (less than 2 min d(-1)), yet, on average, the estimated metabolism of such movement represented 16.8 per cent of daily energy expenditure. Furthermore, owing to their reliance on anaerobic pathways during such activity, movement resulted in the wild scallops having a raised metabolic rate for, on average, an estimated 7.8 per cent of the time, during which oxygen debts accumulated during movement were paid off. Hatchery scallops also typically spent only 0.1 per cent of the time moving but estimated metabolism of such movement represented 41.8 per cent of daily energy expenditure. Estimated mean daily metabolism of scallops in the hatchery was significantly higher than scallops in the wild (169.1 versus 120.7 mg O(2) d(-1)) because anthropogenic disturbance in the hatchery caused energetically costly non-feeding behaviours. Consequently, hatchery scallops also spent a far greater amount of time with a raised metabolic rate (an estimated 26.6% of the time) than wild scallops. While short-term bursts of movement in pectinid bivalves may appear innocuous, they result in large expenditures of energy and an oxygen debt that is paid off over long periods of time that together limit further movement. These findings have implications for the farming industry; mitigating anthropogenic disturbances to farmed colonies may minimize non-feeding behaviours and hence maximize growth rates by reducing the costs of such movements and increasing the opportunity to feed. PMID- 22219398 TI - Design and analysis of DNA strand displacement devices using probabilistic model checking. AB - Designing correct, robust DNA devices is difficult because of the many possibilities for unwanted interference between molecules in the system. DNA strand displacement has been proposed as a design paradigm for DNA devices, and the DNA strand displacement (DSD) programming language has been developed as a means of formally programming and analysing these devices to check for unwanted interference. We demonstrate, for the first time, the use of probabilistic verification techniques to analyse the correctness, reliability and performance of DNA devices during the design phase. We use the probabilistic model checker prism, in combination with the DSD language, to design and debug DNA strand displacement components and to investigate their kinetics. We show how our techniques can be used to identify design flaws and to evaluate the merits of contrasting design decisions, even on devices comprising relatively few inputs. We then demonstrate the use of these components to construct a DNA strand displacement device for approximate majority voting. Finally, we discuss some of the challenges and possible directions for applying these methods to more complex designs. PMID- 22219399 TI - Computational modelling of cell chain migration reveals mechanisms that sustain follow-the-leader behaviour. AB - Follow-the-leader chain migration is a striking cell migratory behaviour observed during vertebrate development, adult neurogenesis and cancer metastasis. Although cell-cell contact and extracellular matrix (ECM) cues have been proposed to promote this phenomenon, mechanisms that underlie chain migration persistence remain unclear. Here, we developed a quantitative agent-based modelling framework to test mechanistic hypotheses of chain migration persistence. We defined chain migration and its persistence based on evidence from the highly migratory neural crest model system, where cells within a chain extend and retract filopodia in short-lived cell contacts and move together as a collective. In our agent-based simulations, we began with a set of agents arranged as a chain and systematically probed the influence of model parameters to identify factors critical to the maintenance of the chain migration pattern. We discovered that chain migration persistence requires a high degree of directional bias in both lead and follower cells towards the target. Chain migration persistence was also promoted when lead cells maintained cell contact with followers, but not vice-versa. Finally, providing a path of least resistance in the ECM was not sufficient alone to drive chain persistence. Our results indicate that chain migration persistence depends on the interplay of directional cell movement and biased cell-cell contact. PMID- 22219400 TI - Differences in psychological perception of lung cancer between patients, medical staff and medical students. AB - OBJECTIVES: In clinical practice, medical staff is often unaware that what they think about patient's disease differs much from the perceptions and feelings of the patient. The aim of the study was to analyse the differences in psychological perception of lung cancer between patients treated with combined regimen for lung cancer (n = 30), medical staff (n = 94) and medical students (n = 303). METHODS: A total of 427 persons were enrolled in this questionnaire study using Imagination and Perception of Illness Scale (IPIS) by Sak. The IPIS scale items described: loss of motivation to carry out specific activities (eight items), mental sphere destruction (six items), physical sphere destruction (eight items), pessimism (four items), being a burden to others (three items) and loss of control over the illness (three items). A seven-point scale from '0', meaning the choice of maximum positive feature, to '6', meaning the choice of maximum negative feature, was used. The higher result obtained within a given factor signified the more negative perception of the illness. RESULTS: In all IPIS items, the results among patients were significantly lower than among medical staff or students (P = 0.018 and P = 0.001, respectively). Medical staff and students perceive lung cancer as causing more profound destruction in patient's mental and physical spheres than patients do. CONCLUSIONS: Patients treated for lung cancer with combined regimen perceive their disease more optimistically than what is imagined by medical staff and students, and may underestimate the threat. It may be explained by psychological adaptation of patients to their disease during prolonged treatment. We believe that informing lung cancer patients in detail about their illness should be recommended to enhance self-awareness and doctor-patient cooperation. PMID- 22219402 TI - Angiographic evaluation of flow distribution in sequential and composite arterial grafts for three vessel disease. AB - OBJECTIVES: We sought to delineate the effects of the severity of target lesions and their combinations on the occurrence of competitive flow, especially in the composite Y-graft and to establish an optimal strategy for graft arrangement and patient selection. METHODS: We reviewed early and late angiograms of 2514 bypass grafts in 601 patients, who underwent off-pump coronary revascularization to three-vessel vascular regions using the internal thoracic artery (ITA) and radial artery (RA) without aortic manipulation. As a standard technique, the left anterior descending artery (LAD) was bypassed with the in situ ITA, and the left circumflex and right coronary arteries (RCA) were bypassed with the composite RA. Bypass flow was graded as antegrade, competitive or no flow. RESULTS: The early patency rate was 98.1% (2466/2514), while competitive flow was detected in 6.4% (162/2514). For the LAD, the individual and sequential in situ ITA provided lower incidence of competitive flow than the composite graft (0.3% (1/298) versus 7.6% (23/303), P < 0.0001). Regarding the RA to non-LAD bypass, 86.3% (113/131) of competitive flow occurred at the distal end of the I- or Y-graft, and the cumulative patency rate was significantly lower than that of sequential proximal anastomosis (80.1 versus 56.6% at 5 years, P < 0.0001). The number of sequential anastomoses did not affect the cumulative patency rate (P = 0.09). For the composite Y-graft to three-vessel regions, the rate of antegrade flow in patients with 76-100% stenosis in both the LAD and the RCA was 95.7% (178/186), which was significantly higher than that of 78.1% (100/128) in patients with 76-100% stenosis in the LAD and 51-75% stenosis in RCA (P < 0.0001). CONCLUSIONS: Sequential and composite grafting was considered reliable, exclusively in appropriately selected situations. To secure entire patency of the Y-graft to three-vessel regions, balanced bypass flow toward LAD and RCA would be crucial. PMID- 22219403 TI - Primary benign cardiac tumours: long-term results. AB - OBJECTIVES: Primary heart tumours are rare lesions with variegated histological types. We reviewed our 35 years experience with a significant number of primary benign cardiac tumour cases. METHODS: The patient database at University of Bologna was searched to identify patients with primary cardiac tumours between 1974 and 2009. Benign tumours were classified as myxomas and non-myxomas. Ninety four were myxomas (mean age of 59.1 +/- 15.6), and 13 were benign non-myxomas tumours (mean age of 39.7 +/- 24.9; P = 0.0001). Complete resection of the masses was performed in all cases except in one. RESULTS: In-hospital mortality was 3% in the myxoma group and 8% in the non-myxoma group. The mean follow-up was 15.1 and 7.4 years for the myxoma and non-myxoma groups, respectively. The long-term survival of discharged patients was 68 +/- 7% for the myxoma group and 100% for the non-myxoma group at 20 years, respectively. Recurrence of a tumour occurred only in the myxoma group (four cases) after 1, 3, 5 and 8 years, respectively. Twenty patients had an extracardiac tumour that was diagnosed before operation in 12 (11 in the myxoma group) and during the follow-up in 8 patients (only in the myxoma group). CONCLUSIONS: Primary cardiac tumours can be surgically treated with good short- and long-term results. Mortality and morbidity are mainly due to the status of preoperative patients'. An accurate follow-up is mandatory in order to detect the recurrence of a cardiac tumour such as to exclude the presence or the development of extracardiac tumours that we found frequently associated with the myxoma. PMID- 22219404 TI - Lung transplant for interstitial lung disease: outcomes before and after implementation of the united network for organ sharing lung allocation scoring system. AB - OBJECTIVES: This study was undertaken to evaluate whether the adoption of the united network for organ sharing lung allocation score (LAS) was associated with significant changes in lung transplantation (LTX) outcomes for patients with interstitial lung disease (ILD) who underwent LTX at the University of Wisconsin Hospital and Clinics. METHODS: Outcomes for 107 consecutive patients with various forms of ILD who underwent LTX between January 1993 and March 2009 were examined. Patients transplanted following the implementation of the LAS system (LAS, n = 56) were compared with those transplanted prior to LAS implementation (pre-LAS, n = 51) for whom LAS scores were calculated. RESULTS: Patients with idiopathic pulmonary fibrosis (IPF) comprised the majority of patients with ILD. Recipients transplanted after the implementation of the LAS were significantly older (pre LAS: 50.4 vs. LAS: 56.7 years, P < 0.01), required more supplemental oxygen (3 vs. 5 l/min, P < 0.01) and displayed lower cardiac index values (3.1 vs. 2.6 l/m(2), P < 0.01). The estimated LAS was significantly increased from 38.3 (pre LAS) to 43.3 (LAS), P < 0.01. However, waiting time decreased from 266 to 78 days (P < 0.01). The rate of bilateral vs. single LTX was lower (35 vs. 16%, P = 0.02) for the post-LAS group. Cold ischaemic time was shorter in the post-LAS group (434 vs. 299 min, P < 0.01), and the length of hospital stay decreased from 24 to 11 days (P < 0.01). Hospital mortality (11 vs. 7%, P = 0.51) and post-transplant survival did not differ between the groups. CONCLUSIONS: Post-transplant outcomes for patients with ILD or the subset of recipients with IPF were not adversely affected by the implementation of the LAS. PMID- 22219405 TI - Adverse effects of fibrin sealants in thoracic surgery: the safety of a new fibrin sealant: multicentre, randomized, controlled, clinical trial. AB - OBJECTIVES: The safety of fibrin sealants (FS) has been questioned in the light of recent reports of adverse effects. We evaluated the safety of a new FS in a randomized controlled trial (RCT). METHODS: Multicentre, open-label Phase II/III RCT to evaluate the safety of the new FS. The trial was approved by the Ethic Committee of each three participating Centre. FS includes two components (component 1: fibrinogen; component 2: thrombin), each of them subjected to two viral inactivation procedures. Out of 200 screened patients, 185 eligible patients (49 females, 136 males), aged between 18 and 75 years, undergoing major thoracic surgery were randomized to receive FS (#91 patients) as an adjuvant for air leak control or no treatment (#94 patients, control group). Safety variables were: percentage of subjects with adverse events associated with the therapy; formation of antibodies against bovine aprotinin; vital signs (blood pressure, body temperature, heart and respiratory rate); laboratory parameters. RESULTS: Overall operative mortality was 3.2% (6/185), 1.1% in the FS group and 5.3% in the control group, respectively. Twenty patients (22%) had adverse events in the FS group and 22 (23.4%) in the control group. Atrial fibrillation (five patients in the FS group and four in the control group) and hyperpyrexia (five and seven patients, respectively, in the two groups) were the most common adverse events. No patient reported thromboembolic events (pulmonary embolism or deep vein thrombosis) during the in hospital stay or within 1 month from discharge. None of the adverse events was considered as treatment related. The formation of bovine aprotinin antibodies was reported in a total of 34 patients (37.4%) in the FS group and was not related to any adverse effect. CONCLUSIONS: The present RCT did not show any increased risk of adverse events, and of surgical complications, related to the use of the new FS. PMID- 22219406 TI - An instrument facilitates mitral valve repair training at home. AB - The importance of surgical simulation has grown in the quickly changing climate of modern surgical training. Prior to operating on human hearts, practice in appropriate experimental models is necessary to attain adequate experience. Nowadays, training of surgery residents has shifted to simulation workshops and residency programmes outside the operating theatre. We have experience in training our residents to perform mitral valve repair techniques in bovine hearts. Previously, the heart would be fixed on the tablecloth with simple stitches, which proved to be a complex and difficult technique while performing surgery. Moving forwards, we have built a successful 'surgical table' to achieve better stabilization and to simplify the surgery. This paper describes our model, which could be a helpful tool for any cardiac surgeon performing surgical techniques successfully at home. PMID- 22219407 TI - Curved cutter stapler for the application of bronchial sutures in anatomic pulmonary resections: the clinical experience of 139 cases. AB - OBJECTIVES: One of the fundamental steps in an anatomical pulmonary resection is the main and lobar bronchus suture. Nowadays, two different types of staplers are on the market: the linear TA stapler for open surgery (Tyco Healthcare Group LP, Norwalk, CT, USA), which is based on a 'guillotine' mechanism, sewing, but not cutting the bronchus, and the endoscopic linear stapler which both cuts and sews. This study aimed to fill the void in the use of an instrument used to staple and cut at the same time in 'open' thoracic surgery, eliminating the need for a scalpel: the curved cutter stapler (Contour Curved Cutter Stapler; Ethicon Endo Surgery, Inc., Cincinnati, OH, USA). METHODS: Between May 2009 and March 2011, the Contour Curved Stapler (Ethicon) was used for the bronchus in 139 cases of non-small cell lung carcinoma (NSCLC)-29 females and 110 males ranging between 48 and 85 years (average 71.1)-and comprising 115 lobectomies (8 bilobectomies) and 24 pneumonectomies (8 on the right lung, 16 on the left lung). RESULTS: All patients underwent a bronchoscopic check-up 30 days after they were discharged: in all cases, the bronchial stump was clearly within normal limits. No cases of bronchopleural fistulas were observed in the 139 patients. CONCLUSIONS: On the basis of this study, the curved cutter stapler showed to be a satisfactory device for securing the bronchus during an anatomic resection (whether lobar or main), in 'open' thoracic surgery. However, even though there were no cases of fistula, we consider that our data is still too limited to be statistically significant. PMID- 22219409 TI - Benefit of ablation of first diagnosed paroxysmal atrial fibrillation during coronary artery bypass grafting: a pilot study. AB - OBJECTIVES: Whether patients with recent onset of paroxysmal atrial fibrillation (PAF) might benefit of epicardial atrial fibrillation (AF) ablation concomitant to coronary artery bypass graft (CABG) is not known. The aim of this prospective, randomized, single-centre pilot study is the comparison of patients with first diagnosed AF submitted to CABG and treated with and without epicardial pulmonary vein isolation (PVI). METHODS: Patients with first diagnosed PAF and indication for CABG were enrolled in this prospective randomized pilot study. The primary endpoint was AF-free survival (AF burden <0.5%) between the two groups at 18 month follow-up. The secondary endpoints were the percentage of AF burden defined through continuous monitoring using an implantable loop recorder, thromboembolic events and procedural complications. All patients were implanted with a subcutaneous cardiac monitor to track the cardiac rhythm and measure the AF burden. RESULTS: This study enrolled 35 patients (mean age 59 +/- 7 years, 74% males), followed up for 18 months after CABG. The patients were randomly allocated to two groups, CABG alone (n = 17) and CABG with concomitant PVI (n = 18). At 18-month follow-up after surgery, 16 (89%) patients in the CABG + PVI group were AF-free (i.e. AF% < 0.5%) vs 8 (47%) in the CABG only group (log-rank test, P = 0.007). At the end of follow-up, the mean AF burden in the CABG and the CABG + PVI group was 7.8 +/- 5.1 and 1.6 +/- 1.8%, respectively (P < 0.001). Two (18.2%) of the 11 patients with AF recurrences were completely asymptomatic. CONCLUSIONS: Patients with recent-onset AF submitted to CABG may benefit of concomitant ablation of the arrhythmia for preventing recurrences. PMID- 22219410 TI - Single site venovenous extracorporeal membrane oxygenation as an alternative to invasive ventilation in post-pneumonectomy fistula with acute respiratory failure. AB - We report the use of venovenous extracorporeal membrane oxygenation with a single dual lumen cannula in a 42-year-old patient suffering from a post-pneumonectomy fistula and severe respiratory insufficiency, avoiding the classical approach of invasive mechanical ventilation. We discussed the potential advantages of extracorporeal oxygenation as the main support in this particular clinical setting. PMID- 22219411 TI - Demolishing the tower of babel. PMID- 22219412 TI - Incidence, predictors and outcomes of incomplete revascularization after percutaneous coronary intervention and coronary artery bypass grafting: a subgroup analysis of 3-year SYNTAX data. AB - OBJECTIVE: To assess whether incomplete revascularization by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) has an effect on long-term outcomes. METHODS: During a heart team discussion to evaluate whether patients were eligible for randomization in the SYNTAX trial, both the cardiologist and surgeon agreed on which vessels needed revascularization. This statement was compared with the actual revascularization after treatment. Incomplete revascularization was defined as when a preoperatively identified vessel with a lesion was not revascularized. Outcomes were major adverse cardiac or cerebrovascular events (MACCE), the composite safety endpoint of death/stroke/myocardial infarction (MI), and individual MACCE components death, MI and repeat revascularization at 3 years. Predictors of incomplete revascularization were explored. RESULTS: Incomplete revascularization was found in 43.3% (388/896) PCI and 36.8% (320/870) CABG patients. Patients with complete revascularization by PCI had lower rates of MACCE (66.5 versus 76.2%, P < 0.001), the composite safety endpoint (83.4 versus 87.9%, P = 0.05) and repeat revascularization (75.5 versus 83.9%, P < 0.001), but not death and MI. In the CABG group, no difference in outcomes was seen between incomplete and complete revascularization groups. Incomplete revascularization was identified as independent predictor of MACCE in PCI (HR = 1.55, 95% CI 1.15-2.08, P = 0.004) but not CABG patients. Independent predictors of incomplete revascularization by PCI were hyperlipidaemia (OR = 1.59, 95% CI 1.04-2.42, P = 0.031), a total occlusion (OR = 2.46, 95% CI 1.66-3.64, P < 0.001) and the number of vessels (OR = 1.58, 95% CI 1.41-1.77, P < 0.001). Independent predictors of incomplete revascularization by CABG were unstable angina (OR = 1.42, 95% CI 1.02-1.98, P = 0.038), diffuse disease or narrowed ( < 2 mm) segment distal to the lesion (OR = 1.87, 95% CI 1.31-2.69, P = 0.001) and the number of vessels (OR = 1.70, 95% CI 1.53-1.89, P < 0.001). CONCLUSIONS: Despite the hypothesis-generating nature of this data, this study demonstrates that incomplete revascularization is associated with adverse events during follow-up after PCI but not CABG. PMID- 22219413 TI - Does the outcome improve after radiofrequency ablation for atrial fibrillation in patients undergoing cardiac surgery? A propensity-matched comparison. AB - OBJECTIVES: Preoperative atrial fibrillation (AF) significantly reduces the survival rate post cardiac surgery. It has been shown that patients in persistent or paroxysmal AF have higher mid- and long-term mortality post cardiac surgery compared with those in sinus rhythm. In this study we aimed to assess whether radiofrequency (RF) ablation during cardiac surgery in these patients improves the survival. METHODS: For a period of 5 years (2005-10), we studied all the patients who underwent ablation for AF during cardiac surgery for persistent/paroxysmal AF in our institution. We used RF ablation on 113 patients who had AF for <5 years and where the atrial dimension measured <5.5 cm. A 1:2 propensity matching was performed to adjust for the preoperative and operative characteristics with a group in persistent/paroxysmal AF, who had cardiac surgery during the same period of time (2005-10) and did not undergo ablation. We compared the postoperative outcome and survival rates between the two groups. RESULTS: Before and after adjusting for the preoperative and operative characteristics, inotropic support, renal failure, stroke, intensive care unit and hospital stay, as well as in-hospital mortality were similar between the two groups. After 5 years the difference in the survival was significant between the groups; 91.1 and 83.2%, with and without ablation, respectively (P value = 0.038). CONCLUSIONS: Despite, the similar postoperative outcome with or without ablation in persistent/paroxysmal AF, 5-year survival was found to be significantly higher with the ablation during cardiac surgery. This improvement can be due to the fall in the incidence of cerebro-vascular events or bleeding with AF or warfarin. Ablation during cardiac surgery is a simple and quick procedure and should be considered if indicated. PMID- 22219414 TI - Control of post-thoracotomy pain by transcutaneous electrical nerve stimulation: effect on serum cytokine levels, visual analogue scale, pulmonary function and medication. AB - OBJECTIVES: Transcutaneous electrical nerve stimulation (TENS) has been used to control post-thoracotomy pain with contrasting results. We aimed to assess the efficacy of TENS on post-thoracotomy pain in relation of four criterion measurements as: (i) cytokines; (ii) pain; (iii) respiratory function and (iv) intake of narcotic medication. METHODS: Between January 2008 and October 2010, 58 patients underwent standard posterolateral thoracotomy for resectable lung cancer. Fifty patients were enrolled in the present study and randomized in two groups: TENS group (25 patients) who received postoperatively TENS for 5 days and placebo group (25 patients) without TENS. In both groups (i) serum cytokines (IL 6, IL-10, TNF-alpha) were measured by ELISA before surgery and at 6, 12, 24, 48, 72, 96 and 120 postoperative hours (POHs); (ii) at the same POHs, the pain score was measured using visual analogue scale (VAS) ranging from 0 to 10 levels; (iii) respiratory function (FEV 1% and FVC % of predicted value) were valuated on 72, 96 and 120 POHs; (iv) the total intake of narcotic medication given during postoperative period of 5 days was recorded. Repeated measures of analysis of variance assess the difference between two study groups. A value of P < 0.05 was considered statistically significant. RESULTS: Of the 50 patients enrolled, two patients of TENS group and two patients of the placebo group were lost to follow up. (i) Serum IL-6 (P = 0.001), IL-10 (P = 0.001) and TNF-alpha (P = 0.001) levels in TENS group were significantly lower than in the control group; (ii) VAS score in TENS group was significantly lower than in the control group (P < 0.001); (iii) recovery of FEV 1 (P = 0.02) and of FVC (P = 0.02) was statistically better in the TENS group than in control group; (iv) morphine requirement was lower in the TENS group with respect to placebo TENS (P = 0.004). After 48 POHs, no patient required supplementary dose of morphine. TENS group compared with placebo-group presented a significant reduction of non-opioid consumption (P = 0.002). CONCLUSIONS: TENS is a valuable strategy to alleviate post-thoracotomy pain with reduction of cytokine production and of analgesic consumption, and with positive effects on pulmonary ventilation function. PMID- 22219415 TI - Significance of a new fluorodeoxyglucose-positive lesion on restaging positron emission tomography/computed tomography after induction therapy for non-small cell lung cancer. AB - OBJECTIVES: Restaging of patients with locally advanced non-small-cell lung cancer (NSCLC) is of paramount importance, since only patients with down-staging after induction therapy will benefit from surgery. In this study, we assessed the aetiology of new (18)fluoro-2-deoxy-d-glucose (FDG)-positive focal abnormalities on restaging positron emission tomography/computed tomography (PET/CT) in patients with a good response after induction chemotherapy in the primary tumour and lymph nodes. METHODS: Between 2004 and 2008, 31 patients with histological proven stage III NSCLC had a PET/CT prior and after induction chemotherapy. Their medical charts were retrospectively reviewed. RESULTS: Restaging PET/CT revealed a new FDG-positive lesion in 6 of 31 (20%) patients. The initial clinical stage of the disease was IIIA N2 in four and IIIB T4 in two patients. The maximal standard uptake value in the primary tumour (P = 0.043) and in the initially involved mediastinal nodes (P = 0.068) decreased after induction treatment in all patients. The new PET/CT findings were located in an ipsilateral cervical lymph node in two patients, a contralateral mediastinal in one patient and an ipsilateral mammary internal lymph node in one patient. Two other patients had a lesion on the contralateral lung. Malignant lymph node infiltrations were excluded following fine-needle puncture, intraoperative biopsy or follow-up PET/CT. Contralateral pulmonary lesions were diagnosed as benign following mini thoracotomy and pulmonary wedge resection. CONCLUSIONS: New solitary FDG-positive lesions on restaging PET/CT after induction chemotherapy for NSCLC are not rare in good responders to chemotherapy. In our experience, all these lesions were not associated with malignancy. PMID- 22219416 TI - Aortic arch enlargement and coarctation repair through a left thoracotomy: significance of ductal perfusion. AB - OBJECTIVE: To analyse the technique of neonatal aortic arch enlargement without cardiopulmonary bypass through a left posterior thoracotomy, as an adjunct to extended resection for Coarctation and severe arch hypoplasia. METHODS: Ten neonates with coarctation, severe arch hypoplasia and a persistent ductus arteriosus (PDA) were subjected to arch repair through a left posterior thoracotomy. Nine of these patients had associated significant intracardiac anomalies; three of them received pulmonary artery (PA) banding. After exclusion from circulation, the roof of the intervening arch between left carotid and left subclavian was enlarged using a patch. After adequate reperfusion, a classic resection and extended end-to-end anastomosis was performed. Median age and weight were 5.5 (1-10) days and 3.3 (2.2-4.1) kg respectively. The median preoperative arch diameter was 1.07 (0.75-1.32) mm/kg body weight. RESULTS: All patients could be successfully operated with this approach. The non-ischaemic and ischaemic aortic clamp times were 40 (15-68) and 23 (18-32) min, respectively. The median postoperative arch diameter achieved was 1.43 (1.06-1.46) mm/kg body weight. None of the patients had significant gradient early postoperatively. Two patients with recurrent stenosis were successfully treated with balloon dilatation (1) or surgery with cardiopulmonary bypass (CPB) (1). One patient has a corrected gradient of 16 mmHg in the proximal arch which is being observed. The remaining patients are free from stenosis at a median follow-up of 30.1 (13.2 57.8) months. CONCLUSIONS: Use of PDA for lower body perfusion allows complex reconstruction of the arch without incurring lower body ischaemia. The extended resection could then be performed without excessive stretch. This modification saves these patients from undergoing a complex arch reconstruction with CPB in the early neonatal period. PMID- 22219417 TI - An unusual cervical thymoma. PMID- 22219418 TI - Standard uptake value of positron emission tomography in clinical stage I lung cancer: clinical application and pathological correlation. AB - OBJECTIVES: The aim of this study was to assess the standard uptake value in clinical stage I non-small cell lung cancer (NSCLC) and its correlation with pathological status and prognosis. METHODS: We retrospectively reviewed 674 patients diagnosed with NSCLC between January 2002 and June 2005. Patients with clinical stage I diseases undergone a preoperative positron emission tomography computed tomography scan followed by anatomic resection. We reviewed the clinical features of 152 patients with an average follow-up of 87 months. RESULTS: We analysed the clinical features of 108 patients with stage I NSCLC and 44 patients with non-stage I NSCLC. There were no statistical differences in age, histological type, location or tumour differentiation between the two groups. In the Stage I group, the patients had lower maximum standard uptake value (SUVmax; 3.80 +/- 3.17 vs 5.73 +/- 3.65, P = 0.001), lower carcinoembryonic antigen (CEA) levels (2.86 +/- 4.80 vs 9.11 +/- 17.21 ng/ml, P = 0.027) and smaller tumour size (2.39 +/- 0.98 vs 3.73 +/- 2.04 cm, P < 0.001). The patients with higher SUVmax had a more advanced pathological stage, poorer tumour differentiation and larger tumour size. A higher SUVmax was an independent factor predicting an advanced pathological stage (SUVmax >= 3.3, odds ratio 3.246). The median survival of patients with SUVmax >= 3.3 and SUVmax <3.3 were 64.32 and 53.08 months, respectively (P = 0.654). CONCLUSIONS: Higher preoperative 18-fluorodeoxyglucose uptake by a tumour was significantly associated with an advanced pathological stage but not correlated with a poorer prognosis. An aggressive preoperative work up for occult N2 disease should be emphasized, avoiding inappropriate thoracotomy. PMID- 22219419 TI - Midterm follow-up dynamic echocardiography evaluation after ascending aorta replacement and reimplantation of the aortic valve (David operation) in a matched control study. AB - OBJECTIVE: Dynamic performance of the aortic valve (AV) after ascending aorta replacement with reimplantation of the native AV (David) was investigated. METHODS: We prospectively evaluated 17 patients who underwent David procedure. Rest/stress echocardiography follow-up was performed and results were compared with those of matched healthy controls. RESULTS: There were no significant differences in terms of age, height, weight, BSA, left ventricular mass, left ventricular ejection fraction (LVEF) and tele-diastolic volume between the David and control group. At rest echocardiography, patients in the David group had a lower indexed aortic valve area (IAVA) (1.1 +/- 0.2 vs. 1.5 +/- 0.2 cm(2)/m(2), P < 0.0001), with comparable transvalvular gradients (TVG). At maximal physical stress, although the IAVA in the David group was significantly increased from the rest values (P = 0.001), the difference with the control group persisted (David 1.4 +/- 0.3 vs. Control 1.7 +/- 0.2 cm(2)/m(2), P < 0.0001) maintaining similar peak TVG (David 13.6 +/- 5.3 vs. Control 11.7 +/- 4.5 mmHg, P = ns) and mean TVG (David 7.2 +/- 3.0 vs. 6.2 +/- 2.4 mmHg, P = ns). AV regurgitation in the David group was absent in five (29.4%), grade I in nine (52.9%) and grade II in three (17.6%) patients and remained unchanged during stress. At multiple linear regression, David operation was inversely correlated to rest IAVA (OR = -0.4; P = 0.01; CI: -0.7-0.1). CONCLUSIONS: Although IAVA is significantly smaller after David procedure in comparison with matched controls, no pathological increase in TVG is noticed. A significant increase in the IAVA during physical stress documents the preserved pliability/elasticity of the aortic unit after David procedure preventing pathological increase in the TVG even during strenuous effort. PMID- 22219420 TI - Correlation between matrix metalloproteinase 9 and 18F-2-fluoro-2-deoxyglucose positron emission tomography as diagnostic markers of lung cancer. AB - OBJECTIVES: This study was conducted to evaluate the diagnostic role of matrix metalloproteinase 9 (MMP9) measured in bronchoalveolar lavage (BAL), serum and tissue samples of patients with indeterminate lung lesions and its correlation with F-18-2-fluoro-2-deoxyglucose-positron emission tomography ((18)FDG-PET) findings in diagnostic work. METHODS: MMP9 levels (ng/ml) in serum and BAL were analysed using enzyme-linked immunosorbent assay in 60 consecutive patients with lung mass. (18)FDG-PET was performed on all patients and a standard uptake value (SUV) threshold of 2.5 was used to differentiate benign from malignant lesions. In tissue samples of resectable patients, MMP9 expression was also revealed by immunohistochemical staining. RESULTS: Twenty patients had benign disease and 40 patients had malignant lesions, of which 7 (17.5%) were classified as Stage I, 18 (45%) as Stage II, 7 (17.5%) as Stage III and 8 (20%) as Stage IV. MMP9 levels in serum were significantly higher in malignant than in benign lesions (673 +/- 182 versus 309 +/- 96, respectively, P < 0.0001), and were significantly higher in patients with metastatic disease than in patients of other stage groups; no significant difference was found between different histological types. MMP9 levels in BAL were higher in malignant than in benign lesions (502 +/- 137 versus 325 +/- 118, respectively, P = 0.001); no significant differences were found between different stages or histological groups. In patients with malignant lesions, MMP9 levels in BAL were inversely correlated with FEV(1) (volume that has been exhaled at the end of the first second of forced expiration) and FVC (forced vital capacity of maximally forced expiratory effort) values. In patients with SUV > 2.5, MMP9 levels in serum and BAL had a sensitivity, specificity, positive predictive value and negative predictive value of 73, 100, 100 and 81% (cut-off point of 601; area under the curve (AUC): 0.7) and 94, 100, 100 and 83% (cut-off point of 745; AUC: 0.9), respectively. In patients with SUV < 2.5, MMP9 levels in serum and BAL had a sensitivity, specificity, positive predictive value and negative predictive value of 94, 100, 100 and 75% (cut-off point of 240; AUC: 0.9) and 70, 100, 100 and 73% (cut-off point of 321; AUC: 0.7), respectively. Of the 26 tumour samples, 9 (34%) showed positive immunohistochemical staining for MMP9. CONCLUSIONS: The measurement of MMP9 levels helps to differentiate benign from malignant lung mass. Its use in combination with PET study adds further information to the diagnosis work-up of lesions to select patients who may or may not benefit from additional invasive procedures. PMID- 22219421 TI - Aortic valve haemodynamics after aortic valve-sparing operations. PMID- 22219422 TI - A rare case of left ventricular non-compaction in early infancy. PMID- 22219423 TI - Angiographic evaluation of the coronary artery anatomy in patients with hypoplastic left heart syndrome. AB - OBJECTIVES: Evaluation of coronary anatomy in survivors of staged palliation for hypoplastic left heart syndrome might be capable of identifying anomalies and morphologic changes of the coronary arteries that may have implications for outcome. METHODS: We reviewed coronary angiograms obtained by native aortic root injection of 84 patients (mitral atresia/aortic atresia, n = 39; mitral stenosis/aortic stenosis, n = 25; mitral stenosis/aortic atresia (MS/AA), n = 13 and mitral atresia/aortic stenosis, n = 7). Epicardial course, anomalies, coronary dominance and native ascending aorta dimensions were analysed. RESULTS: Right dominance was present in 51%, left in 37% and balanced type in 12%. Dominance was unrelated to anatomic subtypes (P = 0.16). Ventriculocoronary connections (VCCs) were found in 15 (18%) and tortuosity was seen in 28 (33%) patients. Both occurred more often with MS/AA (tortuosity: 12 of 13 patients, P < 0.001; VCCs: 6 of 13 patients, P = 0.001). Collaterals to extra-cardiac vessels were visualized in 41 (49%) patients. Native ascending aorta dimensions were smaller with aortic atresia [40 (18-107) vs. 127 (32-328) mm(2)/m(2), P < 0.001]. In 18 patients with a relatively large native aorta [106 (36-328) vs. 44 (18-248) mm(2)/m(2), P < 0.001] retention of contrast in the aortic root identified areas of low blood flow. CONCLUSIONS: Left coronary dominance was more prevalent compared with the normal population. The impact of observed anomalies is unclear. Most VCCs are small and probably have no impact on coronary perfusion. Native ascending aorta dimensions were larger in patients with aortic stenosis. Larger aortic roots may predispose to thrombus formation and effective anticoagulation might be considered. PMID- 22219424 TI - Concomitant frozen elephant trunk procedure and pulmonary embolectomy. AB - The antegrade stented (frozen) elephant trunk procedure and pulmonary embolectomy are complex cardiac surgical operations for extensive aortic and pulmonary arterial disease, respectively. We report the first known case of concomitant antegrade stented elephant trunk and pulmonary embolectomy in order to highlight pre- and intra-operative management strategies for this uncommon disease combination. PMID- 22219425 TI - The impact of chest tube removal on pain and pulmonary function after pulmonary resection. AB - OBJECTIVE: The aim of this study was to assess the immediate influence of chest tube removal on chest pain and forced expiratory volume in 1 s (FEV1) after pulmonary resection. METHODS: Prospective longitudinal investigation on 104 consecutive patients (53 wedge/segmentectomies and 51 lobectomies; 69 muscle and nerve-sparing lateral thoracotomy and 35 video-assisted thoracoscopic surgery (VATS)). Post-operative chest pain was controlled in all patients by a standardized combination of oral and intravenous non-opioid analgesics. All patients had one chest tube (24 French). Static and dynamic (after forced expiratory effort) pain and FEV1 were assessed before and 1 h after the chest tube removal by the same operator. No additional analgesics were administered before or after the chest tube removal. The pain level was assessed by the numeric pain scale [range: 0 (no pain)-10 (excruciating pain)]. FEV1 was assessed by a portable spirometer. Bronchodilators were not used in these patients. Pre- and post-removal measurements were compared by the Wilcoxon signed rank test. RESULTS: The average pre-removal static and dynamic pain scores were 2.6 and 4.1, respectively. The static and dynamic pain scores decreased by 42 and 41%, respectively, after the tube removal (P < 0.0001). The average FEV1 before the chest tube removal was 1.5 l or 53% of the predicted value and increased by 13% after the tube removal (P = 0.0004). In total, 56 and 78% of patients reported static and dynamic pain scores improvement and 67% showed an FEV1 improvement after the chest tube removal. Similar results were observed in patients operated on through VATS or thoracotomy. Compared with patients whose chest tube was removed later, those who had their chest tube removed before post operative day 3 (POD3), showed a greater reduction in the static pain score (41 vs. 31%, P = 0.05) and greater improvement in FEV1 (18 vs. 0.01%, P = 0.02). CONCLUSIONS: The removal of a chest tube reduces pain and improves ventilatory function, independent of surgical access and particularly in the early post-operative phase. A fast track chest tube removal policy may favour patients' recovery. PMID- 22219427 TI - Reconstruction of the free margin of the anterior leaflet of the mitral valve and replacement of the anterior leaflet of the tricuspid valve with autologous pericardium. PMID- 22219426 TI - Fibrinogen/thrombin-based collagen fleece (TachoComb(R)) promotes regeneration in pulmonary arterial injury. AB - OBJECTIVES: To repair unexpected damage of the pulmonary artery (PA) during thoracic surgery, fibrinogen/thrombin-based collagen fleece (TachoComb((r)) [TC]) can be applied as a haemostatic material. The progression of vessel restoration with TC has not been elucidated. In this study, we investigate details of the healing process with TC after PA injury using a canine model. METHODS: Left thoracotomy was performed on female beagles under general anaesthesia. PA injury was induced and repaired using TC. Repair sites were histologically evaluated 2, 4 and 8 weeks after surgery (n = 3 in each group). RESULTS: Haemostasis of PA injury was achieved promptly after TC application. After surgery, no bleeding was found in the thoracic cavity, and no repair sites revealed stenosis, thrombi or false aneurism formation. Two weeks after surgery, inflammatory cells had infiltrated around the vascular defect, and vascular endothelium had regenerated on the innermost surface of TC applied to the defect. At Week 4, elastic and smooth muscle fibres had begun to extend into the defect between the endothelial layer and collagen fleece. By Week 8, elastic fibres and smooth muscle had completely regenerated in the medial layer. The adventitial layer had also fully regenerated. CONCLUSIONS: Haemostasis of injured PA using TC was safe and reliable. TC provided a mechanical scaffold on which vascular regeneration occurred. Three layers reconstructed in the PA defect were identical to those in normal structures. PMID- 22219428 TI - Thyroid cancers with laryngotracheal invasion. AB - OBJECTIVES: Management of thyroid cancers with laryngotracheal invasion is controversial. METHODS: A retrospective analysis of our database found 69 patients (38 females, mean age 59.6 +/- 11.6) between March 1995 and July 2010; of them 42 (61%) were managed by non-resectional methods due to the extensive airway or regional involvement, severe co-morbidities, diffuse metastases or patient's preference. Segmental airway resection was performed in 27 (39%) patients; concurrent with thyroidectomy in 17 (Immediate group (IG)), and as a delayed procedure in 10 referred patients (Delayed group (DG)), who had previously undergone thyroidectomy with conservative airway management, like shaving procedures. Follow-up was completed in 81% of patients with a mean duration of 30 months. RESULTS: Tracheal or laryngotracheal resection and reconstruction was performed in 18, laryngectomy in eight and pharyngolaryngectomy in one patient. There were two anastomotic dehiscence (11.1%), one resulted in mortality (3.7%). One or a combination of bronchoscopic core-out, laser, tracheostomy and stent placement was performed in 42 non resected patients with two mortalities (4.7%). Overall 1-, 2-, 3- and 5-year survival was 85, 85, 68 and 49% in resected group, as well as 56, 46, 40 and 31% in non-resected group (P = 0.049), respectively. Among resected group, the overall 1-, 2-, 3- and 5-year survival was 92, 92, 76 and 61% in the IG as well as 75, 75, 56 and 28% in the DG (P = 0.43). CONCLUSIONS: Complete segmental airway resection during or even after thyroidectomy could be safely performed, might be curative and may be associated with improved survival. PMID- 22219429 TI - A clinicopathological study of peripheral, small-sized high-grade neuroendocrine tumours of the lung: differences between small-cell lung carcinoma and large-cell neuroendocrine carcinoma. AB - OBJECTIVES: Small-cell lung carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC) are categorized as high-grade neuroendocrine tumours because of their poor prognosis compared with those of other neuroendocrine tumours of the lung. There have been no clinicopathological studies focusing on small-sized high grade neuroendocrine tumours. We analysed clinicopathological features of peripheral, small-sized high-grade neuroendocrine tumours of the lung retrospectively. METHODS: A total of 28 patients with peripheral, small-sized tumours (maximum diameter of 3.0 cm) of SCLC and LCNEC underwent surgical resection in our hospital and were enrolled in this study. RESULTS: Of 28 tumours, 18 were SCLC and 10 were LCNEC. In terms of serum tumour marker levels, carcinoembryonic antigen was elevated in 50% of both types of tumour, and progastrin-releasing peptide was elevated in 28% of SCLC and 10% of LCNEC. With regard to preoperative diagnosis, only seven SCLC cases were correctly diagnosed as SCLC, but no LCNEC case was correctly diagnosed before surgery. Lymphatic involvement was significantly more frequent in SCLC than in LCNEC (P = 0.013). Although adjuvant chemotherapy was carried out more frequently in the patients with SCLC than LCNEC, the recurrence rate after the standard surgery was significantly higher in the patients with SCLC than LCNEC (P = 0.0037). There was a significant difference between SCLC and LCNEC in terms of overall survival in clinical-stage IA small-sized tumours (P = 0.029). CONCLUSIONS: In peripheral, small-sized high-grade neuroendocrine tumours, there are several clinicopathological differences between SCLC and LCNEC. This study suggested that the prognosis of patients with LCNEC tended to be better than for those with SCLC in small-sized tumours. PMID- 22219430 TI - Suboptimal perception of illness due to self-realization constraints impairs psychological welfare in surgical patients. AB - OBJECTIVE: Recognizing patients' psychological problems and understanding their social needs constitute important tasks for medical personnel, because these issues substantially contribute to overall outcome of treatment. People afflicted with surgical diseases need to determine the sense of everyday pursuits and activities and balance it against the therapeutic process. The aim of the study was to assess the relationships between the perception of illness, satisfaction with life and meaning of life among surgical patients. METHODS: A total of 225 patients undergoing surgical treatment in the thoracic surgery department were enrolled in the questionnaire study using Multidimensional Essence of Disease and Illness Scale (MEDIS), Satisfaction With Life Scale (SWLS) and Life Meaningfulness Scale (LMS). Relationships between variables were assessed with Pearson's correlation. RESULTS: The analysis disclosed negative correlations between the perception of the disease in the light of self-realization constraints and the feeling of satisfaction with one's life (R = -0.25; P < 0.01), an affective component of the LMS (R = -0.29; P < 0.001) and the total result of the LMS (R = -0.21; P < 0.01). Similar relationships were observed between the MEDIS dimension describing a disease as a social withdrawal and the total result of the SWLS (R = -0.21; P < 0.05) and the affective component of the LMS (R = -0.23; P < 0.01). CONCLUSIONS: Suboptimal hospitalization-related perception of the disease due to self-realization constraints profoundly impairs psychological welfare of patients and may exert negative impact on the overall outcome of treatment. We believe that surgical patients require early psychological, social and spiritual support to prevent these harmful psycho social consequences of illness and hospital stay. Preoperative clinical application of presented scales may be useful to select patients who require more psychological attention in providing information about planned surgical treatment and expected outcomes. PMID- 22219431 TI - Iodine pleurodesis--a word of caution. PMID- 22219432 TI - Transthoracic migration of a Kirschner wire from the humerus to the abdomen. AB - Migration of Kirschner wires after fracture fixation is a rare complication. Several cases of intrathoracic migration after humeral or clavicle fixation with this technique have been reported though. We describe an even rarer case where a wire migrated from the proximal humerus to the abdomen perforating the left thoracic cavity and hemidiaphragm. The distal end of the wire was located next to the spleen and its proximal end at the fifth intercostal space. This particular case could be managed with a simple direct removal through an incision at the fifth intercostal space. The postoperative course was uneventful. PMID- 22219433 TI - A rescue option procedure post-transapical transcatheter aortic-valve implantation. PMID- 22219434 TI - Current status on stentless aortic bioprosthesis: a clinical and experimental perspective. AB - Introduction of stentless valves into clinical practice has not replaced stented valve prosthesis as expected a decade ago. With respect to clinical parameters such as transvalvular pressure differences, left ventricular mass regression as well as a possible survival benefit, there are many contradictory studies published. The overall dilemma is the absence of large randomized studies. This review, therefore, focuses on two issues: Experimental research in order to disclose design advantages or drawbacks and clinical trials expressing the real benefit or risk for the patient. In general, both clinical and experimental studies show that stentless valves have several biomechanical and haemodynamic benefits when compared with stented valves though new generation pericardial valves have excellent blood flow profiles. However, stentless and stented valves seem to perform equally well when it comes to various clinical parameters. In most cases, a stented valve is therefore preferable because of the simpler implantation technique. In order to gain a more widespread clinical use, the design of the stentless valve needs to be improved in order to simplify the implantation. PMID- 22219435 TI - A giant pseudoaneurysm of the sinus of Valsalva with pulmonary artery obstruction. PMID- 22219436 TI - Lung cancer invading the fissure to the adjacent lobe: more a question of spreading mode than a staging problem. AB - OBJECTIVES: Lung cancer invading beyond the interlobar pleura, classified as T2a in the new TNM, is a rare entity with a poor outcome. Our purpose was a better understanding of the mechanisms of this particular behaviour and its prognostic value. METHODS: Patients who underwent surgery between 1984 and 2007 were reviewed. We focused on T1 and T2 tumours. Tumours not traversing the pleural elastic layer were defined as PL0, extending through the layer as PL1 and extending to the surface of the visceral pleura as PL2. We considered three groups: group 1, tumours invading the lobar fissure, group 2, PL0-tumours and group 3, PL1 + PL2 tumours and studied their pathology and prognostic characteristics. RESULTS: The distribution was as follows: group 1 n = 154, group 2 n = 2310 and group 3 n = 651. Pneumonectomy was necessary in 55.2% and bilobectomy in 19.5% of group 1, and N-involvement was present in 55.8% (significantly more than other groups). The mean tumour size (42.7 +/- 12 mm) was bigger in group 1. Post-operative mortality was as follows: -5.2, -3.5 and 3.2% in groups 1, 2 and 3, respectively (P = 0.49). Five-year survival rates were: group 1: 38.9%, group 2: 52.5% and group 3: 43.4%; P = 0.00002. Survival was not different between groups concerning pN1 and pN2, but poorer in groups 1 and 3 than in group 2 in pN0 patients, P = 0.0057. Survival was 48.1, 37.9 and 38.4% for tumours between 31 and 70 mm in groups 2, 1 and 3, respectively, P = 0.0024 (but P = 0.65 between groups 1 and 3). Pneumonectomy was a poor prognostic factor in all groups, but survival between pneumonectomy and bilobectomy was not different in group 1. Multivariate analysis confirmed intralobar invasion to be an independent factor of poor prognosis, as well as visceral pleura invasion. CONCLUSIONS: Tumours invading through the fissure have a significant effect on long-term survival in the first stages of lung cancer but also in all stages because of their size and important locoregional spread. Their prognostic value is due to pleural invasion, whose role in lung cancer dissemination is worth further research. PMID- 22219437 TI - Utility of 18F-fluorodeoxyglucose positron emission tomography for distinguishing between the histological types of early stage thymic epithelial tumours. AB - OBJECTIVES: Recent studies have shown the usefulness of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in differentiating between World Health Organization (WHO) histological subgroups of thymic epithelial tumours. However, these reports may have included many advanced cases of these lesions (Masaoka stage III or IV) of high-risk subtypes. The objective of our present study was to assess the usefulness of FDG-PET for distinguishing the histological subtypes of early stage thymic epithelial tumours (Masaoka stage I or II). METHODS: Twenty patients who had undergone an FDG-PET examination prior to treatment and had been diagnosed with an early stage thymic epithelial tumour between July 2005 and July 2011 were enrolled in the present study. All patients underwent a total thymectomy. This cohort was divided into two groups according to the WHO histological classification of their lesion, i.e. low-risk tumours (types A, AB or B1) in one group and high-risk tumours (types B2, B3 or thymic carcinoma) in the other. Focal FDG accumulation was evaluated by determining the maximum standardized uptake value (SUV-max). RESULTS: The patient cohort for this study included 13 men and 7 women ranging in age from 26 to 70 years (mean 55 years). The low-risk group included seven cases (type A, 0; type AB, 7; type B1, 0), and the high-risk group comprised 13 cases (type B2, 7; type B3, 3; thymic carcinoma, 3). The SUV-max values of the low-risk and high-risk tumours were 3.09 +/- 0.51 and 6.19 +/- 3.13, respectively, and this was a significant difference. For the differential diagnosis of low-risk and high-risk tumours, sensitivity and specificity were 92.3% and 83.3%, respectively, when an SUV-max of 3.5 was used as a cutoff. CONCLUSIONS: FDG-PET is a useful method for distinguishing histological types of early stage thymic epithelial tumours. PMID- 22219438 TI - Giant intramuscular haemangioma of the chest wall with osteolytic change. AB - Intramuscular haemangioma of the chest wall is very rare, and only few cases associated with rib destruction has been reported. Here, we describe a 37-year old woman with a giant intramuscular haemangioma arising in the left back and associated with rib destruction. PMID- 22219439 TI - Myocardial protection strategy for conventional aortic valve replacement following previous coronary surgery: should it be patient-specific? PMID- 22219441 TI - Feasibility of hybrid thoracoscopic lobectomy and en-bloc chest wall resection. AB - OBJECTIVES: Lobectomy with an en-bloc chest wall resection is an effective but potentially morbid treatment of lung cancer invading the chest wall. Minimally invasive approaches to lobectomy have reduced morbidity compared with thoracotomy for early stage lung cancer, but there is insufficient evidence regarding the feasibility of hybrid thoracoscopic lobectomy chest wall resection. We reviewed our experience with an en-bloc chest wall resection and lobectomy to evaluate the outcomes of a hybrid approach using thoracoscopic lobectomy combined with the chest wall resection where rib spreading is avoided. METHODS: All patients who underwent lobectomy and en-bloc chest wall resection with ribs for primary non small cell lung cancer from January 2000 to July 2010 were reviewed. Starting in April 2003, a hybrid approach was introduced where thoracoscopic techniques were utilized to accomplish the pulmonary resection and a limited counter incision was used to perform the en-bloc resection of the chest wall, avoiding scapular mobilization and rib spreading. Preoperative, perioperative and outcome variables were assessed using the standard descriptive statistics. RESULTS: During the study period, 105 patients underwent en-bloc lobectomy and chest wall resection, including 93 patients with resection via thoracotomy and 12 patients with resection via the hybrid thoracoscopic approach. Complete resection was achieved in all patients in both groups. Tumour size and the extent of resection were similar in the two groups. There were no conversions and no perioperative mortality in the hybrid group. Post-operative outcomes were similar, although patients who underwent the hybrid approach had a shorter length of stay (P = 0.03). CONCLUSIONS: A hybrid approach that combines thoracoscopic lobectomy and chest wall resection is feasible and effective in selected patients. The use of a limited counter incision without rib spreading does not compromise oncologic efficacy. Further experience is needed to determine if this approach provides any advantage in outcomes, including post-operative morbidity. PMID- 22219442 TI - Multimodal analgesic treatment in video-assisted thoracic surgery lobectomy using an intraoperative intercostal catheter. AB - OBJECTIVES: No golden standard for analgesia in video-assisted thoracic surgery (VATS) lobectomy exists. A simple multimodal approach using an intercostal catheter (ICC) may be of benefit since acute post-operative pain following VATS lobectomy primarily originates from the chest drain area. METHODS: Prospective observational cohort. Forty-eight consecutive patients received a standardized regimen consisting of paracetamol, non-steroidal anti-inflammatory drug and gabapentin. Further, surgeons performed a single-shot paravertebral block (PVB) at five levels (15 ml of 0.5% bupivacaine) and inserted an ICC at the drain site level for continuous delivery of 6 ml of 0.25% bupivacaine h(-1). Pain scores at rest, mobilization and with the extended arms were followed until discharge or for 4 days. RESULTS: Forty-eight patients, mean age 64 years (CI: 61-68), were included. The mean time for the PVB and ICC placement was 5 min (CI: 4.7-5.9). The mean pain score at rest using a numerical rating scale (NRS, 0-10) was <3 for 1-16 h and decreased from 4.7 to 1.7 (NRS day 1-4, getting out of bed). The ICC was removed with the drain in 48/73/92% on day 1/2/3 after surgery. The median day of discharge was 3 (interquartile range 2-4) with >85% of patients reporting satisfactory or very satisfactory pain treatment all days. CONCLUSIONS: Acute pain after VATS lobectomy may be adequately controlled using a multimodal non opioid regime including PVB and an ICC. The low pain scores and reduced time used inserting the ICC may present an alternative to continuous epidural analgesia or conventional PVB. PMID- 22219443 TI - Comparison of three software programs for three-dimensional graphic imaging as contrasted with operative findings. AB - OBJECTIVES: Several types of practical three-dimensional (3D) imaging software programs are available, including those attached to computed tomographic devices. Three different software programs (Advantage Workstation Volume Share 4, OsiriX and CTTRY) were used to generate 3D images on the basis of imaging data obtained by 64-slice multidetector-row computed tomography in the same patient. METHODS: Surgery was then performed referring to these 3D images in five patients. The characteristics, advantages, disadvantages and utility in the operative field of the images generated with each software program were compared with respect to actual operative findings. RESULTS: There were no marked differences in vascular images at the segmental level among the software programs, and all three were considered useful for surgery. However, vascular images at the subsegmental level differed among the three programs. CONCLUSIONS: The depiction of blood vessels at the subsegmental level lacked accuracy when compared with operative findings. PMID- 22219444 TI - Surgical treatment of a cavernous haemangioma of the heart. AB - Cardiac haemangioma is an extremely rare, benign vascular tumour. A 42-year-old female patient who was previously very active presented with complaints of exertional chest pain as well as lower extremity oedema. Computed tomography and magnetic resonance imaging showed a large mass in the anterior mediastinum originating from the right atrioventricular groove and abutting the superior vena cava, right atrium, right ventricular outflow tract and aortic root. Open biopsy via right mini-thoracotomy revealed cavernous haemangioma. After the biopsy, the patient was treated with three doses of bevacizumab but symptoms worsened and the mass did not regress. Therefore, the patient underwent median sternotomy and resection of the large tumour that encroached upon the right coronary artery. Final histopathological examination revealed cavernous haemangioma. The patient made an uneventful recovery. PMID- 22219445 TI - Transapical aortic valve implantation after ascending aortic endovascular repair. PMID- 22219446 TI - Timing for surgery in patients with infective endocarditis and cerebrovascular complications--waiting may be best but results of early surgery are acceptable and improvements in neurology are common. PMID- 22219448 TI - A morbidity score for congenital heart surgery based on observed complications. AB - OBJECTIVES: The aim of this study was to develop a morbidity score based on observed postoperative complications after congenital heart surgery. METHODS: Conditions or diseases that impair patients after congenital heart surgery or increase costs of hospital stay were called complications and attributed to scores ranging from 1 (mild) to 4 (severe) points, according to estimated severity or costliness. 'No complication' was assigned 0.5 points. From January to March 2011, scores for each observed 'complication' for every main (primary) surgical procedure were recorded and a morbidity score was calculated. In conformity with the Aristotle score methodology, if the sum of observed complication scores amounted to more than 5 points, a morbidity score of only 5 points was attributed. The estimated morbidity score was compared with the morbidity score attributed by the Aristotle basic complexity (ABC) score. RESULTS: One hundred and thirty-nine primary procedures were carried out. The mean ABC and Aristotle comprehensive complexity scores reached 8.31 +/- 2.52 and 9.62 +/- 3.47 points, respectively. Two patients died. No complication was detected after 46 procedures. Overall, there were 185 listed 'morbidity' conditions in connection with the other 93 surgical procedures, rendering a total score of 385 points. The most frequent event was 'mechanical ventilation 25-95 h': n = 39. The mean morbidity score was 2.14 +/- 1.63. The morbidity scores ranged from 0.5 points (n = 46) to 5 points (n = 23) with a median of 2.0 points. The scores for 11 different procedures that were performed at least five times positively correlated with the corresponding Aristotle morbidity scores: Pearson's coefficient r = 0.75. But the morbidity score for bidirectional cavopulmonary anastomosis (3.14 +/- 1.77) was higher than the corresponding Aristotle morbidity score (2.0). It was lower for 'conduit placement, right ventricle to pulmonary artery': 1.08 +/- 0.97, versus 2.0, and for arterial switch operation: 2.08 +/- 1.11, versus 3.0. CONCLUSIONS: The reported morbidity scores need to be tested on larger series and in different institutions. The introduced morbidity score has the potential to quantify postoperative complications accurately. Its estimation over time can facilitate the assessment of quality of congenital heart surgery. It will allow comparison of morbidity outcomes across institutions with different case-mixes. PMID- 22219449 TI - Associated double-orifice mitral and tricuspid valves without ostium primum defect. AB - The simultaneous existence of double orifice right and left atrioventricular valves in the absence of ostium primum defects is rare and scarcely reported. We present the case of a 20-month old boy diagnosed with tetralogy of Fallot with pulmonary atresia who was found to have associated double-orifice mitral and tricuspid valves. PMID- 22219450 TI - Biomechanical comparison of human pulmonary and aortic roots. AB - OBJECTIVE: Significant dilation of the pulmonary autograft is problematic after the Ross operation and may require reoperation. Pulmonary autograft remodelling occurs in response to the immediate rise in pressure and consequently wall stress. Stress-strain response of the pulmonary root plays an important role in understanding autograft function and remodelling following the Ross procedure. However, limited data are available on mechanical properties of fresh human pulmonary roots. The aim of this study was to compare mechanical properties of fresh human pulmonary and aortic roots prior to the Ross operation. METHODS: Fresh healthy human hearts (n = 21) were obtained from California Transplant Donor Network (Oakland, CA, USA). Five regions of pulmonary and aortic roots, anterior and posterior artery and three sinuses, were subjected to displacement controlled equibiaxial stretch testing within 24 h of cross-clamp time. Different regions of pulmonary and aortic roots were compared using a paired-comparison approach based on tissue stiffness at systemic pressure. Furthermore, histologic analysis was performed to compare the fibrous structure of pulmonary and aortic roots. RESULTS: Human pulmonary and aortic roots demonstrated nonlinear response to biaxial loading in both circumferential and longitudinal directions. Pulmonary artery was found to be significantly stiffer than ascending aorta at systemic pressure in the two principal directions (P < 0.001). Similarly, pulmonary sinuses were significantly stiffer than the aortic sinuses at systemic pressure in the two directions (P < 0.001). Histological analysis revealed that aortic roots had tight denser weave of elastin than pulmonary roots. CONCLUSIONS: Significant differences were found in the compliance and fibrous structure of human pulmonary and aortic roots. These regional differences may impact pulmonary autograft remodelling and influence late autograft dilation. PMID- 22219451 TI - Transcatheter aortic valve implantation after previous coronary artery bypass grafting: a potential gold standard of care. PMID- 22219452 TI - Scoring complications after congenital heart surgery: gut feelings versus calculations. PMID- 22219453 TI - Improved cardiopulmonary exercise function after modified Nuss operation for pectus excavatum. AB - OBJECTIVES: Patients with pectus excavatum have compromised cardiac function during exercise. We hypothesized that the Nuss technique would improve cardiopulmonary function during exercise. METHODS: We investigated 75 teenagers (49 patients and 26 controls) at rest and during bicycle exercise prior to surgery and 1 year postoperative. RESULTS: Prior to surgery, patients had a lower cardiac index 6.6 +/- 1.1 l/min/m(2) when compared with controls 8.1 +/- 1.0 l/min/m(2) during submaximal exercise, P = 0.0001. There was no difference in heart rate or increase in heart rate between the two groups. One year after surgery, cardiac index had significantly increased in the pectus group, P = 0.0054 although cardiac index was still significantly lower 7.2 +/- 1.0 l/min/m(2) when compared with the control subjects (8.5 +/- 1.6 l/min/m(2), P = 0.0008). Both the patients and the controls increased their VO(2) max during the one-year study period although the controls increased most. Right ventricular diastolic dimension increased in both groups over the one-year study period and left ventricular dimensions increased in the patients. Before operation, the patients had lower forced expiratory capacity FEV(1) 86 +/- 13% when compared with controls 94 +/- 10%, P = 0.009. Patients increased FEV(1)/forced vital capacity over the one-year long study course although there were no differences between groups. CONCLUSION: Patients with pectus excavatum have lower cardiac index at submaximal exercise when compared with healthy age-matched controls. Their cardiac index and FEV(1) are increased one year after the modified Nuss operation. PMID- 22219454 TI - Is increased perfusion pressure really necessary during cardiopulmonary bypass? PMID- 22219455 TI - Left atrial size predicts the onset of atrial fibrillation after major pulmonary resections. AB - OBJECTIVES: Atrial fibrillation (AF) is a frequent complication after pulmonary resections. Notwithstanding prevention and early treatment it may show a negative impact on the outcome. We assessed the role of echocardiographic variables to predict the onset of this complication. METHODS: One-hundred and thirty-four patients were prospectively evaluated: 72 (53.7%) (Group I) underwent lobectomy or pneumonectomy; 62 (46.3%) receiving minor thoracic procedures were included in Group II. Previous AF was the only exclusion criteria. All patients preoperatively underwent bidimensional echocardiography. Demographics, type of resection, histology, staging, diagnosis of chronic obstructive pulmonary disease , induction chemotherapy, smoking history, magnesium levels, other cardiologic diseases, electrocardiographic and echocardiographic findings (atrial and ventricular diameters, left atrial area, left ventricular ejection fraction and diastolic dysfunction) were assessed. RESULTS: Preoperative variables did no't show any statistically significant difference between the groups. In 21 patients (15.7%) AF was observed 3.7 +/- 1.8 days after surgery. All AF episodes occurred in Group I. Three patients (2.2%) with AF died during the postoperative course. The left atrial diameter and area were significantly enlarged in patients with AF (P = 0.001 and P < 0.0002); 18 AF episodes (86%) occurred in patients with atrial enlargement. At univariate analysis low postoperative magnesium levels, LV diastolic dysfunction, left atrial antero-posterior diameter >40 mm, left atrial area above 20 mm(2) and extended resections were statistically significant. At multivariate analysis only left atrial area enlargement was an independent predictive prognostic factor for postoperative AF. CONCLUSIONS: Echocardiographic left atrial size evaluation may be useful to predict the onset of postoperative AF in patients undergoing lobectomy and pneumonectomy. PMID- 22219456 TI - Reviewing alpha-Gal in valve immunology. PMID- 22219458 TI - Repair of pectus excavatum. Are we doing it better just to make it look better? PMID- 22219459 TI - Surgical time out checklist with debriefing and multidisciplinary feedback improves venous thromboembolism prophylaxis in thoracic surgery: a prospective audit. AB - OBJECTIVES: There is a significant global burden of preventable morbidity and mortality after surgery caused by avoidable adverse events. Venous thromboembolism (VTE) prophylaxis, despite evidence for its efficacy, is not reliably and consistently prescribed, and is currently a serious concern for patient safety. The aim of this study was to prospectively audit errors captured by an extended surgical time out checklist and relate them to the introduction of a safety culture. METHODS: The use of an extended surgical time out checklist was prospectively audited, in consecutive patients in one operating theatre over a period of two years. Errors captured were analysed and related to other improvements to safety culture; human factors training, debriefing and regular departmental meetings. RESULTS: Time out was performed in 959 patients of 990 (96.8%) undergoing thoracic surgery. Performance was consistent over time. Errors were categorized as VTE prophylaxis (n = 53, 6%), blood products (n = 11), clerical (n = 5), imaging (n = 2) and miscellaneous (n = 2). After a lag period of 15 months, during which the team underwent human factors training, introduced debriefing and escalated VTE prophylaxis to regular departmental meetings, VTE prophylaxis errors were substantially reduced. The temporal relationship between error capture and error elimination is explored. CONCLUSIONS: Use of checklists alongside appropriate human factors training, debriefing and regular multidisciplinary communication can substantially improve VTE prophylaxis in patients undergoing surgery. PMID- 22219460 TI - CD26/DPP-4 inhibition recruits regenerative stem cells via stromal cell-derived factor-1 and beneficially influences ischaemia-reperfusion injury in mouse lung transplantation. AB - OBJECTIVES: The CD26 antigen is a transmembrane glycoprotein that is constitutively expressed on activated lymphocytes and in pulmonary parenchyma. This molecule is also identified as dipeptidyl peptidase-4 (DPP-4) that cleaves a host of biologically active peptides. Here, we aimed to identify an important substrate of CD26/DPP-4-stromal cell-derived factor-1 (SDF-1/CXCL12)-as a key modulator for stem-cell homing together with its receptor CXCR4 in response to ischaemic injury of the lung. METHODS: Orthotopic single lung transplantation (Tx) was performed between syngeneic C57BL/6 mice. Inhibition of CD26/DPP-4 activity in recipients was achieved using vildagliptin (10 mg/kg, every 12 h) subcutaneously, and 6 h ischaemia time was applied prior to implantation. Forty eight hours after Tx, lung histology, SDF-1 levels (enzyme-linked immunosorbent assay) in lung, spleen and plasma, and expression of the SDF-1 receptor CXCR4 in blood and lung were assessed. Homing of regenerative progenitor cells to the transplanted lung was evaluated using fluorescent-activated cell sorting. RESULTS: Compared with untreated lung transplanted mice, systemic DPP-4 inhibition of Tx recipients resulted in an increase in protein concentration of SDF-1 in plasma, spleen and lung. Concordantly, the frequency of cells bearing the SDF-1 receptor CXCR4 rose significantly in the circulation and also in the lungs of DPP-4-inhibited recipients. We found co-expression of CXCR4/CD34 in the grafts of animals treated with vildagliptin, and the stem-cell markers Flt-3 and c-kit were present on a significantly increased number of cells. The morphology of grafts from DPP-4 inhibitor-treated recipients revealed less alveolar oedema when compared with untreated recipients. CONCLUSIONS: Targeting the SDF-1-CXCR4 axis through CD26/DPP-4 inhibition increased the intragraft number of progenitor cells contributing to the recovery from ischaemia-reperfusion lung injury. Stabilization of endogenous SDF-1 is achievable and may be a promising strategy to intensify sequestration of regenerative stem cells and thus emerges as a novel therapeutic concept. PMID- 22219461 TI - Extended cervical mediastinoscopy: mature results of a clinical protocol for staging bronchogenic carcinoma of the left lung. AB - OBJECTIVE: The objective of this study is to evaluate the accuracy of extended cervical mediastinoscopy (ECM) in the staging of bronchogenic carcinoma (BC) of the left lung based on our updated experience. METHODS: From 1998 to 2003, 89 patients underwent routine ECM for staging of BC of the left lung. In 2004, routine positron emission tomography (PET) was included in our staging protocol and ECM was reserved for those with positive mediastinal or hilar PET images, large lymph nodes on computed tomography (CT) scan or central tumours. Following this protocol, from 2004 to 2010, we performed 132 selective ECM. ECM was considered positive when metastatic nodes or tumour involvement directly in the subaortic or para-aortic regions was confirmed pathologically. Patients with negative ECM underwent subsequent thoracotomy for tumour resection and systematic nodal dissection (SND). RESULTS: Two hundred and twenty-one ECMs were performed from 1998 to 2010 (89 routine and 132 selective). In the routine ECM protocol, four cases were positive and thoracotomy was contraindicated. The remaining 85 patients were operated and five had nodal disease in subaortic (LN5) or para aortic (LN6) stations. In the selective ECM protocol (n = 188), 132 patients underwent ECM and in 19 it was positive; the remaining 113 patients underwent thoracotomy and SND found involved LN5 or LN6 in six patients; the other 56 patients underwent direct thoracotomy and four had positive LN5 or LN6. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of ECM were 0.67, 1, 1, 0.94 and 0.95, respectively. The staging values of routine/selective ECM protocols were 0.44/0.65, 1/1, 1/1, 0.94/0.94 and 0.94/0.95, respectively. CONCLUSIONS: Selective ECM protocol according to CT and PET findings has high negative predictive value and accuracy. Therefore, its selective use is recommended because it saves around 30% ECM without decreasing staging values of the current protocol. PMID- 22219462 TI - Prospective trial evaluating sonography after thoracic surgery in postoperative care and decision making. AB - OBJECTIVE: Following thoracic surgery, daily chest X-rays (CXRs) are performed to assess patient evolution and to make decisions regarding chest tube removal and patient discharge. Sonography after thoracic surgery (SATS) has the potential to be an effective, convenient, inexpensive and easy to learn tool in the post operative management of thoracic surgery patients. We hypothesized that SATS could alleviate the need for repetitive CXRs, thus reducing the related risks, costs and inconvenience. METHODS: This study consisted of a prospective cohort trial. All patients scheduled to undergo thoracic surgery at a single academic medical centre were eligible. Post-operative bedside pleural ultrasound was performed whenever a CXR was ordered by the treating team. Investigators specifically assessed patients with the goals of identifying pleural effusions and pneumothoraces. Study investigators were blinded to CXR results. SATS findings were compared with CXRs, which were considered the gold standard in routine post-operative pleural space evaluation. RESULTS: One hundred and twenty patients were prospectively enrolled over a 5.5-month period. Three hundred and fifty-two ultrasound examinations were performed (mean = 3.0 +/- 2.4 exams per patient). The time interval between the ultrasound and the comparative CXR was 166 +/- 149 min. The mean time required to perform SATS was 11 +/- 6 min per exam. In the detection of pleural effusion, SATS yielded a sensitivity of 83.1% and a specificity of 59.3%. In the detection of pneumothoraces, a sensitivity of 21.2% and a specificity of 94.7% were obtained. CONCLUSIONS: Post-operative ultrasound may alleviate the need to perform routine CXR in patients with a previously ruled out pneumothorax. SATS used selectively may be able to reduce the number of routine CXRs performed; however, it does not have high enough accuracy to replace CXRs. PMID- 22219463 TI - Endoscopic management of post-lung transplantation anastomotic stenosis: metallic, silicone or biodegradable stents. PMID- 22219464 TI - Favourable outcomes after high-risk conventional aortic valve replacement: can we do even better? PMID- 22219467 TI - Use of surveillance criteria reduces interstage mortality after the Norwood operation for hypoplastic left heart syndrome. AB - OBJECTIVES: While hospital mortality after the Norwood operation for hypoplastic left heart syndrome (HLHS) has decreased steadily, interstage mortality until the superior cavopulmonary anastomosis (SCPA) remains a major concern. Our aim was to institute a home surveillance programme to decrease interstage mortality. METHODS: We enrolled 45 HLHS patients surviving the Norwood operation into our home surveillance programme and compared them with 97 patients treated before the initiation of the programme and with a third group of 20 patients not discharged between the first- and the second-stage operation. While still in hospital, parents were taught to record weight and fluid intake as well as oxygen saturations with the help of a vital sign monitor. During the last week of the hospital stay, the following criteria had to be met: oxygen saturation >75%, weight gain of at least 20-30 g in 3 days and a maximum weight loss of 30 g in a day. After discharge, these criteria had to be maintained at all times or the parents were supposed to call our hospital. Additionally, an experienced paediatric cardiologist from our centre called the parents at home once a week. RESULTS: Interstage mortality was reduced significantly from 12.4% (12/97) to 2.2% (1/45) (P = 0.042). The number of patients, who were not discharged before the SCPA, was significantly higher after the start of the home surveillance programme (12/57 vs. 8/105, P = 0.022). After discharge, 14 (31%) infants breached the surveillance criteria. Of these, one patient died and eight patients were operated earlier (SCPA, n = 6; shunt replacement, n = 2). The remaining five patients could be discharged home after observation. Children in the home surveillance programme were younger [102 (67-299) vs. 152 (77-1372) days, P = 0.001] and weighed less (5.09 +/- 0.79 vs. 5.75 +/- 1.22 kg, P = 0.001) at the SCPA compared with the remainder. Early survival after SCPA was not different. CONCLUSIONS: The home surveillance programme led to an important decrease in interstage mortality. The adherence to the surveillance criteria before discharge resulted in a larger number of patients receiving inpatient treatment until SCPA. Earlier SCPA in the surveillance group had no negative impact on early survival after SCPA. PMID- 22219468 TI - Unusual presentation of cryolife O'Brien(R) stentless aortic valve bioprosthesis dysfunction mimicking infective endocarditis. AB - OBJECTIVES: We previously reported a possible but unusual prosthetic-valve infective endocarditis (PV-IE) occurring on a Cryolife O'Brien Stentless Porcine Xenograft (CLOB) (anatomic damages suggestive of IE but negative inflammatory and microbiological markers). We reviewed all cases of aortic PV-IE admitted in our institution and compared the clinical presentation, bacteriological and echocardiographic features according to the type of prosthesis. METHODS: Sixty consecutive cases with possible or definite aortic PV-IE (23 CLOB, 26 mechanical valve and 11 stented bioprosthesis) were admitted between 2002 and 2008. RESULTS: Patients with CLOB had more prosthetic dehiscence (P = 0.006) and severe regurgitation (P = 0.01) than those with mechanical or stented prosthetic valves. In contrast, they had less fever (P = 0.003), lower C-reactive protein (CRP) levels (P = 0.02) and more frequently negative blood cultures (P = 0.08). Differences were due to seven patients who presented with no fever, low CRP, negative blood culture, negative valve culture and PCR when performed, despite echocardiographic features suggestive of IE (abscess or valve dehiscence). All were first operated on since 2004 when the manufacturing process changed and required a second surgery. The French Authority of Health was informed leading to the withdrawal of the CLOB from the market in 2010. CONCLUSIONS: One-third of patients with CLOB admitted for possible or definite PV-IE presented with anatomic damages suggestive of IE but with negative inflammatory and microbiological markers. The exact aetiology remains unclear, but the present data have led to the worldwide withdrawal of prosthesis in 2010. A close follow up of patients implanted with CLOB should be advised, especially if it has been manufactured since 2004. PMID- 22219469 TI - Long-term survival after lung-sparing total pleurectomy for locally advanced (International Mesothelioma Interest Group Stage T3-T4) non-sarcomatoid malignant pleural mesothelioma. AB - OBJECTIVES: There is a body of opinion that advocates extrapleural pneumonectomy (EPP) as the only radical treatment option for locally advanced (T3/T4) malignant pleural mesothelioma (MPM). We tested the hypothesis that lung-sparing total pleurectomy (LSTP) can be as effective as EPP in locally advanced MPM with reduced risk. METHODS: We analysed prospective data on 165 patients (128 with epithelioid and 37 with biphasic MPM) with pT3 (n = 108) and pT4 (n = 57) tumours. Ninety-eight (59.4%) of the patients underwent EPP and 67 (40.6%) LSTP. We compared intergroup differences in: length of stay (LOS), post-operative complications, survival, pattern of disease progression and disease-free interval (DFI). RESULTS: There were significantly more complications after EPP: 67 (68%) vs. 29 (43%) in LSTP, P = 0.002. Thirty-day mortality was 7% for EPP and 3% for LSTP (P = 0.31). LOS was similar (mean 19 days for EPP, 15 days for LSTP, P = 0.19). We noted only minor differences in the initial site of disease progression. In 33 (41%) of EPP patients, disease progressed locally compared with 22 (44%) after LSTP. Seventeen patients post-EPP (21%) had distal progression compared with only three (6%) post-LSTP and synchronous distal and local recurrence was similar: 15 (19%) post-EPP vs. 12% for LSTP (P = 0.11). There was no significant intergroup difference in median survival: EPP 14.7 months (SE 1.3, 95% CI 12.2-17.2) vs. LSTP 13.4 months (SE 1.9, 95% CI 9.7-17.1), P = 0.91, nor in DFI: EPP 10.7 months (SE 0.8, 95% CI 9-12) vs. LSTP 16 months (SE 1, 95% CI 9-22). In chemonaive patients (n = 124), adjuvant chemotherapy was received by significantly more patients after LSTP (32/53 LSTP vs. 26/71 EPP patients, P = 0.011). Estimated 1-5 years survival for EPP was 58, 30, 11, 9 and 6% and for LSTP 52, 28, 20, 13 and 4%. CONCLUSIONS: In disagreement with standard opinion, we advocate LSTP as the procedure of choice in locally advanced MPM: it offers at least equally as good oncological results as EPP in this group of patients with reduced early complications. Despite a tendency for increased local recurrence in the LSTP group, overall survival is not compromised. PMID- 22219470 TI - Totally thoracoscopic closure for atrial septal defect on perfused beating hearts. AB - OBJECTIVES: To investigate the feasibility and safety of non-robotically assisted totally thoracoscopic closure for atrial septal defect (ASD) on perfused beating hearts. METHODS: Twenty-four patients (8-45 years, mean 14.4 +/- 18.7) underwent ASD closure on beating hearts by a totally thoracoscopic approach without the aid of a robotic surgical system. Additional 72 patients undergoing totally thoracoscopic ASD closure on cardioplegic arrested hearts were selected as a control. Cardiopulmonary bypass (CPB) was achieved peripherally. The aorta was not cross-clamped in the study group but it was cross-clamped in the control group. RESULTS: ASD closure was successful in all study and control group patients without in-hospital mortality or major complications. The total duration of operation (76 +/- 9 vs. 98 +/- 6 min, P = 0.012), CPB time (32 +/- 5 vs. 48 +/ 4 min, P = 0.001), duration of intensive care stay (10.0 +/- 5.1 vs. 19.2 +/- 4.2 h, P = 0.003) and post-operative hospital stay (4.5 +/- 0.8 vs. 5.0 +/- 1.1 days, P = 0.045) in the study group were shorter than in the control group. There was no statistically significant difference in the proportion of patients requiring in-operation blood transfusion between study group and control group (25.0 vs. 36.1%, P = 0.226). Follow-up transthoracic echocardiography on Day 5 and Day 30 showed no residual shunts in study or control group patients. CONCLUSIONS: Non-robotically assisted totally thoracoscopic closures of ASD on perfused beating hearts are feasible and safe. These procedures are associated with a shorter operation time and a shorter hospital stay than in surgeries on cardioplegic arrested hearts. PMID- 22219471 TI - Caveats in using vacuum-assisted closure for post-pneumonectomy empyema. AB - OBJECTIVES: Vacuum-assisted closure (VAC) of chronic empyemas can potentially set challenging patients free of prolonged hospitalization by warranting outpatient care. We wanted to test this concept in post-pneumonectomy empyema patients. METHODS: Three patients with post-pneumonectomy bronchopleural fistula were subjected to open window thoracostomy (OWT) and subsequently to VAC. The BPFs were closed by endobronchial stents in 2 of the patients. The VAC system was applied at a median time of 35 days (range, 23-113) after pneumonectomy. The patients were scheduled for outpatient visits every three days with complete change of the VAC sponges. RESULTS: Hypotension and acute thoracic pain despite minimal suction applied to the VAC sponges were observed during treatment and eventually caused VAC discontinuation. In one patient, the sponges of the VAC system could not be directly removed through the OWT and careful dissection through VATS under deep sedation was needed. CONCLUSIONS: VAC can be of help to obliterate the post-pneumonectomy empyema cavity but its use can trigger clinically significant complications. Cautious monitoring of the VAC system must be exercised in the early period prior to discharging patients to the outpatient clinic. PMID- 22219472 TI - Primary pericardial spindle cell sarcoma mimicking left main coronary artery disease. AB - Primary spindle cell sarcoma in the heart is a very uncommon disease. Although primary atrial or pulmonary vein spindle cell sarcomas have been sporadically reported, pericardial spindle cell sarcoma is rarely seen in currently available data. The commentary here is on a primary pericardial spindle cell sarcoma that was preliminarily misjudged to be left main coronary artery disease. PMID- 22219473 TI - Renal impairment and transapical aortic valve implantation: impact of contrast medium dose on kidney function and survival. AB - OBJECTIVE: Patients undergoing transapical aortic valve implantation (TA-AVI) are usually over 80 years old and have a high prevalence of chronic kidney disease. However, transcatheter valve therapies require the use of contrast injections with the risk of nephrotoxicity. The aim of this study was to evaluate post operative kidney function and survival in patients with pre-existing renal impairment with regard to the amount of contrast media used during TA-AVI. METHODS: From January 2008 to March 2011, 50 patients (52% females, mean age 80.7 +/- 5.3 years) with a serum creatinine level of >1.3 mg/dl were investigated. Patients receiving a dose of <100 ml of a contrast agent (low-dose group, n = 24) were separated from those who received >100 ml of a contrast agent (high-dose group, n = 26). An acute contrast-induced nephropathy (CIN) was defined as a serum creatinine increase of 0.5 mg/dl or by >25% of a baseline value within 48 h from contrast medium administration. Patients in both groups had similar characteristics in terms of age, sex, body mass index and comorbidities. RESULTS: The median pre-contrast creatinine was 1.67 (1.37-1.83) mg/dl in the low-dose group and 1.51 (1.26-1.98) mg/dl in the high-dose group (P = 0.76). The post contrast creatinine at 48 h was 1.53 (1.33-2.05) and 2.29 (1.67-2.86) mg/dl in the groups receiving low- and high-dose contrast agents, respectively (P = 0.007). CIN occurred in 41.7% (n = 10) of patients in the low-dose contrast group and in 69.2% (n = 18) in the high-dose contrast group (P = 0.046). Haemodialysis is necessary for 16.7% of the low-dose group and 38.5% of the high-dose group (P = 0.12). Trends towards longer intensive care unit and hospital stay were seen in patients with an extensive use of contrast media [4.3 (2.5-6.5) vs. 5 (3-7.8) days and 12 (9-14.3) vs. 13 (9-18) days, P = 0.091 vs. P = 0.546, respectively]. Regarding death, 3-month and 3-year mortality were significantly higher in the high-dose group (8.3 vs. 30.8%, P = 0.036 and 25 vs. 61.5%, P = 0.004, respectively). CONCLUSIONS: Our results indicate a possible association between higher CIN and mortality rate and the extensive use of contrast media during TA AVI among high-risk patients with pre-existing renal impairment. PMID- 22219474 TI - Role of osteopontin in the development of neointimal hyperplasia in vein grafts. AB - OBJECTIVES: Neointimal hyperplasia and superimposed atherosclerosis are central to late vein graft failure following coronary artery bypass grafting. Recent studies on post-injury arterial vessels have suggested a role of osteopontin (OPN) in the process of vascular remodelling. This study was designed to assess the in vivo performance of OPN following vein grafting. METHODS: Bilateral saphenous vein-carotid artery interposition grafting was performed in 16 Large White pigs (35-45 kg). All patent vein grafts were removed and fixed at 1, 2, 4 (n = 8 grafts in each group) and 12 weeks (n = 6 grafts) following surgery. Multiple histological sections from each graft were prepared. The expression of OPN in the vein grafts was determined by immunostaining and western blot assay. Proliferating cell nuclear antigen (PCNA) was detected by immunocytochemistry. Vein graft morphology was assessed using computer-aided planimetry. RESULTS: The expression of OPN remarkably increased in the intima of the vein grafts at the first week postoperatively and then gradually declined from the second postoperative week, although OPN expression remained significantly higher than the baseline level at the end of the 3-month study period. More importantly, the number of PCNA-positive cells and matrix metalloproteinases (MMPs) expression correlated well with the OPN expression. CONCLUSIONS: Early induction of OPN in vein grafts may contribute to the subsequent increase in MMPs activities as well as vascular smooth muscle cell proliferation. Therefore, OPN could play an important role in the development of neointimal hyperplasia in venous conduits after coronary artery bypass grafting. PMID- 22219475 TI - A dose-response study of levosimendan in a porcine model of acute ischaemic heart failure. AB - OBJECTIVES: Levosimendan is a novel inotropic agent claimed to improve myocardial contractility by a calcium-sensitizing effect. Our aim was to evaluate dose dependent effects of levosimendan on left ventricular (LV) contractility and energetic properties in an acute, ischaemic heart failure porcine model. METHODS: Six pigs were used in an anaesthetized in vivo open-chest model. The time points of measurements were: baseline, after heart failure induction and after dose 1-4 (D1-D4). Heart failure was induced by microembolization of the left coronary artery before infusion of four different doses (D1: 2.5 ug/kg, D2: 10 ug/kg, D3: 40 ug/kg, D4: 80 ug/kg) of levosimendan. Haemodynamics were assessed by the pressure-conductance catheter technique. LV oxygen consumption was calculated from coronary flow measurements and coronary sinus blood gases. Mitochondrial respiration was studied in biopsies of the LV. RESULTS: Levosimendan had no significant, load-independent effect on contractile force (slope of preload recruitable stroke work was 34 mmHg immediately following failure and 39 (P = 0.406), 42 (P = 0.219), 46 (P = 0.067) and 41 (P = 0.267) at D1-D4), although the more load-dependent contractility indicator of dP/dt(max) was slightly increased at dose 4 (P < 0.05). LV energy conversion efficiency (PVA-MVO2 relationship) remained unaltered at all doses. Maximal mitochondrial respiration decreased after induction of failure and remained at an unaltered low level during levosimendan infusion. CONCLUSIONS: Surprisingly, levosimendan had no significant effect on contractility, energy efficiency and mitochondrial respiration of the LV, in a porcine model of acute heart failure. At high doses, levosimendan induced vasodilatation and increased heart rate and cardiac output. PMID- 22219476 TI - Double-orifice mitral valve: a rare congenital anomaly. PMID- 22219477 TI - Mid-term outcomes after off-pump coronary surgery in patients with prior intracoronary stent. AB - OBJECTIVE: An increasing number of patients undergoing heart surgery have had a prior coronary stent placement. This study was designed to examine the effect of this situation on the mid-term outcomes of off-pump coronary artery bypass graft (OP-CABG) surgery. METHODS: A comparative retrospective non-randomized comparison was performed as follows: all patients undergoing OP-CABG from January 2005 to December 2009 at our centre were divided into two groups: those who did or did not have stents at the time of surgery. We compared the incidences of the following events: (i) death and (ii) combined major adverse cardiac events (MACEs): death, myocardial infarction (MI) and repeat revascularization. Cox's proportional hazards analysis adjusted by a propensity score (n:m) were performed to determine the effects of prior stent placement on the risks of such events. RESULTS: A total of 1020 patients were included, of which 156 (15.6%) had at least one stent. The median follow-up was 32.32 months (interquartile rank 18.08 48). The overall 1, 3 and 5-year survival rates were 95, 92 and 91% for the without-stent group vs. 82, 77 and 74% for the with-stent group, respectively. The 1, 3 and 5-year survival rates free from MACEs were: 92, 87 and 76% for patients without stent vs. 77, 66 and 56% for those with stents. Patients with stent showed an increased risk of death [hazard ratio (HR) 3.631, 95% confidence interval (CI) 2.29-5.756] and MACEs (HR 2.784, 95% CI 1.962-3.951). When adjusted by the propensity score, prior stent placement continued to increase the risks of death (HR 3.795, 95% CI 2.319-6.21) and MACEs (HR 2.89, 95% CI 2.008-4.158). CONCLUSIONS: Patients with intracoronary stents have a lower survival rate and a greater risk of death, MI or need for repeat revascularization during the mid term follow-up after OP-CABG. PMID- 22219478 TI - Aortic valve replacement in patients with previous coronary artery bypass grafting: 10-year experience. AB - OBJECTIVES; This study aimed to investigate the early and late outcomes of patients undergoing aortic valve replacement (AVR) with previous coronary artery bypass grafting (CABG) and patent grafts. METHODS: Between January 2000 and March 2010, 104 patients (87 males) with previous CABG +/- concomitant surgery and patent grafts underwent AVR. The median age of the patients was 75 years (range: 37-90 years; inter-quartile range: 69-79 years) and the mean logistic EuroScore was 25.37 +/- 16.8. The median time since the previous operation was 9 years (range 1-25; inter-quartile range: 7-14 years). The left internal mammary artery (LIMA) had been used in 75 patients (72.1%) and remained patent in 72 cases (96.0%). RESULTS: Thirty-day mortality was 7.7% (n = 8), which is less than the predicted mean logistic EuroScore. Isolated AVR was performed in 66 patients (63.5%). The LIMA was dissected and isolated (clamped or blocked with balloon) in 60 patients. The median hospital stay was 10 days (range: 4-183 days; inter quartile range: 7-15.25 days). Nineteen patients (18.3%) had pulmonary complications, while 12 (11.5%) had acute kidney injury. Seven patients (6.7%) required permanent pacemaker. Six LIMAs (8.3%) were injured and repaired. Prolonged aortic cross-clamp (AXC) time (P = 0.038) and the presence of a previous LIMA graft (P = 0.045) were identified as independent predictors of 30 day mortality. The actuarial survival at 1 and 5 years was 89.4 +/- 0.3 and 81.5 +/- 0.5%, respectively. Perioperative intra-aortic balloon pump use (P = 0.036), prolonged AXC time (P = 0.004) and prolonged cardiopulmonary bypass time (P = 0.022) were associated with worse long-term overall survival on multivariate analysis. CONCLUSIONS: AVR post-CABG with patent grafts can be performed in high risk patients with excellent short- and long-term outcomes and appears to be superior to published catheter-based interventions. In the absence of randomized trial data, we believe that open AVR remains the treatment of choice for aortic valve disease following prior CABG. PMID- 22219479 TI - Giant left ventricular pseudoaneurysm following coronary artery bypass graft surgery. PMID- 22219480 TI - Carcinoid heart disease: outcomes after surgical valve replacement. AB - OBJECTIVES: To describe the early and late outcomes of carcinoid patients undergoing surgical heart valve replacement. METHODS: In a retrospective study, records of patients with symptomatic carcinoid heart disease referred for valve surgery between 1993 and 2010 at two academic centres were reviewed. The perioperative and postoperative outcomes were analysed. RESULTS: Nineteen patients, with a mean age of 56 +/- 9.6 years, underwent cardiac surgery for carcinoid syndrome. Sixteen patients underwent implantation of one or more mechanical bileaflet valve prosthesis and three patients had one or more bioprosthetic valves implanted. Survival after 1 and 5 years was 71 and 43%, respectively. Six out of nine survivors were at last follow-up in New York Heart Association class I. Valve-related events such as valve thrombosis or bleeding complications were not registered. Echocardiography showed improvement of right ventricular dilatation in 80% of patients. CONCLUSIONS: Despite advanced cardiac morbidity at the time of operation, early postoperative survival was 90%. Long term survival of patients with carcinoid heart disease undergoing valve replacement is determined by carcinoid progression. The surviving patients had a persistent improvement in functional capacity without valve-related complications of the mechanical prosthesis. PMID- 22219481 TI - Impact of preoperative mitral valve regurgitation on outcomes after transcatheter aortic valve implantation. AB - OBJECTIVES: The aim of this single-centre prospective study was to assess the impact of preoperative mitral valve regurgitation (MR) on outcomes of patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: From June 2007 to January 2011, 176 consecutive patients underwent TAVI at our institution. Patients were divided into two groups according to the degree of MR: <2+, the NoMR group (133 patients); >=2+, the MR group (43 patients). Clinical and echocardiographic examination were performed before the procedure, at discharge, 1, 3, 6, 12 months after TAVI and yearly thereafter. The mean follow-up was 10.4 +/- 7.7 months (range 1-36). RESULTS: MR patients had higher EuroSCORE (27 +/- 16 vs. 20 +/- 11%, P < 0.001), lower ejection fraction (49 +/- 13 vs. 57 +/- 12%, P = 0.001), higher systolic pulmonary pressure (50 +/- 17 vs. 39 +/- 10 mmHg, P < 0.001) and larger left ventricular volumes (end-diastolic volume index: 78 +/- 29 vs. 66 +/- 20 ml/m(2), P = 0.002) than NoMR. Hospital mortality was 9.3% (four patients) and 3% (four patients) in MR and NoMR groups, respectively (P = 0.10). The Kaplan-Meier survival at 20 months was 78 +/- 8 and 75 +/- 6% in MR and NoMR groups, respectively (P: n.s.). At follow-up, the degree of MR in the MR group decreased to trivial-mild in 28% of patients. Patients of both groups experienced a significant reduction in the New York Hear Association class, being in class I II in 91% of cases. CONCLUSIONS: Patients undergoing TAVI with preoperative MR >= 2+ have a higher surgical risk profile and a trend towards higher hospital mortality. MR was not identified as a risk factor for mortality. At follow-up, a reduction in MR and an improvement of echocardiographic parameters were observed in the MR group. PMID- 22219482 TI - Which factors are associated with actual 5-year survival of oesophageal squamous cell carcinoma? AB - OBJECTIVES; The demographic and clinicopathologic factors associated with 5-year survivors have not been well documented in oesophageal squamous cell carcinoma (OSCC). We evaluated factors predictive of actual 5-year survival in the present research. METHODS: We analysed 1241 patients underwent oesophagectomy for invasive OSCC retrospectively. The demographic and clinicopathologic characteristics were compared between patients who were alive >5 years after oesophagectomy and patients who died within 5 years of oesophagectomy. RESULTS: Univariate analysis showed significant differences between the two groups regarding 11 different factors. Further analysis by logistic regression showed that eight factors were identified as independent predictors of actual 5-year survival. CONCLUSIONS: The independent positive predictors for actual 5-year survival are younger patients, female gender, absence of weight loss, R0 resection, lower pathological T stage, lower pathological N stage, higher histologic grade and more resected lymph nodes. PMID- 22219483 TI - Giant ascending aorta streptococcal endaortitis. PMID- 22219484 TI - Lung transplantation research: impact of a new surgical model. PMID- 22219485 TI - Usefulness of 3D transoesophageal echocardiography in the evaluation of prosthetic valve dehiscence. PMID- 22219486 TI - Mitral valve replacement with posterior transposition of the anterior mitral leaflet which covers and buttresses partially decalcified posterior mitral annular bed. AB - Mitral valve replacement (MVR) in the presence of the extensive calcification of the mitral annulus is a technical challenge. The heavily calcified annulus can cause great difficulty in the insertion of a prosthetic valve and periprosthetic leakage later on. Vigorous annular decalcification may cause circumflex coronary artery injury, atrioventricular rupture and thromboembolic events. We herein describe a surgical technique for MVR in such cases while focusing on partial decalcification of the posterior mitral annulus and its reinforcement and buttressing with the transferred anterior mitral leaflet (AML). At the same time, the transferred AML supports the posterior annular region and maintains ventricular-annular continuity, thus preserving the left ventricular function. PMID- 22219487 TI - Early and late failure of tissue-engineered pulmonary valve conduits used for right ventricular outflow tract reconstruction in patients with congenital heart disease. AB - OBJECTIVES: To identify factors associated with the surgical outcome in patients undergoing right ventricular outflow tract reconstruction (RVOTR) using decellularized tissue-engineered pulmonary valve conduits (TEPVc) and to study their safety and longevity. METHODS: From April 2006 to April 2010, 93 patients underwent either palliative or corrective RVOTR using Matrix P (37) and Matrix P Plus (56) xenogenic decellularized TEPVc (size range 11-27 mm). Median age and weight at operation were 20 (0.16-290) months and 10.15 (2.65-86) kg respectively. Primary and redo surgery occurred in 40 and 60% of cases, respectively. Eighty-eight patients (94.6%) received conduit implantation in the framework of corrective surgery, whereas in 5 (5.4%) a palliative procedure was undertaken. Follow-up was complete in 91% of patients, with a median duration of 12 months (range: 2 days-51 months). Data analysis included diagnosis, type of surgery (palliative vs. corrective) and age at surgery. Predetermined primary outcomes were represented by conduit failure or dysfunction. RESULTS: Two patients with Matrix P and two with Matrix P Plus died in the early post operatively phase (4.3%). None of the deaths were conduit-related. One patient died at conduit replacement. Thirty-three patients (35.5%) experienced conduit failure whereas conduit dysfunction occurred in 27 patients (29%). Two-year freedom from conduit failure and dysfunction was 60.2% (95% CI: 50.1-69.6) and 77.4% (95% CI: 67.9-84.7), respectively. Reasons for failure were conduit stenosis in 20 cases (61%), pseudoaneurysm in 3 (9%), conduit dilatation (>50% of original diameter) in 2 (6%), stenosis of distal anastomosis involving pulmonary bifurcation in 6 (18%) and allograft dissection in 2 (6%). Histological examination showed inflammatory giant-type cells in the presence of a poor autologous cell seeding in all explanted specimens. Univariate and multivariate analyses showed an association between age at surgery <=1 year and conduit dysfunction (adjusted HR: 2.29; 95% CI: 1.01-5.20, P = 0.04). CONCLUSIONS: Compared with the other conduit for RVOTR Matrix conduits showed a high incidence of failure. Our results suggest that the use of Matrix conduits for RVOTR should be considered with caution. PMID- 22219488 TI - Does listing for heart transplant for longer than 30 days before ventricular assist device implantation influence utilization of psychotherapeutic support and outcome? AB - OBJECTIVES: Previous studies indicate that patients with mechanical ventricular assist devices (VADs) experience high psychosocial and emotional distress. Listing for transplant may trigger psychosocial adjustment to the transplantation as an upcoming critical life-event. We hypothesized that patients could profit from this adaptation when implantation of a VAD becomes necessary. METHODS: We arbitrarily chose a cut-off at 30 days after being put on the heart transplantation (HTX) waiting list. Eighteen patients were listed for HTX for >30 days (referred to as 'listed') and 26 for shorter periods or not at all ('non listed'). Survival, the occurrence of mental disorders, the number of contacts of the patient with the psychologist and times spent on psychotherapeutic support for both patient groups and for their families were analysed. RESULTS: Survival after VAD implantation (observation time) and mental disorders were comparable for listed and non-listed patients. Mental disorders were developed in 80% of all patients irrespective of the listing group. The utilization of supportive psychotherapy did not differ between the listed and the non-listed group with regard to the number of contacts and to the time needed for individual therapy. Moreover, the number of families who requested support did not differ between the groups nor did the time spent on family therapy. However, the number of contacts and the time for individual psychotherapeutic support correlated with the observation time, whereas the time spent on family therapy did not. In contrast, family therapy correlated inversely with age. In addition, we compared bridge-to transplantation patients with destination therapy patients. There were no differences in the occurrence of mental disorders, the number of contacts or in the time expenses for individual and for family therapy, neither for all patients nor after stratification for listing. CONCLUSIONS: Our data indicate that listing for HTX for >30 days before VAD implantation does not reduce the utilization of psychotherapeutic support by VAD patients. We assume that structured emotional and psychosocial support by the interdisciplinary VAD team, including professional supportive psychotherapy, is indispensable for successful coping of VAD patients and their families. PMID- 22219489 TI - Ewing's sarcoma presenting as an isolated intra-cardiac mass. PMID- 22219490 TI - A rare association of tetralogy of Fallot and hypertrophic cardiomyopathy. AB - Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease. It is often associated with other congenital cardiac or non-cardiac defects. However, its association with hypertrophic cardiomyopathy (HCM) is rarely reported. We reported two cases. The first case is a full-term girl receiving modified Blalock-Taussig shunt creation and the second case is an 8 month old boy receiving total correction for TOF. Although they tolerated the operation well, both of them developed congestive heart failure and died of malignant cardiac arrhythmia several months after the operation. We made a literature review and only 11 case reports were found. There is currently no treatment guideline for this group of patients. From our limited experience and case reports, the physiology of HCM and TOF should both be taken into consideration when managing these patients. Close echocardiography follow-up with early myectomy and preventive implantation of implantable cardioverter defibrillator may be beneficial for them. PMID- 22219491 TI - Long-term survival after coronary artery bypass surgery stratified by EuroSCORE. AB - OBJECTIVES: Coronary artery bypass grafting (CABG) is performed for symptoms and for prognostic reasons. The EuroSCORE is widely utilized as a pre-operative risk prediction tool. We evaluated our long-term survival figures based on EuroSCORE. METHODS: A prospective database was retrospectively analysed and cross correlated with the UK strategic tracking service to evaluate survival after primary CABG. Patients were grouped based on their logistic EuroSCORE 0 to <5, 5 to <10, 10 to <15, 15 to <20, 20 to <25 and >=25. RESULTS: We analysed 13,337 primary cardiac procedures. A total of 9961 procedures had a logistic EuroSCORE of 0 to <5, 2041 of 5 to <10, 636 of 10 to <15, 281 of 15 to <20, 137 of 20 to <25 and 281>=25. Long-term survival is significantly affected by logistic EuroSCORE, P < 0.001. Patients with a logistic EuroSCORE <5% had significantly better initial survival and a lower rate of death over a 10-year period, P<0.001. Patients with a logistic score over 25 had a significantly worse 5-year survival, P<0.001. Logistic EuroSCORE was poor at predicting survival when >5 and <25. Cox multivariate regression and neuronal network analysis confirmed that the additional factors, diabetes, body mass index (BMI), post-operative myocardial creatinine kinase myocardial isoenzyme (CKMB) and left internal mammary artery (LIMA) usage, which are not incorporated in EuroSCORE significantly predict long term survival. CONCLUSIONS: Logistic EuroSCORE is a reasonable approximation for long-term survival after CABG, if the score is <5; however, its predictive capacity is limited due to the absence of LIMA usage, BMI, diabetes and CKMB in its calculation, all of which are significant factors affecting long-term survival. PMID- 22219492 TI - Urinary retention due to pelvic arteriovenous fistula following aortic valve replacement. PMID- 22219493 TI - Airway transplantation using aortic allografts: a 'hot topic'. PMID- 22219494 TI - Coronary artery bypass surgery in a patient with congenital absence of the left pericardium. PMID- 22219495 TI - A new look for EJCTS, ICVTS and MMCTS: better service for our readers with the support of our new publisher, the Oxford University Press. PMID- 22219496 TI - Aortic valve repair: a glimpse into the future. PMID- 22219497 TI - The challenge of defining procedural endpoints for the surgical treatment of atrial fibrillation. PMID- 22219498 TI - Excision or exclusion of left atrial appendage? PMID- 22219499 TI - Function of regulatory T-cells improved by dexamethasone in Graves' disease. AB - OBJECTIVE: Intrathyroid injection of dexamethasone (DEX) has been used to treat Graves' disease (GD); however, the mechanism of this treatment remains poorly understood. The objective of this study was to investigate the effects of DEX on the function of regulatory T (Treg) cells (CD4(+)CD25(+)T cells) in patients with GD. METHODS: Peripheral blood was obtained from 20 patients with GD, and peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll-Hypaque density gradient separation. CD4(+)CD25(-)/CD4(+)CD25(+)T cells were isolated by immunomagnetic selection and DEX was co-cultured with PBMCs or isolated T-cells for 72 h. Treg cell function was analyzed using the proliferation rate of CD4(+)CD25(-)T cells. RESULTS: The proportion of Treg cells and the transcription factor forkhead box P3 (FOXP3) mRNA expression in PBMCs decreased in GD patients compared with healthy subjects, and Treg cell function was impaired in patients with GD. Although the proportion of Treg cells and FOXP3 mRNA expression in PBMCs did not increase, the function of Treg cells improved after the treatment with DEX. Moreover, the proportion of T-helper 2 (Th2) cells was decreased by the DEX treatment. CONCLUSIONS: DEX could effectively improve the function of Treg cells and set up a new balance of Th1/Th2 in GD patients. This study might help to further understand the immune mechanism of the intrathyroid injection of DEX in the treatment of GD and facilitate the potential use of this therapy. PMID- 22219500 TI - Echocardiographic quantification of regional deformation helps to distinguish isolated left ventricular non-compaction from dilated cardiomyopathy. AB - AIMS: Pronounced trabeculation is presented in both left ventricular non compaction (LVNC) and dilated cardiomyopathy (DCM), which sometimes makes the differentiation difficult. We hypothesized that echocardiographic deformation analysis would help to differentiate these two cardiomyopathies. METHODS AND RESULTS: We investigated 15 patients with LVNC (9 males; 42 +/- 9 years), 15 age- and gender-matched DCM patients, and 15 healthy controls. The echocardiographic diagnosis of LVNC was confirmed by magnetic resonance imaging. In all subjects standard echocardiography and tissue Doppler imaging (TDI) to study regional LV deformation were carried out. No statistical difference was observed in standard echocardiographic parameters between LVNC and DCM patients. Compared with controls, both patient groups showed significantly reduced annular displacements (septal: controls 14 +/- 2 mm vs. DCM 6 +/- 3 mm vs. LVNC 7 +/- 3 mm) and reduced strain values of the LV segments. A characteristic deformation pattern with significantly higher values in the LV base compared with the apex was observed in patients with LVNC by deformation measurements with TDI. This gradient was found particularly in the lateral and inferior wall but spared the anteroseptal wall; non-compaction was not found in basal segments throughout the ventricle and also spared the anteroseptal midventricular wall. In DCM the strain and strain rate values were homogeneously reduced in all LV segments. CONCLUSION: A special regional deformation pattern (preserved deformation in basal segments of LVNC) seems to be of major diagnostic help for the definite differential diagnosis of LVNC and DCM. PMID- 22219501 TI - Detection, monitoring, and management of trastuzumab-induced left ventricular dysfunction: an actual challenge. AB - The antibody trastuzumab, targeted to inhibit the signalling of ErbB2, a tyrosine kinase receptor overexpressed in 20-30% of breast cancers, improves the prognosis in women affected by this tumour, but produces cardiotoxicity, since ErbB2 is also involved in myocardial homeostasis. In this review, we discuss the pathophysiology of trastuzumab cardiomyopathy and the complex interplay between ErbB2 inhibition and anthracyclines, and we focus on the actual challenges of detecting, monitoring, and managing trastuzumab cardiotoxicity: the research of new, sensitive markers of early trastuzumab toxicity, before the ejection fraction is reduced, is an active field of research. PMID- 22219502 TI - Variation in HbA1c prescription for patients with diabetes in French general practice: an observational study prior to the implementation of a P4P programme. AB - BACKGROUND: Prior to a large diffusion of a pay-for-performance programme (P4P) in primary care in France, it seemed of particular interest to identify, the doctors not performing optimally who could be the main target of this programme. Based on the example of HbA1c prescription for patients with diabetes, this study examined the impact of general practitioner's (GPs) characteristics on the variation of a P4P indicator for diabetes care, i.e. the percentage of patients undergoing three or four HbA1c tests during one year. METHODS: We used a large database from the national health insurance fund for salaried workers in Brittany to select a cohort of patients with diabetes who had been attended to by their doctors for 1 year. In all, 2545 GPs attending to 41,453 patients with diabetes were included. A two-level hierarchical logistic model was used to analyse the data. RESULTS: Thirty-six per cent (SD = 22.3) of patients with diabetes underwent three or four HbA1c tests during the year (the target objective was 65% in a patient list). There was a large variability between GPs, even after adjusting for patient characteristics. Doctors who were female, young, working in a group practice, participating in quality-control groups, and who had a lower patient load prescribed the three or four recommended tests more often. DISCUSSION: The results indicate a target group of doctors which require attention. There is still room to improve the quality of care for patients with diabetes in general practice, notably by encouraging doctors to train better and practice in groups. PMID- 22219503 TI - Socio-demographic correlates of physical activity and physical fitness in German children and adolescents. AB - AIM: Identifying factors that influence children's and adolescents' participation in physical activity (PA), as well as their physical fitness (PF), is essential for the development of effective intervention strategies. The aim of this study was to investigate and compare influential socio-demographic factors that affect PA such as socio-economic status (SES), rural-urban differences, immigration and age, as well as the effects of age and PA on PF as differentiated by gender. Subjects and METHODS: German children between 6 and 9 years and adolescents between 10 and 17 years of age (n = 2574) participated in the representative, nationwide, cross-sectional 'Motorik'-Module study between 2003 and 2006. RESULTS: Results revealed that immigrant children and children with a lower SES background were less physically active and that this inactivity subsequently resulted in lower levels of PF as compared with non-immigrant children and children with a higher SES background. PA was further positively associated with age for children. All of these three socio-demographic factors were comparably meaningful for PA. In adolescents, the only PA-relevant socio-demographic parameter was SES with lower PA again resulting in lower PF levels observed in adolescents from lower income families. PF in childhood as well as adolescence was mostly positively affected by age, followed by PA, except for in female adolescents for whom PA and age were nearly equally significant. CONCLUSIONS: An intervention aiming to improve PA levels, and consequently PF levels, must, with respect to age and gender, refer to SES, as well as immigration background, but not to rural-urban differences. PMID- 22219504 TI - Cervical screening among migrant women: a qualitative study of Polish, Slovak and Romanian women in London, UK. AB - OBJECTIVE: To explore awareness of and participation in cervical screening services in women from Poland, Slovakia and Romania living in London, UK. METHODS: Three qualitative studies were carried out in London in 2008-2009: an interview study of professionals working with Central and Eastern European migrants (n=11); a focus group study including three Polish, one Slovak and one Romanian focus group; and an interview study of Polish (n=11), Slovak (n=7) and Romanian (n=2) women. RESULTS: Awareness of the cervical screening programme was good, but understanding of the purpose of screening was sometimes limited. Some women were fully engaged with the UK screening programme; others used screening both in the UK and their countries of origin; and a third group only had screening in their home countries. Women welcomed the fact that screening is free and that reminders are sent, but some were concerned about the screening interval and the age of the first invitation. CONCLUSIONS: Migrant women from Poland, Slovakia and Romania living in London vary in their level of participation in the National Health Service Cervical Screening Programme. More needs to be done to address concerns regarding screening services, and to ensure that language is not a barrier to participation. PMID- 22219505 TI - James F. Crow: his life in public service. AB - The readers of this journal may well be aware of Professor Crow's scientific achievements and his role as the editor of Perspectives. In addition, for many thousands of students at the University of Wisconsin over many generations, James F. Crow was one of the most memorable teachers at both the undergraduate and graduate levels. What is less known is his major role in public service where he served as chair of many important committees for the National Academy of Sciences, the National Institutes of Health, the National Institutes of Justice as well as various international programs. In all of these efforts, Professor Crow has left a lasting impact. PMID- 22219506 TI - The effects of deleterious mutations on evolution at linked sites. AB - The process of evolution at a given site in the genome can be influenced by the action of selection at other sites, especially when these are closely linked to it. Such selection reduces the effective population size experienced by the site in question (the Hill-Robertson effect), reducing the level of variability and the efficacy of selection. In particular, deleterious variants are continually being produced by mutation and then eliminated by selection at sites throughout the genome. The resulting reduction in variability at linked neutral or nearly neutral sites can be predicted from the theory of background selection, which assumes that deleterious mutations have such large effects that their behavior in the population is effectively deterministic. More weakly selected mutations can accumulate by Muller's ratchet after a shutdown of recombination, as in an evolving Y chromosome. Many functionally significant sites are probably so weakly selected that Hill-Robertson interference undermines the effective strength of selection upon them, when recombination is rare or absent. This leads to large departures from deterministic equilibrium and smaller effects on linked neutral sites than under background selection or Muller's ratchet. Evidence is discussed that is consistent with the action of these processes in shaping genome-wide patterns of variation and evolution. PMID- 22219510 TI - Retrotransposon Ty1 integration targets specifically positioned asymmetric nucleosomal DNA segments in tRNA hotspots. AB - The Saccharomyces cerevisiae genome contains about 35 copies of dispersed retrotransposons called Ty1 elements. Ty1 elements target regions upstream of tRNA genes and other Pol III-transcribed genes when retrotransposing to new sites. We used deep sequencing of Ty1-flanking sequence amplicons to characterize Ty1 integration. Surprisingly, some insertions were found in mitochondrial DNA sequences, presumably reflecting insertion into mitochondrial DNA segments that had migrated to the nucleus. The overwhelming majority of insertions were associated with the 5' regions of Pol III transcribed genes; alignment of Ty1 insertion sites revealed a strong sequence motif centered on but extending beyond the target site duplication. A strong sequence-independent preference for nucleosomal integration sites was observed, in distinction to the preferences of the Hermes DNA transposon engineered to jump in yeast and the Tf1 retrotransposon of Schizosaccharomyces pombe, both of which prefer nucleosome free regions. Remarkably, an exquisitely specific relationship between Ty1 integration and nucleosomal position was revealed by alignment of hotspot Ty1 insertion position regions to peak nucleosome positions, geographically implicating nucleosomal DNA segments at specific positions on the nucleosome lateral surface as targets, near the "bottom" of the nucleosome. The specificity is observed in the three tRNA 5' proximal nucleosomes, with insertion frequency dropping off sharply 5' of the tRNA gene. The sites are disposed asymmetrically on the nucleosome relative to its dyad axis, ruling out several simple molecular models for Ty1 targeting, and instead suggesting association with a dynamic or directional process such as nucleosome remodeling associated with these regions. PMID- 22219507 TI - The regulation of filamentous growth in yeast. AB - Filamentous growth is a nutrient-regulated growth response that occurs in many fungal species. In pathogens, filamentous growth is critical for host-cell attachment, invasion into tissues, and virulence. The budding yeast Saccharomyces cerevisiae undergoes filamentous growth, which provides a genetically tractable system to study the molecular basis of the response. Filamentous growth is regulated by evolutionarily conserved signaling pathways. One of these pathways is a mitogen activated protein kinase (MAPK) pathway. A remarkable feature of the filamentous growth MAPK pathway is that it is composed of factors that also function in other pathways. An intriguing challenge therefore has been to understand how pathways that share components establish and maintain their identity. Other canonical signaling pathways-rat sarcoma/protein kinase A (RAS/PKA), sucrose nonfermentable (SNF), and target of rapamycin (TOR)-also regulate filamentous growth, which raises the question of how signals from multiple pathways become integrated into a coordinated response. Together, these pathways regulate cell differentiation to the filamentous type, which is characterized by changes in cell adhesion, cell polarity, and cell shape. How these changes are accomplished is also discussed. High-throughput genomics approaches have recently uncovered new connections to filamentous growth regulation. These connections suggest that filamentous growth is a more complex and globally regulated behavior than is currently appreciated, which may help to pave the way for future investigations into this eukaryotic cell differentiation behavior. PMID- 22219511 TI - A nucleosomal surface defines an integration hotspot for the Saccharomyces cerevisiae Ty1 retrotransposon. AB - Ty1, the most abundant retrotransposon in Saccharomyces cerevisiae, integrates preferentially upstream of genes transcribed by RNA polymerase III (Pol III). Targeting is likely due to interactions between the Ty1 integration complex and a feature of chromatin characteristic of sites of Pol III transcription. To better understand Ty1 targeting determinants, >150,000 Ty1 insertions were mapped onto the S. cerevisiae genome sequence. Logistic regression was used to assess relationships between patterns of Ty1 integration and various genomic features, including genome-wide data sets of histone modifications and transcription-factor binding sites. Nucleosomes were positively associated with Ty1 insertions, and fine-scale mapping of insertions upstream of genes transcribed by Pol III indicated that Ty1 preferentially integrates into nucleosome-bound DNA near the H2A/H2B interface. Outside of genes transcribed by Pol III, Ty1 avoids coding sequences, a pattern that is not due to selection, but rather reflects a preference for nucleosome-rich sites flanking genes. Ty1 insertion sites were also mapped in four mutant lines that affect Ty1 transposition frequency or integration specificity (rrm3Delta, hos2Delta, rtt109Delta, and rad6Delta). Patterns of integration were largely preserved in the mutants, although significantly more insertions into coding sequences were observed in the rad6Delta strain, suggesting a loosening of target specificity in this mutant that lacks an enzyme involved in ubiquitinating H2A. Overall, our data suggest that nucleosomes are necessary for Ty1 integration, and that a secondary factor, likely a histone modification or nucleosome-bound factor enriched at sites of Pol III transcription, determines preferred target sites. PMID- 22219508 TI - Morphogenesis and the cell cycle. AB - Studies of the processes leading to the construction of a bud and its separation from the mother cell in Saccharomyces cerevisiae have provided foundational paradigms for the mechanisms of polarity establishment, cytoskeletal organization, and cytokinesis. Here we review our current understanding of how these morphogenetic events occur and how they are controlled by the cell-cycle regulatory cyclin-CDK system. In addition, defects in morphogenesis provide signals that feed back on the cyclin-CDK system, and we review what is known regarding regulation of cell-cycle progression in response to such defects, primarily acting through the kinase Swe1p. The bidirectional communication between morphogenesis and the cell cycle is crucial for successful proliferation, and its study has illuminated many elegant and often unexpected regulatory mechanisms. Despite considerable progress, however, many of the most puzzling mysteries in this field remain to be resolved. PMID- 22219512 TI - Cell-type-specific nuclei purification from whole animals for genome-wide expression and chromatin profiling. AB - An understanding of developmental processes requires knowledge of transcriptional and epigenetic landscapes at the level of tissues and ultimately individual cells. However, obtaining tissue- or cell-type-specific expression and chromatin profiles for animals has been challenging. Here we describe a method for purifying nuclei from specific cell types of animal models that allows simultaneous determination of both expression and chromatin profiles. The method is based on in vivo biotin-labeling of the nuclear envelope and subsequent affinity purification of nuclei. We describe the use of the method to isolate nuclei from muscle of adult Caenorhabditis elegans and from mesoderm of Drosophila melanogaster embryos. As a case study, we determined expression and nucleosome occupancy profiles for affinity-purified nuclei from C. elegans muscle. We identified hundreds of genes that are specifically expressed in muscle tissues and found that these genes are depleted of nucleosomes at promoters and gene bodies in muscle relative to other tissues. This method should be universally applicable to all model systems that allow transgenesis and will make it possible to determine epigenetic and expression profiles of different tissues and cell types. PMID- 22219513 TI - Age-associated proinflammatory secretory phenotype in vascular smooth muscle cells from the non-human primate Macaca mulatta: reversal by resveratrol treatment. AB - There is increasing evidence that age-associated chronic low-grade inflammation promotes the development of both large-vessel disease (myocardial infarction, stroke, peripheral arterial disease) and small-vessel pathologies (including vascular cognitive impairment) in older persons. However, the source of age related chronic vascular inflammation remains unclear. To test the hypothesis that cell-autonomous mechanisms contribute to the proinflammatory changes in vascular phenotype that accompanies advancing age, we analyzed the cytokine secretion profile of primary vascular smooth muscle cells (VSMCs) derived from young (~13 years old) and aged (~21 years old) Macaca mulatta. Aged VSMCs cultured in the absence of systemic factors exhibited significantly increased secretion of interleukin-1beta, MCP-1, and tumor necrosis factoralpha compared with young control cells. Secretion of interleukin-6 also tended to increase in aged VSMCs. This age-associated proinflammatory shift in the cellular secretory phenotype was associated with an increased mitochondrial O(2)(-) production and nuclear factor kappa-light-chain-enhancer of activated B cells activation. Treatment of aged VSMCs with a physiologically relevant concentration of resveratrol (1 MUM) exerted significant anti-inflammatory effects, reversing aging-induced alterations in the cellular cytokine secretion profile and inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells. Resveratrol also attenuated mitochondrial O(2)(-) production and upregulated the transcriptional activity of Nrf2 in aged VSMCs. Thus, in non-human primates, cell autonomous activation of nuclear factor kappa-light-chain-enhancer of activated B cells and expression of an inflammatory secretome likely contribute to vascular inflammation in aging. Resveratrol treatment prevents the proinflammatory properties of the aged VSMC secretome, an effect that likely contributes to the demonstrated vasoprotective action of resveratrol in animal models of aging. PMID- 22219514 TI - Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. AB - We analyze the relationship between age of survival, morbidity, and disability among centenarians (age 100-104 years), semisupercentenarians (age 105-109 years), and supercentenarians (age 110-119 years). One hundred and four supercentenarians, 430 semisupercentenarians, 884 centenarians, 343 nonagenarians, and 436 controls were prospectively followed for an average of 3 years (range 0-13 years). The older the age group, generally, the later the onset of diseases, such as cancer, cardiovascular disease, dementia, and stroke, as well as of cognitive and functional decline. The hazard ratios for these individual diseases became progressively less with older and older age, and the relative period of time spent with disease was lower with increasing age group. We observed a progressive delay in the age of onset of physical and cognitive function impairment, age-related diseases, and overall morbidity with increasing age. As the limit of human life span was effectively approached with supercentenarians, compression of morbidity was generally observed. PMID- 22219515 TI - Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging. AB - The redox-sensitive transcription factor NF-E2-related factor 2 (Nrf2) plays a key role in preserving a healthy endothelial phenotype and maintaining the functional integrity of the vasculature. Previous studies demonstrated that aging is associated with Nrf2 dysfunction in endothelial cells, which alters redox signaling and likely promotes the development of large vessel disease. Much less is known about the consequences of Nrf2 dysfunction at the level of the microcirculation. To test the hypothesis that Nrf2 regulates angiogenic capacity of endothelial cells, we determined whether disruption of Nrf2 signaling (by siRNA knockdown of Nrf2 and overexpression of Keap1, the cytosolic repressor of Nrf2) impairs angiogenic processes in cultured human coronary arterial endothelial cells stimulated with vascular endothelial growth factor and insulin like growth factor-1. In the absence of functional Nrf2, coronary arterial endothelial cells exhibited impaired proliferation and adhesion to vitronectin and collagen. Disruption of Nrf2 signaling also reduced cellular migration (measured by a wound-healing assay using electric cell-substrate impedance sensing technology) and impaired the ability of coronary arterial endothelial cells to form capillary-like structures. Collectively, we find that Nrf2 is essential for normal endothelial angiogenic processes, suggesting that Nrf2 dysfunction may be a potential mechanism underlying impaired angiogenesis and microvascular rarefaction in aging. PMID- 22219516 TI - Testing the oxidative stress hypothesis of aging in primate fibroblasts: is there a correlation between species longevity and cellular ROS production? AB - The present study was conducted to test predictions of the oxidative stress theory of aging assessing reactive oxygen species production and oxidative stress resistance in cultured fibroblasts from 13 primate species ranging in body size from 0.25 to 120 kg and in longevity from 20 to 90 years. We assessed both basal and stress-induced reactive oxygen species production in fibroblasts from five great apes (human, chimpanzee, bonobo, gorilla, and orangutan), four Old World monkeys (baboon, rhesus and crested black macaques, and patas monkey), three New World monkeys (common marmoset, red-bellied tamarin, and woolly monkey), and one lemur (ring-tailed lemur). Measurements of cellular MitoSox fluorescence, an indicator of mitochondrial superoxide (O2(.-)) generation, showed an inverse correlation between longevity and steady state or metabolic stress-induced mitochondrial O2(.-) production, but this correlation was lost when the effects of body mass were removed, and the data were analyzed using phylogenetically independent contrasts. Fibroblasts from longer-lived primate species also exhibited superior resistance to H(2)O(2)-induced apoptotic cell death than cells from shorter-living primates. After correction for body mass and lack of phylogenetic independence, this correlation, although still discernible, fell short of significance by regression analysis. Thus, increased longevity in this sample of primates is not causally associated with low cellular reactive oxygen species generation, but further studies are warranted to test the association between increased cellular resistance to oxidative stressor and primate longevity. PMID- 22219517 TI - Pilot study of resveratrol in older adults with impaired glucose tolerance. AB - BACKGROUND: Resveratrol, a plant-derived polyphenol, has shown promising effects on insulin sensitivity and glucose tolerance in animal models and is also reported to have cardioprotective properties, but human studies are limited. In a pilot study, we tested the hypothesis that resveratrol improves glucose metabolism and vascular function in older adults with impaired glucose tolerance (IGT). METHODS: Ten subjects aged 72 +/- 3 years (M +/- SD) with IGT were enrolled in a 4-week open-label study of resveratrol (daily dose 1, 1.5, or 2 g). Following a standard mixed meal (110 g carbohydrate, 20 g protein, 20 g fat), we measured 3-hour glucose and insulin area under the curve (AUC), insulin sensitivity (Matsuda index), and secretion (corrected insulin response at 30 minutes). Endothelial function was assessed by reactive hyperemia peripheral arterial tonometry (reactive hyperemia index) before and 90 minutes postmeal. Results did not differ by dose, so data were combined for analysis. RESULTS: At baseline, body mass index was 29 +/- 5 kg/m(2), fasting plasma glucose 110 +/- 13 mg/dL, and 2-hour glucose 183 +/- 33 mg/dL. After 4 weeks of resveratrol, fasting plasma glucose was unchanged, but peak postmeal (185 +/- 10 vs 166 +/- 9 mg/dL, p = .003) and 3-hour glucose AUC (469 +/- 23 vs 428 +/- 19, p = .001) declined. Matsuda index improved (3.1 +/- 0.5 vs 3.8 +/- 0.5, p = .03), and corrected insulin response at 30 minutes was unchanged (0.6 +/- 0.1 vs 0.5 +/- 0.5, p = .49). There was a trend toward improved postmeal reactive hyperemia index (baseline vs resveratrol postmeal delta -0.4 +/- 0.2 vs 0.2 +/- 0.3, p = .06). Weight, blood pressure, and lipids were unchanged. CONCLUSIONS: At doses between 1 and 2 g/day, resveratrol improves insulin sensitivity and postmeal plasma glucose in subjects with IGT. These preliminary findings support the conduct of larger studies to further investigate the effects of resveratrol on metabolism and vascular function. PMID- 22219519 TI - Biogerontology and the intellectual virtues. AB - The case for prioritizing the study of the biology of aging can be persuasively made by making explicit its connection to the exercise of the intellectual virtues needed to realize well-ordered science. These intellectual virtues include a range of attitudes and dispositions integral to all areas of science (e.g. sensitivity to details, adaptability of intellect, the detective's virtues), but the so-called "teaching virtues" are especially important for biogerontology. Without the foresight to anticipate how their audience will likely respond, biogerontologists risk marginalizing the field's importance to well-ordered science as the general public are likely to dismiss, or underestimate, the health and economic benefits of an intervention that retards the rate of biological aging. PMID- 22219518 TI - The pattern of recovery of ambulation after hip fracture differs with age in elderly patients. AB - BACKGROUND: The main objective of this study was to analyze the independent effect of increasing age on the recovery of different areas of functioning 1 year after hip fracture. METHODS: Consecutive 1-year survivors aged >= 65 years (n = 362) admitted to a single hospital for acute hip fracture surgery were followed prospectively for 1 year. Age was stratified as <75, 75-84, and >= 85 years. Basic activities of daily living and ambulation were measured by personal interview during hospitalization and phone contact at 3, 6, and 12 months. Longitudinal data of recovery in these areas were analyzed using generalized estimating equations. RESULTS: Older age was strongly associated with poor recovery in all areas of function, except eating. The pattern of recovery of ambulation differed with age, peaking at 6 months in the younger group and continuing for at least 12 months in the eldest group. The pattern of recovery of overall and individual activities of daily living was similar in the three age groups. Recovery of areas associated with upper extremity function peaked at 3 months, whereas areas associated with lower extremity function peaked at 6 months. CONCLUSIONS: The patterns of functional disability after hip fracture differ with areas of function and age with the oldest patients having a particular risk of decline and a prolonged time to recovery of ambulation. PMID- 22219520 TI - Polypharmacy in nursing home in Europe: results from the SHELTER study. AB - BACKGROUND: This study assesses prevalence and patients characteristics related to polypharmacy in a sample of nursing home residents. METHODS: We conducted a cross-sectional analysis on 4,023 nursing home residents participating to the Services and Health for Elderly in Long TERm care (SHELTER) project, a study collecting information on residents admitted to 57 nursing home in 8 countries. Data were collected using the interRAI instrument for long-term care facilities. Polypharmacy status was categorized in 3 groups: non-polypharmacy (0-4 drugs), polypharmacy (5-9 drugs) and excessive polypharmacy (>= 10 drugs). RESULTS: Polypharmacy was observed in 2,000 (49.7%) residents and excessive polypharmacy in 979 (24.3%) residents. As compared with non-polypharmacy, excessive polypharmacy was directly associated not only with presence of chronic diseases but also with depression (odds ratio [OR] 1.81; 95% confidence interval [CI] 1.38 2.37), pain (OR 2.31; 95% CI 1.80-2.97), dyspnoea (OR 2.29; 95% CI 1.61-3.27), and gastrointestinal symptoms (OR 1.73; 95% CI 1.35-2.21). An inverse association with excessive polypharmacy was shown for age (OR for 10 years increment 0.85; 95% CI 0.74-0.96), activities of daily living disability (OR for assistance required vs independent 0.90; 95% CI 0.64-1.26; OR for dependent vs independent 0.59; 95% CI 0.40-0.86), and cognitive impairment (OR for mild or moderate vs intact 0.64; 95% CI 0.47-0.88; OR for severe vs intact 0.39; 95% CI 0.26-0.57). CONCLUSIONS: Polypharmacy and excessive polypharmacy are common among nursing home residents in Europe. Determinants of polypharmacy status include not only comorbidity but also specific symptoms, age, functional, and cognitive status. PMID- 22219521 TI - Diurnal cortisol and functional outcomes in post-acute rehabilitation patients. AB - BACKGROUND: Cortisol is a stress-related hormone with a robust circadian rhythm where levels typically peak in the morning hours and decline across the day. Although acute cortisol increases resulting from stressors are adaptive, chronic elevated cortisol levels are associated with poor functioning. Studies have shown age-related changes in cortisol levels. The present study investigated the relationship between salivary diurnal cortisol and functional outcomes among older adults undergoing inpatient post-acute rehabilitation. METHODS: Thirty-two older adults (mean age 78 years; 84% men) in a Veterans Administration inpatient post-acute rehabilitation unit were studied. Functional outcomes were assessed with the motor component of the Functional Independence Measure (mFIM; where mFIM change = discharge - admission score). Saliva samples were collected on 1 day at wake time, 45 minutes later, 11:30 AM, 2 PM, 4:30 PM, and bedtime. We analyzed the relationship between cortisol measures and functional outcomes, demographics, and health measures. RESULTS: The analyses consistently showed that greater functional improvement (mFIM change) from admission to discharge was associated with lower comorbidity scores and higher cortisol levels at 2 PM, 4:30 PM, and bedtime. A morning cortisol rise was also associated with greater mFIM change. CONCLUSIONS: Measurement of cortisol in saliva may be a useful biological marker for identification of patients who are "at risk" of lower benefits from inpatient rehabilitation services and who may require additional assistance or intervention during their post-acute care stay. PMID- 22219523 TI - An evaluation and comparison of time-out procedures with and without release contingencies. AB - A common recommendation for implementing time-out procedures is to include a release contingency such that the individual is not allowed to leave time-out until no problem behavior has occurred for a specific amount of time (e.g, 30 s). We compared a fixed-duration time-out procedure to a release contingency time-out procedure with 4 young children (3- and 4-year-olds) using a reversal and multielement design. Results demonstrated that both time-out procedures were effective at reducing problem behavior outside time-out, problem behavior occurred in time-out during both procedures, and problem behavior in time-out was not predictive of problem behavior outside time-out. PMID- 22219522 TI - Proteomic screening of glycoproteins in human plasma for frailty biomarkers. AB - The application of proteomics methodology for analyzing human blood samples is of increasing importance as a noninvasive method for understanding, detecting, and monitoring disease. In particular, glycoproteomic analysis may be useful in the study of age-related diseases and syndromes, such as frailty. This study demonstrates the use of methodology for isolating plasma glycoproteins using lectins, comparing the glycoproteome by frailty status using two-dimensional polyacrylamide gel electrophoresis and identifying glycoproteins using mass spectrometry. In a pilot study, we found seven glycoproteins to differ by at least twofold in prefrail compared with nonfrail older adults, including haptoglobin, transferrin, and fibrinogen, consistent with known inflammatory and hematologic changes associated with frailty. Enzyme-linked immunosorbent assay analysis found that plasma transferrin concentration was increased in frail and prefrail older adults compared with nonfrail, confirming our proteomic findings. This work provides evidence for using a reproducible methodology for conducting clinical proteomic comparative studies of age-related diseases. PMID- 22219524 TI - The influence of presession factors in the assessment of deviant arousal. AB - Three adult male sex offenders with developmental disabilities participated in an evaluation of presession factors that may influence levels of sexual arousal measured with a penile plethysmograph. We evaluated the effects of presession masturbation (1 participant) and arousal-suppression strategies (2 participants). Results showed that presession masturbation lowered arousal levels and both participants suppressed arousal to varying degrees. These outcomes suggest the potential for consideration and manipulation of presession factors as treatment components for sex offenders with developmental disabilities. PMID- 22219525 TI - Escape as reinforcement and escape extinction in the treatment of feeding problems. AB - Given the effectiveness of putative escape extinction as treatment for feeding problems, it is surprising that little is known about the effects of escape as reinforcement for appropriate eating during treatment. In the current investigation, we examined the effectiveness of escape as reinforcement for mouth clean (a product measure of swallowing), escape as reinforcement for mouth clean plus escape extinction (EE), and EE alone as treatment for the food refusal of 5 children. Results were similar to those of previous studies, in that reinforcement alone did not result in increases in mouth clean or decreases in inappropriate behavior (e.g., Piazza, Patel, Gulotta, Sevin, & Layer, 2003). Increases in mouth clean and decreases in inappropriate behavior occurred when the therapist implemented EE independent of the presence or absence of reinforcement. Results are discussed in terms of the role of negative reinforcement in the etiology and treatment of feeding problems. PMID- 22219526 TI - False-positive tangible outcomes of functional analyses. AB - Functional analysis (FA) methodology is the most precise method for identifying variables that maintain problem behavior. Occasionally, however, results of an FA may be influenced by idiosyncratic sensitivity to aspects of the assessment conditions. For example, data from several studies suggest that inclusion of a tangible condition during an FA may be prone to a false-positive outcome, although the extent to which tangible reinforcement routinely produces such outcomes is unknown. We examined susceptibility to tangible reinforcement by determining whether a new response was acquired more readily when exposed to a tangible contingency relative to others commonly used in an FA (Study 1), and whether problem behavior known not to have a social function nevertheless emerged when exposed to tangible reinforcement (Study 2). Results indicated that inclusion of items in the tangible condition should be done with care and that selection should be based on those items typically found in the individual's environment. PMID- 22219527 TI - Establishing verbal repertoires in children with autism using function-based video modeling. AB - Previous research suggests that language-training procedures for children with autism might be enhanced following an assessment of conditions that evoke emerging verbal behavior. The present investigation examined a methodology to teach recognizable mands based on environmental variables known to evoke participants' idiosyncratic communicative responses in the natural environment. An alternating treatments design was used during Experiment 1 to identify the variables that were functionally related to gestures emitted by 4 children with autism. Results showed that gestures functioned as requests for attention for 1 participant and as requests for assistance to obtain a preferred item or event for 3 participants. Video modeling was used during Experiment 2 to compare mand acquisition when video sequences were either related or unrelated to the results of the functional analysis. An alternating treatments within multiple probe design showed that participants repeatedly acquired mands during the function based condition but not during the nonfunction-based condition. In addition, generalization of the response was observed during the former but not the latter condition. PMID- 22219528 TI - Data-based decision making: the impact of data variability, training, and context. AB - The current study examines agreement among individuals with varying expertise in behavior analysis about the length of baseline when data were presented point by point. Participants were asked to respond to baseline data and to indicate when to terminate the baseline phase. When only minimal information was provided about the data set, experts and Board Certified Behavior Analyst participants generated baselines of similar lengths, whereas novices did not. Agreement was similar across participants when variability was low but deteriorated as variability in the data set increased. Participants generated shorter baselines when provided with information regarding the independent or dependent variable. Implications for training and the use of visual inspection are discussed. PMID- 22219529 TI - A comparison of two flash-card methods for improving sight-word reading. AB - Flash cards have been shown to be useful for teaching sight-word reading. To date, the most effective flash-card instruction method is incremental rehearsal (IR). This method involves the instructor interspersing unknown stimulus items into the presentation of known stimulus items. In this study, we compared IR to a modified IR procedure-strategic incremental rehearsal (SIR)-to determine whether the effects of IR might be improved by incorporating variables likely to increase word acquisition. These included increased opportunities to respond to unknown stimuli, using learner responding as a basis for changing instructional items, and systematic prompting methods. An A-B-A-B design was used to compare the effects of IR and SIR for increasing sight-word reading with 4 elementary school students. Results indicated that students read more words correctly with SIR than with IR. In addition, similar patterns of responding were seen at a 2-week follow up. PMID- 22219530 TI - An assessment of the efficiency of and child preference for forward and backward chaining. AB - Comparative studies of forward and backward chaining have led some to suggest that sensitivity to each teaching procedure may be idiosyncratic across learners and tasks. The purposes of the current study were threefold. First, we assessed differential sensitivity to each chaining procedure within children when presented with multiple learning tasks of similar content but different complexity. Second, we evaluated whether differential sensitivity to a chaining procedure during a brief task predicted differential sensitivity during the teaching of longer tasks. Third, we directly assessed children's preferences for each teaching procedure via a concurrent-chains preference assessment. Learners acquired all target skills introduced under both chaining conditions, but individual children did not consistently learn more efficiently with either procedure. Short-duration tasks were not predictive of performance in tasks of longer duration. Both chaining procedures were preferred over a baseline condition without prompting, but participants did not demonstrate a preference for either procedure. PMID- 22219531 TI - Functional analysis in public schools: a summary of 90 functional analyses. AB - Several review and epidemiological studies have been conducted over recent years to inform behavior analysts of functional analysis outcomes. None to date have closely examined demographic and clinical data for functional analyses conducted exclusively in public school settings. The current paper presents a data-based summary of 90 functional analyses conducted in public school settings from 2006 through 2009 for 69 students. Specifically, we present data on gender, age, race, diagnosis, topography of target behaviors, number of conditions, duration of sessions, duration of analysis, functional outcomes, setting, and person serving the role of therapist. Results suggest that functional analyses in schools are possible, practical, and produce results that are comparable to those in past research. PMID- 22219532 TI - Comparison of a stimulus equivalence protocol and traditional lecture for teaching single-subject designs. AB - This study compared the effects of a computer-based stimulus equivalence protocol to a traditional lecture format in teaching single-subject experimental design concepts to undergraduate students. Participants were assigned to either an equivalence or a lecture group, and performance on a paper-and-pencil test that targeted relations among the names of experimental designs, design definitions, design graphs, and clinical vignettes was compared. Generalization of responding to novel graphs and novel clinical vignettes, as well as the emergence of a topography-based tact response after selection-based training, were evaluated for the equivalence group. Performance on the paper-and-pencil test following teaching was comparable for participants in the equivalence and lecture groups. All participants in the equivalence group showed generalization to novel graphs, and 6 participants showed generalization to novel clinical vignettes. Three of the 4 participants demonstrated the emergence of a topography-based tact response following training on the stimulus equivalence protocol. PMID- 22219533 TI - Evaluation of the rate of problem behavior maintained by different reinforcers across preference assessments. AB - The rates of problem behavior maintained by different reinforcers were evaluated across 3 preference assessment formats (i.e., paired stimulus, multiple-stimulus without replacement, and free operant). The experimenter administered each assessment format 5 times in a random order for 7 children with developmental disabilities whose problem behavior was maintained by attention, tangible items, or escape. Results demonstrated different effects related to the occurrence of problem behavior, suggesting an interaction between function of problem behavior and assessment format. Implications for practitioners are discussed with respect to assessing preferences of individuals with developmental disabilities who exhibit problem behavior. PMID- 22219534 TI - Preference for fluent versus disfluent work schedules. AB - Two studies were conducted that examined the preference of a student diagnosed with a brain injury. In Study 1, a preference assessment was followed by a three choice concurrent-operants reinforcer assessment. Two choices resulted in access to preferred activities for completing work, and a third choice resulted in access to nothing (i.e., no activity). Unpredictably, the participant consistently chose the no-activity option. Study 2 examined why this student preferred work associated with no activity over preferred activities. Through a variety of concurrent-operants procedures, it was determined that she preferred fluent work followed by reinforcers rather than work that was broken up by access to preferred activities. Implications for research on preference are discussed. PMID- 22219535 TI - A review of recommendations for sequencing receptive and expressive language instruction. AB - We review recommendations for sequencing instruction in receptive and expressive language objectives in early and intensive behavioral intervention (EIBI) programs. Several books recommend completing receptive protocols before introducing corresponding expressive protocols. However, this recommendation has little empirical support, and some evidence exists that the reverse sequence may be more efficient. Alternative recommendations include teaching receptive and expressive skills simultaneously (M. L. Sundberg & Partington, 1998) and building learning histories that lead to acquisition of receptive and expressive skills without direct instruction (Greer & Ross, 2008). Empirical support for these recommendations also is limited. Future research should assess the relative efficiency of receptive-before-expressive, expressive-before-receptive, and simultaneous training with children who have diagnoses of autism spectrum disorders. In addition, further evaluation is needed of the potential benefits of multiple-exemplar training and other variables that may influence the efficiency of receptive and expressive instruction. PMID- 22219536 TI - Behavioral momentum theory: equations and applications. AB - Behavioral momentum theory provides a quantitative account of how reinforcers experienced within a discriminative stimulus context govern the persistence of behavior that occurs in that context. The theory suggests that all reinforcers obtained in the presence of a discriminative stimulus increase resistance to change, regardless of whether those reinforcers are contingent on the target behavior, are noncontingent, or are even contingent on an alternative behavior. In this paper, we describe the equations that constitute the theory and address their application to issues of particular importance in applied settings. The theory provides a framework within which to consider the effects of interventions such as extinction, noncontingent reinforcement, differential reinforcement of alternative behavior, and other phenomena (e.g., resurgence). Finally, the theory predicts some counterintuitive and potentially counterproductive effects of alternative reinforcement, and can serve as an integrative guide for intervention when its terms are identified with the relevant conditions of applied settings. PMID- 22219537 TI - Studying as fun and games: effects on college students' quiz performance. AB - We examined college students' participation in a game activity for studying course material on their subsequent quiz performance. Game conditions were alternated with another activity counterbalanced across two groups of students in a multielement design. Overall, the mean percentage correct on quizzes was higher during the game condition than in the no-game condition. PMID- 22219538 TI - Differential reinforcement with and without blocking as treatment for elopement. AB - Blocking is a frequent component of treatments for elopement. Unfortunately, blocking may not always be feasible because elopement often occurs when supervision is low or the behavior cannot be prevented. The present study evaluated the use of blocking in the treatment of elopement by using differential reinforcement of other behavior with and without blocking. In this case, results suggested that blocking may be an essential component for differential reinforcement-based treatments of elopement. PMID- 22219539 TI - Using conditional discrimination training to produce emergent relations between coins and their values in children with autism. AB - The current study evaluated the effects of conditional discrimination (listener) training with coins on the emergence of novel stimulus relations, textual behavior, tacts, and intraverbals. Two preschoolers with autism were taught 3 relations among coins, their names, and values. After initial training, 4 relations emerged for the first participant and 7 for the second participant, suggesting that this technology can be incorporated into educational curricula for teaching prerequisite money skills to children with autism. PMID- 22219540 TI - Using negative reinforcement to increase self-feeding in a child with food selectivity. AB - We examined the effects of a negative reinforcement-based treatment on the self feeding of 1 child with food selectivity by type and texture. Self-feeding increased when the child could choose to either self-feed 1 bite of a target food or be fed 1 bite of the target food and 5 bites of another food. Possible mechanisms that underlie the effectiveness of the intervention and implications for future research are discussed. PMID- 22219541 TI - Using words instead of jumbled characters as stimuli in keyboard training facilitates fluent performance. AB - Keyboarding skill is an important target for adult education programs due to the ubiquity of computers in modern work environments. A previous study showed that novice typists learned key locations quickly but that fluency took a relatively long time to develop. In the present study, novice typists achieved fluent performance in nearly half the time when words rather than jumbled characters were used as stimuli. This suggests that using real words in the keyboarding program can enhance the efficiency of training. PMID- 22219542 TI - Evaluation of response blocking and re-presentation in a competing stimulus assessment. AB - Competing stimulus assessments (CSA) have been used to identify stimuli that are associated with reduced levels of problem behavior, presumably as a function of reinforcer competition. Following a standard CSA in which stimuli simply were made available, 2 more CSAs were conducted with additional components designed to enhance reinforcer competition: re-presentation of stimuli and response blocking for self-injury. The results obtained from each CSA were validated in an extended treatment analysis. The study illustrates how the effects of additional components designed to enhance reinforcer competition can be evaluated efficiently in the context of a CSA. PMID- 22219543 TI - Effects of preference on verification of discriminated mands. AB - Previous research suggests that motivating operation (MO) manipulations may assist in assessing discriminated manding (Gutierrez et al., 2007). The current study partially replicated and extended previous research by varying access to concurrently available reinforcers with different preference values (i.e., MO manipulations). Manding did not occur (a) for reinforcers that were freely available and (b) for lower preference items when relatively higher preference reinforcers were freely available. Results further demonstrated the utility of manipulating MOs to verify discriminated mands but suggest that relative preference of alternative reinforcers should be controlled during these assessments. PMID- 22219544 TI - Interteaching: the impact of lectures on student performance. AB - Several studies suggest that interteaching improves student learning more than traditional lectures, but few have examined which components of interteaching contribute to its efficacy. We examined whether the lecture component of interteaching affected students' exam grades and cumulative point totals in a research methods course. Although students who received lectures had consistently higher exam scores than students who did not, the differences were statistically significant on only 2 of 5 exams. Students who received lectures, however, earned significantly more points during the semester. PMID- 22219545 TI - Manipulation of motivating operations and use of a script-fading procedure to teach mands for location to children with language delays. AB - The effects of contriving motivating operations (MOs) and script fading on the acquisition of the mand "Where's [object]?" were evaluated in 2 boys with language delays. During each session, trials were alternated in which high preference items were present (abolishing operation [AO] trials) or missing (establishing operation [EO] trials) from their typical locations. Both participants learned to mand during EO trials and not to mand during AO trials during training. Generalization of manding was demonstrated across novel instructors, stimuli, and settings and maintained 3 to 4 weeks following the intervention. PMID- 22219547 TI - Direct and distal effects of noncontingent juice on rumination exhibited by a child with autism. AB - Previous research has demonstrated the efficacy of the noncontingent delivery of foods and liquids at suppressing rumination, the repeated regurgitation and rechewing of partially digested food. However, it is unclear how long this reduction is maintained after caregivers terminate this procedure. The current study examined the direct and distal effects of noncontingent juice on rumination by measuring the duration of rumination during juice delivery and immediately following the termination of juice delivery. Noncontingent juice suppressed rumination, but this suppression was not maintained after delivery termination. PMID- 22219546 TI - Spoon-to-cup fading as treatment for cup drinking in a child with intestinal failure. AB - We treated a child with intestinal failure who consumed solids on a spoon but not liquids from a cup. We used spoon-to-cup fading, which consisted of taping a spoon to a cup and then gradually moving the bowl of the spoon closer to the edge of the cup. Spoon-to-cup fading was effective for increasing consumption of liquids from a cup. PMID- 22219548 TI - A flipped spoon and chin prompt to increase mouth clean. AB - We treated the liquid refusal of a 15-month-old girl using 2 antecedent manipulations: flipped spoon and chin prompt. Use of the chin prompt in the absence of the flipped spoon failed to produce increases in mouth clean (a product measure of swallowing). By contrast, modest increases in mouth clean resulted from the implementation of the flipped spoon alone. The greatest increases in mouth clean resulted from the combination of the 2 manipulations. PMID- 22219549 TI - Adherence with universal precautions after immediate, personalized performance feedback. AB - We evaluated the effects of immediate, personalized performance feedback on adherence with hand hygiene by health-care staff in the context of a multiple baseline design across participants. Target behaviors reached mastery levels and were maintained near 100% throughout 2 months of maintenance probes. PMID- 22219551 TI - Can an understanding of basic research facilitate the effectiveness of practitioners? Reflections and personal perspectives. AB - I have written before about the importance of applied behavior analysis to basic researchers. That relationship is, however, reciprocal; it is also critical for practitioners to understand and even to participate in basic research. Although applied problems are rarely the same as those investigated in the laboratory, practitioners who understand their basic research background are often able to place their particular problem in a more general context and thereby deal with it successfully. Also the procedures of applied behavior analysis are often the same as those that characterize basic research; the scientist-practitioner will appreciate the relation between what he or she is doing and what basic experimenters do, and as a consequence, will be able to apply therapeutic techniques more creatively and effectively. PMID- 22219552 TI - Topographical and functional properties of precursors to severe problem behavior. AB - A literature search identified 17 articles reporting data on 34 subjects who engaged in precursors to severe problem behavior, which we examined to identify topographical and functional characteristics. Unintelligible vocalization was the most common precursor to aggression (27%) and property destruction (29%), whereas self- or nondirected movement was the most common precursor to SIB (32%). Unintelligible vocalization and object-directed movement were the most common precursors to behavior maintained by social-positive reinforcement (27% each), and unintelligible vocalization was the most common precursor to behavior maintained by social-negative reinforcement (29%). Only one precursor was reported for behavior maintained by automatic reinforcement. PMID- 22219554 TI - Review of sports performance research with youth, collegiate, and elite athletes. AB - This brief review summarizes translational and intervention research in the area of sports performance. We describe studies with youth, collegiate, and elite athletes; identify recent trends; and propose recommendations for future research. PMID- 22219556 TI - Decreased anti-inflammatory responses to vitamin D in neonatal neutrophils. AB - Neutrophil activity is prolonged in newborns, suggesting decreased exposure and/or responses to immunosuppressive modulators, such as 1,25-hydroxyvitamin D(3) (1,25-vit D(3)). We hypothesized that 1,25-vit D(3) suppresses neutrophil activation and that this response is impaired in newborns. Consistent with this, 1,25-vit D(3) decreased LPS-induced expression of macrophage inflammatory protein 1beta and VEGF in adult, but not neonatal, neutrophils. Expression of vitamin D receptor (VDR) and 25-hydroxyvitamin D(3)-1alpha-hydroxylase was reduced in neonatal, relative to adult neutrophils. Moreover, 1,25-vit D(3) induced VDR gene expression in activated adult, but not neonatal, neutrophils. 1,25-vit D(3) also suppressed expression of cyclooxygenase-2 and induced expression of 5 lipoxygenase in LPS-exposed adult neutrophils, while neonatal cells were not affected. 1,25-vit D(3) had no effect on respiratory burst in either adult or neonatal cells. Anti-inflammatory activity of vitamin D is impaired in neonatal neutrophils, and this may be due to decreased expression of VDR and 1alpha hydroxylase. Insensitivity to 1,25-vit D(3) may contribute to chronic inflammation in neonates. PMID- 22219557 TI - Mycobacterium avium subspecies Paratuberculosis and Crohn's regional ileitis: how strong is association? AB - Mycobacterium avium subsp. paratuberculosis (MAP) is a well-established etiological agent of Johne's disease in animals. In humans, similar clinical condition, first described by Crohn as regional ileitis in 1932, now known as Crohn's diseases (CD), has also been associated with this mycobacterial species. However, there are two schools of thoughts, one favoring MAP as its etiological agent while the second considers it as an immune-inflammatory condition triggered by an external factor. Onset of CD requires a series of events including predisposition of certain inherited genetic traits, associated environmental stimuli, and immune-inflammatory response. A combination of these factors probably leads to this disease. Recently, some human genes have also been identified which regulate ability to respond appropriately to the external factors. Added to these factors are concerns about the selection of clinical specimens and poor adherence to laboratory quality controls. The literature is full of contradictory findings, but there a lack of uniformity in the materials and methods used by many of these researchers. In this review, we provide our perspective under above circumstances and give our point of view which may open a platform for debate regarding the MAP as the etiological agent of human CD. PMID- 22219558 TI - Models of latent tuberculosis: their salient features, limitations, and development. AB - Latent tuberculosis is a subclinical condition caused by Mycobacterium tuberculosis, which affects about one-third of the population across the world. To abridge the chemotherapy of tuberculosis, it is necessary to have active drugs against latent form of M. tuberculosis. Therefore, it is imperative to devise in vitro and models of latent tuberculosis to explore potential drugs. In vitro models such as hypoxia, nutrient starvation, and multiple stresses are based on adverse conditions encountered by bacilli in granuloma. Bacilli experience oxygen depletion condition in hypoxia model, whereas the nutrient starvation model is based on deprivation of total nutrients from a culture medium. In the multiple stress model dormancy is induced by more than one type of stress. In silico mathematical models have also been developed to predict the interactions of bacilli with the host immune system and to propose structures for potential anti tuberculosis compounds. Besides these in vitro and in silico models, there are a number of in vivo animal models like mouse, guinea pig, rabbit, etc. Although they simulate human latent tuberculosis up to a certain extent but do not truly replicate human infection. All these models have their inherent merits and demerits. However, there is no perfect model for latent tuberculosis. Therefore, it is imperative to upgrade and refine existing models or develop a new model. However, battery of models will always be a better alternative to any single model as they will complement each other by overcoming their limitations. PMID- 22219559 TI - Prevalence of bla (CTX M) extended spectrum beta lactamase gene in enterobacteriaceae from critical care patients. AB - CONTEXT: Critical care units provide a favourable environment for the antimicrobial resistant organisms to disseminate. There is recent increase in number of extended spectrum beta lactamase (ESBL) producers because of the emergence of CTX M Beta lactamases produced by Enterobacteriaceae. They colonize the intestinal flora and spread with greater intensity in the community and hospital. Usage of Carbapenems becomes mandatory as the ESBL inhibitor combination antibiotics (Amoxicillin/Clavulanate) are not effective especially against CTX M ESBLs. AIM: The aim of this study is to detect ESBL producing bla CTX M gene in Enterobacteriaceae from infections in Critical care patients and to stress on the intensity of the problem and to make interventions to curb the emergence and dissemination of CTX M ESBLs. MATERIALS AND METHODS: A total of 118 Enterobacteriaceae isolates from Critical care unit patients were recovered from a variety of clinical specimens. Antimicrobial susceptibility test was done and isolates with resistance or with reduced susceptibility to any of the third generation Cephalosporins were selected for the study. Phenotypic confirmation of ESBL production was done by Double Disc Synergy Test and confirmed by minimum inhibitory concentration. Multiplex polymerase chain reaction was performed to screen the four groups of CTX-M ESBLs. RESULTS: Among the 118 isolates of Enterobacteriaceae 54 isolates were positive for CTX-M group I ESBL which constitutes 45.7 %. CONCLUSIONS: Early detection of CTX M producing Enterobacteriaceae by continuous surveillance and thereby reducing their spread and restricted use of third generation Cephalosporins (3GC) antibiotics could be the possible routes to prevent the emergence and spread of CTX M ESBL producing organisms. PMID- 22219560 TI - Pathology of synovial lipomatosis and its clinical significance. AB - BACKGROUND: Synovial lipomatosis is a rare disorder of the synovium, commonly affecting the knee joint, resulting in joint pain, swelling, and effusion. The etiology of this condition still remains unclear. AIM: This was a study done to evaluate the disease process in synovial lipomatosis, with respect to the clinical parameters and pathological features. MATERIALS AND METHODS: Case files of synovial lipomatosis diagnosed on histopathology between 2007 and 2009 were perused, to study the case history, and tissue sections were reviewed for the histomorphological changes. RESULTS: Eight cases of synovial lipomatosis were diagnosed on histopathology from year 2007 to 2009, of which one occurred in the wrist joint and the rest were localized to the knee joint. Age ranged from one year to seventy-three years, with a male preponderance. Pain and swelling were major complaints. Three had a significant past history, one occurring post trauma, one following chikungunya, and another with septic arthritis. Three of the cases had osteoarthritis. Body mass index was elevated in four cases and one case had protein energy malnutrition. On histopathological examination, all the cases showed villous proliferation of the synovium, with focal and diffuse infiltration by mature adipocytes. Four cases showed focal hyperplasia of the lining epithelium and five cases revealed variable fibrosis. CONCLUSION: Synovial lipomatosis may mimic tumorous, lesion-like synovial lipoma or hemangioma and its distinct histomorphology helps in distinguishing it from these lesions. It possibly represents a secondary phenomenon following the degenerative process of articular disease of the joints. PMID- 22219561 TI - Inducible clindamycin resistance in Staphylococcus aureus isolated from nursing and pharmacy students. AB - AIMS: Emergence of resistant isolates of Staphylococcus aureus (S. aureus) has resulted in failure of clindamycin therapy. The prevalence of inducible clindamycin resistance in S. aureus isolated from nursing students and pharmacy students (representing carriers exposed and not exposed to hospital environment respectively) was evaluated. MATERIALS AND METHODS: Nasal, throat, and palmar swabs were collected from 119 nursing students and 100 pharmacy students. S. aureus was identified and antibiogram obtained by Clinical and Laboratory Standards Institute guidelines. Inducible clindamycin resistance was detected by the D-test. RESULTS: 36 and 34 individuals in the exposed and non-exposed groups respectively were carriers of S. aureus. 16.7% and 5.9% isolates showed inducible clindamycin resistance in exposed and non-exposed groups, respectively. The percentage of inducible clindamycin resistance was higher among methicillin resistant S. aureus (MRSA) (27.8%) compared to methicillin-sensitive S. aureus (5.8%). CONCLUSION: S. aureus isolates resistant to beta-lactams can also show inducible clindamycin resistance. Exposure to hospital environment was not found to be a risk factor for carriage of S. aureus with MLSBi phenotype. PMID- 22219562 TI - Metallo-beta-lactamase-producing clinical isolates from patients of a tertiary care hospital. AB - BACKGROUND: The growing increase in the rates of antibiotic resistance is a major cause for concern in both non-fermenting bacilli and isolates of the Enterobacteriaceae family. beta-lactams have been the mainstay of treatment for serious infections, and the most active of these are the carbapenems. Acquired metallo-beta-lactamases (MBL) have recently emerged as one of the most worrisome resistance mechanisms owing to their capacity to hydrolyze all beta-lactams, including carbapenems. We have undertaken this investigation to ascertain the prevalence of MBL-producing non-fermenting bacilli and Enterobacteriaceae. MATERIALS AND METHODS: The study was conducted over a period of 4 months in a 1200-bedded teaching hospital. Isolates included in the study were screened for imipenem resistance both by conventional methods and mini analytical profile index (miniAPI). The isolates that showed imipenem resistance were tested for MBL production by imipenem (IMP)-ethylenediaminetetraacetic acid combined disc test. Imipenem-resistant non-MBL isolates also tested for Modified Hodge test and AmpC beta-lactamases production to detect other mechanisms of carbapenem resistance. RESULTS: Of 638 gram negative bacilli isolates and 3.39% showed imipenem resistance, 2.9% showed MBL production, of which 1.7% were non-fermenters and 1.25% were Enterobacteriaceae, 0.3% showing non-MBL KPC carbapenemas. Most isolates were from the intensive care unit and from post-operative patients. Our findings show that there are significant numbers of isolates having MBL production along with multidrug resistance. There is a need for active surveillance to detect MBL producers. PMID- 22219563 TI - Rising prevalence of antimicrobial resistance in urinary tract infections during pregnancy: necessity for exploring newer treatment options. AB - BACKGROUND: Urinary tract infections (UTI) are one of the most common medical complications of pregnancy. The emergence of drug resistance and particularly the Extended-spectrum beta-lactamase production by Escherichia coli and methicillin resistance in Staphylococci, limits the choice of antimicrobials. MATERIALS AND METHODS: Patients in different stages of pregnancy with or without symptoms of urinary tract infection attending the antenatal clinic of obstetrics and gynaecology were screened for significant bacteriuria, by standard loop method on 5% sheep blood agar and teepol lactose agar. Isolates were identified by using standard biochemical tests and antimicrobial susceptibility testing was done using Kirby Bauer disc diffusion method. RESULTS: A total of 4290 (51.2%) urine samples from pregnant females showed growth on culture. Prevalence of asymptomatic bacteriuria 3210 (74.8%) was higher than symptomatic UTI 1080 (25.2%). Escherichia coli was the most common pathogen accounting for 1800 (41.9%) of the urinary isolates. Among the gram-positive cocci, coagulase negative species of Staphylococci 270 (6.4%) were the most common pathogen. Significantly high resistance was shown by the gram negative bacilli as well as gram positive cocci to the beta-lactam group of antimicrobials, flouroquinolones and aminoglycosides. Most alarming was the presence of ESBL in 846 (47%) isolates of Escherichia coli and 344 (36.9%) isolates of Klebsiella pneumoniae, along with the presence of methicillin resistance in 41% of Staphylococcus species and high level aminoglycoside resistance in 45(30%) isolates of Enterococcus species. Glycopeptides and carbepenems were the only group of drugs to which all the strains of gram positive cocci and gram negative bacilli were uniformly sensitive, respectively. CONCLUSIONS: Regular screening should be done for the presence of symptomatic or asymptomatic bacteriuria in pregnancy and specific guidelines should be issued for testing antimicrobial susceptibility with safe drugs in pregnant women so that these can be used for the treatment. For empirical treatment cefoperazone-sulbactum can be recommended, which is a safe drug, covering both gram positive and gram negative organisms and with a good sensitivity. PMID- 22219564 TI - Agreement of two different laboratory methods used to measure electrolytes. AB - AIM: The aim of our study was to do an agreement analysis of two different laboratory methods used to measure electrolytes i.e., between the ISE based Beckman Coulter Synchron CX9 PRO Biochemistry analyzer and RAL's Ion3 Flame Photometer (Tecnica para el Laboratorio, Barcelona, Spain), in serum samples. MATERIALS AND METHODS: This cross sectional study was done over a period of three months from September'09 through December'09 on routine biochemistry samples. A total of 6492 samples were received for routine biochemistry analysis from those 630 blood samples were randomly processed for this study. Two ml of sample was taken in a plain gel tube (LABTECH Disposables, Ahmedabad, India), centrifuged and further processed using both systems within one hour of the sampling to obtain the Na and K concentrations in the samples. The bias and variability of differences in measured values were analyzed according to Bland and Altman method. RESULTS: Flame photometry method has drawbacks such as low throughput, requires manual operation, is a time consuming procedure. Ion selective electrodes technique is a more universal method for the high throughput determination of electrolytes in physiological samples; Beckman Coulter Synchron CX9 PRO is an example of such a system. The mean difference between the two methods (standard minus test) and 95% limits of agreement for sodium in serum was -7.8+/-17.3 (-42.2 to 26.6) and in urine was -22+/-41 (-104 to 60). Similarly, the mean difference between the two methods for potassium values in serum was found to be -0.25+/-0.75 (-1.75 to 1.25) and in urine was -5.3+/-38.9 (-83.1 to 72.5). With 95% confidence interval, the value of sodium and potassium as determined by both the methods lie between the upper and lower limit showing 95% limits of agreement. CONCLUSION: Good degree of agreement was seen on comparing the two methods for measuring the electrolytes; the use of Synchron CX9 in place of Flame photometer for electrolyte analysis in serum and urine is justified or use the two interchangeably. PMID- 22219565 TI - De-novo histoid leprosy. AB - Histoid leprosy is a rare form of multibacillary leprosy with distinct clinical and histopathological features. It is a variant of lepromatous leprosy. It occurs in lepromatous patients, who relapse after dapsone monotherapy, in the presence of dapsone resistance or at times 'de-novo'. We describe here a case of histoid leprosy, clinically mimicking neurofibromatosis. PMID- 22219566 TI - Unusual cause of childhood anemia: Imerslund Grasbeck syndrome. AB - Imerslund Grasbeck syndrome (IGS) is a rare autosomal recessive childhood disorder characterized by selective Vitamin (vit) B 12 malabsorption with asymptomatic proteinuria without any structural renal pathology. The patients stay healthy for decades with life-long parenteral vit B12. We report a case of young female who presented with pancytopenia and proteinuria, evaluated in local hospitals as chronic hemolytic anemia (autoimmune cause), finally diagnosed as IGS on complete evaluation. She was treated with injectable vit B12 (1000 MUg cyanocobalalmin) and showed drastic recovery. IGS should be considered in patients with megaloblastic anemia not responding to oral vit B12 and associated proteinuria. PMID- 22219567 TI - Two cases of eosinophilic variant chromophobe renal cell carcinoma, with a rare association of right atrial myxoma in one of them. AB - Chromophobe renal cell carcinoma is a relatively uncommon variant of renal cell carcinoma. Eosinophilic variant of chromophobe renal cell carcinoma (EVCRCC) is still less frequent and is composed predominantly of small to medium-sized cells with abundant granular eosinophilic cytoplasm. We report two cases of EVCRCC, with one having a rare association of right atrial myxoma. We present these cases, due to the rarity of EVCRCC and an unusual association of right atrial myxoma in one of them. Both patients recovered well after surgery, with no recurrence or metastasis after 2 years of follow-up. PMID- 22219568 TI - Atypical presentation of visceral leishmaniasis in a HIV-positive patient from a nonendemic area. AB - Visceral leishmaniasis (VL), though widely prevalent in India, is not seen in the Rajasthan where the dry, hot and arid climatic conditions create a hostile environment for the growth of the parasite or its vector, the sandfly. We present a case of VL in a patient co-infected with HIV from this region. A 34-year-old known case of a HIV-positive patient presented to the skin department of our hospital with multiple, nontender, erythematous, papulonodular lesions all over the body for 6 months with history of weight loss and low-grade fever. Important examination findings were pallor, inguinal lymphadenopathy and hepatosplenomegaly. Laboratory findings included anemia, leucopenia, hypergammaglobulinemia and altered leucocytes to erythrocyte ratio. Buffy coat examination and bone marrow aspirates showed the presence of leishman bodies inside monocytes and macrophages respectively as well as extracellularly also. The patient was treated with amphotericin B intravenously and responded well to the treatment. PMID- 22219569 TI - Subcutaneous phaeohyphomycosis of foot in an immunocompetent host. AB - We report a case of subcutaneous phaeohyphomycosis of foot, which is a mycotic disease that produces brown pigmented hyphae, pseudohyphae and yeast form in combination. The patient was immunocompetent and had injury 23 years before, and developed a non healing foot ulcer which was clinically suspected as tuberculous or carcinomatous etiology. Local wide excision was done and sent in formalin for histopathological examination. Microscopically pigmented septate, hyphae and yeast forms were identified on hematoxylin and eosin stained sections which were confirmed by special stains such as periodic acid-Schiff and Gomori's methenamine silver stains. PMID- 22219570 TI - Calcinosis cutis: report of 4 cases. AB - Calcinosis cutis is a condition of accumulation of calcium salts within the dermis. We are presenting four cases of calcinosis cutis, with different clinical presentations, occurring in healthy individuals, with normal serum calcium and phosphorus levels. Histologically, all cases showed similar morphology, the lesions were composed of large and small deposits of calcium. Foreign-body giant cell reaction was seen in one case. Another case had intact and ruptured epidermal cysts and calcification within the cyst. PMID- 22219571 TI - Multifocal keloids associated with Mycobacterium fortuitum following intralesional steroid therapy. AB - We report a case of subcutaneous abscess formation with Mycobacterium fortuitum following intralesional steroid injection into multifocal keloids. A high index of suspicion of atypical mycobacteria infection is needed in patients with a history of skin and soft tissue infections, in particular late-onset infections, which are negative for routine bacterial cultures and without a clinical response to antibiotics used for acute pyogenic infections. PMID- 22219572 TI - Retraction notice. PMID- 22219573 TI - In the quest of drugs for bad bugs: are newer fluoroquinolones any better? PMID- 22219574 TI - Reactive thrombocytosis in H1N1 infection. PMID- 22219575 TI - Renal type clear cell carcinoma of the prostate: a diagnostic dilemma. PMID- 22219576 TI - Hepatitis-B associated cryoglobulinemia presenting as pseudoleucocytosis. PMID- 22219577 TI - Seroprevalence of hepatitis B and C in HIV seropositive and chronic renal failure patients in North India. PMID- 22219578 TI - Type 2 first branchial cleft cyst presenting as childhood deafness. PMID- 22219579 TI - Limitation of EPR: A thing to be noted. PMID- 22219580 TI - The Nigerian health care system: Need for integrating adequate medical intelligence and surveillance systems. AB - OBJECTIVES: As an important element of national security, public health not only functions to provide adequate and timely medical care but also track, monitor, and control disease outbreak. The Nigerian health care had suffered several infectious disease outbreaks year after year. Hence, there is need to tackle the problem. This study aims to review the state of the Nigerian health care system and to provide possible recommendations to the worsening state of health care in the country. To give up-to-date recommendations for the Nigerian health care system, this study also aims at reviewing the dynamics of health care in the United States, Britain, and Europe with regards to methods of medical intelligence/surveillance. MATERIALS AND METHODS: DATABASES WERE SEARCHED FOR RELEVANT LITERATURES USING THE FOLLOWING KEYWORDS: Nigerian health care, Nigerian health care system, and Nigerian primary health care system. Additional keywords used in the search were as follows: United States (OR Europe) health care dynamics, Medical Intelligence, Medical Intelligence systems, Public health surveillance systems, Nigerian medical intelligence, Nigerian surveillance systems, and Nigerian health information system. Literatures were searched in scientific databases Pubmed and African Journals OnLine. Internet searches were based on Google and Search Nigeria. RESULTS: Medical intelligence and surveillance represent a very useful component in the health care system and control diseases outbreak, bioattack, etc. There is increasing role of automated based medical intelligence and surveillance systems, in addition to the traditional manual pattern of document retrieval in advanced medical setting such as those in western and European countries. CONCLUSION: The Nigerian health care system is poorly developed. No adequate and functional surveillance systems are developed. To achieve success in health care in this modern era, a system well grounded in routine surveillance and medical intelligence as the backbone of the health sector is necessary, besides adequate management couple with strong leadership principles. PMID- 22219581 TI - Is propolis safe as an alternative medicine? AB - Propolis is a resinous substance produced by honeybees as defense against intruders. It has relevant therapeutic properties that have been used since ancient times. Nowadays, propolis is of increasing importance as a therapeutic, alone or included in many medicines and homeopathic products or in cosmetics. Propolis is produced worldwide and honeybees use the flora surrounding their beehives for its production. Therefore its chemical composition may change according to the flora. The phenolic and volatile fractions of propolis have been revised in the present study, as well as some of the biological properties attributed to this natural product. An alert is given about the need to standardize this product, with quality control. This has already been initiated by some authors, mainly in the propolis from the poplar-type. Only this product can constitute a good complementary and alternative medicine under internationally acceptable quality control. PMID- 22219582 TI - Bacterial vaginosis: Etiology and modalities of treatment-A brief note. AB - A large women population of the world is suffering from a vaginal infection commonly known as bacterial vaginosis. The disease is associated with the decrease in the lactobacilli count in the vagina. Till date, there is a lack of full proof treatment modalities for the cure of the disease. The treatment includes the use of antimicrobials and/or acidifying agents and probiotics, either separately or in combination. This note discusses about the etiology and the various present-day modalities of treatment of bacterial vaginosis. PMID- 22219583 TI - Alternative therapies useful in the management of diabetes: A systematic review. AB - Diabetes mellitus is a metabolic disorder in the endocrine system. This dreadful disease is found in all parts of the world and becoming a serious threat of mankind health. There are lots of chemical agents available to control and to treat diabetic patients, but total recovery from diabetes has not been reported up to this date. In addition to adverse effects, drug treatments are not always satisfactory in maintaining euglycemia and avoiding late stage diabetic complications. Alternative to these synthetic agents, plants provided a potential source of hypoglycemic drugs and are widely used in several traditional systems of medicine to prevent diabetes. Several medicinal plants have been investigated for their beneficial effect in different type of diabetes. Other alternative therapies such as dietary supplements, acupuncture, hydrotherapy, and yoga therapies less likely to have the side effects of conventional approaches for diabetes. PMID- 22219584 TI - Prevalence and determinants of diabetes mellitus in Puducherry, South India. AB - BACKGROUND: Diabetes mellitus is an emerging global health problem. It is a chronic, noncommunicable, and expensive public health disease. AIMS AND OBJECTIVES: To determine the prevalence and the risk factors of type 2 diabetes mellitus among the adult population of Puducherry, South India. MATERIALS AND METHODS: This was a population-based cross-sectional study carried out during 1(st) May 2007-30(th) November 2007 in the rural and urban field practice area of Mahatma Gandhi Medical College and Research Institute, Puducherry. Simple random sampling technique was used for the selection of 1370 adult 20 years of age and above. Main outcome measures were the assessment of the prevalence of prevalence and correlates of diabetes among the adult population. Predesigned and pretested questionnaire was used to elicit the information on family and individual sociodemographic variables. Height, weight, waist, and hip circumference, blood pressure was measured and venous blood was also collected to measure fasting blood glucose, blood cholesterol. RESULTS: Overall, 8.47% study subjects were diagnosed as diabetic. The univariate analysis and multivariate logistic regression analysis showed that the important correlates of diabetes mellitus were age, blood cholesterol, and family history of diabetes. The findings were found to be statistically significant. CONCLUSIONS: In our study we observed that adults having increased age, hypercholesterolemia, and family history of diabetes mellitus are more likely to develop diabetes mellitus. PMID- 22219585 TI - Effect of amiloride: An Na / H exchange inhibitor in the middle cerebral artery occlusion model of focal cerebral ischemia in rats. AB - PURPOSE: The effect of pretreatment with amiloride (AML), an Na(+) / H(+) exchange inhibitor was studied in the middle cerebral artery occlusion (MCAO) model of focal cerebral ischemia in rats. MATERIALS AND METHODS: Male wistar rats were subjected to 2 hr of MCAO followed by 22-hr reperfusion. Grip strength, locomotor activity, and spontaneous alternation performance were assessed after 24 hr. Immediately after behavioral activities, animals were sacrificed and the oxidative stress markers were estimated in brains. RESULTS: An elevation of thiobarbituric acid reactive substances (TBARS), reduction in glutathione, and antioxidant enzymes activities, namely glutathione-S-transferase, glutathione peroxidase (GPx), glutathione reductase (GR), and superoxide dismutase (SOD) were observed following MCA occluded rats. Pretreatment with AML (0.91 and 1.82 mg/kg p.o) significantly reversed the MCAO-induced elevation in TBARS but could not reverse the other parameters. Paradoxically, AML further reduced the levels of GPx, GR, and SOD, but no significant changes were observed in the catalase activity, grip strength, and spontaneous alternation behavior of rats. Locomotor activity was reduced slightly but reversed on pretreatment with AML. CONCLUSIONS: Although pretreatment with single dose of AML showed reduction in oxidative stress markers, further multiple doses of AML as pre- and post-treatments are required to establish its potential to be used in cerebral ischemia. PMID- 22219587 TI - Antibiotic prescription patterns at admission into a tertiary level intensive care unit in Northern India. AB - CONTEXT: An audit of antibiotic prescribing patterns is an important indicator of the quality and standard of clinical practice. AIMS: To study the (1) antibiotic prescription and consumption patterns at admission into the intensive care unit (ICU); (2) average costs of antibiotics prescribed; and (3) correlation of antibiotic usage and the costs incurred with age, severity of illness, and diagnosis. SETTINGS AND DESIGN: A 13-bedded tertiary level ICU. A prospective, observational audit. MATERIALS AND METHODS: Two hundred consecutive prescriptions on patients admitted to the ICU from August to October, 2008, were audited. The total number of drugs and antibiotics, the class, dose, route, and cost of antibiotics were noted and the Defined Daily Dose/100 bed-days (DDD/100 bed-days) of the 10 most frequently prescribed antibiotics were calculated. STATISTICAL ANALYSIS USED: Univariate analysis was performed using Epi Info software (version 8.0). RESULTS: A total of 1246 drugs and 418 antibiotics were prescribed in the 200 patients studied, that is, an average of 6.23 (+/- SD 2.73) drugs/prescription and 2.09 (+/- SD 1.27) antibiotics/prescription. Antibiotics were prescribed on 190 patients (95%) at admission. There was a significant correlation between the number of patients prescribed three or more antibiotics and mortality rates (53% nonsurvivors vs. 33.5% survivors (P = 0.015). The average cost of the antibiotics was Rupees 1995.08 (+/- SD 2099.99) per patient and antibiotics expenditure accounted for 73.2% of the total drug costs. CONCLUSIONS: Antibiotics are commonly prescribed to most ICU patients at admission and contribute significantly to the total drug costs. Antibiotic restriction policies and a multidisciplinary effort to reduce usage are urgently required. PMID- 22219586 TI - Resistant patterns of bacteria isolated from bloodstream infections at a university hospital in Delhi. AB - BACKGROUND: The choice of antimicrobial therapy for bloodstream infections is often empirical and based on the knowledge of local antimicrobial activity profiles of the most common bacteria causing such infections. AIMS: The present study was aimed to investigate frequency of bacterial pathogens causing septicemia and their antimicrobial resistant pattern in hospital admitted patients. SETTINGS AND DESIGN: It was a prospective study, conducted at Majeedia Hospital, Hamdard University, New Delhi, India. MATERIAL AND METHODS: We examined prospectively, 168 bacterial strains isolated from 186 clinically diagnosed septicemia cases admitted at a University Hospital in New Delhi, over a period of six months from July 2009 to December 2009. Antimicrobial susceptibility was performed according to Clinical and Laboratory Standards Institute (CLSI, USA) guidelines. RESULTS: The most frequently identified Gram-positive bacteria were coagulase-negative staphylococci 63.5%, Staphylococcus aureus 23.1%, enterococci 5.8% and alpha-haemolytic streptococci 5.8%. The most frequently Gram-negative bacteria identified were Acinetobacter species 31%, Salmonella typhi 24.1%, Escherichia coli 23.3% and Pseudomonas aeruginosa 13.8%. Coagulase-negative staphylococci showed maximum resistance to cefaclor 57.1% and ampicillin 46.9%. Staphylococcus aureus showed maximum resistance to amoxicillin 100% and ampicillin 91.7%. Acinetobacter species showed maximum resistance to amoxicillin 89.7%, amoxiclav 87.1% and ampicillin 85.7%. Salmonella typhi, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae showed maximum resistance to ampicillin, 46.4%, 92%, 93.8% and 100%, respectively. CONCLUSIONS: Gram-negative pathogens predominated in bloodstream infections. Resistance to most of the antimicrobial agents for a number of pathogens implicated in bloodstream infections, especially in Gram-negative bacteria, has reached worrisome levels and continues to increase. PMID- 22219588 TI - Ageing in Puducherry, South India: An overview of morbidity profile. AB - BACKGROUND: The geriatric health problems are related to chronic disease as a result of increasing life expectancy. OBJECTIVE: This study was undertaken to assess the health problems of the elderly in Puducherry. MATERIALS AND METHODS: This cross-sectional study was carried out on 214 elderly persons from the age group of 60 years and above using a pre-designed and pre-tested questionnaire that addressed the disease magnitude in comparison with the socioeconomic variables. RESULTS: Overall, 43% of the participants were diabetic, 47.7% hypertensive, 86% anemic and 68.2% visually impaired. All the morbidities were noted to be higher in the 70-79 years age group. Diabetes was significantly higher in participants from urban areas, with family history and increasing waist hip ratio, but significantly lower in the below poverty line areas. Hypertension risk was significantly higher among females, among those leading sedentary life, those eating vegetarian food, those addicted to tobacco and with abdominal obesity. Anemia was significantly lower among urban vegetarians. Overweight and obese were noted in 31% of the participants, and were higher in females (87.5%). Rural residence, female sex, living in joint family, literacy, sedentary life style, decreasing per capita income and decreasing body mass index (BMI) were significantly associated with visual impairment. CONCLUSION: This study highlights the burden of health problems of elderly individuals in South India. PMID- 22219589 TI - Blue cures blue but be cautious. AB - Methemoglobinemia is a disorder characterized by the presence of >1% methemoglobin (metHb) in the blood. Spontaneous formation of methemoglobin is normally counteracted by protective enzyme systems, for example, nicotinamide adenine dinucleotide phosphate (NADPH) methemoglobin reductase. Methemoglobinemia is treated with supplemental oxygen and methylene blue (1-2 mg/kg) administered slow intravenously, which acts by providing an artificial electron acceptor for NADPH methemoglobin reductase. But known or suspected glucose-6-phosphate dehydrogenase (G6PD) deficiency is a relative contraindication to the use of methylene blue because G6PD is the key enzyme in the formation of NADPH through pentose phosphate pathway and G6PD-deficient individuals generate insufficient NADPH to efficiently reduce methylene blue to leukomethylene blue, which is necessary for the activation of the NADPH-dependent methemoglobin reductase system. So, we should be careful using methylene blue in methemoglobinemia patient before G6PD levels. PMID- 22219590 TI - Ipilimumab: Melanoma and beyond. PMID- 22219591 TI - miRNAs in precancerous lesions of the gastrointestinal tract. AB - In spite of the well-established understanding of the phenotypic lesions occurring in the shift from native epithelia to invasive (adeno) carcinoma, the molecular typing of the precancerous changes in the gastrointestinal tract remains unreliable. In recent years, no biomarkers have aroused as much interest as the miRNAs, a class of non-coding RNA molecules that function as endogenous silencers of numerous target genes. Aberrant miRNA expression is a hallmark of human disease, including cancer. Unlike most mRNAs, miRNAs are both long-living in vivo and very stable in vitro. Such characteristics allow their testing in paraffin-embedded tissue samples, which is essential in the biological profiling of small (phenotypically characterized) preneoplastic lesions of the gastrointestinal tract (as well as in other fields of human pathology). The upcoming challenge lies in the reliable identification of disease-specific targets of dysregulated miRNAs, to enable miRNA testing in the clinical management of the secondary prevention of gastrointestinal cancer. PMID- 22219592 TI - Impact of liver diseases on the development of type 2 diabetes mellitus. AB - The prevalence of type 2 diabetes mellitus (T2DM) is higher in patients who have liver diseases such as nonalcoholic fatty liver disease, chronic viral hepatitis, hemochromatosis, alcoholic liver disease and cirrhosis. It is suggested that there is a pathogenic link between the presence of T2DM and the severity of liver injury. However, evidence related to the impact of hepatic inflammation on the development of T2DM has not yet emerged. This article provides an overview of the evidence for an increased prevalence of diabetes in a range of liver diseases, the impact of liver diseases on insulin resistance and beta cell dysfunction, and the potential mechanisms whereby coexistent liver diseases exacerbate the development of T2DM. PMID- 22219594 TI - Hepatocellular carcinoma-specific immunotherapy with synthesized alpha1,3- galactosyl epitope-pulsed dendritic cells and cytokine-induced killer cells. AB - AIM: To evaluate the safety and clinical efficacy of a new immunotherapy using both alpha-Gal epitope-pulsed dendritic cells (DCs) and cytokine-induced killer cells. METHODS: Freshly collected hepatocellular carcinoma (HCC) tumor tissues were incubated with a mixture of neuraminidase and recombinant alpha1,3 galactosyltransferase (alpha1,3GT) to synthesize alpha-Gal epitopes on carbohydrate chains of the glycoproteins of tumor membranes. The subsequent incubation of the processed membranes in the presence of human natural anti-Gal IgG resulted in the effective phagocytosis to the tumor membrane by DCs. Eighteen patients aged 38-78 years with stage III primary HCC were randomLy chosen for the study; 9 patients served as controls, and 9 patients were enrolled in the study group. RESULTS: The evaluation demonstrated that the procedure was safe; no serious side effects or autoimmune diseases were observed. The therapy significantly prolonged the survival of treated patients as compared with the controls (17.1 +/- 2.01 mo vs 10.1 +/- 4.5 mo, P = 0.00121). After treatment, all patients in the study group had positive delayed hypersensitivity and robust systemic cytotoxicity in response to tumor lysate as measured by interferon-gamma expression in peripheral blood mononuclear cells using enzyme-linked immunosorbent spot assay. They also displayed increased numbers of CD8-, CD45RO- and CD56-positive cells in the peripheral blood and decreased alpha-fetoprotein level in the serum. CONCLUSION: This new tumor-specific immunotherapy is safe, effective and has a great potential for the treatment of tumors. PMID- 22219596 TI - Impact of early or delayed elective resection in complicated diverticulitis. AB - AIM: To investigate the outcomes of early and delayed elective resection after initial antibiotic treatment in patients with complicated diverticulitis. METHODS: The study, a non-randomized comparison of the two approaches, included 421 consecutive patients who underwent surgical resection for complicated sigmoid diverticulitis (Hinchey classification I-II) at the Department of Surgery, University Medical Center Hamburg-Eppendorf between 2004 and 2009. The operating procedure, duration of hospital and intensive care unit stay, outcome, complications and socioeconomic costs were analyzed, with comparison made between the early and delayed elective resection strategies. RESULTS: The severity of the diverticulitis and American Society of Anesthesiologists score were comparable for the two groups. Patients who underwent delayed elective resection had a shorter hospital stay and operating time, and the rate of successfully completed laparoscopic resections was higher (80% vs 75%). Eight patients who were scheduled for delayed elective resection required urgent surgery because of complications of the diverticulitis, which resulted in a high rate of morbidity. Analysis of the socioeconomic effects showed that hospitalization costs were significantly higher for delayed elective resection compared with early elective resection (9296 ? +/- 694 ? vs 8423 ? +/- 968 ?; P = 0.001). Delayed elective resection showed a trend toward lower complications, and the operation appeared simpler to perform than early elective resection. Nevertheless, delayed elective resection carries a risk of complications occurring during the period of 6-8 wk that could necessitate an urgent resection with its consequent high morbidity, which counterbalanced many of the advantages. CONCLUSION: Overall, early elective resection for complicated, non-perforated diverticulitis is shown to be a suitable alternative to delayed elective resection after 6-8 wk, with additional beneficial socioeconomic effects. PMID- 22219593 TI - Role of genetics in the diagnosis and prognosis of Crohn's disease. AB - Considering the epidemiological, genetic and immunological data, we can conclude that the inflammatory bowel diseases are heterogeneous disorders of multifactorial etiology in which hereditability and environment interact to produce the disease. It is probable that patients have a genetic predisposition for the development of the disease coupled with disturbances in immunoregulation. Several genes have so far been related to the diagnosis of Crohn's disease. These genes are related to innate pattern recognition receptors, to epithelial barrier homeostasis and maintenance of epithelial barrier integrity, to autophagy and to lymphocyte differentiation. So far, the strongest and most replicated associations with Crohn's disease have been demonstrated with NOD2, IL23R and ATG16L1 genes. Many genes have so far been implicated in the prognosis of Crohn's disease and many attempts have been made for classification of genetic profiles in Crohn's disease. CARD15 seems to be not only a susceptibility gene, but also a disease-modifier gene for Crohn's disease. Enriching our understanding of Crohn's disease genetics is of value, but when combining genetic data with functional data the outcome could be of major importance to clinicians. PMID- 22219595 TI - Decreased hepatic peroxisome proliferator-activated receptor-gamma contributes to increased sensitivity to endotoxin in obstructive jaundice. AB - AIM: To investigate the role of hepatic peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in increased susceptibility to endotoxin-induced toxicity in rats with bile duct ligation during endotoxemia. METHODS: Male Sprague-Dawley rats were subjected to bile duct ligation (BDL). Sham-operated animals served as controls. DNA binding were determined by polymerase chain reaction, Western blotting analysis, and electrophoretic mobility shift assay, respectively. BDL and sham-operated rats received a non-lethal dose of intraperitoneal lipopolysaccharide (LPS) injection (3 mg/kg, i.p.). Additionally, the potential beneficial effects of the PPAR-gamma agonist rosiglitazone were determined in BDL and sham-operated rats treated with a non-lethal dose of LPS. Survival was assessed in BDL rats treated with a non-lethal dose of LPS and in sham-operated rats treated at a lethal dose of LPS (6 mg/kg, i.p.). RESULTS: PPAR gamma activity in rats undergoing BDL was significantly lower than in the sham controls. Hepatic PPAR-gamma gene expression was downregulated at both the mRNA and protein levels. In a parallel group, serum levels of pro-inflammatory cytokines were nearly undetectable in the sham-operated rats. When challenged with a non-lethal dose of LPS (3 mg/kg), the BDL rats had approximately a 2.4 fold increase in serum IL-6, a 2.7 fold increase in serum TNF-alpha, 2.2-fold increase in serum IL-1 and 4.2-fold increase in serum ALT. The survival rate was significantly lower as compared with that in sham-operated group. Additionally, rosiglitazone significantly reduced the concentration of TNF-alpha, IL-1beta, IL 6 and ALT in sham-operated rats, but not in BDL rats, in response to LPS (3 mg/kg). Also, the survival was improved by rosiglitazone in sham-operated rats challenged with a lethal dose of LPS, but not in BDL rats, even with a non-lethal dose of LPS (3 mg/kg). CONCLUSION: Obstructive jaundice downregulates hepatic PPAR-gamma expression, which in turn may contribute to hypersensitivity towards endotoxin. PMID- 22219597 TI - Serum Bcl-2 concentrations in overweight-obese subjects with nonalcoholic fatty liver disease. AB - AIM: To shed some light on the relationship between anti-apoptotic serum Bcl-2 concentrations and metabolic status, anthropometric parameters, inflammation indices, and non-alcoholic fatty liver disease severity were investigated in 43 young individuals with fatty liver (FL) and 41 with nonalcoholic steatohepatitis (NASH). METHODS: Circulating levels of Bcl-2 were detected in 84 patients with ultrasonographic findings of "bright liver" and/or hyper-transaminasemia of unknown origin and/or increase in gamma-glutamyl-transpeptidase (gamma-GT) strictly in the absence of other acute or chronic liver disease, whose age was not advanced, who gave consent to liver biopsy and were then divided on the basis of the histological results into two groups (43 with FL and 41 with NASH). Twenty lean subjects, apparently healthy and young, were chosen as controls. RESULTS: Serum Bcl-2 concentrations were significantly higher in the FL group than in the NASH group. Insulin resistance and gamma-GT activity were significantly higher in NASH subjects. Apoptotic hepatocytes were significantly more numerous in NASH patients. NASH patients presented with larger spleens and augmented C-reactive protein (CRP) concentrations than healthy subjects. Steatosis grade at histology was similar in both NASH and FL populations. The number of apoptotic cells was significantly related to anti-apoptotic Bcl-2 protein values in FL patients. Bcl 2 serum levels positively correlated to body mass index (BMI) values (P <= 0.0001) but not to age of the population. Triglycerides/HDL ratio correlated well to waist circumference in males (P = 0.0008). gamma-GT activity was associated with homeostatic metabolic assessment (HOMA) (P = 0.0003) and with serum ferritin (P = 0.02). Bcl-2 concentrations were not related to either spleen size or CRP values. NASH patients presented a weak negative correlation between lobular inflammation and Bcl-2 levels. A prediction by low values of serum Bcl-2 towards a greater presence of metabolically unhealthy overweight/obese patients (MUOs) was evidenced. HOMA, BMI and uric acid, in that sequence, best predicted serum Bcl-2 concentrations. CONCLUSION: MUOs could be detected by Bcl-2 levels. By favoring the life span of hepatocytes, and enhancing triglyceride formation, the anti-apoptotic process inhibits free fatty acids toxicity in FL. PMID- 22219598 TI - Impact of changing our cannulation method on the incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis after pancreatic guidewire placement. AB - AIM: To clarify whether the incidence of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) after pancreatic guidewire placement (PGW) can be reduced by using a different cannulation method. METHODS: Between April 2001 and October 2009, PGW was performed in 142 patients with native papilla to overcome difficult biliary cannulation. Our cannulation method for ERCP was changed from contrast injection (CI) using a single-lumen catheter (April 2001-May 2008) to wire-guided cannulation (WGC) using a double-lumen catheter (June 2008-October 2009). The CI protocol was also changed during the study period: in the first period it was used for routine pancreatography for detecting small pancreatic cancer (April 2001-November 2002), whereas in the second period it was not (December 2002-May 2008). In PGW with CI using a single lumen catheter, the contrast medium in the catheter lumen was injected into the pancreatic duct. The success rate of biliary cannulation, the incidence of PEP according to the cannulation method, and the impact of CI using a single-lumen catheter on PEP in comparison with WGC using a double-lumen catheter were investigated. RESULTS: CI with routine pancreatography, CI without routine pancreatography, and WGC were performed in 27 patients, 77 patients and 38 patients, respectively. Routine pancreatography did not contribute to the early diagnosis of pancreatic cancer in our study period. In CI without routine pancreatography and WGC, diagnostic pancreatography was performed in 17 patients and no patients, respectively. The success rate of biliary cannulation by PGW alone was 69%, and the final success rate was increased to 80.3% by the addition of consecutive maneuvers or a second ERCP. PEP occurred in 22 patients (15.5%), and the severity was mild in all cases. When analyzed according to cannulation method, the incidence of PEP was 37.0% (10/27) in the patients who underwent CI with routine pancreatography, 14.3% (11/77) in those who underwent CI without routine pancreatography, and 2.6% (1/38) in those who underwent WGC. In all patients who underwent CI using a single-lumen catheter, the incidence of PEP was 20% (21/104), which was significantly higher than that in WGC using a double lumen catheter. In univariate and multivariate analysis, CI using a single-lumen catheter showed a high, statistically significant, odds ratio for PEP after PGW. CONCLUSION: The practice of a cannulation method involving the use of a double lumen catheter minimizes the CI dose administered to the pancreatic duct and reduces the incidence of PEP after PGW. PMID- 22219599 TI - Human papillomavirus in upper digestive tract tumors from three countries. AB - AIM: To clarify human papillomavirus (HPV) involvement in carcinogenesis of the upper digestive tract of virological and pathological analyses. METHODS: The present study examined the presence of HPV in squamous cell carcinomas of the oral cavity (n = 71), and esophagus (n = 166) collected from Japan, Pakistan and Colombia, with different HPV exposure risk and genetic backgrounds. The viral load and physical status of HPV16 and HPV16-E6 variants were examined. Comparison of p53 and p16(INK4a) expression in HPV-positive and HPV-negative cases was also made. RESULTS: HPV16 was found in 39 (55%) oral carcinomas (OCs) and 24 (14%) esophageal carcinomas (ECs). This site-specific difference in HPV detection between OCs and ECs was statistically significant (P < 0.001). There was a significant difference in the geographical distribution of HPV16-E6 variants. Multiple infections of different HPV types were found in 13 ECs, but multiple infections were not found in OCs. This difference was statistically significant (P = 0.001). The geometric means (95% confidence interval) of HPV16 viral load in OCs and ECs were 0.06 (0.02-0.18) and 0.12 (0.05-0.27) copies per cell, respectively. The expression of p16(INK4a) proteins was increased by the presence of HPV in ECs (53% and 33% in HPV-positive and -negative ECs, respectively; P = 0.036), and the high-risk type of the HPV genome was not detected in surrounding normal esophageal mucosa of HPV-positive ECs. CONCLUSION: Based on our results, we cannot deny the possibility of HPV16 involvement in the carcinogenesis of the esophagus. PMID- 22219600 TI - Constant serum levels of secreted asialoglycoprotein receptor sH2a and decrease with cirrhosis. AB - AIM: To investigate the existence and levels of sH2a, a soluble secreted form of the asialoglycoprotein receptor in human serum. METHODS: Production of recombinant sH2a and development of a monoclonal antibody and an enzyme-linked immunosorbent assay (ELISA). This assay was used to determine the presence and concentration of sH2a in human sera of individuals of both sexes and a wide range of ages. RESULTS: The recombinant protein was produced successfully and a specific ELISA assay was developed. The levels of sH2a in sera from 62 healthy individuals varied minimally (147 +/- 19 ng/mL). In contrast, 5 hepatitis C patients with cirrhosis showed much decreased sH2a levels (50 +/- 9 ng/mL). CONCLUSION: Constant sH2a levels suggest constitutive secretion from hepatocytes in healthy individuals. This constant level and the decrease with cirrhosis suggest a diagnostic potential. PMID- 22219601 TI - Predicting tumor response after preoperative chemoradiation using clinical parameters in rectal cancer. AB - AIM: To evaluate the clinical parameters and identify a better method of predicting pathological complete response (pCR). METHODS: We enrolled 249 patients from a database of 544 consecutive rectal cancer patients who underwent surgical resection after preoperative chemoradiation therapy (PCRT). A retrospective review of morphological characteristics was then performed to collect data regarding rectal examination findings. A scoring model to predict pCR was then created. To validate the ability of the scoring model to predict complete regression. RESULTS: Seventy patients (12.9%) achieved a pCR. A multivariate analysis found that pre-CRT movability (P = 0.024), post-CRT size (P = 0.018), post-CRT morphology (P = 0.023), and gross change (P = 0.009) were independent predictors of pCR. The accuracy of the scoring model was 76.8% for predicting pCR with the threshold set at 4.5. In the validation set, the accuracy was 86.7%. CONCLUSION: Gross changes and morphological findings are important predictors of pathological response. Accordingly, PCRT response is best predicted by a combination of clinical, laboratory and metabolic information. PMID- 22219602 TI - Mutations around interferon sensitivity-determining region: a pilot resistance report of hepatitis C virus 1b in a Hong Kong population. AB - AIM: To explore mutations around the interferon sensitivity-determining region (ISDR) which are associated with the resistance of hepatitis C virus 1b (HCV-1b) to interferon-alpha treatment. METHODS: Thirty-seven HCV-1b samples were obtained from Hong Kong patients who had completed the combined interferon-alpha/ribavirin treatment for more than one year with available response data. Nineteen of them were sustained virological responders, while 18 were non-responders. The amino acid sequences of the extended ISDR (eISDR) covering 64 amino acids upstream and 67 amino acids downstream from the previously reported ISDR were analyzed. RESULTS: One amino acid variation (I2268V, P = 0.023) was significantly correlated with treatment outcome in this pilot study with a limited number of patients, while two amino acid variations (R2260H, P = 0.05 and S2278T, P = 0.05) were weakly associated with treatment outcome. The extent of amino acid variations within the ISDR or eISDR was not correlated with treatment outcome as previously reported. CONCLUSION: Three amino acid mutations near but outside of ISDR may associate with interferon treatment resistance of HCV-1b patients in Hong Kong. PMID- 22219603 TI - Ischemic colitis masquerading as colonic tumor: case report with review of literature. AB - Ischemic colitis can mimic a carcinoma on computed tomographic (CT) imaging or endoscopic examination. A coexisting colonic carcinoma or another potentially obstructing lesion has also been described in 20% of the cases of ischemic colitis. CT scan can differentiate it from colon cancer in 75% of cases. However, colonoscopy is the preferred method for diagnosing ischemic colitis as it allows for direct visualization with tissue sampling. Varied presentations of ischemic colitis have been described as an ulcerated or submucosal mass or as a narrowed segment of colon with ulcerated mucosa on colonoscopy. Awareness and early recognition of such varied presentations of a common condition is necessary to differentiate from a colonic carcinoma, and to avoid unnecessary surgery and related complications. PMID- 22219604 TI - Self-expanding metallic esophageal stents: a long way to go before a particular stent can be recommended. AB - We agree that the covered self-expanding metal stents (SEMSs) fare better than the uncovered stents as recurrent dysphagia due to tumor ingrowth is common with uncovered stent. Recent American College of Gastroenterology Practice Guideline on the Role of Esophageal Stents in Benign and Malignant Diseases concludes that SEMSs cannot be routinely recommended in conjunction with chemo-radiation. The comparison of ultraflex and choostent in the Italian study found no difference in the palliation of dysphagia, rate of complications and survival rate. PMID- 22219605 TI - Foodborne eosinophilia due to visceral larva migrans: a disease abandoned. PMID- 22219606 TI - Cellular toxicity of surfactants used as herbicide additives. AB - The cellular toxicities of surfactants, a solvent, and an antifreeze that are included in herbicide formulations were assessed by measuring their effects on membrane integrity, metabolic activity, mitochondrial activity, and total protein synthesis rate in a cell culture. Polyethylene glycol, propylene glycol, and monoethylene glycol exhibited no cellular toxicity even at a high concentration of 100 mM. Sodium lauryl ether sulfate and polyoxyethylene lauryl ether significantly damaged the membrane, disturbed cellular metabolic activity, and decreased mitochondrial activity and the protein synthesis rate; however, their toxicity was far below those of the severely toxic chemicals at comparable concentrations. The severely toxic category included polyoxypropylene glycol block copolymer, polyoxyethylene tallow amine, and polyoxyethylene lauryl amine ether. These surfactants were cytotoxic between 3.125 uM and 100 uM in a dose dependent manner. However, the toxicity graph of concentration vs toxicity had a point of inflection at 25 uM. The slope of the toxicity graph was gentle when the concentration was below 25 uM and steep when the concentration was greater than 25 uM. In conclusion, our results suggest that the toxicity of surfactants be taken care of pertinent treatment of acute herbicide intoxication. PMID- 22219607 TI - Real-time nucleic acid sequence-based amplification to predict the clinical outcome of invasive aspergillosis. AB - Monitoring the response to therapy for invasive aspergillosis (IA) is essential for the management of patients with hematologic diseases. We evaluated the correlation between the outcome of real-time nucleic acid sequence-based amplification (RTi-NASBA) for Aspergillus 18S rRNA and the clinical outcome of IA. A total of 157 serum samples from 29 patients with IA were tested for RTi NASBA. The treatment response and mortality were compared with the NASBA outcome (whether the NASBA value was converted to negative or not) at 12 weeks after the start of antifungal therapy. At 12 weeks, there was a moderate correlation between the treatment failure and persistently positive NASBA (kappa = 0.482; P = 0.019). Deaths attributable to IA were more prevalent in patients without negative conversion of NASBA than in those with negative conversion (50% vs 5%; P = 0.013). Significant factors of treatment failure at 12 weeks were the status of hematologic disease (nonremission; P = 0.041) and the NASBA outcome (failure of negative conversion; P = 0.024). Survival was significantly better in patients with negative conversion of NASBA than those with persistently positive values (P = 0.036). This study suggests that the serial monitoring of RTi-NASBA could be useful for prediction of the clinical outcome in hematologic patients with IA. PMID- 22219608 TI - Prevalence of widespread pain and its influence on quality of life: population study in Korea. AB - The objective of this study was to examine the prevalence and risk factors for widespread pain and its influence on quality of life in residents of Korean communities. A rural and an urban community were selected, and 5,037 subjects were surveyed. Participants were asked if they had pain, aching, or stiffness in any of their joints on most days. Widespread pain was defined as pain above the waist, below the waist, on both sides of the body and in the axial region. The prevalence of widespread pain was 12% (16.2% and 5.5% in females and males, respectively). It was more frequent among females and increased with age in both genders. Age, female gender, and the presence of hand or knee arthritis were significantly associated with widespread pain after multivariate analysis. Except for mental health, all the items in the SF-12 were adversely affected in the widespread pain group after adjustment for confounding factors. Our findings show that the prevalence of widespread pain among residents of Korean communities is comparable to that reported among Caucasians. The significantly worse quality of life among subjects with widespread pain suggests that it may cause major health issues in the aging population. PMID- 22219609 TI - Induction of remission is difficult due to frequent relapse during tapering steroids in Korean patients with polymyalgia rheumatica. AB - Polymyalgia rheumatica is an inflammatory disease affecting elderly and involving the shoulder and pelvic girdles. No epidemiological study of polymyalgia rheumatica was conducted in Korea. We retrospectively evaluated patients with polymyalgia rheumatica followed up at the rheumatology clinics of 10 tertiary hospitals. In total 51 patients, 36 patients (70.6%) were female. Age at disease onset was 67.4 yr. Twenty-three patients (45.1%) developed polymyalgia rheumatica in winter. Shoulder girdle ache was observed in 45 patients (90%) and elevated erythrocyte sedimentation rate (> 40 mm/h) in 49 patients (96.1%). Initial steroid dose was 23.3 mg/d prednisolone equivalent. Time to normal erythrocyte sedimentation rate was 4.1 months. Only 8 patients (15.7%) achieved remission. Among 41 patients followed up, 28 patients (68.3%) had flare at least once. Number of flares was 1.5 +/- 1.6. The frequency of flare was significantly lower in patients with remission (P = 0.02). In Korea, polymyalgia rheumatica commonly develops during winter. Initial response to steroid is fairly good, but the prognosis is not benign because remission is rare with frequent relapse requiring long-term steroid treatment. PMID- 22219610 TI - LPS-induced migration of peritoneal B-1 cells is associated with upregulation of CXCR4 and increased migratory sensitivity to CXCL12. AB - B-1 cells, which constitute a predominant lymphocyte subset in serosal cavities and produce most of natural antibodies, are subdivided into the CD5(+) B-1a and CD5(-) B-1b cell subpopulations, but the differential roles of B-1a and B-1b cells are not well understood. We report that B-1a cells preferentially migrate out of the peritoneal cavity and upregulate the expression of CXCR4 with heightened sensitivity to CXCL12 and CXCL13 upon LPS treatment compared to B-1b and B-2 cells. Whereas B-1a cells were slightly more abundant than B-1b and B-2 cells in the homeostatic condition, the number of B-1a cells preferentially decreased 48 hr after LPS treatment. The decrease in the peritoneal B-1a cell number was accompanied with increased migration of B-1a cells toward CXCL-12 and CXCL-13 in in vitro transmigration assay using peritoneal B cells from LPS treated mice. The expression level of CXCR4, but not of CXCR5, was also more prominently increased in B-1a cells upon LPS stimulation. LPS-stimulated B-1a cells did not accumulate in omental milky spots in contrast to B-2 cells. These results suggest that B-1a cells actively migrate out of the peritoneal cavity through the regulation of the migratory responsiveness to chemokines and actively participate in systemic immune responses. PMID- 22219611 TI - Optimal number of endoscopic biopsies in diagnosis of advanced gastric and colorectal cancer. AB - Endoscopic biopsy is necessary to confirm a histopathologic diagnosis. Currently, 6 to 8 biopsies are recommended for diagnosis of a suspected malignant lesion. However, multiple biopsies may result in several problems, such as an increased risk of bleeding, procedure prolongation, and increased workload to pathologists. The aim of this study was to clarify the optimal number of endoscopic biopsy specimens required in diagnosis of advanced gastrointestinal cancer. Patients who were diagnosed with advanced gastrointestinal cancer during endoscopy were included. Five specimens were obtained sequentially from viable tissue of the cancer margin. Experienced pathologists evaluated each specimen and provided diagnoses. A total of 91 patients were enrolled. Fifty-nine subjects had advanced gastric cancer, and 32 had advanced colon cancer. Positive diagnosis rates of the first, second, and third advanced gastric cancer specimens were 81.3%, 94.9%, and 98.3%, respectively, while positive diagnosis rates of advanced colon cancer specimens were 78.1%, 87.5%, and 93.8%. Further biopsies did not increase positive diagnosis cumulative rates. This study demonstrated that three specimens were sufficient to make correct pathologic diagnoses in advanced gastrointestinal cancer. Therefore, we recommend 3 or 4 biopsies from viable tissue in advanced gastrointestinal cancer to make a pathologic diagnosis during endoscopy. PMID- 22219612 TI - Optimal baseline prostate-specific antigen level to distinguish risk of prostate cancer in healthy men between 40 and 69 years of age. AB - The present study evaluated optimal baseline prostate-specific antigen (PSA) level at different ages in order to determine the risk of developing prostate cancer (CaP). We analyzed 6,651 Korean men, aged 40-69 yr. The serum PSA levels for these men were measured at one institute from 2000 to 2004 and were determined to be between 0-4 ng/mL. Patients were divided into 4 groups of 25th percentile intervals, based on initial PSA level. Of these, the group with an increased risk was selected, and the optimal value was determined by the maximal area under a receiver-operating characteristic curve within the selected group. The risk of CaP diagnosis was evaluated by Cox regression. The mean follow-up period was 8.3 yr. CaP was detected in 27 of the 6,651 subjects. CaP detection rate was increased according to age. The optimal PSA value to distinguish the risk of CaP was 2.0 ng/mL for 50- to 69-yr-olds. Patients with a baseline PSA level greater than the optimal value had a 27.78 fold increase in the prostate cancer risk. Baseline PSA values are useful for determining the risk of developing CaP in Korean men for 50- and 69-yr-old. We suggest that PSA testing intervals be modified based on their baseline PSA levels. PMID- 22219613 TI - Nodal stations and diagnostic performances of endobronchial ultrasound-guided transbronchial needle aspiration in patients with non-small cell lung cancer. AB - There are no accurate data on the relationship between nodal station and diagnostic performance of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). We evaluated the impact of nodal station and size on the diagnostic performance of EBUS-TBNA in patients with non-small cell lung cancer (NSCLC). Consecutive patients who underwent EBUS-TBNA of mediastinal or hilar lymph nodes for staging or diagnosis of NSCLC were included in this retrospective study. Between May 2009 and February 2010, EBUS-TBNA was performed in 373 mediastinal and hilar lymph nodes in 151 patients. The overall diagnostic sensitivity, specificity, accuracy and negative predictive value (NPV) of EBUS TBNA were 91.6%, 98.6%, 93.8%, and 84.3%, respectively. NPV of the left side nodal group was significantly lower than those of the other groups (P = 0.047) and sensitivity of the left side nodal group tended to decrease (P = 0.096) compared with those of the other groups. Diagnostic sensitivity and NPV of 4L lymph node were 83.3% and 66.7%, respectively. However, diagnostic performances of EBUS-TBNA did not differ according to nodal size. Bronchoscopists should consider the impact of nodal stations on diagnostic performances of EBUS-TBNA. PMID- 22219614 TI - APACHE II score, rather than cardiac function, may predict poor prognosis in patients with stress-induced cardiomyopathy. AB - While the disease course of stress-induced cardiomyopathy (SIC) is usually benign, it can be fatal. The prognostic factors to predict poorer outcome are not well established, however. We analyzed the Acute Physiology And Chronic Health Evaluation (APACHE) II score to assess its value for predicting poor prognosis in patients with SIC. Thirty-seven consecutive patients with SIC were followed prospectively during their hospitalization. Clinical factors, including APACHE II score, coronary angiogram, echocardiography and cardiac enzymes at presentation were analyzed. Of the 37 patients, 27 patients (73%) were women. The mean age was 66.1 +/- 15.6 yr, and the most common presentation was chest pain (38%). Initial echocardiographic left ventricular ejection fraction (EF) was 42.5% +/- 9.3%, and the wall motion score index (WMSI) was 1.9 +/- 0.3. Six patients (16%) expired during the follow-up period of hospitalization. Based on the analysis of characteristics and clinical factors, the only predictable variable in prognosis was APACHE II score. The patients with APACHE II score greater than 20 had tendency to expire than the others (P = 0.001). Based on present study, APACHE II score more than 20, rather than cardiac function, is associated with mortality in patients with SIC. PMID- 22219615 TI - Low cholesterol is associated with mortality from cardiovascular diseases: a dynamic cohort study in Korean adults. AB - This study was conducted to evaluate the association of single serum total cholesterol (TC) measurement with cardiovascular diseases (CVD) deaths in Korean adults. The study subjects were taken from the multi-site collaborative dynamic prospective cohort for epidemiologic investigation on cancer risk in residents nearby nuclear power plants in Korea. A total of 12,740 adults aged 40 to 69 yr who underwent a mass screening examination were followed up from 1993 to 2008. Occurring CVD deaths were confirmed by the death certificates in the National Statistical Office, Korea. Groups with the lowest group having TC < 160 mg/dL as well as the highest group having >= 240 mg/dL were associated with higher CVD mortality in Cox proportional hazards analysis adjusting for age, sex, smoking and drinking status, body mass index, level of blood pressure, triglyceride and high density lipoprotein cholesterol. The distribution of adjusted hazard ratios showed the U-shaped curve. Based on the results of this study, caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk in Korean adults. PMID- 22219616 TI - Lower residual renal function is a risk factor for depression and impaired health related quality of life in Korean peritoneal dialysis patients. AB - We retrospectively evaluated demographic and biochemical parameters associated with depression and health-related quality of life (HRQOL) in maintenance peritoneal dialysis (PD) patients. This study included 105 patients maintaining PD at Seoul National University Hospital. Data were collected from electronic medical record. Korean Beck's Depression Inventory and Korean version of Kidney Disease Quality of Life short form, version 1.3 were used to evaluate depression and HRQOL, respectively. Moderate to severe depression was found in 24.8% of patients. Patients with lower normalized protein equivalent of nitrogen appearance (nPNA) (< 1.2 g/kg/day), lower weekly renal Kt/V(urea) (< 0.2), and lower serum albumin level (<= 4.0 g/dL) were associated with depression (P < 0.05). Among them, lower weekly renal Kt/V(urea) was the only independent risk factor associated with depression (OR = 3.1, P = 0.007). Depressed patients showed significantly lower scores in every dimension of HRQOL (P < 0.001). Lower weekly renal Kt/V(urea) (beta = 0.24, P = 0.005) and lower nPNA (beta = 0.15, P = 0.03) were the independent risk factors associated with lower kidney dialysis component summary, whereas lower plasma hemoglobin level was the consistent risk factor for lower physical component summary (beta = 0.22, P = 0.03) and mental component summary (beta = 0.22, P = 0.01). Depression is a prevalent psychological problem in PD population. Residual renal function is the most important factor associated with depression and impaired HRQOL in PD patients. PMID- 22219617 TI - Association between toll-like receptors/CD14 gene polymorphisms and inflammatory bowel disease in Korean population. AB - The innate immune response in patients who develop inflammatory bowel disease (IBD) may be abnormal. However, the exact role of Toll-like receptors (TLRs) / CD14 gene in the pathogenesis of IBD has not been fully elucidated. We aimed to investigate the association between polymorphisms of TLR1, 2, 4, 6, and CD14 gene and susceptibility to IBD in Korean population. A total 144 patients of IBD (99 patients with ulcerative colitis, 45 patients with Crohn's disease) and 178 healthy controls were enrolled. Using a PCR-RFLP, we evaluated mutations of TLR1 (Arg80Thr), TLR2 (Arg753Gln and Arg677Trp), TLR4 (Asp299Gly and Thr399Ile), TLR6 (Ser249Pro) genes and the -159 C/T promoter polymorphism of CD14 gene. No TLR polymorphisms were detected in Korean subjects. T allele and TT genotype frequencies of CD14 gene were significantly higher in IBD patients than in healthy controls. In subgroup analysis, T allelic frequency was higher in pancolitis phenotype of ulcerative colitis. In Korean population, the promoter polymorphism at -159 C/T of the CD14 gene is positively associated with IBD, both ulcerative colitis and Crohn's disease. PMID- 22219618 TI - Assessment of serologic immunity to diphtheria-tetanus-pertussis after treatment of Korean pediatric hematology and oncology patients. AB - The aim of this study was to investigate the diphtheria-tetanus-pertussis antibody titers after antineoplastic treatment and to suggest an appropriate vaccination approach for pediatric hemato-oncologic patients. A total of 146 children with either malignancy in remission after cessation of therapy or bone marrow failure were recruited. All children had received routine immunization including diphtheria-tetanus-acellular pertussis vaccination before diagnosis of cancer. The serologic immunity to diphtheria, tetanus and pertussis was classified as: completely protective, partially protective, or non-protective. Non-protective serum antibody titer for diphtheria, tetanus and pertussis was detected in 6.2%, 11.6%, and 62.3% of patients, respectively, and partial protective serum antibody titer for diphtheria, tetanus and pertussis was seen in 37%, 28.1%, and 8.9% of patients. There was no significant correlation between the severity of immune defect and age, gender or underlying disease. Revaccination after antineoplastic therapy showed significantly higher levels of antibody for each vaccine antigen. Our data indicates that a large proportion of children lacked protective serum concentrations of antibodies against diphtheria, tetanus, and pertussis. This suggests that reimmunization of these patients is necessary after completion of antineoplastic treatment. Also, prospective studies should be undertaken with the aim of devising a common strategy of revaccination. PMID- 22219619 TI - Ischemic stroke in rats enhances bone resorption in vitro. AB - We hypothesized that the formation and differentialtion of osteoclasts are accelerated and the potential of bone resorption is increased in the hemiplegic bone marrow in the early stage of stroke. We randomly divided white female Sprague-Dawley (SD) rats (n = 30) into two groups, stroke (n = 15) and sham group (n = 15). On the 7th day after stroke, after cutting away the epiphyses of the femurs and tibias, diaphyseal channels were flushed using alpha-minimum essential medium (alpha-MEM) and bone marrow cells were collected. Bone marrow stem cells, which were extracted from the femur and tibia, were cultured on the 7th day after middle cerebral artery occlusion. We then estimated the ratio of non-adherent cells to total bone marrow cells that included osteoclast precursor cells. After culturing these cells separately, cells that tested positive on the tartrate resistant acid phosphatase (TRAP) were counted and bone resorption was evaluated by using the OAASTM plate. In comparison to the control group, the stroke group showed a higher increase of non-adherent cells in the hemiplegic side bone marrow. In addition, after the primary culture, the stroke group showed an increased number of TRAP positive cells and a higher degree of bone resorption estimated by OAASTM plate. As a result, osteoclastogenesis and osteoclast differentiation are accelerated and the potential of bone resorption is increased in the hemiplegic bone marrow and these changes are detected as early as within the first week after middle cerebral artery occlusion in SD rats. PMID- 22219620 TI - Collision of three histologically distinct endometrial cancers of the uterus. AB - A collision tumor is defined by the presence of two separate masses in one organ, which are pathologically distinct. We described a 70-yr-old patient who complained of abnormal vaginal bleeding with a collision tumor of the uterine corpus. The patient received total hysterectomy, bilateral salphingo oophorectomy, bilateral pelvic-paraaortic lymphadenectomy, omentectomy, and intraperitoneal chemotherapy. The uterine corpus revealed three separate masses, which were located at the fundus, anterior and posterior wall. Each tumor revealed three pathologically different components, which were malignant mixed mullerian tumor, papillary serous carcinoma, and endometrioid adenocarcinoma. Among these components, only the papillary serous carcinoma component invaded the underlying myometrium and metastasized to the regional lymph node. Adjuvant chemotherapy and radiation therapy were performed. The patient is still alive and has been healthy for the last 8 yr. We have reviewed previously reported cases of collision tumors which have occurred in the uterine corpus. PMID- 22219621 TI - Silicosis caused by chronic inhalation of snail shell powder. AB - A 70-yr-old woman visited our hospital for shortness of breath. Chest CT showed ground glass opacity and traction bronchiectasis at right middle, lower lobe and left lingular division. Video-assisted thoracic surgical biopsy at right lower lobe and pathologic examination revealed mixed dust pneumoconiosis. Polarized optical microscopy showed lung lesions were consisted of silica and carbon materials. She was a housewife and never been exposed to silica dusts occupationally. She has taken freshwater snails as a health-promoting food for 40 yr and ground shell powder was piled up on her backyard where she spent day-time. Energy dispersive X-ray spectroscopy of snail shell and scanning electron microscopy with energy dispersive x-ray spectroscopy of lung lesion revealed that silica occupies important portion. Herein, we report the first known case of silicosis due to chronic inhalation of shell powder of freshwater snail. PMID- 22219622 TI - Early-onset childhood sarcoidosis with incidental multiple enchondromatosis. AB - The triad of rash, arthritis, and uveitis seems to be characteristic for early onset childhood sarcoidosis. We describe an interesting case of early-onset childhood sarcoidosis coexisting enchondromatosis, which clinically masquerade as Langerhans cell histiocytosis. A 33 months old girl presented with skin rash, subcutaneous nodules with polyarthritis, and revealed the involvement of lymph nodes as well as spleen during work-up. She also presented with multiple osteolytic lesions which pathologically proven enchondromatosis. Oral prednisone was prescribed at 2 mg/kg/day for 2 months until when subcutaneous nodules and joint swellings almost disappeared, and then slowly tapered over a period of 5 months. We report an unusual case of early-onset childhood sarcoidosis presented with osteolytic bone lesions which were irrelevant to sarcoidosis. PMID- 22219623 TI - Severe jaundice in two children with Kawasaki disease: a possible association with Gilbert syndrome. AB - Kawasaki disease is a systemic vasculitis, mainly encountered in children. It may affect any organ. Acute cholestasis and severe obstructive jaundice is an atypical manifestation of the disease. We herein present two children with Kawasaki disease and severe direct hypebilibirunemia who also were homozygous and heterozygous respectively for the (TA)(7) promoter polymorphism of Gilbert syndrome. Intravenous immunoglobulin was administered to both patients at the acute phase of the disease and the fever remitted within 24 hr following the immunoglobulin administration. Furthermore oral aspirin at a dose of 80-100 mg/kg/24 hr was also given. The first child did not develop any coronary ectasia or aneurysm, whereas dilation of the right coronary artery was identified in the second child, one month after the disease onset. We discuss the possible contribution of Gilbert syndrome to the development of jaundice in our patients. PMID- 22219624 TI - Migraine-like headache in a patient with complement 1 inhibitor deficient hereditary angioedema. AB - We report on an angioedema patient with a genetic defect in complement 1 inhibitor, manifesting migraine-like episodes of headache, effective prophylaxis with Danazol, and triptan for a treatment of acute clinical episode. The patient was 44-yr-old Korean man with abdominal pain and headache, who was brought into the Emergency Department of Seoul National University Hospital, Seoul. He suffered from frequent attacks of migraine-like headache (3-7 per month), pulsating in nature associated with nausea. Severities were aggravated by activity and his headache had shown recent progression with abdominal pain. No remarkable findings were observed on radiologic examination, brain magnetic resonance images and intracranial and extracranial magnetic resonance angiography. Danazol 200 mg every other day was subsequently used. Following administration of Danazol, symptoms showed improvement and the patient was discharged. While taking Danazol, the migraine-like episodes appeared to be prevented for about 2 yr. At the eighth month, he suffered a moderate degree of migraine-like headache; however, administration of naratriptan 2.5 mg resolved his problem. A case of genetic defect of C1-INH deficiency presented with headache episodes, and was controlled by Danazol and triptan. It suggests that pathogenic mechanism of headache in hereditary angioedema may be mediated by the neurogenic inflammatory-like physiology of migraine. PMID- 22219625 TI - Correlation of DEFA1 gene copy number variation with intestinal involvement in Behcet's disease. AB - Copy number variation has been associated with various autoimmune diseases. We investigated the copy number (CN) of the DEFA1 gene encoding alpha-defensin-1 in samples from Korean individuals with Behcet's disease (BD) compared to healthy controls (HC). We recruited 55 BD patients and 35 HC. A duplex Taqman(r) real time PCR assay was used to assess CN. Most samples (31.1%) had a CN of 5 with a mean CN of 5.4 +/- 0.2. There was no significant difference in the CN of the DEFA1 gene between BD patients and HC. A high DEFA1 gene CN was significantly associated with intestinal involvement in BD patients. Variable DEFA1 gene CNs were observed in both BD patients and HC and a high DEFA1 gene CN may be associated with susceptibility to intestinal involvement in BD. PMID- 22219626 TI - Understanding the alpha-crystallin cell membrane conjunction. AB - PURPOSE: It is well established that levels of soluble alpha-crystallin in the lens cytoplasm fall steadily with age, accompanied by a corresponding increase in the amount of membrane-bound alpha-crystallin. Less well understood, is the mechanism driving this age-dependent membrane association. The aim of this study was to investigate the role of the membrane and its associated proteins and peptides in the binding of alpha-crystallin. METHODS: Fiber cell membranes from human and bovine lenses were separated from soluble proteins by centrifugation. Membranes were stripped of associated proteins with successive aqueous, urea, and alkaline solutions. Protein constituents of the respective membrane isolates were examined by SDS-PAGE and western immunoblotting. Recombinant alphaA- and alphaB crystallins were fluorescently-labeled with Alexa350(r) dye and incubated with the membrane isolates and the binding capacity of membrane for alpha-crystallin was determined. RESULTS: The binding capacity of human membranes was consistently higher than that of bovine membranes. Urea- and alkali-treated membranes from the nucleus had similar binding capacities for alphaA-crystallin, which were significantly higher than both cortical membrane extracts. alphaB-Crystallin also had a higher affinity for nuclear membrane. However, urea-treated nuclear membrane had three times the binding capacity for alphaB-crystallin as compared to the alkali-treated nuclear membrane. Modulation of the membrane-crystallin interaction was achieved by the inclusion of an NH2-terminal peptide of alphaB crystallin in the assays, which significantly increased the binding. Remarkably, following extraction with alkali, full length alphaA- and alphaB-crystallins were found to remain associated with both bovine and human lens membranes. CONCLUSIONS: Fiber cell membrane isolated from the lens has an inherent capacity to bind alpha-crystallin. For alphaB-crystallin, this binding was found to be proportional to the level of extrinsic membrane proteins in cells isolated from the lens nucleus, indicating these proteins may play a role in the recruitment of alphaB-crystallin. No such relationship was evident for alphaA-crystallin in the nucleus, or for cortical membrane binding. Intrinsic lens peptides, which increase in abundance with age, may also function to modulate the interaction between soluble alpha-crystallin and the membrane. In addition, the tight association between alpha-crystallin and the lens membrane suggests that the protein may be an intrinsic component of the membrane structure. PMID- 22219627 TI - Lack of phenotypic effect of triallelic variation in SPATA7 in a family with Leber congenital amaurosis resulting from CRB1 mutations. AB - PURPOSE: To identify the causative gene for autosomal recessive Leber congenital amaurosis (LCA) in a Chinese family. METHODS: One Chinese LCA family was identified and an ophthalmologic examination was performed. The genetic defects were analyzed simultaneously by a genome-wide linkage scan with 382 polymorphic microsatellite markers, as well as by comprehensive mutational screening of 15 genes known to associate with LCA on the genomic DNA of this family. RESULTS: Suggestive linkages were found in 13 chromosomal regions, of which only one harbored a known causative gene, crumbs homolog 1 (CRB1), on chromosome 1. Sanger sequencing of CRB1 identified two novel heterozygous mutations, c.3221T>C (p.L1074S) and c.2677-2A>C. In addition, a novel missense heterozygous mutation, c.938C>A (p.A313D), in spermatogenesis associated 7 (SPATA7), was detected in the proband after screening of the other 14 LCA causative genes. All three affected individuals of the family had compound heterozygous CRB1 mutations, and one of the three (the proband) had an additional mutation in SPATA7. The unaffected mother had the heterozygous c.3221T>C mutation in CRB1 and the heterozygous c.938C>A mutation in SPATA7. The unaffected father could not be tested, but presumably had the heterozygous c.2677-2A>C mutation in CRB1. The proband, with triallelic mutations in CRB1 and SPATA7, had a phenotype similar to other two affected brothers, suggesting the additional mutant allele in SPATA7 might not contribute to the disease. Similarly, the mother, with digenic mutations in CRB1 and SPATA7, had normal vision and fundi, suggesting the digenic mutations in these two genes might not cause disease. CONCLUSIONS: Digenic and triallelic mutations of CRB1 and SPATA7 were detected in a family with LCA. Our results imply that CRB1 and SPATA7 may not interact with each other directly. This emphasizes that care should be taken in invoking a mutation-disease association for digenic and triallelic mutations. PMID- 22219628 TI - Crystalline cataract caused by a heterozygous missense mutation in gammaD crystallin (CRYGD). AB - PURPOSE: To describe phenotypic characteristics of two pedigrees manifesting early onset crystalline cataract with mutations in the gammaD-crystallin gene (CRYGD). METHODS: A detailed medical history was obtained from two Caucasian pedigrees manifesting autosomal dominant congenital cataracts. Genomic DNA was extracted from saliva (DNA Genotek). Single Nucleotide Polymorphism (SNP) based genome analysis of the larger pedigree revealed linkage to an 8.2 MB region on chromosome 2q33-q35 which encompassed the crystallin-gamma gene cluster (CRYG). Exons and flanking introns of CRYGA, CRYGB, CRYGC and CRYGD were amplified and sequenced to identify disease-causing mutations. RESULTS: A morphologically unique cataract with extensive refractile "crystals" scattered throughout the nucleus and perinuclear cortex was found in the probands from both pedigrees. A heterozygous C->A mutation was identified at position 109 of the coding sequence (R36S of the processed protein) in exon 2 of CRYGD and this missense mutation was found to cosegregate with the disease in the larger family; this mutation was then identified in affected individuals of pedigree 2 as well. CONCLUSIONS: The heterozygous 109C->A CRYGD missense mutation is associated with a distinct crystalline cataract in two US Caucasian pedigrees. This confirms crystalline cataract formation with this mutation, as previously reported in sporadic childhood case from the Czech Republic and in members of a Chinese family. PMID- 22219629 TI - Evaluation of cytotoxicity of bevacizumab on VEGF-enriched corneal endothelial cells. AB - PURPOSE: To evaluate the cytotoxicity of varying doses of Bevacizumab on corneal endothelial cells in the presence of a range of concentrations of vascular endothelial growth factor (VEGF). Bevacizumab, a drug widely used in the treatment of neovascular glaucoma neutralizes all isoforms of VEGF and ameliorates neovascularization after intracameral administration. However, the safety of intracameral administration of Bevacizumab and dose-dependent toxicity on corneal endothelial cells has not been established. METHODS: Bovine corneal endothelial (BCE) cells were treated with VEGF (50 ng/ml) and/or Bevacizumab (0.1 2 mg/ml) for 72 h. Cell proliferation was measured with the water soluble tetrazolium salts (WST-1) assay. Morphological changes were recorded by bright field microscopy of cells. Cytotoxicity in response to Bevacizumab was evaluated by trypan blue exclusion, as well as annexin V/propidium iodide (PI) staining. RESULTS: Bevacizumab was not cytotoxic at the concentrations tested and the percentage of Bevacizumab-treated cells staining positively for both PI and Annexin V was less than 1%. The anti-proliferative effects of Bevacizumab on BCE cells were dose-dependent; a dose of 1.5 mg/ml or 2 mg/ml produced a 33% (p=0.005) or 47% (p=0.001) decrease in cell proliferation compared to controls. Similar results were obtained in cells treated with a combination of Bevacizumab and VEGF. VEGF (50 ng/ml) had no significant effect on cell proliferation compared to controls. Morphology of cells was unchanged after treatment with Bevacizumab and/or VEGF compared to controls. CONCLUSIONS: Bevacizumab was safe and not toxic to BCE cells at concentrations commonly used in clinical practice. PMID- 22219630 TI - Retinal and anterior eye compartments derive from a common progenitor pool in the avian optic cup. AB - PURPOSE: The optic cup is created through invagination of the optic vesicle. The morphogenetic rearrangement creates a double-layered cup, with a hinge (the Optic Cup Lip) where the epithelium bends back upon itself. Shortly after the optic cup forms, it is thought to be sub-divided into separate lineages: i) pigmented epithelium in the outer layer; ii) presumptive iris and ciliary body at the most anterior aspect of the inner layer; and iii) presumptive neural retina in the remainder of the inner layer. We test the native developmental potential of the anterior cup to determine if it normally contributes to the retina. METHODS: Vital dye and green fluorescent protein (GFP) expressing replication-incompetent retroviral vectors were used to label cells in the nascent optic cup and follow their direct progeny throughout development. Label was applied to either the optic cup lip (n=40), or to the domain just posterior to the lip (n=20). Retroviral labeling is a permanent lineage marker and enabled the analysis of advanced stages of development. RESULTS: Labeling within the optic cup gave rise to labeled progeny in the posterior optic cup that differentiated as neural retina (20 of 20). In contrast, labeling cells in the optic cup lip gave rise to progeny of labeled cells arrayed in a linear progression, from the lip into the neural retina (36 of 40). Label was retained in cells at the optic cup lip, regardless of age at examination. In older embryos, labeled progeny delaminated from the optic cup lip to differentiate as muscle of the pupillary margin. CONCLUSIONS: The data show that the cells at the optic cup lip are a common progenitor population for pigmented epithelium, anterior eye tissues (ciliary body, iris, and pupillary muscle) and retinal neurons. The findings are supportive of an interpretation where the optic cup lip is a specialized niche containing a multipotent progenitor population. PMID- 22219631 TI - Genoprotective effect of hyaluronic acid against benzalkonium chloride-induced DNA damage in human corneal epithelial cells. AB - PURPOSE: The aim of this study was to investigate hyaluronic acid (HA) protection on cultured human corneal epithelial cells (HCEs) against benzalkonium chloride (BAC)-induced DNA damage and intracellular reactive oxygen species (ROS) increase. METHODS: Cells were incubated with different concentrations of BAC with or without the presence of 0.2% HA for 30 min. DNA damage to HCEs was examined by alkaline comet assay and by immunofluorescence microscopic detection of the phosphorylated form of histone variant H2AX (gammaH2AX) foci. ROS production was assessed by the fluorescent probe, 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA). Cell apoptosis was determined with annexin V staining by flow cytometry. RESULTS: HA significantly reduced BAC-induced DNA damage as indicated by the tail length (TL) and tail moment (TM) of alkaline comet assay and by gammaH2AX foci formation, respectively. Moreover, HA significantly decreased BAC induced ROS increase and cell apoptosis. However, exposure to HA alone did not produce any significant change in DNA damage, ROS generation, or cell apoptosis. CONCLUSIONS: BAC could induce DNA damage and cell apoptosis in HCEs, probably through increasing oxidative stress. Furthermore, HA was an effective protective agent that had antioxidant properties and could decrease DNA damage and cell apoptosis induced by BAC. PMID- 22219632 TI - Cysteamine suppresses human peripheral blood mononuclear cells--human corneal endothelial cell reaction via reactive oxygen species reduction. AB - PURPOSE: To investigate the effect of cysteamine (CYS) on mixed peripheral blood mononuclear cells (PBMCs)--human corneal endothelial cell (HCEC) reaction (MLER). METHODS: PBMC stimulation assay was performed using cultured HCEC. MLERs were treated with various concentrations of CYS (0-20 mM). The proliferation rate and secretion profiles of transforming growth factor-beta1 (TGF-beta1) and interleukin-6 (IL-6) of PBMCs stimulated by cultured HCEC were determined using bromodeoxyuridine proliferation assay and enzyme-linked immunosorbent assay, respectively. RESULTS: CYS suppressed PBMC proliferation in a dose-dependent manner (p<0.001). The intracellular reactive oxygen species (ROS) levels decreased with an increase in CYS concentration (p<0.001). The levels of TGF beta1 and IL-6 decreased in a dose-dependent manner as well (p=0.011 and 0.003, respectively). CONCLUSIONS: This study showed that CYS decreased PBMC proliferation, IL-6 and TGF-beta1 levels via ROS formation. Our results suggest that CYS could suppress inflammation associated with PBMCs to corneal endothelial cells. PMID- 22219633 TI - An association study of the COL1A1 gene and high myopia in a Han Chinese population. AB - PURPOSE: Single nucleotide polymorphisms (SNPs) in the collagen type I (COL1A1) gene have been shown to be significantly associated with high myopia in a Japanese population. This present study was conducted to investigate whether COL1A1 is associated with high myopia in a Han Chinese population. METHODS: High myopia is defined by a spherical equivalent of less than or equal to -6.00 diopter sphere and an axial length longer than or equal to 26.0 mm in the affected eye. We genotyped rs2075555 and rs2269336 SNPs in COL1A1 in a Ha n Chinese group composed of 697 high myopia patients and 762 normal controls. RESULTS: Neither of the two SNPs showed significant association with high myopia (p(allelic)=0.252 for rs2075555, and p(allelic)=0.699 for rs2269336). CONCLUSIONS: Our study revealed that SNPs in COL1A1 are not significantly associated with high myopia in the Han Chinese population. PMID- 22219634 TI - High glucose may decrease the innate immune through TLRs in cornea epithelium. AB - PURPOSE: The purpose of this study was to investigate the high potential of glucose in inhibiting the innate immune in cultured human cornea epithelial cells (HCEC) and try to determine whether the role of high glucose on the HCEC relate to toll-like receptor (TLR)2 and TLR4. METHODS: Cells were cultured for 3 days in 5 mmol/l (normal glucose). Then high glucose (25 mmol/l) was added along with normal glucose with daily changes in media for 24 h. The cells were also treated with mannitol as an osmotic control. The cellular abundance of the mRNAs for TLR2 and TLR4 was determined by real-time polymerase chain reaction analysis. The proteins of TLR2 and TLR4 were also compared by immunofluorescent staining and western blot. The release of interleukin 6 (IL-6) and IL-8 from cultured HCEC was measured using enzyme-linked immunosorbent assays (ELISA) in the presence and absence of specific blocking antibodies to TLR2 and TLR4. RESULTS: Incubation of HCEC with high glucose showed that the mRNA expression of TLR2 and TLR4 was markedly inhibited. Immunofluorescent staining and western blot analysis confirmed that the protein expression of TLR2 and TLR4 was downregulated in response to high glucose. The result of ELISA also showed that the release of IL 6 and IL-8 can be inhibited by high glucose, but these inhibitions were partly counteracted after pretreatment with anti-TLR2 and/or anti-TLR4 monoclonal antibody. The results also showed that the osmotic control did not affect the expression of TLR2, TLR4, and IL-6, 8. CONCLUSIONS: High glucose may decrease the innate immune through TLRs in cornea epithelium. PMID- 22219635 TI - Contact lens physical properties and lipid deposition in a novel characterized artificial tear solution. AB - PURPOSE: To characterize various properties of a physiologically-relevant artificial tear solution (ATS) containing a range of tear film components within a complex salt solution, and to measure contact lens parameters and lipid deposition of a variety of contact lens materials after incubation in this ATS. METHODS: A complex ATS was developed that contains a range of salts, proteins, lipids, mucin, and other tear film constituents in tear-film relevant concentrations. This ATS was tested to confirm that its pH, osmolality, surface tension, and homogeneity are similar to human tears and remain so throughout the material incubation process, for up to 4 weeks. To confirm that silicone hydrogel and conventional hydrogel contact lens materials do not alter in physical characteristics beyond what is allowed by the International Organization for Standardization (ISO) 18369-2. The diameter, center thickness, and calculated base curve were measured for five different lens materials directly out of the blister pack, after a rinse in saline and then following a two week incubation in the modified ATS. To test the ATS and the effect of its composition on lipid deposition, two lens materials were incubated in the ATS and a modified version for several time points. Both ATS solutions contained trace amounts of carbon-14 cholesterol and phosphatidylcholine, such that deposition of these specific lipids could be quantified using standard methods. RESULTS: This ATS is a complex mixture that remains stable at physiologically relevant pH (7.3-7.6), osmolality (304-306 mmol/kg), surface tension (40-46 dynes/cm) and homogeneity over an incubation period of three weeks or more. The physical parameters of the lenses tested showed no changes beyond that allowed by the ISO guidelines. Incubations with the ATS found that balafilcon A lenses deposit significantly more cholesterol and phosphatidylcholine than omafilcon A lenses (p<0.05) and that removing lactoferrin and immunoglobulin G from the ATS can significantly decrease the mass of lipid deposited. CONCLUSIONS: This paper describes a novel complex artificial tear solution specially designed for in-vial incubation of contact lens materials. This solution was stable and did not adversely affect the physical parameters of the soft contact lenses incubated within it and showed that lipid deposition was responsive to changes in ATS composition. PMID- 22219636 TI - Rapamycin prevents endothelial cell migration by inhibiting the endothelial-to mesenchymal transition and matrix metalloproteinase-2 and -9: an in vitro study. AB - PURPOSE: To evaluate the influence of rapamycin on endothelial-mesenchymal transition and matrix metalloproteinase (MMP) secretion by human umbilical vein endothelial cell line EA.hy926 and explore rapamycin's angiogenesis inhibition mechanism. METHODS: EA.hy926 cells were cultivated in vitro. After the cells attained complete confluency, an artificial scratch was made through the monolayer with a sterile plastic 100 MUl micropipette tip. Cell morphology changes were observed. The expression of vascular endothelial (VE)-cadherin, vimentin, and Twist protein were examined by immunofluorescence. After scratching, the cells were treated with 10, 100, and 1,000 ng/ml rapamycin for durations of 24, 48, and 72 h. Cell proliferation was then assessed using methyl thiazolyl tetrazolium assay. Cell migration ability was examined, and the expression of VE-cadherin, vimentin, and the Twist transcription factor in mRNA levels was evaluated with reverse transcriptase PCR. The expression of gelatinases (MMP-2 and MMP-9) was examined using gelatin zymography. RESULTS: After scratching, the endothelial cells were able to migrate via an endothelial to-mesenchymal transition, which was related to Twist expression. Finally, mesenchymal cells transitioned into endothelial cells and reached cell confluency again. The growth of EA.hy926 cells was not affected by rapamycin concentrations of 10 ng/ml or 100 ng/ml during treatment periods of 1, 2, and 3 days; however, cell growth was inhibited by 1,000 ng/ml rapamycin with a three-day treatment period. Rapamycin successfully inhibited cell migration at concentrations of 10 ng/ml, 100 ng/ml, and 1,000 ng/ml for a treatment period of up to 8 h. Different concentrations of rapamycin induced the expression of VE-cadherin, inhibited vimentin and Twist expression in the endothelial cells, and inhibited endothelial cell secretion of MMP-2 and MMP-9. CONCLUSIONS: Rapamycin inhibited cell migration and extracellular matrix degradation by inhibiting endothelial-to mesenchymal transition and the endothelial cell secretion of MMP-2 and MMP-9; these may be possible mechanisms for the inhibition of angiogenesis by rapamycin. PMID- 22219637 TI - Inhibition by female sex hormones of collagen degradation by corneal fibroblasts. AB - PURPOSE: Corneal fibroblasts contribute to collagen remodeling in the corneal stroma in part by mediating collagen degradation. Given that corneal structure is influenced by sex hormone status, we examined the effects of sex hormones on collagen degradation by corneal fibroblasts. METHODS: Rabbit corneal fibroblasts were cultured in three-dimensional collagen gels with or without sex hormones including 17beta-estradiol, progesterone, testosterone, and dehydroepiandrosterone (DHEA). Collagen degradation was determined by measurement of hydroxyproline after acid hydrolysis. The expression and activity of matrix metalloproteinases (MMPs) were evaluated by immunoblot analysis and gelatin zymography. The phosphorylation of mitogen-activated protein kinases (MAPKs) and the nuclear factor-kappa B (NF-kappaB) inhibitor NF kappa B Inhibitor-alpha (IkappaB-alpha) in corneal fibroblasts was examined by immunoblot analysis. Cell proliferation and viability were evaluated by measurement of bromodeoxyuridine incorporation and the release of lactate dehydrogenase, respectively. RESULTS: 17beta-Estradiol and progesterone each inhibited interleukin (IL)-1beta-induced collagen degradation by corneal fibroblasts in a concentration-dependent manner, whereas testosterone and DHEA had no such effect. MMP expression and activation in corneal fibroblasts exposed to IL-1beta were also inhibited by 17beta estradiol and progesterone. These female sex hormones did not affect cell proliferation or viability. Both 17beta-estradiol and progesterone inhibited the IL-1beta-induced phosphorylation of p38 MAPK without affecting that of the MAPKs extracellular Signal-regulated Kinase (ERK) or c-jun N-terminal kinase (JNK). 17beta-Estradiol also inhibited the IL-1beta-induced phosphorylation of IkappaB alpha. CONCLUSIONS: 17beta-Estradiol and progesterone inhibited MMP expression and activity in IL-1beta-stimulated corneal fibroblasts and thereby suppressed collagen degradation by these cells. PMID- 22219638 TI - Proteomics analysis of water insoluble-urea soluble crystallins from normal and dexamethasone exposed lens. AB - PURPOSE: The aim of this study was to identify glucocorticoid induced cataracts (GIC)-specific modified water insoluble-urea soluble (WI-US) crystallins and related changes after rat lens were exposed to dexamethasone (Dex). METHODS: We separated WI-US lens proteins by two-dimensional electrophoresis (2-DE). The crystallins were then analyzed with matrix assisted laser desorption/ionization time-of-flight tandem mass spectrometry (MALDI-TOF-MS/MS). Protein levels and morphological changes of alphaA- and alphaB-crystallins were also determined. Electronic microscope of lens and native-page analysis of crystallins were further determined. RESULTS: Measured masses, isoelectric points (pIs), and amino acid sequences of all detected crystallins matched previously-reported data. Analysis by 2-DE indicated that alphaA- and alphaB-crystallin increased when the lens was viewed under 1 uM and 10 uM Dex, which was identical with the results of western-blot, immuno histochemistry or fluorescence; betaB2- and betaA3 crystallin increased when lens was viewed under 1 uM Dex and 100 uM Dex. betaA1-, betaA4-, and betaB1-crystallins decreased under 0.1-100 uM Dex. Electronic microscope figures showed the condition of the lens center gradually worsened and cracked between fiber cells that became larger under 1-100 uM Dex. Moreover, alphaA-crystallins were associated with increased phosphorylation (PI decreased).The newly protein spots: betaA2-, betaA3-, betaB1-, and gammas crystallin appeared under 0.1-100 uM Dex. Native-page showed alpha-crystallin increased when the lens was exposed to 1 uM Dex; however, beta-crystallin did not decrease under 0.1-100 uM Dex. The percentage of alpha-crystallin gradually decreased, however beta-crystallin gradually increased, perhaps because the emergence of newly appeared beta-crystallin under Dex. CONCLUSIONS: Our results showed multiple WI-US crystallins may be more vulnerable to glucocorticoid stress because of diminished important roles, which will in turn provide a mechanism for GIC from a proteomics perspective. PMID- 22219639 TI - Cornea lenticule viability and structural integrity after refractive lenticule extraction (ReLEx) and cryopreservation. AB - PURPOSE: To assess and compare keratocyte viability and collagen structure in cornea stroma lenticules collected immediately after refractive lenticule extraction (ReLEx) and one month after cryopreservation. METHODS: The fresh and cryopreserved human stroma lenticules procured after ReLEx were processed for ultrastructural analysis of keratocytes and collagen fibrils with transmission electron microscopy (TEM), apoptotic cell detection with deoxynucleotidyl transferase-mediated nick end labeling assay (TUNEL) assay, and cultured for keratocyte-specific gene expression analysis using reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: The periphery of the lenticule had greater TUNEL-positive cells compared to the center of the lenticule in both fresh and cryopreserved groups. There was an increase in TUNEL-positive cells after cryopreservation, which was significantly higher in the center of the lenticule, but not in the periphery. TEM showed apoptotic, necrotic and viable quiescent keratocytes in fresh and cryopreserved lenticules. Collagen analysis with TEM showed a well preserved and well aligned structure in fresh and cryopreserved lenticules; without significant change in the total number of collagen fibrils but with an increased collagen fibril density (CFD) after cryopreservation. In vitro, isolated keratocytes derived from fresh and cryopreserved lenticules exhibited a typical fibroblastic phenotype. RT-PCR showed a positive gene expression for keratocan (KERA) and aldehyde dehydrogenase 3A1 (ALDH3A1) in cells isolated from fresh and cryopreserved lenticules. CONCLUSIONS: The stromal lenticules extracted from ReLEx surgery remain viable after cryopreservation. Although they showed a decrease in CFD, the collagen architecture was preserved and there was good cellular viability. PMID- 22219640 TI - Cytotoxic effect of HIV-1 gp120 on primary cultured human retinal capillary endothelial cells. AB - PURPOSE: This research was conducted to make a primary culture of human retinal capillary endothelial cells (HRCEC) and to study the cytotoxic effect of human immunodeficiency virus-1 (envelope) glycoprotein 120 (HIV-1 gp120) on cultured HRCEC. METHODS: HRCEC were isolated and primarily cultured as dissociated single cell cultures. Immunohistochemistry and immunofluorescence were used to identify specific markers of HRCEC and to reveal HIV-1 gp120 related receptors (cluster of differentiation 4 [CD4], C-X-C chemokine receptor type 4 [CXCR4], and C-C chemokine receptor type 5 [CCR5]). The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay was used to demonstrate the effect of HIV-1 gp120 on cell viability at seven different concentrations (0.01-0.15 mg/l) for 24 h or at a fixed concentration of 0.08 mg/l for varying time intervals (4-72 h). After 0.08, 0.1, 0.12, and 0.15 mg/l HIV-1 gp120 were applied to HRCEC for 24 h, cell apoptotic rates and the mitochondrial membrane potential were measured with flow cytometry; pro-caspase-9 and cleaved caspase-9 were evaluated with immunoblotting. Under each research condition, 0.15 mg/l of HIV-1 gp120 mutated proteins (423 I/P) were used as controls. RESULTS: Primary cultures of pure HRCEC were established, and the cells were characterized with their specific markers. HIV-1 gp120 receptors CXCR4 and CCR5 were found on the cell surface of HRCEC; however, CD4 was negative. Treatment of HRCEC with HIV-1 gp120 at concentrations <0.08 mg/l did not influence cell viability. However, a concentration- and time dependent increase of HIV-1 gp120-induced cell inhibition was demonstrated with MTT, when the concentration of HIV-1 gp120 was more than 0.08 mg/l (r=-0.763, p<0.01). With increasing concentrations of HIV-1 gp120, the numbers of apoptotic cells and expression of cleaved caspase-9 protein increased, but Rho123 staining mitochondrial membrane potential decreased. CONCLUSIONS: HIV-1 gp120 assistant receptors CXCR4 and CCR5 are expressed on the cell surface of HRCEC, and HIV-1 gp120 can inhibit cell viability and induce apoptosis of HRCEC. The mitochondrial pathway is probably involved in HIV-1 gp120-induced apoptosis of HRCEC, but the specific mechanisms remain to be uncovered. PMID- 22219641 TI - Effect of contact lens material on cytotoxicity potential of multipurpose solutions using human corneal epithelial cells. AB - PURPOSE: Multipurpose solutions (MPS) are used daily to clean and disinfect silicone hydrogel (SiHy) contact lenses. This in vitro study was undertaken to identify the potential for interaction between MPS, SiHy surface treatments, and lens materials, which may lead to changes in the response of human corneal epithelial cells (HCEC) to MPS-soaked lenses. METHODS: The MPS tested were renu fresh (formerly known as ReNu MultiPlus; ReNu), OptiFree Express (OFX), OptiFree RepleniSH, SoloCare Aqua, and Complete Moisture Plus. The SiHy materials evaluated were lotrafilcon A, lotrafilcon B, comfilcon A, galyfilcon A, and balafilcon A (BA). MPS-soaked lenses were placed on top of adherent HCEC. The effect of MPS dilutions (0.1 to 10% final concentration in medium) was also characterized. Cell viability, adhesion phenotype and caspase activation were studied after 24-h cell exposure. OFX released from lenses was determined using UV absorbance. RESULTS: A significant reduction in viability (between 30 to 50%) was observed with cells exposed to lenses soaked in ReNu and OFX. A significant downregulation of alpha(3) and beta(1) integrins, with integrin expression ranging from 60% to 75% of control (cells with no lens), was also observed with OFX and ReNu-soaked lenses. With the exception of BA, all other lenses soaked in OFX resulted in significant caspase activation, whereby over 18% of cells stained positive for caspases. Minimal caspase activation was observed in cells exposed to ReNu and Solo soaked lenses. For both OFX and ReNu, exposing cells to at least a 5% dilution had a significant effect on viability and integrin expression. While Complete and Solo did not lead to reduction in viability, cells exposed to a 10% dilution showed reduced integrin expression down to less than 70% of control value. Comparing cell response to diluted MPS solutions and various MPS soaked lenses showed that it is not possible to reliably use cell response to MPS dilution alone to assess MPS biocompatibility. CONCLUSIONS: Our results demonstrate that the reaction of HCEC to MPS are affected by the type of lenses the MPS is released from and may potentially be influenced by the surface treatment (or lack of it) of SiHy materials. PMID- 22219643 TI - Identification of a novel FBN1 mutation in a Chinese family with isolated ectopia lentis. AB - PURPOSE: To identify the genetic defect in a Chinese family with autosomal dominant inherited ectopia lentis. METHODS: twenty-one family members, including seven patients underwent general physical and fully ophthalmic examinations. Genomic DNA was extracted from leukocytes of venous blood of these individuals in the family. Polymerase chain reaction (PCR) amplification and direct sequencing of all 65 coding exons of the fibrillin-1 gene (FBN1) were analyzed. RESULTS: Mutation screening in FBN1 identified a T>C transition at nucleotide position c,1759 leading to substitution of Cysteine for Arginine at codon 587 (C587R). This nucleotide substitution was not seen in any unaffected member of the family. CONCLUSIONS: We detected a novel mutation in FBN1. Our result expands the mutation spectrum of FBN1 and help in the study of the molecular pathogenesis of Marfan syndrome and Marfan-related diseases. PMID- 22219642 TI - Cyclooxygenase-2-expressing macrophages in human pterygium co-express vascular endothelial growth factor. AB - PURPOSE: To evaluate cyclooxygenase-2 (COX-2) expression and to characterize COX 2-expressing stromal cells in human pterygium. METHODS: Primary pterygium tissue of Korean patients (eight males and nine females) was analyzed. The clinical characteristics were classified, and immunohistochemical staining using primary antibodies against cyclooxygenease-2, vascular endothelial growth factor-A, cluster of differentiation (CD)68, CD3, CD20, and leukocyte common antigen was performed. RESULTS: COX-2 expression was detected in all pterygium tissues evaluated (17 primary pterygia). Diffuse expression of COX-2 in the epithelial layer was observed in nine samples. Infiltration of strongly positive COX-2 cells into the epithelial layer was a more common observation than diffuse epithelial COX-2 expression. Scattered COX-2-expressing cells in the stromal layer were found in all samples. Some COX-2-positive cells were found within microvessels. In addition to stromal COX-2-expressing cells, a few vascular endothelial cells strongly expressed COX-2; however most of the vessels were negative for COX-2 expression. Stromal COX-2-expressing cells were positive for the macrophage marker CD68 and co-expressed vascular endothelial growth factor. COX-2 expression in normal conjunctiva was not observed in seven control samples. CONCLUSIONS: These COX-2- and vascular endothelial growth factor-expressing macrophages may have relevance to the pathogenesis of pterygium. PMID- 22219644 TI - Upregulation of DR3 expression in CD4+ T cells promotes secretion of IL-17 in experimental autoimmune uveitis. AB - PURPOSE: This study investigated the role of death receptor 3 (DR3) in experimental autoimmune uveitis (EAU). METHODS: EAU was induced in B10.RIII mice by subcutaneous injection of interphotoreceptor retinoid-binding protein (IRBP) 161-180 emulsified with complete Freund's adjuvant and evaluated with clinical and histopathologic observation. Total protein of draining lymph nodes (DLNs) was extracted from the control, EAU, or recovery phase mice. CD4+ T cells were separated from lymphocytes with magnetic-assisted cell sorting. At the same time, some of the CD4+ T cells were cultured with or without recombinant TL1A (rTL1A, the DR3 ligand) for three days, and the supernatants were collected for the interleukin-17 (IL-17) test. DR3 mRNA and protein levels in CD4+ T cells and the endogenous concentration of TL1A in mice DLNs were assessed with real-time PCR or western blotting. Levels of IL-17 in the supernatants were determined with enzyme linked immunosorbent assay. RESULTS: Histopathological and clinical data revealed severe intraocular inflammation in the immunized mice. The inflammation reached its peak on day 14 in EAU and had resolved in the recovery phase (weeks 4-5 or more after IRBP immunization). CD4+ T cells obtained from EAU (day 7 or 14) had higher levels of DR3 mRNA and protein expression compared with the control group treated with complete Freund's adjuvant alone and the recovery group. However, the DR3 mRNA and protein levels on day 21 in EAU were similar to those observed in the control and recovery groups. The endogenous levels of TL1A were upregulated in EAU, and decreased in the recovery phase mice. Adding rTL1A increased the production of IL-17 by CD4+ T cells isolated from mice DLNs. Moreover, the increased IL-17 levels in the culture supernatant of CD4+ T cells from EAU were much higher than those from the control and recovery phase mice. However, the effects on promoting IL-17 production in TL1A-stimulated CD4+ T cells were similar between the controland recovery groups. CONCLUSIONS: Our data suggest that DR3 expression is induced during EAU and may be involved in the development of this disease, possibly by promoting IL-17 secretion. PMID- 22219646 TI - Protective effect of paeoniflorin against oxidative stress in human retinal pigment epithelium in vitro. AB - PURPOSE: This study was conducted to determine whether paeoniflorin (PF) could prevent H2O2-induced oxidative stress in ARPE-19 cells and to elucidate the molecular pathways involved in this protection. METHODS: Cultured ARPE-19 cells were subjected to oxidative stress with H2O2 in the presence and absence of PF. The preventive effective of PF on reactive oxygen species (ROS) production and retinal pigment epithelium (RPE) cell death induced by H2O2 was determined by 2',7'- dichlorodihydrofluorescein diacetate (H2DCFDA) fluorescence and 3-(4, 5 dimethylthiazol-2-yl)-2, 5 diphenyl tetrazolium bromide (MTT) assay. The ability of PF to protect RPE cells against ROS-mediated apoptosis was assessed by caspase 3 activity and 4', 6-diamidino-2-phenylindole (DAPI) staining. Furthermore, the protective effect of PF via the mitogen-activated protein kinase (MAPK) pathway was determined by western blot analysis. RESULTS: PF protected ARPE-19 cells from H2O2-induced cell death with low toxicity. H2O2-induced oxidative stress increased ROS production and caspase-3 activity, which was significantly inhibited by PF in a dose-dependent manner. Pretreatment with PF attenuated H2O2 induced p38MAPK and extracellular signal regulated kinase (ERK) phosphorylation in human RPE cells, which contributed to cell viability in ARPE-19 cells. CONCLUSIONS: This is the first report to show that PF can protect ARPE-19 cells from the cellular apoptosis induced by oxidative stress. The results of this study open new avenues for the use of PF in treatment of ocular diseases, such as age-related macular degeneration (AMD), where oxidative stress plays a major role in disease pathogenesis. PMID- 22219645 TI - Optimization of immunolocalization of cell cycle proteins in human corneal endothelial cells. AB - PURPOSE: En face observation of corneal endothelial cells (ECs) using flat mounted whole corneas is theoretically much more informative than observation of cross-sections that show only a few cells. Nevertheless, it is not widespread for immunolocalization (IL) of proteins, probably because the endothelium, a superficial monolayer, behaves neither like a tissue in immunohistochemistry (IHC) nor like a cell culture in immunocytochemistry (ICC). In our study we optimized IL for ECs of flat-mounted human corneas to study the expression of cell cycle-related proteins. METHODS: We systematically screened 15 fixation and five antigen retrieval (AR) methods on 118 human fresh or stored corneas (organ culture at 31 degrees C), followed by conventional immunofluorescence labeling. First, in an attempt to define a universal protocol, we selected combinations able to correctly localize four proteins that are perfectly defined in ECs (zonula occludens-1 [ZO-1] and actin) or ubiquitous (heterogeneous nuclear ribonucleoprotein L [hnRNP L] and histone H3). Second, we screened protocols adapted to the revelation of 9 cell cycle proteins: Ki67, proliferating cell nuclear antigen (PCNA), minichromosome maintenance protein 2 (MCM2), cyclin D1, cyclin E, cyclin A, p16(Ink4a), p21(Cip1) and p27(Kip1). Primary antibody controls (positive controls) were performed on both epithelial cells of the same, simultaneously-stained whole corneas, and by ICC on human ECs in in vitro non confluent cultures. Both controls are known to contain proliferating cells. IL efficiency was evaluated by two observers in a masked fashion. Correct localization at optical microscopy level in ECs was define as clear labeling with no background, homogeneous staining, agreement with previous works on ECs and/or protein functions, as well as a meaningful IL in proliferating cells of both controls. RESULTS: The common fixation with 4% formaldehyde (gold standard for IHC) failed to reveal 12 of the 13 proteins. In contrast, they were all revealed using either 0.5% formaldehyde at room temperature (RT) during 30 min alone or followed by AR with sodium dodecyl sulfate or trypsin, or pure methanol for 30 min at RT. Individual optimization was nevertheless often required to optimize the labeling. Ki67 was absent in both fresh and stored corneas, whereas PCNA was found in the nucleus, and MCM2 in the cytoplasm, of all ECs. Cyclin D1 was found in the cytoplasm in a paranuclear pattern much more visible after corneal storage. Cyclin E and cyclin A were respectively nuclear and cytoplasmic, unmodified by storage. P21 was not found in ECs with three different antibodies. P16 and p27 were exclusively nuclear, unmodified by storage. CONCLUSIONS: IL in ECs of flat-mounted whole human corneas requires a specific sample preparation, especially to avoid overfixation with aldehydes that probably easily masks epitopes. En face observation allows easy analysis of labeling pattern within the endothelial layer and clear subcellular localization, neither of which had previously been described for PCNA, MCM2, or cyclin D1. PMID- 22219647 TI - A study of KIR genes and HLA-C in Vogt-Koyanagi-Harada disease in Saudi Arabia. AB - PURPOSE: Vogt-Koyanagi-Harada (VKH) disease is a serious ocular inflammatory autoimmune insult directed against antigens associated with melanocytes. The repertoire of killer cell immunoglobulin-like receptors (KIRs) is known to play a significant role in the pathogenesis of various autoimmune disorders. Accordingly, we sought to determine the incidence of KIR genes and KIR ligand (Human leukocytes antigen [HLA-C]) interaction in a cohort of Saudi VKH patients and to compare the findings to normal controls. METHODS: A total of 30 patients with VKH and 125 control subjects were included. PCR using sequence-specific oligonucleotide primers were employed to determine the genotype of the KIR genes and HLA-C alleles. RESULTS: The frequency of KIR2DS3 was significantly higher in the VKH patients than in the control group (p=0.048). Two unique genotypes; VKHN*1 and VKHN*2 were observed in the VKH patients and not in normal controls. In addition, the majority of the VKH patients (82%) in this study carry Bx genotypes that encode 2-5 activating KIR receptors. The genotype Bx5 was found to be positively associated with the VKH patients (p=0.053). Significantly higher homozygosity of HLA-C2 was observed in the VKH patients than in controls (p=0.005). Furthermore, HLA-C alleles-Cw*14 and Cw*17 were significantly prevalent in the VKH patients (p=0.037 and p=0.0001, respectively), whereas, Cw*15 significantly increased in the control group (p=0.0205). Among potential KIR-HLA interactions, we observed KIR2DL2/2DL3+HLA-C1 to be higher in the control subjects compared with the VKH patients (p=0.018). CONCLUSIONS: Our findings indicated that KIR2DS3 and HLA-class I alleles (-Cw*14 and -Cw*17) may play a role in the pathogenesis of VKH disease. Additionally, the predominance of KIR2DL2/2DL3+HLA-C1 in the controls may imply that this KIR-ligand interaction could possibly play a role in the prevention of VKH disease, or could decrease its severity. These observations may contribute to our understanding of the pathogenesis of VKH and other autoimmune diseases. PMID- 22219648 TI - Exome capture sequencing identifies a novel mutation in BBS4. AB - PURPOSE: Leber congenital amaurosis (LCA) is one of the most severe eye dystrophies characterized by severe vision loss at an early stage and accounts for approximately 5% of all retinal dystrophies. The purpose of this study was to identify a novel LCA disease allele or gene and to develop an approach combining genetic mapping with whole exome sequencing. METHODS: Three patients from King Khaled Eye Specialist Hospital (KKESH205) underwent whole genome single nucleotide polymorphism genotyping, and a single candidate region was identified. Taking advantage of next-generation high-throughput DNA sequencing technologies, whole exome capture sequencing was performed on patient KKESH205#7. Sanger direct sequencing was used during the validation step. The zebrafish model was used to examine the function of the mutant allele. RESULTS: A novel missense mutation in Bardet-Biedl syndrome 4 protein (BBS4) was identified in a consanguineous family from Saudi Arabia. This missense mutation in the fifth exon (c.253G>C;p.E85Q) of BBS4 is likely a disease-causing mutation as it segregates with the disease. The mutation is not found in the single nucleotide polymorphism (SNP) database, the 1000 Genomes Project, or matching normal controls. Functional analysis of this mutation in zebrafish indicates that the G253C allele is pathogenic. Coinjection of the G253C allele cannot rescue the mislocalization of rhodopsin in the retina when BBS4 is knocked down by morpholino injection. Immunofluorescence analysis in cell culture shows that this missense mutation in BBS4 does not cause obvious defects in protein expression or pericentriolar localization. CONCLUSIONS: This mutation likely mainly reduces or abolishes BBS4 function in the retina. Further studies of this allele will provide important insights concerning the pleiotropic nature of BBS4 function. PMID- 22219649 TI - Mutational analysis of the RB1 gene in Moroccan patients with retinoblastoma. AB - PURPOSE: Retinoblastoma (RB), the most common intraocular tumor occurring in infancy and early childhood, is most often related to mutations in the RB1 gene. In this study, we screened the RB1 germline mutations in 41 unrelated Moroccan patients with retinoblastoma, 25 heritable cases, and 16 sporadic unilateral cases. METHODS: After complete ophthalmic examinations were performed and consent obtained, DNA was extracted from peripheral blood, and screening of RB1 mutations was performed with PCR direct sequencing of the promoter and the 27 coding exons of the RB1 gene. RESULTS: We identified ten germline mutations in 10/41 (24.39%) unrelated patients, among which three had not been previously reported. The mutation detection rate was 40% (10/25) in the heritable cases and 0% (0/16) in the sporadic unilateral cases. Of these mutations, six were nonsense, and three were frameshifts, all associated with severe phenotypes resulting in bilateral and multifocal tumors. One splice site mutation was found in a familial case associated with a low expressivity phenotype resulting in unilateral and unifocal tumors. Moreover, eight intronic variants were identified, three of which were novel. CONCLUSIONS: This first report of RB1 gene screening in Moroccan patients with retinoblastoma shows a comparable mutational spectrum to those reported previously, which has evident importance for managing patients with retinoblastoma and their families. PMID- 22219650 TI - Novel mutations of MYO7A and USH1G in Israeli Arab families with Usher syndrome type 1. AB - PURPOSE: This study investigated the genetic basis for Usher syndrome type 1 (USH1) in four consanguineous Israeli Arab families. METHODS: Haplotype analysis for all known USH1 loci was performed in each family. In families for which haplotype analysis was inconclusive, we performed genome-wide homozygosity mapping using a single nucleotide polymorphism (SNP) array. For mutation analysis, specific primers were used to PCR amplify the coding exons of the MYO7A, USH1C, and USH1G genes including intron-exon boundaries. Mutation screening was performed with direct sequencing. RESULTS: A combination of haplotype analysis and genome-wide homozygosity mapping indicated linkage to the USH1B locus in two families, USH1C in one family and USH1G in another family. Sequence analysis of the relevant genes (MYO7A, USH1C, and USH1G) led to the identification of pathogenic mutations in all families. Two of the identified mutations are novel (c.1135-1147dup in MYO7A and c.206-207insC in USH1G). CONCLUSIONS: USH1 is a genetically heterogenous condition. Of the five USH1 genes identified to date, USH1C and USH1G are the rarest contributors to USH1 etiology worldwide. It is therefore interesting that two of the four Israeli Arab families reported here have mutations in these two genes. This finding further demonstrates the unique genetic structure of the Israeli population in general, and the Israeli Arab population in particular, which due to high rates of consanguinity segregates many rare autosomal recessive genetic conditions. PMID- 22219652 TI - Retro-orbital injection of FITC-dextran is an effective and economical method for observing mouse retinal vessels. AB - PURPOSE: To assess the effects of retro-orbital (RO) injection of fluorescein isothiocyanate dextran (FITC-dextran) for observing mouse retinal vessels. METHODS: Oxygen-induced retinopathy (OIR) was induced in 7-day postnatal (P7) C57BL/6J mice by exposing them to a 75% oxygen atmosphere for 5 days and then returning them to room air at P12. At P17, 45 P17 OIR mice and 12 normal mice received an RO injection of FITC-dextran. Five P17 OIR mice were perfused with FITC-dextran via the left ventricle. Retinal flatmounts were viewed under a fluorescence microscope and a confocal microscope. Following RO injection or left ventricular (LV) perfusion, the areas of neovascularization, as well as the total retina areas, were measured and analyzed using Image Pro-Plus 5.1 software. RESULTS: The suitable volume of FITC-dextran for RO injection to observe the retinal vessels of a P17 OIR mouse was 0.05 ml, the 5% volume required to achieve similar results by administering FITC-dextran using LV perfusion. The total retinal vessels in P17 OIR mice could be fully observed under a fluorescence microscope 3 s after RO injection of FITC-dextran. Our study showed that RO injection of FITC-dextran was suitable for observing the retinal vessels of all postnatal mice. There was no significant difference in evaluating retinal neovascularization between RO injection and LV perfusion of FITC-dextran (p>0.05). CONCLUSIONS: Retro-orbital injection of FITC-dextran is an economical method for observing retinal vessels in mice, when compared with LV perfusion of FITC-dextran. PMID- 22219651 TI - Unoprostone reduces oxidative stress- and light-induced retinal cell death, and phagocytotic dysfunction, by activating BK channels. AB - PURPOSE: Unoprostone isopropyl (unoprostone) is a docosanoid currently used as an antiglaucoma agent. Unoprostone is known to have neuroprotective effects and to activate large conductance Ca2+-activated K+ (BK) channels. Recently, unoprostone has been tested in clinical studies as a therapeutic agent for retinitis pigmentosa (RP) and studies have demonstrated an improvement in retinal sensitivity and in the protection of central retinal sensitivity with its use. However, the mechanism of action underlying unoprostone's protective effect in RP is not fully known. It is well known that the pathogenesis of RP can be accelerated by oxidative stress or light irradiation. Therefore, the current study investigated the effects and the underlying mechanism of action of unoprostone on oxidative stress- and light irradiation-induced damage in photoreceptor and retinal pigment epithelial cultures. METHODS: The study used the mouse retinal cone-cell line 661W to investigate the effects of unoprostone and its major metabolite, unoprostone-free acid (M1), on oxidative stress- or light irradiation-induced cell death, and a human retinal pigment epithelial cell line (ARPE-19), was used to investigate the effects on light-induced disruption of phagocytotic function in a latex bead assay. Additionally, we examined whether the effects of unoprostone and M1 were mediated by BK channels using iberiotoxin, a selective inhibitor of BK channels. RESULTS: Unoprostone and M1 protected against light- or H2O2-induced cell death in 661W cells, and against light induced phagocytotic dysfunction in ARPE-19 cells. Additionally, iberiotoxin inhibited the protective effects of unoprostone and M1. CONCLUSIONS: These findings indicate that unoprostone has protective effects on oxidative stress- and light irradiation-induced damage in vitro and that these effects are mediated by activation of BK channels. This confirms that unoprostone represents a promising therapeutic agent for the treatment of RP and other retinal diseases. PMID- 22219653 TI - Difference between age-related macular degeneration and polypoidal choroidal vasculopathy in the hereditary contribution of the A69S variant of the age related maculopathy susceptibility 2 gene (ARMS2). AB - PURPOSE: To investigate whether the A69S variant of the age-related maculopathy susceptibility 2 gene (ARMS2) has a different hereditary contribution in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). METHODS: We initially conducted a comparative genetic analysis of neovascular AMD and PCV, genotyping the ARMS2 A69S variant in 181 subjects with neovascular AMD, 198 subjects with PCV, and 203 controls in a Japanese population. Genotyping was conducted using TaqMan technology. Results were then integrated into a meta-analysis of previous studies representing an assessment of the association between the ARMS2 A69S variant and neovascular AMD and/or PCV, comprising a total of 3,828 subjects of Asian descent. The Q statistic test was used to assess between-study heterogeneity. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a fixed effects model. RESULTS: The genetic effect of the A69S variant was stronger in neovascular AMD (allelic summary OR=3.09 [95% CI, 2.71-3.51], fixed effects p<0.001) than in PCV (allelic summary OR=2.13 [95% CI, 1.91-2.38], fixed effects p<0.001). The pooled risk allele frequency was significantly higher in neovascular AMD (64.7%) than in PCV (55.6%). The population attributable risks for the variant allele were estimated to be 43.9% (95% CI, 39.0%-48.4%) and 29.7% (95% CI, 25.4%-34.0%) for neovascular AMD and PCV, respectively. No significant between-study heterogeneity was observed in any statistical analysis in this meta analysis. CONCLUSIONS: Our meta-analysis provides substantial evidence that the ARMS2 A69S variant confers a significantly higher risk of neovascular AMD than PCV. Furthermore, there is compelling evidence that the risk attributable to the A69S variant differs between geographic atrophy and neovascular AMD. Together with defining the molecular basis of susceptibility, understanding the relationships between this genomic region and disease subtypes will yield important insights, elucidating the biologic architecture of this phenotypically heterogeneous disorder. PMID- 22219654 TI - Analysis of copy number variation using whole genome exon-focused array CGH in Korean patients with primary congenital glaucoma. AB - PURPOSE: Primary congenital glaucoma (PCG) is an autosomal recessive form of glaucoma that manifests within the first year of life and if left untreated, leads to irreversible blindness. Cytochrome P450 1B1 (CYP1B1) is the major gene known to be associated with PCG. The role of the CYP1B1 gene in disease pathogenesis and the relatively low detection rate of CYP1B1 mutations in some populations, especially Asians, remain unexplained. We hypothesized that altered gene dosage of CYP1B1 or anterior segmental dysgenesis causative genes may be involved in the pathogenesis of PCG. METHODS: We performed whole genome exon focused array comparative genome hybridization (aCGH) to identify copy number variation (CNV) in 20 Korean PCG patients and their parents. RESULTS: We identified 12 patients with at least one rare gene-containing copy number variation each, corresponding to 25 CNVs (5 deletions and 20 duplications) at frequencies of 5-30% in PCG patients and 0% in controls. The 25 CNVs were not located at known chromosomal loci for PCG, namely GLC3A, which harbors CYP1B1 (2p21), GLC3B (1p36.2-p36.1), or GLC3C (14q23), and did not include any target genes associated with PCG or anterior segmental dysgenesis. CONCLUSIONS: Further genetic studies with larger cohorts of patients are necessary to validate our results and to elucidate other genetic mechanisms underlying PCG, because the identified CNVs might be PCG-specific pathogenic variants and may explain the disease pathogenesis of PCG. PMID- 22219656 TI - Targeted therapies development in the treatment of advanced nonsmall cell lung cancer. PMID- 22219655 TI - ENU mutagenesis screen to establish motor phenotypes in wild-type mice and modifiers of a pre-existing motor phenotype in tau mutant mice. AB - Modifier screening is a powerful genetic tool. While not widely used in the vertebrate system, we applied these tools to transgenic mouse strains that recapitulate key aspects of Alzheimer's disease (AD), such as tau-expressing mice. These are characterized by a robust pathology including both motor and memory impairment. The phenotype can be modulated by ENU mutagenesis, which results in novel mutant mouse strains and allows identifying the underlying gene/mutation. Here we discuss this strategy in detail. We firstly obtained pedigrees that modify the tau-related motor phenotype, with mapping ongoing. We further obtained transgene-independent motor pedigrees: (i) hyperactive, circling ENU 37 mice with a causal mutation in the Tbx1 gene-the complete knock-out of Tbx1 models DiGeorge Syndrome; (ii) ENU12/301 mice that show sudden jerky movements and tremor constantly; they have a causal mutation in the Kcnq1 gene, modelling aspects of the Romano-Ward and Jervell and Lange-Nielsen syndromes; and (iii) ENU16/069 mice with tremor and hypermetric gait that have a causal mutation in the Mpz (Myelin Protein Zero) gene, modelling Charcot-Marie-Tooth disease type 1 (CMT1B). Together, we provide evidence for a real potential of an ENU mutagenesis to dissect motor functions in wild-type and tau mutant mice. PMID- 22219657 TI - Regulatory T-cell-associated cytokines in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production, complement activation, and immune complex deposition, resulting in tissue and organ damage. An understanding of the mechanisms responsible for homeostatic control of inflammation, which involve both innate and adoptive immune responses, will enable the development of novel therapies for SLE. Regulatory T cells (Treg) play critical roles in the induction of peripheral tolerance to self- and foreign antigens. Naturally occurring CD4+CD25+ Treg, which characteristically express the transcription factor forkhead box protein P3 (Foxp3), have been intensively studied because their deficiency abrogates self tolerance and causes autoimmune disease. Moreover, regulatory cytokines such as interleukin-10 (IL-10) also play a central role in controlling inflammatory processes. This paper focuses on Tregs and Treg-associated cytokines which might regulate the pathogenesis of SLE and, hence, have clinical applications. PMID- 22219658 TI - Neurotrophic features of human adipose tissue-derived stromal cells: in vitro and in vivo studies. AB - Due to its abundance, easy retrieval, and plasticity characteristics, adipose tissue-derived stromal cells (ATSCs) present unquestionable advantages over other adult-tissue-derived stem cells. Based on the in silico analysis of our previous data reporting the ATSC-specific expression profiles, the present study attempted to clarify and validate at the functional level the expression of the neurospecific genes expressed by ATSC both in vitro and in vivo. This allowed evidencing that ATSCs express neuro-specific trophins, metabolic genes, and neuroprotective molecules. They were in fact able to induce neurite outgrowth in vitro, along with tissue-specific commitment along the neural lineage and the expression of the TRKA neurotrophin receptor in vivo. Our observation adds useful information to recent evidence proposing these cells as a suitable tool for cell based applications in neuroregenerative medicine. PMID- 22219659 TI - Modulation of specific and allergy-related immune responses by helminths. AB - Helminths are master regulators of host immune responses utilising complex mechanisms to dampen host protective Th2-type responses and favour long-term persistence. Such evasion mechanisms ensure mutual survival of both the parasite and the host. In this paper, we present recent findings on the cells that are targeted by helminths and the molecules and mechanisms that are induced during infection. We discuss the impact of these factors on the host response as well as their effect in preventing the development of aberrant allergic inflammation. We also examine recent findings on helminth-derived molecules that can be used as tools to pinpoint the underlying mechanisms of immune regulation or to determine new anti-inflammatory therapeutics. PMID- 22219661 TI - Development and validation of spectrophotometric, atomic absorption and kinetic methods for determination of moxifloxacin hydrochloride. AB - Three simple spectrophotometric and atomic absorption spectrometric methods are developed and validated for the determination of moxifloxacin HCl in pure form and in pharmaceutical formulations. Method (A) is a kinetic method based on the oxidation of moxifloxacin HCl by Fe(3+) ion in the presence of 1,10 o phenanthroline (o-phen). Method (B) describes spectrophotometric procedures for determination of moxifloxacin HCl based on its ability to reduce Fe (III) to Fe (II), which was rapidly converted to the corresponding stable coloured complex after reacting with 2,2' bipyridyl (bipy). The formation of the tris-complex formed in both methods (A) and (B) were carefully studied and their absorbance were measured at 510 and 520 nm respectively. Method (C) is based on the formation of ion- pair associated between the drug and bismuth (III) tetraiodide in acidic medium to form orange-red ion-pair associates. This associate can be quantitatively determined by three different procedures. The formed precipitate is either filtered off, dissolved in acetone and quantified spectrophotometrically at 462 nm (Procedure 1), or decomposed by hydrochloric acid, and the bismuth content is determined by direct atomic absorption spectrometric (Procedure 2). Also the residual unreacted metal complex in the filtrate is determined through its metal content using indirect atomic absorption spectrometric technique (procedure 3). All the proposed methods were validated according to the International Conference on Harmonization (ICH) guidelines, the three proposed methods permit the determination of moxifloxacin HCl in the range of (0.8-6, 0.8-4) for methods A and B, (16-96, 16-96 and 16-72) for procedures 1 3 in method C. The limits of detection and quantitation were calculated, the precision of the methods were satisfactory; the values of relative standard deviations did not exceed 2%. The proposed methods were successfully applied to determine the drug in its pharmaceutical formulations without interference from the common excipients. The results obtained by the proposed methods were comparable with those obtained by the reference method. PMID- 22219662 TI - Transversely excited multipass photoacoustic cell using electromechanical film as microphone. AB - A novel multipass photoacoustic cell with five stacked electromechanical films as a microphone has been constructed, tested and characterized. The photoacoustic cell is an open rectangular structure with two steel plates facing each other. The longitudinal acoustic resonances are excited transversely in an optical multipass configuration. A detection limit of 22 ppb (10(-9)) was achieved for flowing NO(2) in N(2) at normal pressure by using the maximum of 70 laser beams between the resonator plates. The corresponding minimum detectable absorption and the normalized noise-equivalent absorption coefficients were 2.2 * 10(-7) cm(-1) and 3.2 * 10(-9) cm(-1) WHz(-1/2), respectively. PMID- 22219660 TI - Rapid molecular detection methods for arboviruses of livestock of importance to northern Europe. AB - Arthropod-borne viruses (arboviruses) have been responsible for some of the most explosive epidemics of emerging infectious diseases over the past decade. Their impact on both human and livestock populations has been dramatic. The early detection either through surveillance or diagnosis of virus will be a critical feature in responding and resolving the emergence of such epidemics in the future. Although some of the most important emerging arboviruses are human pathogens, this paper aims to highlight those diseases that primarily affect livestock, although many are zoonotic and some occasionally cause human mortality. This paper also highlights the molecular detection methods specific to each virus and identifies those emerging diseases for which a rapid detection methods are not yet developed. PMID- 22219663 TI - Electrochemical microsensors for the detection of cadmium(II) and lead(II) ions in plants. AB - Routine determination of trace metals in complex media is still a difficult task for many analytical instruments. The aim of this work was to compare three electro-chemical instruments [a standard potentiostat (Autolab), a commercially available miniaturized potentiostat (PalmSens) and a homemade micropotentiostat] for easy-to-use and sensitive determination of cadmium(II) and lead(II) ions. The lowest detection limits (hundreds of pM) for both metals was achieved by using of the standard potentiostat, followed by the miniaturized potentiostat (tens of nM) and the homemade instrument (hundreds of nM). Nevertheless, all potentiostats were sensitive enough to evaluate contamination of the environment, because the environmental limits for both metals are higher than detection limits of the instruments. Further, we tested all used potentiostats and working electrodes on analysis of environmental samples (rainwater, flour and plant extract) with artificially added cadmium(II) and lead(II). Based on the similar results obtained for all potentiostats we choose a homemade instrument with a carbon tip working electrode for our subsequent environmental experiments, in which we analyzed maize and sunflower seedlings and rainwater obtained from various sites in the Czech Republic. PMID- 22219664 TI - Lazy approaches for interval timing correlation of sensor data streams. AB - We propose novel algorithms for the timing correlation of streaming sensor data. The sensor data are assumed to have interval timestamps so that they can represent temporal uncertainties. The proposed algorithms can support efficient timing correlation for various timing predicates such as deadline, delay, and within. In addition to the classical techniques, lazy evaluation and result cache are utilized to improve the algorithm performance. The proposed algorithms are implemented and compared under various workloads. PMID- 22219665 TI - A low frequency electromagnetic sensor for indirect measurement of glucose concentration: in vitro experiments in different conductive solutions. AB - In recent years there has been considerable interest in the study of glucose induced dielectric property variations of human tissues as a possible approach for non-invasive glycaemia monitoring. We have developed an electromagnetic sensor, and we tested in vitro its ability to estimate variations in glucose concentration of different solutions with similarities to blood (sodium chloride and Ringer-lactate solutions), differing though in the lack of any cellular components. The sensor was able to detect the effect of glucose variations over a wide range of concentrations (~78-5,000 mg/dL), with a sensitivity of ~0.22 mV/(mg/dL). Our proposed system may thus be useful in a new approach for non invasive and non-contact glucose monitoring. PMID- 22219666 TI - Real-time gas identification by analyzing the transient response of capillary attached conductive gas sensor. AB - In this study, the ability of the Capillary-attached conductive gas sensor (CGS) in real-time gas identification was investigated. The structure of the prototype fabricated CGS is presented. Portions were selected from the beginning of the CGS transient response including the first 11 samples to the first 100 samples. Different feature extraction and classification methods were applied on the selected portions. Validation of methods was evaluated to study the ability of an early portion of the CGS transient response in target gas (TG) identification. Experimental results proved that applying extracted features from an early part of the CGS transient response along with a classifier can distinguish short-chain alcohols from each other perfectly. Decreasing time of exposition in the interaction between target gas and sensing element improved the reliability of the sensor. Classification rate was also improved and time of identification was decreased. Moreover, the results indicated the optimum interval of the early transient response of the CGS for selecting portions to achieve the best classification rates. PMID- 22219667 TI - Integration of a multi-camera vision system and strapdown inertial navigation system (SDINS) with a modified Kalman filter. AB - This paper describes the development of a modified Kalman filter to integrate a multi-camera vision system and strapdown inertial navigation system (SDINS) for tracking a hand-held moving device for slow or nearly static applications over extended periods of time. In this algorithm, the magnitude of the changes in position and velocity are estimated and then added to the previous estimation of the position and velocity, respectively. The experimental results of the hybrid vision/SDINS design show that the position error of the tool tip in all directions is about one millimeter RMS. The proposed Kalman filter removes the effect of the gravitational force in the state-space model. As a result, the resulting error is eliminated and the resulting position is smoother and ripple free. PMID- 22219668 TI - Data acquisition, analysis and transmission platform for a Pay-As-You-Drive system. AB - This paper presents a platform used to acquire, analyse and transmit data from a vehicle to a Control Centre as part of a Pay-As-You-Drive system. The aim is to monitor vehicle usage (how much, when, where and how) and, based on this information, assess the associated risk and set an appropriate insurance premium. To determine vehicle usage, the system analyses the driver's respect for speed limits, driving style (aggressive or non-aggressive), mobile telephone use and the number of vehicle passengers. An electronic system on board the vehicle acquires these data, processes them and transmits them by mobile telephone (GPRS/UMTS) to a Control Centre, at which the insurance company assesses the risk associated with vehicles monitored by the system. The system provides insurance companies and their customers with an enhanced service and could potentially increase responsible driving habits and reduce the number of road accidents. PMID- 22219669 TI - Immunosensor incorporating anti-His (C-term) IgG F(ab') fragments attached to gold nanorods for detection of His-tagged proteins in culture medium. AB - Immunosensors based on gold electrodes (electrochemical) or gold discs (optical) modified with 1,6-hexanedithiol, gold nanorods and Anti-His (C-term) monoclonal antibody F(ab') fragment are described. The antigen detected by the sensing platform is a recombinant histidine-tagged silk proteinase inhibitor (rSPI2 His(6)). Electrochemical impedance spectroscopy (EIS) and surface plasmon resonance (SPR) techniques were used as methods for detection of the antigen. This approach allows to detect the antigen protein in concentration of 10 pg per mL (0.13 pM) of culture medium. The immunosensor shows good reproducibility due to covalent immobilization of F(ab') fragments to gold nanorods layer. PMID- 22219670 TI - A differential evolution-based routing algorithm for environmental monitoring wireless sensor networks. AB - The traditional Low Energy Adaptive Cluster Hierarchy (LEACH) routing protocol is a clustering-based protocol. The uneven selection of cluster heads results in premature death of cluster heads and premature blind nodes inside the clusters, thus reducing the overall lifetime of the network. With a full consideration of information on energy and distance distribution of neighboring nodes inside the clusters, this paper proposes a new routing algorithm based on differential evolution (DE) to improve the LEACH routing protocol. To meet the requirements of monitoring applications in outdoor environments such as the meteorological, hydrological and wetland ecological environments, the proposed algorithm uses the simple and fast search features of DE to optimize the multi-objective selection of cluster heads and prevent blind nodes for improved energy efficiency and system stability. Simulation results show that the proposed new LEACH routing algorithm has better performance, effectively extends the working lifetime of the system, and improves the quality of the wireless sensor networks. PMID- 22219671 TI - Modeling of current consumption in 802.15.4/ZigBee sensor motes. AB - Battery consumption is a key aspect in the performance of wireless sensor networks. One of the most promising technologies for this type of networks is 802.15.4/ZigBee. This paper presents an empirical characterization of battery consumption in commercial 802.15.4/ZigBee motes. This characterization is based on the measurement of the current that is drained from the power source under different 802.15.4 communication operations. The measurements permit the definition of an analytical model to predict the maximum, minimum and mean expected battery lifetime of a sensor networking application as a function of the sensor duty cycle and the size of the sensed data. PMID- 22219672 TI - Metal oxide semi-conductor gas sensors in environmental monitoring. AB - Metal oxide semiconductor gas sensors are utilised in a variety of different roles and industries. They are relatively inexpensive compared to other sensing technologies, robust, lightweight, long lasting and benefit from high material sensitivity and quick response times. They have been used extensively to measure and monitor trace amounts of environmentally important gases such as carbon monoxide and nitrogen dioxide. In this review the nature of the gas response and how it is fundamentally linked to surface structure is explored. Synthetic routes to metal oxide semiconductor gas sensors are also discussed and related to their affect on surface structure. An overview of important contributions and recent advances are discussed for the use of metal oxide semiconductor sensors for the detection of a variety of gases--CO, NO(x), NH(3) and the particularly challenging case of CO(2). Finally a description of recent advances in work completed at University College London is presented including the use of selective zeolites layers, new perovskite type materials and an innovative chemical vapour deposition approach to film deposition. PMID- 22219673 TI - Studies of scattering, reflectivity, and transmitivity in WBAN channel: feasibility of using UWB. AB - The Wireless Personal Area Network (WPAN) is one of the fledging paradigms that the next generation of wireless systems is sprouting towards. Among them, a more specific category is the Wireless Body Area Network (WBAN) used for health monitoring. On the other hand, Ultra-Wideband (UWB) comes with a number of desirable features at the physical layer for wireless communications. One big challenge in adoption of UWB in WBAN is the fact that signals get attenuated exponentially. Due to the intrinsic structural complexity in human body, electromagnetic waves show a profound variation during propagation through it. The reflection and transmission coefficients of human body are highly dependent upon the dielectric constants as well as upon the frequency. The difference in structural materials such as fat, muscles and blood essentially makes electromagnetic wave attenuation to be different along the way. Thus, a complete characterization of body channel is a challenging task. The connection between attenuation and frequency of the signal makes the investigation of UWB in WBAN an interesting proposition. In this paper, we study analytically the impact of body channels on electromagnetic signal propagation with reference to UWB. In the process, scattering, reflectivity and transmitivity have been addressed with analysis of approximate layer-wise modeling, and with numerical depictions. Pulses with Gaussian profile have been employed in our analysis. It shows that, under reasonable practical approximations, the human body channel can be modeled in layers so as to have the effects of total reflections or total transmissions in certain frequency bands. This could help decide such design issues as antenna characteristics of implant devices for WBAN employing UWB. PMID- 22219674 TI - Illumination-based synchronization of high-speed vision sensors. AB - To acquire images of dynamic scenes from multiple points of view simultaneously, the acquisition time of vision sensors should be synchronized. This paper describes an illumination-based synchronization method derived from the phase locked loop (PLL) algorithm. Incident light to a vision sensor from an intensity modulated illumination source serves as the reference signal for synchronization. Analog and digital computation within the vision sensor forms a PLL to regulate the output signal, which corresponds to the vision frame timing, to be synchronized with the reference. Simulated and experimental results show that a 1,000 Hz frame rate vision sensor was successfully synchronized with 32 MUs jitters. PMID- 22219675 TI - An energy-efficient rate adaptive media access protocol (RA-MAC) for long-lived sensor networks. AB - We introduce an energy-efficient Rate Adaptive Media Access Control (RA-MAC) algorithm for long-lived Wireless Sensor Networks (WSNs). Previous research shows that the dynamic and lossy nature of wireless communications is one of the major challenges to reliable data delivery in WSNs. RA-MAC achieves high link reliability in such situations by dynamically trading off data rate for channel gain. The extra gain that can be achieved reduces the packet loss rate which contributes to reduced energy expenditure through a reduced numbers of retransmissions. We achieve this at the expense of raw bit rate which generally far exceeds the application's link requirement. To minimize communication energy consumption, RA-MAC selects the optimal data rate based on the estimated link quality at each data rate and an analytical model of the energy consumption. Our model shows how the selected data rate depends on different channel conditions in order to minimize energy consumption. We have implemented RA-MAC in TinyOS for an off-the-shelf sensor platform (the TinyNode) on top of a state-of-the-art WSN Media Access Control Protocol, SCP-MAC, and evaluated its performance by comparing our implementation with the original SCP-MAC using both simulation and experiment. PMID- 22219676 TI - Modeling and analysis of energy conservation scheme based on duty cycling in wireless ad hoc sensor network. AB - In sensor network, energy conservation is one of the most critical issues since sensor nodes should perform a sensing task for a long time (e.g., lasting a few years) but the battery of them cannot be replaced in most practical situations. For this purpose, numerous energy conservation schemes have been proposed and duty cycling scheme is considered the most suitable power conservation technique, where sensor nodes alternate between states having different levels of power consumption. In order to analyze the energy consumption of energy conservation scheme based on duty cycling, it is essential to obtain the probability of each state. In this paper, we analytically derive steady state probability of sensor node states, i.e., sleep, listen, and active states, based on traffic characteristics and timer values, i.e., sleep timer, listen timer, and active timer. The effect of traffic characteristics and timer values on the steady state probability and energy consumption is analyzed in detail. Our work can provide sensor network operators guideline for selecting appropriate timer values for efficient energy conservation. The analytical methodology developed in this paper can be extended to other energy conservation schemes based on duty cycling with different sensor node states, without much difficulty. PMID- 22219677 TI - Electrical conductivity response of poly(phenylene-vinylene)/zeolite composites exposed to ammonium nitrate. AB - Poly(p-phenylenevinylene) (PPV) was chemically synthesized via the polymerization of p-xylene-bis(tetrahydrothiophenium chloride) monomer and doped with H(2)SO(4). To improve the electrical conductivity sensitivity of the conductive polymer, Zeolites Y (Si/Al = 5.1, 30, 60, 80) were added into the conductive polymer matrix. All composite samples show definite positive responses towards NH(4)NO(3). The electrical conductivity sensitivities of the composite sensors increase linearly with increasing Si/Al ratio: with values of 0.201, 1.37, 2.80 and 3.18, respectively. The interactions between NH(4)NO(3) molecules and the PPV/zeolite composites with respect to the electrical conductivity sensitivity were investigated through the infrared spectroscopy. PMID- 22219678 TI - Comparison of several methods for determining the internal resistance of lithium ion cells. AB - The internal resistance is the key parameter for determining power, energy efficiency and lost heat of a lithium ion cell. Precise knowledge of this value is vital for designing battery systems for automotive applications. Internal resistance of a cell was determined by current step methods, AC (alternating current) methods, electrochemical impedance spectroscopy and thermal loss methods. The outcomes of these measurements have been compared with each other. If charge or discharge of the cell is limited, current step methods provide the same results as energy loss methods. PMID- 22219679 TI - On the use of piezoelectric sensors in structural mechanics: some novel strategies. AB - In the present paper, a review on piezoelectric sensing of mechanical deformations and vibrations of so-called smart or intelligent structures is given. After a short introduction into piezoelectric sensing and actuation of such controlled structures, we pay special emphasis on the description of some own work, which has been performed at the Institute of Technical Mechanics of the Johannes Kepler University of Linz (JKU) in the last years. Among other aspects, this work has been motivated by the fact that collocated control of smart structures requires a sensor output that is work-conjugated to the input by the actuator. This fact in turn brings into the play the more general question of how to measure mechanically meaningful structural quantities, such as displacements, slopes, or other quantities, which form the work-conjugated quantities of the actuation, by means piezoelectric sensors. At least in the range of small strains, there is confidence that distributed piezoelectric sensors or sensor patches in smart structures do measure weighted integrals over their domain. Therefore, there is a need of distributing or shaping the sensor activity in order to be able to re-interpret the sensor signals in the desired mechanical sense. We sketch a general strategy that is based on a special application of work principles, more generally on displacement virials. We also review our work in the past on bringing this concept to application in smart structures, such as beams, rods and plates. PMID- 22219681 TI - The role of PAS kinase in PASsing the glucose signal. AB - PAS kinase is an evolutionarily conserved nutrient responsive protein kinase that regulates glucose homeostasis. Mammalian PAS kinase is activated by glucose in pancreatic beta cells, and knockout mice are protected from obesity, liver triglyceride accumulation, and insulin resistance when fed a high-fat diet. Yeast PAS kinase is regulated by both carbon source and cell integrity stress and stimulates the partitioning of glucose toward structural carbohydrate biosynthesis. In our current model for PAS kinase regulation, a small molecule metabolite binds the sensory PAS domain and activates the enzyme. Although bona fide PAS kinase substrates are scarce, in vitro substrate searches provide putative targets for exploration. PMID- 22219680 TI - Methodology of pulsed photoacoustics and its application to probe photosystems and receptors. AB - We review recent advances in the methodology of pulsed time-resolved photoacoustics and its application to studies of photosynthetic reaction centers and membrane receptors such as the G protein-coupled receptor rhodopsin. The experimental parameters accessible to photoacoustics include molecular volume change and photoreaction enthalpy change. Light-driven volume change secondary to protein conformational changes or electrostriction is directly related to the photoreaction and thus can be a useful measurement of activity and function. The enthalpy changes of the photochemical reactions observed can be measured directly by photoacoustics. With the measurement of enthalpy change, the reaction entropy can also be calculated when free energy is known. Dissecting the free energy of a photoreaction into enthalpic and entropic components may provide critical information about photoactivation mechanisms of photosystems and photoreceptors. The potential limitations and future applications of time-resolved photoacoustics are also discussed. PMID- 22219682 TI - Gait event detection on level ground and incline walking using a rate gyroscope. AB - Gyroscopes have been proposed as sensors for ambulatory gait analysis and functional electrical stimulation systems. Accurate determination of the Initial Contact of the foot with the floor (IC) and the final contact or Foot Off (FO) on different terrains is important. This paper describes the evaluation of a gyroscope placed on the shank for determination of IC and FO in subjects walking outdoors on level ground, and up and down an incline. Performance was compared with a reference pressure measurement system. The mean difference between the gyroscope and the reference was less than -25 ms for IC and less than 75 ms for FO for all terrains. Detection success was over 98%. These results provide preliminary evidence supporting the use of the gyroscope for gait event detection on inclines as well as level walking. PMID- 22219683 TI - Real-time plasma process condition sensing and abnormal process detection. AB - The plasma process is often used in the fabrication of semiconductor wafers. However, due to the lack of real-time etching control, this may result in some unacceptable process performances and thus leads to significant waste and lower wafer yield. In order to maximize the product wafer yield, a timely and accurately process fault or abnormal detection in a plasma reactor is needed. Optical emission spectroscopy (OES) is one of the most frequently used metrologies in in-situ process monitoring. Even though OES has the advantage of non-invasiveness, it is required to provide a huge amount of information. As a result, the data analysis of OES becomes a big challenge. To accomplish real-time detection, this work employed the sigma matching method technique, which is the time series of OES full spectrum intensity. First, the response model of a healthy plasma spectrum was developed. Then, we defined a matching rate as an indictor for comparing the difference between the tested wafers response and the health sigma model. The experimental results showed that this proposal method can detect process faults in real-time, even in plasma etching tools. PMID- 22219685 TI - Enzymatic determination of diglyceride using an iridium nano-particle based single use, disposable biosensor. AB - A single use, disposable iridium-nano particle contained biosensor had been developed for the determination of diglyceride (DG). In this study hydrogen peroxide, formed through the enzymatic breakdown of DG via lipase, glycerol kinase and glycerol 3-phosphate oxidase, was electrochemically oxidized at an applied potential of +0.5 V versus the Ag/AgCl reference electrode. The oxidation current was then used to quantify the diglyceride concentration. Optimum enzyme concentrations and the surfactant loading used were established for successful sensor response. Good linear performance was observed over a DG concentration range of 0 to 25 MUM in phosphate buffer and bovine serum media. PMID- 22219684 TI - Windows on the human body--in vivo high-field magnetic resonance research and applications in medicine and psychology. AB - Analogous to the evolution of biological sensor-systems, the progress in "medical sensor-systems", i.e., diagnostic procedures, is paradigmatically described. Outstanding highlights of this progress are magnetic resonance imaging (MRI) and spectroscopy (MRS), which enable non-invasive, in vivo acquisition of morphological, functional, and metabolic information from the human body with unsurpassed quality. Recent achievements in high and ultra-high field MR (at 3 and 7 Tesla) are described, and representative research applications in Medicine and Psychology in Austria are discussed. Finally, an overview of current and prospective research in multi-modal imaging, potential clinical applications, as well as current limitations and challenges is given. PMID- 22219686 TI - Sensor systems for prognostics and health management. AB - Prognostics and health management (PHM) is an enabling discipline consisting of technologies and methods to assess the reliability of a product in its actual life cycle conditions to determine the advent of failure and mitigate system risk. Sensor systems are needed for PHM to monitor environmental, operational, and performance-related characteristics. The gathered data can be analyzed to assess product health and predict remaining life. In this paper, the considerations for sensor system selection for PHM applications, including the parameters to be measured, the performance needs, the electrical and physical attributes, reliability, and cost of the sensor system, are discussed. The state of-the-art sensor systems for PHM and the emerging trends in technologies of sensor systems for PHM are presented. PMID- 22219688 TI - Power consumption analysis of operating systems for wireless sensor networks. AB - In this paper four wireless sensor network operating systems are compared in terms of power consumption. The analysis takes into account the most common operating systems--TinyOS v1.0, TinyOS v2.0, Mantis and Contiki--running on Tmote Sky and MICAz devices. With the objective of ensuring a fair evaluation, a benchmark composed of four applications has been developed, covering the most typical tasks that a Wireless Sensor Network performs. The results show the instant and average current consumption of the devices during the execution of these applications. The experimental measurements provide a good insight into the power mode in which the device components are running at every moment, and they can be used to compare the performance of different operating systems executing the same tasks. PMID- 22219687 TI - Label free detection of CD4+ and CD8+ T cells using the optofluidic ring resonator. AB - We have demonstrated label free detection of CD4+ and CD8+ T-Lymphocyte whole cells and CD4+ T-Lymphocyte cell lysis using the optofluidic ring resonator (OFRR) sensor. The OFRR sensing platform incorporates microfluidics and photonics in a setup that utilizes small sample volume and achieves a fast detection time. In this work, white blood cells were isolated from healthy blood and the concentrations were adjusted to match T-Lymphocyte levels of individuals infected with HIV. Detection was accomplished by immobilizing CD4 and CD8 antibodies on the inner surface of the OFRR. Sensing results show excellent detection of CD4+ and CD8+ T-Lymphocyte cells at medically significant concentrations with a detection time of approximately 30 minutes. This work will lead to a rapid and low-cost sensing device that can provide a CD4 and CD8 count as a measure of HIV progression. PMID- 22219689 TI - Using automated point dendrometers to analyze tropical treeline stem growth at Nevado de Colima, Mexico. AB - The relationship between wood growth and environmental variability at the tropical treeline of North America was investigated using automated, solar powered sensors (a meteorological station and two dendrometer clusters) installed on Nevado de Colima, Mexico (19 degrees 35' N, 103 degrees 37' W, 3,760 m a.s.l.). Pure stands of Pinus hartwegii Lindl. (Mexican mountain pine) were targeted because of their suitability for tree-ring analysis in low-latitude, high-elevation, North American Monsoon environments. Stem size and hydroclimatic variables recorded at half-hour intervals were summarized on a daily timescale. Power outages, insect outbreaks, and sensor failures limited the analysis to non consecutive months during 2001-2003 at one dendrometer site, and during 2002-2005 at the other. Combined data from the two sites showed that maximum radial growth rates occur in late spring (May), as soil temperature increases, and incoming short-wave radiation reaches its highest values. Early season (April-May) radial increment correlated directly with temperature, especially of the soil, and with solar radiation. Stem expansion at the start of the summer monsoon (June-July) was mostly influenced by moisture, and revealed a drought signal, while late season relationships were more varied. PMID- 22219690 TI - Microfabricated thin film impedance sensor & AC impedance measurements. AB - Thin film microfabrication technique was employed to fabricate a platinum based parallel-electrode structured impedance sensor. Electrochemical impedance spectroscopy (EIS) and equivalent circuit analysis of the small amplitude (+/-5 mV) AC impedance measurements (frequency range: 1 MHz to 0.1 Hz) at ambient temperature were carried out. Testing media include 0.001 M, 0.01 M, 0.1 M NaCl and KCl solutions, and alumina (~3 MUm) and sand (~300 MUm) particulate layers saturated with NaCl solutions with the thicknesses ranging from 0.6 mm to 8 mm in a testing cell, and the results were used to assess the effect of the thickness of the particulate layer on the conductivity of the testing solution. The calculated resistances were approximately around 20 MOmega, 4 MOmega, and 0.5 MOmega for 0.001 M, 0.01 M, and 0.1 M NaCl solutions, respectively. The presence of the sand particulates increased the impedance dramatically (6 times and 3 times for 0.001 M and 0.1 M NaCl solutions, respectively). A cell constant methodology was also developed to assess the measurement of the bulk conductivity of the electrolyte solution. The cell constant ranged from 1.2 to 0.8 and it decreased with the increase of the solution thickness. PMID- 22219691 TI - Development of a quartz crystal microbalance biosensor with aptamers as bio recognition element. AB - The ultimate goal in any biosensor development project is its use for actual sample detection. Recently, there has been an interest in biosensors with aptamers as bio-recognition elements, but reported examples all deal with standards, not human serum. In order to verify the differences of aptamer-based biosensor and antibody-based biosensor in clinical detection, a comparison of the performance of aptamer-based and antibody-based quartz crystal microbalance (QCM) biosensors for the detection of immunoglobulin E (IgE) in human serum was carried out. Aptamers (or antibodies) specific to IgE were immobilized on the gold surface of a quartz crystal. The frequency shifts of the QCM were measured. The linear range with the antibody (10-240 MUg/L) compared to that of the aptamer (2.5-200 MUg/L), but a lower detection limit could be observed in the aptamer based biosensor. The reproducibility of the two biosensors was comparable. The aptamers were equivalent or superior to antibodies in terms of specificity and sensitivity. In addition, the aptamer receptors could tolerate repeated affine layer regeneration after ligand binding and recycling of the biosensor with little loss of sensitivity. When stored for three weeks, the frequency shifts of the aptamer-coated crystals were all greater than 90% of those on the response at the first day. PMID- 22219692 TI - An RFID-based intelligent vehicle speed controller using active traffic signals. AB - These days, mass-produced vehicles benefit from research on Intelligent Transportation System (ITS). One prime example of ITS is vehicle Cruise Control (CC), which allows it to maintain a pre-defined reference speed, to economize on fuel or energy consumption, to avoid speeding fines, or to focus all of the driver's attention on the steering of the vehicle. However, achieving efficient Cruise Control is not easy in roads or urban streets where sudden changes of the speed limit can happen, due to the presence of unexpected obstacles or maintenance work, causing, in inattentive drivers, traffic accidents. In this communication we present a new Infrastructure to Vehicles (I2V) communication and control system for intelligent speed control, which is based upon Radio Frequency Identification (RFID) technology for identification of traffic signals on the road, and high accuracy vehicle speed measurement with a Hall effect-based sensor. A fuzzy logic controller, based on sensor fusion of the information provided by the I2V infrastructure, allows the efficient adaptation of the speed of the vehicle to the circumstances of the road. The performance of the system is checked empirically, with promising results. PMID- 22219693 TI - Liquid-phase packaging of a glucose oxidase solution with parylene direct encapsulation and an ultraviolet curing adhesive cover for glucose sensors. AB - We have developed a package for disposable glucose sensor chips using Parylene encapsulation of a glucose oxidase solution in the liquid phase and a cover structure made of an ultraviolet (UV) curable adhesive. Parylene was directly deposited onto a small volume (1 MUL) of glucose oxidase solution through chemical vapor deposition. The cover and reaction chamber were constructed on Parylene film using a UV-curable adhesive and photolithography. The package was processed at room temperature to avoid denaturation of the glucose oxidase. The glucose oxidase solution was encapsulated and unsealed. Glucose sensing was demonstrated using standard amperometric detection at glucose concentrations between 0.1 and 100 mM, which covers the glucose concentration range of diabetic patients. Our proposed Parylene encapsulation and UV-adhesive cover form a liquid phase glucose-oxidase package that has the advantages of room temperature processing and direct liquid encapsulation of a small volume solution without use of conventional solidifying chemicals. PMID- 22219694 TI - GPS-free localization algorithm for wireless sensor networks. AB - Localization is one of the most fundamental problems in wireless sensor networks, since the locations of the sensor nodes are critical to both network operations and most application level tasks. A GPS-free localization scheme for wireless sensor networks is presented in this paper. First, we develop a standardized clustering-based approach for the local coordinate system formation wherein a multiplication factor is introduced to regulate the number of master and slave nodes and the degree of connectivity among master nodes. Second, using homogeneous coordinates, we derive a transformation matrix between two Cartesian coordinate systems to efficiently merge them into a global coordinate system and effectively overcome the flip ambiguity problem. The algorithm operates asynchronously without a centralized controller; and does not require that the location of the sensors be known a priori. A set of parameter-setting guidelines for the proposed algorithm is derived based on a probability model and the energy requirements are also investigated. A simulation analysis on a specific numerical example is conducted to validate the mathematical analytical results. We also compare the performance of the proposed algorithm under a variety multiplication factor, node density and node communication radius scenario. Experiments show that our algorithm outperforms existing mechanisms in terms of accuracy and convergence time. PMID- 22219696 TI - Application of a hybrid 3D-2D laser scanning system to the characterization of slate slabs. AB - Dimensional control based on 3D laser scanning techniques is widely used in practice. We describe the application of a hybrid 3D-2D laser scanning system to the characterization of slate slabs with structural defects that are difficult for the human eye to characterize objectively. Our study is based on automating the process using a 3D laser scanner and a 2D camera. Our results demonstrate that the application of this hybrid system optimally characterizes slate slabs in terms of the defects described by the Spanish UNE-EN 12326-1 standard. PMID- 22219695 TI - Recent applications of fluorescence recovery after photobleaching (FRAP) to membrane bio-macromolecules. AB - This review examines some recent applications of fluorescence recovery after photobleaching (FRAP) to biopolymers, while mainly focusing on membrane protein studies. Initially, we discuss the lateral diffusion of membrane proteins, as measured by FRAP. Then, we talk about the use of FRAP to probe interactions between membrane proteins by obtaining fundamental information such as geometry and stoichiometry of the interacting complex. Afterwards, we discuss some applications of FRAP at the cellular level as well as the level of organisms. We conclude by comparing diffusion coefficients obtained by FRAP and several other alternative methods. PMID- 22219697 TI - Exploring infrared sensoring for real time welding defects monitoring in GTAW. AB - This paper presents an evaluation of an infrared sensor for monitoring the welding pool temperature in a Gas Tungsten Arc Welding (GTAW) process. The purpose of the study is to develop a real time system control. It is known that the arc welding pool temperature is related to the weld penetration depth; therefore, by monitoring the temperature, the arc pool temperature and penetration depth are also monitored. Various experiments were performed; in some of them the current was varied and the temperature changes were registered, in others, defects were induced throughout the path of the weld bead for a fixed current. These simulated defects resulted in abrupt changes in the average temperature values, thus providing an indication of the presence of a defect. The data has been registered with an acquisition card. To identify defects in the samples under infrared emissions, the timing series were analyzed through graphics and statistic methods. The selection of this technique demonstrates the potential for infrared emission as a welding monitoring parameter sensor. PMID- 22219698 TI - A fiber optic Doppler sensor and its application in debonding detection for composite structures. AB - Debonding is one of the most important damage forms in fiber-reinforced composite structures. This work was devoted to the debonding damage detection of lap splice joints in carbon fiber reinforced plastic (CFRP) structures, which is based on guided ultrasonic wave signals captured by using fiber optic Doppler (FOD) sensor with spiral shape. Interferometers based on two types of laser sources, namely the He-Ne laser and the infrared semiconductor laser, are proposed and compared in this study for the purpose of measuring Doppler frequency shift of the FOD sensor. Locations of the FOD sensors are optimized based on mechanical characteristics of lap splice joint. The FOD sensors are subsequently used to detect the guided ultrasonic waves propagating in the CFRP structures. By taking advantage of signal processing approaches, features of the guided wave signals can be revealed. The results demonstrate that debonding in the lap splice joint results in arrival time delay of the first package in the guided wave signals, which can be the characteristic for debonding damage inspection and damage extent estimation. PMID- 22219699 TI - Wavelet analysis for wind fields estimation. AB - Wind field analysis from synthetic aperture radar images allows the estimation of wind direction and speed based on image descriptors. In this paper, we propose a framework to automate wind direction retrieval based on wavelet decomposition associated with spectral processing. We extend existing undecimated wavelet transform approaches, by including a trous with B(3) spline scaling function, in addition to other wavelet bases as Gabor and Mexican-hat. The purpose is to extract more reliable directional information, when wind speed values range from 5 to 10 ms(-1). Using C-band empirical models, associated with the estimated directional information, we calculate local wind speed values and compare our results with QuikSCAT scatterometer data. The proposed approach has potential application in the evaluation of oil spills and wind farms. PMID- 22219700 TI - Fast scene recognition and camera relocalisation for wide area augmented reality systems. AB - This paper focuses on online scene learning and fast camera relocalisation which are two key problems currently limiting the performance of wide area augmented reality systems. Firstly, we propose to use adaptive random trees to deal with the online scene learning problem. The algorithm can provide more accurate recognition rates than traditional methods, especially with large scale workspaces. Secondly, we use the enhanced PROSAC algorithm to obtain a fast camera relocalisation method. Compared with traditional algorithms, our method can significantly reduce the computation complexity, which facilitates to a large degree the process of online camera relocalisation. Finally, we implement our algorithms in a multithreaded manner by using a parallel-computing scheme. Camera tracking, scene mapping, scene learning and relocalisation are separated into four threads by using multi-CPU hardware architecture. While providing real-time tracking performance, the resulting system also possesses the ability to track multiple maps simultaneously. Some experiments have been conducted to demonstrate the validity of our methods. PMID- 22219701 TI - A new collaborative knowledge-based approach for wireless sensor networks. AB - This work presents a new approach for collaboration among sensors in Wireless Sensor Networks. These networks are composed of a large number of sensor nodes with constrained resources: limited computational capability, memory, power sources, etc. Nowadays, there is a growing interest in the integration of Soft Computing technologies into Wireless Sensor Networks. However, little attention has been paid to integrating Fuzzy Rule-Based Systems into collaborative Wireless Sensor Networks. The objective of this work is to design a collaborative knowledge-based network, in which each sensor executes an adapted Fuzzy Rule Based System, which presents significant advantages such as: experts can define interpretable knowledge with uncertainty and imprecision, collaborative knowledge can be separated from control or modeling knowledge and the collaborative approach may support neighbor sensor failures and communication errors. As a real world application of this approach, we demonstrate a collaborative modeling system for pests, in which an alarm about the development of olive tree fly is inferred. The results show that knowledge-based sensors are suitable for a wide range of applications and that the behavior of a knowledge-based sensor may be modified by inferences and knowledge of neighbor sensors in order to obtain a more accurate and reliable output. PMID- 22219702 TI - Arrhythmia ECG noise reduction by ensemble empirical mode decomposition. AB - A novel noise filtering algorithm based on ensemble empirical mode decomposition (EEMD) is proposed to remove artifacts in electrocardiogram (ECG) traces. Three noise patterns with different power--50 Hz, EMG, and base line wander--were embedded into simulated and real ECG signals. Traditional IIR filter, Wiener filter, empirical mode decomposition (EMD) and EEMD were used to compare filtering performance. Mean square error between clean and filtered ECGs was used as filtering performance indexes. Results showed that high noise reduction is the major advantage of the EEMD based filter, especially on arrhythmia ECGs. PMID- 22219703 TI - A compact tunable diode laser absorption spectrometer to monitor CO2 at 2.7 MUm wavelength in hypersonic flows. AB - Since the beginning of the Mars planet exploration, the characterization of carbon dioxide hypersonic flows to simulate a spaceship's Mars atmosphere entry conditions has been an important issue. We have developed a Tunable Diode Laser Absorption Spectrometer with a new room-temperature operating antimony-based distributed feedback laser (DFB) diode laser to characterize the velocity, the temperature and the density of such flows. This instrument has been tested during two measurement campaigns in a free piston tunnel cold hypersonic facility and in a high enthalpy arc jet wind tunnel. These tests also demonstrate the feasibility of mid-infrared fiber optics coupling of the spectrometer to a wind tunnel for integrated or local flow characterization with an optical probe placed in the flow. PMID- 22219704 TI - Background subtraction approach based on independent component analysis. AB - In this work, a new approach to background subtraction based on independent component analysis is presented. This approach assumes that background and foreground information are mixed in a given sequence of images. Then, foreground and background components are identified, if their probability density functions are separable from a mixed space. Afterwards, the components estimation process consists in calculating an unmixed matrix. The estimation of an unmixed matrix is based on a fast ICA algorithm, which is estimated as a Newton-Raphson maximization approach. Next, the motion components are represented by the mid significant eigenvalues from the unmixed matrix. Finally, the results show the approach capabilities to detect efficiently motion in outdoors and indoors scenarios. The results show that the approach is robust to luminance conditions changes at scene. PMID- 22219705 TI - Development of an ion sensitive field effect transistor based urea biosensor with solid state reference systems. AB - Ion sensitive field-effect transistor (ISFET) based urease biosensors with solid state reference systems for single-ended and two-ended differential readout electronics were investigated. The sensing membranes of the biosensors were fabricated with urease immobilized in a conducting polymer-based matrix. The responses of 12.9~198.1 mV for the urea concentrations of 8~240 mg/dL reveal that the activity of the enzyme was not significantly decreased. Biosensors combined with solid state reference systems were fabricated, and the evaluation results demonstrated the feasibility of miniaturization. For the differential system, the optimal transconductance match for biosensor and reference field-effect transistors (REFET) pair was determined through the modification of the membranes of the REFETs and enzyme field-effect transistors (EnFETs). The results show that the transconductance curve of polymer based REFET can match with that of the EnFET by adjusting the photoresist/NafionTM ratio. The match of the transconductance curves for the differential pairs provides a wide dynamic operating measurement range. Accordingly, the miniaturized quasi-reference electrode (QRE)/REFET/EnFET combination with differential arrangement achieved similar urea response curves as those measured by a conventional large sized discrete sensor. PMID- 22219706 TI - An emergency-adaptive routing scheme for wireless sensor networks for building fire hazard monitoring. AB - Fire hazard monitoring and evacuation for building environments is a novel application area for the deployment of wireless sensor networks. In this context, adaptive routing is essential in order to ensure safe and timely data delivery in building evacuation and fire fighting resource applications. Existing routing mechanisms for wireless sensor networks are not well suited for building fires, especially as they do not consider critical and dynamic network scenarios. In this paper, an emergency-adaptive, real-time and robust routing protocol is presented for emergency situations such as building fire hazard applications. The protocol adapts to handle dynamic emergency scenarios and works well with the routing hole problem. Theoretical analysis and simulation results indicate that our protocol provides a real-time routing mechanism that is well suited for dynamic emergency scenarios in building fires when compared with other related work. PMID- 22219707 TI - Review on the modeling of electrostatic MEMS. AB - Electrostatic-driven microelectromechanical systems devices, in most cases, consist of couplings of such energy domains as electromechanics, optical electricity, thermoelectricity, and electromagnetism. Their nonlinear working state makes their analysis complex and complicated. This article introduces the physical model of pull-in voltage, dynamic characteristic analysis, air damping effect, reliability, numerical modeling method, and application of electrostatic driven MEMS devices. PMID- 22219708 TI - SirT1--a sensor for monitoring self-renewal and aging process in retinal stem cells. AB - Retinal stem cells bear potency of proliferation, self-renewal, and differentiation into many retinal cells. Utilizing appropriate sensors one can effectively detect the self-renewal and aging process abilities. Silencing information regulator (SirT1), a member of the sirtuin family, is a NAD-dependent histone deacetylase and an essential mediator for longevity in normal cells by calorie restriction. We firstly investigate the SirT1 mRNA expression in retinal stem cells from rats and 19 human eyes of different ages. Results revealed that SirT1 expression was significantly decreased in in vivo aged eyes, associated with poor self-renewal abilities. Additionally, SirT1 mRNA levels were dose dependently increased in resveratrol- treated retinal stem cells. The expression of SirT1 on oxidative stress-induced damage was significantly decreased, negatively correlated with the level of intracellular reactive oxygen species production. Treatment with resveratrol could effectively further reduce oxidative stress induced by H(2)O(2) treatment in retinal stem cells. Importantly, the anti oxidant effects of resveratrol in H(2)O(2)-treated retinal stem cells were significantly abolished by knockdown of SirT1 expression (sh-SirT1). SirT1 expression provides a feasible sensor in assessing self-renewal and aging process in retinal stem cells. Resveratrol can prevent reactive oxygen species-induced damages via increased retinal SirT1 expression. PMID- 22219710 TI - A nitrite biosensor based on co-immobilization of nitrite reductase and viologen modified chitosan on a glassy carbon electrode. AB - An electrochemical nitrite biosensor based on co-immobilization of copper containing nitrite reductase (Cu-NiR, from Rhodopseudomonas sphaeroides forma sp. denitrificans) and viologen-modified chitosan (CHIT-V) on a glassy carbon electrode (GCE) is presented. Electron transfer (ET) between a conventional GCE and immobilized Cu-NiR was mediated by the co-immobilized CHIT-V. Redox-active viologen was covalently linked to a chitosan backbone, and the thus produced CHIT V was co-immobilized with Cu-NiR on the GCE surface by drop-coating of hydrophilic polyurethane (HPU). The electrode responded to nitrite with a limit of detection (LOD) of 40 nM (S/N = 3). The sensitivity, linear response range, and response time (t(90%)) were 14.9 nA/MUM, 0.04-11 MUM (r(2) = 0.999) and 15 s, respectively. The corresponding Lineweaver-Burk plot showed that the apparent Michaelis-Menten constant (K(M) (app)) was 65 MUM. Storage stability of the biosensor (retaining 80% of initial activity) was 65 days under ambient air and room temperature storage conditions. Reproducibility of the sensor showed a relative standard deviation (RSD) of 2.8% (n = 5) for detection of 1 MUM of nitrite. An interference study showed that anions commonly found in water samples such as chlorate, chloride, sulfate and sulfite did not interfere with the nitrite detection. However, nitrate interfered with a relative sensitivity of 64% and this interference effect was due to the intrinsic character of the NiR employed in this study. PMID- 22219711 TI - Optical sensors based on whispering gallery modes in fluorescent microbeads: response to specific interactions. AB - Whispering gallery modes (WGMs) in surface-fixated fluorescent polystyrene microbeads are studied in view of their capability of sensing the formation of biochemical adsorption layers on their outer surface with the well-established biotin-streptavidin specific binding as the model system. Three different methods for analysis of the observed shifts in the WGM wavelength positions are applied and used to quantify the adsorbed mass densities, which are then compared with the results of a comparative surface plasmon resonance (SPR) study. PMID- 22219712 TI - Delayed intracerebral hemorrhage secondary to ventriculoperitoneal shunt: two case reports and a literature review. AB - Ventriculoperitoneal (VP) shunt has become a popular operation to achieve cerebrospinal fluid (CSF) diversion, but is associated with many complications. Postoperative delayed intracerebral hemorrhage is a kind of rare but severe event, which has not thus far been reported in retrospective case analyses. Here we present two cases of delayed intracerebral hemorrhage, along the path of the ventricular catheter, which occurred on postoperative days 3 and 5. We also provide a literature review regarding this rare complication. PMID- 22219709 TI - Glucose signaling-mediated coordination of cell growth and cell cycle in Saccharomyces cerevisiae. AB - Besides being the favorite carbon and energy source for the budding yeast Sacchromyces cerevisiae, glucose can act as a signaling molecule to regulate multiple aspects of yeast physiology. Yeast cells have evolved several mechanisms for monitoring the level of glucose in their habitat and respond quickly to frequent changes in the sugar availability in the environment: the cAMP/PKA pathways (with its two branches comprising Ras and the Gpr1/Gpa2 module), the Rgt2/Snf3-Rgt1 pathway and the main repression pathway involving the kinase Snf1. The cAMP/PKA pathway plays the prominent role in responding to changes in glucose availability and initiating the signaling processes that promote cell growth and division. Snf1 (the yeast homologous to mammalian AMP-activated protein kinase) is primarily required for the adaptation of yeast cell to glucose limitation and for growth on alternative carbon source, but it is also involved in the cellular response to various environmental stresses. The Rgt2/Snf3-Rgt1 pathway regulates the expression of genes required for glucose uptake. Many interconnections exist between the diverse glucose sensing systems, which enables yeast cells to fine tune cell growth, cell cycle and their coordination in response to nutritional changes. PMID- 22219713 TI - A monitoring network on acidification in Flanders, Belgium. AB - This paper presents the monitoring of acid deposition in Flanders (Belgium) and the change of the measurement objectives, recently towards measurement of ammonia. The monitoring network on acidification has provided results for 10 years. Analysis of acidifying pollutants between 2005 and 2010 shows decreasing concentrations throughout the whole period. NO(2) has no significant trend, although the average total deposition in 2010 (2027 Eq/ha.y) is still higher than the objectives of the Flemish environmental policy plan for 2015 (1800 Eq/ha.y). Given the contribution of ammonia, the Flemish Environmental Agency has the aim to develop a policy-oriented monitoring network on ammonia. Studies on this subject have already been extensively conducted. PMID- 22219714 TI - New role for L-arginine in regulation of inducible nitric-oxide-synthase-derived superoxide anion production in raw 264.7 macrophages. AB - Dietary supplementation with L-arginine was shown to improve immune responses in various inflammatory models. However, the molecular mechanisms underlying L arginine effects on immune cells remain unrecognized. Herein, we tested the hypothesis that a limitation of L-arginine could lead to the uncoupled state of murine macrophage inducible nitric oxide synthase and, therefore, increase inducible nitric-oxide-synthase-derived superoxide anion formation. Importantly, we demonstrated that L-arginine dose- and time dependently potentiated superoxide anion production in bacterial endotoxin-stimulated macrophages, although it did not influence NADPH oxidase expression and activity. Detailed analysis of macrophage activation showed the time dependence between LPS-induced iNOS expression and increased O(2)(?-) formation. Moreover, downregulation of macrophage iNOS expression, as well as the inhibition of iNOS activity by NOS inhibitors, unveiled an important role of this enzyme in controlling O(2)(?-) and peroxynitrite formation during macrophage stimulation. In conclusion, our data demonstrated that simultaneous induction of NADPH oxidase, together with the iNOS enzyme, can result in the uncoupled state of iNOS resulting in the production of functionally important levels of O(2)(?-) soon after macrophage activation with LPS. Moreover, we demonstrated, for the first time that increased concentrations of L-arginine further potentiate iNOS-dependent O(2) (?-) formation in inflammatory macrophages. PMID- 22219715 TI - Integrating bioinformatics tools to handle glycosylation. PMID- 22219716 TI - Of toasters and molecular ticker tapes. AB - Experiments in systems neuroscience can be seen as consisting of three steps: (1) selecting the signals we are interested in, (2) probing the system with carefully chosen stimuli, and (3) getting data out of the brain. Here I discuss how emerging techniques in molecular biology are starting to improve these three steps. To estimate its future impact on experimental neuroscience, I will stress the analogy of ongoing progress with that of microprocessor production techniques. These techniques have allowed computers to simplify countless problems; because they are easier to use than mechanical timers, they are even built into toasters. Molecular biology may advance even faster than computer speeds and has made immense progress in understanding and designing molecules. These advancements may in turn produce impressive improvements to each of the three steps, ultimately shifting the bottleneck from obtaining data to interpreting it. PMID- 22219717 TI - Probabilistic inference in general graphical models through sampling in stochastic networks of spiking neurons. AB - An important open problem of computational neuroscience is the generic organization of computations in networks of neurons in the brain. We show here through rigorous theoretical analysis that inherent stochastic features of spiking neurons, in combination with simple nonlinear computational operations in specific network motifs and dendritic arbors, enable networks of spiking neurons to carry out probabilistic inference through sampling in general graphical models. In particular, it enables them to carry out probabilistic inference in Bayesian networks with converging arrows ("explaining away") and with undirected loops, that occur in many real-world tasks. Ubiquitous stochastic features of networks of spiking neurons, such as trial-to-trial variability and spontaneous activity, are necessary ingredients of the underlying computational organization. We demonstrate through computer simulations that this approach can be scaled up to neural emulations of probabilistic inference in fairly large graphical models, yielding some of the most complex computations that have been carried out so far in networks of spiking neurons. PMID- 22219718 TI - Recovering protein-protein and domain-domain interactions from aggregation of IP MS proteomics of coregulator complexes. AB - Coregulator proteins (CoRegs) are part of multi-protein complexes that transiently assemble with transcription factors and chromatin modifiers to regulate gene expression. In this study we analyzed data from 3,290 immuno precipitations (IP) followed by mass spectrometry (MS) applied to human cell lines aimed at identifying CoRegs complexes. Using the semi-quantitative spectral counts, we scored binary protein-protein and domain-domain associations with several equations. Unlike previous applications, our methods scored prey-prey protein-protein interactions regardless of the baits used. We also predicted domain-domain interactions underlying predicted protein-protein interactions. The quality of predicted protein-protein and domain-domain interactions was evaluated using known binary interactions from the literature, whereas one protein-protein interaction, between STRN and CTTNBP2NL, was validated experimentally; and one domain-domain interaction, between the HEAT domain of PPP2R1A and the Pkinase domain of STK25, was validated using molecular docking simulations. The scoring schemes presented here recovered known, and predicted many new, complexes, protein-protein, and domain-domain interactions. The networks that resulted from the predictions are provided as a web-based interactive application at http://maayanlab.net/HT-IP-MS-2-PPI-DDI/. PMID- 22219719 TI - Spatial guilds in the Serengeti food web revealed by a Bayesian group model. AB - Food webs, networks of feeding relationships in an ecosystem, provide fundamental insights into mechanisms that determine ecosystem stability and persistence. A standard approach in food-web analysis, and network analysis in general, has been to identify compartments, or modules, defined by many links within compartments and few links between them. This approach can identify large habitat boundaries in the network but may fail to identify other important structures. Empirical analyses of food webs have been further limited by low-resolution data for primary producers. In this paper, we present a Bayesian computational method for identifying group structure using a flexible definition that can describe both functional trophic roles and standard compartments. We apply this method to a newly compiled plant-mammal food web from the Serengeti ecosystem that includes high taxonomic resolution at the plant level, allowing a simultaneous examination of the signature of both habitat and trophic roles in network structure. We find that groups at the plant level reflect habitat structure, coupled at higher trophic levels by groups of herbivores, which are in turn coupled by carnivore groups. Thus the group structure of the Serengeti web represents a mixture of trophic guild structure and spatial pattern, in contrast to the standard compartments typically identified. The network topology supports recent ideas on spatial coupling and energy channels in ecosystems that have been proposed as important for persistence. Furthermore, our Bayesian approach provides a powerful, flexible framework for the study of network structure, and we believe it will prove instrumental in a variety of biological contexts. PMID- 22219721 TI - Prediction of drug combinations by integrating molecular and pharmacological data. AB - Combinatorial therapy is a promising strategy for combating complex disorders due to improved efficacy and reduced side effects. However, screening new drug combinations exhaustively is impractical considering all possible combinations between drugs. Here, we present a novel computational approach to predict drug combinations by integrating molecular and pharmacological data. Specifically, drugs are represented by a set of their properties, such as their targets or indications. By integrating several of these features, we show that feature patterns enriched in approved drug combinations are not only predictive for new drug combinations but also provide insights into mechanisms underlying combinatorial therapy. Further analysis confirmed that among our top ranked predictions of effective combinations, 69% are supported by literature, while the others represent novel potential drug combinations. We believe that our proposed approach can help to limit the search space of drug combinations and provide a new way to effectively utilize existing drugs for new purposes. PMID- 22219720 TI - Evidence for sequential and increasing activation of replication origins along replication timing gradients in the human genome. AB - Genome-wide replication timing studies have suggested that mammalian chromosomes consist of megabase-scale domains of coordinated origin firing separated by large originless transition regions. Here, we report a quantitative genome-wide analysis of DNA replication kinetics in several human cell types that contradicts this view. DNA combing in HeLa cells sorted into four temporal compartments of S phase shows that replication origins are spaced at 40 kb intervals and fire as small clusters whose synchrony increases during S phase and that replication fork velocity (mean 0.7 kb/min, maximum 2.0 kb/min) remains constant and narrowly distributed through S phase. However, multi-scale analysis of a genome-wide replication timing profile shows a broad distribution of replication timing gradients with practically no regions larger than 100 kb replicating at less than 2 kb/min. Therefore, HeLa cells lack large regions of unidirectional fork progression. Temporal transition regions are replicated by sequential activation of origins at a rate that increases during S phase and replication timing gradients are set by the delay and the spacing between successive origin firings rather than by the velocity of single forks. Activation of internal origins in a specific temporal transition region is directly demonstrated by DNA combing of the IGH locus in HeLa cells. Analysis of published origin maps in HeLa cells and published replication timing and DNA combing data in several other cell types corroborate these findings, with the interesting exception of embryonic stem cells where regions of unidirectional fork progression seem more abundant. These results can be explained if origins fire independently of each other but under the control of long-range chromatin structure, or if replication forks progressing from early origins stimulate initiation in nearby unreplicated DNA. These findings shed a new light on the replication timing program of mammalian genomes and provide a general model for their replication kinetics. PMID- 22219723 TI - Using multiple microenvironments to find similar ligand-binding sites: application to kinase inhibitor binding. AB - The recognition of cryptic small-molecular binding sites in protein structures is important for understanding off-target side effects and for recognizing potential new indications for existing drugs. Current methods focus on the geometry and detailed chemical interactions within putative binding pockets, but may not recognize distant similarities where dynamics or modified interactions allow one ligand to bind apparently divergent binding pockets. In this paper, we introduce an algorithm that seeks similar microenvironments within two binding sites, and assesses overall binding site similarity by the presence of multiple shared microenvironments. The method has relatively weak geometric requirements (to allow for conformational change or dynamics in both the ligand and the pocket) and uses multiple biophysical and biochemical measures to characterize the microenvironments (to allow for diverse modes of ligand binding). We term the algorithm PocketFEATURE, since it focuses on pockets using the FEATURE system for characterizing microenvironments. We validate PocketFEATURE first by showing that it can better discriminate sites that bind similar ligands from those that do not, and by showing that we can recognize FAD-binding sites on a proteome scale with Area Under the Curve (AUC) of 92%. We then apply PocketFEATURE to evolutionarily distant kinases, for which the method recognizes several proven distant relationships, and predicts unexpected shared ligand binding. Using experimental data from ChEMBL and Ambit, we show that at high significance level, 40 kinase pairs are predicted to share ligands. Some of these pairs offer new opportunities for inhibiting two proteins in a single pathway. PMID- 22219722 TI - The rates of protein synthesis and degradation account for the differential response of neurons to spaced and massed training protocols. AB - The sensory-motor neuron synapse of Aplysia is an excellent model system for investigating the biochemical changes underlying memory formation. In this system, training that is separated by rest periods (spaced training) leads to persistent changes in synaptic strength that depend on biochemical pathways that are different from those that occur when the training lacks rest periods (massed training). Recently, we have shown that in isolated sensory neurons, applications of serotonin, the neurotransmitter implicated in inducing these synaptic changes during memory formation, lead to desensitization of the PKC Apl II response, in a manner that depends on the method of application (spaced versus massed). Here, we develop a mathematical model of this response in order to gain insight into how neurons sense these different training protocols. The model was developed incrementally, and each component was experimentally validated, leading to two novel findings: First, the increased desensitization due to PKA-mediated heterologous desensitization is coupled to a faster recovery than the homologous desensitization that occurs in the absence of PKA activity. Second, the model suggests that increased spacing leads to greater desensitization due to the short half-life of a hypothetical protein, whose production prevents homologous desensitization. Thus, we predict that the effects of differential spacing are largely driven by the rates of production and degradation of proteins. This prediction suggests a powerful mechanism by which information about time is incorporated into neuronal processing. PMID- 22219724 TI - Radial and spiral stream formation in Proteus mirabilis colonies. AB - The enteric bacterium Proteus mirabilis, which is a pathogen that forms biofilms in vivo, can swarm over hard surfaces and form a variety of spatial patterns in colonies. Colony formation involves two distinct cell types: swarmer cells that dominate near the surface and the leading edge, and swimmer cells that prefer a less viscous medium, but the mechanisms underlying pattern formation are not understood. New experimental investigations reported here show that swimmer cells in the center of the colony stream inward toward the inoculation site and in the process form many complex patterns, including radial and spiral streams, in addition to previously-reported concentric rings. These new observations suggest that swimmers are motile and that indirect interactions between them are essential in the pattern formation. To explain these observations we develop a hybrid model comprising cell-based and continuum components that incorporates a chemotactic response of swimmers to a chemical they produce. The model predicts that formation of radial streams can be explained as the modulation of the local attractant concentration by the cells, and that the chirality of the spiral streams results from a swimming bias of the cells near the surface of the substrate. The spatial patterns generated from the model are in qualitative agreement with the experimental observations. PMID- 22219726 TI - Penta-terbium lithium tris-tannide, Tb(5)LiSn(3). AB - The new ternary phase penta-terbium lithium tris-tannide, Tb(5)LiSn(3), crystallizes in the hexa-gonal Hf(5)CuSn(3) structure type, which is a 'filled' version of the binary RE(5)Sn(3) phases (Mn(5)Si(3)-type) (RE is rare earth). The asymmetric unit contains two Tb sites (site symmetries 3.2 and m2m), one Li site (site symmetry [Formula: see text].m) and one Sn site (site symmetry m2m). The 14 vertex Frank-Kasper polyhedra are typical for Li and Tb atoms. The environment of the Sn atom is a pseudo-Frank-Kasper polyhedron with a coordination number of 13 for the tin atom. One of the Tb atoms is enclosed in a 17-vertex polyhedron. The metallic type of bonding was indicated by an analysis of the inter-atomic distances. PMID- 22219725 TI - Genetic co-occurrence network across sequenced microbes. AB - The phenotype of any organism on earth is, in large part, the consequence of interplay between numerous gene products encoded in the genome, and such interplay between gene products affects the evolutionary fate of the genome itself through the resulting phenotype. In this regard, contemporary genomes can be used as molecular records that reveal associations of various genes working in their natural lifestyles. By analyzing thousands of orthologs across ~600 bacterial species, we constructed a map of gene-gene co-occurrence across much of the sequenced biome. If genes preferentially co-occur in the same organisms, they were called herein correlogs; in the opposite case, called anti-correlogs. To quantify correlogy and anti-correlogy, we alleviated the contribution of indirect correlations between genes by adapting ideas developed for reverse engineering of transcriptional regulatory networks. Resultant correlogous associations are highly enriched for physically interacting proteins and for co-expressed transcripts, clearly differentiating a subgroup of functionally-obligatory protein interactions from conditional or transient interactions. Other biochemical and phylogenetic properties were also found to be reflected in correlogous and anti-correlogous relationships. Additionally, our study elucidates the global organization of the gene association map, in which various modules of correlogous genes are strikingly interconnected by anti-correlogous crosstalk between the modules. We then demonstrate the effectiveness of such associations along different domains of life and environmental microbial communities. These phylogenetic profiling approaches infer functional coupling of genes regardless of mechanistic details, and may be useful to guide exogenous gene import in synthetic biology. PMID- 22219727 TI - Cu(4.35)Cd(1.65)As(16): the first polyarsenic compound in the Cu-Cd-As system. AB - The first polyarsenic compound in the Cu-Cd-As system was obtained by solid-state reaction of the elements and has a refined composition of Cu(4.35 (2))Cd(1.65 (2))As(16) (tetra-copper dicadmium hexa-deca-arsenide). It adopts the Cu(5)InP(16) structure type. The asymmetric unit consists of one Cu site, a split Cu/Cd site and four As sites. The polyanionic structure can be described as being composed of As(6) rings in chair conformations which are connected in the 1-, 2-, 4- and 5-positions. The resulting layers evolve along the c axis perpendicular to the ab plane. One Cu atom exhibits site symmetry 2 and is tetra-hedrally coordinated by four As atoms. The other Cu atom, representing the split site, and the corresponding Cd atom have different coordination spheres. While the Cu atom is tetra-hedrally coordinated by four As atoms, the Cd atom has a [3 + 1] coordination with a considerably longer Cd-As distance. PMID- 22219728 TI - AgNa(2)Mo(3)O(9)AsO(4). AB - The title compound, silver disodium trimolybdenum(VI) nonaoxide arsenate, AgNa(2)Mo(3)O(9)AsO(4), was prepared by a solid-state reaction at 808 K. The structure consists of an infinite (Mo(3)AsO(13))(n) ribbon, parallel to the c axis, composed of AsO(4) tetra-hedra and MoO(6) octa-hedra sharing edges and corners. The Na and Ag ions partially occupy several independent close positions, with various occupancies, in the inter-ribbon space delimited by the one dimensional framework. The composition was refined to Ag(1.06(1))Na(1.94(1))Mo(3)O(9)AsO(4). PMID- 22219729 TI - Heptasodium tetra-aluminium tetra-kis-(diphosphate) orthophosphate, Na(7)Al(4)(P(2)O(7))(4)(PO(4)). AB - The asymmetric unit of title compound contains three Na(+), one Al(3+), three P(5+) and eight O(2-) atoms, with one Na(+) atom lying on a twofold rotation axis and one Na(+) and one P(5+) atom on fourfold rotoinversion axes. The fundamental building units of the title structure are isolated PO(4) tetra-hedra, AlO(6) octa hedra and P(2)O(7) groups, which are further inter-locked by corner-sharing O atoms, forming a three-dimensional framework structure. The Na(+) atoms are located within the cavities of the framework, showing coordination numbers of 4, 6 and 7. PMID- 22219731 TI - A cubic calcium oxynitrido-silicate, Ca(2.89)Si(2)N(1.76)O(4.24). AB - The title compound, tricalcium oxynitride silicate, with composition Ca(3 x)Si(2)N(2-2x)O(4+2x) (x ? 0.12), is a perovskite-related calcium oxynitrido silicate containing isolated oxynitrido silicate 12-rings. The N atoms are statistically disordered with O atoms (occupancy ratio N:O = 0.88:0.12) and occupy the bridging positions in the 12 ring oxynitrido silicate anion, while the remaining O atoms are located at the terminal positions of the Si(O,N)(4) tetrahedra. The majority of the Ca(2+) cations fill the channels along [100] in the packing of the 12-ring anions. The rest of these cations are located at several positions, with partial occupancy, in channels along the body diagonals. PMID- 22219730 TI - La(5)Zn(2)Sn. AB - A single crystal of penta-lanthanum dizinc stannide, La(5)Zn(2)Sn, was obtained from the elements in a resistance furnace. It belongs to the Mo(5)SiB(2) structure type, which is a ternary ordered variant of the Cr(5)B(3) structure type. The space is filled by bicapped tetra-gonal anti-prisms from lanthanum atoms around tin atoms sharing their vertices. Zinc atoms fill voids between these bicapped tetra-gonal anti-prisms. All four atoms in the asymmetric unit reside on special positions with the following site symmetries: La1 (..m); La2 (4/m..); Zn (m.2m); Sn (422). PMID- 22219732 TI - Potassium penta-borate. AB - The title compound, K[B(5)O(7)(OH)(2)], was obtained from a hydro-thermal reaction. The structure is composed of one K(+) cation and a polyborate (1) (infinity)[B(5)O(7)(OH)(2)](-) anion, which consists of two six-membered rings linked by a common BO(4) tetra-hedron. The [B(5)O(7)(OH)(2)](-) units are linked together through two exocyclic O atoms to neighbouring units, forming a helical chain structure extending parallel to [010]. Adjacent chains are further connected into a three-dimensional structure by K-O bonds and weak O-H?O hydrogen bond inter-actions. PMID- 22219733 TI - (Methanol-kappaO)(methano-lato-kappaO)oxido{N'-[1-(2-oxidonaphthalen-1-yl kappaO)ethyl-idene]nicotinohydrazidato-kappaN',O}vanadium(V). AB - The title oxovanadium(V) complex, [V(C(18)H(13)N(3)O(2))(CH(3)O)O(CH(3)OH)], was obtained by the reaction of 1-(2-hy-droxy-naphthalen-1-yl)ethanone, nicotinohydrazide and vanadyl sulfate in methanol. The V(V) atom is six coordinated by the N,N,O-tridentate Schiff base ligand, one methano-late O atom, one methanol O atom and one oxide O atom, forming a distorted octa-hedral geometry. The methanol O atom lies trans to the V=O group. The dihedral angle between the pyridine ring and the naphthalene ring system is 31.52 (10) degrees . In the crystal, inversion dimers linked by pairs of O-H?N hydrogen bonds occur. PMID- 22219734 TI - Poly[[MU(2)-2,2'-diethyl-1,1'-(butane-1,4-di-yl)diimidazole-kappaN:N](MU(2)-5 hydroxy-isophthalato-kappaO:O)zinc]. AB - In the title coordination polymer, [Zn(C(8)H(4)O(5))(C(14)H(22)N(4))](n), the Zn(II) cation is coordinated by an O(2)N(2) donor set in a distorted tetra-hedral geometry. The Zn(II) ions are linked by MU(2)-OH-bdc (OH-H(2)bdc = 5-hy-droxy isophthalic acid) and bbie ligands [bbie = 2,2'-diethyl-1,1'-(butane-1,4-di yl)diimidazole], forming a two-dimensional layer parallel to the ab plane. The layers are further connected through intermolecular C-H?O and O-H?O hydrogen bonds, forming a three-dimensional supramolecular structure. In the bbie ligand, the two C atoms in the ethyl group are each disordered over two positions with a site-occupancy ratio of 0.69:0.31. PMID- 22219735 TI - Poly[[tetra-aqua-tetra-kis-[MU(3)-5-(pyridine-4-carboxamido) isophthalato]cobalt(II)dierbium(III)] tetra-hydrate]. AB - In the centrosymmetric polymeric title compound, {[CoEr(2)(C(14)H(8)N(2)O(5))(4)(H(2)O)(4)].4H(2)O}(n), the Er(III) cation has a coordination number of eight and is surrounded by seven carboxyl-ate O atoms from four 5-(pyridine-4-carboxamido)-isophthalate (L) ligands and one water mol-ecule, forming a distorted square-anti-prismatic arrangement. The Co(II) cation is located on an inversion center and is coordinated by two pyridine N atoms, two carboxyl-ate O atoms and two water mol-ecules in a distorted octa-hedral geometry. The asymmetric unit contains two anionic L ligands. One bridges two Er(III) cations and one Co(II) cation through two carboxyl-ate groups and one pyridine N atom, while the other bridges two Er(III) cations and one Co(II) cation through two carboxyl-ate groups. Extensive O-H?O, O-H?N and N-H?O hydrogen bonding inter-actions are present in the crystal, involving all uncoordinated water mol-ecules and the uncoordinated pyridine N atom of one of the ligands bonded to an adjacent coordinated water mol-ecule. The title compound is isotypic with the gadolinium analogue. PMID- 22219736 TI - catena-Poly[[[diaqua-manganese(II)]-bis-[MU-1,3-bis-(1H-imidazol-1-ylmeth yl)benzene-kappaN:N]] dinitrate]. AB - In the title compound, {[Mn(C(14)H(14)N(4))(2)(H(2)O)(2)](NO(3))(2)}(n), the Mn(II) ion is located on an inversion center and is coordinated by four N atoms from four 1,3-bis-(1H-imidazol-1-ylmeth-yl)benzene (L) ligands and two water mol ecules in a distorted octa-hedral geometry. Two L ligands are related by a centre of symmetry and bridge Mn(II) ions, forming a positively charged polymeric chain in [101]. Uncoordinated nitrate anions further link these chains into layers parallel to the ac plane via O-H?O hydrogen bonds. PMID- 22219737 TI - {2,2'-[o-Phenyl-enebis(nitrilo-methanylyl-idene)]diphenolato kappaO,N,N',O'}nickel(II) monohydrate. AB - The Ni(II) atom in the title monohydrate, [Ni(C(20)H(14)N(2)O(2))].H(2)O, is coordinated within a cis-N(2)O(2) square-planar donor set provided by the tetra dentate Schiff base ligand. Overall, the mol-ecule has a curved shape with the dihedral angle formed between the planes of the outer benzene rings being 13.92 (18) degrees . The water mol-ecule was found to be disordered over two positions [ratio 0.80 (1):0.20 (1)] and the major component is linked to the complex via an O-H?O hydrogen bond. PMID- 22219738 TI - Hexa-MU(2)-acetato-kappaO:O'-(azido-kappaN)bis-(methanol-kappaO)-MU(3)-oxido trichromium(III) methanol monosolvate. AB - In the crystal structure of the title complex, [Cr(3)(CH(3)CO(2))(6)(N(3))O(CH(3)OH)(2)].CH(3)OH, the trinuclear core has a central O atom; two methanol mol-ecules and an azide ion are coordinated to the Cr(III) atoms in the core. The three Cr(III) atoms form vertices of a nearly equilateral triangle. Each of the six acetate carboxyl-ate groups bridges a Cr-O Cr fragment. In the crystal, the molecules inter-act with methanol solvent mol ecules through O-H?O and O-H?N hydrogen bonds, forming a two-dimensional hydrogen bonded network parallel to (100). PMID- 22219739 TI - Bis[N'-(9H-fluoren-9-yl-idene)benzohydrazidato-kappaN',O]copper(II). AB - In the title complex, [Cu(C(20)H(13)N(2)O)(2)], the Cu(II) ion is tetra coordinated by an N(2)O(2) set of two ligands in a distorted recta-ngular-planar geometry. The dihedral angle between the two coordinated five-membered metalla rings is 37.5 (3) degrees . The mol-ecular configuration is stabilized by two C H?O and two C-H?N intra-molecular hydrogen bonds. The crystal packing is dominated by van der Waals inter-actions. Three atoms of the phenyl ring of the benzohydrazidate moiety are disordered over two sets of sites in a 0.625 (18):0.375 (18) ratio. PMID- 22219740 TI - Bis[bis-(1H-pyrazol-1-yl)methane-kappaN,N](formato-kappaO,O')copper(II) perchlorate. AB - In the crystal structure of the title compound, [Cu(HCO(2))(C(7)H(8)N(4))(2)]ClO(4), the Cu(II) ion is octa-hedrally coordinated by one bidentate formate ion and two bidentate bis-(1H-pyrazol-1-yl)methane ligands. There are C-H?O hydrogen bonds and pi-pi inter-actions [centroid centroid distance = 3.487 (3) A] in the crystal structure. The perchlorate anion is disordered over two positions with an occupancy ratio of 0.628 (9):0.372 (9). PMID- 22219741 TI - [2,2'-Bis(pyridin-2-ylmeth-oxy)biphenyl-kappaN,O,O',N']bis-(nitrato kappaO,O')cadmium. AB - In the title compound, [Cd(NO(3))(2)(C(24)H(20)N(2)O(2))], the Cd(II) ion is eight-coordinated by one ligand and two nitrate ions. There are C-H?O hydrogen bonds and C-H?pi inter-actions and pi-pi inter-actions [centroid-centroid distance = 3.319 (1) A] in the crystal structure. PMID- 22219742 TI - Poly[bis-(N,N-dimethyl-acetamide)-1kappaO,2kappaO-bis-(MU(4)-thio-phene-2,5-di car-boxyl-ato-1:2:1':2'kappaO:O:O:O)dizinc]. AB - In the title polymeric complex, [Zn(2)(C(6)H(2)O(4)S)(2)(C(4)H(9)NO)(2)](n), each carboxyl-ate group of the thio-phene-2,5-dicarboxyl-ate dianion bridges a pair of inversion-related dimethyl-acetamide-coordinated Zn(II) atoms, generating a layer motif parallel to (101). The Zn(II) atom shows a distorted square-pyramidal coordination; the apical site is occupied by the O atom of the dimethyl-acetamide mol-ecule, whereas the four basal sites are occupied by carboxyl-ate O atoms. In the crystal, the dimethyl-acetamide mol-ecule is disordered over two positions in a 0.72 (1):0.28 (1) ratio in respect of the C atoms. PMID- 22219743 TI - Aqua-(4,4'-bipyridine-kappaN)bis-(1,4-dioxo-1,4-dihydronaphthalen-2-olato kappaO,O)zinc 4,4'-bipyridine mono-solvate dihydrate. AB - The reaction of 2-hy-droxy-1,4-naphtho-quinone and 4,4'-bipyridine with zinc acetate produced the title compound, [Zn(C(10)H(5)O(3))(2)(C(10)H(8)N(2))(H(2)O)].C(10)H(8)N(2).2H(2)O. The bond lengths and angles around the metal atom indicate a deviation from octa-hedral geometry. The two naphtho-quinone ligands coordinate in a cis fashion, with the 4,4'-bipyridine ligand and the water mol-ecules completing the coordination sphere of the metal atom. The asymmetric unit contains also one free 4,4' bipyridine mol-ecule and two uncoordinated water mol-ecules. These mol-ecules make contacts with the complex through O-H?N and O-H?O hydrogen bonds, creating a layer two-dimensional network parallel to (121). PMID- 22219744 TI - Dibromidobis(3,5-dimethyl-1H-pyrazole-kappaN)cobalt(II). AB - In the mononuclear title complex, [CoBr(2)(C(5)H(8)N(2))(2)], the Co(II) atom is coordinated by two N atoms from two monodentate 3,5-dimethyl-pyrazole ligands and two Br atoms in a highly distorted tetra-hedral geometry. In the crystal, the complex mol-ecules are linked by inter-molecular N-H?Br hydrogen bonds into chains along [101]. An intra-molecular N-H?Br hydrogen bond is also present. PMID- 22219745 TI - Dichloridobis[3-meth-oxy-methyl-4-phenyl-5-(2-pyrid-yl)-4H-1,2,4-triazole kappaN,N]chromium(III) chloride. AB - In the title complex, [CrCl(2)(C(15)H(14)N(4)O)(2)]Cl, the Cr(III) atom is located on a twofold rotation axis and is coordinated by two N,N'-bidentate triazole derivatives and two chloride ions in a distorted octa-hedral CrN(2)N'(2)Cl(2) geometry. One of the two independent Cl(-) counter-anions sits on a special position (site symmetry [Formula: see text].) and is fully occupied, whereas the other is disordered around a twofold rotation axis over two positions in a 2:3 ratio. PMID- 22219746 TI - Poly[[(MU-benzene-1,4-dicarboxyl-ato)bis-[MU-4-(1H-1,3,7,8-tetra-aza-cyclo-penta [l]phenanthren-2-yl)benzoato]dizinc] tetra-hydrate]. AB - In the title complex, [Zn(2)(C(8)H(4)O(4))(C(20)H(11)N(4)O(2))(2)].4H(2)O, the Zn(II) atom is six-coordinated by two carboxyl-ate O atoms from one bidentate benzene-1,4-dicarboxyl-ate (1,4-BDC) ligand, two carboxyl-ate O atoms from two different monodentate 4-(1H-1,3,7,8-tetra-aza-cyclo-penta-[l]phenanthren-2 yl)benzoate (HNCP) ligands and two HNCP N atoms. The Zn(II) atoms are bridged by the centrosymmetric 1,4-BDC ligands, forming an extended single-chain structure. Neighbouring single chains are connected by the HNCP ligands from two opposite directions, resulting in a sheet. In addition, there are N-H?O hydrogen-bonding inter-actions between adjacent layers. As a result, the polymeric sheets are further extended into a three-dimensional supra-molecular structure. PMID- 22219747 TI - (Methano-lato-kappaO)[N'-(3-meth-oxy-2-oxidobenzyl-idene-kappaO)-4-nitro-benzo hydrazidato-kappaN',O]oxidovanadium(V). AB - The title oxidovanadium(V) complex, [V(C(15)H(11)N(3)O(5))(CH(3)O)O], was obtained by the reaction of 2-hy-droxy-3-meth-oxy-benzaldehyde, 4-nitro benzohydrazide and vanadyl sulfate in methanol. The V(V) atom is five-coordinated by the two O and one N donor atoms of the Schiff base ligand, one methano-late O atom and one oxido O atom, forming a distorted square-pyramidal geometry. PMID- 22219748 TI - Dichlorido{N-[2-(diphenylphosphanyl)benzylidene]-2,6-diisopropylaniline kappaP,N}platinum(II). AB - The title compound, [PtCl(2)(C(31)H(32)NP)], is a Pt(II) complex with an NPCl(2) coordination sphere in which the Pt(II) atom is coordinated to the imino N and phosphane P atoms of the ligand and to two cis Cl ions, giving a slightly distorted square-planar geometry. The P-Pt-N angle is 89.80 (5) degrees and the corresponding angle between the Cl ions is 87.92 (2) degrees . PMID- 22219749 TI - Dichlorido[2-diphenyl-phosphanyl-N-(pyridin-3-ylmeth-yl)benzyl-idenamine kappaP,N]platinum(II). AB - The title compound, [PtCl(2)(C(25)H(21)N(2)P)], is a Pt(II) complex with an NPCl(2) coordination sphere in which the metal is coordinated to the imino N and phosphane P atoms of the ligand and to two chloride ions. The Pt(II) atom is in a distorted square-planar environment and is bound to the ligand via the P and amine N atoms in a cis fashion, with the chlorine atoms located at the two remaining sites. PMID- 22219750 TI - (SP-4-2)-Chlorido{N-[2-(diphenyl-phosphan-yl)benzyl-idene]benzyl-amine kappaP,N}(meth-yl)palladium(II). AB - In the title Pd(II) complex, [Pd(CH(3))Cl(C(26)H(22)NP)], the Pd(II) atom is coordinated in a slightly distorted square-planar geometry by the imino N and phosphane P atoms of the ligand, by one chloride ion and by a methyl ligand. The methyl group is trans to the N atom of the ligand. PMID- 22219751 TI - Tetra-kis(triphenyl-phosphane-kappaP)silver(I) trifluoro-methane-sulfonate dichloro-methane monosolvate. AB - In the title compound, [Ag(C(18)H(15)P)(4)]CF(3)O(3)S.CH(2)Cl(2), the Ag atom is coordinated by four P atoms from four PPh(3) ligands. The P-Ag-P angles are in the range 108.02 (6)-110.15 (6) degrees , which confirms the distorted tetra hedral environment around the Ag atom. PMID- 22219752 TI - [1,2-Bis(diphenyl-phosphan-yl)ethane-2kappaP,P']tetra-carbonyl-1kappaC,2kappaC (MU-2-cyclo-pentyl-2-aza-propane-1,3-dithiol-ato-1:2kappaS,S':S,S')diiron(II)(Fe Fe). AB - In the title compound, [Fe(2)(C(7)H(13)NS(2))(C(26)H(24)P(2))(CO)(4)], the Fe(2)S(2) core exhibits a butterfly-like shape, with two S atoms bridging the Fe Fe dumbbell. Each of the two Fe atoms exhibits a distorted octa-hedral environment. One Fe atom is additionally bonded to three carbonyl C atoms, whereas the other Fe atom is additionally bonded to one carbonyl C atom and two P atoms of the chelating dppe [dppe = 1,2-bis-(diphenyl-phosphan-yl)ethane] ligand. Non-classical intra-molecular C-H?S hydrogen-bonding inter-actions are present in the structure. The packing of adjacent mol-ecules along [100] is accomplished mainly through van der Waals forces. PMID- 22219753 TI - MU-Propane-1,3-dithiol-ato-kappaS,S':S,S'-bis-[dicarbon-yl(triphenyl-phosphane kappaP)iron(II)](Fe-Fe). AB - The title compound, [Fe(2)(C(3)H(6)S(2))(C(18)H(15)P)(2)(CO)(4)], which might serve as an active-site model of [FeFe]-hydrogenase, contains two fused Fe/S/C/C/C/S six-membered rings, one of which has a chair conformation and the other a boat conformation. Each Fe atom is coordinated by two carbonyl ligands, a triphenyl-phosphane ligand and a bis-bidentate dithiol-ate ligand, and also forms an Fe-Fe bond [2.5167 (16) A]. Together, the six bonded atoms form a very distorted octa-hedral arrangement. PMID- 22219754 TI - catena-Poly[(E)-4,4'-(ethane-1,2-di-yl)dipyridinium [[bis-(thio-cyanato kappaN)ferrate(II)]-di-MU-thio-cyanato-kappaN:S;kappaS:N]]. AB - In the crystal structure of the title compound, {(C(12)H(14)N(2))[Fe(NCS)(4)]}(n), the iron(II) cation is coordinated by four N bonded and two S-bonded thio-cyanate anions in a distorted octa-hedral coordination mode. The asymmetric unit consists of half an iron(II) cation and half a protonated (E)-4,4'-(ethane-1,2-di-yl)dipyridinium dication, each located on a centre of inversion. In addition, there are two thio-cyanate anions in general positions. The crystal structure consists of Fe-(NCS)(2)-Fe chains in which each iron(II) cation is additionally coordinated by two terminal N-bonded thio-cyanate anions. Non-coordinating dipyridinium dications are present between the thiocyanatoferrate(II) chains and are connected to the anions via N-H?N and N H?S hydrogen-bond interactions. PMID- 22219755 TI - Dichloridobis[4,4,5,5-tetra-methyl-2-(5-methyl-1H-imidazol-4-yl-kappaN)-2 imidazoline-1-oxyl 3-oxide-kappaO]copper(II). AB - In the title complex, [CuCl(2)(C(11)H(17)N(4)O(2))(2)], the Cu(II) ion, lying on an inversion center, is six-coordinated in a distorted octa-hedral [Cu(N(2)O(2)Cl(2))] environment by two N,O-bidentate nitronyl nitroxide radical ligands and two trans-chloride anions. In the imidazoline-1-oxyl-3-oxide unit of the ligand, the four methyl groups and the C atoms to which they are bonded are disordered over two sets of sites, with a refined occupancy ratio of 0.737 (5):0.263 (5). PMID- 22219756 TI - catena-Poly[[tris[silver(I)-MU-4,4'-bi-pyridine-kappaN:N']] tris-(perchlorate) di hydrate]. AB - In the title compound, {[Ag(3)(C(10)H(8)N(2))(3)](ClO(4))(3).2H(2)O}(n), one of the Ag(I) ions, one of the 4,4'-bipyridine (bipy) ligands and one of the perchlorate anions are each situated on a twofold rotation axis. Each Ag(I) ion is coordinated by two N atoms from two bridging bipy ligands, forming chains along [101]. pi-pi inter-actions between the pyridine rings [centroid-centroid distances = 3.638 (8) and 3.688 (8) A] connect the chains. Inter-molecular O-H?O hydrogen bonds link the uncoord-inated water mol-ecules and the perchlorate anions. PMID- 22219757 TI - Bis(nitrato-kappaO)bis-[4,4,5,5-tetra-methyl-2-(5-methyl-1H-imidazol-4-yl-kappaN) 2-imidazoline-1-oxyl 3-oxide-kappaO]nickel(II). AB - In the centrosymmetric mononuclear title complex, [Ni(NO(3))(2)(C(11)H(17)N(4)O(2))(2)], the Ni(II) atom displays a distorted octa hedral coordination geometry and is six-coordinated by two N,O-bidentate nitronyl nitroxide radical ligands and two monodentate nitrate anions. PMID- 22219758 TI - Bromidotris(triphenyl-phosphane)silver acetonitrile monosolvate monohydrate. AB - In the title compound, [AgBr(C(18)H(15)P)(3)].C(2)H(3)N.H(2)O, the coordination of the Ag atom is close to ideal tetra-hedral, with the three Ag-P bond lengths almost equal [2.5441 (10), 2.5523 (9) and 2.5647 (10) degrees A] and the Ag-Br bond slightly longer [2.7242 (5) A]. The coordination tetra-hedron is slightly flattened, the Ag atom is closer to the PPP plane; the P-Ag-P angles are wider than the Br-Ag-P angles. The voids in the crystal structure are filled with ordered acetonitrile solvent mol-ecules. The remaining electron density was inter preted as a water mol-ecule, disordered over three alternative positions. Neither of the solvent mol-ecules is connected by any directional specific inter-actions with the complex. PMID- 22219759 TI - A potential anti-cancer agent: 5-chloro-7-iodo-8-hy-droxy-quinolinium dichlorido(5-chloro-7-iodo-quinolin-8-olato-kappaN,O)palladium(II) dihydrate. AB - The title Pd(II) coordination compound, (C(9)H(6)ClINO)[PdCl(2)(C(9)H(4)ClINO)].2H(2)O, was prepared as a potential anti cancer agent. Its structure is ionic and consists of a square-planar [PdCl(2)(CQ)](-) complex anion (CQ is 5-chloro-7-iodo-quinolin-8-olate), with the Pd(II) atom surrounded by two chloride ligands in a cis configuration and one N,O bidentate CQ mol-ecule, a protonated anion of CQ as counter-cation and two non coordinated water mol-ecules. The water mol-ecules are involved in O-H?O and N H?O hydrogen bonds, which inter-connect the HCQ(+) cations into a chain parallel to [010]. Apart from these inter-actions, the structure is also stabilized by face-to-face pi-pi inter-actions [centroid-centroid = 3.546 (3) A], which occur between the phenolic parts of the complex anions and cations. PMID- 22219760 TI - (4,4',6,6'-Tetra-tert-butyl-2,2'-{[2-(di-methyl-amino)-ethyl]-nitrilo-bis-(methyl ene)}diphenolato)dioxidomolyb-denum(VI) chloro-form monosolvate. AB - In the title compound, [Mo(C(34)H(54)N(2)O(2))O(2)].CHCl(3), the molybdenum(VI) ion exhibits a cis-dioxide distorted octa-hedral geometry. Two anionic phenolate O-atom donors and two neutral N-atom donors of the ligand are trans and cis, respectively. The Mo=O bond lengths and the O=Mo=O bond angle are typical for six coordinated dioxomolyb-denum(VI) complexes. The Mo-N bond lengths are longer than 2.30 A, as expected for a trans O=Mo-N structure. PMID- 22219761 TI - Bis(methanol-kappaO)bis-(quinoline-2-carboxyl-ato-kappaN,O)nickel(II). AB - In the title complex, [Ni(C(10)H(6)NO(2))(2)(CH(3)OH)(2)], the Ni(II) ion lies on an inversion center and is coordinated by two quinoline-2-carboxyl-ate ligands in the equatorial sites and two axial methanol ligands, forming a distorted octa hedral environment. In the crystal, mol-ecules are linked via O-H?O hydrogen bonds into a two-dimensional network parallel to (10[Formula: see text]). PMID- 22219762 TI - catena-Poly[[(acetato-kappaO)[4-(1H-pyrazol-3-yl)pyridine-kappaN]zinc]-MU-acetato kappaO:O']. AB - In the title compound, [Zn(CH(3)CO(2))(2)(C(8)H(7)N(3))](n), the Zn(II) atom is coordinated by one N atom from a 4-(1H-pyrazol-3-yl)pyridine ligand and three O atoms from two bridging and one terminal acetate ligands, forming a distorted tetra-hedral geometry. The bridging acetate ligands link the Zn atoms into a chain along [001]. N-H?O hydrogen bonds and pi-pi inter-actions between the pyridine and pyrazole rings [centroid-centroid distance = 3.927 (3) A] connect the chains into a layer parallel to (011). PMID- 22219763 TI - (3-Benzoyl-1,7,7-trimethyl-bicyclo-[2.2.1]heptan-2-olato-kappaO,O)bis-[2-(2-pyrid yl)phenyl-kappaC,N]iridium(III). AB - The title compound, [Ir(C(11)H(8)N)(2)(C(17)H(19)O(2))], has an octa-hedral coordination geometry around the Ir(III) atom, retaining the cis-C,C,trans-N,N chelate disposition of the two 2-phenyl-pyridine ligands. The chelate rings are nearly mutually perpendicular [the inter-planar angles range from 85.48 (17) to 89.17 (19) degrees ]. The two 2-(2-pyrid-yl)phenyl ligands are approximately planar, with the plane of the phenyl ring being inclined to that of the pyridine ring by 2.3 (3) and 5.1 (3) degrees in the two ligands. The inter-planar angle between the phenyl ring in 3-benzoyl-camphor and the IrO(2)C(3) chelate ring is 35.5 (2) degrees . PMID- 22219764 TI - Di-MU-pivalato-kappaO,O':O';kappaO:O,O'-bis-[(methanol-kappaO)bis-(2,2,6,6-tetra methylhepta-ne-3,5-dionato)praseo-dymium(III)]. AB - In the centrosymmetric dimeric title compound, [Pr(2)(C(5)H(9)O(2))(2)(C(11)H(19)O(2))(4)(CH(3)OH)(2)], the two praseodymium(III) atoms are eight-coordinate and are bridged by O atoms from the two pivalate anions. Each Pr(III) ion is further coordinated by two chelating 2,2,6,6-tetra-methyl-3,5-hepta-nedionate (thd(-)) ligands and one methanol mol ecule. The distance between the two Pr(III) ions is 4.273 (5) A. Intra-molecular hydrogen bonds exists between the methanol hy-droxy group on one Pr(III) atom and a chelating O atom of a thd(-) ligand coordinated to the symmetry-related Pr(III) atom. PMID- 22219765 TI - Bis[2,2'-(2-amino-ethyl-imino)-di(ethyl-ammonium)] di-MU-sulfido-bis[disulfido stannate(IV)]. AB - The asymmetric unit of the title compound, (C(6)H(20)N(4))(2)[Sn(2)S(6)], comprises half of a [Sn(2)S(6)](4-) anion and a diprotonated tris-(2-amino-eth yl)amine cation. The anion lies on an inversion center, while the atoms of the cation occupy general positions. An intra-molecular N-H?N hydrogen bond is observed in the cation. In the crystal, strong N-H?S hydrogen bonding between the terminal sulfur atoms of the anion and the protonated amine N atoms of the cations result in a three-dimensional network. PMID- 22219766 TI - Bis(methyl xanthato)-kappaS;kappaS:S'-(triphenyl-phosphane-kappaP)palladium(II). AB - The title compound, [Pd(C(2)H(3)OS(2))(2)(C(18)H(15)P)], features a palladium complex with a triphenyl-phosphane ligand and two xanthate ligands, one of them coordinates in a bidentate and the other in a monodentate fashion, giving rise to a slightly distorted square-planar coordination of the Pd(II) ion. As a result of this difference in the coordination modes, the C-S bond lengths are different, viz. 1.687 (2) and 1.692 (2) A in the bidentate ligand and 1.723 (2) A in the monodentate ligand, whereas the non-coordinating S atom has a C-S distance of 1.649 (2) A. The crystal packing is stabilized by C-H?O inter-actions. PMID- 22219767 TI - Hexaaqua-cobalt(II) bis-[4-(pyridin-2-yl-meth-oxy)benzoate] dihydrate. AB - The Co(II) atom in the title salt, [Co(H(2)O)(6)](C(13)H(10)NO(3))(2).2H(2)O, lies on a center of inversion in an octa-hedron of water mol-ecules. The cations, anions and uncoordinated water mol-ecules are linked by O-H?O and O-H?N hydrogen bonds into a three-dimensional network. The anion is essentially planar, with an r.m.s. deviation of all non-H atoms of 0.066 A. PMID- 22219768 TI - Hexaaqua-manganese(II) bis-[4-(pyridin-2-ylmeth-oxy)benzoate] dihydrate. AB - The Mn(II) atom in the title salt, [Mn(H(2)O)(6)](C(13)H(10)NO(3))(2).2H(2)O, lies on a center of inversion in an octa-hedron of water mol-ecules. The cations, anions and uncoordinated water mol-ecules are linked by O-H?O and O-H?N hydrogen bonds into a three-dimensional network. The anion is essentially planar, with an r.m.s. deviation of all non-H atoms of 0.068 A. PMID- 22219769 TI - Hexaaqua-cobalt(II) bis-(2,2'-sulfanediyldiacetato-kappaO,S,O')cobaltate(II) tetra-hydrate. AB - The two Co(II) atoms in the title salt, [Co(H(2)O)(6)][Co(C(4)H(4)O(4)S)(2)].4H(2)O, exist in an octa-hedral coordination environment. In the cation, the Co atom is surrounded by six water mol-ecules, and in the anion, it is bis-O,S,O'-chelated by the thio-acetate ligands. The cations, anions and uncoordinated water mol-ecules are linked by O-H?O hydrogen bonds into a three-dimensional network. PMID- 22219770 TI - catena-Poly[[bis-(MU-2-formyl-6-meth-oxy-phenolato)copper(II)sodium]-MU-nitrato]. AB - In the title heterodinuclear complex, [CuNa(C(8)H(7)O(3))(2)(NO(3))](n), the Cu(II) ion is five-coordinated in a square-pyramidal arrangement by four atoms of two different ligand molecules in equatorial positions and one remote nitrate O atom in the apical position. The Na(+) ion is eight-coordinated by four ligand O atoms and four nitrate O atoms. The ligand links the Cu(II) and Na ions, forming a layered arrangement extending parallel to (001). PMID- 22219771 TI - Bis[MU-3,5-bis-(2-pyrid-yl)pyrazolato]bis-(hydrogensulfato)-dicopper(II) methanol disolvate. AB - The title compound, [Cu(2)(C(13)H(9)N(4))(2)(HSO(4))(2)].2CH(3)OH, consists of discrete centrosymmetric dinuclear complex mol-ecules and methanol solvent mol ecules. The Cu(II) atom shows a square-pyramidal coordination geometry and is bonded to four N atoms of the two bis-chelating 3,5-bis-(2-pyrid-yl)pyrazol-ate ions (bpypz(-)) and one O atom of the hydrogensulfate ion. The bpypz(-) ligands in the complex mol-ecule are virtually coplanar [dihedral angle between the mean ligand planes = 0.000(1) degrees ] with the Cu(II) atom deviating in opposite directions from their best plane by 0.2080 (12) A. pi-pi stacking inter-actions between the pyridyl and pyrazole rings [centroid-centroid distance = 3.391 (3) A] and strong O-H?O hydrogen bonds between the hydrogensulfate ligands and the methanol mol-ecules assemble the mol-ecules into a one-dimensional polymeric structure extending along the a axis. The methanol mol-ecule acts both as an accepter and a donor in the hydrogen bonding. PMID- 22219772 TI - Tetrakis(MU(3)-9-oxa-10-boraanthracen-10-olato)tetrakis[(diethyl ether)lithium]. AB - The title compound, [Li(4)O(4)(C(12)H(8)BO)(4)(C(4)H(10)O)(4)], features a Li(4)O(4) cube. Each Li atom in the cube is additionally coordinated by a diethyl ether mol-ecule and each O atom in the cube carries a 9-oxa-10-boraanthracene residue. The crystal studied was a non-merohedral twin [twin law (-1 0 0 / 0 0 1 / 0 1 0); the contribution of the major twin component refined to 0.553 (3)] emulating apparent tetra-gonal symmetry, whereas the actual crystal system is just ortho-rhom-bic. PMID- 22219773 TI - Tris(3-amino-5,6-dimethyl-1,2,4-triazine-kappaN)silver(I) trifluromethane sulfonate-3-amino-5,6-dimethyl-1,2,4-triazine (1/1). AB - The asymmetric unit of the title compound, [Ag(C(5)H(8)N(4))(3)](CF(3)O(3)S).C(5)H(8)N(4), contains two cations, two anions and two uncoordinated 3-amino-5,6-dimethyl-1,2,4-triazine (admt) ligands. It was prepared from the reaction of silver trifluoro-methane-sulfonate and admt in a 2:3 molar ratio. Both silver(I) ions are bonded to three admt mol-ecules via their 2-position triazine N atoms in almost regular trigonal-planar geometries. Three intra-molecular N-H?N hydrogen bonds between adjacent admt mol-ecules in each cation help to maintain their overall near planarities (r.m.s. deviations for the 28 non-H atoms = 0.139 and 0.153 A). In the crystal, numerous N-H?N, N H?O, C-H?O, C-H?N and C-H?F hydrogen-bonding interactions link the components into a three-dimensional network. PMID- 22219774 TI - catena-Poly[[aqua-copper(II)]-MU(2)-imino-diacetato-kappaO,N,O':O']. AB - In the title compound, [Cu(C(4)H(5)O(4))(H(2)O)](n), the imino-diacetate (ida) ligands link the Cu(II) atoms into polymeric zigzag chains running along [010]. Each Cu(II) ion is five-coordinated in a distorted square-pyramidal geometry by one N and two O atoms from an ida ligand, one O atom from the neighbouring ida ligand and one water O atom. In the crystal, the polymeric chains are held together via inter-molecular O-H?O and N-H?O hydrogen bonds. PMID- 22219775 TI - Poly[bis-[MU-1,3-bis-(diphenyl-phosphan-yl)propane-kappaP:P']-di-MU-thio-cyanato kappaS:N;kappaN:S-disilver(I)]. AB - In the title coordination polymer, [Ag(2)(NCS)(2)(C(27)H(26)P(2))(2)](n), two centrosymmetrically related Ag(+) cations are linked by two thio-cyanate anions into binuclear eight-membered macrocycles. The Ag?Ag separation within the macrocycle is 5.4400 (6) A. The distorted tetra-hedral coordination about each metal atom is completed by the P atoms of two bridging 1,3-bis-(diphenyl-phosphan yl)propane ligands, forming polymeric ribbons parallel to the a axis. PMID- 22219776 TI - (RS)-Tricarbon-yl(eta-1,3-diacet-oxy-5,5-dimethyl-cyclo-hexa-1,3-diene)iron(0). AB - In the title compound, [Fe(C(12)H(16)O(4))(CO)(3)], the diene moiety of the mol ecule is virtually planar, with a C-C-C-C torsion angle of -1.4 (2) degrees . The six-membered ring exhibits a boat conformation, with torsion angles of 46.2 (2) and 46.5 (3) degrees for a double-bond and the two attached Csp(3) atoms. The Fe atom is coordinated to all four of the diene C atoms, with bond lengths between 2.041 (2) and 2.117 (2) A. The Fe(CO)(3) tripod adopts a conformation with one CO ligand eclipsing the Csp(3)-Csp(3) single bond. PMID- 22219777 TI - Bis(7-amino-1,2,4-triazolo[1,5-a]pyrimidin-4-ium) bis-(oxalato kappaO,O)cuprate(II) dihydrate. AB - The structure of the title ionic compound, (C(5)H(6)N(5))(2)[Cu(C(2)O(4))(2)].2H(2)O, consists of a centrosymmetric copper(II) oxalate dianion, two monoprotonated mol-ecules of the adenine analog 7 amino-1,2,4-triazolo[1,5-a]pyrimidine (7atp) and two water mol-ecules of crystallization. The Cu(II) ion, located on an inversion center, exhibits a sligthly distorted square-planar coordination geometry, in which two oxalate anions bind in a bidentate fashion. The triazolopyrimidine ligand is protonated at the N atom in position 4, instead of its most basic N atom in position 3. This fact may be explained by the network stability, which is provided through the formation of a two-dimensional wave-like network parallel to (50[Formula: see text]) by N-H?O, O-H?N and O-H?O hydrogen bonds. These nets are further connected via C-H?O inter-actions. PMID- 22219778 TI - 1,1'-Bis(1-acetyl-5-methyl-1H-pyrazol-3-yl)ferrocene. AB - The title compound, [Fe(C(11)H(11)N(2)O)(2)], crystallizes with two independent mol-ecules in the asymmetric unit which have have different conformations. In one mol-ecule, the two ferrocene cyclo-penta-dienyl rings are fully eclipsed and the two pyrazole rings are syn to each other; in the other, the two cyclo-penta dienyl rings are synclinal and the pyrazole rings are anti. In both mol-ecules, the acetyl group attached to the pyrazole ring is oriented away from the iron cyclo-penta-dienyl group of ferrocene. PMID- 22219779 TI - MU(4)-Orthothio-carbonato-tetra-kis-[tri-carbonyl-iron(I)](2 Fe-Fe). AB - The fused bis-butterfly-shaped title compound, [Fe(4)(CS(4))(CO)(12)], possesses an orthothio-carbonate (CS(4) (4-)) ligand that acts as a bridge between two Fe(2)(CO)(6) units. A short intra-molecular S?S contact [2.6984 (8) and 2.6977 (8) A] occurs in each S(2)Fe(2)(CO)(6) fragment. PMID- 22219780 TI - Bis{MU-(E)-methyl 4-[(2-carbamothio-ylhydrazinyl-idene)meth-yl]benzoate kappaS:S}bis-[iodido(triphenyl-phosphane-kappaP)copper(I)]. AB - The title complex, [Cu(2)I(2)(C(10)H(11)N(3)O(2)S)(2)(C(18)H(15)P)(2)], is a centrosymmetric sulfur-bridged dimer of Cu(I) with PPh(3) and iodine. The Cu(I) atom shows a distorted tetra-hedral geometry, with bite angles ranging from 98.61 (2) to 120.16 (3) degrees . The intra-molecular Cu?Cu distance is 2.8228 (12) A. The thio-semicarbazone ligand is coordinated only through the S atom. In the crystal, the complex mol-ecules are linked via inter-molecular N-H?O hydrogen bonds, resulting in a hydrogen-bonded chain along the b axis. PMID- 22219781 TI - (2-Carbamoylethyl-kappaC,O)triiodidotin(IV). AB - Two independent but virtually identical mol-ecules comprise the asymmetric unit of the title compound, [Sn(C(3)H(6)NO)I(3)]. The CI(3)O coordination geometry around the Sn(IV) atom is defined by a chelating carbamoylethyl ligand (C(1),O bidentate) and three I atoms, and is based on a distorted trigonal bipyramid with the carbonyl O atom occupying a position trans to one of the I atoms which forms the longer of the Sn-I bonds. The independent mol-ecules are linked via N-H?O hydrogen bonds, which leads to the formation on an eight-membered amide {?HNCO}(2) synthon. N-H?I hydrogen-bonding inter-actions are also present between neighbouring mol-ecules. PMID- 22219782 TI - [N'-(3-Eth-oxy-2-oxidobenzyl-idene-kappaO)-4-methyl-benzohydrazidato kappaO,N'](methano-lato-kappaO)oxidovanadium(V). AB - The title oxidovanadium(V) complex, [V(C(17)H(16)N(2)O(3))(CH(3)O)O], was obtained by the reaction of 3-eth-oxy-2-hy-droxy-benzaldehyde, 4-methyl benzohydrazide and vanadyl sulfate in methanol. The V(V) atom is coordinated by the O,N,O'-tridentate Schiff base ligand, one methano-late O atom and one oxide O atom, forming a distorted VO(4)N square-pyramidal coordination geometry. The oxide O atom lies at the apex of the square pyramid and the N atom of the ligand and the methano-late O atom are trans. The dihedral angle between the benzene rings of the ligand is 1.8 (3) degrees . PMID- 22219783 TI - Di-MU-chlorido-bis-[(2-{(E)-[(2,3-dihy-droxy-prop-yl)imino]-meth yl}phenolato)copper(II)] methanol monosolvate. AB - In the title compound, [Cu(2)Cl(2)(C(10)H(12)NO(3))(2)].CH(3)OH, each of the two Cu(II) atoms is bound to two O and one N atoms of the bis-chelating monoanionic Schiff base and two bridging chloride ligands. The metal atoms each show a distorted square-pyramidal coordination geometry. Intra-molecular O-H?O hydrogen bonds occur. In the crystal, O-H?O hydrogen bonds join the components into a chain extending along the a axis. PMID- 22219784 TI - Poly[(MU(2)-1,3-di-4-pyridyl-propane)(MU(3)-1,3-phenyl-enediacetato)-cadmium]. AB - In the title compound, [Cd(C(10)H(8)O(4))(C(13)H(14)N(2))](n), two symmetry related Cd atoms are bridged by two carboxyl-ate O atoms into a binuclear Cd(2) subunit around an inversion center. The Cd atom has a distorted penta-gonal bipyramidal environment, defined by five O atoms from three different 1,3 phenylendiacetate (1,3-pda) ligands and two N atoms from two 1,3-di-4-pyridyl propane (bpp) ligands. Each Cd(2) subunit is linked to four different Cd(2) subunits by four 1,3-pda ligands and four bpp ligands, forming a two-dimensional network with rhombic grids (12.50 * 12.50 A(2)) extending along the ab plane. PMID- 22219785 TI - catena-Poly[[[aqua-(1,10-phenanthro-line)manganese(II)]-MU-adamantane-1,3 dicarboxyl-ato] monohydrate]. AB - In the title coordination polymer, {[Mn(C(12)H(14)O(4))(C(12)H(8)N(2))(H(2)O)].H(2)O}(n), the Mn(II) atom has a highly distorted cis-MnN(2)O(4) octa-hedral geometry arising from its coordination by a bidentate phenanthroline ligand, a water mol-ecule and monodentate and bidentate adamantane-1,3-dicarboxyl-ate dianions. The bridging dianion leads to [001] chains in the crystal. The chains are linked by O-H?O hydrogen bonds, involving both the coordinated and uncoordinated water mol ecules, thereby forming a two-dimensional network. PMID- 22219786 TI - Diaqua-tetra-kis-(1,3-di-4-pyridylpropane-kappaN)-manganese(II) bis-(perchlorate) ses-qui-hydrate. AB - In the title complex, [Mn(C(13)H(14)N(2))(4)(H(2)O)(2)](ClO(4))(2).1.5H(2)O, the Mn(II) ion is coordinated by four N atoms from four different 1,3-di-4-pyridyl propane mol-ecules and two O atoms from two coordinated water mol-ecules, leading to a distorted MnN(4)O(2) octa-hedral geometry. Each 1,3-di-4-pyridyl-propane ligand displays a monodentate coordinating mode. In the crystal, there exist O H?O, O-H?N and C-H?O hydrogen bonds. The perchlorate anions and the coordinated and lattice water mol-ecules play an important role in the formation of these hydrogen bonds. One of the two lattice water molecules shows half-occupancy. PMID- 22219787 TI - Poly[[MU-2,2'-diethyl-1,1'-(propane-1,3-di-yl)di-1H-imidazole-kappaN:N](MU-5-hy droxy-isophthalato-kappaO:O)zinc]. AB - In the title coordination polymer, [Zn(C(8)H(4)O(5))(C(13)H(20)N(4))](n), the Zn(II) ion is coordinated by an O(2)N(2) donor set in a distorted tetra-hedral geometry. The Zn(II) ions are connected by 5-hy-droxy-isophthalate (hbdc) and 2,2'-diethyl-1,1'-(propane-1,3-di-yl)di-1H-imidazole (pbie) ligands, forming a threefold inter-penetrating diamondoid framework. In the pbie ligand, one of the ethyl-imidazole groups is disordered over two positions, with a site-occupancy ratio of 0.670 (9):0.330 (9). An inter-molecular O-H?O hydrogen bond is formed between the hy-droxy and carboxyl-ate groups of the hbdc ligands. PMID- 22219788 TI - Poly[[diaqua-bis-(MU(3)-3-carboxyl-ato-4-hy-droxy-benzene-sulfonato)-tri-MU(2) pyrazine-tetra-silver(I)] dihydrate]. AB - The title coordination polymer, {[Ag(4)(C(7)H(4)O(6)S)(2)(C(4)H(4)N(2))(3)(H(2)O)(2)].2H(2)O}(n), contains two independent Ag(I) ions. One Ag(I) ion is coordinated by one O atom from a 3 carboxyl-ato-4-hy-droxy-benzene-sulfonate (L) ligand, two N atoms from two pyrazine ligands and a water mol-ecule. The other Ag(I) ion is coordinated by two O atoms from two L ligands and one N atom from a pyrazine ligand. One of the pyrazine ligands lies on an inversion center. The L and pyrazine ligands link the Ag(I) ions into polymeric layers parallel to the ac plane. The layers are connected by inter-molecular O-H?O hydrogen bonds. An intra-molecular O-H?O hydrogen bond is also present in the L ligand. PMID- 22219789 TI - catena-Poly[[[(2,2'-bipyridine-kappaN,N')cobalt(II)]-MU-(E)-3,3'-(but-2-ene-2,3 di-yl)dibenzoato-kappaO,O':O'',O'''] hemihydrate]. AB - The title coordination polymer, {[Co(C(18)H(14)O(4))(C(10)H(8)N(2))].0.5H(2)O}(n), features a helical polymeric chain that runs along the b axis. The Co atoms are chelated by the carboxyl-ate groups of two 3,3'-(but-2-ene-2,3-di-yl)dibenzoate ligands and the N atoms of a 2,2'-bipyridine ligand. The lattice water mol-ecule is disordered about a center of inversion and is connected to the chain by an O-H?O hydrogen bond. The Co(II) atom shows a distorted octa-hedral coordination. PMID- 22219790 TI - Poly[[diaqua[MU(5)-(R,S)-2-({2-[(1,2-di-carboxyl-atoeth-yl)amino]-eth-yl}amino) butane-dioato]cobaltate(III)sodium] di-hydrate]. AB - In the asymmetric unit of the title coordination polymer, {[CoNa(C(10)H(12)N(2)O(8))(H(2)O)(2)].2H(2)O}(n), the Co(II) ion is coord-inated in a distorted octa-hedral environment, defined by two N atoms and four carboxyl ate O atoms. Two Co(II) ions and two 2-({2-[(1,2-dicarboxyl-atoeth-yl)amino]-eth yl}amino)-butane-dio-ate (EDDS) ligands form a dimeric complex dianion [Co(2)(EDDS)(2)]. These dimeric units are connected via Na(+) ions, forming a three-dimensional polymeric structure. In the crystal, the ligand N-H groups and the coordinated and solvent water mol-ecules are involved in inter-molecular N H?O and O-H?O hydrogen bonding, reinforcing the three-dimensional polymeric structure. PMID- 22219791 TI - The one-dimensional coordination polymer poly[tetra-kis-[(4-chloro-phen yl)methanaminium] [cadmate-MU-cyclo-hexa-phospho-rato]]. AB - Cyclo-hexa-phospho-ric acid (P(6)O(18)H(6)) reacts with cadmium carbonate and 4 chloro-benzyl-amine (CBA) to give the mononuclear title complex, (C(7)H(9)ClN)(4)[Cd(P(6)O(18))](n), in which the Cd(II) atom, lying on an inversion centre, has an octa-hedral coordination built of six O atoms of two centrosymmetric P(6)O(18) rings. Each P(6)O(18) ligand acts as a bridge, linking two Cd(II) atoms and forming an anionic coordination polymer [Cd(P(6)O(18))(4 )](n) extending along [010]. Adjacent polymeric chains are connected through N H?O and C-H?O hydrogen bonds, generating a three-dimensional supra-molecular network. PMID- 22219792 TI - Tris[(1,4,7,10,13,16-hexa-oxacyclo-octa-deca-ne)rubidium] heptaantimonide-ammonia (1/4). AB - The crystal structure of the title compound, [Rb(C(12)H(24)O(6))](3)[Sb(7)].4NH(3), fills the gap between the already known Zintl anion ammoniates {[Cs(18-crown-6)](3)Sb(7)}(2).9NH(3) [Wiesler (2007 ?). Dissertation, Universitat Regensburg, Germany] and [K(18-crown-6)](3)Sb(7).4NH(3) [Hanauer (2007 ?). Dissertation, Universitat Regensburg, Germany]. As in the two known compounds, the anti-mony cage anion in this crystal structure is coordinated by three alkali cations. The coordination spheres of each of the cations are saturated by 18-crown-6 mol-ecules. The ammonia mol-ecules of crystallization are situated between the crown ethers. The neutral, mol-ecular [Rb(18-crown-6)](3)Sb(7) units are inter-connected by multiple dipole-dipole interactions between ammonia and 18-crown-6. PMID- 22219793 TI - Penta-carbonyl-1kappaC,2kappaC-[(diphenyl-phosphor-yl)diphenyl-phosphane-1kappaP] MU-ethane-1,2-dithiol-ato-1:2kappaS,S':S,S'-diiron(I)(Fe-Fe). AB - The dinuclear title compound, [Fe(2)(C(2)H(4)S(2))(C(24)H(20)OP(2))(CO)(5)] or (MU-SCH(2)CH(2)S-MU)Fe(2)(CO)(5)[Ph(2)PP(O)Ph(2)], con-tains a butterfly-shaped Fe(2)S(2) core in which the Fe?Fe separation is 2.5275 (6) A. One of the Fe atoms is also coordinated to three carbonyl ligands and the other to two carbonyl ligands and one phosphane ligand [Ph(2)PP(O)Ph(2)]. Both Fe-atom geometries could be described as grossly distorted octa-hedral and the Ph(2)PP(O)Ph(2) ligand lies trans to the Fe?Fe link. PMID- 22219794 TI - catena-Poly[[[bis-(4-bromo-benzoato-kappaO)zinc]-MU-1,2-bis-(4-pyrid-yl)ethene kappaN:N'] acetonitrile monosolvate]. AB - In the title coordination compound, {[Zn(C(7)H(4)BrO(2))(2)(C(12)H(10)N(2))].CH(3)CN}(n), the Zn(II) atom is four coordinated in a distorted tetra-hedral environment by two carboxyl-ate O atoms from two different 4-bromo-benzoate (bpe) ligands and two N atoms from two symmetry-related 1,2-bis-(4-pyrid-yl)ethene ligands. The Zn(II) atoms are bridged by the bpe ligands, which lie across centres of inversion, forming a zigzag chain along [001]. The void space of each unit cell is occupied by an acetonitrile solvent mol-ecule, which is connected to the complex mol-ecule by a weak C-H?N hydrogen bond. PMID- 22219795 TI - Tetra-MU-acetato-kappaO:O'-bis-[(3-cyano-pyridine-kappaN)ruthenium(II,III)](Ru Ru) hexa-fluoridophosphate 1,2-dichloro-ethane monosolvate. AB - The title compound, [Ru(2)(CH(3)CO(2))(4)(C(6)H(4)N(2))(2)]PF(6).C(2)H(4)Cl(2), was obtained via a rapid substitution reaction in 2-propanol whereby 3-cyano pyridine replaces the axial water mol-ecules in the diaquatetra-MU-acetato diruthenium(II,III) hexa-fluorido-phosphate starting material. The product rapidly precipated and crystals were grown from 1,2-dichloro-ethane. The 1,2 dichloro-ethane mol-ecule of solvation exhibits disorder with two different orientations [occupancy ratio 0.51 (6):0.49 (6)]. All three parts, the cation, the anion and the disordered solvent mol-ecule lie on crystallographic inversion centers. The Ru-Ru bond length of 2.2702 (6) A fits nicely into the range seen for similar complexes and correlates well with the reduction potential of the complex and donor strength of the axial ligand, 3-cyano-pyridine, as postulated in a previous study [Vamvounis et al. (2000 ?). Inorg. Chim. Acta, 305, 87-98]. The 3-cyano-pyridine ligands orient themselves in an anti configuration with respect to each other and the Ru-Ru-N angle [174.27 (7) degrees ] is close to being linear. PMID- 22219796 TI - Dichlorido{N-[1-(pyrazin-2-yl)ethyl-idene-kappaN]ethane-1,2-diamine kappaN,N'}zinc. AB - The Zn(II) atom in the title complex, [ZnCl(2)(C(8)H(12)N(4))], is coordinated by two Cl atoms and three N atoms of the N-[1-(pyrazin-2-yl)ethyl-idene]ethane-1,2 diamine ligand, and displays a distorted square-pyramidal geometry with the apical position occupied by a Cl atom. In the crystal, inter-molecular N-H?Cl and C-H?Cl hydrogen bonds link the mol-ecules into a three-dimensional framework. PMID- 22219797 TI - Dibromido{2-[(4-nitro-phen-yl)imino-meth-yl]pyridine-kappaN,N'}zinc(II). AB - In the title compound, [ZnBr(2)(C(12)H(9)N(3)O(2))], the Zn(II) ion is bonded to two Br ions and two N atoms of the diimine ligand in a distorted tetra-hedral geometry. With the exception of the Br atoms, all other atoms are disordered over two sets of sites corresponding to a 180 degrees rotation of the mol-ecule along [[Formula: see text]02]. The refined occupancies of the components are 0.809 (2) and 0.191 (2). In addition, the crystal studied was a non-merohedral twin with a refined component ratio of 0.343 (2):0.657 (2). PMID- 22219798 TI - Poly[(MU(3)-biphenyl-3,3'-dicarboxyl-ato)(1,10-phenanthroline)cadmium]. AB - In the title compound, [Cd(C(14)H(8)O(4))(C(12)H(8)N(2))](n), the Cd(II) ion is seven-coordinated in a distorted penta-gonal-bipyramidal coordination geometry by five O atoms from bridging biphenyl-3,3'-dicarboylate (dpda) ligands and two N atoms from a 1,10-phenanthroline (1,10-phen) ligand. In the crystal, dinuclear units with a Cd?Cd separation of 3.8208 (7) A are observed. Each of these dinuclear units is bridged via 3,3'-bpda in a chelating/chelating and bridging fashion, generating a zigzag chain along the c axis. Neighboring chains are further packed via weak pi-pi inter-actions between inter-chain parallel 1,10 phen rings [centroid-centroid distance = 3.5197 (9) A] into a three-dimensional supra-molecular architecture. PMID- 22219799 TI - Diaqua-bis-(pyridine-2-carboxyl-ato-kappaN,O)manganese(II) dimethyl-formamide hemisolvate. AB - There are two crystallographically independent complex mol-ecules with very similar geometries in the unit cell of the title compound, [Mn(C(6)H(4)NO(2))(2)(H(2)O)(2)].0.5C(3)H(7)NO. The central ion is situated in a distorted octa-hedral environment of two N- and four O-donor atoms from two pyridine-2-carboxyl-ate ligands and two cis-disposed water mol-ecules. The carboxyl-ate ligands are coordinated in a chelate fashion with the formation of two five-membered rings. In the crystal, the complex mol-ecules are connected by O-H?O hydrogen bonds between the coordinated water mol-ecules and the uncoordinated carboxyl-ate O atoms, thus forming hydrogen-bonded walls disposed perpendicularly to the bc plane. PMID- 22219800 TI - catena-Poly[(triaqua-cadmium)-MU-5-hy-droxy-isophthalato-kappaO,O:O]. AB - The title compound, [Cd(C(8)H(4)O(5))(H(2)O)(3)](n), a one-dimensional chain complex of 5-hy-droxy-isophthalate with Cd(II), was prepared by a hydro-thermal reaction. The Cd(II) ion is coordinated by three water O atoms and three carboxyl ate O atoms of two different 5-hy-droxy-isophthalate ligands, which act as bidentate and monodentate ligands. The crystal structure is stabilized by O-H?O hydrogen bonds. PMID- 22219801 TI - cyclo-Tetra-MU-fluorido-1:2kappaF;2:3kappaF;3:4kappaF;1:4kappaF-octa-nitrato 1kappaO,O';3kappaO,O'-tetra-kis-(1,10-phenanthroline)-2kappaN,N';4kappaN,N'-2,4 dichromium(III)-1,3-dineodymium(III) methanol tetra-solvate monohydrate. AB - In the title compound, [Cr(2)Nd(2)F(4)(NO(2))(8)(C(12)H(8)N(2))(4)].4CH(3)OH.H(2)O, two cis difluoridobis(1,10-phenanthroline)chromium(III) fragments containing octa hedrally coordinated chromium(III) bridge via fluoride ions to two tetra nitratoneodymate(III) fragments, forming an uncharged tetra-nuclear square-like core. The fluoride bridges are fairly linear, with Cr-F-Nd angles of 168.74 (8) degrees . Cr-F bond lengths are 1.8815 (15) A, slightly elongated compared to those of the parent chromium(III) complex, which has bond lengths ranging from 1.8444 (10) to 1.8621 (10) A. The tetra-nuclear complex is centered at a fourfold rotoinversion axis, with the Cr and Nd atoms situated on two perpendicular twofold rotation axes. The uncoordinated water mol-ecule resides on a fourfold rotation axis. The four methanol solvent mol-ecules are located around this axis, forming a cyclic hydrogen-bonded arrangement. The title compound is the first structurally characterized example of unsupported fluoride bridges between lanthanide and transition metal ions. PMID- 22219802 TI - Hexa-kis-(dimethyl-formamide-kappaO)manganese(II) MU-oxido-bis-[trichlorido ferrate(III)]. AB - The title compound, [Mn(C(3)H(7)NO)(6)][Fe(2)Cl(6)O], was obtained unintentionally as a product of an attempted synthesis of heterometallic complexes with Schiff base ligands using manganese powder and FeCl(3).6H(2)O as starting materials. In the [Fe(2)OCl(6)](2-) anion, the O atom and the Fe atom occupy positions with site symmetry [Formula: see text] and 3, respectively, resulting in a linear Fe-O-Fe angle and a staggered conformation. The octa hedrally surrounded cation (site symmetry [Formula: see text]) and the [Fe(2)Cl(6)O](2-) anion are alternately stacked along [001]. PMID- 22219803 TI - Tetra-MU-2-methyl-benzoato-kappaO:O'-bis-[(ethanol-kappaO)copper(II)]. AB - In the title dinuclear complex, [Cu(2)(C(8)H(7)O(2))(4)(C(2)H(5)OH)(2)], four 2 methyl-benzoato anions form a cage around two Cu(II) ions in a syn-anti configuration. Two ethanol mol-ecules coordinate the Cu atoms in apical positions, giving an overall square-pyramidal coordination geometry. The Cu?Cu separation is 2.600 (1) A. In the crystal, mol-ecules are assembled into chains extending in [001] through O-H?O hydrogen bonds. PMID- 22219804 TI - Bis{MU-1,3-bis-[(2-methyl-1H-benzimid-azol-1-yl)meth-yl]benzene-kappaN:N}bis (diiodidocadmium). AB - In the title compound, [Cd(2)I(4)(C(24)H(22)N(4))(2)], the 1,3-bis-[(2-methyl-1H benzimidazol-1-yl)meth-yl]benzene ligand bridges two CdI(2) units, forming a centrosymmetric dinuclear complex. The Cd(II) atom adopts a distorted tetra hedral coordination geometry. In the crystal, complex mol-ecules are linked into columns parallel to [101] by pi-pi stacking inter-actions, with centroid-centroid distances of 3.558 (2) A. PMID- 22219805 TI - 1-Butyl-pyridinium bis-(1,2-dicyano-ethene-1,2-dithiol-ato)nickelate(III). AB - The Ni(III) atom in the anion of the title complex, (C(9)H(14)N)[Ni(C(4)N(2)S(2))(2)], is coordinated by four S atoms of two maleonitrile-dithiol-ate ligands, and exhibits a square-planar coordination geometry. PMID- 22219806 TI - MU-Oxido-bis-[bis-(phenanthroline-kappaN,N')(sulfato-kappaO)iron(III)] octa hydrate. AB - The title complex, [Fe(2)O(SO(4))(2)(C(12)H(8)N(2))(4)].8H(2)O, contains two unique Fe(III) cations, one oxide anion, four 1,10-phenanthroline (phen) ligands, two coordinated sulfate anions and eight lattice water mol-ecules. Each Fe(III) ion has an approximate octa-hedral geometry, coordinated by four N atoms from two phen mol-ecules, two O atoms from oxide and sulfate anions, respectively. The parallel phen mol-ecules form two-dimensional supermolecules through pi-pi stacking inter-actions [centroid-centroid distances = 3.684 (3), 3.711 (3), 3.790 (3), 3.847 (3), 3.746 (3), 3.732 (3) and 3.729 (3) A]. This architecture is further stabilized by O-H?O hydrogen bonds involving the lattice water mol-ecules and sulfate O atoms. PMID- 22219807 TI - 1-(3,4-Dichloro-benz-yl)pyridinium bis-(2-sulfanyl-idene-1,3-dithiole-4,5-dithiol ato-kappaS,S')nickelate(III). AB - The title compound, (C(12)H(10)Cl(2)N)[Ni(C(3)S(5))(2)], is an ion-pair complex consisting of 1-(3,4-dichloro-benz-yl)pyridinium cations and [Ni(dmit)(2)] anions (dmit = 2-sulfanyl-idene-1,3-dithiole-4,5-dithiol-ate). In the anion, the Ni(III) ion exhibits a square-planar coordination involving four S atoms from two dmit ligands. In the crystal, weak S?S [3.368 (2) and 3.482 (3) A], Ni?S [3.680 (2) A] and Cl?S [3.491 (2) A] inter-actions and C-H?S hydrogen bonds lead to a three dimensional supra-molecular network. PMID- 22219808 TI - [N,N-Bis(diphenyl-phosphan-yl)benzyl-amine-kappaP,P']dichloridonickel(II) dichloro-methane monosolvate. AB - In the title solvated complex, [NiCl(2)(C(31)H(27)NP(2))].CH(2)Cl(2), the Ni(2+) ion is coordinated by two chloride ions and two P atoms of the chelating N,N-bis (diphenyl-phosphan-yl)benzyl ligand to generate a strongly distorted cis NiCl(2)P(2) square-planar geometry for the metal ion. In the crystal, the components are linked by C-H?Cl inter-actions. PMID- 22219809 TI - [N,N-Bis(diphenyl-phosphan-yl)propanamine-kappaP,P']dichloridonickel(II). AB - In the title complex, [NiCl(2)(C(27)H(27)NP(2))], the Ni(2+) ion is coordinated by two chloride ions and two P atoms of the bidentate N,N-bis-(diphenyl-phosphan yl)propyl ligand to generate a strongly distorted cis-NiCl(2)P(2) square-planar geometry for the metal ion. A NiP(2)N rhombus occurs within the chelating ligand. PMID- 22219810 TI - [1-tert-Butyl-3-(pyridin-2-ylmethyl-kappaN)imidazol-2-yl-idene-kappaC]carbonyl dichlorido(dimethyl sulfoxide-kappaS)ruthenium(II). AB - In the title complex, [RuCl(2)(C(13)H(17)N(3))(C(2)H(6)OS)(CO)], the coordination environment around the Ru atom is slightly distorted octa-hedral. The Cl atoms are mutually trans to the dimethyl sulfoxide ligand and the imidazole carbene C atom, respectively. The carbonyl ligand is located trans to the pyridine N atom. PMID- 22219811 TI - Poly[[tetra-aqua-tetra-kis-[MU(3)-5-(pyridine-4-carboxamido)-isophthalato] cobalt(II)-diholmium(III)] tetra-hydrate]. AB - In the centrosymmetric polymeric title compound, {[CoHo(2)(C(14)H(8)N(2)O(5))(4)(H(2)O)(4)].4H(2)O}(n), the Ho(III) ion is coordinated by one water mol-ecule and four 5-(pyridine-4-carboxamido) isophthalate (L) ligands in a distorted square-anti-prismatic arrangement. The Co(II) ion, located on an inversion center, is coordinated by two pyridine N atoms, two carboxyl-ate O atoms and two water mol-ecules in a distorted octa hedral geometry. One L ligand bridges two Ho ions and one Co ion through two carboxyl-ate groups and one pyridine N atom. The other L ligand bridges two Ho ions and one Co ion through two carboxyl-ate groups, while the uncoordinated pyridine N atom accepts a hydrogen bond from an adjacent coordinated water mol ecule. Extensive O-H?O, N-H?O and O-H?N hydrogen bonding is present in the crystal. PMID- 22219812 TI - trans-(5,7,7,12,14,14-Hexamethyl-1,4,8,11-tetra-aza-cyclo-tetra-deca-4,11-diene kappaN,N',N'',N''')bis-(nitrito-kappaN)cobalt(III) perchlorate hemihydrate. AB - The asymmetric unit of the title Co(III) complex, [Co(NO(2))(2)(C(16)H(32)N(4))]ClO(4).0.5H(2)O, comprises two complex cations, two perchlorate anions and a water mol-ecule of crystallization. The Co(III) atoms exist within distorted octa-hedral N(6) geometries defined by four N atoms of the macrocycle ligand and trans-N atoms derived from the nitrite anions. Systematic variations in the Co-N bond lengths are correlated with the presence of intra molecular N-H?O(nitrite) hydrogen bonds. In the crystal, water-O-H?O(perchlorate) hydrogen bonds, involving one of the independent perchlorate anions only, lead to supra-molecular chains along the b-axis direction. The three-dimensional architecture is consolidated by numerous C-H?O inter-actions. The crystal studied was a non-merohedral, racemic twin. PMID- 22219813 TI - Bis(MU-diethyl-phosphido-kappaP:P)bis-[bis(2,4,6-trimethyl-phen-yl)indium(III)]. AB - The title compound, [In(2)(C(9)H(11))(4)(C(4)H(10)P)(2)], contains a centrosymmetric In(2)P(2) core with short inter-molecular In-P bonds. This core has acute P-In-P and obtuse In-P-In bond angles compared with other [R(2)InPR'(2)](2) analogues, due to the presence of the bulky aromatic substituents on the In atom and the non-sterically demanding ethyl substituents on the P atom. PMID- 22219814 TI - Di-MU-benzoato-kappaO,O':O';kappaO:O,O'-bis[aqua-bis-(benzoato kappaO,O')(dimethylformamide-kappaO)europium(III)]. AB - The title dimeric complex, [Eu(2)(C(7)H(5)O(2))(6)(C(3)H(7)NO)(2)(H(2)O)(2)], is centrosymmetric, implying that pairs of equivalent Eu(3+) ions and ligands lie trans to each other and that the two Eu(3+) ions have exactly the same coordination environment. Each Eu(3+) ion is nine-coordinated by two bidentate benzoate ligands, two bridging tridentate chelating benzoate ligands, and one dimethylformamide and one water molecule. The coordination polyhedron of each Eu(3+) ion can be described with a distorted monocapped square-anti-prismatic geometry. The mol-ecular structure is stabilized by intra- and inter-molecular hydrogen bonds between the water mol-ecules and benzoate O atoms. PMID- 22219815 TI - [(4E,11E)-5,7,12,14-Tetra-benzyl-7,14-dimethyl-1,4,8,11-tetra-aza-cyclo-tetra deca-4,11-diene]copper(II) bis(per-chlorate). AB - The complete cation in the title compound, [Cu(C(40)H(48)N(4))](ClO(4))(2), is generated by the operation of a crystallographic centre of inversion. The Cu(II) ion exists in a tetra-gonally distorted trans-N(4)O(2) coordination geometry defined by the four N atoms of the macrocyclic ligand and two weakly bound perchlorate-O atoms from two anions. The N-H atoms form intra-molecular N H?O(perchlorate) hydrogen bonds. Disorder was resolved in the -CH(2)-NH- portion of the macrocycle with the major component having a site-occupancy factor of 0.570 (6). PMID- 22219816 TI - catena-Poly[[lead(II)-MU-(2-oxidobenz-aldehyde isonicotinoylhydrazonato)] methanol monosolvate]. AB - The Pb atom in the polymeric title compound, {[Pb(C(13)H(9)N(3)O(2))].CH(3)OH}(n), is five-coordinated within an N(2)O(2) donor set and a lone pair of electrons, as the N-isonicotinamido salicylaldiminate ligand coordinates the Pb(II) atom via the O,N,O'-donors and simultaneously bridges a neighbouring Pb atom via the pyridine N atom; the coordination geometry is based on a trigonal bipyramid with the O atoms in axial positions. The resulting supra-molecular chain is a 3(1) helix along the c axis. These chains are linked via inter-molecular Pb?O,N inter-actions, as well as O H?O hydrogen bonds. PMID- 22219817 TI - catena-Poly[2-methyl-1H-imidazol-3-ium [(aqua-chloridocadmate)-di-MU-chlorido]]. AB - The asymmetric unit of the title compound, {(C(4)H(7)N(2))[CdCl(3)(H(2)O)]}(n), contains one 1-methyl-1H-imidazol-3-ium cation, one Cd(II) atom, three Cl atoms and one water mol-ecule. Adjacent Cd ions are inter-connected alternately by paired Cl(-) bridges to generate an infinite one-dimensional coordination chain along the b axis. In the chain, the crystallographically unique Cd(II) atom, with a distorted octa-hedral geometry, is coordinated by five Cl(-) ions and one water mol-ecule. Intra-chain O-H?Cl hydrogen bonding and N-H?Cl hydrogen bonding between the cations and the anionic chains consolidate the crystal packing. PMID- 22219818 TI - catena-Poly[[bis-(1-ethyl-1H-imidazole-kappaN)copper(II)]-MU-oxalato kappaO,O:O,O]. AB - The title compound, [Cu(C(2)O(4))(C(5)H(8)N(2))(2)](n), is composed of one dimensional linear chains running parallel to the a axis. In the chain, trans [Cu(imidazole)(2)](2+) units are sequentially bridged by bis-bidentate oxalate ligands, resulting in an octa-hedral CuO(4)N(2) donor set. The Cu?Cu separation through the oxalate bridge is 5.620 (5) A. Both the Cu atoms and the C-C bond of the oxalate bridge are bis-ected by inversion centres. PMID- 22219819 TI - Bis(benzyl-trimethyl-ammonium) dichromate(VI). AB - The asymmetric part of the title compound, (C(10)H(16)N)(2)[Cr(2)O(7)], contains one cation and a half of the dichromate dianion, which has a staggered conformation and exhibits disorder of the bridging O atom around the inversion center over two positions in a 1:1 ratio. Weak inter-molecular C-H?O hydrogen bonds link cations and anions into a three-dimensional structure. PMID- 22219820 TI - Poly[(MU(2)-4,4'-bipyridine-kappaN:N')bis-(MU(2)-2-phen-oxy-propionato kappaO:O')cobalt(II)]. AB - In the polymeric title compound, [Co(C(9)H(9)O(3))(2)(C(10)H(8)N(2))](n), the Co(II) ion is located on a twofold rotation axis and is six-coordinated by two N atoms from two 4,4'-bipyridine (4,4'-bipy) ligands in axial positions and by four O atoms from four 2-phen-oxy-propionate (POPA) anions in equatorial positions, defining a slightly distorted octa-hedral geometry. The carboxyl-ate group of the POPA anion displays a bis-monodentate mode, linking pairs of Co(II) ions into a chain parallel to [001]. Adjacent chains are connected in a perpendicular manner through 4,4'-bipy ligands into layers parallel to (100). The 4,4'-bipy ligand is likewise located on a twofold rotation axis, with a dihedral angle between the two pyridine rings of 57.05 (7) degrees . C-H?O hydrogen-bonding inter-actions are present within the layers. pi-pi stacking inter-actions between the POPA benzene rings of neighbouring layers [centroid-to-centroid distance = 3.976 (3) A and plane-to-plane distance = 3.618 (3) A] stabilize the packing of the structure. PMID- 22219821 TI - Tris(2,2'-bi-1H-imidazole-kappaN,N)-nickel(II) dinitrate N,N-dimethyl-formamide monosolvate. AB - The reaction of nickel salts and 4,4'-bipyridine with 2,2'-bi-imidazole (H(2)biim) yielded the title complex, [Ni(C(6)H(6)N(4))(3)](NO(3))(2).C(3)H(7)NO. The Ni(II) atom is chelated by three H(2)biim ligands in a distorted octa-hedral coordination geometry. The two nitrate anions and one dimethyl-formamide (DMF) mol-ecule are not coordinated. The compound has a three-dimensional structure, formed by extensive hydrogen bonding between [Ni(H(2)biim)(3)](2+) cations and nitrate anions, each nitrate anion forming hydrogen bonds with an R(1) (2)(4) motif. The DMF molecule is disordered over three sets of sites, with occupancy ratios of 0.341 (16):0.350 (17):0.309 (19). PMID- 22219822 TI - Poly[tetra-aquadi-MU(4)-oxalato-lutetium(III)potassium]. AB - In the title compound, [KLu(C(2)O(4))(2)(H(2)O)(4)](n), the Lu(III) ion lies on a site of [Formula: see text] symmetry in a dodeca-hedron defined by eight O atoms from four oxalate ligands. The K atom lies on another site of the same symmetry and is coordinated by four oxalate O atoms and four O water atoms. The mid-point of the C-C bond of the oxalate group lies on an inversion center. In the packing structure, each oxalate ligand links two Lu(III) and two K atoms, forming a three dimensional open framework with channels running along [001]. Inter-molecular O H?O hydrogen bonds occur. PMID- 22219823 TI - Dichlorido(furfuryl-amine-kappaN)(eta-hexa-methyl-benzene)-ruthenium(II). AB - The single-crystal X-ray structure analysis of [RuCl(2)(C(12)H(18))(C(5)H(7)NO)] reveals a distorted piano-stool geometry around the Ru(II) atom, with a hexa methyl-benzene ligand, two chloride ligands and a furfuryl-amine ligand, the latter coordinating through the amine group. In the crystal, a dimeric structure is observed as a result of N-H?Cl inter-actions between two symmetry-related mol ecules. PMID- 22219824 TI - Poly[(MU(2)-4,4'-bipyridine-kappaN:N')(MU(2)-2,2-dimeth-yl-cyclo-pentane-1,3 dicarboxyl-ato-kappaO,O:O,O)cadmium]. AB - In the title polymeric compound, [Cd(C(9)H(12)O(4))(C(10)H(8)N(2))](n), the Cd(II) atom is located on a twofold rotation axis and is coordinated by two 4,4' bipyridine ligands and two 2,2-dimethyl-cyclo-pentane-1,3-dicarboxyl-ate ions. The carboxyl-ate ion and the N-heterocycle both function as bridges to link adjacent Cd(II) atoms to result in the formation of a layer structure parallel to (010). The mid-point of the central C-C bond of the 4,4'-bipyridine ligand is located on an inversion center. In the crystal, the carboxyl-ate ion is disordered over a twofold rotation axis in respect of its methyl group and the cyclo-pentane ring. PMID- 22219825 TI - Poly[tetra-MU-aqua-diaqua-tetra-kis-[MU-(E)-2-nitro-cinnamato]tetra-rubidium]. AB - In the structure of the title compound, [Rb(4)(C(9)H(6)NO(4))(4)(H(2)O)(6)](n), the asymmetric unit comprises four rubidium cations, two of which have an RbO(7) coordination polyhedron with a monocapped distorted octa-hedral stereochemistry and two of which have a distorted RbO(6) octa-hedral coordination. The bonding about both the seven-coordinate cations is similar, comprising one monodentate water mol-ecule together with three bridging water mol-ecules and three carboxyl ate O-atom donors, two of which are bridging. The environments around the six coordinate cations are also similar, comprising a monodentate nitro O-atom donor, a bridging water mol-ecule and four bridging carboxyl-ate O-atom donors [overall Rb-O range = 2.849 (2)-3.190 (2) A]. The coordination leads to a two-dimensional polymeric structure extending parallel to (001), which is stabilized by inter layer water O-H?O hydrogen-bonding associations to water, carboxyl and nitro O atom acceptors, together with weak inter-ring pi-pi inter-actions [minimum ring centroid-centroid separation = 3.5319 (19) A]. PMID- 22219826 TI - fac-Tris(pyridine-2-carboxyl-ato-kappaN,O)cobalt(III). AB - In the title compound, [Co(C(6)H(4)NO(2))(3)], the Co(III) ion lies on a threefold rotation axis and is in a distorted octa-hedral environment defined by three N and three O donor atoms from three fac-disposed pyridine-2-carboxyl-ate ligands. The ligands are coordinated in a chelate fashion, forming three five membered rings. In the crystal, translationally related complex molecules are organized into columns along [001] via C-H?O hydrogen bonds. PMID- 22219827 TI - Bis{MU-2-[1-(pyridin-2-yl-methyl-imino)-eth-yl]phenolato}bis-(azido-zinc). AB - The title compound, [Zn(2)(C(14)H(13)N(2)O)(2)(N(3))(2)], is a phenolate-bridged centrosymmetric dinuclear zinc(II) complex. The Zn?Zn distance is 3.076 (1) A. Each Zn atom is five-coordinated by two O and two N atoms from two Schiff base ligands, and by one azide N atom, forming a square-pyramidal geometry. PMID- 22219828 TI - Poly[[MU(2)-1,2-bis-(4-pyrid-yl)ethene](MU(3)-1,3-phenyl-enediacetato)-cadmium]. AB - In the title coordination polymer, [Cd(C(10)H(8)O(4))(C(12)H(10)N(2))](n), two centrosymmetrically related Cd(II) atoms are bridged by two 1,3-phenyl enediacetate ligands forming a chain along the [100] direction. The distorted penta-gonal-bipyramidal coordination about each metal atom is completed by the N atoms of bridging 1,2-bis-(4-pyrid-yl)ethene ligands, which link these one dimensional chains into a two-dimensional net extending along the (101) plane. PMID- 22219829 TI - Hexa-kis-(1H-imidazole-kappaN)iron(II) sulfate-1H-imidazole (1/2). AB - The asymmetric unit of the title compound, [Fe(C(3)H(4)N(2))(6)]SO(4).2C(3)H(4)N(2), contains two complex cations, two sulfate anions and four imidazole mol-ecules. In both cations, the Fe(II) atom is coordinated by six monodentate imidazole ligands and exhibits a slightly distorted octa-hedral coordination geometry. The Fe-N distances [2.184 (4)-2.218 (4) A] point to a high-spin state of the Fe(2+) ions. N-H?O hydrogen bonds between the ionic components generate a three-dimensional framework containing corrugated channels along [001], which are filled by N-H?N hydrogen-bonded imidazole chains. PMID- 22219830 TI - Tris(2-amino-pyridinium) hexa-chlorido-indate(III). AB - The Schiff base (E)-4-chloro-2-[(pyridin-2-yl-imino)-meth-yl]phenol was reacted with InCl(3).4H(2)O, generating the title molecular salt, (C(5)H(7)N(2))(3)[InCl(6)]. The octa-hedral hexa-chlorido-indate(III) anion is located on an inversion centre, and one half of the anion and two crystallographically independent cations form the asymmetric unit. One of the cations is located on a twofold rotation axis and its intra-ring C and N atoms simulate this symmetry by exchanging their positions in statistical disorder. In the crystal, weak N-H?Cl hydrogen bonds and two types of pi-pi interactions with centroid-centroid separations of 4.047 (3) and 4.202 (3) A are observed. PMID- 22219831 TI - trans-Bis(thio-cyanato-kappaN)tetra-kis-(3,4,5-trimethyl-1H-pyrazole kappaN)nickel(II)-3,4,5-trimethyl-1H-pyrazole (1/1). AB - In the title compound, [Ni(NCS)(2)(C(6)H(10)N(2))(4)].C(6)H(10)N(2), the asymmetric unit comprises a Ni(II) complex and a co-crystallised mol-ecule of 3,4,5-trimethyl-1H-pyrazole (PzMe(3)). The Ni(II) atom is coordinated by four PzMe(3) mol-ecules and two thio-cyanate anions to define a trans N(4)S(2) distorted octa-hedral geometry. A number of intra-molecular N-H?N, N-H?S and C H?N inter-actions contribute to the stability of the complex. The crystal structure is stabilized by inter-molecular N-H?S inter-actions, which link neighbouring mol-ecules into chains along the a axis. PMID- 22219832 TI - 1-Methyl-piperazine-1,4-diium tetra-chloridozincate hemihydrate. AB - The crystal structure of the title compound, (C(5)H(14)N(2))[ZnCl(4)].0.5H(2)O, is built up from discrete 1-methyl-piperazine-diium cations with chair conformation, tetrahedral tetrachloridozincate anions and uncoordinated solvent water mol-ecules linked together by three types of inter-molecular hydrogen bonds, viz. N-H?Cl, N-H?O and O-H?Cl. PMID- 22219833 TI - Bis{1-[4-(benz-yloxy)phen-yl]-4,4,4-tri-fluoro-butane-1,3-dionato(1-)}dipyri-dine cobalt(II). AB - In the title compound, [Co(C(17)H(12)F(3)O(3))(2)(C(5)H(5)N)(2)], the Co(II) ion is situated on a twofold rotation axis, coordinated by four O atoms from two 1-[4 (benz-yloxy)phen-yl]-4,4,4-trifluoro-butane-1,3-dionate(1-) (L) ligands and two N atoms from two pyridine ligands in a distorted octa-hedral geometry. The two pyridine rings form a dihedral angle of 84.63 (7) degrees . The two benzene rings in L are twisted at 58.83 (5) degrees . Weak inter-molecular C-H?F hydrogen bonds consolidate the crystal packing. PMID- 22219834 TI - 1-(4-Iodo-benz-yl)-3-methyl-pyridinium bis-(benzene-1,2-dithiol ato)nickelate(III). AB - The asymmetric unit of the title compound, (C(13)H(13)IN)[Ni(C(6)H(4)S(2))(2)], contains half each of two centrosymmetric anions and a single cation in a general position. In the anions, the Ni(III) ions are surrounded by four S atoms in a distorted square-planar geometry. In the crystal, the anions exhibit two different packing modes by stacking along the a axis in face-to-face and side-by side fashions. Inter-ionic C-H?S hydrogen bonds and pi-pi stacking inter-actions [centroid-centroid distance = 3.6947 (5) A] are observed. PMID- 22219835 TI - catena-Poly[[zinc-MU-[2-(2-{[2-(2-hy-droxy-benzo-yl)hydrazinyl-idene]meth-yl}phen oxy)acetato-(2-)]] monohydrate]. AB - In the title compound, {[Zn(C(16)H(12)N(2)O(5))].H(2)O}(n), the unique Zn(II) ion is coordinated in a distorted square-pyramidal environment by three O atoms and one N atom from a symmetry-unique ligand. A symmetry-related ligand provides an O atom from a carboxyl-ate group to complete the coordination in the apical site and generate a one-dimensional polymer parallel to [010]. In addition to an intra molecular O-H?N hydrogen bond, inter-molecular O-H?O and weak C-H?O hydrogen bonds are observed within the one-dimensional structure. PMID- 22219836 TI - Diaqua-bis-(1,10-phenanthroline-kappaN,N')cadmium sulfate hexa-hydrate. AB - The title compound, [Cd(C(12)H(8)N(2))(2)(H(2)O)(2)]SO(4).6H(2)O, was obtained unexpectedly during an attempt to synthesize a cadmium complex with bidentate bridging sulfate ligands via hydro-thermal synthesis. The Cd(II) metal ion is six coordinated by two chelating 1,10-phenanthroline ligands and two water mol ecules, resulting in a distorted octa-hedral geometry for the metal ion. The two chelating N(2)C(2) groups are almost perpendicular to each other [dihedral angle = 86.75 (2) degrees ]. In the crystal, the [Cd(C(12)H(8)N(2))(2)(H(2)O)(2)](2+) complex cations join with the sulfate anions through two O(water)-H?O(sulfate) hydrogen bonds. These ion pairs are further inter-linked into a two-dimensional supermolecular structure via additional O-H?O hydrogen bonds. PMID- 22219837 TI - Bis[2,4-dichloro-6-(ethyl-imino-meth-yl)phenolato-kappaN,O]nickel(II). AB - In the title compound, [Ni(C(9)H(8)Cl(2)NO)(2)], the Ni(II) ion lies on an inversion centre and is coordinated in a slightly distorted square-planar geometry by an N and an O atom from two symmetry-related bidentate 2,4-dichloro-6 (ethyl-imino-meth-yl)phenolate ligands. In the crystal structure, there are short Cl?Cl distances of 3.506 (1) and 3.350 (1) A. PMID- 22219838 TI - Bis[MU-2-(pyridin-2-yl)ethano-lato]bis-[bromidocopper(II)]. AB - The title compound, [Cu(2)Br(2)(C(7)H(8)NO)(2)], was synthesized by reaction of CuBr(2) with 2-(pyridin-2-yl)ethanol (hep-H) in methanol. The asymmetric unit consists of one hep ligand and a CuBr unit. The Cu(2+) ion is thereby coordinated by the N atom and the deprotonated hydroxy O atom in a distorted square-planar geometry that is completed by another O atom. The latter acts as bridging ligand towards the second, symmetry-equivalent, Cu atom, thus generating a centrosymmetric dimeric unit, with the inversion centre halfway between the Cu atoms. These units are linked via C-H?Br and C-H?O hydrogen bonds, leading to the formation of a hydrogen-bonded one-dimensional-polymeric chain along a.. PMID- 22219839 TI - Dichlorido[1-(2-chloro-eth-yl)-3-(pyridin-4-ylmethyl-kappaN)urea](eta-hexa-methyl benzene)-ruthenium(II) chloro-form monosolvate. AB - The Ru(II) atom in the title compound, [RuCl(2)(C(12)H(18))(C(9)H(12)ClN(3)O)].CHCl(3), exhibits a typical piano-stool coordination, defined by a hexa-methyl-benzene ligand, two chloride ligands and a pyridyl-urea ligand coordinated through the pyridine N atom. In the crystal, a dimeric structure is observed due to two strong N-H?Cl inter-actions between the NH groups of urea and the two chloride ligands of neighbouring mol-ecules. In addition, the C=O group of the urea moiety inter-acts with the solvent mol-ecule through weak C-H?O interactions. PMID- 22219840 TI - The low-temperature structure of diethyl ether magnesium oxybromide. AB - The crystal structure of the title compound, hexa-MU(2)-bromido-MU(4)-oxido-tetra kis-[(diethyl ether)magnesium], [Mg(4)Br(6)O(C(4)H(10)O)(4)], determined from data measured at 173 K, differs from the previously known structure of diethyl ether magnesium oxybromide, which was determined from room-temperature data [Stucky & Rundle (1964 ?). J. Am. Chem. Soc. 86, 4821-4825]. The title compound crystallizes in the tetra-gonal space group I[Formula: see text], whereas the previously known structure crystallizes in a different tetra-gonal space group, namely P[Formula: see text]2(1)c. Both molecules have crystallographic [Formula: see text] symmetry and show almost identical geometric parameters for the Mg, Br and O atoms. The crystal of the title compound turned out to be a merohedral twin emulating a structure with apparent Laue symmetry 4/mmm, whereas the correct Laue group is just 4/m. The fractional contribution of the minor twin component converged to 0.462 (1). PMID- 22219841 TI - Dichlorido(2,3-di-2-pyridyl-pyrazine-kappaN,N)palladium(II). AB - The Pd(II) ion in the title complex, [PdCl(2)(C(14)H(10)N(4))], has a slightly distorted square-planar environment defined by the two pyridine N atoms of the chelating 2,3-di-2-pyridyl-pyrazine ligand and two chloride anions. The pyridine rings are considerably inclined to the least-squares plane of the PdCl(2)N(2) unit [maximum deviation = 0.073 (1) A], with dihedral angles of 64.19 (9) and 66.55 (9) degrees . The pyrazine ring is almost perpendicular to this plane and the dihedral angle is 88.2 (1) degrees . Two independent inter-molecular C-H?Cl hydrogen bonds, both involving the same Cl atom as a hydrogen-bond acceptor, give rise to chains running along the a and b axes, generating a layer structure extending parallel to (001). Mol-ecules are stacked in columns along the a axis. Along the b axis, successive mol-ecules stack in opposite directions. PMID- 22219842 TI - (2-{[1-(Pyridin-2-yl)ethyl-idene]amino-meth-yl}pyridine-kappaN,N',N'')bis-(thio cyanato-kappaN)zinc. AB - The complete mol-ecule of the title mononuclear zinc(II) complex, [Zn(NCS)(2)(C(13)H(13)N(3))], is generated by crystallographic twofold symmetry, with the metal atom lying on the rotation axis. The pendant methyl group of the ligand is statistically disordered over two sites. The Zn(2+) cation is coordinated by the N,N',N''-tridentate Schiff base ligand, and by two thio cyanate N atoms, forming a distorted ZnN(5) trigonal-bipyramidal geometry. PMID- 22219843 TI - catena-Poly[diaqua-(cis-cyclo-hexane-1,2-dicarboxyl-ato)cadmium]. AB - In the title polymer, [Cd(C(8)H(10)O(4))(H(2)O)(2)](n), the Cd(II) cation is coordinated by five carboxyl-ate O atoms from three different cyclo-hexane-1,2 dicarboxyl-ate anions and two O atoms from two water mol-ecules, displaying a distorted CdO(7) pentagonal-bipyramidal geometry. Each anion acts as a MU(3) bridge, linking symmetry-related Cd(II) ions into a layer parallel to (010). In the crystal, numerous O-H?O and C-H?O hydrogen bonds occur. The coordinated water mol-ecules and carboxyl-ate O atoms act as donors or acceptors in the formation of these hydrogen-bonding inter-actions. PMID- 22219844 TI - [6-(Hy-droxy-meth-yl)pyridin-2-yl]methyl ferrocene-1-carboxyl-ate. AB - The crystal structure of the title ferrocene derivative, [Fe(C(5)H(5))(C(13)H(12)NO(3))], shows strong inter-molecular O-H?N hydrogen bonds between the alcohol function and the pyridine group of a neighbouring mol ecule, while the pyridine function forms another hydrogen bond with the alcohol function of another neighbouring mol-ecule, resulting in the formation of chains along the a-axis direction. PMID- 22219845 TI - (R)-N-(Ferrocenylmeth-yl)-1-hy-droxy-3-phenyl-propan-2-aminium (E)-but-2-enoate. AB - The crystal structure of the title salt, [Fe(C(5)H(5))(C(15)H(19)NO)](C(4)H(5)O(2)), consists of discrete ammonium and carboxyl-ate ions, which associate into infinite chains parallel to [100] by means of N-H?O and O-H?O inter-actions. These chains are further cross-linked into a three-dimensional network by additional C-H?O contacts and by offset pi-pi stacking inter-actions of inversion-related aromatic rings [centroid-centroid distance = 3.7040 (14) A]. The mol-ecular parameters of the ionic components are in no way unexpected, the geometry of the ammonium cation being similar to that found in other structurally characterized salts obtained from N-ferrocenylmethyl beta-amino-alcohols. The (E)-but-2-enoate anion consists of two approximately planar subunits, viz the delocalized carboxyl-ate unit and the butenyl group (the latter being planar within ca. 0.002 A), which are mutually rotated by 30.3 (4) degrees . PMID- 22219846 TI - Bis(MU-4-bromo-benzoato)-kappaO,O':O';O:O,O'-bis-[MU-1,3-bis-(pyridin-4 yl)propane-kappaN:N']bis-[(4-bromo-benzoato-kappaO,O')cadmium]. AB - The dinuclear complex, [Cd(2)(C(7)H(4)BrO(2))(4)(C(13)H(14)N(2))(2)], lies on a twofold rotation axis crossing midway between the two metal atoms. The Cd(II) cation is seven-coordinated with a geometry that can be considered as distorted penta-gonal bipyramidal, with the N atom of the N-heterocyclic units occupying the apical sites and the O atoms of the 4-bromo-benzoate units in the equatorial plane. The middle methyl-ene group of the 1,3-bis-(4-pyrid-yl)propane ligands is located outside of the twofold rotation axis and consequently is disordered over two sites around this symmetry element with fixed occupancies factors of 0.5. PMID- 22219847 TI - Tris(3-methyl-anilinium) tetra-chlorido-zincate chloride hemihydrate. AB - The asymmetric unit of the title compound, (C(7)H(10)N)(3)[ZnCl(4)]Cl.0.5H(2)O, consists of three 3-methyl-anilinium cations, one tetrahedral tetra chloridozincate anion and one chloride anion and a water mol-ecule, which lies on a twofold axis. The components are linked into chains parallel to the a axis by N H?Cl hydrogen bonds. PMID- 22219848 TI - Bis[5-(4-bromo-phen-yl)-4-(tert-but-oxy-carbon-yl)pyrrolidine-2-carboxyl ato]copper(II) dihydrate. AB - In the title compound, [Cu(C(16)H(19)BrNO(4))(2)].2H(2)O, the Cu(II) ion resides on an inversion centre and is coordinated by two O and two N atoms from two enanti-omeric 5-(4-bromo-phen-yl)-4-(tert-but-oxy-carbon-yl)pyrrolidine-2 carboxyl-ate ligands in a distorted square-planar geometry. The relative stereochemistry of the three stereogenic C atoms in each ligand has been determined. In the crystal, inter-molecular N-H?O and O-H?O hydrogen bonds link the mol-ecules into layers parallel to the bc plane. The crystal studied was twinned by pseudo-merohedry with twin fractions of 0.719 (3) and 0.281 (3). PMID- 22219849 TI - Dichlorido{2-[(3,4-dimethyl-phen-yl)imino-meth-yl]pyridine-kappaN,N'}copper(II). AB - In the title complex, [CuCl(2)(C(14)H(14)N(2))], the Cu(II) atom exhibits a very distorted tetra-hedral coordination geometry involving two chloride ions and two N-atom donors from the Schiff base ligand. The range for the six bond angles about the Cu(2+) cation is 81.49 (11)-145.95 (9) degrees . The chelate ring including the Cu(II) atom is approximately planar, with a maximum deviation of 0.039 (4) A for one of the C atoms; this plane forms a dihedral angle of 46.69 (9) degrees with the CuCl(2) plane. PMID- 22219850 TI - Chlorido{N-[2-(diphenyl-phosphan-yl)benz-yl]-1-(pyridin-2-yl)methanamine kappaP}gold(I). AB - In the title compound, [AuCl(C(25)H(23)N(2)P)], the Au(I) atom is in a typical almost linear coordination environment defined by phosphane P and Cl atoms [bond angle = 175.48 (4) degrees ]. Helical supra-molecular chains along the b axis and mediated by N-H?Cl hydrogen bonds feature in the crystal packing. PMID- 22219851 TI - (2,3-Di-2-pyridyl-pyrazine-kappaN,N)diiodidopalladium(II). AB - The Pd(II) ion in the title complex, [PdI(2)(C(14)H(10)N(4))], is four coordinated in a slightly distorted square-planar environment by the two pyridine N atoms of the chelating 2,3-di-2-pyridyl-pyrazine (dpp) ligand and two iodide anions. In the crystal, the pyridine rings are considerably inclined to the least squares plane of the PdI(2)N(2) unit [maximum deviation = 0.090 (2) A], making dihedral angles of 65.0 (2) and 66.6 (2) degrees . The pyrazine ring is perpendicular to the unit plane, with a dihedral angle of 89.9 (2) degrees . The complex mol-ecules are connected by C-H?I hydrogen bonds, forming a helical chain along the b axis. PMID- 22219852 TI - (MU-Piperazine-1,4-dicarbodithio-ato-kappaS,S:S,S)bis-[bis-(triphenyl-phos-phane kappaP)gold(I)] chloro-form disolvate. AB - In the title compound, [Au(2)(C(6)H(8)N(2)S(4))(C(18)H(15)P)(4)].2CHCl(3), the digold complex resides on a crystallographic inversion center and co-crystallizes with two mol-ecules of chloro-form solvent. The piperazine-1,4-dicarbodithio-ate linker has an almost ideal chair conformation. The geometry about the gold atoms is severely distorted tetra-hedral punctuated by a very acute S-Au-S bite angle. PMID- 22219853 TI - fac-Tricarbon-yl(pyridine-kappaN)(1,1,1-trifluoro-acetyl-acetonato kappaO,O')rhenium(I). AB - In the title compound, [Re(C(5)H(4)F(3)O(2))(C(5)H(5)N)(CO)(3)], the Re(I) atom is six-coordinated owing to bonding by three carbonyl ligands arranged in a fac configuration, two O atoms from the bidentate 1,1,1-trifluoro-acetyl-acetonate ligand and an N atom from a pyridine ligand. In the crystal, the mol-ecules pack in layers, diagonally, in a head-to-tail fashion across the ab plane. These layers are stabilsed by inter-molecular C-H?O and C-H?F hydrogen bonds. PMID- 22219854 TI - Tris(pyridin-2-yl-methanol)nickel(II) hexa-fluoridophosphate trifluoro-acetate. AB - In the crystal structure of the title complex, [Ni(C(6)H(7)NO)(3)](PF(6))(C(2)F(3)O(2)), the Ni(II) ion is in a slightly distorted octa-hedral NiO(3)N(3) coordination geometry with each of the three N and three O atoms in a meridional coordination. In the crystal, the complex mol ecules and the trifluoro-acetate anions are connected via O-H?O hydrogen bonding into layers parallel to the ab plane. PMID- 22219855 TI - Poly[bis-[MU(2)-1,4-bis-(1H-imidazol-1-yl)butane]-dichloridonickel(II)]. AB - The asymmetric unit of the title compound, [NiCl(2)(C(10)H(14)N(4))(2)](n), consists of one Ni(2+) ion which is located on an inversion center, one 1,4-bis (imidazol-1-yl)butane (bimb) and one chloride ion. The Ni(2+) ion exhibits a distorted octa-hedral coordination environment defined by four N atoms from four bimb ligands in the equatorial plane and two chloride ions in axial positions. The bridging coordination mode of the bimb ligands leads to the formation of inter-penetrating square Ni(4)(bimb)(4) units that are arranged parallel to (001). The separation between the Ni atoms in these units is 13.740 (3) A. PMID- 22219856 TI - Dichlorido(2,3-di-2-pyridyl-pyrazine-kappaN,N)palladium(II). AB - The Pd(II) ion in the title complex, [PdCl(2)(C(14)H(10)N(4))], is four coordinated in a distorted square-planar environment defined by two N atoms of a chelating 2,3-di-2-pyridyl-pyrazine (dpp) ligand and two chloride anions. The pyridine ring coordinated to the Pd atom is inclined slightly to its carrier pyrazine ring [dihedral angle = 14.4 (3) degrees ], whereas the uncoordinated pyridine ring is inclined considerably to the pyrazine ring [dihedral angle = 52.2 (2) degrees ]. The dihedral angle between the two pyridine rings is 58.8 (2) degrees . In the crystal, complex mol-ecules are connected by inter-molecular C H?Cl and C-H?N hydrogen bonds, forming a three-dimensional network. Intra molecular C-H?Cl hydrogen bonds are also present. PMID- 22219857 TI - Diaqua-bis-(dimethyl sulfoxide-kappaO)-disaccharinatocadmium. AB - The title compound, [Cd(C(7)H(4)NO(3)S)(2)(C(2)H(6)OS)(2)(H(2)O)(2)], contains a Cd(2+) cation in an octahedral coordination environment. The metal atom is surrounded by the two different neutral ligands dimethyl sulfoxide (DMSO) and water, each coordin-ating through the O atom. The anionic saccharinate (sac; 1,1,3-trioxo-2,3-dihydro-1lambda(6),2-benzothia-zol-2-ide) ligand coordin-ates through the N atom. Each of the three similar ligand pairs is in a trans configuration with respect to each other. The Cd atom lies on a crystallographic center of symmetry. The DMSO ligand coordinates through the lone pair of electrons on the O atom, as can be seen from the Cd-O-S bond angle of 123.96 (9) degrees . PMID- 22219858 TI - Tetra-MU-acetato-kappaO:O'-bis-{[N-(4-methyl-phen-yl)pyridin-2-amine kappaN]copper(II)}(Cu-Cu). AB - The complete dinuclear mol-ecule of the title complex, [Cu(2)(CH(3)COO)(4)(C(12)H(12)N(2))(2)], is generated by a centre of inversion. The Cu(II) atoms are connected [Cu-Cu = 2.6329 (16) A] and bridged by four acetate ligands. The distorted octa-hedral coordination geometry is completed by a terminal pyridine N atom. The amine H atom forms an intra-molecular N-H?O hydrogen bond. PMID- 22219859 TI - Tetra-MU-acetato-kappaO:O'-bis-[(2-phen-oxy-pyrimidine-kappaN)copper(II)](Cu-Cu). AB - The complete dinuclear mol-ecule of the title complex, [Cu(2)(CH(3)COO)(4)(C(10)H(8)N(2)O)(2)], is generated by a centre of inversion. The Cu(II) atom is in a distorted octa-hedral coordination geometry defined by four O atoms derived from four bridging acetate ligands, a terminally connected pyrimidine N atom and a Cu atom. PMID- 22219861 TI - Tris{2-[(furan-2-meth-yl)imino-meth-yl]-4-methyl-phenolato}cobalt(III). AB - In title compound, [Co(C(13)H(12)NO(2))(3)], the Co(III) ion is six-coordinated by three bidentate Schiff base ligands in a distorted octa-hedral environment. Adjacent complex mol-ecules are linked through C-H?O hydrogen bonds. PMID- 22219860 TI - trans-Diaqua-bis-(4-fluoro-benzoato-kappaO)bis-(nicotinamide-kappaN)nickel(II). AB - In the mononuclear Ni(II) title complex, [Ni(C(7)H(4)FO(2))(2)(C(6)H(6)N(2)O)(2)(H(2)O)(2)], the Ni(II) atom, located on an inversion center, is coordinated by two nicotinamide and two 4-fluoro-benzoate ligands and two water mol-ecules in a distorted N(2)O(4) octa-hedral geometry. The dihedral angle between the carboxyl-ate group and the adjacent benzene ring is 8.95 (8) degrees , while the pyridine ring and the benzene ring are oriented at a dihedral angle of 75.01 (7) degrees . The water mol-ecule links the adjacent carboxyl-ate O atom via an intra-molecular O-H?O hydrogen bond. In the crystal, O H?O, N-H?O, C-H?O and C-H?F hydrogen bonds link the mol-ecules into a three dimensional network. pi-pi stacking between parallel pyridine rings [centroid centroid distance = 3.7287 (11) A] is also observed. PMID- 22219862 TI - Poly[tetra-n-butyl-ammonium [(MU(5)-benzene-1,3,5-tricarboxyl-ato)(MU(4)-benzene 1,3,5-tricarboxyl-ato)-MU(3)-hydroxido-trizincate] 0.25-hydrate]. AB - In the asymmetric unit of title coordination polymer, {(C(16)H(36)N)[Zn(3)(C(9)H(3)O(6))(2)(OH)].0.25H(2)O}(n), there are three independent Zn(2+) cations, two benzene-1,3,5-tricarboxyl-ate ligands and a MU(3) bridging hydroxide group, together with a tetra-n-butyl-ammonium counter-cation and a partially occupied water molecule of solvation (occupancy 0.25). Each Zn ion is coordinated by three carboxyl-ate O atoms and one O atom from the bridging hydroxide ion, displaying a slightly distorted tetra-hedral stereochemistry [overall Zn-O range = 1.875 (3)-1.987 (2) A]. An intra-molecular hydrogen bond involving the hydroxide H atom and a carboxyl-ate O-atom acceptor is also present in the complex unit. The bridging benzene-1,3,5-tricarboxyl-ate anions generate a three-dimensional framework structure. PMID- 22219863 TI - Bis{2,4-dibromo-6-[(2-phenyl-eth-yl)imino-meth-yl]phenolato-kappaN,O}cobalt(II). AB - In the title complex, [Co(C(15)H(12)Br(2)NO)(2)], the Co(II) atom is four coordinated by two N,O-bidentate chelate Schiff base ligands, displaying a flattened tetra-hedral coordination environment. The Co(II) atom occupies a special position on a twofold rotation axis. In the crystal, mol-ecules are linked via weak C-H?Br inter-actions. PMID- 22219864 TI - Diethyl 4,4'-dihy-droxy-3,3'-{[(3aRS,7aRS)-2,3,3a,4,5,6,7,7a-octa-hydro-1H-1,3 benzimidazole-1,3-di-yl]bis-(methyl-ene)}dibenzoate. AB - The heterocyclic ring in the title compound, C(27)H(34)N(2)O(6), has an envelope conformation on one of the bridgehead C atoms [Q(2) = 0.4487 (19) A and phi = 291.3 (2) degrees ]. Two strong intra-molecular O-H?N hydrogen bonds stabilize the mol-ecular conformation. The benzoate groups differ in the relative orientations of the ethyl groups, as quanti-fied by the values of the C-O-C-C torsion angles of -86.5 (2) and -178.97 (17) degrees . The carbonyl groups are nearly coplanar with the benzene rings, forming C-C-C-O torsion angles of 0.9 (3) and 3.4 (3) degrees . The crystal structure is stabilized by weak inter-molecular C-H?O inter-actions. PMID- 22219865 TI - 1,1'-(Ethane-1,2-di-yl)bis-(3-phenyl-thio-urea). AB - The complete molecule of the title compound, C(16)H(18)N(4)S(2), is generated by crystallographic inversion symmetry. The dihedral angle between the phenyl ring and the thio-urea group is 52.9 (4) degrees . The crystal structure displays inter-molecular N-H?S hydrogen bonding, which generates sheets in the ab plane. PMID- 22219866 TI - Dimethyl 2,6-dimethyl-4-(2-nitro-phen-yl)pyridine-3,5-dicarboxyl-ate. AB - The title compound, C(17)H(16)N(2)O(6), is a decomposition product of the hypertension drug nifedipine [systematic name: dimethyl 2,6-dimethyl-4-(2-nitro phen-yl)-1,4-dihydro-pyridine-3,5-dicarboxyl-ate]. The dihedral angle between the nitro-sophenyl ring and the pyridine ring is 67.1 (5) degrees . PMID- 22219867 TI - 2-Trifluoro-methyl-1H-benzimidazol-3-ium perchlorate. AB - In the title salt, C(8)H(6)F(3)N(2) (+).ClO(4) (-), the atoms of the benzimidazole ring (including H atoms) are nearly coplanar (r.m.s. deviation of the fitted atoms = 0.0122 A) and the triflouromethyl group lies out of this plane. The perchlorate anion adopts a distorted tetra-hedral conformation with the Cl-O bond distances ranging from 1.412 (3) to 1.439 (2) A. The benzimidazolium cations are linked to adjacent anions by inter-molecular N-H?O hydrogen bonds, forming chains. PMID- 22219868 TI - 4-(1,3-Diphenyl-4,5-dihydro-1H-pyrazol-5-yl)-1,3-diphenyl-1H-pyrazole. AB - The title compound, C(30)H(24)N(4), contains two pyrazole rings and four phenyl rings. The pyrazole rings are essentially planar, with maximum deviations of 0.003 (1) and 0.066 (1) A and make a dihedral angle of 73.43 (6) degrees . The two pyrazole rings make dihedral angles of 40.08 (6), 9.28 (6), 15.78 (8) and 17.25 (7) degrees with their attached phenyl rings. In the crystal, there are no significant inter-molecular hydrogen-bonding inter-actions. The crystal structure is stabilized by C-H?pi inter-actions. PMID- 22219869 TI - 2,4-Dichloro-N-(2,4-dimethyl-phen-yl)benzene-sulfonamide. AB - In the title compound, C(14)H(13)Cl(2)NO(2)S, the C-SO(2)-NH-C torsion angle is 71.4 (4) degrees . The sulfonyl and aniline benzene rings are tilted relative to one another by 44.6 (1) degrees . The crystal structure features inversion related dimers linked by pairs of N-H?O hydrogen bonds. PMID- 22219870 TI - 4-Chloro-N'-(2-hy-droxy-4-meth-oxy-benzyl-idene)benzohydrazide methanol monosolvate. AB - The title compound, C(15)H(13)ClN(2)O(3).CH(3)OH, was synthesized by the condensation reaction of 2-hy-droxy-4-meth-oxy-benzaldehyde with 4-chloro benzohydrazide in methanol. The Schiff base mol-ecule displays a trans configuration with respect to the C=N and C-N bonds. The dihedral angle between the two benzene rings is 5.3 (2) degrees . In the crystal, mol-ecules are linked by N-H?O and O-H?O hydrogen-bond inter-actions into chains running parallel to the a axis. An intra-molecular O-H?N hydrogen bond is observed. PMID- 22219871 TI - (1S,2R,3R,8R,10S)-3-Chloro-2,8-dihy-droxy-3,7-dimethyl-11-methyl-idene-13 oxabicyclo-[8.3.0]tridec-6-en-12-one. AB - The title compound, C(15)H(21)ClO(4), was synthesized from 9alpha-hy-droxy parthenolide (9alpha-hy-droxy-4,8-dimethyl-12-methylen-3,14-dioxatricyclo [9.3.0.0(2,4)]tetra-dec-7-en-13-one), which was isolated from the chloro-form extract of the aerial parts of Anvillea radiata. The mol-ecule is built up from fused five- and ten-membered rings. The five-membered lactone ring has an envelope conformation with the flap atom, C(H)-C-C(H), displaced by 0.2325 (15) A from the mean plane through the remaining four atoms, whereas the ten-membered ring displays an approximate chair-chair conformation. The dihedral angle between the two rings is 66.4 (2) degrees . In the crystal, mol-ecules are linked into chains propagating along the a axis by O-H?O hydrogen bonds. PMID- 22219872 TI - 4-({(E)-[2-(But-3-en-1-yl)-1-(prop-2-en-1-yl)-4-sulfanyl-1H-imidazol-5-yl]methyl idene}amino)-3-phenyl-1H-1,2,4-triazole-5(4H)-thione. AB - In the title compound, C(19)H(20)N(6)S(2), the dihedral angle between the phenyl and triazole rings is 24.1 (2) degrees while the dihedral angles between the imidazole ring and the triazole and phenyl rings are 39.9 (2) and 55.3 (2) degrees , respectively. The crystal structure is stabilized by inter-molecular N H?N hydrogen bonds which form chains along [10[Formula: see text]]. PMID- 22219873 TI - 7-Phenyl-sulfonyl-7H-benzofurano[2,3-b]carbazole. AB - In the title compound, C(24)H(15)NO(3)S, the dihedral angle between the phenyl ring and the carbozole system is 74.91 (6) degrees . The S atom exhibits a distorted tetra-hedral geometry [N-S-C = 104.85 (8) degrees ; O-S-O = 119.59 (9) degrees ]. The crystal structure is established by weak inter-molecular pi-pi inter-actions [centroid-centroid distances = 3.583 (2)-3.782 (2) A]. PMID- 22219874 TI - (E)-Ethyl 2-cyano-3-(2,4-dimeth-oxy-phen-yl)prop-2-enoate. AB - The C=C bond in the title compound, C(14)H(15)NO(4), is in an E configuration. With the exception of the methyl C atoms, the non-H atoms of the mol-ecule all lie approximately on a plane (r.m.s. deviation = 0.096 A). pi-pi stacking is observed between parallel benzene rings of adjacent mol-ecules, the centroid centroid distance being 3.7924 (8) A. PMID- 22219875 TI - N-(1-Naphth-yl)benzene-sulfonamide. AB - In the title compound, C(16)H(13)NO(2)S, the C-SO(2)-NH-C torsion angle is -70.1 (2) degrees . The dihedral angle between the planes of the naphthyl ring system and the phenyl ring is 34.67 (4) degrees . In the crystal, mol-ecules are linked by inter-molecular N-H?O hydrogen bonds into chains along [100]. There are also pi-pi inter-actions between adjacent naphthyl groups [inter-planar spacing = 3.541 (3) A] for mol-ecules stacked along [100]. PMID- 22219876 TI - 2-(2-Bromo-eth-yl)isoindoline-1,3-dione. AB - The asymmetric unit of the title compound, C(10)H(8)BrNO(2), contains three crystallographically independent mol-ecules. Two of the N-C-C-Br side chains adopt anti conformations [torsion angles = -179.8 (5) and -179.4 (4) degrees ] and the other is gauche [-66.5 (6) degrees ]. The crystal structure features short Br?O [3.162 (5) A] contacts, C-H?O hydrogen bonds and numerous pi-pi stacking inter-actions [centroid-centroid separations = 3.517 (4)-3.950 (4) A]. PMID- 22219877 TI - 3-Amino-benzonitrile-3,5-dinitro-benzoic acid (1/1). AB - The asymmetric unit of the title co-crystal, C(7)H(6)N(2).C(7)H(4)N(2)O(6), contains two formula units of both components. The crystal structure is stabilized by inter-molecular O-H?O, N-H?O, N-H?N and C-H?O hydrogen bonds, generating a two-dimensional wave-like network. pi-pi stacking inter-actions [centroid-centroid distances = 3.702 (2), 3.660 (2)and 3.671 (2) A] stabilize the crystal packing. PMID- 22219878 TI - 8-{[(E)-3-(2-Chloro-phen-yl)acrylo-yloxy]imino}-12,13-ep-oxy-trichethec-9-en-4-yl (E)-3-(2-chloro-phen-yl)acrylate. AB - In the title compound, C(33)H(31)Cl(2)NO(6), the five-membered ring displays an envelope conformation, whereas the two six-membered rings both exhibit a chair conformation. As for the seven-membered ring, the dihedral angle between the mean planes formed by the four C atoms of the envelope unit and the three C and one O atoms of the six-membered chair is 69.08 (4) degrees , and these two mean planes are nearly perpendicular to the ep-oxy ring, making dihedral angles of 87.53 (4) and 88.67 (4) degrees , respectively. PMID- 22219879 TI - N'-(4-Fluoro-benzyl-idene)-2-(4-fluoro-phen-yl)acetohydrazide. AB - In the title compound, C(15)H(12)F(2)N(2)O, the dihedral angle between the two benzene rings is 48.73 (8) degrees . The hydrazine group is twisted slightly, with a C-N-N-C torsion angle of 172.48 (12) degrees . In the crystal, mol-ecules are connected by strong N-H?O and weak C-H?O hydrogen bonds, forming supra molecular chains along the c axis. The structure is consolidated by pi-pi [centroid-centroid separation = 3.6579 (10) A] and C-H?pi inter-actions. PMID- 22219880 TI - 2-(4-Fluoro-phen-yl)-2-oxoethyl 3-(trifluoro-meth-yl)benzoate. AB - In the title compound, C(16)H(10)F(4)O(3), the fluoro-form group is disordered over two orientations with an occupancy ratio of 0.834 (4):0.166 (4). The dihedral angle between the two aromatic rings is 20.34 (9) degrees . In the crystal, C-H?O hydrogen bonds link the mol-ecules into layers lying parallel to the bc plane. PMID- 22219881 TI - 2-Sulfanylidene-1,3-dithiolo[4,5-b]naphtho-[2,3-e][1,4]dithiine-5,10-dione. AB - The title mol-ecule, C(13)H(4)O(2)S(5), is folded by 47.83 (6) degrees along the S?S vector of the [1,4]dithiine six-membered ring, with the naphtho-quinone and [1,3]dithiole-2-thione moieties being nearly planar [largest deviations from least-squares planes = 0.028 (2) and 0.016 (1) A, respectively]. This boat conformation is close to that observed in the analogous compound [Mendez-Rojas et al. (2001). J. Chem. Crystallogr.31, 17-28] including a 2-oxo group [folding angle: 42.3 (1) degrees at 213 (2) K]. Both compounds are indeed isomorphous, and the small difference in the folding angle probably results from the involvement of the thioxo group of the title compound in inter-molecular S?S contacts [3.5761 (13) A]. In the crystal structure, mol-ecules are stacked in the [100] direction, with dithiole rings making pi-pi inter-actions. In a stack, alternating short and long separations are observed between the centroids of dithiole rings, 3.5254 (17) and 4.7010 (18) A. PMID- 22219882 TI - 6-Bromo-imidazo[1,2-a]pyridin-8-amine. AB - The title compound, C(7)H(6)BrN(3), crystallizes with three independent mol ecules in the asymmetric unit. The mol-ecules are approximately planar (r.m.s. deviations for all non-H atoms = 0.016, 0.023 and 0.024 A). The primary amine groups show pyramidal coordination. In the crystal, adjacent mol-ecules are linked by N-H?N hydrogen bonds. For two independent mol-ecules, the amine groups are hydrogen-bond donors via one H atom to one acceptor atom, whereas for the third independent mol-ecule, the amine group is a hydrogen-bond donor to two acceptor atoms. PMID- 22219883 TI - 6-(3,5-Dimethyl-benz-yl)-5-ethyl-1-[(2-phen-oxy-eth-oxy)meth-yl]-1,2,3,4-tetra hydro-pyrimidine-2,4-dione. AB - The six-membered ring of the uracil part of the title compound, C(24)H(28)N(2)O(4), is nearly planar (r.m.s. deviation = 0.013 A); the aromatic ring of the 3,5-dimethyl-benzyl substitutent is aligned at 85.4 (1) degrees with respect to this mean plane. The phenyl ring of the substituent at the 1-position takes up two orientations in a 1:1 ratio. In the crystal, two mol-ecules are liked by a pair of N-H?O hydrogen bonds, generating a centrosymmetric hydrogen bonded dimer. PMID- 22219884 TI - Phenyl 4,6-di-O-acetyl-2,3-dide-oxy-1-thio-alpha-d-erythro-hex-2-enopyran-oside. AB - The pyranosyl ring in the title compound, C(16)H(18)O(5)S, adopts an envelope conformation, with the acetyl groups in equatorial positions. In the crystal, weak C-H?O inter-actions link the molecules into chains. PMID- 22219885 TI - 2,4-Dichloro-N-(3,5-dimethyl-phen-yl)benzene-sulfonamide. AB - In the crystal of the title compound, C(14)H(13)Cl(2)NO(2)S, the N-H bond in the C-SO(2)-NH-C segment is syn to one of the meta-methyl groups in the aniline benzene ring and anti to the other. Further, the conformation of the N-C bond in the C-SO(2)-NH-C segment is gauche with respect to the S=O bonds. The C-SO(2)-NH C torsion angle is 54.9 (2) degrees . The sulfonyl and aniline benzene rings are tilted relative to each other by 82.8 (1) degrees . The crystal structure features inversion-related dimers linked by pairs of N-H?O hydrogen bonds. There are also weak C-H?O hydrogen bonds between these dimers. PMID- 22219886 TI - Dicyclo-hexyl-ammonium thio-cyanate: monoclinic polymorph. AB - The title salt, C(12)H(24)N(+).NCS(-), represents a monoclinic polymorph of the previously reported ortho-rhom-bic form [Khawar Rauf et al. (2008 ?). Acta Cryst. E64, o366]. Two independent formula units comprise the asymmetric unit with the major difference in their mol-ecular structures relating to the relative dispositions of the cyclo-hexyl rings [dihedral angles = 79.88 (6) and 67.72 (5) degrees ]. Further, the independent anions form distinctive patterns of hydrogen bonding inter-actions, i.e. 2 * N-H?N versus N-H?N and N-H?S. The resulting supra molecular architecture is a supra-molecular chain along the c axis based on a square-wave topology. PMID- 22219887 TI - (9R,10R,10aR)-9-(2-Bromo-phen-yl)-10-nitro-6-phenyl-10,10a-dihydro-9H benzo[c]chromene-8-carbaldehyde. AB - The title compound, C(26)H(18)BrNO(4), features a functionalized chromene. The cyclo-hexene ring adopts a sofa conformation and has the nitro group and the bromo-phenyl ring in an axial position. The ten atoms of the chromene moiety lie close to a common plane (r.m.s. deviation = 0.066 A). The attached phenyl ring is twisted by 32.89 (10) degrees from the chromene plane. The crystal packing is stabilized by C-H?O inter-actions. PMID- 22219888 TI - 2-(4-Methyl-phen-yl)-1-(phenyl-sulfon-yl)propan-2-ol. AB - The title compound, C(16)H(18)O(3)S, features a U-shape mol-ecular structure with a dihedral angle between the terminal benzene rings of 20.8 (1) degrees . An intra-molecular O-H?O hydrogen bond helps to stabilize the mol-ecular structure. Inter-molecular classical O-H?O and weak C-H?O hydrogen bonding is present in the crystal structure. PMID- 22219889 TI - Ethyl 2-methyl-4-phenyl-pyrido[1,2-a]benzimidazole-3-carboxyl-ate. AB - The title compound, C(21)H(18)N(2)O(2), was synthesized using a novel tandem annulation reaction between (1H-benzimidazol-2-yl)(phen-yl)methanone and (E) ethyl 4-bromo-but-2-enoate under mild conditions. The dihedral angles between the mean planes of the five-membered imidazole ring and the pyridine, benzene and phenyl rings are 0.45 (6), 1.69 (1) and 70.96 (8) degrees , respectively. In the crystal, mol-ecules are linked through inter-molecular C-H?N hydrogen bonds. PMID- 22219890 TI - N'-(4-Chloro-benzyl-idene)-2-[4-(methyl-sulfan-yl)phen-yl]acetohydrazide. AB - In the title compound, C(16)H(15)ClN(2)OS, the hydrazine group is twisted slightly: the C-N-N-C torsion angle is 175.46 (13) degrees . The dihedral angle between the two terminal aromatic rings is 87.01 (8) degrees . In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R(2) (2)(8) loops. The dimers are further linked by weak C-H?pi inter-actions. PMID- 22219891 TI - N,N'-Di-tert-butyl-N''-(2-chloro-acet-yl)phospho-ric triamide. AB - The P atom in the title mol-ecule, C(10)H(23)ClN(3)O(2)P, has a distorted tetra hedral coordination. In the C(O)NHP(O) unit, which has syn-oriented phosphoryl and N-H groups, the P-N bond of 1.703 (2) A is longer and the O-P-N angle of 103.86 (7) degrees is contracted compared with the respective values in the two P(O)NHC(CH(3))(3) units [P-N = 1.632 (2) and 1.624 (2) A; O-P-N = 116.80 (8) and 115.32 (8) degrees ]. In the crystal, each mol-ecule is hydrogen bonded to two adjacent mol-ecules via N-H?O hydrogen bonds, forming a linear sequence of alternating R(2) (2)(8) and R(2) (2)(12)/R(2) (1)(6)-fused rings along [010]. The O atom of the carbonyl group acts as a double H-atom acceptor. PMID- 22219892 TI - (E)-2-{[2-(2-Hy-droxy-ethyl-amino)-ethyl-imino]-meth-yl}phenol. AB - The asymmetric unit of the title compound, C(11)H(16)N(2)O(2), contains two independent conformational isomers which show intra-molecular aromatic-imine O H?N hydrogen bonds. In the crystal, neighboring mol-ecules are linked through inter-molecular aliphatic-aliphatic O-H?N, aliphatic-aromatic N-H?O and C-H?O inter-actions into hydrogen-bonded layers parallel to the ab plane. PMID- 22219893 TI - 2-(3,4-Dichloro-phen-yl)-4-phenyl-benzo[h]quinoline. AB - In the title compound, C(25)H(15)Cl(2)N, the benzo[h]quinoline system exhibits an approximately planar conformation with an r.m.s. deviation of 0.0202A and a maximum deviation of 0.039 (1) A. The aryl group at position 2 is nearly coplanar with the parent ring [dihedral angle = 6.68 (7) degrees ] while the parent ring and the phenyl subsitituent at position 4 form a dihedral angle of 67.11 (4) degrees . Inter-molecular C-H?pi inter-actions stabilize the crystal packing. PMID- 22219894 TI - Monoclinic polymorph of 3,7-dimethyl-1-(5-oxohex-yl)-3,7-dihydro-1H-purine-2,6 dione. AB - The structure of the title compound, pentoxifylline, C(13)H(18)N(4)O(3), has been previously characterized as a triclinic polymorph [Pavelcik et al. (1989 ?). Acta Cryst. C45, 836-837]. We have discovered the monoclinic form. There are no strong hydrogen bonds in the crystal structure, rather, moderate C-H?O hydrogen bonds are present, which serve to stabilize the three-dimensional architecture. PMID- 22219895 TI - Methyl (9aR*,10S*,11R*,13aS*,13bS*)-9-oxo-6,7,9,9a,10,11-hexa-hydro-5H,13bH 11,13a-ep-oxy-pyrrolo-[2',1':3,4][1,4]diazepino[2,1-a]isoindole-10-carboxyl-ate. AB - The title compound, C(17)H(18)N(2)O(4), is the methyl ester of the adduct of intra-molecular Diels-Alder reaction between maleic anhydride and 1-(2-fur-yl) 2,3,4,5-tetra-hydro-1H-pyrrolo-[1,2-a][1,4]diazepine. The mol-ecule comprises a fused penta-cyclic system containing four five-membered rings (viz. pyrrole, 2 pyrrolidinone, tetra-hydro-furan and dihydro-furan) and one seven-membered ring (1,4-diazepane). The pyrrole ring is approximately planar (r.m.s. deviation = 0.003 A) while the 2-pyrrolidinone, tetra-hydro-furan and dihydro-furan five membered rings have the usual envelope conformations. The central seven-membered diazepane ring adopts a boat conformation. In the crystal, mol-ecules are bound by weak inter-molecular C-H?O hydrogen-bonding inter-actions into zigzag chains propagating in [010]. In the crystal packing, the chains are stacked along the a axis. PMID- 22219896 TI - 2-(4-Bromo-phen-yl)-2-oxoethyl 4-hy-droxy-benzoate. AB - In the title compound, C(15)H(11)BrO(4), the dihedral angle between the aromatic rings is 66.77 (8) degrees . In the crystal, O-H?O, C-H?Br and C-H?O hydrogen bonds link the mol-ecules, forming layers lying parallel to (101). The crystal packing is further consolidated by C-H?pi inter-actions and pi-pi stacking inter actions [centroid-centroid distance = 3.5476 (7) A]. PMID- 22219897 TI - (E)-N'-{7-Meth-oxy-spiro-[chromeno[4,3-d]thia-zole-4,1'-cyclo-hexa-n]-2-yl}-N,N dimethyl-acetimidamide. AB - In the chromenothia-zole ring system of the title mol-ecule, C(20)H(25)N(3)O(2)S, the pyran ring is in a half-chair conformation. The dihedral angle between the thia-zole and benzene rings is 14.78 (6) degrees . The cyclo-hexane ring is in a chair conformation. The crystal structure is stabilized by weak inter-molecular C H?N and C-H?O hydrogen bonds. PMID- 22219898 TI - N'-[(1E)-3-Bromo-5-chloro-2-hy-droxy-benzyl-idene]-4-tert-butyl-benzo-hydrazide ethanol monosolvate. AB - In the title compound, C(18)H(18)BrClN(2)O(2).C(2)H(6)O, the hy-droxy group forms an intra-molecular O-H?N hydrogen bond, which influences the conformation of the Shiff base mol-ecule, where the two aromatic rings form a dihedral angle of 21.67 (8) degrees . Inter-molecular N-H?O and O-H?O hydrogen bonds link two Shiff base mol-ecules and two solvent mol-ecules into a centrosymmetric heterotetra-mer. Weak inter-molecular C-H?O inter-actions link further tetra-mers related by translation along the a axis into chains. PMID- 22219899 TI - 1-(5-Nitro-2-oxoindolin-3-yl-idene)thio-semicarbazide. AB - In the title molecule, C(9)H(7)N(5)O(3)S, there is an intramolecular N-H?O. The molecule is essentially planar, with the maximum deviation from the mean plane of the 18 non-H atoms being 0.135 (2) A for the amine N atom. In the crystal, the molecules are connected via intermolecular N-H?O and N-H?S hydrogen bonds, forming two-dimensional networks lying parallel to (10[Formula: see text]). They are separated by an interplanar distance of 3.3214 (9) A, leading to pi-pi interactions which stabilize the crystal structure. PMID- 22219900 TI - (Phen-yl)(3-phenyl-sulfonyl-1,2-dihydro-pyrrolo-[1,2-a]quinoxalin-1-yl)methanone. AB - In the title mol-ecule, C(24)H(18)N(2)O(3)S, the 13-atom ring system comprising the quinoxaline and fused five-membered ring exhibits an r.m.s. deviation from coplanarity of 0.039 A, with a maximum deviation of 0.0710 (10) A for the PhCO bearing C atom of the five-membered ring. The 10-membered C(8)N(2) quinoxaline ring system has an r.m.s. deviation from coplanarity of 0.022 A, with a maximum deviation of 0.0403 (9) A for the C atom involved in the C=C bond in the five membered ring. The three atoms of the five-membered ring fused to the quinoxaline ring system show deviations of up to 0.118 (2) A for the PhCO-bearing C atom. C-N bond distances in the quinoxaline ring system of the title mol-ecule deviate from those in unsubstituted quinoxaline. In particular, the two C-N distances to the N atom involved in the five-membered ring are essentially equal, with values of 1.3786 (17) and 1.3773 (16) A, unlike the difference of nearly 0.06 A in quinoxaline. PMID- 22219901 TI - Diphenyl chloro-thio-phospho-nate. AB - The complete mol-ecule of the title compound, C(12)H(10)ClO(2)PS, is generated by crystallographic mirror symmetry, with the P, S and Cl atoms lying on the mirror plane. The resulting PO(2)SCl tetra-hedron is significantly distorted [O-P-O = 96.79 (9) degrees ]. The crystal packing exhibits no directional inter-actions. PMID- 22219902 TI - 2-(2-Hy-droxy-phen-yl)-1,3-benzothia-zole-6-carbaldehyde. AB - The mol-ecule of the title compound, C(14)H(9)NO(2)S, is nearly planar, the maximum atomic deviation being 0.081 (2) A. An intra-molecular O-H?N bond generates an S(6) ring motif. In the crystal, inversion-related mol-ecules linked by a pair of weak C-H?O hydrogen bonds form a supra-molecular dimer. pi-pi stacking is observed between the thia-zole and benzene rings of adjacent mol ecules, the centroid-centroid distance being 3.7679 (9) A. PMID- 22219903 TI - 2,5-Dioxopyrrolidin-1-yl 3-(furan-2-yl)acrylate. AB - The title compound, C(11)H(9)NO(5), was prepared by the reaction of 2-furan acrylic acid and N-hy-droxy-succinimide. The mol-ecule consists of two approximately planar moieties, viz. a succinimide group and the rest of the mol ecule [the largest deviations from the least-squares planes are 0.120 (1) and 0.210 (1) A, respectively]. The dihedral angle between these fragments is 63.70 (5) degrees . In the crystal, mol-ecules are linked by C-H?O hydrogen bonds into two-dimensional nets. PMID- 22219904 TI - 3-Carb-oxy-2-(2-cyclo-propyl-amino-4-methyl-pyridinium-3-yl-amino)-pyridinium dinitrate dihydrate. AB - The two benzene rings in the cation of the title compound, C(15)H(18)N(4)O(2) (2+).2NO(3) (-).2H(2)O, are almost perpendicular [dihedral angle = 91.6 (2) degrees ]. In the crystal, the components are linked by O-H?O, N-H?O and C-H?O hydrogen bonds. PMID- 22219905 TI - N-(4-Hy-droxy-phen-yl)-3,4,5-trimeth-oxy-benzamide. AB - In the title amide compound, C(16)H(17)NO(5), the dihedral angle between the benzene rings is 71.59 (4) degrees . In the crystal, inter-molecular N-H?O and O H?O hydrogen bonds link the mol-ecules into a two-dimensional array parallel to the ab plane. PMID- 22219906 TI - N-{4-[(3-Methyl-phen-yl)sulfamo-yl]phen-yl}benzamide. AB - In the title compound, C(20)H(18)N(2)O(3)S, the dihedral angle between the central benzene ring and the amide group is 24.1 (3) degrees and that between this ring and the aromatic ring of the tolyl group is 68.2 (16) degrees . In the crystal, adjacent mol-ecules are linked by N-H?O hydrogen bonds into a linear chain running along [100]. Weak C-H?O contacts also occur. Extensive weak pi-pi inter-actions exist from both face-to-face and face-to-edge inter-actions occur between the aromatic rings [centroid-centroid distances = 3.612 (2) and 4.843 (2) A]. PMID- 22219907 TI - Selective crystallization of indigo B by a modified sublimation method and its redetermined structure. AB - Good-quality single crystals of the title compound, indigo B [systematic name: 2 (3-oxoindolin-2-yl-idene)indolin-3-one], C(16)H(10)N(2)O(2), have been prepared with high selectivity by a sublimation process. The previous structure of indigo B [Susse & Wolf (1980 ?). Naturwissenschaften, 67, 453], which showed that the complete mol-ecule is generated by crystallographic inversion symmetry has been confirmed, but the present study reports more realistic geometrical parameters and modern standards of precision (e.g. sigma for C-C bonds = 0.002-0.003 A). Each mol-ecule features two intra-molecular N-H?O hydrogen bonds. In the crystal, mol-ecules are linked by strong face-to-face pi-pi stacking inter-actions involving both the six- and five-membered rings [centroid-centroid separations = 3.6290 (14) and 3.6506 (14) A] and inter-molecular N-H?O hydrogen bonds. PMID- 22219908 TI - 3-Chloro-N-(4-meth-oxy-phen-yl)propanamide. AB - The title compound, C(10)H(12)ClNO(2), is a halogenated derivative of a secondary amide bearing an aromatic substituent. The C(=O)-N(H)-C(ar)-C(ar) torsion angle of -33.70 (18) degrees rules out the presence of resonance spanning the amide as well as the aromatic system. In the crystal, classical N-H?O hydrogen bonds, as well as C-H?O contacts connect the mol-ecules into chains propagating along the a axis. PMID- 22219909 TI - 4-Methyl-phenyl 4-bromo-benzoate. AB - In the title compound, C(14)H(11)BrO(2), an ester formed from the reaction of 4 methyl-phenol with 4-bromo-benzoyl-chloride, the dihedral angle between the benzene rings is 54.43 (7) degrees , indicating a twist in the mol-ecule. In the crystal, weak C-H?O inter-actions link the mol-ecules into supra-molecular layers in the bc plane, and these are connected along the a axis by Br?Br contacts [3.6328 (5) A]. PMID- 22219910 TI - (4aR,6aS,10aR,10bS)-7,7,10a-Trimethyl-1,4,4a,5,6,6a,7,8,9,10,10a,10b-dodecahydro 2H-naphtho-[2,1-c]pyran (Pyamber). AB - The crystal structure of the title compound, C(16)H(28)O, features C-H?O hydrogen bonds making C(6) zigzag chains along one 2(1) screw axis. Within the limits of the data collection affected by crystal quality, the Hooft parameter gave correct indications of the known molecular chirality based on the single O atom anomalous dispersion in contrast to the indeterminate Flack value. Synthetic steps starting from manool are reported. PMID- 22219911 TI - Pentyl (E)-3-(3,4-dihy-droxy-phen-yl)acrylate. AB - In the mol-ecule of the title compound, C(14)H(18)O(4), the C=C double bond is in an E configuration. The mol-ecule is almost planar (r.m.s. deviation of all non-H atoms = 0.04 A). An intra-molecular O-H?O hydrogen bond occurs. In the crystal, inter-molecular O-H?O inter-actions link the mol-ecules into ribbons extending in [110]. PMID- 22219912 TI - 2-Amino-4-phenyl-5,6-dihydro-benzo[h]quinoline-3-carbonitrile-3-amino-1-phenyl 9,10-dihydro-phenanthrene-2,4-dicarbonitrile (5/3). AB - The asymmetric unit of the 5:3 title co-crystal of 2-amino-4-phenyl-5,6-dihydro benzo[h]quinoline-3-carbonitrile and 3-amino-1-phenyl-9,10-dihydro-phenanthrene 2,4-dicarbonitrile, 0.625C(20)H(15)N(3).0.375C(22)H(15)N(3), has the atoms of the fused-ring system and those of the amino, cyano and phenyl substitutents overlapped. The fused-ring system is buckled owing to the ethyl-ene linkage in the central ring, the two flanking aromatic rings being twisted by 20.1 (1) degrees . This ethyl-ene portion is disordered over two positions in a 1:1 ratio. The phenyl ring is twisted by 69.5 (1) degrees relative to the amino- and cyano bearing aromatic ring. In the crystal, two mol-ecules are linked by an N-H?N hydrogen bond, generating a a helical chain along [010]. PMID- 22219913 TI - 2-Amino-4-(3,4-dimeth-oxy-phen-yl)-5,6-dihydro-benzo[h]quinoline-3-carbo-nitrile 3-amino-1-(3,4-dimeth-oxy-phen-yl)-9,10-dihydro-phenanthrene-2,4-dicarbonitrile (1/19). AB - The asymmetric unit of the 1:19 title co-crystal of 2-amino-4-(3,4-dimeth-oxy phen-yl)-5,6-dihydro-benzo[h]quinoline-3-carbo-nitrile and 3-amino-1-(3,4-dimeth oxy-phen-yl)-9,10-dihydro-phenanthrene-2,4-dicarbonitrile, 0.05C(22)H(19)N(3)O(2).0.95C(24)H(19)N(3)O(2), has the atoms of the fused-ring system and those of the amino, cyano and dimeth-oxy-phenyl substitutents overlapped. The fused-ring system is buckled owing to the ethyl-ene linkage in the central ring with the two flanking aromatic rings being twisted by 31.9 (1) degrees . The ring of the dimeth-oxy-phenyl substituent is twisted by 72.4 (1) degrees relative to the amino- and cyano-bearing aromatic ring. In the crystal, mol-ecules are linked by duplex amine N-H?O(meth-oxy) hydrogen bonds in a cyclic association [graph-set R(2) (2)(7)], generating a helical chain structure extending along [201]. PMID- 22219914 TI - 2-Amino-4-(4-chloro-phen-yl)-5,6-dihydro-benzo[h]quinoline-3-carbonitrile-3-amino 1-(4-chloro-phen-yl)-9,10-dihydro-phenanthrene-2,4-dicarbonitrile (1/4). AB - The asymmetric unit of the 1:4 title co-crystal of 2-amino-4-(4-chloro-phen-yl) 5,6-dihydro-benzo[h]quinoline-3-carbonitrile and 3-amino-1-(4-chloro-phen-yl) 9,10-dihydro-phenanthrene-2,4-dicarbonitrile, 0.2C(20)H(14)ClN(3).0.8C(22)H(14)ClN(3), has the atoms of the fused-ring system and those of the amino, cyano and chloro-phenyl substitutents overlapped. The fused-ring system is buckled owing to the ethyl-ene linkage in the central ring. There are two independent overlapped mol-ecules in the asymmetric unit. In one independent mol-ecule, the two flanking aromatic rings are twisted by 24.4 (1) degrees and the ring of the chloro-phenyl substituent is twisted by 87.3 (1) degrees relative to the amino- and cyano-bearing aromatic ring. In the second mol-ecule, the respective dihedral angles are 26.1 (1) and 57.8 (1) degrees . The two independent mol-ecules are linked by N-H?N hydrogen bonds into dimers. PMID- 22219915 TI - (S)-N-[1-(5-Benzyl-sulfan-yl-1,3,4-oxa-diazol-2-yl)-2-phenyl-eth-yl]-4-methyl benzene-sulfonamide. AB - The title compound, C(24)H(23)N(3)O(3)S(2), crystallizes with two independent mol ecules in the asymmetric unit. They differ essentially in the orientation of the tolyl rings, between which there is pi-pi stacking (centroid-centroid distance = 3.01 A). The absolute configuration was confirmed by the determination of the Flack parameter [x = 0.008 (9)]. In the crystal, mol-ecules are connected by two classical N-H?N hydrogen bonds and two weak but very short C-H?O(sulfon-yl) inter actions, forming layers lying parallel to the bc plane. PMID- 22219916 TI - 5-[(E)-Benzyl-idene]-2-hy-droxy-8,9-di-phenyl-3,10-diaza-hexa-cyclo [10.7.1.1.0.0.0]henicosa-1(19),12(20),13,15,17-pentaen-6-one. AB - In the title compound, C(38)H(30)N(2)O(2), the acenaphthyl-ene ring is close to being planar [maximum deviation = 0.1047 (11) A]. The dihedral angles between the three benzene rings and the acenaphthyl-ene system are 39.47 (3), 37.65 (3) and 44.47 (3) degrees . An intra-molecular O-H?N inter-action forms an S(5) hydrogen bond ring motif. In the crystal, mol-ecules are linked into [101] chains by a set of C-H?O inter-actions. PMID- 22219917 TI - 5-[(E)-4-Fluoro-benzyl-idene]-8-(4-fluoro-phen-yl)-2-hy-droxy-9-phenyl-3,10-diaza hexa-cyclo-[10.7.1.1.0.0.0]henicosa-1(20),12,14,16,18-pentaen-6-one. AB - In the title compound, C(38)H(28)F(2)N(2)O(2), the piperidine ring adopts a chair conformation and the pyrrolidine ring adopts an envelope conformation with the spiro C atom as the flap atom. The naphthalene ring system makes dihedral angles of 39.89 (8), 35.33 (8) and 46.45 (8) degrees with the two fluoro-substituted benzene rings and the phenyl ring, respectively, while the dihedral angle between the two fluoro-substituted benzene rings is 75.21 (10) degrees . An intra molecular O-H?N hydrogen bond generates an S(5) ring. In the crystal, mol-ecules are connected by C-H?O hydrogen bonds, forming supra-molecular chains propagating along the c-axis direction. Weak C-H?pi inter-actions further consolidate the structure. PMID- 22219918 TI - 14-Hy-droxy-11-[(E)-4-meth-oxy-benzyl-idene]-8-(4-meth-oxy-phen-yl)-5-thia-3,13 diaza-hepta-cyclo-[13.7.1.1.0.0.0.0]tetra-cosa-1(22),15(23),16,18,20-pentaen-10 one. AB - In the title compound, C(36)H(32)N(2)O(4)S, the piperidine ring adopts a chair conformation, while the five-membered pyrrolidine (with a C atom as the flap atom) and thia-zolidine (with the S atom as the flap atom) rings adopt envelope conformations. The naphthalene ring system makes dihedral angles of 18.82 (5) and 40.92 (5) degrees with the two meth-oxy-substituted benzene rings. In the crystal, centrosymmetrically-related mol-ecules are linked into dimers via pairs of C-H?O and C-H?N hydrogen bonds. An intra-molecular O-H?N hydrogen bond is also observed. The crystal structure is further stabilized by C-H?pi inter-actions. PMID- 22219919 TI - 2-Chloro-4-nitro-benzoic acid-quinoline (1/1). AB - In the title compound, C(7)H(4)ClNO(4).C(9)H(7)N, the two components are connected by an O-H?N hydrogen bond. In the hydrogen-bonded unit, the dihedral angle between the quinoline ring system and the benzene ring of benzoic acid is 3.15 (7) degrees . In the crystal, units are linked by inter-molecular C-H?O hydrogen bonds, forming a tape along the c axis. The tapes are stacked along the b axis through a C-H?O hydrogen bond into a layer parallel to the bc plane. PMID- 22219920 TI - (5E)-5-(2,4-Dichloro-benzyl-idene)-2-(piperidin-1-yl)-1,3-thia-zol-4(5H)-one. AB - In the title compound, C(15)H(14)Cl(2)N(2)OS, the piperidine ring adopts a chair conformation. The dihedral angle between the thia-zolidine ring and the dichloro benzene ring is 9.30 (4) degrees ; this near coplanar conformation is stabilized by the formation of an intra-molecular C-H?S hydrogen bond, which generates an S(6) ring. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming [001] chains. Weak pi-pi inter-actions [centroid-centroid separation = 3.5460 (5) A] consolidate the structure. PMID- 22219921 TI - (2E)-2-(4-Fluoro-benzyl-idene)hydrazinecarboxamide. AB - In the title compound, C(8)H(8)FN(3)O, the semicarbazide group is close to being planar, with a maximum deviation of 0.020 (1) A, and subtends a dihedral angle of 16.63 (9) degrees with its attached fluoro-benzene ring. In the crystal, mol ecules are linked by N-H?O hydrogen bonds, forming layers lying parallel to the bc plane. PMID- 22219922 TI - N-Trityl-2-(tritylsulfan-yl)aniline. AB - The title compound, C(44)H(35)NS, is a derivative of amino-thio-phenol and possesses a protected S-triphenyl-methyl thio-ether and an N-triphenyl-methyl amine functional group. The trityl groups show an anti orientation, with C-C-N-C and C-C-S-C torsion angles of -151.0 (3) and -105.3 (2) degrees , respectively. There is an intra-molecular N-H?S hydrogen bond. PMID- 22219923 TI - 1,5-Anhydro-3,6-di-O-benzyl-2-de-oxy-1,2-C-dichloro-methyl-ene-d-glycero-d-gulo hexitol. AB - In the title compound, C(21)H(22)Cl(2)O(4), the pyranosyl ring adopts a twist boat conformation with the O-benzyl groups in equatorial positions. In the crystal, O-H?O hydrogen bonding results in infinite chains of mol-ecules along [100]. The structure is further consolidated by weak C-H?O, C-H?Cl and C-H?pi inter-actions. The absolute structure was determined. PMID- 22219924 TI - 1,3-Bis(2-meth-oxy-phen-yl)thio-urea. AB - In the title compound, C(15)H(16)N(2)O(2)S, the N-C(=S) bond lengths are indicative of the presence of amide-type resonance. The dihedral angles between the thio-urea unit and the attached aromatic rings are 59.80 (5) and 73.41 (4) degrees while the dihedral angle between the rings is 56.83 (4) degrees . In the crystal, inversion dimers linked by pairs of N-H?S hydrogen bonds occur. An N H?pi inter-action is observed for the second amino group. The shortest centroid centroid distance between two aromatic systems is 4.0958 (8) A. PMID- 22219925 TI - 4-Chloro-N-(2,6-dimethyl-phen-yl)-2-methyl-benzene-sulfonamide. AB - In the title compound, C(15)H(16)ClNO(2)S, the C-SO(2)-NH-C torsion angle is 61.15 (16) degrees . The sulfonyl and aniline benzene rings are tilted relative to each other by 38.8 (1) degrees . The crystal structure features inversion related dimers linked by pairs of N-H?O hydrogen bonds. PMID- 22219926 TI - 4-Chloro-N-(2,5-dimethyl-phen-yl)-2-methyl-benzene-sulfonamide. AB - The asymmetric unit of the title compound, C(15)H(16)ClNO(2)S, contains three independent moleules. The conformation of the N-H bonds are anti to the ortho methyl groups of the sulfonyl benzene rings in all the mol-ecules. The sulfonyl and the aniline benzene rings are tilted relative to each other by 43.0 (2), 37.0 (2) and by 46.0 (1) degrees in the three mol-ecules. In the crystal, inter molecular N-H?O hydrogen bonds link each of the mol-ecules into centrosymmetric dimers. PMID- 22219927 TI - 1-[3-(4-Nitro-phen-yl)propano-yl]urea acetic acid monosolvate. AB - The title compound, C(10)H(11)N(3)O(4).C(2)H(4)O(2), was prepared by an electrochemical technique. In the crystal, acetic acid mol-ecules are involved in hydrogen bonding to two separate propano-ylurea mol-ecules, acting as a donor in an O-H?O inter-action and as an acceptor in two N-H?O inter-actions. The propano ylurea mol-ecules inter-act with each other via N-H?O hydrogen bonds. C-H?O inter actions also stabilize the crystal structure. PMID- 22219928 TI - 2,4-Dichloro-N-(2,3-dichloro-phen-yl)benzene-sulfonamide. AB - In the title compound, C(12)H(7)Cl(4)NO(2)S, the conformation of the N-C bond in the C-SO(2)-NH-C segment is gauche with respect to the S=O bonds. Further, the N H bond in the C-SO(2)-NH-C segment is syn with respect to the ortho-Cl atoms in the aniline and sulfonyl benzene rings. The C-SO(2)-NH-C torsion angle is -51.98 (18) degrees . The sulfonyl and aniline benzene rings are tilted by 67.7 (1) degrees relative to each other. An intra-molecular N-H?Cl hydrogen bond occurs. PMID- 22219929 TI - 3-Methyl-N-(4-methyl-phen-yl)benzamide. AB - In the title compound, C(15)H(15)NO, the two aromatic rings make a dihedral angle of 70.06 (3) degrees , while the central amide core -NH-C(=O)- is twisted by 30.24 (4) and 40.16 (3) degrees out of the planes of the 3-methyphenyl and 4 methyphenyl rings, respectively. The methyl groups are disordered over two equally occupied positions. In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules into infinite chains running along the a axis. PMID- 22219930 TI - 6-Benzyl-6,7-dihydro-5H-pyrrolo-[3,4-b]pyridine-5,7-dione. AB - In the title compound, C(14)H(10)N(2)O(2), the dihedral angle between the heterocyclic ring system and the phenyl ring is 45.8 (5) degrees . Weak inter molecular C-H?N hydrogen bonding is present in the crystal structure. PMID- 22219931 TI - N,N,N',N'-Tetra-isobutyl-pyridine-2,6-dicarboxamide. AB - In the title compound, C(23)H(39)N(3)O(2), the amide O atoms are displaced by 1.020 (1) and 1.211 (1) A from the mean plane of the central pyridine ring. In the crystal, mol-ecules are connected by weak C-H?O hydrogen bonds between methyl ene groups in the isobutyl substituents and the amide O atoms. PMID- 22219932 TI - 2-[2-(2,4-Dinitro-phen-yl)eth-yl]-1,3,5-trinitro-benzene. AB - In the title compound, C(14)H(9)N(5)O(10), the two benzene rings are inclined at a dihedral angle of 14.81 (5) degrees , and the nitro groups are twisted with respect to the benzene rings to which they are attached, making dihedral angles of 57.89 (7), 14.93 (7), 62.58 (7), 2.80 (12) and 22.38 (12) degrees . Weak inter molecular C-H?O hydrogen bonding is present in the crystal structure. PMID- 22219933 TI - N-(3-Chloro-phen-yl)-4-methyl-benzamide hemihydrate. AB - In the title compound, C(14)H(12)ClNO.0.5H(2)O, the water mol-ecule is located on a twofold axis of symmetry. The meta-Cl atom in the aniline ring is positioned anti to the N-H bond. The two benzene rings make a dihedral angle of 40.40 (11) degrees . The crystal structure is stabilized by inter-molecular N-H?O and O-H?O hydrogen bonds, which link the mol-ecules into chains along the a axis. PMID- 22219934 TI - (E,E)-1,2-Bis[4-(prop-2-yn-1-yl-oxy)benzyl-idene]hydrazine. AB - The mol-ecule of the title compound, C(20)H(16)N(2)O(2), is centrosymmetric with the mid-point of the central N-N bond located on an inversion center. The configuration around the C=N bond is E. The whole mol-ecule (except for the H atoms) is approximately planar, with an r.m.s. deviation of 0.07 A. In the crystal, the presence of weak inter-molecular C-H?O hydrogen bonding involving each acetyl-ene H atom and the adjacent phen-oxy O atom results in the formation of supra-molecular chains. PMID- 22219935 TI - N,N-Dimethyl-ethane-1,2-diaminium bis-(3-hy-droxy-benzoate). AB - In the title compound, C(4)H(14)N(2) (2+).2C(7)H(5)O(3) (-), both the N,N dimethyl-ethylenediamine N atoms are protonated and two 3-hy-droxy-benzoate anions act as counter-ions. In the crystal, anions and cations are linked by a network of N-H?O and O-H?O hydrogen bonds. PMID- 22219936 TI - 2-Methyl-1-phenyl-1H-indole-3-carbo-nitrile. AB - In the title compound, C(16)H(12)N(2), the dihedral angle between the indole ring system and the pendant phenyl ring is 64.92 (5) degrees . The crystal packing features aromatic pi-pi stacking [centroid-centroid separation = 3.9504 (9) A] and C-H?pi inter-actions. PMID- 22219937 TI - 4-Chloro-N-(3-methyl-phen-yl)benzamide. AB - In the title compound, C(14)H(12)ClNO, the meta-methyl substituent in the aniline ring is positioned anti to the N-H bond. The dihedral angle between the rings is 12.4 (1) degrees . The crystal structure is stabilized by inter-molecular N-H?O hydrogen bonds, which link the mol-ecules into C(4) chains running along the c axis direction. PMID- 22219938 TI - 2-Diethyl-amino-6-methyl-pyrimidin-4(3H)-one. AB - The title compound, C(9)H(15)N(3)O, contains four mol-ecules (A, B, C and D) in the asymmetric unit. In the crystal, the A+A and D+D pairs form inversion dimers linked by pairs of N-H?O hydrogen bonds. The B+C pairing is linked by the same bonds. The dimers are further linked by weak C-H?O inter-actions. PMID- 22219939 TI - Creatininium hydrogen maleate. AB - In the title compound, C(4)H(8)N(3)O(+).C(4)H(3)O(4) (-), the cations and anions are linked through N-H?O hydrogen bonds making a ionic pair with an R(2) (2)(8) ring motif. These ionic pairs are further connected through another N-H?O hydrogen bond, leading to an R(6) (6)(16) ring motif around the inversion centres of the unit cell. These approximately planar aggregates are further connected through weak van der Waals inter-actions in the unit cell. The anions have a characteristic intra-molecular O-H?O hydrogen bond with a self-associated ring S(7) motif. PMID- 22219940 TI - 1-(1-Adamantylmeth-yl)-1H-benzimidazole. AB - The asymmetric unit of the title compound, C(18)H(22)N(2), contains two independent mol-ecules which differ slightly with respect to the torsion angles involving the atoms joining the adamantyl and benzimidazole groups. The bond angles in the adamantane cage vary within the range 108.27 (9)-110.55 (10) degrees . The benzimidazole ring system in both mol-ecules is essentially planar, the maximum deviations from the best planes being 0.0134 (15) and 0.0229 (14) A. In the crystal, weak C-H?pi inter-actions link the molecules. PMID- 22219941 TI - 4,10,16,22-Tetra-kis(2-chloro-acet-oxy)-6,12,18,24-tetra-meth-oxy-2,8,14,20-tetra pentyl-resorcin[4]arene. AB - The title compound, C(60)H(76)Cl(4)O(12), has a macrocyclic structure and both the upper and lower rim have disordered atoms. There are no hydrogen bonds or pi pi stacking inter-actions in the crystal. PMID- 22219942 TI - 1,1'-[m-Phenyl-enebis(nitrilo-methanylyl-idene)]dinaphthalen-2-ol-1,1'-[m-phenyl enebis(imino-methanylyl-idene)]dinaphthalen-2(1H)-one (0.58/0.42). AB - In the solid state the title Schiff base, 0.58C(28)H(20)N(2)O(2).0.42C(28)H(20)N(2)O(2), exists both as the keto-imino and as the enol-amino tautomer, which is manifested in the disorder of the H atom in the intra-molecular hydrogen-bonded ring. The naphthalene ring systems show some distortion, which is consistent with the quinoid effect. The ratio of the enol form refined to 58 (5)%. The mol-ecule has crystallographically imposed symmetry: a twofold axis passes through the central benzene ring. Crystals are built up of layers parallel to (010). Stacking interactions between the layers involve only standard van der Waals attraction forces between apolar groups. The alignment of the aromatic rings in neighbouring layers shows a herringbone motif. A weak C-H?O inter-action is observed. PMID- 22219943 TI - 3-Meth-oxy-methyl-16beta,17beta-epiestriol-16beta,17beta-diyl sulfate. AB - The title compound, C(20)H(26)O(6)S, synthesized by the reaction of 3-O-meth-oxy methyl-16beta-epiestriol and sulfonyl-diimidazole, is composed of a 3-meth-oxy methyl group connected via two O atoms to a 16,17-O-sulfuryl-16-epiestriol group. In the crystal, weak inter-molecular C-H?O hydrogen bonds link the mol-ecules into [001] chains. PMID- 22219944 TI - Dimethyl 4,4'-dihy-droxy-3,3'-{[(3aRS,7aRS)-2,3,3a,4,5,6,7,7a-octa-hydro-1H-1,3 benzimidazole-1,3-di-yl]bis-(methyl-ene)}dibenzoate. AB - The title compound, C(25)H(30)N(2)O(6), has the imidazolidine ring in an envelope conformation. There are two intra-molecular O-H?N hydrogen-bond inter-actions with graph-set motif S(6). The cyclo-hexane ring adopts a slightly distorted chair conformation. One methyl carboxyl-ate substituent forms a dihedral angle of 12.00 (5) degrees with the plane of the benzene ring, while the other methyl carboxyl-ate group is almost coplanar, making a dihedral angle of 2.26 (9) degrees . In the crystal, pairs of inter-molecular C-H?O hydrogen bonds form racemic dimers, corresponding to an R(2) (2)(18) graph-set motif. Further weak C H?O inter-actions generate a chain running along the c axis. PMID- 22219945 TI - (2,4-Difluoro-phen-yl)[1-(1H-1,2,4-triazol-1-yl)cyclo-prop-yl]methanone. AB - The asymmetric unit of the title compound, C(12)H(9)F(2)N(3)O, contains two independent mol-ecules (A and B) in which the benzene and cyclo-propane rings form dihedral angles of 33.0 (1) and 29.7 (1) degrees , respectively. In the crystal, weak inter-molecular C-H?O hydrogen bonds link alternating A and B mol ecules into chains along [010]. PMID- 22219946 TI - (E)-2'-[(3,5-Di-tert-butyl-2-hy-droxy-benzyl-idene)amino]-1,1'-binaphthalen-2-ol methanol monosolvate. AB - The title compound, C(35)H(35)NO(2).CH(4)O, was obtained by the reaction of rac-2 amino-2-hy-droxy-1,1-binaphthyl and 3,5-di-tert-butyl-2-hy-droxy-benzaldehyde in absolute methanol. In the Schiff base mol-ecule, the two naphthyl bicycles are twisted by 71.15 (5) degrees . One hy-droxy group is involved in intra-molecular O-H?N hydrogen bond, while the methanol solvent mol-ecule is linked to another hy droxy group via an inter-molecular O-H?O hydrogen bond. PMID- 22219947 TI - 4-Meth-oxy-2-nitro-4'-(trifluoro-meth-yl)biphen-yl. AB - The title compound, C(14)H(10)F(3)NO(3), was prepared by a palladium-catalysed Suzuki-Miyaura coupling reaction. The dihedral angle between the nitro group and its parent benzene ring is 66.85 (19) degrees while the dihedral angle between the two benzene rings is 49.98 (9) degrees . The CF(3) group is disordered over two sets of sites with occupancies of 0.457 (8) and 0.543 (8). PMID- 22219948 TI - 2-{[4-(Pyridin-2-yl)pyrimidin-2-yl]sulfan-yl}acetic acid. AB - In the title mol-ecule, C(11)H(9)N(3)O(2)S, the pyridine and pyrimidine rings are almost parallel [dihedral angle = 6.7 (1) degrees ]. In the crystal, adjacent mol ecules are joined by O-H?N and C-H?O hydrogen bonds, leading to the formation of a sheet parallel to (10[Formula: see text]). PMID- 22219949 TI - Ethyl 4-chloro-3,5-dinitro-benzoate. AB - In the title compound, C(9)H(7)ClN(2)O(6), the nitro groups and the ester group make dihedral angles of 44.0 (1), 89.6 (1) and 164.1 (1) degrees , respectively, with the benzene ring. In the crystal, mol-ecules are linked through weak C-H?O hydrogen-bonding inter-actions. Mol-ecules are stacked via pi-pi inter-actions about inversion centers, with a centroid-centroid distance of 3.671 (2) A. PMID- 22219950 TI - 3alpha-Dimethyl-amino-20-(N-methyl-acetamido)-pregn-5-ene. AB - The title compond, C(26)H(44)N(2)O, is an steroidal alkaloid isolated from the medicinally important plant Sarcococca saligna. The mol-ecule consists of four fused rings (A-D), having chair, half-chair, chair and envelope conformations, respectively. The dimethyl-amino group is axially oriented on ring A, whereas the (N-methyl-acetamido)-ethyl group is attached equatorially on ring D. The crystal structure is stabilized only by van der Waals forces. PMID- 22219951 TI - Methyl (E)-3-(2-bromo-4,5-dimeth-oxy-benzyl-idene)dithio-carbazate. AB - The title compound, C(11)H(13)BrN(2)O(2)S(2), was obtained from the condensation reaction of methyl dithio-carbazate and 2-bromo-4,5-dimeth-oxy-benzaldehyde. In the mol-ecule, the benzene ring and dithio-carbazate fragment are located on opposite sides of the C=N bond, showing an E conformation. The dithio-carbazate fragment is approximately planar (r.m.s deviation = 0.0281 A) and the mean plane is oriented at a dihedral angle of 11.38 (15) degrees with respect to the benzene ring. In the crystal, pairs of N-H?S hydrogen bonds link the mol-ecules into centrosymmetric dimers. PMID- 22219952 TI - 2-(1,3-Benzothia-zol-2-yl)guanidin-2-ium acetate. AB - In the title compound, C(8)H(9)N(4)S(-).C(2)H(3)O(2) (-), the cation is essentially planar (r.m.s deviation = 0.037 A) with the guanidine unit bent out of the plane of the fused-ring system by 4.6 (3) degrees . In the asymmetric unit, the cations and anions are linked into R(2) (2)(8) motifs. In the crystal, further N-H?O and N-H?N hydrogen bonds link the components into a two-dimensional network. PMID- 22219953 TI - N-[(R)-(6-Bromo-2-meth-oxy-quinolin-3-yl)(phen-yl)meth-yl]-N-[(S)-1-(4-meth-oxy phen-yl)eth-yl]-2-(piperazin-1-yl)acetamide. AB - In the title compound, C(32)H(35)BrN(4)O(3), the piperazine ring exists in a chair conformation. The quinoline ring system is oriented at dihedral angles of 82.70 (17) and 19.54 (17) degrees to the phenyl and meth-oxy-phenyl rings, respectively. Weak inter-molecular C-H?pi inter-actions are present in the crystal structure. PMID- 22219954 TI - 1-[1-(3-Methyl-phen-yl)-5-phenyl-4-phenyl-sulfonyl-1H-pyrazol-3-yl]ethanone. AB - Both the acetyl and phenyl substituents of the central pyrazole ring in the title compound, C(24)H(20)N(2)O(3)S, are twisted with respect to the pyrazole ring, with the twist involving the phenyl ring being greater [67.4 (1) and 29.6 (2) degrees ]. The tolyl substituent is disordered over two positions in a 1:1 ratio; the mean planes of the aromatic ring are aligned at 67.7 (3) and 69.4 (3) degrees with respect to the pyrazole ring. PMID- 22219955 TI - 4,4'-Di-tert-butyl-2,2'-[(3aRS,7aRS)-2,3,3a,4,5,6,7,7a-octa-hydro-1H-1,3 benzimidazole-1,3-di-yl)bis-(methyl-ene)]diphenol. AB - In the title compound, C(29)H(42)N(2)O(2), the heterocyclic ring has a twist conformation. The cyclohexane ring adopts a chair conformation. The dihedral angle between the aromatic rings is 32.74 (6) degrees . The mol-ecular conformation is stabilized by two intramolecular O-H?N hydrogen bonds with graph set motif S(6). The crystal packing is stabilized by C-H?O and C-H?pi inter actions. PMID- 22219956 TI - 3-Fluoro-anilinium 4-methyl-benzene-sulfonate. AB - In the crystal structure of the title salt, C(6)H(7)FN(+).C(7)H(7)O(3)S(-), the components are linked into chains along [010] via N-H?O hydrogen bonds. Further stabilization is is provided by weak pi-pi stacking inter-actions, with a centroid-centroid distance of 3.7156 (12) A. PMID- 22219957 TI - 3-Chloro-anilinium 4-methyl-benzene-sulfonate. AB - In the crystal structure of the title salt, C(6)H(7)ClN(+).C(7)H(7)O(3)S(-), the cations and anions are linked via N-H?O hydrogen bonds into doubled chains in [010]. Weak inter-molecular C-H?pi inter-actions further link these chains into layers parallel to the bc plane. PMID- 22219958 TI - N-(4-Bromo-phen-yl)-2-(naphthalen-1-yl)acetamide. AB - In the title compound, C(18)H(14)BrNO, the naphthalene ring system and the benzene ring form dihedral angles of 78.8 (2) and 19.7 (2) degrees , respectively, with the acetamide C-C(=O)-N plane. The naphthalene ring system forms a dihedral angle of 64.88 (19) degrees with the benzene ring. In the crystal, mol-ecules are linked via inter-molecular bifurcated (N,C)-H?O hydrogen bonds, generating an R(2) (1)(6) ring motif, forming chains along the b axis. PMID- 22219959 TI - 3-(4-Bromo-phen-yl)quinazolin-4(3H)-one. AB - In the title compound, C(14)H(9)BrN(2)O, the quinazoline unit is essentially planar, with a mean deviation of 0.058 (2) A from the least-squares plane defined by the ten constituent ring atoms. The dihedral angle between the mean plane of the quinazoline ring system and the 4-bromo-phenyl ring is 47.6 (1) degrees . In the crystal, mol-ecules are linked by inter-molecular C-H?N and C-H?O hydrogen bonds, forming infinite chains of alternating R(2) (2)(6) dimers and R(2) (2)(14) ring motifs. PMID- 22219960 TI - (E)-3-(1-Phenyl-ethyl-idene)indolin-2-one. AB - In the title mol-ecule, C(16)H(13)NO, the indoline-2-one ring system is nearly planar [maximum atomic deviation = 0.082 (2) A] and is oriented at a dihedral angle of 66.60 (12) degrees with respect to the phenyl ring. In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules into supra-molecular dimers. PMID- 22219961 TI - 4-Chloro-N-(3,4-dimethyl-phen-yl)-2-methyl-benzene-sulfonamide. AB - In the title compound, C(15)H(16)ClNO(2)S, the conformation of the N-C bond in the C-SO(2)-NH-C segment is gauche with respect to the S=O bonds. Further, the N H bond in the C-SO(2)-NH-C segment is syn with respect to the meta-methyl group in the aniline benzene ring and the ortho-methyl group in the sulfonyl benzene ring. The C-SO(2)-NH-C torsion angle is -49.72 (18) degrees . The sulfonyl and aniline benzene rings are tilted relative to each other by 71.6 (1) degrees . The crystal structure features inversion-related dimers linked by pairs of N-H?O hydrogen bonds. PMID- 22219962 TI - (E)-1-[2-Hy-droxy-4,6-bis-(meth-oxy-meth-oxy)phen-yl]-3-[3-meth-oxy-4-(meth-oxy meth-oxy)phen-yl]prop-2-en-1-one. AB - The title compound, C(22)H(26)O(9), crystallizes with two independent mol-ecules in the asymmetric unit in which the dihedral angles between the two benzene rings are 21.4 (2) and 5.1 (2) degrees . An intra-molecular O-H?O hydrogen bond occurs in each mol-ecule. Inter-molecular C-H?O hydrogen bonds stabilize the crystal structure. PMID- 22219963 TI - N-Benzyl-4-methyl-6-phenyl-pyrimidin-2-amine. AB - In the title compound, C(18)H(17)N(3), the dihedral angles between the central pyrimidine ring and its directly-bonded and N-bonded pendant phenyl rings are 25.48 (6) and 80.33 (6) degrees , respectively. The dihedral angle between the phenyl rings is 79.66 (6) degrees . In the crystal, inversion dimers linked by pairs of N-H?N hydrogen bonds generate R(2) (2)(8) loops. The crystal structure also features weak pi-pi [centroid-centroid separation = 3.6720 (7) A] and C-H?pi inter-actions. PMID- 22219964 TI - 4-Aza-1-azoniabicyclo-[2.2.2]octa-ne-2-amino-benzoate-2-amino-benzoic acid (1/1/1). AB - A 4-aza-1-azoniabicyclo-[2.2.2]octane cation, a 2-amino-benzoate anion and a neutral 2-amino-benzoic acid mol-ecule comprise the asymmetric unit of the title compound, C(6)H(13)N(2) (+).C(7)H(6)NO(2) (-).C(7)H(7)NO(2). An intra-molecular N H?O hydrogen bond occurs in the anion and in the neutral 2-amino-benzoic acid mol ecule. The cation provides a charge-assisted N-H?O hydrogen bond to the anion, and the 2-amino-benzoic acid mol-ecule forms an O-H?N hydrogen bond to the unprotonated amino N atom in the cation. In this way, a three-component aggregate is formed. These are connected into a three-dimensional network by amino-carboxyl ate N-H?O hydrogen bonds. N-H?N hydrogen bonds are also observed. PMID- 22219965 TI - [1-(3-Chloro-phen-yl)-1H-1,2,3-triazol-4-yl]methanol hemihydrate. AB - The asymmetric unit of the title hydrate, C(9)H(8)ClN(3)O.0.5H(2)O, comprises two independent 1,2,3-triazole mol-ecules and a water mol-ecule of crystallization. The dihedral angles between the six- and five-membered rings in the 1,2,3 triazole mol-ecules are 12.71 (19) and 17.3 (2) degrees . The most significant different between them is found in the relative orientations of the terminal CH(2)OH groups with one being close to perpendicular to the five-membered ring [N C-C-O torsion angle = 82.2 (5) degrees ], while in the other mol-ecule, a notable deviation from a perpendicular disposition is found [torsion angle = -60.3 (5) degrees ]. Supra-molecular chains feature in the crystal packing sustained by O H?(O,N) inter-actions along the a-axis direction. The chains are connected via C H?N inter-actions and the resultant layers stack along the b axis. PMID- 22219966 TI - 5-Chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde. AB - In the title compound, C(6)H(7)ClN(2)O, the mol-ecules are situated on mirror planes, so H atoms of two methyl groups were treated as rotationally disordered over two orientations each. The crystal packing exhibits weak inter-molecular C H?O inter-actions and short Cl?N contacts of 3.046 (2) A. PMID- 22219967 TI - 1-Decyl-6-nitro-1H-benzimidazol-2(3H)-one. AB - The title mol-ecule, C(17)H(25)N(3)O(3), is built up from fused six- and five membered rings linked to a -C(10)H(21) chain. The fused-ring system is essentially planar, the largest deviation from the mean plane being 0.009 (2) A. The chain is roughly perpendic-ular to this plane, making a dihedral angle of 79.5 (2) degrees . In the crystal, N-H?O hydrogen bonds build infinite chains along [010]. There are channels in the structure containing disordered hexane. The contribution of this solvent to the scattering power was suppressed using the SQUEEZE option in PLATON [Spek (2009 ?). Acta Cryst. D65, 148-155]. PMID- 22219968 TI - Ethyl 1-sec-butyl-2-(4-fluoro-phen-yl)-1H-benzimidazole-5-carboxyl-ate. AB - In the title compound, C(20)H(21)FN(2)O(2), the benzene ring and the benzimidazole ring system are inclined at a dihedral angle of 44.40 (9) degrees . In the crystal, mol-ecules are linked by inter-molecular C-H?O hydrogen bonds, forming a zigzag chain along the b-axis direction. An intra-molecular C-H?pi inter-action is also observed. PMID- 22219969 TI - 4-Chloro-N-(3,4-dichloro-phen-yl)-2-methyl-benzene-sulfonamide. AB - In the title compound, C(13)H(10)Cl(3)NO(2)S, the N-C bond in the C-SO(2)-NH-C segment forms trans and gauche torsion angles with respect to the S=O bonds. Further, the N-H bond in the C-SO(2)-NH-C segment is anti to the meta-Cl atom in the anilino benzene ring and nearly syn with respect to the ortho-methyl group in the sulfonyl benzene ring. The C-SO(2)-NH-C torsion angle is -49.4 (2) degrees . The sulfonyl and aniline benzene rings are tilted relative to each other by 54.6 (1) degrees . In the crystal, mol-ecules are linked into chains along the c-axis direction by inter-molecular N-H?O hydrogen bonds. PMID- 22219970 TI - 2-Chloro-N-(4-methyl-phen-yl)benzamide. AB - In the title compound, C(14)H(12)ClNO, the ortho-Cl atom in the benzoyl ring is positioned syn to the C=O bond. The benzoyl and aniline benzene rings are tilted relative to each other by 82.8 (1) degrees . In the crystal, inter-molecular N H?O hydrogen bonds link the mol-ecules into infinite chains running along the c axis direction. PMID- 22219971 TI - N-(3,5-Dichloro-phen-yl)-2-(naphthalen-1-yl)acetamide. AB - In the title compound, C(18)H(13)Cl(2)NO, the naphthalene ring system [maximum deviation = 0.038 (4) A] and the benzene ring form dihedral angles of 69.5 (2) and 37.2 (2) degrees , respectively, with the essentially planar acetamide unit [maximum deviation = 0.004 (4) A]. The naphthalene ring system forms a dihedral angle of 52.36 (18) degrees with the benzene ring. In the crystal, mol-ecules are linked via inter-molecular N-H?O hydrogen bonds, forming chains along [001]. PMID- 22219972 TI - Bis(1H-benzimidazol-1-yl)methane monohydrate. AB - In the title compound, C(15)H(12)N(4).H(2)O, the organic mol-ecule displays approximate non-crystallographic twofold symmetry: the dihedral angle between the benzimidazole ring systems is 81.37 (12) degrees . In the crystal, the components are linked by O-H?N hydrogen bonds, forming chains propagating in [101]. Aromatic pi-pi stacking [centroid-centroid separation = 3.595 (2) A] helps to consolidate the structure. PMID- 22219973 TI - 2,6-Bis(4H-1,2,4-triazol-4-yl)pyridine dihydrate. AB - The asymmetric unit of the title compound, C(9)H(7)N(7).2H(2)O, comprises three formula units. The dihedral angles between the triazole rings and the respective central pyridine rings are 4.87 (16)/1.39 (17), 6.46 (16)/7.61 (16) and 7.00 (16)/3.77 (17) degrees . The water mol-ecules form O-H?O hydrogen bonds between themselves and O-H?N hydrogen bonds with the N-atom acceptors of the triazole rings, producing a three-dimensional framework. PMID- 22219974 TI - Paliperidone: 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]eth-yl}-9-hy droxy-2-methyl-1,6,7,8,9,9a-hexa-hydro-pyrido[1,2-a]pyrimidin-4-one. AB - The title compound (also known as 9-hy-droxy-risperidone), C(23)H(27)FN(4)O(3), is a heterocyclic compound with manifold pharmacological properties. The hy-droxy group shows disorder over two positions, with site-occupancy factors of 0.856 (2) and 0.144 (2). The piperidine ring adopts a chair conformation, while the annulated ring bearing the hy-droxy group is present in a half-chair conformation. Classical O-H?O hydrogen bonds as well as C-H?N contacts connect the mol-ecules into undulating sheets lying perpendicular to the crystallographic b axis. The shortest centroid-centroid distance between two centers of gravity is 3.5867 (8) A and is apparent between the benzoxazole moiety and the six-membered ring bearing the keto substituent. PMID- 22219975 TI - 1-Carb-oxy-3-phenyl-propan-2-aminium chloride. AB - The title compound, C(9)H(12)NO(2) (+).Cl(-), is the hydro-chloride of an N substituted glycine derivative. The non-H atoms of the alkyl part of the mol ecule lie nearly in a plane (r.m.s. deviation of all fitted non-H atoms = 0.0142 A). In the crystal structure, O-H?Cl, N-H?Cl and C-H?O hydrogen bonds involving both O atoms as well as C-H?Cl contacts connect the components of the title compound into a three-dimensional network. PMID- 22219976 TI - Thailandepsin a. AB - THAILANDEPSIN A [SYSTEMATIC NAME: (E)-(1S,5S,6R,9S,20R)-6-[(2S)-butan-2-yl]-5-hy droxy-20-[2-(meth-yl-sulfan-yl)eth-yl]-2-oxa-11,12-dithia-7,19,22-triaza-bicyclo [7.7.6]docosa-15-ene-3,8,18,21-tetra-one], C(23)H(37)N(3)O(6)S(3), is a newly reported [Wang et al. (2011). J. Nat. Prod. doi:10.1021/np200324x] bicyclic depsipeptide that has potent histone deacetyl-ase inhibitory activity and broad spectrum anti-proliferative activity. The absolute configuration of thailandepsin A has been determined from the anomalous dispersion and the stereochemistry of all chiral C atoms. Intra-molecular N-H?O and N-H?S hydrogen bonds occur. Inter molecular N-H?O and O-H?O hydrogen bonds are observed in the crystal structure. PMID- 22219977 TI - 1,2-Dimeth-oxy-4-methyl-3-[(S)-p-tolyl-sulfin-yl]benzene. AB - In the title compound, C(16)H(18)O(3)S, the dihedral angle between the benzene rings is 75.48 (8) degrees . The absolute configuration at the stereogenic S-atom center was determined as S. The crystal structure is stabilized by inter molecular C-H?O contacts. PMID- 22219978 TI - [(2R,3S,5R)-3-Acet-oxy-5-(5-formyl-2,4-dioxo-1,2,3,4-tetra-hydro-pyrimidin-1-yl) 2,3,4,5-tetra-hydro-furan-2-yl]methyl acetate. AB - In the two independent but very similar mol-ecules (A and B) of the title compound, C(14)H(16)N(2)O(8), both six-membered pyrimidine rings are nearly planar [maximum deviations = 0.010 (3) A in A and 0.028 (3) A in B]. The five membered furan-ose ring in mol-ecule A adopts an envelope conformation, while the same ring in mol-ecule B has a twisted conformation. In the crystal, the A mol ecules are linked via a pair of inter-molecular N-H?O hydrogen bonds, forming dimers. Each A mol-ecule is further linked to a B mol-ecule via a second N-H?O hydrogen bond. There are also a number of C-H?.O inter-actions present, leading to the formation of a three-dimensional network. PMID- 22219979 TI - N,N'-Bis(4-methyl-benzyl-idene)benzene-1,4-diamine. AB - The centrosymmetric title compound, C(22)H(20)N(2), crystallizes with one half mol-ecule in the asymmetric unit. The dihedral angle between the central and outer benzene rings is 46.2 (2) degrees . PMID- 22219980 TI - 4,4',6,6'-Tetra-tert-butyl-2,2'-[butane-1,4-diylbis(nitrilo-methanylyl idene)]diphenol. AB - The title compound, C(34)H(52)N(2)O(2), is centrosymmetric, the mid-point of the central C-C bond being located on an inversion centre. Intra-molecular O-H?N and weak C-H?O hydrogen bonds are observed, but no significant inter-molecular inter actions occur in the crystal structure. PMID- 22219981 TI - rac-Dimethyl 2-(tert-butyl-amino)-5-oxo-4,5-dihydro-pyrano[3,2-c]chromene-3,4 dicarboxyl-ate. AB - The title compound, C(20)H(21)NO(7), is asymmetric with a chiral centre located in the pyran ring and crystallizes as a racemate. The mol-ecular framework is somewhat bent; the coumarin moiety and the pyran ring are inclined by 7.85 (5) degrees . The mol-ecular structure is characterized by an intra-molecular N-H?O hydrogen bond, which generates an S(6) ring motif, and the crystal packing is stabilized by inter-molecular C-H?O hydrogen bonds. The 3-carboxyl-ate O atom is involved in both of them, having a bifurcated character. PMID- 22219982 TI - N-Butyl-4,6-diphenyl-pyrimidin-2-amine. AB - In the title compound, C(20)H(21)N(3), the pyrimidine ring is inclined at dihedral angles of 51.57 (4) and 2.49 (4) degrees to the two phenyl rings. The dihedral angle between the two terminal phenyl rings is 50.44 (4) degrees . In the crystal, adjacent mol-ecules are linked via a pair of N-H?N hydrogen bonds, forming an inversion dimer with an R(2) (2)(8) ring motif. Furthermore, the crystal structure is stabilized by a weak pi-pi inter-action, with a centroid centroid distance of 3.6065 (5) A. PMID- 22219983 TI - 6beta,8beta-Dihy-droxy-eremophil-7(11)-en-8alpha,12-olide. AB - The title compound, C(15)H(22)O(4), an eremophilane sesquiternoid, was isolated from the roots of Ligularia virgaurea. Both six-membered rings (A and B) adopt chair conformations and the five-membered ring is almost planar (r.m.s. deviation = 0.016 A). The two methyl and two hy-droxy groups adopt a syn conformation and the A/B ring junction is cis-fused. An intra-molecular O-H?O hydrogen bond generates an S(6) ring. In the crystal, O-H?O hydrogen bonds link the mol-ecules into [100] chains. PMID- 22219984 TI - 1-[(4-{[(2-Oxo-1,2-dihydro-naphthalen-1-yl-idene)meth-yl]amino}-anilino)methyl idene]naphthalen-2(1H)-one dihydrate. AB - The title compound, C(28)H(20)N(2)O(2).2H(2)O, comprises a Schiff base mol-ecule with an imposed inversion centre in the middle of p-phenyl-enediamine unit and water mol-ecules of crystallization. In the structure, the Schiff base mol-ecule is present as the keto-amino tautomer with a strong intra-molecular N-H?O hydrogen bond. The Schiff base mol-ecules and water mol-ecules of crystallization create infinite [010] columns through O-H?O hydrogen bonds. Inter-molecular attractions within columns are through additional pi-pi inter-actions [centroid centroid distance = 3.352 (1) A] between parallel Schiff base mol-ecules. The columns are joined into infinite (011) layers through weak C-H?O hydrogen bonds. The layers pack in an assembly by van der Waals attractions, only being effective between bordering non-polar naphthalene ring systems. PMID- 22219985 TI - N'-(2-Hy-droxy-4-meth-oxy-benzyl-idene)-3-nitro-benzohydrazide. AB - In the mol-ecule of the title compound, C(15)H(13)N(3)O(3), an intra-molecular O H?N hydrogen bond influences the planarity of the conformation; the dihedral angle between the benzene rings is 11.4 (3) degrees . In the crystal, mol-ecules are linked by N-H?O hydrogen bonds into chains in [101]. PMID- 22219986 TI - (Z)-2-(4-Nitro-benzyl-idene)-1-benzofuran-3(2H)-one. AB - In the crystal structure of the title compound, C(15)H(9)NO(4), weak C-H?O inter actions generate rings with R(2) (2)(8) motifs. The supra-molecular aggregation is completed by the presence of C-H?O and van der Waals inter-actions. PMID- 22219987 TI - 3-(4-Meth-oxy-phen-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde. AB - Four independent mol-ecules comprise the asymmetric unit of the title compound, C(17)H(14)N(2)O(2). The central pyrazoline ring is flanked by an N-bound benzene ring and a C-bound meth-oxy-substituted benzene ring. The greatest difference between the independent mol-ecules is found in the relative orientations of the benzene rings with the range of dihedral angles being 23.59 (6)-42.55 (6) degrees . In the crystal, extensive C-H?O inter-actions link mol-ecules into layers parallel to (02[Formula: see text]) and these are linked by C-H?pi contacts. PMID- 22219988 TI - 2-[N-(3-Amino-4-nitro-phen-yl)carboximido-yl]phenol. AB - The title compound, C(13)H(11)N(3)O(3), is essentially planar (r.m.s. for the 19 non-H atoms = 0.031 A), a conformation stabilized in part by intra-molecular O H?N and N-H?O hydrogen bonds. The configuration about the imine bond [1.2919 (12) A] is E. The presence of N-H?O(nitro) hydrogen bonds leads to the formation of supra-molecular tapes in the crystal structure. These are connected into layers by pi-pi inter-actions [centroid-centroid distance = 3.6046 (6) A] occurring between the hy-droxy- and amino-substituted benzene rings. PMID- 22219989 TI - 1,3-Bis(2-chloro-phen-yl)thio-urea: a monoclinic polymorph. AB - The title compound, C(13)H(10)Cl(2)N(2)S, represents a monoclinic polymorph of the previously reported ortho-rhom-bic form [Ramnathan et al. (1996 ?). Acta Cryst. C52, 134-136]. The mol-ecule is twisted with the dihedral angle between the benzene rings being 55.37 (7) degrees . The N-H atoms are syn to each other, which contrasts their anti disposition in the ortho-rhom-bic form. In the crystal, mol-ecules assemble into zigzag chains along the c axis via N-H?S hydrogen bonds. Chains are connected into layers via C-H?Cl inter-actions, and these stack along the a axis. PMID- 22219990 TI - Ethane-1,2-diaminium 4,4'-sulfonyl-dibenzoate. AB - In the title salt, C(2)H(10)N(2) (2+).C(14)H(8)O(6)S(2-), both the ethyl-ene diaminium cations and the 4,4'-sulfonyl-dibenzoate dianions have crystallographic twofold rotational symmetry. They are inter-linked by aminium N-H?O(carboxyl-ate) hydrogen-bonding associations, giving sheets parallel to (101) and are further linked along [010], forming a three-dimensional structure. PMID- 22219991 TI - 2,3-Dichloro-1,4-hydro-quinone 2,3-dichloro-1,4-benzoquinone monohydrate: a quinhydrone-type 1:1 donor-acceptor [D-A] charge-transfer complex. AB - IN THE CRYSTAL STRUCTURE OF THE TITLE COMPOUND (SYSTEMATIC NAME: 2,3-dichloro benzene-1,4-diol 2,3-dichloro-cyclo-hexa-2,5-diene-1,4-dione monohydrate), C(6)H(4)Cl(2)O(2).C(6)H(2)Cl(2)O(2).H(2)O, the 2,3-dichloro-1,4-hydro-quinone donor (D) and the 2,3-dichloro-1,4-benzoquinone acceptor (A) mol-ecules form alternating stacks along [100]. Their mol-ecular planes [maximum deviations for non-H atoms: 0.0133 (14) (D) and 0.0763 (14) A (A)] are inclined to one another by 1.45 (3) degrees and are thus almost parallel. There are pi-pi inter-actions involving the D and A mol-ecules, with centroid-centroid distances of 3.5043 (9) and 3.9548 (9) A. Inter-molecular O-H?O hydrogen bonds involving the water mol ecule and the hy-droxy and ketone groups lead to the formation of two-dimensional networks lying parallel to (001). These networks are linked by C-H?O inter actions, forming a three-dimensional structure. PMID- 22219992 TI - 3-(4-Bromo-phen-yl)-N,N-dimethyl-3-oxopropan-1-aminium chloride. AB - The title compound, C(11)H(15)BrNO(+).Cl(-), was obtained as a precursor within our current program for the synthesis of new beta-amino-alcohols via a Mannich type reaction. The protonated amino N atom is hydrogen bonded to the chloride anion. With exception of one methyl group, the cation is approximately planar (r.m.s. deviation for all non H-atoms = 0.069 A). PMID- 22219993 TI - 3-(2H-1,3-Benzodioxol-5-ylmeth-yl)-2-(2-meth-oxy-phen-yl)-1,3-thia-zolidin-4-one. AB - The title mol-ecule, C(18)H(17)NO(4)S, features a 1,3-thia-zolidine ring that is twisted about the S-C(methyl-ene) bond. With reference to this ring, the 1,3 benzodioxole and benzene rings lie to either side and form dihedral angles of 69.72 (16) and 83.60 (14) degrees , respectively, with the central ring. Significant twisting in the mol-ecule is confirmed by the dihedral angle of 79.91 (13) degrees formed between the outer rings. Linear supra-molecular chains along the a-axis direction mediated by C-H?O inter-actions feature in the crystal packing. PMID- 22219994 TI - 2-(3-Eth-oxy-2-hy-droxy-benz-ylidene)-N-phenyl-hydrazinecarboxamide. AB - The title compound, C(16)H(17)N(3)O(3), exists in the E configuration with respect to the azomethine double bond. The mol-ecule is close to planar, with a dihedral angle of 6.7 (1) degrees between the aromatic rings. The phenolic O atom functions as donor and acceptor by forming intramolec-ular O-H?O and inter molecular N-H?O hydrogen bonds, respectively. Two-dimensional packing is fashioned through an inter-molecular hydrogen bonding network in an offset manner. PMID- 22219995 TI - 1-Meth-oxy-4-methyl-9,10-anthraquinone. AB - The non-H atoms of the title compound, C(16)H(12)O(3), lie approximately in a common plane (r.m.s. deviation = 0.032 A). The methyl C atom is forced away from the carbonyl O atom which can be seen by the widened C(fused ring)-C(benzene) C(meth-yl) angle of 125.8 (2) degrees . PMID- 22219996 TI - Ethyl 8-chloro-1-cyclo-propyl-6,7-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxyl ate. AB - In the mol-ecule of the title compound, C(15)H(12)ClF(2)NO(3), the quinoline ring system is not planar, the dihedral angle between the pyridine and benzene rings being 3.55 (8) degrees . In the crystal, inter-molecular C-H?O hydrogen bonds link the mol-ecules into layers parallel to (101). PMID- 22219997 TI - exo-10,11-Dibromo-tricyclo-[6.3.1.0]dodeca-2,4,6,9-tetra-ene. AB - The title compound, C(12)H(10)Br(2), is a bridged ring system based on a homobenzonorbornadiene framework. The exo configuration of one of the Br atoms was previously assigned via NMR correlations and has now been confirmed by the geometry of the solid-state structure. The compound features a Br-C-C-Br torsion angle of 66.68 (12) degrees , whereby the C atoms in the calculation are respectively sp(3)- and sp(2)-hybridized. PMID- 22219998 TI - 2,4-Dichloro-N-(3,5-dichloro-phen-yl)benzene-sulfonamide. AB - In the title compound, C(12)H(7)Cl(4)NO(2)S, the N-H bond in the C-SO(2)-NH-C segment is syn with respect to the ortho-Cl atom of the sulfonyl-benzene ring and one of the meta-Cl atoms of the aniline ring. The C-SO(2)-NH-C torsion angle is 93.9 (2) degrees . The benzene rings are tilted relative to each other by 61.9 (1) degrees . The crystal structure features inversion-related dimers linked by pairs of N-H?O hydrogen bonds. PMID- 22219999 TI - rac-syn-Diethyl 2-hy-droxy-4-oxo-1-phenyl-cyclo-hexane-1,2-dicarboxyl-ate. AB - The title compound, C(18)H(22)O(6), was obtained by the domino oxa-Michael-aldol (DOMA) reaction and has the cyclo-hexa-none ring in a chair conformation with intra-annular torsion angles in the range 49.9 (2)-58.9 (2) degrees . The two eth oxy-carbonyl substituents on the cyclo-hexa-none ring adopt a syn configurations. In the crystal, the mol-ecules self-assemble through duplex inter-molecular hy droxy-carbonyl O-H?O hydrogen bonds, giving centrosymmetric cyclic dimers [graph set R(2) (2)(12)] which inter-associate through weak C-H?O hydrogen-bonding inter actions. PMID- 22220000 TI - Diisopropyl 1-(4-meth-oxy-phen-yl)-2,6-dimethyl-4-(3-nitro-phen-yl)-1,4-dihydro pyridine-3,5-dicarboxyl-ate. AB - In the title compound, C(28)H(32)N(2)O(7), the 1,4-dihydro-pyridine ring adopts a flattened boat conformation. The two benzene rings are approximately perpendicular to the dihydro-pyridine ring, forming dihedral angles of 84.29 (9) and 82.96 (9) degrees with the mean plane of the 1,4-dihydro-pyridine unit, whereas the ester groups are only slightly twisted relative to this plane, with dihedral angles of 10.6 (1) and 9.0 (1) degrees . PMID- 22220001 TI - Tris(dicyclo-hexyl-ammonium) hydrogen [1-hy-droxy-2-(1H-imidazol-1-yl)-1-phospho natoethane]-phospho-nate ethanol monosolvate mono-hydrate. AB - In the title compound, 3C(12)H(24)N(+).C(5)H(7)N(2)O(7)P(2) (3-).C(2)H(6)O.H(2)O, the zoledronic acid mol-ecule is singly protonated and stabilized by an intra molecular O-H?O inter-action. The three-dimensional crystal structure is stabilized by inter-molecular O-H?O, O-H?N and N-H?O inter-actions. The ethanol solvent mol-ecule is disordered over two positions; the site-occupancy factor of the major component is 0.510 (4). PMID- 22220002 TI - 10alpha-Hy-droxy-4,9-dimethyl-13-[(4-phenyl-piperazin-1-yl)meth-yl]-3,8,15 trioxatetra-cyclo-[10.3.0.0.0]tetra-decan-14-one. AB - The title compound, C(25)H(34)N(2)O(5), was synthesized from 9alpha-hy-droxy parthenolide (9alpha-hy-droxy-4,8-dimethyl-12-methyl-ene-3,14-dioxatricyclo [9.3.0.0(2,4)]tetra-dec-7-en-13-one), which was isolated from the chloro-form extract of the aerial parts of Anvillea radiata. The mol-ecule contains a fused five- and ten-membered ring system. The ten-membered ring adopts an approximate chair-chair conformation, while the five-membered ring is in an envelope conformation, with the C atom closest to the hy-droxy group forming the flap. The piperazine ring is in a chair conformation. In the crystal, O-H?O hydrogen bonds connect mol-ecules into chains along [100]. Weak inter-molecular C-H?O hydrogen bonds are also present. PMID- 22220003 TI - 5,5'-Seleno-bis-(2-hy-droxy-benzaldehyde). AB - In the title mol-ecule, C(14)H(10)O(4)Se, the dihedral angle between the two benzene rings is 74.6 (1) degrees . Both hy-droxy-benzaldehyde groups form intra molecular O-H?O hydrogen bonds. In the crystal, pairs of mol-ecules are linked by pairs of weak C-H?pi(arene) inter-actions, forming centrosymmetric dimers. In addition, mol-ecules are linked by pi-pi stacking inter-actions, with a centroid centroid distance of 3.785 (2) A, forming chains along the c axis. PMID- 22220004 TI - (E)-4-Chloro-2-{[4-(3,5-dichloro-pyridin-2-yl-oxy)phenyl-imino]-meth-yl}phenol. AB - In the title mol-ecule, C(18)H(11)Cl(3)N(2)O(2), the central benzene ring is oriented at 8.44 (12) and 70.57 (11) degrees with respect to the terminal chloro phenol and dichloro-pyridine rings, respectively. The mol-ecular structure is stabilized by an intra-molecular O-H?N hydrogen bond, which generates an S(6) ring motif. In the crystal, pi-pi stacking between parallel pyridine rings is observed [centroid-centroid distance = 3.6561 (14) A]. PMID- 22220005 TI - (E)-4-Hy-droxy-N'-(3,4,5-trimeth-oxy-benzyl-idene)benzohydrazide. AB - The title benzohydrazide derivative, C(17)H(18)N(2)O(5), exists in a trans conformation with respect to the C=N double bond. The dihedral angle between the benzene rings is 19.41 (5) degrees . The two meth-oxy groups at the meta positions of the trimeth-oxy-benzene group are almost coplanar with the ring [C-O C-C = 1.62 (16) and 178.33 (10) degrees ], whereas the third meth-oxy group, at the para position, is (+)-synclinal with the ring. In the crystal, mol-ecules are linked by N-H?O and bifurcated O-H?(N,O) hydrogen bonds, as well as weak C-H?O inter-actions, into sheets lying parallel to the ac plane. A C-H?pi inter-action also occurs. PMID- 22220006 TI - 2-{[2-(Piperazin-4-ium-1-yl)ethyl-iminio]meth-yl}phenolate 0.06-chloride 0.94 perchlorate. AB - The structure of the title salt, C(13)H(20)N(3)O(+).0.94ClO(4) (-).0.06Cl(-), contains a zwitterionic Schiff base with a net positive charge and a perchlorate anion having substitutional disorder with Cl. In the cation, the azomethine N atom is protonated and donates hydrogen bonds to the phenolate O atom and to the tertiary N atom of the piperazine ring. In the crystal, two Schiff base mol ecules are linked about a center of inversion by a pair of N-H?O hydrogen bonds. The resulting dimers are N-H?O and C-H?O hydrogen bonded to the perchlorate anions, forming a three-dimensional structure. The network is further consolidated by C-H?pi inter-actions. PMID- 22220007 TI - (E)-N,N'-Bis[2-(5-bromo-1H-indol-3-yl)eth-yl]-N,N'-(but-2-ene-1,4-di-yl)bis-(4 methyl-benzene-sulfonamide). AB - In the title compound, C(38)H(38)Br(2)N(4)O(4)S(2), there is a crystallographic inversion center located at the mid-point of the alkene bond. The dihedral angle between the aromatic ring systems in the asymmetric unit is 87.69 (19) degrees . In the crystal, adjacent mol-ecules are linked by pairs of N-H?O hydrogen bonds, generating R(2) (2)(16) loops within [1[Formula: see text]0] chains. Short Br?Br contacts [3.6148 (9) A] are observed between adjacent mol-ecules. PMID- 22220008 TI - N,N'-(Ethane-1,2-diyldi-o-phenyl-ene)bis-(pyridine-2-carboxamide). AB - The title mol-ecule, C(26)H(22)N(4)O(2), is centrosymmetric and adopts an anti conformation. Two intra-molecular hydrogen bonds, viz. amide-pyridine N-H?N and phen-yl-amide C-H?O, stabilize the trans conformation of the (pyridine-2 carboxamido)-phenyl group about the amide plane. In the crystal, the presence of weak inter-molecular C-H?O hydrogen bonds results in the formation of a three dimensional network. PMID- 22220009 TI - 4-[2-(Cyclo-hexa-1,4-dien-1-yl)eth-oxy]benzene-1,2-dicarbonitrile. AB - In the title compound, C(16)H(14)N(2)O, the dihedral angle between the aromatic rings is 70.23 (6) degrees . The linking chain has a zigzag conformation. In the crystal, mol-ecules are linked by weak inter-molecular C-H?N hydrogen bonds, forming a zigzag chain along the c axis. PMID- 22220010 TI - 1-Allyl-3-phenyl-quinoxalin-2(1H)-one. AB - The title compound, C(17)H(14)N(2)O, crystallizes with two mol-ecules in the asymmetric unit. The dihedral angles between the mean planes of the quinoxaline ring system and the phenyl ring in the two mol-ecules are 38.27 (10) and 37.14 (8) degrees . In the crystal, pi-stacking along the b axis contributes to the crystal cohesion with an average distance between quinoxaline units of 3.397 (3) A. Weak C-H?O interactions also occur. PMID- 22220011 TI - (1R,2S)-Methyl 1-(4-chloro-phen-yl)-3-oxo-1,2,3,4-tetra-hydro-cyclo-penta [b]indole-2-carboxyl-ate 0.2-hydrate. AB - The title compound, C(19)H(14)ClNO(3).0.2H(2)O, crystallizes with five mol-ecules and a disordered water mol-ecule in the asymmetric unit. Four of the five mol ecules form hydrogen-bonded dimers via N-H?O hydrogen bonds towards another symmetry-independent mol-ecule, whereas the fifth mol-ecule forms a hydrogen bonded dimer with its symmetry equivalent, also via N-H?O hydrogen bonds. The dihedral angle between the planes of the fused benzene ring and the five-membered ring to which it is attached is 79.45 (13), 49.00 (15), 72.49 (16), 81.91 (18) and 76.38 (16) degrees for the five mol-ecules in the asymmetric unit. PMID- 22220012 TI - (E)-1-(4-Benzhydrylpiperazin-1-yl)-3-(3,4-dieth-oxy-phen-yl)prop-2-en-1-one ethanol monosolvate. AB - In the title compound, C(30)H(34)N(2)O(3).C(2)H(6)O, the piperazine ring adopts a chair conformation and the ethene bond exhibits an E conformation. In the crystal, the two components are linked by an O-H?O hydrogen bond. PMID- 22220013 TI - Ethyl 6-methyl-3-(2-methyl-prop-1-en-yl)-2-oxo-4-phenyl-1,2,3,4-tetra-hydro pyrimidine-5-carboxyl-ate. AB - In the mol-ecule of the title compound, C(18)H(22)N(2)O(3), the dihydro pyrimidinone ring adopts an envelope conformation. The dihedral angle between the phenyl ring and the mean plane through the enamine fragment is 86.04 (7) degrees . The mol-ecular conformation is stabilized by an intra-molecular C-H?O hydrogen bond. In the crystal, inter-molecular N-H?O hydrogen bonds link pairs of mol ecules into centrosymmetric dimers. PMID- 22220014 TI - Opipramol dihydro-chloride. AB - THE TITLE COMPOUND (SYSTEMATIC NAME: 4-{3-[2-aza-tricyclo-[9.4.0.0(3,8)]penta deca-1(15),3,5,7,11,13-hexaen-2-yl]prop-yl}-1-(2-hy-droxy-eth-yl)piperazine-1,4 diium dichloride), C(23)H(31)N(3)O(+).2Cl(-), is the dihydro-chloride of a piperazine derivative bearing a bulky 3-(5H-dibenz[b,f]azepin-5-yl)propyl substituent. Protonation took place on both N atoms of the piperazine unit. The diaza-cyclo-hexane ring adopts a chair conformation. N-H?Cl, O-H?Cl and C-H?Cl hydrogen bonding as well as C-H?O contacts connect the components into a three dimensional network in the crystal. Two C-H?pi contacts are also observed. PMID- 22220015 TI - (2E)-1-(4,4''-Difluoro-5'-meth-oxy-1,1':3',1''-terphenyl-4'-yl)-3-(4-fluoro-phen yl)prop-2-en-1-one. AB - In the title compound, C(28)H(19)F(3)O(2), the C=C double bond has an E configuration. In the crystal, C-H?F contacts link the mol-ecules into chains along [111]. The shortest centroid-centroid distance between two pi systems is 3.8087 (8) A and is apparent between the para-fluoro-phenyl group attached to the Michael system and its symmetry-generated equivalent. PMID- 22220016 TI - 1,3,3-Tribenzyl-indolin-2-one. AB - In the title compound, C(29)H(25)NO, the dihedral angles between the indolin-2 one ring system and the three benzene rings are 62.78 (9), 31.69 (9) and 80.94 (9) degrees . PMID- 22220017 TI - 3-[Chloro-(phen-yl)meth-yl]-6-methyl-1,2-benzoxazole. AB - The title compound, C(15)H(12)ClNO, is a functionalized 1,2-benzoxazole with a chloro-(phen-yl)methyl substituent. The mol-ecule is V-shaped, the dihedral angle between the mean plane of the 1,2-benzoxazole system [maximum deviation = 0.023 (3) A for the N atom] and the phenyl ring being 70.33 (14) degrees . There are no hydrogen-bonding inter-actions in the crystal structure, which is stabilized by van der Waals inter-actions only. PMID- 22220018 TI - 4-(Dodec-yloxy)benzonitrile. AB - In the title compound, C(19)H(29)NO, the C-C and C-N bond distances of the benzonitrile group are 1.445 (2) and 1.157 (2) A, respectively. The aliphatic fragment adopts a bent zigzag arangement which differs from the planar zigzag arrangement normally observed in n-alkanes or long-chain alkyl-benzenes. In the crystal, inversion dimers linked by pairs of C-H?O hydrogen bonds occur. A C-H?N inter-action also occurs. In the crystal, mol-ecules are packed with the nitrile and aliphatic groups oriented in a head-to-tail fashion involving, forming a ripple-like motif along the a axis. PMID- 22220019 TI - 2-Cyano-N'-[1-(2-hy-droxy-phen-yl)ethyl-idene]acetohydrazide monohydrate. AB - The title compound, C(11)H(11)N(3)O(2).H(2)O, was obtained by the reaction of 2 acetyl-phenol with cyano-acetohydrazide in methanol. The asymmetric unit contains two hydrazone mol-ecules and two water mol-ecules of crystallization. There is an intra-molecular O-H?N hydrogen bond in each hydrazone mol-ecule. The crystal structure is stabilized by inter-molecular N-H?O, O-H?O and O-H?N hydrogen bonds. PMID- 22220020 TI - N'-(5-Bromo-2-hy-droxy-benzyl-idene)-3-nitro-benzohydrazide methanol mono solvate. AB - In the title compound, C(14)H(10)BrN(3)O(4).CH(4)O, the dihedral angle between the two benzene rings in the hydrazone mol-ecule is 5.8 (3) degrees and an intra molecular O-H?N hydrogen bond generates an S(6) ring motif. An O-H?O hydrogen bond occurs between the hydrazone mol-ecule and the methanol solvent mol-ecule. In the crystal, the components are linked by inter-molecular N-H?O hydrogen bonds, forming chains along the a axis. PMID- 22220021 TI - 10alpha-Hy-droxy-4,9-dimethyl-13-(pipyridin-1-ylmethyl)-3,8,15-trioxatetra-cyclo [10.3.0.0.0]tetra-decan-14-one. AB - The title compound, C(20)H(31)NO(5), was synthesized from 9alpha-hy-droxy parthenolide (9alpha-hy-droxy-4,8-dimethyl-12-methylen-3,14-dioxa-tricyclo [9.3.0.0(2),(4)]tetra-dec-7-en-13-one), which was isolated from the chloro-form extract of the aerial parts of Anvillea radiata. The mol-ecule is built up from fused five-and ten-membered rings with the pipyridin-1-yl-methyl group as a substituent. The ten-membered ring adopts an approximate chair-chair conformation, while the six- and five-membered rings display chair and envelope conformations, respectively. The dihedral angle between the mean planes of the ten-membered ring and the lactone ring is 20.8 (3) degrees . An intra-molecular O H?N hydrogen-bond occurs. The crystal structure is stabilized by weak inter molecular C-H?O hydrogen bonds. PMID- 22220022 TI - (E)-2-(2-Methyl-cyclo-hexyl-idene)hydrazinecarbothio-amide. AB - In the crystal of the title compound, C(8)H(15)N(3)S, mol-ecules are linked by N H?S hydrogen bonds, forming chains along [1[Formula: see text]0]. An intra molecular N-H?N hydrogen bond is also present. PMID- 22220023 TI - 2-(3-Fluoro-phen-yl)-3-methyl-sulfanyl-5-phenyl-1-benzofuran. AB - In the title compound, C(21)H(15)FOS, the dihedral angles between the mean plane of the benzofuran fragment and the pendant 3-fluoro-phenyl and phenyl rings are 1.76 (5) and 32.29 (5) degrees , respectively. In the crystal, mol-ecules are linked by a slipped pi-pi inter-action between the furan and benzene rings of neighbouring mol-ecules [centroid-centroid distance = 3.665 (2) A, inter-planar distance = 3.391 (2) A and slippage = 1.390 (2) A]. PMID- 22220024 TI - Heptane-1,7-diaminium dinitrate. AB - In the title molecular salt, C(7)H(20)N(2) (2+).2NO(3) (-), the crystal structure exhibits an unusual back-to-back paired double-stacked packing arrangement culminating in an overall double zigzag pattern of the dications. The nitrate anions form a ring around one pair of double-stacked dications. An intricate three-dimensional N-H?O and N-H?(O,O) hydrogen-bonding network exists in the crystal structure. PMID- 22220025 TI - Decane-1,10-diaminium dinitrate. AB - The crystal structure of the title compound, C(10)H(26)N(2) (2+).2NO(3) (-), exhibits a back-to-back paired double-stacked packing arrangement culminating in an overall double zigzag pattern of the dications. Each pair of double-stacked dications is surrounded by a ring of ten nitrate anions. An intricate three dimensional N---H...O and N---H...(O,O) hydrogen-bonding network exists in the crystal structure. PMID- 22220026 TI - Ethyl (Z)-2-(2-fluoro-benzyl-idene)-7-methyl-3-oxo-5-phenyl-3,5-dihydro-2H-thia zolo[3,2-a]pyrimidine-6-carboxyl-ate. AB - The title compound, C(23)H(19)FN(2)O(3)S, a fused-pyrimidine derivative, displays dihedral angles between the thia-zole ring and the benzene ring and substituted benzene ring of 7.10 (14) and 3.48 (12) degrees , respectively. The dihydro pyrimidine ring adopts a flattened boat conformation. The olefinic double bond is in a Z configuration. PMID- 22220027 TI - 4-(3-Fluoro-phen-yl)-1-(propan-2-yl-idene)thio-semicarbazone. AB - The title compound, C(10)H(12)FN(3)S, crystallizes in the same space group (P2(1)/c) as two polymorphic forms of 4-phenyl-1-(propan-2-yl-idene)thio semicarbazone [Jian et al. (2005). Acta Cryst. E61, o653-o654; Venkatraman et al. (2005). Acta Cryst. E61, o3914-o3916]. The arrangement of mol-ecules relative to the twofold screw axes is similar to that in the crystal structure of the lower density polymorph. In the solid state, the mol-ecular conformation is stabilized by an intra-molecular N-H?N hydrogen bond. The mol-ecules form centrosymmetric R(2) (2)(8) dimers in the crystal through pairs of N-H?S hydrogen bonds. PMID- 22220028 TI - Benzyl (E)-3-(4-meth-oxy-benzyl-idene)dithio-carbazate. AB - The title compound, C(16)H(16)N(2)OS(2), was obtained from a condensation reaction of benzyl dithio-carbazate and 4-meth-oxy-benzaldehyde. In the mol ecule, the meth-oxy-phenyl ring and dithio-carbazate fragment are located on opposite sides of the C=N double bond, showing an E configuration. The dithio carbazate fragment is approximately planar (r.m.s. deviation = 0.0052 A); its mean plane is oriented at dihedral angles of 8.19 (15) and 85.70 (13) degrees , respectively, to the meth-oxy-phenyl and phenyl rings. Inter-molecular N-H?S hydrogen bonds and weak C-H?pi inter-actions are observed in the crystal structure. PMID- 22220029 TI - 4-Chloro-6,7-dimeth-oxy-quinoline. AB - The title mol-ecule, C(11)H(10)ClNO(2), is almost planar with the C atoms of the meth-oxy groups deviating by -0.082 (2) and 0.020 (2) A from the least-squares plane defined by the atoms of the quinoline ring system (r.m.s. deviation = 0.002 A). An intra-molecular C-H?Cl inter-action generates an S(5) ring motif. PMID- 22220030 TI - N-Benzyl-3-nitro-aniline. AB - The mol-ecule of the title compound, C(13)H(12)N(2)O(2), has a bent conformation with a torsion angle about the central C-N bond of 72.55 (19) degrees . In the crystal, the mol-ecules are connected via classical N-H?O and non-classical C-H?O hydrogen bonds into chains along [10[Formula: see text]]. The dihedral angle between the ring planes is 86.0 (6) degrees . PMID- 22220031 TI - Ortho-rhom-bic polymorph of 4-[(1H-benzimidazol-1-yl)meth-yl]benzoic acid. AB - We reported recently the first polymorph of the title compound [Kuai & Cheng (2011a ?). Acta Cryst., E67, o2787]. A second polymorph of the title compound, C(15)H(12)N(2)O(2), was unexpectedly obtained by the hydro-thermal reaction of the title compound with manganese chloride in the presence of potassium hydroxide at 413 K. The benzimidazole ring system is almost planar, with a maximum deviation from the mean plane of 0.015 (2) A. The benzimidazole and benzene rings are inclined at a dihedral angle of 79.00 (1) degrees . In the crystal, adjacent mol-ecules are connected through O-H?N hydrogen bonds into a one-dimensional chain along the [001] direction. PMID- 22220032 TI - Benzyl (E)-3-(2-bromo-5-meth-oxy-benzyl-idene)dithio-carbazate. AB - The title compound, C(16)H(15)BrN(2)OS(2), was obtained from the condensation reaction of benzyl dithio-carbazate and 2-bromo-5-meth-oxy-lbenzaldehyde. In the mol-ecule, the bromo-meth-oxy-phenyl ring and dithio-carbazate fragment are located on the opposite sides of the C=N double bond, showing the E conformation. The dithio-carbazate fragment is approximately planar (r.m.s deviation 0.0187 A); its mean plane is oriented with respect to the bromo-meth-oxy-phenyl and phenyl rings at 7.60 (12) and 60.08 (9) degrees , respectively. In the crystal, inversion dimers linked by pairs of N-H?S hydrogen bonds occur. A short Br?Br contact of 3.5526 (12) A is observed in the crystal structure. PMID- 22220033 TI - 1,1'-{2,2'-[1,4-Phenyl-enebis(methyl-ene)]bis-(-oxy)bis-(2,1-phenyl ene)}diethanone. AB - The asymmetric unit of the title compound, C(24)H(22)O(4), contains one half-mol ecule, the other half being generated by a crystallographic center of inversion. The central benzene ring makes a dihedral angle of 72.49 (5) degrees with the terminal benzene ring. In the crystal, adjacent mol-ecules are linked through C H?O inter-actions, forming a sheet structure parallel to the bc plane. The sheets are stacked along the a axis via pi-pi inter-actions formed between the terminal benzene rings [centroid-centroid separation = 3.7276 (6) A]. PMID- 22220035 TI - rac-Ethyl 6-hy-droxy-6-methyl-3-oxo-4-phenyl-1,3,4,5,6,7-hexa-hydro benzo[c][1,2]oxazole-5-carboxyl-ate. AB - In the title compound, C(17)H(19)NO(5), the cyclo-hexene ring is in a half-chair conformation and the isoxazole ring in an envelope conformation with the N atom as the flap. The C atoms in the 4- and 6-positions are of the same absolute configuration, whereas the C atom in the 5-position is of the opposite configuration, i.e. (4S*,5R*,6S*). The methyl fragment of the eth-oxy-carbonyl group at position 5 is disordered over two sets of sites in a 0.60:0.40 ratio. The crystal packing displays inter-molecular N-H?O and O-H?O hydrogen bonds. PMID- 22220034 TI - (E)-N'-(2-Chloro-benzyl-idene)-3,5-di-hydroxy-benzohydrazide dihydrate. AB - In the Schiff base mol-ecule of the title compound, C(14)H(11)ClN(2)O(3).2H(2)O, the benzene rings form a dihedral angle of 20.6 (1) degrees . The water molecules of crystallization are involved in the formation of a three-dimensional hydrogen bonding network via O-H?O and N-H?O hydrogen bonds. PMID- 22220036 TI - 2-{[2,8-Bis(trifluoro-meth-yl)quinolin-4-yl](hy-droxy)meth-yl}piperidin-1-ium 3 amino-5-nitro-benzoate sesquihydrate. AB - The asymmetric unit of the title salt solvate, C(17)H(17)F(6)N(2)O(+).C(7)H(5)N(2)O(4) (-).1.5H(2)O, comprises a piperidin-1-ium cation, a 3-amino-5-nitro-benzoate anion, and three fractionally occupied [i.e. 0.414 (3), 0.627 (6) and 0.459 (5)] disordered water mol-ecules of solvation. The cation has an L shape with a C-C-C-C torsion angle of -102.9 (3) degrees for the atoms linking the quinolinyl group to the rest of the cation. In the anion, the carboxyl-ate and nitro groups are essentially coplanar with the benzene ring [O-C C-C torsion angle = 179.7 (2) degrees and O-N-C-C torsion angle = -3.9 (3) degrees ]. In the crystal, extensive O-H?O, O-H?F and N-H?.O hydrogen bonding leads to the formation of a layer in the ab plane. PMID- 22220037 TI - 1,1',1''-{[4-(3,4-Ethyl-ene-dioxy-thio-phen-2-yl)phen-yl]methane-tri-yl}tris-(1H pyra-zole). AB - In the title complex, C(22)H(18)N(6)O(2)S, two of the pyrazole rings are disordered over two sets of sites with ratios of refined occupancies of 0.58 (2):0.42 (2) and 0.517 (12):0.483 (12). The dioxane ring is in a half-chair conformation and the two -CH(2)- groups of this ring are disordered over two sets of sites, the ratio of refined occupancies being 0.855 (19):0.145 (19). The essentially planar thio-phene ring [largest deviation = 0.0444 (2) A] forms a dihedral angle of 19.59 (3) degrees with the benzene ring. PMID- 22220038 TI - 2-Amino-6-[(2,6-dichloro-phen-yl)imino]-3-oxocyclo-hexa-1,4-dienecarbaldehyde. AB - The title compound, C(13)H(8)Cl(2)N(2)O(2), was obtained by the oxidation of diclofenac {systematic name: 2-[2-(2,6-dichloro-phenyl-amino)-phen-yl]acetic acid}, an anti-inflammatory drug, with hydrogen peroxide catalysed by chlorido[5,10,15,20-tetra-kis-(2,6-dichloro-phen-yl)porphyrinato]manganese(III), using ammonium acetate as co-catalyst. The asymmetric unit contains two crystallographically independent mol-ecules of the title compound (Z' = 2). The close packing of individual mol-ecules is mediated by a series of strong and rather directional N-H?Cl and N-H?O hydrogen bonds, plus weak pi-pi [distance between the individual double bonds of symmetry-related imino-quinone rings = 3.7604 (13) A] and Cl?O inter-actions [3.0287 (18) A]. PMID- 22220039 TI - N-(1-Acryloyl-2,2,6,6-tetra-methyl-piperidin-4-yl)acryl-amide. AB - The title compound, C(15)H(24)N(2)O(2), crystallizes with two unique mol-ecules, (I) and (II), in the asymmetric unit, differing in the orientation of the acryloyl units with respect to the piperidine rings. The acryl-amide units are essentially planar in both mol-ecules (r.m.s. deviations = 0.042 and 0.024 A, respectively), as are the C(3)N chains of the acryloyl units. The carbonyl O atoms of the acryloyl systems lie significantly out of these planes, viz. by 0.171 (9) A for molecule (I) and by 0.33 (1) A for molecule (II). The acryl-amide and acryloyl planes are inclined at 68.7 (4) degrees and 59.8 (3) degrees in the two mol-ecules. The piperidine rings each adopt twist boat conformations. In the crystal, strong N-H?O hydrogen bonds link the mol-ecules into zigzag C(4) chains along b. Additional C-H?O contacts result in the formation of stacks along a. PMID- 22220040 TI - 2-(3-Cyano-4-{7-[1-(2-hy-droxy-eth-yl)-3,3-dimethyl-indolin-2-yl-idene]hepta 1,3,5-trien-yl}-5,5-dimethyl-2,5-dihydro-furan-2-yl-idene)malononitrile. AB - The title compound, C(29)H(28)N(4)O(2), excluding the hydroxyethyl and methyl groups, is slightly twisted from planarity so that the terminating indol-2-yl idene and furan-2-yl-idene moiety planes subtend a dihedral angle of 6.27 (8) degrees . A small inwards fold in the polymethine atom chain is consistent with centrosymmetric dimer formation via O-H?N(cyano) hydrogen bonds. In the crystal, the mol-ecules pack in layers approximately parallel to the (10[Formula: see text]) plane via pairs of O-H?N and C-H?N(cyano) inter-actions. PMID- 22220041 TI - N,N'-Dicyclo-hexyl-N''-(2,6-difluoro-benzo-yl)-N,N'-dimethyl-phospho-ric triamide. AB - In the title mol-ecule, C(21)H(32)F(2)N(3)O(2)P, the P=O and N-H groups are syn with respect to each other, and the P atom is bonded in a distorted tetra-hedral environment. The phosphoryl group adopts an anti orientation with respect to the carbonyl group. The angles at the tertiary N atoms (with bond-angle sums of 358.4 and 357.0 degrees ) confirm their sp(2) character. In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R(2) (2)(8) loops. PMID- 22220042 TI - N,N'-Dicyclo-hexyl-N''-(3-fluoro-benzo-yl)-N,N'-dimethyl-phospho-ric triamide. AB - In the title compound, C(21)H(33)FN(3)O(2)P, the P atom has a distorted tetra hedral environment and the N atoms display geometries consistent with a model of sp(2) hybridization (with bond-angle sums for the tertiary N atoms of 357.8 and 358.7 degrees ). The phosphoryl and carbonyl groups are anti with respect to each other. In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R(2) (2)(8) loops. PMID- 22220043 TI - 2-(4-Chloro-phen-yl)-2-oxoethyl 4-methyl-benzoate. AB - In the title compound, C(16)H(13)ClO(3), the dihedral angle between the benzene rings is 80.74 (8) degrees . In the crystal, C-H?O hydrogen bonds link the mol ecules to form C(11) chains propagating in [010]. PMID- 22220044 TI - (6aS*,6bS*,11R*,11aR*)-6-(2-Furyl-methyl)-5,12-dioxo-5,6,6a,6b,7,11,11a,12-octa hydro-furo[3',2':5,6]isoindolo[2,1-a]quinazoline-11-carb-oxy-lic acid. AB - The title compound, C(23)H(18)N(2)O(6), is the product of an intra-molecular thermal cyclo-addition within 1-malein-2-[(E)-2-(2-fur-yl)vin-yl]-4-oxo-3,4 dihydro-quinazoline. The mol-ecule comprises a previously unknown fused penta cyclic system containing two five-membered rings (2-pyrrolidinone and furan) and three six-membered rings (benzene, 2,3-dihydro-4-pyrimidinone and dihydro-cyclo hexa-ne). The central five-membered pyrrolidinone ring has the usual envelope conformation. The six-membered dihydro-pyrimidinone and dihydro-cyclo-hexane rings adopt a half-boat and a half-chair conformation, respectively. The dihedral angle between the planes of the terminal benzene and furan rings is 45.99 (7) degrees . In the crystal, O-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers. Weak C-H?O hydrogen bonds consolidate further the crystal packing, which exhibits pi-pi inter-actions, with a short distance of 3.556 (3) A between the centroids of benzene rings of neighbouring mol-ecules. PMID- 22220045 TI - Ethyl 3-benzoyl-indolizine-1-carboxyl-ate. AB - The title compound, C(18)H(15)NO(3), consists of an indolizine ring system and an aromatic ring. The two ring systems are not coplanar, the dihedral angle between the two being 54.26 (7) degrees . In the crystal, inversion dimers are formed by weak C-H?O interactions. These dimeric groups are further extended to form a regular two-dimensional structure by additional weak C-H?O inter-actions. PMID- 22220046 TI - N-(3-Fluoro-benzo-yl)-N',N''-bis-(4-methyl-phen-yl)phospho-ric triamide. AB - In the title compound, C(21)H(21)FN(3)O(2)P, the NH and P(=O) groups of the C(=O)NHP(=O) fragment are in a syn arrangement with respect to each other, as are the two amide H atoms of the two CH(3)-4-C(6)H(4)-NH moieties. In the crystal, mol-ecules are linked through N-H?O(=P) and N-H?O(=C) hydrogen bonds, forming R(2) (2)(8) and R(2) (2)(12) rings, which are arranged in chains parallel to [010]. PMID- 22220047 TI - 2-Nitro-anilinium bromide. AB - The title compound, C(6)H(7)N(2)O(2) (+).Br(-), is isomorphous with 2-nitro anilinium chloride and contains an characteristic intra-molecular N-H?O hydrogen bond, forming an S(6) motif. Inter-molecular N-H?Br hydrogen bonds occur in the crystal structure. Two zigzag chains of C(2) (1)(4) motifs extend along the b axis direction. These primary chain motifs inter-sect like a double helix structure, leading to R(6) (3)(12) ring motifs, which are arranged in tandem along the b axis. Hence, hydro-philic layers are generated at z = 1/4 and 3/4, which are sandwiched between alternate hydro-phobic layers across z = 0 and 1/2. PMID- 22220048 TI - [2-(2-Meth-oxy-1-naphtho-yl)phen-yl](1-naphth-yl)methanone. AB - The title compound, C(29)H(20)O(3), adopts an 'S' conformation with a dihedral angle of 68.5 (2) degrees beween the two acetone planes. The central phenyl ring forms dihedral angles of 83.8 (4) and 84.5 (4) degrees with the naphthalene and meth-oxy-substituted naphthalene mean planes, respectively. Both carbonyl-group O atoms deviate significantly from the naphthalene moiety and the meth-oxy substituted naphthalene moiety [0.574 (1) and -1.053 (1) A, respectively]. The crystal packing is stabilized by C-H?O inter-molecular inter-actions, generating C(7) chain and R(2) (2)(10) graph-set motifs. PMID- 22220049 TI - N,N'-[1,3-Phenylenebis(methyl-ene)]dibenzene-sulfonamide. AB - The complete mol-ecule of the title compound, C(20)H(20)N(2)O(4)S(2), is generated by crystallographic twofold symmetry, with two C atoms lying on the rotation axis. The dihedral angle between the central benzene ring and the pendant ring is 68.42 (6) degrees and the dihedral angle between the pendant rings is 45.11 (5) degrees . The torsion angles for the C-S-N-C and S-N-C-C fragments are -73.22 (15) and -150.45 (13) degrees , respectively. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, generating corrugated (001) sheets. Aromatic pi-pi stacking [centroid-centroid separation = 3.8925 (12) and 3.9777 (12) A] and weak C-H?O inter-actions also occur. PMID- 22220050 TI - N,N'-Diethyl-N,N'-[1,3-phenylene-bis(methyl-ene)]dibenzene-sulfonamide. AB - In the title compound, C(24)H(28)N(2)O(4)S(2), the dihedral angles between the central benzene ring and the pendant rings are 77.44 (11) and 79.23 (10) degrees , and the dihedral angle between the pendant rings is 23.31 (12) degrees . Both sulfonamide groups project to the same side of the central benzene ring and the mol-ecule has approximate non-crystallographic mirror symmetry. One of the ethyl side chains is disordered over two sets of sites in a 0.526 (14):0.474 (14) ratio. In the crystal, inversion dimers linked by pairs of weak C-H?O inter actions occur, generating R(2) (2)(28) loops. PMID- 22220051 TI - Benzene-1,3-dicarb-oxy-lic acid-1,2-bis-(4-pyrid-yl)ethene (1/1). AB - In the title compound, C(12)H(10)N(2).C(8)H(6)O(4), the asymmetric unit contains two halves of 1,2-bis-(4-pyrid-yl)ethene (bpe) mol-ecules and one benzene-1,3 dicarb-oxy-lic acid (1,3-H(2)BDC) mol-ecule. These bpe and 1,3-H(2)BDC mol-ecules are linked by classical O-H?N hydrogen bonds, forming an extended one-dimensional zigzag chain. Each chain is further linked with neighboring ones by pi-pi inter actions between the pyridine and aromatic rings [centroid-centroid distances = 3.9306 (15) A] and the pyridine rings of pairs of symmetry-related mol-ecules [centroid-centroid distances = 3.5751 (15), 3.7350 (15) and 3.6882 (15) A], with the formation of a three-dimensional supra-molecular framework. PMID- 22220052 TI - 4-Chloro-N-(2,3-dichloro-phen-yl)-2-methyl-benzene-sulfonamide. AB - The torsion angle of the C-SO(2)-NH-C moiety in the title compound, C(13)H(10)Cl(3)NO(2)S, is 50.4 (2) degrees . The sulfonyl and aniline benzene rings are tilted relative to each other by 69.6 (1) degrees . The crystal structure is stabilized by N-H?O hydrogen bonds, linking the mol-ecules into zigzag chains parallel to the b axis. PMID- 22220053 TI - meso-3,6-Dioxopiperazine-2,5-diacet-amide. AB - The title compound, C(8)H(12)N(4)O(4), was obtained by cyclization of the two l asparagine mol-ecules and reveals a crystallographic inversion symmetry, and accordingly the two stereogenic centres are of opposite chirality. Thus, an asymmetric unit comprises a half of a mol-ecule. The mol-ecules are assembled into a three-dimensional hydrogen-bonding network by N-H?O hydrogen bonds. PMID- 22220054 TI - 9-{[4-(Dimethyl-amino)-benzyl]amino}-5-(4-hy-droxy-3,5-dimeth-oxy-phenyl) 5,5a,8a,9-tetra-hydro-furo[3',4':6,7]naphtho-[2,3-d][1,3]dioxol-6(8H)-one methanol monosolvate. AB - In the title compound, C(30)H(32)N(2)O(7).CH(4)O, the tetra-hydro-furan ring and the six-membered ring fused to it both display envelope conformations, with the ring C atom opposite the carbonyl group and the adjacent bridgehead C atom as the flaps, respectively. In the crystal structure, inter-molecular O-H?O hydrogen bonds link all moieties into ribbons along [010]. Weak inter-molecular C-H?O inter-actions consolidate the crystal packing further. PMID- 22220055 TI - N'-[1-(4-Chloro-phen-yl)ethyl-idene]benzo-hydrazide. AB - In the title mol-ecule, C(15)H(13)ClN(2)O, the two benzene rings form a dihedral angle of 5.48 (4) degrees . In the crystal, N-H?O hydrogen bonds link mol-ecules related by translation along the a axis into chains, which are further aggregated into layers parallel to the ac plane through weak C-H?O and C-H?N inter-actions. PMID- 22220056 TI - 1,2-Bis(2,4,6-trinitro-phen-yl)ethane. AB - The title compound, C(14)H(8)N(6)O(12), is centrosymmetric, the mid-point of the central C-C bond being located on an inversion centre. Two of the three independent nitro groups are disordered over two sites, with a site-occupancy ratio of 0.513 (3):0.487 (3). Weak inter-molecular C-H?O hydrogen bonding is present in the crystal structure. PMID- 22220057 TI - 4-[Tris(1H-pyrazol-1-yl)meth-yl]phenol. AB - The title compound, C(16)H(14)N(6)O, was prepared by the condensation of 4 (trifluoro-meth-yl)phenol and sodium pyrazol-1-ide in a yield of 58%. The dihedral angles formed by the planes of the pyrazole rings are 50.7 (2), 71.2 (3) and 95.8 (2) degrees . The mol-ecules are associated into dimers by pairs of inter-molecular O-H?N hydrogen bonds involving the hy-droxy groups and pyrazole N atoms. In addition, pi-pi stacking between the phenol rings of these inversion related dimers is observed, with a ring centroid-to-centroid distance of 3.9247 (10) A. PMID- 22220058 TI - C-H?pi packing inter-actions in 2-[5,5-bis-(4-benzyl-oxyphen-yl)-3-cyano-4-methyl 2,5-dihydro-furan-2-yl-idene]malononitrile. AB - The title mol-ecule, C(35)H(25)N(3)O(3), packs utilizing C-H?pi attractive inter actions causing the identical 4-benzyl-oxyphenyl groups to pack with different conformational angles. This difference is consistent with the variable inter planar dihedral angles found in closely related structures. PMID- 22220059 TI - Bis(diisopropyl-ammonium) naphthalene-1,5-disulfonate. AB - In the title compound, 2C(6)H(16)N(+).C(10)H(6)O(6)S(2) (2-), the cations and anions are associated via N-H?O and C-H?O hydrogen-bonding inter-actions. PMID- 22220060 TI - 3-[2-Chloro-4-(trifluoro-meth-yl)phen-oxy]benzoic acid. AB - The asymmetric unit of the title compound, C(14)H(8)ClF(3)O(3), comprises two independent mol-ecules. The rings in each molecule are connected together via O H?O hydrogen bonds to form classical hydrogen-bonded carb-oxy-lic acid dimers. The dihedral angles between the benzene rings are 80.7 (1) and 68.7 (1) degrees . PMID- 22220061 TI - 1,3-Benzothia-zole-2(3H)-selone. AB - The title compound, C(7)H(5)NSSe, is the product of the reaction of 2-chloro benzothia-zole with sodium hydro-selenide. The mol-ecule is almost planar (r.m.s. deviation = 0.018 A) owing to the presence of the long chain of conjugated bonds (Se=C-N-C=C-C=C-C=C). The geometrical parameters correspond well to those of the analog N-methyl-benzothia-zole-2(3H)-selone, demonstrating that the S atom does not take a significant role in the electron delocalization within the mol-ecule. In the crystal, mol-ecules form centrosymmetric dimers by means of inter molecular N-H?Se hydrogen bonds. The dimers have a nonplanar ladder-like structure. Furthermore, the dimers are linked into ribbons propagating in [010] by weak attractive Se?S [3.7593 (4) A] inter-actions. PMID- 22220062 TI - 2-(1,2-Dimethyl-1H-indol-3-yl)-1-{5-[3-(1,3-dioxolan-2-yl)phen-yl]-2-methyl-thio phen-3-yl}-3,3,4,4,5,5-hexa-fluoro-cyclo-pent-1-ene. AB - The title compound, C(29)H(23)F(6)NO(2)S, a member of a new family of photochromic diaryl-ethene compounds having an unsymmetrically substituted hexa fluoro-cyclo-pentene unit, displays dihedral angles between the indole and thio phene rings of 52.5 (4) degrees , and between the indole ring and the planar C C=C-C unit of the cyclopentene ring of 53.8 (6) degrees . The distance between the potentially reactive C atoms from the two heteroaryl substituents of 3.817 (6) A is proven to be short enough for photocyclization to occur. PMID- 22220063 TI - Propargylaminyl 3alpha-hy-droxy-11-oxo-18beta-olean-12-en-29-oate. AB - The title compound, C(33)H(49)NO(3), is the propargyl-amide of 18beta glycyrrhetinic acid, a penta-cyclic triterpenoid of inter-est as a therapeutic agent. The five six-membered rings of the glycyrrhetinic acid moiety show normal geometries, with four rings in chair conformations and the unsaturated ring C in a half-chair conformation. In the crystal, the terminal N-propargylcarboxamide group has remarkable structural effects on weak hydrogen-bond-like inter-actions. Particularly noteworthy are an inter-molecular O-H?pi inter-action accepted side on by the terminal alkyne group [O?C = 3.097 (2) and 3.356 (2) A] and a short inter-molecular C-H?O inter-action [C?O = 3.115 (2) A] donated by the alkyne C-H group. An N-H?O [N?O = 3.251 (2) A] and a C(alkyl)-H?O [C?O = 3.254 (2) A] interaction complement the crystal structure. PMID- 22220064 TI - (RS)-2-Oxo-4-(1-phenyl-ethyl-amino)-1,2-dihydro-quinoline-3-carb-oxy-lic acid. AB - The mol-ecular structure of the title compound, C(18)H(16)N(2)O(3), does not differ in the crystals of the racemic mixture, (I), and the pure enantiomer, (II). In their crystal structures, inversion dimers occur in (I) via N-H?O hydrogen bonds and infinite chains in (II) also via N-H?O hydrogen bonds. PMID- 22220065 TI - (Furan-2-yl)[(furan-2-yl)carbonyl-disul-fanyl]methanone. AB - The mol-ecule of the title compound, C(10)H(6)O(4)S(2), has crystallographically imposed twofold symmetry. The dihedral angle formed by the furan rings is 80.90 (8) degrees . In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds into chains running parallel to the a axis [C-S-S-C torsion angle = 82.04 (11) degrees ]. PMID- 22220066 TI - Tuberostemoamide hemihydrate. AB - In the crystal structure of the title compound {systematic name: (1'S,2R,2'R,3'S,6'R)-3'-ethyl-4-methyl-5H-5'-oxa-10'-aza-spiro-[furan-2,4' tricyclo-[8.3.0.0(2,6)]trideca-ne]-5,11'-dione hemihydrate}, C(17)H(23)NO(4).0.5H(2)O, the asymmetric unit contains two mol-ecules of tuberostemoamide with similar conformations and one water mol-ecule. The tuberostemoamide mol-ecule is composed of one seven-membered ring (A) and three five-membered rings (B, C and D). Ring A exists in a chair conformation, both rings B and C exist in envelope conformations, and ring D is almost planar with a mean deviation of 0.0143 (4) A in one molecule and 0.0095 (3) A in the other.. The dihedral angles between the planes of rings C and D are 75.1 (3) degrees in one mol-ecule and 74.5 (3) degrees for the other. The solvent water mol-ecule links the tuberostemoamide mol-ecules through O-H?O(ketone) hydrogen bonds. Weak C-H?O inter-actions are also present, involving both the water mol-ecule and a heterocyclic ether O-atom acceptor. PMID- 22220067 TI - tert-Butyl (2S)-2-{3-[(R)-bis-(tert-but-oxy-carbon-yl)amino]-2-oxopiperidin-1-yl} 3-methyl-butano-ate. AB - The title compound, C(24)H(42)N(2)O(7), is a chiral lactam-constrained amino acid with a six-membered ring backbone and isopropyl and tert-butyl ester side chains. The conformation of the six-membered ring can be described as a half chair, with two CH(2) C atoms lying 0.443 (1) and -0.310 (1) A out of the best plane of the other four atoms (mean deviation = 0.042 A). Both N atoms are sp(2) hybridized, lying 0.0413 (9) and 0.067 (1) A out of the planes defined by the three C atoms bonded to them. The absolute configuration was determined, based on resonant scattering of light atoms in Cu Kalpha radiation. PMID- 22220068 TI - (2E)-1-(2,5-Dimeth-oxy-phen-yl)-3-(3-nitro-phen-yl)prop-2-en-1-one. AB - In the title compound, C(17)H(15)NO(5), an intra-molecular C-H?O hydrogen bond generates an S(6) ring motif. The benzene rings form a dihedral angle of 6.45 (7) degrees with each other. In the crystal, inversion dimers linked by pairs of C H?O hydrogen bonds generate R(2) (2)(8) loops. Adjacent dimers are further connected by C-H?O hydrogen bonds into an infinite chain along the [011] direction. PMID- 22220069 TI - Ethyl 2-(4-bromophenyl)-1-[3-(1H-imidazol-1-yl)prop-yl]-1H-benzimidazole-5 carboxyl-ate monohydrate. AB - In the title compound, C(22)H(21)BrN(4)O(2).H(2)O, the two pyrazole rings are essentially planar [maximum deviations 0.002 (1) and 0.002 (1) A], and form a dihedral angle of 73.46 (9) degrees . The dihedral angle between the benzene rings is 29.33 (7) degrees . In the crystal, mol-ecules are connected via C-H?O and O-H?N hydrogen bonds, forming layers in the ab plane. PMID- 22220070 TI - 3-[(Z)-Benzyl-idene]-2,3-dihydro-1,5-benzothia-zepin-4(5H)-one. AB - In the title compound, C(16)H(13)NOS, the seven-membered ring adopts a distorted half-chair conformation. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, forming chains running along the b axis. The crystal packing is further stabilized by C-H?O inter-actions. PMID- 22220071 TI - (3,6-Dimeth-oxy-naphthalen-2-yl)(2,4,6-trimethyl-phen-yl)methanone. AB - In the title compound, C(22)H(22)O(3), the dihedral angle between the naphthalene ring system and the benzene ring is 79.95 (5) degrees . The bridging carbonyl C C(=O)-C group makes dihedral angles of 24.21 (7) and 82.43 (8) degrees , respectively, with the naphthalene ring system and the benzene ring. In the crystal, weak inter-molecular C-H?O inter-actions link mol-ecules into chains parallel to the c axis. PMID- 22220072 TI - 5,5'-[(1,4-Phenyl-enedimethyl-ene)bis-(sulfanedi-yl)]bis-(1-methyl-1H-1,2,3,4 tetra-zole). AB - The title mol-ecule, C(12)H(14)N(8)S(2), has point symmetry [Formula: see text] since it is situated on a crystallographic centre of symmetry. The 1-meth-yl/5 thio groups are in an anti-periplanar conformation. The dihedral angle between the benzene and tetra-zole rings is 84.33 (2) degrees . In the crystal, C-H?N hydrogen bonds link mol-ecules into ladder-like chains running along the b axis. There are also C-H?pi inter-actions present in the crystal structure. PMID- 22220073 TI - N,N'-Bis(pyridin-3-yl)terephthalamide-terephthalic acid (1/1). AB - In the title compound, C(18)H(14)N(4)O(2).C(8)H(6)O(4), both types of mol-ecule lie on inversion centers. In the N,N'-bis-(pyridin-3-yl)terephthalamide mol ecule, the pyridine ring forms a dihedral angle of 11.33 (9) degrees with the central benzene ring. In the crystal, N-H?O and O-H?N hydrogen bonds connect the components into a three-dimensional network. PMID- 22220074 TI - N-(4-Chloro-phen-yl)-4-methyl-benzamide. AB - In the title compound, C(14)H(12)ClNO, the aromatic rings make a dihedral angle of 59.25 (5) degrees . The methyl group is disordered over two equally occupied positions. In the crystal, N-H?O hydrogen bonds link the mol-ecules into infinite C(4) chains running along the a axis. PMID- 22220075 TI - 4-Chloro-N-(3,5-dichloro-phen-yl)-2-methyl-benzene-sulfonamide. AB - In the title compound, C(13)H(10)Cl(3)NO(2)S, torsion angle of the C-SO(2)-NH-C group in the mol-ecule is -58.57 (26) degrees . The sulfonyl and aniline benzene rings are tilted relative to each other by 84.2 (1) degrees . The crystal structure features inversion-related dimers linked by pairs of N-H?O hydrogen bonds. PMID- 22220076 TI - 2-Amino-4-[4-(dimethyl-amino)-phen-yl]-5-oxo-5,6,7,8-tetra-hydro-4H-chromene-3 carbonitrile. AB - In the title mol-ecule, C(18)H(19)N(3)O(2), the fused cyclo-hexenone and pyran rings adopt sofa conformations. Inter-molecular N-H?N and N-H?O hydrogen bonds link mol-ecules into corrugated layers parallel to the bc plane. PMID- 22220077 TI - 7-(3-Nitro-phen-yl)-9,10-dihydro-7H-benzo[h]cyclo-penta-[b]quinolin-8(11H)-one. AB - In the title compound, C(22)H(16)N(2)O(3), the naphthalene ring, the 1,4-dihydro pyridine ring and the cyclo-pent-2-enone ring are nearly coplanar, with the dihedral angles between the neighbouring rings being 1.93 (11) and 2.30 (9) degrees , respectively. The benzene ring group at position 7 and the 1,4-dihydro pyridine ring form a dihedral angle of 78.75 (4) degrees . Inter-molecular N-H?O hydrogen bonds and C-H?pi inter-actions stabilize the crystal packing. PMID- 22220078 TI - Ethyl 4-(1,3-benzodioxol-5-yl)-6-methyl-2-sulfanylidene-1,2,3,4-tetra-hydro pyrimidine-5-carboxyl-ate. AB - In the title compound, C(15)H(16)N(2)O(4)S, the dihedral angles between the planes of the benzodioxole and ester groups and the plane of the six-membered tetra-hydro-pyrimidine ring are 89.5 (1) and 20.2 (1) degrees , respectively. Inter-molecular N-H?S hydrogen bonds assemble the mol-ecules into dimers, which are further connected via N-H?O inter-actions into chains parallel to [010]. Weak C-H?S and C-H?pi inter-actions enhance the stability of the crystal structure. PMID- 22220079 TI - 1,1'-[(2,3,3a,4,5,6,7,7a-Octa-hydro-1H-1,3-benzimidazole-1,3-di-yl)bis-(methyl ene)]bis-(1H-benzotriazole). AB - The cyclo-hexane ring in the title compound, C(21)H(24)N(8), adopts a chair conformation and the five-membered heterocyclic ring to which it is fused adopts a twist conformation on their common C-C bond. The substituents on the N atoms of the central five-membered heterocycle are arranged trans with respect to the central ring. The terminal benzotriazole rings are oriented at angles of 74.66 (8) and 84.18 (8) degrees with respect to the mean plane of the central heterocycle. The angle between the two benzotriazole rings is 30.80 (9) degrees . The bond lengths and angles are within normal ranges; the largest deviation from expecta-tion is for a long N-CH(2) bond length [1.476 (2) A] as a consequence of an anomeric effect. In the crystal, mol-ecules are connected by C-H?N hydrogen bonds. PMID- 22220080 TI - 1-Methyl-5-nitro-1H-imidazole. AB - In the title compound, C(4)H(5)N(3)O(2), the nitro group is twisted with respect to the imidazole ring by a dihedral angle of 5.60 (2) degrees . Weak inter molecular C-H?O and C-H?N hydrogen bonding is present in the crystal structure. PMID- 22220081 TI - Benzene-1,4-diol-5-(1H-imidazol-1-yl)pyrimidine (1/1). AB - The asymmetric unit of title compound, C(7)H(6)N(4).C(6)H(6)O(2), contains one 5 (1H-imidazol-1-yl)pyrimidine mol-ecule and two half benzene-1,4-diol mol-ecules; the benzene-1,4-diol mol-ecules are located on individual inversion centers. In the pyrimidine mol-ecule, the imidazole ring is twisted with respect to the pyrimidine ring at a dihedral angle of 25.73 (7) degrees . In the crystal, O-H?N hydrogen bonds link the mol-ecules to form supra-molecular chains. pi-pi stacking is also observed in the crystal, the centroid-centroid distance between parallel imdazole rings being 3.5543 (16) A. PMID- 22220082 TI - (E)-1-(Thio-phen-2-yl)-3-(2,4,6-tri-meth-oxy-phen-yl)prop-2-en-1-one. AB - There are two crystallograpically independent mol-ecules in the asymmetric unit of the title heteroaryl chalcone derivative, C(16)H(16)O(4)S, with slightly different conformations. The thienyl ring of one mol-ecule is disordered over two positions, with a refined site-occupancy ratio of 0.713 (5):0.287 (5). The mol ecules are twisted: the dihedral angle between the thienyl and benzene rings is 9.72 (19) degrees in the ordered mol-ecule, and 3.8 (4) and 2.1 (8) degrees for the major and minor components, respectively, in the disordered mol-ecule. In both mol-ecules, all three substituted meth-oxy groups are coplanar with the benzene ring to which they are attached. In each mol-ecule, a weak intra molecular C-H?O inter-action generates an S(6) ring motif. In the crystal structure, adjacent mol-ecules are linked into a three-dimensional network by weak C-H?O inter-actions. PMID- 22220083 TI - N-(3-Chloro-phen-yl)-3-nitro-pyridin-2-amine. AB - The dihedral angle between the benzene and pyridyl rings in the title compound, C(11)H(8)ClN(3)O(2), is 22.65 (10) degrees , indicating a twisted mol-ecule. The amine H and nitro O atoms form a donor-acceptor pair for an intra-molecular N-H?O hydrogen bond so that the nitro group is almost coplanar with the pyridine ring to which it is connected [O-N-C-C torsion angle = 7.4 (3) degrees ]. The pyridine N and Cl atoms are approximately syn. The crystal packing features C-H?Cl inter actions that lead to undulating supra-molecular chains along [101]. These are connected into sheets by pi-pi inter-actions occurring between the benzene rings and between the pyridine rings of translationally related mol-ecules along the b axis [centroid-centroid distances = length of b axis = 3.7157 (2) A]. PMID- 22220084 TI - 2-(4-Methyl-phen-oxy)-5-nitro-pyridine. AB - The title mol-ecule, C(12)H(10)N(2)O(3), is twisted, the dihedral angle between the rings being 61.16 (13) degrees . The nitro group is approximately coplanar with the pyridine ring to which it is attached [O-N-C-C torsion angle = -178.1 (3) degrees ]. Supra-molecular chains along [010] and mediated by C-H?O and pi-pi [centroid(pyrid-yl)-(benzene) distance = 3.8259 (18) A] contacts feature in the crystal packing. PMID- 22220085 TI - 4-Methyl-N-(3-methyl-phen-yl)pyridin-2-amine. AB - The title amine, C(13)H(14)N(2), is twisted with a dihedral angle between the rings of 60.07 (9) degrees . The amine N-H group and pyridine N atom are syn allowing for the formation of centrosymmetric eight-membered {?HNCN}(2) synthons via N-H?N hydrogen bonds. The two-mol-ecule aggregates are sustained in the three dimensional crystal packing via C-H?pi and pi-pi inter-actions [centroid-centroid distance for pyridyl rings = 3.7535 (12) A]. PMID- 22220086 TI - 2-(Naphthalen-2-yl-oxy)-5-nitro-pyridine. AB - A nearly orthogonal relationship is found for the ring systems in the title compound, C(15)H(10)N(2)O(3), with the dihedral angle between the rings being 86.13 (11) degrees . The nitro group is approximately coplanar with the pyridine ring to which it is connected [the O-N-C-C torsion angle = -1.8 (4) degrees ]. This coplanarity allows for the close approach of these residues in the crystal structure enabling the formation of N-O?pi(pyridine) inter-actions [3.547 (4) A]. Further consolidation of the crystal packing is afforded by weak pi-pi inter actions [centroid-centroid distances = 3.9576 (16) and 3.9822 (16) A]. PMID- 22220087 TI - 4-Nitro-benzoic acid-N-(pyrimidin-2-yl)aniline (1/1). AB - Four independent mol-ecules comprise the asymmetric unit of the title co-crystal, C(10)H(9)N(3).C(7)H(5)NO(4), two for each component. Small conformational differences are noted for the benzoic acid derivatives, notably in the twists of the carb-oxy-lic acid residue out of the plane of the benzene ring to which it is connected [torsion angles = 167.62 (17) and 174.54 (17) degrees ]. In the aniline derivative, the major difference is observed in the dihedral angles formed between the CN(3) and phenyl least-squares planes [1.51 (5) and 6.25 (6) degrees ]. Pairs of mol-ecules associate via O-H?N and N-H?O hydrogen bonds leading to eight-membered {?HOCO?HNCN} hetero-synthons. The two-mol-ecule aggregates are consolidated in the crystal structure by C-H?O(nitro) and pi-pi inter-actions [shortest centroid-centroid distance between benzene rings = 3.6242 (10) A]. PMID- 22220088 TI - 4-Allyl-2-meth-oxy-phenyl 3,4-dichloro-benzene-sulfonate. AB - The title compound, C(16)H(14)Cl(2)O(4)S, was obtained by the reaction of eugenol (4-allyl-2-meth-oxy-phenol) and 3,4-dichloro-benzene-sulfonyl chloride. The dihedral angle between the benzene rings in the mol-ecule is 40.53 (4) degrees . No significantly short inter-molecular contacts are observed in the crystal structure. PMID- 22220089 TI - 4-Chloro-selanyl-3,5-diethyl-1H-pyrazol-2-ium chloride. AB - In the cation of the title compound, C(7)H(12)ClN(2)Se(+).Cl(-), the ethyl-ene groups and the Se-Cl fragment adopt a cis configuration with a C-Se-Cl angle of 96.09 (6) degrees . In the crystal, inter-molecular N-H?Cl hydrogen bonds link two cations and two chlorine anions into centrosymmetric clusters. pi-pi inter actions between the pyrazole rings [centroid-centroid distance of 3.530 (2) A] link these clusters into columns along [001] with short inter-molecular Se?Cl(-) contacts of 2.995 (1) A. PMID- 22220090 TI - (E)-1-(2,4-Dinitro-phen-yl)-2-[1-(2-nitro-phen-yl)ethyl-idene]hydrazine. AB - The title compound, C(14)H(11)N(5)O(6), was obtained from the condensation reaction of 2,4-dinitro-phenyl-hydrazine and 2-nitro-acetophenone. The mol-ecule displays an E conformation about the C=N double bond and an intra-molecular N-H?O hydrogen bond generates an S(6) ring motif. The dihedral angle between the benzene rings is 7.84 (6) degrees . In the crystal, mol-ecules are linked by C H?O hydrogen bonds and pi-pi stacking inter-actions [centroid-centroid distance = 3.6447 (8) A] into a three-dimensional network. PMID- 22220091 TI - 3-(4-Bromo-phen-yl)-4-[2-(4-nitro-phen-yl)hydrazin-yl]furan-2(5H)-one. AB - In the title compound, C(16)H(12)BrN(3)O(4), the furan-2(5H)-one ring forms a dihedral angle of 33.19 (9) degrees with the 4-bromo-benzene unit and is nearly perpendicular to the 4-nitro-benzene segment, making a dihedral angle of 89.93 (10) degrees . In the crystal, N-H?O hydrogen bonds link the mol-ecules, generating an infinite chain along [010]. The chains are linked into a three dimensional network by C-H?O, C-H?pi and pi-pi contacts [centroid-centroid separation = 3.805 (2) A]. PMID- 22220092 TI - 4-[1-(4-Hy-droxy-3-meth-oxy-benz-yl)-1H-benzimidazol-2-yl]-2-meth-oxy-phenol. AB - In the title mol-ecule, C(22)H(20)N(2)O(4), the dihedral angles between the benzimidazole ring system and the benzene rings are 44.26 (2) and 82.91 (2) degrees . Intra-molecular O-H?O hydrogen bonds occur. In the crystal, O-H?N and O H?O hydrogen bonds connect the mol-ecules into a two-dimension network parallel to (10[Formula: see text]) and weak inter-molecular C-H?O hydrogen bonds complete the formation of a three-dimensional network. PMID- 22220093 TI - 2-(2-Meth-oxy-phen-oxy)pyrazine. AB - A significant twist is observed in the title molecule, C(11)H(10)N(2)O(2), as seen in the dihedral angle between the pyrazine and benzene rings of 72.79 (8) degrees . The meth-oxy group is almost coplanar with the benzene ring to which it is attached [C-O-C-C torsion angle = 175.83 (15) degrees ]. Centrosymmetric dimers are formed in the crystal structure which are held together by weak pi-pi inter-actions between pyrazine rings [centroid-centroid distance = 3.8534 (10) A]. PMID- 22220094 TI - 2,3-Dimethyl-anilinium chloride monohydrate. AB - The crystal structure of the title salt, C(8)H(12)N(+).Cl(-).H(2)O, consists of discrete organic cations, chloride anions and water mol-ecules which are connected by N-H?Cl, N-H?O and O-H?Cl hydrogen bonds. These inter-actions lead to the formation of layers lying parallel to the ab plane. PMID- 22220095 TI - N'-(5-Bromo-2-hy-droxy-benzyl-idene)-4-methyl-benzohydrazide. AB - The mol-ecule of the title compound, C(15)H(13)BrN(2)O(2), displays an E conformation with respect to the C=N double bond and the dihedral angle between the planes of the benzene rings is 3.1 (2) degrees . An intra-molecular O-H?N inter-action generates an S(6) ring. In the crystal, mol-ecules are linked by N H?O hydrogen bonds, forming C(4) chains along the c-axis direction. PMID- 22220096 TI - 4-(2-Chloro-anilino)-3-phenyl-furan-2(5H)-one. AB - The title compound, C(16)H(12)ClNO(2), featuring a furan-2(5H)-one (gamma butyrolactone) core, contains two mol-ecules (A and B) in the asymmetric unit, with different dihedral angles between the central ring and the pendant phenyl and chloro-benzene rings [43.33 (8) and 20.16 (8) degrees , respectively, for A, and 47.79 (8) and 13.87 (8) degrees , respectively, for B]. In the crystal, the A mol-ecules are linked into [001] chains by single C-H?O inter-actions. The B mol ecules also form [001] chains, but their relative orientations in the chains are quite different to those of the A mol-ecules so that adjacent B mol-ecules are linked by two C-H?O hydrogen bonds. Finally, C-H?O inter-actions and aromatic pi pi stacking contacts [centroid-centroid separations = 3.754 (1) and 3.817 (1) A] link the chains into a two-dimensional array parallel to (010). PMID- 22220097 TI - 4-(2,6-Dibromo-4-fluoro-anilino)pent-3-en-2-one. AB - The title enamino-ketone, C(11)H(10)Br(2)FNO, has a roughly planar pentenone chain; the maximum displacement of an atom from the pentenone plane is 0.071 (4) A. The dihedral angle between the benzene ring and the pentenone unit is 77.2 (1) degrees . Inter-molecular C-H?Br and C-H?O inter-actions, as well as an intra molecular N-H?O inter-action, are observed. In both methyl groups, each H atom is disordered equally over two sites. PMID- 22220099 TI - A third polymorph of N,N'-bis-(pyridin-2-yl)benzene-1,4-diamine. AB - A third polymorph of the title compound, C(16)H(14)N(4), has been obtained. The mol-ecule adopts a non-planar conformation with an E configuration at the two partially double exo C N bonds of the 2-pyridyl-amine units. Like in the triclinic form [Bensemann et al. (2002 ?). New J. Chem.26, 448-456], the recognition process between 2-pyridyl-amine units takes place through formation of a cyclic R(2) (2)(8) hydrogen-bond motif, leading to the creation of tapes parallel to [001]. PMID- 22220098 TI - 1,4-Bis(4-tert-but-ylbenz-yl)piperazine. AB - The complete mol-ecule of the title compound, C(26)H(38)N(2), is generated by a crystallographic inversion centre. The piperazine ring adopts a chair conformation with pseudo-equatorial substituents. In the crystal, mol-ecules inter-act only by van der Waals forces. PMID- 22220100 TI - Gallic acid pyridine monosolvate. AB - IN THE TITLE COMPOUND (SYSTENATIC NAME: 3,4,5-trihy-droxy-benzoic acid pyridine monosolvate), C(5)H(5)N.C(7)H(6)O(5), the gallic acid mol-ecule is essentially planar (r.m.s deviation = 0.0766 A for non-H atoms) and is linked to the pyridine mol-ecule by an O-H?N hydrogen bond. An intra-molecular O-H?O hydrogen bond occurs in the gallic acid mol-ecule. The gallic acid and pyridine mean planes make a dihedral angle 12.6 (3) degrees . Inter-molecular O-H?O and O-H?N hydrogen bonding involving the hy-droxy and carboxyl groups and the pyridine mol-ecule, and pi-pi inter-actions between inversion-related pyridines [centroid-centroid distance = 3.459 (6) A] and between pyridine and benzene rings [centroid-centroid distance = 3.548 (6) A], lead to a three-dimensional network in the crystal. PMID- 22220101 TI - Thieno[3,4-d][1,3]dithiole-2-thione. AB - In the title compound, C(5)H(2)S(4), the terminal monocyclic S atom deviates by 0.117 (1) A from the mean plane of the other non-H atoms (r.m.s. deviation = 0.001 A). All six C-S bonds and the central C-C bond in the rings are characterized by pi-conjugated lengths, endowing the mol-ecule with high pi conjugation. In the crystal, the mol-ecules are parallel packed, forming columnar stacks along the a axis. Short inter-molecular S?S contacts [3.397 (1) and 3.486 (1) A], are observed. PMID- 22220102 TI - Ammonia-triphenyl-borane. AB - The asymmetric unit of the title compound, C(18)H(18)BN or (C(6)H(5))(3)B.NH(3), comprises two crystallographically independent but virtually identical mol ecules. Mol-ecules of one type are linked with each other by N-H?pi inter actions, generating an infinite column aligned along the b-axis direction. The columns of different types of mol-ecules are inter-connected by C-H?pi inter actions, producing a three-dimensional array. PMID- 22220103 TI - 2-Amino-4-(2-chloro-phen-yl)-5-oxo-5,6,7,8-tetra-hydro-4H-chromene-3-carbonitrile ethanol monosolvate. AB - In the title compound, C(16)H(13)ClN(2)O(2).C(2)H(6)O, the fused cyclo-hexene and pyran rings adopt envelope and flattened boat conformations, respectively. In the crystal, N-H?O and O-H?O hydrogen bonds link the chromene and ethanol solvent mol ecules into infinite chains along the c axis, and N-H?N hydrogen bonds link these chains into a three-dimensional framework. Weak C-H?pi inter-actions are also present. PMID- 22220104 TI - 2-Amino-4-(4-meth-oxy-phen-yl)-5-oxo-5,6,7,8-tetra-hydro-4H-chromene-3 carbonitrile. AB - The title compound, C(17)H(16)N(2)O(3), crystallizes with two independent mol ecules in the asymmetric unit. In both mol-ecules, the fused cyclo-hexenone ring adopts a sofa conformation. In the crystal, N-H?N and N-H?O hydrogen bonds link the mol-ecules into corrugated layers parallel to the (101) plane. PMID- 22220105 TI - (6R,7R)-3-Hydroxymethyl-7-(2-phenyl-acetamido)-3-cephem-4-carboxylic acid lactone. AB - In the title compound {systematic name: N-[(4R,5R)-3,11-dioxo-10-oxa-6-thia-2-aza tricyclo-[6.3.0.0(2,5)]undec-1(8)-en-4-yl]-2-phenyl-acetamide}, C(16)H(14)N(2)O(4)S, the four- and five-membered rings adopt planar conformations (with r.m.s. deviations of 0.0349 and 0.0108 A respectively) while the six membered ring adopts a half-chair, or envelope-like, conformation with the S atom in the flap position. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds. PMID- 22220106 TI - (E)-1-(2,4-Dichloro-phen-yl)-3-(1,3-diphenyl-1H-pyrazol-4-yl)prop-2-en-1-one. AB - In the title mol-ecule, C(24)H(16)Cl(2)N(2)O, the dihedral angles between the pyrazole ring and its N- and C-bonded phenyl rings are 7.06 (10) and 53.15 (10) degrees , respectively. The dihedral angle between the two pendant rings is 52.32 (10) degrees . The mol-ecule exists in a trans conformation with respect to the acyclic C=C bond. In the crystal, inversion dimers occur in which each mol-ecule is linked to the other by two C-H?O hydrogen bonds to the same acceptor O atom. There are also short Cl?Cl contacts [3.3492 (9) A] and C-H?pi inter-actions. PMID- 22220107 TI - (E)-3-[3-(4-Bromo-phen-yl)-1-phenyl-1H-pyrazol-4-yl]-1-(2,4-dichloro-phen-yl)prop 2-en-1-one. AB - In the title mol-ecule, C(24)H(15)BrCl(2)N(2)O, the dihedral angles betwen the pyrazole ring and its N-bonded phenyl (A) and C-bonded bromo-benzene (B) rings are 10.34 (16) and 40.95 (15) degrees , respectively. The dihedral angle between rings A and B is 56.89 (17) degrees . The title mol-ecule exists in a trans conformation with respect to the acyclic C=C bond. In the crystal, mol-ecules are linked into inversion dimers by pairs of C-H?O hydrogen bonds, generating R(2) (2)(14) loops. The crystal structure is further consolidated by C-H?pi inter actions. PMID- 22220108 TI - (E)-1-(2,4-Dichloro-phen-yl)-3-[3-(4-meth-oxy-phen-yl)-1-phenyl-1H-pyrazol-4 yl]prop-2-en-1-one. AB - In the title mol-ecule, C(25)H(18)Cl(2)N(2)O(2), the dihedral angles between the pyrazole ring and its N- and C-bonded benzene rings are 8.28 (11) and 40.89 (10) degrees , respectively. The dihedral angle between the benzene rings is 39.03 (11) degrees . The title mol-ecule exists in a trans conformation with respect to the acyclic C=C bond. In the crystal, mol-ecules are linked into inversion dimers by pairs of inter-molecular C-H?O hydrogen bonds, generating R(2) (2)(14) loops. PMID- 22220109 TI - 4-[4-(1H-Tetra-zol-5-yl)phen-oxy]benzaldehyde. AB - The asymmetric unit of the title compound, C(14)H(10)N(4)O(2), contains two independent mol-ecules with similar structures. In one mol-ecule, the tetra-zole ring is oriented at dihedral angles of 17.71 (16) and 57.13 (17) degrees , respectively, to the central benzene ring and the terminal benzene ring; in the other mol-ecule, the corresponding dihedral angles are 16.46 (18) and 75.87 (18) degrees . Inter-molecular N-H?N hydrogen bonds and weak C-H?O and C-H?N hydrogen bonds occur in the crystal structure. PMID- 22220110 TI - (E,E)-N,N-Bis(2,6-difluoro-benzyl-idene)ethane-1,2-diamine. AB - The asymmetric unit of the title compound, C(16)H(12)F(4)N(2), comprises half of the potentially bidentate Schiff base ligand, with an inversion centre located at the mid-point of the central C-C bond. The crystal packing is stabilized by inter molecular C-H?N and pi-pi inter-actions [centroid-centroid distance = 3.6793 (12) A and inter-planar spacing = 3.4999 (7) A]. PMID- 22220111 TI - (E,E)-N,N-Bis(2,6-difluoro-benzyl-idene)butane-1,4-diamine. AB - The asymmetric unit of the title compound, C(18)H(16)F(4)N(2), comprises two half crystallographically independent potentially bidentate Schiff base ligands, with an inversion centre located at the mid-point of the central C-C bond. The crystal packing is stabilized by inter-molecular C-H?F and pi-pi inter-actions [centroid centroid distance = 3.8283 (11) A]. PMID- 22220112 TI - N'-[(2-Methoxynaphthalen-1-yl)methyl-idene]-4-methyl-benzohydrazide. AB - In the title compound, C(20)H(18)N(2)O(2), the mean planes of the naphthyl system and the benzene ring form a dihedral angle of 88.48 (10) degrees . In the crystal, N-H?O hydrogen bonds link the mol-ecules into C(4) chains, which propagate along the b-axis direction. PMID- 22220113 TI - 3-(Trimethyl-sil-yl)prop-2-ynyl p-toluene-sulfonate. AB - In the title compound, C(13)H(18)O(3)SSi, the SO(3) group displays a partial rotational (ca 50 degrees ) disorder about the C-S bond, with relative proportions 0.7744 (13):0.2256 (13). This disorder also forces the propynyl CH(2) group to be disordered. PMID- 22220114 TI - 2-(1H-Imidazol-1-yl)-4,6-dimethyl-pyrimidine. AB - The asymmetric unit of the title compound, C(9)H(10)N(4), consists of two mol ecules in which the dihedral angles between the planes of the imidazole and pyrimidine rings are 4.8 (1) and 2.1 (1) degrees . PMID- 22220115 TI - 2-(5-Fluoro-3-isopropyl-sulfanyl-1-benzofuran-2-yl)acetic acid. AB - The title compound, C(13)H(13)FO(3)S, was prepared by alkaline hydrolysis of ethyl 2-(5-fluoro-3-isopropyl-sulfanyl-1-benzofuran-2-yl)acetate. In the crystal, the carb-oxy groups are involved in inter-molecular O-H?O hydrogen bonds, which link the mol-ecules into centrosymmetric dimers. These dimers are further packed into stacks along the b axis by a slipped pi-pi inter-action between the furan and benzene rings of neighbouring mol-ecules [centroid-centroid distance = 3.727 (2) A, inter-planar distance = 3.465 (2) A and slippage = 1.373 (2) A]. The crystal structure also exhibits a short S?O contact [S?O = 3.219 (2) A]. PMID- 22220116 TI - 3-(3-Fluoro-phenyl-sulfin-yl)-2,4,6-trimethyl-1-benzofuran. AB - In the title compound, C(17)H(15)FO(2)S, the 3-fluoro-phenyl ring makes a dihedral angle of 78.38 (4) degrees with the mean plane of the benzofuran fragment. In the crystal, mol-ecules are linked by weak C-H?O and C-H?pi inter actions. The crystal structure also exhibits a slipped pi-pi inter-action between the furan and benzene rings of neighbouring mol-ecules [centroid-centroid distances = 3.628 (2) A, inter-planar distance = 3.417 (2) A and slippage = 1.219 (2) A]. PMID- 22220117 TI - 4-Nitro-phenyl 4-bromo-benzoate. AB - In the crystal structure of the title compound, C(13)H(8)BrNO(4), mol-ecules are linked into chains along [101] by weak C-H?O hydrogen bonds and Br?O contacts [3.140 (4) A]. The planes of the nitrated and brominated aryl rings form a dihedral angle of 64.98 (10) degrees , indicating a twist in the mol-ecule. PMID- 22220118 TI - 4-(o-Tol-yl)piperazin-1-ium chloride. AB - In the title mol-ecular salt, C(11)H(17)N(2) (+).Cl(-), the piperazin-1-ium ring adopts a chair conformation with the aromatic ring in a pseudo-equatorial orientation. The dihedral angle between the benzene ring and the mean plane of the piperazin-1-ium ring is 51.22 (6) degrees . In the crystal, N-H?Cl hydrogen bonds link the mol-ecules into chains propagating in [100]. Weak C-H?pi inter actions also ocur. PMID- 22220119 TI - 4-[(2,4-Difluoro-phen-yl)hydrazinyl-idene]-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole 1-carbothio-amide. AB - In the title compound, C(11)H(9)F(2)N(5)OS, the pyrazole ring forms a dihedral angle of 16.42 (6) degrees with the benzene ring. Intra-molecular N-H?O hydrogen bonds generate two S(6) ring motifs. In the crystal, an R(2) (2)(8) ring motif is formed by a pair of inter-molecular N-H?S hydrogen bonds. Inter-molecular C-H?F hydrogen bonds further link the mol-ecules into a three-dimensional network. PMID- 22220120 TI - 4-(4-Methyl-piperazin-1-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-7-(trifluoro-meth yl)quinoline. AB - In the title compound, C(23)H(20)F(3)N(5)O, the piperazine ring adopts a chair conformation. The quinoline ring makes dihedral angles of 56.61 (11), 49.94 (12) and 42.58 (14) degrees with the piperazine ring, the 1,3,4-oxadiazole ring and the benzene ring, respectively. An intra-molecular C-H?O hydrogen bond generates an S(7) ring motif. In the crystal, mol-ecules are linked into infinite chains along the b axis by C-H?N hydrogen bonds. PMID- 22220121 TI - 2-(4-Bromo-phen-yl)-2-oxoethyl 2-methyl-benzoate. AB - In the title compound, C(16)H(13)BrO(3), the dihedral angle formed between the bromo- and methyl-substituted benzene rings is 66.66 (8) degrees . In the crystal, mol-ecules are linked by inter-molecular C-H?O hydrogen bonds, forming a two-dimensional network parallel to the ac plane. The crystal packing is further consolidated by C-H?pi inter-actions. PMID- 22220122 TI - Methyl pyrido[2,3-b]pyrazine-3-carboxyl-ate. AB - The asymmetric unit of the title compound, C(9)H(7)N(3)O(2), is composed of two independent mol-ecules. The crystal structure is stabilized by C-H?O and C-H?N hydrogen bonds, forming a three-dimensional network. The crystal structure also features pyrazine-pyrazine pi-pi inter-actions [centroid-centroid distance = 3.6994 (5) A] and also pyridine-pyrazine pi-pi inter-actions [centroid-centroid distance = 3.6374 (5) A]. PMID- 22220123 TI - 2,3-Diamino-pyridinium 2-hy-droxy-benzoate. AB - In the title mol-ecular salt, C(5)H(8)N(3) (+).C(7)H(5)O(3) (-), the 2,3-diamino pyridinium cation is essentially planar, with a maximum deviation of 0.006 (2) A. In the crystal, adjacent cations and anions are linked by pairs of N-H?O hydrogen bonds, generating R(2) (2)(8) loops. These dimers are linked by further N-H?O hydrogen bonds and C-H?O inter-actions to form sheets lying parallel to (001). A typical intra-molecular O-H?O hydrogen bond is also observed in the salicylate (2 hy-droxy-benzoate) anion, which generates an S(6) ring. The crystal structure also features pi-pi stacking inter-actions between the pyridinium rings of the cations, with a centroid-centroid distance of 3.5896 (15) A. PMID- 22220124 TI - 2,3-Diamino-pyridinium 3-carb-oxy-4-hy-droxy-benzene-sulfonate monohydrate. AB - In the title hydrated mol-ecular salt, C(5)H(8)N(3) (+).C(7)H(5)O(6)S(-).H(2)O, the ion pairs and water mol-ecules are connected by N-H?O, O-H?O and C-H?O hydrogen bonds, thereby forming a three-dimensional network. There is an intra molecular O-H?O hydrogen bond in the 3-carb-oxy-4-hy-droxy-benzene-sulfonate anion, which generates an S(6) ring motif. PMID- 22220125 TI - 2,3-Diamino-pyridinium 4-carb-oxy-butano-ate. AB - In the title mol-ecular salt, C(5)H(8)N(3) (+).C(5)H(7)O(4) (-), the 2,3-diamino pyridine mol-ecule is protonated at the pyridine N atom. The cation is essentially planar, with a maximum deviation of 0.015 (2) A, and the anion adopts an extended conformation. In the crystal, the hydrogen glutarate (4-carb-oxy butano-ate) anions are self-assembled through O-H?O hydrogen bonds, forming chains. The cations are connected to the anion chains via N-H?O hydrogen bonds, forming a three-dimensional network. The crystal structure also features aromatic pi-pi inter-actions between the pyridinium cations, with a centroid-centroid distance of 3.4464 (10) A. PMID- 22220126 TI - 4'-(4-Bromo-phen-yl)-1'-methyl-dispiro-[indan-2,2'-pyrrolidine-3',2''-indan] 1,3,1''-trione. AB - In the title compound, C(27)H(20)BrNO(3), the pyrrolidine ring adopts a half chair conformation, while the other five-membered rings adopt flattened envelope conformations with the spiro C atoms as the flap atoms. An intra-molecular C-H?O hydrogen bond occurs, generating an S(6) ring. In the crystal, mol-ecules are connected via weak C-H?O hydrogen bonds, forming chains along the c axis. PMID- 22220127 TI - 1'-Methyl-4'-[4-(trifluoro-meth-yl)phen-yl]dispiro-[indan-2,2'-pyrrolidine-3',2'' indan]-1,3,1''-trione. AB - In the title compound, C(28)H(20)F(3)NO(3), the pyrrolidine ring adopts a half chair conformation. The other five-membered rings adopt envelope conformations with the spiro and methylene C atoms as the flap atoms. In the crystal, mol ecules are connected via weak C-H?O hydrogen bonds, forming sheets parallel to the bc plane. PMID- 22220128 TI - 2-Benzyl-sulfanyl-4-pentyl-6-(phenyl-sulfan-yl)pyrimidine-5-carbonitrile. AB - In the title pyrimidine derivative, C(23)H(23)N(3)S(2), the phenyl-sulfanyl and benzyl-sulfanyl benzene rings are orientated away from the carbonitrile group and are twisted out of the plane of the central ring with dihedral angles of 77.66 (6) and 64.73 (5) degrees , respectively. The n-pentyl group has an extended trans conformation. In the crystal, supra-molecular layers in the ab plane are sustained by C-H?pi and pi-pi inter-actions [pyrimidine-phenyl-sulfanyl centroid centroid distance = 3.8087 (7) A]. PMID- 22220129 TI - N'-(Adamantan-2-yl-idene)thio-phene-2-carbohydrazide. AB - In the title mol-ecule, C(15)H(18)N(2)OS, a small twist is noted, with the dihedral angle between the central carbohydrazone residue (r.m.s. deviation = 0.029 A) and the thio-phene ring being 12.47 (10) degrees . The syn arrangement of the amide H and carbonyl O atoms allows for the formation of centrosymmetric dimers via N-H?O hydrogen bonds. These are linked in the three-dimensional structure by C-H?pi inter-actions. The thio-phene ring is disordered over two co planar orientations, the major component having a site-occupancy factor of 0.833 (2). PMID- 22220130 TI - 3'-(4-Chloro-benzo-yl)-4'-(4-chloro-phen-yl)-1'-methyl-spiro-[indoline-3,2' pyrrolidin]-2-one. AB - In the title compound, C(25)H(20)Cl(2)N(2)O(2), the pyrrolidine ring adopts an envelope conformation and the best plane through the five ring atoms makes a dihedral angle of 87.03 (8) degrees with the indoline ring. Mol-ecules are connected by pairs of N-H?O hydrogen bonds into centrosymmetric dimers with an R(2) (2)(8) graph-set ring motif. C-H?O hydrogen bonds stabilize the crystal structure. PMID- 22220131 TI - 5-[2-(4-Acetyl-oxyphen-yl)ethen-yl]benzene-1,3-diyl diacetate. AB - The title compound, C(20)H(18)O(6), was prepared from resveratrol {systematic name: 5-[(E)-2-(4-hy-droxy-phen-yl)ethen-yl]ben-z-ene-1,3-diol}, which can be isolated from grapes, through triacetyl-ation with using acetic anhydride in pyridine. The two benzene rings are approximately coplanar, making a dihedral angle of 6.64 (14) degrees , and the three acet-oxy group are located on the same side of the plane. The skeleton of the compound resembles a table with three legs. In the crystal, mol-ecules are linked via C-H?O interactions, forming inversion dimers. These dimers are further linked via C-H?O interactions, forming a three-dimensional structure. PMID- 22220132 TI - 6,6'-(Pyridine-2,6-di-yl)bis-(pyrrolo-[3,4-b]pyridine-5,7-dione). AB - The title compound, C(19)H(9)N(5)O(4), has crystallographically imposed twofold rotational symmetry. The asymmetric unit contains one half-mol-ecule. The crystal structure is stabilized by pi-pi stacking of inversion-related pyrrolo-[3,4 b]pyridine rings, with a centroid-centroid distance between stacked pyridines of 3.6960 (8) A. The dihedral angle between the central pyridine ring and the pyrrolo-pyridine side rings is 77.86 (2) degrees while the angle between the two side chains is 60.87 (2) degrees . PMID- 22220133 TI - N-(4,6-Dimethyl-pyrimidin-2-yl)-1,3-benzothia-zol-2-amine. AB - In the title compound, C(13)H(12)N(4)S, an amino N atom is connected to a 1,3 benzothia-zole fused-ring system and a dimethyl-substituted pyrimidine ring, these components being aligned [inter-planar dihedral angle = 1.9 (1) degrees ]. The secondary amino N atom forms an inter-molecular N-H?N hydrogen bond to an N atom of the fused ring of an adjacent mol-ecule, generating a centrosymmetric cyclic hydrogen-bonded dimer [graph set R(2) (2)(8)]. PMID- 22220134 TI - 2-(1,3-Benzothia-zol-2-yl)guanidinium chloride. AB - The non-H atoms of the cation of the title salt, C(8)H(9)N(4)S(+).Cl(-), are approximately co-planar (r.m.s. deviation = 0.037 A), with one amino group forming an intra-molecular hydrogen bond to the tertiary N atom of the benzothia zole fused-ring system. The cations and anions are linked by cyclic R(2) (1)(6) N H?Cl hydrogen-bonding associations, generating helical chains running along the b axis direction. PMID- 22220135 TI - 2-(1,3-Benzoxazol-2-yl)guanidinium chloride. AB - The non-H atoms of the cation of the title salt, C(8)H(9)N(4)O(+).Cl(-), are approximately co-planar (r.m.s. deviation = 0.024 A) with one amino group forming an intra-molecular hydrogen bond to the tertiary N atom of the benzoxazole fused ring system. The cations and anions are linked by cyclic R(2) (1)(6) N-H?Cl hydrogen-bonding associations, generating linear chains running along the a-axis direction. PMID- 22220136 TI - 2-Chloro-5-methyl-3-nitro-pyridine. AB - The title compound, C(6)H(5)ClN(2)O(2), crystallizes with two independent mol ecules in the asymmetric unit. Inter-molecular C-H?O hydrogen bonds stabilize the crystal structure. PMID- 22220137 TI - 3-[3-Methyl-4-(4-nitro-benzyl-idene-amino)-5-sulfanyl-idene-4,5-dihydro-1H-1,2,4 triazol-1-yl]-1,3-diphenyl-propan-1-one dichloro-methane monosolvate. AB - In the title compound, C(25)H(21)N(5)O(3)S.CH(2)Cl(2), the dichloro-methane solvent mol-ecule is disordered over four positions, with an occupancy ratio of 0.271 (3):0.3884 (18):0.298 (2):0.0424 (15). The 1,2,4-triazole ring makes dihedral angles of 47.3 (2)/87.3 (2) and 3.6 (2) degrees with the phenyl and nitro-phenyl rings, respectively. An intra-molecular C-H?S hydrogen bond results in the formation of an almost planar six-membered ring [r.m.s. derivation = 0.0051 (2) A]. Inter-molecular C-H?O hydrogen bonding consolidates the structure. PMID- 22220138 TI - (4R,4aS,4bS,7R,10aR)-4-Hy-droxy-4a,7-dimethyl-2-(propan-2-yl) 1,4,4a,4b,5,6,7,8,10,10a-deca-hydro-phenanthren-1-one. AB - In the title compound, C(19)H(28)O(2), the A ring adopts a chair conformation, and each of the B and C rings adopts a distorted half-chair conformation with the methine C atom in the CH(2)C(H)C(=O) residue, common to both rings, lying 0.6397 (19) and 0.6328 (18) A out of the approximate plane defined by the remaining five C atoms (r.m.s. deviations = 0.0791 and 0.0901 A for rings B and C, respectively). Helical supra-molecular chains along the a axis mediated by hy droxy-carbonyl O-H?O hydrogen bonds feature in the crystal packing. PMID- 22220139 TI - Esophageal squamous cell carcinoma with marked eosinophil infiltration. AB - We report a case of esophageal squamous cell carcinoma (SCC) with marked eosinophil infiltration which was identified postoperatively in the esophageal wall in areas not surrounding the SCC. The eosinophil infiltration was seen in the submucosa, muscle and adventitia, but not in the mucosa. Eosinophilic esophagitis (EoE) is a pathological condition defined as eosinophil infiltration within the esophageal mucosa. Eosinophil infiltration at the invasion front of esophageal SCC is termed tumor-associated tissue eosinophilia (TATE). However, the eosinophil infiltration in this case may be pathologically different from both EoE and TATE. To our knowledge, this is the first report of esophageal SCC with eosinophil infiltration. PMID- 22220140 TI - Gallbladder agenesis. AB - Gallbladder agenesis is a rare entity with an estimated incidence of 10-65 per 100,000. Females are more commonly affected (ratio 3:1), typically presenting in the 2nd or 3rd decade of life. Despite an absent gallbladder, half of patients present with symptoms similar to biliary colic, which is poorly understood. Clinicians should have a strong index of suspicion if nonvisualization is suggested by an ultrasound. HIDA scans are typically not helpful since nonvisualization of the gallbladder remains typical of cystic duct obstruction as well as of agenesis. While there are no specific guidelines for management of gallbladder agenesis, conservative management with smooth muscle relaxants is preferred. Sphincterotomy also has been reported in severe cases. Here, we report a case of a 21-year-old woman who presented with recurrent biliary colic and was diagnosed to have gallbladder agenesis on magnetic resonance cholangiopancreatography. A comparison with other cases and a review of the literature are presented. PMID- 22220141 TI - Recurrent upper quadrant pain: a fish bone secondary to gastric perforation and liver abscess. AB - A 60-year-old male patient was admitted to our hospital for recurrent upper quadrant pain for 1 month. He had a past history of coronary artery disease. After admission, he repeatedly suffered from high-grade fever, chills and upper quadrant pain. Computed tomography (CT) showed a round hypodense mass in the left lobe of the liver, approximately 2.7 * 2.2 cm in size, and a fish bone was confirmed by surgery in the left lobe of liver. The patient was cured completely after surgical removal of the fish bone and liver abscess. CT scan 1 month after discharge showed that the liver abscess had disappeared completely. PMID- 22220142 TI - Peripheral Blood CD64 Levels Decrease in Crohn's Disease following Granulocyte and Monocyte Adsorptive Apheresis. AB - Granulocyte and monocyte adsorptive apheresis (GMA) is reportedly useful as induction therapy for Crohn's disease (CD). However, the effects of GMA on CD64 have not been well characterized. We report here our assessment of CD64 expression on neutrophils before and after treatment with GMA in two patients with CD. The severity of CD was assessed with the CD activity index (CDAI). The duration of each GMA session was 60 min at a flow rate of 30 ml/min as per protocol. CD64 expression on neutrophils was measured by analyzing whole blood with a FACScan flow cytometer. In case 1, CD64 levels after each session of GMA tended to decrease compared to pretreatment levels, whereas in case 2, CD64 levels dropped significantly after treatment. The CDAI decreased after GMA in both cases 1 and 2. A significant correlation was noted between CDAI scores and CD64 levels in both cases. In conclusion, GMA reduced blood CD64 levels, which would be an important factor for the decrease of CDAI scores. PMID- 22220143 TI - Epidermolysis bullosa nevi: report of a case and review of the literature. AB - A 10-year-old female patient, being treated for dystrophic bullous epidermolysis in a Pediatric Hospital, was referred to our Dermoscopy Ambulatory because of a newly observed mole in the submandibular area. Clinically, the lesion presented as an irregular double-colored macule of about 2 cm in diameter, with irregular borders, suspicious of malignancy. Dermoscopy showed a multicomponent pattern, with multiple colors, ill-defined network, black blotches, streaks, multiple dots, a blue-whitish veil and granularity at the periphery. Although it had a clinical appearance of malignancy, dermoscopy every semester was proposed due to the revision of a recently described entity, named bullous epidermolysis nevi, that we made in these children. The fragile skin of this particular patient was also taken into account, and overtreatment was avoided. Bullous epidermolysis nevi is the term given to large, asymmetrical and often irregularly pigmented melanocytic nevi that occur in former areas of blistering in patients with the dystrophic forms of the disease. Despite its atypical clinical appearance, and sometimes also atypical dermoscopy, malignant transformation has not been reported yet. Similarly to recurrent nevi, where melanocytes proliferate in a previous area of trauma, clinical aspect, dermoscopy, and histopathology may tempt clinicians to diagnose benign moles as melanoma. Here we report one case of this entity, scarcely reported on in literature, and review clinical and dermatoscopical features of epidermolysis bullosa nevi confronting it with recurrent nevi. The usefulness of dermoscopy as a treatment strategy is stressed. PMID- 22220144 TI - Blastic plasmacytoid dendritic cell neoplasm on the scalp. AB - We describe a 75-year-old Japanese woman with blastic plasmacytoid dendritic cell neoplasm. On her first visit, there were multiple areas of disseminated, elastic hard nodules with multicentric purpura on her scalp. Histopathologically, there were atypical large lymphocytes densely infiltrated through the upper dermis to subcutaneous tissue. Immunohistochemical staining revealed that these infiltrated lymphocytes were CD4, CD56 and vimentin positive. Although we administered several courses of intensive chemotherapy soon after the diagnosis, the patient died 5 months after the first visit. PMID- 22220145 TI - Erythrodermic lymphomatoid granulomatosis: a case report. AB - A 70-year-old man was admitted to our hospital for evaluation of a rapidly progressive erythrodermia. He had superficial lymph node swelling and gluteal/inguinal nodosum-like lesions. A skin biopsy of the erythrodermia showed dense mixed infiltrates distributed throughout the whole dermis, predominantly consisting of small lymphocytes and histiocytes with multinucleated giant cells presenting with a granulomatous appearance. The dense infiltrates showed a characteristic angiocentric pattern surrounding the upward vasculature interconnecting the subcutaneous/subpapillary plexus in the dermis. Some infiltrating lymphocytes showed mild atypia with somewhat irregularly shaped nuclei. Their immunologic staining profiles supported the diagnosis of lymphomatoid granulomatosis. Despite the dense angiocentric infiltration in the dermis, typical angiodestructive infiltration with necrotic changes was not seen on pathological examination. In this case, in situ hybridization yielded negative findings for Epstein-Barr virus-encoded RNAs. Three months after the onset of erythrodermia, the patient developed pulmonary lymphomatoid granulomatosis. Corticosteroid pulse therapy was effective for the treatment of severe pulmonary infiltrations and erythrodermia. However, there had been mild recurrence of the condition or hypereosinophilia during the 4 years of follow-up. Low maintenance doses of cyclophosphamide and corticosteroid provided the patient symptomatic relief to date. PMID- 22220146 TI - A case of yellow nail syndrome with dramatically improved nail discoloration by oral clarithromycin. AB - An 80-year-old woman was admitted to our hospital with pneumonia and exacerbation of sinobronchial syndrome (SBS). She presented with yellow discoloration of the nail beds of all fingers and toes, and her nails were recognized as growing slowly. Chest X-ray revealed bronchiectasis in the bilateral lower lobe and bilateral pleural effusion. We diagnosed her as having yellow nail syndrome (YNS), based on the triad of yellow nails, lymphedema, and lung disease. After treatment with antibiotics [ampicillin/sulbactam and clarithromycin (CAM)] for pneumonia and SBS, her general condition improved, and the yellow nails disappeared in some fingers. When she was previously treated with 200 mg CAM for SBS, her yellow nails had not shown improvement. This time, her yellow nails improved after treatment with 400 mg CAM. The literature reports vitamin E, zinc, and topical corticosteroid plus active vitamin D3 to be effective in the treatment of yellow nails. Two studies have reported treatment for YNS using CAM, though they found a lack of efficacy. Thus, the present case is the first to report improved yellow nails using CAM alone. We conclude that not only SBS and lung disease but also YNS were improved by treatment with 400 mg CAM. PMID- 22220147 TI - Bullous Variant of Sweet's Syndrome after Herpes Zoster Virus Infection. AB - AIM: Cutaneous manifestations of Sweet's syndrome (SS) are typically painful plaque-forming erythematous papules, while bullae are quite uncommon. We present a case of bullous variant of SS in acute myeloid leukaemia. In this case, herpes infection of the left mandible had preceded the development of SS. CASE REPORT: A 75-year-old male with myelodysplastic syndrome first presented with herpes zoster virus infection-like bullae and erosive plaques on the left side of the face and neck. Treatment with valacyclovir and antibiotics was effective only for the initial lesions, whereas the other bullae kept developing predominantly on the left side. Histopathological study revealed epidermal bulla formation, pandermal neutrophilic infiltration, erythrocyte extravasation and subepidermal oedema, but no vasculitis. The findings suggested the diagnosis of bullous variant of SS. DISCUSSION: Our case was unique in that bullous SS symptoms developed predominantly on one side of the cheek and neck where the herpes zoster infection occurred prior to SS. The tendency may explain the possible association between viral infection and development of SS. PMID- 22220148 TI - Chlamydophila pneumoniae Infection Induced Nodular Vasculitis. AB - We present the case history of a 48-year-old male patient with Chlamydophila (Chlamydia) pneumoniae who developed a nodular vasculitis. He developed a cutaneous vasculitis with the onset of respiratory symptoms. The diagnosis of Chlamydophila pneumoniae infection was based on serology. Since this infection is very common in our population, although often asymptomatic, it should be systematically considered as a causative agent of nodular vasculitis. PMID- 22220149 TI - Two cases of cerebral sinus venous thrombosis following chemotherapy for non seminomatous germ cell tumor. AB - We report on two patients with cerebral sinus venous thrombosis following chemotherapy with cisplatin, bleomycin and etoposide for non-seminomatous germ cell tumor. Headache and neurological deficits were the leading symptoms. Cancer and cisplatin chemotherapy are well-known risk factors for thromboembolic events. The therapeutic strategy is an anticoagulant therapy. Symptoms are usually reversible within weeks under this therapy. Therefore, in patients with testicular cancer and chemotherapy who present with neurological symptoms, cerebral sinus venous thrombosis should be considered in the differential diagnosis. PMID- 22220150 TI - Primary malignant lymphoma of the uterus: a case report and review of the literature. AB - Primary malignant lymphomas in the female genital tract are rare. Most cases are non-Hodgkin lymphomas of which diffuse large B-cell lymphomas are most commonly seen. Symptoms are associated with other, more common diseases; therefore, a doctors' delay can be expected. In this case a woman presented with complaints of urinary obstruction due to a large tumour in the pelvic area. A laparotomy was performed. A very large tumour of the uterus was found with adherence to the pelvic wall and urinary bladder. Diagnostic histological examination showed a diffuse large B-cell lymphoma. Treatment with R-CHOP chemotherapy was started shortly after the operation. The treatment of patients with a primary malignant lymphoma of the uterus should be individualized with the following options: surgery, radiotherapy and/or chemotherapy. PMID- 22220151 TI - Napsin a and thyroid transcription factor-1-positive cerebellar tumor with epidermal growth factor receptor mutation. AB - We present a very rare case of cerebellar metastasis of unknown origin, in which a primary lung adenocarcinoma was diagnosed by pathological examination of a cerebellar metastatic tumor, using immunohistochemical markers and epidermal growth factor receptor (EGFR) mutation of primary lung cancer. A 69-year-old woman was admitted to our hospital because of a hemorrhagic cerebellar tumor and multiple small brain tumors. She underwent cerebellar tumor resection. On pathological examination, the tumor was diagnosed as adenocarcinoma. However, the primary tumor site was unidentifiable even with several imaging inspections. On immunohistochemical analysis, the resected tumor was positive for napsin A and thyroid transcription factor-1. In addition, an EGFR mutation was detected in the tumor. Therefore, primary lung cancer was diagnosed and the patient was started on gefitinib (250 mg/day) therapy. PMID- 22220152 TI - False-Positive Mediastinal Lymphadenopathy on 18F-Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography after Rectal Cancer Resection: A Case Report of Thoracoscopic Surgery in the Prone Position. AB - (18)F-fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (integrated FDG PET/CT) has been used to diagnose recurrence and differentiate postoperative changes from lymph node metastasis in colorectal cancer, although its accuracy is questionable. We report a prone thoracoscopic surgery for a rectal cancer patient in which false-positive mediastinal lymph nodes were found on FDG-PET/CT. A 60-year-old man underwent a laparoscopic high anterior resection and D3 lymph node dissection for rectal cancer. The histopathological diagnosis was moderately differentiated adenocarcinoma of the rectum, stage IIIB (pT3N1M0), necessitating oral fluoropyrimidine agent S-1. After the primary surgery, a solitary mediastinal lymph node measuring 30 mm in diameter was detected, and abnormal accumulation was confirmed by FDG-PET/CT (SUV(max), 11.7). Thoracoscopic resection was performed in the prone position, but histopathological results showed no metastasis. He was subsequently diagnosed with reactive lymphadenitis. The patient was discharged on postoperative day 4 in good condition and is alive without recurrence 12 months after surgery. PET/CT is useful for the detection of colorectal cancer recurrence; however, it does have a high false-positive rate for mediastinal lymph nodes. There is a limit to its diagnostic accuracy, and one must determine the indication for surgical treatment carefully. Surgery in the prone position is a useful and minimally invasive approach to the mediastinum and allows aggressive resection to be performed. PMID- 22220153 TI - Chronic headache as the first symptom of an undiagnosed renal cell carcinoma. AB - Renal cell carcinoma (RCC) is an uncommon tumor that rarely metastasizes primarily to the brain. Brain metastases are commonly observed in patients with metastatic RCC, with a reported incidence of 2-17%. The prognosis of brain metastatic RCC is poor. In this carcinoma type, the source is commonly evident. We report a case of a patient with undiagnosed incidental RCC, who presented chronic headache as the first manifestation. PMID- 22220154 TI - An unusual metastatic renal cell carcinoma with maintained complete response to sunitinib treatment. AB - Recently, metastatic renal cell carcinoma (mRCC) treatment has changed dramatically with the onset of new therapies against molecular targets replacing immunotherapy as standard treatment. We report the case of a 49-year-old patient with a moderately differentiated renal clear cell carcinoma without extracapsular extension who underwent radical nephrectomy. Eight months after surgery, he developed a thyroid metastasis which was also treated surgically with a hemithyroidectomy. Seventy-five months after nephrectomy, the patient presented an upper gastrointestinal bleeding due to a duodenal metastasis that infiltrates the head of the pancreas. The treatment applied was surgery by duodenopancreatectomy, with positive surgical margins in the pathologic study. In addition to this, the extension study showed lung metastases requiring initiation of systemic treatment with sunitinib. The patient presented an excellent response to treatment, showing complete clinical and radiological response at 5 months of treatment (RECIST criteria) and a disease-free survival of 48 months until now, without evidence of toxicity. RCC has the potential to metastasize to almost any location, but thyroid and duodenal metastases in RCC are extremely rare. Moreover, this case also highlights the good responses that can be achieved in terms of disease-free survival, low toxicity and quality of life in this new era of therapies against molecular targets. PMID- 22220155 TI - Small cell carcinoma of the tonsil treated with irinotecan and Cisplatin: a case report and literature review. AB - We report a rare case of extrapulmonary small cell carcinoma arising in the palatine tonsil treated by combined chemotherapy with irinotecan/cisplatin following irradiation therapy. This chemotherapy regimen was recently found to be effective for small cell lung carcinoma. Our case is the first report of combined irinotecan/cisplatin chemotherapy to treat extrapulmonary small cell carcinoma of the oropharynx. PMID- 22220156 TI - A Case Report of Hodgkin's Lymphoma in a Patient with Carcinosarcoma of the Bladder. AB - The screening of patients with a known primary extrathoracic malignancy for pulmonary metastasis may result in the identification of solitary or multiple pulmonary nodules. Radiologic features of these pulmonary nodules may suggest a diagnosis, but these features cannot reliably distinguish between benign and malignant etiologies. We present the case of a patient, diagnosed with carcinosarcoma of the bladder, who was found to have multiple pulmonary nodules by CT evaluation. Physical examination of the patient demonstrated the presence of cervical and axillary lymphadenopathy. An excisional biopsy of an axillary lymph node confirmed the diagnosis of Hodgkin's lymphoma. This case report demonstrates that radiographic information obtained by CT scan must be carefully correlated with the history and physical examination of the patient. This case report also demonstrates the importance of diagnostic biopsy of pulmonary nodularity discovered in patients with a known primary extrathoracic malignancy. The assumption that these pulmonary nodules represented metastatic malignancies would have had crucial prognostic and therapeutic implications. PMID- 22220157 TI - An Autopsy Case of Amyotrophic Lateral Sclerosis with Waldenstrom Macroglobulinemia and Anti-MAG Gammopathy. AB - We report the case of a 71-year-old woman with typical signs of bulbar amyotrophic lateral sclerosis (ALS) associated with immunoglobulin M (IgM) monoclonal gammopathy and anti-MAG (myelin-associated glycoprotein) antibodies. This unusual association between ALS and anti-MAG antibodies has previously been reported in a single case. Our present case, at neuropathological examination, demonstrated no causative link between anti-MAG antibodies and ALS. PMID- 22220158 TI - Carotid embolectomy and endarterectomy for symptomatic complete occlusion of the carotid artery as a rescue therapy in acute ischemic stroke. AB - Emergency endarterectomy of an occluded internal carotid artery (ICA) has not been investigated as an option of rescue therapy for severe acute ischemic stroke in the era of intravenous (IV) thrombolysis treatment neither as a primary treatment nor after failed IV thrombolysis. Data from the pre-IV thrombolysis era are conflicting and therefore emergency endarterectomy has not been recommended. The number of patients reaching the emergency room within the IV thrombolysis time window has vastly grown due to advanced acute stroke treatment protocols. The efficacy of mechanical thrombectomy as a primary or add-on to IV thrombolysis therapy option is being actively investigated. We herein report 2 cases of acute ischemic stroke with computerized tomography (CT) angiography-documented occlusion of an ICA that were treated with emergency carotid endarterectomy and embolectomy to restore cerebral blood flow. Both cases presented with severe stroke symptoms and signs not responding to IV thrombolysis and showed severe CT perfusion deficits mainly representing ischemic penumbra. Blood flow was surgically restored after 5 h of symptom onset. Both patients achieved a favorable outcome. We conclude that timely surgical approach of acute ICA occlusion after failed thrombolysis as a rescue therapy may be a viable option in well-selected patients. PMID- 22220159 TI - Lens epithelial cell death secondary to acanthamoeba keratitis: absence of capsular bag opacification six years after cataract surgery. AB - PURPOSE: To show the evolution of anterior chamber structures 6 years after cataract surgery in a case with Acanthamoeba keratitis (AK). METHODS: A 37-year old woman with AK receiving long-term treatment with chlorhexidine, propamidine isethionate and steroids developed a white cataract and iris atrophy. Penetrating keratoplasty and cataract surgery were performed with subsequent intraocular pressure elevation requiring Molteno shunt implantation. Two years after the last surgery, endothelial decompensation developed and another penetrating keratoplasty was performed. Intraoperatively, the anterior and posterior capsules were completely transparent. RESULTS: Six years after cataract surgery, the intraocular lens was centered with clear anterior and posterior capsules without lens epithelial cells proliferation. No Soemmering's ring formation or posterior capsule opacification was found. Also, no zonular damage or pseudophacodonesis was observed. CONCLUSIONS: This case suggests that AK infection and AK treatment not only cause white progressive cataract but also lens epithelial cell death. The capsules may be completely clear 6 years after cataract surgery, with a good quality of vision regardless of intraocular lens material or design. PMID- 22220161 TI - The Effect of Infliximab Therapy on Maculopathy in Behcet's Panuveitis: A Case Report. AB - AIM: To report a case of Behcet's panuveitis and unilateral inflammatory maculopathy which was refractory to conventional immunosuppressive therapy but responded well to long-term treatment with the tumor necrosis factor-alpha inhibitor infliximab. METHODS: Reporting the effect of intravenous infliximab infusion therapy for 54 weeks in a case of Behcet's panuveitis and unilateral inflammatory maculopathy. The patient's best corrected visual acuity was monitored, and biomicroscopic and fundus examinations as well as macular thickness map analysis by stratus optical coherence tomography were performed. RESULTS: The best corrected visual acuity in his right eye improved after the resolution of inflammatory signs on biomicroscopic and fundus examinations as well as on stratus optical coherence tomography macular thickness analysis reports. No significant systemic side effects were noted. CONCLUSIONS: Long-term therapy with infliximab is effective and safe for refractory inflammatory maculopathy in Behcet's disease. We report this case to contribute to the few previously reported cases showing the beneficial effect of long-term infliximab therapy for Behcet's panuveitis. In conclusion, early initiation of infliximab therapy for inflammatory maculopathy in Behcet's disease preserves and improves visual acuity. PMID- 22220160 TI - Exophthalmos as a first manifestation of small cell lung cancer: a long-term follow-up. AB - Small cell lung cancer is characterized by rapid growth and early metastasis. Despite its sensitivity to cytotoxic therapy, until now treatments have failed to control or cure this disease in most patients. Orbital metastases are a rare manifestation of systemic malignancies. Breast and lung cancers represent more than two thirds of the primary cancer sites. Metastases to the eye and orbit develop in approximately 0.7-12% of patients with lung cancer. Here, we report a rare case of exophthalmos as the first manifestation of a metastatic carcinoma due to small cell lung cancer, and a 6-months follow-up with complete exophthalmic response to chemotherapy. PMID- 22220162 TI - Papilledema in the setting of x-linked hypophosphatemic rickets with craniosynostosis. AB - PURPOSE: INTRODUCTION TO THE OPHTHALMIC LITERATURE OF AN UNUSUAL CAUSE OF PAPILLEDEMA AND SUBSEQUENT OPTIC ATROPHY: X-linked hypophosphatemic rickets (XLH). METHODS: Case report of a 3-year-old female presenting with papilledema resulting from craniosynostosis secondary to XLH. RESULTS: Early intervention with craniofacial surgery prevented the development of optic atrophy. CONCLUSION: Children with XLH should be screened for ophthalmic evidence of elevated intracranial pressure to aid early intervention and prevention of permanent loss of vision. PMID- 22220163 TI - Regression of late onset choroidal metastasis from a breast carcinoma with letrozole. AB - We report the case of a 50-year-old woman with a history of diabetes mellitus who underwent left breast lumpectomy and ipsilateral lymphadenectomy in 1994 because of an infiltrating ductal carcinoma. Chemotherapy followed by radiotherapy to the breast and nodal areas were performed. In 2010, in a routine screening for diabetic retinopathy, two choroidal elevated masses above and below the optic nerve associated to serous retinal detachment of her right eye were noted. The patient was asymptomatic. Carcinoma was positive for hormone receptor. Hormone treatment with letrozole was established. Complete regression of the choroidal metastasis was observed 3 months later. Ophthalmologic screening in asymptomatic patients with breast cancer has the advantage of being a noninvasive procedure and enables an early treatment in isolated cases. However, some studies are an argument against the usefulness of eye screening due to the low incidence of asymptomatic choroidal metastasis and the cost that involves performing it routinely in a large number of patients. Aromatase inhibitors are well-tolerated drugs that may be a powerful tool in the management of metastatic breast cancer that express hormone receptors. PMID- 22220164 TI - Long-term follow-up of intravitreal bevacizumab in retinal arterial macroaneurysm: a case report. AB - PURPOSE: To present the long-term effect of intravitreal bevacizumab (Avastin((r))) therapy in a patient suffering from retinal arterial macroaneurysm. METHODS: Case report of a 72-year-old female diagnosed with retinal macroaneurysm in the superior temporal artery leading to macular edema. Functional and morphological data at baseline, 4 weeks, 2 months, and 13 months following treatment with two consecutive intravitreal bevacizumab injections are presented. RESULTS: Best-corrected visual acuity improved from 20/160 at baseline to 20/20 at the 3-months follow-up and remained stable through 13 months of follow-up. Central retinal thickness measured by optical coherence tomography decreased from 364 MUm at baseline to 248 MUm at the 13-months follow-up. No ocular or systemic side effects were detected. CONCLUSIONS: Intravitreal bevacizumab therapy may lead to resolution of macular edema associated with retinal macroaneurysm and consequently visual improvement. This treatment may promise a long-lasting effect but warrant further investigation in larger series. PMID- 22220165 TI - Peripheral ulcerative keratitis and necrotizing scleritis initiated by trauma in the setting of mixed cryoglobulinemia. AB - PURPOSE: To report a case of peripheral ulcerative keratitis and necrotizing scleritis precipitated by trauma in a patient with mixed cryoglobulinemia due to hepatitis C viral infection. METHODS: Case report and literature review. RESULTS: A 62-year-old man with a history of mixed cryoglobulinemia developed an episode of necrotizing scleritis and peripheral ulcerative keratitis one month after repair of a traumatic scleral defect with patch grafting. This episode resolved following treatment with high-dose corticosteroids and the patient underwent successful repeat patch grafting along with a free conjunctival autograft. This is the second reported case of necrotizing scleritis and peripheral ulcerative keratitis associated with mixed cryoglobulinemia. CONCLUSION: Ophthalmologists should be aware of the association between mixed cryoglobulinemia and necrotizing scleritis/peripheral ulcerative keratitis. Patients with this condition experiencing ocular trauma or undergoing ocular surgery should be monitored closely. PMID- 22220166 TI - Rosiglitazone and pioglitazone alter aromatase kinetic properties in human granulosa cells. AB - We have previously reported that, in human granulosa cells, thiazolidinediones rosiglitazone and pioglitazone inhibit estrogen synthesis by interfering with androgen binding to aromatase, without an effect on aromatase mRNA or protein expression. In the current paper, we explore the effects of rosiglitazone and pioglitazone on the aromatase enzyme kinetic properties in human granulosa cells. The cells were incubated with various concentrations of testosterone or androstenedione, with or without rosiglitazone or pioglitazone. Estradiol and estrone concentrations in the conditioned tissue culture medium were measured by radioimmunoassay or immunosorbent assay. When testosterone was used as substrate, rosiglitazone or pioglitazone inhibited the V(max) by 35% (P < 0.001) and 24% (P < 0.001), respectively. When androstenedione was used as substrate, both rosiglitazone or pioglitazone inhibited V(max) by 13% (P < 0.007). We conclude that rosiglitazone or pioglitazone has no effect on K(m) but inhibits V(max) of aromatase in human granulosa cells, therefore, acting as noncompetitive inhibitors. PMID- 22220167 TI - Chromosome visualization tool: a whole genome viewer. AB - CViT (chromosome visualization tool) is a Perl utility for quickly generating images of features on a whole genome at once. It reads GFF3-formated data representing chromosomes (linkage groups or pseudomolecules) and sets of features on those chromosomes. It can display features on any chromosomal unit system, including genetic (centimorgan), cytological (centiMcClintock), and DNA unit (base-pair) coordinates. CViT has been used to track sequencing progress (status of genome sequencing, location and number of gaps), to visualize BLAST hits on a whole genome view, to associate maps with one another, to locate regions of repeat densities to display syntenic regions, and to visualize centromeres and knobs on chromosomes. PMID- 22220168 TI - Evaluation of lentiviral-mediated expression of sodium iodide symporter in anaplastic thyroid cancer and the efficacy of in vivo imaging and therapy. AB - Anaplastic thyroid carcinoma (ATC) is one of the most deadly cancers. With intensive multimodalities of treatment, the survival remains low. ATC is not sensitive to (131)I therapy due to loss of sodium iodide symporter (NIS) gene expression. We have previously generated a stable human NIS-expressing ATC cell line, ARO, and the ability of iodide accumulation was restored. To make NIS mediated gene therapy more applicable, this study aimed to establish a lentiviral system for transferring hNIS gene to cells and to evaluate the efficacy of in vitro and in vivo radioiodide accumulation for imaging and therapy. Lentivirus containing hNIS cDNA were produced to transduce ARO cells which do not concentrate iodide. Gene expression, cell function, radioiodide imaging and treatment were evaluated in vitro and in vivo. Results showed that the transduced cells were restored to express hNIS and accumulated higher amount of radioiodide than parental cells. Therapeutic dose of (131)I effectively inhibited the tumor growth derived from transduced cells as compared to saline-treated mice. Our results suggest that the lentiviral system efficiently transferred and expressed hNIS gene in ATC cells. The transduced cells showed a promising result of tumor imaging and therapy. PMID- 22220170 TI - Plasma vascular endothelial growth factor dysregulation in defining aggressiveness of head and neck squamous cell carcinoma. AB - Background. High circulating vascular endothelial growth factor (VEGF) levels tend to reflect tumor aggressiveness for being associated with tumor progression and prognosis. Measurement of soluble VEGF receptor-1 (sVEGFR-1) may improve diagnostic power of VEGF assay. Methods. This study investigated regulation of plasma VEGF by sVEGFR-1 in 82 patients with head and neck squamous cell carcinoma compared with 32 healthy subjects to obtain information for assay characterization. Results. Normality or abnormality of VEGF/sVEGFR-1secretion patterns was rated into five diagnostic levels from definitely abnormal (likelihood ratios) (LRs = 4-infinity) to definitely normal (LRs = 0-0.17). Because of ineffective VEGF regulation, high grade tumor had a greater chance (62.5%) than low grade tumor (20%) in expressing a definitely abnormal pattern and a lower chance to express the normal pattern (P = 0.007). VEGF alone had much lower diagnostic power in differentiating between normal (LRs = 0.3-0.9) and abnormal secretion patterns (LRs = 2.2-2.4). Conclusions. VEGF dysregulation is suggestive of tumor aggressiveness for causing persistent plasma VEGF elevation. sVEGFR-1 improves diagnostic power of VEGF assay particularly in identifying subset of low grade tumor with underlying aggressive disease and ruling out aggressiveness in subset of high grade tumor. PMID- 22220169 TI - Molecular Mechanism and Potential Targets for Blocking HPV-Induced Lesion Development. AB - Persistent infection with high-risk HPV is the etiologic agent associated with the development of cervical cancer (CC) development. However, environmental, social, epidemiological, genetic, and host factors may have a joint influence on the risk of disease progression. Cervical lesions caused by HPV infection can be removed naturally by the host immune response and only a small percentage may progress to cancer; thus, the immune response is essential for the control of precursor lesions and CC. We present a review of recent research on the molecular mechanisms that allow HPV-infected cells to evade immune surveillance and potential targets of molecular therapy to inhibit tumor immune escape. PMID- 22220171 TI - Growth and identification of bacteria in N-halamine dental unit waterline tubing using an ultrapure water source. AB - This study examined bacterial growth and type on biofilm-controlling dental unit waterline (DUWL) tubing (T) and control manufacturer's tubing (C) in a laboratory DUWL model using ultrapure source water that was cycled through the lines. Sections of tubing lines were detached and examined for biofilm growth using SEM imaging at six sampling periods. Bacteria from inside surfaces of T and C, source unit, and reservoir were cultured and enumerated. At six months, organisms were molecularly identified from the alignment matches obtained from the top three BLAST searches for the 16S region. There was a 1-3 log increase in organism growth in a clean, nonsterile reservoir within an hour. Biofilm was established on the inside surfaces of C within three weeks, but not on T. Proteobacteria, and Sphingomonas spp. were identified in the source reservoir and C line, and a variation of the genera was found in T line. PMID- 22220174 TI - Impact of laparoscopic fundoplication for the treatment of laryngopharyngeal reflux: review of the literature. AB - Laryngopharyngeal reflux (LPR) is part of the so-called extraesophageal manifestations of gastroesophageal reflux disease (GERD). It is presented by unspecific symptoms and signs and is believed to be caused by the reflux of gastric content to the proximal esophagus and larynx. However, evidence considering the role of the antireflux surgery for LPR has failed to demonstrate results comparable to those for GERD. The aim of this paper is to review the current literature regarding the impact of laparoscopic fundoplication for the treatment of LPR. PMID- 22220173 TI - Eosinophilic esophagitis for the otolaryngologist. AB - Objectives. This paper focuses on current diagnostic and treatment options for Eosinophilic Esophagitis (EE). Study Design. literature review. Results. EE can be suspected on history and endoscopy although definitive diagnosis is strictly based on histopathology. It is a relatively new entity and is often misdiagnosed as gastroesophageal reflux (GERD). Eosinophilic infiltration of the esophageal mucosa is responsible for esophageal symptoms which can range from mild to debilitating dysphagia and food impaction, when untreated. In fact recurrent foreign body and food impaction can often be blamed for undiagnosed EE. There seems to be a strong familial component and association with allergy. The introduction of transnasal esophagoscopy in adult laryngology has enabled otolaryngologists to readily diagnose EE and promoted awareness of this often difficult to recognize entity. Conclusions. Despite higher awareness, the literature suggests that EE remains a commonly misdiagnosed condition especially in the otolaryngology community. Genetic studies are required to unfold the true familial and genetic component of this fascinating entity. PMID- 22220175 TI - New advances in urogynecology. PMID- 22220176 TI - Breastfeeding self-efficacy and the use of prescription medication: a pilot study. AB - Objective. To examine the association of self-efficacy, perception of milk production, and lactating women's use of medication prescribed to increase breast milk in a cohort of 18-40-year-old mothers over six months. Methods. Mothers (n = 76) attending community clinics completed the Breastfeeding Self-Efficacy Scale and the Humenick/Hill Lactation Scale, a measure of perceived milk production, three times. Results. Domperidone, a dopamine antagonist, was used by 28% of participants. On average, those using domperidone had lower self-efficacy scores than those not using it (P < 0.05) and were more likely to have used formula (Pearson chi-square test statistic = 6.87, df = 1, P < 0.05). Breastfeeding self efficacy and perception of milk production were positively correlated. Conclusion. Breastfeeding assessment conducted prior to prescription of galactogogues is recommended for mothers and healthy term babies. Following Baby Friendly hospital protocols and increasing self-efficacy for lactating women may be most effective in sustaining breastfeeding. Risks and benefits of various galactogogues are discussed. PMID- 22220172 TI - Scientific rationale for the use of alpha-adrenergic agonists and glucocorticoids in the therapy of pediatric stridor. AB - Purpose. The most common pharmacological therapies used in the treatment of stridor in children are glucocorticosteroids (GC) and alpha-adrenergic (alphaAR) agonists. Despite the long-standing reported efficacy of these medications, there is a paucity of data relating to their actual mechanisms of action in the upper airway. Summary. There is compelling scientific evidence supporting the use of alphaAR-agonists and GCs in pediatric stridor. alphaAR signaling and GCs regulate the vasomotor tone in the upper airway mucosa. The latter translates into better airflow dynamics, as delineated by human and nonhuman upper airway physiological models. In turn, clinical trials have demonstrated that GCs and the nonselective alphaAR agonist, epinephrine, improve respiratory distress scores and reduce the need for further medical care in children with stridor. Future research is needed to investigate the role of selective alphaAR agonists and the potential synergism of GCs and alphaAR-signaling in the treatment of upper airway obstruction and stridor. PMID- 22220177 TI - The Promise and Therapeutic Potential of Human ES and iPS Cells. PMID- 22220178 TI - The potential of stem cells in the treatment of skeletal muscle injury and disease. AB - Tissue engineering is a pioneering field with huge advances in recent times. These advances are not only in the understanding of how cells can be manipulated but also in potential clinical applications. Thus, tissue engineering, when applied to skeletal muscle cells, is an area of huge prospective benefit to patients with muscle disease/damage. This could include damage to muscle from trauma and include genetic abnormalities, for example, muscular dystrophies. Much of this research thus far has been focused on satellite cells, however, mesenchymal stem cells have more recently come to the fore. In particular, results of trials and further research into their use in heart failure, stress incontinence, and muscular dystrophies are eagerly awaited. Although no doubt, stem cells will have much to offer in the future, the results of further research still limit their use. PMID- 22220180 TI - Treatment of chronic patellar tendinopathy with autologous bone marrow stem cells: a 5-year-followup. AB - The purpose of this study is to determine if patients with chronic patellar tendinopathy will improve clinically after the inoculation of bone marrow mononuclear cells (BM-MNCs). Eight patients with chronic patellar tendinopathy were included. Patients averaged 24 years old (range 14-35). All patients were refractory to conservative treatment for at least 6 months before the procedure. BM-MNCs were harvested from the iliac bone crest and inoculated under ultrasound guide in the patellar tendon lesion. Improvement was assessed through established clinical scores and ultrasound. At 5-year followup, statistically significant improvement was seen for most clinical scores. Seven of eight patients said they would have the procedure again if they had the same problem in the opposite knee and were completely satisfied with the procedure. Seven of 8 patients thought that the results of the procedure were excellent. According to our results, inoculation of BM-MNCs could be considered as a potential therapy for those patients with chronic patellar tendinopathy refractory to nonoperative treatments. PMID- 22220181 TI - Comparison of direct fluorescence assay and real-time rt-PCR as diagnostics for respiratory syncytial virus in young children. AB - Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children worldwide. Early detection of RSV is critical to initiate proper care. Two methods, the direct fluorescence assay (DFA) and the real-time reverse-transcription polymerase chain reaction (rt-RT-PCR), that are used for RSV detection were compared. A total of 451 nasopharyngeal aspirates from children 5 years of age or less were tested for RSV using both methods. The overall prevalence rate of the RSV among the children was 23.7% with a significantly higher prevalence among children under the age of 6 months of age when compared to other age groups. The sensitivity of DFA in comparison to rt-RT PCR was highest (86%) during the first 3 days of symptoms onset and decreased gradually till it reached 65% after the first week. The specificity of DFA in comparison to rt-RT-PCR ranged between 99 and 100% irrespective of the date of collection. We concluded that, although the rt-RT-PCR is more sensitive for RSV detection, the DFA offers a reliable point-of-care alternative detection method especially during the first few days of illness. PMID- 22220179 TI - Biological strategies to enhance healing of the avascular area of the meniscus. AB - Meniscal injuries in the vascularized peripheral part of the meniscus have a better healing potential than tears in the central avascular zone because meniscal healing principally depends on its vascular supply. Several biological strategies have been proposed to enhance healing of the avascular area of the meniscus: abrasion therapy, fibrin clot, organ culture, cell therapy, and applications of growth factors. However, data are too heterogeneous to achieve definitive conclusions on the use of these techniques for routine management of meniscal lesions. Although most preclinical and clinical studies are very promising, they are still at an experimental stage. More prospective randomised controlled trials are needed to compare the different techniques for clinical results, applicability, and cost-effectiveness. PMID- 22220183 TI - An all-endo Approach to Complete Ureteral Duplications Complicated by Ureterocele and/or Vesicoureteral Reflux: Feasibility, Limitations, and Results. AB - Purpose. Totally endoscopic management (all-endo) of patients with a duplicated renal system (DS) associated with severe vesicoureteral reflux (VUR) or obstructive ureterocele (UC) is an attractive alternative to traditional open procedures. The authors discuss feasibility and results of an all-endo approach on a consecutive series of patients. Methods. From 1999 to 2009, all patients with a complete DS associated with UC and/or VUR were proposed for primary all endo approach. UC puncture was performed using a 3 Fr Bugbee electrode. Deflux (dextranomer/hyaluronic acid copolymer) injection was administered for VUR. The need for secondary surgery was evaluated on followup. Results. Of the 62 patients recruited, 46 were treated using a primary all-endo approach and 16 patients received no treatment. Of the 46 treated patients with 56 affected renal units, 32 (97%) UCs collapsed following puncture and 29 (63%) VURs were resolved or downgraded. Secondary VUR occurred in 13 (39%) renal units. Secondary surgery was performed on 23 (41%) renal units. Conclusion. The all-endo approach for VUR in DS is an effective therapeutic option. UC collapse was achieved by puncture in most of the patients; secondary VUR was the main complication in a small group of extravesical UC. PMID- 22220182 TI - Human polymorphisms as clinical predictors in leprosy. AB - Genetic and serum markers in human host can predict leprosy susceptibility per se as well as be useful in classification and/or prediction of clinical variants and immunological responses in leprosy. Adequate and timely assessment of potential risks associated with these 38 host leprosy genes could diminish epidemiological burden and improve life quality of patients with this still prevalent mycobacterial disease. PMID- 22220185 TI - Modern aspects of phototherapy for atopic dermatitis. AB - Phototherapy has still great importance in the treatment of atopic dermatitis, though costs, compliance, and long-term risks narrow its relevance. In spite of its long history, up to now, the therapeutic regimes are mostly empirical. Narrowband UVB und UVA1 are the most frequently applied regimens in atopic dermatitis with proven efficacy. However, even for these modalities randomized prospective and controlled studies are still pending. Advances in photoimmunology and molecular biology had demonstrated that phototherapy targets inflammatory cells, alters cytokine production, and has a significant antimicrobial effect within atopic skin. This paper summarizes the current literature on the different regimes of phototherapy and also discusses therapeutic modalities like photochemotherapy and extracorporeal photopheresis. These more complex regimes should be restricted to severe cases of atopic dermatitis, which are refractory to topical treatment. PMID- 22220186 TI - Insomnia symptoms and cardiovascular disease among older American Indians: the Native Elder Care Study. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death among American Indians. It is not known if symptoms of insomnia are associated with CVD in this population. METHODS: We examined 449 American Indians aged >= 55 years from the Native Elder Care Study. The main outcome-of-interest was self-reported CVD. RESULTS: Short sleep duration, daytime sleepiness, and difficulty falling asleep were positively associated with CVD after adjusting for demographic, lifestyle, and clinical risk factors. Compared with a sleep duration of 7 h, the multivariable odds ratio (OR) (95% confidence interval [CI]) of CVD among those with sleep duration <= 5 h was 2.89 (1.17-7.16). Similarly, the multivariable OR (95% CI) of CVD was 4.45 (1.85-10.72) and 2.60 (1.25-5.42) for daytime sleepiness >2 h and difficulty falling asleep often/always. CONCLUSION: Symptoms of insomnia including short sleep duration, daytime sleepiness, and difficulty falling asleep are independently associated with CVD in American Indians aged >= 55 years. PMID- 22220184 TI - The pivotal role of airway smooth muscle in asthma pathophysiology. AB - Asthma is characterized by the association of airway hyperresponsiveness (AHR), inflammation, and remodelling. The aim of the present article is to review the pivotal role of airway smooth muscle (ASM) in the pathophysiology of asthma. ASM is the main effector of AHR. The mechanisms of AHR in asthma may involve a larger release of contractile mediators and/or a lower release of relaxant mediators, an improved ASM cell excitation/contraction coupling, and/or an alteration in the contraction/load coupling. Beyond its contractile function, ASM is also involved in bronchial inflammation and remodelling. Whereas ASM is a target of the inflammatory process, it can also display proinflammatory and immunomodulatory functions, through its synthetic properties and the expression of a wide range of cell surface molecules. ASM remodelling represents a key feature of asthmatic bronchial remodelling. ASM also plays a role in promoting complementary airway structural alterations, in particular by its synthetic function. PMID- 22220187 TI - A water-damaged home and health of occupants: a case study. AB - A family of five and pet dog who rented a water-damaged home and developed multiple health problems. The home was analyzed for species of mold and bacteria. The diagnostics included MRI for chronic sinusitis with ENT and sinus surgery, and neurological testing for neurocognitive deficits. Bulk samples from the home, tissue from the sinuses, urine, nasal secretions, placenta, umbilical cord, and breast milk were tested for the presence of trichothecenes, aflatoxins, and Ochratoxin A. The family had the following diagnosed conditions: chronic sinusitis, neurological deficits, coughing with wheeze, nose bleeds, and fatigue among other symptoms. An infant was born with a total body flare, developed multiple Cafe-au-Lait pigmented skin spots and diagnoses with NF1 at age 2. The mycotoxins were detected in bulk samples, urine and nasal secretions, breast milk, placenta, and umbilical cord. Pseudomonas aueroginosa, Acinetobacter, Penicillium, and Aspergillus fumigatus were cultured from nasal secretions (father and daughter). RT-PCR revealed A. fumigatus DNA in sinus tissues of the daughter. The dog had 72 skin lesions (sebaceous glands and lipomas) from which trichothecenes and ochratoxin A. were detected. The health of the family is discussed in relation to the most recent published literature regarding microbial contamination and toxic by-products present in water-damaged buildings. PMID- 22220188 TI - Psychophysical evaluation of achromatic and chromatic vision of workers chronically exposed to organic solvents. AB - The purpose of this paper was to evaluate achromatic and chromatic vision of workers chronically exposed to organic solvents through psychophysical methods. Thirty-one gas station workers (31.5 +/- 8.4 years old) were evaluated. Psychophysical tests were achromatic tests (Snellen chart, spatial and temporal contrast sensitivity, and visual perimetry) and chromatic tests (Ishihara's test, color discrimination ellipses, and Farnsworth-Munsell 100 hue test--FM100). Spatial contrast sensitivities of exposed workers were lower than the control at spatial frequencies of 20 and 30 cpd whilst the temporal contrast sensitivity was preserved. Visual field losses were found in 10-30 degrees of eccentricity in the solvent exposed workers. The exposed workers group had higher error values of FM100 and wider color discrimination ellipses area compared to the controls. Workers occupationally exposed to organic solvents had abnormal visual functions, mainly color vision losses and visual field constriction. PMID- 22220190 TI - Functional connectivity analyses in imaging genetics: considerations on methods and data interpretation. AB - Functional magnetic resonance imaging (fMRI) can be combined with genotype assessment to identify brain systems that mediate genetic vulnerability to mental disorders ("imaging genetics"). A data analysis approach that is widely applied is "functional connectivity". In this approach, the temporal correlation between the fMRI signal from a pre-defined brain region (the so-called "seed point") and other brain voxels is determined. In this technical note, we show how the choice of freely selectable data analysis parameters strongly influences the assessment of the genetic modulation of connectivity features. In our data analysis we exemplarily focus on three methodological parameters: (i) seed voxel selection, (ii) noise reduction algorithms, and (iii) use of additional second level covariates. Our results show that even small variations in the implementation of a functional connectivity analysis can have an impact on the connectivity pattern that is as strong as the potential modulation by genetic allele variants. Some effects of genetic variation can only be found for one specific implementation of the connectivity analysis. A reoccurring difficulty in the field of psychiatric genetics is the non-replication of initially promising findings, partly caused by the small effects of single genes. The replication of imaging genetic results is therefore crucial for the long-term assessment of genetic effects on neural connectivity parameters. For a meaningful comparison of imaging genetics studies however, it is therefore necessary to provide more details on specific methodological parameters (e.g., seed voxel distribution) and to give information how robust effects are across the choice of methodological parameters. PMID- 22220189 TI - Comprehensive gene-based association study of a chromosome 20 linked region implicates novel risk loci for depressive symptoms in psychotic illness. AB - BACKGROUND: Prior genomewide scans of schizophrenia support evidence of linkage to regions of chromosome 20. However, association analyses have yet to provide support for any etiologically relevant variants. METHODS: We analyzed 2988 LD tagging single nucleotide polymorphisms (SNPs) in 327 genes on chromosome 20, to test for association with schizophrenia in 270 Irish high-density families (ISHDSF, N = 270 families, 1408 subjects). These SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Given a previous report of novel linkage with chromosome 20p using latent classes of psychotic illness in this sample, association analysis was also conducted for each of five factor-derived scores based on the Operational Criteria Checklist for Psychotic Illness (delusions, hallucinations, mania, depression, and negative symptoms). Tests of association were conducted using the PDTPHASE and QPDTPHASE packages of UNPHASED. Empirical estimates of gene-wise significance were obtained by adaptive permutation of a) the smallest observed P-value and b) the threshold truncated product of P-values for each locus. RESULTS: While no single variant was significant after LD-corrected Bonferroni-correction, our gene-dropping analyses identified loci which exceeded empirical significance criteria for both gene-based tests. Namely, R3HDML and C20orf39 are significantly associated with depressive symptoms of schizophrenia (P(emp)<2*10-5) based on the minimum P-value and truncated-product methods, respectively. CONCLUSIONS: Using a gene-based approach to family-based association, R3HDML and C20orf39 were found to be significantly associated with clinical dimensions of schizophrenia. These findings demonstrate the efficacy of gene-based analysis and support previous evidence that chromosome 20 may harbor schizophrenia susceptibility or modifier loci. PMID- 22220191 TI - Homogeneous datasets of triple negative breast cancers enable the identification of novel prognostic and predictive signatures. AB - BACKGROUND: Current prognostic gene signatures for breast cancer mainly reflect proliferation status and have limited value in triple-negative (TNBC) cancers. The identification of prognostic signatures from TNBC cohorts was limited in the past due to small sample sizes. METHODOLOGY/PRINCIPAL FINDINGS: We assembled all currently publically available TNBC gene expression datasets generated on Affymetrix gene chips. Inter-laboratory variation was minimized by filtering methods for both samples and genes. Supervised analysis was performed to identify prognostic signatures from 394 cases which were subsequently tested on an independent validation cohort (n = 261 cases). CONCLUSIONS/SIGNIFICANCE: Using two distinct false discovery rate thresholds, 25% and <3.5%, a larger (n = 264 probesets) and a smaller (n = 26 probesets) prognostic gene sets were identified and used as prognostic predictors. Most of these genes were positively associated with poor prognosis and correlated to metagenes for inflammation and angiogenesis. No correlation to other previously published prognostic signatures (recurrence score, genomic grade index, 70-gene signature, wound response signature, 7-gene immune response module, stroma derived prognostic predictor, and a medullary like signature) was observed. In multivariate analyses in the validation cohort the two signatures showed hazard ratios of 4.03 (95% confidence interval [CI] 1.71-9.48; P = 0.001) and 4.08 (95% CI 1.79-9.28; P = 0.001), respectively. The 10-year event-free survival was 70% for the good risk and 20% for the high risk group. The 26-gene signatures had modest predictive value (AUC = 0.588) to predict response to neoadjuvant chemotherapy, however, the combination of a B-cell metagene with the prognostic signatures increased its response predictive value. We identified a 264-gene prognostic signature for TNBC which is unrelated to previously known prognostic signatures. PMID- 22220192 TI - DNaseI hypersensitivity and ultraconservation reveal novel, interdependent long range enhancers at the complex Pax6 cis-regulatory region. AB - The PAX6 gene plays a crucial role in development of the eye, brain, olfactory system and endocrine pancreas. Consistent with its pleiotropic role the gene exhibits a complex developmental expression pattern which is subject to strict spatial, temporal and quantitative regulation. Control of expression depends on a large array of cis-elements residing in an extended genomic domain around the coding region of the gene. The minimal essential region required for proper regulation of this complex locus has been defined through analysis of human aniridia-associated breakpoints and YAC transgenic rescue studies of the mouse smalleye mutant. We have carried out a systematic DNase I hypersensitive site (HS) analysis across 200 kb of this critical region of mouse chromosome 2E3 to identify putative regulatory elements. Mapping the identified HSs onto a percent identity plot (PIP) shows many HSs correspond to recognisable genomic features such as evolutionarily conserved sequences, CpG islands and retrotransposon derived repeats. We then focussed on a region previously shown to contain essential long range cis-regulatory information, the Pax6 downstream regulatory region (DRR), allowing comparison of mouse HS data with previous human HS data for this region. Reporter transgenic mice for two of the HS sites, HS5 and HS6, show that they function as tissue specific regulatory elements. In addition we have characterised enhancer activity of an ultra-conserved cis-regulatory region located near Pax6, termed E60. All three cis-elements exhibit multiple spatio temporal activities in the embryo that overlap between themselves and other elements in the locus. Using a deletion set of YAC reporter transgenic mice we demonstrate functional interdependence of the elements. Finally, we use the HS6 enhancer as a marker for the migration of precerebellar neuro-epithelium cells to the hindbrain precerebellar nuclei along the posterior and anterior extramural streams allowing visualisation of migratory defects in both pathways in Pax6(Sey/Sey) mice. PMID- 22220193 TI - Early mortality in adults initiating antiretroviral therapy (ART) in low- and middle-income countries (LMIC): a systematic review and meta-analysis. AB - BACKGROUND: We systematically reviewed observational studies of early mortality post-antiretroviral therapy (ART) initiation in low- and middle-income countries (LMIC) in Asia, Africa, and Central and South America, as defined by the World Bank, to summarize what is known. METHODS AND FINDINGS: Studies published in English between January 1996 and December 2010 were searched in Medline and EMBASE. Three independent reviewers examined studies of mortality within one year post-ART. An article was included if the study was conducted in a LMIC, participants were initiating ART in a non-clinical trial setting and were >=15 years. Fifty studies were included; 38 (76%) from sub-Saharan Africa (SSA), 5 (10%) from Asia, 2 (4%) from the Americas, and 5 (10%) were multi-regional. Median follow-up time and pre-ART CD4 cell count ranged from 3-55 months and 11 192 cells/mm(3), respectively. Loss-to-follow-up, reported in 40 (80%) studies, ranged from 0.3%-27%. Overall, SSA had the highest pooled 12-month mortality probability of 0.17 (95% CI 0.11-0.24) versus 0.11 (95% CI 0.10-0.13) for Asia, and 0.07 (95% CI 0.007-0.20) for the Americas. Of 14 (28%) studies reporting cause-specific mortality, tuberculosis (TB) (5%-44%), wasting (5%-53%), advanced HIV (20%-37%), and chronic diarrhea (10%-25%) were most common. Independent factors associated with early mortality in 30 (60%) studies included: low baseline CD4 cell count, male sex, advanced World Health Organization clinical stage, low body mass index, anemia, age greater than 40 years, and pre-ART quantitative HIV RNA. CONCLUSIONS: Significant heterogeneity in outcomes and in methods of reporting outcomes exist among published studies evaluating mortality in the first year after ART initiation in LMIC. Early mortality rates are highest in SSA, and opportunistic illnesses such as TB and wasting syndrome are the most common reported causes of death. Strategies addressing modifiable risk factors associated with early death are urgently needed. PMID- 22220194 TI - Porcine FcgammaRIIb mediates enhancement of porcine reproductive and respiratory syndrome virus (PRRSV) infection. AB - Antibody-dependent enhancement (ADE) of virus infection caused by the uptake of virus-antibody complexes by FcgammaRs is a significant obstacle to the development of effective vaccines to control certain human and animal viral diseases. The activation FcgammaRs, including FcgammaRI and FcgammaRIIa have been shown to mediate ADE infection of virus. In the present paper, we showed that pocine FcgammaRIIb, an inhibitory FcgammaR, mediates ADE of PRRSV infection. Stable Marc-145 cell lines expressing poFcgammaRIIb (Marc-poFcgammaRII) were established. The relative yield of progeny virus was significantly increased in the presence of sub-neutralization anti-PRRSV antibody. The Fab fragment and normal porcine sera had no effect. Anti-poFcgammaRII antibody inhibited the enhancement of infection when cells were infected in the presence of anti-PRRSV antibody, but not when cells were infected in the absence of antibody. These results indicate that enhancement of infection in these cells by anti-PRRSV virus antibody is FcgammaRII-mediated. Identification of the inhibitory FcgammaR mediating ADE infection should expand our understanding of the mechanisms of pathogenesis for a broad range of infectious diseases and may open many approaches for improvements to the treatment and prevention of such diseases. PMID- 22220195 TI - Intraspecific variation in Pinus pinaster PSII photochemical efficiency in response to winter stress and freezing temperatures. AB - As part of a program to select maritime pine (Pinus pinaster Ait.) genotypes for resistance to low winter temperatures, we examined variation in photosystem II activity by chlorophyll fluorescence. Populations and families within populations from contrasting climates were tested during two consecutive winters through two progeny trials, one located at a continental and xeric site and one at a mesic site with Atlantic influence. We also obtained the LT50, or the temperature that causes 50% damage, by controlled freezing and the subsequent analysis of chlorophyll fluorescence in needles and stems that were collected from populations at the continental trial site.P. pinaster showed sensitivity to winter stress at the continental site, during the colder winter. The combination of low temperatures, high solar irradiation and low precipitation caused sustained decreases in maximal photochemical efficiency (F(v)/F(m)), quantum yield of non-cyclic electron transport (Phi(PSII)) and photochemical quenching (qP). The variation in photochemical parameters was larger among families than among populations, and population differences appeared only under the harshest conditions at the continental site. As expected, the environmental effects (winter and site) on the photochemical parameters were much larger than the genotypic effects (population or family). LT50 was closely related to the minimum winter temperatures of the population's range. The dark-adapted F(v)/F(m) ratio discriminated clearly between interior and coastal populations.In conclusion, variations in F(v)/F(m), Phi(PSII), qP and non-photochemical quenching (NPQ) in response to winter stress were primarily due to the differences between the winter conditions and the sites and secondarily due to the differences among families and their interactions with the environment. Populations from continental climates showed higher frost tolerance (LT50) than coastal populations that typically experience mild winters. Therefore, LT50, as estimated by F(v)/F(m), is a reliable indicator of frost tolerance among P. pinaster populations. PMID- 22220196 TI - Cytokine profiles in sepsis have limited relevance for stratifying patients in the emergency department: a prospective observational study. AB - INTRODUCTION: Morbidity, mortality and social cost of sepsis are high. Previous studies have suggested that individual cytokines levels could be used as sepsis markers. Therefore, we assessed whether the multiplex technology could identify useful cytokine profiles in Emergency Department (ED) patients. METHODS: ED patients were included in a single tertiary-care center prospective study. Eligible patients were >18 years and met at least one of the following criteria: fever, suspected systemic infection, >= 2 systemic inflammatory response syndrome (SIRS) criteria, hypotension or shock. Multiplex cytokine measurements were performed on serum samples collected at inclusion. Associations between cytokine levels and sepsis were assessed using univariate and multivariate logistic regressions, principal component analysis (PCA) and agglomerative hierarchical clustering (AHC). RESULTS: Among the 126 patients (71 men, 55 women; median age: 54 years [19-96 years]) included, 102 had SIRS (81%), 55 (44%) had severe sepsis and 10 (8%) had septic shock. Univariate analysis revealed weak associations between cytokine levels and sepsis. Multivariate analysis revealed independent association between sIL-2R (p = 0.01) and severe sepsis, as well as between sIL 2R (p = 0.04), IL-1beta (p = 0.046), IL-8 (p = 0.02) and septic shock. However, neither PCA nor AHC distinguished profiles characteristic of sepsis. CONCLUSIONS: Previous non-multiparametric studies might have reached inappropriate conclusions. Indeed, well-defined clinical conditions do not translate into particular cytokine profiles. Additional and larger trials are now required to validate the limited interest of expensive multiplex cytokine profiling for staging septic patients. PMID- 22220197 TI - Advantages of a mechanistic codon substitution model for evolutionary analysis of protein-coding sequences. AB - BACKGROUND: A mechanistic codon substitution model, in which each codon substitution rate is proportional to the product of a codon mutation rate and the average fixation probability depending on the type of amino acid replacement, has advantages over nucleotide, amino acid, and empirical codon substitution models in evolutionary analysis of protein-coding sequences. It can approximate a wide range of codon substitution processes. If no selection pressure on amino acids is taken into account, it will become equivalent to a nucleotide substitution model. If mutation rates are assumed not to depend on the codon type, then it will become essentially equivalent to an amino acid substitution model. Mutation at the nucleotide level and selection at the amino acid level can be separately evaluated. RESULTS: The present scheme for single nucleotide mutations is equivalent to the general time-reversible model, but multiple nucleotide changes in infinitesimal time are allowed. Selective constraints on the respective types of amino acid replacements are tailored to each gene in a linear function of a given estimate of selective constraints. Their good estimates are those calculated by maximizing the respective likelihoods of empirical amino acid or codon substitution frequency matrices. Akaike and Bayesian information criteria indicate that the present model performs far better than the other substitution models for all five phylogenetic trees of highly-divergent to highly-homologous sequences of chloroplast, mitochondrial, and nuclear genes. It is also shown that multiple nucleotide changes in infinitesimal time are significant in long branches, although they may be caused by compensatory substitutions or other mechanisms. The variation of selective constraint over sites fits the datasets significantly better than variable mutation rates, except for 10 slow-evolving nuclear genes of 10 mammals. An critical finding for phylogenetic analysis is that assuming variable mutation rates over sites lead to the overestimation of branch lengths. PMID- 22220199 TI - Effectiveness of biosecurity measures in preventing badger visits to farm buildings. AB - BACKGROUND: Bovine tuberculosis caused by Mycobacterium bovis is a serious and economically important disease of cattle. Badgers have been implicated in the transmission and maintenance of the disease in the UK since the 1970s. Recent studies have provided substantial evidence of widespread and frequent visits by badgers to farm buildings during which there is the potential for close direct contact with cattle and contamination of cattle feed. METHODOLOGY: Here we evaluated the effectiveness of simple exclusion measures in improving farm biosecurity and preventing badger visits to farm buildings. In the first phase of the study, 32 farms were surveyed using motion-triggered infrared cameras on potential entrances to farm buildings to determine the background level of badger visits experienced by each farm. In the second phase, they were divided into four treatment groups; "Control", "Feed Storage", "Cattle Housing" and "Both", whereby no exclusion measures were installed, exclusion measures were installed on feed storage areas only, cattle housing only or both feed storage and cattle housing, respectively. Badger exclusion measures included sheet metal gates, adjustable metal panels for gates, sheet metal fencing, feed bins and electric fencing. Cameras were deployed for at least 365 nights in each phase on each farm. RESULTS: Badger visits to farm buildings occurred on 19 of the 32 farms in phase one. In phase two, the simple exclusion measures were 100% effective in preventing badger entry into farm buildings, as long as they were appropriately deployed. Furthermore, the installation of exclusion measures also reduced the level of badger visits to the rest of the farmyard. The findings of the present study clearly demonstrate how relatively simple practical measures can substantially reduce the likelihood of badger visits to buildings and reduce some of the potential for contact and disease transmission between badgers and cattle. PMID- 22220198 TI - Effects of aberrant Pax6 gene dosage on mouse corneal pathophysiology and corneal epithelial homeostasis. AB - BACKGROUND: Altered dosage of the transcription factor PAX6 causes multiple human eye pathophysiologies. PAX6+/- heterozygotes suffer from aniridia and aniridia related keratopathy (ARK), a corneal deterioration that probably involves a limbal epithelial stem cell (LESC) deficiency. Heterozygous Pax6(+/Sey-Neu) (Pax6+/-) mice recapitulate the human disease and are a good model of ARK. Corneal pathologies also occur in other mouse Pax6 mutants and in PAX77(Tg/-) transgenics, which over-express Pax6 and model human PAX6 duplication. METHODOLOGY/PRINCIPAL FINDINGS: We used electron microscopy to investigate ocular defects in Pax6+/- heterozygotes (low Pax6 levels) and PAX77(Tg/-) transgenics (high Pax6 levels). As well as the well-documented epithelial defects, aberrant Pax6 dosage had profound effects on the corneal stroma and endothelium in both genotypes, including cellular vacuolation, similar to that reported for human macular corneal dystrophy. We used mosaic expression of an X-linked LacZ transgene in X-inactivation mosaic female (XLacZ(Tg/-)) mice to investigate corneal epithelial maintenance by LESC clones in Pax6+/- and PAX77(Tg/-) mosaic mice. PAX77(Tg/-) mosaics, over-expressing Pax6, produced normal corneal epithelial radial striped patterns (despite other corneal defects), suggesting that centripetal cell movement was unaffected. Moderately disrupted patterns in Pax6+/- mosaics were corrected by introducing the PAX77 transgene (in Pax6+/-, PAX77(Tg/-) mosaics). Pax6(Leca4/+), XLacZ(Tg/-) mosaic mice (heterozygous for the Pax6(Leca4) missense mutation) showed more severely disrupted mosaic patterns. Corrected corneal epithelial stripe numbers (an indirect estimate of active LESC clone numbers) declined with age (between 15 and 30 weeks) in wild type XLacZ(Tg/-) mosaics. In contrast, corrected stripe numbers were already low at 15 weeks in Pax6+/- and PAX77(Tg/-) mosaic corneas, suggesting Pax6 under- and over-expression both affect LESC clones. CONCLUSIONS/SIGNIFICANCE: Pax6+/- and PAX77(Tg/-) genotypes have only relatively minor effects on LESC clone numbers but cause more severe corneal endothelial and stromal defects. This should prompt further investigations of the pathophysiology underlying human aniridia and ARK. PMID- 22220200 TI - Mitotic spindle orients perpendicular to the forces imposed by dynamic shear. AB - Orientation of the division axis can determine cell fate in the presence of morphogenetic gradients. Understanding how mitotic cells integrate directional cues is therefore an important question in embryogenesis. Here, we investigate the effect of dynamic shear forces on confined mitotic cells. We found that human epithelial cells (hTERT-RPE1) as well as MC3T3 osteoblasts align their mitotic spindle perpendicular to the external force. Spindle orientation appears to be a consequence of cell elongation along the zero-force direction in response to the dynamic shear. This process is a nonlinear response to the strain amplitude, requires actomyosin activity and correlates with redistribution of myosin II. Mechanosteered cells divide normally, suggesting that this mechanism is compatible with biological functions. PMID- 22220201 TI - Right heart structural changes are independently associated with exercise capacity in non-severe COPD. AB - BACKGROUND: Pulmonary hypertension (PH) occurs frequently and results in functional limitation in advanced COPD. Data regarding the functional consequence of PH in less severe COPD are limited. Whether echocardiographic evidence of right sided heart pathology is associated with functional outcomes in patients with non-severe COPD is unknown. METHODS: We evaluated pulmonary function, six minute walk distance, and echocardiography in 74 consecutive patients with non severe COPD. We performed multivariable linear regression to evaluate the association between right heart echocardiographic parameters and six minute walk distance adjusting for lung function, age, sex, race, and BMI. MAIN RESULTS: The mean six minute walk distance was 324+/-106 meters. All subjects had preserved left ventricular (LV) systolic function (LV ejection fraction 62.3%+/-6.1%). 54.1% had evidence of some degree of diastolic dysfunction. 17.6% of subjects had evidence of right ventricular enlargement and 36.5% had right atrial enlargement. In univariate analysis RV wall thickness (beta = -68.6; p = 0.002), log right atrial area (beta = -297.9; p = 0.004), LV mass index (beta = -1.3; p = 0.03), E/E' ratio (beta = -5.5; p = 0.02), and degree of diastolic dysfunction (beta = 42.8; p = 0.006) were associated with six minute walk distance. After adjustment for co-variables, the associations between right atrial area (log right atrial area beta = -349.8; p = 0.003) and right ventricular wall thickness (beta = 43.8; p = 0.04) with lower six minute walk distance remained significant independent of forced expiratory volume in one second (FEV1). LV mass index, E/E' ratio, and degree of diastolic dysfunction were not independent predictors of six minute walk distance. CONCLUSION: In patients with non-severe COPD right sided cardiac structural changes are associated with lower six minute walk distance independent of lung function. These findings may indicate that echocardiographic evidence of pulmonary hypertension is present in patients with non-severe COPD and has important functional consequences. PMID- 22220202 TI - Retinoid signaling in pancreatic cancer, injury and regeneration. AB - BACKGROUND: Activation of embryonic signaling pathways quiescent in the adult pancreas is a feature of pancreatic cancer (PC). These discoveries have led to the development of novel inhibitors of pathways such as Notch and Hedgehog signaling that are currently in early phase clinical trials in the treatment of several cancer types. Retinoid signaling is also essential for pancreatic development, and retinoid therapy is used successfully in other malignancies such as leukemia, but little is known concerning retinoid signaling in PC. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the role of retinoid signaling in vitro and in vivo in normal pancreas, pancreatic injury, regeneration and cancer. Retinoid signaling is active in occasional cells in the adult pancreas but is markedly augmented throughout the parenchyma during injury and regeneration. Both chemically induced and genetically engineered mouse models of PC exhibit a lack of retinoid signaling activity compared to normal pancreas. As a consequence, we investigated Cellular Retinoid Binding Protein 1 (CRBP1), a key regulator of retinoid signaling known to play a role in breast cancer development, as a potential therapeutic target. Loss, or significant downregulation of CRBP1 was present in 70% of human PC, and was evident in the very earliest precursor lesions (PanIN-1A). However, in vitro gain and loss of function studies and CRBP1 knockout mice suggested that loss of CRBP1 expression alone was not sufficient to induce carcinogenesis or to alter PC sensitivity to retinoid based therapies. CONCLUSIONS/SIGNIFICANCE: In conclusion, retinoid signalling appears to play a role in pancreatic regeneration and carcinogenesis, but unlike breast cancer, it is not mediated directly by CRBP1. PMID- 22220203 TI - Resveratrol protects rats from Abeta-induced neurotoxicity by the reduction of iNOS expression and lipid peroxidation. AB - Alzheimer disease (AD) is an age-dependent neurodegenerative disease characterized by the formation of beta-amyloid (Abeta)-containing senile plaque. The disease could be induced by the administration of Abeta peptide, which was also known to upregulate inducible nitric oxide synthase (iNOS) and stimulate neuronal apoptosis. The present study is aimed to elucidate the cellular effect of resveratrol, a natural phytoestrogen with neuroprotective activities, on Abeta induced hippocampal neuron loss and memory impairment. On adult Sprague-Dawley rats, we found the injection of Abeta could result in a significant impairment in spatial memory, a marked increase in the cellular level of iNOS and lipid peroxidation, and an apparent decrease in the expression of heme oxygenase-1 (HO 1). By combining the treatment with Abeta, resveratrol was able to confer a significant improvement in spatial memory, and protect animals from Abeta-induced neurotoxicity. These neurological protection effects of resveratrol were associated with a reduction in the cellular levels of iNOS and lipid peroxidation and an increase in the production of HO-1. Moreover, the similar neurological and cellular response were also observed when Abeta treatment was combined with the administration of a NOS inhibitor, N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME). These findings strongly implicate that iNOS is involved in the Abeta-induced lipid peroxidation and HO-1 downregulation, and resveratrol protects animals from Abeta-induced neurotoxicity by suppressing iNOS production. PMID- 22220204 TI - Lack of awareness among future medical professionals about the risk of consuming hidden phosphate-containing processed food and drinks. AB - Phosphate toxicity is an important determinant of mortality in patients with chronic kidney disease (CKD), particularly those undergoing hemodialysis treatments. CKD patients are advised to take a low phosphate-containing diet, and are additionally prescribed with phosphate-lowering drugs. Since these patients usually seek guidance from their physicians and nurses for their dietary options, we conducted a survey to determine the levels of awareness regarding the high phosphate content in commercially processed food and drinks among medical and nursing students at the Hirosaki University School of Medicine in Japan. For this survey, 190 medical and nursing students (average age 21.7+/-3 years) were randomly selected, and provided with a list of questions aimed at evaluating their awareness of food and drinks containing artificially added phosphate ingredients. While 98.9% of these students were aware of the presence of sugar in commercially available soda drinks, only 6.9% were aware of the presence of phosphate (phosphoric acid). Similarly, only 11.6% of these students were aware of the presence of phosphate in commercially processed food, such as hamburgers and pizza. Moreover, around two thirds of the surveyed students (67.7%) were unaware of the harmful effects of unrestricted consumption of phosphate containing food and drinks. About 28% of the surveyed students consume such "fast food" once a week, while 40% drink at least 1~5 cans of soda drinks/week. After realizing the potential long-term risks of consuming excessive phosphate containing food and drinks, 40.5% of the survey participants considered reducing their phosphate intake by minimizing the consumption of commercially processed "fast food" items and soda drinks. Moreover, another 48.4% of students showed interest in obtaining more information on the negative health effects of consuming excessive amounts of phosphate. This survey emphasizes the need for educational initiative to raise awareness of the health risks posed by excessive consumption of phosphate additives. PMID- 22220205 TI - Kv4.2 mediates histamine modulation of preoptic neuron activity and body temperature. AB - Histamine regulates arousal, circadian rhythms, and thermoregulation. Activation of H3 histamine receptors expressed by preoptic GABAergic neurons results in a decrease of their firing rate and hyperthermia. Here we report that an increase in the A-type K+ current in preoptic GABAergic neurons in response to activation of H3 histamine receptors results in decreased firing rate and hyperthermia in mice. The Kv4.2 subunit is required for these actions in spite of the fact that Kv4.2-/- preoptic GABAergic neurons display A-type currents and firing characteristics similar to those of wild-type neurons. This electrical remodeling is achieved by robust upregulation of the expression of the Kv4.1 subunit and of a delayed rectifier current. Dynamic clamp experiments indicate that enhancement of the A-type current by a similar amount to that induced by histamine is sufficient to mimic its robust effect on firing rates. These data indicate a central role played by the Kv4.2 subunit in histamine regulation of body temperature and its interaction with pERK1/2 downstream of the H3 receptor. We also reveal that this pathway provides a mechanism for selective modulation of body temperature at the beginning of the active phase of the circadian cycle. PMID- 22220207 TI - Investigation on Mycobacterium tuberculosis diversity in China and the origin of the Beijing clade. AB - BACKGROUND: Investigation of the genetic diversity of Mycobacterium tuberculosis in China has shown that Beijing genotype strains play a dominant role in the tuberculosis (TB) epidemic. In order to examine the strain diversity in the whole country, and to study the evolutionary development of Beijing strains, we sought to genotype a large collection of isolates using different methods. METHODOLOGY/PRINCIPAL FINDINGS: We applied a 15-loci VNTR typing analysis on 1,586 isolates from the Beijing municipality and 12 Chinese provinces or autonomous regions. The data was compared to that of 900 isolates from various other worldwide geographic regions outside of China. A total of 1,162/1,586 (73.2%) of the isolates, distributed into 472 VNTR types, were found to belong to the Beijing genotype family and this represented 56 to 94% of the isolates in each of the localizations. VNTR typing revealed that the majority of the non Beijing isolates fall into two genotype families, which represented 17% of the total number of isolates, and seem largely restricted to China. A small number of East African Indian genotype strains was also observed in this collection. Ancient Beijing strains with an intact region of difference (RD) 181, as well as strains presumably resembling ancestors of the whole Beijing genotype family, were mainly found in the Guangxi autonomous region. CONCLUSIONS/SIGNIFICANCE: This is the largest M. tuberculosis VNTR-based genotyping study performed in China to date. The high percentage of Beijing isolates in the whole country and the presence in the South of strains representing early branching points may be an indication that the Beijing lineage originated from China, probably in the Guangxi region. Two modern lineages are shown here to represent the majority of non-Beijing Chinese isolates. The observed geographic distribution of the different lineages within China suggests that natural frontiers are major factors in their diffusion. PMID- 22220206 TI - Enhanced discrimination of malignant from benign pancreatic disease by measuring the CA 19-9 antigen on specific protein carriers. AB - The CA 19-9 assay detects a carbohydrate antigen on multiple protein carriers, some of which may be preferential carriers of the antigen in cancer. We tested the hypothesis that the measurement of the CA 19-9 antigen on individual proteins could improve performance over the standard CA 19-9 assay. We used antibody arrays to measure the levels of the CA 19-9 antigen on multiple proteins in serum or plasma samples from patients with pancreatic adenocarcinoma or pancreatitis. Sample sets from three different institutions were examined, comprising 531 individual samples. The measurement of the CA 19-9 antigen on any individual protein did not improve upon the performance of the standard CA 19-9 assay (82% sensitivity at 75% specificity for early-stage cancer), owing to diversity among patients in their CA 19-9 protein carriers. However, a subset of cancer patients with no elevation in the standard CA 19-9 assay showed elevations of the CA 19-9 antigen specifically on the proteins MUC5AC or MUC16 in all sample sets. By combining measurements of the standard CA 19-9 assay with detection of CA 19-9 on MUC5AC and MUC16, the sensitivity of cancer detection was improved relative to CA 19-9 alone in each sample set, achieving 67-80% sensitivity at 98% specificity. This finding demonstrates the value of measuring glycans on specific proteins for improving biomarker performance. Diagnostic tests with improved sensitivity for detecting pancreatic cancer could have important applications for improving the treatment and management of patients suffering from this disease. PMID- 22220208 TI - Varying herbivore population structure correlates with lack of local adaptation in a geographic variable plant-herbivore interaction. AB - Local adaptation of parasites to their hosts due to coevolution is a central prediction of many theories in evolutionary biology. However, empirical studies looking for parasite local adaptation show great variation in outcomes, and the reasons for such variation are largely unknown. In a previous study, we showed adaptive differentiation in the arctiid moth Utetheisa ornatrix to its host plant, the pyrrolizidine alkaloid-bearing legume Crotalaria pallida, at the continental scale, but found no differentiation at the regional scale. In the present study, we sampled the same sites to investigate factors that may contribute to the lack of differentiation at the regional scale. We performed field observations that show that specialist and non-specialist polyphagous herbivore incidence varies among populations at both scales. With a series of common-garden experiments we show that some plant traits that may affect herbivory (pyrrolizidine alkaloids and extrafloral nectaries) vary at the regional scale, while other traits (trichomes and nitrogen content) just vary at the continental scale. These results, combined with our previous evidence for plant population differentiation based on larval performance on fresh fruits, suggest that U. ornatrix is subjected to divergent selection even at the regional scale. Finally, with a microsatellite study we investigated population structure of U. ornatrix. We found that population structure is not stable over time: we found population differentiation at the regional scale in the first year of sampling, but not in the second year. Unstable population structure of the herbivore is the most likely cause of the lack of regional adaptation. PMID- 22220209 TI - Exogenous IFN-alpha administration reduces influenza A virus replication in the lower respiratory tract of rhesus macaques. AB - To determine the role of innate immune responses in controlling influenza A virus replication, rhesus macaques (RM) were administered pegylated IFN-alpha prior to virus challenge. Systemic and mucosal pegylated IFN-alpha administration induced expression of the interferon-stimulated genes (ISG) MxA and OAS in the airways. RM treated with IFN-alpha 24 hours prior to influenza virus challenge had significantly lower peak vRNA levels in the trachea compared to untreated animals. In addition to blunting viral replication, IFN-alpha treatment minimized the weight loss and spike in body temperature after influenza infection of RM. These results confirm the importance of IFN-alpha induced innate immune responses in the rapid control of influenza A virus replication in primates. PMID- 22220210 TI - Minimal absent words in four human genome assemblies. AB - Minimal absent words have been computed in genomes of organisms from all domains of life. Here, we aim to contribute to the catalogue of human genomic variation by investigating the variation in number and content of minimal absent words within a species, using four human genome assemblies. We compare the reference human genome GRCh37 assembly, the HuRef assembly of the genome of Craig Venter, the NA12878 assembly from cell line GM12878, and the YH assembly of the genome of a Han Chinese individual. We find the variation in number and content of minimal absent words between assemblies more significant for large and very large minimal absent words, where the biases of sequencing and assembly methodologies become more pronounced. Moreover, we find generally greater similarity between the human genome assemblies sequenced with capillary-based technologies (GRCh37 and HuRef) than between the human genome assemblies sequenced with massively parallel technologies (NA12878 and YH). Finally, as expected, we find the overall variation in number and content of minimal absent words within a species to be generally smaller than the variation between species. PMID- 22220211 TI - Knockout of 5-lipoxygenase results in age-dependent anxiety-like behavior in female mice. AB - BACKGROUND: The enzyme 5-lipoxygenase (5LO) has been implicated in a variety of neurological and psychiatric disorders including anxiety. Knockout of 5LO has previously been shown to alter anxiety-like behavior in mice at a young age but the effect of 5LO knockout on older animals has not been characterized. METHODOLOGY/PRINCIPAL FINDINGS: Here we used the elevated plus maze behavioral paradigm to measure anxiety-like behavior in female mice lacking 5LO (5LO-KO) at three different ages. Adolescent 5LO-KO animals did not significantly differ from wild-type (WT) animals in anxiety-like behavior. However, adult and older mice exhibited increased anxiety-like behavior compared to WT controls. CONCLUSIONS: These results indicate that 5LO plays a role in the development of the anxiety like phenotype in an age-dependent manner in female mice. Future work should further investigate this interaction as 5LO may prove to be an important molecular target for the development of novel anxiolytic therapies. PMID- 22220213 TI - Predicting biological functions of compounds based on chemical-chemical interactions. AB - Given a compound, how can we effectively predict its biological function? It is a fundamentally important problem because the information thus obtained may benefit the understanding of many basic biological processes and provide useful clues for drug design. In this study, based on the information of chemical-chemical interactions, a novel method was developed that can be used to identify which of the following eleven metabolic pathway classes a query compound may be involved with: (1) Carbohydrate Metabolism, (2) Energy Metabolism, (3) Lipid Metabolism, (4) Nucleotide Metabolism, (5) Amino Acid Metabolism, (6) Metabolism of Other Amino Acids, (7) Glycan Biosynthesis and Metabolism, (8) Metabolism of Cofactors and Vitamins, (9) Metabolism of Terpenoids and Polyketides, (10) Biosynthesis of Other Secondary Metabolites, (11) Xenobiotics Biodegradation and Metabolism. It was observed that the overall success rate obtained by the method via the 5-fold cross-validation test on a benchmark dataset consisting of 3,137 compounds was 77.97%, which is much higher than 10.45%, the corresponding success rate obtained by the random guesses. Besides, to deal with the situation that some compounds may be involved with more than one metabolic pathway class, the method presented here is featured by the capacity able to provide a series of potential metabolic pathway classes ranked according to the descending order of their likelihood for each of the query compounds concerned. Furthermore, our method was also applied to predict 5,549 compounds whose metabolic pathway classes are unknown. Interestingly, the results thus obtained are quite consistent with the deductions from the reports by other investigators. It is anticipated that, with the continuous increase of the chemical-chemical interaction data, the current method will be further enhanced in its power and accuracy, so as to become a useful complementary vehicle in annotating uncharacterized compounds for their biological functions. PMID- 22220212 TI - Epigenetic changes of CXCR4 and its ligand CXCL12 as prognostic factors for sporadic breast cancer. AB - Chemokines and their receptors are involved in the development and cancer progression. The chemokine CXCL12 interacts with its receptor, CXCR4, to promote cellular adhesion, survival, proliferation and migration. The CXCR4 gene is upregulated in several types of cancers, including skin, lung, pancreas, brain and breast tumors. In pancreatic cancer and melanoma, CXCR4 expression is regulated by DNA methylation within its promoter region. In this study we examined the role of cytosine methylation in the regulation of CXCR4 expression in breast cancer cell lines and also correlated the methylation pattern with the clinicopathological aspects of sixty-nine primary breast tumors from a cohort of Brazilian women. RT-PCR showed that the PMC-42, MCF7 and MDA-MB-436 breast tumor cell lines expressed high levels of CXCR4. Conversely, the MDA-MB-435 cell line only expressed CXCR4 after treatment with 5-Aza-CdR, which suggests that CXCR4 expression is regulated by DNA methylation. To confirm this hypothesis, a 184 bp fragment of the CXCR4 gene promoter region was cloned after sodium bisulfite DNA treatment. Sequencing data showed that cell lines that expressed CXCR4 had only 15% of methylated CpG dinucleotides, while the cell line that not have CXCR4 expression, had a high density of methylation (91%). Loss of DNA methylation in the CXCR4 promoter was detected in 67% of the breast cancer analyzed. The absence of CXCR4 methylation was associated with the tumor stage, size, histological grade, lymph node status, ESR1 methylation and CXCL12 methylation, metastasis and patient death. Kaplan-Meier curves demonstrated that patients with an unmethylated CXCR4 promoter had a poorer overall survival and disease-free survival. Furthermore, patients with both CXCL12 methylation and unmethylated CXCR4 had a shorter overall survival and disease-free survival. These findings suggest that the DNA methylation status of both CXCR4 and CXCL12 genes could be used as a biomarker for prognosis in breast cancer. PMID- 22220214 TI - Levetiracetam reverses synaptic deficits produced by overexpression of SV2A. AB - Levetiracetam is an FDA-approved drug used to treat epilepsy and other disorders of the nervous system. Although it is known that levetiracetam binds the synaptic vesicle protein SV2A, how drug binding affects synaptic functioning remains unknown. Here we report that levetiracetam reverses the effects of excess SV2A in autaptic hippocampal neurons. Expression of an SV2A-EGFP fusion protein produced a ~1.5-fold increase in synaptic levels of SV2, and resulted in reduced synaptic release probability. The overexpression phenotype parallels that seen in neurons from SV2 knockout mice, which experience severe seizures. Overexpression of SV2A also increased synaptic levels of the calcium-sensor protein synaptotagmin, an SV2-binding protein whose stability and trafficking are regulated by SV2. Treatment with levetiracetam rescued normal neurotransmission and restored normal levels of SV2 and synaptotagmin at the synapse. These results indicate that changes in SV2 expression in either direction impact neurotransmission, and suggest that levetiracetam may modulate SV2 protein interactions. PMID- 22220215 TI - Induction of cytoplasmic rods and rings structures by inhibition of the CTP and GTP synthetic pathway in mammalian cells. AB - BACKGROUND: Cytoplasmic filamentous rods and rings (RR) structures were identified using human autoantibodies as probes. In the present study, the formation of these conserved structures in mammalian cells and functions linked to these structures were examined. METHODOLOGY/PRINCIPAL FINDINGS: Distinct cytoplasmic rods (~3-10 um in length) and rings (~2-5 um in diameter) in HEp-2 cells were initially observed in immunofluorescence using human autoantibodies. Co-localization studies revealed that, although RR had filament-like features, they were not enriched in actin, tubulin, or vimentin, and not associated with centrosomes or other known cytoplasmic structures. Further independent studies revealed that two key enzymes in the nucleotide synthetic pathway cytidine triphosphate synthase 1 (CTPS1) and inosine monophosphate dehydrogenase 2 (IMPDH2) were highly enriched in RR. CTPS1 enzyme inhibitors 6-diazo-5-oxo-L norleucine and Acivicin as well as the IMPDH2 inhibitor Ribavirin exhibited dose dependent induction of RR in >95% of cells in all cancer cell lines tested as well as mouse primary cells. RR formation by lower concentration of Ribavirin was enhanced in IMPDH2-knockdown HeLa cells whereas it was inhibited in GFP-IMPDH2 overexpressed HeLa cells. Interestingly, RR were detected readily in untreated mouse embryonic stem cells (>95%); upon retinoic acid differentiation, RR disassembled in these cells but reformed when treated with Acivicin. CONCLUSIONS/SIGNIFICANCE: RR formation represented response to disturbances in the CTP or GTP synthetic pathways in cancer cell lines and mouse primary cells and RR are the convergence physical structures in these pathways. The availability of specific markers for these conserved structures and the ability to induce formation in vitro will allow further investigations in structure and function of RR in many biological systems in health and diseases. PMID- 22220216 TI - Triple combination antiviral drug (TCAD) composed of amantadine, oseltamivir, and ribavirin impedes the selection of drug-resistant influenza A virus. AB - Widespread resistance among circulating influenza A strains to at least one of the anti-influenza drugs is a major public health concern. A triple combination antiviral drug (TCAD) regimen comprised of amantadine, oseltamivir, and ribavirin has been shown to have synergistic and broad spectrum activity against influenza A strains, including drug resistant strains. Here, we used mathematical modeling along with three different experimental approaches to understand the effects of single agents, double combinations, and the TCAD regimen on resistance in influenza in vitro, including: 1) serial passage at constant drug concentrations, 2) serial passage at escalating drug concentrations, and 3) evaluation of the contribution of each component of the TCAD regimen to the suppression of resistance. Consistent with the modeling which demonstrated that three drugs were required to suppress the emergence of resistance in influenza A, treatment with the TCAD regimen resulted in the sustained suppression of drug resistant viruses, whereas treatment with amantadine alone or the amantadine-oseltamivir double combination led to the rapid selection of resistant variants which comprised ~100% of the population. Furthermore, the TCAD regimen imposed a high genetic barrier to resistance, requiring multiple mutations in order to escape the effects of all the drugs in the regimen. Finally, we demonstrate that each drug in the TCAD regimen made a significant contribution to the suppression of virus breakthrough and resistance at clinically achievable concentrations. Taken together, these data demonstrate that the TCAD regimen was superior to double combinations and single agents at suppressing resistance, and that three drugs at a minimum were required to impede the selection of drug resistant variants in influenza A virus. The use of mathematical modeling with multiple experimental designs and molecular readouts to evaluate and optimize combination drug regimens for the suppression of resistance may be broadly applicable to other infectious diseases. PMID- 22220217 TI - Dermal perfusion of common donor sites free flaps in chronic smokers and nonsmokers. AB - OBJECTIVE: The smoking behavior of the patient influences the indication of plastic surgeon in his reconstruction procedure on the assumption that smoking may increase the complication risks. In the present study, we evaluate the particular aspect of topographic differences in dermal perfusion in chronic smokers and nonsmokers. METHODS: The perfusion parameter of 8 common donor sites for free flap transplantation were investigated in 152 smoking and nonsmoking subjects (n = 152; women: n = 78, 51%; men: n = 74, 49%; smokers: n = 38, 25%; nonsmokers: n = 114, 75%) using the O2C device (LAE Medizintechnik Giessen GmbH, Giebetaen, Germany). Oxygen saturation (%), relative hemoglobin concentration (AU [arbitrary unit]), Velocity (AU) and Flow (AU) were monitored noninvasively and compared. RESULTS: All monitored regions did not show any significant differences in parameters oxygen saturation (smokers = 40%, nonsmokers = 44.5%), relative hemoglobin concentration (smokers = 60 AU, nonsmokers = 60 AU), flow (smokers = 19.5 AU, nonsmokers = 16.5 AU) and velocity (smokers = 10 AU, nonsmokers = 10 AU) between chronic smoking and nonsmoking subjects (P < .05). Also, a distinction between smokers and nonsmokers as a function of gender (women: n = 78, 51%; men: n = 74, 49%) showed no significant differences in all 4 parameters. CONCLUSIONS: Varied statements regarding surgical complications in chronic and acute smokers were described in the literature. This raises the question of how far restricting the indication of reconstruction procedure for smoking patients due to higher complications is justified. In our study, there is no significant drop of dermal perfusion parameters after chronic tobacco consumption. Nonetheless, the unfavorable effects of smoking in general to human body and health remain undoubted. PMID- 22220218 TI - Immunomodulatory role of Ocimum gratissimum and ascorbic acid against nicotine induced murine peritoneal macrophages in vitro. AB - The aim of this present study was to evaluate the immune functions and immune responses in nicotine-induced (10 mM) macrophages and concurrently establish the immunomodulatory role of aqueous extract of Ocimum gratissimum (Ae-Og) and ascorbic acid. In this study, nitrite generations and some phenotype functions by macrophages were studied. Beside that, release of Th1 cytokines (TNF-alpha, IL 12) and Th2 cytokines (IL-10, TGF-beta) was measured by ELISA, and the expression of these cytokines at mRNA level was analyzed by real-time PCR. Ae-Og, at a dose of 10 MUg/mL, significantly reduced the nicotine-induced NO generation and iNOSII expression. Similar kinds of response were observed with supplementation of ascorbic acid (0.01 mM). The administration of Ae-Og and ascorbic acid increased the decreased adherence, chemotaxis, phagocytosis, and intracellular killing of bacteria in nicotine-treated macrophages. Ae-Og and ascorbic acid were found to protect the murine peritoneal macrophages through downregulation of Th1 cytokines in nicotine-treated macrophages with concurrent activation of Th2 responses. These findings strongly enhanced our understanding of the molecular mechanism leading to nicotine-induced suppression of immune functions and provide additional rationale for application of anti-inflammatory therapeutic approaches by O. gratissimum and ascorbic acid for different inflammatory disease prevention and treatment during nicotine toxicity. PMID- 22220219 TI - Clinical use of dexmedetomidine in monitored anesthesia care. PMID- 22220220 TI - Dexmedetomidine is effective for monitored anesthesia care in outpatients undergoing cataract surgery. AB - BACKGROUND: Dexmedetomidine has a sedative analgesic property without respiratory depression. This study evaluated the efficacy of dexmedetomidine as an appropriate sedative drug for monitored anesthesia care (MAC) in outpatients undergoing cataract surgery on both eyes compared with combination of propofol and alfentanil. METHODS: Thirty-one eligible patients were randomly divided into two groups on the first operation day. Dexmedetomidine was administered in group D at 0.6 ug/kg/h, and propofol and alfentanil was infused concomitantly in group P at a rate of 2 mg/kg/h and 20 ug/kg/h, respectively. Sedation was titrated at Ramsay sedation score 3. Iowa satisfaction with anesthesia scale (ISAS) of the patients was evaluated postoperatively. Systolic blood pressure (SBP), heart rate (HR), respiration rate (RR), and peripheral oxygen saturation (SpO(2)) were recorded throughout the surgery. For the second operation, the group assignments were exchanged. RESULTS: Postoperative ISAS was 50.3 (6.2) in group D and 42.7 (8.7) in group P, which was statistically significant (P < 0.001). SBP was significantly lower in group D compared with group P from the beginning of the operation. HR, RR, and SpO(2) were comparable between the two groups. There were 8 cases (25.8%) of hypertension in group P, and 1 case (3.2%) in group D (P < 0.05). In contrast, 1 case (3.2%) of hypotension and 1 case (3.2%) of bradycardia occurred in group D. CONCLUSIONS: Compared with the combined use of propofol and alfentanil, dexmedetomidine could be used appropriately for MAC in cataract surgery with better satisfaction from the patients and a more stable cardiovascular state. PMID- 22220221 TI - The effect of pyridostigmine on bispectral index during recovery from sevoflurane anesthesia. AB - BACKGROUND: There have been some conflicting reports showing that muscle relaxants and anticholinesterases affect the level of the bispectral index (BIS). The purpose of this study was to investigate whether pyridostigmine affects the level of the BIS during recovery from sevoflurane anesthesia. METHODS: Fifty-two adult patients scheduled for laparoscopic cholecystectomy and laparoscopic appendectomy. Anesthesia was induced with thiopental 4 mg/kg and rocuronium 0.6 mg/kg. The lung was mechanically ventilated with 1-3 vol% sevoflurane, 50% oxygen and 50% nitrous oxide. After a specimen was removed, the sevoflurane concentration was maintained at 1.5 vol%. When skin closure began, sevoflurane was stopped; however, 50% oxygen and 50% nitrous oxide were maintained. The patients then received either (1) a group that received an injection of glycopyrrolate 0.04 mg/kg and pyridostigmine 0.2 mg/kg (reverse (R) group, n = 26) or (2) a group that received normal saline (control (C) group, n = 26). Group assignment was random. Pyridostigmine, a reversible cholinesterase inhibitor, is a parasympathomimetic. End-tidal sevoflurane concentration, train of four (TOF) ratio, bispectral index (BIS), blood pressure and heart rate were measured from the end of the operation to 15 min after inject of pyridostigmine or placebo. RESULTS: There were no significant between group differences in the time dependent decrease in end-tidal sevoflurane concentration (P = 0.0642). There were significant differences between the two groups for the time course for increases in the TOF value (P < 0.0001). There were significant differences between the two groups for the time course for increases in the BIS value (P = 0.0107). There were no significant differences in the mean BIS value up to 10 minutes after administering drug, but 15 minutes after administrating the reverse drug or the control drug, the BIS value showed significantly different BIS values: 68.2 +/- 6.2 (Group R) and 63.2 +/- 6.2 (Group C) (P = 0.0058). CONCLUSIONS: The finding that pyridostigmine increases TOF and BIS suggests that pyridostigmine may enhance recovery during recovery from sevoflurane anesthesia. PMID- 22220222 TI - Dilution and slow injection reduces the incidence of rocuronium-induced withdrawal movements in children. AB - BACKGROUND: The aim of this study was to evaluate whether slow injection of diluted rocuronium could reduce rocuronium-induced withdrawal movements effectively in children. METHODS: After loss of consciousness, rocuronium 0.6 mg/kg was administered into 171 children according to the pre-assigned groups as follows: Group CF, injection of non-diluted rocuronium over 5 seconds; Group CS, injection of non-diluted rocuronium over 1 minute; Group DF, injection of diluted rocuronium (10 times) over 5 seconds; Group DS, injection of diluted rocuronium over 1 minute. An investigator who was blind to the injection techniques recorded patient movements followed by rocuronium injection. RESULTS: The incidence of withdrawal movement in Group CF was highest among the groups (all P < 0.0001). Moreover, withdrawal movement was less frequently observed in Group DS than in Groups CS and DF (P = 0.021 and P = 0.007, respectively). CONCLUSIONS: Slow injection of diluted rocuronium reduced the incidence of withdrawal movements in children. PMID- 22220223 TI - The effect of the humidifier on sore throat and cough after thyroidectomy. AB - BACKGROUND: This study was performed to determine the effects of a humidifier with heated wire circuits on the incidence and severity of postoperative sore throat (POST) and cough after thyroidectomy. METHODS: A total of 61 patients scheduled for elective thyroid surgery under general anesthesia were included in this prospective study. We randomized the patients in to two groups, "without active warming and humidification" (Group C) and "using a heated humidifier" (Group H). The patients were interviewed to obtain the POST and cough scores at 1, 6, 24 and 48 hours after thyroidectomy. RESULTS: The incidence of POST was significantly lower in Group H compared to Group C at 6 hours (57% vs 84%, P = 0.041), 24 hours (37% vs 65%, P = 0.045), and 48 hours (10% vs 52%, P = 0.001). Also the incidence of cough was significantly lower in Group H at 6 hours (27% vs 71%, P = 0.001), 24 hours (13% vs 45%, P = 0.015), and 48 hours (7% vs 32%, P = 0.028). The severity of POST was significantly lower in Group H at all times. In addition, the severity of cough was lower in Group H at other times except at 1 hour. CONCLUSIONS: This result suggests that an active humidification of inspired gases may have the appreciable effect on reducing the incidence and severity of sore throat and cough after thyroid surgery using the endotracheal tube. PMID- 22220224 TI - Feasibility of ultrasound-guided posterior approach for interscalene catheter placement during arthroscopic shoulder surgery. AB - BACKGROUND: Continuous interscalene block has been known to improve postoperative analgesia after arthroscopic shoulder surgery. This was a prospective study investigating the ultrasound-guided posterior approach for placement of an interscalene catheter, clinical efficacy and complications after placement of the catheter. METHODS: Forty-two patients undergoing elective arthroscopic shoulder surgery were included in this study and an interscalene catheter was inserted under the guidance of ultrasound with posterior approach. With the inplane approach, the 17 G Tuohy needle was advanced until the tip was placed between the C5 and C6 nerve roots. After a bolus injection of 20 ml of 0.2% ropivacaine, a catheter was threaded and secured. A continuous infusion of ropivacaine 0.2% 4 ml/hr with patient-controlled 5 ml boluses every hour was used over 2 days. Difficulties in placement of the catheter, clinical efficacy of analgesia and complications were recorded. All patients were monitored for 48 hours and examined by the surgeon for complications within 2 weeks of hospital discharge. RESULTS: Easy placement of the catheter was achieved in 100% of the patients and the success rate of catheter placement during the 48 hr period was 92.9%. Postoperative analgesia was effective in 88.1% of the patients in the post anesthetic care unit. The major complications included nausea (7.1%), vomiting (4.8%), dyspnea (4.8%) and unintended vascular punctures (2.4%). Other complications such as neurologic deficits and local infection around the puncture site did not occur. CONCLUSIONS: The ultrasound-guided interscalene block with a posterior approach is associated with a success high rate in placement of the interscalene catheter and a low rate of complications. However, the small sample size limits us to draw definite conclusions. Therefore, a well-designed randomized controlled trial is required to confirm our preliminary study. PMID- 22220225 TI - Hemodynamic effects of continuous intravenous injection and bolus plus continuous intravenous injection of oxytocin in cesarean section. AB - BACKGROUND: Oxytocin may cause adverse cardiovascular effects, including tachycardia and hypotension, whereas the optimal dose of oxytocin at elective cesarean section is unclear. To determine the lowest effective dose of oxytocin, we studied the hemodynamic effects of three doses during spinal anesthesia for elective single cesarean delivery. METHODS: Sixty women received oxytocin by continuous (0.5 IU/min) or bolus-continuous (2 or 5 IU prior to 0.25 IU/min continuous intravenous injection) intravenous injection after clamping of the umbilical cord. We compared changes in heart rate (HR), mean arterial pressure (MAP) and estimated blood loss (EBL). Uterine tone (UT) was assessed by palpation on a linear analog scale (LAS) at 5, 10, 15, 20 and 25 minutes after the oxytocin injection. In addition, oxytocin-related side-effects such as nausea and vomiting were recorded. RESULTS: Marked hemodynamic changes such as HR and MAP occurred in the bolus-continuous groups but not in the continuous groups. Although we were not able to observe a variation of EBL in each group, the UT significantly increased in the bolus-continuous groups when compared with that the continuous groups. In addition, the hemodynamic changes such as HR and MAP were lower in the two IU bolus-continuous group than those in the five IU group. CONCLUSIONS: Although bolus-continuous injection of oxytocin resulted in more hemodynamic changes than continuous injection, bolus-continuous injection had a greater effect on uterine contraction. Furthermore, two IU bolus-continuous injection showed lower hemodynamic changes than in the five IU bolus-continuous injection. PMID- 22220226 TI - Comparison of ramosetron's and ondansetron's preventive anti-emetic effects in highly susceptible patients undergoing abdominal hysterectomy. AB - BACKGROUND: This study compared the preventive effects of ramosetron and ondansetron on postoperative nausea and vomiting (PONV) in highly susceptible patients undergoing abdominal hysterectomy. METHODS: In a prospective, randomized, double-blinded study, a total of 120 highly susceptible women (nonsmokers, those receiving opioid-based IV patient-controlled analgesia [PCA]) undergoing abdominal hysterectomy were included in the study. Patients were divided into 2 groups and each group received either 0.3 mg of ramosetron or 4 mg of ondansetron, IV. All patients received fentanyl-based IV PCA during the 48 h postoperative periods. The incidences of PONV and side effects of 5-HT(3) antagonists (headache and dizziness) were assessed at 3 intervals (<2 h, 2-24 h and 24-48 h) postoperatively. RESULTS: Patients in the ramosetron group showed a significantly higher ratio of complete response and lower incidence of nausea during the 24-48 h interval after surgery compared with those the ondansetron group. CONCLUSIONS: Ramosetron (0.3 mg) is more effective in preventing delayed PONV in highly susceptible women undergoing abdominal hysterectomy compared with ondansetron (4 mg). PMID- 22220227 TI - Insulin effect on bupivacaine-induced cardiotoxicity in rabbits. AB - BACKGROUND: Resuscitation following bupivacaine-induced cardiovascular collapse is difficult and often refractory to conventional treatment. This study was performed to assess the effect of insulin on bupivacaine-induced cardiovascular collapse in pentobarbital-anesthetized rabbits. METHODS: Bupivacaine was administered at 0.75 mg/kg/min until the heart rate decreased to 65 beats/min. A bolus of regular insulin (2 U/kg) was administered intravenously at the bupivacaine infusion endpoint (BIE) in the insulin group (n = 8), and 2 mL of 0.9% NaCl was administered to the control group (n = 8). RESULTS: All animals in the insulin group survived and four animals died in the control group. Arrythymia was rare 10 minutes after the BIE in the insulin group. CONCLUSIONS: Bupivacaine induced cardiovascular collapse can be effectively reversed with an insulin injection, probably through facilitation of cardiac conduction and contraction. PMID- 22220228 TI - Myocardial protective effect by ulinastatin via an anti-inflammatory response after regional ischemia/reperfusion injury in an in vivo rat heart model. AB - BACKGROUND: Ulinastatin has anti-inflammatory properties and protects organs from ischemia/reperfusion-induced injury. The aim of this study was to investigate whether ulinastatin provides a protective effect on a regional myocardial ischemia/reperfusion injury in an in vivo rat heart model and to determine whether the anti-inflammatory response is related to its myocardial protective effect. METHODS: Rats were randomized to two groups. One group is received ulinastatin (50,000 U/kg or 100,000 U/kg) diluted in normal saline and the other group is received normal saline, which was administered intraperitoneally 30 min before the ischemic insult. Reperfusion after 30 min of ischemia of the left coronary artery territory was applied. Hemodynamic measurements were recorded serially during 6 h after reperfusion. After the 6 h reperfusion, myocardial infarct size, cardiac enzymes, myeloperoxidase activity, and inflammatory cytokine levels were compared between the ulinastatin treated and untreated groups. RESULTS: Ulinastatin improved cardiac function and reduced infarct size after regional ischemia/reperfusion injury. Ulinastatin significantly attenuated tumor necrosis factor-alpha expression and reduced myeloperoxidase activity. CONCLUSIONS: Ulinastatin showed a myocardial protective effect after regional ischemia/reperfusion injury in an in vivo rat heart model. This protective effect of ulinastatin might be related in part to ulinastatin's ability to inhibit myeloperoxidase activity and decrease expression of tumor necrosis factor-alpha. PMID- 22220229 TI - Aging impairs vasodilatory responses in rats. AB - BACKGROUND: Aging causes profound changes of stiffness and compliance in the cardiovascular system, which contributes to decreased cardiovascular reserve. Mechanisms of the underlying endothelial vasodilator dysfunction in vasodilator signaling pathways may occur at multiple sites within any of these pathways. METHODS: Age-related changes in the vasculature were investigated in adult young (3-6 months, Y) and old (26-29 month, O) Wistar rats (n = 6). The aortas were carefully dissected from the rat and cut into rings 1.5-2.0 mm in length to measure in vitro isometric tension. Vasorelaxant responses of aortic rings to acetylcholine (ACh), sodium nitroprusside (SNP) and P1075 were examined using Dose Response software (AD Instruments, Mountain View, CA). RESULTS: Endothelium dependent vasodilator function was impaired. The endothelium of aging rats impaired endothelial NO dependent vasodilation, but the machinery for vasodilation was not impaired. CONCLUSIONS: Age-related NO-mediated vasorelaxation in the aging endothelium was inhibited and appears to be major mechanism of vascular change and impaired vascular regulation. PMID- 22220230 TI - Inappropriate elevation of bispectral index values in robot assisted thyroidectomy with electromyographic endotracheal tube -A case report-. AB - We report a case of an erroneously elevated bispectral index (BIS) during robot assisted thyroidectomy using an electromyographic endotracheal tube (EMG tube), which is safe and useful for laryngeal electromyographic monitoring. Ten minutes after start of the operation, a sudden increase of BIS value up to 98 was noticed. The BIS values were not decreased to < 65 with supplemental anesthetics. The anesthetic method was changed from total intravenous anesthesia to balanced anesthesia. The BIS sensor and monitor were changed and other models were used. These interventions did not alter BIS values. BIS levels remained between 60 and 70 throughout the main procedure and intermittently increased to the mid-90s without any trace of poor signal quality. At the end of the surgery, the BIS values returned to normal range. The patient did not complain of intraoperative recall. Knowledge of potential interference from the use of an EMG tube must be considered when interpreting BIS. PMID- 22220231 TI - Fatal pulmonary embolism and coincidental cerebral infarction after spinal anesthesia -A case report-. AB - A pulmonary embolism and cerebral infarction are the second and third most common acute cardiovascular diseases after a myocardial infarction. Early diagnosis and appropriate management are important clinical challenges. In this case, a fatal pulmonary embolism and extensive cerebral infarction caused cardiac arrest during spinal anesthesia for total hip replacement surgery. Transesophageal echocardiography indicated a pulmonary embolism and brain CT showed large area of acute infarction at right middle cerebral artery territory. Pulmonary CT angiogram revealed massive pulmonary embolism findings. This paper reviews this case and suggests other preventive modalities. PMID- 22220232 TI - Hypocalcemia and hypokalemia due to hyperventilation syndrome in spinal anesthesia -A case report-. AB - Hyperventilation syndrome (HVS) often occurs under stressful conditions, and has been reported during or after anesthesia and operation. HVS, characterized by multiple somatic symptoms and electrolyte imbalances induced by inappropriate hyperventilation, should be managed as an emergency. We report a rare case of HVS during spinal anesthesia. The patient was a previously healthy 51-year-old female without psychogenic conditions. During spinal anesthesia for lower extremity surgery, the patient complained of nausea, headache, paresthesia in the upper extremities and perioral numbness. We found carpal spasm in both hands and flattening of T wave on electrocardiogram (ECG). Emergent arterial blood gas analysis (ABGA) revealed markedly decreased PaCO(2), hypocalcemia and hypokalemia. We managed the patient with verbal sedation, electrolytes replacement therapy and closed mask inhalation. HVS subsided gradually. We conclude that monitoring for possible HVS during anesthesia is very important for patient safety. PMID- 22220233 TI - Spinal epidural hematoma related to an epidural catheter in a cardiac surgery patient -A case report-. AB - The addition of thoracic epidural anesthesia to general anesthesia during cardiac surgery may have a beneficial effect on clinical outcome. However, epidural catheter insertion in a patient anticoagulated with heparin may increase the risk of epidural hematoma. We report a case of epidural hematoma in a 55-year-old male patient who had a thoracic epidural placed under general anesthesia preceding uneventful mitral valve replacement and tricuspid valve annular plasty. During the immediate postoperative period and first postoperative day, prothrombin time (PT) and activate partial thromboplastin time (aPTT) were mildly prolonged. On the first postoperative day, he complained of motor weakness of the lower limbs and back pain. An immediate MRI of the spine was performed and it revealed an epidural hematoma at the T5-6 level. Rapid surgical decompression resulted in a recovery of his neurological abnormalities to near normal levels. Management and preventing strategies of epidural hematoma are discussed. PMID- 22220234 TI - Anesthetic experiences of myxoma removal surgery in two patients with Carney complex -A report of two cases-. AB - Carney complex is an autosomal dominant disorder that occurs due to a mutation in PRKAR1A, which encodes protein kinase A. The clinical features are multiple endocrine gland neoplasms, skin tumors, pigmented skin lesions, myxomas, and schwannomas. In Carney complex, the cardiac myxoma is a common co-morbidity. It occurs in multiples, during young age, regardless of gender and cardiac chamber and is known to recur frequently. Therefore there are high risks of adhesion and massive bleeding due to repeated surgeries. Such surgical risks account for over 50% of disease-specific mortality of Carney complex patients. Here, we present anesthetic experiences of myxoma removal surgery in two patients with Carney complex. PMID- 22220235 TI - Hyperkalemia from preoperative non-steroidal anti-inflammatory drugs and angiotensin II receptor blockers in patients with nephropathy. PMID- 22220236 TI - Sign of decreased coronary blood flow from ST depression and PVCs during a left lower lobectomy of the lung in a patient with a left internal mammary arterial bypass graft. PMID- 22220237 TI - Dexmedetomidine for the treatment of acute pain from complex regional pain syndrome. PMID- 22220238 TI - Roles of serotonergic and adrenergic receptors in the antinociception of selective cyclooxygenase-2 inhibitor in the rat spinal cord. AB - BACKGROUND: The analgesic mechanisms of cyclooxygenase (COX)-2 inhibitors have been explained mainly on the basis of the inhibition of prostaglandin biosynthesis. However, several lines of evidence suggest that their analgesic effects are mediated through serotonergic or adrenergic transmissions. We investigated the roles of these neurotransmitters in the antinociception of a selective COX-2 inhibitor at the spinal level. METHODS: DUP-697, a selective COX 2 inhibitor, was delivered through an intrathecal catheter to male Sprague-Dawley rats to examine its effect on the flinching responses evoked by formalin injection into the hindpaw. Subsequently, the effects of intrathecal pretreatment with dihydroergocristine, prazosin, and yohimbine, which are serotonergic, alpha1 adrenergic and alpha2 adrenergic receptor antagonists, respectively, on the analgesia induced by DUP-697 were assessed. RESULTS: Intrathecal DUP-697 reduced the flinching response evoked by formalin injection during phase 1 and 2. But, intrathecal dihydroergocristine, prazosin, and yohimbine had little effect on the antinociception of intrathecal DUP-697 during both phases of the formalin test. CONCLUSIONS: Intrathecal DUP-697, a selective COX-2 inhibitor, effectively relieved inflammatory pain in rats. Either the serotonergic or adrenergic transmissions might not be involved in the analgesic activity of COX-2 inhibitors at the spinal level. PMID- 22220239 TI - Tumor Necrosis Factor-alpha and Apoptosis Following Spinal Nerve Ligation Injury in Rats. AB - BACKGROUND: Spinal nerve ligation (SNL) injury in rats produces a pain syndrome that includes mechanical and thermal allodynia. Previous studies have indicated that proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) play an important role in peripheral mediation of neuropathic pain, and that altered dorsal root ganglion (DRG) function and degree of DRG neuronal apoptosis are associated with spinal nerve injury. The present study was conducted to evaluate the expression of TNF-alpha and the extent of apoptosis in the dorsal root ganglion after SNL in rats. METHODS: Sprague-Dawley rats were subjected to SNL of the left L5 and L6 spinal nerves distal to the DRG and proximal to the formation of the sciatic nerve. At postoperative day 8, TNF-alpha protein levels in the L5-6 DRG were compared between SNL and naive groups using ELISA. In addition, we compared the percentage of neurons injured in the DRG using immunostaining for apoptosis and localization of activated caspase-3. RESULTS: SNL injury produced significant mechanical and cold allodynia throughout the 7 day experimental period. TNF-alpha protein levels were increased in the DRG in rats that had undergone SNL (12.7 +/- 3.2 pg/100 ug, P < 0.001) when compared with naive rats (4.1 +/- 1.4 pg/100 ug). The percentage of neurons or satellite cells co-localized with activated caspase-3 were also significantly higher in rats with SNL than in naive rats (P < 0.001, P < 0.05, respectively). CONCLUSIONS: SNL injury produces mechanical and cold allodynia, as well as TNF alpha elevation and apoptosis in the DRG. PMID- 22220240 TI - Effects of low and high molecular weight hyaluronic acids on peridural fibrosis and inflammation in lumbar laminectomized rats. AB - BACKGROUND: Postlaminectomy peridural fibrosis is inevitable. Some studies have compared and identified the effects of high molecular weight hyaluronic acids (HMWHA) and low molecular weight hyaluronic acids (LMWHA) on peridural fibrosis in postlaminectomy animal models. However, no studies have been found that compare pain behaviors between hyaluronic acids or among hyaluronic acids and other solid materials. The purpose of this study was to examine the correlation between pain-related behaviors and histopathologic changes in laminectomized rats using various peridurally administered materials. METHODS: Forty male Sprague Dawley rats, laminectomized at the L5 and L6 levels, were divided into four groups: group C, laminectomy only; group L, laminectomy and LMWHA application; group H, laminectomy and HMWHA application; group F, laminectomy and fat interposition. Pain behaviors were checked before, 3 days, 1 week, and 3 weeks after surgery. Histopathological changes were checked at the L5 level 3 weeks after the surgery. RESULTS: The 50% withdrawal thresholds in groups L and H were higher than that in groups C and F three days after laminectomy (P < 0.05). The paw withdrawal time did not change among the groups and in each group during the study period. Peridural fibrosis in group F was significantly lower than in the other groups (P < 0.05). CONCLUSIONS: Hyaluronic acids significantly reduced mechanical allodynia but not thermal hyperalgesia. Peridural fibrosis did not show any correlation with pain behaviors. There have been limited studies on the correlation between peridural fibrosis and pain behavioral change, which should be verified by further studies. PMID- 22220241 TI - A Study to Compare the Radiation Absorbed Dose of the C-arm Fluoroscopic Modes. AB - BACKGROUND: Although many clinicians know about the reducing effects of the pulsed and low-dose modes for fluoroscopic radiation when performing interventional procedures, few studies have quantified the reduction of radiation absorbed doses (RADs). The aim of this study is to compare how much the RADs from a fluoroscopy are reduced according to the C-arm fluoroscopic modes used. METHODS: We measured the RADs in the C-arm fluoroscopic modes including 'conventional mode', 'pulsed mode', 'low-dose mode', and 'pulsed + low-dose mode'. Clinical imaging conditions were simulated using a lead apron instead of a patient. According to each mode, one experimenter radiographed the lead apron, which was on the table, consecutively 5 times on the AP views. We regarded this as one set and a total of 10 sets were done according to each mode. Cumulative exposure time, RADs, peak X-ray energy, and current, which were viewed on the monitor, were recorded. RESULTS: Pulsed, low-dose, and pulsed + low-dose modes showed significantly decreased RADs by 32%, 57%, and 83% compared to the conventional mode. The mean cumulative exposure time was significantly lower in the pulsed and pulsed + low-dose modes than in the conventional mode. All modes had pretty much the same peak X-ray energy. The mean current was significantly lower in the low-dose and pulsed + low-dose modes than in the conventional mode. CONCLUSIONS: The use of the pulsed and low-dose modes together significantly reduced the RADs compared to the conventional mode. Therefore, the proper use of the fluoroscopy and its C-arm modes will reduce the radiation exposure of patients and clinicians. PMID- 22220242 TI - Interventional pain management in rheumatological diseases - a three years physiatric experience in a tertiary medical college hospital in bangladesh. AB - BACKGROUND: Interventional pain management (IPM) is a branch of medical science that deals with management of painful medical conditions using specially equipped X-ray machines and anatomical landmarks. Interventional physiatry is a branch of physical medicine and rehabilitation that treats painful conditions through intervention in peripheral joints, the spine, and soft tissues. METHODS: A cross sectional study was conducted using three years of hospital records (2006 to 2008) from the Physical Medicine and Rehabilitation Department at Chittagong Medical College Hospital in Bangladesh, with a view toward highlighting current interventional pain practice in a tertiary medical college hospital. RESULTS: The maximum amount of intervention was done in degenerative peripheral joint disorders (600, 46.0%), followed by inflammatory joint diseases (300, 23.0%), soft tissue rheumatism (300, 23.0%), and radicular or referred lower back conditions (100, 8.0%). Of the peripheral joints, the knee was the most common site of intervention. Motor stimulation-guided intralesional injection of methylprednisolone into the piriformis muscle was given in 10 cases of piriformis syndrome refractory to both oral medications and therapeutic exercises. Soft tissue rheumatism of unknown etiology was most common in the form of adhesive capsulitis (90, 64.3%), and is discussed separately. Epidural steroid injection was practiced for various causes of lumbar radiculopathy, with the exception of infective discitis. CONCLUSIONS: All procedures were performed using anatomical landmarks, as there were no facilities for the C-arm/diagnostic ultrasound required for accurate and safe intervention. A dedicated IPM setup should be a requirement in all PMR departments, to provide better pain management and to reduce the burden on other specialties. PMID- 22220243 TI - Analysis of influencing factors to depth of epidural space for lumbar transforaminal epidural block in korean. AB - BACKGROUND: Transforaminal epidural steroid injection is one of the effective treatments in managing radicular pain. There have been some prospective studies on the depth to the epidural space with the transforaminal approach. However, there have been no studies about the depth in Asians, especially Koreans. This study was carried out in order to evaluate the depth to the epidural space and the oblique angle and factors that influence the depth to the epidural space during lumbar transforaminal epidural injection. METHODS: A total of 248 patients undergoing fluoroscopically guided transforaminal epidural steroid injections were evaluated. At the L3-4, L4-5, L5-S1, and S1 levels, we measured the oblique angle and depth to the epidural space. RESULTS: Needle depth was positively associated with body mass index (correlation coefficient 0.52, P = 0.004). The median depths (in centimeters) to the epidural space were 6.13 cm, 6.42 cm, and 7.13 cm for 50-60 kg, 60-70 kg, and 70-80 kg groups, respectively, at L5-S1. Age and height were not significantly associated with the needle depth. CONCLUSIONS: There is a positive association between the BMI (and weight) and transforaminal epidural depth but not with age, sex, and height. PMID- 22220244 TI - Anaphylactic shock caused by the epidurally-administered hyalurinidase. AB - Hyaluronidase is an enzyme that has temporary and reversible enzymatic effects on the matrix of connective tissue. When added to local anesthetics in pain treatments, it enhances their infiltration and dispersal into tissues. It is widely used in anesthesia for ocular, dental, and plastic surgery. Reports of drug hypersensitivity to hyaluronidase are rare and are usually confined to peribulbar or retrobulbar anesthesia during ophthalmic surgery. However, few reports exist on adverse drug reaction after epidural injection. We have observed two patients experiencing anaphylactic shock caused by hyaluronidase following epidural injection. Most of the patients with a hypersensitivity to hyaluronidase had one previous uneventful injection containing hyaluronidase, implying that sensitization had taken place. However, hypersensitivity occurring at the first administration is possible. A positive skin test can help establish the diagnosis. Although rare, the possibility of an allergic reaction to hyaluronidase should be considered even in patients with no known previous exposure. PMID- 22220246 TI - Spontaneous Vertebral Reduction during the Procedure of Kyphoplasty in a Patient with Kummell's Disease. AB - Kummell's disease is a spinal disorder characterized by delayed post-traumatic collapse of a vertebral body with avascular necrosis. Although definitive treatment for Kummell's disease has not been established, it has been reported that percutaneous vertebroplasty or kyphoplasty has shown good results. However, these procedures are not recommended for severely collapsed vertebral bodies because of the risk of cement leakage or technical difficulties. Authors report a rare case of spontaneous reduction in vertebral height by the insertion of a working cannula into the vertebral body in Kummell's disease. PMID- 22220245 TI - Lumbar plexopathy caused by metastatic tumor, which was mistaken for postoperative femoral neuropathy. AB - Surgical excision was performed on a 30-years old woman with a painful mass on her left thigh. The pathologic findings on the mass indicated fibromatosis. After the operation, she complained of allodynia and spontaneous pain at the operation site and ipsilateral lower leg. We treated her based on postoperative femoral neuropathy, but symptom was aggravated. We found a large liposarcoma in her left iliopsoas muscle which compressed the lumbar plexus. In conclusion, the cause of pain was lumbar plexopathy related to a mass in the left iliopsoas muscle. Prompt diagnosis of acute neuropathic pain after an operation is important and management must be based on exact causes. PMID- 22220247 TI - Spontaneous height restoration of vertebral compression fracture - a case report . AB - Vertebral compression fractures result in vertebral height loss and alter sagittal spinal alignment, which in turn can lead to increased morbidity and mortality. Acute osteoporotic vertebral compression fractures are known to increase mobility and instability of the spine. There are limited published data correlating the degree of dynamic mobility and the efficacy of kyphoplasty on vertebral compression fractures. Here we report a 73-year-old female with a severe acute osteoporotic L2 compression fracture who obtained total vertebral height restoration following kyphoplasty, with resolution of back pain. PMID- 22220248 TI - Intraarticular pulsed mode radiofrequency lesioning of glenohumeral joint in chronic shoulder pain: 3 cases. PMID- 22220249 TI - Similarities and differences between therapy-related and elderly acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a clonal disorder of the hematopoietic stem cell, typical of the elderly, with a median age of over 60 years at diagnosis. In AML, older age is one of the strongest independent adverse prognostic factor, associated with decreased complete response rate, worse disease-free and overall survival, with highest rates of treatment related mortality, resistant disease and relapse, compared to younger patients. Outcomes are compromised in older patients not only by increased comorbidities and susceptibility to toxicity from therapy, but it is now recognized that elderly AML has peculiar biologic characteristics with a negative impact on treatment response.In older individuals prolonged exposure to environmental carcinogens may be the basis for similarities to therapy-related myeloid malignancies (t-MN), which result from toxic effects of previous cytotoxic treatments on hematopoietic stem cells. Age is itself a risk factor for t-MN, which are more frequent in elderly patients, where also a shorter latency between treatment of primary tumor and t-MN has been reported. t MN following chemotherapy with alkylating agents and elderly AML frequently present MDS-related cytogenetic abnormalities, including complex or monosomal karyotype, and a myelodysplastic phase preceding the diagnosis of overt leukemia. Similarly, t-MN and elderly-AML share common molecular abnormalities, such as reduced frequency of NPM1, FLT3 and CEBPA mutations and increased MDR1 expression.Given the unfavorable prognosis of elderly and t-MN and the similar clinical and molecular aspects, this is a promising field for implementation of new treatment protocols including alternative biological drugs. PMID- 22220250 TI - Acute promyelocytic leukemia: an experience on 95 greek patients treated in the all-trans-retinoic Acid era. AB - Acute promyelocytic leukemia (APL) is highly curable with the combination of all transretinoic acid (ATRA) and anthracycline based chemotherapy, but the percentage of early deaths remains high. In the present study, we report the clinical, immunophenotypic, cytogenetic and molecular characteristics and outcome of APL patients diagnosed and treated in various Hospitals of Greece and Cyprus.We describe the data of ninety-five APL patients who were diagnosed during the last 15 years. Seven (7.4%) newly diagnosed APL patients died due to intracranial hemorrhage within 72 hours of presentation. All but two patients were induced with ATRA alone or ATRA plus chemotherapy. The early death rate was 14.9%. After induction all 80 evaluable patients achieved complete hematologic remission. The cumulative incidence of relapse was 18.3%. Eight of the ten relapsed patients were successfully salvaged, while both patients with molecularly resistant disease died during salvage treatment. Overall survival (OS) at 5 years was 78.4% and disease free survival (DFS) 73.6%. In multivariate analysis of OS age over 60 years, DIC at diagnosis and marginally major hemorrhage at presentation were identified as adverse prognostic factors. In the subgroup of patients with available data on FLT3 mutation status (49 out of 94), ITD positivity also remained as an independent prognostic factor in the final model of OS, together with major hemorrhage and marginally high Sanz score. We found a close correlation between the CD2 expression and the development of the differentiation syndrome (DS). In conclusion, the main problem in managing patients with APL is still the high early death rate. PMID- 22220251 TI - Epidemiology of Prothrombin G20210A Mutation in the Mediterranean Region. AB - There are many genetic and acquired risk factors that are known to cause venous thromboembolic disorders (VTE). One of these is the Prothrombin G20210A mutation, which has been identified in 1996. Prothrombin G20210A mutation causes higher levels of the clotting factor prothrombin in the blood of carriers, which creates a higher tendency towards blood clotting (hypercoagulability), and therefore the carriers become at higher risk of developing VTE. High prevalence of Prothrombin G20210A mutation was reported in Caucasian populations, but the prevalence was almost absent in non-Caucasians. That was most obvious in countries of South Europe and the Mediterranean region. This review article discusses Prothrombin G20210A mutation, how it causes VTE, the origin of the mutation, and its distribution worldwide with special concentration on the Mediterranean area. PMID- 22220252 TI - Prognostic Significance of NRAS Gene Mutations in Children with Acute Myelogenous Leukemia. AB - BACKGROUND: NRAS mutations are the most commonly detected molecular abnormalities in hematologic malignancies, especially in those of myeloid origin. OBJECTIVE: We aimed to determine the frequency of NRAS (NRAS(mutant)) mutation; and its prognostic significance in Egyptian children with acute myelogenous leukemia (AML). SUBJECT AND METHODS: Peripheral blood and bone marrow (BM) samples were taken from 39 de novo pediatric AML patients. Twenty subjects with matched age and sex were selected as a control group. Samples from patients and control were analyzed for Exons 1, 2 of NRAS gene using genomic PCR-SSCP method. RESULTS: NRAS mutations at the time of diagnosis was found in 6/39 (15.4%) AML cases. Patients with NRAS(mutant) had no significant improved clinical outcome than patients without mutation. Patients with NRAS(mutant) had similar complete remission (CR) rates compared with non-mutated patients (66.7% vs. 69.5%, P=0.43). Those in CR had a similar relapse rate regardless of the presence of NRAS(mutant) (RR 33.4% vs. 30.2%, P=0.26). However, an adverse prognosis for 3 year overall survival (OS) was associated with the presence of NRAS mutations. This adverse prognosis associated with NRAS mutations was also observed in terms of disease-free survival (DFS) (P=0.007). Univariate analysis showed that unfavorable prognostic factors for DFS were cytogenetic data (P = 0.005) and the NRAS gene mutation (P = 0.002). CONCLUSION: NRAS(mutant) did not contribute to increase the disease recurrence, however NRAS(mutant) was found to be a poor prognostic factor for children with AML. Further studies to confirm these findings are required because of the small number of patients with NRAS mutation. PMID- 22220253 TI - Treatment of acute promyelocytic leukemia with single-agent arsenic trioxide. AB - It is well recognized that arsenic trioxide (ATO) is an efficacious agent for the treatment of acute promyelocytic leukemia (APL). Use of single agent ATO in the treatment of APL leads to remissions which are durable in the majority. ATO is probably the most effective single agent in the treatment of APL and there have been very few reports of primary resistance. It has been used both as a single agent and in combination with other conventional drugs to treat APL. Use of ATO is the accepted standard of care in the management of relapsed APL, where it is often used effectively as a bridge to a stem cell transplant. However, its role in newly diagnosed APL remains controversial. ATO probably has multiple mechanisms of action. Better understanding of its mechanisms of action/s is likely to lead to more rationale use of this agent or its derivatives either alone or in combination with other drugs. There is limited data on the kinetics of leukemia clearance and normal haematopoietic recovery after the administration of single agent ATO for the treatment of APL, preliminary data suggests that it is likely to be different from conventional therapy. There have been a number of concerns of the potential short and long term toxicity of this agent. Most such concerns arise from the toxicity profile noted in people exposed to long term arsenic exposure in the environment. With the therapeutic doses and schedules of administration of ATO in the treatment of malignancies the overall toxicity profile has been favorable. In a resource constrained environments the use of a single agent ATO based regimen is a realistic and acceptable option to treat almost all patients. In the developed world it has the potential in combination with other agents to improve the clinical outcome with reduction of dose intensity of chemotherapy and remains an option for patients who would not tolerate conventional therapy. In this review we focus on the use of single agent ATO for the treatment of APL and summarize our experience and review the literature. PMID- 22220255 TI - Hepatitis C Virus Infection Among non-IDU HIV-Infected and Uninfected Men who Have Sex with Men. PMID- 22220254 TI - Quality of life assessment in multiple myeloma patients undergoing dose-reduced tandem autologous stem cell transplantation. AB - Few studies exist that consider health-related quality of life (HR-QoL) in patients with multiple myeloma (MM) undergoing tandem autologous stem cell transplantation (TASCT). Eighteen patients with advanced MM who underwent dose modified TASCT were enrolled in this study between March 2006 and March 2008. Patients <60 year old (10) received conditioning with melphalan 140 mg/m(2) and patients who were >=60 years (8) received 100 mg/m(2). The median age was 57.5 years (range 35-69). We conducted the European Organization of Research and Treatment of Cancer (EORTC) QLQ-C30 and the QLQ-MY24 questionnaires via interviews at presentation, after each ASCT and thereafter every 3 months for 24 months. Mean global health measure improved from 3.44 before transplant to 4.50 (1=very poor, 7=excellent) at the second and subsequent follow-up visits (P<0.001) and the mean global quality of life score improved from 3.61 to 4.71 (P<0.001). Pain symptoms were reduced (P=0.001), and physical functioning improved (P<0.001) throughout the period of post-transplant follow-up. Our study showed that dose-reduced TASCT is well tolerated with low toxicity albeit the transient reduction in QoL during both transplants. Post-transplant follow-up showed significant improvement in overall HR-QoL that reflects positively on the overall disease-outcome. Furthermore, a sole focus on patient-survival does not adequately provide indication regarding the tolerability and effectiveness of a proposed treatment on the patient's perceived quality of life. As clinicians, our primary concern should be toward patient-welfare as well as survival. Therefore, we should employ the tools of QoL in conjunction with overall survival in order to deliver the best possible patient outcomes. The EORTC-QLQ-MY24 is a practical tool in measuring QoL in myeloma patients. PMID- 22220256 TI - The differentiation syndrome in patients with acute promyelocytic leukemia: experience of the pethema group and review of the literature. AB - Differentiation syndrome (DS), formerly known as retinoic acid syndrome, is the main life-threatening complication of therapy with differentiating agents (all trans retinoic acid [ATRA] or arsenic trioxide [ATO]) in patients with acute promyelocytic leukemia (APL). The differentiation of leukemic blasts and promyelocytes induced by ATRA and/or ATO may lead to cellular migration, endothelial activation, and release of interleukins and vascular factors responsible of tissue damage. Roughly one quarter of patients with APL undergoing induction therapy will develop the DS, characterized by unexplained fever, acute respiratory distress with interstitial pulmonary infiltrates, and/or a vascular capillary leak syndrome leading to acute renal failure. Although the development of the DS, particularly of the severe form, is still associated with a significant increase in morbidity and mortality during induction, the early administration of high-dose dexamethasone at the onset of the first symptoms seems likely to have dramatically reduced the mortality rate of this complication. In this article, we will review the clinical features, incidence, prognostic factors, management, and outcome of the DS reported in the scientific literature. We will make focus in the experience of the three consecutive Programa Espanol de Tratamientos en Hematologia trials (PETHEMA LPA96, LPA99, and LPA2005), in which more than one thousand patients were treated with ATRA plus idarubicin for induction. PMID- 22220257 TI - Clinical features and treatment outcome of acute promyelocytic leukemia patients treated at cairo national cancer institute in egypt. AB - The current study reports the clinical features and treatment outcome of 67 patients with acute promyelocytic leukemia (APL) treated at National Cancer Institute (NCI-Cairo), in Egypt from January 2007 to January 2011. The median age at presentation was 29 years. Bleeding was the most common presenting symptom (79%). Most patients had an intermediate risk Sanz score (49%) and 34% had a high risk score. The median follow-up time was 36 months. All evaluable patients were treated for induction with the simultaneous administration of all-trans retinoic acid (ATRA) and an anthracycline. The original AIDA treatment protocol was modified due to resource limitations at the NCI-Cairo by replacing of idarubicin with daunorubicin or doxorubicin in most of the cases and the inclusion of cytarabine during the consolidation phase only in pediatric patients. All patients who achieved molecular complete remission after consolidation received two-year maintenance treatment with low dose chemotherapy composed of 6 mercaptopurine, methotrexate and intermittent ATRA courses. Five patients died before treatment initiation due to bleeding, three died during induction chemotherapy due to infectious complications (n=2) and bleeding (n=1) and one patient died during consolidation therapy due to infection. The main therapeutic complications during the induction phase were febrile neutropenia (42%), bleeding (18%) and differentiation syndrome (11%). All patients achieved molecular CR at end of consolidation therapy at a median time of 100 days. The 3-year OS was 89%. Two patients relapsed at 13 and 24 months, respectively. Adapting standard AIDA treatment protocols to limited resources by reducing dose-intensity during consolidation, using ATRA in the consolidation phase and alternative anthracyclin (doxorubicin) may be a valid treatment option for APL in developing countries. In spite of the increased incidence of high and intermediate risk disease in our cohort, we reported an acceptable CR rate, toxicity and OS. PMID- 22220258 TI - Pseudo differentiation syndrome. PMID- 22220259 TI - Prevention of post-transfusion hepatitis by screening of antibody to hepatitis B core antigen in healthy blood donors. AB - BACKGROUND: Transfusion-associated hepatitis B viral infection continues to be a major problem in India even after adoption of mandatory screening for HBsAg by ELISA method. The high incidence of TAHBV is reported in patients receiving multiple transfusions. OBJECTIVE: To study the seroprevalence of hepatitis B core antibody among healthy voluntary blood donors SUBJECTS AND METHODS: The study was conducted in the department of Transfusion Medicine of a tertiary care referral hospital. A total of 12,232 volunteers after passing through the stringent criteria were selected for blood donation. Donor samples were tested for all mandatory transfusion transmissible infections and anti HBc IgM (Monolisa HBc IgM PLUS:BIO-RAD, France). Reactive results were confirmed by repeat testing in duplicate. Donor data was analyzed using SPSS software and Chi-square test was used to calculate the significance of difference between the groups. RESULTS: A total of 12,232 healthy voluntary blood donors were recruited. Majority (93.4%) were males. Median age of donor population was 26 years (range: 18-60 years). Eighty six (0.7%) were positive for HBsAg, which comes under "low prevalence (<2%) zone" as per WHO. On screening for HBcAg Ig M, 15 (0.1%) were found to be positive and none were HBsAg reactive. There was no significance of difference in the mean age between reactive and non-reactive donors. CONCLUSION: Evaluating the usefulness of anti-HBc screening is critical. Anti HBcAg IgM screening may be included in routine screening of donors as it is an indicator of occult HBV during window period. The cost and the unnecessary wastage of the blood units when they are positive for anti HBsAg along with the core antibody need to be studied. PMID- 22220260 TI - Causes of adult splanchnic vein thrombosis in the mediterranean area. AB - The term splanchnic vein thrombosis encompasses Budd-Chiari syndrome (BCS), extrahepatic portal vein obstruction (EHPVO), and mesenteric vein thrombosis.Risk factors can be local or systemic. A local precipitating factor is rare in BCS, while it is common in patients with portal vein thrombosis. Chronic myeloproliferative neoplasms (MPN) are the leading systemic cause of splanchnic vein thrombosis, and are diagnosed in half BCS patients and one-third of EHPVO patients; the somatic mutation JAK2 V617F is detectable in a large majority of patients with overt MPN, and up to 40% of patients without overt MPN. Inherited thrombophilia is present in at least one-third of patients, and the factor V Leiden or the prothrombin G20210A mutations are the most common mutations found in BCS or EHPVO patients, respectively. Multiple factors are present in approximately one-third of patients with BCS and two- thirds of patients with portal vein thrombosis.In a few patient series from the Southern Mediterranean area the high prevalence of MPN and thrombophilia as underlying cause of BCS is confirmed, although the data should be considered preliminary. Peculiar risk factors present in the area are Behcet's disease and hydatidosis; moreover, membraneous webs, typically found in Asian patients, are present in a significant portion of cases. PMID- 22220261 TI - Newly diagnosed acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) represents a medical emergency with a high rate of early mortality. As a consequence, as soon as the diagnosis is suspected based upon cytologic criteria, it is necessary to start all- trans retinoic acid (ATRA) treatment without delay. For patients with newly diagnosed APL, induction therapy with ATRA plus anthracycline based chemotherapy is recommended. At present the combination of arsenic trioxide plus ATRA should be considered for patients who are not candidates for anthracycline-based therapy. For pediatric and adult patients with APL aged < 60 years who achieve a CR with induction, I recommend 3 intensive courses of consolidation chemotherapy associated to ATRA, targeted on the basis of the risk group at diagnosis. In patients treated with a very intensive consolidation chemotherapy maintenance treatment can be omitted. However If a maintenance treatment has to be adopted I suggest the use of intermittent ATRA for 15 days every 3 months for a period of 2 years, rather than ATRA associated to chemotherapy. Moreover, taking into account the medical literature, a reduced dosage of ATRA ( 25 mg/m(2)) in pediatric patients and a consolidation chemotherapy of reduced intensity in elderly patients is recommended. Furthermore, in order to maximize survival, careful attention should be reserved to the coagulopathy and to the appearance of the differentiation syndrome. Finally, PCR for the PML/RARA fusion gene on a bone marrow specimen every three months for two years, and then every six months for additional three years are needed during the follow-up. PMID- 22220262 TI - Therapy-related myeloid neoplasm in non-hodgkin lymphoma survivors. AB - Relatively little data on secondary cancers is available regarding patients treated for non-Hodgkin lymphoma (NHL), compared with those treated for Hodgkin lymphoma. Evolving treatment regimens have improved survival outcomes for NHL patients. As a result of this improvement, secondary malignancies are becoming an important issue in NHL survivors. This review aims to report data on this topic previously published by our group, adding unpublished results from the Modena Cancer Registry (MCR). We recently performed four studies about secondary neoplasms in NHL survivors: two studies analysing the risk of secondary neoplasms in patients treated for indolent and aggressive NHL; a meta-analysis of 23 studies investigating the risk of secondary malignant neoplasm (SMN) after NHL treatment; and a still-unpublished study evaluating the incidence of therapy related myeloid neoplasm (t-MN) in patients treated for NHL (from the MCR database). The first two studies analysed 563 patients with indolent NHL and 1280 patients with diffuse large B-cell lymphoma (DLBCL) enrolled in the Gruppo Italiano Studio Linfomi (GISL) trials. Results showed that the cumulative incidence of secondary tumours was 10.5% at 12 years for indolent NHL and 8.2% at 15 years for DLBCL. Results of the meta-analysis indicated that NHL patients experienced a 1.88-fold increased risk for SMN compared with the general population; the standardized incidence risk (SIR) for secondary acute myeloid leukaemia (AML) was 11.07. Based on data from the MCR from 2000 through 2008, we found that the SIR was 1.63 for developing a secondary malignancy after NHL, and 1.99 for developing secondary haematological malignancies. Regarding myelodysplastic syndrome and/or AML incidence, nine NHL patients developed t-MN with a higher risk than expected (SIR 8.8, 95% CI: 4.0-16.6). In conclusion, patients treated for NHL are at increased risk of developing SMN. Regarding t-MN, data from the meta-analysis and the MCR demonstrate an excessive risk of developing AML (SIR 11.07 and 5.7, respectively) compared with solid SMN after treatment for NHL. Thus long-term monitoring should be considered for NHL survivors. PMID- 22220263 TI - Extramedullary disease in acute promyelocytic leukemia: two-in-one disease. AB - In acute promyelocytic leukemia (APL), extramedullary disease (EMD) is particularly rare and shows special clinical and biological features. It is estimated that about 3-5% of APL patients will suffer extramedullary relapse. The most common site of EMD in APL is the central nervous system (CNS). At present, there are still many issues of EMD in APL needing further clarification, including pathogenesis, risk factors, prognosis and treatment. A better understanding of the biological mechanisms underlying EMD is important to be able to devise more effective CNS prophylaxis and induction-consolidation therapeutic strategies. PMID- 22220264 TI - History of acute promyelocytic leukemia: a tale of endless revolution. PMID- 22220266 TI - Incidence of acute myeloid leukemia after breast cancer. AB - Breast cancer is the most frequent cancer among women and the leading cause of death among middle-aged women. Early detection by mammography screening and improvement of therapeutic options have increased breast cancer survival rates, with the consequence that late side effects of cancer treatment become increasingly important. In particular, patients treated with adjuvant chemotherapy regimens, commonly including alkylating agents and anthracyclines, are at increased risk of developing leukemia, further enhanced by the use of radiotherapy. In the last few years also the use of growth factors seems to increase the risk of secondary leukemia. The purpose of this review is to update epidemiology of therapy-related myeloid neoplasms occurring in breast cancer patients. PMID- 22220265 TI - Pathogenesis and treatment of thrombohemorrhagic diathesis in acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) is a distinct subtype of myeloid leukemia characterized by t(15;17) chromosomal translocation, which involves the retinoic acid receptor-alpha (RAR-alpha). APL typically presents with a life-threatening hemorrhagic diathesis. Before the introduction of all-trans retinoic acid (ATRA) for the cure of APL, fatal hemorrhages due, at least in part, to the APL associated coagulopathy, were a major cause of induction remission failure. The laboratory abnormalities of blood coagulation found in these patients indicate the occurrence of a hypercoagulable state. Major determinants of the coagulopathy of APL are endogenous factors expressed by the leukemic cells, including procoagulant factors, fibrinolytic proteins, and non-specific proteolytic enzymes. In addition, these cells have an increased capacity to adhere to the vascular endothelium, and to secrete inflammatory cytokines [i.e. interleukin 1beta (IL-1beta) and tumor necrosis factor (TNF-alpha)], which in turn stimulate the expression of prothrombotic activities by endothelial cells and leukocytes. ATRA can interfere with each of the principal hemostatic properties of the leukemic cell, thus reducing the APL cell procoagulant potential, in parallel to the induction of cellular differentiation. This effect occurs in vivo, in the bone marrow of APL patients receiving ATRA, and is associated with the improvement of the bleeding symptoms. Therapy with arsenic trioxide (ATO) also beneficially affects coagulation in APL. However, early deaths from bleeding still remain a major problem in APL and further research is required in this field. In this review, we will summarize our current knowledge of the pathogenesis of the APL-associated coagulopathy and will overview the therapeutic approaches for the management of this complication. PMID- 22220267 TI - Induction of protective genes leads to islet survival and function. AB - Islet transplantation is the most valid approach to the treatment of type 1 diabetes. However, the function of transplanted islets is often compromised since a large number of beta cells undergo apoptosis induced by stress and the immune rejection response elicited by the recipient after transplantation. Conventional treatment for islet transplantation is to administer immunosuppressive drugs to the recipient to suppress the immune rejection response mounted against transplanted islets. Induction of protective genes in the recipient (e.g., heme oxygenase-1 (HO-1), A20/tumor necrosis factor alpha inducible protein3 (tnfaip3), biliverdin reductase (BVR), Bcl2, and others) or administration of one or more of the products of HO-1 to the donor, the islets themselves, and/or the recipient offers an alternative or synergistic approach to improve islet graft survival and function. In this perspective, we summarize studies describing the protective effects of these genes on islet survival and function in rodent allogeneic and xenogeneic transplantation models and the prevention of onset of diabetes, with emphasis on HO-1, A20, and BVR. Such approaches are also appealing to islet autotransplantation in patients with chronic pancreatitis after total pancreatectomy, a procedure that currently only leads to 1/3 of transplanted patients being diabetes-free. PMID- 22220268 TI - Attempted depletion of passenger leukocytes by irradiation in pigs. AB - Allograft/xenograft rejection is associated with "passenger leukocyte" migration from the organ into recipient lymph nodes. In Study 1, we attempted to deplete leukocytes from potential kidney "donor" pigs, using two regimens of total body irradiation. A dose of 700 cGy was administered, followed by either 800 cGy ("low dose") or 1,300 cGy ("high dose") with the kidneys shielded. Neither regimen was entirely successful in depleting all leukocytes, although remaining T and 8 cell numbers were negligible. Study 2 was aimed at providing an indication of whether near-complete depletion of leukocytes had any major impact on kidney allograft survival. In non-immunosuppressed recipient pigs, survival of a kidney from a donor that received high-dose irradiation was compared with that of a kidney taken from a non-irradiated donor. Kidney graft survival was 9 and 7 days, respectively, suggesting that depletion had little impact on graft survival. The lack of effect may have been related to (i) inadequate depletion of passenger leukocytes, thus not preventing a direct T cell response, (ii) the presence of dead or dying leukocytes (antigens), thus not preventing an indirect T cell response, or (iii) constitutive expression of MHC class II and B7 molecules on the porcine vascular endothelium, activating recipient T cells. PMID- 22220271 TI - Update on exercise and weight control. PMID- 22220270 TI - Obesity and Cancer Screening according to Race and Gender. AB - The relationship between obesity and cancer screening varies by screening test, race, and gender. Most studies on cervical cancer screening found a negative association between increasing weight and screening, and this negative association was most consistent in white women. Recent literature on mammography reports no association with weight. However, some studies show a negative association in white, but not black, women. In contrast, obese/overweight men reported higher rates of prostate-specific antigen (PSA) testing. Comparison of prostate cancer screening, mammography, and Pap smears implies a gender difference in the relationship between screening behavior and weight. In colorectal cancer (CRC) screening, the relationship between weight and screening in men is inconsistent, while there is a trend towards lower CRC screening in higher weight women. PMID- 22220269 TI - Development of Anti-VEGF Therapies for Intraocular Use: A Guide for Clinicians. AB - Angiogenesis is the process by which new blood vessels form from existing vessel networks. In the past three decades, significant progress has been made in our understanding of angiogenesis; progress driven in large part by the increasing realization that blood vessel growth can promote or facilitate disease. By the early 1990s, it had become clear that the recently discovered "vascular endothelial growth factor" (VEGF) was a powerful mediator of angiogenesis. As a result, several groups targeted this molecule as a potential mediator of retinal ischemia-induced neovascularization in disorders such as diabetic retinopathy and retinal vein occlusion. Around this time, it also became clear that increased intraocular VEGF production was not limited to ischemic retinal diseases but was also a feature of choroidal vascular diseases such as neovascular age-related macular degeneration (AMD). Thus, a new therapeutic era emerged, utilizing VEGF blockade for the management of chorioretinal diseases characterized by vascular hyperpermeability and/or neovascularization. In this review, we provide a guide for clinicians on the development of anti-VEGF therapies for intraocular use. PMID- 22220272 TI - Cigarette Smoking and Alcohol Use among Adolescents and Young Adults with Asthma. AB - Asthma is one of the most common, serious chronic diseases in pediatric and young adult populations. Health-risk behaviors, including cigarette smoking and alcohol use, may exacerbate chronic diseases and complicate their management. The aim of this study was to longitudinally analyze rates of cigarette smoking and alcohol use in adolescents and young adults who have asthma and those who do not have asthma. A secondary analysis of data from the National Longitudinal Study of Adolescent Health was undertaken. Individuals with asthma were found to exhibit increasing rates of cigarette smoking and alcohol use as they aged. When an adolescent with a chronic health issue begins health-risk-taking behaviors, behavior change interventions must be planned. Pediatric nurses, practitioners, and clinicians are uniquely positioned to assess for health-risk behaviors in youth with asthma and to intervene with plans of care that are tailored for the needs of this vulnerable population. PMID- 22220273 TI - Advanced practice nursing education: challenges and strategies. AB - Nursing education programs may face significant difficulty as they struggle to prepare sufficient numbers of advanced practice registered nurses to fulfill the vision of helping to design an improved US healthcare system as described in the Institute of Medicine's "Future of nursing" report. This paper describes specific challenges and provides strategies to improve advanced practice nursing clinical education in order to ensure that a sufficient number of APRNs are available to work in educational, practice, and research settings. Best practices are identified through a review of classic and current nursing literature. Strategies include intensive interprofessional collaborations and radical curriculum revisions such as increased use of simulation and domestic and international service work. Nurse educators must work with all stakeholders to create effective and lasting change. PMID- 22220274 TI - Glutamate Transporter GLT-1 Upregulation Attenuates Visceral Nociception and Hyperalgesia via Spinal Mechanisms Not Related to Anti-Inflammatory or Probiotic Effects. AB - Visceral pain is the most common reason for physician visits in US. Glutamate is the major excitatory neurotransmitter and mediates visceral nociceptive neuro transmission and hypersensitivity. Removal of extracellular glutamate is predominantly mediated by glial glutamate transporter-1 (GLT-1). The pharmacological approach to up-regulate GLT-1 by 1 week administration of ceftriaxone (CTX) has been successful to mitigate visceral nociception. The present study shows that intrathecal delivery of selective GLT-1 antagonist dihydrokainate reversed CTX-blunted visceral nociceptive response, suggesting a spinal site of action. The role of GLT-1 up-regulation in animal models of colitis was studied. CTX treatment reversed TNBS-induced visceral hypersensitivity. In addition, CTX treatment initiated one week after the onset of DSS-induced visceral inflammation also attenuated visceral hypersensitivity, revealing a potential therapeutic effect. Cephalothin, a cephalosporin antibiotic lacking GLT-1 induction activity, failed to attenuate visceral nociception. CTX induced changes in fecal microbiota do not support a role of probiotic effects in mitigating visceral nociception/hypersensitivity. Finally, adeno-associated virus serotype 9-mediated GLT-1 over-expression was effective to mitigate visceromotor response to 60 mmHg colo-rectal distension. These studies indicate that GLT-1 over-expression is a novel and effective method to attenuate visceral nociception, and is deserving of further study as a translationally relevant approach to treat visceral pain. PMID- 22220275 TI - Advances in drug design of radiometal-based imaging agents for bone disorders. AB - Nuclear medicine bone imaging has been the optimum diagnosis for the detection of bone disorders because the lesion could be detectable before the appearance of symptomatic and radiographic changes. Over the past three decades, (99m)Tc-MDP and (99m)Tc-HMDP have been used as bone scintigraphic agents because of their superior biodistribution characteristics, although they are far from optimal from a chemical and pharmaceutical point of view. Recently, a more logical drug design has been proposed as a concept of bifunctional radiopharmaceuticals in which the carrier molecules (bisphosphonates) and radiometal chelating groups are separated within a molecule, specifically, (99m)Tc-mononuclear complex-conjugated bisphosphonate. Some of the (99m)Tc-mononuclear complex-conjugated bisphosphonate compounds showed superior biodistribution in preclinical studies. Moreover, the drug design concept could be applied to (68)Ga PET bone imaging agents. These studies would provide useful information for the development of radiometal-based imaging and therapeutic agents for bone disorders such as bone metastases. PMID- 22220276 TI - Redox Regulation of Nonmuscle Myosin Heavy Chain during Integrin Engagement. AB - On the basis of our findings reporting that cell adhesion induces the generation of reactive oxygen species (ROS) after integrin engagement, we were interested in identifying redox-regulated proteins during this process. Mass spectrometry analysis led us to identify nonmuscle myosin heavy chain (nmMHC) as a target of ROS. Our results show that, while nmMHC is reduced in detached/rounded cells, it turns towards an oxidized state in adherent/spread cells due to the integrin engaged ROS machinery. The functional role of nmMHC redox regulation is suggested by the redox sensitivity of its association with actin, suggesting a role of nmMHC oxidation in cytoskeleton movement. Analysis of muscle MHC (mMHC) redox state during muscle differentiation, a process linked to a great and stable decrease of ROS content, shows that the protein does not undergo a redox control. Hence, we propose that the redox regulation of MHC in nonprofessional muscle cells is mandatory for actin binding during dynamic cytoskeleton rearrangement, but it is dispensable for static and highly organized cytoskeletal contractile architecture in differentiating myotubes. PMID- 22220277 TI - Negotiating the joint career: couples adapting to Alzheimer's and aging in place. AB - To understand the impact of memory loss on aging in place, this paper investigated dyads where one spouse had been diagnosed with memory loss. In-depth qualitative interviews were conducted with ten couples (N = 20). Grounded theory methods were used to collect, code, and analyze data into themes. Data revealed consensus among and between dyads that it was best to focus on living, rather than what had been or might someday be lost. Nonetheless, differences according to gender and cognitive status (e.g., diagnosed or spouse) were reported. Given population aging, identifying the impact of gender roles and social norms on the potential for aging in place with memory loss is critical. Community services and care practices must be sensitive to the ways that couples prioritized and organized their relationship prior to diagnosis in order to encourage positive patterns of care between couples, foster successful adaptation to changing needs, and support in-home arrangements as long as possible. PMID- 22220278 TI - Validation of the danish version of functional assessment of multiple sclerosis: a quality of life instrument. AB - The functional assessment of multiple sclerosis (FAMS) is a disease-specific instrument that describes functional status of individuals with multiple sclerosis. The instrument was originally developed in the US and has been adapted to different languages including Danish. This study is a validation of the Danish version of FAMS in a sample of individuals referred to a four-week rehabilitation program at either of the two Multiple Sclerosis Rehabilitation centers in Denmark. FAMS data were obtained through self-completed questionnaires from 190 individuals who attended the rehabilitation centers after referral by their general practitioner or specialist neurologist. The validation of the FAMS included assessment of data quality, scale assumptions, acceptability, construct validity, and reliability. Responsiveness was assessed by comparing individual FAMS scores at admission with the discharge score for groups of respondents who reported no change, improvement, or deterioration in their ability to cope with their illness. The Danish version of FAMS appears to be an acceptable, valid, and reliable measure of current health and functional status of individuals with multiple sclerosis. PMID- 22220279 TI - Peripheral arterial disease in patients presenting with acute coronary syndrome in six middle eastern countries. AB - To describe prevalence and impact of peripheral arterial disease (PAD) in patients with acute coronary syndrome (ACS), data were collected over 5 months from 6 Middle Eastern countries. Patients were divided into 2 groups (with and without PAD). Out of 6705 consecutive ACS patients, PAD was reported in 177 patients. In comparison to non-PAD, PAD patients were older and more likely to have cardiovascular risk factors. They were more likely to have high Killip class, high GRACE risk score, and non-ST elevation ACS (NSTEACS) at presentation. Thrombolytics, antiplatelet use, and coronary intervention were comparable in both groups. When presented with ST-elevation myocardial infarction (STEMI), patients with PAD had worse outcomes, while in NSTEACS; PAD was associated with higher rate of heart failure in comparison to non-PAD patients. In diabetics, PAD was associated with 2-fold increase in mortality when compared to non-PAD (P = 0.028). After adjustment, PAD was associated with high mortality in STEMI (adjusted OR 2.6; 95% CI 1.23-5.65, P = 0.01). Prevalence of PAD in ACS in the Gulf region is low. Patients with PAD and ACS constitute a high risk group and require more attention. PAD in patients with STEMI is an independent predictor of in-hospital death. PMID- 22220280 TI - The evolving paradigm in the management of intracranial atherosclerotic disease. AB - Intracranial atherosclerotic disease (ICAD) is a major cause of ischemic stroke worldwide and represents a significant health problem. The pathogenesis and natural history of ICAD are poorly understood, and rigorous treatment paradigms do not exist as they do for extracranial atherosclerosis. Currently, the best treatment for ICAD remains aspirin therapy, but many patients who are placed on aspirin continue to experience recurrent strokes. As microsurgical and endovascular techniques continue to evolve, the role of extracranial to intracranial bypass operations and stenting are increasingly being reconsidered. We performed a PubMed review of the English literature with a particular focus on treatment options for ICAD and present evidence-based data for the role of surgery and stenting in ICAD against medical therapy alone. PMID- 22220282 TI - Management of melanoma brain metastases in the era of targeted therapy. AB - Disseminated metastatic disease, including brain metastases, is commonly encountered in malignant melanoma. The classical treatment approach for melanoma brain metastases has been neurosurgical resection followed by whole brain radiotherapy. Traditionally, if lesions were either too numerous or surgical intervention would cause substantial neurologic deficits, patients were either treated with whole brain radiotherapy or referred to hospice and supportive care. Chemotherapy has not proven effective in treating brain metastases. Improvements in surgery, radiosurgery, and new drug discoveries have provided a wider range of treatment options. Additionally, recently discovered mutations in the melanoma genome have led to the development of "targeted therapy." These vastly improved options are resulting in novel treatment paradigms for approaching melanoma brain metastases in patients with and without systemic metastatic disease. It is therefore likely that improved survival can currently be achieved in at least a subset of melanoma patients with brain metastases. PMID- 22220281 TI - Adjuvant therapy: melanoma. AB - With an incidence that is increasing at 2-5% per year, cutaneous melanoma is an international scourge that disproportionately targets young individuals. Despite much research, the treatment of advanced disease is still quite challenging. Immunotherapy with high-dose interferon-alpha2b or interleukin-2 benefits a select group of patients in the adjuvant and metastatic settings, respectively, with significant attendant toxicity. Advances in the biology of malignant melanoma and the role of immunomodulatory therapy have produced advances that have stunned the field. In this paper, we review the data for the use of interferon-alpha2b in various dosing ranges, vaccine therapy, and the role of radiotherapy in the adjuvant setting for malignant melanoma. Recent trials in the metastatic setting using anticytoxic T-lymphocyte antigen-4 (anti-CTLA-4) monoclonal antibody therapy and BRAF inhibitor therapy have demonstrated clear benefit with prolongation of survival. Trials investigating combinations of these novel agents with existing immunomodulators are at present underway. PMID- 22220283 TI - Lymph Node Staging with Choline PET/CT in Patients with Prostate Cancer: A Review. AB - Due to its prevalence, prostate cancer represents a serious health problem. The treatment, when required, may be local in case of limited disease, locoregional if lymph nodes are involved, and systemic when distant metastases are present. In order to choose the best treatment regimen, an accurate disease staging is mandatory. However, the accuracy of conventional imaging modalities in detecting lymph node and bone metastases is low. In the last decade, molecular imaging, particularly, choline PET-CT has been evaluated in this setting. Choline PET represents the more accurate exam to stage high-risk prostate cancer, and it is useful in staging patients with biochemical relapse, in particular when PSA kinetics is high and/or PSA levels are more than 2 pg/ml. The present paper reports results of available papers on these issues, with particular attention to lymph node staging. PMID- 22220284 TI - Biochemical bone turnover markers and osteoporosis in older men: where are we? AB - In men aged less than 60, the association of serum and urinary levels of biochemical bone turnover markers (BTMs) and bone mineral density (BMD) is weak or not significant. After this age, higher BTM levels are correlated weakly, but significantly, with lower BMD and faster bone loss. Limited data from the cohort studies suggest that BTM measurement does not improve the prediction of fragility fractures in older men in comparison with age, BMD, history of falls and fragility fractures. Testosterone replacement therapy (TRT) decreases bone resorption. During TRT, bone formation markers slightly increase (direct effect on osteoblasts), then decrease (slowdown of bone turnover). Bisphosphonates (alendronate, risedronate, ibandronate, zoledronate) induce a rapid decrease in bone resorption followed by a milder decrease in bone formation. In men receiving antiresorptive therapy for prostate cancer, zoledronate, denosumab and toremifene decrease significantly levels of bone resorption and bone formation markers. Teriparatide induced a rapid increase in serum concentrations of bone formation markers followed by an increase in bone resorption. We need more studies on the utility of BTM measurement for the improvement of the persistence and adherence to the anti-osteoporotic treatment in men. PMID- 22220286 TI - Communication impairments in Parkinson's disease. PMID- 22220287 TI - Animal models of Parkinson's disease. PMID- 22220285 TI - The Link between Thyroid Function and Depression. AB - The relation between thyroid function and depression has long been recognized. Patients with thyroid disorders are more prone to develop depressive symptoms and conversely depression may be accompanied by various subtle thyroid abnormalities. Traditionally, the most commonly documented abnormalities are elevated T4 levels, low T3, elevated rT3, a blunted TSH response to TRH, positive antithyroid antibodies, and elevated CSF TRH concentrations. In addition, thyroid hormone supplements appear to accelerate and enhance the clinical response to antidepressant drugs. However, the mechanisms underlying the interaction between thyroid function and depression remain to be further clarified. Recently, advances in biochemical, genetic, and neuroimaging fields have provided new insights into the thyroid-depression relationship. PMID- 22220288 TI - Effect of Deep Brain Stimulation on Parkinson's Nonmotor Symptoms following Unilateral DBS: A Pilot Study. AB - Parkinson's disease (PD) management has traditionally focused largely on motor symptoms. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) are effective treatments for motor symptoms. Nonmotor symptoms (NMSs) may also profoundly affect the quality of life. The purpose of this pilot study was to evaluate NMS changes pre- and post-DBS utilizing two recently developed questionnaires. Methods. NMS-Q (questionnaire) and NMS-S (scale) were administered to PD patients before/after unilateral DBS (STN/GPi targets). Results. Ten PD patients (9 STN implants, 1 GPi implant) were included. The three most frequent NMS symptoms identified utilizing NMS-Q in pre surgical patients were gastrointestinal (100%), sleep (100%), and urinary (90%). NMS sleep subscore significantly decreased (-1.6 points +/- 1.8, P = 0.03). The three most frequent NMS symptoms identified in pre-surgical patients using NMS-S were gastrointestinal (90%), mood (80%), and cardiovascular (80%). The largest mean decrease of NMS scores was seen in miscellaneous symptoms (pain, anosmia, weight change, and sweating) (-7 points +/- 8.7), and cardiovascular/falls (-1.9, P = 0.02). Conclusion. Non-motor symptoms improved on two separate questionnaires following unilateral DBS for PD. Future studies are needed to confirm these findings and determine their clinical significance as well as to examine the strengths/weaknesses of each questionnaire/scale. PMID- 22220289 TI - Behcet's Disease and Endocrine System. AB - Behcet's disease (BD) is a chronic disease which is characterized by recurrent oral apthous ulcerations, recurrent genital ulcerations, skin eruptions, ocular involvements and other various systemic manifestations as well as systemic vasculitis. Endocrine involvement in BD regarding various systems can be seen. Hypophysis is one of the best and dense vascularized organs of the body, thus it is likely that it can be affected by BD. Not only anterior hypophysis functions, but posterior hypophysis functions as well can be affected. As BD is a disease of autoimmune process, it may be possible that adrenal insufficiency or alterations in the cortisol levels could be expected. Another concern is whether or not there is insulin resistance in patients with BD. The avaliable data suggests that there is an increased susceptibility to insulin resistance in patients with BD. PMID- 22220290 TI - A 2012 health care wish list. PMID- 22220291 TI - Shoulder pain: 3 cases to test your diagnostic skills. PMID- 22220292 TI - Exercise-induced proteinuria? PMID- 22220293 TI - Genetic blood disorders: questions you need to ask. PMID- 22220294 TI - HPV vaccine is now routinely indicated for males. PMID- 22220295 TI - PURLs: combatting lice in a single treatment. PMID- 22220296 TI - Asymptomatic crusted lesions on the palms. PMID- 22220297 TI - Clinical inquiry: Does ultrasound screening for abdominal aortic aneurysm reduce mortality? PMID- 22220298 TI - Clinical inquiry: Does cervical membrane stripping in women with group B Streptococcus put the fetus at risk? PMID- 22220299 TI - Knee OA: which patients are unlikely to benefit from manual PT and exercise? AB - BACKGROUND: The combination of manual physical therapy and exercise provides important benefit for more than 80% of patients with knee osteoarthritis (OA). Our objective was to determine predictor variables for patients unlikely to respond to these interventions. METHODS: We used a retrospective combined cohort study design to develop a preliminary clinical prediction rule (CPR). To determine useful predictors of nonsuccess, we used an extensive set of 167 baseline variables. These variables were extracted from standardized examination forms used with 101 patients(64 women and 37 men with a mean age of 60.5}11.8 and 63.6}9.3 years, respectively) in 2 previously published clinical trials. We classified patients based on whether they achieved a clinically meaningful benefit of at least 12%improvement in Western Ontario MacMaster(WOMAC) scores after 4 weeks of treatment using the smallest and most efficient subset of predictors. RESULTS: The variables of patellofemoral pain, anterior cruciate ligament laxity, and height >1.71 m (5'7'') comprise the CPR. Patients with at least 2 positive tests yield eda posttest probability of 88% for nonsuccess with this treatment (positive likelihood ratio=36.7). The overall prognostic accuracy of the CPR was 96%. CONCLUSION: Most patients with knee OA will benefit from a low-risk, cost-effective program of manual physical therapy and supporting exercise.1,2 The few patients who may not benefit from such a program are identifiable by a simple (preliminary) CPR. After validation,this rule could improve primary patient management,allowing more appropriate referrals and choices in intervention. PMID- 22220300 TI - Hepatitis B immunization policies, HCV in prisoners and acrylamide. PMID- 22220301 TI - A range of areas in animal cognition. Susan Healy. PMID- 22220302 TI - Dearth of clinically useful diagnostics limits growth of personalized medicine. PMID- 22220304 TI - Retraction notice to "A role for the annexin A2 amino-terminal peptide in the plasmin-induced activation of human peripheral monocytes" [Mol. Immunol. 47 (14) (2010) 2405-2410]. PMID- 22220303 TI - Electric field dependent photocurrent generation in a thin-film organic photovoltaic device with a [70]fullerene-benzodifuranone dyad. AB - A [70]fullerene-benzodifuranone acceptor dyad synthesized by a Ag+-mediated coupling reaction was used to construct a thin-film organic solar cell. The fullerene and the benzodifuranone dye in the dyad have close-lying LUMO levels in the range of 3.7-3.9 eV, so that energy transfer from the dye to the fullerene can take place. A p-n heterojunction photovoltaic device consisting of a tetrabenzoporphyrin and a [70]fullerene-benzodifuranone dyad showed a weak but discernible contribution from light absorption of the dyad to the photocurrent under both a positive and a negative effective bias. These results indicate that the benzodifuranone moiety attached to the acceptor contributes to light harvesting by energy transfer. PMID- 22220305 TI - The high sex ratio in China: what do the Chinese think? AB - High sex ratios are well documented in many Asian countries, including China. This study was conducted in three Chinese provinces to explore awareness of the high sex ratios and its effects. Questionnaires were completed by 7435 respondents; 46% were urban and 53% were female. Sixty-four per cent were aware of the high sex ratio, and the majority were able to identify a range of consequences both for society and for unmarried men. These high levels of awareness of the negative impacts of high sex ratios should ultimately help to reduce the sex ratio at birth. PMID- 22220306 TI - Adverse drug reactions to osteoporosis treatments. AB - Treatments for postmenopausal osteoporosis are generally safe, but are linked to some rare serious adverse drug reactions, for which causality is not always certain. The bisphosphonates are associated with gastrointestinal effects, acute phase reactions, and musculoskeletal pain, and, more rarely, cases of atrial fibrillation, subtrochanteric fracture, osteonecrosis of the jaw, cutaneous hypersensitivity reactions and renal impairment. It is too soon for pharmacovigilance data on denosumab, but it has been associated with cutaneous effects and possibly osteonecrosis of the jaw (to date, only in metastatic cancer). The selective estrogen receptor modulators may induce hot flushes and leg cramps, and--more rarely--venous thromboembolism and stroke. Strontium ranelate is associated with headache, nausea and diarrhea, and, more rarely, cutaneous hypersensitivity reactions and venous thromboembolism, while teriparatide and parathyroid hormone(1-84) are associated with headache, nausea, dizziness and limb pain. The management of osteoporosis should entail weighing the probability of adverse reactions against the benefits of therapy--that is, reduction of fracture risk. PMID- 22220307 TI - Pharmacodynamics of bisphosphonates in arthritis. AB - Inflammatory arthritis is a group of autoimmune diseases characterized by chronic inflammation of the joints. Rheumatoid arthritis, the most common form of arthritis, is associated with local joint destruction and systemic bone loss. Osteoclasts, the only cells of the body able to resorbe bone, are key players in these two types of bone loss. Bisphosphonates are analogs of pyrophosphate that inhibit osteoclast action and bone resorption. They are indicated in pathology associated with excess resorption. Besides their effect on bone they also exhibit extra-osseous properties, acting on tumor cells, inflammation and angiogenesis. As a result, they have been trialed in the context of arthritis. It is now clear that they do not have any significant direct effect on disease activity or pain. If their indication in the prevention of glucocorticoid-induced osteoporosis is clear, any beneficial effects on bone erosions are still controversial but interesting preliminary results warrant further investigations. PMID- 22220309 TI - Job insecurity and staff anxiety putting standards of care at risk. PMID- 22220310 TI - Survival of the fittest. PMID- 22220308 TI - [X-linked adrenoleukodystrophy (X-ALD)]. PMID- 22220328 TI - Primary care networks: Alberta's primary care experiment is a success--now what? PMID- 22220329 TI - Re: Nurses think reporting patient safety events is just futile. PMID- 22220330 TI - [From Joan of Arc to Madeleine de Vercheres: the woman warrior in ancien regime society]. PMID- 22220331 TI - Proceedings of Liquid Chromatography-Isotope Ratio Mass Spectrometry Users Meeting, November 23-24, 2010, University of Oxford, UK. PMID- 22220332 TI - [Physical exercises and the curing of the mind during the 18th and 19th centuries]. PMID- 22220333 TI - Selected papers from the 31st Annual Conference on Peritoneal Dialysis, February 20-22, 2011, Phoenix, Arizona. PMID- 22220334 TI - [The institutional construction of Spanish biochemistry, 1945-70: the role of exchanges with Northern Europe and America]. PMID- 22220335 TI - [Abbe Gregoire's alleged colored sister-in-law: did a namesake cause the Club Massiac's blunder?]. PMID- 22220336 TI - [The Church in the town: processions in Limoges in the 19th century]. PMID- 22220337 TI - [Parisian Catholics and social action in the mid-19th century]. PMID- 22220339 TI - [The metamorphoses of organicism in ecology: from plant community to ecosystems]. PMID- 22220338 TI - [Urban elites and the horse-racing world in the city of Rio de Janeiro, 1848 1932]. PMID- 22220340 TI - [The virtues of "work": research on the feminization of the labor of needlework, 16th-18th centuries]. PMID- 22220341 TI - [The evolution of children's clothing in the 18th century: political and social concerns]. PMID- 22220342 TI - Caenorhabditis elegans: molecular genetics and development. PMID- 22220343 TI - "A la recherche d'un komsomol perdu": who really built Komsomol'sk-na-Amure, and why? PMID- 22220344 TI - [The search for new ways to interpret phenomena of nobility in modern France: nobility as "essence" or social relationship?]. PMID- 22220345 TI - [How many Jews in Tunisia and Libya, 1850-1970?]. PMID- 22220346 TI - [Isolation of V.vulnificus from the environment]. PMID- 22220347 TI - Independence at risk: older Californians with disabilities struggle to remain at home as public supports shrink. AB - This policy brief presents findings from a yearlong study that closely followed a small but typical set of older Californians with disabilities who depend on fragile arrangements of paid public programs and unpaid help to live safely and independently at home. Many of these older adults have physical and mental health needs that can rise or fall with little warning; most are struggling with increasing disability as they age. In spite of these challenges, most display resilience and fortitude, and all share a common determination to maintain their independence at almost any cost. Declines in health status and other personal circumstances among aging Californians have been exacerbated by recent reductions in public support, and will be made even worse by significant additional cuts that are pending. Policy recommendations include consolidating long-term care programs and enhancing support for caregivers. PMID- 22220348 TI - A novel bunyavirus causing fever and thrombocytopenia: more questions than answers. PMID- 22220349 TI - [Paradigm shift in drug design]. PMID- 22220350 TI - [Present condition in and future prospects of therapeutic strategy for acute lung injuries]. PMID- 22220351 TI - In praise of contamination. PMID- 22220352 TI - Nomothetics and idiography in developmental biology. AB - Successions of space-temporal structures arisen during development of multicellular organisms are the most regular, complex and reproducible ones among all taking place in the entire nature without a human's intervention. Therefore, the question whether it would be possible to embrace them by a common physicalistic law (nomothetic approach) or they can be only enumerated and described one after another (idiography) is of an overall importance for the natural sciences in general. We review several nomothetic attempts performed in XX century biology and suggest that such laws may have a structure of feedback contours between the active and passive mechanical stresses generated in developing embryos. We trace several steps towards creating such contours and show that they couple mechanics with geometry providing thus a progressive complication of embryonic structure. Then we discuss, in what way genome can influence these morphomechanical laws. We speculate that the main developmental function of genome is to set up the values of the parameters, introduced in these laws. We emphasize that these parameters values acquire a definite meaning only within the context of the laws into which they are introduced. PMID- 22220353 TI - Evolution is a cooperative process: the biodiversity-related niches differentiation theory (BNDT) can explain why. AB - A. McFayden and G.E. Hutchinson defined a niche as a multidimensional space or hypervolume within the environment that allows an individual or a species to survive, we consider niches as a fundamental ecological variable that regulate species' composition and relation in ecosystems. Successively the niche concept has been associated to the genetic term "phenotype" by MacArthurstressing the importance on what a species or a genome can show outside, either in the environmental functions or in body characteristics. Several indexes have been developed to evaluate the grade of overlapping and similarities of species' niches, even utilizing the theory of information. However, which are the factors that determine the number of species that can coexist in a determinate environment and why a generalist species do not compete until the exclusion of the remaining species to maximize its fitness, is still quite unknown. Moreover, there are few studies and theories that clearly explain why the number of niches is so variable through ecosystems and how can several species live in the same basal niche, intended in a comprehensive sense as the range of basic conditions (temperature, humidity, food-guild, etc.). Here I show that the number of niches in an ecosystem depends on the number of species present in a particular moment and that the species themselves allow the enhancement of niches in terms of space and number. I found that using a three-dimensional model as hypervolume and testing the theory on a Mediterranean, temperate and tropical forest ecosystem it is possible to demonstrate that each species plays a fundamental role in facilitating the colonization by other species by simply modifying the environment and exponentially increasing the available niches' space and number. I resumed these hypothesis, after some preliminary empiric tests, in the Biodiversity-related Niches Differentiation Theory (BNDT), stressing with these definition that the process of niches differentiation is strictly addressed by species. This approach has various consequences, first in consideration of relations among species and second in terms of a better understanding of cooperation/competition dynamics. PMID- 22220354 TI - Viruses: are they living entities? AB - The essence (living or nonliving entities) of viruses has today become an aporia, i.e. a difficulty inherent in reasoning because they shared four fundamental characteristics with livings (multiplication, genetic information, mutation and evolution) without having the capacity to have an independent life. For much time, however, they were considered minuscule pathogenetic micro-organisms in observance of Koch and Pasteur's 'germ theory' albeit no microbiologist could show their existence except their filterability and pathogenetic action. Only some voices based on experimental results raised against this dogmatic view, in particular those of Beijerinck, Baur and Mrowka, without dipping effectively into the dominant theory. The discovery relative to their nucleoprotein nature made between 1934 and 1936 (Schlesinger as for the phage, and Bawden and co-operators as for Tobacco mosaic virus; TMV), together with the first demonstrations of their structures thanks to electron microscopy (from 1939 onwards) started on casting a new light on their true identity, which could be more clearly identified when, from 1955 onwards, phage and TMV proved to be decisive factors to understand the strategies of replication of the genetic material. Following the new knowledge, the theoretical view relative to viruses changed rather radically and the current view looks on these pathogenetic agents as nonliving aggregates of macromolecules provided with biological properties. There is, however, a current of thought, made explicitly by Lwoff that places viruses as compromise between living and non living and, perhaps, as primitive forms of life which have had great importance for the evolution of cellular life. At any rate, viruses are peculiar entities whose importance cannot be unacknowledged. PMID- 22220355 TI - Revealing remote protein homology with sequence similarity and a modularity-based approach. AB - An important task in functional genomics is to cluster homologous proteins, which may share common functions. Annotating proteins of unknown function by transferring annotations from their homologues of known annotations is one of the most efficient ways to predict protein function. In this paper, we use a modularity-based method called CD for grouping together homologous proteins. The method employs a global heuristic search strategy to find the partitioning of the weighted adjacency graph with the largest modularity. The weighted adjacency graph is constructed by the sigmodal transformation of all pairwise sequence similarities between all protein sequences in a given dataset. The method has been extensively tested on several subsets from the superfamily level of the SCOP (Structural Classification of Proteins) database, where some homologous proteins have very low sequence similarity. Compared with a widely used method MCL, we observe that the number of clusters obtained by CD is closer to the number of superfamilies in the dataset, the value of the F-measure given by CD is 10% better than MCL on average, and CD is more tolerant to noise to the sequence similarity. The experiment results indicate that CD is ideally suitable for clustering homologous proteins when sequence similarity is low. PMID- 22220356 TI - The neurobiology of the human memory. AB - Memory can be defined as the ability to acquire, process, store, and retrieve information. Memory is indispensable for learning, adaptation, and survival of every living organism. In humans, the remembering process has acquired great flexibility and complexity, reaching close links with other mental functions, such as thinking and emotions. Changes in synaptic connectivity and interactions among multiple neural networks provide the neurobiological substrates for memory encoding, retention, and consolidation. Memory may be categorized as short-term and long-term memory (according to the storage temporal duration), as implicit and explicit memory (with respect to the consciousness of remembering), as declarative (knowing that [fact]) and procedural (knowing how [skill]) memory, or as sensory (echoic, iconic and haptil), semantic, and episodic memory (according to the various remembering domains). Significant advances have been obtained in understanding memory neurobiology, but much remains to be learned in its cognitive, psychological, and phenomenological aspects. PMID- 22220357 TI - The problem of antibiotic resistant bacteria. The important role of environmentally responsive mutagenesis, its relevance to a new paradigm that may allow a solution. AB - The frequent creation of antibiotic resistant bacteria through mutation poses a severe medical problem. As a way towards solving the problem, mutations conferring antibiotic sensitivity could be induced in such bacteria at very high frequency through the controlled process of environmentally responsive mutagenesis, an adaptively responsive mutator process. Such induction, as a necessary developmental stage towards global adaptation, would be enabled by patterns of mild stresses. The stresses and their patterns would be elucidated through in vitro experiments and clinical trials. The effective application of this ordered process, whose detection was allowed through a change in experimental design, requires a new and more comprehensive paradigm of mutagenesis than the one currently applied. This would be a new paradigm that has holistic and developmental features. Yet, the effective and ongoing emergence of such a paradigm will depend on experimental setups that will enable or provide, unlike previous experimental arrangements, new insights as to the developmental connections between innerly controlled mutagenesis and its environments. This should demonstrate controlled ways to generate and make manifest those genomic changes that, as developmental stages, give rise to antibiotic sensitivity in antibiotic resistant bacteria. The ultimate consequence of such a developed paradigm of mutagenesis may very well be a major and benign medical and biotechnical revolution. PMID- 22220358 TI - Band together to say 'no' to tick-box culture. PMID- 22220359 TI - Interview: how can we win the numbers game? Interview by Louise Hunt. PMID- 22220360 TI - Into the unknown. PMID- 22220361 TI - A framework to support practice teachers in the assessment process. AB - This paper describes a local initiative that aimed to resolve difficulties experienced by practice teachers in assessing the practice of students undertaking a BSc graduate diploma in community nursing. Practice teachers initially raised a concern that they were unable to make a holistic assessment of a student, as they had no criteria that enabled them to address issues relating to values, attitude and behaviour. Practice teachers and academic staff worked together over a period of time to update assessment practices, developing a Practice Assessment Grid (PAG). The PAG identifies a common language with which practice teachers can benchmark their own values, enabling them to justify their decisions. Evaluation to date indicates that the PAG enables practice teachers to break down the intuitive aspect of the assessment process relating to behaviour, so that they can objectively identify component attributes that are essential to becoming a professional and complete a holistic assessment of the student. As such, this grid has improved confidence in the process of assessing practice by addressing a potentially subjective aspect of assessment. PMID- 22220362 TI - A review of postnatal debriefing of mothers following traumatic delivery. AB - This paper reviews the literature on the effectiveness of the debriefing of mothers after giving birth and considers the recommendations in relation to health visiting practice. Studies suggest a correlation between negative birth experiences and depression in women and a small percentage of women meet the criteria for post-traumatic stress disorder (PTSD). Studies on debriefing were examined, some of which suggested that midwife-led debriefing after an operative birth was ineffective in reducing maternal morbidity and the possibility of contributing to emotional health problems could not be excluded. Significant influencing factors were the timing and construction of the debriefing that was carried out. Guidance was found to give clear recommendations for maternity staff and other health professionals to support women who wish to talk about their experiences, but that no formal debriefing should be routinely offered to women who have experienced a traumatic birth. The author considered that the term debriefing may not be the correct term for health visitors listening to mothers' birth experiences, and that further research from a health visiting perspective would be beneficial. PMID- 22220363 TI - Post-traumatic stress disorder in children and adolescents. AB - Post-traumatic stress disorder (PTSD) is a syndrome defined by the intrusive re experiencing of trauma, avoidance of reminders of the trauma and increased hyperarousal. Although the condition is well established in adults, there is little research into PTSD in children and adolescents. The available research shows that young people experience similar symptoms to adults. Risk factors include family dysfunction, peer problems, greater exposure to the trauma and the presence of pre-existing psychiatric disorder such as anxiety. Protective factors include good coping skills, good relationship with a parent and support from others in the community. This article reviews treatment approaches to PTSD in young people in particular the use of cognitive behavioural therapy (CBT). PMID- 22220364 TI - View from the jungle. PMID- 22220365 TI - Different cultures, different needs. PMID- 22220366 TI - What to wear? PMID- 22220367 TI - High stakes. PMID- 22220368 TI - The influence of restorations and prosthetic crowns finishing lines on inflammatory levels after non-surgical periodontal therapy. AB - OBJECTIVE: The aim of the present study was to evaluate the inflammatory response in sites where crowns were placed supragingivally, at the level of the gingival margin and subgingivally. These were measured clinically and through the levels of interleukin-1 3 and matrix metalloproteinase-2, inflammatory mediators, before and after periodontal therapy. METHODS: From 68 patients analyzed, 10 were selected for this study. The gingival crevicular fluid of the patients was collected and analyzed using standard enzyme-linked immunosorbent assay (ELISA). The clinical parameters were measured and correlated with interleukin-1beta and matrix metalloproteinase-2. Both analyses were realized before (baseline) and 2 months after non-surgical periodontal therapy. The two-way variance analysis (two way ANOVA), Tukey-Kramer multiple comparisons test (post hoc) and Pearson parametric correlation test were performed in statistical analysis. RESULTS: There were statistically significant differences before and after nonsurgical periodontal therapy when comparing supra- and subgingival margins for the plaque and bleeding indexes (p < 0.05). There was a tendency toward correlation between the reduction of plaque index and the reduction of interleukin-1beta levels, both for supragingival (r = 0.694, p = 0.026) and subgingival margins (r = 0.715, p = 0.020) post non-surgical periodontal therapy. The levels of matrix metalloproteinase-2 were not detectable by ELISA because they were below the detection threshold of the assay. CONCLUSION: Supragingival restorations appeared to be more adequate in promoting periodontal health when compared with the other possible marginal finish lines. They also presented a better response to basic periodontal treatment, according to clinical and inflammatory findings. PMID- 22220369 TI - Root proximity characteristics and type of alveolar bone loss: a case-control study. AB - OBJECTIVE: This study assessed root proximity (RP) in patients with and without periodontitis in terms of prevalence, distribution, location along the root, width and severity, and explored the role of RP characteristics in the type of alveolar bone loss (horizontal or angular). MATERIALS AND METHODS: Root proximity was studied in the interdental spaces of 250 patients with periodontitis and 80 patients without disease. Linear measurements were performed in digitized radiographs. Root proximity was classified by location along the root, width and severity. Bone defect type (horizontal or angular) at the RP site was recorded. RESULTS: Root proximity prevalence did not differ between periodontitis and non periodontitis groups. For both groups, most RPs were located at the middle root third. Root proximity width and severity in periodontitis sites were different between horizontal and angular bone loss sites. Root proximity width was greater in horizontal bone loss sites. In periodontitis, a unit (pixel) increase in the RP width decreased the probability to detect an angular bone defect by 20%, while a unit decrease in RP severity increased the possibility to detect angular bone loss by 71%. CONCLUSION: Root proximity prevalence was similar for both patients with and without periodontitis. The RP location along the root was not related to the existence of periodontitis. Root proximity width and severity differed between horizontal and angular bone loss sites. Root proximities had greater width in horizontal than angular bone loss sites. PMID- 22220370 TI - The effects of thyroid hormone abnormalities on periodontal disease status. AB - Thyroid hormones play an important role in the regulation of physiologic processes. Thyroid disease can lead to imbalance in the homeostasis of the body and affect the healing capacity of tissues. However, limited data are available regarding the relationship between thyroid hormone imbalance (thyroid disease) and periodontal health. This review is carried out to summarize the relationship between thyroid disease and periodontal status. PUBMED and MEDLINE searches of both human and animal studies were performed to investigate the relationship between thyroid disease, periodontal status, and dental implants. Results suggest that thyroid diseases may affect the status of periodontal diseases, especially in hypothyroid conditions. The duration from disease onset to treatment of thyroid disorders may be critical, since uncontrolled thyroid disease may result in destruction of the periodontium. Further controlled studies are needed to explore the relationship between thyroid hormone imbalance and periodontal status. Periodontal therapies, including dental implant placement, appear to be safe with no increase in treatment failure, so long as the status of the thyroid gland is controlled. PMID- 22220371 TI - Inflammatory response to dental polishing and prophylaxis materials in rats. AB - OBJECTIVE: To describe the tissue response to implanted polishing and prophylaxis materials using a rat model system. MATERIAL AND METHODS: Two polishing pastes (diamond polishing paste and aluminum polishing paste), two prophylaxis materials (prophylaxis paste with fluoride and air polishing prophylaxis powder) and negative and positive controls were subcutaneously implanted in rats. Tissue specimens obtained after 2 days, 1, 4, 6 and 8 weeks after implantation were processed for routine hematoxylin and eosin staining and polarized light evaluation. RESULTS: Air polishing prophylaxis powder produced a mild inflammatory response. A more intense inflammation was elicited by diamond polishing paste, and the prophylaxis paste with fluoride elicited an even greater response. The aluminum polishing paste produced the most severe and persistent tissue response, which was of the granulomatous type. CONCLUSIONS: This finding suggests that foreign body reaction should be considered in a gingivitis that does not respond to plaque control or does not represent a mucocutaneous lesion. PMID- 22220372 TI - Osborne lands new blow as nurses strike. PMID- 22220373 TI - Thousands join biggest protest in 30 years. PMID- 22220374 TI - "Beware politicians who push conflict to drive their ideology". PMID- 22220375 TI - "You can hand out packets of cornflakes-- but not dignity". PMID- 22220376 TI - "We need to do research and shout about it--or fall behind". PMID- 22220377 TI - Can failure to rescue be a key indicator of patient safety? PMID- 22220378 TI - Perinatal support to protect maternal mental health. AB - Family Action is a charity that helps more than 45,000 vulnerable families and children across England a year by offering emotional, practical and financial support. A pilot of a perinatal support project in Southwark, London was found to reduce mental health problems in vulnerable women and is now being extended. Such schemes complement the work of health visitors and other health professionals. Commissioners need to be aware of the long-term impact of such low-cost interventions in the early years. PMID- 22220379 TI - Broaching sexual health issues with patients. AB - Sexual health is complex, diverse and applies to everyone from childhood to old age, whether they are sexually active or not. This article discusses sexual health and how it applies to nurses in everyday practice. It highlights some of the consequences of poor sexual health and gives advice on how nurses can introduce the topic with patients. PMID- 22220380 TI - Evaluating a critical care course. PMID- 22220381 TI - A pillar of support. PMID- 22220383 TI - Call to boost sister role. PMID- 22220382 TI - How to build on the talents of your staff. PMID- 22220384 TI - "High earners keep tax breaks while NHS pensions are attacked". PMID- 22220385 TI - "Total Wipeout's big red balls could separate the fit from the ill". PMID- 22220386 TI - "Compulsory training would help every HCA spot moisture lesions". PMID- 22220387 TI - How skill mix affects quality of care. AB - While the media has reported failings in care as failures in nursing, it has not distinguished between care delivered by nurses and that delivered by unregistered healthcare assistants and other support staff. This article examines the role of nurses in an evolving healthcare climate. PMID- 22220388 TI - Communication skills training in end-of-life care. AB - Health professionals lack confidence in end-of-life care issues, particularly in communicating with dying patients and their families. University Hospitals Coventry and Warwickshire Trust set up a two-day training course on communication skills in end-of-life care for healthcare assistants. Evaluations showed this increased staff confidence. PMID- 22220389 TI - Use of emollients in dry skin conditions. AB - As nurses receive inadequate training in dermatology, they may lack knowledge in prescribing and using emollients. This article outlines the physiology of the skin, the role of emollient therapy and how to use it in clinical practice. PMID- 22220390 TI - Managing eczema. AB - Eczema is an extremely common condition, with atopic eczema affecting at least 10% of infants at some stage. Nurses have a vital role in supporting patients and families by providing information about the condition and explaining the correct technique for applying topical medication. This article describes the different types of eczema and discusses the principles of care. Although treatment plans vary depending on the type of eczema, the underlying principles are the same. PMID- 22220391 TI - Intensive caring. PMID- 22220392 TI - Being assertive benefits everyone. PMID- 22220393 TI - Contribution of the association "Albert Einstein" through a 5-year existance. PMID- 22220394 TI - Daily variation of UV-A and UV-B solar radiation on the Adriatic Sea. AB - During the summer months, from June thru September, in Opatija and island of Rab area, we conducted UVA and UVB measurements using a professional detector: Solar Light Co., Inc. USA. Ordering: PMA2110 UV-A and PMA2101 UV-B detector. We conducted global UVA and UVB measurements in the 2006 to 2011 period. Results of the measurements show June to September daily, 10 am to 3 pm, UVA and UVB variations to be above allowed values especially in the maritime area. The measurements were performed in cooperation with "Dr. B. Vojnikovic" Daily eye clinic and the University of Applied Sciences Velika Gorica, Velika Gorica, Croatia. PMID- 22220395 TI - Expression of matrix metalloproteinase 9 in primary and recurrent breast carcinomas. AB - The matrix metalloproteinases (MMPs) comprise a family of zinc-dependent endopeptidases that are secreted as inactive precursors, which are activated by cleavage of an N-terminal pro-peptide. Their basic mechanisms of action include cancer cell growth, differentiation, apoptosis, migration and invasion, and the regulation of tumour angiogenesis and immune surveillance. The expression of MMP2 and MMP9 has been associated with high potential of metastasis in several human carcinomas including breast cancer. The 29 female patients, 9 premenopausal and 20 postmenopausal, aged from 37 to 79 years were included in this study. Tissue samples were examined in 29 primary and 48 recurrent carcinomas using the tissue microarrays which included 102 cores of primary breast carcinomas and 96 of recurrent breast carcinomas. Immunohistochemistry determined a pattern of expression for MMP9. The staining was diffuse cytoplasmic, strong, moderate, faint/weak and negative. The majority of the breast carcinomas stained homogenously for MMP9 on tumor cells. Statistically significant correlation was found for the expression of MMP9 between primary and recurrent breast carcinomas in general (p < 0.001) and in tumors that were grouped as recurrence before (p = 0.039) and after 24 months (p < 0.001). Strong expression of MMP9 was observed in primary tumors that recurred after 24 months, median: 162.5 (score range 0-300) and those tumors that recurred before 24 months of the initial diagnosis, median: 102.5 (score range 0-250) (p = 0.026). PMID- 22220396 TI - 1-year follow-up study of endothelial cell density loss after penetrating keratoplasty. AB - High endothelial cell density (ECD) is essential for the corneal graft clarity. We evaluated ECD loss in 120 eyes that underwent penetrating keratoplasty (PK) in Eye Clinic Svjetlost in a one year follow up period. Patients were divided into 3 groups of high (N = 35), intermediate (N = 31) and low risk (N = 54) for graft failure. Postoperative central endothelial density, coefficient of variation in cell area (polymegathism), percentage of hexagonal cells (pleomorphism) in comparison to preoperative donor cell measurements were determined in the following postoperative time-points of 1, 2, 3, 6, 9 and 12 months. There were no significant differences in the preoperative ECD values, storage time, donor age or surgical procedures between groups. Throughout all time points intermediate group had the greatest statistically significant ECD loss as compared to high and low risk groups. There were no significant differences between high and low risk group. After 12 month post PK, intermediate risk group had 28.38% ECD loss as compared to 24.07% in high and 23.03% ECD loss in low risk group. Coefficient of variation in cell area (CV) was for high risk group 0.34, intermediate 0.40 and low risk 0.31 which was not significantly different between groups. Percentage of plemorphism in high risk was 54%, intermediate 58% and in low risk 48% which was significantly different as compared to other two groups. Our study showed that corneal pathology is among others, very important prognostic factor for ECD after PK. However, longer follow up period is needed. PMID- 22220397 TI - Anti-VEGF in treatment of diabetic macular edema. AB - Diabetic macular edema is the leading cause of moderate visual deterioration in patients with diabetic retinopathy. Ranibizumab) blocks vascular endothelial growth factor (VEGF) induced hyperpermeability of blood vessels. In this prospective case series we investigated the efficacy and safety of anti-VEGF treatment in reduction of central retinal thickness (CRT) and improvement in visual acuity (VA) in patients with diabetic macular edema (DME). 9 patients were followed up for 6 months and treated monthly with intravitreal ranibizumab. VA and CRT were measured at each visit. Treatment was discontinued as the peak improvement of either parameter was reached and reinstituted in case of deterioration/recurrence of edema. Study endpoints included: VA using ETDRS chart, CRT and number of injections at 6 months. Mean VA from all 9 patients increased by 0.3 lines of logMAR (p < 0.05 compared to baseline), and CRT decreased from 515 +/- 123 microm to 310 +/- 110 microm. The improvement of VA after ranibizumab injection was in correlation with a decrease in CRT. Mean of 4 injections were needed to control the disease during the follow-up period. Ranibizumab treatment was effective in VA and reducing CRT. Several injections were needed to control the disease. Regular OCT examinations and retreatment are advised in order to maintain initially reached VA. PMID- 22220398 TI - Histomorphometric analysis of subchondral bone of the femoral head in osteoarthritis and osteoporosis. AB - There have been reports both supporting and refuting an inverse relationship between hip fracture and hip osteoarthritis (OA). We have investigated this relationship using histomorphometric study of femoral head subchondral bone. We studied 74 subjects with hip fracture (74% females) and 24 subjects with osteoarthritis (45% females). By histomorphometric analysis of parafined sections, we analysed followed subhondral trabecular bone parameters bone volume (BV), bone volume/tissue volume (BV/TV), trabecular thickness (Tb.Th.), trabecular number (Tb.N.) and trabecular separation (Tb.S.). The subjects with osteoarthritis and subjects with hip fracture had BV/TV 31.3% and 19.6% respectively. BV/TV of osteoarthritis group was rather uniform whereas BV/TV of hip fracture group was greatly ranged and we divided it into three subgroups, 13.2%, 19.8% and 25.9% respectively. The OA group and hip fracture groups had Tb.Th. as followed 0.205 mm, 0.148 mm, 0.170 mm and 0.183 mm respectively. The OA group and hip fracture three subgroups had Tb.N. as followed 1.454/mm, 0.897/mm, 1.170/mm and 1.425/mm respectively. The OA group and hip fracture three subgroups had Tb.S. as followed 0.518 mm, 0.681 mm, 0.620 mm and 0.550 mm respectively. The results of our study support an inverse relationship between hip fracture and hip osteoarthritis. PMID- 22220399 TI - Seasonal, daily and intradiurnal variation of PM10, NO2, NO and O3 in residential part of Zagreb, Croatia. AB - Pollutants such as particulate matter, nitrogen oxides, carbon oxides, ground level ozone, etc. are harmful to human health. Study of pollutant variation and its relationship with both dynamic and thermodynamic atmospheric boundary layer (ABL) structures is of importance not only for environmental protection but also for the public at large. The aim of this study was to analyze seasonal, daily and intradiurnal variation of PM10, NO2, NO and O3 in a residential part of an urban area, and the effect of some meteorological parameters. The study was conducted from January 1 till December 31, 2004 in the City of Zagreb using following methods: beta radiation absorption, chemiluminescence and UV photometry. The results presented in this article, show the dependence of air pollution levels upon traffic density, seasons and meteorological conditions. Considering the level of air pollution relative to the regulated limit and tolerated values, the measured 24-hour concentrations of all study pollutants exceeded the borderline values and/or tolerated values, however, the number of days with such pollutant concentrations did not exceed the allowed frequency. This is a preliminary study with the main objectives to point to the possible identification of the source of pollution and to assess the level of air contamination according to the new national legislation coordinated with European regulations. Future measurements and studies should evaluate in detail the causes of the concentration levels detected. PMID- 22220401 TI - Clinical experience with Ex-press Mini Glaucoma Shunt implantation. AB - In this prospective study we wanted to report our experience and to evaluate the efficacy and safety of Ex-press Mini-Glaucoma Shunt implantation under a superficial scleral flap, as a newly and improved surgical technology in a treatment of POAG (Primary open-angle glaucoma) and refractory glaucoma. 44 eyes (35 patients) underwent an implantation of Ex-Press Mini Glaucoma Shunt. We had 21 patients with POAG (60%) and 14 patients with PEXG-pseudoexfoliation glaucoma (40%). The follow-up period was 8.62 + 7.48 months (range 2-22 months). Main outcome measures included postoperative IOP control, postoperative medications and early postoperative complications. The IOP was measured in the following postoperative time-points of 1 day, 1 week, 1, 3, 6, 9 and 12 months. The mean IOP values 1 year postoperatively were reduced for 52.8% compared to preoperative values and the use of medications were reduced for 77%. We had complications like postoperative hypotony (3.5%), choroidal ablation (7%), intraocular hemorrhage (3.5%) and postoperative shunt closure (3.5%). The Ex PRESS Mini Glaucoma Shunt implanted under a superficial scleral flap is relatively safe and effective surgical procedure and provides satisfactory IOP control and medication reduction. However, device related complications remain still a problem. PMID- 22220400 TI - Micro-regional hypersensitivity variations to inhalant allergens in the city of Zagreb and Zagreb County. AB - Depending on the geographic and climatic region and vegetation, allergenic plants are characteristic for certain areas and the pollen concentrations of various plant species depend on the fenophase of each single species and most of all on the climatic and meteorological conditions of a certain area. It is precisely because of these specific characteristics that the hypersensitivity of patients to various types of pollen allergens differs according to the geographic regions. The aim of this paper is to determine the frequency of inhalation allergies in adult population (> 19 years of age) caused by single types of allergens according to the defined space units (micro-regions) with special emphasis on the rural and urban areas. A number of 2,192 patients have been tested for allergy skin prick tests over a period of four years. Every patient was asked to fill in the questionnaire which contained 29 questions. The results of skin prick testing show that out of a total of 2,192 patients 86.72% were sensitized to pollen, 36.45% to mites, 2.46% to spores of fungi and mould and 5.1% of patients to other allergens which include the allergens of cockroaches, feathers and animal hair (p < 0.001). The largest number of poly-sensitized persons allergic to pollen allergens was sensitized to allergens from the pollen of plants that belong to the botanical family of grass. There were 25.36% patients mono-sensitized to individual allergens. In the northern and western parts of the city and the county, the majority of persons were sensitized to the birch pollen allergens, and this is statistically much more than the share of patients with the place of residence in the southern and eastern parts of the city and the county. In the southern and eastern locations prevails the share of sensitized persons to ambrosia which is statistically much more than the share of patients with the place of residence in the northern and western part of the city and the county. PMID- 22220402 TI - Diurnal variation in airborne pollen concentrations of the selected taxa in Zagreb, Croatia. AB - The number of individuals allergic to plant pollen has recently been on a constant increase. The knowledge of diurnal distribution and abundance of allergenic pollen types, their patterns and response to source position and weather is useful to correlate hay fever symptoms with the presence of allergenic pollen in the atmosphere. The aim of this study was to determine diurnal distribution of total airborne pollen, pollen of particular allergenic taxa, possible variation in diurnal pollen distribution at measuring sites placed at different heights, and effect of some meteorological parameters on airborne pollen concentrations. A 7-day Hirst-type volumetric pollen trap was used for pollen sampling. Qualitative and quantitative pollen analysis was performed under a light microscope (magnification x400). Total pollen of all plant taxa (Ambrosia sp., Betula sp., Cupressaceae, Urticaceae, Poaceae, Quercus sp., Fraxinus sp., Alnus sp., Corylus sp., Populus sp., Pinus sp., Picea sp.) observed showed a regular diurnal distribution at both sampling sites in both study years, with a rise in the pollen concentration recorded after 4.00 a.m. and 6.00 a.m., respectively. The peak pollen concentration occurred between 12.00 a.m. and 4.00 p.m., and the lowest diurnal pollen concentrations were recorded overnight. About 50% of the 24-h pollen concentration were released to the atmosphere between 10.00 a.m. and 4.00 p.m. The timing and size of diurnal peaks were closely related to high temperature, low humidity and south-west maximum wind direction. PMID- 22220403 TI - The influence of aesthetic surgery on the profile of emotion. AB - In the clinical practise it has been observed that the person changes physically, too, after aesthetic surgery. The aim of this work was to examine, by objective psychological measurements, what changes occur, and what personality features change. Forty six subjects that had an aesthetic surgery were examined; they were tested before, and eighteen month after the surgery by the Profile Index of Emotion (PIE). Before the re-testing the subjects were analyzed by "The Life Events Scale" to exclude the possibility of the influence of new life events on the results of the re-test. The control group of 29 volunteers was tested by the same psychological instruments. The control group never verbalized the wish for an aesthetic surgery; they were never in psychiatric treatment, and the corresponded to the experimental group in the age, sex and education level. Analysis of the data obtained from PIE test before and after the operation shows a statistical significant increase of the adaptability segments and an improvement of capacity for taking and giving. Emotional conflict does not disappear, but a new balance is established, satisfaction is higher, and the identity is more integrated. PMID- 22220404 TI - Cross-talk between NKT and regulatory T cells (Tregs) in modulation of immune response in patients with colorectal cancer following different pain management techniques. AB - Natural killer T (NKT) and regulatory T cells (Tregs) play an important role in innate immune response. Natural killer (NK) and NKT cells are indispensable factors in the body's ongoing defense against tumor development, as well as viral infection. NKT cells are a subset of T cells that shares properties of natural killer cells and conventional T cells. They are involved in innate immune responses, tumor rejection, post transplantation immunotherapy, immune surveillance and control of autoimmune diseases. They may also play both protective and harmful roles in the progression of certain autoimmune diseases, such as diabetes, lupus, atherosclerosis, and allergen-induced asthma. Immune surveillance involves the process whereby precancerous and malignant cells are recognized by the host immune system as damaged and are consequently targeted for elimination. The pharmacological management of postoperative pain in patients with malignancies uses very different techniques whose possible cytotoxic functions we still known very poor. The present study compared effects of two different postoperative pain management techniques in patients undergoing colorectal cancer surgery on the innate immunity. Our data indicate that the patients with colorectal cancer have significantly increased the percentage of Tregs and NKT cells. The values were statistically higher during epidural analgesia in comparison with intravenous analgesia, indicating that epidural pain management technique ameliorate the immune suppression after surgery. PMID- 22220405 TI - Immunomodulation of cell-mediated cytotoxicity after chronic exposure to vapors. AB - Cytotoxic T lymphocytes and natural killer (NK) cells represent two major types of immune cytotoxic cells that have a crucial role in innate immunity. Urban air pollution represents a common and difficult problem in the majority of metropolises, which contain high levels of traffic congestion generating great amounts of genotoxic substances. Diesel exhaust particles act as adjuvant in the immune response and may lead to the enhancement of proinflammatory and proallergic response without exposure to allergen. The activities of diesel exhaust particles (DEPs) and their benzene extracts may cause the increasing respiratory mortality and morbidity. Since the lung inflammatory response to DEPs is compartmentalized, the importance of finding the suppressive substances, whose function will be to elucidate the DEPs effects, is fundamental. The objectives of this study were to examine the NK-mediated cytotoxicity against human NK sensitive target, as well as the values of BTEX (benzene, toluene, ethylbenzene and xylene isomers) in urine in people from industrial area and those from rural fields. NK-mediated cytotoxicity of peripheral blood mononuclear cells was investigated against human NK-sensitive K-562 tumor cell line. BTEX were analyzed from urine by a HS-SPME method. All exposed individuals were demonstrated the significant decreased of NK-mediated cytotoxicity against human NK-sensitive target and increasing BTEX values. BTEX-analyze in urine and determination of NK mediated cytotoxicity, as an important methods represent good markers in environmental monitoring, which contribute to the better protection of air pollutants and quicker diagnosis of environmental diseases. PMID- 22220406 TI - Augmentation of regulatory T cells (CD4+CD25+Foxp3+) correlates with tumor stage in patients with colorectal cancer. AB - Recent evidence suggests that decline of regulatory T cells (Tregs) play a critical role in the prevalence of autoimmune diseases inhibiting the maintenance of peripheral self tolerance, while its augmentation leads to insufficient antitumor response, accompanied with poor prognosis in various malignancies. Increased number of Tregs (CD4+CD25+FoxP3+) were noticed in peripheral blood mononuclear cells (PBMCs), tumor-infiltrating lymphocytes (TILs) and/or regional lymph nodes lymphocytes (LNLs) of patients with gastrointestinal tumors. The aim of our study was to investigate the correlation between the percentage of Tregs in peripheral blood of patients with colorectal carcinoma, using flow cytometric technique and tumor stages, classified as Dukes' A, B, C or D and by stage of differentiation. Peripheral blood venous samples were obtained from 92 patients with colorectal cancer and from 30 healthy adult volunteers. STATISTICAL ANALYSIS: Linear regression equations were generated using a least-squares method and analyzed for differences of covariance. Statistical significance was calculated by Mann Whitney U-test. Our data has shown that 15% patients with colorectal cancer were classified as Dukes' A, 41% were Dukes' B, 35% were Dukes' C and 9% were Dukes' D. 54% patients with CRC were well differentiated, 11% were poorly differentiated, 20 were moderately differentiated, tage, 4% were mucinous carcinoma and rest of 11% were partly good differentiated with mucinous components. The increased percentage of Tregs in colorectal cancer patients correlates with tumor stage. These results indicate a possible involvement of regulatory T cells in disease progression. New strategies using inhibition or depletion of Tregs are necessary to elucidate the complexity of defective tumor immunity. PMID- 22220407 TI - Prevalence of severe retinopathy of prematurity in a geographically defined population in Croatia. AB - The aim of this study was to evaluate the prevalence of stage III of retinopathy of prematurity (ROP) among newborns of birth weight < 1500 g and gestational age (GA) < or = 32 weeks, and to compare these prevalences during two time periods (1998-2002 and 2003-2007). The investigation was conducted at the Department of Gynecology and Obstetrics, University Hospital in Rijeka, Croatia. The screening for ROP was performed by an ophthalmologist using a binocular indirect ophthalmoscope. Over a period of 10 years, there were 28,627 liveborn newborns, with 136 (0.48%) premature newborns with a birth weights < 1500 g and 226 (0.79%) newborns with GA at birth < or = 32 weeks. The proportions of survivors among newborns with birth weights < 1500 g (51.1% vs. 70.5%) and among newborns with GA at birth < or = 32 weeks (67.9% vs. 77.0%) were significantly higher in the later period. During the period 2003-2007, the proportion examined for ROP was higher among newborns with birth weight < 1500 g (52.9% vs. 97.1%) and among newborns with GA at birth < or = 32 weeks (46.5% vs. 96.9%). The prevalence of stage III ROP was significantly lower in 2003-2007 compared to that in 1998-2002 among newborns with birth weight < 1500 g (30.6% vs. 14.0%) and newborns with GA at birth < or = 32 weeks (22.4% vs. 8.8%). The prevalence of total ROP among newborns was significantly lower in 2003-2007 compared with 1998-2002. This decrease in prevalence may be explained by advances in neonatal intensive care unit, increased survival of very low birth weight infants and carefully timed retinal examinations. PMID- 22220408 TI - Regular dog-walking improves physical capacity in elderly patients after myocardial infarction. AB - Various positive effects of pet ownership on cardiovascular health are well known. The aim of this prospective and controlled longitudinal study was to determine the effects of everyday dog-walking on physical capacity in elderly patients during the first year after myocardial infarction. Regularly dog-walking for at least 15 minutes three times a day is related to significantly higher work load on the bicycle exercise test (72.5 +/- 10.75 versus 67.6 +/- 11.6 W p < 0.05) in the "dog-walking" group (N = 29, mean age 72.5 years) at 12 months compared to the control group (N = 30, mean age 71.7 years). Our results suggest that dogs may help to maintain continuous physical activity in elderly cardiovascular patients promoting their physical capacity. Further researches are needed to confirm this association as well to identify other possible influences of dog ownership on the cardiovascular health and on the outcome in patients after myocardial infarction. PMID- 22220409 TI - The incidence of skin squamous cell carcinoma in Osijek-Baranja County--an epidemiological study. AB - The aim of this study is to show the incidence of squamous cell carcinoma of the skin in Osijek Baranja County, Eastern Croatia, in period from 2004 to 2009. This is the first report of epidemiological features of squamous cell skin carcinoma in this region. In this period we registered 469 patients with SCC of the skin, from which 237 females (50.5%) and 232 males (49.5%). World age-standardised rates (ASRW per 100,000) incidence in this period was 11.8/100,000 (16.8/ 100,000 for men and 9.0/100,000 for women). SCC of the skin occur in elderly commonly after 70 years. Most common localization is on the photoexposed areas, for example head, neck and backs of the hands. These localization varied in males and females (in females 2.5 times more in the nose area than males while 6 times more on the ear). The relation between photoexposed and photo non-exposed areas is 5:1. These results will serve as reference for studying the patterns of descriptive epidemiology of squamous cell carcinoma of the skin in the Osijek Baranja County and the surrounding region. PMID- 22220410 TI - The impact of psoriasis on the quality of life and psychological characteristics of persons suffering from psoriasis. AB - Psoriasis, as same as other skin diseases, has an influence on many spheres of patient's life. It influences the mental image the patients have of themselves and it indirectly shapes their personality traits as well as it defines the quality of their lives. The purpose of the study was to examine the impact of psoriasis on the quality of life and gender differences in the quality of life and explore presence of neurotic symptoms among persons suffering from psoriasis in comparison to general population. During the treatment of persons suffering from psoriasis at the special hospital Naftalan in Ivanic Grad personality questionnaire and Quality of life scale were administered to 61 participants (m = 25; f = 36). Our results showed few gender differences in the satisfaction with specific life domains, but only differences in the satisfaction with sexual life could be related to the different effects psoriasis has on the quality of life of men and women. Our participants experience more anxiety and depression symptoms as well phobic fears in comparison to general population. Found genders differences in the presence and intensity of anxiety symptoms closely resemble those documented in the general population therefore aren't typical for people suffering from psoriasis. PMID- 22220411 TI - Surgical technique in the rat model of kidney transplantation. AB - Today successful kidney transplantation procedures, techniques and immunosuppression protocols are a consequence of extensive research on animal models. During every transplantation surgery there are two crucial points for the success of the entire procedure: vascular (arterial end venous) and ureteral or ureterovesical anastomosis. Renal artery and vein of the donor kidney can be anastomosed end-to-side to the abdominal aorta and vena cava of the recipient (heterotopic transplantation), or end-to-end to the remains of renal artery and vain of the recipient (orthotopic transplantation) after nephrectomy. The ureter can be anastomosed also end-to-end or we can connect it directly to the urinary bladder (ureterocystoneostomy). The aim of this study was to elucidate which technique has better results according to: animal survival, reperfusion and perfusion of the transplanted kidney, elimination of the urine from the transplanted kidney and procedure costs. The study included 240 (120 donors and 120 recipients) male Wistar rats (3 months old; weight 250-300 g Our results are clearly showing that the end-to-end vascular anastomosis, and Paquins ureterovesical anastomosis have better results in transplanted rat kidneys survival and urine drainage compared to end-to-side vascular anastomosis and end to-end ureteral anastomosis. Based on our experience we can conclude that described methods of end-to-end vascular anastomosis and Paquins ureterovesical anastomosis are less technically demanding and have a shorter learning curve. Therefore, we can recommend the use of described methods in kidney transplantation related researches. PMID- 22220412 TI - Effect of hyperbaric oxygen treatment on myogenic transcriptional factors in regenerating rat masseter muscle. AB - Hyperbaric oxygen (HBO) treatment was shown to be beneficial as an additional treatment for ischemic muscles in crush injuries and ischemia-reperfusion injuries. The purpose of this study was to assess the influence of hyperbaric oxygen treatment on transcriptional myogenic factors during muscle regeneration. Those factors (MyoD, myf5, myogenin, mrf4) are essential for determination and differentiation of skeletal muscle tissue and together with several other factors control gene expression during myogenesis. The process of regeneration in rat masseter muscle was provoked with injection of local anesthetic bupivacaine hydrochloride. Following injection, the animals were treated once daily in hyperbaric chamber from one to ten days and than sacrificed. Immunohistochemical and Western blot analysis of frozen masseter muscle samples showed a transient upregulation of myoD and myogenin transcriptional factors in the muscles of hyperbaric oxygen treated rats and of rats that have not been treated after the injury. HBO treatment had no effect on the expression of MyoD and myogenin transcriptional factors in the regenerating rat masseter muscle. PMID- 22220413 TI - Basics of voice dysfunction--etiology and prevention of voice damage. AB - Voice is one of the most important means of communication and as such should be taken care of. The etiology of voice disorders is diverse. Due to the development of the society we live in, way of life, environmental factors, and exposure to pharmacological agents as well as demands we make towards our voice, there is a substantial growth in the number of people with voice disorders. We tasked ourselves to find out if it is possible to enlighten people on the importance of voice, to motivate them to take care of it, to notice the changes in its quality and eventually ask for help. We assessed in which measure do we understand the importance of a healthy voice, and do we know which is the most important factor that adds to its decline. For a long number of years voice therapists and other experts in the voice disorder field have been discussing the optimal voice impostation as well as vocal exercises and methods behind voice recovery. They have all come to the same conclusion that phonation is dependant on the sort of the voice disorder and the patient motivation. We wanted to go one step further and investigate, dependence of voice quality and the damage etiology (organic - functional), which are the predominant causes, what are the factors that account for the damage and how the disorder motivates the patient and therefore influences the rehabilitation success rate. PMID- 22220414 TI - Application of wound dressing Molndal technique in clean and potentially contamined postoperative wounds--initial comparative study. AB - Because of a possible delayed wound healing, critical colonization and infection of wounds present a problem for surgeons, particularly in patients with compromised immune system or in case where the wound is heavy contaminated or poorly perfused. Molndal technique of wound dressing has proven to be effective in prevention of infection. In our study we wanted to describe the benefits of the application of Molndal technique wound dressing compared to traditional wound dressing technique at potentially contaminated and clean postoperative wounds. We examined postoperative wound after radical excision of pilonidal sinus and after implantation of partial endoprosthesis in hip fracture. Molndal technique consisted of wound dressing with Aquacel Ag - Hydrofiber. Traditional technique was performed using gauze compresses and hypoallergic adhesives. We analyzed the results of 50 patients after radical excision of pilonidal sinus. 25 patients were treated by Molndal technique and 25 patients by the traditional technique of wound dressing. In the group treated by Molndal technique only 1 (4%) patient has revealed a wound infection, proven by positive microbiological examination and suppuration. In the traditional technique group 4 (16%) patients developed wound infection as inflammation and secretion as a sign of superficial infection. In the other group we analyzed the results of 50 patients after implantation of partial endoprosthesis after hip fracture. 20 patients were treated by Molndal technique and 30 patients by the traditional technique of wound dressing. In the group treated by Molndal technique no patient has revealed a wound infection (0%). In the traditional technique group 4 (13%) patients developed wound infection. All complication in both group were superficial incisional surgical infection (according to HPSC). There was no deep incisional surgical site infection or organ/space surgical site infection. Our results are clearly showing that Molndal technique is effective in preventing the postoperative wound infection. PMID- 22220415 TI - Ten-year study on the correlation of clinical and pathohistological diagnosis of dysplastic nevi. AB - The aim of the study was to analyze the clinical prevalence and pathohistological correlation of dysplastic nevi. In the period between 2000 and 2009, in the Outpatient Clinic of Referral Centre for Melanoma of the Ministry of Health and Social Welfare of the Republic of Croatia, 12,344 patients were examined, and 35.07% of them were surgically removed in the same institution. Among the patients, 69.16% had clinically diagnosed melanocytic tumor. Out of them, 28.39% were dysplastic. Dysplastic nevus was pathohistologically diagnosed in 20.02% of pathohistologically diagnosed melanocytic tumors. There was women predominace among patients with clinically diagnosed dysplastic nevi (65.22%). The most frequent localization was the trunk in both sexes, women 78.18%, men 76.75%. The coincidence of clinical and pathohistological diagnosis of dysplastic nevus was 30.70%. The results of this study, based on a large number of patients could be a significant contribution in understanding characteristics of dysplastic nevus, its clinical and pathohistological complexity. We hope that the data will contribute to the creation of general accepted protocols in the diagnostics of dysplastic nevus. PMID- 22220416 TI - Evaluation of adjuvant chemotherapy in patients with colorectal cancer in Primorsko-Goranska and Istarska County--a twenty years retrospective study. AB - Colorectal cancer is the second most common malignant disease in developed countries, with about one million new cases worldwide every year, accompanied with high mortality rate. We examined the survival rate and recurrence (occurrence of distant metastases and/or local recurrence) of patients with colorectal cancer in Primorsko-Goranska and Istarska County who received adjuvant chemotherapy, compared to those who did not in the period since 1980. until 1999. This study involves 483 patients with colorectal cancer stages II and III of Primorsko-Goranska and Istarska County, which were underwent curative resections of colorectal cancer at the Clinical Hospital Centre Rijeka, and then treated with chemotherapy (288) or without Chemotherapy (195). We analyzed the five year survival rate and the recurrence of malignant disease in the adjuvant treatment group in comparison with not treated group with chemotherapy, depending on the stage of disease, degree of histological differentiation, patient age and location of cancer (colon or rectum). After follow-up of 60 months died 44.79% (129/288) of patients who received chemotherapy and 53.33% (104/195) of patients who did not receive chemotherapy. The relative risk of death (from any cause) in chemotherapy-treated group versus the group without chemotherapy was 0.82 (p < 0.008). Recurrence of malignant disease in the chemotherapy group was 38.54% (111/288), and in the group without chemotherapy was 46.15% (90/195). The relative risk of recurrence of malignant disease in the chemotherapy group versus the group without chemotherapy was 0.78 (p < 0.001). There was no difference in treatment efficacy regard to the localization of the tumor, but there were differences in efficiency with respect to disease stage, grade and age. Chemotherapy with 5-fluorouracil and leukovorin ameliorate the survival and reduces recurrence and distant metastases in patients with colorectal cancer stages II and III. PMID- 22220417 TI - Influence of personality traits on sexual functioning of patients suffering from schizophrenia or depression. AB - Aim of this research was to establish effects and influence of personality traits on sexual functioning of schizophrenic and depressive patients, compared to healthy individuals. 300 participants were included in this research. For patients suffering from schizophrenia it was established that the more they are open to experience and the less they are neurotic their sexual drive is stronger. For patients suffering from depression it was established that the more they are open to experience and conscientious and the less they are agreeable their sexual drive is stronger. Furthermore, higher openness is a significant predictor for easier sexual arousal and the more those patients are conscientious and the less they are agreeable easier is for them to achieve orgasms. Personality traits proved to be significant predictors of sexual functioning in schizophrenic and depressive patients, but not in healthy individuals. PMID- 22220418 TI - Renal function outcomes after nephrectomy for kidney cancer in elderly patients. AB - The kidneys are organs with multiple functions and essential to maintain life. Ablative procedures, such as nephrectomy, diminish nephron mass and can have a potentially negative impact on renal function. We investigated renal function outcome in patients who underwent nephrectomy for renal cell cancer with special emphasize on elderly patients. Data from 104 patients who underwent nephrectomy for kidney cancer in the Department of Urology, University Hospital Rijeka from January 2005 to December 2010 were retrospectively analyzed. All patients had a normal concentration of serum creatinine and a normal contralateral kidney before surgery. Renal function, as estimated by the glomerular filtration rate (eGFR), was determined before and after nephrectomy using the abbreviated Modification of Diet in Renal Disease equation. We compared the eGFR before and after nephrectomy in the patients of different age. The mean preoperative eGFR was 75.2 mL/min, and the mean postoperative eGFR was 52.7 mL/min (p < 0.0001). In the group of patients > or = 65 years old, the mean preoperative GFR was 69.2 mL/min, and the mean postoperative eGFR was 47.4 mL/min (p < 0.0001). Our data indicate that the eGFR significantly decreased after nephrectomy for kidney cancer. In elderly patients, diminished renal function following nephrectomy was more prominent. PMID- 22220419 TI - Attachment style in parents of children with chronic gastrointestinal disease. AB - Attachment is a point of interest in psychosomatic research since it influences a wide array of biopsychosocial phenomena. Data from literature highlights the role of this concept in the context of Inflammatory Bowel disease (IBD), still, there is a lack of data regarding attachment among parents of children with chronic gastrointestinal diseases. The main hypothesis for the current study is that parents of children with IBD will have a more insecure attachment than parents of children with celiac disease (CD) and parents of healthy children. The second hypothesis is that insecure attachment among parents of sick children will be associated with lower parental quality of life (QoL). 46 parents of children with IBD, 42 parents of children with CD and 43 parents of healthy children completed the validated modification of the Brennan's Experiences in Close Relationship Inventory. Results were categorized as secure and insecure attachment. In order to assess parental QoL, the WHOQOL-BREF questionnaire was used. The Total QoL was calculated as a sum of all domain items. Secure attachment was found in 45.7% parents of children with IBD, in 35.7% parents of children with CD and in 32.6% parents of healthy children. Surprisingly, the lowest rate of secure attachment was found in parents of healthy children. However, significant differences among groups do not exist. For all groups of parents the attachment style is associated with Total QoL, although only among parents of children with IBD, the secure attachment independently and significantly predicts higher parental Total QoL. According to results, we might say that parental attachment style does not have a role that exclusively belongs in the context of paediatric chronic gastrointestinal diseases. However, parents of children with IBD who have insecure attachment represent target group for psychosocial support in order to improve their QoL. PMID- 22220420 TI - Cranial nerve lesion in diabetic patients. AB - The retrospective investigation was done about relationships between diabetes and cranial nerve lesions (CNL) on the sample of hospitalized neurological patients in Clinical Hospital Dubrava (CHD) in 6 yrs. period (2001-2006). The goal was to expand the cognition about CNL as a complication of diabetes, to investigate possibility of better therapy models as well as to investigate the prevention possibilities. The results show that CNL are significantly more present by the diabetic patients vrs. the other hospitalized neurological patients. The main risk factors for CNL development are the duration of diabetes, patient's age and diabetes per se. No significant differences between masculine and feminine patients were registered nor by diabetics neither by other patients. For CNL are also not from significant importance the successfully treatment of diabetes, as well as type of antidiabetic and other medication. This investigation can not confirm the suspicion that some of antidiabetic medicaments are responsible for CNL due to their neurotoxic side effects. PMID- 22220421 TI - Epidemiological and clinical characteristics of malignant melanoma in area of West Herzegovina from 1997 to 2010. AB - Incidence rate of cutaneous malignant melanoma (MM), one of the most aggressive skin tumours, is increasing nowadays. Etiology of MM has not been fully understood. Various etiological factors are of relevance for the occurrence of the disease. The solar radiation as well as long term exposure to ultraviolet radiation has the greatest impact on development of this skin tumour. Melanoma risk factors have different associations with melanoma on body sites. This study investigates the epidemiological and clinical characteristics of MM such as age, gender, distribution of MM on the body and type of melanoma in the area of West Herzegovina, on the sample of 205 patients. It presents the occurrence of MM in the period from 1997. to 2010. Both, females and males have increased the risk of melanoma on the trunk (45.9%). Different body sites receive various amounts of sun exposure, yet melanomas occur on all parts of the body. This may represent different pathways in the etiology of melanoma based on body location. The most frequent type of MM was superficial spreading melanoma (SSM) 47.8%. According to our investigation incidence rate was 18.6% (per 1000 patients). PMID- 22220422 TI - Stigmatization of patients suffering from schizophrenia. AB - For the general public, but also for healthcare professionals, schizophrenia is still one of those areas of medicine connected with feelings of unease, fear and prejudice. These feelings lead to stigmatization and discrimination which are unjust processes which put patients suffering from mental illnesses into undesirable and unequal positions. Aim of this research was to establish the extent of stigmatization of mentally ill patients among the population of healthcare professionals and future healthcare professionals and if they differ from general population. Results show that stigmatization of schizophrenic patients is high among all included populations. Although there were no statistical differences between groups regarding the assessment of schizophrenic patients, nurses employed in psychiatric wards exhibited a tendency towards higher acceptance of schizophrenic patients, as well as better understanding of that illness. This data emphasizes a growing need for continuous education of general population but also of healthcare professionals. PMID- 22220423 TI - The mechanisms of action of phototherapy in the treatment of the most common dermatoses. AB - Phototherapy denotes the use of ultraviolet (UV) light in the management of several dermatoses. Most phototherapy regimens utilize ultraviolet radiation of different wavelenghts. Currently, irradiations with broadband UVB (290-320 nm), narrowband UVB (311-313 nm), 308 nm excimer laser, UVA 1 (340-400 nm), UVA with psoralen (PUVA), and extracorporeal photochemotherapy (photopheresis) are being used. The interplay of the various photobiologic pathways is far from being completely understood. Disordes that may benefit from such approach are numerous, with psoriasis, atopic dermatitis, cutaneous T-cell lymphomas, morphea, and vitiligo as main indications. The immunomodulatory effects of UVB radiation primarily affect the epidermis and superficial dermis, while UVA radiation affects mid and deep dermal components, especially blood vessels. UVB radiation is absorbed by endogenous chromophores, such as nuclear DNA, which initiates a cascade of events. Absorption of UV light by nucleotides causes the formation of DNA photoproducts and suppresses DNA synthesis. In addition UV light stimulates synthesis of prostaglandins and cytokines that play important roles in immune suppression. It may reduce the number of Langerhans cells, cutaneous T lymphocytes and mast cells in the dermis. UV radiation can also affect extranuclear molecular targets located in the cytoplasm and cell membrane. Immune suppression, alteration in cytokine expression, and cell cycle arrest may all contribute to the suppression of disease activity. PUVA is a form of chemophototherapy which uses UVA light to activate chemicals known as psoralens, hence psoralen ultraviolet A. The conjunction of psoralens with epidermal DNA inhibits DNA replication and causes cell cycle arrest. Psoralen photosensitization also causes an alteration in the expression of cytokines and cytokine receptors. Psoralens interact with RNA, proteins and other cellular components and indirectly modify proteins and lipids via singlet oxygen-mediated reactions or by generating of free radicals. Infiltrating lymphocytes are strongly suppressed by PUVA, with variable effects on different T-cell subsets. Psoralens and UV radiation also stimulate melanogenesis. Extracorporeal photopheresis is technique used in treatment of erythrodermic cutaneous lymphomas. It is very potent in induction of lymphocyte apoptosis. Despite the introduction of numerous effective systemic medications and biologic agents in dermatology, phototherapy remains a reliable, and often preferred option for several dermatoses. PMID- 22220424 TI - Determination of enzyme matrix metalloproteinases-9 and immune status as indicators of development of the environmental diseases. AB - The majority of environmental diseases are multifactorial airway illnesses, including genetic background and exposure to different kind of airborne irritants and allergens. Altered lifestyle and changes in environmental exposures contribute to the occurring of these diseases. The term of environmental illnesses includes the disease primarily caused by pollution of air and water, chemical and physical agents, radiation, contaminated food and direct contact with the toxins we are exposed to natural and/or working environment. The members of the matrix metalloproteinase (MMP) family are involved in the pathogenesis of COPD. MMPs comprise a large family of structurally related zinc metalloendopeptidases with different substrate specificities and possibilities to degrade protein constituents of the extracellular matrix. We investigated immunological status and level of MMP-9 in workers occupationally exposed to volatile aromatic hydrocarbons compared to urban residents and rural areas. The phenotypic profiles of peripheral blood lymphocytes were done by flow cytometry. The method of enzyme immunoassay (ELISA) was used to determine enzyme expression of matrix metalloproteinase-9 (MMP-9). The occupationally exposed group had a significantly elevated level of enzyme MMP-9 in the urine, accompanied with augmentation of cells of innate immunity in peripheral blood, which could contribute to the monitoring, early detection of environmental diseases and consequent earlier and more effective treatment. PMID- 22220425 TI - The role of the spectral domain ocular coherence tomography in detection of age related macular degeneration. AB - Age-related macular degeneration (ARMD) is one of the most common causes of the vision loss and blindness in developed countries. Among other harmful effects, exposure to the UV radiation is the most prominent factor for the development of the disorder. Using the method of SD OCT (Spectral Domain Ocular Coherence Tomography) we performed measurement of the neurosensory retinal thickness of 19 eyes of low vision patients from the population of Primorsko-Goranska County of Republic of Croatia, with dry form of the terminal macular degeneration. These results we compared with control measurements performed on 28 eyes of healthy, normal vision subjects from same County. We determined following parameters: central foveal thickness (CFT), macular volume (MV) and mean foveal thickness (MFT) in the both groups. Results showed statistically significant reduction of CFT in the group of normal vision female patients when compared to males, while any significant difference of CFT between total groups of normal vision individuals and low vision patients was not detected. Furthermore, we noticed statistically significant (p < 0.000001) decrease of the MV in the group of the low vision patients in comparison to healthy subjects and statistically significant (p < 0.000001) reduction of the MFT of the low vision patients when compared to normal vision individuals. In our study we detected the absence of any significant difference of the CFT between healthy and low vision population, what looks like controversial finding, because neurosensory retina in the ARMD is thin and atrophic, but on the other side it is known that fixation point in low vision patients is translocated from the damaged fovea to extrafoveal region, usually above the fovea, where neurosensory retina is of the normal thickness, but with the less sensitivity. Furthermore, our results suggest possible connection of higher incidence of ARMD with lower CFT in females. Owing to the thicker neurosensory retina in males and better protection, damaging effect of the UV irradiation, which is the proven factor of ARMD development, is smaller. From the evolutionary point of view it is possible that males in all vertebrates have more resistant macula because during the evolutionary process they have spent much more time outside in the sunlight than females. PMID- 22220426 TI - First results of Intracor procedure in Croatia. AB - This study reports early outcomes of a cohort of presbyopic patients treated with Intracor. The study took place from December 2010 to May 2011 and was conducted in University Eye Hospital "Svjetlost", Zagreb, Croatia. 95 eyes were enrolled in this prospective clinical trial (49 patients with non dominant eye and 23 with bilateral treatment). All patients gave informed consent prior to enrollment. Follow up consisted of uncorrected and corrected distant and near visual acuity, record of topographic changes, visual disturbances and patient satisfaction at 1 week, 1 and 3 months after the surgery. In this study Intracor procedure presented as both safe and effective with all eyes gaining several lines of uncorrected near visual acuity (UNVA), and achieving good uncorrected distant visual acuity(UDVA) as well. UDVA was affected by a mild myopic shift, which was effective in reducing mild preexisting hyperopia in some patients but led to a mild myopic outcome in previously emmetropic patients. Statistically significant improvement in UDVA and UNVA was observed in all time points. At 3 months of postoperative follow up all patients gained several lines of UNVA with monocular UNVA Jaeger system 1.67 +/- 0.28. UDVA showed slight improvement over time and initial myopic shift showed tendency of slight decrease with all patients achieving 1.0. Overall patients satisfaction was very high (98%) with only a few (3 patients, 5 eyes) reporting mild halo and glare at 3 months postop.Intracor procedure has proven its short-term safety and efficacy in treating presbyopia. However, longer follow up period is needed. PMID- 22220427 TI - Transplantation of amniotic membrane in corneal ulcers and persistant epithelial defects. AB - Amniotic membrane transplantation (AMT) leads to reduction of inflammatory symptoms and causes faster epithelisation in corneal ulcers and persistant epithelial defect. 21 patients with corneal ulcer (n = 18) or non-healing epithelial defect (n = 3) unresponsive to conventional treatment were included in the study. All patients were treated by AMT. Corneal epithelial cells in patients suffering from corneal ulcer secreted 3.51 +/- 1.79 of IL-1alpha, 64.27 +/- 31.53 pg/mL of TNFalpha and 209.07 +/- 201.82 pg/mL of VEGF. Levels of all 3 investigated cytokines were significantly higher as compared to controls (p < 0.005). Amniotic membranes that were used contained 775.69 +/- 613.98 pg/mL of IL 1alpha, 0.036 +/- 0.033 pg/mL of sTNF and 175.01 +/- 166.63 pg/mL of VEGF-R. Supporting effect of the AMT could be explained by the fact that AM secretes its natural antinflammatory antagonists IL-1ra, sTNF and VEGF-R. PMID- 22220428 TI - The expression of interleukin-1 alpha, TNF and VEGF in corneal cells of patients with bullous keratopathy. AB - Bullous keratopathy (BK) is a chronic corneal edema with or without subepithelial bullae as a result of a loss of the endothelial cells. 15 patients with BK after cataract surgery with intraocular lens implantation, due to Fuchs dystrophy (n = 3) or corneal endothelial trauma (n = 12) were included in the study. All patients were treated by amniotic membrane transplantation (AMT). Corneal epithelial cells in patients suffering from BK secreted 3.91 +/- 3.09 pg/mL of IL 1 alpha, 4446 +/- 16.8 pg/mL of TNF and 81.43 +/- 37.81 pg/mL of VEGF-I. Levels of all 3 investigated cytokines were significantly higher as compared to controls (p < 0.005). Amniotic membranes that were used to treat investigated patients contained 638.98 +/- 613.98 pg/mL of IL-1ra, 0.026 +/- 0.009 pg/mL of sTNF and 81.39 +/- 21.01 pg/mL of VEGF-R. Beneficial clinical effect of the AMT in treating BK could be explained by its natural production of pro-inflammatory cytokine antagonists such as IL-ra, sTNF antagonist and VEGF-R. PMID- 22220429 TI - Kidney transplantation in elderly patients. AB - The Eurotransplant Senior Program (ESP) allocates kidneys from elderly donors to elderly recipients (> or = 65 years old). During the last 39 years, 922 kidney transplantations were performed in our transplant center. We retrospectively analysed patients included in the ESP from the our center. Eleven patients > or = 65 years old recieved kidney from donors 65 years old. Cold ischemia time was approximately 15 hours. Dual kidney transplantation was performed in one patient. Appropriate immunosuppressive protocol was given to all patients. Surgical complications were relatively common and included dissection of renal artery (1 patient), thrombosis of renal artery (1 patient), ureterovesical obstruction (1), lymphocele (1), bleeding (1), acute abdomen (2) and wound dehiscence (1). One rejection episode was registered. Delayed graft function was observed in the two patients with full recovery of kidney function. Seven patients until now have good functioning graft. Four kidneys were lost. One patient died because of pneumonia. Kidney transplantation in elderly is feasible procedure but with greater number of complications than usually. PMID- 22220430 TI - Epilepsy in the elderly and depression. AB - Epilepsy is one of the most common neurological problems affecting approximately 1% of the world's population with higher incidence among elderly individuals. Although depression is a common comorbid condition in patients with epilepsy, there is a paucity of information regarding depression in geriatric patients with epilepsy. This study analysed a group of 83 patients affected by different epilepsy phenotypes accompanied by mental disorders, especially depression. Antiepileptic and antipsychotic drug treatment has been evaluated, particularly a positive effect of the new antiepileptics (monotherapy and polytherapy) both on the reduction of seizures and mental disorders. PMID- 22220431 TI - Analgesic effect of high intensity laser therapy in knee osteoarthritis. AB - Knee osteoarthritis (KOA), the most common type of osteoarthritis (OA), is associated with pain and inflammation of the joint capsule, impaired muscular stabilization, reduced range of motion and functional disability. High-intensity laser therapy (HILT) involves higher-intensity laser radiation and causes minor and slow light absorption by chromophores. Light stimulation of the deep structures, due to high intensity laser therapy, activates cell metabolism through photochemical effect. The transmissions of pain stimulus are slowed down and result in a quick achievement of pain relief. The aim of our research was to investigate the prompt analgesic effect of HILT on patients with KOA. Knee radiographs were performed on all patients and consequently graded using the Kellgren-Lawrence grading scale (K/L). A group of 96 patients (75 female, 21 male, mean age 59.2) with K/L 2 and 3 were submitted to HILT therapy. Pain intensity was evaluated with visual analogue scale (VAS) before and after the treatment. HILT consisted in one daily application, over a period of ten days, using protocol wavelength, frequency and duration. The results showed statistically significant decrease in VAS after the treatment (p < 0.001). Considering these results, HILT enables prompt analgesic effects in KOA treatment. Therefore HILT is a reliable option in KOA physical therapy. PMID- 22220432 TI - Clinical and medicolegal characteristics of neck injuries. AB - The predominance in performing surgery of major spine injuries by neurosurgeons usually has the consequence of treating all types of spine injuries by neurosurgeons - neurotraumatologists. In the neurosurgical wards of Clinical Hospital Rijeka, we take care of the majority of these patients, following both the major, as well as minor--whiplash injuries of the neck. This article is an overview of the patients admitted in the one year period (October 1st 2009 October 1st 2010) where 1077 cases of neck injuries were analyzed. Vast majority of these injuries were due to traffic accidents (over 94%), and only a small proportion were serious injuries that needed a surgical approach--decompression and stabilization (c1%). We analyzed minor neck injuries thoroughly both because of the increasing number of whiplash neck injuries and because more complicated diagnostic and therapeutic protocols occupy too much time in the ambulatory practice of our neurotraumatologists each year thus representing a growing financial burden to the health organizations and to the society as a whole. Our results proved that the majority of the injured are male (over 60%), young and active (almost two thirds 21-40 years of age), had commonly sustained a Quebec Task Force (QTF) injury of grades 2 and 3 (almost 90%), and, if properly treated, recovered completely after a mean therapy period of ten weeks. Only a minority complained of prolonged residual symptoms, some of them connected with medico legal issues (less than 20%). The results shown are in contrast with the general opinion that malingerers in search of financial compensation prevail in these cases, and leads to the conclusion that minor neck injuries (including whiplash) as well as Whiplash Associated Disorder (WAD) are real traumatological entities, that have to be seriously dealt with. PMID- 22220433 TI - "Brilliant Blue G" and "Membrane Blue Dual" assisted vitrectomy for macular hole. AB - The aim of this study is to evaluate vital dyes "Brilliant Blue G" (BBG) and "Membrane Blue Dual" (MBD) for intraoperative staining of the inner limiting membrane (ILM) during vitrectomy for macular hole (MH). Retrospective, comparative case series on 18 eyes with macular holes who underwent "23 and 25 gauge" pars plana vitrectomy. Main outcome measurements were staining intensity and characteristics, visual acuity, visual field, OCT measurements and complications over a period of 6 months. With the help of BBG and MBD successfully was removed complete ILM in 14 eyes. Postoperative visual acuity was improved in 12 patients, unchanged in 2 patients and worse in 4 patients. Central retinal thickness showed significant postoperative reduction with closure of macular hole. OCT values range were from -10 to -250 microm. No visual field defects and no adverse effects were found. BBG and MBD successfully identificate internal limiting membrane during vitrectomy for MH. Good anatomical and functional results are achieved with the use of both vital dyes. PMID- 22220434 TI - Skin growths of the head and neck region in elderly patients--analysis of two five-year periods in General Hospital Karlovac, Croatia. AB - Skin lesions, benign and malignant, are more common in the older than younger people. Due to the aging of the skin and greater exposure to the impact of ultraviolet rays, their long-term cumulative negative effect, skin lesions are more common in the head and neck area than on other parts of the skin. This paper analyses the pathohistological diagnosis of material after the surgical excision of tumors of the skin on the head and neck of persons older than 60, at the General Hospital Karlovac through two five-year period. The first period is the period from 2006 to 2010 and the second one from 1996 to 2000. The aim was to determine for each period the type and variety of skin lesions, the prevalence of the disease, the age and gender structure, and finally to compare the two periods. The total number of excisions in the first period was 1200, and in the second 513. In both periods more excisions was done in women than men, if compared it comes to 1.4:1. The ratio of malignant (basocellular carcinoma, squamous cell carcinoma and melanomas), and benign tumors (seborrheic keratoses, moles and others) in the first period was 49.3 to 46.3%, and in the second 56.7 to 42.1%. Precancerous lesions (actinic keratoses and Mb Bowen's disease) accounted for 4.3% of lesions in the first and 1.2% in the second period. The total number of basocellular carcinoma was 481/232, which makes 81.3% of all malignant tumors in the first, or 79.7% in the second period. Our results showed that around half of all skin lesions removed in both periods consisted of malignant tumors, among which the most common were basal cell carcinomas. High prevalence of malignant non-melanoma skin cancers, 48.7 and 56%, indicate the importance of protection from UV radiation, and early detection and treatment of skin cancer and precancerous lesions. PMID- 22220435 TI - Our experiences in treatment of prostate carcinoma in patients over the age of 70. AB - The goal of our study was to present our long-standing experience of the treatment of prostate carcinoma in patients over the age of 70. During the 20 years period (from 1991 to 2010) we diagnosed the prostate carcinoma in 1998 patients. More than 58% of the patients were over 70 years old. The most frequent symptoms of the prostate carcinoma were frequent urination and backache. At the first examination 36% of the patients had both prostate lobes involved, and 27% of them had metastases. The most frequent ones (26%) were those in the bone system (pelvis and spine), while in only 1% metastases were found in solid organs (lungs and liver). According to the TNM classification, T1 and T2 were diagnosed in 818 (71%) patients. Histopathological examination discovered Gleason score 2 in 70% of patients and Gleason score 3 in 24% of them. Most often the combination of castration and antiandrogen therapy (in 68% of the patients) and the combination of castration and Estracyt therapy (in 19% of the patients) were applied. In conclusion, intensified efforts should be made in promoting preventive urological examinations because of the great number of patients (27%) with metastases at the first examination. PMID- 22220436 TI - Gender related differences in quality of life and affective status in patients with inflammatory bowel disease. AB - According to the literature, quality of life has been shown to be reduced in females compared with males with Inflammatory Bowel Disease (IBD). Psychosocial factors are also playing an important role in IBD, especially emotional lability. The aims of study was to investigate the sex differences in general and specific health-related quality of life (HRQoL), anxiety and depression in IBD patients. Hundred and twelve outpatients of the Gastroenterology Division, Clinical Hospital Centre Rijeka, were enrolled in our study and divided in two groups: 50 females (31 with ulcerative colitis, UC and 19 with Crohn disease, CD) and 62 males (30 with UC and 32 with CD), age range 19 to 74 (M = 41.46; SD = 13.06). Most patients have been in long clinical remission or with mild disease according to Clinical Disease Activity Index (CDAI) score for CD and Clinical Activity Index (CAI) score for UC. There were significant differences in physical (F = 13.96, p < .0001) and mental (F = 9.44, p < .001) component of the general HRQoL, emotional domain ((F = 9.26, p < .001) and bowel symptoms (F = 7.04, p < .001) of the Inflammatory Bowel Disease Quality of life (IBDQoL), as well as, in anxiety (F = 7.03, p < .001) and depression (F = 12.09, p < .0001) between men and women with IBD. Women have expressed significantly lower level of the general HRQoL and more emotional disturbances connected with their disease as well as more frequent bowel symptoms compared with men. Effect sizes of those differences were large. Results of this study confirm that women with IBD are more prone to the negative impact of the disease on their HRQoL than men. Women with higher level of depression and anxiety experienced more emotional disturbances, bowel and systemic symptoms and lower general HRQoL. These results should deserve more considerations in the clinical treatment of IBD patients. PMID- 22220437 TI - Voice quality in Parkinson's disease in the Croatian language speakers. AB - Parkinson's disease (PD) is well known to cause voice impairments. The aim of this study is to evaluate subjective and objective changes in voice quality in patients with PD in Croatian language speakers. Twenty one patients (11 male and 10 female) with PD and twenty one age-matched (10 male and 11 female) of the control group were assessed. Voice impairment was scored according to Voice Handicap Index (VHI). Patient's perceptual voice analysis was assessed using GRBAS scale including Grade of Dysphonia, Roughness, Breathiness, Asthenia and Strain items. The analysed objective voice parametars were: fundamental frequency, highest frequency, lowest frequency, voice range, jitter, shimmer, maximum phonation time and s/z ratio. In all patients we performed videolaryngostroboscopic examination. Compared with the control group we found the significant differences in VHI, in GRBAS scale (p < 0.05 in all items except asthenia). On videostroboscopic examination, laryngeal tremor was present only in PD group (6 patients), abnormalities of the mucosal wave was found more frequent in PD group (17 versus 8 patients) and also non-closure glottis pattern (11 versus 6 patients). There was no significant difference in the objective voice parametars except in maximum phonation time which was shorter in PD group (15.8 seconds and 23 seconds, p = 0.014) and voice range, which was shorter in PD group (111 Hz versus 147 Hz, p = 0.0465). No one of patients with PD was included in any form of speech therapy. The voice disability in PD is generally well known, but very often underestimated. In this study we found which components of voice were more affected. The voice quality has a significant impact on life quality and potential in assessment for severity of disease state and for the efficacy of treatment. PMID- 22220438 TI - Patient satisfaction and quality in home health care of elderly islanders. AB - Patient satisfaction has been a widely investigated subject in health care research. Quality of care from the patient perspective, especially in home health care, however has been investigated only very recently. Home health care is a system of care provided by skilled practitioners to patients in their homes under the direction of a physician. Multidisciplinary nature of home health care services present challenges to quality measurement that differ from those found in a more traditional hospital settings. The aim of the study was to investigate the satisfaction of elderly patients living on islands with home health care. Participants receiving skilled nursing care in their homes, for any diagnosis, who met selection criteria, were surveyed about their perception of the quality of health care. The research was conducted during the year 2010 among the residents of Kvarnerian islands (Krk, Cres and Mali Losinj) under the authority of Croatian Institute for Health Insurance that approved the protocols employed in the investigation. Most older patients (96.2%) reported high levels of satisfaction with health services delivery. Common leading diagnosis among home health care patient include diseases of circulatory system (28.9% of patients), nutritional and metabolic disease (14.5%), malignant diseases (13.2%), musculoskeletal and connective tissue disease (11.8%), diseases of the nervous system (9.2%), followed by injury and poisoning (7.9%). Provision of home health care was well received by elderly patients. Home health care providers seek to provide high quality, safe care in ways that honour patient autonomy and accommodate the individual characteristics of each patients home and family. The demographics of an aging society will sustain the trend towards home-based care. Therefore, research on effective practices, conducted in home health care settings, is necessary to support excellent and evidence-based care. PMID- 22220439 TI - Implementation of program of prevention and early detection of osteoporosis among women of Primorsko-goranska County. AB - The aim of this paper is to present preliminary data of Program of prevention and early detection of osteoporosis among women in Primorsko-goranska County. Osteoporosis is recognized as a public health problem for which clearly preventive measures are defined. Measurement of bone density was done by ultrasound densitometry of the calcaneus among women aged from 45 to 69 years old. 688 women were examined and they were classified in five five-year age groups. The women with the osteoporosis (T-score < or = 2.5) were 141; osteopenia (T-score from -2.5 to -1) were found in 400 women, and those with normal range of T-score were 147. All of five groups of women had T-score in range of osteopenia (T-score < or = 1). A statistically significant difference was between the first and fourth groups of women (p = 0.002) and the second and fourth groups (p = 0.001). After examination, depending on the value of T-score, women were recommended to visit family doctor and they also got educative booklet with advices for healthy nutrition and physical activity. Implementation of this program indicated the importance of proper lifestyle in the prevention of osteoporosis. Average T-scores of all five groups of women show that osteopenia occurs also in the youngest ones. This indicates the need for a systematic approach to preventing osteoporosis through education of women including younger ones and creating conditions for organized physical activities at the community level. PMID- 22220440 TI - Radial extracorporeal shock wave therapy in the treatment of shoulder calcific tendinitis. AB - Shoulder calcific lesions of the rotator cuff are a common problem in physiatric and orthopedic practice. The lesions are mostly located in the supraspinatus tendon, close to the insertion area in the critical zone. Patients are usually treated conservatively by nonsteroid antiinflammatory drugs, analgesic drugs, local injections, physiotherapy and rarely by applying surgical procedures. Painful shoulder gives rise to functional disabilities and may sometimes lead to pharmacological overuse. In the last twenty years, extracorporeal shock wave therapy (ESWT) has been frequently used in the treatment of calcific tendinopathies. We have evaluated the effectiveness of radial ESWT on the group of 30 patients, aged between 28 and 58 years, with calcific tendinitis of the shoulder. Criotherapy, medical exercises and radial ESWT were applied. We used the radial ESWT device (BTL-5000 SWT, Columbia, USA), 3 bars pressure, 10 Hz frequency, 2000 shocks. Patients were examined before the beginning of the treatment, immediately after the treatment, and 6 months later. The treatment included measurement of the range of motion (ROM), measurement of voluntary isometric contraction of shoulder muscles with manual muscle test (MMT), and subjective assessment of pain intensity with visual analogue scale (VAS). X-ray was done before and 6 month after treatment. The study has shown the efficiency of the treatment with radial ESWT. The level of statistical significance was determined with student t-test. Radial ESWT applied to patients with shoulder calcific lesions of the rotator cuff resulted in pain relief increase in the range of motion and increase in the muscular strength. As shown by X-ray, these results were followed by the decrease in the size of the rotator cuff calcifications. PMID- 22220441 TI - Analysis of senior population visits to physical medicine in Croatia. AB - The aim of the study was to analyze the senior population when deciding to choose either going to the private or public physical medicine practice in Croatia. 240 patients (public and private group, 120 participants each) from the Croatian medium large county Primorje-Gorski kotar, were enrolled from 6 physical medicine practices (3 public and 3 private). Between December 1st 2009 and January 31st 2010, in the public and private practices seniors aged 65 to 85 years were 64.17%, 52.40% respectively, of all interviewed participants in single group. The results showed that in Croatia majority of seniors visiting the physical medicine were females in revisit and dependents of government health insurance. Study suggested the great influence of general practitioner, closeness to home and time of the appointment for patients going to public physical medicine, while in private peers and sooner appointment outweigh. In either practice seniors were satisfied with the overall quality of health services and graded the best average higher in favor for the private. Elderly Croatian residents showed to be the important feature in physical medicine and rehabilitation and to participate actively in their health issues. Following those results, we will perform the study in the rest of the country and compare it to this data. That could enable the specific improvement for the health care of seniors in Croatia. PMID- 22220442 TI - Polytrauma in elderly. AB - The aim of this study is to present certain particularities in treating polytraumatized patients age of 65 and above. All of the patients were treated in our hospital. 413 patients were included in this 4 year study (2006-2010). Injury severity score was 17 and above (ISS > 17). Patients aged above 65 were sub grouped. In this 4-year period, we treated 52 or 13% elderly patients. In this subgroup there were 30 (58%) males and 22 (42%) females, with mean age of 74 (max age 95 years old). Demographic factors, injury mechanisms, patients resuscitation protocols, imaging used, etc. were also included as variables. Mortality rate in elderly patients was 31%, while in patients below 65 years of age as 12%. Taking relevant data into consideration, a special emphasis was given to certain circumstances of intensive and surgical treatment of elderly patients. A large portion of polytraumatized patients are consisted of elderly. Patients aged 65 and above have higher mortality rate with lower ISS in the mortal group and falls are the most frequent mechanism of trauma. In this study, we tried to emphasize some clinical implications when treating those patients, as well as importance in continuous medical staff education in trauma principles to minimize mortality rates. PMID- 22220443 TI - Cervical cancer in Osijek-Baranja County--possibilities for prevention. AB - In Osijek-Baranja County, there was a rise in the number of non-invasive and fall of invasive cervical cancer in the period 2000-2008, but cervical cancer still represents an important public health problem in Osijek-Baranja County. Cervical cancer in 2008 was the ninth female cancer site and represents 3.5% of all malignant diseases in women. In the same year it was also at the ninth place of all cancer deaths in women with a share of 3.3%. The large number of women cervical cancer was detected at an advanced stage of the disease so that there is an pincrease in mortality from cervical cancer. Although the incidence of cervical cancer is lower in relation to Croatia and other countries in the region, the mortality rate is still higher than in the countries of Western Europe. In order to reduce the incidence and mortality of cervical cancer primary task of the public health system is the introduction of secondary prevention through properly organized screening program. The program should be tailored to the financial and human resources and local specificities, with the agreement on a strategy that will give the best results. PMID- 22220444 TI - Personal experiences of the psoriasis and its relation to the stressful life events. AB - Psoriasis is a disease with a profound impact on the psychological and social aspects of the patient, particularly because of its visibility. Quality of life is impaired and different mental health disorders like depression, anxiety, alcoholism, posttraumatic stress disorder (PTSD) are found among persons suffering from psoriasis. Studies have shown the influence of stressful life events on onset, exacerbation and relapse of psoriasis. Rare studies explored prevalence of psoriasis during war times and relations between psoriasis and war provoked PTSD. Psoriasis is a disease with multiple possible causes and additional caution is necessary among medical professional to recognize all contributing factors. This report describes a case of a person whose first episode of psoriasis appeared six months after engaging in combat activities. He is diagnosed with psoriasis vulgaris, psoriatic arthritis and permanent personality changes after the traumatic experiences caused by war participation. His occupational history is burdened with additional causational factors; work with heavy metals and metal dusts. Cumulative effects of different aetiological factors can contribute to psoriasis with intensive trauma induced stressors serving as a trigger. His medical history indicates cognitive difficulties typical for early dementia which makes this case even more interesting. Research results suggesting common aetiology of psoriasis, autoimmune diseases and neurodegenerative diseases, indicate a need, as in the case of our patient, for multidisciplinary approach to studying aetiology of psoriasis. PMID- 22220445 TI - Changes in life-quality, a possible symptom of dementia development. AB - Dementia is a chronic and irreversible brain impairment characterised by significant cognitive deficits. Severe symptoms of the aforesaid disease interfere with normal life functions and daily activities. Dementia usually develops with advancing age, i.e. after the age of 85, and when it develops in people younger than age 65, it is referred to as early onset dementia. This paper presents a 53-year-old male patient. Provisional diagnosis was established while further diagnostic workup included psycho-diagnostic assessment, neurological exam, and brain CT Such workup confirmed the development of dementia, i.e. early onset Alzheimer's disease accompanied by depressed mood with impaired vision. PMID- 22220446 TI - Quality of life in people with physical disabilities. AB - The aim of this study was to examine the possible differences in self-reported quality of life of people with physical disabilities with regard to both socio demographic and disability-related characteristics. Testing was conducted on 153 respondents with physical disabilities, residents of the City of Zagreb. Positive correlations were found between the quality of life and income satisfaction, residence size (per capita floor area) and level of residence equipment. Multivariate analysis of variance showed statistically significant differences in quality of life among respondents with regard to the marital status, work status and home ownership. Statistically significant differences in the quality of life were found among the participants depending on their level of physical mobility and type of physical disability. The level of physical mobility is associated with general satisfaction with the accomplishment of goals, aspirations and hopes. The type of physical disability is related to the satisfaction with leisure activities, with the material status, expectations to achieve in the future what has not formerly been achieved. There was also a significant relation between the type of physical disability and general satisfaction with life in the past year. Positive correlations between duration of disability and quality of life were found. Membership in associations of persons with physical disability and related benefits were shown to contribute to the quality of life. PMID- 22220447 TI - Efficancy of decompressive craniectomy in treatment of severe brain injury at the Rijeka University Hospital Centre. AB - Decompressive Craniectomy (DC) is a treatment option for severe brain injury (SBI). This method is applied when the growth of intracranial pressure (ICP) can no longer be controlled with conservative methods. DC belongs to class III "Guidelines"--"option" which has not clear clinical certainty. They do not correspond to "Standards" (class I) in treatment protocol for SBI, which is common in most neurotraumatological centers. We have analyzed retrospectively 95 patients with SBI who were admitted to the Clinical Hospital Centre Rijeka. All patients were managed based on a protocol of current Brain Trauma Foundations (BTF) Guidelines. 39 patients underwent DC while 34 patients underwent standard craniotomy. 22 patients did not undergo any surgical procedures. In each patient we analyzed ICP changes within the first 11 days and in that way we correlated them statistically with the initial Glasgow Coma Scale (GCS) and then with Glasgow Outcome Scale (GOS), after the end of the treatment. We particularly analyzed the outcome with reference to the time of the operation and the size of DC. The standard measurement of ICP shows statistical significance in recovery in the group without DC after 5 days of intensive treatment, when the pressure is stabilized between 20-25 mm Hg. The stabilization of ICP in the DC group is observed already after 3 days of intensive treatment. Furthermore, better functional recovery according to GOS, which is statistically significant, was observed in patients who underwent DC where the area of craniectomy was larger than 25 cm2, within the first 24 hours from the time of injury. The use of DC considerably reduces the need for CT check-ups. Increase in the number of encephalocele was noted, which is to be expected considering that dural decompression is used in DC procedure. The results of our study indicate that the utilization of DC is characterized with lower mortality and better functional recovery if it is applied at an early stage of treatment and if the size of DC is satisfactory. PMID- 22220448 TI - Importance of correct therapeutic procedure selection in voice recovery. AB - Psychological and physical patient state as well as the influence of other social factor is of great influence voice rehabilitation. A team of experts in the field of voice and its function are involved in voice therapy. Our research was focused on the successfulness of voice recovery depending on the patient vocal disorder approach. We made a comparison of two methods: RVT and Accent method. We attempted to evaluate clinically relevant voice disorders in relation to certain vocal methods, we propose that a lot can be learned about voice trough therapeutic procedures, which can also be used to enhance the practical application of vocal methods and raise the level of success in dealing with people that suffer from voice pathology. PMID- 22220449 TI - Early identification of patients with the risk for postoperative carotid restenosis development. AB - Multiple randomized trials over the last decade for both symptomatic and asymptomatic carotid stenosis have proven the efficacy of carotid endarterectomy (CEA) in reducing the risk of stroke. The aim of this prospective non-randomizing cohort study was to determine the incidence of carotid arteries restenosis after CEA as well as to ascertain the clinical and etiological characteristics for the development of restenosis. Treatment data from 178 KBC Rijeka patients that had undergone CEA in the period 1. 09. 2005-30. 8. 2009 has been processed. All patients are monitored trough our Neurosonology laboratory algorythm--first Doppler ultrasound examination within the first week after CEA and the following after 1, 3, 6 and 12 months. After this time once a years. The average monitoring time was 21 month (1-36 months). In the stated period 27 restenosis was diagnosed (15.16%). Only four of them were symptomatic (14.81%). Patient survival rate is 98% in the first 12 and 92% in the first 36 months. Carotid restenosis is usually asymptomatic. Non-invasive postoperative carotid arteries color Doppler screening is essential in the early identification of patients with the risk for the development of restenosis. PMID- 22220450 TI - Increasing burden of melanoma in Croatia. AB - Melanoma consists 4-5% of all skin cancers, but it contributes to 71-80% of skin cancers deaths. It is controversial whether worldwide increases in melanoma incidence represent a true epidemic but at the same time that dramatic increase in incidence occur in setting of relatively stable mortality trends, observed in Croatia also. The majority of authors accept that main risk factors for melanoma relate to environmental exposure and genetics with epidemiologic studies linking sun exposure to melanoma development. Data were obtained from Croatian cancer register for patients diagnosed between 1999 and 2008, for malignant melanoma of the skin (ICD-10 code C43) at national level and from 2003 to 2008, at the County level (Primorsko-goranska County). Melanoma incidence nearly doubled in males from 8.75 to 13.4/10(5) per year, fold in females from 9.1 at the start of observation to the end of 12.0/10(5) per year in Croatia. Melanoma incidence rates were much more higher for Primorsko-goranska County with range from 10.1 to 17.5/10(5) per year. The greatest increase of melanoma incidence rates was in males 60 years and over year group at diagnosis. National comparison of variation in cancer incidence by region and age can provide basis for public health prevention. It requires the integration of information on risk factors, incidence that could help to reduce regional inequalities in incidence and reduce the future cancer incidence. PMID- 22220451 TI - Comparison between carotid stenting and carotid endarterectomy in early outcome. AB - Carotid artery stenting (CAS) is a widely used method in prevention of stroke for carotid artery stenosis as an alternative to surgical treatment. Initial studies reveal higher morbidity and mortality rates for CAS than acceptable standards for carotid endarterectomy (CEA). The aim of this study was to compare results in a series of CAS with concurrent risk-matched group of CEA patients. The study included two groups of 50 patients with internal carotid artery stenosis. We compared early outcome (30 days after procedure) in risk-matched groups of patients that underwent these procedures. Post procedural complications were equally frequent in both groups. There was no significant difference in perioperative complication rates (P = 0.871). Comparison of these two methods shows that CAS and CEA are competitive methods for treatment of carotid artery stenosis. Particularly in symptomatic patients with high risk for surgery CAS is alternative treatment. PMID- 22220452 TI - Parental quality of life in the framework of paediatric chronic gastrointestinal disease. AB - Chronic gastrointestinal diseases, such as inflammatory bowel disease (IBD) and celiac disease (CD), might have impact not only on the affected child but also on their parents since inside the family framework, a change in each member may have influence on the whole system. The aim of this study was to test the hypothesis that parents whose children have IBD or CD will have a lower quality of life (QoL) compared to parents of healthy children, as well as that lower QoL will be found among parents who perceive lower health related quality of life (HRQOL) of their child. 55 parents of children with IBD, 49 of CD and 53 parents of healthy children were included in the study. Children were aged 7-18 years. In order to measure parental QoL, a Croatian version of the WHOQOL-BREF questionnaire was administered, with four domains: physical health, psychological health, social relationship and environment. The Total QoL was calculated as a sum of all domain items. The parent-proxy report of children's HRQOL, PedsQL 4.0 Generic Core Scales was used. Main result shows that parents of children with IBD report a significantly lower psychological health, compared to parents of other children, and significantly lower physical health compared to parents of healthy children. Among parents of children with CD and parents of healthy children, better parental Total QoL was significantly correlated with better parental report of children's HRQOL, while for parents of children with IBD those associations were not found. Results of study show association between presence of the disease in offspring with poorer parental QoL, thus highlight the importance of supporting not only children with chronic disease but also involving their parents in psychosocial interventions, as well as supporting the patient's association groups which gather both children with chronic disease and their parents. PMID- 22220453 TI - Resolution of pseudophakic cystoid macular edema with combination therapy of topical corticosteroids and nonsteroidal anti-inflammatory drugs. AB - A 69 years old women underwent uneventful cataract surgery of her left eye with phacoemulsification and posterior chamber intraocular lens implantation in topical anesthesia. Patient was postoperatively treated with combination of antibiotic and steroid in decreasing dosages during five weeks: one drop five times a day the first week, three times a day second to forth week and one time a day the fifth week. In each checkup, performed first postoperative day, 7 days, 5 weeks and 12 weeks after the operation, visual acuity with and without correction, tonometry, corneal transparency, biomicroscopy of posterior pole and measure of macular thickness by optical coherence tomography (OCT) were performed. At first day follow-up visit, the patient's visual acuity was 20/25 but 6 weeks after the operation, the patient's vision had worsened to 20/60 after a slow steroid tapper. At that time OCT showed foveal thickening and cystic changes specific for cystoid macular edema (CME). Combination of corticosteroid and non-steroidal anti-inflammatory drug four times daily was included in therapy. The dose was tapered off over the ensuing 8 weeks. The total treatment duration was 12 weeks. At the patient's 2-month follow-up visit, vision has improved to 20/20 and the fovea appeared flat. OCT showed complete resolution of foveal thickening and cystic changes. Combination of corticosteroid and NSAID is effective and safe therapy for treating pseudophakic CME. Patient showed significant improvement in visual acuity and retinal thickness at 2 months post treatment. PMID- 22220455 TI - Aggressive multifocal form of epithelioid hemangioendothelioma--case report. AB - Epithelioid hemangioendothelioma (EHE) is a rare tumor of the vascular origin. It was first described in its pulmonary form by Dail and Leibow in 1975 and named "intravascular bronchioalveolar tumor" (IVBAT). Since then, reports of occurrences of the tumor have been made for number of locations, but most often tumor can be found in soft tissues, liver, lungs, bone and skin. It is considered to be a low or borderline malignant tumor with, usually, slow progression, but aggressive forms have been described. We here report a case of a 46-year old female patient with multifocal malignant tumor spreading to lungs, liver, spleen and with synchronous involvement of lumbal vertebrae, illiac bones and central nervous system dissemination. To the best of the authors knowledge, no case of malignant EHE with multiorgan involvement of this proportions and synchronous central nervous system and bone involvement in one patient has been reported to this date in English-speaking literature. PMID- 22220454 TI - Tuberculous orchiepididymitis, meningoencephalitis and hydrocephalus. AB - Tuberculous meningoencephalitis (TBM) is a rare and serious, often fatal presentation of active tuberculosis and account for about 1% of cases. Early diagnosis and prompt treatment of TBM is essential to reduce morbidity and mortality. Here, we report a case of TBM in 60-year-old man. TBM was considered on the basis of clinical presentation, laboratory findings (hyponatraemia), cerebrospinal fluid studies, radiological findings (hydrocephalus on multi-slice computed tomography), and history of orchiepididymitis of unknown origin one year earlier, together with information that the patient originated from Kosovo where incidence of tuberculosis is still high. Mycobacterium tuberculosis was cultured from cerebrospinal fluid on Lowenstein-Jensen medium confirming diagnosis of TBM. Subsequently, acid-fast bacilli (AFB) staining on samples obtained after orchiectomy a year ago was performed, revealing AFB. Anti-tuberculosis therapy is still in course. This is the second case of tuberculous meningoencephalitis with the same disease pattern (i.e. tuberculous orchiepididymitis - meningoencephalitis) in our Department, and this fact was crucial for the presumptive diagnosis and urgent treatment of TBM. The former case was described five years ago. PMID- 22220456 TI - Conjunctival amelanotic melanoma--a case report. AB - Conjunctival melanoma is a relatively rare malignancy. It is presented as pigmented nodule in any area of conjunctiva, amelanotic tumors are pink with smooth appearance. The authors describe an amelanotic melanoma of the conjunctiva in an 82-year-old female patient. Cytological, histopathological and immunohistochemical studies revealed an invasive amelanotic melanoma exhibiting S 100 and MART-1 positivity. The patient undervent surgical and chemotherapy treatment and three years after the initial treatment is in the terminal stage of metastatic disease. Absence of pigmentation delayed early clinical detection and treatment. Awareness of this nonpigmented melanoma is crucial for early recognition and appropriate management. PMID- 22220457 TI - Surgical treatment of residual esotropia. AB - Residual esotropia is a common problem following bilateral medial rectus (MR) recessions for esotropia. The patient was 30 years old men who underwent bilateral MR recession of both eyes in the childhood. Recession was repeated on the right eye few years after the first surgery, but residual esotropia progressed. Prior to our surgery residual angle of esotropia was 50PD degrees with restriction of abduction and elevation of the left eye. Sinechiolysis et myectomia of right MR and sinechiolysis and recession of left MR were performed using operating microskop. One week after surgery residual angle was 4 PD. Motility of both eyes was free except slight residual reduction of left eye elevation. During postoperative period of 2 years residual angle was not greater than 8 PD, with good motility of both eyes. We suggest that sinechiolysis and myectomia of MR together with recession of the prior operated muscle, when possible, can be a reasonable surgical option in the treatment of large-angle residual esotropia. PMID- 22220458 TI - Corneal thickness in pseudoexfoliative glaucoma. AB - Measurements of central cornea thickness (CCT) have a very important value in glaucoma patients; if the central cornea is thinner than it suggests, then the intraocular pressure is falsely low. This study compares the central cornea thickness between patients with pseudoexfoliative glaucoma, open angle glaucoma, angle closure glaucoma and control group. This study included 34 patients with pseudoexfoliative glaucoma, 31 patient with open angle laucoma, 28 patients with angle closure laucoma and 36 normal subjects in a control group. Patients in all groups and also normal subjects in control group had no other corneal disorders, no history of trauma, corneal surgery and were not patients with contacts lens use. Patients with pseudoexfoliative glaucoma and also patients with open angle glaucoma had significantly lower values of central cornea thickness compared with normal subjects in control group. Tomey EM 3000 is a non contact specular microscope which was used to measure central corneal thickness in this study. Pachymetry is an important method for diagnoses of glaucoma and for examination of the intraocular pressure in glaucoma patients, because values of the central corneal thickness affect the exact intraocular pressure readings. PMID- 22220459 TI - Corneal thickness in congenital glaucoma. AB - Central corneal thickness is very important measurement in glaucoma treatment because it influences the eye pressure measurements. A thinner cornea gives us artifactually lower intraocular pressure and a thicker cornea gives higher intraocular pressure reading, so it has to be corrected in both cases. The aim of this study is to compare central corneal thickness between congenital glaucoma patients and normal subjects. Prospective study included 27 patients with congenital glaucoma and 35 patients in control group. First group was subdivided in two subgroups: A--8 earlier operated patients, B--19 patients treated with topic therapy. Patients had no other corneal disorders, history of trauma, corneal surgery and they were not contact lens wearers. Measurements were performed by specular microscope Tomey EM 3000 on central corneas. This study showed that patients with congenital glaucoma have lower central corneal thickness than normal subjects. Also, the study showed that antiglaucomatous operation doesn't influence central corneal thickness. Central corneal thickness need to be a routine part of examination measurements because of need to correct intraocular pressure according to it, but also the thinner corneas values can suggest congenital glaucoma diagnosis beside the other parameters. PMID- 22220460 TI - The role of omega6 to omega3 ratio in development and progression of age-related macular degeneration. AB - The aim of this study is to investigate possible connection between omega-6/omega 3 fatty acid ratio and development and progression of Age-Related Macular Degeneration (ARMD). We examined 125 patients diagnosed with ARMD and divided into 5 groups of 25 patients according to CARMS (Clinical Age-Related Maculopathy Staging System). Control group consists of 51 patients with similar ages, without ARMD. All of them underwent stereobiomicroscopy, fundus photography and fluorescein angiography. Dietary fatty acids intake was measured using food frequency questionnaire (FFQ). The FFQ was based on previously validated questionnaire (DIETQ, Tinuviel Software, Warington, Ches, UK) and FFQ2 from Blue MountainEye Study. The data were analysed using food nutritient dana from McCance and Widdowson's Food Composition Tables, supplemented with a food fatty acid content database (Foodbase, London, UK). We noticed statistically significant difference between omega-6/omega-3 ratio in neovascular ARMD (stage 5) and all other groups including control group (p = 0.000020). The ratio in Stage 5 was about 11:1 like in Western diet. Stage 4-geographic atrophy (GA) has statistically significant difference in o-mega-6/omega-3 ratio compared with stage 1 (p = 0.000571), stage 2 (p = 0.000112) and stage3 (p = 0.000430). The ratio in first three groups is about 7-7.5:1 (greater then Mediteran-4-5:1, but lower then Western Diet-10-20:1). There is no statistically significant difference between first three stages (p > 0.05) and stage 4 and control group (p = 0.172388). Omega-6/omega-3 ratio is connected with development of neovascular ARMD. Decreased ratio protects against neovascular ARMD. On the contrary, GA seems to be connected with prolonged sunlight exposure (the ratio is about 6:1). It is good to know that changing nutrition habits someone can prevent development of severe neovascular form of ARMD because intravitreal anti-VEGF therapy limitations. PMID- 22220461 TI - Dysplastic nevus--risk factor or disguise for melanoma. AB - Dysplastic nevus is an acquired or hereditary nevus that clinically seems atypical and pathohistologically dysplastic. The term of dysplastic nevus has changed through history and even until now the dermatologists and pathologists have not found the same conclusion for name and definition of dysplastic nevus. Epidemiology of dysplastic nevus is different depending on geographic lattitude, being three times higher in Australia than in Great Britain. Genetic factors play a role in etiology of dysplastic nevus but are still not well defined. UV radiation is indisputable main etiological factor in developing dysplastic nevus. Many studies confirm that children who have been using sun protection creams with SPF have less dysplastic nevi than those who did not. Nevus with geographic shape and muddy borders, dominately macular, red to brown colored and has 5 mm or more in diameter is clinically dysplastic nevus. ABCDE rules count for dysplastic nevus as well as for melanoma but prefferable diagnostic criteria for dysplastic nevus would be "ugly duckling sign". Pathohistologic analysis is the key in confirming the diagnosis of dysplastic nevus. Great experience and knowledge in dermatopathology field is essential for pathologists to make a distinction between dysplastic nevus and melanoma in situ. Likewise great experience in dermatooncology field is essential in differentiating dysplastic nevus from other nevi. Surgical excision is the only therapy that should be done for dysplastic nevus. Regular follow up is highly recommended for patients with dysplastic nevus and syndroma naevi dysplastic. Education about sun protection measures and self examination techniques is essential for all patients with dysplastic nevi and their family. PMID- 22220462 TI - Melasma--updated treatments. AB - Melasma is a common, acquired facial skin disorder, mostly involving sun-exposed areas like cheeks, forehead and upper lip. Melasma occurs in both sexes, although almost 90 percent of the affected are women. It is more common in darker skin types (Fitzpatrick skin types IV to VI) especially Hispanics/Latinos, Asians and African-Americans. The onset of the melasma is at puberty or later, with exception of darker skin types, who tend to develop this problem in the first decade of life. The etiology is still unknown, although there are a number of triggering factors related to the onset of melasma. The most important are sun exposure and genetic factors in both sexes, while hormonal activity has more important role in females. In addition, stress and some cosmetic products and drugs containing phototoxic agents can cause outbreaks of this condition. Melasma should be treated using monotherapies or combination of therapy, mainly fixed triple or dual combinations containing hydroquinone, tretinoin, corticosteroids or azelaic acid. Modified Kligman's formula is also very effective. Above mentioned therapy regimens in combination with UVA and UVB blocking sunscreens are mostly effective in epidermal melasma. Discontinuation of the use of birth control pills, scented cosmetic products, and phototoxic drugs coupled with UV protection are also benefitial in clearing of melasma. Alternative treatment including chemical peels and glicolic acid, seem to have the best result as a second line treatment after bleaching creams. Laser treatments show limited efficacy and should rarely be used in the treatment of melasma. Combining topical agents like hydroquinone, tretinoin and a corticosteroid in addition to sun avoidance, regular use of sunscreen throughout the year and patient education is the best treatment in this difficult to treat condition. PMID- 22220463 TI - Placebo in the treatment of pain. AB - Placebo is the use of the substance or procedure without specific activity for the condition that is trying to be healed. In medicine, benefits of placebo effect are used since 1985 and 1978 placebo effect was first scientifically confirmed. It was found that placebo induced analgesia depends on the release of endogenous opiates in the brain and that the placebo effect can be undone using the opiates antagonist naloxone. Functional magnetic resonance imaging of the brain showed that placebo analgesia was obtained regarding the activation and increased functional relationship between ant. cingulate, prefrontal, orbitofrontal, and insular cortex, nucleus accumlens, amygdala, periaqueduktalne gray matter and spinal cord. Placebo also facilitates descending inhibition of nociceptive reflexes through periacvaeductal gray substance. Placebo effect can be achieved in several ways: by using pharmacological preparations or simulation of operating or other procedures. This phenomenon is associated with perception and expectation of the patient. To achieve the effect of placebo it is essential degree of the suggestions of the person who prescribe a placebo, and the degree of belief of the person receiving the placebo. Expected effect of placebo is to achieve the same effect as the right remedy. Achieved placebo effect depends on the way of presentation. If a substance is presented as harmful, it may cause harmful effects, called 'nocebo" effect. Placebo effect is not equal in all patients, same as the real effect of the drug is not always equal in all patients. Application of placebo in terms of analgesia will cause a positive response in 35% of patients. Almost the same percentage (36%) of patients will respond to treatment with morphine in medium doses (6-8 mg). Therefore, one should remember that response to placebo does not mean that a person simulates the pain and then it is unethical to withhold the correct treatment especially in light of findings that the prefrontal cortex is activated expecting liberation of pain and how this action reduce activities in brain regions responsible for sensation of pain (thalamus, somatosensory cortex and other parts of the cortex). However, the use of placebos is ethically, legally and morally very dubious. The basis for the placebo effect is deception. It undermines honest relationship and trust between doctor and patient which is extremely important for successful treatment. Consciously giving placebos to patients for a condition that can be adequately treated, with prejudice the right of patients to the best care possible, opens up many bioethical issues. Despite all the current knowledge level, placebo effect remains still a scientific mystery. PMID- 22220464 TI - Actinic reticuloid--photosensitivity or pseudolymphoma?--A review. AB - Actinic reticuloid (AR) or chronic actinic dermatitis is considered a sunlight induced pseudolymphoma (PSL) on light exposed areas of the skin, which primarily affects elderly males. The disease is a severe, chronic photosensitive dermatosis, first described by Ive et al. in 1969. PSL is a group of non cancerous lymphocytic skin disorders that simulate malignant lymphomas, but the changes usually spontaneously regress. The clinical appearance of Actinic reticuloid is variable, usually characterized by an eczematous, pruritic eruption, predominantly present on the head and neck, or other sun exposed areas, but can involve any area of the body. Thereby, crucial characteristic is photosensitivity, where at action spectrum involves UVB, UVA and visible light beyond 400 nm. The disease is considered as PSL which histologically resembles lymphoma with immunohistochemical analysis of the cutaneous infiltrate revealing presence of activated T cells, numerous histiocytes, macrophages and B cells. Moreover, the development of malignant (non-cutaneous) T cell lymphoma in the course of AR has been reported. As the disease has chronic character, it requires significant changes in the patient's lifestyle and avoidance of provoking factors such as contact allergens or sources of intense light. Thus AR should be considered in every patient who presents with persistent, unclear, erythematous skin changes on the face and neck that are related to sun exposure. PMID- 22220465 TI - Epidemiology of central nervous system tumors in Karlovac area (Croatia), 1995 2010. AB - The aim of this study was to provide an overview of the central nervous system (CNS) tumours epidemiology in Karlovac region, over the 1995-2010 period. We analyzed data on 359 patients (194 men and 165 women), diagnosed with CNS tumours according to the World Health Organization's diagnostic criteria, in period 1995 2010. The data were obtained from the Neurology and Neurosurgery Department, including other medical records. The data were analysed with t-test and chi square test. A total of 359 cases of tumours in CNS were recorded for the period of 1995-2010, with slight predominance of men (194;54.0%) over women (165;46.0%). Under the assumption of gender equality, we did not detect a significant gender difference in tumour diagnosis (p = 0.279). Mean age at the diagnosis was 64.1 +/ 12.6 years, with significant gender difference: mean age at diagnosis for men was 62.8 +/- 11.6 years, while for women it was 65.7 +/- 13.5 (p = 0.029). The commonest type of all tumours was metastases (144;40.1%). When only primary tumours were analysed, the commonest type was glioblastoma (125;58.15%), followed by meningeoma (44;20.5%). The remaining types were much less frequent, with i.e. 5 recorded cases of the following three types: astrocytoma, ependimoma and oligodendroglyoma (2.3%). These results suggest a commonly encountered epidemiological profile in the region, with commonest metastases, and glioblastoma as the most common primary tumour. Due to difficulties related to patient gravitating hospitals admittance and overall small sample size for more detailed analyses, it remains for future studies to determine potential association of the Homeland war (1991-1995) and the occurrence of CNS tumours. PMID- 22220466 TI - Clinical utility of red cell distribution width in alcoholic and non-alcoholic liver cirrhosis. AB - Red blood cell distribution width (RDW) is a measure of the variation of red blood cell width that is reported as apart of standard complete blood count. Red blood cell distribution width results are often used together with mean corpuscular volume (MCV) results to figure out mixed anemia. The aim of our study was to compare the values of RDW in alcoholic and non-alcoholic liver cirrhosis and to determine if RDW follows the severity of disease according to Child-Pugh score. We retrospectively analyzed 241 patients (176 men and 65 women) with liver cirrhosis and anemia, defined as a hemoglobin value < 130 g/L in men and < 120 g/L in women, which were hospitalized in our Division in a period between 2006 and 2008. Patients were divided in two groups; in first were patients with alcoholic liver cirrhosis, and in second with non-alcoholic cirrhosis. Severity of disease was determined according to Child-Pugh score. Red blood cells distribution width Normal reference range is 11-15%. Alcoholic liver cirrhosis had 204 patients (85%) while non-alcoholic cirrhosis had 37 patients (15%). In group of alcoholic cirrhosis the average RDW was 16.8%. In relation to severity of disease the average RDW for Child-Pugh A was 16.80%, for Child-Pugh B was 16.92%, for Child-Pugh C was 17.10%. In the group of non-alcoholic cirrhosis the average RDW was 16.73% and in relation to severity of disease for Child-Pugh A was 16.25%, for Child-Pugh B 17.01% and for Child-Pugh C was 16.87%. We didn't find statistically significant difference of RDW between alcoholic and non alcoholic cirrhosis (p > 0.05) and we didn't proved any statistically significant increase of RDW in relation to severity of disease in group of alcoholic cirrhosis (p = 0.915) nor in group of patients with non-alcoholic cirrhosis (p = 0.697). Our study showed that RDW had not any clinical value in differentiation of anemia neither in alcoholic and non-alcoholic liver cirrhosis nor in severity of liver disease. PMID- 22220467 TI - UV-radiation, apoptosis and skin. AB - Apoptosis or programmed cell death is a key function in regulating skin development, homeostasis and tumorigenesis. The epidermis is exposed to various external stimuli and one of the most important is UV radiation. The UVA and UVB spectra differ in their biological effects and in their depth of penetration through the skin layers. UVB rays are absorbed directly by DNA which results in its damage. UVA can also cause DNA damage but primarily by the generation of reactive oxygen species. By eliminating photodamaged cells, apoptosis has an important function in the prevention of epidermal carcinogenesis. UV-induced apoptosis is a complex event involving different pathways. These include: 1. activation of the tumour suppressor gene p53; 2. triggering of cell death receptors directly by UV or by autocrine release of death ligands; 3. mitochondrial damage and cytochrome C release. The extrinsic pathway through death receptors such as fibroblast-associated, tumour necrosis factor receptor and TNF related apoptosis inducing ligand receptor activate caspase cascade. The intrinsic or mitochondrial pathway of apoptosis is regulated by the Bcl-2 family of proteins, anti-apoptotic (Bcl-2, Bcl-xl, Bcl-w) and the pro-apoptotic (Bax, Bak, Bid). The balance between the pro-apoptotic and anti-apoptotic proteins determines cell survival or death. We discuss recent findings in the molecular mechanisms of UV induced apoptosis. PMID- 22220468 TI - Protection against solar ultraviolet radiation in childhood. AB - In the last decade, awareness of the harmful effects of solar ultraviolet radiation has increased. Modern lifestyles, outdoor occupations, sports and other activities make total sun avoidance impossible. Children spend more time outdoors than adults and there is compelling evidence that childhood is a particularly vulnerable time for the photocarcinogenic effects of the sun. Sun exposure among infants and pre-school age children is largely depend on the discretion of adult care providers. It is important to learn safe habits about sun-safety behaviours during the childhood. Children deserve to live and play in safe environments, and it is the responsibility of every adult to help children stay safe. Protecting children from excessive sun exposure is protection from sunburn today and other forms of sun damages, especially skin cancers, in the future. PMID- 22220469 TI - Personal identification by eyes. AB - Identification of persons through the eyes is in the field of biometrical science. Many security systems are based on biometric methods of personal identification, to determine whether a person is presenting itself truly. The human eye contains an extremely large number of individual characteristics that make it particularly suitable for the process of identifying a person. Today, the eye is considered to be one of the most reliable body parts for human identification. Systems using iris recognition are among the most secure biometric systems. PMID- 22220470 TI - Advances in enzymology and related areas of molecular biology. Preface. PMID- 22220471 TI - Structure and regulation of type 2 transglutaminase in relation to its physiological functions and pathological roles. PMID- 22220472 TI - Physiopathological roles of human transglutaminase 2. PMID- 22220473 TI - Transglutaminase in epidermis and neurological disease or what makes a good cross linking substrate. PMID- 22220474 TI - Transglutaminase 2: a new paradigm for NF-kappaB involvement in disease. PMID- 22220475 TI - Transglutaminase 2 at the crossroads between cell death and survival. PMID- 22220476 TI - Tissue transglutaminase and its role in human cancer progression. PMID- 22220477 TI - Transglutaminase 2 dysfunctions in the development of autoimmune disorders: celiac disease and TG2-/- mouse. PMID- 22220478 TI - Effects and analysis of transglutamination on protein aggregation and clearance in neurodegenerative diseases. PMID- 22220479 TI - Transglutaminase-mediated remodeling of the human erythrocyte membrane skeleton: relevance for erythrocyte diseases with shortened cell lifespan. PMID- 22220480 TI - Irreversible inhibitors of tissue transglutaminase. PMID- 22220481 TI - Methionine adenosyltransferase (s-adenosylmethionine synthetase). PMID- 22220482 TI - [Sense of coherence and coping styles among parents of adult children with schizophrenia]. AB - AIM: The aim of the research was an answer to the question if sense of coherence correlates with coping styles among parents looking after adult children with schizophrenia. METHODS: 50 parents (38 mothers and 12 fathers) at age 46-84 (mean: 60) were examined. SOC-29 and CISS questionnaires were used to diagnose traits of sense of coherence and coping styles. RESULTS: Coping style focused on problems was the most frequent one in the examined group. Sense of coherence and coping styles correlate among those in the investigated group. CONCLUSIONS: There is a correlation between sense of coherence and coping styles in the group of parents with adult children with schizophrenia. There is also a view of a statistical carer who is the mother aged about 60 years looking after the son aged 35 years diagnosed with schizophrenia. PMID- 22220484 TI - [Body attitudes and self-representation in women with eating disorders. Research based on Edward Tory Higgins' self-discrepancy theory]. AB - AIM: The purpose was to evaluate the relationship between negative body-related attitudes and self-representation among patients with anorexia and bulimia nervosa. METHOD: A sample of 33 female anorexic, 38 female bulimic and 40 female students without eating disorders participated in present study. We used The Figure Rating Scale (Stunkard et al., 1983) and the Body Attitude Test (Probst et al., 1995). RESULTS: The results showed that there are statistically significant differences in the ideal self, the ought self, actual-ideal discrepancy, actual ought discrepancy, negative appreciation of body size, lack of familiarity with one's own body and general body dissatisfaction in the three examined groups. The results also indicate that the negative appreciation of body size and general body dissatisfaction are associated with actual-ideal discrepancy and actual ought discrepancy in both groups of eating disordered patients. CONCLUSION: Anorexia and bulimia nervosa are related to self-discrepancies as well as negative body-related attitudes. PMID- 22220483 TI - [Psychological profile of bodily self features of young Polish women--comparative analysis of bodily self structure of woman with eating disorders and psychosis]. AB - AIM: The aim of the study was psychological diagnosis of body self structure in Polish group of women (120 young women) suffering from eating disorders (anorexia and bulimia nervosa) and schizophrenic psychosis. METHOD: The authoress used the following method: Eating Disorder Inventory EDI D.Garner, Satisfaction of Body Questionnaire T.Thompson and projection methods: Thompson's Figures Test and drawing test "body image". 120 women in age 20-26 took part in the study. RESULTS: Conducted statistical analysis (focussing analysis) indicated the presence of five main clusters (types) of women who expose a variety self bodily constellation. It allowed to form psychological profile of the features of these types. CONCLUSIONS: Preparation of bodily structure's psychological profile can diversify and direct the psychological diagnosis process and psychological therapy of this group suffering women. PMID- 22220485 TI - [Anxiety and body image among women growing up in families with addiction problem]. AB - AIM: The aim of the study was to analyse the correlation between body image and anxiety symptoms as well as psychological discomfort experienced by women growing up in alcoholic families. METHOD: The group of 61 women (27 years old on average) was surveyed with Body Self Questionnaire and MMPI-2 personality test questionnaires and the results were measured on Scale 7 (Pt). All the participants also attended psychotherapy sessions focused on disorders resulting from growing up in families with alcohol problems. RESULTS: The analysis showed negative correlation (p < 0.05) between the results of Scale 7 (Pt) and one's body acceptance (r = -0.44), attitude to eating (r = -0.3), femininity disclosure (r = -0.28)and the experience of intimate relations (r = -0.27). CONCLUSIONS: The study showed that disordered body image is related to the symptoms described by Scale 7 (Pt): tendency to react with fear, worriment, stronger discomfort in social situations, fear of rejection, difficulties in interpersonal relations, poor self-confidence as well as perfectionism and tensed behaviour. A crucial factor that could improve the effectiveness of therapies for women from alcoholic families appears to be an attempt to combine the experience of oneself in physical and emotional spheres, as well as functioning cognitive schemes. PMID- 22220486 TI - [Attachment patterns and anxiety in adolescents suffering from mixed disorders of conduct and emotions]. AB - AIM: The paper presents results of research concerning attachment patterns and anxiety in adolescents suffering from mixed disorders of conduct and emotions. METHOD: Both clinical and control group completed the Parental Bonding Instrument and State-Trait Anxiety Inventory. The first questionnaire measures parental style as perceived by the child, it consists of two scales: care and control. The second one the temporary condition of "state anxiety" and the more general and long-standing quality of "trait anxiety". RESULTS: The study revealed that adolescents from the clinical group perceive their parents as less protective than the control. Adolescents from the clinical group revealed also a higher level of anxiety, both as a state and as a trait. CONCLUSIONS: The basic conclusion is that there are differences between groups in family functioning- adolescents from the clinical group received less protection from parents, which may influence their behaviours aimed at providing them more safety. PMID- 22220487 TI - [Attachment patterns and aggressive behaviours in adolescents suffering from mixed disorders of conduct and emotions]. AB - AIM: The paper presents results of research concerning attachment patterns and aggressive behaviours in adolescents suffering from mixed disorders of conduct and emotions. METHOD: Both the clinical and the control group completed Parental Bonding Instrument and Polish version of Buss-Durkee Inventory. The first questionnaire measures parental style as perceived by the child, it consists of two scales: care and control. The second one measures some dimensions of aggression. RESULTS: The study revealed that adolescents from the clinical group perceive their parents as less protective than the control. It showed very weak relations between relations with the parents and expression of aggression. These results are discussed. CONCLUSIONS: The basic conclusion is that there are differences between groups in family functioning--adolescents from the clinical group received less protection from their parents what may influence their behaviours aimed at providing them more safety. Results concerning the relation between family relations and aggression indicate that future research must take into consideration other social relations of adolescents. PMID- 22220488 TI - [The effects of lead level in the blood on social functioning in children with developmental disabilities]. AB - AIM: The aim of the study was to assess the relationship between lead levels in children's blood and the development of social disorders. METHOD: Lead levels were measured in every child's blood test and following on from that the influence of this toxin on children's behaviour was assessed. Manfred Cierpka questionnaire was used as the assessment tool examining children's family relationships and Children's Health Questionnaire Parent Form-28 was used to assess the subjects' health profile. RESULTS: The statistical analysis revealed a statistically significant relationship between lead concentration in the child's blood and whether or not the child was able to meet social expectations (p = 0.018), form affective relationships (p = 0.046), its nervousness (p = 0.024) and a generally lower assessment of his/her behavior in comparison with the peer group (p = 0.024). CONCLUSIONS: Neurotoxic influence of lead on the developing child's organism results in developmental disabilities in its behaviour. These dysfunctions can lead to disorders in the child's social development and they can hinder its functioning. An increased concentration of metal toxins in the child's blood can be responsible for difficulties in meeting social expectation, which in turn is connected with increased nervousness and disorders in forming relationships. Children facing these problems often receive negative marks for their behaviour in comparison with the peer group. Such difficulties can lead to the child's social exclusion and predispose it to making antisocial or criminal decisions in the future. PMID- 22220490 TI - [Psychotherapy as cultural discourse]. AB - It is impossible to think about psychotherapy without reference to the cultural context. In order to understand the development of this domain it is helpful to apply the concept of cultural discourse. When we think about the over one hundred years' history of psychotherapy it becomes clear that understanding of a person, his/her difficulties, psychopathology, the role of a psychotherapist, psychotherapy and its limitations have been changing. It depended on the acknowledged epistemological horizon. Therefore it is important to observe the process of creating discourses related to psychotherapeutic "reality". These discourses are not simply descriptive but they participate in creation of reality. They are not neutral, on the contrary, their application has broad practical, theoretical, ethical and legal consequences. An attempt to describe the culture, or better cultures, we are immersed in, is an attempt to describe the identity of contemporary psychotherapists. This article, referring to the constructionists' perspective and works of Michael Foucault, presents how cultural changes influence psychotherapists' ways of thinking, their practice and presence in social space. PMID- 22220489 TI - [Therapeutic relationship in community psychiatry in the patient and therapist's perspective]. AB - AIM: Relationship between therapist and his patient remain the principle in psychiatric health care, being related to the treatment course and results. Sustaining a good therapeutic relationship is a key element in community team work, it promotes the creation and maintaining of the therapeutic bond, trust, good contact with patients, which allows outpatient treatment. Authors explore how the therapeutic relationship is estimated by the patients diagnosed with psychosis and their therapists. METHOD: STAR questionnaire was used to measure the therapeutic relationship in patient's and therapist's perspective. RESULTS: Those patients who has children or other experience of a close relationship estimate higher their relationship with therapist. There is an influence of patient's gender, independence and psychiatric symptoms on the therapeutic relationship from the therapist's perspective. Therapist's positive collaboration effects symptoms improvement in patients diagnosed with psychosis. CONCLUSIONS: The therapists have to be aware of the other than therapeutic factors which influence the relationship with the patient. There is a need of further studies on therapeutic relationship because the study point out that a positive relationship reduce the psychotic symptoms. It is particularly important to distinguish factors favouring therapeutic relationship maintenance as well as those causing negative effect on therapeutic relationship. PMID- 22220491 TI - [Asperger's syndrome: continuum or spectrum of autistic disorders?]. AB - Pervasive Developmental Disorders (PPD) refers to the group of disorders characterised by delayed or inappropriate development of multiple basic functions including socialisation, communication, behaviour and cognitive functioning. The term,,autistic spectrum disorders" was established as a result of the magnitude of the intensity of symptoms and their proportions observed in all types of pervasive developmental disorders. Asperger's Syndrome (AS) remains the most controversial diagnosis in terms of its place within autism spectrum disorders. AS if often described as an equivalent of High Functioning Autism (HFA) or as a separate spectrum-related disorder with unique diagnostic criteria. Another important issue is the relationship between AS and speech disorders. Although it is relatively easy to draw a line between children with classical autism and speech disorders, the clear cut frontiers between them still remain to be found. The main distinguishing feature is the lack of stereotypic interests and unimpaired social interaction observed in children with speech disorders, such as semantic-pragmatic disorder. PMID- 22220492 TI - [Obsessive-compulsive symptoms, tics, stereotypic movements or need for absolute consistency? The occurrence of repetitive activities in patients with pervasive developmental disorders--case studies]. AB - Repetitive and stereotyped behaviours in the form of stereotyped interests or specific routine activities are one ofthe diagnostic criteria in pervasive developmental disorders. The occurrence of repetitive behaviours in patients with pervasive developmental disorders is a starting point for questions about the type and classification criteria of such behaviours. The aim of the article is to present case studies of patients with pervasive developmental disorders and co morbid symptoms in the form of routine activities, tics, obsessive-compulsive symptoms or stereotyped behaviours. The first case study describes a patient with Asperger's syndrome and obsessive compulsive symptoms. The diagnostic problems regarding complex motor tics are discussed in the second case study which describes a patient with Asperger's syndrome and Gilles de la Tourette syndrome. The third and fourth case study describes mono-zygotic twins with so called High Functioning Autism whose repetitive activities point to either obsessive compulsive symptoms, stereotypic movements, need for absolute consistency or echopraxia. The possible comorbidity of pervasive developmental disorders and symptoms in the form of repetitive behaviours, possible interactions as well as diagnostic challenges is discussed in the article. PMID- 22220493 TI - Ultrastructure of the intramandibular gland of workers and queens of the stingless bee, Melipona quadrifasciata. AB - The intramandibular glands of workers and queens of Melipona quadrifasciata Lepeletier (Hymenoptera: Apidae), at different ages and from different functional groups, were studied using light and transmission electron microscopy. The results demonstrated that these glands are composed of two types of secretory structures: 1.A hypertrophied epidermis on the dorsal side of the mandible that is an epithelial gland. 2. Free secretory cells filling the inner spaces of the appendices that constitute a unicellular gland. The epithelial gland is larger in the young (1-2-day-old workers), and the gland becomes involuted during the nurse worker stage. The unicellular glands of the workers posses some secretion during all of the studied phases, but secretory activity is more intensive in the foraging workers. Vesicles of secretion are absent in the unicellular glands of queens. These results demonstrate that these glands show functional adaptations in different castes corresponding to the functions of each caste. PMID- 22220494 TI - Structural studies of AntD: an N-Acyltransferase involved in the biosynthesis of D-Anthrose. AB - The unusual dideoxy sugar d-anthrose has been identified as an important component in the endospores of infectious agents such as Bacillus anthracis and Bacillus cereus. Specifically, it is the terminal sugar on the bacterium's exosporium, and it provides a point of interaction between the spore and the host. The biosynthesis of d-anthrose involves numerous steps starting from alpha d-glucose 1-phosphate. Here we present a combined structural and functional investigation of AntD from B. cereus. This enzyme plays a key role in d-anthrose biosynthesis by catalyzing the acylation of the C-4" amino group of dTDP-4-amino 4,6-dideoxyglucose using 3-hydroxy-3-methylbutyryl-CoA as the acyl donor. For this investigation, two ternary complexes of AntD were determined to 1.8 A resolution: one in which the protein contained bound beta-hydroxybutyryl-CoA and dTDP and the second with CoA and dTDP-4-amino-4,6-dideoxyglucose. On the basis of these high-resolution structures, it was shown that the side chain of Asp 94 lies within hydrogen bonding distance of the sugar C-4" amino group, and the side chain of Ser 84 resides near the carbonyl oxygen of beta-hydroxybutyryl-CoA. To test the roles of these residues in the catalytic mechanism of AntD, various site directed mutant proteins were prepared and subjected to kinetic and structural analyses. The D94A and D94N mutant proteins demonstrated enzymatic activity, albeit with significantly reduced catalytic efficiencies. The S84A mutant protein showed an approximate 10-fold decrease in activity. Interestingly, the S84C and S84T mutant proteins were both active but demonstrated substrate inhibition. The three-dimensional structures of all of the mutant proteins were nearly identical to that of the wild-type enzyme, indicating that the changes in their kinetic parameters were not due to major conformational changes. Taken together, these data suggest that Asp 94 is important for substrate binding, but probably does not function as an enzymatic base, and that Ser 84 most likely plays a role in the formation of an oxyanion hole. PMID- 22220495 TI - Sensitization of lanthanoid luminescence by organic and inorganic ligands in lanthanoid-organic-polyoxometalates. AB - The reaction of terbium and europium salts with the lacunary polyxometalate (POM) [As(2)W(19)O(67)(H(2)O)](14-) and 2-picolinic acid (picH) affords the ternary lanthanoid-organic-polyoxometalate (Ln-org-POM) complexes [Tb(2)(pic)(H(2)O)(2)(B beta-AsW(8)O(30))(2)(WO(2)(pic))(3)](10-) (1), [Tb(8)(pic)(6)(H(2)O)(22)(B-beta AsW(8)O(30))(4)(WO(2)(pic))(6)](12-) (2), and [Eu(8)(pic)(6)(H(2)O)(22)(B-beta AsW(8)O(30))(4)(WO(2)(pic))(6)](12-) (3). A detailed synthetic investigation has established the conditions required to isolate pure bulk samples of the three complexes as the mixed salts H(0.5)K(8.5)Na[1].30H(2)O, K(4)Li(4)H(4)[2].58H(2)O, and Eu(1.66)K(7)[3].54H(2)O, each of which has been characterized by single crystal X-ray diffraction. Complexes 2 and 3 are isostructural and can be considered to be composed of two molecules of 1 linked through an inversion center with four additional picolinate-chelated lanthanoid centers. When irradiated with a laboratory UV lamp at room temperature, compounds K(4)Li(4)H(4)[2].58H(2)O and Eu(1.66)K(7)[3].54H(2)O visibly luminesce green and red, respectively, while compound H(0.5)K(8.5)Na[1].30H(2)O is not luminescent. A variable temperature photophysical investigation of the three compounds has revealed that both the organic picolinate ligands and the inorganic POM ligands sensitize the lanthanoid(III) luminescence, following excitation with UV light. However, considerably different temperature dependencies are observed for Tb(III) versus Eu(III) through the two distinct sensitization pathways. PMID- 22220496 TI - Peak nothing: recent trends in mineral resource production. AB - The Hubbert-type analysis used to analyze the production history of oil is applied here to other raw materials. Many resources commonly thought of as being close to "peaking" such as lithium, helium, copper, and the rare earth elements, show no evidence of logistic behavior at any point in their production histories. Although many resources have exhibited logistic behavior in the past, many now show exponential or superexponential growth. In most cases, the transition has occurred in the last ten to twenty years. PMID- 22220497 TI - Theoretical study of the aluminum distribution effects on the double proton transfer mechanisms upon adsorption of 4,4'-bipyridine on H-ZSM-5. AB - The aluminum distribution effects on the adsorption of 4,4'-bipyridine (44BPY) in the straight channel of H-ZSM-5 simulated by two ten-membered ring clusters (2 10T) have been investigated by DFT methods. The energetic and structural properties of the complexes formed upon interaction of 44BPY with the zeolite Bronsted acid sites for six different aluminum distributions were determined by B3LYP/6-31+G* calculations. Dispersion energies were estimated by performing single point calculations at the MP2 and M06-2X levels. Interaction energies were corrected for basis set superposition error (BSSE). The minimum energy pathways of the double proton transfer from H-ZSM-5 to 44BPY were characterized. Two mechanisms are proposed: a concerted mechanism in which both protons are simultaneously transferred giving the bidentate ion pair complex (44BPYH22+/2 10T2-) and a consecutive mechanism in which one proton is transferred directly leading to the monodentate ion pair complex (44BPYH+/2-10T-), whereas the second proton can be transferred according to Al distribution. The formation of monodentate or bidentate complexes strongly depends on the Al distribution. PMID- 22220499 TI - Production of two bacteriocins in various growth conditions produced by gram positive bacteria isolated from chicken cecum. AB - Lactobacillus plantarum CLP29 and Enterococcus faecium CLE34 isolated from the cecal contents of young broiler chicks were identified based on physiological and biochemical characteristics, and identification was confirmed by 16S rRNA sequencing. Both bacteria showed a broad range of inhibitory action against bacteria such as Salmonella and Escherichia coli and produced two peptides, plantaricin CLP29 and enterocin CLE34. Treatment with proteinase K, trypase, or benase resulted in the loss of activity of the two peptides, confirming their proteinaceous nature. The highest activity levels for both bacteria were recorded in de Man - Rogosa - Sharpe agar at pH 5.0, 6.0, and 7.0, at 37 degrees C. Carbon and nitrogen sources affected the antibacterial activities of the two bacteriocins in different combinations, which suggested that the antibacterial abilities of different bacteriocins produced in nutrient sources were various. PMID- 22220500 TI - Molecular layer deposition of an organic-based magnetic semiconducting laminate. AB - Organic-based magnets are intriguing materials with unique magnetic and electronic properties that can be tailored by chemical methodology. By using molecular layer deposition (MLD), we demonstrate the thin film fabrication of V[TCNE: tetracyanoethylene](x), of the first known room temperature organic-based magnet. The resulting films exhibit improvement in surface morphology, larger coercivity (80 Oe), and higher Curie temperature/thermal stability (up to 400 K). Recently, the MLD method has been widely studied to implement fine control of organic film growth for various applications. This work broadens its application to magnetic and charge transfer materials and opens new opportunities for metal organic hybrid material development and their applications in various multilayer film device structures. Finally, we demonstrate the applicability of the multilayer V[TCNE](x) as a spin injector combining LSMO, an standard inorganic magnetic semiconductor, for spintronics applications. PMID- 22220501 TI - Photochromogenic nanosheet crystallites of tungstate with a 2D bronze structure. AB - Layered rubidium tungstate, Rb(4)W(11)O(35), with a two-dimensional (2D) bronze type tunnel structure was successfully delaminated into colloidal nanosheets via a soft-chemical process involving acid exchange and subsequent intercalation of tetrabutylammonium ions. Characterizations by transmission electron microscopy and atomic force microscopy confirmed the formation of unilamellar 2D nanosheet crystallites with a unique thickness of ~3 nm and an average lateral size of 400 nm. The obtained nanosheets exhibited reversible color change upon UV-light excitation via an optical band gap of 3.5 eV. The ultimate 2D aspect ratio favorable for an adsorption of charge-compensating cations to trapped electrons working as a color center is presumably responsible for highly efficient photochromic behavior. Its coloration mainly consists of a broad band at a wavelength of 1800 nm and longer, which is much different from that of the common tungstate nanomaterials. Thus, the chromogenic nanosheet obtained in this study features the intense UV absorption and optically switchable visible-to-IR absorption, which may be useful for window applications such as cutoff filters and heat-absorbing films. PMID- 22220498 TI - Pioglitazone treatment increases COX-2-derived prostacyclin production and reduces oxidative stress in hypertensive rats: role in vascular function. AB - BACKGROUND AND PURPOSE: PPARgamma agonists, glitazones, have cardioprotective and anti-inflammatory actions associated with gene transcription interference. In this study, we determined whether chronic treatment of adult spontaneously hypertensive rats (SHR) with pioglitazone alters BP and vascular structure and function, and the possible mechanisms involved. EXPERIMENTAL APPROACH: Mesenteric resistance arteries from untreated or pioglitazone-treated (2.5 mg.kg-1 .day-1 , 28 days) SHR and normotensive [Wistar Kyoto (WKY)] rats were used. Vascular structure was studied by pressure myography, vascular function by wire myography, protein expression by Western blot and immunohistochemistry, mRNA levels by RT PCR, prostanoid levels by commercial kits and reactive oxygen species (ROS) production by dihydroethidium-emitted fluorescence. KEY RESULTS: In SHR, pioglitazone did not modify either BP or vascular structural and mechanical alterations or phenylephrine-induced contraction, but it increased vascular COX-2 levels, prostacyclin (PGI2) production and the inhibitory effects of NS 398, SQ 29,548 and tranylcypromine on phenylephrine responses. The contractile phase of the iloprost response, which was reduced by SQ 29,548, was greater in pioglitazone-treated and pioglitazone-untreated SHR than WKY. In addition, pioglitazone abolished the increased vascular ROS production, NOX-1 levels and the inhibitory effect of apocynin and allopurinol on phenylephrine contraction, whereas it did not modify eNOS expression but restored the potentiating effect of N-nitro-L-arginine methyl ester on phenylephrine responses. CONCLUSIONS AND IMPLICATIONS: Although pioglitazone did not reduce BP in SHR, it increased COX-2 derived PGI2 production, reduced oxidative stress, and increased NO bioavailability, which are all involved in vasoconstrictor responses in resistance arteries. These effects would contribute to the cardioprotective effect of glitazones reported in several pathologies. PMID- 22220502 TI - A brief survey to characterize oxycodone abuse patterns in adolescents enrolled in two substance abuse recovery high schools. AB - BACKGROUND: Although oxycodone is one of the most widely available and abused opioids, little published information exists on the abuse of immediate-release oxycodone. OBJECTIVE: To obtain information on abuse of oxycodone and the effectiveness of abuse-deterrent strategies, especially for immediate-release oxycodone, we surveyed oxycodone abuse patterns in a population of experienced opioid abusers. METHODS: Students or recent graduates of two substance abuse recovery high schools in Massachusetts were surveyed on abuse behaviors with short-acting single-entity oxycodone (e.g., Roxicodone), short-acting combination oxycodone (e.g., Percocet), and extended-release oxycodone. RESULTS: Twenty-four students completed surveys. Mean age was 17.7 years (range 16-19), and mean age at first abuse of oxycodone was 15 (range 13-18). Overall, 56% of students reported oxycodone as their favorite prescription opioid to abuse. The primary preferred method of abuse of all oxycodone formulations was intranasal administration: 83% of single-entity oxycodone abusers preferred intranasal administration compared with 67% of combination oxycodone abusers and 69% of extended-release oxycodone abusers. Approximately half of our respondents preferred to ingest oxycodone orally, 25-38% of respondents swallowed the pill intact, and another 13-17% chewed the pill before swallowing. Maximum dose ever abused at one time ranged from 15 to 400 mg. Most respondents had abused >=60 mg of oxycodone at a time. CONCLUSIONS: In this small study, adolescent oxycodone abusers use high quantities of oxycodone at a time, alter routes of administration for not only extended-release but also immediate-release products, and commonly abuse single-entity oxycodone products. Abuse-deterrent formulations may be one strategy for addressing such behaviors. PMID- 22220503 TI - Photodynamic therapy for skin field cancerization: an international consensus. International Society for Photodynamic Therapy in Dermatology. AB - Field cancerization is a term that describes the presence of genetic abnormalities in a tissue chronically exposed to a carcinogen. These abnormalities are responsible for the presence of multilocular clinical and sub clinical cancerous lesions that explains the increased risks of multiple cancers in this area. With respect to the skin, this term is used to define the presence of multiple non-melanoma skin cancer, its precursors, actinic keratoses and dysplastic keratinocytes in sun exposed areas. The multiplicity of the lesions and the extent of the area influence the treatment decision. Providing at least equivalent efficacy and tolerability, field directed therapies are therefore often more worthwhile than lesion targeted approaches. Photodynamic therapy (PDT) with its selective sensitization and destruction of diseased tissue is one ideal form of therapy for this indication. In the following paper the use of PDT for the treatment of field cancerized skin is reviewed and recommendations are given for its use. PMID- 22220504 TI - Extending photocatalytic activity of TiO2 nanoparticles to visible region of illumination by doping of cerium. AB - Cerium-doped Titanium dioxide (TiO(2)) nanoparticles are prepared by sol-gel method. Doping shifts the UV absorption edge of TiO(2) to the visible region, making it efficient for visible light photocatalysis. Incorporation of cerium decreases the effective band gap of TiO(2) and increases the Urbach energy levels. At the dopant concentrations of 0.015 and 0.025 mol the luminescence intensity increases compared to undoped TiO(2); however, the luminescence is quenched at 0.035 mol. Quenching of luminescence indicates efficient separation of charge carriers. Undoped TiO(2) is showing poor performance in the photocatalytic degradation of methyl orange under visible light. However, on cerium doping its photoactivity is increased, and is drastically enhanced at 0.035 mol of cerium. Further increase in Ce(3+) doping level to 0.045 mol results in the reduction of the photodegradation of the dye. On UV irradiation, entire samples show good photocatalytic activity up to 30 min, but their efficiency decreases when irradiation time is increased to 45 min. Irradiation for longer time results in negative charging of the TiO(2) surface with migrating electrons. The negatively charged surface repels the OH(-) ion and O(2) molecule from adsorbing on its surface thus decreasing the availability of hydroxyl and superoxide radical for dye degradation. PMID- 22220505 TI - Recovery of content and temporal order memory for performed activities following moderate to severe traumatic brain injury. AB - Few studies have investigated the complex nature of everyday activity memory following traumatic brain injury (TBI). This study examined recovery of content and temporal order memory for performed activities during the first year in individuals who suffered moderate to severe TBI. TBI and control participants completed eight different cognitive activities at baseline (i.e., acutely following injury for TBI) and then again approximately one year later (follow up). Participants' free recall of the activities provided a measure of content memory. Temporal order memory was assessed with a reconstruction task. Self report and informant report of everyday memory problems at follow-up were used to examine the relationship between activity memory performances and everyday memory. TBI participants showed significant recovery in both content and temporal order memory for activities during the first year. Despite showing significant recovery, the TBI group's activity memory performances remained poorer than that of controls at follow-up. Greater self- and informant report of everyday memory difficulties was associated with poorer temporal order memory but not content memory for activities. These findings demonstrate recovery in multiple memory processes that support activity memory following moderate to severe TBI. The findings also suggest a stronger link between everyday memory abilities and temporal order memory for activities than activity memory content in a TBI population. PMID- 22220506 TI - Antimicrobial susceptibility of gram-negative pathogens isolated from patients with complicated intra-abdominal infections in South African hospitals (SMART Study 2004-2009): impact of the new carbapenem breakpoints. AB - BACKGROUND: The Study for Monitoring Antimicrobial Resistance Trends (SMART) follows trends in resistance among aerobic and facultative anaerobic gram negative bacilli (GNB) isolated from complicated intra-abdominal infections (cIAIs) in patients around the world. METHODS: During 2004-2009, three centralized clinical microbiology laboratories serving 59 private hospitals in three large South African cities collected 1,218 GNB from complicated intra abdominal infections (cIAIs) and tested them for susceptibility to 12 antibiotics according to the 2011 Clinical Laboratory Standards Institute (CLSI) guidelines. RESULTS: Enterobacteriaceae comprised 83.7% of the isolates. Escherichia coli was the species isolated most commonly (46.4%), and 7.6% of these were extended spectrum beta-lactamase (ESBL)-positive. The highest ESBL rate was documented for Klebsiella pneumoniae (41.2%). Overall, ertapenem was the antibiotic most active against susceptible species for which it has breakpoints (94.6%) followed by amikacin (91.9%), piperacillin-tazobactam (89.3%), and imipenem-cilastatin (87.1%), whereas rates of resistance to ceftriaxone, cefotaxime, ciprofloxacin, and levofloxacin were documented to be 29.7%, 28.7%, 22.5%, and 21.1%, respectively. Multi-drug resistance (MDR), defined as resistance to three or more antibiotic classes, was significantly more common in K. pneumoniae (27.9%) than in E. coli (4.9%; p<0.0001) or Proteus mirabilis (4.1%; p<0.05). Applying the new CLSI breakpoints for carbapenems, susceptibility to ertapenem was reduced significantly in ESBL-positive E. coli compared with ESBL-negative isolates (91% vs. 98%; p<0.05), but this did not apply to imipenem-cilastatin (95% vs. 99%; p=0.0928). A large disparity between imipenem-cilastatin and ertapenem susceptibility in P. mirabilis and Morganella morganii was documented (24% vs. 96% and 15% vs. 92%, respectively), as most isolates of these two species had imipenem-cilastatin minimum inhibitory concentrations in the 2-4 mcg/mL range, which is no longer regarded as susceptible. CONCLUSIONS: This study documented substantial resistance to standard antimicrobial therapy among GNB commonly isolated from cIAIs in South Africa. With the application of the new CLSI carbapenem breakpoints, discrepancies were noted between ertapenem and imipenem cilastatin with regard to the changes in their individual susceptibilities. Longitudinal surveillance of susceptibility patterns is useful to guide recommendations for empiric antibiotic use in cIAIs. PMID- 22220507 TI - Passing in the night: a tipping point in surgical training. PMID- 22220508 TI - Melatonin treatment protects against spinal cord injury induced functional and biochemical changes in rat urinary bladder. AB - Oxidative stress induced by spinal cord injury (SCI) has deleterious effects on the function of several organ systems including the urinary bladder. In this study, we investigated the possible protective actions of melatonin on SCI induced oxidative damage and urinary bladder dysfunction. Wistar albino rats (n = 24) were divided randomly as control, vehicle- or melatonin (10 mg/kg, ip) treated SCI groups. To induce SCI, a standard weight-drop method that induced a moderately severe injury at T10 was used. Injured animals were given either vehicle or melatonin 15 min postinjury. One week postinjury, each rat was neurologically examined and then decapitated; blood samples were taken to evaluate neuron-specific enolase (NSE) and soluble protein 100beta (S-100beta). Spinal cord (SC) and urinary bladder samples were taken for functional studies and histological examination or stored for the measurement of malondialdehyde (MDA), glutathione (GSH) and nerve growth factor (NGF) levels and caspase-3 activity. Isometric contractions in bladder strips were induced by carbachol. In the SCI rats, decreased contractile responses of the bladder strips were found to be restored by melatonin treatment. Serum S-100beta levels and NSE activities and tissue MDA levels and caspase-3 activities, all of which were elevated in the vehicle-treated SCI animals as compared to the control values, were reversed by melatonin treatment. On the other hand, reduced GSH and NGF levels due to SCI were restored by melatonin treatment. Furthermore, melatonin treatment improved histological findings. These findings suggest that melatonin reduces SCI-induced tissue injury and improves bladder functions through its effects on oxidative stress and NGF. PMID- 22220509 TI - Changes in soft tissues around immediate full-arch rehabilitations: a prospective study. AB - INTRODUCTION: Nowadays, aesthetic appearance is receiving more and more attention from clinicians and patients. Therefore, it is of paramount importance for the surgeon to maintain or to improve the quality and the stability of the soft tissue-implant interface. The scientific literature supports the idea that the immediate placement and provisionalization of endosseus implants and abutments can indeed offer additional clinical control over the peri-implant tissue architecture. On this basis, this prospective study aims to evaluate the changes in soft tissues around immediately loaded dental implants in full-arch rehabilitations, over a period of 3 months. MATERIALS AND METHODS: Fifteen subjects were treated for immediate full-arch rehabilitations. Following implant placement, provisional rehabilitations made of bisphenol-A-glycidyldimethacrylate (BIS-GMA) and resin were placed. All records were made using a periodontal probe. The facial soft-tissue level was measured evaluating the distance between the soft-tissue margin and the incisal edge of the crown. Moreover, papilla levels were measured at the mesial and distal sites from a reference line connecting the occlusal edge of the crowns. RESULTS: The average value at the mesial site was 0.035 mm (+/-1, median 0 mm), while at the midfacial site, it was 0 mm (+/-0.76, median 0 mm) and at the distal site, -0.05 mm (+/-0.92, median 0 mm). The plaque score index showed a reduction during the follow-up period. DISCUSSION: Our data indicate that no differences at the midfacial point were detectable over the observation period. This is in agreement with several studies; it is plausible that these results are linked to a correct position of the implant in the alveolar socket. Moreover, comparing our results with what has been reported by other authors, it is surprising that while other studies highlight that papilla loss at the mesial and distal aspect is an expected consequence of immediate implant restorations, our data do not show any changes. The explanation of these results remains unclear. Further studies are needed to support our data and to clarify what mechanisms are involved in the maintenance of soft tissue. PMID- 22220510 TI - Unsaturated fatty alcohol derivatives of olive oil phenolic compounds with potential low-density lipoprotein (LDL) antioxidant and antiobesity properties. AB - A new route for the synthesis of fatty alcohol derivatives of hydroxytyrosol and other olive oil phenolic compounds was developed to allow the preparation of unsaturated derivatives. The biological activity of synthesized compounds was evaluated. Most of the compounds presented a significant antioxidant activity on low-density lipoprotein (LDL) particles. The activity of the tested products was significantly influenced by the number and position of unsaturations as well as modifications on the polar head of the synthesized compounds. Some of them presented modulation of food intake in rats and, due to their molecular similarity with CB(1) endogenous ligands, the endocannabinoid system and PPAR alpha were also evaluated as potential targets. The pharmacodynamics could not be totally explained by CB(1) and PPAR-alpha receptor interactions because only two of the four compounds with biological activity showed a CB(1) activity and all of them presented low PPAR-alpha affinity, not justifying its whole in vivo activity. The hydroxytyrosol linoleylether (7) increased LDL resistance to oxidation with a capacity similar to that of hydroxytyrosol and was the most active in vivo compound with a hypophagic effect comparable to that of oleoylethanolamine. We consider that this compound could be a good lead compound for future drug development in obesity treatments. PMID- 22220512 TI - Acute migraine treatment: "stratified" care. PMID- 22220511 TI - Non-cell autonomous influence of the astrocyte system xc- on hypoglycaemic neuronal cell death. AB - Despite longstanding evidence that hypoglycaemic neuronal injury is mediated by glutamate excitotoxicity, the cellular and molecular mechanisms involved remain incompletely defined. Here, we demonstrate that the excitotoxic neuronal death that follows GD (glucose deprivation) is initiated by glutamate extruded from astrocytes via system xc---an amino acid transporter that imports L-cystine and exports L-glutamate. Specifically, we find that depriving mixed cortical cell cultures of glucose for up to 8 h injures neurons, but not astrocytes. Neuronal death is prevented by ionotropic glutamate receptor antagonism and is partially sensitive to tetanus toxin. Removal of amino acids during the deprivation period prevents--whereas addition of L-cystine restores--GD-induced neuronal death, implicating the cystine/glutamate antiporter, system xc-. Indeed, drugs known to inhibit system xc- ameliorate GD-induced neuronal death. Further, a dramatic reduction in neuronal death is observed in chimaeric cultures consisting of neurons derived from WT (wild-type) mice plated on top of astrocytes derived from sut mice, which harbour a naturally occurring null mutation in the gene (Slc7a11) that encodes the substrate-specific light chain of system xc- (xCT). Finally, enhancement of astrocytic system xc- expression and function via IL-1beta (interleukin-1beta) exposure potentiates hypoglycaemic neuronal death, the process of which is prevented by removal of l-cystine and/or addition of system xc- inhibitors. Thus, under the conditions of GD, our studies demonstrate that astrocytes, via system xc-, have a direct, non-cell autonomous effect on cortical neuron survival. PMID- 22220513 TI - The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy. AB - The pharmacologic profile of retigabine [RTG (international nonproprietary name); ezogabine, EZG (U.S. adopted name)], is different from all currently approved antiepileptic drugs (AEDs). Its primary mechanism of action (MoA) as a positive allosteric modulator of KCNQ2-5 (K(v) 7.2-7.5) ion channels defines RTG/EZG as the first neuronal potassium (K(+)) channel opener for the treatment of epilepsy. KCNQ2-5 channels are predominantly expressed in neurons and are important determinants of cellular excitability, as indicated by the occurrence of human genetic mutations in KCNQ channels that underlie inheritable disorders including, in the case of KCNQ2/3, the syndrome of benign familial neonatal convulsions. In vitro pharmacologic studies demonstrate that the most potent action of RTG/EZG is at KCNQ2-5 channels, particularly heteromeric KCNQ2/3. Furthermore, mutagenesis and modeling studies have pinpointed the RTG/EZG binding site to a hydrophobic pocket near the channel gate, indicating how RTG/EZG can stabilize the open form of KCNQ2-5 channels; the absence of this site in KCNQ1 also provides a clear explanation for the inbuilt selectivity RTG/EZG has for potassium channels other than the KCNQ cardiac channel. KCNQ channels are active at the normal cell resting membrane potential (RMP) and contribute a continual hyperpolarizing influence that stabilizes cellular excitability. The MoA of RTG/EZG increases the number of KCNQ channels that are open at rest and also primes the cell to retort with a larger, more rapid, and more prolonged response to membrane depolarization or increased neuronal excitability. In this way, RTG/EZG amplifies this natural inhibitory force in the brain, acting like a brake to prevent the high levels of neuronal action potential burst firing (epileptiform activity) that may accompany sustained depolarizations associated with the initiation and propagation of seizures. This action to restore physiologic levels of neuronal activity is thought to underlie the efficacy of RTG/EZG as an anticonvulsant in a broad spectrum of preclinical seizure models and in placebo-controlled trials in patients with partial epilepsy. In this article, we consider the pharmacologic characteristics of RTG/EZG at the receptor, cellular, and network levels as a means of understanding the novel and efficacious MoA of this new AED as defined in both preclinical and clinical research. PMID- 22220514 TI - Intracranial extramedullary hematopoiesis in patients with thalassemia: a case report and review of the literature. AB - BACKGROUND: Extramedullary hematopoiesis (EH) is a compensatory phenomenon that results in the production of blood cell precursors outside the marrow in patients with chronic hemolytic anemia and ineffective erythropoiesis. EH usually involves the liver, spleen, and lymph nodes. It can also be found at paravertebral, intrathoracic, or pelvic locations. Intracranial EH is a rare entity and often asymptomatic but can sometimes lead to symptomatic tumor-like masses. Treatment options are controversial and include hypertransfusion, surgical excision, radiotherapy, and hydroxyurea (HU). STUDY DESIGN AND METHODS: Successful treatment of an intracranial EH mass with HU and blood transfusions in a beta thalassemia major patient was discussed along with a review of the published literature on intracranial EH in thalassemia. RESULTS: In our patient, the extramedullary hematopoietic mass in the interhemispheric fissure showed a marked improvement after 6 months of HU and hypertransfusion therapy. In the English literature, there are a few cases with intracranial EH and thalassemia, which were treated with different treatment modalities, with different outcomes. CONCLUSION: There is no standard treatment approach in patients with symptomatic EH. HU with hypertransfusion regimen is a reasonable first-choice modality in treating intracranial EH masses. PMID- 22220515 TI - From the editors. Inoperability input-output model. PMID- 22220516 TI - Letter to the editor. On the local sensitivity analysis of the inoperability input-output model. PMID- 22220518 TI - Fine needle aspirate cell blocks are reliable for detection of hormone receptors and HER-2 by immunohistochemistry in breast carcinoma. AB - AIMS: To evaluate the reliability of fine needle aspirate cell blocks in the assessment of oestrogen receptor (ER), progesterone receptor (PR) and HER-2/neu proteins by immunohistochemistry in comparison with surgical specimens. MATERIALS AND METHODS: This is a retrospective study of 62 cases of breast carcinoma diagnosed by fine needle aspiration cytology (FNAC) and confirmed using the surgical specimen. Immunohistochemical tests were performed to assess the presence of oestrogen receptor (ER), progesterone receptor (PR) and HER-2/neu proteins in cell blocks and the corresponding surgical specimens. The cell block method used alcohol prior to formalin fixation. Cases with 10% or more stained cells were considered positive for ER and PR. Positivity for HER-2/neu was assessed on a scale of 0-3+. The criterion for positivity was a score of 3+. RESULTS: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of the cell blocks in the investigation of ER, PR and HER-2/neu protein (3+) were (%): ER, 92.7, 85.7, 92.7, 85.7 and 90.3; PR, 92.7, 94.7, 97.4, 87.0 and 93.5; HER-2/neu, 70.0, 100.0, 100.0, 94.5 and 95.2. Discrepancies were seen in cell blocks in the 1+ and 2+ HER-2/neu staining scores: two of 12 cases scoring 2+ and one case of 26 scoring 1+ on cell blocks scored 3+ on surgical specimens. The correlation index between cell block and corresponding surgical specimen varied from 90% to 94%. CONCLUSION: Cell blocks provide a useful method of assessing ER, PR and HER-2/neu, mainly for inoperable and recurrent cases, but consideration should be given to carrying out FISH analysis on 1+ as well as 2+ HER-2/neu results. PMID- 22220519 TI - Methyl 2-(methylthio)benzoate: a sex attractant for the June beetles, Phyllophaga tristis and P. apicata. AB - Male antennae of Phyllophaga tristis (Fabricius) (Coleoptera: Scarabaeidae: Melolonthinae) were tested using a coupled gas chromatograph-electroantennogram detector (GC-EAD) system for electrophysiological responses to five sex pheromones identified from other Phyllophaga species including L-valine methyl ester, L-isoleucine methyl ester, L-leucine methyl ester, methyl 2(methylthio)benzoate and methyl 2-amino benzoate. Male antennae responded only to methyl 2(methylthio)benzoate. In a 2003 field test near Greensburg, Kansas, cross-vane traps baited with rubber septa containing 1 mg of methyl 2 (methylthio)benzoate captured 466 male P. tristis. Control traps baited with rubber septa loaded with only hexane captured none. Similarly, in a field test in 2010 in Gainesville, Florida, 265 male P. apicata Reinhard were captured in traps baited with 1 mg of methyl 2-(methylthio)benzoate whereas control traps captured only a single male. PMID- 22220521 TI - Antisymmetric exchange in triangular tricopper(II) complexes: correlation among structural, magnetic, and electron paramagnetic resonance parameters. AB - Two new trinuclear copper(II) complexes, [Cu(3)(MU(3) OH)(daat)(Hdat)(2)(ClO(4))(2)(H(2)O)(3)](ClO(4))(2).2H(2)O (1) and [Cu(3)(MU(3) OH)(aaat)(3)(H(2)O)(3)](ClO(4))(2).3H(2)O (2) (daat = 3,5-diacetylamino-1,2,4 triazolate, Hdat = 3,5-diamino-1,2,4-triazole, and aaat = 3-acetylamino-5-amino 1,2,4-triazolate), have been prepared from 1,2,4-triazole derivatives and structurally characterized by X-ray crystallography. The structures of 1 and 2 consist of cationic trinuclear copper(II) complexes with a Cu(3)OH core held by three N,N-triazole bridges between each pair of copper(II) atoms. The copper atoms are five-coordinate with distorted square-pyramidal geometries. The magnetic properties of 1 and 2 and those of five other related 1,2,4-triazolato tricopper(II) complexes with the same triangular structure (3-7) (whose crystal structures were already reported) have been investigated in the temperature range of 1.9-300 K. The formulas of 3-7 are [Cu(3)(MU(3) OH)(aaat)(3)(H(2)O)(3)](NO(3))(2).H(2)O (3), {[Cu(3)(MU(3)-OH)(aat)(3)(MU(3) SO(4))].6H(2)O}(n) (4), and [Cu(3)(MU(3)-OH)(aat)(3)A(H(2)O)(2)]A.xH(2)O [A = NO(3)(-) (5), CF(3)SO(3)(-) (6), or ClO(4)(-) (7); x = 0 or 2] (aat =3 acetylamino-1,2,4-triazolate). The magnetic and electron paramagnetic resonance (EPR) data have been analyzed by using the following isotropic and antisymmetric exchange Hamiltonian: H = -J[S(1)S(2) + S(2)S(3)] - j[S(1)S(3)] + G[S(1) * S(2) + S(2) * S(3) + S(1) * S(3)]. 1-7 exhibit strong antiferromagnetic coupling (values for both -J and -j in the range of 210-142 cm(-1)) and antisymmetric exchange (G varying from to 27 to 36 cm(-1)). At low temperatures, their EPR spectra display high-field (g < 2.0) signals indicating that the triangles present symmetry lower than equilateral and that the antisymmetric exchange is operative. A magneto structural study showing a lineal correlation between the Cu-O-Cu angle of the Cu(3)OH core and the isotropic exchange parameters (J and j) has been conducted. Moreover, a model based on Moriya's theory that allows the prediction of the occurrence of antisymmetric exchange in the tricopper(II) triangles, via analysis of the overlap between the ground and excited states of the local Cu(II) ions, has been proposed. In addition, analytical expressions for evaluating both the isotropic and antisymmetric exchange parameters from the experimental magnetic susceptibility data of triangular complexes with local spins (S) of (1)/(2), (3)/(2), or (5)/(2) have been purposely derived. Finally, the magnetic and EPR results of this work are discussed and compared with those of other tricopper(II) triangles reported in the literature. PMID- 22220551 TI - Plasmodesmatal pores in the torus of bordered pit membranes affect cavitation resistance of conifer xylem. AB - The pit membrane in bordered pits of conifer tracheids is characterized by a porous margo and central thickening (torus), which is traditionally considered to function as an impermeable safety valve against air-seeding. However, electron microscopy based on 33 conifer species, including five families and 19 genera, reveals that pores occur in the torus of 13 of the species studied. The pores have a plasmodesmatal origin with an average diameter of 51 nm and grouped arrangement. Evidence for embolism spreading via pores in tori is supported by the pore sizes, which correspond relatively well with the pressure inducing cavitation. Predictions based on earlier correlations between pit structure and cavitation resistance were only weakly supported for species with punctured tori. Moreover, species with punctured tori are significantly less resistant to cavitation than species with non-punctured tori. Nevertheless, absolute pore diameters must be treated with caution and correlations between theoretical and measured air-seeding pressures are weak. Because most pores appear not to traverse the torus but are limited to one torus pad, only complete pores would trigger air-seeding. Embolism spreading through a leaky torus is not universal across gymnosperms and unlikely to represent the only air-seeding mechanism. PMID- 22220552 TI - Theoretical insight into stereoselective reaction mechanisms of 2,4-pentanediol tethered ketene-olefin [2 + 2] cycloaddition. AB - We report ab initio molecular dynamics calculations based on density functional theory performed on an intramolecular [2 + 2] cycloaddition between ketene and olefin linked with a 2,4-pentanediol (PD) tether. We find that the encounter of the ketene and olefin moieties could be prearranged in the thermal equilibrated state before the cycloaddition. The reaction mechanism is found to be stepwise, similar to that of intermolecular ketene [2 + 2] cycloadditions with ordinary alkenes. A distinct feature of the reaction pathway for a major diastereoisomer is a differential activation free energy of about 1.5 kcal/mol, including 2.8 kcal/mol as the differential activation entropy, with a transition state consisting of a flexible nine-membered ring in the olefin-PD-ketene moiety. This theoretical study provides a reasonable explanation for the strict stereocontrollability of the PD-tethered ketene-olefin cycloaddition, irrespective of reaction types or conditions. PMID- 22220553 TI - Early progress in epigenetic regulation of endothelin pathway genes. AB - Control of gene transcription is a major regulatory determinant for function of the endothelin pathway. Epigenetic mechanisms act on tissue-specific gene expression during development and in response to physiological stimuli. Most of the limited evidence available on epigenetic regulation of the endothelin pathway focuses on the EDN1 and EDNRB genes. Examination of whole genome databases suggests that both genes are influenced by histone modifications and DNA methylation. This interpretation is supported by studies directed at detecting epigenetic action on the two genes. The clearest illustration of epigenetic factors altering endothelin signalling is DNA methylation-associated EDNRB silencing during tumourigenesis. This review summarizes our current understanding of epigenetic regulation of the endothelin pathway genes. LINKED ARTICLES This article is part of a themed section on Endothelin. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.168.issue-1. PMID- 22220554 TI - Arbuscular mycorrhizal fungi assemblages in Chernozem great groups revealed by massively parallel pyrosequencing. AB - The arbuscular mycorrhizal (AM) fungal resources present in wheat fields of the Canadian Prairie were explored using 454 pyrosequencing. Of the 33 dominant AM fungal operational taxonomic units (OTUs) found in the 76 wheat fields surveyed at anthesis in 2009, 14 clustered as Funneliformis - Rhizophagus, 16 as Claroideoglomus, and 3 as Diversisporales. An OTU of Funneliformis mosseae and one OTU of Diversisporales each accounted for approximately 16% of all AM fungal OTUs. The former was ubiquitous, and the latter was mainly restricted to the Black and Dark Brown Chernozems. AM fungal OTU community composition was better explained by the Chernozem great groups (P = 0.044) than by measured soil properties. Fifty-two percent of the AM fungal OTUs were unrelated to measured soil properties. Black Chernozems hosted the largest AM fungal OTU diversity and almost twice the number of AM fungal sequences seen in Dark Brown Chernozems, the great group ranking second for AM fungal sequence abundance. Brown Chernozems hosted the lowest AM fungal abundance and an AM fungal diversity as low as that seen in Gray soils. We concluded that Black Chernozems are most conducive to AM fungal proliferation. AM fungi are generally distributed according to Chernozem great groups in the Canadian Prairie, although some taxa are evenly distributed in all soil groups. PMID- 22220555 TI - Establishment of a microplate-formatted cell-based immunoassay for rapid analysis of nucleotide excision repair ability in human primary cells. AB - DNA photolesions induced by UV, cyclobutane pyrimidine dimer (CPD) and (6-4) photoproduct (6-4PP), are repaired by nucleotide excision repair (NER) in human cells. Various immunoassays using monoclonal antibodies specific for the photolesions have been developed and widely used for the analysis of cellular NER activity. In this study, we have newly developed a microplate-formatted cell based immunoassay, based on indirect immunofluorescence staining with lesion specific antibodies combined with an infrared imaging system. Using this assay, we show the repair kinetics of CPD and 6-4PP in various fibroblasts from newborn and adult donors with no age-related difference. Furthermore, epidermal keratinocytes and melanocytes exhibit comparable NER activity, and calcium ion induced differentiation of keratinocytes has no significant impacts on their NER activity. We also evaluated the effects of a proteasome inhibitor, MG132, and a histone deacetylase inhibitor, sodium butyrate, on NER efficiency using this assay. All these results suggest that the new assay is highly useful for the rapid and quantitative analysis of NER activity in various primary cells with limited growth activity and is applicable to a screening system for drugs affecting NER efficiency. PMID- 22220556 TI - Measures of attentional bias and relational responding are associated with behavioral treatment outcome for cocaine dependence. AB - BACKGROUND: Psychosocial interventions for substance dependence have demonstrated efficacy. However, the mechanisms by which specific intervention strategies exert their effect have not been clearly identified. OBJECTIVE: This study investigated the prospective relationships between two psychological processes, an attentional bias toward cocaine stimuli and beliefs about the consequences of cocaine use, and treatment outcome. METHOD: Twenty-five cocaine-dependent participants enrolled in a 6-month outpatient treatment program that included voucher incentives for abstinence. All participants were asked to complete two implicit assessment procedures, a Drug Stroop protocol and an Implicit Relational Assessment Procedure (IRAP), as well as explicit measures of cocaine craving and the consequences of cocaine use, prior to beginning treatment. Pearson's correlation coefficients tested the prospective relationships between treatment outcome and the implicit and explicit assessments. RESULTS: Stronger implicit beliefs about the positive effects of cocaine use prior to treatment were associated with poorer treatment outcome when an escalating voucher-incentive program was in place. Further, an attentional bias for cocaine-related stimuli was associated with better treatment outcome when an escalating voucher-incentive program was removed. No association between cocaine use beliefs and treatment outcome was found when beliefs were measured with self-report instruments. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These findings highlight the potential utility of performance-based measures for delineating the psychological mechanisms associated with variation in response to treatment for drug dependence. PMID- 22220558 TI - Abdominal exploration in captive collared peccaries (Tayassu tajacu) by ultrasonography. AB - This study determines the morphology and ultrasound features of the abdominal organs in male, nestling and healthy collared peccaries. The bladder wall is hyperechogenic, with a thickness of 0.2 +/- 0.08 cm. The kidneys present a well defined cortex, medulla and pelvis, and the dimensions are 2.56 +/- 0.3 * 4.6 +/- 0.8 cm for the left and 2.51 +/- 0.4 * 4.86 +/- 1.1 cm for the right kidney. The spleen has a uniform echotexture over its entire surface. The largest dimensions of the liver are 2.0 +/- 0.57 cm for the left lobe and 1.42 +/- 0.66 cm for the caudate lobe. The liver presents a homogeneous echotexture in the majority of cases, but sometimes some hyperechoic spots are present. The stomach wall has a thickness of 0.42 +/- 0.28 cm. The bowel loops show alternate hyperechoic and hypoechoic layers with a uniform diameter and a wall thickness of 0.19 +/- 0.07 cm. PMID- 22220559 TI - Experimental evidence and DFT studies of next-nearest-neighbor magnetic interactions through diamagnetic 3d and 4d ions. AB - The copper template effect allows the preparation of tridentate ligands that chelate copper ions, leaving unoccupied the fourth basal coordination position and at least one axial position of the copper coordination polyhedron. Two such cationic complexes, [LCu](+) and [L(1)Cu](+) (L(-) = 2-{(E)-[(2 aminoethyl)imino]methyl}phenoxo] and L(1-) = 2-{(E)-[(2 aminopropyl)imino]methyl}phenoxo), react with diamagnetic polycyanometalate tectons such as Ni(CN)(4)(2-) or Ag(CN)(2)(-) to yield different neutral 1D complexes. In {[(LCu)(2)Ni(CN)(4)]}(n) (1) the four cyano nitrogen atoms are involved in coordination with copper ions in such a manner that each copper atom is pentacoordinated and linked to two cyano functions that occupy axial and equatorial coordination positions. Two L(1)Cu(+) cationic entities are linked, through their equatorial plane, to two trans cyano groups of the Ni(CN)(4)(2-) tecton in complex [(L(1)Cu)(2)Ni(CN)(4)] (2), the two uncoordinated cyano groups being involved in hydrogen bonds. 2 is a racemate, a S stereoisomer being associated with a R one in each [(L(1)Cu)(2)Ni(CN)(4)] unit. Zigzag Cu-Ag chains are present in [(LCu)Ag(CN)(2)] (3), where the copper centers are pentacoordinated and connected to the cyano groups in an alternate axial equatorial coordination scheme. A bidimensional structure is developed by interchain argentophilic interactions. In complex 4, {(L(1)CuMeOH)(L(1)Cu)[Ag(CN)(2)](2)}, two L(1)Cu units are connected by a NC-Ag CN bridge in an equatorial position. These resulting units exhibit argentophilic interactions with [Ag(CN(2))](-) entities that are monocoordinated in the equatorial position to the next unit, ultimately leading to a chain. Weak Cu-Cu magnetic interactions are detected in the four compounds, antiferromagnetic in the case of equatorial-equatorial copper interactions, ferromagnetic for orthogonal interacting copper orbitals (axial-equatorial interactions), while axial-axial bridges are characterized by an absence of interaction. The presence of weak ferromagnetic interactions through large NC-Ni-CN or NC-Ag-CN bridges (Cu...Cu distances larger than 10 A) furnishes experimental evidence for the existence of next-nearest-neighbor interactions through diamagnetic centers. DFT calculations do confirm the existence of these magnetic transmission pathways through the diamagnetic metal bridge. PMID- 22220561 TI - Mutations analysis in filaggrin gene in northern China patients with atopic dermatitis. AB - BACKGROUND: Recently, we have reported filaggrin mutations (FLG) of atopic dermatitis in southern China. However, there have been few detailed reports of FLG mutations of patients with AD in northern China by now. OBJECTIVES: The present aim was to establish the mutation spectrum of FLG gene in AD patients in northern China. METHODS: A total of 339 cases met Hanifin and Rajka diagnostic criteria of AD were recruited. A comprehensive sequencing of the entire FLG coding region in these patients was conducted. All detected FLG null mutations were screened in a cohort of 301 normal controls. RESULTS: Seven novel mutations (478insA, Q1070X, 4026delT, Q1712X, Q2397X, 7145del4 and 8001del4) and eleven reported mutations (3222del4, 3321delA, 4271delAA, S1515X, Q1790X, 5757del4, 6834del5, Q2417X, E2422X, 7945delA and K4671X) in AD were identified. Mutations 3321delA and K4671X were two of the most common mutations in AD. FLG null mutations were present in 26.0% of AD patients. FLG null alleles (compound genotypes) were significantly higher in AD (P < 0.001) than in the controls. The compound genotypes for all FLG variants were significantly associated with IV (P < 0.001) and palmar hyperlinearity (P < 0.001). The common mutation, K4671X, was significantly associated with AD-coexistent allergic rhinitis (P = 0.005). CONCLUSIONS: Our study increases the total number of FLG mutations. We clearly demonstrated that FLG loss-of-function mutations were significantly associated with AD in northern China. The FLG null mutations in the Chinese population differed not only from that in the European population but also from that in sub populations of Asians outside of the Chinese mainland. PMID- 22220560 TI - Pervasive olfactory impairment after bilateral limbic system destruction. AB - What pattern of brain damage could completely obliterate the sense of olfaction in humans? We had an opportunity to address this intriguing question in Patient B., who has extensive bilateral damage to most of the limbic system, including the medial and lateral temporal lobes, orbital frontal cortex, insular cortex, anterior cingulate cortex, and basal forebrain, caused by herpes simplex encephalitis. The patient demonstrated profound impairments in odor identification and recognition. Moreover, he could not discriminate between olfactory stimuli, and he had severe impairments in odor detection. Reliable stimulus detection was obtained only for solutions of the organic solvent acetone and highly concentrated solutions of ethanol. In contrast to the more circumscribed olfactory deficits demonstrated in patients with damage confined to either the temporal lobes or orbitofrontal cortex (which tend to involve odor identification but not odor detection), Patient B. demonstrated a strikingly severe and complete anosmia. This contrast in olfactory abilities and deficits as a result of different anatomical pathology affords new insights into the neural substrates of olfactory processing in humans. PMID- 22220562 TI - Melatonin improves metabolic syndrome induced by high fructose intake in rats. AB - In this study, we examined whether melatonin improves metabolic syndrome induced by high fructose intake in male Wistar rats. Feeding of a diet containing 60% fructose (HFD) for 4 or 6 wk caused increased serum insulin, triglyceride, total cholesterol, free fatty acids, uric acid, leptin, and lipid peroxide concentrations as well as hepatic triglyceride and cholesterol concentrations, and relative intra-abdominal fat and liver weights. The 4- or 6-wk HFD feeding reduced serum high-density lipoprotein cholesterol and adiponectin concentrations. The 6-wk HFD feeding increased serum tumor necrosis factor-alpha concentration and hepatic lipid peroxide concentration and lowered hepatic reduced glutathione concentration. Daily intraperitoneal administration of melatonin (1 or 10mg/kg body weight), starting at 4-wk HFD feeding, attenuated these changes at 6-wk HFD feeding more effectively at its higher dose than at its lower dose. In an oral glucose tolerance test, rats with 4- or 6-wk HFD feeding showed higher serum insulin response curve and normal serum glucose response curve when compared with the corresponding animals that received the control diet. The 4- or 6-wk HFD feeding caused insulin resistance, judging from the scores of HOMR-IR and QUICKI, which are indices of insulin resistance. The daily administered melatonin (1 or 10mg/kg body weight) ameliorated the higher serum insulin response curve in the oral glucose tolerance test and insulin resistance at 6-wk HFD feeding more effectively at its higher dose than at its lower dose. These results indicate that melatonin improves metabolic syndrome induced by high fructose intake in rats. PMID- 22220563 TI - Stability and plasticizing and crystallization effects of vitamins in amorphous sugar systems. AB - Increased molecular mobility and structural changes resulting from water plasticization of glassy solids may lead to loss of the entrapped compounds from encapsulant systems. In the present study, the stability of water-soluble vitamins, vitamin B(1) (vB(1), thiamin hydrochloride) and vitamin C (vC, ascorbic acid), in freeze-dried lactose and trehalose at various water activities was studied. Water sorption of lactose-vB(1), lactose-vC, trehalose-vB(1), and trehalose-vC systems was determined gravimetrically. Glass transition and crystallization of anhydrous and plasticized sugar-vitamin systems were determined using thermal analysis. Critical water activity was calculated using water sorption and glass transition data. The retention of the vitamins was measured spectrophotometrically. The results showed that the amorphous structure protected the entrapped vitamins at low a(w). Crystallization of lactose accelerated vitamin degradation, whereas trehalose retained much higher amounts of the vitamins. Glass transition and critical water activity of solids and crystallization of component sugars should be considered in the stabilization of sensitive components. PMID- 22220564 TI - Clinical genetic studies in benign childhood epilepsy with centrotemporal spikes. AB - PURPOSE: To accurately determine the frequency and nature of the family history of seizures in patients with benign childhood epilepsy with centrotemporal spikes (BECTS). METHOD: Participants with BECTS were recruited from the electroencephalography (EEG) laboratories of three pediatric centers and by referral. Pedigrees were constructed for up to three degrees of relatedness for each proband. All available affected and unaffected individuals underwent phenotyping using a validated seizure questionnaire. The proportion of affected relatives according to degree of relatedness was calculated and phenotypic patterns were analyzed. KEY FINDINGS: Fifty-three probands with BECTS had a mean age of seizure onset at 7.8 years (range 2-12 years). Thirty-four (64%) of 53 patients were male. For 51 participants, pedigrees were available for three degrees of relatedness. Fifty-seven (2.7%) of 2,085 relatives had a history of seizures: Twenty-one (9.8%) of 214 first-degree, 15 (3%) of 494 second-degree, and 21 (1.5%) of 1,377 third-degree relatives. Febrile seizures were the most frequent phenotype, occurring in 26 of 57 affected relatives. There were 34 relatives with epilepsy: 6.5% (14 of 214) first-degree, 1.8% (9 of 494) second degree, and 0.8% (11 of 1,377) third-degree relatives. Of 21 affected first degree relatives: 8 of 21 had febrile seizures (FS), 4 had BECTS, 2 had epilepsy aphasia spectrum disorder, one had temporal lobe epilepsy with hippocampal sclerosis, 2 had focal epilepsy of unknown cause, 2 had genetic generalized epilepsies, and 3 had miscellaneous. SIGNIFICANCE: The frequency of epilepsies in relatives and the heterogeneous syndromes observed suggest that BECTS has a genetic component consistent with complex inheritance. Focal epilepsies are the most common seizure disorder observed in relatives, especially BECTS and epilepsy aphasia spectrum disorder. Additional acquired or environmental factors are likely to be necessary for expression of the seizure disorder. PMID- 22220565 TI - Histomorphometric and immunohistochemical analysis of human maxillary sinus-floor augmentation using porous beta-tricalcium phosphate for dental implant treatment. AB - OBJECTIVES: This study utilized the constitution and expression of Runx2/Cbfa1 to conduct 6-month-post-operation histomorphometrical and histochemical analysis of osteocalcin in bone regeneration following sinus-floor augmentation procedures using beta-tricalcium phosphate (beta-TCP) and autogenous cortical bone. MATERIAL AND METHODS: Thirteen sinuses of nine patients were treated with sinus-floor augmentation using 50% beta-TCP and 50% autogenous cancellous bone harvested from the ramus of the mandible. Biopsies of augmented sinuses were taken at 6 months for histomorphometric and immunohistochemical measurements. RESULTS: Runx2/Cbfa1- and osteocalcin-positive cells were found around TCP particles and on the bone surface. Approximately 60% of cells found around TCP particles stained positive for Runx2/Cbfa1. Fewer cells stained positive for osteocalcin. These positive cells decreased apically with increasing vertical distance from the maxillary bone surface. Histomorphometric analysis showed that the augmented site close to residual bone and periosteum contained approximately 42% bony tissue and 42% soft connective tissue, and the remaining 16% consisted of TCP particles. On the other hand, the augmented bone far from residual bone and periosteum contained 35% bony tissue and 50% soft connective tissue. CONCLUSIONS: Our data suggest that TCP particles attract osteoprogenitor cells that migrate into the interconnecting micropores of the bone-substitute material by 6 months. The augmented site close to residual bone contained a higher proportion of bony tissue and a lower proportion of soft connective tissue than did the augmented site far from residual bone. PMID- 22220566 TI - Discovery and synthesis of hydronaphthoquinones as novel proteasome inhibitors. AB - Screening efforts led to the identification of PI-8182 (1), an inhibitor of the chymotrypsin-like (CT-L) activity of the proteasome. Compound 1 contains a hydronaphthoquinone pharmacophore with a thioglycolic acid side chain at position 2 and thiophene sulfonamide at position 4. An efficient synthetic route to the hydronaphthoquinone sulfonamide scaffold was developed, and compound 1 was synthesized in-house to confirm the structure and activity (IC(50) = 3.0 +/- 1.6 MUM [n = 25]). Novel hydronaphthoquinone derivatives of 1 were designed, synthesized, and evaluated as proteasome inhibitors. The structure-activity relationship (SAR) guided synthesis of more than 170 derivatives revealed that the thioglycolic acid side chain is required and the carboxylic acid group of this side chain is critical to the CT-L inhibitory activity of compound 1. Furthermore, replacement of the carboxylic acid with carboxylic acid isosteres such as tetrazole or triazole greatly improves potency. Compounds with a thio tetrazole or thio-triazole side chain in position 2, where the thiophene was replaced by hydrophobic aryl moieties, were the most active compounds with up to 20-fold greater CT-L inhibition than compound 1 (compounds 15e, 15f, 15h, 15j, IC(50) values around 200 nM, and compound 29, IC(50) = 150 nM). The synthetic iterations described here not only led to improving potency in vitro but also resulted in the identification of compounds that are more active such as 39 (IC(50) = 0.44 to 1.01 MUM) than 1 (IC(50) = 3.54 to 7.22 MUM) at inhibiting the proteasome CT-L activity in intact breast cancer cells. Treatment with 39 also resulted in the accumulation of ubiquitinated cellular proteins and inhibition of tumor cell proliferation of breast cancer cells. The hit 1 and its analogue 39 inhibited proteasome CT-L activity irreversibly. PMID- 22220569 TI - Precise pH measuring of platelet concentrates containing additive solution--the impact of the temperature. AB - BACKGROUND AND OBJECTIVES: Blood gas analysers measuring pH at 37 degrees C (pH37) are widely used for pH determination of platelet (PLT) concentrates (PCs). For reporting pH at 22 degrees C (pH22), converting of pH37 using the correct conversion factor is mandatory. For PCs stored in PLT additive solution (PAS), such conversion factors are not yet widely available. We studied pH in samples of PCs with different PAS/plasma ratios during warming from 22 to 37 degrees C. MATERIALS AND METHODS: We measured pH in 39 samples containing modified PAS-III (PAS-IIIM) with a plasma carryover of 20%, 30% or 40% or no PAS-IIIM. Differences between pH22 and pH37 (dpH) were compared within and between study groups. Correlation between pH22 and dpH was tested. Additional measurements in 33 samples with three different PLT counts were performed to study the influence of PLT count on dpH. RESULTS: pH22 and pH37 within each group and dpH or dpH/dT between study groups differed significantly. The dpH was 0.135 +/- 0.040, 0.021 +/- 0.009, 0.033 +/- 0.011 and 0.048 +/- 0.017 for samples containing 100%, 20%, 30% or 40% plasma, respectively. Correlation between dpH and pH22 was strong in 100% (r = 0.696, P < 0.001), weaker in 30% and 40% (r = 0.367, P = 0.022 and r = 0.345, P = 0.032, respectively) and not existing in 20% plasma (r = 0.153, P = 0.354). PLT count did not influence the dpH significantly. CONCLUSION: The dpH is dependent on different PAS-IIIM/plasma ratios and pH range. For precise reporting of pH22, the respective dpH must be used if converting is necessary. Preferably, the pH should be reported at 37 degrees C or measured directly at 22 degrees C. PMID- 22220568 TI - Catalytic residues and a predicted structure of tetrahydrobiopterin-dependent alkylglycerol mono-oxygenase. AB - Alkylglycerol mono-oxygenase (EC 1.14.16.5) forms a third, distinct, class among tetrahydrobiopterin-dependent enzymes in addition to aromatic amino acid hydroxylases and nitric oxide synthases. Its protein sequence contains the fatty acid hydroxylase motif, a signature indicative of a di-iron centre, which contains eight conserved histidine residues. Membrane enzymes containing this motif, including alkylglycerol mono-oxygenase, are especially labile and so far have not been purified to homogeneity in active form. To obtain a first insight into structure-function relationships of this enzyme, we performed site-directed mutagenesis of 26 selected amino acid residues and expressed wild-type and mutant proteins containing a C-terminal Myc tag together with fatty aldehyde dehydrogenase in Chinese-hamster ovary cells. Among all of the acidic residues within the eight-histidine motif, only mutation of Glu137 to alanine led to an 18 fold increase in the Michaelis-Menten constant for tetrahydrobiopterin, suggesting a role in tetrahydrobiopterin interaction. A ninth additional histidine residue essential for activity was also identified. Nine membrane domains were predicted by four programs: ESKW, TMHMM, MEMSAT and Phobius. Prediction of a part of the structure using the Rosetta membrane ab initio method led to a plausible suggestion for a structure of the catalytic site of alkylglycerol mono-oxygenase. PMID- 22220570 TI - Modeling the interaction between integrin-binding peptide (RGD) and rutile surface: the effect of cation mediation on Asp adsorption. AB - The binding of a negatively charged residue, aspartic acid (Asp) in tripeptide arginine-glycine-aspartic acid, onto a negatively charged hydroxylated rutile (110) surface in aqueous solution, containing divalent (Mg(2+), Ca(2+), or Sr(2+)) or monovalent (Na(+), K(+), or Rb(+)) cations, was studied by molecular dynamics (MD) simulations. The results indicate that ionic radii and charges will significantly affect the hydration, adsorption geometry, and distance of cations from the rutile surface, thereby regulating the Asp/rutile binding mode. The adsorption strength of monovalent cations on the rutile surface in the order Na(+) > K(+) > Rb(+) shows a "reverse" lyotropic trend, while the divalent cations on the same surface exhibit a "regular" lyotropic behavior with decreasing crystallographic radii (the adsorption strength of divalent cations: Sr(2+) > Ca(2+) > Mg(2+)). The Asp side chain in NaCl, KCl, and RbCl solutions remains stably H-bonded to the surface hydroxyls and the inner-sphere adsorbed compensating monovalent cations act as a bridge between the COO(-) group and the rutile, helping to "trap" the negatively charged Asp side chain on the negatively charged surface. In contrast, the mediating divalent cations actively participate in linking the COO(-) group to the rutile surface; thus the Asp side chain can remain stably on the rutile (110) surface, even if it is not involved in any hydrogen bonds with the surface hydroxyls. Inner- and outer-sphere geometries are all possible mediation modes for divalent cations in bridging the peptide to the rutile surface. PMID- 22220571 TI - Tris(5-methylpyrazolyl)methane: synthesis and properties of its iron(II) complex. AB - The new ligand, tris(5-methylpyrazolyl)methane (1), has been prepared by the reaction of n-butyl lithium with tris(pyrazolyl)methane followed by trimethylation of the tetralithiated species with methyl iodide. The BF(4)(-), ClO(4)(-), and BPh(3)CN(-) salts of the Fe(II) complex of this ligand were also synthesized. The X-ray crystal structure of the BF(4)(-) complex (2) at 100 K had Fe-N bond lengths of 1.976 A, indicative of a low spin Fe(II) complex, while at room temperature, the structure of this complex had a Fe-N bond distance close to 2.07 A, indicative of an admixture of approximately 50% low-spin and 50% high spin. The solid-state structure of the complex with a ClO(4)(-) counterion was determined at 5 different temperatures between 173 and 293 K, which allowed the thermodynamic parameters for the spin-crossover to be estimated. Mossbauer spectra of the BF(4)(-) complex further support spin-state crossover in the solid state with a transition temperature near 300 K. UV-visible spectroscopy and (1)H NMR studies of 2 show that the transition temperature in solution is closer to 400 K. No spin-crossover was observed for [Fe(1)(2)](2+).2BPh(3)CN(-). The results allow the separation of effects of groups in the 3-position from those in the 5-position on tpm ligands, and also point toward a small cooperative effect in the spin-crossover for the Fe(II) complex. PMID- 22220572 TI - Influence of weather variables and plant communities on grasshopper density in the Southern Pampas, Argentina. AB - A study was conducted to evaluate the influence of weather (precipitation and temperature) and plant communities on grasshopper density over a 14-year period (1996-2009) in Benito Juarez County, Southern Pampas, Argentina. Total density strongly varied among plant communities. Highest values were registered in 2001 and 2003 in highly disturbed pastures and in 2002 and 2009 in halophilous grasslands. Native grasslands had the lowest density values. Seasonal precipitation and temperature had no significant effect on total grasshopper density. Dichroplus elongatus (Giglio-Tos) (Orthoptera: Acridoidea), Covasacris pallidinota (Bruner), Dichroplus pratensis Bruner, Scotussa lemniscata Stal, Borellia bruneri (Rehn) and Dichroplus maculipennis (Blanchard) comprised, on average, 64% of the grasshopper assemblages during low density years and 79% during high density years. Dichroplus elongatus, S. lemniscata and C. pallidinota were the most abundant species in 2001, 2002 and 2003, while D. elongatus, B. brunneri and C. pallidinota in 2009. Dichroplus elongatus and D. pratensis, mixed feeders species, were positively affected by summer rainfall. This suggests that the increase in summer precipitation had a positive effect on the quantity and quality forage production, affecting these grasshopper populations. Scotussa lemniscata and C. pallidinota were negatively affected by winter and fall temperature, possibly affecting the embryonic development before diapause and hatching. Dichroplus elongatus and D. pratensis were associated with highly disturbed pastures, S. lemniscata with pastures and B. bruneri and D. maculipennis with halophilous grasslands. Covasacris pallidinota was closely associated with halophilous grasslands and moderately disturbed pastures. Weather conditions changed over the years, with 2001, 2002 and 2003 having excessive rainfall while 2008 and 2009 were the driest years since the study started. We suggest that although seasonal precipitation and temperature had no significant effect on total grasshopper density, these weather variables and plant communities had differential influence on the dominant grasshopper species. PMID- 22220573 TI - Cytomorphological features of extra-genital metastases in SurePathTM cervical liquid-based cytology: a series of eight cases. PMID- 22220575 TI - The exhausting dilemmas faced by home-care service providers when enhancing participation among older adults receiving home care. AB - Older adults wish to stay at home, participate in society and manage on their own as long as possible. Many older adults will, however, eventually become dependent on care and help to maintain their daily living. Thus, to enhance activity and participation also among older adults that receive home-based services, there is a strong need for development of knowledge-based practice regarding participation. The specific aim of this study is to explore how service providers perceive that their working conditions influence on their possibilities to promote participation among older adults, and more specifically, how they perceive the influence of their working conditions. A purposeful sampling strategy was applied, and six focus groups with professionals in two municipalities were conducted. The focus groups comprised four and six participants of varying ages, length of working experience and professions. A total of 30 service providers participated. The data were analysed by a constant comparative method following the guidelines from Grounded Theory. The analysis identified the categories 'encountering needs that cannot be met', 'expectations about participation', 'organisation of services' and 'professional standards' influencing the service delivery. During this analytical process, 'being on the verge' emerged as a core category that describes the service providers' experience of a stressful workday, i.e. when they had the feeling of working against their own professional standards and being pushed to their limits. The findings indicate how the professional standards of service providers on the whole are in line with health policy for in-home services. Policy objectives are, however, not always followed owing to different constraints at the level of service delivery. Along the path from political ideals to the practical execution of services, external circumstances related to the organisation of services are perceived as crucial. PMID- 22220576 TI - Controlled release of drugs from gradient hydrogels for high-throughput analysis of cell-drug interactions. AB - In this paper, we report a method to fabricate microengineered hydrogels that contain a concentration gradient of a drug for high-throughput analysis of cell drug interactions. A microfluidic gradient generator was used to create a concentration gradient of okadaic acid (OA) as a model drug within poly(ethylene glycol) diacrylate hydrogels. These hydrogels were then incubated with MC3T3-E1 cell seeded glass slides to investigate the cell viability through the spatially controlled release of OA. The drug was released from the hydrogel in a gradient manner and induced a gradient of the cell viability. The drug concentration gradient containing hydrogels developed in this study have the potential to be used for drug discovery and diagnostics applications due to their ability to simultaneously test the effects of different concentrations of various chemicals. PMID- 22220578 TI - Four-electron, three-orbital model for the low-energy electronic structure of cationic diarylmethanes: notes on a "Pauling Point". AB - We examine a four-electron, three-orbital complete active space self-consistent field (SA-CASSCF) and multistate multireference perturbation theory (MS-MRPT2) model of the electronic structure associated with the two lowest-lying electronic excitations of a series of cationic diarylmethanes related to Michler's Hydrol Blue. These dyes are of interest because of the sensitivity of their excited state dynamics to environmental influence in biological and other condensed phases. We show that the model corresponds to an easily understandable physical approximation where the dye electronic structure is mapped onto the pi-electron system of an allyl anion. We show that reported trends in solution-state absorbance bands and transition dipole moments associated with the first two electronic excitations can be described within reasonable accuracy by the model. We also show, for Michler's Hydrol Blue, that the four-electron, three-orbital model provides a more balanced description of the electronic difference densities associated with electronic excitation calculated with the full pi-electron space than can be achieved with active space models intermediate between these limits. The valence excitation energies predicted by the model are not sensitive to the underlying basis set, so that considerable computational savings may be possible by using split-valence basis sets with a limited number of polarization functions. We conclude that the model meets the criteria for a "Pauling Point": a point where the cancellation of large errors leads to physically balanced model, and where further elaboration degrades, rather than improves, the quality of description. We advocate that this Pauling Point be exploited in condensed-phase dynamical models where the computational overhead associated with the electronic structure must kept to a minimum (for example, nonadiabatic dynamics simulations coupled to QM/MM environmental models). PMID- 22220579 TI - Wheat WRKY genes TaWRKY2 and TaWRKY19 regulate abiotic stress tolerance in transgenic Arabidopsis plants. AB - WRKY-type transcription factors are involved in multiple aspects of plant growth, development and stress response. WRKY genes have been found to be responsive to abiotic stresses; however, their roles in abiotic stress tolerance are largely unknown especially in crops. Here, we identified stress-responsive WRKY genes from wheat (Triticum aestivum L.) and studied their functions in stress tolerance. Forty-three putative TaWRKY genes were identified and two multiple stress-induced genes, TaWRKY2 and TaWRKY19, were further characterized. TaWRKY2 and TaWRKY19 are nuclear proteins, and displayed specific binding to typical cis element W box. Transgenic Arabidopsis plants overexpressing TaWRKY2 exhibited salt and drought tolerance compared with controls. Overexpression of TaWRKY19 conferred tolerance to salt, drought and freezing stresses in transgenic plants. TaWRKY2 enhanced expressions of STZ and RD29B, and bound to their promoters. TaWRKY19 activated expressions of DREB2A, RD29A, RD29B and Cor6.6, and bound to DREB2A and Cor6.6 promoters. The two TaWRKY proteins may regulate the downstream genes through direct binding to the gene promoter or via indirect mechanism. Manipulation of TaWRKY2 and TaWRKY19 in wheat or other crops should improve their performance under various abiotic stress conditions. PMID- 22220580 TI - Reactive silver inks for patterning high-conductivity features at mild temperatures. AB - Reactive silver inks for printing highly conductive features (>10(4) S/cm) at room temperature have been created. These inks are stable, particle-free, and suitable for a wide range of patterning techniques. Upon annealing at 90 degrees C, the printed electrodes exhibit an electrical conductivity equivalent to that of bulk silver. PMID- 22220581 TI - Bacterial endophyte communities of two wheatgrass varieties following propagation in different growing media. AB - Bacterial endophyte communities of two wheatgrass varieties currently being used in the revegetation of military training ranges were studied. Culturable and direct 16S rDNA PCR amplification techniques were used to describe bacterial communities present in Siberian and slender wheatgrass seeds, leaf tissues, and root tissues following propagation in either sand or a peat-based growing mix. Our hypothesis was that the resulting plant endophytic communities would be distinct, showing not only the presence of endophytes originating from the seed but also the characteristics of growth in the two different growing media. Both culture and culture-independent assays showed the likely translocation of Actinobacteria, Firmicutes, and Gammaproteobacteria from seed to mature plant tissues as well as subsequent colonization by exogenous organisms. Statistical analysis of 16S terminal restriction fragment profiles identified growing media as having a greater significant effect on the formation of the endpoint endophytic communities than either plant tissue or wheatgrass variety. In silico digests of the ribosomal database produced putative identifications indicating an increase in overall species diversity and increased relative abundances of Firmicutes and Cyanobacteria following propagation in sand and Betaproteobacteria following propagation in the peat-based growing mix. Results indicated a substantial translocation of endophytes from seed to mature plant tissues for both growing media and that growing medium was a dominant determinant of the final taxonomy of the endpoint plant endophytic communities. PMID- 22220583 TI - Molecular thioamide <-> iminothiolate switches for sulfur mustards. AB - SNS platinum(II) pincer complexes reversibly bind and release the surrogate half sulfur mustard, 2-chloroethyl ethyl sulfide (CEES). The switch-like behavior of the pincers is attributed to a reversible transformation between the thioamide and iminothiolate forms of the pincer skeleton under slightly acidic and basic conditions, respectively. An amide-based palladium(II) pincer complex also binds CEES, as confirmed crystallographically and by NMR. PMID- 22220582 TI - Endothelial actions of atrial and B-type natriuretic peptides. AB - The cardiac hormone atrial natriuretic peptide (ANP) is critically involved in the maintenance of arterial blood pressure and intravascular volume homeostasis. Its cGMP-producing GC-A receptor is densely expressed in the microvascular endothelium of the lung and systemic circulation, but the functional relevance is controversial. Some studies reported that ANP stimulates endothelial cell permeability, whereas others described that the peptide attenuates endothelial barrier dysfunction provoked by inflammatory agents such as thrombin or histamine. Many studies in vitro addressed the effects of ANP on endothelial proliferation and migration. Again, both pro- and anti-angiogenic properties were described. To unravel the role of the endothelial actions of ANP in vivo, we inactivated the murine GC-A gene selectively in endothelial cells by homologous loxP/Cre-mediated recombination. Our studies in these mice indicate that ANP, via endothelial GC-A, increases endothelial albumin permeability in the microcirculation of the skin and skeletal muscle. This effect is critically involved in the endocrine hypovolaemic, hypotensive actions of the cardiac hormone. On the other hand the homologous GC-A-activating B-type NP (BNP), which is produced by cardiac myocytes and many other cell types in response to stressors such as hypoxia, possibly exerts more paracrine than endocrine actions. For instance, within the ischaemic skeletal muscle BNP released from activated satellite cells can improve the regeneration of neighbouring endothelia. This review will focus on recent advancements in our understanding of endothelial NP/GC-A signalling in the pulmonary versus systemic circulation. It will discuss possible mechanisms accounting for the discrepant observations made for the endothelial actions of this hormone-receptor system and distinguish between (patho)physiological and pharmacological actions. Lastly it will emphasize the potential therapeutical implications derived from the actions of NPs on endothelial permeability and regeneration. PMID- 22220584 TI - Phloroglucinol attenuates ultraviolet B radiation-induced matrix metalloproteinase-1 production in human keratinocytes via inhibitory actions against mitogen-activated protein kinases and activator protein-1. AB - Excessive amounts of reactive oxygen species (ROS) induced by ultraviolet (UV) radiation cause skin aging via basement membrane/extracellular matrix degradation resulting from the action of matrix metalloproteinases (MMPs). Recently, phloroglucinol (1,3,5-trihydroxybenzene) was demonstrated to attenuate the cell damage induced by oxidative stress by quenching ROS and stimulating antioxidant systems. In the current study, the effect of phloroglucinol on UVB-induced photoaging was investigated in human HaCaT keratinocytes. Phloroglucinol significantly inhibited the UVB-induced (1) upregulation of MMP-1 mRNA, protein and activity; (2) augmentation of intracellular Ca(2+) levels; (3) phosphorylation of mitogen-activated protein kinases (MAPKs); (4) expression of c Fos and phospho c-Jun; and (5) enhancement of activator protein-1 (AP-1) binding to the MMP-1 promoter. In addition, the knockdown of MAPKs significantly inhibited UVB-induced MMP-1 expression. The results of this study suggest that phloroglucinol may be useful as a photoprotective compound for the skin. PMID- 22220585 TI - Personality differences between drug injectors and non-injectors among substance dependent patients in substitution treatment. AB - BACKGROUND: Understanding personality differences between injectors and non injectors in substitution treatment may provide new insights to help improve treatment programs. OBJECTIVE: The aim of this study was to compare drug injectors and non-injectors in terms of personality disorders and dimensions. METHODS: Forty participants recruited from substance abuse treatment centers (23 injectors and 17 non-injectors) completed the self-report Personality Diagnostic Questionnaire 4th version and Temperament and Character Inventory. Mann-Whitney U tests were used to compare means of personality disorder traits, temperament, and character differences between injectors and non-injectors. RESULTS: The mean (SD) age of the sample (72.5% male) was 36.5 (8.7) years. Injectors reported more borderline personality disorders and increased global personality disturbance (p < .05). Similarly, Anticipatory worry, Shyness, and Fatigability facet scores were higher among injectors (p < .01). Attachment, Purposeful, and Congruent second nature facet scores were higher among non-injectors (p < .01). CONCLUSION: According to the route of drug administration, drug dependents differed in terms of personality disorders and dimensions. SCIENTIFIC SIGNIFICANCE: These results may have implications for the implementation of treatment programs. New research in this area may contribute to the understanding and prevention of intravenous drug use. PMID- 22220586 TI - Names and numberplates: quasi-everyday associative memory tasks for distinguishing amnestic mild cognitive impairment from healthy aging. AB - Amnestic mild cognitive impairment (aMCI) delineates a population at high risk for subsequently developing Alzheimer's disease (AD)--that is, people with preclinical AD. Associative episodic memory tasks are particularly sensitive to preclinical AD; however, they often lack ecological validity, which is important when evaluating performance in daily activities. We describe the development of two quasi-everyday associative memory tasks--the La Trobe Face-Name test and the La Trobe Numberplate task--and their utility in profiling and separating 70 aMCI participants from 101 healthy older adults (HOA) compared with standard episodic memory tasks. aMCI participants performed significantly worse overall and demonstrated a greater forgetting rate than HOA on both tasks. The everyday tasks separated aMCI from HOA participants as effectively as standard episodic memory tasks and were well tolerated. These tasks provide a valuable addition to neuropsychologists' toolkits with enhanced ecological (verisimilitude) and face validity for assisting in counseling clients, measuring the effect of interventions, and profiling everyday memory performance in HOA and aMCI. PMID- 22220587 TI - Cathepsin K expression in basal cell carcinoma. AB - BACKGROUND: Cathepsin K is a cysteine protease with strong collagenolytic and elastolytic properties. Recently, cathepsin K expression in tumour cells of malignant melanoma and in the stromal cells of squamous cell carcinoma of the skin has been reported to play an important role in tumour progression. However, its expression profile in basal cell carcinoma (BCC) has not yet been clarified. OBJECTIVE: The aim of this study is to examine the expression profile of cathepsin K in both the tumour cells and the peritumoural stromal cells of BCC in comparison with its expression in normal skin. METHODS: Fifty consecutive operative cases of BCC, 10 cases of actinic keratosis, 10 cases of Bowen's disease and five normal skin tissues were assessed for cathepsin K expression by immunohistochemical methods. RESULTS: In normal skin, cathepsin K expression was observed in the stratum corneum, mature sebaceous cells and outer root sheath of the hair follicles. Cathepsin K was expressed in the tumour cells of all BCC cases, in which 90% showed diffuse expression (>51% of tumour cells), as well as in the peritumoural stromal cells in all BCC cases. Focal cathepsin K expression was observed in the tumour cells of Bowen's disease (2/10 cases), but not in any of actinic keratosis (0/10 cases). CONCLUSION: Cathepsin K expression may contribute to tumour invasion and peculiar histopathological features, such as fibromucinous stroma around the tumour nests by mediating extracellular matrix degradation in BCC. PMID- 22220588 TI - A proteomic analysis of pediatric seizure cases associated with astrocytic inclusions. AB - Cerebral hyaline astrocytic inclusions have been observed in a subset of patients with early onset epilepsy, brain structural anomalies, and developmental delay, which indicates that it may represent a unique clinicopathologic entity. To further characterize this condition we use proteomics to investigate differentially expressed proteins in epileptic brain tissue from three pediatric epileptic patients with cerebral hyaline astrocytic inclusions, ranging in age from 5-13 years, and compare to brain tissue from two normal controls. Catalase and carbonic anhydrase I both exhibited increased expression in epileptic brain tissue compared to controls. These findings were confirmed by Western blot analysis. Furthermore, both proteins were localized to astrocytes and in epileptic brain were located within the cerebral hyaline astrocytic inclusions, suggesting a potential role in the generation of this pathologic feature of early onset epilepsy with cerebral hyaline astrocytic inclusions. PMID- 22220589 TI - Bioactive polyphenols in leaves, stems, and berries of Saskatoon (Amelanchier alnifolia Nutt.) cultivars. AB - The Saskatoon berry is currently cultivated in many parts of the world for its suitability for various food products and due to its high content of nutrients and polyphenols. To determine the phytochemical profile of a Saskatoon plant, polyphenols from leaves, stems, and berries were screened from four cultivars grown in Finland using HPLC-DAD and HPLC-ESI/MS. The phenolic composition and concentrations varied among plant parts and cultivars. The main berry components were cyanidin-based anthocyanins (63% of the phenols), quercetin-derived flavonol glycosides, and hydroxycinnamic acids. The total anthocyanin content varied between 258.7 and 517.9 mg/100 fresh weight among cultivars. Protocatechuic acid was found for the first time in Saskatoon berries. The leaves consisted of quercetin- and kaempferol-derived glycosides (41% of the phenols), hydroxycinnamic acids (36%), catechins, and some neolignans. Quercetin 3 galactoside and 3-glucoside, (-)-epicatechin, and chlorogenic acid were the main phenolics in the leaves of all cultivars. The stem components were flavanone and flavonol glycosides (55% of the phenols), catechins (38%), and hydroxybenzoic acids. Concentrations of the main compound, eriodictyol 7-glucoside, varied among cultivars from 3.3 to 6.5 mg/g of stem dry weight. Very high proanthocyanidin contents were found in stems and leaves (10-14% of dry biomass), whereas berries contained a low amount of proanthocyanidins (3% of dry biomass). The findings reveal that leaves and stems of Saskatoon cultivars possess high amounts of various phenolic compounds that may offer new functional raw materials for a wide range of food and health products. PMID- 22220590 TI - The histological evaluation of osseointegration of surface enhanced microimplants immediately loaded in conjunction with sinuslifting in humans. AB - OBJECTIVE: The aim was to investigate histomorphometrically whether or not implant surface nanotopography improves the bone response under immediate loading simultaneous to sinus grafting. MATERIALS AND METHODS: Dual acid-etched titanium microimplants with/without crystalline surface deposition of calcium phosphate particles were placed in bilateral sinuslift areas grafted with a mixture of iliac crest bone and BioOss. Surface topography of microimplants was characterized using interferometry. Loaded microimplants (MsL) were immobilized in a provisional bridge supported by four normal size implants. Some patients had unloaded microimplants as controls (MsU). Biopsies were trephined after 2 or 4 months and histomorphometric analysis of bone area (BA) and bone-to-implant contact (BC) was performed. Nonparametric methods for dependent data were used to compare effect of surface modification, and healing time (2 vs. 4 months). RESULTS: A total of 53 biopsies were available from 13 patients. A total of 4/28 and 1/11 MsL failed after resp. 2 and 4 months vs. 0/6 and 1/5 MsU. Many loaded biopsies were damaged at the apical portion and showed no bone adhesion. MsL decreased in BA from coronal to apical from 2 to 4 months; Coronal > Middle (P = 0.047), Coronal > Apical (P < 0.001) and Middle > Apical (P < 0.001). This gradual decrease was not observed for BC; Coronal < Middle and Middle > Apical (P < 0.001). Only the middle part showed significant bone contact after 2 months. For MsL there was no statistically significant difference between surface or time indicating that improvement of osseointegration over time due to maturation of the graft was poor. The MsU did not show any difference between Osseotite and Nanotite for BIC and BA (P > 0.05) but doubled both their BA and BIC (P < 0.05) between 2 and 4 months. CONCLUSIONS: Osseointegration in sinus-grafted bone mixed with BioOss was poor irrespective of healing time or nanotopographical surface modification. The apex of MsL showed minimal bone contact suggesting that the graft does not add to the loading capacity. Surface enhancement was not beneficial despite the enlarged surface area. Overloading, most critical coronally of an implant, increases risks for implant failure and jeopardizes bone healing especially under immediate loading conditions with high load. PMID- 22220591 TI - Melatonin osteoporosis prevention study (MOPS): a randomized, double-blind, placebo-controlled study examining the effects of melatonin on bone health and quality of life in perimenopausal women. AB - The purpose of this double-blind study was to assess the effects of nightly melatonin supplementation on bone health and quality of life in perimenopausal women. A total of 18 women (ages 45-54) were randomized to receive melatonin (3mg, p.o., n=13) or placebo (n=5) nightly for 6months. Bone density was measured by calcaneal ultrasound. Bone turnover marker (osteocalcin, OC for bone formation and NTX for bone resorption) levels were measured bimonthly in serum. Participants completed Menopause-Specific Quality of Life-Intervention (MENQOL) and Pittsburgh Sleep Quality Index (PSQI) questionnaires before and after treatment. Subjects also kept daily diaries recording menstrual cycling, well being, and sleep patterns. The results from this study showed no significant change (6-month-baseline) in bone density, NTX, or OC between groups; however, the ratio of NTX:OC trended downward over time toward a ratio of 1:1 in the melatonin group. Melatonin had no effect on vasomotor, psychosocial, or sexual MENQOL domain scores; however, it did improve physical domain scores compared to placebo (mean change melatonin: -0.6 versus placebo: 0.1, P<0.05). Menstrual cycling was reduced in women taking melatonin (mean cycles melatonin: 4.3 versus placebo: 6.5, P<0.05), and days between cycles were longer (mean days melatonin: 51.2 versus placebo: 24.1, P<0.05). No differences in duration of menses occurred between groups. The overall PSQI score and average number of hours slept were similar between groups. These findings show that melatonin supplementation was well tolerated, improved physical symptoms associated with perimenopause, and may restore imbalances in bone remodeling to prevent bone loss. Further investigation is warranted. PMID- 22220592 TI - Discovery of 1,2,4-triazine derivatives as adenosine A(2A) antagonists using structure based drug design. AB - Potent, ligand efficient, selective, and orally efficacious 1,2,4-triazine derivatives have been identified using structure based drug design approaches as antagonists of the adenosine A(2A) receptor. The X-ray crystal structures of compounds 4e and 4g bound to the GPCR illustrate that the molecules bind deeply inside the orthosteric binding cavity. In vivo pharmacokinetic and efficacy data for compound 4k are presented, demonstrating the potential of this series of compounds for the treatment of Parkinson's disease. PMID- 22220594 TI - Synthesis and crystal structure of an oxovanadium(IV) complex with a pyrazolone ligand and its use as a heterogeneous catalyst for the oxidation of styrene under mild conditions. AB - 1-Phenyl-3-methyl-4-touloyl-5-pyrazolone (ligand) was synthesized and used to prepare an oxovanadium(IV) complex. The complex was characterized by single crystal X-ray analysis and various spectroscopic techniques. The single-crystal X ray analysis of the complex shows that the ligands are coordinated in a syn configuration to each other and create a distorted octahedral environment around the metal ion. A heterogeneous catalyst comprising an oxovanadium(IV) complex and hydrous zirconia was synthesized, characterized by various physicochemical techniques, and successfully used for the solvent-free oxidation of styrene. The influence of the reaction parameters (percent loading, molar ratio of the substrate to H(2)O(2), amount of catalyst, and reaction time) was studied. The catalyst was reused three times without any significant loss in the catalytic activity. PMID- 22220593 TI - Serum copper as a novel biomarker for resistance to thyroid hormone. AB - Thyroid hormone action is mediated by the thyroid hormone receptors TRalpha1 and TRbeta. Defects in TRbeta lead to RTH (resistance to thyroid hormone) beta, a syndrome characterized by high levels of thyroid hormone and non-suppressed TSH (thyroid-stimulating hormone). However, a correct diagnosis of RTHbeta patients is difficult as the clinical picture varies. A biochemical serum marker indicative of defects in TRbeta signalling is needed and could simplify the diagnosis of RTHbeta, in particular the differentiation to TSH-secreting pituitary adenomas, which present with clinically similar symptoms. In the present paper we show that serum copper levels are regulated by thyroid hormone, which stimulates the synthesis and the export of the hepatic copper-transport protein ceruloplasmin into the serum. This is accompanied by a concerted reduction in the mRNA levels of other copper-containing proteins such as metallothioneins 1 and 2 or superoxide dismutase 1. The induction of serum copper is abolished in genetically hyperthyroid mice lacking TRbeta and human RTHbeta patients, demonstrating an important role of TRbeta for this process. Together with a previously reported TRalpha1 specific regulation of serum selenium, we show that the ratio of serum copper and selenium, which is largely independent of thyroid hormone levels, volume changes or sample degradation, can constitute a valuable novel biomarker for RTHbeta. Moreover, it could also provide a suitable large-scale screening parameter to identify RTHalpha patients, which have not been identified to date. PMID- 22220595 TI - Genetic heterogeneity in a cyclical forest pest, the southern pine beetle, Dendroctonus frontalis, is differentiated into east and west groups in the southeastern United States. AB - The southern pine beetle, Dendroctonus frontalis Zimmerman (Coleoptera: Curculionidae) is an economically important pest species throughout the southeastern United States, Arizona, Mexico, and Central America. Previous research identified population structure among widely distant locations, yet failed to detect population structure among national forests in the state of Mississippi. This study uses microsatellite variation throughout the southeastern United States to compare the southern pine beetle's pattern of population structure to phylogeographic patterns in the region, and to provide information about dispersal. Bayesian clustering identified east and west genetic groups spanning multiple states. The east group had lower heterozygosity, possibly indicating greater habitat fragmentation or a more recent colonization. Significant genetic differentiation (theta(ST) = 0.01, p < 0.0001) followed an isolation-by-distance pattern (r = 0.39, p < 0.001) among samples, and a hierarchical AMOVA indicated slightly more differentiation occurred between multi state groups. The observed population structure matches a previously identified phylogeographic pattern, division of groups along the Appalachian Mountain/Apalachicola River axis. Our results indicate that the species likely occurs as a large, stable metapopulation with considerable gene flow among subpopulations. Also, the relatively low magnitude of genetic differentiation among samples suggests that southern pine beetles may respond similarly to management across their range. PMID- 22220596 TI - Multiple heat pulses during PCR extension enabling amplification of GC-rich sequences and reducing amplification bias. AB - PCR amplification over GC-rich and/or long repetitive sequences is challenging because of thermo-stable structures resulting from incomplete denaturation, reannealing, and self-annealing of target sequences. These structures block the DNA polymerase during the extension step, leading to formation of incomplete extension products and favoring amplification of nonspecific products rather than specific ones. We have introduced multiple heat pulses in the extension step of a PCR cycling protocol to temporarily destabilize such blocking structures, in order to enhance DNA polymerase extension over GC-rich sequences. With this novel type of protocol, we were able to amplify all expansions of CGG repeats in five Fragile X cell lines, as well as extremely GC-rich nonrepetitive segments of the GNAQ and GP1BB genes. The longest Fragile X expansion contained 940 CGG repeats, corresponding to about 2.8 kilo bases of 100% GC content. For the GNAQ and GP1BB genes, different length PCR products in the range of 700 bases to 2 kilobases could be amplified without addition of cosolvents. As this technique improves the balance of amplification efficiencies between GC-rich target sequences of different length, we were able to amplify all of the allelic expansions even in the presence of the unexpanded allele. PMID- 22220597 TI - Investigation of the hydration of nonfouling material poly(ethylene glycol) by low-field nuclear magnetic resonance. AB - The strong surface hydration layer of nonfouling materials plays a key role in their resistance to nonspecific protein adsorption. Poly(ethylene glycol) (PEG) is an effective example of materials that can resist nonspecific protein adsorption and cell adhesion. Thus, the strong interaction between water molecules and PEG was investigated through each T(2) component in water/PEG mixtures using multiexponential inversion of T(2) relaxation time measured by the Carr-Purcell-Meiboom-Gill (CPMG) sequence of low-field nuclear magnetic resonance (LF-NMR). Results show that about one water molecule is tightly bound with one ethylene glycol (EG) unit, and additional water molecules over 1:1 ratio mainly swell the PEG matrix and are not tightly bound with PEG. This result was also supported by the endothermic behavior of water/PEG mixtures measured by differential scanning calorimetry (DSC). It is believed that the method developed could be also applied to investigate various interactions between macromolecules and other small molecules without using deuterium samples, which might open a novel route to quantitatively measure guest-host interactions in the future. PMID- 22220599 TI - Endometrial adenocarcinoma mimicking cervical glandular neoplasia in liquid-based cervical cytology samples. PMID- 22220625 TI - How new is new: the late sampling strategy with rapid bacterial screening of platelet concentrates? PMID- 22220627 TI - Adverse reactions to beta-lactam antimicrobials. AB - INTRODUCTION: Beta-lactam antibiotics are among the most clinically useful antimicrobials used in medicine. Unfortunately, adverse events related to their use remain poorly understood by many clinicians and, in particular, the misdiagnosis of beta-lactam allergy and misunderstanding of crossreactivity among members of the beta-lactam antibiotics may effectively eliminate a whole class of antimicrobials from use and require the use of broader spectrum agents with less well-established safety profiles. AREAS COVERED: This review describes the range, diagnosis and management of adverse events associated with beta-lactam antimicrobials, particularly focusing on recognition, diagnosis and management of true allergy and risk of cross-sensitivity between beta-lactam antibiotics. A literature review was undertaken using PubMed, focusing primarily on literature published in the past 10 years relating to beta-lactam adverse events and allergy. EXPERT OPINION: Beta-lactams are generally safe drugs and serious adverse events are rare and allergy is overdiagnosed. Accurate diagnosis can usually be achieved through careful history and in some instances skin or in vitro testing is required. Even among individuals with true immediate-type allergy to penicillin, most cephalosporins are readily tolerated and desensitization is usually an option in cases where no alternate antimicrobials are available. Other allergic reactions (Type II, III and IV) are rare and avoidance of the culprit agent is generally recommended. Nonallergic or morbilliform rashes are generally not allergic in nature and should not prompt drug or class avoidance. Other adverse events are frequently dose-related and can be avoided by appropriate dosing and consideration of renal function. PMID- 22220626 TI - Drug-like actions of autoantibodies against receptors of the autonomous nervous system and their impact on human heart function. AB - Antibodies against cholinergic and adrenergic receptors (adrenoceptors) are frequent in serum of patients with chronic heart failure. Their prevalence is associated with Chagas' disease, idiopathic dilated cardiomyopathy (DCM), and ischaemic heart disease. Among the epitopes targeted are first and second extracellular loops of the beta-adrenergic (beta-adrenoceptor) and M2 muscarinic receptor. beta(1)-adrenoceptor autoantibodies affect radioligand binding and cardiomyocyte function similar to agonists. Corresponding rodent immunizations induce symptoms compatible with chronic heart failure that are reversible upon removal of the antibodies, transferable via the serum and abrogated by adrenergic antagonists. In DCM patients, prevalence and stimulatory efficacy of beta(1) adrenoceptor autoantibodies are correlated to the decline in cardiac function, ventricular arrhythmia and higher incidence of cardiac death. In conclusion, such autoantibodies seem to cause or promote chronic human left ventricular dysfunction by acting on their receptor targets in a drug-like fashion. However, the pharmacology of this interaction is poorly understood. It is unclear how the autoantibodies trigger changes in receptor activity and second messenger coupling and how that is related to the pathogenesis and severity of the associated diseases. Here, we summarize the available evidence regarding these issues and discuss these findings in the light of recent knowledge about the conformational activation of the human beta(2)-adrenoceptor and the properties of bona fide cardiopathogenic autoantibodies derived from immune-adsorption therapy of DCM patients. These considerations might contribute to the conception of therapy regimen aimed at counteracting or neutralizing cardiopathogenic receptor autoantibodies. PMID- 22220628 TI - Lysosomal signaling enhances mitochondria-mediated photodynamic therapy in A431 cancer cells: role of iron. AB - In photodynamic therapy (PDT), light activates a photosensitizer added to a tissue, resulting in singlet oxygen formation and cell death. The photosensitizer phthalocyanine 4 (Pc 4) localizes primarily to mitochondrial membranes in cancer cells, resulting in mitochondria-mediated cell death. The aim of this study was to determine how lysosomes contribute to PDT-induced cell killing by mitochondria targeted photosensitizers such as Pc 4. We monitored cell killing of A431 cells after Pc 4-PDT in the presence and absence of bafilomycin, an inhibitor of the vacuolar proton pump of lysosomes and endosomes. Bafilomycin was not toxic by itself, but greatly enhanced Pc 4-PDT-induced cell killing. To investigate whether iron loading of lysosomes affects bafilomycin-induced killing, cells were incubated with ammonium ferric citrate (30 MUM) for 30 h prior to PDT. Ammonium ferric citrate enhanced Pc 4 plus bafilomycin-induced cell killing without having toxicity by itself. Iron chelators (desferrioxamine and starch-desferrioxamine) and the inhibitor of the mitochondrial calcium (and ferrous iron) uniporter, Ru360, protected against Pc 4 plus bafilomycin toxicity. These results support the conclusion that chelatable iron stored in the lysosomes enhances the efficacy of bafilomycin-mediated PDT and that lysosomal disruption augments PDT with Pc 4. PMID- 22220629 TI - Ligand exchange and spin state equilibria of Fe(II)(N4Py) and related complexes in aqueous media. AB - We report the characterization and solution chemistry of a series of Fe(II) complexes based on the pentadentate ligands N4Py (1,1-di(pyridin-2-yl)-N,N bis(pyridin-2-ylmethyl)methanamine), MeN4Py (1,1-di(pyridin-2-yl)-N,N-bis(pyridin 2-ylmethyl)ethanamine), and the tetradentate ligand Bn-N3Py (N-benzyl-1,1 di(pyridin-2-yl)-N-(pyridin-2-ylmethyl)methanamine) ligands, i.e., [Fe(N4Py)(CH(3)CN)](ClO(4))(2) (1), [Fe(MeN4Py)(CH(3)CN)](ClO(4))(2) (2), and [Fe(Bn-N3Py)(CH(3)CN)(2)](ClO(4))(2) (3), respectively. Complexes 2 and 3 are characterized by X-ray crystallography, which indicates that they are low-spin Fe(II) complexes in the solid state. The solution properties of 1-3 are investigated using (1)H NMR, UV/vis absorption, and resonance Raman spectroscopies, cyclic voltammetry, and ESI-MS. These data confirm that in acetonitrile the complexes retain their solid-state structure, but in water immediate ligand exchange of the CH(3)CN ligand(s) for hydroxide or aqua ligands occurs with full dissociation of the polypyridyl ligand at low (<3) and high (>9) pH. pH jumping experiments confirm that over at least several minutes the ligand dissociation observed is fully reversible for complexes 1 and 2. In the pH range between 5 and 8, complexes 1 and 2 show an equilibrium between two different species. Furthermore, the aquated complexes show a spin equilibrium between low- and high-spin states with the equilibrium favoring the high-spin state for 1 but favoring the low-spin state for 2. Complex 3 forms only one species over the pH range 4-8, outside of which ligand dissociation occurs. The speciation analysis and the observation of an equilibrium between spin states in aqueous solution is proposed to be the origin of the effectiveness of complex 1 in cleaving DNA in water with (3)O(2) as terminal oxidant. PMID- 22220630 TI - Reinforcement sensitivity theory and alcohol outcome expectancies in early adolescence. AB - BACKGROUND: Little research has examined the development of alcohol expectancies in childhood, a notable omission as expectancies are viable targets for prevention programs. Moreover, limited alcohol expectancies research has been conducted from the perspective of psychobiological models of motivation despite the strong conceptual links between such models and cognitive models of alcohol use. OBJECTIVE: To examine if the associations between individual differences from the revised reinforcement sensitivity theory (Gray JA, McNaughton N. The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo hippocampal System (2nd ed.). Oxford, UK: Oxford University Press, 2000) and alcohol use is mediated by alcohol expectancies in a large community sample of early adolescents using a prospective design. METHODS: 378 families (1 caregiver; 1 child) were recruited via random digit phone call using a prospective design. RESULTS: Our findings suggest that both a strong behavioral approach system and fight-flight or freeze system were associated with high levels of positive outcome expectancies, which subsequently predicted an increase in likelihood of alcohol use. There was also some evidence that drive (an aspect of behavioral approach system) was also positively associated with negative expectancies, which subsequently predicted a low probability of alcohol use. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Individual differences in reinforcement sensitivity may influence the acquisition of positive and negative outcome expectancies, thereby potentially influencing the likelihood of alcohol use in early adolescence. Thus, reinforcement sensitivity theory is a promising theory to account for the link between neural models of addiction and early acquisition of alcohol use in humans. PMID- 22220631 TI - Spatio-temporal control of hepatic stellate cell-endothelial cell interactions for reconstruction of liver sinusoids in vitro. AB - Vascularization of engineered tissues in vitro remains a major challenge in liver tissue engineering. Liver microvessels, termed liver sinusoids, have highly specialized structures, and recapturing these sinusoidal structures is essential for reconstruction of functional liver tissue in vitro. Liver sinusoids are composed of hepatocytes, hepatic stellate cells (HSCs), and endothelial cells (ECs). Direct HSC-EC contacts are increasingly recognized for their roles in EC capillary morphogenesis. However, the hypothetical role of HSC-EC contacts in morphogenesis remains unclear in hepatocyte-HSC-EC triculture. In the present study, we first determined the effects of direct HSC-EC contacts on EC capillary morphogenesis using a hepatocyte-HSC-EC triculture model where HSC behavior was spatially controlled to achieve HSC-mediated proximal layers of hepatocytes and ECs. EC capillary morphogenesis was induced by overlaying Matrigel on an EC layer. Direct HSC-EC contacts inhibited EC capillary morphogenesis, suggesting that the HSC-EC contacts may be an important factor in capillary formation. We next tested the hypothesis that, in addition to spatial control, temporal control of HSC behavior is also important in achieving capillary morphogenesis in the triculture. ECs responded to the induction of capillary morphogenesis before the formation of direct HSC-EC contacts, while the ECs remained to form monolayers when capillary morphogenesis was induced after the HSC-EC contacts were established. When capillary morphogenesis was successfully achieved in the triculture, HSCs tended to preferably localize near the preformed capillary-like structures, resulting in the reconstruction of liver sinusoidal structures. In these structures, hepatocyte maturation was induced. Our findings indicate that control, both spatial and temporal, of HSC behavior is a key engineering strategy for the vascularization of engineered liver tissue in vitro. PMID- 22220632 TI - Characterization and quantitation of low and high molecular weight phenolic compounds in apple seeds. AB - The phenolic constituents of seeds of 12 different apple cultivars were fractionated by sequential extraction with aqueous acetone (30:70, v/v) and ethyl acetate after hexane extraction of the lipids. Low molecular weight phenolic compounds were individually quantitated by RP-HPLC-DAD. The contents of extractable and nonextractable procyanidins were determined by applying RP-HPLC following thiolysis and n-butanol/HCl hydrolysis, respectively. As expected, the results revealed marked differences of the ethyl acetate extracts, aqueous acetone extracts, and insoluble residues with regard to contents and mean degrees of polymerization of procyanidins. Total phenolic contents in the defatted apple seed residues ranged between 18.4 and 99.8 mg/g. Phloridzin was the most abundant phenolic compound, representing 79-92% of monomeric polyphenols. Yields of phenolic compounds significantly differed among the cultivars under study, with seeds of cider apples generally being richer in phloridzin and catechins than seeds of dessert apple cultivars. This is the first study presenting comprehensive data on the contents of phenolic compounds in apple seeds comprising extractable and nonextractable procyanidins. Furthermore, the present work points out a strategy for the sustainable and complete exploitation of apple seeds as valuable agro-industrial byproducts, in particular as a rich source of phloridzin and antioxidant flavanols. PMID- 22220633 TI - Large-scale synthesis of high-quality hexagonal boron nitride nanosheets for large-area graphene electronics. AB - Hexagonal boron nitride (h-BN) has received a great deal of attention as a substrate material for high-performance graphene electronics because it has an atomically smooth surface, lattice constant similar to that of graphene, large optical phonon modes, and a large electrical band gap. Herein, we report the large-scale synthesis of high-quality h-BN nanosheets in a chemical vapor deposition (CVD) process by controlling the surface morphologies of the copper (Cu) catalysts. It was found that morphology control of the Cu foil is much critical for the formation of the pure h-BN nanosheets as well as the improvement of their crystallinity. For the first time, we demonstrate the performance enhancement of CVD-based graphene devices with large-scale h-BN nanosheets. The mobility of the graphene device on the h-BN nanosheets was increased 3 times compared to that without the h-BN nanosheets. The on-off ratio of the drain current is 2 times higher than that of the graphene device without h-BN. This work suggests that high-quality h-BN nanosheets based on CVD are very promising for high-performance large-area graphene electronics. PMID- 22220634 TI - Digital dermatoscopic follow-up of 1027 melanocytic lesions in 121 patients at risk of malignant melanoma. AB - OBJECTIVE: The aim of the presented prospective study was to use a digital dermatoscopic system to follow-up patients with multiple melanocytic naevi, and to evaluate the frequency and character of dermatoscopic changes. METHODS: We monitored selected melanocytic lesions with the use of a 6-month follow-up interval between check-ups. We searched for changes in size, shape, symmetry, structure and colour. We defined the criteria for surgical excision and histopathological examination of changing lesions. We created a small group of excised unchanged atypical melanocytic naevi. RESULTS: We completed dermatoscopic monitoring of 1027 melanocytic lesions in 121 patients at risk of developing malignant melanoma. The average total follow-up interval was 21.0 months. We noticed a substantial enlargement of monitored lesions in 4.5% of cases, and there was a change of shape in 1.3% and change of asymmetry in 2.0%. The appearance of new structures, frequently being associated with malignant melanoma, was observed in 10 lesions, and it was predictive for the histopathological confirmation of this diagnosis in all cases. About 80% of monitored lesions remained unchanged. We excised 38 monitored lesions (seven melanomas in situ, four thin invasive melanomas and 27 melanocytic naevi). There was no melanoma excised in the group of unchanged atypical melanocytic lesions. CONCLUSION: Digital dermatoscopic follow-up facilitates the recognition of thin malignant melanomas and helps to reduce the number of unnecessary excisions. PMID- 22220635 TI - Chromophenazines from the terrestrial Streptomyces sp. Ank 315. AB - The new chromophenazines A-F [9-methyl-5-(3'-methylbut-2'-enyl)-5H benzo[a]phenazin-7-one (1a), 9-methyl-5-(3'-methylbut-2'-enyl)-7-oxo-5,7 dihydrobenzo[a]phenazine-1-carboxylic acid (1b), 5-(3'-methylbut-2'-enyl)-7-oxo 5,7-dihydrophenazine-1-carboxamide (2), 3-benzoyl-5-(3'-methylbut-2'-enyl)-5,10 dihydrophenazine-1-carboxylic acid (5a), 3,7-dibenzoyl-5-(3'-methylbut-2'-enyl) 5,10-dihydrophenazine-1-carboxylic acid (5b), and 3,7-dibenzoyl-5-(3'-methylbut 2'-enyl)-5,10-dihydrophenazine-1-carboxamide (5c)], together with phenazine-1 carboxylic acid, 1-phenazinecarboxamide, 1-phenazinol, tryptophol, and anthranilic acid, were isolated from Streptomyces sp. Ank 315. The structures of the new compounds were established on the basis of spectroscopic data, 1D NOE, 2D NMR, and ESIMS measurements and comparison with literature values. PMID- 22220637 TI - Visual ability and searching behavior of adult Laricobius nigrinus, a hemlock woolly adelgid predator. AB - Very little is known about the searching behavior and sensory cues that Laricobius spp. (Coleoptera: Derodontidae) predators use to locate suitable habitats and prey, which limits our ability to collect and monitor them for classical biological control of adelgids (Hemiptera: Adelgidae). The aim of this study was to examine the visual ability and the searching behavior of newly emerged L. nigrinus Fender, a host-specific predator of the hemlock woolly adelgid, Adelges tsugae Annand (Hemiptera: Phylloxeroidea: Adelgidae). In a laboratory bioassay, individual adults attempting to locate an uninfested eastern hemlock seedling under either light or dark conditions were observed in an arena. In another bioassay, individual adults searching for prey on hemlock seedlings (infested or uninfested) were continuously video-recorded. Beetles located and began climbing the seedling stem in light significantly more than in dark, indicating that vision is an important sensory modality. Our primary finding was that searching behavior of L. nigrinus, as in most species, was related to food abundance. Beetles did not fly in the presence of high A. tsugae densities and flew when A. tsugae was absent, which agrees with observed aggregations of beetles on heavily infested trees in the field. At close range of prey, slow crawling and frequent turning suggest the use of non-visual cues such as olfaction and contact chemoreception. Based on the beetles' visual ability to locate tree stems and their climbing behavior, a bole trap may be an effective collection and monitoring tool. PMID- 22220636 TI - Risk stratification in cardiovascular disease primary prevention - scoring systems, novel markers, and imaging techniques. AB - The aim of this paper is to review and discuss current methods of risk stratification for cardiovascular disease (CVD) prevention, emerging biomarkers, and imaging techniques, and their relative merits and limitations. This report is based on discussions that took place among experts in the area during a special CardioVascular Clinical Trialists workshop organized by the European Society of Cardiology Working Group on Cardiovascular Pharmacology and Drug Therapy in September 2009. Classical risk factors such as blood pressure and low-density lipoprotein cholesterol levels remain the cornerstone of risk estimation in primary prevention but their use as a guide to management is limited by several factors: (i) thresholds for drug treatment vary with the available evidence for cost-effectiveness and benefit-to-risk ratios; (ii) assessment may be imprecise; (iii) residual risk may remain, even with effective control of dyslipidemia and hypertension. Novel measures include C-reactive protein, lipoprotein-associated phospholipase A(2) , genetic markers, and markers of subclinical organ damage, for which there are varying levels of evidence. High-resolution ultrasound and magnetic resonance imaging to assess carotid atherosclerotic lesions have potential but require further validation, standardization, and proof of clinical usefulness in the general population. In conclusion, classical risk scoring systems are available and inexpensive but have a number of limitations. Novel risk markers and imaging techniques may have a place in drug development and clinical trial design. However, their additional value above and beyond classical risk factors has yet to be determined for risk-guided therapy in CVD prevention. PMID- 22220638 TI - Focal administration of neuropeptide Y into the S2 somatosensory cortex maximally suppresses absence seizures in a genetic rat model. AB - PURPOSE: Neuropeptide Y (NPY) is an inhibitory neurotransmitter that suppresses focal and generalized seizures in animal models. In this study, we investigated the sites within the thalamocortical circuit that NPY acts to suppress seizures in genetic absence epilepsy rats from Strasbourg (GAERS). METHODS: In conscious freely moving GAERS, NPY was administered via intracerebral microcannulae implanted bilaterally into one of the following regions: primary somatosensory cortex (S1), secondary somatosensory cortex (S2), the primary motor cortex (M1), caudal nucleus reticular thalamus (nRT), or ventrobasal thalamus (VB). Animals received vehicle and up to three doses of NPY, in a randomized order. Electroencephalography (EEG) recordings were carried out for 30 min prior to injection and 90 min after the injection of NPY or vehicle. KEY FINDINGS: Focal microinjections of NPY into the S2 cortex suppressed seizures in a dose-dependent manner, with the response being significantly different at the highest dose (1.5 mm) compared to vehicle for total time in seizures postinjection (7.2 +/- 3.0% of saline, p < 0.01) and average number of seizures (9.4 +/- 4.9% of saline, p < 0.05). In contrast NPY microinjections into the VB resulted in an aggravation of seizures. SIGNIFICANCE: NPY produces contrasting effects on absence-like seizures in GAERS depending on the site of injection within the thalamocortical circuit. The S2 is the site at which NPY most potently acts to suppress absence-like seizures in GAERS, whereas seizure-aggravating effects are seen in the VB. These results provide further evidence to support the proposition that these electroclinically "generalized" seizures are being driven by a topographically restricted region within the somatosensory cortex. PMID- 22220640 TI - Platelet concentrate transport in pneumatic tube systems--does it work? AB - Blood sample transport via pneumatic tube systems (PTS) reduces the turnaround time of laboratories, but it might influence analysis results. Its effect on platelet concentrates (PCs) is not known. Platelet function was investigated after single and multiple PTS transport in comparison with storage and irradiation. Optical and impedance aggregation, CD-62, and microparticles changed as a result of storage, but not due to transport. Irradiation lowered platelet function independently. Multiple transport impaired thrombin receptor-activating peptide-induced aggregation. This investigation demonstrates the feasibility of PTS transport. As platelet function depends on storage, it may be more important to transfuse fresh PCs. PMID- 22220641 TI - Real-time shape-based particle separation and detailed in situ particle shape characterization. AB - Particle shape is an important attribute in determining particle properties and behavior, but it is difficult to control and characterize. We present a new portable system that offers, for the first time, the ability to separate particles with different shapes and characterize their chemical and physical properties, including their dynamic shape factors (DSFs) in the transition and free-molecular regimes, with high precision, in situ, and in real-time. The system uses an aerosol particle mass analyzer (APM) to classify particles of one mass-to-charge ratio, transporting them to a differential mobility analyzer (DMA) that is tuned to select particles of one charge, mobility diameter, and for particles with one density, one shape. These uniform particles are then ready for use and/or characterization by any application or analytical tool. We combine the APM and DMA with our single-particle mass spectrometer, SPLAT II, to form the ADS and demonstrate its utility to measure individual particle compositions, vacuum aerodynamic diameters, and particle DSFs in two flow regimes for each selected shape. We applied the ADS to the characterization of aspherical ammonium sulfate and NaCl particles, demonstrating that both have a wide distribution of particle shapes with DSFs from approximately 1 to 1.5. PMID- 22220639 TI - Do regional modifications in tissue mineral content and microscopic mineralization heterogeneity adapt trabecular bone tracts for habitual bending? Analysis in the context of trabecular architecture of deer calcanei. AB - Calcanei of mature mule deer have the largest mineral content (percent ash) difference between their dorsal 'compression' and plantar 'tension' cortices of any bone that has been studied. The opposing trabecular tracts, which are contiguous with the cortices, might also show important mineral content differences and microscopic mineralization heterogeneity (reflecting increased hemi-osteonal renewal) that optimize mechanical behaviors in tension vs. compression. Support for these hypotheses could reveal a largely unrecognized capacity for phenotypic plasticity - the adaptability of trabecular bone material as a means for differentially enhancing mechanical properties for local strain environments produced by habitual bending. Fifteen skeletally mature and 15 immature deer calcanei were cut transversely into two segments (40% and 50% shaft length), and cores were removed to determine mineral (ash) content from 'tension' and 'compression' trabecular tracts and their adjacent cortices. Seven bones/group were analyzed for differences between tracts in: first, microscopic trabecular bone packets and mineralization heterogeneity (backscattered electron imaging, BSE); and second, trabecular architecture (micro-computed tomography). Among the eight architectural characteristics evaluated [including bone volume fraction (BVF) and structural model index (SMI)]: first, only the 'tension' tract of immature bones showed significantly greater BVF and more negative SMI (i.e. increased honeycomb morphology) than the 'compression' tract of immature bones; and second, the 'compression' tracts of both groups showed significantly greater structural order/alignment than the corresponding 'tension' tracts. Although mineralization heterogeneity differed between the tracts in only the immature group, in both groups the mineral content derived from BSE images was significantly greater (P < 0.01), and bulk mineral (ash) content tended to be greater in the 'compression' tracts (immature 3.6%, P = 0.03; mature 3.1%, P = 0.09). These differences are much less than the approximately 8% greater mineral content of their 'compression' cortices (P < 0.001). Published data, suggesting that these small mineralization differences are not mechanically important in the context of conventional tests, support the probability that architectural modifications primarily adapt the tracts for local demands. However, greater hemi osteonal packets in the tension trabecular tract of only the mature bones (P = 0.006) might have an important role, and possible synergism with mineralization and/or microarchitecture, in differential toughening at the trabeculum level for tension vs. compression strains. PMID- 22220642 TI - An organoselenium-based highly sensitive and selective fluorescent "turn-on" probe for the Hg2+ ion. AB - An organoselenium-based NSe(3) type of tripodal system 2 as a Hg(2+)-selective fluorescence "turn-on" probe is described. The "turn-on" fluorescence behavior of this selenotripod 2 is significant because it depends on Hg-Se bond formation and acts as a reporting unit for this system. The system exhibits immediate response (15 s) with a subnanomolar detection limit (0.1 nM) for the Hg(2+) ion. It efficiently detects both aqueous and nonaqueous Hg(2+) at 2 nM concentration. PMID- 22220644 TI - Association between plasma 25-OH vitamin D and testosterone levels in men. AB - OBJECTIVE: A small randomized controlled trial suggested that vitamin D might increase the production of testosterone in men, which is supported by experimental studies in animals and a cross-sectional study showing positive associations between plasma 25-hydroxyvitamin D [25(OH)D] and testosterone and concordant seasonal variation of both biomarkers. DESIGN AND MEASUREMENTS: We investigated the cross-sectional association of plasma 25(OH)D levels and total and free testosterone measured by immunoassay in 1362 male participants of the Health Professionals Follow-up Study who were selected for a nested case-control study on prostate cancer using multivariate-adjusted linear and restricted cubic spline regression models. RESULTS: 25(OH)D was positively associated with total and free testosterone levels. From the lowest to the highest 25(OH)D quintile, multivariate-adjusted means (95% confidence interval) were 18.5 (17.7; 19.4), 19.4 (18.6; 20.2), 19.6 (18.8; 20.4), 20.1 (19.3; 20.9) and 20.0 (19.1; 20.8; P trend = 0.003) for total testosterone and 97.7 (93.9; 101.5), 98.2 (94.1; 102.2), 99.2 (95.2; 103.2), 100.7 (96.9; 104.5) and 101.5 (97.6; 105.4; P-trend = 0.03) for free testosterone. The shapes of the dose-response curves indicate that the association between 25(OH)D and total and free testosterone is linear at lower levels of 25(OH)D (below approximately 75-85 nmol/l), reaching a plateau at higher levels. Unlike for 25(OH)D, we did not observe any seasonal variation of testosterone concentrations. CONCLUSION: This study supports previously reported positive associations between vitamin D and testosterone although we did not observe parallel seasonal variation patterns. Possible causality and direction of the vitamin D-testosterone association deserve further scientific investigation. PMID- 22220674 TI - Copper(II) carboxylate dimers prepared from ligands designed to form a robust pi...pi stacking synthon: supramolecular structures and molecular properties. AB - The reactions of bifunctional carboxylate ligands (1,8-naphthalimido)propanoate, (L(C2)(-)), (1,8-naphthalimido)ethanoate, (L(C1)(-)), and (1,8 naphthalimido)benzoate, (L(C4)(-)) with Cu(2)(O(2)CCH(3))(4)(H(2)O)(2) in methanol or ethanol at room temperature lead to the formation of novel dimeric [Cu(2)(L(C2))(4)(MeOH)(2)] (1), [Cu(2)(L(C1))(4)(MeOH)(2)].2(CH(2)Cl(2)) (2), [Cu(2)(L(C4))(4)(EtOH)(2)].2(CH(2)Cl(2)) (3) complexes. When the reaction of L(C1)(-) with Cu(2)(O(2)CCH(3))(4)(H(2)O)(2) was carried out at -20 degrees C in the presence of pyridine, [Cu(2)(L(C1))(4)(py)(4)].2(CH(2)Cl(2)) (4) was produced. At the core of complexes 1-3 lies the square Cu(2)(O(2)CR)(4) "paddlewheel" secondary building unit, where the two copper centers have a nearly square pyramidal geometry with methanol or ethanol occupying the axial coordination sites. Complex 4 contains a different type of dimeric core generated by two kappa(1)-bridging carboxylate ligands. Additionally, two terminal carboxylates and four trans situated pyridine molecules complete the coordination environment of the five-coordinate copper(II) centers. In all four compounds, robust pi...pi stacking interactions of the naphthalimide rings organize the dimeric units into two-dimensional sheets. These two-dimensional networks are organized into a three-dimensional architecture by two different noncovalent interactions: strong pi...pi stacking of the naphthalimide rings (also the pyridine rings for 4) in 1, 3, and 4, and intermolecular hydrogen bonding of the coordinated methanol or ethanol molecules in 1-3. Magnetic measurements show that the copper ions in the paddlewheel complexes 1-3 are strongly antiferromagnetically coupled with -J values ranging from 255 to 325 cm(-1), whereas the copper ions in 4 are only weakly antiferromagnetically coupled. Typical values of the zero-field splitting parameter D were found from EPR studies of 1-3and the related known complexes [Cu(2)(L(C2))(4)(py)(2)].2(CH(2)Cl(2)).(CH(3)OH), [Cu(2)(L(C3))(4)(py)(2)].2(CH(2)Cl(2)) and [Cu(2)(L(C3))(4)(bipy)].(CH(3)OH)(2).(CH(2)Cl(2))(3.37) (L(C3)(-) = (1,8 naphthalimido)butanoate)), while its abnormal magnitude in [Cu(2)(L(C2))(4)(bipy)] was qualitatively rationalized by structural analysis and DFT calculations. PMID- 22220673 TI - Triptolide increases transcript and protein levels of survival motor neurons in human SMA fibroblasts and improves survival in SMA-like mice. AB - BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease. Since disease severity is related to the amount of survival motor neuron (SMN) protein, up-regulated functional SMN protein levels from the SMN2 gene are considered a major SMA drug-discovery strategy. In this study, we investigated the possible effects of triptolide, a diterpene triepoxide purified from Tripterygium wilfordii Hook. F., as a new compound for increasing SMN protein. EXPERIMENTAL APPROACH: The effects and mechanisms of triptolide on the production of SMA protein were determined by cell-based assays using the motor neuronal cell line NSC34 and skin fibroblasts from SMA patients. Wild-type (Smn(+/+) SMN2(-/-) , C57BL/6) and SMA-like (Smn(-/-) SMN2) mice were injected with triptolide (0.01 or 0.1 mg.kg(-1) .day(-1) , i.p.) and their survival rate and level of change in SMN protein in neurons and muscle tissue measured. KEY RESULTS: In NSC34 cells and human SMA fibroblasts, pM concentrations of triptolide significantly increased SMN protein expression and the levels of SMN complex component (Gemin2 and Gemin3). In human SMA fibroblasts, triptolide increased SMN-containing nuclear gems and the ratio of full-length transcripts (FL-SMN2) to SMN2 transcripts lacking exon 7 (SMN2Delta7). Furthermore, in SMA like mice, triptolide significantly increased SMN protein levels in the brain, spinal cord and gastrocnemius muscle. Furthermore, triptolide treatment increased survival and reduced weight loss in SMA-like mice. CONCLUSION AND IMPLICATIONS: Triptolide enhanced SMN protein production by promoting SMN2 activation, exon 7 inclusion and increasing nuclear gems, and increased survival in SMA mice, which suggests triptolide might be a potential candidate for SMA therapy. PMID- 22220675 TI - Human adipose tissue-derived stromal cell therapy prevents bone loss in ovariectomized nude mouse. AB - Osteoporosis is a skeletal disorder characterized by reduced bone mineral density (BMD) and increased risk of fracture. We studied the effects of cell therapy of human adipose tissue-derived stromal cell (ADSC) on ovariectomy-induced bone loss in T cell deficient nude mice. Twelve-week-old female nude mice underwent ovariectomy and were treated with ADSC, estrogen, or phosphate buffered saline (PBS). Whole body BMD revealed that treatment of ADSC was more protective against ovariectomy-induced attenuation in bone mass gain compared with PBS control after cell therapy (8.4+/-1.1 vs. 2.4%+/-1.4%, p<0.05 at 4 weeks, 13.7+/-1.3 vs. 7.7%+/ 1.8%, p<0.05 at 8 weeks) and this effect was comparable to that of estrogen. MUCT analysis revealed that the effect of ADSCs was specific to trabecular bone. Serum osteocalcin levels were increased 4 weeks after ovariectomy and treatment with ADSCs (76.4+/-11.6 ng/mL) increased osteocalcin to a greater extent when compared with estrogen (63.1+/-6.7 ng/mL, p<0.05) or PBS treatment (58.0+/-9.2 ng/mL, p<0.05). Flow cytometry analysis for PKH26-labeled ADSCs and quantitative real time PCR analysis for human beta-globin from bone revealed that transplanted ADSCs were trafficking in bone 48 h after injection and subsequently disappeared. There was no evidence of long-term engraftment of infused ADSCs in bone. In vitro, treatment with ADSC-conditioned medium enhanced osteogenic differentiation in stromal cells and preosteoblasts. These results suggest that cell therapy of ADSCs protects against ovariectomy-induced bone loss in nude mice in a paracrine manner. PMID- 22220676 TI - Results of kidney transplantation from controlled donors after cardio-circulatory death: a single center experience. AB - The aim of this study was to determine results of kidney transplantation (KT) from controlled donation after cardio-circulatory death (DCD). Primary end-points were graft and patient survival, and post-transplant complications. The influence of delayed graft function (DGF) on graft survival and DGF risk factors were analyzed as secondary end-points. This is a retrospective mono-center review of a consecutive series of 59 DCD-KT performed between 2005 and 2010. Overall graft survival was 96.6%, 94.6%, and 90.7% at 3 months, 1 and 3 years, respectively. Main cause of graft loss was patient's death with a functioning graft. No primary nonfunction grafts. Renal graft function was suboptimal at hospital discharge, but nearly normalized at 3 months. DGF was observed in 45.6% of all DCD-KT. DGF significantly increased postoperative length of hospitalization, but had no deleterious impact on graft function or survival. Donor body mass index >=30 was the only donor factor that was found to significantly increase the risk of DGF (P < 0.05). Despite a higher rate of DGF, controlled DCD-KT offers a valuable contribution to the pool of deceased donor kidney grafts, with comparable mid term results to those procured after brain death. PMID- 22220677 TI - Adhesion of Aggregatibacter actinomycetemcomitans and Fusobacterium nucleatum on bioactive TiO(2) surfaces. AB - BACKGROUND: Bioactive TiO(2) coatings have been found to enhance fibroblast adhesion and gingival attachment on the titanium surfaces, but no information is available whether the coatings also promote the adhesion of periodontal pathogens. AIM: The purpose of this study was to investigate protein adsorption and the adhesion of Aggregatibacter actinomycetemcomitans (Aa) and Fusobacterium nucleatum (Fn) on bioactive TiO2 surfaces. MATERIALS AND METHODS: Commercially pure titanium discs (diameter 11.0 mm, grade 2) were coated with sol-gel derived bioactive TiO2 coatings (MetAlive, Vivoxid, Turku, Finland) and preincubated in 1.5 ml PBS/diluted serum/diluted saliva at room temperature to mimic the clinical situation after implantation and to allow serum/saliva proteins to adhere on the substrates. Uncoated titanium discs were used as controls. RESULTS: SDS-PAGE revealed similar protein profiles on bioactive and control titanium substrates. No differences were noticed in Aa or Fn adhesion between bioactive and control titanium. However, serum and saliva conditioning diminished Aa adhesion on both surfaces (p<0.001). CONCLUSION: It can be concluded that bioactive TiO2 coating does not promote adhesion of Aa and Fn. PMID- 22220678 TI - Perinatal outcome for pregnancies complicated with thrombocytopenia. AB - INTRODUCTION: Thrombocytopenia affects about 10% of all pregnancies. Preeclampsia/HELLP syndrome induced thrombocytopenia may associate perinatal morbidity, preterm delivery, or low-birth-weight newborns. OBJECTIVE: To assess perinatal outcome and complications of pregnancy in women presenting with thrombocytopenia. METHODS: We retrospectively analyzed 936 consecutive pregnant women admitted during a 6-month period. RESULTS: Incidence of thrombocytopenia in pregnancy was 11.11% (104/936). Thrombocytopenia represented a risk factor for premature delivery - highest risk for severe thrombocytopenia (RR=8.69, p<0.01). Thrombocytopenic preeclampsia or HELLP syndrome associated the highest rates of prematurity (RR=7.97, p=0.00, respectively 12.32). Thrombocytopenia also represented a risk factor for low-birth-weight newborns, especially severe thrombocytopenia - 2047.50 +/- 938.98 g (p=0.02) versus 3224.86 +/- 496.00 g in controls. Again, thrombocytopenic preeclampsia was significantly associated with low-birth-weight newborns (RR=11.94, p=0.00), with medium weight of 2462.05 +/- 794.54 g versus 2932.37 +/- 708.91 g in thrombocytopenic pregnancies, respectively 3224.86 +/- 496.00 g (p=0.00) in normal pregnancies. CONCLUSIONS: Thrombocytopenia in pregnancy was associated with perinatal morbidity, with the strongest association for preeclampsia and HELLP syndrome - for both prematurity and low-birth-weight: the lower the platelet count, the higher the risks for the fetus/newborn. Therefore, we strongly recommend close surveillance of thrombocytopenic mothers and their babies, in order to establish the etiology and the best moment for intervention. PMID- 22220679 TI - Pregnancies and their obstetric outcome in two selected age groups of teenage women in Greece. AB - AIM: The aim of this study was to evaluate the outcome of pregnancies in adolescents in the Department of Obstetrics and Gynaecology of Democritus University of Thrace, North-Eastern Greece. MATERIAL AND METHODS: We retrospectively reviewed 194 cases of adolescent pregnancies, with an average maternal age of 16.5 years, from 1st January 2006 to December 30th 2008. Socioeconomic characteristics, type of delivery and complications, such as preterm labor, preeclampsia, intra- and post-partum complications, were evaluated. RESULTS: The median age at first intercourse was 14.2 years and the average period between first intercourse and pregnancy was 1.2 years. Most teen mothers (86.6%) did not use any contraceptive method. Among the teen mothers recruited for the study, 89.7% were married. Adolescent pregnancies accounted for 9.02% of all deliveries (2150) in our Department. In 49 (25.3%) of the pregnant adolescents, no previous pregnancy was reported. The rates of preterm birth of teen mothers were 11.3%, 41.3% and 47.4% in correlation to <32 weeks, 32-34 weeks and >34 weeks, respectively. In 95.4% of the cases, deliveries were not complicated. According to our results, the main complications, especially in very young girls, are preterm labor, anaemia, hypertensive disease, obstructed labor after premature rupture of the membranes and increased neonatal mortality and morbidity. Antenatal care is often inadequate. CONCLUSION: Early teenage pregnancies have always been considered of increased risk for obstetric complications. Prevention of adolescent pregnancy, by wide use of effective contraception programs, would decrease its frequency and intensive care of pregnant adolescents may reduce the pregnancy complications. PMID- 22220680 TI - Assessing the quality of evidence for preterm labor tocolytic trials. AB - OBJECTIVE: To assess the quality of tocolysis randomized controlled trials (RCTs) and to determine trial factors contributing to better quality evidence. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, MEDLINE In-Process, EMBASE and CINAHL were searched for terms "preterm labor," "tocolytic" or "obstetric labor, premature" up to 1 August 2009.Data regarding study design, characteristics, number of participants and outcomes reported were extracted by at least two review authors. Study quality was assigned using the Cochrane Collaboration Handbook methodology and categories. Trends for quality over time, the impact of study size and the individual drugs compared were analyzed for impact on overall quality of trials. RESULTS: Of the 3197 titles initially identified, 89 RCTs of tocolytic therapy were reviewed. Of the six quality areas, 10 (11.2%) trials satisfied all areas, while only one trial (1.1%) met one area. The mean number of adequate areas was 4.1 +/- 1.2. Overall, 52 (58.4%) of the trials achieved high-quality categorization. Controlling for multiple trial factors, the trial continent and decade were significant predictors of overall trial quality. CONCLUSION: The majority of tocolysis RCTs are of high quality. Larger trials, more recent trials and placebo-controlled trials were associated with higher quality scores. PMID- 22220681 TI - A turn-on fluorescent sensor for pyrophosphate based on the disassembly of Cu2+ mediated perylene diimide aggregates. AB - A complex between an anionic perylene diimide derivative (PDI-GlyAsp) and cupric ion has been prepared and applied to be turn-on fluorescent probe for the detection of pyrophosphate (PPi) in 100% aqueous solution. The complex formation process and PPi detection have been studied by absorption and emission spectroscopy. It was confirmed that the introduction of cupric ion into PDI GlyAsp solution resulted in the assembly of PDI-GlyAsp into PDI-GlyAsp/Cu(2+) aggregates, leading to the fluorescence quenching of PDI-GlyAsp. Upon addition of PPi into the above solution led to the disassembly of the aggregates due to the competitive binding of PPi with Cu(2+) in the PDI-GlyAsp/Cu(2+) complex, and a recovery of PDI-GlyAsp emission was observed. Therefore, the PDI-GlyAsp/Cu(2+) complex can be applied as a turn-on fluorescent probe for detecting PPi with high selectivity and sensitivity. PMID- 22220683 TI - Spontaneous formation of stable capillary bridges for firming compact colloidal microstructures in phase separating liquids: a computational study. AB - Computer modeling and simulations are performed to investigate capillary bridges spontaneously formed between closely packed colloidal particles in phase separating liquids. The simulations reveal a self-stabilization mechanism that operates through diffusive equilibrium of two-phase liquid morphologies. Such mechanism renders desired microstructural stability and uniformity to the capillary bridges that are spontaneously formed during liquid solution phase separation. This self-stabilization behavior is in contrast to conventional coarsening processes during phase separation. The volume fraction limit of the separated liquid phases as well as the adhesion strength and thermodynamic stability of the capillary bridges are discussed. Capillary bridge formations in various compact colloid assemblies are considered. The study sheds light on a promising route to in situ (in-liquid) firming of fragile colloidal crystals and other compact colloidal microstructures via capillary bridges. PMID- 22220682 TI - Mechanistic aspects of photoinactivation of Candida albicans by exogenous porphyrins. AB - The mechanism of photoinactivation of Candida albicans by 3.5 MUM uncharged, cationic or anionic porphyrins under blue light (407-420 nm) was found to be dependent on the uptake of porphyrins into yeast cells, and was also dependent on the presence or absence of proteins in the photosensitization medium. In a very protein-rich medium, a decrease in viability was observed only with the uncharged porphyrin. Photoinactivation by uncharged or cationic porphyrins in a protein poorer medium resulted in total eradication, whereas no significant decrease was observed with the anionic porphyrin. Phototreatment in PBS resulted in eradication with all three porphyrins. X-ray microanalysis after phototreatment by the uncharged or cationic porphyrins in the protein-poor medium exhibited ion loss, indicating cell-membrane damage. Transmission electron microscopy indicated cellular and chromosomal damage. No ion loss or cell damage was observed in this medium with the anionic porphyrin. The efficiency of photoeradication of C. albicans is dependent on porphyrin uptake, which might lead (upon illumination) to processes that facilitate the formation of reactive oxygen species that damage the cells. Uptake of charged porphyrins is dependent on protein quantity and quality in the photosensitization microenvironment. This fact must be taken into account when using charged photosensitizers. PMID- 22220684 TI - Decrease in lipoatrophy in a pilot study using a short-term treatment interruption strategy for 48 weeks in Sao Paulo, Brazil. PMID- 22220686 TI - Dactylomelatriol, a biogenetically intriguing omphalane-derived marine sesquiterpene. AB - Dactylomelatriol (1), obtained from the sea hare Aplysia dactylomela, is the first naturally occurring omphalane-derived sesquiterpene from the marine environment. From this species the known chamigrene and modified bisabolene sesquiterpenes 2-6 were also isolated. The structure and relative configuration of 1 were established by spectroscopic evidence. Its chemical structure is related to omphalic acid, the unique terrestrial-derived omphalane sesquiterpene isolated from a liverwort. A biogenetic route for this compound is proposed. The antimicrobial activities of compounds 1-6 were evaluated against a panel of microorganisms. PMID- 22220685 TI - Serine hydroxymethyltransferase 1 and 2: gene sequence variation and functional genomic characterization. AB - Serine hydroxymethyltransferase (SHMT) catalyzes the transfer of a beta-carbon from serine to tetrahydrofolate to form glycine and 5,10-methylene tetrahydrofolate. This reaction plays an important role in neurotransmitter synthesis and metabolism. We set out to resequence SHMT1 and SHMT2, followed by functional genomic studies. We identified 87 and 60 polymorphisms in SHMT1 and SHMT2, respectively. We observed no significant functional effect of the 13 non synonymous single-nucleotide polymorphism (SNPs) in these genes, either on catalytic activity or protein quantity. We imputed additional variants across the two genes using '1000 Genomes' data, and identified 14 variants that were significantly associated (p<1.0E-10) with SHMT1 messenger RNA expression in lymphoblastoid cell lines. Many of these SNPs were also significantly correlated with basal SHMT1 protein expression in 268 human liver biopsy samples. Reporter gene assays suggested that the SHMT1 promoter SNP, rs669340, contributed to this variation. Finally, SHMT1 and SHMT2 expression were significantly correlated with those of other Folate and Methionine Cycle genes at both the messenger RNA and protein levels. These experiments represent a comprehensive study of SHMT1 and SHMT2 gene sequence variation and its functional implications. In addition, we obtained preliminary indications that these genes may be co-regulated with other Folate and Methionine Cycle genes. PMID- 22220689 TI - Screening of plant extracts for human tyrosinase inhibiting effects. AB - Screening for tyrosinase (TYR) inhibitors potentially useful for control of skin pigmentation has been hampered by the limited availability of human TYR. To overcome this hurdle, we have established human embryonic kidney (HEK293)-TYR cells that constitutively express human TYR. In the current study, we assayed human TYR inhibition activities of 50 plant extracts using the lysates of transformed HEK293-TYR cells. The strongest inhibition of human TYR was shown by the extract of Vaccinium bracteatum Thunberg, followed by the extract of Morus bombycis Koidzumi. The former extract did not inhibit mushroom TYR activity whereas significant inhibition was observed with the latter extract, demonstrating the importance of using human TYR in the screening for human TYR inhibitors. Upon liquid-liquid partitioning of the extract from V. bracteatum, the active constituents were enriched in the ethyl acetate fraction, and the subsequent preparatory thin-layer chromatography identified p-coumaric acid (PCA) as the main active constituent. The hypo-pigmentation of PCA was verified in the MelanoDermTM Skin Model. This study demonstrates that transformed HEK293-TYR cells could expedite the discovery of human TYR-specific inhibitors from natural sources which might be useful in the control of skin pigmentation. PMID- 22220688 TI - A neurocognitive endophenotype associated with rolandic epilepsy. AB - PURPOSE: Children with rolandic epilepsy (RE) experience difficulties with reading, language, and attention. Their siblings are at high risk of dyslexia but are not otherwise known to have neurocognitive deficits. We therefore sought evidence for an RE-associated neurocognitive endophenotype. METHODS: Thirteen probands (male-to-female ratio 9:4) and 11 epilepsy-free siblings (male-to-female ratio 5:6) completed a neurocognitive evaluation within the domains of reading, language, and attention. Frequencies of impairment were compared, and mean standardized scores of children with RE and their siblings were each compared against population means. KEY FINDINGS: Frequency of impairment in each domain was comparable for siblings and probands: 9% of siblings and 31% of probands were reading impaired; 36% of siblings and 54% of probands were language impaired; and 70% of siblings and 67% of probands had attention impairments. Comparison of differences between sample and population means revealed evidence of a similar pattern of language deficits in both groups, specifically for picture naming and attention to competing words. For measures of attention, both groups made significantly higher omission errors and were impaired in their ability to sustain attention. SIGNIFICANCE: Children with RE and unaffected siblings demonstrate neurocognitive impairments in the domains of language and attention that are likely to remain undetected with general clinical protocols. Neurocognitively impaired probands and siblings showed a remarkably similar profile of deficits in language and attention that could explain poor academic performance. Early evaluation and intervention may benefit these children academically. PMID- 22220691 TI - Invasive fungal infections during the neonatal period: diagnosis, treatment and prophylaxis. AB - INTRODUCTION: The incidence of preterm births seems to be increased in many countries around the world, in parallel to the advances in neonatal medicine. However, this has resulted in longer hospital stays and more exposure to invasive interventions, both of which can lead to an increase in late-onset nosocomial infections in the newborn period. In addition to bacteria, fungi are thought to be an important cause of hospital infections. AREAS COVERED: The present article reviews the diagnosis, treatment and prophylaxis of invasive fungal infections (IFIs) during the neonatal period. IFIs are associated with high morbidity and mortality in preterm neonates. The main risk factors are multiple antibiotics, central venous catheters, parenteral nutrition, immunodepression, very low birth weight, and fungal colonization. Successful management of IFIs relies on early recognition and rapid initiation of effective treatment. EXPERT OPINION: Invasive fungal-infection-related morbidity and mortality is a major concern for most neonatal intensive care units worldwide. Incidence rates are increasing for preterm neonates. Preterm infants display clinical characteristics that make them prone to fungal infections, and there is a high frequency of neurodevelopmental sequelae in those who survive after neonatal fungal infections. Specific prevention - rather than treatment - should be the optimal strategy. Both fluconazole and nystatin prophylaxis reduce the incidence of IFI and fungal colonization in very preterm infants. PMID- 22220690 TI - Unprecedented occurrence of isoaspartic acid in a plant cyclopeptide. AB - Three structurally related cycloheptapeptides, cyclocitropsides A-C, have been isolated from a MeOH extract of the root bark of Citropsis articulata, a medicinal plant in Uganda. Their sequences were elucidated on the basis of their MS/MS fragmentation, extensive 2D-NMR, chemical degradation, and biochemical modifications. Surprisingly, the sequence of cyclocitropside C differed from that of cyclocitropside B only by an Asp(5)/isoAsp(5) substitution. This is the first report of an isoAsp residue in a plant cyclic peptide. PMID- 22220692 TI - High-yield platelet units revealed immediate pH decline and delayed mitochondrial dysfunction during storage in 100% plasma as compared with storage in SSP+. AB - BACKGROUND AND OBJECTIVES: Initial elevated and prolonged high carbon dioxide levels related to mitochondrial dysfunction are recently being suggested as a contributing factor to rapid pH decline in platelet (PLT) units. The use of different storage environments may influence this phenomenon. This study has two objectives (i) to investigate the relationship of mitochondrial function and apoptotic events with different storage environments capability of pH control and (ii) to examine the cause and relationship between pH decline in PLT units, carbon dioxide levels and mitochondrial function. MATERIALS AND METHODS: Platelet units were prepared for storage in (A) 70% SSP+, 300-400 * 10(9) /unit, (B) 70% SSP+, 550-600 * 10(9) /unit, (C) 100% plasma, 550-600 * 10(9) /unit, and (D) additional 100% plasma, >600 * 10(9) /unit. In vitro variables including mitochondrial function (JC-1), reactive oxygen species (ROS) and caspase 3 activity were analysed on days 2, 5 and 7. RESULTS: Glucose/lactate was higher, pH, ATP, Hypotonic shock response (HSR) and extent of shape change (ESC) decreased (P < 0.001 on day 7), CD62P (P < 0.001 on day 7) increased, the JC-1 positive PLTs were lower (P < 0.001 on day 7), and ROS was higher (P < 0.001 days 2-7) in the plasma (C) units as compared with the SSP+ (A) and (B) units. All plasma (D) units showed rapid pH and pCO(2) decline from day 2 but by means of >80% maintenance of mitochondrial function until day 7. CONCLUSIONS: The use of SSP+ instead of plasma may reduce the risk of triggering pro-apoptotic events in high-yield PLT units. A rapid decline in pH in PLT units cannot be explained with initial elevated and prolonged high carbon dioxide levels and mitochondrial dysfunction. PMID- 22220694 TI - High-performance liquid chromatography-electrospray ionization-mass spectrometry ligand fishing assay: a method for screening triplex DNA binders from natural plant extracts. AB - A novel ligand fishing assay was established to screen triplex DNA binders from complicated samples by a combination of immobilization of triplex DNA on agarose beads and high-performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS). The biotinylated oligodeoxynucleotides were first bound to the streptavidin agarose beads and then incubated with the duplex DNA as the baits for ligand fishing. This assay was validated by the testing ligand library consisting of coralyne, ethidium bromide, vitexin, and formononetin. The binding affinities of ligands to target DNA were also obtained based on the calibration curves of ligands. Two components (berberine and palmatine) in the extract of Phellodendron chinense Schneid cortexes were fished out as triplex DNA binders by this assay, which indicated its feasibility for screening triplex DNA binders from complicated samples. This preliminary assay can be used for not only screening binders of triplex DNA from natural products extracts but also can obtain their binding affinity information. PMID- 22220696 TI - Influence of halogen atoms on a homologous series of bis-cyclometalated iridium(III) complexes. AB - A series of homologous bis-cyclometalated iridium(III) complexes Ir(2,4-di-X phenyl-pyridine)(2)(picolinate) (X = H, F, Cl, Br) HIrPic, FIrPic, ClIrPic, and BrIrPic has been synthesized and characterized by NMR, X-ray crystallography, UV vis absorption and emission spectroscopy, and electrochemical methods. The addition of halogen substituents results in the emission being localized on the main cyclometalated ligand. In addition, halogen substitution induces a blue shift of the emission maxima, especially in the case of the fluoro-based analogue but less pronounced for chlorine and bromine substituents. Supported by ground and excited state theoretical calculations, we rationalized this effect in a simple manner by taking into account the sigmap and sigmam Hammett constants on both the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energy levels. Furthermore, in comparison with FIrPic and ClIrPic, the impact of the large bromine atom remarkably decreases the photoluminescence quantum yield of BrIrPic and switches the corresponding lifetime from mono to biexponential decay. We performed theoretical calculations based on linear-response time-dependent density functional theory (LR-TDDFT) including spin-orbit coupling (SOC), and unrestricted DFT (U-DFT) to obtain information about the absorption and emission processes and to gain insight into the reasons behind this remarkable change in photophysical properties along the homologous series of complexes. According to theoretical geometries for the lowest triplet state, the large halogen substituents contribute to sizable distortions of specific phenylpyridine ligands for ClIrPic and BrIrPic, which are likely to play a role in the emissive and nonradiative properties when coupled with the heavy-atom effect. PMID- 22220695 TI - Inflammatory muscle pain is dependent on the activation of kinin B1 and B2 receptors and intracellular kinase pathways. AB - BACKGROUND AND PURPOSE: B(1) and B(2) kinin receptors are involved in pain transmission but they may have different roles in the muscle pain induced by intense exercise or inflammation. We investigated the contribution of each of these receptors, and the intracellular pathways involved, in the initial development and maintenance of the muscle pain associated with inflammation induced tissue damage. EXPERIMENTAL APPROACH: Mechanical hyperalgesia was measured using the Randall-Selitto apparatus after injecting 5% formalin solution into the gastrocnemius muscle in mice treated with selective antagonists for B(1) or B(2) receptors. The expression of kinin receptors and cytokines and the activation of intracellular kinases were monitored by real-time PCR and immunohistochemistry. KEY RESULTS: The i.m. injection of formalin induced an overexpression of B(1) and B(2) receptors. This overexpression was associated with the mechanical hyperalgesia induced by formalin because treatment with B(1) receptor antagonists (des-Arg(9) [Leu(8)]-BK, DALBK, and SSR240612) or B(2) receptor antagonists (HOE 140 and FR173657) prevented the hyperalgesia. Formalin increased myeloperoxidase activity, and up-regulated TNF-alpha, IL-1beta and IL-6 in gastrocnemius. Myeloperoxidase activity and TNF-alpha mRNA expression were inhibited by either DALBK or HOE 140, whereas IL-6 was inhibited only by HOE 140. The hyperalgesia induced by i.m. formalin was dependent on the activation of intracellular MAPKs p38, JNK and PKC. CONCLUSIONS AND IMPLICATIONS: Inflammatory muscle pain involves a cascade of events that is dependent on the activation of PKC, p38 and JNK, and the synthesis of IL-1beta, TNF-alpha and IL-6 associated with the up-regulation of both B(1) and B(2) kinin receptors. PMID- 22220712 TI - Species richness at the guild level: effects of species pool and local environmental conditions on stream macroinvertebrate communities. AB - 1. A fundamental question in ecology is which factors determine species richness. Here, we studied the relative importance of regional species pool and local environmental characteristics in determining local species richness (LSR). Typically, this question has been studied using whole communities or a certain taxonomic group, although including species with widely varying biological traits in the same analysis may hinder the detection of ecologically meaningful patterns. 2. We studied the question above for whole stream macroinvertebrate community and within functional feeding guilds. We defined the local scale as a riffle site and the regional scale (i.e. representing the regional species pool) as a stream. Such intermediate-sized regional scale is rarely studied in this context. 3. We sampled altogether 100 sites, ten riffles (local scale) in each of ten streams (regional scale). We used the local-regional richness regression plots to study the overall effect of regional species pool on LSR. Variation partitioning was used to determine the relative importance of regional species pool and local environmental conditions for species richness. 4. The local regional richness relationship was mainly linear, suggesting strong species pool effects. Only one guild showed some signs of curvilinearity. However, variation partitioning showed that local environmental characteristics accounted for a larger fraction of variance in LSR than regional species pool. Also, the relative importance of the fractions differed between the whole community and guilds, as well as among guilds. 5. This study indicates that the importance of the local and regional processes may vary depending on feeding guild and trophic level. We conclude that both the size of the regional species pool and local habitat characteristics are important in determining LSR of stream macroinvertebrates. Our results are in agreement with recent large-scale studies conducted in highly different study systems and complement the previous findings by showing that the interplay of regional and local factors is also important at intermediate regional scales. PMID- 22220714 TI - Nanofibrous collagen nerve conduits for spinal cord repair. AB - Nerve regeneration in an injured spinal cord is often restricted, contributing to the devastating outcome of neurologic impairment below the site of injury. Although implantation of tissue-engineered scaffolds has evolved as a potential treatment method, the outcomes remain sub-optimal. One possible reason may be the lack of topographical signals from these constructs to provide contact guidance to invading cells or regrowing axons. Nanofibers mimic the natural extracellular matrix architecturally and may therefore promote physiologically relevant cellular phenotypes. In this study, the potential application of electrospun collagen nanofibers (diameter=208.2+/-90.4 nm) for spinal cord injury (SCI) treatment was evaluated in vitro and in vivo. Primary rat astrocytes and dorsal root ganglias (DRGs) were seeded on collagen-coated glass cover slips (two dimensional [2D] substrate controls), and randomly oriented or aligned collagen fibers to evaluate scaffold topographical effects on astrocyte behavior and neurite outgrowth, respectively. When cultured on collagen nanofibers, astrocyte proliferation and expression of glial fibrillary acidic protein (GFAP) were suppressed as compared to cells on 2D controls at days 3 (p<0.05) and 7 (p<0.01). Aligned fibers resulted in elongated astrocytes (elongation factor >4, p<0.01) and directed the orientation of neurite outgrowth from DRGs along fiber axes. In the contrast, neurites emanated radially on randomly oriented collagen fibers. By forming collagen scaffolds into spiral tubular structures, we demonstrated the feasibility of using electrospun nanofibers for the treatment of acute SCI using a rat hemi-section model. At days 10 and 30 postimplantation, extensive cellular penetration into the constructs was observed regardless of fiber orientation. However, scaffolds with aligned fibers appeared more structurally intact at day 30. ED1 immunofluorescent staining revealed macrophage invasion by day 10, which decreased significantly by day 30. Neural fiber sprouting as evaluated by neurofilament staining was observed as early as day 10. In addition, GFAP immunostained astrocytes were found only at the boundary of the lesion site, and no astrocyte accumulation was observed in the implantation area at any time point. These findings indicate the feasibility of fabricating 3D spiral constructs using electrospun collagen fibers and demonstrated the potential of these scaffolds for SCI repair. PMID- 22220715 TI - Position of the mental foramen on panoramic radiographs and its relation to the horizontal course of the mandibular canal: a computed tomographic analysis. AB - AIM: The purposes of this study were (1) to investigate the bucco-lingual course of the mandibular canal in the bony structure and (2) to figure out the relationship between the position of mental foramen on panoramic radiographs and the horizontal course of the mandibular canal. MATERIALS AND METHODS: A database of panoramic radiography and spiral computed tomography (CT) scans was searched and 100 subjects were selected based on the criteria. Mental foramina were classified into four groups according to its antero-posterior position. Three measurements were made on each slice of coronal CT scans at three different points: (1) apex of second premolar; (2) median point of two root apexes of first molar; and (3) median point of two root apexes of second molar. The bucco-lingual ratios were calculated to access the relative bucco-lingual position of the mandibular canal. RESULTS: The distribution of subjects according to the type of mental foramen was: (1) type 3, 67%; (2) type 2, 26%; (3) type 4, 5%; and (4) type 1, 2%. The overall horizontal course of the mandibular canal was relatively constant from the second molar to first molar, whereas much significant directional change was found on the remaining course. Between types 2 and 3, no statistically significant differences were found at the level of the second molar and first molar (P = 0.461 and 0.965, respectively). Only below the second premolar, significant differences were found (P = 0.001). CONCLUSIONS: Based on the findings of our computed tomographic image analysis, the position of mental foramen on panoramic radiographs was affected by its horizontal course of inferior alveolar nerve. The significant horizontal direction change of the course was found after the canal passing below the mandibular first molar regardless of the antero-posterior position of mental foramen. PMID- 22220716 TI - Bis-cyclometalated iridium(III) complexes bearing ancillary guanidinate ligands. Synthesis, structure, and highly efficient electroluminescence. AB - We report the synthesis, structure, and photophysical and electroluminescent (EL) properties of a series of heteroleptic bis(pyridylphenyl)iridium(III) complexes with various ancillary guanidinate ligands. The reaction of the bis(pyridylphenyl)iridium(III) chloride [(ppy)(2)Ir(MU-Cl)](2) with the lithium salt of various guanidine ligands Li{(N(i)Pr)(2)C(NR(1)R(2))} at 80 degrees C gave in 60-80% yield the corresponding heteroleptic bis(pyridylphenyl)/guanidinate iridium(III) complexes having a general formula of [(ppy)(2)Ir{(N(i)Pr)(2)C(NR(1)R(2))}], where NR(1)R(2) = NPh(2) (1), N(C(6)H(4)(t)Bu-4)(2) (2), carbazolyl (3), 3,6-bis(tert-butyl)carbazolyl (4), N(C(6)H(4))(2)S (5), N(C(6)H(4))(2)O (6), indolyl (7), NEt(2) (8), N(i)Pr(2) (9), N(i)Bu(2) (10), and N(SiMe(3))(2) (11). These heteroleptic cyclometalated (C^N) iridium(III) complexes showed intense absorption bands in the UV region assignable to pi-pi* transitions and weaker metal-to-ligand charge-transfer transitions extending to the visible region. These complexes also showed intense emissions at room temperature. Their photoluminescence spectra were influenced to some extent by the ancillary guanidinate ligands, giving lambda(max) values in the range of 528-560 nm with quantum yields (Phi) of 0.16-0.37 and lifetimes of 0.61-1.43 MUs. Organic light-emitting diodes were fabricated by the use of these complexes as dopants in various concentrations (5-100%) in a N,N' dicarbazolylbiphenyl host. High current efficiency (eta(c); up to 137.4 cd/A) and power efficiency (eta(p); up to 45.7 lm/W) were observed under appropriate conditions. Their high EL efficiency may result from efficient trapping and radiative relaxation of the excitons formed in the EL process. Because of the steric hindrance of the guanidinate ligands, no significant intermolecular interaction was observed in these complexes, thus leading to the reduction of self-quenching and triplet-triplet annihilation at high currents. The EL emission color could be changed in the range of green to yellow by choosing appropriate guanidinate ligands. PMID- 22220717 TI - Association between vitamin D receptor genetic polymorphisms and acute cellular rejection in liver-transplanted patients. AB - Vitamin D receptor (VDR) polymorphisms may confer susceptibility to immunologically mediated liver diseases. We aimed to verify whether recipient VDR polymorphisms might affect the incidence of acute cellular rejection (ACR) of the graft after liver transplantation (LT). Two hundred and fifty-one liver transplanted patients surviving at least 1month were studied. ACR in the first post-LT year was graded according to the Banff score. Recipients genotyping for VDR polymorphic sites (FokI C>T, BsmI G>A, ApaI T>G, TaqI T>C) was performed. A significant difference was found between patients with and without ACR episodes in allele frequencies of BsmI (G: 0.660 vs. 0.545, P=0.017) and TaqI (T: 0.667 vs. 0.543, P=0.010). Patients carrying the G-*-T/G-*-T diplotypes of the BsmI G>A, ApaI T>G and TaqI T>C experienced more frequently ACR: 33/79 Vs 42/172, P=0.005. Carriage of G-*-T/G-*-T diplotypes was an independent predictor of ACR (OR 2.41, P=0.006), with CMV reactivation (OR 2.34, P=0.033) and HCV aetiology (OR 1.86, P=0.036). In conclusion, recipient VDR polymorphic loci are strongly associated with ACR occurrence during the first year after LT. The knowledge of VDR genetic polymorphisms may be helpful in identifying recipients at higher risk of ACR and in selecting them for a more aggressive immunosuppressive therapy. PMID- 22220718 TI - Thymus and immune reconstitution after allogeneic hematopoietic stem cell transplantation in humans: never say never again. AB - Assessment of the host immune status is becoming a key issue in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the long-term follow-up of these patients, severe post-transplant infections, relapse or secondary malignancies may be directly related to persistent immune defects. In allo-HSCT, T-cell differentiation of donor progenitors within the recipient thymus is required to generate naive recent T-cell emigrants (RTE). These cells account for a durable T-cell reconstitution, generating a diverse T-cell receptor (TCR) repertoire and robust response to infections. It is now possible to quantify the production of RTE by measuring thymic T-cell receptor excision circles or 'TREC' which are small circular DNA produced during the recombination of the genomic segments encoding the TCR alpha chain. Here we discuss the role of thymic function in allo-HSCT. The pre-transplant recipient thymic function correlates with clinical outcome in terms of survival and occurrence of severe infections. Post-transplant, TREC analysis showed that the thymus is a sensitive target to the allogeneic acute graft-versus-host disease (GvHD) reaction but is also prone to recovery in young adult patients. In all, thymus is a key player for the quality of immune reconstitution and clinical outcome after allo-HSCT. Thymic tissue is plastic and it is a future challenge to halt or reverse thymic GVHD therapeutically by acting at the level of T-cell progenitors generation, thymic homing and/or epithelial thymic tissue preservation. PMID- 22220719 TI - Killer-cell immunoglobulin-like receptors and malaria caused by Plasmodium falciparum in The Gambia. AB - The relevance of innate immune responses to Plasmodium falciparum infection, in particular the central role of natural killer (NK) cell-derived interferon gamma (IFN-gamma), is becoming increasingly recognised. Recently, it has been shown that IFN-gamma production in response to P. falciparum antigens is in part regulated by killer-cell immunoglobulin-like receptor (KIR) genes, and a study from malaria-exposed Melanesians suggested an association between KIR genotypes and susceptibility to infection. This prompted us to determine and compare the frequencies of 15 KIR genes in Gambian children presenting with either severe malaria (n = 133) or uncomplicated malaria (n = 188) and in cord-blood population control samples (n = 314) collected from the same area. While no significant differences were observed between severe and uncomplicated cases, proportions of individuals with KIR2DS2+C1 and KIR2DL2+C1 were significantly higher among malaria cases overall than in population control samples. In an exploratory analysis, activating KIR genes KIR2DS2, KIR3DS1 and KIR2DS5 were slightly higher in children in disease subgroups associated with the highest mortality. In addition, our data suggest that homozygosity for KIR genotype A might be associated with different malaria outcomes including protection from infection and higher blood parasitaemia levels in those that do get infected. These findings are consistent with a probable role of KIR genes in determining susceptibility to malaria, and further studies are warranted in different populations. PMID- 22220723 TI - Short communication: impact of hepatitis C viral clearance on CD4+ T-lymphocyte course in HIV/HCV-coinfected patients treated with pegylated interferon plus ribavirin. AB - The long-term impact of pegylated-interferon plus ribavirin (Peg-IFN-RBV) treatment outcome on CD4 T cell course in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is unknown. The aim of this study was to investigate the impact of HCV-RNA clearance by standard anti HCV therapy on long-term CD4 cells recovery in HIV/HCV patients on successful combined antiretroviral therapy (cART). We retrospectively enrolled HIV/HCV coinfected patients on stable cART, treated with Peg-IFN-RBV between 2005 and 2009. CD4(+) T cell counts were registered at baseline (pre-Peg-IFN-RBV), after 6, 12, and 24 months of follow-up from therapy discontinuation. Multiple linear regression analysis was performed to identify independent predictors of CD4(+) T cell change following the anti-HCV treatment outcome. Of the 116 patients enrolled, 54 (46.6%) reached a sustained virological response (SVR) and 62 (53.4%) did not. Throughout a median follow-up of 24 months, the SVR group showed a mean annual increase in CD4(+) T cell from baseline of 84 cells/MUl at 1 year and of a further 38 cells/MUl within the second year (p=0.01, 0.001, respectively). A nonsignificant mean increase of 77 cells/MUl occurred in the non SVR group within month 24 (p=0.06). Variables associated with greater CD4 gains were higher nadir and lower pre-interferon CD4 counts, and lower body mass index (BMI). The achievement of SVR was not significantly associated with the change in CD4(+) count. The clearance of HCV replication did not affect the CD4(+) changes after Peg-IFN-RBV therapy in coinfected patients on efficient cART. Liver fibrosis and higher BMI were negative determinants of immune recovery. PMID- 22220724 TI - VBM-DTI correlates of verbal intelligence: a potential link to Broca's area. AB - Human brain lesion studies first investigated the biological roots of cognitive functions including language in the late 1800s. Neuroimaging studies have reported correlation findings with general intelligence predominantly in fronto parietal cortical areas. However, there is still little evidence about the relationship between verbal intelligence and structural properties of the brain. We predicted that verbal performance is related to language regions of Broca's and Wernicke's areas. Verbal intelligence quotient (vIQ) was assessed in 30 healthy young subjects. T1-weighted MRI and diffusion tensor imaging data sets were acquired. Voxel-wise regression analyses were used to correlate fractional anisotropy (FA) and mean diffusivity values with vIQ. Moreover, regression analyses of regional brain volume with vIQ were performed adopting voxel-based morphometry (VBM) and ROI methodology. Our analyses revealed a significant negative correlation between vIQ and FA and a significant positive correlation between vIQ and mean diffusivity in the left-hemispheric Broca's area. VBM regression analyses did not show significant results, whereas a subsequent ROI analysis of Broca's area FA peak cluster demonstrated a positive correlation of gray matter volume and vIQ. These findings suggest that cortical thickness in Broca's area contributes to verbal intelligence. Diffusion parameters predicted gray matter ratio in Broca's area more sensitive than VBM methodology. PMID- 22220722 TI - Retinal cone and rod photoreceptor cells exhibit differential susceptibility to light-induced damage. AB - All-trans-retinal and its condensation-products can cause retinal degeneration in a light-dependent manner and contribute to the pathogenesis of human macular diseases such as Stargardt's disease and age-related macular degeneration. Although these toxic retinoid by-products originate from rod and cone photoreceptor cells, the contribution of each cell type to light-induced retinal degeneration is unknown. In this study, the primary objective was to learn whether rods or cones are more susceptible to light-induced, all-trans-retinal mediated damage. Previously, we reported that mice lacking enzymes that clear all trans-retinal from the retina, ATP-binding cassette transporter 4 and retinol dehydrogenase 8, manifested light-induced retinal dystrophy. We first examined early-stage age-related macular degeneration patients and found retinal degenerative changes in rod-rich rather than cone-rich regions of the macula. We then evaluated transgenic mice with rod-only and cone-like-only retinas in addition to progenies of such mice inbred with Rdh8(-/-) Abca4(-/-) mice. Of all these strains, Rdh8(-/-) Abca4(-/-) mice with a mixed rod-cone population showed the most severe retinal degeneration under regular cyclic light conditions. Intense light exposure induced acute retinal damage in Rdh8(-/-) Abca4(-/-) and rod-only mice but not cone-like-only mice. These findings suggest that progression of retinal degeneration in Rdh8(-/-) Abca4(-/-) mice is affected by differential vulnerability of rods and cones to light. PMID- 22220725 TI - Characterizing episodic memory retrieval: electrophysiological evidence for diminished familiarity following unitization. AB - Episodic memory relies on both recollection and familiarity; why these processes are differentially engaged during retrieval remains unclear. Traditionally, recollection has been considered necessary for tasks requiring associative retrieval, whereas familiarity supports recognition of items. Recently, however, familiarity has been shown to contribute to associative recognition if stimuli are "unitized" at encoding (a single representation is created from multiple elements)-the "benefit" of unitization. Here, we ask if there is also a "cost" of unitization; are the elements of unitized representations less accessible via familiarity? We manipulated unitization during encoding and used ERPs to index familiarity and recollection at retrieval. The data revealed a selective reduction in the neural correlate of familiarity for individual words originally encoded in unitized compared with nonunitized word pairs. This finding reveals a measurable cost of unitization, suggesting that the nature of to-be-remembered stimuli is critical in determining whether familiarity contributes to episodic memory. PMID- 22220726 TI - Dissociation between awareness and spatial coding: evidence from unilateral neglect. AB - Prevalent theories about consciousness propose a causal relation between lack of spatial coding and absence of conscious experience: The failure to code the position of an object is assumed to prevent this object from entering consciousness. This is consistent with influential theories of unilateral neglect following brain damage, according to which spatial coding of neglected stimuli is defective, and this would keep their processing at the nonconscious level. Contrary to this view, we report evidence showing that spatial coding and consciousness can dissociate. A patient with left neglect, who was not aware of contralesional stimuli, was able to process their color and position. However, in contrast to (ipsilesional) consciously perceived stimuli, color and position of neglected stimuli were processed separately. We propose that individual object features, including position, can be processed without attention and consciousness and that conscious perception of an object depends on the binding of its features into an integrated percept. PMID- 22220727 TI - The differential contributions of pFC and temporo-parietal cortex to multimodal semantic control: exploring refractory effects in semantic aphasia. AB - Aphasic patients with multimodal semantic impairment following pFC or temporo parietal (TP) cortex damage (semantic aphasia [SA]) have deficits characterized by poor control of semantic activation/retrieval, as opposed to loss of semantic knowledge per se. In line with this, SA patients show "refractory effects"; that is, declining accuracy in cyclical word-picture matching tasks when semantically related sets are presented rapidly and repeatedly. This is argued to follow a build-up of competition between targets and distractors. However, the link between poor semantic control and refractory effects is still controversial for two reasons. (1) Some theories propose that refractory effects are specific to verbal or auditory tasks, yet SA patients show poor control over semantic processing in both word and picture semantic tasks. (2) SA can result from lesions to either the left pFC or TP cortex, yet previous work suggests that refractory effects are specifically linked to the left inferior frontal cortex. For the first time, verbal, visual, and nonverbal auditory refractory effects were explored in nine SA patients who had pFC (pFC+) or TP cortex (TP-only) lesions. In all modalities, patient accuracy declined significantly over repetitions. This refractory effect at the group level was driven by pFC+ patients and was not shown by individuals with TP-only lesions. These findings support the theory that SA patients have reduced control over multimodal semantic retrieval and, additionally, suggest there may be functional specialization within the posterior versus pFC elements of the semantic control network. PMID- 22220728 TI - What makes different people's representations alike: neural similarity space solves the problem of across-subject fMRI decoding. AB - A central goal in neuroscience is to interpret neural activation and, moreover, to do so in a way that captures universal principles by generalizing across individuals. Recent research in multivoxel pattern-based fMRI analysis has led to considerable success at decoding within individual subjects. However, the goal of being able to decode across subjects is still challenging: It has remained unclear what population-level regularities of neural representation there might be. Here, we present a novel and highly accurate solution to this problem, which decodes across subjects between eight different stimulus conditions. The key to finding this solution was questioning the seemingly obvious idea that neural decoding should work directly on neural activation patterns. On the contrary, to decode across subjects, it is beneficial to abstract away from subject-specific patterns of neural activity and, instead, to operate on the similarity relations between those patterns: Our new approach performs decoding purely within similarity space. These results demonstrate a hitherto unknown population-level regularity in neural representation and also reveal a striking convergence between our empirical findings in fMRI and discussions in the philosophy of mind addressing the problem of conceptual similarity across neural diversity. PMID- 22220729 TI - The neuroanatomy of visual enumeration: differentiating necessary neural correlates for subitizing versus counting in a neuropsychological voxel-based morphometry study. AB - This study is the first to assess lesion-symptom relations for subitizing and counting impairments in a large sample of neuropsychological patients (41 patients) using an observer-independent voxel-based approach. We tested for differential effects of enumerating small versus large numbers of items while controlling for hemianopia and visual attention deficits. Overall impairments in the enumeration of any numbers (small or large) were associated with an extended network, including bilateral occipital and fronto-parietal regions. Within this network, severe impairments in accuracy when enumerating small sets of items (in the subitizing range) were associated with damage to the left posterior occipital cortex, bilateral lateral occipital and right superior frontal cortices. Lesions to the right calcarine extending to the precuneus led to patients serially counting even small numbers of items (indicated by a steep response slope), again demonstrating an impaired subitizing ability. In contrast, impairments in counting large numerosities were associated with damage to the left intraparietal sulcus. The data support the argument for some distinctive processes and neural areas necessary to support subitization and counting with subitizing relying on processes of posterior occipital cortex and with counting associated with processing in the parietal cortex. PMID- 22220730 TI - Figure-ground representation and its decay in primary visual cortex. AB - We used fMRI to study figure-ground representation and its decay in primary visual cortex (V1). Human observers viewed a motion-defined figure that gradually became camouflaged by a cluttered background after it stopped moving. V1 showed positive fMRI responses corresponding to the moving figure and negative fMRI responses corresponding to the static background. This positive-negative delineation of V1 "figure" and "background" fMRI responses defined a retinotopically organized figure-ground representation that persisted after the figure stopped moving but eventually decayed. The temporal dynamics of V1 "figure" and "background" fMRI responses differed substantially. Positive "figure" responses continued to increase for several seconds after the figure stopped moving and remained elevated after the figure had disappeared. We propose that the sustained positive V1 "figure" fMRI responses reflected both persistent figure-ground representation and sustained attention to the location of the figure after its disappearance, as did subjects' reports of persistence. The decreasing "background" fMRI responses were relatively shorter-lived and less biased by spatial attention. Our results show that the transition from a vivid figure-ground percept to its disappearance corresponds to the concurrent decay of figure enhancement and background suppression in V1, both of which play a role in form-based perceptual memory. PMID- 22220732 TI - Enhanced dielectric properties of ferroelectric polymer composites induced by metal-semiconductor Zn-ZnO core-shell structure. AB - The effect of metal-semiconductor Zn-ZnO core-shell structure on dielectric properties of polyvinylidene fluoride (PVDF) composites was investigated. Zn-ZnO fillers were obtained by the heat-treatment of raw Zn particles under air. The enhanced dielectric constant of Zn-ZnO/PVDF composites results from the duplex interfacial polarizations induced by metal-semiconductor interface and semiconductor-insulator interface. The dielectric loss is still low because of the presence of ZnO semiconductor shell between Zn metal core and insulator PVDF matrix. Furthermore, the dielectric performance of as-prepared composites could be further optimized through adjusting the thickness of semiconductor shell. PMID- 22220731 TI - An organophosphonate strategy for functionalizing silicon photonic biosensors. AB - Silicon photonic microring resonators have established their potential for label free and low-cost biosensing applications. However, the long-term performance of this optical sensing platform requires robust surface modification and biofunctionalization. Herein, we demonstrate a conjugation strategy based on an organophosphonate surface coating and vinyl sulfone linker to biofunctionalize silicon resonators for biomolecular sensing. To validate this method, a series of glycans, including carbohydrates and glycoconjugates, were immobilized on divinyl sulfone (DVS)/organophosphonate-modified microrings and used to characterize carbohydrate-protein and norovirus particle interactions. This biofunctional platform was able to orthogonally detect multiple specific carbohydrate-protein interactions simultaneously. Additionally, the platform was capable of reproducible binding after multiple regenerations by high-salt, high-pH, or low pH solutions and after 1 month storage in ambient conditions. This remarkable stability and durability of the organophosphonate immobilization strategy will facilitate the application of silicon microring resonators in various sensing conditions, prolong their lifetime, and minimize the cost for storage and delivery; these characteristics are requisite for developing biosensors for point of-care and distributed diagnostics and other biomedical applications. In addition, the platform demonstrated its ability to characterize carbohydrate mediated host-virus interactions, providing a facile method for discovering new antiviral agents to prevent infectious disease. PMID- 22220734 TI - Facile synthesis of 3a,6a-dihydro-furo[2,3-b]furans and polysubstituted furans involving dearomatization of furan ring via electrocyclic ring-closure. AB - A facile and atom-economic method for the synthesis of 3a,6a-dihydro-furo[2,3 b]furan derivatives and polysubstituted furans starting from furylcarbionls has been developed. This protocol involved a domino Claisen rearrangement/dearomatizing electrocyclic ring-closure/aromatizing electrocyclic ring-opening sequence. PMID- 22220735 TI - Grade and laterality of intraventricular haemorrhage to predict 18-22 month neurodevelopmental outcomes in extremely low birthweight infants. AB - AIM: To determine whether extremely low-birthweight (ELBW) infants with bilateral compared to unilateral intraventricular haemorrhage (IVH) have worse neurodevelopmental outcomes at 18-22 months. METHODS: A total of 166 ELBW infants (<1000 g) admitted to a Cincinnati NICU from 1998 to 2005 with a head ultrasound showing Grade I-IV IVH and neurodevelopmental assessment at 18-22 months corrected age were included. Multivariable linear and logistic regression models were developed to determine the impact of laterality and grade of IVH and other clinical variables to predict scores on the Bayley Scales of Infant Development, Second Edition, Mental Development Index and Psychomotor Development Index and the combined outcome of neurodevelopmental impairment (NDI). RESULTS: Infants with bilateral grade IV IVH had lower adjusted mean Bayley scores compared with infants with unilateral grade IV IVH. For grades I, II and III IVH, bilaterality of IVH was not associated with lower mean Bayley scores. Infants with grade IV IVH had the highest odds of NDI. The probability of NDI increased with sepsis and postnatal steroid use. CONCLUSION: ELBW infants with bilateral compared to those with unilateral grade IV IVH had worse neurodevelopmental outcomes. Infants with grades I-III IVH had similar outcomes whether they had unilateral or bilateral IVH. PMID- 22220737 TI - Quantum dots as simultaneous acceptors and donors in time-gated Forster resonance energy transfer relays: characterization and biosensing. AB - The unique photophysical properties of semiconductor quantum dot (QD) bioconjugates offer many advantages for active sensing, imaging, and optical diagnostics. In particular, QDs have been widely adopted as either donors or acceptors in Forster resonance energy transfer (FRET)-based assays and biosensors. Here, we expand their utility by demonstrating that QDs can function in a simultaneous role as acceptors and donors within time-gated FRET relays. To achieve this configuration, the QD was used as a central nanoplatform and coassembled with peptides or oligonucleotides that were labeled with either a long lifetime luminescent terbium(III) complex (Tb) or a fluorescent dye, Alexa Fluor 647 (A647). Within the FRET relay, the QD served as a critical intermediary where (1) an excited-state Tb donor transferred energy to the ground-state QD following a suitable microsecond delay and (2) the QD subsequently transferred that energy to an A647 acceptor. A detailed photophysical analysis was undertaken for each step of the FRET relay. The assembly of increasing ratios of Tb/QD was found to linearly increase the magnitude of the FRET-sensitized time-gated QD photoluminescence intensity. Importantly, the Tb was found to sensitize the subsequent QD-A647 donor-acceptor FRET pair without significantly affecting the intrinsic energy transfer efficiency within the second step in the relay. The utility of incorporating QDs into this type of time-gated energy transfer configuration was demonstrated in prototypical bioassays for monitoring protease activity and nucleic acid hybridization; the latter included a dual target format where each orthogonal FRET step transduced a separate binding event. Potential benefits of this time-gated FRET approach include: eliminating background fluorescence, accessing two approximately independent FRET mechanisms in a single QD-bioconjugate, and multiplexed biosensing based on spectrotemporal resolution of QD-FRET without requiring multiple colors of QD. PMID- 22220738 TI - Management options in multiple sclerosis-associated fatigue. AB - INTRODUCTION: Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the CNS. Its characteristic early clinical course includes exacerbations and remissions of neurologic disability. Fatigue is one of the most common symptoms of MS and is associated with a reduced quality of life; it is described as the worst symptom of the disease by 50 - 60% of patients. Yet, due to limitations of available evidence, current therapeutic approaches for treating fatigue are based mainly on preliminary studies and expert consensus. AREAS COVERED: This review summarizes current knowledge on the physiopathology, diagnosis and therapeutic options for MS-associated fatigue, including both pharmacological and non-pharmacological strategies. EXPERT OPINION: Large, rigorously designed trials can provide more reliable results on the efficacy of interventions for fatigue, their functional impact on everyday activities and patient quality of life. Future research should also address a better understanding of the physiopathologic mechanisms of fatigue and the development and validation of objective assessment tools to be used together with patient self-ratings. PMID- 22220739 TI - How to improve blood safety with respect to bacterial contaminations? PMID- 22220740 TI - Habenula regulates cardiovascular activities in the insula cortex in a rat model of epilepsy. AB - BACKGROUND: Epilepsy has a high mortality rate due to sudden death, which is poorly understood. However, recent research has indicated that it may be associated with fatal arrhythmia, which occurs commonly in insular epilepsy. OBJECTIVE: To examine the effects of the habenular nucleus on cardiovascular activities in a rat model of insular epilepsy. METHODS: Adult rats (n = 32) were divided into four groups: Group A (normal control); Group B (insular epilepsy); Group C (habenular nuclei injury alone); and Group D (bilateral habenular nuclei injury one week prior to the insular epilepsy). A rat model of epilepsy was made in the right insula by microinjection of kainic acid (KA, 0.3 MUL). Behavioral activities were observed according to Racine scales. The habenular nuclei were injured by direct current electric shock. Heart rate, blood pressure, and plasma norepinephrine were measured in the four groups under quite conditions or during seizure. RESULTS: We found that the rats in Group B have significantly higher heart rate, blood pressure, and plasma norepinephrine than those in Group A or Group D during seizure; however, there was no difference in blood pressure, heart rate, or plasma norepinephrine between Groups A and C. Moreover, the rats in the Group D had a significant lower blood pressure when compared with those in the Group C; however, no difference was observed in the heart rate and norepinephrine during seizure. CONCLUSION: The insula cortex has close association with cardiovascular activities in rats from our insula epilepsy model. The habenular nuclei can regulate cardiovascular activities during insular epilepsy. PMID- 22220741 TI - Do mood instability symptoms in epilepsy represent formal bipolar disorder? AB - We aimed to assess rates of bipolar symptoms versus bipolar disorder in epilepsy, and the effect of bipolar symptoms on quality of life (QOL) in epilepsy. Bipolar, disability, and QOL instruments were administered to 99 tertiary epilepsy center patients. Patients who scored positive on the Mood Disorder Questionnaire (MDQ) also completed depression scales and a structured psychiatric interview. Results indicated MDQ+ patients (10.1%) had worse QOL and more work, social, and family life disruptions. Most MDQ+ patients did not have bipolar disorder. There was close overlap between depressive and bipolar symptomatology. Based on results of this study, bipolar symptom is not synonymous with bipolar disorder. Symptoms picked up by the MDQ may be epilepsy-related depressive symptoms. Bipolar symptoms are associated with more disability, worse QOL, and may have treatment implications. PMID- 22220742 TI - Microfluidic dual emitter electrospray ionization source for accurate mass measurements. AB - A glass microfluidic device with two independent electrospray ionization (ESI) emitters has been designed to sequentially generate ions from different solutions for mass analysis. Rapid modulation between the emitters is accomplished by turning on and off the voltage that simultaneously generates the fluid flow rate and ESI potential. The time required to switch between the two electrospray signals is less than 70 ms. Using the second emitter to introduce a reference compound for internal calibration, accurate mass measurements (less than 3 ppm mass error) were obtained with a time-of-flight mass spectrometer. PMID- 22220745 TI - Sonochemical synthesis and properties of nanoparticles of FeSbO4. AB - A sonochemical method was employed to prepare reactive nanoparticles of FeSbO(4) at 300 degrees C, which is the lowest calcination temperature reported so far for preparing FeSbO(4). A systematic evolution of the FeSbO(4) phase formation as a function of temperature was monitored by in situ synchrotron X-ray measurements. The 300 and 450 degrees C calcined powders exhibited specific surface areas of 116 and 75 m(2)/g, respectively. The X-ray photoelectron spectra analysis confirmed the presence of mainly Fe(3+) and Sb(5+) in the calcined powder. The response of the fabricated sensors (using both 300 and 450 degrees C calcined powders) toward 1000 ppm and 1, 2, 4, and 8% hydrogen, respectively, has been monitored at various operating temperatures. The sensors fabricated using 300 degrees C calcined powder exhibited a response of 76% toward 4% H(2) gas at an operating temperature of 300 degrees C, while those fabricated using 450 degrees C calcined powder exhibited a higher response of 91% with a quick recovery toward 4% H(2) gas at 300 degrees C. The results confirmed that a higher calcination temperature was preferred to achieve better sensitivity and selectivity toward hydrogen in comparison to other reducing gases such as butane and methane. The experimental results confirmed that the sonochemical process can be easily used to prepare FeSbO(4) nanoparticles for various catalytic applications as demonstrated. Here, we project FeSbO(4) as a new class of material exhibiting high sensitivity toward a wide range of hydrogen gas. Such sensors that could detect high concentrations of hydrogen may find application in nuclear reactors where there will be a leakage of hydrogen. PMID- 22220746 TI - Better off alone! Reproductive competition and ecological constraints determine sociality in the African striped mouse (Rhabdomys pumilio). AB - 1. While the reasons for group-living have been studied for decades, little is known about why individuals become solitary. 2. Several previous experimental studies could demonstrate that group-living can arises as a consequence of ecological constraints. 3. It has been argued that reproductive competition between group members leads to significant costs of group-living, being a main reason of solitary-living. However, so far, no studies tested experimentally whether reproductive competition can explain solitary-living. 4. Using a socially flexible species, the African striped mouse (Rhabdomys pumilio), we tested experimentally in the field whether dispersal and solitary-living are more likely to occur when reproductive competition is present. 5. We investigated ecological constraints, here expressed as a function of population density, by removing groups of striped mice and creating vacant territories. To control for the effect of reproductive competition, which occurs only during the breeding season, we performed experiments during both the breeding and the non-breeding season. This is the first removal experiment performed in a species with communal breeding during the non-breeding season. 6. During the breeding season, when population density was low, more striped mice from experimental groups moved into the vacant territories and became solitary than striped mice from control groups. This is in support of the ecological constraints hypothesis. 7. During the non-breeding season, striped mice remained group-living despite the availability of free territories. Significantly, more striped mice became solitary-living during the breeding than during the non-breeding season. This is the first experimental support for the reproductive competition hypothesis explaining solitary-living. 8. Analysis of the sexual maturity of males showed that males which became solitary had a higher reproductive potential than males that remained group living. Analysis of the body mass data of females showed that more solitary females reproduced than group-living females. These results indicate that by becoming solitary individuals of both sexes avoided costs of reproductive competition within groups. 9. Our study provides experimental evidence that reproductive competition within groups can lead to dispersal and solitary-living. PMID- 22220747 TI - Bone regeneration in a rabbit critical-sized calvarial model using tyrosine derived polycarbonate scaffolds. AB - Porous three-dimensional tyrosine-derived polycarbonate (TyrPC) scaffolds with a bimodal pore distribution were fabricated to mimic bone architecture using a combination of salt-leaching and phase separation techniques. TyrPC scaffolds degraded in register with bone regeneration during the 6-week study period and compressive moduli of the scaffolds were maintained >0.5 MPa at 6 weeks of incubation in PBS at 37 degrees C. The TyrPC scaffolds either unsupplemented or supplemented with recombinant human bone morphogenetic protein-2 (rhBMP-2) were implanted in a rabbit calvarial critical-sized defect (CSD) model and the TyrPC scaffolds treated with rhBMP-2 or TyrPC coated with calcium phosphate scaffold alone promoted bone regeneration in a rabbit calvarial CSD at 6 weeks postimplantation. A synthetic TyrPC polymeric scaffold either without a biological supplement or with a minimal dose of rhBMP-2 induced bone regeneration comparable to a commercially available bone graft substitute in a nonrodent CSD animal model. PMID- 22220748 TI - Gaucher disease: a pyrosequencing frequency analysis of the N370S and L444P mutations in the Spanish population. PMID- 22220749 TI - Crystal structure, fluorescence, and nanostructuration studies of the first Zn(II) anthracene-based curcuminoid. AB - In the following article the coordination properties of a recently reported curcuminoid 9Accm (9Accm = 1,7-(di-9-anthracene)-1,6-heptadiene-3,5-dione) with Zn(II) are reported. Preparation, crystal structure, and fluorescence spectroscopic studies of [Zn(II)(9Accm)(2)(py)] (1) are presented, as well as preliminary AFM and confocal microscopy studies on graphite surfaces. Complex 1 is the first crystallographically characterized Zn-curcuminoid in the literature; the intrinsic features of the complex are contrasted with the free ligand, 9Accm, and [Cu(II)(9Accm)(2)(py)] (2), a similar copper system, which has been recently described by us. It is shown that complex 1 exhibits a chelation enhancement of fluorescence (CHEF) and 2 a chelation enhancement of quenching (CHEQ) with respect to the fluorescence response of the free ligand, demonstrating the highly sensitive response of 9Accm versus these two metals. All studies are supported by density functional theory (DFT) calculations. PMID- 22220750 TI - A novel allele: MICA*064N with a stop codon in exon 4. AB - MICA*064N is similar to MICA*027 except for one nucleotide mutation at position 801(G>A), resulting in a premature stop codon in exon 4. PMID- 22220751 TI - Pre- and postoperative assessment of sinus grafting procedures using cone-beam computed tomography compared with panoramic radiographs. AB - OBJECTIVES: The present study evaluated the clinical validity of cone-beam computed tomography (CBCT) scans in comparison to panoramic radiographs regarding preoperative implant planning in combination with sinus grafting procedures. MATERIALS AND METHODS: Preoperative assessment of the maxillary sinuses and implant planning using panoramic radiographs and CBCT scans was performed on 16 sinuses (13 patients) and comprised choice of treatment, timing of implant placement, sinus morphology, level of confidence, complication prediction and graft volume assessment. Six examiners were involved in the study. RESULTS: In the majority of cases there was a concordance between the treatment type based on either panoramic radiographs or CBCT. If any difference was found, this was due to an overestimation of bone quantity and quality on panoramic radiographs. The assessment of sinus morphology showed a significantly higher detection rate of sinus mucosal hypertrophy on CBCT. The most appealing result is a significant increase in surgical confidence and a significantly better prediction of complications when using CBCT. CONCLUSIONS: A preoperative planning based on CBCT seems to improve sinus diagnostics and surgical confidence. PMID- 22220753 TI - Modulating contact angle hysteresis to direct fluid droplets along a homogenous surface. AB - The shape and motion of drops on surfaces is governed by the balance between the driving and the pinning forces. Here we demonstrate control over the motion of droplets on an inclined surface by exerting control over the contact angle hysteresis. The external modulation of contact angle hysteresis is achieved through a voltage-induced local molecular reorganization within the surface film at the solid-liquid interface. We show that tuning contact angle hysteresis alone is sufficient to direct and deform drops when subjected to a constant external driving force, here gravity, in the absence of a pre-defined surface energy gradient or pattern. We also show that the observed stretching and contraction of the drops mimic the motion of an inchworm. Such reversible manipulation of the pinning forces could be an attractive means to direct drops, especially with the dominance of surface forces at micro-/nanoscale. PMID- 22220752 TI - The Cbln family of proteins interact with multiple signaling pathways. AB - Cerebellin precursor protein (Cbln1) is essential for synapse integrity in cerebellum through assembly into complexes that bridge pre-synaptic beta neurexins (Nrxn) to post-synaptic GluRdelta2. However, GluRdelta2 is largely cerebellum-specific, yet Cbln1 and its little studied family members, Cbln2 and Cbln4, are expressed throughout brain. Therefore, we investigated whether additional proteins mediate Cbln family actions. Whereas Cbln1 and Cbln2 bound to GluRdelta2 and Nrxns1-3, Cbln4 bound weakly or not at all, suggesting it has distinct binding partners. In a candidate receptor-screening assay, Cbln4 (but not Cbln1 or Cbln2) bound selectively to the netrin receptor, (deleted in colorectal cancer (DCC) in a netrin-displaceable fashion. To determine whether Cbln4 had a netrin-like function, Cbln4-null mice were generated. Cbln4-null mice did not phenocopy netrin-null mice. Cbln1 and Cbln4 were likely co-localized in neurons thought to be responsible for synaptic changes in striatum of Cbln1-null mice. Furthermore, complexes containing Cbln1 and Cbln4 had greatly reduced affinity to DCC but increased affinity to Nrxns, suggesting a functional interaction. However, Cbln4-null mice lacked the striatal synaptic changes seen in Cbln null mice. Thus, Cbln family members interact with multiple receptors/signaling pathways in a subunit composition-dependent manner and have independent functions with Cbln4 potentially involved in the less well characterized role of netrin/DCC in adult brain. PMID- 22220754 TI - TbPIF8, a Trypanosoma brucei protein related to the yeast Pif1 helicase, is essential for cell viability and mitochondrial genome maintenance. AB - The trypanosome mitochondrial genome, kinetoplast DNA (kDNA), is a massive network of interlocked DNA rings, including several thousand minicircles and dozens of maxicircles. The unusual complexity of kDNA would indicate that numerous proteins must be involved in its condensation, replication, segregation and gene expression. During our investigation of trypanosome mitochondrial PIF1 like helicases, we found that TbPIF8 is the smallest and most divergent. It lacks some conserved helicase domains, thus implying that unlike other mitochondrial PIF1-like helicases, this protein may have no enzymatic activity. TbPIF8 is positioned on the distal face of kDNA disk and its localization patterns vary with different kDNA replication stages. Stem-loop RNAi of TbPIF8 arrests cell growth and causes defects in kDNA segregation. RNAi of TbPIF8 causes only limited kDNA shrinkage but the networks become disorganized. Electron microcopy of thin sections of TbPIF8-depleted cells shows heterogeneous electron densities in the kinetoplast disk. Although we do not yet know its exact function, we conclude that TbPIF8 is essential for cell viability and is important for maintenance of kDNA. PMID- 22220756 TI - Drinking guidelines are essential in combating alcohol-related harm: comments on the new Australian and Canadian guidelines. PMID- 22220755 TI - Hyperparathyroidism and complications associated with vitamin D deficiency in HIV infected adults in New York City, New York. AB - Although recent studies report a high prevalence of vitamin D deficiency in HIV infected adults similar to that in the general population, metabolic complications of vitamin D deficiency may be worsened with HIV infection and remain insufficiently characterized. We conducted a retrospective cross-sectional cohort study to determine prevalence and correlates of vitamin D deficiency and hyperparathyroidism among HIV-infected patients attending an urban clinic. Vitamin D deficiency was defined as 25(OH)-vitamin D <20 ng/ml and insufficiency as 20 to <30 ng/ml, and hyperparathyroidism as parathyroid-hormone >65 pg/ml. We used the X(2) test to compare proportions and logistic regression to assess for associations. Among 463 HIV-infected patients, the prevalence of vitamin D deficiency was 59%. The prevalence of hyperparathyroidism was 30% among patients with vitamin D deficiency, 23% among those with insufficiency, and 12% among those with sufficient vitamin D levels. Vitamin D deficiency was associated with increased odds of hyperparathyroidism. Severe vitamin D deficiency was associated with elevated alkaline phosphatase, a marker for increased bone turnover. Although efavirenz use was associated with vitamin D deficiency, and protease inhibitor use with decreased odds of vitamin D deficiency, there was no statistical difference in rates of hyperparathyroidism stratified by combination antiretroviral therapy (cART) use. Given the increased risk of osteopenia with HIV infection and cART use, vitamin D supplementation for all HIV-infected patients on cART should be prescribed in accordance with the 2011 Endocrine Society guidelines. In HIV-infected patients with severe vitamin D deficiency or hyperparathyroidism, screening for osteomalacia and osteopenia may be warranted. PMID- 22220757 TI - Protein secondary structure imaging with ultrabroadband multiplex coherent anti Stokes Raman scattering (CARS) microspectroscopy. AB - Protein secondary structures in human hair have been studied with ultrabroadband multiplex coherent anti-Stokes Raman scattering (CARS) microspectroscopy. The CARS peak-shift mapping method has been developed and applied to hair samples with and without treatments by chemical reduction and mechanical extension. It clearly visualizes the treatment induced changes in protein secondary structures and their spatial distributions. Using the new imaging technique, we found a multilayered structure in the human hair cortex. PMID- 22220758 TI - SANS and SAXS analysis of charged nanoparticle adsorption at oil-water interfaces. AB - A systematic study of the adsorption of charged nanoparticles at dispersed oil-in water emulsion interfaces is presented. The interaction potentials for negatively charged hexadecane droplets with anionic polystyrene latex particles or cationic gold particles are calculated using DLVO theory. Calculations demonstrate that increased ionic strength decreases the decay length of the electrostatic repulsion leading to enhanced particle adsorption. For the case of anionic PS latex particles, the energy barrier for particle adsorption is also reduced when the surface charge is neutralized through changes in pH. Complementary small angle scattering experiments show that the highest particle adsorption for PS latex occurs at moderate ionic strength and low pH. For cationic gold particles, simple DLVO calculations also explain scattering results showing that the highest particle adsorption occurs at neutral pH due to the electrostatic attraction between oppositely charged surfaces. This work demonstrates that surface charges of particles and oil droplets are critical parameters to consider when engineering particle-stabilized emulsions. PMID- 22220759 TI - A naphthalimide-based glyoxal hydrazone for selective fluorescence turn-on sensing of Cys and Hcy. AB - A fluorescent turn-on probe for Cys/Hcy based on inhibiting the C?N isomerization quenching process by an intramolecular hydrogen bond was reported. The probe exhibited higher selectivity toward Cys/Hcy over other amino acids as well as thiol-containing compounds. PMID- 22220760 TI - S100A7 is present in human sperm and a homologous pig sperm protein interacts with sperm-binding glycoprotein (SBG). AB - In sows, the oviductal sperm-binding glycoprotein (SBG), which binds to the periacrosomal region of boar sperm, has been shown to be involved in sperm selection. In this work, we isolated porcine sperm proteins that interact with SBG. One of them is identified as a homologue of human S100A7 (psoriasin). Anti human S100A7 antibodies show that this homologous protein localises to the head of sperm. The isolation of a homologue of S100A7 based on affinity to SBG and its localisation at the head of sperm leads us to suggest that S100A7's homologous protein may be involved in the negative selection of sperm by SBG in pigs. Human S100A7 shows antibacterial properties, particularly over Escherichia coli, a species that has demonstrated deleterious effects on human sperm. We searched for S100A7 in human sperm and found that it is present and localises at the acrosomal region. Thus, we report the presence of S100A7 in human sperm and of a homologous protein in pig, with similar localisations. In humans, an antimicrobial role seems likely for psoriasin; in porcine sperm the studied protein binds to SBG suggesting a function in sperm selection, but an antimicrobial function cannot be ruled out. PMID- 22220762 TI - Traumatic brain injury in an aging population. AB - The epidemiology of traumatic brain injury (TBI) is changing in several Western countries, with an increasing proportion of elderly TBI patients admitted to the intensive care unit (ICU). We describe a series of 1366 adult patients admitted to three neuro-ICUs in which 44% of cases were 50 years of age or older. The health status before trauma (rated using the APACHE score) was worse in older patients. In all 604 patients had emergency removal of intracranial masses, with extradural hematomas more frequent in young cases and subdural hematomas more frequent in older patients. Outcomes were classified according to the Glasgow Outcome Scale (GOS) 6 months post-trauma, as favorable (GOS score 4-5), or unfavorable (GOS score 1-3). Favorable outcomes were achieved by 50% of patients, but the proportions of unfavorable outcomes rose with age. Mortality was the main cause of unfavorable outcomes 6 months after injury in older patients. Logistic regression analysis indicates that several parameters independently contributed to outcome, including the motor component of the Glasgow Coma Scale (GCS), pupils, CT findings, and early hypotension. Additionally, the odds ratios were very high for age and health status before TBI. Patients admitted to the ICU are increasingly older, have co-morbidities, and have specific types of intracranial lesions. Early rescue, surgical treatment, and intensive care of these patients may produce excellent results up to the age of 59 years, with favorable outcomes still possible for 39% of cases aged 60-69 years, without an excessive burden of severely disabled patients. PMID- 22220763 TI - Linear lupus panniculitis of the scalp presenting as alopecia along Blaschko's lines: a distinct variant of lupus panniculitis in East Asians? AB - A 32-year-old Taiwanese man presented to our clinic with a 6-month history of linear hair loss in a wavy and curved pattern across the parietal and occipital scalp, resembling the distribution of Blaschko's lines. Physical examination showed interfollicular erythema and follicular plugging without skin atrophy or sclerotic change. Histopathology revealed a lymphoplasmacytic infiltrate in the perifollicular dermis and subcutis with abundant mucin deposition, consistent with the diagnosis of lupus panniculitis. Treatment with hydroxychloroquine and local steroid injection resulted in complete hair regrowth but recurrence was noted. Linear lupus panniculitis of the scalp presenting as alopecia along Blaschko's lines had so far been reported exclusively in five East Asians. Apart from classical lupus panniculitis, it had distinct clinical and histopathological features such as younger age of onset, male predominance, reversible clinical course without scarring, fewer associations with systemic lupus erythematosus, exclusive involvement of scalp, sparse inflammatory infiltration, abundant mucin deposition, higher degree of hyaline fat degeneration and negative results of immunofluorescent studies. Therefore, we propose linear lupus panniculitis of the scalp to be a distinct variant of lupus panniculitis and should be included in the differential diagnosis for focal or linear alopecia, especially in East Asians. PMID- 22220764 TI - Reliability of the fluid balance in neonates. AB - AIM: To assess the reliability of fluid balance charts in neonates. METHODS: An observational study in 170 nonbreastfed neonates, requiring continuous monitoring on a high-care unit, but not critically ill. The fluid balance was compared to daily body weight changes using Bland-Altman analysis. Differences more than 20% of daily fluid intake were considered clinically relevant. RESULTS: The mean gestational age was 36 + 2 weeks (SD 18.7 days) and mean birth weight 2782 g (SD 749 g). The mean difference between 394 fluid balances over 24 h (in mL) and daily weight changes (in g) was -12.1 (limits of agreement -128.1 to 103.8). In 40% of comparisons, the difference with daily weight change was more than 20% of daily fluid intake. CONCLUSION: Fluid balance charts both over- and underestimate body weight changes in an unpredictable pattern and are therefore unreliable as a single measure of fluid status in neonates. PMID- 22220765 TI - NanoHPLC-nanoESI(+)-MS/MS quantitation of bis-N7-guanine DNA-DNA cross-links in tissues of B6C3F1 mice exposed to subppm levels of 1,3-butadiene. AB - 1,3-Butadiene (BD) is an important industrial chemical and a common environmental pollutant present in urban air. BD is classified as a human carcinogen based on epidemiological evidence for an increased incidence of leukemia in workers occupationally exposed to BD and its potent carcinogenicity in laboratory mice. A diepoxide metabolite of BD, 1,2,3,4-diepoxybutane (DEB), is considered the ultimate carcinogenic species of BD due to its ability to form genotoxic DNA-DNA cross-links. We have previously employed capillary HPLC-ESI(+)-MS/MS (liquid chromatography-electrospray ionization tandem mass spectrometry) methods to quantify DEB-induced DNA-DNA conjugates, e.g. 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD), 1-(guan-7-yl)-4-(aden-1-yl)-2,3-butanediol (N7G-N1A-BD), and 1,N(6) (1-hydroxymethyl-2-hydroxypropan-1,3-diyl)-2'-deoxyadenosine (1,N(6)-HMHP-dA), in tissues of laboratory mice exposed to 6.25-625 ppm BD (Goggin et al. Cancer Res. 2009, 69(6), 2479-2486). However, typical BD human exposure levels are 0.01 to 3.2 ppb in urban air and 1-2.0 ppm in an occupational setting, requiring greater detection sensitivity for these critical lesions. In the present study, a nanoHPLC-nanoESI(+)-MS/MS method was developed for ultrasensitive, accurate, and precise quantitation of bis-N7G-BD in tissues of laboratory mice treated with low ppm and subppm concentrations of BD. The LOD value of the new method is 0.5 fmol/100 MUg DNA, and the LOQ is 1.0 fmol/100 MUg DNA, making it possible to quantify bis-N7G-BD adducts present at concentrations of 3 per 10(9) nucleotides. Bis-N7G-BD adduct amounts in liver tissues of mice exposed to 0.5, 1.0, and 1.5 ppm BD for 2 weeks were 5.7 +/- 3.3, 9.2 +/- 1.5, and 18.6 +/- 6.9 adducts per 10(9) nucleotides, respectively, suggesting that bis-N7G-BD adduct formation is more efficient under low exposure conditions. To our knowledge, this is the first quantitative analysis of DEB specific DNA adducts following low ppm and subppm exposure to BD. PMID- 22220766 TI - Effect of gingivitis on azithromycin concentrations in gingival crevicular fluid. AB - BACKGROUND: Macrolide antibiotics yield high concentrations in inflamed tissue, suggesting that their levels in gingival crevicular fluid (GCF) could be increased at gingivitis sites. However, the increased volume of GCF associated with gingivitis could potentially dilute macrolides. To determine whether these assumptions are correct, the bioavailability of systemically administered azithromycin was compared in GCF from healthy and gingivitis sites. METHODS: Experimental gingivitis was induced in one maxillary posterior sextant in nine healthy individuals. Contralateral healthy sextants served as controls. Participants ingested 500 mg azithromycin, followed by a 250-mg dose 24 hours later. Four hours after the second dose, plaque was removed from experimental sites. GCF was collected from eight surfaces in both the experimental and control sextants and pooled separately. GCF samples were subsequently collected on days 2, 3, 8, and 15, and azithromycin content was determined by agar diffusion bioassay. RESULTS: On days 2 and 3, the pooled GCF volume at experimental sites was significantly higher than at control sites (P <0.01), and the total azithromycin mass in 30-second GCF samples pooled from experimental sites was significantly higher than at control sites (P <0.02). However, there were no significant differences in azithromycin concentration between the experimental and control pools at any point. Concentrations exceeded 7.3 MUg/mL on day 2 and 2.5 MUg/mL on day 15. CONCLUSION: Azithromycin concentrations are similar in GCF from gingivitis sites and healthy sites, suggesting that the processes that regulate GCF azithromycin concentration can compensate for local inflammatory changes. PMID- 22220767 TI - Effectiveness of systemic amoxicillin/metronidazole as adjunctive therapy to scaling and root planing in the treatment of chronic periodontitis: a systematic review and meta-analysis. AB - BACKGROUND: The combination of Amoxicillin and metronidazole (AMX/MET) as an adjunctive treatment to scaling root planing (SRP) has been proposed for the treatment of chronic periodontitis; however, its effectiveness and clinical safety remain to be defined. The purpose of the present meta-analysis is to assess the effectiveness of SRP + AMX/MET compared to SRP alone. METHODS: An electronic search of eight databases from their earliest records through October 8, 2011 and a hand search of international dental journals for the last 15 years were conducted. Gain in clinical attachment level (CAL), reduction in probing depth (PD), secondary outcomes, and adverse events were analyzed. A random-effect model was used to pool the extracted data. The weighted mean difference (WMD) with 95% confidence interval (CI) was calculated for continuous outcomes; heterogeneity was assessed with the Cochrane chi(2) and I(2) tests. The level of significance was set at P <0.05. RESULTS: After the selection process, four randomized clinical trials were included. Results of the meta-analysis showed significant CAL gain (WMD = 0.21; 95% CI = 0.02 to 0.4; P <0.05) and PD reduction (WMD = 0.43; 95% CI = 0.24 to 0.63; P <0.05) in favor of SRP + AMX/MET. No significant differences were found for bleeding on probing (WMD = 10.77; 95% CI = -3.43 to 24.97; P >0.05) or suppuration (WMD = 1.77; 95% CI = -1.7 to 5.24; P >0.05). CONCLUSION: The findings of this meta-analysis seem to support the effectiveness of SRP + AMX/MET; however, future studies are needed to confirm these results. PMID- 22220768 TI - A 10-year evaluation of implants placed in fresh extraction sockets: a prospective cohort study. AB - BACKGROUND: The placement of an implant into a fresh extraction socket has been identified as a reliable technique, allowing a reduction in the time needed for prosthetic rehabilitation. This treatment modality is widely reported in the scientific literature; however, the long-term outcomes and the need for guided bone regeneration (GBR) are still topics of debate. The aim of this prospective study is to evaluate the clinical and radiologic findings from the 10-year follow up of immediately placed implants, with and without the GBR procedure. METHODS: A total of 159 implants in 91 patients are included in this study; 101 implants required a GBR procedure simultaneously with placement. All implants were used to support a single crown restoration. The clinical/radiographic measurements were repeated each year up to the 10-year follow-up. At the 10-year follow-up visit, the papilla index and the apico-coronal location of mid-buccal soft tissue positions were recorded. RESULTS: The 10-year cumulative success rate was 91.8% (87.9% in the non-GBR group and 94.1% in the GBR group). The clinical attachment level (CAL) measurements were stable throughout the study, and 82% of the implants showed marginal bone loss (MBL) of 0.6 to 1.5 mm at the 10-year visit; moreover, these two parameters did not show significant differences between the GBR and non-GBR groups. Seventy percent of the implant sites showed acceptable outcomes in terms of interproximal papilla. The facial gingival level was more apical in the non-GBR group than in the GBR group (P <0.05). CONCLUSIONS: The present prospective clinical study shows that implants placed in fresh extraction sockets had a high cumulative success rate, namely 91.8% after 10 years. No differences were detected in survival and success rate of implants whether GBR procedures were performed or not. The CAL, MBL, and marginal level of soft tissue measurements were stable throughout the 10-year evaluation. PMID- 22220769 TI - Effects of low-dose doxycycline and bisphosphonate clodronate on alveolar bone loss and gingival levels of matrix metalloproteinase-9 and interleukin-1beta in rats with diabetes: a histomorphometric and immunohistochemical study. AB - BACKGROUND: Bisphosphonates (BPs) and low-dose doxycycline (LDD) have been shown to inhibit bone resorption and to improve the levels of proinflammatory mediators and destructive enzymes in gingival tissues, respectively. The purpose of this study is to evaluate the effect of mono and combined BP clodronate and LDD therapies in reducing gingival levels of matrix metalloproteinase-9 (MMP-9), interleukin-1beta (IL-1beta), and alveolar bone loss in rats with diabetes. METHODS: Fifty adult Wistar rats were divided into five study groups as follows: 1) group 1 = diabetes control; 2) group 2 = diabetes + periodontitis; 3) group 3 = diabetes + periodontitis + LDD; 4) group 4 = diabetes + periodontitis + clodronate; and 5) group 5 = diabetes + periodontitis + LDD + clodronate. LDD and clodronate were given as a single agent or as combination therapy during the 7 days of the post-experimental periodontitis period. On day 7, the rats were sacrificed, the mobility of the tooth was recorded, and block biopsies were removed. The gingival tissues were analyzed histologically and immunohistochemically for expression of MMP-9 and IL-1beta. Alveolar bone loss was evaluated morphometrically under a light microscope. Data analysis was performed statistically by Kruskal-Wallis and post hoc Tukey and Spearman correlation tests. RESULTS: Alveolar bone loss was significantly greater in groups 2 through 5 than group 1 (P <0.05) but was not significantly different among groups 2 through 5 (P >0.05). Animals with periodontitis (group 2) expressed significantly higher levels of MMP-9 and IL-1beta compared with those without periodontitis (group 1) (P <0.05). MMP-9 expression was significantly lower in group 3 than groups 1, 2, and 5 (P <0.05). IL-1beta expression was significantly lower in the groups 1, 3, 4, and 5 than 2 (P <0.01) but was not significantly different among groups 1, 3, 4, and 5. Positive correlations were found between alveolar bone loss and density of inflammation (rho = 0.319, P = 0.021) and between MMP-9 and IL-1beta (rho = 0.418, P = 0.002), respectively. CONCLUSION: Our findings suggest that ligature-induced periodontitis in animals with diabetes results in significantly higher levels of MMP-9 and IL-1beta expression in gingiva. The use of mono and combined clodronate and LDD administrations may significantly reduce levels of MMP-9 and IL-1beta expression. However, drug administration did not affect alveolar bone levels during the study period. PMID- 22220770 TI - Vertical ridge augmentation using an equine bone and collagen block infused with recombinant human platelet-derived growth factor-BB: a randomized single-masked histologic study in non-human primates. AB - BACKGROUND: This study tests the effectiveness of hydroxyapatite and collagen bone blocks of equine origin (eHAC), infused with recombinant human platelet derived growth factor-BB (rhPDGF-BB), to augment localized posterior mandibular defects in non-human primates (Papio hamadryas). METHODS: Bilateral critical sized defects simulating severe atrophy were created at the time of the posterior teeth extraction. Test and control blocks (without growth factor) were randomly grafted into the respective sites in each non-human primate. RESULTS: All sites exhibited vertical ridge augmentation, with physiologic hard- and soft-tissue integration of the blocks when clinical and histologic examinations were done at 4 months after the vertical ridge augmentation procedure. There was a clear, although non-significant, tendency to increased regeneration in the test sites. As in the first two preclinical studies in this series using canines, experimental eHAC blocks infused with rhPDGF-BB proved to be a predictable and technically viable method to predictably regenerate bone and soft tissue in critical-sized defects. CONCLUSION: This investigation supplies additional evidence that eHAC blocks infused with rhPDGF-BB growth factor is a predictable and technically feasible option for vertical augmentation of severely resorbed ridges. PMID- 22220771 TI - Quality of reporting in abstracts of randomized controlled trials published in leading journals of periodontology and implant dentistry: a survey. AB - BACKGROUND: Most readers, reviewers, and editors rely on abstracts to decide whether to assess the full text of an article. A research abstract should, therefore, be as informative as possible. The standard of reporting in abstracts of randomized controlled trials (RCTs) in periodontology and implant dentistry has not yet been assessed. The objectives of this review are: 1) to assess the quality of reporting in abstracts of RCTs in periodontology and implant dentistry, and 2) to investigate changes in the quality of reporting by comparing samples from different periods. METHODS: The authors searched the PubMed electronic database, independently and in duplicate, for abstracts of RCTs published in seven leading journals of periodontology and implant dentistry from 2005 to 2007 and from 2009 to 2011. The quality of reporting in selected abstracts with reference to the CONSORT (Consolidated Standards of Reporting Trials) for Abstracts checklist published in January 2008 was assessed independently and in duplicate. Cohen kappa statistic was used to determine the extent of agreement of the reviewers. Pearson chi(2) test and/or Fisher exact test were used to assess differences in reporting in the two samples. Level of significance was set at P <0.05. RESULTS: Three hundred ninety-two abstracts are included in this review. Three items (intervention, objective, and conclusions) were almost fully reported in both samples. In contrast, other items (randomization, trial registration, and funding) were never reported. There were significant changes in reporting for only two items, trial design and title (items better reported in the pre- and post-CONSORT samples, respectively). Most topics, however, were similarly poorly reported in both samples of abstracts. CONCLUSIONS: The quality of reporting in abstracts of RCTs in periodontology and implant dentistry can be improved. Authors should follow the CONSORT for Abstracts guidelines, and journal editors should promote clear rules to improve authors' adherence to these guidelines. PMID- 22220772 TI - Systemic ornidazole as an adjunct to non-surgical periodontal therapy in the treatment of chronic periodontitis: a randomized, double-masked, placebo controlled clinical trial. AB - BACKGROUND: The purpose of this clinical trial is to evaluate the adjunctive clinical effects of the systemic administration of ornidazole (ORN) in the full mouth scaling and root planing (SRP) of individuals with moderate-to-advanced chronic periodontitis. METHODS: Fifty-eight individuals presenting >=12 teeth with probing depth (PD) >=4 mm were selected. All participants were instructed on strict oral hygiene measures and were advised to use 0.2% chlorhexidine mouthwash for 1 week before being allocated to two groups. Thirty participants were randomly assigned to full-mouth SRP + placebo (control group), and 28 participants were assigned to full-mouth SRP + ORN (test group). The clinical outcomes evaluated were plaque index, gingival index, clinical attachment level (CAL), and PD. RESULTS: Fifty participants could be evaluated by <=6 months. At 6 months, the test group had greater mean reduction (2.84 mm) in PD compared to the control group (0.84 mm) (P <0.05), and there was also a greater mean CAL reduction (2.92 mm) in the test group compared to the control group (0.92 mm) (P <0.05). CONCLUSION: The systemic use of ORN, when used in conjunction with initial periodontal treatment consisting of SRP in adults with periodontitis, achieves significantly better clinical results than initial periodontal treatment alone. PMID- 22220773 TI - Influence of placement depth on bone remodeling around tapered internal connection implant: a clinical and radiographic study in dogs. AB - BACKGROUND: The aim of this study is to evaluate the influence of placement depth on bone remodeling around implants with two different types of tapered internal implant-abutment interface (IAI): tapped-in (TI) tapered internal IAI and screwed in (SI) tapered internal IAI in dogs. METHODS: The second, third, and fourth premolars and the first molar in mandibles of six beagle dogs were extracted. After 8 weeks, two SI implants and two TI implants were placed in one side of the mandible. There were four experimental groups: 1) SI placed crestally (SIC); 2) TI placed crestally (TIC); 3) SI placed 1.5 mm subcrestally (SIS); and 4) TI placed 1.5 mm subcrestally (TIS). Healing abutments were connected 12 weeks after implant surgery. Implants and teeth were brushed every second day during the healing period. Clinical and radiographic parameters were recorded at 4, 10, and 16 weeks after second-stage surgery. RESULTS: Differences between SI and TI implants inserted in the same vertical position were not significant for peri implant probing depth (PD), clinical attachment level (CAL), or bone resorption (P >0.05). Subcrestal placement of both implants had greater PD and CAL compared to crestal groups. However, distance from IAI to the first bone-implant contact was lower in subcrestal groups compared to crestal groups (1.27 +/- 0.42 mm for SIC versus 0.46 +/- 0.26 mm for SIS, P <0.05; 1.36 +/- 0.31 mm for TIC versus 0.78 +/- 0.42 mm for TIS, P <0.05). CONCLUSIONS: Tapered internal IAI configuration had no significant effect on crestal bone resorption. Moreover, subcrestal placement of tapered internal IAI had a positive impact on crestal bone preservation around the cervix of the implant. PMID- 22220775 TI - Occurrence of hepatitis E virus RNA in plasma donations from Sweden, Germany and the United States. PMID- 22220776 TI - Is major depressive disorder specifically associated with mesial temporal sclerosis? AB - PURPOSE: Whether a specific lesion such as mesial temporal sclerosis (MTS) increases the risk for a mood disorder in epilepsy remains subject to debate. Despite evidence of limbic system involvement in the genesis of emotional symptoms, recent studies fail to support an association between depression and MTS. We aimed to clarify this controversial issue by overcoming prior methodologic limitations, hypothesizing that rates of major depressive disorder (MDD) would be higher in patients with MTS. METHODS: Three hundred eight patients with focal epilepsy (International League Against Epilepsy [ILAE] criteria), were classified into three groups on the basis of neuroimaging findings: MTS, a lesion different from MTS, or absence of lesion. Patients were assessed using the Structured Interview for DSM-IV axis I psychiatric disorders (SCID-I), by a psychiatrist blinded to epilepsy subtype. The Spanish version of the Hospital Anxiety and Depression Scale (HADS) was also administered. A complete logistic regression analysis was performed to investigate the association between MTS and MDD. KEY FINDINGS: MTS increased the likelihood of a lifetime MDD by nearly 2.5. No other current or "postseizure onset" lifetime Axis I DSM-IV psychiatric disorder was associated with MTS. Female gender, primary education, comorbid anxiety disorders, and antidepressant treatment were also associated with an increased risk of MDD. Marriage was found to be a protective factor for MDD. SIGNIFICANCE: Our results support a specific association between MTS and lifetime "postseizure onset," MDD. The lack of association with current depression is in line with the hypothesis that the link between MTS and depression is more of a chronic than a state-dependent condition. PMID- 22220777 TI - Lanthanide complexes of macrocyclic polyoxovanadates by VO4 units: synthesis, characterization, and structure elucidation by X-ray crystallography and EXAFS spectroscopy. AB - Reactions of a tetravanadate anion, [V(4)O(12)](4-), with a series of lanthanide(III) salts yield three types of lanthanide complexes of macrocyclic polyoxovanadates: (Et(4)N)(6)[Ln(III)V(9)O(27)] [Ln = Nd (1), Sm (2), Eu (3), Gd (4), Tb (5), Dy (6)], (Et(4)N)(5)[(H(2)O)Ho(III)(V(4)O(12))(2)] (7), and (Et(4)N)(7)[Ln(III)V(10)O(30)] [Ln = Er (8), Tm (9), Yb (10), Lu (11)]. Lanthanide complexes 1-11 are isolated and characterized by IR, elemental analysis, single-crystal X-ray diffraction, and extended X-ray absorption fine structure spectroscopy (EXAFS). Lanthanide complexes 1-6 are composed of a square antiprism eight-coordinated Ln(III) center with a macrocyclic polyoxovanadate that is constructed from nine VO(4) tetrahedra through vertex sharing. The structure of 7 is composed of a seven-coordinated Ho(III) center, which exhibits a capped trigonal-prism coordination environment by the sandwiching of two cyclic tetravanadates with a capping H(2)O ligand. Lanthanide complexes 8-11 have a six coordinated Ln(III) center with a 10-membered vanadate ligand. The structural trend to adopt a larger coordination number for a larger lanthanide ion among the three types of structures is accompanied by a change in the vanadate ring sizes. These lanthanide complexes are examined by EXAFS spectroscopies on lanthanide L(III) absorption edges, and the EXAFS oscillations of each of the samples in the solid state and in acetonitrile are identical. The Ln-O and Ln...V bond lengths obtained from fits of the EXAFS data are consistent with the data from the single crystal X-ray studies, reflecting retention of the structures in acetonitrile. PMID- 22220778 TI - InforMatrix: ADP antagonists in acute coronary syndromes. AB - INTRODUCTION: InforMatrix is an interactive matrix model, in which pharmacotherapeutic strategies are supported in a rational manner, by means of a transparent selection methodology. AREAS COVERED: In this paper, InforMatrix is applied to ADP antagonists, including clopidogrel, prasugrel and ticagrelor. These drugs are important additions to the treatment of acute coronary syndromes. The drugs are compared using the following selection criteria: efficacy, safety, tolerability, ease of use, applicability and cost. All direct comparative studies, as well as placebo-controlled or double-blind comparisons with other drugs, were used in the assessment. EXPERT OPINION: By means of the interactive program, users may assign their own individual weight to each criterion and to the properties of the individual drugs, which stimulates concrete discussions on the relative importance of the various aspects of the drugs. When applied to ADP antagonists, the discussion focuses on the documentation of relative efficacy, safety and acquisition cost. The extensive clinical experience with clopidogrel must be balanced against the potential advantages of the other two compounds concerning efficacy. In those countries where generic clopidogrel is available, there are also major differences in acquisition cost between generic clopidogrel and patented prasugrel and ticagrelor. The interactive program provides the opportunity to quantify existing differences in opinion on the (importance of) various properties of the drugs, which greatly facilitates concrete discussions and rational formulary decision making. PMID- 22220806 TI - Time-dependent control of hole-opening degree of porous ZnO hollow microspheres. AB - Well-designed, monodispersed porous ZnO hollow microspheres with controlled hole opening were successfully synthesized by a facile two-step solution route at low temperature. The hollow microspheres having average diameter of 3-4 MUm showed time-dependent hole-opening, i.e. 4-100% for 15-75 min. The hole-opening percentage increases linearly with time until complete opening. The ZnO hollow microspheres also exhibited a high surface area (34 m(2) g(-1)), a large pore volume (0.19 cm(3) g(-1)) and an average pore diameter of 3.8 nm. A plausible growth mechanism for the formation of ZnO hollow microspheres was also proposed. PMID- 22220805 TI - Epigenetic dysregulation of the dopamine system in diet-induced obesity. AB - Chronic intake of high-fat (HF) diet is known to alter brain neurotransmitter systems that participate in the central regulation of food intake. Dopamine (DA) system changes in response to HF diet have been observed in the hypothalamus, important in the homeostatic control of food intake, as well as within the central reward circuitry [ventral tegmental area (VTA), nucleus accumbens (NAc), and pre-frontal cortex (PFC)], critical for coding the rewarding properties of palatable food and important in hedonically driven feeding behavior. Using a mouse model of diet-induced obesity (DIO), significant alterations in the expression of DA-related genes were documented in adult animals, and the general pattern of gene expression changes was opposite within the hypothalamus versus the reward circuitry (increased vs. decreased, respectively). Differential DNA methylation was identified within the promoter regions of tyrosine hydroxylase (TH) and dopamine transporter (DAT), and the pattern of this response was consistent with the pattern of gene expression. Behaviors consistent with increased hypothalamic DA and decreased reward circuitry DA were observed. These data identify differential DNA methylation as an epigenetic mechanism linking the chronic intake of HF diet with altered DA-related gene expression, and this response varies by brain region and DNA sequence. PMID- 22220807 TI - A comparative study of hair shafts in scalp psoriasis and seborrheic dermatitis using atomic force microscopy. AB - BACKGROUND: As the inflammatory scalp conditions share similar clinical manifestations of scaling, inflammation, and pruritus, the differential diagnosis of these lesions; especially between scalp psoriasis (SP) and seborrheic dermatitis (SD) is sometimes difficult. OBJECTIVES: The aim of this study was to investigate the differences on the hair surface in SP and SD for a clinical diagnosis, using atomic force microscopy (AFM). METHODS: The hair shafts of 14 patients and 28 patients with SP and SD respectively, were taken from the lesional region. Hairs from healthy adults not having any hair diseases were also examined in the same way for the controls. Surface characteristics of SP and SD affected hair shafts such as, pitting, scale thickness, and roughness, were observed on the AFM images. RESULTS: One hundred percentage and four percentage of the patients with SP and SD respectively had macropits on their hair shafts. In both the SP and SD-affected hairs, the scale thickness was more than 4-fold than that in the control hairs. The surface of SP-affected hairs was rougher than that of SD-affected and control hairs. CONCLUSION: The differences in hair shafts between SP and SD were investigated noninvasively using AFM. The presence of macropits could be helpful in the differentiation between SP and SD. PMID- 22220808 TI - Variant late-infantile neuronal ceroid lipofuscinosis due to a novel heterozygous CLN8 mutation and de novo 8p23.3 deletion. PMID- 22220809 TI - Progress in the tissue engineering and stem cell industry "are we there yet?". AB - This report presents a detailed update to our 2008 publication on the tissue engineering (TE) and stem cell industry. Data are reported through mid 2011 showing an almost three-fold growth in commercial sales over the past 4 years. In addition, the number of companies selling products or offering services has increased over two-fold to 106, and they are generating a remarkable $3.5 billion in sales. Overall, the TE and stem cell sector is spending $3.6 billion and employing almost 14,000 employees. These data suggest the TE and stem cell industry has stabilized and is on a path pointing toward continued success. PMID- 22220810 TI - Genomic analysis of resistance/susceptibility to melanoma in Old Kladruber greying horses. PMID- 22220811 TI - Sex recognition by odour and variation in the uropygial gland secretion in starlings. AB - 1. Although a growing body of evidence supports that olfaction based on chemical compounds emitted by birds may play a role in individual recognition, the possible role of chemical cues in sexual selection of birds has been only preliminarily studied. 2. We investigated for the first time whether a passerine bird, the spotless starling Sturnus unicolor, was able to discriminate the sex of conspecifics by using olfactory cues and whether the size and secretion composition of the uropygial gland convey information on sex, age and reproductive status in this species. 3. We performed a blind choice experiment during mating, and we found that starlings were able to discriminate the sex of conspecifics by using chemical cues alone. Both male and female starlings preferred male scents. Furthermore, the analysis of the chemical composition of the uropygial gland secretion by using gas chromatography-mass spectrometry (GC MS) revealed differences between sexes, ages and reproductive status. 4. In conclusion, our study reveals for first time that a passerine species can discriminate the sex of conspecifics by relying on chemical cues and suggests that the uropygial gland secretion may potentially function as a chemical signal used in mate choice and/or intrasexual competition in this species. PMID- 22220812 TI - Solvent-adoptable polymer Ni/NiCo alloy nanochains: highly active and versatile catalysts for various organic reactions in both aqueous and nonaqueous media. AB - The synthesis of solvent-adoptable monometallic Ni and NiCo alloy nanochains by a one-pot solution phase reduction method in the presence of poly(4-vinylphenol) (PVPh) is demonstrated. The elemental compositions of the as-prepared alloys are determined by inductively coupled plasma optical emission spectroscopy (ICP-OES) and energy-dispersive X-ray spectroscopy (EDS), which are matching well with the target compositions. The morphology analysis by TEM and FESEM confirms that the nanochains are made up of organized spherical monometallic Ni or bimetallic NiCo alloy nanoparticles (NPs). However, there is no nanochain formation when the alloy is prepared without the polymer PVPh. A possible mechanism for the formation of such NiCo alloy nanochains is discussed. The X-ray diffraction and selected area electron diffraction patterns reveal that the Ni/NiCo alloys are polycrystalline with fcc structure. The obtained Ni or NiCo alloy nanostructures are ferromagnetic with very high coercivity. The polymer Ni/NiCo alloy nanochains are dispersible in both water and organic media that makes them versatile enough to use as catalysts in the reactions carried out in both types of media. The catalytic activities of these Ni/NiCo alloy nanochains are extremely high in the borohydride reduction of p-nitrophenol in water. In organic solvents, these nanochains can act as efficient catalysts, under ligand-free condition, for the C S cross-coupling reactions of various aryl iodides and aryl thiols for obtaining the corresponding cross-coupled products in good to excellent yield up to 96%. The NiCo nanochain also successfully catalyzes the C-O cross-coupling reaction in organic medium. A possible mechanism for NiCo alloy nanochain-catalyzed cross coupling reaction is proposed. PMID- 22220814 TI - Dissociation constants of parabens and limiting conductances of their ions in water. AB - Precise measurements of electrical conductivities of methylparaben, ethylparaben, propylparaben, and butylparaben sodium salts in dilute aqueous solutions were performed from 278.15 to 313.15 K in 5 K intervals. Experimental conductivity data were analyzed applying the Quint-Viallard conductivity equations by taking into account the salt hydrolysis in aqueous solutions. These evaluations yield the limiting conductances of paraben anions and the dissociation constants of the investigated parabens in water. From temperature dependence of dissociation constants, the thermodynamic functions associated with the dissociation process were estimated. It was discovered that the contributions of enthalpy and entropy to the Gibbs free energy are quite similar. The Walden products of paraben anions in water are independent of temperature, indicating that the hydrodynamic radii are not significantly affected by temperature. PMID- 22220813 TI - Deciphering cell wall integrity signalling in Aspergillus fumigatus: identification and functional characterization of cell wall stress sensors and relevant Rho GTPases. AB - The fungal cell wall, a conserved and highly dynamic structure, is essential for virulence and viability of fungal pathogens and is an important antifungal drug target. The cell wall integrity (CWI) signalling pathway regulates shape and biosynthesis of the cell wall. In this work we identified, localized and functionally characterized four putative CWI stress sensors of Aspergillus fumigatus, an airborne opportunistic human pathogen and the cause of invasive aspergillosis. We show that Wsc1 is specifically required for resistance to echinocandin antifungals. MidA is specifically required for elevated temperature tolerance and resistance to the cell wall perturbing agents congo red and calcofluor white. Wsc1, Wsc3 and MidA additionally have overlapping functions and are redundantly required for radial growth and conidiation. We have also analysed the roles of three Rho GTPases that have been implicated in CWI signalling in other fungi. We show that Rho1 is essential and that conditional downregulation of rho1 or deletion of rho2 or rho4 results in severely impaired CWI. Our data indicate significant functional differences between the CWI stress sensors of yeasts and moulds. PMID- 22220815 TI - Synthesis of new 4,5-dihydrofuranoindoles and their evaluation as HCV NS5B polymerase inhibitors. AB - The synthesis of substituted 3,4-dihydrofuranoindoles is reported. These new indole compounds were used to synthesize potent HCV NS5B inhibitors. The binding mode of the dihydrofuranoindole-derived inhibitors was established via X-ray crystallographic studies. PMID- 22220816 TI - Ternary asymmetric particles with controllable patchiness. AB - This work demonstrated a facile approach to the fabrication of the ternary asymmetric silica particles that consisted of different components on the opposite poles, such as metal or fluorescent quantum dots, with the aid of the mask-unmask method and double-sided etching and modifying. By controlling the thickness of the polymer mask, the surface of the particle was precisely further controlled for functional modification. At the same time, as-prepared ternary particles could self-assemble into dimers and trimers. Asymmetric patch could be clearly distinguished by SEM, EDS mapping, TEM, and fluorescence microscopy. The asymmetric particles are stable and show the potential applications in supraparticle assembly and catalysis, etc. PMID- 22220817 TI - Perceptions of low-risk drinking levels among Australians during a period of change in the official drinking guidelines. AB - INTRODUCTION AND AIMS: In 2009, the National Health and Medical Research Council released a revision of Australia's official low-risk alcohol guidelines, specifying low-risk consumption levels for both short- and long-term consumption. This study aims to assess how the general population's assessment of low-risk drinking levels compares to these guidelines and to examine whether the changes to the official guidelines corresponded with changes in perceptions of low-risk drinking levels in the population. DESIGN AND METHODS: The study uses two waves of a large, general population survey which was run in 2007 (n = 19 818) and 2010 (n = 26 648), providing before and after measures of respondents' estimates of low-risk drinking levels. RESULTS: In the 2010 survey, less than 5% of respondents estimated low-risk drinking levels that matched those in the 2009 guidelines. Generally speaking, younger respondents and heavier drinkers provided higher estimates of low-risk drinking thresholds. There was little change in estimates between 2007 and 2010, although there was some evidence that the changes to the guidelines had influenced perceptions of safe drinking. CONCLUSIONS: There is very little knowledge of the official drinking guidelines among the general Australian population. If drinking guidelines are to have any effect on levels of consumption, a more concerted effort to publicise them is necessary. PMID- 22220818 TI - The multifaceted reactivity of o-fluoranil. AB - In addition to Diels-Alder and hetero-Diels-Alder reactions, tetrafluoro-o benzoquinone (o-fluoranil) undergoes nucleophilic additions, addition eliminations, dioxole formation, and charge-transfer complexation, reacting at every site on the molecular skeleton. It also effects dehydrogenations and other oxidations. The quinone can function as a (CF)(4) synthon. PMID- 22220819 TI - Validity of a pediatric version of the Glasgow Outcome Scale-Extended. AB - The Glasgow Outcome Scale (GOS) and its most recent revision, the GOS-Extended (GOS-E), provide the gold standard for measuring traumatic brain injury (TBI) outcome. The GOS-E exhibits validity when used with adults and some adolescents, but validity with younger children is not established. Because the GOS-E lacks the developmental specificity necessary to evaluate children, toddlers, and infants, we modified the original version to create the GOS-E Pediatric Revision (GOS-E Peds), a developmentally appropriate structured interview, to classify younger patients. The criterion, predictive, and discriminant validity of the GOS E Peds was measured in 159 subjects following TBI (mild: 36%; moderate: 12%; severe: 50%) at 3 and 6 months after injury. Participants were included from two studies completed at the Pediatric Neurotrauma Center at Children's Hospital of Pittsburgh. We assessed the relationship among GOS-E Peds, the GOS, and the Vineland Adaptive Behavior Scales as well as other standardized measures of functional, behavioral, intellectual, and neuropsychological outcome. Premorbid function was assessed 24-36 h after injury. The GOS-E Peds showed a strong correlation with the GOS at 3 and 6 month time points. Criterion-related validity was also indicated by GOS-E Peds' association with most measures at both time points and at injury severity levels. The 3 month GOS-E Peds was associated with the 6 month GOS-E Peds, everyday function, behavior, and most cognitive abilities. Discriminant validity is suggested by weak correlations between both 3 and 6 month GOS-E Peds and premorbid measures. The GOS-E Peds is sensitive to severity of injury and is associated with changes in TBI sequelae over time. This pediatric revision provides a valid outcome measure in infants, toddlers, children, and adolescents through age 16. Findings support using the GOS-E Peds as the primary outcome variable in pediatric clinical trials. PMID- 22220820 TI - Simultaneous quantification of eleven thiopurine nucleotides by liquid chromatography-tandem mass spectrometry. AB - The prodrugs azathioprine and 6-mercaptopurine, which are well-established anticancer and immunosuppressive agents, are extensively metabolized by activating and inactivating enzymes. Whereas the 6-thioguanine nucleotides (TGN) are currently being considered as major active metabolites, methylthioinosine nucleotides seem to contribute to the cytotoxic effect as well. Thiopurine related adverse drug reactions and thiopurine failure are frequent. Thus, therapeutic monitoring of TGN and methylthioinosine derivatives has been suggested to improve thiopurine therapy, however with limited success. To elucidate systematically underlying molecular mechanisms as potential explanation for interindividual variability of thiopurine response, we developed a novel highly specific and sensitive liquid chromatography-tandem mass spectrometry (LC MS/MS) method for simultaneous quantitation of eleven mono-, di-, and triphosphates of thioguanosine, methylthioinosine, methylthioguanosine, and thioinosine. Using stable isotope-labeled analogues as internal standards obtained by chemical synthesis, an intra- and interassay variability below 8% and an accuracy of 92% to 107% were achieved in spiked quality control samples with known standards. All eleven metabolites could be determined in red blood cells from patients with inflammatory bowel diseases and long-term azathioprine therapy. Thus, our novel method opens a new avenue for the understanding of the thiopurine metabolism by quantitation of all important thiopurine nucleotide metabolites in one run. PMID- 22220821 TI - Native FKBP12 engineering by ligand-directed tosyl chemistry: labeling properties and application to photo-cross-linking of protein complexes in vitro and in living cells. AB - The ability to modify target "native" (endogenous) proteins selectively in living cells with synthetic molecules should provide powerful tools for chemical biology. To this end, we recently developed a novel protein labeling technique termed ligand-directed tosyl (LDT) chemistry. This method uses labeling reagents in which a protein ligand and a synthetic probe are connected by a tosylate ester group. We previously demonstrated its applicability to the selective chemical labeling of several native proteins in living cells and mice. However, many fundamental features of this chemistry remain to be studied. In this work, we investigated the relationship between the LDT reagent structure and labeling properties by using native FK506-binding protein 12 (FKBP12) as a target protein. In vitro experiments revealed that the length and rigidity of the spacer structure linking the protein ligand and the tosylate group have significant effects on the overall labeling yield and labeling site. In addition to histidine, which we reported previously, tyrosine and glutamate residues were identified as amino acids that are modified by LDT-mediated labeling. Through the screening of various spacer structures, piperazine was found to be optimal for FKBP12 labeling in terms of labeling efficiency and site specificity. Using a piperazine-based LDT reagent containing a photoreactive probe, we successfully demonstrated the labeling and UV-induced covalent cross-linking of FKBP12 and its interacting proteins in vitro and in living cells. This study not only furthers our understanding of the basic reaction properties of LDT chemistry but also extends the applicability of this method to the investigation of biological processes in mammalian cells. PMID- 22220822 TI - Full-mouth disinfection and systemic antimicrobial therapy in generalized aggressive periodontitis: a randomized, placebo-controlled trial. AB - AIM: The present investigation aimed to analyse clinical and microbiological effects of systemic administration of metronidazole and amoxicillin combined with the One-Stage-Full-Mouth-Disinfection protocol (OSFMD) in generalized aggressive periodontitis patients (G-AgP). MATERIALS AND METHODS: Thirty-nine systemically healthy patients with G-AgP were consecutively included. The test group (n = 19) received amoxicillin-metronidazole combination (500 mg of each, three times a day for 7 days) and the OSFMD, the control group (n = 20) received the OSFMD and a placebo. In addition to clinical parameters subgingival plaque samples from moderate (4-5 mm) and deep (>= 6 mm) pocket sites were analysed for the presence of Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola using polymerase chain reaction. RESULTS: Both therapies led to a statistically significant decrease in clinical and microbiological parameters compared to baseline (p < 0.001). The most beneficial changes were observed in the test group which showed significantly greater improvements in probing depth and clinical attachment level and a lower prevalence of Aggregatibacter actinomycetemcomitans, Treponema denticola, and Tannerella forsythia compared to the control one (p < 0.05). CONCLUSIONS: Systemic administration of metronidazole and amoxicillin as an adjunct to OSFMD therapy significantly improved clinical and microbiological outcomes in patients with G-AgP over a 6-month period. PMID- 22220824 TI - Evolution of definitions of response, progression-free survival and event-free survival in front-line studies of chronic myeloid leukemia. AB - Standardized definitions of response and outcome are useful to evaluate study data, facilitate treatment guideline adherence and aid clinical decision-making. Although definitions of response in chronic myeloid leukemia (CML) have been standardized, definitions of disease progression have not been standardized, despite widespread adoption of the term to reflect development of advanced disease. This article reviews definitions of response and disease progression used for progression-free survival and event-free survival in key CML studies and implications for interpreting patient response. It is proposed that adherence to definitions of progression from the European LeukmiaNet may aid future research and therapeutic decision-making. PMID- 22220825 TI - Improving treatment adherence to antihypertensive therapy: the role of single pill combinations. AB - INTRODUCTION: The majority of patients with hypertension require combination therapy to achieve their blood pressure (BP) goal. Studies have consistently shown that polypharmacy and complex treatment regimens have a detrimental effect on treatment compliance, adherence and persistence (herein referred to as treatment adherence). AREAS COVERED: This paper reviews the available clinical evidence, as well as guidelines, which propose combinations of an angiotensin II receptor blocker (ARB) or an angiotensin-converting enzyme (ACE) inhibitor plus a calcium channel blocker (CCB) or diuretic. EXPERT OPINION: ARBs are associated with better tolerability compared with ACE inhibitors, and data suggest that ARB/CCB combinations may be better tolerated than CCB monotherapy. The use of true once-daily single-pill combination therapy with effective and well-tolerated agents will reduce pill burden, simplify treatment regimens and improve treatment adherence, which will, in turn, help patients to reach and maintain their BP target and achieve the short- and long-term treatment goal of cardiovascular risk reduction. PMID- 22220827 TI - The series of molecular conductors and superconductors ET4[AFe(C2O4)3].PhX (ET = bis(ethylenedithio)tetrathiafulvalene; (C2O4)2- = oxalate; A+ = H3O+, K+; X = F, Cl, Br, and I): influence of the halobenzene guest molecules on the crystal structure and superconducting properties. AB - An extensive series of radical salts formed by the organic donor bis(ethylenedithio)tetrathiafulvalene (ET), the paramagnetic tris(oxalato)ferrate(III) anion [Fe(C(2)O(4))(3)](3-), and halobenzene guest molecules has been synthesized and characterized. The change of the halogen atom in this series has allowed the study of the effect of the size and charge polarization on the crystal structures and physical properties while keeping the geometry of the guest molecule. The general formula of the salts is ET(4)[A(I)Fe(C(2)O(4))(3)].G with A/G = H(3)O(+)/PhF (1); H(3)O(+)/PhCl (2); H(3)O(+)/PhBr (3), and K(+)/PhI (4), (crystal data at room temperature: (1) monoclinic, space group C2/c with a = 10.3123(2) A, b = 20.0205(3) A, c = 35.2732(4) A, beta = 92.511(2) degrees , V = 7275.4(2) A(3), Z = 4; (2) monoclinic, space group C2/c with a = 10.2899(4) A, b = 20.026(10) A, c = 35.411(10) A, beta = 92.974 degrees , V = 7287(4) A(3), Z = 4; (3) monoclinic, space group C2/c with a = 10.2875(3) A, b = 20.0546(15) A, c = 35.513(2) A, beta = 93.238(5) degrees , V = 7315.0(7) A(3), Z = 4; (4) monoclinic, space group C2/c with a = 10.2260(2) A, b = 19.9234(2) A, c = 35.9064(6) A, beta = 93.3664(6) degrees , V = 7302.83(18) A(3), Z = 4). The crystal structures at 120 K evidence that compounds 1-3 undergo a structural transition to a lower symmetry phase when the temperature is lowered (crystal data at 120 K: (1) triclinic, space group P1 with a = 10.2595(3) A, b = 11.1403(3) A, c = 34.9516(9) A, alpha = 89.149(2) degrees , beta = 86.762(2) degrees , gamma = 62.578(3) degrees , V = 3539.96(19) A(3), Z = 2; (2) triclinic, space group P1 with a = 10.25276(14) A, b = 11.15081(13) A, c = 35.1363(5) A, alpha = 89.0829(10) degrees , beta = 86.5203(11) degrees , gamma = 62.6678(13) degrees , V = 3561.65(8) A(3), Z = 2; (3) triclinic, space group P1 with a = 10.25554(17) A, b = 11.16966(18) A, c = 35.1997(5) A, alpha = 62.7251(16) degrees , beta = 86.3083(12) degrees , gamma = 62.7251(16) degrees , V = 3575.99(10) A(3), Z = 2; (4) monoclinic, space group C2/c with a = 10.1637(3) A, b = 19.7251(6) A, c = 35.6405(11) A, beta = 93.895(3) degrees , V = 7128.7(4) A(3), Z = 4). A detailed crystallographic study shows a change in the symmetry of the crystal for compound 3 at about 200 K. This structural transition arises from the partial ordering of some ethylene groups in the ET molecules and involves a slight movement of the halobenzene guest molecules (which occupy hexagonal cavities in the anionic layers) toward one of the adjacent organic layers, giving rise to two nonequivalent organic layers at 120 K (compared to only one at room temperature). The structural transition at about 200 K is also observed in the electrical properties of 1-3 and in the magnetic properties of 1. The direct current (dc) conductivity shows metallic behavior in salts 1-3 with superconducting transitions at about 4.0 and 1.0 K in salts 3 and 1, respectively. Salt 4 shows a semiconductor behavior in the temperature range 300-50 K with an activation energy of 64 meV. The magnetic measurements confirm the presence of high spin S = 5/2 [Fe(C(2)O(4))(3)](3-) isolated monomers together with a Pauli paramagnetism, typical of metals, in compounds 1-3. The magnetic properties can be very well reproduced in the whole temperature range with a simple model of isolated S = 5/2 ions with a zero field splitting plus a temperature independent paramagnetism (Nalpha) with the following parameters: g = 1.965, |D| = 0.31 cm(-1), and Nalpha = 1.5 * 10(-3) emu mol(-1) for 1, g = 2.024, |D| = 0.65 cm(-1), and Nalpha = 1.4 * 10(-3) emu mol( 1) for 2, and g = 2.001, |D| = 0.52 cm(-1), and Nalpha = 1.5 * 10(-3) emu mol(-1) for 3. PMID- 22220826 TI - Dilated cardiomyopathy in a spider monkey (Ateles paniscus). AB - BACKGROUND: A spider monkey with severe dyspnea was referred to our clinic. METHODS AND RESULTS: Radiographs revealed an enlarged cardiac silhouette. Ventricular tachycardia and ST segment depression were also diagnosed after an ECG. These findings coupled with the postmortem examination confirmed dilatative cardiomyopathy. CONCLUSIONS: This case is worthy of presentation since dilatative cardiomyopathy has been rarely encountered in spider monkeys. PMID- 22220828 TI - Ambulatory blood pressure monitoring in solid organ transplantation. AB - Solid organ transplant recipients are at an increased risk for hypertension and cardiovascular disease. To assist in their management, 24-h ambulatory blood pressure monitoring (ABPM) has become increasingly used in both clinical research settings and practice. ABPM has been used to better define post-transplant hypertension incidence and prevalence in different solid organ transplantation populations. ABPM provides additional information on cardiovascular risk beyond that obtained by clinic-based readings, based on its ability to assess 24-h blood pressure (BP) load, detect nocturnal non-dipping, and predict target organ damage. It has provided some assurance about the safety of living kidney donation. Information from ABPM can be used to guide living kidney donor selection, and because ABPM-related data has been correlated with clinically important kidney and heart transplant recipient outcomes, it may be a valuable adjunct in their management. Despite these advantages, barriers to wider use of ABPM include expense, clinical inertia in hypertension management, lack of prospective clinical trial data, and clinical problems that compete with hypertension for attention such as acute or chronic allograft dysfunction. The increasing amount of research and clinical use for ABPM may allow for closer assessment and intervention to help address the increased cardiovascular risk faced by many solid organ transplant recipients. PMID- 22220830 TI - Predictive value of resistive index, detrusor wall thickness and ultrasound estimated bladder weight regarding the outcome after transurethral prostatectomy for patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. AB - OBJECTIVES: To evaluate the value of three parameters from preoperative ultrasonography in predicting the outcome of transurethral prostatectomy in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. METHODS: A total of 239 patients with lower urinary tract symptoms suggestive of benign prostatic obstruction entering our department for surgical therapy were prospectively recruited. All of them underwent both ultrasound and urodynamics before receiving standard transurethral prostatectomy by the same team of surgeons. For 202 patients, 6-month follow-up data were available after the surgery, including the International Prostate Symptom Score, the Quality of Life score and the maximum flow rate. Preoperative data stratified by different degree of recovery were compared and the influence of ultrasound parameters on the surgical outcome was analyzed by using logistic regression and receiver operator characteristic curve analyses. RESULTS: Baseline transitional zone index, intravesical prostatic protrusion, resistive index, detrusor wall thickness and ultrasonic estimation of bladder weight were significantly different between patients with an effective outcome and those with an ineffective outcome (P < 0.05). Resistive index, detrusor wall thickness and ultrasonic estimation of bladder weight were selected as independent factors correlated with the efficacy of transurethral prostatectomy by logistic regression (P < 0.05). All three factors had adequate area under receiver operator characteristic curve with resistive index having the largest area (0.816, 95% CI 0.759-0.874). The combined positive predictive value in effective surgical outcome of resistive index, detrusor wall thickness and ultrasonic estimation was 96.3%. CONCLUSIONS: Resistive index, detrusor wall thickness and ultrasonic estimation adequately predict the outcome of transurethral prostatectomy. Measuring these parameters by preoperative ultrasound might aid in determining the need for surgical intervention. PMID- 22220831 TI - Cdk5/p35 phosphorylates lemur tyrosine kinase-2 to regulate protein phosphatase 1C phosphorylation and activity. AB - Cyclin-dependent kinase-5 (cdk5)/p35 and protein phosphatase-1 (PP1) are two major enzymes that control a variety of physiological processes within the nervous system including neuronal differentiation, synaptic plasticity and axonal transport. Defective cdk5/p35 and PP1 function are also implicated in several major human neurodegenerative diseases. Cdk5/p35 and the catalytic subunit of PP1 (PP1C) both bind to the brain-enriched, serine-threonine kinase lemur tyrosine kinase-2 (LMTK2). Moreover, LMTK2 phosphorylates PP1C on threonine-320 (PP1Cthr320) to inhibit its activity. Here, we demonstrate that LMTK2 is phosphorylated on serine-1418 (LMTK2ser1418) by cdk5/p35 and present evidence that this regulates its ability to phosphorylate PP1Cthr320. We thus describe a new signalling pathway within the nervous system that links cdk5/p35 with PP1C and which has implications for a number of neuronal functions and neuronal dysfunction. PMID- 22220833 TI - Effects of the alkali-metal cation size on molecular and extended structures: formation of coordination polymers and hybrid materials in the homologous series [(4-Et-C6H4OM).(diox)n], M = Li, Na, K, Rb, Cs. AB - The complete series of group 1 metal 4-ethylphenoxide (4-Et-C(6)H(4)O(-)) networks have been synthesized using 1,4-dioxane (diox) as a neutral linker. [{(4 Et-C(6)H(4)OLi)(4).(diox)(2.5)}.diox](infinity) (1) and [{(4-Et C(6)H(4)ONa)(6).(diox)(3)}(infinity)] (2) form 2D and 3D networks, respectively, composed of discrete aggregates linked by diox. Compound 1 forms a hexagonal layered structure with Li(4)O(4) cubanes acting as nodes, whereas compound 2 forms a primitive cubic network (pcu) with Na(6)O(6) hexameric nodes. [{(4-Et C(6)H(4)OK)(3).diox}(infinity)] (3), [{(4-Et C(6)H(4)ORb)(2).(diox)(0.5)}(infinity)] (4), and [{(4-Et C(6)H(4)OCs)(2).(diox)(0.5)}(infinity)] (5) are composed of isostructural 1D inorganic rods that are linked through diox to form pcu-type networks. Compound 5 is the first example of a network built from cesium inorganic rods. PMID- 22220834 TI - Crystalline transformation of colloidal nanoparticles on graphene oxide. AB - Emergence of novel two-dimensional (2-D) templates, e.g., graphene oxide, has signified new intriguing opportunities to couple nanocrystals electronically to the microscopic 2-D contacts. A promising approach to uniform dispersion of inorganic nanocrystals on the 2-D interfaces is to graft them through chemical bonding. The 2-D dispersion would offer a unique opportunity to address one of the primary challenges in the field of nanotechnology: fulfilling excellent chemical and physical properties of the nanocrystals in electronic solid-state devices. In this study, we blended colloidal nanocrystals with graphene oxide in aqueous solution in attempts to bind the nanocrystals on reactive sites of the graphene oxide surface, thereby achieving uniform loading. Interestingly, the nanocrystals undergo significant crystalline transformation even under relatively moderate reaction conditions. The growth of particle size and the drastic crystalline deformation, e.g., from wurtzite CdSe to amorphous Se, appear to take place in the proximity of acidic functional groups on graphene oxide. Photocarriers also play a key role in the reaction: under room light, the transformation yielded dramatic size increase and crystalline transformation, whereas in the dark, the change was suppressed. The experimental results presented in this study provide guidelines for uniform 2-D loading of colloidal nanocrystals on graphene oxide. The findings suggest that the surface acidity be titrated for colloidal nanocrystals to deposit on the graphitic layer and to avoid unwanted changes of nanocrystal size and properties. PMID- 22220835 TI - Cautioning against causal alcohol-cardiovascular assumptions. PMID- 22220836 TI - Spring open two-plus-two electron storage in a disulfide-strapped methyl viologen derivative. AB - The synthesis of a disulfide-strapped viologen derivative is described starting from 4,4'-bipyridinyl-3,3'-diol. The first two one-electron reduction potentials, as determined by cyclic voltammetry, occur at E(1/2) = -0.03 V and E(1/2) = -0.16 V vs Ag/AgCl. This is accompanied by two more well separated one-electron reductions at E(1/2) = -1.26 V and E(1/2) = -1.54 V vs Ag/AgCl and the breaking of the disulfide bridge. To alleviate electrostatic repulsion between the two thiolate ions the molecular system must twist or "spring open" to accommodate the final two electrons. PMID- 22220837 TI - A role for a single-stranded junction in RNA binding and specificity by the Tetrahymena group I ribozyme. AB - We have investigated the role of a single-stranded RNA junction, J1/2, that connects the substrate-containing P1 duplex to the remainder of the Tetrahymena group I ribozyme. Single-turnover kinetics, fluorescence anisotropy, and single molecule fluorescence resonance energy transfer studies of a series of J1/2 mutants were used to probe the sequence dependence of the catalytic activity, the P1 dynamics, and the thermodynamics of docking of the P1 duplex into the ribozyme's catalytic core. We found that A29, the center A of three adenosine residues in J1/2, contributes 2 orders of magnitude to the overall ribozyme activity, and double-mutant cycles suggested that J1/2 stabilizes the docked state of P1 over the undocked state via a tertiary interaction involving A29 and the first base pair in helix P2 of the ribozyme, A31.U56. Comparative sequence analysis of this group I intron subclass suggests that the A29 interaction sets one end of a molecular ruler whose other end specifies the 5'-splice site and that this molecular ruler is conserved among a subclass of group I introns related to the Tetrahymena intron. Our results reveal substantial functional effects from a seemingly simple single-stranded RNA junction and suggest that junction sequences may evolve rapidly to provide important interactions in functional RNAs. PMID- 22220838 TI - Dynamics of molecular rotors confined in two dimensions: transition from a 2D rotational glass to a 2D rotational fluid in a periodic mesoporous organosilica. AB - The motional behavior of p-phenylene-d(4) rotators confined within the 2D layers of a hierarchically ordered periodic mesoporous p-divinylbenzenesilica has been elucidated to evaluate the effects of reduced dimensionality on the engineered dynamics of artificial molecular machines. The hybrid mesoporous material, characterized by a honeycomb lattice structure, has arrays of alternating p divinylbenzene rotors and siloxane layers forming the molecularly ordered walls of the mesoscopic channels. The p-divinylbenzene rotors are strongly anchored between two adjacent siloxane sheets, so that the p-phenylene rotators are unable to experience translational diffusion and are allowed to rotate about only one fixed axis. Variable-temperature (2)H NMR experiments revealed that the p phenylene rotators undergo an exchange process between sites related by 180 degrees and a non-Arrhenius temperature dependence of the dynamics, with reorientational rates ranging from 10(3) to 10(8) Hz between 215 to 305 K. The regime of motion changes rapidly at about 280 K indicating the occurrence of a dynamical transition. The transition was also recognized by a steep change in the heat capacity at constant pressure. As a result of the robust lamellar architecture comprising the pore walls, the orientational dynamic disorder related to the phase transition is only realized in two dimensions within the layers, that is in the plane perpendicular to the channel axis. Thus, the aligned rotors that form the organic layers exhibit unique anisotropic dynamical properties as a result of the architecture's reduced dimensionality. The dynamical disorder restricted to two dimensions constitutes a highly mobile fluidlike rotational phase at room temperature, which upon cooling undergoes a transition to a more rigid glasslike phase. Activation energies of 5.9 and 9.5 kcal/mol respectively have been measured for the two dynamical regimes of rotation. Collectively, our investigation has led to the discovery of an orientationally disordered 2D rotational glass and its transition from rigid to soft at increasing temperature. The spectral narrowing observed in the (2)H NMR experiments at higher temperatures (310-420 K) is consistent with fast rotational dynamics, which remain anisotropic in nature within the robust lamellar architecture. This study suggests that exploiting reduced dimensionality in the design of solid-state artificial molecular machines and functional materials may yield access to behavior previously unrealized in 3D materials. PMID- 22220839 TI - Liquid triarylamines: the scope and limitations of Piers-Rubinsztajn conditions for obtaining triarylamine-siloxane hybrid materials. AB - New liquid triarylamine-siloxane hybrid materials are produced using the Piers Rubinsztajn reaction. Under mild conditions, liquid analogues of conventional and commonly crystalline triarylamines are easily synthesized from readily available or accessible intermediates. Using a diverse selection of triarylamines, we explored the effects of siloxane group and substitution pattern on the physical properties of these materials, and we have demonstrated that relatively large molecular liquids with desirable electrochemical properties can be produced. The interactions between the strongly Lewis acidic catalyst used for this transformation, tris(pentafluorophenyl)borane (BCF), and the Lewis basic triarylamine substrates were studied. Through UV-vis-NIR and (19)F NMR spectroscopy, we have proposed that the catalyst undergoes a reversible redox reaction with the substrates to produce a charge transfer complex. The formation of this charge transfer complex is sensitive to the oxidation potential of the triarylamine and can greatly affect the kinetics of the Piers-Rubinsztajn reaction. PMID- 22220840 TI - Split-face trial of CO(2) laser-induced ring abrasion and high-dose tacalcitol in the treatment of disseminated superficial actinic porokeratosis. PMID- 22220841 TI - Association of poly I:C RNA and plasmid DNA onto MnO nanorods mediated by PAMAM. AB - In this study, manganese oxide (MnO) nanorods and its association with polyamidoamine dendrimer (PAMAM) and macromolecular RNA were analyzed. Because manganese is found naturally in cells and tissues and binds proteins and nucleic acids, nanomaterials derived from manganese, such as first generation MnO, may have potential as a biocompatible delivery agent for therapeutic or diagnostic biomedical applications. Nucleic acids have a powerful influence over cell processes, such as gene transcription and RNA processing; however, macromolecular RNA is particularly difficult to stabilize as a nanoparticle and to transport across cell membranes while maintaining structure and function. PAMAM is a cationic, branching dendrimer known to form strong complexes with nucleic acids and to protect them from degradation and is also considered to be a cell penetrating material. There is currently much interest in polyinosinic:polycytidylic RNA (poly I:C) because of its potent and specific immunogenic properties and as a solo or combination therapy. In order to address this potential, here, as a first step, we used PAMAM to attach poly I:C onto MnO nanorods. Morphology of the MnO nanorods was examined by field emission scanning electron microscopy (FESEM) and their composition by energy dispersive X-ray microanalysis (EDX). Evidence was generated for RNA:PAMAM:MnO nanorod binding by a gel shift assay using gel electrophoresis, a sedimentation assay using UV spectroscopy, and zeta potential shifts using dynamic laser light scattering. The data suggest that RNA was successfully attached to the MnO nanorods using PAMAM, and this suggestion was supported by direct visualization of the ternary complexes with FESEM characterizations. In order to confirm that the associations were biocompatible and taken up by cells, MTT assays were carried out to assess the metabolic activity of HeLa cells after incubation with the complexes and appropriate controls. Subsequently, we performed transfection assays using PAMAM:MnO complexes with pDNA encoding a green fluorescent protein reporter gene instead of RNA. The results suggest that the complexes had minimal impact on metabolic activity and were readily taken up by cells, and the fluorescent protein was expressed. From the evidence, we conclude that complexes of PAMAM:MnO interact with nucleic acids to form associations that are well-tolerated and readily taken up by cells. PMID- 22220842 TI - Perceptions of soft tissue laser use in orthodontics. AB - OBJECTIVES: To compare attitudes of orthodontists, periodontists, and general dentists regarding the use of soft tissue lasers by orthodontists during the course of orthodontic treatment. MATERIALS AND METHODS: An analogous survey was developed to evaluate and compare the current opinions of a representative sample (n = 538) of orthodontists (61.3%), periodontists (24.3%), and general dentists (14.3%) regarding orthodontists' use of soft tissue lasers. RESULTS: The majority (84%) of orthodontists, periodontists, and general dentists regarded the use of a soft tissue laser by orthodontists as appropriate. When compared to orthodontists and general dentists, a lower percentage of periodontists indicated that soft tissue laser use by orthodontists was appropriate (P < .01). For each of the eight specific soft tissue laser procedures investigated, periodontists reported a significantly lower level of appropriateness than did orthodontists and general dentists (P < .01). Around 75% of the total sample believed that referral would not be affected by the use of soft tissue lasers by orthodontists. CONCLUSIONS: Orthodontists, periodontists, and general dentists differed in their opinions of the perceived appropriateness of soft tissue laser use by orthodontists, with periodontists reporting a lower level of appropriateness. Clinicians need to communicate effectively to ensure that orthodontic patients in need of adjunctive soft tissue surgery are treated to the accepted standard of care. PMID- 22220843 TI - Gummy smile and facial profile correction using miniscrew anchorage. AB - This case report describes the treatment of a case involving a skeletal Class II facial profile with a gummy smile. While treating a facial profile and a gummy smile, the outcome may not always be successful with orthodontic therapy alone. For this reason, surgical therapy is often chosen to gain an esthetic facial profile and a good smile. However, sometimes the patients reject surgical treatment and an alternative method must be considered. Skeletal anchorage systems such as miniscrews are now frequently used for correcting severe malocclusion that should be treated by surgical therapy. In this case report, we treated a skeletal Class II malocclusion with a convex profile and a gummy smile using miniscrews, which were placed in the upper posterior and anterior areas. The active treatment period was 3.5 years, and the patient's teeth continued to be stable after a retention period of 36 months. PMID- 22220846 TI - Re: New treatment modality for maxillary hypoplasia in cleft patients. Protraction facemask with miniplate anchorage. Angle Orthod.2010;80:595-603. By Baek SH, Kim KW, Choi JY. PMID- 22220848 TI - Gratitude and the academy. PMID- 22220851 TI - Role of the sintering temperature and doping level in the structural and spectral properties of Eu-doped nanocrystalline YVO4. AB - A sol-gel approach was employed to prepare nanosized YVO(4) nanopowders doped with Eu(3+) ions. Raw nanomaterials were thermally treated at 700-1000 degrees C for 3 h. X-ray diffraction (XRD) analysis demonstrated that single-phase nanopowders with high crystallite dispersion were obtained. Our studies were focused on relating the luminescence properties of the Eu(3+) dopant to the nanocrystallite (NC) size. Depending on the thermal treatment, the average NC size was calculated to range from 20 nm to 1.1 MUm. We have found that the size effect manifests mainly in the expansion of the cell volume and broadening of XRD peaks, as indicated by Rietveld analysis. Moreover, emission and excitation spectra, although typical for the Eu(3+) ions, demonstrated some degree of correlation with the calcination temperature and doping concentration. To explain these differences a detailed analysis of the luminescence spectra by the Judd Ofelt theory has been performed. PMID- 22220852 TI - Effect of deception and expected exercise duration on psychological and physiological variables during treadmill running and cycling. AB - Effects of deception and expected duration on the rating of perceived exertion (RPE), affect, and heart rate (HR) were examined during treadmill (n=12) and cycling (n=8) exercise. Participants completed three conditions: (1) 20 MIN exercise for 20 min, stop after 20 min; (2) 10 MIN-exercise for 10 min, in 10th min be told to exercise for 10 min more; and (3) UNKNOWN-no information about duration. Intensities were set at 70% and 65% of peak oxygen uptake for treadmill and cycling, respectively. RPE increased (treadmill) and affect decreased (treadmill and cycling) in the absence of changes in HR and oxygen uptake in the 10 MIN conditions. These changes suggest a disruption to a feed-forward/feedback system. The lower HR in the UNKNOWN conditions suggests a subconscious attempt to conserve energy when the duration of the exercise task is unknown. PMID- 22220853 TI - Formation of soluble hexanuclear neptunium(IV) nanoclusters in aqueous solution: growth termination of actinide(IV) hydrous oxides by carboxylates. AB - Complexation of Np(IV) with several carboxylates (RCOO(-); R = H, CH(3), or CHR'NH(2); R' = H, CH(3), or CH(2)SH) in moderately acidic aqueous solutions was studied by using UV-vis-NIR and X-ray absorption spectroscopy. As the pH increased, all investigated carboxylates initiated formation of water-soluble hexanuclear complexes, Np(6)(MU-RCOO)(12)(MU(3)-O)(4)(MU(3)-OH)(4), in which the neighboring Np atoms are connected by RCOO(-)syn-syn bridges and the triangular faces of the Np(6) octahedron are capped with MU(3)-O(2-)/MU(3)-OH(-). The structure information of Np(6)(MU-RCOO)(12)(MU(3)-O)(4)(MU(3)-OH)(4) in aqueous solution was extracted from the extended X-ray absorption fine structure data: Np O(2-) = 2.22-2.23 A (coordination number N = 1.9-2.2), Np-O(RCOO(-)) and Np-OH(-) = 2.42-2.43 A (N = 5.6-6.7 in total), Np...C(RCOO(-)) = 3.43 A (N = 3.3-3.9), Np...Np(neighbor) = 3.80-3.82 A (N = 3.6-4.0), and Np...Np(terminal) = 5.39-5.41 A (N = 1.0-1.2). For the simpler carboxylates, the gross stability constants of Np(6)(MU-RCOO)(12)(MU(3)-O)(4)(MU(3)-OH)(4) and related monomers, Np(RCOO)(OH)(2)(+), were determined from the UV-vis-NIR titration data: when R = H, log beta(6,12,-12) = 42.7 +/- 1.2 and log beta(1,1,-2) = 2.51 +/- 0.05 at I = 0.62 M and 295 K; when R = CH(3), log beta(6,12,-12) = 52.0 +/- 0.7 and log beta(1,1,-2) = 3.86 +/- 0.03 at I = 0.66 M and 295 K. PMID- 22220854 TI - p53 protein expression in chronic lymphocytic leukemia. AB - Alterations in the function of the p53 pathway are frequently described in chronic lymphocytic leukemia (CLL), mostly associated with deletion of 17p13 and/or mutations of the TP53 gene. In the present study, we investigated 103 CLLs for the impact of protein expression of full-length p53 and its isoforms beta and gamma. A strong correlation between deletions of 17p13 and an accumulation of full-length p53 protein was found and was associated with a worse outcome compared to CLL with normal p53 (treatment-free survival p < 0.001, overall survival p = 0.04). Interestingly, the relative expression levels between full length p53 protein and its isoforms beta and gamma were significantly altered in CLL even without deletions of 17p13, compared to normal B-cells (p = 0.005). Furthermore, CLLs with higher p53 protein ratios showed worse clinical courses compared to CLLs with lower p53 protein ratios. Taken together, the differential expression of p53 isoforms could disrupt the p53 response and contribute to CLL pathogenesis. PMID- 22220855 TI - Thromboprophylaxis, bleeding and post-operative prosthetic joint infection in total hip and knee arthroplasty: a comprehensive literature review. AB - INTRODUCTION: Concerns regarding risk versus benefit, that is, the possible impact of surgical-site bleeding on post-operative joint infections, have contributed to a continuing debate over recommendations for venous thromboembolism (VTE) prophylaxis in post-surgical orthopedic patients undergoing total hip and knee arthroplasty (THA/TKA). AREAS COVERED: A comprehensive literature search using MEDLINE covering the period 2004-2009 was conducted, and published studies that focused on THA and TKA and contained data applicable to thromboprophylaxis, post-surgical wound infection and bleeding are reviewed in this paper. The search strategy included various combinations of terms related to lower limb joint arthroplasty, anticoagulant drugs, post-operative bleeding and prosthetic joint infection (wound infection). Methodological constraints included failure in some studies to define an infection, variations among the studies in the definitions of bleeding and differences in the follow-up time for capturing infection and bleeding events. Despite this, this comprehensive review identified observational, 'real-world' data that can contribute in important ways to the existing evidence base. EXPERT OPINION: There are insufficient data to either confirm or refute the hypothesis that post-operative bleeding is a mediating pathophysiologic factor linking pharmacologic VTE prophylaxis to an increased risk for wound infection. Studies specifically designed to examine the interrelationship between thromboprophylaxis, bleeding and wound infections following THA/TKA are warranted. PMID- 22220856 TI - Clinical outcome analysis of male and female genital burn injuries: a 15-year experience at a level-1 burn center. AB - OBJECTIVES: The American Burn Association classifies a burn to the genitalia as a major injury. Isolated burns to the penis, scrotum or vulva are rare as a result of protection provided by the thighs and abdomen. Thus, burned genitalia represent an ominous sign of a more extensive total body surface area burn. METHODS: A retrospective analysis of consecutive patients admitted to a Level-1 Burn Unit with a burn involving the genitalia from January 1995 to December 2009 comprised the study population. RESULTS: A total of 393 patients of 5878 patients (6.7%) admitted to the Burn Unit suffered a burn involving the genitalia, including 253 males (64.4%) and 140 females (35.6%). The median total body surface area was 12% (range 1-100%), the most common cause of genital burn was scald (n = 246, 62.9%) and median length of stay was 9 days (range 1-472 days). A total of 269 patients (68.4%) were discharged to home from the hospital, and in hospital mortality was 20.9%. CONCLUSIONS: The typical profile for those sustaining a genital burn include younger patients (<=30 years-of-age), sustaining a median total body surface area burn of 12% from a scald injury, with extensive genitalia involvement. Length of stay for genital burns is usually extended and, as a result of concomitant injuries, is associated with a 20% in hospital death rate. PMID- 22220861 TI - QTL linkage mapping of zebra finch beak color shows an oligogenic control of a sexually selected trait. AB - Mate choice based on sexual ornaments can impose strong selection, which raises the question of how genetic variation in ornaments is maintained. One mechanism that has been proposed is genic capture. If ornament expression is influenced by general condition and condition is under polygenic control, selection will be inefficient in removing genetic variation. Here we analyze whether the genetic architecture of beak color in a population of zebra finches supports this hypothesis. Zebra finch beak color is commonly assumed to be under strong selection by mate choice, although some of the evidence is ambiguous. We show that beak redness has a heritability of 34% in our population and that it is strongly genetically correlated between the sexes, suggesting that it is largely controlled by the same genes in males and females. We mapped variation in beak redness based on 1404 single-nucleotide polymorphism (SNP) markers genotyped in a large pedigree. We find evidence for linkage on four chromosomes (Tgu1, Tgu5, Tgu13, Tgu21), which together explain a large part of the additive genetic variance. Our finding of genomic regions with major additive effects is not consistent with directional selection and genic capture, but rather suggests a role of antagonistic pleiotropy in maintaining genetic variation. PMID- 22220862 TI - Mating unplugged: a model for the evolution of mating plug (dis-)placement. AB - Mating plugs are male-derived structures that may impede female remating by physically obstructing the female genital tract. Although mating plugs exist in many taxa, the forces shaping their evolution are poorly understood. A male can clearly benefit if his mating plug secures his paternity. It is unclear, however, how plug efficacy can be maintained over evolutionary time in the face of counteracting selection on males' ability to remove any plugs placed by their rivals. Here, I present a game-theory model and a simulation model to address this problem. The models predict that evolutionarily stable levels of mating-plug efficacy should be high when (1) the number of mating attempts per female is low; (2) the sex ratio is male-biased, and (3) males are sperm-limited. I discuss these results in the light of empirical data. PMID- 22220860 TI - The QTN program and the alleles that matter for evolution: all that's gold does not glitter. AB - The search for the alleles that matter, the quantitative trait nucleotides (QTNs) that underlie heritable variation within populations and divergence among them, is a popular pursuit. But what is the question to which QTNs are the answer? Although their pursuit is often invoked as a means of addressing the molecular basis of phenotypic evolution or of estimating the roles of evolutionary forces, the QTNs that are accessible to experimentalists, QTNs of relatively large effect, may be uninformative about these issues if large-effect variants are unrepresentative of the alleles that matter. Although 20th century evolutionary biology generally viewed large-effect variants as atypical, the field has recently undergone a quiet realignment toward a view of readily discoverable large-effect alleles as the primary molecular substrates for evolution. I argue that neither theory nor data justify this realignment. Models and experimental findings covering broad swaths of evolutionary phenomena suggest that evolution often acts via large numbers of small-effect polygenes, individually undetectable. Moreover, these small-effect variants are different in kind, at the molecular level, from the large-effect alleles accessible to experimentalists. Although discoverable QTNs address some fundamental evolutionary questions, they are essentially misleading about many others. PMID- 22220863 TI - Sexual selection and the evolution of genital shape and complexity in water striders. AB - Animal genitalia show two striking but incompletely understood evolutionary trends: a great evolutionary divergence in the shape of genitalic structures, and characteristic structural complexity. Both features are thought to result from sexual selection, but explicit comparative tests are hampered by the fact that it is difficult to quantify both morphological complexity and divergence in shape. We undertake a comparative study of multiple nongenitalic and male genital traits in a clade of 15 water strider species to quantify complexity and shape divergence. We show that genital structures are more complex and their shape more divergent among species than nongenital traits. Further, intromittent genital traits are more complex and have evolved more divergently than nonintromittent genital traits. More importantly, shape and complexity of nonintromittent genital traits show correlated evolution with indices of premating sexual selection and intromittent genital traits with postmating sexual selection, suggesting that the evolution of different components of genital morphology are shaped independently by distinct forms of sexual selection. Our quantitative results provide direct comparative support for the hypothesis that sexual selection is associated with morphological complexity in genitalic traits and highlight the importance of quantifying morphological shape and complexity, rather than size in studies of genital evolution. PMID- 22220864 TI - Ploidally antagonistic selection maintains stable genetic polymorphism. AB - Understanding the maintenance of genetic variation in the face of selection remains a key issue in evolutionary biology. One potential mechanism for the maintenance of genetic variation is opposing selection during the diploid and haploid stages of biphasic life cycles universal among eukaryotic sexual organisms. If haploid and diploid gene expression both occur, selection can act in each phase, potentially in opposing directions. In addition, sex-specific selection during haploid phases is likely simply because male and female gametophytes/gametes tend to have contrasting life histories. We explored the potential for the maintenance of a stable polymorphism under ploidally antagonistic as well as sex-specific selection. Furthermore, we examined the role of the chromosomal location of alleles (autosomal or sex-linked). Our analyses show that the most permissible conditions for the maintenance of polymorphism occur under negative ploidy-by-sex interactions, where stronger selection for an allele in female than male diploids is coupled with weaker selection against the allele in female than male haploids. Such ploidy-by-sex interactions also promote allele frequency differences between the sexes. With constant fitness, ploidally antagonistic selection can maintain stable polymorphisms for autosomal and X linked genes but not for Y-linked genes. We discuss the implications of our results and outline a number of biological settings where the scenarios modeled may apply. PMID- 22220865 TI - Sexual selection without sexual dimorphism: Bateman gradients in a simultaneous hermaphrodite. AB - One of the most general patterns in sexual selection is stronger selection on mating activity in males than in females. This asymmetry is thought to result from the higher energetic cost of producing one female compared to one male gamete (anisogamy). However, most studies focused on gonochoric species with strong sexual dimorphism, in which males and females are necessarily under different selection regimes. The question remains whether anisogamy alone would suffice to produce such differences. In simultaneous hermaphrodites one can compare sexual selection on the male and female functions in the absence of sexual dimorphism. Here we quantify sexual selection in the hermaphroditic freshwater snail Physa acuta under laboratory conditions. We combine exhaustive behavioral records of mating activity in mating groups and molecular paternity assignment to measure the mating success and reproductive success of 120 individuals. Our results validate the prediction of stronger selection to gain mating partners in the male than in the female function. Moreover, we did not detect cross-sex effects on fitness, or correlations between male and female production of offspring over the course of our experiment. We conclude that with respect to sexual selection P. acuta is comparable to gonochorists, confirming that anisogamy is a sufficient explanation for the differences in sexual selection regimes between sexes. PMID- 22220866 TI - Experimental evolution of the Caenorhabditis elegans sex determination pathway. AB - Sex determination is a critical developmental decision with major ecological and evolutionary consequences, yet a large variety of sex determination mechanisms exist and we have a poor understanding of how they evolve. Theoretical and empirical work suggest that compensatory adaptations to mutations in genes involved in sex determination may play a role in the evolution of these pathways. Here, we directly address this problem using experimental evolution in Caenorhabditis elegans lines fixed for a pair of mutations in two key sex determining genes that jointly render sex determination temperature-sensitive and cause intersexual (but still weakly to moderately fertile) phenotypes at intermediate temperatures. After 50 generations, evolved lines clearly recovered toward wild-type phenotypes. However, changes in transcript levels of key sex determining genes in evolved lines cannot explain their partially (or in some cases, nearly completely) rescued phenotypes, implying that wild-type phenotypes can be restored independently of the transcriptional effects of these mutations. Our findings highlight the microevolutionary flexibility of sex determination pathways and suggest that compensatory adaptation to mutations can elicit novel and unpredictable evolutionary trajectories in these pathways, mirroring the phylogenetic diversity, and macroevolutionary dynamics of sex determination mechanisms. PMID- 22220867 TI - Does genetic diversity reduce sibling competition? AB - An enduring hypothesis for the proximal benefits of sex is that recombination increases the genetic variation among offspring and that this genetic variation increases offspring performance. A corollary of this hypothesis is that mothers that mate multiply increase genetic variation within a clutch and gain benefits due to genetic diversity alone. Many studies have demonstrated that multiple mating can increase offspring performance, but most attribute this increase to sexual selection and the role of genetic diversity has received less attention. Here, we used a breeding design to generate populations of full-siblings, half siblings, and unrelated individuals of the solitary ascidian Ciona intestinalis. Importantly, we preclude the potentially confounding influences of maternal effects and sexual selection. We found that individuals in populations with greater genetic diversity had greater performance (metamorphic success, postmetamorphic survival, and postmetamorphic size) than individuals in populations with lower genetic diversity. Furthermore, we show that by mating with multiple males and thereby increasing genetic variation within a single clutch of offspring, females gain indirect fitness benefits in the absence of mate-choice. Our results show that when siblings are likely to interact, genetic variation among individuals can decrease competition for resources and generate substantial fitness benefits within a single generation. PMID- 22220868 TI - Human actuarial aging increases faster when background death rates are lower: a consequence of differential heterogeneity? AB - Many analyses of human populations have found that age-specific mortality rates increase faster across most of adulthood when overall mortality levels decline. This contradicts the relationship often expected from Williams' classic hypothesis about the effects of natural selection on the evolution of senescence. More likely, much of the within-species difference in actuarial aging is not due to variation in senescence, but to the strength of filters on the heterogeneity of frailty in older survivors. A challenge to this differential frailty hypothesis was recently posed by an analysis of life tables from historical European populations and traditional societies that reported variation in actuarial aging consistent with Williams' hypothesis after all. To investigate the challenge, we reconsidered those cases and aging measures. Here we show that the discrepancy depends on Ricklefs' aging rate measure, omega, which decreases as mortality levels drop because it is an index of mortality level itself, not the rate of increase in mortality with age. We also show unappreciated correspondence among the parameters of Gompertz-Makeham and Weibull survival models. Finally, we compare the relationships among mortality parameters of the traditional societies and the historical series, providing further suggestive evidence that differential heterogeneity has strong effects on actuarial aging. PMID- 22220869 TI - Optimal lineage principle for age-structured populations. AB - We present a formulation of branching and aging processes that allows age distributions along lineages to be studied within populations, and provides a new interpretation of classical results in the theory of aging. We establish a variational principle for the stable age distribution along lineages. Using this optimal lineage principle, we show that the response of a population's growth rate to age-specific changes in mortality and fecundity--a key quantity that was first calculated by Hamilton--is given directly by the age distribution along lineages. We apply our method also to the Bellman-Harris process, in which both mother and progeny are rejuvenated at each reproduction event, and show that this process can be mapped to the classic aging process such that age statistics in the population and along lineages are identical. Our approach provides both a theoretical framework for understanding the statistics of aging in a population, and a new method of analytical calculations for populations with age structure. We discuss generalizations for populations with multiple phenotypes, and more complex aging processes. We also provide a first experimental test of our theory applied to bacterial populations growing in a microfluidics device. PMID- 22220870 TI - A new phylogenetic method for identifying exceptional phenotypic diversification. AB - Currently available phylogenetic methods for studying the rate of evolution in a continuously valued character assume that the rate is constant throughout the tree or that it changes along specific branches according to an a priori hypothesis of rate variation provided by the user. Herein, we describe a new method for studying evolutionary rate variation in continuously valued characters given an estimate of the phylogenetic history of the species in our study. According to this method, we propose no specific prior hypothesis for how the variation in evolutionary rate is structured throughout the history of the species in our study. Instead, we use a bayesian Markov Chain Monte Carlo approach to estimate evolutionary rates and the shift point between rates on the tree. We do this by simultaneously sampling rates and shift points in proportion to their posterior probability, and then collapsing the posterior sample into an estimate of the parameters of interest. We use simulation to show that the method is quite successful at identifying the phylogenetic position of a shift in the rate of evolution, and that estimated rates are asymptotically unbiased. We also provide an empirical example of the method using data for Anolis lizards. PMID- 22220871 TI - How do geological sampling biases affect studies of morphological evolution in deep time? A case study of pterosaur (Reptilia: Archosauria) disparity. AB - A fundamental contribution of paleobiology to macroevolutionary theory has been the illumination of deep time patterns of diversification. However, recent work has suggested that taxonomic diversity counts taken from the fossil record may be strongly biased by uneven spatiotemporal sampling. Although morphological diversity (disparity) is also frequently used to examine evolutionary radiations, no empirical work has yet addressed how disparity might be affected by uneven fossil record sampling. Here, we use pterosaurs (Mesozoic flying reptiles) as an exemplar group to address this problem. We calculate multiple disparity metrics based upon a comprehensive anatomical dataset including a novel phylogenetic correction for missing data, statistically compare these metrics to four geological sampling proxies, and use multiple regression modeling to assess the importance of uneven sampling and exceptional fossil deposits (Lagerstatten). We find that range-based disparity metrics are strongly affected by uneven fossil record sampling, and should therefore be interpreted cautiously. The robustness of variance-based metrics to sample size and geological sampling suggests that they can be more confidently interpreted as reflecting true biological signals. In addition, our results highlight the problem of high levels of missing data for disparity analyses, indicating a pressing need for more theoretical and empirical work. PMID- 22220872 TI - Extinction, ecological opportunity, and the origins of global snake diversity. AB - Snake diversity varies by at least two orders of magnitude among extant lineages, with numerous groups containing only one or two species, and several young clades exhibiting exceptional richness (>700 taxa). With a phylogeny containing all known families and subfamilies, we find that these patterns cannot be explained by background rates of speciation and extinction. The majority of diversity appears to derive from a radiation within the superfamily Colubroidea, potentially stemming from the colonization of new areas and the evolution of advanced venom-delivery systems. In contrast, negative relationships between clade age, clade size, and diversification rate suggest the potential for possible bias in estimated diversification rates, interpreted by some recent authors as support for ecologically mediated limits on diversity. However, evidence from the fossil record indicates that numerous lineages were far more diverse in the past, and that extinction has had an important impact on extant diversity patterns. Thus, failure to adequately account for extinction appears to prevent both rate- and diversity-limited models from fully characterizing richness dynamics in snakes. We suggest that clade-level extinction may provide a key mechanism for explaining negative or hump-shaped relationships between clade age and diversity, and the prevalence of ancient, species-poor lineages in numerous groups. PMID- 22220873 TI - Diversification and biogeographic patterns in four island radiations of passerine birds. AB - Declining diversification rates over time are a well-established evolutionary pattern, often interpreted as indicating initial rapid radiation with filling of ecological niche space. Here, we test the hypothesis that island radiations may show constant net diversification rates over time, due to continued expansion into new niche space in highly dispersive taxa. We investigate diversification patterns of four passerine bird families originating from the Indo-Pacific archipelagos, and link these to biogeographic patterns to provide independent indications of niche filling. We find a declining diversification rate for only one family, the Paradisaeidae (41 species). These are almost completely restricted to New Guinea, and have on average smaller species ranges and higher levels of species richness within grid cells than the other three families. In contrast, we cannot reject constant diversification rates for Campephagidae (93 species), Oriolidae (35 species), and Pachycephalidae (53 species), groups that have independently colonized neighboring archipelagos and continents. We propose that Paradisaeidae have reached the diversity limit imposed by their restricted distribution, whereas high dispersal and colonization success across the geologically dynamic Indo-Pacific archipelagos may have sustained high speciation rates for the other three families. Alternatively, increasing extinction rates may have obscured declining speciation rates in those three phylogenies. PMID- 22220874 TI - Large brains buffer energetic effects of seasonal habitats in catarrhine primates. AB - Ecological factors have been shown to be important for brain size evolution. In this comparative study among catarrhine primates, we examine two different ways in which seasonality may be related to brain size. First, seasonality may impose energetic constraints on the brain because it forces animals to deal with periods of food scarcity (Expensive Brain hypothesis). Second, seasonality may act as a selective pressure to increase brain size, as behavioral flexibility helps to overcome periods of food scarcity (Cognitive Buffer hypothesis). Controlling for phylogeny, we found a strong negative relationship between brain size (relative to body mass) and the degree of experienced seasonality, as estimated by the variation in net energy intake. However, we also found a significant positive relationship between relative brain size and the effect of so-called cognitive buffering, proxied by the difference between environmental seasonality and the seasonality in net energy intake actually experienced by the animals. These results show that both energetic constraints of seasonal habitats as well as cognitive buffering affect brain size evolution, leaving environmental seasonality uncorrelated to brain size. With this study we show the importance of simultaneously considering both costs and benefits in models of brain size evolution. PMID- 22220875 TI - Accessory costs of seed production and the evolution of angiosperms. AB - Accessory costs of reproduction frequently equal or exceed direct investment in offspring, and can limit the evolution of small offspring sizes. Early angiosperms had minimum seed sizes, an order of magnitude smaller than their contemporaries. It has been proposed that changes to reproductive features at the base of the angiosperm clade reduced accessory costs thus removing the fitness disadvantage of small seeds. We measured accessory costs of reproduction in 25 extant gymnosperms and angiosperms, to test whether angiosperms can produce small seeds more economically than gymnosperms. Total accessory costs scaled isometrically to seed mass for angiosperms but less than isometrically for gymnosperms, so that smaller seeds were proportionally more expensive for gymnosperms to produce. In particular, costs of abortions and packaging structures were significantly higher in gymnosperms. Also, the relationship between seed:ovule ratio and seed size was negative in angiosperms but positive in gymnosperms. We argue that the carpel was a key evolutionary innovation reducing accessory costs in angiosperms by allowing sporophytic control of pre- and postzygotic mate selection and timing of resource allocation. The resulting reduction in costs of aborting unfertilized ovules or genetically inferior embryos would have lowered total reproductive costs enabling early angiosperms to evolve small seed sizes and short generation times. PMID- 22220876 TI - The promiscuous and the chaste: frequent allopolyploid speciation and its genomic consequences in American daisies (Melampodium sect. Melampodium; Asteraceae). AB - Polyploidy, an important factor in eukaryotic evolution, is especially abundant in angiosperms, where it often acts in concert with hybridization to produce allopolyploids. The application of molecular phylogenetic techniques has identified the origins of numerous allopolyploids, but little is known on genomic and chromosomal consequences of allopolyploidization, despite their important role in conferring divergence of allopolyploids from their parental species. Here, using several plastid and nuclear sequence markers, we clarify the origin of tetra- and hexaploids in a group of American daisies, allowing characterization of genome dynamics in polyploids compared to their diploid ancestors. All polyploid species are allopolyploids. Among the four diploid gene pools, the propensity for allopolyploidization is unevenly distributed phylogenetically with a few species apparently more prone to participate, but the underlying causes remain unclear. Polyploid genomes are characterized by differential loss of ribosomal DNA loci (5S and 35S rDNA), known hotspots of chromosomal evolution, but show genome size additivity, suggesting limited changes beyond those affecting rDNA loci or the presence of processes counterbalancing genome reduction. Patterns of rDNA sequence conversion and provenance of the lost loci are highly idiosyncratic and differ even between allopolyploids of identical parentage, indicating that allopolyploids deriving from the same lower-ploid parental species can follow different evolutionary trajectories. PMID- 22220877 TI - Can reinforcement complete speciation? AB - Hybridization is common in nature, even between "good" species. This observation poses the question of why reinforcement is not always successful in leading to the evolution of complete reproductive isolation. To study this question, we developed a new "quasi-linkage disequilibrium" (QLD) approximation to obtain the first analytic results for the evolution of modifiers that increase mate discrimination against hybrids and heterospecifics. When such modifiers have small effects, they evolve more readily under a one-allele than a two-allele mechanism (sensu Felsenstein 1981). The strength of selection on the modifier decreases as hybrids decrease in frequency, and so further reinforcement may not occur once hybridization is sufficiently rare. The outcome is qualitatively different when modifiers have large effects, however, for example, when a single mutation can cause complete reproductive isolation. In this case, modifiers in a two-allele mechanism can be selected as or more strongly than those in a one allele mechanism. Furthermore, they can spread under quite general conditions. Thus, whether complete closure of genetic introgression by reinforcement occurs may depend on the size of effects that mutations have on the sensory systems used in mate choice. PMID- 22220878 TI - A test of hybrid growth disadvantage in wild, free-ranging species pairs of threespine stickleback (Gasterosteus aculeatus) and its implications for ecological speciation. AB - Ecological speciation is the evolution of reproductive isolation as a direct or indirect consequence of divergent natural selection. Reduced performance of hybrids in nature is thought to be an important process by which natural selection can favor the evolution of assortative mating and drive speciation. Benthic and limnetic sympatric species of threespine stickleback (Gasterosteus aculeatus) are adapted to alternative trophic niches (bottom browsing vs. open water planktivory, respectively) and reduced feeding performance of hybrids is thought to have contributed to the evolution of reproductive isolation. We tested this "hybrid-disadvantage hypothesis" by inferring growth rates from otoliths sampled from wild, free-ranging benthic, limnetic, and hybrid sticklebacks in two lakes. There were significant differences in growth rate between lakes, life history stages, and among years (maximum P = 0.02), as well as interactions between most factors, but not between hybrid and parental species sticklebacks in most comparisons. Our results provide little evidence of a growth disadvantage in hybrid sticklebacks when free-ranging in nature. Although trophic ecology per se may contribute less to ecological speciation than envisioned, it may act in concert with other aspects of stickleback biology, such as interactions with parasites, predators, competitors, and/or sexual selection, to present strong multifarious selection against hybrids. PMID- 22220879 TI - Do larval traits re-evolve? Evidence from the embryogenesis of a direct developing salamander, Plethodon cinereus. AB - Recent molecular phylogenies suggest the surprising reacquisition of posthatching metamorphosis within an otherwise direct-developing clade of lungless salamanders (family Plethodontidae). Metamorphosis was long regarded as plesiomorphic for plethodontids, yet the genus Desmognathus, which primarily includes metamorphosing species, is now nested within a much larger clade of direct developing species. The extent to which the putative reacquisition of metamorphosis in Desmognathus represents a true evolutionary reversal is contingent upon the extent to which both larva-specific features and metamorphosis were actually lost during the evolution of direct development. In this study we analyze development of the hyobranchial skeleton, which is dramatically remodeled during salamander metamorphosis, in the direct-developing red-backed salamander, Plethodon cinereus. We find dramatic remodeling of the hyobranchial skeleton during embryogenesis in P. cinereus and the transient appearance of larva-specific cartilages. Hyobranchial development in this direct developing plethodontid is highly similar to that in metamorphosing plethodontids (e.g., Desmognathus). The proposed reacquisition of hyobranchial metamorphosis within Desmognathus does not represent the "re-evolution" of a lost phenotype, but instead the elaboration of an existing developmental sequence. PMID- 22220880 TI - Does phenotypic plasticity for adult size versus food level in Drosophila melanogaster evolve in response to adaptation to different rearing densities? AB - Recent studies with Drosophila have suggested that there is extensive genetic variability for phenotypic plasticity of body size versus food level. If true, we expect that the outcome of evolution at very different food levels should yield genotypes whose adult size show different patterns of phenotypic plasticity. We have tested this prediction with six independent populations of Drosophila melanogaster kept at extreme densities for 125 generations. We found that the phenotypic plasticity of body size versus food level is not affected by selection or the presence of competitors of a different genotype. However, we document increasing among population variation in phenotypic plasticity due to random genetic drift. Several reasons are explored to explain these results including the possibility that the use of highly inbred lines to make inferences about the evolution of genetically variable populations may be misleading. PMID- 22220881 TI - Variation in offspring size with birth order in placental fish: a role for asymmetric sibling competition? AB - Asymmetric sibling competition arises when siblings with different competitive abilities share a limited resource. Such competition occurs in species with postnatal parental care and may also occur when mothers provision embryos between fertilization and birth (matrotrophy). We hypothesized that the combination of matrotrophy and the simultaneous provisioning of embryos in different stages of development (superfetation) leads to asymmetric competition between sibling embryos. Moreover, we expect the intensity of this competition to increase with the level of superfetation as high levels of superfetation result in greater temporal overlap between broods. This hypothesis predicts that offspring from early broods, which predominantly compete with less-developed siblings, will be larger at birth than offspring from later broods, which experience competition from more and less-developed siblings. Data on offspring size at birth from two populations of the highly matrotrophic fish, Heterandria formosa, and similar studies of poeciliid fish spanning a range of life histories are consistent with our hypothesis. Together these results suggest that sibling competition is a direct consequence of the evolution of matrotrophy and superfetation in poeciliid fish. PMID- 22220882 TI - Recent social history alters male courtship preferences. AB - Phenotypically plastic mating behavior may allow males to modify their reproductive behavior to suit the prevailing social conditions, but we do not know if males only react to immediate social stimuli or change their inherent mate preferences according to their social history. Here we examine the effect of social experiences on the subsequent reproductive behavior of male guppies under standard conditions, allowing us to distinguish the effect of past and immediate social conditions. Males experienced experimental conditioning periods during which they interacted with three females, either of variable size or of similar size. Females arrived either simultaneously or consecutively. In subsequent standard assays, only males that had experienced females of variable size preferentially courted large females. Further, males exposed to sequential female arrival courted subsequent females more vigorously than males that had experienced simultaneous female arrival. In contrast, males did not alter their coercive mating attempts in relation to their recent social history. These results demonstrate that males use past experiences to modify their subsequent reproductive behavior rather than reacting only to immediate stimuli, and reveal the sophisticated ways in which males alter their reproductive tactics to suit the social environment and maximize fitness across changing selective landscapes. PMID- 22220883 TI - Shift in diversification in sister-clade comparisons: a more powerful test. AB - Tests of shift in diversification associated with key innovations or directional environmental change can be performed with sister-clade comparisons. This approach is attractive because it does not require detailed phylogenetic information. I propose a new likelihood ratio test based on fitting two models of diversification. I show how this test differs from a previous likelihood ratio test based on the geometric distribution. With simulations from a wide range of situations, I show that the new test performs much better than this test and the traditional test by Slowinski and Guyer. The proposed test performs at least as well as the species richness contrast test that has been proposed by several authors in four versions. A power analysis with low number of pairs of sister clades showed that the new test could detect a shift in diversification with five or less pairs of sister clades, whereas the diversity contrast test cannot detect any shift in this situation. The former appears as more powerful than the latter, and therefore is recommended when the number of pairs of sister clades is low (less than 10). All other tests should not be used as the present study showed they lack statistical power and robustness. PMID- 22220884 TI - Fitness costs of rapid cold-hardening in Ceratitis capitata. AB - Rapid cold-hardening (RCH) is a unique form of phenotypic plasticity which confers survival advantages at low temperature. The fitness costs of RCH are generally poorly elucidated and are important to understanding the evolution of plastic physiology. This study examined whether RCH responses, induced by ecologically relevant diel temperature fluctuations, carry metabolic, survival, or fecundity costs. We predicted that potential costs in RCH would be manifested as differences in metabolic rate, fecundity, or survival in flies which have hardened versus those which have not, or flies that have experienced more RCH events would show greater costs than those which have experienced fewer events. One group of flies cooled to 10 degrees C for 2 h for 11 consecutive days experienced daily RCH (Hardened), whereas the other group exposed to 15 degrees C for the same 2-h period each day formed a Control group. Hardened flies had higher survival at -5 degrees C for 2 h than control flies (69 +/- 9% vs. 44 +/- 19%, P = 0.04). Hardened flies showed no metabolic or fecundity costs, but had reduced average survival (P = 0.0403). Thus, a major cost to repeated low temperature exposures in Ceratitis capitata is through direct mortality caused by chilling injury, although this appears not to be a direct cost of RCH. PMID- 22220885 TI - Cytotoxicity and hydrolysis of trans-Ti(IV) complexes of salen ligands: structure activity relationship studies. AB - Eleven bis(dimethylphenolato) Ti(IV) complexes of salen ligands with different steric and electronic properties due to different aromatic substituents at the ortho and para positions are reported, and their cytotoxicity toward HT-29 and OVCAR-1 cells and its dependence on hydrolytic behavior are discussed. Eight complexes of this series were analyzed by X-ray crystallography, confirming the trans geometry of the labile ligands with otherwise relatively similar coordination features to those of cis-salan analogues. Relatively high and similar hydrolytic stability is observed for all complexes, with t(1/2) values for labile ligand hydrolysis of 2-11 h in 10% D(2)O solutions. In contrast, varying cytotoxicities were achieved, identifying selected members as the first trans-Ti(IV) complexes reported as anticancer agents. Steric bulk all around the complex diminished the activity, where a complex with no aromatic substitutions is especially active and complexes substituted particularly at the ortho positions are mostly inactive, including ortho-halogenated and ortho-tert butylated, with one exception of the ortho-methoxylated complex demonstrating appreciable activity. In contrast, para-halogenation provided the complexes of highest cytotoxic activity in this series (IC(50) as low as 1.0 +/- 0.3 MUM), with activity exceeding that of cisplatin by up to 15-fold. Reaction of a representative complex with ortho-catechol yielded a "cis"-Ti(IV) complex following rearrangement of the salen ligand on the metal center, with highly similar coordination features and geometry to those of the catecholato salan analogues, suggesting that the complexes operate by similar mechanisms and rearrangement of the salen ligand may occur upon introduction of a suitable chelating target. In additional cytotoxicity measurements, a salen complex was preincubated in the biological medium for varying periods prior to cell addition, revealing that marked cytotoxicity of the salen complex is retained for longer preincubation periods relative to known Ti(IV) complexes, suggesting that the hydrolysis products may also induce cytotoxic effects, thus reducing stability concerns. PMID- 22220886 TI - Genetic variation for tolerance to acidic water in salmonids. AB - Water pH is an important factor affecting the general water quality as well as quality traits in fishes, and the magnitude of the effect varies among species. The massive and negative effect of acidification of rivers and lakes became evident during the 1960s and 1970s and caused the depletion of fish stocks in several countries in the northern hemisphere. Significant variation in tolerance to acidic water has been documented among salmonid species, and large genetic variation has been identified among strains of brown trout Salmo trutta, brook trout Salvelinus fontinalis and Atlantic salmon Salmo salar. For S. trutta, S. fontinalis and S. salar, there is considerable additive genetic variation in tolerance to acidic water, with heritabilities (h(2)) ranging from 0.09 to 0.27 for dead eyed-eggs (the period most sensitive to low pH). The main reasons for depletion of freshwater fish stocks are discussed. PMID- 22220887 TI - Similarity in parasite community structure may be used to trace latitudinal migrations of Odontesthes smitti along Argentinean coasts. AB - The aims of this study were to determine the existence of migratory movements and to identify ecological stocks of the silverside Odontesthes smitti along its distribution in the Southern Atlantic Ocean, using metazoan parasites as biological tags. Samples were obtained from San Jose Gulf (SJ) (42 degrees 25' S; 64 degrees 07' W) and Nuevo Gulf (NG) (42 degrees 47' S; 65 degrees 02' W) in north Patagonia during winter and summer and in waters off Mar del Plata (MDP) (38 degrees 03' S; 57 degrees 32' W), Bonaerense region, during winter. Fifteen parasite species were collected. Multivariate statistical procedures on parasite community data showed strong effect of host size on the structure of parasite assemblages. Taking into account the variations among samples due to host size, the differential structure of parasite communities between SJ and NG suggests that fish inhabiting these localities could belong to different ecological stocks. Fish from MDP and SJ caught in summer showed similar composition in their parasite assemblages, which is congruent with a migratory cycle that implies that fish caught in MDP during winter inhabit SJ during summer. Further evidence of the Patagonian origin of MDP O. smitti is the presence of the digenean Proctotrema bartolii in fish from both regions. Proctotrema bartolii is acquired by O. smitti only in the Magellanic province, where its intermediate host, Darina solenoides, is distributed. The analyses suggest that O. smitti inhabiting north Patagonian gulfs could belong to different ecological stocks and that O. smitti caught in MDP could have come from SJ. PMID- 22220888 TI - Dentition of eight species of Mediterranean Sea Gobiidae: do dentition characters of gobies reflect phylogenetic relationships? AB - Oral and pharyngeal dentition was analysed in eight Mediterranean species of five different genera using scanning electron microscopy (SEM). Number, position, shape and size of teeth in the jaws and the pharyngeal tooth plates were used as a basis for comparison among taxa. Three different groups could be established based on the dental morphology among the species investigated and homoplasy due to feeding ecology cannot be considered the reason for similarity among them. The established groups are suggested to reflect phylogenetic relationships and correspond with the scarce published data on the topic. PMID- 22220889 TI - Phenotypic variation and associated predation risk of juvenile common carp Cyprinus carpio. AB - Juvenile common carp Cyprinus carpio were collected from 10 lakes with variable predator abundance over 4 months to evaluate if morphological defences increased with increasing predation risk. Cyprinus carpio dorsal and pectoral spines were longer and body depth was deeper when predators were more abundant, with differences becoming more pronounced from July to October. To determine if morphological plasticity successfully reduced predation risk, prey selection of largemouth bass Micropterus salmoides foraging on deep- and shallow-bodied C. carpio was evaluated in open and vegetated environments. Predators typically selected deep- over shallow-bodied phenotypes in open habitats and neutrally selected both phenotypes in vegetated habitats. When exposed to predators, shallow-bodied C. carpio phenotypes shoaled in open habitat, whereas deep-bodied phenotypes occupied vegetation. Although deep-bodied phenotypes required additional handling time, shallow-bodied phenotypes were more difficult to capture. These results suggest that juvenile C. carpio gradually develop deeper bodies and larger spines as predation risk increases. Morphological defences made it more difficult for predators to consume these prey but resulted in higher vulnerability to predation in some instances. PMID- 22220890 TI - Phylogeography of isolated freshwater three-spined stickleback Gasterosteus aculeatus populations in the Adriatic Sea basin. AB - Analyses of mitochondrial (mt) DNA and microsatellite variation were carried out to examine the relationships between 10 freshwater populations of three-spined sticklebacks Gasterosteus aculeatus along the eastern coast of the Adriatic Sea. Partial sequences of the mtDNA control region and cytochrome b gene, in addition to 15 microsatellite loci, were used to analyse populations from four isolated river catchments. Results uncovered an Adriatic lineage that was clearly divergent from the European lineage, and confirmed that the most divergent and ancient populations are located within the Adriatic lineage as compared with other European populations. Two northern Adriatic populations formed independent clades within the European mitochondrial lineage, suggesting different colonization histories of the different Adriatic populations. Nuclear marker analyses also indicated deep divergence between Adriatic and European populations, albeit with some discordance between the mtDNA phylogeny of the northern Adriatic populations, further highlighting the strong differentiation among the Adriatic populations. The southern populations within the Adriatic lineage were further organized into distinct clades corresponding to respective river catchments and sub-clades corresponding to river tributaries, reflecting a high degree of population structuring within a small geographic region, concurrent with suggestions of existence of several microrefugia within the Balkan Peninsula. The highly divergent clades and haplotypes unique to the southern Adriatic populations further suggest, in accordance with an earlier, more limited survey, that southern Adriatic populations represent an important reservoir for ancient genetic diversity of G. aculeatus. PMID- 22220891 TI - Ontogenetic scaling of the morphology and biomechanics of the feeding apparatus in the Pacific hagfish Eptatretus stoutii. AB - The form and function of the support skeleton, musculature and teeth were examined in an ontogenetic series of Pacific hagfish Eptatretus stoutii spanning about a six-fold range in total length (L(T)). Tooth area, feeding apparatus length, basal plate size, theoretical dental plate retractile force, penetration force and applied tooth stress were measured relative to body size. Morphological variables (e.g. tooth area and basal plate size) scaled with positive allometry and functional variables (e.g. retractile force and applied tooth stress) scaled isometrically with L(T). These results suggest that juveniles do not undergo ontogenetic dietary changes and consume functionally equivalent prey to adults, although adults can grasp proportionally larger portions of food. Low tooth stress in juveniles and adults imposes mechanical constraints to puncturing and tearing, which are circumvented by a preference for softer prey tissue or the inclusion of knotting behaviours for reducing tougher prey. PMID- 22220892 TI - Spatial-temporal expression of pum1 and pum2 in medaka Oryzias latipes. AB - Two pumilios, pum1 and pum2, were identified in medaka Oryzias latipes. Oryzias latipes pum1 and pum2 are ubiquitous in the adult tissues but with specific expression in the germ cells of gonads, ovary and testis. Pum1 is expressed in the spermatogonia to spermatocytes whilst pum2 presents in spermatocytes of testis only. Oryzias latipes pum1 and pum2 are maternally supplied RNA with ubiquitous expression in the early stages, and embryonic expression of pum1 and pum2 may begin from early gastrula. Both pum1 and pum2 are expressed in the tissues including brain, eye and trunk, and both are expressed in the gonads after hatching. Taken together, Pum1 and Pum2 may play important roles in embryonic and germ cell development of O. latipes. PMID- 22220893 TI - A phylogeny of the temperate seabasses (Moronidae) characterized by a translocation of the mt-nd6 gene. AB - The entire mitochondrial genome of the striped bass Morone saxatilis was sequenced together with the mitochondrial (mt) control regions of the white bass Morone chrysops, white perch Morone americana, yellow bass Morone mississippiensis, spotted seabass Dicentrarchus punctatus, European seabass Dicentrarchus labrax and the Japanese seabass Lateolabrax japonicus. The resultant 17 580 base pair circular genome of M. saxatilis contains 38 genes (13 proteins, 23 transfer RNAs and two ribosomal RNAs) and a control region bordered by the proline and phenylalanine mitochondrial tRNAs. Gene arrangement was similar to other vertebrates, except that the mt-nd6 gene was found within the control region rather than the canonical position between the mt-nd5 and mt-cyb genes. This translocation was found in all the Morone and Dicentrarchus species studied without functional copies or pseudogenes in the ancestral position. In L. japonicus, the mt-nd6 gene was found in the canonical position without evidence of an mt-nd6 gene in the control region. A Bayesian analysis of these and published mt-nd6 sequences from 45 other Perciformes grouped the Morone and Dicentrarchus species monophyletically with a probability of 1.00 with respect to L. japonicus and all other perciforms, and placed the Dicentrarchus species in the basal position. These data reinforce current placement of L. japonicus outside the Moronidae and provide a clear evolutionary character to define this family. The phylogeny of the Moronidae presented here also supports the hypothesis of an anadromous common ancestor to this family that gave rise to the North American estuarine and freshwater species. A series of tandem repeats previously reported in M. saxatilis was found in the control region of all Morone species between the mt-nd6 and mt-rnr1 genes, but not in either Dicentrarchus species, which reinforces the continued use of these two separate genera. PMID- 22220894 TI - Reduction of sexual dimorphism in stream-resident forms of three-spined stickleback Gasterosteus aculeatus. AB - Sexual dimorphism in geometric body shape and external morphology was compared between marine and stream-resident forms of three-spined stickleback Gasterosteus aculeatus collected from North America and Japan. Some aspects of sexual dimorphism were shared between ecotypes: males had larger heads than females with no significant effect of ecotype on the magnitude of sexual dimorphism. By contrast, a significant sex-by-ecotype interaction was found for body depth. Males tended to have deeper bodies than females in both forms, but the magnitude of sexual dimorphism was reduced in stream-resident forms. Although females were generally larger in standard length and had larger pelvic girdles, significant sexual dimorphism in these traits was not consistently found across populations or ecotypes. These results suggest that some aspects of sexual dimorphism were shared between ecotypes, while others were unique to each population. The results further suggest that ecology may influence the evolution of sexual dimorphism in some external morphological traits, such as body depth. PMID- 22220895 TI - Male primer endocrine responses to preovulatory female cyprinids under natural conditions in Sweden. AB - This study investigated two related aspects of male-female reproductive interactions in the family Cyprinidae: (1) whether ovulating female rudd Scardinius erythrophthalmus (subfamily Leuciscinae) induce endocrine and gonadal priming responses in conspecific males, a phenomenon which has been described only in species from the subfamily Cyprininae such as goldfish, Carassius auratus, crucian carp Carassius carassius and common carp, Cyprinus carpio and (2) whether the stimuli mediating these responses are species-specific. Field studies of three sympatric European cyprinids, two leuciscins (S. erythrophthalmus and white bream Blicca bjoerkna) and one cyprinin (C. carassius), were conducted on fishes captured in Sweden in the spawning season and held in net pens under natural conditions. As previously reported in C. carassius, male S. erythrophthalmus increased milt (sperm and seminal fluid) volume and plasma concentrations of the sperm maturation hormone 4-pregnen 17,20beta-diol-3-one (17,20beta-P) when they were held with female S. erythrophthalmus induced to ovulate by injection of Ovaprim (GnRH analogue plus dopamine antagonist). Male S. erythrophthalmus had larger milt volumes than male C. carassius prior to and following exposure to ovulatory conspecifics, but exhibited a smaller proportional milt increase in response to stimulation, suggesting species differences in sperm allocation at spawning. The presence of female S. erythrophthalmus and B. bjoerkna did not affect milt volumes of C. carassius under two experimental conditions: (1) ovulating S. erythrophthalmus and B. bjoerkna did not increase the milt volumes of C. carassius and (2) S. erythrophthalmus and B. bjoerkna did not interfere with the milt volume increase induced in male C. carassius by ovulating conspecifics. These results suggest that, as in C. auratus, C. carassius and C. carpio (subfamily Cyprininae), female S. erythrophthalmus (subfamily Leuciscinae) release a preovulatory pheromone that exerts priming effects on male hormones and sperm allocation. The findings also indicate that C. carassius discriminate between the reproductive odours of conspecifics and heterospecifics. PMID- 22220896 TI - Does the cylinder model of gastric evacuation predict observed evacuation of mixed meals of prey of contrasting geometries in a piscivorous fish? AB - The simple surface abstraction of the cylinder model (each prey as well as the total stomach contents is considered a cylinder that is gradually reduced by successive peeling off its curved side) was challenged by data on evacuation of a meal composed of three sandeels Ammodytes tobianus and a dab Limanda limanda fed to Atlantic cod Gadus morhua. While the body shape of A. tobianus comes close to that of a cylinder, the flatfish L. limanda takes a discoid form. As opposed to a modified form of the cylinder model, where the contrasting geometries of the fish prey were implemented, the simple, original cylinder model held the potential to predict evacuation of the individual prey types as well as the total stomach contents. Thus, the present study adds significantly to the increasing evidence that points to the generic nature of the model and its implicit square root function. Also, the present study corroborated a basic assumption that the variability of evacuation data not accounted for by the cylinder model primarily can be ascribed to the intraspecific variation in gastric performance of the predator. PMID- 22220897 TI - Individual genetic tagging for teleosts: an empirical validation and a guideline for ecologists. AB - The efficiency of individual genetic tagging was determined by using passive integrated transponders (PIT) as a comparative conventional tagging method. Fifty five common dace Leuciscus leuciscus were captured in the wild, PIT tagged and fin clipped (for DNA analysis). Thirty fish were recaptured on three occasions and tissue samples were collected. Using 18 microsatellite loci, 79-94% of the recaptures were correctly assigned. Experience with scoring L. leuciscus microsatellites led to more individuals correctly assigned. Allowing matches that differed by one or two alleles resulted in 100% of all recaptures successfully assigned irrespective of the observer. Reducing the set of loci to five to six loci appropriately selected did not affect the assignment rate, demonstrating that costs can be subsequently reduced. Despite their potential benefits, the application of genetic tags for teleosts has been limited. Here, it was demonstrated that genetic tagging could be applied, and a clear guideline (flowchart) is provided on how this method can be developed for teleosts and other organisms, with subsequent practical applications to ecology, evolutionary biology and conservation management. PMID- 22220898 TI - The effects of turbidity, prey density and environmental complexity on the feeding of juvenile Murray cod Maccullochella peelii. AB - Juvenile Murray cod Maccullochella peelii exhibited a type II functional response while preying on blackworms Lumbriculus variegatus, and the parameters of the type II model did not differ significantly between clear (0 NTU) and turbid (150 NTU) treatments. Further experiments showed that vision may not be necessary for prey detection and capture by juvenile M. peelii; consumption of inanimate prey was not significantly different between light and dark (<1 * 10(-4) uE m(-2) s( 1)) trials. These results imply that the sensory physiology of M. peelii is well adapted to a turbid visual environment. In addition, habitat complexity increased the food consumption rate of juvenile M. peelii, perhaps by relaxing innate predator avoidance behaviours that depress foraging in more open environments. PMID- 22220899 TI - Genetic mixed-stock analysis of Atlantic sturgeon Acipenser oxyrinchus oxyrinchus in a heavily exploited marine habitat indicates the need for routine genetic monitoring. AB - Although a previous genetic mixed-stock analysis (gMSA) conducted in the early 1990s showed that marine-captured New York Bight Atlantic sturgeon Acipenser oxyrinchus oxyrinchus almost exclusively originated from the Hudson River, fish from southern U.S. rivers were well represented within this contemporary sample (n = 364 fish), at least during the autumn. Widely distributed spawning stocks are therefore exposed to heavy fishing activity and habitat degradation in this relatively small area, illustrating the need for spatial management across multiple management jurisdictions and routine gMSA to account for temporal change. PMID- 22220900 TI - Morphological, physiological and behavioural response patterns of carp gudgeon Hypseleotris spp. to food deprivation: implications for assessing health. AB - Morphological (growth, Fulton's condition factor), physiological (per cent dry mass, total lipid content) and behavioural (activity levels) response patterns of carp gudgeon Hypseleotris spp. were examined in response to food deprivation during a 56 day experiment. Considerable variability in the nature and magnitude of these response patterns was observed, suggesting that caution should be taken when interpreting changes in the health of small-bodied fishes based on individual response variables. PMID- 22220901 TI - Stable isotopes challenge the perception of ocean sunfish Mola mola as obligate jellyfish predators. AB - Evidence is provided from stable isotope analysis that aggregations of small ocean sunfish Mola mola (total length <1 m) feed broadly within coastal food webs and their classification as obligate predators of gelatinous zooplankton requires revision. PMID- 22220903 TI - Group IVA phospholipase A2 is necessary for growth cone repulsion and collapse. AB - The repellent semaphorin 3A (Sema3A) causes growth cone turning or collapse by triggering cytoskeletal rearrangements and detachment of adhesion sites. Growth cone detachment is dependent on eicosanoid activation of protein kinase C epsilon (PKCepsilon), but the characterization of the phospholipase A(2) (PLA(2) ) that releases arachidonic acid (AA) for eicosanoid synthesis has remained elusive. Here, we show, in rat dorsal root ganglion (DRG) neurons, that Sema3A stimulates PLA(2) activity, that Sema3A-induced growth cone turning and collapse are dependent on the release of AA, and that the primary PLA(2) involved is the group IV alpha isoform (GIVA). Silencing GIVA expression renders growth cones resistant to Sema3A-induced collapse, and GIVA inhibition reverses Sema3A-induced repulsion into attraction. These studies identify a novel, early step in Sema3A-signaling and a PLA(2) necessary for growth cone repulsion and collapse. PMID- 22220904 TI - Mixed polymer brushes with locking switching. AB - Mixed polymer brushes, made of two different kinds of polymers randomly grafted to the same solid substrate, were introduced as switchable interfaces for a number of promising applications. The switching properties of the mixed polymer brushes are substantially dependent on grafting density, molecular weight, compatibility of two distinct grafted polymers, and their interaction with the solvent. This work reports the mixed polymer brushes with the property of locking switching. The wetting properties of such a mixed brush can be switched between the wetting properties of individual constituting polymers by appropriate selection of solvent. However, the mixed polymer brushes wetting behavior can be locked in the hydrophobic state. This kinetically frozen methastable state, however, can be unlocked via treatment by proper "unlocking" solvent. This locking and unlocking of the hydrophobic state of the mixed brush with specific solvents could find useful applications for the development of functional materials. PMID- 22220906 TI - Application of an untargeted metabolomics approach for the identification of compounds that may be responsible for observed differential effects in chickens fed an organic and a conventional diet. AB - The aim of this study was to apply an untargeted NMR and LC-MS-based metabolomics approach to detect potential differences between an organically and a conventionally produced feed, which caused statistically significant differences in growth, in the response to an immunological challenge and in the gene expression profiles in the small intestine of laying hens. A fractionation procedure was set up to create multiple fractions of the feed, which were subsequently analysed by NMR and UPLC-TOF/MS operating in positive mode. Comparison of the profiles revealed that the most apparent differences came from the isoflavones in the soy as well as a compound with a molecular mass of 441.202 (M + 1)+, which was identified as N,N'-diferuloylputrescine (DFP) and came from the corn. Whether the observed differences in effects are due to the higher levels of isoflavones and DFP is unclear, as is the fact whether the observed differences are typical for organic or conventional produced corn and soy. However, this study shows that this metabolomics approach is suitable for detecting potential differences between products, even in levels of compounds that would have been overlooked with a more targeted approach. As such, the method is suitable for a more systematic study on differences between conventionally and organically produced food. PMID- 22220908 TI - Organic letters: now in the 21st century. PMID- 22220907 TI - The RGSGR amino acid motif of the intercellular signalling protein, HetN, is required for patterning of heterocysts in Anabaena sp. strain PCC 7120. AB - Nitrogen-fixing heterocysts are arranged in a periodic pattern on filaments of the cyanobacterium Anabaena sp. strain PCC 7120 under conditions of limiting combined nitrogen. Patterning requires two inhibitors of heterocyst differentiation, PatS and HetN, which work at different stages of differentiation by laterally suppressing levels of an activator of differentiation, HetR, in cells adjacent to source cells. Here we show that the RGSGR sequence in the 287 amino-acid HetN protein, which is shared by PatS, is critical for patterning. Conservative substitutions in any of the five amino acids lowered the extent to which HetN inhibited differentiation when overproduced and altered the pattern of heterocysts in filaments with an otherwise wild-type genetic background. Conversely, substitution of amino acids comprising the putative catalytic triad of this predicted reductase had no effect on inhibition or patterning. Deletion of putative domains of HetN suggested that the RGSGR motif is the primary component of HetN required for both its inhibitory and patterning activity, and that localization to the cell envelope is not required for patterning of heterocysts. The intercellular signalling proteins PatS and HetN use the same amino acid motif to regulate different stages of heterocyst patterning. PMID- 22220905 TI - Deregulation of the CXCL12/CXCR4 axis in methotrexate chemotherapy-induced damage and recovery of the bone marrow microenvironment. AB - Cancer chemotherapy disrupts the bone marrow (BM) microenvironment affecting steady-state proliferation, differentiation and maintenance of haematopoietic (HSC) and stromal stem and progenitor cells; yet the underlying mechanisms and recovery potential of chemotherapy-induced myelosuppression and bone loss remain unclear. While the CXCL12/CXCR4 chemotactic axis has been demonstrated to be critical in maintaining interactions between cells of the two lineages and progenitor cell homing to regions of need upon injury, whether it is involved in chemotherapy-induced BM damage and repair is not clear. Here, a rat model of chemotherapy treatment with the commonly used antimetabolite methotrexate (MTX) (five once-daily injections at 0.75 mg/kg/day) was used to investigate potential roles of CXCL12/CXCR4 axis in damage and recovery of the BM cell pool. Methotrexate treatment reduced marrow cellularity, which was accompanied by altered CXCL12 protein levels (increased in blood plasma but decreased in BM) and reduced CXCR4 mRNA expression in BM HSC cells. Accompanying the lower marrow CXCL12 protein levels (despite its increased mRNA expression in stromal cells) was increased gene and protein levels of metalloproteinase MMP-9 in bone and BM. Furthermore, recombinant MMP-9 was able to degrade CXCL12 in vitro. These findings suggest that MTX chemotherapy transiently alters BM cellularity and composition and that the reduced cellularity may be associated with increased MMP 9 expression and deregulated CXCL12/CXCR4 chemotactic signalling. PMID- 22220909 TI - Atom probe tomography characterization of thin copper layers on aluminum deposited by galvanic displacement. AB - "Ultrathin" metallization layers on the order of nanometers in thickness are increasingly used in semiconductor interconnects and other nanostructures. Aqueous deposition methods are attractive methods to produce such layers due to their low cost, but formation of ultrathin layers has proven challenging, particularly on oxide-coated substrates. This work focused on the formation of thin copper layers on aluminum, by galvanic displacement from alkaline aqueous solutions. Analysis by atom probe tomography (APT) showed that continuous copper films of approximately 1 nm thickness were formed, apparently the first demonstration of deposition of ultrathin metal layers on oxidized substrates from aqueous solutions. The APT reconstructions indicate that deposited copper replaced a portion of the surface oxide film on aluminum. The results are consistent with mechanisms in which surface hydride species on aluminum mediate deposition, either by directly reducing cupric ions or by inducing electronic conduction in the oxide, thus enabling cupric ion reduction by Al metal. PMID- 22220910 TI - It was the best of times, it was the worst of times: a psychophysiologist's view of cognitive aging. AB - This paper reviews research on age-related changes in working memory and attention control. This work is interpreted within a framework labeled "GOLDEN aging" (growing of lifelong differences explains normal aging), which is based on the idea that normal aging (as opposed to pathological aging) represents maturational processes causing progressive shifts in the distributions of mental abilities over the lifespan. As such, brain phenomena observed in normal aging are already apparent, under appropriate conditions, in younger adults. Among the phenomena that can be interpreted according to the GOLDEN aging framework are reductions in working memory capacity, impairments of inhibitory processes, increases in frontal lobe activation, and lack of suppression of responses as a function of repetition. PMID- 22220911 TI - Fingerprinting TCE in a bedrock aquifer using compound-specific isotope analysis. AB - A dual isotope approach based on compound-specific isotope analysis (CSIA) of carbon (C) and chlorine (Cl) was used to identify sources of persistent trichloroethylene (TCE) that caused the shut-down in 1994 of a municipal well in an extensive fractured dolostone aquifer beneath Guelph, Ontario. Several nearby industrial properties have known subsurface TCE contamination; however, only one has created a comprehensive monitoring network in the bedrock. The impacted municipal well and many monitoring wells were sampled for volatile organic compounds (VOCs), inorganic parameters, and CSIA. A wide range in isotope values was observed at the study site. The TCE varies between -35.60/00 and -21.80/00 and from 1.60/00 to 3.20/00 for delta(13) C and delta(37) Cl, respectively. In case of cis-1,2-dichloroethene, the isotope values range between -36.30/00 and 18.90/00 and from 2.40/00 to 4.70/00 for delta(13) C and delta(37) Cl, respectively. The dual isotope approach represented by a plot of delta(13) C vs. delta(37) Cl shows the municipal well samples grouped in a domain clearly separate from all other samples from the property with the comprehensive well network. The CSIA results collected under non-pumping and short-term pumping conditions thus indicate that this particular property, which has been studied intensively for several years, is not a substantial contributor of the TCE presently in the municipal well under non-pumping conditions. This case study demonstrates that CSIA signatures would have been useful much earlier in the quest to examine sources of the TCE in the municipal well if bedrock monitoring wells had been located at several depths beneath each of the potential TCE contributing properties. Moreover, the CSIA results show that microbial reductive dechlorination of TCE occurs in some parts of the bedrock aquifer. At this site, the use of CSIA for C and Cl in combination with analyses of VOC and redox parameters proved to be important due to the complexity introduced by biodegradation in the complex fractured rock aquifer. It is highly recommended to revisit the study when the municipal well is back into full operation. PMID- 22220912 TI - Letter to the editor--Combating bias: the next step in fighting cognitive and psychological contamination. PMID- 22220913 TI - Comparison of particle-size distributions determined by optical scanning and by sieving in the assessment of masticatory performance. AB - Aim of this study was to introduce a feasible and valid technique for the assessment of masticatory performance that is comparable to the standard sieving method. Twenty-one chewing samples (Optosil) comminuted by healthy dentate adults were analysed with a sieving and scanning method. Scanning was performed using a conventional flatbed scanner (1200dpi). All scanned images underwent image analysis (ImageJ), which yielded descriptive parameters such as area, best fitting ellipse for each particle. Of the 2D-image, a volume was estimated for each particle, which was converted into a weight. To receive a discrete distribution of particle sizes comparable to sieving, five chewing samples were used to calculate a size-dependent area-volume-conversion factor. The sieving procedure was carried out with a stack of 10 sieves, and the retained particles per sieve were weighed. The cumulated weights yielded by either method were curve fitted with the Rosin-Rammler distribution to determine the median particle size x(50) . The Rosin-Rammler distributions for sieving and scanning resemble each other. The distributions show a high correlation (0.919-1.0, n= 21, P<0.01, Pearson's correlation coefficient). The median particle sizes vary between 3.83 and 4.77mm (mean: 4.31) for scanning and 3.53 and 4.55mm (mean: 4.21) for sieving. On average, scanning overestimates the x(50) values by 2.4%. A modified Bland-Altman plot reveals that 95% of the x(50) values fall within 10% of the average x(50) . The scanning method is a valid, simple and feasible method to determine masticatory performance. PMID- 22220914 TI - Founder mutation c.676insC in three unrelated Kindler syndrome families belonging to a particular clan from Pakistan. PMID- 22220915 TI - 2-(2'-Pyridyl)benzimidazole as a fluorescent probe of hydration of nafion membranes. AB - 2,2'-(Pyridyl)benzimidazole is used as a probe to explore proton transfer through nafion membranes. The probe marks the availability of water in native as well as cation-exchanged membrane. Using steady state and time-resolved fluorescence studies, it has been shown that the rotation of the pyridyl and benzimidazole rings with respect to each other, which is ultrafast in higher water contents, is hindered as the water content in the membranes is decreased. In cation-exchanged membranes, it is observed that the formation of the ESPT (excited state proton transfer) state is reduced to a large extent. Thus, it may be inferred that the proton transport is observed to be hindered even in molecular dimensions of one water molecule thereby bolstering the contention that it may not be essential for water channels to break for proton conductivity to decrease. PMID- 22220916 TI - Botulinum toxin type A for the treatment of lower urinary tract disorders. AB - Many papers report the clinical success of botulinum toxin A as a method of management of various bladder dysfunctions. The rationale was that botulinum toxin A was able to block the presynaptic release of acetylcholine from the parasympathetic efferent nerve. The efficacy might result not only from an inhibitory effect on detrusor muscle, but also some effects might be mediated by altering the afferent nerve input. This systematic literature review discusses the efficacy and safety of botulinum toxin A therapy for idiopathic detrusor overactivity, neurogenic detrusor overactivity, interstitial cystitis/painful bladder syndrome and benign prostatic hyperplasia. The information was gathered from a PubMed literature research for abstracts from recent urological meetings. Injection of botulinum toxin A appears to have a positive therapeutic effect in multiple urological conditions, such as refractory idiopathic detrusor overactivity, neurogenic detrusor overactivity, interstitial cystitis/painful bladder syndrome and benign prostatic hyperplasia. Because the United States Food and Drug Administration has approved botulinum toxin A (Botox) for injection for the treatment of urinary incontinence as a result of neurogenic detrusor overactivity (e.g. spinal cord injury, multiple sclerosis) in adults who have an inadequate response to or are intolerant of an ant cholinergic medication, the use of botulinum toxin A will spread and be a more familiar therapy in the urological arena. However, further robust evidence should be awaited. We will discuss the current use of this agent within the urological field. PMID- 22220917 TI - The role of phosphatase and tensin homolog deleted on chromosome 10 and focal adhesion kinase in aggressive multiple myeloma. PMID- 22220919 TI - Tuning of the emission efficiency and HOMO-LUMO band gap for ester-functionalized {Al(salophen)(H2O)2}+ blue luminophors. AB - A series of [AlL(H(2)O)(2)(NO(3))] complexes, with L standing for an ester substituted salophen-type ligand, has been synthesized, and the luminescence properties have been investigated. These derivatives differ by the nature of the ester-R group introduced at the C5 position of their salicylidene rings (i.e., phenyl, 7a,a'; naphthyl, 7b,b'; pentafluorophenyl, 7c,c'; and p-nitrophenyl, 7d) and by the bis-imino bridge (i.e., 1,2- phenylene, 7a-d; and 1,2-naphthalene, 7a' c'). All the complexes are characterized by luminescence in the blue range, the chemical diversity having no effect on the emission wavelength (480-485 nm). However, the emission efficiency was found to be strongly dependent on the Schiff base ligand with quantum yields ranging from phi = 22% to 44%, the highest values being for the salophen derivatives with the electron-withdrawing ester-R groups (7a, 34%; 7a', 23%; 7b, 31%; 7b', 22%; 7c, 40%; 7c', 29%, and 7d, 44%). Both the electrochemical data and DFT calculations show that the HOMO-LUMO band gap is modified as a function of the ester R group (from 2.92 to 3.16 eV, based on the redox potentials). The crystal structures for the N,N'-bis(5 (phenoxycarbonyl)salicylidene)-1,2-phenylenediamine and the N,N'-bis(5-(p nitrophenoxycarbonyl)salicylidene)-1,2-phenylenediamine aluminum complexes (7a and 7d) are reported. PMID- 22220921 TI - An unexpected mechanism of hydrosilylation by a silyl hydride complex of molybdenum. AB - Carbonyl hydrosilylation catalyzed by (ArN)Mo(H)(SiH(2)Ph)(PMe(3))(3) (3) is unusual in that it does not involve the expected Si-O elimination from intermediate (ArN)Mo(SiH(2)Ph)(O(i)Pr)(PMe(3))(2) (7). Instead, 7 reversibly transfers beta-CH hydrogen from the alkoxide ligand to metal. PMID- 22220922 TI - High-power resistance exercise induces MAPK phosphorylation in weightlifting trained men. AB - Power is critical to muscle performance, specifically in athletic populations. Mitogen-activated protein kinase (MAPK) pathways (extracellular signal-regulated protein kinase (ERK 1/2), p38, and c-Jun NH(2)-terminal kinase (JNK)) are intracellular signal transduction mechanisms that partially regulate exercise induced skeletal muscle alterations. These pathways are highly responsive to exercise, but their reaction to high power, multi-joint resistance exercise is yet to be examined. Nine weightlifting-trained men performed 15 sets of three repetitions of a dynamic clean pull exercise at 85% of their one repetition maximum. Vastus lateralis biopsies were obtained prior to (pre) and after the 8th (mid) and 15th set (post) of exercise. Three subjects returned to serve as non exercising controls for a similar sequence of biopsies (CON). The ratio of phosphorylated MAPK to total MAPK increased significantly for p38 (3.0 fold, p < 0.05) and JNK (2.4 fold, p < 0.05) by the mid biopsy. ERK 1/2 phosphorylation followed a similar trend (2.3 fold) (p = 0.052). The ratio of phosphorylation to total MAPK did not differ from mid to post biopsy. None of the pathways were phosphorylated above resting in the CON condition (p > 0.05), and thus the biopsy procedure itself did not account for the entire increase in MAPK phosphorylation during EX. These data indicate MAPK pathways are activated early and remain elevated throughout the duration of high power resistance exercise. These findings help describe the mechanisms partially responsible for chronic adaptations in response to high intensity, high power resistance training in humans. PMID- 22220923 TI - Series of metal organic frameworks assembled from Ln(III), Na(I), and chiral flexible-achiral rigid dicarboxylates exhibiting tunable UV-vis-IR light emission. AB - Two series of isoreticular chiral metal-organic frameworks assembled from Ln(III) (Ln = Sm, Eu, Gd, Tb, Dy, Ho, Er, Yb), Na(I), and chiral flexible-achiral rigid dicarboxylate ligands, formulated as [NaLn(Tart)(BDC)(H(2)O)(2)] (S1) and [NaLn(Tart)(biBDC)(H(2)O)(2)] (S2) (H(2)Tart = tartaric acid; H(2)BDC = terephthalic acid; H(2)biBDC = biphenyl-4,4'-dicarboxylic acid), were obtained as single phases under hydrothermal conditions. The compounds have been studied by single-crystal and powder X-ray diffraction, thermal analyses (TG-MS and DSC), vibrational spectroscopy (FTIR), scanning electron microscopy (SEM-EDX), elemental analysis, and X-ray thermodiffractometry. The catalytic activity has been also investigated. The photoluminescence properties of selected compounds have been investigated, exhibiting room temperature tunable UV-vis-IR light emission. PMID- 22220924 TI - A fast and easy real-time PCR genotyping method for the HLA-G 14-bp insertion/deletion polymorphism in the 3' untranslated region. AB - Human leukocyte antigen-G (HLA-G) is a non-classical HLA class Ib molecule shown to exhibit immunomodulatory function in a wide range of immune-based disorders. A number of functional HLA-G gene polymorphisms have been identified, including a 14-bp insertion/deletion polymorphism in exon 8 of the 3' untranslated region of the HLA-G gene, which has been associated with HLA-G mRNA stability. Moreover, studies show that homozygosity for the 14-bp insertion/deletion polymorphism is associated with lower HLA-G mRNA and protein levels and unique alternative splicing patterns. Here, we introduce a quick and reliable method to screen for the HLA-G 14-bp insertion/deletion polymorphism using an optimized real-time polymerase chain reaction protocol. The genotyping assay has been validated by comparison with conventional methods. As results can be obtained within a few hours, the assay will have a potential for clinical use. PMID- 22220925 TI - Automated localisation and boundary identification of superficial femoral artery on MRI sequences. AB - In this paper, an automated method to localise the right superficial femoral artery (SFA) and identify its boundary on magnetic resonance imaging (MRI) sequences without contrast medium injection is proposed. Some anatomical knowledge combined with the mathematical morphology is used to distinguish SFA from other vessels. Afterwards, the directional gradient, continuity and the local contrast are applied as features to identify the artery's boundary using dynamic programming. The accuracy analysis shows that the system has average unsigned errors 3.1 +/- 3.1% on five sequences compared to experts' manual tracings. PMID- 22220928 TI - Graphene as a quencher of electronic excited states of photochemical probes. AB - Graphene sheets quench the singlet and triplet excited states of a series of six photochemical probes including pyrene, acridine orange, tris(2,2 bipyridyl)ruthenium(II) dichloride, methylene blue, meso tetrakis(phenylsulphonate)porphyrin, and 5,10,15,20-tetraphenyl-21H,28H-porphine zinc. It was found that Stern-Volmer fluorescence quenching can fit to one or two different quenching regimes depending on the probe. In addition, the quenching can be either static or dynamic depending on the fluorophore. The occurrence of several quenching regimes has been interpreted considering that quenching arises from the crowding of the fluorophore on both graphene faces, or site isolation on the graphene sheets. Laser flash photolysis has shown that the triplet lifetime of the probes generally decreases due to graphene quenching and that no new transients appear except in the case of methylene blue, where a new absorption spectrum characterized by a continuous absorption band is observed and attributed to graphene radical ion. This spectroscopic evidence suggests that the most general quenching mechanism is energy transfer from the singlet or triplet excited state of the dye to graphene. This raises the issue of determining the energy of the electronic excited states of graphene. PMID- 22220926 TI - Selective small molecule inhibition of poly(ADP-ribose) glycohydrolase (PARG). AB - The poly(ADP-ribose) (PAR) post-translational modification is essential for diverse cellular functions, including regulation of transcription, response to DNA damage, and mitosis. Cellular PAR is predominantly synthesized by the enzyme poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is a critical node in the DNA damage response pathway, and multiple potent PARP-1 inhibitors have been described, some of which show considerable promise in the clinic for the treatment of certain cancers. Cellular PAR is efficiently degraded by poly(ADP ribose) glycohydrolase (PARG), an enzyme for which no potent, readily accessible, and specific inhibitors exist. Herein we report the discovery of small molecules that effectively inhibit PARG in vitro and in cellular lysates. These potent PARG inhibitors can be produced in two chemical steps from commercial starting materials and have complete specificity for PARG over the other known PAR glycohydrolase (ADP-ribosylhydrolase 3, ARH3) and over PARP-1 and thus will be useful tools for studying the biochemistry of PAR signaling. PMID- 22220929 TI - Diagnosis of depression and use of antidepressant pharmacotherapy among adults in the United States: does a disparity persist by ethnicity/race? AB - BACKGROUND AND OBJECTIVE: Both the rate of diagnosis of depression in the US and the rate of prescribing an antidepressant for its treatment have increased substantially over the past two decades. Previous research has also indicated that the rates of diagnosis and treatment of depression with an antidepressant vary widely by ethnicity/race. The objective of this study was to discern ethnic/race-specific (non-Hispanic Black; Hispanic; non-Hispanic White) population-adjusted rates of US office-based physician-patient encounters (office based visits) documenting a diagnosis of depression, and the extent of the use of antidepressant pharmacotherapy for its treatment. METHODS: Data from the US National Ambulatory Medical Care Survey (NAMCS) for the years 1992-1997 and 2003 2008 were utilized for this analysis. The years 1998-2002 were excluded due to the magnitude of missing data for the variable ethnicity. The US NAMCS is a national probability sample designed and conducted by the US National Center for Health Statistics of the US Centers for Disease Control and Prevention. Depression was defined via International Classification of Diseases, 9th Revision, Clinical Modification codes 296.2-296.36; 300.4; 311. Antidepressants were defined as US National Drug Code category 0630 prior to 2005, and category 249 in Lexicon Plus(r) thereafter. Data were partitioned into six 2-year time intervals for trend analysis of population-adjusted rates (per 100) among patients aged 20-79 years. Rates per 2-year time interval are based on US Census Bureau national resident population estimates for the ethnicity/race categories examined. Comparisons within and across time-frames were assessed by chi-squared (chi2) analysis. The a priori level of significance for all statistical tests was set at p < 0.05. Analyses were performed using SAS Release 9.1.3. RESULTS: Over the 12-year time-frame examined, the rate of office-based visits documenting a diagnosis of depression increased 28.4% for non-Hispanic Whites (from 10.9 to 14.0 per 100; p < 0.001), 54.8% for non-Hispanic Blacks (from 4.2 to 6.5 per 100; p < 0.001), and 37.5% for Hispanics (from 4.8 to 6.6 per 100; p < 0.001). The rate of office-based visits with a recorded diagnosis of depression in concert with the prescribing of an antidepressant increased 66.2% for non-Hispanic Whites (from 6.5 to 10.8 per 100; p < 0.001), 69.2% for non-Hispanic Blacks (from 2.6 to 4.4 per 100; p < 0.001), and 36.7% for Hispanics (from 3.0 to 4.1 per 100; p < 0.001). CONCLUSION: By 2003-2004, the population-adjusted rates for non-Hispanic Blacks and Hispanics were similar, and remained so through 2007-2008. However, over the 12-year time-frame examined, the rates for both minority groups were, in each 2-year interval, far less than that observed in non-Hispanic Whites. Disparities remain by ethnicity/race in the diagnosis and treatment of depression in the US. PMID- 22220931 TI - Berberine ameliorates inflammation in patients with acute coronary syndrome following percutaneous coronary intervention. AB - 1. Inflammation is central to the pathogenesis of acute coronary syndrome (ACS) and is associated with adverse clinical outcomes after percutaneous coronary intervention (PCI). Recent in vitro work has demonstrated the anti-inflammatory effect of berberine, a primary component of the traditional Chinese medicine 'umbellatine'. In the present study, we further tested whether berberine had any beneficial effects on ACS patients following PCI. 2.In all, 130 ACS patients undergoing PCI were recruited to the present study. Sixty-one patients were treated with berberine (300 mg, t.i.d., for 30 days) in addition to standard therapy, whereas the remaining patients received standard therapy alone. Circulating inflammatory markers were measured by ELISA, whereas serum lipid profiles were measured by routine chemical assays. 3.In the berberine-treated group, matrix metalloproteinase (MMP)-9, intercellular adhesion molecule (ICAM) 1, vascular cell adhesion molecule (VCAM)-1, C-reactive protein, interleukin-6 and monocyte chemoattractant protein-1 were significantly reduced relative to baseline values. Furthermore, the changes in MMP-9, ICAM-1 and VCAM-1 from baseline to after 1 month of treatment differed significantly between the two patient groups. There was a tendency for berberine to induce a slightly greater reduction in low-density lipoprotein cholesterol and triglycerides than standard therapy alone, without affecting high-density lipoprotein cholesterol, but the differences failed to reach statistical significance. No severe adverse effects of berberine were observed. 4.The results of the present study provide the first clinical evidence of the anti-inflammatory action of berberine in ACS patients following PCI. Berberine may become adjunct therapy to further improve clinical outcomes via its anti-inflammatory effect in ACS patients. PMID- 22220930 TI - Frontal EEG asymmetry moderates the effects of stressful life events on internalizing symptoms in children at familial risk for depression. AB - This study examined whether frontal alpha electroencephalographic (EEG) asymmetry moderates the association between stressful life events and depressive symptoms in children at familial risk for depression. Participants included 135 children ages 6 to 13, whose mothers had either a history of depression or no history of major psychiatric conditions. Frontal EEG was recorded while participants watched emotion-eliciting films. Symptoms and stressful life events were obtained via the Child Behavior Check List and a clinical interview, respectively. High-risk children displayed greater relative right lateral frontal activation (F7/F8) than their low-risk peers during the films. For high-risk children, greater relative left lateral frontal activation moderated the association between stressful life events and internalizing symptoms. Specifically, greater relative left lateral frontal activation mitigated the effects of stress in at-risk children. PMID- 22220932 TI - Groundwater biofilm dynamics grown in situ along a nutrient gradient. AB - This paper describes the in situ response of groundwater biofilms in an alluvial gravel aquifer system on the Canterbury Plains, New Zealand. Biofilms were developed on aquifer gravel, encased in fine mesh bags and suspended in protective columns in monitoring wells for at least 20 weeks. Four sites were selected in the same groundwater system where previous analyses indicated a gradient of increasing nitrate down the hydraulic gradient from Sites 1 to 4. Measurements during the current study classified the groundwater as oligotrophic. Biofilm responses to the nutrient gradients were assessed using bioassays, with biomass determined using protein and cellular and nucleic acid staining and biofilm activity using enzyme assays for lipid, carbohydrate, phosphate metabolism, and cell viability. In general, biofilm activity decreased as nitrate levels increased from Sites 1 to 4, with the opposite relationship for carbon and phosphorus concentrations. These results showed that the groundwater system supported biofilm growth and that the upper catchment supported efficient and productive biofilms (high ratio of activity per unit biomass). PMID- 22220933 TI - Sudden cardiac death in young adults: environmental risk factors and genetic aspects of premature atherosclerosis. AB - Familial hypercholesterolemia (FH) is a genetic disorder that may lead to premature coronary heart disease (CHD) and sudden cardiac death (SCD). Mutations in the LDLR or APOB genes cause FH. We have screened the LDLR and the ligand binding region of APOB genes in 52 cases of SCD. Deceased patients were younger than 40 years of age and were suspected of having FH. The LDLR and APOB genes were examined via PCR, high-resolution melting, and DNA sequencing. Therein, it was observed that 7.7% of the screened patients exhibited a rare sequence variant in the LDLR gene, with 5.7% suspected of being pathogenic mutations. Lipid profiles and genetic testing for FH could be considered when autopsy reveals significant atherosclerosis of the coronary arteries in young adults. First degree family members are advised to seek medical advice and testing to determine their own risks of atherosclerosis to prevent premature CHD and SCD. PMID- 22220934 TI - Photorejuvenation using long-pulsed alexandrite and long-pulsed neodymium:yttrium aluminum-garnet lasers: a pilot study of clinical outcome and patients' satisfaction in Koreans. AB - Long-pulsed 755-nm alexandrite and long-pulsed 1064-nm neodymium:yttrium-aluminum garnet (Nd:YAG) lasers have been used for photorejuvenation of the face. The aim of this study was to investigate the safety and efficacy of long-pulsed alexandrite and long-pulsed Nd:YAG lasers for photorejuvenation in Korea. One hundred and sixteen Korean patients with photo-aged facial skin were enrolled. Sixty-two patients with facial pigmentation underwent long-pulsed alexandrite laser treatment. Eleven patients that wanted to improve facial pigmentation with minimal pain had quasi-long-pulsed alexandrite laser treatment. Forty three patients had long-pulsed Nd:YAG laser therapy. Outcome assessments included standard photographs and global evaluation by blinded investigators. The self assessment grade was provided in questionnaires. Forty-four percent of patients reported excellent or good improvement of their pigmentary lesions (>50% improvement) using a long-pulsed alexandrite laser. Of patients who underwent long-pulsed Nd:YAG laser treatment, 36% reported excellent or good improvement in skin tightening, 50% in facial flushing and 45% in pigmentary lesions. We conclude that long-pulsed alexandrite and long-pulsed Nd:YAG lasers are safe and effective for facial photorejuvenation in Koreans. PMID- 22220936 TI - BCNU-associated pneumonitis: portrait of a toxicity. PMID- 22220935 TI - Immediate effects of monochromatic infrared energy on microcirculation in healthy subjects. AB - OBJECTIVE: The purpose of this study was to evaluate the influence of monochromatic infrared energy (MIRE) on the microcirculation of the skin surface of the feet in healthy subjects. BACKGROUND DATA: Near-infrared energy was shown to increase microcirculation in an animal study. In humans, only one case study demonstrated that MIRE increases microcirculation in the skin of the lower limbs. METHODS: Thirty healthy volunteers were recruited and randomly allocated into three groups to receive either: (1) active MIRE; (2) sham MIRE (placebo group); or (3) warm packs (control group) on the feet. The MIRE device comprised an array of 60 x 890 nm LEDs attached to flexible pads (3*7.5 cm). Each diode spot size was 0.2 cm(2), and each LED power was 12 mW with a power density of 60 mW/cm(2). The arrays were placed in direct contact with the skin for 30 min delivering a total fluence of 108 J/cm(2) over an area of 22.5 cm(2). Capillary blood cell velocity (CBV) and superficial skin blood flow (flux) were recorded before and after intervention. RESULTS: Significant differences among the three groups were recorded in both CBV and flux (both p<0.05). Post-hoc comparisons indicated that a significantly greater increase in both CBV and flux occurred in the active MIRE group than in the placebo group and control group (all p<0.05). CONCLUSIONS: A 30 min MIRE produced a significantly greater increase in the CBV and flux of the feet in the active MIRE group than in the placebo and control groups. PMID- 22220937 TI - Laparoscopic management of giant hygroma renalis. PMID- 22220938 TI - Distribution and diversity of archaeal communities in selected Chinese soils. AB - To understand the distribution and diversity of archaea in Chinese soils, the archaeal communities in a series of topsoils and soil profiles were investigated using quantitative PCR, T-RFLP combining sequencing methods. Archaeal 16S rRNA gene copy numbers, ranging from 4.96 * 10(6) to 1.30 * 10(8) copies g(-1) dry soil, were positively correlated with soil pH, organic carbon and total nitrogen in the topsoils. In the soil profiles, archaeal abundance was positively correlated with soil pH but negatively with depth profile. The relative abundance of archaea in the prokaryotes (sum of bacteria and archaea) ranged from 0.20% to 9.26% and tended to increase along the depth profile. T-RFLP and phylogenetic analyses revealed that the structure of archaeal communities in cinnamon soils, brown soils, and fluvo-aquic soils was similar and dominated by Crenarchaeota group 1.1b and 1.1a. These were different from those in red soils, which were dominated by Crenarchaeota group 1.3 and 1.1c. Canonical correspondence analysis indicated that the archaeal community was primarily influenced by soil pH. PMID- 22220939 TI - A sterically demanding iminopyridine ligand affords redox-active complexes of aluminum(III) and gallium(III). AB - The combination of an electrophilic metal center with a redox active ligand set has the potential to provide reactivity unique from transition metal redox chemistry. In this report, substituted iminopyridine complexes containing monoanionic and dianionic (Me)IP(Mes) ligands have been characterized structurally and electronically. Green ((Me)IP(Mes)(-))AlCl(2) (1), ((Me)IP(Mes)( ))AlMe(2) (2), and ((Me)IP(Mes)(-))GaCl(2) (5) have a doublet spin state which results from the anion radical form of (Me)IP(Mes). Purple ((Me)IP(Mes)(2 ))AlCl(OEt(2)) (3), ((Me)IP(Mes)(2-))AlMe(OEt(2)) (4), and ((Me)IP(Mes)(2 ))GaCl(OEt(2)) (6) are each diamagnetic. We have also investigated the solvent dependence of the decomposition of the (Me)IP(Mes) anion radical. Complexes 1 and 2 can be obtained from benzene and hexanes whereas the use of ether solvents results in the formation of undesirable ((CH2)IP(Mes)(-))AlCl(2) (1a) and ((CH2)IP(Mes)(-))AlCl(2) (2a) formed by loss of a hydrogen atom from the (Me)IP(Mes)(-) ligand. Electrochemical measurements indicate that 1, 2, and 5 are redox active. PMID- 22220942 TI - Chromatographic detection of lignin-carbohydrate complexes in annual plants by derivatization in ionic liquid. AB - The opportunity for detecting the presence and the amount of lignin-carbohydrate complexes (LCCs) in renewable feedstocks is a major issue for the complete utilization of biomass. Indeed, LCCs are known to shield cellulose from enzymatic hydrolysis, reducing the efficiency of the digestion processes needed for the production of biobased products. This study is focused on the chromatographic characterization of lignocellulose from agricultural residues (rice husk, wheat straw) and herbaceous energy crops ( Arundo donax , Miscanthus sinesis ) and their fractionation products (hemicellulose, cellulose, and lignin). Exploiting alternative chemical derivatizations on the aforementioned samples, it was possible to discern the connectivity among the various lignocellulosic components. The complete acetylation and benzoylation of the milled native substrates in ionic liquid media, and the systematic comparison between their GPC UV chromatograms collected at different wavelengths has revealed itself as a straightforward technique in the detection of LCCs. This novel approach proved an extensive connectivity between the lignin and the hemicellulosic for all the analyzed specimens, whereas the cellulosic fraction was conceived as a substantially unbound moiety, accounting for the sample composition at higher molecular weights. Moreover, the collected lignin fractions were extensively characterized by means of (31)P NMR and 2D-HSQC techniques. PMID- 22220944 TI - 2-Aminoisobutyric acid in Co(II) and Co(II)/Ln(III) chemistry: homometallic and heterometallic clusters. AB - The synthesis and magnetic properties of 13 new homo- and heterometallic Co(II) complexes containing the artificial amino acid 2-amino-isobutyric acid, aibH, are reported: [Co(II)(4)(aib)(3)(aibH)(3)(NO(3))](NO(3))(4).2.8CH(3)OH.0.2H(2)O (1.2.8CH(3)OH.0.2H(2)O), {Na(2)[Co(II)(2)(aib)(2)(N(3))(4)(CH(3)OH)(4)]}(n) (2), [Co(II)(6)La(III)(aib)(6)(OH)(3)(NO(3))(2)(H(2)O)(4)(CH(3)CN)(2)].0.5[La(NO(3))(6 ].0.75(ClO(4)).1.75(NO(3)).3.2CH(3)CN.5.9H(2)O (3.3.2CH(3)CN.5.9H(2)O), [Co(II)(6)Pr(III)(aib)(6)(OH)(3)(NO(3))(3)(CH(3)CN)(6)].[Pr(NO(3))(5)].0.41[Pr(NO 3))(3)(ClO(4))(0.5)(H(2)O)(1.5)].0.59[Co(NO(3))(3)(H(2)O)].0.2(ClO(4)).0.25H(2)O (4.0.25H(2)O), [Co(II)(6)Nd(III)(aib)(6)(OH)(3)(NO(3))(2.8)(CH(3)OH)(4.7)(H(2)O)(1.5)].2.7(ClO(4 ).0.5(NO(3)).2.26CH(3)OH.0.24H(2)O (5.2.26CH(3)OH.0.24H(2)O), [Co(II)(6)Sm(III)(aib)(6)(OH)(3)(NO(3))(3)(CH(3)CN)(6)].[Sm(NO(3))(5)].0.44[Sm(NO 3))(3)(ClO(4))(0.5)(H(2)O)(1.5)].0.56[Co(NO(3))(3)(H(2)O)].0.22(ClO(4)).0.3H(2)O (6.0.3H(2)O), [Co(II)(6)Eu(III)(aib)(6)(OH)(3)(NO(3))(3)(CH(3)OH)(4.87)(H(2)O)(1.13)](ClO(4))(2 5)(NO(3))(0.5).2.43CH(3)OH.0.92H(2)O (7.2.43CH(3)OH.0.92H(2)O), [Co(II)(6)Gd(III)(aib)(6)(OH)(3)(NO(3))(2.9)(CH(3)OH)(4.9)(H(2)O)(1.2)].2.6(ClO(4 ).0.5(NO(3)).2.58CH(3)OH.0.47H(2)O (8.2.58CH(3)OH.0.47H(2)O), [Co(II)(6)Tb(III)(aib)(6)(OH)(3)(NO(3))(3)(CH(3)CN)(6)].[Tb(NO(3))(5)].0.034[Tb(N (3))(3)(ClO(4))(0.5)(H(2)O)(0.5)].0.656[Co(NO(3))(3)(H(2)O)].0.343(ClO(4)).0.3H(2 O (9.0.3H(2)O), [Co(II)(6)Dy(III)(aib)(6)(OH)(3)(NO(3))(2.9)(CH(3)OH)(4.92)(H(2)O)(1.18)](ClO(4)) 2.6)(NO(3))(0.5).2.5CH(3)OH.0.5H(2)O (10.2.5CH(3)OH.0.5H(2)O), [Co(II)(6)Ho(III)(aib)(6)(OH)(3)(NO(3))(3)(CH(3)CN)(6)].0.27[Ho(NO(3))(3)(ClO(4)) 0.35)(H(2)O)(0.15)].0.656[Co(NO(3))(3)(H(2)O)].0.171(ClO(4)) (11), [Co(II)(6)Er(III)(aib)(6)(OH)(4)(NO(3))(2)(CH(3)CN)(2.5)(H(2)O)(3.5)](ClO(4))(3). H(3)CN.0.75H(2)O (12.CH(3)CN.0.75H(2)O), and [Co(II)(6)Tm(III)(aib)(6)(OH)(3)(NO(3))(3)(H(2)O)(6)].1.48(ClO(4)).1.52(NO(3)).3H 2)O (13.3H(2)O). Complex 1 describes a distorted tetrahedral metallic cluster, while complex 2 can be considered to be a 2-D coordination polymer. Complexes 3 13 can all be regarded as metallo-cryptand encapsulated lanthanides in which the central lanthanide ion is captivated within a [Co(II)(6)] trigonal prism. dc and ac magnetic susceptibility studies have been carried out in the 2-300 K range for complexes 1, 3, 5, 7, 8, 10, 12, and 13, revealing the possibility of single molecule magnetism behavior for complex 10. PMID- 22220943 TI - The characterization of the Caenorhabditis elegans mitochondrial thioredoxin system uncovers an unexpected protective role of thioredoxin reductase 2 in beta amyloid peptide toxicity. AB - AIM: Functional in vivo studies on the mitochondrial thioredoxin system are hampered by the embryonic or larval lethal phenotypes displayed by murine or Drosophila knock-out models. Thus, the access to alternative metazoan knock-out models for the mitochondrial thioredoxin system is of critical importance. RESULTS: We report here the characterization of the mitochondrial thioredoxin system of Caenorhabditis elegans that is composed of the genes trx-2 and trxr-2. We demonstrate that the proteins thioredoxin 2 (TRX-2) and thioredoxin reductase 2 (TRXR-2) localize to the mitochondria of several cells and tissues of the nematode and that trx-2 and trxr-2 are upregulated upon induction of the mitochondrial unfolded protein response. Surprisingly, C. elegans trx-2 (lof ) and trxr-2 (null) single and double mutants are viable and display similar growth rates as wild-type controls. Moreover, the lack of the mitochondrial thioredoxin system does not affect longevity, reactive oxygen species production or the apoptotic program. Interestingly, we found a protective role of TRXR-2 in a transgenic nematode model of Alzheimer's disease (AD) that expresses human beta amyloid peptide and causes an age-dependent progressive paralysis. Hence, trxr-2 downregulation enhanced the paralysis phenotype, while a strong decrease of beta amyloid peptide and amyloid deposits occurred when TRXR-2 was overexpressed. INNOVATION: C. elegans provides the first viable metazoan knock-out model for the mitochondrial thioredoxin system and identifies a novel role of this system in beta-amyloid peptide toxicity and AD. CONCLUSION: The nematode strains characterized in this work make C. elegans an ideal model organism to study the pathophysiology of the mitochondrial thioredoxin system at the level of a complete organism. PMID- 22220945 TI - Effects of intravenous dexmedetomidine on low-dose bupivacaine spinal anaesthesia in elderly patients. AB - BACKGROUND: Dexmedetomidine (DMT) has been shown to prolong spinal anaesthesia. We evaluated the effects of intravenous DMT on low-dose bupivacaine spinal anaesthesia in elderly patients. METHODS: Fifty-one elderly patients undergoing transurethral resection of the prostate were randomized into two groups receiving either 1.0 MUg/kg DMT (DMT group, n = 26) or normal saline (control group n = 25) intravenously prior to spinal anaesthesia with 1.2 ml of bupivacaine, 5 mg/ml. RESULTS: The mean time to two-segment regression (39 min vs. 78 min for cold, 41 min vs. 61 min for pinprick) and that to motor regression (23 min vs. 46 min) were longer in the DMT group than in the control group. The atropine-requiring bradycardia was more frequent in the DMT group than in the control group (24.0% vs. 3.8%). The median sedation scores (ranges) during surgery were 4 (2-6) in the DMT group and 2 (1-3) in the control group (P < 0.001). Two patients in the DMT group showed oxygen desaturation (peripheral oxygen saturation < 90%) during surgery. The duration of post-operative care unit stay was longer in the DMT group than in the control group (58 min vs. 96 min). Post-operative pain intensity was lower and the mean time to first request for post-operative analgesia was longer in the DMT group compared to the control group (6.6 h vs. 2.1 h). CONCLUSION: Intravenous DMT prolonged the duration of spinal anaesthesia and improved post-operative analgesia. However, more profound sedation with desaturation was observed with more frequent bradycardia, and delayed recovery should be considered in elderly patients. PMID- 22220946 TI - CFD analysis of the human airways under impedance-based boundary conditions: application to healthy, diseased and stented trachea. AB - A computational fluid dynamics model of a healthy, a stenotic and a post operatory stented human trachea was developed to study the respiration under physiological boundary conditions. For this, outflow pressure waveforms were computed from patient-specific spirometries by means of a method that allows to compute the peripheral impedance of the truncated bronchial generation, modelling the lungs as fractal networks. Intratracheal flow pattern was analysed under different scenarios. First, results obtained using different outflow conditions were compared for the healthy trachea in order to assess the importance of using impedance-based conditions. The resulted intratracheal pressures were affected by the different boundary conditions, while the resulted velocity field was unaffected. Impedance conditions were finally applied to the diseased and the stented trachea. The proposed impedance method represents an attractive tool to compute physiological pressure conditions that are not possible to extract in vivo. This method can be applied to healthy, pre- and post-operatory tracheas showing the possibility of predicting, through numerical simulation, the flow and the pressure field before and after surgery. PMID- 22220947 TI - 1H NMR, electron paramagnetic resonance, and density functional theory study of dinuclear pentaammineruthenium dicyanamidobenzene complexes. AB - Paramagnetic (1)H NMR and electron paramagnetic resonance (EPR) spectroscopies and density functional theory (DFT) spin density calculations were selectively performed on the [{(NH(3))(5)Ru}(2)(MU-L)](3+, 4+, 5+) complexes, where L is 2,3,5,6-tetrachloro-, 2,5-dichloro-, 2,5-dimethyl-, and unsubstituted 1,4 dicyanamidobenzene dianion, to characterize the electronic structure of these complexes. EPR spectra of the [{(NH(3))(5)Ru}(2)(MU-L)](3+) complexes in N,N' dimethylformamide at 4 K showed a ruthenium axial signal, and thus the complexes are [Ru(II),L(2-), Ru(III)] mixed-valence systems. DFT spin density calculations of [{(NH(3))(5)Ru}(2)(MU-L)](3+) where L = 1,4-dicyanamidobenzene dianion gave mostly bridging-ligand centered spin distribution for both vacuum and implicit solvent calculations, in poor agreement with EPR, but more realistic results were obtained when explicit electrostatic interactions between solute and solvent were included in modeling. For the [{(NH(3))(5)Ru}(2)(MU-L)](4+) complexes, EPR spectroscopy showed no signal down to 4 K. Nevertheless, solvent-dependent (1)H NMR data and analysis support a [Ru(III),L(2-), Ru(III)] state. Hyperfine coupling constants (A(c)/h) of trans- and cis-ammine and phenyl hydrogens were determined to be 17.2, 3.8, and -1.5 MHz respectively. EPR studies of the [{(NH(3))(5)Ru}(2)(MU-L)](5+) complexes showed a metal-radical axial signal and based on previously published (1)H NMR data, a [Ru(IV),L(2-), Ru(III)] state is favored over a [Ru(III),L(-), Ru(III)] state. PMID- 22220948 TI - Unpredictable drug shortages: an ethical framework for short-term rationing in hospitals. AB - Periodic and unexpected shortages of drugs, biologics, and even medical devices have become commonplace in the United States. When shortages occur, hospitals and clinics need to decide how to ration their available stock. When such situations arise, institutions can choose from several different allocation schemes, such as first-come, first-served, a lottery, or a more rational and calculated approach. While the first two approaches sound reasonable at first glance, there are a number of problems associated with them, including the inability to make fine, individual patient-centered decisions. They also do not discriminate between what kinds of patients and what types of uses may be more deserving or reasonable than others. In this article I outline an ethically acceptable procedure for rationing drugs during a shortage in which demand outstrips supply. PMID- 22220949 TI - Interventions and persons. PMID- 22220950 TI - Beyond the framework. PMID- 22220951 TI - Are we asking the right ethics questions on drug shortages? Suggestions for a global and anticipatory ethics framework. PMID- 22220952 TI - A paradoxical ethical framework for unpredictable drug shortages. PMID- 22220953 TI - Patents and drug shortages: will the new congressional efforts save us from impending drug shortages? PMID- 22220954 TI - The tensions and challenges of unpredictable drug shortages. PMID- 22220955 TI - A new justification for pediatric research without the potential for clinical benefit. AB - Pediatric research without the potential for clinical benefit is vital to improving pediatric medical care. This research also raises ethical concern and is regarded by courts and commentators as unethical. While at least 10 justifications have been proposed in response, all have fundamental limitations. This article describes and defends a new justification based on the fact that enrollment in clinical research offers children the opportunity to contribute to a valuable project. Contributing as children to valuable projects can benefit individuals in two ways. First, individuals may come to "embrace" the contributions they made as children. Second, contributing to valuable projects can lead to a better overall life. Because these potential benefits can outweigh small research risks, they provide a justification for pediatric research without the potential for clinical benefit, when it poses low risks and has the potential to benefit others in important ways. PMID- 22220956 TI - On justifying pediatric research without the prospect of clinical benefit. PMID- 22220957 TI - Why even inappropriate parental consent might be enough to justify minimal risk pediatric research without clinical benefit. PMID- 22220958 TI - Consent to pediatric research: a couple of distinctions. PMID- 22220959 TI - The context of clinical research and its ethical relevance: the COMPAS trial as a case study. PMID- 22220960 TI - On Wendler's new justification for pediatric research. PMID- 22220961 TI - Justifying pediatric research not expected to benefit child subjects. PMID- 22220962 TI - A more persuasive justification for pediatric research. PMID- 22220963 TI - Dr. Goold's (2011) observations and criticisms. Letter to the editors. PMID- 22220965 TI - Protecting patient privacy redux: response to open peer commentaries on "'you don't know me, but ...': access to patient data and subject recruitment in human subjects research". PMID- 22220967 TI - Investigation and quantification of key periodontal pathogens in patients with type 2 diabetes. AB - BACKGROUND AND OBJECTIVE: Diabetes is a recognized risk factor for periodontitis. There are conflicting data regarding whether healthy diabetic patients or diabetic patients with chronic periodontitis have an altered subgingival microbiota compared with nondiabetic individuals. The aim of the present study was to detect quantitative differences in selected periodontopathogens in the subgingival plaque of diabetic patients using TaqMan quantitative PCR. MATERIAL AND METHODS: Type 2 diabetes mellitus patients with (n=9) or without chronic periodontal disease (n=15) were recruited and matched to nondiabetic control subjects (n=12 periodontally healthy, n=12 chronic periodontitis). Subgingival plaque samples were collected from deep (>4 mm probing depth) and shallow sites (<=3 mm probing depth) using paper points, and Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum and Porphyromonas gingivalis were quantified. RESULTS: Forty-eight subjects (69 samples) were recruited. Marked differences were seen in the levels of all three bacterial species, relative to the total bacterial population, according to periodontal health status. Using real-time quantitative PCR, bacterial counts for P. gingivalis were significantly higher in deep pockets of diabetic and nondiabetic subjects compared with periodontally healthy subjects (p<0.05) but did not differ significantly between diabetics and nondiabetics. A. actinomycetemcomitans was detected in all groups in low quantities, and counts did not differ significantly between groups (p>0.05). F. nucleatum was abundant in all groups, with no clear significant differences between groups. P. gingivalis was found in higher quantities in periodontitis than in periodontally healthy subjects (p<0.05). Statistically significant positive correlations were identified between pocket depth and counts for all three species tested (p<0.05). CONCLUSION: A. actinomycetemcomitans, F. nucleatum and P. gingivalis were present in significantly different quantities and proportions in subgingival plaque, according to periodontal disease status. No significant differences were identified between the subgingival microbiota of type 2 diabetes mellitus patients compared with nondiabetic subjects. PMID- 22220968 TI - The rheological and structural properties of Fmoc-peptide-based hydrogels: the effect of aromatic molecular architecture on self-assembly and physical characteristics. AB - Biocompatible hydrogels are of high interest as a class of biomaterials for tissue engineering, regenerative medicine, and controlled drug delivery. These materials offer three-dimensional scaffolds to support the growth of cells and development of hierarchical tissue structures. Fmoc-peptides were previously demonstrated as attractive building blocks for biocompatible hydrogels. Here, we further investigate the biophysical properties of Fmoc-peptide-based hydrogels for medical applications. We describe the structural and thermal properties of these Fmoc-peptides, as well as their self-assembly process. Additionally, we study the role of interactions between aromatic moieties in the self-assembly process and on the physical and structural properties of the hydrogels. PMID- 22220969 TI - Are phonological representations in bilinguals language specific? An ERP study on interlingual homophones. AB - Event-related potentials (ERPs) served to investigate whether phonological representations from both the first (L1) and second (L2) language of bilinguals are activated during silent reading of L2 words. French-English late bilinguals and control monolingual English speakers read interlingual homophones (e.g., "knee" in English, which has substantial phonological overlap with the French word "nid," meaning "nest") and matched control words. Results showed a reduction in N400 amplitude in response to interlingual homophones in comparison to control words for bilinguals, but not for English monolinguals. The reduced N400 response to homophones in bilinguals suggests facilitation of word recognition. These results suggest parallel activation of both L1 and L2 phonological representations when reading silently in the L2. These findings point to a language nonspecific model for bilinguals at the phonological level of representation. PMID- 22220966 TI - Current chemical biology approaches to interrogate protein methyltransferases. AB - Protein methyltransferases (PMTs) play various physiological and pathological roles through methylating histone and nonhistone targets. However, most PMTs including more than 60 human PMTs remain to be fully characterized. The current approaches to elucidate the functions of PMTs have been diversified by many emerging chemical biology technologies. This review focuses on progress in these aspects and is organized into four discussion modules (assays, substrates, cofactors, and inhibitors) that are important to elucidate biological functions of PMTs. These modules are expected to provide general guidance and present emerging methods for researchers to select and combine suitable PMT-activity assays, well-defined substrates, novel SAM surrogates, and PMT inhibitors to interrogate PMTs. PMID- 22220970 TI - Trigeminal trophic syndrome from stroke: an under-recognized central neuropathic itch syndrome. AB - Trigeminal trophic syndrome (TTS) is the historic name for neuropathic self induced facial ulceration from abnormal sensory symptoms leading to uncontrolled scratching. Anatomic co-localization of sensory loss (numbness) plus neuropathic itch and pain permits painless scratching. If the itch is severe, some patients will scratch to the point of causing self-injury. Patients may be unaware or may conceal the fact that their lesions are self-induced and thus the diagnosis presents a clinical challenge. Many cases remain undiagnosed, leading to unnecessary and ineffective tests, procedures, and prescribing. We document a patient with a central cause of TTS - multiple cerebral vascular accidents - and summarize the presentation, pathogenesis, and treatment options. PMID- 22220972 TI - Schizophrenia as variation in the sapiens-specific epigenetic instruction to the embryo. AB - The psychoses (schizophrenia and bipolar disorder) occur in all populations with approximately uniform incidence and sex-dependent age of onset. Core symptoms involve aspects of language; brain structural deviations are sex and hemisphere related. Genetic predisposition is unaccounted for by linkage or association. The hypothesis is proposed that the 'missing heritability' is epigenetic in form and generated in meiosis on a species-specific XY chromosomal template. A duplication from Xq21.3 to Yp11.2 that occurred 6 million years ago is proposed as critical to hominin evolution. Within this block of homology the Protocadherin11XY gene pair is expressed as a cell surface adhesion factor in both X and Y forms; it has undergone a series of coding changes (16 in the Y sequence and 5 in the X including two to cysteines) in the hominin lineage. According to the hypothesis these sequence changes, together with one or more deletions and a paracentric inversion in the Y block, were successively selected; late events in this series established cerebral asymmetry (the 'torque') as the defining characteristic of the human brain. Built around this reference frame, an epigenetic message channels early development of the embryo in a sapiens-specific format. Diversity in meiotic pairing is postulated as the basis for species-specific deviations in development associated with psychosis. PMID- 22220973 TI - Vigilance to behavioral problems needed for children with developmental disability. PMID- 22220971 TI - Genomic expression patterns in menstrual-related migraine in adolescents. AB - BACKGROUND: Exacerbation of migraine with menses is common in adolescent girls and women with migraine, occurring in up to 60% of females with migraine. These migraines are oftentimes longer and more disabling and may be related to estrogen levels and hormonal fluctuations. OBJECTIVE: This study identifies the unique genomic expression pattern of menstrual-related migraine (MRM) in comparison to migraine occurring outside the menstrual period and headache-free controls. METHODS: Whole blood samples were obtained from female subjects having an acute migraine during their menstrual period (MRM) or outside of their menstrual period (non-MRM) and controls (C)--females having a menstrual period without any history of headache. The messenger RNA was isolated from these samples, and genomic profile was assessed. Affymetrix Human Exon ST 1.0 (Affymetrix, Santa Clara, CA, USA) arrays were used to examine the genomic expression pattern differences between these 3 groups. RESULTS: Blood genomic expression patterns were obtained on 56 subjects (MRM = 18, non-MRM = 18, and controls = 20). Unique genomic expression patterns were observed for both MRM and non-MRM. For MRM, 77 genes were identified that were unique to MRM, while 61 genes were commonly expressed for MRM and non-MRM, and 127 genes appeared to have a unique expression pattern for non-MRM. In addition, there were 279 genes that differentially expressed for MRM compared to non-MRM that were not differentially expressed for non-MRM. Gene ontology of these samples indicated many of these groups of genes were functionally related and included categories of immunomodulation/inflammation, mitochondrial function, and DNA homeostasis. CONCLUSIONS: Blood genomic patterns can accurately differentiate MRM from non-MRM. These results indicate that MRM involves a unique molecular biology pathway that can be identified with a specific biomarker and suggest that individuals with MRM have a different underlying genetic etiology. PMID- 22220974 TI - Preparation of pyrolysis reference samples: evaluation of a standard method using a tube furnace. AB - A new, simple method for the reproducible creation of pyrolysis products from different materials that may be found at a fire scene is described. A temperature programmable steady-state tube furnace was used to generate pyrolysis products from different substrates, including softwoods, paper, vinyl sheet flooring, and carpet. The temperature profile of the tube furnace was characterized, and the suitability of the method to reproducibly create pyrolysates similar to those found in real fire debris was assessed. The use of this method to create proficiency tests to realistically test an examiner's ability to interpret complex gas chromatograph-mass spectrometric fire debris data, and to create a library of pyrolsates generated from materials commonly found at a fire scene, is demonstrated. PMID- 22220976 TI - Microwave-assisted synthesis of a series of lanthanide metal-organic frameworks and gas sorption properties. AB - A series of isostructural microporous lanthanide metal-organic frameworks (MOFs) formulated as [Ln(2)(TPO)(2)(HCOO)].(Me(2)NH(2)).(DMF)(4).(H(2)O)(6) {Ln = Y (1), Sm (2), Eu (3), Gd (4), Tb (5), Dy (6), Ho (7), Er (8), Tm (9), Yb (10), and Lu (11); H(3)TPO = tris-(4-carboxylphenyl)phosphineoxide; DMF = N,N dimethylformamide} has been synthesized under microwave-assisted solvothermal reaction for 30 min. Alternatively, if a conventional solvothermal reaction is carried out under the same temperature, a much longer time (3 days) is needed for the same phase in similar yield. Structure analysis reveals that the framework is a 4,8-connected network with point symbol (4(10).6(16).8(2)) (4(5).6)(2), which is the subnet of alb net. Thermal gravimetric analyses performed on as synthesized MOFs reveal that the frameworks have high thermal stability. The luminescent properties of 2, 3, 5, and 6 were investigated and show characteristic emissions for Sm(III), Eu(III), Tb(III), and Dy(III) at room temperature, respectively. Gas sorption properties of 1 and 3 were studied by experimentally measuring nitrogen, argon, carbon dioxide, methane, and hydrogen sorption isotherms. The resulting materials show high and preferential CO(2) adsorption over N(2) gas at ambient temperature, indicating that the present materials can be applied in a CO(2) capture process. PMID- 22220977 TI - Paraneoplastic neurological and hematological syndromes associated with prostate cancer. AB - Paraneoplastic neurological syndromes are defined as the remote effects of cancer on the nervous system. Here we report a 68-year-old man who initially presented with worsening paresthesia in the lower extremities. Although the culprit lesion remained to be identified, he coincidentally had diagnosis of prostate cancer by an annual prostate-specific antigen examination. Leukocytosis and elevated granulocyte colony-stimulating factor in serum were also detected. Neurological symptoms and leukocytosis improved after initiation of androgen-deprivation therapy followed by external beam radiotherapy. A total of 9 months after treatment, the patient showed no evidence of cancer recurrence or neurological signs. Paraneoplastic neurological syndromes are rare in prostate cancer and therefore have received little attention. We should be aware that when paraneoplastic neurological syndromes occur, they usually occur as the first sign of or during progression of prostate cancer. Furthermore, we should take into account the existence of malignancy when the cause of neurological symptoms cannot be specified. PMID- 22220979 TI - Development of an optimized random amplified polymorphic DNA protocol for fingerprinting of Klebsiella pneumoniae. AB - AIMS: To develop an optimized random amplified polymorphic DNA (RAPD) protocol for fingerprinting clinical isolates of Klebsiella pneumoniae. METHODS AND RESULTS: Employing factorial design of experiments, repeatable amplification patterns were obtained for 54 nosocomial isolates using 1 MUmol 1(-1) primer, 4 mmol 1(-1) MgCl(2), 0.4 mmol 1(-1) dNTPs, 2.5 U Taq DNA polymerase and 90 ng DNA template in a total volume of 25 MUl. The optimum thermocycling program was: initial denaturation at 94 degrees C for 4 min followed by 50 cycles of 1 min at 94 degrees C, 2 min at 34 degrees C, 2 min at 72 degrees C and a final extension at 72 degrees C for 10 min. The optimized RAPD protocol was highly discriminatory (Simpson's diversity index, 0.982), and all isolates were typable with repeatable patterns (Pearson's similarity coefficient ~ 100%). Seven main clusters were obtained on a similarity level of 70% and 32 distinct clusters on a similarity level of 85%, reflecting the heterogeneity of the isolates. CONCLUSIONS: Systematic optimization of RAPD generated reliable DNA fingerprints for nosocomial isolates of K. pneumoniae. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report on RAPD optimization based on factorial design of experiments for discrimination of K. pneumoniae. PMID- 22220980 TI - Effects on airways of short-term exposure to two kinds of wood smoke in a chamber study of healthy humans. AB - INTRODUCTION: Air pollution causes respiratory symptoms and pulmonary disease. Airway inflammation may be involved in the mechanism also for cardiovascular disease. Wood smoke is a significant contributor to air pollution, with complex and varying composition. We examined airway effects of two kinds of wood smoke in a chamber study. MATERIALS AND METHODS: Thirteen subjects were exposed to filtered air and to wood smoke from the start-up phase and the burn-out phase of the wood-burning cycle. Levels of PM(2.5) were 295 ug/m(3) and 146 ug/m(3), number concentrations 140 000/cm(3) and 100 000/cm(3). Biomarkers in blood, breath and urine were measured before and on several occasions after exposure. Effects of wood smoke exposure were assessed adjusting for results with filtered air. RESULTS: After exposure to wood smoke from the start-up, but not the burn out session, Clara cell protein 16 (CC16) increased in serum after 4 hours, and in urine the next morning. CC16 showed a clear diurnal variation. Fraction of exhaled nitric oxide (FENO) increased after wood smoke exposure from the burn-out phase, but partly due to a decrease after exposure to filtered air. No other airway markers increased. CONCLUSIONS: The results indicate that relatively low levels of wood smoke exposure induce effects on airways. Effects on airway epithelial permeability was shown for the start-up phase of wood burning, while FENO increased after the burn-out session. CC16 seems to be a sensitive marker of effects of air pollution both in serum and urine, but its function and the significance need to be clarified. PMID- 22220982 TI - Spin-canting magnetization in an unusual Co4 cluster-based layer compound from a 2,3-dihydroxyquinoxaline ligand. AB - The self-assembly of Co(O(2)CPh)(2) with a 2,3-dihydroxyquinoxaline (H(2)dhq) linker has revealed a new two-dimensional cluster-based compound, [Co(4)(OMe)(2)(O(2)CPh)(2)(dhq)(2)(MeOH)(2)](n), which shows spin-canted magnetization and a definite magnetic hysteresis loop. PMID- 22220983 TI - Smooth emergence in men undergoing nasal surgery: the effect site concentration of remifentanil for preventing cough after sevoflurane-balanced anaesthesia. AB - BACKGROUND: Suppression of cough during emergence after nasal surgery is practical to avoid bleeding from the surgical site. Previously recommended effect site concentration of remifentanil for preventing cough during emergence is restricted to female patients undergoing thyroid surgery, so we evaluated effective effect-site concentration of remifentanil for preventing cough during emergence for men undergoing nasal surgery. METHODS: Twenty-four American Society of Anesthesiologists (ASA) physical status I or II, between the ages of 18 and 60 years old, non-smoker male patients undergoing nasal surgery were enrolled in this study. The effective effect-site concentration for 50% of patients (EC(50) ) and and that for 95% of patients (EC(95) ) of remifentanil for preventing cough were determined by Dixon's up-and-down method and by isotonic regression method with a bootstrapping approach. Haemodynamic variables were compared in patients with cough and without cough during emergence. RESULTS: The EC(50) of remifentanil for preventing cough during emergence by Dixon's method was 2.17 ng/ml [standard deviation (SD) 0.38]. The estimated EC(50) and EC(95) of remifentanil using isotonic regression model with a bootstrapping approach were 2.35 ng/ml [95% confidence interval (CI) 1.89-2.66] and 2.94 ng/ml (95% CI 2.83 2.97), respectively. Mean arterial pressure and heart rate were significantly higher in patients with cough during emergence. Three out of 13 patients that received more than 2.5 ng/ml of remifentanil experienced a brief episode of bradypnea. CONCLUSIONS: The EC(95) of remifentanil for preventing cough in men after nasal surgery is 2.94 ng/ml. Remifentanil target-controlled infusion with established effect-site concentration could suppress cough in men during emergence from sevoflurane anaesthesia after nasal surgery, though reversible respiratory depression might arise at high effect-site concentration of remifentanil. PMID- 22220984 TI - The physiological functions of mammalian endoplasmic oxidoreductin 1: on disulfides and more. AB - SIGNIFICANCE: The oxidative process of disulfide-bond formation is essential for the folding of most secretory and membrane proteins in the endoplasmic reticulum (ER). It is driven by electron relay pathways that transfer two electrons derived from the fusion of two adjacent cysteinyl side chains onto various types of chemical oxidants. The conserved, ER-resident endoplasmic oxidoreductin 1 (Ero1) sulfhydryl oxidases that reduce molecular oxygen to generate an active-site disulfide represent one of these pathways. In mammals, two family members exist, Ero1alpha and Ero1beta. RECENT ADVANCES: The two mammalian Ero1 enzymes differ in transcriptional and post-translational regulation, tissue distribution, and catalytic turnover. A specific protein-protein interaction between either isoform and protein disulfide isomerase (PDI) facilitates the propagation of disulfides from Ero1 via PDI to nascent polypeptides, and inbuilt oxidative shutdown mechanisms in Ero1alpha and Ero1beta prevent excessive oxidation of PDI. CRITICAL ISSUES: Besides disulfide-bond generation, Ero1alpha also regulates calcium release from the ER and the secretion of disulfide-linked oligomers through its reversible association with the chaperone ERp44. This review explores the functional repertoire and possible redundancy of mammalian Ero1 enzymes. FUTURE DIRECTIONS: Systematic analyses of different knockout mouse models will be the most promising strategy to shed new light on unique and tissue-specific roles of Ero1alpha and Ero1beta. Moreover, in-depth characterization of the known physical interactions of Ero1 with peroxidases and PDI family members will help broaden our functional and mechanistic understanding of Ero1 enzymes. PMID- 22220985 TI - Understanding the "tailoring synthesis" of CdS nanorods by O2. AB - Parameters such as solution concentrations and composition of the ambient atmosphere are known to be important in phase and morphology control in the solvothermal synthesis of CdS semiconductor nanorods (NRs), but a clear understanding of the underlying mechanisms involved is lacking. In this work, a series of experiments were performed to demonstrate that the key factor affecting the phase and morphology of CdS NRs is the amount of O(2) in the space above the reaction solution in the sealed vessel relative to the amount of precursors in solution: O(2)-depleted conditions resulted in more cubic phase CdS and thick polycrystalline NRs with an aspect ratio usually less than 3, which have small blue shifts in band-edge emission and little surface trap emission, while O(2) rich conditions resulted in more hexagonal-phase CdS and slim single-crystal NRs, which have significantly blue shifted band-edge emission and relatively strong surface trap emission. Thus, increasing the amount of solution in the vessel, changing the ambient atmosphere from air to N(2), and increasing the reagent concentration all lower the molar ratio of O(2) to reagents and lead to more cubic phase and thicker NRs. The results indicate that the composition of the "empty" section of the reaction vessel plays as important a role as the composition of the liquid in determining the phase and morphology, something that has been overlooked in earlier work. A mechanism to explain the effect of oxygen on the nucleation and growth stages has been proposed on the basis of those results and further supported by shaking experiments and ZnS NR synthesis manipulation. The CdS NRs synthesized under different conditions showed obvious differences in photocatalytic activity, which indicated that controlling the synthetic process can lead to materials with tailored photocatalytic activity. PMID- 22220986 TI - Bendamustine: more ammunition in the battle against mantle cell lymphoma. PMID- 22220987 TI - Nadifloxacin downregulates the production of matrix metalloproteinases in the human epidermal keratinocyte cell line HaCaT. PMID- 22220988 TI - Multireference nature of chemistry: the coupled-cluster view. PMID- 22220989 TI - Narrative gerontology coming into its own. PMID- 22220990 TI - Nursing home social services directors and elder abuse staff training. AB - In a nationally representative study of 1,071 nursing home social services directors 80% of social services departments provided resident rights training and 60-70% were involved in abuse training. Departments headed by recent grads and in chain nursing homes or in the northeast were more likely to be involved in training. Seventy-two percent of social services directors were able to provide one-on-one training about reporting suspected abuse; education and licensure were related to ability to train. PMID- 22220991 TI - Assessment in Adult Protective Services: do multidisciplinary teams make a difference? AB - This study compared 2 approaches to the assessment of Adult Protective Services (APS) cases. Using administrative data from 869 cases in 2 counties in Maryland, the differences between a nurse/social worker team and a lone social worker in case disposition, risk reduction, recidivism, and cost effectiveness were examined. Lone social workers were significantly more likely to confirm financial exploitation, physical abuse, and neglect by others; while the team approach resulted in significantly greater risk reduction. No differences were observed in relation to recidivism, self-neglect and cost savings. Given limited resources, research that examines optimal staffing patterns in APS agencies is warranted. PMID- 22220992 TI - Family well-being concerns of grandparents in skipped generation families. AB - This study examined the family well-being concerns of grandparents in skipped generation families. Co-resident grandparents who are responsible for raising their grandchildren completed surveys, focus groups, or individual interviews. Service providers to skipped-generation families also participated in individual interviews to provide an additional perspective to grandparents' concerns. Results indicated 5 levels of concerns: intrapersonal, interpersonal, organizational or institutional, policy, and societal. Concerns at different levels were interrelated and pointed to the need for multilevel interventions to help these families. Implications of the findings for future interventions with skipped-generation families are discussed. PMID- 22220993 TI - The effects of sociocultural factors on older Asian Americans' access to care. AB - Most Asian American elders are immigrants to the United States, and sociocultural factors such as English proficiency and immigration status are prominent factors in their lives. Using data from the California Health Interview Surveys to focus on Asian Americans over age 50, this study seeks to identify interethnic differences, and the effects of English proficiency and immigration status in the way older Asian Americans access healthcare. The results indicated that Asian ethnicity, English proficiency, and immigration status have significant independent effects on older Asian Americans' access to care. Implications for social work's role in addressing access disparities are discussed. PMID- 22220994 TI - "Talking in a new way": older individuals' experiences of group work in an acute psychiatric ward. AB - Group work is frequently used in mental health, however qualitative studies on service-users' views are rare. Semistructured interviews explored 12 participants' experiences of a cafe-style social group and a mutual-aid group offered on an older persons psychiatric ward in Christchurch, New Zealand. The values of the strengths-based approach underpinning the groups were reflected back in the experience of an affirming environment, an exchange of strengths, and the capacity to change. The appeal of the cafe-style may be culturally specific to European women however, reinforcing the importance of an awareness of culture and diversity. PMID- 22220996 TI - Evaluation of a solid-supported tagging strategy for mass spectrometric analysis of peptides. AB - We have explored two divinylbenzene cross-linked polystyrene supports for use in a solid-supported N-terminal peptide tagging strategy. Resin-bound tags designed to be cleaved in a single step at the N-terminus of peptides have been devised and explored as peptide N-terminal tagging reagents (constructs) for subsequent mass spectrometric analysis. While the brominated tagging approach shows promise, the use of these specific solid supports has drawbacks, in terms of tagging reaction scale, for real applications in proteomics. PMID- 22220998 TI - Analysis of proteins in human gingival crevicular fluid by mass spectrometry. AB - BACKGROUND AND OBJECTIVE: Gingival crevicular fluid is a bodily fluid transuded from periodontal tissues into the gingival crevice and periodontal pocket, and contains many species of components. Proteins in gingival crevicular fluid have been studied as markers for periodontal diseases. Mass spectrometric analysis is used for the analyses of proteins, lipids, saccharides and metals, and expected as an approach for disease diagnosis. For better analysis of the protein components in gingival crevicular fluid, we investigated proteins in gingival crevicular fluid samples from the healthy gingival crevice and periodontal pocket using mass spectrometry. MATERIAL AND METHODS: Gingival crevicular fluid samples were collected from subjects who gave their informed consent and were periodontally healthy or had diseased pockets. These samples were electrophoretically separated, and each fraction on the gels was analysed by nano liquid chromatography coupled with tandem mass spectrometry. Antimicrobial peptides detected in gingival crevicular fluid were confirmed by western blotting. RESULTS: One hundred and four proteins were detected in gingival crevicular fluid samples from both healthy sites and sites of periodontitis; 64 proteins were contained only in gingival crevicular fluid from healthy sites and 63 proteins were observed only in gingival crevicular fluid from periodontitis sites. These proteins were blood-, cytoskeleton-, immunity-, inflammation- and lipid-related proteins and enzymes. Some proteins, including ceruloplasmin, glycogen phosphorylase, glutathione S-transferase, phosphoglycerate mutase, psoriasin, S100A11 and resistin, were identified for the first time in gingival crevicular fluid. Antimicrobial peptides, such as lactoferrin, alpha1 antitrypsin, lipocalin, S100A7, S100A8, S100A9 and cathelicidin, were observed by mass spectrometry and western blotting. CONCLUSION: Multiple protein components in gingival crevicular fluid were analysed at the same time using mass spectrometry, and this approach may be useful for the diagnosis of periodontal diseases. PMID- 22220999 TI - Controlled deposition of structured polymer films: chemical and rheological factors in chitosan film formation. AB - The technique of "spread coating" has been used to create thin films from solutions of deacetylated and butyl-modified chitosan polymer, and the effect of deposition rate on film thickness has been characterized. Results show that films of controlled thickness can be reproducibly produced and that hydrophobic modification of the polymer can extend the range over which a linear response between film thickness and deposition rate is achieved. Viscometry and fluorescence spectroscopy were also employed to characterize the micellar characteristics of solutions of both deacetylated and butyl-modified chitosan polymer. Although both deacetylated and butyl-modified chitosan solutions were found to have inter- and intramolecular interactions, as well as hydrophobic domains able to incorporate fluorophores, deacetylated chitosan was found to be more interconnected via intermolecular interactions at higher concentrations. These results are important as having the ability to understand how the introduction of hydrophobic modification, a technique shown to introduce solution based micelle structure and micellar aggregates that support enzyme immobilization, affects film thickness and morphology of spread coated thin films will aid the long-term development and deployment of chitosan-based biofuel cell electrodes. PMID- 22221000 TI - Saxagliptin: a review of its use as combination therapy in the management of type 2 diabetes mellitus in the EU. AB - Saxagliptin (OnglyzaTM) is a dipeptidyl peptidase 4 inhibitor widely approved for the treatment of type 2 diabetes mellitus. In the EU, saxagliptin is indicated as combination therapy with metformin, a sulfonylurea, a thiazolidinedione, or insulin (with or without metformin) for the treatment of adult patients with type 2 diabetes, including those with mild to severe renal impairment. This article reviews the clinical efficacy and tolerability of add-on saxagliptin therapy in patients with type 2 diabetes, in line with its approved indications in the EU, and summarizes the drug's pharmacological properties. The clinical efficacy of saxagliptin 5 mg/day in combination with metformin, glibenclamide (glyburide), a thiazolidinedione, or insulin (with or without metformin) has been demonstrated in several randomized, double-blind, placebo-controlled, multicentre, phase III trials (18-104 weeks in duration) in patients with type 2 diabetes. In these trials, glycosylated haemoglobin (HbA(1c)) was changed from baseline (primary endpoint) by a greater extent with add-on saxagliptin 5 mg/day (-1.09% to +0.03%) than with comparator regimens (-0.44% to +0.69%). Two other randomized, double blind trials showed that saxagliptin 5 mg/day as add-on therapy to metformin was noninferior to uptitrated glipizide in terms of lowering HbA(1c) (-0.74% vs 0.80%) at 52 weeks, or sitagliptin (-0.52% vs -0.62%) at 18 weeks. Saxagliptin 2.5 mg/day as add-on to existing anti-diabetic therapy was also effective for up to 52 weeks in a randomized, double-blind, placebo-controlled, multicentre trial in patients with type 2 diabetes and renal impairment (HbA(1c) was reduced by 1.08% vs 0.36%; p <= 0.007). Saxagliptin as add-on therapy for up to 4 years was generally well tolerated in clinical trials. Treatment with saxagliptin did not increase the risk of hypoglycaemia or cardiovascular outcomes relative to placebo or active comparators, and was generally weight neutral. In conclusion, saxagliptin is a useful option as add-on therapy to metformin, a sulfonylurea, a thiazolidinedione, or insulin (with or without metformin) in patients with type 2 diabetes who require combination therapy. PMID- 22221001 TI - Combined hormonal contraceptives: is it time to reassess their role in migraine? AB - OBJECTIVE: This paper will review the extensive array of hormonal contraceptives. It will examine the benefits and risks associated with them - particularly with regard to stroke risk - and shed light on divergent findings in the literature. BACKGROUND: Menstrual-related migraine is a particularly disabling presentation of migraine often deserving of specific prevention. There is accumulating evidence that hormonal preventives may offer such protection. Although a legacy of research shows an increased risk of stroke with high-dose oral contraceptives (OCs) (those containing 50-150ug of estrogen), there is evidence to suggest that this does not apply to ultralow-dose OCs - those containing <25ug ethinyl estradiol - when used in appropriate populations (ie, normotensive non-smokers). Migraine with aura (MwA) increases stroke risk, and that risk is directly correlated to the frequency of aura, a factor that can be modified - either upward or downward - by combined hormonal contraceptives (CHCs). The argument against using CHCs in MwA is based on the concerns that (1) OCs increase stroke risk, (2) MwA increases stroke risk, and (3) combining these risk factors might produce additive or synergistic risk. Evidence does not support concerns (1) and (3), and suggests otherwise. SUMMARY: The risk/benefit analysis of CHCs is shifting. There is growing evidence for a potential role for CHCs in the prevention of menstrual-related migraine. At the same time, the risk of these products is declining, as newer and lower dose formulations replace their historical predecessors. And although migraine aura is a risk factor for stroke, there is not convincing evidence to suggest that the addition of a low-dose CHC alters that risk in non-smoking, normotensive users. Selected hormonal preventives could potentially decrease stroke risk in MwA via reduction in aura frequency achieved by reducing peak estrogen exposure. With this shift in risk/benefit analysis, it is time to reconsider the role of CHCs in migraine - both with and without aura. PMID- 22221002 TI - piRNAs and their involvement in male germline development in mice. AB - Piwi-interacting RNAs (piRNAs) are a class of small non-coding RNAs expressed in the animal gonads. They are implicated in silencing the genome instability threat posed by mobile genetic elements called transposons. Unlike other small RNAs, which use double-stranded precursors, piRNAs seem to arise from long single stranded precursor transcripts expressed from discrete genomic regions. In mice, the Piwi pathway is essential for male fertility, and its loss-of-function mutations affect several distinct stages of spermatogenesis. While this small RNA pathway primarily operates post-transcriptionally, it also impacts DNA methylation of target retrotransposon loci, representing an intriguing model of RNA-directed epigenetic control in mammals. Remarkably the Piwi pathway components are specifically localized at germinal granule/nuage, an evolutionarily conserved but still enigmatic ribonucleoprotein compartment in the germline. The inaccessibility of the germline for easy experimental manipulation has meant that this class of RNAs has remained enigmatic. However, recent advances in the use of cell culture models and cell-free systems have greatly advanced our understanding. In this review, we briefly summarize our current understanding of the Piwi pathway, focusing on its developmental regulation, piRNA biogenesis and key function in male germline development from fetal spermatogonial stem cell stage to postnatal haploid spermiogenesis in mice. PMID- 22221003 TI - In situ structural characterization of platinum dendrimer-encapsulated oxygen reduction electrocatalysts. AB - In situ electrochemical extended X-ray absorption fine structure (EXAFS) was used to evaluate the structure of Pt dendrimer-encapsulated nanoparticles (DENs) during the oxygen reduction reaction (ORR). The DENs contained an average of just 225 atoms each. The results indicate that the Pt coordination number (CN) decreases when the electrode potential is moved to positive values. The results are interpreted in terms of an ordered core, disordered shell model. The structure of the DENs is not significantly impacted by the presence of dioxygen, but other electrogenerated species may have a significant impact on nanoparticle structure. PMID- 22221004 TI - Finding the missing stimulus mismatch negativity (MMN): emitted MMN to violations of an auditory gestalt. AB - Deviations from repetitive auditory stimuli evoke a mismatch negativity (MMN). Counterintuitively, omissions of repetitive stimuli do not. Violations of patterns reflecting complex rules also evoke MMN. To detect a MMN to missing stimuli, we developed an auditory gestalt task using one stimulus. Groups of six pips (50 ms duration, 330 ms stimulus onset asynchrony [SOA], 400 trials), were presented with an intertrial interval (ITI) of 750 ms while subjects (n=16) watched a silent video. Occasional deviant groups had missing 4th or 6th tones (50 trials each). Missing stimuli evoked a MMN (p<.05). The missing 4th (-0.8 uV, p<.01) and the missing 6th stimuli (-1.1 uV, p<.05) were more negative than standard 6th stimuli (0.3 uV). MMN can be elicited by a missing stimulus at long SOAs by violation of a gestalt grouping rule. Patterned stimuli appear more sensitive to omissions and ITI than homogenous streams. PMID- 22221005 TI - Passive range of motion in a population-based sample of children with spastic cerebral palsy who walk. AB - While passive range of motion (PROM) is commonly used to inform decisions on therapeutic management, knowledge of PROM of children with spastic cerebral palsy (CP) is limited. A population-based sample of 178 children with spastic CP (110 male; unilateral, n = 94; bilateral, n = 84; age range 4-17 years) and 68 typically developing children (24 male; age range 4-17 years) were recruited to the study. All children were able to walk a minimum of 10 m over a straight flat course, with or without assistive devices. Gross Motor Function Classification System (GMFCS) levels of participants with CP were: Level I = 55, Level II = 88, Level III = 21, and Level IV = 14. Ankle dorsiflexion, knee extension, popliteal angle, hip abduction, hip internal rotation, and hip external rotation were measured using a goniometer. The results indicate that the children with CP had significantly reduced PROM compared to the children with typical development. Children with CP demonstrated reduced length in the hamstrings, hip adductor, iliopsoas and gastrocnemius-soleus musculature, and contracture at the knee joint. Among children with CP, there were significant reductions in range with increasing functional limitation (higher GMFCS level) and variations based on unilateral or bilateral involvement. This was particularly the case for the hamstrings and hip adductor musculature, where PROM varied considerably across GMFCS Levels I to IV. PMID- 22221006 TI - Development and validation of a simple GC-MS method for the simultaneous determination of 11 anticholinesterase pesticides in blood--clinical and forensic toxicology applications. AB - Anticholinesterase pesticides are widely used, and as a result they are involved in numerous acute and even fatal poisonings. The aim of this study was the development, optimization, and validation of a simple, rapid, specific, and sensitive gas chromatography-mass spectrometry method for the determination of 11 anticholinesterase pesticides (aldicarb, azinphos methyl, carbofuran, chlorpyrifos, dialifos, diazinon, malathion, methamidophos, methidathion, methomyl, and terbufos) in blood. Only 500 MUL of blood was used, and the recoveries after liquid-liquid extraction (toluene/chloroform, 4:1, v/v) were more than 65.6%. The calibration curves were linear (R(2) >= 0.996). Limit of detections and limit of quantifications were found to be between 1.00-10.0 and 3.00-30.0 MUg/L, respectively. Accuracy expressed as the %E(r) was found to be between -11.0 and 7.8%. Precision expressed as the percent relative standard deviation was found to be <9.4%. The developed method can be applied for the investigation of both forensic and clinical cases of accidental or suicidal poisoning with these pesticides. PMID- 22221008 TI - Pheochromocytoma crisis caused by Campylobacter fetus. AB - Pheochromocytoma crisis is a life-threatening endocrine emergency associated with symptoms of excess release of catecholamines. It might present spontaneously or be unmasked by triggers including trauma, surgery and certain medications that provoke catecholamine release by tumors. Here we report a case of pheochromocytoma crisis associated with abscess formation in the tumor and bacteremia of Campylobacter fetus, which was successfully treated with antibiotics and a surgical resection. This case appears to be the first reported case in the literature of abscess formation by C. fetus in pheochromocytoma, leading to catecholamine crisis. PMID- 22221009 TI - Paediatric nurse practitioner managed cardiology clinics: patient satisfaction and appointment access. AB - AIM: This article summarizes a comparative study of patient/family satisfaction and appointment wait times in physician managed vs. paediatric nurse practitioner managed cardiology clinics. BACKGROUND: Appointment wait times exceeded 40 days in the outpatient cardiology department at a children's hospital. To address the gap in available appointments, paediatric nurse practitioner managed cardiology clinics were implemented. METHODS: A sample of 128 patients who presented concurrently in physician or paediatric nurse practitioner managed cardiology clinics from December 2009 through February 2010 was recruited for participation. The hospital's ambulatory patient satisfaction survey was utilized to measure level of patient satisfaction with care. Survey responses were evaluated using Fisher's exact test. Appointment wait times were compared pre and post implementation of paediatric nurse practitioner managed clinics. RESULTS: Sixty five physician families and 63 paediatric nurse practitioner families completed the satisfaction survey. There was no statistically significant difference in patient satisfaction between clinic types. Appointment wait time decreased from 46 to 43 days, which was not statistically significant. Paediatric nurse practitioner clinics included a statistically higher percentage total of urgent appointments compared to that in physician clinics. CONCLUSIONS: Paediatric nurse practitioner managed cardiology clinics are a strategic solution for improving patient access and facilitating high quality patient care while earning high levels of patient satisfaction. This healthcare delivery model illustrates the potential for expanded utilization of advanced practice nurses. PMID- 22221010 TI - Tolerogenic DNA vaccine for prevention of autoimmune ovarian disease. AB - DNA vaccines have been widely used to induce immune responses against molecular targets. In this study, we explored the possibility of using DNA vaccine combined with the immunosuppressant FK506 (tacrolimus) to antigen-specifically suppress unwanted immune responses and prevent autoimmune ovarian disease. To that end, we immunized C57BL/6 mice with a DNA vaccine encoding mouse zona pellucida 3 (ZP3) together with FK506. The immunization induced ZP3-specific CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg), which suppressed the induction of ZP3-specific delayed type hypersensitivity in the animals. Significantly, the immunization also protected the animals from experimentally induced autoimmune ovarian disease. These results suggest that DNA vaccination in the presence of FK506 may be used to induce Treg cells and prevent AOD. PMID- 22221012 TI - Epigenetic influences that modulate infant growth, development, and disease. AB - SIGNIFICANCE: Epigenetic modifications are key processes in understanding normal human development and are largely responsible for the myriad cell and tissue types that originate from a single-celled fertilized ovum. The three most common processes involved in bringing about epigenetic changes are DNA methylation, histone modification, and miRNA effects. There are critical periods in the development of the zygote, the embryo, and the fetus where in the organism is most susceptible to epigenetic influences because of normal demethylation and de novo methylation processes that occur in the womb. RECENT ADVANCES: A number of epigenetic modifications of normal growth patterns have been recognized, leading to altered development and disease states in the mammalian fetus and infant. 'Fetal programming' due to these epigenetic changes has been implicated in pathogenesis of adult-onset disease such as hypertension, diabetes, and cardiovascular disease. There may also be transgenerational effects of such epigenetic modifications. CRITICAL ISSUES: The impact of environmental agents and endogenous factors such as stress at critical periods of infant development has immediate, life-long and even multi-generational effects. Both the timing and the degree of insult may be important. Understanding these influences may help prevent onset of disease and promote normal growth. FUTURE DIRECTIONS: Use of one carbon metabolism modifying agents such as folic acid during critical periods of epigenetic modulation may have significant clinical impact. Their use as therapeutic agents in targeted epigenetic modulation of genes may be the new frontier for clinical therapeutics. PMID- 22221013 TI - CaSO4 and its pressure-induced phase transitions. A density functional theory study. AB - Theoretical investigations concerning possible calcium sulfate, CaSO(4), high pressure polymorphs have been carried out. Total-energy calculations and geometry optimizations have been performed by using density functional theory at the B3LYP level for all crystal structures considered. The following sequence of pressure driven structural transitions has been found: anhydrite, Cmcm (in parentheses the transition pressure) -> monazite-type, P2(1)/n (5 GPa) -> barite-type, Pnma (8 GPa), and scheelite-type, I4(1)/a (8 GPa). The equation of state of the different polymorphs is determined, while their corresponding vibrational properties have been calculated and compared with previous theoretical results and experimental data. PMID- 22221014 TI - Effects of adductor-canal-blockade on pain and ambulation after total knee arthroplasty: a randomized study. AB - BACKGROUND: Total knee arthroplasty (TKA) is associated with intense post operative pain. Besides providing optimal analgesia, reduction in side effects and enhanced mobilization are important in this elderly population. The adductor canal-blockade is theoretically an almost pure sensory blockade. We hypothesized that the adductor-canal-blockade may reduce morphine consumption (primary endpoint), improve pain relief, enhance early ambulation ability, and reduce side effects (secondary endpoints) after TKA compared with placebo. METHODS: Patients aged 50-85 years scheduled for TKA were included in this parallel double-blind, placebo-controlled randomized trial. The patients were allocated to receive a continuous adductor-canal-blockade with intermittent boluses via a catheter with either ropivacaine 0.75% (n = 34) or placebo (n = 37) (http://www.clinicaltrials.gov Identifier: NCT01104883). RESULTS: Seventy-five patients were randomized in a 1 : 1 ratio and 71 patients were analyzed. Morphine consumption from 0 to 24 h was significantly reduced in the ropivacaine group compared with the placebo group (40 +/- 21 vs. 56 +/- 26 mg, P = 0.006). Pain was significantly reduced in the ropivacaine group during 45 degrees flexion of the knee (P = 0.01), but not at rest (P = 0.06). Patients in the ropivacaine group performed the ambulation test, the Timed-Up-and-Go (TUG) test, at 24 h significantly faster than patients in the placebo group (36 +/- 17 vs. 50 +/- 29 s, P = 0.03). CONCLUSION: The adductor-canal-blockade significantly reduced morphine consumption and pain during 45 degrees flexion of the knee compared with placebo. In addition, the adductor-canal-blockade significantly enhanced ambulation ability assessed by the TUG test. PMID- 22221015 TI - Binary group 15 polyazides. structural characterization of [Bi(N3)4]-, [Bi(N3)5]2 , [bipy.Bi(N3)5]2-, [Bi(N3)6]3-, bipy.As(N3)3, bipy.Sb(N3)3, and [(bipy)2.Bi(N3)3]2 and on the lone pair activation of valence electrons. AB - The binary group 15 polyazides As(N(3))(3), Sb(N(3))(3), and Bi(N(3))(3) were stabilized by either anion or donor-acceptor adduct formation. Crystal structures are reported for [Bi(N(3))(4)](-), [Bi(N(3))(5)](2-), [bipy.Bi(N(3))(5)](2-), [Bi(N(3))(6)](3-), bipy.As(N(3))(3), bipy.Sb(N(3))(3), and [(bipy)(2).Bi(N(3))(3)](2). The lone valence electron pair on the central atom of these pnictogen(+III) compounds can be either sterically active or inactive. The [Bi(N(3))(5)](2-) anion possesses a sterically active lone pair and a monomeric pseudo-octahedral structure with a coordination number of 6, whereas its 2,2' bipyridine adduct exhibits a pseudo-monocapped trigonal prismatic structure with CN 7 and a sterically inactive lone pair. Because of the high oxidizing power of Bi(+V), reactions aimed at Bi(N(3))(5) and [Bi(N(3))(6)](-) resulted in the reduction to bismuth(+III) compounds by [N(3)](-). The powder X-ray diffraction pattern of Bi(N(3))(3) was recorded at 298 K and is distinct from that calculated for Sb(N(3))(3) from its single-crystal data at 223 K. The [(bipy)(2).Bi(N(3))(3)](2) adduct is dimeric and derived from two BiN(8) square antiprisms sharing an edge consisting of two MU(1,1)-bridging N(3) ligands and with bismuth having CN 8 and a sterically inactive lone pair. The novel bipy.As(N(3))(3) and bipy.Sb(N(3))(3) adducts are monomeric and isostructural and contain a sterically active lone pair on their central atom and a CN of 6. A systematic quantum chemical analysis of the structures of these polyazides suggests that the M06-2X density functional is well suited for the prediction of the steric activity of lone pairs in main-group chemistry. Furthermore, it was found that the solid-state structures can strongly differ from those of the free gas-phase species or those in solutions and that lone pairs that are sterically inactive in a chemical surrounding can become activated in the free isolated species. PMID- 22221017 TI - Nevoid urticaria pigmentosa along Blaschko's line. PMID- 22221018 TI - New policy on the publication of obituaries in Animal Genetics. PMID- 22221019 TI - Genetic characterization of Latin-American Creole cattle using microsatellite markers. AB - Genetic diversity in and relationships among 26 Creole cattle breeds from 10 American countries were assessed using 19 microsatellites. Heterozygosities, F statistics estimates, genetic distances, multivariate analyses and assignment tests were performed. The levels of within-breed diversity detected in Creole cattle were considerable and higher than those previously reported for European breeds, but similar to those found in other Latin American breeds. Differences among breeds accounted for 8.4% of the total genetic variability. Most breeds clustered separately when the number of pre-defined populations was 21 (the most probable K value), with the exception of some closely related breeds that shared the same cluster and others that were admixed. Despite the high genetic diversity detected, significant inbreeding was also observed within some breeds, and heterozygote excess was detected in others. These results indicate that Creoles represent important reservoirs of cattle genetic diversity and that appropriate conservation measures should be implemented for these native breeds in order to minimize inbreeding and uncontrolled crossbreeding. PMID- 22221020 TI - Identification of an FBN1 mutation in bovine Marfan syndrome-like disease. AB - Mutations in the gene encoding fibrillin-1 (FBN1), a component of the extracellular microfibril, cause Marfan syndrome (MFS). Frequent observation of cattle with a normal withers height, but lower body weight than age-matched normal cattle, was recently reported among cattle sired by phenotypically normal Bull A, in Japanese Black cattle. These cattle also showed other characteristic features similar to the clinical phenotype of human MFS, such as a long phalanx proximalis, oval face and crystalline lens cloudiness. We first screened a paternal half-sib family comprising 36 affected and 10 normal offspring of Bull A using the BovineSNP50 BeadChip (illumina). Twenty-two microsatellite markers mapped to a significant region on BTA10 were subsequently genotyped on the family. The bovine Marfan syndrome-like disease (MFSL) was mapped onto BTA10. As FBN1 is located in the significant region, FBN1 was sequenced in Bull A, and three affected and one normal cattle. A G>A mutation at the intron64 splicing accepter site (c.8227-1G>A) was detected in 31 of 36 affected animals (84.7%). The c.8227-1G>A polymorphism was not found in 20 normal offspring of Bull A or in 93 normal cattle unrelated to Bull A. The mutation caused a 1-base shift of the intron64 splicing accepter site to the 3' direction, and a 1-base deletion in processed mRNA. This 1-base deletion creates a premature termination codon, and a 125-amino acid shorter Fibrillin-1 protein is produced from the mutant mRNA. We therefore conclude that the c.8227-1G>A mutation is causative for MFSL. Furthermore, it was suggested that Bull A exhibited germline mosaicism for the mutation, and that the frequency of the mutant sperm was 14.9%. PMID- 22221021 TI - A whole-genome association study for pig reproductive traits. AB - A whole-genome association study was performed for reproductive traits in commercial sows using the PorcineSNP60 BeadChip and Bayesian statistical methods. The traits included total number born (TNB), number born alive (NBA), number of stillborn (SB), number of mummified foetuses at birth (MUM) and gestation length (GL) in each of the first three parities. We report the associations of informative QTL and the genes within the QTL for each reproductive trait in different parities. These results provide evidence of gene effects having temporal impacts on reproductive traits in different parities. Many QTL identified in this study are new for pig reproductive traits. Around 48% of total genes located in the identified QTL regions were predicted to be involved in placental functions. The genomic regions containing genes important for foetal developmental (e.g. MEF2C) and uterine functions (e.g. PLSCR4) were associated with TNB and NBA in the first two parities. Similarly, QTL in other foetal developmental (e.g. HNRNPD and AHR) and placental (e.g. RELL1 and CD96) genes were associated with SB and MUM in different parities. The QTL with genes related to utero-placental blood flow (e.g. VEGFA) and hematopoiesis (e.g. MAFB) were associated with GL differences among sows in this population. Pathway analyses using genes within QTL identified some modest underlying biological pathways, which are interesting candidates (e.g. the nucleotide metabolism pathway for SB) for pig reproductive traits in different parities. Further validation studies on large populations are warranted to improve our understanding of the complex genetic architecture for pig reproductive traits. PMID- 22221022 TI - Genome-wide mapping for fatty acid composition and melting point of fat in a purebred Duroc pig population. AB - The fatty acid composition and melting point of fatty tissue are among the most important economic traits in pig breeding because of their influence on the eating quality of meat. Identifying the quantitative trait locus (QTL) of these traits may help reveal the genetic structure of fatty acid composition and the melting point of fatty tissue and improve meat-quality traits by marker-assisted selection. We conducted whole-genome QTL analysis for fatty acid composition and melting point of inner and outer subcutaneous fat and inter- and intramuscular fat in a purebred Duroc population. A total of 129 markers were genotyped and used for QTL analysis. For fatty acid compositions of inner and outer subcutaneous fat, three significant QTL and 17 suggestive QTL were detected on SSC2, 4, 6, 8, 9, 10, 11, 12, 14 and 18. For the melting point of inner and outer subcutaneous fat, two significant QTL were detected on the same region of SSC14. For fatty acid compositions of inter- and intramuscular fat, five significant QTL and 13 suggestive QTL were detected on SSC2, 4, 6, 8, 9, 10, 14 and 15. On SSC14, significant QTL for C18:0 and C18:1 of outer subcutaneous fat and intramuscular fat, and melting point of subcutaneous fat, which had high likelihood of odds (LOD) scores (2.67-5.78), were detected in the same region. This study determined QTL affecting fatty acid composition and melting point of different fat tissues in purebred Duroc pigs. PMID- 22221023 TI - Mitochondrial lineages reveal intense gene flow between Iberian wild boars and South Iberian pig breeds. AB - The phylogeography of wild boars (WB) and domestic pigs (Sus scrofa) has contributed important insights into where and when domestication occurred. The geographic distribution of two core haplotypes (E1a and E1c) of the main European phylogenetic clade suggests that Central Europe was an early domestication centre, although the complexity of the pattern does not exclude the possibility that multiple domestication events occurred in different regions. To investigate the relationships among WB and domestic pig breeds in Iberia, a fragment of the mitochondrial DNA control region from a large sample (n=409) of WB and local pig breeds was co-analysed with published sequences from other European populations. The Iberian sample revealed a high frequency of a sub-cluster (E1c) of the European haplogroup E1 in 77% of total Iberian samples, 96% of WB, 90% of Alentejano (Portugal) and 87% of Iberian breed pigs (Spain; Black Hairy, Black Hairless and Red varieties). Low genetic distance (F'(ST) = 0.105) was observed between Alentejano (Portugal) and Iberian breed pigs (Spain). Alentejano and Iberian breed pigs showed low genetic distances to both Iberian and Central European WB (average F'(ST) =0.345 and 0.215, respectively). This pattern suggests that early pig husbandry in the Iberian Peninsula did not solely rely on imported Central European stock, but also included the recruitment of local WB. PMID- 22221024 TI - A cohort study of racing performance in Japanese Thoroughbred racehorses using genome information on ECA18. AB - Using 1710 Thoroughbred racehorses in Japan, a cohort study was performed to evaluate the influence of genotypes at four single nucleotide polymorphisms (SNPs) on equine chromosome 18 (ECA18), which were associated in a previous genome-wide association study for racing performance with lifetime earnings and performance rank. In males, both g.65809482T>C and g.65868604G>T were related to performance rank (P= 0.005). In females, g.65809482T>C (P = 1.76E-6), g.65868604G>T (P=6.81E-6) and g.66493737C>T (P=4.42E-5) were strongly related to performance rank and also to lifetime earnings (P < 0.05). When win-race distance (WRD) among all winning racehorses and best race distance (BRD) among elite racehorses were considered as the phenotypes, significant associations (P<0.001) were observed for all four SNPs. The favourable race distance of both elite (BRD) and novice racehorses (WRD) was also associated with genotypes in the ECA18 region, indicating the presence of a gene in this region influencing optimum race distance in Thoroughbred racehorses. Therefore, the association with performance rank is likely due to the bias in the race distances. The location of the SNPs within and proximal to the gene encoding myostatin (MSTN) strongly suggests that regulation of the MSTN gene affects racing performance. In particular, the g.65809482T>C, g.65868604G>T and g.66493737C>T SNPs, or their combinations, may be genetic diagnostic markers for racing performance indicators such as WRD and BRD. PMID- 22221025 TI - A microsatellite analysis of five Colonial Spanish horse populations of the southeastern United States. AB - The domestic horse (Equus caballus) was re-introduced to the Americas by Spanish explorers. Although horses from other parts of Europe were subsequently introduced, some New World populations maintain characteristics ascribed to their Spanish heritage. The southeastern United States has a history of Spanish invasion and settlement, and this influence on local feral horse populations includes two feral-recaptured breeds: the Florida Cracker and the Marsh Tacky, both of which are classified as Colonial Spanish horses. The feral Banker horses found on islands off the coast of North Carolina, which include, among others, the Shackleford Banks, the Corolla and the Ocracoke, are also Colonial Spanish horses. Herein we analyse 15 microsatellite loci from 532 feral and 2583 domestic horses in order to compare the genetic variation of these five Colonial Spanish Horse populations to 40 modern horse breeds. We find that the Corolla horse has very low heterozygosity and that both the Corolla and Ocracoke populations have a low mean number of alleles. We also find that the Florida Cracker population has a heterozygosity deficit. In addition, we find evidence of similarity of the Shackleford Banks, Marsh Tacky and Florida Cracker populations to New World Iberian horse breeds, while the origins of the other two populations are less clear. PMID- 22221026 TI - Identification of quantitative trait loci affecting resistance to gastrointestinal parasites in a double backcross population of Red Maasai and Dorper sheep. AB - A genome-wide scan for quantitative trait loci (QTL) affecting gastrointestinal nematode resistance in sheep was completed using a double backcross population derived from Red Maasai and Dorper ewes bred to F(1) rams. This design provided an opportunity to map potentially unique genetic variation associated with a parasite-tolerant breed like Red Maasai, a breed developed to survive East African grazing conditions. Parasite indicator phenotypes (blood packed cell volume - PCV and faecal egg count - FEC) were collected on a weekly basis from 1064 lambs during a single 3-month post-weaning grazing challenge on infected pastures. The averages of last measurements for FEC (AVFEC) and PCV (AVPCV), along with decline in PCV from challenge start to end (PCVD), were used to select lambs (N = 371) for genotyping that represented the tails (10% threshold) of the phenotypic distributions. Marker genotypes for 172 microsatellite loci covering 25 of 26 autosomes (1560.7 cm) were scored and corrected by Genoprob prior to qxpak analysis that included Box-Cox transformed AVFEC and arcsine transformed PCV statistics. Significant QTL for AVFEC and AVPCV were detected on four chromosomes, and this included a novel AVFEC QTL on chromosome 6 that would have remained undetected without Box-Cox transformation methods. The most significant P-values for AVFEC, AVPCV and PCVD overlapped the same marker interval on chromosome 22, suggesting the potential for a single causative mutation, which remains unknown. In all cases, the favourable QTL allele was always contributed from Red Maasai, providing support for the idea that future marker-assisted selection for genetic improvement of production in East Africa will rely on markers in linkage disequilibrium with these QTL. PMID- 22221027 TI - Accuracy of genotype imputation in sheep breeds. AB - Although genomic selection offers the prospect of improving the rate of genetic gain in meat, wool and dairy sheep breeding programs, the key constraint is likely to be the cost of genotyping. Potentially, this constraint can be overcome by genotyping selection candidates for a low density (low cost) panel of SNPs with sparse genotype coverage, imputing a much higher density of SNP genotypes using a densely genotyped reference population. These imputed genotypes would then be used with a prediction equation to produce genomic estimated breeding values. In the future, it may also be desirable to impute very dense marker genotypes or even whole genome re-sequence data from moderate density SNP panels. Such a strategy could lead to an accurate prediction of genomic estimated breeding values across breeds, for example. We used genotypes from 48 640 (50K) SNPs genotyped in four sheep breeds to investigate both the accuracy of imputation of the 50K SNPs from low density SNP panels, as well as prospects for imputing very dense or whole genome re-sequence data from the 50K SNPs (by leaving out a small number of the 50K SNPs at random). Accuracy of imputation was low if the sparse panel had less than 5000 (5K) markers. Across breeds, it was clear that the accuracy of imputing from sparse marker panels to 50K was higher if the genetic diversity within a breed was lower, such that relationships among animals in that breed were higher. The accuracy of imputation from sparse genotypes to 50K genotypes was higher when the imputation was performed within breed rather than when pooling all the data, despite the fact that the pooled reference set was much larger. For Border Leicesters, Poll Dorsets and White Suffolks, 5K sparse genotypes were sufficient to impute 50K with 80% accuracy. For Merinos, the accuracy of imputing 50K from 5K was lower at 71%, despite a large number of animals with full genotypes (2215) being used as a reference. For all breeds, the relationship of individuals to the reference explained up to 64% of the variation in accuracy of imputation, demonstrating that accuracy of imputation can be increased if sires and other ancestors of the individuals to be imputed are included in the reference population. The accuracy of imputation could also be increased if pedigree information was available and was used in tracking inheritance of large chromosome segments within families. In our study, we only considered methods of imputation based on population-wide linkage disequilibrium (largely because the pedigree for some of the populations was incomplete). Finally, in the scenarios designed to mimic imputation of high density or whole genome re-sequence data from the 50K panel, the accuracy of imputation was much higher (86-96%). This is promising, suggesting that in silico genome re-sequencing is possible in sheep if a suitable pool of key ancestors is sequenced for each breed. PMID- 22221028 TI - Single nucleotide polymorphisms in the imprinted bovine insulin-like growth factor 2 receptor gene (IGF2R) are associated with body size traits in Irish Holstein-Friesian cattle. AB - The regulation of the bioavailability of insulin-like growth factors (IGFs) is critical for normal mammalian growth and development. The imprinted insulin-like growth factor 2 receptor gene (IGF2R) encodes a transmembrane protein receptor that acts to sequester and degrade excess circulating insulin-like growth factor 2 (IGF-II) - a potent foetal mitogen - and is considered an important inhibitor of growth. Consequently, IGF2R may serve as a candidate gene underlying important growth- and body-related quantitative traits in domestic mammalian livestock. In this study, we have quantified genotype-phenotype associations between three previously validated intronic bovine IGF2R single nucleotide polymorphisms (SNPs) (IGF2R:g.64614T>C, IGF2R:g.65037T>C and IGF2R:g.86262C>T) and a range of performance traits in 848 progeny-tested Irish Holstein-Friesian artificial insemination sires. Notably, all three polymorphisms analysed were associated (P <= 0.05) with at least one of a number of performance traits related to animal body size: angularity, body depth, chest width, rump width, and animal stature. In addition, the C-to-T transition at the IGF2R:g.65037T>C polymorphism was positively associated with cow carcass weight and angularity. Correction for multiple testing resulted in the retention of two genotype-phenotype associations (animal stature and rump width). None of the SNPs analysed were associated with any of the milk traits examined. Analysis of pairwise r(2) measures of linkage disequilibrium between all three assayed SNPs ranged between 0.41 and 0.79, suggesting that some of the observed SNP associations with performance may be independent. To our knowledge, this is one of the first studies demonstrating associations between IGF2R polymorphisms and growth- and body-related traits in cattle. These results also support the increasing body of evidence that imprinted genes harbour polymorphisms that contribute to heritable variation in phenotypic traits in domestic livestock species. PMID- 22221029 TI - Identification of polymorphisms in the malic enzyme 1, NADP(+)-dependent, cytosolic and nuclear receptor subfamily 0, group B, member 2 genes and their associations with meat and carcass quality traits in commercial Angus cattle. AB - Genes involved in the physiological control of energy and triglyceride synthesis, such as malic enzyme 1, NADP(+)-dependent, cytosolic (ME1) and nuclear receptor subfamily 0, group B, member 2 (NR0B2), are key candidates that may have effects on meat and carcass quality traits. These genes were sequenced in Aberdeen Angus beef cattle, and the possibility of associations between SNPs and economically important carcass and meat quality traits was tested. Six novel SNPs, five in ME1 and one in NR0B2, were identified. A SNP in exon eight of ME1 resulted in a non synonymous amino acid change from valine to isoleucine. Phenotypic data were recorded on 536 commercial Aberdeen Angus-cross beef cattle, which comprised 28 carcass quality, tenderness and sensory traits. The majority of the SNPs were associated with at least one of these traits, including an association between the NR0B2 SNP and fat class, and associations between at least one of the ME1 SNPs and eye muscle area, sirloin weight before maturation, sirloin steak tail length, and juiciness. PMID- 22221030 TI - Association analyses of single nucleotide polymorphisms in bovine stearoyl-CoA desaturase and fatty acid synthase genes with fatty acid composition in commercial cross-bred beef steers. AB - Two previously reported non-synonymous coding single nucleotide polymorphisms (SNPs) of bovine stearoyl-CoA desaturase (delta-9-desaturase) (SCD) (c.878C>T) and fatty acid synthase (FASN) (g:17924A>G) were assessed for their associations with 72 individual and 12 groups of fatty acids in brisket adipose tissue of 223 Canadian commercial cross-bred beef steers. It was found that the 'CC' genotype of the SCD SNP was significantly associated with lower concentrations of saturated fatty acids (SFA) including 10:0, 14:0 and 20:0, higher concentrations of monounsaturated fatty acids including 9c-14:1, 12c-16:1 and 13c-18:1, higher concentrations of polyunsaturated fatty acids (PUFA) including 9c,15c-18:2, 10c,12c-18:2, 11c,13t-18:2 and 12c,14t-18:2, but lower concentrations of other PUFA of 9c,13t/8t,12c and 20:2n-6 (P < 0.05). The 'AA' genotype of the FASN SNP was significantly associated with higher concentrations of SFAs of 10:0, 12:0, 13:0, 14:0 and 15:0, lower concentrations of unsaturated fatty acids of 9c-18:1 and 20:3n-6, and higher concentrations of unsaturated fatty acids of 9c-14:1 and 12c-16:1 (P < 0.05). Significant epistatic effects between the SCD and FASN SNP genotypes were also found for several fatty acids including 10:0, 23:0, 6t/7t/8t 18:1, 12t-18:1, 13t/14t-18:1, 16t-18:1, total trans18:1 and 9c,13t/8t,12c-18:2 (P < 0.05). These results further suggest that SCD and FASN are strong candidate genes influencing fatty acid composition in beef cattle. PMID- 22221031 TI - Genetic relationships between Japanese native and commercial breeds using 70 chicken autosomal SNP genotypes by the DigiTag2 assay. AB - Recently, single nucleotide polymorphisms (SNPs) have been used to identify genes or genomic regions responsible for economic traits, including genetic diseases in domestic animals, and to examine genetic diversity of populations. In this study, we genotyped 70 chicken autosomal SNPs using DigiTag2 assay to understand the genetic structure of the Japanese native chicken breeds Satsumadori and Ingie, and the relationship of these breeds with other established breeds, Rhode Island Red (RIR), commercial broiler and layer. Five breeds, each consisting of approximately 20 chickens, were subjected to the assay, revealing the following: Average expected heterozygosities of broiler, Satsumadori, RIR, layer and Ingie were 0.265, 0.254, 0.244, 0.179 and 0.176, respectively. Phylogenetic analysis using the concatenated 70 autosomal SNP genotypes distinguished all chickens and formed clusters of chickens belonging to the respective breeds. In addition, the 2-D scatter plot of the first two principal components was consistent with the phylogenic tree. Taken together with the pairwise F(st) distances, broiler and RIR were closely positioned near each other, while Ingie was positioned far from the other breeds. Structure analysis revealed that the probable number of genetic clusters (K) was six and four with maximum likelihood and DeltaK values, respectively. The clustering with maximum likelihood revealed that, in addition to the clustering of the other five breeds, the Satsumadori was subdivided into two genetic clusters. The clustering with DeltaK value indicated that the broiler and Rhode Island Red were assigned to the same genetic cluster. PMID- 22221032 TI - Polymorphism identification in the goat KITLG gene and association analysis with litter size. AB - This study reported the analysis of KIT ligand (KITLG) gene polymorphisms in 681 goats of three breeds: Xinong Saanen (SN), Guanzhong (GZ), and Boer (BG). In addition, the study identified three allelic variants: g.769T>C and g.817G>T in SN and GZ breeds, and g.9760G>C in the three goat breeds. The g.769T>C and g.817G>T loci were closely linked (r(2) > 0.33). All the single nucleotide polymorphism loci were in Hardy-Weinberg disequilibrium (P < 0.05). Significant associations were found for litter size with all three loci. Therefore, these results suggest that the KITLG gene is a strong candidate gene affecting litter size in goats. PMID- 22221033 TI - Genetic variability and individual assignment of Chinese indigenous sheep populations (Ovis aries) using microsatellites. AB - The purpose of this study was to assess the genetic characteristics of six breeds of Chinese local sheep using 19 microsatellite loci and to effectively validate statistical methods for individual assignment based on informative microsatellites. All the six breeds deviated from Hardy-Weinberg equilibrium expectations, while the majority of markers complied. The polymorphism information content (PIC) of overall loci for the six populations ranged from 0.283 (SRCRSP5) to 0.852 (OarVH72). Tibetan sheep were the most diverse population with the highest mean allelic richness (6.895), while Ujmuqin (UQ) harboured the lowest allelic richness (6.000). The F-statistics for the six populations were F(IS) = -0.172, F(IT) = -0.082 and F(ST) = 0.077, respectively. Furthermore, the pair-wise F(IS) revealed a moderate genetic differentiation among populations (P < 0.01), indicating that all breeds can be considered genetically independent entities. The lowest genetic differentiation was between Tengchong (TC) and UQ (F(ST) = 0.041), and the highest one was between TC and Fat-tailed Han (F(ST) = 0.111). In comparing the three statistical models, we note that the seven microsatellite loci (MAF65, OarJMP58, SRCRSP9, MCM140, OarAE129, BM8125 and SRCRSP5) commonly used for individual assignment will ensure a powerful detection of individual origin, with accuracy up to 91.87%, when the likelihood-based method is used. Overall, these findings shed light onto the genetic characteristics of Chinese indigenous sheep and offer a set of microsatellite loci that is simple, economic and highly informative for individual assignment of Chinese sheep. PMID- 22221034 TI - Exclusion of COL2A1 in canine Legg-Calve-Perthes disease. PMID- 22221035 TI - Evaluation of polymorphisms within the genes GHSR and SLC2A2 that are within a region on bovine chromosome 1 (BTA1) previously associated with feed intake and weight gain. PMID- 22221036 TI - Risk factors associated with Clostridium difficile infection in adult oncology patients with a history of recent hospitalization for febrile neutropenia. PMID- 22221037 TI - Upconversion and downconversion fluorescent graphene quantum dots: ultrasonic preparation and photocatalysis. AB - A facile ultrasonic route for the fabrication of graphene quantum dots (GQDs) with upconverted emission is presented. The as-prepared GQDs exhibit an excitation-independent downconversion and upconversion photoluminescent (PL) behavior, and the complex photocatalysts (rutile TiO(2)/GQD and anatase TiO(2)/GQD systems) were designed to harness the visible spectrum of sunlight. It is interesting that the photocatalytic rate of the rutile TiO(2)/GQD complex system is ca. 9 times larger than that of the anatase TiO(2)/GQD complex under visible light (lambda > 420 nm) irradiation in the degradation of methylene blue. PMID- 22221038 TI - PARP1 polymorphisms increase the risk of gastric cancer in a Chinese population. AB - BACKGROUND AND OBJECTIVE: Poly(adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1), a protein involved in the DNA repair mechanism, plays an important role in carcinogenesis. In this study, we investigated whether single nucleotide polymorphisms of PARP1 contribute to gastric cancer (GC) and its precursor lesions (gastric precancerous lesions; GPL) in a case-control study conducted in the Hexi area of China, a high-risk area for GC. METHODS: PARP1 162C>G (Phe54Leu) and 2819A>G (Lys940Arg) polymorphisms were genotyped by real-time PCR using a TaqMan assay in 140 GC cases, 110 GPL cases, and 120 controls. Data were statistically analyzed using the chi-squared test and a logistic regression model. RESULTS: The presence of the PARP1 2819G allele was associated with an increased risk of GC (odds ratio [OR] 2.354; 95% CI 1.140, 4.861; p = 0.018), especially for cardia GC and diffuse-type GC (ORs 2.988 and 3.784, respectively). We also observed an interaction between Helicobacter pylori infection, GC family history, and the presence of the PARP1 2819G allele. In contrast, the PARP1 162C>G polymorphism was not significantly associated with GPL or GC. CONCLUSION: The study suggests that the PARP1 2819G allele is associated with an increased risk of GC. In addition, H. pylori-positive status and family history jointly contribute to a higher risk of GC. PMID- 22221039 TI - Subgingival microbiota in adult Down syndrome periodontitis. AB - BACKGROUND AND OBJECTIVE: The subgingival microbiota in Down syndrome and non Down syndrome adults receiving periodic dental care was examined for 40 bacterial species using checkerboard DNA-DNA hybridization and the results were related to clinical periodontal attachment loss. MATERIAL AND METHODS: A total of 44 Down syndrome, 66 non-Down syndrome mentally retarded and 83 mentally normal adults were clinically evaluated. This involved, for each subject, the removal of subgingival specimens from three interproximal sites on different teeth; all subgingival samples per subject were then pooled and assessed for the presence and levels of 40 bacterial species using species-specific whole-genomic DNA probes and checkerboard DNA-DNA hybridization. Significant group differences in species proportions averaged across subjects were evaluated using the Kruskal Wallis test, and associations between subgingival species and mean subject attachment loss within Down syndrome and non-Down syndrome subject groups were quantified using Pearson correlation and multiple linear regression analysis. RESULTS: Down syndrome subjects exhibited greater attachment loss than non-Down syndrome subjects (p=0.05). Most microbial species were present in Down syndrome subjects at levels similar to non-Down syndrome subjects, except for higher proportions of Selenomonas noxia, Propionibacterium acnes, Streptococcus gordonii, Streptococcus mitis and Streptococcus oralis in Down syndrome subjects compared with non-Down syndrome study subjects, higher proportions of Treponema socranskii in Down syndrome subjects compared with non-Down syndrome mentally retarded subjects, and higher proportions of Streptococcus constellatus in Down syndrome subjects compared with mentally normal subjects. Down syndrome adults classified with periodontitis revealed higher subgingival levels of T. socranskii than Down syndrome subjects with no periodontitis (p=0.02). Higher subgingival proportions of S. constellatus, Fusobacterium nucleatum ssp. nucleatum, S. noxia and Prevotella nigrescens showed significant positive correlations (r=0.35-0.42) and higher proportions of Actinomyces naeslundii II and Actinomyces odontolyticus showed negative correlations (r=-0.36 to -0.40), with increasing mean subject attachment loss in Down syndrome adults. CONCLUSION: Individuals with Down syndrome show higher levels of some subgingival bacterial species and specific associations between certain subgingival bacterial species and loss of periodontal attachment. These findings are consistent with the notion that certain subgingival bacteria may contribute to the increased level of periodontal disease seen in Down syndrome individuals and raise the question as to the reason for increased colonization in Down syndrome. PMID- 22221040 TI - X-ray studies of carbon dioxide intercalation in Na-fluorohectorite clay at near ambient conditions. AB - We show experimentally that gaseous CO(2) intercalates into the interlayer space of the synthetic smectite clay Na-fluorohectorite at conditions not too far from ambient. The mean interlayer repetition distance of the clay when CO(2) is intercalated is found to be 12.5 A for the conditions -20 degrees C and 15 bar. The magnitude of the expansion of the interlayer upon intercalation is indistinguishable from that observed in the dehydrated-monohydrated transition for H(2)O, but the possibility of water intercalation is ruled out by a careful analysis of the experimental conditions and repeating the measurements exposing the clay to nitrogen gas. The dynamics of the process is observed to be dependent on the pressure, with a higher intercalation rate at increased pressure. The rate of CO(2) intercalation at the studied conditions is found to be several orders of magnitude slower than the intercalation rate of water or humidity at ambient pressure and temperature. PMID- 22221041 TI - Letter to Freud: on the plight of psychoanalysis. AB - In the form of a letter, the writer communicates to Freud her appreciation for the incomparable richness and complexity of the psychoanalytic enterprise in its century-long evolution from classical, Freudian origins to new developments in theory and technique. At the same time, concern is expressed about the continuity and survival of psychoanalysis in a cultural milieu that has absorbed its once radical ideas about sexuality and unconscious motivation while resisting its viability as a method of treatment. PMID- 22221042 TI - The teachings of honorary Professor of Psychiatry Daniel Paul Schreber, J.D., to psychiatrists and psychoanalysts, or dramatology's challenge to psychiatry and psychoanalysis. AB - The paper addresses the question: How does one read Schreber? Should one read ideas into his text to make sense of it, or should one listen to Schreber's own ideas? Freud read theories into Schreber and so did generations of psychiatric and psychoanalytic readers thereafter, creating Schreber, a myth. Looking for Schreber, the man, the author read Schreber from the perspective of history and dramatology so as to retranslate symptoms, syndromes, and systems back into Schreber's life dramas. As an interpreter and thinker in his own right, Schreber crafted a multilayered first-person narrative containing many lessons useful to patients, psychiatrists, and psychoanalysts. PMID- 22221043 TI - Interpreting psychoanalytic interpretation: a fourfold perspective. AB - Following an overview of psychoanalytic interpretation in theory, practice, and historical context, as well as the question of whether interpretations have scientific validity, the author holds that hermeneutics, the philosophical and psychological study of interpretation, provides a rich understanding of recent developments in self psychology, inter-subjective and relational perspectives, attachment theory, and psycho-spiritual views on psychoanalytic process. He then offers four distinct hermeneutical vantage points regarding interpretation in the psychoanalytic context, including (1) Freud's adaptation of the Aristotelian view of interpretation as the uncovering of a set of predetermined meanings and structures; (2) the phenomenological view of interpretation as the laying bare of "the things themselves," that is, removing the coverings of objectification and concretization imposed by social norms and the conscious ego; (3) the dialogical existential view of interpretation as an ongoing relational process; and (4) the transformational understanding in which interpretation evokes a "presence" that transforms both patient and analyst. He concludes by contending that these perspectives are not mutually exclusive ways of conducting an analysis, but rather that all occur within the analyst's suspended attention, the caregiving and holding essential to good therapeutic outcomes, and the mutuality of the psychoanalytic dialogue. PMID- 22221044 TI - What's so different about Lacan's approach to psychoanalysis? AB - Clinical work based on Lacanian principles is rarely compared in the psychoanalytic literature with that based on other principles. The author attempts to highlight a few important theoretical differences regarding language, desire, affect, and time between a Lacanian approach and certain others that lead to differences in focus and technique, related, for example, to interpretation, scansion, and countertransference. Lacanian techniques are illustrated with brief clinical vignettes. In the interest of confidentiality, identifying information and certain circumstances have been changed or omitted in the material presented. PMID- 22221045 TI - Resurrecting the buried self: fairy tales and the analytic encounter. AB - The author uses the lens of myth and fairy tales to examine the narratives generated by the analytic experience. Fairy tales are understood as representing fundamental developmental conflicts, accounting for their enduring power over time. The analytic encounter is seen as an analogue of the fairy tale in which the hidden self, damaged by loss and abandonment, reemerges only through the redemptive power of [an] other's love. Clinical material is presented in which hidden parts of the patient's self are projected into the analyst for safekeeping; these hidden parts resonate with the analyst's own lost, unrealized potential and form an intersubjective experience which the author believes is transformative. The patient's dormant powers emerge in a newly experienced atmosphere of recognition, and in this way, the analytic encounter resembles the fairy tale in providing an identificatory bond and a protective space for the patient's hidden vitality. PMID- 22221050 TI - The changes of fourier transform infrared spectrum in rat brain. AB - Estimation of the time since death (postmortem interval [PMI]) is one of the most difficult problems in forensic investigations, and many methods currently are utilized to estimate the PMI. The goal of this study was to investigate the changes of attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectra of rat brain from postmortem time 0-144 h. The intensity ratios of major absorbance bands were examined (I(1066)/I(1392), I(1168)/I(1392), I(1234)/I(1454), I(1301)/I(1392), I(1647)/I(2956), I(2921)/I(2850), and I(1647)/I(1539)). The spectra of rat brain displayed prominent changes with increasing PMI. The band at 2871 and 1737 per cm became weak with the time increasing and even disappeared at postmortem 96 and 72 h, respectively. A close linear correlation was shown between the relative absorption intensity and the PMI, and the I(1234) /I(1454) offered a stronger correlation (r = 0.973). Our results indicate that ATR-FTIR spectroscopy may be a useful technique for estimating the PMI. PMID- 22221052 TI - Modern omics-based platform for high throughput screening for novel drug targets. PMID- 22221053 TI - Mapping the high throughput SEREX technology screening for novel tumor antigens. AB - Advances in novel tumor-associated antigen (TAA) screening strategy have accelerated the identification and characterization of biomarkers and potential target molecules for tumor subtyping, diagnosis and therapeutics, which may facilitate early detection and diagnosis of the diseases individually and enhance treatment approaches for cancer. Over the past decades, a plethora of non invasive methodologies dedicated to identify novel target molecules have been primarily focusing on the discovery of human tumor antigens recognized by the autologous antibody repertoire or cytotoxic T lymphocytes, among which serological analysis of recombinant cDNA expression libraries (SEREX) technology is chronologically first established and is of outstanding sensitivity and antigen coverage. This approach involves immunoscreening cDNA libraries extracted from fresh tumor tissues with sera from cancer patients to identify gene products recognized by IgG antibody. SEREX-defined clones can be directly sequenced and their expression profiles can be readily determined, allowing for immediate structural definition of the antigenic target and subsequent identification of TAAs and their cognate autoantibodies. This review is not only devoted to outline the SEREX technology and its advantages, drawbacks and recent modifications currently available for discovering provocative tumor antigens, but also to translate these SEREX-defined peptides into valuable cancer-specific signatures that would aid in the development of diagnostics, prognostics and therapeutics for cancer patients. PMID- 22221054 TI - Advent of the cancer methylome. AB - DNA hypermethylation of CpG islands plays an important role in gene regulation during cancer development. Many techniques have been developed to detect global DNA methylation in cancer cells compared to normal tissues. This knowledge helps us to better understand cancer progression and also aids in the development of new biomarker for early cancer detection. New prognostic tools for monitoring drug efficacy during cancer treatment can also be developed. In this review, we will examine the different techniques that have been used to study DNA methylation, as well as the emerging high resolution, high throughput techniques for identification of methylated regions to defining cancer related genes in the cancer methylome. PMID- 22221055 TI - Quantitative proteomics for cancer biomarker discovery. AB - The mass spectrometry (MS)-based quantitative proteomics is powerful to discover disease biomarkers that can provide diagnostic, prognostic and therapeutic targets, and it also can address important problems in clinical and translational medical research. The current status of MS-based quantification strategy and technical advances of several main quantitative assays (two-dimensional (2-D) gel based methods, stable isotope labeling with amino acids in cell culture (SILAC), isotope-coded affinity tag (ICAT), the isobaric tags for relative and absolute quantification (iTRAQ), 18O labeling, absolute quantitation and label-free quantitation) have been summarized and reviewed. At present, except 2-D gel-based methods, several stable isotope labeling quantitative techniques, including SILAC, ICAT and iTRAQ, etc, have been widely applied in identification of differential expression of proteins, post-translational modifications and protein protein interactions in order to look for novel candidate cancer biomarkers from different physiological states of cells, body fluids or tissue samples. Also, the advantages and challenges of different quantitative proteomic approaches are discussed in identification and validation of candidate targets. PMID- 22221056 TI - High throughput screening (HTS) in identification new ligands and drugable targets of G protein-coupled receptors (GPCRs). AB - G protein-coupled receptors (GPCRs) which constitute one of the largest and most versatile families of cell surface receptors are involved in a wide spectrum of physiological functions, such as, neuronal transmission, chemotaxis, pacemaker activity and embryonic development. Therefore, in the past a few years GPCR families have become very important targets in pharmaceutical design. However, according to the human genome project, there are approximately 1000 genes encoding GPCRs, only about 200 of GPCRs have known ligands and functions. Searching for ligands of the unknown GPCRs and better modulators of known GPCRs are currently attracting lots of interest. High throughput screening (HTS), which is commonly defined as an automatic process of testing potential drug candidates efficiently, is widely used in drug discovery. In this review, the use of high throughput screening (HTS) in studying GPCRs and the choice of screening technology in different G-protein signaling pathways were summarized. PMID- 22221057 TI - High throughput screening technology and the small molecules modulating aging related signals. AB - Aging and its related diseases are severe issues in modern society. Many efforts have been made to understand the mechanisms of aging and to find the ways to prevent age-related diseases. Identifying the compounds targeting aging-related signals is a challenging work because there are so many proteins and signals involved. Recently, alone with the progresses in high throughput screening (HTS) technology, increasing numbers of small molecules targeting aging-related pathologic processes have been identified. In this review, we introduce the basic workflow, classification and assay strategies of HTS technology, and sort out known small molecules identified via HTS technology by their roles in aging related diseases, such as neural degenerative diseases, diabetes and tumors. Given the fact that application of HTS on aging research is still at an early stage, we also summarize the cellular mechanisms about aging process, paralleled with the compounds which can modulate the functions of proteins important for aging signals. Finally, we briefly discuss some advanced HTS technologies for their potent applications on the discovery of anti-aging compounds. The main purpose of this review is to provide updated and useful information to those who are interested in pharmacology and HTS technology, but not familiar with aging biology, or vice versa. PMID- 22221058 TI - Proteomics annotation of lipid rafts modified by virus infection. AB - Lipid rafts are sphingolipid- and cholesterol-enriched membrane microdomains, which are involved in entry, assembly and budding of various types of viruses. Identification of rafts associated proteins modified by virus infection could therefore provide novel insights into the mechanisms of virus infection as well as the development of new biomarkers for diagnosis and drug development. Proteomic approaches, such as LC-ESI-MS/MS, two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), two-dimensional difference gel electrophoresis (2D DIGE), isotope-coded affinity tags (ICAT), Proteolytic 18O Labeling, isotope Tags for Relative and Absolute Quantification (iTRAQ), Stable Isotope Labeling with Amino acids in Cell culture (SILAC) and Multidimensional Protein Identification Technology (MudPIT), provide the large scale and unbiased platform to determine the dynamic profiles of the lipid rafts proteome. In this review, we summarized the research advance regarding modern proteomics analysis of host lipid rafts alterations in response to diverse virus infection. PMID- 22221059 TI - Metabolomics: a revolution for novel cancer marker identification. AB - The repertoire of small-molecular-weight substances present in cells, tissue and body fluids are known as the metabolites. The global analysis of metabolites, such as by high-resolution 1H nuclear magnetic resonance spectroscopy and mass spectrometry, is integral to the rapidly expanding field of metabolomics, which is making progress in various diseases. In the area of cancer and metabolic phenotype, the integrated analysis of metabolites may provide a powerful platform for detecting changes related to cancer diagnosis and discovering novel biomarkers. In this review, metabolomics including the technologies in metabolomics research and extracting information from metabolomics datasets are described. Then we discuss the challenges and opportunities in metabolomics for finding metabolic processes in cancer and discovering novel cancer biomarkers. Finally, we assess the clinical applicability of metabolomics. PMID- 22221060 TI - Identification and functional study of cytokines and chemokines involved in tumorigenesis. AB - Tumorigenesis may be affected by various cellular components in the tumor cells and/or by tumor microenvironmental factors. Cytokines, including chemokines (chemotactic cytokines) are polypeptides or small soluble proteins generated by leukocytes and non-leukocytes, including cancer cells and stromal cells, for example, fibroblasts, mesenchymal stem cells (MSCs) and epithelial cells. Cytokines exert their functions on the cells that secrete them, on nearby cells, or on distant cells. Chemokines have expanded beyond their initial roles in impinging on every aspect of the immune system and leukocyte biology. They display multifunctional effects for regulating angiogenesis, tumor cell proliferation and apoptosis, mediating tumor cell metastasis in an organ-specific manner. This review will focus on the structural and functional aspects of chemokines as well as the roles that cytokines and their receptors play in angiogenesis, tumor invasion and metastasis, and discuss their potential value as important therapeutic targets for intervention in cancer. PMID- 22221061 TI - Integrative system biology strategies for disease biomarker discovery. AB - Biomarkers are currently widely used to diagnose diseases, monitor treatments, and evaluate potential drug candidates. Research of differential Omics accelerate the advancements of biomarkers' discovery. By extracting biological knowledge from the 'omics' through integration, integrative system biology creates predictive models of cells, organs, biochemical processes and complete organisms, in addition to identifying human disease biomarkers. Recent development in high throughput methods enables analysis of genome, transcriptome, proteome, and metabolome at an unprecedented scale, thus contributing to the deluge of experimental data in numerous public databases. Several integrative system biology approaches have been developed and applied to the discovery of disease biomarkers from databases. In this review, we highlight several of these approaches and identify future steps in the context of the field of integrative system biology. PMID- 22221062 TI - The application of high throughput siRNA screening technology to study host pathogen interactions. AB - Recent advances in high throughput screening technologies have accelerated the identification and characterization of potential factors involved in host-virus interactions, facilitating early detection and diagnosis of diseases, as well as providing promising drug targets. The last decade has seen a plethora of successful examples of high throughput screening approaches, especially siRNA screening. With support from protein interaction studies, mRNA expression profiling, and bioinformatics, siRNA screening has also been successfully utilized to identify host factors required for a number of viruses including HIV, West Nile virus and H1N1 virus. Such studies have raised the awareness of virologists, and have opened a new chapter of global analysis of host-pathogen interactions. However, to play a more defining role in prognostics, diagnostics and therapeutics for virus diseases, acknowledged drawbacks, including false positives and negatives, inherent in this technology, must be successfully addressed. PMID- 22221063 TI - Recent advances in screening of natural products for antimicrobial agents. AB - It has been a very long history for human to resist diseases. During this period, a large number of drugs that could kill or inhibit the growth of microbe has been discovered, most of which were natural products. However, there may still be a large amount of antimicrobial medicines in natural compounds which have not been found yet. The ways of screening for antimicrobial always cost a long time and need a lot of manpower before. However, in recent years, a lot of new antimicrobial targets, antimicrobial drugs and screening methods which are simpler, faster and more efficient have been invented. In this paper the newly discovered targets, natural products and representative technologies were reviewed, which were expected to make some contributions to the research and development of medicines. PMID- 22221064 TI - Chemistry-based functional proteomics to identify novel deubiquitylating enzymes involved in viral infection. AB - Ubiquitylation is a reversible post-translational modification pathway that regulates a variety of cellular processes including protein degradation and trafficking, intracellular localization, DNA repair, immune response and cellcycle progression. Deubiquitylating enzymes (DUBs) can remove the ubiquitin from the modified proteins and reverse the ubiquitylation-induced biological processes; hence it isn't hard to understand that viral pathogens take advantage of the host cell ubiquitin system through disturbing DUBs, for infection and replication. Although accumulated virus-related DUBs have been defined, but how viruses regulate their expression and activities is poor understand because of limitation of technologies. Recently, chemistry-based functional proteomics, which can not only monitor the alteration of abundance but also changes in activity of enzymes, was used to study the function of DUBs involved in virus infection and held much promise. Theses works suggest that chemistry-based functional proteomics is a potent strategy for high throughput screening of virus related DUBs and exploring their roles in virus infection. PMID- 22221065 TI - Computer-aided drug design: lead discovery and optimization. AB - Over the past decade, there have been remarkable advances in the area of computer aided drug design (CADD), which has been applied at almost all stages in the drug discovery pipeline. The generation of initial lead compounds and the subsequent optimization aimed at improving potency and pharmacological properties are the core activities among all. The development in these aspects over the past years will be the focus of this review. PMID- 22221066 TI - Children and adolescents living with atopic eczema: an interpretive phenomenological study with Chinese mothers. AB - AIM: This article is a report on a phenomenological study of Chinese mothers' experiences of caring for their children who were living with atopic eczema. BACKGROUND: A mother's attitude and personality may have a direct influence on her child's adherence to treatment for atopic eczema. Thus, good communication between healthcare professionals and the mother is essential. Treatment and care should also be culturally appropriate. METHODS: Using an interpretive phenomenological method, 14 interviews were conducted in Hong Kong, China from September 2007 to August 2008, with nine mothers caring for their children who were living with atopic eczema. Crist and Tanner's circular process of hermeneutic interpretive phenomenology was chosen to guide the data analysis. FINDINGS: Mothers' coping patterns involved persistently dealing with enduring demands and seeking alternative therapies that were aimed at curing the disease. Four themes finally emerged from the data: (1) dealing with extra mothering, (2) giving up their life, (3) becoming an expert and (4) living with blame and worry. Mothers' coping patterns involved persistently finding ways to relieve their children's suffering with the aim of curing the disease and dealing with their own emotions related to the frustration resulting from giving up their life and living with blame and worry. CONCLUSION: The study findings provide nurses with an empathic insight into mothers' feelings and the enduring demands of caring for children with atopic eczema, and help nurses to develop culturally sensitive interventions, reinforce positive coping strategies, increase family function and improve health outcomes. PMID- 22221068 TI - Rocuronium and sugammadex for rapid sequence induction of obstetric general anaesthesia. PMID- 22221070 TI - Variations in the management of children with cerebral venous sinus thrombosis in the UK and Ireland. PMID- 22221073 TI - Multiple linear bowenoid papulosis without surrounding papules. PMID- 22221071 TI - Inhaled hydrogen sulfide prevents endotoxin-induced systemic inflammation and improves survival by altering sulfide metabolism in mice. AB - AIMS: The role of hydrogen sulfide (H(2)S) in endotoxin (lipopolysaccharide [LPS])-induced inflammation is incompletely understood. We examined the impact of H(2)S breathing on LPS-induced changes in sulfide metabolism, systemic inflammation, and survival in mice. RESULTS: Mice that breathed air alone exhibited decreased plasma sulfide levels and poor survival rate at 72 h after LPS challenge. Endotoxemia markedly increased alanine aminotransferase (ALT) activity and nitrite/nitrate (NOx) levels in plasma and lung myeloperoxidase (MPO) activity in mice that breathed air. In contrast, breathing air supplemented with 80 ppm of H(2)S for 6 h after LPS challenge markedly improved survival rate compared to mice that breathed air alone (p<0.05). H(2)S breathing attenuated LPS induced increase of plasma ALT activity and NOx levels and lung MPO activity. Inhaled H(2)S suppressed LPS-induced upregulation of inflammatory cytokines, while it markedly induced anti-inflammatory interleukin (IL)-10 in the liver. Beneficial effects of H(2)S inhalation after LPS challenge were associated with restored sulfide levels and markedly increased thiosulfate levels in plasma. Increased thiosulfate levels after LPS challenge were associated with upregulation of rhodanese, but not cystathionine-gamma-lyase (CSE), in the liver. Administration of sodium thiosulfate dose-dependently improved survival after LPS challenge in mice. INNOVATION: By measuring changes in plasma levels of sulfide and sulfide metabolites using an advanced analytical method, this study revealed a critical role of thiosulfate in the protective effects of H(2)S breathing during endotoxemia. CONCLUSION: These observations suggest that H(2)S breathing prevents inflammation and improves survival after LPS challenge by altering sulfide metabolism in mice. PMID- 22221075 TI - Prospective trial comparing transrectal ultrasonography and transurethral seminal vesiculoscopy for persistent hematospermia. AB - OBJECTIVE: To compare the diagnostic yield of transrectal ultrasonography and transurethral seminal vesiculoscopy in patients with persistent hematospermia, and to determine the advantages and disadvantages of both modalities. METHODS: We prospectively enrolled 106 patients with persistent hematospermia of mean duration 20.5 months. All patients were evaluated by both transrectal ultrasonography and transurethral seminal vesiculoscopy after excluding definite etiological lesions beyond the reproductive duct system. The diagnostic yield and other technical parameters of both modalities were compared. RESULTS: Final diagnoses were made in 93 patients (87.7%), with transrectal ultrasonography and transurethral seminal vesiculoscopy showing overall diagnostic yields of 45.3% and 74.5%, respectively (P < 0.001). The diagnostic yield of combining transrectal ultrasonography and transurethral seminal vesiculoscopy was significantly higher than that of each modality alone (both P < 0.001). Of the 114 findings of diagnostic value, the most frequent was calculus (47.4%, n = 54), followed by obstruction/stricture (37.7%, n = 43), cyst (8.8%, n = 10), dysplasia (3.5%, n = 4), polyp (1.8%, n = 2) and benign mass (0.9%, n = 1). Transurethral seminal vesiculoscopy showed significant superiority in detecting calculi and obstruction/stricture. Hematospermia disappeared in 95.3% (101/106) of all patients and in 97.6% (83/85) of patients receiving transurethral seminal vesiculoscopy therapy during follow up. No major adverse effects occurred during and after examination. CONCLUSIONS: The diagnostic yield of transurethral seminal vesiculoscopy for persistent hematospermia was significantly superior to that of transrectal ultrasonography, especially in lesions diagnosed with calculi and obstruction/stricture. Combining both modalities might provide extra benefits for patients with persistent hematospermia. PMID- 22221076 TI - Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease. AB - OBJECTIVE: To evaluate the efficacy of telcagepant in patients with migraine and coronary artery disease. BACKGROUND: Calcitonin gene-related peptide receptor antagonists, such as telcagepant, may be useful for acute migraine treatment in patients with cardiovascular disease, a population for whom triptans are contraindicated. METHODS: Randomized, double-blind, two-period (6 weeks per period) crossover study in patients with stable coronary artery disease and migraine. Patients were randomized 1:1 to either: (1) Period 1: telcagepant (280 mg tablet/300-mg capsule), Period 2: acetaminophen (1000-mg); or (2) Period 1: placebo for attack 1 then acetaminophen for subsequent attacks, Period 2: telcagepant. Patients could treat up to 12 migraine attacks per period to assess the tolerability of telcagepant. The primary efficacy analysis evaluated telcagepant vs placebo on 2-hour pain freedom during the first attack of Period 1. RESULTS: One hundred and sixty-five of the planned 400 patients were enrolled, and 114 took at least one dose of treatment. Telcagepant was not statistically different from placebo for 2-hour pain freedom (25.0% vs 18.9%, odds ratio = 1.62 [95% confidence interval: 0.62, 4.25]). The median number of attacks treated per period was 3. No cardiovascular thrombotic adverse events occurred within 14 days of dosing. CONCLUSION: The study was underpowered due to enrollment difficulties and did not demonstrate a significant efficacy difference between telcagepant and placebo for the treatment of a migraine attack in patients with stable coronary artery disease. Telcagepant was generally well tolerated for acute intermittent migraine treatment in these patients. PMID- 22221078 TI - Important role for NKp30 in synapse formation and activation of NK cells. AB - Natural killer (NK) cells play an important role in host defense against viral infections and tumor cells. NK cells require contact with target cells and must subsequently form an NK cell immunological synapse (NKIS). The NKIS represents the interface formed between NK cells and their target cells via receptor recognition and adhesion molecule binding, and it is essential for NK cell cytotoxicity, which is mediated through degranulation and release of cytolytic enzymes. In this study, NKp30-mediated signaling and the role of NKp30 in the formation of the NKIS were investigated. The results from confocal microscopy studies showed that the activating receptor, NKp30, and the adhesion molecule, LFA-1 (CD11a), accumulated at the interface between NK92 cells, which are a human NK cell line, and HeLa cells, which are a human tumor cell line (NK92-HeLa). Blockade of NKp30 inhibited NK cell degranulation, cytotoxicity and cytokine secretion but did not affect the conjugation between NK and target cells. Additionally, ligation with HeLa cells activated the Erk1/2 signaling pathway in NK92 cells, and blockade of NKp30 decreased the phosphorylation of Erk1/2. Therefore, NKp30 is a triggering receptor downstream of adhesion and plays an important role in NK cell activation, degranulation and cytotoxicity. PMID- 22221077 TI - How word frequency modulates masked repetition priming: an ERP investigation. AB - The present study used event-related potentials (ERPs) to provide precise temporal information about the modulation of masked repetition priming effects * word frequency during the course of target word recognition. Contrary to the pattern seen with behavioral response times in prior research, we predicted that high-frequency words should generate larger and earlier peaking repetition priming effects than low-frequency words in the N400 time window. This prediction was supported by the results of two experiments. Furthermore, repetition priming effects in the N250 time window were found for low-frequency words in both experiments, whereas for high-frequency words these effects were seen only at the shorter (50 ms stimulus onset asynchrony [SOA]) used in Experiment 2, and not in Experiment 1 (70 ms SOA). We explain this pattern as resulting from reset mechanisms operating on the form representations activated by prime stimuli when primes and targets are processed as separate perceptual events. PMID- 22221079 TI - P3HT nanopillars for organic photovoltaic devices nanoimprinted by AAO templates. AB - Free-standing nanorod arrays of poly(3-hexylthiophene) (P3HT) were fabricated on indium tin oxide/glass substrates using anodic aluminum oxide (AAO) templates. The AAO templates were treated with a low molecular weight polydimethylsiloxane mold-release agent to reduce their surface energy of the template and interactions with the P3HT. Using a thermal nanoimprinting process, the templates were easily removed, generating nanorods on the surfaces of P3HT thin films. These unique structures were investigated for application in organic photovoltaic devices. PMID- 22221080 TI - Microstructure-controlled aerosol-gel synthesis of ZnO quantum dots dispersed in SiO2 nanospheres. AB - ZnO quantum dots dispersed in a silica matrix were synthesized from a TEOS:Zn(NO(3))(2) solution by a one-step aerosol-gel method. It was demonstrated that the molar concentration ratio of Zn to Si (Zn/Si) in the aqueous solution was an efficient parameter with which to control the size, the degree of agglomeration, and the microstructure of ZnO quantum dots (QDs) in the SiO(2) matrix. When Zn/Si <= 0.5, unaggregated quantum dots as small as 2 nm were distributed preferentially inside SiO(2) spheres. When Zn/Si >= 1.0, however, ZnO QDs of ~7 nm were agglomerated and reached the SiO(2) surface. When decreasing the ratio of the Zn/Si, a blue shift in the band gap of ZnO was observed from the UV/Visible absorption spectra, representing the quantum size effect. The photoluminescence emission spectra at room temperature denoted two wide peaks of deep-level defect-related emissions at 2.2-2.8 eV. When decreasing Zn/Si, the first peak at ~2.3 eV was blue-shifted in keeping with the decrease in the size of the QDs. Interestingly, the second visible peak at 2.8 eV disappeared in the surface-exposed ZnO QDs when Zn/Si >= 1.0. PMID- 22221081 TI - Differences in phenotype and disease course in adult and paediatric inflammatory bowel disease. PMID- 22221083 TI - Evolution of GERD over 5 years. PMID- 22221085 TI - Mortality in patients hospitalised with Crohn's disease. PMID- 22221087 TI - Prucalopride for chronic intestinal pseudo-obstruction. PMID- 22221088 TI - Why thiopurine metabolites are relevant. PMID- 22221092 TI - Role of PPARg2 transcription factor in thiazolidinedione-induced insulin sensitization. AB - OBJECTIVES: Adipose tissue is the key regulator of energy balance, playing an active role in lipid storage and metabolism and may be a dynamic buffer to control fatty acid flux. Peroxisome proliferator-activated receptor gamma isoform 2 (PPARg2), an isoform of the nuclear hormone receptor superfamily, has been implicated in almost all aspects of human metabolic alterations such as obesity, insulin resistance, type-2 diabetes and dyslipidaemia. The PPARg2 isoform is highly present in adipose tissue where it functions as a thrifty phenotype, which promotes adipocyte differentiation and triglyceride storage. Thiazolidinediones, antidiabetic drugs, induce insulin sensitivity by controlling adipokines. The thiazolidinediones bind with PPARg2 in adipocytes and exert an agonist effect by enhancing adipogenesis and fatty acid uptake. Thiazolidinediones stimulate PPARg2, by which they down-regulate tumour necrosis factor-alpha, leptin, interleukin-6 and plasminogen and also enhance insulin sensitivity. The aim of this work is to define role of PPARg2 transcription factor in thiazolidinedione induced insulin sensitization. KEY FINDINGS: The PPARg2 alters the transcription of the target gene. This altered gene transcription results in the up-regulation of insulin-sensitizing factors and down-regulation of insulin-resistant factors. The variant Pro12Ala of the PPARg2 gene is an important modulator in metabolic control in the body. Thiazolidinediones stimulate PPARg2 transcription factor by which PPARg2 binds to responsive elements located in the promoter regions of many genes and modulates their transcriptive activity. There is a strong mutual relationship between receptor binding and agonism, which is evidence of the insulin-sensitizing target of thiazolidinediones in PPARg2. This evidently increases the biological potency of the glucose-lowering effect of thiazolidinediones in vivo as well as their antidiabetic activity. CONCLUSIONS: PPARg2 transcription factor plays an important role in treatment of type-2 diabetes with thiazolidindiones. The variant Pro12Ala of the PPARg2 gene promotes the activity of thiazolidinediones in minimizing insulin resistance. Transcriptional activity of Pro12Ala variant improves the activity of insulin. Thus thiazolidinediones promote the phosphorylation of PPARg2 to induce insulin sensitivity. PMID- 22221091 TI - The Burkholderia cenocepacia BDSF quorum sensing fatty acid is synthesized by a bifunctional crotonase homologue having both dehydratase and thioesterase activities. AB - Signal molecules of the diffusible signal factor (DSF) family have been shown recently to be involved in regulation of pathogenesis and biofilm formation in diverse Gram-negative bacteria. DSF signals are reported to be active not only on their cognate bacteria, but also on unrelated bacteria and the pathogenic yeast, Candida albicans. DSFs are monounsaturated fatty acids of medium chain length containing an unusual cis-2 double bond. Although genetic analyses had identified genes involved in DSF synthesis, the pathway of DSF synthesis was unknown. The DSF of the important human pathogen Burkholderia cenocepacia (called BDSF) is cis 2-dodecenoic acid. We report that BDSF is synthesized from a fatty acid synthetic intermediate, the acyl carrier protein (ACP) thioester of 3-hydroxydodecanoic acid. This intermediate is intercepted by protein Bcam0581 and converted to cis-2 dodecenoyl-ACP. Bcam0581 is annotated as a homologue of crotonase, the first enzyme of the fatty acid degradation pathway. We demonstrated Bcam0581to be a bifunctional protein that not only catalysed dehydration of 3-hydroxydodecanoyl ACP to cis-2-dodecenoyl-ACP, but also cleaved the thioester bond to give the free acid. Both activities required the same set of active-site residues. Although dehydratase and thioesterase activities are known activities of the crotonase superfamily, Bcam0581 is the first protein shown to have both activities. PMID- 22221093 TI - Ethnobotanical and scientific aspects of Malva sylvestris L.: a millennial herbal medicine. AB - OBJECTIVES: Malva sylvestris L., known as common mallow, is native to Europe, North Africa and Asia. In the Mediterranean region, this species has a long history of use as food, and due to its therapeutic relevance, some parts of this plant have been employed in traditional and ethnoveterinary medicines. The leaves in particular have been reported to have potent anti-inflammatory, antioxidant, anti-complementary, anticancer and skin tissue integrity activity. Additionally, an anti-ulcerogenic effect was recently proven, demonstrating that the aqueous extract was more effective than cimetidine, a potent medicine used to treat gastric ulcers. Due to its wide use and medicinal importance, many studies have been conducted; however, the information in the literature is very extensive and disseminated, making it difficult to use. KEY FINDINGS: A complete review involving the ethnobotanical and scientific aspects of M. sylvestris has been made. The research has provided evidence that M. sylvestris has potential use as a medicinal plant and has highlighted a need for more studies involving clinical and toxicological aspects of its use. SUMMARY: This review can contribute to the field with its historical context, and by describing the progress made, new ideas for researchers can arise. PMID- 22221094 TI - Pharmacokinetics and tissue distribution profile of icariin propylene glycol liposome intraperitoneal injection in mice. AB - OBJECTIVES: The pharmacokinetics and tissue distribution of icariin propylene glycol-liposome suspension (ICA-PG-liposomes) have been investigated. METHODS: ICA-PG-liposomes or ICA-PG-solution were prepared and intraperitoneally injected to mice. Morphology and size distribution of ICA-PG-liposomes were observed by transmission electron microscopy (TEM) and laser particle sizer. Plasma and tissues were collected at different times after intraperitoneal injection and icariin concentrations were determined by HPLC. KEY FINDINGS: From TEM, ICA-PG liposomes showed spherical vesicles with a mean particle size of 182.4 nm. The encapsulation efficiency of ICA-PG-liposomes reached 92.6%. Pharmacokinetics of ICA-PG-liposomes displayed the three open compartments model. ICA-PG-liposomes enhanced icariin absorption from the abdominal cavity, prolonged mean retention time (MRT((0-t))), increased area under curve (AUC((0-t))) and maximum concentration in plasma. Compared with ICA-PG-solution, ICA-PG-liposomes resulted in larger amounts of icariin being distributed into spleen (60.38% total icariin), liver (16.68%), lung (6.21%), kidney (4.64%), heart (1.43%) and brain (1.83%). AUC((0-t)) values in most tissues (except lung) of mice administered ICA PG-liposomes were higher than those administered ICA-PG-solution, while Clearance in most tissues (except brain and lung) decreased. The MRT((0-t)) values of ICA PG-liposomes in all tissues and half lives of most tissues (except brain) were prolonged. From Targeted efficiency and relative uptake data, the spleen was the target tissue of the ICA-PG-liposomes. CONCLUSIONS: ICA-PG-liposomes changed the pharmacokinetic behaviour and enhanced icariin distribution in tissues. With nanometer size, high encapsulation efficiency and improved pharmacokinetics, ICA PG-liposomes might be developed as promising carriers for icariin injection. PMID- 22221095 TI - Contribution of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 to hepatic uptake of nateglinide, and the prediction of drug-drug interactions via these transporters. AB - OBJECTIVES: We have investigated the contributions of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 to the hepatic uptake of nateglinide, and the possibility of drug-drug interactions via these transporters. METHODS: Uptake studies using transporter-expressing HEK293 cells and cryopreserved human hepatocytes were performed to examine the contributions of each transporter. Inhibition studies using cryopreserved human hepatocytes were performed to examine the possibility of drug-drug interactions. KEY FINDINGS: The rate of saturable hepatic uptake of nateglinide using human hepatocytes was 47.6%. A certain increase in uptake was observed in the examination using transporter expressing HEK293 cells, indicating contributions of OATP1B1 and OATP1B3 to hepatic nateglinide uptake. The 50% inhibitory concentration (IC50) values of nateglinide using cryopreserved human hepatocytes for uptake of estrone 3-sulfate (substrate of OATP1B1), and cholecystokinin octapeptide (substrate of OATP1B3) were 168 and 17.4 umol/l, respectively. Moreover, ciclosporin inhibited saturable hepatic uptake of nateglinide with an IC50 value of 6.05 umol/l. The calculated 1 + I(in,max,u) /IC50 values for inhibition of OATP1B1 and OATP1B3 by nateglinide, and the inhibition of saturable uptake of nateglinide by ciclosporin, were all close to 1, indicating a low clinical risk of drug-drug interaction with nateglinide taken up via OATP1B1 and OATP1B3. CONCLUSIONS: OATP1B1 and OATP1B3 may have contributed to the hepatic uptake of nateglinide, but the possibility of drug-drug interactions appeared to be low. PMID- 22221096 TI - Synbiotic (probiotic and ginger extract) loaded floating beads: a novel therapeutic option in an experimental paradigm of gastric ulcer. AB - OBJECTIVE: This study investigated the use of a bioactive phytochemical, namely ginger extract (GE), for its antioxidant and antiulcer effects, and also for supporting probiotic growth and activity. Use of probiotics is limited in therapy because of their transience and inability to survive the adverse physiological conditions of the gastrointestinal tract. Packaging probiotics in a suitably designed pharmaceutical system with GE may facilitate their establishment in the stomach mucosa. METHODS: A probiotic (Lactobacillus acidophilus) and GE were simultaneously and individually encapsulated/immobilized in alginate floating beads. The developed system was evaluated for diameter, buoyancy, entrapment, porosity, in-vitro viability/release and pharmacodynamics in a cold restraint stress induced gastric ulcer model in rats. KEY FINDING: The developed floating beads stayed in the stomach for more than 10 h and both agents were released slowly and over a prolonged period from these beads. Significant and promising results were obtained for the combination (synbiotic) system in terms of ulcer index, mucus secretion, oxidative stress and histopathological parameters, as compared with the individual agents. The developed system could completely revert the damage induced in ulcerated stomachs at physiological (ulcer index and mucus secretion), biochemical (oxidative stress) and histological levels. CONCLUSION: This study establishes that suitable packaging of GE and Lactobacillus acidophilus together in floating beads can help exploit their prospects as therapeutic curative agents rather than potential preventive agents. PMID- 22221097 TI - Mucus thickness in the gastrointestinal tract of laboratory animals. AB - OBJECTIVES: The objective of this study was to systematically assess the mucus thickness in the gastrointestinal tract of laboratory animals commonly used in preclinical studies. METHODS: Mucus thickness was studied post-mortem in the rat, rabbit and pig, using cryosections stained by the modified periodic acid Schiff/Alcian blue method. KEY FINDINGS: The mucus thickness in the fundus region of the stomach was higher in the pig (190.7 +/- 80.7 um) than in the rabbit (155.1 +/- 85.8 um) and the rat (31.3 +/- 11.4 um). However, along the small intestine (ileum), mucus was thicker in the rabbit (147.8 +/- 115.6 um), followed by the pig (53.8 +/- 22.1 um) and the rat (34.1 +/- 14.9 um). This rank order was also observed in the ascending colon. CONCLUSIONS: Inter-species variability in mucus thickness along the gut was demonstrated and suggests that the pig resembles more closely the mucus pattern of humans. This may be highly relevant when preclinical animal models are used in drug absorption studies or in the development of oral mucoadhesive drug delivery systems. PMID- 22221098 TI - Enhanced anti-neuroblastoma activity of a fenretinide complexed form after intravenous administration. AB - OBJECTIVES: The major limitation to successful chemotherapy of neuroblastoma (NB) is the toxicity and the poor bioavailability of traditional drugs. METHODS: We synthesised an amphiphilic dextrin derivative (DX-OL) able to host fenretinide (4 HPR) by complexation. In this study, we have investigated the effects of 4-HPR loaded amphipilic dextrin (DX-OL/4-HPR) in comparison with 4-HPR alone both in vitro on human NB cells and in vivo in pseudometastatic NB models. The haemolysis assay was used as a measure of the potential damage caused by the pharmaceutical formulation in vivo. Pharmacokinetic experiments were performed to assess drug plasma levels in mice treated with free or complexed 4-HPR. KEY FINDINGS: DX-OL/4 HPR exerted a more potent cytotoxic activity on NB cells. Complexed 4-HPR significantly increased the proportion of sub-G1 cells with respect to free 4 HPR. Dextrin derivatives showed no haemolytic activity, indicating their suitability for parenteral administration. DX-OL/4-HPR increased the lifespan and the long-term survival of treated mice over controls. The analysis of drug plasma levels indicates that the complexed drug has a higher AUC due to a reduced clearance from the blood. CONCLUSIONS: Our data suggest that DX-OL/4-HPR is an injectable formulation that is able to improve drug aqueous solubility and bioavailability. PMID- 22221099 TI - Metabolism of cryptolepine and 2-fluorocryptolepine by aldehyde oxidase. AB - OBJECTIVES: To investigate the metabolism of cryptolepine and some cryptolepine analogues by aldehyde oxidase, and to assess the implications of the results on the potential of cryptolepine analogues as antimalarial agents. METHODS: The products resulting from the oxidation of cryptolepine and 2-fluorocryptolepine by a rabbit liver preparation of aldehyde oxidase were isolated and identified using chromatographic and spectroscopic techniques. The antiplasmodial activity of cryptolepine-11-one was assessed against Plasmodium falciparum using the parasite lactate dehydrogenase assay. KEY FINDINGS: Cryptolepine was oxidized by aldehyde oxidase give cryptolepine-11-one. Although 2-fluorocryptolepine was found to have less affinity for the enzyme than cryptolepine, it was a better substrate for aldehyde oxidase than the parent compound. In contrast, quindoline, the 11-chloro , 2,7-dibromo- and 2-methoxy analogues of cryptolepine were not readily oxidized. Cryptolepine-11-one was found to be inactive against P. falciparum in vitro raising the possibility that the effectiveness of cryptolepine as an antimalarial, may be compromised by metabolism to an inactive metabolite by liver aldehyde oxidase. CONCLUSIONS: Cryptolepine and 2-fluorocryptolepine are substrates for aldehyde oxidase. This may have implications for the design and development of cryptolepine analogues as antimalarial agents. PMID- 22221100 TI - Comparison of sildenafil with strontium fructose diphosphate in improving erectile dysfunction against upregulated cavernosal NADPH oxidase, protein kinase Cepsilon, and endothelin system in diabetic rats. AB - OBJECTIVES: Phosphodiesterase type 5 inhibitors are potent in relieving erectile dysfunction (ED), however, they are less satisfactory in diabetic patients, probably due to the pro-inflammatory biomarkers caused by diabetes. Therefore, it was interesting to compare the effects of sildenafil with strontium fructose 1,6 diphosphate (FDP-Sr) on cavernosal vascular activity and expressions of pro inflammatory biomarkers in diabetic rats. METHODS: Male Sprague-Dawley rats were injected with streptozocin (60 mg/kg, i.p.) to develop diabetes. The animals were diabetic for eight weeks with sildenafil (12 mg/kg per day) or FDP-Sr (200 mg/kg per day) being administered for the last four of those eight weeks. KEY FINDINGS: Sildenafil was more effective in relieving reduced vascular dilatation (relevant to ED), but less in attenuating over-expressions of NADPH oxidase p22, p47 and p67 subunits, and ET(A/B) R (endothelin receptor type A and type B) in the diabetic cavernosum. In contrast, FDP-Sr was less effective in improving ED, but more effective in normalizing the abnormal NADPH oxidase and ET(A/B) R. CONCLUSIONS: The activated NADPH oxidase and upregulated ET(A) R and ET(B) R due to diabetic lesions played a minor or moderate role in ED. By offering extra ATP, FPD-Sr suppressed these abnormalities, however, sildenafil did not. A combined therapy of sildenafil with FDP-Sr may be more effective in relieving ED in diabetic patients through normalizing pro-inflammatory cytokines and improving the nitric oxide/cGMP pathway in the cavernosum. PMID- 22221101 TI - Transient receptor potential vanilloid-1 participates in the inhibitory effect of ginsenoside Rg1 on capsaicin-induced interleukin-8 and prostaglandin E2 production in HaCaT cells. AB - OBJECTIVES: Ginsenoside Rg1 (GRg1), one of the major active constituents of Panax notoginseng, has shown anti-inflammatory and antinocioceptic activity, but its role in keratinocytes needs further study. We have examined the inhibitory effect of GRg1 on transient receptor potential vanilloid-1 (TRPV1) activation in keratinocyte HaCaT cells and explored its involved mechanism. METHODS: HEK 293T cells over-expressing exogenous TRPV1 were constructed and named HEK 293T-TRPV1 cells. The effects of GRg1 on production of interleukin-8 (IL-8) and prostaglandin E(2) (PGE(2) ), calcium influx, the expression of cyclooxygenase-2 (COX-2) and nuclear factor-kappaB (NF-kappaB) transcriptional activity in HEK 293T-TRPV1 and HaCaT cells were examined by ELISA, Fluo 3-AM fluorescence probe, Western blot and Dual-Luciferase Reporter Assay, respectively. KEY FINDINGS: The results showed that GRg1 blocked intracellular calcium by both capsaicin and proton activation in a TRPV1-dependent manner. Furthermore, GRg1 inhibited the expression of COX-2 and NF-kappaB transcriptional activity induced by capsaicin in keratinocytes. The inhibitory effect of GRg1 was similar to capsazepine, an antagonist of TRPV1. More importantly, GRg1 dose-dependently inhibited capsaicin induced PGE(2) and IL-8 secretion in HaCaT cells and HEK 293T-TRPV1 cells. CONCLUSIONS: These data showed that GRg1 could inhibit TRPV1 mediated responses in HaCaT cells, indicating that GRg1 acted as a TRPV1 antagonist. PMID- 22221102 TI - Modulatory effects of gentisic acid against genotoxicity and hepatotoxicity induced by cyclophosphamide in Swiss albino mice. AB - OBJECTIVES: This study evaluated the protective effects of gentisic acid (GA) against genotoxicity and hepatotoxicity induced by cyclophosphamide (CP) in Swiss albino mice. METHODS: Mice were pretreated with GA orally at doses of 50 and 100 mg/kg for 14 consecutive days before the administration of a single intraperitoneal dose of 50 mg/kg CP. The ameliorative effect of GA on genotoxicity was studied using the in-vivo bone marrow micronuclei induction test, DNA integrity and alkaline unwinding assay. The activity of various oxidative stress enzymes were estimated in hepatic tissue. KEY FINDINGS: A single intraperitoneal administration of CP in mice increased the malondialdehyde level, depleted the glutathione content and antioxidant enzyme activity (glutathione peroxidase, glutathione reductase, catalase and quinone reductase), and induced DNA strand breaks and micronuclei induction. Oral pretreatment with GA at both doses caused a significant reduction in malondialdehyde and glutathione levels, restoration of antioxidant enzyme activity, reduction in micronuclei formation and DNA fragmentation. Serum toxicity marker enzymes such as aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase were increased after CP treatment but restored in GA pretreated groups. CONCLUSION: The results support the protective effect of GA against CP induced genotoxicity and hepatotoxicity. PMID- 22221103 TI - Vitis vinifera L. grape skin extract activates the insulin-signalling cascade and reduces hyperglycaemia in alloxan-induced diabetic mice. AB - OBJECTIVES: This study examined the effect of Vitis vinifera grape skin extract (ACH09) on hyperglycaemia and the insulin-signalling cascade in alloxan-treated mice. METHODS: Glycaemia, serum insulin and Western blot analysis of insulin cascade proteins were evaluated in the gastrocnemius muscles of four groups of adult mice: control, ACH09 (200 mg/kg per day, p.o.), alloxan (300 mg/kg, i.p.) and alloxan + ACH09. Insulin secretion in isolated pancreatic islets was also studied. KEY FINDINGS: Glycaemia values in the alloxan + ACH09 and ACH09 groups were significantly lower than in the alloxan-treated and control groups, respectively. Increased insulin resistance (HOMA index) was observed in the alloxan-treated group but not in the alloxan + ACH09 group. Insulin receptor content and Akt phosphorylation were significantly greater in the alloxan + ACH09 group compared with the alloxan-treated group. The glucose transporter (GLUT-4) content was reduced in alloxan-treated mice compared with the control group, while alloxan + ACH09 and ACH09-treated mice showed a significant increase in GLUT-4 content. ACH09 treatment did not change glucose-induced insulin secretion in isolated pancreatic islets. CONCLUSIONS: The results suggest that ACH09 has hypoglycaemic and antihyperglycaemic effects that are independent of an increase in insulin release but are probably dependent on an increase in insulin sensitivity resulting from an activation of the insulin-signalling cascade in skeletal muscle. PMID- 22221104 TI - Augmentative effect of spinosin on pentobarbital-induced loss of righting reflex in mice associated with presynaptic 5-HT1A receptor. AB - OBJECTIVES: This study investigated whether spinosin potentiates pentobarbital induced loss of righting reflex (LORR) in mice via 5-HT(1A) receptors. METHODS: Our primary endpoint for sedation was LORR. In addition, the basal rectal temperature was measured. KEY FINDINGS: The results demonstrated that the 5 HT(1A) agonist 8-OH-DPAT (s.c.) induced reductions in duration of LORR at 0.1, 0.5 and 1.0 mg/kg (P < 0.01), and prolongation of LORR latency at 0.5 and 1.0 mg/kg (s.c., P < 0.01) in pentobarbital (45 mg/kg, i.p.)-treated mice. This effect of 8-OH-DPAT was antagonized either by 5-HT(1A) antagonist p-MPPI (5 mg/kg, i.p.) or by spinosin (15 mg/kg, i.g.) with significance, respectively. Co administration of spinosin and p-MPPI both at ineffective doses (spinosin at 5.0 mg/kg, i.g. and p-MPPI at 1.0 mg/kg, i.p.) showed significant augmentative effects in reducing latency to LORR, and increasing LORR duration (P < 0.01) in pentobarbital-treated mice. On the other hand, spinosin inhibited 8-OH-DPAT induced hypothermia, which has been generally attributed to the activation of somatodendritic 5-HT(1A) autoreceptors in mice. CONCLUSIONS: Based on our previous results and the present data, it should be presumed that presynaptic 5 HT(1A) autoreceptor mechanisms may be involved in the inhibitory effect of spinosin on 8-OH-DPAT-induced hypothermia and also in the potentiating effect of spinosin on pentobarbital-induced LORR in mice. PMID- 22221105 TI - Antinociceptive activity of the monoterpene alpha-phellandrene in rodents: possible mechanisms of action. AB - OBJECTIVES: The aim of this work was to investigate the antinociceptive property of alpha-phellandrene (alpha-PHE) in experimental nociception models and possible mechanisms involved. METHODS: Mass spectrometry was used to evaluate the purity and molecular mass of alpha-PHE. Macrophages from mice peritoneal cavity were used in an MTT test. Rodents were used in tests of chemical and mechanical nociception. In the study of the mechanisms, the animals were treated with pharmacological tools and then submitted to the glutamate test. KEY FINDINGS: alpha-PHE purity was 98.2% and molecular mass 136.1 Da. alpha-PHE did not show cytotoxicity. In the writhing and capsaicin tests, alpha-PHE promoted the antinociceptive effect in all evaluated doses (minimum dose 3.125 mg/kg). In the formalin test, alpha-PHE (50 mg/kg) was effective in inhibiting both phases. In the glutamate test, the monoterpene (12.5 mg/kg) decreased the nociceptive response. In carrageenan-induced hyperalgesia, alpha-PHE (50 mg/kg) decreased the hypernociception index. In the study of the mechanisms involved, pretreatment with naloxone reversed the alpha-PHE antinociceptive effect, the same occurred with glibenclamide, l-arginine, atropine and yohimbine. alpha-PHE did not show muscle relaxant activity or central depressant effects in open field and rota rod tests. CONCLUSIONS: alpha-PHE has an antinociceptive effect and it possibly involves the glutamatergic, opioid, nitrergic, cholinergic and adrenergic systems. PMID- 22221106 TI - NO-1886 ameliorates glycogen metabolism in insulin-resistant HepG2 cells by GSK 3beta signalling. AB - OBJECTIVES: The aim of the study was to elucidate the possible role and mechanism of NO-1886 (ibrolipim, a lipoprotein lipase activator) in ameliorating insulin resistance induced by high palmitate. METHODS: HepG2 cells were cultured in RPMI 1640 medium and were treated with palmitate to induce insulin resistance. Free fatty acids (FFAs), glucose, glycogen, cell viability and mRNA and protein levels were analysed separately. KEY FINDINGS: We found that HepG2 cells treated with 0.5 mm palmitate for 48 h led to a significant decrease of insulin-induced glucose consumption (from 2.89 +/- 0.85 mm in the control to 0.57 +/- 0.44 mm in palmitate). Insulin resistance (IR) of HepG2 cells was induced by 0.5 mm palmitate for 48 h. NO-1886 stimulated glucose consumption, glycogen synthesis and FFA absorption in insulin-resistant HepG2 cells. Maximum stimulation effects were observed with 10 um NO-1886 for 24 h. Compared with the dimethyl sulfoxide treated group, 2.5 um NO-1886 or higher could induce the mRNA expression of lipoprotein lipase. Meanwhile, NO-1886 increased the protein content of P-GSK 3betaser(9) and decreased the protein level of GSK-3beta in insulin-resistant HepG2 cells, but NO-1886 didn't change the protein levels of PI3-Kp85 and Akt2. CONCLUSION: Lipoprotein lipase activator NO-1886 could increase glycogen synthesis in HepG2 cells and could ameliorate the insulin resistance, which was associated with GSK-3 signalling. PMID- 22221107 TI - Effects of isoflurane on learning and memory functions of wild-type and glutamate transporter type 3 knockout mice. AB - OBJECTIVES: General anesthetics may contribute to the post-operative cognitive dysfunction. This study was designed to determine the effects of isoflurane on the learning and memory of healthy animals or animals with a decreased brain antioxidative capacity. METHODS: Seven- to nine-week-old female CD-1 wild-type mice or glutamate transporter type 3 (EAAT3) knockout mice whose brains have a decreased glutathione level were exposed to or were not exposed to 1.3% isoflurane for 2 h. They were subjected to fear conditioning or Barnes maze tests 1 week later. KEY FINDINGS: The EAAT3 knockout mice had less freezing behaviour than the wild-type mice in tone-related fear. Isoflurane did not affect the freezing behaviour of the wild-type and EAAT3 knockout mice. The time for the wild-type and EAAT3 knockout mice to identify the target hole in the training sessions and memory test with the Barnes maze was not affected by isoflurane. However, the EAAT3 knockout mice took longer to identify the target hole than the wild-type mice in these tests. CONCLUSIONS: These results suggest that EAAT3 knockout mice have significant cognitive impairment. Isoflurane may not significantly affect the cognition of wild-type and EAAT3 knockout mice in a delayed phase after isoflurane exposure. PMID- 22221108 TI - Pyeongwee-San extract (KMP6): a new anti-allergic effect. AB - OBJECTIVES: The prevalence of allergic diseases is increasing due to rapid industrialization and changes in lifestyle. Pyeongwee-San (KMP6) is a traditional Korean medicine that has been used as a basic prescription for digestive disorders. This study investigated the efficacy of KMP6 and its component hesperidin on experimental allergic models. METHODS: The anti-allergic effect of KMP6 was studied against a compound 48/80-induced systemic anaphylactic reaction and the ear swelling response. In addition, a human mast cell line (HMC-1) was used to analyze the activity of histidine decarboxylase. Passive cutaneous anaphylaxis (PCA) from immunoglobulin E (IgE) was used. KEY FINDINGS: KMP6 and hesperidin inhibited the compound 48/80-induced systemic anaphylactic reaction and the ear swelling response as well as histamine release, intracellular calcium levels and tryptase release from rat peritoneal mast cells. KMP6 inhibited histidine decarboxylase activity in stimulated HMC-1 cells and macrophages. In addition, KMP6 inhibited the PCA reaction induced by IgE as well as the levels of IgE, interleukin (IL)-4, IL-5, IL-6 and IL-13 in serum from mice. CONCLUSIONS: These results suggest that KMP6 may exert an anti-allergic effect through not only the inhibition of mast cell degranulation but also the inhibition of histamine synthesis. PMID- 22221109 TI - Paraneoplastic large vessel arteritis complicating myelodysplastic syndrome. PMID- 22221110 TI - Application of serial sectioning FIB/SEM tomography in the comprehensive analysis of arrays of metal nanotubes. AB - The ever-increasing interest in nanostructured materials and shrinking dimensions of state-of-the-art devices pose new challenges both in synthesis and metrology. Although an extensive range of nanotubular materials of different compositions and for various applications are reported in the literature, often detailed structural characterisation of these materials is limited. This is due to the fact that techniques and characterisation protocols for structural analysis of 'buried' nano-scale features, defects or inhomogenities that are difficult to obtain by conventional imaging methods, are still not fully developed. In the case of 1D nanoporous structures, the continuity of the nano-tubular channels, their uniformity and orientation is of particular interest. Herein, we employ a serial sectioning technique on a dual beam FIB followed by 3D volume reconstruction for comprehensive analysis of tubular metal nanostructures encapsulated within porous anodic alumina. Using this technique, we demonstrate a nano-tomography characterisation protocol that can be used for analysis of nanoporous structures with emphasis on their channel uniformity and orientation. We demonstrate that high-resolution nano-tomography can be performed to visualise pores as small as 60 nm in diameter, with conical or globular shapes, and to quantitatively estimate their localisation and distribution along one-dimensional metal structures. We specifically chose to examine Cu-nanotubes, deposited electrochemically within anodic alumina template, because there is a great deal of debate regarding the deposition process. Hence, the comprehensive analysis shown here is not only demonstrating the applicability of the developed characterisation methodology but it is also, in conjunction with other advanced electron microscopy methods such as elemental nano-scale STEM/EDX mapping, providing conclusive evidence of the key factors at play during the deposition process. PMID- 22221111 TI - The manipulation of drugs to obtain the required dose: systematic review. AB - AIM: To describe the development of a systematic review protocol that maps the evidence relating to drug manipulations conducted to obtain the required dose. This process included defining a search strategy and methods to assess the quality and to synthesize the evidence retrieved. BACKGROUND: Economic constraints mean that marketed formulations may not meet the needs of all patients. Consequently, it is sometimes necessary to manipulate marketed products with the aim of obtaining the required dose. Most clinical practice appears to be guided by ad hoc approaches and informal literature reviews. METHODS: This systematic review protocol has been designed to identify the evidence available on drug manipulation. The review aims to identify what evidence is available and where the gaps appear in the current evidence. This report describes the challenges of developing a systematic review in an area that potentially involves many drugs and considers outcomes other than effectiveness. In particular, searches required the use of non-specific terms and the iterative development of a complex search strategy. The development of quality assessment criteria is also described. Funding commenced in April 2009. DISCUSSION: The systematic review described here will capture a broad selection of research about drug manipulations and may also be of interest to those conducting reviews in broad remit subject areas that are not easy to define using accepted terminology. PMID- 22221113 TI - Do primigravidae and their carers have a realistic expectation of uncomplicated labour and delivery?: a survey of primigravidae in late pregnancy, obstetric staff and medical students. AB - BACKGROUND: Women who experience unexpected labour and birth interventions describe feeling distressed and have an increased risk of postnatal depression. Primigravidae who have an unrealistic expectation of labour and birth may be at higher risk of these outcomes. AIMS: To determine whether primigravidae and their carers have a realistic expectation of uncomplicated labour and birth. METHODS: One hundered and ninety-five primigravidae, 32 obstetricians, 76 midwives, 198 medical students prior to their obstetric term and 131 medical students after their obstetric term completed a short questionnaire about the likelihood of primigravid women undergoing spontaneous onset of labour, no augmentation of labour and a cephalic vaginal birth without instrumental assistance, defined as birth without intervention. This number was compared to the local published data. RESULTS: Overall, the study subjects believed that women had a 48% chance of birth without intervention, and a 26% chance of birth without intervention or perineal sutures. The statewide published figures for these two outcomes are 21 and 8%, respectively. Staff, both obstetric and midwifery, were more accurate than medical students who were in turn more accurate than pregnant women. Attendance at antenatal education classes by pregnant women did not improve accuracy. Level of experience did not improve accuracy by medical staff. Medical students were more accurate after teaching than before teaching. CONCLUSION: Primigravidae in late pregnancy and maternity staff do not have a realistic expectation of a labour and birth that is free from medical intervention. This may impact on choices women make about care in pregnancy and labour. PMID- 22221115 TI - Physiological and biochemical parameters controlling waterlogging stress tolerance in Prunus before and after drainage. AB - Waterlogging is associated with poor soil drainage. As a consequence oxygen levels decrease in the root environment inducing root asphyxia and affecting plant growth. Some plants can survive under these conditions triggering complex anatomical and biochemical adaptations, mostly in the roots. Long- and short-term responses to waterlogging stress were compared in two trials using a set of two myrobalans (Prunus cerasifera Erhr), 'P.2175' and 'P.2980', as tolerant rootstocks and two almond * peach [Prunus amygdalus Batsch *Prunus persica (L.) Batsch] interspecific hybrids, 'Garnem' and 'Felinem', as sensitive ones in two consecutive years. Stomatal conductance and chlorophyll content were measured in the long-term trials to assess survival performance, while the enzyme activities of superoxide dismutase (SOD, EC 1.15.1.1), guaiacol peroxidase (POD, EC 1.11.1.7), and catalase (CAT, EC 1.11.1.6) were measured in the short-term trials to study early antioxidant response. The incidence of the stress in the root environment was different as a result of the different plant development at the moment of the treatment, as a consequence of different environmental conditions both before and during the treatment between the 2 years. The activity of the different enzymes was higher in the sensitive genotype 'Felinem' than in the tolerant 'P.2175'. This result shows an activation of the antioxidant system and has been observed to depend of the different nature of the roots between the 2 years. As the antioxidant enzymes seem to work more efficiently when roots are more aerated, we cannot conclude that they are responsible for the higher tolerance observed in the myrobalan plums. PMID- 22221116 TI - Progressive conduction defects and cardiac death in late infantile neuronal ceroid lipofuscinosis. AB - This article reports the case of a female with late infantile neuronal ceroid lipofuscinosis who developed right and left anterior bundle branch blocks and episodic bradycardia at 23 years of age. Several episodes of supraventricular tachycardia manifested at 23 and 27 years of age. In addition, a transient second degree atrioventricular conduction block also emerged at 27 years of age. Atrial fibrillation and aggravation of the atrioventricular conduction block resulted in progressive bradycardia and cardiac death at the age of 28 years. Cardiac involvement and accumulation of lipopigments in the myocardium and cardiac conduction system have been recognized in juvenile neuronal ceroid lipofuscinosis, but this is the first report to describe progressive conduction defects in a case of late infantile neuronal ceroid lipofuscinosis. PMID- 22221135 TI - Formation of a uranium trithiocarbonate complex via the nucleophilic addition of a sulfide-bridged uranium complex to CS2. AB - The uranium(IV)/uranium(IV) MU-sulfide complex [{(((Ad)ArO)(3)N)U}(2)(MU-S)] reacts with CS(2) to form the trithiocarbonate-bridged complex [{(((Ad)ArO)(3)N)U}(2)(MU-kappa(2):kappa(2)-CS(3))]. The trithiocarbonate complex can alternatively be formed in low yields from low-valent [(((Ad)ArO)(3)N)U(DME)] through the reductive cleavage of CS(2). PMID- 22221117 TI - Spaceflight transcriptomes: unique responses to a novel environment. AB - The spaceflight environment presents unique challenges to terrestrial biology, including but not limited to the direct effects of gravity. As we near the end of the Space Shuttle era, there remain fundamental questions about the response and adaptation of plants to orbital spaceflight conditions. We address a key baseline question of whether gene expression changes are induced by the orbital environment, and then we ask whether undifferentiated cells, cells presumably lacking the typical gravity response mechanisms, perceive spaceflight. Arabidopsis seedlings and undifferentiated cultured Arabidopsis cells were launched in April, 2010, as part of the BRIC-16 flight experiment on STS-131. Biologically replicated DNA microarray and averaged RNA digital transcript profiling revealed several hundred genes in seedlings and cell cultures that were significantly affected by launch and spaceflight. The response was moderate in seedlings; only a few genes were induced by more than 7-fold, and the overall intrinsic expression level for most differentially expressed genes was low. In contrast, cell cultures displayed a more dramatic response, with dozens of genes showing this level of differential expression, a list comprised primarily of heat shock-related and stress-related genes. This baseline transcriptome profiling of seedlings and cultured cells confirms the fundamental hypothesis that survival of the spaceflight environment requires adaptive changes that are both governed and displayed by alterations in gene expression. The comparison of intact plants with cultures of undifferentiated cells confirms a second hypothesis: undifferentiated cells can detect spaceflight in the absence of specialized tissue or organized developmental structures known to detect gravity. PMID- 22221136 TI - Older Australian women use complementary fertility care: a practice audit. PMID- 22221137 TI - Effect of distigmine combined with propiverine on bladder activity in rats with spinal cord injury. AB - It is not uncommon for patients with spinal cord injury to have both detrusor overactivity during the storage phase and detrusor underactivity during the voiding phase. However, there has been no information about the efficacy of combined treatment with cholinesterase inhibitors and anti-muscarinic agents for this condition. Therefore, the effect of co-administration of distigmine bromide (a cholinesterase inhibitor) and propiverine hydrochloride (an anti-muscarinic agent) on bladder activity was examined in rats with spinal cord injury. Rats were anesthetized with isoflurane and the lower thoracic spinal cord was transected. The bladder was emptied by abdominal compression twice a day for 14 days after surgery. A total of 4 weeks after surgery, the animals were anesthetized with urethane, and the effect of intravenous injection of distigmine (0.01-1 mg/kg) followed by propiverine (1 mg/kg) on continuous cystometry parameters was examined. After injection of distigmine (0.1 and 1 mg/kg), the maximum bladder contraction pressure was significantly increased, and the duration of bladder contraction and the interval between bladder contractions were significantly prolonged. The baseline bladder pressure was not changed by injection of distigmine. After the addition of propiverine, the interval between bladder contractions was significantly further prolonged without any change of the maximum contraction pressure, baseline pressure or duration of bladder contraction. The residual volume after voiding bladder contraction was less than 0.1 mL in all animals. In conclusion, co-administration of distigmine with propiverine might improve both bladder underactivity during the voiding phase and bladder overactivity during the storage phase. PMID- 22221138 TI - Novel stannatranes of the type N(CH2CMe2O)3SnX (X = OR, SR, OC(O)R, SP(S)Ph2, halogen). Synthesis, molecular structures, and electrochemical properties. AB - The syntheses of the stannatrane derivatives of the type N(CH(2)CMe(2)O)(3)SnX (1, X = Ot-Bu; 2, X = Oi-Pr; 3, X = 2,6-Me(2)C(6)H(3)O; 4, X = p-t-BuC(6)H(4)O; 5, X = p-NO(2)C(6)H(4)O; 6, X = p-FC(6)H(4)O; 7, X = p-PPh(2)C(6)H(4)O; 8, X = p MeC(6)H(4)S; 9, X = o-NH(2)C(6)H(4)O; 10, X = OCPh(2)CH(2)NMe(2); 11, X = Ph(2)P(S)S; 12, X = p-t-BuC(6)H(4)C(O)O; 13, X = Cl; 14, X = Br; 15, X = I; 16, X = p-N(CH(2)CMe(2)O)(3)SnOSiMe(2)C(6)H(4)SiMe(2)O) are reported. The compounds are characterized by X-ray diffraction analyses (3-8, 11-16), multinuclear NMR spectroscopy, (13)C CP MAS (14) and (119)Sn CP MAS NMR (13, 14) spectroscopy, mass spectrometry and osmometric molecular weight determination (13). Electrochemical measurements show that anodic oxidation of the stannatranes 4 and 8 occurs via electrochemically reversible electron transfer resulting in the corresponding cation radicals. The latter were detected by cyclic voltammetry (CV) and real-time electron paramagnetic resonance spectroscopy (EPR). DFT calculations were performed to compare the stannatranes 4, 8, and 13 with the corresponding cation radicals 4(+*), 8(+*), and 13(+*), respectively. PMID- 22221139 TI - Irregular fibrillar pattern is an artifactual expression of parallel ridge pattern on the pressure-loaded area of the sole: the efficacy of oblique view dermoscopy. PMID- 22221141 TI - Understanding children's dental anxiety and psychological approaches to its reduction. AB - BACKGROUND: Dental anxiety is a common problem, which can affect people of all ages, but appears to develop mostly in childhood and adolescence. Childhood dental anxiety is not only distressing for the child and their family but is also associated with poor oral health outcomes and an increased reliance on costly specialist dental services. AIM: This article will consider the prevalence, development, and implications of children's dental anxiety. It will also discuss the opportunities for and challenges of psychological approaches such as cognitive behavioural therapy aimed at the reduction of dental anxiety in children. PMID- 22221140 TI - Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot study. AB - BACKGROUND: Irritable bowel syndrome is characterised by chronic abdominal pain and frequent comorbid anxiety. The substance P / neurokinin-1 receptor system is implicated in the regulation of both pain and anxiety, suggesting a potential therapeutic target in IBS. AIM: To determine whether inhibition of the neurokinin 1 receptor (NK1R) will change pain ratings and brain responses to experimental visceral pain and anxiety symptoms in women with IBS or not. METHODS: Rome II positive IBS women were recruited for a double-blind, placebo-controlled, cross over study of NK1R antagonist AV608. Treatment periods were 3 weeks with a 2-week washout period. Functional MRI during a visceral distension paradigm was performed before first treatment and after treatment blocks. SPM8 was used to compare brain activity during painful and nonpainful visceral stimuli in regions associated with emotional arousal and interoception. Negative affect, anxiety symptoms and pain ratings were assessed. RESULTS: Eleven subjects completed the study and eight subjects provided fMRI data. AV608, compared with placebo, was associated with reduced anxiety, negative affect, and pain ratings. During AV608 treatment, the amygdala, hippocampus and anterior cingulate gyrus showed decreased activity during visceral distension. AV608 was also associated with decreases in activity in brain regions associated with interoception (posterior insula, anterior mid-cingulate gyrus). CONCLUSIONS: Chronic treatment with AV608 in IBS is associated with improved mood and pain ratings and activity of emotional arousal related brain regions. This suggests that further exploration of NK1R antagonists is warranted in visceral pain disorders, particularly in patients with comorbid anxiety symptoms. PMID- 22221142 TI - JAK3, STAT3 and CD3-zeta signaling proteins status in regard to the lymphocytes function in patients with ovarian cancer. AB - Several groups of author have published that, in most cases of carcinoma, circulating lymphocytes are unable to carry out immune functions successfully. A molecular mechanism responsible for T lymphocytes defective reactivity in cancer patients is not completely defined. We evaluated whether the impaired function of peripheral blood lymphocytes (PBLs) from ovarian cancer patients could be associated with signaling elements such as JAK3, STAT3 and CD3-zeta chain. The study addressed to the simultaneous expression and phosphorylation status of mentioned molecules evaluation in regard to lymphocyte function in patients with advanced ovarian cancer has not yet been demonstrated by others. We found that PBLs of cancer patients showed lower JAK3, CD3-zeta molecules expression levels, as well as lower STAT3 and CD3-zeta phosphorylation levels than cells of control. The lower proliferative response and IL-2 production capacity of cancer patients PBLs in comparison with that of the control group cells were the functional consequences of reported in this study signaling abnormalities. PMID- 22221144 TI - Solution pH that minimizes self-association of three monoclonal antibodies is strongly dependent on ionic strength. AB - Monoclonal antibodies display highly variable solution properties such as solubility and viscosity at elevated concentrations (>50 mg/mL), which complicates antibody formulation and delivery. To understand this complex behavior, it is critical to measure the underlying protein self-interactions that govern the solution properties of antibody suspensions. We have evaluated the pH dependent self-association behavior of three monoclonal antibodies using self interaction chromatography for a range of pH values commonly used in antibody formulations (pH 4.4-6). At low ionic strength (<25 mM), we find that each antibody is more associative at near-neutral pH (pH 6) than at low pH (pH 4.4). At high ionic strength (>100 mM), we observe the opposite pH-dependent pattern of antibody self-association. Importantly, this inversion in self-association behavior is not unique to multidomain antibodies, as similar pH-dependent behavior is observed for some small globular proteins (e.g., ribonuclease A and alpha-chymotrypsinogen). We also find that the opalescence of concentrated antibody solutions (90 mg/mL) is minimized at low ionic strength at pH 4.4 and high ionic strength at pH 6, in agreement with the self-interaction measurements conducted at low antibody concentrations (5 mg/mL). Our results highlight the complexity of antibody self-association and emphasize the need for systematic approaches to optimize the solution properties of concentrated antibody formulations. PMID- 22221143 TI - Circulating plasmacytoid dendritic cells in patients with primary and Helicobacter pylori-associated immune thrombocytopenia. AB - OBJECTIVES: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by the production of autoreactive antibodies against platelet antigens. Although dysfunction of multiple aspects of cellular immunity is considered to be important in the pathogenesis of ITP, it has not been clarified which cell types play a principal role. METHODS: We enrolled 46 untreated patients with chronic ITP and 47 healthy adult volunteers, and investigated by flow cytometry the percentage and absolute number of cells in their peripheral blood that participate in the regulation of cellular immunity. These included plasmacytoid dendritic cells (pDCs), myeloid dendritic cells (mDCs), natural killer (NK) cells, natural killer T (NKT) cells, regulatory T (Treg) cells, and Th17 cells. RESULTS: We found a significant reduction in the absolute number of pDCs, but not of mDCs, in patients with ITP when compared with healthy controls (P < 0.001). Reduced numbers of circulating pDCs were observed in both Helicobacter pylori (H. pylori)-positive and Helicobacter pylori (H. pylori)-negative patients with ITP. In contrast, there were no significant differences in the numbers of circulating Treg cells, Th17 cells, NK cells, or NKT cells. Interestingly, we observed increases in the number of pDCs after H. pylori eradication by antibiotics in responders but not in non-responders, while pDCs and mDCs decreased markedly after prednisolone therapy in both responders and non-responders. In patients without treatment, low pDC numbers persisted during the observational period. CONCLUSIONS: We demonstrated that the number of circulating pDCs is low in patients with primary and H. pylori-associated ITP and that it changes depending on treatment modality. Further investigation is warranted with regard to the role of pDCs in the immunopathogenesis of ITP. PMID- 22221146 TI - Age-related differences in word-retrieval but not in meaning generation. AB - This study examines age-associated changes in retrieval on a picture-naming task, phonemic and semantic fluency tasks, and the Homophone Meaning Generation Test (HMGT). The sample included 152 Hebrew-speaking adults, half young (mean age 22.75) and half old (mean age 76.05). Groups differed on the picture-naming task and on both verbal fluency tasks, but not on the HMGT. Age explained a greater share of the variance than did education level on these three tests, whereas the opposite pattern of results was seen on the HMGT. We suggest that age-related word finding difficulties are attenuated when performance allows for semantic rather than phonological access. PMID- 22221147 TI - What lies between: the evolution of stomatal traits on the road to C4 photosynthesis. PMID- 22221148 TI - Adapting with the enemy: local adaptation in plant-herbivore interactions. PMID- 22221149 TI - Polyploids integrate genomic changes and ecological shifts. 13th Congress of the European Society for Evolutionary Biology, Tuebingen, Germany, August 2011. PMID- 22221150 TI - Fire and plant evolution. MEDECOS Special Session on 'Fire as an evolutionary pressure shaping plant traits', Los Angeles, CA, USA, September 2011. PMID- 22221151 TI - Pharmacological synergy: the next frontier on therapeutic advancement for migraine. AB - The burden of migraine significantly impacts the individual sufferer, their families, the workplace, and society. The World Health Organization has identified migraine as an urgent public health priority and has initiated a global initiative to reduce the burden of migraine. Underlying the World Health Organization initiative is the need to discover means of optimizing migraine treatments and make them accessible to the broader portion of the world population. Development of acute migraine medications over the past several decades has largely centered on engineering highly specific receptor molecules that alter migraine pathophysiological mechanisms to abort or reverse the acute attack of migraine. The first product of this line of discovery was sumatriptan and heralded as a landmark therapeutic breakthrough. Sumatriptan is a 5-HT-1B/D receptor agonist considered to activate receptors involved in the pathophysiology specific to migraine. Large-scale regulatory/clinical studies demonstrated statistical superiority for sumatriptan over placebo in reduction or elimination of headache, nausea, photophobia, and phonophobia. Since the introduction of sumatriptan, 6 other triptan products have been released in the United States as acute treatments for migraine, all having the same mechanism of action and similar efficacy. Despite their utility as migraine abortive medications, the triptans do not successfully treat all attacks of migraine or necessarily treat all migraine associated symptoms. In fact, in less than 25% of attacks do subjects obtain and maintain a migraine-free response to treatment for at least beyond 24 hours. A wide range of non-triptan medications also have demonstrated efficacy in acute migraine. These include non-steroidal anti-inflammatory drugs (NSAIDs), opioids, phenothiazines, and valproic acid to name a few. Given the distinctly different mechanisms of actions of these various medications, it is likely that several unique pathophysiological mechanisms are involved in terminating acute episodes of migraine. Clinicians now capitalize on this observation and use migraine medication in combination with another to improve patient outcomes, for example, using an antiemetic with an opioid or a triptan and NSAIDs. More recently, the Food and Drug Adminstration has approved a combination product containing 85mg of sumatriptan plus 500mg of naproxen sodium for acute treatment of migraine. Clinical trials conducted prior to approval demonstrated that the combination of sumatriptan and naproxen was more effective as a migraine abortive than either of its components but that each component and the combination were more effective than placebo. Exactly how sumatriptan and naproxen interact to create therapeutic synergism is unknown though its mere occurrence suggests that models assisting medical understanding and prediction of pharmacological synergism may improve clinical outcome over products acting through a single receptor mechanism. Migraine is a syndrome, meaning it is defined by observed symptoms rather than known pathophysiology. Multiple pathogenic mechanisms are likely involved in generating this diverse array of symptoms understood as the migraine symptom complex. Sumatriptan and naproxen have independent mechanisms of action and target distinct aspects of the vascular and inflammatory processes hypothesized to underlie migraine. Sumatriptan acts on the 5-HT(1B) and 5-HT(1D) receptors, whereas naproxen inhibits the COX-1 and COX 2 enzymes. Sumatriptan has vasoconstricting effects as well as effects on neurogenic inflammation by decreasing the release of substance P and calcitonin gene-related peptide. In contrast, naproxen affects prostaglandins and other inflammatory mediators. Because sumatriptan and naproxen both relieve migraine yet interact with different cellular targets within the migraine pathway, it is reasonable to assume there is a unique synergy between these medications that improves treatment outcomes. Clinical trials supported this contention by demonstrating the combination of sumatriptan/naproxen alleviated migraine pain quickly (primarily based on the sumatriptan mechanism of action), and sustained the response longer (primarily based on the naproxen mechanism of action) than is possible when either drug is given alone. The working hypothesis is that when sumatriptan and naproxen are given at the same time, they affect different mechanisms of the migraine pathway and produce an enhanced therapeutic effect. The purpose of this article is to apply statistical analyses to data from phase II and phase III studies of the combination of sumatriptan and naproxen to determine if this enhanced therapeutic effect is synergistic. This methodology of accessing synergy can be used in the development of future combination migraine treatments to improve treatment outcomes. PMID- 22221152 TI - Factors associated with sleep disturbance in women of Mexican descent. AB - AIMS: The aims were to identify the most useful parameters of acculturation in relation to self-reported sleep disturbance and describe risk factors for sleep disturbance in women of Mexican descent. BACKGROUND: Little is known about acculturation as a factor for poor sleep in the context of other personal factors such as income or sense of resilience or mastery for Latinas in the United States. DESIGN: This study was a secondary analysis of cross sectional survey data. METHODS: Personal factors were incorporated into a modification of the conceptual framework of impaired sleep to guide our secondary analysis of self reported sleep disturbance. Data were collected from a convenience sample of 312 women of Mexican descent of childbearing age (21-40 years) located in an urban California community were collected and previously analysed in relation to depressive symptoms and post-traumatic stress disorder. The general sleep disturbance scale (in English and Spanish) was used to assess sleep disturbance. Data was collected in 1998 from September through December. RESULTS: Early socialization to the United States during childhood was the most useful acculturation parameter for understanding self-reported sleep disturbance in this sample. In a multivariate regression analysis, three factors (higher acculturation, lower income and higher depressive symptoms) were statistically significant in accounting for 40% of the variance in sleep disturbance. CONCLUSION: When low income Latinas of Mexican descent report sleep problems, clinicians should probe for environmental sleep factors associated with low income, such as noise, over-crowding and exposure to trauma and violence, and refer the woman to psychotherapy and counselling rather than merely prescribing a sleep medication. PMID- 22221153 TI - N for AsN - O for strOcture? A strand-loop-strand motif for prokaryotic O glycosylation. AB - So far, it has not been possible to identify a general sequence motif for O glycosylation in bacteria. In this issue, Charbonneau et al. (2012) demonstrate why O-glycosylation is mediated by a 13-residue strand-loop-strand motif which is part of a 19-residue imperfect repeat in the passenger domain of bacterial autotransporters. This motif provides a convenient 'glycosylation cassette' and raises intriguing questions about the structural regulation of the glycosylation pathway. PMID- 22221154 TI - Efficacy of uterine artery embolisation for treatment of symptomatic fibroids and adenomyosis - an interim report on an Australian experience. AB - BACKGROUND: Uterine artery embolisation (UAE) has been widely described internationally, however there is a paucity of data reported from Australia. AIM: To conduct a local audit on the efficacy and safety of UAE treating symptomatic fibroids and adenomyosis. METHODS: Clinical data of 76 consecutive UAEs were reviewed. Degree of fibroid-related symptoms before embolisation and at follow-up visits were compared. Procedural and subsequent complications were recorded. Uterine and fibroid volumes were measured on MRI at baseline and six months post UAE. RESULTS: Seventy-six UAEs were performed in 75 women. Fifty-nine women had follow-up duration of more than six months, and one woman was lost to follow-up. Clinical success was 93% overall (n = 59) and 96% for menorrhagia (n = 49). For dysmenorrhoea (n = 36), 89% of women had at least some improvement, 75% had significant improvement and 56% had resolution of pain. For urinary symptoms (n = 32), 97% of women had at least some improvement and 50% had resolution of all urinary symptoms. Adenomyosis was found in 17 (29%) women treated. The primary success rate was 96%, and secondary success rate (after repeat UAE) was 100%. MRI showed 50% uterine volume reduction and 60% dominant fibroid volume reduction. There were no significant procedural-related acute complications. There were three possible cases of endometritis, two managed conservatively and one required hysterectomy. CONCLUSIONS: This audit, based on local Australian experience, has confirmed that UAE is a safe and highly effective treatment for women with symptomatic fibroids and/or adenomyosis. PMID- 22221155 TI - Sex differences in lipid metabolism and metabolic disease risk. AB - The ability of nutrients to regulate specific metabolic pathways is often overshadowed by their role in basic sustenance. Consequently, the mechanisms whereby these nutrients protect against or promote a variety of acquired metabolic syndromes remains poorly understood. Premenopausal women are generally protected from the adverse effects of obesity despite having a greater proportion of body fat than men. Menopause is often associated with a transformation in body fat morphology and a gradual increase in the susceptibility to metabolic complications, eventually reaching the point where women and men are at equal risk. These phenomena are not explained solely by changes in food preference or nutrient intake suggesting an important role for the sex hormones in regulating the metabolic fate of nutrients and protecting against metabolic disease pathophysiology. Here, we discuss how differences in the acquisition, trafficking, and subceullular metabolism of fats and other lipid soluble nutrients in major organ systems can create overt sex-specific phenotypes, modulate metabolic disease risk, and contribute to the rise in obesity in the modern sedentary climate. Identifying the molecular mechanisms underpinning sex differences in fat metabolism requires the unravelling of the interactions among sex chromosome effects, the hormonal milieu, and diet composition. Understanding the mechanisms that give rise to sex differences in metabolism will help to rationalize treatment strategies for the management of sex-specific metabolic disease risk factors. PMID- 22221156 TI - C1A cysteine-proteases and their inhibitors in plants. AB - Plant cysteine-proteases (CysProt) represent a well-characterized type of proteolytic enzymes that fulfill tightly regulated physiological functions (senescence and seed germination among others) and defense roles. This article is focused on the group of papain-proteases C1A (family C1, clan CA) and their inhibitors, phytocystatins (PhyCys). In particular, the protease-inhibitor interaction and their mutual participation in specific pathways throughout the plant's life are reviewed. C1A CysProt and PhyCys have been molecularly characterized, and comparative sequence analyses have identified consensus functional motifs. A correlation can be established between the number of identified CysProt and PhyCys in angiosperms. Thus, evolutionary forces may have determined a control role of cystatins on both endogenous and pest-exogenous proteases in these species. Tagging the proteases and inhibitors with fluorescence proteins revealed common patterns of subcellular localization in the endoplasmic reticulum-Golgi network in transiently transformed onion epidermal cells. Further in vivo interactions were demonstrated by bimolecular fluorescent complementation, suggesting their participation in the same physiological processes. PMID- 22221158 TI - Resveratrate protects human skin from damage due to repetitive ultraviolet irradiation. AB - BACKGROUND: Ultraviolet (UV) exposure results in the production reactive oxygen species. Resveratrol has attracted considerable attentions owing to its natural abundance and multiple biological effects. OBJECTIVE: To investigate the protective effects of resveratrate against damage to human skin induced by repetitive solar simulator ultraviolet radiation (ssUVR). MATERIALS AND METHODS: Fifteen healthy volunteers were enrolled, and six sites on the non-exposed dorsal skin of each volunteer were marked for study. Sites 1-4 were exposed to ssUVR at a dosage of 1.5 minimal erythema dose for consecutive 4 days. Immediately after each exposure, one test material (resveratrate + antioxidant, antioxidant, resveratrate, vehicle) was applied to one of the four sites. Site 5 and site 6 were marked as positive control site (UVR only) and baseline control site (no treatment, no UVR). L*a*b values were assessed preprocedure and postprocedure. Skin biopsies were taken 24 h after the last irradiation. The specimens were stained to determine the number of sunburn cells and melanin content melanin. RESULTS: On resveratrate treated sites, erythema was barely seen with only slight decrease of L value and insignificant increase of *a value. Furthermore, resveratrate significantly inhibited sunburn cell formation, and decreased Fontana-Masson staining in skin samples. CONCLUSIONS: Resveratrate exerts protective effects against repetitive ssUVR-induced sunburn and suntan. PMID- 22221159 TI - Antiepileptic drug selection for people with HIV/AIDS: evidence-based guidelines from the ILAE and AAN. AB - A joint panel of the American Academy of Neurology (AAN) and the International League Against Epilepsy (ILAE) convened to develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. Key findings from this literature search included the following: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of approximately 50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of approximately 50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors because pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C). PMID- 22221161 TI - Commentary on the new ILAE classification system for focal cortical dysplasias. PMID- 22221160 TI - The International League Against Epilepsy at the threshold of its second century: year 2. PMID- 22221162 TI - Going beyond hippocampocentricity in the concept of mesial temporal lobe epilepsy. PMID- 22221164 TI - Temporal patterns of extremely low frequency magnetic field-induced motor behavior changes in Mongolian gerbils of different age. AB - PURPOSE: The aim of this study was to investigate the influence of extremely low frequency magnetic field (ELF-MF) on different behavior parameters (locomotion, stereotypy, and immobility) in 3- and 10-month-old male Mongolian gerbils. MATERIALS AND METHODS: The animals were continuously exposed to ELF-MF (50 Hz; 0.1, 0.25 and 0.5 mT) for seven days. Their behavior was monitored for 60 min in the open field after the 1st, 2nd, 4th, and 7th day of exposure (immediate effect), and three days after ELF-MF exposure had been ceased (delayed effect). RESULTS: In 3-month-old gerbils, exposure to ELF-MF (0.1, 0.25 and 0.5 mT) increased motor behavior (locomotion and stereotypy), and consequently decreased immobility. Additionally, ELF-MF had delayed effect (except 0.25 mT) on stereotypy and immobility. In 10-month-old gerbils, ELF-MF of 0.1, 0.25 and 0.5 mT induced decrease, slight increase, and pronounced stimulation of motor behavior, respectively. Regardless of magnetic induction value, increased motor behavior was observed three days after ELF-MF exposure has been ceased (delayed effect). CONCLUSIONS: It can be proposed that the specific temporal patterns of ELF-MF-induced motor behavior changes in 3- and 10-month-old gerbils are a consequence of age-dependent morpho-functional differences in the brain structures responsible for a control of motor behavior. PMID- 22221163 TI - The effects of proton radiation on the prothrombin and partial thromboplastin times of irradiated ferrets. AB - PURPOSE: To determine whether proton radiation affects coagulation. MATERIAL AND METHODS: Ferrets were exposed to solar particle event-like proton radiation at doses of 0, 25, 100, or 200 centigray (cGy), and dose rates of 50 cGy/minute (high dose rate or HDR) or 50 cGy/hour (low dose rate or LDR). Plasma was isolated from blood collected prior to radiation exposure and at 3-7 h post radiation. Prothrombin time (PT) assays and activated partial thromboplastin time (aPTT) assays were performed as were mixing studies to determine the coagulation factors involved. RESULTS: HDR and LDR exposure led to statistically significant increases in PT values. It was determined that the HDR-induced increase in PT was due to Factor VII, while Factors II, V, and VII contributed to the LDR-induced increase in PT values. Only acute LDR exposure caused an increase in aPTT values, which remained elevated for 48 h post-irradiation (which was the latest time assayed in these studies). Mixing studies revealed that Factor IX contributed to the increased aPTT values. A majority of the animals exposed at the LDR had an International Normalized Ratio approaching or surpassing 2.0. CONCLUSIONS: PT/aPTT assays resulted in increased clotting times due to different coagulation factors, indicating potential radiation-induced coagulopathy. PMID- 22221167 TI - Pharmacokinetics and bioavailability of cefquinome in crossbred wild boars. PMID- 22221168 TI - Siloxanol-functionalized copper iodide cluster as a thermochromic luminescent building block. AB - A copper iodide cluster bearing reactive silanol groups exhibits thermochromic luminescence properties sensitive to its chemical environment and is thus a suitable building block for the synthesis of optically active materials. PMID- 22221169 TI - LiGaGe2Se6: a new IR nonlinear optical material with low melting point. AB - The new compound LiGaGe(2)Se(6) has been synthesized. It crystallizes in the orthorhombic space group Fdd2 with a = 12.501(3) A, b = 23.683(5) A, c = 7.1196(14) A, and Z = 8. The structure is a three-dimensional framework composed of corner-sharing LiSe(4), GaSe(4), and GeSe(4) tetrahedra. The compound exhibits a powder second harmonic generation signal at 2 MUm that is about half that of the benchmark material AgGaSe(2) and possesses a wide band gap of about 2.64(2) eV. LiGaGe(2)Se(6) melts congruently at a rather low temperature of 710 degrees C, which indicates that bulk crystals can be obtained by the Bridgman-Stockbarger technique. According to a first-principles calculation, there is strong hybridization of the 4s and 4p orbitals of Ga, Ge, and Se around the Fermi level. The calculated birefractive index is Deltan = 0.04 for lambda >= 1 MUm, and the calculated major SHG tensor elements are d(15) = 18.6 pm/V and d(33) = 12.8 pm/V. This new material is promising for application in IR nonlinear optics. PMID- 22221170 TI - "Add to subtract": a simple method to remove complex background signals from the 1H nuclear magnetic resonance spectra of mixtures. AB - Because of its highly reproducible and quantitative nature and minimal requirements for sample preparation or separation, (1)H nuclear magnetic resonance (NMR) spectroscopy is widely used for profiling small-molecule metabolites in biofluids. However (1)H NMR spectra contain many overlapped peaks. In particular, blood serum/plasma and diabetic urine samples contain high concentrations of glucose, which produce strong peaks between 3.2 ppm and 4.0 ppm. Signals from most metabolites in this region are overwhelmed by the glucose background signals and become invisible. We propose a simple "Add to Subtract" background subtraction method and show that it can reduce the glucose signals by 98% to allow retrieval of the hidden information. This procedure includes adding a small drop of concentrated glucose solution to the sample in the NMR tube, mixing, waiting for an equilibration time, and acquisition of a second spectrum. The glucose-free spectra are then generated by spectral subtraction using Bruker Topspin software. Subsequent multivariate statistical analysis can then be used to identify biomarker candidate signals for distinguishing different types of biological samples. The principle of this approach is generally applicable for all quantitative spectral data and should find utility in a variety of NMR-based mixture analyses as well as in metabolite profiling. PMID- 22221171 TI - The efficacy of mirtazapine in the treatment of cocaine dependence with comorbid depression. AB - BACKGROUND: Prior findings concerning the use of mirtazapine in the treatment of a variety of substance use disorders and its antagonistic actions at the serotonin 5-HT(2A) receptor suggest that this drug may have efficacy in the treatment of cocaine dependence in the presence of a depressive disorder. METHODS: Depressed cocaine-dependent subjects received either mirtazapine (target dose 45 mg daily) or placebo for 12 weeks. Urine concentrations of benzoylecgonine and self-report were used to assess cocaine consumption. Depression and sleep quality were evaluated using the Hamilton Depression Rating Scale (HAM-D) and the Pittsburgh Sleep Quality Index, respectively. RESULTS: Cocaine consumption during the treatment period did not differ significantly between the mirtazapine (n = 11) and placebo (n = 13) groups in this study. In week 4 sleep latency was significantly lower in the active medication than in the placebo group. Positive effects of mirtazapine treatment on early insomnia were suggested by an item analysis of the HAM-D. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The results of this study suggest that mirtazapine is superior to placebo in improving sleep in patients with comorbid depression and cocaine dependence, but is not more effective than placebo in reducing cocaine use. PMID- 22221172 TI - Point of care diagnostics: status and future. PMID- 22221173 TI - High dose ursodeoxycholic acid in primary sclerosing cholangitis does not prevent colorectal neoplasia. AB - BACKGROUND: Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) have a high risk of developing colorectal cancer and dysplasia. Ursodeoxycholic acid (UDCA) has been suggested to have chemopreventive effects on the development of colorectal cancer and dysplasia but long-term data and larger trials are lacking. AIM: To evaluate the effect of high dose (17-23 mg/kg/day) UDCA on colorectal neoplasia in a cohort of patients with PSC and IBD. METHODS: From our previous 5-year randomised controlled trial of UDCA vs. placebo in PSC, we performed a follow-up of 98 patients with concomitant IBD from entry of the trial 1996-1997 until 2009 for development of colorectal cancer or dysplasia. RESULTS: The total follow-up time was 760 person-years. Dysplasia/cancer-free survival was compared between placebo- (n = 50) and UDCA treated (n = 48) patients. There was a similar frequency of dysplasia or cancer after 5 years between patients originally assigned to UDCA or placebo (13% vs. 16%) and no difference in dysplasia/cancer-free survival (P = 0.46, log rank test). At the end of 2009 no difference in cancer-free survival was detected, 30% of the placebo patients compared with 27% of UDCA patients had developed colorectal cancer or dysplasia. CONCLUSIONS: Long-term high dose ursodeoxycholic acid does not prevent colorectal cancer or dysplasia in patients with primary sclerosing cholangitis-associated inflammatory bowel disease. PMID- 22221175 TI - Damselflies (Zygoptera: Odonata) of Pakistan: part 1. AB - The present study is an effort to document bio-geographical distribution for Zygoptera of Pakistan. Damselflies were collected throughout the country and territory of Azad Jammu and Kashmir during 2004-2009. A total of 2692 specimens were collected yielding 9 families, 21 genera, and 48 species and subspecies. Three of these species, Libellago lineata lineata (Burmeister), Elattoneura atkinsoni (Selys), and Elattoneura souteri (Fraser), are recorded for the first time from Pakistan. Distribution, habitats, previous records, and Zoogeographic affiliation for all collected taxa are discussed. Help was also taken from published literature on Zygoptera of Pakistan, and specimens housed at National Insect Museum were also studied. In total, 53 species are accounted for providing an updated record for all modern taxa of damselfly fauna of Pakistan. PMID- 22221174 TI - The influence of smear layer removal on primary tooth pulpectomy outcome: a 24 month, double-blind, randomized, and controlled clinical trial evaluation. AB - BACKGROUND: The effect of smear layer (SL) removal on primary tooth pulpectomy outcome has not been well elucidated. AIM: To determine the effect of SL removal on primary tooth pulpectomy outcome. METHODS: This is a double-blind, randomized, and controlled clinical trial. Forty-eight patients were randomly divided into SL removal (G1 = 40 teeth) or smear layer nonremoval (G2 = 42 teeth) groups. Following the chemomechanical preparation with K-files and 2.5% sodium hypochlorite (NaOCl), teeth were irrigated with either 6% citric acid and 0.9% physiologic solution (G1) or only 0.9% physiologic solution (G2). Camphorated paramonochlorophenol was used as intracanal medication. At the second appointment, 1 week after, root canals were filled with zinc oxide-eugenol paste. Clinical and radiographical baseline criteria were stipulated equally for both groups. RESULTS: The success rate (G1 = 91.2%; G2 = 70.0%) was statistically different (P = 0.04) between the groups. In G2, the outcome was affected significantly by pulpal necrosis (P = 0.02), pre-operatory symptoms (P = 0.02), and periapical/inter-radicular radiolucency (P = 0.04). CONCLUSION: The pulpectomy outcome was improved by smear layer removal. The outcome for teeth with pulpal necrosis, pre-operatory symptoms, or periapical/inter-radicular radiolucency was significantly improved by removal of the smear layer. PMID- 22221176 TI - Degradation of polyamide nanofiltration and reverse osmosis membranes by hypochlorite. AB - The degradation of polyamide (PA) nanofiltration and reverse osmosis membranes by chlorine needs to be understood in order to develop chlorine-resistant membranes. Coated and uncoated fully aromatic (FA) and piperazine (PIP) semi-aromatic PA membranes were treated with hypochlorite solution and analyzed by X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR). XPS results showed that in chlorine treated FA PA membranes the ratio of bound chlorine to surface nitrogen was 1:1 whereas it was only 1:6 in the case of PIP PA membranes. Surface oxygen of uncoated FA and PIP membranes increased with increasing hypochlorite concentration whereas it decreased for coated FA membranes. High resolution XPS data support that chlorination increased the number of carboxylic groups on the PA surface, which appear to form by hydrolysis of the amide bonds (C(O)-N). FTIR data indicated the disappearance of the amide II band (1541 cm(-1)) and aromatic amide peak (1609 cm(-1)) in both coated and uncoated chlorinated FA membranes, consistent with the N-chlorination suggested by the XPS results. Furthermore, the surface charge of chlorinated membranes at low pH (<6) became negative, consistent with amide-nitrogen chlorination. Chlorination appeared to both increase and decrease membrane hydrophobicity depending on chlorination exposure conditions, which implied that N-chlorination and hydrolysis may be competing processes. The effects of property changes on the membrane performance were also observed for NF90, BW30, and NF270 membranes. PMID- 22221177 TI - Omalizumab markedly improves urticaria activity scores and quality of life scores in chronic spontaneous urticaria patients: a real life survey. AB - Treatment of chronic urticaria consists of antihistamines as the first-line treatment. For more severe symptoms, combinations can be necessary as well as dose augmentations. The recent guidelines suggest the possibility of using omalizumab in resistant cases, but this therapy is still investigational. We treated two patients with idiopathic recurrent angioedema and 12 patients with chronic spontaneous urticaria (CSU) with omalizumab, who had not benefited from the recommended first-line, second-line and third-line treatments. To evaluate the efficacy of the omalizumab treatment, urticaria activity scores (UAS) and chronic urticaria quality of life (CU-Q2oL) scores were measured at baseline, and at the end of the first and sixth month of the therapy. The dosage and intervals of omalizumab therapy were determined according to the rules suggested for severe asthma treatment. CU-Q2oL scores and UAS displayed significant improvements in all 14 patients. None of the patients reported any adverse effect during the treatment until the submission of this data. Our results show that omalizumab apparently improves CU-Q2oL as well as UAS in treatment-resistant CSU in a real life setting. PMID- 22221178 TI - Clinical bleeding events and laboratory coagulation profiles in acute promyelocytic leukemia. AB - BACKGROUND: Bleeding is the leading cause of death for patients with acute promyelocytic leukemia (APL). Blood component transfusion to correct coagulopathy is the keystone in reducing bleeding. The benefit of fresh frozen plasma transfusion is unproven. Using laboratory profiles to predict bleeding is important guidance for the determination of transfusion policies in the treatment of APL. DESIGN AND METHODS: For 116 patients of APL, bleeding events were collected and correlated with various hematologic and coagulation parameters, including leukemic cell percentages, white blood cell (WBC) and platelet counts, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen levels, and disseminated intravascular coagulation (DIC) scores. RESULTS: Overt DIC occurred in 77.6% of patients. Severity of DIC was associated with bone marrow leukemic cell percentages but unrelated to bleeding. Patients with bleeding had significantly higher WBC counts (26.73 +/- 6.18 vs. 13.03 +/- 3.03 per MUL, P = 0.026) and more prolonged PT (4.85 +/- 0.70 vs. 2.59 +/- 0.28 s, P = 0.002) and APTT (3.98 +/- 1.68 vs. 0.96 +/- 0.93 s, P = 0.017). Fibrinogen levels, platelet counts, and leukemia cell percentages were not significantly different between bleeding and non-bleeding patients. PT is valuable in prediction of bleeding. Patients with PT ? 5 s had a relative risk of 6.14 for bleeding. Seven patients had severe bleeding before initiation of all-trans retinoic acid (ATRA). CONCLUSIONS: Patients with APL are susceptible to DIC and subsequent bleeding events. Prompt ATRA administration is crucial in preventing hemorrhagic events. High WBC counts, prolonged PT, and APTT are associated with clinical bleeding in our series. PT is the most accurate parameter in predicting bleeding. Based on these findings, supportive care should be directed toward correction of coagulopathy to prevent bleeding complications and fresh frozen plasma appears to be indicated for coagulopathy associated with APL. PMID- 22221180 TI - Plasticity of prospective memory through a familiarization intervention in old adults. AB - Younger adults consistently outperform older adults in laboratory prospective memory tasks. This study examines the effectiveness of an intervention that familiarizes older adults with the sequence of ongoing events to compensate their reduced prospective memory performance. We compared performance and electrophysiological measures of an intervention group (N = 20, 69-83 years) receiving a familiarization intervention to an individually matched control group (N = 20). As ongoing activity a 2-back working memory task was administered. Neural correlates were studied using event related potentials (ERPs) and source localization (standardized low-resolution brain electromagnetic tomography). Behavioural data showed faster reaction times in correct prospective trials and fewer prospective false alarms in the familiarization intervention group. ERP analyses displayed differential patterns for the two groups and source localization measures distinctively presented group differences in prospective memory trials with the control group recruiting more resources for a successful prospective memory performance. Together our data support the hypothesis that the familiarity with the sequence of ongoing events increases prospective memory performance and that this might be based on a higher efficiency of attentional monitoring resources and evaluation processes in the intervention group. PMID- 22221181 TI - A time-series DDP for functional proteomics profiles. AB - Using a new type of array technology, the reverse phase protein array (RPPA), we measure time-course protein expression for a set of selected markers that are known to coregulate biological functions in a pathway structure. To accommodate the complex dependent nature of the data, including temporal correlation and pathway dependence for the protein markers, we propose a mixed effects model with temporal and protein-specific components. We develop a sequence of random probability measures (RPM) to account for the dependence in time of the protein expression measurements. Marginally, for each RPM we assume a Dirichlet process model. The dependence is introduced by defining multivariate beta distributions for the unnormalized weights of the stick-breaking representation. We also acknowledge the pathway dependence among proteins via a conditionally autoregressive model. Applying our model to the RPPA data, we reveal a pathway dependent functional profile for the set of proteins as well as marginal expression profiles over time for individual markers. PMID- 22221179 TI - Bicelles at low concentrations. AB - Bilayered detergent-lipid assemblies known as bicelles have been widely used as model membranes in structural biological studies and are being explored for wider applications, including pharmaceutical use. Most studies to date have involved the use of concentrated bicelle mixtures, such that little is known about the capacity of bicellar mixtures to be diluted without unwanted transitions to nonisotropic phases. Here, different detergent/lipid mixtures have been explored, leading to the identification of two different families of bicelles for which it is possible to lower the total amphiphile (detergent + lipid) concentration to <1% (w/v) while retaining isotropic assemblies. These include a novel family of bicelles based on mixtures of 6-cyclohexyl-1-hexylphosphocholine (Cyclofos-6) and the lipid dimyristoylphosphatidylcholine (DMPC). Bicelles formed by these mixtures can be diluted to <0.5% and also have attractive biochemical properties. However, a caveat of our results is that the diffusion coefficients measured for the lipid component of the different bicelles tested were seen to be dependent on sample history, even though all samples were optically transparent. This suggests that the phase behavior of bicelles at low lipid-to-detergent ratios may be more complex than previously appreciated. PMID- 22221182 TI - Epigenetic regulation of the nitrosative stress response and intracellular macrophage survival by extraintestinal pathogenic Escherichia coli. AB - Extraintestinal pathogenic Escherichia coli (ExPEC) reside in the enteric tract as a commensal reservoir, but can transition to a pathogenic state by invading normally sterile niches, establishing infection and disseminating to invasive sites like the bloodstream. Macrophages are required for ExPEC dissemination, suggesting the pathogen has developed mechanisms to persist within professional phagocytes. Here, we report that FimX, an ExPEC-associated DNA invertase that regulates the major virulence factor type 1 pili (T1P), is also an epigenetic regulator of a LuxR-like response regulator HyxR. FimX regulated hyxR expression through bidirectional phase inversion of its promoter region at sites different from the type 1 pili promoter and independent of integration host factor (IHF). In vitro, transition from high to low HyxR expression produced enhanced tolerance of reactive nitrogen intermediates (RNIs), primarily through de-repression of hmpA, encoding a nitric oxide-detoxifying flavohaemoglobin. However, in the macrophage, HyxR produced large effects on intracellular survival in the presence and absence of RNI and independent of Hmp. Collectively, we have shown that the ability of ExPEC to survive in macrophages is contingent upon the proper transition from high to low HyxR expression through epigenetic regulatory control by FimX. PMID- 22221183 TI - How does the migraine attack stop? It is NOT the trigger: common headache triggers do not predict cessation of pain. PMID- 22221185 TI - Hope, older adults, and chronic illness: a metasynthesis of qualitative research. AB - AIM: To report a metasynthesis review of qualitative research studies exploring the hope experience of older persons with chronic illness. BACKGROUND: Hope is a psychosocial resource used by persons to deal with their chronic illness experience. DATA SOURCES: A comprehensive search of multiple databases for studies of the hope experience (published 1980-2010) was completed. Inclusion criteria were included qualitative studies of the hope experience of persons (all genders; mean age 60 years and older), with chronic illnesses, and publications in any language and country. REVIEW METHODS: The metasynthesis followed four procedural steps: (a) comprehensive search, (b) quality appraisal, (c) classification of studies, and (d) synthesis of findings. RESULTS: Twenty studies were included in the metasynthesis representing research from a variety of different countries and populations with differing medical diagnoses. The characteristics of hope included: (a) dynamic or situational nature, (b) multiple co-existing types, (c) objects that were desirable realistic possibilities, (d) future-focused, and (e) involvement of choice/will. Hope as 'transcending possibilities' represented the integration of two processes of transcendence and positive reappraisal. Reaching inwardly and outwardly and finding meaning and purpose were sub-processes of transcendence, whereas re-evaluating hope in light of illness and finding positive possibilities were sub-processes of positive reappraisal. CONCLUSIONS: The concept of hope may differ for older adults vs. younger adults in its interaction with suffering. Resources for hope are both internal and external. Finding meaning and positive reappraisal are important strategies to help older adults with chronic illness maintain their hope. PMID- 22221186 TI - The planarity of the stickface motion in the field hockey hit. AB - The field hockey hit is an important but poorly understood stroke. In this study, we investigated the planarity of the stickface motion during the downswing to better characterize the kinematics and to assess the suitability of planar pendulum models for simulating the hit. Thirteen experienced female field hockey players were filmed executing hits with a single approach step, and the kinematics of the centre of the stickface were measured. A method was developed for identifying how far back from impact the stickface motion was planar. Orthogonal regression was used to fit least-squares planes to the stickface path during sections of the downswing of varying length, with each section ending at impact. A section was considered planar if the root mean square residual between the stickface path and the fitted plane was less than 0.25% of the distance travelled by the stickface during that period. On average, the stickface motion was planar for the last 83 +/- 12% of its downswing path, with the length of the planar section ranging from 1.85 m to 2.70 m. The suitability of a planar model for the stickface motion was supported, but further investigation of the stick and arm kinematics is warranted. PMID- 22221189 TI - Ionic crystals [M3O(OOCC6H5)6(H2O)3]4[alpha-SiW12O40] (M = Cr, Fe) as heterogeneous catalysts for pinacol rearrangement. AB - Complexation of trinuclear oxo-centered carboxylates with a silicododecatungstate resulted in the formation of ionic crystals of [M(3)O(OOCC(6)H(5))(6)(H(2)O)(3)](4)[alpha-SiW(12)O(40)].nH(2)O.mCH(3)COCH(3) [M = Cr (Ia), Fe (IIa)]. Treatments of Ia and IIa at 373 K in vacuo formed guest free phases Ib and IIb, respectively. Compounds Ib and IIb heterogeneously catalyzed the pinacol rearrangement to pinacolone with high conversion at 373 K, and the catalysis is suggested to proceed size selectively in the solid bulk. PMID- 22221190 TI - "Bath salt" ingestion leading to severe intoxication delirium: two cases and a brief review of the emergence of mephedrone use. AB - BACKGROUND: Recreational use of designer substances containing synthetic cathinones such as mephedrone, commonly sold as "bath salts," has recently been increasing in the United States (National Institute on Drug Abuse. Available at: http://www.nida.nih.gov/about/welcome/MessageBathSalts211.html. Accessed March 25, 2011; The Washington Post. Available at: http://www.washingtonpost.com/national/officials-fear-bath-salts-becoming-the next-big-drug-menace/2011/01/22/ABybyRJ_story.html. Accessed March 25, 2011). "Bath salt" ingestion can generate an intense stimulant toxidrome and has been associated with significant morbidity. OBJECTIVES: The authors seek to alert clinicians to the potential for profound delirium, psychosis, and other medical and behavioral sequelae of "bath salt" use. METHODS: Case series. RESULTS: We describe our recent experience with two highly agitated and delirious patients following "bath salt" ingestion and offer a brief review of the emergence of this phenomenon. CONCLUSIONS: Challenges and strategies surrounding diagnosis and treatment are described, which may be useful as "bath salt" use becomes more widespread. SCIENTIFIC SIGNIFICANCE: As an emerging trend, bath salt intoxication delirium appears to cause intense psychosis that can be managed with antipsychotic medications. Clinicians should be aware of this phenomenon until more precise detection methods are available. PMID- 22221192 TI - Estimation of tissue osteopontin levels before and after different traditional therapeutic modalities in psoriatic patients. AB - BACKGROUND: Several lines of evidences support a major role for Th1 cells in psoriasis. Treatment of psoriasis with cyclosporine, methotrexate and psoralen plus ultraviolet A (PUVA) is associated with clinical improvement and decrease in epidermal hyperplasia. Osteopontin (OPN) exerts a T-helper type 1 (Th1) cytokine function, regulating inflammatory cell accumulation and function. OBJECTIVE: To detect the effects of methotrexate, cyclosporine and PUVA on OPN expression in psoriatic plaques, and whether these changes correlate with clinical response. METHODS: For three groups of psoriatic patients (each including 12 patients), the Psoriasis Area Severity Index (PASI) and levels of lesional skin OPN were determined using enzyme-linked immunosorbent assays before and after treatment with methotrexate, cyclosporine or PUVA. Skin biopsies from 20 healthy volunteers served as control for OPN levels in normal skin. RESULTS: Baseline lesional skin of psoriatic patients showed a statistically significant elevation of OPN levels in comparison to controls. Three months after therapy, the three therapeutic modalities were associated with a significant decrease in the mean levels of PASI and tissue OPN, with the PUVA group showing the highest level of reduction in OPN levels and cyclosporine group showing the highest level of reduction in PASI. CONCLUSION: Our study points to the possible role played by OPN in the pathogenesis of psoriasis and in reflecting disease severity. These standard therapeutic modalities used in the current study were associated with a significant decrease in PASI and OPN levels. They constitute highly effective therapeutic modalities for psoriasis, which might exert their anti-psoriatic activity partially through altering the expression of OPN. PMID- 22221193 TI - Gene flow and simulation of transgene dispersal from hybrid poplar plantations. AB - Gene flow is a primary determinant of potential ecological impacts of transgenic trees. However, gene flow is a complex process that must be assessed in the context of realistic genetic, management, and environmental conditions. We measured gene flow from hybrid poplar plantations using morphological and genetic markers, and developed a spatially explicit landscape model to simulate pollination, dispersal, establishment, and mortality in the context of historical and projected disturbance and land-use regimes. Most pollination and seed establishment occurred within 450 m of the source, with a very long tail. Modeled transgene flow was highly context-dependent, strongly influenced by the competitive effects of transgenes, transgenic fertility, plantation rotation length, disturbance regime, and spatial and temporal variation in selection. The use of linked infertility genes even if imperfect, substantially reduced transgene flow in a wide range of modeled scenarios. The significance of seed and vegetative dispersal was highly dependent on plantation size. Our empirical and modeling studies suggest that transgene spread can be spatially extensive. However, the amount of spread is highly dependent on ecological and management context, and can be greatly limited or prevented by management or mitigation genes such as those that cause sexual infertility. PMID- 22221191 TI - Epilepsy is associated with unmet health care needs compared to the general population despite higher health resource utilization--a Canadian population based study. AB - PURPOSE: (1) To determine whether health resource utilization (HRU) and unmet health care needs differ for individuals with epilepsy compared to the general population or to those with another chronic condition (asthma, diabetes, migraine); and (2) to assess the association among epilepsy status, sociodemographic variables and HRU. METHODS: Data on HRU were assessed using the 2001-2005 Canadian Community Health Surveys, a nationally representative population-based survey. Weighted estimates of association were produced as adjusted odds ratio with 95% confidence intervals, and logistic regression was used to explore the association between sociodemographic variables and HRU in those with epilepsy. All data on disease status, HRU, and unmet health care needs were self-reported. KEY FINDINGS: Individuals with epilepsy had the highest rate of hospitalizations and the highest mean number of consultations with physicians. Despite higher rates of consultation with psychologists and social workers compared to the general population, those with epilepsy were significantly more likely to say they had unmet mental health care needs. People with epilepsy were also less likely to use dental services compared to the general population. Epilepsy was a significant predictor of HRU in logistic regression models. SIGNIFICANCE: Given the prevalence of psychiatric comorbidities in those with epilepsy, it is concerning that this group perceives unmet mental health care needs. It is also troublesome that there was decreased utilization of dental health care resources in those with epilepsy considering that these patients are more likely to have poor oral health. Although individuals with epilepsy use more health care services than the general population, this increase appears to be insufficient to address their health care needs. PMID- 22221194 TI - Deception detection from written accounts. AB - Most research into deception detection in written accounts has been conducted on transcripts instead of written messages, and has focused on identifying valid verbal deception correlates instead of also examining untrained readers' spontaneous lie-detection attempts (accuracy rates, the cues they use, and so on). Also, the question of whether good liars are also good detectors has not been examined using written accounts. In Study 1, 78 participants handwrote a story and then judged the veracity of another participant's story. Accuracy was at chance level. Good liars were not better detectors than poor liars, but participants who thought they were good liars also thought they were good detectors. The higher the participants' fluidity scores on a standardized test, the poorer liars they were and the better liars they thought they were. The cues participants said they used were related to their judgments but unrelated to actual veracity. In Study 2, some Linguistic Inquiry and Word Count (LIWC) categories (with the Spanish-language dictionary) permitted a 68% classification rate of the written accounts of Study 1. PMID- 22221195 TI - Lifelong prophylaxis in a large cohort of adult patients with severe haemophilia: a beneficial effect on orthopaedic outcome and quality of life. AB - BACKGROUND: In the 1950s, Sweden initiated prophylaxis as a lifelong treatment for haemophilia. It was the first country to do so. OBJECTIVES: To describe and evaluate dosing and outcome of prophylactic treatment in a large cohort of adult people with severe haemophilia who have been using prophylaxis most of their lives. METHODS: Eighty-one patients born between 1932 and1992 were divided into two groups (Group A started prophylaxis at the age of <= 3 yr; Group B at three or more years of age) and evaluated retrospectively. Outcome was evaluated using the Hemophilia Joint Health Score (HJHS) and SF-36, a measure of quality of life. RESULTS: The median number of joint bleeds per year was 0 in both study groups; however, the annual number of joint bleeds during the final 3 yr of observation was higher in group B than in group A (P < 0.006). Twenty-five of 30 patients in group A and 27/51 patients in group B had no joint bleeds in that period. Group A had significantly better joint outcomes than group B. Patients in group A experienced better physical and social health than those in group B. CONCLUSIONS: This follow-up has provided for the first time more extensive and detailed information regarding the practice of prophylactic treatment in a large cohort of adults with severe haemophilia. The present study confirms that early start of prophylaxis continuing throughout the lifespan has been successful in virtually eliminating joint bleeds, preserving a close to normal joint status, and keeping patients healthy and able to live normal lives. PMID- 22221196 TI - Modulatory effects of sex steroid hormones on brain-derived neurotrophic factor tyrosine kinase B expression during adolescent development in C57Bl/6 mice. AB - Sex steroid hormones and neurotrophic factors are involved in pruning and shaping the adolescent brain and have been implicated in the pathogenesis of neurodevelopmental disorders, including mental illness. We aimed to determine the association between altered levels of sex steroid hormones during adolescent development and neurotrophic signalling in the C57Bl/6 mouse. We first performed a week by week analysis from pre-pubescence to adulthood in male and female C57Bl/6 mice, measuring serum levels of testosterone and oestradiol in conjunction with western blot analysis of neurotrophin expression in the forebrain and hippocampal regions. Second, we manipulated adolescent sex steroid hormone levels by gonadectomy and hormone replacement at the pre-pubescent age of 5 weeks. Young-adult forebrain and hippocampal neurotrophin expression was then determined. Male mice showed significant changes in brain-derived neurotrophic factor (BDNF) expression in the forebrain regions during weeks 7-10, which corresponded significantly with a surge in serum testosterone. Castration and testosterone or di-hydrotestosterone replacement experiments revealed an androgen receptor-dependent effect on BDNF-tyrosine kinase (Trk) B signalling in the forebrain and hippocampal regions during adolescence. Female mice showed changes in BDNF-TrkB signalling at a much earlier time point (weeks 4-8) in the forebrain and hippocampal regions and these did not correspond with changes in serum oestradiol. Ovariectomy actually increased BDNF expression but decreased TrkB phosphorylation in the forebrain regions. 17beta-Oestradiol replacement had no effect, suggesting a role for other ovarian hormones in regulating BDNF-TrkB signalling in the adolescent female mouse brain. These results suggest the differential actions of sex steroid hormones in modulating BDNF-TrkB signalling during adolescence. These data provide insight into how the male and female brain changes in response to altered levels of circulating sex steroid hormones and could help to explain some of the developmental sex differences in the pathogenesis of neurodevelopmental disorders, including mental illness. PMID- 22221197 TI - Exploring the role of "treatment as prevention". PMID- 22221199 TI - Phosphodiester cleavage properties of copper(II) complexes of 1,4,7 triazacyclononane ligands bearing single alkyl guanidine pendants. AB - Three new metal-coordinating ligands, L(1).4HCl [1-(2-guanidinoethyl)-1,4,7 triazacyclononane tetrahydrochloride], L(2).4HCl [1-(3-guanidinopropyl)-1,4,7 triazacyclononane tetrahydrochloride], and L(3).4HCl [1-(4-guanidinobutyl)-1,4,7 triazacyclononane tetrahydrochloride], have been prepared via the selective N functionalization of 1,4,7-triazacyclononane (tacn) with ethylguanidine, propylguanidine, and butylguanidine pendants, respectively. Reaction of L(1).4HCl with Cu(ClO(4))(2).6H(2)O in basic aqueous solution led to the crystallization of a monohydroxo-bridged binuclear copper(II) complex, [Cu(2)L(1)(2)(MU OH)](ClO(4))(3).H(2)O (C1), while for L(2) and L(3), mononuclear complexes of composition [Cu(L(2)H)Cl(2)]Cl.(MeOH)(0.5).(H(2)O)(0.5) (C2) and [Cu(L(3)H)Cl(2)]Cl.(DMF)(0.5).(H(2)O)(0.5) (C3) were crystallized from methanol and DMF solutions, respectively. X-ray crystallography revealed that in addition to a tacn ring from L(1) ligand, each copper(II) center in C1 is coordinated to a neutral guanidine pendant. In contrast, the guanidinium pendants in C2 and C3 are protonated and extend away from the Cu(II)-tacn units. Complex C1 features a single MU-hydroxo bridge between the two copper(II) centers, which mediates strong antiferromagnetic coupling between the metal centers. Complexes C2 and C3 cleave two model phosphodiesters, bis(p-nitrophenyl)phosphate (BNPP) and 2 hydroxypropyl-p-nitrophenylphosphate (HPNPP), more rapidly than C1, which displays similar reactivity to [Cu(tacn)(OH(2))(2)](2+). All three complexes cleave supercoiled plasmid DNA (pBR 322) at significantly faster rates than the corresponding bis(alkylguanidine) complexes and [Cu(tacn)(OH(2))(2)](2+). The high DNA cleavage rate for C1 {k(obs) = 1.30 (+/-0.01) * 10(-4) s(-1) vs 1.23 (+/ 0.37) * 10(-5) s(-1) for [Cu(tacn)(OH(2))(2)](2+) and 1.58 (+/-0.05) * 10(-5) s( 1) for the corresponding bis(ethylguanidine) analogue} indicates that the coordinated guanidine group in C1 may be displaced to allow for substrate binding/activation. Comparison of the phosphate ester cleavage properties of complexes C1-C3 with those of related complexes suggests some degree of cooperativity between the Cu(II) centers and the guanidinium groups. PMID- 22221200 TI - Bond strength and morphology of resin materials applied to the occlusal surface of primary molars. AB - BACKGROUND: Hydrophilic adhesives may be used as pit and fissure sealants (sealants), but there is concern about the ability of self-etching adhesives to bond sealants to enamel. AIM: To study the bond strength (BS) and morphology of adhesive systems used as sealants. DESIGN: OptiBond FL, OptiBond All-in-One, combined OptiBond All-in-One+OptiBond FL adhesive, and Fluroshield were applied to the occlusal surfaces of 16 primary molars (n = 4). Teeth were stored in distilled water (24 h at 37 degrees C) and sectioned through the interface to obtain sticks (0.8 mm(2) ) tested under a tensile load (0.5 mm/min). Failure modes were observed. Data were analysed by ANOVA and Tukey's tests (alpha = 5%). The morphology of 12 primary molars was examined in terms of the etching pattern and resin reproduction. RESULTS: Differences in the BS were found (P = 0.001), with OptiBond FL showing the highest (36.84 +/- 5.7 MPa), Fluroshield (24.26 +/- 2.13 MPa) and OptiBond All-in-One (17.12 +/- 4.97 MPa) similar, and OptiBond All in-One + OptiBond FL adhesive the lowest (9.8 +/- 2.94 MPA). OptiBond FL showed the best results in terms of morphology. CONCLUSION: Under the conditions of this study, OptiBond FL was the best material to be used for sealing. PMID- 22221198 TI - Cognitive plasticity in foraging Vespula germanica wasps. AB - Vespula germanica (F.) (Hymenoptera: Vespidae) is a highly invasive social wasp that exhibits a rich behavioral repertoire in which learning and memory play a fundamental role in foraging. The learning abilities of these wasps were analyzed while relocating a food source and whether V. germanica foragers are capable of discriminating between different orientation patterns and generalizing their choice to a new pattern. Foraging wasps were trained to associate two different stripe orientation patterns with their respective food locations. Their response to a novel configuration that maintained the orientation of one of the learned patterns but differed in other aspects (e.g. width of stripes) was then evaluated. The results support the hypothesis that V. germanica wasps are able to associate a particular oriented pattern with the location of a feeder and to generalize their choice to a new pattern, which differed in quality, but presented the same orientation. PMID- 22221201 TI - VX-322: a novel dual receptor tyrosine kinase inhibitor for the treatment of acute myelogenous leukemia. AB - In acute myelogenous leukemia (AML), the FLT3 receptor tyrosine kinase (RTK) is highly expressed with 30% of patients expressing a mutated, constitutively active form of this protein. To inhibit this receptor, VX-322 was developed and found to be very potent against both the FLT3 and c-KIT RTKs with enzyme K(i) values of <1 nM and a cellular IC(50) between 1 and 5 nM. It was efficacious in a FLT3-ITD dependent myeloproliferative mouse model, doubling survival compared to other FLT3 inhibitors, with 25% of the mice cured. Upon treatment of primary AML patient blast cells, the dual inhibition of FLT3 and c-KIT was superior to inhibitors targeting a single RTK. Thus, this compound may represent an improved pharmacologic and selectivity profile that could be effective in the treatment of AML. PMID- 22221203 TI - Review article: a decision-making algorithm for the management of pregnancy in the inflammatory bowel disease patient. AB - BACKGROUND: Inflammatory bowel disease affects patients who are in their reproductive years. There are many questions regarding the management of IBD patients who are considering or who are already pregnant. These include the effect of the disease and the medications on fertility and on the pregnancy outcome. AIM: To create an evidence-based decision-making algorithm to help guide physicians through the management of pregnancy in the IBD patient. METHODS: A literature review using phrases that include: 'inflammatory bowel disease', 'Crohn's disease', 'ulcerative colitis', 'pregnancy', 'fertility', 'breast feeding', 'delivery', 'surgery', 'immunomodulators', 'azathioprine', 'mercaptopurine', 'biologics', 'infliximab', 'adalimumab', 'certolizumab'. CONCLUSIONS: The four decision-making nodes in the algorithm for the management of pregnancy in the IBD patient, and the key points for each one are as follows: (i) preconception counselling - pregnancy outcome is better if patients remain in remission during pregnancy, (ii) contemplating pregnancy or is already pregnant - drugs used to treat IBD appear to be safe during pregnancy, with the exception of methotrexate and thalidomide, (iii) delivery and (iv) breast feeding - drugs used to treat IBD appear to be safe during lactation, except for ciclosporin. Another key point is that biological agents may be continued up to 30 weeks gestation. The management of pregnancy in the IBD patient should be multi-disciplinary involving the patient and her partner, the family physician, the gastroenterologist and the obstetrician. PMID- 22221204 TI - Another year of prosperity for Current Molecular Medicine. PMID- 22221205 TI - Mechanisms and therapies of various human diseases. PMID- 22221206 TI - Noncovalent interactions of Zn+ with N-donor ligands (pyridine, 4,4'-dipyridyl, 2,2'-dipyridyl, and 1,10-phenanthroline): collision-induced dissociation and theoretical studies. AB - The binding interactions in complexes of Zn(+) with nitrogen donor ligands, (N-L) = pyridine (x = 1-4), 4,4'-dipyridyl (x = 1-3), 2,2'-dipyridyl (x = 1-2), and 1,10-phenanthroline (x = 1-2), are examined in detail. The bond dissociation energies (BDEs) for loss of an intact ligand from the Zn(+)(N-L)(x) complexes are reported. Experimental BDEs are obtained from thermochemical analyses of the threshold regions of the collision-induced dissociation cross sections of Zn(+)(N L)(x) complexes. Density functional theory calculations at the B3LYP/6-31G* level of theory are performed to determine stable structures of these species and to provide molecular parameters needed for the thermochemical analysis of experimental data. Relative stabilities of the various conformations of these N donor ligands and their complexes to Zn(+) as well as theoretical BDEs are determined from single point energy calculations at the B3LYP/6-311+G(2d,2p) and M06/6-311+G(2d,2p) levels of theory using the B3LYP/6-31G* optimized geometries. The experimental BDEs for the Zn(+)(N-L)(x) complexes are in reasonably good agreement with values derived from density functional theory calculations. BDEs derived from M06 calculations provide better agreement with the measured values than those based on B3LYP calculations. Trends in the sequential BDEs are explained in terms of sp polarization of Zn(+) and repulsive ligand-ligand interactions. Comparisons are made to the analogous Cu(+)(N-L)(x) and Ni(+)(N L)(x) complexes previously studied. PMID- 22221207 TI - What to know and how to get to know? A fieldwork study outlining the understanding of knowing the patient in facilities for short-term stay. AB - AIM: To report a descriptive study of nursing in facilities for short-term stay aiming to outline what 'knowing the patient' means in an endoscopic outpatient clinic. BACKGROUND: 'Knowing the patient' is indispensable to the effort of tailoring nursing to the individual patient's needs. Structural changes in the practice environments, however, reduce the amount of time a nurse spends getting to know the patient. Despite recent years' focus on the subject, no uniform description of 'knowing the patient' in facilities for short-term stay exists. DESIGN: A fieldwork study influenced by practical ethnographic principles was performed in a high-technology endoscopic outpatient clinic during 2008-2010. METHODS: Data were collected using participant observation for 12 weeks and semi structured interviews with eight patients and four nurses. FINDINGS: Findings were summarized into two categories 'What to know?' and 'How to get to know?' The former concerned practical issues in relation to gastroscopy and was described in terms of the patient's level of anxiety, wish for medication and previous experiences. The latter 'How to get to know?' concerned instruments employed in getting to know the patient and was described in terms of the use of communication and sensing. CONCLUSIONS: 'Knowing the patient' in the endoscopic outpatient clinic was understood in a very practical sense. Conversation and the use of the eyes and physical touch enabled a situational awareness. It helped tailor nursing to the patient's needs and allowed the nurse to treat every patient as a unique individual. PMID- 22221208 TI - The effects of age, enactment, and cue-action relatedness on memory for intentions in the Virtual Week task. AB - The current study investigated the influence of encoding modality and cue-action relatedness on prospective memory (PM) performance in young and older adults using a modified version of the Virtual Week task. Participants encoded regular and irregular intentions either verbally or by physically performing the action during encoding. For half of the intentions there was a close semantic relation between the retrieval cue and the intended action, while for the remaining intentions the cue and action were semantically unrelated. For irregular tasks, both age groups showed superior PM for related intentions compared to unrelated intentions in both encoding conditions. While older adults retrieved fewer irregular intentions than young adults after verbal encoding, there was no age difference following enactment. Possible mechanisms of enactment and relatedness effects are discussed in the context of current theories of event-based PM. PMID- 22221209 TI - High immunoglobulin E in a Chinese Papillon-Lefevre syndrome patient with novel compound mutations of cathepsin C. PMID- 22221210 TI - Status of oxidative stress on lesional skin surface of plantar warts. AB - BACKGROUND: Warts are abnormal skin growths caused by human papilloma virus (HPV) infections within the skin of the patients. Sometimes the disease is difficult to treatment, and also, the relationship between HPV and some forms of skin cancers is important. The cutaneous oxidative stress status of warts is absent in the literature. OBJECTIVES: To evaluate the role of oxidative stress in affected skin areas in a group of patients with plantar warts. METHODS: Thirty-six consecutive patients with a diagnosis of plantar warts were enrolled. The samples were obtained by scraping the skin surface. Superoxide dismutase (SOD) and catalase (CAT) activities and malondialdehyde (MDA) levels were measured spectrophotometrically at samples. RESULTS: The SOD activity was significantly lower, and the MDA level was significantly higher on the lesional area than on the non-lesional area (P < 0.001 for each), and there was no significant difference in the CAT activity between both areas (P = 0.11). CONCLUSION: Cutaneous oxidative stress in patients with plantar warts may play a role in pathogenesis of the disease. The addition of topical drugs with antioxidative effects may be valuable in the treatment of warts. PMID- 22221211 TI - Neutral acyclic anion receptor with thiadiazole spacer: halide binding study and halide-directed self-assembly in the solid state. AB - A halide binding study of a newly synthesized neutral acyclic receptor LH(2) with a thiadiazole spacer has been methodically performed both in solution and in the solid state. Crystal structure analysis of the halide complexes elucidate the fact that fluoride forms an unusual 1:1 hyrogen-bonded complex with monodeprotonated receptor, whereas in the case of other congeners, such as chloride and bromide, the receptor binds two halide anions along with formation of a halide-bridged 1D polymeric chain network by participation of N-H...X(-) and aromatic C-H...X(-) hydrogen-bonding (where X = Cl and Br) interactions. The presence of a rigid thiadiazole spacer presumably opens up enough space for capturing two halide anions by a single receptor molecule, where the coordinated NH protons are pointed in the same direction with respect to the spacer and eventually favor formation of halide (Cl(-) and Br(-)) induced polymeric architecture, although no obvious chloride- or bromide-directed polymeric assembly is found in solution. A significant red shift of 243 nm in the absorption spectra of LH(2) was solely observed in the presence of excess fluoride anion, which enables LH(2) as an efficient colorimetric sensor for optical detection of fluoride anion (yellow to blue). Furthermore, spectroscopic titration experiments with increasing equivalents of fluoride anion suggest formation of a H-bonded complex with subsequent stepwise deprotonation of two N-H groups, which can be visually monitored by a change in color from yellow to blue via pink. PMID- 22221214 TI - Alternative therapies for the prevention and treatment of osteoporosis. AB - Osteoporosis is a medical condition that affects millions of men and women. People with this condition have low bone mass, which places them at increased risk for bone fracture after minor trauma. The surgeries and treatments required to repair and heal bone fractures involve long recovery periods and can be expensive. Because osteoporosis occurs frequently in the elderly, the financial burden it places on society is likely to be large. In the United States, the Food and Drug Administration has approved several drugs for use in the prevention and treatment of osteoporosis. However, all of the currently available agents have severe side effects that limit their efficacy and underscore the urgent need for new treatment options. One promising approach is the development of alternative (nonpharmaceutical) strategies for bone maintenance, as well as for the prevention and treatment of osteoporosis. This review examines the currently available nonpharmaceutical alternatives that have been evaluated in in vitro and in vivo studies. Certain plants from the following families have shown the greatest benefits on bone: Alliceae, Asteraceae, Thecaceae, Fabaceae, Oleaceae, Rosaceae, Ranunculaceae, Vitaceae, Zingiberaceae. The present review discusses the most promising findings from studies of these plant families. PMID- 22221213 TI - Global nutrition transition and the pandemic of obesity in developing countries. AB - Decades ago, discussion of an impending global pandemic of obesity was thought of as heresy. But in the 1970s, diets began to shift towards increased reliance upon processed foods, increased away-from-home food intake, and increased use of edible oils and sugar-sweetened beverages. Reductions in physical activity and increases in sedentary behavior began to be seen as well. The negative effects of these changes began to be recognized in the early 1990s, primarily in low- and middle-income populations, but they did not become clearly acknowledged until diabetes, hypertension, and obesity began to dominate the globe. Now, rapid increases in the rates of obesity and overweight are widely documented, from urban and rural areas in the poorest countries of sub-Saharan Africa and South Asia to populations in countries with higher income levels. Concurrent rapid shifts in diet and activity are well documented as well. An array of large-scale programmatic and policy measures are being explored in a few countries; however, few countries are engaged in serious efforts to prevent the serious dietary challenges being faced. PMID- 22221215 TI - Therapeutic potential of green tea in nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is a constellation of progressive liver disorders that are closely related to obesity, diabetes, and insulin resistance and may afflict over 70 million Americans. NAFLD may occur as relatively benign, nonprogressive liver steatosis, but in many individuals it may progress in severity to nonalcoholic steatohepatitis, fibrosis, cirrhosis, and liver failure or hepatocellular carcinoma. No validated treatments currently exist for NAFLD except for weight loss, which has a poor long-term success rate. Thus, dietary strategies that prevent the development of liver steatosis or its progression to nonalcoholic steatohepatitis are critically needed. Green tea is rich in polyphenolic catechins that have hypolipidemic, thermogenic, antioxidant, and anti-inflammatory activities that may mitigate the occurrence and progression of NAFLD. This review presents the experimental evidence demonstrating the hepatoprotective properties of green tea and its catechins and the proposed mechanisms by which these targeted dietary agents protect against NAFLD. PMID- 22221216 TI - Sarcopenic obesity in the elderly and strategies for weight management. AB - Sarcopenia is a multifactorial age-related condition associated with a sedentary lifestyle and protein intakes during weight loss that are inadequate to maintain muscle mass. Sarcopenic obesity in the elderly is associated with a loss of independence and metabolic complications and represents a major public health challenge in individuals over the age of 65 years. It is likely that age-related losses of muscle mass and coincident increases in fat mass could be reduced through regular resistance exercise combined with adequate protein intake to maintain muscle mass. It has been established that increased protein intake will maintain muscle mass during calorie-restricted diets to a greater extent than usual protein intake. Other strategies, including the use of high-protein meal replacements or supplementation with specific ergogenic or branched-chain amino acids, may be beneficial. PMID- 22221218 TI - Modeling of bias for the analysis of receptor signaling in biochemical systems. AB - Ligand bias is a recently introduced concept in the receptor signaling field that underlies innovative strategies for targeted drug design. Ligands, as a consequence of conformational selectivity, produce signaling bias in which some downstream biochemical pathways are favored over others, and this contributes to variability in physiological responsiveness. Though the concept of bias and its implications for receptor signaling have become more important, its working definition in biochemical signaling is sufficiently imprecise as to impede the use of bias as an analytical tool. In this work, we provide a precise mathematical definition for receptor signaling bias using a formalism expressly applied to logistic response functions, models of most physiological behaviors. We show that signaling-response bias of biological processes may be represented by hyperbolae, or more generally as families of bias coordinates that index hyperbolae. Furthermore, we show bias is a property of a parametric mapping of these indexes into vertical strings that reside within a cylinder of stacked Poincare disks and that bias factors representing signaling probabilities are the radial distance of the strings from the cylinder axis. The utility of the formalism is demonstrated with logistic hyperbolic plots, by transducer ratio modeling, and with novel examples of Poincare disk plots of Gi and beta-arrestin biased dopamine 2 receptor signaling. Our results provide a platform for categorizing compounds using distance relationships in the Poincare disk, indicate that signaling bias is a relatively common phenomenon at low ligand concentrations, and suggest that potent partial agonists and signaling pathway modulators may be preferred leads for signal bias-based therapies. PMID- 22221222 TI - Decision to transfuse comfort zones: move out or get pushed out. PMID- 22221219 TI - Synchronized translation for detection of temporal stalling of ribosome during single-turnover translation. AB - Arrhythmic translation caused by temporal stalling of ribosome during translation elongation is essential for gene expression and protein folding. To analyze the positions of the temporarily stalled ribosome and length of the stalling, the ribosomes must be synchronized during translation elongation. In this study, we designed a two-step translation reaction to synchronize the ribosome during a single-turnover translation. First, ribosomes decoding mRNA were artificially and specifically halted before isoleucine codon by reducing isoleucyl-tRNA synthetase from reaction mixture of in vitro translation. Then, translation elongation was restarted simultaneously to synchronize the translation. It enabled evaluation of translation elongation with time resolving capacity shorter than ever before. In addition, position-specific incorporation of fluorescent amino acid and mass spectrometry analyses enabled trace of translation elongation after gel electrophoresis and accurate determination of ribosome positions temporarily stalled before rare codons, respectively. The synchronized translation demonstrated here would be useful to evaluate trans- and cis-elements that affect rate of the translation elongation. PMID- 22221224 TI - Another case of acute cardiopulmonary toxicity with cord blood infusion: is dextran the culprit? PMID- 22221225 TI - Isoimmune neonatal neutropenia in a North African newborn due to anti-Fcgamma RIIIb. PMID- 22221226 TI - Syncope after whole blood donation: factors associated with increased donor injury. PMID- 22221227 TI - Generation and characterization of LIF-dependent canine induced pluripotent stem cells from adult dermal fibroblasts. AB - Dogs provide a more clinically relevant model of human disease than rodents, particularly with respect to hereditary diseases. Thus, the availability of canine stem cells will greatly facilitate the use of the dog in the development of stem cell-based gene therapies and regenerative medicine. In this study we describe the production of canine induced pluripotent stem cells (ciPSCs) from adult dermal fibroblasts. These cells have a morphology resembling previously described canine embryonic stem cells, a normal karyotype, and express pluripotency markers including alkaline phosphatase, Nanog, Oct4, Telomerase, SSEA1, SSEA4, TRA1-60, TRA1-81, and Rex1. Furthermore, the inactive X chromosome is reactivated indicating a ground-state pluripotency. In culture they readily form embryoid bodies, which in turn give rise to cell types from all 3 embryonic germ layers, as indicated by expression of the definitive endoderm markers Cxcr4 and alpha-fetoprotein, mesoderm markers Collagen IIA and Gata2, and ectoderm markers betaIII-tubulin, Enolase, and Nestin. Of particular significance is the observation that these ciPSCs are dependent only on leukemia inhibitory factor (LIF), making them similar to mouse and canine embryonic stem cells, but strikingly unlike the ciPSCs recently described in two other studies, which were dependent on both basic fibroblast growth factor and LIF in order to maintain their pluripotency. Thus, our ciPSCs closely resemble mouse ESCs derived from the inner cell mass of preimplantation embryos, while the previously described ciPSCs appear to be more representative of cells from the epiblast of mouse postimplantation embryos. PMID- 22221229 TI - Drug interactions between common illicit drugs and prescription therapies. AB - OBJECTIVE: The aim was to summarize the clinical literature on interactions between common illicit drugs and prescription therapies. METHODS: Medline, Iowa Drug Information Service, International Pharmaceutical Abstracts, EBSCO Academic Search Premier, and Google Scholar were searched from date of origin of database to March 2011. Search terms were cocaine, marijuana, cannabis, methamphetamine, amphetamine, ecstasy, N-methyl-3,4-methylenedioxymethamphetamine, methylenedioxymethamphetamine, heroin, gamma-hydroxybutyrate, sodium oxybate, and combined with interactions, drug interactions, and drug-drug interactions. This review focuses on established clinical evidence. All applicable full-text English language articles and abstracts found were evaluated and included in the review as appropriate. RESULTS: The interactions of illicit drugs with prescription therapies have the ability to potentiate or attenuate the effects of both the illicit agent and/or the prescription therapeutic agent, which can lead to toxic effects or a reduction in the prescription agent's therapeutic activity. Most texts and databases focus on theoretical or probable interactions due to the kinetic properties of the drugs and do not fully explore the pharmacodynamic and clinical implications of these interactions. Clinical trials with coadministration of illicit drugs and prescription drugs are discussed along with case reports that demonstrate a potential interaction between agents. The illicit drugs discussed are cocaine, marijuana, amphetamines, methylenedioxymethamphetamine, heroin, and sodium oxybate. CONCLUSION: Although the use of illicit drugs is widespread, there are little experimental or clinical data regarding the effects of these agents on common prescription therapies. SCIENTIFIC SIGNIFICANCE: Potential drug interactions between illicit drugs and prescription drugs are described and evaluated on the Drug Interaction Probability Scale by Horn and Hansten. PMID- 22221230 TI - Physiological responses of laying hens during whole-house killing with carbon dioxide. AB - 1. Poultry on farms are sometimes required to be killed in an emergency, such as during a disease epidemic, yet none of the available methods are ideal. Whole house carbon dioxide (CO(2)) administration has practical advantages, but gives rise to welfare concerns. 2. The study measured the body temperature, respiration, cardiac and brain activity (EEG) responses of 10 adult hens placed in tiered cages in a deep pit house while the entire flock (28,000 end-of-lay hens) was killed with CO(2). Video and thermographic images were also recorded. Liquid CO(2) was injected into the building producing a gaseous concentration of 45% within 19 min. 3. Those hens nearest the gas delivery site showed delayed respiratory, cardiac and EEG responses compared with those at more distant locations. Although sub-zero temperatures were recorded in the immediate vicinity of some birds, body temperatures indicated that they did not die of hypothermia. 4. EEG characteristics strongly associated with unconsciousness were used to determine an unequivocal time to loss of consciousness; this ranged from 6.0 to 10.5 (average 7.8) min after onset of gas injection. Distinctive cardiac and respiratory responses were seen following gas exposure; in particular, birds responded to inhalation of CO(2) by deep breathing. 5. The primary welfare concern is the duration of unpleasant respiratory effects, such as deep breathing, while the birds were substantively conscious. However, the concentration of CO(2) to which the birds were exposed while conscious would not have stimulated nasal and oral nociceptors. Time to death varied between 12.0 and 22.1 min after gas delivery. PMID- 22221231 TI - Effect of different concentrations of Bacillus subtilis on growth performance, carcase quality, gut microflora and immune response of broiler chickens. AB - 1. An experiment was conducted to study the effects of different Bacillus subtilis concentrations on productivity, carcase quality, immune response and the gut microflora of broiler chickens. 2. There were 5 treatment groups: control, with no added Bacillus subtilis supplementation; and 4 treatment groups receiving feed supplemented with different concentrations of B. subtilis. 3. Weight gain was significantly higher and the feed conversion rate was significantly better in all groups receiving feed supplemented with B. subtilis, regardless of its concentration. The groups given B. subtilis supplementation produced relatively bigger breasts, and smaller carcases and thighs, compared with the control group. 4. The appearance of increased diffuse lymphohistiocytic infiltration and solitary lymphoid follicles in the mucosa, and a stronger response to NDV vaccination, indicate increased immunological responses in chickens fed with the B. subtilis supplemented diet. 5. The higher inclusion rate of B. subtilis did not increase Lactobacillus concentrations in the ileum or in the caecum, but decreased the E. coli population significantly. PMID- 22221232 TI - Effect of low light and high noise on behavioural activity, physiological indicators of stress and production in laying hens. AB - 1. Commercial laying hens are commonly housed in noisy and dim environments, yet relatively little is known about whether these conditions, particularly in combination, have any effect on welfare or egg production. 2. The study was designed to investigate whether chronic exposure to continuous noise (60 dB(A) vs. 80 dB(A)) and/or light intensity (150 lux vs. 5 lux) during the critical period of coming into lay (16-24 weeks of age) influenced behaviour (activity, resting and feather maintenance), physiological stress (plasma corticosterone and heterophil to lymphocyte ratio) and production (number and weight of eggs laid) in laying hens. 3. Hens in the low light pens were less active and preened and dust-bathed more than those housed in 150 lux; hens in the high noise pens rested more frequently than those in quieter pens. 4. There was no evidence that chronic exposure to low light or high noise caused appreciable physiological stress but egg production was affected by these conditions. Hens kept in pens with low light or high noise laid fewer eggs per day than those kept in high light or low noise pens. These effects were additive, so that the fewest eggs were laid by hens subject to both low light and high noise. 5. These results show that low light intensity and continual high background noise have a detrimental effect on egg production in the early laying phase as well as influencing the time allocated to different behaviours. However there was no strong evidence for a physiological stress response to either of these conditions or their combination. PMID- 22221233 TI - Genetics of hyperpigmentation associated with the Fibromelanosis gene (Fm) and analysis of growth and meat quality traits in crosses of native Indian Kadaknath chickens and non-indigenous breeds. AB - 1. The study investigated the extent of hyperpigmentation (a trait fixed in native Indian Kadaknath chickens), bodyweight, carcase quality and leanness at 12 weeks of age in F(1) and back-crosses of Kadaknath with White Leghorn, White Plymouth Rock and Aseel Peela chickens. 2. The objective of the study was to determine if hyperpigmentation was affected by the major gene Fibromelanosis (Fm) and to evaluate the effects of different proportions of Kadaknath genes on growth and carcase quality. 3. The pigmentation pattern of skin indicated that Fm behaved as the primary locus affecting dermal-hyperpigmentation and that the sex linked Id locus produced an epistatic effect. 4. The results suggested that variable allelic forms of Id were acting in different crosses, which resulted in variation in melanosis of the host. However, no conclusive pattern for shank pigmentation could be explained through genotyping of the Id and Fm loci. 5. Analysis of quantitative traits indicated the positive impact of a Kadaknath genomic proportion of 50% or more on meat texture and carcase leanness. Improvement in leanness occurred in White Rock crosses but not in White Leghorn and Aseel Peela crosses. 6. Thigh-meat texture was influenced more by enhanced Kadaknath genomic proportions than the breast-meat. It was concluded that introgression of Kadaknath genomic proportion beyond 50% in a cross with meat type chickens, irrespective of the impact Fm, brought improvement in meat quality whereas no such advantage was obtained for growth traits. 7. The beneficial impact of the Kadaknath genome on meat quality calls for further studies to identify causative genes for their selective use to improve meat quality in Kadaknath crossbred chickens. PMID- 22221234 TI - Inheritance of plumage colour variations in a large flock of Japanese quail. AB - 1. The inheritance of various plumage colour variants and their underlying interactions were investigated in a large flock of Japanese quail maintained at CARI (India) by conducting reciprocal crosses between four breeding stocks inheriting Pharaoh, White Breasted, White and Brown plumages, followed by test crosses. 2. Based on the proportion of plumage-colour types in the progeny, putative genotypes were determined for parents and offspring for each of the crosses. 3. The White and Brown phenotypes were attributed to the Panda (S) and Roux (Br) loci respectively in agreement with contemporary quail stocks. 4. The White Breasted plumage type present in our stock was caused by a novel mutation with dominant gene action at an autosomal locus that was not allelic to either Panda or the White feather locus. 5. A recessive epistatic action of the Panda locus (S) on White Breasted (Wb) resulted in a White colour phenotype. 6. A novel phenotype, White Breasted-Brown was co-expressed with the Br and Wb loci. 7. It was concluded that breeding for customized feather colour phenotypes in Japanese quail using colour mutations was feasible and would be advantageous in order to overcome the limitations of legislation to protect wildlife in India. PMID- 22221235 TI - Effects of hydrolysed Saccharomyces cerevisiae yeast and yeast cell wall components on live performance, intestinal histo-morphology and humoral immune response of broilers. AB - 1. The effects of enzymatically hydrolysed whole Saccharomyces cerevisiae yeast (HY) and the pellets of yeast cell wall (YCW) on production traits, the microbiology and histo-morphology of the small intestine, and humoral immune responses against Newcastle disease virus (NDV), of Ross 308 broilers were investigated. 2. The control group received a maize-soyabean meal based basal diet for 42 days. In the treated groups the basal diet was supplemented with 1 g/kg of HY and YCW. There were 8 replicate pens per group (n = 12 birds/pen). 3. HY and YCW supplementation improved live weight (P = 0.006) and FCR (P = 0.003) at 42-d as compared with the control group. 4. In the small intestine, Salmonella spp and Escherichia coli numbers were higher (P = 0.01) in the mucosa and lower (P = 0.01) in the digesta of the HY and the YCW fed groups at 25 d of age. Lactobacillus in the duodenal and jejunal digesta was higher (P < 0.05) in the HY and the YCW fed groups as compared with the control. 5. Following oral challenge with Salmonella pullorum, Escherichia coli and Lactobacillus increased (P < 0.05) in the mucosa and decreased in the digesta (P < 0.05) of the HY and YCW supplemented groups, relative to the control. 6. Supplementation of HY and YCW increased villus height in the jejunum (P = 0.02), width of villus in the ileum (P = 0.034) and number of goblet cells in villi of the jejunum (P = 0.006) and ileum (P = 0.01). 7. YCW increased antibody level against NDV at 21 and 42 d of age compared with the control and the HY supplemented diets (P < 0.05). 8. It was concluded that HY and YCW improved growth and feed efficiency in broilers, and considering the improvements in production traits and humoral immune responses, yeast cell wall may be a better dietary tool than the hydrolysed whole yeast cell as a performance enhancer for broilers. PMID- 22221236 TI - Effect of dietary energy source on deposition and fatty acid synthesis in the liver of the laying hen. AB - 1. This experiment was conducted to determine the effect of different dietary energy sources on hepatic lipid deposition and fatty acid synthesis in the layer's liver. 2. A total of 120 Lohmann Pink commercial layers were divided into three groups of 40 birds each and restricted-fed so that they had similar metabolisable energy intakes. Experimental diets were prepared as follows: (1) maize-soybean meal basal diet (CS) fed at 108 g/d, (2) soybean isolated protein plus lard diet (SL) fed at 63 g/d, (3) soybean isolated protein plus maize starch diet (SC) fed at 94.4 g/d. All feed intakes were limited so that the birds consumed similar quantities of the major nutrient daily; all the birds were fed 4 times/d. 3. Compared with chicks fed on the CS and SC, hepatic EE (ether extraction) and triglyceride of the SL group were increased significantly and the total of cholesterol and phospholipids was increased. However, there were no significant reductions in plasma VLDL and ApoB100 concentrations. 4. The birds fed on the maize starch diets up-regulated srebp-1c and chrebp mRNA transcription levels significantly. The maize starch diet also increased the activity of acetyl CoA carboxylase (ACC) and fatty acid synthase (FAS) significantly. However, the lard diet led to a decrease of ACC activity, but had no significant effect on FAS. 5. These results showed that dietary carbohydrates can induce hepatic lipid deposition by increasing the ACC and FAS activities and up-regulating the srebp-1c and chrebp mRNA transcription levels in the layer's liver much more readily than dietary fat, and layers fed on high carbohydrate diets tend to have more fatty livers. PMID- 22221237 TI - Effect of caprylic acid and Yucca schidigera extract on production performance, egg quality, blood characteristics, and excreta microflora in laying hens. AB - 1. A total of 240 Hy-line brown laying hens (36-week-old), were used in this 8 week experiment to evaluate the effect of caprylic acid and Yucca schidigera extract (CY) on production performance, egg quality, blood characteristics, and excreta microflora. 2. Layers were divided into 5 dietary treatment groups which consisted of: (1) NC, basal diet; (2) PC, basal diet + 110 mg/kg of tylosin; (3) CY1, basal diet + 30 mg/kg caprylic acid + 30 mg/kg Yucca extract; (4) CY2, basal diet + 60 mg/kg caprylic acid + 60 mg/kg Yucca extract; (5) CY3, basal diet + 120 mg/kg caprylic acid + 120 mg/kg Yucca extract. The Yucca extract contained 12.5% saponins. 3. Egg production was unaffected, whereas egg weights and feed efficiency were linearly improved by the addition of CY. There were no differences in the egg quality parameters throughout the experimental period. Plasma total triglyceride and cholesterol concentration in plasma and egg yolk were decreased as utilisation of CY increased. The Escherichia coli counts were linearly inhibited by the CY treatments when compared with the NC treatment at both the 5 and 8 week stages. No difference was observed on the Lactobacillus population through the whole experimental period. 4. In conclusion, the addition of 120 mg/kg caprylic acid and 120 mg/kg Yucca extract exerted positive effects on egg weight and feed efficiency, decreased the serum and yolk cholesterol concentration and reduced the proliferation of Escherichia coli. PMID- 22221238 TI - Effects of dietary calcium content and vitamin D source on skeletal properties in growing turkeys. AB - 1. The aim of the study was to investigate the effects of feeding fast growing turkeys with differentiated dietary calcium (Ca) content, and the partial replacement of vitamin D(3) in the feed with 25-hydroxycholecalciferol (25(OH)D(3)), on skeletal properties. 2. One-day-old Big-6 male turkeys (n = 1008) were randomly divided into 4 groups, and two subgroups were created within each group. The groups were differentiated with 4 levels of Ca provision in the feed, namely 85% of the National Research Council (NRC) recommendation (Group Ca(1)); 95% as above (Group Ca(2)); 105% as above (Group Ca(3)); and 115% as above (Group Ca(4)). The first subgroup received the recommended dosage of cholecalciferol (vitamin D(3) subgroup) in the feed, while in the second subgroup (Hy-D subgroup), half of the dosage of cholecalciferol was replaced with 25(OH)D(3). At the ages of 4, 8, 12 and 20 weeks, 7 turkeys from each subgroup were randomly selected and killed to obtain the right tibia for densitometric, geometric and mechanical analyses. 3. This study showed advantageous effects of increased calcium supply in the diet on skeletal system properties, that were increased and produced the most desirable traits in turkeys receiving 95%, 105% and 115% of the NRC calcium recommendation. Benefits resulting from administration of 25(OH)D(3) in the diet were also obtained in the skeletal formation of turkeys, and the most advantageous effects were present in the group receiving 105% of recommended dietary Ca. 4. Effects on the metabolic response of the skeleton of turkeys to manipulation of dietary calcium content and vitamin D(3) source were the most evident in the groups between 4 and 12 weeks of life, and demonstrated a limited ability to induce a positive influence on bone properties at advanced stages of the production cycle by alteration of these dietary factors. PMID- 22221239 TI - Effects of dietary energy concentration, nonstarch polysaccharide concentration, and particle sizes of nonstarch polysaccharides on digesta mean retention time and gut development in laying hens. AB - 1. From an experiment with 504 laying hens (ISA Brown strain, 18-40 weeks of age), 90 40-week old hens were used for determining digesta mean retention time (MRT) and gut weight development. This experiment comprised 6 dietary treatments according to a 2 * 3 factorial design. Factors were dietary apparent metabolisable energy (AME) concentration (11.8 vs 10.6 MJ/kg), insoluble nonstarch polysaccharides (NSP) concentration (65 vs 134 g/kg), and fine vs coarse particle sizes of added NSP. Titanium recovery in different gut segments was used as an indicator of MRT. 2. Increasing NSP concentration prolonged MRT in the crop (68 vs 34 min) and total foregut (91 vs 57 min) compared with control NSP. Reducing energy concentration prolonged MRT in the colon (26 vs 7 min), and total hind gut (30 vs 9 min), compared with control energy. Overall MRT was not affected by dietary treatments. 3. Increasing NSP concentration increased relative weights of the empty proventriculus-gizzard and its contents by 30% (25.2 vs 19.4 g/kg) and 18% (15.4 vs 13.0 g/kg), respectively, compared with control NSP diets. 4. MRT in the foregut was prolonged as daily insoluble NSP intake increased, and this was more pronounced in hens given coarsely ground NSP, compared with finely ground. A prolonged MRT in the foregut seemed to indicate a higher level of satiety, which may contribute to a lower feather pecking pressure in laying hens. PMID- 22221240 TI - Effects of sex and inclusion of dried distillers grains with solubles on slaughter yield and meat characteristics of Pekin ducks. AB - 1. The effects of dried distillers grains with solubles (DDGS) dietary inclusion concentration, and sex, on body weight, slaughter efficiency and meat characteristics of Pekin ducks (Anas platyrhynchos f. domestica, strain P55) were studied. 2. Sexed ducklings (n = 160) were divided randomly into 4 groups (each with 4 replicates). From d 1 to d 21, all the birds received the same commercial feed, then from 22 to 49 d of age the ducks were fed in the following groups: control (commercial feed) and three experimental groups (15%, 25% and 30% inclusion of DDGS). All ducks were weighed individually at d 1, 21 and 49. On the day of slaughter, 5 males and 5 females, of body weight close to the average weight for group and sex, were selected from each group, slaughtered and the following parameters were evaluated: slaughter yield, weight, and percentage of particular elements of carcase, physical and chemical characteristics of meat. 3. The results obtained showed that DDGS included from 22 to 49 d of rearing, at concentrations up to 30%, in a commercial Pekin duck diet did not affect the live body weight, slaughter yield, weight, and percentage of breast and leg muscle, skin with subcutaneous fat, and abdominal fat. There were no differences in physical characteristics (pH(15), pH(24,) meat colour values L*, a*and b*, and hygroscopicity) of breast muscle, as well as in cholesterol content. DDGS addition at 30% significantly increased fat content in male, and crude protein in female, breast meat. Sex effect was observed only in a few traits and was diet dependent. Final body weight of females fed 30% DDGS was significantly lower than males; in the control and 15% DDGS group females had higher percentage of skin with subcutaneous fat. 4. The results obtained, and relative costs of feeds produced, allows the recommendation of DDGS addition at up to 30% to commercial Pekin duck diets from 22 d of age. PMID- 22221241 TI - Omega-3 enriched egg production: the effect of alpha -linolenic omega -3 fatty acid sources on laying hen performance and yolk lipid content and fatty acid composition. AB - 1. Diets high in total lipids, saturated fatty acids, trans fatty acids, and having high omega-6:omega-3 fatty acid ratios, have been shown to be related to increased instances of coronary heart disease, while diets high in omega-3 fatty acids have been shown to decrease the risk. 2. Feeding omega-3 fatty acid diets to laying hens has been shown to improve the quality of eggs produced in terms of saturation and omega-3 content. 3. A study was undertaken to determine if the omega-3 fatty acid source, when fed to hens, influences the amount transferred to eggs. 4. Flaxseed and flaxseed oil, along with chia seed and chia seed oil, were the two main sources of omega-3 fatty acid examined during the 84 d trial. 5. All alpha-linolenic enriched treatments yielded significantly higher omega-3 fatty acid contents per g of yolk and per yolk, than the non-alpha-linolenic enriched diets. Chia oil and chia seed yielded 54.5 and 63.5% more mg of omega-3 fatty acid per g of yolk for the 56 d test period, and 13.4 and 66.2% more for the 84 d test period, than flaxseed oil and flaxseed, respectively. 6. The differences in omega-3 content were significant, except for the chia oil compared with the flax oil, at the end of the trial. 7. This trial has shown that differences in conversion exist among omega-3 fatty acid sources, at least when fed to hens, and indicates that chia may hold a significant potential as a source of omega-3 fatty acid for enriching foods, thereby making these foods a healthier choice for consumers. PMID- 22221242 TI - The effect of dietary calcium concentration and particle size on performance, eggshell quality, bone mechanical properties and tibia mineral contents in moulted laying hens. AB - 1. A total of 72 H&N Brown Nick laying hens, 76 weeks of age (moulted at 60 weeks of age), were randomly assigned into a 3 * 3 factorial arrangement with three limestone particle sizes and three dietary Ca concentrations (30, 36 and 42 g/kg Ca); with 8 replicates per treatments, and one hen (individual) per experimental unit. 2. Particle sizes of the limestone were: distributions smaller than 2 mm (Fine), between 2 to 5 mm (Medium), and larger than 5 mm (Large). The fine, medium and large limestone particles were all obtained from the same source, and sieve sizes used had screen sizes 2 mm and 5 mm. 3. The different concentrations of dietary Ca, particle size or interactions had no significant effect on egg production, egg weight, egg mass, feed intake or feed conversion ratio. 4. The concentrations of dietary Ca and particle sizes had no significant effect on egg breaking strength, eggshell as % by weight of whole egg or eggshell thickness. The interactions between Ca concentrations and particle sizes had a significant effect on eggshell breaking strength, but not on other parameters. 5. Different dietary particle sizes had no significant effect on the Ca, P and Mg mineral contents of eggshell. While the different concentrations of Ca in diets had a significant effect on the P content of eggshell, they had no significant effect on Ca and Mg contents. 6. Different dietary concentrations of Ca had a significant effect on shear stress, and Ca and Mg contents of tibiae, but not other parameters. Also, dietary particle sizes had a significant effect on shear stress and Ca contents of tibiae. The interaction between Ca concentrations and particle sizes had a significant effect on tibia shear force and Ca content. 7. According to the results of this study, moulted brown laying hens should be fed 36 g/kg Ca and a medium limestone particle size (2-5 mm) in the diet to maintain performance, eggshell and bone quality. PMID- 22221243 TI - Rice bran lysolecithin as a source of energy in broiler chicken diet. AB - 1. Rice bran lysolecithin (RBL) was evaluated in broiler chicken diets. In the first experiment, RBL was included in diet at 0, 0.5, 2, 8 and 32 g/kg and fed to 250 broiler chickens from 0 to 42 d of age. In the second experiment, RBL was fed at 0, 25 and 50 g/kg diet to 405 day-old broiler chickens until 21 d of age, while during the finisher phase (22-35 d of age) chickens receiving each concentration of RBL were given all three concentrations of RBL in a 3 * 3 factorial manner. The diets were isocaloric. 2. Body weight, food consumption and food conversion efficiency were unaffected by feeding RBL, while the weight of pancreas increased at >=2 g/kg of RBL in diet (experiment 1). In experiment 2, body weight was greater in the chickens receiving RBL at either 25 or 50 g/kg (21 d) and 50 g/kg (35 d of age). At 21 d of age, food consumption was greater at 25 or 50 g RBL/kg diet, while food conversion efficiency improved with 50 g RBL/kg diet. 3. Fat digestibility increased with RBL at 32 g/kg (experiment 1) and <=25 g/kg (experiment 2). Rice bran lysolecithin increased ready to cook weight at 50 g/kg during starter phase and decreased abdominal fat at 25 and 50 g/kg during finisher phase (experiment 2). Liver and meat fat content were not affected. 4. It is concluded that lysolecithin from rice bran oil could be used as energy supplement in broiler chicken diet. PMID- 22221244 TI - Nutritional value of narrow-leafed lupin (Lupinus angustifolius) for broilers. AB - 1. Two experiments were conducted to evaluate the nutritional value of three cultivars (Wallan, Tanjil and Borre) of narrow-leafed lupin (Lupinus angustifolius) for broilers. 2. In Experiment 1, the apparent metabolisable energy (AME) and the apparent ileal amino acid digestibility of the three cultivars were determined. The cultivar effects were not significant for AME and apparent ileal amino acid digestibility coefficients. In general, amino acids in narrow-leafed lupin were well digested, with the notable exception of methionine. Among the indispensable amino acids, arginine had the highest digestibility coefficient (0.92-0.95), while the lowest was for methionine (0.74-0.83). 3. In Experiment 2, using the energy and digestible amino acid values determined in Experiment 1, diets containing 200 g/kg of the three lupin cultivars were formulated and the effects of feeding these diets on the performance and the digestive tract development of broiler starters were investigated. 4. Weight gain, feed intake and feed per gain of broilers fed narrow-leafed lupins diets were similar to those fed on the maize-soy basal diet. The performance of birds fed on diets containing different cultivars of lupins was also similar. Birds fed on lupin diets had similar excreta scores to those fed on the basal diet. 5. Inclusion of 200 g/kg lupins in broiler diets had no effects on the relative weight and length of the intestinal tract. Broilers fed on lupin diets, however, had higher relative weights of liver. 6. These results suggest that narrow leafed lupins are good sources of protein, but poor sources of AME and sulphur containing amino acids. It is concluded that, when diets are properly balanced in terms of AME and digestible amino acids, lupins can be included at 200 g/kg inclusion level in broiler starter diets with no adverse effects on performance. PMID- 22221245 TI - Changes in plasma gonadotrophins, testosterone, prolactin, thyroxine and triiodothyronine concentrations in male Japanese quail (Coturnix coturnix japonica) of a heavy body weight line during photo-induced testicular growth and regression. AB - 1. Simultaneous changes of cloacal gland area (CGA) and plasma luteinising hormone (LH), follicle stimulating hormone (FSH), testosterone (T), prolactin (PRL), thyroxine (T(4)) and triiodothyronine (T(3)) during photo-induced testicular growth and regression were measured in commercially bred Japanese quail from a heavy body weight line. 2. Somatically mature male Japanese quail were transferred from short days (light:dark 8L:16D) at 10 degrees C, to long days (16L:8D) at 20 degrees C; and sexually mature male Japanese quail were transferred from long to short days. All variables were measured at transfer and every 5 d thereafter for 35 d. 3. Transfer from short to long days caused significant increases in LH, FSH, T and testis weight (TW) after 5 d, and in CGA after 10 d. T(3) decreased after 5 d, whereas T(4) increased significantly after 25 long days and PRL did not undergo any consistent change. The testicular growth rate was k = 0.1146. 4. Transferring quail from long to short days caused significant decreases in LH and FSH after 5 d, and decreases in T, TW and CGA after 10 d. T(4) decreased after 5 d whilst T(3) increased significantly by day 15. PRL decreased significantly after 10 d then rose before declining again. The testicular regression rate was k = 0.0582. 5. The rates of photo-induced testicular development and regression in a strain of large Japanese quail did not differ from rates reported for other strains of quail. CGA was a better indicator of TW than plasma T concentrations during growth and regression. The role of PRL in photo-induced reproductive cycles in male Japanese quail remains to be determined. 6. The photoperiod-induced changes in gonad size and hormone concentrations, together provide valuable information that can be used in future studies of the endocrinology and neuroendocrinology of photoperiodism in birds. PMID- 22221246 TI - Neurogenic inflammation in the upper digestive tract of the mule duck: effect of a chemical algogen and force-feeding. AB - 1.The objectives were to quantify the presence of neurogenic inflammation in 4 regions of the upper digestive tract of anaesthetised ducks (post-pharynx, pseudo crop, transition between the pseudo-crop and the proventriculus, and proventriculus) after application of HCl stimulation of up to 4 M in the pseudo crop. 2.The second objective was to quantify the presence of neurogenic inflammation in the same digestive tract regions as mentioned above during 4 feeding periods of foie gras production (rearing, preparation to force-feeding, and second and last meals of the force-feeding period). 3. Extravasation increased above a HCl stimulation threshold of 2 M. Furthermore, more extravasation was observed in the proventriculus compared to the other regions (P < 0.001). 4.Highest extravasation responses were observed in the proventriculus and the pseudo-crop at the end of the preparation period, and in the proventriculus after the second forced meal, compared with the rearing period (P < 0.01), with a return to rearing level at the end of force-feeding. 5.Such a kinetic could be indicative of a relative mildness of the irritant components associated with this feeding practice. PMID- 22221247 TI - Sex-based responses of plasma creatine kinase in broilers to thermoneutral constant and cyclic high temperatures. AB - 1. The plasma creatine kinase (CK) activities of male and female broilers under different temperature regimens were studied to investigate the suitability of plasma CK as an indicator of muscle damage due to heat exposure (HE). 2. This study characterises the responses of plasma CK concentration of Arbor Acres broilers to thermoneutral (TN) constant (22 degrees C) or warm cyclic (WC) temperatures (ranging from 27.9 degrees C to 37.9 degrees C). 3. The daily mean CK of the females tended to be higher than those of the males, and significant differences in plasma CK were observed between the genders during the first 5-d test period, namely 2-d TN constant and 3-d WC temperatures. 4. During a 5-d HE to the WC regimens, CK of both genders fluctuated with HE time but exhibited somewhat different profiles. Specifically, the daily mean CK of the females was significantly higher on d 5 of HE than any other daily means, whereas significant difference in daily CK of the males occurred on d 4 of HE. 5. Repetitive blood sampling over 5 d of HE had significant effects on the plasma CK of the females regardless of the number of repeated bleeding times. 6. Profiles of the plasma CK for each gender during d 1 of HE were similar to those under the TN condition, implying that heat stress affects the range of broiler plasma CK concentration but with a 1-d lag. 7. Plasma CK activities of female and male broilers showed a response to HE. However, both the gender and the time of blood sampling should be taken into account when plasma CK is used as an indicator of HE for market size broilers. PMID- 22221249 TI - Switching from bonding to nonbonding: temperature-dependent metal coordination in a zinc(II) sulfadiazine complex. AB - The metal coordination in the mononuclear complex diamminebis(sulfadiazine)zinc shows a unique temperature dependence: High-resolution diffraction data prove that the coordination is almost tetrahedral at 100 K, whereas a fifth longer interaction becomes relevant at 200 K. The change in the geometry is fully reversible and is also reflected in the charge density of the compound. PMID- 22221250 TI - Amplified segment in the 'Down syndrome critical region' on HSA21 shared between Down syndrome and euploid AML-M0 excludes RUNX1, ERG and ETS2. AB - Children with Down syndrome have a 20- to 50-fold increased risk of acute lymphocytic or myeloid leukaemia. Whole or partial gains of chromosome 21 have been described in multiple childhood leukaemias, and have recently been reported as a likely primary event in B-precursor-acute lymphoblastic leukaemia. It is unclear which amplified gene(s) on chromosome 21 play a key role in leukaemia progression. We describe a minimal amplified segment within the so-called 'Down syndrome critical region' shared between two cases of AML-M0; a Down syndrome, and a constitutionally normal individual. Interestingly, the amplified region does not include the oncogenes RUNX1, ETS2 and ERG. PMID- 22221251 TI - A new development of triterpene acid-containing extracts from Viscum album L. displays synergistic induction of apoptosis in acute lymphoblastic leukaemia. AB - OBJECTIVES: Aqueous Viscum album L. extracts are widely used for anti-cancer therapies. Due to their low solubility, triterpenes (which are known to act on cancers), do not occur in aqueous extracts in significant amounts. Using cyclodextrins, we have found it possible to solubilize mistletoe triterpene acids and to determine their effects on acute lymphoblastic leukaemia (ALL) in vitro and in vivo. MATERIALS AND METHODS: A C.B-17/SCID model of pre-B ALL (NALM-6) was used to test efficacy and mechanisms of treatment with lectin- and triterpene acid containing preparations in vivo. Cytotoxicity of increasing concentrations of V. album L. preparations was assessed in vitro. Apoptosis was determined using mitochondrial membrane potential measurements, annexin V/PI, western blot analyses and caspase inhibitor assays. RESULTS: Solubilized triterpene acid- or lectin-containing V. album L. extracts inhibited cell proliferation and demonstrated cytotoxic properties in vitro. Annexin V/PI and mitochondrial membrane potential assays indicated that dose-dependent induction of apoptosis was the main mechanism. Combination (viscumTT) of lectin- (viscum) and triterpene containing (TT) extracts resulted in greatest induction of apoptosis. Furthermore, caspase activity demonstrated that these extracts were able to induce apoptosis through both caspase-8 and -9 dependent pathways. In vivo experimentation showed that treatment of mice with viscumTT combination prolonged mean survival to 50.5 days compared to 39.3 days in the phosphate-buffered saline group. CONCLUSION: Here for the first time, we have demonstrated that either solubilized triterpene acids or lectins and combinations thereof, induce dose dependent apoptosis in the ALL cell line NALM-6 via caspase-8 and -9 dependent pathways. PMID- 22221252 TI - Uncertainty during perimenopause: perceptions of older first-time mothers. AB - AIM: This article is a report of a study exploring older first-time mothers' perceptions of health during their transition to menopause. BACKGROUND: Increasing numbers of women world-wide are delaying motherhood, yet little is known about the unique phenomenon created when midlife motherhood is closely followed by the transition to menopause. A literature search revealed that the effect of these overlapping life transitions on women's health was unknown. DESIGN: A hermeneutic phenomenological approach utilizing Gadamer's philosophical underpinnings guided the study. METHOD: A purposive sample of thirteen women aged 45-56 years who were mothering children aged 12 years or younger and experiencing symptoms of perimenopause was recruited. Two in-depth interviews were conducted with each woman and meaning was mutually negotiated through participative dialogue with the women, ongoing construction and thematic analysis of data collected between 2004 and 2007. FINDINGS: The key theme 'Perimenopause as a State of Uncertainty' is an interpretation of older first-time mothers' perceptions of health during perimenopause and is the focus of this article. Hermeneutic interpretation culminated in the construct 'uncertainty' as theoretical embodiment of the women's lived experience. An uncertain temporality, projection of the lifespan and valuing health as precious enabled these women to transform uncertainty into opportunities for health promotion to 'be there' for their children. CONCLUSION: Nurses, nurse practitioners and midwives will increasingly be caring for midlife mothers and need to understand the unique issues of older mothers to offer education and health promotion that support healthy transitions to menopause. PMID- 22221253 TI - A systematic review and meta-analysis of heart rate variability in epilepsy and antiepileptic drugs. AB - PURPOSE: Epilepsy is associated with near-fatal and fatal arrhythmias, and sudden unexpected death in epilepsy (SUDEP) is partly related to cardiac events. Dysfunction of the autonomous nervous system causes arrhythmias and, although previous studies have investigated the effects of epilepsy on the autonomic control of the heart, the results are still mixed regarding whether imbalance of sympathetic, vagal, or both systems is present in epilepsy, and also the importance of anticonvulsant treatment on the autonomic system. Therefore, we aimed to investigate epilepsy and its treatment impact on heart rate variability (HRV), assessed by sympathetic and parasympathetic activity expressed as low frequency (LF) and high-frequency (HF) power spectrum, respectively. METHOD: We performed a systematic review from the first date available to July 2011 in Medline and other databases; key search terms were "epilepsy"; "anticonvulsants"; "heart rate variability"; "vagal"; and "autonomous nervous system." Original studies that reported data and/or statistics of at least one HRV value were included, with data being extracted by two independent authors. We used a random effects model with Hedges's g as the measurement of effect size to perform two main meta-analyses comparing LF and HF HRV values in (1) epilepsy patients versus controls; (2) patients receiving versus not receiving treatment; and (3) well controlled versus refractory patients. Secondary analyses assessed other time- and frequency-domain measurements (nonlinear methods were not analyzed due to lack of sufficient data sets). Quality assessment of each study was verified and also meta-analytic techniques to identify and control bias. Meta-regression for age and gender was performed. KEY FINDINGS: Initially, 366 references were identified. According to our eligibility criteria, 30 references (39 studies) were included in our analysis. Regarding HF, epilepsy patients presented lower values (g -0.69) than controls, with the 95% confidence interval (CI) ranging from -1.05 to -0.33. No significant differences were observed for LF (g -0.18; 95% CI -0.71 to 0.35). Patients receiving treatment presented HF values to those not receiving treatment (g -0.05; 95% CI -0.37 to 0.27), with a trend for having higher LF values (g 0.1; 95% CI -0.13 to 0.33), which was more pronounced in those receiving antiepileptic drugs (vs. vagus nerve stimulation). No differences were observed for well-controlled versus refractory patients, possibly due to the low number of studies. Regression for age and gender did not influence the results. Finally, secondary time-domain analyses also showed lower HRV and lower vagal activity in patients with epilepsy, as shown by the standard deviation of normal-to-normal interval (SDNN) and the root mean square of successive differences (RMSSD) indexes, respectively. SIGNIFICANCE: We confirmed and extended the hypothesis of sympathovagal imbalance in epilepsy, as showed by lower HF, SDNN, and RMSSD values when compared to controls. In addition, there was a trend for higher LF values in patients receiving pharmacotherapy. As lower vagal (HF) and higher sympathetic (LF) tone are predictors of morbidity and mortality in cardiovascular samples, our findings highlight the importance of investigating autonomic function in patients with epilepsy in clinical practice. Assessing HRV might also be useful when planning therapeutic interventions, as some antiepileptic drugs can show hazardous effects in cardiac excitability, potentially leading to cardiac arrhythmia. PMID- 22221254 TI - Moderately increased risk of urinary stone disease in patients with biopsy verified coeliac disease. AB - BACKGROUND: Urinary stone disease is a mal-absorptive disorder that is a significant health problem because of its high prevalence and incidence. However, there are few population-based studies on the risk of urinary stone disease in patients with coeliac disease (CD). AIM: To examine the risk of urinary stone disease in CD. METHODS: Population-based cohort study. Using small intestinal biopsy report data from 1969 to 2008 obtained from all Swedish pathology departments (n = 28), we identified 28 735 patients with CD (equal to Marsh 3: villous atrophy). Patients were then matched for gender, age, county and calendar year to 142 177 reference individuals from the Swedish general population. We used Cox regression to estimate hazard ratios (HRs) for future urinary stone disease and conditional logistic regression to calculate odds ratios (ORs) for urinary stone disease before diagnosis of CD. Individuals with urinary stone disease were identified through the Swedish National Patient Register that contains data on inpatient care, outpatient care and day surgery. RESULTS: During follow-up, 314 individuals with CD and 1142 reference individuals developed urinary stone disease. This corresponded to a 27% increased risk of urinary stone disease in CD [95% confidence interval (CI) = 1.12-1.44]. CD patients had an absolute risk of urinary stone disease of 107/100 000 person-years (excess risk of 23/100 000). Risk estimates were similar in men and women, and did not differ according to age at CD diagnosis. Conditional logistic regression found that patients with CD were at a slightly increased risk also of prior urinary stone disease (OR = 1.19; 95% CI = 1.06-1.33). CONCLUSION: In this study, coeliac disease was associated with a moderately increased risk of urinary stone disease both before and after coeliac disease diagnosis. PMID- 22221255 TI - Toxicity of three insecticides to Lysiphlebus fabarum, a parasitoid of the black bean aphid, Aphis fabae. AB - The toxicity of three insecticides to Lysiphlebus fabarum (Marshall) (Hymenoptera: Braconidae: Aphidiinae), a parasitoid of Aphis fabae Scopoli (Hemiptera: Aphididae), was investigated using IOBC/wprs protocols. Abamectin 1.8 EC, imidacloprid 350 SC, and pymetrozine 25 WP were tested under laboratory conditions at recommended field rates. Immature stages of the parasitoid were exposed to materials by briefly dipping mummified aphids into insecticide solutions/suspensions or water (controls). Abamectin, imidacloprid, and pymetrozine caused 44.8, 58.5, and 14.5% mortality of mummies, respectively. Insecticides were also applied to broad bean foliage until run-off using a hand sprayer and the contact toxicity of residues was investigated after 1, 5, 16 and 30 day periods of outdoor weathering by caging adult wasps on treated plants for 24 h. One day-old residues of abamectin, imidacloprid, and pymetrozine produced 52.5, 90.0 and 57.0% mortality, respectively, and 5 day-old residues produced 28.1, 77.0 and 18.6% mortality. Sixteen day-old residues produced 8.8, 22.4 and 13.6% mortality, whereas 30 day-old residues produced 0.0, 3.2 and 1.1% mortality, respectively. On the basis of these results, abamectin and pymetrozine were classified as short-lived compounds (Class A) and imidacloprid as a slightly persistent compound (Class B). PMID- 22221256 TI - Molecular characterization and tissue-specific gene expression of Dermacentor variabilis alpha-catenin in response to rickettsial infection. AB - Alpha catenin is a cytoskeleton protein that acts as a regulator of actin rearrangement by forming an E-cadherin adhesion complex. In Dermacentor variabilis, a putative alpha-catenin (Dvalpha-catenin) was previously identified as differentially regulated in ovaries of ticks chronically infected with Rickettsia montanensis. To begin characterizing the role(s) of Dvalpha-catenin during rickettsial infection, the full-length Dvalpha-catenin cDNA was cloned and analysed. Comparative sequence analysis demonstrates a 3069-bp cDNA with a 2718 bp open reading frame with a sequence similar to Ixodes scapularisalpha-catenin. A portion of Dvalpha-catenin is homologous to the vinculin-conserved domain containing a putative actin-binding region and beta-catenin-binding and dimerization regions. Quantitative reverse-transcription PCR analysis demonstrated that Dvalpha-catenin is predominantly expressed in tick ovaries and is responsive to tick feeding. The tissue-specific gene expression analysis of ticks exposed to Rickettsia demonstrates that Dvalpha-catenin expression was significantly downregulated 12 h after exposure to R. montanensis, but not in Rickettsia amblyommii-exposed ovaries, compared with Rickettsia-unexposed ticks. Studying tick-derived molecules associated with rickettsial infection will provide a better understanding of the transmission dynamics of tick-borne rickettsial diseases. PMID- 22221257 TI - Branched, tripartite-interfering RNAs silence multiple target genes with long guide strands. AB - Structural modifications could provide classical small interfering RNA (siRNA) structure with several advantages, including reduced off-target effects and increased silencing activity. Thus, RNA interference (RNAi)-triggering molecules with diverse structural modifications have been investigated by introducing variations on duplex length and overhang structure. However, most of siRNA structural variants are based on the linear duplex structure. In this study, we introduce a branched, non-linear tripartite-interfering RNA (tiRNA) structure that could induce silencing of multiple target genes. Surprisingly, the gene silencing by tiRNA structure does not require Dicer-mediated processing into smaller RNA units, and the 38-nt-long guide strands can trigger specific gene silencing through the RNAi machinery in mammalian cells. tiRNA also shows improved gene silencing potency over the classical siRNA structure when complexed with cationic delivery vehicles due to the enhanced intracellular delivery. These results demonstrate that tiRNA is a novel RNA nanostructure for executing multi target gene silencing with increased potency, which could be utilized as a structural platform to develop efficient anticancer or antiviral RNAi therapeutics. PMID- 22221258 TI - Isolation and characterization of high affinity aptamers against DNA polymerase iota. AB - Human DNA-polymerase iota (Pol iota) is an extremely error-prone enzyme and the fidelity depends on the sequence context of the template. Using the in vitro systematic evolution of ligands by exponential enrichment (SELEX) procedure, we obtained an oligoribonucleotide with a high affinity to human Pol iota, named aptamer IKL5. We determined its dissociation constant with homogenous preparation of Pol iota and predicted its putative secondary structure. The aptamer IKL5 specifically inhibits DNA-polymerase activity of the purified enzyme Pol iota, but did not inhibit the DNA-polymerase activities of human DNA polymerases beta and kappa. IKL5 suppressed the error-prone DNA-polymerase activity of Pol iota also in cellular extracts of the tumor cell line SKOV-3. The aptamer IKL5 is useful for studies of the biological role of Pol iota and as a potential drug to suppress the increase of the activity of this enzyme in malignant cells. PMID- 22221259 TI - Periosteal-derived cells for bone bioengineering: a promising candidate. AB - PURPOSE: Over the last years so many efforts have been made in order to indentify natural sources of osteogenic cells for the success of bone bioengineering. Among them, periosteum tissue has emerged as an interesting candidate. Thus, we decided to evaluate the osteogenic potential of periosteal-derived cells by describing a sequence of biological events since initial morphological changes to mineralization of extracellular matrix (ECM). METHODS: Periosteal-derived cells were obtained from calvarial of adult rats. After the primary culture and expansion, the adherent cells were cultured at 7, 14, 21 and 28 days under a classical osteogenic culture medium in order to evaluate the differentiation of those cells in mature osteoblast. It was monitored by evaluating a time-line of alkaline phosphatase (ALP) activity (biomarker of osteoblast differentiation) and afterwards nodules of mineralization (measured by von Kossa staining and calcium content). RESULTS: Analysis from phase-contrast microscopy revealed mainly morphological changes ranging since fibroblast-shaped (7 days, semi-confluent culture at exponential growth) to polyhedral-shaped cells (14-28 days, confluent culture during differentiation process). ALP activity was linearly increased since 14-28 days while amount of protein remained unchanged. Interesting, our data from von Kossa staining reveled a highest incidence of mineralization nodules at 28 days. CONCLUSION: Taken our results together, we can suggest that periosteal-derived cells present an interesting potential to differentiate in mature osteoblast able to promote mineralization in vitro by incorporating to ECM circulating calcium from extracellular compartment. From our point of view, this source of osteogenic cells can be explored by bioengineers in order to advance therapeutic protocols able to solve bone degenerative lesions. PMID- 22221260 TI - Serotonin syndrome: SSRIs, SNRIs, triptans, and current clinical practice. PMID- 22221261 TI - Paraneoplastic pemphigus in association with Castleman disease of the pararenal retroperitoneum. PMID- 22221263 TI - Grapefruit juices impair the bioaccessibility of beta-carotene from orange fleshed sweet potato but not its intestinal uptake by Caco-2 cells. AB - Among various factors influencing beta-carotene (Bc) bioavailability, information on interactions between carotenoids or other micronutrients such as flavonoids during a meal that contains different plant-derived foods is quite limited. Because orange-fleshed sweet potato (OFSP) is an important Bc-rich staple food, a source of vitamin A in developing countries, this study focused on the effect of citrus fruit juice carotenoids and flavonoids on Bc bioaccessibility from OFSP. In vitro digestion coupled with the Caco-2 cell culture model was used to evaluate the bioaccessibility and cellular uptake of Bc from OFSP in the presence of pink grapefruit (pGF) or white grapefruit (wGF) juices. The addition of grapefruit juices significantly decreased the bioaccessibility, by up to 30%, but not the cellular uptake of Bc from boiled OFSP. Lycopene, but more probably naringin, present in grapefruit juices was suspected to be responsible for the inhibitory effect of the citrus juices on Bc bioaccessibility. This inhibition was apparently due in part to competition for incorporation between Bc and naringin into mixed micelles during in vitro digestion. In contrast, Bc uptake from dietary micelles was not impaired by naringin. PMID- 22221264 TI - Intramolecular interactions in crystals of tris(2,6 diisopropylphenoxy)silanethiol and its sodium salts. AB - Hydrolytically stable silanethiol tris(2,6-diisopropylphenoxy)silanethiol (TDST) has been synthesized and reacted with sodium metal. In solid state TDST exhibits pi-interactions between the S-H unit and the pi-system of the arene, replaced by cation-pi interactions in its sodium salts. The interactions are documented by crystal structures and FT-IR spectroscopy. PMID- 22221266 TI - Correlation of antibodies against desmogleins 1 and 3 with indirect immunofluorescence and disease status in a Greek population with pemphigus vulgaris. AB - BACKGROUND: The use of ELISA testing of antibodies to desmogleins 1 and 3 (anti Dsg1 and anti-Dsg3) and indirect immunofluorescence (IIF) has been strongly supported for the serologic diagnosis of pemphigus. The purpose of this study was to correlate anti-Dsg1 and anti-Dsg3 with IIF values, disease localization, treatment and clinical course in Greek patients with pemphigus vulgaris (PV). METHODS: A total of 54 patients with PV had ELISA serum testing for the presence and titers of anti-Dsg1, anti-Dsg3 and IIF. Anti-Dsg1, anti-Dsg3 and IIF were correlated with treatment and disease localization. For 40 patients, titers of anti-Dsg1 and anti-Dsg3 were assessed in relation to treatment and clinical course after 12 months. RESULTS: Anti-Dsg3 and anti-Dsg1 positivity in patients with negative IIF was 70.6% and 58.8%, respectively. Anti-Dsg1 and anti-Dsg3 were positive in 89.3% and 100% of patients with mucocutaneous disease, respectively, 88.9% and 66.7% of patients with skin limited disease, respectively and 52.9% and 76.5% of patients with mucosal limited disease, respectively. Both antibody titers showed significant correlation with IIF and treatment status. Improvement of clinical status was associated with significant decrease of both anti-Dsg1 and anti-Dsg3 after 12 months. CONCLUSIONS: Serum testing of anti-Dsg1 and anti-Dsg3 in PV patients not only provides significant correlations with IIF, treatment and disease type, but may serve as a monitoring tool for clinical course and treatment guidance. PMID- 22221265 TI - Solution structure of CCL21 and identification of a putative CCR7 binding site. AB - CCL21 is a human chemokine that recruits normal immune cells and metastasizing tumor cells to lymph nodes through activation of the G protein-coupled receptor CCR7. The CCL21 structure solved by NMR contains a conserved chemokine domain followed by an extended, unstructured C-terminus that is not typical of most other chemokines. A sedimentation equilibrium study showed CCL21 to be monomeric. Chemical shift mapping indicates that the CCR7 N-terminus binds to the N-loop and third beta-strand of CCL21's chemokine domain. Details of CCL21-receptor recognition may enable structure-based drug discovery of novel antimetastatic agents. PMID- 22221267 TI - The microbiologic safety of umbilical cord blood transfusion for children with severe anemia in Mombasa, Kenya. AB - BACKGROUND: Severe anemia requiring blood transfusion is common in hospitalized young children in sub-Saharan Africa but blood is often in short supply. Umbilical cord blood may be a useful source of blood if microbiologic safety concerns can be addressed. STUDY DESIGN AND METHODS: Cord blood, donated on the labor ward at the provincial hospital in Mombasa, was cultured soon after collection (screening culture) and after a period of storage (poststorage culture). Conventional blood transfused to children at the hospital was cultured only at the time of issue (poststorage culture). Maternal sera (cord blood) and conventional blood donations were also screened for transfusion-transmitted infection. RESULTS: At poststorage culture, the overall contamination rate of cord blood was one-third that of conventional blood (13/449 vs. 38/434; odds ratio [OR], 0.31; 95% confidence interval [CI], 0.15-0.61) and for bacteria of high pathogenic potential it was half that of conventional blood (4/449 vs. 7/434; OR, 0.55; 95% CI, 0.12-2.18). Screening cultures were positive in 50% (2/4) of cord blood packs where an organism of high pathogenic potential was isolated at poststorage culture. Cord blood donors had a lower seroreactivity than conventional donors for human immunodeficiency virus (OR, 0.63; 95% CI, 0.29 1.18), hepatitis B virus (OR, 0.32; 95% CI, 0.16-0.59), and hepatitis C virus (OR, 0.20; 95% CI, 0.24-0.76). For syphilis, initial seroreactivity in cord blood donors was 3.8% compared to 1.8% in conventional blood donors (OR, 2.10; 95% CI, 1.15-3.60) but was 0.5% after retesting. CONCLUSION: With respect to bacterial contamination and seroreactivity for transfusion-transmitted infection, the safety of cord blood in Mombasa compares favorably with conventional blood. Clinical trials of cord blood transfusion are justified. PMID- 22221269 TI - Photochemistry and Photobiology. Editorial. PMID- 22221268 TI - Neurolymphomatosis in a patient with lymphoblastic lymphoma. PMID- 22221270 TI - Kinetic effects of the complexation reaction in the facilitated ion transfer at liquid membrane systems of one and two polarized interfaces. Theoretical insights. AB - An in-depth study of the ion transfer facilitated by complexation in the organic phase (TOC mechanism) in liquid membrane systems of one and two polarized interfaces is carried out by taking into account the kinetic effects associated with the complexation reaction. Explicit analytical equations for the normal pulse voltammetric (I/E) and chronoamperometric (I/t) responses with an explicit dependence on the kinetic parameters of the chemical complexation are presented for both kinds of membrane system, which could be useful for modeling artificial and biological membranes. The equations are compared with those obtained by using the widely used approximation of total equilibrium conditions that leads to the transfer by interfacial complexation mechanism (TIC), which only depends on thermodynamic parameters. Simple methods are proposed that allow quantitative determination of the equilibrium and kinetic constants of the complexation reaction in the organic phase for both kinds of membrane system. PMID- 22221271 TI - The expression of the class 1 glucose transporter isoforms in human embryonic stem cells, and the potential use of GLUT2 as a marker for pancreatic progenitor enrichment. AB - Even before the first appearance of the developing pancreas, glucose is the major substrate in the growing embryo. The transport of glucose across cell membranes is facilitated by a family of membranal glucose transporters (GLUT). We analyzed changes in expression of class 1 glucose transporters (GLUT1-4) during human embryonic stem cell (hESC) and human induced pluripotent stem cell (hiPSC) differentiation, from undifferentiated cells to 28-day-old embryoid bodies (EBs). We also examined the potential use of GLUT2 as a marker for differentiating pancreatic progenitor cells. Using quantitative real time polymerase chain reaction (qPCR), western blot, and immunofluorescence, we observed enhanced expression of GLUT1 and GLUT2 during differentiation, but only minor change in GLUT3 expression. GLUT4 expression was found to be very low both at the RNA and in the protein levels. Expression of the early pancreatic transcription factor, pancreatic duodenal homeobox gene 1 (PDX1), correlated with GLUT2 expression, suggesting the potential use of GLUT2 as a surface marker for tracking pancreatic precursor cells. After sorting EBs according to their membranal GLUT2 expression, GLUT2 and PDX1 expression were found elevated, as was expression of other endodermal markers such as PAX4, NGN3, CXCR4, and SOX17. This simple method may be used to differentiate embryonic stem cells and to isolate from them, using GLUT2 as a surface marker, an enriched pancreatic progenitor cell population in order to achieve insulin-producing cells. The sorted GLUT2 cells may potentially be used in the future as insulin-producing cells for beta cell therapies. PMID- 22221272 TI - Investigation of the reactivity between a ruthenium hexacationic prism and biological ligands. AB - The relative affinity of the cationic triangular metallaprism, [(pCH(3)C(6)H(4)Pr(i))(6)Ru(6)(tpt)(2)(dhbq)(3)](6+) ([1](6+)), for various amino acids, ascorbic acid, and glutathione (GSH) has been studied at 37 degrees C in aqueous solutions at pD 7, using NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS). The metallaprism [1](6+), which is constituted of six (pCH(3)C(6)H(4)Pr(i))Ru corners bridged by three 1,4-benzoquinonato (dhbq) ligands and connected by two 2,4,6tri(pyridin4yl)1,3,5-triazine (tpt) triangular panels, disassembled in the presence of Arg, His, and Lys, while it remains intact with Met. Coordination to the imidazole nitrogen atom in His or to the basic NH/NH(2) groups in Arg and Lys displaces the dhbq and tpt ligands from the (p-cymene)Ru units, and subsequent coordination to the amino and carboxylato groups forms stable N,N,O metallacycles. The binding to amino acids proceeds rapidly, as determined by NMR spectroscopy. Interestingly, solutions of [1](6+) are able to catalyze oxidation of the thiol group of Cys and GSH to give the corresponding disulfides and of ascorbic acid to give the corresponding dehydroascorbic acid. Competition experiments with Arg, Cys, His, and Lys show the simultaneous formation of one single adduct, the (p-cymene)Ru-His complex, and oxidation of Cys to cystine. Furthermore, the (p-cymene)Ru-His complex formed upon the addition of His to [1][CF(3)SO(3)](6) is able to oxidize Cys to cystine much more efficiently than [1](6+). These results provide evidence against interaction with proteins as process in the release of encapsulated guest molecules. Oxidation of Cys and GSH to give the corresponding disulfides may explain the in vitro anticancer activity of [1](6+). PMID- 22221273 TI - The immediate hemodynamic effects of enhanced external counterpulsation on the left ventricular function. AB - OBJECTIVES: Enhanced external counterpulsation (EECP) is a non-invasive therapy with long-term anti-anginal effects offered to patients with refractory angina pectoris. The purpose of the present study was to investigate the effect of EECP on myocardial contractility measured as global longitudinal strain (GLS) during EECP treatment. DESIGN: Patients with known refractory angina were enrolled by invitation and underwent 1 h of EECP treatment. Two-dimensional echocardiography and Doppler echocardiography were performed before and during EECP treatment with 15-minute intervals. The peak diastolic/systolic blood pressure ratio (D/S ratio) was monitored with finger pletysmography. GLS was assessed offline with speckle tracking software (EchoPAC GE Healthcare USA). RESULTS: Twenty patients were included (mean age 65.0 +/- 8.2; 85% males). During EECP treatment, the systolic function of the left ventricle (LV) expressed in terms of an increasing GLS ( 17.9 vs. -16.2% p < 0.05) and a rising cardiac output (5.5 vs. 4.6 l/min p < 0.05) were improved. D/S ratio during the EECP procedure was inversely correlated to LV filling pressure (E/Em ratio r = - 0.5 p = 0.035). CONCLUSIONS: In conclusion, we demonstrated that EECP improved left ventricular GLS and systolic function in an acute setting. Future studies must explore whether these immediate hemodynamic changes are associated to the clinical effect of EECP treatment. PMID- 22221274 TI - Editorial: Impact factors and clinical specialty nursing journals. PMID- 22221275 TI - Commentary on ST Houweling, N Kleefstra, KJJ van Hateren, KH Groenier, B Meyboom de Jong & HJG Bilo (2011) Can diabetes management be safely transferred to practice nurses in a primary care setting? A randomised controlled trial. Journal of Clinical Nursing 20, 1264-1272. PMID- 22221276 TI - Commentary on Nyman MH, Johansson JE, Persson K & Gustafsson M (2011) A prospective study of nosocomial urinary tract infection in hip fracture patients. Journal Clinical Nursing 20, 2531-2539. PMID- 22221277 TI - Behavioral treatment + naltrexone reduces drug use and legal problems in the Republic of Georgia. AB - BACKGROUND: Known drug users in the Republic of Georgia are 99% male. Georgian social context includes close family social structure, intense police scrutiny over daily life, and minimal social service infrastructure. Drug use is dangerous and individuals rely on family support to address socially stigmatizing problems. OBJECTIVE: The aim was to examine the changes in problem severity over time experienced by 40 adult opioid-injecting men with drug-free female partners in the Republic of Georgia who participated in a randomized clinical trial examining the feasibility and efficacy of a 22-week comprehensive intervention that paired behavioral treatment with naltrexone. METHODS: This secondary data analysis study examined the results from a project that had randomized participants to either a comprehensive intervention that paired behavioral treatment with naltrexone or usual care (UC) and examined changes in Addiction Severity Index (ASI) composite scores. RESULTS: The comprehensive intervention showed three times the decline in ASI drug use and legal composite scores than did the UC condition in males in the Republic of Georgia, both p < .009. CONCLUSION: The results suggest that the use of a comprehensive behavioral intervention paired with naltrexone leads to significant reductions in drug use and legal problems in opioid-injecting males in the Republic of Georgia. SCIENTIFIC SIGNIFICANCE: A comprehensive intervention that paired behavioral treatment with naltrexone provides a promising approach to protect drug users against relapse and legal risks. PMID- 22221278 TI - Four-electron oxygen reduction by brominated cobalt corrole. AB - The carbon-supported cobalt(III) complex of beta-pyrrole-brominated 5,10,15 tris(pentafluorophenyl)corrole [Co(tpfc)Br(8)/C] is introduced as a nonplatinum alternative for electrocatalytic oxygen reduction in aqueous solutions. Through systematic work, the basic kinetic parameters of this reaction were studied, using rotating ring disk electrode electrochemical methods in the pH range of 0 11. Pronounced catalytic activity was detected in acid solutions along with shifts of the Co(II)/Co(III) and O(2) redox couples to more positive values (onset of 0.56 V at pH 0). A series of independent measurements have been used to prove that the dominant mechanism for oxygen reduction by Co(tpfc)Br(8)/C catalysis is the direct four-electron pathway to water. PMID- 22221279 TI - Hydroxylation catalysis by mononuclear and dinuclear iron oxo catalysts: a methane monooxygenase model system versus the Fenton reagent Fe(IV)O(H2O)5(2+). AB - Hydroxylation of aliphatic C-H bonds is a chemically and biologically important reaction, which is catalyzed by the oxidoiron group FeO(2+) in both mononuclear (heme and nonheme) and dinuclear complexes. We investigate the similarities and dissimilarities of the action of the FeO(2+) group in these two configurations, using the Fenton-type reagent [FeO(2+) in a water solution, FeO(H(2)O)(5)(2+)] and a model system for the methane monooxygenase (MMO) enzyme as representatives. The high-valent iron oxo intermediate MMOH(Q) (compound Q) is regarded as the active species in methane oxidation. We show that the electronic structure of compound Q can be understood as a dimer of two Fe(IV)O(2+) units. This implies that the insights from the past years in the oxidative action of this ubiquitous moiety in oxidation catalysis can be applied immediately to MMOH(Q). Electronically the dinuclear system is not fundamentally different from the mononuclear system. However, there is an important difference of MMOH(Q) from FeO(H(2)O)(5)(2+): the largest contribution to the transition state (TS) barrier in the case of MMOH(Q) is not the activation strain (which is in this case the energy for the C-H bond lengthening to the TS value), but it is the steric hindrance of the incoming CH(4) with the ligands representing glutamate residues. The importance of the steric factor in the dinuclear system suggests that it may be exploited, through variation in the ligand framework, to build a synthetic oxidation catalyst with the desired selectivity for the methane substrate. PMID- 22221280 TI - Thermally induced defluorination during a mer to fac transformation of a blue green phosphorescent cyclometalated iridium(III) complex. AB - The new homoleptic tris-cyclometalated [Ir(C^N)(3)] complexes mer-8, fac-8, and fac-9 incorporating gamma-carboline ligands are reported. Reaction of 3-(2,4 difluorophenyl)-5-(2-ethylhexyl)-pyrido[4,3-b]indole 6 with iridium(III) chloride under standard cyclometalating conditions gave the homoleptic complex mer-8 in 63% yield. The X-ray crystal structure of mer-8 is described. The Ir-C and Ir-N bonds show the expected bond length alternations for the differing trans influence of phenyl and pyridyl ligands. mer-8 quantitatively isomerized to fac-8 upon irradiation with UV light. However, heating mer-8 at 290 degrees C in glycerol led to an unusual regioselective loss of one fluorine atom from each of the ligands, yielding fac-9 in 58% yield. fac-8 is thermally very stable: no decomposition was observed when fac-8 was heated in glycerol at 290 degrees C for 48 h. The gamma-carboline system of fac-8 enhances thermal stability compared to the pyridyl analogue fac-Ir(46dfppy)(3)10, which decomposes extensively upon being heated in glycerol at 290 degrees C for 2 h. Complexes mer-8, fac-8, and fac-9 are emitters of blue-green light (lambda(max)(em) = 477, 476, and 494 nm, respectively). The triplet lifetimes for fac-8 and fac-9 are ~4.5 MUs at room temperature; solution Phi(PL) values are 0.31 and 0.22, respectively. PMID- 22221281 TI - Synthesis, structure, and electronic properties of RuN6 dinuclear Ru-Hbpp complexes. AB - A series of RuN(6) dinuclear Ru-Hbpp complexes (Hbpp is the dinucleating tetraaza ligand 3,5-bis(pyridyl)pyrazole) of general formula {[Ru(II)(R(2) trpy)(MeCN)](2)(MU-R(1)-bpp)}(3+), 10(3+)-14(3+), (R(1) = H, Me, or NO(2). and R(2) = H, Me, MeO; see Scheme 1) has been prepared from their Cl(-) or AcO(-) bridged precursors. The complexes have been characterized by UV-vis, NMR, CV, and some by X-ray. Complexes 10(3+)-14(3+), Ru(2)(II,II), were oxidized by 1 equiv in solution, leading to the mixed valence Ru(2)(II,III) complexes 10(4+)-14(4+) containing one unpaired electron and were characterized by EPR and UV-vis-near IR, which showed metal-centered spin and the presence of low-energy IVCT bands. The H(ab) parameter indicates a relatively strong electronic coupling between the two ruthenium centers (class II). Further two electron oxidation in solution of the 10(3+)-14(3+) led to the formation of EPR silent Ru(2)(III,III) complexes 10(5+)-14(5+), that were further characterized by UV-vis-NIR. TD-DFT calculations are employed to assign the nature of the UV-vis transitions for the complexes in the various oxidation states, which are of metal to ligand charge transfer (MLCT) type for Ru(2)(II,II) and ligand to metal charge transfer (LMCT) type for Ru(2)(III,II) and Ru(2)(III,III). PMID- 22221282 TI - Stereochemical inversion of phosphonothioate methanolysis by La(III) and Zn(II): mechanistic implications for the degradation of organophosphate neurotoxins. AB - The utility of phosphonothioate methanolysis to degrade organophosphate neurotoxins has prompted the stereochemical investigation of this useful transformation. The methanolysis of enantiomerically pure O,S-diethyl phenylphosphonothioate (5) was studied both in the presence and in the absence of metal ions known to catalyze the phosphonothioate -> phosphonate transformation. This report outlines the syntheses of enantiomerically pure 5 and its methanolysis product O-ethyl O-methyl phenylphosphonate (7). Compound 7 results from exclusive P-S scission of 5, which is the desired mode of phosphonothioate methanolysis (E(a) = 14.5 +/- 0.5 kcal/mol). The stereochemical analysis of the phosphonothioate methanolysis was done for the first time with beta-cyclodextrin, and it shows complete inversion on the phosphorus center upon methoxide displacement of ethanethiolate. The presence of La(III) or Zn(II) complexes do not alter this S(N)2-like substitution which sheds new light on the mechanism of methanolysis of phosphonothioates. PMID- 22221283 TI - Using high pressure to prepare polymorphs of the Ba2Co(1-x)Zn(x)S3 (0 <= x <= 1.0) compounds. AB - In this work, high pressure was used as a tool to induce structural transition and prepare metastable polymorphs of ternary sulfides. Structural transformations under high pressure of compounds belonging to the Ba(2)Co(1-x)Zn(x)S(3) (0 <= x <= 1.0) series were studied using X-ray diffraction and electron microscopy. All members of the Ba(2)Co(1-x)Zn(x)S(3) series show the Ba(2)CoS(3)-type one dimensional structure, but, after heating under pressure, the Ba(2)CoS(3) compound (x = 0) separates into BaS and the two-dimensional BaCoS(2-delta) (delta ~ 0), while Ba(2)Co(1-x)Zn(x)S(3) compounds with x >= 0.25 maintain their one dimensional features but rearrange into polymorphs showing the Ba(2)MnS(3)-type structure. All structural transformations can be linked to shortening in interchain metal-metal distances caused by the high pressure, and the role of the zinc in preventing loss of one-dimensionality is discussed. PMID- 22221284 TI - Synthesis of hafnium oxide-gold core-shell nanoparticles. AB - Developing cheap composite nanoparticle systems that combines a high dielectric constant with good conductivity is important for the future of the electronic industry. In this study, two different sizes, 7.3 +/- 2.2 and 5.6 +/- 1.9 nm, of HfO(2)@Au core-shell nanoparticles are prepared by using a high-temperature reduction method. The core-shell nanoparticles are characterized by powder X-ray diffraction, high-resolution transmission electron microscopy (HRTEM), energy dispersive X-ray analysis (EDX), and UV-visible absorption spectroscopy. HfO(2) exhibits no absorption in the visible region, but the HfO(2)@Au core-shell nanoparticles show a plasmon absorption band at 555 nm that is 25 nm red-shifted as compared to pure gold nanoparticles. According to transmission electron microscopy and energy dispersive X-ray analysis, the HfO(2) particles are coated with approximately three atomic layers of gold. PMID- 22221285 TI - Complexation of metal ions with TRAP (1,4,7-triazacyclononane phosphinic acid) ligands and 1,4,7-triazacyclononane-1,4,7-triacetic acid: phosphinate-containing ligands as unique chelators for trivalent gallium. AB - Three phosphinic acid 1,4,7-triazacyclononane (TACN) derivatives bearing methylphosphinic (TRAP-H), methyl(phenyl)phosphinic (TRAP-Ph), or methyl(hydroxymethyl)phosphinic acid (TRAP-OH) pendant arms were investigated as members of a new family of efficient Ga(3+) chelators, TRAP ligands (triazacyclononane phosphinic acids). Stepwise protonation constants of ligands and stability constants of their complexes with Ga(3+), selected divalent metal, and Ln(3+) ions were determined by potentiometry. For comparison, equilibrium data for the metal ion-NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) systems were redetermined. These ligands exhibit high thermodynamic selectivity for Ga(3+) over the other metal ions (log K(GaL) - log K(ML) = 7-9) and a selective complexation of smaller Mg(2+) over Ca(2+). Stabilities of the Ga(3+) complexes are dependent on the basicity of the donor atoms: [Ga(NOTA)] (log K(GaL) = 29.6) > [Ga(TRAP-OH)] (log K(GaL) = 23.3) > [Ga(TRAP-H)] (log K(GaL) = 21.9). The [Ga(TRAP-OH)] complex exhibits unusual reversible rearrangement of the "in-cage" N(3)O(3) complex to the "out-of-cage" O(6) complex. The in-cage complex is present in acidic solutions, and at neutral pH, Ga(3+) ion binds hydroxide anion, induces deprotonation and coordination of the P-hydroxymethyl group(s), and moves out of the macrocyclic cavity; the hypothesis is supported by a combination of results from potentiometry, multinuclear nuclear magnetic resonance spectrometry, and density functional theory calculations. Isomerism of the phosphinate Ga(3+) complexes caused by a combination of the chelate ring conformation, the helicity of coordinated pendant arms, and the chirality of the coordinated phosphinate groups was observed. All Ga(3+) complexes are kinetically inert in both acidic and alkaline solutions. Complex formation studies in acidic solutions indicate that Ga(3+) complexes of the phosphinate ligands are formed quickly (minutes) and quantitatively even at pH <2. Compared to common Ga(3+) chelators (e.g., 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivatives), these novel ligands show fast complexation of Ga(3+) over a broad pH range. The discussed TRAP ligands are suitable alternatives for the development of (68)Ga radiopharmaceuticals. PMID- 22221286 TI - Investigations on the interaction of dichloroaluminum carboxylates with Lewis bases and water: an efficient road toward oxo- and hydroxoaluminum carboxylate complexes. AB - A series of dichloroaluminum carboxylates [Cl(2)Al(O(2)CR)](2) (were R = Ph (1a), (t)Bu (1b), CHCH(2) (1c) and C(11)H(23) (1d)) were prepared and extended investigations on their structure and reactivity toward various Lewis bases and H(2)O performed. Compounds [Cl(2)Al(O(2)CR)](2) and their adducts with Lewis bases show a large structural variety, featuring both molecular and ionic forms with different coordination numbers of the metal center and various coordination modes of the carboxylate ligand. Upon addition of a Lewis base of moderate strength the molecular form [Cl(2)Al(O(2)CR)](2) equilibrates with new ionic forms. In the presences of 4-methylpyridine the six-coordinate Lewis acid-base adducts [Cl(2)Al(lambda(2)-O(2)CR)(py-Me)(2)] [R = Ph (3a), (t)Bu (3b)] with a chelating carboxylate ligand were formed. The reactions of 1a, 1b, and 1d with 0.33 equiv of H(2)O in THF-toluene solution lead to oxo carboxylates [(Al(3)O)(O(2)CR)(6)(THF)(3)] [AlCl(4)] [where R = Ph (4a(THF)), (t)Bu (4b(THF)), and C(11)H(23) (4d(THF))] in high yield. The similar reaction of 1c in tetrahydrofuran (THF) afforded the chloro(hydroxo)aluminum acrylate [(ClAl)(2)(OH)(O(2)CC(2)H(3))(2) (THF)(4)][AlCl(4)] (5), while the hydrolysis of 1b in MeCN lead to the hydroxoaluminum carboxylate [Al(2)(OH)(O(2)C(t)Bu)(2)(MeCN)(6)][AlCl(4))(3)] (6). All compounds were characterized by elemental analysis, (1)H, (27)Al NMR, and IR spectroscopy, and the molecular structure of 1a, 3a, 3b, 4a(THF), 4b(THF), 4b(py-Me'), 5, and 6 were determined by single-crystal X-ray diffraction. The study provides a platform for testing transformations of secondary building units in Al-Metal Organic Frameworks toward H(2)O and neutral donor ligands. PMID- 22221287 TI - Development of Purkinje cells in the ovine brain. AB - Purkinje cells are involved in many vital functions within the body. Twenty ovine fetuses ranging from 2 to 5 months of gestation, two lambs in the first week after birth and three adult sheep were studied. Sections of the cerebellum were stained with haematoxylin and eosin, cresyl violet and Kluver-Barrera. This study indicates that Purkinje cells began to appear after the 15(th) week of gestation. There were varying degrees of development of Purkinje cells in different zones of the cerebellum. Our findings in sheep fetuses suggest that the maturation of Purkinje cells starts in the caudal regions of the cerebellum and that the process begins in the vermis before it does in the cerebellar hemispheres. The alignment of Purkinje cells was found to be very regular in the caudal regions of the cerebellum. A partial absence of Purkinje cells in the rostral regions of the cerebellum was observed in both sheep fetuses and adult sheep. In the first post natal week, some ectopic Purkinje cells were found in the white matter of the cerebellum. PMID- 22221288 TI - Type II focal cortical dysplasia: electroclinical phenotype and surgical outcome related to imaging. AB - PURPOSE: Type II focal cortical dysplasia (TTFCD), a highly epileptogenic lesion with severe epilepsy curable by surgery, is missed by magnetic resonance imaging (MRI) in about one third of cases. Little is known about the electroclinical presentation in these MRI-negative patients and a poor surgical outcome is frequently reported. We compared the clinical and neurophysiologic features in MRI-negative and MRI-positive cases in order to better identify candidates for surgery. METHODS: Among 62 consecutive TTFCD patients (38 male, 24 female; 7-52 years old; 22 children) operated for intractable epilepsy, 25 (40%) presented negative MRI findings. We compared the history of epilepsy; the type, frequency, and distribution of seizures; neurologic examination cognitive and psychiatric impairment; interictal-ictal electroencephalography (EEG) and stereo-EEG (SEEG) data, fluorodeoxyglucose positron emission tomography (FDG-PET) data, neuropathologic findings; and surgical outcome in the MRI-negative and the MRI positive groups. KEY FINDINGS: Severe partial epilepsy beginning in childhood, high seizure frequency including status epilepticus, stereotyped seizures suggestive of precise brain localization, extratemporal location and functional area involvement were characteristic and similarly found in both groups. On EEG, pseudorhythmic activity was found in about 40% of patients in each group. SEEG recordings demonstrated the typical pattern characterizing TTFCD in both groups. FDG-PET had a localization value in 84% of the MRI-negative cases and helped to delineate the dysplastic cortex in 65% of the MRI-positive cases. The combination of imaging and neurophysiologic data allowed us to perform safe and restricted resections, limited to a single gyrus in more than half of all cases. In addition, we were able to avoid invasive monitoring in most MRI-positive cases and even in some selected MRI-negative cases. The proportion of patients with a favorable surgical outcome was comparable in both groups (88% in MRI-negative and 94% in MRI-positive cases). The main difference between the groups was a significantly higher frequency of sleep-related epilepsy in the MRI-negative group (p = 0.028). This phenotypic characteristic provides a new argument for TTFCD in MRI-negative extratemporal epilepsy. SIGNIFICANCE: These results lead us to consider that children or adult patients in whom electroclinical data suggest TTFCD, are highly suitable for surgery, especially for cryptogenic sleep-related epilepsy. PMID- 22221289 TI - Low prevalence of Helicobacter pylori infection among patients with inflammatory bowel disease. AB - BACKGROUND: There is some preliminary evidence to suggest that patients with inflammatory bowel disease (IBD) are less frequently infected with Helicobacter pylori than the general population. AIM: To examine whether the prevalence of Helicobacter pylori (H. pylori) is lower among IBD patients compared with non-IBD individuals based on results from surgical pathology. METHODS: From a database of surgical pathology reports, we recruited a sample of unique patients who underwent a same-day bidirectional gastrointestinal endoscopy with biopsies. Of the total 65,515 patients, 1061 served as cases with IBD and 64,451 as controls without IBD. The histological presence of H. pylori was correlated with the patients' demographic characteristics and histological presence of any oesophageal disease, Crohn's disease (CD), ulcerative colitis (UC) and indeterminate colitis (IND). Results were expressed as odds ratios (OR), using multivariate logistic regression to adjust for the cofounding influence of comorbidities and demographic characteristics. RESULTS: The presence of H. pylori was inversely associated with IBD, the adjusted OR and their 95% confidence intervals being 0.48 (0.27-0.79) for CD, 0.59 (0.39-0.84) for UC and 0.43 (0.15 0.95) for IND. In contradistinction, H. pylori-negative gastritis was positively associated with IBD, the adjusted OR being 11.06 (7.98-15.02) for CD, 2.25 (1.31 3.60) for UC and 6.91 (3.50-12.30) for IND. CONCLUSIONS: Our study confirms an inverse association between H. pylori and IBD and a positive association between the H. pylori-negative gastritis and IBD. These relationships may open new avenues to study the pathogenesis of IBD. PMID- 22221290 TI - The nest architecture of three species of north Florida Aphaenogaster ants. AB - The architecture of the subterranean nests of Aphaenogaster floridana Smith (Hymenoptera: Formicidae), A. treatae Forel and A. ashmeadi (Emery), was studied from plaster, wax, or metal casts. After structural features were quantified from digital images, the entombed ants were retrieved from the plaster by dissolution or wax casts by melting and counted. Nests of all three species were rather simple, small and vertical, with horizontal chambers connected by vertical shafts. Shafts descending to lower chambers tended to arise from chamber edges, whereas those connecting to a chamber above tended to arise from chamber centers. A. floridana had the largest nests and colonies, and multiple shafts commonly connected upper chambers, a feature lacking in the other two species. In A. floridana nests a higher proportion of chamber area and greater spacing between chambers occurred in the deeper parts of the nest, regardless of nest size. The other two species showed no vertical differentiation of any size-free measure at any nest size. In all three species, nest size increased more slowly than the worker population, so crowding was greater in large colonies than in small, in contrast to the situation in three other ant species for which data were available. An appendix with stereo images of all casts is provided. PMID- 22221291 TI - Dissociation between online and offline learning in developmental dyslexia. AB - Most studies investigating procedural learning in developmental dyslexia (DD) have focused on the acquisition stage, ignoring later stages involved in the process of skill learning. The current study examined sequence learning among DD and control groups in two sessions. Both groups completed a sequence-learning task over a first session (online learning) and a second session 24 hours later (offline learning). While both groups showed improvements in performance during offline learning, only the control group showed improvements in performance during online learning. Moreover, the DD group differed from the control group in their ability to recover from the introduction of a different sequence. PMID- 22221292 TI - Social and medical vulnerability factors of emergency department frequent users in a universal health insurance system. AB - OBJECTIVES: The objectives were to identify the social and medical factors associated with emergency department (ED) frequent use and to determine if frequent users were more likely to have a combination of these factors in a universal health insurance system. METHODS: This was a retrospective chart review case-control study comparing randomized samples of frequent users and nonfrequent users at the Lausanne University Hospital, Switzerland. The authors defined frequent users as patients with four or more ED visits within the previous 12 months. Adult patients who visited the ED between April 2008 and March 2009 (study period) were included, and patients leaving the ED without medical discharge were excluded. For each patient, the first ED electronic record within the study period was considered for data extraction. Along with basic demographics, variables of interest included social (employment or housing status) and medical (ED primary diagnosis) characteristics. Significant social and medical factors were used to construct a logistic regression model, to determine factors associated with frequent ED use. In addition, comparison of the combination of social and medical factors was examined. RESULTS: A total of 359 of 1,591 frequent and 360 of 34,263 nonfrequent users were selected. Frequent users accounted for less than a 20th of all ED patients (4.4%), but for 12.1% of all visits (5,813 of 48,117), with a maximum of 73 ED visits. No difference in terms of age or sex occurred, but more frequent users had a nationality other than Swiss or European (n = 117 [32.6%] vs. n = 83 [23.1%], p = 0.003). Adjusted multivariate analysis showed that social and specific medical vulnerability factors most increased the risk of frequent ED use: being under guardianship (adjusted odds ratio [OR] = 15.8; 95% confidence interval [CI] = 1.7 to 147.3), living closer to the ED (adjusted OR = 4.6; 95% CI = 2.8 to 7.6), being uninsured (adjusted OR = 2.5; 95% CI = 1.1 to 5.8), being unemployed or dependent on government welfare (adjusted OR = 2.1; 95% CI = 1.3 to 3.4), the number of psychiatric hospitalizations (adjusted OR = 4.6; 95% CI = 1.5 to 14.1), and the use of five or more clinical departments over 12 months (adjusted OR = 4.5; 95% CI = 2.5 to 8.1). Having two of four social factors increased the odds of frequent ED use (adjusted = OR 5.4; 95% CI = 2.9 to 9.9), and similar results were found for medical factors (adjusted OR = 7.9; 95% CI = 4.6 to 13.4). A combination of social and medical factors was markedly associated with ED frequent use, as frequent users were 10 times more likely to have three of them (on a total of eight factors; 95% CI = 5.1 to 19.6). CONCLUSIONS: Frequent users accounted for a moderate proportion of visits at the Lausanne ED. Social and medical vulnerability factors were associated with frequent ED use. In addition, frequent users were more likely to have both social and medical vulnerabilities than were other patients. Case management strategies might address the vulnerability factors of frequent users to prevent inequities in health care and related costs. PMID- 22221293 TI - Effect of exposure to non-esterified fatty acid on progressive deterioration of insulin secretion in patients with Type 2 diabetes: a long-term follow-up study. AB - AIM: The aim of the study was to determine whether fasting serum non-esterified fatty acid (NEFA) could be associated with long-term progressive deterioration of insulin secretion in patients with Type 2 diabetes. METHODS: Seventy-seven Japanese patients with Type 2 diabetes (mean BMI 23.3 kg/m(2) ) were followed for 10 years. We measured fasting C-peptide level every 1-2 years. By using the slope of regression line between fasting C-peptide level and duration, we calculated its individual annual decline as an index of insulin secretion. During the follow up periods of C-peptide, the patients were evaluated for fasting serum non esterified fatty acid, LDL cholesterol, HDL cholesterol and HbA(1c) levels for the last 8 years. We excluded patients who had renal dysfunction or anti-insulin antibodies from among the insulin-treated patients. Association between the individual annual decline of fasting C-peptide level and related factors were evaluated. RESULTS: The mean individual annual decline of fasting serum C-peptide level was -0.013 +/- 0.027 nmol/l/year. Fasting serum non-esterified fatty acid level had no significant difference between the first and the last 2 years of the 8-year observation period of non-esterified fatty acid. Using multiple regression analysis, mean fasting serum non-esterified fatty acid level was associated with the individual annual decline of fasting serum C-peptide level (standardized regression coefficient -0.358, P=0.0056), although other related factors, including HbA(1c) level, were not associated. CONCLUSIONS: Mean fasting serum non esterified fatty acid level during an 8-year observation was independently associated with long-term progressive deterioration of insulin secretion in Japanese patients with Type 2 diabetes. PMID- 22221294 TI - MBL2, MASP2, AMELX, and ENAM gene polymorphisms and dental caries in Polish children. AB - OBJECTIVE: The aim of the study was to examine whether the MBL2 C(-290)G and G161A, MASP2 A359G, AMELX C287T and C522T, and ENAM C2452T polymorphisms are associated with dental caries. SUBJECTS AND METHODS: Genomic DNA of 95 Polish children with 'higher caries experience' (HC) and 84 subjects with 'lower caries experience' (LC) belonging to two age-groups (5 and 13 years old) was extracted from the buccal mucosa. SNPs were genotyped with PCR-RFLP methods. RESULTS: Among 5-year-old children, we found significantly higher percentage of subjects carrying MBL2 (-290)G allele in HC group compared with LC group (43.2%vs 17.6%, P = 0.023). MBL2 C(-290)G-G161A C-G haplotype was overrepresented in LC group in 5 year-olds (P = 0.01), while the opposite association was observed in 13-year olds, where C-G was overrepresented in HC group (P = 0.028). In 5-year-old children, the frequency of MBL2 G-G haplotype was higher in HC group compared with LC subjects (P = 0.045), while the opposite association (with borderline significance) was observed in 13-year-old children (P = 0.057). SNPs in MASP2, AMELX, and ENAM were not associated with dental caries. CONCLUSION: MBL2 gene polymorphism is associated with caries experience in Polish children, but the direction of this association seems to be opposite in primary and permanent dentition. PMID- 22221295 TI - Nutrient additions in pristine Patagonian Sphagnum bog vegetation: can phosphorus addition alleviate (the effects of) increased nitrogen loads. AB - Sphagnum-bog ecosystems have a limited capability to retain carbon and nutrients when subjected to increased nitrogen (N) deposition. Although it has been proposed that phosphorus (P) can dilute negative effects of nitrogen by increasing biomass production of Sphagnum mosses, it is still unclear whether P addition can alleviate physiological N-stress in Sphagnum plants. A 3-year fertilisation experiment was conducted in lawns of a pristine Sphagnum magellanicum bog in Patagonia, where competing vascular plants were practically absent. Background wet deposition of nitrogen was low (~ 0.1-0.2 g . N . m(-2) . year(-1)). Nitrogen (4 g . N . m(-2) . year(-1)) and phosphorus (1 g . P . m(-2) . year(-1)) were applied, separately and in combination, six times during the growing season. P-addition substantially increased biomass production of Sphagnum. Nitrogen and phosphorus changed the morphology of Sphagnum mosses by enhancing height increment, but lowering moss stem density. In contrast to expectations, phosphorus failed to alleviate physiological stress imposed by excess nitrogen (e.g. amino acid accumulation, N-saturation and decline in photosynthetic rates). We conclude that despite improving growth conditions by P addition, Sphagnum-bog ecosystems remain highly susceptible to nitrogen additions. Increased susceptibility to desiccation by nutrients may even worsen the negative effects of excess nitrogen especially in windy climates like in Patagonia. PMID- 22221296 TI - Unanswered questions in headache: how does a migraine attack stop? AB - Much research in migraine focuses on understanding its initiation. But as migraine is typically self-limited, its offset may be as important as its onset. We pose the question "how does migraine stop?" to three investigators with different backgrounds. The consensus is that the termination of a migraine attack, rather than being the passive loss of a trigger, must itself be an active biologic process. PMID- 22221297 TI - Global analysis of non-coding small RNAs in Arabidopsis in response to jasmonate treatment by deep sequencing technology. AB - In plants, non-coding small RNAs play a vital role in plant development and stress responses. To explore the possible role of non-coding small RNAs in the regulation of the jasmonate (JA) pathway, we compared the non-coding small RNAs between the JA-deficient aos mutant and the JA-treated wild type Arabidopsis via high-throughput sequencing. Thirty new miRNAs and 27 new miRNA candidates were identified through bioinformatics approach. Forty-nine known miRNAs (belonging to 24 families), 15 new miRNAs and new miRNA candidates (belonging to 11 families) and 3 tasiRNA families were induced by JA, whereas 1 new miRNA, 1 tasiRNA family and 22 known miRNAs (belonging to 9 families) were repressed by JA. PMID- 22221298 TI - Systematic review of family and home-based interventions targeting paediatric overweight and obesity. AB - The family and home environment is a highly influential psychosocial antecedent of paediatric obesity. The purpose of this investigation was to systematically analyze family and home-based randomized control trials aimed at treating overweight and obesity in children ages 2-7 years. In gathering materials for this review, a search of Cumulative Index to Nursing and Allied Health, MEDLINE, Education Resources Information Center, Psychology and Behavioural Sciences Collection and CENTRAL databases was conducted for the time frame of January 2001 to August 2011. The data extraction spanned three phases resulting in a total of nine interventions that met the specified inclusion criteria. Among the identified studies, eight produced significant outcomes. The majority of the programmes incorporated educational sessions targeting parents as the primary modality for intervention delivery. Less than one-quarter of the interventions included home visitations; however, all of the interventions included home-based activities to reinforce behaviour modification. Only three of the interventions applied social and behavioural theory, and only two interventions employed process evaluation. Additional research is needed to gauge the efficacy of the home and family milieu for treating paediatric obesity. PMID- 22221301 TI - New Year's resolutions. PMID- 22221300 TI - A nursing educational intervention helped by One Touch UltraSmart improves monitoring and glycated haemoglobin levels in type I diabetic children. AB - OBJECTIVES: To improve the monitoring and control of glycated haemoglobin in insulin-dependent children. This article describes an educational intervention for this purpose where One Touch UltraSmart Software was used to manage diabetes. The results showed that this intervention helped to reduce the levels of blood glucose and glycated haemoglobin to less than 7%. BACKGROUND: Various research studies have been performed on the effective control of glycated haemoglobin values in diabetic children by means of technological devices. However, none of this research has evaluated the impact of an educational intervention in conjunction with the use of monitoring instruments such as One Touch UltraSmart. DESIGN: We present an 18-month longitudinal, analytical and observational study of 37 type 1 diabetic patients, 9-16 years of age. For each patient, initial and final values of glycated haemoglobin and the number of blood glucose controls were recorded. METHODOLOGY: For the purposes of our study seven educational workshops, attended by diabetic children and their parents, were conducted. In addition, participants were asked to complete a brief questionnaire so that information could be gathered regarding the eating and exercise habits of the patients. RESULTS: This educational intervention using One Touch UltraSmart led to a statistically significant average reduction of glycated haemoglobin. CONCLUSIONS: Our research showed that the use of One Touch UltraSmart in the context of an educational intervention raised the awareness of the diabetic children and thus helped them to effectively control their disease and to fully understand the necessity of having good dietary and exercise habits. RELEVANCE TO CLINICAL PRACTICE: It can be concluded that the educational intervention led to a significant improvement in the dietary habits of these patients and also helped them to exercise regularly, all of which has a positive impact on their health. PMID- 22221299 TI - Copeptin does not accurately predict disease severity in imported malaria. AB - BACKGROUND: Copeptin has recently been identified to be a stable surrogate marker for the unstable hormone arginine vasopressin (AVP). Copeptin has been shown to correlate with disease severity in leptospirosis and bacterial sepsis. Hyponatraemia is common in severe imported malaria and dysregulation of AVP release has been hypothesized as an underlying pathophysiological mechanism. The aim of the present study was to evaluate the performance of copeptin as a predictor of disease severity in imported malaria. METHODS: Copeptin was measured in stored serum samples of 204 patients with imported malaria that were admitted to our Institute for Tropical Diseases in Rotterdam in the period 1999-2010. The occurrence of WHO defined severe malaria was the primary end-point. The diagnostic performance of copeptin was compared to that of previously evaluated biomarkers C-reactive protein, procalcitonin, lactate and sodium. RESULTS: Of the 204 patients (141 Plasmodium falciparum, 63 non-falciparum infection), 25 had severe malaria. The Area Under the ROC curve of copeptin for severe disease (0.66 [95% confidence interval 0.59-0.72]) was comparable to that of lactate, sodium and procalcitonin. C-reactive protein (0.84 [95% CI 0.79-0.89]) had a significantly better performance as a biomarker for severe malaria than the other biomarkers. CONCLUSIONS: C-reactive protein but not copeptin was found to be an accurate predictor for disease severity in imported malaria. The applicability of copeptin as a marker for severe malaria in clinical practice is limited to exclusion of severe malaria. PMID- 22221302 TI - How much global is global? PMID- 22221305 TI - Testis implant. PMID- 22221307 TI - How to evaluate the efficacy of the phosphodiesterase type 5 inhibitors. AB - INTRODUCTION: Several methods have been so far proposed to compare the effectiveness of the three available phosphodiesterase type 5 inhibitors (PDE5Is). METHODS: Two urologists (E.C. and G.B.B.), together with the Controversy's Editor (E.A.J.), with expertise in the area of medical treatment of erectile dysfunction (ED) present the various perspectives on the evaluation of PDE5Is in ED. The use of the most popular psychometric tool, the International Index of Erectile Function, is presented by an expert psychologist (L.R.D.). MAIN OUTCOME MEASURES: Expert opinion supported by the critical review of the currently available literature. RESULTS: Trials have demonstrated that the PDE5Is are excellent drugs with a great specificity of action and an almost perfect tolerance profile. Some instruments for comparison of clinical efficacy have to be considered subjective (psychometry, patient's preference, changes in quality of general, or sexual life). Some others are more objective (hardness, hormonal levels, and local circulation). An evidence-based comparison of the three PDE5Is should in the future be rooted in both subjective and objective methods. This will be of paramount importance in the drug trial design of new, forthcoming PDE5Is. CONCLUSIONS: Comparison between PDE5Is using both subjective and objective parameters will permit to individuate, on the basis of the evidence, the subset of couples where one drug, or one dose, or dose regimen, is to be considered of first choice. PMID- 22221308 TI - Surgical management of ischemic priapism. AB - INTRODUCTION: Surgery is a mainstay in the management of ischemic priapism. The surgical armamentarium for this condition has recently been expanded with the introduction of several innovative procedures. AIM: To review surgical procedures offered in the treatment of ischemic priapism and present a rational framework for their use. METHODS: Medline searches through July 2010 were conducted using the terms priapism, surgery, shunt, and prosthesis. MAIN OUTCOME MEASURE: Expert opinion was based on review of the medical literature related to this subject matter. RESULTS: A host of surgical procedures exist to address the genital complications of both acute presentations of ischemic priapism and its non-acute pathologic sequelae, which include penile deformities and erectile dysfunction. For the former, the intervention is used principally in an emergent context with the intention to relieve the acute pathologic effects of the condition and preserve erectile function. For the latter, the intervention is aimed generally toward restoring anatomic normalcy and the functional ability to perform sexual intercourse. A rational framework for surgical management, based on the circumstances of the clinical presentation, is described. CONCLUSIONS: The surgical management for ischemic priapism has evolved with the application of a host of surgical procedures. These procedures address acute and non-acute genital complications of the condition and are intended to retain or restore sexual ability effectively and safely. They can be applied using a rational clinical management framework. PMID- 22221309 TI - Preliminary development and content validity of a measure of Australian Aboriginal cultural engagement. AB - OBJECTIVES: Aboriginal people form one of the populations most in need of mental health and substance abuse services within Australia, although many services are not adequately sensitive to, or inclusive of, relevant aspects of Aboriginal culture in their programmes. The Aboriginal Cultural Engagement Survey (ACES) was developed with the objective of assessing the level of cultural engagement of Aboriginal clients. A measure of cultural engagement is an important step in establishing an association between culture and health benefits, so that future interventions may be designed which better meet the cultural needs of Aboriginal Australians within health services. DESIGN: The process of development of the ACES involved four stages of scale development utilising a series of group discussions and reviews with Aboriginal consultants. Assessment of content validity is conducted using the Content Validity Index (CVI). RESULTS: The ACES was found to have excellent content validity with CVIs over 0.80 for all items in the final version. CONCLUSION: The ACES shows promise for being a useful tool in assessing the cultural engagement of Australian Aboriginal clients. There is a need for further psychometric assessment and field trials to assess its utility. PMID- 22221310 TI - Falciparum malaria parasitemia index for predicting severe malaria. AB - INTRODUCTION: While hyperparasitemia is considered an important indicator for the development of severe malaria, there is currently no consensus on the quantitative definition of hyperparasitemia. This study was conducted to establish a cutoff point for peripheral parasitemia among patients with Plasmodium falciparum malaria, to define severe malaria. METHODS: The clinical presentations of 200 uncomplicated P. falciparum malaria, and 189 severe P. falciparum malaria, patients, admitted to the Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, were analyzed. RESULTS: A peripheral parasitemia of 0.5% was found to be the optimal cutoff point for defining severe malaria, demonstrating highest sensitivity (85.1%), specificity (62.0%), and accuracy (73.2%). CONCLUSION: Symptoms of severe falciparum malaria depend on many factors. For the definition of hyperparasitemia in areas of low or seasonal transmission, peripheral parasitemia of 0.5% might be considered a cutoff point for discrimination between severity levels. This value might be useful for the clinical management of malaria, particularly in hypo-endemic areas, unstable transmission areas, and other areas with similar transmission patterns. PMID- 22221311 TI - Deep tissue hypersensitivity to pressure pain in individuals with unilateral acute inversion ankle sprain. AB - OBJECTIVE: The objective of this study was to investigate whether pressure hypersensitivity over deep tissues is a feature of acute inversion ankle sprain. DESIGN: This is a cross-sectional study. SETTING: No study has previously investigated peripheral and central sensitization mechanisms in a clinical acute pain model such as inversion ankle sprain. PATIENTS: Twenty individuals with unilateral inversion ankle sprain (10 women/10 men, age: 31 +/- 7 years) and 19 comparable healthy controls (11 women/8 men, age: 30 +/- 6 years) participated in this study. OUTCOMES: Pressure pain thresholds (PPTs) over anterior talofibular, calcaneofibular, and deltoid ligaments; the lateral and medial malleolus; the tibialis anterior muscle; second metacarpal; and median, radial, and ulnar nerves were bilaterally assessed. RESULTS: The analysis of variance (ANOVA) revealed that PPT levels over the affected anterior talofibular (P = 0.048) and calcaneofibular (P = 0.002) ligaments, and over the affected lateral malleolus (P < 0.001) were lower compared with the non-affected side within patients and both sides in controls. The patients also showed bilateral lower PPT levels over the deltoid ligament than controls (P < 0.05). No significant differences for PPT over the medial malleolus; the second metacarpal; the tibialis anterior muscle; and the median, ulnar, radial nerves were found. Significant negative correlations between intensity of ongoing pain and PPT over the anterior talofibular and deltoid ligaments were found: the higher the pain intensity, the lower the PPT. CONCLUSIONS: This study showed the presence of localized pressure pain hypersensitivity over ankle ligaments in patients with unilateral acute inversion ankle sprain, confirming the presence of localized peripheral sensitization. PMID- 22221312 TI - Thiazolidinedione-dependent activation of sphingosine kinase 1 causes an anti fibrotic effect in renal mesangial cells. AB - BACKGROUND AND PURPOSE: PPARgamma agonists [thiazolidinediones (TZDs)] are known to exert anti-fibrotic effects in the kidney. In addition, we previously demonstrated that sphingosine kinase 1 (SK-1) and intracellular sphingosine-1 phosphate (S1P), by reducing the expression of connective tissue growth factor (CTGF), have a protective role in the fibrotic process. EXPERIMENTAL APPROACH: Here, we investigated the effect of TZDs on intracellular sphingolipid levels and the transcriptional regulation of SK-1 in mesangial cells to evaluate potential novel aspects of the anti-fibrotic capacity of TZDs. KEY RESULTS: Stimulation with the TZDs, troglitazone and rosiglitazone, led to increased S1P levels in rat mesangial cells. This was paralleled by increased SK-1 activity as a consequence of direct effects of the TZDs on SK-1 expression. GW-9662, a PPARgamma antagonist, inhibited the stimulating effect of TZDs on SK-1 mRNA and activity levels and intracellular S1P concentrations. Furthermore, SK-1 up-regulation by TZDs was functionally coupled with lower amounts of pro-fibrotic CTGF. SK-1 inhibition with SKI II almost completely abolished this effect in a dose dependent manner. Moreover, the CTGF lowering effect of TZDs was fully blocked in MC isolated from SK-1 deficient mice (SK-1(-/-) ) as well as in glomeruli of SK 1(-/-) mice compared with wild-type mice treated with TRO and RSG. CONCLUSION AND IMPLICATIONS: These data show that TZD-induced SK-1 up-regulation results in lower amounts of CTGF, demonstrating novel facets for the anti-fibrotic effects of this class of drugs. PMID- 22221313 TI - Self-organizing ontology of biochemically relevant small molecules. AB - BACKGROUND: The advent of high-throughput experimentation in biochemistry has led to the generation of vast amounts of chemical data, necessitating the development of novel analysis, characterization, and cataloguing techniques and tools. Recently, a movement to publically release such data has advanced biochemical structure-activity relationship research, while providing new challenges, the biggest being the curation, annotation, and classification of this information to facilitate useful biochemical pattern analysis. Unfortunately, the human resources currently employed by the organizations supporting these efforts (e.g. ChEBI) are expanding linearly, while new useful scientific information is being released in a seemingly exponential fashion. Compounding this, currently existing chemical classification and annotation systems are not amenable to automated classification, formal and transparent chemical class definition axiomatization, facile class redefinition, or novel class integration, thus further limiting chemical ontology growth by necessitating human involvement in curation. Clearly, there is a need for the automation of this process, especially for novel chemical entities of biological interest. RESULTS: To address this, we present a formal framework based on Semantic Web technologies for the automatic design of chemical ontology which can be used for automated classification of novel entities. We demonstrate the automatic self-assembly of a structure-based chemical ontology based on 60 MeSH and 40 ChEBI chemical classes. This ontology is then used to classify 200 compounds with an accuracy of 92.7%. We extend these structure-based classes with molecular feature information and demonstrate the utility of our framework for classification of functionally relevant chemicals. Finally, we discuss an iterative approach that we envision for future biochemical ontology development. CONCLUSIONS: We conclude that the proposed methodology can ease the burden of chemical data annotators and dramatically increase their productivity. We anticipate that the use of formal logic in our proposed framework will make chemical classification criteria more transparent to humans and machines alike and will thus facilitate predictive and integrative bioactivity model development. PMID- 22221314 TI - Synthesis and characteristics of NH2-functionalized polymer films to align and immobilize DNA molecules. AB - We developed a method to use NH2-functionalized polymer films to align and immobilize DNA molecules on a Si substrate. The plasma-polymerized cyclohexane film was deposited on the Si substrate according to the radio frequency plasma enhanced chemical vapor deposition method using a single molecular precursor, and it was then treated by the dielectric barrier discharge method in a nitrogen environment under atmospheric pressure. Changes in the chemistry of the surface functional groups were studied using X-ray photoelectron spectroscopy and Fourier transformed infrared spectroscopy. The wettability of the surfaces was examined using dynamic contact angle measurements, and the surface morphology was evaluated using atomic force microscopy.We utilized a tilting method to align lambda-DNA molecules that were immobilized by the electrostatic interaction between the amine groups in NH2-functionalized polymer films and the phosphate groups in the DNA. The DNA was treated with positively charged gold nanoparticles to make a conductive nanowire that uses the DNA as a template. We observed that the NH2-functionalized polymer film was useful for aligning and immobilizing the DNA, and thus the DNA-templated nanowires. PMID- 22221315 TI - Characterization of thermally aged AlPO4-coated LiCoO2 thin films. AB - The electrochemical properties and stability during storage of pristine and AlPO4-coated LiCoO2 thin films were characterized. The wide and smooth surface of the thin film electrode might provide an opportunity for one to observe surface reactions with an electrolyte. The rate capability and cyclic performance of the LiCoO2 thin film were enhanced by AlPO4 surface coating. Based on secondary ion mass spectrometry analysis and scanning electron microscopy images of the surface, it was confirmed that the coating layer was successfully protected from the reactive electrolyte during storage at 90 degrees C. In contrast, the surface of the pristine sample was severely damaged after storage. PMID- 22221316 TI - Improvement in dielectric and mechanical performance of CaCu3.1Ti4O12.1 by addition of Al2O3 nanoparticles. AB - The properties of CaCu3.1Ti4O12.1 [CC3.1TO] ceramics with the addition of Al2O3 nanoparticles, prepared via a solid-state reaction technique, were investigated. The nanoparticle additive was found to inhibit grain growth with the average grain size decreasing from approximately 7.5 MUm for CC3.1TO to approximately 2.0 MUm for the unmodified samples, while the Knoop hardness value was found to improve with a maximum value of 9.8 GPa for the 1 vol.% Al2O3 sample. A very high dielectric constant > 60,000 with a low loss tangent (approximately 0.09) was observed for the 0.5 vol.% Al2O3 sample at 1 kHz and at room temperature. These data suggest that nanocomposites have a great potential for dielectric applications. PMID- 22221317 TI - Review article: the pathophysiological roles of the renin-angiotensin system in the gastrointestinal tract. AB - BACKGROUND: The renin-angiotensin system (RAS) is a homeostatic pathway widely known to regulate cardiovascular and renal physiology; however, little is known about its influence in gastrointestinal tissues. AIM: To elicit the anatomical distribution and physiological significance of the components of the RAS in the gastrointestinal tract. METHODS: An extensive online literature review including Pubmed and Medline. RESULTS: There is evidence for RAS involvement in gastrointestinal physiology and pathophysiology, with all the components required for autonomous regulation identified throughout the gastrointestinal tract. The RAS is implicated in the regulation of glucose, amino acid, fluid and electrolyte absorption and secretion, motility, inflammation, blood flow and possibly malignant disease within the gastrointestinal tract. Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. Given the ready availability of drugs that modify the RAS and their excellent safety profile, an opportunity exists for investigation of their possible therapeutic role in a variety of human gastrointestinal diseases. CONCLUSIONS: The gastrointestinal renin-angiotensin system appears to be intricately involved in a number of physiological processes, and provides a possible target for novel investigative and therapeutic approaches. PMID- 22221318 TI - The spectrum of anticonvulsant efficacy of retigabine (ezogabine) in animal models: implications for clinical use. AB - Retigabine [RTG (international nonproprietary name); ezogabine (EZG; U.S. adopted name)] is a first-in-class antiepileptic drug (AED) that reduces neuronal excitability by enhancing the activity of KCNQ (K(v)7) potassium (K(+)) channels. RTG/EZG has recently been approved by the European Medicines Agency and the U.S. Food and Drug Administration as adjunctive therapy in adults with partial-onset seizures. In this review we discuss the activity that RTG/EZG has demonstrated across a broad spectrum of in vitro/in vivo animal models of seizures, including generalized tonic-clonic, primary generalized (absence), and partial seizures, in addition to the compound's ability to resist and block the occurrence of seizures induced by a range of stimuli across different regions of the brain. The potency of RTG/EZG in models refractory to several conventional AEDs and the work done to assess antiepileptogenesis and neuroprotection are discussed. Studies that have evaluated the central nervous system side effects of RTG/EZG in animals are reviewed in order to compare these effects with adverse events observed in patients with epilepsy. Based on its demonstrated effect in a number of animal epilepsy models, the synergistic and additive activity of RTG/EZG with other AEDs supports its potential use in therapeutic combinations for different seizure types. The distinct mechanism of action of RTG/EZG from those of currently available AEDs, along with its broad preclinical activity, underscores the key role of KCNQ (K(v)7) K(+) channels in neuronal excitability, and further supports the potential efficacy of this unique molecule in the treatment of epilepsy. PMID- 22221319 TI - Visualization and identification of health space, based on personalized molecular phenotype and treatment response to relevant underlying biological processes. AB - BACKGROUND: Being able to visualize multivariate biological treatment effects can be insightful. However the axes in visualizations are often solely defined by variation and thus have no biological meaning. This makes the effects of treatment difficult to interpret. METHODS: A statistical visualization method is presented, which analyses and visualizes the effects of treatment in individual subjects. The visualization is based on predefined biological processes as determined by systems-biological datasets (metabolomics proteomics and transcriptomics). This allows one to evaluate biological effects depending on shifts of either groups or subjects in the space predefined by the axes, which illustrate specific biological processes. We built validated multivariate models for each axis to represent several biological processes. In this space each subject has his or her own score on each axis/process, indicating to which extent the treatment affects the related process. RESULTS: The health space model was applied to visualize the effects of a nutritional intervention, with the goal of applying diet to improve health. The model was therefore named the 'health space' model. The 36 study subjects received a 5-week dietary intervention containing several anti-inflammatory ingredients. Plasma concentrations of 79 proteins and 145 metabolites were quantified prior to and after treatment. The principal processes modulated by the intervention were oxidative stress, inflammation, and metabolism. These processes formed the axes of the 'health space'. The approach distinguished the treated and untreated groups, as well as two different response subgroups. One subgroup reacted mainly by modulating its metabolic stress profile, while a second subgroup showed a specific inflammatory and oxidative response to treatment. CONCLUSIONS: The 'health space' model allows visualization of multiple results and to interpret them. The model presents treatment group effects, subgroups and individual responses. PMID- 22221320 TI - Effects of pentacene-doped PEDOT:PSS as a hole-conducting layer on the performance characteristics of polymer photovoltaic cells. AB - We have investigated the effect of pentacene-doped poly(3,4 ethylenedioxythiophene:poly(4-styrenesulfonate) [PEDOT:PSS] films as a hole conducting layer on the performance of polymer photovoltaic cells. By increasing the amount of pentacene and the annealing temperature of pentacene-doped PEDOT:PSS layer, the changes of performance characteristics were evaluated. Pentacene-doped PEDOT:PSS thin films were prepared by dissolving pentacene in 1 methyl-2-pyrrolidinone solvent and mixing with PEDOT:PSS. As the amount of pentacene in the PEDOT:PSS solution was increased, UV-visible transmittance also increased dramatically. By increasing the amount of pentacene in PEDOT:PSS films, dramatic decreases in both the work function and surface resistance were observed. However, the work function and surface resistance began to sharply increase above the doping amount of pentacene at 7.7 and 9.9 mg, respectively. As the annealing temperature was increased, the surface roughness of pentacene-doped PEDOT:PSS films also increased, leading to the formation of PEDOT:PSS aggregates. The films of pentacene-doped PEDOT:PSS were characterized by AFM, SEM, UV-visible transmittance, surface analyzer, surface resistance, and photovoltaic response analysis. PMID- 22221321 TI - Novel serum and urine markers for pediatric appendicitis. AB - OBJECTIVES: The objective was to describe the association between two novel biomarkers, calprotectin and leucine-rich alpha glycoprotein-1 (LRG), and appendicitis in children. METHODS: This was a prospective, cross-sectional study of children 3 to 18 years old presenting to a pediatric emergency department (ED) with possible appendicitis. Blood and urine samples were assayed for calprotectin and LRG via enzyme-linked immunosorbent assay (ELISA). Final diagnosis was determined by histopathology or telephone follow-up. Biomarker levels were compared for subjects with and without appendicitis. Recursive partitioning was used to identify thresholds that predicted appendicitis. RESULTS: Of 176 subjects, mean (+/-SD) age was 11.6 (+/-4.0) years and 52% were male. Fifty-eight patients (34%) were diagnosed with appendicitis. Median plasma calprotectin, serum LRG, and urine LRG levels were higher in appendicitis versus nonappendicitis (p < 0.008). When stratified by perforation status, median plasma calprotectin and serum LRG levels were higher in nonperforated appendicitis versus nonappendicitis (p < 0.01). Median serum LRG, urine LRG, and plasma calprotectin levels were higher in perforated appendicitis compared to nonperforated appendicitis (p < 0.05). Urine calprotectin did not differ among groups. A serum LRG < 40,150 ng/mL, a urine LRG < 42 ng/mL, and a plasma calprotectin < 159 ng/mL, each provided a sensitivity and negative predictive value of 100% to identify children at low risk for appendicitis, but with specificities ranging from 23% to 35%. The standard white blood cell (WBC) count achieved 100% sensitivity at a higher specificity than both novel biomarkers. CONCLUSIONS: Plasma calprotectin and serum/urine LRG are elevated in pediatric appendicitis. No individual marker performed as well as the WBC count. PMID- 22221322 TI - Demographic and behavioural profiles of patients with common oral mucosal lesions by a homogeneity analysis. AB - OBJECTIVE: The aim of this study is to assess the main oral mucosal lesions (OMLs) within a hospital base and to provide an anamnestic, diagnostic model based on homogeneity analysis of some variables. METHODS: The demographic and behavioural data (i.e. gender, age, smoking status, alcohol consumption and therapeutic drug usage) of 1753 patients with at least one OML were considered. Multiple correspondence analysis (MCA) and multivariate tests of the simultaneous marginal homogeneity hypothesis (SMH) were used to analyse the evidence of any differences between the demographic and behavioural profiles relating to OMLs diagnoses. Statistical significance of P < 0.05 was chosen. RESULTS: With respect to the model used, patients affected by oral squamous cell carcinoma (n = 65; 3.5%) and oral leukoplakia (n = 73; 4.0%) differed significantly for demographic and behavioural characteristics analyzed, in particular with respect to gender (63.9%vs 50.1% males) and alcohol consumption (29.1%vs 12.1%). Patients affected by burning mouth syndrome (n = 134; 7.3%) and bisphosphonate-related osteonecrosis of the jaw (n = 40; 2.2%) differed significantly for chronic use of drugs (45.7%vs 71.6%). Finally, patients with halitosis (n = 60; 3.3%) and recurrent aphthous stomatitis (n = 103; 5.6%) showed similar profile, mainly in terms of men (47.6%), drinker (4.8%), drug user (34.9%), >=60 years old (20.8%) and smoker (6.4%). CONCLUSION: Knowledge of some similarities in patients' profile could help in positing the likely presence of OML when making diagnosis process by either general physicians or dentists, especially those without extensive experience in the field of oral medicine. PMID- 22221324 TI - Antioxidant content and activity of the Indian fresh-water pearl mussel in the prevention of arthritis in an experimental animal model. AB - The flesh of the Indian fresh-water mussel, Lamellidens marginalis (LM; Lamarck, 1819), is the byproduct of pearl culture and a cheap protein source. The present study investigated the antioxidant content of this ethnomedicinally cited species to outline its importance in food security and disease prevention. LM was found to be rich in polyphenol antioxidants with good correlation with its reducing capacity. LM also showed a significant free-radical-scavenging activity, H(2)O(2) scavenging activity and Fe-chelating activity. To study the effect of this dietary antioxidant against oxidative stress, we took inflammatory arthritis as a model. LM-treated arthritis rats showed a higher antioxidant defence system with elevated superoxide dismutase, total thiol, glutathione S transferase, glutathione peroxidase, total antioxidant status and catalase concentration of haemolysate. Oxidative stress markers like serum thiobarbituric acid-reacting substances, methyl glyoxal, NO and total oxidant status levels were decreased in LM-treated arthritis rats. Hence, the dietary antioxidants of LM were found to be effective in the prevention of oxidative stress in inflammatory arthritis. In conclusion, LM, the cash-crop byproduct, provides a rare opportunity for income and nutrition, not only by providing cheap and available energy, protein and dietary factors, but also by providing antioxidants effective against chronic inflammatory disease. PMID- 22221325 TI - Status of two species of lac insects in the genus Kerria from China based on morphological, cellular, and molecular evidence. AB - The taxonomic status of the Chinese lac insects Kerria yunnanensis (Ou and Hong) (Hemiptera: Kerridae) and K. ruralis (Wang, Yao, Teiu and Liang) were analyzed in this paper by comparing morphological, cellular, and molecular data. Cladistic analysis showed K. yunnanensis and K. ruralis to be distinct from other Kerria species such as K. lacca and K. chinensis. The karyotype of K. yunnanensis was 3A and the chromosome structure was K = 6 m + 2 sm + 10T, while in K. ruralis the karyotype was 3B and the chromosome structure was K = 8 m + 10 T. Kerria ruralis and K. yunnanensis had the closest relationship among species in the genus as they had the most similar karyotype homology. Based on the karyotype analysis, K. sindica and K. lacca formed a sister group with K. ruralis and K. yunnanensis. Kerria pusana and K. nepalensis were clustered as a sister branch, indicating the close relationship of these taxa. The karyotype of K. chinensis was however, different from the other six species and formed a separate branch. RAPD analysis also showed that K. yunnanensis and K. ruralis had distinct differences from other species of Kerria, although they did not form sister taxa. Molecular analysis based on the EF1alpha gene using ML, MP, and Mr. Bayes' methods indicated that seven species of lac insects cluster in two major groups. In group 1, K. sindica and K. lacca formed a sister clade and were primitive members of the genus. In group 2, K. chinensis formed the earliest diverging branch followed by K. ruralis. Kerria yunnanensis was the next to diverge followed by the cluster containing K. pusana and K. nepalensis. Hybridization testing showed that crosses neither between K. yunnanensis and K. sindica, nor between K. yunnanensis and K. lacca could produce first generation larvae. This was indicative that K. yunnanensis had a distant genetic relationship from the other species. Morphological, cellular, molecular, and hybridization results confirmed the independent status of the Chinese endemic species K. yunnanensis and K. ruralis. Kerria ruralis was genetically closely related to K. yunnanensis, but relatively far from K. lacca. The main commercial species in China was K. yunnanensis, while in Thailand it was K. chinensis. The commercial species in Myanmar included K. nepalensis and K. pusana, the latter being most widely used in lac production. PMID- 22221326 TI - Vitamin A and Alzheimer's disease. AB - The deposition of amyloid beta-protein (Abeta) in the brain is an invariant feature of Alzheimer's disease (AD). Vitamin A, which has been traditionally considered an anti-oxidant compound, plays a role in maintaining higher function in the central nervous system. Plasma or cerebrospinal fluid concentrations of vitamin A and beta-carotene have been reported to be lower in AD patients, and these vitamins have been clinically shown to slow the progression of dementia. Vitamin A (retinol, retinal and retinoic acid) and beta-carotene have been shown in in vitro studies to inhibit the formation, extension and destabilizing effects of beta-amyloid fibrils. Recently, the inhibition of the oligomerization of Abeta has been suggested as a possible therapeutic target for the treatment of AD. We have recently shown the inhibitory effects of vitamin A and beta-carotene on the oligomerization of Abeta40 and Abeta42 in vitro. In previous in vivo studies, intraperitoneal injections of vitamin A decreased brain Abeta deposition and tau phosphorylation in transgenic mouse models of AD, attenuated neuronal degeneration, and improved spatial learning and memory. Thus, vitamin A and beta carotene could be key molecules for the prevention and therapy of AD. PMID- 22221327 TI - Expression of mitochondrial gene fragments within the tapetum induce male sterility by limiting the biogenesis of the respiratory machinery in transgenic tobacco. AB - Plant mitochondrial genomes (mtDNAs) are large and undergo frequent recombination events. A common phenotype that emerges as a consequence of altered mtDNA structure is cytoplasmic-male sterility (CMS). The molecular basis for CMS remains unclear, but it seems logical that altered respiration activities would result in reduced pollen production. Analysis of tobacco (Nicotiana tabacum) mtDNAs indicated that CMS-associated loci often contain fragments of known organellar genes. These may assemble with organellar complexes and thereby interfere with normal respiratory functions. Here, we analyzed whether the expression of truncated fragments of mitochondrial genes (i.e. atp4, cox1 and rps3) may induce male sterility by limiting the biogenesis of the respiratory machinery. cDNA fragments corresponding to atp4f, cox1f and rps3f were cloned in frame to a mitochondrial localization signal and a C-termini HA-tag under a tapetum-specific promoter and introduced to tobacco plants by Agrobacterium mediated transformation. The constructs were then analyzed for their effect on mitochondrial activity and pollen fertility. Atp4f, Cox1f and Rps3f plants demonstrated male sterility phenotypes, which were tightly correlated with the expression of the recombinant fragments in the floral meristem. Fractionation of native organellar extracts showed that the recombinant ATP4f-HA, COX1f-HA and RPS3f-HA proteins are found in large membrane-associated particles. Analysis of the respiratory activities and protein profiles indicated that organellar complex I was altered in Atp4f, Cox1f and Rps3f plants. PMID- 22221328 TI - First clinical trial of cancer vaccine therapy with artificially synthesized helper/ killer-hybrid epitope long peptide of MAGE-A4 cancer antigen. AB - A patient with pulmonary metastasis of colon cancer was treated with artificially synthesized helper/killer-hybrid epitope long peptide (H/K-HELP) of MAGE-A4 cancer antigen. The patient was vaccinated with MAGE-A4-H/K-HELP combined with OK432 and Montanide ISA-51. There were no severe side-effects except for a skin reaction at the injection site. MAGE-A4-H/K-HELP induced MAGE-A4-specific Th1 and Tc1 immune responses and the production of MAGE-A4-specific complement-fixing IgG antibodies. Tumor growth and carcinoembryonic antigen tumor marker were significantly decreased in the final diagnosis. This is the first report that artificially synthesized MAGE-A4-H/K-HELP induces Th1-dependent cellular and humoral immune responses in a human cancer patient. PMID- 22221323 TI - Speciation in the Rana chensinensis species complex and its relationship to the uplift of the Qinghai-Tibetan Plateau. AB - Speciation remains a fundamental issue in biology. Herein, we report an investigation into speciation in the Rana chensinensis species complex using DNA sequence data from one mitochondrial and five nuclear genes. A phylogenetic analysis of the data revealed four major clades in the complex, and each of them was found to likely represent a species, including one cryptic species. Ecological niche models were generated from 19 climatic variables for three of the four major clades, which were represented by widespread sampling, including R. chensinensis, Rana kukunoris and the potential cryptic species. Each clade is associated with a unique ecological unit, and this indicates that ecological divergence probably drove speciation. Ecological divergence is likely related to the late Cenozoic orogenesis of the Qinghai-Tibetan Plateau. In addition, gene flow between species was detected but only in peripheral portions of the ranges of the four major clades, thus likely had little influence on the speciation processes. Discordances between mitochondrial and nuclear genes were also found; the nominal species, R. chensinensis, contains multiple maternal clades, suggesting potential mitochondrial introgression between R. chensinensis and R. kukunoris. PMID- 22221331 TI - Patient satisfaction with residents vs attending following fluoroscopy-guided pain injections. AB - OBJECTIVE: Patient satisfaction has been the object of interest in health care for some time and is now increasingly used as the basis for quality management and improvement. This study compares patient satisfaction between residents and attending in a pain clinic setting following fluoroscopy-guided steroid injections. DESIGN: This is a retrospective cohort design study. SETTING: The study was performed at an academic university pain management center. SUBJECTS: A total of 242 patients (119 female and 123 male) presenting with low back pain were evaluated and offered fluoroscopically guided steroid injections as part of a conservative care treatment plan. INTERVENTIONS: All injections were performed consecutively over a 4-month period by one attending and three senior residents (two anesthesia and one psychiatry resident). A staff member specifically asked each participant about their satisfaction following the procedure. Answers were documented as "Expected,""Better," or "Worse" than expected. OUTCOME MEASURES: Two main outcome measures were recorded: 1) table and fluoroscopy time for residents and attending, and 2) patient satisfaction through subjective reporting. RESULTS: Overall, residents had longer mean table time and mean fluoroscopy time as compared with the attending physician (P < 0.05). Patients treated by residents were more often likely to rate their experience as "worse" compared with those treated by the attending (P < 0.05). Otherwise, the proportion of patients rating their experience "as expected" or "better" was not significantly different statistically between the two groups. In addition, as table time increased, satisfaction level decreased in both resident and attending groups. CONCLUSION: Patients treated by residents are more likely to rate their experience as worse compared with the attending. However, majority of patients in both groups were satisfied in that they perceived their procedure as expected or better than expected. PMID- 22221334 TI - Albuminuria is an independent risk factor of erectile dysfunction in men with type 2 diabetes. AB - INTRODUCTION: Erectile dysfunction (ED) is a frequent comorbidity in men with diabetes and is frequently overlooked in routine clinical evaluation. Albuminuria, a marker of endothelial dysfunction, may link to ED. AIM: The study evaluated the association of albuminuria with risk factors of ED in men with type 2 diabetes. METHODS: The diagnosis of ED was based on a self-administered questionnaire containing Sexual Health Inventory for Men. Urinary albumin excretion rate was determined by urine albumin-to-creatinine ratio (UACR) in spot urine. MAIN OUTCOME MEASURES: The clinical variables and diabetes-associated complications to risk of ED were evaluated. RESULTS: Of 666 patients who received the questionnaire, 455 patients completed it. Among them, 82.0%, 28.1%, and 35.8% reported having ED, severe ED, and albuminuria, respectively. The UACR level was significantly higher in ED (0.20 +/- 0.83) and severe ED (0.34 +/- 1.18) groups compared with non-ED group (0.07 +/- 0.33). The presence of albuminuria adjusted for age and duration of diabetes was significantly associated with ED (OR = 2.76), and macroalbuminuria has stronger impact (OR = 4.49) than microalbuminuria (OR = 2.48). The other associated risk factors included hypertension, higher level of systolic blood pressure, lower level of serum hemoglobin, and estimated glomerular filtration rate. The presence of retinopathy, neuropathy, insulin therapy, using calcium channel blocker, and higher level of HbA1c further correlated with severe ED. Men with severe ED have higher prevalence of subnormal testosterone than the no ED patients. The high sensitivity C-reactive protein level, and the presence of metabolic syndrome were not risk factors. The 211 nonrespondents to the questionnaire had similar or worse risk profiles compared with the ED patients. CONCLUSION: Albuminuria is an important independent risk factor of ED in men with diabetes after adjustment of age and diabetes mellitus duration. Identification and control of albuminuria and other associated risk factors might play a role in the prevention or reversal of ED. PMID- 22221333 TI - Identification and characterization of Rhodopseudomonas palustris TIE-1 hopanoid biosynthesis mutants. AB - Hopanes preserved in both modern and ancient sediments are recognized as the molecular fossils of bacteriohopanepolyols, pentacyclic hopanoid lipids. Based on the phylogenetic distribution of hopanoid production by extant bacteria, hopanes have been used as indicators of specific bacterial groups and/or their metabolisms. However, our ability to interpret them ultimately depends on understanding the physiological roles of hopanoids in modern bacteria. Toward this end, we set out to identify genes required for hopanoid biosynthesis in the anoxygenic phototroph Rhodopseudomonas palustris TIE-1 to enable selective control of hopanoid production. We attempted to delete 17 genes within a putative hopanoid biosynthetic gene cluster to determine their role, if any, in hopanoid biosynthesis. Two genes, hpnH and hpnG, are required to produce both bacteriohopanetetrol and aminobacteriohopanetriol, whereas a third gene, hpnO, is required only for aminobacteriohopanetriol production. None of the genes in this cluster are required to exclusively synthesize bacteriohopanetetrol, indicating that at least one other hopanoid biosynthesis gene is located elsewhere on the chromosome. Physiological studies with the different deletion mutants demonstrated that unmethylated and C(30) hopanoids are sufficient to maintain cytoplasmic but not outer membrane integrity. These results imply that hopanoid modifications, including methylation of the A-ring and the addition of a polar head group, may have biologic functions beyond playing a role in membrane permeability. PMID- 22221336 TI - The use of long-term on-line turbidity measurements for the calculation of urban stormwater pollutant concentrations, loads, pollutographs and intra-event fluxes. AB - This paper presents one of the largest databases on the quality of urban wet weather discharges measured since the development of continuous in-sewer water quality sensors in the late 1990s. Five years of continuous turbidity measurements enabled the validation of 263 and 239 rainfall events, respectively on two experimental catchments in Lyon (France), Chassieu (185 ha separate sewer) and Ecully (245 ha combined sewer). Except for high rainfall events of summer and second half of winter, analysis of database representativeness showed that all seasons were relatively well represented. As a first analysis of the database, traditional tools used in the urban drainage field were applied to assess: i) statistics and analysis of distributions of TSS and COD events loads and event mean concentrations (EMCs) and ii) the correlations between these statistics and events characteristics and iii) M(V) curves describing the intra-event mass distribution. Results showed that: i) EMCs and loads were approximately log normally distributed, with a clear impact from wastewater contribution in Ecully, ii) EMCs are not correlated with storm event characteristics, whereas loads have shown significant correlation with key storm event variables such as total event volume, rainfall depth, maximum rainfall intensity and discharge and iii) M(V) curves dynamic could be classified in three categories, however with no clear correlation with storm event characteristics. The visual analysis of continuous time series of TSS and COD pollutographs, derived from turbidity time series showed that event pollutographs were highly variable, due to complex interacting processes during and between events, and suggests that further progress in knowledge and modelling of urban wet weather pollutant loads and pollutographs should be based on more detailed analyses of continuous time series rather, than on the traditional single event approach. PMID- 22221337 TI - Synergistic effect of the sequential use of UV irradiation and chlorine to disinfect reclaimed water. AB - The effectiveness of UV and chlorination, used individually and sequentially, was investigated in killing pathogenic microorganisms and inhibiting the formation of disinfection by-products in two different municipal wastewaters for the source water of reclaimed water, which were from a microfilter (W1) and membrane bioreactor (W2) respectively. Heterotrophic plate count (HPC), total bacteria count (TBC), and total coliform (TC) were selected to evaluate the efficiency of different disinfection processes. UV inactivation of the three bacteria followed first-order kinetics in W1 wastewater, but in W2 wastewater, the UV dose-response curve trailed beyond approximately 10 mJ/cm2 UV. The higher number of particles in the W2 might have protected the bacteria against UV damage, as UV light alone was not effective in killing HPC in W2 wastewater with higher turbidity. However, chlorine was more effective in W2 than in W1 for the three bacteria inactivation owing to the greater formation of inorganic and organic chloramines in W1 wastewater. Complete inactivation of HPC in W1 wastewater required a chlorine dose higher than 5.5 mg/L, whereas 4.5 mg/L chlorine gave the equivalent result in W2 wastewater. In contrast, sequential UV and chlorine treatment produced a synergistic effect in both wastewater systems and was the most effective option for complete removal of all three bacteria. UV disinfection lowered the required chlorine dose in W1, but not in W2, because of the higher chlorine consumption in W2 wastewater. However, UV irradiation decreased total trihalomethane formation during chlorination in both wastewaters. PMID- 22221338 TI - Cohesiveness and hydrodynamic properties of young drinking water biofilms. AB - Drinking water biofilms are complex microbial systems mainly composed of clusters of different size and age. Atomic force microscopy (AFM) measurements were performed on 4, 8 and 12 weeks old biofilms in order to quantify the mechanical detachment shear stress of the clusters, to estimate the biofilm entanglement rate xi. This AFM approach showed that the removal of the clusters occurred generally for mechanical shear stress of about 100 kPa only for clusters volumes greater than 200 MUm3. This value appears 1000 times higher than hydrodynamic shear stress technically available meaning that the cleaning of pipe surfaces by water flushing remains always incomplete. To predict hydrodynamic detachment of biofilm clusters, a theoretical model has been developed regarding the averaging of elastic and viscous stresses in the cluster and by including the entanglement rate xi. The results highlighted a slight increase of the detachment shear stress with age and also the dependence between the posting of clusters and their volume. Indeed, the experimental values of xi allow predicting biofilm hydrodynamic detachment with same order of magnitude than was what reported in the literature. The apparent discrepancy between the mechanical and the hydrodynamic detachment is mainly due to the fact that AFM mechanical experiments are related to the clusters local properties whereas hydrodynamic measurements reflected the global properties of the whole biofilm. PMID- 22221339 TI - Porphyrin nanofiber patterning by air/water interfacial assembly: effect of molecular structure, surface pressure, and ionic liquid doped subphase. AB - Porphyrin nanofiber patterning was generated by air/water interfacial assembly. The air/water interfacial aggregation behavior of two prophyrins, both of which contain two hydrophobic alkyl chains and two carboxylic acid substituent groups at different positions, was investigated using UV spectra, FT-IR spectra, and AFM measurements on the corresponding transferred films. The porphyrin nanofiber patterning can only be produced on ionic liquid (IL) doped water subphases by the assembly of the building blocks with two carboxylic acids located at the para position (TPPA2b-A). The results suggest that the bulky cations of ionic liquids (ILs) can interact with the carboxylate of porphyrin electrostatically. The appropriate molecular geometries, ionic liquid (IL) doped water subphases, and relatively high surface pressures help the TPPA2b-A to form nanofiber patterns. PMID- 22221340 TI - Time-resolved small angle X-ray scattering study of sol-gel precursor solutions of lead zirconate titanate and zirconia. AB - The evolution of nanostructure in sol-gel derived lead zirconate titanate (PZT) and zirconia precursor sols at different hydrolysis ratios was investigated by small angle X-ray scattering (SAXS). The shape of the clusters in the zirconia sol could be described by the length-polydisperse cylindrical form factor. The zirconia-based clusters were characterized by a cross-sectional radius, r(0), of 0.28 nm and a practically monodisperse length of ca. 1.85 nm. These clusters were probably constructed of zirconia-related tetrameric building blocks. Similar cylindrical structural motifs were observed in PZT precursor sols with [H(2)O]/[Zr+Ti]=9.26 and 27.6, but the polydispersity in length was much higher. Clear scattering contributions from Ti and Pb centers were not detected, which was interpreted in terms of a homogeneous distribution of unbound lead ions in solution and the relatively low scattering intensity from any Ti-based clusters or oligomers that may have been present in the sols. PMID- 22221341 TI - Facile controlled synthesis and growth mechanisms of flower-like and tubular MnO2 nanostructures by microwave-assisted hydrothermal method. AB - Birnessite flower-like and alpha-type tubular MnO(2) nanostructures were selectively synthesized through simple decomposition of KMnO(4) under hydrochloric acid condition by controlling reaction temperature using a microwave assisted hydrothermal method. The as-prepared samples were characterized in detail by various techniques including X-ray diffraction, field emission scanning electron microscopy, transmission electron microscopy, high-resolution transmission electron microscopy, Fourier transform-infrared spectroscopy, and Raman scattering spectroscopy. While the growth of flower-like birnessite-MnO(2) might follow a widely accepted Ostwald ripening process, we proposed a formation mechanism of the nanotubular alpha-MnO(2) based on our evidence, which was assembly of nanorods through an "oriented attachment" process. PMID- 22221342 TI - Hidden diversity in diatoms of Kenyan Lake Naivasha: a genetic approach detects temporal variation. AB - This study provides insights into the morphological and genetic diversity in diatoms occurring in core sediments from tropical lakes in Kenya. We developed a genetic survey technique specific for diatoms utilizing a short region (76-67 bp) of the ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit (rbcL) gene as genetic barcode. Our analyses (i) validated the use of rbcL as a barcoding marker for diatoms, applied to sediment samples, (ii) showed a significant correlation between the results obtained by morphological and molecular data and (iii) indicated temporal variation in diatom assemblages on the inter- and intra specific level. Diatom assemblages from a short core from Lake Naivasha show a drastic shift over the last 200 years, as littoral species (e.g. Navicula) are replaced by more planktonic ones (e.g. Aulacoseira). Within that same period, we detected periodic changes in the respective frequencies of distinct haplotype groups of Navicula, which coincide with wet and dry periods of Lake Naivasha between 1820 and 1938 AD. Our genetic analyses on historical lake sediments revealed inter- and intra-specific variation in diatoms, which is partially hidden behind single morphotypes. The occurrence of particular genetic lineages is probably correlated with environmental factors. PMID- 22221343 TI - Influence of oral conditions on colonization by highly toxigenic Staphylococcus aureus strains. AB - OBJECTIVES: As the oral cavity is regarded as a relevant site for Staphylococcus aureus colonization and interhuman transmission, this study aimed to investigate whether different oral conditions influence the rates of S. aureus oral carriage and genetic characters of S. aureus isolates. SUBJECTS AND METHODS: Staphylococcus aureus was searched in samples collected from cheek, gingival margin, and anterior nares of 45 healthy subjects, 27 periodontitis affected subjects, and 29 subjects with fixed prosthetic restorations. Isolates were screened for 17 genetic determinants, and Partial Least Square Discriminant Analysis was performed to evaluate whether specific characters correlated with oral condition or site of isolation. RESULTS: The three subject groups showed comparable nasal carriage rates but, both the periodontitis and prosthetic restoration groups showed significantly higher oral carriage rates, as compared to healthy subjects (P = 0.01 and 0.02, respectively). Moreover, periodontitis affected subjects hosted strains possessing a distinct genotypic and phenotypic background, characterized by the presence of a larger number of exotoxins encoding genes. CONCLUSIONS: These data confirm that the oral cavity is an important site of S. aureus colonization and demonstrate that conditions modifying the oral environment, as the presence of periodontitis and of fixed prosthetic restorations, promote S. aureus carriage and may favor the spread of more pathogenic strains. PMID- 22221345 TI - Importance of polyethylene thickness in total shoulder arthroplasty: a finite element analysis. AB - BACKGROUND: Articular surfaces reconstruction is essential in total shoulder arthroplasty. Because of the limited glenoid bone support, thin glenoid component could improve anatomical reconstruction, but adverse mechanical effects might appear. METHODS: With a numerical musculoskeletal shoulder model, we analysed and compared three values of thickness of a typical all-polyethylene glenoid component: 2, 4 (reference) and 6mm. A loaded movement of abduction in the scapular plane was simulated. We evaluated the humeral head translation, the muscle moment arms, the joint force, the articular contact pattern, and the polyethylene and cement stress. Findings Decreasing polyethylene thickness from 6 to 2mm slightly increased humeral head translation and muscle moment arms. This induced a small decreased of the joint reaction force, but important increase of stress within the polyethylene and the cement mantel. Interpretation The reference thickness of 4mm seems a good compromise to avoid stress concentration and joint stuffing. PMID- 22221344 TI - Gait asymmetry of transfemoral amputees using mechanical and microprocessor controlled prosthetic knees. AB - BACKGROUND: Amputees walk with an asymmetrical gait, which may lead to future musculoskeletal degenerative changes. The purpose of this study was to compare the gait asymmetry of active transfemoral amputees while using a passive mechanical knee joint or a microprocessor-controlled knee joint. METHODS: Objective 3D gait measurements were obtained in 15 subjects (12 men and 3 women; age 42, range 26-57). Research participants were longtime users of a mechanical prosthesis (mean 20 years, range 3-36 years). Joint symmetry was calculated using a novel method that includes the entire waveform throughout the gait cycle. FINDINGS: There was no significant difference in hip, knee and ankle kinematics symmetry when using the different knee prostheses. In contrast, the results demonstrated a significant improvement in lower extremity joint kinetics symmetry when using the microprocessor-controlled knee. INTERPRETATION: Use of the microprocessor-controlled knee joint resulted in improved gait symmetry. These improvements may lead to a reduction in the degenerative musculoskeletal changes often experienced by amputees. PMID- 22221347 TI - Scientific editors' report volume 74 December 31, 2011. PMID- 22221346 TI - The relationship between shift work, sleep, and cognition in career emergency physicians. AB - OBJECTIVES: The 24-hour physician coverage of the emergency department (ED) requires shift work, which can result in desynchronosis and cognitive decline. We measured changes in cognition and sleep disturbance in attending emergency physicians (EPs) before and after day and overnight shifts. METHODS: Thirteen EPs were tested before and after day and overnight shifts using the Paced Auditory Serial Addition Test (PASAT), the University of Southern California Repeatable Episodic Memory Test (REMT), the Trail Making Test (TMT), and the Stroop Color Word Test. Sleep quality and fatigue were assessed using the Pittsburgh Sleep Quality Index (PSQI) and Chalder Fatigue Questionnaire (CFQ). Saliva samples were collected from each physician immediately before and after day shifts and night shifts for neurohormonal assays. RESULTS: Significantly fewer words were recalled on the REMT after both day (-2.4, 95% confidence interval [CI] = -4.4 to -0.4) and overnight shifts (-4.6, 95% CI = -6.4 to -2.8). There was a significant postshift increase in words recalled from the last third of the REMT list after overnight shifts (6.6, 95% CI = 2.8 to 10.4). Sleep quality was worse in EPs (mean PSQI = 4.8, SD +/- 2.5) compared to the normal population, with 31% of subjects reporting poor sleep quality. Postshift fatigue was correlated with the perceived difficulty of the shift. Salivary cortisol and melatonin demonstrated diurnal variation consistent with normal circadian rhythms. Morning cortisol peak was decreased or delayed in samples from physicians after a night shift. CONCLUSIONS: These data indicate that short-term memory appears to decline after day and overnight shifts and confirms the high incidence of disturbed sleep in this population. PMID- 22221348 TI - Impact factors and the journal of food protection. PMID- 22221349 TI - Soil solarization reduces Escherichia coli O157:H7 and total Escherichia coli on cattle feedlot pen surfaces. AB - Feedlot pen soil is a source for transmission of Escherichia coli O157:H7, and therefore a target for preharvest strategies to reduce this pathogen in cattle. The objective of this study was to determine the ability of soil solarization to reduce E. coli O157:H7 in feedlot surface material (FSM). A feedlot pen was identified in which naturally occurring E. coli O157:H7 was prevalent and evenly distributed in the FSM. Forty plots 3 by 3 m were randomly assigned such that five plots of each of the solarization times of 0, 1, 2, 3, 4, 6, 8, and 10 weeks were examined. Temperature loggers were placed 7.5 cm below the surface of each plot, and plots to be solarized were covered with clear 6-mil polyethylene. At each sampling time, five FSM samples were collected from each of five solarized and five unsolarized plots. E. coli concentrations and E. coli O157:H7 presence by immunomagnetic separation and plating were determined for each FSM sample. Initial percentages of E. coli O157:H7-positive samples in control and solarized FSM were 84 and 80%, respectively, and did not differ (P > 0.05). E. coli O157:H7 was no longer detectable by 8 weeks of solarization, but was still detected in unsolarized FSM at 10 weeks. The average initial concentration of E. coli in FSM was 5.56 log CFU/g and did not differ between treatments (P > 0.05). There was a 2.0-log decrease of E. coli after 1 week of solarization, and a >3.0 log reduction of E. coli by week 6 of solarization (P, 0.05). E. coli levels remained unchanged in unsolarized FSM (P > 0.05). Daily peak FSM temperatures were on average 8.7 degrees C higher for solarized FSM compared with unsolarized FSM, and reached temperatures as high as 57 degrees C. Because soil solarization reduces E. coli O157:H7, this technique may be useful for reduction of persistence and transmission of this pathogen in cattle production, in addition to remediation of E. coli O157:H7-contaminated soil used to grow food crops. PMID- 22221350 TI - Investigation of chemical rinses suitable for very small meat plants to reduce pathogens on beef surfaces. AB - Numerous antimicrobial interventions are capable of reducing the prevalence of harmful bacteria on raw meat products. There is a need to identify effective and inexpensive antimicrobial interventions that could, in practice, be used in very small meat plants because of limited financial, space, and labor resources. Eight antimicrobial compounds (acetic acid, citric acid, lactic acid, peroxyacetic acid, acidified sodium chlorite, chlorine dioxide, sodium hypochlorite, and aqueous ozone) were applied at various concentrations with small, hand-held spraying equipment, and bactericidal effectiveness was examined. Beef plate pieces were inoculated with fecal slurry containing a pathogen cocktail (Escherichia coli O157:H7, Salmonella Typhimurium, Campylobacter coli, and Campylobacter jejuni) and natural populations of aerobic plate counts, coliforms, and E. coli. Antimicrobial solutions were applied to beef surfaces via a portable, pressurized hand-held spray tank, and treated surfaces were subjected to appropriate methods for the enumeration and isolation of pathogens and hygiene indicators. Relative antimicrobial effectiveness was determined (from greatest to least): (i) organic acids, (ii) peroxyacetic acid, (iii) chlorinated compounds, and (iv) aqueous ozone. Using the equipment described, a 2% lactic acid rinse provided 3.5- to 6.4-log CFU/cm(2) reductions across all bacterial populations studied. Conversely, aqueous ozone yielded 0.02 to 2.9-log CFU/cm(2) reductions in pathogens and hygiene indicators, and did not differ significantly from a control tap water rinse (P = 0.055 to 0.731). This 2% lactic acid rinse will be subsequently combined with a previously described water wash to create a multistep antimicrobial intervention that will be examined under laboratory conditions and validated in very small meat plants. PMID- 22221351 TI - Treatment of raw poultry with nonthermal dielectric barrier discharge plasma to reduce Campylobacter jejuni and Salmonella enterica. AB - Nonthermal plasma has been shown to be effective in reducing pathogens on the surface of a range of fresh produce products. The research presented here investigated the effectiveness of nonthermal dielectric barrier discharge plasma on Salmonella enterica and Campylobacter jejuni inoculated onto the surface of boneless skinless chicken breast and chicken thigh with skin. Chicken samples were inoculated with antibiotic-resistant strains of S. enterica and C. jejuni at levels of 10(1) to 10(4) CFU and exposed to plasma for a range of time points (0 to 180 s in 15-s intervals). Surviving antibiotic-resistant pathogens were recovered and counted on appropriate agar. In order to determine the effect of plasma on background microflora, noninoculated skinless chicken breast and thighs with skin were exposed to air plasma at ambient pressure. Treatment with plasma resulted in elimination of low levels (10(1) CFU) of both S. enterica and C. jejuni on chicken breasts and C. jejuni from chicken skin, but viable S. enterica cells remained on chicken skin even after 20 s of exposure to plasma. Inoculum levels of 10(2), 10(3), and 10(4) CFU of S. enterica on chicken breast and chicken skin resulted in maximum reduction levels of 1.85, 2.61, and 2.54 log, respectively, on chicken breast and 1.25, 1.08, and 1.31 log, respectively, on chicken skin following 3 min of plasma exposure. Inoculum levels of 10(2), 10(3), and 10(4) CFU of C. jejuni on chicken breast and chicken skin resulted in maximum reduction levels of 1.65, 2.45, and 2.45 log, respectively, on chicken breast and 1.42, 1.87, and 3.11 log, respectively, on chicken skin following 3 min of plasma exposure. Plasma exposure for 30 s reduced background microflora on breast and skin by an average of 0.85 and 0.21 log, respectively. This research demonstrates the feasibility of nonthermal dielectric barrier discharge plasma as an intervention to help reduce foodborne pathogens on the surface of raw poultry. PMID- 22221352 TI - Comparison of destructive and nondestructive sampling techniques of retail chicken carcasses for enumeration of hygiene indicator microorganisms. AB - The type of sampling technique used to obtain food samples is fundamental to the success of microbiological analysis. Destructive and nondestructive techniques, such as tissue excision and rinsing, respectively, are widely employed in obtaining samples from chicken carcasses. In this study, four sampling techniques used for chicken carcasses were compared to evaluate their performances in the enumeration of hygiene indicator microorganisms. Sixty fresh chicken carcasses were sampled by rinsing, tissue excision, superficial swabbing, and skin excision. All samples were submitted for enumeration of mesophilic aerobes, Enterobacteriaceae, coliforms, and Escherichia coli. The results were compared to determine the statistical significance of differences and correlation (P < 0.05). Tissue excision provided the highest microbial counts compared with the other procedures, with significant differences obtained only for coliforms and E. coli (P < 0.05). Significant correlations (P < 0.05) were observed for all the sampling techniques evaluated for most of the hygiene indicators. Despite presenting a higher recovery ability, tissue excision did not present significant differences for microorganism enumeration compared with other nondestructive techniques, such as rinsing, indicating its adequacy for microbiological analysis of chicken carcasses. PMID- 22221353 TI - Campylobacter, Salmonella, Listeria monocytogenes, verotoxigenic Escherichia coli, and Escherichia coli prevalence, enumeration, and subtypes on retail chicken breasts with and without skin. AB - This study examined the prevalence, counts, and subtypes of Campylobacter, Salmonella, Listeria monocytogenes, verotoxigenic Escherichia coli (VTEC), and E. coli on raw retail chicken breast with the skin on versus the skin off. From January to December 2007, 187 raw skin-on chicken breasts and 131 skin-off chicken breasts were collected from randomly selected retail grocery stores in the Region of Waterloo, Ontario, Canada. Campylobacter isolates were recovered from a higher proportion of the skin-off chicken breasts, 55 (42%) of 131, than of the skin-on chicken breasts tested, 55 (29%) of 187 (P = 0.023). There was no difference in the proportion of Salmonella isolates recovered from the two meat types (P = 0.715): 40 (31%) of 131 skin-off chicken breasts versus 61 (33%) of 187 skin-on chicken breasts. L. monocytogenes isolates were recovered from a statistically lower proportion of the skin-off chicken breasts, 15 (15%) of 99, than of the skin-on chicken breasts, 64 (34%) of 187 (P = 0.001). There was no difference in the proportion of E. coli isolates recovered from the skin-off chicken breasts, 33 (33%) of 99, than from the skin-on chicken breasts, 77 (41%) of 187 (P = 0.204). VTEC was detected on a single skin-off chicken breast. Campylobacter jejuni was the most frequent species isolated on both types of chicken meat: skin-on, 48 (87%) of 55, and skin-off, 51 (94%) of 54. Salmonella serotypes Kentucky and Heidelberg and L. monocytogenes serotype 1/2a were the most frequently detected serotypes from both skin-off and skin-on chicken breasts. Although there appeared to be a trend toward higher enumeration values of these pathogens and E. coli on the skin-on chicken, the differences did not exceed 1 log. This study suggested that skin-off chicken breast may represent a higher risk of consumer exposure to Campylobacter, a similar risk for Salmonella, VTEC, and E. coli, and a lower risk for L. monocytogenes than skin-on chicken breast. PMID- 22221354 TI - Prevalence and antimicrobial susceptibilities of Vibrio, salmonella, and Aeromonas isolates from various uncooked seafoods in Thailand. AB - Uncooked seafood samples were collected from open markets and supermarkets in Bangkok, Thailand, and were examined for the presence of Vibrio, Salmonella, and Aeromonas species from January to February 2008. From 120 samples, 272 bacterial isolates were identified through biochemical testing. Of all sea bass, shrimp, oyster, and blood cockle samples (30 of each) that were processed for culture, 114 (95%) samples had at least one detectable isolate of Vibrio, Salmonella, or Aeromonas, leaving only 6 (5%) samples free of them. All oyster sample (100%) had at least one pathogen, followed by sea bass (97%), blood cockles (97%), and shrimp (90%). Overall, 111 (92%) of all samples had detectable Vibrio spp., 32 (27%) had detectable Aeromonas spp., and 25 (21%) had detectable Salmonella enterica. There was no overall difference between positive samples collected from fresh markets versus supermarkets (relative risk, 0.97; 95% CI, 0.89 to 1.05). Resistance to ampicillin among isolated pathogens was relatively high (56%), while resistance to 12 other antibiotics, including azithromycin, ciprofloxacin, and trimethoprim-sulfamethoxazole, was relatively low (0, 0, and 3%, respectively). Study results indicate that uncooked seafood in Bangkok, Thailand, commonly harbors enteric pathogens and that consumption of uncooked seafood should be avoided to reduce foodborne illnesses. PMID- 22221355 TI - Evaluating lethality of beef roast cooking treatments against Escherichia coli O157:H7. AB - Added salt, seasonings, and phosphates, along with slow- and/or low-temperature cooking impart desirable characteristics to whole-muscle beef, but might enhance Escherichia coli O157:H7 survival. We investigated the effects of added salt, seasoning, and phosphates on E. coli O157:H7 thermotolerance in ground beef, compared E. coli O157:H7 thermotolerance in seasoned roasts and ground beef, and evaluated ground beef-derived D- and z-values for predicting destruction of E. coli O157:H7 in whole-muscle beef cooking. Inoculated seasoned and unseasoned ground beef was heated at constant temperatures of 54.4, 60.0, and 65.5 degrees C to determine D- and z-values, and E. coli O157:H7 survival was monitored in seasoned ground beef during simulated slow cooking. Inoculated, seasoned whole muscle beef roasts were slow cooked in a commercial smokehouse, and experimentally determined lethality was compared with predicted process lethality. Adding 5% seasoning significantly decreased E. coli O157:H7 thermotolerance in ground beef at 54.4 degrees C, but not at 60 or 65.5 degrees C. Under nonisothermal conditions, E. coli O157:H7 thermotolerance was greater in seasoned whole-muscle beef than in seasoned ground beef. Meeting U.S. Government (U.S. Department of Agriculture, Food Safety and Inspection Service, 1999, Appendix A) whole-muscle beef cooking guidance, which targets Salmonella destruction, would not ensure >=6.5-log CFU/g reduction of E. coli O157:H7 in ground beef systems, but generally ensured $ 6.5-log CFU/g reduction of this pathogen in seasoned whole-muscle beef. Calculations based on D- and z-values obtained from isothermal ground beef studies increasingly overestimated destruction of E. coli O157:H7 in commercially cooked whole-muscle beef as process severity increased, with a regression line equation of observed reduction = 0.299 (predicted reduction) + 1.4373. PMID- 22221356 TI - Fate of Shiga toxin-producing O157:H7 and non-O157:H7 Escherichia coli cells within blade-tenderized beef steaks after cooking on a commercial open-flame gas grill. AB - We compared the fate of cells of both Shiga toxin-producing Escherichia coli O157:H7 (ECOH) and Shiga toxin-producing non-O157:H7 E. coli (STEC) in blade tenderized steaks after tenderization and cooking on a gas grill. In phase I, beef subprimal cuts were inoculated on the lean side with about 5.5 log CFU/g of a five-strain mixture of ECOH or STEC and then passed once through a mechanical blade tenderizer with the lean side facing up. In each of two trials, 10 core samples were removed from each of two tenderized subprimals and cut into six consecutive segments starting from the inoculated side. Ten total cores also were obtained from two nontenderized (control) subprimals, but only segment 1 (the topmost segment) was sampled. The levels of ECOH and STEC recovered from segment 1 were about 6.0 and 5.3 log CFU/g, respectively, for the control subprimals and about 5.7 and 5.0 log CFU/g, respectively, for the tenderized subprimals. However, both ECOH and STEC behaved similarly in terms of translocation, and cells of both pathogen cocktails were recovered from all six segments of the cores obtained from tenderized subprimals, albeit at lower levels in segments 2 to 6 than those found in segment 1. In phase II, steaks (2.54 and 3.81 cm thick) cut from tenderized subprimals were subsequently cooked (three steaks per treatment) on a commercial open-flame gas grill to internal temperatures of 48.9, 54.4, 60.0, 65.6, and 71.1 degrees C. Regardless of temperature or thickness, we observed 2.0- to 4.1-log and 1.5- to 4.5-log reductions in ECOH and STEC levels, respectively. Both ECOH and STEC behaved similarly in response to heat, in that cooking eliminated significant numbers of both pathogen types; however, some survivors were recovered due, presumably, to uneven heating of the blade tenderized steaks. PMID- 22221357 TI - Widespread listeriosis outbreak attributable to pasteurized cheese, which led to extensive cross-contamination affecting cheese retailers, Quebec, Canada, 2008. AB - A major Listeria monocytogenes outbreak occurred in the province of Quebec, Canada, in 2008, involving a strain of L. monocytogenes (LM P93) characterized by pulsed-field gel electrophoresis (PFGE) and associated with the consumption of pasteurized milk cheese. This report describes the results of the ensuing investigation. All individuals affected with LM P93 across the province were interviewed with a standardized questionnaire. Microbiological and environmental investigations were conducted by the Quebec's Food Inspection Branch of Ministere de l'Agriculture, des Pecheries et de l'Alimentation du Quebec among retailers and cheese plants involved in the outbreak. Between 8 June and 31 December 2008, 38 confirmed cases of LM P93 were reported to public health authorities, including 16 maternal-neonatal cases (14 pregnant women, and two babies born to asymptomatic mothers). The traceback of many brands of cheese that tested positive for LM P93 collected from retailers identified two cheese plants contaminated by L. monocytogenes strains on 3 and 4 September. PFGE profiles became available for both plants on 8 September, and confirmed that a single plant was associated with the outbreak. Products from these two plants were distributed to more than 300 retailers in the province, leading to extensive cross-contamination of retail stock. L. monocytogenes is ubiquitous, and contamination can occur subsequent to heat treatment, which usually precedes cheese production. Contaminated soft-textured cheese is particularly prone to bacterial growth. Ongoing regulatory and industry efforts are needed to decrease the presence of Listeria in foods, including pasteurized products. Retailers should be instructed about the risk of cross-contamination, even with soft pasteurized cheese and apply methods to avoid it. PMID- 22221358 TI - Incidence of Salmonella, Listeria monocytogenes, Escherichia coli O157:H7, and Staphylococcal enterotoxin in two types of Mexican fresh cheeses. AB - Handcrafted fresh cheeses are popular among consumers in Mexico. However, unsafe raw materials and inadequate food safety practices during cheese manufacture and preservation make them a potential public health risk. The incidence of Salmonella, Listeria, Escherichia coli O157:H7, and staphylococcal enterotoxin was analyzed in two types of fresh cheese (panela and adobera) commonly marketed in Mexico. A total of 200 samples, 100 panela and 100 adobera, were acquired from 100 wholesale milk product distributors who supply small retailers in the Guadalajara metropolitan area, Jalisco State, Mexico. Pathogens were identified using culture and immunoassay (miniVidas) methods. The presence of staphylococcal enterotoxin was determined by an immunoassay method. Of the 200 analyzed samples, 92 were positive for at least one of the pathogens. The incidence in the panela samples was 56%: 34% Salmonella, 16% E. coli O157:H7, and 6% L. monocytogenes. In the adobera samples, incidence was 36%: 20% Salmonella, 4% E. coli O157:H7, and 12% L. monocytogenes. Staphylococcal enterotoxin was not detected in any of the 200 samples. Choice of technique had no effect on detection of pathogen incidence, although the immunoassay method identified more Salmonella serotypes than the culture method. Handcrafted panela and adobera fresh cheeses in Mexico frequently contain pathogenic bacteria and therefore pose a public health risk. PMID- 22221359 TI - Development of a PCR protocol to detect aflatoxigenic molds in food products. AB - Aflatoxins are secondary metabolites produced mainly by Aspergillus species growing in foodstuffs. Because aflatoxins have important health effects, the detection of early contamination of foods by aflatoxigenic molds should be useful. In the present work, a reliable conventional PCR method for detecting aflatoxigenic molds of various species was developed. Fifty-six aflatoxigenic and nonaflatoxigenic strains commonly reported in foodstuffs were tested. Aflatoxin production was first confirmed by micellar electrokinetic capillary electrophoresis or/and high-pressure liquid chromatography-mass spectrometry. Based on the conserved regions of the O-methyltransferase gene (omt-1) involved in the aflatoxin biosynthetic pathway, six primer pairs were designed. With only the designed primer pair AFF1-AFR3, the expected PCR product (381 bp) was obtained in all of the tested aflatoxigenic strains of various species and genera. Amplification products were not obtained with this primer pair for any of the nonaflatoxigenic reference molds. However, an amplicon of 453 bp was obtained for all aflatoxigenic and nonaflatoxigenic mold reference strains with a PCR protocol based on the constitutive fungal beta-tubulin gene, which was used as a positive fungal control. The PCR protocol based on omt-1 detected as little as 15 pg of DNA from aflatoxigenic molds and 10(2) to 10(3) CFU/g in contaminated food samples. This PCR protocol should be used as a routine technique to detect aflatoxigenic molds in foods. PMID- 22221360 TI - Microbial performance of food safety management systems implemented in the lamb production chain. AB - The actual microbial status of the lamb production chain at three slaughterhouses, one processing plant, and five butcher shops selling whole or cut lamb carcasses to consumers was assessed with a previously developed microbial assessment scheme. All studied establishments had a food safety management system (FSMS) that was implemented according to legislative requirements. Microbial safety level profiles were constructed for each establishment and provided clear indications of which pathogens, hygiene indicators, or utility parameters required attention to improve the performance of the microbiological control protocols of the implemented FSMS. The highest contamination was found in the slaughterhouses in samples taken from the meat products (aerobic mesophilic plate counts [AMPs] of 3.40 to 6.63 log CFU/cm(2) and Enterobacteriaceae counts of 1.00 to 4.62 log CFU/cm(2)), contact surfaces (AMPs of 2.44 to 8.92 log CFU/cm(2)), and operators' hands and/or gloves (AMPs of 2.84 to 8.09 log CFU/cm(2)), especially after hide removal and evisceration. The microbial assessment scheme is a useful tool for providing insight into the actual microbiological results achieved with an FSMS implemented in establishments at various stages along the lamb production chain. PMID- 22221361 TI - Role of Oregano (Origanum vulgare) essential oil as a surface fungus inhibitor on fermented sausages: evaluation of its effect on microbial and physicochemical characteristics. AB - Oregano essential oil (OEO) was evaluated to determine its effect on the growth of natural contaminating molds on the surface of Spanish fermented sausage, the development of the internal microbial population of the sausage, and the physicochemical properties of the sausage. Results indicated a dramatic reduction in the contaminant molds. At the end of ripening, the main endogenous fungal species in control samples were Mucor racemosus (55%), Aspergillus fumigatus (20.6%), Cladosporium sphaerospermum (11.1%), Acremonium strictum (7.9%), and Aspergillus niger (4.7%). In samples treated with OEO, M. racemosus and A. fumigatus were the only species isolated; the treatment was more effective against A. fumigatus than against M. racemosus. The use of OEO to inhibit surface fungi did not affect the sausage drying process, pH, water activity, or color changes during ripening. These parameters change in a typical pattern for fermented dry-cured sausages during ripening. At the end of ripening, OEO-treated sausages had lower hardness and greater chewiness than the control but showed similar textural properties to sausages treated with potassium sorbate. PMID- 22221362 TI - Colloidal gold-based immunochromatographic test strip for rapid detection of abrin in food samples. AB - In the present study, we developed a convenient, rapid, and sensitive immunochromatographic (IC) test strip to detect abrin in assay buffer and spiked abrin in test food samples. The abrin IC test strip was based on a sandwich format consisting of a monoclonal antibody and a polyclonal antibody. The anti abrin A chain monoclonal antibody from mice was immobilized on a porous nitrocellulose membrane as a capture antibody, while the anti-abrin polyclonal antibody from rabbits was conjugated to colloidal gold particles, serving as a detection antibody. Both visual observation and quantitative analysis indicated that the lower detection of the strip was about 3 ng/ml when abrin was directly spiked into milk, orange juice, and drinking water at a concentration of 3 to 60 ng/ml; the analytical recovery rate was 92.2 to 128%. With this method, abrin spiked into food could be detected in less than 10 min. Moreover, the IC test strip showed no cross-reaction with the closely related phytotoxin ricin. Therefore, our test strip is an ideal candidate for the development of a kit for rapid and quantitative detection of abrin in food samples. PMID- 22221363 TI - Food protective effects of Periploca sepium oil and its active component against stored food mites. AB - The aim of this study was to examine the acaricidal activity of Periploca sepium oil and its active component against Tyrophagus putrescentiae. Based on its 50% lethal dose (LD(50) ) value, P. sepium oil (8.45 MUg/cm(2)) was highly active against T. putrescentiae. The active constituent of P. sepium was isolated by chromatographic techniques and identified as 2-hydroxy-4-methoxybenzaldehyde. In the comparison with synthetic acaricides, the acaricidal activity of 2-hydroxy-4 methoxybenzaldehyde (0.94 MUg/cm(2)) against T. putrescentiae was 12.2- and 31.2 fold greater than those of benzyl benzoate (11.45 MUg/cm(2)) and N,N-diethyl-m toluamide (29.33 MUg/cm(2)), respectively. To establish structure-activity relationships, the acaricidal activities of 2-hydroxy-4-methoxybenzaldehyde and its derivatives against T. putrescentiae were determined by using an impregnated fabric disk bioassay. On the basis of LD(50) values, 4-methoxybenzaldehyde (0.48 MUg/cm(2)) was the most effective against T. putrescentiae, followed by 3 methoxybenzaldehyde (0.82 MUg/cm(2)), 2-hydroxy-5-methoxybenzaldehyde (0.92 MUg/cm(2)), 2-methoxybenzaldehyde (0.95 MUg/cm(2)), 2-hydroxybenzaldehyde (0.97 MUg/cm(2)), and 2-hydroxy-3-methoxybenzaldehyde (2.35 MUg/cm(2)). These results indicate that the introduction of a hydroxyl and/or methoxy group into the benzaldehyde skeleton increased the acaricidal activity. Therefore, 2-hydroxy-4 methoxybenzaldehyde and its derivatives could potentially be used as potent mite control agents. PMID- 22221364 TI - Economic burden from health losses due to foodborne illness in the United States. AB - The Centers for Disease Control and Prevention (CDC) recently revised their estimates for the annual number of foodborne illnesses; 48 million Americans suffer from domestically acquired foodborne illness associated with 31 identified pathogens and a broad category of unspecified agents. Consequently, economic studies based on the previous estimates are now obsolete. This study was conducted to provide improved and updated estimates of the cost of foodborne illness by adding a replication of the 2011 CDC model to existing cost-of-illness models. The basic cost-of-illness model includes economic estimates for medical costs, productivity losses, and illness-related mortality (based on hedonic value of-statistical-life studies). The enhanced cost-of-illness model replaces the productivity loss estimates with a more inclusive pain, suffering, and functional disability measure based on monetized quality-adjusted life year estimates. Costs are estimated for each pathogen and a broader class of unknown pathogens. The addition of updated cost data and improvements to methodology enhanced the performance of each existing economic model. Uncertainty in these models was characterized using Monte Carlo simulations in @Risk version 5.5. With this model, the average cost per case of foodborne illness was $1,626 (90% credible interval [CI], $607 to $3,073) for the enhanced cost-of-illness model and $1,068 (90% CI, $683 to $1,646) for the basic model. The resulting aggregated annual cost of illness was $77.7 billion (90% CI, $28.6 to $144.6 billion) and $51.0 billion (90% CI, $31.2 to $76.1 billion) for the enhanced and basic models, respectively. PMID- 22221365 TI - Microbial quality of bagged baby spinach and romaine lettuce: effects of top versus bottom sampling. AB - Contamination with Escherichia coli O157:H7 and Salmonella have called into question the safety and microbial quality of bagged ready-to-eat leafy greens. This study expands on previous findings that these goods have high total bacteria counts (TBC) and coliform counts, variation in counts among different lots, that Escherichia coli is present, and disparities in counts when bags are top or bottom sampled. Nearly 100 bags of baby spinach and hearts of romaine lettuce from a single brand were subjected to both top and bottom sampling. Product was blended, and a portion serially diluted and plated to obtain TBC. Total coliform and E. coli levels were estimated by the most-probable-number (MPN) technique with ColiComplete discs. Top-sampled TBC from bags of baby spinach (48 bags, 13 different lots) ranged from 3.9 to 8.1 log CFU/g and bottom-sampled TBC ranged from 4.0 to 8.2 log CFU/g, with 52% of the bags (or 39% of the lots) producing TBC higher in bottom samples. For hearts of romaine (47 bags from 19 different lots), top-sampled bags had TBC ranging from 2.4 to 7.0 log, and bottom-sampled bags had TBC from 3.3 to 7.3 log, with 64% of the bags (or 63% of the lots) showing higher TBC in bottom samples. However, we are unable to reject the hypothesis that the top and bottom samples from either commodity contain the same TBC (P >= 0.08). No E. coli was detected and total coliform bacteria counts were, with few exceptions, >=210 MPN/g, irrespective of TBC. In general, lots with the most number of days before the printed "use-by" date had lower TBC. However, the R(2) values for either baby spinach (0.4085) or hearts of romaine (0.2946) suggest that age might not be a very good predictor of higher TBC. TBC varied widely between lots and even more so within same-lot samples, as indicated by the sum of squares results. This finding, along with higher TBC in bottom samples, suggests further consideration when a microbiological sampling scheme of bagged produce is designed. PMID- 22221366 TI - Escherichia coli producing CMY-2 beta-lactamase in bovine mastitis milk. AB - An Escherichia coli isolate producing the CMY-2 beta-lactamase was found in the milk of a cow with recurrent subclinical mastitis. The isolate was resistant to the antibiotics commonly used for intramammary mastitis treatment, such as penicillins, cephalosporins, beta-lactam/beta-lactamase inhibitor combinations, aminoglycosides, tetracyclines, and sulfonamides. This is the first report of a plasmid-mediated AmpC-producing Enterobacteriaceae in bovine milk. PMID- 22221367 TI - Quantification of campylobacter in swine before, during, and after the slaughter process. AB - Campylobacter has been implicated as a major cause of foodborne illness worldwide. Pigs can be subclinically infected, and fecal contamination of meat during slaughter is a food safety risk. The objective of this study was to determine the association between the concentration of Campylobacter pre- and periharvest with postharvest contamination in swine. Samples were collected from 100 individually identified swine during the pre-, peri-, and postharvest periods. For each animal, the following phases were sampled: on farm (fecal sample), in lairage (hide swab), post-stunning and exsanguination (rectal contents), prechilling (carcass swab), and final product (rib meat) sample. The proportions of samples that were Campylobacter positive were 90, 95, 76, 100, and 49% for fecal, rectal content, hide, carcass, and rib meat samples, respectively. The mean Campylobacter concentrations for each sample were fecal sample, 1.7 * 10(6) CFU/g; rectal content, 1.2 * 10(7) CFU/g; hide swab, 1.4 CFU/cm(2); carcass swab, 1.7 * 10(3) CFU per half carcass; and rib meat, 18 CFU/g. There was a positive correlation between Campylobacter concentrations in fecal samples (R = 0.20, P = 0.065) and concentration of Campylobacter on rib meat, and between rectal content sample concentration (R = 0.20, P = 0.068) and the concentration on rib meat. There was no association between the isolation of Campylobacter on rib meat and the isolation of Campylobacter at any pre- or periharvest stage. This could indicate that the risk of a meat product being contaminated is associated with pigs that shed higher concentrations of Campylobacter before slaughter. PMID- 22221368 TI - Enhanced control of microbiological contamination of product at a large beef packing plant. AB - Swab samples were obtained from groups of 25 carcasses at various stages of processing at a large beef packing plant. The log mean number of aerobes recovered from carcasses after skinning was 2.2 log CFU/cm(2). Spraying the uneviscerated carcasses with 5% lactic acid reduced the numbers of aerobes by about 1 log unit; but subsequent carcass dressing operations, a second treatment with 5% lactic acid, pasteurizing, and carcass cooling had no substantial effect upon the number of aerobes on carcasses. The total numbers of coliforms or Escherichia coli cells recovered from skinned carcasses were <2 log CFU/2,500 cm(2). The numbers were reduced by the washing of uneviscerated carcasses but increased after evisceration operations. The numbers were reduced by spraying with lactic acid and pasteurizing, with no coliforms or E. coli being recovered from pasteurized carcass sides. No coliforms or E. coli cells were recovered from the forequarters of cooled carcass sides, but E. coli cells were recovered from the hindquarters of 1 of 50 cooled carcass sides, at 1.4 log CFU/1,000 cm(2). The numbers of aerobes on conveyor belts in the carcass breaking facility were similar to the numbers on cooled carcass, but the numbers of aerobes on cuts and trimmings and the number of coliforms and E. coli cells on the products and belts were higher than the numbers on carcasses. The findings indicate that most cooled carcasses produced at the plant carry E. coli at numbers <1 CFU/10,000 cm(2) but that product can be contaminated with small numbers of E. coli (<1 CFU/100 cm(2)) during carcass breaking. PMID- 22221369 TI - Evaluation of most-probable-number-PCR method with internal amplification control for the counting of total and pathogenic Vibrio parahaemolyticus in frozen shrimps. AB - The most-probable-number (MPN) method is often time-consuming for the isolation, detection, and quantification of Vibrio parahaemolyticus from natural sources. MPN counting of V. parahaemolyticus bacteria usually involves the isolation of typical V. parahaemolyticus colonies on selective medium, with subsequent confirmation by biochemical identification. In this study, we evaluated the use of a PCR on MPN enrichment cultures (MPN-PCR) for the direct detection of total and pathogenic V. parahaemolyticus cells in frozen shrimp. This reaction targeted the R72H, tdh, and trh sequences. An internal amplification control was added to the samples before R72H amplification. There was an excellent correlation between the results of the two methods for artificially inoculated and natural shrimp samples. Of 36 natural samples, 28 tested positive for the presence of V. parahaemolyticus, with an MPN value of 2 * 10(-1) to 9.2 * 10(1) per g. No pathogenic V. parahaemolyticus cells were detected. The test had a detection limit of one V. parahaemolyticus organism per g and was completed within two working days. These results support the use of the combination of PCR with MPN for the detection of total or potentially pathogenic V. parahaemolyticus cells in frozen shrimp. PMID- 22221370 TI - Observational study of the prevalence and antibiotic resistance of Campylobacter spp. from different poultry production systems in KwaZulu-Natal, South Africa. AB - Campylobacter bacteria are important foodborne pathogens that cause acute diarrheal illness, and infection is often associated with contaminated poultry. In a blind observational study, the prevalence and resistance profiles of thermophilic Campylobacter strains collected from different poultry production systems were tested against the clinically used antibiotics ciprofloxacin, tetracycline, erythromycin, gentamicin, and streptomycin. Campylobacter strains were isolated from chickens in rural production systems, a free-range commercial facility, and industrially raised broiler and egg-laying chickens all situated in KwaZulu-Natal, South Africa. Isolates were collected from the chicken cecae and were identified with conventional methods and tested for antibiotic resistance with the Clinical and Laboratory Standards Institute agar dilution method. The prevalence of Campylobacter spp. isolates in chickens was 68% (56 samples) in rural production, 47% (140 samples) in commercial free-range broilers, 47% (133 samples) in industrial broilers, and 94% (34 samples) in industrial layer hens. Isolates from the rurally raised chickens showed significantly (P < 0.01) less resistance against ciprofloxacin (7.9%), erythromycin (0%), and tetracycline (21.6%) than those from commercially produced chickens. Isolates from the commercially raised chickens (free range and industrial) were highly resistant to tetracycline (98.9 to 100%). The incidence of gentamicin and streptomycin resistance was 1.6 and 11.5%, respectively, in commercial free-range broilers, 1.7 and 16.4%, respectively, in industrially raised broilers, and 12.9 and 40%, respectively, in industrially raised layers. It is possible that variations among the poultry production systems, including antimicrobial usage, result in differences in antibiotic resistance profiles in Campylobacter. PMID- 22221371 TI - Monitoring of shrimp and farmed fish sold in Canada for cyanobacterial toxins. AB - Sixty-one samples of shrimp and 32 samples of farmed fish collected from retail markets across Canada were analyzed for cyanobacterial toxins, including microcystins, paralytic shellfish poisons (saxitoxins), cylindrospermopsin, and beta-N-methylamino-L-alanine, using established methods of analysis. None of these toxins were detected in any of the samples. Some shrimp samples screened for paralytic shellfish poisons showed the presence of unknown peaks in the chromatogram after periodate oxidation. PMID- 22221372 TI - Growth of Salmonella Typhimurium DT104 at 30 degrees C is not affected by anatomical location on the chicken carcass. AB - Development of models for growth of Salmonella in the chicken food matrix is time consuming and expensive. The current study was undertaken to examine growth of Salmonella on different anatomical locations of the chicken carcass. The purpose was to determine whether anatomical location should be included as an independent variable in predictive models for chicken. Eleven anatomical locations were studied: skin (wing, breast, drumstick, and thigh), meat surface (wing, breast, drumstick, and thigh), and meat interior (breast, drumstick, and thigh). Background microflora, pH, and growth (lag time, lambda; growth rate, MU; and time for a 3-log increase, t(3)) at 30 degrees C for a small inoculum size (0.92 +/- 0.30 log per portion) of Salmonella Typhimurium DT104 were examined. Four or six replicate storage trials were conducted per anatomical location (n = 46 growth curves). Portion sizes were 1.12 +/- 0.17 g (mean +/- standard deviation) for meat and 0.25 +/- 0.08 g for skin. A two-phase linear model was used to determine lambda and MU. The effect of anatomical location on dependent variables was assessed by one-way analysis of variance. pH values differed (P < 0.001) among anatomical locations, with skin (6.86 +/- 0.20). dark meat (6.39 +/- 0.20) . white meat (5.97 +/- 0.20). Background microflora (4.32 +/ 1.66 log per portion) was variable and not affected (P > 0.05) by anatomical location. Likewise, lambda (1.90 +/- 0.75 h), MU (0.648 +/- 0.120 log/h), and t(3) (6.71 +/- 0.82 h) at 30 degrees C were not affected (P > 0.05) by anatomical location. Although there were differences in pH among anatomical locations, these differences were not sufficient to affect growth of Salmonella Typhimurium DT104 at 30 degrees C. If this observation holds for other storage conditions and strains, then anatomical location does not need to be included as an independent variable in predictive models for chicken. This would save significant time and money for the predictive microbiologist. PMID- 22221373 TI - Effect of high hydrostatic pressure and pressure cycling on a pathogenic Salmonella enterica serovar cocktail inoculated into creamy peanut butter. AB - The ability of Salmonella enterica serovars to survive in high fat content, low water activity foods like peanut butter has been demonstrated by large foodborne illness outbreaks in recent years. This study investigates the potential of high hydrostatic pressure processing, including pressure cycling, to inactivate Salmonella inoculated into creamy peanut butter. A cocktail of pathogenic strains of Salmonella Enteritidis PT30, Salmonella Tennessee, Salmonella Oranienburg, Salmonella Anatum, Salmonella Enteritidis PT 9c, and Salmonella Montevideo obtained from peanut butter- and nut-related outbreaks was inoculated (10(6) to 10(7) CFU/g) into creamy peanut butter and high pressure processed under five different sets of conditions, which varied from 400 to 600 MPa and from 4 to 18 min. The log CFU reductions achieved varied from 1.6 to 1.9. Control experiments in which Salmonella was inoculated (10(9) CFU/g) into 0.1% peptone buffer and high pressure processed at 600 MPa for 18 min showed inactivation to below the detection limit of 100 CFU/g, confirming that high pressure processing is effective at destroying Salmonella in high-moisture environments. Pressure cycling under three sets of conditions consisting of pressures from 400 to 600 MPa, 3 to 10 pressure cycles, and hold times of 6 min for each cycle showed reductions similar to those seen in noncycling experiments. The results of our experiments suggest that the peanut butter food matrix facilitates the survival of Salmonella when exposed to high hydrostatic pressure processing. PMID- 22221374 TI - Characterization of Staphylococcus aureus isolates from retail chicken carcasses and pet workers in Northwest Arkansas. AB - Staphylococcus aureus can be carried on the skin and nasal passages of humans and animals as a commensal. A case of human methicillin-resistant S. aureus infection resulting from contact with pork has been reported. Poultry carcasses are sold at retail with the skin intact, but pork and beef typically are not. Thus, the risk of methicillin-resistant S. aureus human infection from whole raw poultry carcasses may be greater than that of exposure from pork or beef. The objective of this study was to isolate and characterize S. aureus from whole retail poultry carcasses and compare the isolates to S. aureus isolates from humans. A total of 25 S. aureus isolates were collected from 222 whole poultry carcasses. The isolates were characterized phenotypically with antibiotic resistance disc diffusion assays and genotypically using multilocus sequence typing. A total of 17 S. aureus isolates obtained from healthy humans were included and characterized in the same way as the poultry isolates. Staphylococcus spp. were recovered from all poultry carcasses. Only 25 poultry carcasses (11.2%) were contaminated with S. aureus. Of these 25 isolates, 36% were resistant to at least one of the antibiotics tested and 20% were resistant to two or more antibiotics tested. However, 100% of the human isolates were resistant to at least one of the antibiotics and 94% were resistant to two or more antibiotics. The results of the multilocus sequence typing indicate that most of the isolates grouped according to source. These results indicate a low prevalence of S. aureus present in poultry, and the isolates were not phenotypically similar to human isolates. The low number of S. aureus isolates from this study indicates that chicken carcasses would appear to not be a significant source of this bacterium. PMID- 22221375 TI - Detection of foreign bodies in foods using continuous wave terahertz imaging. AB - Foreign bodies (FBs) in food are health hazards and quality issues for many food manufacturers and enforcement authorities. In this study, continuous wave (CW) terahertz (THz) imaging at 0.2 THz with an output power of 10 mW was compared with X-ray imaging as techniques for inspection of food for FBs. High-density FBs, i.e., aluminum and granite pieces of various sizes, were embedded in a powdered instant noodle product and detected using THz and X-ray imaging. All aluminum and granite pieces (regular hexahedrons with an edge length of 1 to 5 mm) were visualized by both CW THz and X-ray imaging. THz imaging also detected maggots (length = 8 to 22 mm) and crickets (length = 35 and 50 mm), which were embedded in samples as low density FBs. However, not all sizes of maggot pieces embedded in powdered instant noodle were detected with X-ray imaging, although larger crickets (length = 50 mm and thickness = 10 mm) were detected. These results suggest that CW THz imaging has potential for detecting both high-density and low-density FBs embedded in food. PMID- 22221376 TI - Chlorine treatment to inactivate norovirus on food contact surfaces. AB - This study was conducted to determine the concentration and optimal treatment time of chlorine for reducing feline calicivirus (FCV) and murine norovirus (MNV) as surrogates of norovirus (NoV) on stainless steel surfaces and to develop a predictive inactivation method using a response surface methodology. The reduction levels of FCV VR-782 and MNV on stainless steel surfaces after treatment with various concentrations of chlorine (0 to 5,000 ppm) for various times (0 to 5 min) were measured. The reduction values of both FCV and MNV on stainless steel surfaces after 5,000 ppm of chlorine treatment for 5 min were 5.20 TCID(50) per coupon. The predictive results obtained by central composite design were analyzed by standard analysis of variance. The application of multiple regression analysis was related to the following polynomial equations: (i) FCV (log TCID(50) per coupon) = -0.3714 + 0.8362x(1) + 0.0011x(2) + 0.0001x(1)x(2) - 0.1143x(2)(1) -0.0001x(2)(2) (x(1), time; x(2), concentration) and (ii) MNV (log TCID(50) per coupon) = + 0.0471 + 0.0807x(1) + 0.0011x(2) + 0.0001x(1)x(2) -0.0910x(2)(1) -0.0001x(2)(2) (x(1), time; x(2), concentration). It was concluded that these polynomial equation models of reduction of FCV and MNV could be used to determine the minimum concentration of chlorine and exposure times to control human NoV on food contact surfaces. PMID- 22221377 TI - Toxic metals (Hg, Cd, and Pb) in fishery products imported into Italy: suitability for human consumption. AB - Mercury, cadmium, and lead concentrations were determined in various fishery products (fishes, cephalopod molluscs, and crustaceans) imported into Italy from many European and non-European coastal countries. Considerable differences were found in the concentrations of these metals among the products tested. The highest mean Hg concentration was found in fishes (0.21 MUg g(-1) wet weight), whereas cephalopods had the highest mean Cd concentration (0.35 MUg g(-1) wet weight). Swordfish (0.80 MUg g(-1) wet weight), longtail tuna (0.53 MUg g(-1) wet weight), and thornback ray (0.52 MUg g(-1) wet weight) had the highest concentrations of Hg, whereas maximum Cd concentrations were found in samples of common cuttlefish (0.85 MUg g(-1) wet weight) and common octopus (0.64 MUg g(-1) wet weight). The majority of the samples analyzed were in compliance with European Union legislation, except for a few cases. The calculated mean weekly intakes of Hg, Cd, and Pb through consumption of the fishery products tested were all below the legislated respective provisional tolerable weekly intakes. In general, the samples analyzed were considered safe to eat with regard to the metal concentrations found and the allowable intakes based on legislation. Nevertheless, the consumption of some species may be of significant importance for consumer health. PMID- 22221378 TI - Role of attachment to surfaces on the prevalence and survival of Campylobacter through food systems. AB - Campylobacter continues to be one of the bacterial pathogens most frequently associated with human gastrointestinal illness worldwide. Because Campylobacter primarily colonizes the intestines of animals used for food production, food products of animal origin can become contaminated with this pathogen and thus represent a significant risk factor. Despite application of numerous physical and chemical interventions to control Campylobacter during food processing, the high isolation rate of this pathogen from some retail meat products indicates that Campylobacter is able to persist from animal slaughterhouses through food systems. Given the fastidious growth requirements and high susceptibility of this pathogen to environmental conditions, the ability of Campylobacter to attach to food and food-related surfaces is likely to play an important role in food contamination and movement through food systems. This review was compiled to (i) describe how the attachment of Campylobacter to surfaces influences the prevalence and survival of the organism through food systems, (ii) examine the potential factors affecting the ability of Campylobacter to attach to surfaces, and (iii) suggest strategies for controlling this attachment process. PMID- 22221379 TI - Cytolethal distending toxin (CDT) of the Haemophilus parasuis SC096 strain contributes to serum resistance and adherence to and invasion of PK-15 and PUVEC cells. AB - Cytolethal distending toxin (CDT) is proposed to be an important virulence determinant of many pathogens. Although two cdt gene cluster loci have been identified in Haemophilus parasuis strain SH0165, the characteristics of CDTs associated with pathogenesis remain unclear. In this study, three CDT-deficient mutants, cdt-1, cdt-2 and the double-knockout cdt-1cdt-2 (Deltacdt-1, Deltacdt-2 and Deltacdt-1Deltacdt-2, respectively), were obtained in the H. parasuis serovar 4 clinical strain SC096 using a natural transformation method. Compared to the wild-type SC096 strain, the Deltacdt-1, Deltacdt-2 and Deltacdt-1Deltacdt-2 mutants showed subtle growth defects and clearly exhibited an increased sensitivity to the bactericidal action of porcine and rabbit sera. Additionally, these mutants had a significantly reduced ability to adhere to and invade porcine umbilicus vein endothelial cells (PUVEC) and porcine kidney epithelial cells (PK 15). These findings suggest that both CDTs in the H. parasuis SC096 strain are involved in serum resistance and adherence and invasion of host cells. PMID- 22221381 TI - Genetic and phylogenetic analysis of South Korean sacbrood virus isolates from infected honey bees (Apis cerana). AB - Sacbrood virus (SBV) is one of the most destructive honey bee viruses. The virus causes failure to pupate and death in both larvae and adult bees. Genetic analysis of SBV infected honey bees (Apis cerana) from five different provinces was carried out based on three nucleotide sequences; one partial structural protein coding sequence and two non-structural protein coding sequences. Sequences amplified by three specific primer pairs were aligned and compared with reference sequences deposited in the GenBank database. Sequence alignments revealed a low level of sequence variation among Korean isolates (>= 98.6% nucleotide identity), regardless of the genome regions studied or the geographic origins of the strains. Multiple sequence comparisons indicated that Korean SBV isolates are genetically closely related to Chinese and other Asian strains. Interestingly, the Korean SBV isolates showed a number of unique nucleotides and amino acids that had not been observed in other published strains. Korean and other Asian isolates from the host A. cerana and the UK, European and Japanese strains from the host Apis mellifera showed differences in nucleotide and deduced amino acid identities. This suggests that host-specificity exists among SBV strains isolated from different species. Phylogenetic relatedness between compared sequences was analyzed by MEGA 4.1 software using the neighbor-joining (NJ) method with a boot-strap value of 1000 replicates. Obtained topologies were in agreement with previous studies, in which a distinct group of SBV was formed by UK and European genotypes and another group was comprised of Asian genotypes including strains that originated from China, Japan (japonica), India and Nepal. However, phylogeny based on a partial protein structural coding sequence grouped all Korean SBV isolates identified in A. cerana as a separate cluster. Our findings suggest that further study, including Korean SBV isolated from A. mellifera, is needed. PMID- 22221380 TI - Analysis of gene expression in canine sino-nasal aspergillosis and idiopathic lymphoplasmacytic rhinitis: a transcriptomic analysis. AB - Sino-nasal aspergillosis (SNA) and lymphoplasmacytic rhinitis (LPR) are two common causes of nasal discharge in dog. SNA is typically due to an invasion of Aspergillus fumigatus in the surface of nasal mucosa. The etiology of LPR is poorly understood and a possible implication of fungi is suspected. The purpose of the present study was to explore the immunopathogenesis of these diseases by comparing gene expression in the nasal mucosa from dogs affected by SNA or LPR with healthy dogs, using a canine-specific microarray and quantitative real-time reverse transcriptase polymerase chain reaction for confirmation of the findings of the microarray study. Total RNA was isolated from biopsies of nasal mucosa and gene expression was analyzed via hybridation to the Affymetrix GeneChip((r)) Canine Genome 2.0 Array. Selected Affimetrix probes sets identifiers were downloaded into the Database for Annotation, Visualization and Integrated Discovery. Genes of interest were chosen after their fold change and their possible implication in immunopathogenesis of SNA or LPR. The results presented here were in concordance with previous studies on SNA and LPR and highlighted new molecules potentially involved in the pathogenesis of SNA. The over-expression of interleukin (IL)-16, natural killer cell group 7 and chemokine ligand 10 might be related to a potential protective Th1 immunity counterbalanced by other molecules such as DNA-binding protein Ikaros. PMID- 22221382 TI - Evaluation of serological tests for H5N1 avian influenza on field samples from domestic poultry populations in Vietnam: consequences for surveillance. AB - In Vietnam, serological post H5N1 vaccination surveillance using the HI test is applied to assess the efficiency of the vaccination in addition to virological monitoring. In this paper we report on the evaluations of the performances of the haemagglutination inhibition (HI) test and of a H5-ELISA, using chicken and duck field samples. The evaluations were conducted by comparison with a pseudotyped based virus neutralization test (H5pp VNT) performed in a reference laboratory and considered as a "gold standard" and also by using methods developed for imperfect reference test. Their global accuracy and best cut-offs were also estimated. Results from the HI test for several haemagglutinin subtypes and from a commercial type A influenza competition ELISA were also compared. The results showed that performance of the HI test was very good in comparison with the H5pp VNT. Data also clearly supported the cut-off of >= 4 log(2) used for the HI test for chickens but, a 3 log(2) positivity cut-off would be more appropriate for ducks. When compared with the VNT, the H5-ELISA showed poor specificity when using the positivity cut-off specified by the manufacturer but could be used as a screening test if confirmed by the HI test or the H5ppVNT which presents some interests for large scale testing (no need for biosafety level 3 conditions and high performance). A general and highly sensitive pre-screening can also be achieved using the detection of NP-specific antibodies with a competition ELISA. This appears of little interest in a context of high subtypes diversity where only a subtype is targeted for surveillance and control. PMID- 22221384 TI - Structure and electrical properties of sputtered TiO2/ZrO2 bilayer composite dielectrics upon annealing in nitrogen. AB - The high-k dielectric TiO2/ZrO2 bilayer composite film was prepared on a Si substrate by radio frequency magnetron sputtering and post annealing in N2 at various temperatures in the range of 573 K to 973 K. Transmission electron microscopy observation revealed that the bilayer film fully mixed together and had good interfacial property at 773 K. Metal-oxide-semiconductor capacitors with high-k gate dielectric TiO2/ZrO2/p-Si were fabricated using Pt as the top gate electrode and as the bottom side electrode. The largest property permittivity of 46.1 and a very low leakage current density of 3.35 * 10-5 A/cm2 were achieved for the sample of TiO2/ZrO2/Si after annealing at 773 K. PMID- 22221385 TI - A single copy integration vector that integrates at an engineered site on the Staphylococcus aureus chromosome. AB - BACKGROUND: Single-copy integration vectors based upon the site-specific recombination systems of bacteriophage are invaluable tools in the study of bacterial pathogenesis. The utility of such vectors is often limited, however, by the fact that integration often results in the inactivation of bacterial genes or has undesirable effects on gene transcription. The aim of this study is to develop an integration vector that does not have a detectable effect on gene transcription upon integration. FINDINGS: We have developed a single-copy integration system that enables the cloning vector to integrate at a specific engineered site, within an untranscribed intergenic region, in the chromosome of Staphylococcus aureus. This system is based on the lysogenic phage L54a site specific recombination system in which the L54a phage (attP) and chromosome (attB) attachment sites, which share an 18-bp identical core sequence, were modified with identical mutations. The integration vector, pLL102, was constructed to contain the modified L54a attP site (attP2) that was altered at 5 nucleotide positions within the core sequence. In the recipient strain, the similarly modified attB site (attB2) was inserted in an intergenic region devoid of detectable transcription read-through. Integration of the vector, which is unable to replicate in S. aureus extrachromosomally, was achieved by providing the L54a integrase gene in a plasmid in the recipient. We showed that pLL102 integrated specifically at the engineered site rather than at the native L54a attB site and that integration did not have a significant effect on transcription of genes immediately upstream or downstream of the integration site. CONCLUSIONS: In this work, we describe an E. coli-S. aureus shuttle vector that can be used to introduce any cloned gene into the S. aureus chromosome at a select site without affecting gene expression. The vector should be useful for genetic manipulation of S. aureus and for marking strains for in vivo studies. PMID- 22221386 TI - Structural and optical properties of ZnO nanorods by electrochemical growth using multi-walled carbon nanotube-composed seed layers. AB - We reported the enhancement of the structural and optical properties of electrochemically synthesized zinc oxide [ZnO] nanorod arrays [NRAs] using the multi-walled carbon nanotube [MWCNT]-composed seed layers, which were formed by spin-coating the aqueous seed solution containing MWCNTs on the indium tin oxide coated glass substrate. The MWCNT-composed seed layer served as the efficient nucleation surface as well as the film with better electrical conductivity, thus leading to a more uniform high-density ZnO NRAs with an improved crystal quality during the electrochemical deposition process. For ZnO NRAs grown on the seed layer containing MWCNTs (2 wt.%), the photoluminescence peak intensity of the near-band-edge emission at a wavelength of approximately 375 nm was enhanced by 2.8 times compared with that of the ZnO nanorods grown without the seed layer due to the high crystallinity of ZnO NRAs and the surface plasmon-meditated emission enhancement by MWCNTs. The effect of the MWCNT-composed seed layer on the surface wettability was also investigated.PACS: 81.07.-b; 81.16.-c; 81.07.Pr; 61.48.De. PMID- 22221387 TI - Mental health research in Norway, exemplified by a project on depression in primary care. PMID- 22221383 TI - Molecular analysis of methanogenic archaea in the forestomach of the alpaca (Vicugna pacos). AB - BACKGROUND: Methanogens that populate the gastrointestinal tract of livestock ruminants contribute significantly to methane emissions from the agriculture industry. There is a great need to analyze archaeal microbiomes from a broad range of host species in order to establish causal relationships between the structure of methanogen communities and their potential for methane emission. In this report, we present an investigation of methanogenic archaeal populations in the foregut of alpacas. RESULTS: We constructed individual 16S rRNA gene clone libraries from five sampled animals and recovered a total of 947 sequences which were assigned to 51 species-level OTUs. Individuals were found to each have between 21 and 27 OTUs, of which two to six OTUs were unique. As reported in other host species, Methanobrevibacter was the dominant genus in the alpaca, representing 88.3% of clones. However, the alpaca archaeal microbiome was different from other reported host species, as clones showing species-level identity to Methanobrevibacter millerae were the most abundant. CONCLUSION: From our analysis, we propose a model to describe the population structure of Methanobrevibacter-related methanogens in the alpaca and in previously reported host species, which may contribute in unraveling the complexity of symbiotic archaeal communities in herbivores. PMID- 22221389 TI - Stability of SiNX/SiNX double stack antireflection coating for single crystalline silicon solar cells. AB - Double stack antireflection coatings have significant advantages over single layer antireflection coatings due to their broad-range coverage of the solar spectrum. A solar cell with 60-nm/20-nm SiNX:H double stack coatings has 17.8% efficiency, while that with a 80-nm SiNX:H single coating has 17.2% efficiency. The improvement of the efficiency is due to the effect of better passivation and better antireflection of the double stack antireflection coating. It is important that SiNX:H films have strong resistance against stress factors since they are used as antireflective coating for solar cells. However, the tolerance of SiNX:H films to external stresses has never been studied. In this paper, the stability of SiNX:H films prepared by a plasma-enhanced chemical vapor deposition system is studied. The stability tests are conducted using various forms of stress, such as prolonged thermal cycle, humidity, and UV exposure. The heat and damp test was conducted for 100 h, maintaining humidity at 85% and applying thermal cycles of rapidly changing temperatures from -20 degrees C to 85 degrees C over 5 h. UV exposure was conducted for 50 h using a 180-W UV lamp. This confirmed that the double stack antireflection coating is stable against external stress. PMID- 22221390 TI - Vitamin D deficiency in women with fibromyalgia in Saudi Arabia. AB - BACKGROUND: The relation between low levels of 25-hydroxyvitamin D and nonspecific musculoskeletal pain, including fibromyalgia syndrome, is debatable. Many studies have reported "a positive relation" and others "found no relation." OBJECTIVES: To determine the prevalence of vitamin D deficiency among patients with fibromyalgia in a neurology clinic in the Kingdom of Saudi Arabia (KSA). METHODS: This study was done at a neurology clinic of Bugshan Hospital, Jeddah, KSA, from January to April 2011. Thirty female patients were diagnosed with fibromyalgia according to new clinical fibromyalgia diagnostic criteria; their serum vitamin D levels were screened. Vitamin D deficiency is defined as <20 ng/mL, vitamin D insufficiency is defined as 21-29 ng/mL, and vitamin D sufficiency is equal to or >30 ng/mL. RESULT: Thirty female patients were included in the study. The mean age was 34.56 +/- 8.1 years. Mean vitamin D level was 4.76 +/- 1.46 ng/mL. A significant negative correlation between vitamin D level and widespread pain index was found. Thirty percent of the patients were Saudi Arabian of whom 100% were veiled; 70% were non-Saudi Arabian of whom 47.6% were veiled and 52.4% wore long pants and/or full sleeved clothes. Vitamin D deficiency was equally prevalent among veiled (4.77 +/- 1.37 ng/mL) and nonveiled (4.75 +/- 1.68 ng/mL). Treatment with high-dose vitamin D resulted in clinical improvement in all patients. CONCLUSION: Vitamin D deficiency is often seen in patients diagnosed with fibromyalgia in our population. This was equally true in veiled and nonveiled, but conservatively dressed populations. Effective treatment with high-dose vitamin D could lead to resolution of almost all symptoms. Further study of these populations and fortification of foods with vitamin D may be essential. PMID- 22221391 TI - Being a mentor: what's in it for me? AB - The benefits of mentorship for the protege are well established and include increased career satisfaction, advancement, and income. Mentors can derive satisfaction from personal and professional networks within their institutions and specialties. However, the advantages of being a mentor are underreported in the medical literature. The purpose of this review is to investigate the effect of the mentoring relationship on the mentors and institutions in disciplines that have studied it widely and to draw parallels to academic medicine. Literature in the fields of business, organizational psychology, and kindergarten through high school (K-12) education describe benefits of serving as a mentor to the individual, organization, and discipline. Potential mentors are intensely self motivated and derive satisfaction from developing junior colleagues and improving their institutions. Business mentors take pride in junior colleagues' achievements and enjoy improved recognition by superiors, favorable perception within the organization, increased job satisfaction, accelerated promotion rates, higher salaries, development of managerial skills, and improved technical expertise. Organizations enjoy worker longevity from both members of the partnership and benefit from the formation of networks. In the K-12 education model, master teachers who train novices are more likely to remain in the classroom or advance to an administrative role. Application of the principles from these disciplines to academic medicine is likely to produce similarly positive outcomes of personal satisfaction, collaboration, and academic and institutional advancement. PMID- 22221392 TI - Exploring the transcriptomic variation caused by the Finnish founder mutation of lysinuric protein intolerance (LPI). AB - Lysinuric protein intolerance (LPI) is an autosomal recessive disorder caused by mutations in cationic amino acid transporter gene SLC7A7. Although all Finnish patients share the same homozygous mutation, their clinical manifestations vary greatly. The symptoms range from failure to thrive, protein aversion, anemia and hyperammonaemia, to immunological abnormalities, nephropathy and pulmonary alveolar proteinosis. To unravel the molecular mechanisms behind those symptoms not explained directly by the primary mutation, gene expression profiles of LPI patients were studied using genome-wide microarray technology. As a result, we discovered 926 differentially-expressed genes, including cationic and neutral amino acid transporters. The functional annotation analysis revealed a significant accumulation of such biological processes as inflammatory response, immune system processes and apoptosis. We conclude that changes in the expression of genes other than SLC7A7 may be linked to the various symptoms of LPI, indicating a complex interplay between amino acid transporters and various cellular processes. PMID- 22221395 TI - The heart of the matter: cardiometabolic care in youth with psychosis. AB - AIM: Weight gain, obesity and metabolic disturbances in youth with psychosis are significant contributors to the health burden of people with psychosis, with a two- to threefold increase in rates compared with the general population and a 20% reduction in life expectancy. Several studies have now described cardiometabolic benefits of a range of interventions, including a structured diet and exercise programmes and metformin for patients receiving antipsychotic medications. Despite the development of Australian consensus guidelines and screening algorithms to detect such metabolic abnormalities, there is a lack of guidelines for clinicians to determine appropriate, timely, targeted prevention and intervention to manage these complications in the youth population. METHODS: The Bondi Early Psychosis Programme targets young people (aged 15-25 years) experiencing their first episode of psychosis. This service has developed a model of metabolic screening and a treatment algorithm to provide clinicians with recommendations for targeted interventions. RESULTS: Positive Cardiometabolic Health: an early intervention framework for patients on psychotropic medication describes a method for early detection, prevention and intervention strategies targeting antipsychotic-induced metabolic abnormalities and cardiovascular risk factors. CONCLUSION: Although further research is required, there is sufficient evidence to support early intervention and prevention strategies to improve physical health outcomes in young people with first-episode psychosis. PMID- 22221394 TI - Polymorphisms of the pfmdr1 but not the pfnhe-1 gene is associated with in vitro quinine sensitivity in Thai isolates of Plasmodium falciparum. AB - BACKGROUND: The emergence of Plasmodium falciparum resistance to most currently used anti-malarial drugs is a major problem in malaria control along the Thai Myanmar and Thai-Cambodia borders. Quinine (QN) with tetracycline/doxycycline has been used as the second-line treatment for uncomplicated falciparum malaria. In addition, QN monotherapy has been the first-line treatment for falciparum malaria in pregnant women. However, reduced in vitro and in vivo responses to QN have been reported. To date, a few genetic markers for QN resistance have been proposed including Plasmodium falciparum chloroquine resistance transporter (pfcrt), P. falciparum multidrug resistance 1 (pfmdr1), and P. falciparum Na+/H+ exchanger (pfnhe-1). This study was to investigate the role of the pfmdr1 and pfnhe-1 gene on in vitro QN sensitivity in Thai isolates of P. falciparum. METHODS: Eighty-five Thai isolates of P. falciparum from the Thai-Myanmar and Thai-Cambodia borders from 2003-2008 were determined for in vitro QN sensitivity using radioisotopic assay. Polymorphisms of the pfmdr1 and pfnhe-1 gene were determined by PCR-RFLP and sequence analysis. Associations between the in vitro QN sensitivity and the polymorphisms of the pfmdr1 and pfnhe-1 gene were evaluated. RESULTS: The mean QN IC50 was 202.8 nM (range 25.7-654.4 nM). Only four isolates were QN resistant when the IC50 of >500 nM was used as the cut-off point. Significant associations were found between the pfmdr1 mutations at codons N86Y and N1042D and in vitro QN sensitivity. However, no associations with the number of DNNND, DDNNNDNHNDD, and NHNDNHNNDDD repeats in the microsatellite ms4760 of the pfnhe-1 gene were identified. CONCLUSION: Data from the present study put doubt regarding the pfnhe-1 gene as to whether it could be used as the suitable marker for QN resistance in Thailand. In contrast, it confirms the influence of the pfmdr1 gene on in vitro QN sensitivity. PMID- 22221393 TI - Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations. AB - Pantothenate kinase-associated neurodegeneration (PKAN) is a rare, inborn error of metabolism characterized by iron accumulation in the basal ganglia and by the presence of dystonia, dysarthria, and retinal degeneration. Mutations in pantothenate kinase 2 (PANK2), the rate-limiting enzyme in mitochondrial coenzyme A biosynthesis, represent the most common genetic cause of this disorder. How mutations in this core metabolic enzyme give rise to such a broad clinical spectrum of pathology remains a mystery. To systematically explore its pathogenesis, we performed global metabolic profiling on plasma from a cohort of 14 genetically defined patients and 18 controls. Notably, lactate is elevated in PKAN patients, suggesting dysfunctional mitochondrial metabolism. As predicted, but never previously reported, pantothenate levels are higher in patients with premature stop mutations in PANK2. Global metabolic profiling and follow-up studies in patient-derived fibroblasts also reveal defects in bile acid conjugation and lipid metabolism, pathways that require coenzyme A. These findings raise a novel therapeutic hypothesis, namely, that dietary fats and bile acid supplements may hold potential as disease-modifying interventions. Our study illustrates the value of metabolic profiling as a tool for systematically exploring the biochemical basis of inherited metabolic diseases. PMID- 22221396 TI - Smoking influences salivary histamine levels in periodontal disease. AB - OBJECTIVES: Histamine, a potent vasoactive amine, is increased in saliva of periodontitis patients. The present study aimed to further investigate the diagnostic potential of histamine for periodontal disease and assessed smoking, a major risk factor of periodontitis, as a possible influencing factor. METHODS: Salivary and serum samples of 106 participants (60 periodontitis patients, 46 controls) were collected. Salivary histamine was determined by a commercially available ELISA kit, and serum C-reactive protein was measured by a routine laboratory test. Cigarettes per day and packyears were assessed as smoking exposure parameters. RESULTS: Statistically significantly increased levels of salivary histamine and serum C-reactive protein were detected between the patient and control group (P = 0.022 and P = 0.001). Salivary histamine levels were significantly higher in smoking compared with non-smoking patients (P < 0.001), and salivary histamine as well as serum C-reactive protein correlated significantly positively with smoking exposure parameters (P < 0.05). CONCLUSIONS: Smoking, an established and common risk factor of periodontitis, was assessed as a possible influencing factor for salivary histamine. Most interestingly, salivary histamine differed highly significantly between smoking and non-smoking periodontitis patients. Our results suggest a possible involvement of histamine in tobacco-exacerbated periodontal disease, but do not suggest salivary histamine as a reliable diagnostic marker for periodontitis. PMID- 22221397 TI - Effect of vitamin D3 in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats. AB - Diabetes mellitus is a growing health problem worldwide and is associated with severe liver complications. The aim of the present study is to analyse the status of metabolic and free-radical-scavenging enzymes and second messengers in the liver of streptozotocin (STZ)-induced diabetic rats, and to determine the hepatoprotective role of vitamin D(3). All studies were performed using the liver of adult male Wistar rats. Gene expression studies were carried out using real time PCR with specific probes. Second messenger levels were determined using (3)H labelled Biotrak assay kits, and glucose uptake assay with D-[(14)C]glucose. The present results show that there was a decrease in hepatic glucose uptake, malate dehydrogenase activity, glycogen content, inositol triphosphate (IP(3)) and cyclic GMP levels, and superoxide dismutase, glutathione peroxidase, phospholipase C, cyclic AMP-responsive element-binding protein, vitamin D receptor (VDR) and insulin receptor (INSR) gene expression in the diabetic rats when compared with the controls (all P < 0.05), while cyclic AMP levels and GLUT2 expression were increased (P < 0.05). Treatment of the diabetic rats with vitamin D(3) and insulin reversed the altered parameters to near control values. In conclusion, the data suggest a novel role of vitamin D(3) in restoring impaired liver metabolism in STZ-induced diabetic rats by regulating glucose uptake, storage and metabolism. We demonstrated that the restoring effect of vitamin D(3) is mediated through VDR modulation, thereby improving signal transduction and controlling free radicals in the liver of diabetic rats. These data suggest a potential role for vitamin D(3) in the treatment of diabetes-associated hepatic complications. PMID- 22221399 TI - Human telomerase reverse transcriptase transfection reduces apoptosis in human penile smooth muscle cells and slows down cellular aging. AB - INTRODUCTION: Erectile dysfunction (ED) is one of the most common diseases in male urology that greatly affects the quality of life in senior people. Relaxation of corpus cavernosum smooth muscle is the key to penile erection. AIM: To explore effects of human telomerase reverse transcriptase (hTERT) gene transfection on biological behaviors of human penile smooth muscle cells. METHODS: Human penile smooth muscle cells were grown in primary culture. A fluorescent eukaryotic expression vector, hTERT-internal ribosome entry site 2 (IRES2)-enhanced green fluorescent protein (EGFP), was constructed and transfected into human penile smooth muscle cells using Lipofectin reagent. MAIN OUTCOME MEASURE: The telomerase activity, mitotic index, cell apoptosis, and cell growth curves of transfected smooth muscle cells were determined; the potential formation of malignant phenotypes in these transfected cells was investigated. RESULTS: Telomerase activity, mitotic index, and cell growth of hTERT-transfected cells were significantly higher than those of nontransfected cells and cells transfected with the empty EGFP vector, while apoptosis rates were the lowest in hTERT-transfected cells. No changes in cell morphology, chromosome number, and tumorigenicity were observed between hTERT-transfected cells and control cells. CONCLUSION: In this study, for the first time, the hTERT gene was transfected into human penile smooth muscle cells, and the gene increased telomerase activity in cells, reduced cell apoptosis, and slowed down cell aging. We believe that this finding is of potential clinical value in the prevention and treatment of organic ED. PMID- 22221400 TI - Transparent SiON/Ag/SiON multilayer passivation grown on a flexible polyethersulfone substrate using a continuous roll-to-roll sputtering system. AB - We have investigated the characteristics of a silicon oxynitride/silver/silicon oxynitride [SiON/Ag/SiON] multilayer passivation grown using a specially designed roll-to-roll [R2R] sputtering system on a flexible polyethersulfone substrate. Optical, structural, and surface properties of the R2R grown SiON/Ag/SiON multilayer were investigated as a function of the SiON thickness at a constant Ag thickness of 12 nm. The flexible SiON/Ag/SiON multilayer has a high optical transmittance of 87.7% at optimized conditions due to the antireflection and surface plasmon effects in the oxide-metal-oxide structure. The water vapor transmission rate of the SiON/Ag/SiON multilayer is 0.031 g/m2 day at an optimized SiON thickness of 110 nm. This indicates that R2R grown SiON/Ag/SiON is a promising thin-film passivation for flexible organic light-emitting diodes and flexible organic photovoltaics due to its simple and low-temperature process. PMID- 22221398 TI - Time-series analysis of two hydrothermal plumes at 9 degrees 50'N East Pacific Rise reveals distinct, heterogeneous bacterial populations. AB - We deployed sediment traps adjacent to two active hydrothermal vents at 9 degrees 50'N on the East Pacific Rise (EPR) to assess the variability in bacterial community structure associated with plume particles on the timescale of weeks to months, to determine whether an endemic population of plume microbes exists, and to establish ecological relationships between bacterial populations and vent chemistry. Automated rRNA intergenic spacer analysis (ARISA) indicated that there are separate communities at the two different vents and temporal community variations between each vent. Correlation analysis between chemistry and microbiology indicated that shifts in the coarse particulate (>1 mm) Fe/(Fe+Mn+Al), Cu, V, Ca, Al, (232) Th, and Ti as well as fine-grained particulate (<1 mm) Fe/(Fe+Mn+Al), Fe, Ca, and Co are reflected in shifts in microbial populations. 16S rRNA clone libraries from each trap at three time points revealed a high percentage of Epsilonproteobacteria clones and hyperthermophilic Aquificae. There is a shift toward the end of the experiment to more Gammaproteobacteria and Alphaproteobacteria, many of whom likely participate in Fe and S cycling. The particle-attached plume environment is genetically distinct from the surrounding seawater. While work to date in hydrothermal environments has focused on determining the microbial communities on hydrothermal chimneys and the basaltic lavas that form the surrounding seafloor, little comparable data exist on the plume environment that physically and chemically connects them. By employing sediment traps for a time-series approach to sampling, we show that bacterial community composition on plume particles changes on timescales much shorter than previously known. PMID- 22221401 TI - Outcome of extralevator abdominoperineal excision compared with standard surgery: results from a single centre. AB - AIM: Extralevator abdominoperineal excision (APE) for low rectal tumours has been introduced to achieve improved local radicality. Fewer positive margins and intraoperative perforations have been reported compared with standard APE. The aim of this retrospective study was to compare short-term complications and results of the two techniques in our institution. METHOD: Consecutive patients with rectal cancer undergoing APE between 2004 and 2009 were included. They were divided into two groups of 79 patients in extralevator APE and 79 in standard APE. Patients with recurrence and those having a palliative procedure were excluded. Data were collected from hospital records and the colorectal cancer registry. Main endpoints were wound infection, perineal wound revision, oncological data and length of hospital stay. RESULTS: Circumferential resection margin positivity did not differ significantly between groups (17% extralevator APE; 20% standard APE). Intraoperative perforation (13%vs 10%) or local recurrence (seven in each group) were no different. Perineal wound infection was more common after extralevator APE (46%vs 28%, P<0.05) as was perineal wound revision (22%vs 8%, P<0.05). Hospital stay was longer after extralevator APE (median 12 vs 11days, P<0.05). Tumour height (median 4cm) and pTNM classification did not differ. CONCLUSION: The results do not show any advantage for extralevator APE. The oncological data were no better and postoperative morbidity was increased. Further studies are needed before extralevator APE is widely adopted in clinical practice. PMID- 22221402 TI - Strong intraspecific variation in genetic diversity and genetic differentiation in Daphnia magna: the effects of population turnover and population size. AB - Theory predicts that genetic diversity and genetic differentiation may strongly vary among populations of the same species depending on population turnover and local population sizes. Yet, despite the importance of these predictions for evolutionary and conservation issues, empirical studies comparing high-turnover and low-turnover populations of the same species are scarce. In this study, we used Daphnia magna, a freshwater crustacean, as a model organism for such a comparison. In the southern/central part of its range, D. magna inhabits medium sized, stable ponds, whereas in the north, it occurs in small rock pools with strong population turnover. We found that these northern populations have a significantly lower genetic diversity and higher genetic differentiation compared to the southern/central populations. Total genetic diversity across populations was only about half and average within-population diversity only about a third of that in southern/central populations. Moreover, an average southern population contains more genetic diversity than the whole metapopulation system in the north. We based our analyses both on silent sites and microsatellites. The similarity of our results despite the contrasting mutation rates of these markers suggests that the differences are caused by contemporary rather than by historical processes. Our findings show that variation in population turnover and population size may have a major impact on the genetic diversity and differentiation of populations, and hence may lead to differences in evolutionary processes like local adaptation, hybrid vigour and breeding system evolution in different parts of a species range. PMID- 22221404 TI - Schools as potential vaccination venue for vaccines outside regular EPI schedule: results from a school census in Pakistan. AB - BACKGROUND: Vaccines are the most effective public health intervention. Expanded Program on Immunization (EPI) provides routine vaccination in developing countries. However, vaccines that cannot be given in EPI schedule such as typhoid fever vaccine need alternative venues. In areas where school enrolment is high, schools provide a cost effective opportunity for vaccination. Prior to start of a school-based typhoid vaccination program, interviews were conducted with staff of educational institutions in two townships of Karachi, Pakistan to collect baseline information about the school system and to plan a typhoid vaccination program. Data collection teams administered a structured questionnaire to all schools in the two townships. The administrative staff was requested information on school fee, class enrolment, past history of involvement and willingness of parents to participate in a vaccination campaign. RESULTS: A total of 304,836 students were enrolled in 1,096 public, private, and religious schools (Madrasahs) of the two towns. Five percent of schools refused to participate in the school census. Twenty-five percent of schools had a total enrolment of less than 100 students whereas 3% had more than 1,000 students. Health education programs were available in less than 8% of public schools, 17% of private schools, and 14% of Madrasahs. One-quarter of public schools, 41% of private schools, and 43% of Madrasahs had previously participated in a school-based vaccination campaign. The most common vaccination campaign in which schools participated was Polio eradication program. Cost of the vaccine, side effects, and parents' lack of information were highlighted as important limiting factors by school administration for school-based immunization programs. Permission from parents, appropriateness of vaccine-related information, and involvement of teachers were considered as important factors to improve participation. CONCLUSIONS: Health education programs are not part of the regular school curriculum in developing countries including Pakistan. Many schools in the targeted townships participated in immunization activities but they were not carried out regularly. In the wake of low immunization coverage in Pakistan, schools can be used as a potential venue not only for non-EPI vaccines, but for a catch up vaccination of routine vaccines. PMID- 22221405 TI - A novel method for crystalline silicon solar cells with low contact resistance and antireflection coating by an oxidized Mg layer. AB - One of the key issues in the solar industry is lowering dopant concentration of emitter for high-efficiency crystalline solar cells. However, it is well known that a low surface concentration of dopants results in poor contact formation between the front Ag electrode and the n-layer of Si. In this paper, an evaporated Mg layer is used to reduce series resistance of c-Si solar cells. A layer of Mg metal is deposited on a lightly doped n-type Si emitter by evaporation. Ag electrode is screen printed to collect the generated electrons. Small work function difference between Mg and n-type silicon reduces the contact resistance. During a co-firing process, Mg is oxidized, and the oxidized layer serves as an antireflection layer. The measurement of an Ag/Mg/n-Si solar cell shows that Voc, Jsc, FF, and efficiency are 602 mV, 36.9 mA/cm2, 80.1%, and 17.75%, respectively. It can be applied to the manufacturing of low-cost, simple, and high-efficiency solar cells. PMID- 22221403 TI - Chronic fluoxetine treatment in middle-aged rats induces changes in the expression of plasticity-related molecules and in neurogenesis. AB - BACKGROUND: Antidepressants promote neuronal structural plasticity in young-adult rodents, but little is known of their effects on older animals. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) may mediate these structural changes through its anti-adhesive properties. PSA-NCAM is expressed in immature neurons and in a subpopulation of mature interneurons and its expression is modulated by antidepressants in the telencephalon of young adult rodents. RESULTS: We have analyzed the effects of 14 days of fluoxetine treatment on the density of puncta expressing PSA-NCAM and different presynaptic markers in the medial prefrontal cortex, hippocampus and amygdala of middle-aged (8 months old) rats. The density of puncta expressing PSA-NCAM increased in the dorsal cingulate cortex, as well as in different hippocampal and amygdaloid regions. In these later regions there were also increases in the density of puncta expressing glutamic acid decarboxylase 65/67 (GAD6), synaptophysin (SYN), PSA-NCAM/SYN and PSA-NCAM/GAD6, but a decrease of those expressing vesicular glutamate transporter 1 (VGluT1). Since there is controversy on the effects of antidepressants on neurogenesis during aging, we analyzed the number of proliferating cells expressing Ki67 and that of immature neurons expressing doublecortin or PSA-NCAM. No significant changes were found in the subgranular zone, but the number of proliferating cells decreased in the subventricular zone. CONCLUSIONS: These results indicate that the effects of fluoxetine in middle-aged rats are different to those previously described in young-adult animals, being more restricted in the mPFC and even following an opposite direction in the amygdala or the subventricular zone. PMID- 22221406 TI - Catalytic ozone oxidation of benzene at low temperature over MnOx/Al-SBA-16 catalyst. AB - The low-temperature catalytic ozone oxidation of benzene was investigated. In this study, Al-SBA-16 (Si/Al = 20) that has a three-dimensional cubic Im3m structure and a high specific surface area was used for catalytic ozone oxidation for the first time. Two different Mn precursors, i.e., Mn acetate and Mn nitrate, were used to synthesize Mn-impregnated Al-SBA-16 catalysts. The characteristics of these two catalysts were investigated by instrumental analyses using the Brunauer-Emmett-Teller method, X-ray diffraction, X-ray photoelectron spectroscopy, and temperature-programmed reduction. A higher catalytic activity was exhibited when Mn acetate was used as the Mn precursor, which is attributed to high Mn dispersion and a high degree of reduction of Mn oxides formed by Mn acetate than those formed by Mn nitrate. PMID- 22221407 TI - Adsorption behavior of Eu(III) on partially Fe(III)- or Ti(IV)-coated silica. AB - The adsorption behavior of Eu(III) onto silica surface, which was partially coated with Fe(III) or Ti(IV), was investigated to determine Fe(III) or Ti(IV) effects on the surface reaction of lanthanides on mineral surfaces in groundwater. Compared with a parallel uncoated silica, the Fe(III)-coated silica did not enhance the adsorption of Eu(III). However, enhanced adsorption of Eu(III) on the Ti(IV)-coated silica was observed by increasing the amount of Ti(IV) on the silica surface. PMID- 22221408 TI - Duration of untreated psychosis in a rural/suburban region of Japan. AB - AIMS: We examined the duration of untreated psychosis (DUP) and its social and clinical correlates in patients with schizophrenia in a rural/suburban region of Japan. METHODS: We conducted a retrospective cohort study of patients with first episode psychosis from 11 hospitals in Kochi Prefecture. There were 108 patients who met the eligibility criteria, and data regarding their DUP and social/clinical variables were collected. RESULTS: The median (mean) DUP of our cohort was 10.5 (34.6) months. Longer DUP was associated with younger age at onset, older age at first consultation, less educational attainment, insidious mode of onset and not being accompanied by another person at first consultation. After adjusting for confounding factors, age at onset, age at first consultation and mode of onset remained significantly and independently associated with DUP. In terms of treatment and response, longer DUP was associated with less antipsychotics prescribed upon first visit, and worse Clinical Global Impression Severity and Improvement scores after 1 year. CONCLUSION: The patients treated in a rural/suburban region of Japan had a long DUP, and shortening their DUP through promoting family involvement could improve their outcomes. PMID- 22221409 TI - Response variability to clopidogrel: is tailored treatment, based on laboratory testing, the right solution? AB - Clopidogrel is an antithrombotic prodrug, whose active metabolite inhibits platelet function by irreversibly binding to the platelet receptor for adenosine diphosphate, P2Y(12). Wide inter-individual variability of response to clopidogrel has been reported in several studies: a significant proportion of treated patients (about one-third) exhibit a suboptimal inhibition of platelet function. Genetic and environmental factors that influence the absorption and/or the extent of metabolism of clopidogrel to its active metabolite account for the observed variability of response. Tailored treatment based on the results of laboratory tests of platelet function has been proposed as a solution to this problem, which has important clinical implications. Although it is often considered a desirable evolution of modern medicine, tailored treatment based on laboratory tests is actually an old remedy (of yet unproven efficacy, in the case of antiplatelet therapy) for the problem of response variability to antithrombotic drugs with unpredictable bioavailability. When possible, the use of alternative drugs with more uniform and predictable bioavailability, and with favourable profiles in terms of risk/benefit and cost-benefit ratios should be preferred. Moreover, tailored treatment with laboratory tests must be validated in randomized clinical trials before its implementation can be recommended. We still need to identify and standardize the laboratory test for this purpose, as well as answer basic questions on its clinical utility and cost-effectiveness, before tailoring clopidogrel therapy based on laboratory tests can be recommended in clinical practise. PMID- 22221410 TI - Sacral nerve stimulation enhances epithelial barrier of the rectum: results from a porcine model. AB - BACKGROUND: The mechanism of action of sacral nerve stimulation (SNS) remains largely elusive. The aims of this study were to develop a clinically relevant animal model for percutaneous SNS and to describe its effect on the epithelial barrier of the rectum. METHODS: Under general anesthesia and after percutaneous electrode placement for S3 nerve root stimulation, six pigs underwent unilateral stimulation and six bilateral stimulation. Animals were stimulated for 3 h using an external pulse generator (1-2.5 V; 14 Hz; 210 MUs). Six animals underwent electrode implantation without stimulation and served as controls. Full-thickness rectal biopsies were performed prior to and after stimulation. Paracellular permeability was evaluated by measuring sulfonic acid flux across the rectal mucosa in Ussing chambers. Histological assessment of mucosal thickness, epithelial desquamation, and mucus expression were performed. KEY RESULTS: Percutaneous stimulation resulted in successful anal contractions whose amplitude and uniformity was enhanced following bilateral compared with unilateral stimulation. In controls, paracellular permeability significantly increased during the stimulation period whereas it remained unchanged following unilateral stimulation. In contrast, permeability was significantly reduced by bilateral stimulation. This effect was associated with a concomitant reduction in mucosal thickness and a trend toward increased amount of mucus on surface epithelium compared with controls. CONCLUSIONS & INFERENCES: The development of a porcine model of percutaneous SNS revealed the ability of neuromodulation to reinforce rectal epithelial barrier. Furthermore, our results suggest that SNS could be used for treatment of gastrointestinal pathologies with reduced rectal mucosal barrier functions. PMID- 22221411 TI - Palmitic and linoleic acids induce ER stress and apoptosis in hepatoma cells. AB - OBJECTIVES: Hepatic inflammation and degeneration induced by lipid depositions may be the major cause of nonalcoholic fatty liver disease. In this study, we tried to investigate the effects of saturated and unsaturated fatty acids on hepatoma cell apoptosis. METHODS: H4IIE liver cells were treated with palmitic acid, linoleic acid, or both with or without the calcium-specific chelator BAPTA AM after which the expression of proteins associated with endoplasmic reticulum (ER) stress, apoptosis, caspase-3 levels, and calcium flux were measured. RESULTS: Palmitic or linoleic acid (250 MUM) induced H4IIE cell apoptosis, which required calcium flux but not caspase-3. Apoptosis was not observed when cells were co-treated with linoleic acid (125 MUM) and palmitic acid (250 MUM). Importantly, the release of cytochrome C from mitochondria into cytoplasm during cell apoptosis was specifically detected only when linoleic acid (125 MUM), but not palmitic acid (250 MUM), was added to the cells. Depletion of intracellular calcium flux by the calcium-specific chelator, BAPTA-AM, abolished linoleic acid induced apoptosis. Moreover, in the presence of BAPTA-AM, expression of the unfolded protein response (UPR)-associated genes, CHOP, GRP78, and GRP94, was induced by linoleic acid, but not palmitic acid. CONCLUSIONS: The results suggest that linoleic acid promotes cell apoptosis through the release of cytochrome C, only if the intracellular calcium flux is unperturbed and intact. These results confirm that ER stress contributes to fatty acid-induced liver cell apoptosis. PMID- 22221412 TI - Control of voluntary feed intake in fish: a role for dietary oxygen demand in Nile tilapia (Oreochromis niloticus) fed diets with different macronutrient profiles. AB - It has been hypothesised that, at non-limiting water oxygen conditions, voluntary feed intake (FI) in fish is limited by the maximal physiological capacity of oxygen use (i.e. an 'oxystatic control of FI in fish'). This implies that fish will adjust FI when fed diets differing in oxygen demand, resulting in identical oxygen consumption. Therefore, FI, digestible energy (DE) intake, energy balance and oxygen consumption were monitored at non-limiting water oxygen conditions in Nile tilapia fed diets with contrasting macronutrient composition. Diets were formulated in a 2 * 2 factorial design in order to create contrasts in oxygen demand: two ratios of digestible protein (DP):DE ('high' v. 'low'); and a contrast in the type of non-protein energy source ('starch' v. 'fat'). Triplicate groups of tilapia were fed each diet twice daily to satiation for 48 d. FI (g DM/kg(0.8) per d) was significantly lower (9.5%) in tilapia fed the starch diets relative to the fat diets. The DP:DE ratio affected DE intakes (P < 0.05), being 11% lower with 'high' than with 'low' DP:DE ratio diets, which was in line with the 11.9% higher oxygen demand of these diets. Indeed, DE intakes of fish showed an inverse linear relationship with dietary oxygen demand (DOD; R 2 0.81, P < 0.001). As hypothesised ('oxystatic' theory), oxygen consumption of fish was identical among three out of the four diets. Altogether, these results demonstrate the involvement of metabolic oxygen use and DOD in the control of FI in tilapia. PMID- 22221413 TI - Models of case management for working with young children: implications for mental health nurses. AB - The care of children with behavioural disorders/mental illnesses is an important and emerging role for mental health nurses. Unfortunately, there is little evidence on which to base their practice. Children, because of their rapid emotional, physical, and cognitive development, and their dependence on their families, need special consideration in their mental health care. The limited evidence available indicates that this special consideration should include a focus, not only on the child, but also on the parents and social and school networks of the child. Evidence from the adult literature indicates the most effective case management models are the ones in which the case manager offers as many services as possible, including talking therapies. This also seems to be true when working with children. Mental health nurses, because of their background and commitment to holistic care, are ideally suited to offer this type of service. However, mental health nurses have not been good at articulating what they do. This can limit the recognition of the contribution they make and their opportunities. PMID- 22221414 TI - Mapping of quantitative trait loci controlling lifespan in the short-lived fish Nothobranchius furzeri--a new vertebrate model for age research. AB - The African annual fish Nothobranchius furzeri emerged as a new model for age research over recent years. Nothobranchius furzeri show an exceptionally short lifespan, age-dependent cognitive/behavioral decline, expression of age-related biomarkers, and susceptibility to lifespan manipulation. In addition, laboratory strains differ largely in lifespan. Here, we set out to study the genetics of lifespan determination. We crossed a short- to a long-lived strain, recorded lifespan, and established polymorphic markers. On the basis of genotypes of 411 marker loci in 404 F(2) progeny, we built a genetic map comprising 355 markers at an average spacing of 5.5 cM, 22 linkage groups (LGs) and 1965 cM. By combining marker data with lifespan values, we identified one genome-wide highly significant quantitative trait locus (QTL) on LG 9 (P < 0.01), which explained 11.3% of the F(2) lifespan variance, and three suggestive QTLs on LG 11, 14, and 17. We characterized the highly significant QTL by synteny analysis, because a genome sequence of N. furzeri was not available. We located the syntenic region on medaka chromosome 5, identified candidate genes, and performed fine mapping, resulting in a c. 40% reduction of the initial 95% confidence interval. We show both that lifespan determination in N. furzeri is polygenic, and that candidate gene detection is easily feasible by cross-species analysis. Our work provides first results on the way to identify loci controlling lifespan in N. furzeri and illustrates the potential of this vertebrate species as a genetic model for age research. PMID- 22221415 TI - Diagnostic characteristics of S100A8/A9 in a multicenter study of patients with acute right lower quadrant abdominal pain. AB - OBJECTIVES: Over the past decade, clinicians have become increasingly reliant on computed tomography (CT) for the evaluation of patients with suspected acute appendicitis. To limit the radiation risks and costs of CT, investigators have searched for biomarkers to aid in diagnostic decision-making. We evaluated one such biomarker, calprotectin or S100A8/A9, and determined the diagnostic performance characteristics of a developmental biomarker assay in a multicenter investigation of patients presenting with acute right lower quadrant abdominal pain. METHODS: This was a prospective, double-blinded, single-arm, multicenter investigation performed in 13 emergency departments (EDs) from August 2009 to April 2010 of patients presenting with acute right lower quadrant abdominal pain. Plasma samples were tested using the investigational S100A8/A9 assay. The primary outcome of acute appendicitis was determined by histopathology for patients undergoing appendectomy or 2-week telephone follow-up for patients discharged without surgery. The sensitivity, specificity, negative likelihood ratio (LR-), and positive likelihood ratio (LR+) of the biomarker assay were calculated using the prespecified cutoff value of 14 units. A post hoc stability study was performed to investigate the potential effect of time and courier transport on the measured value of the S100A8/A9 assay test results. RESULTS: Of 1,052 enrolled patients, 848 met criteria for analysis. The median age was 24.5 years (interquartile range [IQR] = 16-38 years), 57% were female, and 50% were white. There was a 27.5% prevalence of acute appendicitis. The sensitivity and specificity for the investigational S100A8/A9 assay in diagnosing acute appendicitis were estimated to be 96% (95% confidence interval [CI] = 93% to 98%) and 16% (95% CI = 13% to 19%), respectively. The LR- ratio was 0.24 (95% CI = 0.12 to 0.47), and the LR+ was 1.14 (95% CI = 1.10 to 1.19). The post hoc stability study demonstrated that in the samples that were shipped, the estimated time coefficient was 7.6 * 10(-3) +/- 2.0 * 10(-3) log units/hour, representing an average increase of 43% in the measured value over 48 hours; in the samples that were not shipped, the estimated time coefficient was 2.5 * 10(-3) +/- 0.4 * 10(-3) log units/hour, representing a 13% increase on average in the measured value over 48 hours, which was the maximum delay allowed by the study protocol. Thus, adjusting the cutoff value of 14 units by the magnitude of systematic inflation observed in the stability study at 48 hours would result in a new cutoff value of 20 units and a "corrected" sensitivity and specificity of 91 and 28%, respectively. CONCLUSIONS: In patients presenting with acute right lower quadrant abdominal pain, we found the investigational enzyme-linked immunosorbent assay (ELISA) test for S100A8/A9 to perform with high sensitivity but very limited specificity. We found that shipping effect and delay in analysis resulted in a subsequent rise in test values, thereby increasing the sensitivity and decreasing the specificity of the test. Further investigation with hospital-based laboratory analyzers is the next critical step for determining the ultimate clinical utility of the ELISA test for S100A8/A9 in ED patients presenting with acute right lower quadrant abdominal pain. PMID- 22221416 TI - The study of subjective experience as a scientific task for psychopathology. A commentary on Stoyanov, D., Machamer, P.K. & Schaffner, K.F. (2012). Journal of Evaluation in Clinical Practice 18 (1) 149-154. PMID- 22221417 TI - Is incremental validity too incremental in the long run? A commentary on Stoyanov D., Machamer P.K. & Schaffner, K.F. (2012). Journal of Evaluation in Clinical Practice, 18 (1) 149-154. PMID- 22221418 TI - Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the Norwegian HUNT 2 study. PMID- 22221419 TI - Leadership and transitions: maintaining the science in complexity and complex systems. AB - It is the 'moral compass', however subtle, that underpins leadership. Leadership, meaning showing the way, demands as much conviction as gentile diplomacy in the discourse with supporters and detractors. In particular, leadership defends the goal by safeguarding its principles from its detractors. The authors writing in the Forum on Complexity in Medicine and Healthcare since its inception are leaders in an intellectual transition to complex systems thinking in medicine and health. PMID- 22221420 TI - Understanding health system reform - a complex adaptive systems perspective. AB - BACKGROUND: Everyone wants a sustainable well-functioning health system. However, this notion has different meaning to policy makers and funders compared to clinicians and patients. The former perceive public policy and economic constraints, the latter clinical or patient-centred strategies as the means to achieving a desired outcome. DESIGN: Theoretical development and critical analysis of a complex health system model. RESULTS AND CONCLUSIONS: We introduce the concept of the health care vortex as a metaphor by which to understand the complex adaptive nature of health systems, and the degree to which their behaviour is predetermined by their 'shared values' or attractors. We contrast the likely functions and outcomes of a health system with a people-centred attractor and one with a financial attractor. This analysis suggests a shift in the system's attractor is fundamental to progress health reform thinking. PMID- 22221423 TI - Resurrecting an extinct salmon evolutionarily significant unit: archived scales, historical DNA and implications for restoration. AB - Archival scales from 603 sockeye salmon (Oncorhynchus nerka), sampled from May to July 1924 in the lower Columbia River, were analysed for genetic variability at 12 microsatellite loci and compared to 17 present-day O. nerka populations exhibiting either anadromous (sockeye salmon) or nonanadromous (kokanee) life histories-from throughout the Columbia River Basin, including areas upstream of impassable dams built subsequent to 1924. Statistical analyses identified four major genetic assemblages of sockeye salmon in the 1924 samples. Two of these putative historical groupings were found to be genetically similar to extant evolutionarily significant units (ESUs) in the Okanogan and Wenatchee Rivers (pairwise F(ST) = 0.004 and 0.002, respectively), and assignment tests were able to allocate 77% of the fish in these two historical groupings to the contemporary Okanogan River and Lake Wenatchee ESUs. A third historical genetic grouping was most closely aligned with contemporary sockeye salmon in Redfish Lake, Idaho, although the association was less robust (pairwise F(ST) = 0.060). However, a fourth genetic grouping did not appear to be related to any contemporary sockeye salmon or kokanee population, assigned poorly to the O. nerka baseline, and had distinctive early return migration timing, suggesting that this group represents a historical ESU originating in headwater lakes in British Columbia that was probably extirpated sometime after 1924. The lack of a contemporary O. nerka population possessing the genetic legacy of this extinct ESU indicates that efforts to reestablish early-migrating sockeye salmon to the headwater lakes region of the Columbia River will be difficult. PMID- 22221422 TI - Differential effects of AdOx on gene expression in P19 embryonal carcinoma cells. AB - BACKGROUND: Pluripotent cells maintain a unique gene expression pattern and specific chromatin signature. In this study, we explored the effect of the methyltransferase inhibitor adenosine dialdehyde (AdOx) on pluripotency maintenance and gene expression in P19 embryonal carcinoma cells. RESULTS: After AdOx treatment, the pluripotency-related gene network became disordered, and the early developmental genes were released from the repression. Remarkably, AdOx caused contrasting effects on the expression of two key pluripotency genes, nanog and oct3/4, with the reduction of the repressive histone marks H3K27me3, H3K9me3 and H3K9me2 only in the nanog gene. CONCLUSIONS: Key pluripotency genes were controlled by different mechanisms, including the differential enrichment of repressive histone methylation marks. These data provided novel clues regarding the critical role of histone methylation in the maintenance of pluripotency and the determination of cell fate in P19 pluripotent cells. PMID- 22221424 TI - Adherence to isoniazid preventive therapy in Indonesian children: A quantitative and qualitative investigation. AB - BACKGROUND: It is recommended that young child contacts of sputum smear positive tuberculosis cases receive isoniazid preventive therapy (IPT) but reported adherence is low and risk factors for poor adherence in children are largely unknown. METHODS: We prospectively determined rates of IPT adherence in children < 5 yrs in an Indonesian lung clinic. Possible risk factors for poor adherence, defined as <=3 months prescription collection, were calculated using logistic regression. To further investigate adherence barriers in-depth interviews were conducted with caregivers of children with good and poor adherence. RESULTS: Eighty-two children eligible for IPT were included, 61 (74.4%) of which had poor adherence. High transport costs (OR 3.3, 95% CI 1.1-10.2) and medication costs (OR 20.0, 95% CI 2.7-414.5) were significantly associated with poor adherence in univariate analysis. Access, medication barriers, disease and health service experience and caregiver TB and IPT knowledge and beliefs were found to be important determinants of adherence in qualitative analysis. CONCLUSION: Adherence to IPT in this setting in Indonesia is extremely low and may result from a combination of financial, knowledge, health service and medication related barriers. Successful reduction of childhood TB urgently requires evidence-based interventions that address poor adherence to IPT. PMID- 22221425 TI - Indoor formaldehyde removal over CMK-3. AB - The removal of formaldehyde at low concentrations is important in indoor air pollution research. In this study, mesoporous carbon with a large specific surface area was used for the adsorption of low-concentration indoor formaldehyde. A mesoporous carbon material, CMK-3, was synthesized using the nano replication method. SBA-15 was used as a mesoporous template. The surface of CMK 3 was activated using a 2N H2SO4 solution and NH3 gas to prepare CMK-3-H2SO4 and CMK-3-NH3, respectively. The activated samples were characterized by N2 adsorption-desorption, X-ray diffraction, and X-ray photoelectron spectroscopy. The formaldehyde adsorption performance of the mesoporous carbons was in the order of CMK-3-NH3 > CMK-3-H2SO4 > CMK-3. The difference in the adsorption performance was explained by oxygen and nitrogen functional groups formed during the activation process and by the specific surface area and pore structure of mesoporous carbon. PMID- 22221426 TI - Durability test with fuel starvation using a Pt/CNF catalyst in PEMFC. AB - In this study, a catalyst was synthesized on carbon nanofibers [CNFs] with a herringbone-type morphology. The Pt/CNF catalyst exhibited low hydrophilicity, low surface area, high dispersion, and high graphitic behavior on physical analysis. Electrodes (5 cm2) were prepared by a spray method, and the durability of the Pt/CNF was evaluated by fuel starvation. The performance was compared with a commercial catalyst before and after accelerated tests. The fuel starvation caused carbon corrosion with a reverse voltage drop. The polarization curve, EIS, and cyclic voltammetry were analyzed in order to characterize the electrochemical properties of the Pt/CNF. The performance of a membrane electrode assembly fabricated from the Pt/CNF was maintained, and the electrochemical surface area and cell resistance showed the same trend. Therefore, CNFs are expected to be a good support in polymer electrolyte membrane fuel cells. PMID- 22221427 TI - Effects on small airway obstruction of long-term treatments with beclomethasone/formoterol hydrofluoroalkane (metered-dose inhaler) versus fluticasone/salmeterol (dry-powder inhaler) in asthma: a preliminary study. AB - New formulations of extrafine particles of long-acting beta-2 agonists plus inhaled corticosteroids (LABA + ICS) have been shown to reach peripheral regions of the lung. The aim of the study was to assess the effect on small airway obstruction of long-term treatments with two different LABA + ICS formulations in asthma. Ten subjects with moderate persistent asthma were enrolled. After a 4 week washout period they were treated in a randomized crossover design for 24 weeks with formoterol, 12 micrograms, and beclomethasone, 200 micrograms, hydrofluoroalkane (HFA; by metered-dose inhaler) b.i.d. (FB) or salmeterol, 50 micrograms, and fluticasone, 250 micrograms (by dry-powder inhaler), b.i.d. (SF). At baseline and at the end of each period subjects underwent an Asthma Control Test (ACT) and Pulmonary Function Testing. The N(2) phase III slope and closing volume (CV) during single-breath washout test and difference between the maximal expiratory flow rates with air and heliox at isovolume corresponding to 50% [Delta(heliox-air)MEF(50%)] were measured to assess changes on peripheral airways function. Two subjects dropped out and eight completed the study. After SF and FB, forced expiratory volume at 1 second (FEV(1); p < 0.01) and FEV(1)/forced vital capacity (FVC; p < 0.01 for SF and p < 0.05 for FB) increased when compared with baseline. Although both FB and SF treatments slightly increased delta(heliox air)MEF(50% isovolume) versus baseline, only after FB the N(2) phase III slope and CV decreased from 1.61 +/- 0.61%/L to 1.35 +/- 0.49 N(2)%/L (p = 0.054) and from 0.98 +/- 0.56 L to 0.88 +/- 0.58 L (p < 0.05), respectively. ACT score raised from 19 +/- 5 (baseline) to 23 +/- 1 after FB (p < 0.02) and 23 +/- 2 after SF (p < 0.05). When compared with baseline and in contrast to SF (50/250 micrograms b.i.d.), FB HFA (12/200 micrograms b.i.d.) significantly improved functional parameters reflecting small airway obstruction in asthmatic patients. Registered in the public trial registry at www.ClinicalTrials.gov identifier: NCT01255579. PMID- 22221428 TI - Economic burden of asthma in Korea. AB - Understanding the magnitude of the economic impact of an illness on society is fundamental to planning and implementing relevant policies. South Korea operates a compulsory universal health insurance system providing favorable conditions for evaluating the nationwide economic burden of illnesses. The aim of this study was to estimate the economic costs of asthma imposed on Korean society. The Korean National Health Insurance claims database was used for determining the health care services provided to asthma patients defined as having at least one inpatient or outpatient claim(s) with a primary diagnosis of asthma in 2008. Both direct and indirect costs were included. Direct costs were those associated directly with treatment, medication, and transportation. Indirect costs were assessed in terms of the loss of productivity in asthma patients and their caregivers and consisted of morbidity cost, mortality cost, and caregivers' time cost. The estimated cost for 2,273,290 asthma patients in 2008 was $831 million, with an average per capita cost of $336. Among the cost components, outpatient and medication costs represented the largest cost burden. Although the costs for children accounted for the largest proportion of the total cost, the per capita cost was highest among patients >=50 years old. The economic burden of asthma in Korea is considerable. Considering that the burden will increase with the rising prevalence, implementation of effective national prevention approaches aimed at the appropriate target populations is imperative. PMID- 22221429 TI - Prevalence of attention deficit/hyperactivity disorder in pediatric allergic rhinitis: a nationwide population-based study. AB - Allergic rhinitis (AR) is the most common chronic condition in pediatric populations. Characteristic symptoms in AR may bother daily activities and disturb sleep, leading to daytime inattention, irritability, and hyperactivity, which are also components of attention deficit/hyperactivity disorder (ADHD). Conflicting data exist in the literature regarding the relationship between ADHD and AR. The aim of this nationwide population-based study was to examine the prevalence and risk of ADHD among AR patients in a pediatric group. Data from a total of 226,550 pediatric patients <18 years old were collected from Taiwan's National Health Insurance Research Database from January 1 to December 31, 2005 and analyzed. We calculated the prevalence of allergic diseases based on various demographic variables, as well as in ADHD patients. We also used multivariable logistic regression to analyze the risk factors of ADHD. In 2005, the period prevalence rates of atopy and ADHD in patients <18 years of age were 15.35 and 0.6%, respectively. Pediatric patients with AR had a substantially increased rate of ADHD (p < 0.001) in terms of period prevalence and odds ratio. This significance existed across various demographic groups regardless of age, gender, area, or degree of urbanization. Neither comorbidity of atopic dermatitis nor bronchial asthma carried high risk for ADHD in AR patients. The present study revealed an increased rate of ADHD among AR patients. Therefore, evaluation of ADHD is advised for treatment of AR children. PMID- 22221430 TI - Phenotypes of IgE-mediated food allergy in Turkish children. AB - Data on food allergy-related comorbid diseases and the knowledge on factors associating specific food types with specific allergic outcomes are limited. The aim of this study was to determine the clinical spectrum of IgE-dependent food allergy and the specific food-related phenotypes in a group of children with IgE mediated food allergy. Children diagnosed with IgE-mediated food allergy were included in a cross-sectional study. IgE-mediated food allergy was diagnosed in the presence of specific IgE or skin-prick test and a consistent and clear-cut history of food-related symptoms or positive open provocation test. Egg (57.8%), cow's milk (55.9%), hazelnut (21.9%), peanut (11.7%), walnut (7.6%), lentil (7.0%), wheat (5.7%), and beef (5.7%) were the most common food allergies in children with food allergy. The respiratory symptoms and pollen sensitization were more frequent in children with isolated tree nuts-peanut allergy compared with those with egg or milk allergy (p < 0.001); whereas atopic dermatitis was more frequent in children with isolated egg allergy compared with those with isolated cow's milk and tree nuts-peanut allergy (p < 0.001). Children with food allergy were 3.1 (p = 0.003) and 2.3 (p = 0.003) times more likely to have asthma in the presence of allergic rhinitis and tree nuts-peanut allergy, respectively. Interestingly, children with atopic dermatitis were 0.5 (p = 0.005) times less likely to have asthma. Asthma (odds ratio [OR], 2.3; p = 0.002) and having multiple food allergies (OR, 5.4; p < 0.001) were significant risk factors for anaphylaxis. The phenotypes of IgE-mediated food allergy are highly heterogeneous and some clinical phenotypes may be associated with the specific type of food and the number of food allergies. PMID- 22221432 TI - Hereditary angioedema: classification, pathogenesis, and diagnosis. AB - Hereditary angioedema (HAE) is a rare autosomal dominant genetic disorder associated with a deficiency in C1 inhibitor. More than 200 mutations in this gene, located on chromosome 11, have been identified. Although HAE is often inherited, 20-25% of cases are from new spontaneous mutations and they have no family history of swelling. Decreased C1 inhibitor activity leads to inappropriate activation of multiple pathways, including the complement and contact systems and the fibrinolysis and coagulation systems. Reduced C1 inhibitor activity results in increased activation of plasma kallikrein-kinin system proteases and increased bradykinin levels. Bradykinin is felt to be the main mediator of symptoms in HAE. Patients with HAE have recurrent episodes of swelling of the extremities, abdomen, face, and upper airway. Angioedema involving the gastrointestinal tract can lead to intestinal wall edema, which results in abdominal pain, nausea, vomiting, and diarrhea. Laryngeal swelling is life-threatening and may lead to asphyxia. Common triggers of an attack include trauma, stress, infection, menstruation, oral contraceptives, hormone replacement therapy, and angiotensin-converting enzyme inhibitors. Laboratory testing including C4, C1 inhibitor level, and function is needed to confirm or rule out the diagnosis of HAE. The treatment of HAE has improved significantly in recent years with the availability of several safe and effective therapies. Several consensus guidelines have been created to further assist in the management of HAE patients. This review will provide an update on the classification, pathophysiology, clinical presentation, and diagnosis of HAE. PMID- 22221431 TI - Prevalence trends of rhinoconjunctivitis, eczema, and atopic asthma in Greek schoolchildren: four surveys during 1991-2008. AB - After a continuous increase of asthma, hay fever, and eczema during 1991-2003 among schoolchildren in Patras, Greece, the prevalence of current wheeze/asthma (diagnosed wheezing and/or asthma in the past 2 years) has reached a plateau (6.9%) during the period 2004-2008. Using methodology identical to the three previously conducted cross-sectional, parental questionnaire surveys (1991, n = 2417; 1998, n = 3076; 2003, n = 2725) we examined further trends in the prevalence of rhinoconjunctivitis and eczema in the same urban environment among third and fourth grade schoolchildren (8-9 years old) in 2008 (n = 2688). In the four surveys, respective prevalence rates of rhinoconjunctivitis were 2.1, 3.4, 4.6, and 5.1% (absolute prevalence increase: 1998 versus 1991, 61.9%; 2003 versus 1998, 35.5%; 2008 versus 2003, 10.9%) and those of eczema were 4.5, 6.3, 9.5, and 10.8% (absolute prevalence increase: 1998 versus 1991, 40.0%; 2003 versus 1998, 50.8%; 2008 versus 2003, 13.7%; sex-adjusted p for trend, <0.001). Among current wheezer/asthmatic patients there was an increase in lifetime rhinoconjunctivitis (sex-adjusted p for trend, <0.001) and lifetime eczema (sex adjusted p for tend, <0.001) over the period 1991-2008. The proportion of atopic wheeze/asthma (current asthma with lifetime rhinoconjunctivitis and/or eczema) increased further during 2003-2008 (p < 0.05; p for trend during 1991-2008, <0.001). In conclusion, there is a continuous increase in the prevalence of allergic manifestations-rhinoconjunctivitis and eczema-among preadolescent children in Patras, Greece, during the period 1991-2008. After a steep rise during 1991-2003, the frequency of atopic wheeze/asthma continued to increase at a decelerating rate during 2003-2008, while wheeze/asthma prevalence remained unchanged during the same 5-year period. PMID- 22221433 TI - Update on angioedema: evaluation, diagnosis, and treatment. AB - Hereditary Angioedema (HAE) is a multisystem, autosomal dominant disease that affects ~1:10,000 to 1:50,000 individuals in the United States. The disease has several clinical characteristics that distinguish it from other forms of angioedema. Recurrent swelling attacks involve the abdomen, face, extremities, genitalia, oropharynx, or larynx without urticaria. The swelling attacks are typically unilateral, nonpitting, nonpruritic, and, although uncomfortable, are often painless. Other forms of isolated angioedema such as acquired angioedema and angiotensin-converting enzyme-induced angioedema have similar characteristics of HAE. Therefore, evaluation of patients with recurrent angioedema should be directed at excluding these different forms of angioedema before a diagnosis of idiopathic angioedema is made. The objective of this article is to provide an overview of the differential diagnosis of angioedema that reflects the angioedema guidelines that are currently in development. PMID- 22221434 TI - Safety update regarding intranasal corticosteroids for the treatment of allergic rhinitis. AB - Intranasal corticosteroids (INSs) are the most efficacious medication for the treatment of allergic rhinitis. In 2006, the Joint Task Force of the American College of Allergy, Asthma, and Immunology, and the American Academy of Allergy, Asthma, and Immunology, published a white paper on the potential over-the-counter switch of INS (Bielory L, Blaiss M, Fineman SM, et al. Concerns about intranasal corticosteroids for over-the-counter use: Position statement of the Joint Task Force for the American Academy of Allergy, Asthma and Immunology and the American College of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 96:514-525, 2006). The concern of the paper was the safety of the use of these agents without oversight by a health care professional. The objective of this paper was to review published literature on the safety of INS since the publication of the task force white paper. Recent studies, which evaluated topical and systemic adverse events associated with ciclesonide (CIC), fluticasone furoate (FF), mometasone furoate (MF), triamcinolone acetonide, fluticasone propionate, budesonide, and beclomethasone dipropionate were summarized. In general, no significant topical or systemic complications were observed in these studies, although none were >1 year in duration. The newer formulations of topical corticosteroids for allergic rhinitis, such as CIC, FF, and MF, which have less systemic bioavailability, may be safer for long-term use. New studies continue to add to the reassurance of the safety of INSs in the treatment of allergic rhinitis but still do not answer the question if these agents are appropriate for long-term use without oversight by a health care professional. PMID- 22221435 TI - Antidepressants in chronic idiopathic urticaria. AB - Chronic idiopathic urticaria (CIU) is a common disease estimated to affect 0.1% of the population and can be very difficult to treat. Many psychotropic medications have been reported to be successful in treating refractory CIU. The purpose of this article was to discuss the pathophysiology of chronic urticaria and provide practicing allergists and dermatologists alternative treatment options in the management of refractory CIU, especially in those who have concurrent psychiatric comorbidity. A review was performed of pertinent literature pertaining to the pathophysiology of CIU and the many psychotropic medications reportedly successful in disease management. Although more research is needed, this article serves to broaden the mind of the physician treating CIU. PMID- 22221436 TI - Exercise-induced bronchospasm in children with asthma in the United States: results from the Exercise-Induced Bronchospasm Landmark Survey. AB - Despite the availability of effective therapies, uncontrolled asthma remains a common problem. Previous large surveys suggest that exercise-related respiratory symptoms may be a significant element of uncontrolled asthma. The Exercise Induced Bronchospasm (EIB) Landmark Survey is the first comprehensive, national survey evaluating EIB awareness and impact among the general public, asthma patients, and health care providers. This study was designed to evaluate the prevalence and impact of exercise-related respiratory symptoms in children (aged 4-17 years) with asthma. A national survey was conducted with parents of 516 children diagnosed with asthma or taking medications for asthma in the prior year. The majority of parents reported that their child experienced one or more exercise-related respiratory symptom and almost one-half (47.4%) experienced four or more symptoms. Most commonly reported symptoms were coughing, shortness of breath, and wheezing. Respondents reported that asthma limited their child's ability to participate either "a lot" or "some" in sports (30%), other outdoor activities (26.3%), and normal physical exertion (20.9%). Only 23.1% of children with exercise-related respiratory symptoms were reported to take short-acting beta-agonists such as albuterol "always" or "most of the time" before exercising. Exercise-related respiratory symptoms among pediatric asthma patients are common and substantially limit the ability of children to participate normally and perform optimally in physical activities. Such symptoms may reflect uncontrolled underlying asthma that should be evaluated and treated with appropriate controller medications. Despite the availability of preventative therapy, many children do not use short-acting bronchodilators before exercise as recommended in national guidelines. PMID- 22221437 TI - Impact of exercise-related respiratory symptoms in adults with asthma: Exercise Induced Bronchospasm Landmark National Survey. AB - An estimated 5-20% of the general population and up to 90% of people with asthma experience exercise-induced bronchospasm (EIB). The EIB Landmark Survey is the first comprehensive study on exercise-related respiratory symptoms in the United States. Two surveys were conducted: the first surveyed adults (>=18 years) in the general public and the second surveyed adults with asthma or taking medications for asthma in the prior year. Parameters assessed included exercise-related respiratory symptoms, activity levels, and short-acting beta-antagonist (SABA) use. In the general public survey (n = 1085), 8% were currently diagnosed with asthma. However, 29% reported experiencing one or more of six respiratory-related symptoms during or immediately after exercising. In the EIB in adult asthma survey (n = 1001), although >80% of adults experienced one or more of six exercise-related respiratory symptoms, only 30.6% reported a diagnosis of EIB. Almost one-half (45.6%) of adults with asthma reported that they avoid physical activities because of symptoms. Despite symptoms, only 22.2% of respondents took SABAs before exercise "always" or "most of the time"; 36.3% took rescue medications after or during exercise. Exercise-related respiratory symptoms limit physical activities and negatively impact daily lives. However, adults in the United States lack awareness of EIB. Although many subjects stated that their asthma symptoms limit their physical activity, few adhered to treatment guidelines by using SABAs appropriately before exercising. Findings from this survey support the need for better communication about the proper evaluation and management of EIB in the community and in asthma patients. PMID- 22221438 TI - Vitamin D deficiency as a risk factor for allergic disorders and immune mechanisms. AB - Vitamin D deficiency (VDD) has been reported in very high rates in the U.S. population. Deficiency has been implicated in various diseases such as diabetes, high blood pressure, cardiovascular disease, and many cancers. It has also been implicated in several allergic disorders and immune system dysregulation. The National Health and Nutrition examination survey (NHANES) in 2005-2006 was a cross-sectional survey performed in the noninstitutionalized population of the United States by the Center for Disease Control and Prevention and National Center for Health Statistics. It consists of an extensive interview performed at home and an examination performed at a mobile center. An allergy questionnaire was provided as interview data on self-reported allergic diseases including allergic rhinitis, allergies, and atopic dermatitis. Data were collected using the question, "Has the doctor or other health professional ever told you that you have allergies?" The laboratory parameter of vitamin D < 10 ng/mL was used to define severe VDD. The data were analyzed by logistic regression with SAS Version 9.1 (SAS Institute, Inc., Cary, NC) using the Procedure survey methods. Of 10,348 people who participated in the 2005-2006 NHANES survey, our final sample consisted of 4979 people in whom serum 25-hydroxyvitamin D levels were completed after excluding subjects <20 years of age and those with missing vitamin D values. The VDD was positively correlated with prevalence of allergies. After adjusting the model for age, gender, race, smoking, alcohol, and educational status, the odds ratio still remained significant. There was also a positive correlation with allergy subtypes such as prevalence of rashes, sneezing, and sinus infections with low vitamin D. VDD related to the immune system dysregulation has been extensively reviewed. PMID- 22221440 TI - Onset and duration of attenuation of exercise-induced bronchoconstriction in children by single-dose of montelukast. AB - Single-dose montelukast attenuates exercise-induced bronchoconstriction (EIB) in adults within 2 hours postdose and lasting through 24 hours. This study evaluated the onset and duration of EIB attenuation in children after a single dose of montelukast. A randomized, double-blind, placebo-controlled, two-period crossover study was performed. Patients (n = 66) aged 4-14 years, with preexercise forced expiratory volume in 1 second of (FEV(1)) >=70% predicted and maximum percentage fall in FEV(1) of >=20% at two screening exercise challenges were eligible. Patients were to receive single-dose montelukast (4 or 5 mg) or placebo before performing standardized exercise challenges at 2 and 24 hours postdose. A 3- to-7 day washout separated the two crossover periods. The primary end point was maximum percentage fall in FEV(1) after exercise challenge 2 hours postdose. Secondary end points included maximum percentage fall in FEV(1) after the 24-hour postdose challenge; each of the following at 2 and 24 hours postdose-maximum percentage fall in FEV(1) categorized as <10%, 10-20%, or >20%; area under the curve (AUC) during 60 minutes postchallenge; time to recovery of FEV(1) to within 5% of preexercise baseline; and need for rescue medication. The mean maximum percentage fall in FEV(1) after the 2-hour postdose exercise challenge was significantly attenuated after single-dose montelukast compared with placebo (15.35% versus 20.00%; p = 0.020). Montelukast was also significantly more effective than placebo for maximum percentage fall after the 24-hour challenge (12.92% versus 17.25%; p = 0.005), the categorized maximum percent fall in FEV(1) at 2 hours (p = 0.034), and AUC at 2 hours (p = 0.022) and 24 hours (p = 0.013). Single-dose montelukast provided rapid and sustained EIB attenuation in children. Clinicaltrials.gov identifier: NCT00534976. PMID- 22221441 TI - Clinical and laboratory features of antihistamine-resistant chronic idiopathic urticaria. AB - Chronic idiopathic (spontaneous) urticaria (CIU) is sometimes resistant to the conventional and high doses of antihistamines (AHs). This study compares the clinical and laboratory characteristics of AH responsive and AH-resistant CIU subjects. Clinical and laboratory data were retrospectively collected from 385 CIU patients. Urticaria activity score (UAS), concomitant angioedema, dermatographism, positive autologous serum skin (ASST), and laboratory data were collected. The control group consisted of 44 sex- and age-matched healthy individuals. Two hundred forty-five CIU patients controlled with AH medications were included in the CIU group. Forty-six patients failed to show clinical improvement during 8 weeks of treatment with fourfold AH doses and were included in the resistant CIU (R-CIU) group. The R-CIU group was characterized with a higher incidence (58.7%) of angioedema than the CIU group (28.5%; p < 0.001), more cases concomitant physical urticaria (23.9% in R-CIU versus 12.2% in CIU; p = 0.014), more positive ASST (73.9% in R-CIU versus 45.4% in CIU; p < 0.001), and higher baseline UAS (5.28 +/- 0.81 in R-CIU versus 3.32 +/- 1.25 in CIU; <0.001). R-CIU was characterized with more severe basopenia (0.04 +/- 0.07 cell/mm(3) versus 0.16 +/- 0.13 cell/mm(3); p < 0.001), higher mean platelet volume (10.87 +/- 2.21 femtoliter (fl) versus 8.65 +/- 1.74 fl; p < 0.001), higher levels of C reactive protein (8.62 +/- 3.91 mg/L versus 2.49 +/- 1.34 mg/L; <0.001), and higher levels of serum C3 (1.66 +/- 0.36 g/L versus 1.19 +/- 0.35 g/L; p < 0.001. R-CIU is a clinically more severe disease with laboratory features of low-grade inflammation and platelet activation. PMID- 22221439 TI - Serum 25-hydroxyvitamin D is associated with enhanced pneumococcal antibody levels in individuals with asthma. AB - Recent studies suggest that vitamin D modulates innate immunity and reduces the risk of microbial infections. Little is known about the role of vitamin D in antipneumococcal immunity in individuals with asthma. We determined the correlation between serum 25-hydroxyvitamin D (25[OH]D) levels and pneumococcal antibody levels in individuals with asthma, atopic dermatitis, or allergic rhinitis, and atopic sensitization status. A cross-sectional study was conducted for 21 subjects with asthma and 23 subjects without asthma. Pearson's correlation coefficient between serum 25(OH)D concentrations and the number of positive serotype-specific antibody levels was calculated among individuals with and without asthma, atopic dermatitis, and/or allergic rhinitis and atopic sensitization status. The overall correlation between serum 25(OH)D concentrations and positive pneumococcal antibody levels in all subjects regardless of asthma was not significant (r = -0.14; p = 0.38). Stratified analysis results showed that there was a positive correlation between serum 25(OH)D concentrations and positive pneumococcal antibody levels in asthmatic patients (r = 0.45; p < 0.05) and an inverse correlation was observed in nonasthmatic patients (r = -0.53; p < 0.05). These trends were similar for subjects with and without atopic dermatitis and/or allergic rhinitis (r = 0.58 and p = 0.008 versus r = -0.63 and p = 0.001). Despite similar trends in the correlation between serum 25(OH)D and pneumococcal antibody concentrations among those with and without atopic sensitization status (r = 0.27 and p = 0.19 versus r = -0.41 and p = 0.08), they did not reach statistical significance. The 25(OH)D may enhance humoral immunity against Streptococcus pneumonia in subjects with atopic conditions but not without atopic conditions. Atopic conditions may have an important effect modifier in the relationship between serum 25(OH)D concentrations and immune function. PMID- 22221443 TI - Characterization of patients with suspected seminal plasma hypersensitivity. AB - The epidemiology of seminal plasma hypersensitivity (SPH) is unknown. Case reports and a previous survey have identified two distinct phenotypes: localized and systemic reactors. The objective of this study was to use an Internet-based questionnaire to characterize and examine the differences among a population of women with suspected SPH. A questionnaire designed to distinguish women with probable SPH was made available via the Internet. Systemic symptoms included generalized pruritus, urticaria, angioedema, wheezing, chest tightness, shortness of breath, dizziness, and loss of consciousness whereas localized symptoms included vaginal burning, pain, swelling, erythema, or blister formation. Respondents with localized or systemic symptoms and whose symptoms were prevented with the use of a condom were included in the analysis. Frequency and means were calculated and further analyzed using chi-square and t-test analyses. A total of 165 women with probable SPH, 79 with systemic symptoms and 86 with only localized symptoms, were included in the analysis. Systemic compared with localized respondents were significantly older (mean age, 29.2 years versus 26.4 years; p = 0.01), had longer duration of symptoms (mean, 58 months versus 40.8 months; p = 0.03), and more frequently reported a family history of atopy (65.8% versus 50%; p < 0.05). Interestingly, significantly more systemic compared with localized respondents reported dog sensitization (11.4% versus 2.3%; p = 0.02). Localized and systemic SPH are more common than previously realized and should be considered in the differential diagnosis of anaphylaxis, vulvovaginitis, and dyspareunia. Additional research investigating the epidemiology, immunopathogenesis, and treatment of this disorder is warranted. PMID- 22221444 TI - Recurrent diarrhea in a 26-year-old man. AB - This is a case report of a 26-year-old healthy man with chronic diarrhea for 2 years. He was initially believed to have irritable bowel syndrome by his primary care physician after all stool studies yielded negative results. His symptoms persisted, which prompted a referral to a gastroenterology specialist. The patient's esophagogastroduodenoscopy revealed variable villous blunting and a paucity of CD 138 plasma cells, which helped reveal the final diagnosis. This cases illustrates a unique presentation of a common primary immunodeficiency that allergy/immunology specialists, along with primary care specialists, will likely encounter. PMID- 22221445 TI - Electrical properties of lead-free 0.98(Na0.5K0.5)NbO3-0.02Ba(Zr0.52Ti0.48)O3 piezoelectric ceramics by optimizing sintering temperature. AB - Lead-free 0.98(Na0.5K0.5)NbO3-0.02Ba(Zr0.52Ti0.48)O3 [0.98NKN-0.02BZT] ceramics were fabricated by the conventional mixed oxide method with sintering temperature at 1,080 degrees C to 1,120 degrees C. The results indicate that the sintering temperature obviously influences the structural and electrical properties of the sample. For the 0.98NKN-0.02BZT ceramics sintered at 1,080 degrees C to 1,120 degrees C, the bulk density increased with increasing sintering temperature and showed a maximum value at a sintering temperature of 1,090 degrees C. The dielectric constant, piezoelectric constant [d33], electromechanical coupling coefficient [kp], and remnant polarization [Pr] increased with increasing sintering temperature, which might be related to the increase in the relative density. However, the samples would be deteriorated when they are sintered above the optimum temperature. High piezoelectric properties of d33 = 217 pC/N, kp = 41%, dielectric constant = 1,951, and ferroelectric properties of Pr = 10.3 MUC/cm2 were obtained for the 0.98NKN-0.02BZT ceramics sintered at 1,090 degrees C for 4 h. PMID- 22221446 TI - Electrospray deposition of polymer thin films for organic light-emitting diodes. AB - Electrospray process was developed for organic layer deposition onto polymer organic light-emitting diode [PLED] devices in this work. An electrospray can be used to produce nanometer-scale thin films by electric repulsion of microscale fine droplets. PLED devices made by an electrospray process were compared with spin-coated ones. The PLED device fabricated by the electrospray process showed maximum current efficiency of 24 cd/A, which was comparable with that of the spin coating process. The electrospray process required a higher concentration of hole and electron transport materials in the inks than spin-coating processes to achieve PLED maximum performance. Photoluminescence [PL] at 407 nm was observed using electrosprayed poly(N-vinyl carbazole) films, whereas a peak at 410 nm was observed with the spin-coated ones. Similar difference in peak position was observed between aromatic and nonaromatic solvents in the spin-coating process. PLED devices made by the electrospray process showed lower current density than that of spin-coated ones. The PL peak shift and reduced current of electrosprayed films can therefore be attributed to the conformation of the polymer. PMID- 22221447 TI - The effect of cognitive behavioral group therapy for depression: a meta-analysis 2000-2010. AB - OBJECTIVE: The goals of the meta-analysis were to investigate the overall effectiveness of cognitive behavioral group therapy (CBGT) for depression and relapse prevention in depression from 2000 to 2010, and to investigate how the variables (episode, residual symptoms, group size, control group, group manual, therapist experience, therapy frequency, session length, and take-home assignment) of a CBGT study could affect the effect size. METHOD: This study collected actual study designs sought of CBGT for depression published from 2000 to 2010. These studies were then cross-referenced using Medical Subject Headings (MeSH) with the following keywords: group therapy, cognitive therapy, cognitive behavioral therapy, cognitive behavioral group therapy, psychotherapy, depression, relapse, and recurrence. The quality of the studies was evaluated using Cochrane Collaboration Guidelines. The effect size of CBGT on depression and relapse prevention in depression used the formula devised by Hedges and Olkin (1985). RESULTS: The study investigated the results of 32 studies on the effect of CBGT for depression. The CBGT had an immediate (g=-0.40) and continuous effect over 6 months (g=-0.38), but no continuous effect after 6 months (g=-0.06). The CBGT lowered the relapse rate of depression (RD = 0.16). Variables significantly different from each other in terms of immediate effect were: CBGT versus usual care, therapy sessions lasting longer than 1 hour, and take-home assignments. Preintervention severity of depression and patient turnover rate were found to be significantly related to the size of the immediate effect. The relapse rate after 6 months was significantly related only to "participants have no residual symptoms/participants did not mention residual symptoms." CONCLUSIONS: Researchers and clinicians should take note that CBGT had a moderate effect on the level of depression and a small effect on the relapse rate of depression. The results of this study suggest that the patient should receive a course of therapy at least every 6 months. PMID- 22221448 TI - Dietary restriction, caloric value and the accumulation of hepatic fat. AB - BACKGROUND: Studies using laboratory animals under what are considered to be "standard" conditions normally offer unrestricted amounts of food to the animals, which can lead to metabolic disorders. Moreover, standard diets have different compositions. AIM: Therefore, the aim of the present study was to assess the effects of two non-isocaloric diets (commercial Purina(r) and AIN-93M), which are considered standard diets, on the accumulation of fat in the liver of rats when offered ad libitum or in a restricted amount. METHODS: Thus, 40 Wistar rats (90 days old) were separated into 4 groups according to the amount of food offered (ad libitum or dietary restriction) and the type of diet (commercial diet, 3,028.0 kcal/g or AIN-93M, 3,802.7 kcal/g): animals fed the commercial Purina(r) diet ad libitum (AP), animals fed restricted amounts of the commercial Purina(r) diet (RP), animals fed the AIN-93M diet ad libitum (AD), and animals fed restricted amounts of the AIN-93M diet (RD). Dietary restriction consisted of pair-feeding the RP and RD groups with 60% of the total food consumed by the corresponding ad libitum groups. RESULTS: Because of its higher carbohydrate and calorie content, AIN-93M was found to accelerate weight gain, reduce glucose tolerance and peripheral insulin sensitivity, and increase the amount of fat in the liver when compared to the commercial diet. Conversely, a 40% dietary restriction assisted in weight loss without causing malnutrition, contributing to an improved glucose tolerance and higher levels of HDL cholesterol. CONCLUSION: Therefore, differences in the amount of carbohydrates and calories provided by the diet can lead to important metabolic disorders, such as impaired tolerance and accumulation of hepatic fat, and dietary restriction improves serum and tissue lipid profiles in laboratory animals. PMID- 22221449 TI - Diclofenac and 2-anilinophenylacetate degradation by combined activity of biogenic manganese oxides and silver. AB - The occurrence of a range of recalcitrant organic micropollutants in our aquatic environment has led to the development of various tertiary wastewater treatment methods. In this study, biogenic manganese oxides (Bio-MnOx), biogenic silver nanoparticles (Bio-Ag(0)) and ionic silver were used for the oxidative removal of the frequently encountered drug diclofenac and its dechlorinated form, 2 anilinophenylacetate (APA). Diclofenac was rapidly degraded during ongoing manganese oxidation by Pseudomonas putida MnB6. Furthermore, whereas preoxidized Bio-MnOx, Bio-Ag(0) and Ag(+) separately did not show any removal capacity for diclofenac, an enhanced removal occurred when Bio-MnOx and silver species were combined. Similar results were obtained for APA. Finally, a slow removal of diclofenac but more rapid APA degradation was observed when silver was added to manganese-free P. putida biomass. Combining these results, three mechanisms of diclofenac and APA removal could be distinguished: (i) a co-metabolic removal during active Mn(2+) oxidation by P. putida; (ii) a synergistic interaction between preoxidized Bio-MnOx and silver species; and (iii) a (bio)chemical process by biomass enriched with silver catalysts. This paper demonstrates the use of P. putida for water treatment purposes and is the first report of the application of silver combined with biogenic manganese for the removal of organic water contaminants. PMID- 22221451 TI - Monitoring of cellular senescence by DNA-methylation at specific CpG sites. AB - Replicative senescence has fundamental implications on cell morphology, proliferation, and differentiation potential. Here, we describe a simple method to track long-term culture based on continuous DNA-methylation changes at six specific CpG sites. This epigenetic senescence signature can be used as biomarker for various cell types to predict the state of cellular senescence with regard to the number of passages, population doublings, or days of in vitro culture. PMID- 22221450 TI - Regulation of the expression of key genes involved in HDL metabolism by unsaturated fatty acids. AB - The cardioprotective effects of HDL have been largely attributed to their role in the reverse cholesterol transport pathway, whose efficiency is affected by many proteins involved in the formation and remodelling of HDL. The aim of the present study was to determine the effects, and possible mechanisms of action, of unsaturated fatty acids on the expression of genes involved in HDL metabolism in HepG2 cells. The mRNA concentration of target genes was assessed by real-time PCR. Protein concentrations were determined by Western blot or immunoassays. PPAR and liver X receptor (LXR) activities were assessed in transfection experiments. Compared with the SFA palmitic acid (PA), the PUFA arachidonic acid (AA), EPA and DHA significantly decreased apoA-I, ATP-binding cassette A1 (ABCA1), lecithin cholesterol acyltransferase (LCAT) and phospholipid transfer protein mRNA levels. EPA and DHA significantly lowered the protein concentration of apoA-I and LCAT in the media, as well as the cellular ABCA1 protein content. In addition, DHA repressed the apoA-I promoter activity. AA lowered only the protein concentration of LCAT in the media. The activity of PPAR was increased by DHA, while the activity of LXR was lowered by both DHA and AA, relative to PA. The regulation of these transcription factors by PUFA may explain some of the PUFA effects on gene expression. The observed n-3 PUFA-mediated changes in gene expression are predicted to reduce the rate of HDL particle formation and maturation. PMID- 22221452 TI - Moving from continuous dopaminergic stimulation to continuous drug delivery in the treatment of Parkinson's disease. AB - Motor fluctuations and motor complications are a major consequence of the treatment and progression of Parkinson's disease (PD) and they have, in particular, been linked to L-dopa therapy. Using continuous dopaminergic stimulation (CDS) by employing longer acting dopaminergic drugs has been proposed as a means of avoiding or lowering their occurrence. However, both the preclinical and clinical evidence base suggest that this concept does not fully explain the differences between L-dopa and dopamine (DA) agonist drugs and that their pharmacological profiles may also be important. In addition, the way in which drugs are delivered in PD appears to have a marked influence on both efficacy and side-effect profile. As a consequence, the concept of continuous drug delivery (CDD) has arisen to explain the differences between the intermittent and continuous delivery of both L-dopa and DA agonists. This review presents the evidence for using CDD as a working concept for the early and later stages of PD and in the treatment of motor complications and motor fluctuations. CDD as an approach to the treatment of PD may improve the outcome of therapy and explain the differences between drug classes and the delivery systems employed. PMID- 22221454 TI - Rheological studies on solid lipid nanoparticle based carbopol gels of aceclofenac. AB - Solid lipid nanoparticles (SLN) of aceclofenac were prepared using Taguchi experimental design by Trotta method. The prepared SLN were formulated into a gel preparation, using carbopol 940. Gels were evaluated for drug content, bioadhesion and their stability against change of temperature and shear. The viscosity of prepared gels was found to be temperature independent. Rheological behavior of gels with changing shear was rather complex. Viscosity varied inversely with shear but remained almost constant during short spans of time when shear was kept constant. Viscosity of the gels did not change if shear was not varied. In vitro diffusion studies exhibited an immediate release followed by a sustained release. This could help in maintaining the concentration of bioactives such as aceclofenac in desirable levels at sites of inflammation and injury. PMID- 22221455 TI - Deposition kinetics of MS2 bacteriophages on clay mineral surfaces. AB - The deposition of bacteriophage MS2 on bare and clay-coated silica surfaces was examined in both monovalent (NaCl) and divalent (CaCl(2) and MgCl(2)) solutions under a wide range of environmentally relevant ionic strength and pH conditions by utilizing a quartz crystal microbalance with dissipation (QCM-D). Two types of clay, bentonite and kaolinite, were concerned in this study. To better understand MS2 deposition mechanisms, QCM-D data were complemented by zeta potentials measurements and Derjaguin-Landau-Verwey-Overbeek (DLVO) interaction forces calculation. In both monovalent and divalent solutions, deposition efficiencies of MS2 increased with increasing ionic strength both on bare and clay-coated surfaces, which agreed with the trends of interaction forces between MS2 and solid surface and thus was consistent with DLVO theory. The presence of divalent ions (Ca(2+) and Mg(2+)) in solutions greatly increased virus deposition on both silica and clay deposited surfaces. Coating silica surfaces with clay minerals, either kaolinite or bentonite, could significantly increase MS2 deposition. PMID- 22221456 TI - Plasma treatment induced wetting transitions on biological tissue (pigeon feathers). AB - We report first the wetting transition from superhydrophobicity to superhydrophilicity observed on nitrogen and air plasma irradiated biological tissue (pigeon feathers). Non-irradiated feathers demonstrate pronounced Cassie Baxter ("fakir") wetting characterized by high apparent contact angles and low sliding angles. Plasma-irradiated feathers are superhydrophilic. Plasma treatment does not affect the barbs/barbules keratin-built network constituting pigeon pennae, but it changes the Young, advancing and receding angles of the tissue. The mechanism of wetting transition is discussed. PMID- 22221457 TI - Volumetric characterization of ester- and ether-linked lipid bilayers by pressure perturbation calorimetry and densitometry. AB - We investigated the thermotropic volume behavior of dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC) and dihexadecylphosphatidylcholine (DHPC) membranes using pressure perturbation calorimetry (PPC) and densitometry. The ln phi(2) vs temperature curves (phi(2): apparent molar volume of phospholipid) obtained from the PPC data using an analysis method that we developed agreed with the results from the density measurements for these lipids within the relative difference of about 0.62%. From those curves, the volume changes with the main transition were estimated at 18.0+/-0.49, 23.5+/-2.33 and 23.0+/-0.33 cm(3) mol(-1) for DMPC, DPPC and DHPC, respectively. For DPPC and DMPC, the average volume per methylene group of the hydrocarbon chains v(CH2) calculated by referring to the procedure by Nagle and Wilkinson was consistent with the previous result, which indicates that the DPPC bilayer in the gel state has denser hydrophobic bilayer core than the DMPC bilayer. For DHPC, the volume of the headgroup region v(H) was calculated to be 244 A(3) by assuming that v(CH2) of DHPC equals that of DPPC above 45 degrees C. This value was comparable to that of DPPC when the volume of the carbonyl groups was considered, which may signify that there is no significant conformational difference in the polar headgroups of both phospholipids. However, it was suggested from the consideration on v(H) of DHPC at 20 degrees C that expansion of the headgroup region should occur as the interdigitated structure is formed, which means some conformational change of the headgroup region is induced by the interdigitation. PMID- 22221458 TI - Evaluation of antioxidant activity of chrysanthemum extracts and tea beverages by gold nanoparticles-based assay. AB - A gold nanoparticles-based (GNPs-based) assay was developed for evaluating antioxidant activity of chrysanthemum extracts and tea beverages. Briefly, a GNPs growth system consisted of designated concentrations of hydrogen tetrachloroaurate, cetyltrimethyl ammonium bromide, sodium citrate, and phosphate buffer was designed, followed by the addition of 1 mL different level of test samples. After a 10-min reaction at 45 degrees C, GNPs was formed in the reduction of metallic ions to zero valence gold by chrysanthemum extracts or tea beverages. And the resultant solution exhibited a characteristic surface plasmon resonance band of GNPs centered at about 545 nm, responsible for its vivid light pink or wine red color. The optical properties of GNPs formed correlate well with antioxidant activity of test samples. As a result, the antioxidant functional evaluation of chrysanthemum extracts and beverages could be performed by this GNPs-based assay with a spectrophotometer or in visual analysis to a certain extent. Our present method based on the sample-mediated generation and growth of GNPs is rapid, convenient, inexpensive, and also demonstrates a new possibility for the application of nanotechnology in food science. Moreover, this present work provides some useful information for in-depth research of involving chrysanthemum. PMID- 22221459 TI - Cross-linked chitosan microspheres for oral delivery of insulin: Taguchi design and in vivo testing. AB - Insulin-loaded chitosan microspheres were engineered by emulsion cross-linking method using glutaraldehyde as cross-linker. Taguchi orthogonal method was applied to optimize the production time and reduce the number of experiments required to obtain an optimized formulation. Three variables were evaluated, i.e. chitosan and glutaraldehyde concentrations, and cross-linking time at three levels. The dependent variables were the mean particle size and the encapsulation efficiency. The optimal formulation was obtained with chitosan 3% (w/v), glutaraldehyde 3.5% (v/v), and cross-linking time of 5h, characterized by microspheres with a mean particle size of 29.5 MUm, and insulin encapsulation efficiency of 71.6+/-1.3%. In vivo studies were carried out using male Wistar albino rats, revealing a significant reduction in blood glucose level after administration of the optimized formulation, in comparison to a subcutaneous insulin injection. Chitosan microspheres were superior in terms of sustaining protein release over conventional insulin therapy. PMID- 22221460 TI - Batch and continuous (fixed-bed column) biosorption of crystal violet by Artocarpus heterophyllus (jackfruit) leaf powder. AB - In this study, batch and fixed-bed column experiments were performed to investigate the biosorption potential of Artocarpus heterophyllus (jackfruit) leaf powder (JLP) to remove crystal violet (CV) from aqueous solutions. Batch biosorption studies were carried out as a function of solution pH, contact time, initial dye concentration and temperature. The biosorption equilibrium data showed excellent fit to the Langmuir isotherm model with maximum monolayer biosorption capacity of 43.39 mg g(-1) at pH 7.0, initial dye concentration=50 mg L(-1), temperature=293 K and contact time=120 min. According to Dubinin Radushkevich (D-R) isotherm model, biosorption of CV by JLP was chemisorption. The biosorption kinetics followed the pseudo-second-order kinetic model. Thermodynamic analysis revealed that biosorption of CV from aqueous solution by JLP was a spontaneous and exothermic process. In order to ascertain the practical applicability of the biosorbent, fixed-bed column studies were also performed. The breakthrough time increased with increasing bed height and decreased with increasing flow rate. The Thomas model as well as the BDST model showed good agreement with the experimental results at all the process parameters studied. It can be concluded that JLP is a promising biosorbent for removal of CV from aqueous solutions. PMID- 22221461 TI - Does understanding relational terminology mediate effects of intervention on compare word problems? AB - The purpose of this study was to assess whether understanding relational terminology (i.e., more, less, and fewer) mediates the effects of intervention on compare word problems. Second-grade classrooms (N=31) were randomly assigned to one of three conditions: researcher-designed word-problem intervention, researcher-designed calculation intervention, or business-as-usual (teacher designed) control. Students in word-problem intervention classrooms received instruction on the compare problem type, which included a focus on understanding relational terminology within compare word problems. Analyses, which accounted for variance associated with classroom clustering, indicated that (a) compared with the calculation intervention and business-as-usual conditions, word-problem intervention significantly increased performance on all three subtypes of compare problems and on understanding relational terminology, and (b) the intervention effect was fully mediated by students' understanding of relational terminology for one subtype of compare problems and partially mediated by students' understanding of relational terminology for the other two subtypes. PMID- 22221462 TI - Development of a portable isotropic neutron spectrometer. AB - A portable neutron spectrometry and dosimetry measurement device is in the process of development, which will be capable of accurate characterisation of neutron fields. The instrument is an amalgamation of two well-known techniques the Bonner-sphere and the surface barrier detector. Recent developments in semiconductor materials have allowed the growth of large-area thin-film based semiconductors upon high density polyethylene substrates, on which this detector is formed. Herein we discuss three plausible detection devices and test their results. PMID- 22221463 TI - Barrel inspection utilizing a 14 MeV neutron beam and associate alpha particle method. AB - A multi-sensor system was evaluated for the determination of barrel content with regard to eventual pollution hazards. The proposed system is able to investigate (in situ) the interior of a barrel filled with various unknown substances ranging from chemical and radioactive waste, raw sewage sludge, municipal incinerator ashes to common household trash. The crucial part of the system is a neutron sensor, which enables the identification of substance content without actually opening the barrel at all. A comparative laboratory test with the 3"*3" and 5"*5"*10" NaI(Tl) gamma ray detectors was made after which 3"*3" detector was selected and incorporated in the submarine called "Surveyor". A field test was made in the Croatian Adriatic coast on the island Losinj. Field tests show that the commercial system utilizing the described method could be constructed for barrel inspection regardless of the measurement environment (underwater, on land, dumping site, isolated location, etc.). PMID- 22221464 TI - Energy loss straggling of 5.486 MeV alpha particles in Melinex, Al, Ni and Cu. AB - Energy loss straggling of 5.486 MeV alpha particles passing through Melinex, Al, Ni and Cu has been studied as a function of energy loss. The reduction in straggling towards the end of the particle range is predicted by considering the reduction of the stopping power and of the effective charge in the capture and loss of electrons at lower energies. These measurements are compared with theoretical predictions of Bohr (1915) and Titeica (1939). The measured values agreed with Titeica results at high and intermediate energy region, and large discrepancies at low energy region are found. Titeica results are greater than Bohr results by a factor of about 1.5-2. PMID- 22221466 TI - Luminescent characteristics of CaSO4:Dy films obtained by spray pyrolysis method. AB - The present paper reports the experimental results of dysprosium doped calcium sulphate (CaSO4:Dy) films deposited by spray pyrolysis method. CaSO4:Dy films were deposited on three different surfaces: glass, aluminum and quartz substrates at temperatures in the range from 450 to 600 degrees C. Structural and morphological characteristics of CaSO4:Dy films were observed. Thermoluminescent characteristics of films were determined by irradiating ultraviolet energy region. Thermoluminescent glow curve of CaSO4:Dy films with glass and aluminum substrates showed a peak under environmental irradiation. Both TL response glow shape and intensity of CaSO4:Dy films UV irradiated as a function of substrates were studied. PMID- 22221465 TI - Improvement of a method for the sequential determination of 210Pb, 226Ra, and uranium isotopes by LSC and alpha-particle spectrometry. AB - In a previous paper the authors proposed a sequential method for the determination of isotopes of uranium, thorium, radium, and lead from environmental samples using alpha-particle spectrometry and LSC techniques. Although the radiochemical yields were suitable when the assays were performed on synthetic samples, application to real environmental samples caused a major decrease in the radiochemical yield, especially for uranium in inorganic samples (soils). A modification of the procedure is described that overcomes this drawback. PMID- 22221467 TI - A kinematic analysis of the association between impulsivity and manual aiming control. AB - Two characteristics usually found in impulsive behavior are deficits in response inhibition and the inability to delay gratification. The former behavior is called motor impulsivity, and the second is called cognitive impulsivity. This study investigates the association of motor and cognitive impulsivity with manual aiming control. We administered two neuropsychological tests to 81 healthy participants to measure their levels of motor and cognitive impulsivity. A manual aiming motor task was also applied. Subsequently, from the initial group of 81 participants, two subgroups of 27 individuals were selected by their scores on (1) motor impulsivity and (2) cognitive impulsivity, and their motor performances were compared. While a group was comprised by the top 33.3% high-impulsive participants, the other was comprised by the bottom 33.3% low-impulsives participants. The results indicate that motor impulsivity is more related to motor control than cognitive impulsivity. Differences between motor impulsivity groups were found in the duration of the primary submovement, peak velocity, score of response inhibition errors and incorrect hits score. It was found that in situations in which the temporal and spatial demands to the motor system were high, the impulsivity had a functional, adaptive effect on motor control. PMID- 22221468 TI - Altered postural control strategies and sensory organization in children with developmental coordination disorder. AB - The postural control of children with and without developmental coordination disorder (DCD) was compared under conditions of reduced or conflicting sensory input. Twenty-two children with DCD (16 males, 6 females; mean age 7 years 6 months, SD 1 year 5 months) and 19 children with normal motor development were tested (13 males, 6 females; mean age 6 years 11 months, SD 1 year 1 month). Standing balance, sensory organization and motor control strategy were evaluated using the sensory organization test (SOT). The results revealed that children with DCD had lower composite equilibrium scores (p<.001), visual ratios (p=.005) and vestibular ratios (p=.002) than normal children in the control group. No significant between-group difference in their average somatosensory ratio was observed. Additionally, children with DCD had lower motor strategy scores (swayed more on their hips) than the normal children when forced to depend on vestibular cues alone to balance (p<.05). We conclude that children with DCD had deficits in standing balance control in conditions that included reduced or conflicting sensory signals. The visual and vestibular systems tended to be more involved in contributing to the balance deficits than the somatosensory system. Moreover, children with DCD tended to use hip strategy excessively when forced to rely primarily on vestibular signals to maintain postural stability. PMID- 22221469 TI - Auditory sustained field responses to periodic noise. AB - BACKGROUND: Auditory sustained responses have been recently suggested to reflect neural processing of speech sounds in the auditory cortex. As periodic fluctuations below the pitch range are important for speech perception, it is necessary to investigate how low frequency periodic sounds are processed in the human auditory cortex. Auditory sustained responses have been shown to be sensitive to temporal regularity but the relationship between the amplitudes of auditory evoked sustained responses and the repetitive rates of auditory inputs remains elusive. As the temporal and spectral features of sounds enhance different components of sustained responses, previous studies with click trains and vowel stimuli presented diverging results. In order to investigate the effect of repetition rate on cortical responses, we analyzed the auditory sustained fields evoked by periodic and aperiodic noises using magnetoencephalography. RESULTS: Sustained fields were elicited by white noise and repeating frozen noise stimuli with repetition rates of 5-, 10-, 50-, 200- and 500 Hz. The sustained field amplitudes were significantly larger for all the periodic stimuli than for white noise. Although the sustained field amplitudes showed a rising and falling pattern within the repetition rate range, the response amplitudes to 5 Hz repetition rate were significantly larger than to 500 Hz. CONCLUSIONS: The enhanced sustained field responses to periodic noises show that cortical sensitivity to periodic sounds is maintained for a wide range of repetition rates. Persistence of periodicity sensitivity below the pitch range suggests that in addition to processing the fundamental frequency of voice, sustained field generators can also resolve low frequency temporal modulations in speech envelope. PMID- 22221470 TI - Evaluation of clinical benefits achievable by using different optimization algorithms during real-time prostate brachytherapy. AB - BACKGROUND AND PURPOSE: High dose rate (HDR) brachytherapy is a clinically used procedure in prostate cancer treatment. The purpose of this study was to present the influence of using different optimization algorithms in 3D-CBRT planning on the treatment plan quality. MATERIALS AND METHODS: Treatment plans were calculated for 15 patients--three plans for each patient using: geometrical optimization (GO), inverse optimization (IO) and blind inverse optimization (BIO). For each patient, PTV and OAR volumes, number of needles and geometry of the implant were set equal. Differences between dose distributions were tracked using: D90, V100, V200, Dmax (for prostate); D10, Dmax (for urethra); D10, V100, Dmax (for rectum). RESULTS: The analysis of mean values of D90 and V100 in the prostate showed that inverse algorithms gave the best results (mean D90 was 12.1% for BIO and 9.3% for IO better than for GO, mean V100 was 8.2% for BIO and 6.3% for IO better than for GO). From a clinical point of view, GO diminished the doses in the PTV and urethra in all analyzed parameters. The lowest mean doses in the rectum were achieved for plans optimized with IO and BIO (mean D10: 61.2% for GO, 58.1% for IO, 58.0% for BIO; mean Dmax: 92.8% for GO, 85.1% for IO, 83.6% for BIO). CONCLUSIONS: Application of the blind inverse optimization (BIO) algorithm led to clinically best dose parameters for PTV and the rectum. Use of geometrical optimization (GO) led to smaller doses in the urethra, which was however associated with a certain dose decrease also in PTV. PMID- 22221471 TI - JVIR grows and evolves; JVIR fast. PMID- 22221472 TI - Preexisting chronic kidney disease and renal tumor ablation: preliminary answers and persistent questions. PMID- 22221473 TI - Patients with multiple sclerosis with structural venous abnormalities on MR imaging exhibit an abnormal flow distribution of the internal jugular veins. AB - PURPOSE: To evaluate extracranial venous structural and flow characteristics in patients with multiple sclerosis (MS). MATERIALS AND METHODS: Two hundred subjects with MS from two sites (n = 100 each) were evaluated with magnetic resonance (MR) imaging at 3 T. Contrast-enhanced time-resolved MR angiography and time-of-flight MR venography were used to assess vascular anatomy. Two dimensional phase-contrast MR imaging was used to quantify blood flow. The MS population was divided into two groups: those with evident internal jugular vein (IJV) stenoses (stenotic group) and those without (nonstenotic group). RESULTS: Of the 200 patients, 136 (68%) showed IJV structural abnormalities, including unilateral or bilateral stenoses at different levels in the neck (n = 101; 50.5%) and atresia (n = 35; 17.5%). The total IJV flow normalized to the total arterial flow of the stenotic group (56% +/- 22) was significantly lower than that of the nonstenotic group (77% +/- 14; P < .001). The arterial/venous flow mismatch in the stenotic group (12% +/- 15) was significantly greater than that in the nonstenotic group (6% +/- 12; P < .001). The ratio of subdominant venous flow rate (Fsd) to dominant venous flow rate (Fd) for the stenotic group (0.38 +/- 0.27) was significantly lower than for the nonstenotic group (0.59 +/- 0.23; P < .001). The majority of the stenotic group (67%) also had an Fsd of less than 3 mL/s, a Fd/Fsd ratio greater than 3:1, and/or a total IJV flow rate of less than 8 mL/s. CONCLUSIONS: MR imaging provides a noninvasive means to separate stenotic from nonstenotic MS cases. The former group was more prevalent in the present MS population and carried significantly less flow in the IJVs than the latter. PMID- 22221474 TI - Guidelines are local, commentary on "Analysis of infection risk following covered stent exclusion of pseudoaneurysms in prosthetic arteriovenous hemodialysis access grafts". PMID- 22221475 TI - Mechanisms matter. PMID- 22221476 TI - How long should peripherally inserted central catheterization be delayed in the context of recently documented bloodstream infection? AB - The risk of relapsing bacteremia was assessed retrospectively among a cohort of 348 patients who underwent peripherally inserted central catheter (PICC) insertion within 6 weeks of a documented bacteremia. The overall risk of relapsing bacteremia was low (three of 348; 0.9%) when PICC insertion was performed in the context of a recent bloodstream infection. The relapse risk was higher when PICCs were inserted within 2 days (two of 31; 6.5%) versus at least 3 days (one of 317; 0.3%) after documentation of bacteremia (P = .02). PMID- 22221477 TI - Bronchiolitis obliterans organizing pneumonia after radiofrequency ablation of lung cancer: report of three cases. AB - The present report describes three cases of a bronchiolitis obliterans organizing pneumonia (BOOP)-like reactive pneumonitis following radiofrequency (RF) ablation for lung cancer. The incidence of BOOP-like reactive pneumonitis after RF ablation at the authors' institution was estimated to be approximately 0.4% (three of 840 sessions). The patients presented with nonspecific symptoms. Computed tomography images showed consolidation or ground-glass opacity in a peripheral-dominant distribution and/or patchy air-space opacities. The disease was nonresponsive to antibiotic therapy but responded favorably to pulse therapy of steroids. BOOP-like reactive pneumonitis should be recognized as a complication following lung RF ablation. PMID- 22221478 TI - Endovascular exclusion of a splenic artery aneurysm using a pipeline embolization device. AB - The Pipeline Embolization Device (ev3 Endovascular Inc, Plymouth, Minnesota) is a new endovascular device designed to exclude suitable intracranial aneurysms. A 56 year-old woman presented with a symptomatic 4.1-cm splenic artery aneurysm (SAA) that was successfully managed with a two-staged treatment plan involving selective segmental splenic artery embolization and subsequent deployment of a Pipeline Embolization Device across the aneurysm neck to exclude the aneurysm and maintain splenic perfusion. PMID- 22221479 TI - Intravascular ultrasound-guided mesocaval shunt creation in patients with portal or mesenteric venous occlusion. AB - Extrahepatic mesocaval shunts were successfully created in three patients with refractory variceal hemorrhage, complete portal vein or superior mesenteric vein occlusion, and contraindications to shunt surgery. The use of intravascular ultrasound guidance and covered stents allowed safe and effective transvenous shunt creation without the necessity of percutaneous transabdominal mesenteric venous puncture. PMID- 22221481 TI - The bumper stitch for drainage tube securement: preliminary study. AB - Tube dislodgment is a common problem in drainage procedures. The present report compares a securement technique known as the bumper stitch, which aims to reduce tube motion and suture erosion, versus the traditional air knot. A total of 61 patients were enrolled, and 12 bumper stitches and 54 air knots were observed. Eighty-three percent of bumper tubes had no play (ie, in-and-out motion), versus 41% of the air knot tubes (P = .02); the mean amount of play with the bumper was 0.4 mm, versus 4.7 mm for the air knot (P = .007). The bumper stitch significantly reduces tube play and may therefore aid in reducing dislodgment. PMID- 22221480 TI - Percutaneous irreversible electroporation of surgically unresectable pancreatic cancer: a case report. AB - The present report describes a case of percutaneous irreversible electroporation (IRE) in a 78-year-old man with surgically unresectable stage III (tumor/node/metastasis stages, T4N0M0) pancreatic adenocarcinoma. Two ablations were performed for a 4.1-cm mass encasing the celiac and superior mesenteric artery. At 3 months, a solitary liver metastasis developed, which was treated with radiofrequency ablation followed by gemcitabine chemotherapy. At 6-month follow-up, magnetic resonance imaging demonstrated no residual disease and a decreasing cancer antigen 19-9 level. Percutaneous IRE shows promise as a feasible and potentially safe method for local tumor control in patients with surgically unresectable disease. PMID- 22221482 TI - Cardiac-gated bright blood MR imaging to determine retrieval feasibility of a chronic foreign body. PMID- 22221483 TI - Discussions of the kidney disease trajectory by elderly patients and nephrologists: a qualitative study. AB - BACKGROUND: Elderly patients with advanced kidney disease experience considerable disability, morbidity, and mortality. Little is known about the impact of physician-patient interactions on patient preparation for the illness trajectory. We sought to describe how nephrologists and older patients discuss and understand the prognosis and course of kidney disease leading to renal replacement therapy. METHODS: We conducted focus groups and interviews with 11 nephrologists and 29 patients older than 65 years with advanced chronic kidney disease or receiving hemodialysis. Interviews were audiorecorded and transcribed. We used qualitative analytic methods to identify common and recurrent themes related to the primary research question. RESULTS: We identified 6 themes that describe how the kidney disease trajectory is discussed and understood: (1) patients are shocked by their diagnosis, (2) patients are uncertain how their disease will progress, (3) patients lack preparation for living with dialysis, (4) nephrologists struggle to explain illness complexity, (5) nephrologists manage a disease over which they have little control, and (6) nephrologists tend to avoid discussions of the future. Patients and nephrologists acknowledged that prognosis discussions are rare. Patients tended to cope with thoughts of the future through avoidance by focusing on their present clinical status. Nephrologists reported uncertainty and concern for evoking negative reactions as barriers to these conversations. CONCLUSIONS: Patients and nephrologists face challenges in understanding and preparing for the kidney disease trajectory. Communication interventions that acknowledge the role of patient emotion and address uncertainty may improve how nephrologists discuss disease trajectory with patients and thereby enhance their understanding and preparation for the future. PMID- 22221484 TI - Serum cystatin C may diagnose rather than predict acute kidney injury. PMID- 22221485 TI - Knowledge, attitude and skills before and after a module on pharmaceutical promotion in a Nepalese medical school. AB - BACKGROUND: Pharmaceutical promotion is widespread and can impact prescribing by health professionals. Little research has been conducted on interactions between medical students and the pharmaceutical industry. Teaching about pharmaceutical promotion is inadequate. A survey showed that many schools spend only about two hours teaching this important topic while others spend around six hours. Recently a manual on understanding and responding to promotion has been published by Health Action International (HAI) and the World Health Organization (WHO). From April to August 2011 the department of Clinical Pharmacology at KIST Medical College, Lalitpur, Nepal conducted a module on pharmaceutical promotion for second year students based on the manual. The module used active learning strategies such as brainstorming sessions, role plays and group activities. The study worked on the hypothesis that a module on pharmaceutical promotion will be effective in improving the knowledge, attitude and skills of medical students regarding pharmaceutical promotion. The impact of the module on knowledge, attitude and skills was tested using a retrospective-pre questionnaire. The scores according to gender and method of financing of medical education before and after the module were compared using appropriate non-parametric tests. RESULTS: Eighty-seven of the 100 second year students (87%) participated in the study. 47 were females (54%) and 39 (44.83%) were males and one did not state the gender. Seventy-seven students (88.5%) were self-financing while 9 were scholarship students. The median knowledge, attitude and skills score before the module were 9, 13 and 6 respectively while the overall score was 28. The scores increased significantly to 16, 15 and 14 respectively after the module while the overall score increased to 45. The median attitude scores and total scores were significantly higher among females both before and after the module. The scores did not vary with method of financing of medical education. All scores increased significantly at the end of the module. CONCLUSIONS: The nine hour module held over a period of four months was effective in improving respondents' knowledge, attitudes and skills about pharmaceutical promotion. The module was not resource intensive and used resources already available in the institution. Similar modules can be considered in other medical and health profession schools in Nepal, South Asia and other developing countries. PMID- 22221486 TI - Electrochemical performance of NixCo1-xMoO4 (0 <= x <= 1) nanowire anodes for lithium-ion batteries. AB - NixCo1-xMoO4 (0 <= x <= 1) nanowire electrodes for lithium-ion rechargeable batteries have been synthesized via a hydrothermal method, followed by thermal post-annealing at 500 degrees C for 2 h. The chemical composition of the nanowires was varied, and their morphological features and crystalline structures were characterized using field-emission scanning electron microscopy and X-ray powder diffraction. The reversible capacity of NiMoO4 and Ni0.75Co0.25MoO4 nanowire electrodes was larger (~520 mA h/g after 20 cycles at a rate of 196 mA/g) than that of the other nanowires. This enhanced electrochemical performance of NixCo1-xMoO4 nanowires with high Ni content was ascribed to their larger surface area and efficient electron transport path facilitated by their one dimensional nanostructure. PMID- 22221487 TI - Phenotypic plasticity allows the Mediterranean parsley frog Pelodytes punctatus to exploit two temporal niches under continuous gene flow. AB - Environmental changes, such as climate change, lead to the opening of new niches. In such situations, species that adapt to new niches can survive and/or expand their ranges. However, gene flow can hamper genetic adaptation to new environments. Alternatively, recent models have highlighted the importance of phenotypic plasticity in tracking environmental change. Here, we investigate whether phenotypic plasticity or genetic evolution (or both) allows an amphibian species to exploit two divergent climatic niches. In the Mediterranean region, the parsley frog Pelodytes punctatus breeds both in spring, as do most other species, and in autumn, a temporal niche not exploited by most other species, but which may become increasingly important with global warming. Conditions of development are dramatically different between the two seasons and deeply impact tadpole life-history traits. To determine whether these temporal niches are exploited by two genetically differentiated subpopulations, or whether the bimodal phenology arises in a panmictic population displaying plastic life history traits, we use two complementary approaches. We measure both molecular genetic differentiation and quantitative-trait differentiation between spring and autumn cohorts, using microsatellites and common garden experiments, respectively. Seasonal cohorts were not genetically differentiated and differences in tadpole life history between cohorts were not maintained in laboratory conditions. We conclude that phenotypic plasticity, rather than genetic adaptation, allows Parsley frog to exploit two contrasting temporal niches. PMID- 22221488 TI - Enhanced electrochemical properties of fluoride-coated LiCoO2 thin films. AB - The electrochemical properties of fluoride-coated lithium cobalt oxide [LiCoO2] thin films were characterized. Aluminum fluoride [AlF3] and lanthanum fluoride [LaF3] coating layers were fabricated on a pristine LiCoO2 thin film by using a spin-coating process. The AlF3- and LaF3-coated films exhibited a higher rate capability, cyclic performance, and stability at high temperature than the pristine film. This indicates that the AlF3 and LaF3 layers effectively protected the surface of the pristine LiCoO2 film from the reactive electrolyte. PMID- 22221490 TI - Catalytic dechlorination of diclofenac by biogenic palladium in a microbial electrolysis cell. AB - Diclofenac is one of the most commonly detected pharmaceuticals in wastewater treatment plant (WWTP) effluents and the receiving water bodies. In this study, biogenic Pd nanoparticles ('bio-Pd') were successfully applied in a microbial electrolysis cell (MEC) for the catalytic reduction of diclofenac. Hydrogen gas was produced in the cathodic compartment, and consumed as a hydrogen donor by the bio-Pd on the graphite electrodes. In this way, complete dechlorination of 1 mg diclofenac l(-1) was achieved during batch recirculation experiments, whereas no significant removal was observed in the absence of the biocatalyst. The complete dechlorination of diclofenac was demonstrated by the concomitant production of 2 anilinophenylacetate (APA). Through the addition of -0.8 V to the circuit, continuous and complete removal of diclofenac was achieved in synthetic medium at a minimal HRT of 2 h. Continuous treatment of hospital WWTP effluent containing 1.28 ug diclofenac l(-1) resulted in a lower removal efficiency of 57%, which can probably be attributed to the affinity of other environmental constituents for the bio-Pd catalyst. Nevertheless, reductive catalysis coupled to sustainable hydrogen production in a MEC offers potential to lower the release of micropollutants from point-sources such as hospital WWTPs. PMID- 22221491 TI - Correlation between genetic polymorphisms and stroke recovery: analysis of the GAIN Americas and GAIN International Studies. AB - BACKGROUND AND PURPOSE: Recovery after stroke occurs on the basis of specific molecular events. Genetic polymorphisms associated with impaired neural repair or plasticity might reduce recovery from stroke and might also account for some of the intersubject variability in stroke recovery. This study hypothesized that the ApoE epsilon4 polymorphism and the val(66) met polymorphism for brain-derived neurotrophic factor (BDNF) are each associated with poorer outcome after stroke. Associations with mitochondrial genotype were also explored. METHODS: Genotypes were determined in 255 stroke patients who also received behavioral evaluations in the Glycine Antagonist In Neuroprotection (GAIN) clinical trials. The primary outcome measure was recovery during the first month post-stroke, as this is the time when neural repair is at a maximum and so when genetic influences might have their largest impact. Two secondary outcome measures at 3 months post-stroke were also examined. RESULTS: Genotype groups were similar acutely post-stroke. Presence of the ApoE epsilon4 polymorphism was associated with significantly poorer recovery over the first month post-stroke (P = 0.023) and with a lower proportion of subjects with minimal or no disability (modified Rankin score 0-1, P = 0.01) at 3 months post-stroke. Indeed, those with this polymorphism were approximately half as likely to achieve minimal or no disability (18.2%) versus those with polymorphism absent (35.5%). Findings were confirmed in multivariate models. Results suggested possible effects from the val(66) met BDNF polymorphism and from the R0 mitochondrial DNA haplotype. CONCLUSIONS: Genetic factors, particularly the ApoE epsilon4 polymorphism, might contribute to variability in outcomes after stroke. PMID- 22221489 TI - Health effects of dietary phospholipids. AB - Beneficial effects of dietary phospholipids (PLs) have been mentioned since the early 1900's in relation to different illnesses and symptoms, e.g. coronary heart disease, inflammation or cancer. This article gives a summary of the most common therapeutic uses of dietary PLs to provide an overview of their approved and proposed benefits; and to identify further investigational needs.From the majority of the studies it became evident that dietary PLs have a positive impact in several diseases, apparently without severe side effects. Furthermore, they were shown to reduce side effects of some drugs. Both effects can partially be explained by the fact that PL are highly effective in delivering their fatty acid (FA) residues for incorporation into the membranes of cells involved in different diseases, e.g. immune or cancer cells. The altered membrane composition is assumed to have effects on the activity of membrane proteins (e.g. receptors) by affecting the microstructure of membranes and, therefore, the characteristics of the cellular membrane, e.g. of lipid rafts, or by influencing the biosynthesis of FA derived lipid second messengers. However, since the FAs originally bound to the applied PLs are increased in the cellular membrane after their consumption or supplementation, the FA composition of the PL and thus the type of PL is crucial for its effect. Here, we have reviewed the effects of PL from soy, egg yolk, milk and marine sources. Most studies have been performed in vitro or in animals and only limited evidence is available for the benefit of PL supplementation in humans. More research is needed to understand the impact of PL supplementation and confirm its health benefits. PMID- 22221492 TI - Dietary inclusion of salmon, herring and pompano as oily fish reduces CVD risk markers in dyslipidaemic middle-aged and elderly Chinese women. AB - Dietary intervention studies to assess the cardioprotective effects of oily fish are scarce in China. The present study aimed to examine the effects of the oily fish, Norwegian salmon, herring and local farmed pompano (Trachinotus ovatus) on CVD risk markers when included in the Chinese diet. In this 8-week, parallel-arm, randomised intervention study, 126 Chinese women with hypertriacylglycerolaemia, aged 35-70 years, were assigned to four groups to consume an experimental lunch containing 80 g fillets of either one of three oily fish or a mix of commonly eaten meats (pork/chicken/beef/lean fish) for 5 d/week. The results showed that inclusion of the three oily fish significantly increased the intake of n-3 long chain PUFA (LC-PUFA) while decreasing the dietary n-6:n-3 PUFA ratio. Compared to the control group, significant increases of DHA, EPA+DHA and total n-3 PUFA in plasma choline phosphoglyceride were observed in the three oily fish groups. Plasma TAG levels were significantly reduced only in the salmon and herring groups. When compared to the baseline level, the three oily fish diets significantly decreased serum concentrations of TAG, apoB, apoCII and apoCIII, but only the salmon and herring diets significantly lowered TNF-alpha and raised adiponectin levels in serum. The salmon diet additionally decreased the serum concentration of IL-6. To conclude, dietary inclusion of salmon, herring and pompano as oily fish can effectively increase serum n-3 LC-PUFA content and are associated with favourable biochemical changes in dyslipidaemic middle-aged and elderly Chinese women, and these beneficial effects are mainly associated with n 3 LC-PUFA contents. PMID- 22221493 TI - S-OtrH3N2 viruses: use of sequence data for description of the molecular characteristics of the viruses and their relatedness to previously circulating H3N2 human viruses. AB - Emergence of influenza viruses from the animal reservoir is a permanent challenge. The rapid description and immediate sharing of information on these viruses is invaluable for influenza surveillance networks and for pandemic preparedness. With the help of data generated from the World Health Organization Collaborating Centre for Reference and Research on Influenza at the United States Centers for Disease Control and Prevention, we provide here information on the swine-origin triple reassortant influenza A(H3N2) viruses detected in human cases in the north-east of the United States. PMID- 22221494 TI - Preliminary implications for Europe of the 2011 influenza season in five temperate southern hemisphere countries. AB - The 2011 influenza season (May to October) in the southern hemisphere was dominated by the A(H1N1) viruses that emerged during the 2009 influenza A(H1N1) pandemic and influenza B viruses, although the proportion of these two varied between and within countries. Some influenza A(H3N2) viruses were also seen. We discuss here the preliminary implications for Europe of the 2011 influenza season in five temperate southern hemisphere countries. PMID- 22221495 TI - A case of diphtheria in Sweden, October 2011. AB - In October 2011, a child who had arrived in Sweden from Somalia presented with atypical tonsillitis, was treated with penicillin and the symptoms resolved. A throat swab was positive for toxigenic Corynebacterium diphtheriae. The child's family were then vaccinated with diphtheria, tetanus and pertussis vaccine and screened for C. diphtheriae. No secondary cases were found. A high level of adherence to childhood vaccination programmes is an effective way to protect populations against diphtheria. PMID- 22221496 TI - A case of OXA-48 carbapenemase-producing Klebsiella pneumoniae in a patient transferred to Slovenia from Libya, November 2011. AB - We report the first documented case of OXA-48-producing Klebsiella pneumoniae in Slovenia isolated from rectal surveillance cultures from a patient transferred from Libya. The patient was colonised with both ESBL-producing Escherichia coli and ESBL- and OXA-48-producing K. pneumoniae. Three further patients were colonised with ESBL-producing E. coli. This underscores the importance of an early warning system on European level and screening upon admission of patients transferred across borders and between healthcare systems. PMID- 22221498 TI - The European Commission proposes new measures against cross-border health threats. PMID- 22221497 TI - Outbreak of Salmonella Montevideo associated with a dietary food supplement flagged in the Rapid Alert System for Food and Feed (RASFF) in Germany, 2010. AB - In March 2010 the Rapid Alert System for Food and Feed (RASFF) was used to inform about Salmonella Montevideo in a herbal food supplement, formulated in capsules, distributed under a Dutch label in Germany. Simultaneous to the first RASFF notice, in the last two weeks of March 2010 an unusual number of 15 infections with S. Montevideo was notified within the electronic reporting system for infectious diseases at the Robert Koch Institute. Adult women (median age: 43, range: 1-90 years) were mainly affected. An outbreak was suspected and the food supplement hypothesised to be its vehicle. Cases were notified from six federal states throughout Germany, which required efficient coordination of information and activities. A case-control study (n=55) among adult women showed an association between consumption of the specific food supplement and the disease (odds ratio (OR): 27.5, 95% confidence interval (CI): 3.1-infinity, p value=0.002). Restricting the case-control study to the period when the outbreak peaked (between 29 March and 11 April 2010) resulted in an OR of 43.5 (95% CI: 4.8-infinity, p-value=0.001). Trace-back of the supplement's main ingredient, hemp seed flour, and subsequent microbiological testing by pulsed-field gel electrophoresis supported its likely role in transmission. This outbreak investigation illustrates that information from RASFF may aid in hypothesis generation in outbreak investigations, though likely late in the outbreak. PMID- 22221500 TI - [Psoriasis in infants about five cases]. AB - INTRODUCTION: Psoriasis is a skin disease very common. The diagnosis is clinical with a scaly erythema. Given the increasing frequency of cases of psoriasis of the child, we are interested in studying the role of this disease especially in infants. We report five cases of psoriasis collected in units of pediatric dermatology at Children's Hospital of Rabat. RESULTS: It is about a girl and four boys ranging in age between 41 days and 2 years. There is in three cases a family history of autoimmune disease, in two cases a notion of family atopee. Three cases among the five cases have plaque psoriasis, a case of psoriasis vulgaris, and one case of psoriatic diaper rash. All cases in our series were treated with emollients and topical corticosteroids. The outcome was favorable in five cases. CONCLUSION: Psoriasis is a multifactorial disease complex, multiple mechanisms, not well known, with combination of genetic, immunological and environmental factors. Treatment is in the light with corticosteroids, anti-inflammatory and immunomodulators obtained by genetic engineering techniques raises considerable hope in severe forms. PMID- 22221501 TI - Fabrication and characterization of carbon-based counter electrodes prepared by electrophoretic deposition for dye-sensitized solar cells. AB - Three different carbon-based counter electrodes are investigated in light of catalytic activities such as electrochemical frequencies and interface impedances. We fabricated carbon-based counter electrodes of dye-sensitized solar cells [DSSCs] using graphene, single-walled carbon nanotubes [SWNTs], and graphene-SWNT composites by electrophoretic deposition method. We observed the optical and electrochemical properties of the carbon-based counter electrodes. The DSSC with the graphene-deposited counter electrode demonstrated the best conversion efficiency of 5.87% under AM 1.5 and 1 sun condition. It could be utilized for a low-cost and high-throughput process for DSSCs. PMID- 22221502 TI - Partial nephrectomy for renal masses >= 7 cm: technical, oncological and functional outcomes. AB - What's known on the subject? and What does the study add? Partial nephrectomy for the pT1 renal mass has demonstrated acceptable oncological outcomes in addition to improved overall long-term survival when compared with radical nephrectomy. Previous reports for lesions >= 7 cm have shown mixed data concerning oncological outcomes and technological success. We demonstrate that partial nephrectomy for renal masses >= 7 cm has acceptable oncological, technical, and functional outcomes. As such, partial nephrectomy should be a surgical option when feasible regardless of tumour size. Study Type - Therapy (case series) Level of Evidence 4. OBJECTIVE: To present outcomes for patients with renal masses >= 7 cm in size who are treated with partial nephrectomy (PN) at our institution and to summarize the cumulative published experience. PATIENTS AND METHODS: We reviewed our prospectively maintained institutional kidney cancer database and identified patients undergoing PN for tumours >7 cm in size. Technical, oncological and renal functional data were analyzed and compared with the existing published experience of PNs for tumours >7 cm in size. RESULTS: In total, 46 patients with 49 renal tumours >7 cm in size who underwent PN were identified. With a median (range) follow-up of 13.1 (0.2-170.0) months, there were 16 complications, including four (8.2%) blood transfusions and six (12.2%) urinary fistulae. The 5- and 10-year overall and renal cell carcinoma (RCC)-specific survivals were 94.5% and 70.9%. There were five (10.9%) patients who had an upward migration in their chronic kidney disease status after PN. There were six previous series totalling 280 tumours encompassing the published experience of PN for tumours >7 cm in size. The incidence of urinary fistulae and postoperative haemorrhage, respectively, was in the range 3.3-18.8% and 0-3%. Although oncological outcomes showed cancer-specific survival in the range 66-97.0%, series matching PN and RN in patients with T2 RCC show equivalency in RCC-specific and overall survivals. When reported, PN for tumours >7 cm in size was associated with better renal functional preservation. CONCLUSION: The findings of the present study show that PN can safely be performed in tumours >= 7 cm in size with acceptable technical, oncological and functional outcomes. Further studies are warranted. PMID- 22221503 TI - Synthesis and characterization of CuO nanowires by a simple wet chemical method. AB - We report a successful synthesis of copper oxide nanowires with an average diameter of 90 nm and lengths of several micrometers by using a simple and inexpensive wet chemical method. The CuO nanowires prepared via this method are advantageous for industrial applications which require mass production and low thermal budget technique. It is found that the concentration and the quantity of precursors are the critical factors for obtaining the desired one-dimensional morphology. Field emission scanning electron microscopy images indicate the influence of thioglycerol on the dispersity of the prepared CuO nanowires possibly due to the stabilization effect of the surface caused by the organic molecule thioglycerol. The Fourier transform infrared spectrum analysis, energy dispersive X-ray analysis, X-ray diffraction analysis, and X-ray photoemission spectrum analysis confirm clearly the formation of a pure phase high-quality CuO with monoclinic crystal structure. PMID- 22221504 TI - Homocysteine impairs endothelial wound healing by activating metabotropic glutamate receptor 5. AB - OBJECTIVE: Hcy is an independent risk factor for cerebrovascular disease and cognitive impairment. The purpose of this study was to elucidate the role of mGluR5 in Hcy-mediated impairment of cerebral endothelial wound repair. METHODS: Mouse CMVECs (bEnd.3) were used in conjunction with directed pharmacology and shRNA. AutoDock was used to simulate the docking of ligand-receptor interactions. RESULTS: Hcy (20 MUM) significantly increased Cx43-pS368 by mGluR5- and PKC dependent mechanisms. Hcy attenuated wound repair by an mGluR5-dependent mechanism over the six-day study period but did not alter cell proliferation in a proliferation assay, suggesting that the attenuation of wound repair may be due to dysfunctional migration in HHcy. Hcy increased the expression of Cx43 and Cx43 pS368 at the wound edge by activating mGluR5. Direct activation of mGluR5, using the specific agonist CHPG, was sufficient to reproduce the results whereas KO of mGluR5 with shRNA, or inhibition with MPEP, blocked the response to Hcy. CONCLUSIONS: Inhibition of mGluR5 activation could be a novel strategy for promoting endothelial wound repair in patients with HHcy. Activation of mGluR5 may be a viable strategy for disrupting angiogenesis. PMID- 22221505 TI - Hands-on...handoff. PMID- 22221506 TI - The year in Cardiothoracic and Vascular Anesthesia: selected highlights from 2011. AB - There have been rapid advances in oral anticoagulation. The oral factor Xa inhibitors rivaroxaban and apixaban and the oral direct thrombin inhibitor dabigatran recently have been rigorously evaluated. These novel anticoagulants will usher in a new paradigm for perioperative anticoagulation. Perioperative blood conservation in cardiac surgery recently has been highlighted in the updated guidelines by the Society of Cardiovascular Anesthesiologists and the Society of Thoracic Surgeons. These recommendations reflect a comprehensive evaluation of the recent evidence to optimize transfusion practice. Transcatheter mitral valve repair continues to mature. Transcatheter aortic valve implantation for aortic stenosis has entered the clinical mainstream, with randomized trials showing its superiority over medical management and its equivalency to surgical valve replacement in high-risk patients. This transformational technology represents a major leadership opportunity for the cardiac anesthesiologist. Minimally invasive valve surgery has shown effectiveness in high-risk patients. Radial access is equivalent to femoral access for percutaneous coronary intervention in acute coronary syndromes but significantly reduces the risk of local vascular complications. Recent trials have further clarified the roles of medical therapy, percutaneous coronary intervention, and coronary artery bypass surgery in patients with significant coronary artery disease and left ventricular dysfunction. The past year has witnessed major advances in cardiovascular practice with new drugs, new devices, and new guidelines. The coming year most likely will advance these achievements to enhance the care of patients. PMID- 22221507 TI - Case 1--2012. A perfect storm: fatality resulting from metoclopramide unmasking a pheochromocytoma and its management. PMID- 22221508 TI - Advances in the management of carotid artery disease: focus on recent evidence and guidelines. AB - Recent landmark randomized trials and society guidelines have significantly revised the management of carotid artery disease. Duplex ultrasonography is the recommended initial diagnostic test for the assessment of extracranial carotid artery stenosis. Carotid artery imaging is reasonable in select patients scheduled for coronary artery bypass graft (CABG) surgery. Carotid revascularization can be achieved safely and effectively with carotid endarterectomy or carotid artery stenting. Because each procedure has a different risk/benefit profile, the optimal approach is to match the particular patient to the intervention that maximizes outcome benefit. Carotid revascularization is recommended in patients scheduled for CABG surgery when the carotid artery stenosis is symptomatic and/or bilateral. Further trials are required to guide the management of asymptomatic unilateral carotid artery stenosis in patients undergoing CABG surgery. Aggressive medical therapy remains the gold standard for intracranial carotid artery disease because landmark trials have shown no outcome improvement with vascular bypass or percutaneous angioplasty and stenting. A large recent trial showed that local anesthesia, as compared with general anesthesia, for carotid endarterectomy has no major clinical outcome advantage. Although carotid artery stenting is associated with a reduced risk of myocardial ischemia, it still has important risks of stroke and hemodynamic instability that significantly affect clinical outcome. The timing and choice of carotid revascularization technique ultimately depends on multiple clinical factors. PMID- 22221510 TI - Photoluminescence characteristics of Cd1-xMnxTe single crystals grown by the vertical Bridgman method. AB - In this paper, we report a systematic investigation of band-edge photoluminescence for Cd1-xMnxTe crystals grown by the vertical Bridgman method. The near-band-edge emissions of neutral acceptor-bound excitons (labeled as L1) were systematically investigated as a function of temperature and of alloy composition. The parameters that describe the temperature variation of the energy were evaluated by the semiempirical Varshni relation. From the temperature dependence of the full width at half maximum of the L1 emission line, the broadening factors Gamma(T) were determined from the fit to the data. The activation energies of thermal quenching were obtained for the L1 peak from the temperature dependence of the bound exciton peaks and were found to decrease with increasing Mn concentration. PMID- 22221509 TI - General practitioners' and practice nurses' views and experience of managing depression in coronary heart disease: a qualitative interview study. AB - BACKGROUND: Depression is common in coronary heart disease (CHD). Affected patients have an increased incidence of coronary symptoms and death. Little is known about how best to manage primary care patients with both CHD and depression. This study is part of the UPBEAT-UK programme of research and was designed to understand general practitioners' (GPs) and practice nurses' (PNs) views and experience of managing depression in CHD. METHODS: Individual in-depth interviews with 10 GPs and 12 PNs in South East London. Data were analysed using constant comparison. RESULTS: GPs and PNs had similar views. Distress following diagnosis or a cardiac event was considered to resolve spontaneously; if it endured or became severe it was treated as depression. GPs and PNs felt that psychosocial problems contributed to depression in patients with CHD. However, uncertainty was expressed as to their perceived role and responsibility in addressing these. In this respect, depression in patients with CHD was considered similar to depression in other patients and no coherent management approach specific for depression in CHD was identified. An individualised approach was favoured, but clinicians were unsure how to achieve this in the face of conflicting patient preferences and the treatment options they considered available. CONCLUSIONS: GPs and PNs view depression in CHD similarly to depression uncomplicated by physical illness. However, uncertainty exists as to how best to manage depression associated psychosocial issues. Personalised interventions are needed which account for individual need and which enable and encourage clinicians and patients to make use of existing resources to address the psychosocial factors which contribute to depression. PMID- 22221512 TI - Construction of an artificial cell membrane anchor using DARC as a fitting for artificial extracellular functionalities of eukaryotic cells. AB - The need to functionalize cell membranes in a directed way for specific applications as single cell arrays or to force close cell-to-cell contact for artificial intercellular interaction and/or induction concerning stem cell manipulation or in general to have a tool for membrane and cell surface associated processes, we envisaged a neutral inactive membrane anchor for extracellular entities to facillitate the above mentioned functionalities. The silent Duffy antigen/receptor for chemokines (DARC) is a receptor-like membrane protein of erythrocytes and mediates no cell transduction not at least regarding a missing or truncated G-loop and therefore it seemed to be the candidate for our cell membrane anchor. We isolated the genetic information of DARC from human genomic DNA and cloned it in a mammalian cell line as a fusion protein via a suitable plasmid vector. In this report we demonstrate that the human plasma membrane protein DARC can be used as an artificial anchor molecule in cell surface engineering applications. We constructed the fusion protein SNAP-tag DARC, consisting of DARC and the self-labeling protein tag SNAP-tag(r) (Covalys). The SNAP-tag(r) served as an example for a molecular-technological developed protein that is artificially attached to the extracellular side of the plasma membrane through our DARC-anchor. SnapTag should serve as an example for any extracellular entity and was easy to detect by a commercial detection system. The synthesis of SNAP-tag-DARC, its correct incorporation into the cell membrane and the functionality of the SNAP-tag(r) were verified by RT-PCR, Western blotting and confocal fluorescence microscopy and showed the desired functionality as an membrane anchor for an extracellular application entity. PMID- 22221511 TI - Intramedullary nailing of femoral shaft fractures in polytraumatized patients. a longitudinal, prospective and observational study of the procedure-related impact on cardiopulmonary- and inflammatory responses. AB - BACKGROUND: Early intramedullary nailing (IMN) of long bone fractures in severely injured patients has been evaluated as beneficial, but has also been associated with increased inflammation, multi organ failure (MOF) and morbidity. This study was initiated to evaluate the impact of primary femoral IMN on coagulation-, fibrinolysis-, inflammatory- and cardiopulmonary responses in polytraumatized patients. METHODS: Twelve adult polytraumatized patients with femoral shaft fractures were included. Serial blood samples were collected to evaluate coagulation-, fibrinolytic-, and cytokine activation in arterial blood. A flow directed pulmonary artery (PA) catheter was inserted prior to IMN. Cardiopulmonary function parameters were recorded peri- and postoperatively. The clinical course of the patients and complications were monitored and recorded daily. RESULTS: Mean Injury Severity Score (ISS) was 31 +/- 2.6. No procedure related effect of the primary IMN on coagulation- and fibrinolysis activation was evident. Tumor necrosis factor alpha (TNF-alpha) increased significantly from 6 hours post procedure to peak levels on the third postoperative day. Interleukin-6 (IL-6) increased from the first to the third postoperative day. Interleukin-10 (IL-10) peaked on the first postoperative day. A procedure-related transient hemodynamic response was observed on indexed pulmonary vascular resistance (PVRI) two hours post procedure. 11/12 patients developed systemic inflammatory response syndrome (SIRS), 7/12 pneumonia, 3/12 acute lung injury (ALI), 3/12 adult respiratory distress syndrome (ARDS), 3/12 sepsis, 0/12 wound infection. CONCLUSION: In the polytraumatized patients with femoral shaft fractures operated with primary IMN we observed a substantial response related to the initial trauma. We could not demonstrate any major additional IMN-related impact on the inflammatory responses or on the cardiopulmonary function parameters. These results have to be interpreted carefully due to the relatively few patients included. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00981877. PMID- 22221513 TI - Combination injuries 2. The risk of pulp necrosis in permanent teeth with subluxation injuries and concomitant crown fractures. AB - BACKGROUND: The reported risk of pulp necrosis (PN) is generally low in teeth with subluxation injuries. A concomitant crown fracture may increase the risk of PN in such teeth. AIM: To analyse the influence of a concomitant trauma-related infraction, enamel-, enamel-dentin- or enamel-dentin-pulp fracture on the risk of PN in permanent teeth with subluxation injury. MATERIAL AND METHODS: The study included 404 permanent incisors with subluxation injury from 289 patients (188 male, 101 female). Of these teeth, 137 had also suffered a concomitant crown fracture. All the teeth were examined and treated according to a standardized protocol. STATISTICAL ANALYSIS: The risk of PN was analysed separately for teeth with immature and mature root development by the Kaplan-Meier method, the log-rank test and Cox regression analysis. The level of significance was set at 5%. Risk factors included in the analysis were gender, patient age, crown fracture type, mobility and response to an electric pulp test (EPT) at the initial examination. RESULTS: Teeth with immature root development: The risk of PN was increased in teeth with a concomitant enamel fracture (log-rank test: P = 0.002), enamel-dentin fracture (log-rank test: P < 0.0001), enamel-dentin-pulp fracture (log-rank test: P < 0.0001) and in teeth with no response to EPT at the initial examination [hazard ratio: 21 (95% confidence interval, CI: 2.5-172.5), P = 0.005]. Teeth with mature root development: the risk of PN was increased in teeth with an enamel-dentin fracture [hazard ratio: 12.2 (95% CI: 5.0-29.8), P < 0.0001], infraction [hazard ratio: 5.1 (95% CI: 1.2-21.4) P = 0.04] and in teeth with no response to EPT at the initial examination [hazard ratio: 8 (95% CI: 3.3 19.5), P < 0.0001]. CONCLUSION: A concomitant crown fracture and no response to EPT at the initial examination may be used to identify teeth at increased risk of PN following subluxation injury. PMID- 22221514 TI - Numts help to reconstruct the demographic history of the ocellated lizard (Lacerta lepida) in a secondary contact zone. AB - In northwestern Iberia, two largely allopatric Lacerta lepida mitochondrial lineages occur, L5 occurring to the south of Douro River and L3 to the north, with a zone of putative secondary contact in the region of the Douro River valley. Cytochrome b sequence chromatograms with polymorphisms at nucleotide sites diagnostic for the two lineages were detected in individuals in the region of the Douro River and further north within the range of L3. We show that these polymorphisms are caused by the presence of four different numts (I-IV) co occurring with the L3 genome, together with low levels of heteroplasmy. Two of the numts (I and II) are similar to the mitochondrial genome of L5 but are quite divergent from the mitochondrial genome of L3 where they occur. We show that these numts are derived from the mitochondrial genome of L5 and were incorporated in L3 through hybridization at the time of secondary contact between the lineages. The additional incidence of these numts to the north of the putative contact zone is consistent with an earlier postglacial northward range expansion of L5, preceding that of L3. We show that genetic exchange between the lineages responsible for the origin of these numts in L3 after secondary contact occurred prior to, or coincident with, the northward expansion of L3. This study shows that, in the context of phylogeographic analysis, numts can provide evidence for past demographic events and can be useful tools for the reconstruction of complex evolutionary histories. PMID- 22221515 TI - Risk of extrathymic cancer in patients with myasthenia gravis in Taiwan: a nationwide population-based study. AB - BACKGROUND AND PURPOSE: The relationship between myasthenia gravis (MG) and extrathymic malignancies has not been determined. This study aimed to explore the risk of extrathymic malignancy in patients with MG based on a nationwide population-based dataset. METHODS: We identified 2614 patients with MG from the Taiwan National Health Insurance database between 1997 and 2005 and compared the incidence rates of extrathymic malignancies with 15, 684 randomly selected age-, sex-, and comorbidity-matched subjects without MG. Both cohorts were followed until the end of 2009. Cox proportional hazard model was used to evaluate the predictors of extrathymic malignancy in the MG cohort, including age, sex, comorbidities, and prescription drugs. RESULTS: After an average follow-up of 8 years, the MG cohort had a higher risk of extrathymic cancers with an incidence rate ratio (IRR) of 1.38 (95% CI 1.12-1.68, P = 0.002) than the control cohort. Although breast cancer was the most common cancer found, no statistically significant relationship between MG and any specific malignancy was observed. Cox multivariate proportional hazards analysis showed that only age (HR = 1.05, 95% CI 1.04-1.06, P < 0.001) and liver cirrhosis (IRR = 3.85, 95% CI 1.22-12.14, P = 0.021) were predictors of extrathymic cancers in the MG cohort. CONCLUSIONS: Our study showed that patients with MG had an increased risk of extrathymic malignancy in a follow-up of 8 years, but no specific susceptibility to certain malignancies was found. PMID- 22221516 TI - Radionuclide therapy in neuroendocrine tumours: a systematic review. AB - The purpose of this systematic review was to investigate the effects of therapeutic radiopharmaceuticals in patients with different types of advanced neuroendocrine tumour (NETs). A literature search was carried out in MEDLINE and EMBASE from January 1998 to November 2010. The Cochrane Library (to Issue 10, 2010) and the Standards and Guidelines Evidence Inventory of Cancer Guidelines, including over 1100 English-language cancer guidelines from January 2003 to June 2010, were also checked. No existing systematic reviews or clinical practice guidelines based on a systematic review or randomised controlled trials focusing on this topic were found. Twenty-four fully published articles were abstracted and summarised: 16 articles focused on five peptide receptor radionuclide therapy ((111)In-DTPAOC, (90)Y-DOTALAN, (90)Y-DOTATOC, (90)Y-DOTATATE, and (177)Lu DOTATATE) and eight focused on (131)I-MIBG treatment. Limited evidence from a historical comparison of studies in one centre supported that (177)Lu-DOTATATE might be associated with greater clinical outcomes compared with (90)Y-DOTATOC or (111)In-DTPAOC. The severe toxicities for (177)Lu-DOTATATE included hepatic insufficiency in 0.6%, myelodysplastic syndrome in 0.8% and renal insufficiency in 0.4% of patients in this study. Insufficient evidence suggested efficacy of (131)I-MIBG in adult NET patients, but the overall tumour response rate from (131)I-MIBG was 27-75% for malignant neuroblastoma, paraganglioma or pheochromocytoma. Haematological toxicities were the main severe side-effects after (131)I-MIBG and 4% of patients developed secondary malignancies in one study. To date, peptide receptor radionuclide therapy seems to be an acceptable option and is relatively safe in adult advanced NET patients with receptor uptake positive on scintigraphy, but patients' renal function must be monitored. (131)I MIBG may be effective for malignant neuroblastoma, paraganglioma or pheochromocytoma, but its side-effects need to be considered. No strong evidence exists to support that one therapeutic radiopharmaceutical is more effective than others. Well-designed and good-quality randomised controlled trials are required on this research topic. PMID- 22221517 TI - Sex differences in the impact of the Mediterranean diet on cardiovascular risk profile. AB - The traditional Mediterranean diet (MedDiet) is now widely recommended in the prevention of CVD. However, it is not known whether the MedDiet has the same beneficial cardiovascular effects in women and in men. The objective of the present study was to investigate sex-related differences with regard to changes in cardiometabolic variables in response to a 4-week isoenergetic MedDiet. Participants were thirty-eight men and thirty-two premenopausal women aged between 25 and 50 years who had slightly elevated LDL-cholesterol (LDL-C) concentrations (3.4-4.9 mmol/l) or total cholesterol:HDL-cholesterol ratio >= 5.0. A 4-week run-in period preceded the MedDiet in order to control the inter- and intra-individual variability. Cardiometabolic variables were measured before and after the MedDiet. Total cholesterol, LDL-C, apoB and apoA-1 plasma concentrations as well as diastolic blood pressure decreased (P < 0.05) in both men and women (respectively, 10, 10, 10, 6 and 5% for men and 6, 7, 9, 4 and 4% for women). ApoA-2 concentrations and insulin concentrations 2 h after the oral administration of 75 g of glucose demonstrated sex * time interactions (respectively, P = 0.05 and P = 0.03) and only men experienced a decrease for these variables (respectively, 8 and 25%). In conclusion, consuming a MedDiet led to significant changes in plasma lipid profile in both men and women, while only men had significant improvements in insulin homeostasis. These results support the importance of investigating sex-related differences in response to diet in order to perhaps further individualise dietary guidelines in the prevention of CVD and type 2 diabetes. PMID- 22221518 TI - Effects of process parameters on sheet resistance uniformity of fluorine-doped tin oxide thin films. AB - An alternative indium-free material for transparent conducting oxides of fluorine-doped tin oxide [FTO] thin films deposited on polyethylene terephthalate [PET] was prepared by electron cyclotron resonance - metal organic chemical vapor deposition [ECR-MOCVD]. One of the essential issues regarding metal oxide film deposition is the sheet resistance uniformity of the film. Variations in process parameters, in this case, working and bubbler pressures of ECR-MOCVD, can lead to a change in resistance uniformity. Both the optical transmittance and electrical resistance uniformity of FTO film-coated PET were investigated. The result shows that sheet resistance uniformity and the transmittance of the film are affected significantly by the changes in bubbler pressure but are less influenced by the working pressure of the ECR-MOCVD system. PMID- 22221519 TI - Ferroelectric properties of PZT/BFO multilayer thin films prepared using the sol gel method. AB - In this study, Pb(Zr0.52Ti0.48)O3/BiFeO3 [PZT/BFO] multilayer thin films were fabricated using the spin-coating method on a Pt(200 nm)/Ti(10 nm)/SiO2(100 nm)/p Si(100) substrate alternately using BFO and PZT metal alkoxide solutions. The coating-and-heating procedure was repeated several times to form the multilayer thin films. All PZT/BFO multilayer thin films show a void-free, uniform grain structure without the presence of rosette structures. The relative dielectric constant and dielectric loss of the six-coated PZT/BFO [PZT/BFO-6] thin film were approximately 405 and 0.03%, respectively. As the number of coatings increased, the remanent polarization and coercive field increased. The values for the BFO-6 multilayer thin film were 41.3 C/cm2 and 15.1 MV/cm, respectively. The leakage current density of the BFO-6 multilayer thin film at 5 V was 2.52 * 10-7 A/cm2. PMID- 22221520 TI - Fabrication of a new type of organic-inorganic hybrid superlattice films combined with titanium oxide and polydiacetylene. AB - We fabricated a new organic-inorganic hybrid superlattice film using molecular layer deposition [MLD] combined with atomic layer deposition [ALD]. In the molecular layer deposition process, polydiacetylene [PDA] layers were grown by repeated sequential adsorption of titanium tetrachloride and 2,4-hexadiyne-1,6 diol with ultraviolet polymerization under a substrate temperature of 100 degrees C. Titanium oxide [TiO2] inorganic layers were deposited at the same temperatures with alternating surface-saturating reactions of titanium tetrachloride and water. Ellipsometry analysis showed a self-limiting surface reaction process and linear growth of the nanohybrid films. The transmission electron microscopy analysis of the titanium oxide cross-linked polydiacetylene [TiOPDA]-TiO2 thin films confirmed the MLD growth rate and showed that the films are amorphous superlattices. Composition and polymerization of the films were confirmed by infrared spectroscopy. The TiOPDA-TiO2 nanohybrid superlattice films exhibited good thermal and mechanical stabilities.PACS: 81.07.Pr, organic-inorganic hybrid nanostructures; 82.35.-x, polymerization; 81.15.-z, film deposition; 81.15.Gh, chemical vapor deposition (including plasma enhanced CVD, MOCVD, ALD, etc.). PMID- 22221521 TI - The value of urinary prostate cancer gene 3 (PCA3) scores in predicting pathological features at radical prostatectomy. AB - Study Type - Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? PCA3 scores correlate to numerous histoprognostic factors, specifically tumour volume and positive surgical margins. These results may have a clinical impact in the near future on the selection of patients eligible to undergo active surveillance and nerve-sparing surgery. OBJECTIVE: To assess correlations between Prostate CAncer gene 3 (PCA3) levels and pathological features of radical prostatectomy (RP) specimens, which define cancer aggressiveness. PATIENTS AND METHODS: After digital rectal examination (DRE), first-catch urine was collected from 160 patients with localized prostate cancer. The PCA3 score was calculated using the Gene Probe Progensa(TM) assay. PCA3 scores were then correlated to the pathological features of the RP specimens. RESULTS: PCA3 scores correlated significantly with tumour volume (r= 0.34, P < 0.01). A PCA3 score of >35 was an independent predictor in a multivariate analysis of a tumour volume >0.5 mL (odds ratio [OR] 2.7, P= 0.04). It was also an independent predictor of positive surgical margins (OR 2.4, P= 0.04). Receiver-operator characteristic curves indicated PCA3 as the most accurate predictor of positive margins (area under the curve [AUC] 0.62), in addition to a positive biopsy percentage (AUC 0.52). There was also a significant difference in the mean PCA3 score between Gleason score patient groups (6 vs >= 7) and pathological stage groups (pT0/2 vs pT3/4). CONCLUSIONS: PCA3 scores correlate to numerous histoprognostic factors, specifically tumour volume and positive surgical margins. These results may have a clinical impact in the near future on the selection of patients eligible to undergo active surveillance and nerve-sparing surgery. PMID- 22221522 TI - Genetic polymorphisms in TNFA/TNFR2 genes and Chagas disease in a Colombian endemic population. AB - In this study we investigated the association of functional single nucleotide polymorphisms of tumor necrosis factor-alfa (TNFA) and TNF receptor 2 (TNFR2) genes in determining the susceptibility to Chagas' disease. This study included 313 patients from Colombia serologically positive for Trypanosoma cruzi antigens (cardiomyopathic, N=159; asymptomatic, N=154). Genotypes were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism method. We found a significant difference in the distribution of the TNFA -1031C (p=0.0153, OR=1.69, CI=1.10-2.58) and -308A (p=0.0002, OR=2.60, CI=1.53-4.39) alleles between cardiomyopathic and asymptomatic subjects. In addition, we observed that the TNFR2 +676T allele was monomorphic in our population. Our results suggest that TNFA -1031C and -308A gene polymorphisms may influence the susceptibility to develop chagasic cardiomyopathy in the population under study. PMID- 22221523 TI - Development of resistance in Cronobacter sakazakii ATCC 29544 to thermal and nonthermal processes after exposure to stressing environmental conditions. AB - AIMS: The objective was to study the response of Cronobacter sakazakii ATCC 29544 cells to heat, pulsed electric fields (PEF), ultrasound under pressure (Manosonication, MS) and ultraviolet light (UV-C) treatments after exposure to different sublethal stresses that may be encountered in food-processing environments. METHODS AND RESULTS: Cronobacter sakazakii stationary growth-phase cells (30 degrees C, 24h) were exposed to acid (pH 4.5, 1h), alkaline (pH 9.0, 1h), osmotic (5% NaCl, 1h), oxidative (0.5mmoll(-1) H(2) O(2), 1h), heat (47.5 degrees C, 1h) and cold (4 degrees C, 4h) stress conditions and subjected to the subsequent challenges: heat (60 degrees C), PEF (25kVcm(-1) , 35 degrees C), MS (117MUm, 200kPa, 35 degrees C) and UV-C light (88.55mWcm(-2), 25 degrees C) treatments. The inactivation kinetics of C. sakazakii by the different technologies did not change after exposure to any of the stresses. The combinations of sublethal stress and lethal treatment that were protective were: heat shock-heat, heat shock-PEF and acid pH-PEF. Conversely, the alkaline shock sensitized the cells to heat and UV-C treatments, the osmotic shock to heat treatments and the oxidative shock to UV-C treatments. The maximum adaptive response was observed when heat-shocked cells were subjected to a heat treatment, increasing the time to inactivate 99.9% of the population by 1.6 times. CONCLUSIONS: Cronobacter sakazakii resistance to thermal and nonthermal preservation technologies can increase or decrease as a consequence of previous exposure to stressing conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: The results help in understanding the physiology of the resistance of this emerging pathogen to traditional and novel preservation technologies. PMID- 22221524 TI - Commentary: noninvasive skin tightening: ultrasound and other technologies: where are we in 2011? PMID- 22221525 TI - Commentary: tacrolimus in the treatment of chronic and refractory late-onset immune-mediated adverse effects related to silicone injections. PMID- 22221526 TI - Modified Antia Buch repair for full-thickness middle auricular defect. PMID- 22221527 TI - Letter: regarding an "alternative treatment for varicose veins: ligation plus foam sclerotherapy". PMID- 22221528 TI - Letter: use of a transparent adhesive film in planning local flaps. PMID- 22221530 TI - Composition and crystalline properties of TiNi thin films prepared by pulsed laser deposition under vacuum and in ambient Ar gas. AB - TiNi shape memory alloy thin films were deposited using the pulsed laser deposition under vacuum and in an ambient Ar gas. Our main purpose is to investigate the influences of ambient Ar gas on the composition and the crystallization temperature of TiNi thin films. The deposited films were characterized by energy-dispersive X-ray spectrometry, a surface profiler, and X ray diffraction at room temperature. In the case of TiNi thin films deposited in an ambient Ar gas, the compositions of the films were found to be very close to the composition of target when the substrate was placed at the shock front. The in-situ crystallization temperature (ca. 400 degrees C) of the TiNi film prepared at the shock front in an ambient Ar gas was found to be lowered by ca. 100 degrees C in comparison with that of a TiNi film prepared under vacuum. PMID- 22221529 TI - Letter regarding "electrosurgery and implantable electronic devices: review and implications for office-based procedures". PMID- 22221531 TI - Doctor, doctor. PMID- 22221532 TI - The 25(th) Year. PMID- 22221533 TI - Age disgracefully. PMID- 22221534 TI - Shortages and strategies: ANAC's role in the development of the National HIV/AIDS Strategy. PMID- 22221535 TI - Skeletal Muscle - one year on. PMID- 22221536 TI - Synthesis of manganese oxide nanocrystal by ultrasonic bath: effect of external magnetic field. AB - A novel technique was used for the synthesis of manganese oxide nanocrystal by applying an external magnetic field (EMF) on the precursor solution before sonication with ultrasonic bath. The results were compared in the presence and absence of EMF. Manganese acetate solution as precursor was circulated by a pump at constant speed (7 rpm, equal to flow rate of 51.5 mL/min) in an EMF with intensity of 0.38 T in two exposure times (t(MF), 2h and 24h). Then, the magnetized solution was irradiated indirectly by ultrasonic bath in basic and neutral media. One experiment was designed for the effect of oxygen atmosphere in the case of magnetic treated solution in neutral medium. The as prepared samples were characterized with X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (HRTEM, TEM), energy dispersive spectrum (EDS), and superconducting quantum interference device (SQUID) analysis. In neutral medium, the sonication of magnetized solution (t(MF), 24h) led mainly to a mixture of Mn(3)O(4) (hausmannite) and gamma-MnOOH (manganite) and sonication of unmagnetized solution led to a pure Mn(3)O(4). In point of particle size, the larger and smaller size of nanoparticles was obtained with and without magnetic treatment, respectively. In addition, the EMF was retarded the nucleation process, accelerated the growth of the crystal, and increased the amount of rod-like structure especially in oxygen atmosphere. In basic medium, a difference was observed on the composition of the products between magnetic treated and untreated solution. For these samples, the magnetic measurements as a function of temperature were exhibited a reduction in ferrimagnetic temperature to T(c)=39K, and 40K with and without magnetic treatment, respectively. The ferrimagnetic temperature was reported for the bulk at T(c)=43K. A superparamagnetic behavior was observed at room temperature without any saturation magnetization and hysteresis in the measured field strength. The effect of EMF on the sample prepared in the basic medium was negligible but, in the case of neutral medium, the EMF affected the slope of the magnetization curves. The magnetization at room temperature was higher for the samples obtained in neutral medium without magnetic treatment. In addition, a horizontal shift loop was observed in neutral medium at low temperature. PMID- 22221537 TI - Bacterial persistence increases as environmental fitness decreases. AB - Since persister cells cause chronic infections and since Escherichia coli toxin MqsR increases persisters, we used protein engineering to increase the toxicity of MqsR to gain insights into persister cell formation. Through two amino acid replacements that increased the stability of MqsR, toxicity and persistence were increased. A whole-transcriptome study revealed that the MqsR variant increased persistence by repressing genes for acid resistance, multidrug resistance and osmotic resistance. Corroborating these microarray results, deletion of rpoS, as well as the genes that the master stress response regulator RpoS controls, increased persister formation dramatically to the extent that nearly the whole population became persistent. Furthermore, wild-type cells stressed by prior treatment to acid or hydrogen peroxide increased persistence 12 000-fold. Whole transcriptome analyses of persister cells generated by two different methods (wild-type cells pretreated with hydrogen peroxide and the rpoS deletion) corroborated the importance of suppressing RpoS in persister cell formation. Therefore, the more toxic MqsR increases persistence by decreasing the ability of the cell to respond to antibiotic stress through its RpoS-based regulation of acid resistance, multidrug resistance and osmotic resistance systems. PMID- 22221538 TI - Combination injuries 1. The risk of pulp necrosis in permanent teeth with concussion injuries and concomitant crown fractures. AB - BACKGROUND: The reported risk of pulp necrosis (PN) is low in teeth with concussion injuries. A concomitant crown fracture may affect the risk of PN. AIM: To analyze the influence of a crown fracture (with and without pulp exposure) on the risk of PN in teeth with concussion injury. MATERIAL: The study included 469 permanent incisors with concussion from 358 patients (226 male, 132 female). Among these, 292 had a concomitant crown fracture (70 with and 222 without pulp exposure). All teeth were examined and treated according to standardized protocol. STATISTICAL ANALYSIS: The risk of PN was analyzed by the Kaplan-Meier method and Cox regression. Risk factors included in the analysis: gender, age, stage of root development, type of crown fracture, and response to electric pulp test (EPT) at the initial examination. The level of significance was set at 5%. RESULTS: The risk of PN was low in teeth with immature root development [1.1%, 95% confidence intervals (CI): 0-3.4]. The following factors significantly increased the risk of PN in teeth with mature root development: crown fracture without pulp exposure [hazard ratio 4.1 (95% CI: 1.4-11.9), P = 0.01] and no response to EPT at the initial examination [hazard ratio 30.7 (95% CI: 7.7-121), P < 0.0001]. The overall risk of PN increased from 3.5% (95% CI: 0.2-6.8) to 11.0% (95% CI: 5.2-16.7) when a concomitant crown fracture without pulp exposure was present. If the tooth had both a crown fracture and gave no response to EPT, the risk further increased to 55.0% (95% CI: 34.3-75.8). CONCLUSION: No response to EPT at the initial examination or a concomitant crown fracture significantly increased the risk of PN in teeth with concussion injury and mature root development. If both risk factors were present there was a synergetic effect. PMID- 22221540 TI - Catalytic pyrolysis of waste rice husk over mesoporous materials. AB - Catalytic fast pyrolysis of waste rice husk was carried out using pyrolysis-gas chromatography/mass spectrometry [Py-GC/MS]. Meso-MFI zeolite [Meso-MFI] was used as the catalyst. In addition, a 0.5-wt.% platinum [Pt] was ion-exchanged into Meso-MFI to examine the effect of Pt addition. Using a catalytic upgrading method, the activities of the catalysts were evaluated in terms of product composition and deoxygenation. The structure and acid site characteristics of the catalysts were analyzed by Brunauer-Emmett-Teller surface area measurement and NH3 temperature-programmed desorption analysis. Catalytic upgrading reduced the amount of oxygenates in the product vapor due to the cracking reaction of the catalysts. Levoglucosan, a polymeric oxygenate species, was completely decomposed without being detected. While the amount of heavy phenols was reduced by catalytic upgrading, the amount of light phenols was increased because of the catalytic cracking of heavy phenols into light phenols and aromatics. The amount of aromatics increased remarkably as a result of catalytic upgrading, which is attributed to the strong Bronsted acid sites and the shape selectivity of the Meso-MFI catalyst. The addition of Pt made the Meso-MFI catalyst even more active in deoxygenation and in the production of aromatics. PMID- 22221539 TI - Novel water-soluble polyurethane nanomicelles for cancer chemotherapy: physicochemical characterization and cellular activities. AB - BACKGROUND: Efficient delivery of anticancer chemotherapies such as paclitaxel (PTX) can improve treatment strategy in a variety of tumors such as breast and ovarian cancers. Accordingly, researches on polymeric nanomicelles continue to find suitable delivery systems. However, due to biocompatibility concerns, a few micellar nanoformulations have exquisitely been translated into clinical uses. Here, we report the synthesis of novel water-soluble nanomicelles using bioactive polyurethane (PU) polymer and efficient delivery of PTX in the human breast cancer MCF-7 cells. RESULTS: The amphiphilic polyurethane was prepared through formation of urethane bounds between hydroxyl groups in poly (tetramethylene ether) glycol (PTMEG) and dimethylol propionic acid with isocyanate groups in toluene diisocyanate (TDI). The free isocyanate groups were blocked with phenol, while the free carboxyl groups of dimethylol propionic acid were reacted with triethylamine to attain ionic centers in the polymer backbone. These hydrophobic PTMEG blocks displayed self-assembly forming polymeric nanomicelles in water. The PTX loaded PU nanomicelles showed suitable physical stability, negative zeta potential charge (-43) and high loading efficiency (80%) with low level of critical micelle concentration (CMC). In vitro drug release profile showed a faster rate of drug liberation at pH 5.4 as compared to that of pH 7.4, implying involvement of a pH-sensitive mechanism for drug release from the nanomicelles. The kinetic of release exquisitely obeyed the Higuchi model, confirming involvement of diffusion and somewhat erosion at pH 5.4. These nanomicelles significantly inhibited the growth and proliferation of the human breast cancer MCF-7 cells, leading them to apoptosis. The real time RT-PCR analysis confirmed the activation of apoptosis as result of liberation of cytochrome c in the cells treated with the PTX loaded PU nanomicelles. The comet assay analysis showed somewhat DNA fragmentation in the treated cells. CONCLUSIONS: Based upon these findings, we propose that the bioactive waterborne polyurethane nanomicelles can be used as an effective nanocarrier for delivery of anticancer chemotherapies such as paclitaxel. PMID- 22221541 TI - Elevated levels of IFNgamma and LIGHT in the spinal cord of patients with sporadic amyotrophic lateral sclerosis. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a paralytic and fatal neurodegenerative disorder caused by the gradual loss of both upper and lower motoneurons. There is compelling evidence from ALS experimental models that neuroinflammation actively contributes to motoneuron damage. We recently proposed that interferon gamma (IFNgamma), a potent proinflammatory cytokine, induces motoneuron death by eliciting the activation of the lymphotoxin beta receptor (LT betaR) through its ligand LIGHT. Here, we explore the pertinence of this non-cell autonomous mechanism in human ALS. METHODS: The levels and expression pattern of IFNgamma, LIGHT, and LT-betaR were investigated by Western blot and immunohistochemical analysis in spinal cord of patients with sporadic ALS. RESULTS: We observed significant increased levels of IFNgamma in human ALS spinal cords compared to control cases. We found that large ventral horn neurons as well as glial cells were immunoreactive for IFNgamma in sporadic ALS spinal cord. We further observed that LIGHT and LT-betaR were expressed mainly by motoneurons in both ALS and control cases, and while LT-betaR levels remained constant between ALS and control cases, LIGHT levels were increased in human ALS spinal cords. CONCLUSION: These findings in sporadic ALS cases, which are consistent with the observation made in ALS experimental models, propose that the IFNgamma-triggered LIGHT/LT-betaR-mediated death pathway may contribute to human ALS pathogenesis. PMID- 22221542 TI - Structural and optical properties of a radio frequency magnetron-sputtered ZnO thin film with different growth angles. AB - This study introduces optical properties of a columnar structured zinc oxide [ZnO] antireflection coating for solar cells. We obtained ZnO films of columnar structure on glass substrates using a specially designed radio frequency magnetron sputtering system with different growth angles. Field-emission scanning electron microscopy was utilized to check the growth angles of the ZnO films which were controlled at 0 degrees , 15 degrees , and 30 degrees . The film thickness was fixed at 100 nm to get a constant experiment condition. Grain sizes of the ZnO films were measured by X-ray diffraction. A UV-visible spectrometer was used to measure the transmittance and reflectance of the ZnO film columnar structures as a function of the growth angles. PMID- 22221543 TI - Induction of visual dream reports after transcranial direct current stimulation (tDCs) during Stage 2 sleep. AB - REM sleep is a unique brain state characterized by frontal deactivation alongside activation of the posterior association and limbic cortices. Human brain lesion studies have found that the loss of dreaming is characterized by damage to the frontal and posterior parieto-temporo-occipital association cortex. Therefore, it is reasonable to assume that the function of these brain regions might encapsulate the neural processes of dreaming. The aim of the following two experiments was to investigate the effect of transcranial direct current stimulation (tDCs), applied simultaneously to the frontal and right posterior parietal cortex during Stage 2 sleep, on dreaming. In Experiment 1, 17 healthy participants received tDCs (cathodal-frontal, anodal-parietal) and low-intensity tDCs as well as no tDCs (blank control) during Stage 2 sleep in a counterbalanced order across the night. Dream reports were collected upon awakening after each of the three conditions. In Experiment 2, 10 participants received tDCs (cathodal frontal, anodal-parietal), no tDCs (blank control) and two additional control conditions (reversed polarity and other-cephalic tDCs). In both experiments a significantly greater number of imagery reports were found on awakening after tDCs (cathodal-frontal, anodal-parietal), compared to the blank control conditions. However, in Experiment 2 the frequency of imagery reports from the tDCs (cathodal-frontal, anodal-parietal) was not significantly different from the other two tDC conditions, suggesting a non-specific effect of tDCs. Overall, it was concluded that tDCs (cathodal-frontal, anodal-parietal) increased the frequency of dream reports with visual imagery, possibly via a general arousing effect and/or recreating specific cortical neural activity involved in dreaming. PMID- 22221544 TI - Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. AB - BACKGROUND: A reliable and inexpensive noninvasive marker of hepatic fibrosis is required in patients with nonalcoholic fatty liver disease (NAFLD). FIB4 index (based on age, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels, and platelet counts) is expected to be useful for evaluating hepatic fibrosis. We validated the performance of FIB4 index in a Japanese cohort with NAFLD. METHODS: The areas under the receiver operating characteristic curves (AUROC) for FIB4 and six other markers were compared, based on data from 576 biopsy-proven NAFLD patients. Advanced fibrosis was defined as stage 3-4 fibrosis. FIB4 index was assessed as: age (yr) * AST (IU/L)/(platelet count (10(9)/L) * ?ALT (IU/L)) RESULTS: Advanced fibrosis was found in 64 (11%) patients. The AUROC for FIB4 index was superior to those for the other scoring systems for differentiating between advanced and mild fibrosis. Only 6 of 308 patients with a FIB4 index below the proposed low cut-off point (< 1.45) were under-staged, giving a high negative predictive value of 98%. Twenty-eight of 59 patients with a FIB4 index above the high cut-off point (> 3.25) were over staged, giving a low positive predictive value of 53%. Using these cutoffs, 91% of the 395 patients with FIB-4 values outside 1.45-3.25 would be correctly classified. Implementation of the FIB4 index in the Japanese population would avoid 58% of liver biopsies. CONCLUSION: The FIB4 index was superior to other tested noninvasive markers of fibrosis in Japanese patients with NAFLD, with a high negative predictive value for excluding advanced fibrosis. The small number of cases of advanced fibrosis in this cohort meant that this study had limited power for validating the high cut-off point. PMID- 22221545 TI - Enhanced anti-inflammatory effect of resveratrol and EPA in treated endotoxin activated RAW 264.7 macrophages. AB - Macrophages play an important role in immunogenic challenges by producing reactive oxygen species, NO and proinflammatory cytokines that can aggravate and propagate local inflammation. Multiple mechanisms regulate these inflammatory processes. NF-kappaB and activator protein 1 pathways are crucial in the expression of proinflammatory genes, such as TNF-alpha, IL-1 (alpha or beta) and 6. Some polyphenols, which are present in beverages, vegetables and fruits, and PUFA, which are present in marine oils and fish food, possess anti-inflammatory effects in vivo and in vitro. Our aim in the present study was to assess whether polyphenols and PUFA have synergistic anti-inflammatory effects in murine macrophages in vitro. Inflammation in RAW 264.7 macrophages was induced by lipopolysaccharide at 100 ng/ml. The treatments with molecules were performed by co-incubation for 19 h. A NO production assay by Griess reaction, a phosphoprotein assay by Pathscan ELISA kit and gene expression analysis using the TaqMan(r) Low-density Array for ninety-one genes related to inflammation, oxidative stress and metabolism were performed to assess the synergistic anti inflammatory effects of polyphenols, epigallocatechin gallate and resveratrol (Res; 2.5 MUg/ml), and the PUFA, DHA and EPA (30 MUm). Adding Res+EPA had an enhanced anti-inflammatory effect, in comparison with EPA and Res alone, leading to decreased NO levels; modulating the phospho-stress activated protein kinase/Jun N-terminal kinase (P-SAPK/JNK) level; down-regulating proinflammatory genes, such as IL, chemokines, transcription factors; and up-regulating several antioxidant genes. Therefore, this combination has a stronger anti-inflammatory effect than either of these molecules separately in RAW macrophages. PMID- 22221547 TI - The spectrum of hypothermia: from environmental exposure to therapeutic uses and medical simulation. PMID- 22221548 TI - Densification characteristics of chromia/alumina castables by particle size distribution. AB - The quality of the refractories applied on integrated gasification combined cycle should be a key factor that affects both the reliability and the economics of gasifier operation. To enhance the workability of chromia/alumina castables, three types of ultrafine alumina powder were added to improve the workability. Densification behavior of such castables in the presence of ultrafine alumina was assessed through the measurement of parameters like flow value, viscosity, bulk density, apparent porosity, and microstructure evaluation by an SEM study. It's proved that the specific surface area and particle size distribution of ultrafine powders in matrix parts greatly influence the densification behavior of these castables. PMID- 22221549 TI - Expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder. AB - What's known on the subject? and What does the study add? Steroid hormone receptor signals have been implicated in bladder tumourigenesis and tumour progression. The expression of androgen and/or oestrogen receptors has been assessed in bladder cancer, leading to conflicting data of expression levels and their relationship to histopathological characteristics of the tumours. We simultaneously analyze three receptors in non-neoplastic bladder tissues as well as in primary and metastatic bladder tumour specimens. Our data demonstrate that the expression status correlates with tumour grades/stages and patients' outcomes. OBJECTIVE: To assess the expression of the androgen receptor (AR) and oestrogen receptors (ERs) in bladder tumours because recent studies have shown conflicting results and the prognostic significance of their expression remains unclear. PATIENTS AND METHODS: We investigated the expression of AR, ERalpha and ERbeta in 188 bladder tumour specimens, as well as matched 141 non-neoplastic bladder and 14 lymph node metastasis tissues, by immunohistochemistry. We then evaluated the relationships between their expression and the clinicopathological features available for the present patient cohort. RESULTS: AR/ERalpha/ERbeta was positive in 80%/50%/89% of benign urothelium, 50%/67%/41% of benign stroma, 42%/27%/49% of primary tumours and 71%/64%/71% of metastatic tumours. Significantly lower expression of AR/ERalpha was found in high-grade tumours (36%/23%) and tumours invading muscularis propria (33%/19%) compared to low-grade tumours (55%; P= 0.0232/38%; P= 0.0483) and tumours not invading muscularis propria (51%; P= 0.0181/35%; P= 0.0139), respectively. Significantly higher expression of ERbeta was found in high-grade tumours (58%) and tumours invading muscularis propria (67%) compared to low-grade tumours (29%; P= 0.0002) and tumours not invading muscularis propria (34%; P < 0.0001), respectively. Kaplan Meier and log-rank tests further showed that positivity of ERbeta (but not AR or ERalpha) was associated with the recurrence of low-grade tumours (P= 0.0072); the progression of low-grade tumours (P= 0.0005), high-grade tumours not invading muscularis propria (P= 0.0020) and tumours invading muscularis propria (P= 0.0010); or disease-specific mortality in patients with tumours invading muscularis propria (P= 0.0073). CONCLUSIONS: Compared to benign bladders, a significant decrease in the expression of AR, ERalpha or ERbeta in bladder cancer was seen. Loss of AR or ERalpha was strongly associated with higher grade/more invasive tumours, whereas ERbeta expression was increased in high-grade/invasive tumours and predicted a worse prognosis. PMID- 22221550 TI - Molecular detection and genotyping of human noroviruses in influent and effluent water at a wastewater treatment plant in Japan. AB - AIMS: To investigate the prevalence, seasonality and genotype distribution of human noroviruses (NoVs) in wastewater in Japan. METHODS AND RESULTS: Influent and effluent water samples were collected monthly for a year from a wastewater treatment plant and examined for the presence of genogroups I and II (GI and GII) NoVs. Using real-time reverse transcription (RT)-PCR assays, 12 (100%) influent and six (50%) effluent samples were positive for both GI and GII NoV genomes, with a higher prevalence in winter. A total of 152 different NoV strains, comprising 84 GI and 68 GII strains, were identified using seminested RT-PCR assays followed by cloning and sequence analysis. These strains were classified into nine GI genotypes (GI/1, 2, 4, 5, 8, 9, 11, 12 and 14) and 13 GII genotypes (GII/1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 15 and 16), showing considerable genetic diversity. CONCLUSIONS: Based on the partial capsid gene sequences, we identified a great number of NoV strains belonging to many genotypes, demonstrating that genetically diverse NoV strains are co-circulating in aquatic environments and human populations. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results clearly demonstrate the seasonal trend and genetic diversity of NoVs in wastewater. PMID- 22221551 TI - Comparison of laser versus sclerotherapy in the treatment of lower extremity telangiectases: a prospective study. AB - BACKGROUND: Lower extremity telangiectasia affects approximately 40% of women. The demand for aesthetic treatment of these veins continues to grow. Few studies have compared laser and sclerotherapy to treat leg telangiectasias. OBJECTIVE: To compare the efficacy of conventional sclerotherapy and neodymium-doped yttrium aluminum garnet (Nd:YAG) laser in the treatment of leg telangiectasias. METHODS AND MATERIALS: Thirty women were enrolled in the study. One leg was randomly assigned laser treatment and the other sclerotherapy with 75% glucose solution. All patients were photographed before and after treatment. The applying physician and two independent observers rated photographic improvement of the treated areas. Complications and adverse effects were noted during follow-up. Patients answered a questionnaire that addressed pain, clearing of the vessels, and satisfaction with the results. RESULTS: There was a significant difference between the modes of treatment regarding pain. Twelve patients using laser and 16 using sclerotherapy considered the clearing of the vessels to be good to excellent after three sessions of both laser and scleratherapy. Mean scores after photographic assessment were 7.9 for laser and 7.0 for sclerotherapy. CONCLUSION: Lower extremity telangiectases may be treated equally well using Nd:YAG 1064-nm laser or conventional sclerotherapy. PMID- 22221552 TI - First identification of primary nanoparticles in the aggregation of HMF. AB - 5-Hydroxymethylfurfural [HMF] is an important intermediate compound for fine chemicals. It is often obtained via hydrothermal treatment of biomass-derived carbohydrates, such as fructose, glucose and sucrose. This study investigates the formation of carbonaceous spheres from HMF created by dehydration of fructose under hydrothermal conditions. The carbonaceous spheres, ranging between 0.4 and 10 MUm in diameter, have granulated morphologies both on the surface and in the interior. The residual solution is found to contain a massive number of primary nanoparticles. The chemical structure of the carbonaceous spheres was characterised by means of FTIR and NMR spectroscopies. Based on these observations, a mechanism involving the formation and aggregation of the nanoparticles is proposed. This mechanism differs considerably from the conventional understanding in the open literature. PMID- 22221554 TI - Short people got no reason: gender, height, and disparities in the management of acute lung injury. AB - Though the benefits of lung protective ventilation (LPV) in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) have been known for more than a decade, widespread clinical adoption has been slow. Han and colleagues demonstrate that women with ALI/ARDS are less likely than men to receive LPV, though this disparity resolves when the analysis is adjusted for patient height. This analysis identifies patient height as a significant factor in predicting provider adherence with LPV guidelines, and illuminates why some disparities in intensive care exist and how they may be resolved via improved utilization of evidence-driven protocols. PMID- 22221553 TI - Old and sticky-adhesive mechanisms in the living fossil Nautilus pompilius (Mollusca, Cephalopoda). AB - Nautiloidea is the oldest group within the cephalopoda, and modern Nautilus differs much in its outer morphology from all other recent species; its external shell and pinhole camera eye are the most prominent distinguishing characters. A further unique feature of Nautilus within the cephalopods is the lack of suckers or hooks on the tentacles. Instead, the animals use adhesive structures present on the digital tentacles. Earlier studies focused on the general tentacle morphology and put little attention on the adhesive gland system. Our results show that the epithelial parts on the oral adhesive ridge contain three secretory cell types (columnar, goblet, and cell type 1) that differ in shape and granule size. In the non-adhesive aboral epithelium, two glandular cell types (cell types 2 and 3) are present; these were not mentioned in any earlier study and differ from the cells in the adhesive area. The secretory material of all glandular cell types consists mainly of neutral mucopolysaccharide units, whereas one cell type in the non-adhesive epithelium also reacts positive for acidic mucopolysaccharides. The present data indicate that the glue in Nautilus consists mainly of neutral mucopolysaccharides. The glue seems to be a viscous carbohydrate gel, as known from another cephalopod species. De-attachment is apparently effectuated mechanically, i.e., by muscle contraction of the adhesive ridges and tentacle retraction. PMID- 22221555 TI - Synthesis and characterization of core-shell Fe3O4-gold-chitosan nanostructure. AB - BACKGROUND: Fe3O4-gold-chitosan core-shell nanostructure can be used in biotechnological and biomedical applications such as magnetic bioseparation, water and wastewater treatment, biodetection and bioimaging, drug delivery, and cancer treatment. RESULTS: Magnetite nanoparticles with an average size of 9.8 nm in diameter were synthesized using the chemical co-precipitation method. A gold coated Fe3O4 monotonous core-shell nanostructure was produced with an average size of 15 nm in diameter by glucose reduction of Au3+ which is then stabilized with a chitosan cross linked by formaldehyde. The results of analyses with X-ray diffraction (XRD), Fourier Transformed Infrared Spectroscopy (FTIR), Transmission Electron Microscopy (TEM), and Atomic Force Microscopy (AFM) indicated that the nanoparticles were regularly shaped, and agglomerate-free, with a narrow size distribution. CONCLUSIONS: A rapid, mild method for synthesizing Fe3O4-gold nanoparticles using chitosan was investigated. A magnetic core-shell-chitosan nanocomposite, including both the supermagnetic properties of iron oxide and the optical characteristics of colloidal gold nanoparticles, was synthesized. PMID- 22221556 TI - Polystyrene-Al2O3 composite solid polymer electrolyte for lithium secondary battery. AB - In a common salt-in-polymer electrolyte, a polymer which has polar groups in the molecular chain is necessary because the polar groups dissolve lithium salt and coordinate cations. Based on the above point of view, polystyrene [PS] that has nonpolar groups is not suitable for the polymer matrix. However, in this PS-based composite polymer-in-salt system, the transport of cations is not by segmental motion but by ion-hopping through a lithium percolation path made of high content lithium salt. Moreover, Al2O3 can dissolve salt, instead of polar groups of polymer matrix, by the Lewis acid-base interactions between the surface group of Al2O3 and salt. Notably, the maximum enhancement of ionic conductivity is found in acidic Al2O3 compared with neutral and basic Al2O3 arising from the increase of free ion fraction by dissociation of salt. It was revealed that PS-Al2O3 composite solid polymer electrolyte containing 70 wt.% salt and 10 wt.% acidic Al2O3 showed the highest ionic conductivity of 9.78 * 10-5 Scm-1 at room temperature. PMID- 22221557 TI - Susac syndrome: clinical characteristics and treatment in 29 new cases. AB - BACKGROUND AND PURPOSE: There are few clinical studies on the attempted treatments and outcomes in patients with Susac syndrome (SS) (retinocochleocerebral vasculopathy). METHODS: A retrospective review was performed of all patients presenting with SS at the Mayo Clinic in Rochester, Minnesota, USA (1 January 1998-1 October 2011). RESULTS: There were 29 cases of SS (24 women, mean age at presentation, 35 years; range, 19-65; full triad of brain, eye, and ear involvement, n = 16; mean follow-up time, 29 months). Thirty CSF analyses were performed in 27 cases (mean protein 130 mg/dl, range 35-268; mean cell count 14, range 1-86). MRI of the brain showed corpus callosal involvement (79%), T2-weighted hyperintensities (93%), and gadolinium enhancement (50%). Average lowest modified Rankin Scale score was 2.5 (median 2, range 0-5). Most patients (93%) received immunosuppressive treatment, with a mean time to treatment of 2 months following symptomatic onset. Treatments included intravenous methylprednisolone or dexamethasone (n = 23), oral corticosteroids (n = 24), plasma exchange (PLEX) (n = 9), intravenous immunoglobulin (IVIg) (n = 15), cyclophosphamide (n = 6), mycophenolate mofetil (n = 5), azathioprine (n = 2), and rituximab (n = 1). Most patients also received an antiplatelet agent (n = 21). Improvement or stabilization was noted in eight of 11 cases treated with IVIg in the acute period (three experienced at least partial deterioration) and eight of nine cases of PLEX treatment (one lost to follow up). CONCLUSIONS: Susac syndrome may be severe, disabling, and protracted in some patients. PLEX may be an adjunct or alternative therapy for patients who do not experience symptomatic improvement following steroid treatment. PMID- 22221558 TI - Performance characteristics of polymer photovoltaic solar cells with an additive incorporated active layer. AB - We have investigated the performance characteristics of bulk-heterojunction polymer solar cells based on poly(3-hexylthiophene-2,5-diyl) and [6,6]-phenyl C61 butyric acid methyl ester by adding 1,8-octanedithiol as a processing agent in an active layer. The effects of the additive, 1,8-octanedithiol, on the device performance parameter characteristics have been discussed. The current density voltage measurements, UV-Vis absorption spectra, X-ray diffraction spectra, and scanning probe microscope images have been used to discuss the performance characteristics of polymer solar cells. PMID- 22221559 TI - Bone remodelling analysis of the humerus after a shoulder arthroplasty. AB - The shoulder arthroplasty has become an efficient treatment for some pathologies. However there are complications that can compromise its success. Among them, the stress shielding effect on the humerus has been reported as a possible cause of failure. The objective of this work was to investigate the bone remodelling in the humerus after a shoulder arthroplasty. For this purpose, computational models were developed to analyse the stress shielding contribution to the humeral component failure of shoulder arthroplasties, with a cemented and an uncemented prosthesis. A computational remodelling model was used to characterize the bone apparent density at each site of the humerus. The density distribution was obtained by the solution of a problem that takes into account both structural stiffness and the metabolic cost of bone maintenance. Bone was subjected to 6 load cases that include the glenohumeral reaction force and the action of 10 muscles. In the implanted models, different interface conditions were tested for the bone-implant and the cement-implant interfaces. Moreover, a pathological case defined by a poorer quality of bone was considered. In the healthy situation, the models that better model in vivo conditions showed no significant changes in bone mass. However, the results for the pathological case showed some bone resorption which supports the importance given to the quality of bone in the success of the joint replacement. Bearing in mind the conditions addressed, the results lead to conclude that the stress shielding is not a key factor for the humeral component failure of shoulder arthroplasties in a healthy situation though several issues, including muscle function and bone quality, may heighten its effect. PMID- 22221560 TI - Asparagus officinalis extract controls blood glucose by improving insulin secretion and beta-cell function in streptozotocin-induced type 2 diabetic rats. AB - The aim of the present study was to evaluate the anti-diabetic mechanism of Asparagus officinalis, a dietary agent used for the management of diabetes. Streptozotocin (90 mg/kg) was injected in 2-d-old Wistar rat pups to induce non obese type 2 diabetes. After confirmation of diabetes on the 13th week, diabetic rats were treated with a methanolic extract of A. officinalis seeds (250 and 500 mg/kg per d) or glibenclamide for 28 d. After the treatment, fasting blood glucose, serum insulin and total antioxidant status were measured. The pancreas was examined by haematoxylin-eosin staining and immunostained beta- and alpha cells were observed using a fluorescence microscope. Treatment of the diabetic rats with the A. officinalis extract at doses of 250 and 500 mg/kg suppressed the elevated blood glucose in a dose- and time-dependent manner. The 500 mg/kg, but not 250 mg/kg, dose significantly improved serum insulin levels in the diabetic rats. The insulin:glucose ratio was significantly increased at both doses in the A. officinalis-treated rats. Both qualitative and quantitative improvements in beta-cell function were found in the islets of the A. officinalis-treated rats. The extract showed potent antioxidant activity in an in vitro assay and also improved the total antioxidant status in vivo. In most cases, the efficacy of A. officinalis (500 mg/kg) was very similar to a standard anti-diabetic drug, glibenclamide. Thus, the present study suggests that A. officinalis extract exerts anti-diabetic effects by improving insulin secretion and beta-cell function, as well as the antioxidant status. PMID- 22221561 TI - Decreased risk of graft failure with maternal liver transplantation in patients with biliary atresia. AB - The presence of maternal cells in offspring may promote tolerance to noninherited maternal antigens (NIMAs). Children with biliary atresia (BA) have increased maternal cells in their livers, which may impact tolerance. We hypothesized that patients with BA would have improved outcomes when receiving a maternal liver. We reviewed all pediatric liver transplants recorded in the SRTR database from 1996 to 2010 and compared BA and non-BA recipients of maternal livers with recipients of paternal livers for the incidences of graft failure and retransplantation. Rejection episodes after parental liver transplantation were examined for patients transplanted at our institution. BA patients receiving a maternal graft had lower rates of graft failure compared to those receiving a paternal graft (3.7% vs. 10.5%, p = 0.02) and, consequently, fewer episodes of retransplantation (2.7% vs. 7.5%, p = 0.04). These differences were not seen among non-BA patients or among BA patients who received female deceased donor grafts. In patients transplanted at our institution, paternal liver transplantation was associated with an increased incidence of refractory rejection compared to maternal liver transplantation only in BA. Our data support the concept that maternal cells in BA recipients promote tolerance to NIMAs and may be important in counseling BA patients who require liver transplantation. PMID- 22221562 TI - The Behavior Problems Inventory-Short Form for individuals with intellectual disabilities: part II: reliability and validity. AB - BACKGROUND: The Behavior Problems Inventory-01 (BPI-01) is an informant-based behaviour rating instrument for intellectual disabilities (ID) with 49 items and three sub-scales: Self-injurious Behavior, Stereotyped Behavior and Aggressive/Destructive Behavior. The Behavior Problems Inventory-Short Form (BPI S) is a BPI-01 spin-off with 30 items. METHODS: The psychometric properties of these two versions of the scale were computed using aggregated archival data from nine different sites in the USA, Wales, England, the Netherlands and Romania with a total of 1122 cases with a BPI-01 total score >0. RESULTS: The internal consistency of the BPI-01 and the BPI-S ranged from fair to excellent with the BPI-01 showing slightly stronger reliability. Construct validity (confirmatory and discriminant) was computed by comparing BPI sub-scale scores with the scores of four other behaviour rating scales (the Aberrant Behavior Checklist, the Diagnostic Assessment for the Severely Handicapped-II, the Nisonger Child Behavior Rating Form and the Inventory for Client and Agency Planning). Strong evidence for confirmatory and discriminant validity was found for both the BPI-01 and the BPI-S. Confirmatory fit indices for the BPI and the BPI-S were comparable and suggesting that the factor structures fit the data well. CONCLUSION: In summary, both BPI versions were found to be equally sound psychometrically and can be endorsed for future use. However, independent future studies are needed to replicate the psychometrics of the BPI-S with new data. PMID- 22221563 TI - Fabrication of core/shell ZnWO4/carbon nanorods and their Li electroactivity. AB - Carbon-coated ZnWO4 [C-ZW] nanorods with a one-dimensional core/shell structure were synthesised using hydrothermally prepared ZnWO4 and malic acid as precursors. The effects of the carbon coating on the ZnWO4 nanorods are investigated by thermogravimetry, high-resolution transmission electron microscopy, and Raman spectroscopy. The coating layer was found to be in uniform thickness of approximately 3 nm. Moreover, the D and G bands of carbon were clearly observed at around 1,350 and 1,600 cm-1, respectively, in the Raman spectra of the C-ZW nanorods. Furthermore, lithium electroactivities of the C-ZW nanorods were evaluated using cyclic voltammetry and galvanostatic cycling. In particular, the formed C-ZW nanorods exhibited excellent electrochemical performances, with rate capabilities better than those of bare ZnWO4 nanorods at different current rates, as well as a coulombic efficiency exceeding 98%. The specific capacity of the C-ZW nanorods maintained itself at approximately 170 mAh g-1, even at a high current rate of 3 C, which is much higher than pure ZnWO4 nanorods. PMID- 22221564 TI - The eyes have it! The significance of unilateral ptosis. PMID- 22221565 TI - Influence of race and socioeconomic status on the diagnosis of child abuse: a randomized study. AB - OBJECTIVES: To measure empirically the influence of race and socioeconomic status (SES) on the diagnosis of child abuse and willingness to report to child protection services. STUDY DESIGN: A total of 5000 pediatricians randomly selected from the American Medical Association's Masterfile received 1 of 4 randomly assigned versions of a fictional clinical presentation of a child (black/white + high SES/low SES) that described an unwitnessed event in a mobile 18-month-old child resulting in an oblique femur fracture. Outcome measures included ranking the degree to which the injury was accidental versus abuse and agreement with reporting the injury to child protection services. RESULTS: A total of 2109 of 4423 physicians responded (47.7%). Patient's race did not have an effect on a diagnosis of abuse (black, 45% versus white, 46%). Abuse was more likely to be diagnosed in patients with low SES (48% versus 43%, overall P = .02). CONCLUSION: This study supports earlier work demonstrating physicians' greater willingness to consider abuse as a potential cause of injury in low SES children. It failed to demonstrate the finding of retrospective, real world studies of an increased likelihood to consider abuse in black patients. Future work should try to understand why there remains a differential approach to evaluating minority children for abuse in real world settings. PMID- 22221566 TI - Prospective randomized trial of barbed polyglyconate suture to facilitate vesico urethral anastomosis during robot-assisted radical prostatectomy: time reduction and cost benefit. AB - Study Type - RCT (randomized trial) Level of Evidence 2b. What's known on the subject? and What does the study add? In a previous randomized controlled trial, barbed polyglyconate suture for vesico-urethral anastomosis was associated with more frequent cystogram leaks, longer mean catheterization times and greater suture costs per case. In the current randomized controlled trial, we show that barbed polyglyconate suture is associated with decreased anastomosis time, decreased need to readjust suture tension, cost reduction, and equal continence and early/late urinary complication rates. OBJECTIVE: To examine the effectiveness of barbed polyglyconate suture (V-Loc 180; Covidien, Mansfield, MA, USA) compared with standard monofilament for posterior reconstruction (PR) and vesico-urethral anastomosis (VUA) during robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: A prospective randomized controlled trial was conducted in 70 consecutive RARP cases by a single surgeon (K.C.Z.). Standard VUA was performed using three 4-0 poliglecaprone 25 (Monocryl; Ethicon Endosurgery, Cincinnati, OH, USA) sutures secured with absorbable suture clips (LapraTy, Ethicon; one single 6-inch [15.2 cm] for PR and two attached 6-inch [15.2 cm] for VUA). Barbed suture VUA was performed using two 3-0 6-inch (15.2 cm) barbed polyglyconate sutures. Time to complete the suture set-up by the nursing team, anastomosis time and need to adjust suture tension were recorded. Suture-related complications, validated-questionnaire continence and cost were also examined. RESULTS: Compared with a conventional reconstruction technique, there was a significant reduction in mean nurse set-up time (31 vs. 294 s; P < 0.01) and reconstruction time (13.1 vs. 20.8 min; P < 0.01) for the barbed suture technique. Need to readjust suture tension or to place additional suture clips for watertight closure was greater in the standard monofilament group than in the barbed suture group (6% vs. 24%; P= 0.03). * A cost reduction was recorded at our institution (48.05 vs. 70.25 $CAN) with the barbed suture technique. * With a mean follow-up of 6.2 months, no delayed anastomotic leak or bladder neck contracture was observed in either group. * Pad-free continence outcomes for the monofilament suture vs the barbed suture groups at 1 (64 vs. 69%, P= 0.6), 3 (76 vs. 81%, P= 0.5) and 6 months (88 vs. 92%, P= 0.7) were similar. CONCLUSIONS: * Compared with standard monofilament suture, the unidirectional barbed polyglyconate suture appears to provide safe, efficient and cost-effective PR and VUA during RARP. * Use of the interlocked barbed polyglyconate suture technique prevents slippage, precluding the need for assistance, knot-tying and constant reassessment of anastomosis integrity. PMID- 22221568 TI - Wirsungostomy as a salvage procedure after pancreaticoduodenectomy. AB - BACKGROUND: Mortality rates associated with postoperative peritonitis or haemorrhage secondary to pancreatic fistula (PF) after pancreaticoduodenectomy (PD) remain high. This study analysed the results of an alternative management strategy for these life-threatening complications. METHODS: All patients undergoing PD between January 2004 and April 2011 were identified. Patients who underwent further laparotomy for failure of the pancreatico-digestive anastomosis were identified. Since 2004, this problem has been managed by dismantling the pancreatico-digestive anastomosis and cannulating the pancreatic duct remnant with a thin polyethylene tube (Escat tube), which is then passed through the abdominal wall. Main outcome measures were mortality, morbidity and longterm outcome. RESULTS: From January 2004 to April 2011, 244 patients underwent a PD. Postoperatively, 21 (8.6%) patients required re-laparotomy to facilitate a wirsungostomy. Two patients were transferred from another hospital with life threatening PF after PD. Causes of re-laparotomy were haemorrhage (n= 12), peritonitis (n= 4), septic shock (n= 4) and mesenteric ischaemia (n= 1). Of the 21 patients who underwent wirsungostomy, six patients subsequently died of liver failure (n= 3), refractory septic shock (n= 2) or mesenteric ischaemia (n= 1) and nine patients suffered complications. The median length of hospital stay was 42 days (range: 34-60 days). The polyethylene tube at the pancreatic duct was removed at a median of 4 months (range: 2-11 months). Three patients developed diabetes mellitus during follow-up. CONCLUSIONS: These data suggest that preservation of the pancreatic remnant with wirsungostomy has a role in the management of patients with uncontrolled haemorrhage or peritonitis after PF. PMID- 22221569 TI - Modulation of microcirculatory changes in the late phase of hepatic ischaemia reperfusion injury by remote ischaemic preconditioning. AB - BACKGROUND: Remote ischaemic preconditioning (RIPC) is a novel method of protecting the liver from ischaemia-reperfusion (I-R) injury. Protective effects in the early phase (4-6 h) have been demonstrated, but no studies have focused on the late phase (24 h) of hepatic I-R. This study analysed events in the late phase of I-R following RIPC and focused on the microcirculation, inflammatory cascade and the role of cytokine-induced neutrophil chemoattractant-1 (CINC-1). METHODS: A standard animal model was used. Remote preconditioning prior to I-R was induced by intermittent limb ischaemia. Ischaemia was induced in the left and median lobes of the liver (70%). The animals were recovered after 45 min of liver ischaemia. At 24 h, the animals were re-evaluated under anaesthesia. Hepatic microcirculation, sinusoidal leukocyte adherence and hepatocellular death were assessed by intravital microscopy, hepatocellular injury by standard biochemistry and serum CINC-1 by enzyme-linked immunosorbent assay (ELISA). RESULTS: At 24 h post I-R, RIPC was found to have improved sinusoidal flow by increasing the sinusoidal diameter. There was no effect of preconditioning on the velocity of red blood cells, by contrast with the early phase of hepatic I-R. Remote ischaemic preconditioning significantly reduced hepatocellular injury, neutrophil induced endothelial injury and serum CINC-1 levels. CONCLUSIONS: Remote ischaemic preconditioning is amenable to translation into clinical practice and may improve outcomes in liver resection surgery and transplantation. PMID- 22221567 TI - Review of experimental animal models of biliary acute pancreatitis and recent advances in basic research. AB - Acute pancreatitis (AP) is a formidable disease, which, in severe forms, causes significant mortality. Biliary AP, or gallstone obstruction-associated AP, accounts for 30-50% of all clinical cases of AP. In biliary AP, pancreatic acinar cell (PAC) death (the initiating event in the disease) is believed to occur as acinar cells make contact with bile salts when bile refluxes into the pancreatic duct. Recent advances have unveiled an important receptor responsible for the major function of bile acids on acinar cells, namely, the cell surface G-protein coupled bile acid receptor-1 (Gpbar1), located in the apical pole of the PAC. High concentrations of bile acids induce cytosolic Ca(2+) overload and inhibit mitochondrial adenosine triphosphate (ATP) production, resulting in cell injury to both PACs and pancreatic ductal epithelial cells. Various bile salts are employed to induce experimental AP, most commonly sodium taurocholate. Recent characterization of taurolithocholic acid 3-sulphate on PACs has led researchers to focus on this bile salt because of its potency in causing acinar cell injury at relatively low, sub-detergent concentrations, which strongly implicates action via the receptor Gpbar1. Improved surgical techniques have enabled the infusion of bile salts into the pancreatic duct to induce experimental biliary AP in mice, which allows the use of these transgenic animals as powerful tools. This review summarizes recent findings using transgenic mice in experimental biliary AP. PMID- 22221570 TI - Real-time ultrasound imaging of irreversible electroporation in a porcine liver model adequately characterizes the zone of cellular necrosis. AB - BACKGROUND: Irreversible electroporation (IRE) is a largely non-thermal method for the ablation of solid tumours. The ability of ultrasound (US) to measure the size of the IRE ablation zone was studied in a porcine liver model. METHODS: Three normal pig livers were treated in vivo with a total of 22 ablations using IRE. Ultrasound was used within minutes after ablation and just prior to liver harvest at either 6 h or 24 h after the procedure. The area of cellular necrosis was measured after staining with nitroblue tetrazolium and the percentage of cell death determined by histomorphometry. RESULTS: Visible changes in the hepatic parenchyma were apparent by US after all 22 ablations using IRE. The mean maximum diameter of the ablation zone measured by US during the procedure was 20.1 +/- 2.7 mm. This compared with a mean cellular necrosis zone maximum diameter of 20.3 +/- 2.9 mm as measured histologically. The mean percentage of dead cells within the ablation zone was 77% at 6 h and 98% at 24 h after ablation. CONCLUSIONS: Ultrasound is a useful modality for measuring the ablation zone within minutes of applying IRE to normal liver tissue. The area of parenchymal change measured by US correlates with the area of cellular necrosis. PMID- 22221571 TI - Hyperbaric oxygen therapy reduces the severity of ischaemia, preservation and reperfusion injury in a rat model of liver transplantation. AB - BACKGROUND: Approaches to increase organ availability for orthotopic liver transplantation (OLT) often result in the procurement of marginal livers that are more susceptible to ischaemia, preservation and reperfusion injury (IPRI). METHODS: The effects of post-OLT hyperbaric oxygen (HBO) therapy on IPRI in a syngeneic rat OLT model were examined at various time-points. The effects of IPRI and HBO on hepatocyte necrosis, apoptosis, proliferation, and sinusoidal morphology and ultrastructure were assessed. RESULTS: Post-OLT HBO therapy significantly reduced the severity of IPRI; both apoptosis [at 12 h: 6.4 +/- 0.4% in controls vs. 1.6 +/- 0.7% in the HBO treatment group (p < 0.001); at 48 h: 2.4 +/- 0.2% in controls vs. 0.4 +/- 0.1% in the HBO treatment group (p < 0.001)] and necrosis [at 12 h: 18.7 +/- 1.8% in controls vs. 2.4 +/- 0.4% in the HBO treatment group (p < 0.001); at 48 h: 8.5 +/- 1.3% in controls vs. 3.4 +/- 0.9% in the HBO treatment group (P= 0.019)] were decreased. Serum alanine transaminase was reduced [at 12 h: 1068 +/- 920 IU/l in controls vs. 370 +/- 63 IU/l in the HBO treatment group (P= 0.030); at 48 h: 573 +/- 261 IU/l in controls vs. 160 +/- 10 IU/l in the HBO treatment group (P= 0.029)]. Treatment with HBO also promoted liver regeneration [proliferation at 12 h: 4.5 +/- 0.1% in controls vs. 1.0 +/- 0.3% in the HBO treatment group (p < 0.001); at 48 h: 8.6 +/- 0.7% in controls vs. 2.9 +/- 0.2% in the HBO treatment group (p < 0.01)] and improved sinusoidal diameter and microvascular density index. CONCLUSIONS: Hyperbaric oxygen therapy has persistent positive effects post-OLT that may potentially transfer into clinical practice. PMID- 22221572 TI - Feasibility of bloodless liver resection using Lumagel, a reverse thermoplastic polymer, to produce temporary, targeted hepatic blood flow interruption. AB - BACKGROUND: Lumagel, a reverse thermosensitive polymer (RTP), provides targeted flow interruption to the kidney by reversibly plugging segmental branches of the renal artery, allowing blood-free partial nephrectomy. Extending this technology to the liver requires the development of techniques for temporary occlusion of the hepatic artery and selected portal vein branches. METHODS: A three-phased, 15 swine study was performed to determine feasibility, techniques and survival implications of using Lumagel for occlusion of inflow vessels to targeted portions of the liver. Lumagel was delivered using angiographic techniques to sites determined by pre-operative 3-D vascular reconstructions of arterial and venous branches. During resection, the targeted liver mass was resected without vascular clamping. Three survival swine were sacrificed at 3 weeks; the remainder at 6 weeks for pathological studies. RESULTS: Six animals (100%) survived, with normal growth, blood tests and no adverse events. Three left lateral lobe resections encountered no bleeding during resection; one right median resection bled; two control animals bled significantly. Pre-terminal angiography and autopsy showed no local pathology and no remote organ damage. CONCLUSIONS: Targeted flow interruption to the left lateral lobe of the swine liver is feasible and allows resection without bleeding, toxicity or pathological sequelae. Targeting the remaining liver will require more elaborate plug deposition owing to the extensive collateral venous network. PMID- 22221573 TI - Immunoglobulin subclass 4 for the diagnosis of immunoglobulin subclass 4 associated diseases in an unselected liver and pancreas clinic population. AB - AIMS: The diagnosis of autoimmune pancreatitis (AIP) and immunoglobulin subclass 4 (IgG(4) )-associated cholangitis (IAC) is based on imaging studies, serology, histology and a response to steroid therapy. The major serological finding is an elevation of the serum IgG(4) concentration. Previous studies have shown that its sensitivity is about 70% and its specificity exceeds 90% at a cut off of 140 mg/dl in selected patient populations. The aim of the present study was to assess the performance of serum IgG(4) as a diagnostic parameter in an unselected liver and pancreas clinic population. METHODS AND RESULTS: IgG(4) was prospectively determined in 1412 patients and clinical diagnoses were recorded from a review of patient charts. The prevalence of AIP or IAC in the entire cohort was 1.1% (n= 15). The sensitivity of IgG(4) for the diagnosis of AIP and IAC was 80% and the specificity was 86% at a cut-off value of >=135 mg/dl. The positive predictive value and the negative predictive value were 6% and 99.7%, respectively. The most common differential diagnosis in patients with elevated IgG(4) was liver cirrhosis. CONCLUSION: IgG(4) has a reasonable sensitivity and specificity in a liver and pancreas clinic population, where liver cirrhosis appears to be the most frequent differential diagnosis for elevated IgG(4) concentrations. PMID- 22221574 TI - Differences between bipolar compression and ultrasonic devices for parenchymal transection during laparoscopic liver resection. AB - OBJECTIVES: In laparoscopic liver resection, multiple options for parenchymal transection techniques exist; however, none have emerged as superior. The aim of this study was to compare operative characteristics and outcomes between bipolar compression and ultrasonic devices used for parenchymal transection during laparoscopic liver resection. METHODS: A review of a prospective hepatopancreatobiliary database from December 2002 to August 2009 identified 54 patients who underwent laparoscopic liver resection with parenchymal division using either a bipolar compression (n= 35) or an ultrasonic (n= 19) device. Operative data, histology and 90-day complication rates were compared between the groups using analysis of variance (anova) and Pearson's chi-squared test. RESULTS: The two groups did not differ significantly in terms of age, body mass index, parenchymal steatosis/inflammation or number of segments resected. A shorter time of parenchymal transection was noted for the bipolar compression device (median: 35 min; range: 20-65 min) vs. the ultrasonic device (median: 55 min; range: 29-75 min) (P < 0.001). Median total operative time was also shorter using the bipolar compression device (130 min) than the ultrasonic device (180 min) (P= 0.050). No significant differences between device groups were noted for estimated blood loss, complications of any type or liver-specific complications. CONCLUSIONS: Bipolar compression devices may offer advantages over ultrasonic devices in terms of decreased transection time and total operative time. No differences in postoperative complications in laparoscopic liver resection emerged between patients operated using the devices. PMID- 22221575 TI - Repeated pancreatectomy after pancreato-duodenectomy for a intraductal papillary mucinous tumour: advantage of pancreatico-gastrostomy with a gastric partition. AB - BACKGROUND: Regular follow-up and monitoring of intraductal papillary mucinous neoplasms (IPMN) is important as there is a risk of recurrence in both the non invasive and invasive IPMN. METHODS: Three patients developed pancreatic remnant recurrence after a pancreatico-duodenectomy for IPMN. Pancreatico gastrostomy anastomosis was performed in all patients. Long-term follow-up was performed with radiographical surveillance and by endoscopic gastroscopy. RESULTS: Magnetic resonance imaging (MRI) and endoscopic ultrasonography (EUS) revealed in one patient, 2 years after surgery, a 3-cm mass at the site of the anastomosis and dilatation of the Wirsung duct >6 mm in two other patients (2 and 3 years after surgery, respectively). The diagnosis of recurrence was confirmed endoscopically by the presence of a large amount of mucin at the anastomotic site. Cytological examination revealed moderate dysplasia. Opacification of the Wirsung duct after endoscopic retrograde cholangiopancreatography (ERCP) was only possible in one patient in whom an irregular stenosis of the duct was observed. CONCLUSIONS: Long-term follow-up of the pancreatic remnant after pancreato duodenectomy for IPMN is better achieved with pancreatico-gastrostomy anastomosis. PMID- 22221576 TI - Predictors of surgical site infection after liver resection: a multicentre analysis using National Surgical Quality Improvement Program data. AB - BACKGROUND: Postoperative infections are frequent complications after liver resection and have significant impact on length of stay, morbidity and mortality. Surgical site infection (SSI) is the most common nosocomial infection in surgical patients, accounting for 38% of all such infections. OBJECTIVES: This study aimed to identify predictors of SSI and organ space SSI after liver resection. METHODS: Data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database for patients who underwent liver resection in 2005, 2006 or 2007 in any of 173 hospitals throughout the USA were analysed. All patients who underwent a segmental resection, left hepatectomy, right hepatectomy or trisectionectomy were included. RESULTS: The ACS-NSQIP database contained 2332 patients who underwent hepatectomy during 2005-2007. Rates of SSI varied significantly across primary procedures, ranging from 9.7% in segmental resection patients to 18.3% in trisectionectomy patients. A preoperative open wound, hypernatraemia, hypoalbuminaemia, elevated serum bilirubin, dialysis and longer operative time were independent predictors for SSI and for organ space SSI. CONCLUSIONS: These findings may contribute towards the identification of patients at risk for SSI and the development of strategies to reduce the incidence of SSI and subsequent costs after liver resection. PMID- 22221578 TI - Gastrointestinal stromal tumour of the gallbladder. PMID- 22221577 TI - Surgical resection for hilar cholangiocarcinoma: experience improves resectability. AB - OBJECTIVES: In hilar cholangiocarcinoma, resection provides the only opportunity for longterm survival. A US experience of hilar cholangiocarcinoma was examined to determine the effect of clinical experience on negative margin (R0) resection rates. METHODS: We conducted a retrospective analysis of 110 consecutive hilar cholangiocarcinoma patients presenting over an 18-year period. Analyses were performed using chi-squared, Wilcoxon rank sum and Kaplan-Meier methods, and multivariable Cox and logistic regression modelling. RESULTS: Of the 110 patients in the cohort, 59.1% were male and 90.9% were White. The median patient age was 64 years. A total of 59 (53.6%) patients underwent resection; 37 of these demonstrated R0. The 30-day mortality rate was 5.1%; the complication rate was 39.0%. The rate of resectability increased over time (36.4% vs. 70.9%; P= 0.001), as did the percentage of R0 resections (10.9% vs. 56.5%; P < 0.001). Of the 59 patients who underwent resection, 23 (39.0%) experienced recurrence. Multivariable Cox regression analysis identified resection margins [hazard ratio (HR) = 4.124 for positive vs. negative; P= 0.002] and type of operation (HR = 5.075 for exploration vs. resection; P= 0.001) as significant to survival. CONCLUSIONS: Although R0 resection can be achieved in only a minority of patients, these patients have a reasonable chance of longterm survival. The last decade has seen a significant rise in rates of resectability of Klatskin's tumour at specialty centres. PMID- 22221580 TI - Reconstruction of circumferential skin defect of the penile shaft using a bipedicle scrotal flap. PMID- 22221581 TI - Progress in stem cell therapy for the diabetic foot. AB - The diabetic foot is a common and severe complication of diabetes comprising a group of lesions including vasculopathy, neuropathy, tissue damage and infection. Vasculopathy due to ischemia is a major contributor to the pathogenesis, natural history and outcome of the diabetic foot. Despite conventional revascularization interventions including angioplasty, stenting, atherectomy and bypass grafts to vessels, a high incidence of amputation persists. The need to develop alternative therapeutic options is compelling; stem cell therapy aims to increase revascularization and alleviate limb ischemia or improve wound healing by stimulating new blood vessel formation, and brings new hope for the treatment of the diabetic foot. PMID- 22221583 TI - Definition and characterization of localised meningitis epidemics in Burkina Faso: a longitudinal retrospective study. AB - BACKGROUND: The epidemiology of meningococcal meningitis in the African meningitis belt is characterised by seasonality, localised epidemics and epidemic waves. To facilitate research and surveillance, we aimed to develop a definition for localised epidemics to be used in real-time surveillance based on weekly case reports at the health centre level. METHODS: We used national routine surveillance data on suspected meningitis from January 2004 to December 2008 in six health districts in western and central Burkina Faso. We evaluated eight thresholds composed of weekly incidence rates at health centre level for their performance in predicting annual incidences of 0.4%and 0.8% in health centre areas. The eventually chosen definition was used to describe the spatiotemporal epidemiology and size of localised meningitis epidemics during the included district years. RESULTS: Among eight weekly thresholds evaluated, a weekly incidence rate of 75 cases per 100,000 inhabitants during at least two consecutive weeks with at least 5 cases per week had 100% sensitivity and 98% specificity for predicting an annual incidence of at least 0.8% in health centres. Using this definition, localised epidemics were identified in all but one years during 2004-2008, concerned less than 10% of the districts' population and often were geographically dispersed. Where sufficient laboratory data were available, localised epidemics were exclusively due to meningococci. CONCLUSIONS: This definition of localised epidemics a the health centre level will be useful for risk factor and modelling studies to understand the meningitis belt phenomenon and help documenting vaccine impact against epidemic meningitis where no widespread laboratory surveillance exists for quantifying disease reduction after vaccination. PMID- 22221584 TI - Lung capillary blood volume and membrane diffusion in idiopathic interstitial pneumonia. AB - RATIONALE: Diffusing capacity of the lung for carbon monoxide (DLCO) is a good marker of disease severity in patients with idiopathic interstitial pneumonia (IIP). The combined diffusing capacity of nitric oxide (DLNO) and DLCO determines the two components of diffusion: membrane conductance (Dm, CO) and pulmonary capillary blood volume (Vc). OBJECTIVES: The aim of this study was to evaluate Vc and Dm, CO in patients with fibrosing IIP in order to determine the relative contribution of membrane resistance and vascular resistance to the loss of DLCO. METHODS: 32 patients with IIP (IPF: n = 22, NSIP: n = 10) were evaluated using MRC dyspnea scale, plethysmography, combined DLNO/DLCO, 6-min walk test (6 MWT), echocardiography and chest computed tomography (chest CT). RESULTS: DLCO (41.8 +/ 11.9%pred), Dm, CO (40.5 +/- 12.7%pred) and Vc (41.9 +/- 18%pred) were severely and equally reduced. Dm, CO and Vc were related to MRC scale, FVC, maximal desaturation during 6 MWT, and systolic pulmonary artery pressure (sPAP). There was no correlation with the extent of fibrotic changes on chest CT. CONCLUSIONS: Our main results indicate that Dm, CO and Vc contribute almost equally to DLCO reduction in IIP. Dm, CO and Vc are related to functional indicators of disease severity and to sPAP in agreement with the concept of vascular involvement in IIP. PMID- 22221582 TI - Cytosolic, but not mitochondrial, oxidative stress is a likely contributor to cardiac hypertrophy resulting from cardiac specific GLUT4 deletion in mice. AB - We hypothesized that oxidative stress may contribute to the development of hypertrophy observed in mice with cardiac specific ablation of the insulin sensitive glucose transporter 4 gene (GLUT4, G4H(-/-) ). Measurements of oxidized glutathione (GSSG) in isolated mitochondria and whole heart homogenates were increased resulting in a lower ratio of reduced glutathione (GSH) to GSSG. Membrane translocation of the p67(phox) subunit of cardiac NADPH oxidase 2 (NOX2) was markedly increased in G4H(-/-) mice, suggesting elevated activity. To determine if oxidative stress was contributing to cardiac hypertrophy, 4-week-old control (Con) and G4H(-/-) mice were treated with either tempol (T, 1 mm, drinking water), a whole cell antioxidant, or Mn(III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP, 10 mg.kg(-1) , intraperitoneally), a mitochondrial targeted antioxidant, for 28 days. Tempol attenuated cardiac hypertrophy in G4H( /-) mice (heart : tibia, Con 6.82 +/- 0.35, G4H(-/-) 8.83 +/- 0.34, Con + T 6.82 +/- 0.46, G4H(-/-) + T 7.57 +/- 0.3), without changing GSH : GSSG, glutathione peroxidase 4 or membrane translocation of the p67(phox) . Tempol did not modify phosphorylation of glycogen synthase kinase 3beta or thioredoxin-2. In contrast, MnTBAP lowered mitochondrial GSSG and improved GSH : GSSG, but did not prevent hypertrophy, indicating that mitochondrial oxidative stress may not be critical for hypertrophy in this model. The ability of tempol to attenuate cardiac hypertrophy suggests that a cytosolic source of reactive oxygen species, probably NOX2, may contribute to the hypertrophic phenotype in G4H(-/-) mice. PMID- 22221585 TI - Effect of correcting for long-term variation in major coronary heart disease risk factors: relative hazard estimation and risk prediction in the Atherosclerosis Risk in Communities Study. AB - PURPOSE: To examine the effect of correcting coronary heart disease (CHD) risk factors for long-term within-person variation on CHD risk. METHODS: By using 5533 men and 7301 women from the Atherosclerosis Risk in Communities (ARIC) study, we compared models incorporating risk factors measured at a single visit and models incorporating additional measurements for systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol taken 3 years before baseline. RESULTS: The largest change away from null was observed for systolic blood pressure, ie, hazard ratio (HR) 1.38 to 1.69 (+81%) in women and HR 1.26 to 1.41 (+56%) in men. HRs also decreased for age (-32% in women, -9% in men), race (-67% in women), the presence of diabetes (-13% in men and women), and medication use for hypertension (-27% in women, -26% in men) and cholesterol (-97% in women, HR 1.06-0.93 in men). The area under the ROC curve did not improve significantly in men or women, whereas reclassification was only significant in women (net reclassification improvement 5.4%, p = 0.016). CONCLUSIONS: Modeling long-term variation in CHD risk factors had a substantial impact on HR estimates, with new effect estimates further from the null for some risk factors and closer for others including age and medication use, but only improved risk classification in women. PMID- 22221587 TI - Effective surface oxidation of polymer replica molds for nanoimprint lithography. AB - In nanoimprint lithography, a surface oxidation process is needed to produce an effective poly(dimethylsiloxane) coating that can be used as an anti-adhesive surface of template molds. However, the conventional photooxidation technique or acidic oxidative treatment cannot be easily applied to polymer molds with nanostructures since surface etching by UV radiation or strong acids significantly damages the surface nanostructures in a short space of time. In this study, we developed a basic oxidative treatment method and consequently, an effective generation of hydroxyl groups on a nanostructured surface of polymer replica molds. The surface morphologies and water contact angles of the polymer molds indicate that this new method is relatively nondestructive and more efficient than conventional oxidation treatments. PMID- 22221586 TI - Lack of prognostic significance of p16 and p27 after radical prostatectomy in hormone-naive prostate cancer. AB - BACKGROUND: Loss of normal cell cycle control is an early event in the evolution of cancer. The expression of cyclin-dependent kinase (CDK) inhibitors p16 and p27 has been previously associated with progression of prostate cancer (PC). 70 patients diagnosed with early stage PCwere treated with radical prostatectomy (RP) at our institution and their tumor specimens were immunohistochemically evaluated for expression of p16 and p27. Available clinical data of time to PSA recurrence were correlated with the examined parameters and combined with pre operative PSA level, Gleason score and pathological TNM (pT) stage assessment. RESULTS: Nuclear overexpression of p16 was not associated with time to biochemical failure (BF) (p = 0.572). Same was the case for nuclear p27 overexpression (p = 1.000). Also, no significant correlations were found between either p16 or p27, and pre-operative PSA level, pT stage and Gleason grade. pT stage emerged as the only independent prognostic factor for biochemical recurrence (p = 0.01). CONCLUSIONS: These data question previously reported data supporting the prognostic relevance of both p16 and p27 proteins in early PC. PMID- 22221588 TI - Thermoelectric properties of Cu-dispersed bi0.5sb1.5te3. AB - A novel and simple approach was used to disperse Cu nanoparticles uniformly in the Bi0.5Sb1.5Te3 matrix, and the thermoelectric properties were evaluated for the Cu-dispersed Bi0.5Sb1.5Te3. Polycrystalline Bi0.5Sb1.5Te3 powder prepared by encapsulated melting and grinding was dry-mixed with Cu(OAc)2 powder. After Cu(OAc)2 decomposition, the Cu-dispersed Bi0.5Sb1.5Te3 was hot-pressed. Cu nanoparticles were well-dispersed in the Bi0.5Sb1.5Te3 matrix and acted as effective phonon scattering centers. The electrical conductivity increased systematically with increasing level of Cu nanoparticle dispersion. All specimens had a positive Seebeck coefficient, which confirmed that the electrical charge was transported mainly by holes. The thermoelectric figure of merit was enhanced remarkably over a wide temperature range of 323-523 K.PACS: 72.15.Jf: 72.20.Pa. PMID- 22221590 TI - The role of polysomnography in diagnosing and treating obstructive sleep apnea in pediatric patients. AB - Obstructive sleep apnea in children is associated with serious neurocognitive and cardiovascular morbidity, systemic inflammation, and increased health care use, yet remains underdiagnosed. Although the prevalence of obstructive sleep apnea is 1-3% in the pediatric population, the prevalence of primary snoring (PS) is estimated to be 3-12%. The challenge for pediatricians is to differentiate PS from obstructive sleep apnea in a cost-effective, reliable, and accurate manner before recommending invasive or intrusive therapies, such as surgery or continuous positive airway pressure. The validity of polysomnography as the gold standard for diagnosing obstructive sleep apnea has been challenged, primarily related to concerns that abnormalities on polysomnography do not correlate well with adverse outcomes, that those abnormalities have statistical more than clinical significance, and that performing polysomnograms on all children who snore is a practical impossibility. The aim of this article is to review the clinical utility of diagnostic tests other than polysomnography to diagnose obstructive sleep apnea, to highlight the limitations and strengths of polysomnography, to underscore the threshold levels of abnormalities detected on polysomnography that correlate with morbidity, and to discuss what the practical implications are for treatment. PMID- 22221591 TI - Sex differences in perihemorrhagic edema evolution after spontaneous intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Clinical data on sex differences in perihemorrhagic edema (PHE) after intracerebral hemorrhage (ICH) are lacking. METHODS: Patients with spontaneous supratentorial ICH who had received standard conservative treatment were identified retrospectively. PHE development was assessed over a 14-day period on follow-up CT scans (days 1, 2-4, 5-7, 8-11, and 12-14). ICH and PHE volumes were assessed semiautomatically and compared between men and women. RESULTS: A total of 387 patients (233 men) were included. Starting at days 2-4, women showed lower PHE values (P < 0.05; days 2-4, 8-11) or a trend toward significance (P <= 0.1; days 5-7, 12-14). CONCLUSIONS: Female sex may predict lower PHE volumes. PMID- 22221592 TI - Apolipoprotein E gene (APOE) genotype in Wilson's disease: impact on clinical presentation. AB - BACKGROUND: Wilson's disease (WD), an inherited copper metabolism disorder that leads to pathological tissue copper accumulation and secondary organ damage, is caused by mutations in the ATP-ase 7B gene (ATP7B). The apolipoprotein E gene (APOE) alleles epsilon2, epsilon3, and epsilon4 produce three different apoE isoforms with different biological effects, which can determine risks of many human diseases, including neurodegenerative and liver disease. This study aimed to evaluate the impact of APOE genotype on the variability of WD phenotypic expression. METHODS: We analyzed data on 383 WD consecutive patients in the WD registry. The APOE genotypes (APOE epsilon3/epsilon3 (wild-type), APOE epsilon2 positive, and APOE epsilon4-positive) were determined and the APOE genotype effect on the phenotypic WD presentation was assessed in all symptomatic WD patients, as well as in patient subgroups divided according to sex and ATP7B genotype. RESULTS: APOE genotype had no impact on WD presentation in the general population of symptomatic patients. However, APOE epsilon4-positive women tended to present WD symptoms earlier than women possessing the wild-type APOE epsilon3/epsilon3 genotype (24.2 vs. 27.9 years; p = 0.08). The effect of the APOE epsilon4-positive genotype was more pronounced in ATP7B p.H1069Q homozygous women, in whom disease symptoms started almost 6 years earlier (23.6 vs. 29.9 years; p < 0.05) than in APOE epsilon3/epsilon3 women. CONCLUSIONS: In women, APOE epsilon4-positive genotype is associated with earlier onset of WD symptoms, particularly among ATP7B p.H1069Q homozygous patients. Further studies are needed to understand the mechanisms of these gender-dependent phenotypic effects. PMID- 22221593 TI - A DNA vaccine co-expressing Trichinella spiralis MIF and MCD-1 with murine ubiquitin induces partial protective immunity in mice. AB - Co-expression of Trichinella spiralis macrophage migration inhibitory factor (TsMIF) with T. spiralis cystatin-like domain protein (TsMCD-1) in a DNA vaccine induces a Th1 immune response and partial protection against T. spiralis infection. The present study evaluated whether co-expression of mouse ubiquitin (Ub) with TsMIF and TsMCD-1 might improve the immune response against T. spiralis infection. Groups of BALB/c mice were immunized twice at 2-week intervals with 100 MUg of plasmid DNA encoding either a TsMIF-TsMCD-1 fusion protein (pVAX1 Tsmif-Tsmcd-1) or an Ub-co-expressing triple fusion protein Ub-TsMIF-TsMCD-1 (pVAX1-Ub-Tsmif-Tsmcd-1). Control animals were immunized with pVAX1-Ub or blank vector plasmid. Specific antibody levels (IgG, IgG1, IgG2a, IgG2b, IgM, IgA, IgE) against the recombinant protein TsMIF-TsMCD-1, serum cytokines (interferon (IFN) gamma, interleukin (IL)-4, IL-5, transforming growth factor (TGF)-beta1 and IL 17), CD4+/CD8+ T cells and cytotoxic T lymphocyte (CTL) responses were monitored. Challenge infection was performed 2 weeks after the second immunization and worm burden was assayed at 35 days post-challenge. Antibody responses induced by pVAX1 Ub-Tsmif-Tsmcd-1 were significantly lower than for TsMIF-TsMCD-1, but the vaccine induced increased levels of Th1 cytokine (IFN-gamma) and increased T-cell cytotoxicity. The reduction of worm burden (37.95%) following immunization with pVAX1-Ub-Tsmif-Tsmcd-1 was significantly greater than that induced by the pVAX1 Tsmif-Tsmcd-1 vaccine (23.17%; P< 0.05). PMID- 22221595 TI - Crystal structure and electrical properties of bismuth sodium titanate zirconate ceramics. AB - Lead-free bismuth sodium titanate zirconate (Bi0.5Na0.5Ti1-xZrxO3 where x = 0.20, 0.35, 0.40, 0.45, 0.60, and 0.80 mole fraction) [BNTZ] ceramics were successfully prepared using the conventional mixed-oxide method. The samples were sintered for 2 h at temperatures lower than 1,000 degrees C. The density of the BNTZ samples was at least 95% of the theoretical values. The scanning electron microscopy micrographs showed that small grains were embedded between large grains, causing a relatively wide grain size distribution. The density and grain size increased with increasing Zr concentration. A peak shift in X-ray diffraction patterns as well as the disappearance of several hkl reflections indicated some significant crystal-structure changes in these materials. Preliminary crystal-structure analysis indicated the existence of phase transition from a rhombohedral to an orthorhombic structure. The dielectric and ferroelectric properties were also found to correlate well with the observed phase transition. PMID- 22221594 TI - Topiramate for the treatment of methamphetamine addiction: a multi-center placebo controlled trial. AB - AIMS: Topiramate has shown efficacy at facilitating abstinence from alcohol and cocaine abuse. This double-blind, placebo-controlled out-patient trial tested topiramate for treating methamphetamine addiction. DESIGN: Participants (n = 140) were randomized to receive topiramate or placebo (13 weeks) in escalating doses from 25 mg/day [DOSAGE ERROR CORRECTED] to the target maintenance of 200 mg/day in weeks 6-12 (tapered in week 13). Medication was combined with weekly brief behavioral compliance enhancement treatment. SETTING: The trial was conducted at eight medical centers in the United States. PARTICIPANTS: One hundred and forty methamphetamine-dependent adults took part in the trial. MEASUREMENTS: The primary outcome was abstinence from methamphetamine during weeks 6-12. Secondary outcomes included use reduction versus baseline, as well as psychosocial variables. FINDINGS: In the intent-to-treat analysis, topiramate did not increase abstinence from methamphetamine during weeks 6-12. For secondary outcomes, topiramate reduced weekly median urine methamphetamine levels and observer-rated severity of dependence scores significantly. Subjects with negative urine before randomization (n = 26) had significantly greater abstinence on topiramate versus placebo during study weeks 6-12. Topiramate was safe and well tolerated. CONCLUSIONS: Topiramate does not appear to promote abstinence in methamphetamine users but can reduce the amount taken and reduce relapse rates in those who are already abstinent. PMID- 22221596 TI - A dynamic model of circadian rhythms in rodent tail skin temperature for comparison of drug effects. AB - Menopause-associated thermoregulatory dysfunction can lead to symptoms such as hot flushes severely impairing quality of life of affected women. Treatment effects are often assessed by the ovariectomized rat model providing time series of tail skin temperature measurements in which circadian rhythms are a fundamental ingredient. In this work, a new statistical strategy is presented for analyzing such stochastic-dynamic data with the aim of detecting successful drugs in hot flush treatment. The circadian component is represented by a nonlinear dynamical system which is defined by the van der Pol equation and provides well interpretable model parameters. Results regarding the statistical evaluation of these parameters are presented. PMID- 22221597 TI - Cold storage of deceased donor kidneys: does the solution matter or is the solution elsewhere? PMID- 22221598 TI - Understanding the brain-heart axis in neurological trauma. PMID- 22221599 TI - The impact of trauma admissions in the elderly. PMID- 22221601 TI - Possible pitfalls when measuring the optic nerve sheath with sonography. PMID- 22221600 TI - Human isolates of Cronobacter sakazakii bind efficiently to intestinal epithelial cells in vitro to induce monolayer permeability and apoptosis. AB - BACKGROUND: Cronobacter sakazakii (CS) is an emerging opportunistic pathogen that causes life-threatening infections in infants. This pathogen has been implicated in the outbreaks of necrotizing enterocolitis (NEC) with associated rates of high mortality and morbidity. In this study, we compared the abilities of CS strains isolated from human and environmental sources to bind to intestinal epithelial cells and trigger apoptosis. MATERIALS AND METHODS: CS strains were isolated from human and environmental sources and their abilities to bind to intestinal epithelial cells were determined. Monolayer permeability was determined by transepithelial electrical resistance (TEER) and horseradish peroxidase (HRP) leakage. Apoptosis was examined by ApoTag and AnnexinV-7AAD staining. PKC activation was evaluated by non-radioactive PepTag assay. RESULTS: Human isolates of CS bind to rat and human enterocytes more efficiently than environmental strains. Additionally, these strains induced increased enterocyte monolayer permeability as indicated by a decrease in TEER and an increase in transcellular leakage of exogenously added HRP. Human isolates also caused tight junction disruption and significant apoptosis of enterocytes compared with environmental strains due to increased production of inducible nitric oxide. We also observed that human CS isolates caused 2-fold increase in the activation of phosphokinase C (PKC) than environmental strains. Blocking the PKC activity in enterocytes by an inhibitor, Go 6983, suppressed CS-mediated tight junction disruption, monolayer permeability, and apoptosis of the cells. CONCLUSION: These results suggest that human isolates of CS more efficiently bind to and cause damage to intestinal epithelial cells compared with environmental strains. PMID- 22221602 TI - Fluorescence diagnosis of metastatic lymph nodes using 5-aminolevulinic acid (5 ALA) in a mouse model of colon cancer. AB - BACKGROUND: Lymph node metastasis is one of the most critical prognostic factors in patients with colorectal cancer. Although regional lymph nodes should be surgically resected and pathologically examined, techniques for the intraoperative diagnosis of lymph node metastasis remain to be well established. Fluorescence diagnosis using 5-aminolevulinic acid (5-ALA) is a promising technique for evaluating various malignancies. After exogenous administration of 5-ALA, protoporphyrin IX (PPIX) accumulates in malignant cells and can be detected as red fluorescence. In this study, we investigated the usefulness of fluorescence diagnosis using 5-ALA for the detection of lymph node metastasis in a mouse model of colon cancer. MATERIALS AND METHODS: An orthotopic colon cancer model was prepared by inoculating the cecal wall of nude mice with HCA7, a human colon adenocarcinoma cell line. After 3 wk, 40 mg/kg of 5-ALA was administered intraperitoneally (IP) or orally (PO). Fluorescence diagnosis with a D-Light System (Karl Storz) was then performed after 3 or 6 h. RESULTS: In the IP group, PPIX fluorescence was detected in metastatic lymph nodes as well as in other malignant lesions, including primary tumors and abdominal implantations, while non-metastatic nodes were fluorescence-negative. In contrast, no obvious fluorescence was detected in cancerous tissues in the PO group. CONCLUSIONS: PPIX fluorescence induced by intraperitoneal injection of 5-ALA allows metastatic lymph nodes to be accurately diagnosed in this mouse model. This technique may facilitate the intraoperative diagnosis of lymph node metastases from colon cancer in a clinical setting. PMID- 22221603 TI - Reduction of liver ischemia reperfusion injury by silencing of TNF-alpha gene with shRNA. AB - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a central mediator in the hepatic response to ischemia/reperfusion. Short hairpin RNA (shRNA) has been proven to be an effective means of harnessing the RNA interference pathway in mammalian cells. In the current study, we investigated whether silencing TNF alpha gene with shRNA can prevent liver ischemic reperfusion injury (IRI). METHODS: Male BalB/c mice were randomized to TNF-alpha shRNA, scramble shRNA, or sham operation groups. TNF-alpha shRNA and scramble shRNA groups were injected 48 h before inducing IRI. IRI was induced via microaneurysm clamps applied to the left hepatic artery and portal vein. Six hours after reperfusion, IRI injury was examined by serum level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), liver histopathology, MPO, and MDA level, as well as by relative quantities of TNF-alpha mRNA. RESULTS: TNF-alpha expression induced by ischemia reperfusion in the liver was significantly suppressed after treatment with TNF-alpha shRNA compared with the group treated with scramble shRNA (P < 0.001). Mice treated with TNF-alpha shRNA showed lower peak values of AST and ALT than scramble shRNA treated mice (P < 0.001). On histopathologic slides, mice treated with TNF-alpha shRNA had significantly less ischemia/reperfusion injury based on Suzuki score than the scramble shRNA group, 3.57 +/- 2.30 and 8.83 +/- 0.98 respectively (P < 0.001), while the sham group was not significantly different from the TNF-alpha shRNA group, 0 +/- 0 and 3.57 +/- 2.30, respectively (P = 0.075). Liver tissue MDA levels were significantly lower in mice treated with TNF-alpha shRNA as compared with the group treated with scramble shRNA (P < 0.01). Immunohistochemical staining for MPO was significantly lower in mice treated with TNF-alpha shRNA compared with the group treated with shRNA (compared with treated with scramble shRNA group.) CONCLUSIONS: Liver IRI can be minimized through gene silencing of TNF-alpha. This may represent a novel therapy in the setting of transplantation and in other conditions associated with IRI of the liver. PMID- 22221604 TI - Early urinary biomarkers of warm and cold ischemic injury in an experimental kidney model. AB - BACKGROUND: Early urinary biomarkers may be useful in determining the severity of ischemic injury in donation after circulatory death (DCD) kidneys. The aim of this study was to evaluate the efficacy of a collective series of urinary biomarkers in relation to the warm and cold ischemic intervals. METHODS: Porcine kidneys were retrieved after 0, 10, and 25 min of warm ischemia (WI), then preserved by static cold storage (CS) for period of 2 and 18 h. After preservation, kidneys were reperfused on an isolated organ perfusion system to assess renal function and injury. Levels of IL-6, TNFalpha, endothelin-1 (ET-1), and neutrophil gelatinase-associated lipocalin (NGAL) were measured in urine samples after 3 h of reperfusion. RESULTS: There was no significant difference in renal functional parameters or urinary biomarkers between the WI times when kidneys were stored for 2 h (P > 0.05). After 18 h CS, kidneys with 10 and 25 min of WI demonstrated a significant decline in renal function compared with kidneys without WI (P < 0.05). Levels of ET-1 and NGAL were significantly higher in kidneys with 25 min WI (25 m ET-1, 30.1 +/- 21.2, versus 0 m 2.25 +/- 1.5 pg/mL; P = 0.002: NGAL, 25 m 77 +/- 51 versus 0 m 10 +/- 0.1 pg/mL; P = 0.005). Levels of IL-6 and TNFalpha were significantly higher in kidneys with 10 and 25 min of WI (P = 0.001, 0.001). CONCLUSION: Early urinary biomarkers are a useful means to determine graft injury. ET-1 and NGAL are more accurate in predicting the severity of ischemic injury compared with inflammatory markers. PMID- 22221605 TI - Novel immunocompetent murine models representing advanced local and metastatic pancreatic cancer. AB - BACKGROUND: The development of novel therapeutics for pancreatic cancer has been hindered by a lack of relevant preclinical models. The purpose of this study was to evaluate the clinical relevancy of two pancreatic cancer models using standard of-care therapeutic agent gemcitabine. MATERIALS AND METHODS: Murine Panc02 cells were injected directly into the spleen or pancreas of C57BL/6 mice to respectively create models of metastatic and locally advanced pancreatic cancer. Beginning 7 d post-Panc02 injection, treated mice received 20 mg/kg gemcitabine i.p. every 3 d. Animals were sacrificed when the untreated mice became moribund and tumor/liver weight used to assess tumor burden. RESULTS: Untreated mice became moribund 22 d after pancreatic Panc02 injection. Gross analysis revealed localized pancreatic tumors weighing 1.063 g. Intrasplenic Panc02 injection produced extensive liver metastasis by d 15 when the untreated mice first became moribund. Liver weights at this time averaged 3.6 g compared with the average non tumor-bearing weight of 1.23 g. Gemcitabine therapy resulted in a 54% decrease in localized pancreatic tumor weight and 62.5% decrease in metastatic liver weight. Additionally, gemcitabine therapy extended animal survival to 20.5 d compared with 18.0 d average for the untreated mice. CONCLUSIONS: We describe two models depicting both locally advanced and metastatic pancreatic cancer in immunocompetent mice. In efforts to establish baseline therapeutic efficacy, we determined that gemcitabine reduces tumor burden in both models and enhances survival in the metastatic model. These clinically relevant models provide valuable tools to evaluate novel therapeutics in pancreatic cancer. PMID- 22221606 TI - Individualizing care for locoregional pancreatic cancer? PMID- 22221607 TI - The effect of remnant preservation on patterns of gene expression in a rabbit model of anterior cruciate ligament reconstruction. AB - BACKGROUND: Anterior cruciate ligament (ACL) reconstruction with remnant preservation technique had been thought to be a more favorable milieu for graft reinnervation, revascularization, and ligamentization. However, the influence of preserving tibial residual fibers on mRNA expression during the graft remodeling process has never been investigated. MATERIALS AND METHODS: Healthy mature New Zealand white rabbits were randomly assigned to one of four groups: remnant dissected, remnant preserved, sham operated, and normal control. Ligament tissue was dissected at 2, 6, and 12 wk after surgery, and real-time PCR was performed using primers for VEGF, TGF-beta1, COLlAl, COL3A1, GAP-43, and NT-3. RESULTS: In the remnant preservation group, mRNA levels for matrix components COL l Al, COL3A1, growth factor TGF-beta1, and nerve-related genesGAP-43 all increased 6 wk after surgery, compared with the remnant dissection group (P < 0.05). An increased level of VEGF mRNA was also detected in the remnant preservation group 12 wk after operation (P < 0.05). An increased level of NT-3 mRNA was also observed in the remnant preservation group 2 and 12 wk after operation (P < 0.05). CONCLUSIONS: Our results suggest that there is a time dependent alteration of angiogenesis-promoting, repair-related, and nerve-related gene expression after ACL reconstruction during the process of graft remodeling. Furthermore, they demonstrate that remnant preservation in ACL reconstruction determines the different molecular profiles of these target genes, especially during the early stages of graft remodeling, which perhaps explains the potential role in promoting revascularization, reinnervation, and ligamentization. PMID- 22221608 TI - Pregnancy rate after vasectomy reversal in a contemporary series: influence of smoking, semen quality and post-surgical use of assisted reproductive techniques. AB - Study Type - Outcomes (cohort series). Level of Evidence 2b What's known on the subject? and What does the study add? Microsurgical vasectomy reversal is an effective and cost-effective method of reinstating fertility in a man who has previously had a vasectomy. The current literature indicates that the success rate (i.e. potency and pregnancy rates) are dependent primarily on the time elapsed since vasectomy and the age of the female partner. Using a multivariate Cox regression model, evaluation of the influence of preoperative data (including smoking) and semen parameters indicates a significant influence of post-surgical sperm motility only, on time to first pregnancy. The use of assisted reproductive techniques, when natural pregnancy failed, was successful in ~50% of couples who attempted this procedure and accounted for an absolute increase in pregnancy rate of 14%. OBJECTIVE: * To determine the influence of smoking, postoperative semen characteristics and the use of an assisted reproductive technique (ART) on pregnancy rate in a contemporary series of men undergoing vasectomy reversal. PATIENTS AND METHODS: * Between January 2002 and January 2009, 186 vasectomy reversals were performed. Of the 171 patients who could be contacted for follow up, 162 attempted pregnancy and constitute the study group. * Semen analysis was performed 3 months after the procedure and at subsequent 3-monthly intervals. * Patient characteristics and surgical information were obtained from a computerized database, and follow-up data were collected by telephone interview. * A multivariate Cox regression model was used to discern possible prognosticators with respect to pregnancy outcome. RESULTS: * The overall patency rate was 91.4%, with a natural pregnancy rate of 44.4% and a subsequent 14.2% of patients conceiving using a ARTs resulting in a total pregnancy rate of 58.6%. Multiple pregnancies were obtained by 20.4% of couples. * Smoking of the male or female partner did not influence the probability of conception. * In a multivariate model that included, among other factors, time since vasectomy, female age and semen characteristics, only sperm motility was significantly related to natural pregnancy outcome. * The probability of obtaining a natural pregnancy within 2 years after surgery is 53% for men with sperm motility >20% (WHO a+b) compared to 19% for men with sperm motility <5% (P= 0.003). CONCLUSIONS: * A clear and significant association between sperm motility and the probability of conception was found, whereas smoking, female age and time since vasectomy appeared to have no influence on pregnancy outcome in this patient cohort. * The use of ARTs accounted for an absolute increase in pregnancy rate of 14.2%. PMID- 22221610 TI - Micronutrients (Other than iron) and Helicobacter pylori infection: a systematic review. AB - BACKGROUND: Many micronutrients depend on a healthy stomach for absorption. Helicobacter pylori chronic gastritis may alter gastric physiology affecting homeostasis of vitamins and minerals. OBJECTIVES: Systematic review to assess whether H. pylori infection is associated with reduced micronutrient levels (other than iron) in the plasma or gastric juice and whether low micronutrient levels are modified by eradication treatment. METHOD: Medline was searched for relevant publications from inception to June 2010. Studies describing micronutrient levels in H. pylori-infected and not-infected adults and/or the effect of eradication treatment on micronutrient levels were included. FINDINGS: Fifty-two publications were selected: 46 investigated the association between H. pylori infection and reduced micronutrient levels and 14 the effect of eradication treatment on micronutrient levels. Sixty-four studies investigated vitamins (23 ascorbic acid, four beta-carotene, 21 cobalamin, 11 folate, and five alpha-tocopherol) and 10 addressed minerals (one calcium, one copper, one magnesium, one phosphorus, three selenium, and three zinc). Pooled standardized mean differences in micronutrient levels showed positive associations with H. pylori infection for ascorbic acid (gastric juice, -1.087) and cobalamin ( 0.744), and a positive effect of eradication treatment, which increased ascorbic acid in the gastric juice (-1.408) and serum cobalamin (-1.910). No significant association between infection and low folate levels was observed. Meta-analyses for other micronutrients were not performed owing to insufficient data. CONCLUSIONS: Meta-analyses indicate that H. pylori infection is associated with reduced levels of ascorbic acid and cobalamin, supported by the positive effect of eradication treatment. For other micronutrients, further studies are needed. PMID- 22221609 TI - Kinetochore flexibility: creating a dynamic chromosome-spindle interface. AB - Kinetochores are complex macromolecular assemblies that link chromosomes to the mitotic spindle, mediate forces for chromosome motion, and generate the checkpoint signal delaying anaphase onset until all chromosomes are incorporated into the spindle. Proper execution of these functions depends on precise interactions between kinetochores and microtubules. While the molecular composition of the kinetochore is well described, structural organization of this organelle at the molecular and atomic levels is just beginning to emerge. Recent structural studies across scales suggest that kinetochores should not be viewed as rigid static scaffolds. Instead, these organelles exhibit a surprising degree of flexibility that enables rapid adaptations to various types of interactions with the mitotic spindle. PMID- 22221611 TI - Arginine 66 residue of Fur is required for the regulatory function of this protein in the acid adaptation mechanism of Helicobacter pylori. AB - BACKGROUND: Helicobacter pylori colonizes the gastric mucosa and must survive the acid pH of that environment. Like other enteric bacterial pathogens, including Salmonella enterica, H. pylori develops an acid tolerance response that is dependent on the function of the transcriptional regulator protein Fur. OBJECTIVE: To explore by site-directed mutagenesis whether two particular amino acid residues in the amino acid sequence of the H. pylori Fur protein, arginine 66 and histidine 99, are involved in the acid response mechanism in this bacterium. MATERIALS AND METHODS: Complementation assays in Escherichia coli H1780 (fur null mutant) both with plasmids carrying the H. pylori fur gene bearing substitution mutations R66A or H99A or R66A/H99A and with the H. pylori Fur-R66A mutant were conducted. Wild-type and mutated Fur proteins from H. pylori were assayed by using the fiu::lacZ reporter gene in the E. coli H1780 heterologous system at various pH and iron concentrations. RESULTS: Both bacterial growth and repression of the reporter gene were impaired under acid conditions in E. coli H1780 complemented with pUC19-fur-R66A. Also, in the H. pylori Fur-R66 strain bacterial growth and speA gene expression were impaired under acid conditions. CONCLUSIONS: Arginine 66 but not histidine 99 in H. pylori Fur is required for the regulatory function of the Fur protein in the acid adaptation mechanism of the bacterium. PMID- 22221612 TI - Natural history of Helicobacter pylori infection in childhood: eight-year follow up cohort study in an urban community in northeast of Brazil. AB - BACKGROUND: Helicobacter pylori infection is acquired predominantly in childhood. There is also evidence that children loss the infection. Therefore, factors that account for children remain infected need to be investigated because once established the infection persists throughout the life unless treated. METHODS: This study aimed to evaluate the H. pylori infection in children of a low-income community at baseline and 8years later to determine the predictor factors linked to the maintenance, acquisition, and loss of the infection using regression models of generalized estimating equations. H. pylori status was determined by (13) C-urea breath test. RESULTS: Data from 37.7% (133/353) of the children were available. No difference between the characteristics of the included and nonincluded children was observed. The prevalence of infection increased from 53.4 to 64.7%. Thirty-nine children (29.3%) remained noninfected, 47.4% remained infected, 17.3% became infected, and 6.0% lost the infection. Factors associated with to remain infected compared with to remain noninfected included the age, increased number of children in the household, and the use of well water instead of municipal water. The acquisition of the infection was associated with the male gender. CONCLUSION: Factors linked to remain and to gain H. pylori infection in a poor region were increased number of children in the household and the male gender. Also, the acquisition rates were higher than the loss rates, which lead to an increase in the infection prevalence with age. PMID- 22221613 TI - Inverse association between Helicobacter pylori and pediatric asthma in a high prevalence population. AB - BACKGROUND: Helicobacter pylori-associated disease has led to aggressive diagnostic and eradication protocols that are partially responsible for the decrease in prevalence of H. pylori carriage. Recent evidence indicates that in low-prevalence populations, H. pylori may have protective effects on allergic diseases. The aim of this study was to explore the relationship between pediatric asthma and H. pylori infection in a population with high prevalence of H. pylori infection. MATERIALS AND METHODS: A national referral laboratory was screened for all (13) C urea breath tests performed in children aged 5-18 years between 2007 and 2008, for patient demographics and physician-diagnosed asthma. Data concerning asthma-associated medication usage were extracted from electronic medical records and databases. Data were analyzed using a stepwise logistic regression model. RESULTS: During the study period, 6959 patients underwent urea breath testing (average age 12.4+/-3.5years). Of these, 3175/6959 (45.6%) were positive for H. pylori, and 578/6959 (8.3%) had asthma. Rates of asthma in H. pylori-positive and H. pylori-negative children were 7.3 and 9.1%, respectively (odds ratio 0.82; 95% confidence interval (CI) 0.69-0.98; p=.032). We also confirmed that male gender, urban residence, and age are associated with childhood asthma. CONCLUSIONS: We demonstrate an inverse association between H. pylori and pediatric asthma in a population with a high prevalence of H. pylori. PMID- 22221614 TI - Fluoroquinolone resistance in Helicobacter pylori: role of mutations at position 87 and 91 of GyrA on the level of resistance and identification of a resistance conferring mutation in GyrB. AB - BACKGROUND AND AIMS: Fluoroquinolone-containing regimens have been suggested as an alternate to standard triple therapy for the treatment of Helicobacter pylori infections. To determine the relationship between fluoroquinolone resistance and mutations of GyrA and GyrB in H. pylori, we exchanged the mutations at positions 87 and 91 of GyrA among fluoroquinolone-resistant clinical isolates. GyrB of a strain with no mutations in GyrA was also analyzed to identify mechanisms of resistance to norfloxacin. MATERIALS & METHODS: Natural transformation was performed using the amplified fragment of the gyrA and gyrB gene as donor DNA. The amino acid sequences of GyrA and GyrB were determined by DNA sequencing of the gyrA and gyrB genes. RESULTS: Norfloxacin-resistant strains which had mutations at position 87 and 91 became susceptible when the mutations were converted to the wild type. When the mutation from Asp to Asn at position 91 was exchanged to the mutation from Asn to Lys at position 87, the MIC to levofloxacin, gatifloxacin, and sitafloxacin increased. Norfloxacin-resistant strain TS132 with no mutations in GyrA but had a mutation at position 463 in GyrB. Transformants obtained by natural transformation using gyrB DNA of TS132 had a mutation at position 463 of GyrB and revealed resistant to norfloxacin and levofloxacin. CONCLUSION: Mutation from Asn to Lys at position 87 of GyrA confers higher resistance to levofloxacin and gatifloxacin than does mutation from Asp to Asn at position 91. We propose that mutation at position 463 in GyrB as a novel mechanism of fluoroquinolone resistance in H. pylori. PMID- 22221615 TI - A comparison between sequential therapy and a modified bismuth-based quadruple therapy for Helicobacter pylori eradication in Iran: a randomized clinical trial. AB - BACKGROUND: Sequential regimens have been recently reported to be superior to the standard triple therapies in Helicobacter pylori eradication, but most of these studies were performed in Europe and data from developing countries are lacking. So we designed a study to compare a sequential regimen with a bismuth-based quadruple therapy that contains a short course of furazolidone, in Iran. METHODS: Two hundred and ninety-six patients with duodenal ulcer and naive H. pylori infection were randomized into two groups: 148 patients received (PAB-F) pantoprazole (40mg-bid), amoxicillin (1g-bid), and bismuth subcitrate (240mg-bid) for 2weeks and furazolidone (200mg-bid) just during the first week. And 148 patients received (PA-CT) pantoprazole (40mg-bid) for 10days, amoxicillin (1g bid) for the first 5days, and clarithromycin (500mg-bid) plus tinidazole (500mg bid) just during the second 5days. C(14) -urea breath test was performed 8weeks after the treatment. RESULTS: Two hundred and sixty-one patients completed the study (137 patients in the PA-CT and 124 in the PAB-F group). The results were not statistically different between the two groups in the eradication rates and the severity of side effects. The intention to treat eradication rate was 80.4% in the PAB-F group and 83.7% in the PA-CT group. Per-protocol eradication rates were 88.7% and 89.1%, respectively. CONCLUSION: Because the two regimens showed acceptable and similar abilities in H. pylori eradication and because of much higher cost of clarithromycin in Iran, the furazolidone containing regimen seems to be superior. Further modifications of sequential therapies are needed to make them ideal regimens in developing countries. PMID- 22221616 TI - Evaluation of a four-drug, three-antibiotic, nonbismuth-containing "concomitant" therapy as first-line Helicobacter pylori eradication regimen in Greece. AB - BACKGROUND: The eradication rates of Helicobacter pylori (H. pylori) with standard treatments are decreasing worldwide as in Greece. Studies with new antibiotic combinations are needed to find better methods of eradication. Therefore, the aim of this study was to evaluate efficacy and tolerability of a 10-day, four-drug, three-antibiotic, nonbismuth-containing concomitant regimen. MATERIALS AND METHODS: This is a prospective, open-label, multicenter study that included 131 patients infected with H. pylori. All patients were diagnosed with peptic ulcer disease or nonulcer dyspepsia by endoscopy. H. pylori infection was established by at least two positive tests among rapid urease test, gastric histology, and (13) C-urea breath test. For 10 days, all patients received esomeprazole 40mg, amoxycillin 1000mg, clarithromycin 500mg, and metronidazole 500mg, all b.d. eradication was assessed with (13) C urea breath test 8weeks after the start of treatment. Intention-to-treat and per-protocol eradication rates were determined. RESULTS: One hundred and twenty-seven of the 131 patients completed the study. At intention-to-treat analysis, the eradication rate was 91.6% (95% confidence interval (CI), 85.5-95.7%). For the per-protocol analysis, the eradication rate was 94.5% (95% CI, 89-97.8%). Adverse events were noted in 42 of 131 (32.1%); drug compliance was excellent with 96.9% of the patients taking more than 90% of the prescribed medication. CONCLUSION: A 10-day concomitant regimen appears to be an effective, safe, and well-tolerated treatment option for first-line H. pylori eradication in Greece. PMID- 22221617 TI - Sociocultural and dietary practices among Malay subjects in the north-eastern region of Peninsular Malaysia: a region of low prevalence of Helicobacter pylori infection. AB - BACKGROUND AND AIM: The prevalence of Helicobacter pylori infection is exceptionally low among the Malays in the north-eastern region of Peninsular Malaysia. The reasons are unknown. Our aim was to compare environmental factors that differed in relation to H. pylori prevalence among Malays born and residing in Kelantan. METHODS: A case-control study was conducted among Malays in Kelantan who underwent upper endoscopy between 2000 and 2008. Helicobacter pylori status was determined by gastric histology. Sociocultural and dietary factors were assessed using a validated investigator-directed questionnaire administered after 2008, and the data were analyzed using logistic regression analysis. RESULTS: The study group consisted of 161 subjects (79 H. pylori positive and 82 controls). Univariable analysis identified five poor sanitary practices associated with an increased prevalence of H. pylori infection: use of well water, use of pit latrine, less frequent boiling of drinking water, and infrequent hand wash practice after toilet use and before meals. Multivariable logistic regression analysis identified three variables inversely associated with H. pylori infection: frequent consumption of tea (OR: 0.023, 95% CI: 0.01-0.07), frequent use of "budu" or local anchovy sauce (OR: 0.09, 95% CI: 0.1-0.7), and frequent use of "pegaga" or centenella asiatica (OR: 0.25, 95% CI: 0.1-0.65). CONCLUSIONS: Under the assumption that sanitary, sociocultural, and dietary habits have not changed over the years, we can conclude that an increased risk of H. pylori was associated with unsanitary practices whereas protection was associated with consumption of tea and locally produced foods, "pegaga" and "budu." These dietary factors are candidates for future study on the effects on H. pylori transmission. PMID- 22221618 TI - Mucoid Helicobacter pylori isolates with fast growth under microaerobic and aerobic conditions. AB - BACKGROUND: Helicobacter pylori is microaerobic and turns into coccoid under aerobic conditions. In this study, two mucoid strains, A and D, were isolated from gastric biopsies which grew well on blood agar after 24-hour incubation under aerobic as well as microaerobic conditions. The aim of this study was to identify these strains and compare their growth under aerobic and microaerobic conditions with that of control H. pylori. MATERIALS AND METHODS: The two isolates A and D were identified as H. pylori according to microscopic morphology, urease, catalase and oxidase tests. Their growth under humidified aerobic and microaerobic conditions was compared with that of control H. pylori which grew only under microaerobic conditions. They were further identified by amplification of 16S rRNA, vacA alleles, cagA and ureAB genes by PCR. Their susceptibility to current antimicrobials was also examined. RESULTS: The strains A and D produced mucoid colonies under aerobic and microaerobic conditions after 24-hour, exhibiting the typical spiral morphology of H. pylori. The results of urease, catalase and oxidase tests were positive. Sequencing of amplified products showed 99-100% homology with those of the reference H. pylori strains in GenBank. Both strains exhibited resistance to the high concentrations of antimicrobials. CONCLUSIONS: This study reports the isolation of two mucoid strains of H. pylori with confluent growth under aerobic and microaerobic conditions. It appears that production of exopolysaccharide (EXP) could serve as a physical barrier to reduce oxygen diffusion into the bacterial cell and uptake of antibiotics. EXP protected the mucoid H. pylori isolates against stressful conditions, the result of which could be persistence of bacterial infection in the stomach. PMID- 22221619 TI - The use of AlbuMAX II((r)) as a blood or serum alternative for the culture of Helicobacter pylori. AB - BACKGROUND: Growth of Helicobacter pyloriin vitro depends on supplementation of the medium with blood or serum. However, these supplements often require frozen storage and can show batch-to-batch variation, resulting in differences in bacterial growth. In this study, we introduce the use of a commercially available, lipid-rich supplement called AlbuMAX II((r)) (Gibco BRL, Grand Island, NY, USA) for use as a serum/blood replacement for H. pylori culture. MATERIALS AND METHODS: The growth of H. pylori on solid and liquid media was examined by comparing growth after supplementation with horse blood, fetal calf serum, beta cyclodextrin or AlbuMAX II((r)) (Gibco BRL). Human gastric adenocarcinoma (AGS) cellular responses to H. pylori were measured by NF-kappaB luciferase assays and IL-8 ELISA. RESULTS: We show that the growth of H. pylori on both solid and liquid media containing AlbuMAX II((r)) (Gibco BRL) were comparable to levels obtained on blood agar or liquid media supplemented with serum. Growth was consistently higher in media supplemented with AlbuMAX II((r)) (Gibco BRL) than media containing beta-cyclodextrin. Furthermore, bacteria grown in AlbuMAX II((r)) (Gibco BRL) induced proinflammatory responses in AGS cells. CONCLUSIONS: AlbuMAX II((r)) (Gibco BRL) can be used as a serum/blood replacement for the cultivation of H. pylori in solid and liquid media. This medium could be useful for an improved understanding of H. pylori metabolism or for antigen production. Furthermore, AlbuMAX II((r)) (Gibco BRL) may be suitable for use in remote locations, particularly in areas where frozen storage of serum may be a problem. PMID- 22221620 TI - Patterned Si thin film electrodes for enhancing structural stability. AB - A patterned film (electrode) with lozenge-shaped Si tiles could be successfully fabricated by masking with an expanded metal foil during film deposition. Its electrochemical properties and structural stability during the charge-discharge process were examined and compared with those of a continuous (conventional) film electrode. The patterned electrode exhibited a remarkably improved cycleability (75% capacity retention after 120 cycles) and an enhanced structural stability compared to the continuous electrode. The good electrochemical performance of the patterned electrode was attributed to the space between Si tiles that acted as a buffer against the volume change of the Si electrode. PMID- 22221621 TI - The TERT rs2736100 polymorphism and cancer risk: a meta-analysis based on 25 case control studies. AB - BACKGROUND: The association between the TERT rs2736100 single nucleotide polymorphism (SNP) and cancer risk has been studied by many researchers, but the results remain inconclusive. To further explore this association, we performed a meta-analysis. METHODS: A computerized search of PubMed and Embase database for publications on the TERT rs2736100 polymorphism and cancer risk was performed and the genotype data were analyzed in a meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analysis, test of heterogeneity, cumulative meta-analysis and assessment of bias were performed in our meta-analysis. RESULTS: A significant association between the TERT rs2736100 polymorphism and cancer susceptibility was revealed by the results of the meta-analysis of the 25 case-control studies (GG versus TT: OR = 1.72, 95% CI: 1.58, 1.88; GT versus TT: OR = 1.38, 95% CI: 1.29, 1.47; dominant model-TG + GG versus TT: OR = 1.47, 95% CI: 1.37, 1.58; recessive model-GG versus TT + TG: OR = 1.37, 95% CI 1.31, 1.43; additive model-2GG + TG versus 2TT + TG: OR = 1.30, 95% CI: 1.25, 1.36). Moreover, increased cancer risk in all genetic models was found after stratification of the SNP data by cancer type, ethnicity and source of controls. CONCLUSIONS: In all genetic models, the association between the TERT rs2736100 polymorphism and cancer risk was significant. This meta-analysis suggests that the TERT rs2736100 polymorphism may be a risk factor for cancer. Further functional studies between this polymorphism and cancer risk are warranted. PMID- 22221623 TI - The role of primary physicians in the diagnostic delay of lower urinary tract and pelvic organ prolapse symptoms. AB - OBJECTIVE: To explore the role of primary physicians in the diagnostic delay of lower urinary tract and pelvic organ prolapse symptoms in parous women. STUDY DESIGN: Prospective cohort study of women referred to the Urogynecology Outpatient Clinic of a major medical center by primary physicians in the community for initial assessment of lower urinary tract and pelvic organ prolapse symptoms. RESULTS: Most of the women blamed themselves for the delay. However, the primary physicians were considered responsible for 33.5% of the delays. There was no between-group differences in self-blame (p=0.438). Women with pelvic organ prolapse blamed the gynecologist significantly more often than women with lower urinary tract symptoms (p=0.043); 38.6% of the physicians considered the symptoms not sufficiently severe or a natural part of aging. CONCLUSION: Patients need to receive more information on the availability of specific evaluations and treatments for pelvic floor dysfunction. PMID- 22221624 TI - Australian mental health consumers' priorities for research: qualitative findings from the SCOPE for Research project. AB - BACKGROUND: There is growing acceptance of the importance of the consumer viewpoint in mental health research. Previous studies have identified differences in research priorities between researchers and mental health consumers in Australia defined broadly. However, little is known about the research priorities of consumers with specific mental health conditions. OBJECTIVE: The aim of this study was to explore Australian mental health consumers' priorities for depression and bipolar disorder research. DESIGN: Focus groups with consumers and individual telephone interviews with consumer advocates. Participants were asked to discuss the topics they believed were priorities for depression or bipolar disorder research. Transcripts were thematically analysed using NVivo 7. SETTING AND PARTICIPANTS: Ten people with depression and 19 with bipolar disorder participated in face-to-face focus groups held in three Australian capital cities. Five participants with each disorder participated in online focus groups. Five Australian consumer advocates with experience of depression and six with experience of bipolar disorder were individually interviewed by telephone. RESULTS: Participants raised a broad variety of topics for research. The most salient themes included the need for research on medication, and lifestyle and psychosocial influences on depression and bipolar disorder. CONCLUSIONS: Participants' priorities reflect an interest in a holistic approach to mental health research that examines the influences of everyday life and psychosocial influences both on the development and on the management of these disorders. Their focus was on research that explores individualized care and the active role that consumers can play in their own care and recovery. PMID- 22221626 TI - Somebody has to pay. PMID- 22221625 TI - Research, quality and safety, economics: an international perspective. PMID- 22221627 TI - X-ray astronomy. PMID- 22221628 TI - The search for misvalued services: why is radiology a target? PMID- 22221629 TI - Leadership in conflict: part 1. PMID- 22221630 TI - The walls. PMID- 22221631 TI - ACR appropriateness criteria(r) radiologic management of thoracic nodules and masses. AB - Pulmonary and mediastinal masses represent a wide range of pathologic processes with very different treatment options. Although advances in imaging (such as PET and high-resolution CT) help in many cases with the differential diagnosis of thoracic pathology, tissue samples are frequently needed to determine the best management for patients presenting with thoracic masses. There are many options for obtaining tissue samples, each of which has its own set of benefits and drawbacks. The purposes of this report are to present the most current evidence regarding biopsies of thoracic nodules and masses and to present the most appropriate options for select common clinical scenarios. The ACR Appropriateness Criteria((r)) are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 22221632 TI - Challenges to radiologists: responding to the socioeconomic and political issues keeping radiologists up at night: the third annual open microphone sessions at the 2011 AMCLC. AB - Radiologists and their practices and departments are facing challenges that are increasing in number and intensity. These include higher expectations from hospital administrators and referring physicians, new regulatory requirements, lower reimbursements, and competition from predatory practices. For many radiologists, these forces are having a negative impact on their job satisfaction, their lifestyles, and the time they have available for consultation, teaching, and research. Some radiologists face loss of employment, and the specialty faces existential threats. This article includes surveys of the ACR Council regarding recent challenges and summarizes comments from the councilors, the literature, and the authors with respect to recommendations to radiologists in meeting these challenges. PMID- 22221633 TI - Trends in the utilization of outpatient advanced imaging after the deficit reduction act. AB - PURPOSE: After the Deficit Reduction Act (DRA) took effect in 2007, there was concern that private office-based imaging facilities would close, that advanced imaging would shift to less convenient hospital-based facilities, and that access to advanced imaging might be restricted. The aim of this study was to see if these developments occurred during the years after the DRA. METHODS: Using Medicare data, outpatient CT, MRI, and nuclear medicine trends before and after the DRA were studied. Procedure volumes performed in private offices and hospital outpatient departments (HOPDs) were tabulated separately. Volumes were tracked from 2000 to 2006 (before the DRA) and from 2007 to 2009 (after the DRA), and compound annual growth rates were calculated for the two periods. RESULTS: In all 3 modalities, growth before the DRA was far more rapid than afterward. Compound annual growth rates from 2007 to 2009 in offices and HOPDs were, respectively, +2.1% and +0.5% for CT, -1.1% and +1.0% for MRI, and -1.7% and -2.5% for nuclear medicine. Growth trends in all 3 modalities showed distinct flattening beginning around 2005 to 2006. CONCLUSIONS: From 2007 to 2009 (after the DRA), there was more rapid CT volume growth in offices than in HOPDs. Concurrently, there was some loss of nuclear medicine volume in both settings, but the loss was less in offices. Thus, in CT and nuclear medicine, offices actually fared better after the DRA than HOPDs. In MRI, HOPDs fared slightly better than offices. It thus seems that there has been no shift away from offices and as yet no loss of access to CT or MRI after the DRA. However, some loss of access to nuclear medicine does seem to have occurred. PMID- 22221634 TI - Growth in the use of PET for six cancer types after coverage by medicare: additive or replacement? AB - BACKGROUND: In July 2001, PET became a covered service for Medicare beneficiaries when used for the diagnosis, staging, and restaging of non-small-cell lung, esophageal, colorectal, and head and neck cancers as well as lymphoma and melanoma. Whether physicians use PET as a replacement for or in addition to CT, MRI, or bone scintigraphy (BS) is uncertain. METHODS: A 20% sample of Medicare fee-for-service beneficiaries aged > 64 years from 2004 through 2008 was used. Annually for each cancer type, a cohort of patients was created defined as having at least one admission with a primary cancer diagnosis or two nonhospital claims with a cancer diagnosis >=7 days apart per calendar year. Each year, imaging claims and claim-days were counted by modality and cancer type. The sequence of PET use was examined as before, after, or instead of other imaging. RESULTS: About 125,000 beneficiaries (2.5% of the cohort) met the cancer definition each year. In 2008, the combined annual imaging days per person-year were 2.3 for CT, 0.49 for MRI, 0.70 for PET, and 0.13 for BS. The annual rates of imaging from 2004 to 2008 increased by 0.5% for CT, 3.2% for MRI, and 18.0% for PET (range, 14.6%-19.9% by cancer type) and decreased by 12.7% for BS. The growth in PET use was not associated with meaningful changes in body CT. In 2007 and 2008, body CT preceded PET within 30 days in about half of patients, whereas PET preceded CT in only 22%. CONCLUSIONS: Several years after its introduction, PET continued to grow rapidly, with evidence that it is replacing BS. Growth of PET occurred without evidence of a decline in body CT. About half of PET use occurred shortly after body CT, suggesting an additive or final arbiter role. PMID- 22221635 TI - Use of inpatient imaging services by persons without health insurance. AB - BACKGROUND: Americans without health insurance generally receive fewer health care services than those with insurance. Less studied are the specific types of services for which the uninsured face access and utilization differences. This article fills in some of the knowledge gaps by presenting comparisons between uninsured and insured individuals in the use of imaging services in the hospital inpatient setting. METHODS: The primary data source for this study was the 2003 National Hospital Discharge Survey. The principal source of payment was used to define insurance status. Global relative value units were assigned by imaging procedure. To ensure sufficient numbers of observations, individual imaging procedures were aggregated into 6 modalities. Multivariate regression was used to estimate the utilization and value of imaging services as a function of insurance status and other control variables. RESULTS: Just over 9% of inpatients were uninsured (range, 15.7% aged 18-24 years to 5.8% aged 55-64 years). After controlling for measurable factors, uninsured hospital inpatients who underwent imaging received the same mean number of imaging services (1.51) of the same mean value (11 relative value units) as those for comparable insured persons. The uninsured received fewer interventional and image-guided procedures but more CT studies than insured patients (P < .05). CONCLUSIONS: Because insurance status does not seem to significantly influence the quantity or value of imaging services received by hospital inpatients who receive imaging, efforts to assist uninsured patients with imaging needs would be better directed elsewhere than the hospital inpatient setting. PMID- 22221636 TI - Imaging and insurance: do the uninsured get less imaging in emergency departments? AB - PURPOSE: On average, Americans without health insurance receive fewer health care services than those with insurance. The specific types of services for which the uninsured face access and utilization deficits are not well understood. The authors describe the use of imaging tests in hospital emergency departments (EDs) by nonelderly patients, comparing uninsured, Medicaid, and non-Medicaid insured individuals. METHODS: The main database used was the 2004 National Hospital Ambulatory Medical Care Survey. The survey contained 2 fields critical to the study: source of payment and imaging services rendered during the ED visit. Source of payment was used to sort ED visit episodes into 3 insurance categories: uninsured, Medicaid, and non-Medicaid insured. Relative value units were assigned to imaging procedures. Imaging procedures were aggregated into 6 modalities. Univariate and multivariate methods were used to compare the number of imaging procedures and associated relative value units across insurance categories. Risk adjustment used the immediacy code, reason for visit, disposition, and demographics. RESULTS: Compared with comparable insured persons, nonelderly uninsured and Medicaid patients received fewer services in the ED (8% and 10%, respectively, P < .01), even after adjustment for level of acuity. Similar results were found for the value of imaging services received (13% and 19%, respectively, P < .01). CONCLUSIONS: These results suggest that insurance status influences how much imaging and the intensity of imaging patients receive. Further research is needed to understand whether insured patients receive unnecessary imaging or if uninsured and Medicaid patients receive too little imaging. PMID- 22221637 TI - The impact of socioeconomic status and comorbid medical conditions on ionizing radiation exposure from diagnostic medical imaging in adults. AB - PURPOSE: The aim of this study was to characterize cumulative exposure to ionizing radiation from diagnostic imaging (CEDI) in adult patients and investigate its relationship to a patient's socioeconomic status and comorbid medical conditions. METHODS: A retrospective cohort study was conducted of 54,015 patients seen within the outpatient clinic system of an academic, tertiary care, urban medical center during the month of January 2006, estimating the CEDI from all procedures performed within 3 years of the index visit (until January 2009). Socioeconomic status was estimated from census tract geocoding. Comorbid medical conditions were identified from the electronic medical record. RESULTS: A total of 9,537 adult patients were seen within the index month and underwent imaging tests. Eighty percent were living in areas with >10% poverty. Thirty-six percent of men and 43% of women had diagnoses from the Elixhauser list. Mean CEDI values were 10 +/- 19.09 mSv for those from areas with >10% poverty and 8.9 +/- 22.42 mSv for those living in areas with <10% poverty. Poverty and comorbidities covaried. Estimated CEDI within groups of patients with the same comorbidity was not associated with socioeconomic status. CONCLUSION: At this institution, there is a high prevalence of patients living in poverty. Those living in poverty are at higher risk for comorbid conditions that are associated with increased CEDI. However, controlling for comorbidity, socioeconomic status was no longer predictive of CEDI. PMID- 22221638 TI - Renegotiating expertise: an examination of PACS and the challenges to radiology using a medical anthropologic approach. AB - PURPOSE: The aim of this study was to examine how the adoption of PACS has affected the professional relationships among radiologists and referring providers and to evaluate the effect of PACS on perceptions of radiologists' roles in patient care. METHODS: A medical anthropologic approach was used to assess the impact of PACS among radiologists and a community of clinical subspecialists at a large academic medical center (n = 40). Data collection techniques included 3 months of ethnographic participant observation during the routine medical practice of study participants as well as semistructured interviews and archival research. These data were then analyzed to identify behavioral and narrative patterns and themes among the study populations. RESULTS: The difficulty of establishing and maintaining relationships of trust between referring providers and radiologists due to the drop in post-PACS reading room visits emerged as a major source of concern for study participants. By interacting primarily over the phone or at weekly conferences, radiologists felt that they had fewer opportunities to build personal relationships with other clinicians. Meanwhile, the specialist referring providers stated they generally consulted only radiologists with whom they had established personal relationships and otherwise preferred to interpret their patients' images themselves. CONCLUSIONS: Generating and sustaining relationships of trust and effective communication are vital for radiologists to communicate their expertise in medical imaging to referring providers. Because PACS have caused a reduction in referring provider visits to the reading room, radiologists must seek out new opportunities to form personal relationships with other physicians. PMID- 22221639 TI - Picturing the climate: radiologic assessment of rwandan imaging capacity. PMID- 22221640 TI - When a provider leaves: ten things practices can do to protect themselves now. PMID- 22221641 TI - Pointers for optimizing radiation dose in pediatric CT protocols. PMID- 22221642 TI - Theodore J. Wachowski. PMID- 22221643 TI - Re: "a survey of emergency physician-performed ultrasound: implications for academic radiology departments". PMID- 22221645 TI - Re: "ACR/ABR clinical statement on credentialing and privileging of radiologists for diagnostic nuclear medicine, including multimodality hybrid imaging". PMID- 22221647 TI - Democracy is the worst form of government. PMID- 22221648 TI - Value-added radiology services. PMID- 22221649 TI - 5-Azacytidine is insufficient for cardiogenesis in human adipose-derived stem cells. AB - BACKGROUND: Adipose tissue is a source of multipotent adult stem cells and it has the ability to differentiate into several types of cell lineages such as neuron cells, osteogenic cells and adipogenic cells. Several reports have shown adipose derived stem cells (ASCs) have the ability to undergo cardiomyogenesis. Studies have shown 5-azacytidine can successfully drive stem cells such as bone marrow derived stem cells to differentiate into cardiomyogenic cells. Therefore, in this study, we investigated the effect 5-azacytidine on the cardiogenic ability of ASCs. METHODS: The cardiogenic potential of ASCs was analysed by studying the morphological changes after induction, the changes in the cardiogenic genes expression i.e. GATA4, MLC-2v, MLC-2a, NKX2.5, beta-MHC, alpha-MHC, Atrial natriuretic peptide (ANP), Connexin 43, Cardiac Troponin C, Cardiac Troponin I and myocyte enhancer factor (MEF2C) and the changes of embryonic stem cells genes expression at P5 and P10 using quantitative PCR. RESULTS: Our results showed that the induced ASCs did not show significant morphological difference compared to the non-induced ASCs. While quantitative PCR data indicated that most cardiogenic genes and stemness genes expression level decreased after induction at P5 and P10. CONCLUSION: 5-azacytidine is insufficient for the cardiogenic induction of the ASCs. PMID- 22221650 TI - High anti-EBNA-1 IgG levels are associated with early-onset myasthenia gravis. AB - BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder mediated by antibodies against the acethylcholine receptor (AchR) of the neuromuscular junction in the majority of patients. METHODS: Here, we examined IgG antibodies against the type 1 nuclear antigen of Epstein-Barr virus (EBNA-1) in the sera of 158 patients with MG compared to 184 healthy controls. RESULTS: Although serum concentration in the sera was not different, high anti-EBNA-1 IgG titers (above 90th percentile of the normal values) were more common in the patients (26.6 vs. 16.3%, P=0.024). In addition, high EBNA-1 IgG levels occurred more frequently amongst the 94 patients with early-onset myasthenia gravis (EOMG, 30.8%) as compared to the 64 patients with late-onset disease (LOMG, 14.1%) (P=0.021). Using multiple logistic regression, high serum concentration of the anti-EBNA-1 IgG antibodies was significantly associated with EOMG (OR: 3.17, P=0.027), even after adjustment for sex, presence/absence of anti-AchR antibodies and presence/absence of anti-Titin antibodies. Out of 39 patients with EOMG, who underwent thymectomy, 18 patients (46%) had thymoma, 6 had thymic hyperplasia (15%), and 15 patients had thymic atrophy (39%); there was no difference comparing EBNA-1 antibody titers in the sera. As no correlation was found between the titers of anti-AchR, anti-Titin, and EBNA-1 antibodies, a dysregulated heterogeneous B-cell response was unlikely to be responsible for the elevated levels of EBV-associated antibody in patients. CONCLUSIONS: In summary, our data suggest that high levels of EBNA-1 antibodies are more common in MG compared to healthy controls and are especially associated with EOMG. PMID- 22221651 TI - Characteristics of hydrophobicity loss on silicone rubber surface during a dynamic drop test with direct current voltage application. AB - Dynamic drop test for studying the temporal lowering of hydrophobicity on the surface of silicone rubber with direct current voltage application was carried out. In this study, we evaluated the influence of the temporal lowering of hydrophobicity under various conductivities and dropping rates for water droplets. As a result, it was found that the dropping rate and the conductivity of water droplets greatly influenced the hydrophobicity loss time on the surface of silicone rubber. PMID- 22221652 TI - Child growth in urban deprived settings: does household poverty status matter? At which stage of child development? AB - This paper uses longitudinal data from two informal settlements of Nairobi, Kenya to examine patterns of child growth and how these are affected by four different dimensions of poverty at the household level namely, expenditures poverty, assets poverty, food poverty, and subjective poverty. The descriptive results show a grim picture, with the prevalence of overall stunting reaching nearly 60% in the age group 15-17 months and remaining almost constant thereafter. There is a strong association between food poverty and stunting among children aged 6-11 months (p<0.01), while assets poverty and subjective poverty have stronger relationships (p<0.01) with undernutrition at older age (24 months or older for assets poverty, and 12 months or older for subjective poverty). The effect of expenditures poverty does not reach statistical significant in any age group. These findings shed light on the degree of vulnerability of urban poor infants and children and on the influences of various aspects of poverty measures. PMID- 22221653 TI - Testosterone, SHBG and differential white blood cell count in middle-aged and older men. AB - OBJECTIVE: Low-grade chronic inflammation is increasingly being implicated in cardiovascular disease (CVD) etiology and may represent an alternative pathway through which testosterone and sex hormone-binding globulin (SHBG) influence CVD risk. We examined the associations between endogenous testosterone, SHBG and total and differential white blood cell (WBC) counts in men. METHODS: Cross sectional study of 2418 men aged 40-78 years from the Norfolk population of European Prospective Investigation into Cancer (EPIC-Norfolk) who had no history of CVD or cancer and complete data on sex hormones (total testosterone (TT), SHBG and free testosterone (FT)) and WBC counts. Associations between sex hormones and WBC counts were assessed using linear regression models. RESULTS: Higher SHBG and TT levels were associated with lower WBC counts. After adjustment for age, BMI, smoking, physical activity and diabetes status, total WBC count decreased by 0.163 (95% CI -0.236; -0.091) and 0.102 (-0.170; -0.034) per standard deviation (SD) increase in SHBG and TT respectively. Associations of SHBG and TT with total WBC count were mainly accounted for by a lower granulocyte count (beta coefficient=-0.132 (-0.194; -0.070) per SD increase in SHBG and beta coefficient= 0.104 (-0.161; -0.046) per SD increase in TT). No associations between FT and total and differential WBC counts were found. CONCLUSIONS: Endogenous TT and SHBG levels are inversely associated with total WBC and granulocyte count in middle aged and older men. Even though the underlying mechanism and causal directionality requires further exploration, these results support a link between hormonal status and low-grade inflammation. PMID- 22221654 TI - Rehabilitation after stroke in older people. AB - Stroke is a leading cause of disability and therefore rehabilitation is a major part of patient care. Most interventions do not target aged patient but there is unequivocal evidence to promote rehabilitation in multidisciplinary stroke units or integrated care of a multidisciplinary team in the community. Most research has focused on the effect of interventions on recovery in different forms of impairment and disability. The most promising options for motor recovery of the arm include constraint-induced movement therapy and robotic-assisted strategies. Interventions to improve postural stability and gait include fitness training, high-intensity therapy, and repetitive-task training. However, information about the clinical effect of various strategies of cognitive rehabilitation and strategies for aphasia and dysarthria is scarce. Several large trials of rehabilitation practice are underway to test these interventions in the elderly, either alone or in combination with early mobilisation, cardiorespiratory fitness training and physical exercise. PMID- 22221655 TI - Testing GSTP1 genotypes and haplotypes interactions in Slovenian post-/pre menopausal women: novel involvement of glutathione S-transferases in bone remodeling process. AB - OBJECTIVES: Osteoporosis (OP) is an age-related disease associated with increased production of reactive oxygen species (ROS) and a reduction in antioxidant defense system, such as low activity of glutathione S-transferase (GST) family. The enzyme activity of the member of GSTs, GSTP1, depends on gene polymorphisms such as: Ala114Val and Ile105Val. The aim of this study was to evaluate the association between genetic polymorphisms of the GSTP1 gene and BMD variation and biochemical bone remodeling markers in 523 Slovenian pre- and post-menopausal women. STUDY DESIGN: Observational pilot study in a representative cohort of Slovenian patients with adjustment for potential confounders (age, height, weight, years since menopause, smoking status and glucocorticoid use) using univariate one-way and two-way analyses. MAIN OUTCOME MEASURES: Ala114Val and Ile105Val polymorphisms genotypes of GSTP1 gene, bone mineral density (BMD) values of total hip (_th), femoral neck (_fn) and lumbar spine (_ls), plasma osteocalcin (OC), serum bone alkaline phosphatase (BALP), free soluble RANKL and serum osteoprotegerin (sOPG) concentrations were determined. RESULTS: Our results show that the Ala114Val heterozygotes are (borderline) significantly associated with higher concentrations of pOC (p=0.052) and decreased BMD_fn values (p=0.053) and the same trend is shown for BMD_th and BMD_ls values in osteopenic postmenopausal women. Furthermore, significantly higher concentrations of pOC were determined among Val allele carriers of Ile105Val gene polymorphism (p=0.037) and in carriers with the absent 114Ala-105Ile haplotype combination, again in osteopenic post-menopausal women. In addition, in pre-menopausal women the significant associations between sOPG and Ala114Val genotypes subgroups and between sBALP and Ile105Val genotypes subgroups, alone or in combination with Ala114Val, were determined (0.032, 0.026 and 0.008, respectively). CONCLUSIONS: Since significant associations existed in Ala114Val genotype and 114Ala-105Ile haplotype subgroups, these variations can be useful for determining low BMD and high pOC risk in postmenopausal women. PMID- 22221656 TI - A survey of geriatric psychiatry training across Europe. AB - BACKGROUND: Training, practice, and continuing professional development in old age psychiatry varies across Europe. The aims of this study were to survey current practice and develop recommendations to begin a debate on harmonization. METHODS: A survey was sent out to 38 European countries via email. The survey was sent to members of the European Association of Geriatric Psychiatry (EAGP) Board, members of the World Psychiatric Association, and key old age psychiatrists or other psychiatrists with a special interest in the area for countries where old age psychiatry was not formally a specialty. RESULTS: Through a process of networking, we identified a key individual from each country in Europe to participate in this study, and 30 out of 38 (79%) representatives responded. Training programs and duration varied between countries. Eleven countries reported that they had geriatric psychiatry training programs and most of these required geriatric psychiatry trainees to complete mandatory training for two years within old age psychiatry. Representatives from ten countries reported having specific Continuing Professional Development (CPD) for old age psychiatrists at consultant level. CONCLUSION: There is a clear indication that the recognition of geriatric psychiatry as a specialist discipline in Europe is on the rise. The training procedures and processes in place vary considerably between and sometimes within countries. There are several options for harmonizing old age psychiatry training across Europe with advantages to each. However, support is required from national old age psychiatry bodies across Europe and an agreement needs to be reached on a training strategy that encompasses supervision, development, and appraisal of the knowledge and skills sets of old age psychiatrists. PMID- 22221657 TI - Wet-chemistry processing of powdery raw material for high-tech ceramics. AB - The purpose of this study was to develop wet-chemistry approaches for the synthesis of ultradispersed and mesoporous metal oxide powders and powdery composites intended for usage in the production of ceramic materials with desired properties. The focus is on the development of template synthesis of mesoporous metal silicates as well as obtaining nano- and subnanopowders by a modified sol gel technique and template methods. Families of mesoporous (2 to 300 nm) metal silicates and nano-oxides and subnanopowders (4 to 300 nm) were synthesized by the template method and modified sol-gel technique, respectively. Texture and morphology of the obtained objects have been studied by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, Brunauer-Emmett-Teller analysis, and N2 adsorption desorption. It was found that morphological parameters of the metal oxide obtained by the modified sol-gel technique depend nonlinearly on the initial molar ratio value of the sol stabilizer and metal in the reaction medium as well as the nature of the stabilizer. It has been shown that the nature of structure directing components determines the morphology of the silicate obtained by the template method: dispersion and shape of its particles. The developed laboratory technology corresponds to the conception of soft chemistry and may be adapted to the manufacture of ultradispersed materials for catalysis, solar cells, fuel cells, semiconductors, sensors, low-sized electronic devices of new generation, etc. PMID- 22221658 TI - Genetic influence on disease spread following arrival of infected carriers. AB - Epidemiology in host meta-populations depends on parasite ability to disperse between, establish and persist in distinct sub-populations of hosts. We studied the genetic factors determining the short-term establishment, and long-term maintenance, of pathogens introduced by infected hosts (i.e. carriers) into recipient populations. We used experimental populations of the freshwater ciliate Paramecium caudatum and its bacterial parasite Holospora undulata. Parasite short term spread (approximately one horizontal transmission cycle) was affected mainly by carrier genotype, and its interactions with parasite and recipient genotypes. By contrast, parasite longer term spread (2-3 horizontal transmission cycles) was mostly determined by parasite isolate. Importantly, measures of parasite short term success (reproductive number, R) were not good predictors for longer term prevalence, probably because of the specific interactions between host and parasite genotypes. Analogous to variation in vectorial capacity and super spreader occurrence, two crucial components of epidemiology, we show that carrier genotype can also affect disease spread within meta-populations. PMID- 22221659 TI - Report of four simultaneous pancreas-kidney transplants in HIV-positive recipients with favorable outcomes. AB - The advent of combined antiretroviral therapy (cART) dramatically changed the view of human immunodeficiency virus (HIV) infection as an exclusion criterion for solid organ transplantation, resulting in worldwide reports of successful transplants in HIV-infected individuals. However, there are few reports on simultaneous pancreas-kidney transplant in HIV-positive recipients detailing poor outcomes. A series of four pancreas-kidney transplant performed on HIV-infected individuals between 2006 and 2009 is presented. All recipients reached stably undetectable HIV-RNA after transplantation. All patients experienced early posttransplant infections (median day 30, range 9-128) with urinary tract infections and bacteremia being most commonly observed. In all cases, surgical complications led to laparotomic revisions (median day 18, range 1-44); two patients underwent cholecystectomy. One steroid-responsive acute renal rejection (day 79) and one pancreatic graft failure (month 64) occurred. Frequent dose adjustments were required due to interference between cART and immunosuppressants. At a median follow-up of 45 months (range, 26-67) we observed 100% patient survival with CD4 cell count >300 cells/mm(3) for all patients. Although limited by its small number, this case series represents the largest reported to date with encouraging long-term outcomes in HIV-positive pancreas kidney transplant recipients. PMID- 22221660 TI - Evaluation of Toll-like receptor and adaptor molecule polymorphisms for susceptibility to tuberculosis in a Colombian population. AB - Immunological studies have supported the idea that innate immunity is critical for the control of Mycobacterium tuberculosis (Mtb) infection in humans. Despite the overwhelming evidence showing the critical role of Toll-like receptors (TLRs) in the in vitro recognition of Mtb, the in vivo significance of individual TLRs has been more difficult to demonstrate consistently. We were interested in examining the role of genes of TLRs and molecules involved in their signalling cascades, and a case-control study was designed to test the association of polymorphisms of these innate immune genes with pulmonary tuberculosis (TB) in a Colombian population. In this study, we did not find an association with TLR2, TLR4, TLR9, MyD88 or MAL/TIRAP polymorphic variants. These findings suggest that those genes are not involved as risk factors for pulmonary TB in our population. PMID- 22221661 TI - Spiteful interactions between sympatric natural isolates of Xenorhabdus bovienii benefit kin and reduce virulence. AB - Spite occurs when an individual harms itself in the act of harming others. Spiteful behaviour may be more pervasive in nature than commonly thought. One of the clearest examples of spite is the costly production and release of bacteriocins, antimicrobial toxins noted for their ability to kill conspecifics. A key question is to what extent these toxins provide a fitness advantage to kin of the producer cell, especially in natural communities. Additionally, when bacteria are involved in parasitic relationships, spiteful interactions are predicted to lower bacterial densities within a host, causing a reduction in parasite-induced virulence. Using five sympatric, field-collected genotypes of the insect pathogen Xenorhabdus bovienii, we experimentally demonstrate that bacteriocin production benefits kin within the host, and that it slows the mortality rate of the host. These results confirm that spite among naturally coexisting bacterial clones can be a successful kin-selected strategy that has emergent effects on virulence. PMID- 22221662 TI - suPAR as a prognostic biomarker in sepsis. AB - Sepsis is the clinical syndrome derived from the host response to an infection and severe sepsis is the leading cause of death in critically ill patients. Several biomarkers have been tested for use in diagnosis and prognostication in patients with sepsis. Soluble urokinase-type plasminogen activator receptor (suPAR) levels are increased in various infectious diseases, in the blood and also in other tissues. However, the diagnostic value of suPAR in sepsis has not been well defined, especially compared to other more established biomarkers, such as C-reactive protein (CRP) and procalcitonin (PCT). On the other hand, suPAR levels have been shown to predict outcome in various kinds of bacteremia and recent data suggest they may have predictive value, similar to that of severity scores, in critically ill patients. This narrative review provides a descriptive overview of the clinical value of this biomarker in the diagnosis, prognosis and therapeutic guidance of sepsis. PMID- 22221665 TI - An updated state of the science EQC model for evaluating chemical fate in the environment: application to D5 (decamethylcyclopentasiloxane). AB - The EQuilibrium Criterion (EQC) model developed and published in 1996 has been widely used for screening level evaluations of the multimedia, fugacity-based environmental fate of organic chemicals for educational, industrial, and regulatory purposes. Advances in the science of chemical partitioning and reactivity and the need for more rigorous regulatory evaluations have resulted in a need to update the model. The New EQC model is described which includes an improved treatment of input partitioning and reactivity data, temperature dependence and an easier sensitivity and uncertainty analysis but uses the same multi-level approach, equations and environmental parameters as in the original version. A narrative output is also produced. The New EQC model, which uses a Microsoft Excel platform, is described and applied in detail to decamethylcyclopentasiloxane (D5; CAS No. 541-02-6). The implications of these results for the more detailed exposure and risk assessment of D5 are discussed. The need for rigorous evaluation and documentation of the input parameters is outlined. PMID- 22221664 TI - Occurrence and removal of pharmaceuticals in wastewater treatment plants at the Spanish Mediterranean area of Valencia. AB - A survey on the presence of pharmaceuticals in urban wastewater of a Spanish Mediterranean area (Castellon province) was carried out. The scope of the study included a wide variety of pharmaceuticals belonging to different therapeutical classes. For this purpose, 112 samples, including influent and effluent wastewater, from different conventional wastewater treatment plants were collected. Two monitoring programmes were carried out along several seasons. The first was in June 2008 and January 2009, and the second in April and October 2009. During the first monitoring, the occurrence of 20 analytes in 84 urban wastewater samples (influent and effluent) was studied. The selection of these pharmaceuticals was mainly based on consumption. From these, 17 compounds were detected in the samples, with analgesics and anti-inflammatories, cholesterol lowering statin drugs and lipid regulators being the most frequently detected groups. 4-Aminoantipyrine, bezafibrate, diclofenac, gemfibrozil, ketoprofen, naproxen and venlafaxine were the compounds most frequently found. In the highlight of these results, the number of analytes was increased up to around 50. A lot of antibiotic compounds were added to the target list as they were considered "priority pharmaceuticals" due to their more potential hazardous effects in the aquatic environment. Data obtained during the second monitoring programme (spring and autumn) corroborated the results from the first one (summer and winter). Analgesics and anti-inflammatories, lipid regulators together with quinolone and macrolide antibiotics were the most abundant pharmaceuticals. Similar median concentrations were found over the year and seasonal variation was not clearly observed. The removal efficiency of pharmaceuticals in the wastewater treatment plants was roughly evaluated. Our results indicated that elimination of most of the selected compounds occurred during the treatment process of influent wastewater, although it was incomplete. PMID- 22221666 TI - Variation of As concentration between soil types and rice genotypes and the selection of cultivars for reducing As in the diet. AB - Human exposure to toxic heavy metals via the food chain is of increasing concern. In the present study, the effects of soil type and genotype on variation in arsenic (As) concentrations of different organs were investigated by using nine rice cultivars grown in two soils, with two levels of As contamination. There were significant genotypic differences (P<0.05) in As concentrations of all organs, and As concentrations of polished grain were significantly affected by genotype and soil type. The As concentration in polished grain was higher in red paddy soil under As treatment, with range from 0.24 to 1.03 mg kg(-1), and the As concentration of three cultivars exceeded the concentration of Chinese Food Hygiene Standard (0.7 mg kg(-1)). The As concentrations in stems, leaves and polished grain were all significantly and positively correlated. The As concentrations in polished grain were positively and significantly (P<0.01) correlated with As root-grain translocation factor. The results indicated that As concentration in grain was partially governed by As uptake and the transfer of As from root to grain. The grain As concentration of the nine cultivars was significantly correlated between the two soil types at different levels of As contamination. Some genotypes, such as japonica rice (e.g. Ning jing 1 and Nan jing 32) had consistently low grain As concentrations. The results suggest the possibility of breeding the As rice cultivars to produce grain for safe consumption from soils with slight and moderate levels of As. PMID- 22221667 TI - Localisation and mobility of trace metal in silver fir needles. AB - Trace metals (TM: Co, Ni, Cu, Zn, Cd, and Pb) as well as Al, Mn, and Fe content was measured in needles of a remote silver fir stand in the south of France. TM localisation and behaviour in needles was evaluated by measuring total and internal content of needles of different ages. Measured concentrations fell within background values. Al, Fe, Co, and Pb were trapped in wax following atmospheric particulate deposition. Contrasting accumulation and migration behaviours of the different elements studied were observed. The wax contained less than 10% Mn, Al, Ni, Co, and Zn and 15-45% Fe, Cu, and Cd in the young needles. Lead was mostly located in the wax (50-80%), and this proportion decreased with needle age. Only the internal content of Pb and Fe increased significantly with needle age. Finally, due to atmospheric deposition accumulation, higher input fluxes of Fe, Cu, Cd, and Pb can be expected in forest soil. PMID- 22221668 TI - Impact of pathological tumour characteristics in patients with sarcomatoid renal cell carcinoma. AB - Study Type - Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Sarcomatoid renal cell carcinoma can occur in the setting of all histological subtypes of kidney cancer. These tumours are very aggressive and many patients present with disseminated disease. Long-term survival is poor and the durable responses to systemic therapy are infrequent. Our large cohort analyses the influence of pathological tumour characteristics in determining prognosis for patients with sarcomatoid renal cell carcinoma undergoing surgical resection. This series helps define the prognostic influence of histological subtype, type of sarcomatoid morphology, the percentage necrosis and sarcomatoid features, and the presence of microvascular invasion. OBJECTIVES: To examine the influence of pathological tumour characteristics on survival to aid prognostication and clinical trial design. Patients with sarcomatoid renal cell carcinoma (sRCC) are known to have poor prognosis and response to systemic therapy. PATIENTS AND METHODS: A single-centre database was reviewed to identify all patients with sRCC. Clinical variables and pathological information, including histology, necrosis, percentage of sarcomatoid features (PSF) and microvascular invasion (MVI), were recorded and correlated to outcome. RESULTS: Analyses of 104 patients with sRCC found that the median (range) size of tumours was 9.5 cm (2.5-30), 65% of patients had areas of clear cell histology, and 69.2% had metastatic disease at presentation. The PSF did not influence tumour size, stage, necrosis, MVI, nodes or metastasis. A total of 85 patients (81.7%) died during the follow-up period with a median (95% confidence interval [CI]) survival of 5.9 months (4.7-8.9). In the overall cohort, Eastern Cooperative Group performance status (ECOGPS), tumour size and metastatic disease were independent predictors of poor survival. MVI, PSF and percentage necrosis were strongly associated with outcome but were not independent predictors of outcome. A multivariate risk model was established that incorporated six covariates (tumour size, MVI, ECOGPS, PSF, necrosis, and metastatic disease) to produce a predictive tool. CONCLUSIONS: Both patients with localized and metastatic sRCC have very poor survival outcomes. Pathological features MVI, PSF and necrosis are important predictors of survival and could be used in a prognostic model while grade and histology do not influence prognosis. A prognostic model, if validated, could aid in patient counselling and/or clinical trial design. PMID- 22221669 TI - Redesign of coenzyme B(12) dependent diol dehydratase to be resistant to the mechanism-based inactivation by glycerol and act on longer chain 1,2-diols. AB - Coenzyme B(12) dependent diol dehydratase undergoes mechanism-based inactivation by glycerol, accompanying the irreversible cleavage of the coenzyme Co-C bond. Bachovchin et al. [Biochemistry16, 1082-1092 (1977)] reported that glycerol bound in the G(S) conformation, in which the pro-S-CH(2) OH group is oriented to the hydrogen-abstracting site, primarily contributes to the inactivation reaction. To understand the mechanism of inactivation by glycerol, we analyzed the X-ray structure of diol dehydratase complexed with cyanocobalamin and glycerol. Glycerol is bound to the active site preferentially in the same conformation as that of (S)-1,2-propanediol, i.e. in the G(S) conformation, with its 3-OH group hydrogen bonded to Seralpha301, but not to nearby Glnalpha336. k(inact) of the Salpha301A, Qalpha336A and Salpha301A/Qalpha336A mutants with glycerol was much smaller than that of the wild-type enzyme. k(cat) /k(inact) showed that the Salpha301A and Qalpha336A mutants are substantially more resistant to glycerol inactivation than the wild-type enzyme, suggesting that Seralpha301 and Glnalpha336 are directly or indirectly involved in the inactivation. The degree of preference for (S)-1,2-propanediol decreased on these mutations. The substrate activities towards longer chain 1,2-diols significantly increased on the Salpha301A/Qalpha336A double mutation, probably because these amino acid substitutions yield more space for accommodating a longer alkyl group on C3 of 1,2-diols. Database Structural data are available in the Protein Data Bank under the accession number 3AUJ. Structured digital abstract * Diol dehydrase gamma subunit, Diol dehydrase beta subunit and Diol dehydrase alpha subunit physically interact by X-ray crystallography (View interaction). PMID- 22221670 TI - Randomised controlled trial of improvisational music therapy's effectiveness for children with autism spectrum disorders (TIME-A): study protocol. AB - BACKGROUND: Previous research has suggested that music therapy may facilitate skills in areas typically affected by autism spectrum disorders such as social interaction and communication. However, generalisability of previous findings has been restricted, as studies were limited in either methodological accuracy or the clinical relevance of their approach. The aim of this study is to determine effects of improvisational music therapy on social communication skills of children with autism spectrum disorders. An additional aim of the study is to examine if variation in dose of treatment (i.e., number of music therapy sessions per week) affects outcome of therapy, and to determine cost-effectiveness. METHODS/DESIGN: Children aged between 4;0 and 6;11 years who are diagnosed with autism spectrum disorder will be randomly assigned to one of three conditions. Parents of all participants will receive three sessions of parent counselling (at 0, 2, and 5 months). In addition, children randomised to the two intervention groups will be offered individual, improvisational music therapy over a period of five months, either one session (low-intensity) or three sessions (high intensity) per week. Generalised effects of music therapy will be measured using standardised scales completed by blinded assessors (Autism Diagnostic Observation Schedule, ADOS) and parents (Social Responsiveness Scale, SRS) before and 2, 5, and 12 months after randomisation. Cost effectiveness will be calculated as man years. A group sequential design with first interim look at N = 235 will ensure both power and efficiency. DISCUSSION: Responding to the need for more rigorously designed trials examining the effectiveness of music therapy in autism spectrum disorders, this pragmatic trial sets out to generate findings that will be well generalisable to clinical practice. Addressing the issue of dose variation, this study's results will also provide information on the relevance of session frequency for therapy outcome. TRIAL REGISTRATION: Current Controlled Trials ISRCTN78923965. PMID- 22221671 TI - Squamous cell carcinoma in Barrett's esophagus: field effect versus metastasis. AB - Barrett's esophagus (BE) is a premalignant condition with an increased risk of developing esophageal adenocarcinoma (EAC). Risk factors for EAC overlap with those for esophageal squamous cell carcinoma (ESCC), but ESCC is surprisingly rare in BE. We report two cases of ESCC directly surrounded by BE. Both patients had a previous medical history of cancers, i.e., head and neck squamous cell carcinomas, and were using alcohol and smoking tobacco. Using immunohistochemistry for p63, CK5, CK7, and CDX2, it was confirmed that these carcinomas were pure squamous cell carcinomas, and not EACs or esophageal adenosquamous carcinomas arising from BE. Using TP53 mutation and loss of heterozygosity analysis, we established that the ESCCs in BE were not metastases of the previously diagnosed head and neck squamous cell carcinomas but de novo primary ESCCs. This study shows the strength of molecular analysis as an adjunct to the histopathologic diagnosis for distinguishing between metastases of prior cancers and primary cancers. Furthermore, these cases imply that presence of BE is not protective with regards to developing ESCC in the lower one third of the esophagus. We suggest that their ESCCs arose from islets of squamous epithelium in BE. PMID- 22221672 TI - Fish oil and 3-thia fatty acid have additive effects on lipid metabolism but antagonistic effects on oxidative damage when fed to rats for 50 weeks. AB - The 3-thia fatty acid tetradecylthioacetic acid (TTA) is a synthetic modified fatty acid, which, similar with dietary fish oil (FO), influences the regulation of lipid metabolism, the inflammatory response and redox status. This study was aimed to penetrate the difference in TTA's mode of action compared to FO in a long-term experiment (50 weeks of feeding). Male Wistar rats were fed a control, high-fat (25% w/v) diet or a high-fat diet supplemented with either TTA (0.375% w/v) or FO (10% w/v) or their combination. Plasma fatty acid composition, hepatic lipids and expression of relevant genes in the liver and biomarkers of oxidative damage to protein were assessed at the end point of the experiment. Both supplements given in combination demonstrated an additive effect on the decrease in plasma cholesterol levels. The FO diet alone led to removal of plasma cholesterol and a concurrent cholesterol accumulation in liver; however, with TTA cotreatment, the hepatic cholesterol level was significantly reduced. Dietary FO supplementation led to an increased oxidative damage, as seen by biomarkers of protein oxidation and lipoxidation. Tetradecylthioacetic acid administration reduced the levels of these biomarkers confirming its protective role against lipoxidation and protein oxidative damage. Our findings explore the lipid reducing effects of TTA and FO and demonstrate that these bioactive dietary compounds might act in a different manner. The experiment confirms the antioxidant capacity of TTA, showing an improvement in FO-induced oxidative stress. PMID- 22221673 TI - N-3 long-chain polyunsaturated fatty acids inhibit smooth muscle cell migration by modulating urokinase plasminogen activator receptor through MEK/ERK-dependent and -independent mechanisms. AB - Smooth muscle cell (SMC) migration is a major and complex feature of atherosclerosis and restenosis. N-3 long-chain polyunsaturated fatty acids (LCPUFAs) affect SMC migration; however, the mechanisms involved are unclear. This study investigated the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the MEK/ERK pathway and urokinase plasminogen activator receptor (uPAR) in relation to SMC migration. Transwell migration assays revealed that both EPA and DHA decreased cell migration. Western blotting and real-time reverse transcription polymerase chain reaction showed that n-3 LCPUFAs decreased uPAR expression, but not urokinase plasminogen activator (uPA) expression, without changing plasmin and uPA activity. DHA also inhibited the activation of the MEK/ERK signaling pathway, whereas EPA switched the SMC phenotype from synthetic to contractile. siRNA technology targeting uPAR expression showed that decreased uPAR led to a significant decrease in migration, demonstrating the role of uPAR on SMC migration. We also showed that MEK/ERK pathway activation was involved in the regulation of uPAR gene expression in SMCs. Our results suggest that n-3 LCPUFAs decrease SMC migration through the inhibition of uPAR expression, with DHA affecting its expression via the modulation of MEK/ERK signaling pathway, while EPA induces a change in SMC phenotype. This could represent another means by which to explain how n-3 LCPUFAs exert their preventive properties against atherosclerosis. PMID- 22221674 TI - Curcumin protects against thioacetamide-induced hepatic fibrosis by attenuating the inflammatory response and inducing apoptosis of damaged hepatocytes. AB - Inflammation and hepatic stellate cell (HSC) activation are the most crucial steps in the formation of hepatic fibrosis. Hepatocytes damaged by viral or bacterial infection, alcohol or toxic chemicals initiate an inflammatory response that activates collagen production by HSCs. Recent studies indicate curcumin has liver-protective effects due to its anti-inflammatory, antioxidant and anticancer activities; however, the mechanisms are not well understood. In this study, we show that curcumin protected against hepatic fibrosis in BALB/c mice in vivo by inhibiting HSC activation, inflammatory responses and inducing apoptosis of damaged hepatocytes. Using the thioacetamide (TAA)-induced hepatic fibrosis animal model, we found that curcumin treatment up-regulated P53 protein expression and Bax messenger RNA (mRNA) expression and down-regulated Bcl-2 mRNA expression. Together, these responses increased hepatocyte sensitivity to TAA induced cytotoxicity and forced the damaged cells to undergo apoptosis. Enhancing the tendency of damaged hepatocytes to undergo apoptosis may be the protective mechanism whereby curcumin suppresses inflammatory responses and hepatic fibrogenesis. These results provide a novel insight into the cause of hepatic fibrosis and the cytoprotective effects curcumin has on hepatic fibrosis suppression. PMID- 22221675 TI - Consumption of high-fat diet induces tumor progression and epithelial-mesenchymal transition of colorectal cancer in a mouse xenograft model. AB - Epidemiologic studies suggest that intake of high-fat diet (HFD) promotes colon carcinogenesis. Epithelial-mesenchymal transition (EMT) and inflammation play important roles during tumor progression of colorectal cancer (CRC). Oncogenic pathways such as phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR and mitogen activated protein kinase (MAPK)/ERK signaling cascades induce EMT and inflammation in cancer. No experimental evidence has been demonstrated regarding HFD-mediated tumor progression including EMT in CRC so far. Our results demonstrated that HFD consumption could induce tumor growth and progression, including EMT and inflammation, in a mouse xenograft tumor model. The molecular mechanisms were through activation of MAPK/ERK and PI3K/Akt/mTOR signaling pathways. HFD induced up-regulation of cyclooxygenase-2, cyclin D1 and proliferating cell nuclear antigen proteins concomitant with increases in expression of nuclear factor-kappaB p65 (RelA) and beta-catenin proteins. Surprisingly, HFD consumption could suppress p21(CIP1/WAF1) expression through increases in nuclear histone deacetylase complex (HDAC). Moreover, HFD could mediate the disassembly of E-cadherin adherent complex and the up-regulation of Vimentin and N-cadherin proteins in tumor tissues. Taken together, our novel findings support evidence for HFD-mediated modulation of HDAC activity and activation of oncogenic cascades, which involve EMT and inflammation in CRC, playing important roles in tumor growth and progression in a mouse xenograft model. PMID- 22221676 TI - Effects of physiological quercetin metabolites on interleukin-1beta-induced inducible NOS expression. AB - Cytokines released by inflammatory cells around the pancreatic islets are implicated in the pathogenesis of diabetes mellitus. Specifically, interleukin 1beta (IL-1beta) is known to be involved in islet beta-cell damage by activation of nuclear factor-kappaB (NF-kappaB)-mediated inducible nitric oxide synthase (iNOS) gene expression. Though most flavonoids are shown to have various beneficial effects, little is known about the anti-inflammatory effects of their metabolites. Therefore, we investigated the effects of quercetin and its metabolites quercetin 3'-sulfate, quercetin 3-glucuronide and isorhamnetin 3 glucuronide on IL-1beta-stimulated iNOS gene expression in RINm5F beta-cells. The nitrite level, iNOS protein and its mRNA expression levels and iNOS promoter activity were measured. In addition, IkappaBalpha protein phosphorylation, nuclear translocation of nuclear factor-kappaB (NF-kappaB) and NF-kappaB DNA binding activity were determined. Adenosine 5'-triphosphate disodium salt-induced insulin release was also measured. Quercetin significantly reduced IL-1beta induced nitrite production, iNOS protein and its mRNA expression levels, and it also inhibited IL-1beta-induced IkappaBalpha phosphorylation, NF-kappaB activation and iNOS promoter activity. Additionally, quercetin significantly restored the inhibition of insulin secretion by IL-1beta. Meanwhile, quercetin metabolites did not show any effect on IL-1beta-induced iNOS gene expression and also on insulin secretion. Therefore, in terms of iNOS expression mechanism, dietary ingestion of quercetin is unlikely to show anti-inflammatory effects in rat islet beta-cells exposed to IL-1beta. PMID- 22221677 TI - Adipose tissue proteomes of intrauterine growth-restricted piglets artificially reared on a high-protein neonatal formula. AB - The eventuality that adipose tissues adapt to neonatal nutrition in a way that may program later adiposity or obesity in adulthood is receiving increasing attention in neonatology. This study assessed the immediate effects of a high protein neonatal formula on proteome profiles of adipose tissues in newborn piglets with intrauterine growth restriction. Piglets (10th percentile) were fed milk replacers formulated to provide an adequate (AP) or a high (HP) protein supply from day 2 to the day prior weaning (day 28, n=5 per group). Adipocytes with small diameters were present in greater proportions in subcutaneous and perirenal adipose tissues from HP piglets compared with AP ones at this age. Two dimensional gel electrophoresis analysis of adipose tissue depots revealed a total of 32 protein spots being up- or down-regulated (P<.10) for HP piglets compared with AP piglets; 18 of them were unambiguously identified by mass spectrometry. These proteins were notably related to signal transduction (annexin 2), redox status (peroxiredoxin 6, glutathione S-transferase omega 1, cyclophilin A), carbohydrate metabolism (ribose-5-phosphate dehydrogenase, lactate dehydrogenase), amino acid metabolism (glutamate dehydrogenase 1) and cell cytoskeleton dynamics (dynactin and cofilin-1). Proteomic changes occurred mainly in dorsal subcutaneous adipose tissue, with the notable exception of annexin 1 involved in lipid metabolic process having a lower abundance in HP piglets for perirenal adipose tissue only. Together, modulation in those proteins could represent a novel starting point for elucidating catch-up fat growth observed in later life in growing animals having been fed HP formula. PMID- 22221678 TI - Risk assessment in pulmonary hypertension associated with heart failure and preserved ejection fraction. AB - BACKGROUND: Pulmonary hypertension (PH) is common in patients with left heart failure (HF), especially those with HF and preserved ejection fraction (HFpEF). However, there is limited data on risk stratification in these patients. METHODS: Baseline clinical and hemodynamic variables of 339 patients with World Health Organization (WHO) Group 2 PH, 90% of whom had HFpEF, were studied to derive a multivariate Cox proportional hazards model. A simplified prognostic risk score was created based on the outcome of all-cause mortality. Nine predictors, significant after stepwise multivariable regression (p < 0.05), were used to create the risk score. Components of the risk score were functional class, diastolic blood pressure, pulmonary artery saturation, interstitial lung disease, hypotension on initial presentation, right ventricular hypertrophy, diffusion capacity of the lung for carbon monoxide, and 2 serum creatinine variables (<= 0.9 mg/dl and >= 1.4 mg/dl). RESULTS: Overall 2-year survival was 73.8% +/- 2.4% in the derivation cohort, and 87.5% +/- 2.3%, 66.4% +/- 4.9%, and 24.4% +/- 6.7% for risk scores of 0 to 2, 3 to 4, and 5+, respectively (p < 0.0001 for the trend), with a C-index of 0.76 (95% confidence interval [CI], 0.71-0.81). The risk score was validated in 2 independent PH-HFpEF cohorts: 179 patients with a C index of 0.68 (95% CI, 0.55-0.80) and 117 patients with a C-index of 0.68 (95% CI, 0.53-0.83). For the 3 cohorts combined (N = 635), the overall C-index was 0.72 (95% CI 0.68-0.76). In all 3 cohorts individually and in the 3 cohorts combined, the risk score predicted death (hazard ratio, 1.4-1.6; p < 0.01). CONCLUSIONS: Several clinical factors independently predict death in PH-HFpEF confirmed by validation. A novel risk score composed of these factors can be used to determine prognosis and may be useful in making therapeutic decisions. PMID- 22221679 TI - Gas nitriding and subsequent oxidation of Ti-6Al-4V alloys. AB - Ti-6Al-4V alloys consisting of alpha-Ti grains and intergranular beta-Ti islands were nitrided at 850 degrees C for 1 to 12 h under a nitrogen pressure of 1 Pa. With increasing nitriding time, the Ti-N compound layer became thicker, and the alpha-Ti diffusion zone containing dissolved nitrogen became wider. In the Ti-N compound layer, the initially formed Ti2N became TiN as the nitriding progressed. The nitride layers were oxidized to rutile-TiO2 after oxidation at 700 degrees C for 10 h in air. PMID- 22221680 TI - Prolonged bleeding after exfoliation of a deciduous tooth in a patient with Glanzmann's thrombasthenia. PMID- 22221681 TI - Cross-kingdom interactions matter: fungal-mediated interactions structure an insect community on oak. AB - Although phytophagous insects and plant pathogens frequently share the same host plant, interactions among such phylogenetically distant taxa have received limited attention. Here, we place pathogens and insects in the context of a multitrophic-level community. Focusing on the invasive powdery mildew Erysiphe alphitoides and the insect community on oak (Quercus robur), we demonstrate that mildew-insect interactions may be mediated by both the host plant and by natural enemies, and that the trait-specific outcome of individual interactions can range from negative to positive. Moreover, mildew affects resource selection by insects, thereby modifying the distribution of a specialist herbivore at two spatial scales (within and among trees). Finally, a long-term survey suggests that species-specific responses to mildew scale up to generate landscape-level variation in the insect community structure. Overall, our results show that frequently overlooked cross-kingdom interactions may play a major role in structuring terrestrial plant-based communities. PMID- 22221682 TI - Inhalational anesthetic agents in postoperative cognitive dysfunction. PMID- 22221683 TI - Equal volumes of undiluted nalbuphine and lidocaine and normal diluted saline prevents nalbuphine-induced injection pain. AB - OBJECTIVES: To determine if the intravenous co-administration of equal volumes of lidocaine and nalbuphine, with undiluted normal saline, prevents injection pain caused by nalbuphine. METHODS: Eighty adult patients who were scheduled for minor surgeries under general anesthesia delivered via a laryngeal mask airway (LMA) were enrolled in this prospective, randomized, single-blind clinical trial. In the saline group (control) (n = 40), 1 mL (10 mg) nalbuphine was diluted with 9 mL normal saline. In the lidocaine group (experimental) (n = 40), 1 mL (10 mg) nalbuphine was diluted with 1 mL lidocaine (20 mg). The two respective nalbuphine solutions were injected into the cephalic vein at a rate of 20 mL/minute (0.33 mL/second). Pain scores were categorized into five grades. Pain responses upon intravenous injection of nalbuphine, site of cannulation, size of the catheter, and hemodynamic responses to nalbuphine were also recorded. RESULTS: Overall, the median pain score of patients in the lidocaine group was lower than that of the saline group (p < 0.001). In addition, the incidence of injection pain was lower in the lidocaine group than the saline group (2.5% vs. 30%, p = 0.001). CONCLUSION: A solution of equal volumes of lidocaine and nalbuphine can decrease intravenous nalbuphine-induced injection pain. PMID- 22221684 TI - Closed-loop isoflurane administration with bispectral index in open heart surgery: randomized controlled trial with manual control. AB - OBJECTIVE: Improved anesthetic agent delivery system (IAADS), a modification of closed-loop anesthesia delivery system (CLADS), is designed to deliver inhalational anesthetics and propofol through closed-loop control with bispectral index (BIS) as target. We compared the performance of IAADS with the manual control isoflurane administration during cardiac surgery. METHODS: Forty patients of ASA (American Society of Anesthesiologists) physical status class II-III, undergoing elective cardiac surgery with cardiopulmonary bypass (CPB) in a tertiary care hospital in India were randomized to receive isoflurane through a closed-loop system (IAADS group) or through a Tech 7 vaporizer adjusted manually (manual group) to achieve a target BIS of 50. Patients were induced with a propofol infusion and isoflurane was started after intubation. During CPB, patients received propofol; isoflurane was restarted after separation from CPB. The efficacy of IAADS in controlling depth of anesthesia and hemodynamic variations was compared with that of manual control. RESULTS: IAADS was able to maintain BIS within +/- 10 of target for significantly longer period (84.6 +/- 7.2% in IAADS group vs. 75.9 +/- 11.2 in manual group, p < 0.01). Both overall performance, as assessed by global score (p < 0.01), and precision, as judged by median absolute performance error (MDAPE) (p < 0.04), were significantly better in the IAADS group. The IAADS group required significantly less propofol for induction (1.3 +/- 0.4 mg/kg in IAADS vs. 1.6 +/- 0.5 mg/kg in manual, p < 0.05) and less isoflurane during maintenance of anesthesia (3.3 +/- 0.8 ml/h vs. 3.4 +/ 0.9 ml/h, p < 0.01). CONCLUSION: The present study proves the feasibility and efficacy of inhalation anesthetic administration through closed-loop control. This is the first system that has been developed to control intravenous and inhalational anesthetic agents in a closed-loop model using BIS. PMID- 22221685 TI - Use of laryngeal mask airway in children with upper respiratory tract infection, compared with face mask: randomized, single blind, clinical trial. AB - OBJECTIVE: The incidence of postoperative cough (primary outcome) and adverse respiratory events (secondary outcome) in children who received anesthesia by laryngeal mask airway (LMA) with children who received anesthesia by face mask (FM) was compared in a blind randomized trial with uncomplicated upper respiratory track infection (URI) undergoing general anesthesia. Previous studies of pediatric patients with URI receiving anesthesia by endotracheal tube have reported a greater number of anesthetic complications; however reports concerning adverse effects in pediatric patients with URI receiving anesthesia by LMA or FM are scanty. METHOD: For the present trial, 150 children with uncomplicated URI and requiring general anesthesia for ophthalmic procedures were enrolled. Once the severity of preoperative URI symptoms was stratified, the children were randomized to receive general anesthesia by FM or LMA. Anesthesia was induced with sevoflurane and nitrous oxide in oxygen (N(2)O in O(2)). Respiratory adverse events were evaluated peri- and post-operatively. RESULTS: The two groups did not differ in age, weight, American Society of Anesthesiologists (ASA) physical status, sex, duration of surgery or severity of URI symptoms. The incidences of cough (19% in LMA vs. 42% in FM), vomiting (4% in LMA vs. 12% in FM) and intervention to maintain the patency of the airway were statistically higher in the FM group (p<0.05). There were no differences between the two groups with respect to the incidences of apnea, laryngospasm, desaturation, bronchospasm, readmission and sore throat. CONCLUSION: In children with uncomplicated URI, the administration of inhalation anesthetics in general anesthesia by LMA is likely to cause fewer adverse events than the use of FM. PMID- 22221686 TI - Peribulbar block in 500 patients scheduled for eye procedures and treated with acetyl salicylic acid. AB - OBJECTIVES: No guidelines are available in France for peribulbar block for eye procedures. It is our hypothesis that continued use of acetyl salicylic acid for forestalling myocardial or cerebrovascular ischemic events does not increase the risk of hemorrhage, compared with discontinuation of its use in patients who undergo eye procedures under peribulbar block. METHODS: For this prospective control study we enrolled two groups of 500 patients scheduled for intra-ocular eye surgery requiring a peribulbar block. Patients treated with acetyl salicylic acid were included in group A (500 patients). Patients who had never been treated with acetyl salicylic acid constituted the control group (group B: 500 patients). Hemorrhages were graded as follows: 1=spot ecchymosis; 2=lid ecchymosis involving half of the lid surface area or less; 3=lid ecchymosis all around the eye, without increase in intra-ocular pressure; 4=retrobulbar hemorrhage with increased intraocular pressure. RESULTS: In group A, lid hemorrhages (grade 1) were observed in 30 patients (6.0%). No grade 2, 3 or 4 hemorrhages were encountered in this group. In group B, lid hemorrhage (grade 1) was observed in 20 patients (4.0%) and grade 2 in one patient (0.2 %), but no grade 3 or 4 hemorrhages were encountered. Statistical tests showed the absence of significance between both groups. CONCLUSION: We conclude that between the groups with and without pre-operative acetyl salicylic acid the occurrence rate of lid hemorrhage was not significant in peribulbar block. PMID- 22221687 TI - Biphasic effects of chronic intrathecal gabapentin administration on the expression of protein kinase C gamma in the spinal cord of neuropathic pain rats. AB - OBJECTIVES: Patients suffering from neuropathic pain are difficult to treat and many methods are used to resolve this issue. In this study, we used a model of neuropathic pain comprising rats with chronic constriction injury (CCI) on the left sciatic nerve to investigate the chronic effect of gabapentin via intrathecal administration. We also observed the expression of dorsal spinal protein kinase C gamma subunit (PKCgamma) and other pain-related molecules in the spinal area which included cyclooxygenase 2 (COX2), c-Fos and cyclic AMP dependent transcription factor (ATF3) in the neuropathic pain animals. METHODS: Male Sprague-Dawley (SD) rats (250-380 g) were randomly assigned to four groups, i.e., control, gabapentin (Gaba), MK801, and gabapentin plus MK801 (Gaba+M) groups. A PE-5 catheter was inserted into the lumbar spine area via the cervical spine area. CCI was performed the following day after the intrathecal catheter implant surgery. Gabapentin (1.05 MUmol/day) was then given the following day after CCI surgery. Intrathecal gabapentin was administrated for 14 consecutive days. Pain-related behavior was assessed every 2 days thereafter by measuring the latency of foot withdrawal elicited by noxious radiant heat or Von Frey microfilament applied to the hind-paw plantar surface. MK801 (30 MUg/day), an N methyl-D-aspartate (NMDA) receptor blocker, was also added for potential effect. The tissue of dorsal horn of the lumbar spine was harvested on the 14(th) day for the expression of COX2, c-Fos, ATF3 and PKCgamma with Western blotting, and positive finding protein was then checked on 7(th) day for further evaluation. RESULTS: The beneficial effect of intrathecal gabapentin of statistic significance on thermal duration and mechanical microfilament appeared after 7 day and 11-day consecutive treatment, respectively. Furthermore, the NMDA receptor blocker also potentiated the effect on the behavior of thermal and mechanical stimulations. Gabapentin had no effect on the expression of COX2, c Fos and ATF3. Interestingly, the expression of PKCgamma in the spinal cord was initially inhibited by gabapentin on the 7(th) day but was potentiated on the 14(th) day. CONCLUSIONS: Our results indicate that chronic intrathecal gabapentin has beneficial effects on the behaviors of both thermal and mechanical stimulations in the neuropathic pain animals and the NMDA blocker can potentiate this effect. Furthermore, gabapentin has biphasic effect on the expression of PKCgamma in the spinal cord on Day 7 and Day 14 for the model rats with CCI. PMID- 22221688 TI - Do inhalational anesthetics cause cognitive dysfunction? AB - Increasing evidence indicates that inhalational anesthetics may cause or increase the risk of developing postoperative cognitive dysfunction (POCD), especially in the elderly population. POCD may exist as a transient or long-term complication of surgery and anesthesia and is associated with reduced quality of life. There remains great discrepancy between clinical studies investigating the prevalence of POCD and inhalational anesthetics as many fail to show an association. However, numerous animal studies have suggested that inhalational anesthetics may alter cognitive function via amyloid beta accumulation, modified neurotransmission, synaptic changes and dysregulated calcium homeostasis. Other factors such as neuroinflammation and pro-inflammatory cytokines may also play a role. This paper reviews the role of inhalational anesthetics in the etiology and underlying mechanisms that result in POCD. PMID- 22221689 TI - Hemodynamic monitoring and outcome-a physiological appraisal. AB - Hemodynamic monitoring provides us with refined details about the cardiovascular system. In spite of increased availability of the monitoring process and monitoring equipment, hemodynamic monitoring has not significantly improved survival outcome. Care providers should be cognizant of the role of the cardiovascular system and its importance in oxygen delivery to the cells in order to sustain life. Effective hemodynamic monitoring should be able to delineate how well the system is performing in carrying out this role. Different hemodynamic monitors serve in this role to a different extent; some provide very little information on this. The cardiovascular system is only one of the many systems that need to function optimally for survival; others of equal importance include the integrity of the airway, the breathing process, the adequacy of hemoglobin level, and the health of the tissue bed, especially in the brain and the heart. Advances in hemodynamic monitoring with focus on oxygen delivery at the cellular level may ultimately provide the edge to effective monitoring that can impact outcome. PMID- 22221690 TI - Trachway intubating stylet for tracheal intubation in an ankylosing spondylitis patient undergoing total hip replacement under general anesthesia. AB - The Trachway is a new device which provides better glottic view than conventional direct laryngoscopy during tracheal intubation. This intubating stylet consists of a camera on the distal tip of the style, with a monitor attached to the rechargeable handle, so that it can overcome the difficulty of limited neck motion and mouth opening in tracheal intubation. We present here a 54-year-old man with ankylosing spondylitis, scheduled to undergo total hip replacement. Pre operative airway assessment revealed a recognized difficult airway. The Trachway was successfully used for oral tracheal intubation at the first attempt. The Trachway can be an alternative choice for intubation in ankylosing spondylitis patients. PMID- 22221691 TI - Interference of patent blue dye with pulse oximetry readings, methemoglobin measurements, and blue urine in sentinel lymph node mapping: a case report and review of the literature. AB - Patent blue (PB) dye has been successfully used worldwide in breast and cervix surgeries with few complications. Interference of oxyhemoglobin saturation reading by pulse oximetry (SpO(2)) and methemoglobinemia, from injection of PB dye, have rarely been reported in breast and cervix surgeries. We report here the first case of interference of SpO(2) reading, advent of methemoglobinemia, and blue urine from the use of PB dye, which occurred concurrently in a female undergoing bilateral modified radical mastectomy. The unexpected events might be a consequence of excessive administration of PB dye. We also reviewed the published discourses in literature on the adverse effects of PB dye. PMID- 22221692 TI - Incidence of cardiac arrest increases with the indiscriminate use of dexmedetomidine: a case series and review of published case reports. AB - Dexmedetomidine has predictable, complex, and negative cardiovascular effects that lead to additional adverse effects such as bradycardia and hypotension in up to 42% of patients and might cause profound left ventricular dysfunction and refractory shock. Usually, these temporary effects can be successfully counteracted with atropine, ephedrine, and volume supplementation. Clinicians need to be well informed about the potential of dexmedetomidine to cause bradycardia, which may progress to pulseless electrical activity, particularly in patients older than 50 years and patients with cardiac abnormalities. Here, we report the clinical characteristics of six patients who were scheduled for various neurosurgical procedures within a period of three months and suffered from cardiac arrest following dexmedetomidine administration. We urge clinicians to take caution against the negative effects of dexmedetomidine, especially when it is used in patients older than 50 years with underlying cardiac disease and in combination with cardiodepressant drugs. PMID- 22221693 TI - The impact of uniform and mixed species blood meals on the fitness of the mosquito vector Anopheles gambiae s.s: does a specialist pay for diversifying its host species diet? AB - We investigated the fitness consequences of specialization in an organism whose host choice has an immense impact on human health: the African malaria vector Anopheles gambiae s.s. We tested whether this mosquito's specialism on humans can be attributed to the relative fitness benefits of specialist vs. generalist feeding strategies by contrasting their fecundity and survival on human-only and mixed host diets consisting of blood meals from humans and animals. When given only one blood meal, An. gambiae s.s. survived significantly longer on human and bovine blood, than on canine or avian blood. However, when blood fed repeatedly, there was no evidence that the fitness of An. gambiae s.s. fed a human-only diet was greater than those fed generalist diets. This suggests that the adoption of generalist host feeding strategies in An. gambiae s.s. is not constrained by intraspecific variation in the resource quality of blood from other available host species. PMID- 22221694 TI - Cost-effectiveness analysis on the surveillance for hepatocellular carcinoma in liver cirrhosis patients using contrast-enhanced ultrasonography. AB - AIM: Sonazoid is a new contrast agent for ultrasonography (US). Contrast enhanced ultrasonography (CEUS) using Sonazoid enables Kupffer imaging, which improves the sensitivity of hepatocellular carcinoma (HCC) detection. However, there are no studies on the cost-effectiveness of HCC surveillance using Sonazoid. METHODS: We constructed a Markov model simulating the natural history of HCV-related liver cirrhosis (LC) patients, and compared three strategies (no surveillance, US surveillance and CEUS surveillance). The transition probability and cost data were obtained from published data. The simulation and analysis were performed using TreeAge pro 2009 software. RESULTS: When compared to the no surveillance group, the US and CEUS surveillance groups increased the life expectancy by 1.67 and 1.99 quality-adjusted life-years (QALY), respectively, and the incremental cost effectiveness ratio (ICER) were 17 296 $US/QALY and 18 384 $US/QALY, respectively. These results were both less than the commonly-accepted threshold of $US 50 000/QALY. Even if the CEUS surveillance group was compared with the US surveillance group, the ICER was $US 24 250 and thus cost-effective. Sensitivity analysis showed that the annual incidence of HCC and CEUS sensitivity were two critical parameters. However, when the annual incidence of HCC is more than 2% and/or the CEUS sensitivity is more than 80%, the ICER was also cost effective. CONCLUSIONS: Contrast-enhanced ultrasonography surveillance for HCC is a cost-effective strategy for LC patients and gains their longest additional life years, with similar degree of ICER in the US surveillance group. CEUS surveillance using Sonazoid is expected to be used not only in Japan, but also world-wide. PMID- 22221696 TI - The Chinese version of the Myocardial Infarction Dimensional Assessment Scale (MIDAS): Mokken scaling. AB - BACKGROUND: Hierarchical scales are very useful in clinical practice due to their ability to discriminate precisely between individuals, and the original English version of the Myocardial Infarction Dimensional Assessment Scale has been shown to contain a hierarchy of items. The purpose of this study was to analyse a Mandarin Chinese translation of the Myocardial Infarction Dimensional Assessment Scale for a hierarchy of items according to the criteria of Mokken scaling. Data from 180 Chinese participants who completed the Chinese translation of the Myocardial Infarction Dimensional Assessment Scale were analysed using the Mokken Scaling Procedure and the 'R' statistical programme using the diagnostics available in these programmes. Correlation between Mandarin Chinese items and a Chinese translation of the Short Form (36) Health Survey was also analysed. FINDINGS: Fifteen items from the Mandarin Chinese Myocardial Infarction Dimensional Assessment Scale were retained in a strong and reliable Mokken scale; invariant item ordering was not evident and the Mokken scaled items of the Chinese Myocardial Infarction Dimensional Assessment Scale correlated with the Short Form (36) Health Survey. CONCLUSIONS: Items from the Mandarin Chinese Myocardial Infarction Dimensional Assessment Scale form a Mokken scale and this offers further insight into how the items of the Myocardial Infarction Dimensional Assessment Scale relate to the measurement of health-related quality of life people with a myocardial infarction. PMID- 22221695 TI - Essential role of protein tyrosine phosphatase 1B in obesity-induced inflammation and peripheral insulin resistance during aging. AB - Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes (T2DM). In this study, we have evaluated the role of PTP1B in the development of aging-associated obesity, inflammation, and peripheral insulin resistance by assessing metabolic parameters at 3 and 16 months in PTP1B(-/-) mice maintained on mixed genetic background (C57Bl/6J * 129Sv/J). Whereas fat mass and adipocyte size were increased in wild type control mice at 16 months, these parameters did not change with aging in PTP1B(-/-) mice. Increased levels of pro-inflammatory cytokines, crown-like structures, and hypoxia-inducible factor (HIF)-1alpha were observed only in adipose tissue from 16-month-old wild-type mice. Similarly, islet hyperplasia and hyperinsulinemia were observed in wild-type mice with aging-associated obesity, but not in PTP1B(-/-) animals. Leanness in 16-month-old PTP1B(-/-) mice was associated with increased energy expenditure. Whole-body insulin sensitivity decreased in 16-month-old control mice; however, studies with the hyperinsulinemic-euglycemic clamp revealed that PTP1B deficiency prevented this obesity-related decreased peripheral insulin sensitivity. At a molecular level, PTP1B expression and enzymatic activity were up-regulated in liver and muscle of 16-month-old wild-type mice as were the activation of stress kinases and the expression of p53. Conversely, insulin receptor-mediated Akt/Foxo1 signaling was attenuated in these aged control mice. Collectively, these data implicate PTP1B in the development of inflammation and insulin resistance associated with obesity during aging and suggest that inhibition of this phosphatase by therapeutic strategies might protect against age-dependent T2DM. PMID- 22221697 TI - Relative renal function does not improve after relieving chronic renal obstruction. AB - Study Type - Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Technetium-99m MAG3 renography can be used to quantify relative renal function (RRF). Deterioration of renal function occurs with chronic obstruction. Small studies have previously shown that RRF is not improved in adult patients after pyeloplasty. Some studies have suggested that patients with higher preoperative RRF are more likely to improve. To our knowledge, these data represent the largest review of cases related to this subject. This study verifies past studies' assertions that RRF does not improve after relief of chronic renal obstruction. Using multivariable analysis, we identify lower age and lower preoperative RRF as predictors of >7% improvement in RRF. These data suggest that the aim of relieving obstruction should be to maintain RRF and alleviate symptoms, but not to seek improvement in overall renal function. OBJECTIVE: To determine the change in relative renal function (RRF) after relief of chronic obstruction in adults. PATIENTS AND METHODS: We retrospectively identified 85 adult patients who underwent scintigraphic diuretic renography before and after an intervention to relieve chronic unilateral renal obstruction. Patients were stratified into groups of low (<20%), medium (20-40%) and high (>40%) preoperative RRF in the obstructed kidney. Each group was assessed for change in RRF after relief of obstruction. We performed multivariable logistic regression analysis to determine whether age and pre procedural RRF predicted a >7% improvement in RRF, controlling for medical comorbidities and type of obstruction. RESULTS: The mean (sd) patient age was 43.6 (16.8) years and 66% of patients were female. The mean (sd) pre- and postoperative RRF values were not significantly different (37.6 [12.3] % vs 38.4 [13.6] %; P = 0.31). Patients stratified by low, medium and high preoperative function showed no significant change in postoperative RRF (P = 0.53, 0.39 and 0.77, respectively). In multivariable logistic regression analysis, younger age (odds ratio [OR] 0.90, 95% confidence interval [CI] 0.83-0.98) and lower preoperative RRF (OR 0.90, 95% CI 0.83-0.97) predicted improvement in RRF of >7%, after adjustment. CONCLUSIONS: RRF does not significantly increase after relief of chronic obstruction. The goals of relieving chronic renal obstruction should be to maintain renal function and relieve symptoms, but not to regain renal function. PMID- 22221698 TI - Effects of NiO nanoparticles on the magnetic properties and diffuse phase transition of BZT/NiO composites. AB - A new composite system, Ba(Zr0.07Ti0.93)O3 (BZT93) ceramic/NiO nanoparticles, was fabricated to investigate the effect of NiO nanoparticles on the properties of these composites. M-H hysteresis loops showed an improvement in the magnetic behavior for higher NiO content samples plus modified ferroelectric properties. However, the 1 vol.% samples showed the optimum ferroelectric and ferromagnetic properties. Examination of the dielectric spectra showed that the NiO additive promoted a diffuse phase transition, and the two phase transition temperatures, as observed for BZT93, merged into a single phase transition temperature for the composite samples. PMID- 22221699 TI - Loss of heterozygosity of the PTCH gene in ameloblastoma. AB - Ameloblastoma is a locally aggressive benign neoplasm derived from odontogenic epithelium, with high recurrence rates. Alterations in the Sonic Hedgehog signaling pathway, including PTCH gene mutations, have been associated with the pathogenesis of some odontogenic tumors. The purpose of the present study was to assess loss of heterozygosity at the PTCH locus in ameloblastoma. Twelve ameloblastomas were included, and loss of heterozygosity was assessed by using 3 microsatellite markers D9S252, D9S127, and D9S287 and 3 single-nucleotide polymorphisms rs112794371, rs111446700, and rs357564, all located at the PTCH gene locus. Furthermore, we investigated GLI1 and GLI2 transcription levels by quantitative reverse transcription polymerase chain reaction in 8 ameloblastomas and, concomitantly, PTCH protein levels by immunohistochemical analysis. Loss of heterozygosity at 9q21.33-9q.31 was detected in 4 (40.0%) of 10 informative cases of ameloblastoma. All 8 analyzed samples expressed GLI1 messenger RNA and 7 cases GLI2 messenger RNA. Interestingly, loss of heterozygosity at the PTCH locus was not correlated with GLI1 or GLI2 transcription levels, nor was there any correlation with PTCH protein expression. In conclusion, our findings suggest that loss of heterozygosity in the PTCH region may be relevant to the pathogenesis of ameloblastoma but may target a different gene than PTCH. PMID- 22221700 TI - Significance of E-cadherin, beta-catenin, and vimentin expression as postoperative prognosis indicators in cervical squamous cell carcinoma. AB - Although early-stage cervical cancer can be treated by surgery, distant metastases can be life threatening. It has been a challenge to identify reliable biomarkers as indicators of metastasis or poor prognosis. We investigated the prognostic impact of vimentin, E-cadherin, and beta-catenin expression measured by immunohistochemistry staining in samples from 135 patients with clinical stage I or II cervical squamous cell cancer and in normal cervical tissues from 55 patients who underwent hysterectomy for reasons other than neoplasia. Down regulation of E-cadherin and beta-catenin was positively related to histologic differentiation (P < .001), metastasis (P < .001), and recurrence (P < .001), whereas up-regulation of vimentin was inversely related to histologic differentiation, metastasis, and recurrence (P < .0001, .020, and .000, respectively). In univariate Cox regression analysis, high expression of E cadherin or beta-catenin was a positive prognostic indicator for overall survival (P < .001 and P < .001, respectively), whereas high expression of vimentin was a negative indicator (P < .001). In multivariate Cox regression analysis, high expression of E-cadherin was a positive prognostic indicator for overall survival (P = .002), whereas high expression of vimentin was a negative indicator (P = .034). The expression of E-cadherin and vimentin was associated with survival, and the 2 proteins were independent prognostic factors in univariate and multivariate analyses. The combination of a decrease of E-cadherin and an increase in vimentin might be a valuable survival indictor in cervical squamous cell cancer. PMID- 22221701 TI - Composite ganglioglioma/dysembryoplastic neuroepithelial tumor: a clinicopathologic study of 8 cases. AB - Ganglioglioma and dysembryoplastic neuroepithelial tumor are both low-grade glioneuronal neoplasms that most commonly occur in association with chronic epilepsy. Rare cases of tumors with composite features of ganglioglioma and dysembryoplastic neuroepithelial tumor have been reported. We retrospectively reviewed the clinicopathologic features of 8 composite tumors (7 were female; median age, 20 years). All patients had chronic epilepsy and had tumors in either the temporal or the frontal lobe. Six patients are currently seizure-free (follow up: median, 90 months). All tumors were multinodular. Some nodules had distinct features of each tumor type (range, 5%-85% of the tumor). Seven tumors contained nodules with mixed features of both tumor types. Five of 7 evaluable tumors demonstrated adjacent focal cortical dysplasia (Palmini type I). Mitotic activity, vascular proliferation, or necrosis was not observed in any of the tumors. Three tumors demonstrated focal meningeal extension. Composite tumors commonly arise in the temporal lobe in young patients with chronic epilepsy; they appear to behave as a World Health Organization grade I neoplasm. Histologically, these multinodular tumors appear to maintain distinct areas with features of each tumor and foci where the 2 patterns are merged. A subset of composite tumors are associated with adjacent focal cortical dysplasia. PMID- 22221703 TI - HMGA gene rearrangement is a recurrent somatic alteration in polypoid endometriosis. AB - The pathogenesis of endometriosis is unclear, and several genetic, endocrine, immune, and environmental agents have been evaluated with no putative causative factors identified. Here, we show somatic genetic alterations involving HMGA1 (6p21) and HMGA2 (12q15) in 3 cases of polypoid endometriosis. The lesions involved the small bowel mesentery and perirectal soft tissue in 1 case and the posterior vaginal fornix and sigmoid colon serosa in 2 other cases, respectively. All had a polypoid configuration with cystically dilated irregular glands and fibrotic stroma, containing thick-walled vessels. Conventional cytogenetic analysis of 1 case showed 46,XX,t(5;12)(q13;q15) in all metaphases. Fluorescence in situ hybridization studies confirmed the balanced rearrangement of HMGA2. HMGA1 rearrangements were present in 2 additional cases. Rearrangements were exclusively found in the stromal component but not in the glandular component. These findings suggest that HMGA rearrangements likely contribute to the pathogenesis of endometriosis. However, additional studies are needed to better define the biologic role of this genetic alteration. PMID- 22221702 TI - Serotonin expression in pancreatic neuroendocrine tumors correlates with a trabecular histologic pattern and large duct involvement. AB - Pancreatic neuroendocrine tumors with prominent stromal fibrosis are often clinically, radiographically, and grossly indistinguishable from ductal adenocarcinoma. We recently described a small series of fibrotic pancreatic neuroendocrine tumors that express serotonin. To understand better the relationship between histopathologic patterns and serotonin expression, we reviewed 361 pancreatic neuroendocrine tumors to identify those with prominent stromal fibrosis exceeding 30% of total tumor area. We identified 52 cases and immunolabeled these neoplasms with antibodies to serotonin and Ki-67. Two predominant histologic subtypes were identified: 14 (26.9%) of 52 had a trabecular or trabecular-glandular cellular pattern with interspersed fibrosis, whereas 38 (73.1%) of 52 had solid architecture. Of the 52, 14 (26.9%) pancreatic neuroendocrine tumors showed at least focal serotonin immunoreactivity. Tumors with predominantly trabecular architecture were significantly more likely to express serotonin than those with solid architecture (P < .01). Only 2 of 34 pancreatic neuroendocrine tumors with fibrosis less than 30% of total tumor area expressed serotonin. The 14 serotonin-expressing tumors were less likely to have lymph node metastases (P = .016) and more likely to involve large pancreatic ducts (P < .01) than were the 38 serotonin-negative tumors. The serotonin expressing tumors were also found in a younger patient population (P < .01). There was no significant association of serotonin immunoreactivity with Ki-67 proliferation index, tumor size, or distant metastases. Our data demonstrate a strong correlation between trabecular architecture and serotonin immunoreactivity in pancreatic neuroendocrine tumors with stromal fibrosis. Serotonin-expressing tumors are also less likely to have lymph node metastases and more likely to involve large pancreatic ducts. PMID- 22221704 TI - Factors associated with residual disease after initial breast-conserving surgery for ductal carcinoma in situ. AB - Breast-conserving surgery with radiation therapy has become a standard treatment option in women with localized ductal carcinoma in situ. Re-excision is common in breast-conserving surgery, partly due to lack of consensus on what might constitute an adequate margin. In this study, we aimed to identify potential predictive factors for presence/absence of residual disease after initial breast conserving surgery. Of 232 cases with a diagnosis of ductal carcinoma in situ without invasive carcinoma at initial biopsy between 2005 and 2009, 108 patients underwent breast-conserving surgery, of which 46 had re-excisions due to close margins (<= 2 mm). The notable features significantly associated with ductal carcinoma in situ residuum (19/46; 41%) on univariate logistic regression analysis included the number of close margins, the percentage of sections with ductal carcinoma in situ, and the number of duct spaces with ductal carcinoma in situ (no. of ductal carcinoma in situ ducts) at close margins. Only the percentage of sections with ductal carcinoma in situ remained a significant factor associated with outcomes on multivariate analysis, whereas the number of ductal carcinoma in situ ducts at close margins held borderline predictive value (P = .054). Furthermore, logistic regression and classification and regression tree analysis using the 10-fold cross validation method revealed optimal predicting accuracy by using the 3 significant factors in univariate analysis. The final decision tree was constructed by using the number of ductal carcinoma in situ ducts at close margins and the percentage of sections with ductal carcinoma in situ. Thus, these 2 factors represent the most powerful predictors for residual disease on re-excision. Optimal discriminatory power for prediction of absence of residual disease was achieved with cutoffs of 18 ductal carcinoma in situ ducts at close margins and 51.3% sections with ductal carcinoma in situ. PMID- 22221705 TI - Mantle cell lymphoma as a component of composite lymphoma: clinicopathologic parameters and biologic implications. AB - Composite lymphoma is a rare circumstance in which 2 or more distinct types of lymphoma occur in a single anatomical location. Although composite lymphoma has been increasingly identified with the advent of molecular genetic techniques, this topic has only rarely been a specific focus of the medical scientific literature. In this review, we focus on mantle cell lymphoma occurring as a major pathologic component of composite lymphoma and emphasize the clinicopathologic features of these tumors and associated biologic implications. To date, 26 cases of composite lymphoma including a component of mantle cell lymphoma have been previously published. Issues of clonal relatedness between the individual lymphoma components and emerging biologic implications as well as potential diagnostic pitfalls are evaluated. PMID- 22221706 TI - Foamy gland adenocarcinoma of the prostate: incidence, Gleason grade, and early clinical outcome. AB - Foamy gland carcinoma is a variant of prostatic acinar adenocarcinoma characterized by abundant foamy cytoplasm and often pyknotic nuclei. Limited data exist regarding outcome and the clinicopathologic attributes of this variant. We screened 477 radical prostatectomies for foamy gland carcinoma to determine the incidence, amount, and Gleason grade/score of foamy gland carcinoma within the prostate. Time until prostate-specific antigen biochemical recurrence after radical prostatectomy was compared for both foamy and control/nonfoamy cases. For validation of incidence, Gleason grade, and pathologic stage, a second series of 100 consecutive radical prostatectomies was screened for foamy gland carcinoma. Foamy gland carcinoma was found in 69 (14.5%) of 477 cases. The median Gleason score of the foamy component was 7, which was not significantly different from the Gleason score of the nonfoamy component within those cases or the 408 nonfoamy cases. The most common Gleason score was 7 (44/69). There was no difference between foamy gland and nonfoamy gland cases in recurrence rate (23% versus 22%) or the average time to prostate-specific antigen recurrence (130 versus 151 months). In the second series, foamy gland carcinoma was found in 23% of cases and had a median Gleason score of 7; and the most common Gleason score was 7 (11/23). Foamy gland carcinoma exists in a significant subset of prostatic carcinomas. This variant does not appear to harbor a different prognosis compared with usual acinar adenocarcinoma, but diagnostic recognition of foamy gland carcinoma is important because there is a Gleason grade 4 element in the majority of cases. PMID- 22221707 TI - Identification of two novel HLA-A*02 variants, A*02:319 and A*02:01:64, in two Taiwanese marrow stem cell donors by sequence-based typing. AB - We report here two novel variants of HLA-A*02 allele, A*02:319 and A*02:01:64, discovered in two Taiwanese unrelated volunteer bone marrow donors by sequence based typing (SBT) method. The DNA sequence of A*02:319 is identical to A*02:07 in exons 2 and 3 but varies with one nucleotide at codon 9 (TTC->TCC). The variation caused one amino acid substitution at residue 9 (F->S). On the other hand, the DNA sequence of A*02:01:64 is identical to the sequence of A*02:01:01:01 in exons 2 and 3 except a silent mutation at codon 114 (CAC->CAT). The probable HLA-A, HLA-B and HLA-DRB1 haplotypes in association with A*02:319 and A*02:01:64 were deduced as A*02:319-B*46:01-DRB1*04 and A*02:01:64-B*38:02 DRB1*16:02, respectively. PMID- 22221708 TI - How the DNA damage response determines the fate of HTLV-1 Tax-expressing cells. AB - How the Human T lymphotropic virus type 1 (HTLV-1) Tax protein stimulates proliferation while triggering cell cycle arrest and senescence remains puzzling. There is also a debate about the ability of Tax to activate or inhibit the DNA damage response. Here, we comment on these different activities and propose a conceptual rationale for the apparently conflicting observations. PMID- 22221709 TI - The relationship between small-scale care and activity involvement of residents with dementia. AB - BACKGROUND: Nursing home care for people with dementia is increasingly organized in small-scale care settings. This study focuses on the question of how small scale care is related to the overall activity involvement of residents with dementia, and their involvement in different types of activities. As several studies have indicated, activity involvement is important for the quality of life of residents. METHODS: Data were derived from the first measurement cycle (2008/2009) of the Living Arrangements for people with Dementia study, in which 136 care facilities and 1,327 residents participated. The relationship between two indicators of small-scale dementia care (group living home care characteristics, and the total number of residents with dementia in the facility) and activity involvement (Activity Pursuit Patterns of the Resident Assessment Instrument Minimum Data Set) were studied with multilevel multiple regression analyses. All analyses were adjusted for the residents' age, sex, neuropsychiatric symptoms, and dependency on the activities of daily living. RESULTS: Residents of care facilities with more group living home care characteristics were more involved in overall and preferred activities. Furthermore, they were involved in more diverse activities. Overall, no relationship was found between the number of residents at the facility and activity involvement. CONCLUSIONS: These results indicate that small-scale dementia care has a positive effect on activity involvement of residents. The current study also sheds light on the lack of activity involvement of many residents with dementia, especially those who are older, male, and with higher dependency. PMID- 22221710 TI - Real-time PCR and NASBA for rapid and sensitive detection of Vibrio cholerae in ballast water. AB - Transport of ballast water is one major factor in the transmission of aquatic organisms, including pathogenic bacteria. The IMO-guidelines of the Convention for the Control and Management of Ships' Ballast Water and Sediments, states that ships are to discharge <1 CFU per 100 ml ballast water of toxigenic Vibrio cholerae, emphasizing the need to establish test methods. To our knowledge, there are no methods sensitive and rapid enough available for cholera surveillance of ballast water. In this study real-time PCR and NASBA methods have been evaluated to specifically detect 1 CFU/100ml of V. cholerae in ballast water. Ballast water samples spiked with V. cholerae cells were filtered and enriched in alkaline peptone water before PCR or NASBA detection. The entire method, including sample preparation and analysis was performed within 7 h, and has the potential to be used for analysis of ballast water for inspection and enforcement control. PMID- 22221711 TI - Effect of complexing agents on the electrochemical performance of LiFePO4/C prepared by sol-gel method. AB - LiFePO4/C is synthesized via sol-gel method using Fe3+ as iron sources and different complexing agents, followed by sintering at high temperature for crystallization. The amount of carbon in these composites is less than 6.8 wt.%, and the X-ray diffraction experiment confirms that all samples are pure single phase indexed with the orthorhombic Pnma space group. The particle size of the LiFePO4/C synthesized by acetic acid as a complexing agent is very fine with a size of 200 nm. The electrochemical performance of this material, including reversible capacity, cycle number, and charge-discharge characteristics, is better than those of LiFePO4/C synthesized by other complexing agents. The cell of this sample can deliver a discharge capacity of 161.1 mAh g-1 at the first cycle. After 30 cycles, the capacity decreases to 157.5 mAh g-1, and the capacity fading rate is 2.2%. The mechanism is studied to explain the effect of a complexing agent on the synthesis of LiFePO4/C by sol-gel method. The results show that the complexing agent with a low stability constant may be proper for the synthetic process of LiFePO4/C via sol-gel method. PMID- 22221712 TI - [Perception of objects and scenes in age-related macular degeneration]. AB - Vision related quality of life questionnaires suggest that patients with AMD exhibit difficulties in finding objects and in mobility. In the natural environment, objects seldom appear in isolation. They appear in a spatial context which may obscure them in part or place obstacles in the patient's path. Furthermore, the luminance of a natural scene varies as a function of the hour of the day and the light source, which can alter perception. This study aims to evaluate recognition of objects and natural scenes by patients with AMD, by using photographs of such scenes. Studies demonstrate that AMD patients are able to categorize scenes as nature scenes or urban scenes and to discriminate indoor from outdoor scenes with a high degree of precision. They detect objects better in isolation, in color, or against a white background than in their natural contexts. These patients encounter more difficulties than normally sighted individuals in detecting objects in a low-contrast, black-and-white scene. These results may have implications for rehabilitation, for layout of texts and magazines for the reading-impaired and for the rearrangement of the spatial environment of older AMD patients in order to facilitate mobility, finding objects and reducing the risk of falls. PMID- 22221713 TI - [Orbital cellulitis]. AB - Orbital cellulitis is uncommon in ophthalmologic practice. The majority of cases arise from direct spread of sinus infection or eyelid infection. Clinically, orbital cellulitis is divided into two forms: the preseptal form, anterior to the orbital septum, and the retroseptal form, posterior to the orbital septum. Management and prognosis differ widely between the two types. The retroseptal form or "true" orbital cellulitis is a severe disease with potentially disastrous consequences for vision and survival. Clinical examination and urgent CT scanning are indispensable for correct diagnosis, evaluation of severity, surgical planning and antibiotic selection. PMID- 22221715 TI - Fixation and partitioning of heavy metals in slag after incineration of sewage sludge. AB - Fixation of heavy metals in the slag produced during incineration of sewage sludge will reduce emission of the metals to the atmosphere and make the incineration process more environmentally friendly. The effects of incineration conditions (incineration temperature 500-1100 degrees C, furnace residence time 0 60min, mass fraction of water in the sludge 0-75%) on the fixation rates and species partitioning of Cd, Pb, Cr, Cu, Zn, Mn and Ni in slag were investigated. When the incineration temperature was increased from 500 to 1100 degrees C, the fixation rate of Cd decreased from 87% to 49%, while the fixation rates of Cu and Mn were stable. The maximum fixation rates for Pb and Zn and for Ni and Cr were reached at 900 and 1100 degrees C, respectively. The fixation rates of Cu, Ni, Cd, Cr and Zn decreased as the residence time increased. With a 20min residence time, the fixation rates of Pb and Mn were low. The maximum fixation rates of Ni, Mn, Zn, Cu and Cr were achieved when the mass fraction of water in the sludge was 55%. The fixation rate of Cd decreased as the water mass fraction increased, while the fixation rate of Pb increased. Partitioning analysis of the metals contained in the slag showed that increasing the incineration temperature and residence time promoted complete oxidation of the metals. This reduced the non residual fractions of the metals, which would lower the bioavailability of the metals. The mass fraction of water in the sludge had little effect on the partitioning of the metals. Correlation analysis indicated that the fixation rates of heavy metals in the sludge and the forms of heavy metals in the incinerator slag could be controlled by optimization of the incineration conditions. These results show how the bioavailability of the metals can be reduced for environmentally friendly disposal of the incinerator slag. PMID- 22221716 TI - Positive emotional health and diabetes care: concepts, measurement, and clinical implications. AB - BACKGROUND: Numerous studies describe the effect of emotional problems, including diabetes-related distress and depression, on diabetes outcomes. Little attention has been devoted to positive emotional health and its potential role in facilitating patients' self-management and improved outcomes. OBJECTIVE: This review describes the conceptualization and measurement of three empirically tested aspects of positive emotional health (well-being, positive affect, resilience) in the diabetes literature and their relationship to diabetes outcomes. METHOD: A literature review was conducted using PubMed and the Cochrane Library databases from 1970 to January 2011 to identify studies focused on well being, positive affect, and resilience in diabetes patients. RESULTS: Twenty-two studies were identified based on our inclusion criteria. Well-being studies were least likely to include conceptualizations and relied on two primary measurement instruments compared to more heterogeneous presentations found in positive affect and resilience studies. All three aspects of positive emotional health were linked to health-related outcomes and self-management. CONCLUSION: Positive emotional health may facilitate chronic care self-management and improved health outcomes. We present a model to guide future research and intervention development efforts designed to enhance positive emotional health. PMID- 22221717 TI - Lewd, crude, and rude behavior: the impact of manners and etiquette in the general hospital. AB - BACKGROUND: Lewd, crude, and rude behaviors of patients and staff members have the potential to complicate care; unfortunately, the medical literature on manners and etiquette is sparse. OBJECTIVE: We sought to understand the impact of lewd, crude, and rude behaviors in the general hospital and to provide a context in which to educate clinicians about the management of troublesome behaviors of patients and staff members. METHOD: We reviewed the history of etiquette in the general hospital, and discuss the ethical ramifications and clinical management of inappropriate behaviors. RESULTS: Lewd, crude, and rude language and behaviors are often heard and seen in the general hospital; such behaviors can be understood in a biopsychosocial context. CONCLUSIONS: Teaching trainees about manners and etiquette can help them identify and manage offensive behaviors and can facilitate the provision of effective and ethical care. PMID- 22221719 TI - Clinical, sociodemographic, and psychological correlates of health-related quality of life in chronic hemodialysis patients. AB - BACKGROUND: Physical comorbidities and depression are associated with poor health related quality of life (HRQoL) in patients undergoing chronic hemodialysis, but little is known about the impact of psychological determinants such as coping strategies in this association. This study examined the relation between psychosocial factors, particularly health-related locus of control (HLOC) and quality of life (QoL) in chronic hemodialisys patients. METHODS: Three hundred hemodialysis patients underwent assessment of QoL (SF-36), depression (Beck Depression Inventory score), anxiety (State-Trait Anxiety Inventory), and HLOC profile (Multidimensional Health Locus of Control scale). Comorbidities and sociodemographic factors were assessed. RESULTS: All QoL scores were low. Depression and comorbidities were negatively correlated with physical QoL components and depression, anxiety, and comorbidities were negatively correlated with mental components. However, internal locus of control (LOC) and external LOC (influence of "powerful others") were positively correlated with mental QoL components. Multiple regression analysis showed internal LOC significantly and positively associated with mental QoL components, especially mental health score (P < 0.01). CONCLUSIONS: Altered QoL of patients undergoing chronic hemodialysis is associated with physical and psychiatric comorbidities, in particular depression and anxiety. However, internal and external LOC seem to have differential impact on QoL. Increasing awareness and empowerment of the internal and external components of the LOC could help patients improving QoL. PMID- 22221718 TI - The effect of changes in depressive symptoms on disability status in patients with diabetes. AB - OBJECTIVE: To examine the association between changes in depressive symptoms and disability status in patients with diabetes. METHODS: This 5-year prospective cohort study included 2733 patients with diabetes enrolled in the Pathways Epidemiologic Follow-Up Study who had completed depression and activities of daily living questionnaires at baseline and 5 years. Four depression groups were created using changes in depression scores over 5 years: no depression, improved depression, persistent depression, and development of depression. After controlling for sociodemographic and clinical characteristics, we examined the association between changes in depressive symptoms and incident disability at 5 years using Poisson regression. RESULTS: In patients nondisabled at baseline (n = 2155), the improved depression group had a risk of disability comparable to the no depression reference group [relative risk (RR): 0.70, 95% CI (0.44-1.12)]. The development of depression and persistent depression groups were significantly more likely to develop disability compared with the no depression group [RR: 2.86, 95% CI (2.12-3.86) and RR: 2.16, 95% CI (1.47-3.18), respectively]. Among those who were disabled at baseline, there was no significant change in the disability status of the three depression groups compared with disabled patients with no depressive symptoms at either time point. CONCLUSIONS: Among initially nondisabled patients with diabetes, those whose depression improved had functional outcomes comparable to those who were nondepressed at baseline and 5 years. Patients who developed depression and had persistent depression were more likely to experience disability at 5 years than those who were nondepressed at baseline and 5 years. PMID- 22221720 TI - Conditions comorbid with chronic fatigue in a population-based sample. AB - BACKGROUND: Chronic fatigue syndrome (CFS) has been found to be comorbid with various medical conditions in clinical samples, but little research has investigated CFS comorbidity in population-based samples. OBJECTIVE: This study investigated conditions concurrent with a CFS-like illness among twins in the population-based Mid-Atlantic Twin Registry (MATR), including chronic widespread pain (CWP), irritable bowel syndrome (IBS), and major depressive disorder (MDD). METHOD: A survey was mailed to participants in the MATR in 1999. Generalized estimating equations were used to estimate odds ratios to assess associations between CFS-like illness and each comorbid condition. RESULTS: A total of 4590 completed surveys were collected. Most participants were female (86.3%); mean age was 44.7 years. Among participants with a CFS-like illness, lifetime prevalences of CWP, IBS, and MDD were 41%, 16%, and 57% respectively. Participants reporting at least one of the three comorbid conditions were about 14 times more likely to have CFS-like illness than those without CWP, IBS, or MDD (95% confidence interval 8.1%-21.3%). Only MDD showed a temporal pattern of presentation during the same year as diagnosis of CFS-like illness. Age, gender, body mass index, age at illness onset, exercise level, self-reported health status, fatigue symptoms, and personality measures did not differ between those reporting CFS-like illness with and without comorbidity. CONCLUSION: These results support findings in clinically based samples that CFS-like illness is frequently cormorbid with CWP, IBS, and/or MDD. We found no evidence that CFS-like illnesses with comorbidities are clinically distinct from those without comorbidities. PMID- 22221721 TI - Impact of integrated and measurement-based depression care: clinical experience in an HIV clinic. AB - BACKGROUND: Just as in heart disease and diabetes, depression in HIV/AIDS is associated with negative outcomes. While randomized trials have shown the efficacy of treatment for depression in HIV/AIDS, the implementation of evidence based treatments in real-world settings remains a challenge. OBJECTIVE: The objective of this study was to assess the effectiveness of a collaborative, measurement-based approach to depression care, including psychopharmacologic and ancillary psychological therapies in patients with HIV/AIDS and to examine whether or not effective depression treatment would also improve virologic and immunologic outcomes. METHODS: This was a retrospective chart review of patients referred for depression to a co-located psychiatry consultation service embedded within an infectious diseases outpatient clinic at an urban tertiary hospital. Data extracted at initial assessment and at last appointment included: axis I diagnosis, whether the patient was on an antidepressant, whether the patient was on a stimulant, BDI-II score, HIV RNA level, and CD4 cell count. RESULTS: One hundred twenty-four patient charts were included. Pre- vs. post-treatment analyses revealed significant reductions in depression (average BDI-II score of 23 to 15.7, p = 0.00001) and HIV RNA (14.1 K to 4 K copies/mL, p = 0 .003), and significant increases in CD4 count (518 to 592 cells/MUL, p = 0.001). Additionally, more participants were prescribed antidepressants and stimulants at post- vs. pre-treatment. CONCLUSION: Taking a collaborative, measurement-based approach to depression care appears to be an effective method for improving depression, virologic, and immunologic outcomes in depressed patients with HIV/AIDS illness. PMID- 22221722 TI - Parental-reported health anxiety symptoms in 5- to 7-year-old children: the Copenhagen Child Cohort CCC 2000. AB - OBJECTIVES: Hypochondriasis, now often designated as health anxiety, is important in terms of prevalence, levels of suffering, and health services cost in adults. Whereas the DSM-IV-TR suggests that the condition primarily begins in adulthood, retrospective reports point to a possible origin in childhood with onset as early as preschool age. However, little research has addressed health anxiety in children. In the present study we explored parental-reported health anxiety symptoms (HAS) and their association with physical and mental health in a population-based sample of 5- to 7-year-old children. METHODS: Parents of 1323 children (49.7% boys), recruited from the birth cohort: Copenhagen Child Cohort CCC 2000, completed questionnaires regarding their child's HAS, and physical and mental health. Associations were examined using multiple logistic regression analyses adjusted for concurrent chronic physical disease. RESULTS: HAS were present in 17.6% and present 'a lot' (categorized as considerable HAS) in 2.4% of the children. Children with considerable HAS demonstrated more physical health problems and internalizing disorders than children with no or non-considerable HAS, but in the majority (71.9%) no associated chronic physical disease or other mental disorder was reported. In a subsample of children with functional somatic symptoms (FSS), impairing FSS were more likely among children who reported HAS. CONCLUSIONS: The findings suggest that HAS present as primary complaints early in life and are associated with impairing child health problems in the area of FSS and internalizing disorders. These aspects may be important to understand and also to prevent the development of severe health anxiety. PMID- 22221723 TI - Comparison of self-reported cognitive difficulties in a national sample of long term cancer survivors and cancer-naive controls. AB - BACKGROUND: Evidence that long-term cancer survivors (LTCS) experience greater cognitive dysfunction than individuals without cancer is mixed. This analysis of a population-based sample of United States residents compares self-reported cognitive difficulties in LTCS and cancer naive controls (CNC), controlling for psychiatric disorders. METHODS: National Comorbidity Survey-Replication (NCS-R) interviews were conducted in a nationally-representative sample of 9282 people, of whom 5692 were assessed for cancer history. Long-term survivors of adult cancers were defined as individuals who were at least 18 years old at time of diagnosis; greater than 5 years following diagnosis; and with cancer reportedly in remission or cured. Cognitive dysfunction queries included two screening questions and five items drawn than the World Health Organization (WHO) Disability Assessment Schedule 2.0. Psychiatric disorders were identified using the WHO's Composite International Diagnostic Interview. Odds ratios and 95% confidence intervals were obtained from multivariable logistic regression models fit to evaluate the relationship between cancer status (LTCS versus CNC) and cognitive symptoms. RESULTS: Of NCS-R participants, 225 met criteria for LTCS and 3953 for CNC. Long-term cancer survivors and CNC screened positive for cognitive symptoms at a rate of 19.5% and 20.8%, respectively, for the first screen and 16.0% and 16.4%, respectively, for the second. Adjusting for demographic and psychiatric variables, LTCS did not carry increased odds of experiencing cognitive symptoms [(OR) 1.00 (95% CI, .59 to 1.68); (OR) .95 (95 %CI, .57 to 1.59)]. CONCLUSIONS: Self-reported cognitive symptoms are common among LTCS and CNC. LTCS do not report cognitive symptoms with greater frequency. PMID- 22221724 TI - Escitalopram for severe asthma and major depressive disorder: a randomized, double-blind, placebo-controlled proof-of-concept study. AB - BACKGROUND: Depression is common in asthma and may be a risk factor for asthma related morbidity and mortality. However, minimal data are available on depression treatment in asthma. Previously, we reported greater sustained depression remission and less oral corticosteroid use in asthma patients treated with citalopram. METHOD: A 12-week randomized, double-blind, placebo-controlled, proof-of-concept trial of escitalopram was conducted in 26 outpatients with asthma requiring at least one course of oral corticosteroids in the prior 12 months and major depressive disorder (MDD) with baseline Hamilton Rating Scale for Depression (HAM-D) scores of >= 20. RESULTS: Total evaluable sample (n = 25) showed significant baseline to exit reduction in HAM-D and Inventory of Depressive Symptomatology-Self Report (IDS-SR) scores, with no significant between-group differences, although the findings favored escitalopram. Depression remission on the HAM-D, from week 1 to exit, showed a trend (P = 0.06) favoring escitalopram. Relative risk for remission at week 12 was 6.5 with an estimated remission rate of 39.1% with escitalopram and 6.0% with placebo. Between-group differences in oral corticosteroid use were not significant. Changes in Asthma Control Questionnaire (ACQ) correlated significantly with changes in IDS-SR in the escitalopram, placebo, and combined sample groups (tau = 0.49-0.60, P < 0.05) and with changes in HAM-D only in placebo and combined groups (tau = 0.38-0.58, P < 0.05). CONCLUSIONS: Medium effect sizes and a remission trend were observed favoring escitalopram over placebo on depression measures. Changes in self reported depressive symptoms correlated with changes in asthma symptoms. A larger trial is needed to confirm the findings from this pilot study. PMID- 22221725 TI - Psychiatric consequences of actual versus feared and perceived bed bug infestations: a case series examining a current epidemic. PMID- 22221726 TI - First report of quetiapine use in the management of ketamine-benzodiazepine coma therapy side-effects. PMID- 22221727 TI - Psychotic disorder due to phosphaturic mesenchymal tumor with mixed connective tissue variant. PMID- 22221728 TI - Fluoroquinolone-induced suicidal ideation and suicidality. PMID- 22221729 TI - Suicidal depression related to chemotherapy in a patient with ovarian cancer. PMID- 22221730 TI - SiC formation for a solar cell passivation layer using an RF magnetron co sputtering system. AB - In this paper, we describe a method of amorphous silicon carbide film formation for a solar cell passivation layer. The film was deposited on p-type silicon (100) and glass substrates by an RF magnetron co-sputtering system using a Si target and a C target at a room-temperature condition. Several different SiC [Si1 xCx] film compositions were achieved by controlling the Si target power with a fixed C target power at 150 W. Then, structural, optical, and electrical properties of the Si1-xCx films were studied. The structural properties were investigated by transmission electron microscopy and secondary ion mass spectrometry. The optical properties were achieved by UV-visible spectroscopy and ellipsometry. The performance of Si1-xCx passivation was explored by carrier lifetime measurement. PMID- 22221731 TI - General anesthesia without intravenous access in children--a survey of current practice among members of the APAGBI and UK regional representatives of the APAGBI and the AAGBI. AB - BACKGROUND: The establishment of intravenous (IV) access should be considered for all adults and children undergoing general anesthesia. Inhalational induction prior to the establishment of IV access remains a popular technique in pediatric practice, and most practitioners will subsequently obtain IV access at the earliest opportunity. Previous surveys have indicated that some anesthetists may elect to omit IV access for the duration of anesthesia and surgery; however, the extent of this practice is unclear. A survey of pediatric anesthetists (members of the APAGBI and regional representatives of both the APAGBI and the AAGBI) was conducted to determine the prevalence of anesthesia without IV access in children, together with the circumstances in which this would be considered by practitioners. METHOD: A web-based survey was distributed via email to members of the Association of Paediatric Anaesthetists of Great Britain and Ireland (APAGBI) and regional representatives of both the APAGBI and the Association of Anesthetists of Great Britain and Ireland (AAGBI). In total, 1419 invitations to complete the survey were sent. RESULTS: Seven hundred and twenty seven completed surveys were returned, indicating a response rate of 51%. Twenty-eight respondents reported that they did not anesthetize children age <16 years. Of the remaining 699 respondents, 295 (42%) described circumstances where intravenous access was omitted during general anesthesia. The vast majority (84.7%) indicated that this was a rare occurrence. Only 44 (6.3%) respondents indicated they would always or usually undertake procedures under general anesthesia in children without IV access. Respondents suggested that short procedures, including dental extractions and myringotomy, were circumstances in which this practice was acceptable. CONCLUSION: The majority of respondents to this survey reported that they would usually establish IV access in children undergoing general anesthesia except in specific circumstances. PMID- 22221732 TI - Neuroprotective effects of progranulin in ischemic mice. AB - Progranulin (PGRN) is a widely expressed protein with diverse biological functions. We generated a transgenic mouse overexpressing PGRN and found significantly elevated expression in the forebrain. To explore the neuroprotective capacity of PGRN, we measured brain infarct volume and functional recovery in wild type and transgenic mice following middle cerebral artery occlusion (MCAo). Both neurological and motor functions were rescued by PGRN overexpression, as behaviors recovered more rapidly and to a greater extent following ischemia in PGRN transgenic mice and in wild type mice injected with lentivirus-PGRN. Furthermore, infarct volumes were smaller in transgenic mice compared to wild type (WT) mice as revealed by computerized image analysis. Glial cells overexpressing PGRN were protected from LPS-induced cytotoxicity in vitro. Seven days after LPS treatment, the expression of pro-inflammatory cytokines (IL 1beta, IL-6, and TNF-alpha) was lower in glial cells cultured from PGRN overexpressing mice compared to glia from WT mice, while expression of the anti inflammatory cytokine IL-10 was upregulated in glial cells from transgenic mice. Our results demonstrate consistent and significant improvements in postischemic neurological functions in mice overexpressing PGRN, possibly due to reduced pro inflammatory cytokine release and elevated anti-inflammatory cytokine release. Progranulin is a promising endogenous neuroprotectant with anti-apoptotic and anti-inflammatory properties. PMID- 22221733 TI - Calretinin, parvalbumin and calbindin immunoreactive interneurons in perirhinal cortex and temporal area Te3V of the rat brain: qualitative and quantitative analyses. AB - The perirhinal cortex (PRC) composed of areas 35 and 36 forms an important route for activity transfer between the hippocampus-entorhinal cortex and neocortex. Its function in memory formation and consolidation as well as in the initiation and spreading of epileptic activity was already partially elucidated. We studied the general pattern of calretinin (CR), parvalbumin (PV) and calbindin (CB) immunoreactivity and its corrected relative optical density (cROD) as well as morphological features and density of CR and PV immunoreactive (CR+, PV+) interneurons in the rat PRC. Neighboring neocortical association area Te3V was analyzed as well. The PRC differed from the Te3V in higher CR and lower PV overall immunoreactivity level. On CR immunostained sections, the difference between high cROD value in area 35 and low cROD value in area Te3V reached statistical significance (p<0.05). The pattern of CB immunoreactivity was similar to that of the neocortex. Vertically oriented bipolar neurons were the most common morphological type of CR+ neurons, multipolar neuronal morphology was typical among PV+ neurons and vertically oriented bipolar neurons and multipolar neurons were approximately equally frequent among CB+ neurons. The density of CR+ and PV+ neurons was stereologically measured. While the density of PV+ neurons was not significantly different in PRC when compared to Te3V, density of CR+ neurons in area 35 was significantly higher by comparison with Te3V (p<0.05). Further, the overall neuronal density was measured on Nissl stained sections and the proportion of CR+ and PV+ interneurons was expressed as a percentage of the total neurons counts. The percentage of CR+ interneurons was higher in area 35 by comparison with area Te3 (p<0.05), while the percentage of PV+ interneurons did not significantly differ among the examined areas. In conclusion, the PRC possesses specific interneuronal equipment with unusually high proportion of CR+ interneurons, what might be of importance for the presumed gating function of PRC in normal and diseased states. PMID- 22221734 TI - Induction of hippocampal theta rhythm by electrical stimulation of the ventral tegmental area and its loss after septum inactivation. AB - The ventral tegmental area (VTA), which may be one of the structures involved in regulation of hippocampal theta rhythm, sends direct projections to the hippocampus and also to the forebrain septum, the key centres involved in theta generation. In the present study we aimed at assessing which projections from the VTA (direct or through the septum) participate in regulation of hippocampal electric activity. Experiments were conducted on 3 groups of urethanised male Wistar rats. In the first group (n=6) electrical stimulation of the VTA was used to evoke theta rhythm episodes in hippocampus. Stimulation was repeatedly applied in control conditions and after procainic blockade of the septum. The second group (n=6), subjected to unilateral electrical stimulation of the VTA (30-s stimulation at 10-min intervals during 2h) and to subsequent detection of Fos expression, served to measure neuronal activation of the target mesolimbic structures. Activation levels of selected structures were compared to data from analogous stimulation of the zona incerta (ZI, the third group, n=6). Stimulation of the VTA immediately generated regular theta rhythm in both hippocampi. Inactivation of the septum with procaine temporarily abolished this effect. VTA stimulation increased the density of Fos in the ipsilateral nucleus accumbens. Stimulation of the ZI never generated theta but evoked significant induction of Fos expression in the hippocampus. Our data suggest that the projection through which the VTA enhances theta rhythm is not direct but is incorporated into the main route of theta generation, which involves septum as the main relay node. PMID- 22221735 TI - The neural predictors of choice preference in intertemporal choice. AB - Intertemporal choice may involve two processing stages: a valuation stage and a choice stage. Decision makers must integrate the various dimensions of an option (e.g., money, time) into a single measure of its subjective value (the valuation stage) and then choose the option that is the most valuable (the choice stage). Although previous studies have implicated that subjective values are represented by a diverse set of brain regions (e.g., vmPFC, VStr, and PCC) in intertemporal choice, it is not yet known which of these regions contain information that directly predicts subsequent choice. To address this question, we measured brain activity using functional MRI while participants performed a simple intertemporal choice task. The results found that participants' decision could be encoded by three specific brain areas (vmPFC, ACC, and PCC) even before they were required to make a choice, while the left posterior insula showed positively active in the choice stage when individuals selected the delayed rewards compared to the immediate rewards. These findings suggest that activation patterns in the vmPFC, ACC, and PCC were able to predict the subsequent choice preference; however, left posterior insula may play an important role for choice preference in the choice stage. PMID- 22221736 TI - Modifying neurorepair and neuroregenerative factors with tPA and edaravone after transient middle cerebral artery occlusion in rat brain. AB - Changes in expression of neurorepair and neuroregenerative factors were examined after transient cerebral ischemia in relation to the effects of tissue plasminogen activator (tPA) and the free radical scavenger edaravone. Physiological saline or edaravone was injected twice during 90 min of transient middle cerebral artery occlusion (tMCAO) in rats, followed by the same saline or tPA at reperfusion. Sizes of the infarct and protein factors relating to neurorepair and neuroregeneration were examined at 4d after tMCAO. The protein factors examined were: a chondroitin sulfate proteoglycan neurocan, semaphorin type 3A (Sema3A), a myelin-associated glycoprotein receptor (Nogo receptor, Nogo R), a synaptic regenerative factor (growth associated protein-43, GAP43), and a chemotropic factor netrin receptor (deleted in colorectal cancer, DCC). Two groups treated by edaravone only or edaravone plus tPA showed a reduction in infarct volume compared to the two groups treated by vehicle only or vehicle plus tPA. Immunohistochemistry and western blot analyses indicated that protein expression of neurocan, Sema3A, Nogo-R, GAP43, and DCC was decreased with tPA, but recovered with edaravone. Additive edaravone prevented the reductions of these five proteins induced by tPA. The present study demonstrates for the first time that exogenous tPA reduced protein factors involved in inhibiting and promoting axonal growth, but that edaravone ameliorated such damage in brain repair after acute ischemia. PMID- 22221737 TI - Bronchial hyperresponsiveness in an adult population in Helsinki: decreased FEV1 , the main determinant. AB - INTRODUCTION: Bronchial hyperresponsiveness (BHR) elevates the risk for development of respiratory symptoms and accelerates the decline in forced expiratory volume in the first second (FEV1 ). We thus aimed to assess the prevalence, determinants and quantity of BHR in Helsinki. OBJECTIVES: This study involved 292 randomly selected subjects age 26-66years, women comprising 58%. METHODS: Following a structured interview, a spirometry, a bronchodilation test, and a skin-prick test, we assessed a bronchial challenge test with inhaled histamine using a dosimetric tidal breathing method. Results included the provocative dose inducing a decrease in FEV1 by 15% (PD15 FEV1 ) and the dose response slope. For statistical risk factor-analyses, the severity of BHR was considered; PD15 values <=1.6mg (BHR) and <=0.4mg [moderate or severe BHR (BHRms )] served as cut-off levels. RESULTS: BHR presented in 21.2% and BHRms in 6.2% of the subjects. FEV1<80% of predicted [odds ratio (OR) 4.09], airway obstruction (FEV1 /forced vital capacity<88% of predicted) (OR 4.33) and history of respiratory infection at age <5 (OR 2.65) yielded an increased risk for BHR as ORs in multivariate analysis. For BHRms , the determinants were decreased FEV1 below 80% of predicted (OR 27.18) and airway obstruction (OR 6.16). Respiratory symptoms and asthma medication showed a significant association with BHR. CONCLUSIONS: Of the adult population of Helsinki, 21% showed BHR to inhaled histamine. The main determinants were decreased FEV1 and airway obstruction. Quantitative assessment of BHR by different cut-off levels provides a tool for characterization of phenotypes of airway disorders in epidemiologic and clinical studies. PMID- 22221738 TI - Targeting condom distribution at high risk places increases condom utilization evidence from an intervention study in Livingstone, Zambia. AB - BACKGROUND: The PLACE-method presumes that targeting HIV preventive activities at high risk places is effective in settings with major epidemics. Livingstone, Zambia, has a major HIV epidemic despite many preventive efforts in the city. A baseline survey conducted in 2005 in places where people meet new sexual partners found high partner turnover and unprotected sex to be common among guests. In addition, there were major gaps in on-site condom availability. This study aimed to assess the impact of a condom distribution and peer education intervention targeting places where people meet new sexual partners on condom use and sexual risk taking among people socializing there. METHODS: The 2005 baseline survey assessed the presence of HIV preventive activities and sexual risk taking in places where people meet new sexual partners in Livingstone. One township was selected for a non-randomised intervention study on condom distribution and peer education in high risk venues in 2009. The presence of HIV preventive activities in the venues during the intervention was monitored by an external person. The intervention was evaluated after one year with a follow-up survey in the intervention township and a comparison township. In addition, qualitative interviews and focus group discussions were conducted. RESULTS: Young people between 17-32 years of age were recruited as peer educators, and 40% were females. Out of 72 persons trained before the intervention, 38 quit, and another 11 had to be recruited. The percentage of venues where condoms were reported to always be available at least doubled in both townships, but was significantly higher in the intervention vs. the control venues in both surveys (84% vs. 33% in the follow-up). There was a reduction in reported sexual risk taking among guests socializing in the venues in both areas, but reporting of recent condom use increased more among people interviewed in the intervention (57% to 84%) than in the control community (55% to 68%). CONCLUSIONS: It is likely that the substantial increase in reported condom use in the intervention venues was partially due to the condom distribution and peer education intervention targeting these places. However, substantial changes were observed also in the comparison community over the five year period, and this indicates that major changes had occurred in overall risk taking among people socializing in venues where people meet new sexual partners in Livingstone. TRIAL REGISTRATION: ClinicalTrials.gov NCT01423357. PMID- 22221739 TI - Preservation solutions for static cold storage of kidney allografts: a systematic review and meta-analysis. AB - Static cold storage is the most prevalent method for renal allograft preservation. Several solutions have been designed to counteract the detrimental effects of cold ischemia and reperfusion. The aim of this study was to appraise the evidence for the currently available preservation solutions. We performed a systematic literature search using MEDLINE, EMBASE, the Cochrane Library, the Transplant Library and trial registries. Inclusion criteria specified any comparative, prospective study for deceased donor renal allografts. Studies were assessed for methodological quality. The primary outcome was delayed graft function (DGF). Fifteen trials with a total of 3584 kidneys were included. Eurocollins was associated with a higher risk of DGF than University of Wisconsin solution (UW) in two randomized controlled trials (RCTs) and histidine-tryptophan ketoglutarate (HTK) in two RCTs. UW was associated with an equal risk of DGF compared with Celsior in three RCTs and HTK in two RCTs. There was limited data regarding other comparisons and outcomes. The choice of preservation solution has an effect on the incidence of DGF, which might, in turn, affect long-term outcomes. Both UW and HTK have lower rates of DGF than Eurocollins. There is no difference in the incidence of DGF with the use of Celsior, HTK and UW. These findings are supported by registry data. PMID- 22221740 TI - Prognosis of phrenic nerve injury following thoracic interventions: four new cases and a review. AB - INTRODUCTION: Phrenic nerve lesion is a known complication of thoracic surgical intervention, but it is rarely described following thymectomy and lung surgery. OBJECTIVE: To review the literature on thoracic intervention and phrenic nerve lesion and to describe four new cases, in which regular neurophysiological studies were performed. METHODS: We reviewed the literature concerning phrenic nerve lesion after cardiac, lung and thymus surgical interventions. We described four cases of phrenic nerve lesion, three associated with thymectomy and one in lung surgery. RESULTS: The review shows that cryogenic or thermal injuries during cardiac surgeries are associated with good prognosis. The information on the outcome of phrenic nerve lesion in thymectomy or lung surgery is insufficient. Our cases and this review suggest that phrenic lesion in the last two interventions are associated with a poor recovery. CONCLUSION: Our data suggests that the prognosis of phrenic nerve lesion following thoracic intervention depends on the nature of the damage. Probably, in thymectomy and lung surgery, nerve stretch or laceration are involved, consequently the outcome is poorer in comparison with cardiac surgery, where cold lesion is more frequent. Neurophysiological tests give a direct, quantified and reliable assessment of nerve regeneration. PMID- 22221741 TI - Empathic and non-empathic routes to visuospatial perspective-taking. AB - The present study examined whether strategy moderated the relationship between visuospatial perspective-taking and empathy. Participants (N=96) undertook both a perspective-taking task requiring speeded spatial judgements made from the perspective of an observed figure and the Empathy Quotient questionnaire, a measure of trait empathy. Perspective-taking performance was found to be related to empathy in that more empathic individuals showed facilitated performance particularly for figures sharing their own spatial orientation. This relationship was restricted to participants that reported perspective-taking by mentally transforming their spatial orientation to align with that of the figure; it was absent in those adopting an alternative strategy of transposing left and right whenever confronted with a front-view figure. Our finding that strategy moderates the relationship between empathy and visuospatial perspective-taking enables a reconciliation of the apparently inconclusive findings of previous studies and provides evidence for functionally dissociable empathic and non-empathic routes to visuospatial perspective-taking. PMID- 22221742 TI - Computational approaches to disease-gene prediction: rationale, classification and successes. AB - The identification of genes involved in human hereditary diseases often requires the time-consuming and expensive examination of a great number of possible candidate genes, since genome-wide techniques such as linkage analysis and association studies frequently select many hundreds of 'positional' candidates. Even considering the positive impact of next-generation sequencing technologies, the prioritization of candidate genes may be an important step for disease-gene identification. In this paper we develop a basic classification scheme for computational approaches to disease-gene prediction and apply it to exhaustively review bioinformatics tools that have been developed for this purpose, focusing on conceptual aspects rather than technical detail and performance. Finally, we discuss some past successes obtained by computational approaches to illustrate their beneficial contribution to medical research. PMID- 22221743 TI - Correlating clinical manifestations with factor levels in rare bleeding disorders: a report from Southern India. AB - Data on the clinical manifestations of patients with clotting factor defects other than Haemophilia A, B and von Willebrand disease are limited because of their rarity. Due to their autosomal recessive nature of inheritance, these diseases are more common in areas where there is higher prevalence of consanguinity. There is no previous large series reported from southern India where consanguinity is common. Our aim was to analyze clinical manifestations of patients with rare bleeding disorders and correlate their bleeding symptoms with corresponding factor level. Data were collected in a standardized format from our centre over three decades on 281 patients who were diagnosed with rare bleeding disorders (fibrinogen, prothrombin, factor V (FV), FVII, FX, FXI, FXIII and combined FV or FVIII deficiency). Patients with liver dysfunction or those on medications which can affect factor level were excluded. All patients with <50% factor levels were included in this analysis. Patients were analysed for their salient clinical manifestations and it was correlated with their factor levels. The data shows that FXIII deficiency is the commonest and FXI deficiency is the rarest in Southern India. There was no significant difference in bleeding symptoms among those who were < or >1% factor coagulant activities among all disorders, except for few symptoms in FVII and FX deficiency. An international collaborative study is essential to find out the best way of classifying severity in patients with rare bleeding disorders. PMID- 22221744 TI - Dispersal-mediated trophic interactions can generate apparent patterns of dispersal limitation in aquatic metacommunities. AB - Dispersal is a major organising force in metacommunities, which may facilitate compositional responses of local communities to environmental change and affect ecosystem function. Organism groups differ widely in their dispersal abilities and their communities are therefore expected to have different adaptive abilities. In mesocosms, we studied the simultaneous compositional response of three plankton communities (zoo-, phyto- and bacterioplankton) to a primary productivity gradient and evaluated how this response was mediated by dispersal intensity. Dispersal enhanced responses in all three planktonic groups, which also affected ecosystem functioning. Yet, variation partitioning analyses indicated that responses in phytoplankton and bacterial communities were not only controlled by dispersal directly but also indirectly through complex trophic interactions. Our results indicate that metacommunity patterns emerging from dispersal can cascade through the food web and generate patterns of apparent dispersal limitation in organisms at other trophic levels. PMID- 22221745 TI - Patient time costs and out-of-pocket costs in hepatitis C. AB - BACKGROUND: Hepatitis C virus (HCV) infection is associated with substantial costs to patients, their caregivers and society. AIMS: We evaluated time costs (time spent seeking healthcare) and out-of-pocket (OOP) costs for patients with HCV and their caregivers. METHODS: We measured costs for 738 HCV outpatients in a tertiary-care clinic using a patient-completed questionnaire. Time and OOP costs were compared across disease stages and sociodemographic categories. We examined the association between cost and disease stage using linear regression adjusting for age, gender, marital status, education, income and Index of Coexistent Disease (ICED) comorbidity score. Costs were expressed in 2007 Canadian dollars. RESULTS: The mean annual time cost per patient was $2136 (98 h), and ranged from $281 (18 h) in individuals who had cleared the virus to $9416 in transplant recipients (420 h). Caregiver costs were reported in 10% of patients. The mean annual OOP cost per patient was $1326. Patients receiving active treatment and those with late-stage disease spent $2500-2800 per year on HCV-related healthcare, approximately 7% of their annual income. Patients who had cleared the virus had the lowest time and OOP costs. Low income and unemployed patients had higher costs. CONCLUSIONS: In HCV-infected individuals, OOP and time costs represent a significant economic burden and fall disproportionately upon those least able to afford them. The lower cost burden among those who were successfully treated suggests that wider use of antiviral therapy may reduce economic burden in addition to improving health outcomes. PMID- 22221747 TI - Analysis of var genes cloned from a Plasmodium falciparum isolate in China. AB - OBJECTIVE: To analyse the var gene repertoire and characterise the chondroitin sulphate A (CSA)-binding activity of the Duffy-binding like (DBL) domains encoded by the var2csa gene of a Plasmodium falciparum (P. falciparum) isolate in Hainan Province, China. METHODS: The sequences of var DBL1 regions were PCR-amplified, sequenced and the sequence characteristics was bioinformatically analysed. Recombinant proteins encoded by the var2csa genes were expressed and purified. The binding activities of the recombinant proteins to CSA receptor was detected by ELISA assays. RESULTS: Fifty six unique DBL alpha sequences were obtained, and the sequences represented similar diversity to the var genes of the genome parasite 3D7. There are two var2csa genes in the P. falciparum isolated from Hainan Province. Unlike in other falciparum parasites such as HB3, the two var2csa genes are more diverged. The receptor-binding capacity of DBL-5epsilon and DBL-6epsilon domains of HN var2CSA was studied. CONCLUSIONS: This work represented the diversity of var genes of a P. falciparum isolate in China. PMID- 22221748 TI - Toxicarioside A, isolated from tropical Antiaris toxicaria, blocks endoglin/TGF beta signaling in a bone marrow stromal cell line. AB - OBJECTIVE: To investigate possible mechanism of toxicarioside A in HS-5 bone stromal cells. METHODS: HS-5 bone stromal cells were cultured in media supplemented with various concentrations of toxicarioside A or control DMSO (not treatment). Endoglin and TGF-beta were detected by Northern and Western blot analysis and quantified in a standard method. Downstream molecules of endoglin and TGF-beta (Smad1, Smad2 and their active phosphorylated counterparts, pSmad1 and pSmad2) were also detected and quantified by Western blot analysis. In addition, cell proliferation assay and small interfering RNA (siRNA) against endoglin were used to certificate the function of endolgin in the HS-5 cells. RESULTS: Compared with the not treated (0 MUg/mL) or DMSO treated control HS-5 cells, HS-5 cells treated with toxicarioside A were found significant attenuation of endolgin and TGF-beta expression. Significant inhibition of cell proliferation was also found in the HS-5 cells treated with toxicarioside A. ALK1-related Smad1 and ALK5-related Smad2 were decreased in HS-5 cells treated with toxicarioside A. In addition, phosphorylated Smad1 (pSmad1) and Smad2 (pSmad2) were also found attenuation in toxicarioside A-treated HS-5 cells. RNA interference showed that blockage of endoglin by siRNA also decreased Smad1 and Smad2 expression in HS-5 cells. CONCLUSIONS: Our results indicate that toxicarioside A can influence bone marrow stromal HS-5's function and inhibit HS-5 cell proliferation by alteration of endoglin-related ALK1 (Smad1) and ALK5 (Smad2) signaling. PMID- 22221749 TI - Prevalence of plasmid mediated bla(TEM-1) and bla(CTX-M-15) type extended spectrum beta-lactamases in patients with sepsis. AB - OBJECTIVE: To characterize the bacterial pathogens in patients having gram negative septicaemia. Further, to evaluate the antimicrobial resistance and underlying molecular mechanisms in these strains. METHODS: A total number of 70 cases of gram negative sepsis were included in this prospective, open labeled, observational study. Standard methods for isolation and identification of bacteria were used. Antimicrobial susceptibility and ESBL testing was performed by the standard disc diffusion method. PCR amplification was performed to identify bla(CTX-M), bla(SHV) and bla(TEM) type ESBLs. Conjugation experiments were performed to show resistant marker transfer. RESULTS: The most prevalent isolates Escherichia coli (E. coli) 58.6%, Klebsiella Spp. 32.9% and Pseudomonas 8.6%, were resistant to most of the antimicrobials including cefazolin, ceftriaxone, cefuroxime, ampicillin and co-trimoxazole but sensitive to imipenem and meropenem. ESBL and MBL production was seen 7.3% and 12.2% of E. coli isolates respectively. Three isoaltes were found to have bla(CTX-M-15) and two of them also showed bla(TEM-1) type enxyme. Whereas, none of them showed bla(SHV). Conjugation experiments using J-53 cells confirmed these resistant markers as plasmid mediated. CONCLUSIONS: This work highlights the molecular epidemiology of escalating antimicrobial resistance and likely switch over of bla(CTX-M-15) type extended spectrum beta-lactamases by bla(TEM) type ESBLs in India. Further, the antimicrobial resistance by horizontal gene transfer was predominant among Enterobacteraceae in the community setting. PMID- 22221750 TI - In vitro antiplasmodial effect of ethanolic extracts of traditional medicinal plant Ocimum species against Plasmodium falciparum. AB - OBJECTIVE: To identify the possible antiplasmodial compounds from leaf, stem, root and flower extracts of Ocimum canum (O. canum), Ocimum sanctum (O. sanctum) and Ocimum basilicum (O. basilicum). METHODS: The O. canum, O. sanctum and O. basilicum were collected from Ramanathapuram District, Tamil Nadu and the extraction was carried out in ethanol. The filter sterilized extracts (100, 50, 25, 12.5, 6.25 and 3.125 MUg/mL) of leaf, stem, root and flower extracts of O. canum, O. sanctum and O. basilicum were tested for antiplasmodial activity against Plasmodium falciparum (P. falciparum). The potential extracts were also tested for their phytochemical constituents. RESULTS: The leaf extract of O. sanctum showed excellent antiplasmodial activity (IC(50) 35.58 MUg/mL) followed by leaf extract of O. basilicum (IC(50) 43.81 MUg/mL). The leaf extract of O. canum, root extracts of O. sanctum and O. basilicum, the stem and flower extracts of all the three tested Ocimum species showed IC(50) values between 50 and 100 MUg/mL. Statistical analysis reveals that, significant antiplasmodial activity (P <0.01) was observed between the concentrations and time of exposure. The chemical injury to erythrocytes was also carried out and it shows that, there were no morphological changes in erythrocytes by the ethanolic extract of O. canum, O. sanctum and O. basilicum. The in vitro antiplasmodial activity might be due to the presence of alkaloids, glycosides, flavonoids, phenols, saponins, triterpenoids, proteins, resins, steroids and tannins in the ethanolic extracts of tested plants. CONCLUSIONS: The ethanolic leaf extracts of O. sanctum possess lead compounds for the development of antiplasmodial drugs. PMID- 22221751 TI - Bioinformatics analysis of the structure and linear B-cell epitopes of aquaporin 3 from Schistosoma japonicum. AB - OBJECTIVE: To analyze the structure of aquaporins-3(AQP-3) from Schistosoma japonicum(SJAQP-3) using bioinformatical methods, and to provid of references for vaccine targets research. METHODS: Protparam, BepiPred, TMHMM Server, MLRC, Geno3d, DNA star software packages were used to predict the physical and chemical properties, hydrophilicity plot, flexibility regions, antigenic index, surface probability plot, secondary structure, and tertiary structure of amino acid sequence of SJAQP-3. RESULTS: SJAQP-3 had six transmembrane regions and two half spanning helices that form a central channel. The half-spanning helices fold into the centre of the channel. Either of the half-spanning helix had a conserved motif of NPA common to all aquaporins. Predicted linear B-Cell epitopes were most likely at the N-terminal amino acid residues of 5aa-7aa, 59aa-62aa, 225aa-230aa, 282aa -288aa, 294aa -298aa and 305aa -307aa area. 59aa- 62aa, 225aa-230aa located outside the membrane, the others located inside the cell. CONCLUSIONS: SJAQP-3 is a integral membrane protein in Schistosoma japonicum tegument. There are six potential epitopes in SJAQP-3. It might be a potential molecular target for the development of vaccines. PMID- 22221752 TI - High resolution manometric findings in patients with Chagas' disease esophagopathy. AB - OBJECTIVE: To describe high resolution manometry features of a population of symptomatic patients with Chagas' disease esophagopathy (CDE). METHODS: Sixteen symptomatic dysphagic patients with CDE [mean age (54.81+/-13.43) years, 10 women] were included in this study. All patients underwent a high resolution manometry. RESULTS: Mean lower esophageal sphincter (LES) extension was (3.02+/ 1.17) cm with a mean basal pressure of (15.25+/-7.00) mmHg. Residual pressure was (14.31+/-9.19) mmHg. Aperistalsis was found in all 16 patients. Achalasia with minimal esophageal pressurization (type 1) was present in 25% of patients and achalasia with esophageal compression (type 2) in 75%, according to the Chicago Classification. Upper esophageal sphincter (UES) mean basal pressure was (97.96+/ 54.22) mmHg with a residual pressure of (12.95+/-6.42) mmHg. CONCLUSIONS: Our results show that LES was hypotensive or normotensive in the majority of the patients. Impaired relaxation was found in a minority of our patients. Aperistalsis was seen in 100% of patients. UES had impaired relaxation in a significant number of patients. Further clinical study is needed to investigate whether manometric features can predict outcomes following the studies of idiopathic achalasia. PMID- 22221753 TI - Irritability of malaria vector, Anopheles sacharovi to different insecticides in a malaria-prone area. AB - OBJECTIVE: To determine the susceptibility and irritability level of malaria vector Anopheles sacharovi (An. sachrovi) to different insecticides in a malaria prone area. METHODS: Susceptibility and irritability levels of field collected strain of An. sacharovi to WHO standard papers of DDT 4%, dieldrin 0.4%, malathion 5%, fenitrothion 1%, permethrin 0.75%, and deltamethrin 0.05% were determined in East Azerbaijan of Iran during reemerging of malaria as described by WHO. RESULTS: Results showed that at the diagnostic dose of insecticides this species exhibited resistance to DDT, tolerant to dieldrin and but somehow susceptible to fenitrothion, malathion, permethrin and deltamethrin. The results of irritability of this species to DDT, lambdacyhalothrin, permethrin cyfluthrin and deltamethrin revealed that DDT had had the most and deltamethrin the least irritancy effect. The average number of take offs/fly/minutes for DDT was 0.8+/ 0.2. The order of irritability for permethrin, lambdacyhalothrin, cyfluthrin and deltamethrin were 0.7+/-0.2, 0.5+/-0.2, 0.5+/-0.3, and 0.2+/-0.1, respectively. CONCLUSIONS: Results of this study reveals the responsiveness of the main malaria vector to different insecticides. This phenomenon is depending on several factors such as type and background of insecticide used previously, insecticide properties, and physiology of the species. Careful monitoring of insecticide resistance and irritability level of species could provide a clue for appropriate selection of insecticide for malaria control. PMID- 22221754 TI - Preparation and evaluation of a glycerol-preserved direct agglutination antigen for long-term preservation: a comparative study of the detection of anti Leishmania infantum antibodies in human and dog. AB - OBJECTIVE: To prepare and evaluate a glycerol-preserved antigen from an Iranian strain of Leishmania infantum (L. infantum) for use in glycerol-preserved direct agglutination tests (GP-DAT) as an alternative to freeze dried direct agglutination tests (FD-DAT) that use freeze-dried antigen. METHODS: Glycerol preserved DAT antigen was prepared and stored at different temperatures. We tested antigen stored at 4 degrees C, 22-37 degrees C and 50 degrees C over a period of 365 days. Seven hundred twenty-nine serum samples were collected from different geographical zones of Iran from 2007-2009, and 80 of these samples were pooled to produce sera. Each pooled serum contained 10 sera. All positive and negative pooled sera were separately tested for anti-L. infantum antibodies with GP-DAT, FD-DAT and formaldehyde-fixed direct agglutination test (FF-DAT) antigens; tests were performed on both human and dog sera over a period of 12 months. RESULTS: There was strong agreement between the results obtained using GP DAT and FD-DAT antigens stored at 22-37 degrees C for 12 months for both human (100%) and dog (100%) pooled sera. The direct agglutination test results were highly reproducible (weighted kappa: GP=0.833, FD=0.979 and FF=0.917). CONCLUSIONS: Because GP-DAT antigen is highly stable over a range of temperatures and is easy to transport in the field, this type of antigen may be particularly useful in areas with endemic visceral leishmaniasis. PMID- 22221755 TI - Preventive effect of ethanol extract of Alpinia calcarata Rosc on Ehrlich's ascitic carcinoma cell induced malignant ascites in mice. AB - OBJECTIVE: To explore cytotoxic activity of ethanol extract of Alpinia calcarata Rosc (EEAC) rhizome against Ehrlich ascites carcinoma (EAC) tumor bearing Swiss Albino mice. METHODS: In the present study, its anti-neoplastic activity has been studied by monitoring parameters like tumor weight measurement, survival time, tumor cell growth inhibition, haematological characteristics etc. RESULTS: It was found that EEAC at dose 8 mg/kg/day (i.p.) significantly decreased tumor weight (62.0%; P <0.01), increased life span (70.25%; P <0.01) and reduced tumor cell growth rate (85.7%; P <0.01) in comparison to those of EAC bearing mice. The plant extract also improved the depleted haematological parameters like RBC, WBC, Hb%, differential counts (e.g. lymphocytes, neutrophils, monocytes etc) of EAC bearing mice towards normal. The host toxic effects were not very high and recovered gradually towards normal within a few days after treatment. CONCLUSIONS: EEAC exhibits potent in vivo cytotoxic activity against EAC tumor bearing Swiss Albino mice. So, the plant can be considered as a probable new source of antitumor agents. PMID- 22221756 TI - Antimalarial potency of the leaf extract of Aspilia africana (Pers.) C.D. Adams. AB - OBJECTIVE: To investigate the antimalarial activity of ethanol extract of Aspilia africana (A. africana) leaf. METHODS: The ethanol extract of A. africana leaf (100-400 mg/kg) was screened for blood schizonticidal effect against chloroquine sensitive Plasmodium berghei (P. berghei) in mice both in early and established models of antimalarial studies. RESULTS: The leaf extract exhibited significant (P<0.05) antiplasmodial activity in 4-day early infection and in established infection tests with a considerable mean survival time comparable to that of standard drug, chloroquine (10 mg/kg). CONCLUSIONS: The findings show that ethanol extract of A. africana leaf possesses potent antiplasmodial activity which justify the use in ethnomedicine and can be developed in malaria therapy. PMID- 22221757 TI - Anti-arthritis activity of roots of Hemidesmus indicus R.Br. (Anantmul) in rats. AB - OBJECTIVE: To investigate the protective effects of hydroalcoholic and its fractions from roots of Hemidesmus indicus on arthritis in in vitro models of rodents. METHODS: Preliminary phytochemical analysis and thin-layer chromoatography were performed to analyze constituents of hydroalcoholic extract and its three fraction namely ethyl acetate fraction, chloroform fraction and residual fraction of root of Hemidesmus indicus. Arthritis rats models were established by Complete Freund's Adjuvant. The parameters including paw edema, body weight, arthritic index, erythrocyte sedimentation rate, serum rheumatoid factor, serum C-reactive protein, serum nitrite level, and histopathology of synovial joints were observed. Methotrexate was taken as positive control. RESULTS: Rats treated with hydroalcoholic extract (450 mg/kg, p.o.), ethyl acetate (75 mg/kg, p.o.), chloroform (60 mg/kg, p.o) and residual fractions (270 mg/kg, p.o.), showed significant decrease in physical and biochemical parameters compared with arthritic model rats. Hydroalcoholic extract and its ethyl acetate fraction of Hemidesmus indicus showed significantly higher anti-arthritic activity than chloroform and residual fraction. Histopathological analysis demonstrated that both of hydroalcoholic extract and its ethyl acetate fraction had comparable anti-arthritic activity with methotrexates. CONCLUSIONS: The present study suggests that Hemidesmus indicus has protective activity against arthritis and the activity might be attributed to presence of terpenoid in hydroalcoholic extract, as well as in ethyl acetate fraction. PMID- 22221758 TI - Apoptosis, antimicrobial and antioxidant activities of phytochemicals from Garcinia malaccensis Hk.f. AB - OBJECTIVE: To study the chemical constituents of stembark of Garcinia malaccensis (G. malaccensis) together with apoptotic, antimicrobial and antioxidant activities. METHODS: Purification and structure elucidation were carried out by chromatographic and spectroscopic techniques, respectively. MTT and trypan blue exclusion methods were performed to study the cytotoxic activity. Antibacterial activity was conducted by disc diffusion and microdilution methods, whereas antioxidant activities were done by ferric thiocyanate method and DPPH radical scavenging. RESULTS: The phytochemical study led to the isolation of alpha,beta mangostin and cycloart-24-en-3beta-ol. alpha-Mangostin exhibited cytotoxic activity against HSC-3 cells with an IC(50) of 0.33 MUM. beta- and alpha mangostin showed activity against K562 cells with IC(50) of 0.40 MUM and 0.48 MUM, respectively. alpha-Mangostin was active against Gram-positive bacteria, Staphylococcus aureus (S. aureus) and Bacillus anthracis (B. anthracis) with inhibition zone and MIC value of (19 mm; 0.025 mg/mL) and (20 mm; 0.013 mg/mL), respectively. In antioxidant assay, alpha-mangostin exhibited activity as an inhibitor of lipid peroxidation. CONCLUSIONS: G. malaccensis presence alpha- and beta-mangostin and cycloart-24-en-3beta-ol. beta-Mangostin was found very active against HSC-3 cells and K562. The results suggest that mangostins derivatives have the potential to inhibit the growth of cancer cells by inducing apoptosis. In addition, alpha-and beta-mangostin was found inhibit the growth of Gram positive pathogenic bacteria and also showed the activity as an inhibitor of lipid peroxidation. PMID- 22221759 TI - Antibacterial potential of sponge endosymbiont marine Enterobacter sp at Kavaratti Island, Lakshadweep archipelago. AB - OBJECTIVE: To isolate antibacterial potential of sponge endosymbiotic bacteria from marine sponges at Lakshadweep archipelago. Also to identify the potent bacteria by 16s rDNA sequencing and determine the antibacterial activity against clinical pathogens by MIC. METHODS: Sponge samples was collected from sub-tidal habitats at Kavaratti Island and identified. The endosymbiotic bacteria were isolated and selected potential bacteria which show antibacterial activity in preliminary screening against clinical pathogens Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Salmonella typhi (S. typhi), Klebsiella pneumoniea (K. pneumoniea) and Streptococcus sp. by disc diffusion assay. The crude extracts of potential bacteria LB3 was tested against clinical pathogens by MIC. The LB3 strain was identified by 16s rDNA sequencing, 1 111 bp was submitted in NCBI (HQ589912) and constructed phylogenetic tree. RESULTS: Sponge sample was identified as Dysidea granulosa (D. granulosa) and potential bacteria LB3 identified as Enterobacter sp TTAG. Preliminary screening of sponge isolates against clinical pathogens, LB3 strain was selected as potential producer of secondary metabolites and crude extract was implies on MIC of LB3 have confirmed with lowest concentration of 5.0 mg/mL in broth medium influence of crude extract on growth inhibitory activity after 5 h of incubation period and completed the inhibitory activity at 15 h. CONCLUSIONS: The present study concluded that phylogenetic analysis of endosymbiotic bacteria Enterobacter sp from sponge D. granulosa of Lakshadweep islands showed significant antibacterial activity against clinical bacterial pathogens. PMID- 22221760 TI - Antidiarrheal activity of Pterocarpus erinaceus methanol leaf extract in experimentally-induced diarrhea. AB - OBJECTIVE: To investigate the antidiarrheal activity of the methanol leaf extract of Pterocarpus erinaceus in vivo. METHODS: The methanol leaf extract of Pterocarpus erinaceus was evaluated using different doses (100, 200 and 400 mg/kg body weight) orally for antidiarrheal activity using castor oil-induced diarrhea, charcoal meal transit time and castor oil-induced enteropooling in different groups of albino Wistar mice. The activity of the extract at different doses were compared to diphenoxylate (5 mg/kg) and atropine sulphate (3 mg/kg) which were used as standard reference drugs and also to the distilled water administered negative control group of mice. RESULTS: The extract at the doses used caused a significant (P< 0.01) reduction in the wet faeces passed by the mice in the castor oil-induced diarrhea, decreased the distance travelled by the charcoal meal by up to 54.8% and also caused a dose dependent and significant (P< 0.001) reduction in the intraluminal fluid accumulation in the castor oil-induced enteropooling. CONCLUSIONS: Our results indicate that Pterocarpus erinaceus extract produced significant antidiarrheal activity and the action may attribute to inhibition of gastrointestinal movement and fluid secretion. PMID- 22221761 TI - Eysenck personality and psychosocial status of adult patients with malocclusion. AB - OBJECTIVE: To evaluate the personality and psychosocial status of adult malocclusion patients through the Eysenck Personality Questionnaire (EPQ) and the Symptom Checklist 90 (SCL-90). METHODS: The EPQ and the SCL-90 were administered to 348 adult respondents with Angle's Class I, II, III malocclusion and normal occlusion. Personality and psychosocial traits were analyzed and compared among the groups. RESULTS: Patients in Angle's Class I, II and III groups scored lower on the EPQ-E and higher on the EPQ-N than those in the normal occlusion group, whereas patients in the Class II group scored higher on the EPQ-P. The mean scores of Class I, II and III groups were significantly higher than those of the normal group on somatization, obsessive-compulsiveness, interpersonal sensitivity, depression, anxiety, and paranoid ideation. All SCL-90 scores were significantly positively correlated with EPQ-N. Psychoticism and neuroticism scores of female respondents were higher than those of male respondents. The impact of education was greatest on the EPQ-P and the EPQ-E of adult personality, whereas the impact of deformity was greatest on the EPQ-N of adult personality. CONCLUSIONS: Personality and psychosocial status show differences in adult patients with Class I, II, III malocclusion and normal occlusion and can be influenced by gender, deformity, age and education. PMID- 22221762 TI - An epidemiology study of bronchial asthma in the Li ethnic group in China. AB - OBJECTIVE: To investigate the prevalence and risk factors of bronchial asthma in the Li ethnic group in Hainan, China. METHODS: This study employed a stratified random sample design using custom-designed questionnaires. Subjects with asthma like symptoms were first identified by two rounds of surveys and then confirmed by respiratory physicians using pulmonary function test, bronchial dilation test and challenge test. Demographic data, information on family history of asthma, history of allergies, smoking habits, domestic cooking fuel and other potential risk factors were collected. Logistic regression was performed to evaluate risk factors for asthma. RESULTS: The prevalence of asthma in the Li ethnic group was 3.38%, much higher than the national average level in China. Aging, agriculture industry (the rubber industry in particular), rural residence, family history of asthma, history of allergies, cold air, inhalation of dust and irritant gases, smoking, domestic cooking fuel and living environment were associated with increased risk of asthma. CONCLUSIONS: The high prevalence of asthma in the Li ethnic group highlights the importance of asthma prevention and treatment in this population. Risk factors indentified in this study warrant special attention. Elevating public awareness about asthma in local communities will benefit the prevention of the disease. PMID- 22221763 TI - Study of the hippocampus and the anterior cingulate gyrus by proton MR spectroscopy in patients with post-traumatic stress disorder. AB - OBJECTIVE: To explore the characteristics of metabolic changes in patients with post-traumatic stress disorder through 1H-MRS in neuroanatomical circuit comparing with age-matches controls. METHODS: Fifty patients with post-traumatic stress disorder and 50 gender-and age-matched normal controls were involved. The neurochemical abnormalities including the levels of choline (Cho)/creatine(Cr) and N-acetylaspartate (NAA)/Cr were measured respectively in hippocampus and the anterior cingulate gyrus with three-dimension 1H-proton spectroscopy(3D 1H-MRS). RESULTS: The values of NAA/Cr ratios in hippocampus and the anterior cingulate gyrus were significant lower in patients with post-traumatic stress disorder(1.71+/-0.32, left 1.58+/-0.29, right 1.55+/-0.31) than that in controls(2.24+/-0.41, left 1.98+/-0.27, right 2.02+/-0.36)(P<0.05), but the values of Cho/Cr in hippocampus(left 1.64+/-0.23, right 1.66+/-0.34) were no significant with that of controls (left 1.48+/-0.29, right 1.54+/-0.38). Values of Cho/Cr in cingulate gyrus were significant higher in post-traumatic stress disorder patients (1.88+/-0.44) than that in controls (1.37.+/-0.32) (P<0.05). CONCLUSIONS: The results indicate some special neurochemical and histological structure changes in post-traumatic stress disorder patients, which might occurre earlier in anterior cingulate gyrusthe than in hippocampus. PMID- 22221764 TI - Primary human hepatocyte transplantation in the therapy of hepatic failure: 2 cases report. AB - Liver failure is the end stage of hepatopathy with unfavorable prognosis. In two patients with liver failure, viable primary human hepatocytes, obtained from resected liver tissue of patients with hepatolithiasis, were transplanted into the spleen by interventional therapy through femoral arterial cannula. After transplantation, the patients' clinical symptoms and liver function were significantly improved. However, their bilirubin increased within six days following transplantation. One suffered from hepatic coma and give up treatment and the other patient died fourteen days after transplantation. It is technically safe to treat liver failure by intrasplenic transplantation of adult hepatocytes and the clinical efficacy has been confirmed. How to make transplanted hepatic cells proliferate and functionally survive is the key point to maintain continuous improvement of the recipient's hepatic function. PMID- 22221765 TI - Validity and reliability of the Iranian version of the Pediatric Quality of Life InventoryTM 4.0 (PedsQLTM) Generic Core Scales in children. AB - BACKGROUND: This study aimed to investigate the reliability and validity of the Iranian version of the Pediatric Quality of Life InventoryTM 4.0 (PedsQLTM 4.0) Generic Core Scales in children. METHODS: A standard forward and backward translation procedure was used to translate the US English version of the PedsQLTM 4.0 Generic Core Scales for children into the Iranian language (Persian). The Iranian version of the PedsQLTM 4.0 Generic Core Scales was completed by 503 healthy and 22 chronically ill children aged 8-12 years and their parents. The reliability was evaluated using internal consistency. Known groups discriminant comparisons were made, and exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were conducted. RESULTS: The internal consistency, as measured by Cronbach's alpha coefficients, exceeded the minimum reliability standard of 0.70. All monotrait-multimethod correlations were higher than multitrait-multimethod correlations. The intraclass correlation coefficients (ICC) between the children self-report and parent proxy-reports showed moderate to high agreement. Exploratory factor analysis extracted six factors from the PedsQLTM 4.0 for both self and proxy reports, accounting for 47.9% and 54.8% of total variance, respectively. The results of the confirmatory factor analysis for 6-factor models for both self-report and proxy-report indicated acceptable fit for the proposed models. Regarding health status, as hypothesized from previous studies, healthy children reported significantly higher health-related quality of life than those with chronic illnesses. CONCLUSIONS: The findings support the initial reliability and validity of the Iranian version of the PedsQLTM 4.0 as a generic instrument to measure health-related quality of life of children in Iran. PMID- 22221766 TI - A uniquely modern human pattern of endocranial development. Insights from a new cranial reconstruction of the Neandertal newborn from Mezmaiskaya. AB - The globular braincase of modern humans is distinct from all fossil human species, including our closest extinct relatives, the Neandertals. Such adult shape differences must ultimately be rooted in different developmental patterns, but it is unclear at which point during ontogeny these group characteristics emerge. Here we compared internal shape changes of the braincase from birth to adulthood in Neandertals (N = 10), modern humans (N = 62), and chimpanzees (N = 62). Incomplete fossil specimens, including the two Neandertal newborns from Le Moustier 2 and Mezmaiskaya, were reconstructed using reference-based estimation methods. We used 3D geometric morphometrics to statistically compare shapes of virtual endocasts extracted from computed-tomographic scans. Throughout the analysis, we kept track of possible uncertainties due to the missing data values and small fossil sample sizes. We find that some aspects of endocranial development are shared by the three species. However, in the first year of life, modern humans depart from this presumably ancestral pattern of development. Newborn Neandertals and newborn modern humans have elongated braincases, and similar endocranial volumes. During a 'globularization-phase' modern human endocasts change to the globular shape that is characteristic for Homo sapiens. This phase of early development is unique to modern humans, and absent from chimpanzees and Neandertals. Our results support the notion that Neandertals and modern humans reach comparable adult brain sizes via different developmental pathways. The differences between these two human groups are most prominent directly after birth, a critical phase for cognitive development. PMID- 22221767 TI - Enzyme-linked immunosorbent serum assay specific for the 7S domain of Collagen Type IV (P4NP 7S): A marker related to the extracellular matrix remodeling during liver fibrogenesis. AB - AIM: The present study describes the ability of a newly developed N-terminal pro-peptides of type IV collagen 7S domain (P4NP 7S) competitive enzyme-linked immunosorbent assay (ELISA) for describing liver fibrosis. The assay applies a monoclonal antibody specific for a PIVNP 7S epitope 100% homologous in the human, rat, and mouse species. METHODS: Monoclonal antibodies were raised against selected P4NP 7S specific sequences. Antibodies were screened and a competitive ELISA assay was developed using a selected antibody. The assay was evaluated in relation to technical performance, and in two preclinical liver fibrosis models; the bile duct ligation model (BDL) and the carbon tetrachloride model (CCL4) both performed in rats. RESULTS: A technically robust P4NP 7S ELISA assay using a monoclonal antibody was produced. In the BDL and CCL4 liver fibrosis models it was observed that the P4NP 7S levels were significantly elevated in rat with liver fibrosis as seen by histology (CCL4: 283% elevated in the highest quartile of total hepatic collagen compared with controls, P = 0.001; BDL: 183% elevated at week 4 compared with sham, P < 0.001) and correlated to the amount of hepatic type IV collagen expression in BDL rats (r = 0.49, P < 0.05) in contrast to sham (r = -0.12). P4NP 7S also correlated to total collagen in CCL4 treated livers (P < 0.001, r = 0.67), however, not in controls (r = 0.04). CONCLUSIONS: This newly developed serum assay specific for P4NP 7S was highly related to liver fibrosis and correlated to extent of hepatic fibrosis. This assay may improve fibrosis quantification. PMID- 22221768 TI - Development and application of an antigen capture ELISA assay for diagnosis of Japanese encephalitis virus in swine, human and mosquito. AB - BACKGROUND: Japanese encephalitis (JE) is a serious zoonosis caused by the Japanese encephalitis virus (JEV) which is a mosquito-borne pathogen of the family Flavivirus. However, the application of several developed laboratory methods for the detection of JEV antigens or antibodies are limited by their requirements of laboratory operations, skilled technicians and special facilities. RESULTS: To develop a method for detecting JEV antigen in swine, human, mosquito and other clinical specimens specifically, conveniently and effectively, an antigen capture enzyme-linked immunosorbent assay (ELISA) was established in this study. Sensitivity, specificity, repeatability and stability of the developed method were evaluated, and 60 clinical samples were tested in this study. The results demonstrated that the antigen capture ELISA was capable in detecting JEV antigen with high sensitivity and specificity compared with conventional methods. 14 samples showed the positive result with coincidence rate of 70%, and 46 displayed negative result with coincidence rate of 100% as compared to that of reverse transcription-polymerase chain reaction (RT-PCR). CONCLUSIONS: The developed ELISA assay provides a convenient and specific method for the large-scale determination of JEV antigen in infected swine, human and mosquito samples with high sensitivity and specificity. PMID- 22221769 TI - Cognitive impairment and vitamin B12: a review. AB - BACKGROUND: This review examines the associations between low vitamin B12 levels, neurodegenerative disease, and cognitive impairment. The potential impact of comorbidities and medications associated with vitamin B12 derangements were also investigated. In addition, we reviewed the evidence as to whether vitamin B12 therapy is efficacious for cognitive impairment and dementia. METHODS: A systematic literature search identified 43 studies investigating the association of vitamin B12 and cognitive impairment or dementia. Seventeen studies reported on the efficacy of vitamin B12 therapy for these conditions. RESULTS: Vitamin B12 levels in the subclinical low-normal range (<250 rhomol/L) are associated with Alzheimer's disease, vascular dementia, and Parkinson's disease. Vegetarianism and metformin use contribute to depressed vitamin B12 levels and may independently increase the risk for cognitive impairment. Vitamin B12 deficiency (<150 rhomol/L) is associated with cognitive impairment. Vitamin B12 supplements administered orally or parenterally at high dose (1 mg daily) were effective in correcting biochemical deficiency, but improved cognition only in patients with pre-existing vitamin B12 deficiency (serum vitamin B12 levels <150 rhomol/L or serum homocysteine levels >19.9 MUmol/L). CONCLUSION: Low serum vitamin B12 levels are associated with neurodegenerative disease and cognitive impairment. There is a small subset of dementias that are reversible with vitamin B12 therapy and this treatment is inexpensive and safe. Vitamin B12 therapy does not improve cognition in patients without pre-existing deficiency. There is a need for large, well-resourced clinical trials to close the gaps in our current understanding of the nature of the associations of vitamin B12 insufficiency and neurodegenerative disease. PMID- 22221770 TI - Magnetization reversal of Co/Pd multilayers on nanoporous templates. AB - By making use of an e-beam deposition system, the [Co(2 A)/Pd(10 A)]15 multilayers were prepared on a Si(100) substrate and anodized aluminum oxide [AAO] templates with average pore diameters of around 185, 95, and 40 nm. The mechanism of magnetization reversal of the Co/Pd multilayers was investigated. Wall motion was observed on the Co/Pd multilayers grown on the Si substrate. A combination of wall motion and domain rotation was found in the sample grown on the AAO template with a 185-nm pore diameter. For the samples grown on the AAO templates with pore diameters of around 95 and 40 nm, the reversal mechanism was dominated by domain rotation. The rotational reversal was mainly contributed from the underlying nanoporous AAO templates that provided an additional pinning effect.PACS: 75.30.Gw, magnetic anisotropy; 78.67.Rb, nanoporous materials; 75.60.Jk, magnetization reversal mechanisms. PMID- 22221771 TI - [Control of cardiovascular risk factors in HIV-infected patients with ischemic heart disease]. PMID- 22221772 TI - [The revival of datura and brugmansia as recreational drugs]. PMID- 22221773 TI - [About staphylococci and the Spanish grammar]. PMID- 22221774 TI - [Testicular plasmablastic lymphoma as a first manifestation of HIV infection]. PMID- 22221775 TI - Solution reaction design: electroaccepting and electrodonating powers of ions in solution. AB - By considering a first-order variation in electroaccepting and electrodonating powers, omega+/-, induced by a change from gas to aqueous solution phase, the solvent effect on omega+/- for charged ions is examined. The expression of electroaccepting and electrodonating powers in the solution phase, omega+/-s, is obtained through establishing the quantitative relationship between the change of the omega+/- due to the solvation and the hydration free energy. It is shown that cations are poorer electron acceptors and anions are poorer electron donors in solution compared to those in gas phase. We have proven that the scaled aqueous electroaccepting power, omega+s, of cations can act as a good descriptor of the reduction reaction, which is expected to be applied in the design of solution reactions. PMID- 22221776 TI - Open-label, pilot study examining sequential therapy with oral tacrolimus and topical tacrolimus for severe atopic dermatitis. AB - BACKGROUND: Systemic treatment options for generalized atopic dermatitis (AD) are limited. To our knowledge, there have been no prospective trials examining the use of oral tacrolimus, a calcineurin inhibitor, in AD. OBJECTIVES: We assessed the safety and efficacy of sequential therapy with oral tacrolimus and topical tacrolimus in the treatment of generalized AD using the Eczema Area and Severity Index and the Physician Global Assessment scores as the primary end points. METHODS: Twelve patients with AD covering at least 50% body surface area were enrolled. Patients in both phases of the study received sequential therapy with oral and topical tacrolimus over a 14-week treatment period. Eczema Area and Severity Index, Physician Global Assessment, and pruritus scores were calculated at each study visit. RESULTS: Patients recorded a 67% improvement in the Eczema Area and Severity Index score, a 45% improvement in the Physician Global Assessment score, and a 69% reduction in the pruritus score. LIMITATIONS: This investigator-initiated, open-label, single-center, proof-of-concept study lacks a large sample size and placebo control group. CONCLUSION: Sequential therapy with oral tacrolimus and topical tacrolimus may be an effective treatment for AD. A large, randomized control study is warranted. PMID- 22221777 TI - Effect of triplet multiple quantum well structures on the performance of blue phosphorescent organic light-emitting diodes. AB - We investigate multiple quantum well [MQW] structures with charge control layers [CCLs] to produce highly efficient blue phosphorescent organic light-emitting diodes [PHOLEDs]. Four types of devices from one to four quantum wells are fabricated following the number of CCLs which are mixed p- and n-type materials, maintaining the thickness of the emitting layer [EML]. Remarkably, such PHOLED with an optimized triplet MQW structure achieves maximum luminous and external quantum efficiency values of 19.95 cd/A and 10.05%, respectively. We attribute this improvement to the efficient triplet exciton confinement effect and the suppression of triplet-triplet annihilation which occurs within each EML. It also shows a reduction in the turn-on voltage from 3.5 V (reference device) to 2.5 V by the bipolar property of the CCLs. PMID- 22221778 TI - How can we improve life expectancy and quality of life in long-term survivors after allogeneic stem cell transplantation? PMID- 22221779 TI - Second solid tumors: screening and management guidelines in long-term survivors after allogeneic stem cell transplantation. AB - With greater numbers of patients surviving long-term after allogeneic stem cell transplantation (SCT), second malignancies have increasingly been recognized. Secondary solid tumors, the most prevalent second malignancies after allogeneic SCT, are reviewed with particular emphasis on recent developments in the pathogenesis, early diagnosis, and treatment of these transplant-related complications. PMID- 22221780 TI - Challenges to preventing infectious complications, decreasing re hospitalizations, and reducing cost burden in long-term survivors after allogeneic hematopoietic stem cell transplantation. AB - Even though the overall outcome after allogeneic transplant has improved significantly in the last decades, late infectious diseases are still the most important causes of late morbidity and mortality. Here, impaired immune reconstitution and therapy of chronic graft-versus-host disease (GVHD) represent the major risk factors. In this review, we give a comprehensive overview of late infectious complications and summarize possible diagnostic and therapeutic interventions to prevent these complications. PMID- 22221781 TI - Late pulmonary complications after allogeneic hematopoietic stem cell transplantation: diagnosis, monitoring, prevention, and treatment. AB - Bronchiolitis obliterans syndrome (BOS) is a life-threatening complication that occurs among recipients of allogeneic lung and hematopoietic stem cell transplantation (allo-HSCT). BOS usually occurs within the first 2 years but may develop as late as 5 years after allo-HSCT. Recent prevalence estimates suggest that BOS is likely underdiagnosed in the clinical setting and that 14% of all long-term survivors with chronic graft-versus-host disease (GVHD) may develop BOS. It is difficult to diagnose and once respiratory symptoms appear, most allo HSCT recipients show severe airflow obstruction. This may be due, at least in part, to the low sensitivity of standard spirometry in detecting small airways obstruction and lack of formal recommendations for screening for this complication. The prognosis of BOS is poor with reported 5-year survival of about 15%. A key obstacle in advancing clinical research in BOS is the lack of diagnostic and therapeutic response standards, making interpretation of survival and treatment results between studies difficult. This situation has significantly improved due to the introduction of the National Institutes of Health (NIH) criteria, which provide investigators with common definitions for studying BOS and for assessing the effects of therapeutic interventions. Future advances in the therapy of BOS may need to include development of better early intervention strategies based on identification of reliable early biological markers of the disease. It would be also important to improve understanding of the biological heterogeneity of this devastating complication after allo-HSCT. PMID- 22221782 TI - Cardiovascular complications in long-term survivors after allogeneic hematopoietic stem cell transplantation. AB - Cardiovascular diseases (CVD) are emerging late effects after allogeneic hematopoietic stem cell transplantation (allo-HSCT), leading to considerable morbidity and mortality. These late CVD are in most cases related to enhanced atherosclerosis, promoted by the early appearance after transplantation of cardiovascular risk factors. According to the data obtained from the general population it is very likely that early intervention on these cardiovascular risk factors might defer the appearance of late CVD. This review focuses on the published data of cardiovascular diseases after transplantation, the potential associated risk factors, and the postulated pathophysiological mechanisms. A suggested approach for early identification of patients at risk, optimal surveillance, and screening of the modifiable cardiovascular risk factors and the possible early interventions are also discussed here. Long-term survivors should be assessed lifelong after HSCT; all healthcare providers involved in the follow up of these patients should be aware of premature health threatening of cardiovascular diseases after transplantation. PMID- 22221783 TI - Management of high ferritin in long-term survivors after hematopoietic stem cell transplantation. AB - Management of high serum ferritin levels after allogeneic hematopoietic stem cell transplantation (allo-HSCT) should, from the diagnostic standpoint, be based on the pathophysiological mechanisms underlying the development of hyperferritinemia. This knowledge is essential for differentiating increased serum ferritin due to iron overload from "non-iron overload" situations such as inflammation, metabolic syndrome, or hepatitis. Once body iron overload has been proven, especially by quantifying tissue iron excess with the noninvasive magnetic resonance imaging (MRI) method, it is important, considering the damaging effects of chronic iron overload in these patients, to start iron depletive therapy by oral chelation or phlebotomy. At present, more data are needed to assess the long-term deleterious effects of iron excess in the HSCT population, and to define the most appropriate therapeutic strategy for removing iron burden. Also, preventing iron overload prior to HSCT might prove essential for improving patient prognosis through decreasing HSCT-related mortality. PMID- 22221784 TI - Gastrointestinal, hepatobiliary, pancreatic, and iron-related diseases in long term survivors of allogeneic hematopoietic cell transplantation. AB - Gastrointestinal and hepatobiliary problems in the second year after allogeneic hematopoietic cell transplant (HCT) are usually a continuation of symptoms of protracted acute graft-versus-host disease (GVHD), chronic GVHD, medication side effects, and infection related to immune suppression. As time passes, as tolerance develops, and as immunity improves, the frequency and severity of these problems wane, but new problems involving the gut and liver may arise, sometimes insidiously and sometimes decades after the transplant. Examples are esophageal strictures related to chronic GVHD, gallstones, cirrhosis caused by chronic hepatitis C, secondary malignancy, and rare cases of pancreatic atrophy. One very common complication of transplantation, iron overload, is often associated with substantial iron accumulation in the liver; however, the most troublesome complications are not hepatic but cardiac and endocrine-related. PMID- 22221785 TI - Bone loss and avascular necrosis of bone after hematopoietic cell transplantation. AB - Advances in transplantation technology and supportive care measures have resulted in significant decrease in early mortality resulting in continued growth in the number of long-term hematopoietic cell transplantation (HCT) survivors. The intensity of chemotherapy and total body irradiation regimen used pretransplantation to eradicate the primary disease can lead to organ toxicities, including significant bone complications after HCT. Bone loss is frequent in HCT recipients and results from impaired bone mineralization through disturbances of calcium and vitamin D homeostasis, osteoblast and osteoclast dysfunction, and deficiencies in growth or gonadal hormone secretion. Exposure to glucocorticoids and calcineurin inhibitors for prevention and treatment of graft-versus-host disease (GVHD) represents one of the major causes for the increased risk of osteoporosis and avascular necrosis of bone (AVN) in recipients of allogeneic HCT. In this article we review the incidence, pathogenesis, and risk factors for osteoporosis and AVN after allogeneic HCT and discuss general guidelines for their treatment and monitoring based on the limited available reports. PMID- 22221786 TI - Endocrine complications in long-term survivors after allogeneic stem cell transplant. AB - As survival rates continue to increase after allogeneic stem cell transplant (allo-SCT), the associated long-term complications of transplant need to be taken into consideration. Here, we review the endocrine and metabolic complications associated with transplant survivors, including diabetes, dyslipidemia, hypertension, cardiovascular disease, hypogonadism, vitamin D deficiency, osteoporosis, thyroid disease, adrenal dysfunction, and pituitary disorders, and provide a brief summary of evaluation and treatment of these conditions. PMID- 22221787 TI - Chronic kidney diseases in long-term survivors after allogeneic hematopoietic stem cell transplantation: monitoring and management guidelines. AB - Chronic kidney disease (CKD) occurs commonly (prevalence of approximately 20% in a large series) after allogeneic hematopoietic stem cell transplantation (HSCT). There are three distinct clinical entities that occur after HSCT: thrombotic microangiopathy (TMA), nephrotic syndrome (NS), and idiopathic or graft-versus host disease (GVHD)-related CKD. Acute renal function decline occurs in the majority of patients in the first months after transplantation. This acute kidney injury can persist and is a risk factor for the later development of CKD. However, the potentially independent role of GVHD, chronic inflammation, and chronic exposure to calcineurin inhibitors in the development and progression of CKD warrants further investigation. Careful monitoring of blood pressure, renal function, and proteinuria is mandatory in patients undergoing HSCT, especially older patients with pre-existent renal impairment. Renal function should be evaluated before HSCT and monitoring should occur at least every 6 to 12 months in these patients. Renal biopsies are indicated in patients with proteinuria and persistent or progressive rises in serum creatinine to determine etiology and prevent progression to end-stage renal disease (ESRD). PMID- 22221789 TI - Long-term follow-up and management guidelines in pediatric patients after allogenic hematopoietic stem cell transplantation. AB - Over the past 50 years there has been considerable progress and success in the field of allogeneic hematopoietic stem cell transplant (HSCT) in children. In addition there has been significant improvement in transplant outcomes for both malignant and nonmalignant indications. These improved outcomes have resulted in many long-term survivors who are experiencing substantial long-term morbidities. There are limited data examining the long-term complications of transplant on the various organs. This issue is complicated by the fact that children receive their transplant at different stages of their growth and development (ie, infant, toddler, child, adolescent, and young adult). Each of these developmental stages has different sensitivities to treatment and can result in different sets of complications. We summarize the long-term side effects of allogeneic HSCT in children. PMID- 22221788 TI - Female long-term survivors after allogeneic hematopoietic stem cell transplantation: evaluation and management. AB - Female long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) incur a significant burden of late effects. Genital graft-versus-host disease (GVHD), human papillomavirus (HPV) reactivation, ovarian failure and infertility, sexual dysfunction, and osteoporosis are concerns that can significantly impact quality of life. This review examines the risk, pathogenesis, clinical presentation, and implications of these common complications. Recommendations are provided for evaluation and management of these late effects and other obstetric and gynecologic issues that may arise in this patient population. PMID- 22221790 TI - Quality of life, social challenges, and psychosocial support for long-term survivors after allogeneic hematopoietic stem-cell transplantation. AB - Over the last two decades quality of life (QoL) and the social challenges of allogeneic hematopoietic stem cell transplant (allo-HSCT) survivors have been emerging as subjects of extensive research and are now considered as very important aspects in the pretransplant evaluation and management of allo-HSCT recipients. Recognition of QoL challenges in allo-HSCT survivors allows timely interventions leading to improvement of post-transplant outcomes. It needs to be recognized that long-lasting life changes associated with survivorship after allo HSCT also significantly affect QoL of partners of allo-HSCT survivors. Currently, resources should be focused on how research findings can be used by patients, their partners, and physicians to optimize QoL and psychosocial adjustment. PMID- 22221792 TI - Structural analysis of capsular polysaccharides expressed by Burkholderia mallei and Burkholderia pseudomallei. AB - Capsular polysaccharides (CPSs) were isolated from O-polysaccharide deficient strains of Burkholderia mallei and Burkholderia pseudomallei using a modified hot phenol/water extraction procedure. Glycosyl composition, methylation, MALDI-TOF MS analyses as well as (1)H NMR spectroscopy including COSY, TOCSY, NOESY, HMBC and HSQC experiments identified the presence of two distinct CPS antigens in the samples exhibiting the following structures: This study confirms the ability of B. mallei to express a 6-deoxy-heptan CPS and represents the first report of a mannan CPS being expressed by these bacterial pathogens. PMID- 22221791 TI - Volumetric and acoustic properties of D-mannitol in aqueous sodium or magnesium chloride solutions over temperature range of 293.15-313.15K. AB - Apparent molar volumes and apparent molar compressibilities for d-mannitol in (1, 5 and 10) % aqueous sodium or magnesium chloride have been determined from solution density measurements at T=(293.15, 298.15, 303.15, 308.15, 310.15, and 313.15)K and sound velocity measurements at T=(293.15 and 310.15)K as a function of the concentration of sugar alcohol. The limiting apparent molar volumes and limiting apparent molar compressibilities have been obtained from the Masson equation. The corresponding transfer parameters and expansion coefficients were also estimated. These parameters have been discussed in terms of d-mannitol cosolute (NaCl or MgCl(2)) interactions in aqueous solutions and thus used to understand the mixing effects due to these interactions. PMID- 22221793 TI - Nanoporous impedemetric biosensor for detection of trace atrazine from water samples. AB - Trace contamination of ground water sources has been a problem ever since the introduction of high-soil-mobility pesticides, one such example is atrazine. In this paper we present a novel nanoporous portable bio-sensing device that can identify trace contamination of atrazine through a label-free assay. We have designed a pesticide sensor comprising of a nanoporous alumina membrane integrated with printed circuit board platform. Nanoporous alumina in the biosensor device generates a high density array of nanoscale confined spaces. By leveraging the size based immobilization of atrazine small molecules we have designed electrochemical impedance spectroscopy based biosensor to detect trace amounts of atrazine. We have calibrated the sensor using phosphate buffered saline and demonstrated trace detection from river and bottled drinking water samples. The limit of detection in all the three cases was in the femtogram/mL (fg/mL) (parts-per-trillion) regime with a dynamic range of detection spanning from 10 fg/mL to 1 ng/mL (0.01 ppt to 1 ppm). The selectivity of the device was tested using a competing pesticide; malathion and selectivity in detection was observed in the fg/mL regime in all the three cases. PMID- 22221794 TI - Photoelectrochemical biofuel cell using porphyrin-sensitized nanocrystalline titanium dioxide mesoporous film as photoanode. AB - Electrical energy generated directly from sunlight and biomass solution with a Photoelectrochemical Biofuel Cell (PEBFC) was investigated. The PEBFC consisted of a meso-tetrakis(4-carboxyphenyl)porphyrin (TCPP)-sensitized nanocrystalline titanium dioxide (TiO(2)) mesoporous film (NTDMF) as the photoanode and platinum black as the cathode. The interaction between TCPP sensitizer and NTDMF was evaluated by X-ray photoelectron spectra and FT-IR absorption spectra, indicating that the TCPP sensitizer was adsorbed on the NTDMF by bridging or bidentate coordinate bonds. The spectroscopic properties of pure TCPP ethanol solution and TCPP-sensitized NTDMF were obtained by UV-vis absorption spectra, demonstrating that the characteristic absorption peaks of TCPP on NTDMF displayed slight red shift compared with pure TCPP ethanol solution. The performances of the PEBFC were obtained by photocurrent-photovoltage characteristic curves. The open circuit photovoltage (V(oc)), the short-circuit photocurrent (I(sc)) and the maximum power density (P(max)) was 0.74 V, 69.96 MUA and 33.94 MUWcm(-2) at 0.45 V, respectively. The fill factor (FF) was 0.19 and the incident photo-to-current efficiency (IPCE) was 36.0% at 436 nm. The results demonstrated that the TCPP was an appropriate photosensitizer for PEBFC. PMID- 22221795 TI - A novel automated flow-based biosensor for the determination of organophosphate pesticides in milk. AB - This work describes the development of an automated flow-based biosensor that employs genetically modified acetylcholinesterase (AChE) enzymes B394, B4 and wild type B131. The biosensor was based on a screen printed carbon electrode (SPE) that was integrated into a flow cell. Enzymes were immobilised on cobalt (II) phthalocyanine (CoPC) modified electrodes by entrapment in a photocrosslinkable polymer (PVA-AWP). The automated flow-based biosensor was successfully used to quantify three organophosphate pesticides (OPs) in milk samples. The OPs used were chlorpyriphos-oxon (CPO), ethyl paraoxon (EPOx) and malaoxon (MOx). The total analysis time for the assay was less than 15 min. Initially, the biosensor performance was tested in phosphate buffer solution (PBS) using B394, B131 and B4 biosensors. The best detection limits were obtained with B394; therefore, this biosensor was used to produce calibration data in milk with three OPs in the concentration range of 5 * 10(-6)M to 5 * 10(-12)M. The limit of detection (LOD) obtained in milk for CPO, EPOx and MOx were 5 * 10( 12)M, 5 * 10(-9)M and 5 * 10(-10)M, respectively, with a correlation coefficient R(2)=0.9910. The automated flow-based biosensor successfully quantified the OPs in different fat-containing milk samples. There were no false positives or false negatives observed for the analytical figures of merit for the constructed biosensors. This method is inexpensive, sensitive, portable, non-invasive and provides real-time results. This analytical system can provide rapid detection of highly toxic OPs in food matrices such as milk. PMID- 22221796 TI - Aptamer-DNAzyme hairpins for biosensing of Ochratoxin A. AB - We report an aptasensor for biosensing of Ochratoxin A (OTA) using aptamer DNAzyme hairpin as biorecognition element. The structure of this engineered nucleic acid includes the horseradish peroxidase (HRP)-mimicking DNAzyme and the OTA specific aptamer sequences. A blocking tail captures a part of these sequences in the stem region of the hairpin. In the presence of OTA, the hairpin is opened due to the formation of the aptamer-analyte complex. As a result, self assembly of the active HRP-mimicking DNAzyme occurs. The activity of this DNAzyme is linearly correlated with OTA concentration up to 10 nM, showing a limit of detection of 2.5 nM. PMID- 22221797 TI - Sensitive electrochemical immunosensor for alpha-synuclein based on dual signal amplification using PAMAM dendrimer-encapsulated Au and enhanced gold nanoparticle labels. AB - A novel electrochemical immunosensor for sensitive detection of alpha-synuclein (alpha-SYN), a very important neuronal protein, has been developed based on dual signal amplification strategy. Herein, G4-polyamidoamine dendrimer-encapsulated Au nanoparticles (PAMAM-Au nanocomposites) were covalently bound on the poly-o aminobenzoic acid (poly-o-ABA), which was initially electropolymerized on the electrode surface to perform abundant carboxyl groups. The formed immunosensor platform, PAMAM-Au, was proved to provide numerous amino groups to allow highly dense immobilization of antigen, and facilitate the improvement of electrochemical responses as well. Subsequently, the enhanced gold nanoparticle labels ({HRP-Ab(2)-GNPs}) were fabricated by immobilizing horseradish peroxidase secondary antibody (HRP-Ab(2)) on the surface of gold nanoparticles (GNPs). After an immunoassay process, the {HRP-Ab(2)-GNPs} labels were introduced onto the electrode surface, and produced an electrocatalytic response by reduction of hydrogen peroxide (H(2)O(2)) in the presence of enzymatically oxidized thionine. On the basis of the dual signal amplification of PAMAM-Au and {HRP-Ab(2)-GNPs} labels, the designed immunosensor displayed an excellent analytical performance with high sensitivity and stability. This developed strategy was successfully proved as a simple, cost-effective method, and could be easily extended to other protein analysis schemes. PMID- 22221798 TI - A hairpin DNA aptamer coupled with groove binders as a smart switch for a field effect transistor biosensor. AB - We report here that a hairpin-structured DNA that possesses an anti-ATP aptamer sequence successfully detected target ATP or adenosine in a temperature-dependent manner by nanoscale intramolecular displacement on the surface of a gold electrode as an extended gate of a field-effect transistor (FET). The structural switching of the hairpin aptamer from closed loop to open-loop conformations was accompanied by the release of the preloaded DNA binder (DAPI) from the stem part of the hairpin aptamer into the solution phase. The loss of intrinsic positive charges of DAPI (2+) from the diffusion layer at the gate/solution nano-interface as a result of target capturing was responsible for generating a specific signal by the field-effect. We emphasize a new aspect of the structured DNA aptamer in combination with FET: the DAPI-loaded hairpin aptamer successfully detected even uncharged adenosine, which remains a major challenge for FET-based biosensors. Given the simplicity in design of the primary and secondary structures of oligonucleotide aptamers, it is easy to apply this technology to a wide variety of bio-analytes, irrespective of their electric charges. In view of these advantages, our findings may offer a new trend in the design of stimuli responsive "smart" biomolecular switches for semiconductor-based biosensors. PMID- 22221799 TI - Impedance spectroscopy based measurement system for quantitative and label-free real-time monitoring of tauopathy in hippocampal slice cultures. AB - Alzheimer's disease (AD) and other tauopathies comprise death of cell bodies, synapses and neurites but there is surprising little knowledge of the temporal sequence and the causal relationships among these events. Here, we present a novel biosensoric approach to monitor retrograde neurite degeneration before cell death occurs. We induced tau hyperphosphorylation in organotypic hippocampal slice cultures (OHSC) and applied marker-independent real-time electrical impedance spectroscopy (EIS) for cellular real-time pathology monitoring. Using this approach, we were able to define two distinct phases of neurite degeneration, first a rapid swelling of axonal processes that manifests itself in relative impedance above control levels followed by a slower phase of collapse and subsequent fragmentation indicated by decreased relative impedance below control levels. Initial axon swelling is strictly dose-dependent and swelling intensity correlates with second phase impedance decrease implicating a causative link between both degenerative mechanisms. Moreover, suppressing tau hyperphosphorylation by kinase inhibition nearly prevented both phases of axon degeneration. Our findings demonstrate that the temporal sequence of tau triggered neurite degeneration can be directly visualized by EIS-based, non invasive and label-free monitoring. We therefore suggest this approach as a powerful extension of high content applications to study mechanisms of neurite degeneration and to exploit therapeutic options against AD and tau-related disorders. PMID- 22221800 TI - Identification of two residues essential for the stringent substrate specificity and active site stability of the prokaryotic l-arginine:glycine amidinotransferase CyrA. AB - A novel prokaryotic l-arginine:glycine amidinotransferase (CyrA; EC2.1.4.1) is involved in the biosynthesis of the polyketide-derived cytotoxin cylindrospermopsin in the cyanobacterium Cylindrospermopsis raciborskii AWT250, and was previously characterized with regard to kinetic mechanism and substrate specificity [Muenchhoff J et al. (2010) FEBS J277, 3844-3860]. In order to elucidate the structure-function-stability relationship of this enzyme, two residues in its active site were replaced with the residues that occur in the human l-arginine:glycine amidinotransferase (h-AGAT) at the corresponding positions (F245N and S247M), and a double variant carrying both substitutions was also created. In h-AGAT, both of these residues are critical for the function of this enzyme with regard to substrate binding, ligand-induced structural changes, and stability of the active site. In this study, we demonstrated that both single residue replacements resulted in a dramatic broadening of substrate specificity, but did not affect the kinetic mechanism. Experiments with substrate analogues indicate that donor substrates require a carboxylate group for binding. Evidence from initial velocity studies suggests that CyrA undergoes ligand-induced structural changes that involve Phe245. Stability parameters (T(opt) and T(max) ) of the CyrA variants differed from those of wild-type CyrA. Structural flexibilities of the wild type and all three variants were comparable on the basis of dynamic fluorescence quenching, indicating that changes in T(opt) are most likely attributable to localized effects within the active site. Overall, the results indicated that these two residues are essential for both stringent substrate specificity and the active site stability and flexibility of this unique cyanobacterial enzyme. PMID- 22221801 TI - Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study. PMID- 22221802 TI - Warming, CO2, and nitrogen deposition interactively affect a plant-pollinator mutualism. AB - Environmental changes threaten plant-pollinator mutualisms and their critical ecosystem service. Drivers such as land use, invasions and climate change can affect pollinator diversity or species encounter rates. However, nitrogen deposition, climate warming and CO(2) enrichment could interact to disrupt this crucial mutualism by altering plant chemistry in ways that alter floral attractiveness or even nutritional rewards for pollinators. Using a pumpkin model system, we show that these drivers non-additively affect flower morphology, phenology, flower sex ratios and nectar chemistry (sugar and amino acids), thereby altering the attractiveness of nectar to bumble bee pollinators and reducing worker longevity. Alarmingly, bees were attracted to, and consumed more, nectar from a treatment that reduced their survival by 22%. Thus, three of the five major drivers of global environmental change have previously unknown interactive effects on plant-pollinator mutualisms that could not be predicted from studies of individual drivers in isolation. PMID- 22221803 TI - Accurate estimation of living donor right hemi-liver volume from portal vein diameter measurement and standard liver volume calculation. AB - Lee et al. recently published a method for estimating right hemi-liver volume (RHLV) by using bedside ultrasound measurement of right (R) and left (L) portal vein (PV) diameters and Urata's standard liver volume (SLV) formula where RHLV = SLV*[R(2) /(R(2) +L(2) )]. We calculated RHLV by substituting SLV from 15 different published formulas in the worldwide literature. We also modified Lee's method using right anterior (RA) and posterior (RP) where RHLV = SLV*[(RA(2) +RP(2) )/(RA(2) +RP(2) +L(2) )] for donors with unusual PV branching. We compared the calculated RHLV with RHLV estimated with software-assisted CT (SACT) volumetry and actual graft weight after right-lobe donation in 200 right-lobe donors. This study confirmed that accurate estimates of RHLV can be achieved by SACT volumetry or by the simple method of Lee but using the SLV of only 3 of the 15 published formulas (Lin or Vauthey using body weight or body surface area) rather than Urata's. Our modification of the Lee's formula using RA and RP, PV diameters was also accurate and not different from Lee's formula. These simplified formulas may be used for donor screening for graft size adequacy before expensive evaluation proceeds. PMID- 22221804 TI - Filling gaps on influenza en route and the etiology of influenza during a pandemic year. PMID- 22221805 TI - Latitudinal patterns of travel among returned travelers with influenza: results from the GeoSentinel Surveillance Network, 1997-2007. AB - BACKGROUND: Influenza is a common vaccine-preventable disease among international travelers, but few data exist to guide use of reciprocal hemisphere or out-of season vaccines. METHODS: We analyzed records of ill-returned travelers in the GeoSentinel Surveillance Network to determine latitudinal travel patterns in those who acquired influenza abroad. RESULTS: Among 37,542 ill-returned travelers analyzed, 59 were diagnosed with influenza A and 11 with influenza B. Half of travelers from temperate regions to the tropics departed outside influenza season. Twelve travelers crossed hemispheres from one temperate region to another, five during influenza season. Ten of 12 travelers (83%) with influenza who crossed hemispheres were managed as inpatients. Proportionate morbidity estimates for influenza A acquisition were highest for travel to the East Southeast Asian influenza circulation network with 6.13 (95% CI 4.5-8.2) cases per 1000 ill-returned travelers, a sevenfold increased proportionate morbidity compared to travel outside the network. CONCLUSIONS: Alternate hemisphere and out of-season influenza vaccine availability may benefit a small proportion of travelers. Proportionate morbidity estimates by region of travel can inform pre travel consultation and emphasize the ease of acquisition of infections such as influenza during travel. PMID- 22221806 TI - Pandemic influenza A(H1N1) outbreak among a group of medical students who traveled to the Dominican Republic. AB - BACKGROUND: From the beginning of the influenza pandemic until the time the outbreak described here was detected, 77,201 cases of pandemic influenza A(H1N1) with 332 deaths had been reported worldwide, mostly in the United States and Mexico. All of the cases reported in Spain until then had a recent history of travel to Mexico, the Dominican Republic, or Chile. We describe an outbreak of influenza among medical students who traveled from Spain to the Dominican Republic in June 2009. METHODS: We collected diagnostic samples and clinical histories from consenting medical students who had traveled to the Dominican Republic and from their household contacts after their return to Spain. RESULTS: Of 113 students on the trip, 62 (55%) developed symptoms; 39 (45%) of 86 students tested had laboratory evidence of influenza A(H1N1) infection. Most students developed symptoms either just before departure from the Dominican Republic or within days of returning to Spain. The estimated secondary attack rate of influenza-like illness among residential contacts of ill students after return to Spain was 2.1%. CONCLUSIONS: The attack rate of influenza A(H1N1) can vary widely depending on the circumstances of exposure. We report a high attack rate among a group of traveling medical students but a much lower secondary attack rate among their contacts after return from the trip. These findings may aid the development of recommendations to prevent influenza. PMID- 22221807 TI - Detection of respiratory viruses among pilgrims in Saudi Arabia during the time of a declared influenza A(H1N1) pandemic. AB - BACKGROUND: The objectives of this study were to determine whether pilgrim attendance at the Hajj was associated with an increased risk of acquiring influenza, and other respiratory viruses, and to evaluate the compliance of pilgrims with influenza vaccination and other recommended preventive measures. METHODS: A cross-sectional survey was conducted among pilgrims as they arrived at the King Abdulaziz International Airport in Jeddah for the 2009 Hajj and as they departed from the same airport during the week after the Hajj. Nasopharyngeal and throat swabs were tested for 18 respiratory virus types and subtypes using the xTAG Respiratory Viral Panel FAST assay. RESULTS: A total of 519 arriving pilgrims and 2,699 departing pilgrims were examined. Their mean age was 49 years and 58% were male. In all, 30% of pilgrims stated that they had received pandemic influenza A(H1N1) vaccine before leaving for the Hajj and 35% of arriving pilgrims reported wearing a face mask. Only 50% of arriving pilgrims were aware of preventive measures such as hand hygiene and wearing a mask. The prevalence of any respiratory-virus infection was 14.5% (12.5% among arriving pilgrims and 14.8% among departing pilgrims). The main viruses detected (both groups combined) were rhinovirus-enterovirus (N = 414, 12.9%), coronaviruses (N = 27, 0.8%), respiratory syncytial virus (N = 8, 0.2%), and influenza A virus (N = 8, 0.2%) including pandemic influenza A(H1N1) (N = 3, 0.1%). The prevalence of pandemic influenza A(H1N1) was 0.2% (N = 1) among arriving pilgrims and 0.1% (N = 2) among departing pilgrims. The prevalence of any respiratory virus infection was lower among those who said they received H1N1 vaccine compared to those who said they did not receive it (11.8% vs 15.6%, respectively, p = 0.009). CONCLUSION: We found very low pandemic influenza A(H1N1) prevalence among arriving pilgrims and no evidence that amplification of transmission had occurred among departing pilgrims. PMID- 22221808 TI - Clinical and microbiological evaluation of travel-associated respiratory tract infections in travelers returning from countries affected by pandemic A(H1N1) 2009 influenza. AB - BACKGROUND: Although acute respiratory tract infections (RTI) have been recognized as a significant cause of illness in returning travelers, few studies have specifically evaluated the etiologies of RTI in this population. METHODS: This prospective investigation evaluated travelers returning from countries with endemic influenza A(H1N1) 2009, and who were seen in our department at the onset of the outbreak (April-July 2009). Patients were included if they presented with signs of RTI that occurred during travel or less than 7 days after return from overseas travel. Patients were evaluated for microbial agents with RespiFinder plus assay, and throat culture according to clinical presentation. RESULTS: A total of 113 travelers (M/F ratio 1.2:1; mean age 39 y) were included. They were mainly tourists (n = 50; 44.2%) mostly returning from North America (n = 65; 58%) and Mexico (n = 21; 18.5%). The median duration of travel was 23 days (range 2 540 d). The median lag time between return and onset of illness was 0.2 days (range 10 d prior to 7 d after). The main clinical presentation of RTI was influenza-like illness (n = 76; 67.3%). Among the 99 microbiologically evaluated patients, a pathogen was found by polymerase chain reaction (PCR) or throat culture in 65 patients (65.6%). The main etiological agents were influenza A(H1N1) 2009 (18%), influenza viruses (14%), and rhinovirus (20%). A univariate analysis was unable to show variables associated with influenza A(H1N1) 2009, whereas rhinorrhea was associated with viruses other than influenza (p = 0.04). CONCLUSION: Despite the A(H1N1) 2009 influenza pandemic, rhinovirus and other influenza viruses were also frequent causes of RTI in overseas travelers. Real time reverse transcription-PCR and nasopharyngeal swab cultures are useful diagnostic tools for evaluating travelers with RTI. PMID- 22221809 TI - Cystic echinococcosis of the liver: experience from a Danish tertiary reference center (2002-2010). AB - BACKGROUND: Cystic echinococcosis (CE) of the liver can be treated with ultrasound-guided puncture, aspiration, injection, and re-aspiration (PAIR), with surgery and with benzimidazole derivatives. The aim of this study was to review available data concerning treatment modality and outcome for patients treated for CE of the liver in a Danish tertiary reference center. METHODS: A search was made for patients treated for CE infection between January 1, 2002 and January 1, 2010. All relevant patient records and radiology exams were scrutinized and all cysts were re-classified according to the WHO-IWGE, blinded as to which treatment the patient had received. PAIR was performed as a first choice treatment and surgery was reserved for cases where PAIR was impossible. Inactive cyst stages received medical treatment only. RESULTS: The search revealed 26 cases with confirmed CE of the liver. Nine patients underwent PAIR and nine patients surgery as a first choice treatment. Three patients were treated with PAIR secondary to surgery and one patient was treated with surgery secondary to PAIR. For all PAIR treatments, the success rate was 58% regardless of cyst stage and for surgery the success rate was 70%. The difference between the rates was not statistically significant (p = 0.67). CONCLUSION: CE is a rare disease in Denmark and our study is the first describing clinical management of CE in our institution. PMID- 22221810 TI - Trends in knowledge, attitudes, and practices of travel risk groups toward prevention of hepatitis A: results from the Dutch Schiphol Airport survey 2002 to 2009. AB - BACKGROUND: Previous studies investigating the travelers' knowledge, attitudes, and practices (KAP) profile indicated an important educational need among those traveling to risk destinations. Initiatives to improve such education should target all groups of travelers, including business travelers, those visiting friends and relatives (VFR), and older adult travelers. METHODS: In the years 2002 to 2009, a longitudinal questionnaire-based survey was conducted at the Dutch Schiphol Airport with the aim to study trends in KAP of travel risk groups toward prevention of hepatitis A. The risk groups last-minute travelers, solo travelers, business travelers, travelers VFR, and older adult travelers were specifically studied. RESULTS: A total of 3,045 respondents were included in the survey. Travelers to destinations with a high risk for hepatitis A had significantly less accurate risk perceptions (knowledge) than travelers to low-to intermediate-risk destinations. The relative risk for hepatitis A in travelers to high-risk destinations was probably mitigated by less intended risk-seeking behavior and by higher protection rates against hepatitis A as compared with travelers to low-to-intermediate-risk destinations. Logistic regression analyses showed that an age >60 years was the only significant determinant for improvement of their knowledge. Trend analyses showed a significant change over time in attitude toward more risk-avoiding behavior and toward higher protection rates against hepatitis A in travelers to high-risk destinations. The KAP profile of the risk groups travelers VFR (irrespective of hepatitis A risk of their destination) and solo as well as last-minute travelers to high-risk destinations substantially increased their relative risk for hepatitis A. CONCLUSIONS: The results of this longitudinal survey in Dutch travelers suggest an annual 5% increase in protection rates against hepatitis A coinciding with an annual 1% decrease in intended risk-seeking behavior. This improvement may reflect the continuous efforts of travel health advice providers to create awareness and to propagate safe and healthy travel. The KAP profile of travelers visiting friends and relatives (VFR) and solo as well as last-minute travelers to high-risk destinations substantially increased their relative risk for hepatitis A. These risk groups should be candidates for targeted interventions. PMID- 22221811 TI - Human African trypanosomiasis in non-endemic countries (2000-2010). AB - BACKGROUND: Human African trypanosomiasis (HAT) can affect travelers to sub Saharan Africa, as well as migrants from disease endemic countries (DECs), posing diagnosis challenges to travel health services in non-disease endemic countries (non-DECs). METHODS: Cases reported in journals have been collected through a bibliographic research and complemented by cases reported to the World Health Organization (WHO) during the process to obtain anti-trypanosome drugs. These drugs are distributed to DECs solely by WHO. Drugs are also provided to non-DECs when an HAT case is diagnosed. However, in non-DEC pentamidine can also be purchased in the market due to its indication to treat Pneumocystis and Leishmania infections. Any request for drugs from non-DECs should be accompanied by epidemiological and clinical data on the patient. RESULTS: During the period 2000 to 2010, 94 cases of HAT were reported in 19 non-DECs. Seventy-two percent of them corresponded to the Rhodesiense form, whereas 28% corresponded to the Gambiense. Cases of Rhodesiense HAT were mainly diagnosed in tourists after short visits to DECs, usually within a few days of return. The majority of them were in first stage. Initial misdiagnosis with malaria or tick-borne diseases was frequent. Cases of Gambiense HAT were usually diagnosed several months after initial examination and subsequent to a variety of misdiagnoses. The majority were in second stage. Patients affected were expatriates living in DECs for extended periods and refugees or economic migrants from DECs. CONCLUSIONS: The risk of HAT in travelers and migrants, albeit low, cannot be overlooked. In non DECs, rarity, nonspecific symptoms, and lack of knowledge and awareness in health staff make diagnosis difficult. Misdiagnosis is frequent, thus leading to invasive diagnosis methods, unnecessary treatments, and increased risk of fatality. Centralized distribution of drugs for HAT by WHO enables an HAT surveillance system for non-DECs to be maintained. This system provides valuable information on disease transmission and complements data collected in DECs. PMID- 22221812 TI - When uncommon uncovers: mucosal tuberculosis in a medical tourist from Burundi. AB - Tuberculosis confined to the mucus membranes is a rare presentation in the era of effective chemotherapy. We describe a case of mucosal tuberculosis in a "medical tourist" from Burundi that went undiagnosed for 6 years. Starting as conjunctivitis, the disease has spread to involve the nose and larynx as well. The clinical, pathophysiological, and epidemiological aspects are discussed. PMID- 22221813 TI - Acute primary toxoplasmosis in travelers returning from endemic countries. AB - Fourteen cases of toxoplasmosis in immunocompetent travelers who visited high prevalence countries are described. This represents the first series of toxoplasmosis in returned travelers from North America, substantiating the need to consider toxoplasmosis in returned travelers who present with non-specific symptoms, especially fever, lymphadenopathy, and fatigue. PMID- 22221814 TI - Surveillance of poliovirus circulation among refugees in Italy, 2008-2011. AB - The aim of this study was to evaluate the presence of wild poliovirus or sabin like poliovirus in 152 stool samples from migrants in the Accommodation Center in Italy and liquid waste from the sewage systems. Two surveys were performed in 2008 and 2011. All stool samples were negative for enterovirus and poliovirus. One of the liquid samples analyzed was positive for Coxsackievirus type B5. PMID- 22221815 TI - Imported pulmonary histoplasmosis in three French cavers after a trip to Cuba. AB - Pulmonary histoplasmosis is a rare disease in France, where all cases are imported. Diagnosis is difficult in nonendemic areas, often based on travel history and observation of epidemic in a group. We report three cases of pulmonary histoplasmosis that occurred in a group of 12 French cavers traveling to Cuba. PMID- 22221816 TI - Perniosis in a long-distance cyclist crossing Mongolia. AB - We report a case of severe perniosis in a long-distance cyclist. This case demonstrates the importance of identifying those at risk of cold-related injuries who are about to embark on extensive travel in cold environments. PMID- 22221817 TI - Leptospirosis in a French traveler returning from Mauritius. AB - We report the first case of leptospirosis in a patient with a travel history to Mauritius, where the disease has very occasionally been reported in local populations. Following an initial dengue-like presentation, the patient suffered pancreatic involvement and trigeminal neuralgia, which are two unusual delayed features of leptospirosis. PMID- 22221818 TI - The potential role of prebiotic fibre for treatment and management of non alcoholic fatty liver disease and associated obesity and insulin resistance. AB - Non-alcoholic fatty liver disease (NAFLD) and the more severe non-alcoholic steatohepatitis (NASH) represent a spectrum of diseases involving hepatic fat accumulation and histological features essentially identical to alcoholic liver disease; however, they occur in the absence of excessive alcohol intake. They typically arise in conjunction with one or more features of the metabolic syndrome. Lifestyle mediated weight loss remains the primary mode of therapy for NAFLD and NASH, but this is often ineffective and adjunctive medical and surgical treatments are presently lacking. Prebiotic fibres are a group of non-digestible carbohydrates that modulate the human microbiota in a manner that is advantageous to host health. Rodent studies suggest that dietary supplementation with prebiotic fibres positively impacts NAFLD by modifying the gut microbiota, reducing body fat, and improving glucoregulation. Future research should focus on placebo-controlled, human, clinical trials using histological endpoints to address the effects of prebiotics on NAFLD and NASH. The aim of this review is to summarize current knowledge about prebiotics as an emerging therapeutic target for NAFLD. PMID- 22221819 TI - Intravascular recovery of VWF and FVIII following intraperitoneal injection and differences from intravenous and subcutaneous injection in mice. AB - Intravenous infusion studies in humans suggest that both von Willebrand factor (VWF) and factor VIII (FVIII) remain intravascular in contrast to other coagulation proteins. We explored whether infusion of VWF and FVIII by either intraperitoneal (i.p.) or subcutaneous (s.c.) injection would result in efficient absorption of these large proteins into the vascular circulation. FVIII(null) or VWF(null) mice were infused with plasma-derived or recombinant VWF and/or FVIII by i.p., s.c., or intravenous (i.v.) injection. Both VWF and FVIII were absorbed into the blood circulation after i.p. injection with a peak between 2 and 4 h at levels similar to those observed in mice infused intravenously. In contrast, neither VWF nor FVIII was detected in the plasma following s.c. injection. Although i.v. injection achieved peak plasma levels quickly, both human VWF and FVIII rapidly decreased during the first 2 h following i.v. injection. Following both i.v. and i.p. infusion of VWF, the multimeric structure of circulating VWF was similar to that observed in the infusate. These results demonstrate that both VWF and FVIII can be efficiently absorbed into the blood circulation following i.p., but not s.c. injection, indicating that i.p. administration could be an alternative route for VWF or FVIII infusion. PMID- 22221820 TI - Brain-to-brain coupling: a mechanism for creating and sharing a social world. AB - Cognition materializes in an interpersonal space. The emergence of complex behaviors requires the coordination of actions among individuals according to a shared set of rules. Despite the central role of other individuals in shaping one's mind, most cognitive studies focus on processes that occur within a single individual. We call for a shift from a single-brain to a multi-brain frame of reference. We argue that in many cases the neural processes in one brain are coupled to the neural processes in another brain via the transmission of a signal through the environment. Brain-to-brain coupling constrains and shapes the actions of each individual in a social network, leading to complex joint behaviors that could not have emerged in isolation. PMID- 22221821 TI - Progress towards implementation of ACT malaria case-management in public health facilities in the Republic of Sudan: a cluster-sample survey. AB - BACKGROUND: Effective malaria case-management based on artemisinin-based combination therapy (ACT) and parasitological diagnosis is a major pillar within the 2007-2012 National Malaria Strategic Plan in the Sudan. Three years after the launch of the strategy a health facility survey was undertaken to evaluate case management practices and readiness of the health facilities and health workers to implement a new malaria case-management strategy. METHODS: A cross-sectional, cluster sample survey was undertaken at public health facilities in 15 states of Sudan. Data were collected using quality-of-care assessment methods. The main outcomes were the proportions of facilities with ACTs and malaria diagnostics; proportions of health workers exposed to malaria related health systems support activities; and composite and individual indicators of case-management practices for febrile outpatients stratified by age, availability of ACTs and diagnostics, use of malaria diagnostics, and test result. RESULTS: We evaluated 244 facilities, 294 health workers and 1,643 consultations for febrile outpatients (425 < 5 years and 1,218 >= 5 years). Health facility and health worker readiness was variable: chloroquine was available at only 5% of facilities, 73% stocked recommended artesunate and sulfadoxine/pyrimethamine (AS+SP), 51% had the capacity to perform parasitological diagnosis, 53% of health workers had received in-service training on ACTs, 24% were trained in the use of malaria Rapid Diagnostic Tests, and 19% had received a supervisory visit including malaria case management. At all health facilities 46% of febrile patients were parasitologically tested and 35% of patients were both, tested and treated according to test result. At facilities where AS+SP and malaria diagnostics were available 66% of febrile patients were tested and 51% were both, tested and treated according to test result. Among test positive patients 64% were treated with AS+SP but 24% were treated with artemether monotherapy. Among test negative patients only 17% of patients were treated for malaria. The majority of ACT dispensing and counseling practices were suboptimal. CONCLUSIONS: Five years following change of the policy from chloroquine to ACTs and 3 years before the end of the new malaria strategic plan chloroquine was successfully phased out from public facilities in Sudan, however, an important gap remained in the availability of ACTs, diagnostic capacities and coverage with malaria case management activities. The national scale-up of diagnostics, using the findings of this survey as well as future qualitative research, should present an opportunity not only to expand existing testing capacities but also to implement effective support interventions to bridge the health systems gaps and support corrective case-management measures, including the discontinuation of artemether monotherapy treatment. PMID- 22221822 TI - Clinical characteristics of the primary hepatic malignant fibrous histiocytoma in China: case report and review of the literature. AB - BACKGROUND: A malignant fibrous histiocytoma is a soft tissue tumor that most commonly occurs in the extremities, but rarely involves the liver. The clinical characteristics and therapeutic experiences of primary hepatic malignant fibrous histiocytoma are still limited. METHODS: Two cases of primary hepatic malignant fibrous histiocytoma were analyzed retrospectively, and all the literature concerning primary hepatic malignant fibrous histiocytoma was analyzed. RESULTS: In China, a total of 76 cases had been reported, among which 50 were men, with a male to female ratio of 1.9:1. Mean age of the patients was 51.0 years old, and more than 85 percent were older than 40 years. 82.9 percent (63/76) of hepatic MFH were solitary lesions, with tumor size ranging from 2.5 to 23.5 cm (average 10.3 cm). Major clinical presentation (78.4%) was abdominal pain or discomfort, accompanied with some other non-specific symptoms such as malaise, anorexia, weight loss, jaundice and fever, and small cases (14.9%) were asymptomatic. Computed tomography and ultrasound usually revealed the location of lesions. The rate of pre-operative misdiagnosis was extremely high, and 14.9 percent of patients were even misdiagnosed as a benign liver cyst, liver abscess or hematoma. Integrated resection was performed among the most cases (49/68), among which only a few ones (12 cases) were introduced to have no recurrence or metastasis or be still alive with no detail information provided, while among the cases with palliative operation or only a biopsy, the cases that were followed-up all died. CONCLUSIONS: Hepatic malignant fibrous histiocytoma is a rare malignant mesenchymal tumor. The variable features of clinical presentations and images make the diagnosis difficult. Though the prognosis of primary hepatic malignant fibrous histiocytoma was rather poor, integrated resection might provide a few cases a good opportunity for surviving, suggesting that surgery might be an effective treatment. PMID- 22221823 TI - An analysis of the relationships among engagement, agitated behavior, and affect in nursing home residents with dementia. AB - BACKGROUND: Affect, behavior, and cognition can be considered as basic constructs that dictate human functioning, with intricate and bi-directional relationships among them. Prior to the present study, relationships among these constructs have not been systematically examined within the context of dementia. METHODS: Sample 1 contained 185 nursing home residents with a diagnosis of dementia. Sample 2 contained 117 residents with dementia, all of whom manifested agitated behaviors. Outcome measures included stimulus engagement (assessed via the Observational Measure of Engagement), affect (measured using Lawton's Modified Behavior Stream), and agitation/problem behavior (recorded via the Agitated Behaviors Mapping Instrument). Real time direct observations were collected during both stimulus presentation and control conditions. RESULTS: The relationship of engagement with positive affect, represented by the variables of interest and pleasure, were high and positive. No relationship emerged for engagement with negative affect or agitated behavior. A consistent positive relationship was found between agitated behavior and negative affect, and in Sample 2, a negative relationship between agitated behavior and both pleasure and interest. CONCLUSION: This is the first study to examine relationships among variables that are typically examined individually and, in doing so, has clarified the nomenclature used to describe the constructs of affect, engagement, and agitated behaviors in persons with dementia. The finding that the constructs of engagement, agitated behavior, and affect are multidimensional and that relationships among these constructs occur for some of the dimensions is important for the development of interventions and for clear communication in practice and research. PMID- 22221824 TI - Recreational urethral sounding is associated with high risk sexual behaviour and sexually transmitted infections. AB - What's known on the subject? and What does the study add? Most of the medical literature regarding recreational urethral sounding pertains to foreign body retrieval. Very little is known about men who perform sounding and do not require medical attention. Of >2000 men, who responded to a urinary and sexual wellness survey, 10% had a history of recreational urethral sounding. Compared with men who did not sound, men who did reported higher risk sexual behaviours such as multiple sexual partners, sex with strangers and reported more sexually transmitted infections. Men who seek medical attention for complications resulting from sounding should be counselled regarding the hazards of the practice. Realistic strategies for risk reduction should be discussed with men who engage in recreational sounding. OBJECTIVE: To determine whether men who perform recreational sounding are at increased risk of engaging in unsafe sexual behaviours, developing sexually transmitted infections (STIs) and lower urinary tract symptoms (LUTS). SUBJECTS AND METHODS: In a cross-sectional, international, internet-based survey of the sexual practices of >2000 men who have sex with men, subjects were asked if they had engaged in urethral sounding for sexual gratification. We compared ethnodemographic and health-related variables between the sounding and non-sounding populations. The International Prostate Symptom Score and a modified validated version of the International Index of Erectile Function were used to quantify LUTS and erectile dysfunction (ED) in both populations. RESULTS: There were 2122 respondents with complete data, 228 (10.7%) of whom had engaged in recreational sounding. Men who had engaged in sounding were more likely to report certain high risk sexual behaviours (e.g. multiple sexual partners and sex with partners who were not well known) and had increased odds of reporting STIs. Men who had engaged in sounding had a slight but statistically significant increase in LUTS but no significant difference in prevalence of ED. CONCLUSIONS: Urethral sounding is a sexual practice that is associated with higher risk sexual behaviour and carries the potential for morbidity. Research on means for risk reduction for men who choose to engage in recreational sounding requires further study. PMID- 22221825 TI - Green tea polyphenol epigallocatechin-3-gallate enhances 5-fluorouracil-induced cell growth inhibition of hepatocellular carcinoma cells. AB - AIM: 5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic drugs. Resistance to 5-FU is a major cause of chemotherapy failure in advanced stage hepatocellular carcinoma (HCC). Green tea polyphenol Epigallocatechin-3 gallate (EGCG) plays a critical role in growth inhibition and apoptotic induction in HCC cell lines. The aim of this study is to investigate whether EGCG can enhance 5-FU-induced cell growth inhibition and to explore its potential mechanisms. METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate cell growth. Western blotting analysis was performed to detect the proteins expression in Hep3B cells. Small interfering RNA was used to suppress cyclooxygenase-2 (COX-2) expression. Furthermore, enzyme linked immunosorbent assay was used to test the prostaglandin E(2) (PGE(2) ) production in cell cultures. RESULTS: Epigallocatechin-3-gallate augmented the anti-tumor effect of 5-FU in Hep3B cells. Significant difference was observed between the treated groups and the control group (P < 0.05). EGCG (its concentrations at over 5 umol/L) combined with 5-FU presented a synergic effect. Furthermore, the combination of EGCG and 5-FU abrogated the COX-2 overexpression and PGE(2) secretion induced by 5-FU. The upregulation of COX-2 expression decreased the phosphorylation of Akt (Thr(308) ) expression. These appeared to be followed by the AMPK hyperactivation. CONCLUSION: Epigallocatechin-3-gallate sensitizes HCC cells to 5-FU antitumor activity, and the combination of EGCG and 5-FU exhibits synergism in chemo-resistant cancer cells. The results suggest potential novel therapies for the treatment of advanced-stage liver cancer. PMID- 22221826 TI - Remission in schizophrenia: results of cross-sectional with 6-month follow-up period and 1-year observational therapeutic studies in an outpatient population. AB - BACKGROUND: A standardized definition of remission criteria in schizophrenia was proposed by the International group of NC Andreasen in 2005 (low symptom threshold for the eight core Positive and Negative Syndrome Scale (PANSS) symptoms for at least 6 consecutive months). METHODS: A cross-sectional study of remission rate, using a 6-month follow-up to assess symptomatic stability, was conducted in two healthcare districts (first and second) of an outpatient psychiatric service in Moscow. The key inclusion criteria were outpatients with an International Classification of Diseases, 10th edition (ICD-10) diagnosis of schizophrenia or schizoaffective disorder. Remission was assessed using modern criteria (severity and time criteria), PANSS and Global Assessment of Functioning (GAF). Patients who were stable but did not satisfied the symptomatic criteria were included in a further 1-year observational study, with the first group (first district) receiving risperidone (long-acting, injectable) (RLAI) and the second group (second district) continuing to receiving routine treatment. Symptoms were assessed with PANSS, social functioning with the personal and social performance scale, compliance with rating of medication influences scale, and extrapyramidal side effects with the Simpson-Angus scale. RESULTS: Only 64 (31.5%) of 203 outpatients met the criteria for symptomatic remission in the cross-sectional study, but at the end of the 6-month follow-up period, 158 (77.8%) were stable (irrespective of remission status). Among these only 53 (26.1%) patients fulfilled the remission criteria. The observational study had 42 stable patients in the RLAI group and 35 in the routine treatment group: 19.0% in the RLAI group and 5.7% in the control group met remission criteria after 12 months of therapy. Furthermore, reduction of PANSS total and subscale scores, as well as improvement in social functioning, was more significant in the first group. CONCLUSIONS: Only around one-quarter of our outpatient schizophrenic population met full remission criteria. Use of RLAI gave a better remission rate than achieved in standard care with routine treatment. Criteria for remission should take into account clinical course and functioning to support clinical care. PMID- 22221827 TI - Synthesis and characterization of integrated layered nanocomposites for lithium ion batteries. AB - The series of Li[NixMxLi1/3-xMn2/3-x]O2 cathodes, where M is cobalt or chromium with a wide compositional range x from 0 to 0.33, were prepared by hydroxide coprecipitation method with subsequent quenching. The sample structures were investigated using X-ray diffraction results which were indexed completely on the basis of a trigonal structure of space group R3m with monoclinic C2/m phase as expected. The morphologies and electrochemical properties of the samples obtained were compared as the value of x and substituted transition metal. The particle sizes of cobalt-substituted Li[NixCoxLi1/3-xMn2/3-x]O2 samples are much smaller than those of the Li[NixCrxLi1/3-xMn2/3-x]O2 system. The electrode containing Li[NixCoxLi1/3-xMn2/3-x]O2 with x = 0.10 delivered a discharge capacity of above 200 mAh/g after 10 cycles due to the activation of Li2MnO3.PACS: 82.47.Aa; 82.47. a; 82.45.Fk. PMID- 22221828 TI - Parathyromatosis: a rare yet problematic etiology of recurrent and persistent hyperparathyroidism. AB - Recurrent or persistent hyperparathyroidism is an uncommon yet challenging clinical problem, and parathyromatosis is one of its very rare causes. In this minireview, we review causes of recurrent hyperparathyroidism and all cases of parathyromatosis available in the literature. The clinical course of a case of parathyromatosis with the longest follow-up (1977-2011) is described. Similar cases reported between 1975 and the present are reviewed and analyzed to characterize the clinical presentation, course, and management of this rare condition. Parathyromatosis, which is benign parathyroid tissue seeding, has been detailed in 35 patients in the English literature. The majority were female subjects, with end-stage renal disease, in their fifth to sixth decade of life. In most cases, the diagnosis was made intraoperatively; and the condition was often refractory to surgery. A calcimimetic agent was used in 5 cases with end stage renal disease; serum calcium and/or parathyroid hormone levels decreased in 4 subjects, but only one was reported to experience increments in bone density. Medical management combining a calcimimetic with a bisphosphonate may therefore be a preferred alternative. PMID- 22221829 TI - Assessment of CAD-generated tumor volumes measured using MRI in breast cancers before and after neoadjuvant chemotherapy. AB - OBJECTIVE: To evaluate inter-observer agreement and the predictive value of tumor size measurements using MRI for breast cancer under neoadjuvant chemotherapy (NAC) by comparing the measurements of the longest diameters (LD), total enhanced volumes (TEV) and washout volumes (WOV). METHODS: Thirty-seven female breast cancer patients were prospectively enrolled from August 2008 to October 2010. Two of these patients had locally advanced disease. MRI examinations were acquired within 2 weeks before and after NAC. Interim scans were also conducted in 30 patients. Tumor resection was undertaken within 2 weeks after the cessation of NAC. MRI images were independently measured for LD, TEV and WOV by two experienced radiologists. Inter-observer agreement was evaluated using concordance correlation coefficients (CCCs). Tumor sizes after NAC were evaluated relative to their initial sizes for early prediction of a pathological complete response (pCR). RESULTS: The CCCs were 0.93 (CI: 0.90-0.95) for LD, 0.98 (CI: 0.97-0.98) for TEV and 0.99 (CI: 0.991-0.996) for WOV. All measurements had high inter-observer agreement, but the CCCs were significantly increased in the aforementioned order (P<0.0001). WOV measured after the completion of chemotherapy had significant discriminating ability (P=0.0056) when evaluated using receiver operating characteristic analysis, and was found to be superior to LD (P=0.045). The average WOV size was significantly smaller in pCR cases than in non-pCR cases (P=0.016). CONCLUSION: Computer-aided detection-generated tumor volumes had significantly higher inter-observer concordance than conventional LD measurements. WOV measurements had the highest concordance, and WOV could better predict pCR after NAC at smaller tumor sizes. PMID- 22221830 TI - Structure-property relations of co-doped bismuth layer-structured Bi3.25La0.75(Ti1-xMox)3O12 ceramics. AB - In this work, the fabrication and investigation of substituting higher-valence Mo6+ for Ti4+ ion on the B-site of La3+-doped Bi4Ti3O12 [BLT] structure to form Bi3.25La0.75(Ti1-xMox)3O12 [BLTM] (when x = 0, 0.01, 0.03, 0.05 0.07, 0.09, and 0.10) ceramics were carried out. X-ray diffraction patterns of BLTM ceramics indicated an orthorhombic structure with lattice distortion, especially with a higher concentration of a MoO3 dopant. Microstructural investigation showed that all ceramics composed mainly of plate-like grains. An increase in MoO3 doping content increased the length and thickness of the grain but reduced the density of the ceramics. Electrical conductivity was found to decrease, while the dielectric constant increased with Mo6+ doping concentration. Ferroelectric properties were found to be improved with increasing MoO3 content and were optimized at x = 0.1. PMID- 22221831 TI - Plant production systems for bioactive small molecules. AB - Bioactive small molecules are important dietary components of food, as well as being widely used in diverse industrial sectors, from flavours, fragrances and sweeteners through to natural pesticides and pharmaceuticals. Plants already manufacture many of these bioactives, but often in yields that are not commercially competitive. There are a variety of new pathway engineering, cell culture and molecular breeding strategies in use and in development to improve yield and the robust supply of bioactives in planta. In the future, biorefining applications are likely to play a significant role in providing chemical intermediates for bioactive production from biomass feedstocks. PMID- 22221833 TI - Investigation of a new lead-free Bi0.5(Na0.40K0.10)TiO3-(Ba0.7Sr0.3)TiO3 piezoelectric ceramic. AB - Lead-free piezoelectric compositions of the (1-x)Bi0.5(Na0.40K0.10)TiO3 x(Ba0.7Sr0.3)TiO3 system (when x = 0, 0.05, 0.10, 0.15, and 0.20) were fabricated using a solid-state mixed oxide method and sintered between 1,050 degrees C and 1,175 degrees C for 2 h. The effect of (Ba0.7Sr0.3)TiO3 [BST] content on phase, microstructure, and electrical properties was investigated. The optimum sintering temperature was 1,125 degrees C at which all compositions had densities of at least 98% of their theoretical values. X-ray diffraction patterns that showed tetragonality were increased with the increasing BST. Scanning electron micrographs showed a slight reduction of grain size when BST was added. The addition of BST was also found to improve the dielectric and piezoelectric properties of the BNKT ceramic. A large room-temperature dielectric constant, epsilonr (1,609), and piezoelectric coefficient, d33 (214 pC/N), were obtained at an optimal composition of x = 0.10. PMID- 22221832 TI - Synthetic biological approaches to natural product biosynthesis. AB - Small molecules produced in Nature possess exquisite chemical diversity and continue to be an inspiration for the development of new therapeutic agents. In their host organisms, natural products are assembled and modified using dedicated biosynthetic pathways. By rationally reprogramming and manipulating these pathways, unnatural metabolites containing enhanced structural features that were otherwise inaccessible can be obtained. Additionally, new chemical entities can be synthesized by developing the enzymes that carry out these complicated chemical reactions into biocatalysts. In this review, we will discuss a variety of combinatorial biosynthetic strategies, their technical challenges, and highlight some recent (since 2007) examples of rationally designed metabolites, as well as platforms that have been established for the production and modification of clinically important pharmaceutical compounds. PMID- 22221834 TI - The Fe(II)/alpha-ketoglutarate-dependent taurine dioxygenases from Pseudomonas putida and Escherichia coli are tetramers. AB - Fe(II)/alpha-ketoglutarate-dependent oxygenases are versatile catalysts associated with a number of different biological functions in which they use the oxidizing power of activated dioxygen to convert a variety of substrates. A mononuclear nonheme iron center is used to couple the decarboxylation of the cosubstrate alpha-ketoglutarate with a two-electron oxidation of the substrate, which is a hydroxylation in most cases. Although Fe(II)/alpha-ketoglutarate dependent oxygenases have diverse amino acid sequences and substrate specifity, it is assumed that they share a common mechanism. One representative of this enzyme family is the Fe(II)/alpha-ketoglutarate-dependent taurine dioxygenase that catalyzes the hydroxylation of taurine yielding sulfite and aminoacetaldehyde. Its mechanism has been studied in detail becoming a model system for the whole enzyme family. However, its oligomeric state and architecture have been disputed. Here, we report the biochemical and kinetic characterization of the Fe(II)/alpha-ketoglutarate-dependent taurine dioxygenase from Pseudomonas putida KT2440 (TauD(Pp) ). We also present three crystal structures of the apo form of this enzyme. Comparisons with taurine dioxygenase from Escherichia coli (TauD(Ec) ) demonstrate that both enzymes are quite similar regarding their spectra, structure and kinetics, and only minor differences for the accumulation of intermediates during the reaction have been observed. Structural data and analytical gel filtration, as well as sedimentation velocity analytical ultracentrifugation, show that both TauD(Pp) and TauD(Ec) are tetramers in solution and in the crystals, which is in contrast to the earlier description of taurine dioxygenase from E. coli as a dimer. Database The atomic coordinates and structure factors have been deposited with the Brookhaven Protein Data Bank (entry 3PVJ, 3V15, 3V17) Structured digital abstract * tauDpp and tauDpp bind by molecular sieving (View interaction) * tauDpp and tauDpp bind by x-ray crystallography (View interaction) * tauDEc and tauDEc bind by molecular sieving (View interaction). PMID- 22221835 TI - Role of illness and medication perceptions on adherence to medication in a group of Iranian patients with type 2 diabetes. AB - BACKGROUND: The aim of this study was to examine the role of illness and medication perceptions on medication adherence in a group of Iranian patients with type 2 diabetes. METHODS: A total of 102 patients with type 2 diabetes was recruited from an outpatient clinic in Shiraz, Iran, using the convenience sampling method. The participants completed the Illness Perception Questionnaire Revised (IPQ-R), Belief Medication Questionnaire (BMQ), and Medication Adherence Report Scale (MARS). RESULTS: The findings of the study revealed that illness perception, including timeline (chronic -the belief that diabetes would last a long time), predicted a higher level of medication adherence, while medication belief (concern - holding concerns about the potential negative effects of medicines) predicted a lower level of adherence to medicines. This prediction was above and beyond the relevant and demographic variables such as age and the duration of illness. CONCLUSIONS: The findings of this study suggest that medication beliefs, such as concern about the negative effects of medicines, have an important role in the low level of adherence to medication for diabetic patients in Iran. PMID- 22221836 TI - Kidney allograft inflammation and fibrosis, causes and consequences. AB - This study assessed the development of allograft interstitial fibrosis and inflammation (GIF+"i"), a histologic pattern associated with reduced graft survival. Included are 795 adults, recipients of kidney allografts from 2000 to 2006. GIF+"i" was diagnosed in surveillance and clinical biopsies that had no transplant glomerulopathy. With time, posttransplant increasing number of grafts showed GIF+"i" and these patients had reduced death-censored graft survival (HR = 4.33 (2.49-7.53), p < 0.0001). Development of GIF+"i" was related to prior acute cellular rejection (ACR), BK nephropathy (PVAN), increasing number of HLA mismatches, retransplantation and DGF. However, 46.4% of GIF+"i" cases had no history of ACR or PVAN. Anti-HLA antibodies at transplant did not relate to GIF+"i" and these patients had no increased frequency of new antibody formation posttransplant. Post-ACR biopsies showed that GIF+"i" developed more commonly after clinically and/or histologically more severe ACR. Graft inflammation persisted in 38.7 and 29.6% of grafts 2 and 12 months post-ACR. Twelve months post-ACR, 27.1% of biopsies developed moderate-severe GIF and 51.8% showed GIF and inflammation. Persistent inflammation and progressive GIF is often subclinical but may lead to graft failure. GIF+"i" can be initiated by multiple etiologies but it is often postinfectious or due to persistent cellular immune mediated injury. PMID- 22221837 TI - Living fast and dying of infection: host life history drives interspecific variation in infection and disease risk. AB - Parasite infections often lead to dramatically different outcomes among host species. Although an emerging body of ecoimmunological research proposes that hosts experience a fundamental trade-off between pathogen defences and life history activities, this line of inquiry has rarely been extended to the most essential outcomes of host-pathogen interactions: namely, infection and disease pathology. Using a comparative experimental approach involving 13 amphibian host species and a virulent parasite, we test the hypothesis that 'pace-of-life' predicts parasite infection and host pathology. Trematode exposure increased mortality and malformations in nine host species. After accounting for evolutionary history, species that developed quickly and metamorphosed smaller ('fast-species') were particularly prone to infection and pathology. This pattern likely resulted from both weaker host defences and greater adaptation by parasites to infect common hosts. Broader integration between life history theory and disease ecology can aid in identifying both reservoir hosts and species at risk of disease-driven declines. PMID- 22221838 TI - A seroepidemiological study of pandemic A/H1N1(2009) influenza in a rural population of Mali. AB - The swine-origin H1N1 influenza A virus (pH1N1(2009)) started to circulate worldwide in 2009, and cases were notified in a number of sub-Saharan African countries. However, no epidemiological data allowing estimation of the epidemic burden were available in this region, preventing comprehensive comparisons with other parts of the world. The CoPanFlu-Mali programme studied a cohort of 202 individuals living in the rural commune of Dioro (southern central Mali). Pre pandemic and post-pandemic paired sera (sampled in 2006 and April 2010, respectively) were tested by the haemagglutination inhibition (HI) method. Different estimates of pH1N1(2009) infection during the 2009 first epidemic wave were used (increased prevalence of HI titre of >=1/40 or >=1/80, seroconversions) and provided convergent attack rate values (12.4-14.9%), the highest values being observed in the 0-19-year age group (16.0-18.4%). In all age groups, pre-pandemic HI titres of >=1/40 were associated with complete absence of seroconversion; and geometric mean titres were <15 in individuals who seroconverted and >20 in others. Important variations in seroconversion rate existed among the different villages investigated. Despite limitations resulting from the size and composition of the sample analysed, this study provides strong evidence that the impact of the pH1N1(2009) first wave was more important than previously believed, and that the determinants of the epidemic spread in sub-Saharan populations were quite different from those observed in developed countries. PMID- 22221839 TI - What is the best pharmacologic treatment for sickle cell disease pain crises? PMID- 22221840 TI - Effective discharge communication in the emergency department. AB - Communication at discharge is an important part of high-quality emergency department (ED) care. This review describes the existing literature on patient understanding and implementation of discharge instructions, discusses previous interventions aimed at improving the discharge process, and recommends best practices and future research. MEDLINE and Cochrane databases were searched, using combinations of key terms. Literature from both the adult and pediatric ED populations was reviewed. Multiple reports have shown deficient comprehension at discharge, with patients or parents frequently unable to report their diagnosis, management plan, or reasons to return. Interventions to improve discharge communication have been, at best, moderately successful. Patients need structured content, presented verbally, with written and visual cues to enhance recall. Written instructions need to be provided in the patient's language and at an appropriate reading level. Understanding should be confirmed before the patient leaves the ED. Further research is needed to describe the optimal content, channel, and timing for the ED discharge process and the relationship between discharge process and outcomes. PMID- 22221841 TI - Is continuous nebulized beta-agonist therapy more effective than intermittent beta-agonist therapy at reducing hospital admissions in acute asthma? PMID- 22221842 TI - Safety and efficiency of a chest pain diagnostic algorithm with selective outpatient stress testing for emergency department patients with potential ischemic chest pain. AB - STUDY OBJECTIVE: Chest pain units have been used to monitor and investigate emergency department (ED) patients with potential ischemic chest pain to reduce the possibility of missed acute coronary syndrome. We seek to optimize the use of hospital resources by implementing a chest pain diagnostic algorithm. METHODS: This was a prospective cohort study of ED patients with potential ischemic chest pain. High-risk patients were referred to cardiology, and patients without ECG or biomarker evidence of ischemia were discharged home after 2 to 6 hours of observation. Emergency physicians scheduled discharged patients for outpatient stress ECGs or radionuclide scans at the hospital within 48 hours. Patients with positive provocative test results were immediately referred back to the ED. The primary outcome was the rate of missed diagnosis of acute coronary syndrome at 30 days. RESULTS: We prospectively followed 1,116 consecutive patients who went through the chest pain diagnostic algorithm, of whom 197 (17.7%) were admitted at the index visit and 254 (22.8%) received outpatient testing on discharge. The 30 day acute coronary syndrome event rate was 10.8%, and the 30-day missed acute coronary syndrome rate was 0% (95% confidence interval 0% to 2.4%). Of the 120 acute coronary syndrome cases, 99 (82.5%) were diagnosed at the index ED visit, and 21 patients (17.5%) received the diagnosis during outpatient stress testing. CONCLUSION: In ED patients with chest pain, a structured diagnostic approach with time-focused ED decision points, brief observation, and selective application of early outpatient provocative testing appears both safe and diagnostically efficient, even though some patients with acute coronary syndrome may be discharged for outpatient stress testing on the index ED visit. PMID- 22221843 TI - Spanish society of liver transplantation (SETH) consensus recommendations on hepatitis C virus and liver transplantation. AB - In November 2010, the Spanish Society of Liver Transplantation (Sociedad Espanola de Trasplante Hepatico, SETH) held a consensus conference. One of the topics of debate was liver transplantation in patients with hepatitis C. This document reviews (i) the natural history of post-transplant hepatitis C, (ii) factors associated with post-transplant prognosis in patients with hepatitis C, (iii) the role of immunosuppression in the evolution of recurrent hepatitis C and response to antiviral therapy, (iv) antiviral therapy, both before and after transplantation, (v) follow-up of patients with recurrent hepatitis C and (vi) the role of retransplantation. PMID- 22221844 TI - Factors for life: advances in the treatment of congenital and coagulopathic bleeding disorders. PMID- 22221845 TI - The role of fibrinogen: a new paradigm in the treatment of coagulopathic bleeding. AB - Fibrinogen is involved in both primary and secondary hemostasis, playing an important role in platelet aggregation and the establishment of a fibrin network. Recent evidence suggests that very high levels of fibrinogen act as antithrombin and can reduce endogenous thrombin potential and compromise clot stability, particularly following a low tissue factor stimulus. Several laboratory methods for measuring plasma fibrinogen concentrations are available, but results vary depending on the type of method and the use of artificial colloid plasma expanders. Adopting only the Clauss method can provide erroneously high levels when used in patients who have received colloid plasma expanders. This may contribute to a hazardous delay or complete lack of treatment. Multiple in vitro experiments, animal studies, and proof-of-principle randomized, clinical studies have recently suggested that hemostatic intervention with a fibrinogen concentrate may be efficient and safe in controling perioperative bleeding. In particular, fibrinogen concentrate has a key role in improving clotting function and reducing blood loss in settings such as trauma and cardiothoracic surgery. However, prospective studies are needed to determine the clinical efficacy and safety of fibrinogen concentrate when used as a hemostatic intervention for patients with massive bleeding due to trauma or surgery. PMID- 22221846 TI - Fibrinogen concentrate in the treatment of severe bleeding after aortic aneurysm graft surgery. AB - Aortic aneurysm graft surgery involving cardiopulmonary bypass is often associated with substantial coagulopathic perioperative bleeding, requiring hemostatic intervention with allogeneic blood products, such as fresh frozen plasma, platelet concentrate, and red blood cells. We conducted a pilot study to determine the effects of fibrinogen concentrate in patients with microvascular bleeding during aortic valve surgery with ascending aorta replacement. Dosing of fibrinogen concentrate was individualized based on thromboelastometry. First-line therapy with fibrinogen concentrate reduced the need for allogeneic blood product support, including transfusions of fresh frozen plasma, platelet concentrate, and red blood cells. Similar results were seen in a second cohort study conducted in patients undergoing thoraco-abdominal aortic aneurysm surgery: patients who received fibrinogen concentrate required significantly less allogeneic blood product support following surgery. These results prompted the initiation of a randomized placebo-controlled trial in patients undergoing thoraco-abdominal aortic aneurysm surgery, aortic valve surgery with ascending aorta replacement, or aortic arch surgery. Results are expected to be published soon. Larger, multicenter studies are needed to determine the exact role of fibrinogen concentrate in the management of perioperative bleeding following cardiac surgery and cardiopulmonary bypass. PMID- 22221847 TI - The pathophysiology of von Willebrand disease: therapeutic implications. AB - von Willebrand disease (VWD) is a bleeding disorder characterized by quantitative or qualitative defects in von Willebrand factor (VWF), a multimeric glycoprotein that is essential for platelet-dependent primary hemostasis. High molecular weight multimers of VWF circulate and bind to collagen and platelets to induce primary hemostasis. The activity of VWF and its eventual proteolytic degradation are dependent on shear stress, ensuring that, under normal conditions, VWF is active in a high shear stress environment only. Deficiency in VWF results in mucocutaneous bleeding, including epistaxis, menorrhagia, and excessive bleeding after trauma or surgery. Classification of VWD is based on the combined results of multiple laboratory tests related to VWF amount and activity as well as the relative amounts of large VWF multimers as determined by gel electrophoresis. Recently, specific mutations in the gene encoding VWF have been linked to characteristic multimer profiles and may aid in subtyping patients with VWD and predicting response to therapy. These genotype-phenotype correlations are improving our understanding of the pathophysiology of VWD and helping to provide a more accurate diagnosis and classification with important treatment-related implications. PMID- 22221848 TI - Pioneering designs for recombinant coagulation factors. AB - Coagulation factor replacement therapy has become an established part of the prevention and treatment of bleeding episodes in patients with bleeding disorders, such as hemophilia A, hemophilia B, and von Willebrand disease. Advances in recombinant DNA technology have made it possible to modify recombinant coagulation factor products to enhance their pharmacokinetic properties, biological activity, or other characteristics. CSL Behring has created two novel albumin fusion proteins with the goal of extending the half life of activated recombinant factor VII (rFVIIa) and recombinant factor IX (rFIX) to allow for less frequent dosing. Preclinical evaluation indicates that the resulting recombinant albumin fusion proteins (rVIIa-FP and rIX-FP) have improved pharmacokinetic properties, including an extended half-life, with preservation of hemostatic efficacy. Clinical evaluation of rIX-FP is now underway in patients with hemophilia B. In addition, we have designed a unique recombinant single-chain factor VIII protein (CSL627) that has improved stability during the manufacturing process and a high affinity for von Willebrand factor, relative to other recombinant factor VIII products. Ongoing studies of rVIIa-FP, rIX-FP, and CSL627 will help further define the potential clinical utility of these novel recombinant proteins in the management of patients with bleeding disorders. PMID- 22221849 TI - Heterozygote frequencies of common polymorphic markers of factor VIII (f8) and factor IX (f9) genes in indigenous Nepali population. PMID- 22221850 TI - Abortion-prone mating influences alteration of systemic a2 vacuolar ATPase expression in spleen and blood immune cells. AB - PROBLEM: a2 isoform of vacuolar ATPase (Atp6v0a2) is important for maintaining the delicate immunological balance required for successful pregnancy. The objective of this investigation is to study the dynamic changes in spleen and blood that appear during spontaneous abortion in mice. METHOD OF STUDY: Atp6v0a2 was measured in multiple immune cell populations from spleen and blood recovered from non-abortion-prone and abortion-prone mating combinations. RESULTS: Atp6v0a2 expression was significantly lower (P <= 0.01) in the spleen recovered from abortion-prone ?CBA * ?DBA mating on days 12 and 16 of pregnancy when compared to non-abortion-prone ?BALB/c * ?BALB/c and ?CBA * ?BALB/c matings. Flow cytometric studies showed that significantly decreased expression of Atp6v0a2 in splenic CD4(+), CD8(+), CD19(+), and CD14(+) cells directly correlated with the high percentages of fetal resorption observed in abortion-prone mating on days 12 and 16 of pregnancy. In blood, CD4(+), CD8(+), and CD19(+) cells had a significantly reduced expression of Atp6v0a2 in abortion-prone mating compared to the non abortion-prone mating combinations only on day 12. CONCLUSION: This deceased expression of Atp6v0a2 in the various immune cell populations of the spleen and blood suggests that the maternal environment is not supportive to fetus and leads to poor pregnancy outcome in the abortion-prone mating model. PMID- 22221851 TI - Applying the effort-reward imbalance model to household and family work: a population-based study of German mothers. AB - BACKGROUND: This paper reports on results of a newly developed questionnaire for the assessment of effort-reward imbalance (ERI) in unpaid household and family work. METHODS: Using a cross-sectional population-based survey of German mothers (n = 3129) the dimensional structure of the theoretical ERI model was validated by means of Confirmatory Factor Analysis (CFA). Analyses of Variance were computed to examine relationships between ERI and social factors and health outcomes. RESULTS: CFA revealed good psychometric properties indicating that the subscale 'effort' is based on one latent factor and the subscale 'reward' is composed of four dimensions: 'intrinsic value of family and household work', 'societal esteem', 'recognition from the partner', and 'affection from the child(ren)'. About 19.3% of mothers perceived lack of reciprocity and 23.8% showed high rates of overcommitment in terms of inability to withdraw from household and family obligations. Socially disadvantaged mothers were at higher risk of ERI, in particular with respect to the perception of low societal esteem. Gender inequality in the division of household and family work and work-family conflict accounted most for ERI in household and family work. Analogous to ERI in paid work we could demonstrate that ERI affects self-rated health, somatic complaints, mental health and, to some extent, hypertension. CONCLUSIONS: The newly developed questionnaire demonstrates satisfied validity and promising results for extending the ERI model to household and family work. PMID- 22221852 TI - Glycomics, glycoproteomics and the immune system. AB - Glycomics and glycoproteomics have become indispensible tools in the study of glycoconjugates. Mass spectrometry based methods are standardly used to study the proteome and/or glycome and these approaches are capable of providing both, qualitative and quantitative information using top down techniques. The human immune system marks a particular area of interest for glycomics and glycoproteomics research since a large number of key proteins in innate and adaptive immunity are glycoproteins. In numerous examples, the crucial influence of glycosylation on critical steps such as receptor interaction and binding has been demonstrated. In this review, we focus on different glycomics and glycoproteomics approaches and their application for studying protein glycosylation in the immune system. PMID- 22221853 TI - Current advances in peptide and small molecule microarray technologies. AB - Microarrays offer a compact solution for massively parallel screening. In recent years, microarrays have branched away from the exclusive pursuit of small molecule 'hits' in target centric screens, towards the sophisticated dissection of disease biology and comparative profiling of cellular states. This has led to innovative and instructive ways in which the platform may be deployed, providing new-found methods with which to harness the throughput achievable. Library design and diversity continues to drive success with peptide and small molecule microarrays. Newer synthesis and immobilization strategies extend the already wide repertoire of fabrication methods available. Herein we describe the latest advances in the small molecule and peptide microarray arena, which herald even more exciting breakthroughs in the coming decade. PMID- 22221854 TI - Luminescent sub-nanometer clusters for metal ion sensing: a new direction in nanosensors. AB - We describe the application of a recently discovered family of materials called quantum clusters, which are sub-nanometer particles composed of a few atoms with well-defined molecular formulae, exhibiting intense absorption and emission in the visible region in metal ion sensing, taking Ag(25) as an example. The changes in the optical properties of the cluster, in both absorption and emission upon exposure to various metal ions in aqueous medium are explored. The cluster can detect Hg(2+) down to ppb levels. It can also detect 5d block ions (Pt(2+), Au(3+) and Hg(2+)) down to ppm limits. Hg(2+) interacts with the metal core as well as the functional groups of the capping agents and the interaction is concentration-dependent. To understand the mechanism behind this type of specific interaction, we have used spectroscopic and microscopic techniques such as UV-vis spectroscopy, luminescence spectroscopy, Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), high resolution transmission electron microscopy (HRTEM), and X-ray diffraction (XRD). Specific reasons responsible for the interaction of Hg(2+) have been proposed. PMID- 22221855 TI - Hepatitis C virus core protein upregulates the expression of vascular endothelial growth factor via the nuclear factor-kappaB/hypoxia-inducible factor-1alpha axis under hypoxic conditions. AB - AIM: Hepatitis C virus (HCV) core protein critically contributes to hepatocarcinogenesis, which is often observed in liver cirrhosis. Since the liver cirrhosis microenvironment is affected by hypoxia, we focused on the possible driving force of HCV core protein on signal relay from hypoxia-inducible factor (HIF)-1alpha to vascular endothelial growth factor (VEGF). METHODS: Human hepatocellular carcinoma cells stably overexpressing HCV core (Core cells) and NS5A (NS5A cells) were established; empty vector-transfected (EV) cells were used as controls. Hypoxia was induced by oxygen deprivation or by using cobalt chloride (CoCl(2) ). YC-1 was used to inhibit HIF-1alpha expression. Protein analyses for cultured cells and liver tissues obtained from CoCl(2) -treated HCV core-transgenic (Core-Tg) mice were performed by western blot and/or immunocytochemistry. Cellular mRNA levels were evaluated by quantitative real time reverse transcription-polymerase chain reaction. RESULTS: Under hypoxia, the sustained expression of HIF-1alpha, but not HIF-2alpha, was profoundly observed in Core cells but, was faint in EV and NS5A cells. Immunocytochemistry revealed increased HIF-1alpha in the nucleus. HIF-1alpha mRNA levels were significantly higher in Core cells than in EV cells under both normoxia and hypoxia. The HIF-1alpha-targeted VEGF and Bcl-xL expressions were increased in Core cells under hypoxia and abolished by YC-1 treatment. Hypoxic liver samples of Core-Tg mice indicated significant increases in both HIF-1alpha and VEGF expression compared with the wild type. CONCLUSIONS: Hepatitis C virus core protein has the distinct potential to transcriptionally upregulate and sustain HIF-1alpha expression under hypoxia, thereby contributing to increased VEGF expression, a key regulator in the hypoxic milieu of liver cirrhosis. PMID- 22221856 TI - Clinical practice guidelines within the Southern African Development Community: a descriptive study of the quality of guideline development and concordance with best evidence for five priority diseases. AB - BACKGROUND: Reducing the burden of disease relies on availability of evidence based clinical practice guidelines (CPGs). There is limited data on availability, quality and content of guidelines within the Southern African Development Community (SADC). This evaluation aims to address this gap in knowledge and provide recommendations for regional guideline development. METHODS: We prioritised five diseases: HIV in adults, malaria in children and adults, pre eclampsia, diarrhoea in children and hypertension in primary care. A comprehensive electronic search to locate guidelines was conducted between June and October 2010 and augmented with email contact with SADC Ministries of Health. Independent reviewers used the AGREE II tool to score six quality domains reporting the guideline development process. Alignment of the evidence-base of the guidelines was evaluated by comparing their content with key recommendations from accepted reference guidelines, identified with a content expert, and percentage scores were calculated. FINDINGS: We identified 30 guidelines from 13 countries, publication dates ranging from 2003-2010. Overall the 'scope and purpose' and 'clarity and presentation' domains of the AGREE II instrument scored highest, median 58%(range 19-92) and 83%(range 17-100) respectively. 'Stakeholder involvement' followed with median 39%(range 6-75). 'Applicability', 'rigour of development' and 'editorial independence' scored poorly, all below 25%. Alignment with evidence was variable across member states, the lowest scores occurring in older guidelines or where the guideline being evaluated was part of broader primary healthcare CPG rather than a disease-specific guideline. CONCLUSION: This review identified quality gaps and variable alignment with best evidence in available guidelines within SADC for five priority diseases. Future guideline development processes within SADC should better adhere to global reporting norms requiring broader consultation of stakeholders and transparency of process. A regional guideline support committee could harness local capacity to support context appropriate guideline development. PMID- 22221857 TI - Diabetes-induced alterations in the extracellular matrix and their impact on myocardial function. AB - Diabetes is an increasing public health problem that is expected to escalate in the future due to the growing incidence of obesity in the western world. While this disease is well known for its devastating effects on the kidneys and vascular system, diabetic individuals can develop cardiac dysfunction, termed diabetic cardiomyopathy, in the absence of other cardiovascular risk factors such as hypertension or atherosclerosis. While much effort has gone into understanding the effects of elevated glucose or altered insulin sensitivity on cellular components within the heart, significant changes in the cardiac extracellular matrix (ECM) have also been noted. In this review article we highlight what is currently known regarding the effects diabetes has on both the expression and chemical modification of proteins within the ECM and how the fibrotic response often observed as a consequence of this disease can contribute to reduced cardiac function. PMID- 22221858 TI - Diversity of Micromonospora strains isolated from nitrogen fixing nodules and rhizosphere of Pisum sativum analyzed by multilocus sequence analysis. AB - It was recently reported that Micromonospora inhabits the intracellular tissues of nitrogen fixing nodules of the wild legume Lupinus angustifolius. To determine if Micromonospora populations are also present in nitrogen fixing nodules of cultivated legumes such as Pisum sativum, we carried out the isolation of this actinobacterium from P. sativum plants collected in two man-managed fields in the region of Castilla and Leon (Spain). In this work, we describe the isolation of 93 Micromonospora strains recovered from nitrogen fixing nodules and the rhizosphere of P. sativum. The genomic diversity of the strains was analyzed by amplified ribosomal DNA restriction analysis (ARDRA). Forty-six isolates and 34 reference strains were further analyzed using a multilocus sequence analysis scheme developed to address the phylogeny of the genus Micromonospora and to evaluate the species distribution in the two studied habitats. The MLSA results were evaluated by DNA-DNA hybridization to determine their usefulness for the delineation of Micromonospora at the species level. In most cases, DDH values below 70% were obtained with strains that shared a sequence similarity of 98.5% or less. Thus, MLSA studies clearly supported the established taxonomy of the genus Micromonospora and indicated that genomic species could be delineated as groups of strains that share > 98.5% sequence similarity based on the 5 genes selected. The species diversity of the strains isolated from both the rhizosphere and nodules was very high and in many cases the new strains could not be related to any of the currently described species. PMID- 22221859 TI - Molecular and phenotypic characterization of strains nodulating Anthyllis vulneraria in mine tailings, and proposal of Aminobacter anthyllidis sp. nov., the first definition of Aminobacter as legume-nodulating bacteria. AB - Bacterial strains from Zn-Pb mine tailings were isolated by trapping with Anthyllis vulneraria, a legume-host suitable for mine substratum phytostabilisation. Sequence analysis of the 16S rRNA gene and three housekeeping genes (atpD, dnaK and recA) showed that they were related to those of the genus Aminobacter. DNA-DNA relatedness of representative isolates supported the placement of novel strains in Aminobacter as a new species. Phenotypic data emphasize their differentiation from the other related species of Aminobacter and Mesorhizobium. Aminobacter isolates exhibited nodA sequences tightly related with M. loti as the closest nodA relative. By contrast, their nodA sequences were highly divergent from those of M. metallidurans, another species associated with A. vulneraria that carries two complete copies of nodA. Therefore, the novel bacterial strains efficient on A. vulneraria represented the first occurrence of legume symbionts in the genus Aminobacter. They represent a new species for which the name Aminobacter anthyllidis sp. nov. is proposed (type strain STM4645(T)=LMG26462(T)=CFBP7437(T)). PMID- 22221860 TI - Evolution before genes. AB - BACKGROUND: Our current understanding of evolution is so tightly linked to template-dependent replication of DNA and RNA molecules that the old idea from Oparin of a self-reproducing 'garbage bag' ('coacervate') of chemicals that predated fully-fledged cell-like entities seems to be farfetched to most scientists today. However, this is exactly the kind of scheme we propose for how Darwinian evolution could have occurred prior to template replication. RESULTS: We cannot confirm previous claims that autocatalytic sets of organic polymer molecules could undergo evolution in any interesting sense by themselves. While we and others have previously imagined inhibition would result in selectability, we found that it produced multiple attractors in an autocatalytic set that cannot be selected for. Instead, we discovered that if general conditions are satisfied, the accumulation of adaptations in chemical reaction networks can occur. These conditions are the existence of rare reactions producing viable cores (analogous to a genotype), that sustains a molecular periphery (analogous to a phenotype). CONCLUSIONS: We conclude that only when a chemical reaction network consists of many such viable cores, can it be evolvable. When many cores are enclosed in a compartment there is competition between cores within the same compartment, and when there are many compartments, there is between-compartment competition due to the phenotypic effects of cores and their periphery at the compartment level. Acquisition of cores by rare chemical events, and loss of cores at division, allows macromutation, limited heredity and selectability, thus explaining how a poor man's natural selection could have operated prior to genetic templates. This is the only demonstration to date of a mechanism by which pre-template accumulation of adaptation could occur. PMID- 22221861 TI - Physical and electrochemical properties of synthesized carbon nanotubes [CNTs] on a metal substrate by thermal chemical vapor deposition. AB - Multi-walled carbon nanotubes were synthesized on a Ni/Au/Ti substrate using a thermal chemical vapor deposition process. A Ni layer was used as a catalyst, and an Au layer was applied as a barrier in order to prevent diffusion between Ni and Ti within the substrate during the growth of carbon nanotubes. The results showed that vertically aligned multi-walled carbon nanotubes could be uniformly grown on the Ti substrate (i.e., metal substrate), thus indicating that the Au buffer layer effectively prevented interdiffusion of the catalyst and metal substrate. Synthesized carbon nanotubes on the Ti substrate have the diameter of about 80 to 120 nm and the length of about 5 to 10 MUm. The Ti substrate, with carbon nanotubes, was prepared as an electrode for a lithium rechargeable battery, and its electrochemical properties were investigated. In a Li/CNT cell with carbon nanotubes on a 60-nm Au buffer layer, the first discharge capacity and discharge capacity after the 50th cycle were 210 and 80 MUAh/cm2, respectively. PMID- 22221862 TI - Computational methods and challenges for large-scale circuit mapping. AB - The connectivity architecture of neuronal circuits is essential to understand how brains work, yet our knowledge about the neuronal wiring diagrams remains limited and partial. Technical breakthroughs in labeling and imaging methods starting more than a century ago have advanced knowledge in the field. However, the volume of data associated with imaging a whole brain or a significant fraction thereof, with electron or light microscopy, has only recently become amenable to digital storage and analysis. A mouse brain imaged at light-microscopic resolution is about a terabyte of data, and 1mm(3) of the brain at EM resolution is about half a petabyte. This has given rise to a new field of research, computational analysis of large-scale neuroanatomical data sets, with goals that include reconstructions of the morphology of individual neurons as well as entire circuits. The problems encountered include large data management, segmentation and 3D reconstruction, computational geometry and workflow management allowing for hybrid approaches combining manual and algorithmic processing. Here we review this growing field of neuronal data analysis with emphasis on reconstructing neurons from EM data cubes. PMID- 22221863 TI - Visual homing: an insect perspective. AB - The ability to learn the location of places in the world and to revisit them repeatedly is crucial for all aspects of animal life on earth. It underpins animal foraging, predator avoidance, territoriality, mating, nest construction and parental care. Much theoretical and experimental progress has recently been made in identifying the sensory cues and the computational mechanisms that allow insects (and robots) to find their way back to places, while the neurobiological mechanisms underlying navigational abilities are beginning to be unravelled in vertebrate and invertebrate models. Studying visual homing in insects is interesting, because they allow experimentation and view-reconstruction under natural conditions, because they are likely to have evolved parsimonious, yet robust solutions to the homing problem and because they force us to consider the viewpoint of navigating animals, including their sensory and computational capacities. PMID- 22221864 TI - Smelling on the fly: sensory cues and strategies for olfactory navigation in Drosophila. AB - Navigating toward (or away from) a remote odor source is a challenging problem that requires integrating olfactory information with visual and mechanosensory cues. Drosophila melanogaster is a useful organism for studying the neural mechanisms of these navigation behaviors. There are a wealth of genetic tools in this organism, as well as a history of inventive behavioral experiments. There is also a large and growing literature in Drosophila on the neural coding of olfactory, visual, and mechanosensory stimuli. Here we review recent progress in understanding how these stimulus modalities are encoded in the Drosophila nervous system. We also discuss what strategies a fly might use to navigate in a natural olfactory landscape while making use of all these sources of sensory information. We emphasize that Drosophila are likely to switch between multiple strategies for olfactory navigation, depending on the availability of various sensory cues. Finally, we highlight future research directions that will be important in understanding the neural circuits that underlie these behaviors. PMID- 22221865 TI - New technologies for imaging synaptic partners. AB - Understanding the brain will require unraveling its synaptic circuitry, but methods that can reliably identify connected neurons are often excruciatingly slow. Although light microscopy can provide much higher throughput, synapses are smaller than the diffraction limit and cannot readily be assigned to particular presynaptic and postsynaptic cells without specialized labeling methods. Here we review the ongoing development of techniques that allow direct imaging of neural networks by specifically marking connected cells or their synapses. PMID- 22221867 TI - Bullous pemphigoid eleven years after bilateral hand transplantation. PMID- 22221866 TI - New taxonomy and old collections: integrating DNA barcoding into the collection curation process. AB - Because they house large biodiversity collections and are also research centres with sequencing facilities, natural history museums are well placed to develop DNA barcoding best practices. The main difficulty is generally the vouchering system: it must ensure that all data produced remain attached to the corresponding specimen, from the field to publication in articles and online databases. The Museum National d'Histoire Naturelle in Paris is one of the leading laboratories in the Marine Barcode of Life (MarBOL) project, which was used as a pilot programme to include barcode collections for marine molluscs and crustaceans. The system is based on two relational databases. The first one classically records the data (locality and identification) attached to the specimens. In the second one, tissue-clippings, DNA extractions (both preserved in 2D barcode tubes) and PCR data (including primers) are linked to the corresponding specimen. All the steps of the process [sampling event, specimen identification, molecular processing, data submission to Barcode Of Life Database (BOLD) and GenBank] are thus linked together. Furthermore, we have developed several web-based tools to automatically upload data into the system, control the quality of the sequences produced and facilitate the submission to online databases. This work is the result of a joint effort from several teams in the Museum National d'Histoire Naturelle (MNHN), but also from a collaborative network of taxonomists and molecular systematists outside the museum, resulting in the vouchering so far of ~41,000 sequences and the production of ~11,000 COI sequences. PMID- 22221868 TI - Particulate air pollution and cardiorespiratory hospital admissions in a temperate Australian city: A case-crossover analysis. AB - BACKGROUND: Although ambient air pollution exposure has been linked with poor health in many parts of the world, no previous study has investigated the effect on morbidity in the city of Adelaide, South Australia. OBJECTIVE: To explore the association between particulate matter (PM) and hospitalisations, including respiratory and cardiovascular admissions in Adelaide, South Australia. METHODS: For the study period September 2001 to October 2007, daily counts of all-cause, cardiovascular and respiratory hospital admissions were collected, as well as daily air quality data including concentrations of particulates, ozone and nitrogen dioxide. Visibility codes for present weather conditions identified days when airborne dust or smoke was observed. The associations between PM and hospitalisations were estimated using time-stratified case-crossover analyses controlling for covariates including temperature, relative humidity, other pollutants, day of the week and public holidays. RESULTS: Mean PM(10) concentrations were higher in the warm season, whereas PM(2.5) concentrations were higher in the cool season. Hospital admissions were associated with PM(10) in the cool season and with PM(2.5) in both seasons. No significant effect of PM on all-age respiratory admissions was detected, however cardiovascular admissions were associated with both PM(2.5) and PM(10) in the cool season with the highest effects for PM(2.5) (4.48%, 95% CI: 0.74%, 8.36% increase per 10MUg/m(3) increase in PM(2.5)). CONCLUSION: These findings suggest that despite the city's relatively low levels of air pollution, PM concentrations are associated with increases in morbidity in Adelaide. Further studies are needed to investigate the sources of PM which may be contributing to the higher cool season effects. PMID- 22221869 TI - Influence of releases from a fresh water reservoir on the hydrochemistry of the Tinto River (SW Spain). AB - The Tinto River is an extreme case of pollution by acid mine drainage (AMD), with pH values below 3 and high sulphate, metal and metalloid concentrations along its main course. This study evaluates the impact of releases from a freshwater reservoir on the Tinto River, identifying the metal transport mechanisms. This information is needed to understand the water quality evolution in the long term, and involves the comprehension of interactions between AMD sources, freshwaters, particulate matter and sediments. This work proposes a methodology for quantifying the proportions in which the different sources are contributing. The method is based on the mass balance of solutes and accounts for the uncertainty of end-members. The impact of the releases from the Corumbel Reservoir on the hydrochemistry of the Tinto River was significant, accounting up to a 92% of river discharge. These releases provoked a sharp decrease in dissolved metal concentrations, especially for Fe (approximately 1000 fold) due to dilution and precipitation. Cadmium, Zn, Cu, Co, Ni and Al suffered a dilution to a 12-16 fold decrease while Ca, Sr, Na, Pb and Si were less affected (2-4 folds decrease). However, these releases also gave rise to an increase in particulate transport, mainly Fe, As, Cr, Ba, Pb and Ti, due to sediment remobilisation and Fe precipitation. Aluminium, Li, K, Si, Al, Ni and Sr, together with Cu were present in the particulate phase during the discharge peak. The proposed 2-component mixing model revealed the existence of non-conservative behaviour for Al, Ca, Li, Mn, Ni and Si as a consequence of the interactions between the acidic Tinto waters and the clay-rich reservoir sediments during the bottom outlet opening. These results were improved by a 3-component mixing model, introducing a new end member to account the chemical dissolution of clay-rich sediments by acidic Tinto waters. PMID- 22221870 TI - Genotoxic effects in blood cells of Mus musculus and Iguana iguana living near coal mining areas in Colombia. AB - Coal is a mixture of chemicals with the capacity of promoting biochemical changes that may lead to DNA damage. In this study, the comet assay in peripheral blood cells, and the micronucleus test in blood smears were used to evaluate potential genotoxic effects derived from exposure to coal mining activities on wild populations of Mus musculus and Iguana iguana. Four locations from Colombia were evaluated: La Loma and La Jagua de Ibirico, two municipalities located near coal mining fields at the Department of Cesar; and Valledupar and Arjona, cities used as reference sites, both localized at least 100 and 200km far from the mines, respectively. Compared to Valledupar and Arjona, animals collected in close proximity to coal mining areas showed highest percentages of DNA damage for both species, evidencing that living around coal mining fields may result in an increase of DNA lesions in blood cells of rodents and reptiles. The results for micronucleus test were conflicting. Mice from Arjona had greater number of cells with micronucleus than those from the other studied locations, probably as a result of infection found by blood parasites. In summary, it was demonstrated that animals living around coal mining areas have a greater chance of having DNA damage, as measured by the comet assay, than those from sites far from the coal dust source. PMID- 22221871 TI - The applicability of reflectance micro-Fourier-transform infrared spectroscopy for the detection of synthetic microplastics in marine sediments. AB - Synthetic microplastics (<=5-mm fragments) are globally distributed contaminants within coastal sediments that may transport organic pollutants and additives into food webs. Although micro-Fourier-transform infrared (micro-FT-IR) spectroscopy represents an ideal method for detecting microplastics in sediments, this technique lacks a standardized operating protocol. Herein, an optimized method for the micro-FT-IR analysis of microplastics in vacuum-filtered sediment retentates was developed. Reflectance micro-FT-IR analyses of polyethylene (PE) were compared with attenuated total reflectance FT-IR (ATR-FT-IR) measurements. Molecular mapping as a precursor to the imaging of microplastics was explored in the presence and absence of 150-MUm PE fragments, added to sediment at concentrations of 10, 100, 500 and 1000ppm. Subsequently, polymer spectra were assessed across plastic-spiked sediments from fifteen offshore sites. While all spectra obtained of evenly shaped plastics were typical to PE, reflectance micro FT-IR measurements of irregularly shaped materials must account for refractive error. Additionally, we provide the first evidence that mapping successfully detects microplastics without their visual selection for characterization, despite this technique relying on spectra from small and spatially separated locations. Flotation of microplastics from sediments only enabled a fragment recovery rate of 61 (+/-31 S.D.) %. However, mapping 3-mm(2) areas (within 47-mm filters) detected PE at spiking concentrations of 100ppm and above, displaying 69 (+/-12 S.D.) % of the fragments in these locations. Additionally, mapping detected a potential PE fragment in a non-spiked retentate. These data have important implications for research into the imaging of microplastics. Specifically, the sensitivity and spatial resolution of the present protocol may be improved by visualizing the entire filter with high-throughput detection techniques (e.g., focal plane array-based imaging). Additionally, since micro-FT IR analyses depend on methods of sample collection, our results emphasize the urgency of developing efficient and reproducible techniques to separate microplastics from sediments. PMID- 22221872 TI - Biomonitoring and assessment of monomethylmercury exposure in aqueous systems using the DGT technique. AB - A series of laboratory experiments was conducted under realistic environmental conditions to test the ability of the Diffusive Gradient in Thin film (DGT) technique to mimic monomethylmercury (MMHg) bioaccumulation by a clam (Macoma balthica, Baltic clam). Using isotope enriched MMHg as tracers, bioavailability was determined by comparing the rate of MMHg uptake by novel DGT devices and sentinel organism over time. Experiments were conducted under varying conditions of salinity and MMHg speciation. Depending on MMHg level and speciation in the dissolved phase, MMHg uptake rates by the sentinel organism varied greatly from 0.4 to 2.4Lg(-1)d(-1). Reproducibilities of MMHg uptakes by DGT and clams were estimated at 7 and 38%, respectively. A significant linear relationship (log basis) between MMHg accumulation by DGT and clams was observed (r(2)=0.89). The study demonstrates that DGT results reasonably predict MMHg uptake by clams from the aqueous phase and provide the basis for application of the DGT device as a surrogate for sentinel organism for monitoring bioavailable MMHg. PMID- 22221873 TI - Effect of earthworms on plant Lantana camara Pb-uptake and on bacterial communities in root-adhering soil. AB - The present study aimed to assess the potential abilities of Lantana camara, an invasive plant species for phytoremediation in the presence of earthworm Pontoscolex corethrurus. Effects of earthworm on growth and lead (Pb) uptake by L. camara plant were studied in soil artificially contaminated at 500 or 1000mg of Pb kg(-1) soil. This species has a promising value for phytoremediation because it can uptake as much as 10% of 1000mgkg(-1) of Pb per year. Moreover, the presence of earthworms enhanced plant biomass by about 1.5-2 times and increased the uptake of lead by about 2-3 times. In the presence of earthworm, L. camara was thus able to uptake up 20% of Pb presence in the soil, corresponding to remediation time of 5 years if all organs are removed. As soil microorganisms are known to mediate many interactions between earthworms and plants, we documented the effect of earthworms on the bacterial community of root-adhering soil of L. camara. Cultivable bacterial biomass of root-adhering soil increased in the presence of earthworms. Similar trend was observed on bacterial metabolic activities. The increase of lead concentrations from 500 to 1000mgkg(-1) did not have any significant effect either on plant growth or on bacterial biomass and global activities but affected the structure and functional diversity of the bacterial community. These results showed that we should broaden the ecological context of phytoremediation by considering plant/microbial community/earthworm interactions that influence the absorption of heavy metals. PMID- 22221874 TI - Synthesis of current data for Hg in areas of geologic resource extraction contamination and aquatic systems in China. AB - China has become the largest contributor of anthropogenic atmospheric mercury (Hg) in the world owing to its fast growing economy and the largest of populations. Over the last two decades, Hg has become of increasing environmental concern in China and much has been published on its distribution, transportation, methylation, and bioaccumulation in aquatic systems and areas of geologic resource extraction contaminated sites, such as coal-fired power plants, non ferrous smelters, Hg mining and retorting sites, Au amalgam, landfills, chemical plants, etc.. Environmental compartments, like soil, water, air, and crop from areas of geologic resource extraction contamination, especially from Hg mining regions, exhibit elevated values of total-Hg and MMHg. Risk assessments indicate that the consumption of rice, which has a high bioaccumulation of MMHg, has become the dominant pathway of MMHg exposure of inhabitants living in Hg mining areas. Low concentrations less than 5ngl(-1) in total-Hg can be observed in rivers from remote areas, however, high concentrations that reached 1600ngl(-1) in total-Hg can be found in rivers from industrial and urban areas. The studies of hydropower reservoirs of southwest China indicated the old reservoirs act as net sinks for total-Hg and net sources of MMHg, while newly established ones act as net sinks for both total-Hg and MMHg, which is in sharp contrast to the evolution of biomethylation in reservoirs established in the boreal belt of North America and Eurasia. Fish from those reservoirs have relatively low levels of total-Hg, which do not exceed the maximum total-Hg limit of 0.5mgkg(-1) recommended by WHO. Currently, however, there is still a large data gap regarding Hg even in the areas mentioned above in China, which results in poor understanding of its environmental biogeochemistry. Moreover, for a better understanding of human and environmental health effects caused by the fast growing economy, long-term Hg monitoring campaigns are urgently needed. PMID- 22221875 TI - Platinum group elements (Pt, Pd, Rh) in airborne particulate matter in rural vs. urban areas of Germany: concentrations and spatial patterns of distribution. AB - This study examines platinum group element concentrations (PGE) (i.e. platinum (Pt), palladium (Pd) and rhodium (Rh)) and their spatial distribution in airborne particulate matter fractions (PM) of human health concern in urban and rural areas of Germany. Fractionated airborne dust and PM(10), PM(2.5) and PM(1) samples were collected along a busy road in Frankfurt am Main from July 2008 to April 2010. PM(10) was also sampled in Deuselbach and Neuglobsow between January 2008 and July 2009 to examine their concentrations at rural locations and potential for long-range transport. Pt, Pd and Rh were isolated and pre-enriched in samples using a combination of Te and Hg co-precipitation methods. Concentrations were determined using isotope dilution ICP-Q-MS (in collision mode with He). The highest airborne PGE concentrations were measured in PM(10) from Frankfurt (e.g. 12.4pg Pt/m(3) (mean)), while the rural locations of Deuselbach and Neuglobsow exhibited the lowest levels (e.g. 2pg Pt/m(3) (mean)). PGE concentrations were observed to decline with increasingly smaller PM size fractions from PM(10) to PM(1). All size fractions generally contained higher levels of Pd compared to Pt and Rh, an element of greater concern due to its solubility. PM(2.5) collected in Frankfurt had a mean of 16.1pg Pd/m(3), compared to 9.4pg/m(3) for Pt. PGE concentrations also demonstrated a distinct seasonal relationship, with the greatest levels occurring in winter. Compared to a previous study in 2002, PGE concentrations in fractionated airborne dust have significantly increased over time. Elevated PGE levels were also measured for PM(10) sampled in Neuglobsow and Deuselbach, which could not be attributed to local emission sources. Using the diagnostic meteorological model, CALMET, trajectory analyses confirmed our hypothesis that PGE are being transported over longer distances from other areas of Europe. PMID- 22221876 TI - Noise frequency components and the prevalence of hypertension in workers. AB - Epidemiological studies have demonstrated a relationship between noise exposure and hypertension, but the association between hypertension and noise frequency components remains unclear. This cross-sectional study investigated the association between noise exposure at different frequencies and the prevalence of hypertension in 188 screw-manufacturing workers. Participants were divided into one high-noise-exposure group (>=80 A-weighted decibel, [dBA]; n=68) and two reference groups, including 68 low-noise-exposure workers (75.8+/-3.2 dBA) and 52 office workers (61.5+/-0.5dBA). Personal noise exposure and environmental octave band analyses were performed at work. Multiple logistic regression models were used to estimate odds ratios (ORs) for hypertension between different noise exposure categories after adjustment for potential confounders. Male workers exposed to noise levels at high frequencies of 2000, 4000 or 8000Hz had a higher but non-significant risk of hypertension. Those exposed to >=80dBA for 2-4years, 4-6years and more than 6years had a 4.43-fold (95% CI=1.21-16.15), 1.21-fold (95% CI=0.35-4.21) and 0.95-fold (95% CI=0.16-5.60) risk of hypertension, respectively, compared with reference workers. A significant association was only observed in male workers exposed to >=70dBA at 4000Hz for 2-4years (adjusted OR=4.22; 95% CI=1.15-15.49) and was not found at other frequencies for any periods. These findings suggest that occupational noise exposure above 80dBA for specific periods may be associated with hypertension, and noise frequency at 4000Hz may have the greatest effect on hypertension. PMID- 22221877 TI - Visible emission from Ce-doped ZnO nanorods grown by hydrothermal method without a post thermal annealing process. AB - Visible light-emitting Ce-doped ZnO nanorods [NRs] without a post thermal annealing process were grown by hydrothermal method on a Si (100) substrate at a low temperature of 90 degrees C. The structural investigations of Ce-doped ZnO NRs showed that the Ce3+ ions were successfully incorporated into the ZnO lattice sites without forming unwanted Ce-related compounds or precipitates. The optical investigation by photoluminescence spectra shows that the doped Ce3+ ions in the ZnO NRs act as an efficient luminescence center at 540 nm which corresponds to the optical transition of 5d -> 4f orbitals in the Ce3+ ions. The photoluminescence intensity of the Ce-doped ZnO NRs increased with the increasing content of the Ce-doping agent because the energy transfer of the excited electrons in ZnO to the Ce3+ ions would be enhanced by increased Ce3+ ions. PMID- 22221878 TI - Look@NanoSIMS--a tool for the analysis of nanoSIMS data in environmental microbiology. AB - We describe an open-source freeware programme for high throughput analysis of nanoSIMS (nanometre-scale secondary ion mass spectrometry) data. The programme implements basic data processing and analytical functions, including display and drift-corrected accumulation of scanned planes, interactive and semi-automated definition of regions of interest (ROIs), and export of the ROIs' elemental and isotopic composition in graphical and text-based formats. Additionally, the programme offers new functions that were custom-designed to address the needs of environmental microbiologists. Specifically, it allows manual and automated classification of ROIs based on the information that is derived either from the nanoSIMS dataset itself (e.g. from labelling achieved by halogen in situ hybridization) or is provided externally (e.g. as a fluorescence in situ hybridization image). Moreover, by implementing post-processing routines coupled to built-in statistical tools, the programme allows rapid synthesis and comparative analysis of results from many different datasets. After validation of the programme, we illustrate how these new processing and analytical functions increase flexibility, efficiency and depth of the nanoSIMS data analysis. Through its custom-made and open-source design, the programme provides an efficient, reliable and easily expandable tool that can help a growing community of environmental microbiologists and researchers from other disciplines process and analyse their nanoSIMS data. PMID- 22221879 TI - Cultured fish: integrative biology and management of domestication and interactions with wild fish. AB - Fish aquaculture for commodity production, fisheries enhancement and conservation is expanding rapidly, with many cultured species undergoing inadvertent or controlled domestication. Cultured fish are frequently released, accidentally and deliberately, into natural environments where they may survive well and impact on wild fish populations through ecological, genetic, and technical interactions. Impacts of fish released accidentally or for fisheries enhancement tend to be negative for the wild populations involved, particularly where wild populations are small, and/or highly adapted to local conditions, and/or declining. Captive breeding and supplementation can play a positive role in restoring threatened populations, but the biology of threatened populations and the potential of culture approaches for conserving them remain poorly understood. Approaches to the management of domestication and cultured-wild fish interactions are often ad hoc, fragmented and poorly informed by current science. We develop an integrative biological framework for understanding and managing domestication and cultured wild fish interactions. The framework sets out how management practices in culture and for cultured fish in natural environments affect domestication processes, interactions between cultured and wild fish, and outcomes in terms of commodity production, fisheries yield, and conservation. We also develop a typology of management systems (specific combinations of management practices in culture and in natural environments) that are likely to provide positive outcomes for particular management objectives and situations. We close by setting out avenues for further research that will simultaneously improve fish domestication and management of cultured-wild fish interactions and provide key insights into fundamental biology. PMID- 22221880 TI - A forward genetic screen to study mammalian RNA interference: essential role of RNase IIIa domain of Dicer1 in 3' strand cleavage of dsRNA in vivo. AB - RNA interference is a major post-transcriptional regulatory pathway in many eukaryotes. The RNase III enzyme Dicer1 processes precursor RNAs into small RNA duplexes to be loaded onto Argonaute proteins, the effector components of RNA induced silencing complex. Biochemical studies have shown that the RNase IIIa and RNase IIIb domains of Dicer1 cleave the 3' and 5' strands of dsRNAs, respectively, although the in vivo functional significance of this activity remains unclear. Genetic screening of mammalian cells is useful for studying molecular mechanisms at the cellular level. In the present study, we conducted a novel forward genetic screen for mammalian RNA interference components using Chinese hamster ovary cells and successfully obtained several Dicer1 mutant lines. One mutant bore an intriguing Dicer1 allele in which a conserved glutamic acid in the RNase IIIa domain was substituted with a lysine. Our detailed cell biological study demonstrated that the RNase IIIa domain of Dicer1 was essential for generating small RNAs embedded in the 3' stem of exogenous hairpin-like RNAs. In the mutant cells, the expression of endogenous mature microRNAs derived from the 3' stem of pre-microRNA was repressed more severely than that from the 5' stem. Moreover, appropriate processing and loading of small RNAs were required for the dissociation of Argonaute 2 from Dicer1. The data obtained in the present study demonstrate that this screening method represents a promising strategy for the identification of unknown components of mammalian RNA interference pathways and the study of the biological significance of these components at the cellular level. PMID- 22221881 TI - Physical properties of metal-doped zinc oxide films for surface acoustic wave application. AB - Metal-doped ZnO [MZO] thin films show changes of the following properties by a dopant. First, group III element (Al, In, Ga)-doped ZnO thin films have a high conductivity having an n-type semiconductor characteristic. Second, group I element (Li, Na, K)-doped ZnO thin films have high resistivity due to a dopant that accepts a carrier. The metal-doped ZnO (M = Li, Ag) films were prepared by radio frequency magnetron sputtering on glass substrates with the MZO targets. We investigated on the optical and electrical properties of the as-sputtered MZO films as dependences on the doping contents in the targets. All the MZO films had shown a preferred orientation in the [002] direction. As the quantity and the variety of metal dopants were changed, the crystallinity and the transmittance, as well as optical band gap were changed. The electrical resistivity was also changed with changing metal doping amounts and kinds of dopants. An epitaxial Li doped ZnO film has a high resistivity and very smooth surface; it will have the most optimum conditions which can be used for the piezoelectric devices. PMID- 22221882 TI - Tau acts as an independent genetic risk factor in pathologically proven PD. AB - MAPT has been repeatedly linked with Parkinson's disease (PD) in association studies. Although tau deposition may be seen in PD, its relevance to the pathogenesis of the condition remains unclear. The presence of tau-positive inclusions is, however, the defining feature of progressive supranuclear palsy (PSP), which may often be clinically misdiagnosed as idiopathic PD. On a genetic level, variants in MAPT are the strongest risk factor for PSP. These facts raise the question whether the MAPT association in PD results from contamination with unrecognized cases of PSP. Using only neuropathologically proven PD, we show that the MAPT association remains and is independent of the PSP Association. PMID- 22221883 TI - S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in mice. AB - Methylation reactions linked to homocysteine in the one-carbon metabolism are increasingly elicited in Alzheimer's disease, although the association of hyperhomocysteinemia and of low B vitamin levels with the disease is still debated. We previously demonstrated that hyperhomocysteinemia and DNA hypomethylation induced by B vitamin deficiency are associated with PSEN1 and BACE1 overexpression and amyloid production. The present study is aimed at assessing S-adenosylmethionine effects in mice kept under a condition of B vitamin deficiency. To this end, TgCRND8 mice and wild-type littermates were assigned to control or B vitamin deficient diet, with or without S adenosylmethionine supplementation. We found that S-adenosylmethionine reduced amyloid production, increased spatial memory in TgCRND8 mice and inhibited the upregulation of B vitamin deficiency-induced PSEN1 and BACE1 expression and Tau phosphorylation in TgCRND8 and wild-type mice. Furthermore, S-adenosylmethionine treatment reduced plaque spreading independently on B vitamin deficiency. These results strengthen our previous observations on the possible role of one-carbon metabolism in Alzheimer's disease, highlighting hyperhomocysteinemia-related mechanisms in dementia onset/progression and encourage further studies aimed at evaluating the use of S-adenosylmethionine as a potential candidate drug for the treatment of the disease. PMID- 22221884 TI - Genetic testing in familial and young-onset Alzheimer's disease: mutation spectrum in a Serbian cohort. AB - Alzheimer's disease (AD) is the most common form of dementia. To date, more than 200 mutations in three genes have been identified as cause of early-onset autosomal dominant inherited AD. The aim of this study was to characterize the mutation spectrum and describe genotype-phenotype correlations in Serbian patients with positive family history of AD or/and early-onset AD. We performed a genetic screening for mutations in the coding regions of Presenilins 1 and 2 (PSEN1 and PSEN2), as well as exons 16 and 17 of the Amyloid Precursor Protein gene (APP) in a total of 47 patients from Serbia with a clinical diagnosis of familial and/or early-onset AD (mean age at onset of 60.3 years; range 32-77). We found one novel mutation in PSEN1, one novel variant in PSEN2, and three previously described variants, one in each of the analyzed genes. Interestingly, we identified one patient harboring two heterozygous mutations: one in APP (p.L723P) and one in PSEN1 (p.R108Q). PMID- 22221885 TI - Rapid and transient upregulation of CCL11 (eotaxin-1) in mouse ovary during terminal stages of follicular development. AB - PROBLEM: This study aimed to investigate the regulation of expression, localization and physiological role of the CCL11/CCR3 axis in mouse ovary during the periovulatory period. METHOD OF STUDY: CCL11/CCR3 expression in the mouse ovary after treatment with pregnant mare serum gonadotropin (PMSG) followed by human chorionic gonadotropin (hCG) 48 hr later was assessed in vivo and in 3 dimensional cultures in vitro. RESULTS: Real-time RT-PCR analyses revealed transient CCL11 mRNA upregulation 6 hr after hCG treatment. Immunohistochemical staining of serial ovarian sections demonstrated overlapping expression of CCL11, CCR3 and CD31 endothelial cell marker in the theca-interstitial layer at 10 hr after hCG treatment. In vitro 3-dimensional cultures of periovulatory ovarian tissues demonstrated that treatment with anti-CCL11 neutralizing antibody significantly decreased CD31 transcript. CONCLUSIONS: Gonadotropin surge leads to transient CCL11/CCR3 axis upregulation in the ovarian theca-interstitial layer, suggesting that it is involved in periovulatory physiological processes by affecting follicular vessels. PMID- 22221886 TI - Treatment strategies for periprosthetic infections after primary elbow arthroplasty. AB - BACKGROUND: The goal of this study was to investigate the outcome of different surgical procedures (debridement and retention vs 1- or 2-stage exchange) together with a well-defined antimicrobial regimen. MATERIALS AND METHODS: A total of 236 consecutive patients underwent 262 primary elbow arthroplasties between January 1994 and December 2007. We observed 20 episodes of periprosthetic infections in 19 patients and placed them into 3 groups according to the occurrence of infection after index surgery. A total of 9 early infections (<3 months), 1 delayed infection (3-24 months), and 10 late infections (>24 months) were observed. The treatment among those 3 groups was compared, and the outcome was assessed with a mean follow-up of 60.2 months. RESULTS: In the group with early infections (n = 9), 8 cases were treated by irrigation and debridement and 1 case was treated by a 2-stage exchange without recurrence of infection. The mean Mayo Elbow Performance Score improved from 48.3 points (range, 30-75 points) to 91.7 points (range, 85-100 points). The delayed infection was treated by 1 stage exchange without recurrence of infection. For late infections (n = 10), 3 cases presented recurrence of infection after debridement and irrigation, and the mean Mayo Elbow Performance Score remained nearly unchanged, from 60 points (range, 45-80 points) to 65 points (range, 50-80 points). Eradication of infection could be achieved by staged revision and in 3 cases by debridement. CONCLUSION: Both debridement with retention and staged reimplantation are highly successful for appropriate indications. Staged revisions are successful even against biofilm-active microorganisms, but a prosthesis-free interval of at least 3 months is recommended. PMID- 22221887 TI - Investigation of disease-associated factors in haemophilia A patients without detectable mutations. AB - To investigate disease causing mechanism in haemophilia A patients without detectable mutation. Screening for F8 mutations in 307 haemophilia A patients using: re-sequencing and inversion PCR, reverse transcription (RT-PCR) of mRNA, MLPA analysis, haplotyping using SNP and microsatellite markers. No F8 mutations were detected in 9 of the 307 patients (2.9%) using re-sequencing and inversion PCR. MLPA analysis detected duplication in exon 6 in one patient and RT-PCR showed no products for different regions of mRNA in four other patients, indicating failed transcription. No obvious associations were observed between the phenotypes of the nine patients, their F8 haplotypes and the putative mutations detected. The mutation-positive patients carrying the same haplotypes as the mutation-negative patients show a multitude of different mutations, emphasizing the lack of associations at the haplotype level. VWF mutation screening and factor V measurements ruled out type 2N VWD and combined factor V and VIII deficiency respectively. To further investigate a possible role for FVIII interacting factors the haplotypes/diplotypes of F2, F9, F10 and VWF were compared. The nine patients had no specific haplotype/diplotype combination in common that can explain disease. Duplications and faulty transcription contribute to the mutational spectrum of haemophilia A patients where conventional mutation screening fail to identify mutations. PMID- 22221888 TI - An application of the Impact Evaluation Process for designing a performance measurement and evaluation framework in K-12 environments. AB - This article illustrates the application of the Impact Evaluation Process for the design of a performance measurement and evaluation framework for an urban high school. One of the key aims of this framework is to enhance decision-making by providing timely feedback about the effectiveness of various performance improvement interventions. The framework design process is guided by the Impact Evaluation Process, and included the participation of key stakeholders including administrative and teaching staff who all contributed to the performance measurement and evaluation framework design process. Key performance indicators at the strategic, tactical, and operational levels were derived from the school vision, and linked to specific interventions to facilitate the continuous evaluation and improvement process. PMID- 22221889 TI - Quality and rigor of the concept mapping methodology: a pooled study analysis. AB - The use of concept mapping in research and evaluation has expanded dramatically over the past 20 years. Researchers in academic, organizational, and community based settings have applied concept mapping successfully without the benefit of systematic analyses across studies to identify the features of a methodologically sound study. Quantitative characteristics and estimates of quality and rigor that may guide for future studies are lacking. To address this gap, we conducted a pooled analysis of 69 concept mapping studies to describe characteristics across study phases, generate specific indicators of validity and reliability, and examine the relationship between select study characteristics and quality indicators. Individual study characteristics and estimates were pooled and quantitatively summarized, describing the distribution, variation and parameters for each. In addition, variation in the concept mapping data collection in relation to characteristics and estimates was examined. Overall, results suggest concept mapping yields strong internal representational validity and very strong sorting and rating reliability estimates. Validity and reliability were consistently high despite variation in participation and task completion percentages across data collection modes. The implications of these findings as a practical reference to assess the quality and rigor for future concept mapping studies are discussed. PMID- 22221890 TI - Exceeding parents' expectations in Ear-Nose-Throat outpatient facilities: the development and analysis of a questionnaire. AB - The study attempts to develop an outpatient service quality scale by investigating the key dimensions which assess parental satisfaction and provides a recommendation on an improved health service delivery system. The survey was conducted in an Ear-Nose-Throat outpatient clinic of a Greek public pediatric hospital. A total of 127 parents in outpatient waiting areas were chosen; 74.8% of the sampled parents were under 40, and 78% were mothers. A factor analysis was performed; while a Fischer's exact test and multinomial logistic regression analysis was conducted. All Cronbach's alpha exceeded 0.70 and all factor loadings exceeded 0.50. Twenty-three items were retained through the scale development process and seven factors were formed that appear to be statistically valid and clinically meaningful: access and convenience, doctor's attention, customization, reliability, assurance, satisfaction and loyalty. Findings were discussed in relation to parents' overall satisfaction and intention of reusing and recommending outpatient clinic. Satisfaction was found to be positively affected by access and convenience and doctors' attention. Staff attitude and the telephone procedure of scheduling the child's examination found positively correlated to the likelihood of recommending services to friends and relatives. Time and communication in the waiting room influenced parents' satisfaction. Overall, results reveal the measures that need to be taken in order to improve outpatient service quality. PMID- 22221891 TI - Beyond resistance: exploring health managers' propensity for participatory evaluation in a developing country. AB - The evaluation of interventions is becoming increasing common and now often seeks to involve managers in the process. Such practical participatory evaluation (PPE) aims to increase the use of evaluation results through the participation of stakeholders. This study focuses on the propensity of health managers for PPE, as measured through the components of learning, working in groups, use of judgment and use of systematic methods. We interviewed 16 health managers to determine the meaning they ascribe to these four components in their practice in a developing country, Haiti. We found that learning was often informal and that all managers attached a negative meaning to the use of judgment. Working in groups was favored by all managers, while the health managers viewed the use of systematic methods differently than do evaluators. The administrative health managers generally ranked lower in propensity for PPE than did their clinical colleagues. Implications for the practice of evaluation are discussed in relation to the work styles exhibited by managers in everyday practice, the proactive repetition of actions, the control exercised by formal procedures, and the collective versus "solitary" image of one's environment of action. PMID- 22221892 TI - An introduction to the Safe Schools/Healthy Students Initiative. AB - The Safe Schools/Healthy Students (SS/HS) Initiative offers a unique opportunity to conduct large-scale, multisite, multilevel program evaluation in the context of a federal environment that places many requirements and constraints on how the grants are conducted and managed. Federal programs stress performance-based outcomes, valid and reliable data, addressing important problems, ensuring efficiency and fiscal responsibility, reducing burden on federal staff and grantees, and developing and disseminating useful solutions and recommendations. MANILA Consulting Group, Inc., (MANILA), in partnership with Battelle Centers for Public Health Research and Evaluation (Battelle) and RMC Research Corporation (RMC), has been conducting the SS/HS national cross-site evaluation, which involves the coordinated efforts of federal Project Officers, local education agencies, technical assistance providers, communication specialists, and national and local evaluators across a diverse set of socioeconomic and cultural contexts. To date, the national cross-site evaluation has provided data indicating that the SS/HS Initiative is, in fact, meeting these goals. Findings revealed that fewer students reported they had experienced violence and fewer students reported they had witnessed violence. Fully 96 percent of school staff said SS/HS had improved school safety. There was a 263 percent increase in the number of students who received school-based mental health services and a 519 percent increase in those receiving community-based mental health services. In addition, more than 80 percent of school staff reported that they saw reductions in alcohol and other drug use among their students. These encouraging results stress the need for ongoing coordination at all levels of the Initiative to continue to ensure safer schools and healthier students. This article provides an overview of the initiative and introduces four articles in this special issue. PMID- 22221893 TI - A mixed-method exploration of functioning in Safe Schools/Healthy Students partnerships. AB - This paper presents a mixed-method approach to measuring the functioning of Safe Schools/Healthy Students (SS/HS) Initiative partnerships. The SS/HS national evaluation team developed a survey to collect partners' perceptions of functioning within SS/HS partnerships. Average partnership functioning scores were used to rank each site from lowest to highest. Sites with the most favorable perceptions of partnership functioning were defined as having average scores in the top 10% (n=10) and sites with the least favorable perceptions of partnership functioning were defined as having average scores in the bottom 10% (n=10). Qualitative data for these 20 sites were inductively open coded for emergent themes and analyzed for patterns using grounded theory approach. Six themes emerged that distinguished sites reporting the most favorable and least favorable perceptions of partnership functioning: partner engagement, facilitators, barriers, shared decision making, partnership structure, and sustainability. Sites reporting the most favorable perceptions of partnership functioning effectively utilized collaboration processes that facilitate coalition building, such as shared decision making, effective communication, and developing a clearly defined structure. Qualitative themes from this analysis provide evidence of validity for the partnership functioning scale used and illustrate distinguishing features between sites with the most favorable and least favorable perceptions of partnership functioning. PMID- 22221894 TI - Mutant Hras(G12V) and Kras(G12D) have overlapping, but non-identical effects on hepatocyte growth and transformation frequency in transgenic mice. AB - BACKGROUND: Mouse hepatocarcinogenesis is associated with mutations in Hras, but infrequently in Kras. The effect on carcinogenesis of developmental age at the time of ras mutation remains unknown. AIM: We sought to compare quantitatively the effects of expressing mutant H- or Kras genes in fetal vs. adult mouse liver. METHODS: We established an inducible system of gene expression in mouse liver to define disease pathogenesis associated with activation of oncogene expression. RESULTS: Diffuse expression of either oncogene in fetal or adult hepatocytes caused hepatomegaly. For mutant Hras(G12V), this phenotype was almost fully reversible and accompanied by apoptosis, indicating that maintenance of hepatomegaly requires continuous Hras(G12V) expression. We also examined the effect of ras expression on growth of transplanted hepatocytes in an in vivo system that allows us to quantify hepatocyte growth effects in both permissive and restrictive hepatic growth environments. Mutant Kras(G12D) had no effect on hepatocyte growth in this system. In contrast, Hras(G12V) induced increased hepatocyte focus growth in quiescent liver, the hallmark of a cell autonomous growth stimulus. Hras(G12V) also increased the fraction of donor hepatocyte foci that displayed extreme growth, a characteristic of preneoplastic lesions. CONCLUSIONS: The primary effect of diffuse, whole-liver expression of either mutant ras gene in fetal or adult mouse liver is diffuse and progressive hepatic growth. Hras(G12V) mutation influences hepatocarcinogenesis by conferring cell autonomous growth potential upon foci of expressing cells and by increasing the risk of neoplastic progression. Kras(G12D) does not share these latter carcinogenic effects in mouse liver. PMID- 22221895 TI - A prospective study of complications from comprehensive abortion care services in Nepal. AB - BACKGROUND: In March 2002, Nepal's Parliament approved legislation to permit abortion on request up to 12 weeks of pregnancy. Between 2004 and 2007, 176 comprehensive abortion care (CAC) service sites were established in Nepal, leading to a rise in safe, legal abortions. Though monitoring systems have been developed, reporting of complications has not always been complete or accurate. The purpose of this study was to report the frequency and type of abortion complications arising from CAC procedures in different types of facilities in Nepal. METHODS: A total of 7,386 CAC clients from a sample of facilities across Nepal were enrolled over a three-month period in 2008. Data collection included an initial health questionnaire at the time of abortion care and a follow-up questionnaire assessing complications, administered two weeks after the abortion procedure. A total of 7,007 women (95%) were successfully followed up. Complication rates were assessed overall and by facility type. Multivariable logistic regression was used to assess the association between experiencing a complication and client demographic and facility characteristics. RESULTS: Among the 7,007 clients who were successfully followed, only 1.87% (n = 131) experienced signs and symptoms of complications at the two-week follow up, the most common being retained products of conception (1.37%), suspected sepsis (0.39%), offensive discharge (0.51%) and moderate bleeding (0.26%). Women receiving care at non-governmental organization (NGO) facilities were less likely to experience complications than women at government facilities, adjusting for individual and facility characteristics (AOR = 0.18; 95% CI: 0.08-0.40). Compared to women receiving CAC at 4-5 weeks gestation, women at 10-12 weeks gestation were more likely to experience complications, adjusting for individual and facility characteristics (AOR = 4.21; 95% CI: 1.38-12.82). CONCLUSIONS: The abortion complication rate in Nepali CAC facilities is low and similar to other settings; however, significant differences in complication rates were observed by facility type and gestational age. Interventions such as supportive supervision to improve providers' uterine evacuation skills and investment in equipment for infection control may lower complication rates in government facilities. In addition, there should be increased focus on early pregnancy detection and access to CAC services early in pregnancy in order to prevent complications. PMID- 22221896 TI - Regulation of prokaryotic gene expression by eukaryotic-like enzymes. AB - A growing body of evidence indicates that serine/threonine kinases (STKs) and phosphatases (STPs) regulate gene expression in prokaryotic organisms. As prokaryotic STKs and STPs are not DNA binding proteins, regulation of gene expression is accomplished through post-translational modification of their targets. These include two-component response regulators, DNA binding proteins and proteins that mediate transcription and translation. This review summarizes our current understanding of how STKs and STPs mediate gene expression in prokaryotes. Further studies to identify environmental signals that trigger the signaling cascade and elucidation of mechanisms that regulate crosstalk between eukaryotic-like signaling enzymes, two-component systems, and components of the transcriptional and translational machinery will facilitate a greater understanding of prokaryotic gene regulation. PMID- 22221897 TI - The control of death and lysis in staphylococcal biofilms: a coordination of physiological signals. AB - The processes involved in the development of complex multicellular communities, including the programmed elimination of individual cells during the formation of specialized structures, exhibit fundamental similarities between prokaryotic and eukaryotic organisms. Mechanistic similarities may also exist at the molecular level, as bacterial proteins hypothesized to be related to the apoptosis regulator Bax/Bcl-2 family have been identified, fueling speculation about the existence of bacterial PCD. Here we review the regulatory networks controlling cell death and lysis in Staphylococcus aureus and examine the environmental parameters that might influence them during the development of a biofilm. We hypothesize that the heterogeneous environmental conditions found within a developing biofilm generate distinct physiological signals that coordinate the differential expression of cell death and lysis effectors. PMID- 22221898 TI - Making a beta-barrel: assembly of outer membrane proteins in Gram-negative bacteria. AB - The outer membrane (OM) of Gram-negative bacteria is an essential organelle that serves as a selective permeability barrier by keeping toxic compounds out of the cell while allowing vital nutrients in. How the OM and its constituent lipid and protein components are assembled remains an area of active research. In this review, we describe our current understanding of how outer membrane proteins (OMPs) are delivered to and then assembled in the OM of the model Gram-negative organism Escherichia coli. PMID- 22221899 TI - Distinctive expression of CD133 between intraductal papillary neoplasms of the bile duct and bile duct adenocarcinomas. AB - AIM: Intraductal papillary neoplasm of the bile duct (IPNB), a novel entity of biliary disease, is recently advocated as the counterpart of pancreatic intraductal papillary mucinous neoplasm (IPMN) because both are in common with a large amount of mucin production and papillary growth. Based on our recent finding that expression of CD133, a cancer stem cell marker, is lacking in pancreatic IPMN, we herein focused on CD133 expression of IPNB in comparison with intrahepatic cholangiocellular carcinoma (IHCCC) or hilar bile duct cancer (HBDC). METHODS: Expression of CD133 protein was immunohistochemically determined in patients with IPNB (n = 7), IHCCC (n = 16) or HBDC (n = 8). In addition, morphological and immunohistochemical mucin expression patterns were characterized in IPNB, and clinicopathological features including prognosis were compared between IPNB and other biliary tumors. RESULTS: The IPNB group included significantly more females than the other two groups, and had a longer survival time. While no CD133 expression was observed in IPNB tumor, 16.4% of cancer cells in IHCCC and 17.2% of cells in HBDC expressed CD133. Among seven patients with IPNB, six (86%) were morphologically the pancreatobiliary type and four of six showed mucin expression pattern of the typical pancreatobiliary type (MUC1+/MUC2-/MUC5AC+). CONCLUSION: Loss of CD133 expression supports the hypothesis that IPNB is a counterpart of pancreatic IPMN with a differing carcinogenesis from conventional bile duct adenocarcinomas. PMID- 22221901 TI - Laboratory versus field walking tests in moderate COPD: value in simplicity? PMID- 22221902 TI - Chromatographic fingerprint analysis of yohimbe bark and related dietary supplements using UHPLC/UV/MS. AB - A practical ultra high-performance liquid chromatography (UHPLC) method was developed for fingerprint analysis of and determination of yohimbine in yohimbe barks and related dietary supplements. Good separation was achieved using a Waters Acquity BEH C(18) column with gradient elution using 0.1% (v/v) aqueous ammonium hydroxide and 0.1% ammonium hydroxide in methanol as the mobile phases. The study is the first reported chromatographic method that separates corynanthine from yohimbine in yohimbe bark extract. The chromatographic fingerprint analysis was applied to the analysis of 18 yohimbe commercial dietary supplement samples. Quantitation of yohimbine, the traditional method for analysis of yohimbe barks, were also performed to evaluate the results of the fingerprint analysis. Wide variability was observed in fingerprints and yohimbine content among yohimbe dietary supplement samples. For most of the dietary supplements, the yohimbine content was not consistent with the label claims. PMID- 22221903 TI - Determination of piperazine-type stimulants in human urine by means of microextraction in packed sorbent and high performance liquid chromatography diode array detection. AB - A method using microextraction by packed sorbent (MEPS) and high performance liquid chromatography-diode array detection (HPLC-DAD) is described for the determination of piperazine-type stimulants in human urine. The studied compounds were 1-benzylpiperazine (BZP), 1-(3-trifluoromethylphenyl) piperazine (TFMPP), 1 (3-chlorophenyl) piperazine (mCPP) and 1-(4-methoxyphenyl) piperazine (MeOPP); 1 (2-chlorophenyl)-piperazine (oCPP) was used as internal standard (IS). The factors which might influence the extraction were screened previously using the fractional factorial design approach, and none of them influenced significantly the process. The procedure was linear for concentrations ranging from 0.1 (lower limit of quantitation--LLOQ) to 5 MUg/mL, with determination coefficients (R(2)) higher than 0.99 for all analytes in all runs. The limits of detection were 0.1 MUg/mL for BZP and TFMPP, while for MeOPP and mCPP 0.05 MUg/mL was obtained. Intra- and interday precision ranged from 1 to 14%, and accuracy was within a +/- 15% interval for all analytes, fulfilling the criteria normally accepted in bioanalytical method validation. Under the optimized conditions, extraction efficiency was higher than 80% for all analytes, except BZP (50%). MEPS showed to be a rapid (<2 min) and simple procedure for the determination of piperazine-type stimulants in human urine, allowing reducing the handling time and costs usually associated to this type of analysis. Furthermore, the fact that only 0.1 mL of sample is required make this method a valuable and powerful tool for drug monitoring in human urine in situations where those compounds are involved, for instance in forensic scenarios. PMID- 22221900 TI - Effects of adjuvants on IgG subclasses elicited by virus-like particles. AB - BACKGROUND: Virus-Like Particles (VLPs) represent an efficient strategy to present and deliver conformational antigens to the immune system, inducing both arms of the adaptive immune response. Moreover, their particulate structure surrounded by cell membrane provides an adjuvanted effect to VLP-based immunizations. In the present study, the elicitation of different patterns of IgG subclasses by VLPs, administered in CpG ODN1826 or poly(I:C) adjuvants, has been evaluated in an animal model. RESULTS: Adjuvanted VLPs elicited a higher titer of total specific IgG compared to VLPs alone. Furthermore, while VLPs alone induced a balanced TH2 pattern, VLPs formulated with either adjuvant elicited a TH1 biased IgG subclasses (IgG2a and IgG3), with poly(I:C) more potent than CpG ODN1826. CONCLUSIONS: The results confirmed that adjuvants efficiently improve antigen immunogenicity and represent a suitable strategy to skew the adaptive immune response toward the differentiation of the desired T helper subset, also using VLPs as antigen. PMID- 22221904 TI - Idiopathic granulomatous mastitis associated with risperidone-induced hyperprolactinemia. AB - Idiopathic granulomatous mastitis (IGM) is a rare inflammatory breast disease. The etiology and treatment options of IGM remain controversial. Previous case reports have suggested that hyperprolactinemia may be associated with IGM. In the present report, we describe the first case of IGM associated with risperidone induced hyperprolactinemia. PMID- 22221905 TI - A study on the characteristics of plasma polymer thin film with controlled nitrogen flow rate. AB - Nitrogen-doped thiophene plasma polymer [N-ThioPP] thin films were deposited by radio frequency (13.56 MHz) plasma-enhanced chemical vapor deposition method. Thiophene was used as organic precursor (carbon source) with hydrogen gas as the precursor bubbler gas. Additionally, nitrogen gas [N2] was used as nitrogen dopant. Furthermore, additional argon was used as a carrier gas. The as-grown polymerized thin films were analyzed using ellipsometry, Fourier-transform infrared [FT-IR] spectroscopy, Raman spectroscopy, and water contact angle measurement. The ellipsometry results showed the refractive index change of the N ThioPP film. The FT-IR spectra showed that the N-ThioPP films were completely fragmented and polymerized from thiophene. PMID- 22221906 TI - [Malignant syphilis in an immunocompetent patient]. PMID- 22221907 TI - Use of diuretics and the risk of gouty arthritis: a systematic review. AB - OBJECTIVE: To systematically review the literature investigating the relationship between use of diuretics and the risk of gouty arthritis. METHODS: PubMed (1950 October 2009), Embase (1974-October 2009), and the Cochrane Library (up to October 2009) were searched using keywords and MeSH terms diuretics, adverse effects, and gout. For this review, the technique of "best evidence synthesis" was used. Studies reporting frequency, absolute or relative risks, odds ratio, or rate ratio of gouty arthritis in diuretic users compared with nonusers were selected and evaluated. Studies had to be published in English. Checklists from the Dutch Cochrane Centre were used to assess the quality of randomized controlled trials (RCTs), cohort, and case-control studies. RESULTS: Two RCTs, 6 cohort studies, and 5 case-control studies met the inclusion criteria. The overall quality of the studies was moderate. In a RCT the rate ratio of gout for use of bendrofluazide vs placebo was 11.8 (95% CI 5.2-27.0). The other RCT found a rate ratio of 6.3 (95% CI 0.8-51) for use of hydrochlorothiazide plus triamterene vs placebo. Three cohort studies and 4 case-control studies found higher risks of gouty arthritis in users compared with nonusers of diuretics. CONCLUSIONS: There is a trend toward a higher risk for acute gouty arthritis attacks in patients on loop and thiazide diuretics, but the magnitude and independence is not consistent. Therefore, stopping these useful drugs in patients who develop gouty arthritis is not supported by the results of this review. PMID- 22221908 TI - Treatment of systemic sclerosis-associated calcinosis: a case report of rituximab induced regression of CREST-related calcinosis and review of the literature. AB - OBJECTIVES: Calcinosis is frequently encountered in patients with systemic sclerosis (SSc) and may be associated with significant morbidity. No treatment has shown so far an unequivocal beneficial effect. METHODS: We performed an extensive internet search (MEDLINE) using the keywords calcinosis, calcification, scleroderma, systemic sclerosis, and treatment. RESULTS: Our patient had extensive Calcinosis, Raynaud, Esophagitis, Sclerodactyly, telangiectasia (CREST) related calcinosis, frequently ulcerating and painful. Following 2 rituximab courses (consisting of 4 weekly infusions, 375 mg/m(2) each), calcinosis significantly improved and pain disappeared. Pharmacologic agents used in the treatment of SSc-associated calcinosis include diltiazem, minocycline, warfarin, biphosphonates, and intravenous immunoglobulin. Other therapeutic approaches include surgical excision, laser vaporization, and extracorporeal shock wave lithotripsy. CONCLUSIONS: Evidence for all existing therapies is weak and therefore larger scale controlled studies are needed. Rituximab appears as a promising treatment especially in view of recent evidence that this therapy may be also effective in the underlying disease. PMID- 22221910 TI - En route to a new in vivo diagnostic of malignant pigmented melanoma. PMID- 22221909 TI - A prospective functional MRI study for executive function in patients with systemic lupus erythematosus without neuropsychiatric symptoms. AB - OBJECTIVE: To study the functional brain activation signals before and after sufficient disease control in patients with systemic lupus erythematosus (SLE) without clinical neuropsychiatric symptoms. METHODS: Blood-oxygen-level-dependent signals during event-related functional magnetic resonance imaging brain were recorded, while 14 new-onset SLE patients and 14 demographically and intelligence quotient matched healthy controls performed the computer-based Wisconsin card sorting test for assessing executive function, which probes strategic planning and goal-directed task performance during feedback evaluation (FE) and response selection (RS), respectively. Composite beta maps were constructed by a general linear model to identify regions of cortical activation. Blood-oxygen-level dependent functional magnetic resonance imaging signals were compared between (1) new-onset SLE patients and healthy controls and (2) SLE patients before and after sufficient control of their disease activity. RESULTS: During RS, SLE patients demonstrated significantly higher activation than healthy controls in both caudate bodies and Brodmann area (BA) 9 to enhance event anticipation, attention, and working memory, respectively, to compensate for the reduced activation during FE in BA6, 13, 24, and 32, which serve complex motor planning and decision making, sensory integration, error detection, and conflict processing, respectively. Despite significant reduction of SLE activity, BA32 was activated during RS to compensate for reduced activation during FE in BA6, 9, 37, and 23/32, which serve motor planning, response inhibition and attention, color processing and word recognition, error detection, and conflict evaluation, respectively. CONCLUSIONS: Even without clinically overt neuropsychiatric symptoms, SLE patients recruited additional pathways to execute goal-directed tasks to compensate for their reduced strategic planning skill despite clinically sufficient disease control. PMID- 22221911 TI - Effect of oxygen on the anaerobic methanotroph 'Candidatus Methylomirabilis oxyfera': kinetic and transcriptional analysis. AB - 'Candidatus Methylomirabilis oxyfera' is a denitrifying methanotroph that performs nitrite-dependent anaerobic methane oxidation through a newly discovered intra-aerobic pathway. In this study, we investigated the response of a M. oxyfera enrichment culture to oxygen. Addition of either 2% or 8% oxygen resulted in an instant decrease of methane and nitrite conversion rates. Oxygen exposure also led to a deviation in the nitrite to methane oxidation stoichiometry. Oxygen uptake and inhibition studies with cell-free extracts displayed a change from cytochrome c to quinol as electron donor after exposure to oxygen. The change in global gene expression was monitored by deep sequencing of cDNA using Illumina technology. After 24 h of oxygen exposure, transcription levels of 1109 (out of 2303) genes changed significantly when compared with the anoxic period. Most of the genes encoding enzymes of the methane oxidation pathway were constitutively expressed. Genes from the denitrification pathway, with exception of one of the putative nitric oxide reductases, norZ2, were severely downregulated. The majority of known genes involved in the vital cellular functions, such as nucleic acid and protein biosynthesis and cell division processes, were downregulated. The alkyl hydroperoxide reductase, ahpC, and genes involved in the synthesis/repair of the iron-sulfur clusters were among the few upregulated genes. Further, transcription of the pmoCAB genes of aerobic methanotrophs present in the non-M. oxyfera community were triggered by the presence of oxygen. Our results show that oxygen-exposed cells of M. oxyfera were under oxidative stress and that in spite of its oxygenic capacity, exposure to microoxic conditions has an overall detrimental effect. PMID- 22221912 TI - Carbon-coated iron oxide nanoparticles as contrast agents in magnetic resonance imaging. AB - Coprecipitated ferrite nanoparticles were coated with carbon using a hydrothermal method. From transmission electron microscope pictures, we could see that the coated iron oxide nanoparticles were spherical in shape with an average diameter of 90 nm. The strong bonding of carbon on the nanoparticle surfaces was checked by noting the C = O and C = C vibrations in Fourier transform infrared spectra. The spin-lattice relaxation process [T1] and spin-spin relaxation process [T2] relaxivities of hydrogen protons in the aqueous solution of coated nanoparticles were determined to be 1.139 (mM.s)-1 and 1.115 (mM.s)-1, respectively. These results showed that the carbon-coated iron oxide nanoparticles are applicable as both T1 and T2 contrast agents in magnetic resonance imaging.PACS: 81.05.y; 76.60.Es; 61.46; 75.50.k; 87.61. PMID- 22221913 TI - Novel nitric oxide producing probiotic wound healing patch: preparation and in vivo analysis in a New Zealand white rabbit model of ischaemic and infected wounds. AB - The treatment of chronic wounds poses a significant challenge for clinicians and patients alike. Here we report design and preclinical efficacy of a novel nitric oxide gas (gNO)-producing probiotic patch for wound healing. Specifically, a wound healing patch using lactic acid bacteria in an adhesive gas permeable membrane has been designed and investigated for treating ischaemic and infected full-thickness dermal wounds in a New Zealand white rabbit model for ischaemic wound healing. Kaplan-Meier survival curves showed increased wound closure with gNO-producing patch-treated wounds over 21 days of therapy (log-rank P = 0.0225 and Wilcoxon P = 0.0113). Cox proportional hazard regression showed that gNO producing patch-treated wounds were 2.52 times more likely to close compared with control patches (hazard P = 0.0375, score P = 0.032 and likelihood ratio P = 0.0355), and histological analysis showed improved wound healing in gNO-producing patch-treated animals. This study may provide an effective, safe and less costly alternative for treating chronic wounds. PMID- 22221914 TI - Relationship between diagnosis and intervention in women with inherited bleeding disorders and menorrhagia. AB - Menorrhagia is the most common bleeding manifestation in women with inherited bleeding disorders. There is little known about whether the management of menorrhagia is altered in specific bleeding disorders. Optimizing treatment strategies for each specific diagnosis may improve quality of life in these women. This work aimed to look for a potential relationship between the specific diagnosis of an inherited bleeding disorder and the intervention required to control the menorrhagia. A retrospective chart review was performed for all women seen in the Kingston Women and Bleeding Disorders Clinic. Patients were categorized by diagnosis into two groups: Haemophilia carriers and all others. Treatment options were grouped into two categories: Medical or gynecological/surgical. Overall, 85.7% of haemophilia carriers required gynaecological surgical management, whereas only 31.4% of patients with all other diagnoses required gynaecological/surgical management (P = 0.012, Fisher's exact test). Therefore, carriers of Haemophilia were more likely to have a better outcome in treating their menorrhagia with gynaecological or surgical management compared with medical management. This information may 1 day help to guide treatment choice for menorrhagia in women with bleeding disorders. PMID- 22221915 TI - Alcoholism-related alterations in spectrum, coherence, and phase synchrony of topical electroencephalogram. AB - The objective of present work was to assess differences in spectrum, coherence, and phase synchrony of topical electroencephalogram (EEG) between alcohol dependent individuals and healthy participants. Surface currents were mitigated by a common average spatial filter. Parametric spectral and coherence estimates obtained for consecutive 0.5s-long EEG fragments were generally lower for alcoholics than for controls while evaluated for low EEG rhythms. Phase synchrony computed for 2.34s-long overlapping EEG fragments was lower for alcoholics than for controls while evaluated in alpha(2) and beta(1) rhythms and for specific electrode pairs. Kruskal-Wallis one-way analysis of variance evaluated these alterations as statistically significant. PMID- 22221916 TI - [Usefulness of transpulmonary thermodilution in the management of hypoxemic pediatric patients with varicella pneumonia]. PMID- 22221917 TI - Structural and optical properties of ZnS thin films deposited by RF magnetron sputtering. AB - Zinc sulfide [ZnS] thin films were deposited on glass substrates using radio frequency magnetron sputtering. The substrate temperature was varied in the range of 100 degrees C to 400 degrees C. The structural and optical properties of ZnS thin films were characterized with X-ray diffraction [XRD], field emission scanning electron microscopy [FESEM], energy dispersive analysis of X-rays and UV visible transmission spectra. The XRD analyses indicate that ZnS films have zinc blende structures with (111) preferential orientation, whereas the diffraction patterns sharpen with the increase in substrate temperatures. The FESEM data also reveal that the films have nano-size grains with a grain size of approximately 69 nm. The films grown at 350 degrees C exhibit a relatively high transmittance of 80% in the visible region, with an energy band gap of 3.79 eV. These results show that ZnS films are suitable for use as the buffer layer of the Cu(In, Ga)Se2 solar cells. PMID- 22221918 TI - Revision of the family Duboscquellidae with description of Euduboscquella crenulata n. gen., n. sp. (Dinoflagellata, Syndinea), an intracellular parasite of the ciliate Favella panamensis Kofoid & Campbell. AB - Recent recognition that tintinnids are infected by dinophycean as well as syndinean parasites prompts taxonomic revision of dinoflagellate species that parasitize these ciliates. Long overlooked features of the type species Duboscquella tintinnicola are used to emend the genus and family Duboscquellidae, resulting in both taxa being moved from the Syndinea to the Dinophyceae. Syndinean species previously classified as Duboscquella are relocated to Euduboscquella n. gen., with Euduboscquella crenulata n. sp. as the type. As an endoparasitic species, E. crenulata shares with its congeners processes associated with intracellular development and sporogenesis, but differs from closely related species in nuclear and cortical morphology of the trophont, including a distinctively grooved shield (= episome) that imparts a crenulated appearance in optical section. In addition, E. crenulata produces three morphologically distinct spore types, two of which undergo syngamy to form a uninucleate zygote. The zygote undergoes successive division to produce four daughter cells of unequal size, but that resemble the nonmating spore type. PMID- 22221919 TI - Studies on the genus Mesodinium I: ultrastructure and description of Mesodinium chamaeleon n. sp., a benthic marine species with green or red chloroplasts. AB - We provide here the description of a new marine species that harbors green or red chloroplasts. In contrast to certain other species of the genus, Mesodinium chamaeleon n. sp. can be maintained in culture for short periods only. It captures and ingests flagellates including cryptomonads. The prey is ingested very rapidly into a food vacuole without the cryptomonad flagella being shed and the trichocysts being discharged. The individual food vacuoles subsequently serve as photosynthetic units, each containing the cryptomonad chloroplast, a nucleus, and some mitochondria. The ingested cells are eventually digested. This type of symbiosis differs from other plastid-bearing Mesodinium spp. in retaining ingested cryptomonad cells almost intact. The food strategy of the new species appears to be intermediate between heterotrophic species, such as Mesodinium pulex and Mesodinium pupula, and species with red cryptomonad endosymbionts, such as Mesodinium rubrum. PMID- 22221920 TI - Heat-shock protein 70 from plant biofactories of recombinant antigens activate multiepitope-targeted immune responses. AB - Although a physiological role of heat-shock proteins (HSP) in antigen presentation and immune response activation has not been directly demonstrated, their use as vaccine components is under clinical trial. We have previously demonstrated that the structure of plant-derived HSP70 (pHSP70) can be superimposed to the mammalian homologue and similarly to the mammalian counterpart, pHSP70-polypeptide complexes can activate the immune system. It is here shown that pHSP70 purified from plant tissues transiently expressing the influenza virus nucleoprotein are able to induce both the activation of major histocompatibility complex class I-restricted polyclonal T-cell responses and antibody production in mice of different haplotypes without the need of adjuvant co-delivery. These results indicate that pHSP70 derived from plants producing recombinant antigens may be used to formulate multiepitope vaccines. PMID- 22221921 TI - Serum S100B levels in children with simple febrile seizures. AB - PURPOSE: Recent studies have found that S100B is a useful marker for astroglial activation seen in various neurologic disorders. The purpose of this study was to evaluate whether simple febrile seizures (SFS) was associated with an elevation in serum S100B levels. METHODS: In this study the samples consisted of 39 patients with SFS ranging from 6 to 36 months of age, and age-matched and sex matched controls including 30 patients with fever and 30 healthy subjects. Two serum samples were obtained for S100B from the study group at 0-1h and 6-24h following seizure. Serum samples were drawn once in the control group. The serum samples were then analyzed using ELISA. RESULTS: In the study group, the mean values of the serum S100B concentrations at 0-1h and 6-24h were 32.6+/-7.8pg/ml and 32.1+/-5.8pg/ml, respectively, while the concentrations were 32.1+/-8.8pg/ml and 29.5+/-7.8pg/ml in the control groups. No significant differences were detected in serum S100B levels at 0-1h or 6-24h in the study when compared to the control groups. CONCLUSIONS: These results suggest that SFS do not raise serum S100B concentration above the normal range. PMID- 22221922 TI - Impact of benign childhood epilepsy with centrotemporal spikes (BECTS) on school performance. AB - BECTS represents the vast majority of childhood focal epilepsy. Owing to the age peculiarity of children who suffer from this disease, i.e., school-going age of between 6 and 9 years, the condition is often referred to as a school disorder by parents and teachers. OBJECTIVE: The aim of this study was to evaluate the academic performance of children with BECTS, according to the clinical and electroencephalographic ILAE criteria, and compare the results of neuropsychological tests of language and attention to the frequency of epileptic discharges. METHODS: The performances of 40 school children with BECTS were evaluated by applying a school performance test (SBT), neuropsychological tests (WISC and Trail-Making), and language tests (Illinois Test Psycholinguistic Abilities-ITPA--and Staggered Spondaic Word-SSW). The same tests were applied in the control group. RESULTS: Children with BECTS, when compared to those in the control group, showed lower scores in academic performance (SPT), digits and similarities subtests of WISC, auditory processing subtest of SSW, and ITPA- representational and automatic level. The study showed that epileptic discharges did not influence the results. CONCLUSION: Children with BECTS scored significantly lower scores in tests on academic performance, when compared with those in the control group probably due to executive dysfunction. PMID- 22221923 TI - Increased asymmetric dimethylarginine level after antiepileptic drug treatment may be independent of the changes in plasma homocysteine level. PMID- 22221924 TI - Noninvasive molecular imaging of interferon beta activation in mouse liver. AB - BACKGROUND/AIMS: Interferon beta (IFN-beta) is the priming cytokine in the interferons (IFNs) response that plays essential roles in innate immune system. Only very few studies on IFN activation in animals have been reported before, therefore, we embarked to develop a novel method to dynamically examine IFN-beta activation in mouse liver by noninvasive molecular imaging. METHODS: Interferon beta promoter-directed firefly luciferase gene was integrated into chromosomes of hepatocytes by hydrodynamic injection. Mouse hepatitis virus type 3 (MHV-3) and polyinosinic-polycytidylic acid [poly(I:C)] were used to stimulate the activation of IFN-beta. Luciferase activity was used as an indicator of the IFN-beta promoter activity in vitro and in vivo. The expression level of IFN-beta in the sera and firefly luciferase in the liver was assessed by ELISA and bioluminescence imaging respectively. Western blot was used for detecting proteins expression. RESULTS: A rapid and elevated luciferase expression in the mouse liver induced by poly (I:C) and MHV-3 was detected by bioluminescence imaging. The detectable level of IFN-beta in the sera was not induced by MHV-3. Moreover, IFN-beta activation was significantly inhibited by the hepatitis C virus (HCV) NS3/4A protease in mouse liver. These results were consistent with IFN-beta production in the sera. Therefore, a novel visual method to monitor IFN beta promoter activity was established in the current study. CONCLUSION: This novel sensitive method can be used for not only assessing IFN-beta activation or inhibition in the liver under different conditions, but also screening drug candidates of stimulating or inhibiting of IFN-beta production. PMID- 22221926 TI - Back to the future: 10 years of European health reforms. AB - The challenges facing European health systems have changed little over 30 years but the responses to them have. Policy ideas that emerged in some countries spread to others; however, the way policies were implemented and the impact they have had has been shaped by specific national contexts. Comparative policy analysis has evolved in response to this, moving away from simple classifications of health systems and crude rankings to studies that try and understand more deeply what works, where and why. For policymakers interested in how other countries have dealt with common challenges, it is important that they avoid the naive transplantation of policy solutions but understand the need to translate policies to fit the institutional context of a particular country. Policies that cross borders will necessarily be shaped by the social and political institutions of a country. These dimensions should not be ignored in comparative research. The next decade will require health systems to deliver improved care for people with complex needs while at the same time delivering greater value. Policymakers will benefit from looking backwards as well as to their neighbours in order to develop appropriate policy solutions. PMID- 22221927 TI - Reflections on the evolution of health technology assessment in Europe. AB - Health technology assessment (HTA) has assumed an increasing role in health systems in recent years, with many countries establishing agencies or programmes to evaluate health technology and other interventions to inform policy decisions and clinical practice. This paper reflects upon its development and evolution in Europe over the last decade, with a focus on England, France, Germany and Sweden. In particular, we explore how HTA has evolved over time as well as its impact on policy and practice. While countries share many of the same objectives, there are differences in the way HTA agencies and programmes are organised, operate, and influence decision making. Despite these differences, all systems are faced with opportunities and challenges related to stakeholder involvement and acceptance, the suitability and transparency of assessment requirements and methods, balancing evidence and values in decision making, and demonstrating impact. PMID- 22221928 TI - Choice policies in Northern European health systems. AB - This paper compares the introduction of policies to promote or strengthen patient choice in four Northern European countries - Denmark, England, the Netherlands and Sweden. The paper examines whether there has been convergence in choice policies across Northern Europe. Following Christopher Pollitt's suggestion, the paper distinguishes between rhetorical (discursive) convergence, decision (design) convergence and implementation (operational) convergence (Pollitt, 2002). This leads to the following research question for the article: Is the introduction of policies to strengthen choice in the four countries characterised by discursive, decision and operational convergence? The paper concludes that there seems to be convergence among these four countries in the overall policy rhetoric about the objectives associated with patient choice, embracing both concepts of empowerment (the intrinsic value) and market competition (the instrumental value). It appears that the institutional context and policy concerns such as waiting times have been important in affecting the timing of the introduction of choice policies and implementation, but less so in the design of choice policies. An analysis of the impact of choice policies is beyond the scope of this paper, but it is concluded that further research should investigate how the institutional context and timing of implementation affect differences in how the choice policy works out in practice. PMID- 22221929 TI - Paying for hospital care: the experience with implementing activity-based funding in five European countries. AB - Following the US experience, activity-based funding has become the most common mechanism for reimbursing hospitals in Europe. Focusing on five European countries (England, Finland, France, Germany and Ireland), this paper reviews the motivation for introducing activity-based funding, together with the empirical evidence available to assess the impact of implementation. Despite differences in the prevailing approaches to reimbursement, the five countries shared several common objectives, albeit with different emphasis, in moving to activity-based funding during the 1990s and 2000s. These include increasing efficiency, improving quality of care and enhancing transparency. There is substantial cross country variation in how activity-based funding has been implemented and developed. In Finland and Ireland, for instance, activity-based funding is principally used to determine hospital budgets, whereas the models adopted in the other three countries are more similar to the US approach. Assessing the impact of activity-based funding is complicated by a shortage of rigorous empirical evaluations. What evidence is currently available, though, suggests that the introduction of activity-based funding has been associated with an increase in activity, a decline in length of stay and/or a reduction in the rate of growth in hospital expenditure in most of the countries under consideration. PMID- 22221930 TI - The rise of the regulatory state in health care: a comparative analysis of The Netherlands, England and Italy. AB - In a relatively short time, regulation has become a significant and distinct feature of how modern states wish to govern and steer their economy and society. Whereas the former 'dirigiste' state used to be closely related to public ownership (e.g. hospitals), planning (volume and capacity planning) and centralised administration (e.g. fixed prices and budgets), the new regulatory state relies mainly on the instrument of regulation to achieve its objectives. In this paper, we wish to relate the rise of the 'regulatory state' to the path dependent trajectories and institutional legacies of discrete European health care systems. For this purpose, we compared the Dutch corporatist social health insurance system, the strongly centralised National Health Service (NHS) of England and federal regionalised NHS system of Italy. Comparing these three different health-care systems suggests that it is indeed possible to identify a general trend towards the rise of the regulatory state in health care in the last two decades. However, although the three countries examined in this paper face similar problems of multilevel governance of networks of third-party payers and providers, each system also gives rise to its own distinct regulatory challenges. PMID- 22221931 TI - Overcoming fragmentation in health care: chronic care in Austria, Germany and The Netherlands. AB - The growing recognition of care fragmentation is causing many countries to explore new approaches to healthcare delivery that can bridge the boundaries between professions, providers and institutions and so better support the rising number of people with chronic health problems. This paper examines the role of the regulatory, funding and organisational context for the development and implementation of approaches to chronic care, using examples from Austria, Germany and the Netherlands. We find that the three countries have implemented a range of policies and approaches to achieve better coordination within and across the primary and secondary care interface and so better meet the needs of patients with chronic conditions. This has involved changes to the regulatory framework to support more coordinated approaches to care (Austria, Germany), coupled with financial incentives (Austria, Germany) or changes in payment systems (the Netherlands). What is common to the three countries is the comparative 'novelty' of policies and approaches aimed at fostering coordinated care; however, the evidence of their impact remains unclear. PMID- 22221932 TI - Outcomes 'out of africa': the selection and implementation of outcome measures for palliative care in Africa. AB - BACKGROUND: End-of-life care research across Africa is under-resourced and under developed. A central issue in research in end-of-life care is the measurement of effects and outcomes of care on patients and families. Little is known about the experiences of health professionals' selection and implementation of outcome measures (OM) in clinical care, research, audit, or teaching in Africa. METHODS: An online survey was undertaken of those using outcome measures across the region, as part of the PRISMA project. A questionnaire addressing the use of OMs was developed for a similar survey in Europe and adapted for Africa. Participants were sampled through the contacts database of APCA. Invitation emails were sent out in January 2010 and reminders in February 2010. RESULTS: 168/301 invited contacts (56%) from 24 countries responded, with 78 respondents having previously used OM (65% in clinical practice, 12% in research and 23% for both). Main reasons for not using OM were a lack of guidance/training on using and analysing OM, with 49% saying that they would use the tools if this was provided. 40% of those using OM in clinical practice used POS, and 80% used them to assess, evaluate and monitor change. The POS was also the main tool used in research, with the principle criteria for use being validation in Africa, access to the tool and time needed to complete it. Challenges to the use of tools were shortage of time and resources, lack of guidance and training for the professionals, poor health status of patients and complexity of OM. Researchers also have problems analysing OM data. The APCA African POS was the most common version of the POS used, and was reported as a valuable tool for measuring outcomes. Respondents indicated the ideal outcome tool should be short, multi-dimensional and easy to use. CONCLUSION: This was the first survey on professionals' views on OM in Africa. It showed that the APCA African POS was the most frequently OM used. Training and support are needed to help professionals utilise OM in palliative care, and OMs have an ongoing and important role in palliative care in Africa. PMID- 22221933 TI - Aetiology and clinical phenotype still seem distant in sarcoidosis. PMID- 22221934 TI - Role of inferior vena cava diameter in assessment of volume status: a meta analysis. AB - BACKGROUND AND OBJECTIVE: Hypovolemic shock is an important cause of death in the emergency department (ED). We sought to conduct a meta-analysis to quantify existing evidence on sonographic measurement of inferior vena cava (IVC) diameter in assessing of volume status adult ED patients. METHODS: A search of 5 major databases of biomedical publication, EMBASE, Ovid Medline, evidence-based medicine (EBM) Reviews, Scopus, and Web of Knowledge, was performed in first week of March 2011. Studies meeting the following criteria were included: (1) prospectively conducted, (2) measured IVC diameter using ultrasonography, (3) inpatients under spontaneous ventilation, and (4) reported IVC diameter measurement with volume status or shock. Article search, study quality assessment, and data extraction were done independently and in duplicate. Mean difference in IVC diameter was calculated using RevMan version 5.5 (Cochrane collaboration). RESULTS: A total of 5 studies qualified for study eligibility from 4 different countries, 3 being case-control and 2 before-and-after design, studying 86 cases and 189 controls. Maximal IVC diameter was significantly lower in hypovolemic status compared with euvolemic status; mean difference (95% confidence interval) was 6.3 mm (6.0-6.5 mm). None of the studies blinded interpreters for volume status of participants. CONCLUSION: Moderate level of evidence suggests that the IVC diameter is consistently low in hypovolemic status when compared with euvolemic. Further blinded studies are needed before it could be used in the ED with confidence. PMID- 22221935 TI - Ethnomedicinal study of plants used in villages around Kimboza forest reserve in Morogoro, Tanzania. AB - BACKGROUND: An ethnomedicinal study was conducted to document medicinal plants used in the treatment of ailments in villages surrounding Kimboza forest reserve, a low land catchment forest with high number of endemic plant species. METHODS: Ethnobotanical interviews on medicinal plants used to treat common illnesses were conducted with the traditional medical practitioners using open-ended semi structured questionnaires. Diseases treated, methods of preparation, use and habitat of medicinal plants were recorded. RESULTS: A total of 82 medicinal plant species belonging to 29 families were recorded during the study. The most commonly used plant families recorded were Fabaceae (29%), Euphorbiaceae (20%), Asteraceae and Moraceae (17% each) and Rubiaceae (15%) in that order. The most frequently utilized medicinal plant parts were leaves (41.3%), followed by roots (29.0%), bark (21.7%), seeds (5.31%), and fruits (2.6%). The study revealed that stomach ache was the condition treated with the highest percentage of medicinal plant species (15%), followed by hernia (13%), diarrhea (12), fever and wound (11% each), and coughs (10%). Majority of medicinal plant species (65.9%) were collected from the wild compared to only 26.7% from cultivated land. CONCLUSIONS: A rich diversity of medicinal plant species are used for treating different diseases in villages around Kimboza forest reserve, with the wild habitat being the most important reservoir for the majority of the plants. Awareness programmes on sustainable utilization and active involvement of community in conservation programmes are needed. PMID- 22221936 TI - Global haemostasis assays, from bench to bedside. AB - Bleeding and thrombosis are the ultimate clinical outcomes of aberrations in the haemostatic process. Haemostasis prevents excessive blood loss due to the effort of various compartments like the vasculature, blood cells, coagulation and fibrinolysis. The complexity of all processes involved makes the diagnosis of aberrations difficult, cumbersome and expensive. A single assay to detect any factor disturbing this haemostatic balance with high sensitivity and specificity would be of great value, especially if the outcome of this assay correlates well with clinical outcome. Despite years of research, such an assay is not yet available; however, some interesting candidates are under development and combine the effects of various compartments. This review describes the development of global haemostasis assays and summarizes the current state of the art of these haemostasis assays covering thrombin and plasmin generation, turbidity and thromboelastography/thromboelastometry. Finally, we discuss the applicability of global assays in clinical practice and we provide a future perspective on the ongoing development of automation and miniaturisation as it is our belief that these developments will benefit the standardization of global haemostasis assays. PMID- 22221937 TI - A randomized controlled trial of empiric warfarin dose reduction with the initiation of doxycycline therapy. AB - BACKGROUND: When interacting medications, such as doxycycline, are initiated during warfarin therapy, one method to correct for non-therapeutic international normalized ratio (INR) is adjusting the warfarin dose, if necessary. Another approach is preemptive warfarin dose adjustment. This study's objective was to evaluate the utility of preemptive warfarin dose adjustment for preventing non therapeutic INR following doxycycline-warfarin co-administration. METHODS: Patients were randomized to either a 10% to 20% preemptive warfarin dose reduction (intervention) or reactive warfarin dose adjustment (control) within 72 hours of warfarin-doxycycline co-administration. Subjects received a follow-up INR within 7 days (index INR). Primary outcome was the occurrence of index INR >= 1 point over the INR goal range upper limit. Secondary outcomes included INR control, purchases of prescription vitamin K, and warfarin-associated adverse events in the 30 days after doxycycline initiation. RESULTS: Twenty and 17 patients comprised the intervention and control groups. The intervention group's warfarin dose was reduced by a median of 11%. More control patients (n=2) experienced an INR >= 1 point over the INR goal range upper limit compared to intervention (n=0); however, the difference (12% vs. 0%) was not statistically significant (p=0.20). A higher percentage of intervention patients had subtherapeutic index INRs compared to control (35% vs. 6%, p<0.05). One patient from each group experienced warfarin-associated bleeding. No thromboembolic complications or vitamin K use were observed. CONCLUSIONS: For warfarin patients initiating doxycycline therapy, preemptive warfarin dose reduction did not result in supratherapeutic INRs but increased the likelihood of subtherapeutic INRs compared to INR monitoring with reactive warfarin dose adjustment. PMID- 22221938 TI - Application of propensity score model to examine the prognostic significance of lymph node number as a care quality indicator. AB - PURPOSE: There is a controversy about whether lymph node yield can be used as a proxy of quality care for patient with colorectal cancer. We aim to use propensity score models to investigate the association between lymph node number and long-term survival for colorectal cancer patients. MATERIALS AND METHODS: Taiwan Cancer Database was employed to review all patients with newly diagnosed colorectal cancer from 2003 to 2005. Exclusion criteria included those patients with stage IV disease or without information of lymph node. Propensity score models (examined lymph node >12 or <12 as dependent variable) were applied to group of patients with Stage II or Stage III disease and primary end point was 5 year survival (and mortality). We also report results of Stage I-III for comparison. RESULTS: We identified 15,731 newly diagnosed colorectal cancers during study period, among which a total of 10,517 colorectal cancer patients treated at 32 hospitals fulfilled the inclusion criteria. Pathology reports of about 63 % (6658/10517) patients revealed lymph node retrieval >12. After propensity score matching, there were 2888, 1079, 1094 pairs recruited for Stage I-III, Stage II and Stage III, respectively. According to analysis of these matched pairs, the 5-year risk adjusted overall mortality were lower for lymph node examined >=12 than <12 among Stage II (24.3% vs. 31.1%, p=0.012) and Stage I III (20.8% vs. 23.6%, p=0.003), but insignificant for Stage III (40.2% vs. 45.6%, p=0.073). Similar situation happened with regard to disease-free and disease specific mortality. CONCLUSION: For patients with colorectal cancer undergoing colorectal surgery, the quality metric of lymph node is associated with significantly better 5-year survival except for Stage III disease. PMID- 22221939 TI - A comparison of traditional vs. Canadian tailored prophylaxis dosing of prophylactic factor infusions in children with haemophilia A and B in a single hemophilia treatment center. AB - Prophylactic infusion of clotting factor concentrates is a developing standard of care for individuals with haemophilia. The ideal schedule and techniques of prophylactic infusions remain incompletely defined. Our aim was to determine the optimal techniques and schedules for factor prophylaxis in paediatric patients. A retrospective electronic medical record review of all children treated with prophylactic factor infusions in a single Haemophilia Treatment Center was conducted. Comparison of traditional vs. Canadian dosing regimens and primary vs. secondary prophylaxis was made. Failure of prophylaxis was defined as the first serious bleed. A total of 58 children were identified for review. Five cases were excluded (four due to high titre inhibitors and one due to repeated non compliance), thus there were 53 total cases: 46 with severe haemophilia, 2 with moderate haemophilia, 5 with mild haemophilia, 44 with haemophilia A and 9 with haemophilia B; 32 Traditional dosing and 21 Canadian dosing regimens. Patients on primary prophylaxis had a decreased failure rate (25%) compared to children treated with secondary prophylaxis (67%) regardless of technique of prophylaxis. When compared to a 'Traditional' factor prophylaxis schedule, the 'Canadian' tailored prophylaxis protocol was comparable with the exception of a decreased use of implanted venous devices in the 'Canadian' group. Ongoing bleeding (primarily joint bleeds) occurs with all prophylactic regimens. The lowest incidence of treatment failure was noted in children who began primary prophylaxis at a young age and before initial joint bleeds. Primary prophylaxis is superior to secondary prophylaxis regardless of dosing regimen. Traditional and Canadian dosing regimens were equivalent in outcome when measured over several years of follow-up. PMID- 22221940 TI - Follow-up with exercise test of effort-induced ventricular arrhythmias linked to ryanodine receptor type 2 gene mutations. AB - The aim of this study was to assess exercise test results and efficacy of therapy with a beta blocker (acebutolol) in ryanodine receptor type 2 (RyR2) mutation carriers with documented ventricular arrhythmias (VAs) and long-term follow-up. Twenty RyR2 mutation carriers belonging to 8 families and regularly followed at our center were analyzed using a study protocol involving electrocardiography, exercise tests off and on beta-blocker therapy, 2-dimensional echocardiography, and signal-averaged electrocardiography. Off-therapy exercise testing triggered the onset of VAs at different heart rates (mean 132 +/- 13 beats/min) with various patterns that worsened while exercising and disappeared immediately after stopping. The most severe VAs detected were nonsustained ventricular tachycardia in 35% and ventricular couplets in 35%. In the remaining subjects single ventricular premature beats were recorded. In 15% of patients single monomorphic ventricular premature beats were detected and identified to be linked to RyR2 mutations owing to the presence of sudden deaths of their family members and subsequent family screening. Acebutolol made the VAs disappear completely in 20% of subjects and decreased their complexity in 50%, whereas it did not change VAs appreciably in 30% of patients with less complex VAs. After 11 +/- 8 years of follow-up 2 patients developed syncope. In conclusion, exercise testing was a fundamental tool for assessing the clinical phenotype and efficacy of therapy in RyR2 mutation carriers and therapy with acebutolol led in most subjects to a decreased complexity of the arrhythmic pattern or to complete suppression. PMID- 22221941 TI - Comparison of the effect on long-term outcomes in patients with thoracic aortic aneurysms of taking versus not taking a statin drug. AB - The potential of medical therapy to influence the courses and outcomes of patients with thoracic aortic aneurysms is not known. The aim of this study was to determine whether statin intake is associated with improved long-term outcomes in these patients. A total of 649 patients with thoracic aortic aneurysms were studied, of whom 147 were taking statins at their first presentation and 502 were not. After a median follow-up period of 3.6 years, 30 patients (20%) taking statins had died, compared with 167 patients (33%) not taking statins (hazard ratio 0.68, 95% confidence interval 0.46 to 1, p = 0.049); 87 patients (59%) taking statins reached the composite end point of death, rupture, dissection, or repair compared with 378 patients (75%) not taking statins (hazard ratio 0.72, 95% confidence interval 0.57 to 0.91, p = 0.006). After adjustments for co morbidities, the association between statin therapy and the composite end point was driven mainly by a reduction in aneurysm repairs (hazard ratio 0.57 95% confidence interval 0.4 to 0.83, p = 0.003). On Kaplan-Meier analysis, the survival rate of patients taking statins was significantly better (p = 0.047). In conclusion, the intake of stains was associated with an improvement in long-term outcomes in this cohort of patients with thoracic aortic aneurysms. This was driven mainly by a reduction in aneurysm repairs. PMID- 22221942 TI - Computerized tomographic quantification of chronic obstructive pulmonary disease as the principal determinant of frontal P vector. AB - Verticalization of the P-wave axis is characteristic of chronic obstructive pulmonary disease (COPD). We studied the correlation of P-wave axis and computerized tomographically quantified emphysema in patients with COPD/emphysema. Individual correlation of P-wave axis with different structural types of emphysema was also studied. High-resolution computerized tomographic scans of 23 patients >45 years old with known COPD were reviewed to assess the type and extent of emphysema using computerized tomographic densitometric parameters. Electrocardiograms were then independently reviewed and the P-wave axis was calculated in customary fashion. Degree of the P vector (DOPV) and radiographic percent emphysematous area (RPEA) were compared for statistical correlation. The P vector and RPEA were also directly compared to the forced expiratory volume at 1 second. RPEA and the P vector had a significant positive correlation in all patients (r = +0.77, p <0.0001) but correlation was very strong in patients with predominant lower lobe emphysema (r = +0.89, p <0.001). Forced expiratory volume at 1 second and the P vector had almost a linear inverse correlation in predominantly lower lobe emphysema (r = -0.92, p <0.001). DOPV positively correlated with radiographically quantified emphysema. DOPV and RPEA were strong predictors of qualitative lung function in patients with predominantly lower lobe emphysema. In conclusion, a combination of high DOPV and predominantly lower lobe emphysema indicates severe obstructive lung dysfunction in patients with COPD. PMID- 22221943 TI - Predictors of ten-year event-free survival in patients with acute myocardial infarction (from the Adria, Bassano, Conegliano, and Padova Hospitals [ABC] study on myocardial infarction). AB - The long-term event-free survival (EFS) after acute myocardial infarction (AMI) is largely uninvestigated. We analyzed noninvasive clinical variables in association with long-term EFS after AMI. The present prospective study included 504 consecutive patients with AMI at 3 hospitals from 1995 to 1998 (Adria, Bassano, Conegliano, and Padova Hospitals [ABC] study). Thirty-seven variables were examined, including demographics, cardiovascular risk factors, in-hospital characteristics, and blood components. The end point was 10-year EFS. Logistic and Cox regression models were used to identify the predictive factors. We compared 3 predictive models according to the goodness of fit and C-statistic analyses. At enrollment, the median age was 67 years (interquartile range 58 to 75), 29% were women, 38% had Killip class >1, and the median left ventricular ejection fraction was 51% (interquartile range 43% to 60%). The 10-year EFS rate was 19%. Both logistic and Cox analyses identified independent predictors, including young age (hazard ratio 1.2, 95% confidence interval 1.1 to 1.3, p = 0.0006), no history of angina (hazard ratio 1.4, 95% confidence interval 1.1 to 1.8, p = 0.009), no previous myocardial infarction (hazard ratio 1.4, 95% confidence interval 1.1 to 1.7, p = 0.01), high estimated glomerular filtration rate (hazard ratio 0.8, 95% confidence interval 0.7 to 0.9, p = 0.001), low albumin/creatinine excretion ratio (hazard ratio 1.2, 95% confidence interval 1.1 to 1.3, p <0.0001), and high left ventricular ejection fraction (hazard ratio 0.8, 95% confidence interval 0.7 to 0.9, p = 0.006). These variables had greater predictive power and improved the predictive power of 2 other models, including Framingham cardiovascular risk factors and the recognized predictors of acute heart damage. In conclusion, 10-year EFS was strongly associated with 4 factors (ABC model) typically neglected in studies of AMI survival, including estimated glomerular filtration rate, albumin/creatinine excretion ratio, a history of angina, and previous myocardial infarction. This model had greater predictive power and improved the power of 2 other models using traditional cardiovascular risk factors and indicators of heart damage during AMI. PMID- 22221944 TI - Cost-effectiveness of clopidogrel plus aspirin for stroke prevention in patients with atrial fibrillation in whom warfarin is unsuitable. AB - Guidelines for atrial fibrillation (AF) recommend clopidogrel plus aspirin as an alternative stroke prevention strategy in patients in whom warfarin is unsuitable. A Markov model was conducted from a Medicare prospective using data from the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-A (ACTIVE-A) trial and other published studies. Base-case analysis evaluated patients 65 years old with AF, a CHADS(2) (congestive heart failure, 1 point; hypertension defined as blood pressure consistently >140/90 mm Hg or antihypertension medication, 1 point; age >=75 years, 1 point; diabetes mellitus, 1 point; previous stroke or transient ishemic attack, 2 points) score of 2, and a lower risk for major bleeding. Patients received clopidogrel 75 mg/day plus aspirin or aspirin alone. Patients were followed for up to 35 years. Outcomes included quality-adjusted life-years (QALYs), costs (in 2011 American dollars), and incremental cost-effectiveness ratios. Quality-adjusted life expectancy and costs were 9.37 QALYs and $88,751 with clopidogrel plus aspirin and 9.01 QALYs and $79,057 with aspirin alone. Incremental cost-effectiveness ratio for clopidogrel plus aspirin was $26,928/QALY. With 1-way sensitivity analysis using a willingness-to-pay threshold of $50,000/QALY, clopidogrel plus aspirin was no longer cost effective when the CHADS(2) score was <=1, major bleeding risk with aspirin was >=2.50%/patient-year, the relative risk decrease for ischemic stroke with clopidogrel plus aspirin versus aspirin alone was <25%, and the utility of being healthy with AF on combination therapy decreased to 0.95. Monte Carlo simulation demonstrated that clopidogrel plus aspirin was cost effective in 55% and 73% of 10,000 iterations assuming willingness-to-pay thresholds of $50,000 and $100,000/QALY. In conclusion, clopidogrel plus aspirin appears cost-effective compared to aspirin alone for stroke prevention in patients with AF with a CHADS(2) of >=2 and a lower risk of bleeding. PMID- 22221945 TI - Comparison of bleeding and in-hospital mortality in Asian-Americans versus Caucasian-Americans with ST-elevation myocardial infarction receiving reperfusion therapy. AB - Concern has been raised that Asian-Americans may have a higher bleeding risk than Caucasian-Americans when treated with fibrinolytic and antithrombotic agents. To date there is limited evidence to support or refute this hypothesis or evaluate bleeding risk and its related outcomes in Caucasian-Americans versus Asian Americans with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary interventions (PPCI). We evaluated Asian-Americans and Caucasian-Americans with STEMI receiving reperfusion therapy in the National Registry of Myocardial Infarction (NRMI) 4 and 5 (n = 90,317). We studied risk adjusted major bleeding and in-hospital mortality. Major bleeding rates after fibrinolysis were similar in Asian-Americans (n = 705) and Caucasian-Americans (n = 42,243, 11.1% vs 10.3%, adjusted odds ratio [OR] 0.97, 95% confidence interval [CI] 0.69 to 1.36, p = 0.5002). Although the observed major bleeding rate was higher in Asian-Americans (n = 1,037) compared to Caucasian-Americans (n = 46,332) treated with PPCI (10.3% vs 7.8%, p = 0.0036), these rates differed only marginally after adjusting for baseline clinical variables (OR 1.24, 95% CI 0.97 to 1.59). Overall adjusted mortality was similar in Asian-Americans and Caucasian Americans when treated with fibrinolysis (OR 0.96, 95% CI 0.56 to 1.65) or with PPCI (OR 1.35, 95% CI 0.85 to 2.13). Major bleeding after PPCI or fibrinolysis was associated with similar increased risks for mortality in these ethic groups. In conclusion, despite suggestions to the contrary, Asian-Americans with STEMI treated with fibrinolysis or PPCI had similar bleeding and bleeding-related mortality risks compared to Caucasian-Americans. Given the genotypic and phenotypic differences between the 2 cohorts, similar studies in the rapidly growing Asian-American population are needed to confirm our findings and to understand the safety and effectiveness of newer potent antiplatelet and antithrombotic agents in patients with coronary syndromes. PMID- 22221946 TI - Relations between QRS|T angle, cardiac risk factors, and mortality in the third National Health and Nutrition Examination Survey (NHANES III). AB - On the surface electrocardiogram, an abnormally wide QRS|T angle reflects changes in the regional action potential duration profiles and in the direction of the repolarization sequence, which is thought to increase the risk of ventricular arrhythmia. We investigated the relation between an abnormal QRS|T angle and mortality in a nationally representative sample of subjects without clinically evident heart disease. We studied 7,052 participants >=40 years old in the third National Health and Nutrition Examination Survey with 12-lead electrocardiograms. Those with self-reported or electrocardiographic evidence of a previous myocardial infarction, QRS duration of >=120 ms, or history of heart failure were excluded. Borderline and abnormal spatial QRS|T angles were defined according to gender-specific 75th and 95th percentiles of frequency distributions. All-cause (1,093 women and 1,191 men) and cardiovascular (462 women and 455 men) mortality during the 14-year period was assessed through linkage with the National Death Index. On multivariate analyses, an abnormal spatial QRS|T angle was associated with an increased hazard ratio (HR) for cardiovascular mortality in women (HR 1.82, 95% confidence interval 1.05 to 3.14) and men (HR 2.21, 95% confidence interval 1.32 to 3.68). Also, the multivariate adjusted HR for all-cause mortality associated with an abnormal QRS|T angle was 1.30 (95% confidence interval 0.95 to 1.78) for women and 1.87 (95% confidence interval 1.29 to 2.7) for men. A borderline QRS|T angle was not associated with an increased risk of all-cause or cardiovascular mortality. In conclusion, an abnormal QRS|T angle, as measured on a 12-lead electrocardiogram, was associated with an increased risk of cardiovascular and all-cause mortality in this population-based sample without known heart disease. PMID- 22221947 TI - Comparison of pro-atrial natriuretic peptide and atrial remodeling in marathon versus non-marathon runners. AB - Long-term endurance sports are associated with atrial remodeling and an increased risk for atrial fibrillation (AF) and atrial flutter. Pro-atrial natriuretic peptide (pro-ANP) is a marker of atrial wall tension and elevated in patients with AF. The aim of this study was to test the hypothesis that atrial remodeling would be perpetuated by repetitive episodes of atrial stretching during strenuous competitions, reflected by elevated levels of pro-ANP. A cross-sectional study was performed on nonelite runners scheduled to participate in the 2010 Grand Prix of Bern, a 10-mile race. Four hundred ninety-two marathon and nonmarathon runners applied for participation, 70 were randomly selected, and 56 entered the final analysis. Subjects were stratified according to former marathon participations: a control group (nonmarathon runners, n = 22), group 1 (1 to 4 marathons, n = 16), and group 2 (>=5 marathons, n = 18). Results were adjusted for age, training years, and average weekly endurance training hours. The mean age was 42 +/- 7 years. Compared to the control group, marathon runners in groups 1 and 2 had larger left atria (25 +/- 6 vs 30 +/- 6 vs 34 +/- 7 ml/m(2), p = 0.002) and larger right atria (27 +/- 7 vs 31 +/- 8 vs 35 +/- 5 ml/m(2), p = 0.024). Pro-ANP levels at baseline were higher in marathon runners (1.04 +/- 0.38 vs 1.42 +/- 0.74 vs 1.67 +/- 0.69 nmol/L, p = 0.006). Pro-ANP increased significantly in all groups after the race. In multiple linear regression analysis, marathon participation was an independent predictor of left atrial (beta = 0.427, p <0.001) and right atrial (beta = 0.395, p = 0.006) remodeling. In conclusion, marathon running was associated with progressive left and right atrial remodeling, possibly induced by repetitive episodes of atrial stretching. The altered left and right atrial substrate may facilitate atrial arrhythmias. PMID- 22221948 TI - Relation of systemic-to-pulmonary artery collateral flow in single ventricle physiology to palliative stage and clinical status. AB - Systemic-to-pulmonary collateral arteries (SPCs) are common in patients with single-ventricle physiology, but their impact on clinical outcomes is unclear. The aim of this study was to use retrospective cardiac magnetic resonance data to determine the relation between SPC flow and palliative stage and clinical status in single-ventricle physiology. Of 116 patients, 78 were after Fontan operation (median age 19 years) and 38 were at an earlier palliative stage (median age 2 years). SPC flow was quantified as aortic flow minus total caval flow or total pulmonary vein flow minus total branch pulmonary artery flow. Median SPC flow/body surface area (BSA) was higher in the pre-Fontan group (1.06 vs 0.43 L/min/m(2), p <0.0001) and decreased nonlinearly with increasing age after the Fontan operation (r(2) = 0.17, p <0.0001). In the Fontan group, patients in the highest quartile of SPC flow had larger ventricular end-diastolic volume/BSA (p <0.0001) and were older at the time of Fontan surgery (p = 0.04), but SPC flow/BSA was not associated with heart failure symptoms, atrial or ventricular arrhythmias, atrioventricular valve regurgitation, the ventricular ejection fraction, or peak oxygen consumption. In multivariate analysis of all patients (n = 116), higher SPC flow was independently associated with pre-Fontan status, unilateral branch pulmonary artery stenosis, a diagnosis of hypoplastic left heart syndrome, and previous catheter occlusion of SPCs (model r(2) = 0.37, p <0.0001). In conclusion, in this cross-sectional study of single-ventricle patients, BSA-adjusted SPC flow was highest in pre-Fontan patients and decreased after the Fontan operation with minimal clinical correlates aside from ventricular dilation. PMID- 22221949 TI - Meta-analysis of long-term outcomes for drug-eluting stents versus bare-metal stents in primary percutaneous coronary interventions for ST-segment elevation myocardial infarction. AB - The use of drug-eluting stents (DESs) in primary percutaneous coronary intervention (PPCI) has shown early benefit over bare-metal stents (BMSs) in decreasing adverse cardiac events. However, there are concerns regarding the increased risk of late and very late stent thrombosis (ST) after DES use. With the paucity of ST events individual trials may have been underpowered to detect significant differences. We sought to perform a meta-analysis to evaluate the available literature examining the outcomes of DESs and BMSs in PPCI after >=3 years of follow-up. We analyzed 8 randomized clinical trials (RCTs) and 5 observational studies comparing DESs to BMSs in PPCI. Clinical end-point data were analyzed for RCTs and observational studies separately using random-effect models. RCTs included 5,797 patients in whom first-generation DESs (sirolimus- or paclitaxel-eluting stents) were compared to BMS control arms. Patients receiving DESs had a significantly lower risk of target lesion revascularization (odds ratio [OR] 0.48, confidence interval [CI] 0.37 to 0.61), target vessel revascularization (OR 0.53, CI 0.42 to 0.66), and accordingly major adverse cardiac events (OR 0.69; CI 0.56 to 0.84). Incidence of ST was not different between groups (OR 1.02, CI 0.76 to 1.37). There was no significant difference in mortality (OR 0.88, CI 0.68 to 1.12) or recurrent myocardial infarction (OR 0.97; CI 0.61 to 1.54). Among observational studies (n = 4,650) fewer studies reported on target lesion revascularization and target vessel revascularization, but the trend remained in favor of DESs. A small but statistically significant increase in ST was noted with DES use (OR 1.62, CI 1.18 to 2.21) at >=3 years of follow up, without evidence of recurrent myocardial infarction. Those receiving DESs had a significantly lower mortality compared to those receiving BMSs (OR, 0.65, 95% CI 0.53 to 0.80, p <0.001). In conclusion, this meta-analysis of RCTs examining the long-term outcomes of first-generation DESs versus BMSs in PPCI, DES use resulted in decreased repeat revascularization with no increase in ST, mortality, or recurrent myocardial infarction. PMID- 22221950 TI - Coronary artery disease in patients with psoriasis referred for coronary angiography. AB - Patients with psoriasis may have an increased risk of cardiovascular disease and myocardial infarction. The aim of this study was to investigate whether psoriasis is associated with an increased prevalence of coronary artery disease (CAD) independent of established cardiovascular risk factors in patients undergoing coronary angiography. A retrospective cohort analysis was performed by linking records of all patients undergoing coronary angiography from 2004 through 2009 with dermatology medical records. From an overall cohort of 9,473 patients, we identified 204 patients (2.2%) with psoriasis before coronary angiography. Patients with psoriasis had higher body mass index (31.3 +/- 8.1 vs 29.3 +/- 7.1 kg/m(2), p <0.001) but the prevalence of other risk factors was similar. Median duration of psoriasis before cardiac catheterization was 8 years (interquartile range 2 to 24). Patients with psoriasis were more likely to have CAD (84.3% vs 75.7%, p = 0.005) at coronary angiography. After adjusting for established cardiovascular risk factors, psoriasis was independently associated with presence of angiographically confirmed CAD (adjusted odds ratio 1.8, 95% confidence interval 1.2 to 2.8, p = 0.006). In patients with psoriasis, duration of psoriasis >8 years was also independently associated with angiographically confirmed CAD after adjusting for established cardiovascular risk factors (adjusted odds ratio 3.5, 95% confidence interval 1.3 to 9.6, p = 0.02). In conclusion, patients with psoriasis and especially those with psoriasis for >8 years have a higher prevalence of CAD than patients without psoriasis undergoing coronary angiography. PMID- 22221951 TI - Cardiorespiratory fitness and metabolic risk. AB - The present study sought to evaluate the relation between cardiovascular risk factors and cardiorespiratory fitness (CRF) in a large population. Low CRF has been associated with increased total mortality and cardiovascular mortality. The mechanisms underlying greater cardiovascular mortality have not yet been determined. A series of cardiovascular risk factors were measured in 59,820 men and 22,192 women who had undergone determinations of CRF with maximal exercise testing. The risk factor profiles were segregated into 5 quintiles of CRF. With decreasing CRF, increases occurred in obesity, triglycerides, non-high-density lipoprotein cholesterol, triglyceride/high-density lipoprotein ratios, blood pressure, metabolic syndrome, diabetes, and cigarette smoking. Self-reported physical activity declined with decreasing levels of CRF. In conclusion, it appears likely that the enrichment of cardiovascular risk factors, especially metabolic risk factors, account for a portion of the increased cardiovascular mortality in low-fitness subjects. The mechanisms responsible for this enrichment in subjects with a low CRF represent a challenge for future research. PMID- 22221953 TI - Relation of impaired coronary microcirculation to increased urine albumin excretion in patients with systemic hypertension and no epicardial coronary arterial narrowing. AB - Coronary flow reserve (CFR) is impaired and urinary albumin excretion is increased in patients with essential hypertension. Our aim was to investigate the associations between CFR and cardiac and renal damage in hypertensives. For this purpose we studied 37 never-treated hypertensives (57.9 years old, 16 men) without chest pain but with a positive ischemia stress test result and normal coronary arteries on coronary angiogram. CFR was calculated by a 0.014-inch Doppler guidewire (Flowire, Volcano, San Diego) in the left anterior descending artery in response to bolus intracoronary administration of adenosine (60 MUg) as the ratio of hyperemic to basal average peak velocity of the distal vessel. All participants underwent complete echocardiographic study including left ventricular diastolic function evaluation by tissue Doppler imaging (peak early diastolic velocity/peak atrial systolic velocity) and determination of the albumin-to-creatinine ratio (ACR). Hypertensives with low CFR (<2.5, n = 22) compared to those with high CFR (n = 15) exhibited a larger left ventricular mass index by 10.9 g/m(2) (p = 0.045) and ACR values by 10 mg/g (p <0.001). CFR was negatively correlated with logACR (r = -0.511, p = 0.001). LogACR (beta -0.792, p <0.001), male gender (beta 0.313, p = 0.005), left ventricular mass index (beta 0.329, p = 0.007), and peak early diastolic velocity/peak atrial systolic velocity (beta 0.443, p <0.001) were the only independent predictors of CFR in linear regression analysis (adjusted R(2) = 0.672). In conclusion, never-treated asymptomatic hypertensives who exhibit impaired CFR and angiographically normal epicardial arteries are characterized by intrarenal vascular damage as reflected by increased ACR. These findings suggest a plausible role of ACR estimation in the identification of hypertensive subjects with early coronary microvascular dysfunction. PMID- 22221952 TI - Height and risk of heart failure in the Physicians' Health Study. AB - Although previous studies have reported an association between height and cardiovascular disease, it is unclear whether height is associated with the risk of heart failure (HF). We hypothesized that height would be inversely associated with HF risk. We used prospective data from 22,042 male physicians (mean age 53.8 years) from the Physicians' Health Study. Height was self-reported at baseline. Incident HF was ascertained using follow-up questionnaires and validated through review of the medical records in a subsample. The Cox proportional hazard model was used to compute the hazard ratio (HR) and corresponding 95% confidence interval (CI). The mean height +/- SD was 1.78 +/- 0.07 m. A total of 1,444 HF cases occurred during a mean follow-up of 22.3 years. Compared to subjects in the lowest height category (1.40 to 1.73 m), the HR for HF was 0.86 (95% CI 0.74 to 0.99), 0.82 (95% CI 0.70 to 0.95), and 0.76 (95% CI 0.63 to 0.91) for the height categories of 1.74 to 1.78 m, 1.79 to 1.83 m, and 1.84 to 2.08 m, respectively, after adjustment for age, weight, hypertension, and diabetes mellitus (p for trend = 0.0023). The HR per SD increment in height was 0.92 (95% CI 0.86 to 0.98) in a fully adjusted model. The exclusion of those with prevalent atrial fibrillation, left ventricular hypertrophy, valvular heart disease, and a history of coronary artery bypass grafting yielded similar results (HR per SD 0.88, 95% CI 0.83 to 0.94). In conclusion, our data demonstrated an inverse association between height and incident HF in United States male physicians. Additional studies to elucidate the underlying biologic mechanisms are warranted. PMID- 22221954 TI - Relation of the utility of exercise testing for risk assessment in pediatric patients with ventricular preexcitation to pathway location. AB - The gradual loss of ventricular preexcitation during exercise stress testing (EST) has an unclear risk of an association with life-threatening arrhythmia and could be related to the accessory pathway (AP) location. We compared the loss of preexcitation during EST with the risk assessment during invasive electrophysiology testing and determined whether the loss of preexcitation correlates with the AP location. We retrospectively reviewed patients aged <=21 years with ventricular preexcitation who had undergone both EST and an electrophysiology study. The patients were divided into 3 groups: sudden loss (SL), gradual loss (GL), or no loss (NL) of preexcitation during EST. A total of 76 patients were included, with 11 (14%) in the SL group, 18 (24%) in the GL group, and 47 (62%) in the NL group. The SL group demonstrated a longer cycle length with 1-to-1 conduction by way of the AP during incremental atrial pacing compared with the NL group (375 +/- 135 ms vs 296 +/- 52 ms, p = 0.002), with no difference between the GL and NL groups (325 +/- 96 vs 296 +/- 52 ms, p = NS). Of the patients with 1-to-1 AP conduction of <270 ms, none (0 of 11) were in the SL group compared to 18 of 47 in the NL group (p = 0.0017), with no significant difference in the GL group (5 of 18) compared to the NL group (p = NS). The patients in the GL group were more likely to have a left-sided AP (14 of 18) than the NL group (17 of 47, p = 0.002) and the SL group (3 of 11, p = 0.002). In conclusion, a sudden loss of preexcitation during an EST predicted a long cycle length with 1-to-1 conduction by way of the AP. Also, the AP conduction characteristics in patients with GL compared to those with NL did not differ, and the GL of preexcitation was more frequently seen in patients with a left-sided AP. PMID- 22221955 TI - Exploration of the e-patient phenomenon in nursing informatics. AB - The availability of health information on the Internet has equalized opportunities for knowledge between patients and their health care providers, creating a new phenomenon called the e-patient. E-patients use technology to actively participate in their health care and assume higher levels of responsibility for their own health and wellness. This phenomenon has implications for nursing informatics research related to e-patients and potential collaboration with practitioners in developing a collective wisdom. Nursing informatics can use the data, information, knowledge, and wisdom (DIKW) framework to understand how e-patients and clinicians may achieve this collective wisdom. Nurse informaticists can use constructivism and Gadamerian hermeneutics to bridge each stage of this framework to illustrate the fundamentals of patient and clinician interactions and commonality of language to achieve a collective wisdom. Examining the e-patient phenomenon will help nurse informaticists evaluate, design, develop, and determine the effectiveness of information systems used by e-patients. The Internet can facilitate a partnership between the patient and clinician and cultivate a collective wisdom, enhanced by collaboration between nurse informatics and e-patients. PMID- 22221956 TI - Zenithal alignment of liquid crystal on homeotropic polyimide film irradiated by ion beam. AB - We investigate the pretilt characteristics of a nematic liquid crystal [LC] in terms of ion beam exposure conditions on the homeotropic polyimide alignment layer. The pretilt angle of LCs in the case of high-energy ion beam treatment was decreased considerably almost the same to that of the homogenous alignment layer though we used homeotropic polyimide film at first. Increasing irradiating energy, we could control the pretilt from 90 degrees to 1 degrees with several steps. We believe that this is because the side chain with hydrophobicity in the used polyimide is broken by ion beam exposure. To confirm it, contact angle measurement was carried out. With this result, we can easily control the LC pretilt in the pixel with appropriate exposure conditions which is critical to achieve excellent electrooptic characteristics and good image quality. PMID- 22221957 TI - N and C control of ABC-type bicarbonate transporter Cmp and its LysR-type transcriptional regulator CmpR in a heterocyst-forming cyanobacterium, Anabaena sp. AB - In the model, heterocyst-forming cyanobacterium Anabaena sp. PCC 7120, gene cluster alr2877-alr2880, which encodes an ABC-type transport system, was induced under conditions of carbon limitation and its inactivation impaired the uptake of bicarbonate. Thus, this gene cluster encodes a Cmp bicarbonate transporter. ORF all0862, encoding a LysR-type transcriptional regulator, was expressed under carbon limitation and at higher levels in the absence than in the presence of combined nitrogen, with a positive effect of the N-control transcription factor NtcA. all0862 was expressed from two putative transcription start sites located 164 and 64 bp upstream from the gene respectively. The latter was induced under carbon limitation and was dependent on positive autoregulation by All0862. All0862 was required for the induction of the Cmp bicarbonate transporter, thus representing a CmpR regulator of Anabaena sp. These results show a novel mode of co-regulation by C and N availability through the concerted action of N- and C responsive transcription factors. PMID- 22221958 TI - TEM-EELS: a personal perspective. AB - The development of electron energy-loss spectroscopy in a transmission electron microscope (TEM-EELS) is illustrated through personal anecdote, highlighting some of the basic principles, instrumentation and personalities involved. The current state of the art is reviewed, together with some challenges for the future. PMID- 22221960 TI - Influences of phase transition and microstructure on dielectric properties of Bi0.5Na0.5Zr1-xTixO3 ceramics. AB - Bismuth sodium zirconate titanate ceramics with the formula Bi0.5Na0.5Zr1-xTixO3 [BNZT], where x = 0.3, 0.4, 0.5, and 0.6, were prepared by a conventional solid state sintering method. Phase identification was investigated using an X-ray diffraction technique. All compositions exhibited complete solubility of Ti4+ at the Zr4+ site. Both a decrease of unit cell size and phase transition from an orthorhombic Zr-rich composition to a rhombohedral crystal structure in a Ti-rich composition were observed as a result of Ti4+ substitution. These changes caused dielectric properties of BNZT ceramics to enhance. Microstructural observation carried out employing SEM showed that average grain size decreased when addition of Ti increased. Grain size difference of BNZT above 0.4 mole fraction of Ti4+ displayed a significant increase of dielectric constant at room temperature. PMID- 22221959 TI - Identification and proteomic profiling of exosomes in human cerebrospinal fluid. AB - BACKGROUND: Exosomes are released from multiple cell types, contain protein and RNA species, and have been exploited as a novel reservoir for disease biomarker discovery. They can transfer information between cells and may cause pathology, for example, a role for exosomes has been proposed in the pathophysiology of Alzheimer's disease. Although studied in several biofluids, exosomes have not been extensively studied in the cerebrospinal fluid (CSF) from humans. The objective of this study was to determine: 1) whether human CSF contains exosomes and 2) the variability in exosomal protein content across individuals. METHODS: CSF was collected from 5 study participants undergoing thoraco-abdominal aortic aneurysm repair (around 200 - 500 ml per participant) and low-density membrane vesicles were concentrated by ultracentrifugation. The presence of exosomes was determined by western blot for marker proteins, isopycnic centrifugation on a sucrose step gradient and transmission electron microscopy with immuno-labelling. Whole protein profiling was performed using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR). RESULTS: Flotillin 1 and tumor susceptibility gene 101 (TSG101), two exosomal marker proteins, were identified in the ultracentrifugation pellet using western blot. These markers localized to a density consistent with exosomes following isopycnic centrifugation. Transmission electron microscopy visualized structures consistent with exosomes in size and appearance that labelled positive for flotillin 1. Therefore, the pellet that resulted from ultracentrifugation of human CSF contained exosomes. FT ICR profiling of this pellet was performed and 84-161 ions were detected per study participant. Around one third of these ions were only present in a single study participant and one third were detected in all five. With regard to ion quantity, the median coefficient of variation was 81% for ions detected in two or more samples. CONCLUSIONS: Exosomes were identified in human CSF and their proteome is a potential new reservoir for biomarker discovery in neurological disorders such as Alzheimer's disease. However, techniques used to concentrate exosomes from CSF need refinement to reduce variability. In this study we used relatively large starting volumes of human CSF, future studies will focus on exosome isolation from smaller 'real life' clinical samples; a key challenge in the development of exosomes as translational tools. PMID- 22221961 TI - Skin irritation because of electrocardiograph lead in patients in intensive care unit. PMID- 22221963 TI - [Comparing the perspectives of primary care doctors in the Canary Islands and Alberta (Canada)]. AB - OBJECTIVE: To examine the advantages and disadvantages of two different Health Care Systems from the perspective of Primary Care (PC) physicians. DESIGN: Qualitative research based on the analysis of documents written as diaries for the study. SETTING: Primary Care in the Canary Islands (Spain) and Alberta (Canada) CONTEXT AND PARTICIPANTS: Intentional sample to identify different profiles of physicians. METHOD: Participants were asked to write a document describing their work activities, including the impact of the organisational system and on their personal life. Two representatives of the health care system were asked to write a detailed description about how PC is organised in their country. Nine diaries were collected (5 from the Canary Islands and 4 from Alberta). Ritchie & Spencer framework was used for the analysis. RESULTS: In Alberta, physicians have access to more complementary tests; they can offer hospital care; they have to sort out administrative work; they can choose were to work; and can specialise in different types of health care services. In the Canary Islands physicians can have paid holidays and the administrative issues do not depend on them, patients have a physician assigned and seem to have more institutional support. CONCLUSIONS: The results of this study allow us to constructively analyse the role of PC physicians, assess the advantages and re think the disadvantages related to how we work in order to learn from other health care systems. PMID- 22221964 TI - [Attention deficit/hyperactivity disorder in childhood and adolescence: from the social construct to pharmacological Calvinism]. PMID- 22221965 TI - [The number of medical consultations: is it excessive in Spain?]. PMID- 22221968 TI - Cologne Consensus Conference on pulmonary hypertension. PMID- 22221966 TI - Hepatocellular carcinoma and survival in patients with autoimmune hepatitis (Japanese National Hospital Organization-autoimmune hepatitis prospective study). AB - BACKGROUND/AIMS: Although the outcome of autoimmune hepatitis (AIH) is generally good, the natural course and likelihood of progression to cirrhosis or hepatocellular carcinoma (HCC) remain undefined, and may vary by region and population structure. Our aims were to evaluate risk factors that contribute to poor outcome and particularly development of HCC in a prospective multicentric cohort study of AIH. METHODS: The study group comprised 193 Japanese patients with AIH who were prospectively followed up at annual intervals between 1995 and 2008. The mean follow-up period was 8.0 +/- 4.5 years. RESULTS: Twenty-one (10.9%) patients had cirrhosis at presentation and a further 15 (7.8%) developed cirrhosis during the follow-up period. Survival rates were 94.2% at 10 years and 89.3% at 15 years. HCC was diagnosed in seven of the 193 patients. The presence of cirrhosis at presentation was a risk factor for HCC according to a Cox proportional hazard model, and the HCC-free survival rate was significantly lower in those with cirrhosis compared to those without cirrhosis according to Kaplan Meier analysis. CONCLUSIONS: Although the outcome of AIH is as good if not better among Japanese than for other populations, there was an increased risk of HCC in these patients. Cirrhosis at presentation was predictive of development of HCC in AIH in Japan. PMID- 22221969 TI - Pulmonary hypertension: Hemodynamic evaluation. Updated Recommendations of the Cologne Consensus Conference 2011. AB - The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. The guidelines contain detailed recommendations for the diagnosis of pulmonary hypertension. However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the invasive hemodynamic evaluation of pulmonary hypertension. This manuscript describes in detail the results and recommendations of the working group which were last updated in October 2011. PMID- 22221970 TI - Treatment of pulmonary arterial hypertension (PAH): updated Recommendations of the Cologne Consensus Conference 2011. AB - The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. The guidelines contain detailed recommendations on the diagnosis of pulmonary hypertension (PH). However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the treatment of pulmonary arterial hypertension (PAH). This commentary describes in detail the results and recommendations of the working group on treatment of PAH which were last updated in October 2011. PMID- 22221971 TI - Non-invasive diagnosis of pulmonary hypertension: ESC/ERS Guidelines with Updated Commentary of the Cologne Consensus Conference 2011. AB - The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. The guidelines contain detailed recommendations for the diagnosis of pulmonary hypertension. However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the non-invasive diagnosis of pulmonary hypertension. This manuscript describes in detail the results and recommendations of the working group which were last updated in October 2011. PMID- 22221972 TI - Pulmonary hypertension due to left heart disease: updated Recommendations of the Cologne Consensus Conference 2011. AB - The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension (PH) have been adopted for Germany. While the guidelines contain detailed recommendations regarding pulmonary arterial hypertension (PAH), they contain only a relatively short paragraph on other, much more frequent forms of PH including PH owing to left heart disease. The guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors) have not been sufficiently investigated in other forms of PH. However, despite the lack of respective efficacy data an uncritical use of targeted PAH drugs in patients with PH associated with left heart disease is currently observed at an increasing rate. This development is a matter of concern. On the other hand, PH is a frequent problem that is highly relevant for morbidity and mortality in patients with left heart disease. It that sense, the practical implementation of the European Guidelines in Germany requires the consideration of several specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to PH due to left heart disease. This commentary describes in detail the results and recommendations of the working group which were last updated in October 2011. PMID- 22221973 TI - Pulmonary hypertension due to chronic lung disease: updated Recommendations of the Cologne Consensus Conference 2011. AB - The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. These guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the use of these drugs in patients with chronic lung disease and PH is not recommended. This recommendation, however, is not always in agreement with medical needs as physicians feel sometimes inclined to also treat other forms of pulmonary hypertension which may affect the quality of life and survival of these patients in a similar manner as in PAH. In June 2010, a consensus conference was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology (DGK, DGP and DGPK). To this end, a number of working groups were initiated, one of which was specifically dedicated to the diagnosis and treatment of PH due to chronic lung disease. This manuscript describes in detail the results and recommendations of this working group which were last updated in October 2011. PMID- 22221974 TI - Chronic thromboembolic pulmonary hypertension (CTEPH): updated Recommendations of the Cologne Consensus Conference 2011. AB - In the 2009 European Guidelines on the diagnosis and treatment of pulmonary hypertension (PH), one section covers aspects of pathophysiology, diagnosis and treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The practical implementation of the guidelines for this disease is of crucial importance, because CTEPH is a subset of PH which can potentially be cured by pulmonary endarterectomy (PEA). Nowadays, CTEPH is commonly underdiagnosed and not properly managed. Any patient with unexplained PH should be evaluated for the presence of CTEPH, and a ventilation/perfusion (V/Q) lung scan is recommended as screening method of choice. If the V/Q scan or CT angiography reveals signs of CTEPH, the patient should be referred to a specialized center with expertise in the medical and surgical management of this disease. Every case has to be reviewed by an experienced PEA surgeon for the assessment of operability. In this updated recommendation, important contents of the European guidelines were commented, and more recent information regarding diagnosis and treatment was added. PMID- 22221975 TI - Is a standardized questionnaire useful for tubal rupture screening in patients with ectopic pregnancy? AB - OBJECTIVES: Physical examination, ultrasonography, and laboratory tests fail to reliably establish the preoperative diagnosis of tubal rupture in patients with ectopic pregnancy (EP), leading to a high rate of diagnostic laparoscopy. The aim of this study was to construct and to evaluate a clinical prediction rule for tubal rupture screening based on a self-assessment questionnaire, among patients with EP. METHODS: A standardized questionnaire was constructed via semistructured interviews of patients with acute pelvic pain. Features associated with tubal rupture were then identified in 141 prospectively included patients with tubal pregnancy, including 30 with tubal rupture, in five hospitals. Multiple logistic regression was used to select the best combination of independent features for predicting tubal rupture. Cross-validation was with the jackknife method. The main outcome measure was diagnostic accuracy of the questionnaire for ruling out tubal rupture. RESULTS: Eighty-nine items characterizing acute pelvic pain were identified. Among them, four contributed independently to the diagnosis of tubal rupture: vomiting during pain, diffuse abdominal pain, acute pain for longer than 30 minutes, and flashing pain. The presence of one or more of these features had 93% sensitivity (95% confidence interval [CI] = 84% to 100%) and 44% specificity (95% CI = 35% to 53%) for tubal rupture, with a negative likelihood ratio for ruling out tubal rupture of 0.16. CONCLUSIONS: These results suggest that a standardized questionnaire may contribute to ruling out tubal rupture in patients with EP. PMID- 22221976 TI - Depression is a common and chronic comorbidity in patients with interstitial lung disease. AB - BACKGROUND AND OBJECTIVE: Little is known about depression in interstitial lung disease (ILD). The aim of this study was to determine the prevalence of depression, characterize the association of depression with clinical variables and describe the natural history of depression in patients with ILD. METHODS: In this prospective cohort study, clinical variables were recorded at baseline and 6 months. Depression was measured with the Centre for Epidemiologic Studies Depression scale. Depression prevalence was determined using the established threshold of >15 points. Multivariate linear regression was used to determine the baseline features that independently correlated with baseline depression score and that predicted depression severity at follow-up. RESULTS: Fifty-two subjects were enrolled, and 45 returned for follow-up (three deaths, one lung transplant). Prevalence of depression was 21% at baseline. Independent predictors of depressive symptoms at baseline included dyspnoea severity, pain severity, sleep quality and forced vital capacity (R(2) 0.67). The odds of clinically meaningful depression at follow-up were 34-fold higher for subjects who had clinically meaningful depression at baseline compared with those who were not (95% confidence interval 3.5-422, P < 0.0005). Baseline depression score was the strongest predictor of depression score at follow-up (r 0.59, P < 0.00005). CONCLUSIONS: Depressive symptoms in ILD are common, persistent, and strongly and independently correlated with dyspnoea, pain, sleep quality and forced vital capacity. Clinically meaningful depression at baseline is the most important predictor of depressive symptoms at follow-up. Patients with ILD should routinely be screened for depression. PMID- 22221977 TI - An intellectual property sharing initiative in agricultural biotechnology: development of broadly accessible technologies for plant transformation. AB - The Public Intellectual Property Resource for Agriculture (PIPRA) was founded in 2004 by the Rockefeller Foundation in response to concerns that public investments in agricultural biotechnology benefiting developing countries were facing delays, high transaction costs and lack of access to important technologies due to intellectual property right (IPR) issues. From its inception, PIPRA has worked broadly to support a wide range of research in the public sector, in specialty and minor acreage crops as well as crops important to food security in developing countries. In this paper, we review PIPRA's work, discussing the failures, successes, and lessons learned during its years of operation. To address public sector's limited freedom-to-operate, or legal access to third-party rights, in the area of plant transformation, we describe PIPRA's patent 'pool' approach to develop open-access technologies for plant transformation which consolidate patent and tangible property rights in marker free vector systems. The plant transformation system has been licensed and deployed for both commercial and humanitarian applications in the United States (US) and Africa, respectively. PMID- 22221978 TI - Selective preparation of zero- and one-dimensional gold nanostructures in a TiO2 nanocrystal-containing photoactive mesoporous template. AB - Nanocrystallized SiO2-TiO2 with tubular mesopores was prepared via the sol-gel technique. Gold was deposited in the tubular mesopores of the nanocrystallized SiO2-TiO2. The shape of the gold was varied from one-dimensional [1-D] to zero dimensional [0-D] nanostructures by an increase in TiO2 content and ultraviolet [UV] irradiation during gold deposition. 1-D gold nanostructures [GNSs] were mainly obtained in the mesopores when a small amount of TiO2-containing mesoporous SiO2-TiO2 was used as a template, whereas the use of a template containing a large amount of TiO2 led to the formation of shorter 1-D or 0-D GNSs. UV irradiation also resulted in the formation of 0-D GNSs.PACS: 06.60.Jn (sample preparation); 81.07.Gf (nanowires); 81.16.Be (chemical synthesis methods). PMID- 22221979 TI - Ischemia-modified albumin use as a prognostic factor in coronary bypass surgery. AB - BACKGROUND: Various types of markers have been used so far in order to reveal myocardial perfusion defect. However, these markers usually appear in the necrosis phase or in the late stage. Having been the focus of various investigations recently, ischemia-modified albumin (IMA) is helpful in establishing diagnosis in the early stages of ischemia, before necrosis develops. METHODS AND RESULTS: 30 patients that underwent only coronary bypass surgery due to ischemic heart disease within a specific period of time have been included in the study. IMA levels were studied in the preoperative, intraoperative, and postoperative periods. The albumin cobalt binding assay was used for IMA determination. Hemodynamic parameters (atrial fibrillation, the need for inotropic support, ventricular arrhythmia) of the patients in the postoperative stage were evaluated. Intraoperative measurement values (mean +/- SD) of IMA (0.67677 +/- 0.09985) were statistically significantly higher than those in the preoperative (0.81516 +/- 0.08894) and postoperative (0.70477 +/- 0.07523) measurements. Considering atrial fibrillation and need for inotropics, a parallelism was detected with the levels of IMA. CONCLUSIONS: IMA is an early rising marker of cardiac ischemia and enables providing a direction for the treatment at early phases. PMID- 22221981 TI - Esophageal mass: the importance of clinical history in foreign body imaging. PMID- 22221980 TI - Promoting advance planning for health care and research among older adults: a randomized controlled trial. AB - BACKGROUND: Family members are often required to act as substitute decision makers when health care or research participation decisions must be made for an incapacitated relative. Yet most families are unable to accurately predict older adult preferences regarding future health care and willingness to engage in research studies. Discussion and documentation of preferences could improve proxies' abilities to decide for their loved ones. This trial assesses the efficacy of an advance planning intervention in improving the accuracy of substitute decision-making and increasing the frequency of documented preferences for health care and research. It also investigates the financial impact on the healthcare system of improving substitute decision-making. METHODS/DESIGN: Dyads (n = 240) comprising an older adult and his/her self-selected proxy are randomly allocated to the experimental or control group, after stratification for type of designated proxy and self-report of prior documentation of healthcare preferences. At baseline, clinical and research vignettes are used to elicit older adult preferences and assess the ability of their proxy to predict those preferences. Responses are elicited under four health states, ranging from the subject's current health state to severe dementia. For each state, we estimated the public costs of the healthcare services that would typically be provided to a patient under these scenarios. Experimental dyads are visited at home, twice, by a specially trained facilitator who communicates the dyad-specific results of the concordance assessment, helps older adults convey their wishes to their proxies, and offers assistance in completing a guide entitled My Preferences that we designed specifically for that purpose. In between these meetings, experimental dyads attend a group information session about My Preferences. Control dyads attend three monthly workshops aimed at promoting healthy behaviors. Concordance assessments are repeated at the end of the intervention and 6 months later to assess improvement in predictive accuracy and cost savings, if any. Copies of completed guides are made at the time of these assessments. DISCUSSION: This study will determine whether the tested intervention guides proxies in making decisions that concur with those of older adults, motivates the latter to record their wishes in writing, and yields savings for the healthcare system. TRIAL REGISTRATION: ISRCTN89993391. PMID- 22221982 TI - Complete heart block during potassium therapy in thyrotoxic periodic paralysis. AB - BACKGROUND: Although cardiac dysrhythmia is common in patients with thyrotoxic periodic paralysis (TPP), high-degree atrioventricular (AV) block complicated by cardiogenic shock, even under KCl supplementation, is rarely described. OBJECTIVES: To present a case of TPP in a patient who developed complete AV block with severe consequences due to paradoxical hypokalemia during KCl therapy. In addition, the management of acute hypokalemia in TPP is reviewed. CASE REPORT: A 41-year-old Chinese man with TPP presented to the Emergency Department with a 2 day history of paralysis in the extremities. He developed complete AV block with cardiogenic shock and respiratory failure, necessitating ventilatory support when plasma K(+) level decreased from 1.7 mmol/L to 1.3 mmol/L during KCl replacement of 30 mmol in 2 h. The administration of another 60 mmol KCl over 3 h achieved a plasma K(+) level of 2.1 mmol/L, resulting in the resolution of AV block and successful weaning. However, rebound hyperkalemia (K(+) 5.6 mmol/L) upon recovery was evident and uneventfully corrected. CONCLUSION: A paradoxical fall in serum K(+) concentration with potentially life-threatening complication is still underappreciated in patients with TPP on KCl supplementation. Early recognition and prompt therapy prevent untoward consequences. PMID- 22221983 TI - Do low-dose corticosteroids improve mortality or shock reversal in patients with septic shock? A systematic review and position statement prepared for the American Academy of Emergency Medicine. AB - BACKGROUND: The management of septic shock has undergone a significant evolution in the past decade. A number of trials have been published to evaluate the efficacy of low-dose corticosteroid administration in patients with septic shock. METHODS: The Sepsis Sub-committee of the American Academy of Emergency Medicine Clinical Practice Committee performed an extensive search of the contemporary literature and identified seven relevant trials. RESULTS: Six of the seven trials reported a mortality outcome of patients in septic shock. Analysis of the data revealed that the relative risk (RR) of 28-day all-cause mortality in septic shock patients who received low-dose corticosteroids was 0.92 (95% confidence interval [CI] 0.79-1.07). All seven trials reported data concerning shock reversal or the withdrawal of vasopressors. Pooled results revealed that the RR of shock reversal is 1.17 (95% CI 1.07-1.28), which suggests that there may be significant improvement in shock reversal after corticosteroid administration. It is important to understand that two of the seven studies reviewed were disproportionately represented and accounted for 799 of 1005 patients (80%) considered for this recommendation. CONCLUSIONS: The evidence suggests that low dose corticosteroids may reverse shock faster; however, mortality is not improved for the overall population. PMID- 22221984 TI - Irreducible fracture of the proximal interphalangeal joint of the fifth toe. AB - BACKGROUND: Interphalangeal joint dislocations of toes are relatively rare and can generally be treated by closed reduction. OBJECTIVES: This case presentation intends to emphasize that irreducible lesser toe fractures may represent significant injuries. The minimal external injury and the infrequent presentation of these injuries entail the risk of remaining undiagnosed. CASE REPORT: We present a case of a persistent proximal interphalangeal joint fracture dislocation of the fifth toe. Open reduction was performed because closed reduction remained unsuccessful as a result of interposition of both the flexor tendon and the volar plate into the fracture line. CONCLUSIONS: Even such a minor trauma as a lesser toe injury deserves thorough physical examination, and when indicated on radiological imaging, as significant injuries can easily be overlooked. PMID- 22221985 TI - A two-year experience of an integrated simulation residency curriculum. AB - BACKGROUND: Human Patient Simulation (HPS) is increasingly used in medical education, but its role in Emergency Medicine (EM) residency education is uncertain. STUDY OBJECTIVES: The objective of this study was to evaluate the perceived effectiveness of HPS when fully integrated into an EM residency didactic curriculum. METHODS: The study design was a cross-sectional survey performed in 2006, 2 years after the implementation of an integrated simulation curriculum. Fifty-four residents (postgraduate year [PGY] 1-4) of a 4-year EM residency were surveyed with demographic and curricular questions on the perceived value of simulation relative to other teaching formats. Survey items were rated on a bipolar linear numeric scale of 1 (strongly disagree) to 9 (strongly agree), with 5 being neutral. Data were analyzed using Student t-tests. RESULTS: Forty residents responded to the survey (74% response rate). The perceived effectiveness of HPS was higher for junior residents than senior residents (8.0 vs. 6.2, respectively, p<0.001). There were no differences in perceived effectiveness of lectures (7.8 vs. 7.9, respectively, p=0.1), morbidity and mortality conference (8.5 vs. 8.7, respectively, p=0.3), and trauma conference (8.4 vs. 8.8, respectively, p=0.2) between junior and senior residents. Scores for perceptions of improvement in residency training (knowledge acquisition and clinical decision-making) after the integration of HPS into the curriculum were positive for all residents. CONCLUSION: Residents' perceptions of HPS integration into an EM residency curriculum are positive for both improving knowledge acquisition and learning clinical decision-making. HPS was rated as more effective during junior years than senior years, while the perceived efficacy of more traditional educational modalities remained constant throughout residency training. PMID- 22221986 TI - Hepatic artery pseudoaneurysm rupture: a case report and review of the literature. AB - BACKGROUND: Ruptured hepatic artery pseudoaneurysm, a type of visceral artery aneurysm, is a rare condition that is life threatening if not diagnosed and treated rapidly in the emergency department (ED). Patients presenting with this condition require aggressive resuscitation. Endovascular embolization is the first-line treatment option. OBJECTIVES: We present a case of spontaneously ruptured hepatic artery pseudoaneurysm and provide a review of the current literature on this topic, focusing on appropriate ED management. CASE REPORT: A 41-year-old woman with a history of systemic lupus erythematosus and multiple hepatic bilomas presented to the ED in critical condition with sudden onset of severe abdominal pain and hemodynamic instability. She was found to have a ruptured hepatic artery pseudoaneurysm with marked hemoperitoneum on computed tomography angiography. She was aggressively resuscitated and successfully managed via endovascular embolization. CONCLUSION: Ruptured hepatic artery pseudoaneurysm is a life-threatening condition that must be rapidly diagnosed and managed in the ED. Visceral artery aneurysm rupture is a diagnosis that should be considered in any patient presenting to the ED with hemodynamic instability and abdominal pain. Definitive management is with endovascular embolization. PMID- 22221987 TI - Liquefaction of Typha latifolia by supercritical fluid extraction. AB - Milled Typha latifolia stalk mill was converted to liquid products by using organic solvents (methanol, ethanol, acetone and 2-butanol) with catalysts (10% NaOH or Na(2)CO(3)) and without catalyst in an autoclave at temperatures of 518, 538 and 558 K. The products were extracted by liquid-liquid extraction (benzene and diethyl ether). The percentage yields from supercritical methanol, ethanol, 2 butanol and acetone conversions were 55.0, 58.5, 62.7 and 70.5 at 538 K, respectively. In the catalytic run with NaOH, the highest conversion was obtained by using ethanol as a solvent at the same temperature. Conversion yields were analyzed by GC-MS. The aim of the present study was to obtain an alternative for petroleum derived fuels or chemical raw materials. PMID- 22221988 TI - Microbial carbon capture cell using cyanobacteria for simultaneous power generation, carbon dioxide sequestration and wastewater treatment. AB - Microbial carbon capture cells (MCCs) were constructed with cyanobacteria growing in a photo biocathode in dual-chambered flat plate mediator-less MFCs separated by an anion exchange membrane from the anode compartment containing Shewanella putrefaciens. The performance of the MCC with Anabaena sparged with CO(2)-air mixture was compared with that of a conventional cathode sparged with air only. The power densities achieved were 57.8 mW/m(2) for Anabaena sparged with a CO(2) air mixture, 39.2 mW/m(2) for CO(2)-air mixture sparging only, 29.7 mW/m(2) for Anabaena sparged with air, and 19.6 mW/m(2) for air sparging only. The pH of the cathode containing Anabaena gradually increased from 7 to 9.12 and power generation decreased from 34.7 to 23.8 mW/m(2) 17 due to pH imbalance associated voltage losses without CO(2)-air mixture sparging. Sparging with a 5% CO(2)-air mixture produced maximum power of 100.1 mW/m(2). In addition, the power density of MCC increased by 31% when nitrate was added into the catholyte. PMID- 22221989 TI - Use of Trichoderma reesei RT-P1 crude enzyme powder for ethanol fermentation of sweet sorghum fresh stalks. AB - Use of Trichoderma reesei RT-P1 crude enzyme powder and of this powder with 10%v/v Saccharomyces cerevisiae for ethanol fermentation of sweet sorghum fresh stalks were investigated. The optimal conditions were determined by orthogonal experiment method. With T. reesei crude enzyme powder, the optimal condition for the Keller cultivar was at 25 g with 4 g enzyme loading and for the Cowley cultivar at 30 g with 5 g enzyme loading, both with 8 days fermentation at pH 5 and 30 degrees C. At the optimal conditions above, ethanol concentration, productivity and yield of the Cowley cultivar (35.00 g/L, 0.18 g/Lh and 0.38 g ethanol/g substrate, respectively) were higher than those of the Keller cultivar (20.46 g/L, 0.11 g/Lh and 0.28 g ethanol/g substrate). The addition of 10%v/v S. cerevisiae to fermentation at the optimal conditions showed no significant variations in ethanol concentration, productivity and yield for both cultivars. PMID- 22221990 TI - Use of a new Trichoderma harzianum strain isolated from the Amazon rainforest with pretreated sugar cane bagasse for on-site cellulase production. AB - The on-site production of cellulases is an important strategy for the development of sustainable second-generation ethanol production processes. This study concerns the use of a specific cellulolytic enzyme complex for hydrolysis of pretreated sugar cane bagasse. Glycosyl hydrolases (FPase, xylanase, and beta glucosidase) were produced using a new strain of Trichoderma harzianum, isolated from the Amazon rainforest and cultivated under different conditions. The influence of the carbon source was first investigated using shake-flask cultures. Selected carbon sources were then further studied under different pH conditions using a stirred tank bioreactor. Enzymatic activities up to 121 FPU/g, 8000 IU/g, and 1730 IU/g of delignified steam-exploded bagasse+sucrose were achieved for cellulase, xylanase and beta-glucosidase, respectively. This enzymatic complex was used to hydrolyze pretreated sugar cane bagasse. A comparative evaluation, using an enzymatic extract from Trichoderma reesei RUTC30, indicated similar performance of the T. harzianum enzyme complex, being a potential candidate for on-site production of enzymes. PMID- 22221991 TI - Molasses-based growth and production of oil and astaxanthin by Chlorella zofingiensis. AB - The aim of this study is to evaluate the industrial waste cane molasses as a carbon source for cell growth, lipid and astaxanthin production of Chlorella zofingiensis. Pretreated with cation exchange resin to remove the metal ions, cane molasses provided better productivities of biomass, lipid, and astaxanthin (1.55, 0.71 g L(-1)day(-1) and 1.7 mg L(-1)day(-1), respectively) than glucose. Using a strategy of semi-continuous cultures coupled with feeding at a low concentration, molasses without pretreatment has the same effect as pretreated one on supporting the algal cell growth, lipid and astaxanthin production. The efficient metabolism of molasses triggered the up-regulation of genes involved in fatty acid and also astaxanthin biosynthesis, leading to the very high production of the two metabolites. This study highlights the possibility of using C. zofingiensis to deal with industrial wastes and to produce profitable biodiesel as well as the high-value astaxanthin. PMID- 22221992 TI - Sexual expression, fulfilment and haemophilia: reflections from the 16th Australian and New Zealand Haemophilia Conference. AB - Following a presentation given at the 16th Australian and New Zealand Haemophilia Conference; Enjoying your sex life: Issues and solutions for men with physical impairment [Dune TM. Enjoying your sex life: issues and solutions for men with physical impairment. 16th Australian and New Zealand Haemophilia Conference: Health and Wellbeing - The Decade Ahead. Sydney, Australia: Haemophilia Foundation Australia, 2011], this note summarizes some of the issues and discusses solutions men with haemophilia and chronic illness highlight when negotiating their sexuality. This note also purports that the lack of clinical expertise and empirical research on sexuality and haemophilia hinders to provision of holistic health care. PMID- 22221993 TI - Trends in the utilization of inguinal hernia repair techniques: a population based study. AB - BACKGROUND: The use of inguinal hernia repair techniques in the community setting is poorly understood. METHODS: A retrospective review of all inguinal hernia repairs performed on adult residents of Olmsted County, MN, from 1989 to 2008 was performed through the Rochester Epidemiology Project. RESULTS: A total of 4,433 inguinal hernia repairs among 3,489 individuals were reviewed. Non-mesh-based repairs predominated in the late 1980s (94% in 1989), declined throughout the 1990s (40% in 1996), and are rarely used nowadays (4% in 2008). Open mesh-based repairs comprised 21% in 1990, peaked in 2001 with 72%, and declined to 55% in 2008. The adoption of laparoscopic repairs began in 1992 (6%) and has increased steadily to 41% in 2008 (P < .001). CONCLUSIONS: Although non-mesh-based repairs, once the predominant method, have been supplanted by open mesh-based techniques, nowadays the use of laparoscopic inguinal hernia repair techniques has increased substantially to nearly equal that of open mesh-based techniques. PMID- 22221994 TI - Continued rationale of why hospital mortality is not an appropriate measure of trauma outcomes. AB - BACKGROUND: We hypothesized that standardized withdrawal of care (WOC) practices and an aggressive long-term acute care facility (LTAC) discharge protocol could change hospital mortality and national ranking among trauma centers. STUDY DESIGN: Patients who died while admitted to the trauma service at a level 1 trauma center were classified as either an "LTAC candidate" or "not a LTAC candidate" at 4 time points before death. RESULTS: A total of 216 patients died, and 48% had WOC. Hospital mortality was 3.3%. More than 26% of these qualified as LTAC candidates. The aggressive LTAC discharge protocol reduced hospital mortality by .9%. This was sufficient to move a trauma center into a lower quartile on the National Trauma DataBank benchmark report for 2009. CONCLUSIONS: [corrected] It is possible to reduce hospital mortality and improve quality ranking with standardized WOC and LTAC discharge protocols. This highlights the importance of measuring outcomes beyond discharge. PMID- 22221995 TI - Using manual dexterity to predict the quality of the final product in the small bowel anastomosis after a period of training. AB - OBJECTIVE: The use of aptitude tests in the selection of surgeons has gained recent attention. Few have described its relevance in predicting the acquisition of surgical techniques. We aim to show whether assessing manual dexterity can predict the quality of the final product after a period of training. METHODS: Thirty-six medical students had their manual dexterity assessed completed bench model small bowel anastomosis in 8 consecutive sessions. The fine details (accuracy (number of sutures that traversed full thickness) and number of sutures placed) and gross details (bowel apposition) of quality of final product was objectively assessed. RESULTS: Manual dexterity correlated with grade only in the initial sessions (Pearson correlation coefficient, r = -.578, P < .01). There was no significant correlation with the fine details with any session. CONCLUSIONS: There was a correlation with manual dexterity and outcome measures in the initial sessions of training with grade only. This relationship was eliminated by the end of training sessions. This suggests that the outcome of procedures after a period of training cannot be predicted by measuring manual dexterity skills. PMID- 22221996 TI - The role of transcervical thymectomy in patients with hyperparathyroidism. AB - BACKGROUND: The most common location for supernumerary or ectopic parathyroid glands is the thymus. METHODS: A review of patients who underwent parathyroidectomy for hyperparathyroidism from 1990 to 2010 was completed to determine indications for thymectomy, the yield of parathyroid tissue, and outcome of therapy. RESULTS: Seventy of 379 patients with hyperparathyroidism underwent parathyroidectomy and transcervical thymectomy. Intrathymic parathyroid tissue was present in 23 (33%) patients, including supernumerary glands in 8 patients (11%). Indications for thymectomy were renal hyperparathyroidism in 35 patients (50%) and primary hyperparathyroidism with a missing inferior gland in 20 patients (29%), an ectopic adenoma in 9 patients (13%), hyperplasia in 5 patients (7%), and carcinoma in 1 patient (1%). Cure rates were similar (96% and 98%; P = not significant) and only transient hypocalcemia was higher (51% vs 24%, P < .05) after parathyroidectomy with thymectomy versus parathyroidectomy alone. CONCLUSIONS: Transcervical thymectomy results in a high yield of parathyroid tissue and is essential for cure of selected patients with hyperparathyroidism. PMID- 22221997 TI - Long-term symptom relief and patient satisfaction after Heller myotomy and Toupet fundoplication for achalasia. AB - BACKGROUND: The goal of this study was to review the results, symptom relief, and patient satisfaction after laparoscopic Heller myotomy and Toupet fundoplication. METHODS: A cohort of patients who underwent laparoscopic esophagomyotomy and a Toupet fundoplication was identified. A retrospective chart review was conducted and patients then were interviewed by telephone using a modified 5-point Likert scale. RESULTS: Long-term follow-up data were obtained for 51 patients with a mean of 5.9 years. Thirty-two (63%) patients reported infrequent or no dysphagia. Chest pain, heartburn, or regurgitation were reported in 6 of 51 (12%) patients, 14 of 51 (27%) patients, and 11 of 51 (22%) patients, respectively. Two patients (3.9%) had pneumatic dilation and 1 patient underwent completion esophagectomy (1.9%). Thirty-three (33 of 51; 65%) patients were on acid-suppression therapy. Forty-one (80%) patients reported their overall satisfaction with the procedure was either excellent or good, and 46 of 51 (90%) patients stated they would undergo surgery again. CONCLUSIONS: Our data show acceptable long-term results. PMID- 22221998 TI - Inhibitory effects of recombinant porcine interferon-alpha on high- and low virulence porcine reproductive and respiratory syndrome viruses. AB - The inhibitory effects of recombinant porcine interferon alpha (rPoIFN-alpha) on the propagation of low-virulence PRRSV (lvPRRSV) in MARC-145 cells, and on the progress and severity of high virulence PRRSV (hvPRRSV)-induced infections in pigs, were determined. Pre-treatment of MARC-145 cells with increasing concentrations of rPoIFN-alpha prior to infection with lvPRRSV decreased the observed cytopathic effects (CPEs) in a concentration-dependent manner. Viral propagation and antibody response were temporarily delayed in swine treated with rPoIFN-alpha either at the same time as the hvPRRSV challenge was administered or post-challenge. Exposure of challenged animals to rPoIFN-alpha after the onset of disease symptoms alleviated associated hyperthermia. Variations in lymphocyte subsets indicated that rPoIFN-alpha treatment might alleviate damage to the immune system or enhance propagation of host cytotoxic T-lymphocytes when the treatment was applied simultaneously with the virus or 1dpc, respectively. PMID- 22221999 TI - Bilateral renal ischemia as a model of acute kidney injury in cats. AB - The objective of this study was to evaluate the effect of 1h, bilateral, warm ischemia-reperfusion kidney injury as a model of acute kidney injury in the cat. Four adult healthy cats underwent 60 min of bilateral, in vivo renal warm ischemia; three cats were sham operated controls. Kidney function was evaluated with creatinine and BUN concentration, urine protein: creatinine, and glomerular filtration rate. Post-reperfusion endothelin and renin was measured by ELISA and RT-qPCR. Blood pressure (BP), platelet count, and platelet aggregation were monitored. Renal biopsy specimens were evaluated histopathologically. There was significant reduction in renal function characterized by severe azotemia and proximal tubular brush border loss. Changes in renin or endothelin gene expression or serum concentration were not detected. No changes were detected in BP. Platelet count and hematocrit decreased markedly after ischemia and reperfusion. Sixty minutes bilateral renal ischemia is an effective model for acute renal injury. PMID- 22222000 TI - Chitin colonization, chitin degradation and chitin-induced natural competence of Vibrio cholerae are subject to catabolite repression. AB - Although Vibrio cholerae is a human pathogen its primary habitat are aquatic environments. In this environment, V.cholerae takes advantage of the abundance of zooplankton, whose chitinous exoskeletons provide a nutritious surface. Chitin also induces the developmental programme of natural competence in several species of the genus Vibrio. Because the chitin surface can serve as the sole carbon source for V.cholerae, the link between carbon catabolite repression and chitin induced natural competence for transformation was investigated in this study. Provision of competing phosphoenolpyruvate: carbohydrate phosphotransferase system (PTS)-dependent carbon sources in addition to chitin significantly lowered natural transformability. These sugars are known to interfere with the accumulation of 3',5'-cyclic AMP (cAMP); therefore, the contributions of the cAMP producing enzyme, adenylate cyclase and the cAMP receptor protein (CRP) to chitin surface colonization, chitin degradation and natural transformation were also analysed. The results provided here indicate that cAMP and CRP are important in at least three interlinked areas of the chitin-induced natural competence programme. First, cAMP and CRP are required for the efficient colonization of the chitin surface; second both contribute to chitin degradation and utilization, and third, cAMP plus CRP play a role in increasing competence gene expression. These findings highlight the complex regulatory circuit of chitin-induced natural competence in V.cholerae. PMID- 22222001 TI - LiNi0.4Co0.3Mn0.3O2 thin film electrode by aerosol deposition. AB - LiNi0.4Co0.3Mn0.3O2 thin film electrodes are fabricated from LiNi0.4Co0.3Mn0.3O2 raw powder at room temperature without pretreatments using aerosol deposition that is much faster and easier than conventional methods such as vaporization, pulsed laser deposition, and sputtering. The LiNi0.4Co0.3Mn0.3O2 thin film is composed of fine grains maintaining the crystal structure of the LiNi0.4Co0.3Mn0.3O2 raw powder. In the cyclic voltammogram, the LiNi0.4Co0.3Mn0.3O2 thin film electrode shows a 3.9-V anodic peak and a 3.6-V cathodic peak. The initial discharge capacity is 44.6 MUAh/cm2, and reversible behavior is observed in charge-discharge profiles. Based on the results, the aerosol deposition method is believed to be a potential candidate for the fabrication of thin film electrodes. PMID- 22222002 TI - Pyoderma gangrenosum complicating mammaplasty. PMID- 22222003 TI - Pharmacophore modeling, 3D-QSAR studies, and in-silico ADME prediction of pyrrolidine derivatives as neuraminidase inhibitors. AB - Neuraminidase (NA) is a major glycoprotein of influenza virus which is essential for viral infection. It offers a potential target for antiviral drug development. To develop potent NA inhibitors, pharmacophore models were generated by genetic algorithm with linear assignment for hypermolecular alignment of data sets. 3D QSAR studies were carried out on 49 molecules. Both comparative molecular field analysis (q(2) = 0.720 and r(2) = 0.947) and comparative molecular similarity indices analysis (q(2) = 0.644 and r(2) = 0.885) yielded reasonable results. A preliminary pharmacokinetic profile of these neuraminidase inhibitors was predicted using Volsurf module. PMID- 22222004 TI - Emerging viral diseases in dromedary camels in the Southern Morocco. AB - During the last fifteen years, new viral diseases such Bluetongue (BT), West Nile (WN), African horse sickness (AHS), Epizootic hemorrhagic disease (EHD) and Peste des Petits Ruminants (PPR) have extended their geographic distribution and emerged in North Africa and in Europe. Camel (Camelus dromedarius) is considered as a potential vector in the transmission of some of these diseases while it is host-specific for Camelpox (CP). A serological survey was conducted on 1392 sera to estimate changes of these diseases prevalence in camels over two different time spans (2003 and 2009) and across different sites of South Morocco. Results indicate clearly that BT was circulating in camels before the first notified outbreak in Morocco (2004) with 42% positive sera in Guelmim in 2003. BT and WN prevalence's increased over time from 11 to 25% and from 10 to 13% respectively. Higher prevalence of both diseases was found in camels living in oases indicating an increased intensity of viral circulation in these sites. Camels have been tested negative for AHS, EHD and PPR viruses while higher CP prevalence has been detected in camels living in Smara, the most closed site to eastern borders (i.e. Mauritania). The seroprevalence of CP in camels at interval of 7 years increases from 23% to 37%. This survey could provide information on the possible use of camel as a sentinel animal for surveillance of emerging diseases such BT and WN. PMID- 22222005 TI - Comparison of acute versus convalescent stage high-sensitivity C-Reactive protein level in predicting clinical outcome after acute ischemic stroke and impact of erythropoietin. AB - BACKGROUND AND AIM: Currently, no data on the optimal time point after acute ischemic stroke (IS) at which high-sensitivity C-reactive protein (hs-CRP) level is most predictive of unfavorable outcome. We tested the hypothesis that hs-CRP levels during both acute (48 h after IS) and convalescent (21 days after IS) phases are equally important in predicting 90-day clinical outcome after acute IS. We further evaluated the impact of erythropoietin (EPO), an anti-inflammatory agent, on level of hs-CRP after acute IS. METHODS: Totally 160 patients were prospectively randomized to receive either EPO therapy (group 1, n = 80) (5,000 IU each time, subcutaneously) at 48 h and 72 h after acute IS, or placebo (group 2, n = 80). Serum level of hs-CRP was determined using ELISA at 48 h and on day 21 after IS and once in 60 healthy volunteers. RESULTS: Serum level of hs-CRP was substantially higher in all patients with IS than in healthy controls at 48 h and day 21 after IS (all p < 0.001). Levels of hs-CRP did not differ between group 1 and 2 at 48 h and day 21 after IS (all p > 0.5). Multivariate analysis showed that hs-CRP levels (at 48 h and day 21) were independently predictive of 90-day major adverse neurological event (MANE) (defined as recurrent stroke, NIHSS>=8, or death) (all p < 0.03), whereas EPO therapy was independently predictive of reduced 90-day MANE (all p < 0.02). CONCLUSION: EPO therapy which was independently predictive of freedom from 90-day MANE did not alter the crucial role of hs-CRP levels measured at 48 h and 21-day in predicting unfavorable clinical outcome after IS. PMID- 22222006 TI - Household chemical exposures and the risk of canine malignant lymphoma, a model for human non-Hodgkin's lymphoma. AB - BACKGROUND: Epidemiologic studies of companion animals offer an important opportunity to identify risk factors for cancers in animals and humans. Canine malignant lymphoma (CML) has been established as a model for non-Hodgkin's lymphoma (NHL). Previous studies have suggested that exposure to environmental chemicals may relate to development of CML. METHODS: We assessed the relation of exposure to flea and tick control products and lawn-care products and risk of CML in a case-control study of dogs presented to a tertiary-care veterinary hospital (2000-2006). Cases were 263 dogs with biopsy-confirmed CML. Controls included 240 dogs with benign tumors and 230 dogs undergoing surgeries unrelated to cancer. Dog owners completed a 10-page questionnaire measuring demographic, environmental, and medical factors. RESULTS: After adjustment for age, weight, and other factors, use of specific lawn care products was associated with greater risk of CML. Specifically, the use of professionally applied pesticides was associated with a significant 70% higher risk of CML (odds ratio(OR)=1.7; 95% confidence interval (CI)=1.1-2.7). Risk was also higher in those reporting use of self-applied insect growth regulators (OR=2.7; 95% CI=1.1-6.8). The use of flea and tick control products was unrelated to risk of CML. CONCLUSIONS: Results suggest that use of some lawn care chemicals may increase the risk of CML. Additional analyses are needed to evaluate whether specific chemicals in these products may be related to risk of CML, and perhaps to human NHL as well. PMID- 22222008 TI - The therapeutic efficacy of two antibabesial strategies against Babesia gibsoni. AB - Various combination strategies for treating Babesia gibsoni have been described. However, relapses after administering some combinations of antibabesial drugs and the presence of drug-resistant B. gibsoni still pose significant challenges to veterinarians. To compare the efficacy of a combination of clindamycin, diminazene, and imidocarb (CDI) to that of a combination of atovaquone and azithromycin (AA) for the treatment of B. gibsoni and to correlate drug efficacy with B. gibsoni mutations, 30 client-owned dogs with natural B. gibsoni infections were collected in the study. 17 dogs were treated with AA, and 13 dogs were treated with CDI combination. Hematological parameters were recorded on the day that the dogs were presented for treatment and during treatment. To detect the parasitic DNA, the B. gibsoni 18S rRNA gene was amplified, and to analyze the mutations, the cytochrome b (CYTb) gene was sequenced. The therapy duration for all of the dogs that recovered was 23.3+/-7.8 days in the AA group and 41.7+/ 12.4 days in the CDI group. Nine of the 17 dogs in the AA group and 11 of the 13 dogs in the CDI group completely recovered. Seven dogs in the AA group and 2 dogs in the CDI group relapsed after treatment. The M121I mutation in the B. gibsoni CYTb gene was detected in all of the samples that were collected from AA-relapsed and AA-nonremission dogs. The dogs in the CDI group exhibited higher recovery rates and lower relapse rates during treatment for B. gibsoni infection. In addition, the detected M121I mutation was associated with AA treatment. The CDI combination is a promising alternative treatment strategy for B. gibsoni. PMID- 22222007 TI - Associations between phthalate metabolite urinary concentrations and body size measures in New York City children. AB - OBJECTIVE: To examine prospectively associations between urinary phthalate metabolite concentrations and body size measures in children. METHODS: Urinary concentrations of nine phthalate metabolites: monoethyl (MEP); mono-n-butyl (MBP); mono-(3-carboxypropyl) (MCPP); monobenzyl (MBzP); mono-isobutyl (MiBP); mono-(2-ethylhexyl) (MEHP); mono-(2-ethyl-5-oxohexyl) (MEOHP); mono-(2-ethyl-5 carboxypentyl) (MECPP); and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and the molar sum of the low molecular-weight phthalate metabolites (low MWP: MEP, MBP and MiBP) and high molecular-weight phthalate metabolites (high MWP: MECPP, MEHHP, MEOHP, MEHP and MBzP) and of four di-(2-ethylhexyl) phthalate (DEHP) metabolites (SigmaDEHP: MEHP, MEHHP, MEOHP, MECPP) and anthropometry, including body mass index and waist circumference were measured among 387 Hispanic and Black, New York City children who were between six and eight years at cohort enrollment (2004-2007). Relationships between baseline metabolite concentrations and body size characteristics obtained one year later were examined using multivariate-adjusted geometric means for each body size characteristic by continuous and categories of phthalate metabolite concentrations. Stratified analyses by body size (age/sex specific) were conducted. RESULTS: No significant associations are reported among all girls or boys. Dose response relationships were seen with monoethyl phthalate and the sum of low molecular-weight phthalates and body mass index and waist circumference among overweight children; for increasing monoethyl phthalate concentration quartiles among girls, adjusted mean body mass indexes were as follows: 21.3, 21.7, 23.8, 23.5 and adjusted mean waist circumference (cm) were as follows: 73.4, 73.5, 79.2, 78.8 (p-trend<0.001 for both). CONCLUSION: In this prospective analysis we identified positive relationships between urinary concentrations of monoethyl phthalate and the sum of low molecular-weight phthalates and body size measures in overweight children. These are metabolites with concentrations above 1 MUM. PMID- 22222009 TI - Alteration of helper T-cell related cytokine production in splenocytes during Trichinella spiralis infection. AB - Infection by Trichinella spiralis takes place in two distinct phases: one is the intestinal phase and the other is the muscle phase. To evaluate alterations in cytokine production during a T. spiralis infection, we periodically assessed the cytokine production of splenocytes in mice after infection (AI). The levels of Th2-related cytokines immediately increased after the initiation of T. spiralis larval intestinal invasion (1 week AI). These early elevations in the Th2 response might be associated with the innate immune responses of intestine epithelial cells against T. spiralis larval invasion. IL-4 and IL-13 levels reached a peak prior to the initiation of nurse cell formation (2 weeks AI). Additionally, all Th17-related cytokines, except for IL-17, increased slightly until 2 weeks AI. However, expression levels for all of the Th2 and Th17-related cytokines began to decrease after the initiation of nurse cell formation and reached basal levels at 4 weeks AI, except for IL-5. At the same time, the CD4(+)CD25(+)Foxp3(+) T (regulatory T, T(reg)) cell population increased significantly in the spleen. Additionally, the number of cells in the peripheral lymph nodes increased. In conclusion, T. spiralis larva intestinal invasion induced the production of Th2 and Th17 cell-related cytokines, and the cytokines decreased with T(reg) cell-related cytokine. PMID- 22222010 TI - SCOPS and COWS--'worming it out of UK farmers'. AB - Infections with gastrointestinal roundworms are an important cause of production losses in sheep and cattle. Worm control is a vital part of health and production management in sheep flocks and cattle herds in the UK, and good control is highly dependent on effective anthelmintics. Unfortunately, a direct and unavoidable consequence of using anthelmintics to control worm populations is selection for individuals that are resistant to the chemicals used. If left unchecked, anthelmintic resistance (AR) could prove to be one of the biggest challenges to sheep and cattle production and animal welfare within the UK. As a consequence of increasing reports of AR in sheep, a working group, "SCOPS" (sustainable control of parasites in sheep) was formed in 2003 with representatives from the UK sheep industry to promote practical guidelines for sheep farmers and their advisors. This led to the production of guidelines for 'sustainable worm control strategies for sheep' intended for veterinarians and sheep advisors, plus ongoing promotional literature aimed at farmers. Whilst there is some evidence of emerging resistance in roundworms of cattle, it appears to still be at a very low level in the UK. However the potential presence of such AR in cattle worms has been seen as a timely warning, which if ignored, could lead to a not dissimilar AR situation to that seen in sheep, and in other cattle areas around the world. Reports of AR in UK cattle nematodes have generally been limited to a small number of anecdotal reports of treatment failure with some macrocyclic lactone (ML) products, especially those formulated as pour-on preparations, and invariably involving the dose-limiting species, Cooperia oncophora. As a consequence of these observations, guidelines have been produced similar to those for sheep, for sustainable worm control strategies for cattle "COWS" (control of worms sustainably), and were launched in May 2010. Uptake and effectiveness of SCOPS recommendations are currently being monitored in collaboration with the UK animal health industry, and similar proposals are being considered for uptake of COWS guidelines following the launch this year. PMID- 22222011 TI - Lattice-patterned LC-polymer composites containing various nanoparticles as additives. AB - In this study, we show the effect of various nanoparticle additives on phase separation behavior of a lattice-patterned liquid crystal [LC]-polymer composite system and on interfacial properties between the LC and polymer. Lattice patterned LC-polymer composites were fabricated by exposing to UV light a mixture of a prepolymer, an LC, and SiO2 nanoparticles positioned under a patterned photomask. This resulted in the formation of an LC and prepolymer region through phase separation. We found that the incorporation of SiO2 nanoparticles significantly affected the electro-optical properties of the lattice-patterned LC polymer composites. This effect is a fundamental characteristic of flexible displays. The electro-optical properties depend on the size and surface functional groups of the SiO2 nanoparticles. Compared with untreated pristine SiO2 nanoparticles, which adversely affect the performance of LC molecules surrounded by polymer walls, SiO2 nanoparticles with surface functional groups were found to improve the electro-optical properties of the lattice-patterned LC polymer composites by increasing the quantity of SiO2 nanoparticles. The surface functional groups of the SiO2 nanoparticles were closely related to the distribution of SiO2 nanoparticles in the LC-polymer composites, and they influenced the electro-optical properties of the LC molecules. It is clear from our work that the introduction of nanoparticles into a lattice-patterned LC polymer composite provides a method for controlling and improving the composite's electro-optical properties. This technique can be used to produce flexible substrates for various flexible electronic devices. PMID- 22222012 TI - Lipedematous diseases of the scalp are not separate entities but part of a spectrum of lipomatous lesions. AB - BACKGROUND: Lipedematous lesions of the scalp share a wide range of morphologic criteria with classical lipomatosis. In the past decade, lipedematous scalp and lipedematous alopecia have been described as pathomorphologically related diseases of the scalp, but many clinicians and dermatopathologists disagree with this assessment. Morphologic and pathogenetic concepts remain unclear and raise the concern that a plethora of terms are being used to describe and distinguish phenotypical variations of an identical theme. PATIENT AND METHODS: Here, we report a 15-year-old male Turkish child with what we could consider, according to the currently accepted classifications, lipedematous scalp without associated alopecia. RESULTS: The principal aim of this manuscript is to critically reappraise the current literature on lipomatous lesions and focus on morphologic features in order to reestablish five crucial diagnostic criteria. CONCLUSIONS: Due to the possibility of excluding therapeutic elements by separating the lipomatous lesions into various entities, we propose using the term "localized lipomatosis of the scalp with or without associated alopecia" in order to arrive at a straightforward diagnosis, thereby avoiding numerous partially synonymous terms; moreover, we do not intend to expand the spectrum of distinct lipomatous entities, but propose classification of these diseases within the group of conventional lipomatosis. PMID- 22222013 TI - Association of 25-hydroxyvitamin D levels with liver dysfunction and mortality in chronic liver disease. AB - BACKGROUND: Previous studies suggest that chronic liver disease may be related to vitamin D deficiency. It is, however, not known whether 25(OH)D levels are associated with incident hepatic decompensation and mortality in chronic liver failure. AIMS: We aimed to evaluate whether 25(OH)D serum levels are associated with Child-Pugh (CP) score, model for end-stage liver disease (MELD) score, occurrence of hepatic decompensation, and survival in patients with cirrhosis. METHODS: We enrolled 75 consecutive cirrhotic patients admitted to our outpatient liver clinic (32% females; age: 58 +/- 11 years; aetiology alcohol in 61%). At baseline, 25(OH)D was determined and the degree of liver dysfunction was estimated by CP and MELD score. Thereafter patients were followed-up with respect to hepatic decompensation and mortality. RESULTS: 25(OH)D levels averaged 16.0 +/ 9.2 ng/ml and were inversely correlated with MELD score (r = -0.34, P = 0.003) and CP score (r = -0.21, P = 0.080). Thirty-seven patients developed hepatic decompensation and 24 patients died during a median follow-up of 3.6 years. Age- and gender-adjusted relative risk (with 95% confidence interval) was 6.37 (1.75 23.2; P = 0.005) for hepatic decompensation and 4.31 (1.38-13.5; P = 0.012) for mortality within the first vs the third 25(OH)D tertile but these associations were largely attenuated towards non-significant trends after additional adjustments for CP or MELD score. CONCLUSIONS: Our findings show a significant association of 25(OH)D with the degree of liver dysfunction and suggest that low 25(OH)D levels may predict hepatic decompensation and mortality in patients with chronic liver failure. PMID- 22222014 TI - Molecular interactions of dimethyl methylphosphonate (DMMP) with metalloporphyrins: determination of the binding mechanism by spectroscopic methods. AB - The molecular interactions of 5,10,15,20-tetraphenylporphine zinc (ZnTPP) and 5,10,15,20-tetraphenyl-21H,23H-porphine cobalt(II) (CoTPP) with dimethyl methylphosphonate (DMMP) have been investigated by absorption/absorption difference spectroscopy. The interactions between the metalloporphyrins and DMMP change the absorbance characteristics of the porphyrins resulted from the formation of the metalloporphyrin-DMMP complexes. According to the Benesi Hildebrand (B-H) equation, the equilibrium constants and stoichiometries of the binding systems at four different temperatures (288, 293, 298 and 303 K) were obtained. Experimental results showed that both ZnTPP and CoTPP bind to DMMP via axial coordination, resulting in the formation of 1:1 metalloporphyrin-DMMP complexes. However, it was found that ZnTPP showed stronger binding capacity with the equilibrium constant (K) of 83.864 M(-1) at room temperature, while CoTPP exhibited weaker binding with K of 24.904 M(-1). The thermodynamic parameters, enthalpy change (Delta(r)H(m)(theta)), entropy change (Delta(r)S(m)(theta)) and free energy changes (Delta(r)G(m)(theta)) were also studied for the interactions, indicating that the formation of the metalloporphyrins-DMMP complex was an exothermic reaction. PMID- 22222015 TI - Aqueous solutions of lower alcohols investigated by pyrene fluorescence spectroscopy. AB - The aqueous solutions of lower alcohols such as methanol, ethanol, 1-propanol and 2-propanol, were studied by fluorescence spectroscopy of pyrene, defining the Py scale for polarity. Sigmoidal curves were used to fit the Py values of aqueous alcohol solutions as a function of the logarithm of water-alcohol mole ratio, i.e., log(WAR). The results from curve fittings were discussed in terms of the structural transitions of aqueous alcohol solutions, as well as the dissociation constants for alcohol- and water-pyrene complexes. The microscopic alcohol and water phases were considered to be saturated with each other, and the structures of dilute aqueous alcohol solutions were found to be more complicated than those of concentrated ones. PMID- 22222016 TI - Primary care as a permanent setting for research. AB - AIMS AND BACKGROUND: The critical importance of a closer and structural involvement of primary care in research has been increasingly recognized over the last several years, and has been the object of extensive conceptual and institutional debates and proposals. There is, however, still a gap between the consistency of the recommendations and their translation into practice. METHODS: Based on the most recent literature on the integration of the paradigm of efficacy (evidence-based medicine) with the one on outcomes-effectiveness, as well as on the experience gained with large collaborative studies performed by Italian general practitioners (GPs), the paper discusses the reasons for giving priority to what could be done to bridge the gap and the conditions of feasibility. RESULTS AND CONCLUSIONS: Specifically, the results obtained most recently in a large-scale, epidemiological and experimental project with a prospective cohort of ~12,500 subjects included by 860 GPs across the country in the field of cardiovascular risk prevention (the Rischio e Prevenzione Study) provide the concrete framework for an agenda of action proposed as a way forward, which appears to be highly critical for visibility and cultural autonomy of GPs also at the European level. PMID- 22222017 TI - Educational Research in Primary Care: addressing the challenges through creation of a Special Interest Group and a Doctoral Student Network. PMID- 22222021 TI - [Translational molecular imaging: an investment for the future]. PMID- 22222022 TI - Deaths and complications associated with respiratory endoscopy: a survey by the Japan Society for Respiratory Endoscopy in 2010. AB - BACKGROUND AND OBJECTIVE: In order to survey the current status of the use and complications associated with respiratory endoscopy, the Japan Society for Respiratory Endoscopy conducted a nationwide postal questionnaire survey. METHODS: The survey was mailed to all 538 facilities certified by the society. The subjects were patients who underwent respiratory endoscopy in 2010. The numbers of procedures, and associated complications and deaths were investigated according to lesion and procedure using a specific inventory. RESULTS: The inventory was completed by 483 facilities (89.8%). The total number of diagnostic flexible bronchoscopy procedures performed was 103 978, and four patients died (0.004%). The complication rate according to lesion ranged from 0.51% to 2.06%, with the highest rate being observed in patients with diffuse lesions. The complication rate according to procedure ranged from 0.17% to 1.93%, with the highest rate being observed in patients who underwent forceps biopsy. The complication rate after forceps biopsy of solitary peripheral pulmonary lesions was 1.79% (haemorrhage: 0.73%, pneumothorax: 0.63%), and that after endobronchial ultrasound-guided transbronchial needle aspiration of hilar and/or mediastinal lymph node lesions was 0.46%. Therapeutic bronchoscopy was performed in 3020 patients; one patient (0.03%) died due to haemorrhage induced by insertion of an expandable metallic stent. The complication rate according to procedure was highest for foreign body removal (2.2%). Medical pleuroscopy was performed in 1563 patients. The highest complication rate was for biopsy without electrocautery (1.86%). A total of 228 facilities (47.2%) experienced breakage of bronchoscopes and/or devices. CONCLUSIONS: Respiratory endoscopy was performed safely, but education regarding complications caused by new techniques is necessary. PMID- 22222023 TI - Training medical students to conduct motivational interviewing: a randomized controlled trial. AB - OBJECTIVE: To examine the effectiveness of motivational interviewing (MI) training among medical students. METHODS: All students (n=131) (year 5) at Lausanne Medical School, Switzerland were randomized into an experimental or a control group. After a training in basic communication skills (control condition), an 8-h MI training was completed by 84.8% students in the exprimental group. One week later, students in both groups were invited to meet with two standardized patients. MI skills were coded by blinded research assistants using the Motivational Interviewing Treatment Integrity 3.0. RESULTS: Superior MI performance was shown for trained versus control students, as demonstrated by higher scores for "Empathy" [p<0.001] and "MI Spirit" [p<0.001]. Scores were similar between groups for "Direction", indicating that students in both groups invited the patient to talk about behavior change. Behavior counts assessment demonstrated better performance in MI in trained versus untrained students regarding occurences of MI-adherent behavior [p<0.001], MI non-adherent behavior [p<0.001], Closed questions [p<0.001], Open questions [p=0.001], simple reflections [p=0.03], and Complex reflections [p<0.001]. Occurrences were similar between groups regarding "Giving information". CONCLUSION: An 8-h training workshop was associated with improved MI performance. PRACTICE IMPLICATIONS: These findings lend support for the implementation of MI training in medical schools. PMID- 22222024 TI - Self-management abilities, physical health and depressive symptoms among patients with cardiovascular diseases, chronic obstructive pulmonary disease, and diabetes. AB - OBJECTIVE: This study aimed to identify the predictive role of direct resources (educational level and marital status) and self-management abilities on physical health and depressive symptoms in patients with cardiovascular diseases (CVD), diabetes, or chronic obstructive pulmonary disease (COPD). METHODS: Our cross sectional questionnaire-based study included 1570 CVD patients, 917 COPD patients, and 412 patients with diabetes. RESULTS: Physical health and depressive symptoms of COPD patients was lower than those of CVD and diabetic patients. Correlation analyses indicated that self-management abilities were strong indicators for physical health and depressive symptoms (all p<0.001). This relationship was strongest for depressive symptoms. Self-management abilities were related to educational level in all groups (all p<0.001). Regression analyses revealed that self-management abilities were strong predictors of physical health and depressive symptoms in all three patient groups (all p<0.001). CONCLUSION: This research showed that self-management abilities are strong predictors of physical health and depressive symptoms. PRACTICE IMPLICATIONS: Interventions that improve self-management abilities may counteract a decline in physical health and depressive symptoms. Such interventions may be important tools in the prevention of the loss of self-management abilities, because they may motivate people who are not yet experiencing serious problems. PMID- 22222025 TI - Lung image quality with 320-row wide-volume CT scans: the effect of prospective ECG-gating and comparisons with 64-row helical CT scans. AB - RATIONALES AND OBJECTIVES: To evaluate the image quality of 320-row wide-volume (WV) computed tomography (CT) scans in comparison with 64-row helical scans for the lung. MATERIALS AND METHODS: The Institutional Review Board of each institution approved this prospective, multicenter study and informed consent was obtained. A total of 73 subjects underwent two types of chest CT, including 320 row WV scans and 64-row helical scans. Both scans used the same tube voltage, tube current, exposure time setting, and slice thickness. The helical scans were not electrocardiogram (ECG)-gated. For the WV scans, prospective ECG-gating was used for 38 subjects, whereas the other 35 subjects did not have ECG-gating. Using a 5-point scale from 1 (nondiagnostic) to 5 (excellent), three blinded observers independently evaluated image quality for five lobes and the lingula. The differences in the scores between WV scans and helical scans were compared using Wilcoxon's signed-rank test. RESULTS: The WV scans with ECG-gating had significantly higher scores than 64-row helical scans for all lobes and lingula (right lower lobe, P < .01; other lobes and lingula, P < .0001, respectively). The 320-row WV scans without ECG-gating also had significantly higher scores than 64-row helical scans (P < .05), except for nonsignificant differences for the left upper lobe. CONCLUSIONS: Lung image quality of ECG-gated WV scans, which do not require any additional radiation exposure, is better than that of non-ECG gated 64-row helical scans. Non-ECG-gated 320-row WV scans are comparable or slightly superior to non-ECG-gated 64-row helical scans. PMID- 22222026 TI - Optimal setting of automatic exposure control based on image noise and contrast on iodine-enhanced CT. AB - RATIONALE AND OBJECTIVES: The aim of this study was to investigate variations in image noise and contrast using automatic exposure control (AEC) and different tube voltages on nonenhanced and iodine-enhanced hepatic computed tomography. MATERIALS AND METHODS: Nonenhanced and iodine-enhanced simulated liver phantoms and AEC were used. Tube current was automatically adjusted with the noise index. Two types of assessments were performed: at a fixed noise index of 10 Hounsfield units and at different noise indexes, keeping the same contrast-to-noise ratio at different tube voltages (100, 120, and 130 kV). Image noise was measured, and contrast between the computed tomographic number of the simulated liver and nodule was computed. RESULTS: At a fixed noise index, image noise on iodine enhanced images was 10% to 13% higher than on nonenhanced images at the same tube voltage. At 130 and 100 kV, contrast was 33.86 and 46.90 Hounsfield units, respectively, and image noise was almost the same. Contrast-to-noise ratios at 100, 120, and 130 kV were 3.31, 3.22, and 3.37, respectively, and volume computed tomographic dose index fell from 22.94 to 12.49 mGy with decreasing tube voltage. CONCLUSIONS: With AEC, image noise on iodine-enhanced images was higher than on nonenhanced images despite identical noise index settings. As tube voltage decreased, contrast on iodine-enhanced images increased. Considering noise index and contrast variations at different tube voltages, the optimal use of AEC on iodine-enhanced computed tomography facilitates a reduction in x-ray tube output while maintaining contrast-to-noise ratio. PMID- 22222027 TI - Measurement of focal ground-glass opacity diameters on CT images: interobserver agreement in regard to identifying increases in the size of ground-glass opacities. AB - PURPOSE: To evaluate interobserver agreement in regard to measurements of focal ground-glass opacities (GGO) diameters on computed tomography (CT) images to identify increases in the size of GGOs. MATERIALS AND METHODS: Approval by the institutional review board and informed consent by the patients were obtained. Ten GGOs (mean size, 10.4 mm; range, 6.5-15 mm), one each in 10 patients (mean age, 65.9 years; range, 58-78 years), were used to make the diameter measurements. Eleven radiologists independently measured the diameters of the GGOs on a total of 40 thin-section CT images (the first [n = 10], the second [n = 10], and the third [n = 10] follow-up CT examinations and remeasurement of the first [n = 10] follow-up CT examinations) without comparing time-lapse CT images. Interobserver agreement was assessed by means of Bland-Altman plots. RESULTS: The smallest range of the 95% limits of interobserver agreement between the members of the 55 pairs of the 11 radiologists in regard to maximal diameter was -1.14 to 1.72 mm, and the largest range was -7.7 to 1.7 mm. The mean value of the lower limit of the 95% limits of agreement was -3.1 +/- 1.4 mm, and the mean value of their upper limit was 2.5 +/- 1.1 mm. CONCLUSION: When measurements are made by any two radiologists, an increase in the length of the maximal diameter of more than 1.72 mm would be necessary in order to be able to state that the maximal diameter of a particular GGO had actually increased. PMID- 22222028 TI - The burden of knowing: balancing benefits and barriers in HIV testing decisions. a qualitative study from Zambia. AB - BACKGROUND: Client-initiated HIV counselling and testing has been scaled up in many African countries, in the form of voluntary counselling and testing (VCT). Test rates have remained low, with HIV-related stigma being an important barrier to HIV testing. This study explored HIV testing decisions in one rural and one urban district in Zambia with high HIV prevalence and available antiretroviral treatment. METHODS: Data were collected through 17 in-depth interviews and two focus group discussions with individuals and 10 in-depth interviews with counsellors. Interpretive description methodology was employed to analyse the data. RESULTS: 'To know your status' was found to be a highly charged concept yielding strong barriers against HIV testing. VCT was perceived as a diagnostic device and a gateway to treatment for the severely ill. Known benefits of prevention and early treatment were outweighed by a perceived burden of knowing your HIV status related to stigma and fear. The manner in which the VCT services were organised added to this burden. CONCLUSIONS: This study draws on social stigma theory to enhance the understanding of the continuity of HIV related stigma in the presence of ART, and argues that the burden of knowing an HIV status and the related reluctance to get HIV tested can be understood both as a form of label-avoidance and as strong expressions of the still powerful embodied memories of suffering and death among non-curable AIDS patients over the last decades. Hope lies in the emerging signs of a reduction in HIV related stigma experienced by those who had been tested for HIV. Further research into innovative HIV testing service designs that do not add to the burden of knowing is needed. PMID- 22222030 TI - Carbon nanotube/Co3O4 composite for air electrode of lithium-air battery. AB - A carbon nanotube [CNT]/Co3O4 composite is introduced as a catalyst for the air electrode of lithium-air [Li/air] batteries. Co3O4 nanoparticles are successfully attached to the sidewall of the CNT by a hydrothermal method. A high discharge capacity and a low overvoltage indicate that the CNT/Co3O4 composite is a very promising catalyst for the air electrode of Li/air batteries. PMID- 22222029 TI - Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD like phenotype of APP mice. AB - BACKGROUND: The 5-lipoxygenase (5LO) enzymatic pathway is widely distributed within the central nervous system. Previous works showed that this protein is up regulated in Alzheimer's disease (AD), and that its genetic absence results in a reduction of Amyloid beta (Abeta) levels in the Tg2576 mice.Here by employing an adeno-associated viral (AAV) vector system to over-express 5LO in the same mouse model, we examined its contribution to their cognitive impairments and brain AD like amyloid pathology. RESULTS: Our results showed that compared with controls, 5LO-targeted gene brain over-expression in Tg2576 mice results in significant memory deficits. On the other hand, brain tissues had a significant elevation in the levels of Abeta peptides and deposition, no change in the steady state levels of amyloid-beta precursor protein (APP), BACE-1 or ADAM-10, but a significant increase in PS1, nicastrin, and Pen-2, three major components of the gamma secretase complex. Additional data indicate that the transcription factor CREB was elevated and so were the mRNA levels for PS1, nicastrin and Pen-2. CONCLUSIONS: These data demonstrate that neuronal 5LO plays a functional role in the pathogenesis of AD-like amyloidotic phenotype by modulating the gamma secretase pathway. They support the hypothesis that this enzyme is a novel therapeutic target for the treatment and prevention of AD. PMID- 22222031 TI - Genome-wide DNA polymorphisms in elite indica rice inbreds discovered by whole genome sequencing. AB - Advances in next-generation sequencing technologies have aided discovery of millions of genome-wide DNA polymorphisms, single nucleotide polymorphisms (SNPs) and insertions-deletions (InDels), which are an invaluable resource for marker assisted breeding. Whole-genome resequencing of six elite indica rice inbreds (three cytoplasmic male sterile and three restorer lines) resulted in the generation of 338 million 75-bp paired-end reads, which provided 85.4% coverage of the Nipponbare genome. A total of 2 819 086 nonredundant DNA polymorphisms including 2 495 052 SNPs, 160 478 insertions and 163 556 deletions were discovered between the inbreds and Nipponbare, providing an average of 6.8 SNPs/kb across the genome. Distribution of SNPs and InDels in the chromosome was nonrandom with SNP-rich and SNP-poor regions being evident across the genome. A contiguous 4.3-Mb region on chromosome 5 with extremely low SNP density was identified. Overall, 83 262 nonsynonymous SNPs spanning 16 379 genes and 3620 nonsynonymous InDels in 2625 genes have been discovered which provide valuable insights into the basis underlying performance of the inbreds and the hybrids between these inbred combinations. SNPs and InDels discovered from this diverse set of indica rice inbreds not only enrich SNP resources for molecular breeding but also enable the study of genome-wide variations on hybrid performance. PMID- 22222032 TI - Synthesis and binding affinity at alpha4beta2 and alpha7 nicotinic acetylcholine receptors of new analogs of epibatidine and epiboxidine containing the 7 azabicyclo[2.2.1]hept-2-ene ring system. AB - A group of novel racemic nicotinic ligands structurally related to epibatidine or epiboxidine [(+/-)-10-(+/-)-17] was synthesized through a palladium-catalyzed cross-coupling between the appropriate vinyl triflate and a range of organometallic heterocycles. The target compounds were evaluated for binding affinity at the alpha4beta2 and alpha7 neuronal nicotinic receptors (nAChRs). The set of 3-pyridinyl derivatives (+/-)-10, (+/-)-11 and (+/-)-12 exhibited an affinity for the alpha4beta2 nAChR subtype in the subnanomolar range (K(i) values of 0.20, 0.40 and 0.50nM, respectively) and behaved as alpha4beta2 versus alpha7 subtype selective ligands. Interestingly, the epiboxidine-related dimethylammonium iodide (+/-)-17, which retained a good affinity for the alpha4beta2 nAChR (K(i)=13.30nM), tightly bound also to the alpha7 subtype (K(i)=1.60nM), thus displaying a reversal of the affinity trend among the reference and new nicotinic ligands under investigation. PMID- 22222033 TI - Synthesis and immunological evaluation of the 4-beta-glucoside of HMBPP. AB - HMBPP ((E)-4-hydroxy-3-methyl-2-butenyl pyrophosphate) is a highly potent innate immunogen that stimulates human gammadelta T cells expressing the Vgamma2Vdelta2 T cell antigen receptor. To determine if glycoside conjugates of HMBPP retain activity, the 4-beta-glucoside and its acetylated homolog were synthesized and tested for their ability to stimulate gammadelta T cells. The glycoside HMBPP conjugate stimulated human gammadelta T cells with an EC(50) of 78nM. The tetraacetyl glycoside HMBPP conjugate was also active (EC(50)=360nM). The two isomeric mono-beta-glucosides of the parent (E)-2-methylbut-2-ene-1,4-diol, however, were not active. Thus, HMBPP glycosylated at the 4-OH position stimulates gammadelta T cells as long as the pyrophosphate moiety is present. PMID- 22222034 TI - The discovery of potent, selective, and orally active pyrazoloquinolines as PDE10A inhibitors for the treatment of Schizophrenia. AB - High-throughput screening identified a series of pyrazoloquinolines as PDE10A inhibitors. The SAR development led to the discovery of compound 27 as a potent, selective, and orally active PDE10A inhibitor. Compound 27 inhibits MK-801 induced hyperactivity at 3mg/kg with an ED(50) of 4mg/kg and displays a ~6-fold separation between the ED(50) for inhibition of MK-801 induced hyperactivity and hypolocomotion in rats. PMID- 22222035 TI - Synthesis and DNA cleavage studies of novel quinoline oxime esters. AB - New 2-chloro-3-formyl quinoline oxime esters were synthesized by the reaction of 2-chloro-3-formyl quinoline oximes with various benzoyl chlorides in the presence of triethyl amine and dichloromethane at 0 degrees C. The DNA photo cleavage studies of some new oxime esters were investigated by neutral agarose gel electrophoresis at different concentrations (40MUM and 80MUM). Analysis of the cleavage products in agarose gel indicated that few of quinoline oxime esters (3d i) converted into supercoiled pUC19 plasmid DNA to its nicked or linear form. PMID- 22222036 TI - Small molecule inhibitors of BRAF in clinical trials. AB - Over the last few years, BRAF has emerged as a validated target in melanoma. This review summarises recent advances in the development of BRAF inhibitors, focussing on agents that have been assessed clinically. PMID- 22222037 TI - Tricyclic 3,4-dihydropyrimidine-2-thione derivatives as potent TRPA1 antagonists. AB - The transient receptor potential A1 (TRPA1) channel has been implicated in a number of inflammatory and nociceptive processes, and antagonists of the TRPA1 receptor could offer a potential treatment for conditions such as inflammatory or neuropathic pain, airway disorders, and itch. In a high throughput screen aimed at the identification of TRPA1 antagonists, 4-phenyl-2-thioxo-1,2,3,4-tetrahydro indeno[1,2-d]pyrimidin-5-one (1) was identified as a potent TRPA1 receptor antagonist. A series of analogous tricyclic 3,4-dihydropyrimidine-2-thiones has been prepared via the multi-component Biginelli reaction and subsequent derivatization. This has led to TRPA1 antagonists with potencies around 10nM for both rat and human derived TRPA1 receptors. The activity was shown to reside exclusively in the 4R-enantiomers. PMID- 22222038 TI - Observation of backbone self-crossings of organismal DNAs through atomic force microscopy. AB - It is demonstrated in our studies that intrinsic curvatures of organismal DNAs could lead to the generation of duplex backbone self-crossings in their relaxed forms. In addition, the backbone self-crossings of the organismal DNAs could be readily confirmed through atomic force microscopic examination. PMID- 22222039 TI - Synthesis, pharmacological evaluation and docking studies of N-(benzo[d]thiazol-2 yl)-2-(piperazin-1-yl)acetamide analogs as COX-2 inhibitors. AB - The existing NSAIDs having number of toxicities emphasises the need for discovery of new non-toxic anti-inflammatory agents. In this Letter, we present the simple two step chemical synthesis, in vivo pharmacological screening and docking study of few N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs. Different amino benzothiazoles were chloroacetylated and further reacted with substituted piperazines in presence of a base to get N-(benzo[d]thiazol-2-yl)-2-(piperazin-1 yl)acetamide analogs (A1-C4). These compounds were evaluated for anti inflammatory activity by carragenan induced paw oedema method. Promising compounds were screened for toxicity by evaluating the ulcerogenic potential. Molecular docking experiments were carried out against COX-2 enzyme using Surflex Dock GeomX programme of Sybyl software on Dell T-1500 workstation to confirm the mechanism of action of active compounds among the series. In silico study reveal the binding interactions of N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs with COX-2 protein and is in agreement with the in vivo anti-inflammatory activity. PMID- 22222040 TI - Synthesis of substituted benzimidazolyl curcumin mimics and their anticancer activity. AB - A novel curcumin mimic library (14a-14h and 15a-15h) possessing variously substituted benzimidazole groups was synthesized through the aldol reaction of (E)-4-(4-hydroxy-3-methoxyphenyl)but-3-en-2-one (7) or (E)-4-(3-hydroxy-4 methoxyphenyl)but-3-en-2-one (13) with diversely substituted benzimidazolyl-2 carbaldehyde (12a-12h). The MTT assay of the cancer cells MCF-7, SH-SY5Y, HEP-G2, and H460 showed that compound 14c with IC(50) of 1.0 and 1.9MUM has a strong inhibitory effect on the growth of SH-SY5Y and Hep-G2 cells, respectively, and that compound 15h with IC(50) of 1.9MUM has a strong inhibitory effect on the growth of MCF-7 cancer cells. PMID- 22222041 TI - Inhibitors incorporating zinc-binding groups target the GlcNAc-PI de-N-acetylase in Trypanosoma brucei, the causative agent of African sleeping sickness. AB - Disruption of glycosylphosphatidylinositol biosynthesis is genetically and chemically validated as a drug target against the protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. The N-acetylglucosamine phosphatidylinositol de-N-acetylase (deNAc) is a zinc metalloenzyme responsible for the second step of glycosylphosphatidylinositol biosynthesis. We recently reported the synthesis of eight deoxy-2-C-branched monosaccharides containing carboxylic acid, hydroxamic acid, or N-hydroxyurea substituents at the C2 position that may act as zinc-binding groups. Here, we describe the synthesis of a glucocyclitol-phospholipid incorporating a hydroxamic acid moiety and report the biochemical evaluation of the monosaccharides and the glucocyclitol phospholipid as inhibitors of the trypanosome deNAc in the cell-free system and against recombinant enzyme. Monosaccharides with carboxylic acid or hydroxamic acid substituents were found to be the inhibitors of the trypanosome deNAc with IC(50) values 0.1-1.5mM and the glucocyclitol-phospholipid was found to be a dual inhibitor of the deNAc and the alpha1-4-mannose transferase with an apparent IC(50)= 19+/-0.5MUm. PMID- 22222042 TI - A severe haemophiliac patient with acute coronary syndrome admitted to cardiac rehabilitation. PMID- 22222043 TI - Urinary metabolomic analysis for the identification of renal injury in patients with acute heart failure. AB - OBJECTIVES: Worsening renal function in patients admitted with heart failure is associated with increased morbidity. These changes are not usually apparent initially and often take up to 48 hours to be detected. Using the novel technique of metabolomic analysis, this study aims to determine if markers of renal injury are identifiable at presentation that are associated with the development of worsening renal function in high-risk patients with heart failure. METHODS: A prospective exploratory study enrolled a convenience sample of patients with suspected heart failure. Eligible patients had to be older than 18 years, have a B-type natriuretic peptide (BNP) level over 100 pg/mL, have a history of diabetes or hypertension, meet Boston criteria for heart failure (>8), and require hospital admission as judged by the treating physician. Patients receiving no more than one dose of diuretic prior to enrollment were excluded. Urine was collected during the emergency department (ED) stay. Initial creatinine and the peak value between 24 to 48 hours were used to determine worsening renal function as defined by a change of >0.3 mg/dL or absolute 25% increase. Urine samples underwent gas chromatography/mass spectrometry (GC/MS) profiling. Peak metabolite values were measured and data were log-transformed. Partial least squares discriminant analysis (PLS-DA) was used to identify metabolites associated with worsening renal function. Specific urinary metabolites were ranked based on their regression coefficients. RESULTS: The 24 enrolled subjects had a median age of 58 years (interquartile range [IQR] = 49.5 to 67.5 years) with 58% being male. Worsening renal function occurred in 10 subjects (41.7%). A total of 156 metabolites were identified. The optimal number of metabolites for class discrimination as determined by PLS-DA was three, with a classification accuracy of 78%. These metabolites were taurine, sulfuric acid, and talose. CONCLUSIONS: Urinary metabolites found at the time of presentation may be markers of early renal injury. It is therefore possible that the process of renal injury is initiated prior to ED arrival in patients with suspected heart failure, and these may be used to identify a high-risk patient population. PMID- 22222044 TI - DNA methylation of stress-related genes and LINE-1 repetitive elements across the healthy human placenta. AB - OBJECTIVES: DNA methylation is known to play a critical role in regulating development of placental morphology and physiology. The methylation of genes mediated by glucocorticoid hormones may be particularly vulnerable to intrauterine stress in the placenta. However little is known about DNA methylation of stress-related genes within a healthy placenta, and particularly whether methylation occurs uniformly across different regions of the placenta, which is a critical question for researchers seeking to analyze methylation patterns. We examined DNA methylation across four regions of the placenta to evaluate methylation levels of stress-related genes within a healthy placenta, and to evaluate whether methylation patterns vary by sampling location. STUDY DESIGN: We evaluated levels of DNA methylation of three stress-related genes: NR3C1, BDNF, and 11B-HSD2 and of the repetitive element, LINE-1, in four different sample locations of 20 healthy placentas. MAIN OUTCOME MEASURES: Pyrosequencing was used to quantify levels of methylation at CpG sites within the promoter regions of each of the three stress-related genes, and global methylation of LINE-1. RESULTS: Very low levels of methylation were found across all three stress-related genes; no gene showed a median methylation level greater than 4.20% across placental regions. Variation in methylation between placental regions for stress-related genes and for LINE-1 was minimal. CONCLUSIONS: Our data suggest that these frequently studied stress-related genes have low levels of methylation in healthy placenta tissue. Minimal variation between sites suggests that sampling location does not affect DNA methylation analyses of these genes or of LINE-1 repetitive elements. PMID- 22222046 TI - Letter to the editor. PMID- 22222045 TI - A placental sub-proteome: the apical plasma membrane of the syncytiotrophoblast. AB - As a highly vascularized tissue, the placenta mediates gas and solute exchange between maternal and fetal circulations. In the human placenta, the interface with maternal blood is a unique epithelial structure known as the syncytiotrophoblast. Previously we developed a colloidal-silica based method to generate highly enriched preparations of the apical plasma membrane of the syncytiotrophoblast. Using similar preparations, a proteomics assessment of this important sub-proteome has identified 340 proteins as part of this apical membrane fraction. The expression of 38 of these proteins was previously unknown in the human placental syncytiotrophoblast. Together with previous studies, the current proteomic database expands our knowledge of the proteome of the syncytiotrophoblast apical plasma membrane from normal placentas to include more than 500 proteins. This database is a valuable resource for future comparisons to diseased placentas. Additionally, this data set provides a basis for further experimental studies of placenta and trophoblast function. PMID- 22222047 TI - A survey on the frequency of foot-and-mouth disease virus carriers in cattle in north-east of Iran by RT-PCR: implications for revising disease control strategy. AB - Foot-and-mouth disease (FMD) is endemic in Iran. It is essential to timely evaluate the current disease control programme in Iran. Here, we report the frequency of FMD virus (FMDV) carrier state in cattle slaughtered in Mashhad abattoir, Mashhad, Khorasan Razavi, north-east of Iran, which contains long common borders with Afghanistan and Turkmenistan. Soft palate samples were collected immediately after slaughter for the detection of FMDV by RT-PCR. The results show that 37.7% of cattle (96 of 255) were carriers of the virus. Among positive samples (96), 58 (60.4%) belonged to serotype O. No evidence was detected for the presence of Asia 1 and A serotypes. Nucleotide sequencing and phylogenic dendogram showed close similarity and common lineage between our samples and viruses isolated in Pakistan. With an approximate more than 80% of cattle population vaccination coverage such a high rate of carrier state may show an extensive FMDV exposure. Therefore, limiting control programmes to timely prophylactic vaccination may be insufficient. This is also true when meat market instabilities act as a temptation to import livestock, legally or illegally, through the eastern frontiers. It is recommended to change the current prophylactic vaccination strategy to a well-developed regional control programme, with close monitoring of animal movement through eastern frontiers, supported by government commitment and educational programmes. Timely estimation of the frequency of carrier state both in cattle and small ruminants is also advocated as a gauge to monitor the virus status in the region. PMID- 22222048 TI - Giant coronary artery aneurysms in juvenile polyarteritis nodosa: a case report. AB - Juvenile polyarteritis nodosa (PAN) is a rare, necrotizing vasculitis, primarily affecting small to medium-sized muscular arteries. Cardiac involvement amongst patients with PAN is uncommon and reports of coronary artery aneurysms in juvenile PAN are exceedingly rare. We describe a 16 year old girl who presented with fever, arthritis and two giant coronary artery aneurysms, initially diagnosed as atypical Kawasaki disease and treated with IVIG and methylprednisolone. Her persistent fevers, arthritis, myalgias were refractory to treatment, and onset of a vasculitic rash suggested an alternative diagnosis. Based on angiographic abnormalities, polymyalgia, hypertension and skin involvement, this patient met criteria for juvenile PAN. She was treated with six months of intravenous cyclophosphamide and high dose corticosteroids for presumed PAN related coronary vasculitis. Maintenance therapy was continued with azathioprine and the patient currently remains without evidence of active vasculitis. She remains on anticoagulation for persistence of the aneurysms. This case illustrates a rare and unusual presentation of giant coronary artery aneurysms in the setting of juvenile PAN. PMID- 22222049 TI - Effects of ZnO nanoparticulate addition on the properties of PMNT ceramics. AB - This research was conducted in order to study the effect of ZnO nanoparticulate addition on the properties of 0.9 Pb(Mg1/3Nb2/3)O3-0.1PbTiO3 [PMNT] ceramics. The PMNT ceramics were prepared by a solid-state reaction. The ZnO nanoparticles were added into PMNT ceramics to form PMNT/xZnO (x = 0, 0.05, 0.1, 0.5, and 1.0 wt.%). The PMNT/xZnO ceramics were investigated in terms of phase, microstructure, and mechanical and electrical properties. It was found that the density and grain size of PMNT ceramics tended to increase with an increasing amount of ZnO content. Moreover, a transgranular fracture was observed for the samples containing ZnO, while pure PMNT ceramics showed only a intergranular fracture. An addition of only 0.05 wt.% of ZnO was also found to enhance the hardness and dielectric and ferroelectric properties of the PMNT ceramics. PMID- 22222050 TI - Comparison of acoustic radiation force impulse imaging with transient elastography for the detection of complications in patients with cirrhosis. AB - BACKGROUND: Acoustic radiation force impulse (ARFI) imaging is a new non invasive, ultrasound-based method for the evaluation of liver fibrosis and cirrhosis. AIM: To determine the diagnostic accuracy of ARFI imaging, transient elastography (TE) and Fibrotest for the evaluation of complications in patients with cirrhosis. METHODS: A total of 166 patients (109 male, mean age: 54 +/- 11 years) with chronic liver disease and established cirrhosis were included in this study. ARFI-imaging of the liver and spleen, TE and Fibrotest were performed in all patients. In addition, clinical, laboratory and morphological parameters, including MELD/Child-Pugh scores, presence of oesophageal varices and hepatocellular carcinoma, history of variceal bleeding and history of hepatic encephalopathy were recorded. RESULTS: Acoustic radiation force impulse liver was significantly correlated with ARFI spleen (r = 0.48, P < 0.001), TE (r = 0.75, P < 0.001) and Fibrotest (r = 0.21, P = 0.006). The diagnostic accuracy (AUROC) for the diagnosis of large oesophageal varices was 0.58 (95% CI: 0.48-0.67), 0.58 (0.49-0.67), 0.53 (0.44-0.63) and 0.50 (0.41-0.59) for ARFI liver, spleen, TE and Fibrotest respectively (P > 0.20). The AUROC for the detection of hepatocellular carcinoma (HCC) was 0.54 (0.39-0.70), 0.58 (0.44-0.73), 0.56 (0.40-0.73) and 0.72 (0.60-0.84) respectively (P > 0.20). Multiple logistic regression analysis showed that ARFI spleen better predicted the presence of large oesophageal varices and HCC compared with ARFI liver. CONCLUSIONS: The diagnostic accuracy of ARFI liver and spleen was comparable to TE and Fibrotest for the detection of complications in patients with cirrhosis. PMID- 22222051 TI - Broad reactivity of the Luminex xTAG Respiratory Virus Panel (RVP) assay for the detection of human rhinoviruses. PMID- 22222052 TI - Hepatitis C virus viral kinetics during alpha-2a or alpha-2b pegylated interferon plus ribavirin therapy in liver transplant recipients with different immunosuppression regimes. AB - BACKGROUND: Predictors of sustained virological response (SVR) to antiviral therapy post-liver transplantation (LT) for chronic hepatitis C are needed. In non-transplanted patients, viral kinetics can predict SVR. OBJECTIVES: To determine the early viral kinetics in LT recipients with different immunosuppression (tacrolimus - Tac- vs. cyclosporine - CsA-) during treatment with peg-IFN+RBV. STUDY DESIGN: Prospective pilot study in HCV-1b infected patients: (LT CsA n=8; Tac n=8; non-LT n=4), treated with IFN alpha-2a vs. alpha 2b (180 MUg or 1.5 MUg/kg, respectively) once weekly plus weight-based RBV. Median CsA or Tac baseline trough levels were 141 and 7.70 ng/mL, respectively. HCV-RNA was quantified before treatment and after 3, 6, 12h; days 1-6; and weeks 4, 12, 24, 48 and 78 (follow-up). RESULTS: Different kinetics were observed: early viral load declines with shoulder phase (n=12), delayed monophasic without first phase (n=5, all CsA), and biphasic (n=1) or flat (n=1), without influence of IL28B rs12979860 donor/recipient alleles. In LT, median declines (log(10)UI/mL) at week 4 were -3.62 and -1.49 for Tac vs. CsA; and -2.10 vs.-1.50 for IFN alpha-2a vs. alpha-2b (NS), with a trend for faster declines in Tac patients. Generalized additive models suggested a cut-off for predicting response in LT patients of 30 days for Tac, but beyond day 40 for CsA. CONCLUSION: In LT, the viral kinetics during peg-IFN+RBV treatment is delayed. HCV-RNA at 48 h. may not be predictive of response, and CsA-immunosupressed patients with delayed monophasic declines may potentially achieve ETVR and SVR despite unfavourable or absent early viral load declines. PMID- 22222053 TI - Varicose vein surgery. AB - Venous diseases are common in the general population. After a comprehensive diagnostic evaluation, an individual therapeutic approach should be selected on the basis of the findings, with the aim of treating the diseased vein segments and improving quality of life. Numerous therapeutic options are available for the treatment of varicose veins. In addition to conservative methods such as compression therapy, exercise or drugs, surgical procedures such as traditional surgery, thermal ablation techniques or sclerotherapy can be performed. Recent developments include the use of endoluminal water vapor or mechano-chemical endovenous ablation. PMID- 22222054 TI - Catalytic properties of Co3O4 nanoparticles for rechargeable Li/air batteries. AB - Three types of Co3O4 nanoparticles are synthesized and characterized as a catalyst for the air electrode of a Li/air battery. The shape and size of the nanoparticles are observed using scanning electron microscopy and transmission electron microscopy analyses. The formation of the Co3O4 phase is confirmed by X ray diffraction. The electrochemical property of the air electrodes containing Co3O4 nanoparticles is significantly associated with the shape and size of the nanoparticles. It appears that the capacity of electrodes containing villiform type Co3O4 nanoparticles is superior to that of electrodes containing cube- and flower-type Co3O4 nanoparticles. This is probably due to the sufficient pore spaces of the villiform-type Co3O4 nanoparticles. PMID- 22222055 TI - Distinct recycling of active and inactive beta1 integrins. AB - Integrin trafficking plays an important role in cellular motility and cytokinesis. Integrins undergo constant endo/exocytic shuttling to facilitate the dynamic regulation of cell adhesion. Integrin activity toward the components of the extracellular matrix is regulated by the ability of these receptors to switch between active and inactive conformations. Several cellular signalling pathways have been described in the regulation of integrin traffic under different conditions. However, the interrelationship between integrin activity conformations and their endocytic fate have remained incompletely understood. Here, we have investigated the endocytic trafficking of active and inactive beta1 integrins in cancer cells. Both conformers are endocytosed in a clathrin- and dynamin-dependent manner. The net endocytosis rate of the active beta1 integrins is higher, whereas endocytosis of the inactive beta1 integrin is counteracted by rapid recycling back to the plasma membrane via an ARF6- and early endosome antigen 1-positive compartment in an Rab4a- and actin-dependent manner. Owing to these distinct trafficking routes, the two receptor pools display divergent subcellular localization. At steady state, the inactive beta1 integrin is mainly on the plasma membrane, whereas the active receptor is predominantly intracellular. These data provide new insights into the endocytic traffic of integrins and imply the possibility of a previously unappreciated crosstalk between pathways regulating integrin activity and traffic. PMID- 22222056 TI - [Bacteremia due to Streptococcus gallolyticus. Clinical up-date and diagnosis]. PMID- 22222057 TI - Treatment for nocturnal enuresis: the current state in Japan. AB - Nocturnal enuresis is common problem in children with a prevalence as high as 20% among children aged 5. Though nocturnal enuresis does not directly impose imminent danger to a patient's life, children with enuresis and their parents can be psychologically suffering in day-to-day life, including in school activities. Therefore, it is important to provide an explanation regarding the cause of nocturnal enuresis, how to approach the disorder, the course, and the outlook leading to the planned treatment. The cause of enuresis is considered to be a mismatch between nocturnal diuresis and nocturnal bladder capacity, nocturnal polyuria due to a lack of circadian change in antidiuretic hormones, and a developmental delay in the voiding mechanisms. Therefore, patients can be classified as the type associated with a large amount of urine at night (polyuria type), the type that is associated with a functionally small bladder capacity (bladder type), the type associated with both the aforementioned (mixed type), or the type that does not fall under any of these (normal type). Based on this logic, although the International Children's Continence Society has issued the standardization document, in which the enuresis alarm and desmopressin therapy are recommended as the first line treatment, a different tack has been taken in Japan, where the therapeutic strategy is plotted depending on the type of enuresis; pharmacotherapy for enuretic children aged 6 years or older includes desmopressin acetate for polyuria type, anticholinergic agents for bladder type, and a combination of these agents for mixed type. PMID- 22222058 TI - [Infective endocarditis in the XXI century: epidemiological, therapeutic, and prognosis changes]. AB - Infective endocarditis (IE) is an uncommon and severe disease. Nowadays, in developed countries, IE patients are older, usually have a degenerative heart valve disease, and up to 30% acquire this infection within the health care system. In consequence, staphylococci species are the most frequently isolated microorganisms. Antimicrobial treatment for IE has significantly changed over the last decades. In IE episodes due to Staphylococcus aureus, cloxacillin-resistance makes antimicrobial election more difficult. Other microorganisms, such as enterococci and some species of streptococci, show high rates of resistance to antimicrobial agents established in guidelines. Despite improvements in the diagnosis, and medical and surgical treatment of IE, this disease continues to be associated with high rates of in-hospital mortality. At present, due to epidemiological changes, antimicrobial prophylaxis can avoid few cases of IE. Prevention of nosocomial bacteremia, an early diagnosis of IE, prompt identification of IE patients at a higher risk of mortality, and a multidisciplinary approach of this disease could be valid strategies in order to improve the outcome of these patients. PMID- 22222059 TI - Open vs. robotic-assisted radical prostatectomy: a single surgeon and pathologist comparison of pathologic and oncologic outcomes. AB - OBJECTIVE: To compare the impact surgical technique has on clinicopathologic and oncologic outcomes among patients undergoing radical prostatectomy for clinically localized prostate cancer. MATERIALS AND METHODS: Utilizing the experience of a single surgeon and pathologist, a retrospective review of 1,041 patients undergoing open (RRP) and robotic-assisted (RALP) radical prostatectomy between 1999 and 2010 with pathologic evaluation using whole-mount sectioning techniques and tumor mapping was performed from our prospective database. Differences in the incidence, location, and linear length of positive surgical margins were compared. Additionally, rates of biochemical relapse-free survival according to technique were assessed. RESULTS: A total of 357 RRP and 669 RALP patients were evaluated. The overall incidence of surgical margin positivity when stratified by stage of disease and location of positive margins was nearly identical between groups for organ confined disease. The apex and posterior surfaces represented the 2 most common locations for positive margins. RALP had notably fewer positive margins in pathologic T3 disease and a statistically shorter linear length of margin positivity among all patients. Short and intermediate-term biochemical free survival rates were identical between groups. CONCLUSIONS: RALP is associated with operative oncologic control rates that compare very favorably to RRP. The data suggest that in the hands of an experienced surgeon, RALP has oncologic outcomes that are at least as good if not better than RRP. PMID- 22222060 TI - Cardiac metastasis from epidermoid esophageal cancer mimicking anterior myocardial infarction. AB - Cardiac metastases are more common than primary tumors. Several types of malignant tumors have been reported to metastasize to the heart, mainly lung cancer, but in the setting of esophageal cancer, myocardial metastasis is comparatively rare. We report a case of a cardiac metastasis from esophageal squamous cell carcinoma detected 9 months after surgically curative esophagectomy, which presented mimicking acute myocardial infarction. The use of different imaging modalities was fundamental to a correct diagnosis considering the challenging presentation. PMID- 22222061 TI - [Myocardial infarction after taking zolmitriptan]. AB - Zolmitriptan is a drug used in the acute treatment of migraine, which should not be used in high cardiovascular risk individuals because of its potential to induce vasospasm. We report a rare case of myocardial infarction precipitated by taking zolmitriptan. PMID- 22222062 TI - [Complications of endomyocardial biopsy after heart transplantation: a lesser evil]. AB - Endomyocardial biopsy is still the principal method for diagnosing cardiac allograft rejection. However, this procedure can be associated, albeit rarely, with potentially serious complications. We describe the case of a patient with extensive anterior myocardial infarction without revascularization, who developed cardiogenic shock and required heart transplantation. Post-transplantation, a coronary artery fistula to the right ventricle associated with an aneurysm and two restrictive ventricular septal defects were detected. PMID- 22222063 TI - Unusual type A aortic dissection. PMID- 22222064 TI - Listening to health workers: lessons from Eastern Uganda for strengthening the programme for the prevention of mother-to-child transmission of HIV. AB - BACKGROUND: The implementation and utilization of programmes for the prevention of mother-to-child transmission (PMTCT) of HIV in most low income countries has been described as sub-optimal. As planners and service providers, the views of health workers are important in generating priorities to improve the effectiveness of the PMTCT programme in Uganda. We explored the lessons learnt by health workers involved in the provision of PMTCT services in eastern Uganda to better understand what more needs to be done to strengthen the PMTCT programme. METHODS: A qualitative study was conducted at Mbale Regional Referral Hospital, The AIDS Support Organisation (TASO) Mbale and at eight neighbouring health centres in eastern Uganda, between January and May 2010. Data were collected through 24 individual interviews with the health workers involved in the PMTCT programme and four key informants (2 district officials and 2 officials from TASO). Data were analyzed using the content thematic approach. Study themes and sub-themes were identified following multiple reading of interview transcripts. Relevant quotations have been used in the presentation of study findings. RESULTS: The key lessons for programme improvement were: ensuring constant availability of critical PMTCT supplies, such as HIV testing kits, antiretroviral drugs (ARVs) for mothers and their babies, regular in-service training of health workers to keep them abreast with the rapidly changing knowledge and guidelines for PMTCT, ensuring that lower level health centres provide maternity services and ARVs for women in the PMTCT programme and provision of adequate facilities for effective follow-up and support for mothers. CONCLUSIONS: The voices of health workers in this study revealed that it is imperative for government, civil society organizations and donors that the PMTCT programme addresses the challenges of shortage of critical PMTCT supplies, continuous health worker training and follow-up and support for mothers as urgent needs to strengthen the PMTCT programme. PMID- 22222065 TI - [Three recurrent episodes of Tako-Tsubo cardiomyopathy precipitated by an emotional stressful event: a case report]. AB - Tako-Tsubo cardiomyopathy, first described in 1990 by Sato in Japan, has recently gained increasing consideration when reported in non-Japanese patients, including the United States and Europe. Typical presentation mimics acute coronary syndrome, with acute chest pain and/or dyspnoea, associated to electrocardiographic changes and moderate cardiac biomarkers release, but in which coronary angiography reveals no coronary arteries lesions and echocardiography or left ventriculography shows a reversible left ventricle systolic dysfunction. Prognosis is good, in contrast to acute coronary syndrome, provided that the patients survive the possible life-threatening acute presentation, with correction of the left ventricle systolic dysfunction within several days or weeks. As noted in several reviews, 3.5% to 10% of the patients have a recurrence during the first few years after the initial presentation. Here, we described a case of a 60-year-old female who had three episodes of Tako Tsubo always preceded by severe emotional stress suggesting a potential common etiopathogenesis. PMID- 22222066 TI - [A familial form of ventricular non compaction in a mother and two of his sons in St. Louis, Senegal]. AB - We report a familial form of ventricular non compaction in a mother and two of her sons. It was a young man of 25 years who presented with NYHA stage III dyspnea and a cough with bloody sputum. The clinical examination found left ventricular failure. The echocardiogram done showed left ventricular dilatation with large trabeculae separated by deep intertrabecular recesses in both ventricles suggestive of a non-biventricular compaction. It was possible to note from the family screening by echocardiography of the mother and half-brother a left ventricular non compaction while they were asymptomatic. Thus we concluded a familial form of ventricular non-compaction. This is the first familial case described in Senegal. PMID- 22222067 TI - Fabrication and characterization of silicon wire solar cells having ZnO nanorod antireflection coating on Al-doped ZnO seed layer. AB - In this study, we have fabricated and characterized the silicon [Si] wire solar cells with conformal ZnO nanorod antireflection coating [ARC] grown on a Al-doped ZnO [AZO] seed layer. Vertically aligned Si wire arrays were fabricated by electrochemical etching and, the p-n junction was prepared by spin-on dopant diffusion method. Hydrothermal growth of the ZnO nanorods was followed by AZO film deposition on high aspect ratio Si microwire arrays by atomic layer deposition [ALD]. The introduction of an ALD-deposited AZO film on Si wire arrays not only helps to create the ZnO nanorod arrays, but also has a strong impact on the reduction of surface recombination. The reflectance spectra show that ZnO nanorods were used as an efficient ARC to enhance light absorption by multiple scattering. Also, from the current-voltage results, we found that the combination of the AZO film and ZnO nanorods on Si wire solar cells leads to an increased power conversion efficiency by more than 27% compared to the cells without it. PMID- 22222069 TI - Is three better than two? The use of 3D scanners in the assessment of aesthetic results in local breast cancer treatment. PMID- 22222070 TI - Modeling of leishmaniasis infection dynamics: novel application to the design of effective therapies. AB - BACKGROUND: The WHO considers leishmaniasis as one of the six most important tropical diseases worldwide. It is caused by parasites of the genus Leishmania that are passed on to humans and animals by the phlebotomine sandfly. Despite all of the research, there is still a lack of understanding on the metabolism of the parasite and the progression of the disease. In this study, a mathematical model of disease progression was developed based on experimental data of clinical symptoms, immunological responses, and parasite load for Leishmania amazonensis in BALB/c mice. RESULTS: Four biologically significant variables were chosen to develop a differential equation model based on the GMA power-law formalism. Parameters were determined to minimize error in the model dynamics and time series experimental data. Subsequently, the model robustness was tested and the model predictions were verified by comparing them with experimental observations made in different experimental conditions. The model obtained helps to quantify relationships between the selected variables, leads to a better understanding of disease progression, and aids in the identification of crucial points for introducing therapeutic methods. CONCLUSIONS: Our model can be used to identify the biological factors that must be changed to minimize parasite load in the host body, and contributes to the design of effective therapies. PMID- 22222071 TI - Home monitoring for heart failure management. AB - With a prevalence of 5.8 million in the United States alone, heart failure (HF) is a common syndrome associated with substantial morbidity, mortality, and healthcare expenditures. Close to 1 million HF hospitalizations occur annually in the United States, with the majority of these resulting from worsening congestion in patients previously diagnosed with HF. An estimated $37.2 billion is spent each year on HF in the United States. These statistics emphasize the need to develop and implement more effective strategies to assess, monitor, and treat HF. It has also become increasingly apparent that interventions geared toward identifying and monitoring subclinical congestion would be of value in the home management of chronic HF. Earlier identification and treatment of congestion together with improved care coordination, management of comorbid conditions, and enhanced patient self-management may help to prevent hospitalizations in patients with chronic HF. Such home monitoring extends from the promotion of self-care and home visitations to telemedicine and remote monitoring of external or implantable devices. This paper discusses the challenges in monitoring patients with HF, reviews clinical trials testing different monitoring strategies in HF, and highlights ongoing investigations into the optimal approaches to home monitoring for HF. PMID- 22222072 TI - Percutaneous coronary intervention and drug-eluting stent use among patients >=85 years of age in the United States. AB - OBJECTIVES: This study assessed the comparative effectiveness of drug-eluting stents (DES) versus bare-metal stents (BMS) among patients >=85 years of age. BACKGROUND: Despite an aging population, little is known about the comparative effectiveness of DES versus BMS among patients age >=85 years undergoing percutaneous coronary intervention (PCI). METHODS: We examined 471,006 PCI patients age >=65 years at 947 hospitals in the National Cardiovascular Data Registry between 2004 and 2008 and linked to Medicare claims data. Long-term outcomes (median follow-up 640.8 +/- 423.5 days) were compared between users of DES and BMS. RESULTS: Patients age >=85 years comprise an increasing proportion of PCIs performed among elderly subjects, yet rates of DES use declined the most in this age group. Compared with BMS, use of DES was associated with lower mortality: age >=85 years, 29% versus 38% (adjusted hazard ratio [HR]: 0.80 [95% confidence interval (CI): 0.77 to 0.83]); age 75 to 84 years, 17% versus 25% (HR: 0.77 [95% CI: 0.75 to 0.79]); and age 65 to 74 years, 10% versus 16% (HR: 0.73 [95% CI: 0.71 to 0.75]). However, the adjusted mortality difference narrowed with increasing age (p(interaction) <0.001). In contrast, the adjusted HR for myocardial infarction rehospitalization associated with DES use was significantly lower with increasing age: age >=85 years, 9% versus 12% (HR: 0.77 [95% CI: 0.71 to 0.83]); age 75 to 84 years, 7% versus 9% (HR: 0.81 [95% CI: 0.77 to 0.84]); and age 65 to 74 years, 7% versus 8% (HR: 0.84 [95% CI: 0.80 to 0.88]) (p(interaction) <0.001). CONCLUSIONS: In this national study of older patients undergoing PCI, declines in DES use were most pronounced among those aged >=85 years, yet lower adverse-event rates associated with DES versus BMS use were observed. PMID- 22222073 TI - Percutaneous aortic valve replacement: vascular outcomes with a fully percutaneous procedure. AB - OBJECTIVES: The aim of this study was to evaluate vascular complications in a consecutive patient population undergoing transfemoral percutaneous aortic valve replacement (PAVR) applying current Valve Academic Research Consortium definitions. BACKGROUND: Vascular complications have been the major cause of mortality and morbidity associated with PAVR. Both open surgical and fully percutaneous access site strategies have been advocated. METHODS: All patients undergoing transfemoral PAVR during fiscal years 2009 and 2010 were prospectively evaluated at baseline, after the procedure, and at 30 days. RESULTS: PAVR was performed in 137 consecutive patients. All but 1 patient underwent planned arteriotomy closure using a percutaneous pre-closure technique. Smaller sheaths, rigorous angiographic and computed tomographic screening and patient selection, and percutaneous vascular repair techniques were increasingly used over this period. From 2009 to 2010, major vascular complications decreased from 8% to 1% (p = 0.06), minor vascular complications decreased from 24% to 8% (p < 0.01), major bleeds fell from 14% to 1% (p < 0.01), and unplanned surgery decreased from 28% to 2% (p < 0.01). A minimal artery diameter smaller than the external sheath diameter, moderate or severe calcification, and peripheral vascular disease were associated with higher vascular complication rates. CONCLUSIONS: Vascular complications occur more often if the minimal artery diameter is smaller than the external sheath diameter, in the presence of moderate or severe calcification, and in patients with peripheral vascular disease. With careful patient selection, advanced interventional techniques, and a fully percutaneous procedure, marked reductions in vascular and bleeding complications can be achieved. PMID- 22222074 TI - Deformation dynamics and mechanical properties of the aortic annulus by 4 dimensional computed tomography: insights into the functional anatomy of the aortic valve complex and implications for transcatheter aortic valve therapy. AB - OBJECTIVES: The purpose of this study was to assess deformation dynamics and in vivo mechanical properties of the aortic annulus throughout the cardiac cycle. BACKGROUND: Understanding dynamic aspects of functional aortic valve anatomy is important for beating-heart transcatheter aortic valve implantation. METHODS: Thirty-five patients with aortic stenosis and 11 normal subjects underwent 256 slice computed tomography. The aortic annulus plane was reconstructed in 10% increments over the cardiac cycle. For each phase, minimum diameter, ellipticity index, cross-sectional area (CSA), and perimeter (Perim) were measured. In a subset of 10 patients, Young's elastic module was calculated from the stress strain relationship of the annulus. RESULTS: In both subjects with normal and with calcified aortic valves, minimum diameter increased in systole (12.3 +/- 7.3% and 9.8 +/- 3.4%, respectively; p < 0.001), and ellipticity index decreased (12.7 +/- 8.8% and 10.3 +/- 2.7%, respectively; p < 0.001). The CSA increased by 11.2 +/- 5.4% and 6.2 +/- 4.8%, respectively (p < 0.001). Perim increase was negligible in patients with calcified valves (0.56 +/- 0.85%; p < 0.001) and small even in normal subjects (2.2 +/- 2.2%; p = 0.01). Accordingly, relative percentage differences between maximum and minimum values were significantly smallest for Perim compared with all other parameters. Young's modulus was calculated as 22.6 +/- 9.2 MPa in patients and 13.8 +/- 6.4 MPa in normal subjects. CONCLUSIONS: The aortic annulus, generally elliptic, assumes a more round shape in systole, thus increasing CSA without substantial change in perimeter. Perimeter changes are negligible in patients with calcified valves, because tissue properties allow very little expansion. Aortic annulus perimeter appears therefore ideally suited for accurate sizing in transcatheter aortic valve implantation. PMID- 22222075 TI - Optimizing transcatheter aortic valve sizing and minimizing vascular complications. PMID- 22222076 TI - Acute and 12-month results with catheter-based mitral valve leaflet repair: the EVEREST II (Endovascular Valve Edge-to-Edge Repair) High Risk Study. AB - OBJECTIVES: The EVEREST II (Endovascular Valve Edge-to-Edge Repair) High Risk Study (HRS) assessed the safety and effectiveness of the MitraClip device (Abbott Vascular, Santa Clara, California) in patients with significant mitral regurgitation (MR) at high risk of surgical mortality rate. BACKGROUND: Patients with severe MR (3 to 4+) at high risk of surgery may benefit from percutaneous mitral leaflet repair, a potentially safer approach to reduce MR. METHODS: Patients with severe symptomatic MR and an estimated surgical mortality rate of >=12% were enrolled. A comparator group of patients screened concurrently but not enrolled were identified retrospectively and consented to compare survival in patients treated by standard care. RESULTS: Seventy-eight patients underwent the MitraClip procedure. Their mean age was 77 years, >50% had previous cardiac surgery, and 46 had functional MR and 32 degenerative MR. MitraClip devices were successfully placed in 96% of patients. Protocol-predicted surgical mortality rate in the HRS and concurrent comparator group was 18.2% and 17.4%, respectively, and Society of Thoracic Surgeons calculator estimated mortality rate was 14.2% and 14.9%, respectively. The 30-day procedure-related mortality rate was 7.7% in the HRS and 8.3% in the comparator group (p = NS). The 12-month survival rate was 76% in the HRS and 55% in the concurrent comparator group (p = 0.047). In surviving patients with matched baseline and 12-month data, 78% had an MR grade of <=2+. Left ventricular end-diastolic volume improved from 172 ml to 140 ml and end-systolic volume improved from 82 ml to 73 ml (both p = 0.001). New York Heart Association functional class improved from III/IV at baseline in 89% to class I/II in 74% (p < 0.0001). Quality of life was improved (Short Form-36 physical component score increased from 32.1 to 36.1 [p = 0.014] and the mental component score from 45.5 to 48.7 [p = 0.065]) at 12 months. The annual rate of hospitalization for congestive heart failure in surviving patients with matched data decreased from 0.59 to 0.32 (p = 0.034). CONCLUSIONS: The MitraClip device reduced MR in a majority of patients deemed at high risk of surgery, resulting in improvement in clinical symptoms and significant left ventricular reverse remodeling over 12 months. (Pivotal Study of a Percutaneous Mitral Valve Repair System [EVEREST II]; NCT00209274). PMID- 22222077 TI - An option for the high-comorbidity patient with mitral regurgitation. PMID- 22222078 TI - Procedural complications, rehospitalizations, and repeat procedures after catheter ablation for atrial fibrillation. AB - OBJECTIVES: The purpose of this study was to estimate rates and identify predictors of inpatient complications and 30-day readmissions, as well as repeat hospitalization rates for arrhythmia recurrence following atrial fibrillation (AF) ablation. BACKGROUND: AF is the most common clinically significant arrhythmia and is associated with increased morbidity and mortality. Radiofrequency or cryotherapy ablation of AF is a relatively new treatment option, and data on post-procedural outcomes in large general populations are limited. METHODS: Using data from the California State Inpatient Database, we identified all adult patients who underwent their first AF ablation from 2005 to 2008. We used multivariable logistic regression to identify predictors of complications and/or 30-day readmissions and Kaplan-Meier analyses to estimate rates of all-cause and arrhythmia readmissions. RESULTS: Among 4,156 patients who underwent an initial AF ablation, 5% had periprocedural complications, most commonly vascular, and 9% were readmitted within 30 days. Older age, female, prior AF hospitalizations, and less hospital experience with AF ablation were associated with higher adjusted risk of complications and/or 30-day readmissions. The rate of all-cause hospitalization was 38.5% by 1 year. The rate of readmission for recurrent AF, atrial flutter, and/or repeat ablation was 21.7% by 1 year and 29.6% by 2 years. CONCLUSIONS: Periprocedural complications occurred in 1 of 20 patients undergoing AF ablation, and all-cause and arrhythmia-related rehospitalizations were common. Older age, female sex, prior AF hospitalizations, and recent hospital procedure experience were associated with a higher risk of complications and/or 30-day readmission after AF ablation. PMID- 22222079 TI - Atrial fibrillation ablation in the real world. PMID- 22222081 TI - Monocytes on the scar's edge. PMID- 22222082 TI - Isolated left ventricular diverticulum in an adult patient presenting with acute coronary syndrome. PMID- 22222080 TI - PET/MRI of inflammation in myocardial infarction. AB - OBJECTIVES: The aim of this study was to explore post-myocardial infarction (MI) myocardial inflammation. BACKGROUND: Innate immune cells are centrally involved in infarct healing and are emerging therapeutic targets in cardiovascular disease; however, clinical tools to assess their presence in tissue are scarce. Furthermore, it is currently not known if the nonischemic remote zone recruits monocytes. METHODS: Acute inflammation was followed in mice with coronary ligation by 18-fluorodeoxyglucose ((18)FDG) positron emission tomography/magnetic resonance imaging, fluorescence-activated cell sorting, polymerase chain reaction, and histology. RESULTS: Gd-DTPA-enhanced infarcts showed high (18)FDG uptake on day 5 after MI. Cell depletion and isolation data confirmed that this largely reflected inflammation; CD11b(+) cells had 4-fold higher (18)FDG uptake than the infarct tissue from which they were isolated (p < 0.01). Surprisingly, there was considerable monocyte recruitment in the remote myocardium (approximately 10(4)/mg of myocardium, 5.6-fold increase; p < 0.01), a finding mirrored by macrophage infiltration in the remote myocardium of patients with acute MI. Temporal kinetics of cell recruitment were slower than in the infarct, with peak numbers on day 10 after ischemia. Quantitative polymerase chain reaction showed a robust increase of recruiting adhesion molecules and chemokines in the remote myocardium (e.g., 12-fold increase of monocyte chemoattractant protein-1), although levels were always lower than in the infarct. Finally, matrix metalloproteinase activity was significantly increased in noninfarcted myocardium, suggesting that monocyte recruitment to the remote zone may contribute to post-MI dilation. CONCLUSIONS: This study shed light on the innate inflammatory response in remote myocardium after MI. PMID- 22222083 TI - Real-time magnetic resonance imaging-guided transarterial aortic valve implantation: in vivo evaluation in swine. PMID- 22222084 TI - Relationship between Sprint Fidelis leads and patient mortality. PMID- 22222085 TI - The ATRIA risk scheme to predict warfarin-associated hemorrhage not ready for clinical use. PMID- 22222087 TI - Dynamic variation of transmitral mid-diastolic flow in constrictive pericarditis. PMID- 22222088 TI - Tricuspid valve replacement through a left atriotomy and transseptal approach in a congenitally malformed heart. AB - More and more children with congenital heart disease are surviving into adulthood. These patients are forcing adult congenital cardiac surgeons to develop innovative approaches to correct their complex anatomy and physiology. This report describes a patient with a congenitally malformed heart necessitating a novel approach to access the tricuspid valve--a left atriotomy and transseptal incision. Three-dimensional preoperative imaging allowed for successful surgical planning. PMID- 22222089 TI - ABrowse--a customizable next-generation genome browser framework. AB - BACKGROUND: With the rapid growth of genome sequencing projects, genome browser is becoming indispensable, not only as a visualization system but also as an interactive platform to support open data access and collaborative work. Thus a customizable genome browser framework with rich functions and flexible configuration is needed to facilitate various genome research projects. RESULTS: Based on next-generation web technologies, we have developed a general-purpose genome browser framework ABrowse which provides interactive browsing experience, open data access and collaborative work support. By supporting Google-map-like smooth navigation, ABrowse offers end users highly interactive browsing experience. To facilitate further data analysis, multiple data access approaches are supported for external platforms to retrieve data from ABrowse. To promote collaborative work, an online user-space is provided for end users to create, store and share comments, annotations and landmarks. For data providers, ABrowse is highly customizable and configurable. The framework provides a set of utilities to import annotation data conveniently. To build ABrowse on existing annotation databases, data providers could specify SQL statements according to database schema. And customized pages for detailed information display of annotation entries could be easily plugged in. For developers, new drawing strategies could be integrated into ABrowse for new types of annotation data. In addition, standard web service is provided for data retrieval remotely, providing underlying machine-oriented programming interface for open data access. CONCLUSIONS: ABrowse framework is valuable for end users, data providers and developers by providing rich user functions and flexible customization approaches. The source code is published under GNU Lesser General Public License v3.0 and is accessible at http://www.abrowse.org/. To demonstrate all the features of ABrowse, a live demo for Arabidopsis thaliana genome has been built at http://arabidopsis.cbi.edu.cn/. PMID- 22222090 TI - Enrichment of the inositol 1,4,5-trisphosphate receptor/Ca2+ channels in secretory granules and essential roles of chromogranins. AB - The high capacity, low affinity Ca(2+) storage protein chromogranins are marker proteins of secretory granules that contain the most Ca(2+) in secretory cells. Along with the abundantly expressed chromogranins, the IP(3)R/Ca(2+) channels, the major intracellular Ca(2+) channels, are also expressed in secretory granules the most. Chromogranins not only induce formation of secretory granules but also are suggested to produce the small IP(3)-sensitive nucleoplasmic Ca(2+) store vesicles in the nucleus. Chromogranins A (CGA) and B (CGB) also directly bind the IP(3)Rs and activate the IP(3)R/Ca(2+) channels at the intragranular pH 5.5. But at a near physiological pH 7.5 only CGB interacts with the IP(3)Rs due to stronger interaction of CGB for the IP(3)Rs, which is several orders of magnitude stronger than that of CGA, and activates the IP(3)R/Ca(2+) channels. Therefore, the CGB-IP(3)R coupling is proposed to play key roles in the IP(3)-mediated Ca(2+) signaling mechanisms in the cytoplasm through both secretory granules and the ER, and in the nucleus through the small IP(3)-sensitive nucleoplasmic Ca(2+) store vesicles. Chromogranin B is further suggested to participate in transcription control and to target secretory granule components, including the IP(3)Rs, to newly formed secretory granules. Defects in secretory granule-related functions are directly linked to major human diseases such as Alzheimer's disease, secretory cell cancers, cystic fibrosis, acute pancreatitis, and cardiac hypertrophy. Therefore, realization of secretory granules as the major intracellular Ca(2+) storage and control organelle in secretory cells promises to open new horizon in understanding the Ca(2+) storage, signaling, and control mechanisms throughout the biokingdom. PMID- 22222091 TI - Vesicular Ca(2+) mediates granule motion and exocytosis. AB - Secretory vesicles of chromaffin cells are acidic organelles that maintain an increasing pH gradient towards the cytosol (5.5 vs. 7.3) that is mediated by V ATPase activity. This gradient is primarily responsible for the accumulation of large concentrations of amines and Ca(2+), although the mechanisms mediating Ca(2+) uptake and release from granules, and the physiological relevance of these processes, remain unclear. The presence of a vesicular matrix appears to create a bi-compartmentalised medium in which the major fractions of solutes, including catecholamines, nucleotides and Ca(2+), are strongly associated with vesicle proteins, particularly chromogranins. This association appears to be favoured at acidic pH values. It has been demonstrated that disrupting the pH gradient of secretory vesicles reduces their rate of exocytosis and promotes the leakage of vesicular amines and Ca(2+), dramatically increasing the movement of secretory vesicles and triggering exocytosis. In this short review, we will discuss the data available that highlights the importance of pH in regulating the association between chromogranins, vesicular amines and Ca(2+). We will also address the potential role of vesicular Ca(2+) in two major processes in secretory cells, vesicle movement and exocytosis. PMID- 22222092 TI - Cross sectional study of Australian midwives knowledge and use of sterile water injections for pain relief in labour. AB - BACKGROUND: The effectiveness of sterile water injections (SWI) to relieve back pain in labour is supported by a number of randomised controlled trials. Although the procedure is available in a number of Australian maternity units, there is no information regarding the use of SWI by midwives, in terms of knowledge and availability, clinical application or technique used. Neither is there any data on midwives who do not use SWI nor the specific challengers and barriers encountered by midwives introducing SWI. METHOD: An invitation to participate in an online survey was emailed to 4700 members of the Australian College of Midwives (ACM) and 484 members of CRANAplus (Remote Health Organisation). Nine hundred and seventy midwives completed the survey (19%). RESULTS: Four hundred and seven (42.5%) midwives currently used SWI in their practice and five hundred and fifty-one (57.5%) indicated they did not. Eighty-six percent (n=478/548) indicated they would consider using SWI and 90% (n=500/547) were interested in obtaining further information about SWI. The main reasons cited for not using SWI was the lack of a policy or guideline (n=271, 57.5%) and being unable to access workshops or resource material (n=68, 14.4%). CONCLUSION: This study indicates that SWI is not being used by the majority of midwives participating in the study, although there is a strong desire by midwives to learn about and explore its use. Greater access to information and workshops on SWI is highlighted. In response to the findings of this survey the authors are currently developing an online resource and training to support units to introduce SWI. PMID- 22222093 TI - Effect of HLA DR epitope de-immunization of Factor VIII in vitro and in vivo. AB - T cell-dependent development of anti-Factor VIII (FVIII) antibodies that neutralize FVIII activity is a major obstacle to replacement therapy in hemophilia A. To create a less immunogenic therapeutic protein, recombinant FVIII can be modified to reduce HLA binding of epitopes based on predicted anchoring residues. Here, we used immunoinformatic tools to identify C2 domain HLA DR epitopes and predict site-specific mutations that reduce immunogenicity. Epitope peptides corresponding to original and modified sequences were validated in HLA binding assays and in immunizations of hemophilic E16 mice, DR3 and DR4 mice and DR3*E16 mice. Consistent with immunoinformatic predictions, original epitopes are immunogenic. Immunization with selected modified sequences lowered immunogenicity for particular peptides and revealed residual immunogenicity of incompletely de immunized modified peptides. The stepwise approach to reduce protein immunogenicity by epitope modification illustrated here is being used to design and produce a functional full-length modified FVIII for clinical use. PMID- 22222094 TI - In vitro expansion and functional recovery of mature hepatocytes from mouse adult liver. AB - BACKGROUND: Mature hepatocytes retain the ability to regenerate the liver lobule fully in vivo following injury. Several cytokines and soluble factors (hepatocyte growth factors, epidermal growth factors, insulin and nicotinamide) are known to be important for proliferation of mature hepatocytes in vitro. However, hepatocytes monolayer-cultured on extracellular matrices have gradually lost their specific functions, particularly those in drug metabolism. AIM: We have explored and established a new culture system for expansion of functional hepatocytes. METHODS: We evaluated two approaches for efficient expansion of mature hepatocytes: (i) Co-culture with mouse embryonic fibroblasts (MEF); (ii) Addition to culture of inhibitors of cell signals involved in liver regeneration. After expansion steps, 3-dimensional spheroid-forming culture was used to re induce mature hepatocellular function. RESULTS: The addition of inhibitors for tumour growth factor (TGF) beta and glycogen synthase kinase (GSK) 3beta efficiently induced in vitro expansion of mature hepatocytes. Although expression of hepatocellular functional genes decreased after expansion in monolayer culture, their expression and the activity of cytochrome P450 enzymes significantly increased with spheroid formation. Furthermore, when hepatocytes were co-cultured with MEF, addition of a MAPK/ERK kinase (MEK) inhibitor at the spheroid formation step enhanced drug-metabolism-related gene expression. CONCLUSION: Combination of the MEF co-culture system with the addition of inhibitors of TGFbeta and GSK3beta induced in vitro expansion of hepatocytes. Moreover, expression of mature hepatocellular genes and the activity of drug metabolism enzymes in expanded hepatocytes were re-induced after spheroid culture. PMID- 22222095 TI - Preparation of TiO2 nanotube/nanoparticle composite particles and their applications in dye-sensitized solar cells. AB - Efficiency of dye-sensitized solar cells [DSSCs] was enhanced by combining the use of TiO2 nanotubes [TNTs] and nanoparticles. TNTs were fabricated by a sol-gel method, and TiO2 powders were produced through an alkali hydrothermal transformation. DSSCs were constructed using TNTs and TiO2 nanoparticles at various weight percentages. TNTs and TiO2 nanoparticles were coated onto FTO glass by the screen printing method. The DSSCs were fabricated using ruthenium(II) (N-719) and electrolyte (I3/I3-) dyes. The crystalline structure and morphology were characterized by X-ray diffraction and using a scanning electron microscope. The absorption spectra were measured using an UV-Vis spectrometer. The incident photocurrent conversion efficiency was measured using a solar simulator (100 mW/cm2). The DSSCs based on TNT/TiO2 nanoparticle hybrids showed better photovoltaic performance than cells made purely of TiO2 nanoparticles. PMID- 22222096 TI - Behavior of NiTiNb SMA wires under recovery stress or prestressing. AB - The recovery stress of martensitic shape-memory alloy [SMA] wires can be used to confine concrete, and the confining effectiveness of the SMA wires was previously proved through experimental tests. However, the behavior of SMA wires under recovery stress has not been seriously investigated. Thus, this study conducted a series of tests of NiTiNb martensitic SMA wires under recovery stress with varying degrees of prestrain on the wires and compared the behavior under recovery stress with that under prestressing of the wires. The remaining stress was reduced by the procedure of additional strain loading and unloading. More additional strains reduced more remaining stresses. When the SMA wires were heated up to the transformation temperature under prestress, the stress on the wires increased due to the state transformation. Furthermore, the stress decreased with a decreasing temperature of the wires down to room temperature. The stress of the NiTiNb wires was higher than the prestress, and the developed stress seemed to depend on the composition of the SMAs. When an additional strain was subsequently loaded and unloaded on the prestressed SMA wires, the remaining stress decreased. Finally, the remaining stress becomes zero when loading and unloading a specific large strain. PMID- 22222097 TI - Facile synthesis of nano-Li4 Ti5O12 for high-rate Li-ion battery anodes. AB - One of the most promising anode materials for Li-ion batteries, Li4Ti5O12, has attracted attention because it is a zero-strain Li insertion host having a stable insertion potential. In this study, we suggest two different synthetic processes to prepare Li4Ti5O12 using anatase TiO2 nanoprecursors. TiO2 powders, which have extraordinarily large surface areas of more than 250 m2 g-1, were initially prepared through the urea-forced hydrolysis/precipitation route below 100 degrees C. For the synthesis of Li4Ti5O12, LiOH and Li2CO3 were added to TiO2 solutions prepared in water and ethanol media, respectively. The powders were subsequently dried and calcined at various temperatures. The phase and morphological transitions from TiO2 to Li4Ti5O12 were characterized using X-ray powder diffraction and transmission electron microscopy. The electrochemical performance of nanosized Li4Ti5O12 was evaluated in detail by cyclic voltammetry and galvanostatic cycling. Furthermore, the high-rate performance and long-term cycle stability of Li4Ti5O12 anodes for use in Li-ion batteries were discussed. PMID- 22222098 TI - IVSPlat 1.0: an integrated virtual screening platform with a molecular graphical interface. AB - BACKGROUND: The virtual screening (VS) of lead compounds using molecular docking and pharmacophore detection is now an important tool in drug discovery. VS tasks typically require a combination of several software tools and a molecular graphics system. Thus, the integration of all the requisite tools in a single operating environment could reduce the complexity of running VS experiments. However, only a few freely available integrated software platforms have been developed. RESULTS: A free open-source platform, IVSPlat 1.0, was developed in this study for the management and automation of VS tasks. We integrated several VS-related programs into a molecular graphics system to provide a comprehensive platform for the solution of VS tasks based on molecular docking, pharmacophore detection, and a combination of both methods. This tool can be used to visualize intermediate and final results of the VS execution, while also providing a clustering tool for the analysis of VS results. A case study was conducted to demonstrate the applicability of this platform. CONCLUSIONS: IVSPlat 1.0 provides a plug-in-based solution for the management, automation, and visualization of VS tasks. IVSPlat 1.0 is an open framework that allows the integration of extra software to extend its functionality and modified versions can be freely distributed. The open source code and documentation are available at http://kyc.nenu.edu.cn/IVSPlat/. PMID- 22222099 TI - Low-temperature synthesis of LiFePO4 nanocrystals by solvothermal route. AB - LiFePO4 nanocrystals were synthesized at a very low temperature of 170 degrees C using carbon nanoparticles by a solvothermal process in a polyol medium, namely diethylene glycol without any heat treatment as a post procedure. The powder X ray diffraction pattern of the LiFePO4 was indexed well to a pure orthorhombic system of olivine structure (space group: Pnma) with no undesirable impurities. The LiFePO4 nanocrystals synthesized at low temperature exhibited mono-dispersed and carbon-mixed plate-type LiFePO4 nanoparticles with average length, width, and thickness of approximately 100 to 300 nm, 100 to 200 nm, and 50 nm, respectively. It also appeared to reveal considerably enhanced electrochemical properties when compared to those of pristine LiFePO4. These observed results clearly indicate the effect of carbon in improving the reactivity and synthesis of LiFePO4 nanoparticles at a significantly lower temperature. PMID- 22222100 TI - Using a patient-centered approach to develop a fertility preservation brochure for pediatric oncology patients: a pilot study. AB - STUDY OBJECTIVES: Most pediatric education materials are designed for a parent audience. Social marketing techniques rely on the principles called the "4 P's": product, price, place, and promotion. The objective of this study was to test the design, readability, likelihood to read, and overall opinion of a pediatric fertility preservation brochure with patients, parents, and providers. DESIGN: Qualitative face-to-face interviews. SETTING: The Children's Cancer Center in Tampa, FL, and All Children's Hospital in St. Petersburg, FL. PARTICIPANTS: Male and female cancer patients and survivors aged 12-21 (N = 7), their parents (N = 11), and healthcare providers (N = 6). INTERVENTIONS: Patients, survivors, parents, and healthcare providers were given two versions of gender concordant brochures on fertility preservation designed for both pediatric oncology patients and their parents. OUTCOME MEASURES: Design, readability, likelihood to read, and overall opinion from interviews in order to identify facilitators of involving patients in fertility preservation discussions. RESULTS: Parents and teens differed on the design, readability, and likelihood to read, the highest discord being preferences for medical terminology used in the brochures. While parents remarked that much of the language was 'too advanced,' the majority of teens explained that they understood the terminology and preferred it remained on the brochure. Overall feedback from all three groups was utilized to revise the brochures into final versions to increase the likelihood of reading. CONCLUSION: Information about the development of the 4 P's of social marketing highlights needs from the intended audience. Barriers to patient education in pediatrics can be ameliorated when using the social marketing approach. PMID- 22222101 TI - The effectiveness of glucose in reducing needle-related procedural pain in infants. AB - This systematic review examined the effectiveness of glucose in relieving needle associated pain in infants. Meta-analysis was not undertaken, and there was variation in dose, administration method, concentration, and outcome measurement. Glucose was more effective than placebo in relieving infant pain as measured by behavioral outcomes, but there were mixed findings for physiological outcomes. Based on these findings, 25%-50% glucose appears effective for infant pain management. PMID- 22222103 TI - Time changes for scheduled nursing assessments: impact on clinical decisions and patient discharge. AB - Using a shared governance model, a clinical nursing practice change was implemented to increase collaborative decision making among health care providers at morning rounds. The goal of this project was to improve nursing workflow at the beginning of the shift and improve patient flow by discharging patients earlier. By changing the time of morning vital signs and nursing assessments from 0800 to 0600, staff reported increased collaboration among the multidisciplinary team and improved nursing workflow. PMID- 22222102 TI - Effect of peak flow monitoring on child asthma quality of life. AB - The purpose of this study was to evaluate the effect of peak flow monitoring on asthma quality of life (QOL) for school-age children with asthma (N = 77) who participated in a 16-week asthma self-management program. QOL was measured using the Children's Health Survey for Asthma. Findings indicated significant improvement in asthma QOL from baseline to Week 16 and higher QOL scores for those with better asthma health outcomes. PMID- 22222104 TI - Parental perceptions of sibling relationships in families rearing a child with a chronic condition. AB - This study examined sibling relationships in families raising children with autism, Down syndrome, orthopedic conditions, and diabetes. Parents from 108 families independently completed the 28-item Schaefer Sibling Inventory of Behavior. Parents rated siblings as very empathetic, fairly often kind and involved, and rarely avoidant. Mothers rated sibling empathy higher than fathers did and older siblings more avoidant than younger siblings. Fathers rated male siblings kinder than female siblings; they also rated siblings of children with Down syndrome or autism more kind and involved than siblings of children with orthopedic conditions or diabetes. Sibling intervention efforts should consider these findings and be individualized according to the need of each child and family. PMID- 22222105 TI - Age-appropriate health promotion education: roots firmly established in baccalaureate nursing pediatric rotation. AB - The Essentials of Baccalaureate Education for Professional Nursing Practice [American Association of Colleges of Nursing. (2008, October 8). Retrieved September 11, 2009, from http://www.aacn.nche.edu/Education/pdf/BaccEssentials08.pdf] addresses the importance of health promotion at the individual level across the lifespan to effect optimal population health. This qualitative study explores senior baccalaureate nursing students' perceptions (n = 85) of the teaching and learning experience related to health promotion during their pediatric clinical rotation. Four distinct learning factors of student, client, learning process, and subject matter emerged. Knowledge was enhanced, and students identified that the format of presentation influenced the quality of participant learning. Students' perception of the importance of patient and family teaching evolved over the course of the semester and highlights the importance of providing students with the tools necessary to be effective teachers and change agents to promote healthy behaviors across the lifespan. Fink's Taxonomy of Significant Learning can be applied to facilitate integrated course design for a pediatric baccalaureate nursing curriculum. PMID- 22222106 TI - Tracheal suctioning in children with chronic tracheostomies: a pilot study applying suction both while inserting and removing the catheter. AB - This pilot study compared two methods of tracheal suctioning in the same 18 children with chronic tracheostomies. Use of the American Thoracic Society (ATS) recommendations resulted in a significant increase in secretions obtained (t = 3.96; p = .001) when compared with traditional practice. The ATS-recommended method was also more efficient in children with secretions. When used first, no additional secretions were obtained after 90 minutes using the traditional method. Additional secretions were obtained with the ATS-recommended method when the traditional method was used first. Heart rate and oxygen saturation immediately and 1 minute after suctioning were not significantly different between methods. PMID- 22222107 TI - Emotional needs of teens with polycystic ovary syndrome. AB - Teens with polycystic ovary syndrome have serious health issues that impact them on multiple levels-hormonal concerns affecting female health and fertility, disfiguring body changes causing self-image problems, and lifelong health consequences related to metabolic disorders. Health care providers are now beginning to understand underlying pathophysiologic processes and make earlier diagnoses in the 6%-10% of teens with this disorder. However, the profound psychological and social needs are often inadequately recognized by health care providers, causing many teens turn to peers and the Internet for guidance and support. More research is needed to identify and address the emotional aspects of this common disorder in healthcare settings. PMID- 22222108 TI - Impact of online support for youth with asthma and allergies: pilot study. AB - Youth with asthma and allergies often feel isolated and different from their peers. The objective of this study was to test the impact of online social support for these youth. Three months of support was provided using weekly synchronous chat sessions. Online sessions were facilitated by trained peer mentors (older youth with asthma and/or allergies) and health professionals. Youth could also e-mail one another between chat sessions and post messages on an electronic community bulletin board. Twenty-eight adolescents across Canada participated. Social isolation and loneliness were significantly reduced. Youth reported gaining confidence and a sense of normality. PMID- 22222109 TI - Integrating the synergy model for patient care at children's hospital of Wisconsin. AB - The Synergy Model for Patient Care is a framework for professional nursing practice that emphasizes the unique relationship between patients and clinicians, which can result in optimal outcomes for both. Integrating this model into contemporary nursing practice at a freestanding children's hospital was accomplished by "backing into the model" and developing the "tools" that encompassed both the patient characteristics and the clinician competencies. In addition to creative educational activities for the staff, leadership support and communication strategies were paramount to effective implementation. PMID- 22222110 TI - Review of the effects of dilution of dietary energy with olestra on energy intake. AB - The non-absorbable substitute for dietary triacylglycerol, olestra, has been marketed in the United States for fifteen years. Olestra is comprised of sucrose with six to eight of its hydroxyl groups forming ester links with long-chain fatty acids. Because olestra is not hydrolyzed by fat-splitting enzymes in the small intestine, it is not absorbed from the small intestine into blood and tissues, and therefore provides no energy that can be utilized by the body. The hedonic properties of olestra with a specific fatty acid composition are similar to those of a triacylglycerol with the same fatty acid composition. Its use by consumers has been restricted by federal regulation to the commercial preparation of savory snack food items, principally as a frying medium for potato chips. An important question about the substitution of olestra for absorbable fat in the diet is whether the consumer will sense that a smaller amount of energy has been ingested. If it is sensed, thereby providing no satiation, then consuming additional energy in later meals will compensate for the removal of absorbable energy from the diet. If it is not sensed at all, then there is no compensation, and the person reduces caloric intake. This review first summarizes studies with olestra that have focused on its effect on the physiology of appetite. In general these studies have demonstrated that olestra does not influence signals of satiation including cholecystokinin and stomach emptying. The review then discusses studies of food consumption in experimental animals in which olestra was substituted for fat in the diet. Rodents have been repeatedly observed to compensate completely for the substitution of olestra for normal fat by eating more total diet. Most studies of the effect of olestra on human satiation have found incomplete or no compensation through additional energy consumption when olestra was substituted for dietary fat. In two clinical studies, however, complete compensation was observed, suggesting that experimental conditions and individual variability influence the ability to sense the substitution of olestra for absorbable fat. There is no evidence that dietary olestra causes consumption of more energy than would have been consumed without olestra in the diet. The data from animals and humans strongly suggest that the rodent is not a satisfactory model for the human in the determination of the extent of compensation by substitution of olestra for dietary fat. PMID- 22222111 TI - The new pLAI (lux regulon based auto-inducible) expression system for recombinant protein production in Escherichia coli. AB - BACKGROUND: After many years of intensive research, it is generally assumed that no universal expression system can exist for high-level production of a given recombinant protein. Among the different expression systems, the inducible systems are the most popular for their tight regulation. However, induction is in many cases less favorable due to the high cost and/or toxicity of inducers, incompatibilities with industrial scale-up or detrimental growth conditions. Expression systems using autoinduction (or self-induction) prove to be extremely versatile allowing growth and induction of recombinant proteins without the need to monitor cell density or add inducer. Unfortunately, almost all the actual auto inducible expression systems need endogenous or induced metabolic changes during the growth to trigger induction, both frequently linked to detrimental condition to cell growth. In this context, we use a simple modular approach for a cell density-based genetic regulation in order to assemble an autoinducible recombinant protein expression system in E. coli. RESULT: The newly designed pLAI expression system places the expression of recombinant proteins in Escherichia coli under control of the regulatory genes of the lux regulon of Vibrio fischeri's Quorum Sensing (QS) system.The pLAI system allows a tight regulation of the recombinant gene allowing a negligible basal expression and expression only at high cell density. Sequence optimization of regulative genes of QS of V. fischeri for expression in E. coli upgraded the system to high level expression. Moreover, partition of regulative genes between the plasmid and the host genome and introduction of a molecular safety lock permitted tighter control of gene expression. CONCLUSION: Coupling gene expression to cell density using cell-to cell communication provides a promising approach for recombinant protein production. The system allows the control of expression of the target recombinant gene independently from external inducers or drastic changes in metabolic conditions and enabling tight regulation of expression. PMID- 22222112 TI - GhAGP31, a cotton non-classical arabinogalactan protein, is involved in response to cold stress during early seedling development. AB - Arabinogalactan proteins (AGPs), a superfamily of highly glycosylated hydroxyproline-rich glycoproteins, are widely implicated in plant growth and development. A gene (including its cDNA), designated GhAGP31, encoding a non classical AGP protein was isolated from cotton (Gossypium hirsutum). The deduced GhAGP31 protein contains the conserved features of non-classical AGPs: a putative signal peptide, N-terminal histidine-rich stretch, middle repetitive proline-rich domain and a cysteine-containing 'PAC' domain. GFP fluorescence assay demonstrated that GhAGP31 protein was localised on cell walls. GhAGP31 transcripts were mainly detected in roots, hypocotyls and ovules, but little or almost none were detected in other tissues. In particular, expression of GhAGP31 was developmentally regulated in roots. Further study demonstrated that GhAGP31 expression in cotton roots was remarkably up-regulated by cold stress. Expression of the GUS gene driven by the GhAGP31 promoter was also dramatically enhanced in roots of transgenic Arabidopsis seedlings under cold treatment. Additionally, overexpression of GhAGP31 in yeast and Arabidopsis significantly improved the freezing tolerance of yeast cells and cold tolerance of Arabidopsis seedlings. These data imply that GhAGP31 protein may be involved in the response to cold stress during early root development of cotton. PMID- 22222113 TI - Plant and yeast NHX antiporters: roles in membrane trafficking. AB - The plant NHX gene family encodes Na(+)/H(+) antiporters which are crucial for salt tolerance, potassium homeostasis and cellular pH regulation. Understanding the role of NHX antiporters in membrane trafficking is becoming an increasingly interesting subject of study. Membrane trafficking is a central cellular process during which proteins, lipids and polysaccharides are continuously exchanged among membrane compartments. Yeast ScNhx1p, a prevacuole/ vacuolar Na(+)/H(+) antiporter, plays an important role in regulating pH to control trafficking out of the endosome. Evidence begins to accumulate that plant NHX antiporters might function in regulating membrane trafficking in plants. PMID- 22222114 TI - Rickettsiae in arthropods collected from the North African Hedgehog (Atelerix algirus) and the desert hedgehog (Paraechinus aethiopicus) in Algeria. AB - Hedgehogs have become a popular pet despite their potential role in zoonotic disease transmission. We conducted an entomological study in a mountainous region of northeast Algeria in which we collected 387 fleas (Archeopsylla erinacei) and 342 ticks (Rhipicephalus sanguineus and Haemaphysalis erinacei) from Paraechinus aethiopicus and Atelerix algirus hedgehogs. Of the hedgehogs sampled, 77.7% and 91% were infested with fleas and ticks, respectively. Significantly more ticks and fleas were collected from A. algirus than from P. aethiopicus. Rickettsia felis was detected in 95.5% of fleas and R. massiliae was detected in 6.25% of Rh. sanguineus ticks by molecular tools. A new Rickettsia species of the spotted fever group was detected in 11.25% of Rh. sanguineus and in 77% of H. erinacei ticks. Overall, we show that hedgehogs can act as hosts for ectoparasites infected with several rickettsial agents. These data justify a more detailed investigation of animal reservoirs for Rickettsiae. PMID- 22222115 TI - A CpG oligodeoxynucleotide potentiates the anti-tumor effect of HSP65-Her2 fusion protein against Her2 positive B16 melanoma in mice. AB - Although being promising tumor vaccine candidates in animal models, heat shock protein (HSP)-based tumor vaccines have not yet succeeded in the clinical trials, implying the necessity to be formulated with appropriate adjutants to enhance their immunogenicity. In this study, we investigated whether a B-class CpG ODN (BW006), a TLR9 agonist, could facilitate HSP65-Her2, a recombinant protein between mycobacterial HSP65 and Her2-derived peptide, to induce vigorous anti tumor activity against Her2 positive tumors in mice both prophylactically and therapeutically. It was found that BW006 could enhance prophylactic and therapeutic effect of HSP65-Her2 with improved survival of the mice bearing Her2(+) B16 melanoma and HSP65-Her2 specific Th1 response. PMID- 22222117 TI - Hypertrophic cardiomyopathy: infants, children, and adolescents. AB - Hypertrophic cardiomyopathy (HCM) is characterized by inappropriate left ventricular hypertrophy (LVH) in the setting of a nondilated left ventricle. HCM is often associated with asymmetric LVH, a family history of HCM, sarcomeric genetic mutations, and an increased risk of sudden cardiac death. There is a wide clinical variability in HCM presenting during childhood and a relative lack of data on the pediatric population. This review will cover HCM presenting in infancy, childhood, and adolescence. PMID- 22222116 TI - Involvement of melatonin in autophagy-mediated mouse hepatoma H22 cell survival. AB - The role of autophagy in cancer is controversial. Melatonin has been linked to several aspects of cancer progression and also to regulation of autophagy. Whether melatonin is involved in an autophagy-induced tumor suppressor mechanism or a cyto-protective mechanism is unknown. Therefore, we investigated the effects of melatonin on autophagy and its upstream regulator. We found that melatonin triggers an autophagic process by enhancing Beclin 1 expression and inducing a conversion of microtubule-associated protein 1 light chain 3(LC3)-I to LC3-II, the protein associated with the autophagosome membrane, in hepatoma H22 tumor bearing mice. Moreover, melatonin inhibits the phosphorylation of the mammalian target of the rapamycin (mTOR) and Akt. Knockdown of Beclin 1 by either RNA interference or co-treatment with the autophagy inhibitor, 3-methyladenine(3-MA), significantly enhanced the melatonin-induced apoptosis in mouse hepatoma H22 cells. Our data provides the first evidence that melatonin induces protective autophagy that prevents mouse hepatoma H22 cells from undergoing apoptosis. A combination of melatonin with an autophagy inhibitor might be a useful therapeutic strategy for hepatocellular carcinoma. PMID- 22222118 TI - The night-eating syndrome and obesity. AB - The rising prevalence of obesity is a global concern. Eating behaviour and circadian rhythm are proving to be important factors in the aetiology of obesity. The night-eating syndrome (NES) is characterized by increased late-night eating, insomnia, a depressed mood and distress. It is evident that prevalence is higher among weight-related populations than the general community. The exact relationship between this syndrome and obesity remains unclear. The reasons for the discrepancies found in the literature likely include varying diagnostic criteria and a wide range of study population characteristics. NES does not always lead to weight gain in thus certain individuals may be susceptible to night-eating-related weight gain. Weight loss through surgical and behavioural treatments has shown success in diminishing symptoms. The increasing literature associating obesity with circadian imbalances strengthens the link between the NES and obesity. Circadian genes may play a role in this syndrome. This review will examine different aspects of obesity in the context of the NES. PMID- 22222120 TI - Taiji practice attenuates psychobiological stress reactivity--a randomized controlled trial in healthy subjects. AB - BACKGROUND: Stress reducing effects of Taiji, a mindful and gentle form of body movement, have been reported in previous studies, but standardized and controlled experimental studies are scarce. The present study investigates the effect of regular Taiji practice on psychobiological stress response in healthy men and women. METHODS: 70 participants were randomly assigned to either Taiji classes or a waiting list. After 3 months, 26 (8 men, 18 women) persons in the Taiji group and 23 (9 men, 14 women) in the waiting control group underwent a standardized psychosocial stress test combining public speaking and mental arithmetic in front of an audience. Salivary cortisol and alpha-amylase, heart rate, and psychological responses to psychosocial stress were compared between the study groups. (ClinicalTrials.gov number, NCT01122706.) RESULTS: Stress induced characteristic changes in all psychological and physiological measures. Compared to controls, Taiji participants exhibited a significantly lower stress reactivity of cortisol (p = .028) and heart rate (p = .028), as well as lower alpha-amylase levels (p = .049). They reported a lower increase in perceived stressfulness (p = .006) and maintained a higher level of calmness (p = .019) in response to psychosocial stress. CONCLUSION: Our results consistently suggest that practicing Taiji attenuates psychobiological stress reactivity in healthy subjects. This may underline the role of Taiji as a useful mind-body practice for stress prevention. PMID- 22222122 TI - Facing the noise: addressing the endemic variability in D(LCO) testing. AB - Single-breath diffusing capacity of the lung for carbon monoxide (D(LCO)) is a common pulmonary function test that measures the ability of the lung to exchange gas across the alveolar-capillary interface. D(LCO) testing is used to narrow the differential diagnosis of obstructive and restrictive lung disease, to aid in disability and transplant assessment, and to monitor medication toxicity. The variability in the measurement limits the utility of the test. Variability is attributable to differences in equipment, testing conditions, patient factors, and reference equations. Laboratories can minimize variability by ensuring that equipment meets recommended standards, implementing effective quality control programs, standardizing testing conditions and testing procedures, and accounting for pertinent patient characteristics. PMID- 22222123 TI - What is the clinical value of lung volumes? AB - Lung volumes are considered part of a complete pulmonary function test, but their value for enhancing clinical decision making is unknown. Unlike spirometry and diffusing capacity of the lung for carbon monoxide (D(LCO)), which do contribute to confirming or excluding a diagnosis, there are few clear indications when lung volumes are discriminatory. Confirming "restriction" when vital capacity (VC) or FVC is reduced is perhaps the most important. A restrictive pattern can have many etiologies, and clinicians often use VC or FVC as a primary index of lung volume. This makes "physiologic" sense because, in healthy subjects, and in patients with true restriction, VC comprises most of the total lung capacity (TLC). Mixed obstruction-restriction and the nonspecific pattern (ie, reduced FVC and FEV(1), normal FEV(1)/FVC and TLC) require measuring TLC to confirm the underlying physiology. In obesity, VC and TLC may remain within normal limits, but functional residual capacity (FRC) can exponentially decrease. Increased lung volumes, particularly residual volume (RV), are commonly observed in airway obstruction. TLC may be normal, but is frequently increased in the late stages of COPD. Hyperinflation and air-trapping are terms commonly used to reflect these changes, but are not well standardized. The variability of lung volumes related to degree of obstruction suggests that measuring gas-trapping may be needed to monitor therapy. Changes in inspiratory capacity, RV, or FRC may be important gauges of response to bronchodilators or other hyperinflation-reducing therapies. How lung volumes are measured may be important, especially in patients who have moderate or severe airway obstruction. Body plethysmography is often considered more accurate than gas dilution methods in the presence of obstruction. However, the differences between techniques are not completely understood. Newer approaches such as computed tomography, although not suitable for routine testing, may help to delineate the true underlying physiology. PMID- 22222119 TI - Post-traumatic disorder symptoms and blunted diurnal cortisol production in partners of prostate cancer patients. AB - Prostate cancer (PC) is the most common cancer diagnosed in men, and research suggests that coping with this illness can cause significant distress in patients as well as their partners. This study examined the relationship of caregiving for a partner with PC with diurnal cortisol output in women between the ages of 42 and 75 years old. Participants were women whose partners had PC (n = 19) and women who were in relationships with men with no diagnosed medical illness (n = 26). Women provided saliva samples (4 times per day over 3 days) in their natural environment. The Structured Clinical Interview for DSM-IV Axis-I Disorders was also conducted to assess for the presence of post-traumatic stress disorder (PTSD) and major depression. Partners of men with PC had lower daily cortisol output across the three days than controls, F(1,444.08) = 20.72, p<.001). They were also more likely to report PTSD symptoms with 68.4% of PC partners fulfilling criteria for sub-threshold PTSD as compared to 23.1% of controls (chi(2) = 11.30, p = .01). Mixed model analyses revealed that the presence of sub threshold PTSD symptoms significantly predicted cortisol production, F(1,419.64) = 5.10, p<.01). Regardless of caregiver status, women who reported at least sub threshold PTSD symptoms had lower cortisol production than those with no PTSD symptoms. Major depression did not explain differences in cortisol production between partners of PC patients and controls. Although these findings are preliminary, they highlight the importance of developing interventions aimed at reducing risk of psychopathology in partners of men with PC. PMID- 22222124 TI - What is the best pulmonary diagnostic approach for wheezing patients with normal spirometry? AB - Asthma is characterized by airway inflammation, airway hyper-responsiveness (AHR) and variable air flow obstruction. The diagnosis of asthma, however, is often based upon nonspecific clinical symptoms of cough, wheeze, and shortness of breath. Furthermore, the physical examination and measurements of pulmonary function are often unremarkable in patients with asthma, thereby complicating the diagnosis of the disease. The following discussion will review approaches to the diagnosis of asthma when lung functions are normal, and will largely focus on the use of bronchial provocation tests to detect underlying AHR. PMID- 22222125 TI - Which pulmonary function tests best differentiate between COPD phenotypes? AB - We are still at the early phase of finding useful phenotypes in COPD that can guide therapy. However, in a simple sense, "sick patients die." Many phenotypic measurements of severity correlate with mortality in COPD: FEV(1), the ratio of inspiratory capacity to total lung capacity (IC/TLC), diffusing capacity of the lung for carbon monoxide (D(LCO)), 6-min walk distance, and maximum oxygen (O(2)) consumption or maximum watts on exercise testing. However, composite parameters, such as the BODE index (body mass index, air flow obstruction, dyspnea, exercise capacity), perform better, likely because they capture different aspects of severity that affect functional impairment and risk of death. Bronchodilator responsiveness is just a relative feature that aids in distinction of asthma and COPD but is not diagnostic in this use. A normal D(LCO) helps to rule out exercise-induced O(2) desaturation, but those with a low D(LCO) and COPD need exercise measurements to confirm desaturation. Currently, pulmonary function tests (PFTs) alone do not define subsets who respond to particular therapies. The presence of air flow obstruction and its severity increase the risk of lung cancer in COPD patients. Inflammatory biomarkers (exhaled nitric oxide and eosinophilia in sputum or bronchoalveolar lavage fluid) help distinguish asthma from COPD. Genetics is a promising area to elucidate pathophysiology and treatment for asthma and COPD, but currently alpha-1 antitrypsin deficiency is the only genetically-determined phenotype that has relevance for COPD management. The best promise for the future seems to be in composite phenotypes or scores, both for distinguishing asthma from COPD, and for guiding therapeutic options. It may be better to throw out the old, limiting diagnostic concepts. If, instead, we start from outcomes of interest, perhaps we can work back to predictors of these outcomes, and organize new diagnostic entities that have predictive relevance for treatment choices, functional outcomes, and mortality. PMID- 22222126 TI - Children should not be treated like little adults in the PFT lab. AB - Over the years a great deal of effort has been made to standardize all pulmonary function tests on adults. Many of the "rules" concerning the interpretation of the spirogram have been based entirely on adult observations. In the age of increasing conformity, and attempts to relate "adult" literature to the pediatric population, the latter was given much less emphasis than the former. This review will attempt to show what areas in pulmonary function testing are similar in adults and children, but more specifically will show the areas that are different. The latest standards published by the American Thoracic Society/European Respiratory Society in 2005 have attempted to incorporate some differences for the pediatric population for spirometry, but more work needs to be done in this area. While it is recognized that spirometry is the primary pulmonary function test for children, there are a number of circumstances where the addition of plethysmography and lung diffusion measurements are necessary. The review will state some of the limitations of these tests when performed by children. Lung function testing, particularly spirometry, has much to offer in the diagnosis of lung disease in children and the monitoring of response to therapy. With better standardization of pulmonary function testing in children, and more trained technologists, the age limits for testing can be extended to below 6 years of age and sometimes below 5. Also with better standardization the results obtained are meaningful and when interpreted in context of age offer excellent diagnostic information to better treat the child with lung disease. PMID- 22222127 TI - What is the role of PFTs in monitoring adverse effects of surgery, drug treatments, radiation therapy, and during hospitalization? AB - Measurement of various aspects of pulmonary function is a relatively easy, noninvasive, and inexpensive way to gauge the status of the respiratory system. Interest in using these tests to determine risk from medical and surgical interventions stems from their presumed ability to be more sensitive than history or physical examination in detecting underlying lung disease. When coupled with the assumption that early detection of pulmonary abnormalities will lead to alterations in patient management, the ultimate goal of improved patient outcomes becomes very attractive. However, despite advances in technology, achievement of this goal has proved to be more challenging than expected in many areas. This paper attempts to review the literature addressing several of the more difficult of these areas. It is clear that more research, involving more rigorously designed studies, will be necessary, before definitive answers are available. PMID- 22222128 TI - What does airway resistance tell us about lung function? AB - Spirometry is considered the primary method to detect the air flow limitation associated with obstructive lung disease. However, air flow limitation is the end result of many factors that contribute to obstructive lung disease. One of these factors is increased airway resistance. Airway resistance is traditionally measured by relating air flow and driving pressure using body plethysmography, thus deriving airway resistance (R(aw)), specific airway resistance (sR(aw)), and specific airway conductance (sG(aw)). Other methods to measure airway resistance include the forced oscillation technique (FOT), which allows calculation of respiratory system resistance (R(RS)) and reactance (X(RS)), and the interrupter technique, which allows calculation of interrupter resistance (R(int)). An advantage of these other methods is that they may be easier to perform than spirometry, making them particularly suited to patients who cannot perform spirometry, such as young children, patients with neuromuscular disorders, or patients on mechanical ventilation. Since spirometry also requires a deep inhalation, which can alter airway resistance, these alternative methods may provide more sensitive measures of airway resistance. Furthermore, the FOT provides unique information about lung mechanics that is not available from analysis using spirometry, body plethysmography, or the interrupter technique. However, it is unclear whether any of these measures of airway resistance contribute clinically important information to the traditional measures derived from spirometry (FEV(1), FVC, and FEV(1)/FVC). The purpose of this paper is to review the physiology and methodology of these measures of airway resistance, and then focus on their clinical utility in relation to each other and to spirometry. PMID- 22222129 TI - Exercising your patient: which test(s) and when? AB - With the introduction of the stair climb test of surgical patients in the 1950s, the role of exercise-based testing as a useful diagnostic tool and an adjunct to conventional cardiopulmonary testing was established. Since then, we have witnessed a rapid development of numerous tests, varying in their protocols and clinical applications. The relatively simple "field tests" (shuttle walks, stair climb, 6-minute walk test) require minimal equipment and technical support, and so are generally available to physicians and patients. At the other end of the spectrum is the cardiopulmonary exercise test (CPET), more complex in its equipment requirements, technical support, and with an often complex interpretive strategy. The 6-minute walk test (6MWT), in particular, has evolved into a versatile study with diagnostic utility in many disorders, including COPD, pulmonary hypertension, interstitial lung disease, congestive heart failure, and in the pre-surgical evaluation of patients, among others. With the added dimensions of optional O(2) saturation monitoring and calculated post-exercise heart rate recovery, the 6MWT is providing important clinical information well beyond the measure of distance walked. Is it sufficiently robust and informative to replace the more demanding and less available CPET? In many instances, the clinical applications are overlapping, with the 6MWT functioning as an adequate surrogate. However, in the initial evaluation of unexplained dyspnea, in formal evaluation of impairment and disability, in detailed evaluation of congestive heart failure, and in the selected lung cancer patient prior to resection, CPET remains superior. Investigations of portable metabolic and cardiovascular monitoring devices aiming to enhance the diagnostic capabilities of 6MWT may further narrow or close the remaining gap between these two exercise studies. PMID- 22222130 TI - Quality assurance of the pulmonary function technologist. AB - The skill and work habits of the pulmonary function technologist are central to the quality of patient testing. Pulmonary function technologists should be chosen carefully. The pulmonary function technologists must be intelligent, conscientious, and possess critical thinking skills. Studies are needed to better identify which kinds of personality traits correlate with superior job performance and whether or not such traits can be reliably identified by standardized testing. Monitoring of technologist performance and technologist feedback improves the quality of testing but is utilized by only a minority of clinical laboratories. Pulmonary function laboratory accreditation is urgently needed to protect the public from potential misdiagnosis and inappropriate treatment due to spurious data. PMID- 22222131 TI - PFT interpretive strategies: American Thoracic Society/ European Respiratory Society 2005 guideline gaps. AB - All pulmonologists, including those recently completing training, should be competent in critically evaluating and interpreting pulmonary function tests (PFTs). In addition, some authorities recommend that respiratory therapists learn to provide preliminary PFT interpretations for the medical directors of PFT labs. The 2005 American Thoracic Society/European Respiratory Society guidelines for interpreting PFTs lack recommendations for the best reference equations for lung volumes and diffusing capacity of the lung for carbon monoxide (D(LCO)), and lack reference equations for non-whites. The pre-test probability of lung disease should be determined using a short questionnaire. The "nonspecific pattern" occurs in about 15% of patients referred to a PFT lab, but it has many clinical correlates and the course is usually benign. Less common PFT patterns and those resulting from comorbid conditions (such as obesity, respiratory muscle weakness, or heart failure) are not discussed by the guidelines. More than half of patients with interstitial lung disease have a normal ratio of D(LCO)/V(A) (alveolar volume), and many have a normal total lung capacity. PMID- 22222132 TI - How should the lower limit of the normal range be defined? AB - Lung function parameters vary considerably with age and body size, so that, unlike many laboratory tests, the normal range of expected values must be individualized. For spirometry, only low values are considered to be abnormal, so the lower limit of normal (LLN) is taken to be equal to the 5th percentile of a healthy, non-smoking population. Simple and commonly used "rules of thumb," such as an FEV(1)/FVC < 0.70 to indicate air-flow obstruction, or assuming values < 80% of predicted to be abnormal, are inaccurate and will cause misclassification, specifically under-diagnosis of abnormalities in younger, taller individuals and over-diagnosis in those older or shorter. A much more accurate LLN for the FEV(1)/FVC ratio, which recognizes the change with age of this measurement, can be easily determined by subtracting 10 (10% or 0.10) from the age specific FEV(1)/FVC predicted for any individual. The analysis and mathematical descriptions of reference data have become increasingly sophisticated in recent years, but the interpretation of values near the LLN continues to carry uncertainty, due to an overlap in values between low normal values and those reflecting early disease. Among patients referred to a pulmonary function laboratory, the pre-test probability of disease may be relatively high, so that even individuals with values above the LLN may be more likely than not to have respiratory disease. A future goal for the pulmonary community would be the development of risk stratified outcome data that would allow an estimation of the probability of disease with progressive decrements in lung function. While interpreting spirometry results near the LLN will continue to be problematic, a more important task for the pulmonary community is to focus on finding the pool of individuals with clear-cut, but undiagnosed, COPD. And for this, good quality spirometry remains the best tool and must be widely available. PMID- 22222133 TI - Should we keep pushing for a spirometer in every doctor's office? AB - Professional societies have encouraged primary care providers to conduct spirometry testing for the detection of chronic obstructive pulmonary disease (COPD). In spite of this effort, the success rate is unacceptably low. Simple flow-sensing spirometers have technical flaws that can cause misreadings, and they are rarely checked for accuracy. When spirometry is performed by an experienced technologist, and when payment is made on the criterion of quality, the success rate for adults and school-aged children can be as high as 90%. But testing remains a challenge for younger children and the elderly. Regular feedback for the technologist about their testing results is essential. Even with an accurate spirometer, an able patient, and a skilled technologist, the ordering physician may wrongly interpret the data. Use of spirometry in primary care will continue to be problematic unless high quality testing is tied to reimbursement. Using FEV(1) or peak flow measurements to rule out airway abnormality in the majority of patients, followed by referral for more sophisticated studies in those remaining, may be the best approach. Respiratory therapists should engage in this effort. PMID- 22222134 TI - The future of pulmonary function testing. AB - The pulmonary function lab of today is heavily focused on describing pathophysiology and quantifying the extent of disease. As we move forward, it is important that the results of pulmonary function tests go beyond this and be linked to important outcomes that truly affect clinical decision making. To get there, improvements in device performance are required, high quality technicians are critical, and properly trained interpreting clinicians with good reference standards are mandatory. Moreover, as accessibility to these tests is increased, it is important that quality metrics remain intact. There is a wide array of novel tests that might be performed by pulmonary function labs in the future. These range from modification of current technologies to brand new technologies that are still in early development. Examples include exhaled breath analysis, sophisticated analyses of lung mechanics and gas exchange, cardiac and tissue oxygenation assessments, and imaging technologies. Adoption of any new technology will require, even more than today, clear evidence that the new technology is a real adjunct to clinical decision making. PMID- 22222135 TI - Pulmonary function testing. AB - Pulmonary function testing is often considered the basis for diagnosis in many categories of pulmonary disease. Although most of the testing methodologies are well established and widely employed, there are still many questions regarding how tests should be performed, how to ensure that reliable data are produced, what reference values and rules should be used, and how pulmonary function tests (PFTs) should be interpreted to best support clinical decision making. This conference was organized around a set of questions aimed at many of these issues. Each presenter was asked to address a specific topic regarding what tests should be done, how those test should be performed to answer a particular clinical question, and to relate test results to an accurate diagnosis and appropriate treatment of the patient. These topics included testing of adults and children, with concentration on important disease entities such as COPD, asthma, and unexplained dyspnea. Special emphasis was given to discussing reference values, lower limits of normal, interpretive strategies to optimize disease classification, and those factors directly affecting data quality. Established techniques for spirometry, lung volumes, diffusing capacity, exercise testing, and bronchial challenges were compared and contrasted with new technologies, and with technologies that might be part of pulmonary function laboratories in the near future. PMID- 22222136 TI - Breast cancer screening in developing countries. AB - Diagnosing breast cancer early and efficiently is a critical component of any strategy aimed at decreasing breast cancer mortality in developing countries. In this chapter, I evaluate the evidence behind screening strategies and its controversies. The effect of breast-cancer screening has never been formally evaluated in developing countries, and data from the major screening trials need to be viewed in this context. Screening asymptomatic women by means of breast self-examination, clinical examination or mammography can play a significant role in decreasing breast-cancer mortality in developing countries. Major programmes should not be implemented, however, until adequate diagnostic and therapeutic facilities are in place. The most fundamental interventions in early detection, diagnosis, surgery, radiation therapy, and drug therapy must be integrated, organised and resourced appropriately within existing healthcare structures. PMID- 22222137 TI - Synthesis and biological assessment of novel 2-thiazolylhydrazones and computational analysis of their recognition by monoamine oxidase B. AB - Monoamine oxidase B (MAO-B) is a promising target for the treatment of neurodegenerative disorders. We report the synthesis and the biological evaluation of halogenated derivatives of 1-aryliden-2-(4-phenylthiazol-2 yl)hydrazines. The fluorinated series shows interesting activity and great selectivity toward the human recombinant MAO-B isoform expressed in baculovirus infected BTI insect cells. The multiple crystal structures alignment of the enzyme highlighted pronounced induced fit (IF) adaptations with respect to bound ligands. Therefore, IF docking (IFD) experiments and molecular dynamic (MD) simulations were carried out to reveal the putative binding mode and to explain the experimentally observed differences in the activity of 1-(aryliden-2-(4-(4 chlorophenyl)thiazol-2-yl)hydrazines. The importance of water molecules within the binding site was also investigated. These are known to play an important role in the binding site cavity and to mediate protein-ligand interactions. Detailed analyses of the trajectories provide insights on the chemical features required for the activity of this scaffold. In particular it was highlighted the importance of fluorine atom interacting with the water close to the cofactor and the influence of steric bulkiness of substituents in the arylidene moiety. Free energy perturbation (FEP) analysis confirmed experimental data. The information we deduced will help to develop novel high-affinity MAO-B inhibitors. PMID- 22222138 TI - Dibasic biphenyl H3 receptor antagonists: Steric tolerance for a lipophilic side chain. AB - Within a series of histamine H(3)-antagonists characterized by a biphenyl core and two basic groups, we identified (S)-1-{[4'-((2-methylpyrrolidin-1 yl)methyl)biphenyl-4-yl]methyl}piperidine as a lead scaffold to introduce an additional lipophilic chain at the benzylic carbon close to the pyrrolidine ring. A series of derivatives was synthesized and tested for their binding affinity at human and rat histamine H(3) receptors, and for their antagonist potency. For compounds with two chiral centers, the synthetic procedure provided mixtures of diastereomeric couples, which were separated by flash chromatography. Combination of experimental NMR data and molecular dynamics simulation allowed the assignment of absolute stereochemistry, based on characteristic differences detected within each diastereomeric couple. The additional lipophilic group was tolerated by the receptor, supporting the hypothesis that the two regions described within the H(3) receptor binding site can be simultaneously occupied by antagonists. Diastereoisomers with opposite chirality at the benzylic carbon showed limited or no stereoselectivity at both human and rat receptors. PMID- 22222139 TI - Improved method for the isolation of RNA from bacteria refractory to disruption, including S. aureus producing biofilm. AB - The development of fast, reliable and inexpensive phenol protocol is described for the isolation of RNA from bacterial biofilm producers. The method was tested on Staphylococcus aureus (S. aureus) and other biofilm-producing gram-negative microorganisms and provided the highest integrity of RNA recovery in comparison to other methods reported here. In parallel experiments, bacterial lysis with Qiagen, NucleoSpin RNAII, InnuREP RNA Mini, Trizol and MasterPure RNA extraction Kits using standard protocols consistently gave low RNA yields with an absence of integrity. The boiling method presented here yielded high concentration of RNA that was free from 16S and 23S rRNA, contained 5S RNA. Higher yields due to improved biofilm bacterial cell lysis were achieved with an added hot phenol incubation step without the need for a bead mill or the enzyme. This method when used in conjunction with the Qiagen RNeasy Mini kit, RNA isolation was a success with greater integrity and contained undegraded 16S and 23S rRNA and did not require further purification. Contaminating DNA was a problem with the RNA processing samples; we used quantitative real-time PCR (RT-qPCR) to measure the recovery of RNA from bacterial biofilm cells using the method described here. PMID- 22222140 TI - Association study of microRNA polymorphisms with risk of idiopathic recurrent spontaneous abortion in Korean women. AB - AIM: The aim of this study was to investigate the association of microRNA polymorphisms (miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G) in Korean patients with recurrent spontaneous abortion (RSA). METHODS: We conducted a case control study of 564 Korean women: 330 patients with at least two unexplained consecutive pregnancy losses and 234 healthy controls with at least one live birth and no history of pregnancy loss. RESULTS: RSA patients exhibited significantly different frequencies of the miR-196a2CC (TT+TC vs. CC; adjusted odds ratio [AOR], 1.587; 95% confidence interval [CI], 1.042-2.417) and miR 499AG+GG genotypes (AOR, 1.587; 95% CI, 1.096-2.298) [corrected] compared with the control group. The combination of miR-196a2CC and miR-499AG+GG showed synergistic effects (AOR, 3.541; 95% CI, 1.645-7.624). CONCLUSION: miR-196a2CC, miR-499AG+GG, and the miR-196a2CC/miR-499AG+GG combination are significantly associated with idiopathic RSA in Korean women. PMID- 22222141 TI - Influence of preparation and wall thickness on the resistance to fracture of zirconia implant abutments. AB - BACKGROUND: Studies about the effect of grinding procedures as well as material thickness on the resistance of zirconia implant abutments are in short supply. PURPOSE: This study evaluated the effect of wall thickness as well as preparation on the resistance of zirconia implant abutments. MATERIALS AND METHOD: Sixty-four implants received titanium (group Ti) and zirconia abutments (groups Zr-8, Zr-18, and Zr-1). The abutments of group Zr-8 had a 0.8-mm wall thickness, whereas the wall thickness of group Zr-18 was reduced by preparation from 1 mm to 0.8 mm. The abutments of group Zr-1 had a wall thickness of 1 mm. Standardized maxillary central incisor metal crowns were cemented on all abutments. All specimens were then tested in a universal testing machine for their resistance to fracture before and after masticatory simulation (n = 8). RESULTS: The median resistance to fracture values (N) before and after aging were, respectively: group Ti: 500 504; group Zr-8: 487-491; group Zr-18: 490-451; and group Zr-1: 519-480. No significant effects of group, aging, or combinations were found (p > .05). CONCLUSION: All tested abutments have the potential to withstand physiologic occlusal forces in the anterior region (> 200 N). The applicability of the results to other implant systems should be verified. PMID- 22222142 TI - Understanding the mechanism of heat stress tolerance caused by high trehalose accumulation in Saccharomyces cerevisiae using DNA microarray. AB - DNA microarray analysis was performed to examine the stress tolerance mechanism of a Saccharomyces cerevisiae recombinant strain exhibiting high trehalose accumulation and heat stress tolerance. Results suggest that the upregulation of sugar transporter genes is one of the key events for heat stress tolerance of the recombinant strain. PMID- 22222143 TI - Reliability, validity, and responsiveness of myotonometric measurement of muscle tone, elasticity, and stiffness in patients with stroke. AB - OBJECTIVE: To assess the metric properties of a myotonometer. DESIGN: Metric study. SETTING: Three medical centers. PARTICIPANTS: Stroke patients (N=67). INTERVENTION: Upper-extremity rehabilitation programs. MAIN OUTCOME MEASURES: The tone, elasticity, and stiffness of relaxed extensor digitorum, flexor carpi radialis, and flexor carpi ulnaris were measured using the myotonometer. Fifty eight patients completed the myotonometer measures twice at pretreatment. The myotonometric measurement and the criteria measures, including hand strength (grip, lateral pinch, and palmar pinch strength) and Action Research Arm Test (ARAT) were administered at pretreatment and posttreatment. RESULTS: The myotonometer showed high test-retest reliability for muscle properties in 3 muscles. Significant correlations existed between the tone and stiffness of the 3 muscles and palmar pinch strength, between those of the flexor carpi muscles and lateral pinch strength, and between those of the flexor carpi radialis and the ARAT at posttreatment. The posttreatment elasticity of the 2 flexor carpi muscles was significantly correlated with grip strength. The pretreatment elasticity of the flexor carpi ulnaris was significantly correlated with posttreatment grip strength, and the pretreatment muscle tone and stiffness of the flexor carpi radialis were significantly correlated with palmar pinch strength and the ARAT. The responsiveness of the extensor digitorum was higher than that of the flexor carpi radialis and ulnaris. Muscle stiffness was more responsive than tone and elasticity in 3 muscles. CONCLUSIONS: Myotonometry can be a reliable, valid, and responsive outcome measure for assessing muscle properties after stroke rehabilitation. PMID- 22222144 TI - Flexible IZO/Ag/IZO/Ag multilayer electrode grown on a polyethylene terephthalate substrate using roll-to-roll sputtering. AB - We investigated the optical, electrical, structural, and surface properties of roll-to-roll [R2R] sputter-grown flexible IZO/Ag/IZO/Ag [IAIA] multilayer films on polyethylene terephthalate substrates as a function of the top indium zinc oxide [IZO] thickness. It was found that the optical transmittance of the IAIA multilayer was significantly influenced by the top IZO layer thickness, which was grown on identical AIA multilayers. However, the sheet resistance of the IAIA multilayer was maintained between the range 5.01 to 5.1 Omega/square regardless of the top IZO thickness because the sheet resistance of the IAIA multilayer was mainly dependent on the thickness of the Ag layers. Notably, the optimized IAIA multilayer had a constant resistance change (DeltaR/R0) under repeated outer bending tests with a radius of 10 mm. The mechanical integrity of the R2R sputtered IAIA multilayer indicated that hybridization of an IZO and Ag metal layer is a promising flexible electrode scheme for the next-generation flexible optoelectronics. PMID- 22222145 TI - Microstructure and adhesion characteristics of a silver nanopaste screen-printed on Si substrate. AB - The microstructural evolution and the adhesion of an Ag nanopaste screen-printed on a silicon substrate were investigated as a function of sintering temperature. Through the two thermal analysis methods, such as differential scanning calorimeter and thermo-gravimetric analysis, the sintering conditions were defined where the temperature was raised from 150 degrees C to 300 degrees C, all with a fixed sintering time of 30 min. The microstructure and the volume of the printed Ag nanopaste were observed using a field emission scanning electron microscope and a 3-D surface profiler, respectively. The apparent density of the printed Ag nanopaste was calculated depending on the sintering conditions, and the adhesion was evaluated by a scratch test. As the sintering temperature increased from 150 degrees C to 300 degrees C, the apparent density and the adhesion increased by 22.7% and 43%, respectively. It is confirmed that the printed Ag nanopaste sintered at higher temperatures showed higher apparent density in the microstructural evolution and void aggregation, resulting in the lower electrical resistivity and various scratched fractures. PMID- 22222147 TI - Cement-augmented dorsal instrumentation of the spine as a safe adjunct to the multimodal management of metastatic pheochromocytoma: a case report. AB - Malignant pheochromocytoma is a neuroendocrine tumor that originates from chromaffin tissue. Although osseous metastases are common, metastatic dissemination to the spine rarely occurs.Five years after primary diagnosis of extra-adrenal, abdominal pheochromocytoma and laparoscopic extirpation, a 53-year old patient presented with recurrence of pheochromocytoma involving the spine, the pelvis, both proximal femora and the right humerus. Magnetic resonance imaging and computed tomography revealed osteolytic lesions of numerous vertebrae (T1, T5, T10, and T12). In the case of T10, total destruction of the vertebral body with involvement of the rear edge resulted in the risk of vertebral collapse and subsequent spinal stenosis. Thus, dorsal instrumentation (T8-T12) and cement augmentation of T12 was performed after perioperative alpha- and beta-adrenergic blockade with phenoxybenzamine and bisoprolol.After thorough preoperative evaluation to assess the risk for surgery and anesthesia, and appropriate perioperative management including pharmacological antihypertensive treatment, dorsal instrumentation of T8-T12 and cement augmentation of T12 prior to placing the corresponding pedicle screws did not result in hypertensive crisis or hemodynamic instability due to the release of catecholamines from metastatic lesions.To the authors' knowledge, this is the first report describing cement augmentation in combination with dorsal instrumentation to prevent osteolytic vertebral collapse in a patient with metastatic pheochromocytoma. With appropriate preoperative measures, cement-augmented dorsal instrumentation represents a safe approach to stabilize vertebral bodies with metastatic malignant pheochromocytoma. Nevertheless, direct manipulation of metastatic lesions should be avoided as far as possible in order to minimize the risk of hemodynamic complications. PMID- 22222146 TI - The PRECISE RCT: evolution of an early septic shock fluid resuscitation trial. AB - Severe sepsis and septic shock are the most common reasons for admission to an intensive care unit; and the risk of death is substantial, estimated at approximately 40%. Evidence suggests that early resuscitation strategies that include the use of resuscitation fluids, antibiotics, blood, and inotropes reduce death. Although fluid resuscitation is an immediate life-saving intervention, a fundamental question that remains unanswered is whether the type of resuscitation fluid impacts survival when it is initiated very early in the course of septic shock. A randomized controlled trial published in 2008 confirmed that hydroxyethyl starch fluids cause acute renal failure defined by the requirement for renal replacement therapy. In contrast, a subgroup analysis from a randomized controlled trial suggests that 4% albumin fluid may reduce death from severe sepsis; however, these findings require confirmation in a large randomized trial. Our team is planning a pragmatic early septic shock fluid resuscitation trial that will compare the effectiveness of 5% albumin vs normal saline on 90-day mortality (PRECISE). In this article, we summarize the scientific rationale and inherent challenges associated with the conduct of PRECISE, the background work and planning elements that have been undertaken, and the PRECISE RCT protocol with rationale and justifications provided for the chosen population, the interventions, and the outcome measures. PMID- 22222148 TI - Ga-doped ZnO transparent electrodes with TiO2 blocking layer/nanoparticles for dye-sensitized solar cells. AB - Ga-doped ZnO [GZO] thin films were employed for the transparent electrodes in dye-sensitized solar cells [DSSCs]. The electrical property of the deposited GZO films was as good as that of commercially used fluorine-doped tin oxide [FTO]. In order to protect the GZO and enhance the photovoltaic properties, a TiO2 blocking layer was deposited on the GZO surface. Then, TiO2 nanoparticles were coated on the blocking layer, and dye was attached for the fabrication of DSSCs. The fabricated DSSCs with the GZO/TiO2 glasses showed an enhanced conversion efficiency of 4.02% compared to the devices with the normal GZO glasses (3.36%). Furthermore, they showed better characteristics even than those using the FTO glasses, which can be attributed to the reduced charge recombination and series resistance. PMID- 22222149 TI - Improvement of antioxidant activity of chitosan by chemical treatment and ionizing radiation. AB - Modification of chitosan (CS) to N-maleoylchitosan (NMCS), N-phthaloylchitosan (NPhCS) and sulfonated-chitosan (SCS) was done using maleic anhydride, phthalic anhydride and chlorosulfonic acid, respectively followed by exposing them to gamma-rays at different doses. The molecular weights and structural changes of irradiated chitosan derivatives were determined by GPC, FT-IR and UV-vis spectrophotometer. The molecular weights decreased with increasing irradiation dose. Results revealed that the main polysaccharide structure remained after irradiation. To investigate the enhancement of antioxidant activity of chitosan and its derivatives of different molecular weights, radical mediated lipid peroxidation inhibition, scavenging effect of DPPH radicals, reducing power and ferrous ion chelating activity assays were used. Chitosan derivatives with different molecular weights exhibit antioxidant activity. The lower the molecular weights of chitosan and its derivatives, the higher the antioxidant activity. NMCS possessed high scavenging effect on DPPH radicals compared with NPhCS, SCS and ascorbic acid. The irradiated chitosan and its derivatives could be used as natural antioxidants. PMID- 22222151 TI - The incorporation of a zone of calcified cartilage improves the interfacial shear strength between in vitro-formed cartilage and the underlying substrate. AB - A major challenge for cartilage tissue engineering remains the proper integration of constructs with surrounding tissues in the joint. Biphasic osteochondral constructs that can be anchored in a joint through bone ingrowth partially address this requirement. In this study, a methodology was devised to generate a cell-mediated zone of calcified cartilage (ZCC) between the in vitro-formed cartilage and a porous calcium polyphosphate (CPP) bone substitute in an attempt to improve the mechanical integrity of that interface. To do so, a calcium phosphate (CaP) film was deposited on CPP by a sol-gel process to prevent the accumulation of polyphosphates and associated inhibition of mineralization as the substrate degrades. Cartilage formed in vitro on the top surface of CaP-coated CPP by deep-zone chondrocytes was histologically and biochemically comparable to that formed on uncoated CPP. Furthermore, the mineral in the ZCC was similar in crystal structure, morphology and length to that formed on uncoated CPP and native articular cartilage. The generation of a ZCC at the cartilage-CPP interface led to a 3.3-fold increase in the interfacial shear strength of biphasic constructs. Improved interfacial strength of these constructs may be critical to their clinical success for the repair of large cartilage defects. PMID- 22222150 TI - Optic disc margin anatomy in patients with glaucoma and normal controls with spectral domain optical coherence tomography. AB - OBJECTIVE: To characterize optic nerve head (ONH) anatomy related to the clinical optic disc margin with spectral domain-optical coherence tomography (SD-OCT). DESIGN: Cross-sectional study. PARTICIPANTS: Patients with open-angle glaucoma with focal, diffuse, and sclerotic optic disc damage, and age-matched normal controls. METHODS: High-resolution radial SD-OCT B-scans centered on the ONH were analyzed at each clock hour. For each scan, the border tissue of Elschnig was classified for obliqueness (internally oblique, externally oblique, or nonoblique) and the presence of Bruch's membrane overhanging the border tissue. Optic disc stereophotographs were co-localized to SD-OCT data with customized software. The frequency with which the disc margin identified in stereophotographs coincided with (1) Bruch's membrane opening (BMO), defined as the innermost edge of Bruch's membrane; (2) Bruch's membrane/border tissue, defined as any aspect of either outside BMO or border tissue; or (3) border tissue, defined as any aspect of border tissue alone, in the B-scans was computed at each clock hour. MAIN OUTCOME MEASURES: The SD-OCT structures coinciding with the disc margin in stereophotographs. RESULTS: There were 30 patients (10 with each type of disc damage) and 10 controls, with a median (range) age of 68.1 (42 86) years and 63.5 (42-77) years, respectively. Although 28 patients (93%) had 2 or more border tissue configurations, the most predominant one was internally oblique, primarily superiorly and nasally, frequently with Bruch's membrane overhang. Externally oblique border tissue was less frequent, observed mostly inferiorly and temporally. In controls, there was predominantly internally oblique configuration around the disc. Although the configurations were not statistically different between patients and controls, they were among the 3 glaucoma groups. At most locations, the SD-OCT structure most frequently identified as the disc margin was some aspect of Bruch's membrane and border tissue external to BMO. Bruch's membrane overhang was regionally present in the majority of patients with glaucoma and controls; however, in most cases it was not visible as the disc margin. CONCLUSIONS: The clinically perceived disc margin is most likely not the innermost edge of Bruch's membrane detected by SD-OCT. These findings have important implications for the automated detection of the disc margin and estimates of the neuroretinal rim. PMID- 22222153 TI - MicroRNAs-based network: a novel therapeutic agent in pituitary adenoma. AB - Pituitary adenomas are common benign intracranial neoplasms representing about 10 25% of all intracranial neoplasm. Significant morbidity can occur along with pituitary adenomas due to hormonal dysfunction and mass effects. The pathogenesis of pituitary adenoma is unclear, however, etiologic factors include genetic events, hormonal stimulation, and growth factors [1], all of which promote cell proliferation and transformation in the tumor. However, genetic events play the most important role in tumorigenesis. MicroRNAs (miRNAs), a class of non-coding RNAs, not only have function in pituitary cell proliferation and apoptosis but also in neoplastic transformation. It has been shown that miRNAs are differentially expressed in pituitary adenoma when compared with the normal pituitary gland; moreover, miRNAs have been identified as a predictive signature of pituitary adenoma and can be used to predict the histotype. The expression of miRNAs can be used not only to differentiate microadenomas from macroadenomas, but to also distinguish samples of treated patients from samples of non-treated patients. Therefore, we hypothesized that a miRNA-based network may be involved in pituitary tumorigenesis and it can potentially serve as useful diagnostic markers to improve the classification of pituitary adenomas. Here, we reviewed the therapeutic potential that different types of miRNAs may play in tumorigenesis. Moreover, miRNAs may emerge as potential therapeutic targets. We speculated the mechanism of miR-21 is involved in tumorigenesis, leading to improvements in therapies and prevention of metastasis. PMID- 22222152 TI - Effect of malaria on placental volume measured using three-dimensional ultrasound: a pilot study. AB - BACKGROUND: The presence of malaria parasites and histopathological changes in the placenta are associated with a reduction in birth weight, principally due to intrauterine growth restriction. The aim of this study was to examine the feasibility of studying early pregnancy placental volumes using three-dimensional (3D) ultrasound in a malaria endemic area, as a small volume in the second trimester may be an indicator of intra-uterine growth restriction and placental insufficiency. METHODS: Placenta volumes were acquired using a portable ultrasound machine and a 3D ultrasound transducer and estimated using the Virtual Organ Computer-aided AnaLysis (VOCAL) image analysis software package. Intra observer reliability and limits of agreement of the placenta volume measurements were calculated. Polynomial regression models for the mean and standard deviation as a function of gestational age for the placental volumes of uninfected women were created and tested. Based on these equations each measurement was converted into a z -score. The z-scores of the placental volumes of malaria infected and uninfected women were then compared. RESULTS: Eighty-four women (uninfected = 65; infected = 19) with a posterior placenta delivered congenitally normal, live born, single babies. The mean placental volumes in the uninfected women were modeled to fit 5th, 10th, 50th, 90th and 95th centiles for 14-24 weeks' gestation. Most placenta volumes in the infected women were below the 50th centile for gestational age; most of those with Plasmodium falciparum were below the 10th centile. The 95% intra-observer limits of agreement for first and second measurements were +/- 37.0 mL and +/- 25.4 mL at 30 degrees and 15 degrees rotation respectively. CONCLUSION: The new technique of 3D ultrasound volumetry of the placenta may be useful to improve our understanding of the pathophysiological constraints on foetal growth caused by malaria infection in early pregnancy. PMID- 22222154 TI - Possible role of calcium permselectivity in bone adaptation. AB - According to the core activity of calcium in the bone cellular expression, a new hypothesis linking calcium transport with the mechanical loading is proposed to explain the mechano-adaptation of bone tissue. Due to the piezoelectric coupling, the tensile and compressive areas of bone produce different electrical environments for the osteocytic cells that are embedded in the lacuno-canalicular porosity. This electrical asymmetry engenders a calcium enrichment-exclusion effect that strongly changes the calcium concentration in the lacuno-canalicular fluid and thus modifies the remodelling process. A bibliographic body of evidence supporting this idea is given and its experimental validation is suggested. PMID- 22222155 TI - Anomalous origin of the right coronary artery from the pulmonary artery diagnosed as an incidental finding. AB - A 2-year-old boy was referred for evaluation of a systolic heart murmur. Two dimensional Doppler echocardiogram showed an abnormal flow through the interventricular septum, directed upward and toward the posterior wall of the main pulmonary artery. Left coronary angiogram showed a normal distribution of the anterior descending and circumflex arteries. The right coronary artery (RCA) was fully filled through collaterals from the left coronary system, and arising from the main pulmonary artery. Successful surgical reimplantation of the RCA was undertaken. Although uncommon, it is important to recognize the anomalous origin of the RCA arising from the pulmonary artery since it can be associated with serious adverse cardiac events. PMID- 22222156 TI - Novel diamino imidazole and pyrrole-containing polyamides: Synthesis and DNA binding studies of mono- and diamino-phenyl-ImPy*Im polyamides designed to target 5'-ACGCGT-3'. AB - Pyrrole- and imidazole-containing polyamides are widely investigated as DNA sequence selective binding agents that have potential use as gene control agents. The key challenges that must be overcome to realize this goal is the development of polyamides with low molar mass so the molecules can readily diffuse into cells and concentrate in the nucleus. In addition, the molecules must have appreciable water solubility, bind DNA sequence specifically, and with high affinity. It is on this basis that the orthogonally positioned diamino/dicationic polyamide Ph ImPy*Im 5 was designed to target the sequence 5'-ACGCGT-3'. Py* denotes the pyrrole unit that contains a N-substituted aminopropyl pendant group. The DNA binding properties of diamino polyamide 5 were determined using a number of techniques including CD, DeltaT(M), DNase I footprinting, SPR and ITC studies. The effects of the second amino moiety in Py* on DNA binding affinity over its monoamino counterpart Ph-ImPyIm 3 were assessed by conducting DNA binding studies of 3 in parallel with 5. The results confirmed the minor groove binding and selectivity of both polyamides for the cognate sequence 5'-ACGCGT-3'. The diamino/dicationic polyamide 5 showed enhanced binding affinity and higher solubility in aqueous media over its monoamino/monocationic counterpart Ph-ImPyIm 3. The binding constant of 5, determined from SPR studies, was found to be 1.5 * 10(7)M(-1), which is ~3 times higher than that for its monoamino analog 3 (4.8 * 10(6)M(-1)). The affinity of 5 is now approaching that of the parent compound f ImPyIm 1 and its diamino equivalent 4. The advantages of the design of diamino polyamide 5 over 1 and 4 are its sequence specificity and the ease of synthesis compared to the N-terminus pyrrole analog 2. PMID- 22222157 TI - Structure-activity relationships for naturally occurring coumarins as beta secretase inhibitor. AB - The present study was demonstrated to evaluate the effects of naturally occurring coumarins (NOCs) including simple coumarins, furanocoumarins, and pyranocoumarins on the inhibition of beta-secretase (BACE1) activity. Of 41 NOCs examined, some furanocoumarins inhibited BACE1 activity, but simple coumarins and pyranocoumarins did not affect. The most potent inhibitor was 5-geranyloxy-8 methoxypsoralen (31), which has an IC(50) value of 9.9 MUM. Other furanocoumarin derivatives, for example, 8-geranyloxy-5-methoxypsoralen (35), 8 geranyloxypsoralen (24), and bergamottin (18) inhibited BACE1 activity, with the IC(50) values <25.0 MUM. Analyses of the inhibition mechanism by Dixon plots and Cornish-Bowden plots showed that compounds 18, 31 and 35 were mixed-type inhibitor. The kinetics of inhibition of BACE1 by coumarins 24 was non competitive inhibitors. PMID- 22222158 TI - Synthesis physicochemical profile and PAMPA study of new NO-donor edaravone co drugs. AB - A new class of co-drugs were synthesised by joining antioxidant edaravone with a vasodilating substructure containing NO-donor nitrooxy functions, and characterised for their stability in different media, lipophilicity and permeability profile. The products display good stability in water/co-solvent at different pH. Conversely, they are rapidly metabolised into edaravone and NO donor moieties when incubated in human serum or rat-liver homogenates. In the latter conditions time dependent production of nitrite/nitrate (NO(x)) occurs. The compounds display wide-ranging lipophilicity. PAMPA studies predict good gastrointestinal absorption for a number of these compounds. The title products are potentially useful for treating ROS-related conditions accompanied by decreased NO availability. PMID- 22222159 TI - Studies on the biosynthesis of the lipodepsipeptide antibiotic Ramoplanin A2. AB - Ramoplanin, a non-ribosomally synthesized peptide antibiotic, is highly effective against several drug-resistant Gram-positive bacteria, including vancomycin resistant Enterococcus faecium (VRE) and methicillin-resistant Staphylococcus aureus (MRSA), two important opportunistic human pathogens. Recently, the biosynthetic cluster from the ramoplanin producer Actinoplanes ATCC 33076 was sequenced, revealing an unusual architecture of fatty acid and non-ribosomal peptide synthetase biosynthetic genes (NRPSs). The first steps towards understanding how these biosynthetic enzymes cooperatively interact to produce the depsipeptide product are expression and isolation of each enzyme to probe its specificity and function. Here we describe the successful production of soluble enzymes from within the ramoplanin locus and the confirmation of their specific role in biosynthesis. These methods may be broadly applicable to the production of biosynthetic enzymes from other natural product biosynthetic gene clusters, especially those that have been refractory to production in heterologous hosts despite standard expression optimization methods. PMID- 22222160 TI - Softening the Rule of Five--where to draw the line? AB - In order to improve the discovery and development of new drugs, a broad effort is being made to assess the 'drug-like' properties of molecules in early stages of the discovery-research process. Although there are numerous approaches to this problem, perhaps the simplest and most widespread one is that developed by Chris Lipinski and his co-workers at Pfizer, which is generally referred either as the Lipinski Rules or the Rule of Five (ROF). The ROF is based on four properties of molecules, namely, molecular weight (MW), log P, number of hydrogen bond donors (HBD), and the number of hydrogen bond acceptors (HBA). A 'flag' is set if the value of a given property exceeds the chosen threshold value for that property-MW 500 Da, log P 5, the number of HBDs 5, and the number of HBAs 10. Each flag corresponds to an ROF violation. The total number of violations is the ROF-Score, which lies between '0' and '4'. Molecules with ROF-Scores greater than one are considered to be marginal for further development. The difficulty with this approach is that two molecules with nearly identical property values can, nonetheless, possess ROF-Scores that can differ by two or more. Thus, one molecule could be considered for further studies while the other, nearly identical molecule (in terms of its four ROF properties), would most likely not be. This problem arises because of the sharp thresholds imposed by the present formulation of the ROF, which is based upon classical sets. In the current work an alternative approach based on the use of utility functions, within the framework of the analytic hierarchy process (AHP), are employed to 'soften' the sharp boundaries inherent in classical sets. This provides a more realistic assessment of compounds in terms of their potential suitability in drug-discovery research programs. PMID- 22222161 TI - [Unusual cause of peripheral arterial thromboses]. PMID- 22222162 TI - Ethanol-induced oxidative stress is associated with EGF receptor phosphorylation in MCF-10A cells overexpressing CYP2E1. AB - Breast cancer is the most common cancer and the second leading cause of cancer related mortality worldwide. The etiology of breast cancer is very diverse and ethanol (EtOH) consumption is a well-established risk factor for breast cancer in women. However, the mechanism by which EtOH exerts its carcinogenic activity in breast tissue remains unknown. CYP2E1 is known to metabolize ethanol and produce reactive oxygen species (ROS), including superoxide in epithelial cells. Therefore, in the present studies, we investigated whether there is an increase in ROS following overexpression of CYP2E1 in MCF-10A cells. We found that 30 and 100 mM EtOH increased ROS levels after 2 h treatment in CYP2E1 overexpressing cells. Based on these results and our previous studies with ROS-producing chemicals, we also examined epidermal growth factor receptor (EGFR) activation following exposure to ethanol. We found that there was an increase in phosphorylation of pY1086 EGFR after 18 h EtOH treatment in CYP2E1 overexpressing cells. These studies support a hypothesis that EtOH might increase human mammary cell activation, via an EGFR-dependent signaling mechanism associated with oxidative stress. PMID- 22222163 TI - Evaluation of aortic bioprosthesis stenosis by multidetector CT. AB - Because visualization the bioprosthesis leaflets is often hampered by shadowing artifacts from to the metal in the annulus or the struts, visualization and determination of the etiology of bioprosthesis valve dysfunction may be often difficult by transthoracic and even transesophageal echocardiography. We demonstrate two cases in which 256 slice-multidetector row computed tomography was able to visualize acute aortic bioprosthesis thrombosis. In the first case we could demonstrate thrombosis of the valve by comparing images to a computed tomography exam performed 4 months earlier. In the second case we demonstrate the disappearance the thrombus and normalization of restrained valve opening in a follow-up CT study, performed after 2 months of oral anticoagulation. PMID- 22222164 TI - Comparison of dual-source 64-slice adenosine stress CT perfusion with stress gated SPECT-MPI for evaluation of left ventricular function and volumes. AB - BACKGROUND: Evaluation of left ventricular (LV) volumes and ejection fraction (LVEF) represent important components of pharmacologic stress imaging with either myocardial CT perfusion (CTP) or gated single-photon emission CT (SPECT) myocardial perfusion imaging (SPECT-MPI). OBJECTIVES: We compared measurements of left ventricular function and volumes obtained with CTP and SPECT-MPI. METHODS: Forty-seven patients (mean age, 62 +/- 11 years; male, n = 39) underwent stress CTP and SPECT-MPI. LVEF (in %), end-systolic volume (ESV; in mL), and end diastolic volume (EDV; in mL) derived from stress CTP images were compared with SPECT-MPI. RESULTS: Stress CTP was in good agreement with SPECT-MPI for quantification of LVEF (r = 0.91), EDV (r = 0.75), and ESV (r = 0.83; all P < 0.001). The mean LVEF measured by stress CTP (66% +/- 17%) was similar to SPECT MPI (64% +/- 15%). Similar values were also derived for mean EDV (123 +/- 30 mL vs 120 +/- 34 mL) and ESV (44 +/- 28 mL vs 51 +/- 34 mL) for CTP and SPECT-MPI, respectively. Good agreement was also shown between both techniques for the assessment of regional wall motion with identical wall motion scores in 95.3% of the segments (kappa = 0.79). CONCLUSIONS: LVEF and LV volume parameters as determined by dual-source 64-slice adenosine stress CTP show a high correlation with values obtained with stress-gated SPECT-MPI. PMID- 22222165 TI - Relationship between NF-kappaB expression and malignancy of canine mammary gland tumor tissues. AB - In this study, the nuclear expression of nuclear factor kappa B (NF-kappaB) in 48 tissues specimens from 25 canine spontaneous mammary gland tumor (MGT) patients was assessed by immunohistochemistry to compare their levels with clinical features, histological types, prognostic outcomes and proliferative activities, including the mitotic index (MI) and cylcinD1 expression. Twelve of eighteen (66.7%) malignant tumor tissues showed greater than 10% nuclear staining, while benign tumor and hyperplastic tissues showed less than 10% nuclear staining. Higher nuclear expression of NF-kappaB was positively correlated with larger tumor size, lymph node metastasis and higher MI; however, no correlation was observed with distant metastasis and cyclin D1 expression. Higher NF-kappaB nuclear expression correlated with shorter patient survival. These findings suggest that NF-kappaB is a useful prognostic factor for canine MGT patients. PMID- 22222166 TI - Risk factors of subsequent vertebral compression fractures after vertebroplasty. AB - OBJECTIVE: To elucidate the risk factors for a subsequent vertebral compression fracture following percutaneous vertebroplasty, we analyzed the potential predictors of vertebral compression fractures adjacent to or remote from fractures previously treated with percutaneous vertebroplasty. DESIGN: This is a retrospective cohort study. BACKGROUND: A major concern after percutaneous vertebroplasty in patients with osteoporosis is the occurrence of subsequent vertebral compression fractures in the untreated vertebral bodies. The risk factors for the development of subsequent vertebral compression fractures after percutaneous vertebroplasty are unclear. METHODS: Two hundred four consecutive patients underwent percutaneous vertebroplasty for acute vertebral compression fractures between January 2007 and December 2008. Forty-nine patients were excluded. Subsequent vertebral compression fractures were diagnosed by bone edema changes on magnetic resonance imaging. Patient's demographic data were used for univariate and multivariable binary logistic regression analyses. RESULTS: Forty three (27.7%) of the 155 patients had subsequent vertebral compression fractures within 2 years of percutaneous vertebroplasty, with 21 (48.8%) of these patients having fractures detected within 3 months. Adjacent vertebral compression fractures tended to occur sooner, although not significantly (log-rank test, P = 0.112). On multivariate analyses, only the T-score of bone mineral density was significantly associated with subsequent vertebral compression fractures (P < 0.0001; odds ratio = 0.27; 95% confidence interval, 0.15-0.49). CONCLUSIONS: The only risk factor significantly associated with subsequent vertebral compression fractures following percutaneous vertebroplasty was a low bone mineral density T score. Patients with lower bone mineral density have a higher incidence of vertebral compression fractures and thus need more intensive clinical and radiological follow-up. PMID- 22222167 TI - The epidemiology of injury for an elite junior Australian Football cohort. AB - OBJECTIVES: To implement an injury recording protocol in a junior elite Australian Football competition and determine the injury profile of this population. DESIGN: Longitudinal cohort study. METHODS: Players from an elite Under 18 Australian Football competition were tracked throughout one football season in terms of participation or non-participation in the football competition. Injury reporting forms were collected for all players who were not available for selection as a result of injury. RESULTS: The cohort consisted of 532 players who provided consent for inclusion in the study (100% of players in the competition). There were 256 injuries sustained during the season. Results were standardised to a 40 man team to allow comparison with results from the Australian Football League. The injury incidence was 17.1 new injuries per club (95% CI 14.1-19.4), and prevalence 63.3 missed matches per club (95% CI 59.1 67.1). The category "Ankle joint injuries" was the most commonly reported (n=34) and "Collision with another player" was the main injury mechanism (n=75). CONCLUSIONS: The most commonly injured region in junior elite Australian Football was the ankle and collision with another player was the most common injury mechanism. As with previous reports on junior Australian Football, injury incidence was low in comparison to the senior elite competition. Defining the injury profile guides injury prevention strategies. Analysis of injury in junior elite football may provide a unique opportunity to affect both junior and senior injury rates. PMID- 22222168 TI - Exploring the cell uptake mechanism of phospholipid and polyethylene glycol coated gold nanoparticles. AB - Recently, there has been a lot of interest in using gold nanoparticles (GNPs) for biomedical applications due to their biocompatibility. To increase GNP cell uptake and circulation half-life, and to improve its bio-distribution in vivo, we chose to coat GNPs with 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac glycerol) (sodium salt) (POPG) and polyethylene glycol (PEG). Two different methods were used to synthesize POPG-GNPs or PEG-GNPs, but the resulting nanoparticle sizes and morphologies were similar. Under the same incubation conditions, POPG-GNPs can be uptaken quicker than PEG-GNPs by cells-specifically, the maximum uptake was 8 h versus 16 h after incubation. In addition, the uptake amount of POPG-GNPs was more than that of PEG-GNPs. The uptake processes were confirmed by SEM and TEM images. The main reason for the greater uptake of POPG GNPs can be attributed to the structural similarities between the POPG coating and the cell membrane as well as GNP aggregation. PMID- 22222169 TI - Ureteral stents placed at the time of urinary diversion decreases postoperative morbidity. AB - OBJECTIVE: To determine the impact of stenting ureteroenteric anastomoses on postoperative stricture rate and gastrointestinal recovery in continent and noncontinent urinary diversions (UDs). PATIENTS AND METHODS: We retrospectively reviewed the clinical and pathologic data on 192 consecutive patients who underwent a radical cystectomy and UD. Patients received either a continent or noncontinent UD with or without stent placement through the ureteroenteric anastomoses. Stricture rate, gastrointestinal recovery, length of hospital stay, and stricture characteristics were analyzed. Study endpoints were compared between four groups--stented and nonstented continent and stented and nonstented noncontinent UDs. RESULTS: 36% of patients were stented and 64% were nonstented at the time of UD. Total ureteral stricture rate was 9.9%. There was no statistically significant difference in stricture rate (p = 0.11) or length of hospital stay (p = 0.081) in stented compared to nonstented patients. There was a significantly (p = 0.014) greater rate of ileus in patients who were nonstented in both continent and noncontinent UDs. CONCLUSION: Stenting of ureteroenteric anastomoses in both continent and noncontinent UD has no effect on postoperative stricture rate, but is associated with lower rates of postoperative ileus. PMID- 22222170 TI - Treatment with simvastatin inhibits the formation of abdominal aortic aneurysms in rabbits. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) is a common and lethal disease. AAAs are associated with atherosclerosis, chronic inflammation, and extracellular matrix degradation. The aim of this study was to determine whether treatment with simvastatin can influence the development of experimental aortic aneurysms in a rabbit model. MATERIALS AND METHODS: A total of 76 rabbits were randomized in four groups: in group I (n = 12), where the abdominal aortas were exposed to 0.9% NaCl, and in group II (n = 24), group III (n = 24) and group IV (n = 18), where the aortas were exposed to CaCl2 0.5 mol/L for 15 minutes after laparotomy. Group III received 2 mg/kg simvastatin daily starting 7 days before laparotomy, and in group IV, the daily treatment with simvastatin started 7 days after laparotomy. Animals were sacrificed at intervals of first, second, third, and fourth week to obtain measurements of aortic diameter and histological examination. Moreover, immunohistochemistry was used in order to examine the relative distribution of matrix metalloproteinases (MMPs) 2 and 9 (MMP-2 and MMP-9, respectively) and tissue inhibitor 1 of MMPs within the aortic aneurysms. RESULTS: The increase of aortic diameter in animals of group I ranged from 4.6% to 7.6%; in group II, from 41% to 85% (P < 0.001 vs. group I); in group III, from 9% to 18% (group II vs. group III, P < 0.001); and in group IV; from 36% to 38%. Moreover, aortic specimens of group II presented a statistically significant increase in MMP-2 and MMP-9 immunoexpression compared with other groups (I, III, IV) (P < 0.05 for all comparisons), with the exception of animals of group IV at the end of second week. Immunoreactivity of tissue inhibitor 1 of MMPs was not statistically different among groups II, III, and IV. CONCLUSIONS: Simvastatin may prove clinically significant in suppressing the development and expansion of AAAs and, thereby, in reducing the risk of rupture and the need for repair. PMID- 22222171 TI - Towards erythropoietin equations that estimate oxygen delivery rather than static hemoglobin targets. AB - Although we have known since the 19th century that oxygen tension affects erythrocyte production, we have only recently begun to understand many subtleties of erythropoietin physiology. The unanticipated increase in mortality associated with erythropoietin use found in recent randomized studies is prompting a reassessment of static hemoglobin targets. Hemoglobin levels in dialysis patients do not correlate with endogenous erythropoietin production and may be related to differences in oxygen delivery resulting from shifts in the oxygen-hemoglobin dissociation curve. The time may have arrived to develop more physiologic targets such as oxygen delivery that would mimic the natural response to hypoxia. There are several equations that already exist that can compensate for the effects of the concentration of inorganic and organic phosphates as well as pH, carbon dioxide, and temperature on the delivery of oxygen. However, since the shape and dispersion of the oxygen-hemoglobin dissociation curve may actually change in different disease states, more work is needed. PMID- 22222172 TI - Peripheral administration of poly I:C disrupts contextual fear memory consolidation and BDNF expression in mice. AB - In the current study, administration of poly I:C induced a deficit in contextual, but not auditory-cue, fear memory consolidation. This memory deficit coincided with a decrease in hippocampal and cortical BDNF mRNA expression. These results extend prior work, and suggest that a single peripheral injection of poly I:C disrupts contextual fear memory consolidation processes in adult mice, and that these deficits may potentially be mediated by diminished BDNF expression. PMID- 22222173 TI - The influence of subcortical ischemic lesions on cognitive function and quality of life in late life depression. AB - OBJECTIVES: Subcortical ischemic lesions (SIL) are known to contribute to the pathogenesis of late life depression. The present study examined the influence of SIL on cognitive function and quality of life in elderly Koreans with major depressive disorder (MDD). METHODS: MDD patients (n=86) underwent CT scans and were classified as having SIL if they had a score of 2 or above on age-related white matter changes (ARWMC) scale. Demographic data, psychiatric, medical history, neuropsychological test, quality of life, and depressive symptomatology were compared between MDD patients with and without SIL. RESULTS: SIL with grade 2 or above were found in deep white matter of 22 (25.6%) depressed patients and in basal ganglia of 9 (10.5%) depressed patients. Depressed patients with deep white matter lesions showed poor performance on MMSE-KC and decreased quality of life, particularly in physical function and physical role limitation, as compared to depressed patients without deep white matter lesions. CONCLUSION: These data support that SIL may cause general cognitive dysfunction and poor physical health. More attention should be paid to detection and management of SIL in late life depression in clinical setting. PMID- 22222174 TI - fMRI responses to emotional faces in children and adolescents at genetic risk for psychiatric illness share some of the features of depression. AB - BACKGROUND: Fronto-limbic regions of the brain including the sub-genual (sgPFC) and medial prefrontal (mPFC) cortices are central to processing emotionally salient and hedonic stimuli (Mayberg, 2009) and implicated in depression. The relevance of cortico-limbic models of emotion and reward processing in children with genetic risk for psychiatric disorders has not been assessed. METHODS: Here we studied adolescents at risk for schizophrenia (HRS) and controls (HC) using an event-related fMRI continuous affective appraisal task. HRS were divided into sub groups based on the presence or absence of negative symptoms (Miller et al., 2003), HRS_NS+ and HRS_NS- respectively. Brain responses to positive, negative and neutral emotional stimuli were estimated. RESULTS: Consistent with observations in the depressive phenotype, for positively valenced stimuli, HRS_NS+ (relative to HC and HRS_NS-) were characterized by hypo-responsivity of the sgPFC and the mPFC, but hyper-responsivity of the mid-brain. sgPFC and mPFC signals were coupled across groups. LIMITATIONS: Such studies can benefit from larger sample sizes, though our observed effect sizes were in the moderate to large range. CONCLUSIONS: Children and adolescents at risk for psychiatric illness and who evince reliably present negative symptoms show brain responses to socially rewarding stimuli similar to those observed in depression. Studies in at risk children and adolescents may be important in understanding how early manifestations of depression-like characteristics impact brain function. PMID- 22222175 TI - COMT Met (158) modulates facial emotion recognition in bipolar I disorder mood episodes. AB - BACKGROUND: One of the many cognitive deficits reported in bipolar disorder (BD) patients is facial emotion recognition (FER), which has recently been associated with dopaminergic catabolism. Catechol-O-methyltransferase (COMT) is one of the main enzymes involved in the metabolic degradation of dopamine (DA) in the prefrontal cortex (PFC). The COMT gene polymorphism rs4680 (Val158Met) Met allele is associated with decreased activity of this enzyme in healthy controls. The objective of this study was to evaluate the influence of Val158Met on FER during manic and depressive episodes in BD patients and in healthy controls. MATERIALS AND METHODS: 64 BD type I patients (39 in manic and 25 in depressive episodes) and 75 healthy controls were genotyped for COMT rs4680 and assessed for FER using the Ekman 60 Faces (EK60) and Emotion Hexagon (Hx) tests. RESULTS: Bipolar manic patients carrying the Met allele recognized fewer surprised faces, while depressed patients with the Met allele recognized fewer "angry" and "happy" faces. Healthy homozygous subjects with the Met allele had higher FER scores on the Hx total score, as well as on "disgust" and "angry" faces than other genotypes. CONCLUSION: This is the first study suggesting that COMT rs4680 modulates FER differently during BD episodes and in healthy controls. This provides evidence that PFC DA is part of the neurobiological mechanisms of social cognition. Further studies on other COMT polymorphisms that include euthymic BD patients are warranted. Clinicaltrials.gov identifier: NCT00969. PMID- 22222176 TI - Pulse wave velocity in Korean American men and women. AB - Arterial stiffness is an important clinical marker of cardiovascular diseases. Although many studies have been conducted on different racial groups, less is known about arterial stiffness in Asian Americans. Korean Americans constitute the fifth largest subgroup in the Asian American population and reportedly have a noticeably high prevalence of hypertension. The aims of this study were to assess arterial stiffness and blood pressure and to examine the effect of age and gender on arterial stiffness and blood pressure in 102 Korean American men and women aged 21 to 60 years. The values of arterial stiffness for Korean Americans in this study were compared to published reference values for other racial and ethnic groups. Arterial stiffness was measured by carotid-femoral pulse wave velocity, which is the gold standard for determining arterial stiffness. Findings indicated that aging was an important determinant of arterial stiffness, which increased linearly with age. Although there was no gender difference observed in arterial stiffness, the effect of age on arterial stiffness was greater in women than in men. After adjusting for covariates including age, body mass index, and smoking, multiple regression models showed that arterial stiffness and gender were significant predictors of systolic and diastolic blood pressure. The comparisons of these findings to those from several other studies that used the same method to measure arterial stiffness showed that Korean Americans may have levels of arterial stiffness that are similar to or slightly higher than those of other racial groups. Considering that arterial stiffness is an independent predictor of future development of hypertension, more studies are required to examine cardiovascular risk of this understudied group. PMID- 22222177 TI - A program of 3 physical therapy modalities improves peripheral arterial disease in diabetes type 2 patients: a randomized controlled trial. AB - BACKGROUND AND OBJECTIVE: Type 2 diabetes is one of the main causes of peripheral vascular disease. The beneficial effects of exercise on glucose homeostasis include a marked stimulation of blood glucose utilization during and after its performance. The objective of this study was to determine the effects of a program of 3 physical therapy modalities on blood circulation in patients with type 2 diabetes with peripheral arterial disease. SUBJECTS AND METHOD: A randomized controlled trial was undertaken. Sixty-eight patients with type 2 diabetes with Leriche-Fontaine stage I or IIa peripheral arterial disease were randomly assigned to an exercise or placebo group. For 20 weeks, the exercise group underwent treatment comprising 3 exercises at proximal, medium, and distal segments of the lower limbs, and the placebo group received sham treatment with disconnected ultrasound equipment. Peripheral arterial disease was determined by evaluating the ankle/brachial index (ABI), Doppler flow velocity, blood parameters, cardiovascular risk score, and heart rate during exercise test. RESULTS: After 20 weeks of treatment, significant differences between groups were found in the following: right (P < .039) and left (P < .023) ABI; Doppler flow velocity (cm/s) in the right (P < .010) and left (P < .026) posterior tibial artery and in the right (P < .012) and left (P < .022) dorsalis pedis artery; and fibrinogen (P < .045), hemoglobin (P < .021), cholesterol (P < .012), high density lipoprotein cholesterol (P < .031), and HbA1c (P < .034) values. There was no significant difference in low-density lipoprotein cholesterol values (P < .110) between the groups. CONCLUSION: A program of these physical therapy modalities improves ABI, Doppler flow velocity, and blood parameters in patients with type 2 diabetes. PMID- 22222178 TI - Microbial transglutaminase-induced structural and rheological changes of cationic and anionic myofibrillar proteins. AB - This study investigated the effects of microbial transglutaminase (TG) on structural changes in porcine myofibrillar protein (MP) under varying pH (2.0 6.0) and two ionic strength conditions (0.1M versus 0.6M NaCl). Lowering the pH below the isoelectric point (pI) of myosin induced protein unfolding as revealed by surface hydrophobicity and differential scanning calorimetry. Although the MP solubility at the low ionic strength (0.1M NaCl) was maximal at pH 3.0, both SDS PAGE profiles and dynamic rheology indicated TG could not cross-link MP under this condition. Based on the carboxyl group content, the TG-catalyzed deamidation was dominant at a pH lower than the pI of myosin (pH 5.0) while cross-linking occurred at higher pH. Moreover, deamidation had no effect on rheological properties of MP. The results indicate that the TG reaction was governed by the pH of substrate protein, and the reaction intensity was related to the solubility of protein. PMID- 22222179 TI - Reduced memory specificity predicts the acquisition of problem solving skills in psychoeducation. AB - BACKGROUND AND OBJECTIVES: Research has shown that overgeneral autobiographical memory (OGM) is a valid predictor for the course of depression. It is not known, however, whether OGM also moderates information uptake and consolidation in a psychoeducation program to prevent stress, anxiety and depression. The present study was designed to investigate whether the Autobiographical Memory Test (AMT; Williams, & Broadbent, 1986) is a valid predictor for the actual unfolding of skills learned through psychoeducation. METHODS: The questionnaire included primarily the AMT and the Stress Anxiety Depression Means-Ends Problem Solving Questionnaire (SAD-MEPS). It was filled in prior to and after the psychoeducational course by 23 participants. RESULTS: Correlations were calculated for the AMT at baseline and the differences between the pre and post measurements on the SAD-MEPS. Significant correlations were observed between the number of specific responses and the changes in the number of relevant means (r = .49, p < .01). LIMITATIONS: The sample size was rather small, but several checks were able to reduce the chance of spurious findings. CONCLUSIONS: These findings may have important implications for the guidance to and the setup of psychoeducational interventions. Suggestions include screening and memory specificity training prior to course commencement. PMID- 22222180 TI - Acousto-optic interaction with leaky surface acoustic waves in Y-cut LiTaO3 crystals. AB - The acousto-optic interaction with leaky surface acoustic wave radiation into the bulk of YX-cut LiTaO(3) crystals has been investigated. The light incidence and diffraction angles corresponding to the strongest acousto-optic interaction were calculated and measured as functions of the acoustic wave frequency. The dependencies of the diffracted light intensity on the amplitude of radio frequency voltage applied to the interdigital transducer (IDT) were studied. Our acousto-optic measurements revealed generation, by the IDTs, of slow shear bulk acoustic waves propagating at different angles depending on their frequency. A secondary acousto-optic interaction from the bulk waves radiated by the receiving IDT has been studied. PMID- 22222181 TI - Intra-isthmus reentry associated with uncorrected double inlet left ventricle and transposition of the great arteries. AB - A 62-year-old man with uncorrected cyanotic congenital heart disease involving double inlet left ventricle with visceral and atrial situs solitus, L-looped ventricles, L-transposed great vessels, and pulmonary stenosis, presented with recurrent atrial tachycardia. Entrainment mapping revealed the arrhythmia mechanism to be an uncommon micro-reentrant cavotricuspid isthmus-dependent circuit (intra-isthmus reentry), which was amenable to radiofrequency ablation. This uncommon right atrial arrhythmia is yet to be reported in patients with complex congenital heart disease and was amenable to radiofrequency ablation. PMID- 22222182 TI - Elevated serum C-reactive protein as a predictive factor for anastomotic leakage in colorectal surgery. AB - BACKGROUND: C-reactive protein (CRP) has been used as an indicator of postoperative complications in abdominal surgery. Its short half-life makes it a reliable marker of the systemic inflammatory response secondary to a surgical procedure or to the appearance of complications, rapidly returning to normal values with the recovery of the patient. AIM: To demonstrate the value of sequential serum determinations of postoperative C-reactive protein (CRP) and white blood cell counts (WBC) in the identification of increased risk of anastomotic leakage after colorectal surgery. METHODS: We reviewed the daily postoperative serum CRP and white blood cell counts in 173 patients who underwent surgery for colorectal disease with anastomosis, between January 2008 and October 2009. Patients with anastomotic leakage (Group A, n = 24) were compared to patients without leakage (Group B, n = 149). Patients with ongoing infections before surgery or with acquired postoperative infections other than leakage were excluded. Mean pre- and postoperative values of CRP and WBC were compared. RESULTS: The diagnosis of anastomotic leakage was made between the 4th and 11th postoperative day (POD; mean 7th POD). The daily average values of serum CRP were significantly higher in group A starting at the 2nd POD and remained significantly elevated until the diagnosis of leakage (p = 0.003). The cut-off value of 140 mg/L on the 3rd POD maximized the sensitivity (78%) and specificity (86%) of serum CRP in assessing the risk of leakage. Comparison of postoperative serum WBC values did not show any significant differences between the two groups until the 6th POD. CONCLUSION: According to these results, an early and persistent elevation of CRP after colorectal surgery with anastomosis, is a marker of anastomotic leakage. A cut-off value > 140 mg/L on POD3 maximizes sensitivity and specificity. PMID- 22222183 TI - Good baseline balance - a prerequisite for valid comparison. PMID- 22222184 TI - Functionalized carriers for the improved delivery of plasminogen activators. AB - Various plasminogen activators have been routinely used for the treatment of thrombotic diseases. However, these agents possess various problems e.g. short half life and other bleeding complications. To improve the effectiveness as well as to reduce the side effects of these drugs, various modifications have been made. For example, fibrin specific plasminogen activators have been developed. However, these agents also demonstrated various bleeding complications, clinically. Nowadays, so many carrier systems have been explored to improve the activity of these agents. Novel carriers not only improve the effectiveness of these drugs but also reduce the side effects. In the present review, we discuss novel carrier based strategies to improve the delivery of the plasminogen activators to site of thrombus. PMID- 22222185 TI - Flow cytometric enumeration of Plasmodium berghei-infected red blood cells stained with SYBR Green I. AB - High-throughput methods for evaluation of in vivo efficacy of candidate compounds against Plasmodium parasites are necessary during the antimalarial drug development process. It is essential that enumeration of parasitemia in the infected blood from experimental host animals is accurate and reliable. Flow cytometric enumeration of parasitized cells stained with fluorescent dye is a rapid alternative method to conventional microscopic counting. In this study, a protocol for flow cytometric enumeration of rodent malaria parasite Plasmodium berghei-infected red blood cells (RBC) stained with SYBR Green I was developed. The optimal concentration of SYBR Green I used to stain infected RBC was 4* for 30 min. This SYBR Green I staining protocol in combination with the bi dimensional FL-1(530)/FL-3(620) detection method accurately detects parasitemia above 0.02%. The dye is stable during the prolonged incubation period necessary for accurate enumeration of parasitemia, with no loss of fluorescent signal over a period of hours. This protocol was validated in an antimalarial assay and the result was comparable to that obtained from conventional microscopic counting. The SYBR Green I flow cytometric protocol is thus a rapid and precise tool for high-throughput in vivo antimalarial drug screening. PMID- 22222186 TI - Dicarbonyl reduction by single enzyme for the preparation of chiral diols. AB - Chiral diols are a group of key building blocks useful for preparing a variety of important chiral chemicals. While the preparation of optically pure diols is generally not an easy task in synthetic organic chemistry, three classes of enzymes, namely dicarbonyl reductase, dioxygenase and epoxide hydrolase, display remarkable ability to stereoselectively introduce two hydroxyl groups in a single step enzymatic conversion. In this tutorial review, we pay special attention to dicarbonyl reductases that directly produce chiral diols through the bio reduction of two carbonyl groups. The dicarbonyl reductases include diketoreductase, alpha-acetoxy ketone reductase and sepiapterin reductase. We present these exceptional enzymes in the context of source and properties, structure and catalytic mechanism as well as biocatalytic application. In addition to the broad substrate specificity, the excellent stereoselectivity and high catalytic efficiency of these enzymes have positioned them as valuable biocatalysts. With more sophisticated understanding of the structure-function relationship, the practical utilities of these enzymes associated with their interesting chemistry will be considerably appreciated over time. Moreover, rational redesign and molecular evolution of these unusual biocatalysts will truly enable their broader applications in the synthesis of chiral diols in the future. PMID- 22222187 TI - Prevalence of dyslipidemia and goal attainment after initiating lipid-modifying therapy: a Thai multicenter study. AB - Previous studies focused on attaining low-density lipoprotein cholesterol (LDL-C) goals after lipid-modifying therapy (LMT), but data on achieving normal levels of triglyceride and high-density lipoprotein cholesterol (HDL-C) are limited. We reviewed medical records of patients initiated on LMT. High risk was defined as patients with coronary heart disease, diabetes, or 10-year Framingham risk >20%. Among 806 patients enrolled, 429 were at high risk. Prior to initiation of LMT, 66%, 35%, and 44% overall and 69%, 35%, and 45% in the high-risk group had elevated LDL-C, elevated triglyceride, and low HDL-C, respectively. After 12 months of LMT, 21%, 32%, and 39% overall and 26%, 25%, and 43% in the high-risk group still had elevated LDL-C, elevated triglyceride, and low HDL-C, respectively. Approximately 1 of 5 patients continued to experience elevated LDL C coupled with elevated triglyceride and/or low HDL-C. In conclusion, a substantial proportion of patients initiated on LMT continued to have lipid abnormalities. PMID- 22222188 TI - Declining kidney function increases the prevalence of sleep apnea and nocturnal hypoxia. AB - BACKGROUND: Sleep apnea is an important comorbidity in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Although the increased prevalence of sleep apnea in patients with ESRD is well established, few studies have investigated the prevalence of sleep apnea in patients with nondialysis dependent kidney disease, and no single study, to our knowledge, has examined the full spectrum of kidney function. We sought to determine the prevalence of sleep apnea and associated nocturnal hypoxia in patients with CKD and ESRD. We hypothesized that the prevalence of sleep apnea would increase progressively as kidney function declines. METHODS: Two hundred fifty-four patients were recruited from outpatient nephrology clinics and hemodialysis units. All patients completed an overnight cardiopulmonary monitoring test to determine the prevalence of sleep apnea (respiratory disturbance index >= 15) and nocturnal hypoxia (oxygen saturation < 90% for >= 12% of monitoring). Patients were stratified into three groups based on estimated glomerular filtration rate (eGFR) as follows: eGFR >= 60 mL/min/1.73 m(2) (n = 55), CKD (eGFR < 60 mL/min/1.73 m(2) not on dialysis, n = 124), and ESRD (on hemodialysis, n = 75). RESULTS: The prevalence of sleep apnea increased as eGFR declined (eGFR >= 60 mL/min/1.73 m(2), 27%; CKD, 41%; ESRD, 57%; P = .002). The prevalence of nocturnal hypoxia was higher in patients with CKD and ESRD (eGFR >= 60 mL/min/1.73 m(2), 16%; CKD, 47%; ESRD, 48%; P < .001). CONCLUSIONS: Sleep apnea is common in patients with CKD and increases as kidney function declines. Almost 50% of patients with CKD and ESRD experience nocturnal hypoxia, which may contribute to loss of kidney function and increased cardiovascular risk. PMID- 22222189 TI - Risk of post-lung transplant renal dysfunction in adults with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) is one of the leading indications for lung transplantation. The incidence and pre-lung transplant risk factors for posttransplant renal dysfunction in the CF population remain undefined. METHODS: We conducted a cohort study using adults (>= 18 years old) in the CF Foundation Patient Registry from 2000 to 2008 to determine the incidence of post-lung transplant renal dysfunction, defined by an estimated glomerular filtration rate of < 60 mL/min/1.73 m(2). Multivariable Cox proportional hazards modeling was used to identify independent pretransplant risk factors for post-lung transplant renal dysfunction. RESULTS: The study cohort included 993 adult lung transplant recipients with CF, with a median follow-up of 2 years. During the study period, 311 individuals developed renal dysfunction, with a 2-year risk of 35% (95% CI, 32%-39%). Risk of posttransplant renal dysfunction increased substantially with increasing age (25 to < 35 years vs 18 to < 25 years: hazard ratio [HR], 1.60; 95% CI, 1.15-2.23; vs >= 35 years: HR, 2.45; 95% CI, 1.73-3.47) and female sex (HR, 1.56; 95% CI, 1.22-1.99). CF-related diabetes requiring insulin therapy (HR, 1.30; 95% CI, 1.02-1.67) and pretransplant renal function impairment (estimated glomerular filtration rate, 60-90 mL/min/m(2) vs > 90 mL/min/m(2): HR, 1.58; 95% CI, 1.19-2.12) also increased the risk of posttransplant renal dysfunction. CONCLUSIONS: Renal dysfunction is common following lung transplant in the adult CF population. Increased age, female sex, CF-related diabetes requiring insulin, and pretransplant renal impairment are significant risk factors. PMID- 22222190 TI - The role of relationship quality and perceived partner responses with pain and disability in those with back pain. AB - OBJECTIVE: The objectives of this study were to investigate the associations of key constructs of relationship quality (cohesion, consensus, and satisfaction) and perceived partner responses to pain behavior (e.g., solicitous and negative responses) with the outcomes of pain and disability in those with long-term low back pain, and to explore the role of the patient's depressive symptom mood state on those associations. METHODS: Self-report questionnaires on pain intensity, disability, relationship quality, perceived partner reactions to pain, and depressive symptoms were collected from participants (N = 174) taking part in a longitudinal study on low back pain within a primary care sample. RESULTS: Participants reporting more consensus (e.g., agreement about sexual intimacy, level of affection) in their relationships had significantly higher pain intensity (P = 0.03), and solicitous partner responses (P = 0.04) were significantly positively associated with disability levels. However, the findings for pain intensity were only present in those with higher levels of depression, while the association of solicitous responses with disability was only significant in those with lower levels of depression, indicating a suppression effect of depression on pain and disability. CONCLUSIONS: Depressive symptoms play a significant role in determining the associations between relationship quality, perceived partner reactions, and pain and disability. The relationship construct of consensus and perceived solicitous responses were associated with pain and disability. These findings illustrate the importance of social context and patient mood state on the outcomes for those with low back pain. PMID- 22222191 TI - Agonist trigger: what is the best approach? Agonist trigger with vitrification of oocytes or embryos. AB - Agonist triggering combined with oocyte vitrification and ET in a subsequent natural cycle avoids ovarian hyperstimulation syndrome in patients at risk and shows excellent cycle outcome. PMID- 22222192 TI - Effects of low molecular weight heparin and heparin-binding epidermal growth factor on human trophoblast in first trimester. AB - OBJECTIVE: To evaluate the effects of low molecular weight heparin (LMWH) and heparin-binding epidermal growth factor (HB-EGF) on the biological function of human trophoblast in first trimester. DESIGN: Control experiment. SETTING: Two academic-based reproductive centers. PATIENT(S): The first trimester human placentas (gestational age, 5-10 weeks) from patients who underwent electively induced abortions. INTERVENTION(S): Cultured trophoblast treated with LMWH or LMWH and HB-EGF. MAIN OUTCOME MEASURE(S): The biological function (proliferation, invasion, and differentiation) of trophoblast and the interaction between LMWH and HB-EGF on trophoblast in vitro. RESULT(S): 1) At a dose of 0.25 IU/mL-2.5 IU/mL LMWH promoted trophoblast proliferation, enhanced their invasion, and increased hCG secretion. The LMWH had little effect or the opposite effect at other concentrations. These differences were statistically significant. 2) Combined use of LMWH and HB-EGF significantly promoted proliferation and invasion, but there was no difference in hCG secretion compared with solo LMWH or solo HB-EGF. CONCLUSION(S): The LMWH exerts a cytoprotective effect by regulating trophoblast proliferation, invasion, and differentiation. The HB-EGF is an important factor in the effects of LMWH on trophoblast function. PMID- 22222193 TI - A randomized, phase II study describing the efficacy, bleeding profile, and safety of two low-dose levonorgestrel-releasing intrauterine contraceptive systems and Mirena. AB - OBJECTIVE: To identify an appropriate dose for a new contraceptive levonorgestrel intrauterine system (LNG-IUS). DESIGN: Randomized, open-label, three-arm, phase II study. SETTING: Thirty-seven centers in five European countries. PATIENT(S): Parous or nulliparous women aged 21-40 years. INTERVENTION(S): Treatment with LNG IUSs with initial in vitro release rates of 12 or 16 MUg/d (LNG-IUS12/16) or 20 MUg/d (Mirena). MAIN OUTCOME MEASURE(S): Pearl index, bleeding profile, ease/pain of placement/removal, adverse events. RESULT(S): A total of 738 subjects had an LNG-IUS placed (LNG-IUS12, n = 239; LNG-IUS16, n = 245; Mirena, n = 254). One, 5, and 0 pregnancies occurred in the LNG-IUS12, LNG-IUS16, and Mirena groups, respectively (3-year unadjusted Pearl indices: 0.17, 0.82, and 0). The bleeding profiles were similar in all groups, although total bleeding and spotting days decreased with increasing LNG dose. During 3 years, 10 subjects in the LNG-IUS12 (2 women), LNG-IUS16 (3 women), and Mirena (5 women) groups reported serious adverse events, possibly related to study treatment. Placement of LNG-IUS12 and LNG-IUS16 was considered easy in 94% versus 86.2% in the Mirena group and 72.3% in the LNG-IUS12/LNG-IUS16 group reported either "no pain" or only "mild pain" during placement versus 57.9% in the Mirena group. CONCLUSION(S): LNG-IUS12 and LNG-IUS16 provided effective contraception, acceptable bleeding patterns, and were well tolerated compared with Mirena. PMID- 22222194 TI - Which patients pursue fertility preservation treatments? A multicenter analysis of the predictors of fertility preservation in women with breast cancer. AB - OBJECTIVE: To evaluate predictors of undergoing fertility preservation treatment (FPT) in women with breast cancer. DESIGN: Secondary analysis of a clinical database. SETTING: Three academic fertility preservation centers. PATIENT(S): One hundred eight patients with breast cancer undergoing FPT and 77 patients with breast cancer not undergoing FPT from 2005 to 2010. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Patients' demographic and medical information. RESULT(S): Women who had FPT were older, wealthier, and had lower cancer stage compared with women who did not have FPT. The rate of the administration of neoadjuvant chemotherapy (NAC) was significantly lower in women who underwent FPT. After adjusting for age, body mass index (BMI), income, cancer stage, and center, a negative correlation persisted between NAC and FPT (odds ratio 0.091, 95% confidence interval 0.009-0.904). When we stratified the women by center, women at center 1 had a significantly lower FPT rate, lower parity, higher BMI, more advanced cancer stage, and lower income compared with centers 2 and 3. The rates of NAC were significantly higher in center 1. CONCLUSION(S): Although age, BMI, income, cancer stage, center, and NAC seem to be associated with undergoing FPT, NAC is the only modifiable variable. Because NAC restricts the time available for FPT, oncologists may consider offering adjuvant chemotherapy, except in cases in which NAC clearly improves survival, in women who are interested in FPT. PMID- 22222195 TI - 11-deoxy prostaglandin F(2alpha), a thromboxane A2 receptor agonist, partially alleviates embryo crowding in Lpar3((-/-)) females. AB - OBJECTIVE: To determine cyclooxygenase-derived prostanoid signaling in alleviating embryo crowding in the Lpar3((-/-)) females. DESIGN: Experimental mouse model. SETTING: Research laboratories. ANIMAL(S): Wild-type, Lpar3((+/-)), and Lpar3((-/-)) mice. INTERVENTION(S): Intraperitoneal (IP) administration of prostaglandin E(2) (PGE(2)), cPGI (a stable analogue of PGI(2)), and 11-deoxy prostaglandin F(2alpha) (11-deoxy PGF(2alpha), a thromboxane A(2) receptor agonist) to preimplantation gestation day 3.5 Lpar3((-/-)) females. MAIN OUTCOME MEASURE(S): Implantation sites were detected by blue dye reaction and embryo spacing was determined by the distribution of the implantation sites along the uterine horns on gestation day 4.5; pregnancy outcome was measured by litter size at birth. RESULT(S): Administration of PGE(2) + cPGI on gestation day 3.5 Lpar3(( /-)) females restored on-time implantation but did not affect embryo spacing or the number of implantation sites detected on gestation day 4.5; PGE(2) + cPGI treatment increased litter size at birth. Administration of PGE(2) + cPGI + 11 deoxy PGF(2alpha) on gestation day 3.5 Lpar3((-/-)) females rescued on-time implantation, partially dispersed the clustered implantation sites normally observed in the Lpar3((-/-)) females, increased the number of implantation sites detected on gestation day 4.5, and increased litter size at birth. CONCLUSION(S): The thromboxane A(2) receptor agonist 11-deoxy PGF(2alpha) can partially alleviate embryo crowding in the Lpar3((-/-)) females and embryo crowding likely contributes to reduced litter size in the Lpar3((-/-)) females. PMID- 22222196 TI - Memory T cell inflation: understanding cause and effect. AB - Typically, during viral infections, T cells encounter antigen, undergo proliferative expansion and ultimately contract into a pool of memory cells. However, after infection with cytomegalovirus, a ubiquitous beta-herpesvirus, T cell populations specific for certain epitopes do not contract but instead are maintained and/or accumulate at high frequencies with a characteristic effector memory phenotype. This feature has also been noted after other infections, for example, by parvoviruses. We discuss this so-called memory T cell inflation and the factors involved in this phenomenon. Also, we consider the potential therapeutic use of memory T cell inflation as a vaccine strategy and the associated implications for immune senescence. PMID- 22222197 TI - Left atrial enlargement is associated with a rapid decline in residual renal function in ESRD patients on peritoneal dialysis. AB - BACKGROUND: Left atrial (LA) volume index (LAVI) has been considered a stable indicator of diastolic dysfunction and an independent predictor of mortality in patients with end-stage renal disease. To date, however, little is known about the relationship between LA enlargement and the changes in residual renal function (RRF). METHODS: This study was undertaken to investigate the association between LA enlargement and the decline in RRF in 121 incident peritoneal dialysis patients. Within 2 months after the initiation of peritoneal dialysis, LA enlargement was determined by echocardiography and RRF by 24-hour urine collection. Subsequently, RRF was measured every 6 months. RESULTS: The rates of decline in RRF were significantly greater in patients with LA enlargement (LAVI > 32 mL/m(2)) compared with those without LA enlargement (-0.17 +/- 0.18 vs -0.07 +/- 0.16 mL/min/month/1.73 m(2), P = .002). In a linear mixed model, there was a significant difference in the rates of RRF decline over time between patients with and without LA enlargement (P < .001). Pearson's correlation analysis revealed that there were significant inverse correlations between the rates of the decline in RRF and LAVI (r = -0.22, P = .018). In multiple linear regression analysis adjusted for other risk factors, LAVI was found to be an independent determinant of the rates of decline in RRF (beta = -0.026, P = .018). CONCLUSIONS: This study shows that a higher LAVI is independently associated with a more rapid decline in RRF in patients with end-stage renal disease on peritoneal dialysis. PMID- 22222198 TI - Prediction of biochemical recurrence after radical prostatectomy using peritumoral lymphatic vessel density in biopsy specimens in patients with localized prostate cancer. AB - INTRODUCTION: Lymphatic invasion has been associated with biochemical recurrence (BCR), and many patients with postoperative elevation of prostate-specific antigen (PSA) develop distant metastases within several years. We previously found peritumoral lymphatic vessel density (PTLD) in biopsy cores to be an independent predictor of lymphatic invasion in radical prostatectomy specimens, so we speculate that PTLD parameters in biopsy specimens could also be independent predictors of BCR after surgery. PATIENTS AND METHODS: We obtained positive biopsy cores from 110 patients who underwent radical prostatectomy at our institution. Biopsy cores were immunostained with the D2-40 monoclonal antibody, which specifically and selectively detects lymphatic endothelium. We evaluated differences between the BCR-free survival rates and used univariate and multivariate analyses to detect independent predictors of BCR. RESULTS: The results of a Cox proportional hazards model showed that lymphatic invasion in prostatectomy specimens was one of the independent postoperative prognostic factors for BCR (p = 0.0338). An additional model showed that one PTLD parameter, maximal PTLD, was among the independent preoperative predictors of lower BCR-free survival rates (p = 0.0200). CONCLUSIONS: Information about PTLD in prostate biopsy specimens could be helpful for selecting patients as radical prostatectomy candidates, and patients with high PTLD values should be carefully monitored after surgery. PMID- 22222199 TI - The effect of adenosine on pro-inflammatory cytokine production by porcine T cells. AB - Adenosine is a well described anti-inflammatory modulator of immune responses. The aim of the present study was to describe the role of common adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) in cytokine production by main porcine T cell subpopulations. TNF-alpha, IFN-gamma, IL-2 and IL-10 were detected by multicolor flow cytometry together with cell surface markers CD3, CD4 and CD8. It was found that NECA inhibits (in a dose-dependent manner) production of pro inflammatory TNF-alpha and Th1-associated cytokines IFN-gamma, IL-2 in all concanavalin A-stimulated T cell subpopulations. Moreover, production of IL-10 was potentiated in all T cell subpopulations tested. These corresponded well with the fact that all T cell subsets expressed mRNA for adenosine receptor (AR) subtypes to comparable extents. Contrary to concanavalin A-stimulated cells, NECA had a moderate effect on PMA-stimulated T cells, suggesting that AR in pigs acts via signaling pathways not associated with protein-kinase C. Non-selective antagonist CGS15943 as well as allosteric modulator SCH202676 failed to reverse the effect of NECA in pigs. In conclusion, NECA has an anti-inflammatory effect on porcine T cell subpopulations. PMID- 22222200 TI - Plasmid-mediated quinolone resistance determinant qepA1 and extended-spectrum beta-lactamase gene blaCTX-M-14 co-located on the same plasmid in two Escherichia coli strains from China. PMID- 22222201 TI - Optimizing culture methods for diagnosis of prosthetic joint infections: a summary of modifications and improvements reported since 1995. AB - Improving diagnosis of prosthetic joint infections (PJIs) has become an increasing challenge due to a steadily rising number of patients with prosthetic implants. Based on a systematic literature search we have ascertained the evidence base for improvement of culture diagnosis. We searched PubMed/MEDLINE using the medical subject heading (MeSH) 'prosthesis-related infections' 1995 through 2010 without further restrictions. An analogous search was conducted for ISI Web of Knowledge. A total of 1409 reports were screened for original results, obtained by methods described in sufficient detail to make replication possible. We gave priority to methods for sample preparation, culture media, culture methods and incubation time. Clinical sensitivity and specificity were calculated where possible. We found evidence to support superiority of cultures obtained from the diluent after sonication of prosthetic implants in comparison with culturing tissue biopsies. Sonication parameters and accessory steps have been studied extensively, and thresholds for significant growth have been defined. Conversely, methods for processing of soft tissue biopsies have been studied to a limited extent. Culture of synovial fluid in blood culture vials has been shown to be more sensitive (90-92 %) than intraoperative swab cultures (68-76 %) and tissue cultures (77-82 %). Formal evaluation of agar media for culturing PJI specimens seemed to be lacking. The polymicrobial nature of PJIs supports the routine use of an assortment of media suitable for recovery of fastidious, slow growing, anaerobic and sublethally damaged bacteria. A number of studies supported an incubation period for up to 14 days. Although we identified evidence based improvements of culture methods, there is a need for more studies especially with regard to tissue biopsies. Culturing remains an important means to identify and characterize pathogenic micro-organisms and supplements the increasing number of culture-independent assays. PMID- 22222202 TI - EGF-functionalized single-walled carbon nanotubes for targeting delivery of etoposide. AB - To enhance the therapeutic potential of etoposide (ETO), we devised a targeted drug delivery system (TDDS) of epidermal growth factor-chitosan-carboxyl single walled carbon nanotubes-ETO (EGF/CHI/SWNT-COOHs/ETO) using modified SWNTs (m SWNTs) as the carrier, EGF-functionalized SWNTs (f-SWNTs) as the targeted moiety and ETO as the drug. After SWNT-COOHs were conjugated with CHI (CHI/SWNT COOHs/ETO), they displayed high solubility and stable dispersion in aqueous solution. The drug loading capacity was approximately 25-27%. The m-SWNTs and f SWNTs had only slight cytotoxicity. ETO was released from EGF/CHI/SWNT-COOHs/ETO at low pH and taken up by tumour cells via adenosine triphosphate (ATP)-dependent endocytosis. The cell death induced by EGF/CHI/SWNT-COOHs/ETO was as much as 2.7 times that due to ETO alone. In summary, these results demonstrated that our TDDS had a greater anticancer effect than free ETO in vitro. PMID- 22222203 TI - HSP90 as a platform for the assembly of more effective cancer chemotherapy. AB - Since initial discovery of the first HSP90 inhibitor over a decade and a half ago, tremendous progress has been made in developing potent and selective compounds with which to target this chaperone in the treatment of cancers. These compounds have been invaluable in dissecting how HSP90 supports the dramatic alterations in cellular physiology that constitute the malignant phenotype and give rise to the clinical manifestations of diverse cancers. Unfortunately, single agent activity for HSP90 inhibitors has been disappointingly modest against recurrent, refractory cancers in most of the clinical trials that have been reported to date. This problem could be due to pharmacological limitations of the first-generation inhibitors that have been most extensively studied. But we suggest it may well be intrinsic to the target itself. This review will focus on how the utilization of HSP90 by cancer cells might be targeted to enhance the activity of other anticancer drugs while at the same time limiting the ability of advanced cancers to adapt and evolve drug resistance; the net result being more durable disease control. A better understanding of these fundamental issues will surely make the ongoing clinical development of HSP90 inhibitors as anticancer drugs less empiric, more efficient and hopefully more successful. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90). PMID- 22222204 TI - Synthetic biology's flywheel. PMID- 22222205 TI - Histone deacetylase 1 enhances microRNA processing via deacetylation of DGCR8. AB - Relatively little is known about the regulatory mechanisms of the Drosha/DGCR8 complex, which processes miRNAs at the initial step of biogenesis. We found that histone deacetylase 1 (HDAC1) increases the expression levels of mature miRNAs despite repressing the transcription of host genes. HDAC1 is an integral component of the Drosha/DGCR8 complex and enhances miRNA processing by increasing the affinity of DGCR8 to primary miRNA transcripts via deacetylation of critical lysine residues in the RNA-binding domains of DGCR8. This finding suggests that HDACs have two arms for gene silencing: transcriptional repression by promoter histone deacetylation and post-transcriptional inhibition by increasing miRNA abundance. PMID- 22222207 TI - Regulation of experimental peritonitis: a complex orchestration. AB - Experimental peritonitis is a frequently used inflammatory model to evaluate leukocyte recruitment. By the intrinsic characteristics of the peritoneal cavity, the various resident cell populations have a role to play in the initiation, the modulation and the resolution of peritoneal inflammation. Through various manipulations of these cell populations, we gained important knowledge on their respective roles in peritoneal inflammation. In this brief review, we will focus on the cellular regulation of leukocyte recruitment in experimental peritonitis. PMID- 22222206 TI - Assurance of mitochondrial integrity and mammalian longevity by the p62-Keap1 Nrf2-Nqo1 cascade. AB - Sqstm1/p62 functions in the non-canonical activation of nuclear factor (erythroid derived 2)-like 2 (Nrf2). However, its physiological relevance is not certain. Here, we show that p62(-/-) mice exhibited an accelerated presentation of ageing phenotypes, and tissues from these mice created a pro-oxidative environment owing to compromised mitochondrial electron transport. Accordingly, mitochondrial function rapidly declined with age in p62(-/-) mice. In addition, p62 enhanced basal Nrf2 activity, conferring a higher steady-state expression of NAD(P)H dehydrogenase, quinone 1 (Nqo1) to maintain mitochondrial membrane potential and, thereby, restrict excess oxidant generation. Together, the p62-Nrf2-Nqo1 cascade functions to assure mammalian longevity by stabilizing mitochondrial integrity. PMID- 22222208 TI - Randomized controlled trial on the effectiveness of metacognitive therapy and intolerance-of-uncertainty therapy for generalized anxiety disorder. AB - This randomized controlled trial compared the effectiveness of metacognitive therapy (MCT) and intolerance-of-uncertainty therapy (IUT) for generalized anxiety disorder (GAD) in an outpatient context. Patients with GAD (N = 126) consecutively referred to an outpatient treatment center for anxiety disorder were randomly allocated to MCT, IUT, or a delayed treatment (DT) condition. Patients were treated individually for up to 14 sessions. Assessments were conducted before treatment (pretreatment), after the last treatment session (posttreatment), and six months after treatment had ended (follow-up). At posttreatment and follow-up assessments, substantial improvements were observed in both treatment conditions across all outcome variables. Both MCT and IUT, but not DT, produced significant reductions in GAD-specific symptoms with large effect sizes (ranging between 0.94 and 2.39) and high proportions of clinically significant change (ranging between 77% and 95%) on various outcome measures, and the vast majority of the patients (i.e., 91% in the MCT group, and 80% in the IUT group) no longer fulfilled the diagnostic criteria for GAD. Results further indicate that MCT produced better results than IUT. This was evident on most outcome measures, and also reflected in effect sizes and degree of clinical response and recovery. PMID- 22222209 TI - Glycosyl-phosphatidylinositol (GPI)-anchored membrane association of the porcine reproductive and respiratory syndrome virus GP4 glycoprotein and its co localization with CD163 in lipid rafts. AB - The porcine reproductive and respiratory syndrome virus (PRRSV) glycoprotein 4 (GP4) resembles a typical type I membrane protein in its structure but lacks a hydrophilic tail at the C-terminus, suggesting that GP4 may be a lipid-anchored membrane protein. Using the human decay-accelerating factor (DAF; CD55), a known glycosyl-phosphatidylinositol (GPI) lipid-anchored protein, chimeric constructs were made to substitute the GPI-anchor domain of DAF with the putative lipid anchor domain of GP4, and their membrane association and lipase cleavage were determined in cells. The DAF-GP4 fusion protein was transported to the plasma membrane and was cleaved by phosphatidylinositol-specific phospholipase C (PI PLC), indicating that the C-terminal domain of GP4 functions as a GPI anchor. Mutational studies for residues adjacent to the GPI modification site and characterization of respective mutant viruses generated from infectious cDNA clones show that the ability of GP4 for membrane association corresponded to virus viability and growth characteristics. The residues T158 (omega-2, where omega is the GPI moiety at E160), P159 (omega-1), and M162 (omega+2) of GP4 were determined to be important for virus replication, with M162 being of particular importance for virus infectivity. The complete removal of the peptide-anchor domain in GP4 resulted in a complete loss of virus infectivity. The depletion of cholesterol from the plasma membrane of cells reduced the virus production, suggesting a role of lipid rafts in PRRSV infection. Remarkably, GP4 was found to co-localize with CD163 in the lipid rafts on the plasma membrane. Since CD163 has been reported as a cellular receptor for PRRSV and GP4 has been shown to interact with this receptor, our data implicates an important role of lipid rafts during entry of the virus. PMID- 22222210 TI - HIV-1 Vpu's lipid raft association is dispensable for counteraction of the particle release restriction imposed by CD317/Tetherin. AB - HIV-1 Vpu antagonizes the block to particle release mediated by CD317 (BST 2/HM1.24/Tetherin) via incompletely understood mechanisms. Vpu and CD317 partially reside in cholesterol-rich lipid rafts where HIV-1 budding preferentially occurs. Here we find that lipid raft association of ectopically expressed or endogenous CD317 was unaltered upon co-expression with Vpu or following HIV-1 infection. Similarly, Vpu's lipid raft association remained unchanged upon expression of CD317. We identify amino acids V25 and Y29 of Vpu as crucial for microdomain partitioning and single substitution of these amino acids resulted in Vpu variants with markedly reduced or undetectable lipid raft association. These mutations did not affect Vpu's subcellular distribution and binding capacity to CD317, nor its ability to downmodulate cell surface CD317 and promote HIV-1 release from CD317-positive cells. We conclude that (i) lipid raft incorporation is dispensable for Vpu-mediated CD317 antagonism and (ii) Vpu does not antagonize CD317 by extraction from lipid rafts. PMID- 22222211 TI - Cathepsins B and L activate Ebola but not Marburg virus glycoproteins for efficient entry into cell lines and macrophages independent of TMPRSS2 expression. AB - Ebola (EBOV) and Marburg virus (MARV) cause severe hemorrhagic fever. The host cell proteases cathepsin B and L activate the Zaire ebolavirus glycoprotein (GP) for cellular entry and constitute potential targets for antiviral intervention. However, it is unclear if different EBOV species and MARV equally depend on cathepsin B/L activity for infection of cell lines and macrophages, important viral target cells. Here, we show that cathepsin B/L inhibitors markedly reduce 293T cell infection driven by the GPs of all EBOV species, independent of the type II transmembrane serine protease TMPRSS2, which cleaved but failed to activate EBOV-GPs. Similarly, a cathepsin B/L inhibitor blocked macrophage infection mediated by different EBOV-GPs. In contrast, MARV-GP-driven entry exhibited little dependence on cathepsin B/L activity. Still, MARV-GP-mediated entry was efficiently blocked by leupeptin. These results suggest that cathepsins B/L promote entry of EBOV while MARV might employ so far unidentified proteases for GP activation. PMID- 22222212 TI - Kinetics of virus production from single cells. AB - The production of virus by infected cells is an essential process for the spread and persistence of viral diseases, the effectiveness of live-viral vaccines, and the manufacture of viruses for diverse applications. Yet despite its importance, methods to precisely measure virus production from cells are lacking. Most methods test infected-cell populations, masking how individual cells behave. Here we measured the kinetics of virus production from single cells. We combined simple steps of liquid-phase infection, serial dilution, centrifugation, and harvesting, without specialized equipment, to track the production of virus particles from BHK cells infected with vesicular stomatitis virus. Remarkably, cell-to-cell differences in latent times to virus release were within a factor of two, while production rates and virus yields spanned over 300-fold, highlighting an extreme diversity in virus production for cells from the same population. These findings have fundamental and technological implications for health and disease. PMID- 22222213 TI - Reaction of complement factors varies with prion strains in vitro and in vivo. AB - Roles of complement factors in prion infection of the central nervous system remain unclear. In this study, we assessed the strain-dependent reactivity of complement factors in prion infections of Neuro2a (N2a) cells and mouse brains. N2a cells persistently infected with either Chandler or 22L scrapie strains were cultured in the presence of normal mouse serum (NMS), followed by staining with phosphatidylserine binding protein and early apoptosis marker Annexin V. The proportion of Annexin V positive cells was increased both in Chandler- and 22L infected cells. Preincubation of NMS with anti-C1q, C3 and/or C9 antibodies reduced Annexin V positive cells in Chandler-infected cells, while only anti-C3 antibodies were effective on 22L-infected cells. The immunohistochemistry showed that deposition of C1q and C3 was different between Chandler- and 22L-infected mouse brains. These results indicate that the reactivity of complement factors differs between prion strains both in vitro and in vivo. PMID- 22222214 TI - Estrogen induces endometrial cancer cell proliferation and invasion by regulating the fat mass and obesity-associated gene via PI3K/AKT and MAPK signaling pathways. AB - Obesity is generally acknowledged as a risk factor for endometrial cancer, as accumulated adipocytes partly contribute to the increased production of estrogen which is involved in dysregulated cell growth and metastasis in early endometrial carcinogenesis. Thus we evaluated in this study expression of the fat mass and obesity-associated (FTO) gene in endometrial tumor tissues and further explored its role in beta-estradiol (E2)-induced endometrial cancer cell proliferation and invasion. IHC staining showed that FTO overexpressed in endometrial carcinoma. Additionally, E2-induced FTO via activation of the PI3K/AKT and MPAK signal pathways contributed to enhanced proliferation and invasion. Therefore, this study provides a new insight on the mechanisms of E2-induced proliferation and invasion and the link between obesity and endometrial cancer, implying the possibility of using FTO as a potential therapeutic target for the treatment of endometrial cancer. PMID- 22222215 TI - A man is not a rat is not a mouse. PMID- 22222216 TI - International symposium on G-protein-coupled receptors (GPCRs), TRP (ion) channels and lipid signalling - GPCR-Helsinki 2010. PMID- 22222218 TI - Individual differences in holistic processing predict face recognition ability. AB - Why do some people recognize faces easily and others frequently make mistakes in recognizing faces? Classic behavioral work has shown that faces are processed in a distinctive holistic manner that is unlike the processing of objects. In the study reported here, we investigated whether individual differences in holistic face processing have a significant influence on face recognition. We found that the magnitude of face-specific recognition accuracy correlated with the extent to which participants processed faces holistically, as indexed by the composite-face effect and the whole-part effect. This association is due to face-specific processing in particular, not to a more general aspect of cognitive processing, such as general intelligence or global attention. This finding provides constraints on computational models of face recognition and may elucidate mechanisms underlying cognitive disorders, such as prosopagnosia and autism, that are associated with deficits in face recognition. PMID- 22222219 TI - Bright minds and dark attitudes: lower cognitive ability predicts greater prejudice through right-wing ideology and low intergroup contact. AB - Despite their important implications for interpersonal behaviors and relations, cognitive abilities have been largely ignored as explanations of prejudice. We proposed and tested mediation models in which lower cognitive ability predicts greater prejudice, an effect mediated through the endorsement of right-wing ideologies (social conservatism, right-wing authoritarianism) and low levels of contact with out-groups. In an analysis of two large-scale, nationally representative United Kingdom data sets (N = 15,874), we found that lower general intelligence (g) in childhood predicts greater racism in adulthood, and this effect was largely mediated via conservative ideology. A secondary analysis of a U.S. data set confirmed a predictive effect of poor abstract-reasoning skills on antihomosexual prejudice, a relation partially mediated by both authoritarianism and low levels of intergroup contact. All analyses controlled for education and socioeconomic status. Our results suggest that cognitive abilities play a critical, albeit underappreciated, role in prejudice. Consequently, we recommend a heightened focus on cognitive ability in research on prejudice and a better integration of cognitive ability into prejudice models. PMID- 22222220 TI - Religiosity, social self-esteem, and psychological adjustment: on the cross cultural specificity of the psychological benefits of religiosity. PMID- 22222221 TI - Highly selective CO2 capture of an agw-type metal-organic framework with inserted amides: experimental and theoretical studies. AB - An amide-inserted metal-organic framework (NJU-Bai3) presents high storage and high selectivity toward CO(2) and combines these two interesting characters which strongly support our expectation that amide groups can significantly enhance the CO(2) binding ability and selectivity of MOFs. PMID- 22222222 TI - Case series of undetected intranasal impression material in patients with clefts. AB - We report the cases of two female patients in their twenties who had had corrective surgery for bilateral cleft lip and palate as babies. They had both had residual palatal fistulas and had had further treatment that required repeated dental impressions. Several years later both had complained of persistent nasal discomfort and discharge, and routine clinical examination and investigations had failed to identify the cause. Full examination of the whole nasal cavity under general anaesthesia, in both cases, showed the presence of displaced dental impression material in the nasal floor. Removal resulted in complete resolution of symptoms. PMID- 22222223 TI - Acrylated stainless steel basket splint for mandibular fractures in children. PMID- 22222224 TI - Pre-emptive analgesia with the combination of tramadol plus meloxicam for third molar surgery: a pilot study. AB - The aim of this pilot study was to evaluate pre-emptive analgesia using the combination tramadol plus meloxicam compared with each individual drug alone for the reduction of pain after extraction of third molars. Fifty-one patients were randomised into three groups (n=17 in each), using a series of random numbers: the first group was given tramadol 25mg and meloxicam 7.5mg; the second tramadol 50mg, and the third meloxicam 15 mg, all intramuscularly. Treatments were prepared in identical syringes by an independent investigator and were given immediately. The teeth were removed 50 min after the analgesics had been given. Intensity of pain, consumption of analgesics, and adverse effects were evaluated. The intensity of pain was evaluated using a visual analogue scale (VAS) and the area under the curve of the VAS showed significant differences amongst the groups. In conclusion, the study showed that the combination of tramadol 25mg and meloxicam 7.5mg had an analgesic effect similar to that of meloxicam 15 mg, but both were better than tramadol 50mg for relief of pain after the extraction of mandibular third molars. PMID- 22222226 TI - ALDH1-bright epithelial ovarian cancer cells are associated with CD44 expression, drug resistance, and poor clinical outcome. AB - The role of aldehyde dehydrogenase 1 (ALDH1) as an ovarian cancer stem cell marker and its clinical significance have rarely been explored. We used an Aldefluor assay to isolate ALDH1-bright (ALDH1(br)) cells from epithelial ovarian cancer cell lines and characterized the properties of the stem cells. ALDH1(br) cells were enriched in ES-2 (1.3%), TOV-21G (1.0%), and CP70 (1.2%) cells. Both ALDH1(br) and ALDH1(low) cells repopulated stem cell heterogeneity, formed spheroids, and grew into tumors in immunocompromised mice, although these processes were more efficient in ALDH1(br) cells. In the ES-2 and CP70 cells, ALDH1(br) cells conferred more chemoresistance, and were more enriched in CD44 (by 1.74-fold and 5.18-fold, respectively) than in CD133 (by 1.39-fold and 1.17 fold, respectively), compared with ALDH1(low) cells. Immunohistochemical staining for ALDH1 on a tissue microarray containing 84 epithelial ovarian cancer samples revealed that patients with higher ALDH1 expression (>50%) had poor overall survival, compared with those with lower ALDH1 (P = 0.004) and yielded an odds ratio of death of 2.43 (95% CI = 1.12 to 5.28) by multivariate analysis. The results did not support ALDH1 alone as an ovarian cancer stem cell marker, but demonstrated that ALDH1 is associated with CD44 expression, chemoresistance, and poor clinical outcome. The use of a combination of ALDH1 with other stem cell markers may help define ovarian cancer stem cells more stringently. PMID- 22222227 TI - p47(phox) directs murine macrophage cell fate decisions. AB - Macrophage differentiation and function are pivotal for cell survival from infection and involve the processing of microenvironmental signals that determine macrophage cell fate decisions to establish appropriate inflammatory balance. NADPH oxidase 2 (Nox2)-deficient chronic granulomatous disease (CGD) mice that lack the gp91(phox) (gp91(phox-/-)) catalytic subunit show high mortality rates compared with wild-type mice when challenged by infection with Listeria monocytogenes (Lm), whereas p47(phox)-deficient (p47(phox-/-)) CGD mice show survival rates that are similar to those of wild-type mice. We demonstrate that such survival results from a skewed macrophage differentiation program in p47(phox-/-) mice that favors the production of higher levels of alternatively activated macrophages (AAMacs) compared with levels of either wild-type or gp91(phox-/-) mice. Furthermore, the adoptive transfer of AAMacs from p47(phox-/ ) mice can rescue gp91(phox-/-) mice during primary Lm infection. Key features of the protective function provided by p47(phox-/-) AAMacs against Lm infection are enhanced production of IL-1alpha and killing of Lm. Molecular analysis of this process indicates that p47(phox-/-) macrophages are hyperresponsive to IL-4 and show higher Stat6 phosphorylation levels and signaling coupled to downstream activation of AAMac transcripts in response to IL-4 stimulation. Notably, restoring p47(phox) protein expression levels reverts the p47(phox)-dependent AAMac phenotype. Our results indicate that p47(phox) is a previously unrecognized regulator for IL-4 signaling pathways that are important for macrophage cell fate choice. PMID- 22222228 TI - Prognostic significance of neutrophil gelatinase-associated lipocalin in ST segment elevation myocardial infarction. AB - OBJECTIVES: This study investigated the prognostic value of neutrophil gelatinase associated lipocalin (NGAL) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Neutrophil gelatinase-associated lipocalin is a promising biomarker for acute kidney injury. Recently, it was concluded that NGAL may be used beyond the boundaries of renal physiopathology. It was found to be an important factor indirectly contributing to the inflammatory processes. Little is known regarding its predictive role in STEMI. METHODS: One hundred six consecutive patients who underwent percutaneous coronary intervention (PCI) for STEMI and control group consisted of age- and sex-matched 60 consecutive patients with chest pain admitted to the hospital for elective PCI. According to median NGAL level, patients were classified into high- and low-NGAL groups. RESULTS: Neutrophil gelatinase-associated lipocalin levels were higher in patients with STEMI compared to the elective PCI group subjects. Inhospital and 1-year mortality rates were found to be significantly greater in patients with high NGAL. In addition, inhospital and 1-year major adverse cardiovascular event rates were significantly greater in the high-NGAL group, compared to the low NGAL group. High NGAL level on admission was a significant predictor for long-term mortality and major adverse cardiovascular events. The receiver operating characteristics curve analysis further illustrated that NGAL level on admission is a strong indicator of mortality, with an area under the curve of 0.76 (95% confidence interval, 0.62-0.89). CONCLUSIONS: High NGAL levels may be associated with poor prognosis after PCI in patients with STEMI. However, further studies with larger numbers of patients and longer follow-up are required to evaluate the usefulness of plasma NGAL level for predicting prognosis of STEMI. PMID- 22222225 TI - Epithelial expression of the cytosolic retinoid chaperone cellular retinol binding protein II is essential for in vivo imprinting of local gut dendritic cells by lumenal retinoids. AB - Dendritic cells (DCs) use all-trans retinoic acid (ATRA) to promote characteristic intestinal responses, including Foxp3(+) Treg conversion, lymphocyte gut homing molecule expression, and IgA production. How this ability to generate ATRA is conferred to DCs in vivo remains largely unstudied. Here, we observed that among DCs, retinaldehyde dehydrogenase (ALDH1), which catalyzes the conversion of retinal to ATRA, was preferentially expressed by small intestine CD103(+) lamina propria (LP) DCs. Retinoids induced LP CD103(+) DCs to generate ATRA via ALDH1 activity. Either biliary or dietary retinoids were required to confer ALDH activity to LP DCs in vivo. Cellular retinol-binding protein II (CRBPII), a cytosolic retinoid chaperone that directs enterocyte retinol and retinal metabolism but is redundant to maintain serum retinol, was required to confer ALDH activity to CD103(+) LP DCs. CRBPII expression was restricted to small intestine epithelial cells, and ALDH activity in CRBPII(-/-) DCs was restored by transfer to a wild-type recipient. CD103(+) LP DCs from CRBPII(-/-) mice had a decreased capacity to promote IgA production. Moreover, CD103(+) DCs preferentially associated with the small intestine epithelium and LP CD103(+) DC ALDH activity, and the ability to promote IgA production was reduced in mice with impaired DC-epithelia associations. These findings demonstrate in vivo roles for the expression of epithelial CRBPII and lumenal retinoids to imprint local gut DCs with an intestinal phenotype. PMID- 22222229 TI - Dose-dependent acute effects of passive smoking on left ventricular cardiac functions in healthy volunteers. AB - OBJECTIVE: We have previously shown that acute passive smoking impaired left ventricular diastolic function in healthy volunteers. The aim of this study was to determine whether length of exposure and/or ambient smoke concentration is the key determinant of this outcome. METHODS: We measured blood carboxyhemoglobin (COHb)and lactate level to investigate the acute effects of passive smoking on tissue oxygenation. A total of 90 healthy nonsmoker volunteers were prospectively enrolled into the study. Each of 30 subjects were exposed to carbon monoxide (CO) less than 5.0 ppm smoke in group A for 30 minutes, to CO 5 to 10 ppm smoke in group B for 30 minutes, and to CO less than 5.0 ppm smoke in group C for 60 minutes. Hemodynamic parameters were obtained, blood samples for measuring COHb and lactate levels were taken and echocardiographic examinations were performed at baseline and after exposure to passive smoking. RESULTS: Mean +/- SD CO levels in groups A, B, and C were 4.2 +/- 0.5 ppm, 9.2 +/- 0.3 ppm, and 4.1 +/- 0.8 ppm, respectively. There was no change in left ventricular systolic functions in all groups. Left ventricular diastolic functions were impaired in groups B and C, whereas no change was observed in group A. Carboxyhemoglobin and lactate levels increased after passive smoking in groups B and C. However, group B had significantly higher COHb and lactate levels compared to group C (P < 0.001). CONCLUSIONS: Our results suggested that passive smoking at a certain dose in relation with length of exposure and ambient smoke concentration seems to cause relative left ventricular diastolic dysfunction. PMID- 22222230 TI - FTO gene polymorphisms and platelet counts in a general Japanese population. AB - The fat mass and obesity-associated (FTO) gene has recently attracted attention as one of the obesity-related genes. Obesity-related gene polymorphisms may be associated with the development of atherothrombosis in relation to platelets. The present study investigated the association between FTO gene polymorphisms (rs1558902, T/A) and hematological parameters, in particular the platelet counts. Anthropometric, hematological, and biochemical parameters, in addition to genotyping by an allele-specific DNA assay, were measured in 209 asymptomatic community-dwelling Japanese subjects (male/female: 80/129; mean age, 65 years; mean [SD] body mass index, 24.0 [3.0] kg/m). The subjects with the A-allele (n = 73) showed significantly higher platelet counts than those without the A-allele (mean [SD], 237 [58] vs 217 [57] * 10/L, P < 0.05). Even when multiple-adjusted analyses were performed, the platelet counts continued to differ significantly and independently of other variables, including obesity-related parameters such as the index of insulin resistance or high-sensitivity C-reactive protein, between the subjects with and without the A-allele. The FTO gene polymorphisms may be associated with the minor but significant modulation of platelet counts in this population. PMID- 22222231 TI - Levels of blood periostin decrease after acute myocardial infarction and are negatively associated with ventricular function after 3 months. AB - BACKGROUND: A recent study showed that periostin (PN) induced reentry of differentiated cardiomyocytes into the cell cycle and improved heart function after acute myocardial infarction (AMI). This study sought to investigate whether PN levels increase after AMI and whether they provide prognostic value. METHODS AND RESULTS: We recruited 123 patients: 45 with AMI, 45 with stable coronary artery disease (CAD), and 33 healthy controls (CON). Blood PN and N-terminal pro brain natriuretic peptide (NT-pro-BNP) levels were measured. Echocardiography was repeated 3 months after AMI. In the AMI group, the PN levels 1.3 +/- 1.2 days after AMI were significantly lower than those in the CAD and CON groups (175 +/- 60, 245 +/- 68, and 232 +/- 63 ng/mL, respectively, P = 0.001). The NT-pro-BNP levels were significantly higher in the AMI group, compared to the CON and CAD groups (10.07 +/- 28.2 [median, 0.70] vs 0.08 +/- 0.06 [median, 0.05] and 1.1 +/- 4.2 [median, 0.09] ng/mL, respectively; P = 0.02). The PN levels further decreased 8 +/- 2 days after AMI (from 175 +/- 60 to 143 +/- 57 ng/mL; P = 0.003). However, NT-pro-BNP levels did not significantly change. With respect to the echocardiographic parameters 3 months after AMI, the PN levels measured before discharge were negatively associated with the left ventricular ejection fraction (rs = -0.50; P = 0.001), end diastolic (rs = 0.42; P = 0.009) and systolic (rs = 0.46; P = 0.004) diameters. The NT-pro-BNP levels were not significantly correlated with these parameters. CONCLUSION: Acute myocardial infarction is associated with a decrease in blood PN levels, and PN concentrations predict cardiac function 3 months after AMI. PMID- 22222233 TI - Clostridium difficile infection is associated with poor outcomes in end-stage renal disease. AB - OBJECTIVE: To investigate the association of Clostridium difficile infection (CDI) with the outcomes of hospitalized patients with end-stage renal disease (ESRD). METHODS: We extracted all adult cases with a discharge diagnosis of ESRD or CDI from the United States Nationwide Inpatient Sample 2009 database. Outcome variables (mortality, length of hospital stay [LOS], and hospitalization charges), demographic information, and comorbidity data were collected. Data were evaluated by univariate and multiple regression analyses. RESULTS: We identified 184,139 cases with ESRD of which 2.8% had CDI. Comparison of patients with ESRD + CDI to those with only ESRD revealed in-hospital mortality (13.2% vs 5.3%; P < 0.001), LOS (17.3 vs 7.1 days; P < 0.001), and charges ($124,846 vs $56,663; P < 0.001) to be more than 2-fold greater. In the ESRD cohort (ESRD only and ESRD + CDI), CDI was independently associated with greater mortality (adjusted odds ratio, 2.15; 95% CI, 2.07-2.24; P < 0.001), longer LOS (mean difference, 9.4 days; 95% CI, 9.2-9.5; P < 0.001), and higher charges (mean difference, $62,824; 95% CI, 61,615-64,033; P < 0.001). CONCLUSIONS: Clostridium difficile infection is associated with significantly worse outcomes in hospitalized patients with ESRD. PMID- 22222232 TI - Human steroid biosynthesis for the oncologist. AB - In 2005, results from the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial ushered in a new era of endocrine therapy for hormone-responsive malignancies. This study demonstrated that, compared with tamoxifen (a selective estrogen receptor modulator), anastrozole (aromatase inhibitor [AI]) prolonged time to recurrence and disease-free survival for postmenopausal women with breast cancer. The advantage was even greater for those with estrogen receptor-positive (ER) tumors, and anastrozole was better tolerated than tamoxifen. Since then, AIs have become first-line adjuvant therapy for ER breast cancer in postmenopausal women.In late 2010, a trial comparing abiraterone acetate (a 17-hydroxylase/17,20 lyase [CYP17A1] inhibitor) plus prednisone versus prednisone alone in men with castration-resistant prostate cancer (CRPC) previously treated with docetaxel chemotherapy was terminated early because of the survival benefit in the abiraterone acetate arm. This result not only validated a new therapy for CRPC but also, with the antecedent phase I-II abiraterone studies, shattered our understanding of the molecular mechanisms underpinning CRPC development and progression.Aromatase inhibitors and CYP17A1 inhibitors will be widely used by oncologists, yet fellowship programs provide little training in steroid biosynthesis, compared with training in the biology of standard chemotherapies. Consequently, these drugs might be used without an appreciation of their caveats and pitfalls. The purpose of this review was to acquaint practicing oncologists with the fundamental principles and pathways of steroid biosynthesis, to improve their understanding of how and why these drugs work, and to alert these physicians to potential problems related to the drugs' mechanisms of action. PMID- 22222234 TI - Synovial fluid omentin-1 levels are inversely correlated with radiographic severity of knee osteoarthritis. AB - OBJECTIVE: The purpose of this study was to demonstrate omentin-1 levels in serum and synovial fluid (SF) of patients with knee osteoarthritis (OA) and to investigate their correlation with radiographic disease severity. METHODS: One hundred and ninety-seven patients with OA and 65 sex- and age-matched healthy controls were enrolled in this study. The radiographic disease severity of OA was assessed by the Kellgren- Lawrence (KL) grading system. The omentin-1 levels in serum and SF were determined by enzyme-linked immunosorbent assay. RESULTS: There were no significant differences in serum omentin-1 levels between patients with OA and healthy controls (P>0.05). There were also no significant differences in serum omentin-1 levels among patients with OA with different KL grades (P>0.05). However, SF omentin-1 levels decreased significantly as the KL grades increased (KL grade 4 < KL grade 3 < KL grade 2; all P<0.01) in the patients with OA. Furthermore, SF omentin-1 levels were negatively correlated with KL grades (r= 0.643; P<0.001). Multinomial logistic regression analysis revealed that there was still a negative correlation between the SF omentin-1 levels and the KL grades after adjusting for confounding factors (P<0.001). CONCLUSIONS: Synovial fluid omentin-1 levels showed an independent and negative correlation with radiographic severity of the disease in patients with knee OA. Omentin-1 in SF might serve as a potential biomarker for reflecting the degenerative process of primary knee OA. PMID- 22222235 TI - Folic acid improves inner ear vascularization in hyperhomocysteinemic mice. AB - More than 29 million adults in the United States have been diagnosed with hearing loss. Interestingly, elevated homocysteine (Hcy) levels, known as hyperhomocysteinemia (HHcy), are also associated with impaired hearing. However, the associated mechanism remains obscure. The collagen receptor such as discoidin domain receptor 1 and matrix metalloproteinase (MMP) play a significant role in inner ear structure and function. We hypothesize that HHcy increases hearing thresholds by compromise in inner ear vasculature resulted from impaired Hcy metabolism, increased oxidative stress, collagen IVa and collagen Ia turnover. The treatment with folic acid (FA) protects elevated hearing thresholds and prevents reduction in vessel density by lowering abundant collagen deposition and oxidative stress in inner ear. To test this hypothesis we employed 8 weeks old male wild type (WT), cystathionine-beta-synthase heterozygote knockout (CBS+/-) mice, WT + FA (0.0057 MUg/g/day, equivalent to a 400 MUg/70 kg/day human dose in drinking water); and CBS(+/-) +FA. The mice were treated for four weeks. The hearing thresholds were determined by recording the auditory brainstem responses. Integrity of vessels was analyzed by perfusion of horseradish peroxidase (HRP) tracer. Endothelial permeability was assessed, which indicated restoration of HRP leakage by FA treatment. A total Hcy level was increased in stria vascularis (SV) and spiral ligament (SL) of CBS+/- mice which was lowered by FA. Interestingly, FA treatment lowered Col IVa Immunostaining by affecting its turnover. The levels of MMP-2, -9, methylenetetrahydrofolate reductase (MTHFR) and cystathione gamma lyase (CSE) were measured by Western blot analysis. The oxidative stress was high in SV and SL of CBS+/- compared to WT however the treatment with FA lowered oxidative stress in CBS+/- mice. These data suggested that hearing loss in CBS+/- mice was primarily due to leakage in inner ear circulation, also partly by induced collagen imbalance, increase in Hcy and oxidative stress in inner ear. PMID- 22222236 TI - The integrality of situated caring in nursing and the environment. AB - Much emphasis has been placed on the importance of the environment as a determinant of health; however, little theoretical work in nursing has specifically articulated the importance of the nursing practice environment as a factor in patient outcomes. This work advances the unitary-transformative-caring paradigm by focusing on the concept of integrality and exploring the nursing meta paradigm concepts (nursing, environment, human being, and health) through integral philosophical inquiry. PMID- 22222237 TI - Sex gender and autoimmunity. AB - The 7th International Congress of Autoimmunity was held in Ljubljana, Slovenia in May 2010. At the conclusion of the Congress, a list was prepared of the major unresolved clinical issues in autoimmunity. The list grew to be extensive but one subject that was found in nearly all of the concerns was geoepidemiology of autoimmunity and, in particular, the increased risk of women to develop autoimmune disease. Indeed, one does not need to be an autoimmunologist to appreciate that the risk of developing rheumatoid arthritis, for example, has been known to be increased in women compared to men, almost from the time of its original description. In fact, although the sex ratios of autoimmune disease have varied from center to center, from country to country, from decade to decade, the data has remained virtually constant. It is not surprising that the very first mouse model of lupus was described in female New Zealand black x white female mice. Although there have been subsequent descriptions of lupus in male murine strains, the initial data on the NZB * NZW F1 mouse led to some of the original descriptions of the relative roles of sex hormones on the immune response. The 8th Congress of Autoimmunity will be held in Granada, Spain in May 2012 and one of the intents of the Congress and of this volume is to address the needs originally noted in Slovenia two years earlier. Towards this extent, this volume contains a special double issue of papers that will be published in the Journal of Autoimmunity and Autoimmunity Reviews, all of whom have the focus of addressing critical issues in sex, gender and autoimmunity. PMID- 22222238 TI - The effects of coexisting fibromyalgia syndrome on pain intensity, disability, and treatment outcome in patients with chronic lateral epicondylitis. AB - OBJECTIVE: The objective of this study was to evaluate the effects of coexisting fibromyalgia syndrome (FS) on pain intensity, disability, and treatment outcome in patients with chronic lateral epicondylitis (LE). METHODS: Seventy-eight patients with chronic unilateral LE and 30 healthy subjects were included. Patients were classified into two groups: group 1 consisted of 46 LE alone patients, while group 2 consisted of 32 LE plus FS patients. A pain questionnaire was used to determine the subjective pain and disability. Pressure pain threshold (PPT) on the lateral epicondyles, isometric hand grip strength (IHGS), lateral pinch grip strength (LPGS), and tender point examinations of groups were performed. A mixture of methylprednisolone and prilocaine was injected 1 cm distal to the lateral epicondyle. All measurements were repeated 2 weeks and 3 months after injection. RESULTS: Compared with healthy subjects, both patient groups had significantly increased pain and disability scores and decreased IHGS, LPGS, and PPT values (P < 0.001). Compared with the LE alone group, pain and disability scores were significantly higher (P < 0.01), and PPT, IHGS, and LPGS values were significantly lower in LE plus FS group (P < 0.05). Pain questionnaire scores of the LE alone and LE plus FS patients showed statistically significant decrease, and IHGS, LPGS, and PPTs showed statistically significant increase at the second week (P < 0.01) and at the third month (P < 0.001) after injection. Improvements in the LE plus FS group were poorer than FS alone group at both second week and third month after injection. CONCLUSION: Coexisting FS may increase the pain intensity and disability, and negatively affect the treatment outcome in patients with chronic LE. PMID- 22222239 TI - Karyotypic evolution of hapalomys inferred from chromosome painting: a detailed characterization contributing new insights into the ancestral murinae karyotype. AB - We report on the construction of a comparative chromosome map between the emblematic laboratory rat, Rattus norvegicus (RNO), and Delacour's Marmoset rat, Hapalomys delacouri (HDE), based on cross-species fluorescence in situ hybridization with R. norvegicus painting probes. Sixteen R. norvegicus chromosomes (RNO 3-6, 8, 10-15, 17-20, and X) were retained in their entirety (as a conserved block or as a single chromosome) in the H. delacouri genome. The remaining 5 R. norvegicus chromosomes (RNO 1, 2, 7, 9, and 16) produced 2 signals in the H. delacouri karyotype. Our analysis allowed the detection of an X autosome translocation between RNO X and 11 that occurred convergently in an unrelated species, Bandicota savilei, and a single B chromosome that accounts for the 2n = 48 karyotype observed in this specimen. In total, the rat chromosome paints revealed 27 segments of conserved synteny in H. delacouri. The analysis showed 7 NOR bearing pairs in H. delacouri (HDE 1, 3, 6, 7, 8, 10, and 13) and the occurrence of an interstitial telomeric signal at the centromeric regions of 8 H. delacouri chromosomes (HDE 3, 10, 11, 12, 13, 16, 19, and 22). These data, together with published comparative maps, enabled a revision of the previously postulated murine ancestral condition suggesting that it probably comprised a wholly acrocentric karyotype with 2n = 46-50. PMID- 22222240 TI - [Establishment of medical specialty system in Japan]. PMID- 22222241 TI - [Renovation of subspecialty program for gastroenterology in Japan]. PMID- 22222242 TI - [Board certified gastroenterologist and surgeon in Japan]. PMID- 22222243 TI - [Fostering future gastroenterology specialists -initiatives and challenges of medical gastroenterology-]. PMID- 22222244 TI - [Prevention of gastric cancer by eradicating Helicobacter pylori]. PMID- 22222245 TI - [Helicobacter pylori CagA diversity associated with the difference of gastric mucosal injury]. PMID- 22222246 TI - [Long-term outcome of patients with gastric MALT lymphoma after Helicobacter pylori eradication therapy]. PMID- 22222247 TI - [NSAID-associated peptic ulcer and H. pylori infection]. PMID- 22222248 TI - Clinical validation of a closed vitrification system in an oocyte-donation programme. AB - Controversy exists about the risk of microbiological contamination from direct contact with unsterile liquid nitrogen during oocyte vitrification. The aim of this observational study was to evaluate the effectiveness of oocyte vitrification using a high-security closed vitrification system in a donation programme. Oocyte vitrification was performed using CBS High Security closed straws (Cryo Bio System) with DMSO/ethylene glycol/sucrose as the cryoprotectant (Irvine Scientific freeze kit). A total of 123 vitrified metaphase-II oocytes were warmed in 20 recipient cycles (6.2 warmed oocytes per recipient); of these, 111 oocytes (90.2%) survived vitrification and warming. All surviving oocytes were microinjected and 86 (77.5%) were normally fertilized, of which 53 (61.6%) developed up to good-quality day 3. Ten embryo transfers resulted in a clinical pregnancy (50.0%) and an ongoing clinical pregnancy rate of 45%. Five revitrified embryos were warmed in three warming cycles (survival rate 100%). These transfers resulted in an additional ongoing twin pregnancy, leading to a cumulative ongoing pregnancy rate per patient of 50% (10/20). The ongoing implantation rate per warmed oocyte and per injected oocyte was 10.6% (13/123) and 11.7% (13/111). The present data demonstrate that oocyte vitrification using a closed vitrification device yields excellent oocyte survival, fertilization and embryo development. PMID- 22222249 TI - Chemotherapy-induced nausea and vomiting in Asian women with breast cancer receiving anthracycline-based adjuvant chemotherapy. AB - BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) remain among the most frequently reported distressing side effects associated with anthracycline-based chemotherapy despite significant advances in antiemetic management. The main risk factor for severity of CINV is the emetogenic potential of the chemotherapeutic agents. However, patient-related risk factors have been identified, including genetic makeup. Although studies have noted that ethnicity influences nausea and vomiting in other contexts, there is a paucity of research regarding the impact of ethnicity on CINV. This study was undertaken to evaluate whether Asian women receiving anthracycline-based chemotherapy experience more CINV than non-Asians. METHODS: A retrospective, comparative, correlational chart review was performed to abstract the relevant variables. RESULTS: Data from a convenience sample of 358 women with breast cancer who received chemotherapy with doxorubicin between 2004 and 2008 at City of Hope in Duarte, California, were evaluated. The sample consisted of Caucasians (45%), Hispanics (27.7%), Asians (19.8%), and African Americans (7.5%). The results indicate that Asian women with breast cancer undergoing anthracycline-based chemotherapy experienced statistically significantly more clinically important CINV than their non-Asian counterparts. LIMITATIONS: The data were collected retrospectively, with a certain population distribution at a specific time. CONCLUSION: This study provides interesting preliminary evidence that Asian ethnicity plays a role in the development of severe CINV. When managing chemotherapy toxicities in women with breast cancer, health-care providers should tailor therapy to individual risk profiles. Specifically, consideration of antiemetic therapy should accommodate patient characteristics, such as Asian descent. PMID- 22222250 TI - Acyclovir prophylaxis against varicella zoster virus reactivation in multiple myeloma patients treated with bortezomib-based therapies: a retrospective analysis of 100 patients. AB - BACKGROUND: Previous studies have indicated that, in patients with multiple myeloma (MM), bortezomib is associated with an increased incidence of herpes zoster, resulting from reactivation of latent varicella zoster virus (VZV). OBJECTIVE: Our objective was to determine whether increased risk of VZV reactivation could be abrogated by using prophylactic acyclovir. METHODS: We retrospectively evaluated 100 consecutive MM patients treated with bortezomib based therapies at the Roswell Park Cancer Institute for development of herpes zoster. Frontline and relapsed/refractory patients were included, and patients received bortezomib alone or in combination with agents such as doxorubicin, melphalan, or dexamethasone. All patients received >4 weeks of acyclovir prophylaxis (400 mg twice daily), which was initiated prior to starting treatment with bortezomib and discontinued 4 weeks following bortezomib. RESULTS: Median patient age was 62 years, 57% were male, and most (56%) had Durie-Salmon stage IIIA MM. None of the 100 MM patients receiving acyclovir prophylaxis developed herpes zoster during treatment with bortezomib, irrespective of patients receiving a wide variety of concomitant antimyeloma therapies and regardless of response to bortezomib-based therapy. One additional patient, found to be noncompliant with acyclovir therapy, experienced VZV reactivation, having received 3 cycles of bortezomib (3 weeks each cycle) in combination with cyclophosphamide and dexamethasone. LIMITATIONS: Limitations of the study include its small size and retrospective nature. CONCLUSIONS: The increased risk of VZV reactivation observed in previous studies of bortezomib-based therapy was completely abrogated in this series of patients who received prophylaxis with acyclovir. PMID- 22222251 TI - Family and caregiver needs over the course of the cancer trajectory. AB - When a patient is diagnosed with cancer, family members often assume responsibility for providing care. They are typically involved not only with the diagnostic and treatment phases of care but also across the care trajectory and into survivorship. These caregivers are a primary source of support to individuals with cancer. The purpose of this article is to present an overview of the challenges, needs, and roles of family caregivers over the course of the cancer treatment trajectory and to discuss what support the professionals can provide. Caregivers require support, coordination, and communication with health care providers if they are to be successful in carrying out tasks of care. Concern for caregivers as partners in patient care and caregiver outcomes deserves attention from health care professionals. Considering the caregivers' value to the health care team, this role should not be underestimated. PMID- 22222252 TI - Expression of tissue transglutaminase on primary olfactory ensheathing cells cultures exposed to stress conditions. AB - Tissue transglutaminase (TG2), a multifunctional enzyme implicated in cellular proliferation and differentiation processes, plays a modulatory role in the cell response to stressors. Herein, we used olfactory ensheathing cells (OECs), representing an unusual population of glial cells to promote axonal regeneration and to provide trophic support, as well as to assess whether the effect of some Growth Factors (GFs), NGF, bFGF or GDNF, on TG2 overexpression induced by stress conditions, such as glutamate or lipopolysaccaride (LPS). Glial Fibrillary Acidic Protein (GFAP) and vimentin were used as markers of astroglial differentiation and cytoskeleton component, respectively. Glutamate or LPS treatment induced a particular increase of TG2 expression. A pre-treatment of the cells with the GFs restored the levels of the protein to that of untreated ones. Our results demonstrate that the treatment of OECs with the GFs was able to restore the OECs oxidative status as modified by stress, also counteracting TG2 overexpression. It suggests that, in OECs, TG2 modulation or inhibition induced by GFs might represent a therapeutic target to control the excitotoxicity and/or inflammation, which are involved in several acute and chronic brain diseases. PMID- 22222254 TI - Contact printing of compositionally graded CdS(x)Se(1-x) nanowire parallel arrays for tunable photodetectors. AB - Spatially composition-graded CdS(x)Se(1-x) (x = 0-1) nanowires are grown and transferred as parallel arrays onto Si/SiO(2) substrates by a one-step, directional contact printing process. Upon subsequent device fabrication, an array of tunable-wavelength photodetectors is demonstrated. From the spectral photoconductivity measurements, the cutoff wavelength for the device array, as determined by the bandgap, is shown to cover a significant portion of the visible spectrum. The ability to transfer a collection of crystalline semiconductor nanowires while preserving the spatially graded composition may enable a wide range of applications, such as tunable lasers and photodetectors, efficient photovoltaics, and multiplexed chemical sensors. PMID- 22222253 TI - The importance of family factors to protect against substance use related problems among Mexican heritage and White youth. AB - INTRODUCTION: This study examined the ability of family cohesion, parental control, and parent-child attachment to prevent adolescents with a history of drug or alcohol use from experiencing subsequent problems related to their use. METHODS: Data came from Wave I and Wave II of the National Longitudinal Study of Adolescent Health and included Mexican heritage and White adolescents who reported alcohol use (n = 4894, 25% prevalence) or any other drug use (n = 2875, 14% prevalence) in their lifetime. RESULTS: Logistic regression results indicate greater parent-child attachment predicted lower risk of experiencing drug use problems (OR = 0.87, 95% CI = 0.77-0.98) while stronger family cohesion predicted lower odds of experiencing drug- (OR = 0.82, 95% CI = 0.70-0.97) or alcohol related (OR = 0.74, 95% CI = 0.65-0.84) problems. Parental control was also negatively associated with odds of problems related to drug use (OR = 0.93, 95% CI = 0.86-0.99) or alcohol use (OR = 0.94, 95% CI = 0.90-0.99). Results also indicated family cohesion was the only protective factor for Mexican heritage youth while family cohesion and parent-child attachment were protective among White youth. Parental control protected White female adolescents from drug use problems more than males. Mexican heritage male adolescents experienced more protection from drug problems compared to females. CONCLUSION: Findings highlight the need for prevention interventions to emphasize parent-child attachment for White youth and family cohesion for both Mexican-heritage and White youth to decrease adolescent substance users' drug- and alcohol-related problems. PMID- 22222255 TI - Update of long-term trends analysis of ambient 8-hour ozone and precursor monitoring data in the South Central U.S.; encouraging news. AB - In the South Central U.S., lower tropospheric ozone pollution continues to be a challenging problem. This paper provides an update on long-term trends analyses of the ambient ozone and precursor monitoring data collected over the past 25 years (1986-2010) in four South Central U.S. cities, following up on a previous published review of 20 year trends (M.E. Sather and K. Cavender, J. Environ. Monit., 2007, 9, 143-150). The results of these analyses should be useful to air quality scientists, managers, planners, and modelers in assessing the effectiveness of nitrogen oxides (NO(x)) and volatile organic compounds (VOC) pollution controls for ambient ozone concentration reduction programs. Large amounts of quantitative information for each South Central U.S. city are concisely synthesized into one graphic per city. Results reported in this paper show significant long-term decreases in ambient ozone and precursor concentrations in all four South Central U.S. cities, especially over the recent five-year period 2006-2010. PMID- 22222256 TI - Changes in respiratory support of preterm infants in the last decade: are we improving? AB - BACKGROUND: Ventilator-induced lung injury has been recognized as a major contributing factor for bronchopulmonary dysplasia (BPD) in preterm infants. In the last decade, focus has shifted towards a more gentle respiratory approach. AIM: To evaluate whether guideline changes in respiratory management in the delivery room and the unit improved the incidence of BPD in very preterm infants. METHODS: Three cohorts of infants <30 weeks of gestation, born at the Leiden University Medical Center in the Netherlands in 1996-1997 (cohort '96), 2003-2004 (cohort '03) and 2008-2009 (cohort '08), were compared retrospectively. The major change was increasing use of continuous positive airway pressure in time, and monitoring the tidal volume during mechanical ventilation in cohort '08. The primary outcome was BPD at 36 weeks. RESULTS: The incidence of BPD did not change from 47% in cohort '96 to 55% in cohort '03 (n.s.), but decreased significantly to 37% in cohort '08 (cohort '96 vs. '08 and cohort '03 vs. '08: p < 0.01). We observed the same effect when only moderate and severe BPD were counted with 27% in cohort '96, 31% in cohort '03 and 14% in '08 (cohort '96 vs. '03: p = n.s., cohort '96 vs. '08: p < 0.01, cohort '03 vs. '08: p < 0.05). The mortality rate was not significantly different between the three cohorts. CONCLUSION: The incidence of BPD in our cohort of preterm infants has decreased during the last decade and could be due to the changes in respiratory management. PMID- 22222257 TI - Validity of EuroQOL-5D, time trade-off, and standard gamble for age-related macular degeneration in the Singapore population. AB - BACKGROUND/AIMS: Utility values of age-related macular degeneration (AMD) in Asian patients are unknown. This study aims to assess utility values and construct validity of the EuroQOL-5D (EQ-5D), time trade-off (TTO), and standard gamble (SG) instruments in the Singapore multi-ethnic AMD population. METHODS: Cross-sectional, two-centre, institution-based study. Visual acuity (VA), clinical AMD severity, and utility scores on the EQ-5D, TTO, and SG were obtained from 338 AMD patients. VA was analysed in terms of the better-seeing eye (BEVA), worse-seeing eye (WEVA), and weighted average of both eyes (WVA). We evaluated SG on the perfect health-death (SG(death)) and binocular perfect vision-binocular blindness (SG(blindness)) scales. Construct validity was determined by testing a priorihypotheses relating the EQ-5D, TTO, and SG utility scores to VA and clinical AMD severity. RESULTS: The mean utilities on the EQ-5D, TTO, SG(death), and SG(blindness) were 0.89, 0.81, 0.86, and 0.90, respectively. EQ-5D scores correlated weakly with BEVA, WEVA, and WVA (Pearson's correlation coefficients 0.291, -0.247, and -0.305 respectively, P<0.001 for all). SG(death) and SG(blindness) demonstrated no correlation with BEVA, WEVA, or WVA (Pearson's correlation coefficients, range -0.06 to -0.125). TTO showed weak association only with WEVA and WVA (correlation coefficients -0.237, -0.228, P<0.0001), but not with BEVA (correlation coefficient -0.161). Clinical AMD severity correlated with EQ-5D and SG(death), but not with TTO and SG(blindness) (P=0.004, 0.002, 0.235, and 0.069, respectively). CONCLUSIONS: AMD has a negative impact on utilities, although utility scores were high compared with Western cohorts. EQ 5D, TTO, and SG showed suboptimal construct validity, suggesting that health status utilities may not be sufficiently robust for cost-utility analyses in this population. PMID- 22222259 TI - Retractable dog leashes: are they as safe as they seem? PMID- 22222260 TI - A case of African crystalline maculopathy. PMID- 22222261 TI - Comment on 'Phakic intraocular lenses outcomes and complications: Artisan vs Visian ICL'. PMID- 22222262 TI - Association between various types of obesity and macular pigment optical density. AB - PURPOSE: To elucidate the association between macular pigment optical density (MPOD) and various types of obesity in the South-Indian population. PATIENTS AND METHODS: In total, 300 eyes of 161 healthy volunteers of South-Indian origin were studied. MPOD was measured psychophysically at 0.25 degrees , 0.50 degrees , 1.00 degrees , and 1.75 degrees eccentricities from fovea. Anthropometric measurements included waist circumference (WC) and waist-to-hip ratio (WHR) and body mass index (BMI). Using the WHO Expert Consultation guidelines, obesity was defined based on BMI alone (BMI >= 23 kg/m(2)), based on WC alone (WC >= 90 cm for men and >= 80 cm for women), and based on WHR alone (>= 0.90 for men and >= 0.85 for women). Isolated generalized obesity was defined as increased BMI and normal WC. Isolated abdominal obesity was defined as increased WC and normal BMI. Combined obesity was defined as increased BMI and increased WC. RESULTS: Mean MPOD at all eccentricities was not significantly different between men and women. Mean MPOD values did not significantly differ in various types of obesity, when compared with the normal subjects. On subgroup analysis, in age group >= 60 years, mean MPOD values were significantly higher in subjects with obesity based on BMI (0.61 vs 0.41, P=0.036), obesity based on WHR (0.67 vs 0.41, P=0.007), and isolated generalized obesity (0.66 vs 0.41, P=0.045) in comparison with normal subjects at 0.25 degrees eccentricity. CONCLUSION: We found lack of an association between MPOD and obesity in the South-Indian population. A similar finding was also noted on age group- and gender-wise analyses. PMID- 22222263 TI - Shared care of patients with ocular hypertension in the Community and Hospital Allied Network Glaucoma Evaluation Scheme (CHANGES). AB - AIMS: The Community and Hospital Allied Network Glaucoma Evaluation Scheme (CHANGES) used accredited community-based optometrists with a special interest (OSIs) in glaucoma to monitor ocular hypertensive (OHT) patients under virtual supervision of the Hospital Glaucoma Service (HGS). The purpose of this paper was to report the outcomes of the first completed community-based visit. METHODS: Eligible patients underwent a glaucoma consultant-led clinical examination before transfer to CHANGES. Individualised intraocular pressure (IOP) and follow-up time interval targets were set for each patient. OSIs used applanation tonometry, slit lamp biomicroscopy, automated visual field testing and digital optic disc photography. The hospital-based glaucoma team evaluated the data virtually. Patients were referred back to the HGS according to specific criteria. RESULTS: One hundred and sixty eight OHT patients were invited to attend their first OSI appointment. Of these, 144 attended their appointment (attendance rate 85.7%). Outcomes of 130 patients with complete data sets are reported. Sixteen patients (12.3%) were referred back to the HGS due to IOP above target, new visual field defects and/or optic nerve changes. The glaucoma consultant retained eight patients (6.1%) within the HGS on the basis of definite or probable glaucomatous conversion. CONCLUSIONS: CHANGES freed up capacity within a busy HGS. However, improvements need to be made regarding non-attendance rates in the community. The relatively high one-year definite or probable conversion rate emphasises the importance of the comprehensive review of OHT patients and of hospital-led virtual supervision to maintain patient safety. PMID- 22222264 TI - Adalimumab specifically induces CD3(+) CD4(+) CD25(high) Foxp3(+) CD127(-) T regulatory cells and decreases vascular endothelial growth factor plasma levels in refractory immuno-mediated uveitis: a non-randomized pilot intervention study. AB - AIM: To explore immunoregulatory and anti-inflammatory pathways specifically targeted by a subcutaneous anti-TNFalphadrug-adalimumab-which might be relevant for controlling refractory uveitis. DESIGN: Non-randomized pilot intervention study on the effects of adalimumab on Treg populations and plasma VEGF levels in refractory uveitis patients. Inflammatory and immunological parameters were measured in 12 patients before therapy, and 1 and 6 months after therapy, and analyzed in the context of ophthalmological outcomes. The results were compared with those obtained in 10 systemic prednisone-treated uveitis patients. RESULTS: After 1 month of treatment, all patients responded, with 67% of adalimumab group and 80% of the corticosteroid group achieving inactivity (P=0.5). Unlike steroid treated patients, a significant increase in T-regulatory CD4(+) CD25(high) Foxp3(+) CD127(-) cells was observed in adalimumab patients after 1 month of treatment, and maintained after 6 months (P=0.003). A significant adalimumab specific drop in plasma VEGF was observed after 1 and 6 months of treatment (P=0.019). In every single patient, Tregs but not VEGF correlated with disease activity. CONCLUSIONS: In refractory uveitis patients treated with adalimumab, clinical efficacy may be mediated through upregulation of Tregs in addition to modulation of VEGF-mediated inflammatory pathways. These biological properties, which were not observed in patients treated with corticosteroids, may reflect the specificity of TNF-alphatargeting. PMID- 22222265 TI - Toxoplasmosis: new challenges for an old disease. AB - More than a century after the identification of Toxoplasma gondii, major issues need to be addressed for the optimal management of ocular disease. Toxoplasmic retinochoroiditis is the main cause of posterior uveitis in several geographical areas. The parasite establishes a love-hate relationship with the eye, manipulating the immune response and inducing variable initial lesions and further relapses. It is now well established that most cases are acquired after birth and not congenital. The severity of the disease is mainly due to the parasite genotype and the host immune status. Diagnosis is based on clinical features, but may be confirmed by biological tools applied to ocular fluids. Combining several techniques improves the diagnostic yield in equivocal cases. Therapeutic management is the most important challenge. Even though evidence based data on the efficacy of anti-parasitic drugs are still missing, new strategies with a good safety profile are available and may be proposed earlier during the course of the disease, but also in selected cases, to reduce sight threatening relapses. Revisiting the therapeutic options and indications may be an important step towards long-term maintenance of the visual function and avoidance of major complications. PMID- 22222267 TI - Distribution, reabsorption, and complications of preretinal blood under silicone oil after vitrectomy for severe proliferative diabetic retinopathy. AB - PURPOSE: To examine the evolution and complications of preretinal hemorrhage under silicone oil after diabetic vitrectomy. METHODS: A total of 44 cases of primary diabetic vitrectomy with silicone oil infusion were reviewed in a 3-year period. Intravitreal bevacizumab was used preoperatively for cases with active proliferation, and in all cases at the end of surgery. Intraoperative bleeding, postoperative extent of preretinal hemorrhage, blood reabsorption time, and reproliferation and treatment results were assessed. RESULTS: Maximal blood distributed in thin and scattered patterns (23 cases), thick and localized patterns (10 cases), or thick and scattered patterns (10 cases) developed within 1 week after surgery, and was largely reabsorbed within a month with improved postoperative vision. Confluent blood extending to the midperiphery (one case) resulted in severe fibrosis and detachment. Complications included fibrotic plaque (two cases), and fibrous band and thick membrane (seven cases). Six cases underwent preretinal tissue removal. Vision improvement >= 3 lines was noted in three cases. CONCLUSION: Most of the rebleeding occurred within the first post-op week, with gradual reabsorption in the posterior pole within 4 weeks; widespread confluent bleeding might result in severe reproliferation and detachment. A major complication of preretinal bleeding was the formation of preretinal fibrosis. Re operation achieved a mild VA improvement. PMID- 22222268 TI - Visual and anatomical outcomes following vitrectomy for complications of diabetic retinopathy: the DRIVE UK study. AB - INTRODUCTION: End-stage diabetic eye disease is an important cause of severe visual impairment in the working-age group. With the increasing availability of refined surgical techniques as well as the early diagnosis of disease because of screening, one would predict that the prevalence of this condition is decreasing and the visual outcome is improving. AIM: To study the prevalence and visual outcome following vitrectomy for complications of diabetic retinopathy. MATERIALS AND METHODS: This study identified the patients who underwent vitrectomy from January 2007 to December 2009 because of diabetes-related complications in South East London. Data collected included baseline demographics, best-corrected visual acuity, indication for the vitrectomy, complication, outcome, and duration of follow-up. RESULTS: The prevalence of people requiring vitrectomy who are registered in the diabetes register of this region was 2 per 1000 people with diabetes. Vitrectomy was required in 185 eyes of 158 patients during this period. These included 83 Caucasians, 51 Afro-Caribbeans, 17 South Asians, and 7 from other ethnic groups. There were 58 patients with type I diabetes and 100 with type II, with a mean duration of diabetes of 23 and 16.5 years, respectively. The reason for vitrectomy included tractional retinal detachment (TRD) in 109 eyes, non-clearing vitreous haemorrhage (NCVH) in 68 eyes, and other causes in 8 eyes. In all, 50% of the eyes with TRD and NCVH, and 87% of the eyes with NCVH improved by at least three ETDRS lines at 12 months. Poor predictors of visual success included longer duration of diabetes (OR: 0.69), use of insulin (OR: 0.04), presence of ischaemic heart disease (OR: 0.04), delay in surgery (OR: 0.59), and the failure to attend clinic appointments (OR: 0.58). Preoperative use of intravitreal bevacizumab in eyes with TRD undergoing vitrectomy showed a marginal beneficial effect on co-existent maculopathy (P=0.08) and required less laser intervention post procedure, but did not affect the number of episodes of late onset vitreous haemorrhage post vitrectomy (P=0.81). CONCLUSION: Visual outcome has improved significantly in eyes with complications due to diabetic retinopathy compared with the previously reported Diabetic Vitrectomy Study. PMID- 22222269 TI - Dynamic changes in anterior segment (AS) parameters in eyes with primary angle closure (PAC) and PAC glaucoma and open-angle eyes assessed using AS optical coherence tomography. AB - PURPOSE: To evaluate serial changes in anterior segment (AS) parameters in terms of variation in pupil diameter (PD) using AS optical coherence tomography (OCT) in eyes with primary angle closure or primary angle closure glaucoma (PCG), age matched open-angle (AO) eyes, and young open-angle (YO) eyes. METHODS: Forty-four PCG (mean +/- SD; 62.2 +/- 7.5 years), 36 AO (62.0 +/- 12.3 years), and 58 YO eyes (29.1 +/- 7.0 years) were imaged under four standardized lighting conditions (3.25, 100.8, 426, and 1420 cd/m(2)). PD, anterior chamber depth (ACD), iris cross-sectional area (IA), iris thicknesses at 750 and 1500 MUm from the scleral spur (IT750, IT1500), iris curvature (IC), lens vault (LV), and anterior chamber area (ACA), were calculated. The slope of the change in each AS parameter in terms of variation in PD was determined by a linear mixed-effect model. RESULTS: The mean ACD was significantly shallower (P < 0.001), the IC higher (P < 0.001), the IT750 greater (P = 0.026), the ACA smaller (P < 0.001), the LV greater (P < 0.001), and the IA wider (P = 0.019) in PCG eyes compared with AO eyes. However, the mean slope of no parameter differed significantly between PCG and AO eyes. The mean slopes of IC, IT1500, and IA differed between AO and YO eyes. CONCLUSIONS: Older eyes showed significantly different dynamic AS parameter responses in terms of change in PD compared with younger eyes. Thus, the authors suggest that changes in the dynamic features of AS parameters with age may contribute to angle closure development, in addition to any predisposing anatomic condition. PMID- 22222271 TI - Involvement of SPARC and MMP-3 in the pathogenesis of human pterygium. AB - PURPOSE: To investigate the expression of SPARC and matrix metalloproteinases (MMPs) in normal conjunctiva and pterygium tissues. METHODS: This study involved paired control or uninvolved conjunctiva and pterygium tissue from 21 patients. Quantitative real-time PCR was performed to assess SPARC and MMP mRNA expression, whereas Western blot analysis was performed to assess SPARC protein levels in normal conjunctiva and pterygium tissue. Tissue localization of SPARC, extracellular matrix proteins, and MMPs were determined by immunofluorescence analyses. RESULTS: SPARC transcript and protein levels were upregulated in pterygium compared with normal conjunctiva. Immunofluorescence analyses showed localization of SPARC to the epithelial basement membrane and stroma of normal conjunctiva tissue. Increased SPARC in the pterygium stroma colocalized partially with elevated collagen I, fibronectin, alpha-SMA, and MMP-3. SPARC and MMP-3 also colocalized in the pterygium epithelium. CONCLUSIONS: SPARC was upregulated in pterygium and may collaborate with increased MMP-3 in some patients to account for many of the phenotypic properties characteristic of pterygium. PMID- 22222270 TI - Blue flash ERG PhNR changes associated with poor long-term glycemic control in adolescents with type 1 diabetes. AB - PURPOSE: To investigate the relationship between long-term glycemic control and photopic negative response (PhNR) changes in the blue flash ERG in adolescents with type 1 diabetes (T1D) without diabetic retinopathy (DR). METHODS: After light adaptation, ERG responses to 1.60 cd.s/m(2) blue (420 nm) flashes (blue flash ERG) and 3.0 cd.s/m(2) white flashes (LA 3.0 ERG) were recorded in 22 patients (age range, 12 to 19 years) and 28 age-similar control subjects. The primary outcome measure was the amplitude of the PhNR. Secondary outcome measures were the amplitude and implicit time of the a-wave and b-wave. Multiple regression analyses were conducted with glycated hemoglobin (HbA(1c)) values and the time since diagnosis of T1D as covariates. RESULTS: Blue flash ERG PhNR amplitudes were reduced (P = 0.005) in patients compared with control subjects. Multiple regression analysis demonstrated that a 1-unit increase in HbA(1c) was associated with a 15% decrease in the blue flash ERG PhNR amplitude (r = 0.61, P = 0.003). Compared with controls blue flash ERG a-waves (P = 0.03) and b-waves (P = 0.02) were delayed in patients but were not significantly associated with HbA(1c) or time since diagnosis of T1D. None of the ERG measures in the LA 3.0 ERG were significantly different in patients compared with controls. CONCLUSIONS: Poorer long-term glycemic control is associated with worsening inner retinal dysfunction involving short-wavelength cone pathways of adolescents with T1D and no clinically visible DR. Future studies are warranted to determine whether changes in the blue flash ERG PhNR are a predictive marker of subclinical DR. PMID- 22222272 TI - 2-D pattern of nerve fiber bundles in glaucoma emerging from spectral-domain optical coherence tomography. AB - PURPOSE: To correlate the thicknesses of focal regions of the macular ganglion cell layer with those of the peripapillary nerve fiber layer using spectral domain optical coherence tomography (SD-OCT) in glaucoma subjects. METHODS: Macula and optic nerve head SD-OCT volumes were obtained in 57 eyes of 57 subjects with open-angle glaucoma or glaucoma suspicion. Using a custom automated computer algorithm, the thickness of 66 macular ganglion cell layer regions and the thickness of 12 peripapillary nerve fiber layer regions were measured from registered SD-OCT volumes. The mean thickness of each ganglion cell layer region was correlated to the mean thickness of each peripapillary nerve fiber layer region across subjects. Each ganglion cell layer region was labeled with the peripapillary nerve fiber layer region with the highest correlation using a color coded map. RESULTS: The resulting color-coded correlation map closely resembled the nerve fiber bundle (NFB) pattern of retinal ganglion cells. The mean r(2) value across all local macular-peripapillary correlations was 0.49 (+/- 0.11). When separately analyzing the 30 glaucoma subjects from the 27 glaucoma-suspect subjects, the mean r(2) value across all local macular-peripapillary correlations was significantly larger in the glaucoma group (0.56 +/- 0.13 vs. 0.37 +/- 0.11; P < 0.001). CONCLUSIONS: A two-dimensional (2-D) spatial NFB map of the retina can be developed using structure-structure relationships from SD-OCT. Such SD-OCT based NFB maps may enhance glaucoma detection and contribute to monitoring change in the future. PMID- 22222273 TI - Slow magnetic relaxation in a pseudotetrahedral cobalt(II) complex with easy plane anisotropy. AB - A pseudotetrahedral cobalt(II) complex with a positive axial zero-field splitting parameter of D = 12.7 cm(-1), as determined by high-field EPR spectroscopy, is shown to exhibit slow magnetic relaxation under an applied dc field. PMID- 22222274 TI - Transition metal-catalyzed N-arylations of amidines and guanidines. AB - Although several recent reviews dealt with transition metal catalyzed N-arylation of amines (all classes), to date no specific review covering the N-arylation of amidines and guanidines appeared. Amidines and guanidines are considered as fundamental entities in medicinal chemistry. The appearance of these functional groups in drugs, agrochemicals and natural products justifies a separate description of the current status of the literature on the N-arylation of the amidine and guanidine functionalities. Both acyclic and cyclic derivatives are taken into account. For cyclic amidines/guanidines only systems which possess an exocyclic nitrogen atom are considered. This critical review is largely organized by the type of amidine/guanidine and transition metal used and covers literature up to May 2011 (200 references). PMID- 22222275 TI - Regulation of nutrient intake in nectar-feeding birds: insights from the geometric framework. AB - A nectar diet is simple in nutritional composition and easily digested, but may vary greatly in its proportions of sugar and water. Here, we apply the geometric framework, a modelling approach for investigating how animals balance nutrient needs in multidimensional and dynamic nutritional environments, to captive whitebellied sunbirds (Cinnyris talatala). We address the question of how these small birds (~8 g) prioritise sugar and water intake, and how dietary salt content interacts with sugar and water intake. Sunbirds kept at 20 degrees C and provided with moderate to high sucrose concentrations (>=1 M), together with supplementary water, converge on an intake target of 2.79 g day(-1) of sucrose and 7.72 g day(-1) of water: equivalent to 0.85 M sucrose. When the birds are given more dilute sucrose concentrations, they defend their sugar intake by over ingesting water, up to a ceiling of 47 g day(-1). Sugar intake thus gets priority over water intake, but the birds have a finite capacity to over-ingest water to gain the target level of sugar. Regulation appears to be less precise when birds are given a choice between two sucrose solutions than when they choose between a sugar solution and supplementary water. Intake targets vary in response to internal and external factors, and sunbirds increase their sugar intake in response to increased activity and cold, irrespective of nectar concentration. They also compensate for interruptions in foraging activity, whether overnight or during the day. Interactive effects become evident when sodium is included as a third nutrient: on very dilute nectar (<=0.1 M), where sunbirds lose body mass, the addition of sodium to the diet helps to achieve the carbohydrate intake target, while raising the ceiling on water intake. This analysis provides a new perspective on nectarivory, while adding to the comparative database on nutrient regulation and emphasising water as a nutrient. PMID- 22222276 TI - Contact force-controlled zero-fluoroscopy catheter ablation of right-sided and left atrial arrhythmia substrates. AB - BACKGROUND: Conventional catheter ablation of cardiac arrhythmias is associated with radiation risks for patients and laboratory personnel. However, nonfluoroscopic catheter guidance may increase the risk for inadvertent cardiac injury. A novel radiofrequency ablation catheter capable of real-time tissue-tip contact force measurements may compensate for nonfluoroscopic safety issues. OBJECTIVE: To investigate the feasibility of contact force-controlled zero fluoroscopy catheter ablation. METHODS: In 30 patients (including 12 pediatric patients), zero-fluoroscopy catheter ablation of right-sided (right atrium, n = 20; right ventricle, n = 2) and left atrial (n = 8) arrhythmias was attempted. Inclusion criteria were symptomatic suspected atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia, focal right atrial and ventricular arrhythmias, and lone atrial fibrillation. A novel irrigated-tip catheter with an integrated contact force sensor was used for nonfluoroscopic 3 dimensional electroanatomical mapping and radiofrequency ablation. Transseptal access was gained under transesophageal guidance for ablation of left-sided arrhythmias. RESULTS: Procedural success without fluoroscopy was achieved in 29 of the 30 patients (97%). In 1 patient, endocardial nonfluoroscopic ablation failed because of an epicardial accessory pathway within a coronary sinus aneurysm. Mean total contact force and amplitude of force undulations were kept below 50 g during mapping and below 40 g during ablation to prevent contact force peaks (>100 g). Apart from a transient second-degree type I atrioventricular block, no complications occurred. The mean procedure time was 2.8 +/- 0.9 hours. There were no arrhythmia recurrences during a mean follow-up of 6.2 +/- 4.2 months. CONCLUSION: Contact force-controlled zero-fluoroscopy catheter ablation is generally feasible in right-sided and left atrial cardiac arrhythmias. PMID- 22222277 TI - Continuous ECGI mapping of spontaneous VT initiation, continuation, and termination with antitachycardia pacing. PMID- 22222278 TI - Reaching the ventricular aspect of the inferior isthmus in a Fontan patient using magnetic navigation. PMID- 22222279 TI - Advanced microtechnologies for detection of chromosome abnormalities by fluorescent in situ hybridization. AB - Cytogenetic and molecular cytogenetic analyses, which aim to detect chromosome abnormalities, are routinely performed in cytogenetic laboratories all over the world. Traditional cytogenetic studies are performed by analyzing the banding pattern of chromosomes, and are complemented by molecular cytogenetic techniques such as fluorescent in situ hybridization (FISH). To improve FISH application in cytogenetic analysis the issues with long experimental time, high volumes of expensive reagents and requirement for trained technicians need to be addressed. The protocol has recently evolved towards on chip detection of chromosome abnormalities with the development of microsystems for FISH analysis. The challenges addressed by the developed microsystems are mainly the automation of the assay performance, reduction in probe volume, as well as reduction of assay time. The recent focus on the development of automated systems for performing FISH on chip is summarized in this review. PMID- 22222280 TI - An ethnopharmacological survey of the traditional medicine utilized in the community of Porvenir, Bajo Paragua Indian Reservation, Bolivia. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Porvenir is a semi-isolated Indian community in the Bajo Paragua Indian Reservation in Bolivian Amazon, one of the two communities of people from the Guarasug'we indigenous nation now close to extinction. The aim of our study was the collection of data on the traditional medicine utilized in the community, and to identify new subjects for further investigation by comparison of the folk-medicinal use with the available scientific literature data. MATERIALS AND METHODS: Field work was conducted for 5 months, which included participant observation, semi-structured interviews with 16 individuals, and the collection of voucher specimens for botanical identification. The knowledge of the inhabitants relating to medicinal plants was analysed by means of the modified method of Gentry and Phillips (1993a,b), which assesses the frequency and the variety of use of plants. Scientific data were gathered on selected species, and the correlations of the traditional uses of the herbs with scientific evidence were assessed. RESULTS: The lifestyle and beliefs in Porvenir, botanical data on the plants used, the frequency and variety of medicinal use, diseases that occur and their possible treatment, and methods of plant application are discussed in detail. 145 plant species were registered with 451 recorded uses. The majority of the plants were utilized to treat gastrointestinal complaints (60 species), followed by diseases of the central nervous system, pain and fever (37 species), diseases of the genitourinary tract (35 species), dermatological disorders (34 species) and diseases of the respiratory system (32 species). One fifth of the species are also applied in traditional medicine in other areas of Bolivia or in other countries. The majority of the 145 species used in the community have not been extensively investigated from phytochemical and pharmacological aspects. There are no data in the scientific literature on one fifth of the species. CONCLUSIONS: The medicine applied in Porvenir and the contemporary knowledge of the people interviewed concerning plants reflect the local traditions and their changes very well, clearly demonstrating the influence exerted by conventional medicine, and how the ancestral knowledge is progressively being forgotten. The present ethnopharmacological survey indicates that 24 species that are frequently and consistently used in the community of Porvenir are perspective for further research, as their chemistry and pharmacology have not been published to date. PMID- 22222281 TI - Effect of Tulbaghia violacea on the blood pressure and heart rate in male spontaneously hypertensive Wistar rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tulbaghia violacea Harv. (Alliaceae) is a small bulbous herb which belongs to the family Alliaceae, most commonly associated with onions and garlic. In South Africa, this herb has been traditionally used in the treatment of various ailments, including fever, colds, asthma, paralysis, hypertension and stomach problems. The aim of this study was to evaluate the effect of methanol leaf extracts (MLE) of Tulbaghia violacea on the blood pressure (BP) and heart rate (HR) in anaesthetized male spontaneously hypertensive rats; and to find out the mechanism(s) by which it acts. MATERIALS AND METHODS: The MLE of Tulbaghia violacea (5-150mg/kg), angiotensin I human acetate salt hydrate (ang I, 3.1-100MUg/kg), angiotensin II human (ang II, 3.1 50MUg/kg), phenylephrine hydrochloride (phenylephrine, 0.01-0.16mg/kg) and dobutamine hydrochloride (dobutamine, 0.2-10.0MUg/kg) were infused intravenously, while the BP and HR were measured via a pressure transducer connecting the femoral artery and the Powerlab. RESULTS: Tulbaghia violacea significantly (p<0.01) reduced the systolic, diastolic, and mean arterial BP; and HR dose dependently. Ang I, ang II, phenylephrine and dobutamine all increased the BP dose-dependently. The hypertensive effect of ang I and the HR-increasing effect of dobutamine were significantly (p<0.01) decreased by their co-infusion with Tulbaghia violacea (60mg/kg). However, the co-infusion of ang II or phenylephrine with Tulbaghia violacea (60mg/kg) did not produce any significant change in BP or HR when compared to the infusion of either agent alone in the same animal. CONCLUSIONS: Tulbaghia violacea reduced BP and HR in the SHR. The reduction in BP may be due to actions of the MLE on the ang I converting enzyme (ACE) and beta(1) adrenoceptors. PMID- 22222282 TI - Placental chorangiosis: the association with oxidative stress and angiogenesis. AB - BACKGROUND/AIMS: Chorangiosis is considered to be strongly associated with fetal, maternal, and placental disorders, and has been found to be correlated with increased fetal morbidity and mortality. In this study, it is aimed to investigate the association of angiogenesis and oxidative stress with the pathogenesis of chorangiosis. METHODS: Expressions of heat shock protein 70 (HSP70), vascular endothelial growth factor-A (VEGF-A) and basic fibroblast growth factor (b-FGF), which are investigated with avidin-biotin-peroxidase method in formalin-fixed, paraffin-embedded sections from placental tissues diagnosed as no chorangiosis (n = 18) and chorangiosis (n = 18), have been evaluated in a semiquantitative manner. RESULTS: There were significant differences between chorangiosis and no chorangiosis cases with respect to birth weight, birth length, and Apgar scores (p < 0.001). Statistically significant (p < 0.001), diffuse and strong expressions with HSP70, VEGF-A and b-FGF were observed in the villous tissue of placental chorangiosis cases when compared with no chorangiosis cases. CONCLUSION: The majority of the chorangiosis cases had an accompanying poor perinatal outcome, and also those with accompanying angiogenesis and increased oxidative stress demonstrated diffuse and strong expressions of HSP70, VEGF-A and b-FGF. The interaction of maternal, placental, and fetal factors with increased oxidative stress and angiogenesis may possibly contribute to this arising pathologic change. PMID- 22222283 TI - Coexistence of hepatitis B surface antigen and anti-HBs in Chinese chronic hepatitis B virus patients relating to genotype C and mutations in the S and P gene reverse transcriptase region. AB - We aimed to determine the prevalence of the coexistence of HBsAg and anti-HBs and to analyze the clinical and virological features of infection, including amino acid (aa) patterns of the S gene and reverse transcriptase (RT) region in Chinese chronic hepatitis B (CHB) patients. Fifty-four (2.90%) CHB patients who were positive for both HBsAg and anti-HBs were tested, and sequences were obtained from 52 of them as well as 48 patients from a control group. S gene and RT region sequences were amplified and sequenced using in-house protocols. There was no significant difference between patients with and without anti-HBs with regard to age, gender, alanine aminotransferase level, and the proportion positive for HBeAg and HBcAb. The occurrence of genotype C (P = 0.001) and anti-HBeAb positivity (P = 0.027) was significantly higher in HBsAg+/anti-HBs+ individuals. In the S gene, the number of mutated residues in the HBsAg+/anti-HBs+ group was markedly higher than in control patients (1.88 versus 1.02 substitutions per 100 amino acids, P = 0.022). The amino acid exchange occurred mostly within the N terminal region (2.15 versus 0.87 substitutions per 100 amino acids, P = 0.023) and the "a" determinant (3.61 versus 1.56 substitutions per 100 amino acids, P = 0.049) in the two groups. In the RT region, the mean number of substitution per 100 aa showed a tendency to be significantly higher in HBsAg+/anti-HBs+ patients than in controls (2.34 versus 1.46, P = 0.040). This study showed a prevalence of coexistence of anti-HBs in HBsAg-positive patients and an increased frequency of genotype C and aa variability within both HBsAg and RT involving functionally important regions of those proteins. PMID- 22222284 TI - SARS-CoV nucleocapsid protein interacts with cellular pyruvate kinase protein and inhibits its activity. AB - The pathogenesis of SARS-CoV remains largely unknown. To study the function of the SARS-CoV nucleocapsid protein, we have conducted a yeast two-hybrid screening experiment to identify cellular proteins that may interact with the SARS-CoV nucleocapsid protein. Pyruvate kinase (liver) was found to interact with SARS-CoV nucleocapsid protein in this experiment. The binding domains of these two proteins were also determined using the yeast two-hybrid system. The physical interaction between the SARS-CoV nucleocapsid and cellular pyruvate kinase (liver) proteins was further confirmed by GST pull-down assay, co immunoprecipitation assay and confocal microscopy. Cellular pyruvate kinase activity in hepatoma cells was repressed by SARS-CoV nucleocapsid protein in either transiently transfected or stably transfected cells. PK deficiency in red blood cells is known to result in human hereditary non-spherocytic hemolytic anemia. It is reasonable to assume that an inhibition of PKL activity due to interaction with SARS-CoV N protein is likely to cause the death of the hepatocytes, which results in the elevation of serum alanine aminotransferase and liver dysfunction noted in most SARS patients. Thus, our results suggest that SARS-CoV could reduce pyruvate kinase activity via its nucleocapsid protein, and this may in turn cause disease. PMID- 22222285 TI - List of drugs in development for neurodegenerative diseases: update October 2011. PMID- 22222286 TI - Let's get started: research and writing. PMID- 22222287 TI - Health care-acquired infections and hospital readmissions: the initial focus on performance measures for public reporting, performance-based payment programs: Craven & Ober Policy Strategists, LLC. PMID- 22222288 TI - Searching the literature: a researcher's perspective. AB - There are many clinical questions that nurses may not have answers for in everyday practice. This dilemma leads many of them to look to the research for answers, guidance, or even more questions. Today's professional nurse should be familiar with common literature search methods. This article leads the nurse researcher through the process of finding relevant literature in a step-by-step method and defines common jargon related to the search. PMID- 22222289 TI - Optimal use of fresh frozen plasma. AB - Fresh frozen plasma contains a number of therapeutically useful substances, most notably coagulation factors. As with any transfusion, there are risks associated with plasma transfusion. Ironically, the risk of viral transmission (human immunodeficiency virus or hepatitis), although widely publicized, is extremely small. On the other hand, less well-known, noninfectious complications are common. Indeed, these noninfectious complications are the most significant cause of morbidity and mortality following transfusion. Although certain patients undeniably benefit from plasma transfusion, the benefit for many patients is less clear. This review will discuss indications for plasma transfusion, the associated risks, and special considerations for plasma administration. PMID- 22222290 TI - Developing an alternative workflow model for peripherally inserted central catheter placement. AB - Many challenges face vascular access nurses as technology improves and patients require more numerous and lengthy intravenous therapies. Nurses began placing peripherally inserted central catheters (PICCs) at the patient bedside in an effort to defray costly interventional radiology procedures and provide for patient comfort. In recent years, the numbers of PICC procedures have increased, and the procedure itself has become more technologically advanced. With these advances have come new logistical, environmental, and ergonomic challenges. This article explores some of these challenges, offers an alternative model to bedside PICC insertions, and describes the process and results of implementing this model in the milieu of a university teaching hospital. PMID- 22222291 TI - A comparative clinical study focusing on the antimicrobial efficacies of chlorhexidine gluconate alcohol for patient skin preparations. AB - Comparative efficacy study data showed that skin preparations formulated with more than 0.5% chlorhexidine gluconate (CHG) in alcohol produced significant reductions in microbial populations at the inguinal, abdominal, and antecubital sites at each sample time (P < .05) relative to baseline, and there were no significant differences statistically, including persistent effects within 24 hours (P > .05). It would be reasonable to expect that a 1% CHG-ethanol skin preparation (with >0.5% CHG in alcohol) could be chosen in Japan that would perform well and have promising potential for catheter preparation/maintenance preparation with consideration for recommendation of the Centers for Disease Control and Prevention's guideline issued in 2011. PMID- 22222292 TI - Parenteral nutrition: risks, complications, and management. AB - Parenteral nutrition is a life-saving modality, but one that also carries risks for potentially life-threatening complications. Comprehensive management of patients receiving parenteral nutrition includes careful selection of candidates, individualizing formulas to meet patients' unique needs, monitoring response to therapy, and implementing strategies designed to avoid complications. Measures to mitigate the risk of central line-associated bloodstream infections are particularly important. As with all complex therapies, a collaborative, multidisciplinary approach promotes optimal outcomes. PMID- 22222293 TI - Child welfare caseworkers as service brokers for youth in foster care: findings from project focus. AB - Youth in the foster care system have substantially higher rates of mental health needs compared to the general population, yet they rarely receive targeted, evidence-based practices (EBPs). Increasingly emerging in the literature on mental health services is the importance of "brokers" or "gateway providers" of services. For youth in foster care, child welfare caseworkers often play this role. This study examines caseworker-level outcomes of Project Focus, a caseworker training and consultation model designed to improve emotional and behavioral outcomes for youth in foster care through increased linkages with EBPs. Project Focus was tested through a small, randomized trial involving four child welfare offices. Caseworkers in the Project Focus intervention group demonstrated an increased awareness of EBPs and a trend toward increased ability to identify appropriate EBP referrals for particular mental health problems but did not have significantly different rates of actual referral to EBPs. Dose of consultation was associated with general awareness of EBPs. Implications for practice and outcomes for youth are discussed. PMID- 22222294 TI - The pathophysiology underlying the obesity paradox. PMID- 22222295 TI - Intravenous free and dipeptide-bound glutamine maintains intestinal microcirculation in experimental endotoxemia. AB - OBJECTIVE: The administration of glutamine (Gln), which is depleted in critical illness, is associated with an improvement of gut metabolism, structure, and function. The aim of the present study was to evaluate the effects of intravenous Gln and its galenic formulation, l-alanyl-l-glutamine dipeptide (AlaGln), on the intestinal microcirculation during experimental endotoxemia using intravital fluorescence microscopy. Gln or AlaGln administration was performed as pretreatment or post-treatment, respectively. To identify further the underlying mechanisms, amino acid levels were studied. METHODS: Sixty male Lewis rats were randomly divided into six groups (n = 10/group): control, LPS (lipopolysaccharide 5 mg/kg intravenously), Gln/LPS (LPS animals pretreated with Gln 0.75 g/kg Gln intravenously), AlaGln/LPS (LPS animals pretreated with AlaGln intravenously, 0.75 g/kg Gln content), LPS/Gln (LPS animals post-treated with Gln 0.75 g/kg intravenously), and LPS/AlaGln (LPS animals post-treated with AlaGln intravenously, 0.75 g/kg Gln content). Two hours after the endotoxin challenge, the microcirculation of the terminal ileum was studied using intravital fluorescence microscopy. Blood samples were drawn at the beginning, during, and the end of the experiment to determine the amino acid levels. RESULTS: The Gln and AlaGln pre- and post-treatment, respectively, prevented the LPS-induced decrease in the functional capillary density of the intestinal muscular and mucosal layers (P < 0.05). The number of adherent leukocytes in the submucosal venules was significantly attenuated after the Gln and AlaGln pre- and post treatment (P < 0.05). CONCLUSION: The Gln and AlaGln administrations improved the intestinal microcirculation by increasing the functional capillary density of the intestinal wall and decreasing the submucosal leukocyte activation. PMID- 22222296 TI - MLPA-based evidence for sequence gain: pitfalls in confirmation and necessity for exclusion of false positives. AB - Multiplex ligation-dependent probe amplification (MLPA) has become a standard method for identifying copy number mutations in diagnostic and research settings. The occurrence of false-positive deletion findings and the underlying causes are well recognized, whereas false-positive duplication/amplification findings have not been appreciated so far. We here present three pertinent cases which were only identified on extended, nonstandard secondary analyses. We also offer and experimentally validate a potential explanation. Our findings imply that MLPA data indicating gain of genomic sequence require validation on an independent sample or by an independent method. PMID- 22222297 TI - Modelling tissue electrophysiology with multiple cell types: applications of the extended bidomain framework. AB - The bidomain framework has been extensively used to model tissue electrophysiology in a variety of applications. One limitation of the bidomain model is that it describes the activity of only one cell type interacting with the extracellular space. If more than one cell type contributes to the tissue electrophysiology, then the bidomain model is not sufficient. Recently, evidence has suggested that this is the case for at least two important applications: cardiac and gastrointestinal tissue electrophysiology. In the heart, fibroblasts ubiquitously interact with myocytes and are believed to play an important role in the organ electrophysiology. Along the GI tract, interstitial cells of Cajal (ICC) generate electrical waves that are passed on to surrounding smooth muscle cells (SMC), which are interconnected with the ICC and with each other. Because of the contribution of more than one cell type to the overall organ electrophysiology, investigators in different fields have independently proposed similar extensions of the bidomain model to incorporate multiple cell types and tested it on simplified geometries. In this paper, we provide a general derivation of such an extended bidomain framework applicable to any tissue and provide a generic and efficient implementation applicable to any geometry. Proof of-concept results of tissue electrophysiology on realistic 3D organ geometries using the extended bidomain framework are presented for the heart and the stomach. PMID- 22222298 TI - Comment on: Transoral gastric volume reduction as an intervention for weight management: 12 month follow-up of the TRIM trial. PMID- 22222299 TI - Superior calcium bioavailability of effervescent potassium calcium citrate over tablet formulation of calcium citrate after Roux-en-Y gastric bypass. AB - BACKGROUND: Calcium supplementation is commonly recommended for patients after Roux-en-Y gastric bypass to avert bone loss. To test the hypothesis that effervescent (liquid) potassium-calcium-citrate (PCC) might be more bioavailable than a tablet formulation of calcium citrate (Citracal Petite), the present study compared a single dose response of the 2 compounds. The present study was conducted at the University of Texas Southwestern Medical School at Dallas. METHODS: A total of 15 patients who had undergone Roux-en-Y gastric bypass were included in a 2-phase, crossover, randomized study comparing the single-dose bioavailability of PCC versus Citracal Petite. After following a restricted diet for 1 week, the participants ingested either a single dose of 400 mg elemental calcium as PCC or Citracal Petite. Sequential serum and urine samples were collected for a 6-hour period after the dose and analyzed for calcium, parathyroid hormone, and acid-base parameters. RESULTS: Compared with citracal petite, PCC significantly increased the serum calcium concentrations at 2, 3, and 4 hours after the oral load. The peak to baseline variation and increment in serum calcium (area under the curve) were significantly greater after PCC (P = .015 and P = .002, respectively). Concurrently, the baseline to nadir variation and decrement in serum parathyroid hormone (area over the curve) were significantly greater after PCC (P = .004 and P = .005, respectively). Moreover, compared with Citracal Petite, PCC caused a significantly greater increment in urinary citrate (P < .0001) and potassium (P = .0004) and a significantly lower increase in urinary ammonium (P = .045). CONCLUSION: In patients who have undergone Roux-en-Y gastric bypass, PCC was superior to Citracal Petite in conferring bioavailable calcium and suppressing parathyroid hormone secretion. PCC also provided an alkali load. PMID- 22222300 TI - Comments regarding a recent article comparing gastric bypass and duodenal switch and its questionable method and results. PMID- 22222301 TI - Halitosis in obese patients and those undergoing bariatric surgery. AB - BACKGROUND: Patients undergoing bariatric surgery often complain of bad breath. However, the relationship between bariatric surgery and halitosis is relatively unknown. The purpose of the present study was to evaluate and compare the occurrence of halitosis among patients before and after a specific type of bariatric surgery, Roux-en-Y gastric bypass, and its relationship with the tongue coating index, plaque index, and salivary flow rate. METHODS: A total of 62 patients with good oral health and in treatment for obesity at the walk-in clinic of Santa Casa Hospital, Belo Horizonte, Brazil, were selected. Of this sample, 31 were bariatric surgery candidates (control group) and 31 had already undergone Roux-en-Y gastric bypass surgery (case group). After completing a questionnaire, all patients underwent an oral clinical examination. Halitosis was measured using an organoleptic scale and a portable sulfide monitor. RESULTS: The Spearman correlation demonstrated a strong positive relation between the organoleptic rates and the concentration of volatile sulfur compounds determined using the sulfide monitor (rs = .58; P = .0001). No difference was found in the prevalence of halitosis between the 2 groups (P = .48). Only the salivary flow rate was significantly reduced in the control group compared with the case group (P = .02). In the case group, the concentration of volatile sulfur compounds correlated negatively with the salivary flow rate (P = .04) and positively with the tongue coating index (P = .005). The tongue coating index was significantly increased in those patients who did not brush the tongue (P < .04) and who had had episodes of vomiting (P = .02). CONCLUSION: These data suggest that no significant association exists between halitosis and Roux-en-Y gastric bypass. However, they do highlight the possible effect of this surgery on the oral cavity. PMID- 22222302 TI - Early prediction of failure to lose weight after obesity surgery. AB - BACKGROUND: After Roux-en-Y gastric bypass (RYGB), failing to lose enough weight or regaining weight is a concern for both patients and healthcare professionals. Our objective was to report the criteria for an early prediction of the failure to lose enough weight in the setting of a private practice and an academic center of obesity surgery. PATIENTS AND METHODS: A retrospective analysis of the 2-year weight loss profiles of patients after RYGB was performed using nonlinear mixed models. A total of 375 morbidly obese adult patients, with a body mass index of 49.3 +/- 7.7 kg/m(2), were included. Weight loss success was determined 2 years after surgery using the percentage of excess weight loss criteria. The surgical treatment and the main outcome measurement was standardized RYGB and the percentage of excess weight loss time profiles. RESULTS: The patients who failed, succeeded, or had intermediate results at 2 years after surgery had different percentage of excess weight loss profiles during this period. At 6 months, 71% of those who had lost <30% of their initial excess weight had not lost >=50% at 24 months. In contrast, those who had lost >45% were unlikely to have lost <50% of their excess weight. CONCLUSION: An early (month 6) prediction of failure to lose significant weight after RYGB can be made, with the threshold at 30% of the initial excess weight loss. Patients who have lost <30% of their initial excess weight are unlikely to have lost >=50% at 24 months. PMID- 22222303 TI - Survey of bariatric surgical patients' experiences with behavioral and psychological services. AB - BACKGROUND: Bariatric surgery continues to grow in popularity as a treatment of obesity; however, weight regain and noncompliance with behavioral recommendations remain an issue. Little is known about the type and frequency of services completed by bariatric patients and their satisfaction with these services. However, preliminary research has shown that the use of behavioral and psychological services is less common after surgery. We assessed the behavioral and psychological services completed by bariatric patients before and after surgery, patient satisfaction with the surgery and services, and the relationship between the completed services and the outcomes. The participants were solicited for participation using an on-line support Web site dedicated to obesity and bariatrics. METHODS: A convenience sample of 380 subjects were included in the present study. They completed an Internet-based survey that assessed the psychological, dietary, exercise, and lifestyle services completed before and after surgery, their satisfaction with these services, and their weight loss outcomes. RESULTS: Overall, the participants reported completing more services before surgery. After surgery, the most frequently reported services completed were support groups and dietary consultation. More than one half of the participants did not meet with either a mental health professional or an exercise professional after surgery. The participants expressed high satisfaction with their surgery and services, with exercise services receiving the lowest satisfaction rating. A statistically significant relationship was found between the total number of postoperative psychological and behavioral services completed and a greater percentage of excess weight lost. The t tests showed that participants who completed group exercise sessions and nutritional consultation after surgery lost more weight than did those who did not complete these services. CONCLUSION: The participants in the present sample reported completing few behavioral and psychological services after surgery. However, our findings showed that these services could promote greater weight loss and maintenance. Thus, it is recommended that bariatric facilities and insurance providers consider requiring patients to complete postoperative behavioral modification programs that target improvement in diet and physical activity behaviors. PMID- 22222304 TI - Effects of surgically induced weight loss by Roux-en-Y gastric bypass on cardiovascular autonomic nerve function. AB - BACKGROUND: Obesity is associated with autonomic imbalance. With respect to cardiovascular autonomic dysfunction, this is characterized by reduced heart rate variability (HRV). Our objective was to determine the effect of surgically induced weight loss on cardiovascular autonomic nerve fiber function in subjects with severe obesity and examine whether an association with reduced insulin resistance exists. The setting was a hospital and private practice in the United States. METHODS: A total of 32 morbidly obese patients (body mass index 51 +/- 11 kg/m(2)) underwent laparoscopic Roux-en-Y gastric bypass. Measures of HRV (e.g., power spectral analysis, RR variation during deep breathing) were used to evaluate autonomic function before and 6 months after surgery. The homeostasis model assessment of insulin resistance index (HOMA-IR) was used to assess insulin resistance. RESULTS: At 6 months after bariatric surgery, the patients had lost 58% excess body mass index with improvement in the HOMA-IR (3.0 +/- 1.4 versus 1.1 +/- .7; P < .001). Measures of RR variation during deep breathing and total spectral power, low frequency (LF) power (influenced by sympathetic and parasympathetic activity), and high frequency (HF) power (parasympathetic activity) increased with weight loss. The LF/HF ratio was lower (1.5 +/- 1.5 versus .9 +/- .7, P < .05) with a reduction in weight. Spectral analysis of HRV combined with spectral analysis of respiratory activity generated the respiration frequency area (RFA) and low frequency area. The RFA was increased, and the LFA/RFA ratio was reduced with weight loss. HOMA-IR and HRV did not correlate. CONCLUSION: Surgically induced weight loss has a favorable effect on autonomic function, but it does not appear to be directly attributable to reduced insulin resistance. PMID- 22222305 TI - Evaluation of neonatal regional cerebral perfusion using power Doppler and the index fractional moving blood volume. AB - BACKGROUND: The high cerebral morbidity of premature neonates is thought to be related to changes in tissue perfusion in vulnerable areas of the brain. Quantification of power Doppler (PD) images using the index fractional moving blood volume (FMBV) may allow measurement of regional cerebral perfusion. OBJECTIVE: To evaluate the reproducibility of calculating FMBV using PD ultrasound images to estimate cerebral perfusion. METHODS: Two experienced clinicians performed head ultrasounds on 24 normally-grown neonates at less than 33 weeks' gestation. Both clinicians independently acquired and stored three PD images in two different coronal planes. FMBV was calculated offline after selecting two predefined regions of interest within these planes (basal ganglia and subependymal regions). Reproducibility was evaluated by calculating the intraclass correlation coefficient (intraCC) and the interclass correlation coefficient (interCC). RESULTS: FMBV was successfully evaluated in 24/24 neonates by both clinicians. The intraCC for repeatability for observer A was 1.00 (95% CI 1.00-1.00) for the basal ganglia and 0.99 (95% CI 0.99-1.00) for the subependymal region, and for observer B was 0.99 (95% CI 0.99-1.00) for the basal ganglia and 0.96 (95% CI 0.92-0.98) for the subependymal region. The interCC was 0.86 (95% CI 0.68-0.94) for the basal ganglia and 0.93 (95% CI 0.86-0.97) for the subependymal region. CONCLUSION: Using standardised settings and a well-defined region of interest, the calculation of FMBV using PD images is a reproducible method of estimating neonatal regional cerebral perfusion. PMID- 22222306 TI - Music training enhances the rapid plasticity of P3a/P3b event-related brain potentials for unattended and attended target sounds. AB - Neurocognitive studies have shown that extensive musical training enhances P3a and P3b event-related potentials for infrequent target sounds, which reflects stronger attention switching and stimulus evaluation in musicians than in nonmusicians. However, it is unknown whether the short-term plasticity of P3a and P3b responses is also enhanced in musicians. We compared the short-term plasticity of P3a and P3b responses to infrequent target sounds in musicians and nonmusicians during auditory perceptual learning tasks. Target sounds, deviating in location, pitch, and duration with three difficulty levels, were interspersed among frequently presented standard sounds in an oddball paradigm. We found that during passive exposure to sounds, musicians had habituation of the P3a, while nonmusicians showed enhancement of the P3a between blocks. Between active tasks, P3b amplitudes for duration deviants were reduced (habituated) in musicians only, and showed a more posterior scalp topography for habituation when compared to P3bs of nonmusicians. In both groups, the P3a and P3b latencies were shortened for deviating sounds. Also, musicians were better than nonmusicians at discriminating target deviants. Regardless of musical training, better discrimination was associated with higher working memory capacity. We concluded that music training enhances short-term P3a/P3b plasticity, indicating training induced changes in attentional skills. PMID- 22222307 TI - Divalent and monovalent autoantibodies cause dysfunction of MuSK by distinct mechanisms in a rabbit model of myasthenia gravis. AB - Muscle-specific kinase (MuSK), a receptor tyrosine kinase, is required for the formation and maintenance of neuromuscular junctions (NMJs). Although autoantibodies against MuSK have been demonstrated to cause myasthenia gravis (MG), the underlying pathogenic mechanism remains unclear because a major subclass of these antibodies is functionally monovalent. We investigated the pathogenic role of MuSK antibodies in the onset of MG in vivo and in vitro. Ultrastructural visualization of NMJs in paretic rabbits with MuSK antibodies indicated that postsynaptic membranes were preserved, despite a significant loss of complexity in the convoluted synaptic folds. In addition, an in vitro assay indicated that both divalent and monovalent antibodies from paretic rabbits could interfere with agrin-induced acetylcholine receptor (AChR) clustering in cultured myotubes. Furthermore, in the absence of agrin, divalent antibodies induced MuSK phosphorylation and accelerated downregulation of Dok-7, an essential intracellular MuSK binding protein, while monovalent antibodies inhibited agrin induced phosphorylation of MuSK, thus demonstrating distinct molecular mechanisms underlying the MuSK dysfunction induced by these two types of antibodies. Taken together, these findings suggest that complement activation is not necessary for the MG onset and that both divalent and monovalent antibodies may cause MG in vivo by inducing MuSK dysfunction. PMID- 22222308 TI - High efficiency GaN-based light-emitting diodes with embedded air voids/SiO2 nanomasks. AB - In this paper, the high performance GaN-based light-emitting diodes (LEDs) with embedded microscale air voids and an SiO(2) nanomask by metal-organic chemical vapor deposition (MOCVD) were demonstrated. Microscale air voids and an SiO(2) nanomask were clearly observed at the interface between GaN nanorods (NRs) and the overgrown GaN layer by scanning electron microscopy (SEM). From the reflectance spectra we show strong reflectance differences due to the different refractive index gradient between the GaN grown on the nanotemplate and sapphire. It can increase the light extraction efficiency due to additional light scattering. The transmission electron microscopy (TEM) images show the threading dislocations were suppressed by nanoscale epitaxial lateral overgrowth (NELOG). The LEDs with embedded microscale air voids and an SiO(2) nanomask exhibit smaller reverse-bias current and large enhancement of the light output (65% at 20 mA) compared with conventional LEDs. PMID- 22222309 TI - Cloning and characterisation of a new 2-deoxy-D-ribose-5-phosphate aldolase from Rhodococcus erythropolis. AB - A new 2-deoxy-D-ribose-5-phoshate aldolase (DERA) gene was cloned from Rhodococcus erythropolis strain DSM 311, recombinantly expressed in Escherichia coli, and purified via affinity chromatography which yielded a homo-dimeric enzyme of 44.3 kDa as apparent by size exclusion chromatography. To characterise the enzyme, investigations about pH and temperature tolerance, stability, as well as analyses on resistance to organic solvents and acetaldehyde were performed. In addition, kinetic constants of the new DERA(RE) were compared to respective values of the DERA from E. coli (DERA(EC)). Stability of DERA(RE) turned out to be a crucial factor: The pH for optimal DERA(RE) activity was determined to be 7.0, whereas the highest stability was achieved at pH 9.0 with a half-life of approximately 20 days. The optimal temperature for DERA(RE) activity was 65 degrees C, but coupled with a rather low stability (half-life of 2 min). The highest stability was achieved at 25 degrees C. The new enzyme exhibits high resistance to organic solvents and acetaldehyde with a half-life being 2.5* higher compared to DERA(EC) under the exposure of 300 mM acetaldehyde. Hence it has the potential as a new promising biocatalyst with applications in organic synthesis. PMID- 22222310 TI - alpha-Chymotrypsin-catalyzed synthesis of poly-l-cysteine in a frozen aqueous solution. AB - Poly-l-cysteine (PLCys) is drawing attention as a potential sorbent of thiol (SH) reactive toxic heavy metal ions in the wastewater and polluted soils. However, preparation of PLCys relies on chemically synthesized polymers, in which SH groups must be protected and deprotected prior to use. On the other hand, alpha chymotrypsin polymerized l-cysteine ethyl ester in a frozen aqueous solution, provides PLCys with degree of polymerization from 6 to 11 without blocking of SH groups. Kinetic analyses suggested that the acylation of alpha-chymotrypsin with the initial substrate was a rate-limiting step in the enzymatic polymerization. The peptide yields reached 85% and 65% of SH groups in PLCys were assumed to be free forms. Although detail information on correlation between the state of SH groups and heavy metal adsorption properties of PLCys should be explored in further studies, the present study for the first time proposed an easy method for synthesis of PLCys requiring neither SH-protection nor -deprotection. PMID- 22222311 TI - Formation and stability of molybdenum-tellurium oxides MoTeO5, Mo2TeO8, Mo3TeO11 and MoTe2O7 in the gas phase. Quantum chemical and mass spectrometry determination of standard enthalpy of formation. AB - The formation of mixed molybdenum-tellurium oxides MoTeO5, Mo2TeO8, Mo3TeO11, MoTe2O7 in the gas phase has been studied by mass spectrometry (MS) experiments at temperatures of about 938 K and studied theoretically by quantum chemical (QC) methods. Structural and thermodynamic data for the molecules was calculated. The mixed oxides MoTeO5, Mo2TeO8, Mo3TeO11 and MoTe2O7 in the gas phase have been reported for the first time. Experimental thermodynamic data have been determined by means of MS and confirmed theoretically by DFT and ab initio (MP2) calculations. Adiabatic ionisation potentials (IPs) were obtained experimentally and compared with theoretical vertical ionisation potentials. The following values are given: Delta(f)H(298)(0) (MoTeO5) = -730.2 kJ mol(-1) (MS), Delta(f)H(298)(0) (MoTeO5) = -735.4 kJ mol(-1) (DFT), -717.3 kJ mol(-1) (MP2), S(298)(0) (MoTeO5) = 389.5 J mol(-1) K(-1) (DFT), c(p)(0)(T)(MoTeO5) = 141.71 + 13.54 * 10(-3)T - 2.53 * 10(6)T(-2) J mol(-1) K(-1) (298 < T < 940 K) (DFT), Delta(f)H(298)(0) (Mo2TeO8) = -1436.3 kJ mol(-1) (MS), Delta(f)H(298)(0) (Mo2TeO8) = -1436.1 kJ mol(-1) (DFT), -1455.9 kJ mol(-1) (MP2), S(298)(0) (Mo2TeO8) = 517.1 J mol(-1) K(-1) (DFT), c(p)(0)(T)(Mo2TeO8) = 228.64 + 24.15 * 10(-3)T - 4.09 * 10(6)T(-2) J mol(-1) K(-1) (298 < T < 940 K) (DFT), Delta(f)H(298)(0) (Mo3TeO11) = -2132.7 kJ mol(-1) (MS), Delta(f)H(298)(0) (Mo3TeO11) = -2110.7 kJ mol(-1) (DFT), -2163.2 kJ mol(-1) (MP2), S(298)(0) (Mo3TeO11) = 629.3 J mol(-1) K(-1) (DFT), c(p)(0)(T)(Mo3TeO11) = 316.40 + 34.10 * 10(-3)T - 5.74 * 10(6)T(-2) J mol(-1) K(-1) (298 < T < 940 K) (DFT), Delta(f)H(298)(0) (MoTe2O7) = -999.7 kJ mol(-1) (MS), Delta(f)H(298)(0) (MoTe2O7) = -1002.7 kJ mol(-1) (DFT), -1000.9 kJ mol(-1) (MP2), S(298)(0) (MoTe2O7) = 504.8 J mol(-1) K(-1) (DFT), c(p)(0)(T)(MoTe2O7) = 211.19 + 18.02 * 10(-3)T - 3.53 * 10(6)T(-2) J mol(-1) K(-1) (298 < T < 940 K) (DFT), IP(MoTeO5) = 10.68 eV (DFT), IP(Mo2TeO8) = 10.4 +/- 0.5 eV (MS), IP(Mo2TeO8) = 10.41 eV (DFT), IP(Mo3TeO11) = 10.7 +/- 0.5 eV (MS), IP(Mo3TeO11) = 10.18 eV (DFT), IP(MoTe2O7) = 9.91 eV (DFT). PMID- 22222312 TI - A genuine nonlinear approach for controller design of a boiler-turbine system. AB - This paper proposes a genuine nonlinear approach for controller design of a drum type boiler-turbine system. Based on a second order nonlinear model, a finite time convergent controller is first designed to drive the states to their setpoints in a finite time. In the case when the state variables are unmeasurable, the system will be regulated using a constant controller or an output feedback controller. An adaptive controller is also designed to stabilize the system since the model parameters may vary under different operating points. The novelty of the proposed controller design approach lies in fully utilizing the system nonlinearities instead of linearizing or canceling them. In addition, the newly developed techniques for finite-time convergent controller are used to guarantee fast convergence of the system. Simulations are conducted under different cases and the results are presented to illustrate the performance of the proposed controllers. PMID- 22222313 TI - A practical strategy to create near-infrared luminescent probes: conversion from fluorescein-based sensors. AB - Luminescent lanthanide complexes incorporating Yb(3+) and Nd(3+) are attracting much attention as imaging agents, but there have been few practical methods to make responsive sensors with these complexes. Here, we introduce a general strategy to synthesize near-infrared luminescent probes by conjugating a Yb(3+) chelate to established fluorescein-based probes. As the first demonstration, we present a complex, based on the green-emitting probe DAF-4, that responds to nitric oxide (NO) in aqueous solution with a significant increase in luminescence intensity at 980 nm. PMID- 22222315 TI - Olmesartan/amlodipine: blood pressure lowering and beyond in special populations. AB - Clinical studies and population-based analyses show that in patients with hypertension, the majority cannot control their blood pressure (BP) by treatment with a single antihypertensive agent. Combining agents from different antihypertensive classes with complementary modes of action significantly increases efficacy and is a treatment strategy recommended by European treatment guidelines, particularly in patients at high cardiovascular risk. The combinations of antihypertensive agents recommended by the European guidelines include an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB). The single-pill combination formulation of the ARB olmesartan medoxomil plus the CCB amlodipine is an effective and well-tolerated treatment that provides greater blood pressure lowering and control than the component monotherapies and favours compliance by not increasing pill burden. Importantly, the efficacy and tolerability of olmesartan plus amlodipine is not affected by age, gender, hypertension severity, diabetes status, race or body mass index. Additional blood pressure lowering effects are observed with stepwise uptitration of olmesartan plus amlodipine with or without hydrochlorothiazide, with more patients achieving blood pressure goals. In addition, olmesartan plus amlodipine has demonstrated effects beyond BP lowering by showing beneficial effects on markers of inflammation, endothelial dysfunction and oxidative stress, as well as metabolic improvements and a reduction in new-onset diabetes incidence in hypertensive patients with metabolic syndrome. PMID- 22222314 TI - Restoration of the blood pressure circadian rhythm by direct renin inhibition and blockade of angiotensin II receptors in mRen2.Lewis hypertensive rats. AB - BACKGROUND: Alterations in the circadian arterial pressure rhythm predict cardiovascular mortality. We examined the circadian arterial pressure rhythm and the effect of renin-angiotensin system blockade in congenic mRen2.Lewis hypertensive rats, a renin-dependent model of hypertension derived from the backcross of transgenic hypertensive [mRen-2]27 rats with Lewis normotensive ones. METHODS: Twenty-nine mRen2.Lewis hypertensive rats were randomly assigned to drink tap water (vehicle; n = 9), valsartan (30 mg/kg/day; n = 10), or valsartan (30 mg/kg/day) combined with aliskiren given subcutaneously (50 mg/kg/day; n = 10) for 2 weeks. Arterial pressure, heart rate, and locomotive activity were recorded with chronically implanted radiotelemetry probes. The awake/asleep ratio was calculated as [awake mean arterial pressure (MAP) mean - asleep MAP mean)] / (awake MAP mean) x 100. Plasma renin activity (PRA) and concentration (PRC), and plasma and kidney angiotensin II (Ang II) were measured by radioimmunoassay (RIAs). RESULTS: Untreated hypertensive rats showed an inverse arterial pressure rhythm, higher at day and lower at night, accompanied by normal rhythms of heart rate and locomotive activity. Treatment with valsartan or aliskiren and valsartan normalized the elevated arterial pressure and the arterial pressure rhythm, with the combination therapy being more effective in reducing MAP and in restoring the awake/asleep ratio. While PRA and PRC increased with the treatments, the addition of aliskiren to valsartan partially reversed the increases in plasma Ang II levels. Valsartan and the aliskiren and valsartan combination markedly reduced the renal cortical content of Ang II. CONCLUSION: The altered circadian arterial pressure rhythm in this renin-dependent hypertension model uncovers a significant role of Ang II in the desynchronization of the circadian rhythm of arterial pressure, heart rate, and locomotive activity. PMID- 22222317 TI - Trace element status and fatty acids metabolism during healthy ageing: an example of a population from the Tunisian eastern coast. AB - Micronutrients as well as essential fatty acids are indispensable for the correct functioning of the organism. The risk of disturbance in the associated nutrition and metabolism is expected to increase during ageing. In addition, it seems that trace elements are involved in the fatty acids metabolism. The aim of the present study was then to assess age-related changes in trace elements status and in plasma essential fatty acids composition with an emphasis on the desaturase activity estimation. Two hundred healthy Tunisian subjects (30-85 years old) were recruited and separated into two subgroups: elderly (65-85 years old) and middle aged (30-60 years old). The findings revealed that plasma zinc and calcium concentrations significantly decreased according to age. The prevalence of zinc deficiency was therefore shown to increase in old age (over 60% of elderly subjects were deficient or at risk of deficiency). No age-related changes were obtained for copper or magnesium status. The Delta6 desaturase, involved in the EFAs conversion, was shown to decrease according to age and to be associated with the plasma zinc level. Since elderly subjects were at risk of nutritional imbalance, it would be interesting to set optimal dietary proportion. This will help to prevent age-associated alterations and diseases for a better and healthy ageing. PMID- 22222316 TI - Staphylococcus aureus secretes coagulase and von Willebrand factor binding protein to modify the coagulation cascade and establish host infections. AB - Clinical isolates of Staphylococcus aureus secrete coagulases, polypeptides that bind to and activate prothrombin, thereby converting fibrinogen to fibrin and promoting the clotting of plasma or blood. Two staphylococcal products, the canonical coagulase (Coa) as well as the recently identified von Willebrand factor binding protein (vWbp), promote similar modifications of the coagulation cascade during host infection. Staphylococcal binding to fibrinogen or fibrin is an important attribute of disease pathogenesis, which leads to the formation of abscesses and bacterial persistence in host tissues and also enables the pathogen to cause lethal sepsis. Circumstantial evidence suggests that the product of coagulase activity, staphylococci captured within a fibrin meshwork, enable this pathogen to disseminate as thromboembolic lesions and to resist opsonophagocytic clearance by host immune cells. In addition, the coagulation products of staphylococci appear to display discrete differences when compared to those of thrombin-mediated coagulation, the latter representing a key innate defense mechanism against many invading pathogens. Preclinical evidence suggests that inactivation or neutralization of coagulases may prevent the pathogenesis of staphylococcal infections, a strategy that could be used to combat the current epidemic of hospital-acquired infections with drug-resistant S. aureus isolates. PMID- 22222319 TI - Hormonal responses to concurrent strength and endurance training with different exercise orders. AB - The purpose of this study was to examine the influence of the intrasession sequencing of concurrent strength and aerobic training on the acute testosterone (TT) and cortisol (COR) responses. Ten recreationally strength-trained young men (23.5 +/- 0.9 years) performed 2 exercise interventions: aerobic-strength (AS) and strength-aerobic (SA), which consisted of 30 minutes of aerobic exercise on a cycle ergometer at 75% of maximal heart rate and 3 sets of 8 repetitions at 75% of 1 repetition maximum (1RM) in 4 strength exercises. Maximal heart rate was determined using a maximal incremental test on a cycle ergometer. Blood samples were collected before, between exercise modalities, and immediately after the concurrent training sessions to determine basal and acute total TT and COR concentrations. There were significant increases in TT after the first modality in both exercise orders (p < 0.05). However, the TT level remained significantly higher than the resting levels after the second exercise modality only in the AS (p < 0.05) which resulted in a significant higher relative total change after the complete concurrent training session compared with SA (p < 0.05). Regarding COR, there were significant increases after the first modality in both AS and SA orders (p < 0.05), but the COR returned to resting levels after the second modality in both AS and SA interventions. During AS and SA, the change observed after the first modality performance was greater than that after the second in both hormones. The present results suggest that the TT response is optimized after the AS order, whereas both AS and SA produced similar hormonal levels at all time points. However, it is important to state that the present results should be applied only when short duration and moderate intensity aerobic training is performed. PMID- 22222318 TI - Determinants of vitamin D status among overweight and obese Puerto Rican adults. AB - BACKGROUND/AIMS: Low vitamin D status is highly prevalent worldwide, and the major determinants are sun exposure and vitamin D intake. We aimed to measure vitamin D status in a sample of overweight/obese adults in Puerto Rico, an area with plenty of sun exposure, and relate it to vitamin D intake, sun exposure and body composition. METHODS: Serum 25(OH)D levels (liquid chromatography-tandem mass spectrometry), body weight and fat (bioimpedance), vitamin D intake and sun exposure (questionnaires) were assessed. Analysis included age-adjusted correlations and multivariate regression. RESULTS: In 98 subjects (66% females; 40-65 years), median serum 25(OH)D levels were 30.7 ng/ml (25-75th percentile 25.0-37.3); 55% had levels >30 ng/ml, 31% had levels between 20 and 30 ng/ml and 14% had levels <20 ng/ml. Total vitamin D intake was 180 IU/day (45-615), and the sun exposure score was 22 (17-27). After adjusting for gender, 25(OH)D levels were significantly correlated with vitamin D intake (r = 0.24, p = 0.018), the sum of sun exposure and vitamin D intake indices (r = 0.34, p = 0.001) and percent body fat (r = -0.25, p = 0.01). After adjusting for age, gender and percent body fat, the sum of sun exposure and vitamin D intake indices remained statistically associated with 25(OH)D levels (beta = 1.5, p < 0.01). CONCLUSIONS: In this group of overweight and obese individuals, 25(OH)D was significantly related to vitamin D intake, sun exposure and vitamin D intake indices and percent body fat. PMID- 22222320 TI - Effects of unilateral and bilateral lower-body heavy resistance exercise on muscle activity and testosterone responses. AB - Unilateral and bilateral lower-body heavy resistance exercises (HREs) are used for strength training. Little research has examined whether muscle activation and testosterone (TES) responses differ between these exercises. Our purpose was to compare the effects of unilateral and bilateral lower-body HRE on muscle activity using surface electromyography (sEMG) and TES concentrations. Ten resistance trained, college-aged male athletes (football, track and field) completed 5 testing sessions in which bilateral (back squat [BS]) and unilateral (pitcher squat [PS]) exercises were performed using a counterbalanced design. Sessions 1 and 2 determined estimated maximum strength (10 repetition maximum [10RM]) in the BS and PS. During testing session 3, muscle activation (sEMG) was measured in the right vastus lateralis, biceps femoris, gluteus maximus, and erector spinae (ES) during both BS and PS (stance leg) exercises. In sessions 4 and 5, total TES concentrations (nanomoles per liter) were measured via blood draws at baseline (preexercise), 0, 5, 10, 15, and 30 minutes postexercise after 4 sets of 10 repetitions at the 10RM. Separate repeated-measures analyses of variance examined differences in sEMG and TES between BS and PS (p < 0.05). The sEMG amplitudes were similar (p = 0.80) for BS (0.22 +/- 0.06 mV) and PS (0.20 +/- 0.07 mV). The TES responses were also similar (p = 0.15) between BS (21.8 +/- 6.9 nmol.L(-1)) and PS (26.2 +/- 10.1 nmol.L(-1)). The similar lower limb and back sEMG and TES responses may indicate that the neuromuscular and hormonal demands were comparable for both the BS and PS exercises despite the absolute work being less in the PS. The PS exercise may be an effective method for including unilateral exercise into lower-body resistance training when designing training programs for ground-based activities. PMID- 22222321 TI - Effects of strength and power training on neuromuscular adaptations and jumping movement pattern and performance. AB - This study aimed at comparing the effects of strength and power training (ST and PT) regimens on neuromuscular adaptations and changes on vertical jump performance, kinetics, and kinematics parameters. Forty physically active men (178.2 +/- 7.0 cm; 75.1 +/- 8.6 kg; 23.6 +/- 3.5 years) with at least 2 years of ST experience were assigned to an ST (n = 14), a PT (n = 14), or a control group (C; n = 12). The training programs were performed during 8 weeks, 3 times per week. Dynamic and isometric maximum strength, cross-sectional area, and muscle activation were assessed before and after the experimental period. Squat jump (SJ) and countermovement jump (CMJ) performance, kinetics, and kinematics parameters were also assessed. Dynamic maximum strength increased similarly (p < 0.05) for the ST (22.8%) and PT (16.6%) groups. The maximum voluntary isometric contraction increased for the ST and PT groups (p < 0.05) in the posttraining assessments. There was a main time effect for muscle fiber cross-sectional area (p < 0.05), but there were no changes in muscle activation. The SJ height increased, after ST and PT, because of a faster concentric phase and a higher rate of force development (p < 0.05). The CMJ height increased only after PT (p < 0.05), but there were no significant changes in its kinetics and kinematics parameters. In conclusion, neuromuscular adaptations were similar between the training groups. The PT seemed more effective than the ST in increasing jumping performance, but neither the ST nor the PT was able to affect the SJ and the CMJ movement pattern (e.g., timing and sequencing of joint extension initiation). PMID- 22222322 TI - Effects of changing from full range of motion to partial range of motion on squat kinetics. AB - It is commonplace for people involved in recreational weight training to limit squat depth to lift heavier loads. This study compares differences in movement kinetics when squatting in the full range of motion (FROM) vs. partial range of motion (PROM). Ten men with a 1-year minimum of resistance training attended 4 sessions each comprising 4 sets of squats following one of FROM for 10 repetitions (FROM10) at an intensity of 67% 1 repetition maximum (1RM) FROM squat, PROM for 10 repetitions (PROM10) at 67% 1RM PROM squat, FROM for 5 repetitions (FROM5) at 83% FROM squat or PROM for 5 repetitions (PROM5) at 83% 1RM PROM squat. Movement velocity was not specified. Squat kinetics data were collected using an optical encoder. Differences between conditions were analyzed by repeated-measures analysis of variance and expressed as mean differences and standardized (Cohen) effect sizes with 95% confidence limits. The PROM5 power was substantially more than the PROM10 (98 W, -21 to 217; mean, lower and upper 95% confidence limits), FROM5 (168 W, 47-289), and FROM10 (255 W, 145-365). The force produced during PROM5 was substantially more than PROM10 (372 N, 254-490), FROM5 (854 N, 731-977), and FROM10 (1,069 N, 911-1227). The peak velocity produced during FROM10 was substantially more than FROM5 (0.105 m.s(-1), 0.044-0.166), PROM10 (0.246 m.s(-1), 0.167-0.325), and PROM5 (0.305 m.s(-1), 0.228-0.382). The FROM5 was substantially more than FROM10 (86 J, 59-113), PROM5 (142 J, 90-194), and PROM10 (211 J, 165-257). Therefore, either range of motion can have practical implications in designing resistance training programs depending on if the training goal is related to power and force development, maximizing work output or speed. Moderate-load PROM training, common among recreational weight trainers, is unlikely to provide higher movement kinetics. PMID- 22222323 TI - Core muscle activation during dynamic upper limb exercises in women. AB - Although several everyday functions and sporting activities demand controlled use of the abdominal and back muscles while working with the upper limbs, the activity of core muscles during dynamic upper limb exercises in the standing position has not been studied extensively. The purpose of this cross-sectional study was to examine abdominal and back muscle activity during dynamic upper limb exercises while standing and to evaluate whether dynamic exercises are appropriate for strengthening muscles. The activation of the rectus abdominis, obliquus externus abdominis, longissimus, and multifidus muscles during dynamic bilateral or unilateral shoulder exercises with or without fixation of the pelvis was measured in 20 healthy women using surface electromyography. Trunk muscle activation during isometric maximum contraction was used as a comparative reference. With bilateral shoulder extension and unilateral shoulder horizontal adduction, abdominal muscle activity was >60% of activity during reference exercises. With unilateral shoulder horizontal abduction and shoulder extension exercises, back muscle activity was >60% of the activity level reference exercise. Muscle activation levels were 35-64% lower during shoulder horizontal adduction and abduction without fixation compared with exercises with fixation. The results indicate that upper limb exercises performed in the standing position are effective for activating core muscles. Bilateral and unilateral shoulder extension and unilateral shoulder horizontal abduction and adduction with the pelvis fixed elicited the greatest activity of the core muscles. PMID- 22222324 TI - A 12-year analysis of pacing strategies in 200- and 400-m individual medley in international swimming competitions. AB - The purpose of this study was to ascertain the pacing strategies employed in 200- and 400-m individual medley events and which style was the most determinant for the final performance as a function of sex and classification in international competitions. Twenty-six international competitions covering a 12-year period (2000-2011) were analyzed retrospectively: Olympic Games, World Championships, European Championships, Commonwealth Games, Pan Pacific Games, U.S. Olympic Team Trials, and Australian Olympic Trials. The data corresponded to a total of 1,643 swimmers' competition histories (821 men, 822 women). A 2-way analysis of variance (sex [2 levels: men, women] * classification [3 levels: 1st to 3rd, 4th to 8th, 9th to 16th]) was performed for each stroke (butterfly, backstroke, breaststroke, and freestyle). The Bonferroni post hoc test was used to compare means. Pearson's simple correlation coefficient was used to determine correlations between the style (sections time) and the final performance (total time). The men employed a smaller percentage of their event times in the breaststroke than did the women and a greater percentage in the freestyle in both the 200- and 400-m distances, with the fastest style for both sexes being the butterfly. Considering only the medalists, in men (200 and 400 m), the backstroke was the style that most determined their final performance, whereas in women, it was the backstroke (200 m) or freestyle (400 m). It was concluded that in general the men apply a positive pacing strategy in the 200- and 400-m individual medley events, whereas the women apply a negative pacing strategy. The practical application of the study is that it suggests the need for a differentiated approach in training men and women individual medley swimmers. PMID- 22222325 TI - Physical and physiological demands of elite team handball. AB - This study aimed to analyze elite team handball physical and physiological demands during match play. Time-motion (N = 30) and heart rate (HR; N = 60) analyses were performed throughout 10 official matches. The defined locomotor categories were standing still, walking, jogging, fast running, sprinting, backwards movement, sideways medium-intensity movement, and sideways high intensity movement, and playing actions studied were jumps, shots, stops when preceded by high-intensity activities, changes of direction and one-on-one situations. During matches, the mean distances covered were 4,370 +/- 702.0 m. Around 80% of the total time was spent standing still (43.0 +/- 9.27%) and walking (35.0 +/- 6.94%) and only 0.4 +/- 0.31% with sprinting. The most frequent high-intensity actions were stops, changes of direction, and one-on-one situations. Effective mean HR was 157 +/- 18.0 b.min(-1) (82 +/- 9.3% of HRmax), and total HR was 139 +/- 31.9 b.min(-1) (72 +/- 16.7% of HRmax). The HR, time spent in high-intensity activities, frequency of stops, changes of direction, one on-one situations, and most intense periods of the game were higher during the first half than during the second half (p <= 0.05). The opposite was observed for the number of time outs and the time between each change of activity (p = 0.00). Handball is an intermittent exercise that primarily uses aerobic metabolism, interspersed by high-intensity actions that greatly tax anaerobic metabolism. Additionally, exercise intensity decreases from the first to the second half of the match, suggesting that neuromuscular fatigue may occur during the game. The training of elite handball players should comprise exercises targeting the ability to perform specific high-intensity actions throughout the game and to rapidly recover during the less intense periods. PMID- 22222326 TI - Dynamic balance abilities of collegiate men for the bench press. AB - This study investigated the dynamic balance detection ability of college men for the bench press exercise. Thirty-five college men (mean +/- SD: age = 22.4 +/- 2.76 years, bench press experience = 8.3 +/- 2.79 years, and estimated 1RM = 120.1 +/- 21.8 kg) completed 1 repetition of the bench press repetitions for each of 3 bar loading arrangements. In a randomized fashion, subjects performed the bench press with a 20-kg barbell loaded with one of the following: a balanced load, one 20-kg plate on each side; an imbalanced asymmetrical load, one 20-kg plate on one side and a 20-kg plate plus a 1.25-kg plate on the other side; or an imbalanced asymmetrical center of mass, 20-kg plate on one side and sixteen 1.25 kg plates on the other side. Subjects were blindfolded and wore ear protection throughout all testing to decrease the ability to otherwise detect loads. Binomial data analysis indicated that subjects correctly detected the imbalance of the imbalanced asymmetrical center of mass condition (p[correct detection] = 0.89, p < 0.01) but did not correctly detect the balanced condition (p[correct detection] = 0.46, p = 0.74) or the imbalanced asymmetrical condition (p[correct detection] = 0.60, p = 0.31). Although it appears that a substantial shift in the center of mass of plates leads to the detection of barbell imbalance, minor changes of the addition of 1.25 kg (2.5 lb) to the asymmetrical condition did not result in consistent detection. Our data indicate that the establishment of a biofeedback loop capable of determining balance detection was only realized under a high degree of imbalance. Although balance detection was not present in either the even or the slightly uneven loading condition, the inclusion of balance training for upper body may be futile if exercises are unable to establish such a feedback loop and thus eliciting an improvement of balance performance. PMID- 22222327 TI - The acute effects of moderately loaded concentric-only quarter squats on vertical jump performance. AB - Limited research exists examining the effect of moderately loaded conditioning activities that are employed as part of a strength-power potentiating complex (SPPC). Additionally, no studies to date have explored the effects of using a concentric-only quarter back squat protocol as part of an SPPC. Therefore, the purpose of this study was to examine the effects of a moderately loaded (50-65% of 1RM) concentric-only quarter back squat protocol on the occurrence of potentiation effects at various time points. Twenty men who could quarter back squat a minimum of 2.4 times their body mass (3.7 +/- 0.7 kg.per body mass) participated in this investigation. All subjects participated in 3 conditions: control (CT), a 50% of 1RM trial (50POT), and a 65% of 1RM trial (65POT). One minute before each condition, a maximal countermovement vertical jump (CMJ) was performed. One minute later, the subject performed 1 of 3 conditions: CT condition, 50POT, or 65POT, followed by vertical jumps at 0.5, 3, 5, 10, and 15 minutes after conditioning activity. A force plate was used to quantify displacement, peak power output, peak force, and the rate of force development for each CMJ. There were no significant differences (p > 0.05) in any of the performance measures quantified during the CMJ trials when comparing the CT, 50POT, and 65POT treatment conditions. However, 48% of the subjects demonstrated some degree of potentiation at the 30 seconds after completing the 65POT trial, but this percent increase was not statistically significant. From a practical perspective, if the goal of the SPPC is to create a maximization of the potentiation effect, moderately loaded activities may not be the best alternative. PMID- 22222328 TI - Estimation of resistance exercise energy expenditure using triaxial accelerometry. AB - Recently, it was demonstrated that a uniaxial accelerometer worn at the hip could estimate resistance exercise energy expenditure. As resistance exercise takes place in more than 1 plane, the use of a triaxial accelerometer may be more effective in estimating resistance exercise energy expenditure. The aims of this study were to estimate the energy cost of resistance exercise using triaxial accelerometry and to determine the optimal location for wearing triaxial accelerometers during resistance exercise. Thirty subjects (15 men and 15 women; age = 21.7 +/- 1.0 years) performed a resistance exercise protocol consisting of 2 sets of 8 exercises (10RM loads). During the resistance exercise protocol, subjects wore triaxial accelerometers on the wrist, waist, and ankle; a heart rate monitor; and a portable metabolic system. Net energy expenditure was significantly correlated with vertical (r = 0.67, p < 0.001), horizontal (r = 0.43, p = 0.02), third axis (r = 0.36, p = 0.048), and sum of 3 axes (r = 0.50, p = 0.005) counts at the waist, and horizontal counts at the wrist (r = -0.40, p = 0.03). Regression analysis using fat-free mass, sex, and the sum of accelerometer counts at the waist as variables was used to develop an equation that explained 73% of the variance of resistance exercise energy expenditure. A triaxial accelerometer worn at the waist can be used to estimate resistance exercise energy expenditure but appears to offer no benefit over uniaxial accelerometry. The use of accelerometers in estimating resistance exercise energy expenditure may prove useful for individuals and athletes who participate in resistance training and are focused on maintaining a tightly regulated energy balance. PMID- 22222329 TI - Serotonin gene polymorphisms and psychiatry comorbidities in temporal lobe epilepsy. AB - OBJECTIVE: Neuropsychiatric comorbidities are frequent in temporal lobe epilepsy (TLE). It is biologically plausible that alterations in serotonin-related genes may be involved in higher susceptibility to psychiatric disease in these individuals. Here we report results of an association study of serotonin gene polymorphisms and psychiatry comorbidities in TLE. METHODS: Case-control study of 155 patients with temporal lobe epilepsy. We evaluate the influence of 5-HTTLPR and 5-HTTVNTR polymorphisms in the 5-HTT gene and the C-1019G polymorphism in the 5-HT1A gene in psychiatric comorbidities of TLE. RESULTS: After logistic regression, female sex (OR=2.34; 95% CI 1.06-5.17; p=0.035) and the presence of C allele of 5-HT1A C-1019G polymorphism (OR=2.77; 95% CI 1.01-7.63; p=0.048) remained independent risk factors for anxiety disorders in temporal lobe epilepsy. CONCLUSION: C allele of 5-HT1A C-1019G polymorphism might be an independent risk factor for anxiety disorders in temporal lobe epilepsy. We believe that other studies in this venue will shade some light on molecular mechanisms involved in psychiatric comorbidities in epilepsy. PMID- 22222330 TI - Novel three-dimensional Boyden chamber system for studying transendothelial transport. AB - The rapid development in combinatorial chemistry of millions of novel potential drug candidates requires in vitro devices for reliable testing of their transendothelial transport and the uptake in specific cells. To date, this is often achieved in vitro by the use of regular planar Boyden chambers, which are not reflecting the three dimensionality of the blood vessel. This technical note describes the fabrication and biological validation of a novel three-dimensional Boyden chamber system for studying transendothelial transport. The key element of this new system is a porous thin-walled microchannel produced by a SMART (substrate modification and replication by thermoforming) process comprising a combination of microthermoforming and ion track technology. The membrane-like microstructure offers the opportunity to grow endothelial cells on the inner side of the channel resembling a more natural curved organization of vessels. After establishment of a confluent HUVECs layer in the porous microchannel this novel Boyden chamber was successfully applied to study the transendothelial transport of a polycationic cell penetrating peptoid through the 3D- or curved endothelial cell layer. Thus, this system will enable the investigation of such synthetic compounds as drug delivery systems with regard to their bioavailability and functionality under organotypic conditions. PMID- 22222331 TI - Scabies crustosa following corticosteroid therapy in an elderly patient. PMID- 22222332 TI - High-altitude pulmonary edema is associated with coagulation and fibrinolytic abnormalities. AB - OBJECTIVES: High-altitude pulmonary edema (HAPE) can develop in unacclimatized persons after acute ascent to high altitude and is associated with fibrinolytic and coagulation abnormalities. The authors investigated whether fibrinolytic and coagulation abnormalities were associated with the severity of HAPE. METHODS: Sixty-one patients who developed HAPE after acute ascent to altitudes above 3600 m were recruited. Twenty unacclimatized controls who acutely ascended to the same altitude and 20 acclimatized inhabitants served as controls. Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) levels were measured using chromogenic substrate assays. Plasma fibrinogen concentration was determined by the sodium sulphite fractionation method. The concentrations of fibrin/fibrinogen degradation products (FDP) and D-dimer were measured by enzyme linked immunosorbent assay. RESULTS: The plasma concentrations of D-dimer, fibrinogen, FDP and t-PA and PAI-1 were significantly higher in patients with HAPE than controls. In addition, these abnormalities were correlated with the severity of HAPE. The plasma concentrations of D-dimer and fibrinogen recovered to normal upon recovery from HAPE while t-PA, PAI-1 and FDP levels in HAPE patients still remained significantly increased over those of unacclimatized controls. CONCLUSION: The development of HAPE is associated with abnormalities in the fibrinolysis and coagulation system, and these abnormalities correlate with the severity of HAPE. PMID- 22222333 TI - Extraparenchymal neurocysticercosis in the United States. AB - Neurocysticercosis (NCC) is endemic in the developing world but is becoming more common in the United States because of immigration. Although NCC is pleomorphic in its presentation, extraparenchymal NCC may be challenging to diagnose and treat. Extraparenchymal NCC is probably more frequent than previously thought. Neurologists and neuroradiologists in the United States are often unaware of the pretreatment/post-treatment radiographic patterns of extraparenchymal NCC and the potentially poor prognosis if not correctly diagnosed and managed. The review of this condition is important given increasing incidence in the United States. PMID- 22222334 TI - The efficacy of abraxane on osteosarcoma xenografts in nude mice and expression of secreted protein, acidic and rich in cysteine. AB - BACKGROUND: Although there have been previous efforts to optimize dose intensity or change the chemotherapy protocol for osteosarcoma, long-term survival has not been markedly improved during the past 15 years. METHOD: Nude mice bearing established OS-732 human osteosarcoma received varying doses of Adriamycin, paclitaxel and Abraxane to assess tumor growth inhibition. For the dose-response experiments, mice were treated with the following agents at the indicated doses: (A) Adriamycin (2.5 mg/kg, ip), (B) paclitaxel (20 mg/kg, ip), (C-E) Abraxane (10, 20 and 40 mg/kg, ip, respectively) and (F) Saline (20 mg/kg, ip). All agents were administered every 4 days. Mean tumor volume and mice weight measurements were recorded every 3 days. Tumor weights were examined after mice were killed. Real-time polymerase chain reaction and Western blot were used to detect the expression levels of secreted protein, acidic and rich in cysteine (SPARC) in osteosarcoma specimens. RESULTS: Administration of 40 mg/kg Abraxane showed a tumor inhibitory rate of 98.8% (tumor weight, 0.033 +/- 0.044 g, P < 0.01), which was significantly higher than Adriamycin (46.1%, tumor weight, 1.455 +/- 1.115 g, P < 0.01) and paclitaxel (40.8%, tumor weight, 1.597 +/- 1.834 g, P < 0.05). Real time polymerase chain reaction and Western blot showed higher expression of SPARC in tumor tissues than in normal tissues. CONCLUSION: The antitumor effect of Abraxane was demonstrated in osteosarcoma xenografts in vivo. It suggests that SPARC tends to be highly expressed in osteosarcoma and further experiments need to explore its clinical relevance and the possible mechanisms. PMID- 22222335 TI - Inhibition of platelet activation and aggregation by furostanol saponins isolated from the bulbs of Allium macrostemon Bunge. AB - Three new furostanol saponins (FSs) were recently isolated from the dried bulbs of Allium macrostemon and were shown to have antiplatelet effects. This study investigated the inhibitory capabilities of these compounds on adenosine diphosphate (ADP)-induced human platelet activation. FS-1, when compared with the other 2, had a potent inhibitory effect on ADP-induced platelet aggregation and on the expression of P-selectin and integrin beta-3. FS-1 also inhibited Ca mobilization and significantly decreased phosphorylated AKT expression in ADP activated platelets. The suppression by FS-1 of ADP-induced platelet activation and aggregation shown in this study indicate its potential for therapeutic applications. PMID- 22222336 TI - Asymptomatic green dialysate. PMID- 22222337 TI - A night with Venus, a lifetime with Mercury: a case of multiple intracranial aneurysms. AB - A 62-year-old African American woman presented to her primary care physician with binocular photopsias increasing in frequency over 1 year. Magnetic resonance angiography of the brain revealed bilateral 3-mm internal carotid artery aneurysms. She was referred to vascular medicine for further work-up. Her physical examination was unremarkable except for a right-sided femoral bruit. Specific testing for causes of multiple intracranial aneurysms was unremarkable except for positive rapid plasma reagin titers and fluorescent treponemal antibody absorption staining. She was referred to Infectious Diseases clinic where it was determined that the patient had a history of congenital syphilis that was not adequately treated until almost 20 years after birth. Few case reports illustrate the relationship between syphilis and intracranial aneurysms. The authors present this case to increase awareness of this uncommon presentation. PMID- 22222338 TI - Premature atherosclerosis is associated with hypovitaminosis D and angiotensin converting enzyme inhibitor non-use in lupus patients. AB - The ultimate goal is to identify and target modifiable risk factors that will reduce major cardiovascular events in African American lupus patients. As a first step toward achieving this goal, this study was designed to explore risk factor models of preclinical atherosclerosis in a predominantly African American group of patients with systemic lupus erythematosus (SLE) using variables historically associated with endothelial function in nonlupus populations. Fifty-one subjects with SLE but without a history of clinical cardiovascular events were enrolled. At entry, a Framingham risk factor history and medication list were recorded. Sera and plasma samples were analyzed for lipids, lupus activity markers and total 25-hydroxyvitamin D (25 OH)D) levels. Carotid ultrasound measurements were performed to determine total plaque area (TPA) in both carotids. Cases had TPA values above age-matched controls from a vascular prevention clinic population. Logistic regression and machine learning analyses were performed to create predictive models. 25(OH)D levels were significantly lower, and SLE disease duration was significantly higher in cases. 25(OH)D levels inversely correlated with age-adjusted TPA. Angiotensin-converting enzyme (ACE) inhibitor nonuse associated with case status. Logistic regression models containing ACE inhibitor use, 25(OH)D levels and low-density lipoprotein levels had a diagnostic accuracy of 84% for predicting accelerated atherosclerosis. Similar results were obtained with machine learning models, but hydroxychlo-roquine use associated with controls in these models. This is the first study to demonstrate an association between atherosclerotic burden and 25(OH)D insufficiency or ACE inhibitor nonuse in lupus patients. These findings provide strong rationale for the study of ACE inhibitors and vitamin D replenishment as preventive therapies in this high-risk population. PMID- 22222339 TI - Impact of a drug-drug interaction intervention on pharmacy and medical students' knowledge and attitudes: a 1-year follow-up. AB - BACKGROUND: There have been many interventions aimed at improving retention of drug-drug interaction (DDI) knowledge of health care professionals. Much less is known about their retention of such knowledge for extended periods of time after an educational intervention. OBJECTIVES: To evaluate pharmacy and medical students' knowledge retention and attitudes 1 year after participating in an educational session on DDIs. METHODS: This study used a pre-post design with an assessment of DDI knowledge and attitude by pharmacy and medical students before and after the final didactic year of their professional education. The intervention was a 1-hour program. RESULTS: A total of 74 of 193 students (38%) completed the pre, post, and final questionnaire. The median numbers of correctly identified DDIs before the program were 8 and 7 for pharmacy and medical students, respectively, out of a possible score of 15. One year after, the median identification knowledge scores were 12 and 8, respectively, for pharmacy and medical students. The median difference scores of correctly managed DDIs on this evaluation 1 year after the program were -4 and -8 for pharmacy and medical students, respectively (P<.05). CONCLUSION: This study found that the ability to identify important DDIs is poor among both pharmacy and medical students 1 year after being exposed to the educational session. PMID- 22222340 TI - Development and initial validation of the Pharmacist Frequency of Interprofessional Collaboration Instrument (FICI-P) in primary care. AB - BACKGROUND: Existing validated measures of pharmacist-physician collaboration focus on measuring attitudes toward collaboration and do not measure frequency of collaborative interactions. OBJECTIVE: To develop and validate an instrument to measure the frequency of collaboration between pharmacists and general practitioners (GPs) from the pharmacist's perspective. METHODS: An 11-item Pharmacist Frequency of Interprofessional Collaboration Instrument (FICI-P) was developed and administered to 586 pharmacists in 8 divisions of general practice in New South Wales, Australia. The initial items were informed by a review of the literature in addition to interviews of pharmacists and GPs. Items were subjected to principal component and Rasch analyses to determine each item's and the overall measure's psychometric properties and for any needed refinements. RESULTS: Two hundred and twenty four (38%) of pharmacist surveys were completed and returned. Principal component analysis suggested removal of 1 item for a final 1-factor solution. The refined 10-item FICI-P demonstrated internal consistency reliability at Cronbach's alpha=0.90. After collapsing the original 5 point response scale to a 4-point response scale, the refined FICI-P demonstrated fit to the Rasch model. Criterion validity of the FICI-P was supported by the correlation of FICI-P scores with scores on a previously validated Physician Pharmacist Collaboration Instrument. Validity was also supported by predicted differences in FICI-P scores between subgroups of respondents stratified on age, colocation with GPs, and interactions during the intern-training period. CONCLUSION: The refined 10-item FICI-P was shown to have good internal consistency, criterion validity, and fit to the Rasch model. The creation of such a tool may allow for the measure of impact in the evaluation of interventions designed to improve interprofessional collaboration between GPs and pharmacists. PMID- 22222341 TI - Exploring patient experiences with prescription medicines to identify unmet patient needs: implications for research and practice. AB - BACKGROUND: Pharmacy services are offered to patients, and often, they decline participation. Research is needed to better understand patients' unmet needs when taking prescribed medications. OBJECTIVE: To identify and characterize patients' unmet needs related to using prescribed medication for chronic conditions. METHODS: Focus groups of patients using prescription medication for chronic conditions discussed their experiences with medications, starting from initial diagnosis to ongoing management. Sessions involved 40 patients from 1 Midwestern U.S. state. Major themes were identified using content analysis. RESULTS: Three major themes emerged. First, patients seek information to understand their health condition and treatment rationale. Patients form an illness perception (its consequence, controllability, cause, and duration) that dictates their actions. Second, patients desire to be involved in treatment decisions, and they often feel that decisions are made for them without their understanding of the risk-to benefit trade-off. Third, patients monitor the impact of treatment decisions to determine if anticipated outcomes are achieved. CONCLUSION: The results were consistent with Dowell's therapeutic alliance model (TAM) and Leventhal's common sense model (CSM). The TAM can be used to model the consultative services between pharmacists and patients. The impact of the new services (or interventions) can be evaluated using the CSM. Patients expressed a strong desire to be involved in their treatment decisions. The effectiveness of medication therapy management services may be enhanced if pharmacists build on patients' desire to be involved in their treatment decisions and assist them to understand the role of medications and their risks and expected outcomes within the context of the patients' perceptions of illness and desired coping strategies. PMID- 22222342 TI - Medication supply and management in rural Queensland: views of key informants in health service provision. AB - BACKGROUND: Rural settings challenge health care providers to provide optimal medication services in a manner that is timely and of high quality. Extending the roles of rural health care providers is often necessary to improve access to medication services; however, there appears to be a lack of pharmacy-based involvement and support within the medication system. OBJECTIVES: This article explores medication supply and management issues in rural settings, based on the governance perspectives of key informants on regulatory aspects, policy, and professional practice. The specific objectives were to (1) identify the key issues and existing facilitators and (2) explore the potential roles of pharmacy to improve medication supply and management services. METHODS: Semi-structured interviews were conducted with representatives within regulatory or professional organizations. The participants were key informants who held leadership and/or managerial roles within their respective organizations and were recruited to provide insights from a governance perspective before data collection in the community. An interview guide, informed by the literature, assisted the flow of interviews, exploring topics, such as key issues, existing initiatives, and potential pharmacy-based facilitators, in relation to medication supply and management in rural settings. RESULTS: Issues identified that hindered the provision of optimal medication supply and management services in the rural areas centered on workforce, interprofessional communication, role structures, and funding opportunities. Legislative and electronic developments and support mechanisms aim to facilitate medication processes in rural areas. Potential initiatives to further enhance medication services and processes could explore extended roles for pharmacists and pharmacy support staff, as well as alternative service delivery models to enhance pharmacy workforce capacity. CONCLUSIONS: The study provided an overview of key issues with medication supply and management and highlighted the potential for increased pharmacy involvement to improve and support medication services in rural areas. The governance views of these key informants could be used to inform policy and practice related to rural medication services. PMID- 22222343 TI - The use of speech disfluency as an indicant of paradigm development in pharmacy's academic subdisciplines. AB - BACKGROUND: Paradigm development among disciplines has implications for faculty productivity, quality of work life, turnover, organizational rewards, and scholarly progress. Although studied in basic fields, paradigm development has not been measured in professional programs, such as pharmacy. OBJECTIVE: The objective of this study was to compare speech disfluency rates in lectures of entry-level pharmacy courses within 5 subdisciplines of pharmacy as a measure of paradigm development. METHODS: Disfluency rates were observed in randomly selected courses in 4 schools of pharmacy. Disfluency rates among course faculty in personal interviews controlled for subjects' inherent disfluency rates. Lecturers completed a modified version of the Brief Fear of Negative Evaluation survey and a self-rated anxiety measure. Correlates of disfluency patterns were determined using analysis of covariance procedures. RESULTS: The overall mean disfluency rate in lectures was 2.11 disfluencies per minute. Average disfluency rates among the 5 subdisciplines ranged from 1.28 to 2.74. The subdiscipline under study, the lecturers' self-rated anxiety, fear of negative evaluation, or any alternative factors were not associated with disfluency rates in the classroom. CONCLUSIONS: Although study results corroborate previous evidence that pharmacy's academic subdisciplines exhibit similar paradigm development, the use of speech disfluency as a measure of paradigm development may have limited utility in the study of disciplinary progress within professional domains. PMID- 22222344 TI - Awareness and knowledge of autism among pharmacists. AB - BACKGROUND: In the past few decades, the prevalence of autism has increased tremendously in the United States. The prevalence of autism is now higher than the combined prevalence of juvenile diabetes, pediatric cancer, and pediatric AIDS. As health care professionals with a high visibility in a community, pharmacists are likely to encounter more and more families having a child affected by this disorder. OBJECTIVES: The purpose of this study was to assess pharmacists' awareness and knowledge of autism. The study aimed to assess pharmacists' familiarity with autism symptoms, treatment medications, and community resources devoted to this disorder. Further, pharmacists' knowledge of common myths associated with autism, etiology, prognosis, and treatment were assessed. METHODS: Using a cross-sectional design, an online survey of pharmacists registered in the state of Mississippi (MS) was conducted, using the Qualtrics software program. Descriptive analysis of study items was conducted. RESULTS: A total of 147 usable responses (5.8%) were received. The results indicated gaps in pharmacists' awareness and knowledge of autism. Approximately, 23% of pharmacists did not know that autism is a developmental disorder, and 32% did not believe that genetics has a major role in autism etiology. More than 18% believed that vaccines can cause autism. Most (>90%) felt that they could benefit from autism continuing education (CE). CONCLUSION: Policy makers and autism agencies should consider providing educational interventions or CE programs to increase pharmacists' awareness and knowledge of autism. PMID- 22222345 TI - A pilot study assessing the frequency and complexity of methadone tapers for opioid abstinence syndrome in children discharged to home. AB - BACKGROUND: Methadone is often prescribed as a taper schedule to prevent/treat opioid abstinence syndrome (OAS) or neonatal abstinence syndrome (NAS). OBJECTIVE: The objective of this study was to determine the percentage of children discharged home on methadone tapers and to develop, assess, and implement an instrument for measuring the complexity of the methadone regimens. METHODS: This study used a descriptive retrospective design to examine patients younger than 18 years from January 1, 2008, to December 31, 2008, administered methadone for prevention/treatment of OAS/NAS and discharged home on a methadone taper. Data collection included demographics and characteristics of methadone regimen. The primary objective was to determine the percentage of children discharged on methadone. Secondary objectives included characterization (ie, number of dosage and interval changes), duration, and complexity of the methadone taper. Descriptive statistics were performed using Stata v10 (StataCorp LP, College Station, TX). Complexity was evaluated using the medication taper complexity score (MTCS) between 4 raters. Reliability of the MTCS was established using interrater correlation analyses of the regimen complexity scores. RESULTS: Thirty-three patients (41.8%) were discharged on methadone. The median (range) age was 0.42 (0-12) years, with most patients (75.8%) initiated on methadone for prevention of OAS. Thirty-one patients were included for further analysis of medication complexity. The median (range) duration of the home taper was 8 days (2-48), which included a median (range) of 4 (1-11) dose changes and at least 1 (0-2) change in the interval. MTCS ranged from 7 to 42, with the tool demonstrating 95% interrater reliability. CONCLUSIONS: More than one-third of patients were discharged home on methadone. The median taper duration was 8 days and included a median of 5 adjustments in either the dose or interval. The MTCS demonstrated very good interrater reliability to measure wide variability in the complexity of individual tapers. Future studies should determine the construct validity of the MTCS and the applicability of this tool for further research and clinical application. PMID- 22222346 TI - U.S. publication trends in social and administrative pharmacy: implications for promotion and tenure. AB - BACKGROUND: There is no consensus on the preferred approach to assess journal quality. Procedures previously used include journal acceptance or rejection policies, impact factors, number of subscribers, citation counts, whether the articles were refereed or not, and journals cited in books within the discipline. This study built on the work of previous authors by using a novel approach to assess journal quality in social and administrative pharmacy (SAdP). OBJECTIVES: To determine U.S. SAdP faculty perceptions of prestigious journals for their research, SAdP faculty perceptions of prestigious journals by their promotion and tenure (P&T) committees, and current research trends in SAdP. METHODS: A census of U.S. colleges and schools of pharmacy was conducted using an e-mailed survey and an open-ended approach requiring respondents to list their preferred journals. RESULTS: Seventy-nine SAdP faculty reported that the 5 most prestigious journals were JAMA, New England Journal of Medicine, Health Affairs, Health Services Research, and Medical Care. These journals were selected because respondents wished to seek broad readership. CONCLUSIONS: Results of this study can be used as a guide by U.S. SAdP faculty and P&T committees to assess the quality of publications by pharmacy administration faculty with the caveat being that pharmacy versus nonpharmacy journals will be chosen based on the fit of the article with the audience. PMID- 22222347 TI - Characterizing healthcare quality in the community pharmacy setting: insights from a focus group study. AB - BACKGROUND: There is currently no common frame of reference defining community pharmacy quality. It can therefore be difficult to know whether the provision of care meets minimum standards and how to improve quality of care. OBJECTIVE: The aim of this research was to develop a conceptual framework characterizing healthcare quality in the community pharmacy setting. METHODS: Ten focus group discussions with 47 participants were conducted across the northwest of England, United Kingdom. All participants had experiences of health care provided by community pharmacies and included patients and their carers, pharmacists and pharmacy staff, and National Health Service staff who commissioned pharmacy services. Constant comparative analysis was used to analyze the verbatim transcripts. RESULTS: Community pharmacy quality can be conceptualized as dynamic with 3 interdependent dimensions. Each dimension was associated with structures, processes, and outcomes. The first dimension (accessibility) emphasized that in addition to patients requiring access to the available services, medicines, and health care advice, it was equally important for pharmacy personnel to have access to adequate structures to provide quality health care. The second dimension (effectiveness) highlighted a shift away from simply supplying medicines to supplying medicines appropriately, from passively providing services and information to individualizing advice to achieve intended outcomes, and from having structures available to using them purposefully to achieve outcomes. The third dimension (positive perceptions of the experience) enabled patients and carers to better care for themselves and for others, and it influenced future access. At the same time, when pharmacy personnel believed themselves to be valued and that they had done a good job, they felt motivated to continue to provide high-quality care. CONCLUSIONS: All 3 dimensions should be considered when the term quality is used in the context of community pharmacy. This research can be used as a springboard for similar studies in other sectors or jurisdictions wishing to characterize quality for their health care services. In particular, this research provides a common frame of reference for those interested in the provision and assessment of quality health care from community pharmacies. PMID- 22222348 TI - Pharmaceutical care in hypertensive patients: a systematic literature review. AB - BACKGROUND: Since the conception of pharmaceutical care in 1990, many studies have been published purported to implement and/or evaluate interventions under this aegis; however, most have been criticized in methodological approach. As such, there is a need to assess the scientific rigor of the published studies and examine the biases that may compromise the hardiness of their findings. OBJECTIVES: The aim of this review is to describe and appraise published research on the management of patients diagnosed with essential hypertension under the guise of pharmaceutical care. METHODS: MEDLINE, EMBASE, Scopus, and LILACS databases from January 1990 to July 2011 were searched using the keywords "pharmaceutical care," "hypertension," and "blood pressure." Included were clinical trials assessing the impact of pharmaceutical care on outcomes for hypertensive patients. Two independent reviewers abstracted data on descriptive characteristics, research design and outcomes, and study limitations. RESULTS: The literature search identified 917 articles, of which 16 satisfied the inclusion criteria. The studies were conducted primarily in North America (8) and in ambulatory settings (9). Sample sizes ranged from 24 to 235 patients, with most studies reporting a 6-month patient follow-up period. Many studies (9) were randomized clinical trials but generally had a low-quality methods score according to the Jadad scale. Blood pressure (BP) (15), medication adherence (11), and quality of life (9) were the most common outcome measures. As expected, systolic BP was the outcome most positively impacted by the pharmaceutical intervention. CONCLUSIONS: This database search revealed that most of the included studies evaluated the impact of pharmaceutical care on clinical and humanistic outcomes and few studies showed statistically significant improvement in BP. However, a lack of hardiness and many important limitations were common in the studies analyzed. As such, recommendations are made to improve in research design and to demonstrate the effectiveness of the intervention. PMID- 22222349 TI - Seeing the light: photobehavior in fruit fly larvae. AB - Understanding how sensory stimuli drive behavior requires a detailed understanding of the molecular and neural nature through which the stimuli are received and processed. The visual system of the fruit fly Drosophila melanogaster shares marked similarities to that of mammals. Although much focus has been given to the fly visual system, an even further simplified eye and brain makes the visual system of Drosophila larvae an excellent model for dissecting sensory processing and behavioral responses to light. Recent work has identified sensory and central brain neurons required for larval visual behaviors, including circadian rhythms. Here, we review the genes and neurons regulating visual processing in Drosophila larvae and discuss the implications of this work for furthering understanding of more complex visual systems. PMID- 22222351 TI - The cis side of juxtacrine signaling: a new role in the development of the nervous system. AB - Cell-cell communication by juxtacrine signaling plays a key role in the development of the nervous system, from cell fate determination through axonal guidance to synaptogenesis. Interestingly, several juxtacrine signaling systems exhibit an inhibitory interaction between receptors and ligands in the same cell, termed cis inhibition. These include the Notch, semaphorin and ephrin signaling systems. Here we review the role of cis inhibition in these signaling systems in the development of the nervous system. We compare and contrast cis inhibition mechanisms and discuss their potential cellular function as a threshold generating mechanism. The prevalence of cis inhibition suggests that these interactions and their functional regulatory roles may serve as a general design principle for juxtacrine signaling-mediated processes during and beyond neurodevelopment. PMID- 22222350 TI - Postsynaptic signaling during plasticity of dendritic spines. AB - Dendritic spines, small bulbous postsynaptic compartments emanating from neuronal dendrites, have been thought to serve as basic units of memory storage. Despite their small size (~0.1 femtoliter), thousands of species of proteins exist in the spine, including receptors, channels, scaffolding proteins and signaling enzymes. Biochemical signaling mediated by these molecules leads to morphological and functional plasticity of dendritic spines, and ultimately learning and memory in the brain. Here, we review new insights into the mechanisms underlying spine plasticity brought about by recent advances in imaging techniques to monitor molecular events in single dendritic spines. The activity of each protein displays a specific spatiotemporal pattern, coordinating downstream events at different microdomains to change the function and morphology of dendritic spines. PMID- 22222352 TI - On-site management of investigational products and drug delivery systems in conformity with Good Clinical Practices (GCPs). AB - BACKGROUND: Investigators and research teams participating in clinical trials have to deal with complex investigational products, study designs, and research environments. The emergence of new drug delivery systems and investigational products combining more than one drug and the development of biodrugs such as monoclonal antibodies, peptides, siRNA, and gene therapy to treat orphan or common diseases constitute a new challenge for investigators and clinical sites. PURPOSE: We describe the requirements and challenges of drug management in conformity with Good Clinical Practices (GCPs) for investigators and sites participating in clinical trials. Review At all sites participating in clinical trials, standard operating procedures (SOPs) covering the critical path of drug and drug delivery systems management are required. All steps should be auditable, including reception, validation, storage, access, preparation, distribution, techniques of administration, use, return, and destruction of research products. Biodrugs require traceability and specific SOPs on the management of potential immune reactions. Investigational products must be stored under standard auditable conditions. The traceability of storage conditions (including temperature) requires these conditions to be monitored on a continuous basis. A dedicated space with restricted access limited to authorized qualified personnel facilitates the monitoring. CONCLUSIONS: The development of standardized, auditable settings and the application of dedicated, site-specific SOPs for the management of investigational products and drug delivery systems contribute to guarantee the compliance to GCP requirements. PMID- 22222353 TI - Urinary NT-proBNP, NGAL, and H-FABP may predict hemodynamic relevance of patent ductus arteriosus in very low birth weight infants. AB - BACKGROUND: Hemodynamically significant patent ductus arteriosus (hsPDA) is the most common functional cardiovascular disease in preterm infants. The necessity to treat hsPDA can neither be derived solely from clinical nor from echocardiographic criteria. OBJECTIVE: The aim of this study was to establish non invasive parameters which can differentiate hsPDA from non-hsPDA. METHODS: Urinary protein levels of NT-proBNP, NGAL, and H-FABP were measured and correlated with the necessity of therapy for PDA. In 37 neonates (<1,500 g), urinary protein concentrations were tested on days 0, 2, and 7 by ELISA methodology. Of 37 infants, 12 required therapeutic interventions according to current treatment standards. RESULTS: Infants receiving an intervention for PDA showed significantly higher levels of pro-BNP, NGAL, and H-FABP at all time points except for NT-proBNP on day 0. Infants requiring a second or third course of ibuprofen had significantly higher levels of H-FABP and NGAL. In all samples, the concentration of the three proteins correlated positively with each other. CONCLUSIONS: The present study shows that measurement of urinary proteins is a powerful and non-invasive method to quantify the effect of PDA on systemic perfusion in preterm infants. Furthermore, NGAL and H-FABP may be used to indicate the necessity of pharmacological or surgical treatment of PDA. PMID- 22222354 TI - High-valent [MnFe] and [FeFe] cofactors in ribonucleotide reductases. AB - Ribonucleotide reductases (RNRs) are essential for DNA synthesis in most organisms. In class-Ic RNR from Chlamydia trachomatis (Ct), a MnFe cofactor in subunit R2 forms the site required for enzyme activity, instead of an FeFe cofactor plus a redox-active tyrosine in class-Ia RNRs, for example in mouse (Mus musculus, Mm). For R2 proteins from Ct and Mm, either grown in the presence of, or reconstituted with Mn and Fe ions, structural and electronic properties of higher valence MnFe and FeFe sites were determined by X-ray absorption spectroscopy and complementary techniques, in combination with bond-valence-sum and density functional theory calculations. At least ten different cofactor species could be tentatively distinguished. In Ct R2, two different Mn(IV)Fe(III) site configurations were assigned either L(4)Mn(IV)(MUO)(2)Fe(III)L(4) (metal metal distance of ~2.75A, L = ligand) prevailing in metal-grown R2, or L(4)Mn(IV)(MUO)(MUOH)Fe(III)L(4) (~2.90A) dominating in metal-reconstituted R2. Specific spectroscopic features were attributed to an Fe(IV)Fe(III) site (~2.55A) with a L(4)Fe(IV)(MUO)(2)Fe(III)L(3) core structure. Several Mn,Fe(III)Fe(III) (~2.9-3.1A) and Mn,Fe(III)Fe(II) species (~3.3-3.4A) likely showed 5-coordinated Mn(III) or Fe(III). Rapid X-ray photoreduction of iron and shorter metal-metal distances in the high-valent states suggested radiation-induced modifications in most crystal structures of R2. The actual configuration of the MnFe and FeFe cofactors seems to depend on assembly sequences, bound metal type, valence state, and previous catalytic activity involving subunit R1. In Ct R2, the protonation of a bridging oxide in the Mn(IV)(MUO)(MUOH)Fe(III) core may be important for preventing premature site reduction and initiation of the radical chemistry in R1. PMID- 22222355 TI - Light-dependent cold-induced fatty acid unsaturation, changes in membrane fluidity, and alterations in gene expression in Synechocystis. AB - Cold stress causes unsaturation of the membrane lipids. This leads to adjustment of the membrane fluidity, which is necessary for cold acclimation of cells. Here we demonstrate that the cold-induced accumulation of PUFAs in the cyanobacterium Synechocystis is light-dependent. The desA(-)/desD(-) mutant, that lacks the genes for Delta12 and Delta6 desaturases, is still able to adjust the fluidity of its membranes in spite of its inability to synthesize PUFAs and modulate the fatty acid composition of the membrane lipids under cold stress. The expression of cold-induced genes, which are controlled by the cold sensor histidine kinase Hik33, depends on the fluidity of cell membranes and it is regulated by light, though it does not require the activity of the photosynthetic apparatus. The expression of cold-induced genes, which are not controlled by Hik33, does not depend on the membrane fluidity or light. Thus, membrane fluidity determines the temperature dependence of the expression of cold-induced genes that are under control of the Hik33, which might be the sensor of changes in the membrane fluidity. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: from Natural to Artificial. PMID- 22222356 TI - Mammographic density, parity and age at first birth, and risk of breast cancer: an analysis of four case-control studies. AB - Mammographic density is strongly and consistently associated with breast cancer risk. To determine if this association was modified by reproductive factors (parity and age at first birth), data were combined from four case-control studies conducted in the United States and Japan. To overcome the issue of variation in mammographic density assessment among the studies, a single observer re-read all the mammograms using one type of interactive thresholding software. Logistic regression was used to estimate odds ratios (OR) while adjusting for other known breast cancer risk factors. Included were 1,699 breast cancer cases and 2,422 controls, 74% of whom were postmenopausal. A positive association between mammographic density and breast cancer risk was evident in every group defined by parity and age at first birth (OR per doubling of percent mammographic density ranged between 1.20 and 1.39). Nonetheless, the association appeared to be stronger among nulliparous than parous women (OR per doubling of percent mammographic density = 1.39 vs. 1.24; P interaction = 0.054). However, when examined by study location, the effect modification by parity was apparent only in women from Hawaii and when examined by menopausal status, it was apparent in postmenopausal, but not premenopausal, women. Effect modification by parity was not significant in subgroups defined by body mass index or ethnicity. Adjusting for mammographic density did not attenuate the OR for the association between parity and breast cancer risk by more than 16.4%, suggesting that mammographic density explains only a small proportion of the reduction in breast cancer risk associated with parity. In conclusion, this study did not support the hypothesis that parity modifies the breast cancer risk attributed to mammographic density. Even though an effect modification was found in Hawaiian women, no such thing was found in women from the other three locations. PMID- 22222357 TI - A complete carbon-nanotube-based on-chip cooling solution with very high heat dissipation capacity. AB - Heat dissipation is one of the factors limiting the continuous miniaturization of electronics. In the study presented in this paper, we designed an ultra-thin heat sink using carbon nanotubes (CNTs) as micro cooling fins attached directly onto a chip. A metal-enhanced CNT transfer technique was utilized to improve the interface between the CNTs and the chip surface by minimizing the thermal contact resistance and promoting the mechanical strength of the microfins. In order to optimize the geometrical design of the CNT microfin structure, multi-scale modeling was performed. A molecular dynamics simulation (MDS) was carried out to investigate the interaction between water and CNTs at the nanoscale and a finite element method (FEM) modeling was executed to analyze the fluid field and temperature distribution at the macroscale. Experimental results show that water is much more efficient than air as a cooling medium due to its three orders-of magnitude higher heat capacity. For a hotspot with a high power density of 5000 W cm(-2), the CNT microfins can cool down its temperature by more than 40 degrees C. The large heat dissipation capacity could make this cooling solution meet the thermal management requirement of the hottest electronic systems up to date. PMID- 22222358 TI - Monosodium glutamate intake increases hemoglobin level over 5 years among Chinese adults. AB - The aim of this analysis was to determine the relationship between monosodium glutamate (MSG) intake and change in hemoglobin (Hb) levels and the risk of anemia over 5 years in 1197 Chinese men and women who participated in the Jiangsu Nutrition Study (JIN). MSG intake and Hb were quantitatively assessed in 2002 and followed up in 2007. Diet and lifestyle factors were assessed at both time points. There was a positive association between MSG intake and increase in Hb among men but not women. In the multivariate model adjusting for demographic and lifestyle factors as well as baseline dietary pattern, the beta values and 95% confidence interval for Hb changes across quartiles of MSG intake were 0, 0.67(0.04-1.29), 0.99(0.38-1.60), 0.73(0.13-1.34) among men (p for trend 0.091); 0, -0.01(-0.45-0.43), 0.23(-0.25-0.71), and -0.45(-0.96-0.05) among women (p for trend 0.087). Among anemic participants at baseline, there was a significant inverse association between MSG intake and the risk of anemia at follow-up. Comparing extreme quartiles of MSG intake among those anemic at baseline, the relative risk for persistent anemia at follow-up was 0.49 (95% CI: 0.28-0.86, p < 0.01). The association was independent of dietary patterns and lifestyle factors. A dose-response relationship between MSG intake and increase in Hb levels among anemic participants was seen. MSG intake may have independent Hb-increasing effects, especially among men and those anemic at baseline. PMID- 22222359 TI - Working memory and inattentional blindness. AB - Individual differences in working memory predict many aspects of cognitive performance, especially for tasks that demand focused attention. One negative consequence of focused attention is inattentional blindness, the failure to notice unexpected objects when attention is engaged elsewhere. Yet, the relationship between individual differences in working memory and inattentional blindness is unclear; some studies have found that higher working memory capacity is associated with greater noticing, but others have found no direct association. Given the theoretical and practical significance of such individual differences, more definitive tests are needed. In two studies with large samples, we tested the relationship between multiple working memory measures and inattentional blindness. Individual differences in working memory predicted the ability to perform an attention-demanding tracking task, but did not predict the likelihood of noticing an unexpected object present during the task. We discuss the reasons why we might not expect such individual differences in noticing and why other studies may have found them. PMID- 22222360 TI - Influence of terminal substitution on structural, DNA, protein binding, anticancer and antibacterial activities of palladium(II) complexes containing 3 methoxy salicylaldehyde-4(N) substituted thiosemicarbazones. AB - The variable chelating behavior of 3-methoxysalicylaldehyde-4(N)-substituted thiosemicarbazones was observed in equimolar reactions with [PdCl(2)(PPh(3))(2)]. The new complexes were characterized by various analytical, spectroscopic techniques (mass, (1)H-NMR, absorption, IR). All the new complexes were structurally characterized by single crystal X-ray diffraction. Crystallographic results showed that the ligands H(2)L(1) and H(2)L(4) are coordinated as binegative tridentate ONS donor ligands in the complexes 1 and 4 by forming six and five member rings. However, the ligands H(2)L(2) and H(2)L(3) bound to palladium in 2 and 3 as uninegative bidentate NS donors by forming a five member chelate ring. From this study, it was found that the substitution on terminal 4(N)-nitrogen may have an influence on the chelating ability of thiosemicarbazone. The presence of hydrogen bonding in 2 and 3 might be responsible for preventing the coordination of phenolic oxygen to the metal ion. The interaction of the complexes with calf-thymus DNA (CT-DNA) has been explored by absorption and emission titration methods. Based on the observations, an electrostatic binding mode of DNA has been proposed. The protein binding studies were monitored by quenching of tryptophan and tyrosine residues in the presence of complexes using Lysozyme as model protein. Antibacterial activity studies of the complexes have been screened against pathogenic bacteria such as Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia and Pseudomonas aeruginosa. MIC50 values of the complexes showed that they exhibited significant activity against the pathogens and among them, 3 exhibited higher activity. Further, anticancer activity of the complexes on the lung cancer cell line A549 has also been studied. PMID- 22222361 TI - Long-term results of vagus nerve stimulation in children and adolescents with drug-resistant epilepsy. AB - PURPOSE: The purpose of this study was to evaluate long-term seizure reduction and on-demand magnet use in children and adolescents with drug-resistant epilepsy who were treated with vagus nerve stimulation therapy. METHODS: Fifty-seven children and adolescents under 18 years of age with drug-resistant epilepsy were implanted with a vagus nerve stimulation therapy device. Seizure reduction was evaluated at 6, 12, 24, 36, and 48 months after implantation. Magnet effect on seizure frequency was evaluated during the first week after implantation and after 6, 12, 24, 36, and 48 months of treatment. RESULTS: The mean reduction in seizure frequency compared with baseline was significant at all time points up to 48 months post-implantation. At 12 months, the average reduction in seizure frequency was 52.4%, and at 48 months, it was 53.1% (observed case analysis). The use of a magnet to deliver extra "on-demand" stimulation between cycles resulted in cessation of seizures in 16.1% of patients, partial effect in 73.2%, and no effect in 10.7%, when evaluated within 1 week of implantation. The magnet effect decreased slightly with increasing time after implantation. A sub-analysis of children <=12 years of age (N = 34) showed similar results after 36 months of follow-up. The therapy was well tolerated regardless of age. CONCLUSION: Vagus nerve stimulation therapy is a safe and effective adjunctive treatment for children and adolescents of all ages with drug-resistant epilepsy. PMID- 22222362 TI - Analysis of the subcellular targeting of the smaller replicase protein of Pelargonium flower break virus. AB - Replication of all positive RNA viruses occurs in association with intracellular membranes. In many cases, the mechanism of membrane targeting is unknown and there appears to be no correlation between virus phylogeny and the membrane systems recruited for replication. Pelargonium flower break virus (PFBV, genus Carmovirus, family Tombusviridae) encodes two proteins, p27 and its read-through product p86 (the viral RNA dependent-RNA polymerase), that are essential for replication. Recent reports with other members of the family Tombusviridae have shown that the smaller replicase protein is targeted to specific intracellular membranes and it is assumed to determine the subcellular localization of the replication complex. Using in vivo expression of green fluorescent protein (GFP) fusions in plant and yeast cells, we show here that PFBV p27 localizes in mitochondria. The same localization pattern was found for p86 that contains the p27 sequence at its N-terminus. Cellular fractionation of p27GFP-expressing cells confirmed the confocal microscopy observations and biochemical treatments suggested a tight association of the protein to membranes. Analysis of deletion mutants allowed identification of two regions required for targeting of p27 to mitochondria. These regions mapped toward the N- and C-terminus of the protein, respectively, and could function independently though with distinct efficiency. In an attempt to search for putative cellular factors involved in p27 localization, the subcellular distribution of the protein was checked in a selected series of knockout yeast strains and the outcome of this approach is discussed. PMID- 22222363 TI - Pt(II) as a proton shuttle during C-H bond activation in the Shilov process. AB - The C-H activation in Shilov's system on cis- and trans-PtCl(2)(H(2)O)(CH(4)) was investigated by ab initio molecular dynamics in water. Simulations revealed an easy C-H bond cleavage forming a transient 5-coordinated species Pt(H)Cl(2)(H(2)O)(CH(3)) that spontaneously releases a proton to the bulk solution. PMID- 22222365 TI - Effect of decentration on the optical performance in multifocal intraocular lenses. AB - AIMS: To evaluate the influence of decentration on optical performance in multifocal intraocular lenses (IOLs) using eye models. METHODS: This study evaluated 4 types of multifocal IOLs (ReSTOR SA60D3, Alcon; TECNIS Multifocal ZM900, AMO; ReZoom, AMO; SFX-MV1, Hoya). The evaluations were based on measurements of the near and far modulation transfer function (MTF) and visualized actual near images (newspaper) using eye models with the IOL horizontally displaced 0, 0.25, 0.5, 0.75 and 1.0 mm from the center. RESULTS: For the diffractive ReSTOR the near MTF decreased with increasing decentration. The near images (newspaper characters) became difficult to distinguish at a decentration of 1.0 mm. For the diffractive ZM900, the near and far MTFs gradually decreased with increasing decentration. For the refractive ReZoom and SFX-MV1, we observed almost no change in the near MTF from a decentration of 0 1.0 mm. However, the far MTF clearly decreased starting at a decentration of 1.0 mm for ReZoom and 0.75 mm for SFX-MV1. CONCLUSION: The MTFs and near images are affected to a different extent depending on the design of multifocal IOLs; clinically relevant effects are not to be expected up to a decentration of 0.75 mm. PMID- 22222366 TI - WITHDRAWN: The treatment of proximal humerus nonunions in older patients with the reverse shoulder arthroplasty. AB - This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22222367 TI - Prevention of pelvic sepsis in major open pelviperineal injury. AB - Compound pelvic fractures are deemed to be one of the most severe orthopaedic injuries with an extremely high morbidity and mortality. After the initial resuscitation phase the prevention of pelvic sepsis is one of the main treatment goals for patients with an open pelvic fracture. If there is a suspicion of a rectal injury or if the wounds are in the perineal area, The Princess Alexandra Hospital's management plan includes early faecal diversion combined with vigorous soft tissue debridement, VAC((r)) therapy and (if indicated) external fixation of the pelvic fracture. We present our flowchart for the treatment of trauma patients with compound pelvic fractures illustrated by a case report describing a 32 year old patient who sustained an open pelvic ring injury in a workplace accident. The aim of this paper is to underline the importance of a safe, straightforward approach to compound pelvic fractures. PMID- 22222368 TI - Quick genotyping detection of HBV by giant magnetoresistive biochip combined with PCR and line probe assay. AB - Genotyping of human hepatitis B virus (HBV) can be used to direct clinically effective therapeutic drug-selection. Herein we report that a quick genotyping method for human HBV was established by a specially designed giant magnetoresistive (GMR) biochip combined with magnetic nanoclusters (MNCs), PCR and line probe assay. Magnetic nanoclusters of around 180 nm in diameter were prepared and modified with streptavidin, and resultant streptavidin-modified magnetic nanoclusters were used for capturing biotin-labeled hybrid products on the detection interface of the sensor. The gene fragments of HBV's B and C gene types were obtained by PCR based on a template of B- and C-type plasmids. After gene fragments were hybridized with captured probes, streptavidin-modified magnetic nanoclusters could bind with biotin-conjugated gene fragments, and the resultant hydride products could be quickly detected and distinguished by the GMR sensor, with a detection sensitivity of 200 IU mL(-1) target HBV DNA molecules. The novel method has great potential application in clinical HBV genotyping diagnosis, and can be easily extended to other biomedical applications based on molecular recognition. PMID- 22222369 TI - Nuclear localization of lymphocyte-specific protein tyrosine kinase (Lck) and its role in regulating LIM domain only 2 (Lmo2) gene. AB - LIM domain only protein 2 (Lmo2) is a transcription factor that plays a critical role in the development of T-acute lymphoblastic leukemia (T-ALL). A previous report established a link between Lmo2 expression and the nuclear presence of oncogenic Janus kinase 2 (JAK2), a non-receptor protein tyrosine kinase. The oncogenic JAK2 kinase phosphorylates histone H3 on Tyr 41 that leads to the relief of Lmo2 promoter repression and subsequent gene expression. Similar to JAK2, constitutive activation of lymphocyte-specific protein tyrosine kinase (Lck) has been implicated in lymphoid malignancies. However, it is not known whether oncogenic Lck regulates Lmo2 expression through a similar mechanism. We show here that Lmo2 expression is significantly elevated in T cell leukemia LSTRA overexpressing active Lck kinase and in HEK 293 cells expressing oncogenic Y505FLck kinase. Nuclear localization of active Lck kinase was confirmed in both Lck-transformed cells by subcellular fractionation and immunofluorescence microscopy. More importantly, in contrast to oncogenic JAK2, oncogenic Lck kinase does not result in significant increase in histone H3 phosphorylation on Tyr 41. Instead, chromatin immunoprecipitation experiment shows that oncogenic Y505FLck kinase binds to the Lmo2 promoter in vivo. This result raises the possibility that oncogenic Lck may activate Lmo2 promoter through direct interaction. PMID- 22222370 TI - Statins inhibit expression of thioredoxin reductase 1 in rat and human liver and reduce tumour development. AB - BACKGROUND: Statins have been reported to have anti-carcinogenic properties in addition to their cholesterol-lowering effects, but the mechanism is unknown. Thioredoxin reductases (TrxR) are selenium-containing enzymes of great importance for carcinogenesis and their levels are increased in neoplastic cells. The aim of the present study was to investigate if statin treatment is associated with alterations in the hepatic expression of TrxR. METHODS: Human liver biopsies from a study where patients had been randomised to statin treatment or placebo were analysed. In addition we used liver tissue from a human liver bank where statin treated subjects were compared with non-treated. We also used tissue from a rat liver cancer model in which we have previously shown anti-carcinogenic effects of statins. Real-time PCR and activity assay were used to determine TrxR-levels and activity in tissue extracts. RESULTS: In humans 80 mg atorvastatin treatment for 4 weeks (n = 6) was associated with 85% lower levels of TrxR1 and TrxR2 compared to placebo-treated patients (n = 8) (p = 0.03). In liver biopsies from a human donor liver bank 3 statin treated subjects had 90% lower expression of TrxR1 than 15 non-treated subjects (p = 0.04). Statin treatment was associated with 45% lower expression and activity of TrxR1 in a rat model for liver cancer (p = 0.03). There was a clear correlation between inhibition of carcinogenesis and decreased TrxR1-levels (p = 0.003). CONCLUSION: Statin treatment decreases the hepatic expression of TrxR1 in humans and rats. Suppression of TrxR1 expression could explain possible anti-carcinogenic effects of statins. In addition, decreased levels of TrxR1 during statin treatment may shed light on the mechanism of other side-effects of statins. PMID- 22222371 TI - Regulation of enzyme activity of alcohol dehydrogenase through its interactions with pyruvate-ferredoxin oxidoreductase in Thermoanaerobacter tengcongensis. AB - Alcohol dehydrogenases (ADHs) from thermophilic microorganisms are interesting enzymes that have their potential applications in biotechnology and potentially provide insight into the mechanisms of action of thermo-tolerant proteins. The molecular mechanisms of ADHs under thermal stress in vivo have yet to be explored. Herein, we employed a proteomic strategy to survey the possible interactions of secondary-ADH (2-ADH) with other proteins in Thermoanaerobacter tengcongensis (T. tengcongensis) cultured at 75 degrees C and found that 2-ADH, pyruvate-ferredoxin oxidoreductase (PFOR) and several glycolytic enzymes coexisted in a protein complex. Using anion exchange chromatography, the elution profile indicated that the native 2-ADH was present in two forms, PFOR-bound and PFOR-free. Immuno-precipitation and pull down analysis further validated the interactions between 2-ADH and PFOR. The kinetic behaviours of 2-ADH either in the recombinant or native form were evaluated with different substrates. The enzyme activity of 2-ADH was inhibited in a non-competitive mode by PFOR, implying the interaction of 2-ADH and PFOR negatively regulated alcohol formation. In T. tengcongensis, PFOR is an enzyme complex located at the upstream of 2-ADH in the alcohol generation pathway. These findings, therefore, offered a plausible mechanism for how alcohol metabolism is regulated by hetero interactions between 2-ADH and PFOR, especially in anaerobic thermophiles. PMID- 22222372 TI - A natural squamosamide derivative FLZ inhibits homocysteine-induced rat brain microvascular endothelial cells dysfunction. AB - Hyperhomocysteinemia is believed to induce endothelial dysfunction, which is an independent risk factor for atherosclerosis and vascular diseases. Compound FLZ is a novel synthetic squamosamide cyclic analog with several phenolic hydroxy groups, and exhibits strong anti-oxidative and neuroprotective activities in Alzheimer's and Parkinson's models. In the present study, we examined the actions of FLZ against homocysteine-induced injury to primary cultured rat brain microvascular endothelial cell (rBMECs). Cell survival was measured by MTT assay. Cell nuclei were observed by Hoechst 33342 staining. Senescent cells were detected by senescence-associated beta-galactosidase (SA-beta-gal) staining. Reactive oxygen species (ROS) were measured by 2',7'-dichlorofluorescein (DCF) fluorescent microscopy. Homocysteine-induced expression of NF-kappaB, p53, Noxa and Fas, and the release of mitochondrial cytochrome c, were measured by Western blotting. We found that FLZ treatment antagonized homocysteine-induced cell death and apoptosis and increased numbers of senescent cells. These changes were correlated with decreased ROS accumulation. FLZ treatment inhibited activation of NF-kappaB, the upregulation of p53, Noxa, and Fas, and blocked mitochondrial cytochrome c release. These data suggest that FLZ has a protective action against homocysteine-induced toxicity in rBMECs, suggesting that FLZ may have therapeutic potential for the prevention of cardiovascular diseases. PMID- 22222373 TI - Reduction of nuclear encoded enzymes of mitochondrial energy metabolism in cells devoid of mitochondrial DNA. AB - Mitochondrial DNA (mtDNA) depletion syndromes are generally associated with reduced activities of oxidative phosphorylation (OXPHOS) enzymes that contain subunits encoded by mtDNA. Conversely, entirely nuclear encoded mitochondrial enzymes in these syndromes, such as the tricarboxylic acid cycle enzyme citrate synthase (CS) and OXPHOS complex II, usually exhibit normal or compensatory enhanced activities. Here we report that a human cell line devoid of mtDNA (HEK293 rho(0) cells) has diminished activities of both complex II and CS. This finding indicates the existence of a feedback mechanism in rho(0) cells that downregulates the expression of entirely nuclear encoded components of mitochondrial energy metabolism. PMID- 22222374 TI - PrPC displays an essential protective role from oxidative stress in an astrocyte cell line derived from PrPC knockout mice. AB - The PrP(C) protein, which is especially present in the cellular membrane of nervous system cells, has been extensively studied for its controversial antioxidant activity. In this study, we elucidated the free radical scavenger activity of purified murine PrP(C) in solution and its participation as a cell protector in astrocytes that were subjected to treatment with an oxidant. In vitro and using an EPR spin-trapping technique, we observed that PrP(C) decreased the oxidation of the DMPO trap in a Fenton reaction system (Cu(2+)/ascorbate/H(2)O(2)), which was demonstrated by approximately 70% less DMPO/OH(). In cultured PrP(C)-knockout astrocytes from mice, the absence of PrP(C) caused an increase in intracellular ROS (reactive oxygen species) generation during the first 3h of H(2)O(2) treatment. This rapid increase in ROS disrupted the cell cycle in the PrP(C)-knockout astrocytes, which increased the population of cells in the sub-G1 phase when compared with cultured wild-type astrocytes. We conclude that PrP(C) in solution acts as a radical scavenger, and in astrocytes, it is essential for protection from oxidative stress caused by an external chemical agent, which is a likely condition in human neurodegenerative CNS disorders and pathological conditions such as ischemia. PMID- 22222375 TI - RAS oncogenic signal upregulates EZH2 in pancreatic cancer. AB - The neoplastic transformation by mutant RAS is thought to require remodeling of expression of an entire set of genes. However, the underlying mechanism for initiation of gene expression remodeling in tumorigenesis remains elusive. This study was aimed to define the oncogenic role of EZH2, a histone modifier protein that is induced by oncogenic mutant RAS, using pancreatic cancers of transgenic rats exogenously expressing human mutant RAS. Immunohistochemical observation of preneoplastic or cancerous lesions in the animal model suggested that upregulation of Ezh2 protein is an initiating event in pancreatic carcinogenesis. MEK-inhibition or Elk-1-knockdown downregulated EZH2, and MEK-inhibition or EZH2 knockdown restored expression of a tumor suppressor, RUNX3 in human and rat pancreatic cancer cells activated by the oncogenic RAS. Furthermore, Elk-1- or EZH2-knockdown inhibited growth of the cancer cells. These results strongly suggested that the oncogenic RAS upregulates EZH2 through MEK-ERK signaling, resulted in downregulation of tumor suppressors including RUNX3 in pancreatic carcinogenesis. PMID- 22222376 TI - Anti-inflammatory effects of Tat-Annexin protein on ovalbumin-induced airway inflammation in a mouse model of asthma. AB - Chronic airway inflammation is a key feature of bronchial asthma. Annexin-1 (ANX1) is an anti-inflammatory protein that is an important modulator and plays a key role in inflammation. Although the precise action of ANX1 remains unclear, it has emerged as a potential drug target for inflammatory diseases such as asthma. To examine the protective effects of ANX1 protein on ovalbumin (OVA)-induced asthma in animal models, we used a cell-permeable Tat-ANX1 protein. Mice sensitized and challenged with OVA antigen had an increased amount of cytokines and eosinophils in their bronchoalveolar lavage (BAL) fluid. However, administration of Tat-ANX1 protein before OVA challenge significantly decreased the levels of cytokines (interleukin (IL)-4, IL-5, and IL-13) and BAL fluid in lung tissues. Furthermore, OVA significantly increased the activation of mitogen activated protein kinase (MAPK) in lung tissues, whereas Tat-ANX1 protein markedly reduced phosphorylation of MAPKs such as extracellular signal-regulated protein kinase, p38, and stress-activated protein kinase/c-Jun N-terminal kinase. These results suggest that transduced Tat-ANX1 protein may be a potential protein therapeutic agent for the treatment of lung disorders including asthma. PMID- 22222377 TI - Identification of the phosphorylation sites on intact TRPM7 channels from mammalian cells. AB - Transient receptor potential melastatin 7 (TRPM7) channels are divalent cation selective ion channels that are permeable to Ca(2+) and Mg(2+). TRPM7 is ubiquitously expressed in vertebrate cells and contains both an ion channel and a kinase domain. TRPM7 plays an important role in regulating cellular homeostatic levels of Ca(2+) and Mg(2+) in mammalian cells. Although studies have shown that the kinase domain of TRPM7 is required for channel activation and can phosphorylate other target proteins, a systematic analysis of intact TRPM7 channel phosphorylation sites expressed in mammalian cells is lacking. We applied mass spectrometric proteomic techniques to identify and characterize the key phosphorylation sites in TRPM7 channels. We identified 14 phosphorylation sites in the cytoplasmic domain of TRPM7, eight of which have not been previously reported. The identification of phosphorylation sites using antibody-based immunopurification and mass spectrometry is an effective approach for defining the phosphorylation status of TRPM7 channels. The present results show that TRPM7 channels are phosphorylated at multiple sites, which serves as a mechanism to modulate the dynamic functions of TRPM7 channels in mammalian cells. PMID- 22222378 TI - Brief Psychiatric Rating Scale - Excited Component (BPRS-EC) and neuropsychological dysfunction predict aggression, suicidality, and involuntary treatment in first-episode psychosis. AB - OBJECTIVE: Aggression, suicidality and involuntary treatment constitute severe clinical problems in first-episode psychosis (FEP). Although there are studies on prevalence and clinical predictors of these conditions, little is known on the influence of psychopathology and neuropsychological dysfunction. METHOD: 152 FEP inpatients were prospectively assessed using the Brief Psychiatric Rating Scale (BPRS) and a neuropsychological examination covering the domains 'processing speed', 'concentration and attention', 'executive function', 'working memory', 'verbal memory', 'verbal comprehension', 'logical reasoning', 'global cognition', and 'general intelligence'. Clinical data were collected retrospectively in a structured file audit trial. RESULTS: Patients were aged 24.5+/-4.9years, and 112 (74%) were male. At admission, 13 (9%) patients presented with severe aggression, and 28 (18%) with severe suicidality. 31 patients (20%) received involuntary treatment. In multivariate analyses, aggression was predicted by BPRS-Excited Component (BPRS-EC; p=.001), suicidality was predicted by BPRS-EC (p=.013) and general intelligence (p=.016), and predictors for involuntary treatment were BPRS EC (p=.001) and neuropsychological dysfunction in the domain 'concentration and attention' (p=.016). CONCLUSION: Psychopathology and neuropsychological functioning independently predict dangerous behavior in FEP patients. Some correlations with neuropsychology (e.g., of aggression with concentration/attention) are absent in multivariate analyses and may thus constitute a proxy of psychopathological features. In addition to clinical data, BPRS-EC can be used as a predictor of dangerous behavior. Patients with severe aggression and suicidality show different patterns of neuropsychological dysfunction, indicating that suicidality should not be conceptualized as subtype of aggressive behavior. PMID- 22222379 TI - Characteristics and clinical correlates of prospective memory performance in first-episode schizophrenia. AB - OBJECTIVE: The aim of this study was to examine prospective memory (PM) and its socio-demographic, clinical, and neurocognitive correlates in first episode schizophrenia (FES). METHODS: Fifty-one FES patients and 42 healthy controls formed the study sample. Time- and event-based PM (TBPM and EBPM) performance were measured with the Chinese version of the Cambridge Prospective Memory Test (C-CAMPROMPT). A battery of neuropsychological tests was also administered. Patients' clinical symptoms were evaluated with the Positive and Negative Symptom Scale (PANSS). RESULTS: Patients performed significantly worse in both TBPM (8.7 +/- 5.3 vs. 14.8 +/- 3.5) and EBPM (11.3 +/- 4.7 vs. 15.7 +/- 2.7) than the controls. After controlling for age, gender, education level and neurocognitive test score, the difference in performance on the two types of PM tasks between patients and controls was no longer present. In multiple linear regression analyses, longer duration of untreated psychosis (DUP), lower scores of the Hopkins Verbal Learning Test-Revised (HVLT-R) and the categories completed of the Wisconsin Card Sorting Test (WCST-CC) and higher score of the Color Trails Test-2 (CTT-2) contributed to poorer TBPM performance, while lower score of HVLT-R, higher score of the perseverative errors of the Wisconsin Card Sorting Test (WCST PE) and longer DUP contributed to worse performance on EBPM. CONCLUSIONS: Both subtypes of PM are impaired in first-episode schizophrenia suggesting that PM deficits are an integral part of the cognitive dysfunction in the disease process. PMID- 22222380 TI - Neural and personality correlates of individual differences related to the effects of acute tryptophan depletion on future reward evaluation. AB - BACKGROUND/AIMS: In general, humans tend to discount the value of delayed reward. An increase in the rate of discounting leads to an inability to select a delayed reward over a smaller immediate reward (reward-delay impulsivity). Although deficits in the serotonergic system are implicated in this reward-delay impulsivity, there is individual variation in response to serotonin depletion. The aim of the present study was to investigate whether the effects of serotonin depletion on the ability to evaluate future reward are affected by individual personality traits or brain activation. METHODS: Personality traits were assessed using the NEO-Five Factor Inventory and Temperament and Character Inventory. The central serotonergic levels of 16 healthy volunteers were manipulated by dietary tryptophan depletion. Subjects performed a delayed reward choice task that required the continuous estimation of reward value during functional magnetic resonance imaging scanning. RESULTS: Discounting rates were increased in 9 participants, but were unchanged or decreased in 7 participants in response to tryptophan depletion. Participants whose discounting rate was increased by tryptophan depletion had significantly higher neuroticism and lower self directedness. Furthermore, tryptophan depletion differentially affected the groups in terms of hemodynamic responses to the value of predicted future reward in the right insula. CONCLUSIONS: These results suggest that individuals who have high neuroticism and low self-directedness as personality traits are particularly vulnerable to the effect of low serotonin on future reward evaluation accompanied by altered brain activation patterns. PMID- 22222381 TI - Determinants of cognitive performance among community dwelling older adults in an impoverished sub-district of Sao Paulo in Brazil. AB - Determinants of cognitive performance in old age have received limited attention in Latin America. We investigated the association of socio-demographic and health related variables with cognitive performance in a sample of older adults with limited educational experience living in a poor sub-district of the city of Sao Paulo. This was a cross-sectional population-based study which included a sample of 384 seniors 65 years and older. Cognition was assessed by the Mini-Mental State Examination (MMSE) and the Brief Cognitive Screening Battery (BCSB) (episodic memory test with 10 pictures, verbal fluency (VF), Clock Drawing Test (CDT)). Results indicated that age, sex, schooling, depressive symptoms, and systolic blood pressure (SBP) level had a significant impact on the cognitive performance of the sample. Therefore, pharmacological and psychosocial interventions with a focus on improving mood and controlling hypertension may have beneficial effects on cognition among seniors with similar socio-demographic characteristics. PMID- 22222382 TI - Assessment of the relation between IVUS measurements and clinical outcome in elderly patients after sirolimus-eluting stent implantation for de novo coronary lesions. AB - This study aimed to evaluate the impact of vascular response assessed by intravascular ultrasound (IVUS) imaging on clinical outcomes in elderly patients (>= 75 years) undergoing percutaneous coronary intervention (PCI) for de novo lesions with sirolimus-eluting stent (SES) implantation. Repeat coronary angiography with IVUS was performed 1 year after SES-based PCI for de novo lesions in 136 elderly patients (>= 75 years) and 427 younger counterparts (< 75 years) (219 lesions and 635 lesions, respectively). Major adverse cardiac events (MACE) including cardiac death, non-fatal myocardial infarction, and target lesion revascularization (TLR) during 2-year follow-up were recorded. Despite similar angiographic in-stent restenosis and TLR and IVUS-detected incomplete stent apposition (ISA), absolute intimal hyperplasia and percentage of volumetric obstruction were lower in elderly than in younger patients. At 2-year follow-up, cumulative survival freedom from composite death and myocardial infarction or MACE was significantly reduced in elderly patients, but very late stent thrombosis was similar in the two groups. Cox proportional hazards model identified age, diabetes, left ventricular ejection fraction, lesion length,minimal stent cross-sectional area and plaque progression as independent predictors of non-fatal myocardial infarction or mortality. In elderly patients undergoing SES-based PCI, despite similar TLR, neointimal hyperplasia was significantly lower than in younger patients. IVUS measurements except for minimal stent cross-sectional area did not correlate with stent thrombosis and clinical outcomes at 2 years. PMID- 22222383 TI - Medical expenditures among immigrant and nonimmigrant groups in the United States: findings from the Medical Expenditures Panel Survey (2000-2008). AB - OBJECTIVE: The objective of the study was to examine time trends and differences in medical expenditures between noncitizens, foreign-born, and US-born citizens. METHODS: We used multi-year Medical Expenditures Panel Survey (2000-2008) data on noninstitutionalized adults in the United States (N=190,965). Source specific and total medical expenditures were analyzed using regression models, bootstrap prediction techniques, and linear and nonlinear decomposition methods to evaluate the relationship between immigration status and expenditures, controlling for confounding effects. RESULTS: We found that the average health expenditures between 2000 and 2008 for noncitizens immigrants ($1836) were substantially lower compared with both foreign-born ($3737) and US-born citizens ($4478). Differences were maintained after controlling for confounding effects. Decomposition techniques showed that the main determinants of these differences were the availability of a usual source of health care, insurance, and ethnicity/race. CONCLUSIONS: Lower health care expenditures among immigrants result from disparate access to health care. The dissipation of demographic advantages among immigrants could prospectively produce higher pressures on the US health care system as immigrants age and levels of chronic conditions rise. Barring a shift in policy, the brunt of the effects could be borne by an already overextended public health care system. PMID- 22222385 TI - Voices rising: the year in review. PMID- 22222384 TI - Silica-iron oxide magnetic nanoparticles modified for gene delivery: a search for optimum and quantitative criteria. AB - PURPOSE: To optimize silica-iron oxide magnetic nanoparticles with surface phosphonate groups decorated with 25-kD branched polyethylenimine (PEI) for gene delivery. METHODS: Surface composition, charge, colloidal stabilities, associations with adenovirus, magneto-tranduction efficiencies, cell internalizations, in vitro toxicities and MRI relaxivities were tested for the particles decorated with varying amounts of PEI. RESULTS: Moderate PEI-decoration of MNPs results in charge reversal and destabilization. Analysis of space and time resolved concentration changes during centrifugation clearly revealed that at >5% PEI loading flocculation gradually decreases and sufficient stabilization is achieved at >10%. The association with adenovirus occurred efficiently at levels over 5% PEI, resulting in the complexes stable in 50% FCS at a PEI-to-iron w/w ratio of >=7%; the maximum magneto-transduction efficiency was achieved at 9 12% PEI. Primary silica iron oxide nanoparticles and those with 11.5% PEI demonstrated excellent r(2)* relaxivity values (>600 s(-1)(mM Fe)(-1)) for the free and cell-internalized particles. CONCLUSIONS: Surface decoration of the silica-iron oxide nanoparticles with a PEI-to-iron w/w ratio of 10-12% yields stable aqueous suspensions, allows for efficient viral gene delivery and labeled cell detection by MRI. PMID- 22222386 TI - Counting nurses, nurses counting. PMID- 22222387 TI - Preoperative fasting. PMID- 22222388 TI - Preoperative fasting. PMID- 22222389 TI - The top health news story of 2011: health care reform and a system in flux. PMID- 22222394 TI - Challenges to health care delivery in U.S. prisons. PMID- 22222397 TI - Essential nursing resources: one source for evidence-based nursing practice. PMID- 22222403 TI - Cardiac catheterization through the radial artery. PMID- 22222405 TI - Critical analysis, critical care: central venous pressure monitoring: what's the evidence? PMID- 22222406 TI - Information systems and decision support systems. PMID- 22222410 TI - Nurses know. PMID- 22222411 TI - Effects of quercetin on the apoptosis of the human gastric carcinoma cells. AB - Quercetin, a natural constituent abundantly present in grapes, red wine, and other food products, is known to possess potent antiproliferative effects against various malignant cells. The present study aims to investigate the effect of quercetin on the apoptosis and morphology of gastric carcinoma BGC-823 cells, as well as the probable mechanism, in an effort to identify an effective drug as a potential candidate for gastric cancer. Gastric carcinoma BGC-823 cells were treated with quercetin, and cell morphology was determined by light microscopy and transmission electron microscopy. Apoptosis and cell cycle were measured by flow cytometry, using propidium iodide staining. The apoptotic protein expression of caspase-3, Bcl-2 and Bax was detected by Western blot. Quercetin induced apoptosis in BGC-823 cell. Some morphologic features of apoptosis were found, such as cell shrinkage or even apoptosis body. Quercetin changed the apoptotic protein expression. These results indicate that quercetin can induce apoptosis of the BGC-823 cells. A decrease in Bcl-2/Bax ratio with the increased expression of caspase-3 provides evidence that quercetin-induced apoptosis may be mediated via the mitochondrial pathway. PMID- 22222412 TI - The role of imagery-related properties in picture naming: a newly standardized set of 360 pictures for Japanese. AB - Picture naming was investigated primarily to determine its dependence on certain imagery-related variables, with a secondary aim of developing a new set of Japanese norms for 360 pictures. Pictures refined from the original Nishimoto, Miyawaki, Ueda, Une, and Takahashi (Behavior Research Methods 37:398-416, 2005) set were used. Naming behaviors were measured using four imagery-related measures (imageability, vividness, image agreement, and image variability) and four conventional measures (naming time, name agreement, familiarity, and age of acquisition), as well as a number of other measures (17 total). A simultaneous multiple regression analysis performed on naming times showed that the most reliable predictor was H, a measure of name diversity; two image-related measures (image agreement and vividness) and age of acquisition also contributed substantially to the prediction of naming times. The accuracy of picture naming (measured as name agreement) was predicted by vividness, age of acquisition, familiarity, and image agreement. This suggests that certain processes involving mental imagery play a role in picture naming. The full set of norms and pictures may be downloaded from http://www.psychonomic.org/archive/ or along with the article from http://www.springerlink.com . PMID- 22222413 TI - A microfluidic concentration generator for dose-response assays on ion channel pharmacology. AB - We present a microfluidic device to generate either statically spatial or dynamically temporal logarithmic concentrations. The temporal logarithmic concentration generator was also integrated with planar patch-clamp chips for dose-response assays on ion channels. Proposed serial dilution principle controls the flow pattern at each branching point via designing the flow resistance of microchannels. Simple and linear ratios of the flow resistance results in desired logarithmic concentration at outlets, where the concentrations can be dynamically altered by different combination of valve actuations, were demonstrated. Single cell pharmacology on ion channels was implemented by sequentially applying logarithmic drug concentrations to patched cells. Inhibitory activity of potassium channels of human embryonic kidney cells was examined by tetraethylammonium solutions. Resulted IC(50) and Hill slope reveal excellent agreement with assays from manually prepared drug concentrations showing the practicability and preciseness of the present approach. Applications include cellular analysis under various drugs and/or logarithmic concentrations at the single-cell level. PMID- 22222414 TI - Light-emitting property of simple AIE compounds in gel, suspension and precipitates, and application to quantitative determination of enantiomer composition. AB - It was found that simple AIE compounds could emit different intensity of fluorescence in gel, suspension and precipitates for the first time, which could be applied to fluorescence switches and quantitative determination of enantiomer composition. PMID- 22222415 TI - Graphene-nanoplatelet-based photomechanical actuators. AB - This paper reports large light-induced reversible and elastic responses of graphene nanoplatelet (GNP) polymer composites. Homogeneous mixtures of GNP/polydimethylsiloxane (PDMS) composites (0.1-5 wt%) were prepared and their infrared (IR) mechanical responses studied with increasing pre-strains. Using IR illumination, a photomechanically induced change in stress of four orders of magnitude as compared to pristine PDMS polymer was measured. The actuation responses of the graphene polymer composites depended on the applied pre-strains. At low levels of pre-strain (3-9%) the actuators showed reversible expansion while at high levels (15-40%) the actuators exhibited reversible contraction. The GNP/PDMS composites exhibited higher actuation stresses compared to other forms of nanostructured carbon/PDMS composites, including carbon nanotubes (CNTs), for the same fabrication method. An extraordinary optical-to-mechanical energy conversion factor (eta(M)) of 7-9 MPa W(-1) for GNP-based polymer composite actuators is reported. PMID- 22222416 TI - Rehabilitation settings after joint replacement: an application of multiattribute preference elicitation. AB - While advances in medical treatment and technologies have the potential to improve the delivery of health care, their use typically involves making multiple, complex decisions. Patients and their medical providers may share in the decision-making processes and balance a variety of criteria and/or attributes in the pursuit of improved health. This necessitates a stronger understanding of the role of human behavior in health care processes and presents a timely opportunity to use decision analysis tools to contribute to this important aspect of health care operations. This article reports on the application of multiattribute preference elicitation to identify postsurgical rehabilitation setting options for elective hip and knee replacement patients and their discharge planning team prior to placement in these settings. These preferences are analyzed to identify trends in emphases across patients and the discharge planning team, including a comparison with actual outcomes to determine the extent of congruence with each other, an important component of patient-centered care. Variances are identified in what patients and the discharge planning team expected and what actually happened. Reasons for these variances are discussed. PMID- 22222418 TI - Prognostic implication of macrocytosis on adverse outcomes after coronary intervention. AB - BACKGROUND: Macrocytosis, as a qualitative abnormality of erythrocytes, has not drawn attention as a prognostic indicator after PCI, while anemia, as a quantitative abnormality of erythrocytes, has been recognized as a predictor of adverse outcomes. The aim of this study was to perform prognostic risk stratification of patients after PCI based on the presence or absence of macrocytosis. METHODS: The clinical records of 941 consecutive patients who underwent PCI at a single institution were retrospectively reviewed. The prognostic implication of macrocytosis was evaluated by univariate and multivariate Cox's proportional hazard regression analysis. RESULTS: There were 130 (13.8%) patients with macrocytosis. A significantly higher all-cause and cardiac mortality, as well as incidence of composite adverse events were observed in the Macrocytic group. Kaplan-Meier analysis also showed a significantly poorer overall survival in patients with macrocytosis. Even after exclusion of anemic patients, this tendency was still observed. Furthermore, macrocytosis was significantly and independently associated with adverse outcomes after PCI (aHR of cardiac death: 3.45, 95%CI: 1.22-9.80, P=0.019). Interestingly, fewer patients with macrocytosis were prescribed statins compared with those without it (33.8% vs. 47.1%, P=0.005). CONCLUSIONS: The results of the study indicate that measuring mean corpuscular volume (MCV) as a qualitative index of erythrocytes might be helpful for a prognostic risk stratification of patients subjected to PCI. PMID- 22222417 TI - Associations of large artery structure and function with adiposity: effects of age, gender, and hypertension. The SardiNIA Study. AB - In the context of obesity epidemic, no large population study has extensively investigated the relationships between total and abdominal adiposity and large artery structure and function nor have such relationships been examined by gender, by age, by hypertensive status. We investigated these potential relationships in a large cohort of community dwelling volunteers participating the SardiNIA Study. METHODS AND RESULTS: Total and visceral adiposity and arterial properties were assessed in 6148 subjects, aged 14-102 in a cluster of 4 towns in Sardinia, Italy. Arterial stiffness was measured as aortic pulse wave velocity (PWV), arterial thickness and lumen as common carotid artery (CCA) intima-media thickness (IMT) and diameter, respectively. We reported a nonlinear relationship between total and visceral adiposity and arterial stiffness, thickness, and diameter. The association between adiposity and arterial properties was steeper in women than in men, in younger than in older subjects. Waist correlated with arterial properties better than BMI. Within each BMI quartile, increasing waist circumference was associated with further significant changes in arterial structure and function. CONCLUSION: The relationship between total or abdominal adiposity and arterial aging (PWV and CCA IMT) is not linear as described in the current study. Therefore, BMI- and/or waist-specific reference values for arterial measurements might need to be defined. PMID- 22222419 TI - A study of changes in bone metabolism in cases of gender identity disorder. AB - The aim of this study was to determine the effect of increasing estrogen and decreasing androgen in males and increasing androgen and decreasing estrogen in females on bone metabolism in patients with gender identity disorder (GID). We measured and examined bone mineral density (BMD) and bone metabolism markers retrospectively in GID patients who were treated in our hospital. In addition, we studied the effects of treatment on those who had osteoporosis. Patients who underwent a change from male to female (MtF) showed inhibition of bone resorption and increased L2-4 BMD whereas those who underwent a change from female to male (FtM) had increased bone resorption and decreased L2-4 BMD. Six months after administration of risedronate to FtM patients with osteoporosis, L2-4 BMD increased and bone resorption markers decreased. These results indicate that estrogen is an important element with regard to bone metabolism in males. PMID- 22222420 TI - Involvement of endoplasmic reticulum stress in homocysteine-induced apoptosis of osteoblastic cells. AB - Hyperhomocysteinemia has been shown to increase the incidence of osteoporosis and osteoporotic fractures. Endoplasmic reticulum (ER) stress was recently shown to be associated with apoptosis in several types of cells. In this study, we determined the effect of homocysteine (Hcy) on the apoptosis of osteoblastic cells and investigated whether ER stress participates in Hcy-induced osteoblast apoptosis. Human osteoblastic cells were incubated with Hcy. Hcy dose-dependently decreased cell viability and increased apoptosis in osteoblastic cells. Osteoblastic cells are more susceptible to Hcy-mediated cell death than other cell types. Expression of cleaved caspase-3 was significantly increased by Hcy, and pretreatment with caspase-3 inhibitor rescued the cell viability by Hcy. Hcy treatment led to an increase in release of mitochondrial cytochrome c. It also triggered ER stress by increased expression of glucose-regulated protein 78, inositol-requiring transmembrane kinase and endonuclease 1alpha (IRE-1alpha), spliced X-box binding protein, activating transcription factor 4, and C/EBP homologous protein. Silencing IRE-1alpha expression by small interfering RNA effectively suppressed Hcy-induced apoptosis of osteoblastic cells. Our results suggest that hyperhomocysteinemia induces apoptotic cell death in osteoblasts via ER stress. PMID- 22222421 TI - Histone deacetylase activity is required for skin Langerhans cell maturation and phagocytosis. PMID- 22222422 TI - Carotid atherosclerosis predicts lower cognitive test results: a 7-year follow-up study of 4,371 stroke-free subjects - the Tromso study. AB - BACKGROUND: Carotid artery atherosclerosis is a major risk factor for stroke and subsequent cognitive impairment. Prospective population studies have shown associations between carotid intima-media thickness (IMT) and stenosis and cognitive decline and dementia in elderly stroke-free persons, whereas results in the middle-aged are conflicting. METHODS: In this prospective population-based study, 4,371 stroke-free middle-aged participants underwent carotid ultrasound examination and assessment of vascular risk factors at baseline and were tested for cognitive function 7 years later. Associations between IMT, number of plaques and total plaque area and cognitive test scores on verbal memory test, digit symbol-coding test and tapping test were assessed in linear regression models. RESULTS: In the multivariable analyses adjusted for sex, age, education, depression and vascular risk factors, the presence of plaques was significantly associated with lower test scores on the verbal memory test (p = 0.01) and on the digit symbol-coding test (p = 0.03). The number of plaques (p = 0.01) and the total plaque area (p = 0.02) were associated with lower scores on the verbal memory test. No significant association was seen between common carotid artery IMT and cognitive test scores. The tapping test was not associated with the carotid ultrasound variables. CONCLUSIONS: In this middle-aged general population, subclinical carotid atherosclerosis measured as the presence of plaques, number of plaques and total plaque area were independent long-term predictors of lower cognitive test scores. PMID- 22222423 TI - High throughput production of single core double emulsions in a parallelized microfluidic device. AB - Double emulsions are useful templates for microcapsules and complex particles, but no method yet exists for making double emulsions with both high uniformity and high throughput. We present a parallel numbering-up design for microfluidic double emulsion devices, which combines the excellent control of microfluidics with throughput suitable for mass production. We demonstrate the design with devices incorporating up to 15 dropmaker units in a two-dimensional or three dimensional array, producing single-core double emulsion drops at rates over 1 kg day(-1) and with diameter variation less than 6%. This design provides a route to integrating hundreds of dropmakers or more in a single chip, facilitating industrial-scale production rates of many tons per year. PMID- 22222424 TI - The beneficial effects of nebivolol on endothelial functions in arterial hypertension. PMID- 22222426 TI - Late drug eluting stent thrombosis due to acemetacine: type III Kounis syndrome: Kounis syndrome due to acemetacine. PMID- 22222425 TI - Long-term effects of primary early granulo-monocyte colony-stimulating factor treatment on the left ventricular function and remodeling in patients with acute myocardial infarction with five-year follow-up. PMID- 22222427 TI - Hydrogen sulfide-releasing NSAIDs inhibit the growth of human cancer cells: a general property and evidence of a tissue type-independent effect. AB - Hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs (HS-NSAIDs) are an emerging novel class of compounds with significant anti-inflammatory properties. They consist of a traditional NSAID to which an H(2)S-releasing moiety is covalently attached. We examined the effects of four different HS NSAIDs on the growth properties of eleven different human cancer cell lines of six different tissue origins. Human colon, breast, pancreatic, prostate, lung, and leukemia cancer cell lines were treated with HS-aspirin, -sulindac, iburofen, -naproxen, and their traditional counterparts. HS-NSAIDs inhibited the growth of all cancer cell lines studied, with potencies of 28- to >3000-fold greater than that of their traditional counterparts. HS-aspirin (HS-ASA) was consistently the most potent. HS-NSAIDs inhibited cell proliferation, induced apoptosis, and caused G(0)/G(1) cell cycle block. Metabolism of HS-ASA by colon cells showed that the acetyl group of ASA was hydrolyzed rapidly, followed by hydrolysis of the ester bond linking the salicylate anion to the H(2)S releasing moiety, producing salicylic acid and ADT-OH from which H(2)S is released. In reconstitution studies, ASA and ADT-OH were individually less active than the intact HS-ASA towards cell growth inhibition. Additionally, the combination of these two components representing a fairly close approximation to the intact HS ASA, was 95-fold less active than the intact HS-ASA for growth inhibition. Taken together, these results demonstrate that HS-NSAIDs have potential anti-growth activity against a wide variety of human cancer cells. PMID- 22222429 TI - Development of a mathematical model for growth and oxygen transfer in in vitro plant hairy root cultivations. AB - Genetically transformed, "Hairy roots" once developed can serve as a stable parent culture for in vitro production of plant secondary metabolites. However, the major bottleneck in the commercial exploitation of hairy roots remains its successful scale-up due to oxygen transfer limitation in three-dimensionally growing hairy root mass. Mass transfer resistances near the gas-liquid and liquid solid boundary layer affect the oxygen delivery to the growing hairy roots. In addition, the diffusional mass transfer limitation due to increasing size of the root ball (matrix) with growth also plays a limiting role in the oxygen transfer rate. In the present study, a mathematical model is developed which describes the oxygen transfer kinetics in the growing Azadirachta indica hairy root matrix as a case study for offline simulation of process control strategies ensuring non limiting concentrations of oxygen in the medium throughout the hairy root cultivation period. The unstructured model simulates the effect of oxygen transfer limitation in terms of efficiency factor (eta) on specific growth rate (MU) of the hairy root biomass. The model is able to predict effectively the onset of oxygen transfer limitation in the inner core of the growing hairy root matrix such that the bulk oxygen concentration can be increased so as to prevent the subsequent inhibition in growth of the hairy root biomass due to oxygen transfer (diffusional) limitation. PMID- 22222430 TI - Fed-batch anaerobic valorization of slaughterhouse by-products with mesophilic microbial consortia without methane production. AB - This work aimed at setting up a fully instrumented, laboratory-scale bioreactor enabling anaerobic valorization of solid substrates through hydrogen and/or volatile fatty acid (VFA) production using mixed microbial populations (consortia). The substrate used was made of meat-based wastes, especially from slaughterhouses, which are becoming available in large amounts as a consequence of the growing constraints for waste disposal from meat industry. A reconstituted microbial mesophilic consortium without Archaebacteria (methanogens), named PBr, was cultivated in a 5-L anaerobic bioreactor on slaughterhouse wastes. The experiments were carried out with sequential fed-batch operations, including liquid medium removal from the bioreactor and addition of fresh substrate. VFAs and nitrogen were the main metabolites observed, while hydrogen accumulation was very low and no methane production was evidenced. After 1,300 h of culture, yields obtained for VFAs reached 0.38 g/g dry matter. Strain composition of the microbial consortium was also characterized using molecular tools (temporal temperature gradient gel electrophoresis and gene sequencing). PMID- 22222428 TI - Expression and regulation of RAD51 mediate cellular responses to chemotherapeutics. AB - There is evidence that RAD51 expression associates with resistance to commonly used chemotherapeutics. Our previous work demonstrated that inhibitors of thymidylate synthase (TS) induced RAD51-dependent homologous recombination (HR), and depleting the RAD51 recombinase sensitized cells to TS inhibitors. In this study, the consequences of RAD51 over-expression were studied. Over-expression of wild-type RAD51 (~6-fold above endogenous RAD51) conferred resistance to TS inhibitors. In contrast, over-expression of a mutant RAD51 (T309A) that is incapable of being phosphorylated rendered cells more chemosensitive. Moreover, over-expression of the T309A mutant acted in a dominant negative manner over endogenous RAD51 by causing the reduced localization of RAD51 foci following treatment with TS inhibitors. To measure the effect of mutant RAD51 on the cellular response to other DNA damaging chemotherapeutics, the topoisomerase poison etoposide was utilized. Cells over-expressing wild-type RAD51 showed reduced DNA strand breaks, while cells over-expressing the mutant RAD51 showed more than twice as many strand breaks, suggesting that the mutant RAD51 was actively inhibiting strand break resolution. To directly demonstrate an effect on HR, wild-type RAD51 and T309A mutant RAD51 were transiently expressed in HeLa cells that contained an HR reporter construct. HR events provoked by DNA breaks induced by the I-SceI endonuclease increased in cells expressing wild-type RAD51 and decreased in cells expressing the T309A mutant. Collectively, the data suggest that interference with the activation of RAD51-mediated HR represents a potentially useful anticancer target for combination therapies. PMID- 22222431 TI - Purification and characterisation of a 31-kDa chitinase from the Myzus Persicae aphid: a target for hemiptera biocontrol. AB - Hydrolytic enzymes involved in chitin degradation are important to allow moulting during insect development. Chitinases are interesting targets to disturb growth and develop alternative strategies to control insect pests. In this work, a chitinase from the aphid Myzus persicae was purified with a 36-fold purification rate in a three step procedure by ammonium sulphate fractionation, anion-exchange chromatography on a DEAE column and on an affinity Concanavalin A column. The purified chitinase purity assessed by 1D and 2D SDS-PAGE revealed a single band and three spots at 31 kDa, respectively. Chitinases were found to have high homologies with Concanavalins A and B, two chitinase-related proteins, a fungal endochitinase and an aphid acetylhydrolase by peptide identification by Maldi-Tof Tof. The efficiency of two potent chitinase inhibitors, namely allosamidin and psammaplin A, was tested and showed significant rate of enzymatic inhibition. PMID- 22222432 TI - Watermelon rind: agro-waste or superior biosorbent? AB - Biosorption of copper (Cu), zinc (Zn), and lead (Pb) on watermelon rind in a well stirred batch system was investigated. pH showed significant influence on the biosorption process. Optimal pH for Cu, Zn, and Pb biosorption was found to be 5.0, 6.8 and 6.8, respectively. Watermelon rind was in favor of Pb and it could remove up to 99% Pb between pH ranges of 5 and 6.8 when Pb concentration is lower than 100 mg/L. The biosorptive capacity of watermelon on Cu, Zn, and Pb was 6.281, 6.845, and 98.063 mg/g, respectively. The equilibrium data fitted well to Langmuir adsorption isotherm while pseudo-second-order kinetic model exhibited more advantages for describing kinetic data than pseudo-first-order kinetic model. NaOH was found to be a suitable eluent. After desorption in NaOH solution, the resorption efficiency reached as high as 99% of these three metals either in a single-component or multi-component system. From the characterization study, ion exchange and micro-precipitation were estimated to be the main mechanisms. Due to its high metal uptake capacity, reusability, and metal recovery, watermelon rind can be considered as an eco-friendly and economic biosorbent for removing Pb from water and wastewater. PMID- 22222433 TI - Regulation of xylanase biosynthesis in Bacillus cereus BSA1. AB - Microbial xylanases have a promising biotechnological potential to be used in industries. In this study, regulation of xylanase production was examined in Bacillus cereus BSA1. Xylanase production was induced by xylan. The enzyme production further increased in the presence of xylose and arabinose in very low concentration with addition of xylan (0.5% up to 6.02 U/ml). Addition of glucose (about 0.1%) to the media supplemented with xylan repressed xylanase production. Even higher concentration (>0.1%) of xylose and arabinose repressed xylanase biosynthesis. Glucose-mediated repression was partially relived by addition of cyclic adenosine monophosphate. Chemical like 2-4-dinitrophenol, which can inhibit adenosine triphosphate synthesis in cell, repressed xylanase synthesis and it suggested xylanase synthesis to be an energy dependent process. PMID- 22222434 TI - Erosive bladder perforation as a complication of ventriculoperitoneal shunt with extrusion from the urethral meatus: case report and literature review. AB - Ventriculoperitoneal (VP) shunt surgery is the most common technique used in the treatment of hydrocephalus. Erosive bladder perforation is an extremely rare complication of VP shunt surgery. Only 2 cases of erosive bladder perforation by a peritoneal catheter have been reported in the English literature. The authors present the case of a 14-year-old male with a history of cerebral palsy, severe developmental delay and hydrocephalus who presented with VP shunt tubing protruding from his urethral meatus. The patient had no evidence of neurological change. The VP shunt had been last revised over 11 years prior to admission. Imaging demonstrated the VP shunt to be intact, but displaced inferiorly, with the ventricular catheter in the extracranial soft tissue of the neck and the peritoneal catheter passing into the abdomen, bladder, and out through the urethra. Shunt removal was achieved through a multidisciplinary approach, involving both neurosurgery and urology teams. The authors discuss other reported cases of perforation by a VP shunt, potential mechanisms, and considerations for management of this rare complication. PMID- 22222435 TI - Serum protein levels of brain-derived neurotrophic factor and tropomyosin-related kinase B in bipolar disorder: effects of mood stabilizers. AB - AIM: In this study, we investigated serum protein levels of brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) in patients with bipolar disorder. METHODS: Over a 2-year period, 26 patients with bipolar I disorder (manic episode) and 56 healthy controls were recruited. The Young Mania Rating Scale scores of patients with bipolar mania were >26. Serum BDNF and TrkB protein levels were measured with ELISA kits. RESULTS: Using ANCOVA with age adjustment, we found that there were no significant differences in serum BDNF protein levels between patients with bipolar mania and healthy controls (p = 0.582). In contrast, the serum TrkB protein level was significantly higher in bipolar mania patients than in healthy controls (p = 0.001), especially in women (p = 0.001). Of 26 patients with bipolar mania, 21 underwent a second measurement of serum BDNF and TrkB protein levels after a 4-week treatment with mood stabilizers. There were no significant changes in serum BDNF or TrkB protein levels. CONCLUSION: These findings suggest that serum TrkB protein levels may play an important role in the psychopathology of bipolar mania. However, a larger sample size is needed to confirm these results. PMID- 22222436 TI - Long-range electron conduction of Shewanella biofilms mediated by outer membrane C-type cytochromes. AB - We investigated the role of c-type cytochromes (c-Cyts) in electron conduction across biofilms of Shewanella oneidensis MR-1 and the relevance of the electron conductivity for biological current generation. Following the formation of monolayer and multilayer biofilms on indium-tin oxide electrodes, we quantified the c-Cyts that were electrically wired with the electrode surface using whole cell voltammetry. A multilayer biofilm with a thickness of 16MUm exhibited a redox peak with an 8-fold larger coulombic area than that of a monolayer biofilm (about 0.5-MUm thickness), indicating an abundance of c-Cyts that are able to perform redox-cycling reactions with the distant electrode surface. To determine if this electron conduit of c-Cyts participated in biological current generation, we conducted slow-scan voltammetry for multilayer biofilms. A large anodic current of c-Cyts caused by microbial lactate oxidization was observed during the slow-potential scans, demonstrating the transport of respiratory electrons via the sequential redox cycling of c-Cyts. Experiments with deletion mutants deficient in outer-membrane (OM) c-Cyts (DeltamtrC/DeltaomcA, DeltapilD), and the biosynthetic protein of capsular polysaccharide (DeltaSO3177) suggested that cell surface-bound c-Cyts, but those located on pili or extracellular polymeric substrates, play a predominant role in the long-range electron conduction in the biofilm of S. oneidensis MR-1. PMID- 22222437 TI - Severe acute mountain sickness, brain natriuretic peptide and NT-proBNP in humans. AB - AIM: To examine the response of brain natriuretic peptide (BNP) and NT-proBNP to high altitude (HA) both at rest and following exercise. METHODS: We measured NT proBNP and BNP and Lake Louise (LL) acute mountain sickness (AMS) scores in 20 subjects at rest in Kathmandu (Kat; 1300 m), following exercise and at rest at 4270 and 5150 m. RESULTS: BNP and NT-proBNP (pg ml(-1) , mean +/- SEM) rose significantly from Kat (9.2 +/- 2 and 36.9 +/- 6.6, respectively) to arrival at 4270 m after exercise (16.6 +/- 4 and 152 +/- 56.1, P=0.008 and P<0.001, respectively) and remained elevated the next morning at rest (28.9 +/- 9 and 207.4 +/- 65.1, P = 0.004 and P<0.001 respectively). At 5150, immediately following ascent/descent to 5643 m, BNP and NT-proBNP were 32.3 +/- 8.8 and 301.1 +/- 96.3 (P=0.003 and P<0.001 vs. Kat, respectively) and at rest the following morning were 33.3 +/- 9.7 and 258.9 +/- 89.5 (P=0.008 and P=0.001 vs. Kat respectively). NT-proBNP and BNP correlated strongly at 5150 m (rho 0.905, P<0.001 and rho 0.914, P<0.001 for resting and post-exercise samples respectively). At 5150 m, BNP levels were significantly higher among the four subjects with severe (LL score>6) AMS (58.4 +/- 18.7) compared with those without (BNP 22.7 +/- 8.6, P=0.048). There were significant correlations between change in body water from baseline to 5150 m with both BNP and NT-proBNP (rho 0.77, P=0.001, rho 0.745, P=0.002 respectively). CONCLUSION: In conclusion, these data suggest that BNP and NT-proBNP increase with ascent to HA both after exercise and at rest. We also report the novel finding that BNP is significantly greater in those with severe AMS at 5150 m. PMID- 22222439 TI - Tau protein phosphorylation in diverse brain areas of normal and CRH deficient mice: up-regulation by stress. AB - Tau protein misfolding is a pathological mechanism, which plays a critical role in the etiopathogenesis of neurodegeneration. However, it is not entirely known what kind of stimuli can induce the misfolding. It is believed that physical and emotional stresses belong to such risk factors. Although the influence of stress on the onset and progression of Alzheimer's disease (AD) has already been proposed, the molecular links between stresses and AD are still unknown. We have therefore focused our attention on determination of the influence of acute immobilization stress (IMO) in normal mice and mice deficient in corticotropin releasing hormone (CRH). Specifically, we have analyzed levels of hyperphosphorylated tau proteins, bearing the AD-specific phospho-epitopes (AT-8, pT181, and PHF-1), which are implicated in the pathogenesis of AD. We found that IMO induces transient hyperphosphorylation of tau proteins regardless of continuation of the stimulus. Concerning tau modifications, detailed analysis of the mouse brain revealed that neurons in different brain regions including frontal cortex, temporal cortex, hippocampal C1 and CA3 regions, dentate gyrus as well as nucleus basalis Meynert, and several brainstem nuclei such as locus coeruleus but also raphe nucleus and substantia nigra respond similarly to IMO. The strongest tau protein phosphorylation was observed after 30 min of IMO stress. Stress lasting for 120 min led either to the disappearance of tau hyperphosphorylation or to the induction of a second wave of hyperphosphorylation. Noteworthy is the magnitude of pathological phosphorylation of tau protein in CRH and glucocorticoids deficient mice, being much lower in comparison to that observed in wild-type animals, which suggests a critical role of CRH in the pathogenesis of AD. Thus, our results indicate that hyperphosphorylation of tau protein induced by stress may represent the pathogenic event upstream of tau protein misfolding, which leads to progression or eventually initiation of neurodegeneration. The data show that CRH plays an important role in stress induced hyperphosphorylation of tau protein, which might be either a direct effect of CRH innervations in the brain or an effect mediated via the hypothalamo-pituitary-adrenal axis. PMID- 22222438 TI - Beta3 adrenoceptors substitute the role of M(2) muscarinic receptor in coping with cold stress in the heart: evidence from M(2)KO mice. AB - We investigated the role of beta3-adrenoceptors (AR) in cold stress (1 or 7 days in cold) in animals lacking main cardioinhibitive receptors-M2 muscarinic receptors (M(2)KO). There was no change in receptor number in the right ventricles. In the left ventricles, there was decrease in binding to all cardiostimulative receptors (beta1-, and beta2-AR) and increase in cardiodepressive receptors (beta3-AR) in unstressed KO in comparison to WT. The cold stress in WT animals resulted in decrease in binding to beta1- and beta2-AR (to 37%/35% after 1 day in cold and to 27%/28% after 7 days in cold) while beta3 AR were increased (to 216% of control) when 7 days cold was applied. MR were reduced to 46% and 58%, respectively. Gene expression of M2 MR in WT was not changed due to stress, while M3 was changed. The reaction of beta1- and beta2-AR (binding) to cold was similar in KO and WT animals, and beta3-AR in stressed KO animals did not change. Adenylyl cyclase activity was affected by beta3-agonist CL316243 in cold stressed WT animals but CL316243 had almost no effects on adenylyl cyclase activity in stressed KO. Nitric oxide activity (NOS) was not affected by BRL37344 (beta3-agonist) both in WT and KO animals. Similarly, the stress had no effects on NOS activity in WT animals and in KO animals. We conclude that the function of M2 MR is substituted by beta3-AR and that these effects are mediated via adenylyl cyclase rather than NOS. PMID- 22222440 TI - Neuroprotective effect of fucoidan on H2O2-induced apoptosis in PC12 cells via activation of PI3K/Akt pathway. AB - One of the plausible ways to prevent the reactive oxygen species (ROS)-mediated cellular injury is dietary or pharmaceutical augmentation of endogenous antioxidant defense capacity. In this study, we investigated the neuroprotective effect of fucoidan on H(2)O(2)-induced apoptosis in PC12 cells and the possible signaling pathways involved. The results showed that fucoidan inhibited the decrease of cell viability, scavenged ROS formation and reduced lactate dehydrogenase release in H(2)O(2)-induced PC12 cells. These changes were associated with an increase in superoxide dismutase and glutathione peroxidase activity, and reduction in malondialdehyde. In addition, fucoidan treatment inhibited apoptosis in H(2)O(2)-induced PC12 cells by increasing the Bcl-2/Bax ratio and decreasing active caspase-3 expression, as well as enhancing Akt phosphorylation (p-Akt). However, the protection of fucoidan on cell survival, p Akt, the Bcl-2/Bax ratio and caspase-3 activity were abolished by pretreating with phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002. In consequence, fucoidan might protect the neurocytes against H(2)O(2)-induced apoptosis via reducing ROS levels and activating PI3K/Akt signaling pathway. PMID- 22222441 TI - Molecular characterisation and interpretation of genetic diversity within globally distributed germplasm collections of tall fescue (Festuca arundinacea Schreb.) and meadow fescue (F. pratensis Huds.). AB - Allohexaploid tall fescue (Festuca arundinacea Schreb. syn. Lolium arundinaceum [Schreb.] Darbysh.) is an agriculturally important grass cultivated for pasture and turf world-wide. Genetic improvement of tall fescue could benefit from the use of non-domesticated germplasm to diversify breeding populations through the incorporation of novel and superior allele content. However, such potential germplasm must first be characterised, as three major morphotypes (Continental, Mediterranean and rhizomatous) with varying degrees of hybrid interfertility are commonly described within this species. As hexaploid tall fescue is also a member of a polyploid species complex that contains tetraploid, octoploid and decaploid taxa, it is also possible that germplasm collections may have inadvertently sampled some of these sub-species. In this study, 1,040 accessions from the publicly available United States Department of Agriculture tall fescue and meadow fescue germplasm collections were investigated. Sequence of the chloroplast genome-located matK gene and the nuclear ribosomal DNA internal transcribed spacer (rDNA ITS) permitted attribution of accessions to the three previously known morphotypes and also revealed the presence of tall fescue sub-species of varying ploidy levels, as well as other closely related species. The majority of accessions were, however, identified as Continental hexaploid tall fescue. Analysis using 34 simple sequence repeat markers was able to further investigate the level of genetic diversity within each hexaploid tall fescue morphotype group. At least two genetically distinct sub-groups of Continental hexaploid tall fescue were identified which are probably associated with palaeogeographic range expansion of this morphotype. This work has comprehensively characterised a large and complex germplasm collection and has identified genetically diverse accessions which may potentially contribute valuable alleles at agronomic loci for tall fescue cultivar improvement programs. PMID- 22222442 TI - Patterned ion beam implantation of Co ions into a SiO2 thin film via ordered nanoporous alumina masks. AB - Spatially patterned ion beam implantation of 190 keV Co(+) ions into a SiO(2) thin film on a Si substrate has been achieved by using nanoporous anodic aluminum oxide with a pore diameter of 125 nm as a mask. The successful synthesis of periodic embedded Co regions using pattern transfer is demonstrated for the first time using cross-sectional (scanning) transmission electron microscopy (TEM) in combination with analytical TEM. Implanted Co regions are found at the correct relative lateral periodicity given by the mask and at a depth of about 120 nm. PMID- 22222443 TI - Incidence of venous thromboembolism after spine surgery. AB - BACKGROUND: The incidence of venous thromboembolism (VTE) has varied among studies of patients undergoing elective spine surgery. This may be because of differences in prophylaxis for VTE and differences in methods of observation. Furthermore, some studies have reported symptomatic deep vein thrombosis (DVT) or pulmonary thromboembolism (PE), whereas others have included asymptomatic DVT or PE, making comparisons difficult. Therefore, the objective of this study was to determine the incidence of symptomatic and asymptomatic PE in patients undergoing elective spine surgery and to evaluate therapeutic methods for these conditions. METHODS: The subjects were 1975 patients who underwent spine surgery in our hospital from 1990 to 2011. Patients treated from January 1990 to November 1996 (n = 541, Group A) did not receive prophylaxis whereas those treated from January 2000 to February 2011 (n = 1,434, Group B) used a foot pump during and after surgery and subsequently wore elastic stockings. All subjects in Group A began ambulation >=2 weeks after surgery whereas those in Group B began to walk earlier within 3 days for patients who underwent decompression and within 1 week for those treated with fusion. From June 2010 to February 2011, contrast-enhanced computed tomography (CT) was performed 1 week after surgery for 100 patients to evaluate the presence of DVT and PE. Since March 2004, D-dimer was measured 1 week after surgery and patients with a level >=10 MUg/mL were followed up. RESULTS: The incidence of symptomatic PE was significantly higher in Group A than in Group B (8/541, 1.5% vs. 3/1,434, 0.2%). In 3 patients in Group B, PE developed within 1 week postoperatively and D-dimer values at onset were <=10 MUg/mL. In the 100 cases examined by contrast-enhanced computed tomography (CT), asymptomatic PE and VTE were detected in 18 and 19%, respectively. The D-dimer level 1 week after surgery was >=10 MUg/mL in 105 of 841 patients; however, none of these patients had clinically symptomatic VTE for at least 3 months postoperatively. CONCLUSIONS: Mechanical prophylaxis and early ambulation may be effective in reducing the incidence of symptomatic PE after spine surgery. Asymptomatic PE developed in 18% of patients who received mechanical prophylaxis, but the incidence of symptomatic PE was only 0.2%. Prompt diagnosis and treatment are required for patients who develop symptomatic PE. PMID- 22222444 TI - Characteristic shape of the lateral femoral condyle in patients with osteochondritis dissecans accompanied by a discoid lateral meniscus. AB - BACKGROUND: There are various indirect signs of a discoid lateral meniscus in radiographs, for example lateral joint space widening, hypoplasia of the LFC, etc. There has, however, been no previous report of the characteristic shape of the lateral femoral condyle (LFC) in patients with osteochondritis dissecans (OCD) accompanied by a discoid lateral meniscus. The purpose of this study was to evaluate the characteristic shape of the LFC in patients with OCD accompanied by a discoid lateral meniscus, and sex differences associated with the shape of the LFC in those patients. METHODS: This study included 29 males (31 knees) and 29 females (32 knees) of average age 17.7 years. There were 15 knees in 15 patients that were accompanied by OCD of the LFC (9 males, 9 knees; 6 females, 6 knees; average age 14.9 years; OCD group). There were 48 knees in 43 patients that were not accompanied by OCD of the LFC (20 males, 22 knees; 23 females, 26 knees; average age 17.6 years; non-OCD group). Standardized Rosenberg view radiographs of the knee were obtained for all patients. We evaluated the shape of LFC using the Rosenberg view and measured the condylar prominence ratio of the medial and lateral condyles adjacent to the intercondylar notch, in accordance with Ha's procedure. RESULTS: The OCD group had a significantly larger prominence ratio than the non-OCD group. The prominence ratio for males was significantly larger than that for females. CONCLUSION: We clearly demonstrated that the prominence ratio in the OCD group was significantly larger than that in the non-OCD group, indicating that the shape of the LFC and OCD in the LFC may be associated with the development of these lesions. PMID- 22222445 TI - Development of a screening tool for risk of locomotive syndrome in the elderly: the 25-question Geriatric Locomotive Function Scale. AB - OBJECTIVE: To evaluate the reliability and validity of a new questionnaire, the 25-question Geriatric Locomotive Function Scale (GLFS-25), for early detection of locomotive syndrome. METHODS: This new screening tool was designed to detect Japanese individuals under high-risk conditions who may soon require care services because of problems of the locomotive organs. Content validity, construct validity, criterion validity, internal-consistency reliability, and reproducibility (test-retest reliability) were examined using psychometric analysis, and a cutoff score to detect locomotive syndrome was determined. To investigate construct validity of the GLFS-25 and determine the cutoff score, the Akaike Information Criteria (AIC) were used. RESULTS: Study 1 analyzed 711 Japanese elderly people >=65 years old. No floor or ceiling effects were included in the GLFS-25. Internal consistency was confirmed by a Cronbach's alpha reliability coefficient of 0.961. As for the association between the GLFS-25 and European Quality of Life Scale-5 Dimensions (EQ-5D), Spearman's correlation coefficient was 0.85 (P < 0.001), showing excellent concurrent validity of the GLFS-25. Categorical principal component analysis showed that the construct structure consisted of one item cluster or the GLFS-25 was unifactorial. The AIC showed that one cluster of seven items was located in the center, with significant associations with the other five clusters. In study 2, 205 individuals were analyzed, and the test-retest interclass correlation was satisfactory (range 0.712-0.924). The cutoff score for identifying locomotive syndrome was set at 16. Validity and reliability of this new measurement were psychometrically confirmed as sufficient. CONCLUSIONS: The GLFS-25 offers a valid and reliable questionnaire scale for detecting locomotive syndrome in elderly Japanese individuals. PMID- 22222446 TI - The utility of structural biology in drug discovery. AB - Access to detailed three-dimensional structural information on protein drug targets can streamline many aspects of drug discovery, from target selection and target product profile determination, to the discovery of novel molecular scaffolds that form the basis of potential drugs, to lead optimization. The information content of X-ray crystal structures, as well as the utility of structural methods in supporting the different phases of the drug discovery process, are described in this chapter. PMID- 22222447 TI - Genetic construct design and recombinant protein expression for structural biology. AB - Obtaining diffraction quality crystals is frequently an iterative process which traditionally has involved screening large numbers of crystallization conditions. Due to advances in high-throughput gene engineering, recombinant expression, and purification, the protein of interest has now become one of the many variables routinely investigated during crystallization trials. As such, construct design is a critical step in the path toward successful crystallization. In this chapter will we address construct design strategies frequently employed to improve the solution and crystallization behavior of proteins. Topics covered include choosing a recombinant expression system and reducing disorder through truncations and surface mutagenesis. Also covered are strategies to reduce heterogeneity from posttranslational modifications, impurities, and aggregation. PMID- 22222448 TI - Purification of proteins for crystallographic applications. AB - One of the most important parameters correlated with success in protein crystallization experiments is sample purity and monodispersity. Heterologous expression systems have allowed investigators to produce engineered proteins in sufficient quantities which simplify the purification process compared with the days when macromolecules had to be extracted from source tissue. Improvements in the areas of chromatographic media and instrumentation have also dramatically improved throughput and protein yields while maintaining analytical resolution. In a drug discovery setting, efforts can be focused on either a single protein or family of proteins. This requires the development and refinement of general purification methods that can be applied to multiple proteins or construct variants until readily crystallizable forms of the target protein are discovered. It is the aim of this chapter to provide a practical introduction to the techniques and methods used to purify proteins for crystallographic applications. Additionally, a protocol describing the expression, purification, and crystallization of the ATP-binding domain of the important cancer target Hsp90 provides the reader with an example of methods that can be adapted to a wider set of crystallographic target proteins. PMID- 22222449 TI - Protein crystallization for structure-based drug design. AB - The crystallization experiment has one main objective: to obtain diffraction quality crystals. This can be achieved through myriad avenues; here the focus will be on crystallization in support of drug discovery. In drug discovery there are two main paradigms for crystallography: high-throughput, and by any means necessary. Each paradigm requires the investigator to formulate strategies based on different priorities. In the high-throughput environment, the emphasis is on rapid prosecution of a large number of protein targets. In the by any means necessary paradigm the target pool is generally smaller and structural information is absolutely necessary for success. The process of growing diffraction quality protein crystals involves deciding on a crystallization method, initial screening, cryoprotection, initial diffraction analysis, and growth optimization. Furthermore, in structure-based drug design it is necessary to obtain crystal structures of protein-ligand complexes. PMID- 22222450 TI - X-ray sources and high-throughput data collection methods. AB - X-ray diffraction experiments on protein crystals are at the core of the structure determination process. An overview of X-ray sources and data collection methods to support structure-based drug design (SBDD) efforts is presented in this chapter. First, methods of generating and manipulating X-rays for the purpose of protein crystallography, as well as the components of the diffraction experiment setup are discussed. SBDD requires the determination of numerous protein-ligand complex structures in a timely manner, and the second part of this chapter describes how to perform diffraction experiments efficiently on a large number of crystals, including crystal screening and data collection. PMID- 22222451 TI - The use of molecular graphics in structure-based drug design. AB - The use of 3D structures derived from X-ray crystal data in drug development has increased in recent years. Molecular graphics applications are important tools at the end of the data processing pipeline and provide means to build, refine and validate protein models and ligand structures. We describe the requirements on useful data, what such data provide and typical problems in dealing with protein ligand complexes and how one might address them with an emphasis on the use of Coot. PMID- 22222452 TI - Crystallographic fragment screening. AB - Crystallographic fragment screening is a technique for initiating drug discovery in which protein crystals are soaked or grown with high concentrations of small molecule compounds (typically MW 110-250 Da) chosen to represent fragments of potential drugs. Specific binding of these compounds to the protein is subsequently visualized in electron density maps obtained from analysis of X-ray diffraction data collected from these crystals. Theoretical and practical experience indicate that a suitably diverse library of fragment compounds containing only a few hundred compounds may be sufficient to provide a comprehensive screen of the protein target. By soaking crystals in mixtures of 3 10 compounds a fragment screen may be completed within ~100 diffraction data sets. This data collection requirement may be met given reproducible well diffracting protein crystals and robotic sample handling equipment at a high flux X-ray source. The leading practical issue for most crystallography laboratories that wish to launch a fragment screening project is the design and/or procurement of an appropriate fragment library. Although several off-the-shelf fragment libraries are available from chemical suppliers, the numbers, sizes, and solubility of the compounds in relatively few of these libraries are well-match to the specific needs of the crystallographic screening experiment. Informed consideration of the properties of compounds in the screening library, possibly augmented by additional filtering of available compounds with appropriate search tools, is required to design a successful experiment. The analysis of results from crystallographic fragment screening involves highly repetitive application of routine image data processing and structure refinement calculations from many very similar crystals. Efficient handling of the data applies a high-throughput structure determination methodology that conveniently packages the structure solution calculations into a single process that provides the crystallographer analyst with ready-to-view maps for evaluating crystals for bound compounds. PMID- 22222453 TI - The role of enzymology in a structure-based drug discovery program: bacterial DNA gyrase. AB - The capability to accurately, rapidly, and reproducibly determine the affinity of a ligand for a target protein or enzyme is a vital component for a successful structure-based drug design effort. In order to successfully drive a structure based drug design (SBDD) project forward, multiple distinct assays, each with particular strengths and weaknesses, need to be employed. Using bacterial DNA gyrase as an example, a range of assays are described that will fully support an SBDD program. PMID- 22222454 TI - Leveraging structural information for the discovery of new drugs: computational methods. AB - Escalating problems with drug resistance continue to compromise the effectiveness of commercial antibiotics, necessitating the search for novel classes of antimicrobial agents. To circumvent problems with resistance, a multitarget single-pharmacophore approach has been employed to discover inhibitors that possess balanced activity against multiple target enzymes. In this chapter, we examine the application of computational techniques, in particular, structure based drug design approaches, to design new dual-targeting antibacterial agents against bacterial topoisomerases. PMID- 22222455 TI - Chemical informatics: using molecular shape descriptors in structure-based drug design. AB - The concept of molecular shape has been considered in various forms in the context of drug design. The following chapter details the application of molecular shape to the design of compound libraries for assessment of potential biological activity. Whilst the utility of shape descriptors is well documented in the area of ligand similarity, the use of shape descriptors is equally applicable to protein structures. Indeed, work has been published using various descriptors to compare proteins but little published where protein shape descriptors have been used to investigate ligand selectivity. PMID- 22222456 TI - Accounting for solvent in structure-based drug design. AB - Water plays a crucial role in the mediation of protein-ligand interactions, as underscored by the fact that most X-ray crystal structures (of sufficient resolution) of protein-ligand complexes possess water molecules at the protein ligand interface. In this chapter, the accuracy and reliability of ordered waters observed in crystal structures is discussed. Additionally, the thermodynamic aspects of the inclusion of water in ligand binding to proteins is described, with the goal of providing practical guidelines for dealing with ordered water molecules during structure-guided lead optimization. PMID- 22222457 TI - Structure-based drug design on membrane protein targets: human integral membrane protein 5-lipoxygenase-activating protein. AB - Leukotrienes are biologically active lipid metabolites of arachidonic acid that are involved in inflammation and play a significant role in respiratory and cardiovascular disease. The integral nuclear membrane protein 5-lipoxygenase activating protein (FLAP) is essential for leukotriene biosynthesis in response to cellular activation. The crystal structures of human FLAP with two inhibitors were recently determined. Inhibitors are bound within the lipid-exposed portion of FLAP, and the unexpected location of the inhibitor-binding site suggests a transport mechanism for arachidonic acid and provides functional insights into leukotriene biosynthesis. This chapter describes how this human integral membrane crystal structure was solved by pushing the limits of low-resolution structure determination and refinement, demonstrating how a low-resolution structure can impact biology and chemistry, and discusses future opportunities for structure based drug design for this therapeutic target. PMID- 22222458 TI - Application of SBDD to the discovery of new antibacterial drugs. AB - The emergence of bacteria that are multiply resistant to commonly used antibiotics has created the medical need for novel classes of antibacterial agents. The unique challenges to the discovery of new antibacterial drugs include the following: spectrum, selectivity, low emergence of new resistance, and high potency. With the emergence of genomic information, dozens of antibacterial targets have been pursued over the last 2 decades often using SBDD. This chapter reviews the application of structure-based drug design approaches on a selected group of antibacterial targets (DHFR, DHNA, PDF, and FabI) where significant progress has been made. We compare and contrast the different approaches and evaluate the results in terms of the biological profiles of the leads produced. Several common themes have emerged from this survey, resulting in a set of recommendations. PMID- 22222459 TI - Leveraging SBDD in protein therapeutic development: antibody engineering. AB - Antibodies make up the largest, growing segment of protein therapeutics in the pharmaceutical and biotechnology industries. The development or engineering of therapeutic antibodies is based to a large extent on our knowledge of antibody structure and requires sophisticated methods that continue to evolve. In this chapter, after a review of what is known about the structure and functional properties of antibodies, the current, state-of-the-art antibody engineering methods are described. These methods include antibody humanization, antigen affinity optimization, Fc engineering for modulated effector function and extended half-life, and engineering for improved stability and biophysical properties. X-ray crystallographic structures of antibody fragments and their complexes can play a critical role in guiding and, in some cases, accelerating these processes. These approaches represent guidelines for developing antibody therapeutics with the desired affinity, effector function, and biophysical properties. PMID- 22222460 TI - A medicinal chemistry perspective on structure-based drug design and development. AB - The application of X-ray crystallography and molecular modeling can provide valuable insight into the optimization of the molecular interactions of a drug protein complex to achieve potency and selectivity of a drug candidate. For the successful application of SBDD in a drug development program, the impact of these structural modifications required to improve potency and selectivity must be considered in the context of balancing of a multitude of drug properties and other considerations that include solubility, bioavailability, metabolism, distribution, toxicology, chemical stability, and intellectual property space. The utility of structure-based design from the medicinal chemist's perspective is described in this chapter. PMID- 22222461 TI - Dissecting ensemble networks in ES cell populations reveals micro-heterogeneity underlying pluripotency. AB - Analysis of transcription at the level of single cells in prokaryotes and eukaryotes has revealed the existence of heterogeneities in the expression of individual genes within genetically homogeneous populations. This variation is an emerging hallmark of populations of Embryonic Stem (ES) cells and has been ascribed to the stochasticity associated with the biochemical events that mediate gene expression. It has been suggested that these heterogeneities play a role in the maintenance of pluripotency. However, for the most part, studies have focused on individual genes in large cell populations. Here we use an existing dataset on the expression of eight genes involved in pluripotency in eighty-three ES cells to create Gene Regulatory Networks (GRNs) at the single cell level. We observe widespread heterogeneities in the expression of the eight genes, but analysis of correlations within individual cells reveals three distinct classes centered on the expression of Nanog, a marker of pluripotency, and Fgf5, a gene associated with differentiation: high levels of Nanog and low levels of Fgf5, low levels of Nanog and high levels of Fgf5, and low levels of both. Each of these classes is associated with a collection of active sub-networks, with differing degrees of connectivity between their elements, which define a cellular state: self-renewal, primed for differentiation or transition between the two. Though every cell should be governed by the same network, the active sub-networks may emerge due to considerations such as variation in (i) the expression level of active transcription factors (e.g. through post-translational modification or ligand/co factor availability) or (ii) access to the target gene locus (e.g. via changes in chromatin status or epigenetic modifications). We conclude that heterogeneities in gene expression should not be interpreted as representing different states of a single unique network, but as a reflection of the activity of different sub networks in sub-populations of cells. PMID- 22222463 TI - Characterization of oxidation products from 1-palmitoyl-2-linoleoyl-sn glycerophosphatidylcholine in aqueous solutions and their reactions with cysteine, histidine and lysine residues. AB - This report focuses on studies of lipid peroxidation products reactivity towards the side chains of cysteine, histidine, and lysine residues in structurally unordered peptides. Thus we have analyzed linoleic acid peroxidation products (LaPP) obtained by incubating 1-palmitoyl-2-linoleoyl-sn glycerophosphatidylcholine (PLPC) overnight with or without H(2)O(2) in the presence or absence of CuCl. In total, 55 different LaPP were identified with 26 containing reactive carbonyl groups. The strongest oxidation conditions (H(2)O(2) and Cu(I), i.e. a Fenton-like reagent) yielded 51 LaPP, whereas air oxidation produced only 12 LaPP. Independent of the oxidation conditions, around half of all LaPP were short-chain (oxidative cleavage) and the others long-chain (oxygen addition) PLPC oxidation products. The stronger oxidation conditions increased the number of LaPP, but also oxidized the added peptide Ac-PAAPAAPAPAEXTPV-OH (X=Cys, His or Lys) very quickly, especially under Fenton conditions. Thus, PLPC was oxidized by milder conditions (air or Cu(I)), incubated with the peptide and the peptide modifications were then analyzed by nano-RPC-ESI-Orbitrap-MS. Ten LaPP-derived peptide modifications were identified at lysine, whereas nine products were identified for cysteine and only three for histidine. Three high molecular weight LaPP still esterified to the GPC backbone were detected on Lys containing peptide. Furthermore, three LaPP-derived mass shifts were obtained at cysteine, which have not previously been reported. PMID- 22222462 TI - Failure to replicate influence of GRIK4 and GNB3 polymorphisms on treatment outcome in major depression. AB - In the present study, we aimed to confirm the previous finding of an association between GRIK4 and GNB3 variants (rs195478 and rs5443) and remission and treatment resistance in major depression, using a multicenter sample of 223 patients. We did not find any supporting evidence for such associations. These conflicting data may result from difficulties in the replication of candidate gene association studies. PMID- 22222464 TI - A statistical framework for multiparameter analysis at the single-cell level. AB - Phenotypic characterization of individual cells provides crucial insights into intercellular heterogeneity and enables access to information that is unavailable from ensemble averaged, bulk cell analyses. Single-cell studies have attracted significant interest in recent years and spurred the development of a variety of commercially available and research-grade technologies. To quantify cell-to-cell variability of cell populations, we have developed an experimental platform for real-time measurements of oxygen consumption (OC) kinetics at the single-cell level. Unique challenges inherent to these single-cell measurements arise, and no existing data analysis methodology is available to address them. Here we present a data processing and analysis method that addresses challenges encountered with this unique type of data in order to extract biologically relevant information. We applied the method to analyze OC profiles obtained with single cells of two different cell lines derived from metaplastic and dysplastic human Barrett's esophageal epithelium. In terms of method development, three main challenges were considered for this heterogeneous dynamic system: (i) high levels of noise, (ii) the lack of a priori knowledge of single-cell dynamics, and (iii) the role of intercellular variability within and across cell types. Several strategies and solutions to address each of these three challenges are presented. The features such as slopes, intercepts, breakpoint or change-point were extracted for every OC profile and compared across individual cells and cell types. The results demonstrated that the extracted features facilitated exposition of subtle differences between individual cells and their responses to cell-cell interactions. With minor modifications, this method can be used to process and analyze data from other acquisition and experimental modalities at the single cell level, providing a valuable statistical framework for single-cell analysis. PMID- 22222466 TI - A single-cell view of ammonium assimilation in coral-dinoflagellate symbiosis. AB - Assimilation of inorganic nitrogen from nutrient-poor tropical seas is an essential challenge for the endosymbiosis between reef-building corals and dinoflagellates. Despite the clear evidence that reef-building corals can use ammonium as inorganic nitrogen source, the dynamics and precise roles of host and symbionts in this fundamental process remain unclear. Here, we combine high spatial resolution ion microprobe imaging (NanoSIMS) and pulse-chase isotopic labeling in order to track the dynamics of ammonium incorporation within the intact symbiosis between the reef-building coral Acropora aspera and its dinoflagellate symbionts. We demonstrate that both dinoflagellate and animal cells have the capacity to rapidly fix nitrogen from seawater enriched in ammonium (in less than one hour). Further, by establishing the relative strengths of the capability to assimilate nitrogen for each cell compartment, we infer that dinoflagellate symbionts can fix 14 to 23 times more nitrogen than their coral host cells in response to a sudden pulse of ammonium-enriched seawater. Given the importance of nitrogen in cell maintenance, growth and functioning, the capability to fix ammonium from seawater into the symbiotic system may be a key component of coral nutrition. Interestingly, this metabolic response appears to be triggered rapidly by episodic nitrogen availability. The methods and results presented in this study open up for the exploration of dynamics and spatial patterns associated with metabolic activities and nutritional interactions in a multitude of organisms that live in symbiotic relationships. PMID- 22222465 TI - In vitro biocompatibility of thermally gelling liquid mucoadhesive loaded curcuminoids in colorectal cancer chemoprevention. AB - PURPOSE: Colorectal cancer (CRC) is the third leading cause of cancer death in Taiwan; it ranks top three in the cancer mortality rate. Curcuminoids are derived from the rhizome of Curcuma longa. It has shown anti-cancer activity and apoptosis induction in a variety of cancer cell lines. This aims to study the potential of Poloxamer 407 as the thermogelling and mucoadhesive polymer for development of a site-targeting delivery system to enhance the localized delivery of curcuminoids to the colorectal cells for CRC chemotherapy. METHODS: The mucoadhesive strength and rheological properties were measured as a function of poloxamer loaded with curcuminoids. RESULTS: The gelation temperature of Poloxamer 407 was found to vary with its concentration and start gelling at 37 degrees C at the concentration of 15.5% (w/v). To ensure gelation at physiological temperature after intra-rectal application, gelation temperature was determined by rheological measurement as well as by its physical appearance. The results indicated that its mucoadhesive strength also shows a dependency on temperature, which appears to be related to the increment in the maximum strength and average strength of the polymer. CONCLUSION: The results have suggested that Poloxamer 407 could be a potential thermogelling and mucoadhesive polymer for the development of a site-targeting colorectal drug delivery system for curcuminoids in colorectal cancer therapy. PMID- 22222467 TI - Stroke: prevalence and disability in Cotonou, Benin. AB - BACKGROUND: Little is known about the burden of stroke in sub-Saharan Africa that may increase with the ongoing demographic and socioeconomic transition. This study aims to assess the prevalence of stroke, its related disability rate and consequences in the quality of daily life in an urban door- to-door survey in Cotonou, Benin. METHODS: A three-phase door-to-door study was performed in two districts of Cotonou with a broad range of socioeconomic income. A population of 15,155 individuals aged >=15 years was evaluated. The first phase consisted in screening of stroke in the population using the modified WHO questionnaire, the second phase included the medical evaluation of all suspected cases, and in the third phase the diagnosis of stroke was confirmed by CT scan evaluation. RESULTS: Out of 15,155 subjects, 321 cases were identified as possible stroke cases. The diagnosis was confirmed in 70 cases. The crude prevalence of stroke was thus estimated to be 4.6/1,000 (8.7/1,000 and 7.7/1,000 adjusted to the WHO and SEGI World Population). The mean age of the patients at onset was 56 +/- 13 years. Sixty percent of stroke survivors had a Rankin score >=2, and CT scan was found abnormal in 90.0% of them. CONCLUSION: The stroke prevalence in urban areas of Cotonou is higher than that reported in other sub-Saharan countries, and the majority of stroke survivors present with good functional recovery and without severe disability in their everyday life. PMID- 22222468 TI - Hypoxia induces Kv channel current inhibition by increased NADPH oxidase-derived reactive oxygen species. AB - There is current discussion whether reactive oxygen species are up- or downregulated in the pulmonary circulation during hypoxia, from which sources (i.e., mitochondria or NADPH oxidases) they are derived, and what the downstream targets of ROS are. We recently showed that the NADPH oxidase homolog NOX4 is upregulated in hypoxia-induced pulmonary hypertension in mice and contributes to the vascular remodeling in pulmonary hypertension. We here tested the hypothesis that NOX4 regulates K(v) channels via an increased ROS formation after prolonged hypoxia. We showed that (1) NOX4 is upregulated in hypoxia-induced pulmonary hypertension in rats and isolated rat pulmonary arterial smooth muscle cells (PASMC) after 3days of hypoxia, and (2) that NOX4 is a major contributor to increased reactive oxygen species (ROS) after hypoxia. Our data indicate colocalization of K(v)1.5 and NOX4 in isolated PASMC. The NADPH oxidase inhibitor and ROS scavenger apocynin as well as NOX4 siRNA reversed the hypoxia-induced decrease in K(v) current density whereas the protein levels of the channels remain unaffected by siNOX4 treatment. Determination of cysteine oxidation revealed increased NOX4-mediated K(v)1.5 channel oxidation. We conclude that sustained hypoxia decreases K(v) channel currents by a direct effect of a NOX4 derived increase in ROS. PMID- 22222469 TI - Remote ischemic preconditioning applied during isoflurane inhalation provides no benefit to the myocardium of patients undergoing on-pump coronary artery bypass graft surgery: lack of synergy or evidence of antagonism in cardioprotection? AB - BACKGROUND: Two preconditioning stimuli should induce a more consistent overall cell protection. We hypothesized that remote ischemic preconditioning (RIPC, second preconditioning stimulus) applied during isoflurane inhalation (first preconditioning stimulus) would provide more protection to the myocardium of patients undergoing on-pump coronary artery bypass grafting. METHODS: In this placebo-controlled randomized controlled study, patients in the RIPC group received four 5-min cycles of 300 mmHg cuff inflation/deflation of the leg before aortic cross-clamping. Anesthesia consisted of opioids and propofol for induction and isoflurane for maintenance. The primary outcome was high-sensitivity cardiac troponin T release. Secondary endpoints were plasma levels of N-terminal pro brain natriuretic peptide, high-sensitivity C-reactive protein, S100 protein, and short- and long-term clinical outcomes. Gene expression profiles were obtained from atrial tissue using microarrays. RESULTS: RIPC (n = 27) did not reduce high sensitivity cardiac troponin T release when compared with placebo (n = 28). Likewise, N-terminal pro-brain natriuretic peptide, a marker of myocardial dysfunction; high-sensitivity C-reactive protein, a marker of perioperative inflammatory response; and S100, a marker of cerebral injury, were not different between the groups. The incidence for the perioperative composite endpoint combining new arrhythmias and myocardial infarctions was higher in the RIPC group than the placebo group (14/27 vs. 6/28, P = 0.036). However, there was no difference in the 6-month cardiovascular outcome. N-terminal pro-brain natriuretic peptide release correlated with isoflurane-induced transcriptional changes in fatty-acid metabolism (P = 0.001) and DNA-damage signaling (P < 0.001), but not with RIPC-induced changes in gene expression. CONCLUSIONS: RIPC applied during isoflurane inhalation provides no benefit to the myocardium of patients undergoing on-pump coronary artery bypass grafting. PMID- 22222470 TI - Electroacupuncture improves survival in rats with lethal endotoxemia via the autonomic nervous system. AB - BACKGROUND: Recent advances have indicated a complex interplay between the autonomic nervous system and the innate immune system. Targeting neural networks for the treatment of sepsis is being developed as a therapeutic strategy. Because electroacupuncture at select acupoints can modulate activities of the autonomic nervous system, we tested the hypothesis that electroacupuncture at specific acupoints could modulate systemic inflammatory responses and improve survival via its impact on the autonomic nervous system in a rat model of sepsis. METHODS: Sprague-Dawley male rats received electroacupuncture for 45 min before and at 1, 2, or 4 h after a lethal dose of intraperitoneal lipopolysaccharide injection (6 mg/kg). Outcomes included survival and systemic cytokine responses. Also, the possible roles of neural circuitry, including the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, were evaluated. RESULTS: Electroacupuncture pretreatment at the Hegu acupoints significantly attenuate systemic inflammatory responses and improve survival rate from 20% to 80% in rats with lethal endotoxemia. Such a site-specific effect requires the activation of muscarinic receptors in the central nervous system, but not increasing central sympathetic tone. In the periphery synergistic, rather than independent, action of the sympathetic and parasympathetic systems is also necessary. CONCLUSIONS: Electroacupuncture pretreatment has a dramatic survival-enhancing effect in rats with lethal endotoxemia, which involves the activation of efferent neural circuits of the autonomic nervous system (e.g., cholinergic antiinflammatory pathway). This approach could be developed as a prophylactic treatment for sepsis or perioperative conditions related to excessive inflammation. PMID- 22222471 TI - Prognostic implications of preoperative E/e' ratio in patients with off-pump coronary artery surgery. AB - BACKGROUND: The ratio of early transmitral flow velocity to early diastolic velocity of the mitral annulus (E/e') correlates with left ventricular (LV) filling pressure. In particular, an E/e' ratio more than 15 is an excellent predictor of increased LV filling pressure. The authors evaluated the prognostic implications of preoperative estimated LV filling pressure, assessed by E/e' ratio, in patients undergoing off-pump coronary artery bypass graft surgery. METHODS: This observational study investigated 1,048 consecutive adults undergoing elective off-pump coronary artery bypass graft surgery. The primary outcome was occurrence of major adverse cardiac events (MACE), defined as a composite of death, myocardial infarction, malignant ventricular arrhythmia, cardiac dysfunction, or need for new revascularization. Logistic regression and survival analyses were performed. RESULTS: An E/e' ratio more than 15 was independently associated with 30-day MACE (odds ratio 2.4, 95% CI 1.4-3.9, P = 0.001) and 1-yr MACE (hazard ratio 2.1, 95% CI 1.4-3.1, P = 0.001), irrespective of underlying LV ejection fraction. MACE free 1-yr survival rate was significantly decreased in patients with E/e' >15, irrespective of underlying LV ejection fraction. CONCLUSIONS: Increased LV filling pressure, assessed by E/e' ratio, is an independent predictor of 30-day and 1-yr MACE in patients who undergo elective off-pump coronary artery bypass graft surgery. These findings indicate that measurements of E/e' may assist in preoperative risk stratification of these patients. PMID- 22222473 TI - Sevoflurane remifentanil interaction: comparison of different response surface models. AB - BACKGROUND: Various pharmacodynamic response surface models have been developed to quantitatively describe the relationship between two or more drug concentrations with their combined clinical effect. We examined the interaction of remifentanil and sevoflurane on the probability of tolerance to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy in patients to compare the performance of five different response surface models. METHODS: Forty patients preoperatively received different combined concentrations of remifentanil (0-12 ng/ml) and sevoflurane (0.5-3.5 vol.%) according to a criss cross design (160 concentration pairs, four per patient). After having reached pseudosteady state, the response to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy was recorded. For the analysis of the probability of tolerance, five different interaction models were tested: Greco, Reduced Greco, Minto, Scaled C50(O) Hierarchical, and Fixed C50(O) Hierarchical model. All calculations were performed with NONMEM VI (Icon Development Solutions, Ellicott City, MD). RESULTS: The pharmacodynamic interaction between sevoflurane and remifentanil was strongly synergistic for both the hypnotic and the analgesic components of anesthesia. The Greco model did not result in plausible parameter estimates. The Fixed C50(O) Hierarchical model performed slightly better than the Scaled C50(O) Hierarchical and Reduced Greco models, whereas the Minto model fitted less well. CONCLUSION: We showed the importance of exploring various surface model approaches when studying drug interactions. The Fixed C50(O) Hierarchical model fits our data on sevoflurane remifentanil interaction best and appears to be an appropriate model for use in hypnotic-opioid drug interaction. PMID- 22222474 TI - All models are wrong. PMID- 22222476 TI - Effects of regional and whole-body hypothermic treatment before and after median nerve injury on neuropathic pain and glial activation in rat cuneate nucleus. AB - BACKGROUND: Neuroprotective effects of hypothermia on peripheral nerve injury remain uncertain. This study investigated the efficacy of hypothermia in attenuating neuropathic pain and glial activation in the cuneate nucleus in a median nerve chronic constriction injury (CCI) model. METHODS: Sprague-Dawley rats (n = 246) that underwent median nerve ligature at the elbow received various degrees of regional and whole-body hypothermia 15 min before CCI and 5 h, 1, 3, and 5 days after CCI. Hypothermia was maintained for 4 h. Seven days after CCI, behavioral and electrophysiological testings were conducted. Immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay were used for qualitative and quantitative analysis of glial activation and measuring pro-inflammatory cytokines, respectively. RESULTS: Mild (32 degrees C) and deep (28 degrees C) regional hypothermia administered preinjury and 5 h postinjury attenuated neuropathic pain and glial activation. Application of whole-body hypothermia preinjury and 5 h postinjury provided a similar therapeutic effect. However, whole-body hypothermia, but not regional hypothermia, applied 1, 3, and 5 days postinjury attenuated glial activation and neuropathic pain. Similarly, on days 1, 3, and 5 postinjury, only whole-body hypothermia was effective in decreasing proinflammatory cytokine levels. The increase in injury discharge observed after CCI could be suppressed by regional or whole-body hypothermia at different stages of nerve injury. CONCLUSIONS: At the early stage following nerve injury, regional and whole-body hypothermia suppresses ectopic discharges, and consequently inhibits glial activation and neuropathic pain. At the later stage, pain processing is mediated mainly by cytokines released from activated microglia; therefore, only whole-body hypothermia is effective in modulating pain. PMID- 22222475 TI - Anesthetic management and outcome in patients during endovascular therapy for acute stroke. AB - BACKGROUND: Studies of endovascular treatment for acute ischemic stroke have identified general anesthesia as a predictor for poor outcome in comparison with local anesthesia/sedation. This retrospective study attempts to identify modifiable factors associated with poor outcome, while adjusting for baseline stroke severity, in patients receiving general anesthesia. METHODS: We reviewed charts of 129 patients treated between January 2003 and September 2009. The primary outcome was the modified Rankin Score of 0-2 for 3 months poststroke. Predictors of neurologic outcome included baseline National Institutes of Health Stroke Scale score, blood glucose concentration, and age. Additional risk factors evaluated were prolonged stroke onset-treatment interval and systolic blood pressure less than 140 mmHg. Choice of local anesthesia or general anesthesia was recorded. RESULTS: The study group was 96 out of 129 patients for whom modified Rankin Scale scores were available; 48 patients received general anesthesia and 48 local anesthesia. The proportion of patients with "good" outcomes were 15% and 60% in the general anesthesia group and local anesthesia group, respectively (P < 0.001). Lowest systolic blood pressure and general anesthesia were correlated (r = -0.7, P < 0.001). Independent predictors for good neurologic outcome were local anesthesia, systolic blood pressure greater than 140 mmHg, and low baseline stroke scores. CONCLUSIONS: Adjusted for stroke severity, patients who received general anesthesia for treatment are less likely to have a good outcome than those managed with local anesthesia. This may be due to preintervention risk not included in the stroke severity measures. Hypotension, more frequent in the general anesthesia patients, may also contribute. PMID- 22222477 TI - Case scenario: perianesthetic management of laryngospasm in children. PMID- 22222478 TI - Feasibility of closed-loop titration of propofol and remifentanil guided by the spectral M-Entropy monitor. AB - BACKGROUND: This randomized controlled trial describes automated coadministration of propofol and remifentanil, guided by M-Entropy analysis of the electroencephalogram. The authors tested the hypothesis that a novel dual-loop controller with an M-Entropy monitor increases time spent within predetermined target entropy ranges. METHODS: Patients scheduled for elective surgery were randomly assigned in this single-blind study using a computer-generated list, to either dual-loop control using a proportional-integral-derivative controller or skilled manual control of propofol and remifentanil using target-controlled infusion systems. In each group, propofol and remifentanil administration was titrated to a state entropy target of 50 and was subsequently targeted to values between 40 and 60. The primary outcome was the global score, which included the percentage of state entropy or response entropy in the range 40-60, the median absolute performance error and wobble. Data are presented as medians [interquartile range]. RESULTS: Thirty patients assigned to the dual-loop group and 31 assigned to the manual group completed the study. The dual-loop controller was able to provide induction and maintenance for all patients. The Global Score of State Entropy was better maintained with dual-loop than manual control (25 [19 53] vs. 44 [25-110], P = 0.043), and state entropy was more frequently maintained in the range of 40-60 (80 [60-85] vs. 60 [35-82]%, P = 0.046). Propofol (4.1 [2.9 4.9] vs. 4.5 [3.4-6.3] mg . kg(-1) . h(-1)) and remifentanil (0.18 [0.13-0.24] vs. 0.19 [0.15-0.26] MUg . kg(-1) . min(-1)) consumptions and the incidence of somatic side effects were similar. CONCLUSION: Intraoperative automated control of hypnosis and analgesia guided by M-Entropy is clinically feasible and more precise than skilled manual control. PMID- 22222479 TI - First human administration of MR04A3: a novel water-soluble nonbenzodiazepine sedative. AB - BACKGROUND: JM-1232(-), (-)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-phenyl 3,5,6,7-tetrahydrocyclopenta [f]isoindol-1(2H)-one, molecular formula, C(24)H(27)N(3)O(2); molecular weight, 389.49, is a novel isoindoline water soluble benzodiazepine receptor agonist with favorable anesthetic/sedative properties in animals. MR04A3 is a 1% aqueous presentation of JM-1232(-). METHODS: In Step 1, healthy male volunteers received 10-min infusions of MR04A3, 0.05, 0.1, 0.2, 0.4, and 0.8 mg/kg, with three MR04A3 subjects and one placebo subject per dose concentration. In Step 2, doses were 0.025, 0.05, 0.075, 0.1, 0.2, 0.3, and 0.4 mg/kg over 1 min with six MR04A3 subjects and one placebo subject per dose concentration. RESULTS: Hypnotic effects of MR04A3 were seen at all dose concentrations in Step 1 and at doses of 0.075 mg/kg or more in Step 2. Central nervous system effect was seen at all dose concentrations with larger doses of MR04A3 producing a deeper and longer reduction in bispectral index. Ramsay sedation scores were increased with higher doses causing sedation and then unresponsiveness. The adverse event profile of subjects receiving MR04A3 was similar to that of subjects given placebo except that some subjects receiving MR04A3 developed upper airway obstruction while sedated. This responded to simple maneuvers (i.e., chin lift). Changes in systolic arterial blood pressure and heart rate were minimal. CONCLUSIONS: MR04A3 is hypnotic in man with a satisfactory hemodynamic and safety profile. PMID- 22222481 TI - Processed electroencephalogram and depth of anesthesia: window to nowhere or into the brain? PMID- 22222480 TI - Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain. AB - BACKGROUND: Exposure of rhesus macaque fetuses for 24 h or neonates for 9 h to ketamine anesthesia causes neuroapoptosis in the developing brain. The current study clarifies the minimum exposure required for and the extent and spatial distribution of ketamine-induced neuroapoptosis in rhesus fetuses and neonates. METHOD: Ketamine was administered by IV infusion for 5 h to postnatal day 6 rhesus neonates or to pregnant rhesus females at 120 days' gestation (full term = 165 days). Three hours later, fetuses were delivered by cesarean section, and the fetal and neonatal brains were studied for evidence of apoptotic neurodegeneration, as determined by activated caspase-3 staining. RESULTS: Both the fetal (n = 3) and neonatal (n = 4) ketamine-exposed brains had a significant increase in apoptotic profiles compared with drug-naive controls (fetal n = 4; neonatal n = 5). Loss of neurons attributable to ketamine exposure was 2.2 times greater in fetuses than in neonates. The pattern of neurodegeneration in fetuses was different from that in neonates, and all subjects exposed at either age had a pattern characteristic for that age. CONCLUSION: The developing rhesus macaque brain is sensitive to the apoptogenic action of ketamine at both a fetal and neonatal age, and exposure duration of 5 h is sufficient to induce a significant neuroapoptosis response at either age. The pattern of neurodegeneration induced by ketamine in fetuses was different from that in neonates, and loss of neurons attributable to ketamine exposure was 2.2 times greater in the fetal than neonatal brains. PMID- 22222482 TI - Excess iodine and high-fat diet combination modulates lipid profile, thyroid hormone, and hepatic LDLr expression values in mice. AB - The aim of this study was to illustrate the combined effect of excess iodine and high-fat diet on lipid metabolism and its potential molecular mechanism. Sixty Balb/c mice were randomly allocated to three control groups or three excess iodine groups and fed with a high-fat diet in the absence or presence of 1,200 MUg/L iodine for 1, 3, or 6 months, respectively. Serum lipid parameters and serum thyroid hormones were measured. Expressions of scavenger receptor class B type-I (SR-BI) and low density lipoproteins receptor (LDLr) mRNA and protein in liver were detected. Thyroid histology and liver type 1 iodothyronine deiodinase activity were analyzed. At the end of 3 and 6 months, compared with control, serum TC, TG, and LDL-C in excess iodine group were significantly lower (p < 0.05). LDLr expression in liver was increased significantly (p < 0.05) and parallel to the change of serum TC and TG. TT3 and TT4 levels in serum were elevated and TSH decreased significantly (p < 0.05). Liver type I iodothyronine deiodinase activity was significantly higher (p < 0.05) than control at the end of 6 months. Moreover, a time course damage effect of excess iodine combined with high-fat diet on thyroid glands was observed. The present findings demonstrated that excess iodine combined with high-fat diet could cause damage to thyroid glands and lead to thyroid hormone disorder. Those in turn caused the upregulation of hepatic LDLr gene, which resulted in the disorder in serum lipids. PMID- 22222484 TI - A highly selective fluorescent chemosensor for guanosine-5'-triphosphate via excimer formation in aqueous solution of physiological pH. AB - A new water-soluble and fluorescent imidazolium-anthracene cyclophane 1 effectively recognizes and differentiates the biologically important GTP and ATP in 100% aqueous solution of physiological pH 7.4. Fluorescence, (1)H-NMR spectra and ab initio calculations demonstrate that excimer formation and fluorescence enhancement occur upon GTP and ATP binding, respectively, through (C-H)(+)...A(-) hydrogen bond interactions. PMID- 22222485 TI - Neutrophil cell population data: useful indicators for postsurgical bacterial infection. AB - INTRODUCTION: The Coulter LH750 analyzer can determine white blood cell count (WBC) with differentials and determine their intrinsic biophysical properties, known as cell population data (CPD). Previous studies demonstrated that neutrophil CPD, mean neutrophil volume (MNV), and neutrophil volume distribution width (NDW) were significantly increased during bacterial infection. This study investigated the clinical usefulness of MNV/NDW to differentiate postoperative infection. METHODS: Cell population data from 212 controls, 135 patients without postsurgical infection, and 62 with infection were studied. All patients had normal WBC and percent neutrophils prior to surgery. RESULTS: No significant differences in MNV and NDW were observed before surgery between infected and noninfected patients when compared with controls. The MNV and NDW in infected patients were significantly increased after surgery when compared with noninfected patients. Although WBC and percent neutrophils were also increased after surgery, no statistical differences were seen between noninfected and infected patients. A MNV cutoff of >=152.4 and NDW cutoff of >=24.26 produced 90.3% and 88.3% sensitivity and 88.4% and 76.3% specificity, respectively. CONCLUSION: Neutrophil CPD, MNV, and NDW are better indicators for postoperative bacterial infection. The potential clinical usefulness of these parameters merits further exploration in a larger prospective study. PMID- 22222483 TI - A multi-mineral natural product inhibits liver tumor formation in C57BL/6 mice. AB - C57BL/6 mice were maintained for up to 18 months on high-fat and low-fat diets with or without a multi-mineral supplement derived from the skeletal remains of the red marine algae Lithothamnion calcareum. Numerous grossly observable liver masses were visible in animals on the "western-style" high-fat diet sacrificed at 12 and 18 months. The majority of the masses were in male mice (20 out of 100 males versus 3 out of 100 females; p = 0.0002). There were more liver masses in animals on the high-fat diet than on the low-fat diet (15 out of 50 on high-fat versus 5 out of 50 on low-fat; p = 0.0254). The multi-mineral supplement reduced the number of liver masses in mice on both diets (3 out of 25 male mice in the low-fat diet group without the supplement versus 1 out of 25 mice with supplement; 12 of 25 male mice in the high-fat diet group without the supplement versus 3 of 25 mice with supplement [p = 0.0129]). Histological evaluation revealed a total of 17 neoplastic lesions (9 adenomas and 8 hepatocellular carcinomas), and 18 pre-neoplastic lesions. Out of eight hepatocellular carcinomas, seven were found in unsupplemented diet groups. Steatosis was widely observed in livers with and without grossly observable masses, but the multi mineral supplement had no effect on the incidence of steatosis or its severity. Taken together, these findings suggest that a multi-mineral-rich natural product can protect mice against neoplastic and pre-neoplastic proliferative liver lesions that may develop in the face of steatosis. PMID- 22222487 TI - The Basic Empathy Scale: a Chinese validation of a measure of empathy in adolescents. AB - The purpose of this study was to evaluate the reliability and validity of the Chinese version of the Basic Empathy Scale (BES). The Chinese version of BES was administered to a sample (n = 1,524) aged 9-18 and 65 males with conduct disorder aged 13-18. The result of confirmatory factor analysis showed a two-factor structure with four items deleted to be the most adequate model (cognitive empathy, affective empathy). Empathy was positively correlated with a measure of prosocial behaviour and a measure of emotional problems. Boys with conduct disorder scored significantly lower than matched participants on cognitive empathy. Moreover, in line with previous researches, girls were found to score significantly higher on empathy than boys and the scores on both cognitive and affective empathy increased with age. The Chinese revision exhibited satisfactory internal consistency and moderate test-retest reliability. PMID- 22222488 TI - Pre-adoption adversity and self-reported behavior problems in 7 year-old international adoptees. AB - To further investigate the long-term impact of pre-adoption adversity on international adoptees, externalizing and internalizing symptoms were assessed using a self-report measure at school-age in addition to mothers' reports. The sample consisted of 95 adopted children and their mothers. Children's health and developmental status were assessed soon after arrival in their adoptive family. At age 7, the Dominic Interactive, a self-report measure, was used to evaluate externalizing and internalizing symptoms while mothers completed the CBCL. Children's self-reports were compared to their non-adopted peers'. Adopted children reported more symptoms of specific phobia than their peers. A significant correlation was found between mothers' and children's reports but only for externalizing symptoms. Self-reported symptoms were related to indices of nutritional and psychosocial deprivation at arrival, such as low height/age and weight/height ratios. Our results emphasize the importance of considering international adoptees' perception of their psychological adjustment and the long term impact of early risk factors. PMID- 22222486 TI - 14-3-3 checkpoint regulatory proteins interact specifically with DNA repair protein human exonuclease 1 (hEXO1) via a semi-conserved motif. AB - Human exonuclease 1 (hEXO1) acts directly in diverse DNA processing events, including replication, mismatch repair (MMR), and double strand break repair (DSBR), and it was also recently described to function as damage sensor and apoptosis inducer following DNA damage. In contrast, 14-3-3 proteins are regulatory phosphorserine/threonine binding proteins involved in the control of diverse cellular events, including cell cycle checkpoint and apoptosis signaling. hEXO1 is regulated by post-translation Ser/Thr phosphorylation in a yet not fully clarified manner, but evidently three phosphorylation sites are specifically induced by replication inhibition leading to protein ubiquitination and degradation. We demonstrate direct and robust interaction between hEXO1 and six of the seven 14-3-3 isoforms in vitro, suggestive of a novel protein interaction network between DNA repair and cell cycle control. Binding experiments reveal weak affinity of the more selective isoform 14-3-3sigma but both 14-3-3 isoforms eta and sigma significantly stimulate hEXO1 activity, indicating that these regulatory proteins exert a common regulation mode on hEXO1. Results demonstrate that binding involves the phosphorable amino acid S746 in hEXO1 and most likely a second unidentified binding motif. 14-3-3 associations do not appear to directly influence hEXO1 in vitro nuclease activity or in vitro DNA replication initiation. Moreover, specific phosphorylation variants, including hEXO1 S746A, are efficiently imported to the nucleus; to associate with PCNA in distinct replication foci and respond to DNA double strand breaks (DSBs), indicating that 14-3-3 binding does not involve regulating the subcellular distribution of hEXO1. Altogether, these results suggest that association may be related to regulation of hEXO1 availability during the DNA damage response to plausibly prevent extensive DNA resection at the damage site, as supported by recent studies. PMID- 22222489 TI - MTHFR C677T polymorphism and its relationship to myocardial infarction in the Eastern Black Sea region of Turkey. AB - BACKGROUND AND AIMS: An association of homozygous MTHFR 677T genotypes with elevated plasma homocysteine level has been documented, but results are still controversial. We aimed to investigate prevalence of the C677T polymorphism in patients with acute myocardial infarction (MI) in the Eastern Black Sea region of Turkey. METHODS: We studied genomic DNA of 231 unrelated patients (aged 59 +/- 13 years; 175 male, 56 female) with first anterior acute MI and 242 healthy controls (aged 54 +/- 19 years; 182 male, 60 female) using real-time polymerase chain reaction kits for the MTHFR C677T mutation. RESULTS: Prevalence of MTHFR C677T mutant genotype was 49.1% (CT: 45.8%, TT: 3.3%) in controls and 48.45% (CT: 38.5%, TT: 9.95%) in patients with acute MI. The TT mutation was more frequent in patients with acute MI than in controls (9.95 vs. 3.3%) (OR; 3.23, 95% CI; [1.34 8.05], p = 0.003). CONCLUSIONS: The MTHFR gene homozygote TT mutation is a risk factor for patients with MI in the eastern Black Sea Turkish Population. PMID- 22222490 TI - Detection of Helicobacter pylori and cagA gene in nasal polyps and benign laryngeal diseases. AB - BACKGROUND AND AIMS: Helicobacter pylori is the most common etiological factor of chronic infection worldwide. It has also been found in human dental plaques, mouth, saliva, tonsils and adenoid tissue, medial ear or nasal polyps and sinuses mucosa, as well in several benign and malignant lesions of the larynx and pharynx. The aim of the study was to investigate the association of H. pylori colonization in chronic rhinosinusitis and benign laryngeal diseases. METHODS: The prospective, controlled study involved a series of 30 patients with nasal polyps and normal nasal mucosa and 30 patients with benign laryngeal diseases. Samples of 10-15 mg obtained from fresh tissues were used for nucleic acid purification. All samples were subjected to H. pylori ureA detection by the PCR H. pylori diagnostic test. Samples that were positive for ureA H. pylori gene were evaluated for cagA H. pylori gene. RESULTS: H. pylori DNA (ureA gene) was detected in all patients with nasal polyps, concha bullosa and laryngeal diseases. Presence of H. pylori cagA gene was identified in 7 (23.3%) of 30 patients of H. pylori-positive larynx samples and no positive result was observed in nasal polyps and concha bullosa. CONCLUSIONS: Our results reveal the presence of H. pylori DNA in nasal polyps, concha bullosa and benign larynx diseases. cagA positive H. pylori was observed only in laryngeal tissues. These results may have implications for a possible role of H. pylori in laryngeal diseases. PMID- 22222491 TI - Antiquorum sensing and antibiofilm potential of Capparis spinosa. AB - BACKGROUND: Emergence of antibiotic resistance among bacterial pathogens often leads to the failure of existing antibiotics to treat bacterial infections; thus, there is a need to seek alternative treatment measures. The aim of this study was to evaluate the anti-quorum sensing (anti-QS) and antibiofilm potential of Capparis spinosa to prevent the onset of bacterial infections as an alternate to antibiotics. METHODS: The methanolic extract of the dried fruits of C. spinosa was assessed for its activity in inhibiting QS-depedent phenomenon such as violacein pigment production in Chromobacterium violaceum, biosurfactant production in Pseudomonas aeruginosa PAO1, swimming and swarming motility, exopolysaccharide production (EPS) and biofilm formation in Escherichia coli, Proteus mirabilis, Serratia marcescens and PAO1. RESULTS: Extract of C. spinosa showed a higher degree of anti-QS activity in a dose dependent manner without affecting the bacterial growth. At 2 mg/mL, this extract significantly (p <=0.005) inhibited the biofilm formation to 79, 75, 73, 70% and EPS production to 58, 46, 66 and 67% in S. marcescens, PAO1, E. coli and P. mirabilis, respectively. It also exhibited inhibition in swimming and swarming motility of bacterial pathogens. The non-enzymatic nature of the anti-QS compound in C. spinosa was confirmed by proteinase K and heat treatment. CONCLUSIONS: Because the methanolic extract of C. spinosa demonstrated anti-QS and antibiofilm activity at 0.5-2 mg/mL, it could be further exploited for novel molecules to treat the emerging infections of antibiotic resistant bacterial pathogens. PMID- 22222493 TI - Antiangiogenic-induced hypertension: the molecular basis of signaling network. AB - PROBLEM: Preeclampsia, a pregnancy-related hypertensive disorder, is one of the leading causes of fetal and maternal death globally. Angiogenic factors including vascular endothelial growth factor (VEGF) are involved in the formation of new blood vessels required for placental development and function. The hallmark of preeclampsia is similar to the toxicities related to antiangiogenesis therapy. VEGF inhibitors or antagonists promote vasoconstriction, hypertension and proteinuria. VEGF plays a role in attenuating hypertension and improving kidney damage in an animal model; however, the mechanisms underlying this effect remain poorly defined. The aim of this paper is to summarize recent advances in VEGF mediated signaling and the target molecules, and provide new insights into treatment strategies for preeclampsia. METHOD OF STUDY: This article reviews the English-language literature for pathogenesis of preeclampsia based on VEGF signaling and hypertension. RESULTS: VEGF activates downstream signaling molecules, including Ca(2+)/CAMKK, Rac1/NOX, ROS/ERK, Ezrin/Calpain/PI3K/Akt, PLCgamma/PKC and Src/HSP90. Among these signalings, important pathways for receptor-triggered intracellular signaling are (1) the PI3K/Akt-dependent, (2) the PLCgamma-dependent and (3) the ERK/Egr-1-dependent pathway. VEGF is closely involved in receptor-activated signaling events, leading to eNOS-dependent NO synthesis and eNOS-independent endothelial cell proliferation, respectively, and thus modulates vasoactive function and angiogenic response. CONCLUSION: This review highlights the potential role of NO in vasodilation, while stress-related ERK activation might act to strengthen angiogenesis, migration and proliferation. We discuss the similarity between preeclampsia and VEGF-targeted therapy-induced hypertension. PMID- 22222492 TI - Lower serum paraoxonase-1 activity is related to linoleic and docosahexanoic fatty acids in type 2 diabetic patients. AB - BACKGROUND: Serum paraoxonase-1(PON-1) activity is decreased in clinical conditions associated with low high-density lipoprotein cholesterol (HDL-C), increased lipid peroxidation and low-grade chronic inflammation, as in type 2 diabetes mellitus (T2DM). Until now there are no data about the association of any fatty acid (FA) with PON-1 activity in T2DM. METHODS: Twenty patients with T2DM and 16 healthy controls were included in this cross-sectional study. Serum PON-1 activity, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activity as well as plasma glucose, HbA1c, lipids, high-sensitivity C-reactive protein (hs-CRP) and insulin resistance, homeostasis model assessment (HOMA-IR) were measured. The preparation of FA methyl esters and their gas chromatography (GC) analysis were also performed. RESULTS: HbA1c, plasma insulin, HOMA-IR and triglycerides were higher in patients with T2DM, whereas HDL-C was lower in those subjects. Levels of pro-oxidative enzyme malondialdehyde (MDA) and hs-CRP were significantly higher, and anti-oxidative enzymes SOD and PON-1 activity were decreased in T2DM patients. N-6 PUFAs were higher in T2DM patients, particularly linoleic acid (LA, 18:2 n-6) and arachidonic acid (AA, 20:4 n-6), whereas n-3 PUFA, docosahexaenoic acid (DHA, 22:6 n-3) was lower in T2DM patients. Using regression analysis, we have shown that only LA and DHA independently predicted PON-1 activity of all participants, particularly in patients with T2DM. CONCLUSIONS: Decreased serum PON-1 activity may, in part, be influenced by higher levels of LA and lower levels of DHA in patients with T2DM. Prospective, randomized studies are necessary to confirm these preliminary findings. PMID- 22222494 TI - Tactile feedback plays a critical role in maximum finger force production. AB - This study investigates the role of cutaneous feedback on maximum voluntary force (MVF), finger force deficit (FD) and finger independence (FI). FD was calculated as the difference between the sum of maximal individual finger forces during single-finger pressing tasks and the maximal force produced by those fingers during an all-finger pressing task. FI was calculated as the average non-task finger forces normalized by the task-finger forces and subtracted from 100 percent. Twenty young healthy right-handed males participated in the study. Cutaneous feedback was removed by administering ring block digital anesthesia on the 2nd, 3rd, 4th and 5th digits of the right hands. Subjects were asked to press force sensors with maximal effort using individual digits as well as all four digits together, with and without cutaneous feedback. Results from the study showed a 25% decrease in MVF for the individual fingers as well as all the four fingers pressing together after the removal of cutaneous feedback. Additionally, more than 100% increase in FD after the removal of cutaneous feedback was observed in the middle and ring fingers. No changes in FI values were observed between the two conditions. Results of this study suggest that the central nervous system utilizes cutaneous feedback and the feedback mechanism plays a critical role in maximal voluntary force production by the hand digits. PMID- 22222495 TI - Citizens' obligation to obey the law: an empirical study of Guangzhou, China. AB - For thousands of years, China primarily used morality for its social control. Since its economic reform starting in 1978, China has moved toward legal control. Two fundamental questions, however, remain understudied in China: (a) the degree to which citizens feel obligated to obey the law and (b) the sources of citizens' perceived obligation to obey the law. This study was intended to answer these questions based on random surveys of 1,196 residents from Guangzhou, China. The study revealed that the vast majority of citizens in Guangzhou felt obligated to obey the law irrespective of their personal feelings. Normative and instrumental perspectives were important sources of Guangzhou citizens' perceived obligation to obey the law. In addition, Guangzhou citizens' perception of obligation to obey the law was related to not only individual-level variables but also neighborhood contextual factors. PMID- 22222496 TI - Heterologous expression of pneumococcal virulence factor PspC on the surface of Lactococcus lactis confers adhesive properties. AB - Lactococcus lactis is a non-pathogenic bacterium that is used in the food industry but is also used as a heterologous host to reveal protein functions of pathogenic bacteria. The adhesin PspC from Streptococcus pneumoniae is a choline binding protein that is non-covalently anchored to the bacterial cell wall. To assess the exclusive impact of pneumococcal surface protein C (PspC) on the interplay with its host we generated recombinant L. lactis producing a nisin inducible and covalently anchored variant of PspC on the lactococcal cell surface. A translational fusion of the 5'-end of pspC3.4 with the 3'-end of hic (pspC11.4) was designed to decorate the surface of L. lactis with a chimeric PspC. The PspC3.4 part comprises the first 281 aa residues of PspC3.4, while the Hic sequence consists of the proline-rich and sortase-anchored domain. The results demonstrated that PspC is sufficient for adhesion and subsequent invasion of host epithelial cells expressing the human polymeric Ig receptor (hpIgR). Moreover, invasion via hpIgR was even more pronounced when the chimeric PspC was produced by lactococci compared with pneumococci. This study shows also for the first time that PspC plays no significant role during phagocytosis by macrophages. In contrast, recruitment of Factor H via the PspC chimer has a dramatic effect on phagocytosis of recombinant but not wild-type lactococci, as Factor H interacts specifically with the amino-terminal part of PspC and mediates the contact with phagocytes. Furthermore, L. lactis expressing PspC increased intracellular calcium levels in pIgR-expressing epithelial cells, thus resembling the effect of pneumococci, which induced release of Ca(2+) from intracellular stores via the PspC-pIgR mechanism. In conclusion, expression of the chimeric PspC confers adhesive properties to L. lactis and indicates the potential of L. lactis as a suitable host to study the impact of individual bacterial factors on their capacity to interfere with the host and manipulate eukaryotic epithelial cells. PMID- 22222498 TI - Fis regulates the competitiveness of Pseudomonas putida on barley roots by inducing biofilm formation. AB - An important link between the environment and the physiological state of bacteria is the regulation of the transcription of a large number of genes by global transcription factors. One of the global regulators, Fis (factor for inversion stimulation), is well studied in Escherichia coli, but the role of this protein in pseudomonads has only been examined briefly. According to studies in Enterobacteriaceae, Fis regulates positively the flagellar movement of bacteria. In pseudomonads, flagellar movement is an important trait for the colonization of plant roots. Therefore we were interested in the role of the Fis protein in Pseudomonas putida, especially the possible regulation of the colonization of plant roots. We observed that Fis reduced the migration of P. putida onto the apices of barley roots and thereby the competitiveness of bacteria on the roots. Moreover, we observed that overexpression of Fis drastically reduced swimming motility and facilitated P. putida biofilm formation, which could be the reason for the decreased migration of bacteria onto the root apices. It is possible that the elevated expression of Fis is important in the adaptation of P. putida during colonization of plant roots by promoting biofilm formation when the migration of bacteria is no longer favoured. PMID- 22222497 TI - Manganese transporters Yfe and MntH are Fur-regulated and important for the virulence of Yersinia pestis. AB - Yersinia pestis has a flea-mammal-flea transmission cycle, and is a zoonotic pathogen that causes the systemic diseases bubonic and septicaemic plague in rodents and humans, as well as pneumonic plague in humans and non-human primates. Bubonic and pneumonic plague are quite different diseases that result from different routes of infection. Manganese (Mn) acquisition is critical for the growth and pathogenesis of a number of bacteria. The Yfe/Sit and/or MntH systems are the two prominent Mn transporters in Gram-negative bacteria. Previously we showed that the Y. pestis Yfe system transports Fe and Mn. Here we demonstrate that a mutation in yfe or mntH did not significantly affect in vitro aerobic growth under Mn-deficient conditions. A yfe mntH double mutant did exhibit a moderate growth defect which was alleviated by supplementation with Mn. No short term energy-dependent uptake of (54)Mn was observed in this double mutant. Like the yfeA promoter, the mntH promoter was repressed by both Mn and Fe via Fur. Sequences upstream of the Fur binding sequence in the yfeA promoter converted an iron-repressible promoter to one that is also repressed by Mn and Fe. To our knowledge, this is the first report identifying cis promoter elements needed to alter cation specificities involved in transcriptional repression. Finally, the Y. pestis yfe mntH double mutant had an ~133-fold loss of virulence in a mouse model of bubonic plague but no virulence loss in the pneumonic plague model. This suggests that Mn availability, bacterial Mn requirements or Mn transporters used by Y. pestis are different in the lungs (pneumonic plague) compared with systemic disease. PMID- 22222499 TI - Pathogenic Naegleria fowleri and non-pathogenic Naegleria lovaniensis exhibit differential adhesion to, and invasion of, extracellular matrix proteins. AB - Naegleria fowleri and Naegleria lovaniensis are closely related free-living amoebae found in the environment. N. fowleri causes primary amoebic meningoencephalitis (PAM), a rapidly fatal disease of the central nervous system, while N. lovaniensis is non-pathogenic. N. fowleri infection occurs when the amoebae access the nasal passages, attach to the nasal mucosa and its epithelial lining, and migrate to the brain. This process involves interaction with components of the host extracellular matrix (ECM). Since the ability to invade tissues can be a characteristic that distinguishes pathogenic from non-pathogenic amoebae, the objective of this study was to assess adhesion to, and invasion of, the ECM by these two related but distinct Naegleria species. N. fowleri exhibited a higher level of adhesion to the ECM components laminin-1, fibronectin and collagen I. Scanning electron microscopy revealed that N. fowleri attached on ECM substrata exhibited a spread-out appearance that included the presence of focal adhesion-like structures. Western immunoblotting revealed two integrin-like proteins for both species, but one of these, with a molecular mass of approximately 70 kDa, was detected at a higher level in N. fowleri. Confocal microscopy indicated that the integrin-like proteins co-localized to the focal adhesion-like structures. Furthermore, anti-integrin antibody decreased adhesion of N. fowleri to ECM components. Finally, N. fowleri disrupted 3D ECM scaffolds, while N. lovaniensis had a minimal effect. Collectively, these results indicate a distinction in adhesion to, and invasion of, ECM proteins between N. fowleri and N. lovaniensis. PMID- 22222500 TI - Phenotypic comparison of samdc and spe mutants reveals complex relationships of polyamine metabolism in Ustilago maydis. AB - Synthesis of spermidine involves the action of two enzymes, spermidine synthase (Spe) and S-adenosylmethionine decarboxylase (Samdc). Previously we cloned and disrupted the gene encoding Spe as a first approach to unravel the biological function of spermidine in Ustilago maydis. With this background, the present study was designed to provide a better understanding of the role played by Samdc in the regulation of the synthesis of this polyamine. With this aim we proceeded to isolate and delete the gene encoding Samdc from U. maydis, and made a comparative analysis of the phenotypes of samdc and spe mutants. Both spe and samdc mutants behaved as spermidine auxotrophs, and were more sensitive than the wild-type strain to different stress conditions. However, the two mutants displayed significant differences: in contrast to spe mutants, samdc mutants were more sensitive to LiCl stress, high spermidine concentrations counteracted their dimorphic deficiency, and they were completely avirulent. It is suggested that these differences are possibly related to differences in exogenous spermidine uptake or the differential location of the respective enzymes in the cell. Alternatively, since samdc mutants accumulate higher levels of S adenosylmethionine (SAM), whereas spe mutants accumulate decarboxylated SAM, the known opposite roles of these metabolites in the processes of methylation and differentiation offer an additional attractive hypothesis to explain the phenotypic differences of the two mutants, and provide insights into the additional roles of polyamine metabolism in the physiology of the cell. PMID- 22222501 TI - Promoter characterization and genomic organization of the human X11beta gene APBA2. AB - Overexpression of neuronal adaptor protein X11beta has been shown to decrease the production of amyloid-beta, a toxic peptide deposited in Alzheimer's disease brains. Therefore, manipulation of the X11beta level may represent a potential therapeutic strategy for Alzheimer's disease. As X11beta expression can be regulated at the transcription level, we determined the genomic organization and the promoter of the human X11beta gene, amyloid beta A4 precursor protein-binding family A member 2 (APBA2). By RNA ligase-mediated rapid amplification of cDNA ends, a single APBA2 transcription start site and the complete sequence of exon 1 were identified. The APBA2 promoter was located upstream of exon 1 and was more active in neurons. The core promoter contains several CpG dinucleotides, and was strongly suppressed by DNA methylation. In addition, mutagenesis analysis revealed a putative Pax5-binding site within the promoter. Together, APBA2 contains a potent neuronal promoter whose activity may be regulated by DNA methylation and Pax5. PMID- 22222502 TI - Altered insula activation in anticipation of changing emotional states: neural mechanisms underlying cognitive flexibility in Special Operations Forces personnel. AB - Individuals who perform optimally in extreme conditions, such as elite military warriors, can provide valuable insight into the neurobehavioral mechanisms underlying extraordinary performance. In the current study, we examined the degree to which Navy SEALs, when compared with healthy volunteers, could show more right anterior insula activation when shifting from anticipating one emotion to another during functional MRI. Consistent with our hypothesis, SEALs showed attenuated insula activation to negative image relative to positive image anticipation and greater right anterior insula activation during affective set shifting. These findings suggest that elite warriors show combined (a) minimal reactivity during negative stimuli and (b) an enhanced ability to efficiently change their physiological state. These neural changes may underlie their ability to perform well in stressful situations. PMID- 22222503 TI - Lentivirus shRNA Grb10 targeting the pancreas induces apoptosis and improved glucose tolerance due to decreased plasma glucagon levels. AB - AIMS/HYPOTHESIS: The physiological significance of growth factor receptor-bound protein-10 (GRB10) in the pancreas is unclear. We hypothesised that GRB10 is involved in pancreatic apoptosis, as GRB10 binds with a family of cell-survival related proteins implicated in apoptosis. METHODS: Lentiviral vector small hairpin RNA (shRNA) targeting Grb10 was injected in vivo via an intraductal pancreatic route to target pancreatic tissues in adult mice, which were studied 2 weeks post-injection. RESULTS: Using the TUNEL assay, we demonstrated for the first time that in vivo injection of lentivirus shRNA Grb10 directly into the adult mouse pancreas induced apoptosis in both exocrine and endocrine (alpha and beta) cells. This effect was more pronounced in alpha cells. Levels of the pro apoptotic protein BCL2-interacting mediator of cell death (BIM) in islets was higher in lentivirus shRNA Grb10 than in lentivirus shRNA scramble mice. In the apoptotic pathway, BIM initiates apoptosis signalling, leading to activation of the caspase cascade. We propose that, when complexed with GRB10, BIM is inactive. On activation by stress signalling or, in the present study, following injection of lentivirus shRNA Grb10 into pancreas, BIM becomes unbound from GRB10 and activates the caspase cascade. Indeed, caspase-3 activity in islets was higher in the experimental than in the control group. Apoptosis induced by shRNA Grb10 resulted in a 34% decrease in fasting plasma glucagon. Mice injected with shRNA Grb10 had improved glucose tolerance despite reduced insulin secretion compared with shRNA scramble control mice. CONCLUSIONS/INTERPRETATION: GRB10 is critically involved in alpha cell survival and, as a result, plays an important role in regulating basal glucagon secretion and glucose tolerance in adult mice. PMID- 22222504 TI - Insulin glargine and risk of cancer: a cohort study in the French National Healthcare Insurance Database. AB - AIMS/HYPOTHESIS: Using the Echantillon Generaliste de Beneficiaires: random 1/97 permanent sample of the French national healthcare insurance system database (EGB), we investigated whether, as previously suspected, the risk of cancer in insulin glargine (A21Gly,B31Arg,B32Arg human insulin) users is higher than in human insulin users. The investigation period was from 1 January 2003 to 30 June 2010. METHODS: We used Cox proportional hazards time-dependent models that were stratified on propensity score quartiles for use of insulin glargine vs human insulin, and adjusted for insulin, biguanide and sulfonylurea possession rates to assess the risk of cancer or death in all or incident exclusive or predominant (>= 80% use time) users of insulin glargine compared with equivalent human insulin users. RESULTS: Only type 2 diabetic patients were studied. Exposure rates varied from 2,273 and 614 patient-years for incident exclusive users of insulin glargine or human insulin, respectively, to 3125 and 2341 patient-years for all patients predominantly using insulin glargine or human insulin, respectively. All-type cancer HRs with insulin glargine vs human insulin ranged from 0.59 (95% CI 0.28, 1.25) in incident exclusive users to 0.58 (95% CI 0.34, 1.01) in all predominant users. Cancer risk increased with exposure to insulin or sulfonylureas in these patients. Adjusted HRs for death or cancer associated with insulin glargine compared with human insulin ranged from 0.58 (95% CI 0.32, 1.06) to 0.56 (95% CI 0.36, 0.87). CONCLUSIONS/INTERPRETATION: There was no excess risk of cancer in type 2 diabetic patients on insulin glargine alone compared with those on human insulin alone. The overall risk of death or cancer in patients on insulin glargine was about half that of patients on human insulin, thereby excluding a competitive risk bias. PMID- 22222505 TI - Request for clarification from Ruiter et al regarding 'Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study'. PMID- 22222506 TI - Women develop diabetes at higher BMIs than men. PMID- 22222507 TI - Optimization model for UV-riboflavin corneal cross-linking. AB - PURPOSE: To develop a theoretical model for riboflavin ultraviolet-A cross linking treatment that can predict the increase in stiffness of the corneal tissue as a function of the ultraviolet intensity and riboflavin concentration distribution, as well as the treatment time. METHODS: A theoretical model for calculating the increase in corneal cross-linking (polymerization rate) was derived using Fick's second law of diffusion, Lambert-Beer's law of light absorption, and a photopolymerization rate equation. Stress-strain experiments to determine Young's modulus at 5% strain were performed on 43 sets of paired porcine corneal strips at different intensities (3-7 mW/cm2) and different riboflavin concentrations (0.0%-0.5%). The experimental results for Young's modulus increase were correlated with the simulated polymerization increase to determine a relationship between the model and the experimental data. RESULTS: This model allows the calculation of the one-dimensional spatial and temporal intensity and concentration distribution. The total absorbed radiant exposure, defined by intensity, concentration distribution, and treatment time, shows a linear correlation with the measured stiffness increase from which a threshold value of 1.7 J/cm2 can be determined. The relative stiffness increase shows a linear correlation with the theoretical polymer increase per depth of tissue, as calculated by the model. CONCLUSIONS: This theoretical model predicts the spatial distribution of increased stiffness by corneal cross-linking and, as such, can be used to customize treatment, according to the patient's corneal thickness and medical indication. PMID- 22222508 TI - Choroidal changes associated with reticular pseudodrusen. AB - PURPOSE: To analyze choroidal changes associated with reticular pseudodrusen by indocyanine green angiography (ICGA) and enhanced depth imaging spectral-domain optical coherence tomography (EDI SD-OCT). METHODS: Twenty-two consecutive patients (22 eyes) with reticular pseudodrusen, and without medium/large drusen, underwent ICGA and EDI OCT. Twenty-one age- and sex-matched subjects (21 eyes) with early age-related macular degeneration (AMD), and without pseudodrusen, also underwent EDI OCT. RESULTS: Mean age of patients with reticular pseudodrusen and with early AMD was 82.5 +/- 0.9 and 79.3 +/- 4.4 years of age, respectively (P = 0.9), and 59.0% and 76.2% were females, respectively (P = 0.7). On ICGA, reticular patterns appeared as hypofluorescent, not overlying the large choroidal vessels. Areas of iso/hyperfluorescence on ICGA, occurring adjacently to reticular patterns, appeared on OCT as subretinal deposits. The mean subfoveal choroidal thickness was significantly reduced in the group with reticular pseudodrusen compared with that in the control group (174.6 +/- 10.1 and +241.4 +/- 16.5, respectively; P < 0.001). At all measurement points, but the 3000 MUm superior to the fovea, the choroidal thickness of eyes with reticular pseudodrusen appeared thinner than that of the control group. Interestingly, the choroid of eyes with reticular pseudodrusen appeared thicker at 3000 MUm superior to the fovea compared with that at all other measurement points. CONCLUSIONS: It was shown that the reticular patterns appeared as hypofluorescent lesions on ICGA, closely abutting, but not overlying the large choroidal vessels. In eyes with reticular pseudodrusen, EDI OCT revealed an overall thinned choroid. PMID- 22222509 TI - Transsynaptic retinal degeneration in optic neuropathies: optical coherence tomography study. AB - PURPOSE: Recently demonstrated neuronal loss in the inner nuclear layer of the retina in multiple sclerosis (MS) and glaucoma raises the question of a primary (possibly immune-mediated) or secondary (transsynaptic) mechanism of retinal damage in these diseases. In the present study we used optical coherence tomography to investigate retrograde retinal transsynaptic degeneration in patients with long-standing and severe loss of ganglion cells due to optic neuropathy. METHODS: Fifteen eyes of glaucoma patients with visual field defect limited to upper hemifield and 15 eyes of MS patients with previous episode of optic neuritis (ON) and extensive loss of ganglion cells were imaged using spectral-domain optical coherence tomography and compared with two groups of age matched controls. Combined retinal ganglion cell layer/inner plexiform layer (GCL/IPL) thickness and inner nuclear layer (INL) thickness were analyzed. RESULTS: In the glaucoma group there was a significant (P = 0.0005) reduction of GCL/IPL thickness in the lower (affected) retina compared with normal controls; however INL thickness was not statistically reduced (P = 0.49). In the MS group reduction of GCL/IPL thickness in both hemifields of ON eyes was also significant (P = 0.0001 and P < 0.0001 for inferior and superior retina respectively). However, similar to the glaucomatous eyes, there was no significant reduction of INL thickness in both hemifields (P = 0.25 and P = 0.45). CONCLUSIONS: This study demonstrates no significant loss of INL thickness in parts of the retina with long-standing and severe loss of retinal ganglion cells. PMID- 22222510 TI - Amniotic membrane induces peroxisome proliferator-activated receptor-gamma positive alternatively activated macrophages. AB - PURPOSE: Amniotic membrane transplantation (AMT) reportedly improves herpetic stromal keratitis (HSK). Here we studied the role of the amniotic membrane (AM) on macrophages. METHODS: BALB/c mice with necrotizing HSK received an AMT or tarsorrhaphy (TAR) as control. Apoptosis of F4/80+ cells was determined using the annexinV/7-AAD system. Macrophage invasion was determined using a cornea invasion assay. Cytokine secretion was quantified by ELISA. Arginase activity was measured by bioassay. Expression of nuclear factor (NF)-kappaB or peroxisome proliferator activated receptor (PPAR)-gamma related proteins was detected by Western blot analysis, and the expression of costimulatory surface molecules or PPAR-gamma by flow cytometry. Lipid accumulation was observed by Oil red O and Sudan B staining. RESULTS: After AMT apoptotic features of corneal macrophages, but also macrophage invasion increased. IL-6, IL-10, IL-12, TNF-alpha, and NF-kappaB content in HSK corneas had decreased with AMT. AMT increased expression of PPAR gamma, arginase 1 and 2, and arginase activity in AM-treated HSK corneas. In vitro, NF-kappaB, cytokine production, costimulatory molecules (CD80, CD86, CD40), phagocytic capacity, proliferation, viability, and accessory function to herpes simplex virus (HSV)-1 specific draining lymph node (DLN) cells were reduced in bone marrow derived macrophages (BM) cocultured with AM, while CD206, CD204, CD163, and CD68, lipid accumulation in the cytoplasm, PPAR-gamma expression, and arginase activity was increased. An increase in viability and proliferation was observed in the presence of AM combined with apoptotic cells, compared with AM alone. CONCLUSIONS: Based on these results it can be concluded that the action mechanism of AM is associated with modulation of classically activated macrophages into alternatively activated macrophages or macrophage cell death, probably by engaging lipid metabolism and activating the PPAR-gamma pathway, consequently curtailing effector T cell functions. Apoptotic cells induced in the environment with AM support the presence and survival of such macrophages. PMID- 22222511 TI - Interactive effects of ATOH7 and RFTN1 in association with adult-onset primary open-angle glaucoma. AB - PURPOSE: Genome-wide association studies have shown association of the atonal homolog 7 (ATOH7) and raftlin lipid raft linker 1 (RFTN1) genes with glaucoma related optic disc parameters. ATOH7 and RFTN1 sequence variations were investigated in patients with primary open-angle glaucoma (POAG) and their relationships with vertical cup-to-disc ratio (VCDR) and central corneal thickness (CCT) were determined. METHODS: In 289 unrelated controls and 142 patients with adult-onset POAG, including 117 with high-tension glaucoma (HTG) and 25 with normal-tension glaucoma (NTG), the single exon of ATOH7 was sequenced by direct sequencing. Additional single-nucleotide polymorphisms (SNP) at upstream ATOH7 (rs1900004 and rs3858145) and an RFTN1 SNP (rs690037) were genotyped. Quantitative trait and disease associations were analyzed by linear and logistic regression respectively, controlling for sex and age. RESULTS: ATOH7 rs61854782 was associated with VCDR (P = 0.004) in controls and RFTN1 rs690037 was associated with CCT in combined POAG (HTG+NTG; P = 0.026). No coding mutation was detected in POAG, and no SNP was associated with POAG (P between 0.441 and 0.996). However, ATOH7 rs3858145 showed significant interaction with RFTN1 rs690037 in NTG and combined POAG (P = 0.026 and 0.013 respectively). ATOH7 rs3858145 GG combined with RFTN1 rs690037 TT conferred risk for glaucoma in HTG, NTG, and combined POAG (odds ratio = 2.11, 8.44, and 2.69, respectively). CONCLUSIONS: Coding mutations of ATOH7 were unlikely to be involved in POAG. But combination of ATOH7 and RFTN1 SNPs increased risk to POAG, indicating their diversified effects in the complex genetics of glaucoma. PMID- 22222512 TI - Development and pilot testing of a parent education intervention for type 1 diabetes: parent education through simulation-diabetes. AB - PURPOSE: To purpose of the pilot study was to evaluate the use of a pediatric human patient simulator (HPS) to teach parents diabetes management for their children newly diagnosed with type 1 diabetes, referred to as Parent Education Through Simulation-Diabetes. METHODS: A focus group study and 2 pilot studies (1 group study and a randomized 2-group study) were used to develop and test a teaching intervention. Parents were recruited from the Pediatric Diabetes Clinic at UMass Memorial Medical Center. A brainstorming group (n = 6) discussed the simulator concept and what modifications would be necessary to enhance parent teaching; the authors also developed the initial hypoglycemia and hyperglycemia teaching vignettes. Two focus groups (n = 13) discussed the acceptance of using a simulator and the timing and content of the teaching sessions. Based on their recommendations, a 1-group pretest-posttest pilot was conducted with parents (n = 10) receiving hypoglycemia education enhanced with the HPS, followed by a randomized 2-group pilot study (n = 16). Findings The focus group participants enthusiastically supported the use of the pediatric HPS after diagnosis and made recommendations for the timing and content of the teaching sessions. Major findings from the pilot work included (1) successful recruitment of 16 participants from only 1 site within 6 weeks, (2) instrument reliability demonstrated for all scales, and (3) mean change from baseline in the predicted direction for all measures. CONCLUSIONS: The HPS has the potential of providing parents an innovative means of learning diabetes management through visualization during the early months after diagnosis and so warrants a powered study to determine its efficacy. PMID- 22222513 TI - Getting under the skin of clinical inertia in insulin initiation: the Translating Research Into Action for Diabetes (TRIAD) Insulin Starts Project. AB - PURPOSE: The purpose of this cross-sectional study is to explore primary care providers' (PCPs) perceptions about barriers to initiating insulin among patients. Studies suggest that many patients with poorly controlled type 2 diabetes do not receive insulin initiation by PCPs. METHODS: As part of the Translating Research Into Action for Diabetes study, the authors conducted structured interviews in health systems in Indiana, New Jersey, and California, asking PCPs about the importance of insulin initiation and factors affecting this decision. The authors calculated proportions choosing each multiple-choice response option and listed the most frequently offered open-ended response categories. RESULTS: Among 83 PCPs, 45% were women; 60% were white; and they averaged 13.4 years in practice. Four-fifths of PCPs endorsed guideline concordant glycemic targets, but 54% individualized targets based on patient age, life expectancy, medical comorbidities, self-management capacity, and willingness. Most (64%) reported that many patients were resistant to new oral or insulin therapies due to fears about the therapy and what it meant about their disease progression. Two-thirds (64%) cited patient resistance as a barrier to insulin initiation, and 43% cited problems with patient self-management, including cognitive or mental health issues, dexterity, or ability to adhere. Eighty percent felt that patient nonadherence would dissuade them from initiating insulin at least some of the time. CONCLUSIONS: PCPs perceived that patient resistance and poor self- management skills were significant barriers to initiating insulin. Future studies should investigate whether systems-level interventions to improve patient-provider communication about insulin and enhance providers' perceptions of patient self-management capacity can increase guideline concordant, patient-centered insulin initiation. PMID- 22222514 TI - Unmet needs for social support and effects on diabetes self-care activities in Korean Americans with type 2 diabetes. AB - OBJECTIVE: The purpose of this study was (1) to characterize the primary sources of social support and the extent of unmet needs for support (defined as the gap between social support needs and the receipt of social support) in a sample of Korean Americans (KAs) with type 2 diabetes and (2) to examine the effect of unmet needs for support on their self-care activities. METHODS: Baseline data obtained from a community-based intervention trial were used for this study of 83 middle-aged KAs with type 2 diabetes. Study design and data analysis were guided by social cognitive theory. The key variables were dictated the order of the variables in multivariate regression analysis. RESULTS: Our findings indicated that for diabetic KAs, the primary source of social support differed according to gender. Unmet needs for support were significantly associated with self-care activities, but the amount of support needs and of social support received were not. Multivariate analysis also confirmed that unmet needs for social support are a significant strong predictor of inadequate type 2 diabetes self-care activities, after controlling for other covariates. The hierarchical regression model explained about 30% of total variance in self-care activities. CONCLUSIONS: The findings highlight the importance of considering unmet needs for social support when addressing self-care activities in type 2 diabetes patients. Future interventions should focus on filling gaps in social support and tailoring approaches according to key determinants, such as gender or education level, to improve self-care activities in the context of type 2 diabetes care. PMID- 22222516 TI - Use of whole embryo culture for studying heart development. AB - Congenital heart defects occur in approximately 1% of newborns and are a major cause of morbidity and mortality in infants and children. Many adult cardiac diseases also have developmental basis, such as heart valve malformations, among others. Therefore, dissecting the developmental and molecular mechanisms underlying such defects in embryos is of great importance in prevention and developing therapeutics for heart diseases that manifest in infants or later in adults. Whole embryo culture is a valuable tool to study cardiac development in midgestation embryos, in which ventricular chambers are specified and expand, and the myocardium and endocardium interact to form various cardiac structures including heart valves and trabecular myocardium (Cell 118: 649-663, 2004; Dev Cell 14: 298-311, 2008). This technique is essentially growing a midgestation embryo ex utero in a test tube. One of the strengths of embryo culture is that it allows an investigator to easily manipulate or add drugs/chemicals directly to the embryos to test specific hypotheses in situations that are otherwise very difficult to perform for embryos in utero. For instance, embryo culture permits pharmacological rescue experiments to be performed in place of genetic rescue experiments which may require generation of specific mouse strains and crosses. Furthermore, because embryos are grown externally, drugs are directly acting on the cultured embryos rather than being degraded through maternal circulation or excluded from the embryos by the placenta. Drug dosage and kinetics are therefore easier to control with embryo culture. Conversely, drugs that compromise the placental function and are thus unusable for in utero experiments are applicable in cultured embryos since placental function is not required in whole embryo culture. The applications of whole embryo culture in the studies of molecular pathways involved in heart valve formation, myocardial growth, differentiation, and morphogenesis are demonstrated previously (Cell 118: 649-663, 2004; Dev Cell 14: 298-311, 2008; Nature 446: 62-67, 2010). Here we describe a method of embryo culture in a common laboratory setting without using special equipments. PMID- 22222515 TI - Inhibition of cell survival, viability and proliferation by dentin adhesives after direct and indirect exposure in vitro. AB - OBJECTIVES: The influence of dentin adhesive systems (Scotchbond Multi-Purpose, XP Bond, Xeno V, Clearfil Protect Bond, AdheSE) on cell survival, viability and proliferation was characterized after direct and indirect exposure using different cell culture techniques. MATERIALS AND METHODS: The primers and cured bonding parts were directly exposed to cells using cell culture inserts, and complete materials were analyzed in a dentin barrier test. Cell responses were examined in 3T3 mouse fibroblasts after 24- and 72-h exposure periods by the estimation of total cell numbers (survival), apoptosis (viability) and cell proliferation. RESULTS: Cell numbers were effectively reduced by the primers of AdheSE, Protect Bond, and Scotchbond Multi-Purpose as well as XP bond after direct exposure in a cell culture insert test device. Likewise, Scotchbond Multi Purpose primer induced a rate of apoptosis (93.9%) even higher than detected with Protect Bond primer (91.6%). Cell proliferation was entirely inhibited by primers and by Xp Bond as well. The Scotchbond Multi-Purpose was most cytotoxic in a dentin barrier test device after a 24-h indirect exposure. It also increased the percentage of cells in apoptosis to 15.4% compared to untreated controls. CONCLUSION: Unpolymerized primers of dentin adhesives were more cytotoxic than polymerized bonding counterparts. Moreover, total etch dentin adhesives were more cytotoxic than self-etch adhesives. CLINICAL RELEVANCE: When dentin adhesives are used in deep cavities without a protective dentin barrier the leachable hydrophobic and hydrophilic component of dentin adhesive systems can penetrate to the pulp and may induce cytotoxic responses in pulp tissues. PMID- 22222517 TI - Quantifying cardiac functions in embryonic and adult zebrafish. AB - Zebrafish embryos have been extensively used to study heart development and cardiac function, mainly due to the unique embryology and genetics of this model organism. Since most human heart disease occurs during adulthood, adult zebrafish models of heart disease are being created to dissect mechanisms of the disease and discover novel therapies. However, due to its small heart size, the use of cardiac functional assays in the adult zebrafish has been limited. To address this bottleneck, the transparent fish line casper;Tg(cmlc2:nuDsRed) that has a red fluorescent heart can be used to document beating hearts in vivo and to quantify cardiac functions in adult zebrafish. Here, we describe our methods for quantifying shortening fraction and heart rate in embryonic zebrafish, as well as in the juvenile and adult casper;Tg(cmlc2:nuDsRed) fish. In addition, we describe the red blood cell flow rate assay that can be used to reflect cardiac function indirectly in zebrafish at any stage. PMID- 22222518 TI - Analysis of the patterning of cardiac outflow tract and great arteries with angiography and vascular casting. AB - Formation of the cardiac outflow tract and great arteries involves complex morphogenetic processes, whose abnormities result in several clinically important diseases. Studies of these developmental processes are therefore important for understanding congenital vascular defects. However, the three-dimensional structure of arteries makes it challenging to analyze the pattern of vasculature using conventional histological approaches. Here we describe a vascular casting method to visualize the branching and connections of great arteries in developing embryos as well as in adult mice. This technique can be used to study the development of cardiac outflow tract, semilunar valves, and great arteries as demonstrated previously (Circ Res, 2008; Development 135: 3577-3586, 2008). PMID- 22222519 TI - Morpholino injection in Xenopus. AB - The study of gene function in developmental biology has been significantly furthered by advances in antisense technology made in the early 2000s. This was achieved, in particular, by the introduction of morpholino (MO) oligonucleotides. The introduction of antisense MO oligonucleotides into cells enables researchers to readily reduce the levels of their protein of interest without investing huge financial or temporal resources, in both in vivo and in vitro model systems. Historically, the African clawed frog Xenopus has been used to study vertebrate embryological development, due to its ability to produce vast numbers of offspring that develop rapidly, in synchrony, and can be cultured in buffers with ease. The developmental progress of Xenopus embryos has been extensively characterized and this model organism is very easy to maintain. It is these attributes that enable MO-based knockdown strategies to be so effective in Xenopus. In this chapter, we will detail the methods of microinjecting MO oligonucleotides into early embryos of X. laevis and X. tropicalis. We will discuss how MOs can be used to prevent either pre-mRNA splicing or translation of the specific gene of interest resulting in abrogation of that gene's function and advise on what control experiments should be undertaken to verify their efficacy. PMID- 22222520 TI - Chicken chorioallantoic membrane angiogenesis model. AB - The chick embryo chorioallantoic membrane (CAM) is an extraembryonic membrane which serves as a gas exchange surface and its function is supported by a dense capillary network. Because of its extensive vascularization and easy accessibility, the CAM has been broadly used to study the morphofunctional aspects of the angiogenesis process in vivo and to investigate the efficacy and mechanisms of action of proangiogenic and antiangiogenic natural and synthetic molecules. The CAM has long been a favored system for the study of tumor angiogenesis and metastasis, because at this stage the chick immunocompetence system is not fully developed and the conditions for rejection have not been established. The CAM may also be used to verify the ability to inhibit the growth of capillaries by implanting tumors onto the CAM and by comparing tumor growth and vascularization with or without the administration of an antiangiogenic molecule. Other studies using the tumor cells/CAM model have focused on the invasion of the chorionic epithelium and the blood vessels by tumor cells. The cells invade the epithelium and the mesenchymal connective tissue below, where they are found in the form of a dense bed of blood vessels, which is a target for intravasation. PMID- 22222521 TI - Visualizing vascular networks in zebrafish: an introduction to microangiography. AB - Visualizing the circulatory pattern in developing embryos becomes an essential technique for the field of cardiovascular biology. In the zebrafish model system, there are currently several techniques available to visualize the circulatory pattern. Microangiography is a simple technique in which a fluorescent dye is injected directly into the Sinus Venosus and/or the Posterior Cardinal Vein, allowing for the rapid labeling and easy detection of patent vessels. Here, we compare microangiography to other vascular labeling techniques, describe the benefits and potential applications of microangiography, and give step by step instructions for microangiography. PMID- 22222522 TI - Whole-mount confocal microscopy for vascular branching morphogenesis. AB - We introduce a whole-mount immunohistochemistry method for analyzing intricate vascular network formation in mouse embryonic tissues. Laser scanning confocal microscopy with multiple labeling allows for robust imaging of blood and lymphatic vessel branching morphogenesis with excellent resolution. PMID- 22222523 TI - Visualization of mouse embryo angiogenesis by fluorescence-based staining. AB - The establishment of a blood vessel network is fundamental to embryonic development and plays a critical role in many diseases including coronary heart disease and cancer. Vascular endothelial cells are central players in blood vessel formation and line the inside of the entire blood vessel system. PECAM-1 is expressed in all types of endothelial cells and is therefore a useful marker for the detection of blood vessels. In this manuscript, we describe PECAM-1 staining in whole-mount and sectioned tissues in mouse embryos. PMID- 22222524 TI - Miniaturized assays of angiogenesis in vitro. AB - Assays of angiogenesis in vitro provide insights into vascular development and are useful in studies of agents that modulate blood vessel formation. This chapter describes techniques to induce angiogenesis-like sprouting from aortic and microvascular explants cultured in 3-dimensional native collagen gels. The chapter focuses on explants derived from mice and use of a miniaturized format that permits efficient utilization of reagents, ease of processing, rapid analysis, and conventional imaging. PMID- 22222525 TI - Analysis of the endocardial-to-mesenchymal transformation of heart valve development by collagen gel culture assay. AB - Malformations of heart valves are one of the most common serious congenital defects. Heart valves are developed from endocardial cushions of the heart. The endocardial cushion in early heart development consists of two cell layers: an outer myocardial cell layer and an inner endocardial cell layer with abundant extracellular matrix (cardiac jelly) in between. Endocardial cells of the cushion, triggered by signals from myocardial cells, delaminate from the surface of the endocardial cushion and undergo transdifferentiation into mesenchymal cells. This process of endocardial-to-mesenchymal transformation (EMT) begins in the atrioventricular canal at embryonic day 9 (E9) and in the cardiac outflow tract at E10 of mouse development. Once formed by the EMT, the mesenchymal cells invade the cardiac jelly, proliferate, and populate the endocardial cushion. The cellularized endocardial cushion then undergoes morphological remodeling; it lengthens and matures into a thin elongated valve leaflet. Here we describe a method to culture endocardial cushions and measure EMT ex vivo. EMT can thus be analyzed independent of other concurrent developmental defects in mice. This culture method also enables ex vivo manipulations of signaling or gene function during EMT to delineate molecular pathways essential for heart valve development. PMID- 22222526 TI - Quantification of myocyte chemotaxis: a role for FAK in regulating directional motility. AB - Formation of a fully functional four-chambered heart involves an intricate and complex series of events that includes precise spatial-temporal regulation of cell specification, proliferation, and migration. The formation of the ventricular septum during mid-gestation ensures the unidirectional flow of blood, and is necessary for postnatal viability. Notably, a majority of all congenital malformations of the cardiovascular system in humans involve septal abnormalities which afflict 1 out of 100 newborn children in the United States. Thus, a clear understanding of the precise mechanisms involved in this morphogenetic event will undoubtedly reveal important therapeutic targets. The final step in valvuloseptal morphogenesis occurs, in part, by directed movement of flanking myocytes into the cushion mesenchyme. In order to identify the molecular mechanisms that regulate this critical myocyte function, we have developed two in vitro methodologies; a transwell assay to assess population changes in motility and a single-cell tracking assay to identify signals that drive the coordinated movement of these cells. These methods have proven effective to identify focal adhesion kinase (FAK) as an intracellular component that is critical for myocyte chemotaxis. PMID- 22222527 TI - Analysis of neural crest cell fate during cardiovascular development using Cre activated lacZ/beta-galactosidase staining. AB - It is important to identify the mechanisms regulating cardiovascular development. However, complex genetic tools are often required, including transgenic animals that express the lacZ transgene encoding the beta-galactosidase enzyme under the control of a specific promoter or following recombination with the Cre recombinase. The latter can be useful for identifying specific cell populations of the developing cardiovascular system, including neural crest cells. The tracking of these cells can help clarify their fate in mutant embryos and elucidate the etiology of some congenital cardiovascular birth defects. This chapter highlights the methods used to stain embryonic tissues in whole mount or sections to detect the expression of the lacZ transgene with a focus on tracking cardiac neural crest cells using the Wnt1-Cre and R26R mouse lines. We also provide a protocol using fluorescence-activated cell sorting for collecting neural crest cells for further analysis. These protocols can be used with any embryos expressing Cre and lacZ. PMID- 22222528 TI - Indirect immunostaining on mouse embryonic heart for the detection of proliferated cardiomyocyte. AB - The heart is the first organ to form and become functional in a developing embryo and its proper function is critical for most, if not all, subsequent stages of an animal's development. The formation of the heart relies heavily upon the rapid proliferation of cardiomyocytes at a specific stage during early development, and interfering with the ability of these cells to grow during this time frame results in heart defects that include thin ventricle walls, as well as malformed ventricular septums. Thus, since cardiomyocyte proliferation represents a key step in early cardiac development and identifying the mechanisms that underlie cardiomyocyte proliferation has become an important area of study, techniques to identify and study proliferating cardiomyocytes in vivo are needed. Immunofluorescence and immunohistochemistry staining are powerful tools for studying cardiomyocyte proliferation in the developing animal. The phosphorylation of histone H3 at Ser10 (pH3) only occurs in cells undergoing mitosis, making pH3 a marker for labeling proliferating cells. In this manuscript, we described two immunostaining methods (immunofluorescence and immunohistochemistry) for detecting the pH3-positive cardiomyocytes in formalin fixed, paraffin-embedded heart tissues. PMID- 22222529 TI - Isolation and characterization of vascular endothelial cells from murine heart and lung. AB - The formation of blood vessel networks is a fundamental event in vertebrate embryo development. Angiogenesis and vasculogenesis are the essential processes in vascular formation. Endothelial cells play a key role during angiogenesis and vasculogenesis, and cultured vascular endothelial cells provide an indispensable model for exploring the molecular mechanisms of angiogenesis and vasculogenesis. In this chapter, we described a protocol using PECAM-1-coated Dynabeads for the isolation of vascular endothelial cells from mouse heart and lung. This method will provide up to 10(7) endothelial cells with high purity (>85%). The isolated endothelial cells retain their in vivo characteristics, such as the expression of the cell surface markers PECAM-1 and ICAM-2. PMID- 22222530 TI - Isolation and characterization of embryonic and adult epicardium and epicardium derived cells. AB - Epicardium is the outer cell layer of the heart. Its integrity and function are essential for normal heart development. To study the role of epicardium in both fetal and adult hearts, it is desirable to isolate and culture pure populations of these cells. Here we describe methods with Cre-loxP technology to lineage tag epicardial cells (EpiCs) and epicardium-derived cells (EPDCs), dissociate and isolate them by flow-activated cytometry sorting (FACS), and characterize them by quantitative PCR and immunostaining. This platform allows further characterization and manipulation of EpiCs and EPDCs for expression studies and functional assays. PMID- 22222531 TI - Vascular smooth muscle cells: isolation, culture, and characterization. AB - Vascular smooth muscle cells (VSMCs) are the cellular components of the normal blood vessel wall that provides structural integrity and regulates the diameter by contracting and relaxing dynamically in response to vasoactive stimuli. The differentiated state of the VSMC is characterized by specific contractile proteins, ion channels, and cell surface receptors that regulate the contractile process and are thus termed contractile cells. In addition to these normal functions, in response to injury or during development, VSMCs are responsible for the synthesis of extracellular matrix proteins, become migratory and proliferate. This phenotype has been termed synthetic cells. To better understand the mechanisms regulating these and other processes, scientists have depended on cultured cells that can be manipulated in vitro. In this chapter, we will discuss in detail the explant method for isolation of VSMC and will compare it to the enzymatic digestion method. We will also briefly describe methods for characterizing the resulting cells. PMID- 22222532 TI - C-kit expression identifies cardiac precursor cells in neonatal mice. AB - Through directed differentiation of embryonic stem cells, it has been demonstrated that mesodermal lineages in the mammalian heart (smooth muscle, endothelial, and cardiac) develop from a common, multipotent cardiovascular precursor (Dev Biol 265:262-275, 2004; Cell 127:1137-1150, 2006; Dev Cell 11:723 732, 2006). Identification of cardiovascular precursor cells at various stages of lineage commitment has been determined by expression of multiple markers, including the stem cell factor receptor c-kit. Utilizing a bacterial artificial chromosome (BAC) transgenic mouse model in which EGFP expression is placed under control of the c-kit promoter (c-kit(BAC)-EGFP), work from our laboratory indicates that c-kit expression identifies a multipotent cardiovascular precursor cell population within the early postnatal heart that can be isolated, expanded, and differentiated in vitro into all three cell lineages that specify the heart (Proc Natl Acad Sci U S A 106:1808-1813, 2009). PMID- 22222533 TI - Cardiomyocyte apoptosis in heart development: methods and protocols. AB - Apoptosis is the process of programmed cell death that has been identified in the development of heart. It is likely to be regulated by survival and death signals that are also present in many other tissues. To understand cardiomyocyte apoptosis in normal and abnormal development of heart, the cell death detection techniques were applied to various researches. These methods include morphological, histological, or molecular assays based on recent advances in our understanding of the molecular mechanism of cell death, including: (1) terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling of fragmented nuclei, (2) cardiovascular molecular imaging of apoptosis using Annexin V, and (3) immunohistochemical detection of activated caspases. PMID- 22222534 TI - Adenovirus-mediated gene transfection in the isolated lymphatic vessels. AB - The authors describe technical details of experimental protocol of gene transfection in isolated rat mesenteric lymphatic vessels (MLVs). Authors also refer to the recent publication in Microcirculation, which provides wide set of experimental evidences obtained from confocal microscopic imaging and isolated vessels functional tests, which confirmed a successful achievement of the following goals. (1) Optimization of the experimental conditions to maintain the isolated "normal" rat mesenteric vessels in culture for sufficiently long periods of time to permit effective knockdown or overexpression of selected proteins/genes. (2) Development of the effective transfection protocols for lymphatic muscle and/or endothelial cells in intact isolated rat MLVs without nonspecific impairment on lymphatic contractile function due to the transfection protocol per se. PMID- 22222535 TI - Isolation of cardiac myocytes and fibroblasts from neonatal rat pups. AB - Neonatal rat ventricular myocytes (NRVM) and fibroblasts (FBs) serve as in vitro models for studying fundamental mechanisms underlying cardiac pathologies, as well as identifying potential therapeutic targets. Both cell types are relatively easy to culture as monolayers and can be manipulated using molecular and pharmacological tools. Because NRVM cease to proliferate after birth, and FBs undergo phenotypic changes and senescence after a few passages in tissue culture, primary cultures of both cell types are required for experiments. Below we describe methods that provide good cell yield and viability of primary cultures of NRVM and FBs from 0 to 3-day-old neonatal rat pups. PMID- 22222536 TI - The application of genome-wide RNAi screens in exploring varieties of signaling transduction pathways. AB - Cardiovascular development is a precisely coordinated process at multilevels. It involves cross-talking among numerous signaling transduction pathways to ensure proper cell polarity, migration, proliferation, differentiation, and programmed death. Here, genome-wide RNA interference screens in Drosophila cells are introduced as novel approaches to discover potential regulators, with special emphases on (1) cell growth and viability, and (2) receptor tyrosine kinase and extracellular-signal-regulated kinase signaling pathway. PMID- 22222537 TI - Application of atomic force microscopy measurements on cardiovascular cells. AB - The atomic force microscope (AFM) is a state-of-the-art tool that can analyze and characterize samples on a scale from angstroms to 100 MUm by physical interaction between AFM cantilever tip and sample surface. AFM imaging has been used incrementally over last decade in living cells in cardiovascular research. Beyond its high resolution 3D imaging, AFM allows the quantitative assessments on the structure and function of the underlying cytoskeleton and cell organelles, binding probability, adhesion forces, and micromechanical properties of the cell by "sensing" the cell surface with mechanical sharp cantilever tip. AFM measurements have enhanced our understanding of cell mechanics in normal physiological and pathological states. PMID- 22222538 TI - In utero assessment of cardiovascular function in the embryonic mouse heart using high-resolution ultrasound biomicroscopy. AB - Murine models are currently the preferred approach for studying the molecular mechanisms of cardiac dysfunction resulting from changes in gene expression. Transgenic and gene-targeting methods can be used to generate mice with altered cardiac size and function, and as a result, in vivo techniques are indispensible in evaluating cardiac phenotype. Traditionally, the pathologic assessment of sacrificed hearts was used to study cardiac pathophysiology in small animals. Below we describe the use of ultrasound biomicroscopy-Doppler analysis to temporally assess cardiac function in mouse embryos. Methods are described for obtaining 2D, pulsed-wave Doppler, and M-mode imaging using standard clinical cardiac ultrasound imaging planes. PMID- 22222539 TI - Isolation and preparation of RNA from rat blood and lymphatic microvessels for use in microarray analysis. AB - DNA microarray methodologies have proven to be an indispensable tool for genome wide transcriptional profiling of organs, tissues, and cells. Here, we present a protocol for the optimized isolation and preparation of RNA from rat microvessels (including arteries, veins, and lymphatics) for subsequent use in two-color microarray analysis. The investigation of wide-ranging vessel sizes from all three vessel lineages necessitates an RNA isolation strategy that can effectively isolate high-quality RNA from varying and often very small quantities (<1 mg) of fibrous vessel tissue. Additionally, the lack of sample biomass necessitates the use of amplification strategies to generate enough RNA for use in microarray analysis. While the methods presented here were developed for use with two-color microarray analysis, the procedures and general concepts are applicable to most fluorescence-based microarray platforms. PMID- 22222540 TI - Visual data mining of coexpression data to set research priorities in cardiac development research. AB - Over the past decade, an immense amount of biomedical data have become available in the public domain due to the development of ever-more efficient screening tools such as expression microarrays. To fully leverage this important new resource, it has become imperative to develop new methodologies for mining and visualizing data to make inferences beyond the scope of the original experiments. This need motivated the development of a new freely available web-based application called StarNet ( http://vanburenlab.medicine.tamhsc.edu/starnet2.html ). Here we describe the use of StarNet, which functions primarily as a query tool that draws correlation networks centered about a gene of interest. To support inferences and the development of new hypotheses using the resulting correlation network, StarNet queries all genes in the correlation network against a database of known interactions and displays the results in a second graph and provides a statistical test of Gene Ontology term enrichment (keyword enrichment) to provide tentative summary functional annotations for the correlation network. Finally, StarNet provides additional tools for comparing networks drawn from two different selected data sets, thus providing methods for making inferences and developing new hypotheses about differential wiring for different regulatory domains. PMID- 22222541 TI - High-speed confocal imaging of zebrafish heart development. AB - Due to its optical clarity and rudimentary heart structure (i.e., single atrium and ventricle), the zebrafish provides an excellent model for studying the genetic, morphological, and functional basis of normal and pathophysiological heart development in vivo. Recent advances in high-speed confocal imaging have made it possible to capture 2D zebrafish heart wall motions with temporal and spatial resolutions sufficient to characterize the highly dynamic intravital flow structure environment. We have optimized protocols for introducing fluorescent tracer particles into the zebrafish cardiovasculature, imaging intravital heart wall motion, and performing high-resolution blood flow mapping that will be broadly useful in elucidating flow-structure relationships. PMID- 22222542 TI - Measurement of electrical conduction properties of intact embryonic murine hearts by extracellular microelectrode arrays. AB - The study of the embryonic development of the cardiac conduction system and its congenital and toxicological defects requires protocols to measure electrical conduction through the myocardium. However, available methods either lack spatial information, necessitate the hearts to be sliced and mounted, or require specialized equipment. Microelectrode arrays (MEAs) are plates with embedded surface electrodes to measure localized extracellular ionic currents (field potentials) created by the depolarization and repolarization of cultured cells and tissue slices. Here we describe a protocol using MEAs to examine electrical conduction through intact and beating cultured hearts isolated from mouse embryos at 10.5 days postcoitus. This method allows measurements of conduction time, estimates of conduction velocity, atrioventricular conduction delay and block, and heart rate and rhythmicity. PMID- 22222543 TI - First demonstration of the effectiveness of peptide receptor radionuclide therapy (PRRT) with 111In-DTPA-octreotide in a giant PRL-secreting pituitary adenoma resistant to conventional treatment. AB - In prolactin-secreting giant adenomas, cabergoline treatment is the first line approach. Surgery and/or radiotherapy are indicated when the tumour is resistant to medical treatment and continues growing, causing visual field impairment. Data concerning other therapeutic approach are scanty. Although PRL-secreting tumours may express somatostatin receptors type 2, 3 and 5, somatostatin analogs treatment is generally ineffective and peptide receptor radionuclide therapy (PRRT) has never been reported. A 58 year-old woman complaining of severe neurological symptoms caused by a giant prolactinoma, relapsing after surgery and not-responding to dopamine-agonists and octreotide LAR treatment, underwent four cycles of PRRT with 111-Indium-DTPA-octreotide with remarkable tumour shrinkage and a significant improvement in clinical conditions. No side effects were reported. This is the first report on the effectiveness and safety of PRRT with radio-labelled somatostatin analogs in a patient with aggressive giant prolactinoma resistant to conventional treatment. PMID- 22222545 TI - Quantitative nanoscale surface voltage measurement on organic semiconductor blends. AB - We report on the validation of a method based on Kelvin probe force microscopy (KPFM) able to measure the different phases and the relative work function of polymer blend heterojunctions at the nanoscale. The method does not necessitate complex ultra-high vacuum setup. The quantitative information that can be extracted from the topography and the Kelvin probe measurements is critically analysed. Surface voltage difference can be observed at the nanoscale on poly(3 hexyl-thiophene):[6,6]-phenyl-C61-butyric acid methyl ester (P3HT:PCBM) blends and dependence on the annealing condition and the regio-regularity of P3HT is observed. PMID- 22222546 TI - Assessment of left atrial dysfunction in obstructive sleep apnea patients with the two dimensional speckle-tracking echocardiography. AB - BACKGROUND: The aim of this study was to compare left atrial (LA) longutidinal myocardial function in obstructive sleep apnea (OSA) patients with healthy individuals using two-dimensional speckle-tracking echocardiography method (2D STE). METHOD: Twenty one healthy individuals and 58 OSA patients were included. According to the AHI (apnea hypopnea index) patients were examined in mild, moderate and severe OSA groups. Images of the LA were acquired from the apical two- and four-chamber views. LA strain(LA(S)) and strain rate(LA(SR)) parameters [systolic (S), early diastolic (E), late diastolic (A) during atrial contraction] were assessed. RESULTS: LA(S-S), LA(SR-S), LA(S-E) and LA(SR-E) values decreased with severity of OSA. Severe OSA patients have lower LA(S-S) and LA(SR-S) values (p < 0.03). While a difference in the LA(SR-E) value between groups was significant beginning with the moderate OSA group (p < 0.03), no LA(S-E) value differences were observed between moderate and mild OSA groups (p > 0.03). LA(S A) and LA(SR-A) values were increasing with the disease severity up to moderate OSA. LA(S-A) and LA(SR-A) values of moderate OSA were greater than the mild OSA patients and healthy individuals (p < 0.03). These were lower in severe OSA than the moderate OSA (p < 0.03), however, they were greater than the healthy individuals (p < 0.03). The AHI was found to be negatively correlated with the LA(S-S), LA(SR-S) LA(S-E), LA(SR-E), whereas AHI was not correlated with the LA(S A), LA(SR-A) values. CONCLUSION: LA remodeling and dysfunction that accompany OSA can be detected in the subclinical stage with a detailed evaluation of active and passive functions of the LA using the 2D-STE method. PMID- 22222547 TI - Prophylactic indomethacin infusion increases fractional cerebral oxygen extraction in ELBW neonates. AB - OBJECTIVE: Intraventricular hemorrhage (IVH) occurs in up to 25% of very low birth weight (VLBW) preterm neonates. Previous studies found that indomethacin administered in the first 6 h of life reduces the incidence of severe IVH in VLBW neonates and decreases cerebral blood flow, suggesting a decrease in cerebral oxygen delivery. Using near-infrared spectroscopy (NIRS), we monitored cerebral oxygenation before, during and after slow indomethacin infusion in extremely low birth weight (ELBW) neonates to determine whether indomethacin decreases cerebral oxygen saturation and increases cerebral oxygen extraction. STUDY DESIGN: Twenty seven ELBW neonates less than 30 weeks gestational age treated with indomethacin for IVH prophylaxis were monitored for arterial oxygen saturation (SaO(2)) and NIRS-determined regional cerebral oxygen saturation (rSO(2)). At 30 to 60 s intervals, SaO(2), rSO(2) and mean arterial pressure (MAP) were recorded using a VitalSync. Average fractional cerebral oxygen extraction was calculated for the hour before indomethacin infusion, during the infusion and 2 h after infusion. RESULT: Fractional cerebral oxygen extraction increased from baseline after indomethacin administration from 0.23+/-0.11 to 0.25+/-0.10 (P=0.034). CONCLUSION: Fractional cerebral oxygen extraction increased 9% with indomethacin 0.1 mg kg(-1) given over 1 to 2 h. However, the clinical implications of this small increase in extraction, likely representative of decreased cerebral perfusion, are unknown but may be harmful to the developing brain. PMID- 22222548 TI - Increased risk for respiratory distress among white, male, late preterm and term infants. AB - OBJECTIVE: To determine whether race/ethnicity and sex independently increase risk of respiratory distress syndrome (RDS) in late preterm and term infants. STUDY DESIGN: Using a cohort design, we studied the risk of RDS associated with race/ethnicity and sex in infants with gestational age (GA) 34 to 42 weeks born between 1 January 2000 and 31 December 2009 (n=286 454) within 12 hospitals in the Northern California Kaiser Permanente Medical Care Program. RESULT: Male sex (adjusted odds ratio (aOR) 1.68; 95% confidence interval 1.45 to 1.93) and White race/ethnicity (vs Asians (aOR 0.57; 95% confidence interval 0.47 to 0.70), Blacks (aOR 0.66; 95% confidence interval 0.50 to 0.87), and Hispanics (aOR 0.76; 95% confidence interval 0.64 to 0.90)) independently increase risk for RDS regardless of GA. A GA <39 weeks, operative delivery, maternal diabetes, and chorioamnionitis also increased RDS risk in this cohort. CONCLUSION: Male sex and White race/ethnicity independently increase risk for RDS in late preterm and term infants. Timing of elective delivery should acknowledge these risks. PMID- 22222550 TI - Chemical transformation of chiral monolayer-protected gold clusters: observation of ligand size effects on optical and chiroptical responses. AB - Versatile functionalization of metal clusters is a key step in understanding the reactivity of protective monolayers. We here demonstrate that reaction of the outermost amino groups on (S)-/(R)-penicillamine-protected gold clusters with ethyl isocyanate readily modifies the chiral surface structure through carbamoylation. Interestingly, the clusters are electrophoretically separated by the size of the surface ligand, not by the size of the gold core, which is revealed by UV-vis, IR, and energy dispersive X-ray (EDX) spectroscopy as well as SAXS measurements. The ligand size (or length) is extended through additional reactions of the carbamoylated amino groups with isocyanate, while the chemical similarity in ligand structures is realized by their IR spectral similarity. Optical and chiroptical responses of the separated cluster compounds are thus overall similar to each other, but a close inspection reveals that the ligand size has a small but distinct influence on the chiroptical response of the gold clusters. PMID- 22222549 TI - Combining hand techniques with electric pumping increases the caloric content of milk in mothers of preterm infants. AB - OBJECTIVE: We previously reported that preterm mothers' milk production can exceed levels of term mothers by using early hand expression and hands-on pumping (HOP) with the highest production (955 ml per day) in frequent users of hand expression. In this study, we compared milk composition between mothers stratified by early hand expression frequency. STUDY DESIGN: A total of 67 mothers of infants <31 weeks gestation were instructed on hand expression and HOP. Subjects submitted expression records and 1-ml samples from each pumping session over 24 h once weekly for 8 weeks. RESULT: 78% (52/67) of mothers completed the study. But for Week 1, no compositional differences (despite production differences) were noted between the three groups. Protein and lactose tracked reported norms, but fat and energy of mature milk (Weeks 2-8) exceeded norms, 62.5 g l(-1) per fat and 892.7 cal l(-1) (26.4 cal oz(-1)), respectively. CONCLUSION: Mothers combining manual techniques with pumping express high levels of fat-rich, calorie-dense milk, unrelated to production differences. PMID- 22222552 TI - Serotonin transporter gene promoter polymorphism and alexithymia. AB - BACKGROUND: Recent neurobiological studies have reported that alexithymia may result from altered brain function related to emotional processing. Serotonin (5 hydroxytryptamine, 5-HT) has been shown to regulate central nervous system development associated with psychological processing. We investigated the possibility that polymorphism of the 5-HT transporter-linked promoter region (5 HTTLPR) is associated with alexithymia. METHODS: This study included 304 healthy Japanese volunteers (148 males, 156 females). The subjects were categorized according to genotype (L/L, L/S, S/S) and results of the 20-item Toronto Alexithymia Scale (TAS-20), State-Trait Anxiety Inventory (STAI) and Self-Rating Depression Scale (SDS). RESULTS: Subjects with the L/L genotype showed significantly higher TAS-20 scores, as well as significantly higher scores on the difficulty identifying feeling (DIF) subscale, than those with the L/S or S/S genotype (p < 0.05). There was a gender difference in the association between 5 HTTLPR genotype and DIF score. Female subjects with the L/L genotype showed significantly higher DIF scores than those with the L/S or S/S genotype (p <= 0.001). Neither STAI nor SDS was significantly associated with the 5-HTTLPR genotype. CONCLUSION: These results suggest a link between low synaptic 5-HT and alexithymia. PMID- 22222551 TI - Cerebrospinal fluid catecholamine levels as predictors of outcome in subarachnoid hemorrhage. AB - OBJECTIVE: Subarachnoid hemorrhage (SAH) is associated with marked sympathetic activation at the time of ictus. The purpose of this study is to determine whether early central catecholamine levels measured from cerebrospinal fluid (CSF) relate to outcome in patients with SAH. METHODS: Observational study of consecutive SAH grade 3-5 patients who underwent ventriculostomy placement, but did not undergo open craniotomy for aneurysm obliteration. CSF samples were obtained during the first 48 h following symptom onset and assayed for catecholamine levels. Statistical analyses were performed to determine whether the levels predicted mortality by day 15 or mortality/disability by day 30. RESULTS: For the 102 patients included, mean age was 58, and 73% were female - 21% experienced day-15 mortality, and 32% experienced mortality/disability by day 30. Early mortality was related to Hunt-Hess (H/H) grade (p < 0.001), neurogenic cardiomyopathy (NC) (p = 0.003), cerebral infarction (p = 0.001), elevated intracranial pressure (ICP) (p = 0.029), epinephrine (EPI) level (p = 0.002) and norepinephrine/3,4-dihydroxyphenylglycol (NE/DHPG) ratio (p = 0.003). Mortality/disability was related to H/H grade (p < 0.001), NC (p = 0.018), infarction (p < 0.001), elevated ICP (p = 0.002), EPI (p = 0.004) and NE/DHPG (p = 0.014). Logistic regression identified age [OR 1.09 (95% CI 1.01-1.17)], H/H grade [9.52 (1.19-77)], infarction [10.87 (1.22-100)], ICP elevation [32.26 (2 500)], EPI [1.06 (1.01-1.10)], and (inversely) DHPG [0.99 (0.99-1.00)] as independent predictors of early mortality. For mortality/disability, H/H grade [OR 21.74 (95% CI 5.62-83)], ICP elevation [18.52 (1.93-166)], and EPI [1.05 (1.02-1.09)] emerged as independent predictors. Proportional-hazards analysis revealed age [HR 1.041 (95% CI 1.003-1.08)], H/H grade [6.9 (1.54-31.25)], NC [4.31 (1.5-12.35)], and EPI [1.032 (1.009-1.054)] independently predicted early mortality. CONCLUSIONS: CSF catecholamine levels are elevated in SAH patients who experience early mortality or disability. EPI may potentially serve as useful index of outcome in this population of patients with SAH. PMID- 22222553 TI - Preanalytical factors and reference intervals for serum hepcidin LC-MS/MS method. AB - BACKGROUND: Hepcidin is a potential biomarker for anemia of chronic diseases and disorders of iron metabolism. Thus, data of preanalytical factors, reference values and method characteristics are critical for clinical use of hepcidin determination. METHODS: We studied the effects of sample storage, sampling device and a meal on hepcidin levels using a liquid-chromatography tandem mass spectrometric (LC-MS/MS) method for serum hepcidin. Age- and gender-dependent reference values were determined using serum samples from healthy volunteers (n=231). The results were also compared with those obtained by a commercial competitive ELISA for hepcidin. RESULTS: In serum samples, hepcidin is stable for one day at room temperature, six days at +4 degrees C and at least 42 days at -20 degrees C. Breakfast or type of sampling device does not affect hepcidin concentration. Significantly lower hepcidin concentrations were observed in women <=50 than >50 years of age or in men (p<0.0001 for both). Reference values for females aged 18-50 years were 0.4-9.2 nmol/L, for those >50 years 0.7-16.8 nmol/L and for males >=18 years 1.1-15.6 nmol/L. Comparison with a competitive ELISA showed poor correlation. CONCLUSIONS: Fasting before sampling and type of blood collection were not critical. Samples can be transported to laboratory at room temperature if they arrive within a day. Significantly lower concentrations of serum hepcidin were observed in menstruating than in post-menopausal women and in men. PMID- 22222555 TI - Simultaneous HPTLC and RP-HPLC methods for determination of bumadizone in the presence of its alkaline-induced degradation product. AB - Accurate, selective, sensitive and precise HPTLC-densitometric and RP-HPLC methods were developed and validated for determination of bumadizone calcium semi hydrate in the presence of its alkaline-induced degradation product and in pharmaceutical formulation. Method A uses HPTLC-densitometry, depending on separation and quantitation of bumadizone and its alkaline-induced degradation product on TLC silica gel 60 F(254) plates, using hexane-ethyl acetate-glacial acetic acid (8:2:0.2, v/v/v) as a mobile phase followed by densitometric measurement of the bands at 240 nm. Method B comprises RP-HPLC separation of bumadizone and its alkaline-induced degradation product using a mobile phase consisting of methanol-water-acetonitrile (20:30:50, v/v/v) on a Phenomenex C(18) column at a flow-rate of 2 mL/min and UV detection at 235 nm. The proposed methods were successfully applied to the analysis of bumadizone either in bulk powder or in pharmaceutical formulation without interference from other dosage form additives, and the results were statistically compared with the established method. PMID- 22222554 TI - Developmental neurotoxicity of organophosphates targets cell cycle and apoptosis, revealed by transcriptional profiles in vivo and in vitro. AB - Developmental organophosphate exposure reduces the numbers of neural cells, contributing to neurobehavioral deficits. We administered chlorpyrifos or diazinon to newborn rats on postnatal days 1-4, in doses straddling the threshold for barely-detectable cholinesterase inhibition, and evaluated gene expression in the cell cycle and apoptosis pathways on postnatal day 5. Both organophosphates evoked transcriptional changes in 20-25% of the genes in each category; chlorpyrifos and diazinon targeted the same genes, with similar magnitudes of change, as evidenced by high concordance. Furthermore, the same effects were obtained with doses above or below the threshold for cholinesterase inhibition, indicating a mechanism unrelated to anticholinesterase actions. We then evaluated the effects of chlorpyrifos in undifferentiated and differentiating PC12 cells and found even greater targeting of cell cycle and apoptosis genes, affecting up to 40% of all genes in the pathways. Notably, the genes affected in undifferentiated cells were not concordant with those in differentiating cells, pointing to dissimilar outcomes dependent on developmental stage. The in vitro model successfully identified 60-70% of the genes affected by chlorpyrifos in vivo, indicating that the effects are exerted directly on developing neural cells. Our results show that organophosphates target the genes regulating the cell cycle and apoptosis in the developing brain and in neuronotypic cells in culture, with the pattern of vulnerability dependent on the specific stage of development. Equally important, these effects do not reflect actions on cholinesterase and operate at exposures below the threshold for any detectable inhibition of this enzyme. PMID- 22222556 TI - The role of a conserved threonine residue in the leader peptide of lasso peptide precursors. AB - The conserved threonine (Thr) residue in the penultimate position of the leader peptide of lasso peptides microcin J25 and capistruin can be effectively replaced by several amino acids close in size and shape to Thr. These findings suggest a model for lasso peptide biosynthesis in which the Thr sidechain is a recognition element for the lasso peptide maturation machinery. PMID- 22222557 TI - Pancreatic Mucinous Cystadenocarcinoma Presenting with Splenic Infarction in a Young Female. PMID- 22222558 TI - Hepatoprotective effect of coenzyme Q10 in rats with acetaminophen toxicity. AB - The potential protective effect of coenzyme Q10 against acute liver injury induced by a single dose of acetaminophen (700 mg/kg, p.o.) was investigated in rats. Coenzyme Q10 treatment was given as two i.p. injections, 10 mg/kg each, at 1 and 12 h following acetaminophen administration. Coenzyme Q10 significantly reduced the levels of serum aminotransferases, suppressed lipid peroxidation, prevented the decreases of reduced glutathione and catalase activity, decreased the elevations of tumor necrosis factor-alpha and nitric oxide as well as attenuating the reductions of selenium and zinc ions in liver tissue resulting from acetaminophen administration. Histopathological liver tissue damage mediated by acetaminophen was ameliorated by coenzyme Q10. Immunohistochemical analysis revealed that coenzyme Q10 significantly decreased the acetaminophen-induced overexpression of inducible nitric oxide synthase, nuclear factor-kappaB, caspase 3 and p53 in liver tissue. It was concluded that coenzyme Q10 protects rat liver against acute acetaminophen hepatotoxicity, most probably through its antioxidant, anti-inflammatory and antiapoptotic effects. PMID- 22222559 TI - Systemic immunomodulatory effects of topical dinitrochlorobenzene (DNCB) in rats. Activity of peripheral blood polymorphonuclear cells. AB - Topical application of dinitrochlorobenzene (DNCB) is employed in the immunotherapy of skin diseases. Activation of T-cell mediated immune responses (Th1/type1) is the supposed mechanism of the clinical effect of DNCB, but there are no data concerning innate/inflammatory mechanisms. In this study, the effect of repeated topical DNCB application on peripheral blood polymorphonuclear (PMN) leukocytes has been examined in two rat strains which differ in the propensity to mount Th1/type1 or Th2/type2 responses. The dynamics of changes in PMN numbers and effector activities (respiratory burst, nitric oxide production and myeloperoxidase content), as well as in adhesion and TNF-alpha production following the rat skin sensitization with low (0.4%) and high (4%) DNCB doses were measured. Both priming and activation of PMNs were observed following skin sensitization with DNCB, with dose-dependent as well as time-dependent differences in some PMN activities. Obtained data might be relevant for understanding the immune mechanisms of topical DNCB therapy. PMID- 22222561 TI - Surgical treatment of metabolic syndrome. AB - This article explores the surprising finding that bariatric surgery can produce full and durable remission of the metabolic syndrome as well as other comorbidities of obesity including type II diabetes, hypertension, polycystic ovary syndrome, gastroesophageal reflux disease, nonalcoholic steatotic hepatitis, adult asthma and improvement in weight-bearing arthropathy. Such an outcome was previously deemed impossible. One effect of the surgery is the correction of hyperinsulinemia, a common denominator in the various expressions of the metabolic syndrome. Basal insulin levels return to normal levels within a matter of days following surgery, allowing a return of the first phase of insulin secretion. This effect is 'dose related' to the extent of the reduction of contact between food and the gut. The resolution of the spectrum of diseases that comprise the metabolic syndrome following bariatric surgery suggests that hyperinsulinemia may be the common cause that is corrected by lowering contact between food and the gut. If this concept is true, then the cause of the syndrome, including diabetes, could be a diabetogenic signal from the gut that forces the islets to produce excessive and harmful levels of insulin, or the cause could be the removal of a signal that blocks excessive insulin secretion. If either of these mechanisms is proven correct, the current treatment of diabetes with long-term insulin administration deserves review. PMID- 22222560 TI - Gambogenic acid induced mitochondrial-dependent apoptosis and referred to phospho Erk1/2 and phospho-p38 MAPK in human hepatoma HepG2 cells. AB - Gambogenic acid, identified from Gamboge, is responsible for anti-tumor effects, and has been shown to be a potential molecule against human cancers. In this study, the molecular mechanism of gambogenic acid-induced apoptosis in HepG2 cells was investigated. Gambogenic acid significantly inhibited cell proliferation and induced apoptosis. Acridine orange/ethidium bromide (AO/EB) staining was used to observe apoptosis, and then confirmed by transmission electron microscopy. Gambogenic acid induced apoptosis and morphological changes in mitochondria, and intracellular reactive oxygen species (ROS) and mitochondrial membrane permeabilization (MMP) in mitochondrial apoptosis pathway were also examined. Results showed that the levels of phospho-p38 and its downstream phospho-Erk1/2 of HepG2 cells increased in time- and concentration dependent manners after gambogenic acid treatments. Additionally, gambogenic acid increased expression ratio of Bcl-2/Bax in mRNA levels, Western blotting analysis also further confirmed the reduced level of Bcl-2 and increase the expression level of Bax in HepG2 cells. These results indicated that gambogenic acid induced mitochondrial oxidative stress and activated caspases through a caspase-3 and caspase-9-dependent apoptosis pathway. Moreover, gambogenic acid mediated apoptosis and was involved in the phospho-Erk1/2 and phospho-p38 MAPK proteins expression changes in HepG2 cells. PMID- 22222562 TI - The use of negative themes in television food advertising. AB - The ability of food advertising to trigger food consumption and influence social norms relating to food consumption has resulted in increasing attention being given to the prevalence and nature of food advertising. The present study investigated the use of negative themes in food advertisements aired on Australian television to determine the prevalence of depictions of violence/aggression, mocking, nagging, boredom, loneliness, food craving, mood enhancement, and the emotional use of food across 61 days of programming time. The results suggest that advertisers are using negative themes to capture attention and invoke an emotional response in the target audience. Sixteen percent (14,611) of the 93,284 food advertisements contained negative themes, with mood enhancement and food craving being the most commonly depicted negative themes. Advertisements with negative themes were more likely to be for non-core foods and to be aired during children's popular viewing times than at other times. The potential for negative themes in food advertising to promote unhealthy food consumption behaviors among children is likely to be of concern to policy makers. Building on this exploratory study, further research is needed to investigate how nutrition-related decision making is affected by exposure to food advertisements employing negative emotional themes. PMID- 22222563 TI - Individual differences and preference for dietary fat using the Fat Preference Questionnaire((c)) in a UK sample. AB - Dietary fat is a fundamental contributor to the selection of food largely due to its pleasant orosensory characteristics. Consequently high fat foods are often over eaten leading to weight gain and in severe cases, obesity. This paper presents two studies investigating preference for fat. Study 1 is a large-scale questionnaire study which produced both UK normative data for the Fat Preference Questionnaire((c)) and the first normative data for males. The results suggest that the Fat Preference Questionnaire((c)) is a reliable and valid measure of fat preference in a UK population, although some changes to the measure are recommended. Female data was found to closely mirror the existing US data. Sex differences were established in scores of preference for high fat foods and quantities eaten. Study 2 investigated the extent to which individual difference in eating behaviour, body mass and personality predict preference for dietary fat. High scores in Dietary Restraint were found to be the best predictor of high fat intake, especially dietary restraint specific to fat. Personality weakly predicted preference for dietary fat, and high BMI was associated with high intake of fat. PMID- 22222564 TI - Multiscale peak alignment for chromatographic datasets. AB - Chromatography has been extensively applied in many fields, such as metabolomics and quality control of herbal medicines. Preprocessing, especially peak alignment, is a time-consuming task prior to the extraction of useful information from the datasets by chemometrics and statistics. To accurately and rapidly align shift peaks among one-dimensional chromatograms, multiscale peak alignment (MSPA) is presented in this research. Peaks of each chromatogram were detected based on continuous wavelet transform (CWT) and aligned against a reference chromatogram from large to small scale gradually, and the aligning procedure is accelerated by fast Fourier transform cross correlation. The presented method was compared with two widely used alignment methods on chromatographic dataset, which demonstrates that MSPA can preserve the shapes of peaks and has an excellent speed during alignment. Furthermore, MSPA method is robust and not sensitive to noise and baseline. MSPA was implemented and is available at http://code.google.com/p/mspa. PMID- 22222565 TI - Editorial on "Critical overview of selected contemporary sample preparation techniques" by L. Ramos. PMID- 22222567 TI - Physicians just need to be better trained to provide the best care at the end-of life. PMID- 22222566 TI - Association between education in EOL care and variability in EOL practice: a survey of ICU physicians. AB - PURPOSE: This study investigated the association between physician education in EOL and variability in EOL practice, as well as the differences between beliefs and practices regarding EOL in the ICU. METHODS: Physicians from 11 ICUs at a university hospital completed a survey presenting a patient in a vegetative state with no family or advance directives. Questions addressed approaches to EOL care, as well physicians' personal, professional and EOL educational characteristics. RESULTS: The response rate was 89%, with 105 questionnaires analyzed. Mean age was 38 +/- 8 years, with a mean of 14 +/- 7 years since graduation. Physicians who did not apply do-not-resuscitate (DNR) orders were less likely to have attended EOL classes than those who applied written DNR orders [0/7 vs. 31/47, OR = 0.549 (0.356-0.848), P = 0.001]. Physicians who involved nurses in the decision making process were more likely to be ICU specialists [17/22 vs. 46/83, OR = 4.1959 (1.271-13.845), P = 0.013] than physicians who made such decisions among themselves or referred to ethical or judicial committees. Physicians who would apply "full code" had less often read about EOL [3/22 vs. 11/20, OR = 0.0939 (0.012-0.710), P = 0.012] and had less interest in discussing EOL [17/22 vs. 20/20, OR = 0.210 (0.122-0.361), P < 0.001], than physicians who would withdraw life-sustaining therapies. Forty-four percent of respondents would not do what they believed was best for their patient, with 98% of them believing a less aggressive attitude preferable. Legal concerns were the leading cause for this dichotomy. CONCLUSIONS: Physician education about EOL is associated with variability in EOL decisions in the ICU. Moreover, actual practice may differ from what physicians believe is best for the patient. PMID- 22222568 TI - Children's perceptions of dissimilarity in parenting styles are associated with internalizing and externalizing behavior. AB - The purpose of this study was to examine the relationship between children's perception of dissimilarity in parenting styles, and internalizing and externalizing problems in children. Children from the general population (n = 658) reported on the level of emotional warmth, rejection, and overprotection of both parents by filling out the child version of the Egna Minnen Betraffande Uppfostran (EMBU-C) and mothers completed the child behavior checklist (CBCL). Intraclass correlations were computed as measures of dissimilarity between parenting styles of mothers and fathers. Children's perceived dissimilarity in parental emotional warmth is associated with internalizing and externalizing problems (beta = 0.092, p < 0.05; beta = 0.091, p < 0.05). Perceived dissimilarity between parents' overprotection is associated with externalizing problems (beta = 0.097, p < 0.05). Perceived dissimilarity between parenting styles is associated with externalizing and internalizing problems, over and above the effects of the level of the parenting styles. The results highlight the negative consequences of perceived dissimilarity between parents. To conclude, children have more internalizing and externalizing problems when they perceive their parents as more dissimilar in parenting styles. PMID- 22222571 TI - Cautery of the tympanic membrane: the lesser known history of myringoplasty. AB - OBJECTIVE: To present the fascinating, controversial, and tumultuous history of tympanic cautery as a form of myringoplasty and describe the relevance of work more than 150 years old to modern practice and research. DATA SOURCES: More than 70 English, French, and German articles and books published over the last 400 years, which refer to some aspect of tympanic membrane cautery. HISTORY: The first recorded use of silver nitrate to stimulate closure of tympanic membrane perforations is by William Wilde in 1848. Since then, numerous modifications of this technique have been used, and its significance has waxed and waned in response to events within the speciality of otology and the wider world. CONCLUSION: There are lessons to be learned from the rise and fall of this once widely practiced technique. There exists a school of thought that believes that the significance of cautery lies not only in the history of otology but also in its future. PMID- 22222572 TI - Conservative management versus stereotactic radiation for vestibular schwannomas: a meta-analysis of patients with more than 5 years' follow-up. AB - OBJECTIVE: To compare the long-term outcome of hearing and tumor control of small vestibular schwannomas treated with conservative management or radiation therapy. DATA SOURCES: A thorough search for English-language publications and "in process" articles dating from 1948 to January 2011 was performed using Ovid MEDLINE. STUDY SELECTION: The principal criteria were patients with no microsurgical intervention before their treatment, a follow-up of at least 5 years, and a useful hearing level at diagnosis. DATA EXTRACTION: Fourteen studies met our criteria. Hearing preservation outcome (worse, unchanged, and better) and tumor size outcome (growth, unchanged, and regression) data were collected from the articles, as well as all other significant observations. No studies using fractionated stereotactic radiotherapy met our criteria. Stereotactic radiation was the only radiation therapy analyzed. DATA SYNTHESIS: The data were analyzed using the Pearson chi2 test. CONCLUSION: Current data on conservative management and stereotactic radiation do not provide enough evidence to make a clear conclusion on the outcome of useful hearing preservation in a long-term manner. In this study, however, stereotactic radiation is shown to have better tumor control rates than conservative management. Additional studies reporting long term follow-ups of patients are required so as to provide the medical field with a better understanding of vestibular schwannoma treatment therapies. PMID- 22222570 TI - Treatment of vestibular schwannoma cells with ErbB inhibitors. AB - HYPOTHESIS: Aberrant phosphorylation of ErbB family receptor tyrosine kinases (RTK) in human vestibular schwannomas (VSs) renders them susceptible to growth suppression by RTK inhibitors. BACKGROUND: Recent evidence has implicated increased ErbB family receptor tyrosine kinase signaling in VS tumorigenesis; however, the characterization of ErbB receptor activity and the chemotherapeutic potential of RTK inhibitors in VS treatment have not been fully explored. METHODS: To confirm phosphorylation of ErbB receptors in VS, protein extracts from paired VS tumor-vestibular nerve samples were examined using phospho-RTK arrays. ErbB receptor phosphorylation was similarly examined in cultured schwannoma cells, normal Schwann cells, and VS tumor tissues using Western blotting. Also, VS tumor sections were immunostained for members of the ErbB receptor family. The effects of RTK inhibitors on ErbB phosphorylation and cell proliferation were assessed in schwannoma cells after epidermal growth factor receptor (EGFR) inhibitor (Erlotinib) and EGFR/ErbB2 inhibitor (Lapatinib) treatment. RESULTS: VS tumor tissues consistently demonstrated higher levels of phosphorylated ErbB3 compared with paired vestibular nerves. However, cultured VS, malignant schwannoma, and normal Schwann cells demonstrated EGFR phosphorylation. Immunohistochemistry confirmed high expression of ErbB3 in a series of VS tumor sections. Erlotinib inhibited schwannoma cell proliferation with an IC50 value of 2.5 umol/L, whereas Lapatinib was less potent for growth inhibition. Erlotinib treatment resulted in a decrease of multiple phospho-ErbB receptors in schwannoma cells. CONCLUSION: VS variably express activated ErbB receptors with consistently higher levels of phospho-ErbB3 expression relative to paired vestibular nerve samples. Chemotherapeutic targeting of ErbB3 may be a novel means of inhibiting VS growth. PMID- 22222573 TI - Multislice computed tomography in the diagnosis of superior canal dehiscence: how much error, and how to minimize it? AB - HYPOTHESIS: Multi-slice computed tomography (MSCT) overestimates the size of superior semicircular canal dehiscences (SSCDs) and also can misinterpret thin bone over the superior semicircular canal as dehiscent. A threshold of the radiodensity of the bone over the superior semicircular canal may exist that could optimize prediction of an actual SSCD. BACKGROUND: The gold standard for diagnosis of SSCD is MSCT, but there is a higher prevalence of SSCD based on MSCT compared with histologic studies. Overestimation of SSCD can lead to inappropriate diagnosis and treatment. METHODS: We correlated radiographic and surgical findings in SSCD to determine if MSCT overestimated the size of SSCD and if a threshold radiodensity could be defined, below which actual dehiscence could best be predicted. Participants were 34 humans with SSCD confirmed at surgery. MSCT scans were acquired axially with 0.5-mm collimation and a small field of view (24 cm). Dehiscence sizes measured from radial reconstructions were compared with measurements made during surgery. RESULTS: There were significant differences between radiographic and actual length and width, indicating that MSCT tends to overestimate the size of SSCD. Receiver operating characteristic analysis found a threshold in Hounsfield units that optimized the prediction of dehiscence. CONCLUSION: Computed tomographic imaging alone can be misleading for diagnosis of SSCD. It can overestimate the size of the dehiscence, and it can falsely detect dehiscences. Clinical symptoms and other signs must be clearly indicative before surgery, and MSCT cannot be used exclusively for the diagnosis of SSCD. PMID- 22222574 TI - Hearing loss in Paget's disease: a temporal bone histopathology study. AB - BACKGROUND: Hearing loss in Paget's disease of bone (PDB) is typically mixed and bilateral. Although different mechanisms have been proposed, the pathophysiology of hearing impairment remains unclear. OBJECTIVE: The purpose of this study is to describe the histopathologic findings of temporal bones in patients with PDB and elucidate possible pathologic mechanisms related to hearing impairment. METHODS: This is an archival human temporal bone study of 8 subjects diagnosed with Paget's disease from the temporal bone collection of the UCL Ear Institute. RESULTS: A fractured stapes footplate was observed in 1 temporal bone and stapes footplate fixation in 2 other specimens. Obliteration of Cotugno's canal by extensive bone remodeling was observed in 78% of temporal bones. An intracochlear vestibular schwannoma was observed in 1 specimen (previously reported in the literature). Other findings include microfissures and microfractures of the otic capsule, bleeding in the scalae, strial atrophy, and cystic lesions in the spiral ligament. CONCLUSION: This study is the first to report a fractured stapes footplate, as a causative lesion of conductive hearing loss in PDB. Extensive bone remodeling around Cotugno canal also was a frequent finding, not reported before in the literature. We hypothesize that sensorineural hearing loss in patients with PDB of the temporal bone may, in some cases, be attributed to obliteration of Cotugno's canal by remodeling pagetoid bone, thus obstructing the venous drainage of the cochlea, with a subsequent effect on the function of stria vascularis and spiral ligament. This seems to be consistent with experimental studies in animals. PMID- 22222576 TI - An evidence-based algorithm for intraoperative monitoring during cochlear implantation. AB - OBJECTIVE: To generate an evidence-based algorithm for the use of intraoperative testing during cochlear implantation (CI). STUDY DESIGN: Retrospective review. SETTING: Tertiary referral center. PATIENTS: A total of 277 children (aged 6 mo to 17 yr) and adults 18 years and older with normal cochlear anatomy who underwent primary and revision cochlear implantation at a single center between 2005 and 2010 were included. INTERVENTION: Intraoperative electrophysiologic monitoring and intraoperative Stenver's view plain film radiography. MAIN OUTCOME MEASURE: Intraoperative testing included the following: 1) individual electrode impedance measurements; 2) neural response telemetry (tNRT) levels for electrodes E20, E15, E10, and E5; and 3) plain film radiograph assessment of electrode position. RESULTS: No patient demonstrated abnormalities on all 3 modalities. Open or short electrodes on impedance testing were found in 6% of patients; half of these normalized when remeasured. Absent tNRT responses on 1 or more electrodes occurred in 14% of patients, although complete lack of response was rare (1.4%) and did not correlate with a dysfunctional device. Spread of excitation was performed in 1 patient and was consistent with a tip rollover. Intraoperative radiography identified tip-rollover and extracochlear electrode placement in all cases (n = 5, 1.8%) and prompted the use of the backup device. CONCLUSION: Immediate intraoperative determination of device functionality and optimal electrode placement is advantageous. Of the modalities tested, including electrode impedance, tNRT, and plain radiograph, only the radiographic results impacted intraoperative surgical decision making and led to the use of the backup device. PMID- 22222577 TI - Synchronous endoscopy and sonotubometry of the eustachian tube: a pilot study. AB - OBJECTIVE: To describe for the first time a method of recording of Eustachian tube (ET) function by simultaneous and synchronous endoscopy and sonotubometry and explore its advantages compared with the performance of these tests independently. STUDY DESIGN: Observational study. SETTING: Academic tertiary medical center. PATIENTS: Eighteen healthy subjects. INTERVENTION: Endoscopic nasopharyngoscopy with simultaneous, synchronous sonotubometry. Each subject performed three maneuvers: pronouncing the constant "k", swallowing and yawning. MAIN OUTCOME MEASURES: The number of ET opening as a fraction of all efforts to open the tube, the duration of each opening and the sound intensity recorded by sonotubometry. RESULTS: Six (35.3%) of 17 subjects used for data analysis did not open their ET during swallowing. Excluding nonopeners, the ET opened in 3 of 4 of the swallows. The average duration of opening of the ET during swallowing was 0.44 seconds. The ET does not open every time the endoscopic view notes dilation. A negative sound pressure wave was recorded in a number of instances, immediately preceding a swallow-related opening. Contraction of the tensor veli palatini muscle was essential for ET opening. CONCLUSION: Simultaneous synchronous endoscopy and sonotubometry may improve the accuracy of either performed separately as an ET function measurement tool. Sonotubometry may prevent a false positive endoscopy (ET viewed as open but no functional patency achieved). Endoscopy can lower the threshold considered as positive for sonotubometry. A negative pressure wave recorded by sonotubometry may reflect the ET role of clearing the middle ear of secretions toward the nasopharynx. This novel measurement technique provided additional evidence that the tensor veli palatini muscle provides the final opening action of the ET. PMID- 22222578 TI - MICA-STR A.4 is associated with slower hearing loss progression in patients with Meniere's disease. AB - HYPOTHESIS: Immune response may influence hearing outcome in Meniere's disease (MD). BACKGROUND: Major histocompatibility complex class I chain-related A (MICA) encodes a highly polymorphic stress-inducible protein, which interacts with NKGD2 receptor on the surface of NK, gammadelta T cells and T CD8 lymphocytes. We investigated the association of MICA gene with hearing outcome in MD and its linkage disequilibrium (LD) with human leukocyte antigen (HLA)-B. METHODS: MICA short tandem repeat polymorphism (MICA-STR) was genotyped using a polymerase chain reaction-based method in a total of 302 Spanish patients with MD and 420 healthy controls. Genotyping of HLA-B was performed using polymerase chain reaction and detected with reverse sequence-specific oligonucleotide probe system in 292 patients and 1,014 controls. RESULTS: Hearing loss was associated with the duration of MD (p = 0.001). We found that MICA*A5 alelle was significantly associated in the Mediterranean set (Pc = 0.04, odds ratio = 0.51 [95% confidence interval, 0.30-0.84]), but this finding was not replicated in the Galicia population. However, median time to develop hearing loss greater than 40 dB was 16 years (95% confidence interval, 9-23) for patients with the MICA*A.4 allele and 10 years (95% confidence interval, 9-11) for patients with another MICA-STR allele (log-rank test, p = 0.0038). We did not find statistical differences in the distribution of B locus between the MD and the control group. In the LD analysis, MICA*A5.1-HLA-B*07 (8.8%), MICA*A6-HLA-B*44 (8.3%), and MICA*A6-HLA B*51 (8.3%) were the most common haplotypes, and the stronger LD was found for haplotypes MICA*A.4-HLA-B*18 (r2 = 0.41) and MICA*A.4-HLA-B*27(r2 = 0.29). CONCLUSION: The allelic variant MICA*A.4 is significantly associated with slower progression of hearing loss in patients with MD. This suggests that the immune response influence hearing level in MD. PMID- 22222579 TI - How does closure of tympanic membrane perforations affect hearing and middle ear mechanics? An evaluation in a patient cohort and temporal bone models. AB - OBJECTIVE: This study aimed to determine how tympanic membrane (TM) perforations and their closure, using a paper-patch technique, affect middle-ear mechanics and, thus, conductive hearing for different sizes of the TM perforation. STUDY DESIGN: Temporal bone (TB) study and prospective clinical trial. SETTING: Tertiary referral center. PATIENTS: Nine patients with chronic otitis media for more than 3 months. INTERVENTION: The TM perforations were closed with a paper patch in all 9 patients. In 5 of 9 patients, myringoplasty was performed. Matching TM perforations were created in a TB model (n = 8) and closed using the paper patch. MAIN OUTCOME MEASURES: Air-bone gap was measured in all 9 patients of the patient cohort with TM perforations before and after closure and in 5 patients after myringoplasty. Stapes velocity and sound pressure difference between the ear canal and middle-ear cavity were measured in TBs with intact TM, with TM perforations, and with the perforations closed by the paper patch. All measurements in the patient cohort and TBs were performed for different sizes of TM perforations to determine if the effects varied as a function of size. RESULTS: Degree of the air-bone gap differed as a function of size of the TM perforations and its recovery after closure, and myringoplasty was independent of the size of the TM perforation in the frequency range of 0.25 to 4 kHz. In the TB measurements, although pressure difference across the TM was almost fully recovered by closing the perforation with a paper patch, recovery of the stapes motion was limited at frequencies above 4.5 kHz for larger sizes of TM perforations. CONCLUSION: Hearing loss caused by TM perforations depends on the size of the perforation. Hearing returns almost completely across the frequency range after closure except above 4 kHz for larger perforations. This is because the structural damage caused by large TM perforations cannot be completely restored by application of a paper patch. PMID- 22222581 TI - Inter- and intramolecular Mitsunobu reaction and metal complexation study: synthesis of S-amino acids derived chiral 1,2,3,4-tetrahydroquinoxaline, benzo annulated [9]-N3 peraza, [12]-N4 peraza-macrocycles. AB - Substituted 1,2,3,4-tetrahydroquinoxaline, benzo-annulated unsymmetrical chiral [9]-N(3) peraza, and [12]-N(4) peraza-macrocycles have been synthesized employing an inter- and intramolecular Mitsunobu reaction from an amino acid derived common synthetic intermediate 3. The metal complexation study of these macrocycles has been investigated by UV-visible spectroscopic technique with binding constant (K(b)) value 1.84 * 10(3) dm(3) mol(-1) using the Benesi-Hildebrand equation and a Gibbs free energy (DeltaG) -19.4 kJ mol(-1) at 35 degrees C for 14d with Co(2+). The binding properties of the metal were dependent on the structure of polyaza-macrocycles that were confirmed by the DFT optimized structure of two macrocycles. A detailed investigaton of UV-visible spectra of macrocycles and their complete interpretation with the help of TD-DFT along with the frontier molecular orbital calculations are presented. PMID- 22222580 TI - Safety evaluation of a proprietary food-grade, dried fermentate preparation of Saccharomyces cerevisiae. AB - A safety evaluation was performed for EpiCor, a product produced by a proprietary fermentation process using Saccharomyces cerevisiae. Studies included the following assays: bacterial reverse mutation, mouse lymphoma cell mutagenicity, mitogenicity assay in human peripheral lymphocytes, and a cytochrome P450 ([CYP] CYP1A2 and CYP3A4) induction assessment as well as 14-day acute, 90-day subchronic, and 1-year chronic oral toxicity studies in rats. No evidence of genotoxicity or mitogenicity was seen in any of the in vitro or in vivo studies. The CYP assessment showed no interactions or inductions. No toxic clinical symptoms or histopathological lesions were observed in the acute, subchronic, or chronic oral toxicity studies in the rat. Results of the studies performed indicate that EpiCor does not possess genotoxic activity and has a low order of toxicity that is well tolerated when administered orally. The no observable adverse effect level (NOAEL) was 1500 mg/kg body weight (bw)/d for the 90-day study and 800 mg/kg bw/d for the 1 year study, for the highest doses tested. PMID- 22222582 TI - Chemical analysis of surface oxygenated moieties of fluorescent carbon nanoparticles. AB - Water-soluble carbon nanoparticles were prepared by refluxing natural gas soot in concentrated nitric acid. The surface of the resulting nanoparticles was found to be decorated with a variety of oxygenated species, as suggested by spectroscopic measurements. Back potentiometric titration of the nanoparticles was employed to quantify the coverage of carboxylic, lactonic, and phenolic moieties on the particle surface by taking advantage of their vast difference of acidity (pK(a)). The results were largely consistent with those reported in previous studies with other carbonaceous (nano)materials. Additionally, the presence of ortho- and para quinone moieties on the nanoparticle surface was confirmed by selective labelling with o-phenylenediamine, as manifested in X-ray photoelectron spectroscopy, photoluminescence, and electrochemical measurements. The results further supported the arguments that the surface functional moieties that were analogous to 9,10-phenanthrenequinone were responsible for the unique photoluminescence of the nanoparticles and the emission might be regulated by surface charge state, as facilitated by the conjugated graphitic core matrix. PMID- 22222583 TI - GISAXS analysis of 3D nanoparticle assemblies--effect of vertical nanoparticle ordering. AB - We report on grazing-incidence small-angle x-ray scattering (GISAXS) study of 3D nanoparticle arrays prepared by two different methods from colloidal solutions layer-by-layer Langmuir-Schaefer deposition and spontaneous self-assembling during the solvent evaporation. GISAXS results are evaluated within the distorted wave Born approximation (DWBA) considering the multiple scattering effects and employing a simplified multilayer model to reduce the computing time. In the model, particular layers are represented by nanoparticle chains where the positions of individual nanoparticles are generated following a model of cumulative disorder. The nanoparticle size dispersion is considered as well. Three model cases are distinguished-no shift between the neighboring chains (AA stacking), a shift equal to half of the mean interparticle distance (AB stacking) and random shift between the chains. The first two cases correspond to vertically correlated nanoparticle positions across different chains. A comparison of the experimental GISAXS patterns with the model cases enabled us to distinguish important differences between the 3D arrays prepared by the two methods. In particular, laterally ordered layers without vertical correlation of the nanoparticle positions were found in the nanoparticle multilayers prepared by the Langmuir-Schaefer method. On the other hand, the solvent evaporation under particular conditions produced highly ordered 3D nanoparticle assemblies where both laterally and vertically correlated nanoparticle positions were found. PMID- 22222584 TI - Asymmetry of neurodegenerative disease-related pathologies: a cautionary note. PMID- 22222586 TI - Paralympic sports medicine--current evidence in winter sport: considerations in the development of equipment standards for paralympic athletes. AB - OBJECTIVE: To highlight and discuss the considerations for the future development of equipment standards for Winter Paralympic sports. DATA SOURCES: Literature searches were performed (in English) during May 2011 using the key words "technology, winter sport, Olympic, and Paralympic" in the computerized databases PubMed, PsycINFO, Science Direct, and Google Scholar. In addition, personal scientific observations were made at several Winter Paralympic Games. The retrieved articles were screened and assessed for relevance to the biological, biomechanical, and sport medicine aspects of equipment. MAIN RESULTS: There are 3 key areas in which technology has influenced sports performance in Paralympic winter sports, namely, specialized prostheses, crutch skis or outriggers (in lieu of poles), and sport-specific wheelchairs (such as the sit-ski). From a sport medicine perspective, a crucial factor not considered in the standard laboratory test of mechanical efficiency is the influence of the human-equipment connection, such as the stump-to-prosthesis interface or the required human-to-wheelchair control. This connectivity is critical to the effective operation of the assistive device. When assessing the efficiency of this equipment, the not-so obvious, holistic, compensatory factors need to be considered. CONCLUSIONS: Assistive equipment is fundamental for a person with a disability to participate and compete in winter sport activities. Although there have been improvements in the mechanical function of some assistive devices, the key issue is matching the residual function of the person with the assistive equipment. Equitable access to this technology will also ensure that the fundamental spirit of fair play that underpins the Paralympic Games is maintained. PMID- 22222587 TI - Therapeutic bodily assistive devices and paralympic athlete expectations in winter sport. AB - OBJECTIVE: To ascertain the impact of therapeutic bodily assistive devices that enable beyond-the-normal body abilities on sport in general and the Paralympics and Olympics in particular. DESIGN: Cross-sectional survey. SETTING: Online. PARTICIPANTS: Members of the National Council on Rehabilitation Education (United States). Distribution of online survey link to membership. ASSESSMENT OF RISK FACTORS: The survey used a combination of 37 simple yes or no, Likert scale, and opinion rating scale questions. This article is based on 4 of the 37 questions that focus on the impact of therapeutic enhancements on various aspects of sport. MAIN OUTCOME MEASURES: Whether respondents felt that there is an impact of therapeutic bodily assistive devices that enable beyond-the-normal body abilities on the participation of people with disabilities in sport of all levels and the self-identity of athletes with disabilities. Secondary outcome measure was what the respondents felt the impact may be. RESULTS: The respondents indicated that therapeutic bodily assistive devices, which enable beyond-the-normal body abilities, will have an impact on participation of people with disabilities in sport at all levels and on the self-identity of athletes with disabilities. CONCLUSIONS: Given the result that the respondents felt that therapeutic enhancements will impact various aspects of sport, it may be prudent to initiate a broader discourse around therapeutic enhancement and to revise codes of ethics so that they give guidance on this topic. PMID- 22222588 TI - A biomechanical approach to paralympic cross-country sit-ski racing. AB - OBJECTIVE: To analyze the biomechanics of the double poling (DP) gesture in cross country disabled sit-skiers in the field during competition. DESIGN: Cross sectional research. SETTING: One-kilometer sprint race, Winter Paralympic Games, Vancouver 2010, Canada. PARTICIPANTS: Paralympic athletes: 35 men and 15 women, classified in all the 5 classes of the sit-skier category. INTERVENTION: Elite sit-skiers, with different disabilities, were recorded with a high-speed markerless stereophotogrammetric camera system. Reference points were semiautomatically tracked frame-by-frame on video images, according to a biomechanical model consisting of 7 anatomical and 4 technical points. MAIN OUTCOME MEASURES: Coordinates of anatomical and technical points were evaluated for 2-dimensional kinematic analysis of the push gesture both with reference to a ground-fixed frame and with respect to the athletes' seat on the sledges. RESULTS: Several graphical results represent the development of the DP gesture of each athlete with respect to both ground reference frame and sledge reference frame. The progression of the gesture is depicted by body and pole stick diagrams, trends of reference point positions and their gradients, and body joint trajectories in space. In addition, kinematic biomechanical parameters (eg, joints' range of motion) and technical parameters (eg, pole incline, sledge velocity) are reported. CONCLUSIONS: This research demonstrates the feasibility of a markerless kinematic analysis of the poling gesture on a contest field. Results point out a wide variability of the gesture due to the residual functional capabilities and sitting postures of each athlete. However, the poling cycles of subjects classified into different classes present similar features. An original segmentation of the DP gesture in a sequence of 3 phases is proposed in the article. PMID- 22222589 TI - Mental preparation for the 2014 Winter Paralympic Games. AB - OBJECTIVE: The purpose of this review is to describe how Paralympians can prepare for the 2014 Paralympic Games through mental skill use. DATA SOURCES: A search of adapted physical activity, sport psychology, and disability-specific journals was conducted along with electronic databases (eg, ArticleFirst) using the terms sport psychology, Olympics, Paralympics, psychological and mental preparation and skills, imagery, visualization, self-talk, anxiety, confidence, and performance enhancement. Reference lists from relevant articles were then used to continue the search. No constraining dates were used. RESULTS: A review of the results from both qualitative and quantitative research on Paralympians, Olympians, and elite-level athletes suggests that mental preparation and mental skill development can help Paralympians enhance their performances. CONCLUSIONS: Sport psychologists can help Paralympians develop mental skills to manage the unique stressors of the Paralympics to increase the odds of having superior performances. PMID- 22222590 TI - Game performance in ice sledge hockey: an exploratory examination into type of disability and anthropometric parameters. AB - OBJECTIVE: To compare first disability and anthropometric variables and second disability and game efficiency measures. DESIGN: Prospective cohort study. SETTING: Winter Paralympic Games in Vancouver (2010). PARTICIPANTS: A sample of 54 (age, 30.85 +/- 7.99 y) of the 114 elite ice sledge hockey athletes participated in this study. To be included in the analysis, an athlete had to participate for a minimum of 45 minutes in total and in a minimum of 2 games during the tournament. ASSESSMENT OF RISK FACTORS: Athletes were categorized according to type of disability into 4 groups: group 1 (double amputee above and below the knee), group 2 (single amputee above and below the knee), group 3 (spinal cord injury), and group 4 (other physical disabilities, including phocomelia, cerebral palsy, sclerosis multiplex, and lower limb paresis, and players with minimal disability). Before the tournament, athletes completed a Personal Questionnaire Form. Data including anthropometric measurements (seated position and range of arms) and length of the sledge were also collected. MAIN OUTCOME MEASURES: All 20 scheduled games were videotaped using 3 video cameras. The games were analyzed after the tournament by 5 observers. All observations were recorded using the Game Efficiency Sheet for Ice Sledge Hockey developed by the authors. Fourteen game parameters were included for analysis. RESULTS: The instrument was developed specifically for this project's exploratory analysis. Interobserver and intraobserver reliability were established by statistical analysis (r > 0.93 and r > 0.95, respectively). Significant differences between disability groups were found for training frequency (F3,50 = 4.73, P = 0.006), height (F3,50 = 12.54, P = 0.001), and sledge length (F3,50 = 12.35, P = 0.001). The results of the Tukey honestly significant difference post hoc analyses revealed significant differences between groups 1 and 4 (P = 0.026), 2 and 4 (P = 0.007), and 3 and 4 (P = 0.013) for training frequency. There were also significant differences between groups 1 and 2 (P < 0.001), 1 and 4 (P < 0.001), and 2 and 4 (P = 0.021) for body height. In sledge length, significant differences were observed between groups 1 and 2 (P < 0.001), 1 and 3 (P < 0.001), 1 and 4 (P = 0.016), and 2 and 4 (P = 0.028). There was no strong evidence to support disability group differences in game efficiency measures. CONCLUSIONS: The results may confirm the lack of a need for additional classification in sledge hockey beyond minimum eligibility or may enhance the argument that a classification system may be needed because the lower functioning disabilities are not being represented in the sport. PMID- 22222591 TI - Autonomic dysreflexia: current evidence related to unstable arterial blood pressure control among athletes with spinal cord injury. AB - OBJECTIVE: To present the complex issues of the impact of spinal cord injury (SCI) in sport, with a specific focus on autonomic dysreflexia (AD) and the potential debilitating effects of unstable blood pressure control among athletes. DATA SOURCES AND METHODS: A literature review based on a key word electronic literature search of articles, practice guidelines, and review articles pertaining to AD was conducted using MEDLINE, SportDiscus, and EMBASE. RESULTS: Spinal cord injury results not only in devastating paralysis; it also commonly is associated with a range of autonomic dysregulation that can interfere with cardiovascular, bladder, bowel, temperature, and sexual function. Individuals with a cervical or high-thoracic SCI face lifelong abnormalities in systemic arterial pressure control. In general, their resting arterial pressure is lower than that in able-bodied individuals and is commonly associated with persistent orthostatic intolerance. In addition, they experience transient episodes of life threatening hypertension, known as "AD," which often is associated with disturbances in heart rate and rhythm. Autonomic dysreflexia occurs in up to 90% of individuals with a cervical or high-thoracic SCI and requires prompt intervention. It also is known that, during athletic activities, self-induced AD is used by some individuals to improve their performance, a technique known as "boosting." For health safety reasons, boosting is officially banned by the International Paralympic Committee. CONCLUSIONS: Devastating paralysis, a variety of autonomic dysfunctions, and abnormal cardiovascular control after SCI present significant challenges in terms of individuals remaining active in competitive sports. Medical practitioners who are involved in the care of wheelchair athletes should be aware of the unique cardiovascular dysfunction that results from SCI and may occur at any time, even with seemingly innocuous triggers. Prompt recognition and appropriate management of these conditions, including episodes of AD, could be life saving. PMID- 22222592 TI - Antidoping in paralympic sport. AB - This study reports in detail on the antidoping program of the Paralympic Movement to improve knowledge and optimize intervention programs, including educational and awareness initiatives. Data retrieved from annual statistics reports and historical records are complemented with personal observations. An overall incidence proportion of <1% of antidoping rule violations in the Paralympic Movement is reported, mainly resulting from urine testing during in-competition periods. This led to a total of 60 antidoping rule violations (of which 37 in the sport of International Paralympic Committee powerlifting) since 2000. A critical analysis of these data allows for an assessment of risk factors by sport. An efficient transfer of knowledge indicates the need to strengthen educational awareness, preferably imbedded in a multidisciplinary approach toward athletes' health. The particular case of autonomic dysreflexia is addressed as a separate theme. PMID- 22222593 TI - Physical fitness evaluation of paralympic winter sports sitting athletes. AB - OBJECTIVE: To provide normative values of physical fitness in Paralympic winter sports athletes competing in a sitting posture and to identify the components relevant for successful performance. DESIGN: Cross-sectional study with sports. SETTING: The Institute of Sports Medicine and Science of the Italian National Olympic Committee (Rome, Italy). PARTICIPANTS: Fifteen Alpine skiers (3 BP), 16 Nordic skiers (2 BP), 10 curlers (2 BP), and 34 ISH players (7 BP). INDEPENDENT VARIABLES: Curling, Alpine skiing, Nordic skiing, and ice sledge hockey (ISH). MAIN OUTCOME MEASURES: Physical fitness components. Oxygen uptake peak (V[Combining Dot Above]O2peak; L.min and mL.kg.min), mechanical work in a high intensity exhaustion exercise (MW-HIE; kJ and kJ.kg), upper-body strength (N and N.kg), mean explosive power (MEP; W and W.kg) in a 10-second arm cranking ergometer Wingate test, and fat mass (FM) (% body mass) were primary outcome measures when assessed in the whole sport groups and secondary outcome measures when separating the BP from the others. RESULTS: Based on 1-way analysis of variance and Tukey post hoc test (P < 0.05), V[Combining Dot Above]O2peak and MW HIE were highest in Nordic skiers (2.9 +/- 0.53 L.min and 18.3 +/- 3.98 kJ) and similar in ISH players and Alpine skiers (2.5 +/- 0.42 and 2.3 +/- 0.44 L.min and 17.4 +/- 2.62 and 16.8 +/- 7.41 kJ, respectively). Alpine skiers showed the highest absolute strength values (1210.1 +/- 220.92 N). Curlers had the highest FM (26.2% +/- 7.74%) and the lowest V[Combining Dot Above]O2peak (1.8 +/- 0.35 L.min), MW-HIE (11.4 +/- 2.40 kJ), and MEP (251.1 +/- 67.16 W). Among the BP, Nordic skiers, ISH players, and Alpine skiers showed VO2peak, MW-HIE, and strength equal to 3.4 +/- 0.60, 2.9 +/- 0.38, and 2.8 +/- 0.18 L.min-1 and 22.6 +/- 4.04, 19.4 +/- 2.84, and 18.4 +/- 7.86 kJ, and 975.4 +/- 115.03, 1183.4 +/- 60.43, and 1279.2 +/- 279.1 N, [corrected] respectively. CONCLUSIONS: Analyzing physical fitness data of athletes competing in the last 4 winter Paralympic Games, normative values are provided. The specific components that are highly developed in the BP are considered relevant for successful performance. PMID- 22222594 TI - Paralympic medical services for the 2010 paralympic winter games. AB - OBJECTIVE: To present the planning and medical encounters for the 2010 Paralympic Winter Games. DESIGN: Prospective medical encounter study. SETTING: 2010 Paralympic Winter Games. PARTICIPANTS: Athletes, coaches, officials, workforce, volunteers, and media. ASSESSMENT OF RISK FACTORS: Sport type: alpine, Nordic, and sledge hockey and curling. Participant type: athlete, workforce, and spectators. Terrain and speed. MAIN OUTCOME MEASURES: Medical encounters entered in database at competitive (alpine skiing, biathlon, cross-country skiing, sledge hockey, and curling) and noncompetitive (Whistler and Vancouver Polyclinics, presentation centers, opening and closing ceremonies, media center, Paralympic Family Hotel) venues. RESULTS: Forty-two nations participated with 1350 Paralympic athletes, coaches, and officials. There were 2590 accredited medical encounters (657 athletes, 25.4%; 682 International Federation/National Paralympic Committee officials, 26.3%; 57 IPC, 2.2%; 8 media, 0.3%; 1075 workforce, 41.5%; 111 others, 4.3%) and 127 spectator encounters for a total of 2717 encounters. During the preopening period medical services saw 201 accredited personnel. The busiest venues during the Paralympic Games were the Whistler (1633 encounters) and Vancouver (748 encounters) Polyclinics. Alpine, sledge hockey, and curling were the busiest competitive venues. The majority of medical encounters were musculoskeletal (44.6%, n = 1156). Medical services recorded 1657 therapy treatments, 977 pharmaceutical prescriptions dispensed, 204 dental treatments, 353 imaging examinations (more than 50% from alpine skiing), and 390 laboratory tests. There were 24 ambulance transfers with 7 inpatient hospitalizations for a total of 24 inpatient days and 4 outpatient visits. CONCLUSIONS: The mandate to have minimal impact on the health services of Vancouver and the Olympic Corridor while offering excellent medical services to the Games was accomplished. This data will be valuable to future organizing committees. PMID- 22222595 TI - Physiologic responses of competitive Canadian cross-country skiers with disabilities. AB - OBJECTIVE: To examine the acute cardiorespiratory and metabolic responses in competitive cross-country skiers with disabilities. DESIGN: Cross-sectional comparisons using a select group of Canadian athletes training for the Vancouver 2010 Paralympic Winter Games. SETTING: Canmore Nordic Centre Provincial Park, Canmore, Alberta. PARTICIPANTS: Nine competitive cross-country skiers (4 with visual impairment, 1 with traumatic brain injury, 3 with spinal cord injury, and 1 with cerebral palsy). INTERVENTIONS: Three-minute and 12-minute exercise tests in the standing or sitting skiing position to voluntary fatigue. MAIN OUTCOME MEASURES: Cardiorespiratory responses using a telemetric system to compare the physiologic responses among the athletes with different disabilities. Heart rate (HR) and capillary lactate were measured at 2, 5, and 10 minutes of recovery. RESULTS: The t test results indicated that the peak values of the absolute and relative oxygen uptake (VO2peak), HR, and ventilation rate were significantly higher during the 12-minute compared with the 3-minute protocol during standing skiing. However, the oxygen pulse and ventilatory equivalent for oxygen ratio were not significantly (P > 0.05) different between the 2 protocols. Analysis of variance revealed no significant (P > 0.05) differences among the 3 trials for these peak physiologic responses during sitting skiing. Cross-sectional comparisons of the peak physiologic responses between the standing and sitting skiers indicated significantly (P < 0.05) higher values in the standing compared with the sitting position. Cardiorespiratory respiratory efficiency was significantly (P < 0.05) lower in the sitting compared with the standing position. HR during 10 minutes of recovery was significantly correlated with VO2peak. Pearson correlations were not significant between VO2peak and lactate removal during recovery. CONCLUSION: These descriptive findings during the standing and sitting skiing protocols provide preliminary data that would be useful in testing, training, and classification of competitive skiers with disabilities. PMID- 22222596 TI - The injury experience at the 2010 winter paralympic games. AB - OBJECTIVE: The objective of this study was to examine incidence proportion and the characteristics of athlete injuries sustained during the 2010 Vancouver Paralympic Games. DESIGN: Descriptive epidemiological study. SETTING: All medical venues at the 2010 Vancouver Paralympic Games, Canada. PARTICIPANTS: A total of 505 athletes from 44 National Paralympic Committees participating in the 2010 Vancouver Winter Paralympic Games. ASSESSMENT OF RISK FACTORS: Baseline covariates included sport specificity (ie, ice sledge hockey, alpine skiing, Nordic skiing, wheelchair curling), gender, age, and disability classification. MAIN OUTCOME MEASURES: All injuries that occurred during the 2010 Vancouver Paralympic Games. "Injury" was defined as any sport-related musculoskeletal complaint that caused the athlete to seek medical attention during the study period, regardless of the athlete's ability to continue with training or competition. RESULTS: The Injury Surveillance System identified a total of 120 injuries among 505 athletes [incidence proportion = 23.8% (95% confidence interval, 20.11-27.7)] participating in the 2010 Winter Paralympic Games. There was a similar injury incidence proportion among male (22.8%) and female (26.6%) athletes [incidence rate ratio = 1.1 (95% confidence interval, 0.7-1.7)]. Medical encounters for musculoskeletal complaints were generated in 34% of all sledge hockey athletes, 22% of alpine ski racers, 19% of Nordic skiers, and 18% of wheelchair curling athletes. CONCLUSIONS: The Injury Surveillance System identified sport injuries in 24% of all athletes participating in the 2010 Winter Paralympic Games. The injury risk was significantly higher than during the 2002 (9.4%) and 2006 (8.4%) Winter Paralympic Games. This may reflect improved data collection systems but also highlights the high risk of acute injury in alpine skiing and ice sledge hockey at Paralympic Games. These data will assist future Organizing Committees with the delivery of medical care to athletes with a disability and guide future injury prevention research. PMID- 22222597 TI - Effect of infractions in youth hockey on the severity of head impacts. PMID- 22222598 TI - GSK3 is a regulator of RAR-mediated differentiation. AB - Acute myeloid leukemia (AML) is the most common form of leukemia in adults. Unfortunately, the standard therapeutic agents used for this disease have high toxicities and poor efficacy. The one exception to these poor outcomes is the use of the retinoid, all-trans retinoic acid (ATRA), for a rare subtype of AML (APL). The use of the differentiation agent, ATRA, in combination with low-dose chemotherapy leads to the long-term survival and presumed cure of 75-85% of patients. Unfortunately ATRA has not been clinically useful for other subtypes of AML. Though many non-APL leukemic cells respond to ATRA, they require significantly higher concentrations of ATRA for effective differentiation. Here we show that the combination of ATRA with glycogen synthase kinase 3 (GSK3) inhibition significantly enhances ATRA-mediated AML differentiation and growth inhibition. These studies have revealed that ATRA's receptor, the retinoic acid receptor (RAR), is a novel target of GSK3 phosphorylation and that GSK3 can impact the expression and transcriptional activity of the RAR. Overall, our studies suggest the clinical potential of ATRA and GSK3 inhibition for AML and provide a mechanistic framework to explain the promising activity of this combination regimen. PMID- 22222599 TI - Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications. AB - We performed an immunogenetic analysis of 345 IGHV-IGHD-IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; IGHV4-34, 12.8%; IGHV3-23, 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele (*)04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1 2(*)04 peaked at 31%. The IGHV1-2(*)04 rearrangements carried significantly longer complementarity-determining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2(*)04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97-99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2(*)04 allele. PMID- 22222600 TI - Phase I and pharmacokinetic study of elacytarabine, a novel 5'-elaidic acid derivative of cytarabine, in adults with refractory hematological malignancies. PMID- 22222601 TI - Air pollution exposure during pregnancy, ultrasound measures of fetal growth, and adverse birth outcomes: a prospective cohort study. AB - BACKGROUND: Air pollution exposure during pregnancy might have trimester-specific effects on fetal growth. OBJECTIVE: We prospectively evaluated the associations of maternal air pollution exposure with fetal growth characteristics and adverse birth outcomes in 7,772 subjects in the Netherlands. METHODS: Particulate matter with an aerodynamic diameter < 10 MUm (PM10) and nitrogen dioxide (NO2) levels were estimated using dispersion modeling at the home address. Fetal head circumference, length, and weight were estimated in each trimester by ultrasound. Information on birth outcomes was obtained from medical records. RESULTS: In cross-sectional analyses, NO2 levels were inversely associated with fetal femur length in the second and third trimester, and PM10 and NO2 levels both were associated with smaller fetal head circumference in the third trimester [-0.18 mm, 95% confidence interval (CI): -0.24, -0.12 mm; and -0.12 mm, 95% CI: -0.17, 0.06 mm per 1-MUg/m3 increase in PM10 and NO2, respectively]. Average PM10 and NO2 levels during pregnancy were not associated with head circumference and length at birth or neonatally, but were inversely associated with birth weight ( 3.6 g, 95% CI: -6.7, -0.4 g; and -3.4 g, 95% CI: -6.2, -0.6 g, respectively). Longitudinal analyses showed similar patterns for head circumference and weight, but no associations with length. The third and fourth quartiles of PM10 exposure were associated with preterm birth [odds ratio (OR) = 1.40, 95% CI: 1.03, 1.89; and OR = 1.32; 95% CI: 0.96, 1.79, relative to the first quartile]. The third quartile of PM10 exposure, but not the fourth, was associated with small size for gestational age at birth (SGA) (OR = 1.38; 95% CI: 1.00, 1.90). No consistent associations were observed for NO2 levels and adverse birth outcomes. CONCLUSIONS: Results suggest that maternal air pollution exposure is inversely associated with fetal growth during the second and third trimester and with weight at birth. PM10 exposure was positively associated with preterm birth and SGA. PMID- 22222603 TI - Effects of individual and combined administration of ochratoxin A and aflatoxin B1 in tissues and eggs of White Leghorn breeder hens. AB - BACKGROUND: Mycotoxins, the secondary fungal metabolites, are unavoidable contaminants of human and animal food and feeds. The objectives of this study were to evaluate the effect of concurrent feeding of ochratoxin A (OTA) and aflatoxin B(1) (AFB(1) ) to breeder hens, upon their deposition in different tissues and eggs. RESULTS: Residues of OTA and AFB(1) in (ng g(-1) ) were significantly higher in liver followed by kidneys and breast muscles by 22.54 +/- 1.48, 4.22 +/- 0.93 and 0.56 +/- 0.06 for OTA (group fed OTA at 5 mg kg(-1) diet) and 1.44 +/- 0.21, 0.25 +/- 0.01 and 0.03 +/- 0.01 for AFB(1) (group fed AFB(1) at 5 mg kg(-1) diet), respectively. Residues of OTA and AFB(1) in eggs appeared at days 3 and 5 of toxin feeding and disappeared at days 5 and 6 of withdrawal of mycotoxins contaminated feed, respectively. The residues of OTA and AFB(1) were significantly lower in the tissues of hens fed these toxins concurrently compared with the groups fed OTA and AFB(1) independently. CONCLUSIONS: Residues of OTA and AFB(1) appeared in the tissues and eggs of laying hens kept on OTA- and AFB(1) -contaminated diets. Concurrent feeding of OTA and AFB(1) to hens significantly decreased the concentration of OTA and AFB(1) residues in the tissues and eggs. PMID- 22222602 TI - The gamma3 chain of laminin is widely but differentially expressed in murine basement membranes: expression and functional studies. AB - Laminins are heterotrimeric extracellular glycoproteins found in, but not confined to, basement membranes (BMs). They are important components in formation of the molecular networks of BMs as well as in cell polarity, cell differentiation and tissue morphogenesis. Each laminin is composed by an alpha, a beta and a gamma chain. Previous studies have shown that the gamma3 chain is partnered with either the beta1 chain (in placenta) or beta2 chain (in the CNS) (Libby et al., 2000). Several studies, including our own, suggested that the gamma3 chain is expressed in both apical and basal compartments (Koch et al., 1999; Gersdorff et al., 2005; Yan and Cheng, 2006). This study investigates the expression pattern of the gamma3 chain in mouse. We developed three new gamma3 reactive antibodies, and we show that the gamma3 chain is present in BMs. The distribution pattern is considerably more restricted than that of the gamma1 chain and within any tissue there is differential deposition into BM compartments. This is particularly true in the retina and brain, where gamma3 is uniquely expressed in a subset of the vascular basement membranes and the pial surface. We used conventional genetic ablation techniques to remove the gamma3 chain in mice; unlike other laminin null mice (alpha5, beta2, gamma1 nulls), these mice live a normal lifespan and have only minor abnormalities, the most striking of which are ectopic granule cells in the cerebellum and an apparent increase in capillary branching in the outer retina. These data support the suggestion that the gamma3 chain is deposited in BMs and contributes some unique properties to their function, particularly in the nervous system. PMID- 22222604 TI - An AD-related neuroprotector rescues transformed rat retinal ganglion cells from CoCl2-induced apoptosis. AB - Some ocular diseases characterized by apoptotic death of retinal ganglion cells (RGCs) and Alzheimer's disease (AD) are chronic neurodegenerative disorders and have similarities in neuropathology. Humanin (HN) is known for its ability to suppress neuronal death induced by AD-related insults. In present study, we investigated the neuroprotective effects of HN on hypoxia-induced toxicity in RGC 5 cells. Hypoxia mimetic compound cobalt chloride (CoCl2) could increase the cell viability loss and apoptosis, whereas HN can significantly attenuate these effects. This finding may provide new therapeutics for the retinal neurodegenerative diseases targeting neuroprotection. PMID- 22222605 TI - IL-13 polymorphisms contribute to the risk of asthma: a meta-analysis. AB - OBJECTIVES: The purpose of this study was to evaluate the effects of interleukin 13 (IL-13) polymorphisms on the risk of asthma using a meta-analysis. DESIGN AND METHODS: Fifteen publications were identified by searching Pubmed, Embase, ISI, OVID, and EBSCO databases. Odds ratios with corresponding 95% confidence intervals were computed to estimate the association between IL-13 polymorphisms and risk of asthma. RESULTS: The polymorphisms of R130Q (rs20541) and -1112C/T (rs1800925) in IL-13 gene were associated with significantly increased risks of asthma in overall analyses. Subgroup analyses showed that the elevated risks occurred in adult-onset asthma, Caucasians, and high quality studies. CONCLUSIONS: This meta-analysis provides evidence that the R130Q and -1112C/T polymorphisms in IL-13 are risk factors for asthma. PMID- 22222606 TI - Cyclodextrin modified quantum dots with tunable liquid-like behaviour. AB - Supermolecular quantum dots (QDs) nanofluids have been firstly proposed and synthesized by virtue of the strong inclusion interactions between alpha cyclodextrin (alpha-CD) and polyethylene glycol (PEG) chains, resulting in tunable liquid-like behaviour, and controllable assembly of single QDs. PMID- 22222607 TI - LC-ESI-MS/MS method for quantification of ambrisentan in plasma and application to rat pharmacokinetic study. AB - A sensitive high-performance liquid chromatography-positive ion electrospray tandem mass spectrometry method was developed and validated for the quantification of ambrisentan in plasma. The analyte and the internal standard (armodafinil) were extracted from plasma by acetonitrile precipitation and they were separated on a reversed-phase C(18) column with a gradient program. The MS acquisition was performed with multiple reaction monitoring mode using the respective [M + H](+) ions, m/z 379-347 for ambrisentan and m/z 274-167 for the IS. The assay exhibited a linear dynamic range of 1-2000 ng/mL for ambrisentan in plasma. Acceptable precision (<10%) and accuracy (100 +/- 8%) were obtained for concentrations over the standard curve range. The method was successfully applied to quantify ambrisentan concentrations in a rodent pharmacokinetic study after a single oral administration of ambrisentan at 2.5 mg/kg to rats. Following oral administration the maximum mean concentration in plasma (C(max) ; 1197 +/- 179 ng/mL) was achieved at 1.0 +/- 0.9 h (T(max) ), and the area under the curve (AUC) was 6013 +/- 997 ng h/mL. Therefore, development of such a simple and sensitive method in rat plasma should translate into a method for ambrisentan in human plasma for clinical trials. PMID- 22222608 TI - Distribution of risk factors in patients with premature coronary, supra-aortic branches and peripheral atherosclerotic disease. AB - OBJECTIVE: The aim of this study was to determine the distribution of major risk factors among patients with atherosclerotic disease aged <=50 years. SUBJECTS AND METHODS: The study population comprised 944 patients aged <=50 years with clinically significant manifestations of atherosclerotic disease compared with 350 consecutive (control) older patients (age >50 years). RESULTS: The most significant risk factors for atherosclerotic disease of the supra-aortic branches were: smoking (87.5%, p < 0.001), family history of atherosclerosis (52.3%, p < 0.001), diabetes mellitus (28.5%) and being male (56.9%) (p < 0.05 for both). In patients with coronary artery disease, there was considerable disparity in the prevalence of smoking (85.4%), hyperlipoproteinemia (67.4%), and family history of atherosclerosis (68%) (p < 0.001). For peripheral artery disease, the most significant risk factors were smoking (97%, p < 0.001), hyperlipidemia (p < 0.01), and family history of atherosclerotic disease (p < 0.01). When compared to controls, patients with premature atherosclerosis smoked more frequently, had hyperlipidemia, had a family history of atherosclerosis, and were more frequently of male sex. CONCLUSION: Premature atherosclerosis was most frequently associated with smoking, hyperlipidemia, family history of atherosclerotic disease, and male sex. PMID- 22222609 TI - In vitro metabolic stability of iodinated obestatin peptides. AB - Different iodinated mouse obestatin peptides have been characterized toward their in vitro stability in the main metabolic compartments plasma, liver and kidney. Using HPLC-UV for quantification, significant differences in the degradation kinetics of the iodinated peptides, arising from both enzymatic proteolysis and dehalogenation, were found when compared to the native, unmodified peptide. HPLC MS/MS analysis demonstrated that the cleavage sites were dependent upon the biological matrix and the location of the amino acid residue incorporating the iodine atom(s). The degrading proteases were found to target peptide bonds further away from the iodine incorporation, while proteolytic cleavages of nearby peptide bonds were more limited. Diiodinated amino acid residue containing peptides were found to be more susceptible to deiodination than the mono iodinated derivative. In plasma, the percentage of peptide degradation solely attributed to deiodinase activity after 20 min incubation reached up to 25% for 2,5-diiodo-H(19)-obestatin compared to 20% and only 3% for (3,5-diiodo-Y(16))- and (3-iodo-Y(16)) obestatin, respectively. Hence, our results demonstrate that the different iodinated peptides pose significantly different metabolization properties and thus, also different biological activities are expected for peptides upon iodination. PMID- 22222610 TI - Exenatide and feeding: possible peripheral neuronal pathways. AB - Intraperitoneal (i.p.) administration of the synthetic agonist of the glucagon like peptide-1 (GLP-1) receptor exenatide reduces food intake. Here, we evaluated possible peripheral pathways for this reduction. Exenatide (0.5 MUg/kg, i.p.) was given to three, overnight food-deprived, groups of rats: total subdiaphragmatic vagotomy (VGX, severs the vagus nerve), celiaco-mesenteric ganglionectomy (CMGX, severs the splanchnic nerve) and combined VGX/CMGX. Following the injection, meal sizes (MSs) and intermeal intervals (IMIs) were determined for a total of 120 min. We found that exenatide reduced the sizes of the first two meals but failed to prolong the IMI between them, that VGX attenuated the reduction of the first MS, and that VGX, CMGX and combined VGX/CMGX attenuated the reduction of the second MS by exenatide. Therefore, the vagus nerve appears necessary for the reduction of the first MS by exenatide, whereas both nerves appear necessary for the reduction of the second MS by this peptide. PMID- 22222611 TI - Convenient nomenclature of cysteine-rich polypeptide toxins from sea anemones. AB - Polypeptide toxins are the main constituents of natural venoms. Considerable progress in the study of these molecules has resulted in the determination of a large number of structurally related sequences. To classify newly discovered molecules, a rational nomenclature for naming peptide toxins was developed, which takes into account toxin biological activity, the species name, and structural peculiarities of the polypeptide. Herein, we suggest modifications to this nomenclature for cysteine-rich polypeptide toxins from sea anemones and describe 11 novel polypeptide structures deduced after common database revision. PMID- 22222612 TI - Dynamical probing of allosteric control in nuclear receptors. AB - The dynamical behavior of the nuclear receptor LXR/RXR heterodimer was investigated with molecular dynamics simulations. The simulations reveal correlated motion between residues across the dimer interface that depends significantly on occupation of the ligand binding sites of the monomers. These results are broadly consistent with the observed experimental behavior of the dimers, where structural perturbation is thought to be a key element in signal transduction. Our results provide dynamical support for this model of allosteric control. PMID- 22222614 TI - Failed cartilage repair for early osteoarthritis defects: a biochemical, histological and immunohistochemical analysis of the repair tissue after treatment with marrow-stimulation techniques. AB - PURPOSE: To examine the entire repair tissue resulting from marrow-stimulation techniques in patients with early osteoarthritis. METHODS: The repair tissue and adjacent articular cartilage after failed marrow-stimulation techniques (microfracture and Pridie drilling) of 5 patients (47-65 years old) with cartilage defects and radiographic early osteoarthritis (Kellgren-Lawrence grading 1 and 2) was removed during total joint arthroplasty (mean time until analysis: 8.8 months), analysed by histology, polarized light microscopy, immunohistochemistry, biochemistry and by histological score systems. RESULTS: Macroscopic cartilage repair assessment revealed ICRS grades of II (nearly normal) and III (abnormal). Cartilage defects were mostly completely filled with a fibrocartilaginous tissue that had small and large fissures. Cartilage-specific stains of the repair tissue were more intense than the surrounding native cartilage but reduced compared with normal articular cartilage. The subchondral bone was incompletely restored. A new tidemark was absent. The repair tissue always showed positive immunoreactivity for types II and X collagen, and was sometimes positive for type I collagen. Proteoglycan contents of the repair tissue were generally higher than of the surrounding cartilage. The repair tissue was always more cellular than the adjacent articular cartilage. Histological scoring of the repair tissue revealed a mean Sellers score of 17.6 +/- 3.0 and an ICRS grading of 7-9. CONCLUSION: Failed marrow stimulation of articular cartilage defects in patients with early osteoarthritis is characterized by fibrocartilaginous repair. The balance of cell number to extracellular matrix is shifted towards an increased cell number in this tissue. Articular cartilage repair did not reach the quality of normal hyaline articular cartilage. LEVEL OF EVIDENCE: IV. PMID- 22222615 TI - Quantitative assessment of pivot-shift using inertial sensors. AB - PURPOSE: The pivot-shift phenomenon has been identified to be one of the essential signs of functional anterior cruciate ligament (ACL) insufficiency. However, the pivot-shift test remains a surgeon-subjective examination, lacking a general recognized quantitative measurement. The goal of the present study was to validate the use of an inertial sensor for quantifying the pivot-shift test, using a commercial navigation system. METHODS: An expert surgeon intra operatively performed the pivot-shift test on 15 consecutive patients before ACL reconstruction. A single accelerometer and a commercial navigation system simultaneously acquired limb kinematics. An additional optical tracker mounted on the accelerometer allowed following sensor movements. Anteroposterior (a-p) tibial acceleration obtained with the navigation system was compared with three dimensional (3D) acceleration acquired by the accelerometer. The effect of skin artifacts and test-retest positioning were estimated. Repeatability of the acceleration parameter and waveform was analyzed. Correlation between the two measurements was also assessed. RESULTS: Average root mean square (RMS) error in test-retest positioning reported a good value of 5.5 +/- 2.9 mm. Mean RMS displacement due to soft tissue artifacts was 4.9 +/- 2.6 mm. The analysis of acceleration range repetitions reported a good intra-tester repeatability (Cronbach's alpha = 0.86). Inter-patients similarity analysis showed a mean acceleration waveform correlation of 0.88 +/- 0.14. The acceleration ranges demonstrated a good positive correlation between the two measurements (rs = 0.72, P < 0.05). CONCLUSION: This study showed good reliability of the new device and good correlation with the navigation system results. Therefore, the accelerometer is a valid method to assess dynamic joint laxity. LEVEL OF EVIDENCE: II. PMID- 22222617 TI - Transcultural issues in the dynamics of a Balint clinical reflection group for community mental health workers. AB - The author presents transcultural issues in the content, process, and group dynamics of consecutive meetings of a Balint clinical reflection group for community mental health workers at Inala, Australia. Balint work and the context and evolution of the group process are briefly described, as is the consultative research methodology. The process of a Balint group meeting is reported in detail, following the author's consultation with group members. The collaborative work of a culturally diverse team of mental health professionals is examined in the context of discussion of a practitioner-patient relationship in which transcultural, gender, and family conflicts were the focus of affective and cognitive dissonance. For mental health workers engaging with communities of cultural diversity, Balint reflection groups can facilitate insight into cultural countertransferences that adversely affect clinical work. The group served to support the caseworkers' engagement with patients of different cultures, and provided a safe environment for the creative consideration and exploration in fantasy of the emotional pressures and complex ethical dilemmas related to boundaries in transcultural client-practitioner relationships, including those in which open discussion would otherwise be avoided. PMID- 22222616 TI - What does it take to have a high-grade pivot shift? AB - The pivot shift is the most specific clinical test to assess pathological knee joint rotatory laxity following ACL injury. This article attempts to describe the anatomic structures responsible for creating a high-grade pivot shift and their potential role in customizing ACL reconstruction. A review of the literature demonstrates that disruption of the secondary stabilizers of anterior translation of the lateral compartment including the lateral meniscus, anterolateral capsule, and IT band contributes to a high-grade pivot shift in the ACL-deficient knee. The morphology of the lateral tibial plateau, including increased posteroinferior tibial slope and small size, can also contribute to high-grade pivot shift. Factors that may decrease the grade of the pivot shift include medial compartment injury, MCL injury, patient guarding, and osteoarthritis. In conclusion, a high grade pivot shift in the ACL-deficient knee is often associated with incompetence of the lateral soft tissue envelope. Rotatory laxity as assessed by the pivot shift may also be falsely underestimated by concomitant injuries. LEVEL OF EVIDENCE: IV. PMID- 22222618 TI - Experiences of stigma and discrimination among users of mental health services in Poland. AB - Stigmatization is commonly recognized as one of the main barriers to recovery and to social inclusion of people with mental illnesses. This exploratory study investigated the frequency, type, and sources of actual stigma and discrimination experiences among Polish psychiatric patients. A total of 442 people, treated in various psychiatric health care facilities in Warsaw, were interviewed with the use of the Consumer Experiences of Stigma Questionnaire (CESQ). Qualitative data regarding sources of experienced stigma were also obtained. The respondents reported relatively frequent experiences of stigmatization in everyday situations and interpersonal relations, but they seldom complained of any specific instances of discrimination. The most frequently reported source of stigma was employers and supervisors at work, followed by family, and general community members. Implications of the findings for clinical practice and policy are discussed. PMID- 22222619 TI - Spontaneous resolution of acute T cell-mediated rejection in a renal transplant patient. AB - This case report presents spontaneous resolution of acute rejection in a 66-year old man who underwent a kidney transplant and developed acute rejection and pneumonia. Our main concern in this case was how to treat the concurrent infection while maintaining the immunosuppressive therapy with a narrow available therapeutic range, in order to save the renal allograft without increasing antirejection therapy. PMID- 22222620 TI - Association of 276G>T adiponectin gene polymorphism to plasma adiponectin and albuminuria in type 2 diabetic patients. AB - PURPOSE: The 276G>T polymorphism of the adiponectin (ADIPOQ) gene has been correlated with plasma adiponectin, type 2 diabetes (T2D) and its complications. Studies of the role of 276G>T polymorphism in the prevalence of T2D kidney disease are few and contradictory; ethnic differences might play a role. We aimed to assess the relationship of this polymorphism with albuminuria in a cohort of Caucasian T2D patients. METHODS: Consecutive T2D outclinic patients were screened and included upon informed consent; exclusion criteria were glomerular filtration rate (GFR)<30 ml/min, acute intercurrent illness and urinary tract infection. History, standard laboratory evaluation, total plasma adiponectin and genotyping for the 276 ADIPOQ locus were obtained. RESULTS: One hundred and three T2D patients were included. Forty-three (41.7%) of them had GG genotype, 50 (48.5%) had GT and 10 (9.7%) had TT genotype. Plasma adiponectin was significantly higher in TT-allele carriers (19.03+/-3.46 MUg/ml) than in GT (10.14+/-1.78 MUg/ml) and GG carriers (8.71+/-1.60 MUg/ml), P=0.003. Adiponectin was higher in albuminuric (13.97+/-2.07 MUg/ml) than in normoalbuminuric patients (6.91+/-0.88 MUg/ml), P=0.004. The prevalence of T allele was higher in normoalbuminuric patients [36 (69.2%) GT+TT carriers] than in albuminuric ones [24 (47.1%)], P=0.02. Logistic regression identified the following as predictors of albuminuria: GG genotype: P=0.003 (OR 4.2; CI 1.61-10.96); low GFR: P=0.003 (OR 0.97; CI 0.95-0.99); and high plasma adiponectin: P=0.012 (OR 1.07; CI 1.01-1.14). CONCLUSIONS: Our data suggest that 276G>T polymorphism of the ADIPOQ gene is associated with plasma adiponectin levels. By influencing adiponectinemia, 276G>T polymorphism might predict the presence of albuminuria in Caucasian T2D patients. PMID- 22222622 TI - Critical effects of alkyl chain length on fibril structures in benzene-trans(RR)- or (SS)-N,N'-alkanoyl-1,2-diaminocyclohexane gels. AB - Vibrational circular dichroism (VCD) spectra were recorded on benzene-d(6) gels formed by chiral low molecular mass gelators (LMGs), trans(RR)- or trans(SS)-N,N' alkanoyl-1,2-diaminocyclohexane (denoted by RR-C(n) or SS-C(n), respectively; n = the number of carbon atoms in an introduced alkanoyl group). Attention was focused on the effects of alkyl chain length on the structures of the gels. When n was changed from 6 to 12, the signs of the coupled peaks around 1550 cm(-1) in the VCD spectra, which were assigned to the symmetric and asymmetric C=O stretching vibrations from the higher to lower wavenumber, respectively, critically depended on the alkyl chain length. In the case of RR-C(n), for example, the signs of the couplet were plus and minus for n = 8, 9, 10 and 12, while the signs of the same couplet were reversed for n = 6 and 7. The conformations of LMGs in fibrils were determined by comparing the observed IR and VCD spectra with those calculated for a monomeric molecule. The observed reversal of signs in the C=O couplet was rationalized in terms of the different modes of hydrogen bonding. In the case of C(8), C(9), C(10) and C(12), gelator molecules were stacked with their cyclohexyl rings in parallel, forming double anti parallel chains of intermolecular hydrogen bonds using two pairs of >NH and >C=O groups. In case of C(6) and C(7), gelator molecules were stacked through a single chain of intermolecular hydrogen bonds using a pair of >NH and >C=O groups. The remaining pair of >NH and >C=O groups formed an intramolecular hydrogen bond. PMID- 22222621 TI - Cariogram validity in schoolchildren: a two-year follow-up study. AB - The validity of Cariogram in relation to caries increment over a 2-year period was evaluated. In 2007, the caries risk profile in a group of Sardinian schoolchildren (957) aged 7-9 years was assessed using the Cariogram software. A re-examination using the same criteria was performed 2 years later on 861 individuals from the original sample (drop-out 10.0%). The possible correlated variables were analyzed using the principal component analysis (PCA). The performances of Cariogram in predicting caries increment were evaluated by receiver operating characteristic (ROC) analysis. At follow-up examination, 54.4% of the sample had developed new carious lesions (mean DFS 1.6, 95% CI 1.5-1.8). The mean caries increment (DeltaDFS) was 0.5, 95% CI 0.4-0.5. PCA showed that Cariogram, gingival status and dietary sugar frequency, both at baseline and at follow-up, tend to form a separate cluster (goodness of fit >=0.75). Sensitivity and specificity measured by ROC analysis were 0.83 and 0.85, respectively, so the gain in certainty was 1.68, while the area under the ROC curve was 0.93. A strong correlation between caries risk profiles at baseline and caries incidence in the permanent teeth after 2 years was found. The validity of Cariogram was confirmed, the software fulfilling the criteria for a good risk assessment model: precision, accuracy and ease of use. PMID- 22222623 TI - Tailored excitation using nonlinear B0-shims. AB - In high-field MRI, RF flip angle inhomogeneity due to wavelength effects can lead to spatial variations in contrast and sensitivity. Improved flip angle homogeneity can be achieved through multidimensional excitation, but long RF pulse durations limit practical application. A recent approach to reduce RF pulse duration is based on parallel excitation through multiple RF channels. Here, an alternative approach to shorten multidimensional excitation is proposed that makes use of nonlinear spatial variations in the stationary (B(0)) magnetic field during a B(0)-sensitive excitation pulse. As initial demonstration, the method was applied to 2D gradient echo (GE) MRI of human brain at 7 T. Using B(0) shims with up to second-order spatial dependence, it is demonstrated that root-mean squared flip angle variation can be reduced from 20 to 11% with RF pulse lengths that are practical for general GE imaging applications without requiring parallel excitation. The method is expected to improve contrast and sensitivity in GE MRI of human brain at high field. PMID- 22222624 TI - Genetic variations in the dopamine system and facial expression recognition in healthy chinese college students. AB - OBJECTIVE: This study investigated the relation between genetic variations in the dopamine system and facial expression recognition. METHODS: A sample of Chinese college students (n = 478) was given a facial expression recognition task. Subjects were genotyped for 98 loci [96 single-nucleotide polymorphisms (SNPs) and 2 variable number tandem repeats] in 16 genes involved in the dopamine neurotransmitter system, including its 4 subsystems: synthesis (TH, DDC, and DBH), degradation/transport (COMT,MAOA,MAOB, and SLC6A3), receptors (DRD1,DRD2,DRD3,DRD4, and DRD5), and modulation (NTS,NTSR1,NTSR2, and NLN). To quantify the total contributions of the dopamine system to emotion recognition, we used a series of multiple regression models. Permutation analyses were performed to assess the posterior probabilities of obtaining such results. RESULTS: Among the 78 loci that were included in the final analyses (after excluding 12 SNPs that were in high linkage disequilibrium and 8 that were not in Hardy-Weinberg equilibrium), 1 (for fear), 3 (for sadness), 5 (for anger), 13 (for surprise), and 15 (for disgust) loci exhibited main effects on the recognition of facial expressions. Genetic variations in the dopamine system accounted for 3% for fear, 6% for sadness, 7% for anger, 10% for surprise, and 18% for disgust, with the latter surviving a stringent permutation test. CONCLUSIONS: Genetic variations in the dopamine system (especially the dopamine synthesis and modulation subsystems) made significant contributions to individual differences in the recognition of disgust faces. PMID- 22222626 TI - Thermodynamic origins of selective binding affinity between p sulfonatocalix[4,5]arenes with biguanidiniums. AB - The binding geometries, abilities and thermodynamic parameters for the intermolecular complexation of two water-soluble calixarenes, p sulfonatocalix[4]arene (SC4A) and p-sulfonatocalix[5]arene (SC5A), with biguanidinium guests, metformin (MFM) and phenformin (PFM), were investigated by (1)H and 2D NMR spectroscopy, X-ray crystallography, and isothermal titration calorimetry (ITC). The obtained results show that biguanidinium guests are captured by calixarenes with the alkyl or aromatic portion immersed into the cavities and the guanidinium portion fixed at the upper-rims. At both acidic and neutral conditions, SC4A always presents stronger binding affinities to biguanidinium guests than SC5A. Moreover, SC4A prefers to include MFM rather than PFM. As a result, the binding selectivity of MFM is up to 44.7 times for the SC4A/SC5A hosts. The intrinsic relationship between binding structures and selectivities were comprehensively analyzed and discussed from the viewpoint of thermodynamics. Finally, the ITC measurements were further performed in phosphate buffer instead of aqueous solution, to examine the buffer effects, counterion effect, and the differences between thermodynamic and apparent association constants. PMID- 22222625 TI - [The Austrian Tonsil Study 2010 - Part 2: Postoperative haemorrhage]. AB - BACKGROUND: Postoperative haemorrhage is the most common and serious complication of tonsil and adenoid surgery. Definitions, frequency and risk factors of postoperative bleedings are however, controversially discussed in the literature. PATIENTS AND METHODS: In a prospective multicenter cohort study all tonsillectomies (TE), adenotonsillectomies (TE + AE), tonsillotomies (TO), adenotonsillotomies (TO + AE) and adenoidectomies (AE) performed within 9 months from October 1st, 2009 - June 30th, 2010 were collected and evaluated. Postoperative haemorrhage was defined as any bleeding after extubation and was classified into 7 grades A1, A2, B1, B2, C, D and E depending on the therapy needed and the postoperative day. RESULTS: Data from 9 405 patients of 32 ENT departments in Austria were analysed. Overall postoperative haemorrhage rate for TE was 16.0%, for TE + AE 11.8%, for TO+/-AE 2.3% and for AE 0.8%. Surgical revision was necessary in almost one third of patients with a postoperative bleeding event (TE 5.3%, TE + AE 4.1%, TO 0.8% und AE 0.3%). Multiple haemorrhage occurred in every 5th patient, who experienced postoperative bleeding (1.7% of all patients). The frequency of haemorrhage depended on the type of surgery and the age of the individual. Severe bleedings requiring surgical revision were more frequent in children between 6 and 15 years and AE. 9 patients (1.2% of all patients with haemorrhage) experienced a dramatic haemorrhage (grade D), with the need of blood transfusions and difficult surgical control. No deaths occurred during the study period. CONCLUSIONS: Due to a new classification postoperative bleeding episodes could be precisely defined and postoperative risk factors were quantified. Considering all postoperative bleedings, including minor and anamnestic ones, the haemorrhage rate over all types of surgeries was 7.9% (2.7% of all patients required a surgical revision). Tonsillectomy (with or without adenoidectomy) carries the highest statistical risk of postoperative bleeding, with 4.9% of all patients requiring surgical intervention. Patients who experience one - albeit minimal - postoperative haemorrhage, have a 5 times higher risk for further bleeding requiring surgical control, and should therefore be carefully monitored. PMID- 22222627 TI - A validated high-performance liquid chromatographic method with diode-array detection for the estimation of xyloketal B in rat plasma. AB - A sensitive and specific HPLC-UV method was developed and validated for the determination of xyloketal B in rat plasma. Following liquid-liquid extraction, the separation was performed using an isocratic mobile phase of methanol acetonitrile-water (30/30/40, v/v/v) on a Phenomenex C(18) column (4.6mm*250mm, 5MUm). The eluent was monitored at 220nm and at a flow rate of 0.8mlmin(-1). A linear curve over the concentration range of 1-128MUg/ml (r>0.999) was established. The LLOQ of the method was 1MUg/ml. Good precision and accuracy at concentrations of 2.5, 25 and 100MUg/ml were obtained. The recovery of xyloketal B in plasma was >87.91%. The validated method was found to be specific, precise and accurate in the study. The analytic method was satisfactorily applied to perform preclinical pharmacokinetic study of xyloketal B in rat plasma. PMID- 22222628 TI - Development and validation of a liquid chromatography-tandem mass spectrometric method for the quantification of 5-thio-d-glucose in rat and human plasma. AB - A highly selective, sensitive, and robust liquid chromatography-tandem mass spectrometric method for the determination of 5-thio-d-glucose concentrations in rat and human plasma was developed and validated. The sample preparation procedure involved protein precipitation and solid phase extraction, which efficiently removed sources of interference present in the plasma. Chromatographic separation was obtained using an NH(2)-column with distilled water and acetonitrile as the mobile phase under gradient conditions. Detection was performed using tandem mass spectrometry equipped with an electrospray ionization interface in negative ion mode. The selected reaction monitoring (SRM) transitions for 5-thio-d-glucose and an internal standard (5-thio-d-glucose (13)C(6)) were m/z 195->m/z 105 and m/z 201->m/z 108, respectively. The correlation coefficients of the calibration curves ranged from 0.9997 to 0.9999 over a concentration range from 10 to 3000ng/mL plasma. The validated method was successfully applied to a pharmacokinetic study in rats. PMID- 22222629 TI - The antidiabetic drug metformin inhibits gastric cancer cell proliferation in vitro and in vivo. AB - Recent studies suggest that metformin, which is commonly used as an oral anti hyperglycemic agent of the biguanide family, may reduce cancer risk and improve prognosis, but the mechanisms by which metformin affects various cancers, including gastric cancer, remains unknown. The goal of the present study was to evaluate the effects of metformin on human gastric cancer cell proliferation in vitro and in vivo and to study microRNAs (miRNA) associated with antitumor effect of metformin. We used MKN1, MKN45, and MKN74 human gastric cancer cell lines to study the effects of metformin on human gastric cancer cells. Athymic nude mice bearing xenograft tumors were treated with or without metformin. Tumor growth was recorded after 4 weeks, and the expression of cell-cycle-related proteins was determined. In addition, we used miRNA array tips to explore the differences among miRNAs in MKN74 cells bearing xenograft tumors treated with or without metformin in vitro and in vivo. Metformin inhibited the proliferation of MKN1, MKN45, and MKN74 in vitro. Metformin blocked the cell cycle in G(0)-G(1)in vitro and in vivo. This blockade was accompanied by a strong decrease of G(1) cyclins, especially in cyclin D1, cyclin-dependent kinase (Cdk) 4, Cdk6 and by a decrease in retinoblastoma protein (Rb) phosphorylation. In addition, metformin reduced the phosphorylation of epidermal growth factor receptor and insulin-like growth factor-1 receptor in vitro and in vivo. The miRNA expression was markedly altered with the treatment of metformin in vitro and in vivo. Various miRNAs altered by metformin also may contribute to tumor growth in vitro and in vivo. PMID- 22222630 TI - Effects of anti-VEGF on pharmacokinetics, biodistribution, and tumor penetration of trastuzumab in a preclinical breast cancer model. AB - Both human epidermal growth factor receptor 2 (HER-2/neu) and VEGF overexpression correlate with aggressive phenotypes and decreased survival among breast cancer patients. Concordantly, the combination of trastuzumab (anti-HER2) with bevacizumab (anti-VEGF) has shown promising results in preclinical xenograft studies and in clinical trials. However, despite the known antiangiogenic mechanism of anti-VEGF antibodies, relatively little is known about their effects on the pharmacokinetics and tissue distribution of other antibodies. This study aimed to measure the disposition properties, with a particular emphasis on tumor uptake, of trastuzumab in the presence or absence of anti-VEGF. Radiolabeled trastuzumab was administered alone or in combination with an anti-VEGF antibody to mice bearing HER2-expressing KPL-4 breast cancer xenografts. Biodistribution, autoradiography, and single-photon emission computed tomography-X-ray computed tomography imaging all showed that anti-VEGF administration reduced accumulation of trastuzumab in tumors despite comparable blood exposures and similar distributions in most other tissues. A similar trend was also observed for an isotype-matched IgG with no affinity for HER2, showing reduced vascular permeability to macromolecules. Reduced tumor blood flow (P < 0.05) was observed following anti-VEGF treatment, with no significant differences in the other physiologic parameters measured despite immunohistochemical evidence of reduced vascular density. In conclusion, anti-VEGF preadministration decreased tumor uptake of trastuzumab, and this phenomenon was mechanistically attributed to reduced vascular permeability and blood perfusion. These findings may ultimately help inform dosing strategies to achieve improved clinical outcomes. PMID- 22222632 TI - Interplay of the tip-sample junction stability and image contrast reversal on a Cu(111) surface revealed by the 3D force field. AB - Non-contact atomic force microscopy is used to measure the 3D force field on a dense-packed Cu(111) surface. An unexpected image contrast reversal is observed as the tip is moved towards the surface, with atoms appearing first as bright spots, whereas hollow and bridge sites turn bright at smaller tip-sample distances. Computer modeling is used to elucidate the nature of the image contrast. We find that the contrast reversal is essentially a geometrical effect, which, unlike in gold, is observable in Cu due to an unusually large stability of the tip-sample junction over large distances. PMID- 22222631 TI - An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-03814735. AB - PF-03814735 is a novel, reversible inhibitor of Aurora kinases A and B that finished a phase I clinical trial for the treatment of advanced solid tumors. To find predictive biomarkers of drug sensitivity, we screened a diverse panel of 87 cancer cell lines for growth inhibition upon PF-03814735 treatment. Small cell lung cancer (SCLC) and, to a lesser extent, colon cancer lines were very sensitive to PF-03814735. The status of the Myc gene family and retinoblastoma pathway members significantly correlated with the efficacy of PF-03814735. Whereas RB1 inactivation, intact CDKN2A/p16, and normal CCND1/Cyclin D1 status are hallmarks of SCLC, activation or amplification of any of the three Myc genes (MYC, MYCL1, and MYCN) clearly differentiated cell line sensitivity within the SCLC panel. By contrast, we found that expression of Aurora A and B were weak predictors of response. We observed a decrease in histone H3 phosphorylation and polyploidization of sensitive lines, consistent with the phenotype of Aurora B inhibition. In vivo experiments with two SCLC xenograft models confirmed the sensitivity of Myc gene-driven models to PF-03814735 and a possible schedule dependence of MYC/c-Myc-driven tumors. Altogether our results suggest that SCLC and other malignancies driven by the Myc family genes may be suitable indications for treatment by Aurora B kinase inhibitors. PMID- 22222633 TI - A new indicator of fireworks emissions in Rochester, New York. AB - In ambient particle source apportionment studies, data for holidays such as July 4 (US Independence Day) are normally removed because of the high concentrations of chemical species and unusually high particle mass concentrations that are due to fireworks. Many cultures celebrate events with fireworks. A near real-time measurement that could indicate fireworks would be useful in indicating their impact on air quality. Commonly monitored ambient pollutants include PM(2.5), CO, SO(2), O(3), 10-500-nm particle number, and black carbon (BC). Using a two wavelength aethalometer, another parameter, delta-C (UVBC(370 nm)-BC(880 nm), aethalometer), can be calculated. These variables were continuously monitored during July 1-7, 2005-2010, in Rochester, New York. High delta-C values are normally associated with biomass combustion particles. However, statistically higher delta-C values were observed on Independence Day compared to the other period. Back trajectory analysis showed transport of local fireworks smoke to the sampling site on the night of July 4. An enhanced correlation between delta-C and BC during the fireworks episodes suggests changes from the usual BC sources. Fireworks emissions changed the ambient carbonaceous particulate species during these intervals. The delta-C value was found to be a readily measured indicator of fireworks emissions during periods when wood combustion was not likely to be present and provides a tool for monitoring such emissions where they might be more common such as amusement parks. PMID- 22222634 TI - Perampanel in Parkinson disease fluctuations: a double-blind randomized trial with placebo and entacapone. AB - OBJECTIVES: Perampanel is a selective and noncompetitive alpha-amino-3-hydroxy-5 methylisoxazole propionic acid-type glutamate receptor antagonist that improves motor symptoms in animal models of Parkinson disease (PD). The aim of this study was to assess the efficacy and tolerability of perampanel in L-dopa-treated patients with moderately severe PD and motor fluctuations using an active comparator study design. METHODS: This was a prospective, randomized, double blind, 3-arm, parallel-group, controlled study assessing the effects of perampanel (4 mg/d), placebo, or entacapone (200 mg with each dose of L-dopa) in 723 L-dopa-treated patients with PD with "OFF" problems. The primary outcome measure was the change from baseline in mean total daily OFF time based on diaries. Secondary end points included change from baseline in Unified Parkinson's Disease Rating Scale part II while OFF, Unified Parkinson's Disease Rating Scale part III while "ON," and mean total daily ON time without dyskinesias or with nontroublesome dyskinesias. RESULTS: In total, 480 patients (66.4%) completed the study, which was terminated early after negative results of 2 other large placebo-controlled studies became available. Perampanel was not superior to placebo on any efficacy end point, whereas entacapone was superior to placebo on the primary end point (P = 0.034) and most secondary outcomes. Perampanel was generally well tolerated. CONCLUSIONS: Perampanel (4 mg/d) was well tolerated but did not have a clinically significant effect in improving motor symptoms of L-dopa-treated patients with moderately advanced PD and motor fluctuations. These patients did respond to the active comparator, entacapone, confirming the validity of the findings despite the early termination of the study. PMID- 22222636 TI - The spectrum of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma: a description of 10 cases. AB - B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, is a diagnostic provisional category in the World Health Organization (WHO) 2008 classification of lymphomas. This category was designed as a measure to accommodate borderline cases that cannot be reliably classified into a single distinct disease entity after all available morphological, immunophenotypical and molecular studies have been performed. Typically, these cases share features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, or include characteristics of both lymphomas. The rarity of such cases poses a tremendous challenge to both pathologists and oncologists because its differential diagnosis has direct implications for management strategies. In this study, we present 10 cases of B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and classical Hodgkin lymphoma and have organized the criteria described by the WHO into four patterns along with detailed clinical, morphological and immunophenotypic characterization and outcome data. Our findings show a male preponderance, median age of 37 years and a mediastinal presentation in 80% of cases. All cases expressed at least two markers associated with B-cell lineage and good response to combination chemotherapy currently employed for non-Hodgkin lymphomas. PMID- 22222635 TI - Overexpression and oncogenic function of aldo-keto reductase family 1B10 (AKR1B10) in pancreatic carcinoma. AB - Aldo-keto reductase family 1B10 (AKR1B10) exhibits more restricted lipid substrate specificity (including farnesal, geranylgeranial, retinal and carbonyls), and metabolizing these lipid substrates has a crucial role in promoting carcinogenesis. Overexpression of AKR1B10 has been identified in smoking-related carcinomas such as lung cancer. As development of pancreatic cancer is firmly linked to smoking, the aim of the present study was to examine the expression and oncogenic role of AKR1B10 in pancreatic adenocarcinoma. AKR1B10 expression was analyzed in 50 paraffin-embedded clinical pancreatic cancer samples using immunohistochemistry. Oncogenic function of AKR1B10 was examined in pancreatic carcinoma cells in vitro using western blotting and siRNA approaches, mainly on cell apoptosis and protein prenylation including KRAS protein and its downstream signals. Immunohistochemistry analysis revealed that AKR1B10 overexpressed in 70% (35/50) of pancreatic adenocarcinomas and majority of pancreatic intraepithelial neoplasia, but not in adjacent morphologically normal pancreatic tissue. Compared with a normal pancreatic ductal epithelial cell (HPDE6E7), all of the six cultured pancreatic adenocarcinoma cell lines had an overexpression of AKR1B10 using immunoblotting, which correlated with increase of enzyme activity. siRNA-mediated silencing of AKR1B10 expression in pancreatic cancer cells resulted in (1) increased cell apoptosis, (2) increased non farnesyled HDJ2 protein and (3) decreased membrane-bound prenylated KRAS protein and its downstream signaling molecules including phosphorylated ERK and MEK and membrane-bound E-cadherin. Our findings provide first time evidence that AKR1B10 is a unique enzyme involved in pancreatic carcinogenesis possibly via modulation of cell apoptosis and protein prenylation. PMID- 22222637 TI - Accuracy of HER2 status determination on breast core-needle biopsies (immunohistochemistry, FISH, CISH and SISH vs FISH). AB - Preoperative breast cancer diagnosis on core biopsies has become a standard of care in many countries. Controversies exist concerning the accuracy of HER2 testing on biopsies as compared with surgical specimens, and few data exist concerning the use of emerging technologies such as bright-field in-situ hybridization in such a setting. A French multicenter, cross-sectional, histopathological study assessed the concordance of HER2 status determined by immunohistochemistry and silver (SISH) or chromogenic in-situ hybridization (CISH) on core-needle biopsies with HER2 status determined by fluorescence in situ hybridization (FISH) on surgical specimens. The concordance between biopsy and operative results was also assessed for each method. We studied 260 breast tumors from 24 centers between April 2003 and August 2009. Excellent concordance (kappa: 0.92-0.97) was shown between immunohistochemistry and FISH with low discordance rates (2-4%), high specificity (97-98%) and sensitivity values (95 99%), with no significant difference according to the immunohistochemistry interpretation guidelines used. The correlation between SISH and CISH on biopsies and FISH on surgical samples was strong (kappa: 0.96 and 0.94, respectively), with no significant difference between false negative rates or sensitivity and specificity values (2 and 5%, 99 and 96%, 98 and 98%, respectively). Whatever the evaluation technique, excellent concordance between biopsies and surgical specimens was observed (kappa >= 0.97; discordance rates between 1 and 2%), with high sensitivity (98-99%) and specificity (98-100%). Based on these results, when FISH cannot be used, SISH and/or CISH could be proposed as an alternative method to determine HER2 status and to confirm any ambiguous immunohistochemistry results, either for preoperative percutaneous biopsies or for surgical specimens. They could also be used for quality controls and immunohistochemistry calibration. PMID- 22222638 TI - Unique genetic profile of sporadic colorectal cancer liver metastasis versus primary tumors as defined by high-density single-nucleotide polymorphism arrays. AB - Most genetic studies in colorectal carcinomas have focused on those abnormalities that are acquired by primary tumors, particularly in the transition from adenoma to carcinoma, whereas few studies have compared the genetic abnormalities of primary versus paired metastatic samples. In this study, we used high-density 500K single-nucleotide polymorphism arrays to map the overall genetic changes present in liver metastases (n=20) from untreated colorectal carcinoma patients studied at diagnosis versus their paired primary tumors (n=20). MLH1, MSH2 and MSH6 gene expression was measured in parallel by immunohistochemistry. Overall, metastatic tumors systematically contained those genetic abnormalities observed in the primary tumor sample from the same subject. However, liver metastases from many cases (up to 8 out of 20) showed acquisition of genetic aberrations that were not found in their paired primary tumors. These new metastatic aberrations mainly consisted of (1) an increased frequency of genetic lesions of chromosomes that have been associated with metastatic colorectal carcinoma (1p, 7p, 8q, 13q, 17p, 18q, 20q) and, more interestingly, (2) acquisition of new chromosomal abnormalities (eg, losses of chromosomes 4 and 10q and gains of chromosomes 5p and 6p). These genetic changes acquired by metastatic tumors may be associated with either the metastatic process and/or adaption of metastatic cells to the liver microenvironment. Further studies in larger series of patients are necessary to dissect the specific role of each of the altered genes and chromosomal regions in the metastatic spread of colorectal tumors. PMID- 22222639 TI - Immunophenotyping in systemic mastocytosis diagnosis: 'CD25 positive' alone is more informative than the 'CD25 and/or CD2' WHO criterion. AB - Aberrant expression of CD2 and/or CD25 by bone marrow, peripheral blood or other extracutaneous tissue mast cells is currently used as a minor World Health Organization diagnostic criterion for systemic mastocytosis. However, the diagnostic utility of CD2 versus CD25 expression by mast cells has not been prospectively evaluated in a large series of systemic mastocytosis. Here we evaluate the sensitivity and specificity of CD2 versus CD25 expression in the diagnosis of systemic mastocytosis. Mast cells from a total of 886 bone marrow and 153 other non-bone marrow extracutaneous tissue samples were analysed by multiparameter flow cytometry following the guidelines of the Spanish Network on Mastocytosis at two different laboratories. The 'CD25+ and/or CD2+ bone marrow mast cells' World Health Organization criterion showed an overall sensitivity of 100% with 99.0% specificity for the diagnosis of systemic mastocytosis whereas CD25 expression alone presented a similar sensitivity (100%) with a slightly higher specificity (99.2%). Inclusion of CD2 did not improve the sensitivity of the test and it decreased its specificity. In tissues other than bone marrow, the mast cell phenotypic criterion revealed to be less sensitive. In summary, CD2 expression does not contribute to improve the diagnosis of systemic mastocytosis when compared with aberrant CD25 expression alone, which supports the need to update and replace the minor World Health Organization 'CD25+ and/or CD2+' mast cell phenotypic diagnostic criterion by a major criterion based exclusively on CD25 expression. PMID- 22222640 TI - HER2 testing in gastric cancer: a practical approach. AB - Trastuzumab in combination with capecitabine or 5-fluorouracil and cisplatin is approved by the European Medicines Agency for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive (immunohistochemistry 3+ or immunohistochemistry 2+/fluorescence in situ hybridization-positive or immunohistochemistry 2+/silver in situ hybridization-positive) metastatic adenocarcinoma of the stomach or gastro-esophageal junction. Approvals are underway in other countries, with recent approvals granted in the United States and Japan. Experience and data from trastuzumab use in breast cancer have highlighted the importance of quality HER2 testing and scoring to ensure accurate identification of patients eligible for treatment. HER2 testing in gastric cancer differs from testing in breast cancer due to inherent differences in tumor biology; gastric cancer more frequently shows HER2 heterogeneity (focal staining) and incomplete membrane staining. Consequently, gastric cancer-specific HER2 testing protocols have been developed and standardized and it is imperative that these recommendations be adhered to. Given the predictive value of HER2 protein levels with response in the trastuzumab for GAstric cancer study (ToGA), immunohistochemistry should be the initial testing methodology and fluorescence in situ hybridization or silver in situ hybridization should be used to retest immunohistochemistry 2+ samples. Wherever possible, bright-field methodologies should be used as these are considered to be superior to fluorescent methodologies at identifying heterogeneous staining. Specific training is required before embarking on HER2 testing in gastric cancer, irrespective of the experience of HER2 testing in breast cancer. This paper provides the most up-to date practical guidance on HER2 testing and scoring in patients with gastric and gastro-esophageal junction cancer, as agreed by a panel of expert pathologists with extensive experience of HER2 testing particularly reflecting the European Medicines Agency-approved indication. It is anticipated that these recommendations should ensure accurate and consistent HER2 testing, which will allow appropriate selection of patients eligible for treatment with trastuzumab. PMID- 22222641 TI - Mesotheliomas with small cell features: report of eight cases. AB - Mesotheliomas with small cell morphology are rare and only one study of such cases has been published. As a result of their rare occurrence, some investigators have cast doubt on the existence of such a histologic variant of mesothelioma. This investigator reports a series of eight cases of epithelioid mesothelioma with small cell features, all of which originated in the pleura. Seven of the patients were men and one was a woman. Four patients had a history of asbestos exposure. Histologically, four of the mesotheliomas were epithelioid and four biphasic. The proportion of small cells seen in these cases constituted 80 to 100% of the tumor included in the biopsy material and 15 to 20% of the tumor present in the pneumonectomy specimens. Immunoreactivity for calretinin, keratin 5/6, keratin 7, pan-keratin, WT1, podoplanin, and mesothelin was seen in all cases tested for these markers. All of the cases were negative for MOC-31, Ber-EP4, CEA, CD15, TAG-72, TTF-1, chromogranin A, synaptophysin, CD99, and desmin. The mean survival of the six patients for whom this information was available was 8.2 months. It is important for pathologists to be aware that mesotheliomas can present small cell features and, because of this, they can be confused with other malignancies that can exhibit similar morphology. The value of immunohistochemistry in the differential diagnosis of these tumors is discussed. PMID- 22222642 TI - Periarticular infiltration in total hip replacement: effect on heterotopic ossification, analgesic requirements and outcome. AB - BACKGROUND: Up to 80% of patients develop heterotopic ossification (HO) following total hip replacement (THR) and high grades may adversely affect outcome. This study investigated the influence of local infiltration of a NSAID (Ketorolac) and local anaesthetic on the incidence and grade of HO following THR, the effect on post-operative opiate analgesic requirement and on patient reported outcome score. METHODS: A retrospective study was performed on 118 THRs performed without periarticular infiltration from 2003 to 2005, and on 211 performed with infiltration from 2005 to 2008. Pre-operative and 12-month radiographs were examined and HO graded according to the Brooker classification. Peri-operative analgesic requirements and NSAID use were noted and outcome was measured at 1 year with the Oxford Hip Score. RESULTS: Univariate and multivariate analysis indicated that single-dose periarticular NSAID infiltration did not reduce the incidence or grade of HO. Preoperative HO (p = 0.005) and enthesopathy (p = 0.027) were significant predictors of post-operative HO. The use of post operative oral NSAID (except aspirin) significantly reduced HO (p = 0.001). Periarticular infiltration significantly reduced opiate analgesia use in the first 24 h (p < 0.001) and length of inpatient stay (p < 0.001). There was no difference in Oxford Hip Score at 1 year. CONCLUSION: Preoperative enthesopathies are a risk factor for postoperative HO. Periarticular infiltration of NSAID and local anaesthetic does not reduce HO incidence or grade in THR, but does reduce perioperative opiate requirements and length of hospital stay. PMID- 22222643 TI - End-tidal alveolar dead space ratio: a simple and useful parameter for intensivists. PMID- 22222644 TI - A little patience for our patients with lung disease: ECMO... eventually. PMID- 22222645 TI - Looking into the crystal ball: can we predict prognosis in children treated with therapeutic hypothermia after cardiac arrest?. PMID- 22222646 TI - Determination of cardiac output in critically ill children: are we any closer to the ideal methodology?. PMID- 22222647 TI - Refractory primary cardiac arrhythmias: extracorporeal membrane oxygenation bridging will save these lives. PMID- 22222648 TI - What can we learn from pulse oximetry of the newborn in the delivery room?. PMID- 22222649 TI - Right- versus left-sided congenital diaphragmatic hernia--can we trust the data?. PMID- 22222650 TI - The utility of comparing "like with like" in small randomized controlled trials: is this acceptable according to the rules of evidence-based medicine?. PMID- 22222651 TI - Pediatric mass critical care in a pandemic: yes, it is in the cards. PMID- 22222652 TI - Performing and teaching nonelective tracheal intubation in pediatric intensive care: finding the right balance between safety and training. PMID- 22222653 TI - H1N1 in Turkey: more pieces to the puzzle. PMID- 22222654 TI - Nutrition after head injury: challenges and recommendations. PMID- 22222655 TI - Ventilator-associated pneumonia: the unresolved issues of prevention and diagnosis. PMID- 22222656 TI - Acute liver failure: we measure the intracranial pressure and now what?. PMID- 22222657 TI - Intracranial pressure: influence of head-of-bed elevation, and beyond. PMID- 22222658 TI - Altered drug metabolism in critically ill children: a significant source of adverse effects?. PMID- 22222659 TI - Biomarkers for acute kidney injury: is the serum creatinine worthless? PMID- 22222660 TI - You say tomato, I say tomahto. Let's call the chart review off! PMID- 22222661 TI - Daily interruption of sedation in critically ill children. PMID- 22222663 TI - Learning from other industries. PMID- 22222665 TI - Management of severe dengue. PMID- 22222669 TI - Gene therapy for Huntington's disease. AB - Huntington's disease (HD) is a neurodegenerative disease for which there is no cure. Therapies that are efficacious in animal models have to date shown benefit for humans. One potential powerful approach is gene therapy. The ideal method of administration of gene therapy has been hotly debated and viral vectors have provided one method of long-term and wide-spread delivery to the brain. Trophic factors to protect cells from degeneration and RNAi to reduce mutant huntingtin (mHtt) protein expression are 2 main classes of compounds that demonstrate benefit in animal models. This review will examine some commonly used adeno associated viral (AAV) vectors and discuss some therapies that hold promise for HD. PMID- 22222670 TI - Differentiation of diastereotopic bromine atoms in SN2 reactions of gem dibromides. AB - A novel directed S(N)2 reaction of conformationally biased gem-dibromides and an arenesulfinate anion is described. The reaction results in the diastereoselective formation of alpha-bromosulfones. The selectivity originates from pre coordination of the nucleophile to a free hydroxyl group in the gamma-position. PMID- 22222671 TI - Two-stage culture method for optimized polysaccharide production in Spirulina platensis. AB - BACKGROUND: The polysaccharides of Spirulina platensis possess many biological functions. Reproducing the conditions under which S. platensis produces polysaccharides is critical to furthering our understanding of the function of these polysaccharides for commercial mass production. The changes in microalgal polysaccharide production were studied under greenhouse and laboratory conditions using varying light intensities, temperatures, and NaCl concentrations. RESULTS: The polysaccharide yield was positively correlated with culturing under 192 umol photons m(-2) s(-1) light intensity at 38 degrees C or in 0.75 mol L(-1) NaCl. However, NaCl reduced the total biomass productivity of S. platensis. To mitigate the negative effects of environmental stress on maximal polysaccharide production, we proposed a two-stage culture method. The first stage, designed to increase biomass production, involved culturing under 96 umol photons m(-2) s(-1) light intensity at 28 degrees C. Following this, on achieving maximum biomass production, the second stage, designed to stimulate polysaccharide production, involved culturing under 192 umol photons m(-2) s(-1) light intensity at 38 degrees C for 3 days or in a 0.75 mol L(-1) NaCl medium for 2 days. High performance liquid chromatographic analysis revealed that S. platensis polysaccharides were composed of various monosaccharides, including glucose, galactose, rhamnose, mannose, fructose, and mannitol. CONCLUSION: The two-stage culture can be successfully applied to achieve the goal of polysaccharide mass production. The first stage focuses on rapidly increasing microalgal biomass. The second stage of culture conditions requires modification to maximize polysaccharide yield. PMID- 22222672 TI - Posterior vaginal compartment prolapse and defecatory dysfunction: are they related? AB - While posterior vaginal compartment prolapse and defecatory dysfunction are highly prevalent conditions in women with pelvic floor disorders, the relationship between anatomy and symptoms, specifically obstructed defecation, is incompletely understood. This review discusses the anatomy of the posterior vaginal compartment and definitions of defecatory dysfunction and obstructed defecation. A clinically useful classification system for defecatory dysfunction is highlighted. Available tools for the measurement of symptoms, physical findings, and imaging in women with posterior compartment prolapse are discussed. Based on a critical review of the literature, we investigate and summarize whether posterior compartment anatomy correlates with function. Definitions of obstructed defecation and significant posterior compartment prolapse are proposed for future exploration. PMID- 22222673 TI - Impact on quality of life after ring pessary use for pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: The purpose of this study was to evaluate symptoms associated with pelvic organ prolapse (POP) and quality of life (QOL) improvement in patients who continue ring pessary use at 1 year. METHODS: Seventy-seven symptomatic POP patients had successful fitting, and 64 patients (83.1%) continued use at 1 year. The Thai version of Prolapse Quality of Life (P-QOL) questionnaire was used to evaluate symptoms associated with POP and impact on QOL. A higher score represents a greater impairment on the QOL, whereas a lower score represents a better QOL. RESULTS: Mean age was 66.7 +/- 8.6 years, median parity was 4 (range 0-10), 59 patients (92.2%) were menopausal, and none had received hormone treatment. Only nine patients (14.1%) were sexually active. Most patients were in the advanced stage of POP - 32.8% stage 3 and 29.7% stage 4. Improvement of prolapse symptoms and voiding difficulty were reported in 100% and 85.7% of the patients, respectively. Among patients who had lower urinary tract symptoms at pre-treatment, about half of patients improvement in frequency, urgency, and urgency urinary incontinence. Only 9.1% of the patients had improvement in stress urinary incontinence (SUI), and 23.8% of the patients reported new onset of SUI (de novo SUI). The median score from all P-QOL domains except personal relationships were significantly decreased after 1 year of ring pessary use. The median total scores at baseline and at 1 year were 40 and 8, respectively (P < 0.001). CONCLUSIONS: Ring pessary is an effective non-surgical treatment to alleviate symptoms associated with POP. It can improve QOL in symptomatic POP patients. PMID- 22222675 TI - Genetics of pelvic organ prolapse: comment. PMID- 22222677 TI - Molecular basis of arterial stiffening: role of glycation - a mini-review. AB - Arterial stiffening is a progressive, ubiquitous and irreversible aging process that is interwoven with and accelerated by various diseases such as diabetes, atherosclerosis and hypertension. In large arteries, aging is characterized by decreased turnover of collagen and elastin and increased advanced glycation end products (AGEs) and cross-links. Elastic fibers undergo lysis and disorganization subsequent to their replacement by collagen and other matrix components. These events cause the loss of elasticity and induce stiffening. Conceptual approaches to minimize AGE accumulation in arteries include caloric restriction, exercise, low dietary intake of AGEs, deglycation enzymes, increased clearance of AGEs, antagonists of AGE receptors and pharmaceutical interventions. Much optimism exists in the ability of 'AGE breakers' such as alagebrium (ALT-711) to cleave AGE cross-links and reverse the age-related stiffening of arteries. However, there is little evidence that these agents actually break pre-existing AGE cross links in vivo. In contrast, many of these anti-AGE agents share in common the ability to chelate metals, thus acting as inhibitors of metal-catalyzed AGE and protein carbonyl formation. Future work on interventions into the causes of arterial stiffness in aging needs to address more rigorously the relationship between stochastic forms of damage, such a glycation and oxidation, and the changes in elastic fiber structure thought to contribute to loss of arterial elasticity. PMID- 22222676 TI - Circulating levels of persistent organic pollutants (POPs) and carotid atherosclerosis in the elderly. AB - BACKGROUND AND OBJECTIVE: Increased circulating levels of persistent organic pollutants (POPs) have been associated with myocardial infarction. Because myocardial infarction is an atherosclerotic disease, we investigated, in a cross sectional study, whether POP levels are related to atherosclerosis. METHODS: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 1,016 participants 70 years of age), the prevalence of carotid artery plaques was determined by ultrasound. The number of carotid arteries with plaques (0, 1, or 2) was recorded. Also, the intima-media thickness (IMT) and gray scale median of the intima-media complex (IM-GSM) were measured. Twenty-three POPs, comprising 16 polychlorinated biphenyls (PCBs), 5 pesticides, 1 dioxin, and 1 brominated compound (brominated diphenyl ether congener BDE-47), were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry. RESULTS: Seven of the POPs (PCB congeners 153, 156, 157, 170, 180, 206, and 209) were significantly associated with the number of carotid arteries with plaques even after adjusting for multiple risk factors (sex, waist circumference, body mass index, fasting blood glucose, systolic and diastolic blood pressure, high-density lipoprotein and low-density lipoprotein cholesterol, serum triglycerides, smoking, antihypertensive treatment, and statin use; p = 0.002-0.0001). Highly chlorinated PCBs (congeners 194, 206, and 209) were associated with an echolucent IM-GSM (p < 0.0001 after adjustment), whereas associations between POPs and IMT were modest. CONCLUSIONS: Circulating levels of PCBs were associated with atherosclerotic plaques and echogenicity of the intima media complex independent of cardiovascular risk factors, including lipids. This suggests that POPs may be a risk factor for myocardial infarction, but associations need to be confirmed in prospective studies. PMID- 22222678 TI - Use of liquid nitrogen during storage in a cell and tissue bank: contamination risk and effect on the detectability of potential viral contaminants. AB - Cryopreservation is widely used for banking cells and tissues intended for transplantation. Liquid nitrogen provides a very stable ultra-low temperature environment. Thus, it is used for longterm storage. Unlike the exhaustive microbiological monitoring of the environmental conditions during tissue processing, storage is not usually considered as a critical point of potential contamination risk in professional standards for cell and tissue banking. We have analysed the presence of microbial agents inside our nitrogen tanks. We have mainly detected environmental and water-borne bacteria and fungi. In addition, we have studied the effect of liquid nitrogen exposure on virus detectability. Only differences for hepatitis C virus RNA were observed. Measures for contamination risk reduction during storage must be mandatory in cell and tissue banking. PMID- 22222680 TI - Changes to sexual well-being and intimacy after breast cancer. AB - BACKGROUND: Changes to sexual well-being can be one of the most problematic aspects of life after breast cancer, with the impact lasting for many years after treatment, associated with serious physical and emotional adverse effects. However, the primary focus on corporeal changes negates the influence of social and relational constructions of sexuality and illness and the ways in which the meaning of sex is negotiated by individuals and within relationships. OBJECTIVE: The aim of this study was to examine changes to sexuality and intimate relationships in individuals who have experienced breast cancer, from a material discursive-intrapsychic perspective, using mixed-method analysis. METHODS: An online survey containing 47 quantitative and qualitative items was completed by 1965 Australian individuals with breast cancer. Participants were 98% women, with a mean age of 54 years. RESULTS: Decreases in sexual frequency, response, and satisfaction were attributed to a range of factors, including tiredness and pain, psychological distress and body image, and medically induced menopausal changes such as vaginal dryness, hot flushes, and weight gain. Predominant concerns identified in the qualitative analysis were emotional consequences, physical changes, feeling unattractive or lacking femininity, reconciliation of self to changes, and impact on partner or relationship. CONCLUSIONS: These findings support and extend previous research that reports significant changes in sexual well-being after diagnosis and treatment for breast cancer. IMPLICATIONS FOR PRACTICE: The findings are of significance to clinicians because sexual well being is central to psychological well-being and quality of life, and sexual intimacy has been found to make the experience of cancer more manageable and to assist in the recovery process. PMID- 22222681 TI - Confirmatory factor analysis of the Chinese Breast Cancer Screening Beliefs Questionnaire. AB - BACKGROUND: Chinese women have been consistently reported as having low breast cancer screening practices. The Chinese Breast Cancer Screening Beliefs Questionnaire (CBCSB) was designed to assess Chinese Australian women's beliefs, knowledge, and attitudes toward breast cancer and screening practices. OBJECTIVES: The objectives of the study were to confirm the factor structure of the CBCSB with a new, larger sample of immigrant Chinese Australian women and to report its clinical validity. METHODS: A convenience sample of 785 Chinese Australian women was recruited from Chinese community organizations and shopping malls. Cronbach alpha was used to assess internal consistency reliability, and Amos v18 was used for confirmatory factor analysis. Clinical validity was assessed through linear regression using SPSS v18. RESULTS: The 3-factor structure of the CBCSB was confirmed, although the model required respecification to arrive at a suitable model fit as measured by the goodness-of-fit index (0.98), adjusted goodness-of-fit index (0.97), normed fit index (0.95), and root mean square error of approximation (0.031). Internal consistency reliability coefficients were satisfactory (>.6). Women who engaged in all 3 types of screening had more proactive attitudes to health checkups and perceived less barriers to mammographic screening. CONCLUSION: The CBCSB is a valid and reliable tool for assessing Chinese women's beliefs, knowledge, and attitudes about breast cancer and breast cancer screening practices. IMPLICATION FOR PRACTICE: The CBCSB can be used for providing practicing nurses with insights into the provision of culturally sensitive breast health education. PMID- 22222682 TI - Modified repair of interrupted aortic arch utilizing retroesophageal right subclavian artery based on a neonatal hybrid approach in hypoplastic left heart complex. AB - OBJECTIVE: Interrupted aortic arch (IAA) combined with an aberrant right subclavian artery (ARSA) is frequently associated with a hypoplastic ascending aorta. Neonatal surgical therapy carries a high risk particularly for aortic arch obstructions during the further follow-up. METHODS: We performed a modified reconstruction of the aortic arch utilizing the ARSA as a natural substitute in a staged surgical approach. In a novel approach, the distal part of the ARSA is reimplanted into the brachiocephalic trunk. RESULTS: In three patients, a novel arch reconstruction was successfully performed during complete biventricular repair. In a follow-up of 60 to 87 months, the reconstructed aortic arch has grown without any signs of obstruction in all three patients. CONCLUSION: Utilizing the ARSA for surgical aortic arch repair is a satisfactory solution, when postnatal borderline left heart obstruction associated with IAA and ARSA is postponed by an initial hybrid approach. PMID- 22222683 TI - Beneficial effects of vasopressors on right ventricular function in experimental acute right ventricular failure in a rabbit model. AB - BACKGROUND: An acute increase in right ventricular (RV) afterload leads to RV dilation, reduced systolic function, and low cardiac output. It has previously been shown, experimentally, that an additional increase of left ventricular afterload by aortic constriction can reverse some of these changes. We studied the clinically more relevant effects of intravenous vasopressors on this phenomenon in an animal model. METHODS: Acute RV failure was induced by pulmonary artery constriction in adult New Zealand white rabbits. We then assessed the effect of aortic constriction on the functional performance of the failing RV using conductance catheters. We compared the impact of aortic constriction on RV contractility with the effects of 0.05, 0.1, 0.5, and 1 mcg/kg * min(-1) norepinephrine and epinephrine. RESULTS: Aortic constriction lead to increased RV end-systolic pressure-volume relation (RVESPVR 3.2 (+/-0.6) versus 5.2 (+/-0.7) mm Hg/mL (p = 0.0002). Cardiac output (131 (+/-23.7) versus 134.8 (+/-32.5) mL/min), and heart rate remained unchanged. Administration of norepinephrine and epinephrine lead to similar effects on RV contractility with the maximum increase in RVESPVR observed with 0.5 mcg/kg * min(-1) norepinephrine (RVESPVR 4.8 (+/ 0.4) mm Hg/mL, p = 0.007). However, in contrast to aortic constriction, cardiac output also markedly increased during vasopressor therapy, the most significant effect seen with 1 mcg/kg * min(-1) epinephrine (214.8 (+/-46.8) mL/min, p = 0.04). CONCLUSIONS: Aortic constriction improves RV contractility but not cardiac output in acute right heart failure. A comparable effect on RV functional performance with increased cardiac output was achieved by administration of systemic vasopressors. These data may have implications for management of clinical right heart failure. PMID- 22222679 TI - Contribution of serotonergic transmission to the motor and cognitive effects of high-frequency stimulation of the subthalamic nucleus or levodopa in Parkinson's disease. AB - Although they are effective at treating the motor impairments that are the core symptoms of Parkinson's disease, current treatments, namely L: -3,4 dihydroxyphenylalanine (L: -DOPA), the gold standard medication and high frequency stimulation of the subthalamic nucleus (HFS-STN), can lead to cognitive and mood alterations. Many of these side effects, such as depression, anxiety and sleep disturbances, could be related to abnormal functioning of the serotonergic system, but much basic research remains to be done. Molecular studies in humans and animal models of the disease have reported diverse drastic changes to the serotonergic system. It has also been shown that the serotonergic system both plays a major role in the mechanism of action of the current therapies and is altered by the therapies. It has been reported that HFS-STN decreases serotonin release in several regions, mostly via inhibition of serotonergic neuron activity. The involvement of serotonergic neurons in L: -DOPA treatment is even more significant. First, serotonergic neurons, able to convert exogenous L: -DOPA to dopamine, are a major site to release dopamine throughout the brain. Second, the substitution of serotonin by newly synthesized dopamine in serotonin neurons leads to acute and chronic alteration of serotonin release and metabolism. Therefore, both therapeutic approaches, via distinct mechanisms, decrease serotonergic system activity and, rather than alleviating cognitive or mood disorders, tend to aggravate them. Molecular strategies targeting the serotonergic system are being developed and could be decisive in limiting L: DOPA-induced dyskinesia, as well as mood and cognitive symptoms produced by antiparkinsonian therapies. PMID- 22222684 TI - The protective effect of adrenomedullin on renal injury, in a model of abdominal aorta cross-clamping. AB - Renal injury induced by aortic ischemia-reperfusion (IR) is an important factor in the development of postoperative acute renal failure following abdominal aortic surgery. The aim of this study was to examine the effect of adrenomedullin (AM) on kidney injury induced by infrarenal abdominal aortic IR in rats. Thirty two Wistar Albino rats were randomized into four groups (eight per group) as follows: Control group, IR group (120-minute ischemia and 120-minute reperfusion), IR + AM group (a bolus intravenously of 0.05 ug/kg/min AM), and control + AM group. At the end of the experiment, blood and kidney tissue specimens were obtained for biochemical analysis. Immunohistological evaluation of the rat kidney tissues was also done. IR significantly increased (p < 0.05 vs control group) and AM significantly decreased (p < 0.05 vs. IR group) all of the biochemical parameters. Immunohistological evaluation showed that AM attenuated morphological changes as apoptosis associated with kidney injury. The results of this study indicate that AM attenuates both biochemically and immunohistopathologically kidney injury induced by aortic IR in rats. PMID- 22222685 TI - Invited commentary. PMID- 22222686 TI - Fast Monte Carlo simulation for patient-specific CT/CBCT imaging dose calculation. AB - X-ray imaging dose from computed tomography (CT) or cone beam CT (CBCT) scans has become a serious concern. Patient-specific imaging dose calculation has been proposed for the purpose of dose management. While Monte Carlo (MC) dose calculation can be quite accurate for this purpose, it suffers from low computational efficiency. In response to this problem, we have successfully developed a MC dose calculation code, gCTD, on GPU architecture under the NVIDIA CUDA platform for fast and accurate estimation of the x-ray imaging dose received by a patient during a CT or CBCT scan. Techniques have been developed particularly for the GPU architecture to achieve high computational efficiency. Dose calculations using CBCT scanning geometry in a homogeneous water phantom and a heterogeneous Zubal head phantom have shown good agreement between gCTD and EGSnrc, indicating the accuracy of our code. In terms of improved efficiency, it is found that gCTD attains a speed-up of ~400 times in the homogeneous water phantom and ~76.6 times in the Zubal phantom compared to EGSnrc. As for absolute computation time, imaging dose calculation for the Zubal phantom can be accomplished in ~17 s with the average relative standard deviation of 0.4%. Though our gCTD code has been developed and tested in the context of CBCT scans, with simple modification of geometry it can be used for assessing imaging dose in CT scans as well. PMID- 22222687 TI - Prolongation of epidural analgesia using solid lipid nanoparticles as drug carrier for lidocaine. AB - BACKGROUND AND OBJECTIVES: Solid lipid nanoparticles (SLNs), as a drug carrier, are a very attractive strategy for sustained and controlled drug release. In this study, we investigated the feasibility of SLNs to prolong the action of lidocaine for potential application in epidural anesthesia and analgesia. METHODS: Lidocaine-loaded SLNs were prepared with different lipids, including monostearin (MS), glyceryl palmitostearate (GP), and stearic acid (SA). The morphology and crystallinity were characterized with transmission electron microscopy and powder x-ray diffraction. In vitro release studies were carried in phosphate buffer solution of pH 7.4 using cellulose dialysis membrane. The in vivo efficacy of epidural anesthesia was evaluated in rats. RESULTS: Lidocaine was successfully incorporated in SLNs prepared with MS, GP, and SA, respectively. The particle sizes of lidocaine-loaded SLNs were 143 to 388 nm with polydispersity index of 0.29 to 0.45. Powder x-ray diffraction analysis showed that lidocaine was mainly dispersed in SLNs in an amorphous state. The in vitro release within 48 hrs showed that lidocaine released from SLNs was 80% with MS SLNs, 69% with GP SLNs, and 89% with SA SLNs. The epidural efficacy was compared with that of aqueous lidocaine HCl. Single injection of lidocaine SLN suspension produced epidural block for more than 8 hrs with MS SLNs, 12 hrs with GP SLNs, and 4 hrs with SA SLNs. ]The same dose of lidocaine in aqueous solution lasted for less than 2 hrs. CONCLUSIONS: Solid lipid nanoparticles can be exploited as a promising drug carrier for extending the action of lidocaine. PMID- 22222688 TI - Ultrasound-guided suprascapular nerve block, description of a novel supraclavicular approach. AB - BACKGROUND AND OBJECTIVES: The suprascapular nerve (SSN) block is frequently performed for different shoulder pain conditions and for perioperative and postoperative pain control after shoulder surgery. Blind and image-guided techniques have been described, all of which target the nerve within the supraspinous fossa or at the suprascapular notch. This classic target point is not always ideal when ultrasound (US) is used because it is located deep under the muscles, and hence the nerve is not always visible. Blocking the nerve in the supraclavicular region, where it passes underneath the omohyoid muscle, could be an attractive alternative. METHODS: In the first step, 60 volunteers were scanned with US, both in the supraclavicular and the classic target area. The visibility of the SSN in both regions was compared. In the second step, 20 needles were placed into or immediately next to the SSN in the supraclavicular region of 10 cadavers. The accuracy of needle placement was determined by injection of dye and following dissection. RESULTS: In the supraclavicular region of volunteers, the nerve was identified in 81% of examinations (95% confidence interval [CI], 74% 88%) and located at a median depth of 8 mm (interquartile range, 6-9 mm). Near the suprascapular notch (supraspinous fossa), the nerve was unambiguously identified in 36% of examinations (95% CI, 28%-44%) (P < 0.001) and located at a median depth of 35 mm (interquartile range, 31-38 mm; P < 0.001). In the cadaver investigation, the rate of correct needle placement of the supraclavicular approach was 95% (95% CI, 86%-100%). CONCLUSIONS: Visualization of the SSN with US is better in the supraclavicular region as compared with the supraspinous fossa. The anatomic dissections confirmed that our novel supraclavicular SSN block technique is accurate. PMID- 22222689 TI - Inherent correction of motion-induced phase errors in multishot spiral diffusion weighted imaging. AB - Multishot spiral imaging is a promising alternative to echo-planar imaging for high-resolution diffusion-weighted imaging and diffusion tensor imaging. However, subject motion in the presence of diffusion-weighting gradients causes phase inconsistencies among different shots, resulting in signal loss and aliasing artifacts in the reconstructed images. Such artifacts can be reduced using a variable-density spiral trajectory or a navigator echo, however at the cost of a longer scan time. Here, a novel iterative phase correction method is proposed to inherently correct for the motion-induced phase errors without requiring any additional scan time. In this initial study, numerical simulations and in vivo experiments are performed to demonstrate that the proposed method can effectively and efficiently correct for spatially linear phase errors caused by rigid-body motion in multishot spiral diffusion-weighted imaging of the human brain. PMID- 22222691 TI - Positive selection sites in the surface genes of dengue virus: phylogenetic analysis of the interserotypic branches of the four serotypes. AB - The existence of four dengue serotypes is associated with a phenomenon called "Antibody-Dependent Enhancement" that has been suggested to cause a severe form of dengue hemorrhagic fever and shock syndrome. To study the evolutionary event that drove the serotype separation, we employed the maximum likelihood approach by focusing on the Premembrane (prM) and Envelop (E) genes. We showed that the separation of dengue serotypes had been dominantly under purifying selection. In spite of the strong selective constraint, one codon of prM gene and twelve codons of E gene were detected to be under positive selection. This indicates that the E protein might have been under a stronger positive pressure than the PrM protein. The codons under positive selection were identified along the interserotypic branches, suggesting that changes at these sites were probably associated with the emergence of the four serotypes and/or adaptation to the new transmission environments. PMID- 22222690 TI - Genetic structure of Pacific Flyway avian influenza viruses is shaped by geographic location, host species, and sampling period. AB - The eight gene segments of avian influenza virus (AIV) reassort frequently and rapidly to generate novel genotypes and subtypes that are transmissible to a broad range of hosts. There is evidence that AIV can have a restricted host range and can segregate in space and time. Host-virus relationships at the species, geographic, and spatial scales have not been fully defined for AIV populations of the Pacific Flyway, particularly among the diverse waterfowl that occupy the Flyway in Alaska and California. Using the sequence analysis program Bayesian Tip association Significance testing (BaTS) created for analysis of phylogeny-trait associations, we determined whether the genetic structure of Pacific Flyway AIVs sampled between 2006 and 2008 was influenced by the host species, geographic location of virus collection, and time of sampling. In posterior sets of trees, genetically similar viruses clustered by host species for thick-billed murres and glaucous gulls (order Charadriiformes), and for northern shovelers, northern pintails, and mallards (order Anseriformes). AIVs from Alaska and California were strongly spatially structured, clustering separately by region across all segments. The timing of sampling influenced the genetic structure of California AIV gene segments, possibly reflecting waves of host species movement into wintering areas. The strength of phylogeny-trait association varied by virus segment and by trait of interest, which we hypothesize is related to the frequent genetic reassortment and interspecies transmission in waterfowl. PMID- 22222692 TI - Overview of muscarinic receptor subtypes. AB - The physiological role of muscarinic receptors is highly complex and, although not completely understood, has become clearer over the last decade. Recent pharmacological evidence with novel compounds, together with data from transgenic mice, suggests that all five subtypes have defined functions in the nervous system as well as mediating the non neuronal, hormonal actions of acetylcholine. Numerous novel agonists, allosteric regulators, and antagonists have now been identified with authentic subtype specificity in vitro and in vivo. These compounds provide additional pharmacological opportunities for selective subtype modulation as well as a new generation of muscarinic receptor-based therapeutics. PMID- 22222693 TI - Structure-function studies of muscarinic acetylcholine receptors. AB - There has been great interest in the structure-function relationships of the muscarinic acetylcholine receptors (mAChRs) because these prototypical Family A/class 1 G protein-coupled receptors (GPCRs) are attractive therapeutic targets for both peripheral and central nervous system disorders. A multitude of drugs that act at the mAChRs have been identified over the years, but many of these show minimal selectivity for any one of the five mAChR subtypes over the others, which has hampered their development into therapeutics due to adverse side effects. The lack of drug specificity is primarily due to high sequence similarity in this family of receptor, especially in the orthosteric binding pocket. Thus, there remains an ongoing need for a molecular understanding of how mAChRs bind their ligands, and how selectivity in binding and activation can be achieved. Unfortunately, there remains a paucity of solved high-resolution structures of GPCRs, including the mAChRs, and thus most of our knowledge of structure-function mechanisms related to this receptor family to date has been obtained indirectly through approaches such as mutagenesis. Nonetheless, such studies have revealed a wealth of information that has led to novel insights and may be used to guide future rational drug design campaigns. PMID- 22222694 TI - Polymorphisms in human muscarinic receptor subtype genes. AB - A wide range of polymorphisms have been reported in muscarinic receptor subtype genes, mostly in M1 and M2 and, to a lesser extent, M3 receptors. Most studies linking such genetic variability to phenotype have been performed for brain functions, but a more limited amount of information is also available for cardiac and airway function. Unfortunately, for none of the phenotypes under investigation a robust association with genotype has emerged. Moreover, it remains mostly unclear whether a reported association indicates a causative role of the polymorphism under investigation or merely a role as indicator of other polymorphisms affecting expression and/or function of the receptor. Also, most data on genotype-phenotype associations of muscarinic receptor subtypes are based on cross-sectional samples. Mechanistic studies linking polymorphisms to molecular, cellular, and tissue functions are largely missing. Finally, studies on a possible impact of muscarinic receptor polymorphisms on drug responsiveness are also largely missing. Thus, the field of genomics of muscarinic receptor subtypes is still in an early stage and a considerably greater number of studies will be required to judge the role of muscarinic receptor gene variability in physiology, pathophysiology, and drug treatment. PMID- 22222695 TI - Muscarinic receptor trafficking. AB - Knowledge of the mechanisms responsible for the trafficking of neurotransmitter receptors away from the cell surface is of obvious importance in understanding what regulates their expression and function. This chapter will focus on the mechanisms responsible for the internalization and degradation of muscarinic receptors. There are both receptor subtype-specific and cell-type specific differences in muscarinic receptor trafficking. Studies on muscarinic receptor trafficking both in cells in culture and in vivo will be described, and the potential physiological consequences of this trafficking will be discussed. PMID- 22222696 TI - Physiological role of G-protein coupled receptor phosphorylation. AB - It is now well established that G-protein coupled receptors (GPCRs) are hyper phosphorylated following agonist occupation usually at serine and threonine residues contained on the third intracellular loop and C-terminal tail. After some 2 decades of intensive research, the nature of protein kinases involved in this process together with the signalling consequences of receptor phosphorylation has been firmly established. The major challenge that the field currently faces is placing all this information within a physiological context and determining to what extent does phosphoregulation of GPCRs impact on whole animal responses. In this chapter, we address this issue by describing how GPCR phosphorylation might vary depending on the cell type in which the receptor is expressed and how this might be employed to drive selective regulation of physiological responses. PMID- 22222697 TI - Novel muscarinic receptor mutant mouse models. AB - Muscarinic acetylcholine (ACh) receptors (mAChRs; M1-M5) regulate the activity of an extraordinarily large number of important physiological processes. During the past 10-15 years, studies with whole-body M1-M5 mAChR knockout mice have provided many new insights into the physiological and pathophysiological roles of the individual mAChR subtypes. This review will focus on the characterization of a novel generation of mAChR mutant mice, including mice in which distinct mAChR genes have been excised in a tissue- or cell type-specific fashion, various transgenic mouse lines that overexpress wild-type or different mutant M3 mAChRs in certain tissues or cells only, as well as a novel M3 mAChR knockin mouse strain deficient in agonist-induced M3 mAChR phosphorylation. Phenotypic analysis of these new animal models has greatly advanced our understanding of the physiological roles of the various mAChR subtypes and has identified potential targets for the treatment of type 2 diabetes, schizophrenia, Parkinson's disease, drug addiction, cognitive disorders, and several other pathophysiological conditions. PMID- 22222698 TI - Muscarinic receptor pharmacology and circuitry for the modulation of cognition. AB - The muscarinic cholinergic system constitutes an important part of the neuronal circuitry that modulates normal cognition. Muscarinic receptor antagonists are well known to produce or exacerbate impairments in attention, learning, and memory. Conversely, both direct-acting muscarinic receptor agonists and indirect acting muscarinic cholinergic agonists, such as acetylcholinesterase inhibitors, have shown cognition-enhancing properties, including improvements in normal cognitive function, reversal of cognitive deficits induced by muscarinic receptor antagonists, and attenuation of cognitive deficits in psychiatric and neurological disorders, such as Alzheimer's disease and schizophrenia. However, until recently, the lack of small molecule ligands that antagonize or activate specific muscarinic acetylcholine receptor (mAChR) subtypes with high selectivity has been a major obstacle in defining the relative contributions of individual mAChRs to different aspects of cognitive function and for the development of novel therapeutic agents. These limitations may be potentially overcome by the recent discovery of novel mAChR subtype-selective compounds, notably allosteric agonists and positive allosteric modulators, which exhibit greater selectivity for individual mAChR subtypes than previous mAChR orthosteric agonists. In preclinical studies, these novel ligands have shown promising efficacy in several models for the enhancement of cognition. In this chapter, we will review the muscarinic cholinergic circuitry and pharmacology of mAChR agonists and antagonists relevant to the modulation of different aspects of cognition in animals and clinical populations. PMID- 22222699 TI - Muscarinic agonists and antagonists in schizophrenia: recent therapeutic advances and future directions. AB - Existing therapies for schizophrenia have limited efficacy, and significant residual positive, negative, and cognitive symptoms remain in many individuals with the disorder even after treatment with the current arsenal of antipsychotic drugs. Preclinical and clinical data suggest that selective activation of the muscarinic cholinergic system may represent novel therapeutic mechanisms for the treatment of schizophrenia. The therapeutic relevance of earlier muscarinic agonists was limited by their lack of receptor selectivity and adverse event profile arising from activation of nontarget muscarinic receptors. Recent advances in developing compounds that are selective to muscarinic receptor subtypes or activate allosteric receptor sites offer tremendous promise for therapeutic targeting of specific muscarinic receptor subtypes in schizophrenia. PMID- 22222700 TI - Muscarinic pain pharmacology: realizing the promise of novel analgesics by overcoming old challenges. AB - The antinociceptive and analgesic effects of muscarinic receptor ligands in human and nonhuman species have been evident for more than half a century. In this review, we describe the current understanding of the roles of different muscarinic subtypes in pain modulation and their mechanism of action along the pain signaling pathway, including peripheral nociception, spinal cord pain processing, and supraspinal analgesia. Extensive preclinical and clinical validation of these mechanisms points to the development of selective muscarinic agonists as one of the most exciting and promising avenues toward novel pain medications. PMID- 22222701 TI - Muscarinic modulation of striatal function and circuitry. AB - Striatal cholinergic interneurons are pivotal modulators of the striatal circuitry involved in action selection and decision making. Although nicotinic receptors are important transducers of acetylcholine release in the striatum, muscarinic receptors are more pervasive and have been more thoroughly studied. In this review, the effects of muscarinic receptor signaling on the principal cell types in the striatum and its canonical circuits will be discussed, highlighting new insights into their role in synaptic integration and plasticity. These studies, and those that have identified new circuit elements driven by activation of nicotinic receptors, make it clear that temporally patterned activity in cholinergic interneurons must play an important role in determining the effects on striatal circuitry. These effects could be critical to the response to salient environmental stimuli that serve to direct behavior. PMID- 22222702 TI - Muscarinic receptors in brain stem and mesopontine cholinergic arousal functions. AB - All five muscarinic receptor subtypes and mRNAs are found widely in the brain stem, with M2 muscarinic receptors most concentrated in the hindbrain. Three cholinergic cell groups, Ch5: pedunculopontine (PPT); Ch6: laterodorsal tegmental (LDT); Ch8: parabigeminal (PBG), are found in the tegmentum. Ch5,6 neurons are activated by arousing and reward-activating stimuli, and inhibited via M2-like autoreceptors. Ch5,6 ascending projections activate many forebrain regions, including thalamus, basal forebrain, and orexin/hypocretin neurons (via M3 receptors) for waking arousal and attention. Ch5,6 activation of dopamine neurons of the ventral tegmental area and substantia nigra (via M5 receptors) increases reward-seeking and energizes motor functions. M5 receptors on dopamine neurons facilitate brain-stimulation reward, opiate rewards and locomotion, and male ultrasonic vocalizations during mating in rodents. Ch5 cholinergic activation of superior colliculus intermediate layers facilitates fast saccades and approach turns, accompanied by nicotinic and muscarinic inhibition of the startle reflex in pons. Ch8 PBG neurons project to the outer layers of the superior colliculus only, where M2 receptors are associated with retinotectal terminals. Ch5,6 descending projections to dorsal pontine reticular formation contribute to M2 dependent REM sleep. PMID- 22222703 TI - Muscarinic receptor agonists and antagonists: effects on ocular function. AB - Muscarinic agonists act mainly via muscarinic M3 cholinoceptors to cause contraction of the iris sphincter, ciliary muscle and trabecular meshwork as well as increase outflow facility of aqueous humour. In the iris dilator, the effect of muscarinic agonists is species dependent but is predominantly relaxation via muscarinic M3 receptors. In the conjunctiva, muscarinic agonists stimulate goblet cell secretion which contributes to the protective tear film. Muscarinic M2 and M3 receptors appear mainly involved. In the lens muscarinic agonists act via muscarinic M1 receptors to produce depolarization and increase [Ca(2+)](i). All five subtypes of muscarinic receptor are present in the retina. In the developing retina, acetylcholine appears to limit purinergic stimulation of retinal development and decrease cell proliferation. In the adult retina acetylcholine and other muscarinic agonists may have complex effects, for example, enhancing light-evoked neuronal firing in transient ON retinal ganglion cells and inhibiting firing in OFF retinal ganglion cells. In the lacrimal gland, muscarinic agonists activate M3 receptors on secretory globular acinar cells to stimulate tear secretion and also cause contraction of myoepithelial cells. In Sjogren's syndrome, antibodies to the muscarinic M3 receptor disrupt normal gland function leading to xerophthalmia although the mechanism of action of the antibody is still not clear. Atropine and pirenzepine are useful in limiting the development of myopia in children probably by an action on muscarinic receptors in the sclera, although many other muscarinic receptor antagonists are not effective. PMID- 22222704 TI - Muscarinic receptor agonists and antagonists: effects on cardiovascular function. AB - Muscarinic receptor activation plays an essential role in parasympathetic regulation of cardiovascular function. The primary effect of parasympathetic stimulation is to decrease cardiac output by inhibiting heart rate. However, pharmacologically, muscarinic agonists are actually capable of producing both inhibitory and stimulatory effects on the heart as well as vasculature. This reflects the fact that muscarinic receptors are expressed throughout the cardiovascular system, even though they are not always involved in mediating parasympathetic responses. In the heart, in addition to regulating heart rate by altering the electrical activity of the sinoatrial node, activation of M2 receptors can affect conduction of electrical impulses through the atrioventricular node. These same receptors can also regulate the electrical and mechanical activity of the atria and ventricles. In the vasculature, activation of M3 and M5 receptors in epithelial cells can cause vasorelaxation, while activation of M1 or M3 receptors in vascular smooth muscle cells can cause vasoconstriction in the absence of endothelium. This review focuses on our current understanding of the signaling mechanisms involved in mediating these responses. PMID- 22222706 TI - Muscarinic agonists and antagonists: effects on gastrointestinal function. AB - Muscarinic agonists and antagonists are used to treat a handful of gastrointestinal (GI) conditions associated with impaired salivary secretion or altered motility of GI smooth muscle. With regard to exocrine secretion, the major muscarinic receptor expressed in salivary, gastric, and pancreatic glands is the M3 with a small contribution of the M1 receptor. In GI smooth muscle, the major muscarinic receptors expressed are the M2 and M3 with the M2 outnumbering the M3 by a ratio of at least four to one. The antagonism of both smooth muscle contraction and exocrine secretion is usually consistent with an M3 receptor mechanism despite the major presence of the M2 receptor in smooth muscle. These results are consistent with the conditional role of the M2 receptor in smooth muscle. That is, the contractile role of the M2 receptor depends on that of the M3 so that antagonism of the M3 receptor eliminates the response of the M2. The physiological roles of muscarinic receptors in the GI tract are consistent with their known signaling mechanisms. Some so-called tissue-selective M3 antagonists may owe their selectivity to a highly potent interaction with a nonmuscarinic receptor target. PMID- 22222707 TI - Muscarinic agonists and antagonists: effects on the urinary bladder. AB - Voiding of the bladder is the result of a parasympathetic muscarinic receptor activation of the detrusor smooth muscle. However, the maintenance of continence and a normal bladder micturition cycle involves a complex interaction of cholinergic, adrenergic, nitrergic and peptidergic systems that is currently little understood. The cholinergic component of bladder control involves two systems, acetylcholine (ACh) released from parasympathetic nerves and ACh from non-neuronal cells within the urothelium. The actions of ACh on the bladder depend on the presence of muscarinic receptors that are located on the detrusor smooth muscle, where they cause direct (M3) and indirect (M2) contraction; pre junctional nerve terminals where they increase (M1) or decrease (M4) the release of ACh and noradrenaline (NA); sensory nerves where they influence afferent nerve activity; umbrella cells in the urothelium where they stimulate the release of ATP and NO; suburothelial interstitial cells with unknown function; and finally, other unidentified sites in the urothelium from where prostaglandins and inhibitory/relaxatory factors are released. Thus, the actions of muscarinic receptor agonists and antagonists on the bladder may be very complex even when considering only local muscarinic actions. Clinically, muscarinic antagonists remain the mainstay of treatment for the overactive bladder (OAB), while muscarinic agonists have been used to treat hypoactive bladder. The antagonists are effective in treating OAB, but their precise mechanisms and sites of action (detrusor, urothelium, and nerves) have yet to be established. Potentially more selective agents may be developed when the cholinergic systems within the bladder are more fully understood. PMID- 22222705 TI - Muscarinic receptor antagonists: effects on pulmonary function. AB - In healthy lungs, muscarinic receptors control smooth muscle tone, mucus secretion, vasodilation, and inflammation. In chronic obstructive pulmonary disease (COPD) and asthma, cholinergic mechanisms contribute to increased bronchoconstriction and mucus secretion that limit airflow. This chapter reviews neuronal and nonneuronal sources of acetylcholine in the lung and the expression and role of M1, M2, and M3 muscarinic receptor subtypes in lung physiology. It also discusses the evidence for and against the role of parasympathetic nerves in asthma, and the current use and therapeutic potential of muscarinic receptor antagonists in COPD and asthma. PMID- 22222708 TI - Muscarinic receptor agonists and antagonists: effects on inflammation and immunity. AB - In this chapter, we will review what is known about muscarinic regulation of immune cells and the contribution of immune cell muscarinic receptors to inflammatory disease and immunity. In particular, immune cell expression of cholinergic machinery, muscarinic receptor subtypes and functional consequences of agonist stimulation will be reviewed. Lastly, this chapter will discuss the potential therapeutic effects of selective antagonists on immune cell function and inflammatory disease in recent animal studies and human clinical trials. PMID- 22222709 TI - Muscarinic receptor agonists and antagonists: effects on keratinocyte functions. AB - The stratified epithelium enveloping the skin and lining the surfaces of oral and vaginal mucosa is comprised by keratinocytes that synthesize, secrete, degrade, and respond to acetylcholine via muscarinic and nicotinic receptors. The two pathways may compete or synergize with one another, so that net biologic effect represents the biologic sum of the effects of distinct acetylcholine receptors expressed by a keratinocyte at a particular stage of its development. Keratinocytes express a unique combination of muscarinic receptor subtypes at each stage of their development. Experimental results indicate that muscarinic receptors expressed in human keratinocytes regulate their viability, proliferation, migration, adhesion, and terminal differentiation, hair follicle cycling, and secretion of humectants, cytokines, and growth factors. Learning the muscarinic pharmacology of keratinocyte development and functions has salient clinical implications for patients with nonhealing wounds, mucocutaneous cancers, and various autoimmune and inflammatory diseases. Successful therapy of pemphigus lesions with topical pilocarpine and disappearance of psoriatic lesions due to systemic atropine therapy illustrate that such therapeutic approach is feasible. PMID- 22222711 TI - Activation of muscarinic receptors by non-neuronal acetylcholine. AB - The biological role of acetylcholine and the cholinergic system is revisited based particularly on scientific research early and late in the last century. On the one hand, acetylcholine represents the classical neurotransmitter, whereas on the other hand, acetylcholine and the pivotal components of the cholinergic system (high-affinity choline uptake, choline acetyltransferase and its end product acetylcholine, muscarinic and nicotinic receptors and esterase) are expressed by more or less all mammalian cells, i.e. by the majority of cells not innervated by neurons at all. Moreover, it has been demonstrated that acetylcholine and "cholinergic receptors" are expressed in non-neuronal organisms such as plants and protists. Acetylcholine is even synthesized by bacteria and algae representing an extremely old signalling molecule on the evolutionary timescale. The following article summarizes examples, in which non-neuronal acetylcholine is released from primitive organisms as well as from mammalian non neuronal cells and binds to muscarinic receptors to modulate/regulate phenotypic cell functions via auto-/paracrine pathways. The examples demonstrate that non neuronal acetylcholine and the non-neuronal cholinergic system are vital for various types of cells such as epithelial, endothelial and immune cells. PMID- 22222710 TI - Muscarinic receptor agonists and antagonists: effects on cancer. AB - Many epithelial and endothelial cells express a cholinergic autocrine loop in which acetylcholine acts as a growth factor to stimulate cell growth. Cancers derived from these tissues similarly express a cholinergic autocrine loop and ACh secreted by the cancer or neighboring cells interacts with M3 muscarinic receptors expressed on the cancer cells to stimulate tumor growth. Primary proliferative pathways involve MAPK and Akt activation. The ability of muscarinic agonists to stimulate, and M3 antagonists to inhibit tumor growth has clearly been demonstrated for lung and colon cancer. The ability of muscarinic agonists to stimulate growth has been shown for melanoma, pancreatic, breast, ovarian, prostate and brain cancers, suggesting that M3 antagonists will also inhibit growth of these tumors as well. As yet no clinical trials have proven the efficacy of M3 antagonists as cancer therapeutics, though the widespread clinical use and low toxicity of M3 antagonists support the potential role of these drugs as adjuvants to current cancer therapies. PMID- 22222712 TI - Colour-responsive fluorescent oxy radical sensors. AB - A series of fluorene-fused benzoquinones (Q1-Q5) were prepared by thermolysis of 4-fluorenyl-4-hydroxycyclobutenones. Red fluorescence observed for Q2 is switched by reduction to blue fluorescence by formation of the hydroquinone. Reaction with hydrogen peroxide restores the original fluorescence colour. The potential use of compound Q2 as a reactive oxygen species detector is discussed. PMID- 22222713 TI - Two-temperature stage biphasic CO2-H2O pretreatment of lignocellulosic biomass at high solid loadings. AB - Most biomass pretreatment processes for monosaccharide production are run at low solid concentration (<10 wt%) and use significant amounts of chemical catalysts. Biphasic CO(2) -H(2) O mixtures could provide a more sustainable pretreatment medium while using high-solid contents. Using a stirred reactor for high solids (40 wt%, biomass water mixture) biphasic CO(2)-H(2) O pretreatment of lignocellulosic biomass allowed us to explore the effects of particle size and mixing on mixed hardwood and switchgrass pretreatment. Subsequently, a two temperature stage pretreatment was introduced. After optimization, a short high temperature stage at 210 degrees C (16 min for hardwood and 1 min for switchgrass) was followed by a long low-temperature stage at 160 degrees C for 60 min. Glucan to glucose conversion yields of 83% for hardwood and 80% for switchgrass were obtained. Total molar sugar yields of 65% and 55% were obtained for wood and switchgrass, respectively, which consisted of a 10% points improvement over those obtained during our previous study despite a 10-fold increase in particle size. These yields are similar to those obtained with other major pretreatment technologies for wood and within 10% of major technologies for switchgrass despite the absence of chemical catalysts, the use of large particles (0.95 cm) and high solid contents (40 wt%). PMID- 22222714 TI - Effect of fluoride, lesion baseline severity and mineral distribution on lesion progression. AB - The present study investigated the effects of fluoride (F) concentration, lesion baseline severity (DeltaZ(base)) and mineral distribution on lesion progression. Artificial caries lesions were created using three protocols [methylcellulose acid gel (MeC), hydroxyethylcellulose acid gel (HEC), carboxymethylcellulose acid solution (CMC)] and with low and high DeltaZ(base) groups by varying demineralization times within protocols. Subsequently, lesions were immersed in a demineralizing solution for 24 h in the presence of 0, 1, 2 or 5 ppm F. Changes in mineral distribution characteristics of caries lesions were studied using transverse microradiography. At baseline, the protocols yielded lesions with three distinctly different mineral distributions. Secondary demineralization revealed differences in F response between and within lesion types. In general, lowDeltaZ lesions were more responsive to F than highDeltaZ lesions. LowDeltaZ MeC lesions showed the greatest range of response among all lesions, whereas highDeltaZ HEC lesions were almost unaffected by F. Laminations were observed in the presence of F in all but highDeltaZ HEC and CMC lesions. Changes in mineral distribution effected by F were most pronounced in MeC lesions, with remineralization/mineral redeposition in the original lesion body at the expense of sound enamel beyond the original lesion in a dose-response manner. Both DeltaZ(base) and lesion mineral distribution directly impact the F response and the extent of secondary demineralization of caries lesions. Further studies - in situ and on natural white spot lesions - are required to better mimic in vivo caries under laboratory conditions. PMID- 22222715 TI - Ultrastructure of the anterior lens capsule and epithelium in cataracts associated with uveitis. AB - AIMS: To study the ultrastructure of the anterior lens capsule and epithelium, and capsular thickness in uveitic cataracts. METHODS: Capsulorhexis samples from 20 uveitic cataracts were compared to 20 nuclear cataracts using the semi- and ultra-thin techniques. RESULTS: Extensive epithelial and capsular-epithelial border changes and epithelial-mesenchymal transition in some fibrotic capsules were found only in the uveitic group. All these changes were observed predominately in white uveitic cataracts. Mild and moderate ultrastructural changes were seen in both groups. Surface deposition of amorphous material was also found only in uveitic cataracts. Capsular thickness was not different between the two groups. CONCLUSIONS: Uveitic capsules showed more extensive and different ultrastructural changes that probably occurred because of inflammation in the eye and epithelial-mesenchymal transition. These changes might be an additional reason for altered behavior of the lens capsule at capsulorhexis. PMID- 22222716 TI - Long-term follow-up and visual outcome after excision of a traumatic iris cyst by viscoelastic dissection. AB - To report the long-term follow-up and visual outcome after excision of a traumatic iris cyst. A 4-year-old female presented with an iris cyst in her left eye 2 years after corneal laceration repair. An 8 * 7 mm cyst was located between 1 and 6 O'clock on the iris, extending into the anterior chamber. The cyst was surgically removed by dissection from the endothelium and angle by viscoelastic and was submitted for histopathological examination. Postoperative outcomes including visual acuity (VA) and complications over 8 years are reported. Histopathological examination demonstrated fragments of iris tissue extensively covered by a layer of epithelial cells which were present on both the anterior and posterior surfaces of portions of the iris stroma. 8 years post-excision, the patient's VA improved from 20/80 to 20/30 with no evidence of recurrence and no adverse sequelae. Traumatic iris cyst is a diagnostic and therapeutic challenge for ophthalmic surgeons with an overall poor visual prognosis if it is not excised properly. Improved wound management techniques during the repair of a traumatic wound are highly recommended. Careful viscoelastic dissection of the iris cyst from the endothelium and angle provided acceptable long-term outcome and prevented recurrence. PMID- 22222717 TI - Candida dubliniensis endophthalmitis: first case in North America. AB - To report an unusual case of endogenous fungal endophthalmitis due to Candida dubliniensis. Interventional case report of a 27-year-old immunocompetent male with loss of vision, dense vitritis, and chorioretinal infiltrates, who underwent a diagnostic pars plana vitrectomy. Microbiology cultures obtained by a diagnostic vitrectomy were positive for the growth of C. dubliniensis. This infectious process was then appropriately treated with intravitreal amphotericin B and systemic fluconazole with resolution of the endophthalmitis. Endogenous fungal endophthalmitis is a condition that can masquerade other more common causes of endophthalmitis. Atypical cases of endophthalmitis may benefit from diagnostic pars plana vitrectomy for prompt diagnosis and treatment. PMID- 22222718 TI - A hairy affair: tarantula setae-induced panuveitis requiring pars plana vitrectomy. AB - Cases of ocular inflammation following penetration by urticating hairs from caterpillars and tarantulas have been previously reported and although rare, the condition is increasingly being recognised as a cause of chronic panuveitis. The long-term outcomes and prognosis of this condition are not well known. This article describes a case of chronic panuveitis as a result of ocular penetration by tarantula setae, and its challenging management that ultimately required pars plana vitrectomy. Interventional case report: A 29-year-old male presented with chronic panuveitis secondary to tarantula-hair penetration. Initial management with mechanical removal of hairs from the cornea and intensive topical steroid therapy for 18 months did not adequately control his symptoms. Pars plana vitrectomy was carried out and at 6-month follow-up the patient was symptom-free without any pharmacological therapy. We propose early pars plana vitrectomy as a management option for treatment-resistant panuveitis in cases of ophthalmia nodosa secondary to setae-related injury. PMID- 22222719 TI - PET radiotracers for molecular imaging in the brain: past, present and future. AB - Neuroimaging of brain receptors began in the early 1980s. Now, some thirty-five years later, PET imaging is still an expanding field of preclinical and clinical investigations. In addition to improvements in PET cameras and image analysis, the availability of suitable radiotracers is a crucial factor leading this expansion. Radiotracers have been developed to visualize and quantify a growing numbers of brain receptors, transporters, enzymes and other molecular targets. The development of adequate PET radiotracers represents an exciting challenge, given the large number of targets and neurochemical functions that have yet to be explored. In this article, we review the main evolutions led by preclinical radiotracers and clinical radiopharmaceuticals. The current main contributions of PET radiotracers are described in terms of imaging of neuronal metabolism, receptor and transporter quantification and neurodegenerative, neuroinflammatory and neurooncologic process imaging. In the last part, we highlight some applications presenting a potential for novel functional explorations of the brain. PMID- 22222720 TI - Including robustness in multi-criteria optimization for intensity-modulated proton therapy. AB - We present a method to include robustness in a multi-criteria optimization (MCO) framework for intensity-modulated proton therapy (IMPT). The approach allows one to simultaneously explore the trade-off between different objectives as well as the trade-off between robustness and nominal plan quality. In MCO, a database of plans each emphasizing different treatment planning objectives, is pre-computed to approximate the Pareto surface. An IMPT treatment plan that strikes the best balance between the different objectives can be selected by navigating on the Pareto surface. In our approach, robustness is integrated into MCO by adding robustified objectives and constraints to the MCO problem. Uncertainties (or errors) of the robust problem are modeled by pre-calculated dose-influence matrices for a nominal scenario and a number of pre-defined error scenarios (shifted patient positions, proton beam undershoot and overshoot). Objectives and constraints can be defined for the nominal scenario, thus characterizing nominal plan quality. A robustified objective represents the worst objective function value that can be realized for any of the error scenarios and thus provides a measure of plan robustness. The optimization method is based on a linear projection solver and is capable of handling large problem sizes resulting from a fine dose grid resolution, many scenarios, and a large number of proton pencil beams. A base-of-skull case is used to demonstrate the robust optimization method. It is demonstrated that the robust optimization method reduces the sensitivity of the treatment plan to setup and range errors to a degree that is not achieved by a safety margin approach. A chordoma case is analyzed in more detail to demonstrate the involved trade-offs between target underdose and brainstem sparing as well as robustness and nominal plan quality. The latter illustrates the advantage of MCO in the context of robust planning. For all cases examined, the robust optimization for each Pareto optimal plan takes less than 5 min on a standard computer, making a computationally friendly interface possible to the planner. In conclusion, the uncertainty pertinent to the IMPT procedure can be reduced during treatment planning by optimizing plans that emphasize different treatment objectives, including robustness, and then interactively seeking for a most-preferred one from the solution Pareto surface. PMID- 22222722 TI - Myocardial infarction in an young patient associated with oral contraceptive, smoking and elevated cholesterol level. PMID- 22222721 TI - [125I]SD-7015 reveals fine modalities of CB1 cannabinoid receptor density in the prefrontal cortex during progression of Alzheimer's disease. AB - The cannabinoid type-1 receptor (CB1R) is one of the most abundant members of the G protein-coupled receptor family in the central nervous system. Once activated by their cognate ligands, endocannabinoids, CB1Rs generally limit the timing of neurotransmitter release at many cortical synapses. Prior studies have indicated the involvement of CB1R in neurodegeneration and in various neuronal insults, with an emphasis on their neuroprotective role. In the present study we used a novel selective CB1R radioligand to investigate regional variations in CB1R ligand binding as a factor of progressive Braak tau pathology in the frontal cortex of Alzheimer's disease (AD) patients. The frontal cortex was chosen for this study due to the high density of CB1Rs and their well-characterized involvement in the progression of AD. Post-mortem prefrontal cortex samples from AD patients from Braak stages I to VI and controls were subjected to CB1R autoradiography with [125I]SD-7015 as radioligand. Regional concentration of [125I]SD-7015, corresponding to, and thereby representing, regional CB1R densities, were expressed in fM/g_tissue. The results show that CB1R density inversely correlates with Braak tau pathology with the following tendency: controls qter deletion and autism. Herein we describe two cases of autism in unrelated children with BDMR Syndrome, showing physical, cognitive, behavioral, and disease natural history homologies, with a very prominent social impairment in the first 4 years of life. At follow-up evaluations, spanning a 5-years period, both children experienced a progressive reduction of the autistic symptoms, besides retaining compromised cognitive ability. This report supports the hypothesis that genes in the 2q37 region may contribute to the etiology of autism, leading, however, to a peculiar evolution of the disease, with symptoms severity decreasing over time. PMID- 22222776 TI - Brief report: repetitive behaviors in young children with autism spectrum disorder and developmentally similar peers: a follow up to Watt et al. (2008). AB - The present study extended the findings of Watt et al. (J Autism Dev Disord 38:1518-1533, 2008) by investigating repetitive and stereotyped behaviors (RSB) demonstrated by children (n = 50) and typical development (TD; n = 50) matched on developmental age, gender, and parents' education level. RSB were coded from videotaped Communication and Symbolic Behavior Scales Behavior Samples (Wetherby and Prizant 2002) using the Noldus Pro Observer(c) video software. Children with ASD demonstrated significantly higher frequencies of RSB with body objects excluding categories involving banging or tapping objects or surfaces. Behaviors demonstrated by both groups indicated overlapping RSB profiles at this age. These findings highlight the significance of RSB in the early identification and support the need for future research to further determine ASD-specific RSB. PMID- 22222777 TI - PET scanning in plastic and reconstructive surgery. AB - In this report we highlight the use of PET scan in plastic and reconstructive surgery. PET scanning is a very important tool in plastic surgery oncology (melanoma, soft-tissue sarcomas and bone sarcomas, head and neck cancer, peripheral nerve sheath tumors of the extremities and breast cancer after breast esthetic surgery), as diagnosis, staging, treatment planning and follow-up of cancer patients is based on imaging. PET scanning seems also to be useful as a flap monitoring system as well as an infection's imaging tool, for example in the management of diabetic foot ulcer. PET also contributes to the understanding of pathophysiology of keloids which remain a therapeutic challenge. PMID- 22222778 TI - Bone marrow stem cell adherence into old anterior myocardial infarction: a scintigraphic study using Tl-201 and Tc-99m-HMPAO. AB - AIM: The precise localization of bone marrow stem cells (SCs) into the necrotic tissue after intracoronary infusion (ICI) may be important for the therapeutic outcome. This study aims to examine the correlation between Tl-201 and Tc-99m hexa-methyl-propylene-amine-oxime (HMPAO) images. METHODS: Thirteen patients, aged 36-62 years, with an old, nonviable, anterior myocardial infarction (MI) and reduced myocardial contractility (LVEF <40%), underwent ICI of selected CD133(+) and CD133(neg)CD34(+) SCs. One hour after the ICI, SPECT imaging with Tc-99m HMPAO was performed in all patients and the acquired images were compared with the images obtained during the initial imaging for demonstration of viability (myocardial perfusion imaging with pharmacologic stress and Tl-201). Furthermore, two fused bull's eye images of Tc-99m-HMPAO and Tl-201 rest reinjection were created in six patients and regions of interest were set on Tl-201 and Tc-99m HMPAO bull's eye images. RESULTS: The comparison of the two sets of images revealed an intense accumulation of the SCs in the infarcted area with absence of viability as assessed by Tl-201 reinjection images. In the subset of patients in whom fused bull's eye images were produced, the comparison demonstrated that the percentage of the infarcted area with SCs' adherence was 83.2 +/- 17%. CONCLUSIONS: Tl-201 images are complementary with the respective Tc-99m-HMPAO ones, revealing a precise localization of SCs in the infarcted area. Tc-99m-HMPAO labeling of SCs is a reliable method for cell monitoring after ICI in nonviable myocardium after an anterior MI. PMID- 22222779 TI - Outpatient therapeutic nuclear oncology. AB - In the beginning, nuclear medicine was radionuclide therapy, which has evolved into molecular tumour-targeted control of metastatic cancer. Safe, efficacious, clinical practice of therapeutic nuclear oncology may now be based upon accurate personalised dosimetry by quantitative gamma SPECT/CT imaging to prescribe tumoricidal activities without critical organ toxicity. Preferred therapy radionuclides possess gamma emission of modest energy and abundance to enable quantitative SPECT/CT imaging for calculation of the beta therapy dosimetry, without radiation exposure risk to hospital personnel, carers, family or members of the public. The safety of outpatient radiopharmaceutical therapy of cancer with Iodine-131, Samarium-153, Holmium-166, Rhenium-186, Rhenium-188, Lutetium 177 and Indium-111 is reviewed. Measured activity release rates and radiation exposure to carers and the public are all within recommendations and guidelines of international regulatory agencies and, when permitted by local regulatory authorities allow cost-effective, safe, outpatient radionuclide therapy of cancer without isolation in hospital. PMID- 22222780 TI - New method for C-H arylation/alkylation at alpha-position of cyclic aliphatic ethers by iron-oxide mediated reaction. AB - We report a new and efficient iron oxide catalyzed cross-coupling reaction between organometallic species such as alkyl/arylmagnesium halides or organolithium species and alpha-hydrogen bearing cyclic unbranched and branched aliphatic ethers via activation of C(sp(3))-H. In the presence of 1 mol% of iron oxide, five and six membered unbranched cyclic ethers such as tetrahydrofuran and tetrahydropyran gave good to excellent yields of cross-coupled products. Whereas, in case of branched ether such as 2-methyltetrahydrofuran, it was observed that the arylation occurred at both the sides and gave moderate yields of a mixture of regioisomers. Among the organometallic species used, alkyl organometallic reagents gave less yields as compared to aryl organometallics. PMID- 22222781 TI - Portugal. Health system review. AB - The Portuguese population enjoys good health and increasing life expectancy, though at lower levels than other western European countries. All residents in Portugal have access to health care provided by the National Health Service (NHS), financed mainly through taxation. Co-payments have been increasing over time, and the level of cost-sharing is highest for pharmaceutical products. Approximately one-fifth to a quarter of the population enjoys a second (or more) layer of health insurance coverage through health subsystems and voluntary health insurance (VHI). Health care delivery is based on both public and private providers. Public provision is predominant in primary care and hospital care, with a gatekeeping system in place for the former. Pharmaceutical products, diagnostic technologies and private practice by physicians constitute the bulk of private health care provision. The Portuguese health system has not undergone any major changes on the financing side since the early 1990s, despite the steady growth of public health expenditure. On the other hand, many measures have been adopted to improve the performance of the health system, including public private partnerships (PPPs) for new hospitals, a change in NHS hospital management structures, pharmaceutical reforms, the reorganization of primary care and the creation of long-term care networks. Some of these measures have faced opposition from the (local) population, namely those related to the closure of health care facilities. There is an overall awareness, and concern, about the rise in health care expenditure in Portugal. Most of the reforms that have come into effect have done so too recently to measure any effects at present (January 2011). PMID- 22222783 TI - Pleomorphic adenoma of the sublingual salivary gland: an unusual diagnostic challenge. AB - OBJECTIVES: To describe a rare case of pleomorphic adenoma of the sublingual gland. CLINICAL PRESENTATION AND INTERVENTION: An 80-year-old patient presented with a painless solid submucosal mass of 4 months' duration in the anterior floor of the mouth, appearing as a distinct homogeneous, radiolucent lesion in CT imaging. Histologic findings after complete removal were suggestive of a pleomorphic adenoma almost completely surrounded by a fibrous capsule. No recurrence was observed after a 12-month follow-up. CONCLUSION: This case showed the possibility of sublingual salivary gland tumors and highlighted the need to consider them when making a differential diagnosis of masses located in the floor of the mouth. PMID- 22222782 TI - Postmortem genetic testing of the ryanodine receptor 2 (RYR2) gene in a cohort of sudden unexplained death cases. AB - The aim of this investigation was to identify pathogenic variants of the ryanodine receptor 2 (RYR2) gene in a cohort of persons aged 0-40 years who died of sudden unexpected death syndrome (SUD), including a cohort of infants who died of sudden infant death syndrome (SIDS). We genetically screened 29 of the 105 exons of the RYR2 gene associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) in 74 cases of SUD without reported structural abnormalities of the heart. Cases were selected from the case database at the Institute of Forensic Medicine, and subsequent mutational screening by DNA sequencing was performed to detect variants in DNA samples extracted from blood samples of deceased persons. A total of 7 of the examined 74 cases were heterozygous for a rare sequence variant in the RYR2 gene. We identified five novel missense variants (p.Q486H, p.D1872N, p.G2367R, p.E4213D, and p.H4579Y), one synonymous variant (p.L4767L), and one previously reported missense variant (p.G4315E). Follow-up studies were possible in family members of three probands (p.Q486H, p.D1872N, and p.H4579Y), and clinical examinations were conducted in family members of two of these probands (p.Q486H and p.H4579Y). In conclusion, we identified a higher prevalence of variants in the CPVT-associated gene RYR2 than in a previously reported cohort of SIDS (9.4% vs. 1-2%). Segregation studies show that one variant (p.H4579Y) co-segregates with CPVT and is presumed to be pathogenic. PMID- 22222784 TI - Comparative study on signal transduction in endothelial cells after anti-a/b and human leukocyte antigen antibody reaction: implication of accommodation. AB - BACKGROUND: Recent development of immunosuppressive therapy has provided a platform for clinical human leukocyte antigen (HLA)- and ABO-incompatible kidney transplantation. However, the prognosis seems to be different between the two. Accommodation, the condition of no injury even in the presence of antidonor antibody, is one of the key factors for successful transplantation with antidonor antibody. The purpose of this study was to compare signal transduction between anti-A/B and anti-HLA antibody reaction and to elucidate the mechanisms underlying accommodation. METHODS: Blood type A- or B-transferase gene was transfected into human EA.hy926 endothelial cells. After cell sorting, A- or B expressing cells at high levels were obtained. The effects of anti-HLA and anti A/B antibody binding on complement-mediated cytotoxicity and signal transduction were examined. RESULTS: Preincubation with anti-HLA antibodies only at low levels (<10% of saturation level) or anti-A/B antibodies at high levels (even at near saturation levels) for 24 hr resulted in resistance to complement-mediated cytotoxicity. Anti-A/B antibody ligation inactivated ERK1/2 pathway and increased complement regulatory proteins such as CD55 and CD59, whereas anti-HLA ligation activated PI3K/AKT pathway and increased cytoprotective genes such as hemeoxygenase-1 and ferritin H. CONCLUSION: Complement inhibition by upregulation of CD55 and CD59 through ERK1/2 inactivation might play a substantial role in accommodation after ABO-incompatible transplantation, which could also explain the intriguing finding of C4d deposition in the graft without rejection. PMID- 22222785 TI - The ailing gut: a therapeutic role for bone marrow cells? AB - It is obvious that the BM does more than simply supply the GIT with cells of the innate and adaptive immune system. A growing number of studies suggest that BMCs can differentiate into ISEMFs (Lee et al., PLOS ONE 2011;6:e26082) and in the setting of inflammation can be contributors to all lineages of the neovasculature. The role of BMCs in epithelial turnover is more problematic; their contribution after transient mucosal injury seems negligible, but a number of studies in both rodents and man suggest that small numbers of BMCs can be incorporated into the epithelial compartment with more chronic injury (e.g., GvHD in man and chemically induced colitis in rodents); commonly cell fusion seems to be responsible for this. Significantly, this engraftment does not seem to occur in the stem-cell compartment, with the notable single report of the chronically infected murine gastric mucosa, where the BM origin of the stem cells can be the only rational explanation for the complete colonization of the mucosa by BMDCs. In the clinical setting, a role for MSCs in ameliorating colitis seems promising, though the mechanisms by which this is achieved remain somewhat unclear, though both immunomodulatory and regenerative effects of BMCs are likely to be important. PMID- 22222786 TI - Preventative tools of the future: predicting the individual risk of cytomegalovirus infection after transplant. PMID- 22222787 TI - Serotonin (5-HT7) receptor-stimulated activation of cAMP-PKA pathway in bovine corneal epithelial and endothelial cells. AB - BACKGROUND: 5-Hydroxytryptamine (5-HT; serotonin) is a major neurotransmitter, and its receptors are found throughout the whole body. The 5-HT7 receptor subtype was detected in human corneal epithelial and endothelial cells and found to be functionally active in a corneal epithelial cell line. The aim of the present study was to demonstrate that native bovine corneal epithelial and endothelial cells express a functional 5-HT7 receptor positively coupled to adenylyl cyclase and protein kinase A (PKA) formation. METHODS: 5-HT7 receptors were studied using polyclonal antibodies. cAMP concentration after 5-HT7 receptor stimulation with 5 carboxamidotryptamine (5-CT, a 5-HT7 agonist) was tested by enzyme immunoassay, PKA activity was estimated by kinase consumption of ATP. RESULTS: Immunocytochemistry and immunofluorescence revealed the presence of 5-HT7 receptors in corneal epithelial and endothelial cells. Stimulation of corneal 5 HT7 receptors with 5-CT revealed a dose-dependent increase in intracellular cAMP concentration in corneal epithelium (0.01-0.34 pmol/ml) and endothelium (0.01 0.19 pmol/ml) between 10(-10) and 10(-7) mg/ml 5-CT (p = 0.001) with maximal stimulation from 10(-7) to 10(-3) mg/ml 5-CT (0.30 +/- 0.03 and 0.18 +/- 0.01 pmol/ml, respectively). Incubation with 10(-6) mg/ml SB269970 (a selective 5-HT7 antagonist) blocked 5-CT-induced cAMP increase in corneal epithelial (0.03 pmol/ml) and endothelial cells (0.02 pmol/ml; p = 0.001). Stimulation of corneal 5-HT7 receptors with 5-CT revealed a dose-dependent increase in PKA activity between 10(-10) and 10(-8) mg/ml 5-CT in corneal epithelium and endothelium (<1 to >99%; p = 0.013 and p = 0.017, respectively) with maximal stimulation from 10( 8) to 10(-4) mg/ml (>99%) 5-CT. CONCLUSIONS: Our data demonstrate that native corneal epithelial and endothelial cells express a functional 5-HT7 receptor positively coupled to adenylyl cyclase and PKA formation. However, at the present time, the physiological role of 5-HT receptors and the cAMP-PKA pathway in the cornea remains a matter of speculation. PMID- 22222788 TI - Quantitative monitoring of mouse lung tumors by magnetic resonance imaging. AB - Primary lung cancer remains the leading cause of cancer-related death in the Western world, and the lung is a common site for recurrence of extrathoracic malignancies. Small-animal (rodent) models of cancer can have a very valuable role in the development of improved therapeutic strategies. However, detection of mouse pulmonary tumors and their subsequent response to therapy in situ is challenging. We have recently described MRI as a reliable, reproducible and nondestructive modality for the detection and serial monitoring of pulmonary tumors. By combining respiratory-gated data acquisition methods with manual and automated segmentation algorithms described by our laboratory, pulmonary tumor burden can be quantitatively measured in approximately 1 h (data acquisition plus analysis) per mouse. Quantitative, analytical methods are described for measuring tumor burden in both primary (discrete tumors) and metastatic (diffuse tumors) disease. Thus, small-animal MRI represents a novel and unique research tool for preclinical investigation of therapeutic strategies for treatment of pulmonary malignancies, and it may be valuable in evaluating new compounds targeting lung cancer in vivo. PMID- 22222789 TI - Tracking mechanics and volume of globular cells with atomic force microscopy using a constant-height clamp. AB - To understand the role of physical forces at a cellular level, it is necessary to track mechanical properties during cellular processes. Here we present a protocol that uses flat atomic force microscopy (AFM) cantilevers clamped at constant height, and light microscopy to measure the resistance force, mechanical stress and volume of globular animal cells under compression. We describe the AFM and cantilever setup, live cell culture in the AFM, how to ensure stability of AFM measurements during medium perfusion, integration of optical microscopy to measure parameters such as volume and track intracellular dynamics, and interpretation of the physical parameters measured. Although we use this protocol on trypsinized interphase and mitotic HeLa cells, it can also be applied to other cells with a relatively globular shape, especially animal cells in a low-adhesive environment. After a short setup phase, the protocol can be used to investigate approximately one cell per hour. PMID- 22222790 TI - High-throughput ballistic injection nanorheology to measure cell mechanics. AB - High-throughput ballistic injection nanorheology is a method for the quantitative study of cell mechanics. Cell mechanics are measured by ballistic injection of submicron particles into the cytoplasm of living cells and tracking the spontaneous displacement of the particles at high spatial resolution. The trajectories of the cytoplasm-embedded particles are transformed into mean squared displacements, which are subsequently transformed into frequency dependent viscoelastic moduli and time-dependent creep compliance of the cytoplasm. This method allows for the study of a wide range of cellular conditions, including cells inside a 3D matrix, cell subjected to shear flows and biochemical stimuli, and cells in a live animal. Ballistic injection lasts <1 min and is followed by overnight incubation. Multiple particle tracking for one cell lasts <1 min. Forty cells can be examined in <1 h. PMID- 22222792 TI - [Hepatology: from basic science to the clinic]. PMID- 22222793 TI - [Boceprevir-benefit assessment by the Institute for Quality and Efficiency in Health Care (IQWiG) in accordance with AS 35a SGB V (dosage evaluation)]. PMID- 22222791 TI - A transcription activator-like effector toolbox for genome engineering. AB - Transcription activator-like effectors (TALEs) are a class of naturally occurring DNA-binding proteins found in the plant pathogen Xanthomonas sp. The DNA-binding domain of each TALE consists of tandem 34-amino acid repeat modules that can be rearranged according to a simple cipher to target new DNA sequences. Customized TALEs can be used for a wide variety of genome engineering applications, including transcriptional modulation and genome editing. Here we describe a toolbox for rapid construction of custom TALE transcription factors (TALE-TFs) and nucleases (TALENs) using a hierarchical ligation procedure. This toolbox facilitates affordable and rapid construction of custom TALE-TFs and TALENs within 1 week and can be easily scaled up to construct TALEs for multiple targets in parallel. We also provide details for testing the activity in mammalian cells of custom TALE-TFs and TALENs using quantitative reverse-transcription PCR and Surveyor nuclease, respectively. The TALE toolbox described here will enable a broad range of biological applications. PMID- 22222794 TI - [Epidemiology and clinical characteristics of patients with chronic hepatitis B (CHB) in Germany - results of a nationwide cross-sectional study]. AB - BACKGROUND AND AIMS: Knowledge about the epidemiology, demography and social status of patients with replicative chronic hepatitis B (CHB) in Germany is still scarce. This cross-sectional study evaluated in patients with chronic hepatitis B infection, with a serum HBV-DNA concentration of at least 10,000 copies/mL (> 2000 IU/mL) at documentation visit, the epidemiology, socio-demographics, time of diagnosis, history of disease, prior therapies as well the therapeutic decision. METHODS: 74 German centres with predominately hepatologic focus, recorded in an online-survey the pseudonymised data of patients with chronic HBV-infection with a serum HBV-DNA-concentration of at least 10,000 copies/mL (n = 35). RESULTS: 65 % of the patients were male. The mean age was 40 +/- 14 years. 63 % were immigrants (i. e., country of birth not being Germany). 37 % were HBeAg-positive. Mean ALT value 114 +/- 183 IU/mL in males and 77 +/- 176 IU/mL in females. ALT was above the upper limit of normal (ULN) in 59 % and 9 % of the patients were cirrhotic. The large immigrant groups, Turks (22 %), people from the former USSR (11 %) or from Southeast Asia (10 %) differed in terms of age, sex, HBeAg-status and clinical parameters clearly from each other as well as from German patients. 55 % of the patients from SE-Asia were female and overall considerably younger than German patients. 69 % of the patients with HBV-DNA > 10,000 copies/mL combined with ALT-levels above ULN, and 87 % with advanced fibrosis recieved antiviral treatment. CONCLUSIONS: This database currently contains the largest collection of epidemiological data of CHB patients in Germany. It therefore allows a representative overview on the disease in Germany. In Germany CHB epidemiology is triggered by migration from countries with higher CHB prevalence. However, the high proportion of patients coming from states of the former USSR is likely to be a historical peculiarity of Germany. The sometimes weak German language skills as well as the cultural specifics in the different immigrant groups are still a challenge for health-care providers. The high proportion of viraemic patients, already being treated, could indicate a suboptimal efficacy of the available therapeutic options at the time documentation. PMID- 22222795 TI - [Transgastric-, transhepatic endosonography-guided biliary drainage (EUCD) in a patient with locally advanced cholangiocarcinoma]. AB - We report on a 63-year-old female patient with locally advanced cholangiocarcinoma of the extrahepatic biliary tract. She was admitted with progressive obstructive jaundice, initiating cholangitis and distinctive itching. The biliodigestive anastomosis was secondarily barred by tumour infiltration and not accessible via an endoscopic route. Because the patient asked expressively for internal drainage, we successfully performed an endosonography-guided transgastric, transhepatic internal biliary drainage (EUCD). The jaundice and itching were regredient and the patient was discharged in a stable condition. PMID- 22222796 TI - The multiple functions of heme oxygenase-1 in the liver. AB - Heme oxygenases (HO) are essential enzymes which degrade heme into carbon monoxide (CO), biliverdin and free iron. Due to its anti-inflammatory, anti apoptotic and, as recently described, anti-viral properties the inducible HO isoform HO-1 is an important molecule which could find its way into therapy of gastrointestinal diseases. Acute and chronic liver injuries including acute liver failure, alcoholic or viral hepatitis, chronic inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma are life threatening diseases and as a consequence might result in the necessity of liver transplantation. HO-1 as well as its reaction products of heme degradation has been linked to cytoprotection. HO-1 induction in rodent models of acute and chronic hepatic inflammation resulted in improvement of liver damage and down-regulation of pro-inflammatory cytokine levels. Furthermore HO-1 induction interfered with fibrosis progression in mice and partially resolved existing fibrosis. Likewise, HO-1 induction interfered with replication of hepatitis viruses B and C, which frequently are the reason for chronic hepatitis and subsequent tumor growth. Liver transplantation is limited by ischemia/reperfusion (I/R) injury, which is characterized by hypoxia and nutrient deficiency resulting in oxidative stress, apoptosis and immune activation. Induction of HO-1 and application predominantly of CO have been shown to interfere with I/R liver injury and to improve recipient and graft survival. On the other hand HO-1 has been shown to be over-expressed in various tumors, including hepatocellular carcinoma (HCC). Due to its anti-apoptotic properties this bears the risk to promote tumor growth. Anti-apoptotic effects are predominantly mediated by CO. This review aims to summarize beneficial as well as detrimental effects of HO-1 and its products within the liver. PMID- 22222797 TI - [Personalised hepatology - current concepts, developments and expectations in the post-genome era]. AB - Promoted by the decoding of the human genome as part of the human genome project, individualised therapy approaches have become a realistic perspective for therapies that are more effective, less prone to side effects and economically reasonable. This also applies to chronic liver disease. With the aim not only to expand the current knowledge base through basic research on the underlying disease processes and treatment options but also to identify and characterise biomarkers, the creation of genetic fingerprints for individualised diagnosis, prognosis and treatment of patients takes its place in the centre of translational hepatology. For certain liver diseases personalised therapy approaches are already existent. Examples are the determination of viral genotypes, viral kinetics and genotyping of the IL28B polymorphism to optimise the treatment of chronic hepatitis C. The challenges of the next few years relate to the broadening of the knowledge base, the establishment of reliable and standardised technologies, and the development of intelligent bioinformatics strategies for data analysis and data integration. The following review not only summarises the current state of progress and possibilities of personalised medicine in hepatological diseases, but also explains the technical background of the limitations that currently hinder a consistent clinical implementation. PMID- 22222798 TI - [Hepatocellular carcinoma - from immunobiology to immunotherapy]. AB - Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide with an increasing incidence. The clinical outcome is influenced by the underlying liver cirrhosis, the size of the tumour at the time of diagnosis and the few therapeutic options currently available. In recent years there has been a lot of progress in the understanding of HCC immunobiology. This review summarizes our current knowledge of HCC biology, the role of chronic inflammation in carcinogenesis and the role of tumour-specific immune responses. Furthermore, we will present potentially new, immune-based therapies that might open up new avenues for the treatment of HCC. PMID- 22222799 TI - [Expert opinion on boceprevir- and telaprevir-based triple therapies of chronic hepatitis C]. AB - With the approval of boceprevir and telaprevir the standard treatment of chronic hepatitis C virus (HCV) genotype 1 infection will be the triple therapy of a HCV protease inhibitor together with pegylated interferon alfa and ribavirin. In clinical studies a significant increase of sustained virological response rates from 38 - 44 % to 63 - 75 % for treatment-naive and from 17 - 21 % to 59 - 66 % in treatment-experienced patients in comparison to the dual combination therapy with pegylated interferon alfa and ribavirin alone has been demonstrated. In addition, a large number of treatment-naive patients and relapsers benefit from shorten treatment durations to 24 - 28 weeks. However, important differences exist between the administration of boceprevir and telaprevir in terms of a pegylated interferon alfa/ribavirin lead-in phase, the duration of dosing of the protease inhibitor, the overall treatment duration, HCV RNA measurements for response guided treatment durations and stopping rules. Furthermore, triple therapies with boceprevir and telaprevir may be associated with selection of resistant viral variants, new adverse events and clinically relevant drug-drug interactions. The present review gives an overview on the results of underlying clinical studies together with a guideline for the practical management of boceprevir- and telaprevir-based triple therapies. PMID- 22222800 TI - Engineering Yarrowia lipolytica to express secretory invertase with strong FBA1IN promoter. AB - Oleaginous yeast Yarrowia lipolytica is an important host for the production of lipid-derived compounds or heterologous proteins. Selection of strong promoters and effective expression systems is critical for heterologous protein secretion. To search for a strong promoter in Y. lipolytica, activities of FBA1, TDH1 and GPM1 promoters were compared to that of TEF1 promoter by constructing GUS reporter fusions. The FBA1 promoter activity was 2.2 and 5.5 times stronger than the TDH1 and GPM1 promoters, respectively. The FBA1IN promoter (FBA1 sequence of 826 to +169) containing an intron (+64 to +165) showed five-fold higher expression than the FBA1 promoter (-831 to -1). The transcriptional enhancement by the 5'-region within the FBA1 gene was confirmed by GPM1::FBA1 chimeric promoter construction. Using the strong FBA1IN promoter, four different S. cerevisiae SUC2 expression cassettes were tested for the SUC+ phenotype in Y. lipolytica. Functional invertase secretion was facilitated by the Xpr2 prepro region with an additional 13 amino acids of mature Xpr2, or by the native Suc2 signal sequence. However, these two secretory signals in tandem, or the mature Suc2 with no secretory signal, did not direct secretion of functional invertase. Unlike previously reported Y. lipolytica SUC+ strains, our engineered stains secreted most of invertase into the medium. PMID- 22222801 TI - Accuracy of an expanded early warning score for patients in general and trauma surgery wards (Br J Surg 2012; 99: 192-197). PMID- 22222803 TI - Indications for fenestrated endovascular aneurysm repair (Br J Surg 2012; 99: 217 224). PMID- 22222802 TI - Indications for fenestrated endovascular aneurysm repair. AB - BACKGROUND: Endovascular technology has advanced rapidly in the development of fenestrated endovascular aneurysm repair (FEVAR). Current evidence for endovascular aneurysm repair is limited to infra-renal aortic aneurysms. With increased costs and complexity of FEVAR, its current role is unclear. A national multicentre, cross-disciplinary consensus model was developed to propose indications for FEVAR. METHODS: All UK FEVAR centres and a wide selection of high volume aneurysm treatment centres were invited to participate. The RAND appropriateness methodology was used. Five key steps were undertaken: meta analysis of current literature; survey of current UK practice; nominal group establishment and definition of key clinical attributes; round 1--online survey of case vignettes; and round 2--nominal group consensus meeting. RESULTS: More than 90 per cent of UK FEVAR centres participated. Literature review showed heterogeneous case series with no clear indications for use of FEVAR. Survey of current practice showed wide variations in aneurysm management. Consensus agreement on the role of FEVAR was achieved in 68.8 per cent of cases. Consensus for FEVAR was agreed in areas of moderate risk from open repair and need for suprarenal clamping, but it was less likely to be indicated in patients aged 85 years or more with 5.5-6-cm aneurysms, or short-necked infrarenal aortic aneurysms. CONCLUSION: These data record areas of agreement and define the grey area of equipoise. Consequently, guidelines and recommendations can be developed on the indications for FEVAR to inform clinicians, commissioners and health economists. PMID- 22222804 TI - Selective decontamination of the oral and digestive tract in surgical versus non surgical patients in intensive care in a cluster-randomized trial (Br J Surg 2012; 99: 232-237). PMID- 22222805 TI - Quality of life and health status before and after ileal pouch-anal anastomosis for ulcerative colitis (Br J Surg 2012; 99: 263-269). PMID- 22222806 TI - Multicentre observational study of the natural history of left-sided acute diverticulitis (Br J Surg 2012; 99: 276-285). PMID- 22222807 TI - Letter 1: Routine colonoscopy following acute uncomplicated diverticulitis (Br J Surg 2011; 98: 1630-1634). PMID- 22222809 TI - Letter 2: Routine colonoscopy following acute uncomplicated diverticulitis (Br J Surg 2011; 98: 1630-1634). PMID- 22222810 TI - Self-expanding metallic stents for large bowel obstruction (Br J Surg 2011; 98: 1625-1629). PMID- 22222813 TI - Effect of type of alcoholic beverage in causing acute pancreatitis (Br J Surg 2011; 98: 1609-1616). PMID- 22222815 TI - Association of polymorphisms in the promoter region of FCER1A gene with atopic dermatitis, chronic uticaria, asthma, and serum immunoglobulin E levels in a Han Chinese population. AB - The high-affinity receptor for immunoglobulin E (IgE) plays a central role in allergy diseases. Previous studies have reported the association of variants in the proximal promoter of FCER1A with IgE levels as well as allergy disorders. Another promoter gene polymorphism that is located upstream of exon 1 has not been investigated. We investigated the association of variants in the promoter located upstream of FCER1A exon 1 with serum IgE levels and allergy diseases in a Han Chinese population. A total of 97 patients with atopic dermatitis (AD), 123 patients with chronic urticaria (CU), 286 children with asthma, and control groups were screened for polymorphisms in the promoter region located upstream of FCER1A exon 1 by the polymerase chain reaction-ligation detection reaction method. Total serum IgE levels were tested in groups. The rare allele A of the rs2427837 A/G polymorphism was significantly different in the AD group compared with the controls. No association with the polymorphism was observed in the CU group. In asthmatic patients, IgE levels were higher in the mutation genotypes GA of rs2427837 and TC of rs2251746 compared with normal genotype individuals. The minor allele of rs2427837 and rs2251746 in FCER1A is a genetic risk factor of high IgE levels. PMID- 22222816 TI - The possible role of genetic variants in autoimmune-related genes in the development of endometriosis. AB - Numerous hypotheses have been put forward to explain the presence of ectopic endometrial tissue and stroma. The immune system participates in the homeostasis of the peritoneal cavity, and modifications in its functioning have been advanced to explain endometriosis and its consequences. Recently, the powerful anti inflammatory effect of progesterone was recognized as a potential causal factor for endometriosis and could contribute to the autoimmune nature of endometriosis, as well as to more specific local and systemic changes. Autoimmune and inflammatory diseases are a diverse group of complex diseases characterized by loss of self-tolerance causing immune-mediated tissue destruction. Just as in autoimmune diseases, in endometriosis similar immunologic alterations occur, such as an increase in the number and cytotoxicity of macrophages, polyclonal increase in the activity of B lymphocytes, abnormalities in the functions and concentrations of B and T lymphocytes, and reduction in number or activity of natural killer cells. Furthermore, the presence of specific antiendometrial and antiovary antibodies was found both in endometriosis and infertility. Genetic factors play a role in the pathogenesis of endometriosis, and autoimmunity genes are therefore reasonable candidate genes for endometriosis and endometriosis associated infertility. Single nucleotide polymorphisms are common in the human genome and affect the function of crucial components of the T-cell-antigen receptor signaling pathways; they could have profound effects on the function of the immune system and thus on the development of autoimmune diseases. Here, we conducted a critical medical literature review about the possible role of genetic variants in autoimmune-related genes in the development of endometriosis. PMID- 22222818 TI - Fluvastatin suppresses native and recombinant human P2X4 receptor function. AB - Statins have both cholesterol lowering and anti-inflammatory activities, whether mechanisms underlying their activities are independent remains unclear. The ATP gated P2X(4) receptor is a pro-inflammatory mediator. Here, we investigate the action of fluvastatin and other cholesterol depleting agents on native and recombinant human P2X(4) receptor. Fluvastatin and mbetaCD suppressed P2X(4) dependent calcium influx in THP-1 monocytes, without affecting P2Y receptor responses. mbetaCD or filipin III suppressed the current density of recombinant human P2X(4) receptors. Human P2X(2) was insensitive to cholesterol depletion. Cholesterol depletion had no effect on intrinsic P2X(4) receptor properties as judged by ATP concentration-response relationship, receptor rundown or current decay during agonist occupancy. These data suggest fluvastatin suppresses P2X(4) activity in monocytes through cholesterol depletion and not by modulating intrinsic channel properties. PMID- 22222817 TI - CCL2 promotes P2X4 receptor trafficking to the cell surface of microglia. AB - P2X4 receptors (P2X4Rs), a subtype of the purinergic P2X family, play important roles in regulating neuronal and glial functions in the nervous system. We have previously shown that the expression of P2X4Rs is upregulated in activated microglia after peripheral nerve injury and that activation of the receptors by extracellular ATP is crucial for maintaining nerve injury-induced pain hypersensitivity. However, the regulation of P2X4R expression on the cell surface of microglia is poorly understood. Here, we identify the CC chemokine receptor CCR2 as a regulator of P2X4R trafficking to the cell surface of microglia. In a quantitative cell surface biotinylation assay, we found that applying CCL2 or CCL12, endogenous ligands for CCR2, to primary cultured microglial cells, increased the levels of P2X4R protein on the cell surface without changing total cellular expression. This effect of CCL2 was prevented by an antagonist of CCR2. Time-lapse imaging of green fluorescent protein (GFP)-tagged P2X4R in living microglial cells showed that CCL2 stimulation increased the movement of P2X4R-GFP particles. The subcellular localization of P2X4R immunofluorescence was restricted to lysosomes around the perinuclear region. Notably, CCL2 changed the distribution of lysosomes with P2X4R immunofluorescence within microglial cells and induced release of the lysosomal enzyme beta-hexosaminidase, indicating lysosomal exocytosis. Moreover, CCL2-stimulated microglia enhanced Akt phosphorylation by ATP applied extracellularly, a P2X4R-mediated response. These results indicate that CCL2 promotes expression of P2X4R protein on the cell surface of microglia through exocytosis of P2X4R-containing lysosomes, which may be a possible mechanism for pain hypersensitivity after nerve injury. PMID- 22222819 TI - Protein kinases participate in the contraction in response to levobupivacaine in the rat aorta. AB - Levobupivacaine is a long-acting amide local anesthetic that intrinsically produces vasoconstriction both in vivo and in vitro. Levobupivacaine increases intracellular calcium concentrations ([Ca(2+)](i)) in vascular smooth muscle cells. The goals of this in vitro study were to investigate whether levobupivacaine-induced contraction is associated with increased Ca(2+) sensitivity and to identify the protein kinases involved in mediating contraction in response to levobupivacaine in isolated rat aortic smooth muscle. The effect of levobupivacaine and potassium chloride (KCl) on the [Ca(2+)](i) and tension was measured simultaneously with acetoxymethyl ester of fura-2-loaded aortic strips. Cumulative levobupivacaine concentration-response curves were generated in the presence or absence of the following antagonists: GF 109203X; Y-27632; genistein; SP600125; PD 98059; and SB 203580. Levobupivacaine-induced protein kinase C (PKC), extracellular signal-regulated kinase (ERK), and c-Jun NH(2) terminal kinase (JNK) phosphorylation and Rho-kinase (ROCK-2) membrane translocation were detected in rat aortic vascular smooth muscle cells using Western blotting. The slope of the [Ca(2+)](i)-tension curve for levobupivacaine was higher than that for KCl. Y-27632, GF 109203X, and SP600125 attenuated levobupivacaine-induced contraction in a concentration-dependent manner. Genistein, PD 98059, and SB 203580 attenuated levobupivacaine-induced contraction. Pretreatment with GF 109203X and Y-27632 inhibited levobupivacaine induced PKC phosphorylation and Rho-kinase (ROCK-2) membrane translocation, respectively. Pretreatment with SP600125 or PD 98059 attenuated the levobupivacaine-induced phosphorylation of JNK and ERK, respectively. These results indicate that levobupivacaine-induced contraction involving an increase in myofilament Ca(2+) sensitivity involves the primary activation of Rho-kinase-, PKC-, and JNK-mediated pathways of rat aortic smooth muscle. PMID- 22222820 TI - Carbocisteine promotes phagocytosis of apoptotic cells by alveolar macrophages. AB - Clearance of apoptotic cells, so-called efferocytosis, by alveolar macrophages (AMs) is important for lung homeostasis and is impaired in pulmonary inflammatory diseases, such as chronic obstructive pulmonary disease and asthma. Carbocisteine, a mucoregulatory drug, corrects the contents of fucose in airway mucus and has anti-inflammatory properties in airway inflammation. Thus, we conducted the present study to better understand the anti-inflammatory properties of carbocisteine. First, we induced airway inflammation in mice with lipopolysaccharide intratracheally. Carbocisteine significantly decreased neutrophil numbers in bronchoalveolar lavage fluid at the resolution phase of inflammation, implying the promotion of neutrophil clearance. Then, we investigated whether carbocisteine would enhance the efferocytosis by AMs isolated from mice and found that this drug promoted not only the phagocytosis but also the binding of apoptotic cells to AMs in vitro. Furthermore, carbocisteine decreased the fucose residues stained with fluorescent fucose binding lectin, Lens culinaris agglutinin, on the cell surface of AMs. We found here that removing fucose residues from cell surfaces of AMs by fucosidase markedly enhanced both the binding and phagocytosis of apoptotic cells. Finally, AMs from mice orally given carbocisteine also promoted both the binding and phagocytosis ex vivo similarly to in vitro. These results suggest that carbocisteine could promote the clearance of apoptotic cells by AMs in airway. In addition, the present findings suggest that the binding and phagocytosis of apoptotic cells may be modulated by fucose residues on the cell surface of AMs. PMID- 22222821 TI - Pirfenidone restricts Th2 differentiation in vitro and limits Th2 response in experimental liver fibrosis. AB - Polarized T helper type 2 (Th2) response is linked with fibrosis. Here, we evaluated the effect of the anti-fibrotic agent pirfenidone on Th type 1 (Th1) and Th2 responses. For in vivo testing; Wistar rats were made cirrhotic by intraperitoneal administration of thioacetamide. Once hepatic damage was established, pirfenidone was administered intragastrically on a daily basis during three weeks. Gene expression of Th marks was evaluated by RT-PCR and Western blot assays from liver homogenates. Pirfenidone therapy induced down regulation of Th2 transcripts and proteins (GATA3 and IL-4), without affecting significantly Th1 genes expression (T-bet and IFN-gamma). We found that the activated form of p38 MAPK (identified by Western blot) was reduced by pirfenidone treatment, which is consistent with the anti-Th2 activity observed. Pirfenidone reduced GATA3 nuclear localization without modifying its DNA binding activity (evaluated by electrophoretic mobility shift assay). For in vitro testing; human naive CD4+ T cells were cultured in either Th1 or Th2 polarizing conditions in the presence of pirfenidone and flow cytometric analysis of intracellular synthesis of IFN-gamma and IL-4 was conducted. Pirfenidone impaired development of Th2 subpopulation. In conclusion, pirfenidone is capable of impairing Th2 differentiation and limits Th2 profibrogenic response. The mechanism involves p38 inhibition and regulation of GATA3 expression and translocation. PMID- 22222822 TI - Mitochondrial dysfunction induced impairment of spermatogenesis in LPS-treated rats: modulatory role of lycopene. AB - The current study investigates the potential toxicity of lipopolysaccharide (LPS) on the mitochondrial fraction of rat testis and the possible protective efficacy of lycopene. Adult male Wistar rats were categorized into four groups. Two groups were administered LPS (0.1mg/kg/day for 7 days i.p.); one of these groups received lycopene treatment (4 mg/kg/day by oral gavage, 24h before LPS treatment) (Group IV) and the other received LPS alone (Group III). A vehicle treated group (Group I) and a lycopene drug control group (Group II) were also included. Sperm count and motility were significantly decreased in Group III. The testicular mitochondrial fraction of Group III showed significant increase in basal and Fe(2+)-induced lipid peroxidation, along with a significant increase in hydrogen peroxide (H(2)O(2)) level. Moreover, the activities of mitochondrial enzymic (SOD, CAT, GPx, GR and ADH) and non-enzymic (GSH and ascorbate) antioxidants levels were decreased. Group III also showed decline in the activities of TCA enzymes such as SDH, MDH and ICDH. Pretreatment with lycopene showed normal sperm parameters, lipid peroxidation, H(2)O(2) level, antioxidant defenses and TCA enzyme activities. In conclusion, this study indicates that LPS induced oxidative stress leads to functional damages in the testicular mitochondria. Lycopene pretreatment provided a marked normalization in these parameters. PMID- 22222823 TI - Alternative use of isoflurane and propofol confers superior cardioprotection than using one of them alone in a dog model of cardiopulmonary bypass. AB - Our previous clinical study reported that isoflurane preconditioning and high dose propofol posttreatment attenuated myocardial ischemia/reperfusion injury of patients in surgery with cardiopulmonary bypass (CPB). This study was designed to confirm this cardiac protection by use of a dog CPB model and to elucidate the related mechanism. Adult mongrel male dogs undergoing standard CPB were assigned into 4 groups: Sham group, Propofol group, Isoflurane (Iso) group and isoflurane in combination of propofol (pre-Iso+P) group. After induction, anesthesia was maintained with propofol (Propofol group), isoflurane (Iso group) or isoflurane preconditioning in combination with propofol posttreatment (pre-Iso+P group). After 2 h cardiac arrest and CPB, aortic cross-clamping was released to allow 2 h reperfusion. The results demonstrated that joint use of isoflurane and propofol facilitated cardiac functional recovery, improved myocardial oxygen utilization and decreased cardiac enzyme release. Also, the oxidative damage caused by ischemia/reperfusion injury was remarkably attenuated. Linear regression analysis showed that cardiac function performance and oxidative stress status were inversely correlated, indicating the improved cardiac function was in closed association with the attenuation of oxidative stress. In addition, the cardiac oxygen consumption (VO(2)) was found to be significantly associated with the above cardiac function and oxidative stress parameters, suggesting VO(2) was predictive for the levels of cardiac damage and oxidative stress. Therefore, we conclude that alternative use of isoflurane and propofol confers superior cardioprotection against postischemic myocardial injury and dysfunction, and this protection was probably mediated by attenuation of cardiac oxidative damage. PMID- 22222824 TI - Thraustochytrids, a neglected component of organic matter decomposition and food webs in marine sediments. AB - Decomposition of organic matter in marine sediments is a critical step influencing oxygen and carbon fluxes. In addition to heterotrophic bacteria and fungi, osmoheterotrophic protists may contribute to this process, but the extent of their role as decomposers is still unknown. Among saprophytic protists, the thraustochytrids have been isolated from different habitats and substrates. Recently, they have been reported to be particularly abundant in marine sediments characterized by the presence of recalcitrant organic matter such as seagrass and mangrove detritus where they can reach biomass comparable to those of other protists and bacteria. In addition, their capacity to produce a wide spectrum of enzymes suggests a substantial role of thraustochytrids in sedimentary organic decomposition. Moreover, thraustochytrids may represent a food source for several benthic microorganisms and animals and may be involved in the upgrading of nutrient-poor organic detritus. This chapter presents an overview on studies of thraustochytrids in benthic ecosystems and discusses future prospectives and possible methods to quantify their role in benthic food webs. PMID- 22222825 TI - Diseases of fish and shellfish caused by marine fungi. AB - Fungal diseases are problematic in cultured fish and shellfish, their seeds, and sometimes wild marine animals. In this chapter fungal diseases found in marine animals, especially in Japan, are described. Pathogens in the fungal diseases are divided into two groups. One of them is marine Oomycetes, which cause fungal diseases in marine shellfish and abalones. The diseases caused by the fungi of this group and the fungal characteristics are introduced. The pathogens include members of the genera Lagenidium, Haliphthoros, Halocrusticida, Halioticida, Atkinsiella, and Pythium. On the other hand, some fungal diseases caused by mitosporic fungi are also known in marine fish and shellfish. The diseases caused by these fungi and the fungal characteristics are described. The pathogens include members of the genera Fusarium, Ochroconis, Exophiala, Scytalidium, Plectosporium, and Acremonium. PMID- 22222826 TI - Fungal endosymbionts of seaweeds. AB - Seaweeds are being studied for their role in supporting coastal marine life and nutrient cycling and for their bioactive metabolites. For a more complete understanding of seaweed communities, it is essential to obtain information about their interactions with various other components of their ecosystem. While interactions of seaweeds with herbivores such as fish and mesograzers and surface colonizers such as bacteria and microalgae are known, their interactions with marine and marine-derived fungi are little understood. This chapter highlights the need for investigations on the little-known ecological group of fungi, viz. the fungal endosymbionts, that have intimate associations with seaweeds. PMID- 22222827 TI - Diversity and biogeochemical function of planktonic fungi in the ocean. AB - Microbial communities play critical biogeochemical roles in the functioning of marine ecosystems. Recent advances in molecular methods and environmental genomics have greatly advanced our understanding of microbial prokaryotes and their diversity and functional ecology in the world's oceans. Large populations of heterotrophic eukaryotes are well documented in the oceans and yet, their diversity and function remain relatively unknown. Particularly, large populations of planktonic fungi have long been known to exist in coastal and oceanic waters but the diversity and ecology of planktonic fungi remain one of the most under studied microbial topics. Recent studies have revealed novel diversity and interesting ecological functions of planktonic fungi and suggest that they are a potentially important component in marine microbial food web. This chapter will review the diversity and ecology of planktonic fungi in the world's oceans and discuss their significance in ocean carbon and nutrient cycling. PMID- 22222828 TI - Fungi and their role in corals and coral reef ecosystems. AB - Fungi in coral reefs exist as endoliths, endobionts, saprotrophs and as pathogens. Although algal and fungal endoliths in corals were described way back in 1973, their role in microboring, carbonate alteration, discoloration, density banding, symbiotic or parasitic association was postulated almost 25 years later. Fungi, as pathogens in corals, have become a much discussed topic in the last 10 years. It is either due to the availability of better tools for investigations or greater awareness among the research communities. Fungi which are exclusive as endoliths (endemic) in corals or ubiquitous forms seem to play a role in coral reef system. Fungi associated with sponges and their role in production or induction of secondary metabolites in their host is of primary interest to various pharmaceutical industries and funding agencies. Fungal enzymes in degradation of coral mucus, and plant detritus hold great promise in biotechnological applications. Unravelling fungal diversity in corals and associated reef organisms using culture and culture-independent approaches is a subject gaining attention from research community world over. PMID- 22222829 TI - Fungal life in the dead sea. AB - The waters of the Dead Sea currently contain about 348 g/l salts (2 M Mg(2+), 0.5 M Ca(2+), 1.5 M Na(+), 0.2 M K(+), 6.5 M Cl(-), 0.1 M Br(-)). The pH is about 6.0. After rainy winters the surface waters become diluted, triggering development of microbial blooms. The 1980 and 1992 blooms were dominated by the unicellular green alga Dunaliella and red Archaea. At least 70 species (in 26 genera) of Oomycota (Chromista), Mucoromycotina, Ascomycota, and Basidiomycota (Fungi) were isolated from near-shore localities and offshore stations, including from deep waters. Aspergillus and Eurotium were most often recovered. Aspergillus terreus, A. sydowii, A. versicolor, Eurotium herbariorum, Penicillium westlingii, Cladosporium cladosporioides, C. sphaerospermum, C. ramnotellum, and C. halotolerans probably form the stable core of the community. The species Gymnascella marismortui may be endemic. Mycelia of Dead Sea isolates of A. versicolor and Chaetomium globosum remained viable for up to 8 weeks in Dead Sea water; mycelia of other species survived for many weeks in 50% Dead Sea water. Many isolates showed a very high tolerance to magnesium salts. There is no direct proof that fungi contribute to the heterotrophic activity in the Dead Sea, but fungi may be present at least locally and temporarily, and their enzymatic activities such as amylase, protease, and cellulase may play a role in the lake's ecosystem. PMID- 22222830 TI - The mycobiota of the salterns. AB - Solar salterns are constructed as shallow multi-pond systems for the production of halite through evaporation of seawater. The main feature of salterns is the discontinuous salinity gradient that provides a range of well-defined habitats with increasing salinities, from moderate to hypersaline. These present one of the most extreme environments, because of the low levels of biologically available water and the toxic concentrations of ions. Up to the year 2000, hypersaline environments were considered to be populated almost exclusively by prokaryotic microorganisms till fungi were reported to be active inhabitants of solar salterns. Since then, numerous fungal species have been described in hypersaline waters around the world. The mycobiota of salterns is represented by different species of the genus Cladosporium and the related meristematic melanized black yeasts, of non-melanized yeasts, of the filamentous genera Penicillium and Aspergillus and their teleomorphic forms (Eurotium and Emericella), and of the basidiomycetous genus Wallemia. Among these, two species became new model organisms for studying the mechanisms of extreme salt tolerance: the extremely halotolerant ascomycetous black yeast Hortaea werneckii and the obligate halophilic basidiomycete Wallemia ichthyophaga. PMID- 22222831 TI - Morphological evaluation of peridial wall, ascus and ascospore characteristics in the delineation of genera with unfurling ascospore appendages (halosphaeriaceae). AB - In the Halosphaeriaceae, taxa with unfurling ascospore appendages and related species constitute 61 species (in 21 genera). Recent phylogenetic analyses of the rRNA genes have advanced our knowledge on the relationships between genera in the family, especially the group with unfurling ascospore appendages. However, many new genera resulting from these studies lack distinctive morphological characteristics from closely related taxa. In this chapter, peridial wall layers of the ascomata and morphology of asci and ascospores are re-examined to determine if these structures offer useful information for the delineation of genera. In particular, shape parameters (aspect ratio, convexity, elongation, shape factor, sphericity, area, perimeter, diameter max, diameter mean and diameter min) of ascospores were calculated to determine if these parameters can provide extra characters for the delineation of taxa. Results suggest that peridial wall structure alone is insufficient to separate genera in the Halosphaeriaceae. Shape parameters of ascospores can provide additional characters but more taxa are required to test their efficacy. Ascus shape and length of stalk are further characters that should be calculated for taxonomical consideration. Morphology of the ascomatal wall and shape of asci and ascospores in genera with unfurling ascospore appendages in the Halosphaeriaceae are partially concordant with their phylogeny, suggesting a more thorough examination of these characters for the delineation of taxa in the family. PMID- 22222832 TI - Cultured and uncultured fungal diversity in deep-sea environments. AB - The importance of fungi found in deep-sea extreme environments is becoming increasingly recognized. In this chapter, current scientific findings on the fungal diversity in several deep-sea environments by conventional culture and culture-independent methods are reviewed and discussed, primarily focused on culture-independent approaches. Fungal species detected by conventional culture methods mostly belonged to Ascomycota and Basidiomycota phyla. Culture independent approaches have revealed the presence of highly novel fungal phylotypes, including new taxonomic groups placed in deep branches within the phylum Chytridiomycota and unknown ancient fungal groups. Future attempts to culture these unknown fungal groups may provide key insights into the early evolution of fungi and their ecological and physiological significance in deep sea environments. PMID- 22222833 TI - Molecular Diversity of Fungi from Marine Oxygen-Deficient Environments (ODEs). AB - Molecular diversity surveys of marine fungi have demonstrated that the species richness known to date is just the tip of the iceberg and that there is a large extent of unknown fungal diversity in marine habitats. Reports of novel fungal lineages at higher taxonomic levels are documented from a large number of marine habitats, including the various marine oxygen-deficient environments (ODEs). In the past few years, a strong focus of eukaryote diversity research has been on a variety of ODEs, as these environments are considered to harbor a large number of organisms, which are highly divergent to known diversity and could provide insights into the early eukaryotic evolution. ODEs that have been targeted so far include shallow water sediments, hydrothermal vent systems, deep-sea basins, intertidal habitats, and fjords. Most, if not all, molecular diversity studies in marine ODEs have shown, that contrary to previous assumptions, fungi contribute significantly to the micro-eukaryotic community in such habitats. In this chapter, we have reanalyzed the environmental fungal sequences obtained from the molecular diversity survey in 14 different sites to obtain a comprehensive picture of fungal diversity in these marine habitats. The phylogenetic analysis of the fungal environmental sequences from various ODEs have grouped these sequences into seven distinct clades (Clade 1-7) clustering with well-known fungal taxa. Apart from this, four environmental clades (EnvClade A, B, C, and D) with exclusive environmental sequences were also identified. This has provided information on the positioning of the environmental sequences at different taxonomic levels within the major fungal phylums. The taxonomic distribution of these environmental fungal sequences into clusters and clades has also shown that they are not restricted by geographical boundaries. The distribution pattern together with the reports on the respiratory abilities of fungi under reduced oxygen conditions shows that they are highly adaptive and may have a huge ecological role in these oxygen deficient habitats. PMID- 22222834 TI - Assemblage and diversity of fungi on wood and seaweed litter of seven northwest portuguese beaches. AB - Three hundred and fifty woody litter and one hundred and forty seaweed litter sampled from seven beaches of Northwest Portugal were assessed for the filamentous fungal assemblage and diversity. The woody litter was screened for fungi up to 42 months using damp chamber incubation. They consisted of 36 taxa (ascomycetes, 21; basidiomycetes, 3; anamorphic taxa, 12) comprising 10 core group taxa (>=10%) (ascomycetes, 8; basidiomycete, 1; anamorphic taxa, 1). The total fungal isolates ranged between 150 and 243, while the number of fungal taxa per wood ranged between 3 and 4.9. The seaweed litter was screened up to four months in damp chamber incubation. They encompassed 29 taxa (ascomycetes, 16; basidiomycetes, 2; anamorphic taxa, 11) comprising 15 core group taxa (ascomycetes, 9; basidiomycete, 1; anamorphic taxa, 5). Total fungal isolates ranged between 56 and 120, while the number of fungal taxa per seaweed segment ranged between 4.8 and 6.3. Fifteen taxa of ascomycetes, two of basidiomycetes, and four anamorphic taxa were common to wood and seaweed litter. On both the substrates, two arenicolous fungi Arenariomyces trifurcates and Corollospora maritima were the predominant fungi (72.6-85.9%). The species abundance curves showed higher frequency of occurrence of fungal taxa in seaweed than woody litter. Our study revealed rich assemblage and diversity of marine fungi on wood and seaweed litter of Northwest Portugal beaches. The fungal composition and diversity of this survey have been compared with earlier investigations on marine fungi of Portugal coast. PMID- 22222835 TI - Xylariaceae on the fringe. AB - The Xylariaceae is one of the best-known pyrenomycete families (Ascomycota) and is distributed throughout the world. The majority are wood inhabitants and are prevalent in tropical and subtropical regions. Halorosellinia oceanicum is the most widely distributed in mangroves and can be regarded as truly manglicolous being frequently recorded as the dominant member of the family in such environments in S.E. Asia. In Malaysian mangroves, members of the Xylariaceae have been found to be numerically important with up to 9% present in one mangrove ecosystem. A further twelve xylariaceous genera are reported as occurring as their teleomorphs in mangrove forest and their immediate surroundings including Anthostomella, Astrocystis, Biscogniauxia, Camillea, Daldinia, Fasciatispora, Hypoxylon, Kretzschmaria, Nemania, Nipicola, Rosellinia and Xylaria. Furthermore, the presence of species from a number of these taxa, especially species of Anthostomella and Xylaria, are regularly isolated as endophytes from a variety of mangrove plant species. Mangrove Xylariaceae are also well known for their ability to produce novel and often bioactive metabolites. PMID- 22222836 TI - Diversity and Distribution of Marine Fungi on Rhizophora spp. in Mangroves. AB - Rhizophora spp. occurring in mangrove habitats are excellent hosts for marine fungi. The morphological adaptations of this host plant provide suitable niche for the marine fungi. This review deals with diversity and ecology of marine fungi occurring on Rhizophora spp. Two hundred and one fungal species have been recorded on Rhizophora plant species consisting of more than ten fungal species specific to this host. In mangroves, no other genus other than Rhizophora accommodates as many as 201 marine fungi. Rhizophora plant species are highly suitable hosts as they show a variety of niches with vertical zonation, specificity, preferential colonization and succession. Thus this host could be considered as one of the important hosts to investigate marine fungi. The current review provides updated information based on the available literature with checklists on diversity and distribution of fungi on Rhizophora spp. PMID- 22222837 TI - Biotechnology of marine fungi. AB - Filamentous fungi are the most widely used eukaryotes in industrial and pharmaceutical applications. Their biotechnological uses include the production of enzymes, vitamins, polysaccharides, pigments, lipids and others. Marine fungi are a still relatively unexplored group in biotechnology. Taxonomic and habitat diversity form the basis for exploration of marine fungal biotechnology. This review covers what is known of the potential applications of obligate and marine derived fungi obtained from coastal to the oceanic and shallow water to the deep sea habitats. Recent studies indicate that marine fungi are potential candidates for novel enzymes, bioremediation, biosurfactants, polysaccharides, polyunsaturated fatty acids and secondary metabolites. Future studies that focus on culturing rare and novel marine fungi, combined with knowledge of their physiology and biochemistry will provide a firm basis for marine mycotechnology. PMID- 22222838 TI - Degradation of Phthalate Esters by Fusarium sp. DMT-5-3 and Trichosporon sp. DMI 5-1 Isolated from Mangrove Sediments. AB - Phthalate esters (PAEs) are important industrial compounds mainly used as plasticizers to increase flexibility and softness of plastic products. PAEs are of major concern because of their widespread use, ubiquity in the environment, and endocrine-disrupting toxicity. In this study, two fungal strains, Fusarium sp. DMT-5-3 and Trichosporon sp. DMI-5-1 which had the capability to degrade dimethyl phthalate esters (DMPEs), were isolated from mangrove sediments in the Futian Nature Reserve of Shenzhen, China, by enrichment culture technique. These fungi were identified on the basis of spore morphology and molecular typing using 18S rDNA sequence. Comparative investigations on the biodegradation of three isomers of DMPEs, namely dimethyl phthalate (DMP), dimethyl isophthalate (DMI), and dimethyl terephthalate (DMT), were carried out with these two fungi. It was found that both fungi could not completely mineralize DMPEs but transform them to the respective monomethyl phthalate or phthalate acid. Biochemical degradation pathways for different DMPE isomers by both fungi were different. Both fungi could transform DMT to monomethyl terephthalate (MMT) and further to terephthalic acid (TA) by stepwise hydrolysis of two ester bonds. However, they could only carry out one-step ester hydrolysis to transform DMI to monomethyl isophthalate (MMI). Further metabolism of MMI did not proceed. Only Trichosporon sp. was able to transform DMP to monomethyl phthalate (MMP) but not Fusarium sp. The optimal pH for DMI and DMT degradation by Fusarium sp. was 6.0 and 4.5, respectively, whereas for Trichosporon sp., the optimal pH for the degradation of all the three DMPE isomers was at 6.0. These results suggest that the fungal esterases responsible for hydrolysis of the two ester bonds of PAEs are highly substrate specific. PMID- 22222840 TI - Coordination polymers: what has been achieved in going from innocent 4,4' bipyridine to bis-pyridyl ligands having a non-innocent backbone? AB - The last two decades have witnessed the research activities in the area of coordination polymers (CPs), which are structurally diverse and functionally intriguing materials. In this endeavor, the most exploited ligand has been a structurally rigid N-donor compound having an innocent backbone (incapable of forming hydrogen bond) namely 4,4'-bipyridine. Much has been achieved by exploiting this wonder ligand in the area of CPs. However, the positional isomers such as 3,3'-bipyridine or 4,3'-bipyridine (which understandably induce diverse ligating topology as compared to their more symmetrical 4,4' counterpart) were not exploited in much detail presumably because of the difficulty in their synthetic accessibility. To get access to such N-donor ditopic ligands having diverse ligating topology, much efforts have been focused in the last decade or so to design such positional isomers of 4,4'-bipyridine having a non-innocent backbone (capable of forming hydrogen bond). The principal focus of such studies is to decipher the effect of diverse ligating topology and the non-innocent backbone of the ligands on the overall supramolecular structures and functions of the resultant CPs. This tutorial review aims at highlighting some of the developments of such structurally diverse and functionally intriguing CPs derived from N-donor ditopic ligands having a non-innocent backbone. PMID- 22222839 TI - Model-based elastography: a survey of approaches to the inverse elasticity problem. AB - Elastography is emerging as an imaging modality that can distinguish normal versus diseased tissues via their biomechanical properties. This paper reviews current approaches to elastography in three areas--quasi-static, harmonic and transient--and describes inversion schemes for each elastographic imaging approach. Approaches include first-order approximation methods; direct and iterative inversion schemes for linear elastic; isotropic materials and advanced reconstruction methods for recovering parameters that characterize complex mechanical behavior. The paper's objective is to document efforts to develop elastography within the framework of solving an inverse problem, so that elastography may provide reliable estimates of shear modulus and other mechanical parameters. We discuss issues that must be addressed if model-based elastography is to become the prevailing approach to quasi-static, harmonic and transient elastography: (1) developing practical techniques to transform the ill-posed problem with a well-posed one; (2) devising better forward models to capture the complex mechanical behavior of soft tissues and (3) developing better test procedures to evaluate the performance of modulus elastograms. PMID- 22222841 TI - Effort-adapted modes of assisted breathing. AB - PURPOSE OF REVIEW: New developments in mechanical ventilation have focused on increasing the patient's control of the ventilator by implementing information on lung mechanics and respiratory drive. Effort-adapted modes of assisted breathing are presented and their potential advantages are discussed. RECENT FINDINGS: Adaptive support ventilation, proportional assist ventilation with load adjustable gain factors and neurally adjusted ventilatory assist are ventilatory modes that follow the concept of adapting the assist to a defined target, instantaneous changes in respiratory drive or lung mechanics. Improved patient ventilator interaction, sufficient unloading of the respiratory muscles and increased comfort have been recently associated with these ventilator modalities. There are, however, scarce data with regard to outcome improvement, such as length of mechanical ventilation, ICU stay or mortality (commonly accepted targets to demonstrate clinical superiority). SUMMARY: Within recent years, a major step forward in the evolution of assisted (effort-adapted) modes of mechanical ventilation was accomplished. There is growing evidence that supports the physiological concept of closed-loop effort-adapted assisted modes of mechanical ventilation. However, at present, the translation into a clear outcome benefit remains to be proven. In order to fill the knowledge gap that impedes the broader application, larger randomized controlled trials are urgently needed. However, with clearly proven drawbacks of conventional assisted modes such as pressure support ventilation, it is probably about time to leave these modes introduced decades ago behind. PMID- 22222842 TI - Current world literature. PMID- 22222844 TI - Molecular characterization of mulberry (Morus spp.) genotypes via RAPD and ISSR. AB - BACKGROUND: In recent years, DNA-based markers have been used quite extensively because of their many advantages over the traditional morphological and biochemical markers. Many studies have shown that molecular markers are useful in delineating the genetic relationships among closely related mulberry genotypes and cultivars. Thus, in the present study, polymer chain reaction based DNA fingerprinting techniques were used to investigate the genetic relationships among mulberry genotypes growing in different agro-climatic regions of Turkey. RESULTS: 20 RAPD primers generated a total of 173 bands, of which 157 (90.75%) were polymorphic. As for 11 ISSR primers, 124 bands (96.55%) were polymorphic in a total of 128. The similarity index for RAPD technique ranged between 0.24-0.98; 25Is203 with 25Is112 were found to be the closest genotypes, while 24Ke10 and 25Is123 were the most distant ones. According to the ISSR result, the genetic similarity index changed between 0.21-095; 25Is203 with 25Is112 genotypes were the closest, while 25Is08 and 01KaD2 were the most distant ones. CONCLUSION: The RAPD and ISSR markers were found to be promising for assessing genetic diversity in mulberry genotypes. PMID- 22222845 TI - Palladium-catalyzed silyl C(sp3)-H bond activation. AB - The first transition-metal-catalyzed activation of silyl C(sp(3))-H bond was realized and synthetically applied. A variety of organic skeletons substituted with SiMe(3) groups could undergo the Pd-catalyzed intramolecular coupling reaction, resulting in an unprecedented synthetic method for yielding six membered silacycles. It was found that the adjacent Si atom played an essential role for the activation of the C(sp(3))-H bond of the SiMe(3) group; no activation reaction of the C(sp(3))-H bond of the CMe(3) group took place under the same reaction conditions. PMID- 22222846 TI - Infant rat infection modifies phenotypic properties of an invasive nontypeable Haemophilus influenzae. AB - Enhancing the virulence trait of a specific bacterium in an animal model is often performed prior to the use of the strain for ex vivo human studies, such as reactivity with complement and antibody, or with phagocytic cells. For example, in Streptococcus pneumoniae mouse passage is used to enhance capsule production. While investigating an unusual serum-resistant unencapsulated Haemophilus influenzae (R2866), we found that animal passage yielded an isolate (R3392) which had decreased resistance to human serum, but increased virulence in Chang conjunctival cell monolayers, but with less invasion and transcytosis of polar H292 cells. We examined 90 colonies recovered from three infant rats for phase variants of LPS biosynthetic genes. In 88 colonies lgtC was OFF due to tetrameric repeat mediated slipped-strand mispairing at the time of DNA replication, while there was no variation in lic1A, lic2A, lic3A, lexA and oaf A. With lgtC OFF the LPS lacks Galalpha1-4betaGal, an epitope mimicking the human p(k) blood group, and molecular mimicry is lost. Selection for strain susceptible to NHS in the infant rat was not antibody mediated. We conclude that the passage of pathogens virulent in humans and animals may select for phenotypes only relevant for the animal species used. PMID- 22222847 TI - Exploring the acceptance of religious assistance among patients of a psychiatric hospital. AB - BACKGROUND: Spiritual issues are rarely addressed by psychiatric institutions in daily routine practice. AIMS: To report the prevalence of, and factors associated with, inpatients' acceptance of religious assistance in a psychiatric hospital. METHODS: All patients evaluated by the religious assistance service in a psychiatric hospital were included. Patients admitted were asked about their need for religious assistance and were assessed on several religious aspects. Additional information was collected from patients' hospital charts. A comparison between those who accepted the religious assistance and those who did not was performed. RESULTS: Most of the 213 patients evaluated requested religious assistance (85.0%), including those that reported having no religion (79.1%). Patients with a diagnosis of schizophrenia (p = .010) and lower intrinsic religiousness (p = .002) tended to request less religious assistance. More than 80% of patients requested assistance based on religious traditions other than their own. CONCLUSION: Most psychiatric inpatients were willing to participate in religious assistance sessions, even those without formal religious affiliations. Patients with lower intrinsic religiosity and schizophrenia tended to request less assistance. We believe the findings of this study can serve to foster discussion on whether psychiatric hospitals should provide a structured religious care service. PMID- 22222848 TI - Factors associated with long-stay status in patients with schizophrenia: an analysis of national databases covering the entire Korean population. AB - BACKGROUND: Admissions lasting over six months (long-stay) occur frequently among patients with schizophrenia in South Korea. AIMS: To identify some patient-level and institution-level factors associated with long-stay status of patients with schizophrenia. METHODS: This is a retrospective cross-sectional study. We analysed a nationwide population-based reimbursement claims data set consisting of 496,338 claims for 58,287 patients with schizophrenia between 1 January 2005 and 30 June 2006. A two-level random effects logistic regression model was used to identify those factors. RESULTS: Age (<20 years (ref), 60-69 (OR 2.000, 95% CI: 1.640-2.438), >= 70 (2.068, 1.682-2.543)), male gender (1.192, 1.144-1.242), type of national health insurance plan (national health insurance (ref), Medical Care Aid Type 1 (4.299, 4.024-4.593)), secondary diagnosis (none (ref), psychiatric diagnosis (0.719, 0.666-0.777), non-psychiatric diagnosis (0.918, 0.850-0.991)) and type of institution (clinic (ref), psychiatric hospital (2.769, 1.507-5.087)) were associated with likelihood of long-stay status. Institutional variable associated with long-stay status included a higher number of beds (1.073, 1.013-1.137). The number of professionals (0.752, 0.646-0.876) showed negative association with long-stay status. CONCLUSIONS: Researchers could improve their assessment of long-stay status of patients with schizophrenia by using a two-level analysis including patient-level and institution-level factors. This study suggests that mental health interventions to reduce the long stay of patients with schizophrenia focus on older male patients, those enrolled in a national medical care aid programme and those admitted to psychiatric hospitals. PMID- 22222850 TI - Coercion in psychiatric care: can paternalism justify coercion? AB - BACKGROUND: It has long been debated whether coercion can be justified as paternalism in the field of mental health and it is still a continuing issue of controversy today. AIMS: This study analyses whether coercive intervention in mental health can be justified by the basic assumptions of paternalists: the assumption of incompetence, the assumption of dangerousness and the assumption of impairment. METHOD: This study involved 248 patients: 158 (63.7%) were diagnosed with schizophrenia and 90 (36.3%) were diagnosed with mood disorder. In this study, experiences of coercion were divided into legal status, subjective (perceived coercion) and objective experiences (experienced coercion). RESULTS: The assumption of incompetence was justified in all three categories of coercion whereas the assumption of dangerousness was not justified in any. The assumption of impairment was not justified in legal status and perceived coercion, but provided a partial explanation to serve as a basis for justifying experienced coercive measures. CONCLUSIONS: It can be noted that mental health experts who support paternalism without question must reconsider their previous methods. Above all, the reason why the assumption of dangerousness was not justified in any of the categories of coercion was because coercive intervention used to prevent harm to oneself and others must be very carefully carried out. PMID- 22222849 TI - Perceptions of boundaries and cultural influences in Qatar. AB - BACKGROUND: Boundary issues, which regularly arise in therapy, can present dilemmas for most clinicians. There has been substantial literature on boundary excursions in clinician-patient relationships, however, very little empirical research exists and is documented. As mental health researchers, we need to investigate a wide range of sensitive topics to enhance our understanding of the many issues that arise in the psychotherapeutic frame. AIMS: We set out to empirically explore perceptions of what may constitute a boundary violation among the mental health staff in the State of Qatar and their views on the subject. RESULTS: A total of 50 participants (24 psychiatrists, 2 doctorate level psychologists, 24 psychiatric nurses) responded with a response rate of 80%. Participants rated each possible boundary violation according to its degree of harm and professional unacceptability. Three distinct groupings of boundary violations were obtained: (1) core, consisting of the most serious violations; (2) disclosure and greeting behaviour, involving disclosure of information about the therapist and greeting behaviour; and (3) separation of therapist and client lives, involving encounters between therapists and clients outside of therapy. CONCLUSIONS: It is important to ascertain these dilemmas so that these theoretical models can be integrated in clinical practice. PMID- 22222851 TI - Prevalence of insulin resistance in a young adult population. Relationship with weight status. AB - AIM: To estimate the prevalence of insulin resistance using both the Homeostatic Model Assessment (HOMA) index and basal insulinemia, and to analyze its relationship to overweight, as measured by body mass index (BMI) and waist circumference (WC). PATIENTS AND METHODS: A series of 118 non-diabetic young adults aged 18 and 19 years attending a primary care health center were studied. They were contacted by telephone, and their BMI, WC, HOMA and basal insulinemia were measured, among other parameters. RESULTS: HOMA values >= P90 (HOMA >=3.15) were found in 9.3% of the sample (50% in the obesity group). Insulinemia >= P90 (16,9) was found in 11%. Based on BMI, 17.8% were overweight (26.5% of men, 11.6% of women), and 6.8% were obese (6.1% of men, 7.2% of women). Based on WC, 5.71% were obese when waist was measured at the midpoint and 15.38%, when measured at the iliac crest. HOMA was found to be significantly correlated to weight increase, BMI, WC, systolic blood pressure, triglycerides, and blood glucose, while correlation was only found between insulinemia and increased WC and decreased high lipoprotein cholesterol (HDL) levels. CONCLUSION: In this young adult sample, increased BMI and WC were associated to increased insulin resistance. High HOMA values were found in 9.3% of subjects. PMID- 22222852 TI - Thyroid carcinoma in children and adolescents: a retrospective review. AB - OBJECTIVE: To describe clinical presentation, preoperative study, intervention, histology, surgical complications and follow-up characteristics, and survival in patients with thyroid carcinoma (TC) with less than 18 years at presentation. MATERIAL AND METHODS: retrospective analysis of clinical data of all children and adolescents followed in S. Joao Hospital from January 1, 2000 to March 31, 2010 with histologic diagnosis of TC. RESULTS: Twenty-three patients were identified, 19 girls, and 4 boys. Median age at presentation was 17.0 years. Annual incidence was 2.3 cases/year. The main presenting symptom was a solitary thyroid nodule (60.8%). Three (13%) patients had risk factors for TC, 2 of the 3 had previous cervical irradiation. The other was a smoker. Total thyroidectomy was performed in 16 (69.6%), and 10 patients underwent a second surgical procedure. Four (17.4%) patients had postoperative complications. Histologic examination revealed differentiated TC in all, papillary thyroid carcinoma (PTC) in 86.9%, follicular carcinoma in the remaining. All patients received thyroxine suppressive therapy and 20 underwent therapeutic radioactive iodine (131I). During follow-up (7.1 years), 7 out of the 23 patients presented new metastases and needed new treatment. All patients are currently alive. CONCLUSIONS: TC is a reality in pediatric population, thyroid routine examination should take part in all clinical examination in children and adolescents. PMID- 22222853 TI - The dynamics of the vaginal microbiome during infertility therapy with in vitro fertilization-embryo transfer. AB - PURPOSE: To determine the vaginal microbiome in women undergoing IVF-ET and investigate correlations with clinical outcomes. METHODS: Thirty patients had blood drawn for estradiol (E(2)) and progesterone (P(4)) at four time points during the IVF-ET cycle and at 4-6 weeks of gestation, if pregnant. Vaginal swabs were obtained in different hormonal milieu, and the vaginal microbiome determined by deep sequencing of the 16S ribosomal RNA gene. RESULTS: The vaginal microbiome underwent a transition during therapy in some but not all patients. Novel bacteria were found in 33% of women tested during the treatment cycle, but not at 6-8 weeks of gestation. Diversity of species varied across different hormonal milieu, and on the day of embryo transfer correlated with outcome (live birth/no live birth). The species diversity index distinguished women who had a live birth from those who did not. CONCLUSIONS: This metagenomics approach has enabled discovery of novel, previously unidentified bacterial species in the human vagina in different hormonal milieu and supports a shift in the vaginal microbiome during IVF-ET therapy using standard protocols. Furthermore, the data suggest that the vaginal microbiome on the day of embryo transfer affects pregnancy outcome. PMID- 22222854 TI - Live birth from oocytes cryopreserved with slow-freezing protocol and thawed after 6 years of storage. PMID- 22222855 TI - Determination of lipoic acid, Trolox methyl ether and tocopherols in human plasma by liquid-chromatography and ion-trap tandem mass spectrometry. AB - A method for the simultaneous determination of lipoic acid and/or Trolox methyl ether, along with alpha-, gamma- and delta-tocopherol was developed using liquid chromatography-tandem mass spectrometry with negative electrospray ionization (HPLC-ESI-MS/MS) in an ion-trap mass spectrometer. Detection and quantification were accomplished by a multiple reaction monitoring method, using specific transitions from precursor ion to product ion for each analyte. Chromatographic separation was achieved in a 12 min run using a C(18) -bonded phase and methanol aqueous ammonium acetate elution gradient. Linear correlations of the chromatographic peak area (r.u. * s(-1) ) to the injected amount (ng) gave the slope values (r.u. * s(-1) * ng(-1) ) 2.34 * 10(4) for alpha-tocopherol, 5.05 * 10(4) for gamma-tocopherol, 1.27 * 10(5) for delta-tocopherol, 8.86 * 10(5) for lipoic acid and 1.23 * 10(5) for Trolox methyl ether. The lower limit of quantification ranged between 0.02 and 1.22 ng for Trolox methyl ether and lipoic acid. MS(3) experiments of gamma- and delta-tocopherol suggest ion-radical reactions and dependence of the tocopherol fragmentation pattern on the phenolic ring methylation degree. The method is shown to be applicable to measurement of these metabolites in human serum after extraction. PMID- 22222856 TI - Evolution of MS lesions to black holes under DNA vaccine treatment. AB - Persistent black holes (PBH) are associated with axonal loss and disability progression in multiple sclerosis (MS). The objective of this work was to determine if BHT-3009, a DNA plasmid-encoding myelin basic protein (MBP), reduces the risk of new lesions becoming PBH, compared to placebo, and to test if pre treatment serum anti-MBP antibody levels impact on the effect of BHT-3009 treatment. In this retrospective, blinded MRI study, we reviewed MRI scans of 155 MS patients from a double-blind, randomized, phase II trial with three treatment arms (placebo, 0.5 and 1.5 mg BHT-3009). New lesions at weeks 8 and 16 were tracked at week 48 and those appearing as T1-hypointense were classified as PBH. A subset of 46 patients with available pre-treatment serum anti-MBP IgM levels were analyzed separately. Overall, there was no impact of treatment on the risk for PBH. However, there was a significant interaction between anti-MBP antibodies and treatment effect: patients receiving 0.5 mg BHT-3009 showed a reduced risk of PBH with higher antibody levels compared to placebo (p < 0.01). Although we found no overall reduction of the risk for PBH in treated patients, there may be an effect of low-dose BHT-3009, depending on the patients' pre-treatment immune responses. PMID- 22222857 TI - Is adjunctive corticosteroid beneficial in pneumococcal meningitis in a region with high rates of resistance to penicillin and ceftriaxone? AB - The role of adjunctive corticosteroids remains controversial in meningitis by penicillin-resistant pneumococci. We determined the effect of adjunctive corticosteroids in adults with pneumococcal meningitis in a region with a high rate of penicillin resistance. A multicenter, retrospective cohort study was conducted between 1998 and 2008 in Korea. The mortality and neurological sequelae were evaluated. Among 93 patients with pneumococcal meningitis, adequate adjunctive corticosteroids were given in 45.2%. The penicillin resistance rate was 60.0%, and 42.1% were nonsusceptible to ceftriaxone. The 30-day mortality rates in the group receiving adequate corticosteroid therapy, the group in which corticosteroid was not given, and that inadequately given were 24.3, 31.6, and 27.3%, respectively, and there was no difference between the groups. The rates of development of neurological sequelae were 34.3, 33.3, and 43.5%, respectively. Multivariate analysis showed that adequate corticosteroids did not reduce mortality (HR 0.773, 95% CI 0.293-2.040) and neurologic sequelae (HR 0.604, CI 0.262-1.393). Propensity-adjusted analysis showed that adjunctive corticosteroid was not associated with time to death (HR 0.949, CI 0.374-2.408), however, a decreasing tendency was shown in neurologic sequelae in the adequate corticosteroid group (HR 0.479, CI 0.207-1.110). In conclusion, adjunctive corticosteroids did not affect mortality in adults with pneumococcal meningitis in a region with high rates of resistance to penicillin and ceftriaxone; however, the patients receiving adequate corticosteroid therapy tended to develop neurologic sequelae less frequently. PMID- 22222858 TI - Hemifacial spasm: clinical characteristics of 321 Indian patients. AB - Hemifacial spasm (HFS) is a common neurological disorder characterized by involuntary tonic and clonic contractions of the muscles innervated by the facial nerve. We aimed to describe clinical features, common antecedents, triggers and relieving factors in patients with hemifacial spasm to study the correlation of hypertension and HFS, and to compare clinical features of primary and secondary cases of HFS. The data for the study were collected prospectively on a predesigned and pre-tested format at the first attendance in all consecutive HFS patients attending the movement disorders clinic of a tertiary teaching hospital in India. The demographic profile, HFS symptoms, antecedent illnesses and neurological examination were recorded and analyzed. Muscle power in individual muscles innervated by the facial nerve was tested carefully before botulinum toxin injection. Hemifacial spasm occurred in 7.14% (n = 582) of 8,151 cases registered at the movement disorders clinic from 1993 to 2010. Data of 321 patients were complete and were included in the study. Females constituted 49.22% (n = 158). The mean age the patients was 46.02 +/- 11.82 years; ipsilateral ear clicking was observed in 22.74% cases. The most common aggravating factor was stress (44.86%), while the most common relieving factor was sleep (44.24%). Two hundred fifty-two patients (78.5%) had primary HFS. The severity of spasm correlated significantly with disease duration (p < 0.001) and weakness of facial muscles (p < 0.001). We did not observe any correlation between HFS on the left side and hypertension, as has been reported earlier. This is one of the largest studies of HFS patients and the only one that prospectively assesses patients with HFS clinically on their first visit. Interesting observations of this study are lack of female preponderance, presence of clicking in the ipsilateral ear and facial weakness even prior to botulinum toxin injection. PMID- 22222860 TI - Midterm results of percutaneous closure of very large atrial septal defects in children: role of multislice computed tomography. AB - AIMS: The aim of this study was to assess the midterm results of percutaneous closure of very large atrial septal defects (ASD) in children with transthoracic echocardiography (TTE) and multislice computed tomography (MSCT). METHODS AND RESULTS: Among 142 children who underwent percutaneous ASD closure with the AMPLATZER(r) Septal Occluder (ASO) (AGA Medical Corporation, Plymouth, MN, USA) during an eight year period, 51 patients with very large defects, were evaluated by TTE and MSCT after a period of at least two years following ASD closure. Median age at ASD closure was six years (range 4-10), with mean ASD size 20.9+/ 2.9 mm. Median device size was 20 mm (range 15-26) and median device: septal length ratio 0.95 (range 0.8-1). Early complications included one transient complete atrioventricular block and one device embolisation. At a median follow up of 55 months (range 25-92) all patients were clinically asymptomatic and had a normal ECG. TTE did not demonstrate device protrusion across the lumen of either the systemic or pulmonary veins. The mean device: septal length ratio had decreased from 0.96+/-0.05 to 0.8+/-0.02 (p<0.001). There was good correlation between the measure of atrial septum length by TTE and MSCT (r: 0.79, p<0.001). MSCT identified moderate dynamic device protrusion into the lumen of systemic or pulmonary veins in five patients and partial device malpositioning in two patients. CONCLUSIONS: Occlusion of very large ASD in children can be performed with low complications rate. MSCT provides detailed information regarding the location of the device with respect to surrounding anatomic structures and reveals anomalies not evident by TTE. PMID- 22222859 TI - A novel mutation of myelin protein zero associated with late-onset predominantly axonal Charcot-Marie-Tooth disease. AB - We report a case of late-onset predominantly axonal Charcot-Marie-Tooth disease resulting from a novel mutation in the MPZ gene encoding myelin protein zero (P0). Neurological examination, electrophysiological examination and genetic testing were performed on three members of a Finnish family (family A) and one member of a German family (family B). Three other members of the Finnish family were interviewed and genetically tested. Genetic testing was also performed on 95 healthy Finnish controls. Three members in two generations of family A and the member of family B were affected with late-onset axonal more than demyelinating, motor and sensory polyneuropathy. Heterozygous c.316C>T mutation in MPZ leading to p.Arg106Cys in P0 was found in all the affected subjects, but not in the three unaffected members of the Finnish family. None of 95 healthy Finnish controls harbored the mutation. The findings of this study indicate that p.Arg106Cys allele in MPZ causes late-onset predominantly axonal sensory and motor neuropathy. PMID- 22222861 TI - Behavioral effects of alpha,alpha,beta,beta-tetradeutero-5-MeO-DMT in rats: comparison with 5-MeO-DMT administered in combination with a monoamine oxidase inhibitor. AB - RATIONALE: Ayahuasca is a psychoactive tea prepared from a combination of plants that contain a hallucinogenic tryptamine and monoamine oxidase inhibitors (MAOIs). Behavioral pattern monitor (BPM) experiments demonstrated that the combination of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and a behaviorally inactive dose of an MAO(A) inhibitor such as harmaline or clorgyline induces biphasic effects on locomotor activity in rats, initially reducing locomotion and then increasing activity as time progresses. OBJECTIVES: The present study investigated whether the biphasic locomotor profile induced by the combination of 5-MeO-DMT and an MAOI is a consequence of a reduction in the rate of 5-MeO-DMT metabolism. This hypothesis was tested using a deuterated derivative of 5-MeO-DMT (alpha,alpha,beta,beta-tetradeutero-5-MeO-DMT) that is resistant to metabolism by MAO. RESULTS: Confirming our previous findings, 1.0 mg/kg 5-MeO-DMT (s.c.) had biphasic effects on locomotor activity in rats pretreated with a behaviorally inactive dose of the nonselective MAOI pargyline (10 mg/kg). Administration of 5 MeO-DMT alone, even at doses greater than 1.0 mg/kg, produced only reductions in locomotor activity. Although low doses of alpha,alpha,beta,beta-tetradeutero-5 MeO-DMT (0.3 and 1.0 mg/kg, s.c.) produced only hypoactivity in the BPM, a dose of 3.0 mg/kg induced a biphasic locomotor profile similar to that produced by the combination of 5-MeO-DMT and an MAOI. Receptor binding studies demonstrated that deuterium substitution had little effect on the affinity of 5-MeO-DMT for a wide variety of neurotransmitter binding sites. CONCLUSIONS: The finding with alpha,alpha,beta,beta-tetradeutero-5-MeO-DMT indicates that the hyperactivity induced by 5-MeO-DMT after MAO inhibition is a consequence of reduced metabolism of 5-MeO-DMT, leading to prolonged occupation of central serotonin receptors. These results demonstrate that deuterated tryptamines may be useful in behavioral and pharmacological studies to mimic the effects of tryptamine/MAOI combinations. PMID- 22222862 TI - Comparison of the D1 dopamine full agonists, dihydrexidine and doxanthrine, in the 6-OHDA rat model of Parkinson's disease. AB - RATIONALE: Preclinical evidence indicates that D1 dopamine receptor full agonists have potential as therapeutic agents for a variety of neurological conditions. Dihydrexidine (DHX) was the first high potency selective D1 dopamine receptor full agonist and has been studied as a possible treatment for Parkinson's disease (PD). Recently, we discovered doxanthrine (DOX), an oxygen bioisostere of DHX that has even greater selectivity for the D1 dopamine receptor. OBJECTIVES: Using the unilateral 6-hydroxydopamine-lesioned rat model of PD, DOX and DHX were compared at several doses (0.625, 1.25, 2.5, or 5.0 mg/kg) for their ability to elicit contralateral rotation by either intraperitoneal injection or oral gavage. RESULTS: After intraperitoneal administration, both DOX and DHX showed robust contralateral rotation at doses of 2.5 and 5.0 mg/kg compared to vehicle. In addition, after intraperitoneal administration at doses of 2.5 and 5.0 mg/kg, DHX had a significantly longer duration of action than DOX (p < 0.05). Areas under the curves (AUC) for DOX and DHX were not significantly different, however, indicating that DOX and DHX have similar potency after intraperitoneal administration. By contrast, after oral administration, 2.5 and 5.0 mg/kg of DOX produced significant contralateral rotations (p < 0.05), whereas DHX showed no significant activity after oral administration of any dose. CONCLUSION: These results demonstrate that although DHX and DOX have similar activity after intraperitoneal administration, DOX demonstrated greater activity after oral administration compared to DHX. Despite its catechol functionality, DOX may possess sufficient oral availability for development as a human therapeutic agent. PMID- 22222865 TI - Tympanoplasty with island cartilage or temporalis fascia: a comparative study. AB - PURPOSE: To compare clinical and audiological outcomes of the type 1 tympanoplasties where conchal cartilage (island graft) and temporalis fascia were used as the graft material. PROCEDURES: In this retrospective study, the results of type 1 tympanoplasty operations (n = 50) in which cartilage and temporalis fascia were used for graft material were compared. RESULTS: Pre- and postoperative otoscopic findings of both groups were similar (p > 0.05). Preoperatively, the pure tone averages (PTAs) and hearing thresholds of the fascia and cartilage groups were similar (p > 0.05). However, postoperatively, the PTAs and air-bone gap closure were better with temporalis fascia compared to cartilage grafting (p < 0.05). On frequency-specific comparisons, the pure tone thresholds at the frequencies of 0.5, 1 and 2 kHz recovered better with temporalis fascia compared to cartilage (p < 0.05). Although the pure tone recovery was better at 4 kHz with temporalis fascia, the difference between the groups were not significantly different (p > 0.05). CONCLUSION AND MESSAGE: In conclusion, in contrast to many reports in the literature, temporalis fascia grafting seems better in our study than grafting with conchal cartilage. PMID- 22222866 TI - Pitfalls in the sonographic evaluation of adnexal masses. AB - Sonographic evaluation of adnexal masses is subject to a variety of potential pitfalls that can lead to diagnostic overcalls and undercalls. Familiarity with the pitfalls associated with sonographic findings related to normal ovarian physiology, hemorrhagic ovarian cysts, endometriomas, cystic teratomas, extraovarian cystic masses, and exophytic uterine masses helps the imager avoid subjecting patients to unnecessary anxiety and testing, unnecessary or needlessly aggressive surgical evaluation, and incorrect diagnoses. PMID- 22222863 TI - Infralimbic and dorsal raphe microinjection of the 5-HT(1B) receptor agonist CP 93,129: attenuation of aggressive behavior in CFW male mice. AB - RATIONALE: Aggressive behavior and impaired impulse control have been associated with dysregulations in the serotonergic system and with impaired functioning of the prefrontal cortex. 5-HT(1B) receptors have been shown to specifically modulate several types of offensive aggression. OBJECTIVE: This study aims to characterize the relative importance of two populations of 5-HT(1B) receptors in the dorsal raphe nucleus (DRN) and infralimbic cortex (ILC) in the modulation of aggressive behavior. METHODS: Male CFW mice were conditioned on a fixed-ratio 5 schedule of reinforcement to self-administer a 6% (w/v) alcohol solution. Mice repeatedly engaged in 5-min aggressive confrontations until aggressive behavior stabilized. Next, a cannula was implanted into either the DRN or the ILC. After recovery, mice were tested for aggression after self-administration of either 1.0 g/kg alcohol or water prior to a microinjection of the 5-HT(1B) agonist, CP 93,129 (0-1.0 MUg/infusion). RESULTS: In both the DRN and ILC, CP-93,129 reduced aggressive behaviors after both water and alcohol self-administration. Intra raphe CP-93,129 dose-dependently reduced both aggressive and locomotor behaviors. However, the anti-aggressive effects of intra-cortical CP-93,129 were behaviorally specific. CONCLUSIONS: These findings highlight the importance of the serotonergic system in the modulation of aggression and suggest that the behaviorally specific effects of 5-HT(1B) receptor agonists are regionally selective. 5-HT(1B) receptors in a medial subregion of the prefrontal cortex, the ILC, appear to be critically involved in the attenuation of species-typical levels of aggression. PMID- 22222864 TI - Involvement of nucleus accumbens dopamine D1 receptors in ethanol drinking, ethanol-induced conditioned place preference, and ethanol-induced psychomotor sensitization in mice. AB - RATIONALE: Dopamine D1 receptor (D1R) signaling has been associated to ethanol consumption and reward in laboratory animals. OBJECTIVES: Here, we hypothesize that this receptor, which is located within the nucleus accumbens (NAc) neurons, modulates alcohol reward mechanisms. METHODS: To test this hypothesis, we measured alcohol consumption and ethanol-induced psychomotor sensitization and conditioned place preference (CPP) in mice that received bilateral microinjections of small interference RNA (siRNA)-expressing lentiviral vectors (LV-siD1R) producing D1R knock-down. The other group received control (LV-Mock) viral vectors into the NAc. RESULTS: There were no differences in the total fluid consumed and also no differences in the amount of ethanol consumed between groups prior to surgery. However, after surgery, the LV-siD1R group consumed less ethanol than the control group. This difference was not associated to taste neophobia. In addition, results have shown that down-regulation of endogenous D1R using viral-mediated siRNA in the NAc significantly decreased ethanol-induced behavioral sensitization as well as acquisition, but not expression, of ethanol induced place preference. CONCLUSIONS: We conclude that decreased D1R expression into the NAc led to reduced ethanol rewarding properties, thereby leading to lower voluntary ethanol consumption. Together, these findings demonstrate that the D1 receptor pathway within the NAc controls ethanol reward and intake. PMID- 22222867 TI - The asymmetric synthesis of chiral cyclic alpha-hydroxy phosphonates and quaternary cyclic alpha-hydroxy phosphonates. AB - A highly practical, catalytic enantioselective cyclic phosphite addition to aldehydes and ketones was developed. The reaction rate of the asymmetric hydrophosphonylation was significantly enhanced by the addition of silver carbonate. Particularly, significant improvement has been achieved on the asymmetric hydrophosphonylation of unactivated ketones, giving quaternary alpha hydroxy phosphonates with excellent enantioselectivity (up to 99% ee). PMID- 22222868 TI - Oral immunization of mice with recombinant Lactococcus lactis expressing Cu,Zn superoxide dismutase of Brucella abortus triggers protective immunity. AB - Brucella infections mainly occur through mucosal surfaces. Thus, the development of mucosal administered vaccines could be instrumental for the control of brucellosis. Here, we evaluated the usefulness of recombinant Lactococcus lactis secreting Brucella abortus Cu-Zn superoxide dismutase (SOD) as oral antigen delivery system, when administered alone or in combination with L. lactis expressing IL-12. To this end, mice were vaccinated by oral route with L. lactis NZ9000 transformed with pSEC derivatives encoding for SOD (pSEC:SOD) and IL-12 (pSEC:scIL-12). In animals receiving L. lactis pSEC:SOD alone, anti-SOD-specific IgM antibodies were detected in sera at day 28 post-vaccination, together with an IgG2a dominated IgG response. SOD-specific sIgA was also detected in nasal and bronchoalveolar lavages. In addition, T-cell-proliferative responses upon re stimulation with either recombinant SOD or crude Brucella protein extracts were observed up to 6 months after the last boost, suggesting the induction of long term memory. Vaccinated animals were also protected against challenge with the virulent B. abortus 2308 strain. Responses were mildly improved when L. lactis pSEC:SOD was co-administered with L. lactis pSEC:scIL-12. These results indicated that vaccines based on lactococci-derived live carriers are promising interventions against B. abortus infections. PMID- 22222869 TI - A vaccine candidate for eastern equine encephalitis virus based on IRES-mediated attenuation. AB - To develop an effective vaccine against eastern equine encephalitis (EEE), we engineered a recombinant EEE virus (EEEV) that was attenuated and capable of replicating only in vertebrate cells, an important safety feature for live vaccines against mosquito-borne viruses. The subgenomic promoter was inactivated with 13 synonymous mutations and expression of the EEEV structural proteins was placed under the control of an internal ribosomal entry site (IRES) derived from encephalomyocarditis virus (EMCV). We tested this vaccine candidate for virulence, viremia and efficacy in the murine model. A single subcutaneous immunization with 10(4) infectious units protected 100% of mice against intraperitoneal challenge with a highly virulent North American EEEV strain. None of the mice developed any signs of disease or viremia after immunization or following challenge. Our findings suggest that the IRES-based attenuation approach can be used to develop a safe and effective vaccine against EEE and other alphaviral diseases. PMID- 22222870 TI - Avian paramyxovirus serotypes 2-9 (APMV-2-9) vary in the ability to induce protective immunity in chickens against challenge with virulent Newcastle disease virus (APMV-1). AB - The avian paramyxoviruses (APMVs) belong to the genus Avulavirus of family Paramyxoviridae. The APMVs are classified into nine serotypes on the basis of hemagglutination inhibition (HI) and neuraminidase inhibition (NI) assays, although some serologic cross-reaction exists. Newcastle disease virus (NDV), which constitutes serotype 1 (APMV-1), is an important pathogen of poultry, but the pathogenic potential of the other APMV serotypes is poorly understood. Although antibodies to APMV -2 to -9 are prevalent in chickens, the effect of prior exposure to these serotypes on susceptibility to NDV infection and disease was not known. In the present study, chickens were immunized with APMV-2 to -9 by the oculo-nasal route and later were challenged by the same route with a highly virulent strain of NDV. Among APMV-2 to -9, only APMV-3 induced serum antibodies that cross-reacted significantly with NDV and had significant NDV-neutralizing activity in vitro. In mock-immunized chickens, challenge NDV replicated throughout the respiratory tract as well as in the brain, spleen, and enteric tract. In contrast, in APMV-3-immunized chickens, challenge NDV replication was restricted to the upper respiratory tract and trachea. Some of the other APMVs also induced partial restriction of challenge NDV replication: for example, challenge NDV was not detected in the brains of APMV-9-immunized chickens, and shedding from the respiratory tract was reduced in chickens immunized with APMV-8 and -9. All of the chickens immunized with APMV-3 survived the NDV challenge; with APMV-2, -7, -8, and -9 the percentage survival was 30%, 20%, 20%, and 52.5%, respectively; whereas none of the chickens immunized with APMV-4, -5, or -6 survived. These results show that prior infection of chickens with APMV-3 induced substantial protection against NDV challenge, whereas prior infection with APMV 2, -7, -8, and -9 can alter subsequent NDV infection. The induction of NDV neutralizing antibodies was a marker for efficient protection, but partial protection also was observed in their absence. PMID- 22222871 TI - Evaluation of attenuated VSVs with mutated M or/and G proteins as vaccine vectors. AB - Vesicular stomatitis virus (VSV) is a promising vector for vaccine and oncolysis, but it can also produce acute diseases in cattle, horses, and swine characterized by vesiculation and ulceration of the tongue, oral tissues, feet, and teats. In experimental animals (primates, rats, and mice), VSV has been shown to lead to neurotoxicities, such as hind limb paralysis. The virus matrix protein (M) and glycoprotein (G) are both major pathogenic determinants of wild-type VSV and have been the major targets for the production of attenuated strains. Existing strategies for attenuation included: (1) deletion or M51R substitution in the M protein (VSVDeltaM51 or VSVM51R, respectively); (2) truncation of the C-terminus of the G protein (GDelta28). Despite these mutations, recombinant VSV with mutated M protein is only moderately attenuated in animals, whereas there are no detailed reports to determine the pathogenicity of recombinant VSV with truncated G protein at high dose. Thus, a novel recombinant VSV (VSVDeltaM51-GDelta28) as well as other attenuated VSVs (VSVDeltaM51, VSV-GDelta28) were produced to determine their efficacy as vaccine vectors with low pathogenicity. In vitro studies indicated that truncated G protein (GDelta28) could play a more important role than deletion of M51 (DeltaM51) for attenuation of recombinant VSV. VSVDeltaM51-GDelta28 was determined to be the most attenuated virus with low pathogenicity in mice, with VSV-GDelta28 also showing relatively reduced pathogenicity. Further, neutralizing antibodies stimulated by VSV-GDelta28 proved to be significantly higher than in mice treated with VSVDeltaM51-GDelta28. In conclusion, among different attenuated VSVs with mutated M and/or G proteins, recombinant VSV with only truncated G protein (VSV-GDelta28) demonstrated ideal balance between pathogenesis and stimulating a protective immune response. These properties make VSV-GDelta28 a promising vaccine vector and vaccine candidate for preventing vesicular stomatitis disease. PMID- 22222872 TI - The population based socioeconomic burden of pediatric influenza-associated hospitalization in Hong Kong. AB - We described the monetary and non-monetary cost incurred by children hospitalized for virologically confirmed influenza virus infection in a population-based prospective 3-year study. The mean direct and indirect cost of each child hospitalized was $1217.82 (95% CI, 1111.54-1324.23) and $1328.33 (95% CI, $1136.79-1520.00) for influenza A and B, respectively. School age patients took a mean (SD) of 4.70 (3.05) days and 5.31 (3.62) days of sick leave for influenza A and B infection, respectively. Pediatric influenza A and B hospitalization was associated with 662-1046 days of school absenteeism and 214-336 days of parental work loss per 10,000 population <18 years of age per year. We showed that the cost incurred by hospitalization alone, was comparable to the cost of annual universal pediatric influenza vaccination especially in children 6 months to under 6 years of age and vaccination would result in much larger cost-savings when non-monetary costs are included. PMID- 22222873 TI - Airborne lead levels in the Korean peninsula: characterization of temporal and spatial patterns and cancer risk analysis. AB - INTRODUCTION: This study collected long-term airborne lead concentrations in the Korean peninsula and analyzed their temporal, spatial, and cancer risk characterization. METHODS: Approximately, 12,000 airborne samples of total suspended particulate (TSP) were collected from 30 ambient air monitoring stations in inland (Daegu, Daejeon, Gwangju, and Seoul) cities and portal cities (Incheon, Busan, and Ulsan) over a period of 7 years (2004-2010). High volume air samplers were employed to collect daily TSP samples during the second week of the consecutive months throughout the entire study period. The concentrations of Pb extracted from the TSP samples were analyzed using either inductively coupled plasma-atomic emission or flame atomic absorption spectrometry. RESULTS: The long term high mean Pb concentrations were observed in the port cities including Incheon (88 +/- 18 ng/m(3)), Ulsan (61 +/- 7 ng/m(3)), and Busan (58 +/- 6 ng/m(3)). In the temporal analysis, seasonal mean Pb levels were relatively higher in winter and spring than those in summer and fall. In the spatial analysis, the mean Pb levels in spring, winter, and fall from Incheon, which showed the highest seasonal concentrations except summer, were 110 +/- 19, 101 +/ 18, and 76 +/- 23 ng/m(3), respectively. In summer, the highest seasonal mean Pb level was observed in the largest industrial city and the second port city, Ulsan (78 +/- 15 ng/m(3)), followed by Incheon (65 +/- 13 ng/m(3)). CONCLUSION: The estimated excess cancer risk analysis showed that inhalation of Pb could result in cancer for one or two persons per million of population in the Korean peninsula. PMID- 22222874 TI - mPGES-1 in leukemic cells of AML patients. PMID- 22222876 TI - Bacterial hydrolysis of host glycoproteins - powerful protein modification and efficient nutrient acquisition. AB - Glycoproteins are ubiquitous in nature and fundamental to most biological processes, including the human immune system. The glycoprotein carbohydrate moieties, or glycans, are very diverse in their structure and composition, and have major effects on the chemical, physical and biological properties of these glycoproteins. The hydrolysis of glycoprotein glycans by bacterial glycosidases can have dramatic effects on glycoprotein function and, thereby, be beneficial for the bacteria in different ways. This review gives an introduction to the expanding field of extracellular glycosidases from bacterial pathogens with activity on host glycoproteins, describes some known and proposed consequences for the host and the bacteria and discusses some evolutionary and regulatory aspects of bacterial glycosidases. PMID- 22222877 TI - The molecular characterization of new types of Saccharomyces cerevisiae*S. kudriavzevii hybrid yeasts unveils a high genetic diversity. AB - New double- and triple-hybrid Saccharomyces yeasts were characterized using PCR restriction fragment length polymorphism of 35 nuclear genes, located on different chromosome arms, and the sequencing of one nuclear and one mitochondrial gene. Most of these new hybrids were originally isolated from fermentations; however, two of them correspond to clinical and dietary supplement isolates. This is the first time that the presence of double-hybrid S. cerevisiae*S. kudriavzevii in non-fermentative substrates has been reported and investigated. Phylogenetic analysis of the MET6 nuclear gene confirmed the double or triple parental origin of the new hybrids. Restriction analysis of gene regions in these hybrids revealed a high diversity of genome types. From these molecular characterizations, a reduction of the S. kudriavzevii fraction of the hybrid genomes is observed in most hybrids. Mitochondrial inheritance in hybrids was deduced from the analysis of mitochondrial COX2 gene sequences, which showed that most hybrids received the mitochondrial genome from the S. kudriavzevii parent. However, two strains inherited a S. cerevisiae COX2, being the first report of S. cerevisiae*S. kudriavzevii hybrids with S. cerevisiae mitochondrial genomes. These two strains are those showing a higher S. kudriavzevii nuclear genome reduction, especially in the wine hybrid AMH. This may be due to the release of selective pressures acting on the other hybrids to maintain kudriavzevii mitochondria-interacting genes. PMID- 22222878 TI - Commentary on Kemp et al. (2011): Dose and duration of nerve growth factor (NGF) administration determine the extent of behavioral recovery following peripheral nerve injury in the rat. PMID- 22222879 TI - Dermatology community applauds new FDA sunscreen regulations: labeling requirements aim to make it easier for consumers to select a sunscreen. PMID- 22222880 TI - Manufacturer prepares for new requirements. PMID- 22222875 TI - Immunomodulatory functions of type I interferons. AB - Interferon-alpha (IFNalpha) and IFNbeta, collectively known as type I IFNs, are the major effector cytokines of the host immune response against viral infections. However, the production of type I IFNs is also induced in response to bacterial ligands of innate immune receptors and/or bacterial infections, indicating a broader physiological role for these cytokines in host defence and homeostasis than was originally assumed. The main focus of this Review is the underappreciated immunomodulatory functions of type I IFNs in health and disease. We discuss their function in the regulation of innate and adaptive immune responses, the response to bacterial ligands, inflammasome activation, intestinal homeostasis and inflammatory and autoimmune diseases. PMID- 22222881 TI - Celecoxib may prevent lung cancer. PMID- 22222882 TI - Study finds heart transplant patients may be at risk for serious skin cancers. PMID- 22222884 TI - The yin and yang of immunomodulatory biologics: assessing the delicate balance between benefit and risk. AB - A number of therapeutic immunomodulatory biologics, including antibodies, fusion proteins, and recombinant proteins, have been causally linked with serious adverse effects in humans. In nearly all cases, these serious adverse effects have been directly associated with the immunomodulatory biologic's intended pharmacologic activity or exaggerated pharmacology. Examples of immunomodulatory biologics known to cause serious adverse effects in the clinic ranging from immunostimulation and cytokine release syndrome (e.g., TGN1412) to immunosuppression with increased risk of opportunistic infections (e.g., TNF alpha antagonists, anti-integrins) are presented. Specific examples of the nonclinical testing strategy used for the clinical risk assessment of these immunomodulatory biologics are discussed, with an emphasis on the clinical relevance and predictivity of the models. Infectious challenge animal models, in particular, were critically evaluated for their utility in evaluating clinical risk assessment versus understanding mechanism of action. The nonclinical safety testing strategy for an immunomodulatory biologic should be custom tailored to interrogate the biology of the immunologic target in order to best assess potential clinical risk. This nonclinical strategy should include mechanistic and efficacy models of pharmacologic activity and immunologic signaling pathways, in vitro immunologic assays such as cytokine release, and immunophenotypic assessment by flow cytometry, immunohistochemistry, and/or immunofluorescence, as appropriate. PMID- 22222883 TI - Pathomechanistic characterization of two exonic L1CAM variants located in trans in an obligate carrier of X-linked hydrocephalus. AB - Mutations in the gene encoding the neural cell adhesion molecule L1CAM cause several neurological disorders collectively referred to as L1 syndrome. We report here a family case of X-linked hydrocephalus in which an obligate female carrier has two exonic L1CAM missense mutations in trans substituting amino acids in the first (p.W635C) or second (p.V768I) fibronectin-type III domains. We performed various biochemical and cell biological in vitro assays to evaluate the pathogenicity of these variants. Mutant L1-W635C protein accumulates in the endoplasmic reticulum (ER), is not transported into axons, and fails to promote L1CAM-mediated cell-cell adhesion as well as neurite growth. Immunoprecipitation experiments show that L1-W635C associates with the molecular ER chaperone calnexin and is modified by poly-ubiquitination. The mutant L1-V768I protein localizes at the cell surface, is not retained in the ER, and promotes neurite growth similar to wild-type L1CAM. However, the p.V768I mutation impairs L1CAM mediated cell-cell adhesion albeit less severe than L1-W635C. These data indicate that p.W635C is a novel loss-of-function L1 syndrome mutation. The p.V768I mutation may represent a non-pathogenic variant or a variant associated with low penetrance. The poly-ubiquitination of L1-W635C and its association with the ER chaperone calnexin provide further insights into the molecular mechanisms underlying defective cell surface trafficking of L1CAM in L1 syndrome. PMID- 22222885 TI - Influence of air pollutants on allergic sensitization: the paradox of increased allergies and decreased resistance to infection. AB - Air pollution has long been associated with health risks such as increased susceptibility to respiratory infections and potentiation of asthmatic-type responses. Experimental evidence in rodents indicates that air pollutants including diesel exhaust particles (DEPs), gases, and metals cause lung injury, inflammation, reduce aspects of host defense, and may potentiate allergic airway responses. Here we present evidence that diesel exhaust particles delivered by inhalation or aspiration can exacerbate allergic lung disease depending on the material's chemical properties. Genomic analysis of mouse lungs following instillation or inhalation of DEPs shows an alteration spectrum of pathways associated with immune signaling, cell metabolism, and oxidative stress. Diesel exposure also may worsen respiratory infections through depression of protective immune responses. Here we show that mice exposed to diesel and co-infected with influenza had increased influenza virus titers as well as higher levels of lung injury and inflammation in association with increased Th2 cytokines, and a concomitant decrease in Th1 polarization. A simplified model explains how the potentiation of the Th2 arm of immunity by diesel exhaust results in increased allergic sensitization, whereas cell-mediated (protective) immunity against viral infections is simultaneously reduced. PMID- 22222886 TI - Immunology for the toxicologic pathologist. AB - The immune system functions primarily as a defense mechanism to provide protective immunity against microbial pathogens and cancer. The resulting protective responses occur through the complex interaction of tissues, cells, proteins, and molecular pathways that act in concert with other systems (e.g., nervous and endocrine) to provide the host with immunologic responses that cause pathologic processes seen primarily as inflammatory reactions. The pathologic responses can be attributed to either normal responses to infectious organisms and cancer cells, misdirected responses as in the case of hypersensitivity or autoimmune diseases, or deficient responses attributable to deficiencies or defects in components of the immune system. Pathologists need to have a basic understanding of the immune system to not only interpret findings as to their likely pathogenesis, but also to predict when the immune system may be a potential target. This review will be limited to a general overview of the basic immunologic responses and primary components involved. PMID- 22222887 TI - Regulatory T-cells: diverse phenotypes integral to immune homeostasis and suppression. AB - Regulatory T-cells (T(REG)) are diverse populations of lymphocytes that regulate the adaptive immune response in higher vertebrates. T(REG) delete autoreactive T cells, induce tolerance, and dampen inflammation. T(REG) cell deficiency in humans (i.e., IPEX [Immunodysregulation, Polyendocrinopathy and Enteropathy, X linked syndrome]) and animal models (e.g., "Scurfy" mouse) is associated with multisystemic autoimmune disease. T(REG) in humans and laboratory animal species are similar in type and regulatory function. A molecular marker of and the cell lineage specification factor for T(REG) is FOXP3, a forkhead box transcription factor. CD4(+) T(REG) are either natural (nT(REG)), which are thymus-derived CD4(+)CD25(+)FOXP3(+) T-cells, or inducible (i.e., Tr1 cells that secrete IL-10, Th3 cells that secrete TGF-beta and IL-10, and Foxp3(+) Treg). The proinflammatory Th17 subset has been a major focus of research. T(H)17 CD4(+) effector T-cells secrete IL-17, IL-21, and IL-22 in autoimmune and inflammatory disease, and are dynamically balanced with T(REG) cell development. Other lymphocyte subsets with regulatory function include: inducible CD8(+) T(REG), CD3(+)CD4(-)CD8(-) T(REG) (double-negative), CD4(+)Valpha14(+) (NKT(REG)), and gammadelta T-cells. T(REG) have four regulatory modes of action: secretion of inhibitory cytokines (e.g., IL-10 and TGF-beta), granzyme-perforin-induced apoptosis of effector lymphocytes, depriving effector T-cells of cytokines leading to apoptosis, or inhibition of dendritic cell function. The role of T(REG) in mucosal sites, inflammation/infection, pregnancy, and cancer as well as a review of T(REG) as a modulatory target in drug development will be covered. PMID- 22222888 TI - Phidippides cardiomyopathy: a review and case illustration. AB - Phidippides was a Greek messenger who experienced sudden death after running more than 175 miles in two days. In today's world, marathon running and other endurance sports are becoming more popular and raising concern about sudden deaths at these events. Once etiologies such has hypertrophic cardiomyopathy, anomalous coronary arteries, and coronary atherosclerosis have been excluded, there is now an additional consideration termed Phidippides cardiomyopathy. Because endurance sports call for a sustained increase in cardiac output for several hours, the heart is put into a state of volume overload. It has been shown that approximately one-third of marathon runners experience dilation of the right atrium and ventricle, have elevations of cardiac troponin and natriuretic peptides, and in a smaller fraction later develop small patches of cardiac fibrosis that are the likely substrate for ventricular tachyarrhythmias and sudden death. Cardiac magnetic resonance imaging is emerging as the diagnostic test of choice for this condition. This review and case report summarizes the key features of this newly appreciated disorder. PMID- 22222889 TI - Advances in the high performance polymer electrolyte membranes for fuel cells. AB - This critical review tersely and concisely reviews the recent development of the polymer electrolyte membranes and the relationship between their properties and affecting factors like operation temperature. In the first section, the advantages and shortcomings of the corresponding polymer electrolyte membrane fuel cells are analyzed. Then, the limitations of Nafion membranes and their alternatives to large-scale commercial applications are discussed. Secondly, the concepts and approaches of the alternative proton exchange membranes for low temperature and high temperature fuel cells are described. The highlights of the current scientific achievements are given for various aspects of approaches. Thirdly, the progress of anion exchange membranes is presented. Finally, the perspectives of future trends on polymer electrolyte membranes for different applications are commented on (400 references). PMID- 22222890 TI - Cerebrovascular disease. PMID- 22222891 TI - Current world literature. PMID- 22222893 TI - Design of xanthone propionate photolabile protecting group releasing acyclovir for the treatment of ocular herpes simplex virus. AB - We have attached the antiviral drug acyclovir (ACV) to a xanthone photolabile protecting group (or photocage) through the O6 position of acyclovir, a procedure designed for the treatment of ocular herpes simplex virus infections. Acyclovir is photoreleased from the photocage, under physiological conditions, with a quantum yield (Phi(ACV release)) of 0.1-0.3 and an uncaging cross section (Phi.epsilon) of 450-1350 M cm(-1). We demonstrate that this photorelease method outcompetes alternative reaction pathways, such as protonation. Furthermore, complete release of the drug is theoretically possible given a sufficient dose of light . Surprisingly the acyclovir photocage, also showed some antiviral activity towards HSV-1. PMID- 22222895 TI - White adipocytes: more than just fat depots. AB - Globally 30% of adults are overweight or obese. The white adipocyte is a major component of adipose tissue, and as the obesity epidemic increases it is critically important to understand the factors determining adipocyte development and function. Adipogenesis has two distinct phases; determination of the adipocyte from a multipotent stem cell, and terminal differentiation of a pre adipocyte into a mature adipocyte. The environment encountered in early life can alter adipocyte number and size and potentially impact upon adipocyte endocrine function in adulthood. These alterations may contribute to the pathophysiology of chronic diseases and thus targeted therapy of the adipocyte has great potential for treating the current obesity epidemic. PMID- 22222897 TI - [The use of deslorelin acetate (Suprelorin(r)) in companion animal medicine]. AB - In 2009 Suprelorin(r) was released in Switzerland for the temporary suppression of fertility in male dogs. However, in practice it has also been used to treat other conditions in male dogs and in bitches. These include treatment of benign hyperplasia of the prostate, the induction or suppression of oestrus and treatment for the side effects of gonadectomy. Also in feline reproductive medicine GnRH-agonists gain increased importance. These areas of application are listed here in terms of treatment success and possible adverse effects after treatment of which owners have to be informed beforehand. PMID- 22222898 TI - [The seroconversion of Chlamydia abortus in sheep from the region of Vorarlberg before and after Alpine pasturing]. AB - In total, 796 serum samples of sheep on commune alpine pastures in the region of Vorarlberg were investigated by a commercial ELISA kit for antibodies against Chlamydia abortus, the agent of ovine enzootic abortion. The aim of the study was to determine the seroprevalence within this region and to compare these results with the seroprevalence in the neighboring canton Graubunden as well as to obtain data on the seroconversion after alpine pasturing. Therefore, 421 samples were collected before and 375 samples after alpine pasturing, whereas corresponding serum samples were available from 359 sheep. Within the region of Vorarlberg, a mean seroprevalence of 9.2 % was calculated with a threshold of 60 %. Seroconversion for C. abortus occurred in 5.0 % of animals with corresponding serum samples. Seroprevalence values were comparable to Swiss regions with similar management systems, although the neighboring canton Graubunden is known to have a much more higher seroprevalence of 43 %. In conclusion, the traditional animal exchange between these two regions is not significantly favoring the spread of C. abortus. PMID- 22222899 TI - Whole genome scan identifies several chromosomal regions linked to equine sarcoids. AB - Despite the evidence for a genetic predisposition to develop equine sarcoids (ES), no whole genome scan for ES has been performed to date. The objective of this explorative study was to identify chromosome regions associated with ES. The studied population was comprised of two half-sibling sire families, involving a total of 222 horses. Twenty-six of these horses were affected with ES. All horses had been previously genotyped with 315 microsatellite markers. Quantitative trait locus (QTL) signals were suggested where the F statistic exceeded chromosome-wide significance at P < 0.05. The QTL analyses revealed significant signals reaching P < 0.05 on equine chromosome (ECA) 20, 23 and 25, suggesting a polygenic character for this trait. The candidate regions identified on ECA 20, 23 and 25 include genes regulating virus replication and host immune response. Further investigation of the chromosome regions associated with ES and of genes potentially responsible for the development of ES could form the basis for early identification of susceptible animals, breeding selection or the development of new therapeutic targets. PMID- 22222900 TI - [Pericardial effusion in a cat with feline infectious peritonitis]. AB - This case report describes the disease progression of a male cat with pericardial effusion. Clinical signs (dyspnea, lethargy, and weakness) started very acutely. The initial laboratory profile showed only an increase in alanine aminotransferase enzyme activity. Diagnostic imaging revealed pericardial effusion. Effusion analysis showed a Rivalta-positive, modified transudate. Detection of feline coronavirus antigen in macrophages was negative. General condition and laboratory parameters dramatically worsened within seven days. Therefore, the owners decided to euthanize the cat. Even if effusion variables are macroscopically and microscopically suspicious for FIP, a definitive diagnosis of FIP could only be made by histology (including immunhistochemical staining). PMID- 22222901 TI - [Biphasic mesothelioma in a Swiss Braunvieh cow: clinical, histological, immunohistochemical and electron microscopical findings]. AB - A 10-year-old Swiss Braunvieh cow near term was referred to our clinic because of severe abdominal distension, which caused loss of demarcation between the udder and ventral abdominal wall. Ultrasonographic examination revealed marked ascites and multiple echogenic nodules in the greater omentum. Based on the findings, non inflammatory ascites attributable to neoplasia was diagnosed. Rupture of the prepubic tendon from the pubic symphysis was also suspected. Because of a grave prognosis, parturition was induced and a live calf was delivered. The cow was euthanized and a postmortem examination was carried out. The abdominal cavity contained 248.5 litres of clear fluid. The greater omentum was thickened and oedematous and regionally contained fluid-filled cystic structures, which varied in size with a maximum diameter of 10 centimetres. Based on the histological, immunohistochemical and electron microscopical findings, biphasic mesothelioma with cyst formation affecting the entire abdominal cavity was diagnosed. PMID- 22222904 TI - [Defect in the rental property--who must pay?]. PMID- 22222906 TI - Quantum mechanics calculations, basicity and crystal structure: the route to transition metal complexes of azahelicenes. AB - Quantum mechanics density functional calculations provided gas-phase electron distributions and proton affinities for several mono- and diaza[5]helicenes; computational results, together with experimental data concerning crystal structures and propensity to methylation of the nitrogen atom(s), provide a basis for designing azahelicene complexes with transition metal ions. PMID- 22222907 TI - A PAMPA assay as fast predictive model of passive human skin permeability of new synthesized corticosteroid C-21 esters. AB - The permeation properties of twenty newly synthesized alpha-alkoxyalkanoyl and alpha-aryloxyalkanoyl C-21 esters of standard corticosteroids: Fluocinolone acetonide, dexamethasone, triamcinolone acetonide and hydrocortisone were established using a PAMPA assay (70% silicone oil and 30% isopropyl myristate). The data were compared with parent corticosteroids with addition of mometasone furoate and hydrocortisone acetate. All newly synthesized corticosteroid C-21 esters have effective permeability coefficients higher then -6, mostly followed with high values of retention factors and low permeation. The examined compounds were grouped through relationship between obtained retention factors and permeation parameters (groups I-III). The classification confirmed group I (membrane retentions as well as permeation lower then 30%) for all corticosteroid standards except mometasone furoate, a potent topical corticosteroid which, with high membrane retention (81%) and low permeation (7.7%) fits into group III. The largest number of new synthesized corticosteroids C-21 esters, among them all fluocinolone acetonide C-21 esters, have high membrane retentions (32.4%-86.5%) and low permeations (1.3%-27.1%), fitting in group III. The classification was related to previously obtained anti-inflammatory activity data for the fluocinolone acetonide C-21 esters series. According to the PAMPA results the new synthesized esters could be considered as potential new prodrugs with useful benefit/risk ratio. PMID- 22222908 TI - Antimycobacterial activity of salicylanilide benzenesulfonates. AB - A series of eighteen novel esters of salicylanilides with benzenesulfonic acid were designed, synthesized and characterized by IR, 1H-NMR and 13C-NMR. They were evaluated in vitro as potential antimycobacterial agents towards Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii. In general, the minimum inhibitory concentrations range from 1 to 500 umol/L. The most active compound against M. tuberculosis was 4-chloro-2-(4 (trifluoromethyl)phenylcarbamoyl)-phenyl benzenesulfonate, with MIC of 1 umol/L and towards M. kansasii its isomer 5-chloro-2-(4 (trifluoromethyl)phenylcarbamoyl)phenyl benzenesulfonate (MIC of 2-4 umol/L). M. avium was the less susceptible strain. However, generally, salicylanilide benzenesulfonates did not surpass the activity of other salicylanilide esters with carboxylic acids. PMID- 22222909 TI - A new triterpene from the plant of uncaria macrophylla. AB - Our ongoing investigations on the stem bark of Uncaria macrophylla afforded a new ursolic triterpene, 3beta,6beta,19alpha-trihydroxy-urs-12-en-28-oic acid-24 carboxylic acid methyl ester (1), named uncariursanic acid, and three known ursolic triterpenes including 3beta,6beta,19alpha-trihydroxy-23-oxo-urs-12-en-28 oic acid (2), 3beta,6beta,19alpha-trihydroxy-urs-12-en-28-oic acid (3) and ursolic acid (4). Their structures were elucidated by extensive spectral methods, including 1D and 2D NMR and HR-ESI-MS. The cytotoxicities of the four compounds were evaluated against two cancer cell lines (MCF-7 and HepG2) by the MTT method, and only compound 4 exhibited potent activity. PMID- 22222910 TI - The effect of alkali and Ce(III) ions on the response properties of benzoxazine supramolecules prepared via molecular assembly. AB - A series of benzoxazine monomer supramolecules with different substituted groups on their benzene ring was prepared with a Mannich reaction and characterized by FTIR, 1H-NMR and MS. The obtained products were 3,4-dihydro-3-(2' hydroxyethylene)-6-methyl-2H-benzoxazine (BM1), 3,4-dihydro-3-(2' hydroxyethylene)-6-ethyl-2H-benz-oxazine (BM2), and 3,4-dihydro-3-(2' hydroxyethylene)-6-methoxy-2H-benzoxazine (BM3). The efficiency of alkali metal ion extraction from the products was determined with Pedersen's technique, while the complexation of the Ce(III) ion was confirmed by the Job's and the mole ratio methods. The evidence of complex formation between benzoxazine monomers and Ce(III) ions was obtained with FTIR and a computational simulation. Single phase ceria (CeO2) as observed with XRD was successfully prepared by calcinating the Ce(III)-benzoxazine monomer complexes at 600 degrees C for 2 h. In addition, the geometry of the ceria nanoparticles confirmed by TEM is spherical, with an average diameter of 10-20 nm. PMID- 22222912 TI - Aptasensor for ampicillin using gold nanoparticle based dual fluorescence colorimetric methods. AB - A gold nanoparticle based dual fluorescence-colorimetric method was developed as an aptasensor to detect ampicillin using its single-stranded DNA (ssDNA) aptamer, which was discovered by a magnetic bead-based SELEX technique. The selected aptamers, AMP4 (5'-CACGGCATGGTGGGCGTCGTG-3'), AMP17 (5'-GCGGGCGGTTGTATAGCGG-3'), and AMP18 (5'-TTAGTTGGGGTTCAGTTGG-3'), were confirmed to have high sensitivity and specificity to ampicillin (K(d), AMP7 = 9.4 nM, AMP17 = 13.4 nM, and AMP18 = 9.8 nM, respectively). The 5'-fluorescein amidite (FAM)-modified aptamer was used as a dual probe for observing fluorescence differences and color changes simultaneously. The lower limits of detection for this dual method were a 2 ng/mL by fluorescence and a 10 ng/mL by colorimetry for ampicillin in the milk as well as in distilled water. Because these detection limits were below the maximum residue limit of ampicillin, this aptasensor was sensitive enough to detect antibiotics in food products, such as milk and animal tissues. In addition, this dual aptasensor will be a more accurate method for antibiotics in food products as it concurrently uses two detection methods: fluorescence and colorimetry. PMID- 22222911 TI - Characterization of different FAD-dependent glucose dehydrogenases for possible use in glucose-based biosensors and biofuel cells. AB - In this study, different flavin adenine dinucleotide (FAD)-dependent glucose dehydrogenases (FADGDHs) were characterized electrochemically after "wiring" them with an osmium redox polymer [Os(4,4'-dimethyl-2,2'-bipyridine)(2)(PVI)(10)Cl](+) on graphite electrodes. One tested FADGDH was that recently discovered in Glomerella cingulata (GcGDH), another was the recombinant form expressed in Pichia pastoris (rGcGDH), and the third was a commercially available glycosylated enzyme from Aspergillus sp. (AspGDH). The performance of the Os-polymer "wired" GDHs on graphite electrodes was tested with glucose as the substrate. Optimal operational conditions and analytical characteristics like sensitivity, linear ranges and current density of the different FADGDHs were determined. The performance of all three types of FADGDHs was studied at physiological conditions (pH 7.4). The current densities measured at a 20 mM glucose concentration were 494 +/- 17, 370 +/- 24, and 389 +/- 19 MUA cm(-2) for GcGDH, rGcGDH, and AspGDH, respectively. The sensitivities towards glucose were 2.16, 1.90, and 1.42 MUA mM( 1) for GcGDH, rGcGDH, and AspGDH, respectively. Additionally, deglycosylated rGcGDH (dgrGcGDH) was investigated to see whether the reduced glycosylation would have an effect, e.g., a higher current density, which was indeed found. GcGDH/Os polymer modified electrodes were also used and investigated for their selectivity for a number of different sugars. PMID- 22222913 TI - An improved and fast UHPLC-PDA methodology for determination of L-ascorbic and dehydroascorbic acids in fruits and vegetables. Evaluation of degradation rate during storage. AB - This study provides a versatile validated method to determine the total vitamin C content, as the sum of the contents of L-ascorbic acid (L-AA) and dehydroascorbic acid (DHAA), in several fruits and vegetables and its degradability with storage time. Seven horticultural crops from two different origins were analyzed using an ultra-high-performance liquid chromatographic-photodiode array (UHPLC-PDA) system, equipped with a new trifunctional high strength silica (100% silica particle) analytical column (100 mm * 2.1 mm, 1.7 MUm particle size) using 0.1% (v/v) formic acid as mobile phase, in isocratic mode. This new stationary phase, specially designed for polar compounds, overcomes the problems normally encountered in HPLC and is suitable for the analysis of large batches of samples without L-AA degradation. In addition, it proves to be an excellent alternative to conventional C18 columns for the determination of L-AA in fruits and vegetables. The method was fully validated in terms of linearity, detection (LOD) and quantification (LOQ) limits, accuracy, and inter/intra-day precision. Validation experiments revealed very good recovery rate of 96.6 +/- 4.4% for L-AA and 103.1 +/- 4.8 % for total vitamin C, good linearity with r(2)-values >0.999 within the established concentration range, excellent repeatability (0.5%), and reproducibility (1.6%) values. The LOD of the method was 22 ng/mL whereas the LOQ was 67 ng/mL. It was possible to demonstrate that L-AA and DHAA concentrations in the different horticulture products varied oppositely with time of storage not always affecting the total amount of vitamin C during shelf-life. Locally produced fruits have higher concentrations of vitamin C, compared with imported ones, but vegetables showed the opposite trend. Moreover, this UHPLC-PDA methodology proves to be an improved, simple, and fast approach for determining the total content of vitamin C in various food commodities, with high sensitivity, selectivity, and resolving power within 3 min of run analysis. PMID- 22222914 TI - Dispersive micro-solid phase extraction combined with gas chromatography-chemical ionization mass spectrometry for the determination of N-nitrosamines in swimming pool water samples. AB - A simple sample pretreatment technique, dispersive micro-solid phase extraction, was applied for the extraction of N-nitrosodimethylamine (NDMA) and other four N nitrosamines (NAs) from samples of swimming pool water. The parameters affecting the extraction efficiency were systematically investigated. The best extraction conditions involved immersing 75 mg of carbon molecular sieve, CarboxenTM 1003 (as an adsorbent), in a 50-mL water sample (pH 7.0) containing 5% sodium chloride in a sample tube. After 20 min of extraction by vigorous shaking, the adsorbent was collected on a filter and the NAs desorbed by treatment with 150 MUL of dichloromethane. A 10-MUL aliquot was then directly determined by large-volume injection gas chromatography with chemical ionization mass spectrometry using the selected ion storage mode. The limits of quantitation were <0.9 ng/L. The precision for these analytes, as indicated by relative standard deviations, were <8% for both intra- and inter-day analyses. Accuracy, expressed as the mean extraction recovery, was between 62% and 109%. A preliminary analysis of swimming pool water samples revealed that NDMA was present in the highest concentration, in the range from n.d. to 100 ng/L. PMID- 22222915 TI - Rationale for the opposite stereochemistry of the major monoadducts and interstrand crosslinks formed by mitomycin C and its decarbamoylated analogue at CpG steps in DNA and the effect of cytosine modification on reactivity. AB - Mitomycin C (MMC) is a potent antitumour agent that forms a covalent bond with the 2-amino group of selected guanines in the minor groove of double-stranded DNA following intracellular reduction of its quinone ring and opening of its aziridine moiety. At some 5'-CG-3' (CpG) steps the resulting monofunctional adduct can evolve towards a more deleterious bifunctional lesion, which is known as an interstrand crosslink (ICL). MMC reactivity is enhanced when the cytosine bases are methylated (5 MC) and decreased when they are replaced with 5-F cytosine (5FC) whereas the stereochemical preference of alkylation changes upon decarbamoylation. We have studied three duplex oligonucleotides of general formula d(CGATAAXGCTAACG) in which X stands for C, 5MC or 5FC. Using a combination of molecular dynamics simulations in aqueous solution, quantum mechanics and continuum electrostatics, we have been able to (i) obtain a large series of snapshots that facilitate an understanding in atomic detail of the distinct stereochemistry of monoadduct and ICL formation by MMC and its decarbamoylated analogue, (ii) provide an explanation for the altered reactivity of MMC towards DNA molecules containing 5MC or 5FC, and (iii) show the distinct accommodation in the DNA minor groove of the different covalent modifications, particularly the most cytotoxic C1alpha and C1beta ICLs. PMID- 22222916 TI - In vivo characterisation of bioresorbable vascular scaffold strut interfaces using optical coherence tomography with Gaussian line spread function analysis. AB - AIMS: Optical coherence tomography (OCT) of a bioresorbable vascular scaffold (BVS) produces a highly reflective signal outlining struts. This signal interferes with the measurement of strut thickness, as the boundaries cannot be accurately identified, and with the assessment of coverage, because the neointimal backscattering convolutes that of the polymer, frequently making them indistinguishable from one another. We hypothesise that Gaussian line spread functions (LSFs) can facilitate identification of strut boundaries, improving the accuracy of strut thickness measurements and coverage assessment. METHODS AND RESULTS: Forty-eight randomly selected BVS struts from 12 patients in the ABSORB Cohort B clinical study and four Yucatan minipigs were analysed at baseline and follow-up (six months in humans, 28 days in pigs). Signal intensities from the raw OCT backscattering were fit to Gaussian LSFs for each interface, from which peak intensity and full-width-at-half-maximum (FWHM) were calculated. Neointimal coverage resulted in significantly different LSFs and higher FWHM values relative to uncovered struts at baseline (p<0.0001). Abluminal polymer-tissue interfaces were also significantly different between baseline and follow-up (p=0.0004 in humans, p<0.0001 in pigs). Using the location of the half-max of the LSF as the polymer-tissue boundary, the average strut thickness was 158+/-11 um at baseline and 152+/-20 um at six months (p=0.886), not significantly different from nominal strut thickness. CONCLUSIONS: Fitting the raw OCT backscattering signal to a Gaussian LSF facilitates identification of the interfaces between BVS polymer and lumen or tissue. Such analysis enables more precise measurement of the strut thickness and an objective assessment of coverage. PMID- 22222918 TI - Lessons learned: providing access through distance education. PMID- 22222919 TI - Australasian Pancreatic Club (APC) and Sydney Upper Gastrointestinal Surgical Society (SUGSS) Joint Meeting. October 15-16, 2011, Bondi, Sydney, Australia. PMID- 22222917 TI - Zinc: dietary intake and impact of supplementation on immune function in elderly. AB - The diet in the elderly does not provide a sufficient level of nutrients needed to maintain an adequate healthy status leading to micronutrient deficiencies and impaired immune response with subsequent development of degenerative diseases. Nutrient "zinc" is a relevant micronutrient involved in maintaining a good integrity of many body homeostatic mechanisms, including immune efficiency, owing to its requirement for the biological activity of many enzymes, proteins and for cellular proliferation and genomic stability. Old people aged 60-65 years and older have zinc intakes below 50% of the recommended daily allowance on a given day. Many causes can be involved: among them, altered intestinal absorption, inadequate mastication, psychosocial factors, drugs interactions, altered subcellular processes (zinc transporters (Zip and ZnT family), metallothioneins, divalent metal transporter-1). Zinc supplementation may remodel the immune alterations in elderly leading to healthy ageing. Several zinc trials have been carried out with contradictory data, perhaps due to incorrect choice of an effective zinc supplementation in old subjects showing subsequent zinc toxic effects on immunity. Old subjects with specific IL-6 polymorphism (GG allele carriers; named C-) are more prone for zinc supplementation than the entire old population, in whom correct dietary habits with foods containing zinc (Mediterranean diet) may be sufficient in restoring zinc deficiency and impaired immune response. We summarise the main causes of low zinc dietary intake in elderly reporting an update on the impact of zinc supplementation upon the immune response also on the basis of individual IL-6 polymorphism. PMID- 22222920 TI - Prevalence and facility level correlates of need for wheelchair seating assessment among long-term care residents. AB - BACKGROUND: Wheelchairs are frequently prescribed for residents with mobility impairments in long-term care. Many residents receive poorly fitting wheelchairs, compromising functional independence and mobility, and contributing to subsequent health issues such as pressure ulcers. The extent of this problem and the factors that predict poor fit are poorly understood; such evidence would contribute greatly to effective and efficient clinical practice in long-term care. OBJECTIVE: To identify the prevalence of need for wheelchair seating intervention among residents in long-term care facilities in Vancouver and explore the relationship between the need for seating intervention and facility level factors. METHODS: Logistic regression analysis using secondary data from a cross sectional study exploring predictors of resident mobility. A total of 263 residents (183 females and 80 males) were randomly selected from 11 long-term care facilities in the Vancouver health region (mean age 84.2 +/- 8.6 years). The Seating Identification Tool was used to establish subject need for wheelchair seating intervention. Individual item frequency was calculated. Six contextual variables were measured at each facility including occupational therapy staffing, funding source, policies regarding wheelchair-related equipment, and decision making philosophy. RESULTS: The overall prevalence rate of inappropriate seating was 58.6% (95% CI 52.6-64.5), ranging from 30.4 to 81.8% among the individual facilities. Discomfort, poor positioning and mobility, and skin integrity were the most common issues. Two facility level variables were significant predictors of need for seating assessment: ratio of occupational therapists per 100 residents [OR 0.11 (CI 0.04, 0.31)] and expectation that residents purchase wheelchair equipment beyond the basic level [OR 2.78 (1.11, 6.97)]. A negative association between facility prevalence rate and ratio of occupational therapists (r(p) = -0.684, CI -0.143 to -0.910) was found. CONCLUSION: Prevalence of need for seating assessment in long-term care is high overall but it varies considerably between facilities. Increasing access to occupational therapy services appears to mediate this need. PMID- 22222921 TI - Experimental vitreoretinal surgery in porcine eyes. PMID- 22222922 TI - Retinal thickness changes following photodynamic therapy in chronic central serous chorioretinopathy. AB - OBJECTIVE: To evaluate changes in neural retina (NR) thickness and best-corrected visual acuity (BCVA) induced by treatment of chronic central serous chorioretinopathy (CSC) by photodynamic therapy (PDT). PATIENTS AND METHODS: Retrospective study of 25 eyes of 25 patients with chronic CSC treated by "full fluence" PDT. LogMAR BCVA and Stratus optical coherence tomography (OCT) were evaluated before treatment and 1 year after PDT. Twenty-four eyes from 24 patients with non-chronic, non-PDT-treated forms of CSC were evaluated as a control group. RESULTS: NR foveal thickness before PDT was 182 +/- 43.4 MUm (range, 92-246) vs 148.1 +/- 30.9 MUm (range, 101-220) 1 year after treatment (p = 0.004; Student's t-test paired data). NR foveal thickness in the untreated eyes was 204.6 +/- 30.7 MU (range, 132-249) vs 192.5 +/- 26.4 MU (range, 123-235) after self-resolution (p = 0.03; Student's t-test paired data). Basal NR thickness was statistically significant different between both groups (p = 0.04; Student's t-test); this difference continued to be significant at the end of the follow-up (p < 0.01; Student's t-test). All the patients with chronic CSC treated by PDT showed anatomic resolution, and BCVA improved from 0.38 +/- 0.35 to 0.23 +/- 0.29 (p = 0.007; Student's t-test paired data). Final BCVA and basal and final NR thickness showed poor correlation (Pearson = 0.2 and 0.1 respectively). CONCLUSIONS: The use of PDT in chronic CSC induces NR thickness thinning. This change is not correlated with a decrease in BCVA. Spontaneous resolution of classic CCS also showed significant NR thinning. PMID- 22222924 TI - Macular oedema in Kawasaki syndrome. PMID- 22222923 TI - Staurosporine-induced differentiation of the RGC-5 cell line leads to apoptosis and cell death at the lowest differentiating concentration. AB - BACKGROUND: Supplementation of staurosporine is the method of choice for differentiating the solely existing retinal ganglion cell (RGC)-5 cell line. This differentiation was initially claimed to be in the absence of apoptosis, but some publications supposed the induction of apoptosis during staurosporine induced RGC 5 differentiation. In respect to these inconsistencies in the literature, we investigated in detail whether RGC-5 cell differentiation by staurosporine induces apoptosis or not. METHODS: Amounts of 50 nM, 200 nM, 300 nM, and 600 nM of staurosporine were supplemented on RGC-5 cells for 24 h. Cell morphology and cell death, via propidium iodide staining, were evaluated with phase contrast and fluorescence microscopy, respectively. Cell amount, cell proliferation, and cell viability were analyzed by crystal violet staining, CFSE flow cytometry, and MTS assay, respectively. Apoptosis was determined by analyzing caspase 3/7 activity, Annexin-V+/ 7AAD- cells and the quotient of Bax to Bcl-2 mRNA expression via caspase 3/7 activity assay, flow cytometry, and real-time PCR, respectively. RESULTS: RGC-5 cells started to change their morphology and their expression of neuronal markers at 50 nM of staurosporine. This was associated with apoptosis and cell death, as indicated by a 2.1-fold (p < 0.0005) increase in caspase 3/7 activity, a 1.2-fold (p < 0.05) induction of Annexin-V+/ 7AAD- cells, and a 12 fold (p < 0.0005) increase in propidium iodide positive cells, respectively. Furthermore, staurosporine led to a dose-dependent increase in apoptosis and reduction in cell viability, cell density, and cell proliferation. CONCLUSIONS: The lowest staurosporine concentration inducing RGC-5 cell differentiation is accompanied by apoptosis and cell death. PMID- 22222926 TI - Systematic review of effective strategies for reducing screen time among young children. AB - Screen-media use among young children is highly prevalent, disproportionately high among children from lower-income families and racial/ethnic minorities, and may have adverse effects on obesity risk. Few systematic reviews have examined early intervention strategies to limit TV or total screen time; none have examined strategies to discourage parents from putting TVs in their children's bedrooms or remove TVs if they are already there. In order to identify strategies to reduce TV viewing or total screen time among children <12 years of age, we conducted a systematic review of seven electronic databases to June 2011, using the terms "intervention" and "television," "media," or "screen time." Peer reviewed intervention studies that reported frequencies of TV viewing or screen media use in children under age 12 were eligible for inclusion. We identified 144 studies; 47 met our inclusion criteria. Twenty-nine achieved significant reductions in TV viewing or screen-media use. Studies utilizing electronic TV monitoring devices, contingent feedback systems, and clinic-based counseling were most effective. While studies have reduced screen-media use in children, there are several research gaps, including a relative paucity of studies targeting young children (n = 13) or minorities (n = 14), limited long-term (>6 month) follow-up data (n = 5), and few (n = 4) targeting removing TVs from children's bedrooms. Attention to these issues may help increase the effectiveness of existing strategies for screen time reduction and extend them to different populations. PMID- 22222925 TI - Intra-abdominal adipose tissue is independently associated with sex-hormone binding globulin in premenopausal women. AB - Lower serum concentrations of sex-hormone binding globulin (SHBG) are associated with increased risk for several obesity-related diseases in women including hormone-sensitive cancers, type 2 diabetes, metabolic syndrome, and cardiovascular disease. Previous investigations have reported that body composition, specifically central obesity, and/or higher insulin concentrations are key factors associated with lower SHBG in overweight and obese women; however, these studies were limited by their cross-sectional design. We hypothesized that intra-abdominal adipose tissue (IAAT), a fat depot linked with an abnormal metabolic profile, is inversely and independently associated with SHBG. Therefore, we determined the longitudinal associations among SHBG, insulin, and IAAT in 107 premenopausal women enrolled in a weight loss study. Overweight (BMI 27-30 kg/m(2)) women were weight reduced until BMI of <= 24 was achieved. Body composition and IAAT were measured at baseline and after weight loss with dual-energy X-ray absorptiometry and computed tomography, respectively. Serum concentrations of insulin and SHBG were determined. Paired t-test showed that insulin and IAAT decreased significantly and SHBG increased significantly following weight loss (P < 0.0001 for all). Simple correlations from baseline showed no association with insulin and SHBG (r = -0.142, P = 0.143) and a significant inverse association between IAAT and SHBG (r = -0.43, P < 0.0001). Repeated measures mixed-model showed that after adjusting for age and time (weight loss), IAAT was significantly inversely associated with SHBG (P = 0.0002) and there was no association with insulin and SHBG (P = 0.180). We conclude that SHBG concentrations are influenced by IAAT and not insulin in premenopausal women. PMID- 22222928 TI - Anti-diabetic properties of non-polar Toona sinensis Roem extract prepared by supercritical-CO2 fluid. AB - Toona sinensis Roem (T. sinensis) leaves have been used as a nutritious vegetable and been suggested for medical applications; however, the reported bioactive compounds of T. sinensis leaves are, so far, from high to mid-high polar extracts. Our aims in this study were to reveal the non-polar constituents of the T. sinensis leave extract that were prepared by a method of using a supercritical CO2 fluid and to investigate the anti-diabetic potential of this extract. Through a GC/MS analysis, we revealed 24 major components of the non-polar T. sinensis leave extract, the most abundant of which was phytol. The non-polar T. sinensis leave extract showed to prevent the progression of diabetes and hepatosteatosis, the rise of triglycerol levels and the decrease of adiponectin levels in the type 2 diabetic mice. Our results suggest that the non-polar extract of T. sinensis leaves prepared using the supercritical-CO2 fluid may contain effective constituents to prevent type 2 diabetes. PMID- 22222927 TI - Hepatic steatosis and low cardiorespiratory fitness in youth with type 2 diabetes. AB - The purpose of this study was to examine the association between cardiorespiratory fitness, ectopic triglyceride accumulation, and insulin sensitivity among youth with and without type 2 diabetes. Subjects included 137 youth ages 13-18 years including 27 with type 2 diabetes, 97 overweight normoglycemic controls, and 13 healthy weight normoglycemic controls. The primary outcome measure was cardiorespiratory fitness defined as peak oxygen uptake indexed to fat free mass. Secondary outcomes included liver and muscle triglyceride content determined by (1)H-magnetic resonance spectroscopy and insulin sensitivity determined by frequently sampled intravenous glucose tolerance test. Despite similar measures of adiposity, peak oxygen uptake was 11% lower (38.9 +/- 7.9 vs. 43.9 +/- 6.1 ml/kgFFM/min, P = 0.002) and hepatic triglyceride content was nearly threefold higher (14.4 vs. 5.7%, P = 0.001) in youth with type 2 diabetes relative to overweight controls. In all 137 youth, cardiorespiratory fitness was negatively associated with hepatic triglyceride content (r = -0.22, P = 0.02) and positively associated with insulin sensitivity (r = 0.29, P = 0.002) independent of total body and visceral fat mass. Hepatic triglyceride content was also negatively associated with insulin sensitivity (r = -0.35, P < 0.001), independent of adiposity, sex, age, and peak oxygen uptake. This study demonstrated that low cardiorespiratory fitness and elevated hepatic triglyceride content are features of type 2 diabetes in youth. Furthermore, cardiorespiratory fitness and hepatic triglyceride are associated with insulin sensitivity in youth. Taken together, these data suggest that cardiorespiratory fitness and hepatic steatosis are potential clinical biomarkers for type 2 diabetes among youth. PMID- 22222929 TI - Changes in the phenolic and lipophilic composition, in the enzyme inhibition and antiproliferative activity of Ficus carica L. cultivar Dottato fruits during maturation. AB - Fruits of Ficus carica cultivar Dottato from Italy were examined to assess how the stage of ripeness influences their chemical composition, antioxidant activity, pancreatic lipase inhibition and antiproliferative properties on C32 melanoma cells. Fruits of the first harvest (June) showed a major content in furanocoumarins and pyranocoumarins whereas the fruits collected in September showed the highest polyphenolic content (11.9 mg/g of dried material). The total 70% ethanol extracts were portioned between methanol/water and n-hexane, dichloromethane and ethyl acetate, successively. Coumarins and fatty acid esters were the most abundant components of the n-hexane fractions. The dichloromethane fractions showed as major components 2 furanocoumarins (rutarenin and pimpinellin). The total extracts of F. carica cv. Dottato exhibited a significant dose-dependent antiradical and inhibition of lipid peroxidation activity, particularly fruits of the first harvest (June) that showed the highest activity with IC50 of 1.64 mg/mL and 0.004 mg/mL, respectively. Among single fractions, the ethyl acetate fraction from the second harvest (July) showed the highest antiradical activity with an IC50 value of 0.05 mg/mL while the dichloromethane fraction showed the best inhibition of lipid peroxidation with an IC50 value of 0.02 mg/mL. Dichloromethane fractions showed the highest photodynamic cytotoxicity with an IC50<5 MUg/mL. PMID- 22222930 TI - Systemic and local effects of the Fusarium toxin deoxynivalenol (DON) are not alleviated by dietary supplementation of humic substances (HS). AB - The aim of this study was to examine the effects of a control diet (CON) or a Fusarium toxin contaminated diet (FUS) with and without HS (CON-HS and FUS-HS, respectively) on pigs during a 10-week growth trial starting at 35.1+/-3.2 kg live weight (n=12/group). Moreover, 2 additional choice feeding groups were included to test the ability of the pigs to differentiate between the CON and FUS diet. Feeding the FUS diets (~3 mg DON/kg) did not depress feed intake irrespective of HS addition. However, the pigs of the choice feeding groups recognised the FUS diets and acquired an ability to avoid these diets. DON residues were detected exclusively in the blood of pigs exposed to the FUS diets (7-21 ng/mL) but their levels were not affected by HS, suggesting their inefficiency in preventing DON absorption. While zonula occludens-1 protein expression and villus height in jejunum and ileum were not compromised by FUS feeding, the jejunal crypts were significantly deepened at 31% compared to the CON group. These changes had no consequences for nutrient digestibility or LPS levels in systemic blood (0.02-0.08 EU/mL). As portal LPS levels were not measured, FUS effects on intestinal LPS translocation cannot be excluded. PMID- 22222931 TI - DNA damage in organs of mice treated acutely with patulin, a known mycotoxin. AB - Patulin, a known mycotoxin, is considered a significant contaminant in apples, apple-derived products and feeds. This study investigated the genotoxic effects of patulin in multiple organs (brain, kidney, liver and urinary bladder) of mice using an in vivo comet assay. We assessed the mechanism underlying this genotoxicity by measuring the GSH content and the thiobarbituric acid-reactive species (TBARS) level. Male CF-1 mice were given 1.0-3.75 mg/kg patulin intraperitoneally. The effect of patulin was dose-dependent and the highest patulin dose induced DNA strand breaks in the brain (damage index, DI, in hippocampus increased from 36.2 in control animals to 127.5), liver (44.3-138.4) and kidneys (31.5-99); decreased levels of GSH (hippocampus--from 46.9 to 18.4 nmol/mg protein); and an increase in lipid peroxidation (hippocampus--from 5.8 to 20.3 MDA equivalents/mg protein). This finding establishes an interrelationship between the pro-oxidant and genotoxic effects of patulin. Pre-treatment administration of N-acetyl-cysteine reduced patulin-induced DNA damage (hippocampus--DI from 127.5 to 39.8) and lipid peroxidation (hippocampus--20.3 to 12.8 MDA equivalents/mg protein) by restoring cellular GSH levels, reinforcing the positive relationship between patulin-induced GSH depletion and DNA damage caused by systemic administration of this mycotoxin. PMID- 22222932 TI - Lantana macrophylla Schauer (Verbenaceae) ethanolic extract induces activation of ERK1/2 and p38 MAPKs pathway and Ca2+ imbalance in human trophoblasts derived cell lines. AB - Lantana macrophylla Schauer (Verbenaceae) a medicinal plant used to treat menstrual and respiratory disorders was investigated. The ethanolic extract from leaves was subjected to phytochemical and biological analysis. BeWo and JEG-3 cells were used to evaluate human chorionic gonadotropin hormone (hCG) production, syncytial formation, Ca2+ uptake and Ca2+ handling protein expression. The cAMP production and the mitogen-activated protein kinases (MAPKs) phosphorylation were also investigated. Phytochemical analysis yield three triterpenes: oleanolic, ursolic and latonolic acid. Viability assay showed no significant cytotoxic effect. A significant decrease in hCG production but not a disturbance on BeWo cell fusion were observed. The cAMP pathway was not affected by L. macrophylla extract alone; although the cAMP production inducted by forskolin was diminished. Both ERK1/2 and p38 MAPKs pathways were activated. Increased intracellular Ca2+ concentration ([Ca2+]i) was observed after 24 h treatment in a time and dose dependent manner; however only L. macrophylla at 10 MUg/mL induced increased [Ca2+]i after 10 min treatment. CaBP28K and PMCA1/4 were modulated at protein and mRNA levels, respectively. This study showed for the first time the effect of triterpenoids from L. macrophylla leaves on trophoblasts like cells and indicates a potential toxic effect of this plant in the placental development and fetal growth. PMID- 22222933 TI - Avian ecologists and physiologists have different sexual preferences. AB - Seasonal timing is studied by ecologists and physiologists alike and it is now widely recognized that further integration of these fields is needed for a full understanding of phenology. This is especially true in the light of the impact of global climate change on living organisms. In studies of avian reproduction, one obstacle to this integration is that ecologists and physiologists do not allocate their research efforts equally to males and females. The physiological orchestration of breeding stages has been studied almost exclusively in males, while in avian ecology and evolutionary biology females are more often considered. This sex bias has severe implications: sexes differ in the way they use external cues to organize their life cycles, but often cue in on each other's physiology and behavior. The simultaneous investigation of both males and females within single studies is thus essential. In this review, I begin by illustrating the sex-bias in studies and attempt to explain its origin. I then provide a number of examples in which focusing on a single sex would have resulted in misleading conclusions. Finally, I review some classical studies of female reproductive physiology that have promoted and developed research on the "forgotten-sex". PMID- 22222934 TI - Heritability of prevalent vertebral fracture and volumetric bone mineral density and geometry at the lumbar spine in three generations of the Framingham study. AB - Genetic factors likely contribute to the risk for vertebral fractures; however, there are few studies on the genetic contributions to vertebral fracture (VFrx), vertebral volumetric bone mineral density (vBMD), and geometry. Also, the heritability (h(2)) for VFrx and its genetic correlation with phenotypes contributing to VFrx risk have not been established. This study aims to estimate the h(2) of vertebral fracture, vBMD, and cross-sectional area (CSA) derived from quantitative computed tomography (QCT) scans and to estimate the extent to which they share common genetic association in adults of European ancestry from three generations of Framingham Heart Study (FHS) families. Members of the FHS families were assessed for VFrx by lateral radiographs or QCT lateral scout views at 13 vertebral levels (T(4) to L(4)) using Genant's semiquantitative (SQ) scale (grades 0 to 3). Vertebral fracture was defined as having at least 25% reduction in height of any vertebra. We also analyzed QCT scans at the L(3) level for integral (In.BMD) and trabecular (Tb.BMD) vBMD and CSA. Heritability estimates were calculated, and bivariate genetic correlation analysis was performed, adjusting for various covariates. For VFrx, we analyzed 4099 individuals (148 VFrx cases) including 2082 women and 2017 men from three generations. Estimates of crude and multivariable-adjusted h(2) were 0.43 to 0.69 (p < 1.1 * 10(-2)). A total of 3333 individuals including 1737 men and 1596 women from two generations had VFrx status and QCT-derived vBMD and CSA information. Estimates of crude and multivariable-adjusted h(2) for vBMD and CSA ranged from 0.27 to 0.51. In a bivariate analysis, there was a moderate genetic correlation between VFrx and multivariable-adjusted In.BMD (-0.22) and Tb.BMD (-0.29). Our study suggests vertebral fracture, vertebral vBMD, and CSA in adults of European ancestry are heritable, underscoring the importance of further work to identify the specific variants underlying genetic susceptibility to vertebral fracture, bone density, and geometry. PMID- 22222936 TI - Microcephaly associated with Legg-Calve-Perthes disease in two siblings. AB - The co-occurrence of microcephaly and Legg-Calve-Perthes disease (LCPD) in members of the same family has been previously recorded only in two Hungarian brothers. To study the clinical and radiological phenotype in a (second) family with LCPD and microcephaly, clinical, X-ray and MRI follow-up study of two Albanian siblings aged 8 and 11 years, were made. Both siblings had primary microcephaly, seizures and mild-to-moderate mental retardation. At head imaging the boy was found to have skull asymmetry, partial lack of frontal lobe development and partial agenesis of corpus callosum and the girl had a complex brain malformation consisting in thickening of the fronto-temporal cortex, colpocephaly, increased curvature of the Sylvian fissure, elevated tentorium with mild hypoplasia of the cerebellar vermis and dilated cisterna magna. In addition, the brother had ADHD and the sister minor eye anomalies mainly consisting in epicanthic folds and pale bilateral (temporal) optic disk. We recorded (and documented for the first time by brain MRI) a second family with familial co occurrence of LCPD and microcephaly and the first occurrence of complex brain anomalies in the context of a small head circumference. The present report could encourage the observation of similar cases. PMID- 22222935 TI - Plasma Hsp72 (HSPA1A) and Hsp27 (HSPB1) expression under heat stress: influence of exercise intensity. AB - Extracellular heat-shock protein 72 (eHsp72) expression during exercise-heat stress is suggested to increase with the level of hyperthermia attained, independent of the rate of heat storage. This study examined the influence of exercise at various intensities to elucidate this relationship, and investigated the association between eHsp72 and eHsp27. Sixteen male subjects cycled to exhaustion at 60% and 75% of maximal oxygen uptake in hot conditions (40 degrees C, 50% RH). Core temperature, heart rate, oxidative stress, and blood lactate and glucose levels were measured to determine the predictor variables associated with eHsp expression. At exhaustion, heart rate exceeded 96% of maximum in both conditions. Core temperature reached 39.7 degrees C in the 60% trial (58.9 min) and 39.0 degrees C in the 75% trial (27.2 min) (P < 0.001). The rate of rise in core temperature was 2.1 degrees C h(-1) greater in the 75% trial than in the 60% trial (P < 0.001). A significant increase and correlation was observed between eHsp72 and eHsp27 concentrations at exhaustion (P < 0.005). eHsp72 was highly correlated with the core temperature attained (60% trial) and the rate of increase in core temperature (75% trial; P < 0.05). However, no common predictor variable was associated with the expression of both eHsps. The similarity in expression of eHsp72 and eHsp27 during moderate- and high-intensity exercise may relate to the duration (i.e., core temperature attained) and intensity (i.e., rate of increase in core temperature) of exercise. Thus, the immuno-inflammatory release of eHsp72 and eHsp27 in response to exercise in the heat may be duration and intensity dependent. PMID- 22222937 TI - An histologically atypical NF-type 1 patient with a new pathogenic mutation. AB - Here we describe a case of Neurofibromatosis type 1 (NF1) associated with an atypical histiocytic lesion and a new pathogenic mutation. The genetic analysis revealed an heterozygous mutation in the 5' splice site of intron 32, 6,084+1G -> T. Histopathological findings are compatible with juvenile xanthogranuloma. The new, not already described, splicing mutation, is possibly partly responsible of the association between NF1 and the histiocitic lesion. PMID- 22222938 TI - Migraine responsive to warfarin: an update on anticoagulant possible role in migraine prophylaxis. AB - We report the case of a patient suffering from migraine with and without aura who had a complete remission of both during warfarin treatment for pulmonary embolism; the attacks reappeared promptly during two treatment withdrawals. We highlight warfarin as prophylactic drug in migraine prophylaxis and discuss about new, safer and more specific anticoagulants that could be used in migraine treatment. Their use could also clarify literature's conflicting data about anticoagulants' efficacy in migraine prophylaxis and clear if their efficacy in migraine treatment could be related aspecifically to anticoagulation's effect or to a particular mechanism in the coagulation cascade. PMID- 22222939 TI - Medication shortages threaten cancer care: the oncology community and the FDA tackle ongoing drug shortage problem. PMID- 22222941 TI - Notice of duplicate publication. PMID- 22222942 TI - What can we learn from the American Heart Association and American College of Cardiology expert consensus document on geriatric hypertension? PMID- 22222943 TI - Systems chemical biology and the Semantic Web: what they mean for the future of drug discovery research. AB - Systems chemical biology, the integration of chemistry, biology and computation to generate understanding about the way small molecules affect biological systems as a whole, as well as related fields such as chemogenomics, are central to emerging new paradigms of drug discovery such as drug repurposing and personalized medicine. Recent Semantic Web technologies such as RDF and SPARQL are technical enablers of systems chemical biology, facilitating the deployment of advanced algorithms for searching and mining large integrated datasets. In this paper, we aim to demonstrate how these technologies together can change the way that drug discovery is accomplished. PMID- 22222944 TI - How well do COPD patients with chronic respiratory failure and their carers adapt to using long-term oxygen at home? PMID- 22222945 TI - Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes. AB - Bronchodilators are central to the management of chronic obstructive pulmonary disease (COPD). Clinical studies combining different classes of bronchodilators, in particular a long-acting muscarinic antagonist (LAMA) and a long-acting beta2 agonist (LABA), have demonstrated greater improvements in lung function (forced expiratory volume in 1 second, FEV1) in patients with COPD than monotherapy. FEV1 has served as an important diagnostic measurement of COPD, and the majority of clinical studies of currently available pharmacotherapies grade effectiveness of treatment regimens based on improvements in FEV1. However, FEV1 alone may not adequately reflect the overall health status of the patient. Published evidence suggests that LABA/LAMA combination therapies demonstrate greater improvements in patient-centred outcomes such as dyspnoea, symptoms, rescue medication use, and quality of life than individual drugs used alone. Evaluating patient-centred outcomes associated with COPD is likely to play an important role in future research as a measure of overall treatment effectiveness. Raising awareness of the importance of outcomes beyond lung function alone, particularly in primary care where most patients initially present themselves for medical evaluation, should form a fundamental part of a more holistic approach to COPD management. PMID- 22222946 TI - Allergic bronchopulmonary aspergillosis in a patient with chronic obstructive pulmonary disease. AB - Allergic bronchopulmonary aspergillosis (ABPA) is a debilitating lung disease which occurs as a result of interplay between a variety of host and environmental factors. It occurs in certain susceptible individuals who develop hypersensensitivity to the colonised Aspergillus species. ABPA is a complicating factor in 2% of patients with asthma and is also seen in patients with cystic fibrosis. Asthma and chronic obstructive pulmonary disease (COPD) are known to share key elements of pathogenesis. It is well known that ABPA can occur in patients with asthma, but it has recently been reported in patients with COPD as well. We report a 55-year-old male ex-smoker who presented with complaints of exertional breathlessness and productive cough for five years and an episode of haemoptysis four days prior to presentation. Spirometery showed airflow obstruction which was not reversible with bronchodilators. Chest CT scan revealed paraseptal emphysema along with central bronchiectasis (CB) in the right upper lobe and bilateral lower lobes. A type I skin hypersensitivity reaction to Aspergillus species was elicited. He fulfilled the serological criteria for ABPA and was diagnosed as having concomitant COPD and ABPA-CB. The patient was initiated on therapy for COPD along with oral corticosteroids, on which he had remarkable symptomatic improvement. PMID- 22222947 TI - Synthesis, structure and oxygen-sensing properties of iridium(III)-containing coordination polymers with different cations. AB - Four iridium(III)-containing coordination polymers 1-4 using Ir(ppy)(2)(H(2)dcbpy)PF(6) (L-H(2), ppy = 2-phenylpyridine, H(2)dcbpy = 4,4' dicarboxy-2,2'-bipyridine) as the bridging ligand, [ZnL(2)].3DMF.5H(2)O (1), [CdL(2)(H(2)O)(2)].3DMF.6H(2)O (2), [CoL(2)(H(2)O)(2)].2DMF.8H(2)O (3) and [NiL(2)(H(2)O)(2)].3DMF.6H(2)O (4), have been synthesized and structurally characterized. The emissions from 1-4 are ascribed to a metal-to-ligand charge transfer transition (MLCT). The absolute emission quantum yields for 1-4 in single crystals were measured in air to be 0.274, 0.193, 0.001 and 0.002, respectively. The noteworthy oxygen-sensing properties of 1-4 as well as L-H(2) in a single crystal were also evaluated. The Stern-Volmer quenching constant, K(SV) values, of 1-4 and L-H(2) can be deduced to be 0.834, 2.820, 1.328, 1.111 and 2.476, respectively. The results show promising K(SV) values (e.g.2) that are competitive or even larger than those of many known Ir-complexes. Moreover, the short response time (e.g. compound 2) and recovery times toward oxygen of 1-4 have been measured in their single crystal forms. The reversibility experiments for 1-4 were carried out for seven repeated cycles. As a result, >75% recovery of intensity for 1 and 2 on each cycle demonstrates a high degree of reproducibility during the sensing process. It should be noted that iridium(III)-containing coordination polymers with high emission intensity and notable oxygen sensing properties are obscure, especially in the single crystal form. This, in combination with its fine reversibility, leads to success in single crystal oxygen recognition based on photoluminescence imaging. The detection limit could be 0.50% for gaseous oxygen. Moreover, the temperature effect of compound 2 in a single crystal upon application as an oxygen sensor was expected. PMID- 22222948 TI - Current world literature. PMID- 22222950 TI - Gastric heterotopia in the proximal oesophagus ("inlet patch"): Association with adenocarcinomas arising in Barrett mucosa. AB - BACKGROUND: The prevalence of inlet patches and their association with other conditions of the gastrointestinal tract have been studied prospectively in tertiary care facilities; little is known about practice patterns in private outpatient clinics and endoscopy centres. AIMS: To assess prevalence, demographic determinants, and associated clinicopathologic features of inlet patches in patients who had oesophagogastroduodenoscopy in outpatient settings throughout the United States. METHODS: Retrospective analysis of the clinicopathologic records of 487,229 unique patients who had oesophagogastroduodenoscopy with biopsies between January 2008 and December 2010. RESULTS: There were 870 patients with inlet patches with a prevalence of 0.18%. Significant associations included male gender (OR 1.68), dysphagia (OR 1.34), upper respiratory complaints (OR 2.81), globus (OR 5.39) Barrett oesophagus (OR 1.55), and adenocarcinomas arising in Barrett mucosa (OR 5.64). CONCLUSIONS: The prevalence of inlet patches in a tertiary care setting (0.18%) was considerably lower than reported in prospective studies (3.7% on average). Inlet patches were significantly associated with male gender, dysphagia, upper respiratory complaints, globus, Barrett mucosa, and adenocarcinomas arising in Barrett oesophagus. Further studies will be needed to determine if patients with inlet patches and Barrett mucosa benefit from increased surveillance. PMID- 22222951 TI - Probabilistic modeling of selective stimulation of the human sciatic nerve with a flat interface nerve electrode. AB - Ankle control is critical to both standing balance and efficient walking. The hypothesis presented in this paper is that a Flat Interface Nerve Electrode (FINE) placed around the sciatic nerve with a fixed number of contacts at predetermined locations and without a priori knowledge of the nerve's underlying neuroanatomy can selectively control each ankle motion. Models of the human sciatic nerve surrounded by a FINE of varying size were created and used to calculate the probability of selective activation of axons within any arbitrarily designated, contiguous group of fascicles. Simulations support the hypothesis and suggest that currently available implantable technology cannot selectively recruit each target plantar flexor individually but can restore plantar flexion or dorsiflexion from a site on the sciatic nerve without spillover to antagonists. Successful activation of individual ankle muscles in 90% of the population can be achieved by utilizing bipolar stimulation and/or by using a cuff with at least 20 contacts. PMID- 22222954 TI - Ureteral reconstruction using autologous tubular grafts for the management of ureteral strictures and defects: an experimental study. AB - OBJECTIVE: To investigate whether the peritoneal cavity could function as a bioreactor to produce autologous tubular grafts for ureteral reconstruction in beagles. MATERIALS AND METHODS: 8-Fr Silastic tubes were implanted into the peritoneal cavities of 6 female beagles. At 3 weeks, the tubes were harvested and the tubular tissue covering the tubes was gently everted. A segment 3 cm in length of the right mid-ureter, involving two thirds of its diameter, was removed parallel to the ureteral axis, leaving a third of the ureteral wall. A 5-Fr double-J stent was inserted into the ureter through the created defect, and two thirds of the graft were anastomosed to both edges of the ureteral defect. One third of the graft was overlapped with the retained normal ureter and anastomosed to the external surface of the lumens. Thus, the graft was partly encapsulated by the remainder of ureteral wall. The stent was maintained for 6 weeks and removed. Excretory urography was performed at 8 (n = 3) and 12 weeks (n = 3), postoperatively. Meanwhile, the neoureter was harvested and analyzed. The left ureter served as the control and a simple intubated ureterotomy was performed. RESULTS: Histological analysis of the tubular tissue demonstrated transversely arranged myofibroblasts and an outer layer of mesothelium. The tissue was easily everted and transplanted as a ureteral graft. Eight weeks postoperatively, the neoureter demonstrated normal ureteral architecture, composed of multilayers of urothelium surrounded by smooth muscle bundles, which became increasingly organized with time. Excretory urography indicated no stenosis or hydronephrosis. CONCLUSIONS: These results show that autologous tubular tissue grown within the recipients' peritoneal cavity can be used for ureteral reconstruction in the beagle model. PMID- 22222953 TI - Investigation of the origin and spread of a Mammalian transposable element based on current sequence diversity. AB - Almost half the human genome consists of mobile DNA elements, and their analysis is a vital part of understanding the human genome as a whole. Many of these elements are ancient and have persisted in the genome for tens or hundreds of millions of years, providing a window into the evolution of modern mammals. The Golem family have been used as model transposons to highlight computational analyses which can be used to investigate these elements, particularly the use of molecular dating with large transposon families. Whole-genome searches found Golem sequences in 20 mammalian species. Golem A and B subsequences were only found in primates and squirrel. Interestingly, the full-length Golem, found as a few copies in many mammalian genomes, was found abundantly in horse. A phylogenetic profile suggested that Golem originated after the eutherian metatherian divergence and that the A and B subfamilies originated at a much later date. Molecular dating based on sequence diversity suggests an early age, of 175 Mya, for the origin of the family and that the A and B lineages originated much earlier than expected from their current taxonomic distribution and have subsequently been lost in some lineages. Using publically available data, it is possible to investigate the evolutionary history of transposon families. Determining in which organisms a transposon can be found is often used to date the origin and expansion of the families. However, in this analysis, molecular dating, commonly used for determining the age of gene sequences, has been used, reducing the likelihood of errors from deleted lineages. PMID- 22222955 TI - Light-triggered conversion of non-ionic into ionic surfactants: towards chameleon detergents for 2-D gel electrophoresis. AB - Caged non-ionic detergents, comprised of polar oligo(ethylene glycol) and non polar alkyl chains joined by a photocleavable ortho-nitrobenzyl sulfonate linker have been synthesized and characterized. The light-triggered transformation of such chameleon surfactant from a charge-neutral into a charged form offers great potential to improve 2-D gel electrophoretic separation of complex protein mixtures. PMID- 22222957 TI - Another form of publication bias: the unpublished "everyday" clinical researches. PMID- 22222958 TI - EJPRM systematic continuous update on Cochrane reviews in rehabilitation: news from July to December 2011. AB - AIM: Evidence in medicine depends on original studies but also comes from systematic review. The most the literature grows up, the most systematic reviews are needed to synthesize the evidence, since this can help operators in decision making. The Cochrane reviews are considered the most reliable instruments of synthesis, being based on a strict methodology. Since 2007 the EJPRM offer the service of listing and presenting all these reviews systematically. The aim of the present paper was to methodically review all the new rehabilitation papers published from July 2011 up to December 2011 from the Cochrane Library in order to provide to physicians involved in the field a summary of the best evidence nowadays available. METHODS: The authors thoroughly searched all the new papers of rehabilitative interest from the July 14 to December 4, 2011 in the Cochrane Library. The retrieved papers have been consequently divided in subgroups on the base of the topic and the Cochrane Groups. RESULTS: The number of included papers was seven, five were new reviews and two were updates. A synthesis of their abstracts is presented. CONCLUSION: The field of rehabilitation, being cross sectional to the whole medicine, can be of interest for many specialty. This was documented by the large number of Cochrane Group publishing reviews of rehabilitative interest. Reviewing periodically the Cochrane reviews is a good way to remain up to date and to find solid bases for everyday clinical practice. PMID- 22222959 TI - From Garibaldi and the thermae to the Italian National Rehabilitation Plan: a representation of the evolution of Physical and Rehabilitation Medicine specialty. PMID- 22222956 TI - Can humanized mice reflect the complex pathobiology of HIV-associated neurocognitive disorders? AB - There is a rebirth of humanized mouse models in reflecting human immunodeficiency virus (HIV) pathobiology. This has allowed new investigations of viral diversity, immunity and developmental therapeutics. In the past, HIV infection and disease were, in part, mirrored in immune deficient mice reconstituted with human hematopoietic stem cells. What remained from early studies reflected the ability to mirror central nervous system (CNS) disease. As the wide spread use of combination antiretroviral therapies has changed the severity, but not prevalence, of HIV-associated neurocognitive disorders (HAND), mimicking such virus-induced CNS morbidities in humanized animals is essential for HIV/AIDS research activities. To this end, we now review the evidence for how and under what circumstances humanized mice may be utilized for studies of HIV-1 neuropathogenesis. PMID- 22222960 TI - An extraordinary testimonial of thermal rehabilitation: Giuseppe Garibaldi - 2011: 150th Anniversary of the Italian Unification. AB - On the occasion of the 150th Anniversary of the Italian Unification, the discovery of some letters by Giuseppe Garibaldi - referring to a period of thermal treatments at the Baths in Civitavecchia (Rome) - gave us the opportunity for writing a commentary about a not well known experience in the Two World Hero's life: the numerous treatments carried out at many Italian spa centres for treating a rheumatic pathology (probably a rheumatoid polyarthritis) and the outcomes of various war wounds, especially the famous gunshot-wound in his right ankle during the Battle of Aspromonte, in 1862. PMID- 22222961 TI - Rehabilitation national plan: an Italian act. PMID- 22222962 TI - Clean intermittent self-catheterization in neuro-urology. AB - Neurogenic lower urinary tract dysfunction (NLUTD) is commonly encountered in rehabilitation settings, and is caused by a variety of pathologies. The management of spinal cord injury (SCI) has been the model of reference for the management of other pathologies with NLUTD. The introduction of intermittent catheterization (IC) led to decline in renal related mortality in SCI patients and allowed an improvement of quality of life (QoL) in all neurogenic patients with NLUTD. IC could be sterile, aseptic or clean. Sterile intermittent catheterization (SIC) is the preferred method of bladder drainage in emergency medicine units and during spinal shock in SCI patients, but it is costly and time consuming. Catheterizations performed in institutions, such as rehabilitation hospitals and nursing homes, are done aseptically. Clean intermittent catheterization (CIC), i.e. self-catheterization (CISC) or third party catheterization, represents the "gold standard" method for bladder emptying in all neuropathic patients with NLUTD: the technique is safe and effective and results in improved kidney and upper urinary tract status, lessening of vesico ureteral reflux and amelioration of urinary continence. CISC is mandatory in patients with NLUTD secondary to detrusor areflexia/hypocontractility and in patients suffering from neurogenic detrusor overactivity with detrusor external sphincter dyssynergia and high post void residual of urine, often in combination with antimuscarinics/bladder relaxants. The review summarizes the most important aspects of IC and CISC. Attention was focused on the history of urethral catheterization, aims, materials, advantages, indications, and present-day techniques of CISC, emphasizing the importance of teaching in order to perform correctly the catheterization technique. PMID- 22222963 TI - Management of neurogenic bowel dysfunction. AB - There are several modalities for treating neurogenic bowel dysfunction (NBD), including conservative treatments (diet, medications, biofeedback, transanal irrigation, massage, electrical stimulation, anal plug). When conservative treatments fail, clinicians can choose from a variety of therapeutic options, including colostomies, Malone anterograde continence enemas, sacral anterior root stimulator implantations, graciloplasties, and artificial bowel sphincters. We reviewed the various treatments for constipation and/or fecal incontinence in patients with NBD and propose over-reaching stepwise algorithms for the management of NBD. Our review included English language articles, randomized controlled studies, cohort studies, case-control studies, and retrospective studies (if necessary) that assessed the management of NBD. Our literature search identified 577 articles, of which 79 met our inclusion criteria. There is little evidence for the success of conservative but non-pharmacological treatments. There is strong evidence for the success of pharmacological interventions (i.e., prokinetic agents) in the treatment of chronic constipation. While surgical interventions may be considered, there is little evidence of their effectiveness. Bowel management programs for patients with neurologic diseases require a multi faceted approach. While a range of medical and surgical treatments are available, there is little evidence for their effectiveness, with the exception of pharmacological interventions. PMID- 22222964 TI - Ejaculatory dysfunction in spinal cord injury men is suggestive of dyssynergic ejaculation. AB - Spinal cord injury (SCI) is associated with impaired ejaculation. After SCI, more stimuli may be required to trigger what remains of sexual reflexes. Penile vibratory stimulation (PVS) induces a strong afferent nerve stimulation and intense activation of the autonomic nervous system, and is considered first-line treatment. Oral midodrine may come as an adjunct to PVS and enhance the success rate. Electroejaculation (EEJ) is successful in most cases of failed PVS. The typical PVS semen characteristics in chronic SCI men demonstrate a normal mean total sperm count, but a low motility rate. Significantly lower sperm motility rates and total motile sperm counts are seen in EEJ compared to PVS. The coordination between external and internal sphincters is essential. In case of a supraconal lesion, a dyssynergic ejaculation may occur, with imbalance between expulsion of the ejaculatory fluid out the prostatic urethra and impaired relaxation of the urethral external sphincter. This leads to incomplete or absent antegrade ejaculation and would explain the high percentage of retrograde ejaculation and the low ejaculate volume observed in SCI men. In some cases, retrograde ejaculation could simply refer to a fraction of ejaculate present in the posterior urethra. PMID- 22222966 TI - Quertle and KNALIJ: searching PubMed has never been so easy and effective. AB - Quertle and KNALIJ are two innovative tools created to search PubMed in a easier and more effective way. They dramatically reduce time to discover meaningful results. Quertle allows a semantic search in multiple biomedical databases (PubMed included) and runs a query via relationships between concepts, so that you retrieve at ease more pertinent results and can navigate them by "key concepts". KNALIJ is a visualization tool which searches PubMed and presents the results in the form of visual, interactive maps you can zoom, scale, and explore according to new paths. PMID- 22222967 TI - Primary alcohols activate human TRPA1 channel in a carbon chain length-dependent manner. AB - Transient receptor potential ankyrin 1 (TRPA1) is a calcium-permeable non selective cation channel that is mainly expressed in primary nociceptive neurons. TRPA1 is activated by a variety of noxious stimuli, including cold temperatures, pungent compounds such as mustard oil and cinnamaldehyde, and intracellular alkalization. Here, we show that primary alcohols, which have been reported to cause skin, eye or nasal irritation, activate human TRPA1 (hTRPA1). We measured intracellular Ca(2+) changes in HEK293 cells expressing hTRPA1 induced by 1 mM primary alcohols. Higher alcohols (1-butanol to 1-octanol) showed Ca(2+) increases proportional to the carbon chain length. In whole-cell patch-clamp recordings, higher alcohols (1-hexanol to 1-octanol) activated hTRPA1 and the potency increased with the carbon chain length. Higher alcohols evoked single channel opening of hTRPA1 in an inside-out configuration. In addition, cysteine at 665 in the N terminus and histidine at 983 in the C terminus were important for hTRPA1 activation by primary alcohols. Furthermore, straight-chain secondary alcohols increased intracellular Ca(2+) concentrations in HEK293 cells expressing hTRPA1, and both primary and secondary alcohols showed hTRPA1 activation activities that correlated highly with their octanol/water partition coefficients. On the other hand, mouse TRPA1 did not show a strong response to 1 hexanol or 1-octanol, nor did these alcohols evoke significant pain in mice. We conclude that primary and secondary alcohols activate hTRPA1 in a carbon chain length-dependent manner. TRPA1 could be a sensor of alcohols inducing skin, eye and nasal irritation in human. PMID- 22222968 TI - Dual targeting of aminoacyl-tRNA synthetases to the apicoplast and cytosol in Plasmodium falciparum. AB - The causative agent of malaria, Plasmodium, possesses three translationally active compartments: the cytosol, the mitochondrion and a relic plastid called the apicoplast. Aminoacyl-tRNA synthetases to charge tRNA are thus required for all three compartments. However, the Plasmodiumfalciparum genome encodes too few tRNA synthetases to supply a unique enzyme for each amino acid in all three compartments. We have investigated the subcellular localisation of three tRNA synthetases (AlaRS, GlyRS and ThrRS), which occur only once in the nuclear genome, and we show that each of these enzymes is dually localised to the P. falciparum cytosol and the apicoplast. No mitochondrial fraction is apparent for these three enzymes, which suggests that the Plasmodium mitochondrion lacks at least these three tRNA synthetases. The unique Plasmodium ThrRS is the presumed target of the antimalarial compound borrelidin. Borrelidin kills P. falciparum parasites quickly without the delayed death effect typical of apicoplast translation inhibitors and without an observable effect on apicoplast morphology. By contrast, mupirocin, an inhibitor of the apicoplast IleRS, kills with a delayed death effect that inhibits apicoplast growth and division. Because inhibition of dual targeted tRNA synthetases should arrest translation in all compartments of the parasite, these enzymes deserve further investigation as potential targets for antimalarial drug development. PMID- 22222969 TI - Failure to detect significant association between estrogen receptor-alpha gene polymorphisms and endometriosis in Japanese women. AB - OBJECTIVES: The aim of the study was to test whether estrogen receptor 1 (ESR1) gene polymorphisms are correlated with the risk of the development of endometriosis in Japanese women, as a preliminary study. METHODS: To compare allelic frequencies and genotype distributions, a case-control study of 100 affected women and 143 women with no evidence of disease was performed using 10 microsatellite repeat markers and 66 single-nucleotide polymorphisms (SNPs) in the ESR1 gene region. RESULTS: Although our results might be insufficient to detect genetic susceptibility, owing to the small sample size and low genetic power, statistical analysis of the differences in allelic frequency between the cases and controls at each microsatellite locus demonstrated that no microsatellite locus in the ESR1 gene displayed a significant association with the disease when multiple testing was taken into account. Also, there were no statistically significant differences in the SNP allele frequencies and genotypes between the cases and controls when multiple testing was taken into account. CONCLUSION: The findings in our pilot study suggest that ESR1 polymorphisms do not contribute to endometriosis susceptibility. PMID- 22222970 TI - Intraoral pH measurement of carious lesions with qPCR of cariogenic bacteria to differentiate caries activity. AB - OBJECTIVES: A low pH environment is created by cariogenic bacteria. This study was aimed to measure pH of carious lesions intraorally using a micro-pH sensor, and assess predominant acid-producing cariogens by qPCR to differentiate caries activities. METHODS: 103 dentine lesions classified as active or arrested caries based on the clinical and radiological examinations were collected from patients after intraoral measurement of the lesion surface pH using a micro-pH sensor. Quantitative detection of genomic DNA copies of target cariogenic bacteria (mutans streptococci and Lactobacillus spp.) in each lesion was performed using real-time PCR. Correlation between the pH ranges and the number of bacterial species was examined by Spearman test. RESULTS: 50 samples were diagnosed as active and 53 as arrested lesions. Statistically significant difference was observed on average surface pH value between active and arrested lesions (p<0.05). Prevalence of Lactobacillus spp. was higher in active lesions than in arrested lesions (76% vs. 58% of samples, respectively). When the carious lesions were categorised into four different pH ranges (up to 5.5, from 5.6 to 5.8, from 5.9 to 6.1 and 6.2 or above), increased prevalence of Lactobacillus spp. was observed with decrease of pH levels. A significant negative relationship was found between pH value and number of Lactobacillus spp. (r=-0.209, p<0.05) but no such correlation was found for mutans streptococci. CONCLUSIONS: Intraoral pH measurement might be clinically useful to determine acidity of the local environment of carious lesions as one aspect of the caries activity assessment. CLINICAL SIGNIFICANCE: The population of certain bacteria may indicate activity of carious lesions. Intraoral pH measurement of the carious lesions using a micro pH sensor may be a clinically feasible method for assessment of lesion acidity. PMID- 22222971 TI - Expression of concern. PMID- 22222972 TI - Interesting complication of the Medtronic Activa RC impulse pulse generator. PMID- 22222973 TI - Structural changes in metallothionein isoforms revealed by capillary electrophoresis and Brdicka reaction. AB - Metallothionein (MT) as a potential cancer marker is at the center of interest and its properties, functions and behavior under various conditions is intensively studied. In the present study, two major mammalian MT isoforms (MT-1 and MT-2) were separated using capillary electrophoresis (CE) coupled with UV detector in order to describe their basic behavior. Under the optimized conditions, the separation of both isoforms was enabled as well as estimation of detection limits as subunits and units of ng per MUL for MT-2 and MT-1, respectively. Further, the effects of thermal treatment and the presence of denaturing agent such as urea on MT-1 and MT-2 isoforms were studied by CE-UV. Thermal treatment caused an increase in the signals of both isoforms. A new parameter called precipitation rate has been defined based on this finding. This parameter can be expressed as a slope of the linear regression of the time dependency curve recalculated on the MT concentration. The thermal precipitation rate for MT-1 and MT-2 was determined as 1.1 and 0.9 ng of MT/min, respectively. The chemical precipitation rate calculated from the linear regression for both isoforms provided the same value of 0.25 ng of MT/min. The results were confirmed by manual spectrometric measurements and by differential pulse voltammetry Brdicka reaction. Based on these results, a model of MT behavior under the conditions studied was suggested. PMID- 22222974 TI - Systematic comparison of technical details in CBB methods and development of a sensitive GAP stain for comparative proteomic analysis. AB - Considering the importance of CBB staining in visualizing proteins in 2-DE gels, any improvement in the existing protocols with high sensitivity and good MS compatibility is of significant importance. In this study, we systematically evaluated the effects of different staining parameters on CBB methods by 1-DE and 2-DE, and demonstrated that G-250 was more suitable for visualizing low-abundant proteins as well as generating more spots than R-250, whereas R-250 had a superior capability for quick staining of high-abundant proteins. The staining produced by mixing G-250 and R-250 in different ratios showed similar sensitivity. Compared with acetic acid, phosphoric acid produced more protein spots. Ammonium-based stain demonstrated a superior sensitivity than the aluminum based one. Based on these findings, a new protocol using CBB G-250, ammonium sulfate and phosphoric acid (GAP) was developed by incorporating the fixation, sensitization and staining procedures together. The comparison of GAP with other methods revealed that GAP generated more protein spots and had wider applications. The identification of 11 proteins demonstrated that GAP was not only compatible with MS but also obviously reduced in vitro protein modification, and thus could be a preferable protocol in the future proteomic analysis. PMID- 22222975 TI - An insight into the abundant proteome of 46BR.1G1 fibroblasts deficient of DNA ligase I. AB - This work presents the proteome profile of cultured human skin fibroblasts established from a patient affected by DNA ligase I (Lig I) deficiency syndrome, a rare disorder characterized by immunodeficiency, growth retardation and sun sensitivity. 2-DE (in the 3-10 and 4-7 pH ranges) was the separation technique used for the production of maps. MALDI-TOF/MS and LC-MS/MS were the mass spectrometry platforms applied for the identification of proteins in gel spots. A total of 154 proteins, including 41 never detected before in skin fibroblasts with this approach, were identified in gel spots analyzed. This newly generated extensive database provides for the first time a global picture of abundant proteins in 46BR.1G1 skin fibroblasts. While being relevant to the particular disorder considered, these results may be regarded as an intriguing starting point on the way to achieve a reference map of the proteins highly expressed in an inherited syndrome with defect in DNA replication and repair pathways. PMID- 22222976 TI - Electrophoretically driven SDS removal and protein fractionation in the shotgun analysis of membrane proteomes. AB - SDS is mostly used to enhance the solubilization and extraction of membrane proteins due to its strong detergency and low cost. Nevertheless, SDS interferes with the subsequent procedures and needs to be removed from the samples. In this work, a special gradient gel electrophoresis (GGE) system was developed to remove SDS from the SDS-solubilized protein samples. As a proof-of-principle experiment, the GGE system was designed to be composed of an agarose loading layer, six polyacrylamide fractionation layers with different concentrations and a high concentration polyacrylamide sealing layer. The advantages of the GGE system are that it not only can electrophoretically remove SDS efficiently so that the protein loss resulted from the repeated gel washing after electrophoresis was avoided, but also can reduce the complexity of the sample, prevent the precipitation of proteins after loading and avoid the loss of proteins with low molecular weight during the electrophoresis. Using GGE system, about 85% of SDS in the sample and gel was electrophoretically removed and the proteins were fractionated. Compared with the two representative gel-based sample cleanup methods reported in literature, GGE-based strategy significantly improved the identification efficiency of proteins in terms of the number and coverage of the identified proteins. PMID- 22222977 TI - Modeling and simulation of nanoparticle separation through a solid-state nanopore. AB - Recent experimental studies show that electrokinetic phenomena such as electroosmosis and electrophoresis can be used to separate nanoparticles on the basis of their size and charge using nanopore-based devices. However, the efficient separation through a nanopore depends on a number of factors such as externally applied voltage, size and charge density of particle, size and charge density of membrane pore, and the concentration of bulk electrolyte. To design an efficient nanopore-based separation platform, a continuum-based mathematical model is used for fluid. The model is based on Poisson-Nernst-Planck equations along with Navier-Stokes equations for fluid flow and on the Langevin equation for particle translocation. Our numerical study reveals that membrane pore surface charge density is a vital parameter in the separation through a nanopore. In this study, we have simulated high-density lipoprotein (HDL) and low-density lipoprotein (LDL) as the sample nanoparticles to demonstrate the capability of such a platform. Numerical results suggest that efficient separation of HDL from LDL in a 0.2 M KCL solution (resembling blood buffer) through a 150 nm pore is possible if the pore surface charge density is ~ -4.0 mC/m(2). Moreover, we observe that pore length and diameter are relatively less important in the nanoparticle separation process considered here. PMID- 22222978 TI - Gold nanoparticle-coated capillaries for protein and peptide analysis on open tubular capillary electrochromatography. AB - We report a new method of immobilization of gold nanoparticles (AuNPs) on a fused silica capillary through covalent binding. The resulting modified capillary was applied to electrophoretic systems to improve the efficiency of separation and the selectivity of selected solutes. The immobilization of AuNPs on the capillary wall was performed in a very simple and fast way without requiring heating. The surface features of an AuNP-coated capillary column were determined using the scanning electron microscopy. The chromatographic properties of AuNP-coated capillaries were investigated through variation of the buffer pH and separation voltage. Effective separations of synthetic peptides mixture were obtained on the AuNP-coated capillaries. The method shows a remarkable stability since it was reused about 900 times. The capacity factor was duplicated. Therefore, this modification is stable and can be applied to different separation purposes. A complex mixture of tryptic peptide fragments of HSA was analyzed in both the bare and the AuNP-coated capillaries. Better electrophoretic peptide profile was observed when using the AuNP-coated capillary. PMID- 22222979 TI - Agarose gel electrophoresis reveals structural fluidity of a phage T3 DNA packaging intermediate. AB - We find a new aspect of DNA packaging-associated structural fluidity for phage T3 capsids. The procedure is (i) glutaraldehyde cross-linking of in vivo DNA packaging intermediates for the stabilization of structure and then (ii) determining effective radius by two-dimensional agarose gel electrophoresis (2D AGE). The intermediates are capsids with incompletely packaged DNA (ipDNA) and without an external DNA segment; these intermediates are called ipDNA-capsids. We initially increase the production of ipDNA-capsids by raising NaCl concentration during in vivo DNA packaging. By 2D-AGE, we find a new state of contracted shell for some particles of one previously identified ipDNA-capsid. The contracted shell-state is found when the ipDNA length/mature DNA length (F) is above 0.17, but not at lower F. Some contracted-shell ipDNA-capsids have the phage tail; others do not. The contracted-shell ipDNA-capsids are explained by premature DNA maturation cleavage that makes accessible a contracted-shell intermediate of a cycle of the T3 DNA packaging motor. The analysis of ipDNA-capsids, rather than intermediates with uncleaved DNA, provides a simplifying strategy for a complete biochemical analysis of in vivo DNA packaging. PMID- 22222980 TI - Bleach gel: a simple agarose gel for analyzing RNA quality. AB - RNA-based applications requiring high-quality, non-degraded RNA are a foundational element of many research studies. As such, it is paramount that the integrity of experimental RNA is validated prior to cDNA synthesis or other downstream applications. In the absence of expensive equipment such as microfluidic electrophoretic devices, and as an alternative to the costly and time-consuming standard formaldehyde gel, RNA quality can be quickly analyzed by adding small amounts of commercial bleach to TAE buffer-based agarose gels prior to electrophoresis. In the presence of low concentrations of bleach, the secondary structure of RNA is denatured and potential contaminating RNases are destroyed. Because of this, the 'bleach gel' is a functional approach that addresses the need for an inexpensive and safe way to evaluate RNA integrity and will improve the ability of researchers to rapidly analyze RNA quality. PMID- 22222981 TI - Poly(ethylene glycol)-coated microfluidic devices for chip electrophoresis. AB - Herein, we report on a strategy for durable modification of the channel surface in microfluidic glass chips with the neutral hydrophilic-coating material poly(ethylene glycol) PEG-1M-100. Applied in microchip electrophoresis such PEG coated devices exhibit a suppressed electroosmotic flow and reduced analyte adsorption. The PEG-coated chips were successfully applied in chip electrophoresis of FITC-labelled amines and amino acids and native proteins as well as in chiral separations. The performance of the coated chips was found to be superior compared with uncoated microchips. The coated chips exhibited high stability and the relative standard deviation of migration times in PEG-coated devices was less than 2%. PMID- 22222983 TI - Fast investigations from biological matrices using CE--test of a blood-brain barrier model. AB - In order to adopt a general workflow for complex biological matrices with respect to a new blood-brain barrier (BBB) model, a micellar electrokinetic chromatography method has been developed. The cells forming the BBB have been cultivated in a special cell growth medium in which six drugs (acetaminophen, caffeine, carbamazepine, cimetidine, indometacin and propranolol) have been dissolved and tested for their penetration properties. The results showed good to very good accordance to the reference values. Samples were directly injected onto the capillary without any pretreatment (fused silica capillary, id: 50 MUm, L: 48 cm, l: 40 cm). After method development, separations were carried out using a 60 mM borate buffer containing 200 mM of SDS at 30 kV, leading to an analysis time of less than 10 min. Between two runs the capillary was rinsed with a mixture of equal parts of running buffer and isopropanol (70% v/v), which proved to be very effective to remove matrix compounds. An appropriate choice of the detection wavelength (220 or 254 nm) could avoid major interferences between analytes and matrix. The typical RSD% for migration times was approximately 2%, for peak areas, it ranged from 2 to 6%, which was very well acceptable for the generic method used in this study and the low concentrations investigated. The LODs ranged from 10 to 30 ng/mL. PMID- 22222982 TI - Electrophoretic separations in poly(dimethylsiloxane) microchips using a mixture of ionic and zwitterionic surfactants. AB - The use of mixtures of ionic and zwitterionic surfactants in poly(dimethylsiloxane) (PDMS) microchips is reported. The effect of surfactant concentration on electroosmotic flow (EOF) was studied for a single anionic surfactant (sodium dodecyl sulfate, SDS), a single zwitterionic surfactant (N tetradecylammonium-N,N-dimethyl-3-ammonio-1-propanesulfonate, TDAPS), and a mixed SDS/TDAPS surfactant system. SDS increased the EOF as reported previously while TDAPS showed an initial increase in EOF followed by a reduction at higher concentrations. When TDAPS was added to a solution containing SDS, the EOF decreased in a concentration-dependent manner. The EOF for all three surfactant systems followed expected pH trends, with increasing EOF at higher pH. The mixed surfactant system allowed tuning of the EOF across a range of pH and concentration conditions. After establishing the EOF behavior, the adsorption/desorption kinetics were measured and showed a slower adsorption/desorption rate for TDAPS than SDS. Finally, the separation and electrochemical detection of model catecholamines in buffer and reduced glutathione in red blood cell lysate using the mixed surfactant system were explored. The mixed surfactant system provided shorter analysis times and/or improved resolution when compared to the single surfactant systems. PMID- 22222987 TI - Kikuchi Fujimoto's disease appearing as systemic lupus erythematosus. PMID- 22222988 TI - Intrabony tibial tophi in chronic gout. PMID- 22222989 TI - The use of a two-gene sequencing approach to accurately distinguish between the species within the Mycobacterium abscessus complex and Mycobacterium chelonae. AB - Mycobacterium abscessus [M. abscessus (sensu lato) or M. abscessus complex] comprises three closely related species: M. abscessus (sensu stricto), hereafter referred to as M. abscessus, M. bolletii and M. massiliense. We describe here an accurate and robust method for distinguishing M. chelonae from M. abscessus, M. bolletii and M. massiliense, using polymerase chain reaction (PCR) and the sequencing of house-keeping gene targets (hsp65 and rpoB). Sequencing of the sodA gene is of little additional value in discriminating between species, but M. massiliense can be rapidly identified by amplification of the truncated erm(41) gene without the need for amplicon sequencing. We have applied the method to 81 isolates from 40 patients from two hospitals, the majority of whom were cystic fibrosis (CF) patients. Of these patients, 21 had previously been identified as M. chelonae and 59 as M. abscessus complex using commercial line probe assays. We identified these as 46 M. abscessus isolates, 20 M. massiliense isolates, five M. bolletii isolates and nine M. chelonae isolates and confirmed the one M. fortuitum isolate. This is the first study that has identified the individual members of the M. abscessus complex in a UK cohort of mainly CF patients. PMID- 22222991 TI - Spinal Cord is 50 years young in 2012. PMID- 22222990 TI - Chronic gingivitis: the prevalence of periodontopathogens and therapy efficiency. AB - The purpose of this study was to determine the level of gingival inflammation and the prevalence of periodontopathogenic microorganisms in adolescents with chronic gingivitis, as well as to compare the effectiveness of two approaches in gingivitis treatment-basic therapy alone and basic therapy + adjunctive low-level laser therapy (LLLT). After periodontal evaluation, the content of gingival pockets of 140 adolescents with gingivitis was analyzed by multiplex PCR for the presence of P. gingivalis, A. actinomycetemcomitans, T. forsythensis and P. intermedia. Subsequent to bacteria detection, the examinees were divided into two groups with homogenous clinical and microbiological characteristics. Group A was subjected to basic gingivitis therapy, and group B underwent basic therapy along with adjunctive LLLT. A statistically significant difference between the values of plaque-index (PI) and sulcus bleeding index (SBI) before and after therapy was confirmed in both groups (p<0.001), though more pronounced in group B. Following therapy, the incidence of periodontopathogenic microorganisms decreased considerably. The best result was obtained in P. gingivalis eradication by combined therapy (p=0.003). The presence of periodontopathogens in adolescents with gingivitis should be regarded as a sign for dentists to foster more effective oral health programs. LLLT appears to be beneficial as adjuvant to basic therapy. PMID- 22222993 TI - The use of cyprinodont fish, Aphanius fasciatus, as a sentinel organism to detect complex genotoxic mixtures in the coastal lagoon ecosystem. AB - In the present work we aimed to standardise the alkaline comet assay with erythrocytes of the cyprinodont, Mediterranean Killifish, Aphanius fasciatus. The aims of the study were to explore the suitability of this fish to assess biomarkers of genotoxic effects and as a sentinel organism to detect complex genotoxic mixtures in coastal lagoon ecosystems. Following proper optimisation, the application and effectiveness of the comet assay in erythrocytes of A. fasciatus were tested by measuring the tail DNA (%) induced by (a) in vivo exposure of individual fish to X-rays (dose, 3Gy) and (b) following in vitro challenge of erythrocytes with restriction endonucleases Fok-I and Eco-RI, which selectively induce double-strand breaks with cohesive and blunt termini, respectively. Furthermore, in order to evaluate whether circulating fish blood contained actively proliferating cells that could influence the extent of DNA damage in control (untreated) fish, we measured the number of "comets" positive for 5-bromo-2'-deoxyuridine (BrdU) by the use of anti-BrdU antibody and immuno histochemical methods. Both treatments (i.e. with X-rays and restriction endonucleases) induced statistically significant increases in tail DNA (%) values compared with the relevant untreated controls, indicating the effectiveness of the comet assay in the erythrocytes of A. fasciatus to detect different types of DNA lesions. Results from anti-BrdU antibody labelling of erythrocytes indicated a very low percentage (5%) of "comets" positive for BrdU. Following optimisation and validation of the assay under laboratory conditions, fish were collected in the Orbetello lagoon (Tuscany, Italy), considered to be a significantly polluted site. The results showed statistically significant increases for tail DNA (%) compared with corresponding values observed in erythrocytes of fish caught in the unpolluted reference site "Saline di Tarquinia". The effects of physico-chemical parameters of the water (i.e., salinity, pH and oxygen content) did not significantly influence the induction of DNA damage. These results indicate that the comet assay provides a reliable parameter and that A. fasciatus is a promising "sentinel organism" to detect the genotoxic impact of complex mixtures in coastal lagoon ecosystems. PMID- 22222994 TI - Titanium dioxide particles phosphorylate histone H2AX independent of ROS production. AB - With the rising use of nano-sized particles in nanotechnology, harmful effects of TiO(2) particles which have been recognized as a safe material, are of increasing concern. In this study, we examined the genotoxicity of two different sized TiO(2) particles in the lung adenocarcinoma epithelial cell line A549 based on the phosphorylation of histone H2AX (gamma-H2AX), recently regarded as a sensitive marker for DNA damage. TiO(2) particles generated gamma-H2AX, which was more remarkable with the smaller particles. Flow cytometric analysis showed that the generation was independent of cell cycle phases and cells which incorporated larger amounts of TiO(2) particles had more significant gamma-H2AX. Although there are some reports that the incorporation of nanomaterials into cells generates reactive oxygen species (ROS), the level of ROS was low even if large amounts of TiO(2) particles were taken-up. In addition, the generation of gamma H2AX by TiO(2) particles was more significant than that after treatment with hydrogen peroxide. On the other hand, the generation of gamma-H2AX was attenuated by coating the surface of TiO(2) particles with bovine serum albumin. These results suggested that smaller TiO(2) particles were easy to incorporate into cells and generated cell cycle phase-independent gamma-H2AX, which was dependent on the condition of the TiO(2) surface but not on the formation of ROS. PMID- 22222995 TI - Self-assembly, crystal structures, and properties of metal-2-sulfoterephthalate frameworks based on [M4(MU3-OH)2]6+ clusters (M = Co, Mn, Zn and Cd). AB - Hydro- and solvo-thermal reactions of d-block metal ions (Mn(2+), Co(2+), Zn(2+) and Cd(2+)) with monosodium 2-sulfoterephthalate (NaH(2)stp) form six 3D coordination polymers featuring cluster core [M(4)(MU(3)-OH)(2)](6+) in common: [M(2)(MU(3)-OH)(stp)(H(2)O)] (M = Co (1), Mn (2) and Zn (3)), [Zn(2)(MU(3) OH)(stp)(H(2)O)(2)] (4), [Zn(4)(MU(3)-OH)(2)(stp)(2)(bpy)(2)(H(2)O)].3.5H(2)O (5) and [Cd(2)(MU(3)-OH)(stp) (bpp)(2)].H(2)O (6) (stp = 2-sulfoterephthalate, bpy = 4,4'-bipyridine and bpp = 1,3-di(4-pyridyl)propane). All these coordination polymers were characterized by single crystal X-ray diffraction, IR spectroscopy, thermogravimetric and elemental analysis. Complexes 1-3 are isostructural coordination polymers with 3D frameworks based on the chair-like [Zn(4)(MU(3) OH)(2)](6+) core and the quintuple helixes. In complex 4, there exist double helixes in the 3D framework based on the chair-like cluster cores. Complex 5 possesses a 2-fold interpenetration structure constructed from boat-like cluster core and the bridging ligands stp and bpy. For complex 6, the chair-like cluster cores and stp ligands form a 2D (4,4) network which is further pillared by bpp linkers to a 3D architecture. Magnetic studies indicate that complex 1 exhibits magnetic ordering below 4.9 K with spin canting, and complex 2 shows weak antiferromagnetic coupling between the Mn(II) ions with g = 2.02, J(wb) = -2.88 cm(-1), J(bb) = -0.37 cm(-1). The fluorescence studies show that the emissions of complexes 3-6 are attributed to the ligand pi-pi* transition. PMID- 22222996 TI - A new system, the LipiFlow, for the treatment of meibomian gland dysfunction. AB - PURPOSE: To evaluate the safety and effectiveness of the LipiFlow System compared to the iHeat Warm Compress (WC) for adults with meibomian gland dysfunction (MGD). METHODS: This was a non-significant risk, prospective, open-label, randomized, crossover multicenter clinical trial. One hundred thirty-nine subjects were randomized between LipiFlow (n=69) and WC control (n=70). Subjects in the LipiFlow group received a 12-minute LipiFlow treatment and were reexamined at 1 day, 2 weeks and 4 weeks. Control subjects received a 5-minute iHeat treatment with instructions to perform the same treatment daily for 2 weeks. At 2 weeks, they crossed over (LipiFlow Crossover) and received the LipiFlow treatment. Effectiveness parameters: meibomian gland (MG) assessment, tear break up time (TBUT) and dry eye symptoms. Safety parameters: adverse events, ocular health exam, ocular surface staining, intraocular pressure, visual acuity and discomfort. RESULTS: LipiFlow resulted in significant improvement (P < 0.05) in MG secretion at 2 and 4 weeks (mean +/- standard deviation at baseline = 6.3 +/- 3.5; 2 weeks = 14.3 +/- 8.7; 4 weeks = 16.7 +/- 8.7); and TBUT at 2 and 4 weeks: (at baseline = 5.5 +/- 2.9; 2 weeks = 6.9 +/- 5.0; 4 weeks = 7.4 +/- 5.5). There was no significant change in MG secretion or TBUT in the control group. LipiFlow resulted in a greater significant reduction in dry eye symptoms than the iHeat WC. The crossover group demonstrated similar significant improvement 2 weeks post treatment with the LipiFlow. There was no significant difference between groups in the incidence of non-serious, device-related adverse events. CONCLUSION: The LipiFlow System was significantly more effective than iHeat WC. These results support its safety and effectiveness in the treatment of MGD and dry eye symptoms. PMID- 22222997 TI - In vivo confocal microscopic findings in Lisch corneal dystrophy. AB - PURPOSE: To describe the in vivo confocal microscopic and clinicopathologic correlations in Lisch corneal dystrophy. METHODS: This is a retrospective case series of 2 patients with Lisch corneal dystrophy. The diagnosis was made based on clinical findings in both cases and was confirmed histopathologically following epithelial debridement in case 1. In vivo laser scanning confocal microscopy using the Heidelberg Retina Tomograph III with the Rostock Cornea Module was carried out in both cases. RESULTS: Clinical examination of the corneas revealed areas of epithelial opacification that were sharply demarcated in juxtaposition with normal corneal epithelium. The gray feathery appearance of the epithelial lesions in both cases was characteristic of Lisch corneal dystrophy. The central visual axis was involved in case 1, and corneal topography showed irregular astigmatism. Histological analysis of the epithelial cells in this case showed intracytoplasmic vacuoles, confirming the diagnosis of Lisch corneal dystrophy. In vivo confocal microscopy in both cases demonstrated highly hyperreflective epithelial cytoplasm with hypo-reflective nuclei. There was involvement of all epithelial layers extending to the limbus and findings on imaging were confined to the clinically observed areas of corneal opacity. The lesion in case 1 recurred after epitheliectomy of the central cornea without removal of affected limbal cells. CONCLUSIONS: The unique features on in vivo confocal microscopy correlated with the clinical and histopathologic features of Lisch corneal dystrophy may be used to distinguish this disorder from other corneal epithelial conditions. The affected epithelial cells appear to originate from abnormal limbal stem cells. PMID- 22222998 TI - Juvenile xanthogranuloma presenting as infiltrative conjunctival mass in an adult. AB - PURPOSE: To report on the clinical and histopathologic findings of a conjunctival juvenile xanthogranuloma in an adult. METHODS: Case report and literature review. RESULTS: A 43-year-old man developed 2 yellowish conjunctival lumps not associated with other ocular or systemic findings. A half-corneal diameter-sized main mass was located at the 2-o'clock position, and the other 1/8-corneal diameter-sized mass was located at the 4-o'clock position. The masses were vitelliform in appearance with poor supplying vessels. The masses were removed en bloc by conjunctivectomy. Cryotherapy was done along the excision margin. Histopathologic examination revealed dense infiltration by histiocytes with background of multiple lymphocytes and Touton giant cells. Immunohistochemical staining was positive for CD3 (T-cell marker) and CD68 (histiocytic marker) but negative for CD1a and S-100 (Langerhans cell marker). CONCLUSION: Juvenile xanthogranuloma may present as conjunctival infiltrative masses in adults. Immunophenotyping is helpful in differentiating it from a more malignant lesion. PMID- 22223000 TI - Late spontaneous clearing of corneal grafts. PMID- 22222999 TI - Corneal graft survival and intraocular pressure control in coexisting penetrating keratoplasty and pars plana Ahmed Glaucoma Valves. AB - PURPOSE: To evaluate corneal graft survival and intraocular pressure (IOP) control after penetrating keratoplasty (PK) and pars plana Ahmed Glaucoma Valve (AGV) implantation among patients with coexisting glaucoma and corneal disease. METHODS: Retrospective chart review at an institution of 25 eyes (24 patients) that received PK and pars plana AGV. RESULTS: The mean postoperative follow-up was 23 months (range, 2-106 months). Survival of the grafts was 89% (16 of 18 eyes) at 1 year and 63% (5 of 8) at 2 years. IOP control was 78% (15 of 19) at 1 year and 44% (4 of 9) at 2 years. By Kaplan-Meier analysis, the 50% probability of sustained graft clarity occurred at 28 months and that of sustained IOP control at 24 months. By last follow-up, best-corrected visual acuity had improved by at least 1 line in 52% (13 of 25) of eyes compared with preoperative values. Preoperative factors, including peripheral anterior synechiae, were not found to be associated with graft survival, IOP control, or visual acuity at 1 year. CONCLUSION: Pars plana AGV can successfully control IOP in PK patients in the short and intermediate terms, but graft clarity and IOP control diminish over time. Graft decompensation, when it did occur, likely reflects the associated ocular morbidity and clinical complexity of this circumscribed cohort of eyes. PMID- 22223005 TI - Implications of the Mental Health Parity and Addiction Equity Act. PMID- 22223006 TI - Parsing childhood symptoms with more specificity can clarify differential outcomes. PMID- 22223007 TI - Antipsychotics and mortality in dementia. PMID- 22223008 TI - Religion/spirituality and depression: what can we learn from empirical studies? PMID- 22223009 TI - DSM-5: how reliable is reliable enough? PMID- 22223010 TI - Cognitive-behavioral treatment of body image disturbance in a congenitally blind patient with anorexia nervosa. PMID- 22223011 TI - Images in psychiatry. Sabina Spielrein. PMID- 22223012 TI - Combined treatments for depression as for other medical disorders. PMID- 22223014 TI - Overexpression of chromosome 15q11-q13 gene products: a risk factor for schizophrenia and associated psychoses? PMID- 22223015 TI - Additional effect size measures helpful in understanding lithium and valproate trial results. PMID- 22223017 TI - Differential lithium efficacy in reducing suicidal behaviors compared with suicidal thoughts. PMID- 22223027 TI - A simple drug anchoring microfiber scaffold for chondrocyte seeding and proliferation. AB - The structural properties of microfiber meshes made from poly(2-hydroxyethyl methacrylate) (PHEMA) were found to significantly depend on the chemical composition and subsequent cross-linking and nebulization processes. PHEMA microfibres showed promise as scaffolds for chondrocyte seeding and proliferation. Moreover, the peak liposome adhesion to PHEMA microfiber scaffolds observed in our study resulted in the development of a simple drug anchoring system. Attached foetal bovine serum-loaded liposomes significantly improved both chondrocyte adhesion and proliferation. In conclusion, fibrous scaffolds from PHEMA are promising materials for tissue engineering and, in combination with liposomes, can serve as a simple drug delivery tool. PMID- 22223028 TI - Human umbilical vein endothelial cells accelerate oxalate-induced apoptosis of human renal proximal tubule epithelial cells in co-culture system which is prevented by pyrrolidine dithiocarbamate. AB - Oxalate is the most common component of kidney stones and elevated urinary levels induce renal tubular cell toxicity and death which is essential for crystal attachment. Endothelial cells, in some studies have been shown to regulate certain functions of renal proximal tubule cells. The aim of this study was to evaluate the effect of endothelial cells on tubular cell apoptosis in a co culture system mimicking the in vivo renal physiological settings. The human umbilical vein endothelial cells (HUVEC) and human renal proximal tubule epithelial cells (RPTEC) were exposed to increasing concentrations (0-1.0 mM) of oxalate with or without 10 MUM PDTC pretreatment for 24 h. In HUVEC, RPTEC and HUVEC-RPTEC co-cultures, the cell viability was measured using the WST-1 assay and cell death with the TUNEL analysis using the flow cytometry. The treatment of RPTECs with oxalate lead to 8.9-26.2% cell death which was reduced to 0-1.6% with the PDTC pretreatment. The death rate of RPTECs was significantly increased by 15 19% at different oxalate concentrations when co-cultured with HUVECs. In contrast, cell viability was not substantially altered in PDTC pretreated RPTECs that were co-cultured with HUVECs. Apoptosis was the way of cell death as similar rate of apoptosis was observed in cell culture systems. Although cell viability of RPTECs was further reduced when co-cultured with HUVECs, it was restored with the pretreatment of PDTC. This is the first study focusing on the role of endothelial cells on RPTEC apoptosis following hyperoxaluria. PMID- 22223029 TI - Presence of Oxalobacter formigenes in the intestinal tract is associated with the absence of calcium oxalate urolith formation in dogs. AB - The incidence of calcium oxalate (CaOx) urolithiasis in dogs has increased steadily over the last two decades. A potential mechanism to minimize CaOx urolithiasis is to reduce enteric absorption of dietary oxalate by oxalate metabolizing enteric bacteria. Enteric colonization of Oxalobacter formigenes, an anaerobe which exclusively relies on oxalate metabolism for energy, is correlated with absence of hyperoxaluria or CaOx urolithiasis or both in humans and laboratory animals. We thus hypothesized that decreased enteric colonization of O. formigenes is a risk factor for CaOx urolithiasis in dogs. Fecal samples from dogs with CaOx uroliths, clinically healthy, age-, breed- and gender-matched dogs, and healthy non-stone forming breed dogs were screened for the presence of O. formigenes by quantitative PCR to detect the oxalyl CoA decarboxylase (oxc) gene, and by oxalate degrading biochemical activity in fecal cultures. Prevalence of O. formigenes in dogs with CaOx uroliths was 25%, compared to 50% in clinically healthy, age-, breed- and gender-matched dogs, and 75% in healthy non stone forming breeds. The presence of oxc genes of O. formigenes was significantly higher in healthy non-stone forming breed dogs than in the dogs with CaOx stones. Further, dogs with calcium oxalate stones and the stone-forming breed-matched controls showed comparable levels of biochemical oxalate degrading activity. We conclude that the absence of enteric colonization of O. formigenes is a risk factor for CaOx urolithiasis. PMID- 22223030 TI - Radical cations and triplet states of 1,2-disubstituted cyclopropanes: comparison of potential surfaces. AB - Radical ion pairs generated by photo-induced electron transfer from 1,2 disubstituted cyclopropanes to various acceptors undergo return electron transfer in pairs of singlet and triplet multiplicity. The pair energies relative to the reactant ground states and to accessible triplet states, respectively, determine the competition between the recombination pathways. The potential surfaces of the radical cations and triplet states of 1,2-diphenyl-, 1, and 1,2 dimethylcyclopropane, 2, have been examined by density functional theory calculations. The radical cation surfaces have minima at geometries that retain significant bonding between C-1 and C-2, preventing geometric isomerization of the radical cations. The triplet potential surfaces are dissociative with minimal rotational differentiation at long distances between C-1 and C-2. PMID- 22223032 TI - Trojan horse strategies used by pathogens to influence the small ubiquitin-like modifier (SUMO) system of host eukaryotic cells. AB - A remarkable feature of pathogenic organisms is their ability to utilize the cellular machinery of host cells to their advantage in facilitating their survival and propagation. Posttranslational modification of proteins offers a quick way to achieve changes in the localization, binding partners or functions of a target protein. It is no surprise then that pathogens have evolved multiple ways to interfere with host posttranslational modifications and hijack them for their own purposes. Recently, modification of proteins by small ubiquitin-like modifier has emerged as an important posttranslational modification regulating transcription, DNA repair and cell division, and literature has started to emerge documenting how it could be utilized by pathogenic bacteria and viruses during infection. In this brief review, we focus on the host small ubiquitin-like modifier (SUMO) system and how disease causing agents influence SUMO conjugation and deconjugation, highlighting the common theme of global hypoSUMOylation upon infection by pathogens. PMID- 22223033 TI - Life skills: evaluation of a theory-driven behavioral HIV prevention intervention for young transgender women. AB - Young transgender women are at increased risk for HIV infection due to factors related to stigma/marginalization and participation in risky sexual behaviors. To date, no HIV prevention interventions have been developed or proven successful with young transgender women. To address this gap, we developed and pilot tested a homegrown intervention "Life Skills," addressing the unique HIV prevention needs of young transgender women aged 16-24 years. Study aims included assessing the feasibility of a small group-based intervention with the study population and examining participant's engagement in HIV-related risk behaviors pre- and 3 months-post-intervention. Fifty-one (N = 51) young transgender women enrolled in the study. Our overall attendance and retention rates demonstrate that small group-based HIV prevention programs for young transgender women are both feasible and acceptable. Trends in outcome measures suggest that participation in the intervention may reduce HIV-related risk behaviors. Further testing of the intervention with a control group is warranted. PMID- 22223034 TI - A massive infestation of sea snakes by cymothoid isopods. AB - In this study, a massive infestation of the sea snake Enhydrina schistosa by the cymothoid isopod Nerocila serra, commonly parasitizing fishes, is reported for the first time from India. This isopod was found attached on the different parts of the body of the snake. According to the month, the parasitic prevalence ranged from 30.8 to 55.3%, increasing during the monsson period. It was higher in female than in male snakes. PMID- 22223035 TI - Behavioral changes in mice caused by Toxoplasma gondii invasion of brain. AB - Toxoplasma gondii, a protozoan parasite, is capable of infecting a broad range of intermediate warm-blooded hosts including humans. The parasite undergoes sexual reproduction resulting in genetic variability only in the intestine of the definitive host (a member of the cat family). The parasite seems to be capable of altering the natural behavior of the host to favor its transmission in the environment. The aim of this study was to evaluate the number of parasite cysts formed in the hippocampus and amygdala of experimentally infected mice as these regions are involved in defense behaviors control and emotion processing, and to assess the influence of the infection on mice behavior. The obtained results revealed the presence of parasite cysts both in the hippocampus and the amygdala of infected mice; however, no clear region-dependent distribution was observed. Furthermore, infected mice showed significantly diminished exploratory activity described by climbing and rearing, smaller preference for the central, more exposed part of the OF arena and engaged in less grooming behavior compared to uninfected controls. PMID- 22223036 TI - Redefining the genus Spraguea based on ultrastructural and phylogenetic data from Spraguea gastrophysus n. sp. (phylum Microsporidia), a parasite found in Lophius gastrophysus (Teleostei) from Brazil. AB - The ultrastructure of the fish-infecting microsporidium Spraguea gastrophysus found in the dorsal ganglia and kidney of the anglerfish, Lophius gastrophysus (family Lophiidae) collected on the Brazilian Atlantic coast is described. Each whitish xenoma (up to 3.1 * 1.8 mm) contains several groups of parasites. The host cells are hypertrophied and contain various parasite life stages including mature spores and several developmental stages with unpaired nuclei. Monomorphic spores are ellipsoidal, lightly curved and measure about 3.35 * 1.71 MUm. The spore contains a gradually tapering isofilar polar filament with five to six coils arranged in a single row. The nucleus occupies a central zone of the sporoplasm where also several polyribosomes are presented. The posterior vacuole contains a voluminous spherical and granular posterosome measuring up to ~0.65 MUm in diameter. The partial small subunit, intergenic spacer and partial large subunit rRNA gene were sequenced and the phylogenetic analysis places the microsporidian described here in the clade that includes all sequences of the Spraguea genus. The ultrastructural morphology of the xenoma and the spores of this microsporidian parasite, as well as the molecular and phylogenetic analysis, suggest the description of a new species. A redefining of the genus Spraguea is also done. PMID- 22223037 TI - Cationic liposomes containing soluble Leishmania antigens (SLA) plus CpG ODNs induce protection against murine model of leishmaniasis. AB - Development of an effective vaccine against leishmaniasis is possible due to the fact that individuals cured from cutaneous leishmaniasis (CL) are protected from further infection. First generation Leishmania vaccines consisting of whole killed parasites reached to phase 3 clinical trials but failed to show enough efficacies mainly due to the lack of an appropriate adjuvant. In this study, an efficient liposomal protein-based vaccine against Leishmania major infection was developed using soluble Leishmania antigens (SLA) as a first generation vaccine and cytidine phosphate guanosine oligodeoxynucleotides (CpG ODNs) as an immunostimulatory adjuvant. 1, 2-Dioleoyl-3-trimethylammonium-propane was used as a cationic lipid to prepare the liposomes due to its intrinsic adjuvanticity. BALB/c mice were immunized subcutaneously (SC), three times in 2-week intervals, with Lip-SLA-CpG, Lip-SLA, SLA + CpG, SLA, or HEPES buffer. As criteria for protection, footpad swelling at the site of challenge and spleen parasite loads were assessed, and the immune responses were evaluated by determination of IFN gamma and IL-4 levels of cultured splenocytes, and IgG subtypes. The group of mice that received Lip-SLA-CpG showed a significantly smaller footpad swelling, lower spleen parasite burden, higher IgG2a antibody, and lower IL-4 level compared to the control groups. It is concluded that cationic liposomes containing SLA and CpG ODNs are appropriate to induce Th1 type of immune response and protection against leishmaniasis. PMID- 22223038 TI - Effect of serotonin and calcium on the supercontractile muscles of the adult blowfly crop. AB - Bioassays and electrophysiological recordings were conducted to determine the role of serotonin and calcium on the supercontractile pump muscles of the diverticulated crop of adult blowflies. Using in situ crop preparations, serotonin was found to significantly increase the rates of contractions of a specific pump in the crop wall, pump P4. The addition of the serotonin antagonist, mianserin, or calcium free saline, both significantly reduced the contraction rates of this pump. Recordings, using suction electrodes from pump P4, confirm the in situ bioassay data and show that serotonin promotes muscle activity in empty crops in which no pump activity is normally observed. Moreover, our data indicate the crucial role of extracellular calcium ions in crop pump contractile activity. These results provide new information on how the crop of adult dipterans is modulated and suggest that serotonin, possibly supplied by neurons in the thoracico-abdominal neural plexus, may be involved in modulating the pumping of crop contents into the midgut for digestion or triggering antiperistalsis from the foregut in the process known as regurgitation or 'bubbling'. PMID- 22223039 TI - Re-emergent tremor in a dystonic SWEDD case. PMID- 22223040 TI - Nifedipine ameliorates ischemia-induced revascularization in diet-induced obese mice. AB - BACKGROUND: Obesity is a risk factor for the development of cardiovascular diseases that are associated with impaired angiogenesis. Nifedipine, a calcium channel blocker, has a number of blood pressure (BP)-independent effects as well, such as improving endothelial function and decreasing oxidative stress. Here, we investigated whether nifedipine could improve the angiogenic responses in a diet induced obese (DIO) model. METHODS: DIO was induced by allowing 8-week-old C57BL/6J mice ad libitum access to a high-fat/high-sucrose (HF/HS) diet. Mice were randomly divided into two groups that were fed either the HF/HS or normal chow. At the age of 12 weeks, the animals were treated/not treated with nifedipine admixed with food at a concentration of 0.001%. Then, 1 week later, the mice were subjected to unilateral hind limb surgery. RESULTS: Angiogenic repair of the ischemic hind limb was impaired in the DIO mice as compared with that in the control mice as evaluated by laser Doppler blood flowmetry (LDBF) and capillary density analysis. Treatment with nifedipine accelerated angiogenic repair in the DIO mice to a level equal to that seen in the control mice. DIO mice showed increased reactive oxygen species (ROS) production after hind limb ischemia. The number of endothelial progenitor cells (EPCs), which contribute to blood vessel formation, was also significantly lower in these mice. Nifedipine treatment ameliorated the oxidative status and increased the number of EPCs in the DIO mice. CONCLUSIONS: Our observations demonstrated that DIO impaired revascularization in response to tissue ischemia. Nifedipine ameliorated obesity impaired revascularization through suppressing oxidative stress and enhancing the number of EPCs. PMID- 22223041 TI - Validity and reliability of central blood pressure estimated by upper arm oscillometric cuff pressure. AB - BACKGROUND: Noninvasive central blood pressure (BP) independently predicts mortality, but current methods are operator-dependent, requiring skill to obtain quality recordings. The aims of this study were first, to determine the validity of an automatic, upper arm oscillometric cuff method for estimating central BP (O(CBP)) by comparison with the noninvasive reference standard of radial tonometry (T(CBP)). Second, we determined the intratest and intertest reliability of O(CBP). METHODS: To assess validity, central BP was estimated by O(CBP) (Pulsecor R6.5B monitor) and compared with T(CBP) (SphygmoCor) in 47 participants free from cardiovascular disease (aged 57 +/- 9 years) in supine, seated, and standing positions. Brachial mean arterial pressure (MAP) and diastolic BP (DBP) from the O(CBP) device were used to calibrate in both devices. Duplicate measures were recorded in each position on the same day to assess intratest reliability, and participants returned within 10 +/- 7 days for repeat measurements to assess intertest reliability. RESULTS: There was a strong intraclass correlation (ICC = 0.987, P < 0.001) and small mean difference (1.2 +/- 2.2 mm Hg) for central systolic BP (SBP) determined by O(CBP) compared with T(CBP). Ninety-six percent of all comparisons (n = 495 acceptable recordings) were within 5 mm Hg. With respect to reliability, there were strong correlations but higher limits of agreement for the intratest (ICC = 0.975, P < 0.001, mean difference 0.6 +/- 4.5 mm Hg) and intertest (ICC = 0.895, P < 0.001, mean difference 4.3 +/- 8.0 mm Hg) comparisons. CONCLUSIONS: Estimation of central SBP using cuff oscillometry is comparable to radial tonometry and has good reproducibility. As a noninvasive, relatively operator-independent method, O(CBP) may be as useful as T(CBP) for estimating central BP in clinical practice. PMID- 22223042 TI - Cardiovascular and renal manifestations of glutathione depletion induced by buthionine sulfoximine. AB - Oxidative stress contributes to the development of several cardiovascular diseases, including diabetes, renal insufficiency, and arterial hypertension. Animal studies have evidenced the association between higher blood pressure (BP) and increased oxidative stress, and treatment with antioxidants has been shown to reduce BP, while BP reduction due to antihypertensive drugs is associated with reduced oxidative stress. In 2000, it was first reported that oxidative stress and arterial hypertension were produced in normal Sprague-Dawley rats by oral administration of buthionine sulfoximine (BSO), which induces glutathione (GSH) depletion, indicating that oxidative stress may induce hypertension. The contribution of several potential pathogenic factors has been evaluated in the BSO rat model, the prototype of oxidative stress-induced hypertension, including vascular reactivity, endothelium-derived factors, renin-angiotensin system activity, TXA(2)-PGH(2) production, sodium sensitivity, renal dopamine-induced natriuresis, and sympathetic tone. This review summarizes the main factors implicated in the pathogenesis of BSO-induced hypertension and the alterations associated with GSH depletion that are related to renal function or BP control. PMID- 22223044 TI - Initiating RNA polymerase II and TIPs as hallmarks of enhancer activity and tissue-specificity. AB - In past years, many efforts were invested to define epigenetic features associated with enhancers of transcription. We propose that both transcription initiation and the H3K4me3 histone modification are among the best hallmarks of active enhancers in several primary tissues and extend the concept of large transcription initiation platforms (TIPs). PMID- 22223045 TI - Deletion of the oxygen-dependent degradation domain results in impaired transcriptional activity of hypoxia-inducible factors. AB - Hypoxia-inducible factors (HIF1alpha/HIF2alpha) are key transcription factors that promote angiogenesis. The overexpression of degradation-resistant HIF mutants is considered a promising pro-angiogenic therapeutic tool. We compared the transcriptional activity of HIF1alpha/HIF2alpha mutants that obtained their resistance to oxygen-dependent degradation either by deletion of their entire oxygen-dependent degradation (ODD) domain or by replacement of prolyl residues that are crucial for oxygen-dependent degradation. Although all HIF mutants translocated into the nucleus, HIF1alpha and HIF2alpha mutants inclosing the point mutations were significantly more effective in trans-activating the target gene VEGF and in inducing tube formation of endothelial cells than mutants lacking the complete ODD domain. PMID- 22223046 TI - Transcriptional priming of cytoplasmic post-transcriptional regulation. AB - Recent evidence suggests that post-transcriptional events that are executed in the cytoplasm can be predetermined during transcription. Here, I speculate that this is a widespread mode of regulation and discuss the potential mechanisms, advantages and implications of such a regulatory strategy. PMID- 22223047 TI - Revealing the functions of TFIIB. AB - The TFIIB linker domain stimulates the catalytic activity of archaeal RNAP. By characterising a range of super-stimulating mutants we identified a novel rate limiting step in transcription initiation. Our results help to interpret structural findings and pave the way towards higher-resolution structures of the RNAP-TFIIB linker interface. PMID- 22223050 TI - Cancer care challenges in developing countries. AB - BACKGROUND: Health systems in Sub-Saharan Africa are not prepared for the rapid rise in cancer rates projected in the region over the next decades. More must be understood about the current state of cancer care in this region to target improvement efforts. Yaounde General Hospital (YGH) currently is the only site in Cameroon (population: 18.8 million) where adults can receive chemotherapy from trained medical oncologists. The experiences of patients at this facility represent a useful paradigm for describing cancer care in this region. METHODS: In July and August 2010, our multidisciplinary team conducted closed-end interviews with 79 consecutive patients who had confirmed breast cancer, Kaposi sarcoma, or lymphoma. RESULTS: Thirty-five percent of patients waited >6 months to speak to a health care provider after the first sign of their cancer. The delay between first consultation with a health care provider and receipt of a cancer diagnosis was >3 months for 47% of patients. The total delay from the first sign of cancer to receipt of the correct diagnosis was >6 months for 63% of patients. Twenty-three percent of patients traveled for >7 hours to reach YGH, and 40% of patients interviewed spent >$200 on a single round of chemotherapy. CONCLUSIONS: Cancer patients experienced numerous geographic and health care system challenges, resulting in significant delays in receiving diagnosis and treatment, even for cancers highly amenable to early intervention. This unacceptable and unethical situation is likely explained by limited knowledge about cancer among patients and health care professionals, government neglect, poverty, and reliance on traditional healers. PMID- 22223048 TI - CHD chromatin remodelers and the transcription cycle. AB - It is well established that ATP-dependent chromatin remodelers modulate DNA access of transcription factors and RNA polymerases by "opening" or "closing" chromatin structure. However, this view is far too simplistic. Recent findings have demonstrated that these enzymes not only set the stage for the transcription machinery to act but are actively involved at every step of the transcription process. As a consequence, they affect initiation, elongation, termination and RNA processing. In this review we will use the CHD family as a paradigm to illustrate the progress that has been made in revealing these new concepts. PMID- 22223049 TI - Molecular analysis of the genus Anoxybacillus based on sequence similarity of the genes recN, flaA, and ftsY. AB - Genome predictions based on selected genes would be a very welcome approach for taxonomic studies. We analyzed three genes, recN, flaA, and ftsY, for determining if these genes are useful tools for systematic analyses in the genus Anoxybacillus. The genes encoding a DNA repair and genetic recombination protein (recN), the flagellin protein (flaA), and GTPase signal docking protein (ftsY) were sequenced for ten Anoxybacillus species. The sequence comparisons revealed that recN sequence similarities range between 61% and 99% in the genus Anoxybacillus. Comparisons to other bacterial recN genes indicated that levels of similarity did not differ from the levels within genus Anoxybacillus. These data showed that recN is not a useful marker for the genus Anoxybacillus. A 550-600-bp region of the flagellin gene was amplified for all Anoxybacillus strains except for Anoxybacillus contaminans. The sequence similarity of flaA gene varies between 61% and 76%. Comparisons to other bacterial flagellin genes obtained from GenBank (Bacillus, Pectinatus, Proteus, and Vibrio) indicated that the levels of similarity were lower (3-42%). Based on these data, we concluded that the variability in this single gene makes it a particularly useful marker. Another housekeeping gene ftsY suggested to reflect the G+C (mol/mol) content of whole genome was analyzed for Anoxybacillus strains. A mean difference of 1.4% was observed between the G+C content of the gene ftsY and the G+C content of the whole genome. These results showed that the gene ftsY can be used to represent whole G+C content of the Anoxybacillus species. PMID- 22223051 TI - Fragment-based screening for inhibitors of PDE4A using enthalpy arrays and X-ray crystallography. AB - Fragment-based screening has typically relied on X-ray or nuclear magnetic resonance methods to identify low-affinity ligands that bind to therapeutic targets. These techniques are expensive in terms of material and time, so it useful to have a higher throughput method to reliably prescreen a fragment library to identify a subset of compounds for structural analysis. Calorimetry provides a label-free method to assay binding and enzymatic activity that is unaffected by the spectroscopic properties of the sample. Conventional microcalorimetry is hampered by requiring large quantities of reagents and long measurement times. Nanocalorimeters can overcome these limitations of conventional isothermal titration calorimetry. Here we have used enthalpy arrays, which are arrays of nanocalorimeters, to perform an enzyme activity-based fragment screen for competitive inhibitors of phosphodiesterase 4A (PDE4A). Several inhibitors with K ( I ) <2 mM were identified and moved to X-ray crystallization trials. Although the co-crystals did not yield high-resolution data, evidence of binding was observed, and the chemical structures of the hits were consistent with motifs of known PDE4 inhibitors. This study shows how array calorimetry can be used as a prescreening method for fragment-based lead discovery with enzyme targets and provides a list of candidate fragments for inhibition of PDE4A. PMID- 22223052 TI - Identification of influenza virus inhibitors targeting NS1A utilizing fluorescence polarization-based high-throughput assay. AB - This article describes the development of a simple and robust fluorescence polarization (FP)-based binding assay and adaptation to high-throughput identification of small molecules blocking dsRNA binding to NS1A protein (nonstructural protein 1 from type A influenza strains). This homogeneous assay employs fluorescein-labeled 16-mer dsRNA and full-length NS1A protein tagged with glutathione S-transferase to monitor the changes in FP and fluorescence intensity simultaneously. The assay was optimized for high-throughput screening in a 384 well format and achieved a z' score greater than 0.7. Its feasibility for high throughput screening was demonstrated using the National Institutes of Health clinical collection. Six of 446 small molecules were identified as possible ligands in an initial screening. A series of validation tests confirmed epigallocatechine gallate (EGCG) to be active in the submicromolar range. A mechanism of EGCG inhibition involving interaction with the dsRNA-binding motif of NS1A, including Arg38, was proposed. This structural information is anticipated to provide a useful basis for the modeling of antiflu therapeutic reagents. Overall, the FP-based binding assay demonstrated its superior capability for simple, rapid, inexpensive, and robust identification of NS1A inhibitors and validation of their activity targeting NS1A. PMID- 22223053 TI - Long-term health experience of jet engine manufacturing workers: V. Issues with the analysis of non-malignant central nervous system neoplasms. AB - OBJECTIVE: We attempted to examine non-malignant central nervous system (CNS) neoplasms incidence rates for workers at 8 jet engine manufacturing facilities in Connecticut. The objective of this manuscript is to describe difficulties encountered regarding these analyses to aid future studies. METHODS: We traced the cohort for incident cases of CNS neoplasms in states where 95% of deaths in the total cohort occurred. We used external and internal analyses in an attempt to obtain the true risk of non-malignant CNS in the cohort. Because these analyses were limited by data constraints, we conducted sensitivity analyses, including using state driver's license data to adjust person-year stop dates to help minimize underascertainment and more accurately determine cohort risk estimates. RESULTS: We identified 3 unanticipated challenges: case identification, determination of population-based cancer incidence rates, and handling of case underascertainment. These factors precluded an accurate assessment of non-malignant CNS neoplasm incidence risks in this occupational epidemiology study. CONCLUSIONS: The relatively recent (2004) mandate of capturing non-malignant CNS tumor data at the state level means that, in time, it may be possible to conduct external analyses of these data. Meanwhile, similar occupational epidemiology studies may be limited to descriptive analysis of the non-malignant CNS case characteristics. PMID- 22223054 TI - Frequency and determinants of missing data in clinical and prognostic variables recently added to SEER. AB - BACKGROUND: The objectives of the present study were to examine and quantify the frequency of missing information for the collaborative stage (CS) site-specific factors (SSF) added to the Surveillance, Epidemiology and End Results (SEER) data collection in 2004, to evaluate patient-, disease-, and registry-related factors associated with incomplete data, and to quantify time and effort required to collect information for each variable of interest. METHODS: The study included 2 parts: 1) an analysis of existing nationwide SEER data; and 2) an evaluation of time and effort as reported by hospital registrars in the Metropolitan Atlanta and Rural Georgia (MARGA) SEER Registry catchment area. The first analysis examined all SSF for all types of cancers reported to the SEER Program between 2004 and 2007 from all 17 SEER registries. The data for the second analysis were limited to 5 cancer sites: breast, prostate, colon/rectum, testes, and lymphoma. Information for each cancer site was collected from 40 cancer registrars who were asked to estimate the amount of time and effort spent on abstracting each variable of interest. RESULTS: We analyzed 825,952 cases pertaining to 18 different cancer sites and 45 different variables. Of the 45 SSF variables examined in this study, 12 had at least 50% of cases with missing data. Conversely, a total of 21 variables were at least 80% complete. Our analysis of determinants of missing SSF data showed an improvement of reporting since 2004 for most variables. Older patients (80+ years of age) tended to have a higher proportion of missing data compared to 40- to 59-year-olds (reference category). For the specific cancers presented in this paper, patients diagnosed in non metropolitan areas tended to have a slightly higher proportion of missing data compared to those diagnosed in metropolitan areas. We found no discernable patterns of association between probability of having missing data and patients' race, sex, or registry. According to the registrars' reports, data collection for CS SSF requires a median of 2-3 minutes with a range of 1-15 minutes. There was great variability in the perceived level of difficulty associated with finding the necessarily data. CONCLUSIONS: The data completeness for CS SSF ranges widely, and is largely site- and variable-specific. The main barrier to data completeness appears to be the availability of information in the medical records. Our results indicate that for a number of SSF the proportion of missing data is so high that these variables can be of little, if any, use for population based research. The practical implications of our findings with respect to existing and future SSF need to be explored. PMID- 22223055 TI - Assessment of completeness of reporting of oro-facial cleft cases in Arizona using the capture-recapture method. AB - The Arizona Birth Defects Monitoring Program (ABDMP) is mandated to collect data on several birth defects including oro-facial clefts such as cleft lip with and without cleft palate (CL) and cleft palate without cleft lip (CP). Completeness of reporting and ascertainment validations had never been conducted on the birth defects monitored by the program. Two-source capture-recapture modeling was used to evaluate the completeness of incidence reporting of CL and CP. The Lincoln Petersen model and the log-linear model were used to estimate the completeness of reporting of CL and CP cases based on hospital discharge and disease index data. On average, 14 cases of CP per year and 24 cases of CL per year were identified as underreported. Validations of model estimates of CL and CP were done using confirmed cases of CL and CP from the Arizona Birth Defects Registry for the years of 2004 through 2007. The agreement between the observed and estimated number of cases of CP and CL by both models was adequate as demonstrated by the observed coefficient of determination R2. Hospital discharge data had a better percent of completeness than disease index data. Stronger agreements between estimated and observed cases were found using both models for CP cases as compared to CL cases. Neither data source was adequate for complete reporting of CP and CL cases in Arizona. The estimated average case underreporting suggests that appropriate policy provisions and actions are needed to achieve better completeness of case reporting. PMID- 22223056 TI - Creation and implementation of a prospective pediatric clinical outcomes registry. AB - OBJECTIVE: To build a pediatric clinical outcomes registry (COR) using a contemporary information system designed to support research and outcome studies and to improve patient care and quality of life. PATIENTS AND METHODS: In response to physician needs, this process was implemented: 1) database needs assessment survey, 2) evaluate existing systems and vendors, 3) pilot test a COR tool, and 4) build a COR. The COR was designed to include patients with the following conditions: scoliosis, neonatal surgery, urologic surgery, cleft palate, pain management, otitis media, and voice and airway problems. Agency for Healthcare Research and Quality methodology was followed to create the infrastructure and registry. RESULTS: The database needs assessment survey was completed by 99 individuals and most respondents wanted to collect more standardized data than currently available in existing systems. Satisfaction with the existing systems was rated low. The COR was created and a pilot test was successful. The COR was implemented and has been functioning for more than 2 years. CONCLUSIONS: By identifying physicians needs, evaluating existing technology and incorporating a multidisciplinary team, the COR was created and implemented to maintain clinical data on a variety of patient diagnoses and outcomes using a single technology platform that enhances potential research collaborations and minimizes redundant data entry and data collection, such as quality of life assessments for the patients. PMID- 22223057 TI - Preeclampsia mortality in Texas: a capture-recapture analysis. AB - OBJECTIVE: Public health professionals and clinicians rely on hospital discharge data to explore the epidemiology of preeclampsia. Our objective was to compare the concordance in preeclampsia inpatient mortality between hospital inpatient discharge data and death certificate data in Texas during a 2-year period using the capture-recapture technique. METHODS: The statewide Texas hospital inpatient discharge dataset and a statewide death certificate dataset were searched for fatal episodes of preeclampsia or eclampsia. Women who were Texas residents and expired in a hospital in 2006 or 2007 were identified using ICD-9-CM and ICD-10 codes. Using the capture-recapture sampling technique, we estimated the number of inpatient preeclamptic deaths that were missed by both databases, the death certificate database and the hospital inpatient database. RESULTS: The hospital inpatient dataset captured 17 fatal episodes of preeclampsia while the inpatient death certificate database captured 9. Six patients were found in both datasets. Application of the capture-recapture method revealed that the total number of statewide inpatient preeclamptic deaths was 26 during this period. CONCLUSIONS: This pilot study found that 2 prominent sources of statewide health data underestimated the frequency of inpatient deaths in Texas due to preeclampsia. PMID- 22223058 TI - Survival outcomes of pediatric osteosarcoma and Ewing's sarcoma: a comparison of surgery type within the SEER database, 1988-2007. AB - INTRODUCTION: Survival following diagnosis of pediatric Ewing's sarcoma or osteosarcoma is increasing in the United States, but whether survival differs between patients who receive limb salvage surgery compared to amputation has not been evaluated in nationally representative, population-based data. MATERIALS AND METHODS: Multivariable-adjusted survival was calculated using Cox regression models among surgically treated pediatric (age <20) osteosarcoma and Ewing's sarcoma patients with bone cancer of the limbs or joints reported to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program during 1988-2007. RESULTS: Over half (66.3%) of the 890 osteosarcoma patients underwent limb salvage surgery. Five-year overall survival among patients who received limb salvage was 72.7% for osteosarcoma patients and 71.8% for Ewing's sarcoma patients. Among patients who received amputation, 5-year survival was 60.1% for osteosarcoma and 63.1% for Ewing's sarcoma patients. After multivariable adjustment, the mortality was 35% greater for amputation vs limb salvage (HR=1.35, 95% CI: 1.05-1.75). Among 165 Ewing's sarcoma patients, 73.9% underwent limb salvage (vs amputation), and the adjusted mortality was higher for patients receiving amputation, although results were not statistically significant (HR=1.61, 95% CI: 0.80-3.21). CONCLUSION: Limb salvage surgery (vs amputation) is associated with longer survival among pediatric patients with bone cancer of the limbs or joints. Patient and physician characteristics and the effectiveness of neoadjuvant therapy may play a role in surgery choice, but we were unable to control for these factors. PMID- 22223059 TI - Using a statistical process control chart during the quality assessment of cancer registry data. AB - Statistical process control (SPC) charts may be used to detect acute variations in the data while simultaneously evaluating unforeseen aberrations that may warrant further investigation by the data user. Using cancer stage data captured by the Summary Stage 2000 (SS2000) variable, we sought to present a brief report highlighting the utility of the SPC chart during the quality assessment of cancer registry data. Using a county-level caseload for the diagnosis period of 2001 2004 (n=25,648), we found the overall variation of the SS2000 variable to be in control during diagnosis years of 2001 and 2002, exceeded the lower control limit (LCL) in 2003, and exceeded the upper control limit (UCL) in 2004; in situ/localized stages were in control throughout the diagnosis period, regional stage exceeded UCL in 2004, and distant stage exceeded the LCL in 2001 and the UCL in 2004. Our application of the SPC chart with cancer registry data illustrates that the SPC chart may serve as a readily available and timely tool for identifying areas of concern during the data collection and quality assessment of central cancer registry data. PMID- 22223061 TI - Case reports on the potential of fractional laser-assisted photodynamic therapy for basal cell carcinomas. PMID- 22223060 TI - Effects of light emitting diode (LED) therapy and cold water immersion therapy on exercise-induced muscle damage in rats. AB - The aim of this work is to analyze the effects of LED therapy at 940 nm or cold water immersion therapy (CWI) after an acute bout of exercise on markers of muscle damage and inflammation. Thirty-two male Wistar rats were allocated into four groups: animals kept at rest (control), exercised animals (E), exercised + CWI (CWI), and exercised + LED therapy (LED). The animals swam for 100 min, after which blood samples were collected for lactate analysis. Animals in the E group were returned to their cages without treatment, the CWI group was placed in cold water (10 degrees C) for 10 min and the LED group received LED irradiation on both gastrocnemius muscles (4 J/cm(2) each). After 24 h, the animals were killed and the soleus muscles were submitted to histological analysis. Blood samples were used for hematological and CK analyses. The results demonstrated that the LED group presented fewer areas of muscle damage and inflammatory cell infiltration and lower levels of CK activity than the E group. Fewer areas of damaged muscle fiber were observed in the LED group than in CWI. CWI and LED did not reduce edema areas. Hematological analysis showed no significant effect of either treatment on leukocyte counts. The results suggest that LED therapy is more efficient than CWI in preventing muscle damage and local inflammation after exercise. PMID- 22223062 TI - Communication about DTC testing: commentary on a 'family experience of personal genomics'. AB - This paper provides a commentary on 'Family Experience of Personal Genomics' (Corpas 2012). An overview is offered on the communication literature available to help support individuals and families to communicate about genetic information. Despite there being a wealth of evidence, built on years of genetic counseling practice, this does not appear to have been translated clearly to the Direct to Consumer (DTC) testing market. In many countries it is possible to order a DTC genetic test without the involvement of any health professional; there has been heated debate about whether this is appropriate or not. Much of the focus surrounding this has been on whether it is necessary to have a health professional available to offer their clinical knowledge and help with interpreting the DTC genetic test data. What has been missed from this debate is the importance of enabling customers of DTC testing services access to the abundance of information about how to communicate their genetic risks to others, including immediate family. Family communication about health and indeed genetics can be fraught with difficulty. Genetic health professionals, specifically genetic counselors, have particular expertise in family communication about genetics. Such information could be incredibly useful to kinships as they grapple with knowing how to communicate their genomic information with relatives. PMID- 22223063 TI - A family experience of personal genomics. AB - This article presents a personal journey of a close-knit family from Malaga, Spain who engaged with direct-to-consumer (DTC) genomic testing. Whilst the testing was initiated by one member of the family who works as a genome bioinformatician, none of the remaining family had any prior experience with DTC genetic testing. A thoughtful account, written in the first person, is offered on the experience of genome testing across the various members of the family together with a reflection on how it felt to be a custodian of the 'family genome'. The way the family processed their genome information is explored and the difficulties and challenges that resulted are discussed. Whilst there is a wealth of literature that describes how families communicate information surrounding single genes, there is very little which explores the experience of communication about whole, shared genomes. The experiences described in this paper provide an insight into this new territory. PMID- 22223064 TI - Recognize three different human telomeric G-quadruplex conformations by quinacrine. AB - Recognition of different human telomeric G-quadruplex structures has been a very important task for developing anti-cancer drug design. However, it also is a very challenging question since multiple conformational isomers of telomeric G quadruplexes coexist under some conditions. Here, three different conformations including parallel, antiparallel, and mixed-type telomeric G-quadruplex structures have been well recognized by quinacrine (QNA) through monitoring its absorption, fluorescence, and fluorescence lifetime spectra. The multiple structures of H22 G-quadruplexes under physiological K(+) conditions could also be easily determined to coexist as mixed-type and antiparallel G-quadruplexes. The recognition mechanism based on the different binding affinity and binding sites has been further elucidated by association with the nuclear magnetic resonance (NMR) results. PMID- 22223065 TI - Two-step evaluation of binding energy and potential energy surface of van der Waals complexes. AB - Evaluation of intermolecular distance and binding energy (BE) of van der Waals complex/cluster at ab initio level of theory is computationally demanding when many monomers are involved. Starting from MP2 energy, we reached a two-step evaluation method of BE of van der Waals complex/cluster through reasonable approximations; BE = BE(HF) + sum Mi> Mj{BE (Mi- Mj)(MP2 or MP2.5) - BE(Mi Mj)(HF)} where HF represents the Hartree-Fock calculation, Mi, Mj, etc. are interacting monomers, and MP2.5 represents the arithmetic mean of MP2 and MP3. The first term is the usual BE of the complex/cluster evaluated at the HF level. The second term is the sum of the difference in two-body BE between the correlated and HF levels of theory. This equation was applied to various van der Waals complexes consisting of up-to-four monomers at MP2 and MP2.5 levels of theory. We found that this method is capable of providing precise estimate of the BE and reproducing well the potential energy surface of van der Waals complexes/clusters; the maximum error of the BE is less than 1 kcal/mol and 1% in most cases except for several limited cases. The origins of error in these cases are discussed in detail. PMID- 22223067 TI - Percutaneous nephrolithotomy monotherapy for staghorn: paradigm shift for 'staghorn morphometry' based clinical classification. AB - PURPOSE OF REVIEW: The term staghorn is plagued by an unclear morphology There is a need for clinical definition of staghorn that could classify patients in either of the two ends of the treatment spectrum for percutaneous nephrolithotomy (PCNL) monotherapy. RECENT FINDINGS: Staghorn morphometry was identified as a prognostic tool to predict tract(s) and stage(s) for PCNL monotherapy for staghorn. Staghorn morphometry requires a three-dimensional computed tomography urography assessment by volume rendering software. As per the detailed stone morphometric analysis, a clinically important definition of staghorn calculi based on the high odds probability of multiple tract(s) and stage(s) is proposed. Type 1 staghorn has a total stone volume of less than 5000 mm with less than 5% unfavorable calyx stone percentile volume, whereas type 3 staghorn has a total stone volume of more than 20,000 mm with greater than 10% unfavorable calyx stone percentile volume. Type 2 staghorn is in-between type 1 and 2. Based on the prediction model for achieving clearance by PCNL monotherapy, type 1 staghorn would require single tract and stage, type 2 single tract-single/multiple stages or multiple tract-single stage and type 3 multiple tract and stage. SUMMARY: Staghorn morphometry based clinical classification of staghorn is an exciting concept for PCNL monotherapy. Further prospective studies are required to validate the staghorn morphometry based clinical variate of staghorns. The prospective studies should take into account clinical presentations, operative complications, tract and stage required, postoperative complications, hospital stay, operative cost and stone-free status. PMID- 22223066 TI - Eliminating global renal ischemia during partial nephrectomy: an anatomical approach. AB - PURPOSE OF REVIEW: Partial nephrectomy surgery typically requires clamping the main renal artery. This creates the bloodless field necessary for precise tumor excision and reconstruction. However, hilar clamping also renders the entire kidney ischemic, an undesirable albeit unavoidable consequence. We recently developed a novel, anatomical zero-ischemia technique that eliminates global renal ischemia. Herein, we critically evaluate the outcomes of unclamped and zero ischemia partial nephrectomy techniques. RECENT FINDINGS: Our anatomical zero ischemia technique takes advantage of renal segmental and end-arterial anatomy to allow even substantial partial nephrectomy surgery without clamping the main renal artery/vein. Anatomic vascular microdissection is performed to super selectively devascularize the tumor, while maintaining uninterrupted arterial blood flow to the uninvolved kidney. Global renal ischemia is thus eliminated. SUMMARY: Partial nephrectomy can now be safely performed without global renal ischemia, even for complex tumors. Initial perioperative and renal functional outcomes of anatomical zero-ischemia surgery are encouraging. Going forward, clamping the main renal artery appears unnecessary during most partial nephrectomy surgery. PMID- 22223068 TI - Angiotensin II induces tumor necrosis factor-alpha expression and release from cultured human podocytes. AB - OBJECTIVE: High levels of both angiotensin (Ang) II and tumor necrosis factor (TNF)-alpha have been implicated in the pathogenesis of glomerular injury by affecting podocytes. The aim of this study was to investigate the Ang II-TNF alpha relationship in human podocytes. METHODS: Immortalized podocytes were exposed to Ang II for 6 days in the absence or presence of either losartan or PD123,319 (both at 100 nM), AT(1) and AT(2) receptor antagonists, respectively. RESULTS: Ang II, after at least 72 h of repeated treatment, increased basal TNFA gene expression and cytokine release with a biphasic pattern and maximum response at 10 nM. Losartan dampened the effects of Ang II on TNF-alpha production throughout the experimental period, demonstrating an AT(1) receptor contribution. PD123,319 affected the second TNF-alpha production peak, showing also an AT(2) receptor contribution. Moreover, Ang II causes tumor necrosis factor receptor (TNFR) 1 and TNFR2 over-expression in a time-dependent manner. The functional interaction between Ang II and TNF-alpha was demonstrated when the pro proliferative effect of Ang II was antagonized by a neutralizing TNF-alpha antibody. CONCLUSIONS: Our results show a functional interaction between Ang II and TNF-alpha and implicate this cytokine as a mediator in Ang II long-term pathoadaptive podocytes changes. PMID- 22223069 TI - FOXO1 involvement in insulin resistance-related pro-inflammatory cytokine production in hepatocytes. AB - OBJECTIVE: Low-grade inflammation from hepatocytes plays a causal role in hepatic and systemic insulin resistance (IR). We aimed to explore whether and how FOXO1 was involved in IR-related inflammation in hepatocytes. METHODS: We determined FOXO1 expression and activity, insulin and NF-kappaB signaling, and pro inflammatory cytokine production in tumor necrosis factor-alpha (TNF-alpha)- or dexamethasone (DEX)-induced IR model in vitro and in high fat diet-induced obese or diabetic db/db mice in vivo with quantitative RT-PCR and Western blotting. RESULTS: We identified two different but physiologically relevant IR models characterized by attenuated insulin-induced phosphorylation of insulin receptor substrate-1 and AKT in TNF-alpha- or DEX-treated HepG2 cells. DEX largely increased FOXO1 expression in hepatocytes, while TNF-alpha did not. Notably, FOXO1 phosphorylation was attenuated in both models. TNF-alpha-stimulated nuclear translocation of NF-kappaB (p65) and mRNA levels of interleukin (IL)-1, IL-6 and monocyte attractant protein-1 were partly blocked, while the anti-inflammatory role of DEX was largely potentiated by insulin. FOXO1 knockdown by human-specific FOXO1 small interfering RNA exerted an identical role to insulin. Furthermore, augmented hepatic FOXO1 expression and decreased phosphorylation were found to be associated with elevated pro-inflammatory cytokine production in high fat diet induced obese and db/db mice. CONCLUSION: FOXO1 potentiates pro-inflammatory cytokine production in insulin-resistant hepatocytes. PMID- 22223070 TI - Combined effect of invertebrate predation and sublethal pesticide exposure on the behavior and survival of Asellus aquaticus (Crustacea; Isopoda). AB - Invertebrate communities of lentic habitats comprise, amongst others, the crustacean Asellus aquaticus (Isopoda) and the turbellarian Dendrocoelum lacteum (Tricladida). Because D. lacteum preferentially preys on A. aquaticus, contaminants introduced into the aquatic environment may affect this predator prey interaction, finally influencing the performance of the predator. However, no studies investigating implications of organic pollutants on this food web subsystem currently exist. Hence, the present study assessed short-term implications of pesticides with different modes of action, namely, the triazole fungicide tebuconazole and the pyrethroid insecticide lambda-cyhalothrin, during a 72 h trial. The experiments for tebuconazole showed a statistically significant decrease in predatory success of D. lacteum. Lambda-cyhalothrin, in contrast, increased predation success by 40%, which is, however, not statistically significant. Both the decrease and the increase in predation seemed to be primarily driven by an altered activity of the prey A. aquaticus. This may be hypothesized because any shift in the prey's activity influenced its probability to stick to mucus, a viscous substance released by D. lacteum, or to encounter the predator directly. PMID- 22223073 TI - CT findings of spontaneous intraperitoneal rupture of the urinary bladder: two case reports. AB - We report two cases of spontaneous bladder rupture. Preoperative diagnosis was difficult and the correct diagnosis was made at surgery. Reviewing the initial abdominopelvic CT of our second patient, the bladder wall defect and blood attenuation near the bladder were observed. These findings were consistent with the operative findings, and would have led to correct preoperative diagnosis if we had had sufficient knowledge of spontaneous bladder rupture. Under urinary catheterization, ascites and free intraperitoneal air were identified in both patients. These findings were indistinguishable from those for bowel perforation, which was our preoperative diagnosis. Significant changes in ascites volume between pre and post urinary catheterization can be an indication of spontaneous bladder rupture. PMID- 22223075 TI - A case of Proteus syndrome with severe spinal canal stenosis, scoliosis, and thoracic deformity associated with tethered cord. AB - Proteus syndrome is a rare, sporadic, hamartomatous disorder manifesting with multifocal overgrowth of tissue. The features seem to develop most often during childhood. Vertebral overgrowth with severe spinal canal stenosis is unusual, although scoliosis with abnormal vertebral bodies is one of the typical features of Proteus syndrome. We report a case of Proteus syndrome with severe spinal canal stenosis, scoliosis, cervical kyphosis, and thoracic deformity with airway obstruction because of asymmetrical overgrowth of vertebrae and ribs associated with a tethered cord, lipomas, strawberry hemangioma, flat nasal bridge, and bilateral hypoplasty of the first metatarsal bones with hyperplasty of soft tissue. PMID- 22223074 TI - Comparison of local control effects of superselective transcatheter arterial chemoembolization using epirubicin plus mitomycin C and miriplatin for hepatocellular carcinoma. AB - PURPOSE: To compare local control effects of superselective transcatheter arterial chemoembolization (TACE) using epirubicin (EPI) plus mitomycin C (M) and miriplatin (MPT) for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: One hundred and twenty-nine HCCs treated with superselective TACE were divided into three groups according to the type of anticancer drug; EPI-M-TACE (n = 51), MPT TACE (n = 21), and MPT-I-TACE (MPT emulsion) (n = 57). Local recurrence, patterns of recurrence (intratumoral recurrence; IR), and follow-up angiograms were evaluated. RESULTS: Mean tumor diameter and follow-up period for the EPI-M-TACE, MPT-TACE, and MPT-I-TACE groups were 16.9 mm and 15.5 months, 20.7 mm and 12.0 months, and 18.8 mm and 9.6 months, respectively. Local recurrence for the EPI-M TACE, MPT-TACE, and MPT-I-TACE groups at 5, 10, and 15 months was 6.1, 47.6, and 40.1%, 23.5, 67.3, and 63.9%, and 26.2, 75.4, and 72.9%, respectively. IR for the EPI-M-TACE, MPT-TACE, and MPT-I-TACE groups was 23.1, 71.4, and 71.0%, respectively. Local recurrence and IR in the EPI-M-TACE group were significantly less than those in the MPT-TACE and MPT-I-TACE groups. Follow-up angiograms revealed less arterial damage in the MPT-TACE and MPT-I-TACE groups. CONCLUSION: Superselective TACE using MPT resulted in very frequent local recurrence, in particular IR, despite less arterial damage. PMID- 22223076 TI - The oxidative properties of a manganese(IV) hydroperoxide moiety and its relationships with the corresponding manganese(IV) oxo and hydroxo moieties. AB - Clear elucidation of the oxidative relationships of the active metal hydroperoxide moiety with its corresponding metal oxo and hydroxo intermediates would help the understanding of the different roles they may play in redox metalloenzymes and oxidation chemistry. Using an Mn(Me(2)EBC)Cl(2) complex, it was found that, in t-butanol-water (4 : 1) with excess H(2)O(2) at pH 1.5, the Mn(IV)-OOH moiety may exist in the catalytic solution with a mass signal of m/z = 358.1, which provides a particular chance to investigate its oxidative properties. In catalytic oxidations, the Mn(IV)-OOH moiety demonstrates a relatively poor activity in hydrogen abstraction from diphenyl methane and ethylbenzene with TOF of only 1.2 h(-1) and 1.1 h(-1) at 50 degrees C, whereas it can efficiently oxygenate diphenyl sulfide, methyl phenyl sulfide and benzyl phenyl sulfide with TOF of 13.8 h(-1), 15.4 h(-1) and 17.8 h(-1), respectively. In mechanistic studies using H(2)(18)O and H(2)(18)O(2), it was found that, in the Mn(IV)-OOH moiety mediated hydrogen abstraction and sulfide oxygenations, the reaction proceeds by two parallel pathways: one by direct oxygen insertion/transfer, and the other by plausible electron transfer. Together with a good understanding of the corresponding manganese(IV) oxo and hydroxo intermediates, this work provides the first chance to compare the reactivity differences and similarities of the active metal oxo, hydroxo and hydroperoxide intermediates. The available evidence reveals that the Mn(IV)-OOH moiety has a much more powerful oxidizing capability than the corresponding Mn(IV)=O and Mn(IV)-OH functional groups in both hydrogen abstraction and oxygenation. PMID- 22223077 TI - Double dissociation of working memory load effects induced by bilateral parietal modulation. AB - Transcranial magnetic stimulation and neuroimaging data have revealed bilateral posterior parietal cortex (PPC) involvement during verbal n-back working memory (WM). In this task as n (i.e., WM load) increases, subjects show poorer behavioral performance as well as greater activation of this brain area. Moreover, there is evidence that a brief period of practice or even increased familiarity with the task can improve WM performance and lead to activation changes in the PPC. The aim of this study was to investigate, using transcranial direct current stimulation (tDCS), the effects on WM load performance induced by different PPC modulation after increased familiarity with the task. After a short practice, we tested verbal WM using an n-back task (1-back vs. 2-back) before and after the application of bilateral tDCS over PPCs (left anodal-right cathodal, left cathodal-right anodal or sham). ANOVA showed a significant interaction between tDCS and task. In the 1-back task, left anodal-right cathodal modulation abolished improvement in reaction times observed in the other two modulation conditions. Conversely, in the 2-back task the same effect was observed after left cathodal-right anodal modulation relative to the other two modulation conditions. This double dissociation demonstrates either a differential engagement of each PPC or changes in the interhemispheric balance of activity across this brain region. Neuroimaging studies show parametric activation of the PPC as difficulty increases, but activation does not switch sides. Thus, our observed effects cannot be attributed to increased task difficulty, the stimuli used, or the response requirements. Rather, we suggest that these findings reflect the use of different processing strategies to perform these two tasks. In conclusion, after increased familiarity with the task, different tDCS modulations lead to changes in a task-related region depending on differences in processing strategies in 1-back vs. 2-back. PMID- 22223078 TI - Basal ganglia structures differentially contribute to verbal fluency: evidence from Human Immunodeficiency Virus (HIV)-infected adults. AB - BACKGROUND: The basal ganglia (BG) are involved in executive language functions (i.e., verbal fluency) through their connections with cortical structures. The caudate and putamen receive separate inputs from prefrontal and premotor cortices, and may differentially contribute to verbal fluency performance. We examined BG integrity in relation to lexico-semantic verbal fluency performance among older HIV infected adults. METHOD: 20 older (50+ years) HIV+ adults underwent MRI and were administered measures of semantic and phonemic fluency. BG (caudate, putamen) regions of interest were extracted. RESULTS: Performance on phonemic word generation significantly predicted caudate volume, whereas performance on phonemic switching predicted putamen volume. CONCLUSIONS: These findings suggest a double dissociation of BG involvement in verbal fluency tasks with the caudate subserving word generation and the putamen associated with switching. As such, verbal fluency tasks appear to be selective to BG function. PMID- 22223079 TI - Dose dependent dopaminergic modulation of reward-based learning in Parkinson's disease. AB - Learning to select optimal behavior in new and uncertain situations is a crucial aspect of living and requires the ability to quickly associate stimuli with actions that lead to rewarding outcomes. Mathematical models of reinforcement based learning to select rewarding actions distinguish between (1) the formation of stimulus-action-reward associations, such that, at the instant a specific stimulus is presented, it activates a specific action, based on the expectation that that particular action will likely incur reward (or avoid punishment); and (2) the comparison of predicted and actual outcomes to determine whether the specific stimulus-action association yielded the intended outcome or needs revision. Animal electrophysiology and human fMRI studies converge on the notion that dissociable neural circuitries centered on the striatum are differentially involved in different components of this learning process. The modulatory role of dopamine (DA) in these respective circuits and component processes is of particular relevance to the study of reward-based learning in patients diagnosed with Parkinson's disease (PD). Here we show that the first component process, learning to predict which actions yield reward (supported by the anterior putamen and associated motor circuitry) is impaired when PD patients are taken off their DA medication, whereas DA medication has no systematic effects on the second processes, outcome evaluation (supported by caudate and ventral striatum and associated frontal circuitries). However, the effects of DA medication on these processes depend on dosage, with larger daily doses leading to a decrease in predictability of stimulus-action-reward relations and increase in reward prediction errors. PMID- 22223080 TI - Unexpected patterns of sensitivity to drought in three semi-arid grasslands. AB - Global climate models forecast an increase in the frequency and intensity of extreme weather events, including severe droughts. Based on multi-year relationships between precipitation amount and aboveground annual net primary production (ANPP), semi-arid grasslands are projected to be among the most sensitive ecosystems to changes in precipitation. To assess sensitivity to drought, as well as variability within the shortgrass steppe biome, we imposed moderate and severe rainfall reductions for two growing seasons in three undisturbed grasslands that varied in soil type and climate. We predicted strong drought-induced reductions in ANPP at all sites and greater sensitivity to drought in sites with lower average precipitation, consistent with continental scale patterns. Identical experimental infrastructure at each site reduced growing season rainfall events by 50 or 80%, and significantly reduced average soil moisture in both years (by 21 and 46% of control levels, respectively). Despite reductions in soil moisture, ANPP responses varied unexpectedly-from no reduction in ANPP to a 51% decrease. Although sensitivity to drought was highest in the semi-arid grassland with lowest mean annual precipitation, patterns in responses to drought across these grasslands were also strongly related to rainfall event size. When growing season rainfall patterns were dominated by many smaller events, ANPP was significantly reduced by drought but not when rainfall patterns were characterized by large rain events. This interaction between drought sensitivity and rainfall event size suggests that ANPP responses to future droughts may be reduced if growing season rainfall regimes also become more extreme. PMID- 22223081 TI - Technical desiderata for the integration of genomic data into Electronic Health Records. AB - The era of "Personalized Medicine," guided by individual molecular variation in DNA, RNA, expressed proteins and other forms of high volume molecular data brings new requirements and challenges to the design and implementation of Electronic Health Records (EHRs). In this article we describe the characteristics of biomolecular data that differentiate it from other classes of data commonly found in EHRs, enumerate a set of technical desiderata for its management in healthcare settings, and offer a candidate technical approach to its compact and efficient representation in operational systems. PMID- 22223082 TI - Multiple pulmonary nodules in ectopic adrenocorticotropic hormone syndrome: cause or result? AB - OBJECTIVE: To report a case of invasive pulmonary aspergillosis mimicking lung cancer with lung to lung metastases in ectopic adrenocorticotropic hormone syndrome (EAS). CLINICAL PRESENTATION AND INTERVENTION: A 60-year-old man suffering from hypokalemic alkalosis, hypertension and limbs paralysis was referred to our hospital. EAS caused by malignancy of lung was highly suspected due to multiple pulmonary nodules presenting on chest film and positron emission tomography (PET) images. Video-assisted thoracic surgical biopsy tissue was used to confirm invasive aspergillosis instead of malignancy. Finally, the patient died of opportunistic infection. CONCLUSION: This case showed that although EAS is usually associated with solid tumors, multiple pulmonary nodules secondary to opportunistic infections such as invasive aspergillosis must be kept in mind. PMID- 22223083 TI - Taking sides: is handedness involved in motor asymmetry of Parkinson's disease? PMID- 22223084 TI - Irreversible electroporation on the small intestine. AB - BACKGROUND: Non-thermal irreversible electroporation (NTIRE) has recently been conceived as a new minimally invasive ablation method, using microsecond electric fields to produce nanoscale defects in the cell membrane bilayer and induce cell death while keeping all other molecules, including the extracellular matrix, intact. Here, we present the first in vivo study that examines the effects of NTIRE on the small intestine, an organ whose collateral damage is of particular concern in the anticipated use of NTIRE for treatment of abdominal cancers. METHODS: A typical NTIRE electrical protocol was applied directly to the rat small intestine and histological analysis was used to examine the effect of NTIRE over time. RESULTS: The application of NTIRE led to complete cell ablation in the targeted tissue, but the animal did not show any physiological effects of the procedure and the intestine showed signs of recovery, developing an epithelial layer 3 days post treatment and regenerating its distinct layers within a week. CONCLUSION: Our results indicate that this novel procedure can be used for abdominal cancer treatment while minimising collateral damage to adjacent tissues because of the unique ability of the NTIRE ablation method to target the cell membrane. PMID- 22223085 TI - The frequency of T regulatory cells modulates the survival of multiple myeloma patients: detailed characterisation of immune status in multiple myeloma. AB - BACKGROUND: Multiple myeloma (MM) is an immunoproliferative disease characterised by the uncontrolled proliferation of plasma cells, which is accompanied by defects in the immune system. METHODS: This study aimed to characterise the frequency of T regulatory cells (Tregs), dendritic cells (DCs) as well as sub populations of T cells bearing regulatory properties like CD4(+)GITR(+), CD4(+)CD62L(+), CD3(+)TCRgammadelta(+) along with the concentrations of IL-10, TGFbeta, IL-6 in 66 patients with MM. Subsequently, the influence of therapy on those components of immune system was assessed. RESULTS: The percentage of both myeloid and plasmacytoid DC was lower in MM compared with control group while Treg (CD4(+)CD25(high)FOXP3(+)) frequencies were significantly higher in MM patients compared with healthy control (6.16% vs 0.05%, respectively). Also, the percentages of CD4(+)GITR(+), CD4(+)CD62L(+) were increased compared with healthy volunteers. We found that patients with higher percentages of Treg live shorter (median overall survival 21 months vs not-reached, P=0.013). CONCLUSION: This study identifies several abnormalities of immune system in MM, which only partly could be normalised after successful therapy. The dysfunction of immune system such as decreased antigen presentation along with increased frequencies of suppressive cells and cytokines might facilitate progression of the disease and infectious complications limiting survival of MM patients. PMID- 22223086 TI - Dietary fat intake and risk of ovarian cancer in the NIH-AARP Diet and Health Study. AB - BACKGROUND: Fat intake has been postulated to increase risk of ovarian cancer, but previous studies have reported inconsistent results. METHODS: The NIH-AARP Diet and Health Study, a large prospective cohort, assessed diet using a food frequency questionnaire at baseline in 1995-1996. During an average of 9 years of follow-up, 695 ovarian cancer cases were ascertained through the state cancer registry database. The relative risks (RRs) and 95% confidence interval (CI) were estimated using a Cox proportional hazard model. RESULTS: Women in the highest vs the lowest quintile of total fat intake had a 28% increased risk of ovarian cancer (RR(Q5 vs Q1)=1.28, 95% CI: 1.01-1.63). Fat intake from animal sources (RR(Q5 vs Q1)=1.30; 95% CI: 1.02-1.66), but not from plant sources, was positively associated with ovarian cancer risk. Saturated and monounsaturated fat intakes were not related to risk of ovarian cancer, but polyunsaturated fat intake showed a weak positive association. The association between total fat intake and ovarian cancer was stronger in women who were nulliparous or never used oral contraceptives. CONCLUSION: Fat intake, especially from animal sources, was related to an increased risk of ovarian cancer. The association may be modified by parity and oral contraceptive use, which warrants further investigation. PMID- 22223087 TI - ADM3, TFF3 and LGALS3 are discriminative molecular markers in fine-needle aspiration biopsies of benign and malignant thyroid tumours. AB - BACKGROUND: Previously, we reported a six-marker gene set, which allowed a molecular discrimination of benign and malignant thyroid tumours. Now, we evaluated these markers in fine-needle aspiration biopsies (FNAB) in a prospective, independent series of thyroid tumours with proven histological outcome. METHODS: Quantitative RT-PCR was performed (ADM3, HGD1, LGALS3, PLAB, TFF3, TG) in the needle wash-out of 156 FNAB of follicular adenoma (FA), adenomatous nodules, follicular and papillary thyroid cancers (TC) and normal thyroid tissues (NT). RESULTS: Significant expression differences were found for TFF3, HGD1, ADM3 and LGALS3 in FNAB of TC compared with benign thyroid nodules and NT. Using two-marker gene sets, a specific FNAB distinction of benign and malignant tumours was achieved with negative predictive values (NPV) up to 0.78 and positive predictive values (PPV) up to 0.84. Two FNAB marker gene combinations (ADM3/TFF3; ADM3/ACTB) allowed the distinction of FA and malignant follicular neoplasia with NPV up to 0.94 and PPV up to 0.86. CONCLUSION: We demonstrate that molecular FNAB diagnosis of benign and malignant thyroid tumours including follicular neoplasia is possible with recently identified marker gene combinations. We propose multi-centre FNAB studies on these markers to bring this promising diagnostic tool closer to clinical practice. PMID- 22223088 TI - Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours. AB - BACKGROUND: Olaparib (AZD2281) is a potent oral poly(ADP-ribose) polymerase inhibitor with anti-tumour activity and acceptable toxicity as monotherapy in patients with BRCA-deficient cancers. The vascular endothelial growth factor receptor inhibitor bevacizumab has been incorporated into standard of care with chemotherapy in various tumours. This phase I study established the safety, tolerability and clinical pharmacokinetics of olaparib alone and in combination with bevacizumab. METHODS: Patients with advanced solid tumours received increasing doses of continuous oral olaparib (100, 200 and 400 mg b.i.d. capsule formulation) in combination with bevacizumab (10 mg kg(-1) intravenous q2w). RESULTS: In all, 12 patients enrolled and received treatment. The most common adverse events (AEs) related to olaparib were grade 1/2 nausea and fatigue. No haematological parameters were reported as AEs. No serious AEs related to olaparib or dose-limiting toxicities (DLTs) were reported. Three patients discontinued due to AEs, two patients discontinued both olaparib and bevacizumab and one patient discontinued olaparib. Five patients received combination treatment for over 6 months. There was no evidence that bevacizumab affected olaparib. CONCLUSION: The combination of olaparib 400 mg b.i.d. with bevacizumab 10 mg kg(-1) q2w was generally well tolerated with no DLTs. This combination could be considered for future clinical investigation. PMID- 22223089 TI - Differential expression of microRNAs during melanoma progression: miR-200c, miR 205 and miR-211 are downregulated in melanoma and act as tumour suppressors. AB - BACKGROUND: The incidence of malignant melanoma is increasing faster than that for any other cancer. Histological examination of skin excision biopsies remains the standard method for melanoma diagnosis and prognosis. Significant morphological overlap between benign and malignant lesions complicates diagnosis, and tumour thickness is not always an accurate predictor of prognosis. METHODS: To identify improved molecular markers to support histological examination, we used microarray analysis of formalin-fixed and paraffin-embedded samples from different stages of melanomagenesis to identify differentially expressed microRNAs (miRNAs). Differential expression was validated by qRT-PCR, and functional studies were carried out after transfection of miRNA precursors or inhibitors into melanoma cells to modulate miRNA expression. RESULTS: In all, 20 miRNAs showed highly significant differential expression between benign naevi and either primary or metastatic melanomas, the majority being downregulated in melanoma, whereas only 2 miRNAs, namely miR-203 and miR-205, were differentially expressed between primary and metastatic melanomas. In functional in vitro assays, overexpression of miR-200c and miR-205 inhibited anchorage-independent colony formation and overexpression of miR-211 inhibited both anchorage independent colony formation and invasion. CONCLUSION: We have identified a series of differentially expressed miRNAs that could be useful as diagnostic or prognostic markers for melanoma and have shown that three miRNAs (namely miR 200c, miR-205 and miR-211) act as tumour suppressors. PMID- 22223090 TI - Arterial stiffness in prehypertension: a possible vicious cycle. AB - The pathophysiological abnormalities associated with increased arterial stiffness and/or abnormal pressure wave reflection may play crucial roles in increasing the risk of development of cardiovascular events. On the other hand, prehypertension, defined as a systolic blood pressure of 120-139 and/or a diastolic blood pressure of 80-89 mmHg, is a "danger zone" for the later development of hypertension and is also associated with an increased incidence of cardiovascular diseases and cardiovascular mortality. We discuss the association among arterial stiffness/pressure wave reflection, prehypertension, and the later development of hypertension. Several prospective studies have demonstrated that increased arterial stiffness/abnormal pressure wave reflection are risk factors for the later development of hypertension in subjects with prehypertension. On the contrary, persistence of prehypertention accelerates the age-related increase of the arterial stiffness. Thus, arterial stiffness and prehypertension may be elements of a vicious cycle, and other cardiovascular risk factors, such as aging and abnormal glucose metabolism, may aggravate this cycle. In the future, development of a simple technique to assess large/small arterial stiffness and an effective strategy to reduce arterial stiffness in subjects with prehypertension is warranted. PMID- 22223091 TI - Effect of rate-alteration on speech perception in noise in older adults with normal hearing and hearing impairment. AB - PURPOSE: The purpose of this study was to evaluate the effect of using slow and fast speaking rates in competing noise on older adults with normal hearing (NH) and those with hearing impairment (HI). METHOD: Thirty-four older adults (56-85 years) were grouped based on hearing ability-NH (N = 15) and HI (N = 19). Rate altered Quick Speech-in-Noise Test (QuickSIN; Etymotic Research, 2001) stimuli were presented at 3 speech rates (slow, average, and fast), and the signal-to noise ratio (SNR) loss was calculated for each. RESULTS: The older participants with HI had significantly higher SNR loss than the NH participants at all 3 speech rates. The NH participants showed improved speech perception in noise when a slow rate of speech was used. This benefit was not observed for the participants with HI. Both groups performed poorly with the fastest speech rate. CONCLUSION: Results suggest that older adults with HI who are not wearing hearing aids are not able to take advantage of additional processing time afforded by the use of slow speaking rates when speech (70-75 dB HL) is presented in competing noise. Additionally, the use of a fast speaking rate significantly reduces an individual's ability to perceive speech in noise, regardless of hearing status. Decreasing from a fast speaking rate to an average rate is beneficial and should be recommended by audiologists to increase the likelihood of older adults understanding speech in noise. PMID- 22223092 TI - Phagocytosis of bacterial pathogens. AB - Phagocytosis is an evolutionarily ancient, receptor-driven process, by which phagocytic cells recognize invading microbes and destroy them after internalization. The phagocytosis receptor Eater is expressed exclusively on Drosophila phagocytes and is required for the survival of bacterial infections. In a recent study, we explored how Eater can defend fruit flies against different kinds of bacteria. We discovered that Eater bound to certain types of bacteria directly, while for others bacterial binding was dependent on prior disruption of the bacterial envelope. Similar to phagocytes, antimicrobial peptides and lysozymes are ancient components of animal immune systems. Our results suggest that cationic antimicrobial peptides, as well as lysozymes, can facilitate Eater binding to live Gram-negative bacteria. Both types of molecules promote surface exposure of bacterial ligands that otherwise would remain buried and hidden under an outer membrane. We propose that unmasking ligands for phagocytic receptors may be a conserved mechanism operating in many animals, including humans. Thus, studying a Drosophila phagocytosis receptor may advance our understanding of innate immunity in general. PMID- 22223093 TI - The evolution of multiple mating: Costs and benefits of polyandry to females and of polygyny to males. AB - Polyandry is a paradox: why do females mate multiple times when a single ejaculate often provides enough sperm for lifetime egg production? Gowaty et al. addressed explanations for polyandry in Drosophila pseudoobscura from the perspective of hypotheses based on sex differences in costs of reproduction (CoR). Contrary to CoR, Gowaty et al. showed that (1) a single ejaculate was inadequate for lifetime egg production; (2) polyandry provided fitness benefits to females beyond provision of adequate sperm and (3) fitness benefits of polyandry were not offset by costs. Here, I discuss predictions of the ad hoc hypotheses of CoR and three alternative hypotheses to CoR to facilitate a discussion and further development of a strong inference approach to experiments on the adaptive significance of polyandry for females. Each of the hypotheses makes testable predictions; simultaneous tests of the predictions will provide a strong inference approach to understanding the adaptive significance of multiple mating. I describe a sex-symmetric experiment meant to evaluate variation in fitness among lifelong virgins (V); monogamous females and males with one copulation (MOC); monogamous females and males with multiple copulations (MMC); PAND, polyandrous females; and PGYN, polygynous males. Last, I recommend the study of many different species, while taking care in choice of study species and attention to the assumptions of specific hypotheses. I particularly urge the study of many more Drosophila species both in laboratory and the wild to understand the "nature of flies in nature," where opportunities and constraints mold evolutionary responses. PMID- 22223094 TI - Brain and muscle ARNT-like protein BMAL1 regulates ROS homeostasis and senescence: a possible link to hypoxia-inducible factor-mediated pathway. PMID- 22223095 TI - Fine-tuning of the intracellular canonical Notch signaling pathway. AB - Notch signaling plays a pivotal role in the regulation of many fundamental cellular processes, such as proliferation, stem cell maintenance and differentiation during embryonic and adult development. At the molecular level, ligand binding induces the proteolytic cleavage of the Notch receptor. The intracellular domain of Notch translocates subsequently into the nucleus, associates with the central transcription factor RBP-J and activates transcription. Although, this pathway is remarkably short, with no second messenger involved, it regulates expression of more than hundred target genes in a tissue-specific manner. This review summarizes recent studies on transcriptional and chromatin control mechanisms, which set the stage for specific expression of Notch target genes. Furthermore, we review how the canonical (RBP-J dependent) Notch pathway is fine-tuned by downstream effectors and feedback loops in mammals. PMID- 22223096 TI - What's wrong with fear conditioning? AB - Fear conditioning is one of the prime paradigms of behavioural neuroscience and a source of tremendous insight in the fundamentals of learning and memory and the psychology and neurobiology of emotion. It is also widely regarded as a model for the pathogenesis of anxiety disorders in a diathesis-stress model of psychopathology. Starting from the apparent paradox between the adaptive nature of fear conditioning and the dysfunctional nature of pathological anxiety, we present a critique of the human fear conditioning paradigm as an experimental model for psychopathology. We discuss the potential benefits of expanding the human fear conditioning paradigm by (1) including action tendencies as an important index of fear and (2) paying more attention to "weak" (i.e., ambiguous) rather than "strong" fear learning situations (Lissek et al., 2006), such as contained in selective learning procedures. We present preliminary data that illustrate these ideas and discuss the importance of response systems divergence in understanding individual differences in vulnerability for the development of pathological anxiety. PMID- 22223097 TI - Acute ingestion of different macronutrients differentially enhances aspects of memory and attention in healthy young adults. AB - The role of carbohydrates on mood and cognition is fairly well established, however research examining the behavioural effects of the other macronutrients is limited. The current study compared the effects of a 25 g glucose drink to energetically matched protein and fat drinks and an inert placebo. Following a blind, placebo-controlled, randomised crossover design, 18 healthy young adults consumed drinks containing fat, glucose, protein and placebo. Cognitive performance was examined at baseline and again 15- and 60 min post drink. Mood was assessed at baseline and then 10-, 35- and 80 min post drink. Attention and speed were enhanced 15 min following fat or glucose ingestion and working memory was enhanced 15 min following protein ingestion. Sixty minutes post drink memory enhancements were observed after protein and memory impairment was observed following glucose. All drinks increased ratings of alertness. The findings suggest that macronutrients: (i) have different windows of opportunity for effects (ii) target different cognitive domains. PMID- 22223098 TI - Re: use of gentamicin collagen sponges for the treatment of periprosthetic breast implant infection. PMID- 22223099 TI - Highlights from the scientific and educational abstracts presented at the ASER 2011 Annual Scientific Meeting and Postgraduate Course. AB - The American Society of Emergency Radiology (ASER) 2011 Annual Scientific Meeting and Post-Graduate Course encompassed a wide range of topics: traumatic and nontraumatic emergencies, radiation dose management, technical innovations and advancements, emergency preparedness, mass casualties, military radiology and teleradiology. This article highlights the scientific and educational abstracts presented at the meeting. PMID- 22223100 TI - Gastric cancer development after Helicobacter pylori eradication therapy: a new form of gastric neoplasia. AB - BACKGROUND AND AIM: Along with the widespread use of eradication for Helicobacter pylori (H. pylori), the incidence of gastric cancer after eradication has also been increasing. There is a need for clarification of the clinical and biological characteristics of these neoplasms. PATIENTS AND METHODS: We studied 27 cases of gastric cancer that developed after eradication (group AE). Out of the 27, we selected 26 with early-stage gastric cancer and compared them with 78 age-matched gastric cancer patients with H. pylori infection (group Pos) and 20 patients without H. pylori (group Neg). The patient with autoimmune gastritis was not included. Clinicopathological features, mucus patterns and Wnt5a expressions were compared among these groups. RESULTS: Among group AE patients, there were more males than females, and the tumor histology was mainly intestinal type, a significant difference from group Neg. In contrast, macroscopically, the tumors were predominantly of the flat-depressed type, a feature similar to that of group Neg but significantly different from that of group Pos. MUC2 and Wnt5a expression was significantly lower in group AE than in group Pos. CONCLUSION: Gastric cancer development after eradication may have a carcinogenic pathway similar to that in cancer with H. pylori infection, though macroscopic/biological features may be modified by eradication therapy. PMID- 22223101 TI - CYP264B1 from Sorangium cellulosum So ce56: a fascinating norisoprenoid and sesquiterpene hydroxylase. AB - Many terpenes and terpenoid compounds are known as bioactive substances with desirable fragrance and medicinal activities. Modification of such compounds to yield new derivatives with desired properties is particularly attractive. Cytochrome P450 monooxygenases are potential enzymes for these reactions due to their capability of performing different reactions on a variety of substrates. We report here the characterization of CYP264B1 from Sorangium cellulosum So ce56 as a novel sesquiterpene hydroxylase. CYP264B1 was able to convert various sesquiterpenes including nootkatone and norisoprenoids (alpha-ionone and beta ionone). Nootkatone, an important grapefruit aromatic sesquiterpenoid, was hydroxylated mainly at position C-13. The product has been shown to have the highest antiproliferative activity compared with other nootkatone derivatives. In addition, CYP264B1 was found to hydroxylate alpha- and beta-ionone, important aroma compounds of floral scents, regioselectively at position C-3. The products, 3-hydroxy-beta-ionone and 13-hydroxy-nootkatone, were confirmed by (1)H and (13)C NMR. The kinetics of the product formation was analyzed by high-performance liquid chromatography, and the K ( m ) and k (cat) values were calculated. The results of docking alpha-/beta-ionone and nootkatone into a homology model of CYP264B1 revealed insights into the structural basis of these selective hydroxylations. PMID- 22223102 TI - Modification of the TRX2 gene dose in Saccharomyces cerevisiae affects hexokinase 2 gene regulation during wine yeast biomass production. AB - In the industrial yeast biomass production process, cells undergo an oxidative and other stresses which worsen the quality of the produced biomass. The overexpression of the thioredoxin codifying gene TRX2 in a wine Saccharomyces cerevisiae strain increases resistance to oxidative stress and industrial biomass production yield. We observed that variations in the TRX2 gene dose in wine yeast strains are relevant to determine the fermentative capacity throughout the industrial biomass production process. So, we studied the molecular changes using a transcriptomic approach under these conditions. The results provide an overview of the different metabolic pathways affected during industrial biomass production by TRX2 gene manipulation. The oxidative stress-related genes, like those related with the glutathione metabolism, presented outstanding variations. The data also allowed us to propose new thioredoxin targets in S. cerevisiae, such as hexokinase 2, with relevance for industrial fermentation performance. PMID- 22223103 TI - Characterization of the mitochondrial NAD+ -dependent isocitrate dehydrogenase of the oleaginous yeast Rhodosporidium toruloides. AB - Early biochemical studies have demonstrated that lipid accumulation by oleaginous yeasts is linked to the activity of the NAD(+)-dependent isocitrate dehydrogenase (Idh). However, molecular study of Idh of oleaginous microorganisms remains limited. Here, we present the cloning of a mitochondrial NAD(+)-specific Idh from Rhodosporidium toruloides (RtIdh), an excellent microbial lipid producer that uses carbohydrates as the carbon source. The evolutionary relationship analyses among RtIdhs and other yeast Idhs revealed that RtIdh had a closer relationship with the Idhs of Ustilago maydis and Schizophyllum commune. We expressed the RtIDH gene in the yeast Saccharomyces cerevisiae idhDelta mutant. Under the nitrogen-limited condition, the intracellular lipid content and extracellular citrate concentration of the culture of the S. cerevisiae idhDelta carrying the RtIDH gene increased as the carbon/nitrogen molar ratio of the media increased, while the wild-type S. cerevisiae strain showed no correlation. Our data provided valuable information for elucidating the molecular mechanism of microbial oleaginicity and for engineering microorganisms to produce metabolites of fatty acid pathway. PMID- 22223104 TI - Enhanced electrode-reducing rate during the enrichment process in an air-cathode microbial fuel cell. AB - The improvement in electricity generation during the enrichment process of a microbial consortium was analyzed using an air-cathode microbial fuel cell (MFC) repeatedly fed with acetate that was originally inoculated with sludge from an anaerobic digester. The anodic maximum current density produced by the anode biofilm increased from 0.12 mA/cm(2) at day 28 to 1.12 mA/cm(2) at day 105. However, the microbial cell density on the carbon cloth anode increased only three times throughout this same time period from 0.21 to 0.69 mg protein/cm(2), indicating that the biocatalytic activity of the consortium was also enhanced. The microbial activity was calculated to have a per biomass anode-reducing rate of 374 MUmol electron g protein(-1) min(-1) at day 28 and 1,002 MUmol electron g protein(-1) min(-1) at day 105. A bacterial community analysis of the anode biofilm revealed that the dominant phylotype, which was closely related to the known exoelectrogenic bacterium, Geobacter sulfurreducens, showed an increase in abundance from 32% to 70% of the total microbial cells. Fluorescent in situ hybridization observation also showed the increase of Geobacter-like phylotypes from 53% to 72%. These results suggest that the improvement of microbial current generation in microbial fuel cells is a function of both microbial cell growth on the electrode and changes in the bacterial community highly dominated by a known exoelectrogenic bacterium during the enrichment process. PMID- 22223105 TI - Killing cells by targeting mitosis. AB - Cell cycle deregulation is a common feature of human cancer. Tumor cells accumulate mutations that result in unscheduled proliferation, genomic instability and chromosomal instability. Several therapeutic strategies have been proposed for targeting the cell division cycle in cancer. Whereas inhibiting the initial phases of the cell cycle is likely to generate viable quiescent cells, targeting mitosis offers several possibilities for killing cancer cells. Microtubule poisons have proved efficacy in the clinic against a broad range of malignancies, and novel targeted strategies are now evaluating the inhibition of critical activities, such as cyclin-dependent kinase 1, Aurora or Polo kinases or spindle kinesins. Abrogation of the mitotic checkpoint or targeting the energetic or proteotoxic stress of aneuploid or chromosomally instable cells may also provide further benefits by inducing lethal levels of instability. Although cancer cells may display different responses to these treatments, recent data suggest that targeting mitotic exit by inhibiting the anaphase-promoting complex generates metaphase cells that invariably die in mitosis. As the efficacy of cell cycle targeting approaches has been limited so far, further understanding of the molecular pathways modulating mitotic cell death will be required to move forward these new proposals to the clinic. PMID- 22223106 TI - Programming of adipose tissue miR-483-3p and GDF-3 expression by maternal diet in type 2 diabetes. AB - Nutrition during early mammalian development permanently influences health of the adult, including increasing the risk of type 2 diabetes and coronary heart disease. However, the molecular mechanisms underlying such programming are poorly defined. Here we demonstrate that programmed changes in miRNA expression link early-life nutrition to long-term health. Specifically, we show that miR-483-3p is upregulated in adipose tissue from low-birth-weight adult humans and prediabetic adult rats exposed to suboptimal nutrition in early life. We demonstrate that manipulation of miR-483-3p levels in vitro substantially modulates the capacity of adipocytes to differentiate and store lipids. We show that some of these effects are mediated by translational repression of growth/differentiation factor-3, a target of miR-483-3p. We propose that increased miR-483-3p expression in vivo, programmed by early-life nutrition, limits storage of lipids in adipose tissue, causing lipotoxicity and insulin resistance and thus increasing susceptibility to metabolic disease. PMID- 22223108 TI - Heterotopic ossification of the elbow after closed reduction and retrograde intramedullary nailing for radial neck fracture treated by anconeus interposition. AB - Heterotopic ossification around the elbow can lead to considerable functional disability. We describe a case of a 42-year-old man who developed heterotopic ossification of his elbow after closed reduction of the elbow dislocation and radial neck fracture and retrograde intramedullary nailing for radial neck fracture. During the follow-up after initial surgery, movements of the elbow were gradually deteriorated and diagnosed as heterotopic ossification of the elbow. Implant removal, radial head excision along with heterotopic mass, and also interposition of the anconeus muscle resulted in improvement of his elbow mobility. At 18 months of follow-up, patient had elbow flexion arc of 15 degrees 110 degrees , 70 degrees of supination, and 50 degrees of pronation without recurrence of heterotopic ossification. The uniqueness of this case lies in the treatment of heterotopic ossification of the elbow to prevent its recurrence, which was developed after retrograde intramedullary nailing for radial neck fracture following closed reduction. PMID- 22223107 TI - Modular cementless cup for total hip arthroplasty: results at 4-year follow-up. AB - The aim is to perform the assessment of a modular cementless acetabular cup with a tapered internal design for all bearing couplings. In 190 unselected consecutive patients, 207 total hip arthroplasties were implanted. The implants were clinically and radiographically evaluated. Follow-up was 49.7 +/- 8.1 months. The average Harris hip score improved from 55.5 +/- 5.7 to 94.7 +/- 3.4 (P < 0.05). All cups were well-positioned and stable. The Kaplan-Maier cumulative survivorship was 98.5 +/- 0.8%. No significant differences have been noted in dividing patients according to the different liner materials (P < 0.005). The study, whose rationale is the novelty of this kind of implant, suggests the efficacy of the Delta-PF acetabular cup. PMID- 22223109 TI - Functional characterization of CP148, a novel key component for centrosome integrity in Dictyostelium. AB - The Dictyostelium centrosome consists of a layered core structure surrounded by a microtubule-nucleating corona. A tight linkage through the nuclear envelope connects the cytosolic centrosome with the clustered centromeres within the nuclear matrix. At G2/M the corona dissociates, and the core structure duplicates, yielding two spindle poles. CP148 is a novel coiled coil protein of the centrosomal corona. GFP-CP148 exhibited cell cycle-dependent presence and absence at the centrosome, which correlates with dissociation of the corona in prophase and its reformation in late telophase. During telophase, GFP-CP148 formed cytosolic foci, which coalesced and joined the centrosome. This explains the hypertrophic appearance of the corona upon strong overexpression of GFP CP148. Depletion of CP148 by RNAi caused virtual loss of the corona and disorganization of interphase microtubules. Surprisingly, formation of the mitotic spindle and astral microtubules was unaffected. Thus, microtubule nucleation complexes associate with centrosomal core components through different means during interphase and mitosis. Furthermore, CP148 RNAi caused dispersal of centromeres and altered Sun1 distribution at the nuclear envelope, suggesting a role of CP148 in the linkage between centrosomes and centromeres. Taken together, CP148 is an essential factor for the formation of the centrosomal corona, which in turn is required for centrosome/centromere linkage. PMID- 22223111 TI - An extrahepatic bile duct grafting using a bioabsorbable polymer tube. AB - BACKGROUND: Thus far, no ideal substitutions have been developed for completely replacing the extrahepatic bile duct (EHBD). METHODS: We used a bioabsorbable polymer tube (BAPT) for the complete reconstruction of an EHBD in pigs. A 2-cm long EHBD was resected from the duodenal side, and a 4-cm-long BAPT graft was implanted at that site. The animals were re-laparotomized at 1 or 4 months after the grafting; subsequently, gross, histological, and blood chemical studies were performed. RESULTS: At 1 month after grafting, tubular structure was observed in all resected specimens, and the lumen of the graft site had remnants of degraded BAPT. Gross examination at 4 months after grafting revealed that the BAPT had been completely absorbed, and the graft site was indistinguishable from the native extrahepatic bile duct. The lengths of the graft region at 4 months were 70% of the replaced BAPT. Simultaneously performed histological examination revealed the growth of a neo-bile duct at the graft site, with an epithelium identical to that of the native bile duct. CONCLUSION: The BAPT graft implanted in this study completely replaced the EHBD defect. Hence, BAPT has the potential for application as a novel treatment modality for hepatobiliary diseases. PMID- 22223112 TI - Tetrapodal amidoxime ligands I. Coordination isomerism due to self-complementary dimerization of a pyramidal cobalt(III) coordination module. AB - A bis-MU-amidoximato-bridged cobalt(III) dimer obtained with a new tetrapodal ligand possesses interesting structural parameters as a consequence of intramolecular hydrogen bonding intentionally built into the complex. Its synthesis and properties are described. The new ligand type combines attributes of two previously described ligand classes: It binds a metal ion in a tetrapodal pentadentate fashion and forms a pseudomacrocycle through hydrogen bonds, characteristic of chelating oxime ligands. Coordination isomerism, which is a consequence of dimer formation, has been analyzed by means of X-ray crystallography and carbon-13 nuclear magnetic resonance spectroscopy. PMID- 22223113 TI - Ex vivo pig training model for esophageal endoscopic submucosal dissection (ESD) for endoscopists with experience in gastric ESD. AB - BACKGROUND: Esophageal endoscopic submucosal dissection (ESD) has developed in recent years because of its high rate of en bloc resection. However, for many endoscopists, technical difficulty and risks of complications are great barriers to performing esophageal ESD. In this study, we developed an original training model for esophageal ESD using isolated pig esophagus and assessed this ex vivo model in endoscopists with experience in gastric ESD. METHODS: Three endoscopists without experience in esophageal ESD but with some experience in gastric ESD performed esophageal ESD of artificial lesions in 10 consecutive sessions using this ex vivo model. The en bloc resection rate, operation time, number of muscularis propria layer injuries, and presence of perforation were recorded. We evaluated the effectiveness of this training in the three endoscopists by comparing results from the first five sessions (former period) with those from the last five sessions (latter period). RESULTS: All three endoscopists achieved en bloc resections in all trials. In the former period, injury to the muscularis propria layer for each of the three endoscopists occurred a mean of 2.2 (1-3), 0.6 (0-1), and 3.2 (1-6) times, respectively. Perforation occurred in one session performed by one endoscopist. In the latter period, the mean number of muscularis propria layer injuries for each of the three endoscopists decreased to 0.2 (0-1), 0.2 (0-1), and 0.8 (0-2), respectively. The time of operation shortened from 35.0 (25-40), 36.4 (30-50), and 29.8 (23-43) min to 23.0 (16-31), 25.6 (23-28), and 29.2 (21-37) min, respectively. CONCLUSIONS: This original ex vivo training model was helpful to endoscopists with experience in gastric ESD in acquiring the basic skills for performing esophageal ESD. PMID- 22223114 TI - Revisiting vascular patency after spleen-preserving laparoscopic distal pancreatectomy with conservation of splenic vessels. AB - BACKGROUND: We evaluated vascular patency and potential changes in preserved spleens after laparoscopic spleen-preserving distal pancreatectomy (SPDP) with conservation of both splenic vessels. METHODS: We retrospectively analyzed the patency of conserved splenic vessels in patients who underwent laparoscopic or robotic splenic vessel-conserving SPDP from January 2006 to August 2010. The patency of the conserved splenic vessels was evaluated by abdominal computed tomography and classified into three grades according to the degree of severity. RESULTS: Among 30 patients with splenic vessel-conserving laparoscopic SPDP, 29 patients with complete follow-up data were included in this study. During the follow-up period (median: 13.2 months), grades 1 and 2 splenic arterial obliteration were observed in one patient each. A total of five patients (17.2%) showed grade 1 or 2 obliteration in conserved splenic veins. Most patients (82.8%) had patent conserved splenic vein. Four patients (13.8%) eventually developed collateral venous vessels around gastric fundus and reserved spleen, but no spleen infarction was found, and none presented clinical relevant symptoms, such as variceal bleeding. There was no statistical difference in vascular patency between the laparoscopic and robotic groups (P > 0.05). CONCLUSIONS: Most patients showed intact vascular patency in conserved splenic vessels and no secondary changes in the preserved spleen after laparoscopic splenic vessel-conserving SPDP. PMID- 22223115 TI - Laparoscopic transabdominal preperitoneal inguinal hernia repair using needlescopic instruments: a 15-year, single-center experience in 317 patients. AB - BACKGROUND: Laparoscopic inguinal hernia repair is associated with a decrease in postoperative pain, shortened hospital stay, earlier return to normal activity, and decrease in chronic pain. Moreover, laparoscopic surgery performed with needlescopic instruments has more advantages than conventional laparoscopic surgery. However, there are few reports of large-scale laparoscopic transabdominal preperitoneal inguinal hernia repair using needlescopic instruments (nTAPP). This report reviews our experiences with 352 nTAPP in 317 patients during the 15-year period from April 1996 to April 2011. METHODS: We performed nTAPP as the method of choice in 88.5% of all patients presenting with inguinal hernia. To perform the nTAPP, 3-mm instruments were used. A 5-mm laparoscope was inserted from the umbilicus, and surgical instruments were inserted through 5- and 3-mm trocars. After reduction of the hernia sac and dissection of the preperitoneal space, we placed polyester mesh or polypropylene soft mesh with staple fixation. The peritoneum was closed with 3-0 silk interrupted sutures. RESULTS: The mean operative time was 102.9 min for unilateral hernias and 155.8 min for bilateral hernias. There was no conversion to open repair. Forty-three patients (13.6%) used postoperative analgesics, and the mean frequency of use was 0.5 times. Regarding intraoperative complications, we observed one bladder injury, but no bowel injuries or major vessel injuries. Postoperative complications occurred in 32 patients (10.1%). One patient with a retained lipoma required reoperation. There was no incidence of chronic pain or mesh infection. The operative time for experienced surgeons (>= 20 repairs) was significantly shorter than that of inexperienced surgeons (< 20 repairs; P < 0.05). CONCLUSIONS: The nTAPP was a safe and useful technique for inguinal hernia repair. Large prospective, randomized controlled trials will be required to establish the benefit of nTAPP. PMID- 22223110 TI - Chromosome instability and deregulated proliferation: an unavoidable duo. AB - The concept that aneuploidy is a characteristic of malignant cells has long been known; however, the idea that aneuploidy is an active contributor to tumorigenesis, as opposed to being an associated phenotype, is more recent in its evolution. At the same time, we are seeing the emergence of novel roles for tumor suppressor genes and oncogenes in genome stability. These include the adenomatous polyposis coli gene (APC), p53, the retinoblastoma susceptibility gene (RB1), and Ras. Originally, many of these genes were thought to be tumor suppressive or oncogenic solely because of their role in proliferative control. Because of the frequency with which they are disrupted in cancer, chromosome instability caused by their dysfunction may be more central to tumorigenesis than previously thought. Therefore, this review will highlight how the proper function of cell cycle regulatory genes contributes to the maintenance of genome stability, and how their mutation in cancer obligatorily connects proliferation and chromosome instability. PMID- 22223116 TI - Impact of the English National Training Programme for laparoscopic colorectal surgery on training opportunities for senior colorectal trainees. AB - BACKGROUND: There is growing concern that the recently introduced National Training Programme for consultants in laparoscopic colorectal surgery will have a negative impact on the training of senior colorectal trainees by minimizing the opportunities available. This study aimed to determine the impact that local implementation of the National Training Programme has had on the operating experience of senior colorectal trainees. METHODS: A prospective study was conducted at a designated national training center for laparoscopic colorectal surgery based in a large district general hospital in England, United Kingdom. All patients undergoing laparoscopic colorectal surgery in our unit between October 2006-September 2008 and October 2008-September 2010 were included in the study. The study variables included number and type of procedure, patient demographics, American Society of Anesthesiology grade, body mass index, conversion rates, previous abdominal surgery, and median operating time. The main outcome measure was the number of procedures performed by senior colorectal trainees before and after commencement of National Training Programme training in October 2008. RESULTS: A total of 746 laparoscopic colorectal resections were performed. Senior colorectal trainees performed 175 cases before commencement of the National Training Programme and 184 cases afterward. The difference was not significant. National Training Programme consultants performed 126 cases. Data were analyzed using Fisher's exact test and the Mann-Whitney U test. The study groups were found to be well matched. The median operating time was significantly longer after commencement of the National Training Programme. The study was limited in terms of ability to extrapolate results to smaller units wishing to participate in training programs. CONCLUSION: Implementation of the National Training Programme in our hospital has not had a negative impact on the training opportunities for senior colorectal trainees. However, any unit wishing to participate in the National Training Programme must ensure that an adequate operative caseload and extra resources for operative lists are available for training. PMID- 22223117 TI - Histology classification challenges for the endoscopic treatment of early gastric cancer. PMID- 22223118 TI - Ferric ion immobilized on three-dimensional nanoporous gold films modified with self-assembled monolayers for electrochemical detection of hydrogen peroxide. AB - A fast, simple square wave potential method is developed for the fabrication of a three-dimensional (3D) nanoporous gold (NPG) film. The nanostructures are characterized and confirmed by scanning electronic microscopy (SEM) and cyclic voltammetry (CV). The nanostructures modified with self-assembled monolayers (SAMs) are employed as an electrode substrate to immobilize inorganic iron(III) ion. After immobilization, iron(III) ion undergoes an effective direct electron transfer reaction with a pair of well-defined redox peak at -256 +/- 10 mV (pH 7.0). The iron(III) ion modified electrode displays the excellent electrocatalytic performance for reduction of hydrogen peroxide, and thus can be used as an electrochemical sensor for detecting hydrogen peroxide with a low detection limit (1.0 * 10(-9) M), a wide linear range (9.0 * 10(-7)~5.0 * 10(-4) M), as well as good stability, selectivity and reproducibility. PMID- 22223120 TI - Prokr2-deficient mice display vascular dysmorphology of the fetal testes: potential implications for Kallmann syndrome aetiology. AB - Kallmann syndrome is a form of hypogonadotropic hypogonadism also associated with the loss of smell. It is a phenotypically and genetically heterogeneous disorder, with mutations in several known causative genes now accounting for approximately 30% of cases. The prevalence for the disease is also much higher in males than in females, a phenomenon that remains to be fully explained. Here, we show that loss of Prokr2, which is linked to autosomal recessive Kallmann syndrome type 3 (KAL3; OMIM 244200), affects fetal testis differentiation in mice. We find that Prokr2 is specifically expressed in the XY gonads during sex determination and fetal sexual differentiation, and knockout mice display a variable degree of compromised vasculature in the fetal testes. This phenotype offers potential insight into the clinical heterogeneity observed within familial cases, and may contribute to the gender bias in Kallmann syndrome patients. PMID- 22223121 TI - A comparative and exploratory analysis of socio-cultural factors and immigrant women's mental health within a Canadian context. AB - The purpose of this study was to explore the influence of macro-level factors on immigrant and non-immigrant women's mental health status in a Canadian context. This study was part of a larger study examining women's quality of life in south eastern Ontario. Using survey research methods, data were collected through face to-face interviews with 91 women of whom 66 identified their country of origin as "other" than Canada. Descriptive, bivariate and regression analysis of this data revealed that immigrant and non-immigrant women's macro-level predictors of mental health status vary. Overall, for immigrant women's perceptions of neighbourhood social cohesion was a stronger predictor influencing mental health status, while for non-immigrant women social support was more influential. Research with larger, representative samples should explore the findings to ascertain generalizability. PMID- 22223122 TI - Evidence of an association between the scavenger receptor class B member 2 gene and Parkinson's disease. AB - Lysosomal protein 2 (LIMP2), the product of the scavenger receptor class B member 2 (SCARB2) gene, is a ubiquitously expressed transmembrane protein that is the mannose-6-phosphate-independent receptor for glucocerebrosidase (beta-GCase); a deficiency in this protein causes Gaucher disease. Several studies have shown a link between mutations in the beta-GCase gene and diseases characterized clinically by Parkinsonism and by the presence of Lewy body-related pathology. We hypothesized that genetic variants in the SCARB2 gene could be risk factors for Parkinson's disease (PD). A candidate-gene study of 347 Greek patients with sporadic PD and 329 healthy controls was conducted to investigate the association between 5 polymorphisms in the SCARB2 gene (rs6824953, rs6825004, rs4241591, rs9991821, and rs17234715) and the development of PD. The single-locus analysis for the 5 polymorphisms revealed an association only for the rs6825004 polymorphism: the generalized odds ratio (OR(G) ) was 0.68 (95% confidence interval [CI], 0.51-0.90), and the OR for the allelic test was OR = 0.71 (95% CI, 0.56-0.90). Haplotype analysis showed an association for the GCGGT haplotype (P < .01). Our study supports a genetic contribution of the SCARB2 locus to PD; future studies in larger cohorts are necessary to verify this finding. PMID- 22223119 TI - Ca2+-dependent modulation of voltage-gated Ca2+ channels. AB - BACKGROUND: Voltage-gated (Cav) Ca2+ channels are multi-subunit complexes that play diverse roles in a wide variety of tissues. A fundamental mechanism controlling Cav channel function involves the Ca2+ ions that permeate the channel pore. Ca2+ influx through Cav channels mediates feedback regulation to the channel that is both negative (Ca2+-dependent inactivation, CDI) and positive (Ca2+-dependent facilitation, CDF). SCOPE OF REVIEW: This review highlights general mechanisms of CDI and CDF with an emphasis on how these processes have been studied electrophysiologically in native and heterologous expression systems. MAJOR CONCLUSIONS: Electrophysiological analyses have led to detailed insights into the mechanisms and prevalence of CDI and CDF as Cav channel regulatory mechanisms. All Cav channel family members undergo some form of Ca2+ dependent feedback that relies on CaM or a related Ca2+ binding protein. Tremendous progress has been made in characterizing the role of CaM in CDI and CDF. Yet, what contributes to the heterogeneity of CDI/CDF in various cell-types and how Ca2+-dependent regulation of Cav channels controls Ca2+ signaling remain largely unexplored. GENERAL SIGNIFICANCE: Ca2+ influx through Cav channels regulates diverse physiological events including excitation-contraction coupling in muscle, neurotransmitter and hormone release, and Ca2+-dependent gene transcription. Therefore, the mechanisms that regulate channels, such as CDI and CDF, can have a large impact on the signaling potential of excitable cells in various physiological contexts. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signaling. PMID- 22223123 TI - Ab initio calculation of structure and transport properties of He...X (X = Zn, Cd, Hg) van der Waals complexes. AB - The ground state ab initio CCSD(T) potential curves using various basis sets (aug cc-pVXZ-PP (X = D, T, Q, 5)) is obtained for the dimers of helium with IIb group metals. The effect of the position of the (mid) bond-functions on the interaction energy is discussed. A Symmetry Adapted Perturbation Theory decomposition of the interaction energy is provided and the trends in the dimer stabilizing and destabilizing contributions are depicted. The spline fitted potential curves are applied together with rigorous statistical formulae in order to obtain the transport coefficients (viscosity coefficients, diffusion coefficients) and the second virial coefficient both for pure constituents and mixtures. The obtained theoretical results are compared with available experimental data. Molecular dynamics is used to obtain reliable values of the diffusion coefficients for all the systems under study. PMID- 22223125 TI - tBu or not tBu? AB - The regioselectivity in the palladium-catalyzed Heck coupling reaction between an aryl halide and ethyl vinyl ether with four different phosphine ligands: PPh(n)tBu(m) (n=0-3, m=3-n) has been investigated both experimentally and computationally. A zigzag selectivity pattern was experimentally observed upon consecutive replacement of Ph by tBu in the phosphine ligand. Use of a standard DFT method (B3LYP) was shown to give a correct prediction of product preference. However, the trend in relative selectivity among the different ligands could not be correctly described. The use of a more recent DFT functional (M06) parameterized to reproduce dispersion interactions resulted in an improved description. For the sterically most demanding ligands, PtBu(3) and PPhtBu(2), unexpectedly large deviations between experimental and M06 calculated selectivities raised the question of an alternative mechanism for these ligands. In the case of PtBu(3) it was found, in agreement with literature data, that the phosphine ligand could be replaced by a second halide ligand, resulting in an anionic mechanism, with a calculated selectivity in excellent agreement with experimental data. For the PPhtBu(2) ligand, two mechanisms are suggested to operate in parallel, as demonstrated both by computational studies and experimental observation of halide-dependent selectivity. A Halpern effect is observed for all phosphine ligands investigated, that is, the least stable pre complex results in the most abundant product. PMID- 22223124 TI - Moving beyond a limited follow-up in cost-effectiveness analyses of behavioral interventions. AB - BACKGROUND: Cost-effectiveness analyses of behavioral interventions typically use a dichotomous outcome criterion. However, achieving behavioral change is a complex process involving several steps towards a change in behavior. Delayed effects may occur after an intervention period ends, which can lead to underestimation of these interventions. To account for such delayed effects, intermediate outcomes of behavioral change may be used in cost-effectiveness analyses. The aim of this study is to model cognitive parameters of behavioral change into a cost-effectiveness model of a behavioral intervention. METHODS: The cost-effectiveness analysis (CEA) of an existing dataset from an RCT in which an high-intensity smoking cessation intervention was compared with a medium intensity intervention, was re-analyzed by modeling the stages of change of the Transtheoretical Model of behavioral change. Probabilities were obtained from the dataset and literature and a sensitivity analysis was performed. RESULTS: In the original CEA over the first 12 months, the high-intensity intervention dominated in approximately 58% of the cases. After modeling the cognitive parameters to a future 2nd year of follow-up, this was the case in approximately 79%. CONCLUSION: This study showed that modeling of future behavioral change in CEA of a behavioral intervention further strengthened the results of the standard CEA. Ultimately, modeling future behavioral change could have important consequences for health policy development in general and the adoption of behavioral interventions in particular. PMID- 22223126 TI - Discrepant results of adrenal venous sampling in seven patients with primary aldosteronism. AB - BACKGROUND: Adrenal venous sampling serves as a discrimination between uni- and bilateral forms of primary aldosteronism (PA). Even correctly performed adrenal venous sampling may lead to non-diagnostic results in some cases. RESULTS: We describe 7 subjects with PA in whom correct cannulation of adrenal veins (high selectivity index defined as cortisol((adrenal))/cortisol((periphery)) ratio) was associated with aldosterone (ALDO) suppression (ALDO/cortisol((adrenal))/ALDO/cortisol((periphery)) ratio <1) in the left adrenal gland and in whom all subjects underwent a successful adrenalectomy on the right side. In 3 subjects, samples from the right side with lower selectivity indexes (1.11-1.7) compared to those samples with a higher index of selectivity (10.4-44.9) pointed to lateralization. Next, 2 subjects were operated because of relatively large adrenal masses in the right adrenal gland on CT despite ALDO suppression on this side. One subject presented with high selectivity indexes from the right side (19.5 and 37.6), but only one sample showed ALDO secretion. Patient 7 was treated with right-sided adrenalectomy despite a low lateralization index (ALDO/cortisol((right))/ALDO/cortisol((left)) 1.78). CONCLUSIONS: Our results document some uncertainties in interpreting results of adrenal venous sampling in subjects with PA which may result from deep catheter insertion, anomalous venous drainage, or fluctuations in ALDO secretion. PMID- 22223127 TI - Magnetic resonance imaging appearance of scurvy with gelatinous bone marrow transformation. AB - Scurvy is a lethal but treatable disease that is rare in industrialized countries. Caused by vitamin C deficiency, it is most prevalent in persons of low socioeconomic status and smokers. Low levels of circulating vitamin C result in poor collagen fiber formation that, in turn, leads to demineralized bones, microfractures, and poor healing. Here we report a case of scurvy in a 5-year-old boy with normal radiographs in whom initial concern for leukemia based upon magnetic resonance imaging and clinical presentation led to a bone marrow biopsy revealing gelatinous transformation. PMID- 22223128 TI - Palliative care and prehospital emergency medicine--apparently conflicting approaches? PMID- 22223129 TI - A case of acute valproic acid poisoning treated successfully with L-carnitine. PMID- 22223130 TI - A standardized procedure of information to improve comprehension of patients admitted in the emergency observation unit. PMID- 22223131 TI - Survival despite extremely high plasma diltiazem level in a case of acute poisoning treated by the molecular-adsorbent recirculating system. PMID- 22223132 TI - Hypoxia sensitization of hepatocytes to neutrophil elastase-mediated cell death depends on MAPKs and HIF-1alpha. AB - The liver is sensitive to pathological conditions associated with tissue hypoxia (Hx) and the presence of activated neutrophils that secrete the serine protease elastase (EL). We demonstrated previously that cotreatment of rat hepatocytes with nontoxic levels of Hx and EL caused synergistic cell death. Hx is sensed by hypoxia-inducible factor (HIF)-1alpha, a transcription factor that heterodimerizes with HIF-1beta/aryl hydrocarbon receptor nuclear translocator and directs expression of many genes, including the pro-cell death gene Bcl 2/adenovirus E1B-interacting protein 3 (BNIP3). Since cell death from EL or Hx also requires MAPK activation, we tested the hypothesis that the cytotoxic interaction of Hx and EL depends on MAPK and HIF-1alpha signaling. Treatment of Hepa1c1c7 cells with EL in the presence of Hx (2% O(2)) resulted in synergistic cell death. EL reduced phosphorylated ERK in O(2)-replete and Hx-exposed cells, and ERK inhibition enhanced the cytotoxicity of EL alone. Hx-EL cotreatment caused an additive increase in phosphorylated p38, and p38 inhibition attenuated cell death caused by this cotreatment. EL enhanced Hx-induced HIF-1alpha accumulation and transcription of the HIF-1alpha-mediated cell death gene BNIP3, and p38 inhibition attenuated BNIP3 expression and production. Cytotoxicity and BNIP3 expression from EL-Hx cotreatment were reduced in HIF-1beta-deficient HepaC4 cells compared with Hepa1c1c7 cells. These results suggest that p38 signaling contributes to Hx-EL cotreatment-induced cell death via modulation of HIF-1alpha-mediated gene transcription. Finally, lipid peroxidation was enhanced in Hx-EL-cotreated cells compared with cells treated with EL or Hx alone. Vitamin E treatment attenuated lipid peroxidation and protected cells from the cytotoxicity of Hx and EL, suggesting that lipid peroxidation plays a role. PMID- 22223133 TI - RORalpha, a key to the development and functioning of the brain. AB - Studies of staggerer mice, in which retinoid-related orphan receptor-alpha (RORalpha) is mutated, have provided new insights into the critical functions of RORalpha in various physiological processes in peripheral tissues and in the brain. Staggerer mice present an ataxic phenotype caused by a massive neurodegeneration in the cerebellum. As a result, most of studies have focused on the role of RORalpha in the development of the cerebellum. Recent studies have expanded the role of RORalpha to other structures and functions in the brain. RORalpha was considered to be exclusively expressed in neurons in the brain. Recently, it has been shown that, in addition to its neuronal expression, RORalpha is expressed in glial cells and particularly in astrocytes in different brain regions. Moreover, RORalpha has been implicated in the regulation of some astrocyte functions such as the inflammatory function. Several reports have also presented evidence for a role of RORalpha in diverse pathological processes including oxidative stress-induced apoptosis and cerebral hypoxia. This review therefore focuses on the emerging roles of RORalpha in the brain and particularly in astrocytes. PMID- 22223134 TI - Auxiliary ligand-directed structural variation from 2D->3D polythreaded net to 3 fold interpenetrating 3D pillar-layered framework: syntheses, crystal structures and magnetic properties. AB - By auxiliary N-donor ligand-directed assembled, two entangled Co(II)-coordination nets have been constructed from 3,3',5,5'-azobenzenetetracarboxylic acid (H(4)abtc), which present a rare 2D->3D polythreading motif constructed from 2 fold (6,3) polymeric layers with thickness being 10.2 A and a 3-fold interpenetrating pillar-layered framework based on linear trinuclear Co(II)-SBUs. In addition, two Co(II)-complexes both show an antiferromagnetic coupling by long organic spacers and H(2)O bridges, respectively. PMID- 22223135 TI - Attitudes and preferences toward the provision of medication abortion in an urban academic internal medicine practice. AB - BACKGROUND: Mifepristone offers internal medicine doctors the opportunity to greatly expand access to abortion for their patients. Almost 70% of pregnancy terminations, however, still occur in specialized clinics. No studies have examined the preferences of Internal Medicine patients specifically. OBJECTIVE: Determine whether patient preference is a reason for the limited uptake of medication abortion among internal medicine physicians. PARTICIPANTS: Women aged 18-45 recruited from the waiting room in an urban academic internal medicine clinic. MEASURES: A semi-structured questionnaire was used to determine risk of unintended pregnancy and attitudes toward abortion. Support for provision of medication abortion in the internal medicine clinic was assessed with a yes/no question, followed by the open-ended question, "Why do you think this clinic should or should not offer medication abortion?" Subjects were asked whether it was very important, somewhat important, or not important for the internal medicine clinic to provide medication abortion. KEY RESULTS: Of 102 women who met inclusion criteria, 90 completed the survey, yielding a response rate of 88%. Twenty-two percent were at risk of unintended pregnancy. 46.7% had had at least one lifetime abortion. Among those who would consider having an abortion, 67.7% responded yes to the question, "Do you think this clinic should offer medication abortions?" and 83.9% stated that it was "very important" or "somewhat important" to offer this service. Of women open to having an abortion, 87.1% stated that they would be interested in receiving a medication abortion from their primary care doctor. CONCLUSIONS: A clinically significant proportion of women in this urban internal medicine clinic were at risk of unintended pregnancy. Among those open to having an abortion, a wide majority would consider receiving it from their internal medicine doctor. The provision of medication abortion by internal medicine physicians has the potential to greatly expand abortion access for women. PMID- 22223136 TI - Instruments measuring spirituality in clinical research. PMID- 22223137 TI - Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed. AB - The majority of malignant mesothelioma possesses the wild-type p53 gene with a homologous deletion of the INK4A/ARF locus containing the p14(ARF) and the p16(INK4A) genes. We examined whether forced expression of p53 inhibited growth of mesothelioma cells and produced anti-tumor effects by a combination of cisplatin (CDDP) or pemetrexed (PEM), the first-line drugs for mesothelioma treatments. Transduction of mesothelioma cells with adenoviruses bearing the p53 gene (Ad-p53) induced phosphorylation of p53, upregulated Mdm2 and p21 expression levels and decreased phosphorylation of pRb. The transduction generated cleavage of caspase-8 and -3, but not caspase-9. Cell cycle analysis showed increased G0/G1- or G2/M-phase populations and subsequently sub-G1 fractions, depending on cell types and Ad-p53 doses. Transduction with Ad-p53 suppressed viability of mesothelioma cells and augmented the growth inhibition by CDDP or PEM mostly in a synergistic manner. Intrapleural injection of Ad-p53 and systemic administration of CDDP produced anti-tumor effects in an orthotopic animal model. These data collectively suggest that Ad-p53 is a possible agent for mesothelioma in combination with the first-line chemotherapeutics. PMID- 22223139 TI - Biosensors for diagnostic applications. AB - Biosensors combine a transducer with a biorecognition element and thus are able to transform a biochemical event on the transducer surface directly into a measurable signal. By this they have the potential to provide rapid, real-time, and accurate results in a comparatively easy way, which makes them promising analytical devices. Since the first biosensor was introduced in 1962 as an "enzyme electrode" for monitoring glucose in blood, medical applications have been the main driving force for further biosensor development. In this chapter we outline potential biosensor setups, focusing on transduction principles, biorecognition layers, and biosensor test formats, with regard to potential applications. A summary of relevant aspects concerning biosensor integration in efficient analytical setups is included. We describe the latest applications of biosensors in diagnostic applications focusing on detection of molecular biomarkers in real samples. An overview of the current state and future trends of biosensors in this field is given. PMID- 22223138 TI - Differential targeting of androgen and glucocorticoid receptors induces ER stress and apoptosis in prostate cancer cells: a novel therapeutic modality. AB - Androgen (AR) and glucocorticoid (GR) receptor signaling play opposing roles in prostate tumorigenesis: in prostate, AR acts as an oncogene, and GR is a tumor suppressor. Recently, we found that non-steroidal phyto-chemical Compound A (CpdA) is AR/GR modulator acting as anti-inflammatory anti-androgen. CpdA inhibits AR and prevents GR transactivation while enhancing GR transrepression. GR and AR are controlled by proteasomal degradation. We found that prolonged exposure of LNCaP, LNCaP-GR, DU145 and PC3 prostate carcinoma (PCa) cells to proteasome inhibitor Bortezomib (BZ) caused AR degradation and GR accumulation. BZ enhanced CpdA ability to inhibit AR and to augment GR transrepression. We also found that CpdA+BZ differentially regulated GR/AR to cooperatively suppress PCa cell growth and survival and to induce endoplasmic reticulum stress (ERS). Importantly, CpdA+BZ differentially regulated GR-responsive genes. CpdA+BZ blocked activation of glucocorticoid-responsive pro-survival genes, including SGK1, but activated BZ-induced ERS-related genes BIP/HSPA5 and CHOP /GADD153. Using ChIP, we showed that SGK1, BIP/HSPA5 and CHOP regulation was due to effects of CpdA and CpdA+BZ on GR loading on their promoters. We also found that AR and GR are abundant in advanced PCa from patients treated by androgen ablation and/or chemotherapy: 56% of carcinomas from treated patients expressed both receptors, and the other 27% expressed either GR or AR. Overall, our data validate the concept of dual AR/GR targeting in prostate cancer (PC) and suggest that BZ combination with dual-target steroid receptor modulator CpdA has high potential for PC therapy. PMID- 22223140 TI - Resonance Rayleigh scattering spectra of Cu2+-adenine-WO4(2-) system and its analytical application. AB - In pH 6.6-7.2 Tris-HCl buffer, Cu(2+) could react with adenine (A) to form a 1:1 coordination cation [CuA](2+), which only resulted in minor change of the absorption spectrum. However, when this cation further combined with WO(4)(2-) to form a 1:1 ternary ion-association complex [CuA]WO(4), the absorption spectrum changed a lot, and the resonance Rayleigh scattering (RRS), second-order scattering (SOS) and frequency doubling scattering (FDS) enhanced significantly. The maximum wavelengths of RRS, SOS and FDS were located at 310, 592 and 395 nm, respectively. The enhanced intensities of the three methods were proportional to the concentration of adenine in certain ranges, and the detection limit of the most sensitive RRS method was 7.4 * 10(-9) mol L(-1) (1.0 ng mL(-1)), indicating that this method could detect trace adenine. In this work, the optimum reaction conditions and the influencing factors have been studied, some potential interferences and the composition of the ion-association complex have been investigated. Meanwhile, the construction of the product and the reaction mechanism have been investigated by atomic force microscopy, transmission electron microscope and quantum chemical calculation. Accordingly, a novel RRS method for determination of adenine has been proposed and applied to detect adenine in real samples with satisfactory results. PMID- 22223142 TI - Deficient expression of genes involved in the endogenous defense system against transposons in cryptorchid boys with impaired mini-puberty. AB - Mini-puberty is the period between 30 and 80 days after birth when testosterone and gonadotropin surges occur in male infants to induce the transformation of gonocytes into adult/dark spermatogonia. Cryptorchid boys with impaired mini puberty develop infertility despite timely and successful surgical treatment. The decreased germ cell count found in this group of boys could be the result of uncontrolled transposon activity inducing genomic instability and germ cell death. A genome-wide analysis of 18 cryptorchid and 4 control testes was performed with Affymetrix chips. We found that 5 of 8 genes that are important for transposon silencing were not expressed in the high azoospermia risk group of cryptorchid boys but were expressed in the low azoospermia risk and control groups. Two genes, CBX3 and DNMT1, were equally expressed in all 3 groups. Impaired expression of the DDX4, MAEL,MOV10L1, PIWIL2, PIWIL4, and TDRD9 genes in the group of cryptorchid boys at high risk of infertility indicates that gene instability induced by impaired expression of transposon silencing genes contribute to the development of azoospermia. Intact mini-puberty appears to be essential for the development of the endogenous defense system mediated by transposon silencing. PMID- 22223141 TI - Plasma and urinary levels of cytokines in patients with idiopathic hypercalciuria. AB - BACKGROUND: Recent studies suggest that cytokines modulate bone turnover. Idiopathic hypercalciuria (IH) seems to be associated with bone mineral loss. Therefore, the aim of this study was to assess cytokines involved in bone turnover in patients with IH. METHODS: Plasma and spot-urine levels of interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta1 (TGF-beta1), and monocyte chemoattractant protein (MCP-1) were measured in 70 children and adolescents with IH and in 37 healthy controls. Patients with IH were subdivided according to their calciuria at the time of sample collection: >=4 mg/kg/day (persistent IH, n=27) and below 4 mg/kg/day (controlled IH, n=43). Cytokines were determined by enzyme-linked immunoassay. RESULTS: Plasma and urinary concentrations of IL-1beta, IL-6, IL-8, and TNF-alpha were undetectable in all groups. No differences were found between controlled and persistent hypercalciuria for plasma and urinary levels of MCP-1 and TGF-beta1. On the other hand, MCP-1 levels were significantly higher in both subgroups of IH in comparison to healthy controls. Furthermore, urinary MCP-1 levels of IH patients correlated positively with bone mineral content (p=0.013). CONCLUSION: Although cytokine measurements did not allow the differentiation between persistent and controlled IH, our findings suggest that MCP-1 might play a role in patients with IH. PMID- 22223143 TI - Investigation into the antioxidant activity and chemical composition of alcoholic extracts from defatted marigold (Tagetes erecta L.) residue. AB - The influence of various solvents on the yield of polyphenols from defatted marigold residue, the antioxidant activity of the extracts and the composition of antioxidant compounds in the extracts were investigated. The content of total phenolics and flavonoids in the extracts was significantly varied with different solvents (P<0.05) and the extract by ethyl alcohol (EtOH)/water (7:3, v/v) has the highest content of total phenolics and flavonoids, 62.33 mg gallic acid equivalents (GAE)/g and 97.00 mg rutin equivalent (RE)/g, respectively. The antioxidant activity of the extracts was evaluated by radical (2,2'-azino-bis-(3 ethylbenzothiazoline-6-sulfonic acid) (ABTS), 1,1-diphenyl-2-picrylhydrazyl (DPPH)) scavenging and ferric reducing antioxidant power (FRAP) assays. The results of the correlation analysis showed that the antioxidant activity was well correlated with the content of total phenolics and flavonoids (R2>0.900). Antioxidant components in the extracts were identified by combined on-line HPLC ABTS.+ post-column assay and HPLC-DAD-MS method. Gallic acid, gallicin, quercetagetin, 6-hydroxykaempferol-O-hexoside, patuletin-O-hexoside and quercetin were the dominant antioxidant compounds in the extracts, and quercetagetin was identified as the strongest antioxidant capacity. PMID- 22223144 TI - Do medically unexplained somatic symptoms predict depression in older Chinese? AB - OBJECTIVE: To identify the pattern of somatic presentation of depression among older Chinese by examining the association between medically unexplained somatic symptoms and depression. SUBJECTS: The population comprised 1433 Chinese 65 years or older recruited from 11 older community centres distributed across the three main territory regions of Hong Kong. METHOD: Data were collected between January and December 2008, with a response rate of 72.3%. Data on socio-demographic background, medical profile and somatic symptoms were collected. The Mental Health Inventory (five-item) was used for depression screening. Medically unexplained somatic symptoms were defined as those not explained by any known medical pathology. RESULTS: The prevalence of depression among older Chinese was 16.5%. They reported more frequently than did the non-depressed six medically unexplained somatic symptoms. After being adjusted for age, living arrangements, social support, financial strain, major stressful life events and chronic illness, depression was found to be significantly associated with all medically unexplained somatic symptoms (odds ratio: 1.667-2.268). Indeed, depressed older people were more likely to have multiple symptoms than were the non-depressed, the odds ratio increasing from 2.64 (95%CI: 1.884-3.717) for two co-existing symptoms to 4.521 (95%CI: 1.872-10.917) for six symptoms. CONCLUSION: Older Chinese with depression were more likely to have multiple medically unexplained somatic symptoms, particularly fatigue, insomnia, loss of appetite and gastro intestinal problems. Health care professionals need to be aware of this pattern of somatization and take active steps to rule out any underlying psychological etiology. PMID- 22223145 TI - Neuropsychological screening performance and the association with activities of daily living and instrumental activities of daily living in dementia: baseline and 18- to 24-month follow-up. AB - OBJECTIVE: The use of neuropsychological assessment beyond diagnosis is related partly to the extent to which it can indicate everyday function. This study investigates whether the associations between neuropsychological functioning, activities of daily living (ADL) and instrumental activities of daily living (IADL) change over an 18- to 24-month follow-up, exploring whether these change with dementia progression. METHOD: Thirty-four patients with probable Alzheimer's disease were assessed at baseline and again after between 18 and 24 months. Neuropsychological function was assessed using the revised Cambridge Cognitive Examination, which includes in it the Mini mental state examination and an executive functions scale. ADL and IADL were also measured, together with background neuropsychiatric features by using the Neuropsychiatric Inventory. RESULTS: Pearson correlations between the measures of daily functioning and cognitive abilities and neuropsychiatric symptoms showed that initially neuropsychological test results tended to correlate with IADL rather than ADL measures. Neuropsychiatric symptoms were not correlated whether IADL or ADL. At follow-up, none of the neuropsychological function measures correlated with IADL or ADL, but neuropsychiatric symptoms were correlated with IADL. CONCLUSIONS: At baseline, neuropsychological function is associated with IADL but not ADL. At follow-up, the association between neuropsychological function and IADL diminishes, and associations between neuropsychiatric disturbances and IADL emerge. PMID- 22223146 TI - Telephone calls provide effective support for most caregivers of patients with dementia but not for all. PMID- 22223147 TI - Neural correlates of reward processing in late-life depression. PMID- 22223148 TI - Photoelectrochemical hydrogen generation by an [FeFe] hydrogenase active site mimic at a p-type silicon/molecular electrocatalyst junction. PMID- 22223149 TI - C-reactive protein induces interleukin-6 and thrombospondin-1 protein and mRNA expression through activation of nuclear factor-KB in HK-2 cells. AB - BACKGROUND: Although C-reactive protein (CRP) is significantly increased in patients with diabetic nephropathy, whether CRP exerts direct proinflammatory effects on human renal tubular epithelial cells (HK-2 cells) is still unclear. METHODS: HK-2 cells were incubated with purified CRP at clinically relevant concentrations (0, 5, 10, 20 and 40 MUg/ml). The protein and transcript levels of thrombospondin-1 (TSP-1) and interleukin-6 (IL-6) were determined by ELISA and RT PCR. Phosphorylation of p38MAPK was investigated through Western blot analysis in HK-2 cells induced by CRP. The activation of nuclear factor-kappa B (NF-kappaB) was studied via EMSA. A specific p38MAPK inhibitor (SB203580) and an NF-kappaB inhibitor (PDTC; pyrrolidine dithiocarbamate) were used to analyze the signal transduction in CRP induction. To explore the direct or indirect role of CRP in HK-2 cells, IL-6 or TSP-1 antibodies were used. The expression of IL-6, TSP-1 and transforming growth factor-beta(1 )(TGF-beta(1)) were determined through Western blot analysis in HK-2 cells. RESULTS: In HK-2 cells, purified CRP significantly induced protein release and mRNA expression of IL-6 and TSP-1 in a dose- and time dependent manner. TGF-beta(1) protein was overexpressed in HK-2 cells induced by CRP, which cannot be inhibited by IL-6 or TSP-1 antibodies. CRP triggered phosphorylation of p38MAPK and activation of NF-kappaB-mediated signal transduction. SB203580 (5 MUM) and PDTC (50 MUM) efficiently suppressed those effects of CRP in HK-2 cells. CONCLUSIONS: CRP induces IL-6 and TSP-1 protein release and mRNA expression from HK-2 cells via activation of the p38MAPK and NF kappaB signaling pathways and TGF-beta(1) was highly expressed in HK-2 cells, suggesting that CRP plays an important role in the propagation and prolongation of inflammation in renal fibrosis. PMID- 22223150 TI - Nanoarchitectonics: pioneering a new paradigm for nanotechnology in materials development. PMID- 22223151 TI - A plea for science. PMID- 22223152 TI - For young architects of the nanoscale world. PMID- 22223156 TI - Mechanisms of the cascade synthesis of substituted 4-amino-1,2,4-triazol-3-one from Huisgen zwitterion and aldehyde hydrazone: a DFT study. AB - The detailed reaction mechanisms of the title reaction are shed light on by using the density functional theory (DFT). The calculated results have demonstrated that the whole reaction takes place via four processes (processes (I-IV)), among which, three possible reaction mechanisms are proposed for process (II) (channels 1-3) and two for process (IV) (channels 4-5). According to our calculated results, channel 3 and channel 5 are verified to be most energetically favorable. As interpreted in the text, in process (II), the proton transfer should be performed prior to the nucleophilic attack, and the AA-Type transfer strategy is more likely to occur. The global reactivity index (GRI) and frontier molecular orbital (FMO) analyses of the aldehyde hydrazone have further supported the AA Type mechanism. In process (IV), however, the titled product has been demonstrated to be formed by the synergetic elimination of two protons via a six membered ring transition state. Taking an integrated view, the highest energy barrier for the whole reaction along the most favorable pathway is 32.19 kcal/mol, which is consistent with the mild thermal experimental conditions. More interestingly, the qualified mechanisms in this work have given a perfect explanation to the optimal reactants molar ratio of highest yields (R1/R2/R3 = 2/1/1) employed in the experiment. PMID- 22223157 TI - Influence of image metrics when assessing image quality from a test object in cardiac X-ray systems: Part II. AB - The images generated in modern IC laboratories are created with high-quality standard (1,024*1,024 pixels and 10-12 bits/pixel) enabling cardiologists to perform interventions in the best conditions. But these images are in most of the cases archived in a basic quality standard (512*512 pixels and 8 bits/pixel). The purpose of this work is to complete the research developed in a previous paper and analyze the influence of the matrix size and the bit depth reduction on the image quality acquired on a polymethylmethacrylate (PMMA) phantom with a test object. The variation in contrast-to-noise ratio (CNR) and high contrast spatial resolution (HCSR) were investigated when the matrix size and the bit depth were independently modified for different phantom thicknesses. These two image quality parameters did not suffer noticeable alterations under bits depth reduction from 10 to 8 bits. Such a result seems to imply that bits depth reduction could be used to reduce file sizes with a suitable algorithm and without losing perceptible image quality information. But when the matrix size was reduced from 1,024*1,024 to 512*512 pixels, a reduction from 17% to 25% in HCSR was noticed when changing phantom thickness, and an increase of 27% in CNR was observed. These findings should be taken into account and it would be wise to conduct further investigations in the field of clinical images. PMID- 22223158 TI - EMR management system for patient pulse data. AB - The purpose of this study is to build an integrated medical information system for effective database management of clinical information and to improve the existing Electronic Medical Record (EMR)-based system that is currently being used in hospitals. The integrated medical information system of hospitals consists of an Order Communication System (OCS), Picture Archiving Communication System (PACS), and Laboratory Information System (LIS), as well as Electronic Medical Record (EMR). It is designed so that remote health screening and patient data search can be accessed through a high speed network-even in remote areas-in order to effectively manage data on medical treatment that patients received at their respective hospitals. The existing oriental treatment system is one in which the doctor requires the patient to visit the hospital in person, so as to be able to check the patient's pulse and measure it with his hand for proper diagnosis and treatment. However, due to the recent development of digitalized medical measurement equipment, not only can doctors now check a patient's pulse without touching it directly, but the measured data are computerized and stored into the database as the electronic obligation record. Thus, even if a patient cannot visit the hospital, proper medical treatment is available by analyzing the patient's medical history and diagnosis process in the remote area. Furthermore, when a comprehensive medical testing center system including the people medical examination and diverse physical examination is established, the quality of medical service is expected to be improved than now. PMID- 22223159 TI - Site selectivity and reversibility in the reactions of titanium hydrazides with Si-H, Si-X, C-X and H+ reagents: Ti=N(alpha) 1,2-silane addition, Nbeta alkylation, Nalpha protonation and sigma-bond metathesis. AB - We report a combined experimental and computational comparative study of the reactions of the homologous titanium dialkyl- and diphenylhydrazido and imido compounds Cp*Ti{MeC(N(i)Pr)(2)}(NNR(2)) (R = Me (1) or Ph (2)) and Cp*Ti{MeC(N(i)Pr)(2)}(NTol) (3) with silanes, halosilanes, alkyl halides and [Et(3)NH][BPh(4)]. Compound 1 underwent reversible Si-H 1,2-addition to Ti=N(alpha) with RSiH(3) (experimental DeltaH ca. -17 kcal mol(-1)), and irreversible addition with PhSiH(2)X (X = Cl, Br). DFT found that the reaction products and certain intermediates were stabilised by beta-NMe(2) coordination to titanium. The Ti-D bond in Cp*Ti{MeC(N(i)Pr)(2)}(D){N(NMe(2))SiD(2)Ph} underwent sigma-bond metathesis with BuSiH(3) and H(2). Compound 1 reacted with RR'SiCl(2) at N(alpha) to transfer both Cl atoms to Ti; 2 underwent a similar reaction. Compound 3 did not react with RSiH(3) or alkyl halides but formed unstable Ti=N(alpha) 1,2-addition or N(alpha) protonation products with PhSiH(2)X or [Et(3)NH][BPh(4)]. Compound 1 underwent exclusive alkylation at N(beta) with RCH(2)X (R = H, Me or Ph; X = Br or I) whereas protonation using [Et(3)NH][BPh(4)] occurred at N(alpha). DFT studies found that in all cases electrophile addition to N(alpha) (with or without NMe(2) chelation) was thermodynamically favoured compared to addition to N(beta). PMID- 22223161 TI - Corneal endothelial characteristics and central corneal thickness in a population of Turkish cataract patients. AB - OBJECTIVES: The aim was to assess corneal endothelial characteristics and central corneal thickness (CCT) in a population of Turkish cataract patients and to define the impact of age and gender on these parameters. METHODS: Five hundred and seventeen cataract patients were examined with noncontact specular microscope preoperatively. The eye planned to be operated was selected for analysis. The parameters measured were endothelial cell density (ECD), cell area (CA), coefficient of variation (CV) of the CA, percentage of hexagonal cells (PHCs), and CCT. RESULTS: The mean values in ECD, CA, CV, PHC, and CCT in all eyes were 2,258 +/- 474 cells per square millimeter, 468 +/- 130 MUm(2), 39%+/-7%, 49%+/ 12%, and 500 +/- 37 MUm, respectively. Regression analysis revealed a statistically significant decrease in ECD (R=-0.169, P<0.0001), increase in CA (R=0.186, P<0.0001), and decrease in the CCT (R=-0.122, P=0.006) with increase in age. The changes in the CV (R=0.008, P=0.861) and PHC (R=-0,060, P=0.177) were not found to be dependent on age. The parameters showed no sex differences. The number of eyes with ECD below 1,000 and 2,000 cells per square millimeter was 5 (0.97%) and 130 (25.1%), respectively. CONCLUSIONS: The data from our study emphasize that age, but not gender, is the main determinant of ECD. PMID- 22223160 TI - Repeated measurements of the anterior segment during accommodation using long scan depth optical coherence tomography. AB - OBJECTIVES: The aim was to determine the repeatability of ultralong scan depth spectral-domain optical coherence tomography (SD-OCT) measurements of the ocular anterior segment during accommodation. METHODS: The center wavelength of the SD OCT light source was 840 nm with a bandwidth of 50 nm. The ocular axial resolution of the system was approximately 6.0 MUm, and the scan depth was 7.2 mm in air. Twenty eyes of 20 healthy subjects were imaged with a custom-built, ultralong scan depth SD-OCT during 2 visits. The anterior segment images were acquired during nonaccommodative and maximal accommodative states. After image processing and correction, the true values of the morphometric dimensions of the anterior eye were obtained. The variables of the two states from two visits were compared. RESULTS: For the corrected anterior segment images, the variables did not significantly differ from one visit to the next. The values of anterior chamber depth, pupil diameter, and the radius of the lens anterior surface curvature during accommodation were significantly smaller than those during the nonaccommodative state. The lens thickness significantly increased with accommodation. There was no significant difference in the posterior surface curvature of the lens between the two states. CONCLUSIONS: Ultralong scan depth SD-OCT holds promise for quantifying dimensional changes in the eye during accommodation. The instrument demonstrated good repeatability of ocular anterior segment dimensional measurements during accommodation. PMID- 22223162 TI - A rare polymicrobial keratitis involving Chryseobacterium meningosepticum and Delftia acidovorans in a cosmetic contact lens wearer. AB - OBJECTIVE: To report an unusual case of keratitis in a cosmetic contact lens wearer caused by two rare organisms. METHOD: Case report. RESULTS: A 14-year-old cosmetic contact lens user presented with a paracentral corneal ulcer in her right eye. The cosmetic lenses were bought online. The cultures from corneal scrapings and contact lenses demonstrated heavy growth of Chryseobacterium meningosepticum and Delftia acidovorans. The treatment with topical ciprofloxacin and fortified gentamicin was effective, and the infection resolved with corneal scar after 5 weeks. CONCLUSION: Use of cosmetic contact lenses and buying them online is a fairly common practice among teenagers. This can lead to serious eye infection as in this case. To our knowledge, this is the first report of contact lens-related keratitis simultaneously involving these two rare organisms. PMID- 22223163 TI - Variations in the anatomy of the posterior auricular nerve and its potential as a landmark for identification of the facial nerve trunk: a cadaveric study. AB - The posterior auricular nerve (PAN) is the first extracranial branch of the facial nerve trunk. It innervates the posterior belly of the occipitofrontalis and the auricular muscles and contributes cutaneous sensation from the skin covering the mastoid process and parts of the auricle. This study was carried out to provide a detailed account of its anatomy and to ascertain its reliability as a surgical landmark for the facial nerve. Eleven facial sides from six formalin fixed cadavers were dissected. The course and arborisation pattern of the PAN was observed, and its position of emergence from the facial nerve trunk (FNT) was measured. The PAN arose from the posterolateral aspect of the FNT 1.6-11.1 mm from the stylomastoid foramen (5.4 +/- 3.3 mm). It arose as a single branch (45.4%), or from a common trunk that divided into two (36.4%) or three branches (18.2%), with the other branches passing into the parotid gland. The PAN continued deep (63%), or lateral to the mastoid process (9.1%), or through the tissue of the parotid gland (27.3%). In all cases the PAN ran in a consistent, superficial location posterior to the external auditory meatus. The PAN takes a variable course; however, its consistent location behind the external auditory meatus makes it easily identifiable in superficial dissection, and therefore a potential surgical landmark for identifying the FNT. PMID- 22223164 TI - The functional role of stress proteins in ER stress mediated cell death. AB - The endoplasmic reticulum (ER) is an intracellular organelle involved in biosynthesis and the secretory pathway. This organelle has many resident proteins including biosynthetic enzymes and secretory proteins. Recent studies have suggested that dysfunction of the ER or secretory pathway is involved in the pathogenesis of various human diseases. Some stresses acting on the ER, which are designated ER stress, induce the accumulation of unfolded/misfolded proteins in the ER, leading to cell death. Misfolded proteins are retained until they form their native conformation or returned to the cytosol for degradation by the proteasome. Among the ER-resident proteins, molecular chaperones prevent aggregation of proteins within the ER, and orchestrate the ER quality control systems. We have reported the roles of novel stress proteins, namely 150-kDa oxygen-regulated protein, 94-kDa glucose-regulated protein and RA410. These proteins are induced significantly by hypoxia or oxidative stress and have cytoprotective effects under these conditions. These findings suggest that hypoxia and oxidative stress target the ER and secretory pathway, resulting in ER stress, and that these proteins exert cytoprotective effects in various diseases associated with ER stress. PMID- 22223165 TI - Congenital radial head dislocation with a progressive cubitus valgus: a case report. AB - Congenital dislocation of the radial head is rare, although it is the most common congenital anomaly of the elbow. A concomitant progressive cubitus valgus of the elbow has not previously been described in literature. We describe a case of an 8 year-old girl with an unilateral congenital radial head dislocation with a progressive cubitus valgus of 35 degrees , caused by a prematurely closing physis of the lateral humeral condyle. This might be caused by an increased pressure on the lateral physis by the anteriorly dislocated radial head. As no complaints or limitations were present, treatment was non-operative with clinical observation, with satisfactory results after a follow-up of 18 months. A concomitant progressive cubitus valgus can be present in patients with a congenital radial head dislocation. Non-operative treatment can provide satisfactory results. PMID- 22223166 TI - Synergistic inhibition of hepatocellular carcinoma growth by cotargeting chromatin modifying enzymes and poly (ADP-ribose) polymerases. AB - Hepatocellular carcinoma (HCC) is a particularly lethal form of cancer, yet effective therapeutic options for advanced HCC are limited. The poly(ADP-ribose) polymerases (PARPs) and histone deacetylases (HDACs) are emerging to be among the most promising targets in cancer therapy, and sensitivity to PARP inhibition depends on homologous recombination (HR) deficiency and inhibition of HDAC activity blocks the HR pathway. Here, we tested the hypothesis that cotargeting both enzymatic activities could synergistically inhibit HCC growth and defined the molecular determinants of sensitivity to both enzyme inhibitors. We discovered that HCC cells have differential sensitivity to the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and PARP inhibitor olaparib, and identified one pair of cell lines, termed SNU-398 and SNU-449, with sensitive versus resistant phenotype to both enzyme inhibitors, respectively. Coadministration of SAHA and olaparib synergistically inhibited the growth of SNU 398 but not SNU-449 cells, which was associated with increased apoptosis and accumulated unrepaired DNA damage. Multiple lines of evidence demonstrate that the hepatic fibrosis/hepatic stellate cell activation may be an important genetic determinant of cellular sensitivity to both enzymatic inhibitors, and coordinate activation or inactivation of the aryl hydrocarbon receptor (AhR) and cyclic adenosine monophosphate (cAMP)-mediated signaling pathways are involved in cell response to SAHA and olaparib treatment. CONCLUSION: These findings suggest that combination therapy with both enzyme inhibitors may be a strategy for therapy of sensitive HCC cells, and identification of these novel molecular determinants may eventually guide the optimal use of PARP and HDAC inhibitors in the clinic. PMID- 22223167 TI - Enzymatic total synthesis of defucogilvocarcin M and its implications for gilvocarcin biosynthesis. PMID- 22223168 TI - The reliability of glomerular filtration rate measured from plasma clearance: a multi-centre study of 1,878 healthy potential renal transplant donors. AB - PURPOSE: The objective of the study was to undertake a clinical audit of departmental performance in the measurement of glomerular filtration rate (GFR) using the coefficient of variation (CV) of extracellular fluid volume (ECFV) as the benchmark. ECFV is held within narrow limits in healthy subjects, narrower than GFR, and should therefore have a low CV. METHODS: Fifteen departments participated in this retrospective study of healthy renal transplant donors. Data were analysed separately for men (n ranged from 28 to 115 per centre; total = 819) and women (n = 28-146; 1,059). All centres used the slope-intercept method with blood sample numbers ranging from two to five. Subjects did not fast prior to GFR measurement. GFR was scaled to body surface area (BSA) and corrected for the single compartment assumption. GFR scaled to ECFV was calculated as the terminal slope rate constant and corrected for the single compartment assumption. ECFV/BSA was calculated as the ratio of GFR/BSA to GFR/ECFV. RESULTS: The departmental CVs of ECFV/BSA and GFR/BSA ranged from 8.3 to 25.8% and 12.8 to 21.9%, respectively, in men, and from 9.6 to 21.1% and 14.8 to 23.7%, respectively, in women. Both CVs correlated strongly between men and women from the same centre, suggesting department-specific systematic errors. GFR/BSA was higher in men in 14 of 15 centres, whereas GFR/ECFV was higher in women in 14 of 15 centres. Both correlated strongly between men and women, suggesting regional variation in GFR. CONCLUSION: The CV of ECFV/BSA in normal subjects is a useful indicator of the technical robustness with which GFR is measured and, in this study, indicated a wide variation in departmental performance. PMID- 22223170 TI - [Generalized erythrosquamous dermatosis]. AB - A 21-year-old man presented with generalized erythema, erosions and hyperkeratoses since birth. Histology revealed epidermolytic hyperkeratosis with degeneration of the upper epidermis and perinuclear deposits of abnormal keratin aggregations. Epidermolytic ichthyosis was diagnosed. This congenital Ichthyosis occurs due to mutations of keratin 1 or 10 genes that leads to defects of intra- and intercellular structural integrity in the spinous and granular layers with compensatory hyperkeratosis. After childhood, life expectancy is normal but lifelong therapeutic and skin care measures are required. PMID- 22223169 TI - Comparison of 18F-DOPA, 18F-FDG and 68Ga-somatostatin analogue PET/CT in patients with recurrent medullary thyroid carcinoma. AB - PURPOSE: To retrospectively evaluate and compare (18)F-FDG, (18)F-DOPA and (68)Ga somatostatin analogues for PET/CT in patients with residual/recurrent medullary thyroid carcinoma (MTC) suspected on the basis of elevated serum calcitonin levels. METHODS: Included in the study were 18 patients with recurrent MTC in whom functional imaging with the three tracers was performed. The PET/CT results were compared on a per-patient basis and on a per-lesion-basis. RESULTS: At least one focus of abnormal uptake was observed on PET/CT in 13 patients with (18)F DOPA (72.2% sensitivity), in 6 patients with (68)Ga-somatostatin analogues (33.3%) and in 3 patients with (18)F-FDG (16.7%) (p < 0.01). There was a statistically significant difference in sensitivity between (18)F-DOPA and (18)F FDG PET/CT (p < 0.01) and between (18)F-DOPA and (68)Ga-somatostatin analogue PET/CT (p = 0.04). Overall, 72 lesions were identified on PET/CT with the three tracers. (18)F-DOPA PET/CT detected 85% of lesions (61 of 72), (68)Ga somatostatin analogue PET/CT 20% (14 of 72) and (18)F-FDG PET/CT 28% (20 of 72). There was a statistically significant difference in the number of lymph node, liver and bone lesions detected with the three tracers (p < 0.01). In particular, post-hoc tests showed a significant difference in the number of lymph node, liver and bone lesions detected by (18)F-DOPA PET/CT and (18)F-FDG PET/CT (p < 0.01 for all the analyses) and by (18)F-DOPA PET/CT and (68)Ga-somatostatin analogue PET/CT (p < 0.01 for all the analyses). The PET/CT results led to a change in management of eight patients (44%). CONCLUSION: (18)F-DOPA PET/CT seems to be the most useful imaging method for detecting recurrent MTC lesions in patients with elevated serum calcitonin levels, performing better than (18)F-FDG and (68)Ga somatostatin analogue PET/CT. (18)F-FDG may complement (18)F-DOPA in patients with an aggressive tumour. PMID- 22223171 TI - A new reducing polyketide synthase gene from the lichen-forming fungus Cladonia metacorallifera. AB - Lichens produce unique polyketide secondary metabolites including depsides, depsidones, dibenzofurans and depsones. The biosynthesis of these compounds is governed by polyketide synthase (PKS), but the mechanism via which they are produced has remained unclear until now. We reported the 6-methylsalicylic acid synthase (6-MSAS) type of PKS gene, which is a member of the fungal-reducing PKSs. A cultured mycobiont of Cladonia metacorallifera was employed in the isolation and characterization of a polyketide synthase gene (CmPKS1). The complete sequence information for CmPKS1 was acquired via the screening of a Fosmid genomic library with a 456 bp fragment corresponding to part of the acyl transferase (AT) domain as a probe. CmPKS1 contains beta-ketoacyl synthase (KS), AT, dehydratase (DH), ketoreductase (KR) and phosphopantetheine attachment site (PP) domains.: The domain organization of CmPKS1 (KS-AT-DH-KR-PP) is a typical 6 MSAS-type PKS, and the results of phylogenetic analysis showed that CmPKS1 grouped with other fungal-reducing PKSs. Quantitative real time PCR analyses showed that CmPKS1 was expressed preferentially in the early growth stage of the axenically cultured mycobiont. Furthermore CmPKS1 expression was found to be dependent on the carbon sources and concentrations in the medium. PMID- 22223172 TI - Annulatascus aquatorba sp. nov., a lignicolous freshwater ascomycete from Sirindhorn Peat Swamp Forest, Narathiwat, Thailand. AB - As part of a long term study of fungi colonizing submerged wood in freshwater streams a new Annulatascus species, A. aquatorba, is described and illustrated from Erythrophleum teysmannii test blocks from Sirindhorn Peat Swamp Forest, southern Thailand. It differs from other species in the genus in ascospore measurements, thickness of the cell wall, 1-3-septate, fusoid to lunate shape, with central brown cells and subhyaline end cells and without a mucilaginous sheath. Asci are cylindrical, pedicellate, with a distinct, wedge-shaped and non amyloid apical ring. Phylogenetic relationships of this species, based on the combined partial 18S and 28S rDNA, place it in the same clade as A. velatisporus (type species), A. hongkongensis and A. nilensis. PMID- 22223173 TI - Rust fungi on Annonaceae II: the genus Dasyspora Berk. & M.A. Curtis. AB - Dasyspora gregaria, the single species of the allegedly monotypic rust genus Dasyspora (Basidiomycota, Pucciniales), was investigated by light microscopy and DNA sequencing (ITS1-5.8S-ITS2 region, partial LSU and SSU of the nuclear rDNA, mt cytochrome oxidase subunit 3). Both methods indicated that D. gregaria is not a single species but can be split in 11 distinct taxa, each of which appear confined to a single Xylopia species (Annonaceae) host. Herein nine of these are described as new. Both the phylogenetic analyses and morphology show that the species are grouped into two main clades designated Dasyspora gregaria and D. winteri. The first comprises D. gregaria, the type species of the genus, which is restricted to X. cayennensis, two new species on X. aromatica, D. segregaria from northern South America and D. echinata from Brazil. The second clade is formed by D. winteri, recombined from Puccinia winteri on X. sericea, and the new species D. amazonica on X. amazonica, D. emarginatae on X. emarginata, D. frutescentis on X. frutescens, D. ferrugineae on X. frutescens var. ferruginea, D. guianensis on X. benthamii, D. mesoamericana on X. frutescens, and D. nitidae on X. nitida. Dasyspora frutescentis and D. mesoamericana were not clearly distinguishable by their morphology and host associations but differed from another in their sequences and geographic distributions. They are considered cryptic species. An identification key and the distributions are given for all recognized species. Along with molecular data we discuss the systematic position of Dasyspora in the Pucciniales. PMID- 22223174 TI - Glomerella truncata: another Glomerella species with an atypical mating system. AB - In the genus Glomerella all species studied to date do not fit the usual mating system of heterothallic ascomycetes. This study investigated the mating system of G. truncata (anamorph Colletotrichum truncatum), a pathogen responsible for lentil anthracnose. Twenty-two field isolates from the Canadian prairies were crossed in all possible combinations, including selfings. All isolates also were screened for the presence of the MAT1-1 and MAT1-2 idiomorphs by targeting small conserved areas of the MAT genes (the alpha domain and the high mobility group HMG box) with degenerate primers, and a pair of G. truncata-specific HMG primers (CT21HMG) were designed. The results of the classical mating study suggested that G. truncata is heterothallic. Isolates fell into two incompatibility groups, which is consistent with a bipolar mating system but different from what has been described in other Glomerella species. Molecular screening showed that the HMG box used as a marker for the MAT1-2 idiomorph was present in both partners of fertile crosses in G. truncata, unlike in the typical ascomycete system, but as previously described for two other Glomerella species. G. truncata therefore appears to share unusual mating system characteristics with the other Glomerella species studied to date. PMID- 22223175 TI - Head-to-head comparison of transient elastography (TE), real-time tissue elastography (RTE), and acoustic radiation force impulse (ARFI) imaging in the diagnosis of liver fibrosis. AB - BACKGROUND: Real-time tissue elastography (RTE), acoustic radiation force impulse (ARFI) imaging, and transient elastography (TE) are new technologies that are used for liver stiffness evaluation. The aim of this study was to compare these methods in the same population and to determine their diagnostic accuracy in the prediction of liver fibrosis. METHODS: Forty-five consecutive, previously biopsied, patients with chronic liver disease and 27 normal subjects underwent TE, RTE, and ARFI on the right liver lobe. Correlation coefficients between measurements, Metavir fibrosis stage, and histological necro-inflammatory activity (adjusted for fibrosis stage) were evaluated via Spearman's rank order correlation coefficients. Areas under the receiver operating characteristic curve (AUROCs) were calculated to predict each fibrosis stage. RESULTS: Failure or inconsistent results occurred in 12.5% of the attempts at TE, but in none of the attempts at RTE and ARFI. The three methods showed high correlation with fibrosis and poor correlation with necro-inflammatory activity. TE and ARFI exhibited high diagnostic accuracy (AUROCs >=0.9) in diagnosing cirrhosis (F4 Metavir). All three methods presented fair (AUROCs >0.7) to good (AUROCs >0.8) diagnostic accuracy in diagnosing fibrosis (F1-4 Metavir) and significant fibrosis (F2-4 Metavir), with TE showing the best performance (AUROCs were 0.878 for fibrosis and 0.897 for significant fibrosis). CONCLUSIONS: TE and ARFI provide high diagnostic accuracy in the diagnosis of cirrhosis. When feasible, TE may perform better than RTE and ARFI in predicting fibrosis and significant fibrosis, but larger studies are needed. PMID- 22223176 TI - Risk factors of early re-bleeding and mortality in patients with ruptured gastric varices and concomitant hepatocellular carcinoma. AB - BACKGROUND: Most studies of prognostic factors after a variceal hemorrhage have either excluded or only involved a few patients with bleeding from gastric variceal bleeding (GVB) and hepatocellular carcinoma (HCC). We have investigated risk factors for early re-bleeding and mortality in patients with GVB and HCC and attempted to determine the effect of HCC characteristics on portal hypertension related re-bleeding. METHODS: This was a retrospective study of data complied on 109 patients with GVB and concomitant HCC in prospectively collected databases. HCC patients were divided into those with recently developed HCC (rd-HCC; HCC diagnosed within 2 months before or after GVB) and those with previously diagnosed HCC (pd-HCC; HCC diagnosed 2 months before GVB). Predictors for 5-day portal hypertension re-bleeding, 30-day and 5-year mortality were analyzed. RESULTS: The cumulative 5-day re-bleeding rates in the rd-HCC group versus the pd HCC group was 23.5 versus 10.0% (P = 0.019). rd-HCC, a high model for end-stage liver disease (MELD) score (>15), and active bleeding were predictors for 5-day re-bleeding. The cumulative 30-day and 5-year survival for the rd-HCC group versus the pd-HCC group were 76.0 versus 76.5% (P = 0.980) and 16.0 versus 4.7% (P = 0.099), respectively. Advanced tumor stage, high MELD score (>15), and elevated alanine transaminase were predictors of mortality. CONCLUSION: Patients with GVB and concomitant HCC are associated with poor outcomes. Recently developed HCC, a high MELD score, active bleeding, advanced tumor stage, and elevated alanine transaminase are poor prognostic predictors. Apart from pharmacological and endoscopic treatments for GVB, careful investigation of a recently developed HCC in these patients is mandatory. PMID- 22223177 TI - Predictive factors of local recurrence after endoscopic piecemeal mucosal resection. AB - BACKGROUND: Endoscopic piecemeal mucosal resection (EPMR) is a widely accepted treatment for colorectal tumefaction. However, as it is associated with a significant recurrence rate, the technique remains controversial. The purpose of our study was to evaluate the risk factors for the local recurrence of colorectal neoplasms after EPMR. METHODS: The study population of our retrospective evaluation comprised 222 patients who had undergone EPMR from January 2002 to July 2007 and who had had at least 1 surveillance colonoscopy 3-6 months after the initial treatment. RESULTS: Local recurrence was detected in 42 patients (19%) between 6 and 15 months after EPMR. Our multivariate analysis revealed that the resection of 5 or more neoplasm specimens, compared with fewer than 5, was 3 times more likely to result in local recurrence (P = 0.005). No statistically significant correlation of local recurrence with lesion size, location, macroscopic type, or histology was detected. CONCLUSION: The removal of 5 or more neoplasm specimens is an independent risk factor for local recurrence after EPMR. Careful colonoscopic surveillance should be performed after multiple piecemeal resection. PMID- 22223178 TI - Solvent effects of N-nitroso, N-(2-chloroethyl), N',N'-dibenzylsulfamid and its copper(II) and cobalt(II) complexes: fluorescence studies. AB - The structure of N-nitroso, N-(2-chloroethyl), N',N'-dibenzylsulfamid (CENS) was established by X-ray crystallography. The atomic coordinates, factors of isotropic thermal agitation, bond lengths and valence angles were determined. The solvent effects on the electronic absorption and fluorescence spectra of CENS were investigated at room temperature. The effects of solvent polarity and of hydrogen bonding were interpreted by means of linear solvation energy relationships (LSERs). Multiple linear regression analysis indicated that the hydrogen donation properties of the solvent play an important role in determining the position of the absorption maximum, while the classical polarity of the medium is the only dominating parameter in determining the emission maximum and the Stokes' shift. Complexation of the investigated compound by two different transition metal ions was studied. Fluorescence measurements show that fluorescence quenching by cobalt(II) is more important than that by copper(II). This phenomenon can be attributed to good stereo-structural matching between the electronic configuration of the Co(2+) ion and the active site distribution of CENS in aqueous solution. PMID- 22223179 TI - Deuterium incorporation in biomass cell wall components by NMR analysis. AB - A commercially available deuterated kale sample was analyzed for deuterium incorporation by ionic liquid solution (2)H and (1)H nuclear magnetic resonance (NMR). This protocol was found to effectively measure the percent deuterium incorporation at 33%, comparable to the 31% value determined by combustion. The solution NMR technique also suggested by a qualitative analysis that deuterium is preferentially incorporated into the carbohydrate components of the kale sample. PMID- 22223180 TI - Rilonacept (interleukin-1 trap) in the prevention of acute gout flares during initiation of urate-lowering therapy: results of a phase II randomized, double blind, placebo-controlled trial. AB - OBJECTIVE: To evaluate the interleukin-1 inhibitor rilonacept (Interleukin-1 Trap) for prevention of gout flares occurring in the first few months following initiation of urate-lowering therapy. METHODS: In this double-blind study, adult patients with hyperuricemia and gout were randomized to receive rilonacept administered subcutaneously once per week (loading dose 320 mg followed by 160 mg weekly) or placebo, and started on allopurinol (300 mg/day, titrated to serum urate <6 mg/dl). At study visits, physical and laboratory assessments were performed and information on any adverse events was ascertained. RESULTS: Baseline characteristics were similar between the rilonacept and placebo groups (n = 41 and n = 42, respectively). The mean number of gout flares per patient through week 12 (primary efficacy end point) was markedly lower in the rilonacept group than in the placebo group (0.15 [6 flares] versus 0.79 [33 flares]; P = 0.0011). Fewer flares were observed with rilonacept as early as 4 weeks after initiation of treatment (P = 0.007). The proportion of patients experiencing a flare during the 12 weeks was lower in the rilonacept group than in the placebo group (14.6% versus 45.2%; P = 0.0037). No rebound in the flare rate was observed for 6 weeks after discontinuation of rilonacept or placebo at week 16. Adverse events were similar between groups, and no deaths or serious infectious adverse events were reported; the most common adverse events were infections (14.6% and 26.2% of rilonacept- and placebo-treated patients, respectively) and musculoskeletal disorders (14.6% and 21.4%, respectively). A higher percentage of rilonacept-treated patients (98%) compared with placebo-treated patients (79%) completed the primary 12-week evaluation period (P = 0.015). CONCLUSION: The current findings indicate that rilonacept significantly reduces the frequency of gout flares during the initial period of treatment with urate-lowering therapy, with a favorable safety profile. PMID- 22223181 TI - Rapid, comprehensive analysis of the dystrophin transcript by a custom micro fluidic exome array. AB - Duchenne and Becker muscular dystrophies are caused by mutations in the dystrophin gene. Both the enormous size of this gene and heterogeneous set of causative mutations behind these pathologies may hamper and even prevent accurate molecular diagnosis. Often RNA analysis is required not only to identify mutations escaping MLPA/CGH or exon sequencing but also to validate the functional effect of novel variations that may affect the exon composition of the DMD gene. We present the design and experimental validation of a new, simple, and easy-to-use platform we call FluiDMD. This platform is based on the Applied Biosystems 7900HT TaqMan((r)) low-density array technology and is able to define the full-exon composition, profile the dystrophin isoforms present, establish changes in mRNA decay, and potentially identify all deletions/duplications and splicing affecting mutations contemporaneously. Moreover, we demonstrate that this system accurately detects the pathogenic effect of all dystrophin mutations belonging to any category, thereby highlighting the functional validation capacity of this system. The high efficacy and sensitivity of this tool in detecting mutations in the dystrophin transcript can be exploited in a variety of cells/tissues, in particular skin, which is harvested by causing minimum patient discomfort. We therefore propose FluiDMD as a validated diagnostic biomarker for molecular profiling of dystrophinopathies. PMID- 22223182 TI - Does dialysis modality influence the oxidative stress of uremic patients? AB - BACKGROUND/AIMS: Since peritoneal membrane is more compatible and residual renal function better preserved during peritoneal dialysis, we questioned whether the oxidative burden in chronic kidney disease (CKD) is influenced by dialysis modality. METHODS: 49 stable CKD patients, 17 on continuous ambulatory peritoneal dialysis (CAPD), 16 on hemodialysis (HD), and 16 non-dialyzed, and 13 healthy subjects were enrolled. Plasma thiobarbituric acid-reactive substances (TBARS; nmol/g protein), serum total antioxidant activity (TAA), total plasma-free thiols (Pt-SH; MUmol/g protein), albumin and uric acid were measured by spectrophotometry. Serum residual antioxidant activity (RAA) was calculated. RESULTS: TBARS were higher in HD (78.3 +/- 20.3) versus both non-dialyzed (53.1 +/- 27.9, p = 0.007) and CAPD groups (58.3 +/- 19.8, p = 0.008). Pt-SH was reduced in CKD patients, but showed comparable values between dialysis groups. TAA and RAA were similarly increased in HD and CAPD patients than in the other two groups. CONCLUSION: Oxidative stress occurs in all CKD patients and worsens as renal function declines. Lipid peroxidation seems more augmented during chronic HD as compared to CAPD, but the plasma antioxidant status did not differ between the investigated dialysis methods. Therefore, dialysis modality appears to influence lipid peroxidation without changing the extracellular antioxidant defense of CKD patients. PMID- 22223183 TI - Synthesis and photophysical properties of self-assembled metallogels of platinum(II) acetylide complexes with elaborate long-chain pyridine-2,6 dicarboxamides. AB - A series of platinum(II) acetylide complexes with elaborate long-chain pyridine 2,6-dicarboxamides was synthesized. These metal complexes are capable of immobilizing organic solvents to form luminescent metallogels through a combination of intermolecular hydrogen bonding, aromatic pi-pi, and van der Waals interactions. Fibrillar morphologies were identified by TEM for these metallogels. Unique photophysical properties associated with the sol-to-gel transition have been disclosed with luminescence enhancement at elevated temperatures, which is in sharp contrast to typical thermotropic organogels or metallogels reported in the literature. Such unusual luminescence enhancement is attributed to the increased degree of freedom at higher temperatures that results in the formation of favorable molecular aggregates in the excited state through enhanced aromatic pi-pi and metallophilic Pt(II)...Pt(II) interactions. Structurally similar Pt-bp3 is not able to gel any common organic solvents. The inability of Pt-bp3 to form gels illustrates the importance of gelation to the macroscopic photophysical properties; Pt-bp3 does not show emission enhancement at elevated temperatures due to its low tendency to form strong aggregates in the ground state. PMID- 22223185 TI - A time-motion economic analysis of postoperative nausea and vomiting in ambulatory surgery. AB - BACKGROUND: One-third of surgical outpatients experience postoperative nausea and vomiting (PONV) during their hospital stay or post-discharge nausea and vomiting (PDNV) after hospitalization. We determined the incremental costs of PONV/PDNV in ambulatory patients with this time-and-motion study. METHODS: In 100 ambulatory surgery patients, we evaluated the incidence of PONV, time staff spent with patients, use of PONV-related supplies, recovery duration, PONV rescue treatments, and quality-of-life through to the third postoperative morning. Patients with and without PONV/PDNV were compared in relation to PONV-related cost after adjusting for age, American Society of Anesthesiologists status, body mass index, and duration and complexity of surgery. RESULTS: Thirty-seven percent of the patients experienced PONV during hospitalization; this increased to 42% by the first postoperative morning and increased further to 49% by the third postoperative morning. Patients with PONV spent one hour longer in the postanesthesia care unit than patients without PONV (median [interquartile range] 234 [188-287] min vs 171 [144-212] min, respectively; P = 0.001). The amount of nursing time required for patients with PONV was significantly greater than that required for patients without PONV (82 [63-106] min vs 68 [57-79] min, respectively; P = 0.02). The total cost of postoperative recovery was significantly greater for patients with PONV/PDNV than for those without (US$730 vs $640, respectively; P = 0.006). Postoperative nausea and vomiting/PDNV was associated with an adjusted incremental total cost of $75 (95% confidence interval $67 to $86). Postoperative nausea and vomiting was also associated with worsened postoperative quality of life (49% of patients with PONV/PDNV rated quality high in four domains vs 94% of patients without PONV/PDNV; P < 0.001). CONCLUSION: Postoperative nausea and vomiting/PDNV were common; they impaired quality of life and imposed an incremental cost of $75 per patient. This incremental cost is comparable with the cost patients are willing to pay to avoid PONV. PMID- 22223184 TI - How noise in force fields can affect the structural refinement of protein models? AB - Structural refinement of predicted models of biological macromolecules using atomistic or coarse-grained molecular force fields having various degree of error is investigated. The goal of this analysis is to estimate what is the probability for designing an effective structural refinement based on computations of conformational energies using force field, and starting from a structure predicted from the sequence (using template-based or template-free modeling), and refining it to bring the structure into closer proximity to the native state. It is widely believed that it should be possible to develop such a successful structure refinement algorithm by applying an iterative procedure with stochastic sampling and appropriate energy function, which assesses the quality (correctness) of protein decoys. Here, an analysis of noise in an artificially introduced scoring function is investigated for a model of an ideal sampling scheme, where the underlying distribution of RMSDs is assumed to be Gaussian. Sampling of the conformational space is performed by random generation of RMSD values. We demonstrate that whenever the random noise in a force field exceeds some level, it is impossible to obtain reliable structural refinement. The magnitude of the noise, above which a structural refinement, on average is impossible, depends strongly on the quality of sampling scheme and a size of the protein. Finally, possible strategies to overcome the intrinsic limitations in the force fields for impacting the development of successful refinement algorithms are discussed. PMID- 22223186 TI - Field comparison of manual and semi-automatic methods for the measurement of total gaseous mercury in ambient air and assessment of equivalence. AB - The manual and semi-automatic methods for the measurement of total gaseous mercury in ambient air have been compared in a field trial for the first time. The comparison results have shown that whilst the expected random scatter is present, there was no significant systematic bias between the two methods, whose operational differences have also been outlined and analysed in this work. Furthermore it has been observed that because variation in instrument sensitivity is largely random in nature there is little effect on the results of the comparison if the period between instrument calibrations is altered. When the manual and semi-automatic methods are compared according to guidelines produced by the European Commission the results presented here, taken together with other supporting evidence, strongly suggest that the two methods are equivalent. PMID- 22223188 TI - A highly selective ethylene tetramerization catalyst. PMID- 22223187 TI - Solution NMR structures reveal unique homodimer formation by a winged helix-turn helix motif and provide first structures for protein domain family PF10771. AB - High-quality NMR structures of the homo-dimeric proteins Bvu3908 (69-residues in monomeric unit) from Bacteroides vulgatus and Bt2368 (74-residues) from Bacteroides thetaiotaomicron reveal the presence of winged helix-turn-helix (wHTH) motifs mediating tight complex formation. Such homo-dimer formation by winged HTH motifs is otherwise found only in two DNA-binding proteins with known structure: the C-terminal wHTH domain of transcriptional activator FadR from E. coli and protein TubR from B. thurigensis, which is involved in plasmid DNA segregation. However, the relative orientation of the wHTH motifs is different and residues involved in DNA-binding are not conserved in Bvu3908 and Bt2368. Hence, the proteins of the present study are not very likely to bind DNA, but are likely to exhibit a function that has thus far not been ascribed to homo-dimers formed by winged HTH motifs. The structures of Bvu3908 and Bt2368 are the first atomic resolution structures for PFAM family PF10771, a family of unknown function (DUF2582) currently containing 128 members. PMID- 22223189 TI - Rearrangement of HMGA2 in a case of infantile lipoblastoma without Plag1 alteration. AB - Lipoblastoma is a rare benign adipocytic tumor that occurs usually in children. It can be difficult to distinguish a lipoblastoma from other lipogenic tumors. In such cases, the detection of a rearrangement of the PLAG1 gene by fluorescence in situ hybridization analysis is useful for characterizing a lipoblastoma. We present here a novel case of morphological infantile lipoblastoma showing a rearrangement of HMGA2 instead of the classical PLAG1 alteration. HMGA2 is the main target of clonal aberrations encountered in lipomas. This result supports the hypothesis that benign lipomatous tumors harboring PLAG1 or HMGA2 rearrangement could constitute a unique pathogenetic entity. PMID- 22223190 TI - Stress and strain patterns of 1-piece and 2-piece implant systems in bone: a 3 dimensional finite element analysis. AB - STATEMENT OF PROBLEM: The transition from implant to abutment is solid in 1-piece (1P) and broken in 2-piece (2P) implant designs. This difference may affect occlusal load distribution and marginal bone response. PURPOSE: To determine whether 1P and 2P implants with equivalent geometries exhibited stresses and strains differently under applied loading conditions. MATERIALS AND METHODS: Design software simulated 1P and 2P implants restored with metal copings and embedded in 3 cylindrical bone block models that varied in dimensions, density, and percentage of bone-to-implant contact. Three-dimensional, finite element analysis simulated occlusal loading. Experiments evaluated stresses and strains relative to implant design and (1) periimplant bone thickness, (2) cortical bone thickness, (3) magnitude and direction of occlusal loading, and (4) % bone-to implant contact. RESULTS: Implants with equivalent dimensions exhibited comparable stresses and strains in all experimental conditions. Implant diameter and periimplant bone thickness influenced stress levels. Only small-diameter (3.0 mm) 1P implants in low-density bone exhibited stress levels that might adversely affect marginal bone stability. CONCLUSIONS: Implant diameter and periimplant bone thickness influenced load distribution in bone, but the type of implant abutment transition had no significant effect. Small-diameter 1P implants should be limited to dense bone to minimize stress concentrations. PMID- 22223191 TI - Complete oral rehabilitation with implants using CAD/CAM technology, stereolithography, and conoscopic holography. AB - A 64-year-old totally edentulous female initially presented with ill-fitting removable prostheses. A comprehensive treatment plan with dental implants was accepted by the patient. Clinical and laboratory procedures were executed using various computer technologies including computed tomography, rapid prototyping, and optical scanning using conoscopic holography. A review of the patient's treatment and various modalities used are the focus of this patient report. PMID- 22223192 TI - A role for C-terminal cross-linking telopeptide (CTX) level to predict the development of bisphosphonate-related osteonecrosis of the jaws (BRONJ) following oral surgery? AB - BACKGROUND: Bisphosphonates are a class of chemical compounds used in the treatment of a variety of bone-related conditions. Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a well-recognised complication. C-terminal cross-linking telopeptide (CTX) estimation has been suggested as an indicator for the risk of BRONJ. It was reported that values <100 pg/ml represent a high risk of developing BRONJ following surgery and those between 100 and 150 pg/ml, a moderate risk. The aim of this study was to determine the effectiveness of the CTX test in predicting the development of BRONJ. METHODS: This is an 18-month prospective study of patients taking bisphosphonates, referred to a regional Maxillofacial Surgery Unit for dento-alveolar surgery. The following variables were recorded: age, gender, reason for referral, bisphosphonate type, indication for and duration of bisphosphonate treatment, medical co-morbidities, CTX value, development of BRONJ, and follow-up period. RESULTS: 23 patients underwent a fasting CTX test. The mean age was 59 years (range, 44-78 years). Nineteen were taking alendronic acid, two risedronate sodium and two zoledronic acid. The mean duration of bisphosphonate treatment was 30 months (range, 8-72 months). The mean CTX value was 180 pg/ml (range, 50-370 pg/ml), with 11 patients having a value at or less than 150 pg/ml. The mean follow-up period was 5 months (range, 3-11 months). None of the patients, who underwent removal of one or more teeth, subsequently developed BRONJ. CONCLUSION: The CTX test was not predictive for the development of BRONJ following oral surgery. PMID- 22223194 TI - A discriminative Ramachandran potential of mean force aimed at minimizing secondary structure bias. AB - We introduce PMF*, a novel potential of mean force (PMF) for the Ramachandran phi/Psi dihedral plot of the 20 standard amino acids and assess its relevance to the conformation of polypeptides by scoring structures in the protein data bank and decoy datasets. The new energy function is a linear combination of the conventional, unreferenced PMF and the DeltaPMF relative to the free energy of all amino acids in the parameterization set of structures, effectively removing their respective biases toward alpha-helix and beta-strand. It is shown that low resolution crystal structures, NMR structures, and theoretical models have on average significantly higher energies than high-resolution crystal structures; also PMF* is more discriminative for structure quality than the individual PMF and DeltaPMF energy functions. PMF* may be well suited for use as a restraint energy term in the refinement of experimental structures and theoretical models. PMID- 22223193 TI - A survey of the prevalence of smoking and smoking cessation advice received by inpatients in a large teaching hospital in Ireland. AB - BACKGROUND: The adverse effects of smoking are well documented and it is crucial that this modifiable risk factor is addressed routinely. Professional advice can be effective at reducing smoking amongst patients, yet it is not clear if all hospital in-patient smokers receive advice to quit. AIMS: To explore smoking prevalence amongst hospital in-patients and smoking cessation advice given by health professionals in a large university teaching hospital. METHODS: Interviews were carried out over 2 weeks in February 2011 with all eligible in-patients in Beaumont Hospital. RESULTS: Of the 205 patients who completed the survey, 61% stated they had been asked about smoking by a healthcare professional in the past year. Only 44% of current/recent smokers stated they had received smoking cessation advice from a health professional within the same timeframe. CONCLUSIONS: Interventions to increase rates of healthcare professional-provided smoking cessation advice are urgently needed. PMID- 22223195 TI - RhoB is associated with the anti-angiogenic effects of celiac patient transglutaminase 2-targeted autoantibodies. AB - Celiac patient-derived anti-transglutaminase 2 (TG2) antibodies disturb several steps in angiogenesis, but the detailed molecular basis is not known. Therefore, we here analyzed by microarray technology the expression of a set of genes related to angiogenesis and endothelial cell biology in order to identify factors that could explain our previous data related to vascular biology in the context of celiac disease. To this end, in vitro models using human umbilical vein endothelial cells (HUVECs) or in vivo models of angiogenesis were used. A total of 116 genes were analyzed after treatment with celiac patient autoantibodies against TG2. Compared to treatment with control IgA celiac patient, total IgA induced a consistent expression change of 10 genes, the up-regulation of four and down-regulation of six. Of these genes the up-regulated RhoB was selected for further studies. RhoB expression was found to be up-regulated at both messenger RNA and protein level in response to celiac patient total IgA as well as anti-TG2 specific antibody derived from a celiac patient. Interestingly, down-regulation of RhoB by specific small interfering RNA treatment in endothelial cells could rescue the deranged endothelial length and tubule formation caused by celiac disease autoantibodies. RhoB function is controlled by its post-translational modification by farnesylation. This modification of RhoB required for its correct function can be prevented by the cholesterol lowering drug simvastatin, which was also able to abolish the anti-angiogenic effects of celiac anti-TG2 autoantibodies. Taken together, our results would suggest that RhoB plays a key role in the response of endothelial cells to celiac disease-specific anti-TG2 autoantibodies. PMID- 22223197 TI - Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis. AB - Elastin has been linked to maturity of liver fibrosis. To date, the regulation of elastin secretion and its degradation in liver fibrosis has not been characterized. The aim of this work was to define elastin accumulation and the role of the paradigm elastase macrophage metalloelastase (MMP-12) in its turnover during fibrosis. Liver fibrosis was induced by either intraperitoneal injections of carbon tetrachloride (CCl(4) ) for up to 12 weeks (rat and mouse) or oral administration of thioacetamide (TAA) for 1 year (mouse). Elastin synthesis, deposition, and degradation were investigated by immunohistochemistry, quantitative polymerase chain reaction (qPCR), western blotting, and casein zymography. The regulation of MMP-12 elastin degradation was defined mechanistically using CD11b-DTR and MMP-12 knockout mice. In a CCl(4) model of fibrosis in rat, elastin deposition was significantly increased only in advanced fibrosis. Tropoelastin expression increased with duration of injury. MMP-12 protein levels were only modestly changed and in coimmunoprecipitation experiments MMP-12 was bound in greater quantities to its inhibitor TIMP-1 in advanced versus early fibrosis. Immunohistochemistry and macrophage depletion experiments indicated that macrophages were the sole source of MMP-12. Exposure of CCl(4) in MMP-12(-/-) mice led to a similar degree of overall fibrosis compared to wildtype (WT) but increased perisinusoidal elastin. Conversely, oral administration of TAA caused both higher elastin accumulation and higher fibrosis in MMP-12(-/-) mice compared with WT. CONCLUSION: Elastin is regulated at the level of degradation during liver fibrosis. Macrophage-derived MMP-12 regulates elastin degradation even in progressive experimental liver fibrosis. These observations have important implications for the design of antifibrotic therapies. PMID- 22223198 TI - Do we have the tools to manage resistance in the future? AB - Pesticide resistance is a major factor affecting world food and fibre production, but that has been contained so far by the availability of diverse modes of action. Overcoming resistance by switching to a new mode of action is a concept easily grasped by growers but threatened by losses through resistance and new registration requirements. Opportunities for innovation and development of a diversity of novel modes of action exist through harnessing recent advances, fundamental to all eukaryotes and largely funded for medical rather than agricultural objectives, in understanding cell biology and development. The cystoskeleton, cell wall synthesis, signal transduction and RNAi are discussed as examples where new targets are now exposed. However, new modes of action will be delivered not only by sprayer or seed treatment but also through transgenic crops, although these still need to be transferred from experiment to practice. Improvements in modelling protein structures and target-site changes, supplemented by rapid diagnostics to detect resistance early, will improve resistance risk management and integrate chemical, biopesticide, transgenic and conventional breeding around the concept of diversity in modes of action. However, before agronomy can translate this into practical antiresistance strategies, there is a need to direct more resources to the biochemistry and cell biology of pests, diseases and weeds to translate these new discoveries into key tools needed to manage resistance in the future. PMID- 22223196 TI - Knowledge transfer of spinal manipulation skills by student-teachers: a randomised controlled trial. AB - PURPOSE: To assess the use of peer-assisted learning (PAL) of complex manipulative motor skills with respect to gender in medical students. METHODS: In 2007-2010, 292 students in their 3rd and 4th years of medical school were randomly assigned to two groups [Staff group (SG), PAL group (PG)] led by either staff tutors or student-teachers (ST). The students were taught bimanual practical and diagnostic skills (course education module of eight separate lessons) as well as a general introduction to the theory of spinal manipulative therapy. In addition to qualitative data collection (Likert scale), evaluation was performed using a multiple-choice questionnaire in addition to an objective structured clinical examination (OSCE). RESULTS: Complex motor skills as well as palpatory diagnostic competencies could in fact be better taught through professionals than through ST (manipulative OSCE grades/diagnostic OSCE score; SG vs. PG; male: P = 0.017/P < 0.001, female: P < 0.001/P < 0.001). The registration of theoretical knowledge showed equal results in students taught by staff or ST. In both teaching groups (SG: n = 147, PG: n = 145), no significant differences were observed between male and female students in matters of manipulative skills or theoretical knowledge. Diagnostic competencies were better in females than in males in the staff group (P = 0.041) Overall, students were more satisfied with the environment provided by professional teachers than by ST, though male students regarded the PAL system more suspiciously than their female counterparts. CONCLUSIONS: The peer-assisted learning system does not seem to be generally qualified to transfer such complex spatiotemporal demands as spinal manipulative procedures. PMID- 22223199 TI - Virulence of select entomopathogenic fungi to the brown marmorated stink bug, Halyomorpha halys (Stal) (Heteroptera: Pentatomidae). AB - The brown marmorated stink bug. Halyomorpha halys, (BMSB) is an exotic pest causing damage to fruits and vegetables. They also transmit diseases. Integrated pest management strategies are lacking for this invasive. For the first time, information is presented on the virulence of several entomopathogenic fungi against BMSB. Three Beauveria bassiana and two Metarhizium anispoliae isolates were bioassayed against adult BMSB. One B. bassiana isolate was the active ingredient in BotaniGard(r) which produced 85 and 100% mortality in 9 and 12 days post treatment, respectively. Experimental isolates ERL 1170 and ERL 1540 were also efficacious. Metarhizium anispoliae isolates produced lower mortalities than the B. bassiana isolates. Data presented showed the potential for management of BMSB with entomopathogenic fungi. PMID- 22223200 TI - Simulation of movement of pesticides towards drains with a preferential flow version of PEARL. AB - BACKGROUND: As part of the Dutch authorisation procedure for pesticides, an assessment of the effects on aquatic organisms in surface waters adjacent to agricultural fields is required. The peak concentration is considered to be the most important exposure endpoint for the ecotoxicological effect assessment. Macropore flow is an important driver for the peak concentration, so the leaching model PEARL was extended with a macropore module. The new model has two macropore domains: a bypass domain and an internal catchment domain. The model was tested against data from a field leaching study on a cracking clay soil in the Netherlands. RESULTS: Most parameters of the model could be obtained from site specific measurements, pedotransfer functions and general soil structural knowledge; only three macropore-flow-related parameters needed calibration. The flow-related macropore parameters could not be calibrated without using the concentration in drain water. Sequential calibration strategies, in which firstly the water flow model and then the pesticide fate model are calibrated, may therefore be less suitable for preferential flow models. CONCLUSION: After calibration, PEARL could simulate well the observed rapid movement towards drains of two pesticides with contrasting sorption and degradation rate properties. The calibrated value for the fraction of the internal catchment domain was high (90%). This means that a large fraction of water entering the macropores infiltrates into the soil matrix, thus reducing the fraction of rapid flow. PMID- 22223201 TI - Influence of the insecticide pyriproxyfen on the flight muscle differentiation of Apis mellifera (Hymenoptera, Apidae). AB - The Brazilian africanized Apis mellifera is currently considered as one of the most important pollinators threatened by the use of insecticides due to its frequent exposition to their toxic action while foraging in the crops it pollinated. Among the insecticides, the most used in the control of insect pragues has as active agent the pyriproxyfen, analogous to the juvenile hormone (JH). Unfortunately the insecticides used in agriculture affect not only the target insects but also beneficial nontarget ones as bees compromising therefore, the growth rate of their colonies at the boundaries of crop fields. Workers that forage for provisions in contaminated areas can introduce contaminated pollen or/and nectar inside the beehives. As analogous to JH the insecticide pyriproxyfen acts in the bee's larval growth and differentiation during pupation or metamorphosis timing. The flighty muscle is not present in the larvae wingless organisms, but differentiates during pupation/metamorphosis. This work aimed to investigate the effect of pyriproxyfen insecticide on differentiation of such musculature in workers of Brazilian africanized honey bees fed with artificial diet containing the pesticide. The results show that the bees fed with contaminated diet, independent of the insecticide concentration used, show a delay in flight muscle differentiation when compared to the control. PMID- 22223202 TI - Ileal Crohn's disease: CEUS determination of activity. AB - Transabdominal ultrasound is currently accepted as a clinical first-line tool in the assessment of Crohn's disease activity. During recent years, great improvements have been achieved in ultrasound examination with the introduction of high-frequency transducers, ultrasonographic microbubble contrast agents, and dedicated contrast-specific ultrasound software. Therefore, contrast-enhanced ultrasonography (CEUS) is emerging as one of the most important imaging techniques in the diagnosis and follow-up of patients with ileal Crohn's disease. It is non-invasive and non-ionizing, easily repeatable, well-tolerated by patients and has significant diagnostic accuracy. Moreover, the possibility to monitor response to therapies, describing, and quantifying contrast enhancement behavior by specific software, represents an interesting aspect of its utilization, considering the still open questions about the correct use of immunosuppressive and biological agents. The aim of our review is to provide an updated overview of the role of CEUS in the patients who have an ileal localization of Crohn's disease, defining its qualitative and quantitative features. PMID- 22223205 TI - On circadian variation of myocardial reperfusion injury. PMID- 22223204 TI - Fetal cell microchimerism in the maternal heart: baby gives back. PMID- 22223206 TI - A second chance for a PPARgamma targeted therapy? PMID- 22223207 TI - Impact through discovery: a global challenge: Presidential Address at the American Heart Association 2011 Scientific Sessions. PMID- 22223208 TI - Thrombin receptor activation work wins 2011 Lucian Award. PMID- 22223209 TI - The fire within: cardiac inflammatory signaling in health and disease. AB - Inflammatory mediators are operative in the pathogenesis of the most common forms of heart disease. Although in most cases the induction of these pathways is maladaptive and deleterious, there are notable exceptions when inflammatory pathways participate in healing or limiting the extent of injury. The appreciation of the role of these mechanisms in myocardial homeostasis and pathophysiology has led to increased efforts to elucidate the specific signaling pathways most relevant to the heart. Our goal in this introductory overview is to provide context for the five detailed reviews that follow by introducing the major relevant stimuli, the receptors, and pathways that mediate inflammatory signaling in the heart. We try to impart a sense of the scope and complexity of these pathways, as well as their interactions with signaling pathways regulating cell survival and metabolism. These complexities underscore the potential challenges of therapeutically targeting inflammatory mechanisms in heart disease and may help explain the mostly disappointing results of this approach to date. PMID- 22223210 TI - Inflammation in myocardial diseases. AB - Inflammatory processes underlie a broad spectrum of conditions that injure the heart muscle and cause both structural and functional deficits. In this article, we address current knowledge regarding 4 common forms of myocardial inflammation: myocardial ischemia and reperfusion, sepsis, viral myocarditis, and immune rejection. Each of these pathological states has its own unique features in pathogenesis and disease evolution, but all reflect inflammatory mechanisms that are partially shared. From the point of injury to the mobilization of innate and adaptive immune responses and inflammatory amplification, the cellular and soluble mediators and mechanisms examined in this review will be discussed with a view that both beneficial and adverse consequences arise in these human conditions. PMID- 22223211 TI - Autoantibodies in heart failure and cardiac dysfunction. AB - Human heart failure is a disease with multifactorial causes, considerable morbidity, and high mortality. Several circulating autoantibodies, some of them being heart-specific, play a crucial role in the progression and induction of heart failure. However the precise mechanisms on how these autoantibodies perpetuate or even induce an organ specific autoimmune response are not yet fully understood. Also it is being a matter of current research to elucidate a potential pathophysiological role of the innate immune system in generating auto reactive antibodies. In this review we will summarize the current available literature on circulating autoantibodies which are related to human heart failure. We will present clinical and animal studies that demonstrate the occurrence and pathophysiological relevance of several autoantibodies in heart failure, as well as point out biological mechanisms on molecular and cellular level. Finally the beneficial therapeutic effects of numerous clinical studies that target the humoral arm of the immune system by using either intravenous immunoglobulins and/or immunoadsorption will be critically discussed. PMID- 22223214 TI - Hydrogen sulfide as an endothelium-derived hyperpolarizing factor in rodent mesenteric arteries. PMID- 22223215 TI - Cardiomyocyte renewal in humans. PMID- 22223212 TI - Regulation of the inflammatory response in cardiac repair. AB - Myocardial necrosis triggers an inflammatory reaction that clears the wound from dead cells and matrix debris, while activating reparative pathways necessary for scar formation. A growing body of evidence suggests that accentuation, prolongation, or expansion of the postinfarction inflammatory response results in worse remodeling and dysfunction following myocardial infarction. This review manuscript discusses the cellular effectors and endogenous molecular signals implicated in suppression and containment of the inflammatory response in the infarcted heart. Clearance of apoptotic neutrophils, recruitment of inhibitory monocyte subsets and regulatory T cells, macrophage differentiation and pericyte/endothelial interactions may play an active role in restraining postinfarction inflammation. Multiple molecular signals may be involved in suppressing the inflammatory cascade. Negative regulation of toll-like receptor signaling, downmodulation of cytokine responses, and termination of chemokine signals may be mediated through the concerted action of multiple suppressive pathways that prevent extension of injury and protect from adverse remodeling. Expression of soluble endogenous antagonists, decoy receptors, and posttranslational processing of bioactive molecules may limit cytokine and chemokine actions. Interleukin-10, members of the transforming growth factor-beta family, and proresolving lipid mediators (such as lipoxins, resolvins, and protectins) may suppress proinflammatory signaling. In human patients with myocardial infarction, defective suppression, and impaired resolution of inflammation may be important mechanisms in the pathogenesis of remodeling and in progression to heart failure. Understanding of inhibitory and proresolving signals in the infarcted heart and identification of patients with uncontrolled postinfarction inflammation and defective cardiac repair is needed to design novel therapeutic strategies. PMID- 22223217 TI - Effect of ionic liquid on diffusion in P123 gel: fluorescence correlation spectroscopy. AB - The effect of two room-temperature ionic liquids (RTILs) on the diffusion of three fluorescent dyes in the gel phase of a triblock copolymer, (PEO)(20) (PPO)(70)-(PEO)(20) [Pluronic P123; poly ethylene oxide (PEO), poly propylene oxide (PPO)], was studied by using fluorescence correlation spectroscopy (FCS). We used three dyes, 4-(dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H pyran (DCM), coumarin 480 (C480), and coumarin 343 (C343). By field-emission scanning electron microscopy (FESEM), it was observed that the macroscopic structure of the P123 gel remained unaffected upon addition of RTIL. In the absence of RTIL, the diffusion coefficient (D(t)) of the hydrophobic dye DCM (1 MUm(2) s(-1) at the core) is smaller than that of the other two hydrophilic dyes (7 MUm(2) s(-1) for C480 and C343). On addition of RTIL, the D(t) values of all of the dyes increase, indicating a decrease in local viscosity (eta(eff)). The eta(eff) of the core of the RTIL-P123 gel estimated from the D(t) of DCM is lower than that of both the P123 gel (at the core eta=90 cP) and RTIL (eta=110 cP). It is shown that the RTIL affects the structure of the gel by modifying the size of the micellar aggregates and by penetrating the core. PMID- 22223213 TI - Inflammation, endoplasmic reticulum stress, autophagy, and the monocyte chemoattractant protein-1/CCR2 pathway. AB - Numerous inflammatory cytokines have been implicated in the pathogenesis of cardiovascular diseases. Monocyte chemoattractant protein (MCP)-1/CCL2 is expressed by mainly inflammatory cells and stromal cells such as endothelial cells, and its expression is upregulated after proinflammatory stimuli and tissue injury. MCP-1 can function as a traditional chemotactic cytokine and also regulates gene transcription. The recently discovered novel zinc-finger protein, called MCPIP (MCP-1-induced protein), initiates a series of signaling events that causes oxidative and endoplasmic reticulum (ER) stress, leading to autophagy that can result in cell death or differentiation, depending on the cellular context. After a brief review of the basic processes involved in inflammation, ER stress, and autophagy, the recently elucidated role of MCP-1 and MCPIP in inflammatory diseases is reviewed. MCPIP was found to be able to control inflammatory response by inhibition of nuclear factor-kappaB activation through its deubiquitinase activity or by degradation of mRNA encoding a set of inflammatory cytokines through its RNase activity. The potential inclusion of such a novel deubiquitinase in the emerging anti-inflammatory strategies for the treatment of inflammation-related diseases such as cardiovascular diseases and type 2 diabetes is briefly discussed. PMID- 22223216 TI - Mercury(II) ion detection via pyrene-mediated photolysis of disulfide bonds. PMID- 22223218 TI - Effect of low-dose atorvastatin on plasma concentrations of adipokines in patients with metabolic syndrome. AB - OBJECTIVE: It has not been conclusively proven whether or not the beneficial effect of statins on the cardiovascular system is mediated through their influence on adipokine secretion. We designed a prospective open-label study to assess the influence of 6 months' atorvastatin therapy on plasma concentrations of some adipokines in patients with metabolic syndrome. SUBJECTS: 36 adult patients with metabolic syndrome and serum LDL cholesterol >3.5 mmol/l, previously untreated with statins, were included in the study. MEASUREMENTS: Plasma concentrations of adiponectin, leptin, resistin and insulin were measured before initiation and after 2, 4 and 6 months of atorvastatin therapy (10 mg), and 2 months after treatment cessation. RESULTS: Treatment with atorvastatin was followed by a 35.6% decline in LDL cholesterol. Plasma adiponectin concentration decreased by 20.7% after 2 months; however, after 4 and 6 months, this did not differ significantly from the initial values. There was a negative correlation between the initial plasma concentration of leptin and changes in HDL cholesterol (R = -0.358; p = 0.04). CONCLUSIONS: Firstly, the long-term effect of atorvastatin therapy in patients with metabolic syndrome is not mediated by changes in the secretion of adiponectin, leptin and resistin by adipose tissue. Secondly, plasma leptin concentration seems to be a predictor of HDL cholesterol changes during atorvastatin therapy. PMID- 22223220 TI - Development of an electrochemical immunosensor for the detection of HbA1c in serum. AB - An electrochemical immuno-biosensor for detecting glycosylated haemoglobin (HbA1c) is reported based on glassy carbon (GC) electrodes with a mixed layer of an oligo(phenylethynylene) molecular wire (MW) and an oligo(ethylene glycol) (OEG). The mixed layer is formed from in situ-generated aryl diazonium cations. To the distal end of the MW, a redox probe 1,1'-di(aminomethyl)ferrocene (FDMA) was attached followed by the covalent attachment of an epitope N-glycosylated pentapeptide (GPP), an analogon to HbA1c, to which an anti-HbA1c monocolonal antibody IgG can selectively bind. HbA1c was detected by a competitive inhibition assay based on the competition for binding to anti-HbA1c IgG antibodies between the analyte in solution, HbA1c, and the surface bound epitope GPP. Exposure of the GPP modified sensing interface to the mixture of anti-HbA1c IgG antibody and HbA1c results in the attenuation of ferrocene electrochemistry due to free antibody binding to the interface. Higher concentrations of analyte led to higher Faradaic currents as less anti-HbA1c IgG is available to bind to the electrode surface. It was observed that there is a good linear relationship between the relative Faradaic current of FDMA and the concentration of HbA1c from 4.5% to 15.1% of total haemoglobin in serum without the need for washing or rinsing steps. PMID- 22223221 TI - Palladium-catalyzed divergent reactions of alpha-diazocarbonyl compounds with allylic esters: construction of quaternary carbon centers. PMID- 22223219 TI - Computational protein design with explicit consideration of surface hydrophobic patches. AB - De novo protein design requires the identification of amino-acid sequences that favor the target-folded conformation and are soluble in water. One strategy for promoting solubility is to disallow hydrophobic residues on the protein surface during design. However, naturally occurring proteins often have hydrophobic amino acids on their surface that contribute to protein stability via the partial burial of hydrophobic surface area or play a key role in the formation of protein protein interactions. A less restrictive approach for surface design that is used by the modeling program Rosetta is to parameterize the energy function so that the number of hydrophobic amino acids designed on the protein surface is similar to what is observed in naturally occurring monomeric proteins. Previous studies with Rosetta have shown that this limits surface hydrophobics to the naturally occurring frequency (~28%), but that it does not prevent the formation of hydrophobic patches that are considerably larger than those observed in naturally occurring proteins. Here, we describe a new score term that explicitly detects and penalizes the formation of hydrophobic patches during computational protein design. With the new term, we are able to design protein surfaces that include hydrophobic amino acids at naturally occurring frequencies, but do not have large hydrophobic patches. By adjusting the strength of the new score term, the emphasis of surface redesigns can be switched between maintaining solubility and maximizing folding free energy. PMID- 22223222 TI - [International clinical practice guidelines and management of rheumatology in Madagascar]. AB - Developed countries issue recommendations regarding healthcare that aren't constantly appropriate for emergent countries. We suggest some remarks concerning rheumatology in Madagascar, taking account of scientific data, medical ethics, equality and equity. We have studied the minimal cost of care of medical conditions found in our hospital department if we were to follow international recommendations for their management. Then, we have estimated treatment expenses as a percentage of the SMIC (Malagasy minimum monthly salary). Out of 517 patients examined yearly, we have found 62.8% osteoarthritis cases, 6.3% rheumatoid arthritis (RA), and 4,2% septic arthritis. Therefore, the first month of treatment for an arthritis of the knee would absorb 147.3% of the SMIC; diagnosis and treatment of a case of septic arthritis would take up 1762.8% of the minimum wage, and a case of RA without biotherapy would require 175%. According to the American College of Rheumatology criteria which are used as a reference, the treatment of an arthritis of the knee would take only 23% of the SMIC. Caring for septic arthritis would demand 57.5% of the SMIC and while it would yield more arguments for diagnosis such as clinical examination, CRP, and Gram coloration on joint liquid aspiration. We can proceed to RA diagnosis with an acceptable security through precise clinical examination, blood cell count, ESR, CRP, rheumatoid factor and radiography. This means 56% of the SMIC. From this 517 patients, our suggestions would reduce the expense by 35,850% of the SMIC per year. The allocation of such funds onto the treatment of complicated forms of rheumatism would be fair. By refining and evaluating these suggestions, we would come up with appropriate recommendations for emergent countries. PMID- 22223223 TI - Monitoring of heavy metal contaminants using feathers of shorebirds, Korea. AB - This study presents concentrations of iron, zinc, copper, lead and cadmium in the feathers of 3 shorebird species (n = 29) from Okgu Mudflat, Korea in the East Asian-Australian Migration Flyways. Lead concentrations (ANOVA, p < 0.001) in Red necked Stints (geomean = 9.61 MUg g(-1) dry weight) were higher than in Terek Sandpipers (geomean = 5.56 MUg g(-1) dry weight) which in turn were higher than in Great Knots (geomean = 2.78 MUg g(-1) wet weight). Cadmium concentrations (ANOVA, p < 0.001) were higher in Great Knots (geomean = 2.97 MUg g(-1) wet weight) and in Red-necked Stints (geomean = 2.70 MUg g(-1) dry weight) than in Terek Sandpipers (geomean = 0.33 MUg g(-1) dry weight). Lead (r = 0.574, p < 0.01) and cadmium (r = 0.380, p < 0.05) concentrations between feathers and livers of shorebirds were significantly correlated. Lead concentrations in 65.5% (19 individuals) of shorebirds exceeded a toxicity threshold for feathers (4 MUg g(-1) dry weight). Iron, zinc, copper, lead and cadmium concentrations in feathers were within the range of earlier studies for wild birds, but lead concentrations in Red-necked Stints were higher than those reported in other studies. Because lead concentrations in feathers and livers of Red-necked Stints were markedly higher than in other shorebirds, we suggest that Red-necked Stints were exposed to higher lead concentrations than the other shorebirds on their breeding or wintering grounds. PMID- 22223224 TI - Kinetically assembled nanoparticles of bioactive macromolecules exhibit enhanced stability and cell-targeted biological efficacy. PMID- 22223225 TI - Biomimicking polysaccharide nanofibers promote vascular phenotypes: a potential application for vascular tissue engineering. AB - The potential of electrospun pullulan/dextran (P/D) nanofibers (average diameter = 323 nm) for vascular tissue engineering applications is explored. The mechanical properties of the nanofibers are of the same order of magnitude as that of human arteries (Young's modulus ~0.88 MPa; tensile strength ~0.35 MPa). It is demonstrated that the nanofiber topography enables cell adhesion and that the endothelial phenotype is maintained on the nanofibers. Moreover, P/D nanofibers support a stable confluent monolayer of endothelial cells over 14 d. SMCs seeded on nanofibers display similar levels of alpha smooth muscle actin and a lower proliferation rate than cells on 2D cultures. The observations suggest that nanofibers promote a shift to a quiescent contractile phenotype in SMCs. PMID- 22223226 TI - Time-selective chemoprevention of vitamin E and selenium on esophageal carcinogenesis in rats: the possible role of nuclear factor kappaB signaling pathway. AB - Previous human intervention trial demonstrated that vitamin E (Ve) and selenium (Se) supplementation decreased esophageal cancer deaths among younger participants, but may have no effect or produce an opposite effect among older ones. In our study, we intended to mimic this human nutritional trial to determine the chemopreventive effects of Ve/Se supplementation at the early or late stage of esophageal carcinogenesis in rats. Esophageal squamous cell carcinoma (ESCC) was induced in Fischer 344 rats with N-nitrosomethylbenzylamine (NMBzA, 0.35 mg/kg BW, s.c., three times per week for 5 weeks). The rats were maintained on a modified AIN-93M diet with low levels of Ve/Se or supplemented with high levels of Ve/Se at different stages. At Week 25, the number and volume of visible tumors, the numbers of dysplasia and ESCC were significantly lower in rats of supplementation during the early stage (Group C) or during the entire experimental period (Group E), but not during the late stage (Group D). Ve/Se supplementation at the early stage also significantly decreased cell proliferation, nuclear factor kappaB (NFkappaB) activation, protein and mRNA expression of cyclooxygenase 2 and 5-lipoxygenase and biosynthesis of prostaglandin E2 and leukotriene B4 during the carcinogenesis of rat esophagus. Our results demonstrated that the chemopreventive efficacy of Ve/Se supplementation on NMBzA-induced esophageal cancer is time selective and that supplementation during the early stage is clearly effective but probably ineffective during the late stage of carcinogenesis. NFkappaB signaling pathway activation and aberrant arachidonic acid metabolism might be the underlying mechanism. PMID- 22223227 TI - Nosocomial outbreak of carbapenem-resistant Enterobacter cloacae highlighting the interspecies transferability of the blaOXA-48 gene in the gut flora. PMID- 22223228 TI - qnr, aac(6')-Ib-cr and qepA genes in Escherichia coli and Klebsiella spp.: genetic environments and plasmid and chromosomal location. AB - OBJECTIVES: To characterize the location and genetic environments of qnr, aac(6') Ib-cr and qepA genes related to quinolone resistance in 19 Escherichia coli, Klebsiella pneumoniae and Klebsiella oxytoca strains. METHODS: Genetic environments of the indicated genes were studied by cloning, PCR mapping and sequencing. The location of these genes was analysed by S1-PFGE and PFGE-I-CeuI and hybridization with specific probes. Associated antibiotic resistance mechanisms and molecular typing of strains were also investigated. RESULTS: The studied strains carried the aac(6')-Ib-cr, qepA, qnrS1, qnrB6, qnrB4 and oqxAB genes, with aac(6')-Ib-cr being the most prevalent. E. coli strains belonged to sequence types (STs) ST648, ST131, ST224 and ST205, and K. pneumoniae strains to ST433, ST341, ST152, ST15 and ST431. Different genetic environments of quinolone resistance genes were observed, and some of them had not been previously detected and registered in GenBank. The aac(6')-Ib-cr gene was mainly located in class 1 integrons or associated with the Tn1721 transposon in E. coli and associated with the aac(3)-II gene in Klebsiella. All these structures contained mechanisms of gene acquisition and/or dissemination, such as IS26. The studied quinolone resistance genes were mostly detected in IncF and IncN plasmids in E. coli and in IncR plasmids in Klebsiella, but in some strains the chromosomal location of the aac(6')-Ib-cr gene was detected for the first time. The bla(CTX-M-15), bla(OXA 1), tet(A), aac(3)-II and aph(3')-Ia genes and class 1 integrons were found in most strains. CONCLUSIONS: The aac(6')-Ib-cr gene was detected for the first time in the chromosome, although a plasmidic location was the most frequently found, with differentiation of plasmids types in E. coli versus Klebsiella. PMID- 22223229 TI - Mandatory surveillance of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia in England: the first 10 years. AB - Since 2001 it has been mandatory for acute hospital Trusts (groups of hospitals under the same management) in England to report all cases of bacteraemia due to Staphylococcus aureus together with information on their susceptibility or resistance to methicillin. This allowed the incidence of methicillin-resistant S. aureus (MRSA) bacteraemia (expressed as the number of cases per 1000 occupied bed days) to be determined for each Trust. In late 2005, the scheme was enhanced to collect demographic, clinical and epidemiological information on each case using a web-based data collection system. Analysis of this mandatory dataset has provided important information on the trends in MRSA bacteraemia in England and has documented a year-on-year decrease in incidence since 2006, following a government initiative in which Trusts were tasked with halving their MRSA bacteraemia rates over a 3 year period. In addition, the enhanced mandatory surveillance scheme has captured a wealth of data that have helped to further define the epidemiology of MRSA bacteraemia. It is to be hoped that based on the English experience of mandatory surveillance, other countries will consider the implementation of similar schemes, not only for MRSA but for other pathogens of public health importance. PMID- 22223230 TI - Body mass index and thromboembolism in children with hematological malignancies. AB - We evaluated the effects of body mass index (BMI) on the risk of thromboembolism (TE) in children (<18 years) with hematological malignancies during the period 1990-2009 (n = 359). Obesity was prevalent in 12% of patients: 6% versus 17% prior to and after the year 2000 (P = 0.02). Sixty-one (17%) patients developed TE; increasing BMI was associated with increased, but statistically insignificant risk of TE [adjusted odds ratios (OR): 0.75 (95%CI 0.32-1.77), 0.93 (95%CI 0.38 2.30), and 1.01(95%CI 0.42-2.41) for underweight, overweight, and obese group]. A large prospective study is needed to define the impact of BMI on the risk of TE in children. PMID- 22223231 TI - Hydrogen-bonding-mediated J-aggregation and white-light emission from a remarkably simple, single-component, naphthalenediimide chromophore. PMID- 22223232 TI - Sewage sludge toxicity in edaphic organism: analysis of midgut responses in the diplopod Rhinocricus padbergi. AB - Diplopods are agile saprophagous invertebrates with the ability to colonize several soil layers. They feed on waste and decaying organic matter, making the soil in which they are present better aerated and mineral-enriched. Because of their habits, diplopods have been suggested to be used in studies to analyze possible toxic effects of impacted soils in edafic fauna. In that respect, this study aimed at checking the feasibility of using morphological analysis from millipede's midgut as a biomarker for soils exposed to sewage sludge from sewage treatment plants. Histological and histochemical techniques, applied to the species Rhinocricus padbergi's midgut, were used. Two sewage sludge samples were used; they were collected in two small towns in the countryside of Sao Paulo State. Both cities are part of the Piracicaba-Capivari-Jundiai basin (PCJ-1 and PCJ-3). For 7 and 15-day periods, the animals were exposed to 10% concentrations and crude sludge for the PCJ-1sample and to 1, 10, and 50% concentrations and sludge for the PCJ-3 sample. The material exposed to the PCJ-1 sample showed an increase in the presence of cytoplasmic granules in both concentrations in all periods and a slight increase in the rate of epithelial renewal. The material of PCJ-3 sample presented the same alterations observed in PCJ-1 sample in higher frequence and over that high quantity of neutral polysaccharides in the hepatic cells layer. We can conclude that with the increase of sewage sludge concentrations tested, there is an increase in morphophysiologicals alterations frequencies found in the diplopods' midgut. PMID- 22223233 TI - Selective analysis of cell-free DNA in maternal blood for evaluation of fetal trisomy. AB - OBJECTIVE: To develop a novel prenatal assay based on selective analysis of cell free DNA in maternal blood for evaluation of fetal Trisomy 21 (T21) and Trisomy 18 (T18). METHODS: Two hundred ninety-eight pregnancies, including 39 T21 and seven T18 confirmed fetal aneuploidies, were analyzed using a novel, highly multiplexed assay, termed digital analysis of selected regions (DANSRTM). Cell free DNA from maternal blood samples was analyzed using DANSR assays for loci on chromosomes 21 and 18. Products from 96 separate patients were pooled and sequenced together. A standard Z-test of chromosomal proportions was used to distinguish aneuploid samples from average-risk pregnancy samples. DANSR aneuploidy discrimination was evaluated at various sequence depths. RESULTS: At the lowest sequencing depth, corresponding to 204,000 sequencing counts per sample, average-risk cases where distinguished from T21 and T18 cases, with Z statistics for all cases exceeding 3.6. Increasing the sequencing depth to 410,000 counts per sample substantially improved separation of aneuploid and average-risk cases. A further increase to 620,000 counts per sample resulted in only marginal improvement. This depth of sequencing represents less than 5% of that required by massively parallel shotgun sequencing approaches. CONCLUSION: Digital analysis of selected regions enables highly accurate, cost efficient, and scalable noninvasive fetal aneuploidy assessment. PMID- 22223234 TI - ACTIVLIM-Stroke: a crosscultural Rasch-built scale of activity limitations in patients with stroke. AB - BACKGROUND AND PURPOSE: This study describes the development of a Rasch-built scale measuring activity limitations in stroke patients, named ACTIVLIM-Stroke. METHOD: This new Rasch-built measure was constructed based on stroke patients' perceptions of difficulty in performing daily activities. Patients were recruited from inpatient and outpatient rehabilitation departments in Belgium and Benin. A 73-item questionnaire was completed by 204 participants. A random subsample of 83 subjects was given the questionnaire a second time. Data were analyzed using RUMM2030 software. RESULTS: After successive Rasch analyses, the ACTIVLIM-Stroke questionnaire, a unidimensional and linear 20-item measure of activity limitations, was constructed. All 20 items fulfilled Rasch requirements (overall and individual item fit, category discrimination, invariance, local response independence, and nonredundancy in item difficulty). This simple patient-based scale encompasses a large range of activities related to self-care, transfer, mobility, manual ability, and balance. The ACTIVLIM-Stroke questionnaire exhibited high internal validity, excellent internal consistency, and good crosscultural validity. The test-retest reliability of item difficulty hierarchy (intraclass correlation coefficient=0.99) and patient location (intraclass correlation coefficient=0.92) were both excellent. Furthermore, it showed good external construct validity using correlations with the Functional Independence Measure motor and the Barthel Index and a higher discriminating capacity than either of these widely used indices. CONCLUSIONS: The ACTIVLIM-Stroke questionnaire has good psychometric qualities and provides accurate measures of activity limitations in patients with stroke. It is recommended for evaluating clinical and research interventions in patients with stroke, because it provides a higher discrimination and might be more sensitive to change. PMID- 22223236 TI - The argatroban and tissue-type plasminogen activator stroke study: final results of a pilot safety study. PMID- 22223235 TI - The argatroban and tissue-type plasminogen activator stroke study: final results of a pilot safety study. AB - BACKGROUND AND PURPOSE: Argatroban is a direct thrombin inhibitor that safely augments recanalization achieved by tissue-type plasminogen activator (tPA) in animal stroke models. The Argatroban tPA Stroke Study was an open-label, pilot safety study of tPA plus Argatroban in patients with ischemic stroke due to proximal intracranial occlusion. METHODS: During standard-dose intravenous tPA, a 100-MUg/kg bolus of Argatroban and infusion for 48 hours was adjusted to a target partial thromboplastin time of 1.75* baseline. The primary outcome was incidence of significant intracerebral hemorrhage defined as either symptomatic intracerebral hemorrhage or Parenchymal Hematoma Type 2. Recanalization was measured at 2 and 24 hours by transcranial Doppler or CT angiography. RESULTS: Sixty-five patients were enrolled (45% men, mean age 63+/-14 years, median National Institutes of Health Stroke Scale=13). The median (interquartile range) time tPA to Argatroban bolus was 51 (38-60) minutes. Target anticoagulation was reached at a median (interquartile range) of 3 (2-7) hours. Significant intracerebral hemorrhage occurred in 4 patients (6.2%; 95% CI, 1.7-15.0). Of these, 3 were symptomatic (4.6%; 95% CI, 0.9-12.9). Seven patients (10%) died in the first 7 days. Within the 2-hour monitoring period, transcranial Doppler recanalization (n=47) occurred in 29 (61%) patients: complete in 19 (40%) and partial in another 10 (21%). CONCLUSIONS: The combination of Argatroban and intravenous tPA is potentially safe in patients with moderate neurological deficits due to proximal intracranial arterial occlusions and may produce more complete recanalization than tPA alone. Continued evaluation of this treatment combination is warranted. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT00268762. PMID- 22223238 TI - Accuracy of neurovascular fellows' prognostication of outcome after subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: The purpose of this study was to determine the accuracy and optimal timing of physician prognostication in patients with subarachnoid hemorrhage, a prototypical neurological disease characterized by variable outcomes and frequent disability. METHODS: From October 2009 to April 2010, treating neurologists at a tertiary care academic medical center made daily predictions of the modified Rankin Scale at 6 months for consecutive patients with subarachnoid hemorrhage. Actual functional outcomes at 6 months were determined by phone interview and dichotomized into good (modified Rankin Scale 0 2) and poor (modified Rankin Scale 3-6) outcomes. Descriptive statistics were used to assess the accuracy of prognostications. Multiple logistic regression and generalized estimating equations were used to assess changes in prognostication accuracy over time and the relationship between prognostication accuracy and clinical factors. RESULTS: Physicians made 648 prognostications for 66 patients. Overall accuracy ranged from 78% to 88%. Among patients predicted to have a good outcome, 81% (95% CI, 71%-92%) actually had a good outcome, whereas 88% (95% CI, 77%-99%) of patients predicted to do poorly had poor outcomes. No significant trends were seen in prognostication accuracy over time during the hospital course (P=0.72). Increasing age, infection, mechanical ventilation, hydrocephalus, and seizures all significantly worsened physician accuracy. CONCLUSIONS: Neurologists were generally but not perfectly accurate in their prognostications of functional outcomes. The accuracy of prognoses did not correlate with the hospital day on which they were made but was affected by clinical factors that can cloud the neurological examination. PMID- 22223239 TI - Ezetimibe and regression of carotid atherosclerosis: importance of measuring plaque burden. AB - BACKGROUND AND PURPOSE: There has been recent controversy over failure of ezetimibe to reduce carotid intima-media thickness. Much of this is based on failure to understand important differences among ultrasound phenotypes of atherosclerosis. METHODS: We analyzed the effect of adding ezetimibe to the regimen of patients being followed in vascular prevention clinics where measurement of carotid plaque burden (total plaque area) is used to guide therapy. RESULTS: There were complete data in 231 patients with total plaque area for 2 years before and 2 years after initiation of ezetimibe. In the 2 years before and after initiation of ezetimibe, total cholesterol decreased significantly before (P<0.0001) and after initiation of ezetimibe (P<0.0001); low density lipoprotein cholesterol declined significantly before (P<0.0001) and after (P=0.003) initiation of ezetimibe. Triglycerides declined significantly before ezetimibe (P<0.0001) but did not change after addition of ezetimibe (P=0.48). High-density lipoprotein cholesterol did not change significantly before (P=0.87) but declined significantly after ezetimibe (P=0.03). Despite the decline in low-density lipoprotein cholesterol before addition of ezetimibe, there was a significant mean increase in within-individual total plaque area in the 2 years before addition of ezetimibe by 6.89+/-39.57 mm(2) (SD); after addition of ezetimibe, despite the decline in high-density lipoprotein, plaque area decreased by -3.05+/-SD 38.18 mm(2) SD (P<0.01). CONCLUSIONS: Ezetimibe appears to regress carotid plaque burden. To assess effects of antiatherosclerotic therapies, it is important to measure plaque burden. These findings should be tested in a clinical trial. PMID- 22223237 TI - Adjunctive and alternative approaches to current reperfusion therapy. AB - BACKGROUND AND PURPOSE: Current ischemic stroke reperfusion therapy consists of intravenous thrombolysis given in eligible patients after review of a noncontrast CT scan and a time-based window of opportunity. Rapid clot lysis has a strong association with clinical improvement but remains incomplete in many patients. This review appraises novel adjunctive or alternative approaches to current reperfusion strategies being tested in all trial phases. Summary of Review- Alternative approaches to current reperfusion therapy can be separated into 4 main categories: (1) combinatory approaches with other drugs or devices; (2) novel systemic thrombolytic agents; (3) endovascular medical or mechanical reperfusion treatments; and (4) noninvasive or minimally invasive methods to augment cerebral blood flow and alleviate intracranial blood flow steal. CONCLUSIONS: Reperfusion treatments must be provided as fast as possible in patients most likely to benefit. Patients who fail to rapidly reperfuse may benefit from other strategies that maintain collateral flow or protect tissue at risk. PMID- 22223240 TI - Development and validation of a dispatcher identification algorithm for stroke emergencies. AB - BACKGROUND AND PURPOSE: Recent innovations such as CT installation in ambulances may lead to earlier start of stroke-specific treatments. However, such technically complex mobile facilities require effective methods of correctly identifying patients before deployment. We aimed to develop and validate a new dispatcher identification algorithm for stroke emergencies. METHODS: Dispatcher identification algorithm for stroke emergencies was informed by systematic qualitative analysis of the content of emergency calls to ambulance dispatchers for patients with stroke or transient ischemic attack (N=117) and other neurological (N=39) and nonneurological (N=51) diseases (Part A). After training of dispatchers, sensitivity and predictive values were determined prospectively in patients admitted to Charite hospitals by using the discharge diagnosis as reference standard (Part B). RESULTS: Part A: Dysphasic/dysarthric symptoms (33%), unilateral symptoms (22%) and explicitly stated suspicion of stroke (47%) were typically identified in patients with stroke but infrequently in nonstroke cases (all <10%). Convulsive symptoms (41%) were frequent in other neurological diseases but not strokes (3%). Pain (26%) and breathlessness (31%) were often expressed in nonneurological emergencies (6% and 7% in strokes). Part B: Between October 15 and December 16, 2010, 5774 patients were admitted by ambulance with 246 coded with final stroke diagnoses. Sensitivity of dispatcher identification algorithm for stroke emergencies for detecting stroke was 53.3% and positive predictive value was 47.8% for stroke and 59.1% for stroke and transient ischemic attack. Of all 275 patients with stroke dispatcher codes, 215 (78.5%) were confirmed with neurological diagnosis. CONCLUSIONS: Using dispatcher identification algorithm for stroke emergencies, more than half of all patients with stroke admitted by ambulance were correctly identified by dispatchers. Most false-positive stroke codes had other neurological diagnoses. PMID- 22223241 TI - Baroreflex sensitivity to predict malignant middle cerebral artery infarction. AB - BACKGROUND AND PURPOSE: Hemicraniectomy has been shown to be an effective treatment of life-threatening edema (LTE) in malignant middle cerebral artery infarction when performed early. Identifying patients who will develop LTE is therefore imperative. We hypothesize that autonomic shift toward sympathetic dominance may relate to LTE formation. We aimed to investigate the predictive potential of baroreflex sensitivity (BRS) as a marker of autonomic balance for calculating the course of large middle cerebral artery infarction. METHODS: Patients with middle cerebral artery infarction >2/3 of the territory and BRS measurement at admission were analyzed. BRS was estimated using the cross correlational method. Demographic, clinical, and radiological data including stroke severity, infarct size, and basal ganglia involvement were recorded. Malignant course with LTE was defined as clinical deterioration and midline shift >=5 mm in the first 48 hours. RESULTS: Eighteen (62.8%) patients developed LTE. Patients with LTE had lower BRS (2.3 versus 4.4 mm Hg/ms, P=0.007), larger infarcts (214 versus 144 mL, P=0.03), more frequent involvement of the basal ganglia (14 versus 4, P=0.03), and more often underwent thrombolysis combined with endovascular intervention (6 versus 0, P=0.04). In a multivariate model, BRS (OR, 0.36; CI, 0.14-0.93; P=0.03) and basal ganglia involvement (OR, 11.53; CI, 1.15-115.9; P=0.04) were independent predictors for LTE. This model correctly classified 86.2% of the malignant cases. CONCLUSIONS: Decreased BRS, mirroring sympathetic activation, and basal ganglia involvement were associated with development of malignant course with LTE in large middle cerebral artery infarction. The predictive relevance of our findings needs to be confirmed in further studies. PMID- 22223242 TI - Letter by Urra et al regarding article, "Autoimmune responses to the brain after stroke are associated with worse outcome". PMID- 22223243 TI - Netrin-1 hyperexpression in mouse brain promotes angiogenesis and long-term neurological recovery after transient focal ischemia. AB - BACKGROUND AND PURPOSE: Netrin-1 (NT-1) stimulates endothelial cell proliferation and migration in vitro and promotes focal neovascularization in the adult brain in vivo. This in vivo study in mice investigated the effect of NT-1 hyperexpression on focal angiogenesis and long-term functional outcome after transient middle cerebral artery occlusion (tMCAO). METHODS: Adeno-associated viral vectors carrying either the NT-1 gene (AAV-NT-1) or GFP (AAV-GFP) were generated and injected into the brains of separate groups of 93 mice. Seven days later, tMCAO followed by 7-28 days of reperfusion were carried out. Histological outcomes and behavioral deficits were quantified 7-28 days after tMCAO. Small cerebral vessel network and angiogenesis were assessed 28 days after tMCAO, using synchrotron radiation microangiography and immunohistochemistry. RESULTS: Western blot and immunohistochemistry showed that on the day of tMCAO, NT-1 hyperexpression had been achieved in both normal and ischemic hemispheres. Immunofluorescence imaging showed that NT-1 expression was primarily in neurons and astrocytes. Ischemia-induced infarction in the NT-1 hyperexpression group was attenuated in comparison to saline or AAV-GFP-treated groups (P<0.01). Similarly, neurological deficits were greatly improved in AAV-NT-1-treated mice compared with mice in saline or AAV-GFP-treated groups (P<0.05). In addition, angiogenesis was increased in AAV-NT-1-treated mice compared with the other 2 groups (P<0.05). In vivo synchrotron radiation microangiography 28 days after tMCAO revealed more branches in AAV-NT-1-treated mice than in other groups. CONCLUSIONS: AAV-NT-1 induced NT-1 hyperexpression before tMCAO reduced infarct size, enhanced neovascularization, and improved long-term functional recovery. PMID- 22223244 TI - Variable presentations of postpartum angiopathy. AB - BACKGROUND AND PURPOSE: Postpartum angiopathy (PPA), a rare cause of stroke in the puerperium, is heralded by severe headaches within 1-2 weeks after delivery. Angiography demonstrates segmental vasoconstriction that often resolves spontaneously. PPA is generally regarded as benign. We aimed to define clinical presentations, radiological findings, and outcomes of patients with PPA. METHODS: We retrospectively reviewed patients from 3 centers with acute neurological symptoms and angiography showing vasoconstriction in the postpartum period. Patients without neuroimaging and with diagnoses of cerebral venous sinus thrombosis and aneurysmal hemorrhage were excluded. Patient characteristics, clinical symptoms, neuroimaging findings, and clinical condition at hospital discharge were collected. RESULTS: Eighteen patients (mean age, 31 years; range, 15-41) were identified. Median gestation was 38 weeks. Twelve (67%) had a history of prior uneventful pregnancy. Neurological symptoms began on median day 5 postpartum and included headache (n=16, 89%), focal deficit (n=9, 50%), visual disturbance (n=8, 44%), encephalopathy (n=6, 33%), and seizure (n=5, 28%), often in combination. Brain imaging was abnormal in most (n=13, 72%). The most common abnormalities were intracranial hemorrhage (n=7, 39%), vasogenic edema (n=6, 35%), and infarction (n=6, 35%). Clinical outcomes were markedly variable with full recovery seen in 9 (50%), death after a fulminant course in 4 (22%), and residual deficits in 5 (28%). CONCLUSIONS: In contrast to prior reports, this group of patients with PPA had a higher proportion of nonbenign outcomes. Most patients who undergo neuroimaging have parenchymal abnormalities, which are most often stroke (hemorrhagic or ischemic) or reversible vasogenic edema. PMID- 22223245 TI - Chromophores in conjugated polymers--all straight? AB - What is the physical shape of the pi-electron system in a large macromolecule such as a conjugated polymer? Although intuitively one may argue that any departure from rigidity by bending or twisting should disrupt conjugation, leading to the formation of discrete chromophores, single-molecule and ensemble time-resolved studies support the notion that the pi-bond is remarkably persistent in space: even individual chromophores can be bent and twisted, so that caution is warranted when interpreting a wide range of polarisation-based spectroscopies. PMID- 22223246 TI - Visualization of a DNA-PK/PARP1 complex. AB - The DNA-dependent protein kinase (DNA-PK) and Poly(ADP-ribose) polymerase-1 (PARP1) are critical enzymes that reduce genomic damage caused by DNA lesions. They are both activated by DNA strand breaks generated by physiological and environmental factors, and they have been shown to interact. Here, we report in vivo evidence that DNA-PK and PARP1 are equally necessary for rapid repair. We purified a DNA-PK/PARP1 complex loaded on DNA and performed electron microscopy and single particle analysis on its tetrameric and dimer-of-tetramers forms. By comparison with the DNA-PK holoenzyme and fitting crystallographic structures, we see that the PARP1 density is in close contact with the Ku subunit. Crucially, PARP1 binding elicits substantial conformational changes in the DNA-PK synaptic dimer assembly. Taken together, our data support a functional, in-pathway role for DNA-PK and PARP1 in double-strand break (DSB) repair. We also propose a NHEJ model where protein-protein interactions alter substantially the architecture of DNA-PK dimers at DSBs, to trigger subsequent interactions or enzymatic reactions. PMID- 22223248 TI - Generation of mice with a conditional allele for the transforming growth factor beta3 gene. AB - The transforming growth factor beta (TGFbeta) pathway is involved in embryonic development and several inherited and acquired human diseases. The gene for TGFbeta3 (Tgfb3) encodes one of the three ligands for TGFbeta receptors. It is widely expressed in the embryo and its mutation or misexpression is found in human diseases. Tgfb3-/- mice die at birth from cleft palate, precluding functional studies in adults. Here, we generated mice in which exon 6 of Tgfb3 was flanked with LoxP sites (Tgfb3flox/flox). The adult mice were normal and fertile. EIIa-Cre-mediated deletion of exon 6 in Tgfb3flox/flox mice efficiently generated Tgfb3 conditional knockout (Tgfb3cko/cko) mice which died at birth from the same cleft palate defect as Tgfb3-/- mice, indicating that the conditional and knockout alleles are functionally equivalent. This Tgfb3cko allele will now enable studies of TGFbeta3 function in different cell or tissue types in embryonic development and during adulthood. PMID- 22223251 TI - Laplace approximation in measurement error models. AB - Likelihood analysis for regression models with measurement errors in explanatory variables typically involves integrals that do not have a closed-form solution. In this case, numerical methods such as Gaussian quadrature are generally employed. However, when the dimension of the integral is large, these methods become computationally demanding or even unfeasible. This paper proposes the use of the Laplace approximation to deal with measurement error problems when the likelihood function involves high-dimensional integrals. The cases considered are generalized linear models with multiple covariates measured with error and generalized linear mixed models with measurement error in the covariates. The asymptotic order of the approximation and the asymptotic properties of the Laplace-based estimator for these models are derived. The method is illustrated using simulations and real-data analysis. PMID- 22223247 TI - Genome-wide occupancy links Hoxa2 to Wnt-beta-catenin signaling in mouse embryonic development. AB - The regulation of gene expression is central to developmental programs and largely depends on the binding of sequence-specific transcription factors with cis-regulatory elements in the genome. Hox transcription factors specify the spatial coordinates of the body axis in all animals with bilateral symmetry, but a detailed knowledge of their molecular function in instructing cell fates is lacking. Here, we used chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq) to identify Hoxa2 genomic locations in a time and space when it is actively instructing embryonic development in mouse. Our data reveals that Hoxa2 has large genome coverage and potentially regulates thousands of genes. Sequence analysis of Hoxa2-bound regions identifies high occurrence of two main classes of motifs, corresponding to Hox and Pbx-Hox recognition sequences. Examination of the binding targets of Hoxa2 faithfully captures the processes regulated by Hoxa2 during embryonic development; in addition, it uncovers a large cluster of potential targets involved in the Wnt-signaling pathway. In vivo examination of canonical Wnt-beta-catenin signaling reveals activity specifically in Hoxa2 domain of expression, and this is undetectable in Hoxa2 mutant embryos. The comprehensive mapping of Hoxa2-binding sites provides a framework to study Hox regulatory networks in vertebrate developmental processes. PMID- 22223252 TI - ROC curve inference for best linear combination of two biomarkers subject to limits of detection. AB - The receiver operating characteristic (ROC) curve is a tool commonly used to evaluate biomarker utility in clinical diagnosis of disease. Often, multiple biomarkers are developed to evaluate the discrimination for the same outcome. Levels of multiple biomarkers can be combined via best linear combination (BLC) such that their overall discriminatory ability is greater than any of them individually. Biomarker measurements frequently have undetectable levels below a detection limit sometimes denoted as limit of detection (LOD). Ignoring observations below the LOD or substituting some replacement value as a method of correction has been shown to lead to negatively biased estimates of the area under the ROC curve for some distributions of single biomarkers. In this paper, we develop asymptotically unbiased estimators, via the maximum likelihood technique, of the area under the ROC curve of BLC of two bivariate normally distributed biomarkers affected by LODs. We also propose confidence intervals for this area under curve. Point and confidence interval estimates are scrutinized by simulation study, recording bias and root mean square error and coverage probability, respectively. An example using polychlorinated biphenyl (PCB) levels to classify women with and without endometriosis illustrates the potential benefits of our methods. PMID- 22223253 TI - On easily interpretable multivariate reference regions of rectangular shape. AB - Till now, multivariate reference regions have played only a marginal role in the practice of clinical chemistry and laboratory medicine. The major reason for this fact is that such regions are traditionally determined by means of concentration ellipsoids of multidimensional Gaussian distributions yielding reference limits which do not allow statements about possible outlyingness of measurements taken in specific diagnostic tests from a given patient or subject. As a promising way around this difficulty we propose to construct multivariate reference regions as p-dimensional rectangles or (in the one-sided case) rectangular half-spaces whose edges determine univariate percentile ranges of the same probability content in each marginal distribution. In a first step, the corresponding notion of a quantile of a p-dimensional probability distribution of any type and shape is made mathematically precise. Subsequently, both parametric and nonparametric procedures of estimating such a quantile are described. Furthermore, results on sample-size calculation for reference-centile studies based on the proposed definition of multivariate quantiles are presented generalizing the approach of Jennen-Steinmetz and Wellek. PMID- 22223254 TI - Analysis of covariance with pre-treatment measurements in randomized trials under the cases that covariances and post-treatment variances differ between groups. AB - When primary endpoints of randomized trials are continuous variables, the analysis of covariance (ANCOVA) with pre-treatment measurements as a covariate is often used to compare two treatment groups. In the ANCOVA, equal slopes (coefficients of pre-treatment measurements) and equal residual variances are commonly assumed. However, random allocation guarantees only equal variances of pre-treatment measurements. Unequal covariances and variances of post-treatment measurements indicate unequal slopes and, usually, unequal residual variances. For non-normal data with unequal covariances and variances of post-treatment measurements, it is known that the ANCOVA with equal slopes and equal variances using an ordinary least-squares method provides an asymptotically normal estimator for the treatment effect. However, the asymptotic variance of the estimator differs from the variance estimated from a standard formula, and its property is unclear. Furthermore, the asymptotic properties of the ANCOVA with equal slopes and unequal variances using a generalized least-squares method are unclear. In this paper, we consider non-normal data with unequal covariances and variances of post-treatment measurements, and examine the asymptotic properties of the ANCOVA with equal slopes using the variance estimated from a standard formula. Analytically, we show that the actual type I error rate, thus the coverage, of the ANCOVA with equal variances is asymptotically at a nominal level under equal sample sizes. That of the ANCOVA with unequal variances using a generalized least-squares method is asymptotically at a nominal level, even under unequal sample sizes. In conclusion, the ANCOVA with equal slopes can be asymptotically justified under random allocation. PMID- 22223255 TI - A new location-scale test based on a combination of the ideas of Levene and Lepage. AB - Lepage's test combines the Wilcoxon rank-sum and the Ansari-Bradley statistics. We propose to replace the latter statistic by a Wilcoxon rank-sum calculated after Levene's transformation. We use the medians for this transformation, i.e. absolute deviations from sample medians are calculated. The new location-scale test can be carried out as a permutation test based on permutations of the original observations, the Levene transformation has to be applied for each permutation in an intermediate step to calculate the test statistic. Simulations indicate that the new test can be more powerful than an O'Brien-type test and Lepage's test, the latter is the standard nonparametric location-scale test. The new test is illustrated using real data about colony sizes of yellow-eyed penguins and an SAS program to perform the test is freely available. PMID- 22223256 TI - Thermodynamic analysis of water molecules at the surface of proteins and applications to binding site prediction and characterization. AB - Water plays an essential role in determining the structure and function of all biological systems. Recent methodological advances allow for an accurate and efficient estimation of the thermodynamic properties of water molecules at the surface of proteins. In this work, we characterize these thermodynamic properties and relate them to various structural and functional characteristics of the protein. We find that high-energy hydration sites often exist near protein motifs typically characterized as hydrophilic, such as backbone amide groups. We also find that waters around alpha helices and beta sheets tend to be less stable than waters around loops. Furthermore, we find no significant correlation between the hydration site-free energy and the solvent accessible surface area of the site. In addition, we find that the distribution of high-energy hydration sites on the protein surface can be used to identify the location of binding sites and that binding sites of druggable targets tend to have a greater density of thermodynamically unstable hydration sites. Using this information, we characterize the FKBP12 protein and show good agreement between fragment screening hit rates from NMR spectroscopy and hydration site energetics. Finally, we show that water molecules observed in crystal structures are less stable on average than bulk water as a consequence of the high degree of spatial localization, thereby resulting in a significant loss in entropy. These findings should help to better understand the characteristics of waters at the surface of proteins and are expected to lead to insights that can guide structure-based drug design efforts. PMID- 22223257 TI - In vivo therapeutic effect of CDH3/P-cadherin-targeting radioimmunotherapy. AB - PURPOSE: We examined the possible efficacy of the yttrium-90 ((90)Y)-labeled anti CDH3/P-cadherin mouse monoclonal antibody (MAb-6) in radioimmunotherapy (RIT) for lung and colorectal cancers that express CDH3/P-cadherin. EXPERIMENTAL DESIGN: MAb-6 was established using genetic immunization. The biodistribution of MAb-6 in nude mice with lung and colorectal cancers was examined by administering indium 111((111)In)-labeled MAb-6 to mice. The mice were prepared by inoculation of CDH3/P-cadherin-positive (EBC1, H1373, and SW948) and CDH3/P-cadherin-negative (A549 and RKO) tumor cells. Therapeutic effects and toxicity were investigated by administration of (90)Y-labeled MAb-6 ((90)Y-MAb-6) to EBC, H1373, and SW948 inoculated mice. RESULTS: Our in vivo results confirmed the specific binding of MAb-6 to tumor cells after intravenous injections of (111)In-labeled MAb-6 to mice with tumors expressing CDH3/P-cadherin. A single intravenous injection of (90)Y-MAb-6 (100 MUCi) significantly suppressed tumor growth in mice with tumors expressing CDH3/P-cadherin. Furthermore, two injections of (90)Y-MAb-6 led to complete tumor regression in H1373-inoculated mice without any detectable toxicity. CONCLUSIONS: Our findings demonstrate that CDH3/P-cadherin-targeting RIT with (90)Y-MAb-6 is a promising strategy for the treatment for cancers expressing CDH3/P-cadherin. PMID- 22223259 TI - Unveiling the shape of aspirin in the gas phase. PMID- 22223258 TI - Therapeutic effect of intratumoral administration of DCs with conditional expression of combination of different cytokines. AB - In this study, we tested the effect of intratumoral administration of dendritic cells (DCs) with inducible expression of different cytokines, using the novel Rheoswitch Therapeutic System on the experimental models of renal cell cancer (RENCA) and MethA sarcoma. Intratumoral injection of DCs, engineered to express IL-12, IL-21, or IFN-alpha, showed potent therapeutic effect against established tumor. This effect was associated with the induction of potent tumor antigen specific CD8+ T-cell responses, as well as the infiltration of tumors with CD4+ and CD8+ T cells but not with the cytotoxic activity of DCs. Combination of i.t. administration of DCs, producing different cytokines, did not enhance the antitumor effect of therapy with single cytokine. These results indicate that RTS can be a potent tool for conditional topical cytokine delivery, in combination with DC administration. However, combination of different cytokines may not necessarily improve the outcome of treatment. PMID- 22223260 TI - Uncomplicated prior right ventricular perforation due to a pacemaker lead - an incidental finding during coronary artery bypass surgery. AB - An elective coronary artery bypass grafting (CABG) surgery was performed on a 50 year-old male with an implanted two-chamber pacemaker in our clinic. Right ventricular adhesion to the inferior pericardium was detected following pericardiotomy. After the institution of cardiopulmonary bypass (CPB), careful preparation of the adhesion revealed prior perforation due to an indwelling ventricular pacemaker lead. PMID- 22223261 TI - [Types of medical registries - definitions, methodological aspects and quality of the scientific work with registries]. AB - This work presents a comprehensive list of registry definitions including broader and narrower definitions. Compared to each other different methodological issues can be identified. Some of these issues are common for all registry types; some can be assigned more easily to a specific registry type. Instruments for evaluating the quality of registers reflect many of the mentioned aspects. Generally, and especially at registers with a descriptive or exploratory research dimension it is important to consider their intended purpose and in about it was achieved. This includes, for instance, whether the purpose and the methodology are coordinated. From the start of registration an initiator should be - based on the purpose - aware of the methodological dimension of the registry. This helps to apply the correct type of the registry, the appropriate guidance and, ultimately, the arguments for the effort (cost-benefit ratio). PMID- 22223262 TI - Combinatorial chemistry has matured in the last three decades: dedicated to Professor Arpad Furka on the occasion of his 80th birthday. AB - Combinatorial chemistry was introduced in the 1980s. It provided the possibility to produce new compounds in practically unlimited number. New strategies and technologies have also been developed that made it possible to screen very large number of compounds and to identify useful components in mixtures containing millions of different substances. This dramatically changed the drug discovery process and the way of thinking of synthetic chemists. In addition, combinatorial strategies became useful in areas such as pharmaceutical research, agrochemistry, catalyst design, and materials research. Prof. Arpad Furka is one of the pioneers of combinatorial chemistry. PMID- 22223263 TI - Fast and selective modification of thiol proteins/peptides by N (phenylseleno)phthalimide. AB - We previously reported that selenamide reagents such as ebselen and N (phenylseleno)phthalimide (NPSP) can be used to selectively derivatize thiols for mass spectrometric analysis, and the introduced selenium tags are useful as they could survive or removed with collision-induced dissociation (CID). Described herein is the further study of the reactivity of various protein/peptide thiols toward NPSP and its application to derivatize thiol peptides in protein digests. With a modified protocol (i.e., dissolving NPSP in acetonitrile instead of aqueous solvent), we found that quantitative conversion of thiols can be obtained in seconds, using NPSP in a slight excess amount (NPSP:thiol of 1.1-2:1). Further investigation shows that the thiol reactivity toward NPSP reflects its chemical environment and accessibility in proteins/peptides. For instance, adjacent basic amino acid residues increase the thiol reactivity, probably because they could stabilize the thiolate form to facilitate the nucleophilic attack of thiol on NPSP. In the case of creatine phosphokinase, the native protein predominately has one thiol reacted with NPSP while all of four thiol groups of the denatured protein can be derivatized, in accordance with the corresponding protein conformation. In addition, thiol peptides in protein/peptide enzymatic digests can be quickly and effectively tagged by NPSP following tri-n-butylphosphine (TBP) reduction. Notably, all three thiols of the peptide QCCASVCSL in the insulin peptic digest can be modified simultaneously by NPSP. These results suggest a novel and selective method for protecting thiols in the bottom-up approach for protein structure analysis. PMID- 22223264 TI - Direct observation of ferrielectricity at ferroelastic domain boundaries in CaTiO3 by electron microscopy. AB - High-resolution aberration-corrected transmission electron microscopy aided by statistical parameter estimation theory is used to quantify localized displacements at a (110) twin boundary in orthorhombic CaTiO(3). The displacements are 3-6 pm for the Ti atoms and confined to a thin layer. This is the first direct observation of the generation of ferroelectricity by interfaces inside this material which opens the door for domain boundary engineering. PMID- 22223265 TI - Antidepressant-like effect of magnolol on BDNF up-regulation and serotonergic system activity in unpredictable chronic mild stress treated rats. AB - Magnolol is the main constituent identified in the barks of Magnolia officinalis, which has been used for the treatment of mental disorders including depression in China. In this study, we investigated the antidepressant-like effect of magnolol, and its possible mechanisms in rats subjected to unpredictable chronic mild stress (UCMS). High performance liquid chromatography with electrochemical detection (HPLC-ECD) and immunohistochemical staining analysis were applied to explore the mechanisms underlying the antidepressant-like effect of magnolol. Magnolol (20, 40 mg/kg) significantly reversed UCMS-induced reduction in sucrose consumption and deficiency in locomotor activity. In addition, it was observed that administration of magnolol (20, 40 mg/kg) restored brain-derived neurotrophic factor (BDNF) expression, and normalized the serotonergic system changes in the UCMS-treated rats. These results confirmed the antidepressant-like effect of magnolol, which might be based primarily on its ability to increase the BDNF expression and enhance the activity of the serotonergic system in rat brains. PMID- 22223266 TI - MED12 mutations in uterine fibroids--their relationship to cytogenetic subgroups. AB - Recurrent chromosomal alterations are found in roughly 20% of all uterine fibroids but in the majority cytogenetic changes are lacking. Recently, mutations of the gene mediator subcomplex 12 (MED12) have been detected in a majority of fibroids but no information is available whether or not they co-occur with cytogenetic subtypes as, e.g., rearrangements of the genes encoding high mobility group AT-hook (HMGA) proteins. In a total of 80 cytogenetically characterized fibroids from 50 patients, we were not only able to confirm the frequent occurrence of MED12 mutations but also to stratify two mutually exclusive pathways of leiomyomagenesis with either rearrangements of HMGA2 reflected by clonal chromosome abnormalities affecting 12q14~15 or by mutations affecting exon 2 of MED12. On average the latter mutations were associated with a significantly smaller tumor size. However, G>A transitions of nucleotides c.130 or c.131 correlate with a significantly larger size of the fibroids compared to other MED12 mutations thus explaining the high prevalence of the former mutations among clinically detectable fibroids. Interestingly, fibroids with MED12 mutations expressed significantly higher levels of the gene encoding wingless-type MMTV integration site family, member 4 (WNT4). Based on these findings and data from the literature, we hypothesize that estrogen and the mutated MED12 cooperate in activating the Wnt pathway which in turn activates beta-catenin known to cause leiomyoma-like lesions in a mouse model. The occurrence of a "fibroid-type mutation" in a rare histologic subtype of endometrial polyps suggests that this mechanism is not confined to uterine leiomyomas. PMID- 22223267 TI - Definition and risk factors of rapidly declining residual renal function in peritoneal dialysis: an observational study. AB - BACKGROUND: It is critical to preserve residual renal function (RRF) in peritoneal dialysis (PD), as RRF is associated with lower morbidity and mortality. There is no uniform definition of RRF, and rapidly declining RRF has rarely been studied and predominately limited to single factor analysis and not corrected for lead-time bias. METHODS: An observational study in 71 incident PD patients. RRF was defined as urine output (UO) >=500 ml/day and renal glomerular filtration rate (rGFR) >=2 ml/min/1.73 m(2), rapid declining RRF as UO <500 ml/day and rGFR <2 ml/min/1.73 m(2) occurring within 6 months which were separately evaluated. Independent risk factors associated with rapid RRF decline were identified while correcting for lead-time bias. RESULTS: RRF declined rapidly by both definitions in 65% patients 2.5 years after PD start. Both definitions of RRF decline were consistent in 96%. Nephrotoxic drugs, renal transplant failure and absent angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) were independent risk factors associated with rapidly declining RRF defined both by definitions, intravascular radiocontrast additionally for UO decline. CONCLUSIONS: Most PD patients demonstrated rapid RRF decline, independent of its definition. Both definitions are highly consistent and interchangeable. Nephrotoxic drugs and radiocontrast were identified as risk factors of acute, absent ACEI or ARB, and renal transplant failure of chronic renal injury. PMID- 22223269 TI - Acta Crystallographica Section C in 2012. PMID- 22223270 TI - Notes for authors 2012. PMID- 22223268 TI - Morphology, ultrastructure, and probable functions of the sense organs on the ovipositor stylets of the hymenoptran parasitoid, Venturia canescens (Gravenhorst). AB - To help understand the mechanism of host discrimination during oviposition of a parasitoid wasp, Venturia canescens (Gravenhorst) (Hymenoptera: Ichneumonidae), the ultrastructure and morphology of the sense organs on the dorsal and ventral stylets of the ovipositor were examined using scanning and transmission electron microscopy. Ovipositor stylets were scanned for sense organs, because only unsheathed ovipositors are used for probing, stabbing, and host discrimination. Five types of sensilla and secretary pores were identified. Based on their pattern of innervation, the surface-dome and pitted-dome sensilla were thought to have a gustatory function and, thus, are the best candidates for host discrimination. The arrangements of dendrites of type I and type II campaniform sensilla suggested that these acted as pressure- and mechano-receptors, respectively. Coeloconic sensilla might act as thermo-hygroreceptors, whilst secretary pores might provide lubrication during the process of stabbing for oviposition. Surface-dome sensilla were the most numerous type found followed by secretary pores, pitted-dome sensilla, and coeloconic sensilla. Almost all the sensilla and secretary pores were more numerous on the dorsal than on the ventral stylets, and the maximum number of these sensilla and secretary pores occurred on the distal end of the ovipositor stylets and decreased toward the proximal end. The surface-dome sensilla and secretary pores occurred in alternate rows while the pitted-dome sensilla were scattered all over the surface of the ovipositor stylets, especially on the sides of the stylets. PMID- 22223271 TI - PbCa2[Al8O15] with a novel three-dimensional aluminate anion. AB - The asymmetric unit of the title compound, lead(II) dicalcium octaaluminate, contains one Pb, one Ca, four Al and eight O atoms, with the Pb atom and one O atom situated on mirror planes. Three Al atoms exhibit slightly distorted tetrahedral coordinations with a mean Al-O bond length of 1.76 A. The fourth Al atom is in a considerably distorted trigonal-bipyramidal coordination with a mean Al-O bond length of 1.89 A. One AlO(4) tetrahedron forms infinite chains parallel to [100] via corner-sharing. These chains are linked by parallel chains of edge sharing AlO(5) trigonal bipyramids into layers A of six-membered double rings extending parallel to (010). The second layer B is made up of the remaining two AlO(4) tetrahedra. These tetrahedra share corners, resulting in likewise six membered double rings. Finally, the parallel layers A and B are linked into a three-dimensional framework by common corners. Charge compensation is achieved by the Pb(2+) and Ca(2+) cations, which are situated in the cavities of the anionic framework, and which are surrounded by seven and six O atoms, respectively, both within highly irregular coordination polyhedra. PMID- 22223272 TI - Magnesium chloride tetrahydrate, MgCl2.4H2O. AB - The title compound, MgCl(2).4H(2)O, was crystallized at 403 K and its structure determined at 200 K. The structure is built up from MgCl(2)(H(2)O)(4) octahedra with a trans configuration. Each complex is situated on a crystallographic twofold axis, with the rotation axis aligned along one H(2)O-Mg-OH(2) axis. They are connected by a complex network of O-H...Cl hydrogen bonds. The structure contains two-dimensional sections that are essentially identical to those in the reported tetrahydrates of CrCl(2), FeCl(2), FeBr(2) and CoBr(2), but they are stacked in a different manner in MgCl(2).4H(2)O compared with the transition metal structures. PMID- 22223273 TI - [1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene]chloridogold(I). AB - The molecule of the title compound, [AuCl(C(27)H(36)N(2))], which belongs to a class of potentially catalytically active N-heterocyclic carbene complexes, has crystallographic C(2) symmetry and approximate C(2v) symmetry. The structure is isostructural with the Cu(I) and Ag(I) analogues. A previous report of the structure of the title compound as its toluene solvate [Fructos et al. (2005). Angew. Chem. Int. Ed. 44, 5284-5288] has inaccurate geometry for the complex molecule as a consequence of probable incorrect refinement in the space group Cc, instead of C2/c [Marsh (2009). Acta Cryst. B65, 782-783]. The Au-C bond length of 1.998 (4) A in the title compound is more consistent with the mean distance of 1.979 (14) A found in 52 other reported [AuCl(carbene)] complexes than with the shorter distance of 1.942 (3) A given for the refinement in the space group Cc for the toluene solvate and the value of 1.939 A obtained from the recalculation of that structure in C2/c. PMID- 22223274 TI - The conformations of two copper(I) complexes of 1H-benzimidazole-2(3H)-thione and thiosaccharinate. AB - (Acetonitrile-1kappaN)[MU-1H-benzimidazole-2(3H)-thione-1:2kappa(2)S:S][1H benzimidazole-2(3H)-thione-2kappaS]bis(MU-1,1-dioxo-1lambda(6),2-benzothiazole-3 thiolato)-1:2kappa(2)S(3):N;1:2kappa(2)S(3):S(3)-dicopper(I)(Cu-Cu), [Cu(2)(C(7)H(4)NO(2)S(2))(2)(C(7)H(6)N(2)S)(2)(CH(3)CN)] or [Cu(2)(tsac)(2)(Sbim)(2)(CH(3)CN)] [tsac is thiosaccharinate and Sbim is 1H benzimidazole-2(3H)-thione], (I), is a new copper(I) compound that consists of a triply bridged dinuclear Cu-Cu unit. In the complex molecule, two tsac anions and one neutral Sbim ligand bind the metals. One anion bridges via the endocyclic N and exocyclic S atoms (MU-S:N). The other anion and one of the mercaptobenzimidazole molecules bridge the metals through their exocyclic S atoms (MU-S:S). The second Sbim ligand coordinates in a monodentate fashion (kappaS) to one Cu atom, while an acetonitrile molecule coordinates to the other Cu atom. The Cu(I)-Cu(I) distance [2.6286 (6) A] can be considered a strong 'cuprophilic' interaction. In the case of [MU-1H-benzimidazole-2(3H)-thione 1:2kappa(2)S:S]bis[1H-benzimidazole-2(3H)-thione]-1kappaS;2kappaS-bis(MU-1,1 dioxo-1lambda(6),2-benzothiazole-3-thiolato) 1:2kappa(2)S(3):N;1:2kappa(2)S(3):S(3)-dicopper(I)(Cu-Cu), [Cu(2)(C(7)H(4)NO(2)S(2))(2)(C(7)H(6)N(2)S)(3)] or [Cu(2)(tsac)(2)(Sbim)(3)], (II), the acetonitrile molecule is substituted by an additional Sbim ligand, which binds one Cu atom via the exocylic S atom. In this case, the Cu(I)-Cu(I) distance is 2.6068 (11) A. PMID- 22223275 TI - A triclinic polymorph of cyclo-tetra-MU-thiosaccharinato-kappa8S:S tetrakis[(triphenylphosphane-kappaP)silver(I)]. AB - The triclinic structure of the title compound, cyclo-tetrakis(MU-1,1-dioxo 1lambda(6),2-benzothiazole-3-thiolato-kappa(2)S:S)tetrakis[(triphenylphosphane kappaP)silver(I)], [Ag(4)(C(7)H(4)NO(2)S(2))(4)(C(18)H(15)P)(4)], is a polymorph of the previously reported monoclinic structure [Dennehy, Mandolesi, Quinzani & Jennings (2007). Z. Anorg. Allg. Chem. 633, 2746-2752]. In both polymorphs, the complex lies on a crystallographic inversion centre and the bond distances are closely comparable. Some differences can be found in the interatomic angles and torsion angles involving the inner Ag(4)S(4) skeleton. The polymorphs contain essentially identical two-dimensional layers, but with different layer stacking arrangements. In the triclinic form, all layers are related by lattice translation, while in the monoclinic form they are arranged around glide planes so that adjacent layers are mirrored with respect to each other. PMID- 22223276 TI - Poly[di-MU-aqua-MU-1,2-bis(pyridin-4-yl)ethene-kappa2N:N'-tetrakis(4-iodobenzoato kappa2O,O')dicadmium]. AB - Colourless crystals of the title compound, [Cd(2)(C(7)H(4)IO(2))(4)(C(12)H(10)N(2))(H(2)O)(2)](n), were obtained by the self assembly of Cd(NO(3))(2).4H(2)O, 1,2-bis(pyridin-4-yl)ethene (bpe) and 4 iodobenzoic acid (4-IBA). Each Cd(II) atom is seven-coordinated in a pentagonal bipyramidal coordination environment by four carboxylate O atoms from two different 4-IBA ligands, two O atoms from two water molecules and one N atom from a bpe ligand. The Cd(II) centres are bridged by the aqua molecules and bpe ligands, which lie across centres of inversion, to give a two-dimensional net. Topologically, taking the Cd(II) atoms as nodes and the MU-aqua and MU-bpe ligands as linkers, the two-dimensional structure can be simplified as a (6,3) network. PMID- 22223277 TI - Influence of chloroform on crystalline products yielded in reactions of 5,10,15,20-tetraphenylporphyrin with HCl and copper(II) salts. AB - Chloroform was found to occupy the lattice of the protonated porphyrin and to promote crystallization of a different polymorphic form of a metalloporphyrin. The structure of 5,10,15,20-tetraphenylporphyrin-21,23-diium dichloride chloroform octasolvate, C(44)H(32)N(4)(2+).2Cl(-).8CHCl(3), (I), in the solid state is described and compared with related solvates. The porphyrin macrocycle displays a distorted saddle shape, with chloride anions above and below the ring. Seven chloroform molecules are bound via C-H...Cl hydrogen bonds, while the link with the eighth solvent molecule is weaker. A new monoclinic polymorph of (5,10,15,20-tetraphenylporphyrinato)copper(II), [Cu(C(44)H(28)N(4))], (II), crystallized from chloroform, is also presented. PMID- 22223278 TI - A new layered Ca-succinate coordination polymer. AB - A new layered Ca-succinate coordination polymer, poly[MU(3)-succinato calcium(II)], [Ca(C(4)H(5)O(4))](n), was synthesized by reaction of CaCl(2).2H(2)O and succinic acid in an aqueous medium under hydrothermal microwave conditions. The structure contains infinite layers of edge-sharing calcium pentagonal-bipyramidal polyhedra forming six-membered rings connected through succinate ligands. Such an assembly of inorganic building units is unique for calcium metal-organic framework-type structures. Adjacent layers are packed into a final pseudo-three-dimensional structure through weak C-H...O hydrogen bonds. PMID- 22223279 TI - Decaaquabis(MU3-4-hydroxypyridine-2,6-dicarboxylato)bis(4-hydroxypyridine-2,6 dicarboxylato)tetramanganese(II) 3.34-hydrate: a new three-dimensional open metal organic framework based on a tetranuclear Mn(II) complex of chelidamic acid and undecameric stitching water clusters. AB - 4-Hydroxypyridine-2,6-dicarboxylic acid (chelidamic acid, cdaH(3)) reacts with MnCl(2).2H(2)O in the presence of 2-amino-4-methylpyrimidine in water to afford the tetranuclear title complex, [Mn(4)(C(8)H(3)NO(5))(4)(H(2)O)(10)].3.34H(2)O, built through carboxylate bridging. The tetranuclear complex sits on a centre of inversion at (1/2, 1/2, 1/2). In the crystal, discrete undecameric (H(2)O)(10.34) water clusters (involving both coordinated and uncoordinated water molecules, with one site of an uncoordinated water molecule not fully occupied) assemble these tetranuclear Mn(II) complex units via an intricate array of hydrogen bonding into an overall three-dimensional network. The degree of structuring of the (H(2)O)(10.34) supramolecular association of water molecules observed in the present compound, imposed by its environment and vice versa, will be discussed in comparison to that observed for the (H(2)O)(14) supramolecular clusters in the case of the dinuclear complex [Mn(2)(cdaH)(2)(H(2)O)(4)].4H(2)O [Ghosh et al. (2005). Inorg. Chem. 44, 3856-3862]. PMID- 22223280 TI - Benz[cd]indol-2(1H)-one at 298 and 100 K. AB - Weakly diffracting crystals of benz[cd]indol-2(1H)-one (naphtholactam), C(11)H(7)NO, were unsuitable for data collection by early photographic methods. However, a diffractometer data set collected at room temperature in 1989 was solved and refined. The peak scans were broad, and the results indicated disorder or a satellite crystal. Recent data collection (on another crystal from the same sample) with an area detector at 100 K revealed the same disorder, and made it possible to refine two different, more complete, disorder models. Both models assume an occasional 180 degrees rotation of the nearly planar centrosymmetric cis-lactam dimer. The refinements differ, especially in the anisotropic displacement parameters for the -C(=O)-NH- portion of the molecule. Both models at 100 K give a C-N ('amide') bond distance of 1.38 A, about 0.04 A longer than the average distance in saturated gamma-lactams in the Cambridge Structural Database. Cohesive packing interactions between molecules include opposing-dipole dimers; the packing may explain the 10:1 ratio favoring the major-occupancy molecule. PMID- 22223281 TI - Hydrogen-bonded assembly in six closely related pyrazolo[3,4-b]pyridine derivatives; a simple chain, three types of chains of rings and a complex sheet structure. AB - Six closely related pyrazolo[3,4-b]pyridine derivatives, namely 6-chloro-3-methyl 1,4-diphenylpyrazolo[3,4-b]pyridine-5-carbaldehyde, C(20)H(14)ClN(3)O, (I), 6 chloro-3-methyl-4-(4-methylphenyl)-1-phenylpyrazolo[3,4-b]pyridine-5 carbaldehyde, C(21)H(16)ClN(3)O, (II), 6-chloro-4-(4-chlorophenyl)-3-methyl-1 phenylpyrazolo[3,4-b]pyridine-5-carbaldehyde, C(20)H(13)Cl(2)N(3)O, (III), 4-(4 bromophenyl)-6-chloro-3-methyl-1-phenylpyrazolo[3,4-b]pyridine-5-carbaldehyde, C(20)H(13)BrClN(3)O, (IV), 6-chloro-4-(4-methoxyphenyl)-3-methyl-1 phenylpyrazolo[3,4-b]pyridine-5-carbaldehyde, C(21)H(16)ClN(3)O(2), (V), and 6 chloro-3-methyl-4-(4-nitrophenyl)-1-phenylpyrazolo[3,4-b]pyridine-5-carbaldehyde, C(20)H(13)ClN(4)O(3), (VI), which differ only in the identity of a single small substituent on one of the aryl rings, crystallize in four different space groups spanning three crystal systems. The molecules of (I) are linked into a chain of rings by a combination of C-H...N and C-H...pi(arene) hydrogen bonds; those of (II), (IV) and (V), which all crystallize in the space group P 1, are each linked by two independent C-H...O hydrogen bonds to form chains of edge-fused rings running in different directions through the three unit cells; the molecules of (III) are linked into complex sheets by a combination of two C-H...O hydrogen bonds and one C-H...pi(arene) hydrogen bond; finally, the molecules of (VI) are linked by a single C-H...O hydrogen bond to form a simple chain. PMID- 22223282 TI - Probing the relationships between molecular conformation and intermolecular contacts in N,N-dibenzyl-N'-(furan-2-carbonyl)thiourea. AB - In the crystal structure of the title compound, C(20)H(18)N(2)O(2)S, molecules are linked by bifurcated C-H...O hydrogen-bond interactions, giving rise to chains whose links are composed of alternating centrosymmetrically disposed pairs of molecules and characterized by R(2)(2)(10) and R(2)(2)(20) hydrogen-bonding motifs. Also, N-H...S hydrogen bonds form infinite zigzag chains along the [010] direction, which exhibit the C(4) motif. Hirshfeld surface and fingerprint plots were used to explore the intermolecular interactions in the crystal structure. This analysis confirms the important role of C-H...O hydrogen bonds in the molecular conformation and in the crystal structure, providing a potentially useful tool for a full understanding of the intermolecular interactions in acylthiourea derivatives. PMID- 22223283 TI - 2,2'',3,3'',4,4'',5,5''-Octaphenyl-1,1':4',1''-terphenyl and 2',3',5',6' tetrafluoro-2,2'',3,3'',4,4'',5,5''-octaphenyl-1,1':4',1''-terphenyl. AB - The title compounds, C(66)H(46), (I), and C(66)H(42)F(4), (II), are polyphenylated arylenes synthesized by one-step Diels-Alder cycloaddition reactions. In both structures, all molecules lie on crystallographic inversion centers. In the case of (I), there are two half-molecules present in the asymmetric unit, (IA) and (IB); the geometry of each half-molecule differs principally in the magnitudes of the dihedral angles between mean planes fitted through the central aryl ring and the pendant phenyl rings. The crystal used was a non-merohedral twin, with a refined twin scale factor of 0.460 (8). The dihedral angle between the plane of the central tetrafluorinated ring and the adjacent tetraphenylated ring in (II) is 83.87 (4) degrees , significantly greater than the dihedral angles of 49.89 (12) and 54.38 (10) degrees found in the two half-molecules in (IA) and (IB), respectively, and attributed to intermolecular C-H...F hydrogen bonding in (II). Intermolecular C-H...pi bonding is found in (I). Two interactions have the C-H bond oriented towards the centroid (Cg) of a butadiene fragment of a phenyl ring; both H...Cg distances are approximately 2.68 A and the interactions connect adjacent molecules into stacks in the c-axis direction. The composition of the stacks alternates, i.e. (IA)-(IB) (IA)-(IB) etc. A third, weaker, C-H...pi interaction and a phenyl-phenyl close contact connect each end of the long molecular axes of (IB) with an adjacent molecule of (IA) into chains which run perpendicular to the (140) and ( 140) planes. C-H...F interactions in (II) have the most profound influence on the molecular and crystal structure, the main effect of which is the above-mentioned increase in the dihedral angle between the plane of the central tetrafluorinated ring and the adjacent tetraphenylated ring. C-H...F interactions have refined H...F distances of 2.572 (15) and 2.642 (16) A, with approximate C-H...F angles of 123 and 157 degrees , respectively. These form a hydrogen-bonded ribbon structure which propagates in the b-axis direction. PMID- 22223284 TI - Tizanidine and tizanidine hydrochloride: on the correct tautomeric form of tizanidine. AB - A crystallization series of tizanidine hydrochloride, used as a muscle relaxant for spasticity acting centrally as an alpha(2)-adrenergic agonist, yielded single crystals of the free base and the hydrochloride salt. The crystal structures of tizanidine [systematic name: 5-chloro-N-(imidazolidin-2-ylidene)-2,1,3 benzothiadiazol-4-amine], C(9)H(8)ClN(5)S, (I), and tizanidine hydrochloride {systematic name: 2-[(5-chloro-2,1,3-benzothiadiazol-4-yl)amino]imidazolidinium chloride}, C(9)H(9)ClN(5)S(+).Cl(-), (II), have been determined. Tizanidine crystallizes with two almost identical molecules in the asymmetric unit (r.m.s. deviation = 0.179 A for all non-H atoms). The molecules are connected by N-H...N hydrogen bonds forming chains running along [2 11]. The present structure determination corrects the structure determination of tizanidine by John et al. [Acta Cryst. (2011), E67, o838-o839], which shows an incorrect tautomeric form. Tizanidine does not crystallize as the usually drawn 2-amino-imidazoline tautomer, but as the 2-imino-imidazolidine tautomer. This tautomer is present in solution as well, as shown by (1)H NMR analysis. In tizanidine hydrochloride, cations and anions are connected by N-H...Cl hydrogen bonds to form layers parallel to (100). PMID- 22223285 TI - Two succinic acid derivatives of 2-ethyl-6-methylpyridin-3-ol. AB - Crystals of bis(2-ethyl-3-hydroxy-6-methylpyridinium) succinate-succinic acid (1/1), C(8)H(12)NO(+).0.5C(4)H(4)O(4)(2-).0.5C(4)H(6)O(4), (I), and 2-ethyl-3 hydroxy-6-methylpyridinium hydrogen succinate, C(8)H(12)NO(+).C(4)H(5)O(4)(-), (II), were obtained by reaction of 2-ethyl-6-methylpyridin-3-ol with succinic acid. The succinate anion and succinic acid molecule in (I) are located about centres of inversion. Intermolecular O-H...O, N-H...O and C-H...O hydrogen bonds are responsible for the formation of a three-dimensional network in the crystal structure of (I) and a two-dimensional network in the crystal structure of (II). Both structures are additionally stabilized by pi-pi interactions between symmetry-related pyridine rings, forming a rod-like cationic arrangement for (I) and cationic dimers for (II). PMID- 22223286 TI - Disorder and conformational analysis of methyl beta-D-galactopyranosyl-(1->4) beta-D-xylopyranoside. AB - Methyl beta-D-galactopyranosyl-(1->4)-beta-D-xylopyranoside, C(12)H(22)O(10), (II), crystallizes as colorless needles from water with positional disorder in the xylopyranosyl (Xyl) ring and no water molecules in the unit cell. The internal glycosidic linkage conformation in (II) is characterized by a phi' torsion angle (C2'(Gal)-C1'(Gal)-O1'(Gal)-C4(Xyl)) of 156.4 (5) degrees and a psi' torsion angle (C1'(Gal)-O1'(Gal)-C4(Xyl)-C3(Xyl)) of 94.0 (11) degrees , where the ring atom numbering conforms to the convention in which C1 denotes the anomeric C atom, and C5 and C6 denote the hydroxymethyl (-CH(2)OH) C atoms in the beta-Xyl and beta-Gal residues, respectively. By comparison, the internal linkage conformation in the crystal structure of the structurally related disaccharide, methyl beta-lactoside [methyl beta-D-galactopyranosyl-(1->4)-beta-D glucopyranoside], (III) [Stenutz, Shang & Serianni (1999). Acta Cryst. C55, 1719 1721], is characterized by phi' = 153.8 (2) degrees and psi' = 78.4 (2) degrees . A comparison of beta-(1->4)-linked disaccharides shows considerable variability in both phi' and psi', with the range in the latter (~38 degrees ) greater than that in the former (~28 degrees ). Inter-residue hydrogen bonding is observed between atoms O3(Xyl) and O5'(Gal) in the crystal structure of (II), analogous to the inter-residue hydrogen bond detected between atoms O3(Glc) and O5'(Gal) in (III). The exocyclic hydroxymethyl conformations in the Gal residues of (II) and (III) are identical (gauche-trans conformer). PMID- 22223287 TI - Retrospective report of symptomatic postoperative discal pseudocyst after lumbar discectomy. AB - BACKGROUND: Rarely, a symptomatic discal pseudocyst can develop after discectomy. Only very recently one clinical article and one case report about this type of pseudocyst were published: Kang and Park (J Korean Neurosurg Soc 49(1):31-36, 2011); Young PM, Fenton DS, Czervionke LF (Spine J. 9(2):e9-e15, 2009). Here, in an attempt to more clearly discriminate this peculiar cyst, the authors retrospectively report the clinical, radiological, and histological findings in 12 symptomatic patients with cystic lesions attached to an operated disc. METHODS: From January 2007 to May 2010, 12 patients who experienced recurrent symptoms after successful lumbar discectomy were diagnosed with postoperative discal pseudocyst (PDP). After discectomy, the mean time to relapsing radiculopathy was 23.3 days (range, 9-38 days) with a mean of 6.8 +/- 1.3 on the visual analogue scale (VAS). PDPs were detected on magnetic resonance imaging (MRI) at 31.2 days (range, 14-60 days) after the initial surgery. Of these 12 patients, 6 were treated conservatively (group C) and 6 by surgery (group S). RESULTS: In the six patients in group C, the mean duration of relapsing pain was 77.8 days (range, 20-225 days), and near total or total regression of the cyst was detected at a mean of 82.7 days (range, 23-240 days) after initial detection by MRI. Time to spontaneous regression of PDP varied widely. In the six patients in group S, surgical treatment was administered within a few days of MRI diagnosis and achieved successful pain relief. CONCLUSIONS: Postoperative discal pseudocyst appears to develop after lumbar discectomy and can regress spontaneously. PMID- 22223288 TI - Sexual health in patients with rheumatoid arthritis: experiences, needs and communication with health care professionals. AB - Pain, fatigue and decreased joint mobility caused by rheumatoid arthritis (RA) often decrease sexual health in RA patients. Regular physiotherapy interventions in patients with RA are often aimed at improving those factors. The aim of the present study was to explore the experiences and views of patients concerning the impact of RA on their sexual health, the possible impact of physiotherapy interventions, and communication in clinical situations. A self-administered questionnaire was sent to patients with RA at two rehabilitation clinics in Sweden. The questionnaire included questions concerning the impact of RA on intimate relationships and sexual function, as well as experiences of physiotherapy and sexual health communication with health professionals. The questionnaire was answered by 63 patients. The majority of the patients thought that pain, stiffness, fatigue and physical capacity were related to sexual health. Communication between health professionals and patients about sexual health was less common, even if the desire for communication about sexual health was higher in this study than in other studies. The authors concluded that physiotherapists need to be aware that pain, fatigue, decreased joint mobility and physical capacity can affect sexual health and that physiotherapy can make a difference in sexual health in patients with RA. The impact of RA on sexual health is rarely discussed by health professionals and RA patients, and needs greater attention. PMID- 22223289 TI - Correlation between magnetic resonance imaging findings and histological diagnosis of intrinsic brainstem lesions in adults. AB - Management of brainstem mass lesions remains a controversial issue, especially when the lesion cannot be excised and when infiltration occurs; moreover, the benefits of a stereotactic procedure are still under debate. In most studies, treatment decisions are based solely on MRI features and do not include a histopathological diagnosis. In the current study, we compared MRI characteristics with histopathological findings of intrinsic brainstem lesions and identified the characteristics associated with the diagnosis of pathologies other than diffuse glioma. From February 1988 through August 2007, 96 brainstem biopsies were performed at the Roger Salengro Hospital in Lille, France, on adult patients with intrinsic brainstem lesions not amenable to excision. Of the 96 patients, 42 were women and 54 were men, with a mean age of 41 years (range, 18 75 years). Data analysis of the MRI findings revealed focal (P < .05) and contrast enhancing lesions (P < .05), and these lesions were significant factors associated with the diagnosis of pathologies other than diffuse glioma. Focal lesions were a significant factor associated with a diagnosis of nontumor lesions (P < .05). In conclusion, the diagnostic effect of stereotactic biopsy on intrinsic brainstem lesions was greater in patients with focal or enhancing lesions shown by MRI, in whom the diagnosis of diffuse glioma was less frequent. PMID- 22223291 TI - A comprehensive library of blocked dipeptides reveals intrinsic backbone conformational propensities of unfolded proteins. AB - Despite prolonged scientific efforts to elucidate the intrinsic peptide backbone preferences of amino-acids based on understanding of intermolecular forces, many open questions remain, particularly concerning neighboring peptide interaction effects on the backbone conformational distribution of short peptides and unfolded proteins. Here, we show that spectroscopic studies of a complete library of 400 dipeptides reveal that, irrespective of side-chain properties, the backbone conformation distribution is narrow and they adopt polyproline II and beta-strand, indicating the importance of backbone peptide solvation and electronic effects. By directly comparing the dipeptide circular dichroism and NMR results with those of unfolded proteins, the comprehensive dipeptides form a complete set of structural motifs of unfolded proteins. We thus anticipate that the present dipeptide library with spectroscopic data can serve as a useful database for understanding the nature of unfolded protein structures and for further refinements of molecular mechanical parameters. PMID- 22223292 TI - Case-based learning in surgery: lessons learned. AB - BACKGROUND: The aim of the study was to obtain a deepened understanding of the implementation process of case-based learning (CBL) during a surgical semester at the Undergraduate Medical Program at Karolinska Institutet. The objectives are to identify the level of success of the implementation and to identify practical and theoretical implications of importance in connection to the process. METHODS: Based on a qualitative study design, the study explores students' and teachers' perceptions of the educational intervention CBL in context. Five faculty members involved in the entire reform and five students from the second cohort were interviewed 1 year into the implementation phase. Narrative data from the semistructured interviews were coded using a blend of an inductive and deductive approach to derive the coding categories. RESULTS: The results of the study reflect two overarching themes: the importance of a well-functioning implementation process and the misalignment between the student/faculty Teaching Learning Regime and the attributes of CBL. The findings have resulted in a checklist for implementation of CBL in a surgical curriculum. CONCLUSIONS: The implementation of CBL was not satisfactory. Still, exposure of the weaknesses of the implementation process, the misalignment between CBL and the reigning teaching and learning regime, and promotion of the future use of the checklist are key to future successful implementation of CBL in any surgical undergraduate curriculum. PMID- 22223294 TI - Detection and phylogenetic profiling of nodavirus associated with white tail disease in Malaysian Macrobrachium rosenbergii de Man. AB - White tail disease (WTD) is a serious viral disease in the hatcheries and nursery ponds of Macrobrachium rosenbergii in many parts of the world. A new disease similar to WTD was observed in larvae and post larvae of M. rosenbergii cultured in Malaysia. In the present study, RT-PCR assay was used to detect the causative agents of WTD, M. rosenbergii nodavirus (MrNV) and extra small virus (XSV) using specific primers for MrNV RNA2 and XSV. The results showed the presence of MrNV in the samples with or without signs of WTD. However, XSV was only detected in some of the MrNV-positive samples. Phylogenetic analysis showed that the RNA2 of our Malaysian isolates were significantly different from the other isolates. Histopathological studies revealed myofiber degeneration of the tail muscles and liquefactive myopathy in the infected prawns. This was the first report on the occurrence of MrNV in the Malaysian freshwater prawn. PMID- 22223293 TI - Correlation between the pretherapeutic neutrophil to lymphocyte ratio and the pathologic response to neoadjuvant chemotherapy in patients with advanced esophageal cancer. AB - BACKGROUND: An elevation in the neutrophil-to-lymphocyte ratio (NLR) has been shown to be associated with a poorer prognosis in patients with various tumors. The aim of this retrospective study was to clarify the correlation of the pretherapeutic NLR with the prognostic value of the pathologic response to neoadjuvant chemotherapy (NAC) in patients with advanced esophageal cancer. METHODS: This study was a retrospective review of 83 patients undergoing NAC for advanced esophageal cancer following esophagectomy. The NLR was measured before NAC, and the pathologic responses to NAC were evaluated. RESULTS: A comparison was performed for those whose pathology responded (responders) (G3/G2/G1b) and nonresponders (G1a/G0). In a univariate analysis, the cStage (P = 0.005), cN (P = 0.0001), and NLR (P = 0.005) were statistically significant parameters. A multivariate analysis revealed that the factors independently associated with pathologic responses were the pretreatment NLR (<2.2/>=2.2) (P = 0.043) and lymph nodes metastasis (P = 0.002). The pretreatment NLR (<2.2/>=2.2) was found to be a statistically significant useful predictive marker for a pathologic response (P = 0.001). The pathologic response rates were 56% in the patients with an NLR <2.2 and 21% in patients with an NLR of >=2.2. CONCLUSIONS: Our study is the first to demonstrate that the pretherapeutic NLR can be used as a predictor for chemosensitivity of thoracic esophageal cancer. Preoperative evaluation based on the clinical N stage and NLR may be easily used in routine clinical practice. PMID- 22223296 TI - The promise of multimedia technology for STI/HIV prevention: frameworks for understanding improved facilitator delivery and participant learning. AB - There is increasing excitement about multimedia sexually transmitted infection (STI) and HIV prevention interventions, yet there has been limited discussion of how use of multimedia technology may improve STI/HIV prevention efforts. The purpose of this paper is to describe the mechanisms through which multimedia technology may work to improve the delivery and uptake of intervention material. We present conceptual frameworks describing how multimedia technology may improve intervention delivery by increasing standardization and fidelity to the intervention material and the participant's ability to learn by improving attention, cognition, emotional engagement, skills-building, and uptake of sensitive material about sexual and drug risks. In addition, we describe how the non-multimedia behavioral STI/HIV prevention intervention, Project WORTH, was adapted into a multimedia format for women involved in the criminal justice system and provide examples of how multimedia activities can more effectively target key mediators of behavioral change in this intervention. PMID- 22223295 TI - Association of five candidate genes with fatty acid composition in Korean cattle. AB - Fatty acid composition of meat is becoming more important due to consumer demand for high quality and healthy foods. The present study evaluated the associations of five candidate genes (FABP4, FASN, NR1H3, GH and SCD) with fatty acid composition in Korean cattle (Hanwoo). The g.3691G > A single nucleotide polymorphism (SNP) in the FABP4 gene had significant effects on high myristic acid (C14:0; P < 0.01) and palmitic (C16:0; P < 0.05) in animals having the GG genotype, and high arachidonic acid (C20:4; P < 0.05) in the AA genotype of Hanwoo. The FASN SNP at position g.17924G > A was also significantly associated with myristic acid (P < 0.01). In case of the SCD gene, a significant effect was only observed in myristoleic acid (C14:1; P < 0.01). However, SNPs in GH and NR1H3 genes showed no effects on fatty acid composition. The results indicate that SNPs in three candidate genes, FABP4, FASN and SCD, may be influential in breeding design for fatty acid composition in Hanwoo. PMID- 22223297 TI - Social and structural factors associated with consistent condom use among female entertainment workers trading sex in the Philippines. AB - This paper examined socio-structural factors of consistent condom use among female entertainment workers at high risk for acquiring HIV in Metro Manila, Quezon City, Philippines. Entertainers, aged 18 and over, from 25 establishments (spa/saunas, night clubs, karaoke bars), who traded sex during the previous 6 months, underwent cross-sectional surveys. The 143 entertainers (42% not always using condoms, 58% always using condoms) had median age (23), duration in sex work (7 months), education (9 years), and 29% were married/had live-in boyfriends. In a logistic multiple regression model, social-structural vs. individual factors were associated with inconsistent condom use: being forced/deceived into sex work, less manager contact, less STI/HIV prevention knowledge acquired from medical personnel/professionals, not following a co workers' condom use advice, and an interaction between establishment type and alcohol use with establishment guests. Interventions should consider the effects of physical (force/deception into work), social (peer, manager influence), and policy (STI/HIV prevention knowledge acquired from medical personnel/professionals) environments on consistent condom use. PMID- 22223298 TI - Social network and other correlates of HIV testing: findings from male sex workers and other MSM in Shanghai, China. AB - Although the Chinese government provides free-of-charge voluntary HIV counseling and testing, HIV testing rates among men who have sex with men (MSM) are reported to be extremely low. This study examines the association of structural and psychosocial factors and social network characteristics with HIV testing behaviors among "money boys" and general MSM in Shanghai. Overall, 28.5% of "money boys" and 50.5% of general MSM had never tested for HIV despite high rates of reported HIV risk behaviors. Factors associated with not testing for HIV included: not knowing of a testing site, limited HIV knowledge, low perceived HIV risk, concern about HIV testing confidentiality, being a closeted gay, not using the Internet, and having a small social network or network with few members who had tested for HIV. Future efforts to promote HIV testing should focus on outreach to general MSM, confidentiality protection, decreasing the stigma of homosexuality, and encouraging peer education and support through the Internet and social networks. PMID- 22223299 TI - Orphan status and time to first sex among adolescents in northern Malawi. AB - This study examines the effects of orphanhood status on the timing of first sexual intercourse among youth in Malawi. Log-normal models were applied to survey data collected between May and August 2009 from 1,214 adolescents aged 12 18 in Mzuzu, Northern Malawi. Results of this study show that orphanhood is a significant predictor of age at first sex. Male double orphans experienced first sexual intercourse earlier than their male non-orphan peers. Similarly, female maternal and paternal orphans had their sexual debut faster than their non-orphan counterparts. The introduction of social support variables accounted for the orphanhood disadvantage. These findings suggest that in order to delay sexual initiation and reduce HIV risk among orphans in Malawi, policy efforts should focus on enhancing factual knowledge about HIV/AIDS, household food security, social support, and other measures that will strengthen existing social support networks and connectedness of surviving family members. PMID- 22223300 TI - Spectrums of love: examining the relationship between romantic motivations and sexual risk among young gay and bisexual men. AB - We examined the association between HIV/AIDS risk behaviors and romantic feelings among single, young gay and bisexual men (YGBM). Romantic feelings may have positive (romantic ideation) and negative (romantic obsession) connotations. Consequently, we hypothesized that YGBM would report greater risks if they reported having obsessive thoughts about their relationship desires; conversely, we hypothesized that YGBM who envision a romantic relationship would report fewer unprotected partners. Using cross-sectional data from a study examining YGBM's online dating experiences (N = 376; ages 18-24), we found a positive association between romantic obsession and number of partners for unprotected receptive (URAI) and insertive (UIAI) anal intercourse. Conversely, we found a negative association between romantic ideation and number of partners for URAI and UIAI. Is love risky or protective? Our results indicate support for both perspectives. We discuss the implications of our findings, highlighting the importance of addressing romantic pursuits into existing HIV prevention interventions for YGBM. PMID- 22223301 TI - Are we missing the importance of missing values in HIV prevention randomized clinical trials? Review and recommendations. AB - Missing data in HIV prevention trials is a common complication to interpreting outcomes. Even a small proportion of missing values in randomized trials can cause bias, inefficiency and loss of power. We examined the extent of missing data and methods in which HIV prevention randomized clinical trials (RCT) have managed missing values. We used a database maintained by the HIV/AIDS Prevention Research Synthesis (PRS) Project at the Centers for Disease Control and Prevention (CDC) to identify related trials for our review. The PRS cumulative database was searched on June 15, 2010 and all citations that met the following criteria were retrieved: All RCTs which reported HIV/STD/HBV/HCV behavioral interventions with a biological outcome from 2005 to present. Out of the 57 intervention trials identified, all had some level of missing values. We found that the average missing values per study ranged between 3 and 97%. Averaging over all studies the percent of missing values was 26%. None of the studies reported any assumptions for managing missing data in their RCTs. Under some relaxed assumptions discussed below, we expect only 12% of studies to report unbiased results. There is a need for more detailed and thoughtful consideration of the missing data problem in HIV prevention trials. In the current state of managing missing data we risk major biases in interpretations. Several viable alternatives are available for improving the internal validity of RCTs by managing missing data. PMID- 22223303 TI - A high-performance ytterbium-based nanoparticulate contrast agent for in vivo X ray computed tomography imaging. PMID- 22223302 TI - Redox-responsive degradable PEG cryogels as potential cell scaffolds in tissue engineering. AB - A Michael addition strategy involving the reaction between a maleimide double bond and amine groups is investigated for the synthesis of cryogels at subzero temperature. Low-molecular-weight PEG-based building blocks with amine end groups and disulfide-containing building blocks with maleimide end groups are combined to synthesize redox-responsive PEG cryogels. The cryogels exhibit an interconnected macroporous morphology, a high compressive modulus and gelation yields of around 95%. While the cryogels are stable under physiological conditions, complete dissolution of the cryogels into water-soluble products is obtained in the presence of a reducing agent (glutathione) in the medium. Cell seeding experiments and toxicologic analysis demonstrate their potential as scaffolds in tissue engineering. PMID- 22223304 TI - The memristive magnetic tunnel junction as a nanoscopic synapse-neuron system. PMID- 22223305 TI - Quantification of character-impacting compounds in Ocimum basilicum and 'Pesto alla Genovese' with selected ion flow tube mass spectrometry. AB - Basil (Ocimum basilicum) is an important flavourant plant which constitutes the major ingredient of the pasta sauce 'Pesto alla Genovese'. The characteristic smell of basil stems mainly from a handful of terpenoids (methyl cinnamate, eucalyptol, linalool and estragole), the concentration of which varies according to basil cultivars. The simple and rapid analysis of the terpenoid constituents of basil would be useful as a means to optimise harvesting times and to act as a quality control process for basil-containing foodstuffs. Classical analytical techniques such as gas chromatography/mass spectrometry (GC/MS) are, however, slow, technically demanding and therefore less suitable for routine analysis. A new chemical ionisation technique which allows real-time quantification of traces gases, Selected Ion Flow Tube Mass Spectrometry (SIFT-MS), was therefore utilised to determine its usefulness for the assay of terpenoid concentrations in basil and pesto sauce headspace. Trace gas analysis was performed using the NO(+) precursor ion which minimised interference from other compounds. Character impacting compound concentration was measured in basil headspace with good reproducibility and statistically significant differences were observed between cultivars. Quantification of linalool in pesto sauce headspace proved more difficult due to the presence of interfering compounds. This was resolved by careful selection of reaction product ions which allowed us to detect differences between various commercial brands of pesto. We conclude that SIFT-MS may be a valid tool for the fast and reproducible analysis of flavourant terpenoids in basil and basil-derived foodstuffs. PMID- 22223306 TI - Impact of limited oxidation on protein ion mobility and structure of importance to footprinting by radical probe mass spectrometry. AB - The effect of hydroxyl radical induced oxidation on the collision cross-sections of hen egg lysozyme and bovine ubiquitin was investigated by travelling wave ion mobility mass spectrometry for the first time. The oxidized ions of lysozyme and ubiquitin share common collision cross-sections with their unoxidized counterparts suggesting that they share common structures that were unaffected by limited oxidation. In the case of bovine ubiquitin, two distinct conformers were detected for the protein in its unoxidized and oxidized states though no change in the levels of each was observed upon oxidation. This supports the validity of Radical Probe Mass Spectrometry (RP-MS) using an electrical discharge source for protein footprinting experiments. Travelling wave ion mobility mass spectrometry has been used for the first time to confirm that limited oxidation does not have an impact on the global structure of proteins. PMID- 22223307 TI - A system consisting of cation-exchange chromatography, combined surface-activated chemical and electrospray ionization, and ion-trap analysis for the analysis of 8 oxo-7,8-dihydro-2'-deoxyguanosine in urine. AB - RATIONALE: 8-Hydroxy-2'-deoxyguanosine has served as a biomarker for oxidative damage to DNA from different types of biological samples, and various techniques have been used to analyze it. In particular, liquid chromatography coupled to mass spectrometry has been used to identify 8-hydroxy-2'-deoxyguanosine in urine samples. Usually, a triple quadrupole analyzer and multiple reaction monitoring have been employed for its detection. Only a few studies have used a less expensive ion-trap analyzer instead. METHODS: We have developed a new liquid chromatography/mass spectrometry procedure that incorporates cation-exchange chromatography in conjunction with surface-activated and electrospray ionization with an ion trap analyzer for the mass spectral step. RESULTS: The combination of two ionization sources reduced the matrix effect arising from in-source reactions, thus increasing the sensitivity to levels comparable with those obtained by triple quadrupole analyzers. CONCLUSIONS: This new method for 8 hydroxy-2'-deoxyguanosine detection provided increased sensitivity and reduced chemical noise, using a less expensive, stable and accurate mass spectrometric technology. PMID- 22223308 TI - PCDD, PCDF, AND DL-PCB analysis in food: performance evaluation of the high resolution gas chromatography/low-resolution tandem mass spectrometry technique using consensus-based samples. AB - Due to safety concerns regarding dietary exposure to POPs, regulatory bodies are issuing detailed guidelines for testing for polychlorodibenzodioxins (PCDDs) and polychlorodibenzofurans (PCDFs) ('dioxins') and dioxin-like (DL)-PCBs in foods of animal origin. Determination of the aforesaid chemicals at regulatory levels requires highly selective and sensitive testing techniques. The new generation of low-resolution mass spectrometers (triple quadrupoles) allows very low levels of quantification to be reached (in the order of tens of femtograms), thus suggesting a potential for their application in food and feed analysis. The performance of the low-resolution tandem mass spectrometry (LRMS/MS) approach with triple quadrupoles was assessed on a qualified set of food samples from proficiency tests (PTs) and defense analysis. Accuracy was tested comparing the results with data from high-resolution mass spectrometry (HRMS) and with consensus values from PTs. The cumulative TEQ results were characterized by deviations not exceeding 15% of PCDD + PCDF, DL-PCB, and PCDD + PCDF + DL-PCB (TEQ(TOT)) reference consensus values (sample TEQ(TOT) range, 2.29-25.1 pgWHO TEQ(97)/g fat). Congener analytical variabilities did not influence significantly the WHO-TEQ(97) outcome of the corresponding sample. This preliminary performance evaluation highlights the potential of LRMS/MS as a routine technique for quantitative analysis of PCDDs, PCDFs, and DL-PCBs in food. PMID- 22223309 TI - Automating data acquisition affects mass spectrum quality and reproducibility during bacterial profiling using an intact cell sample preparation method with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - The use of matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry (TOF MS) has emerged as a promising tool to rapidly profile bacteria at the genus and species level and, more recently, at the sub-species (strain) level. Recently, it has been proposed that the approach can be enhanced with regard to reproducibility and throughput by automating spectrum acquisition; however, effects of automating spectrum acquisition on spectrum quality and reproducibility have not been investigated. Using an intact cell-based sample preparation method, we directly compared the quality and reproducibility of spectra acquired in a fully automated fashion to those acquired manually by two operators with different levels of experience. While automation tended to increase base peak resolution, other measures of spectrum quality, including signal-to-noise (S:N) ratio, data richness, and reproducibility were reduced. Negative effects of automation on the performance of this approach to bacterial profiling may be particularly important during profiling of closely related strains of bacteria that yield very similar spectra. PMID- 22223310 TI - Isotopic labelling of peptides in tissues enhances mass spectrometric profiling. AB - RATIONALE: There is a need in imaging mass spectrometry to use the acquired isotope distribution to unequivocally determine the identity of a peptide ion. A way of achieving unambiguous differentiation of ions from protonated peptides from other [M + H](+) ions in a tissue would be via the direct on-tissue incorporation of (18)O into peptides. METHODS: Tissues were first digested with trypsin for 3 h at 37 degrees C in a humidified chamber. For the (18)O labelling of digested peptides 1 MUL of H(2)(18)O/50 mM ammonium acetate (at pH 6.75) was added to the array of tryptic spots and incubated at room temperature for 20 min. alpha-Cyano-4-hydroxycinnamic acid was used as a matrix modifier. The mass spectral analysis of tissue sections was carried out using a matrix assisted laser desorption/ionisation tandem time-of-flight (MALDI-TOF-TOF) instrument. RESULTS: On-tissue incorporation of (18)O into peptides cannot be carried out during the digestion step inside a humidified chamber. After tissue digestion for 3 h at 37 degrees C in an humidified chamber, (18)O labelling was carried out for 20 min at room temperature (no humidified chamber). No trypsin was needed to enhance the labelling. CONCLUSIONS: For first time the feasibility of (18)O-labelling of peptides in situ for tissues has been demonstrated. The method decouples protein digestion from peptide labelling and is performed in sequential steps. Furthermore, we observed that (18)O incorporation produces characteristic isotopic peptide distributions, thus making facile distinguishing peptides from other tissue molecular components that ionise in the MALDI ion source. PMID- 22223311 TI - Resolution of isomeric multi-ruthenated porphyrins by travelling wave ion mobility mass spectrometry. AB - The ability of travelling wave ion mobility mass spectrometry (TWIM-MS) to resolve cationic meta/para and cis/trans isomers of mono-, di-, tri- and tetra ruthenated supramolecular porphyrins was investigated. All meta isomers were found to be more compact than the para isomers and therefore mixtures of all isomeric pairs could be properly resolved with baseline or close to baseline peak to-peak resolution (R(p-p)). Di-substituted cis/trans isomers were found, however, to present very similar drift times and could not be resolved. N(2) and CO(2) were tested as the drift gas, and similar alpha but considerably better values of R(p) and R(p-p) were always observed for CO(2). PMID- 22223312 TI - Equal ratio of graphite carbon to activated charcoal for enrichment of N glycopeptides prior to matrix-assisted laser desorption/ionization time-of-flight mass spectrometric identification. AB - Site-specific glycoprofiling of N-glycoproteins is based on the enrichment of glycopeptides. In this study, we develop a simple and economical ZipTip microcolumn packed with a 1:1 ratio of graphite carbon to activated charcoal (w/w) (termed as GA-ZipTip microcolumn) to efficiently isolate and enrich N glycopeptides from digested mixtures of individual glycoproteins and also investigate the ratio effect on the isolation and enrichment of glycopeptides. The experimental data showed that the microcolumn could efficiently and reproducibly isolate N-glycopeptides from enzymatic mixtures of ovalbumin, fetuin, haptoglobin and human plasma. The results obtained here demonstrate that the GA-ZipTip microcolumn is a powerful tool to enrich unbiasedly N glycopeptides, which will be benefit for glycoproteomics and complex biological samples. PMID- 22223313 TI - Measurement uncertainty in single, double and triple isotope dilution mass spectrometry. AB - Triple IDMS has been applied for the first time to the quantification of element concentrations. It has been compared with single and double IDMS obtained on the same sample set in order to evaluate the advantages and disadvantages of triple IDMS over single and double IDMS as an analytical reference procedure. The measurement results of single, double and triple IDMS are indistinguishable, considering rounding due to the individual measurement uncertainties. As expected, the relative expanded uncertainties (k = 2) achieved with double IDMS (0.08%) are dramatically smaller than those obtained with single IDMS (1.4%). Triple IDMS yields the smallest relative expanded uncertainties (k = 2, 0.077%) unfortunately at the expense of a much higher workload. Nevertheless triple IDMS has the huge advantage that the isotope ratio of the spike does not need to be determined. Elements with high memory effects, highly enriched spikes or highest metrological requirements may be typical applications for triple IDMS. PMID- 22223314 TI - Charge state dependent top-down characterisation using electron transfer dissociation. AB - The dissociation of protein ions (5-30 kDa) as a function of charge state has been explored in order to suggest the optimal charge state range for top-down sequencing. Proteins were generated under denaturing conditions and their charge states were modified via ion/ion proton transfer reactions prior to dissociation. Electron transfer dissociation (ETD) data suggested optimal sequence coverage for charge states in the m/z range from 700 to 950 while limited sequence coverage was noted when the precursor m/z was above 1000. Sequence coverage from ETD data was found to be dependent on protein size, with smaller proteins having better sequence coverage. An observed depletion in sequence-related information was mainly attributed to limited instrument (ion trap) performance (m/z range and resolution). For a combined ETD/collision-induced dissociation (CID) approach it is difficult to propose an optimal m/z range since good sequence coverage for CID is at intermediate charge states and the optimal m/z range increases with protein size. When only one charge state can be analysed in a combined ETD/CID approach, a range around 950 m/z is suggested as a starting point. Alternatively, two charge states should be explored, each optimal for either ETD or CID. Overall, these suggestions should be useful to achieve enhanced characterisation of smaller proteins/large protein fragments (generated from denaturing solutions) in minimal analysis times. PMID- 22223315 TI - Identification of tiagabine degradation products using liquid chromatography with electrospray ionization multistage mass spectrometry and ultra-performance liquid chromatography/high-resolution mass spectrometry. AB - RATIONALE: Tiagabine hydrochloride monohydrate drug substance (TGB) is an antiepileptic agent effective in the treatment of seizure disorders. The stability of TGB was studied and its degradation products were identified for the first time. METHODS: TGB was heated in the presence of H(2)O(2). Degradation products were analyzed by liquid chromatography coupled to electrospray ionization multistage mass spectrometry (LC/ESI-MS(n)) and high-resolution mass spectrometry (HR-MS). RESULTS: This study showed that TGB was degraded by oxidative pathways involving attack of oxygen at different centers but mainly at the double bond of the molecule. The oxidative cascade reactions initiated by the epoxidation of the double bond of tiagabine led to dihydroxy, ketohydroxy and ketone derivatives as well as bisthiophene ketone. CONCLUSIONS: Nine degradation products of TGB were identified. Some diagnostic MS/MS product ions, characteristic of the piperidine or thiophene moiety, were highlighted. PMID- 22223317 TI - A simple method to estimate relative stabilities of polyethers cationized by alkali metal ions. AB - Dissociation of doubly cationized polyethers, namely [P + 2X](2+) into [P + X](+) and X(+), where P = polyethylene glycol (PEG), polypropylene glycol (PPG) and polytetrahydrofuran (PTHF) and X = Na, K and Cs, was studied by means of energy dependent collision-induced dissociation tandem mass spectrometry. It was observed that the collision voltage necessary to obtain 50% fragmentation (CV(50)) determined for the doubly cationized polyethers of higher degree of polymerization varied linearly with the number of degrees of freedom (DOF) values. This observation allowed us to correlate these slopes with the corresponding relative gas-phase dissociation energies for binding of alkali ions to polyethers. The relative dissociation energies determined from the corresponding slopes were found to decrease in the order Na(+) > K(+) > Cs(+) for each polyether studied, and an order PPG ~ PEG > PTHF can be established for each alkali metal ion. PMID- 22223316 TI - Rapid screening of drug compounds in urine using a combination of microextraction by packed sorbent and rotating micropillar array electrospray ionization mass spectrometry. AB - RATIONALE: Screening of drugs from urine samples can be non-selective or laborous, using either immunological, gas chromatography/mass spectrometry (GC/MS) or liquid chromatography (LC)/MS methods. Therefore, a rapid screening method for selected drugs in urine sample was developed in a proof-of-principle manner, utilizing simple and fast techniques for both sample treatment and sample analysis. METHODS: Sample treament of spiked urine samples was performed with microextraction by packed sorbent (MEPS). Five different sorbent materials (C(2), C(8), C(18), M1 (cation exchanger), and Sil (pure silica)) were tested for the MEPS. The sample analysis was performed using a circular microchip with 60 micropillar electrospray ionization (MUPESI) tips combined with a mass spectrometer (either a triple-quadrupole or ion-trap mass spectrometer) without any chromatographic step. RESULTS: The sample treatment/analysis setup was tested using three drug compounds at a concentration of 1 MUM. We found that the C(2), C(8) and C(18) sorbents in combination with 96% alkaline methanol as an eluent worked the best. All compounds were easily detected and identified by MS/MS in spiked urine samples. The whole qualitative analytical procedure was rapid as the sample treatment together with the MS analysis took about 5 min per sample. CONCLUSIONS: A rapid screening method for selected drugs from urine samples was developed, providing adequate selectivity and sensitivity, as well as a short total analysis cycle time. This new method can provide a new alternative for screening purposes, as both the extraction and analysis steps could be totally automatized. PMID- 22223318 TI - The oxygen isotope relationship between the phosphate and structural carbonate fractions of human bioapatite. AB - RATIONALE: Oxygen isotope analysis of archaeological human dental enamel is widely used as a proxy for the drinking water composition (delta(18)O(DW)) of the individual and thus can be used as an indicator of their childhood place of origin. In this paper we demonstrate the robustness of structural carbonate oxygen isotope values (delta(18)O(C)) in bioapatite to preserve the life signal of human tooth enamel by comparing it with phosphate oxygen isotope values (delta(18)O(P)) derived from the same archaeological human tooth enamel samples. METHODS: delta(18)O(C) analysis was undertaken on 51 archaeological tooth enamel samples previously analysed for delta(18)O(P) values and strontium isotopes. delta(18)O(C) values were determined on a GV IsoPrime dual inlet mass spectrometer, following a series of methodological tests to assess: (1) The reaction time needed to ensure complete release of CO(2) from structural carbonate in the enamel; (2) The effect of an early pre-treatment with dilute acetic acid to remove diagenetic carbonate; (3) Analytical error; (4) Intra-tooth variation; and (5) Diagenetic alteration. RESULTS: This study establishes a direct relationship between delta(18)O(C) and delta(18)O(P) values from human tooth enamel (delta(18)O(P) = 1.0322 * delta(18)O(C) - 9.6849). We have combined this equation with the drinking water equation of Daux et al. (J. Hum. Evol. 2008, 55, 1138) to allow direct calculation of delta(18)O(DW) values from human bioapatite delta(18)O(C) (delta(18)O(DW) = 1.590 * delta(18)O(C) - 48.634). CONCLUSIONS: This is the first comprehensive study of the relationship between the ionic forms of oxygen (phosphate oxygen and structural carbonate) in archaeological human dental enamel. The new equation will allow direct comparison of data produced by the different methods and allow drinking water values to be calculated from structural carbonate data with confidence. PMID- 22223319 TI - Application of on-line nano-liquid chromatography/mass spectrometry in metabolite identification studies. AB - Metabolite identification is an important part of the drug discovery and development process. High sensitivity is necessary to identify metabolic products in vitro and in vivo. The most common method utilizes standard high-performance liquid chromatography (4.6 mm i.d. column and 1 mL/min flow rate) coupled to tandem mass spectrometry (HPLC/MS/MS). We have developed a method that utilizes a nano-LC system coupled to a high-resolution tandem mass spectrometer to identify metabolites from in vitro and in vivo samples. Using this approach, we were able to increase the sensitivity of analysis by approximately 1000-fold over HPLC/MS. In vitro samples were analyzed after simple acetonitrile precipitation, centrifugation, and dilution. The significant improvement in sensitivity enabled us to conduct experiments at very low substrate concentrations (0.01 MUM), and very low incubation volumes (20 MUL). In vivo samples were injected after simple dilution without any pre-purification. All the metabolites identified by conventional HPLC/MS/MS were also identified using the nano-LC method. This study demonstrates a very sensitive approach to identifying phase I and II metabolites with throughput and separation equivalent to the standard HPLC/MS/MS method. PMID- 22223320 TI - Studying ancient crop provenance: implications from delta(13)C and delta(15)N values of charred barley in a Middle Bronze Age silo at Ebla(NW Syria). AB - The discovery of a storeroom full of barley and other cereals (L.9512) in the proto-historic site of Ebla has provided a unique opportunity to study the centralized storage system of the early city-state from a different perspective. Epigraphic evidence available within the site reveals a complex system of taxation which included gathering grain tributes from satellite sites and redistributing semi-finished products such as flour. In this paper, we intend to explore the possibilities of a combined approach to studying the storage system, based on estimated barley grain volumes and delta(13)C-delta(15)N analyses. This approach is used to distinguish between grain from different harvesting sites and to identify any grain cultivated using special agricultural practices (e.g. manuring or irrigation). The basic assumption for this kind of analysis is that the growth-site conditions, natural or anthropogenic, of harvested cereals are reflected in their grain size and delta(13)C-delta(15)N values. Since the remains found in the storeroom were charred, the first task was to evaluate the effect of carbonization on the delta(13)C-delta(15)N and the size of the grains. Thus, the effect of charring was tested on modern samples of Syrian barley landraces. Once it had been ascertained that fresh grains reduced to charred remains retain their original biometric and isotopic traits, the ancient material was examined. Thirteen groups were identified, each characterized by a specific average volume and specific carbon and nitrogen values. The analysis revealed that what had first appeared to be a homogeneous concentration of grain was in fact an assemblage of barley harvested from different sites. PMID- 22223321 TI - Reduced fragmentation in liquid injection field desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry by use of helium for the thermalization of molecular ions. AB - RATIONALE: To exploit the softness of liquid injection field desorption/ionization (LIFDI), the molecular ions, M(+*), need to be transferred from their origin at the field emitter through the mass analyzer without disrupting their integrity. To preserve the molecular ions, ion-activating events like collisions must therefore be avoided. In hybrid quadrupole Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometers, however, multiple ion guiding and ion-trapping events occur prior to mass analysis. The effects thereof compromised initial spectra from a LIFDI and electrospray ionization (ESI) combination (LIFDI-ESI) ion source and, thus, called for refined experimental conditions. METHODS: A hybrid quadrupole FT-ICR instrument equipped with a new LIFDI-ESI combination ion source was used to obtain LIFDI spectra of polystyrene 1050, of 2,3,4-tridodecyloxybenzaldehyde, and of sewing machine oil as well as a field ionization (FI) spectrum of pentafluoroiodobenzene. The abundance of molecular ions, M(+*), was optimized, in particular by variation of the trapping conditions inside the instrument's accumulation RF-hexapole ion trap. RESULTS: Ion-buffer gas collisions in the instrument's accumulation RF-hexapole ion trap were detrimental to the easy-to-fragment molecular ions of hydrocarbon species, whereas more robust even-electron ions were not affected. Exchanging the instrument's standard supply of argon buffer gas for helium resulted in a remarkable improvement. Together with further adjustments of potentials applied along the ion transfer path, hydrocarbon species could be analyzed. CONCLUSIONS: The use of helium buffer gas remarkably improved LIFDI spectra, because the loss of molecular ions by dissociation during transfer from the LIFDI source into the ICR cell was significantly reduced. Hydrocarbon species could be analyzed while fragmentation of ions was avoided for the most part. PMID- 22223322 TI - Strategic identification of in vitro metabolites of 13-desmethyl spirolide C using liquid chromatography/high-resolution mass spectrometry. AB - A strategy to identify metabolites of a marine biotoxin, 13-desmethyl spirolide C, has been developed using liquid chromatography coupled to high-resolution mass spectrometry (LC/HRMS). Metabolites were generated in vitro through incubation with human liver microsomes. A list of metabolites was established by selecting precursor ions of a common fragment ion characteristic of the spirolide toxin which was known to contain a cyclic imine ring. Accurate mass measurements were subsequently used to confirm the molecular formula of each biotransformation product. Using this approach, a total of nine phase I metabolites was successfully identified with deviations of mass accuracy less than 2 ppm. The biotransformations observed included hydroxylation, dihydroxylation, oxidation of a quaternary methyl group to hydroxymethyl or carboxylic acid groups, dehydrogenation and hydroxylation, as well as demethylation and dihydroxylation reactions. In a second step, tandem mass spectrometry (MS/MS) was performed to elucidate structures of the metabolites. Using the unique fragment ions in the spectra, the structures of the three major metabolites, 13,19-didesmethyl-19 carboxy spirolide C, 13,19-didesmethyl-19-hydroxymethyl spirolide C and 13 desmethyl-17-hydroxy spirolide C, were assigned. Levels of 13-desmethyl spirolide C and its metabolites were monitored at selected time points over a 32-h incubation period with human liver microsomes. It was determined that 13,19 didesmethyl-19-carboxy spirolide C became the predominant metabolite after 2 h of incubation. The stability plot of 13-desmethyl spirolide C showed first-order kinetics for its metabolism and the intrinsic clearance was calculated to be 41 MUL/min/mg, suggesting first-pass metabolism may contribute to limiting oral toxicity of 13-desmethyl spirolide C. PMID- 22223323 TI - A fast and selective method for anthocyanin profiling of red wines by direct infusion pneumatic spray mass spectrometry. AB - RATIONALE: Anthocyanins confer the color to red wines. During wine aging, new anthocyanin derivatives with peculiar chromatic characteristics are formed. A fast and selective method for screening the anthocyanin composition of wine has been developed. METHODS: Direct-infusion electrospray ionization tandem mass spectrometry (ESI-MS/MS) analysis of wine extracts has been performed by operating in positive ion mode with a low spray capillary voltage (0.5 kV) to detect only the species already present in ionic form. The method has been called direct-infusion pneumatic spray (DIPS) mass spectrometry. The anthocyanin profiles of thirteen red wines at different aging stages were studied. Using malvidin-3,5-diglucoside as internal standard, the indices of wine color and of wine color evolution were estimated. RESULTS: By decreasing the spray capillary voltage a dramatic increase in selectivity toward anthocyanins has been observed and the related peaks are the most abundant in the spectra. Several anthocyanins and anthocyanin derivatives (pyranoanthocyanins and derivatives formed by reaction with flavan-3-ols) have been identified in the wines. The younger wines showed higher total anthocyanin index. The aged wines showed color evolution index higher than 20% while it was lower in the younger samples. CONCLUSIONS: The anthocyanin fingerprint is effective for estimating the aging state of wine. The color evolution index can be correlated to barrel conditions during wine aging and used to distinguish between aged and younger wines. The study of pyranoanthocyanins and anthocyanin-flavanol derivatives can be useful to predict wine color stability. PMID- 22223324 TI - Reaction pathways of Rh+ (3F and 1D) with CH3OCH3 in the gas phase. AB - RATIONALE: The mass spectrometric studies of transition metal ion-ether reactions are informative in elucidating the principles of metal ion mediated demethanation and dehydrogenation. In order to obtain a deeper understanding of the role of metal ions, it is essential to explore the detailed reaction mechanisms of these reactions, here studied using Rh(+) and dimethyl ether as a model system. METHODS: The gas-phase demethanation and dehydrogenation pathways of dimethyl ether mediated by Rh(+) ((3)F and (1)D) were investigated by density functional theory in conjunction with the Stuttgart RSC + 6-311 + G(d) basis set. Both singlet and triplet states of reactivity were explored. RESULTS: The results indicate that both C-O and C-H bond activation of dimethyl ether mediated by Rh(+) could induce the demethanation reaction. The triplet state demethanation reaction prefers to proceed through C-O bond activation, while the singlet state demethanation channel via C-H bond activation is energetically more favorable. The singlet state dehydrogenation of the ionic product (formaldehyde/Rh(+)) occurs by decomposition of rhodium carbonyl dihydride, while the triplet state dehydrogenation is induced by dissociation of the carbonyl(eta(2)-dihydrogen) rhodium species. CONCLUSIONS: Based on the results, it is believed that the demethanation reaction of dimethyl ether mediated by transition metal monocation would preferably occur through the C-O bond activation pathway. Combined with previous studies, a general reaction mechanism of the transition metal monocation with dimethyl ether is proposed. PMID- 22223325 TI - The gas-phase ligand exchange reactions of cobalt and zinc acetylacetonate, hexafluoroacetylacetonate, and trifluorotrimethylacetylacetonate complexes. AB - The gas-phase ligand exchange reactions between Co(II) and Zn(II) complexes containing the acetylacetonate (acac), hexafluoroacetylacetonate (hfac), and trifluorotrimethylacetylacetonate (tftm) ligands were investigated using a triple quadrupole mass spectrometer. The gas-phase mixed ligand products of [Cu(acac)(tftm)](+), [Ni(acac)(tftm)](+), [Cu(hfac)(tftm)](+), and [Ni(hfac)(tftm)](+) were formed following the co-sublimation of either homo-metal or hetero-metal precursors and are reported herein for the first time. The fragmentation patterns of these mixed ligand species along with those of Cu(tftm)(2) and Ni(tftm)(2) are also presented. The collision cell of the instrument was utilized to examine the gas-phase reactions between mass-selected ions and specific neutral target compounds. PMID- 22223326 TI - Influence of oxidation state of sulfur on the dissociation of [Tz-(CH2)n-S(O)m (CH2)n-Tz + Na+] adducts generated by electrospray ionization (Tz = tetrazole ring; n = 2, 3; m= 0, 1, 2). AB - Sodium adducts of six organosulfur-alpha,omega-ditetrazole compounds (Tz (CH(2))(n)-S(O)(m)-(CH(2))(n)-Tz; where Tz = tetrazole ring; n = 2, 3; m = 0, 1, 2) were generated via electrospray ionization (ESI) and their fragmentation pattern assessed via collision-induced dissociation (CID). Two main dissociation channels were observed: (a) losses of N(2) and HN(3) from the tetrazole rings; (b) cleavage of the C-S bond. The sulfoxides pass predominantly through the second fragmentation pathway, but for the sulfides and sulfones the tetrazole ring fragmentation occurs. Theoretical calculations at the B3LYP/6-31 + G(d,p) level indicate that for all the adducts (sulfide, sulfoxide, and sulfone) the dissociation pathway that leads to product ions arising from loss of N(2) was the most exothermic. Based on these results and assumptions, it was postulated that the dissociation of the sulfoxide adducts occurs under kinetic control (N(2)-loss pathway via a much more energetic transition state). For the sulfide and sulfone adducts, on the other hand, the dissociation process takes place via a thermodynamically controlled process. PMID- 22223327 TI - Optimization of direct analysis in real time (DART) linear ion trap parameters for the detection and quantitation of glucose. AB - Presented here are findings for the development and optimization of a simple, high-throughput, and rapid method for the analysis of glucose. Because the applications of glucose and other six-carbon sugars is a growing field of interest especially in the production of biofuels, an efficient and rapid method for their quantitation from lignocelluloses is necessary. Glucose was analyzed using direct analysis in real time (DART) ionization and formed adducts (along with fragmentation) were observed with a linear ion trap (LIT) mass spectrometer. Since DART can be considered a complex thermal desorption ionization process, an optimization study of the helium gas temperature and introduction into the ionization region was performed. It was observed these parameters have a significant effect on the overall signal intensity as well as the signal-to-noise ratios in DART mass spectra. Using these optimized parameters, a set of different glucose concentrations (ranging from 10 to 3000 MUM) were analyzed and used to determine a linear dynamic range (with the use of an internal standard). The analysis of the samples was done with minimal sample preparation and found to be reproducible on different days. PMID- 22223328 TI - Quantitative analysis of polydisperse systems via solvent-free matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - Quantitative analysis of partially soluble and insoluble polydisperse materials is challenging due to the lack of both appropriate standards and reliable analytical techniques. To this end, matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) incorporating a solvent-free sample preparation technique was investigated for the quantitative analysis of partially soluble, polydisperse, polycyclic aromatic hydrocarbon (PAH) oligomers. Molecular weight standards consisting of narrow molecular weight dimer and trimer oligomers of the starting M-50 petroleum pitch were produced using both dense-gas/supercritical extraction (DGE/SCE) and preparative-scale, gel permeation chromatography (GPC). The validity of a MALDI-based, quantitative analysis technique using solvent-free sample preparation was first demonstrated by applying the method of standard addition to a pitch of known composition. The standard addition method was then applied to the quantitative analysis of two insoluble petroleum pitch fractions of unknown oligomeric compositions, with both the dimer and trimer compositions of these fractions being accurately determined. To our knowledge, this study represents the first successful MALDI application of solvent-free quantitative analysis to insoluble, polydisperse materials. PMID- 22223329 TI - Childhood leukemia around French nuclear power plants--the Geocap study, 2002 2007. AB - The aim of this work is to study the risk of childhood acute leukemia (AL) around French nuclear power plants (NPPs). The nationwide Geocap case-control study included the 2,753 cases diagnosed in mainland France over 2002-2007 and 30,000 contemporaneous population controls. The last addresses were geocoded and located around the 19 NPPs. The study used distance to NPPs and a dose-based geographic zoning (DBGZ), based on the estimated dose to bone marrow related to NPP gaseous discharges. An odds ratio (OR) of 1.9 [1.0-3.3], based on 14 cases, was evidenced for children living within 5 km of NPPs compared to those living 20 km or further away, and a very similar association was observed in the concomitant incidence study (standardized incidence ratio (SIR)=1.9 [1.0-3.2]). These results were similar for all the 5-year-age groups. They persisted after stratification for several contextual characteristics of the municipalities of residence. Conversely, using the DBGZ resulted in OR and SIR close to one in all of the dose categories. There was no increase in AL incidence over 1990-2001 and over the entire 1990-2007 period. The results suggest a possible excess risk of AL in the close vicinity of French NPPs in 2002-2007. The absence of any association with the DBGZ may indicate that the association is not explained by NPP gaseous discharges. Overall, the findings call for investigation for potential risk factors related to the vicinity of NPP and collaborative analysis of multisite studies conducted in various countries. PMID- 22223330 TI - A naturally occurring rexinoid, honokiol, can serve as a regulator of various retinoid x receptor heterodimers. AB - We investigated the properties of honokiol, a natural rexinoid, as a regulator of retinoid X receptor (RXR) heterodimers with various partner nuclear receptors (NRs), in comparison with those of the synthetic rexinoid bexarotene. Honokiol alone was hardly capable of activating peroxisome proliferator-activated receptor (PPAR) gamma/RXR, RXR/liver X receptor (LXR), and RXR/vitamin D receptor (VDR) heterodimers, whereas it effectively potentiated their activation by agonists for the partner NRs of the RXR heterodimers. These findings were further supported by increased mRNA and protein levels for the respective NR target genes. Bexarotene alone activated PPARgamma/RXR and RXR/LXR heterodimers, but not RXR/VDR heterodimers, and facilitated the activation of all three RXR heterodimers by the respective PPARgamma, LXR, and VDR agonists. When the potencies of honokiol and bexarotene were compared, honokiol was able to serve as a subsidiary agonist in the activation of RXR heterodimers in a similar manner to bexarotene. However, it seemed to potentiate the activation of PPARgamma/RXR heterodimers by the PPARgamma agonist rosiglitazone more efficiently than bexarotene, and was a less potent RXR agonist than bexarotene. In conclusion, we have demonstrated that honokiol is a rexinoid that possesses distinct properties from bexarotene, and mainly has subsidiary roles in the activation of RXR heterodimers by potentiating the activation of RXR heterodimers by agonists for the partner NRs. PMID- 22223331 TI - Antiproliferative and apoptosis-inducing effects of lipophilic vitamins on human melanoma A375 cells in vitro. AB - The effects of six lipophilic vitamins: tretinoin (ATRA), vitamin D(3) (VD(3)), VE, VK(1), VK(3), and VK(5) on cell proliferation and apoptosis in human A375 melanoma cells were investigated. VD(3), VK(3), and VK(5) were found to inhibit cell proliferation significantly at concentration ranges of 10-100 MUmol/L (p<0.01), while the other vitamins did not show inhibitory effects at 100 MUmol/L. VK(3) and VK(5) showed the strongest effects with IC(50) values of less than 10 MUmol/L. Dacarbazine slightly inhibited the proliferation of A375 cells at a concentration range of 25-100 MUmol/L, but the effects were not statistically significant. VK(3) and VK(5) increased annexin-V positive apoptotic cells, as well as activating caspase-3, in A375 cells. Our findings showed that VD(3), VK(3,) and VK(5) inhibited the growth of dacarbazine resistant human melanoma cells, while ATRA, VE, and VK(1) had little effect on the cell growth. The effects of VK(3) and VK(5) were observed at concentrations lower than 10 MUmol/L, which are suggested to have resulted from apoptosis-induction in the melanoma cells. PMID- 22223332 TI - Potentiation of bleomycin in Jurkat cells by fungal pycnidione. AB - Most cancer cells have mutations in genes at the G1 checkpoint and repair DNA only in the G2 phase; therefore, the G2 checkpoint is a potential target to develop novel therapy. In the course of screening, a known compound, pycnidione, was isolated from the fungal culture broth of Gloeotinia sp. FKI-3416. Pycnidione irreversibly abrogated bleomycin-induced G2 arrest in Jurkat cells and synergically potentiated the cytotoxicity of bleomycin. To elucidate the mechanism of action, the effect of pycnidione on the signal transduction of the G2 checkpoint was analyzed, showing that the increased phospho-cyclin dependent kinase-1 (CDK1) level caused by bleomycin was abrogated in the presence of pycnidione, indicating that cells did not arrest at the G2 phase. Moreover, under these conditions, Chk1 and Chk2 levels were markedly down-regulated. Thus, we concluded that pycnidione abrogated bleomycin-induced G2 arrest by decreasing Chk1 and Chk2. PMID- 22223333 TI - Extracellular heme enhances the antimalarial activity of artemisinin. AB - Artemisinin exerts the antimalarial activity through activation by heme. The hemolysis in malaria results in the elevated levels of plasma heme which may affect the activity of artemisinin. We hypothesized that the extracellular heme would potentiate the antimalarial activity of artemisinin. Hemin (ferric heme) at the pathologic concentrations enhanced the activity of artemisinin against Plasmodium falciparum in vitro and increased the levels of the lipid peroxidation products in the presence of artemisinin. The antimalarial activity of artemisinin and potentiation by hemin was decreased by vitamin E. Hemin had no effect on the activity of quinoline drugs (chloroquine, quinine and mefloquine). Furthermore, the oxidative effect of hemin in the presence of artemisinin or quinoline drugs was studied using low-density lipoprotein (LDL) oxidation as a model. Artemisinin enhanced the effects of hemin on lipid peroxidation and a decrease of tryptophan fluorescence in LDL whereas the quinoline drugs inhibited the oxidation by hemin. In conclusion, the extracellular hemin enhances the antimalarial activity of artemisinin as a result of the increasing oxidative effect of hemin. PMID- 22223334 TI - Glycerol-induced renal damage improved by 7-O-galloyl-D-sedoheptulose treatment through attenuating oxidative stress. AB - The protective effect of 7-O-galloyl-D-sedoheptulose (GS), isolated from Corni Fructus as an active component, against acute renal failure (ARF) induced by glycerol was investigated. The administration of GS led to a decline in the levels of blood urea nitrogen and creatinine; on the other hand, it did not have a significant effect on creatinine clearance. Furthermore, GS also significantly decreased the urine volume and fractional excretion of sodium, but it increased the urine osmolarity, suggesting the protective role of GS against renal dysfunction. Oxidative stress under ARF was attenuated by GS through the inhibition of lipid peroxidation, scavenging of reactive oxygen species (ROS), and elevation of the antioxidative status. Renal oxidative stress is related to the overproduction of ROS by nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase; therefore, in the present study, the protein expression of p22(phox) and NAD(P)H oxidase-4 (Nox-4) was investigated. GS down-regulated the protein expression of p22(phox); on the other hand, it did not significantly affect the expression of Nox-4. This indicates that GS inhibits the production of superoxide by regulating a component of NAD(P)H oxidase, p22(phox). Furthermore, GS down-regulated the expressions of nuclear factor-kappaB (NF-kappaBeta) and inducible nitric oxide (NO) synthase (iNOS), suggesting that GS protects against NO-induced inflammatory pathological conditions under ARF through the regulation of NF-kappaB and iNOS expressions. The present study indicates that GS exerts a protective effect against ARF through the recovery of renal dysfunction and attenuation of renal oxidative stress by regulating related protein expression. PMID- 22223335 TI - Effects of Hura crepitans and its active ingredient, daphne factor F3, on dihydrotestosterone-induced neurotrophin-4 activation and hair retardation. AB - Neurotrophin (NT)-4 is known to be an inducer of catagen in the hair cycle, but little is known of its role in the pathogenesis of androgenetic alopecia (AGA). We previously studied the gene expression of dermal papilla cells from AGA patients and controls and found that NT-4 was up-regulated in the AGA patients. In the present study, the etiological relationship between NT-4 and androgen, which is one of the causes of AGA, and the effect of an NT-4 inhibitor on hair growth were investigated. We established a NT-4 luciferase reporter assay system using a roughly 2-kb region upstream of the NT-4 transcriptional start site and investigated an accelerating effect of androgen on NT-4 transcription. We also screened for a NT-4 inhibitor by using the NT-4 reporter assay and evaluated the effects of NT-4 inhibitors on hair growth by using dihydrotestosterone (DHT) implanted mice. The results show that transcriptional activity of NT-4 was accelerated by androgen, and extract of Hura crepitans L. inhibited the DHT induced NT-4 transcriptional activation and ameliorated the retardation of hair regrowth by DHT-implanted mice. We also isolated the active ingredient in H. crepitans and found its structure to be that of 6,7-epoxy-5-hydroxyresiniferonol 14-(2,4-tetradecadienoate), i.e., daphne factor F3. These findings demonstrated that NT-4 activity accelerated by androgen might contribute to the pathogenesis of AGA and indicated that NT-4 inhibitors such as H. crepitans and daphne factor F3 might have a salutary effect on AGA. PMID- 22223336 TI - Search method for inhibitors of Staphyloxanthin production by methicillin resistant Staphylococcus aureus. AB - Staphyloxanthin, a yellow pigment produced by methicillin-resistant Staphylococcus aureus (MRSA), is a virulent factor escaping from the host immune system. A new screening method for inhibitors of staphyloxanthin production by MRSA was established using paper disks. By this screening method, inhibitors of staphyloxanthin production were selected from the natural product library (ca. 300) and from actinomycete culture broths (ca. 1000). From the natural product library, four known inhibitors of lipid metabolism, cerulenin, dihydrobisvertinol, xanthohumol and zaragozic acid, were found to inhibit staphyloxanthin production; however, typical antibiotics used clinically, including vancomycin, had no effect on staphyloxanthin production. From actinomycete culture broths, two known anthraquinones, 6-deoxy-8-O methylrabelomycin and tetrangomycin, were found to inhibit staphyloxanthin production by MRSA in the paper disk assay. These results suggested that this screening method is useful and effective to find compounds targeting staphyloxanthin production, leading to a new type of chemotherapeutics against MRSA infection. PMID- 22223337 TI - Involvement of specific transport system on uptake of lactone form of SN-38 in human intestinal epithelial cell line Caco-2. AB - The aim of this study was to elucidate the characteristics of the transport of lactone and carboxylate forms of SN-38 (SN-38L and SN-38C, respectively), a metabolite of irinotecan hydrochloride (CPT-11), with the human intestinal epithelial cell line, Caco-2. We examined SN-38L and SN-38C uptake from the apical side into Caco-2, and the effects of various compounds on the uptake of SN 38L. SN-38L and SN-38C in the cells were determined by HPLC with a fluorescence detector. When either SN-38L (0.5 uM) or SN-38C (0.5 uM) was added extracellularly at 37 degrees C, the accumulation of SN-38L into the cells was about 10-fold higher than that of SN-38C, suggesting a dominant role of the lactone form in the uptake of SN-38 into Caco-2. The accumulation of SN-38L in Caco-2 increased time-dependently up to 10 min at 37 degrees C, whereas the accumulation markedly decreased at 4 degrees C. The initial uptake rate of SN-38L approached saturation at high concentrations with Michaelis-Menten constant and 'Hill coefficient,' 2.84+/-1.00 MUM and 2.13+/-1.14, respectively (mean+/-S.E.). The accumulation of SN-38L was markedly inhibited by baicalin, an active ingredient of a Chinese herbal medicine, Hange-Shashin-To, as well as CPT-11. The type of inhibition by baicalin was competitive. In contrast, concomitant sulfobromophthalein, taurocholate and estrone 3-sulfate significantly increased SN-38L uptake. These results suggest that apical uptake of SN-38 by Caco-2 is dominantly performed as a lactone form through a specific transporter, which is competitively inhibited by baicalin. PMID- 22223338 TI - Determinants affecting quality of life: implications for pharmacist counseling for patients with breast cancer in Japan. AB - Although pharmacist counseling assumes an important role in the clinical setting, oncology pharmacy practitioners worldwide currently lack adequate guidance. This study aimed to identify the determinants and causal relationships that affect quality of life (QOL) in breast cancer patients before adjuvant systemic therapy for improving pharmacist counseling and guidance. This study analyzed 93 postoperative patients with breast cancer before pharmacist counseling for adjuvant systemic therapy. Patients were asked to complete questionnaires to assess QOL (the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 [EORTC QLQ-C30] and its breast cancer module [EORTC QLQ-BR23]) before pharmacist counseling. We analyzed factors affecting QOL by stepwise multiple linear regression analysis and evaluated causal association using path analysis. In the multiple linear regression model using variables selected by stepwise analysis, the factors affecting global health status (GHS)/QOL included fatigue, emotional functioning, systemic therapy side effects, future perspectives, and appetite loss. In the path analysis model, GHS/QOL were strongly influenced by fatigue directly; and emotional functioning, directly and indirectly via other factors. Our results indicated that fatigue and emotional functioning are strong factors affecting QOL. These factors may be able to predict poor QOL before initiating adjuvant systemic therapy. Thus, our findings suggest that these factors may be potentially useful for pharmacist counseling at the beginning of adjuvant systemic therapy. PMID- 22223339 TI - Identification of small molecule activators of the janus kinase/signal transducer and activator of transcription pathway using a cell-based screen. AB - Type I interferons (IFN-alpha/beta) have been widely used in the treatment of many viral and malignant diseases by activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, but the side effects of protein-based IFN therapy severely limit their clinical use. Discovering small molecules to activate the JAK/STAT pathway will greatly facilitate the development of new drugs which have similar pharmacological function to IFNs but with fewer side effects. To screen a natural products-based library, we established a cell-based screening assay using human hepatoma HepG2 cells stably transfected with a plasmid where the luciferase reporter activity is driven by interferon alpha-stimulated response element (ISRE), the motif specifically recognized by type I IFN-induced activation of JAK/STAT pathway. Among 1,431 natural product compounds screened, four compounds (emodin, quercetin, apigenin and luteolin) were identified as activators of the JAK/STAT pathway. Further studies demonstrated that these four compounds could increase the endogenous antiviral gene expression regulated by the IFN-activated JAK/STAT pathway. The identified small molecule activators are valuable for structural modification and warrant further investigation for use in new antiviral drugs as IFN mimics or adjuvants. PMID- 22223340 TI - Tamsulosin potently and selectively antagonizes human recombinant alpha(1A/1D) adrenoceptors: slow dissociation from the alpha(1A)-adrenoceptor may account for selectivity for alpha(1A)-adrenoceptor over alpha(1B)-adrenoceptor subtype. AB - We determined the binding affinity of tamsulosin, a selective alpha(1) adrenoceptor antagonist, for human alpha(1)-adrenoceptor subtypes in comparison with those of other alpha(1)-adrenoceptor antagonists including silodosin, prazosin, 5-methylurapidil, terazosin, alfuzosin, nafopidil, urapidil and BMY7378. The association and dissociation kinetics of [(3)H]tamsulosin for recombinant human alpha(1)-adrenoceptor subtypes were compared with those of [(3)H]prazosin. Tamsulosin competitively inhibited [(3)H]prazosin binding to human alpha(1A)-, alpha(1B)- and alpha(1D)-adrenoceptors (pK(i) values were 10.38, 9.33, 9.85) indicating 11 and 3.4-fold higher affinities for human alpha(1A)-adrenoceptor than those for alpha(1B)- and alpha(1D)-adrenoceptors, respectively. The affinity of tamsulosin for the human alpha(1A)-adrenoceptor was, respectively, 5, 9.9, 38, 120, 280, 400, 1200 and 10000 fold higher than those of silodosin, prazosin, 5-methylurapidil, terazosin, alfuzosin, naftopidil, urapidil and BMY7378, respectively. [(3)H]Tamsulosin dissociated from the alpha(1A)-adrenoceptor slower than from the alpha(1B)- and alpha(1D) adrenoceptors (alpha(1B)>alpha(1D)>alpha(1A)). Moreover, [(3)H]tamsulosin dissociated slower than [(3)H]prazosin from the alpha(1A)-adrenoceptor and faster from the alpha(1B)- and alpha(1D)-adrenoceptors. In conclusion, tamsulosin potently and selectively antagonized alpha(1A/1D)-adrenoceptor ligand binding, and slowly dissociated from the alpha(1A)-adrenoceptor subtype. PMID- 22223341 TI - Inhibitory effects of Morinda citrifolia extract and its constituents on melanogenesis in murine B16 melanoma cells. AB - The objective of this study was to examine the effects of Morinda citrifolia (noni) extract and its constituents on alpha-melanocyte stimulating hormone (alpha-MSH)-stimulated melanogenesis in cultured murine B16 melanoma cells (B16 cells). A 50% ethanolic extract of noni seeds (MCS-ext) showed significant inhibition of melanogenesis with no effect on cell proliferation. MCS-ext was more active than noni leaf and fruit flesh extracts. Activity guided fractionation of MCS-ext led to the isolation of two lignans, 3,3' bisdemethylpinoresinol (1) and americanin A (2), as active constituents. To elucidate the mechanism of melanogenesis inhibition by the lignans, alpha-MSH stimulated B16 cells were treated with 1 (5 MUM) and 2 (200 MUM). Time-dependent increases of intracellular melanin content and tyrosinase activity, during 24 to 72 h, were inhibited significantly by treatment with the lignans. The activity of 1 was greater than that of 2. Western blot analysis suggested that the lignans inhibited melanogenesis by down regulation of the levels of phosphorylation of p38 mitogen-activated protein kinase, resulting in suppression of tyrosinase expression. PMID- 22223342 TI - Protective effects of 4-phenylbutyrate derivatives on the neuronal cell death and endoplasmic reticulum stress. AB - Endoplasmic reticulum (ER) stress responses play an important role in neurodegenerative diseases. Sodium 4-phenylbutyrate (4-PBA) is a terminal aromatic substituted fatty acid that has been used for the treatment of urea cycle disorders. 4-PBA possesses in vitro chemical chaperone activity and reduces the accumulation of Parkin-associated endothelin receptor-like receptor (Pael-R), which is involved in autosomal recessive juvenile parkinsonism (AR-JP). In this study, we show that terminal aromatic substituted fatty acids, including 3 phenylpropionate (3-PPA), 4-PBA, 5-phenylvaleric acid, and 6-phenylhexanoic acid, prevented the aggregation of lactalbumin and bovine serum albumin. Aggregation inhibition increased relative to the number of carbons in the fatty acids. Moreover, these compounds protected cells against ER stress-induced neuronal cell death. The cytoprotective effect correlated with the in vitro chemical chaperone activity. Similarly, cell viability decreased on treatment with tunicamycin, an ER stress inducer, and was dependent on the number of carbons in the fatty acids. Moreover, the expression of glucose-regulated proteins 94 and 78 (GRP94, 78) decreased according to the number of carbons in the fatty acids. Furthermore, we investigated the effects of these compounds on the accumulation of Pael-R in neuroblastoma cells. 3-PPA and 4-PBA significantly suppressed neuronal cell death caused by ER stress induced by the overexpression of Pael-R. Overexpressed Pael-R accumulated in the ER of cells. With 3-PPA and 4-PBA treatment, the localization of the overexpressed Pael-R shifted away from the ER to the cytoplasmic membrane. These results suggest that terminal aromatic substituted fatty acids are potential candidates for the treatment of neurodegenerative diseases. PMID- 22223343 TI - Roles of histamine in exercise-induced fatigue: favouring endurance and protecting against exhaustion. AB - Exercise necessitates a large supply of O(2) and nutrients and rapid removal of CO(2) and waste products. Histamine is a regulator of the microcirculation (which performs these exchanges), suggesting a possible involvement of histamine in exercise. Histamine is released from either mast cells or non-mast cells. In the latter, histamine is newly formed via the induction of histidine decarboxylase (HDC) in response to an appropriate stimulus, and it is released without being stored. Here, in mice, we examined the role of histamine or HDC induction in exercise. Prolonged walking (PW) (in a cylindrical cage turned electrically) increased HDC mRNA and HDC activity in quadriceps femoris muscles. Mice given a histamine H1-receptor antagonist [fexofenadine (peripherally acting) or pyrilamine (peripherally and centrally acting)] or an irreversible HDC inhibitor (alpha-fluoromethylhistidine) displayed less PW endurance than control mice. Ranitidine (H2-receptor antagonist) tended to reduce endurance. Other histamine receptor (H3 and H4) antagonists had no significant effects on endurance. Mice deficient in HDC or histamine H1-receptors displayed markedly less endurance than control mice, and HDC activity in the quadriceps femoris of H1-deficient mice was rapidly elevated by PW. Fexofenadine significantly reduced the muscle levels of nitric oxide (NO) metabolites and glycogen after PW. The results support the ideas that (i) histamine is involved in protecting against exercise-induced fatigue or exhaustion, (ii) histamine exerts its protective effect via H1 receptors and the ensuing production of NO in skeletal muscle, and (iii) histamine is provided, at least in part, by HDC induction in skeletal muscles during prolonged exercise. PMID- 22223344 TI - Geranyl derivative of phloroacetophenone induces cancer cell-specific apoptosis through Bax-mediated mitochondrial pathway in MCF-7 human breast cancer cells. AB - Plant-derived polyhenols inhibit cancer cell proliferation and induce apoptosis. Recently, prenylflavonoids and alkyl-phloroacetophenones have been reported for their in vitro antitumor activity. In the present study, we examined the cytotoxic activity of prenyl (3-PAP) and geranyl (3-GAP) derivatives of phloroacetophenone, and xanthohumol (XN), a prenyl-chalcone, in human breast cancer (MCF-7) and human sarcoma (HT1080) cell lines in vitro. 3-GAP showed the strongest cytotoxicity in these cell lines with IC(50) values of less than 10 uM. In addition, we report that 3-GAP is a more potent anti-cancer agent for breast cancer than XN which is a well-known anticancer flavonoid. Moreover, 3-GAP did not induce cytotoxicity in the normal cell line, TCMK-1, whereas 3-PAP and XN significantly reduced TCMK-1 cell viability. In 3-GAP-treated MCF-7 cells, nuclear accumulation and transcriptional activity of p53 were increased. In addition, pro-apoptotic Bax but not B-cell lymphoma 2 (Bcl-2) expression was increased by 3-GAP. In accordance with the Bax increase, 3-GAP induced mitochondrial cytochrome c release and activated caspase-9, an initiator of the caspase cascade. In the MCF-7 cell line which does not express caspase-3, activation of caspase-7, a member of the caspase-3 subfamily, was increased by 3 GAP. The present results indicate that synthetic 3-GAP is a safe and effective anti-cancer agent, and the Bax-mediated mitochondrial pathway is the main apoptosis signaling pathway of 3-GAP in MCF-7 cells. PMID- 22223345 TI - Anticancer properties of pomolic acid-induced AMP-activated protein kinase activation in MCF7 human breast cancer cells. AB - AMP-activated protein kinase (AMPK) is a sensor of cellular energy status found in all eukaryotes. Recent studies indicate that AMPK activation strongly suppresses cell proliferation in tumor cells, which requires high rates of protein synthesis and de novo fatty acid synthesis for their rapid growth. Pomolic acid (PA) has been previously described as being active in inhibiting the growth of cancer cells. In this study, we investigated PA activated AMPK, and this activity was related to proliferation and apoptosis in MCF7 breast cancer cells. PA inhibited cell proliferation and induced sub-G(1) arrest, elevating the mRNA levels of the apoptotic genes p53 and p21. PA activated caspase-3, -9, and poly(ADP-ribose) polymerase, and this effect was inhibited by z-VAD-fmk. AMPK activation was increased by treating cells with PA, inactivated by treating cells with a compound C, and co-treatment consisting of PA and aminoimidazole carboxamide ribonucleotide (AICAR) synergistically activated AMPK. These anti cancer potentials of PA were accompanied by effects on de novo fatty acid synthesis as shown by the decreased expression of fatty acid synthase, and decreased acetyl-CoA carboxylase activation and incorporation of [(3)H]acetyl-CoA into fatty acids. In addition, PA inhibited key enzymes involved in protein synthesis such as mammalian target of rapamycin (mTOR), 70 kDa ribosomal protein S6 kinase (p70S6K), and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). These results suggest that PA exerts anti-cancer properties through the modulation of AMPK pathways and its value as an anti-cancer agent in breast cancer therapy. PMID- 22223346 TI - mRNA delivery through fibronectin associated liposome-apatite particles: a new approach for enhanced mRNA transfection to mammalian cell. AB - It was believed for a long time that mRNA is very unstable, and can not be used for therapeutic purposes. In the last decade, however, many research groups proved its transfection feasibility along with advantages and applications. Our investigation is aimed at establishing a potent and efficient mRNA delivery system. We previously reported that an inorganic-organic hybrid carrier by exploiting the advantages of inorganic nano apatite particles onto organic carrier DOTAP {N-[1-(2,3-dioleoloxy)propyl]-N,N,N-trimethyl ammonium chloride} and showed potential effect of carbonate apatite particles on each of the mRNA delivery steps in dividing and non-dividing cell. Here, we report on the development of a more efficient mRNA carrier by complexing ECM protein, fibronectin with the DOTAP-apatite carrier. The carrier showed enhanced uptake of luciferase mRNA both qualitatively and quantitatively. Accelerated cellular endocytosis rate was evaluated using labeled endosome. Finally expression of lucifearse mRNA was higher for fibronectin complexed carrier in compared to the uncoated one. PMID- 22223347 TI - Differential induction of stearoyl-CoA desaturase 1 and 2 genes by fibrates in the liver of rats. AB - The administration of fibrates (fenofibrate, bezafibrate and clofibric acid) to rats induced stearoyl-CoA desaturase (SCD) in the liver, and increased relative expression of mRNAs encoding SCD1 and SCD2 in dose- and time-dependent manners. The magnitudes of the increases in SCD2 mRNA level caused by fenofibrate and clofibric acid were much higher than those of SCD1 at relatively higher doses of the fibrates, and a relatively long time (7 or 14 d) was required for significant induction of SCD2 mRNA expression compared with that of SCD1. Although the absolute number of transcripts for SCD2 was 1,800 times lower than that of SCD1 in the control liver, it was strikingly increased by fibrates. These results suggest that differential regulations operate for the gene expression between SCD1 and SCD2, and that the physiological significance of SCD2 is distinct from that of SCD1 in the liver. PMID- 22223348 TI - Apigenin attenuates 2-deoxy-D-ribose-induced oxidative cell damage in HIT-T15 pancreatic beta-cells. AB - Glucose toxicity contributes to progressive beta-cell failure and the development of overt diabetes. Oxidative stress is an important aspect of glucose toxicity in pancreatic beta-cells. We investigated whether the flavonoid apigenin protects pancreatic beta-cells from 2-deoxy-D-ribose (dRib)-induced oxidative cell damage. HIT-T15 pancreatic beta-cells were cultured with or without apigenin in the presence of dRib. Time- and dose-dependent cell viability was monitored using a cell counting kit (CCK-8), while the induction of apoptosis was analyzed using a cell death enzyme-linked immunosorbent assay (ELISA) kit. Mitochondrial membrane potential (DeltaPsi(m)) was determined using the JC-1 kit. Intracellular oxidative stress was measured by fluorometric analysis of DCFH oxidation using 2',7'-dichlorofluorescin diacetate (DCFH-DA) as the probe. In addition, the DNA binding activity of the oxidative stress-related transcriptional factors nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) were analyzed. dRib reduced cell survival and DeltaPsi(m), while it markedly increased intracellular levels of reactive oxygen species (ROS), apoptosis, and the activity of the oxidative stress-related transcription factors NF-kappaB and AP-1. However, pretreatment of cells with apigenin attenuated all the dRib-induced effects. The anti-oxidants, N-acetyl-L-cysteine (NAC) and alpha lipoic acid (ALA), also prevented both dRib-induced oxidative damage and activation of NF-kappaB and AP 1. Taken together, these results suggest that apigenin attenuates dRib-induced cell damage in pancreatic beta-cells via oxidative stress-related signaling. PMID- 22223349 TI - Chronic administration of cardanol (ginkgol) extracted from ginkgo biloba leaves and cashew nutshell liquid improves working memory-related learning in rats. AB - Cardanol (ginkgol) extracted from Ginkgo biloba leaves and cashew nutshell liquid enhances the growth of NSC-34 immortalized motor neuron-like cells and, when chronically administered to young rats, improves working memory-related learning ability as assessed by eight-arm radial maze tasks. These findings suggest that cardanol is one of the components in Ginkgo biloba leaves that improves cognitive learning ability. PMID- 22223350 TI - Comparison between two different methods for evaluating rumen papillae measures related to different diets. AB - Although the Geographical Information System (GIS), which integrates computerized drawing computer assisted design (CAD) and relational databases (data base management system (DBMS)), is best known for applications in geographical and planning cartography, it can also use many kinds of information concerning the territory. A multidisciplinary project was initiated since 5 years a multidisciplinary study was initiated to use GIS to integrate environmental and ecological data with findings on animal health, ethology, and anatomy. This study is chiefly aimed at comparing two different methods for measuring the absorptive surface of rumen papillae. To this scope, 21 female sheep (Ovis aries) on different alimentary regimes (e.g., milk and forage mixed diet, early herbaceous diet, dry hay diet, and fresh hay diet at the maximum of pasture flowering and at the maximum of pasture dryness) were used; after slaughtering, 20 papillae were randomly removed from each sample collected from four indicator regions of rumen wall, placed near a metric reference and digitally photographed. The images were developed with the ArcGISTM software to calculate the area of rumen papillae by means of GIS and to measure their mid-level width and length to calculate the papillae area as previously performed with a different method. Spatial measurements were analyzed using univariate and multivariate methods. This work demonstrates that the GIS methodology can be efficiently used for measuring the absorptive surface of rumen papillae. In addition, GIS demonstrated to be a rapid, precise, and objective tool when compared with previously used method. PMID- 22223351 TI - When is the best moment to assess the ankle brachial index: pre- or post hemodialysis? AB - BACKGROUND: Cardiovascular disease is an important cause of death in patients on dialysis. Peripheral arterial disease (PAD) is a prognostic factor for cardiovascular disease. The ankle brachial index (ABI) is a noninvasive method used for the diagnosis of PAD. The difference between ABI pre- and post-dialysis had not yet been formally tested, and it was the main objective of this study. METHODS: The ABI was assessed using an automated oscillometric device in incident patients on hemodialysis. All blood pressure readings were taken in triplicate pre- and post-dialysis in three consecutive dialysis sessions (times 1, 2, and 3). RESULTS: One hundred and twenty-three patients (85 men) aged 53 +/- 19 years were enrolled. We found no difference in ABI pre- and post-dialysis on the right or left side, and there was no difference in times 1, 2, and 3. In patients with a history of PAD, the ABI pre- versus post-dialysis were of borderline significance on the right side (p = 0.088). CONCLUSION: ABI measured pre- and post-dialysis presented low variability. The ABI in patients with a history of PAD should be evaluated with caution. The applicability of the current method in predicting mortality among patients on hemodialysis therefore needs further investigation. PMID- 22223352 TI - Reversal of LCH-related diabetes insipidus and reappearance of posterior pituitary bright spot with low-dose chemotherapy. PMID- 22223354 TI - Endosomal actin remodeling by coronin-1A controls lipoprotein uptake and degradation in macrophages. AB - RATIONALE: The actin cytoskeleton has been implicated in the processing of atherogenic lipoproteins in macrophages. However, the functional role of actin and the regulatory proteins involved are unknown. OBJECTIVE: Coronin-1A (Coro1A) was identified as a differentially expressed transcript in wild-type versus Niemann-Pick type C1 deficient macrophages exposed to acetylated low-density lipoproteins (AcLDL). We investigated whether Coro1A plays a role in the uptake or processing of modified lipoproteins in macrophages and if this is related to its actin regulatory functions. METHODS AND RESULTS: In wild-type primary macrophages, filamentous actin transiently decorated AcLDL containing endosomes that also recruited Coro1A. This dynamic association of F-actin with endosomes was disturbed in Coro1A deficient macrophages. In Coro1A knockout macrophages the uptake of AcLDL was increased, rate of AcLDL delivery to lysosomes enhanced, and lipoprotein-derived cholesteryl ester hydrolysis accelerated. Overexpression of wild-type Coro1A normalized AcLDL uptake in Coro1A knockout macrophages while a Coro1A actin binding mutant did not. Furthermore, the effects of macrophage Coro1A silencing on endosomal actin association and AcLDL delivery to lysosomes resembled those of cofilin silencing. CONCLUSIONS: Coro1A controls actin association with endocytic organelles, thereby negatively regulating endo lysosomal delivery, degradation of modified lipoproteins and cholesterol deposition in macrophages. PMID- 22223353 TI - Shortened Ca2+ signaling refractoriness underlies cellular arrhythmogenesis in a postinfarction model of sudden cardiac death. AB - RATIONALE: Diastolic spontaneous Ca(2+) waves (DCWs) are recognized as important contributors to triggered arrhythmias. DCWs are thought to arise when [Ca(2+)] in sarcoplasmic reticulum ([Ca(2+)](SR)) reaches a certain threshold level, which might be reduced in cardiac disease as a consequence of sensitization of ryanodine receptors (RyR2s) to luminal Ca(2+). OBJECTIVE: We investigated the mechanisms of DCW generation in myocytes from normal and diseased hearts, using a canine model of post-myocardial infarction ventricular fibrillation (VF). METHODS AND RESULTS: The frequency of DCWs, recorded during periodic pacing in the presence of a beta-adrenergic receptor agonist isoproterenol, was significantly higher in VF myocytes than in normal controls. Rather than occurring immediately on reaching a final [Ca(2+)](SR), DCWs arose with a distinct time delay after attaining steady [Ca(2+)](SR) in both experimental groups. Although the rate of [Ca(2+)](SR) recovery after the SR Ca(2+) release was similar between the groups, in VF myocytes the latency to DCWs was shorter, and the [Ca(2+)](SR) at DCW initiation was lower. The restitution of depolarization-induced Ca(2+) transients, assessed by a 2-pulse protocol, was significantly faster in VF myocytes than in controls. The VF-related alterations in myocyte Ca(2+) cycling were mimicked by the RyR2 agonist, caffeine. The reducing agent, mercaptopropionylglycine, or the CaMKII inhibitor, KN93, decreased DCW frequency and normalized restitution of Ca(2+) release in VF myocytes. CONCLUSIONS: The attainment of a certain threshold [Ca(2+)](SR) is not sufficient for the generation of DCWs. Postrelease Ca(2+) signaling refractoriness critically influences the occurrence of DCWs. Shortened Ca(2+) signaling refractoriness due to RyR2 phosphorylation and oxidation is responsible for the increased rate of DCWs observed in VF myocytes and could provide a substrate for synchronization of arrhythmogenic events at the tissue level in hearts prone to VF. PMID- 22223355 TI - Left-right symmetry breaking in tissue morphogenesis via cytoskeletal mechanics. AB - RATIONALE: Left-right (LR) asymmetry is ubiquitous in animal development. Cytoskeletal chirality was recently reported to specify LR asymmetry in embryogenesis, suggesting that LR asymmetry in tissue morphogenesis is coordinated by single- or multi-cell organizers. Thus, to organize LR asymmetry at multiscale levels of morphogenesis, cells with chirality must also be present in adequate numbers. However, observation of LR asymmetry is rarely reported in cultured cells. OBJECTIVES: Using cultured vascular mesenchymal cells, we tested whether LR asymmetry occurs at the single cell level and in self-organized multicellular structures. METHODS AND RESULTS: Using micropatterning, immunofluorescence revealed that adult vascular cells polarized rightward and accumulated stress fibers at an unbiased mechanical interface between adhesive and nonadhesive substrates. Green fluorescent protein transfection revealed that the cells each turned rightward at the interface, aligning into a coherent orientation at 20 degrees relative to the interface axis at confluence. During the subsequent aggregation stage, time-lapse videomicroscopy showed that cells migrated along the same 20 degrees angle into neighboring aggregates, resulting in a macroscale structure with LR asymmetry as parallel, diagonal stripes evenly spaced throughout the culture. Removal of substrate interface by shadow mask plating, or inhibition of Rho kinase or nonmuscle myosin attenuated stress fiber accumulation and abrogated LR asymmetry of both single-cell polarity and multicellular coherence, suggesting that the interface triggers asymmetry via cytoskeletal mechanics. Examination of other cell types suggests that LR asymmetry is cell-type specific. CONCLUSIONS: Our results show that adult stem cells retain inherent LR asymmetry that elicits de novo macroscale tissue morphogenesis, indicating that mechanical induction is required for cellular LR specification. PMID- 22223356 TI - Aluminium chloride promotes anchorage-independent growth in human mammary epithelial cells. AB - Aluminium salts used as antiperspirants have been incriminated as contributing to breast cancer incidence in Western societies. To date, very little or no epidemiological or experimental data confirm or infirm this hypothesis. We report here that in MCF-10A human mammary epithelial cells, a well-established normal human mammary epithelial cell model, long-term exposure to aluminium chloride (AlCl(3) ) concentrations of 10-300 u m, i.e. up to 100 000-fold lower than those found in antiperspirants, and in the range of those recently measured in the human breast, results in loss of contact inhibition and anchorage-independent growth. These effects were preceded by an increase of DNA synthesis, DNA double strand breaks (DSBs), and senescence in proliferating cultures. AlCl(3) also induced DSBs and senescence in proliferating primary human mammary epithelial cells. In contrast, it had no similar effects on human keratinocytes or fibroblasts, and was not detectably mutagenic in bacteria. MCF-10A cells morphologically transformed by long-term exposure to AlCl(3) display strong upregulation of the p53/p21(Waf1) pathway, a key mediator of growth arrest and senescence. These results suggest that aluminium is not generically mutagenic, but similar to an activated oncogene, it induces proliferation stress, DSBs and senescence in normal mammary epithelial cells; and that long-term exposure to AlCl(3) generates and selects for cells able to bypass p53/p21(Waf1) -mediated cellular senescence. Our observations do not formally identify aluminium as a breast carcinogen, but challenge the safety ascribed to its widespread use in underarm cosmetics. PMID- 22223357 TI - Robotic-assisted laparoscopic radical cystectomy in the octogenarian. AB - BACKGROUND: The advanced age and comorbidities often associated with bladder cancer patients creates a difficult scenario regarding further management. Robotic-assisted laparoscopic radical cystectomy (RALRC) has had favorable results as a minimally invasive treatment option. We studied perioperative outcomes of RALRC in octogenarians to discern if there is any added benefit in this patient population. METHODS: One hundred and sixty robotic cystectomies have been performed between October 2003 and June 2010. We identified 24 octogenarians who underwent RALRC and form the cohort of the study. RESULTS: Mean patient age was 84.7 years and mean BMI was 24 kg/m2. Most of the patients in the study had serious medical comorbidities, as 82.6% of them had an ASA classification >= 3 and 95.6% had Charlson scores >= 3. There was one open conversion and two patients had positive surgical margins. There were a total of 45 complications in the study, with 14 major complications observed in the 90-day period after surgery. There were five patients who had no complications, and two patients expired as a result of multiple organ failure. At 24 months the overall, disease free and disease-specific survivals were 51.1%, 64.3%, and 79%, respectively. The 90-day mortality rate was 8.7%. CONCLUSIONS: Octogenarians undergoing RALRC have a significant risk of morbidity and mortality. The relationship between advanced age and oncologic outcomes or complications needs to be discerned further as it relates to the octogenarian. Further study is needed to delineate the safety and efficacy of this approach. PMID- 22223358 TI - Apoptosis in extracorporeal preserved inguinal fat flaps of the rat. AB - Fat cells are fragile cells with a short life span outside the body. Ways to reduce cell death in a biochemical way are almost unknown due to scarce information on the type of cellular death that is induced in fat tissue. This study was designed to investigate the apoptotic pathways of fat tissue in a permanent perfusion bioreactor system with the Hannover preservation solution and the Eurocollins solution in fat flaps of rats. In Lewis rats, the inguinal adipofascial flaps were elevated bilaterally and placed in a bioreactor at 37 degrees C. To detect caspases 3, 8, 9 and 12, immunofluorescence stains of fat tissue specimen were analysed at several time points after preservation of flaps were placed in Hannover solution and Eurocollins solution for 10 days. An additional visual assessment of viability by a calcein based life/dead test was performed. It revealed a superior viability of the adipose tissue preserved in Hannover solution. Immunofluorescence staining demonstrated that apoptotic pathways via mitochondria, endoplasmatic reticulum and death receptors were activated, as Caspases 8, 9 and 12 were detected. Caspase 3 as an effector in the common apoptotic pathway was detected as well. Adipose tissue preserved at 37 degrees C ex vivo in a bioreactor system undergoes apoptosis. Immunofluorescence examination of the fat tissue preserved ex vivo revealed that apoptotic pathways via mitochondria, endoplasmatic reticulum and death receptors are being activated. Significantly less activation of Caspase 3, 8, 9 and 12 in flaps preserved in Hannover solution in comparison to Eurocollins was found, supporting the anti apoptotic characteristics of Hannover solution. Based on these findings, further research to modify the apoptotic pathways to ameliorate viability of fat tissue can be performed. PMID- 22223361 TI - A self-powered "sense-act-treat" system that is based on a biofuel cell and controlled by boolean logic. AB - Bio-logic-al: an autonomous, integrated "sense-act-treat" system that is based on an enzymatic biofuel cell has been developed. The system couples a biocomputing logic-detection method with a drug-release system to provide a logic-activated therapeutic intervention in response to a simulated abnormal physiological state, without the need for an external power source, control electronics, or microelectromechanical actuators. PMID- 22223359 TI - Targeting colorectal cancer stem cells with inducible caspase-9. AB - Colorectal cancer stem cells (CSCs) drive tumor growth and are suggested to initiate distant metastases. Moreover, colon CSCs are reportedly more resistant to conventional chemotherapy, which is in part due to upregulation of anti apoptotic Bcl-2 family members. To determine whether we could circumvent this apoptotic blockade, we made use of an inducible active caspase-9 (iCasp9) construct to target CSCs. Dimerization of iCasp9 with AP20187 in HCT116 colorectal cancer cells resulted in massive and rapid induction of apoptosis. In contrast to fluorouracil (5-FU)-induced apoptosis, iCasp9-induced apoptosis was independent of the mitochondrial pathway as evidenced by Bax/Bak double deficient HCT116 cells. Dimerizer treatment of colon CSCs transduced with iCasp9 (CSC iCasp9) also rapidly induced high levels of apoptosis, while these cells were unresponsive to 5-FU in vitro. More importantly, injection of the dimerizer into mice that developed a colon CSC-iCasp9-induced tumor resulted in a strong decrease in tumor size, an increase in tumor cell apoptosis and a clear loss of CD133(+) CSCs. Taken together, our data indicate that dimerization of iCasp9 circumvents the apoptosis block in CSCs, which results in effective tumor regression in vivo. PMID- 22223362 TI - An unique variation of the peroneus tertius muscle. AB - Peroneus tertius (fibularis tertius) is a muscle unique to humans. It often appears to be a part of extensor digitorum longus, and might be described as its "fifth tendon". Although its insertion variation has been reported by many authors, variations of its origin points are not common. A variation of the peroneus tertius muscle was found during routine dissection of a 75-year-old male cadaver. The muscle originated from the extensor hallucis longus. The muscle belly of the extensor hallucis longus arose from the middle two-fourths of the medial surface of the fibula, medial to the extensor digitorum longus, and anterior surface of the interosseous membrane. It lay under the extensor digitorum longus, and lateral to the tibialis anterior muscle. The muscle belly of the extensor hallucis longus divided into medial and lateral parts 17 cm below its origin point. The lateral part, named as peroneus tertius, continued downward to reach the medial part of the dorsal surface of the base of the fifth metatarsal bone. The medial part ran also downward and divided into two tendons reaching the dorsal surface of the base of the distal phalanx of the great toe. This kind of variation may be important during foot or leg surgery. PMID- 22223363 TI - Hemostatic multilayer coatings. AB - Spray layer-by-layer assembly is used to create hemostatic films containing thrombin and tannic acid. The spray assembly technique enables coating of porous and absorbent commercial gelatin sponges with these films. Coated sponges are able to promote instantaneous hemostasis in a porcine spleen bleeding model. PMID- 22223364 TI - Hyperpolarized 129Xe NMR signature of living biological cells. AB - We show that the differentiation between internal and external compartments of various biological cells in suspension can be made via simple NMR spectra of hyperpolarized (129) Xe. The spectral separation between the signals of (129) Xe in these two compartments is already known for red blood cells, because of the strong interaction of the noble gas with hemoglobin. The observation of two separate peaks in the 200-ppm region can be seen with both eukaryotic and prokaryotic cells, some of which are not known to contain paramagnetic proteins in large quantities. Using different experiments in which the cells are lysed, swell or are blocked in G2 phase, we demonstrate that the low-field-shifted peak observed corresponds to xenon in the aqueous pool inside the cells and not in the membranes. The presence of this additional peak is a clear indication of cell integrity, and its integration allows the quantification of the total cell volume. The relaxation time of intracellular xenon is sufficiently long to open up promising perspectives for cell characterization. The exchange time between the inner and outer cell compartments (on the order of 30 ms) renders possible the targeting of intracellular receptors, whereas the observation of chemical shift variations represents a method of revealing the presence of toxic species in the cells. PMID- 22223365 TI - Longitudinal evaluation of intramyocellular lipids (IMCLs) in tibialis anterior muscle of ob/ob and ob/+ control mice using a cryogenic surface coil at 9.4 T. AB - Insulin resistance is a central feature of type II diabetes and is associated with alterations in skeletal muscle lipid metabolism, which manifest themselves, in part, in increased intramyocellular lipid (IMCL) accumulation. The objective of this study was to assess noninvasively the levels of IMCL longitudinally in the tibialis anterior muscle of Lep(ob) /Lep(ob) (ob/ob) mice, a genetic model of obesity and mild diabetes, and Lep(ob) /+ (ob/+) heterozygous control animals, using (1) H MRS at 9.4 T. The use of a cryogenic surface coil transceiver leads to significant increases in sensitivity. Method implementation included the assessment of the reproducibility and spatial heterogeneity of the IMCL signal and the determination of T(2) relaxation times, as IMCL levels were expressed relative to the total creatine signal, and therefore the signal ratios had to be corrected for differences in T(2) relaxation. IMCL levels were found to be significantly higher in ob/ob mice relative to ob/+ heterozygous control mice that do not develop disease. An increase in IMCL levels was observed for ob/ob mice until weeks 16/17; after this time point, IMCL levels decreased again, reaching final levels that were slightly higher than the initial values. These noninvasively detected alterations in skeletal muscle lipid metabolism in ob/ob mice were accompanied by a transient increase in plasma insulin concentrations. This study indicates that IMCL may be reliably assessed in mouse tibialis anterior muscle using a cryogenic surface coil, implying that (1) H MRS at 9.4 T represents a useful technology for the noninvasive measurement of changes in lipid metabolism in the skeletal muscle that accompany obesity. PMID- 22223366 TI - Longitudinal study of tumor-associated macrophages during tumor expansion using MRI. AB - MRI is being used increasingly for the noninvasive longitudinal monitoring of cellular processes in various pathophysiological conditions. Macrophages are the main stromal cells in neoplasms and have been suggested to be the major cell type ingesting superparamagnetic iron oxide (SPIO) nanoparticles. However, no MRI study has described longitudinally the presence of tumor-associated macrophages (TAMs) during tumorigenesis with histological confirmation. To address this, we injected SPIO nanoparticles into the circulation of tumor-bearing mice and used MRI and post-mortem histology to monitor TAMs at different time points. The MRI results demonstrated that TAMs, as hypointense signals, appeared continually with the expansion of the tumor. The histological findings also revealed that SPIO labeled TAMs tended to deposit closer to the vessel lumen with time prior to rapid tumor growth. The present study demonstrates the potential of using MRI to assess longitudinally TAM accumulation during tumorigenesis, and provides the first in vivo insight into the topographical arrangement of TAMs in relation to the progression of tumors. In vivo monitoring of the presence of TAMs could be useful for the development of tumor treatments that target TAM functions. PMID- 22223367 TI - High-resolution diffusion tensor imaging of fixed brain in a mouse model of Pelizaeus-Merzbacher disease: comparison with quantitative measures of white matter pathology. AB - Diffusion tensor imaging (DTI) is a powerful technique for the noninvasive assessment of the central nervous system. To facilitate the application of this technique to in vivo studies, we characterised a mouse model of the leukodystrophy, Pelizaeus-Merzbacher disease (PMD), comparing high-resolution ex vivo DTI findings with quantitative histological analysis of selected areas of the brain. The mice used in this study (Plp1-transgenic) carry transgenic copies of the Plp1 gene and are models for PMD as a result of gene duplication. Plp1 transgenic mice display a mild ataxia and experience frequent seizures around the time at which they were imaged. Axial (lambda(1) ) and radial (RD) diffusivities and fractional anisotropy (FA) data were analysed using an exploratory whole brain voxel-based method, a voxel-based approach using tract-based spatial statistics (TBSS), and by application of conventional region of interest (ROI) analyses to selected white matter tracts. Raw t value maps and TBSS analyses indicated widespread changes throughout the brain of Plp1-transgenic mice compared with the wild-type. ROI analyses of the corpus callosum, anterior commissure and hippocampal fimbria showed that FA was reduced significantly, whereas lambda(1) and RD were increased significantly, in Plp1-transgenic mice compared with the wild-type. The DTI data derived from ROI analyses were subsequently compared with histological measures taken in the same regions. These revealed an almost complete absence of myelin, preservation of axons, marked astrocytosis and increased or unchanged cell densities. These data contribute to our growing understanding of the basis of anisotropic water diffusion in the normal and diseased nervous system. PMID- 22223368 TI - Association of lung adenocarcinoma clinical stage with gene expression pattern in noninvolved lung tissue. AB - Associations between clinical outcome of cancer patients and the gene expression signature in primary tumors at time of diagnosis have been reported. To test whether gene expression patterns in noninvolved lung tissue might correlate with clinical stage in lung adenocarcinoma (ADCA) patients, we compared the transcriptome of noninvolved lung samples from 60 ADCA smoker patients of clinical stage I versus 60 patients with stage>I. Quantitative PCR of 10 genes with the most significant differential expression confirmed the statistical association with clinical stage in eight genes, six of which were downregulated in high-stage patients. Five of these six genes were also downregulated in lung ADCA tissue as compared to noninvolved tissue. Studies in vitro indicated that four of the genes (SLC14A1, SMAD6, TMEM100 and TXNIP) inhibited colony formation of lung cancer cell lines transfected to overexpress the genes, suggesting their potential tumor-suppressor activity. Our findings suggest that individual variations in the transcriptional profile of noninvolved lung tissue may reflect the lung ADCA patient's predisposition to tumor aggressiveness. PMID- 22223369 TI - Development of new methods in organic synthesis and their applications to the synthesis of biologically interesting natural products. AB - 2,6-Dimethyl-9-Aryl-9-phosphabicyclo[3.3.1]nonanes (9-PBN and 9-NapBN) and the chiral diaminophosphine oxides (DIAPHOXs) derived from aspartic acid have been introduced as useful ligands and preligands, respectively, for transition metal catalyzed asymmetric synthesis. anti-Selective asymmetric hydrogenation of alpha amino-beta-ketoesters using Ru-, Rh-, Ir-, and Ni-catalysts through dynamic kinetic resolution have been developed for the first time, producing efficiently important anti beta-hydroxy-alpha-amino acids. The total synthesis of several biologically active natural products was achieved by use of the transition metal catalyzed reaction using DIAPHOX, anti-selective asymmetric hydrogenation, and reactions developed by us. Synthesis of tangutorine, an antitumor indole alkaloid, has been enantioselectively achieved for the first time. Enantioselective synthesis of a martinelline chiral core was accomplished using the asymmetric tandem Michael-Aldol reaction as a key step developed by us. This synthesis represents the formal total synthesis of martinelline and martinellic acid. Papuamide B was synthesized through the elucidation of unknown stereostructures by using the anti-selective asymmetric hydrogenation and reactions developed by us. PMID- 22223370 TI - Formal [4+2] cycloaddition of di-tert-butyl 2-ethoxycyclobutane-1,1-dicarboxylate with ketones or aldehydes and tandem lactonization. AB - A catalytic amount of tin(IV) chloride catalyzed formal [4+2] cycloaddition reaction of di-tert-butyl 2-ethoxycyclobutane-1,1-carboxylate with ketones or aldehydes to give diethyl 6-ethoxydihydro-2H-pyran-3,3(4H)-dicarboxylates, whereas two equivalents of trimethylsilyl triflate promoted tandem [4+2] cycloaddition and lactonization to afford 3-oxo-2,6-dioxabicyclo[2.2.2]octane-4 carboxylate esters. PMID- 22223371 TI - Comparative study of fourteen alkaloids from Uncaria rhynchophylla hooks and leaves using HPLC-diode array detection-atmospheric pressure chemical ionization/MS method. AB - The purpose of the study is to compare alkaloid profile of Uncaria rhynchophylla hooks and leaves. Ten oxindole alkaloids and four glycosidic indole alkaloids were identified using HPLC-diode array detection (DAD) or LC-atmospheric pressure chemical ionization (APCI)-MS method, and a HPLC-UV method for simultaneous quantification of major alkaloids was validated. The hooks are characterized by high levels of four oxindole alkaloids rhynchophylline (R), isorhynchophylline (IR), corynoxeine (C) and isocorynoxeine (IC), while the leaves contained high level of two glycosidic indole alkaloids vincoside lactam (VL) and strictosidine (S). The presented methods have proven its usefulness in chemical characterization of U. rhynchophylla hooks and leaves. PMID- 22223372 TI - Simple method for quantification of gadolinium magnetic resonance imaging contrast agents using ESR spectroscopy. AB - To develop an estimation method of gadolinium magnetic resonance imaging (MRI) contrast agents, the effect of concentration of Gd compounds on the ESR spectrum of nitroxyl radical was examined. A solution of either 4-oxo-2,2,6,6 tetramethylpiperidine-N-oxyl (TEMPONE) or 4-hydroxy-2,2,6,6-tetramethylpiperidine N-oxyl (TEMPOL) was mixed with a solution of Gd compound and the ESR spectrum was recorded. Increased concentration of gadolinium-diethylenetriamine pentaacetic acid chelate (Gd-DTPA), an MRI contrast agent, increased the peak-to-peak line widths of ESR spectra of the nitroxyl radicals, in accordance with a decrease of their signal heights. A linear relationship was observed between concentration of Gd-DTPA and line width of ESR signal, up to approximately 50 mmol/L Gd-DTPA, with a high correlation coefficient. Response of TEMPONE was 1.4-times higher than that of TEMPOL as evaluated from the slopes of the lines. The response was slightly different among Gd compounds; the slopes of calibration curves for acua[N,N-bis[2-[(carboxymethyl)[(methylcarbamoyl)methyl]amino]ethyl]glycinato(3 )]gadolinium hydrate (Gd-DTPA-BMA) (6.22 MUT.L/mmol) and gadolinium-1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid chelate (Gd-DOTA) (6.62 MUT.L/mmol) were steeper than the slope for Gd-DTPA (5.45 MUT.L/mmol), whereas the slope for gadolinium chloride (4.94 MUT.L/mmol) was less steep than that for Gd-DTPA. This method is simple to apply. The results indicate that this method is useful for rough estimation of the concentration of Gd contrast agents if calibration is carried out with each standard compound. It was also found that the plot of the reciprocal square root of signal height against concentrations of contrast agents could be useful for the estimation if a constant volume of sample solution is taken and measured at the same position in the ESR cavity every time. PMID- 22223373 TI - Key role of chemical hardness to compare 2,2-diphenyl-1-picrylhydrazyl radical scavenging power of flavone and flavonol O-glycoside and C-glycoside derivatives. AB - The antioxidant activities of flavonoids and their glycosides were measured with the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH radical, DPPH(.)) scavenging method. The results show that free hydroxyl flavonoids are not necessarily more active than O-glycoside. Quercetin and kaempferol showed higher activity than apigenin. The C- and O-glycosides of flavonoids generally showed higher radical scavenging activity than aglycones; however, kaempferol C3-O-glycoside (astragalin) showed higher activity than kaempferol. In the radical scavenging activity of flavonoids, it was expected that OH substitutions at C3 and C5 and catechol substitution at C2 of B ring and intramolecular hydrogen bonding between OH at C5 and ketone at C3 would increase the activity; however, the reasons have yet to be clarified. We here show that the radical scavenging activities of flavonoids are controlled by their absolute hardness (eta) and absolute electronegativity (chi) as a electronic state. Kaempferol and quercetin provide high radical scavenging activity since (i) OH substitutions at C3 and C5 strikingly decrease eta of flavones, (ii) OH substitutions at C3 and C7 decrease chi and eta of flavones, and (iii) phenol or o-catechol substitution at C2 of B ring decrease chi of flavones. The coordinate r(chi, eta) as the electron state must be small to increase the radical scavenging activity of flavonoids. The results show that chemically soft kaempferol and quercetin have higher DPPH radical scavenging activity than chemically hard genistein and daidzein. PMID- 22223374 TI - Characterization of non-stoichiometric hydration and the dehydration behavior of sitafloxacin hydrate. AB - Sitafloxacin (STFX) hydrate is a non-stoichiometric hydrate. The hydration state of STFX hydrate varies non-stoichiometrically depending on the relative humidity and temperature, though X-ray powder diffraction (XRPD) of STFX hydrate was not affected by storing at low and high relative humidities. The detailed properties of crystalline water of STFX hydrate were estimated in terms of hygroscopicity, thermal analysis combined with X-ray powder diffractometry, crystallography and density functional theory (DFT) calculation. STFX hydrate changed the water contents continuously and reversibly from an equivalent amount of dihydrate through that of sesquihydrate depending on the relative humidity at 25 degrees C. Thermal analysis and X-ray powder diffraction (XRPD) simultaneous measurement also revealed that STFX hydrate dehydrated into a hydrated state equivalent to monohydrate by heating up to 100 degrees C, whereas XRPD patterns were slightly affected. This indicated that the crystal structure of STFX hydrate was retained at the dehydration level of monohydrate. Single-crystal X-ray structural analysis showed that two STFX molecules and four water molecule sites were contained in an asymmetric unit. STFX molecules formed a channel structure where water molecules were included. At the partially dehydrated state, at least two of four water molecules were considered to be disordered in occupancy and/or coordinates. Insight into the crystal structure of STFX hydrate stored at low and high relative humidities and geometry of the hydrogen bond were helpful to estimate the origin of non-stoichiometric hydration of STFX hydrate. PMID- 22223375 TI - Simple and rapid HPLC-UV method using an ultrafine particle octadecylsilane for determination of residual fentanyl in applied Durotep MT transdermal matrix patches and its clinical application. AB - A few complicated and time-consuming methods are available for the determination of residual fentanyl in Durotep MT transdermal patches, however, their application to clinical settings is limited. The aim of this study was to develop a simple and rapid HPLC-UV method using an ultrafine particle octadecylsilane (ODS) for the determination of residual fentanyl in applied Durotep MT transdermal matrix patches. Patch extraction involved sonicating a shredded Durotep MT patch in acetonitrile for 15 min. Fentanyl separation was completed within 2 min using a 2.3-MUm particle ODS column (50 * 4.6 mm i.d.) at a flow rate of 1.5 mL/min. No peaks interfering with fentanyl (1.27 min) and papaverine (0.89 min) as an internal standard were observed. The calibration curve for fentanyl was linear over the range of 0.015-9.0 mg as a Durotep MT patch. The intra- and inter-assay precisions and accuracies of each patch were within 5.3% and 103.9-110.5% and within 8.2% and 97.1-104.3%, respectively. The validated method was applied to determine residual fentanyl in Durotep MT patches used in 35 cancer patients. Although the plasma fentanyl concentration was significantly correlated with its measured absorption rate, the measured absorption rate normalized fentanyl concentration showed a large inter-individual variation. The validated simple and rapid HPLC-UV method established in the present study is helpful for evaluating the absorption rate of fentanyl in patients receiving Durotep MT patches. PMID- 22223376 TI - Structures of two new phenolic glycosides, kaempferiaosides A and B, and hepatoprotective constituents from the rhizomes of Kaempferia parviflora. AB - Two new phenolic glycosides, kaempferiaosides A and B were isolated from the rhizomes of Kaempferia parviflora (Zingiberaceae) together with 24 known compounds. Their structures including absolute stereochemistry were elucidated on the basis of chemical and spectroscopic evidence. Among the isolates, 5,3' dihydroxy-3,7,4'-trimethoxyflavone showed higher activity than silybin, a commercial hepatoprotective agent. PMID- 22223377 TI - Synthesis, dihydrofolate reductase inhibition, anti-proliferative testing, and saturation transfer difference 1H-NMR study of some new 2-substituted-4,6 diaminopyrimidine derivatives. AB - A series of 2-substituted-4,6-diaminipyrimidine derivatives were synthesized and evaluated for their dihydrofolate reductase (DHFR) inhibitory activity. Saturation transfer difference (STD) (1)H-NMR experiments were used to probe the binding characteristics of the compounds with human DHFR enzyme. The most potent molecules, 12 and 15, in enzyme assay study showed the best results in STD experiments indicating their intimate interaction with the receptor. The docking studies were followed to explain the structural basis for the observed interaction between the ligands and DHFR. All the compounds were also assayed in vitro for their growth inhibitory activity on MCF-7, HepG2, SKHep1, and Hela tumor cell lines. Compounds 16, 17, and 22 demonstrated the most potent in vitro anti-proliferative activity among the others. PMID- 22223378 TI - Microwave-assisted synthesis of organometallic complexes of 99mTc(CO)3 and Re(CO)3: its application to radiopharmaceuticals. AB - (99m)Tc-tricarbonyl [(99m)Tc(CO)(3)] complexes have been conventionally synthesized by heating [(99m)Tc(CO)(3)(H(2)O)(3)](+) and a tridentate chelating ligand under atmospheric pressure; however, this method is poor in terms of chemical yield and reproducibility. Moreover, since the half-life of (99m)Tc is very short (6 h), the development of facile and rapid methods of synthesizing (99m)Tc-labeled compounds, which could be used as radioactive tracers for single photon emission computed tomography (SPECT), is required. Thus, we initiated a study on the application of a microwave reaction to the synthesis of (99m)Tc(CO)(3)-2-picolylamine monoacetic acid (PAMA) [(99m)Tc(CO)(3)-PAMA] complexes on the basis of the fact that synthesis of metal complexes proceeds rapidly by microwave irradiation owing to an efficient exothermic phenomenon and heat conduction effect. Formation of by-products could be markedly suppressed by comparison with that in conventional methods. In the present study, rhenium (Re), an element belonging to the same group in the periodic table as technetium (Tc), and which also forms bipyramidal complexes, was first used to investigate the synthetic reaction because no stable isotopes exist for Tc. As a result, when water was used as the solvent under the irradiation of microwaves within 1 min, the Re(CO)(3)-PAMA complex could be directly synthesized from ethyl ester of PAMA (PAMAEE) and [Re(CO)(3)(H(2)O)(3)]Br in one step and with a high yield (94%). Finally, the (99m)Tc(CO)(3)-PAMA complex was successfully synthesized at a high radiochemical yield (>99%) within 1 min of reaction using (99m)Tc instead of Re under the same conditions. PMID- 22223379 TI - A 5% glucose infusion fluid provokes significant precipitation of phenytoin sodium injection via interruption of the cosolvent effect of propylene glycol. AB - The precipitation of phenytoin sodium injection provoked by mixing with infusion fluids renders its use in clinical practice difficult, as rapid intravenous (i.v.) push and i.v. infusion are supposed to be avoided. As some of its aspects remain unclear, this study tried to elucidate this precipitation mechanism. In particular, this study focused on the significant precipitation induced by glucose infusion fluid. The precipitation provoked by 5% glucose infusion fluid was obviously different from the precipitation that accompanied simple pH reduction, in terms of the growth mode and morphology of crystals. In addition, the effect of glucose was partially unrelated to pH reduction. NMR measurements including a two-dimensional nuclear Overhauser effect spectroscopy (2D-NOESY) spectrum indicated the specific interaction between glucose and propylene glycol, which is incorporated into phenytoin sodium injection as a solubilizing agent. These results led to the conclusion that this interaction was crucial for the precipitation of phenytoin, as it diminished the solubilizing effect of propylene glycol, resulting in the enhancement of the crystallization of phenytoin. The determination of phenytoin solubility in aqueous solutions at different pH values revealed that phenytoin incorporated in the admixture could be dissolved completely, as long as the injection was diluted with saline or water. These findings offer a profound insight into the formulation design of phenytoin sodium injection and its use in clinical practice. PMID- 22223380 TI - Synthesis of (+/-)-8-deisopropyladunctin B. AB - (+/-)-8-Deisopropyladunctin B, the deisopropyl form of adunctin B, which was isolated from the leaves of Piper aduncum (Piperaceae) collected in Papua New Guinea, was synthesized in 0.77% overall yield in 17 steps from 5,7 dimethoxycoumarin-3-carboxylate. The key step was our original stereoconvergent skeleton transformation from 1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3 one to 1,2,4a,9b-tetrahydrodibenzofuran-4-ol with dimethylsulfoxonium methylide. PMID- 22223381 TI - Facile synthesis, antioxidant and antimicrobial activity of amino methylene bisphosphonates. AB - A green and efficient preparation method for the amino bisphosphonates is accomplished by simple mixing and stirring of diethylphosphite, triethylorthoformate and various amines in the presence of amberlyst-15 as catalyst at room temperature under solvent free conditions. The title compounds are characterized by IR, (1)H-, (13)C-, (31)P-NMR and mass spectra, also studied their antimicrobial and antioxidant activity. PMID- 22223382 TI - Synthesis and anti-inflammatory activity of some benzofuran and benzopyran-4-one derivatives. AB - New series of furosalicylic acids 3a-c, furosalicylanilides 6a-n, furobenzoxazines 8a-f, 1-benzofuran-3-arylprop-2-en-1-ones 12a,b, 6-(aryl-3 oxoprop-1-enyl)-4H-chromen-4-ones 16a-c and 6-[6-aryl-2-thioxo-2,5 dihydropyrimidin-4-yl]-4H-chromen-4-ones 17a-c were synthesized. Anti inflammatory activity evaluation was performed using carrageenan-induced paw edema model in rats and prostaglandin E(2) (PGE(2)) synthesis inhibition activity. Some of the tested compounds revealed comparable activity with less ulcerogenic effect than Diclofenac at a dose 100 mg/kg. All the synthesized compounds were docked on the active site of cyclooxygenase-2 (COX-2) enzyme and most of them showed good interactions with the amino acids of the active site comparable to the interactions exhibited by Diclofenac. PMID- 22223383 TI - Hyaluronidase inhibitors from Keiskea japonica. AB - An extract of Keiskea japonica MIQ. showed an inhibitory effect on hyaluronidase activity. From the extract, four new phenylpropanoids, two new maltol glycosides, two new monoterpene glycosides, and two new phenolic compounds were isolated together with 19 known compounds. Among these constituents, two phenylpropanoids and a flavone glucuronide were revealed as hyaluronidase inhibitors. PMID- 22223384 TI - Flavonol acylglycosides from flower of Albizia julibrissin and their inhibitory effects on lipid accumulation in 3T3-L1 cells. AB - Obesity is a serious health problem worldwide. We investigated the anti-obesity effect of the flower of Albizia julibrissin DURAZZ. (Leguminosae). A 90% EtOH extract of the flower inhibited adipogenesis in 3T3-L1 preadipocytes, as well as the activity of glycerol-3-phosphate dehydrogenase (GPDH) activity. New flavonol acylglycosides (1-4) and eighteen known compounds (5-22) were isolated by bioassay-directed fractionation. These new glycosides were elucidated to be 3" (E)-p-coumaroylquercitrin (1), 3"-(E)-feruloylquercitrin (2), 3"-(E) cinnamoylquercitrin (3), and 2"-(E)-cinnamoylquercitrin (4) on the basis of spectroscopic and chemical analysis. These compounds inhibited adipogenesis in 3T3-L1 preadipocytes. In particular, 2 exhibited potent inhibitory effects on triglyceride accumulation. Furthermore, GPDH activity was inhibited by 2. Additionally, 2 inhibited glucose uptake in 3T3-L1 adipocytes. These results indicate that the 90% EtOH extract and compounds isolated from the flower of A. julibrissin inhibit adipogenesis in 3T3-L1 preadipocytes and may have anti obesity effect through the inhibition of preadipocyte differentiation. PMID- 22223385 TI - Determination of the absolute structure of (+)-akaterpin. AB - We describe the total synthesis and structural determination of (+)-akaterpin (1), an inhibitor of phosphatidylinositol-specific phospholipase C (PI-PLC). The key features of the synthetic strategy include the resolution of beta,gamma unsaturated ketone (+/-)-2a with chiral sulfoximine 6. The absolute stereochemistry was determined by comparison of the specific optical rotation data of (+)-1 and (-)-1 with that of natural akaterpin. PMID- 22223386 TI - Cardioactive C19-diterpenoid alkaloids from the lateral roots of Aconitum carmichaeli "Fu Zi". AB - Bioassay-guided fractionation of an n-BuOH extract of the lateral roots of Aconitum carmichaeli. led to the isolation of 5 cardioactive C(19)-diterpenoid alkaloids: N-deethylaconine (1), beiwutinine (2), hypaconine (3), mesaconine (4), and 15alpha-hydroxyneoline (5). N-Deethylaconine and beiwutinine are new aconitine-type C(19)-diterpenoid alkaloids. Hypaconine was isolated from this species for the first time. Among them, mesaconine, hypaconine, and beiwutinine showed the strongest cardiac actions on the isolated perfused bullfrog heart. Furthermore, mesaconine has protective effects, including improved inotropic effect and left ventricular diastolic function, on myocardial ischemia reperfusion injury in rat at a dose of 10(-9) mol/L. However, mesaconine has almost no effect on heart rate. PMID- 22223387 TI - Conversion of spirostane and solanidane into pregnane (1)introduction of oxygen function into C-23. AB - A spirosolane derivative possessing a hydroxyl group at C-23, esculeogenin A, a sapogenol of tomato saponin, was found to be easily converted into the corresponding pregnane derivative by refluxing with aqueous pyridine. Therefore, introduction of a hydroxyl group into the C-23 of diosgenin (as representative of spirostane derivatives) and solasodine (as representative of spirosolane derivatives) was attempted by the reaction of NaNO(2)-BF(3) . Et(2)O. In diosgenin, the objective compound was obtained by the reaction in AcOH. However, in solasodine, we obtained a 23-nitroso derivative by the reaction in AcOH and 23,24-bisnorcholanic acid 22-16 lactone, or vespertilin, in AcOH and CHCl(3). PMID- 22223388 TI - Sabiperones A-F, new diterpenoids from Juniperus sabina. AB - Six new diterpenoids, sabiperones A-F (1-6) have been isolated from the aerial part of Juniperus sabina. Their structures were elucidated by spectroscopic methods including 2D NMR techniques. Sabiperone F showed moderate cell growth inhibitory activities against five human cancer cell lines. PMID- 22223389 TI - New 6-hydroxyeunicellins from a soft coral Cladiella sp. AB - Two new 6-hydroxyeunicellin diterpenoids, cladieunicellin G (1) and 6-epi cladieunicellin F (2), were isolated from an Indonesian octocoral Cladiella sp. The structures of eunicellins 1 and 2 were established by spectroscopic methods and 2 was found to be an epimer of the known eunicellin cladieunicellin F (3). Eunicellin 2 displayed inhibitory effects on the generation of superoxide anion and the release of elastase by human neutrophils. PMID- 22223390 TI - Synthesis of BMS-309403-related compounds, including [14C]BMS-309403, a radioligand for adipocyte fatty acid binding protein. AB - Adipocyte fatty acid binding protein (A-FABP; FABP4), which is predominantly expressed in macrophages and adipose tissue, regulates fatty acid storage and lipolysis, and is also an important mediator of inflammation. Here, we report a synthesis of (14)C-labeled 2-[2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3 yloxy]acetic acid (BMS309403), a potent and selective small-molecular FABP4 inhibitor, as a chemical tool for investigating the roles of FABP4 in inflammatory and metabolic disorders. The structure-activity relationship of several BMS derivatives for inhibition of FABP4 is also reported. PMID- 22223391 TI - Disordered eating and suicidal intent: the role of thin ideal internalisation, shame and family criticism. AB - OBJECTIVE: We explored the effect of thin ideal internalisation, shame proneness and family criticism on disordered eating and suicidal intent in female Mexican adolescents. METHOD: We studied a probabilistic sample of 2537 high school students in central Mexico, stratified by marginalisation status and migratory intensity. We used a generalised logistic regression model to estimate the odds of disordered eating and suicidal intent across scores for three predictors: Internalisation of the thin ideal, shame and family criticism. RESULTS: Disordered eating was reported by 4.2% (95% CI = 0.9-7.5%) and suicidal intent by 13.2% (95% CI = 12.0-14.4%) of girls. The unadjusted odds ratios of any disordered eating for thin ideal internalisation, shame proneness and familial criticism were 1.2, 1.1 and 3.2, respectively. The positive association between thin ideal internalisation and disordered eating remained even after controlling for shame proneness and familial criticism. The association of these variables with suicidal intent was weaker. DISCUSSION: Results support stronger effects for disordered eating than suicidal intent across the three unadjusted predictors. It also highlights the presence of the relationship of criticism and disordered eating in female adolescents from low and middle socio-economic backgrounds. PMID- 22223392 TI - Cognitive behavioural therapy for individuals with longstanding anorexia nervosa: adaptations, clinician survival and system issues. AB - Despite recent advances in the treatment of anorexia nervosa, some individuals will progress to a severe and enduring illness, with associated physical, psychological and social consequences. Working with these patients, however, may leave clinicians feeling overwhelmed, risking difficulties in the therapeutic relationship including disengagement or despair. Cognitive behaviour therapy has shown some promise in the treatment of eating disorders, yet some features may not be appropriate for this group. In this paper, we outline the ways in which we have adapted cognitive behaviour therapy to best meet the complex and challenging needs of this group. We stress the importance of maintaining a reassuring, accepting and motivational approach in combination with clear goal setting and boundaries. PMID- 22223393 TI - Anxiety in anorexia nervosa and its management using family-based treatment. AB - Anorexia nervosa (AN) is characterized by its similarity to anxiety disorders, especially obsessive-compulsive disorder (OCD). Family-based treatment (FBT) has shown promising initial results for treatment of AN in adolescents, yet the precise mechanisms of action are unknown. We present a theoretical argument and model, suggesting that FBT may work via exposure (and habituation) to food and its consumption. First, we review the evidence for pathological anxiety in AN, and suggest a framework for identifying specific anxious triggers, emotions (fear and worry) and avoidance strategies. Second, we briefly review evidence indicating that cognitive-behavioural therapy (CBT) and specifically exposure in its various forms is most effective for treating anxiety disorders in youth. Third, we consider distinct approaches to exposure therapy based on the pattern of triggers, anxious emotions and avoidance. We conclude that the interventions utilized in FBT share clear similarities to exposure with response prevention, a type of exposure therapy commonly used with OCD, and may work via facilitating habituation to food and eating in one's natural environment. We also highlight how parents facilitate this process in between sessions by effectively coaching their children and facilitating naturalistic exposure to food and related triggers. Options for future research are considered. PMID- 22223395 TI - Shorter hospitalization trends among children with sickle cell disease. AB - BACKGROUND: Vaso-occlusive crises (VOC) contribute to frequent hospitalizations among children with sickle cell disease (SCD). The objective of this study was to determine whether length of stay (LOS) has decreased for VOC hospitalizations between 1997 and 2009. PROCEDURE: We analyzed pediatric discharges (aged 0-18) with a primary or secondary diagnosis of SCD with crisis from the Kid's Inpatient Database (years 1997, 2003, and 2009), a nationally representative sample of pediatric hospital discharges. We conducted bivariate and multivariate, sample weighted linear regression analyses to determine associations between independent variables (patient demographics, hospital characteristics, co-diagnoses, and procedures) and LOS. RESULTS: Both the number (22,661-21,741) and proportion of VOC hospitalizations (0.34-0.29%) among all pediatric hospitalizations marginally decreased between 1997 and 2009 (P < 0.01). Mean LOS decreased from 4.59 to 4.21 days (P < 0.01). For all study years, older age was the only socio-demographic variable associated with longer LOS, controlling for other factors. Between 1997 and 2009, LOS decreased for all age categories, with the largest statistically significant reduction occurring among adolescents (5.69-4.76 days). CONCLUSIONS: Nationally representative hospital data indicate modest but meaningful reductions in LOS for children with VOC over a 12-year period. Adolescents who typically have the greatest disease severity showed the largest reduction in LOS. However, adolescents continue to account for a large proportion of inpatient stays for VOC. These findings illustrate that the adolescent period is a critical time in the lifespan for targeted intervention. PMID- 22223394 TI - alpha-Tocopherol regulates ectonucleotidase activities in synaptosomes from rats fed a high-fat diet. AB - alpha-Tocopherol (alpha-Toc) is involved in various physiologic processes, which present antioxidant and neuroprotective properties. High-fat diets have an important role in neurodegenerative diseases and neurological disturbances. This study aimed to investigate the effects of treatment with alpha-Toc and the consumption of high-fat diets on ectonucleotidase activities in synaptosomes of cerebral cortex, hippocampus and striatum of rats. Animals were divided into four different groups, which received standard diet (control), high-fat saturated diet (HF), alpha-Toc and high-fat saturated diet plus alpha-Toc (alpha-Toc + HF). High fat saturated diet was administered ad libitum and alpha-Toc by gavage using a dose of 50 mg.kg(-1). After 3 months of treatment, animals were submitted to euthanasia, and cerebral cortex, hippocampus and striatum were collected for biochemical assays. Results showed that adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP) hydrolysis in the cerebral cortex, hippocampus and striatum were decreased in HF in comparison to the other groups (P < 0.05). When rats that received HF were treated with alpha-Toc, the activity of the ectonucleotidases was similar to the control. ATP, ADP and AMP hydrolysis in the cerebral cortex, hippocampus and striatum were increased in the alpha-Toc group when compared with the other groups (P < 0.05). These findings demonstrated that the HF alters the purinergic signaling in the nervous system and that the treatment with alpha-Toc was capable of modulating the adenine nucleotide hydrolysis in this experimental condition. PMID- 22223396 TI - Design and synthesis of 2-iminothiazolidin-4-one moiety-containing compounds as potent antiproliferative agents. AB - A new series of 2,5-diaryliminothiazolidin-4-ones were designed and synthesized as potent antiproliferative agents. The antiproliferative activities of the 25 target compounds were evaluated against three cancer cell lines (A549, H460 and HT29) by MTT assay. Pharmacological data indicated that most of the compounds possessed moderate activity, some showed remarkable activity against one or more cell lines. As the most promising compound, 8s (with IC(50) values of 1.1, 0.01 and 1.3 uM against the A549, H460 and HT29 cell lines) was 1.1- to 270-fold more potent than the reference drug sorafenib. Furthermore, preliminary structure activity relationships (SARs) were summarized to provide guidance for further design and discovery of 2-iminothiazolidin-4-one-based antiproliferative agents. PMID- 22223398 TI - Configuration of a high-content imaging platform for hit identification and pharmacological assessment of JMJD3 demethylase enzyme inhibitors. AB - The biological complexity associated with the regulation of histone demethylases makes it desirable to configure a cellular mechanistic assay format that simultaneously encompasses as many of the relevant cellular processes as possible. In this report, the authors describe the configuration of a JMJD3 high content cellular mechanistic imaging assay that uses single-cell multiparameter measurements to accurately assess cellular viability and the enzyme-dependent demethylation of the H3K27(Me)3 mark by exogenously expressed JMJD3. This approach couples robust statistical analyses with the spatial resolving power of cellular imaging. This enables segregation of expressing and nonexpressing cells into discrete subpopulations and consequently pharmacological quantification of compounds of interest in the expressing population at varying JMJD3 expression levels. Moreover, the authors demonstrate the utility of this hit identification strategy through the successful prosecution of a medium-throughput focused campaign of an 87 500-compound file, which has enabled the identification of JMJD3 cellular-active chemotypes. This study represents the first report of a demethylase high-content imaging assay with the ability to capture a repertoire of pharmacological tools, which are likely both to inform our mechanistic understanding of how JMJD3 is modulated and, more important, to contribute to the identification of novel therapeutic modalities for this demethylase enzyme. PMID- 22223399 TI - Affinity purification using recombinant PXR as a tool to characterize environmental ligands. AB - Many environmental endocrine disrupting compounds act as ligands for nuclear receptors. The human pregnane X receptor (hPXR), for instance, is activated by a variety of environmental ligands such as steroids, pharmaceutical drugs, pesticides, alkylphenols, polychlorinated biphenyls and polybromo diethylethers. Some of us have previously reported the occurrence of hPXR ligands in environmental samples but failed to identify them. The aim of this study was to test whether a PXR-affinity column, in which recombinant hPXR was immobilized on solid support, could help the purification of these chemicals. Using PXR ligands of different affinity (10 nM < EC50 < 10 MUM), we demonstrated that the PXR affinity preferentially column captured ligands with medium to high affinities (EC50 < 1 MUM). Furthermore, by using the PXR-affinity column to analyze an environmental sample containing ERalpha, AhR, AR, and PXR activities, we show that (i) half of the PXR activity of the sample was due to compounds with medium to high affinity for PXR and (ii) PXR shared ligands with ERalpha, AR, and AhR. These findings demonstrate that the newly developed PXR-affinity column coupled to reporter cell lines represents a valuable tool for the characterization of the nature of PXR active compounds and should therefore guide and facilitate their further analysis. PMID- 22223400 TI - Resolutive pulmonary endarterectomy in a non-compliant patient with systemic lupus erythematosus and antiphospholipid syndrome. AB - Patients with chronic thromboembolic pulmonary hypertension (CTEPH) have poor prognosis, and pulmonary endarterectomy (PEA) is considered the treatment of choice for this condition. We report a case and review the literature of successful PEA for CTEPH due to antiphospholipid syndrome associated with systemic lupus erythematosus. The definitive and decisive approach needed to treat this high-risk patient with a history of comorbidity, long-term illness and poor compliance was found with a therapy of PEA. PMID- 22223401 TI - Intramolecular H-Ar ligand exchange between silicon and boron: functionality transfer of Si-H to B-H. AB - o-C(6)H(4)(SiR(3-n)H(n))(BMes(2)) (1; R=Me, Ph; n=1, 2) undergo Mes-H (Mes=mesityl) ligand exchange between the silicon atom and the boron atom to form o-C(6)H(4)(SiMesR(3-n)H(n-1))(BMesH) (6) upon heating. The resulting hydroborane intermediates (6) immediately react with benzaldehyde to afford their corresponding benzyloxyboranes (5). A DFT study of model compounds reveals the transition states of the ligand exchange. A hydride abstraction from the silicon atom by the boron center is key to reaching the transition states, which include the tricoordinate silyl-cation moiety and the tetracoordinate hydridoborate moiety. PMID- 22223402 TI - Lattice expansion of highly oriented 2D phthalocyanine covalent organic framework films. AB - Expanding into application: covalent organic framework (COF) films are ideally suited for vertical charge transport and serve as precursors of ordered heterojunctions. Their pores, however, were previously too small to accommodate continuous networks of complementary electron acceptors. Four phthalocyanine COFs with increased pore size well into the mesoporous regime are now described. PMID- 22223403 TI - Perfluorohexane-encapsulated mesoporous silica nanocapsules as enhancement agents for highly efficient high intensity focused ultrasound (HIFU). PMID- 22223404 TI - Correlation of the vesicular acetylcholine transporter densities in the striata to the clinical abilities of women with Rett syndrome. AB - Rett syndrome (RTT) is a neurodevelopmental disability characterized by mutations in the X-linked methyl-CpG-binding protein 2 located at the Xq28 region. The severity is modified in part by X chromosomal inactivation resulting in wide clinical variability. We hypothesized that the ability to perform the activities of daily living (ADL) is correlated with the density of vesicular acetylcholine transporters in the striata of women with RTT. The density of the vesicular acetylcholine transporters in the living human brain can be estimated by single photon emission-computed tomography (SPECT) after the administration of (-)-5 [123I]iodobenzovesamicol ([123I]IBVM). Twenty-four hours following the intravenous injection of ~333 MBq (9 mCi) [123 I]IBVM, four women with RTT and nine healthy adult volunteer control participants underwent SPECT brain scans for 60 min. The Vesicular Acetylcholine Transporter Binding Site Index (Kuhl et al., 1994), a measurement of the density of vesicular acetylcholine transporters, was estimated in the striatum and the reference structure, the cerebellum. The women with RTT were assessed for certain ADL. Although the striatal Vesicular Acetylcholine Transporter Binding Site Index was not significantly lower in RTT (5.2 +/- 0.9) than in healthy adults (5.7 +/- 1.6), RTT striatal Vesicular Acetylcholine Transporter Binding Site Indices and ADL scores were linearly associated (ADL = 0.89*(Vesicular Acetylcholine Transporter Binding Site Index) + 4.5; R2 = 0.93; P < 0.01), suggesting a correlation between the ability to perform ADL and the density of vesicular acetylcholine transporters in the striata of women with RTT. [123I]IBVM is a promising tool to characterize the pathophysiological mechanisms of RTT and other neurodevelopmental disabilities. PMID- 22223406 TI - Cloperastine rescues impairment of passive avoidance response in mice prenatally exposed to diethylstilbestrol. AB - We previously reported that prenatal exposure to diethylstilbestrol (DES) impaired passive avoidance responses in mice. Apart from the above, we also found that cloperastine, a centrally acting antitussive, ameliorated depression-like and anxiety-like behaviors in rodents at antitussive-effective doses. In this study, we investigated whether or not cloperastine rescues impairment of passive avoidance responses in mice prenatally exposed to DES. Male DES-exposed mice were subcutaneously administered cloperastine at 10 or 30 mg/kg twice a day from 32 to 41 days after birth and subjected to behavioral testing 42 to 46 days after birth. Cloperastine at 10 and 30 mg/kg ameliorated DES-induced impairment of passive avoidance responses. In addition, cloperastine affected the levels of 5 HT1A receptors, GIRK and BDNF in the hippocampus of DES-exposed mice. However, the number of BrdU-positive cells in the hippocampus of DES-exposed mice was not changed by chronic administration of cloperastine. These findings suggest that the action of endocrine disruptors in the brain may not always be irreversible, and that the symptoms caused by endocrine disruptors might be curable with drugs such as cloperastine. PMID- 22223405 TI - The effect of exogenous histone H1 on rat adipose-derived stem cell proliferation, migration, and osteogenic differentiation in vitro. AB - Adipose-derived stem cells (ASCs) are of great interest for the development of novel cell therapies due to their ease of isolation and expansion, immunosuppressive activity, and multilineage differentiation potential. However, the mechanisms underlying the therapeutic potential of ASCs remain to be elucidated. Others and we have shown that nuclear proteins such as histone H1 and high mobility group box 1 (HMGB1) play important roles in the maturation of dendritic cells (DCs). Furthermore, we previously demonstrated translocation of histone H1 from the nucleus to the cytoplasm and activation of mitogen-activated protein kinases (MAPKs) in DCs. In the present study, we confirmed that histone H1 does not alter the immunophenotype and immunosuppression potential of ASCs, but that histone H1 enhanced wound healing and increased interleukin (IL)-6 expression. Moreover, histone H1 treated-ASCs showed up-regulation of MAPKs extracellular-regulated kinase 1/2 (ERK1/2) and sequential NF-kappaB translocation. Finally, we found that culture in differentiation media supplemented with histone H1 enhanced ASC osteogenesis. In contrast, inhibition of histone H1 by small interfering RNA (siRNA) reduced osteogenic differentiation markers including ALP. These results suggest that histone H1 may be useful for induction of mesenchymal stem cells in tissue engineering and future potential ASC therapies. PMID- 22223407 TI - Gene regulatory networks reused to build novel traits: co-option of an eye related gene regulatory network in eye-like organs and red wing patches on insect wings is suggested by optix expression. AB - Co-option of the eye developmental gene regulatory network may have led to the appearance of novel functional traits on the wings of flies and butterflies. The first trait is a recently described wing organ in a species of extinct midge resembling the outer layers of the midge's own compound eye. The second trait is red pigment patches on Heliconius butterfly wings connected to the expression of an eye selector gene, optix. These examples, as well as others, are discussed regarding the type of empirical evidence and burden of proof that have been used to infer gene network co-option underlying the origin of novel traits. A conceptual framework describing increasing confidence in inference of network co option is proposed. Novel research directions to facilitate inference of network co-option are also highlighted, especially in cases where the pre-existent and novel traits do not resemble each other. PMID- 22223408 TI - Pathogen identifi cation using mass spectrometry in the clinical microbiology laboratory. PMID- 22223409 TI - Reduction of Cu(II) and Zn (II) to neutral metal atoms duringdissociation of base ... metal monohydride complex ions. PMID- 22223410 TI - Formation of [M + 15](+) ions from aromatic aldehydes by use of methanol: in source aldolization reaction in electrospray ionization mass spectrometry. AB - Unexpected [M + 15](+) ions were formed during the analysis of aromatic aldehydes by use of methanol in positive-ion electrospray ionization mass spectrometry. Aromatic aldehydes with electron-withdrawing groups or electron-donating groups were all tested to make sure the universality. All the aromatic aldehydes studied with methanol as the solvent could generate [M + 15](+) ion, and for most of them, the [M + 15](+) ion was more intense than the [M + H](+) ion. Deuterium labeling experiment, high-performance liquid chromatography-MS experiment, collision-induced dissociation experiment, and theoretical calculations were performed to identify the formation of [M + 15](+) ion. The proposed reaction mechanism is a gas-phase aldol reaction between protonated aromatic aldehydes and methanol occurring in electrospray source. Understanding and using this unique gas-phase ion/molecule reaction can indeed offer a novel and fast approach for the direct identification of aromatic aldehydes. PMID- 22223411 TI - On the mechanisms of the reactions between some perfluorinated compounds and CH(5) (+) --experimental and theoretical approaches. AB - Five perfluorocompounds [perfluoropentane, 4-(perfluoroethoxy)-perfluorobutane, 5 (perfluoroethyl)-perfluorotetrahydrofuran, 2-(trifluoromethyl) perfluorotetrahydropyran, and 4-(trifluoromethyl)-perfluorotetrahydropyran] were analyzed by electron ionization (EI) and chemical ionization (CI), using methane and isobutane as reagent gases. Under CI conditions, isobutane does not lead to significative results whereas methane leads to high ionic yields [with respect to both CI (isobutane) and EI]. Under EI conditions, practically only fragment ions are observed, with the complete loss of molecular weight. In contrast under CI(CH(4) ) conditions, [M-F](+) ions are produced. Under these conditions, the behavior of oxygen-containing molecules is strongly different from that of perfluoropentane. This is because oxygen can greatly stabilize the formation of the [M-F](+) carbocation by a pi-electron donor effect, especially in the case of cyclic structures. Moreover, pi-stabilization can be considered a useful tool to rationalize the position of tertiary carbon atom in trifluoromethyl-perfluoro pyrane isomeric ions. The experimental data formed the starting point for the theoretical calculation, which allowed us to explore the mechanisms of the reactions of CH(5) (+) ions with selected perfluorocompounds. The computational methods used show that a direct protonation of the perfluoroethers (PFEs) by CH(5) (+) as well as iBu(+) is very unlikely. In the theoretical calculations, the PFE molecule served rather as the F(-) donor, and the elimination of HF molecule occurred when the PFE molecule was placed close to H(+) or CH(5) (+) ions. The fact that the latter is very unstable and decomposes to a proton and methane molecule explains why the use of methane in CI is so successful in the generation of [M-F](+) ion. In contrast, the isobutonium cation rearranges to an isopropyl cation/methane complex rather than that it abstracts F(-) from the PFE molecule. Similar results can be expected for other PFEs and perfluoroalkanes (PFAs) because both CH(5) (+) and H(+) were able to abstract the HF molecule also by attacking along the perfluoroalkyl chain of the PFE. PMID- 22223412 TI - Pathogen identification using mass spectrometry in the clinical microbiology laboratory. AB - The recent application of Matrix-assisted Laser Desorption/Ionization Time-of Flight and Polymerase Chain Reaction Electrospray Ionization Quadrupole Time-of Flight mass spectrometry approaches to microbial identification has initiated a revolution in the clinical microbiology lab. The commercial application of these technologies to pathogen identification has only begun in the last five years, and already new potentially life-saving applications of these technologies are rapidly identifying organisms that in the past have proven notoriously difficult to identify. In this review, we will provide a brief historical perspective on how these developments arose, describe why they are being successfully applied now and provide an overview of current approaches. Using examples involving clinical isolates of Staphylococcus aureus, a perspective on future use and developments of mass spectrometry in the identification of microbial organisms is provided. PMID- 22223413 TI - Matrix-assisted laser desorption/ionisation mass spectrometric response factors of peptides generated using different proteolytic enzymes. AB - Matrix-assisted laser desorption/ionisation (MALDI) mechanisms and the factors that influence the intensity of the ion signal in the mass spectrum remain imperfectly understood. In proteomics, it is often necessary to maximise the peptide response in the mass spectrum, especially for low abundant proteins or for proteolytic peptides of particular significance. We set out to determine which of the common proteolytic enzymes give rise to peptides with the best response factors under MALDI conditions. Standard proteins were enzymatically digested using four common proteases. We assessed relative response factors by coanalyzing the resulting digests. Thus, when tryptic peptides were added in equimolar quantities to their corresponding Asp-N, chymotrypsin and Glu-C digests, tryptic peptide signals were always predominant in the resulting MALDI mass spectra. Observable peaks attributable to non-tryptic peptides generally contained a terminal basic residue. It was proposed that a terminal basic residue has a disproportionate influence upon gas-phase basicity, and this hypothesis was supported by experiments with model isotopically labelled peptides. Experiments applying Cook's kinetic method showed that the peptide with a C-terminal arginine residue was more basic than the equivalent peptide with an N-terminal arginine, which was more basic than the peptide in which the arginine was mid-chain. Thus, the observation of the higher MALDI mass spectrometry response factors of tryptic peptides in comparison with peptides derived using other proteolytic enzymes corresponds with higher gas-phase basicities and may, along with other factors such as the complexity of the digest, influence the choice of enzyme in "bottom up" proteomic experiments. PMID- 22223414 TI - Characterization of barley leaf tissue using direct and indirect desorption electrospray ionization imaging mass spectrometry. AB - Chemical profiling of barley (Hordeum vulgare) leaves was demonstrated using direct and indirect desorption electrospray ionization (DESI) imaging mass spectrometry. Direct DESI analysis of the untreated leaves was not possible despite a significant content of hydroxynitrile glucosides known to reside in the epidermis of the leaves. Instead, the epidermis was stripped off the leaves, thus allowing direct DESI imaging to be performed on the back of the epidermis. Furthermore, indirect DESI imaging was performed by making imprints in porous Teflon of the intact leaves as well as of the stripped epidermis. The DESI images reveal accumulation of hydroxynitrile glucosides in the leaf epidermis, homogeneously distributed throughout the surface. The indirect DESI approach enables relative quantitation, confirming variations of hydroxynitrile glucosides content in primary leaves of three different cultivars of barley seedlings. The study presents an example of how to overcome the morphological barriers from the plant surface and perform rapid and repeatable DESI imaging. In addition, a comparison is made of direct and indirect DESI imaging, contributing to the characterization of the recently developed method of indirect DESI imaging of plant material via porous Teflon imprints. PMID- 22223415 TI - Electron transfer dissociation of dipositive uranyl and plutonyl coordination complexes. AB - Reported here is a comparison of electron transfer dissociation (ETD) and collision-induced dissociation (CID) of solvent-coordinated dipositive uranyl and plutonyl ions generated by electrospray ionization. Fundamental differences between the ETD and CID processes are apparent, as are differences between the intrinsic chemistries of uranyl and plutonyl. Reduction of both charge and oxidation state, which is inherent in ETD activation of [An(VI) O(2) (CH(3) COCH(3) )(4) ](2+) , [An(VI) O(2) (CH(3) CN)(4) ](2) , [U(VI) O(2) (CH(3) COCH(3) )(5) ](2+) and [U(VI) O(2) (CH(3) CN)(5) ](2+) (An = U or Pu), is accompanied by ligand loss. Resulting low-coordinate uranyl(V) complexes add O(2) , whereas plutonyl(V) complexes do not. In contrast, CID of the same complexes generates predominantly doubly-charged products through loss of coordinating ligands. Singly-charged CID products of [U(VI) O(2) (CH(3) COCH(3) )(4,5) ](2+) , [U(VI) O(2) (CH(3) CN)(4,5) ](2+) and [Pu(VI) O(2) (CH(3) CN)(4) ](2+) retain the hexavalent metal oxidation state with the addition of hydroxide or acetone enolate anion ligands. However, CID of [Pu(VI) O(2) (CH(3) COCH(3) )(4) ](2+) generates monopositive plutonyl(V) complexes, reflecting relatively more facile reduction of Pu(VI) to Pu(V). PMID- 22223416 TI - Improved specificity of cardiolipin peroxidation by soybean lipoxygenase: a liquid chromatography - electrospray ionization mass spectrometry investigation. AB - Peroxidation catalysed by Soybean Lypoxigenase was performed on tetralinoleyl cardiolipin with the aim of generating selectively oxidized products, to be used subsequently as standards for studies on cardiolipin oxidation. The reaction products were characterized by LC-ESI-MS and MS/MS, and the process was found to link a hydroperoxylic group on one or more linoleic chains of cardiolipin, up to a total of four groups per molecule. Interestingly, the incidence of other oxidized products, like those arising from multiple hydroxylation or mixed hydroxylation-hydroperoxydation, previously observed after the chemical oxidation of the same cardiolipin, was found to be negligible. Moreover, evidences for the presence of the hydroperoxylic group(s) almost exclusively on carbon 13 of the linoleic chain(s) were obtained by MS/MS measurements. The enzymatic approach, integrated with a preparative separation step, which could be developed by adapting the chromatographic conditions adopted in the present work for analytical purposes, represents a promising strategy for the synthesis of highly specific mono- or multi-peroxidated derivatives of cardiolipins. PMID- 22223417 TI - Do electrospray mass spectra of surfactants mirror their aggregation state in solution? AB - One important feature in the gas phase chemistry of surfactants is to ascertain whether their aggregates produced by electrospray ionization reflect those formed in the starting solution. With this aim, we have performed ESI-MS, ESI-MS/MS and ER-MS spectra of bis(2-ethylhexyl)sulfosuccinate (AOTNa) solutions in different solvents, i.e. water, water/methanol, methanol and n-hexane. The results clearly indicate that, notwithstanding the strongly different aggregation state in solution (direct micelles in water and in water/methanol, molecular dispersion in methanol and reverse micelles in n-hexane) and marked effects of the solvent polarity on the total ionic current, the surfactant aggregates in gas phase show identical structural features. Analogous conclusions can be drawn analyzing the infrared multiple photon dissociation (IRMPD) spectra of AOTNa solutions in water/methanol and n-hexane. Moreover, according to the idea that gas phase can be considered an apolar environment par excellence, data consistently suggest a reverse micelle-like aggregation. Some peculiarities of the mechanisms leading to aggregate formation through electrospray ionization of surfactant solutions in solvent media with different polarity have been also discussed. PMID- 22223418 TI - Direct monitoring of drug degradation by easy ambient sonic-spray ionization mass spectrometry: the case of enalapril. AB - Using enalapril maleate as a test case, the ability of ambient mass spectrometry, namely, via easy ambient sonic-spray ionization mass spectrometry (EASI-MS), to perform direct monitoring of drug degradation has been tested. Two manufacturing processes were investigated (direct compression and wet granulation), and the formation of degradation products was measured via both EASI-MS and high performance liquid chromatography with ultraviolet detection for a total period of 18 months. Both techniques provide comparable results, which indicate that direct analysis by ambient mass spectrometric techniques presents a viable alternative for drug degradation monitoring with superior simplicity, throughput, and reliability (no sample manipulation), and comparable quantitative results. In terms of qualitative monitoring, the full mass spectra with intact species provided by EASI-MS allow for comprehensive monitoring of known and unknown (or unexpected) degradation products. PMID- 22223419 TI - Characterization of Ce(3+) -tributyl phosphate coordination complexes produced by fused droplet electrospray ionization with a target capillary. AB - Coordination complexes containing Ce(III) and tri-n-butyl phosphate (TBP) in the 1+, 2+ and 3+ charge states were generated using both direct infusion electrospray ionization (ESI) and fused droplet (FD) ESI using a target capillary, in which the analyte solutions are impinged by the ESI droplets. The same coordination complexes were produced in each experiment, and their relative abundances were also very close, suggesting that similar processes are occurring in both experiments. The ion species formed in both experiments have the general formula [Ce(NO(3) )(m=0-2) (TBP)(n=3-7) ]((3-m)+) . The appearance of abundant 1+ and 2+ ion pair complexes indicated that the ESI process was modifying the ion populations in the original solutions, which contain predominantly 3+ and 2+ species. The FD ESI experiments were less sensitive for coordination complexes compared to direct infusion ESI; however, mid-picomolar quantities of coordination complexes were measured using the target capillary, indicating that sensitivity would be sufficient for measuring species in many industrial separations processes. PMID- 22223420 TI - Evaluation of relative LC/MS response of metabolites to parent drug in LC/nanospray ionization mass spectrometry: potential implications in MIST assessment. AB - There is an increasing demand for quantitative data on metabolite exposure triggered by regulatory guidances. This contribution describes the accuracy of nanoelectrospray ionization mass spectrometry response of drug compounds and their metabolites from biological matrices compared with radiometric quantification. This is a comprehensive investigation of a set of real-life pharmaceutical compounds in relevant matrices such as urine, bile, feces and plasma. The data suggest that nanoelectrospray mass spectrometry can be used for semi-quantitation of metabolites in the absence of reference standards. Therefore, this approach is suitable to screen out non-relevant metabolites early in development as long as an adequate analytical error margin is applied thus balancing risks and resources. PMID- 22223421 TI - Tandem mass spectrometry of platinated quadruplex DNA. AB - Quadruplexes are higher-order structures formed by G-rich DNA strands that are involved in various processes of cell cycle regulation, such as control of telomere length and participation in gene regulation. Because of these central biological functions, quadruplex DNA represents a promising target for cancer therapy, e.g. by applying organometallic drugs, such as cisplatin. High resolution electrospray tandem mass spectrometry is evaluated as a technique for exploring structural features of unplatinated and platinated quadruplexes. Results of experiments on tetramolecular, bimolecular and monomolecular quadruplexes provide information about the extent of platination and the binding sites of the drug. The dissociation behavior of the different types of quadruplexes is compared. Tetramolecular quadruplexes were found to weave out a strand end in order to provide a platination site, and their fragmentation is characterized by the release of an unplatinated strand and the formation of a platinated triplex. Partial opening of the structure in combination with the loss of small fragments leads to truncated quadruplex ions. For the bimolecular quadruplexes studied, strand separation is the predominant dissociation pathway. Depending on the loop sequence, cross-linking of the loops by cisplatin is demonstrated. Distinct differences in the product ion spectra of unannealed and annealed monomolecular sequences provide proof of quadruplex formation and show that platination preferentially occurs at the terminal regions. PMID- 22223422 TI - Elemental labeling for the identification of proteinaceous-binding media in art works by ICP-MS. AB - In the history of art, artists have used many different organic compounds to dissolve pigments and apply them onto a support to obtain a paint layer. Proteins were used with success from the Middle Ages up to the Renaissance, and the traditional protein sources were animal parts (skins, tendons and bones) or milk and eggs. Moreover, some of these materials are commonly used as adhesive. In this paper, the first application of the metallomic analytical technique to the identification of proteins in artworks is reported. Samples were derivatized with DTPA/Eu and the derivatization procedure was evaluated by matrix-assisted laser desorption/ionization time-of-flight before high performance liquid chromatography inductively coupled plasma MS analysis. This study has been carried out on laboratory models prepared in-house for method development, resulting in the correct identification of the different classes of proteinaceous binders typically used. In addition, some unknown paint layer samples have been analyzed demonstrating that the method is applicable to very small sample amounts (0.6 mg), which are compatible with the amount normally available for this kind of analysis. The results obtained demonstrate the effectiveness of the method, suggesting the potential future use as novel diagnostic tool in the scientific study of artworks. PMID- 22223424 TI - Synthesis, structure, and physical properties of 5,7,14,16-tetraphenyl-8:9,12:13 bisbenzo-hexatwistacene. AB - A novel compound, 5,7,14,16-tetraphenyl-8:9,12:13-bisbenzo-hexatwistacene (TBH), has been successfully synthesized through a retro-Diels-Alder reaction. Single crystal structure analysis indicated that TBH has a twisted configuration with a torsion angle of 27.34 degrees . The HOMO-LUMO gap of TBH calculated from the difference between the half-wave redox potentials (E(1/2) (ox) =+0.40 eV and E(1/2)(red) =-1.78 eV) is 2.18 eV, which is in good agreement with the band gap (2.19 eV) derived from the UV/Vis absorption data. In addition, organic light emitting devices using TBH as emitter have been fabricated. The results revealed that TBH is a promising red light-emitting candidate for applications in organic light-emitting diodes. PMID- 22223425 TI - LTBPs, more than just an escort service. AB - Latent transforming growth factor beta (TGF-beta) binding proteins (LTBPs) are large extracellular glycoproteins structurally similar to fibrillins. They perform intricate and important roles in the extracellular matrix (ECM) and perturbations of their function manifest as a wide range of diseases. LTBPs are major regulators of TGF-beta bioavailability and action. In addition, LTBPs interact with other ECM proteins-from cytokines to large multi-factorial aggregates like microfibrils and elastic fibers, affecting their genesis, structure, and performance. In the present article, we review recent advancements in the field and relate the complex roles of LTBP in development and homeostasis. PMID- 22223428 TI - The bispecific SDF1-GPVI fusion protein preserves myocardial function after transient ischemia in mice. AB - BACKGROUND: CXCR4-positive bone marrow cells (BMCs) are critically involved in cardiac repair mechanisms contributing to preserved cardiac function. Stromal cell-derived factor-1 (SDF-1) is the most prominent BMC homing factor known to augment BMC engraftment, which is a limiting step of stem cell-based therapy. After myocardial infarction, SDF-1 expression is rapidly upregulated and promotes myocardial repair. METHODS AND RESULTS: We have established a bifunctional protein consisting of an SDF-1 domain and a glycoprotein VI (GPVI) domain with high binding affinity to the SDF-1 receptor CXCR4 and extracellular matrix proteins that become exposed after tissue injury. SDF1-GPVI triggers chemotaxis of CXCR4-positive cells, preserves cell survival, enhances endothelial differentiation of BMCs in vitro, and reveals proangiogenic effects in ovo. In a mouse model of myocardial infarction, administration of the bifunctional protein leads to enhanced recruitment of BMCs, increases capillary density, reduces infarct size, and preserves cardiac function. CONCLUSIONS: These results indicate that administration of SDF1-GPVI may be a promising strategy to treat myocardial infarction to promote myocardial repair and to preserve cardiac function. PMID- 22223430 TI - Oxygen-mediated coupling of alcohols over nanoporous gold catalysts at ambient pressures. PMID- 22223429 TI - Hyponatremia, hypernatremia, and mortality in patients with chronic kidney disease with and without congestive heart failure. AB - BACKGROUND: Hyponatremia is common in patients with conditions such as congestive heart failure and is associated with increased mortality in hospitalized patients. Congestive heart failure is common in patients with chronic kidney disease, but the association of serum sodium concentration with mortality in such patients is not well characterized. METHODS AND RESULTS: We examined the association of serum sodium concentration with all-cause mortality in a nationally representative cohort of 655 493 US veterans with non-dialysis dependent chronic kidney disease (95 961 [15%] of them with congestive heart failure). Associations were examined in time-dependent Cox models with adjustment for potential confounders. During a median follow-up of 5.5 years, a total of 193 956 patients died (mortality rate, 62.5/1000 patient-years; 95% confidence interval, 62.2-62.8). The association of serum sodium level with mortality was U shaped, with the lowest mortality seen in patients with sodium level of 140 mEq/L and with both lower and higher levels showing significant associations with increased mortality. Patients with serum sodium levels of <130, 130 to 135.9, 145.1 to 150, and >=150 mEq/L compared with 136 to 145 mEq/L had multivariable adjusted mortality hazard ratios (95% confidence interval) of 1.93 (1.83-2.03), 1.28 (1.26-1.30), 1.33 (1.28-1.38), and 1.56 (1.33-1.83) (P<0.001 for all). The associations remained consistent in subgroups of patients with and without congestive heart failure. CONCLUSIONS: Both lower and higher serum sodium levels are independently associated with higher mortality in patients with non-dialysis dependent chronic kidney disease, irrespective of the presence or absence of congestive heart failure. PMID- 22223431 TI - Directional transport of polymer sheet and a microsphere by a rationally aligned nanowire array. PMID- 22223432 TI - Differences in the frequencies of K-ras c12-13 genotypes by gender and pathologic phenotypes in colorectal tumors measured using the allele discrimination method. AB - The frequencies of different genotypes of the K-ras oncogene in colorectal cancer (CRC) reveal complex relationships among gender, age, and tumor aggression, however, differences among these studies could also be attributed to a lack of standardization of the detection methods used. We developed the allele discrimination assay, which uses dual-color real-time polymerase chain reaction (qPCR) as a fast K-ras genotyping method, and demonstrated higher sensitivity and specificity than DNA sequencing with formalin-fixed paraffin tissues. The assay detected K-ras mutations among 83 of 204 patients with CRC (40.7%); 20.6% of these mutations were G12D (GAT) mutations, 7.4% were G13D (GAC) and G12V (GTT), and 5.3% were other types. A higher proportion of females was observed overall in tumors with K-ras mutations (60.2%, P = 0.01), codon 12 mutations (63.2%, P = 0.005), and transversions (69.6%, P = 0.02), which reflected the higher prevalence of females among the well- to moderately differentiated tumors (29% in males vs. 53% in females; interaction P = 0.03). The opposite was observed for poorly differentiated tumors (47% in males vs. 35% in females). No significant influence of age was found on the prevalence of K-ras mutation. Males with pathological changes and females with poorly differentiated tumors displayed GAT as a less common genotype compared with most other prevalence studies. In conclusion, allele discrimination, with no additional amplification step, is a fast and reliable genotyping method for detecting K-ras c12-13 mutations. Using this method, we demonstrate differences in the frequencies of K-ras genotypes by gender and pathologic phenotypes of CRC. PMID- 22223433 TI - Chromodomain helicase DNA-binding protein 2 affects the repair of X-ray and UV induced DNA damage. AB - Eukaryotic cells have evolved a variety of parallel and redundant DNA damage response pathways that function in a coordinated fashion to prevent the fixation of DNA damage as mutations. Despite the wealth of knowledge on DNA damage signaling on downstream cellular events, the mechanisms of DNA damage recognition, DNA repair as well as DNA damage signaling in the context of chromatin is poorly understood. Chromodomain helicase DNA-binding proteins (CHD) belong to a group of highly conserved chromatin remodeling proteins that are implicated in regulation of transcription. In an effort to understand the physiological role of one of the CHD members in a mammalian model system, we developed a mutant mouse model for the Chd2 gene. The Chd2 mutant mice are highly susceptible to spontaneous lymphoid tumor formation. In this study, we present evidence that the Chd2 mutant cells are defective in their ability to repair DNA damage induced by ionizing and ultraviolet radiation. Consistent with the role of Chd2 in regulating DNA damage responses, the Chd2 mutant cells are also sensitive to DNA damaging agents in clonogenic assays. In summary, our data suggest that the Chd2 protein is involved in regulating the DNA damage responses at the chromatin level. PMID- 22223434 TI - Assessment of micronucleus frequency in the peripheral blood of female rats in persistent estrus treated with selective estrogen receptor modulators. AB - The aim of this study was to evaluate micronucleus (MN) frequency in polychromatic erythrocytes (PCE) of female rats in persistent estrus (a model developed to mimic polycystic ovary syndrome) treated with selective estrogen receptor modulators (SERMs, tamoxifen, and raloxifene). Forty female Wistar Hannover rats were divided into four groups of 10 animals each: Group I (normally cycling rats) and Group II (persistent estrus) both received only vehicle, while Group III (persistent estrus) was treated with tamoxifen (250 MUg/animal/day) and Group IV (persistent estrus) was treated with raloxifene (750 MUg/animal/day). Tamoxifen and raloxifene were given by oral gavage beginning on postnatal day 90 and continuing for 30 consecutive days. Peripheral blood samples were collected from tails 1 day following the last exposure. Blood smears were made on glass slides and stained with 10% Giemsa solution. ANOVA and a Tukey post-hoc test were used for data analysis. Mean percentages of MN were 1.82 +/- 0.13, 5.20 +/- 0.24, 3.32 +/- 0.13, and 3.04 +/- 0.12 in Groups I, II, III, and IV, respectively. The results indicate that tamoxifen and raloxifene similarly reduced the formation of MNPCE of female rats in persistent estrus (P < 0.0001 for Groups III and IV vs. Group II), using the dosages and time periods applied in the present study. The data suggest possibly antimutagenic effects of SERMs under high levels of estrogens. The findings also suggest that this is an interesting animal model for studying the genotoxicity of estrogens. PMID- 22223435 TI - EGFR mutations in non-small-cell lung cancer among smokers and non-smokers: a meta-analysis. AB - Mounting evidence has suggested somatic mutations in the EGFR gene are associated with better responsiveness to EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer (NSCLC). Some, but not all, studies have reported that the mutations were more frequently observed in patients without a smoking history. To comprehensively address this issue, we performed a meta-analysis to evaluate the association between cigarette-smoking history and mutation of the EGFR gene in NSCLC. Twenty-six studies, involving 3,688 patients with NSCLC were included in the analysis. The pooled analysis shows that the incidence of EGFR mutations in NSCLC differs according to cigarette-smoking history. The odds ratio (OR) for the EGFR mutation in non-smokers relative to smokers was 4.829 (95% confidence interval [CI]: 3.598-6.482; P < 0.001). These data may assist clinicians in assessing the likelihood of EGFR mutations in patients with NSCLC when mutational analysis is not feasible. PMID- 22223436 TI - Distribution of caries in children: variations between and within populations. AB - The rapid changes in social and economic conditions in many populations may have significant impacts on health, including child oral health. Understanding trends and variations between and within countries will assist in the development of effective preventive programs. This review aims (1) to document time-trends in child caries experience of countries with different levels of social and economic development, and (2) to compare factors affecting the caries experience of children in two contrasting countries. A time-trend analytical approach of ecological data from countries with different levels of social and economic development and individual data of the two contrasting Vietnamese and Australian child populations were used. The analysis found a significant decline in caries experience of children, mostly driven by the improvement in populations with high social and economic development. Significant variations in caries experience and in associations with risk factors between and within countries were observed. Socio-economic inequality in child oral health existed within developed countries and between countries with different levels of development. Population programs aimed at improving upstream factors are of priority in further improving child oral health in different populations. PMID- 22223438 TI - Protein phosphatases 2A as well as reactive oxygen species involved in tributyltin-induced apoptosis in mouse livers. AB - Tributyltin (TBT), a highly toxic environmental contaminant, has been shown to induce caspase-3-dependent apoptosis in human amniotic cells through protein phosphatase 2A (PP2A) inhibition and consequent JNK activation. This in vivo study was undertaken to further verify the results derived from our previous in vitro study. Mice were orally dosed with 0, 10, 20, and 60 mg/kg of body weight TBT, and levels of PP2A, reactive oxygen species (ROS), mitogen-activated protein kinase (MAPK), Bax/Bcl-2, and caspase-3 were detected in the mouse livers. Apoptosis was also evaluated using the TUNEL assay. The results showed that PP2A activity was inhibited, ROS levels were elevated, and MAPKs including ERK, JNK, and p38 were activated in mouse livers treated with the highest dose of TBT. Additionally, the ratio of Bax/Bcl-2 was increased, caspase-3 was activated, and apoptosis in mouse livers could be detected in the highest dose group. Therefore, a possible signaling pathway in TBT-induced apoptosis in mouse livers involves PP2A inhibition and ROS elevation serving a pivotal function as upstream activators of MAPKs; activation of MAPKs in turn leads to an increase in the Bax/Bcl-2 ratio, ultimately leading to the activation of caspase-3. The results give a comprehensive and novel description of the mechanism of TBT-induced toxicity. PMID- 22223437 TI - Targeting Runx2 expression in hypertrophic chondrocytes impairs endochondral ossification during early skeletal development. AB - Runx2 is a known master transcription factor for osteoblast differentiation, as well as an essential regulator for chondrocyte maturation. Recently, more and more data has shown that Runx2 regulates hypertrophic chondrocyte-specific type X collagen gene (Col10a1) expression in different species. However, how Runx2 regulation of Col10a1 expression impacts chondrocyte maturation, an essential step of endochondral bone formation, remains unknown. We have recently generated transgenic mice in which Flag-tagged Runx2 was driven by a cell-specific Col10a1 control element. Significantly increased level of Runx2 and Col10a1 mRNA transcripts were detected in transgenic mouse limbs at both E17.5 (embryonic day 17.5) and P1 (post-natal day1) stages, suggesting an in vivo correlation of Runx2 and Col10a1 expression. Surprisingly, skeletal staining suggested delayed ossification in both the axial and the appendicular skeleton of transgenic mice from E14.5 until P6. Histological analysis showed elongated hypertrophic zones in transgenic mice, with less von Kossa and TUNEL staining in long bone sections at both E17.5 and P1 stages, suggesting defective mineralization due to delayed chondrocyte maturation or apoptosis. Indeed, we detected increased level of anti apoptotic genes B-cell leukemia/lymphoma 2, Osteopontin, and Sox9 in transgenic mice by real-time RT-PCR. Moreover, immunohistochemistry and Western blotting analysis also suggested increased Sox9 expression in hypertrophic chondrocytes of transgenic mice. Together, our data suggest that targeting Runx2 in hypertrophic chondrocytes upregulates expression of Col10a1 and other marker genes (such as Sox9). This will change the local matrix environment, delay chondrocyte maturation, reduce apoptosis and matrix mineralization, and eventually, lead to impaired endochondral ossification. PMID- 22223439 TI - Genetics and genomics in wildlife studies: implications for ecology, evolution, and conservation biology. PMID- 22223440 TI - Laparoscopy guided Doppler ultrasound measurement of fetal blood flow indices during early to mid-gestation in pigs. AB - The objectives of this study were to obtain relevant blood flow indices of umbilical arteries (UmA) of porcine fetuses using a laparoscopic ultrasound probe and to relate these data with fetal size at early to mid gestation. Fetal parameters and flow indices, i.e., fetal length and area, fetal heart rate (FHR), systolic pulse duration (T1), interpulse duration (T2), T2/T1 ratio, peak systolic velocity (PSV), time averaged velocity (TAV), resistance index (RI) and pulsatility index (PI), were measured in 182 fetuses of 26 pregnant Landrace gilts on pregnancy day (PD) 36 (122 fetuses from 17 gilts), PD42 (19 fetuses from 3 gilts) and PD51 (42 fetuses from 6 gilts). Fetal heart rate was higher on PD36 than on PD42 (P<0.05). No differences (P>0.05) were obtained concerning systolic pulse duration, flow velocities and RI. On PD42, the PI was lower (P<0.05), while the interpulse duration (P=0.06) and T2/T1 ratio tended (P=0.08) to be higher on PD42 compared with PD36 and to PD51. To find differences in UmA blood flow parameters concerning fetal size, i.e., fetal length, fetuses were retrospectively grouped as follows: small (lower 25%), medium (mean 50%) and large (upper 25%), respectively. Although, fetuses differed in size (P<0.001) within and between days of pregnancy, FHR, PSV, TAV, RI and PI did not differ (P>0.05) among the size classes. Only systolic pulse duration tended to be longer (P=0.05) in large compared with small fetuses on PD36, and interpulse duration was lower in large fetuses on PD36 in comparison with PD51 (P<0.05). Though there was no link between fetal blood flow indices and fetal intrauterine growth retardation (IUGR), with further studies based on these flow indices, it might be possible to evaluate nutrient- or stress-related influences on fetal growth and development, particularly in the case of IUGR. PMID- 22223441 TI - Optimization of oxygen concentration for growing bovine oocytes in vitro: constant low and high oxygen concentrations compromise the yield of fully grown oocytes. AB - The oxygen environment in cell culture has a significant impact on the health and performance of cells. Here, we compared the effects of reduced (5%) and ambient (20%) oxygen concentrations on bovine oocyte-granulosa cell complexes, each containing a growing oocyte 90-102 um in diameter, cultured for 14 days. Both oxygen concentrations showed some advantages and disadvantages; in 5% oxygen, the survival rate of oocytes was significantly higher than in 20% oxygen, but the resulting oocytes were significantly smaller, which was a serious disadvantage. During the first 4 days of culture, the growth and viability of oocytes were satisfactory using 5% oxygen. This observation led us to examine the effect of changing the oxygen concentration from 5% to 20% on Day 4 in order to minimize the expected disadvantages of constant 5% and 20% oxygen. The largest population of fully grown oocytes was obtained from cultures in which the oxygen concentration was changed in this way, which also led to higher oocyte viability than in constant 20% oxygen. A similar tendency was found in the frequency of oocytes becoming blastocysts after in vitro fertilization. Surviving oocytes eventually became located within an enlarged dome-like structure, and although the 5% oxygen environment may have been appropriate for oocyte growth in the early stages, 20% oxygen may have been necessary for the growth of oocytes in the dome-like structure. These results indicate an effective way of modulating oxygen concentration according to the growth of oocyte-granulosa cell complexes in vitro. PMID- 22223442 TI - Neuropsychological intra-individual variability explains unique genetic variance of ADHD and shows suggestive linkage to chromosomes 12, 13, and 17. AB - Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric disorder that is usually accompanied by neuropsychological impairments. The use of heritable, psychometrically robust traits that show association with the disorder of interest can increase the power of gene-finding studies. Due to the robust association of intra-individual variability with ADHD on a phenotypic and genetic level, intra-individual variability is a prime candidate for such an attempt. We aimed to combine intra-individual variability measures across tasks into one more heritable measure, to examine the relatedness to other cognitive factors, and to explore the genetic underpinnings through quantitative trait linkage analysis. Intra-individual variability measures from seven tasks were available for 238 ADHD families (350 ADHD-affected and 195 non affected children) and 147 control families (271 children). Intra-individual variability measures from seven different tasks shared common variance and could be used to construct an aggregated measure. This aggregated measure was largely independent from other cognitive factors related to ADHD and showed suggestive linkage to chromosomes 12q24.3 (LOD = 2.93), 13q22.2 (LOD = 2.36), and 17p13.3 (LOD = 2.00). A common intra-individual variability construct can be extracted from very diverse neuropsychological tasks; this construct taps into unique genetic aspects of ADHD and may relate to loci conferring risk for ADHD (12q24.3 and 17p13.3) and possibly autism (12q24.3). Given that joining of data across sites boosts the power for genetic analyses, our findings are promising in showing that intra-individual variability measures are viable candidates for across site analyses where different tasks have been used. PMID- 22223443 TI - Japanese older adults' perspectives on resuming daily life during hospitalization and after returning home. AB - Throughout Japan, occupational therapy for older adults is available in an increasing array of institutional and community settings. However, there is a need for more knowledge of "how" older adults resume their daily lives particularly in the community. The aim of this qualitative research was to identify and describe how some older adults in Japan describe their experiences of resuming daily life during hospitalization and after returning home. Nine older adults with various physical impairments were interviewed. The open interviews were conducted 10 months to 5 years from the onset of their physical impairment. Data analysis on the basis of a constant comparative methodology resulted in three themes that characterize their experiences of resuming daily life: "doing the right thing", "reconciling to dependence" and "becoming invigorated". These themes may inform occupational therapists to take into consideration older clients' perspectives when assisting them to recapture the quality of their daily life according to their preferences. Adaptive change is promoted by assisting older clients to generate the energy they need by judiciously varying approaches appropriate to their goals and by helping older clients to make decisions that are "right" for them, which may fluctuate during processes of resuming daily life. Limitations of this study are found in the small sample size, and additional research may help to clarify how moral aspects, vigour (physical and mental energy/force) and other dimensions shape processes of resuming daily life as well as the influences of time. PMID- 22223444 TI - Miocene dispersal drives island radiations in the palm tribe Trachycarpeae (Arecaceae). AB - The study of three island groups of the palm tribe Trachycarpeae (Arecaceae/Palmae) permits both the analysis of each independent radiation and comparisons across the tribe to address general processes that drive island diversification. Phylogenetic relationships of Trachycarpeae were inferred from three plastid and three low-copy nuclear genes. The incongruent topological position of Brahea in CISP5 was hypothesized to be caused by a gene duplication event and was addressed using uninode coding. The resulting phylogenetic trees were well-resolved and the genera were all highly supported except for Johannesteijsmannia and Serenoa. Divergence time analysis estimated the stem of the tribe to be approximately 86 Ma and the crown to be 38 Ma, indicating that significant extinction may have occurred along this branch. Historical biogeographic analysis suggested that Trachycarpeae are of southern North American, Central American, or Caribbean origin and supports previous hypotheses of a Laurasian origin. The biogeography and disjunctions within the tribe were interpreted with respect to divergence times, the fossil record, and geological factors such as the formation of the Greater Antilles--Aves Ridge, the Bering and the North Atlantic land bridges, tectonic movement in Southeast Asia, climatic shifts between the Eocene and Pliocene, and volcanism in the Pacific basin. In considering the three major island radiations within Trachycarpeae, Miocene dispersal appears to have been the driving force in allopatric speciation and is highlighted here as an emerging pattern across the tree of life. PMID- 22223445 TI - Phylogenetic inference via sequential Monte Carlo. AB - Bayesian inference provides an appealing general framework for phylogenetic analysis, able to incorporate a wide variety of modeling assumptions and to provide a coherent treatment of uncertainty. Existing computational approaches to bayesian inference based on Markov chain Monte Carlo (MCMC) have not, however, kept pace with the scale of the data analysis problems in phylogenetics, and this has hindered the adoption of bayesian methods. In this paper, we present an alternative to MCMC based on Sequential Monte Carlo (SMC). We develop an extension of classical SMC based on partially ordered sets and show how to apply this framework--which we refer to as PosetSMC--to phylogenetic analysis. We provide a theoretical treatment of PosetSMC and also present experimental evaluation of PosetSMC on both synthetic and real data. The empirical results demonstrate that PosetSMC is a very promising alternative to MCMC, providing up to two orders of magnitude faster convergence. We discuss other factors favorable to the adoption of PosetSMC in phylogenetics, including its ability to estimate marginal likelihoods, its ready implementability on parallel and distributed computing platforms, and the possibility of combining with MCMC in hybrid MCMC SMC schemes. Software for PosetSMC is available at http://www.stat.ubc.ca/ bouchard/PosetSMC. PMID- 22223446 TI - Multiple quaternary refugia in the eastern Guiana shield revealed by comparative phylogeography of 12 frog species. AB - The Guiana Shield (GS) is one of the most pristine regions of Amazonia and biologically one of the richest areas on Earth. How and when this massive diversity arose remains the subject of considerable debate. The prevailing hypothesis of Quaternary glacial refugia suggests that a part of the eastern GS, among other areas in Amazonia, served as stable forested refugia during periods of aridity. However, the recently proposed disturbance-vicariance hypothesis proposes that fluctuations in temperature on orbital timescales, with some associated aridity, have driven Neotropical diversification. The expectations of the temporal and spatial organization of biodiversity differ between these two hypotheses. Here, we compare the genetic structure of 12 leaf-litter inhabiting frog species from the GS lowlands using a combination of mitochondrial and nuclear sequences in an integrative analytical approach that includes phylogenetic reconstructions, molecular dating, and Geographic Information System methods. This comparative and integrated approach overcomes the well-known limitations of phylogeographic inference based on single species and single loci. All of the focal species exhibit distinct phylogeographic patterns highlighting taxon-specific historical distributions, ecological tolerances to climatic disturbance, and dispersal abilities. Nevertheless, all but one species exhibit a history of fragmentation/isolation within the eastern GS during the Quaternary with spatial and temporal concordance among species. The signature of isolation in northern French Guiana (FG) during the early Pleistocene is particularly clear. Approximate Bayesian Computation supports the synchrony of the divergence between northern FG and other GS lineages. Substructure observed throughout the GS suggests further Quaternary fragmentation and a role for rivers. Our findings support fragmentation of moist tropical forest in the eastern GS during this period when the refuge hypothesis would have the region serving as a contiguous wet-forest refuge. PMID- 22223447 TI - Effects of phylogenetic signal on ancestral state reconstruction. PMID- 22223448 TI - The evolution of defense mechanisms correlate with the explosive diversification of autodigesting Coprinellus mushrooms (Agaricales, Fungi). AB - Bursts of diversification are known to have contributed significantly to the extant morphological and species diversity, but evidence for many of the theoretical predictions about adaptive radiations have remained contentious. Despite their tremendous diversity, patterns of evolutionary diversification and the contribution of explosive episodes in fungi are largely unknown. Here, using the genus Coprinellus (Psathyrellaceae, Agaricales) as a model, we report the first explosive fungal radiation and infer that the onset of the radiation correlates with a change from a multilayered to a much simpler defense structure on the fruiting bodies. We hypothesize that this change constitutes a key innovation, probably relaxing constraints on diversification imposed by nutritional investment into the development of protective tissues of fruiting bodies. Fossil calibration suggests that Coprinellus mushrooms radiated during the Miocene coinciding with global radiation of large grazing mammals following expansion of dry open grasslands. In addition to diversification rate-based methods, we test the hard polytomy hypothesis, by analyzing the resolvability of internal nodes of the backbone of the putative radiation using Reversible-Jump MCMC. We discuss potential applications and pitfalls of this approach as well as how biologically meaningful polytomies can be distinguished from alignment shortcomings. Our data provide insights into the nature of adaptive radiations in general by revealing a deceleration of morphological diversification through time. The dynamics of morphological diversification was approximated by obtaining the temporal distribution of state changes in discrete traits along the trees and comparing it with the tempo of lineage accumulation. We found that the number of state changes correlate with the number of lineages, even in parts of the tree with short internal branches, and peaks around the onset of the explosive radiation followed by a slowdown, most likely because of the decrease in available niches. PMID- 22223449 TI - Overcoming deep roots, fast rates, and short internodes to resolve the ancient rapid radiation of eupolypod II ferns. AB - Backbone relationships within the large eupolypod II clade, which includes nearly a third of extant fern species, have resisted elucidation by both molecular and morphological data. Earlier studies suggest that much of the phylogenetic intractability of this group is due to three factors: (i) a long root that reduces apparent levels of support in the ingroup; (ii) long ingroup branches subtended by a series of very short backbone internodes (the "ancient rapid radiation" model); and (iii) significantly heterogeneous lineage-specific rates of substitution. To resolve the eupolypod II phylogeny, with a particular emphasis on the backbone internodes, we assembled a data set of five plastid loci (atpA, atpB, matK, rbcL, and trnG-R) from a sample of 81 accessions selected to capture the deepest divergences in the clade. We then evaluated our phylogenetic hypothesis against potential confounding factors, including those induced by rooting, ancient rapid radiation, rate heterogeneity, and the Bayesian star-tree paradox artifact. While the strong support we inferred for the backbone relationships proved robust to these potential problems, their investigation revealed unexpected model-mediated impacts of outgroup composition, divergent effects of methods for countering the star-tree paradox artifact, and gave no support to concerns about the applicability of the unrooted model to data sets with heterogeneous lineage-specific rates of substitution. This study is among few to investigate these factors with empirical data, and the first to compare the performance of the two primary methods for overcoming the Bayesian star-tree paradox artifact. Among the significant phylogenetic results is the near-complete support along the eupolypod II backbone, the demonstrated paraphyly of Woodsiaceae as currently circumscribed, and the well-supported placement of the enigmatic genera Homalosorus, Diplaziopsis, and Woodsia. PMID- 22223450 TI - Regulation of subcutaneous adipose tissue blood flow during exercise in humans. AB - Regulation of subcutaneous adipose tissue blood flow (ATBF) remains poorly elucidated in humans, especially during exercise. In the present study we tested the role of adenosine in the regulation of ATBF adjacent to active and inactive thigh muscles during intermittent isometric knee-extension exercise (1 s contraction followed by 2 s rest with workloads of 50, 100, and 150 N) in six healthy young women. ATBF was measured using positron emission tomography (PET) without and with unspecific adenosine receptor inhibitor theophylline infused intravenously. Adipose regions were localized from fused PET and magnetic resonance images. Blood flow in subcutaneous adipose tissue adjacent to active muscle increased from rest (1.0 +/- 0.3 ml.100 g(-1).min(-1)) to exercise (P < 0.001) and along with increasing exercise intensity (50 N = 4.1 +/- 1.4, 100 N = 5.4 +/- 1.8, and 150 N = 6.9 +/- 3.0 ml.100 g(-1).min(-1), P = 0.03 for the increase). In contrast, ATBF adjacent to inactive muscle remained at resting levels with all intensities (~1.0 +/- 0.5 ml.100 g(-1).min(-1)). During exercise theophylline prevented the increase in ATBF adjacent to active muscle especially during the highest exercise intensity (50 N = 4.3 +/- 1.8 ml.100 g(-1).min(-1), 100 N = 4.0 +/- 1.5 ml.100 g(-1).min(-1), and 150 N = 4.9 +/- 1.8 ml.100 g( 1).min(-1), P = 0.06 for an overall effect) but had no effect on blood flow adjacent to inactive muscle or adipose blood flow in resting contralateral leg. In conclusion, we report in the present study that 1) blood flow in subcutaneous adipose tissue of the leg is increased from rest to exercise in an exercise intensity-dependent manner, but only in the vicinity of working muscle, and 2) adenosine receptor antagonism attenuates this blood flow enhancement at the highest exercise intensities. PMID- 22223451 TI - Corticomuscular coherence with and without additional task in the elderly. AB - Aging and dual-task paradigms often degrade fine motor performance, but the effects of aging on correlated neural activity between motor cortex and contracting muscle are unknown during dual tasks requiring fine motor performance. The purpose of this study was to compare corticomuscular coherence between young and elderly adults during the performance of a unilateral fine motor task and concurrent motor and cognitive tasks. Twenty-nine healthy young (18-38 yr) and elderly (61-75 yr) adults performed unilateral motor, bilateral motor, concurrent motor-cognitive, and cognitive tasks. Peak corticomuscular coherence between the electroencephalogram from the primary motor cortex and surface electromyogram from the first dorsal interosseous muscle was compared during steady abduction of the index finger with visual feedback. In the alpha band (8-14 Hz), corticomuscular coherence was greater in elderly than young adults especially during the motor-cognitive task. The beta-band (15-32 Hz) corticomuscular coherence was higher in elderly than young adults across unilateral motor and dual tasks. In addition, beta-band corticomuscular coherence in the motor-cognitive task was negatively correlated with motor output error across young but not elderly adults. The results suggest that 1) corticomuscular coherence was increased in senior age with a greater influence of an additional cognitive task in the alpha-band and 2) individuals with greater beta-band corticomuscular coherence may exhibit more accurate motor output in young, but not elderly adults, during steady contraction with visual feedback. PMID- 22223452 TI - Low micromolar intravascular cell-free hemoglobin concentration affects vascular NO bioavailability in sickle cell disease: a computational analysis. AB - In sickle cell disease, the changes in RBC morphology destabilize the red blood cell (RBC) membrane and lead to hemolysis. Several experimental and clinical studies have associated intravascular hemolysis with pulmonary hypertension in sickle cell disease. Cell-free hemoglobin (Hb) from intravascular hemolysis has high affinity for nitrixc oxide (NO) and can affect the NO bioavailability in the sickle cell disease, which may eventually lead to pulmonary hypertension. To study the effects of intravascular hemolysis related cell-free Hb concentrations on NO bioavailability, we developed a two-dimensional mathematical model of NO biotransport in 50-MUm arteriole under steady-state sickle cell disease conditions. We analyzed the effects of flow-dependent NO production and axial and radial transport of NO, a recently reported much lower NO-RBC reaction rate constant, and cell-free layer thickness on NO biotransport. Our results show that the presence of cell-free Hb concentrations as low as 0.5 MUM results in an approximately three- to sevenfold reduction in the predicted smooth muscle cell NO concentrations compared with those under physiological conditions. In addition, increasing the diffusional resistance for NO in vascular lumen from cell-free layer or reducing NO-RBC reaction rate did not improve the NO bioavailability at the smooth muscle cell layer significantly for cell-free Hb concentrations >=1 MUM. These results suggest that lower NO bioavailability due to low micromolar cell-free Hb can disturb NO homeostasis and cause insufficient bioavailability at the smooth muscle cell layer. Our results supports the hypothesis that hemolysis-associated reduction in NO bioavailability may play a role in the development of pathophysiological complications like pulmonary hypertension in sickle cell disease that are observed in several clinical and experimental studies. PMID- 22223453 TI - Sympathetic activation by chemical stimulation of white adipose tissues in rats. AB - Injection of leptin into white adipose tissue (WAT) increases sympathetic outflow. The present study was designed to determine the effects of capsaicin and other chemicals in WAT on the sympathetic outflow and blood pressure and the roles of WAT afferents and hypothalamic paraventricular nucleus (PVN) in the adipose afferent reflex (AAR). The AAR was induced by injection of capsaicin, bradykinin, adenosine, adenosine triphosphate (ATP), or leptin into inguinal WAT (iWAT) or retroperitoneal WAT (rWAT) in anesthetized rats. The iWAT injection of capsaicin increased the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) but not the heart rate. Bradykinin, adenosine, or leptin but not ATP in the iWAT caused similar effects to capsaicin on the RSNA and MAP. Intravenous, intramuscular, or intradermal injection of capsaicin had no significant effects on the RSNA and MAP. The effects of capsaicin in rWAT were similar to that in iWAT on the RSNA and MAP. Furthermore, injection of capsaicin into the iWAT increased the WAT afferent nerve activities, WAT efferent nerve activity, and brown adipose tissue efferent nerve activity. The iWAT denervation or chemical lesion of the PVN neurons with kainic acid abolished the AAR induced by the iWAT injection of capsaicin. These results indicate that the stimulation of iWAT afferents with capsaicin, bradykinin, adenosine, or leptin reflexly increases the RSNA and blood pressure. The iWAT afferents and the PVN are involved in the AAR induced by capsaicin in the iWAT. PMID- 22223455 TI - Impact of gender on the cardiac autonomic response to angiotensin II in healthy humans. AB - Premenopausal women have a lower risk of cardiovascular disease (CVD) compared with men of a similar age. Furthermore, the regulation of factors that influence CVD appears to differ between the sexes, including control of the autonomic nervous system (ANS) and the renin-angiotensin system. We examined the cardiac ANS response to angiotensin II (Ang II) challenge in healthy subjects to determine whether differences in women and men exist. Thirty-six healthy subjects (21 women, 15 men, age 38 +/- 2 years) were studied in a high-salt balance. Heart rate variability (HRV) was calculated by spectral power analysis [low-frequency (LF) sympathetic modulation, high-frequency (HF) parasympathetic/vagal modulation, and LF:HF as a measure of overall ANS balance]. HRV was assessed at baseline and in response to graded Ang II infusions (3 ng.kg(-1).min(-1) * 30 min; 6 ng.kg(-1).min(-1) * 30 min). Cardiac ANS tone did not change significantly in women after each Ang II dose [3 ng.kg(-1).min(-1) mean change (Delta)LF:HF (mean +/- SE) 0.5 +/- 0.3, P = 0.8, vs. baseline; 6 ng.kg(-1).min(-1) DeltaLF:HF (mean +/- SE) 0.5 +/- 0.4, P = 0.4, vs. baseline], whereas men exhibited an unfavorable shift in overall cardiac ANS activity in response to Ang II (DeltaLF:HF 2.6 +/- 0.2, P = 0.01, vs. baseline; P = 0.02 vs. female response). This imbalance in sympathovagal tone appeared to be largely driven by a withdrawal in cardioprotective vagal activity in response to Ang II challenge [DeltaHF normalized units (nu), -5.8 +/- 2.9, P = 0.01, vs. baseline; P = 0.006 vs. women] rather than an increase in sympathetic activity (DeltaLF nu, -4.5 +/- 5.7, P = 0.3, vs. baseline; P = 0.5 vs. women). Premenopausal women maintain cardiac ANS tone in response to Ang II challenge, whereas similarly aged men exhibit an unfavorable shift in cardiovagal activity. Understanding the role of gender in ANS modulation may help guide risk-reduction strategies in high-risk CVD populations. PMID- 22223457 TI - Ambident reactivities of methylhydrazines. PMID- 22223454 TI - Titin-based stiffening of muscle fibers in Ehlers-Danlos Syndrome. AB - OBJECTIVE: tenascin-X (TNX) is an extracellular matrix glycoprotein whose absence leads to Ehlers-Danlos Syndrome (EDS). TNX-deficient EDS patients present with joint hypermobility and muscle weakness attributable to increased compliance of the extracellular matrix. We hypothesized that in response to the increased compliance of the extracellular matrix in TNX-deficient EDS patients, intracellular adaptations take place in the elastic properties of the giant muscle protein titin. METHODS: we performed extensive single muscle fiber mechanical studies to determine active and passive properties in TNX-deficient EDS patients. Gel-electrophoresis, Western blotting, and microarray studies were used to evaluate titin expression and phosphorylation. X-ray diffraction was used to measure myofilament lattice spacing. RESULTS: passive tension of muscle fibers from TNX-deficient EDS patients was markedly increased. Myofilament extraction experiments indicated that the increased passive tension is attributable to changes in the properties of the sarcomeric protein titin. Transcript and protein data indicated no changes in titin isoform expression. Instead, differences in posttranslational modifications within titin's elastic region were found. In patients, active tension was not different at maximal activation level, but at submaximal activation level it was augmented attributable to increased calcium sensitivity. This increased calcium sensitivity might be attributable to stiffer titin molecules. CONCLUSION: in response to the increased compliance of the extracellular matrix in muscle of TNX-deficient EDS patients, a marked intracellular stiffening occurs of the giant protein titin. The stiffening of titin partly compensates for the muscle weakness in these patients by augmenting submaximal active tension generation. PMID- 22223458 TI - Advantages and potential of lipid-membrane-incorporating fullerenes prepared by the fullerene-exchange method. AB - Lipid-membrane-incorporating C(60) and C(70) (LMIC(60) and LMIC(70)) were prepared by the fullerene-exchange reaction from the gamma-cyclodextrin cavity to vesicles (we call this method the "exchange method"). An advantage of this method is that the ratios of [C(60)]/[lipids] and [C(70)]/[lipids] can be arbitrarily controlled by adjusting the ratios of the fullerenes and liposome. The maximum ratio (30 mol%) obtained was approximately 14 and 100 times higher than those achieved for LMIC(60) and LMIC(70) , respectively, that were prepared by the classical method, which we call the "premixing method" (dissolving lipids and C(60) or C(70) in chloroform, followed by concentration and extraction with water). Furthermore, the stabilities and photodynamic activities of the LMIC(60) and LMIC(70) solutions prepared by the exchange method were shown to be much higher than those prepared by the premixing method. That is, the exchange method was found to be superior to the premixing method as a preparative method of LMIC(60) and LMIC(70) for applications in photomedical and photomaterials chemistry. PMID- 22223459 TI - Exposure to 17alpha-ethinylestradiol decreases motility and ATP in sperm of male fighting fish Betta splendens. AB - The synthetic estrogen 17alpha-ethinylestradiol (EE2) is an endocrine-disrupting chemical released into aquatic environments from sewage treatment facilities. We tested the effects of two environmentally relevant concentrations of waterborne EE2, 10 and 100 ng L(-1) , on reproductive endpoints in the teleost fish Betta splendens. In the first experiment, testes were removed from males and sperm were exposed to EE2 directly through the activation water. Direct exposure to EE2 had no effect on any measure of sperm swimming performance. In the second experiment, we exposed sexually mature male B. splendens to EE2 using a semi-static exposure protocol for 4 weeks. There were no significant treatment effects in the 10 ng L( 1) treatment group, but at the 100 ng L(-1) dose we found that fish had smaller gonads and reduced sperm swimming velocity. When allowed to interact freely with female conspecifics, males exposed to 100 ng L(-1) EE2 built smaller nests and showed a nonsignificant decrease in fertilization success. To investigate further the potential mechanism underlying the decrease in sperm quality, we repeated the chronic exposure experiment and analyzed the ATP content of sperm from fish in each treatment group. We found that males exposed to 100 ng L(-1) of EE2 had fewer moles of ATP per sperm than did fish in the other two treatment groups, suggesting that a decrease in intracellular ATP caused a reduction in sperm swimming velocity. The current study adds to the growing body of literature that indicates the risks to aquatic organisms of exposure to environmentally relevant concentrations of EE2. PMID- 22223460 TI - High iNOS mRNA and protein localization during late pregnancy suggest a role for nitric oxide in mouse pubic symphysis relaxation. AB - Remodeling and relaxation of the mouse pubic symphysis (PS) are central events in parturition. The mouse PS remodels in a hormone-controlled process that involves the modification of the fibrocartilage into an interpubic ligament (IpL), followed by its relaxation prior to parturition. It is recognized that nitric oxide synthase (NOS) and consequently nitric oxide (NO) generation play important roles in extracellular matrix modification, and may promote cytoskeleton changes that contribute to the remodeling of connective tissue, which precedes the onset of labor. To our knowledge, no studies thus far have investigated inducible nitric oxide synthase (iNOS) expression, protein localization, and NO generation in the mouse PS during pregnancy. In this work, we used a combination of the immunolocalization of iNOS, its relative mRNA expression, and NO production to examine the possible involvement of iNOS in remodeling and relaxation of the mouse IpL during late pregnancy. The presence of iNOS was observed in chondrocytes and fibroblast-like cells in the interpubic tissues. In addition, iNOS mRNA and NO production were higher during preterm labor on Day 19 of pregnancy (D19) than NO production on D18 or in virgin groups. The significant increase in iNOS mRNA expression and NO generation from the partially relaxed IpL at D18 to the completely relaxed IpL at D19 may indicate that NO plays an important role in late pregnancy during relaxation of the mouse IpL. PMID- 22223461 TI - A comparison of in vivo 13C MR brain glycogen quantification at 9.4 and 14.1 T. AB - The high molecular weight and low concentration of brain glycogen render its noninvasive quantification challenging. Therefore, the precision increase of the quantification by localized (13) C MR at 9.4 to 14.1 T was investigated. Signal to-noise ratio increased by 66%, slightly offset by a T(1) increase of 332 +/- 15 to 521 +/- 34 ms. Isotopic enrichment after long-term (13) C administration was comparable (~ 40%) as was the nominal linewidth of glycogen C1 (~ 50 Hz). Among the factors that contributed to the 66% observed increase in signal-to-noise ratio, the T(1) relaxation time impacted the effective signal-to-noise ratio by only 10% at a repetition time = 1 s. The signal-to-noise ratio increase together with the larger spectral dispersion at 14.1 T resulted in a better defined baseline, which allowed for more accurate fitting. Quantified glycogen concentrations were 5.8 +/- 0.9 mM at 9.4 T and 6.0 +/- 0.4 mM at 14.1 T; the decreased standard deviation demonstrates the compounded effect of increased magnetization and improved baseline on the precision of glycogen quantification. PMID- 22223462 TI - Alpha-5 and -3 nicotinic receptor gene variants predict nicotine dependence but not cessation: findings from the COMMIT cohort. AB - Smoking many cigarettes per day (CPD) and short interval to first cigarette (TTF) after waking are two of the most heritable smoking phenotypes and comprise the Heavy Smoking Index (HSI). These phenotypes are often used as proxies for nicotine dependence (ND) and are associated with smoking cessation outcomes. Case control and genome-wide association studies have reported links between single nucleotide polymorphisms (SNPs) in the alpha-5 and -3 nicotinic receptor subunit (CHRNA5 and CHRNA3) genes and CPD but few have examined TTF or cessation outcomes. In this study we longitudinally assessed 1301 European-American smokers at four time-points from 1988 to 2005. One CHRNA5 (rs16969968) and two CHRNA3 (rs1051703, rs6495308) SNPs were examined for their ability to predict smokers who "ever" reported ND based on three phenotypic classifications: (1) 25+ CPD, (2) TTF < 10 min, and (3) HSI >= 4. In a subsample of 1157 quit attempters, we also examined each SNP's ability to predict "ever" quitting for a period of >6 months. Demographically adjusted logistic regressions showed significant allelic and genotypic associations between all three SNPs and CPD but not TTF, HSI, or smoking cessation. Carriers of both the rs16969968-AA and rs6495308-TT genotypes had approximately twofold greater odds for ND defined using CPD or TTF. Results suggest nicotinic receptor variants are associated with greater odds of ND according to CPD and to a lesser extent TTF. Research examining the effect of nicotinic receptor genetic variation on ND phenotypes beyond CPD is warranted. PMID- 22223463 TI - Shielding effect of a customized intraoral mold including lead material in high dose-rate 192-Ir brachytherapy for oral cavity cancer. AB - A high-dose-rate (HDR) 192-Ir brachytherapy using a customized intraoral mold is effective for superficial oral cavity cancer, and the surrounding normal tissue is kept away from the radioactive source with gauze pads and/or mouth piece for reducing the dose on the normal tissues. In the Tokushima university hospital, the mold has a lead shield which utilizes the space prepared with sufficient border-molding by a specific dental technique using modeling compound. In HDR 192 Ir brachytherapy using a lead shielded customized intraoral mold, there are no reports measuring the absorbed dose. The purpose of the present study is to measure the absorbed dose and discuss the optimum thickness of lead in HDR 192-Ir brachytherapy using a customized intraoral mold with lead shield using a 1 cm thickness mimic mold. The thickness of lead in the mold could be changed by varying the arrangement of 0.1 cm thickness sheet of the acrylic resin plate and lead. The measured doses at the lateral surface of the mold with thermo luminescence dosimeter were reduced to 1.12, 0.79, 0.57, 0.41, 0.31, 0.24 and 0.19 Gy and the ratios to the prescription dose were reduced to 56, 40, 29, 21, 16, 12 and 10 percent as lead thickness increased from 0 to 0.6 cm in 0.1 cm increments, respectively. A 0.3 cm thickness lead was considered to be required for a 1 cm thickness mold, and it was necessary to thicken the lead as much as possible with the constraint of limited space in the oral cavity, especially at the fornix vestibule. PMID- 22223465 TI - Total synthesis of (+)-asteriscanolide: further exploration of the rhodium(I) catalyzed [(5+2)+1] reaction of ene-vinylcyclopropanes and CO. AB - The total synthesis of (+)-asteriscanolide is reported. The synthetic route features two key reactions: 1) the rhodium(I)-catalyzed [(5+2)+1] cycloaddition of a chiral ene-vinylcyclopropane (ene-VCP) substrate to construct the [6.3.0] carbocyclic core with excellent asymmetric induction, and 2) an alkoxycarbonyl radical cyclization that builds the bridging butyrolactone ring with high efficiency. Other features of this synthetic route include the catalytic asymmetric alkynylation of an aldehyde to synthesize the chiral ene-VCP substrate, a highly regioselective conversion of the [(5+2)+1] cycloadduct into its enol triflate, and the inversion of the inside-outside tricycle to the outside-outside structure by an ester-reduction/elimination to enol ether/hydrogenation procedure. In addition, density functional theory (DFT) rationalization of the chiral induction of the [(5+2)+1] reaction and the diastereoselectivity of the radical annulation has been presented. Equally important is that we have also developed other routes to synthesize asteriscanolide using the rhodium(I)-catalyzed [(5+2)+1] cycloaddition as the key step. Even though these routes failed to achieve the total synthesis, these experiments gave further useful information about the scope of the [(5+2)+1] reaction and paved the way for its future application in synthesis. PMID- 22223466 TI - Monitoring of liquid-phase organic reactions by photoelectron spectroscopy. AB - There are strings attached: after linking the reacting groups to head groups of ionic liquids to drastically lower the vapour pressures of the reactants, ordinary liquid-phase organic reactions can be monitored by in situ X-ray photoelectron spectroscopy. This approach is demonstrated for the nucleophilic substitution of an alkyl amine and an alkyl chloride moiety, which are attached to the cation and anion of ionic liquids, respectively. PMID- 22223464 TI - Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. AB - Normal aging is often accompanied by a progressive loss of receptor sensitivity in hearing and vision, whose consequences on cellular function in cortical sensory areas have remained largely unknown. By examining the primary auditory (A1) and visual (V1) cortices in two inbred strains of mice undergoing either age related loss of audition (C57BL/6J) or vision (CBA/CaJ), we were able to describe cellular and subcellular changes that were associated with normal aging (occurring in A1 and V1 of both strains) or specifically with age-related sensory loss (only in A1 of C57BL/6J or V1 of CBA/CaJ), using immunocytochemical electron microscopy and light microscopy. While the changes were subtle in neurons, glial cells and especially microglia were transformed in aged animals. Microglia became more numerous and irregularly distributed, displayed more variable cell body and process morphologies, occupied smaller territories, and accumulated phagocytic inclusions that often displayed ultrastructural features of synaptic elements. Additionally, evidence of myelination defects were observed, and aged oligodendrocytes became more numerous and were more often encountered in contiguous pairs. Most of these effects were profoundly exacerbated by age related sensory loss. Together, our results suggest that the age-related alteration of glial cells in sensory cortical areas can be accelerated by activity-driven central mechanisms that result from an age-related loss of peripheral sensitivity. In light of our observations, these age-related changes in sensory function should be considered when investigating cellular, cortical, and behavioral functions throughout the lifespan in these commonly used C57BL/6J and CBA/CaJ mouse models. PMID- 22223467 TI - A sensitive capillary GC-MS method for analysis of topiramate from plasma obtained from single-dose studies. AB - Topiramate (Topamax(r)) is an antiepileptic medication used as adjunctive and monotherapy in patients with epilepsy and for migraine prophylaxis. A GC-MS assay was developed that was capable of detecting topiramate plasma concentrations following a single rectal or oral dose administration. Topiramate plasma samples were prepared by solid-phase extraction and were quantified by GC-MS analysis. The topiramate standard curves were split from 0.1 to 4 ug/mL and from 4 to 40 ug/mL in order to give a more accurate determination of the topiramate concentration. The accuracy of the standards ranged from 94.6 to 107.3% and the precision (%CV) ranged from 1.0 to 5.3% for both curves at all concentrations. The %CV for quality controls was <7.6%. The assay is both accurate and precise and will be used to complete future pharmacokinetic studies. PMID- 22223468 TI - Interrelation between crystal packing and small-molecule organic solar cell performance. AB - X-ray investigations on single crystals of a series of terminally dicyanovinyl substituted quaterthiophenes and co-evaporated blend layers with C(60) give insight into molecular packing behavior and morphology, which are crucial parameters in the field of organic electronics. Structural characteristics on various levels and length scales are correlated with the photovoltaic performance of bulk heterojunction small-molecule organic solar cells. PMID- 22223469 TI - Organic insecticide spinosad causes in vivo oxidative effects in the brain of Oreochromis niloticus. AB - Spinosad is an organic insecticide derived from a naturally occurring soil bacterium and is used in organic farming worldwide. The aim of this study was to evaluate in vivo toxic effects of spinosad in the brain of Oreochromis niloticus as a model organism. The fish were exposed to sublethal spinosad concentrations (25, 50, 75 mg L(-1) ) for 24-48-72 h to determine tGSH, GSH, GSSG, and TBARS contents, GSH/GSSG ratio, and GPx, GR, GST enzymes activities using spectrophotometrical methods, and Hsp70 content by an ELISA technique. Spinosad caused elevations in the contents of tGSH, GSH, GSSG, Hsp70, and reductions in the ratio of GSH/GSSG and GPx activity and an induction in the GR activity. The results indicated that spinosad had oxidative effects in the brain tissue by altering the parameters in GSH-related antioxidant system and Hsp70. It was also suggested that spinosad-induced free-radicals were eliminated by GSH-related antioxidant system in the brain of Oreochromis niloticus. PMID- 22223470 TI - Ductus venosus blood-flow patterns: more than meets the eye? PMID- 22223471 TI - Tissue imprint for molecular mapping of deep surgical margins in patients with head and neck squamous cell carcinoma. AB - BACKGROUND: Tissue imprinting can generate molecular marker maps of tumor cells at deep surgical margins. The purpose of this study was to evaluate the feasibility of this method for detection of residual head and neck squamous cell carcinoma (HNSCC). METHODS: Paired fresh tissue and nitrocellulose membrane imprints of tumor and deep margins were collected from 17 HNSCC resections. DNA was amplified using quantitative methylation-specific polymerase chain reaction (qMSP) for p16, DCC, KIF1A, and EDNRB. Levels of methylation in tumors and deep margins were compared. RESULTS: DNA from imprints was adequate for qMSP. Hypermethylation of target genes was present in 12 of 17 tumors and in 8 deep margins. Methylation level was better from margin imprints than tissue. During follow-up (median, 13 months), local or regional recurrences occurred in 6 cases of which 5 had molecularly positive margins. CONCLUSION: Tissue imprinting is feasible for molecular detection of residual tumor at deep surgical margins and may correlate with locoregional recurrence. PMID- 22223472 TI - Long-term MRI-guided combined anti-TNF-alpha and thiopurine therapy for Crohn's perianal fistulas. AB - BACKGROUND: Anti-tumor necrosis factor (TNF) therapy heals many Crohn's disease (CD) anal fistulas clinically but the rate, extent, and durability of deep tissue healing and factors influencing long-term outcome are unknown. METHODS: Consecutive patients with CD-related perianal (anal, rectovaginal, anolabial) fistulas treated with infliximab or adalimumab were monitored prospectively both clinically and radiologically using magnetic resonance imaging (MRI). RESULTS: Forty-one consecutive patients with CD-related perianal fistulas were treated with infliximab (n = 32) or adalimumab (n = 9; following infliximab failure) in combination with a thiopurine (unless intolerant). Fifty-eight percent of all patients, comprising 66% and 43% of infliximab and adalimumab-treated patients, respectively, demonstrated remission or response at 3 years. Thirty-three percent of infliximab treated patients maintained clinical remission at 3 years. Radiological healing lagged behind clinical remission by a median of 12 months. The likelihood of clinical remission at any time was five times greater in patients who had early clinical response within 6 weeks than those without. A higher number of fistula tracts was associated with reduced clinical remission. All patients who achieved radiological healing maintained healing on infliximab treatment, while only 43% maintained healing after cessation of anti-TNF therapy. CONCLUSIONS: Combination anti-TNF and thiopurine therapy provides sustained benefit in patients with perianal CD fistula. Early clinical response is associated with subsequent clinical remission. Radiological healing is slower than clinical healing. Radiologically healed fistula tracts maintain healing on infliximab but can recur after cessation of therapy. PMID- 22223473 TI - Clinical improvement of the aggressive neurobehavioral phenotype in a patient with a deletion of PITX3 and the absence of L-DOPA in the cerebrospinal fluid. AB - The development of midbrain dopamine (DA) neurons is regulated by several transcription factors, including Nurr1, Wnt1, Lmx1a/1b, En1, En2, Foxa1, Foxa2, and Pitx3. PITX3 is an upstream co-activator of the TH (tyrosine hydroxylase) promoter. Pitx3(-/-) mice have a selective loss of dopaminergic neurons in the substantia nigra and ventral tegmental area, leading to the significantly reduced DA levels in the nigrostriatal pathway and in the dorsal striatum and manifest anomalous striatum-dependent cognitive impairment and neurobehavioral activity. Treatment with L-DOPA, dopamine, or dopamine receptor agonists in these mice reversed several of their sensorimotor impairments. Heterozygous missense mutations in PITX3 have been reported in patients with autosomal dominant congenital cataract and anterior segment (ocular) mesenchymal dysgenesis (ASMD) whereas homozygous missense mutations have been found in patients with microphthalmia and neurological impairment. Using a clinical oligonucleotide array comparative genomic hybridization (aCGH), we have identified an ~317 kb hemizygous deletion in 10q24.32, involving PITX3 in a 17-year-old male with a Smith-Magenis syndrome-like phenotype, including mild intellectual impairment, sleep disturbance, hyperactivity, and aggressive and self-destructive behavior. Interestingly, no eye anomalies were found in our patient. Analysis of neurotransmitters in his cerebrospinal fluid revealed an absence of L-DOPA and significantly decreased levels of catecholamine metabolites. Importantly, L-DOPA treatment of our patient has led to mild mitigation of his aggressive behavior and mild improvement of his attention span, extended time periods of concentration, and better sleep. PMID- 22223474 TI - Combined analyses of bacterial, fungal and nematode communities in andosolic agricultural soils in Japan. AB - We simultaneously examined the bacteria, fungi and nematode communities in Andosols from four agro-geographical sites in Japan using polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and statistical analyses to test the effects of environmental factors including soil properties on these communities depending on geographical sites. Statistical analyses such as Principal component analysis (PCA) and Redundancy analysis (RDA) revealed that the compositions of the three soil biota communities were strongly affected by geographical sites, which were in turn strongly associated with soil characteristics such as total C (TC), total N (TN), C/N ratio and annual mean soil temperature (ST). In particular, the TC, TN and C/N ratio had stronger effects on bacterial and fungal communities than on the nematode community. Additionally, two-way cluster analysis using the combined DGGE profile also indicated that all soil samples were classified into four clusters corresponding to the four sites, showing high site specificity of soil samples, and all DNA bands were classified into four clusters, showing the coexistence of specific DGGE bands of bacteria, fungi and nematodes in Andosol fields. The results of this study suggest that geography relative to soil properties has a simultaneous impact on soil microbial and nematode community compositions. This is the first combined profile analysis of bacteria, fungi and nematodes at different sites with agricultural Andosols. PMID- 22223475 TI - Hydrogel surfaces to promote attachment and spreading of endothelial progenitor cells. AB - Endothelialization of artificial vascular grafts is a challenging process in cardiovascular tissue engineering. Functionalized biomaterials could be promising candidates to promote endothelialization in repair of cardiovascular injuries. The purpose of this study was to synthesize hyaluronic acid (HA) and heparin based hydrogels that could promote adhesion and spreading of endothelial progenitor cells (EPCs). We report that the addition of heparin into HA-based hydrogels provides an attractive surface for EPCs promoting spreading and the formation of an endothelial monolayer on the hydrogel surface. To increase EPC adhesion and spreading, we covalently immobilized CD34 antibody (Ab) on HA heparin hydrogels, using standard EDC/NHS amine-coupling strategies. We found that EPC adhesion and spreading on CD34 Ab-immobilized HA-heparin hydrogels was significantly higher than their non-modified analogues. Once adhered, EPCs spread and formed an endothelial layer on both non-modified and CD34 Ab-modified HA heparin hydrogels after 3 days of culture. We did not observe significant adhesion and spreading when heparin was not included in the control hydrogels. In addition to EPCs, we also used human umbilical cord vein endothelial cells (HUVECs), which adhered and spread on HA-heparin hydrogels. Macrophages exhibited significantly less adhesion compared to EPCs on the same hydrogels. This composite material could possibly be used to develop surface coatings for artificial cardiovascular implants, due to its specificity for EPC and endothelial cells on an otherwise non-thrombogenic surface. PMID- 22223477 TI - Spatial learning and memory impairment and pathological change in rats induced by acute exposure to microcystin-LR. AB - Microcystin-LR (MCLR) is a commonly encountered blue-green algal hepatotoxin and a known inhibitor of cellular protein phosphatase. However, little is known about its neurotoxicity. By using Morris water maze, histopathological and biochemical analysis, we investigated MCLR-induced neurotoxicity on the hippocampus of rat brain. After rats were intrahippocampally injected with MCLR (1 and 10 MUg/L), their learning and memory function was greatly impaired, suggesting the neurotoxic potential of MCLR. Meanwhile, obvious histological and ultrastructural injuries and serious oxidative damage were also observed in the hippocampus. These results suggested that oxidative stress might be involved in the MCLR induced pathological damage in hippocampus, subsequently leading to the spatial learning and memory deficit of rat. Taken together, our results highlighted the MCLR-induced neurotoxicity in the rat, as well as the importance of oxidative stress and pathological impairment in this procedure. PMID- 22223476 TI - Bronsted acid catalyzed asymmetric propargylation of aldehydes. PMID- 22223478 TI - Postpartum uterine involution: sonographic changes in the endometrium between 2 and 6 weeks postpartum related to delivery mode and gestational age at delivery. PMID- 22223479 TI - Genes associated with intestinal permeability in ulcerative colitis: changes in expression following infliximab therapy. AB - BACKGROUND: Alterations in intestinal permeability have been implicated in ulcerative colitis (UC). Infliximab, a monoclonal anti-tumor necrosis factor alpha (TNFalpha) antibody, can induce clinical response in UC. Gene expression in colonic biopsies taken from responders and nonresponders to infliximab can provide insight into the mechanisms of the altered intestinal permeability at a molecular level. METHODS: Colonic biopsies (n = 18 anti-TNFalpha naive UC patients; n = 8 normal controls; n = 80 Active Ulcerative Colitis Trial [ACT] 1 patients) were analyzed for mRNA expression using gene expression microarrays. Computational reverse causal reasoning was applied to build causal network models of UC and response and nonresponse of UC to treatment. Quantitative reverse transcription polymerase chain reaction (qPCR) was used to confirm differentially expressed genes. RESULTS: Reverse causal reasoning on mRNA expression data from anti-TNFalpha-naive UC and normal samples provided a mechanistic disease model of the biology of gene expression observed in UC. mRNA expression data from the ACT 1 study enabled construction of a mechanistic model describing the biology of nonresponders to infliximab, including evidence for increased intestinal permeability compared with normal and responder samples. Gene expression changes identified as central to intestinal permeability dysregulation were confirmed in normal, UC, and infliximab-treated patients by qPCR analysis. Gene expression returned toward normal levels in infliximab responders, but not in nonresponders. CONCLUSION: Gene expression analysis and causal network modeling in combination showed that aberrant mRNA expression of genes involved in intestinal epithelial permeability for infliximab responders was restored toward levels observed in normal samples. Infliximab nonresponders showed no equivalent restoration in the expression of these genes. PMID- 22223480 TI - Why surgeons can say "no": exploring "unilateral withholding". AB - OBJECTIVE: To explore why it is permissible for surgeons to "unilaterally withhold" surgery, whereas it is not commonplace (in the United States) to unilaterally withhold cardiopulmonary resuscitation (CPR) for clinical situations with similar degrees of uncertainty and prognosis. DATA SOURCES: The medical literature was sampled using PubMed and Google search engines, employing a variety of search strategies to capture articles relating to medical/surgical decision-making, risk aversion, acute care surgery, and withholding life-saving therapies. These topics are used to highlight interprovider variability that affects all practitioners-not just surgeons-and to consider why we deem it permissible for surgeons to withhold surgery, whereas-in the United States, at least-it is not routinely permissible for clinicians to unilaterally withhold mechanical ventilation and CPR for cases with similar prognoses. CONCLUSIONS: While there are no published research studies that deal directly with this topic, knowledge, heuristics, experience, variable aversion to risk, and other features inherent in medical-surgical education likely impact decisions to offer or withhold potentially life-saving therapies of all kinds. Both surgeons and clinicians, who request surgical consultation for hospitalized patients, should consider these issues and politely pursue second opinions when there is any doubt whether forgoing surgery is in the patient's best interests. Similarly, while unilateral withholding of CPR is not commonly employed in some medical cultures, including the United States, beneficence can be facilitated through robust informed consent. PMID- 22223481 TI - Identification of a hypochlorite-specific transcription factor from Escherichia coli. AB - Hypochlorite is a powerful oxidant produced by neutrophils to kill invading microorganisms. Despite this important physiological role of HOCl in fighting bacterial infections, no hypochlorite-specific stress response has been identified yet. Here, we identified a hypochlorite-responsive transcription factor, YjiE, which is conserved in proteobacteria and eukaryotes. YjiE forms unusual dodecameric ring-like structures in vitro that undergo large DNA-induced conformational changes to form dimers and tetramers as shown by transmission electron microscopy and analytical ultracentrifugation. Such smaller oligomers are predominant in hypochlorite-stressed cells and are the active species as shown by fluorescence anisotropy and analytical ultracentrifugation. YjiE regulates a large number of genes upon hypochlorite stress. Among them are genes involved in cysteine, methionine biosynthesis, and sulfur metabolism (up regulated) and genes involved in iron acquisition and homeostasis (down regulated), thus supposedly replenishing oxidized metabolites and decreasing the hypochlorite-mediated amplification of intracellular reactive oxygen species. As a result, YjiE specifically confers hypochlorite resistance to E. coli cells. Thus, to our knowledge, YjiE is the first described hypochlorite-specific transcription factor. PMID- 22223482 TI - Quaternary structure controls ligand dynamics in soluble guanylate cyclase. AB - Soluble guanylate cyclase (sGC) is the mammalian endogenous nitric oxide (NO) receptor. The mechanisms of activation and deactivation of this heterodimeric enzyme are unknown. For deciphering them, functional domains can be overexpressed. We have probed the dynamics of the diatomic ligands NO and CO within the isolated heme domain beta(1)(190) of human sGC by piconanosecond absorption spectroscopy. After photo-excitation of nitrosylated sGC, only NO geminate rebinding occurs in 7.5 ps. In beta(1)(190), both photo-dissociation of 5c-NO and photo-oxidation occur, contrary to sGC, followed by NO rebinding (7 ps) and back-reduction (230 ps and 2 ns). In full-length sGC, CO geminate rebinding to the heme does not occur. In contrast, CO geminately rebinds to beta(1)(190) with fast multiphasic process (35, 171, and 18 ns). We measured the bimolecular association rates k(on) = 0.075 +/- 0.01 * 10(6) M(-1) . S(-1) for sGC and 0.83 +/- 0.1 * 10(6) M(-1) . S(-1) for beta(1)(190). These different dynamics reflect conformational changes and less proximal constraints in the isolated heme domain with respect to the dimeric native sGC. We concluded that the alpha-subunit and the beta(1)(191-619) domain exert structural strains on the heme domain. These strains are likely involved in the transmission of the energy and relaxation toward the activated state after Fe(2+)-His bond breaking. This also reveals the heme domain plasticity modulated by the associated domains and subunit. PMID- 22223483 TI - Novel application of human neurons derived from induced pluripotent stem cells for highly sensitive botulinum neurotoxin detection. AB - Human induced pluripotent stem cells (hiPSC) hold great promise for providing various differentiated cell models for in vitro toxigenicity testing. For Clostridium botulinum neurotoxin (BoNT) detection and mechanistic studies, several cell models currently exist, but none examine toxin function with species specific relevance while exhibiting high sensitivity. The most sensitive cell models to date are mouse or rat primary cells and neurons derived from mouse embryonic stem cells, both of which require significant technical expertise for culture preparation. This study describes for the first time the use of hiPSC derived neurons for BoNT detection. The neurons used in this study were differentiated and cryopreserved by Cellular Dynamics International (Madison, WI) and consist of an almost pure pan-neuronal population of predominantly gamma aminoisobutyric acidergic and glutamatergic neurons. Western blot and quantitative PCR data show that these neurons express all the necessary receptors and substrates for BoNT intoxication. BoNT/A intoxication studies demonstrate that the hiPSC-derived neurons reproducibly and quantitatively detect biologically active BoNT/A with high sensitivity (EC(50) ~0.3 U). Additionally, the quantitative detection of BoNT serotypes B, C, E, and BoNT/A complex was demonstrated, and BoNT/A specificity was confirmed through antibody protection studies. A direct comparison of BoNT detection using primary rat spinal cord cells and hiPSC-derived neurons showed equal or increased sensitivity, a steeper dose-response curve and a more complete SNARE protein target cleavage for hiPSC derived neurons. In summary, these data suggest that neurons derived from hiPSCs provide an ideal and highly sensitive platform for BoNT potency determination, neutralizing antibody detection and for mechanistic studies. PMID- 22223484 TI - Protein phosphatase 2A regulates innate immune and proteolytic responses to cigarette smoke exposure in the lung. AB - Protein phosphatase 2A (PP2A) is the primary serine-threonine phosphatase of eukaryotic cells, and changes in its activity have been linked to neoplastic and neurodegenerative diseases. However, the role of PP2A in noncancerous lung diseases such as chronic obstructive pulmonary disease (COPD) has not been previously examined. This study determined that PP2A activity was significantly increased in the lungs of advanced emphysema subjects compared with age-matched controls. Furthermore, we found that cigarette smoke exposure increases PP2A activity in mouse lung in vivo and in primary human small airway epithelial (SAE) cells in vitro. In mice, intratracheal transfection of PP2A protein prior to cigarette smoke exposure prevented acute smoke-induced lung inflammation. Conversely, inhibiting PP2A activity during smoke exposure exacerbated inflammatory responses in the lung. To further determine how PP2A modulates the responses to cigarette smoke in the lung, enzyme levels were manipulated in SAE cells using protein transfection and short hairpin RNA (shRNA) techniques. Increasing PP2A activity in SAE cells via PP2A protein transfection downregulated cytokine expression and prevented the induction of proteases following cigarette smoke extract (CSE) treatment. Conversely, decreasing enzymatic activity by stably transfecting SAE cells with shRNA for the A subunit of PP2A exacerbated these smoke-mediated responses. This study establishes that PP2A induction by cigarette smoke modulates immune and proteolytic responses to cigarette smoke exposure. Together, these findings suggest that manipulation of PP2A activity may be a plausible means to treat COPD and other inflammatory diseases. PMID- 22223485 TI - Differing effects of toxicants (methylmercury, inorganic mercury, lead, amyloid beta, and rotenone) on cultured rat cerebrocortical neurons: differential expression of rho proteins associated with neurotoxicity. AB - Methylmercury (MeHg), inorganic mercury (IHg), lead (Pb), amyloid-beta peptide (Abeta), and rotenone (RTN) are well-known toxicants. Here, we demonstrate that these five toxicants exhibit differing effects on cerebrocortical neurons. The concentration responsible for 30% loss of viability (EC30) values 3 days after exposure was approximately 100nM for MeHg, IHg, and RTN and 10MUM for Abeta. Neuritic degeneration and subsequent apoptotic cell death were observed in these toxicant-treated cells. In contrast, the EC30 value 3 days after exposure to Pb was > 10MUM. We clarified the differential expression of Ras homolog gene (Rho) family proteins (Ras-related C3 botulinum toxin substrate 1 [Rac1], cell division cycle 42, and Ras homolog gene family, member A [RhoA]) upon exposure to these five toxicants. Exposure to 100nM MeHg, IHg, or RTN downregulated the expression of Rac1, related to neuritic extension, but did not affect RhoA, related to retraction. At a higher concentration (1MUM), IHg and RTN also acted through the suppression of Rac1, whereas increased MeHg toxicity was not associated with the expression of Rho family proteins. On the other hand, Pb and Abeta showed no effects on the expression of Rho proteins. Modification of the balance of neuritic extension and retraction by the suppression of Rho A rescued the neurotoxicity of 100nM MeHg, IHg, and RTN. The results indicate that the imbalance of neuritic extension and retraction by the suppression of Rac1 by 100nM MeHg, IHg, and RTN causes cerebrocortical neuron axonal degeneration and cell death. By contrast, the neurotoxicities of Pb, Abeta, and MeHg (at higher concentrations) are conferred by other toxic mechanisms. PMID- 22223487 TI - Development of a supported self-directed learning approach for anatomy education. AB - The ability to deliver sufficient core anatomical knowledge and understanding to medical students with limited time and resources remains a major challenge for anatomy educators. Here, we report the results of switching from a primarily didactic method of teaching to supported self-directed learning for students studying anatomy as part of undergraduate medicine at the University of Edinburgh. The supported self-directed approach we have developed makes use of an integrated range of resources, including formal lectures and practical sessions (incorporating gross anatomy specimens, medical imaging technologies, anatomical models, clinical scenarios, and surface anatomy workstations). In practical sessions, students are provided with a custom-made workbook that guides them through each session, with academic staff, postgraduate tutors, and near-peer teaching assistants present to deal with misunderstandings and explain more complicated topics. This approach retains many of the best attributes of didactic teaching but blends them with the advantages associated with self-directed learning approaches. The switch to supported self-directed learning-initially introduced in 2005-resulted in a significant improvement in anatomy examination scores over the subsequent period of five years, manifesting as an increase in the average anatomy practical spot examination mark, less students failing to obtain the pass mark and more students passing with distinction. We conclude that the introduction of supported self-directed learning improved students' engagement, leading to deeper learning and better understanding and knowledge of anatomy. PMID- 22223488 TI - Enantioselective synthesis of spiro cyclopentane-1,3'-indoles and 2,3,4,9 tetrahydro-1H-carbazoles by iridium-catalyzed allylic dearomatization and stereospecific migration. PMID- 22223486 TI - Excitotoxicity and oxidative damages induced by methylmercury in rat cerebral cortex and the protective effects of tea polyphenols. AB - Methylmercury (MeHg) is a highly neurotoxic environmental pollutant that has a high appetency to the central nervous system. The underlying mechanisms of MeHg induced neurotoxicity have not been elucidated clearly until now. Therefore, to explore the mechanisms contribute to MeHg-induced neurotoxicity, rats were exposed to different dosage of methylmercury chloride (CH3 ClHg) (0, 4, and 12 MUmol kg(-1)) for 4 weeks to evaluate the neurotoxic effects of MeHg. In addition, considering the antioxidative properties of tea polyphenols (TP), 1 mmol kg(-1) TP was pretreated to observe the possible protective effects on MeHg induced neurotoxicity. Then Hg, glutamate (Glu) and glutamine (Gln) levels, glutamine synthetase (GS), phosphate-activated glutaminase (PAG), Na(+)-K(+) ATPase, and Ca(2+)-ATPase activities, intracellular Ca(2+) level were examined, glutathione (GSH), malondialdehyde (MDA), protein sulfhydryl, carbonyl, 8-hydroxy 2-deoxyguanosine (8-OHdG), and reactive oxygen species (ROS) levels, N-methyl-D aspartate receptors (NMDARs) mRNA and protein expressions, apoptosis level and morphological changes in the cerebral cortex were also investigated. Study results showed that compared with those in control, exposure to CH3 ClHg resulted in excitotoxicity in a concentration-dependent manner, which was shown by the Glu Gln cycle disruption and intracellular Ca(2+) homeostasis disturbance. On the other hand, CH3 ClHg exposure resulted in oxidative damages of brain, which were supported by the significant changes on GSH, MDA, sulfhydryl, carbonyl, 8-OHdG, and ROS levels. Moreover, apoptosis rate increased obviously and many morphological changes were found after CH3 ClHg exposure. Furthermore, this research indicated that TP pretreatment significantly mitigated the toxic effects of MeHg. In conclusion, findings from this study indicated that exposure to MeHg could induce excitotoxicity and oxidative damage in cerebral cortex while TP might antagonize the MeHg-induced neurotoxicity. PMID- 22223489 TI - Syntheses, properties, and photoreactions of the hybrid molecules consisting of a Co(II) mononuclear complex and porphyrins. AB - New hybrid molecules consisting of mononuclear Co(II) complexes and porphyrin moieties were synthesized and their new photoreactions were examined. Three porphyrins with different meso-substituents (2,6-dimethoxyphenyl, 3,5-di-tert butylphenyl, and 2,6-difluorophenyl groups) were used to change the redox potentials of the hybrid compounds. The hybrid molecules were prepared by the stepwise condensation of amide bonds. The cyclic voltammograms of these hybrid molecules showed the redox processes of both the cobalt and porphyrin moieties. The redox potentials of the porphyrins showed a systematic change that was consistent with the electronic effects of the meso-substituents. The emission spectra only showed fluorescence of the porphyrins with slightly decreased intensities. When a solution of the hybrid molecule, durohydroquinone, and N,N diisopropylethylamine in CHCl(3)/MeCN was irradiated with visible light (>580 nm), durohydroquinone was converted into duroquinone with the concurrent formation of the reduced product of CHCl(3). The hydroquinone was employed as an electron donor capable of reversible redox reactions, which is in contrast to conventional sacrificial reagents such as EDTA. The course of the photoreaction was followed by (1)H NMR spectroscopy and the amount of produced duroquinone was between 50-60% after 600 min. We propose that the photoreaction involves a photoinduced electron transfer from the hydroquinone to the excited porphyrin, followed by the formation of a Co(I) intermediate by charge shift, thus leading to the reaction with CHCl(3). PMID- 22223491 TI - Subcellular tracking of drug release from carbon nanotube vehicles in living cells. AB - The direct observation of drug release from carbon nanotube vehicles in living cells is realized through a unique two-dye labeling approach. Single-walled carbon nanotubes (SWNTs) are firstly marked with fluorescein isothiocyanate (FITC) to track their location and movement inside the cell. Then a fluorescent anticancer drug doxorubicin (DOX) is attached by means of pi-stacking onto SWNTs. Delivered by SWNTs into cells, DOX will detach from the vehicle in an acidic environment due to the pH-dependent pi-pi stacking interaction between DOX and SWNTs. From observation of the two different kinds of fluorescence (green and red) that respectively represent the carrier SWNTs and drug DOX, the process of drug release inside the living cell can be monitored under a confocal microscope. Results show that the drug DOX detaches from SWNTs inside the lysosomes to yield free molecules and escape into the cytoplasm and finally into the nucleus, while the vehicle SWNTs are trapped inside the lysosomes, without entering the nucleus. The current observations confirm previously proposed mechanisms for drug/DOX release inside cells. The experimental establishment of drug-release mechanisms in living cells here might provide important insights for future design of new drug-delivery and release systems. PMID- 22223490 TI - Prenatal genetic confirmation of a COL4A1 mutation presenting with sonographic fetal intracranial hemorrhage. PMID- 22223492 TI - Plasma gamma-glutamyltransferase (GGT) activity in inflammatory bowel disease: is the clinical laboratory plasma GGT assay sensitive enough for gastroenterology? PMID- 22223493 TI - Family management style framework and its use with families who have a child undergoing palliative care at home. AB - Palliative care settings in many countries acknowledge families as their prime focus of care, but in Brazil, to date, researchers have devoted scant attention to that practice setting. In this article, we report the findings of a study that explored how families define and manage their lives when they have a child or adolescent undergoing palliative care at home. Data included individual semistructured interviews with 14 family members of 11 different families. Interviews were transcribed and the coding procedure featured qualitative content analysis methods. The deductive coding was based on the major components of the Family Management Style Framework and the eight dimensions comprising these components. The analysis provides insight into families' daily practices and problems inherent in managing their everyday lives that are encountered when they have a child in palliative care. The article features discussion of implications for the palliative care related development of family nursing practice. PMID- 22223495 TI - Continued development of the family management style framework. AB - Based on a review of 64 published reports, this article addresses the implications of current research for the further development of the Family Management Style Framework (FMSF). Articles are published in 46 different journals, including 13 in nursing and 12 in interdisciplinary outlets. Most studies are based on samples of less than 50 individuals. The review provides continuing support for the 8 dimensions of the framework, with between 8 and 16 reports supporting the relevance of each. Changes to the sociocultural component of the framework are proposed as well as wording changes to reflect the broader applicability of the framework. The family's social network, health care and education professionals, and resources predominate as key influences on family management. PMID- 22223494 TI - Adapting the family management style framework for families caring for older adults with dementia. AB - This article presents an adaptation of the Family Management Style Framework (FMSF)-a well-established framework of family response to chronic condition care of children-to families caring for older adults with dementia. Using the FMSF to better understand how families manage dementia care can provide clinicians with insights on how to work effectively with families. Using data from interviews with eight female caregivers of older adults with dementia, this secondary analysis adapts the FMSF, and identifies new dimensions that apply specifically to families caring for older adults with dementia. The discussion draws comparisons between the family management of a child with chronic condition to management of an older adult with dementia. The article concludes with a discussion of how understanding how families manage care of an older adult with dementia informs assessment for management styles and the tailoring of interventions specific to family, caregiver, and older adult needs. PMID- 22223496 TI - Family management after the sudden death of a family member. AB - Although more is known about how individuals within families make decisions and manage more discrete issues when a family member is dying, less is known about how families as a unit manage after the sudden death of a family member. The article discusses an investigation that was conducted to better understand how families respond to the life-threatening illness or injury and eventual death of a family member. The purpose of the study was to define Family Management Styles (FMSs) and determine distinctive characteristics of each FMS used by families after the death of a family member who had life-sustaining therapy withdrawn as a result of an unexpected, life-threatening illness or injury. Interviews are conducted with 8 families (22 family members) 1 to 2 years after the death of their family members. A modified typology of FMSs based on a directed analysis that was then inductively modified includes: progressing, accommodating, maintaining, struggling, and floundering. Understanding FMSs and how FMSs may change over time, reflecting the changing focus of family work, will further aid in the development of family-focused interventions as well as develop FMSs within the context of end of life. PMID- 22223497 TI - The process of family management when a baby is diagnosed with a lethal congenital condition. AB - The Family Management Style Framework (FMSF) was used as a conceptual basis for secondary data analysis of 55 previously conducted interviews with mothers and fathers of children with a lethal congenital condition from two surgical treatment eras. The directed content analysis was guided by a coding structure developed from family management dimensions identified in prior research of family response to childhood chronic conditions. Results indicated that application of the FMSF was helpful in differentiating families and their processes of family management at the onset of their infant's illness through to surviving the first surgery and going home. The dimensions of Illness View and Child Identity were central to the parents' capacity to manage their baby's illness demands within their family context. Applying a robust family framework to a complex neonatal condition at illness onset provides compelling direction for clinical interventions and their rigorous evaluation. PMID- 22223498 TI - [Therapeutic potential of induced pluripotent stem cells for spinal cord injury]. AB - Once the safety issue has been overcome, induced pluripotent stem cells (iPSCs), which do not entail ethical or immunological concerns, may become the preferred cell source for regenerative medicine. Various types of iPSCs have been established by different methods, and each type exhibits different biological properties. Before iPSC-based clinical applications can be initiated, detailed evaluations of the cells, including their differentiation potentials and tumorigenic activities in different contexts, should be investigated to establish their safety and effectiveness for cell transplantation therapies. Recently, we demonstrated the directed neural differentiation of mouse iPSCs and examined their therapeutic potential in a mouse spinal cord injury (SCI) model. Mouse iPSC derived neural stem/progenitor cells (NS/PCs), which had been pre-evaluated as non-tumorigenic by their transplantation into nonobese diabetic-severe combined immunodeficiency (NOD-scid) mouse brain, were transplanted into the spinal cord 9 days after SCI. Mouse iPSC-derived NS/PCs differentiated into all three neural lineages without forming teratomas or other tumors. They also participated in re myelination and induced the axonal re-growth, promoting motor functional recovery. Nevertheless, our results constitute only the first step toward clinical application. The safety and effectiveness of human iPSC-derived NS/PCs need to be more intensively investigated in future preclinical studies, for example, using non-human primate SCI models. In particular, human iPSCs established by delivering reprogramming factors using a safer method than retrovirus system, such as an integration-free virus system, virus-free system, or transgene-free system should be evaluated. PMID- 22223499 TI - [A challenge towards the clinical application of induced pluripotent stem cell technology for the treatment of Parkinson's disease]. AB - Parkinson's disease has been so far commonly treated with medication therapy. Although the medication works effectively in the initial phase, it turns out to be less effective at the later stage of the disease. Recently, induced pluripotent stem (iPS) cells have attracted much attention because of their potential to cure diseases such as Parkinson's disease. Due to the accumulating clinical experiences of cell transplantation procedures with aborted fetal tissues, Parkinson's disease has become one of the most promising targets for the clinical application of this iPS cell technology. In this review, we will summarize the ongoing research in the field of iPS cells and Parkinson's disease. The method for establishing iPS cells has advanced rapidly that can be applied in the clinical stage in terms of avoiding the use of viral vectors, xenogenic materials, etc. The differentiation protocol to derive the dopamine neurons from iPS cells has also been improved. However, several issues, such as the risk of tumor formation and the poor survival of the grafted dopamine neurons in vivo remain to be solved before these cells can be used in the clinical settings. Other than cell transplantations, iPS cell technology can also provide a valuable platform for disease analysis and drug development with in vitro systems of human cells. Several lines of iPS cells have already been established from Parkinson's disease patients with either sporadic or genetic background. For patients to achieve maximum benefits of this technology, further research must be conducted in both fields, that is, cell transplantation and the disease modeling with patient-derived iPS cells. PMID- 22223500 TI - [Induced pluripotent stem (iPS) cell-based cell therapy for muscular dystrophy: current progress and future prospects]. AB - Duchenne muscular dystrophy (DMD) is a devastating muscle disorder caused by mutations in the dystrophin gene. There is currently no effective treatment for DMD. Muscle satellite cells are tissue-specific stem cells found in the skeletal muscle; these cells play a central role in postnatal muscle growth and regeneration, and are, therefore, a potential source for stem cell therapy for DMD. However, transplantation of satellite cell-derived myoblasts has not yet been successful in humans. Patient-specific induced pluripotent stem (iPS) cells are expected to be a source for autologous cell transplantation therapy for DMD, because iPS cells can proliferate vigorously in vitro and can differentiate into multiple cell lineages both in vitro and in vivo. Here, we discuss the strategies to generate muscle stem cells from iPS cells. So far, the most promising method for generating muscle stem cells from iPS cells is the conditional overexpression of Pax3 or Pax7 in the differentiating mouse embryoid bodies. However, induction methods for human iPS cells have not yet been developed. Thus, iPS cells are expected to serve as an in vitro disease model system, which will enable us to determine the pathology of muscle diseases and develop pharmaceutical treatments. PMID- 22223501 TI - [Perspectives regarding the potential use of human induced pluripotent stem cells for the development of and research on medicinal products]. AB - Human induced pluripotent stem cells (hiPSCs) are expected to be used in various life science areas, ranging from basic research to medical applications. This article describes perspectives regarding the potential use of hiPSCs, especially in Japan, for manufacturing products related to regenerative medicine as well as for establishing cell-based assay/screening systems that can be used for effective and efficient assessment of candidates for new drugs. The applications of hiPSCs include the following: hiPSC-derived retinal pigment epithelial cells for treating age-related macular degeneration; potential corneal reconstruction by using a combination of various relevant hiPSC-derived differentiated cells; potential treatment of Parkinson's disease by using dopaminergic neurons generated from hiPSCs; potential treatment of spinal cord injury by using neural stem/progenitor cells generated from hiPSCs; potential treatment of chronic heart failure by using hiPSC-derived functional cardiomyocytes; and development of cell based drug toxicity screening and drug effect assay systems involving cells such as cardiomyocytes, hepatocytes, and neural cells that are differentiated from hiPSCs and can be used in the early phase of new drug development. The current situation regarding the development of guidelines for ensuring the quality and safety of hiPSC-derived medicinal products has also been described. PMID- 22223502 TI - [Perspective of pathophysiology and treatment of migraine]. AB - Migraine is a most common neurological disease that affects nearly 10% of the general population. Although the pathophysiology of migraine is obscure, cortical spreading depression (CSD) is believed to be a phenomenon underlying migraine auras. On the other hand, the activation of the trigemino-vascular system is considered to be related to headaches. Furthermore, satellite ganglion cells located around the neurons in the trigeminal ganglion may contribute to migraine headaches. Besides, CSD has also been reported to activate the trigemino-vascular system, which subsequently causes migraine headaches. The present review discusses the recent findings of migraine pathophysiology, and mentions some newly developed calcitonin gene-related peptide (CGRP) receptor antagonists, which have revealed the efficaciousness for acute migraine attacks. PMID- 22223503 TI - [Autism spectrum disorder and genes for synaptic proteins]. AB - Autism spectrum disorder (ASD) is characterized by impaired social interaction and communication, and restricted interests. It is generally accepted that ASD is caused by abnormalities in the structure or functions of the brain. Recent genome wide analyses have identified copy number variations (CNVs) of neuronal genes in the genomes of ASD patients. CNV is a commonly observed phenomenon in human beings. During the first cell division of meiosis, irregular crossing over between homologous chromosomes results in loss or duplication of a segment. From 2007 to 2010, several groups performed a large-scale virtual screening of CNVs in ASD genomes. Genes affected by CNV, de novo CNVs, and rare CNVs were more prevalent in ASD. The results highlighted the CNVs of many neuronal genes associated with ASD. A fraction of these genes was previously identified in ASD but some were newly identified in each study. The CNVs implicated in ASD include neuronal genes belonging to 4 classes. These genes encode (1) neural adhesion molecules, including cadherins, neuroligin, and neurexin; (2) scaffold proteins such as SHANK3; (3) protein kinases and other intracellular signaling molecules; and (4) proteins that regulate protein syntheses. In general, these proteins play a role in synapse of glutamatergic neurons. The CNVs detected in the ASD patient genomes of imply a link between the synaptic proteins and pathological characteristics of ASD. Altered protein dosage by the CNVs may alter the functional quality of ASD patient's synapses, and may consequently affect their development of language and communication skills. There are 2 types of ASD, one is sporadic and, the other is familial. According to some reports, de novo CNVs are more frequently observed in sporadic-type ASD. However, it is generally understood that a combination of particular CNVs and other possible mutations underlie the pathology of ASD regardless of ASD type. The major symptoms of ASD are often curable with behavioral intervention during early childhood. An early diagnosis, followed by early start of treatment is crucial for language development and communication skills. Further and broader research on genomes will eventually provide information on the biological characteristics of ASD, as well as on specific ASD genotypes, thus aiding in the establishment of optimal treatment and medication to meet the biological conditions of each patient. PMID- 22223504 TI - [A case of paraneoplastic limbic encephalitis associated with malignant lymphoma presenting with a late-onset bilateral thalamic lesion]. AB - A 63-year-old man presented with cognitive impairment including disturbance of memory functions and character change. Fluid-attenuated inversion recovery (FLAIR) magnetic resonance (MR) imaging revealed signal hyperintensities in the bilateral medial temporal lobes. Cerebrospinal fluid analysis revealed high protein concentrations, positive results for the oligoclonal band, and a slightly positive result for glutamate receptor epsilon2 (GluRepsilon2) antibody. Voltage gated potassium channel (VGKC) antibody was slightly positive in serum. Computed tomography showed enlargement of the left supraclavicular, left axillary, and renal hilar lymph nodes, and 18 F-fluoro-2-deoxy-D-glucose positron emission tomography revealed increased uptake at the same sites. Lymph node biopsy findings were consistent with diffuse large B-cell lymphoma. Based on these findings, the patient was diagnosed with paraneoplastic limbic encephalitis (PLE) associated with malignant lymphoma. The patient received intravenous injection of immunoglobulin and R-CHOP chemotherapy, but his neurological condition deteriorated. MR imaging showed atrophic changes in the medial temporal lobes during immunotherapy and chemotherapy. FLAIR/T2-weighted imaging revealed signal hyperintensities in the bilateral thalami after the first course of R-CHOP chemotherapy. This is the first report of PLE associated with diffuse large B cell lymphoma presenting with late-onset bilateral thalamic lesions. PMID- 22223505 TI - [A case of cerebral infarction treated with tissue-plasminogen activator exhibiting prolonged cerebral edema for more than 1 month]. AB - A 62-year-old man with hypertension and diabetes mellitus controlled by medication suddenly noticed slight hemiparesis and was admitted to our hospital. Tissue-plasminogen activator (t-PA) was administered as his NIHSS was 6 and there were no contraindications. His symptoms completely resolved after t-PA injection. He was discharged on Day 9 without neurological deficits despite minor bleeding being detected in a small, low-density area in the right post-central region on CT. However, the hemiparesis gradually recurred subsequently and the low-density area had increased. He was readmitted on Day 38 due to deterioration of symptoms and enhanced CT imaging exhibited a large, low-density area in the central parasagittal region with enhancement was seen. An open biopsy was performed on Day 52 for diagnostic purposes. Histology demonstrated increased small vessels surrounded by many non-specific inflammatory cells and abundant reactive astrocytes. To date, reports of prolonged cerebral edema lasting more than 1 month after cerebral infarction are rare. This condition may be due to angiogenesis induced by t-PA. Another reason may have been the location, i.e., the parasagittal region, which is the most common area for severe cerebral edema after gamma knife surgery. PMID- 22223506 TI - [A case of central nervous system lymphomatoid granulomatosis successfully treated with corticosteroids]. PMID- 22223507 TI - [A 65-year-old man, suspicious of bacterial meningitis with rapid progression of multiple organ failure]. PMID- 22223508 TI - Cell cycle deregulation by methyl isocyanate: Implications in liver carcinogenesis. AB - Liver is often exposed to plethora of chemical toxins. Owing to its profound physiological role and central function in metabolism and homeostasis, pertinent succession of cell cycle in liver epithelial cells is of prime importance to maintain cellular proliferation. Although recent evidence has displayed a strong association between exposures to methyl isocyanate (MIC), one of the most toxic isocyanates, and neoplastic transformation, molecular characterization of the longitudinal effects of MIC on cell cycle regulation has never been performed. Here, we sequentially delineated the status of different proteins arbitrating the deregulation of cell cycle in liver epithelial cells treated with MIC. Our data reaffirms the oncogenic capability of MIC with elevated DNA damage response proteins pATM and gamma-H2AX, deregulation of DNA damage check point genes CHK1 and CHK2, altered expression of p53 and p21 proteins involved in cell cycle arrest with perturbation in GADD-45 expression in the treated cells. Further, alterations in cyclin A, cyclin E, CDK2 levels along with overexpression of mitotic spindle checkpoints proteins Aurora A/B, centrosomal pericentrin protein, chromosomal aberrations, and loss of Pot1a was observed. Thus, MIC impacts key proteins involved in cell cycle regulation to trigger genomic instability as a possible mechanism of developmental basis of liver carcinogenesis. PMID- 22223509 TI - Noble metal nanoparticles in DNA detection and delivery. AB - DNA-conjugated metal nanoparticles have attracted enormous attention for biological and medical applications, owing to their unusual DNA melting characteristics as well as unique optical and catalytic properties. The combination of these unique properties has not only led to the development of DNA detection technologies with remarkably high selectivity and sensitivity, but also to the development of gene therapeutic agents with high efficacy and efficiency. In this review, we present a comprehensive coverage on their applications in detecting, manipulating, and delivering genes. PMID- 22223510 TI - Insight into the interactions that control the phase behaviour of new aqueous biphasic systems composed of polyethylene glycol polymers and ionic liquids. AB - New polyethylene glycol (PEG)/ionic liquid aqueous biphasic systems (ABS) are presented. Distinct pairs of PEG polymers and ionic liquids can induce phase separation in aqueous media when dissolved at appropriate concentrations. Phase diagrams have been determined for a large array of systems at 298, 308 and 323 K. A comparison of the binodal curves allowed the analysis of the tunable structural features of the ionic liquid (i.e., anionic nature, cationic core, cationic alkyl side chain length and functionalisation, and number of alkyl substituents in the cation) and the influence of the molecular weight of the PEG polymer on the ability of these solutes to induce an ABS. It was observed that contrary to typical ABS based on ionic liquids and inorganic salts, in which the phase behaviour is dominated by the formation of the hydration complexes of the ions, the interactions between the PEG polymers and ionic liquids control the phase demixing in the polymer-type ABS studied herein. It is shown that both the ionic liquids and PEG polymers can act as the salting-out species; that is, it is an occurrence that is dependent on the structural features of the ionic liquid. For the first time, PEG/ionic liquid ABS are reported and insight into the major interactions that govern the polymer/ionic liquid phase behaviour in aqueous media are provided. The use of two different nonvolatile and tunable species (i.e., ionic liquids and PEG polymers) to form ABS allows the polarities of the phases to be tailored. Hence, the development of environmentally friendly separation processes that make use of these novel systems is envisaged. PMID- 22223511 TI - Intrapartum three-dimensional ultrasonographic imaging of face presentations: report of two cases. PMID- 22223513 TI - High gene expression of CXCL8 is associated with the presence of extraintestinal manifestations and long-term disease in patients with ulcerative colitis. PMID- 22223514 TI - Auger recombination suppression in nanocrystals with asymmetric electron-hole confinement. AB - Type II and quasi-type II nanocrystals with thick shells exhibit reduced blinking. However, after a number of monolayers, the influence of the shell thickness is found to vanish. Using a two-band Kane Hamiltonian, it is shown that this behavior is a consequence of interband coupling and asymmetric confinement of electrons and holes. Interface alloying provides an additional, order-of magnitude contribution to the Auger suppression, in agreement with recent experiments. The existence is predicted of critical shell thicknesses that strongly quench Auger processes for any core size. PMID- 22223515 TI - Regional expression of epithelial MDR1/P-glycoprotein in chronic rhinosinusitis with and without nasal polyposis. AB - BACKGROUND: P-glycoprotein (P-gp) is a 170-kDa transmembrane glycoprotein encoded by the MDR1 (ABCB1) gene and is constitutively expressed on lower airway epithelium. P-gp has been shown to function as an immunomodulator regulating efflux of T-helper 1/T-helper 2 (Th1/Th2) cytokines from its host cell; however, its association with sinonasal inflammation has not been described. The purpose of this study is to determine the pattern and degree of epithelial P-gp expression in chronic rhinosinusitis (CRS) with nasal polyposis (CRSwNP) or CRS without nasal polyposis (CRSsNP). METHODS: Institutional Review Board (IRB) approved study utilizing sinus, septal, and inferior turbinate mucosa in patients with no disease, CRS, and CRSwNP (n = 4 each). Quantitative fluorescent immunohistochemistry (Q-FIHC) was performed using an anti-P-gp antibody and a secondary fluorescein isothiocyanate (FITC)-conjugated Fc specific fragment. Protein expression was quantified by calculating the epithelial to nonspecific background intensity ratio (4 images/subsite). Scores less than 1 suggested negligible expression. Staining ratios between patient groups and subsites were compared using a 2-tailed Student t test. RESULTS: Among the sinus mucosa, P-gp expression in CRSwNP (1.570 +/- 0.354) was significantly greater than both CRS (1.224 +/- 0.248) and control (0.762 +/- 0.128) (p < 0.001, p = 0.002; respectively). CRS scores were significantly greater than control (p = 0.002). Among the septal mucosa, there was no significant difference between CRSwNP (0.914 +/- 0.264), CRS (1.126 +/- 0.476), or control (0.966 +/- 0.327). Among the inferior turbinate mucosa, there was no significant difference between CRSwNP (1.047 +/- 0.157), CRS (1.099 +/- 0.362), or control (0.824 +/- 0.181). CONCLUSION: MDR1/P-gp is overexpressed in the epithelial layer of sinus mucosa in patients with both CRSwNP and CRS relative to other sinonasal subsites. Expression in healthy mucosa is negligible. Given its known immunomodulatory function this suggests that P-gp may play a role in the pathogenesis or maintenance of chronic sinonasal inflammation. PMID- 22223517 TI - [Recent advances in epilepsy management]. PMID- 22223516 TI - Depressive symptoms during pregnancy and the concentration of fatty acids in breast milk. AB - The aim of the present study was to examine the association between depressive symptoms in pregnancy and the concentration of long-chain polyunsaturated fatty acids (LCPUFAs) in breast milk. Women (n = 287) enrolled in the Pregnancy, Infection, and Nutrition Study completed the Center for Epidemiologic Studies Depression Scale in pregnancy (< 20 and 24-29 weeks) and had LCPUFAs measured in breast milk (4 months postpartum). Multiple linear regression was used to examine associations between depressive symptoms and breast milk LCPUFAs. Increasing depressive symptoms at < 20 weeks were associated with lower docosahexaenoic acid concentrations (adjusted beta = -1.15, 95% confidence interval = -2.12, -0.19). No similar associations were observed with other fatty acids nor between symptoms at 24-29 weeks and LCPUFAs. Depressive symptoms, even in the subclinical range, early in pregnancy are inversely associated with breast milk docosahexaenoic acid. This may have implications for the timing of screening and interventions for perinatal depression and the nutritional value of breast milk. PMID- 22223518 TI - [A clinical feature and therapeutic strategy in pituitary adenomas associated with intracranial aneurysms]. AB - We studied the clinical feature and treatment strategy of pituitary adenomas associated with intracranial aneurysms. Among 102 pituitary adenoma patients (mean age: 54.8 years old) who received MR angiography and/or 3D-CT angiography, seven patients (6.9%) had intracranial aneurysms. The association of an aneurysm was more common in large size adenomas (p<0.05). According to the location of the aneurysms, five patients had these in the paraclinoid portion or cavernous portion of the internal carotid artery. Using MR images, we classified the aneurysms associated with pituitary adenomas as non-adjacent, adjacent, and intra adenoma types. In non-adjacent types, an aneurysm is located apart from the adenoma, and has less chance of exposure during transsphenoidal surgery. In adjacent types, an aneurysm is located adjacent to the adenoma, and could be exposed during transsphenoidal surgery. In intra-adenoma types, an aneurysm is encased in the adenoma. In non-adjacent type aneurysms, a resection of the pituitary adenoma can be carried out before aneurysm treatment due to the low risk of rupture during surgery. In adjacent types, a tumor resection can precede aneurysm treatment in cases of low rupture risk aneurysms and untreatable aneurysms. In intra-adenoma types, adenoma resection should come after treatment of the aneurysms. Neurosurgeons should be careful about not only the presence of aneurysms in preoperative images during transsphenoidal surgery planning, but also their locations and proximity to adenomas. Such information may be crucial in deciding the order of treatment. PMID- 22223519 TI - [Research of postoperative complications after coil protrusions in embolization of unruptured cerebral aneurysms]. AB - OBJECTIVES: Postoperative courses in "coil-protruded" cases in embolization of unruptured cerebral aneurysms remain unknown. The purpose of this study is to investigate postoperative complications after coil protrusions. METHODS: From May 2003 to December 2007, 90 consecutive cases with unruptured cerebral aneurysm treated by coil embolization were examined at National Cerebral and Cardiovascular Center. All patients received antiplatelet therapy prior to the procedure. The patterns of protrusions were classified into three; tail (T), loop (L), unraveled (U). RESULTS: Coil protrusions were observed in 17 cases (18.9%). Symptomatic ischemic complications occurred in 7 cases (7.8%). One case occurred in coil protrusions (group P) and 6 cases occurred in no coil protrusions (group N). Infarctions on MR diffusion-weighted image within 7 days after embolization were found in 10 cases (58.8%) in group P and in 28 cases (38.4%) in group N. Infarction on MR fluid attenuated inversion recovery 7 days or later were found in 0 in group P, and in 4 (5.5%) in group N. There were no significant differences. The number of each protrusion pattern was as follows: T was 12 cases, L was 3 cases and U was 2 cases. Symptomatic ischemia was observed in one case (8.3%) in T. Infarctions on MR diffusion-weighted image within 7 days after embolization were found in 7 (58.3%), 1 (33.3%) and 2 (100%), respectively. There were no significant differences between the three morphological patterns. CONCLUSION: In this retrospective study, coil protrusion after embolization of unruptured cerebral aneurysms on antiplatelet therapy, did not increase the incidence of ischemic complications. PMID- 22223520 TI - [A case of glomerulonephritis associated with ventriculo-atrial shunt]. AB - Nephritis associated with a chronically infected ventriculo-atrial (VA) or ventriculo-peritoneal (VP) shunt is known as shunt nephritis. A 60-year-old woman who had a VA shunt implanted for hydrocephalus began to show intermittent low grade fever of an unknown origin, as well as hypertension and lower leg edema. Laboratory findings showed renal insufficiency with proteinuria, and a percutaneous renal biopsy was performed. Light microscopy revealed findings of membranoproliferative glomerulonephritis. Shunt nephritis was suspected. The VA shunt was removed and the VP shunt was replaced subsequently. Signs of renal impairment were recovered after surgery. However, a new VA shunt was implanted because of a shunt malfunction. Shunt nephritis is a rare complication associated with shunt system implantation. It can be treated successfully by removing the shunt system immediately. It should be considered that shunts, especially VA shunts, always carry a risk of nephritis. PMID- 22223521 TI - [Long-standing overt ventriculomegaly in adults (LOVA) needing ventriculo peritoneal shunt with double programmable pressure valves]. AB - A 44-year-old man presented with symptomatic hydrocephalus due to aqueductal stenosis. Endoscopic third ventriculostomy was performed but proved ineffective, so ventriculo-peritoneal shunt using a programmable pressure valve (PPV) was carried out. Subdural hematoma appeared 5 weeks postoperatively and subsequently increased though the pressure setting was maximum. One more valve was implanted in the right chest wall and drainage of the hematoma was performed 2 months after the shunt operation. Adjustment of pressure was repeated. Findings of overdrainage and underdrainage were seen once each afterwards. We followed up the patient with the first valve set at 200 mm H2O and the second valve set at 60 mm H2O. Disturbance of memorization improved. The patient was in a stable condition 10 months after the final pressure settings. Flow volume changes were examined under conditions of various pressures in tandemly connected double programmable valves in vitro. When total pressure increased, flow showed a linear decrease that was not associated with the order of the pressure settings. This method of adding one more PPV was effective, and appears to be a useful choice for treating overdrainage. PMID- 22223522 TI - [Superficial temporal artery-middle cerebral artery anastomosis in a patient of temporal arteritis with internal carotid artery occlusion: a case report]. AB - Temporal arteritis is a rare systemic autoimmune disease and the arteritic process in this case of temporal arteritis involved large and medium-size arteries. Temporal arteritis with internal carotid artery (ICA) occlusion is very rare. We report a case of temporal arteritis with ICA occlusion following superficial temporal artery (STA) -middle cerebral artery (MCA) anastomosis, together with steroid therapy. A 73-year-old female presented with a headache, visual disturbance of left side, and suppression of activity. Left STA was inflammatory and overswelling. Magnetic resonance angiography (MRA) and angiography revealed occlusion of the left internal carotid artery (ICA) at the cervical portion and lowering of vascular reserve on PAO SPECT. Diagnosis as temporal arteritis was conclusive due to the clinical presentation, laboratory studies, and left temporal artery biopsy, so steroid pulse therapy was initiated. Inflammation of left STA disappeared after steroid therapy, but left ICA occlusion on angiography and lowering of vascular reserve on SPECT remained for 3 months afterwards. Because of this, STA-MCA anastomosis was performed. There were no complications after the operation and the donor artery has been patent for two years. Temporal arteritis with ICA occlusion that requires extracranial intracranial bypass (EC-IC bypass) is very rare. STA-MCA anastomosis with steroid therapy is effective for the prevention of cerebral infarction. PMID- 22223523 TI - [The Efficacy of CT angiography using the IVR-CT/angio system for surgical treatment of spinal hemangioblastoma]. AB - We performed 3D-CT angiography (3D-CTA) with contrast injection to a feeding artery through a selectively introduced catheter into the intercostal artery in a patient with spinal hemangioblastoma. It revealed a relative three-dimensional (3D) anatomy between a tumor body, feeding arteries, draining veins, and surrounding vertebrae with superior resolution to 3D-CTA with intravenous contrast injection. This observation was used for preoperative planning facilitating tumor removal, through reconstructed 3D fly-through animation providing intraoperative identification and obliteration of feeding arteries. This examination was carried out without difficulty by utilizing IVR-CT/angio system (IVR: interventional radiology) which combines angiographic and CT equipment with a single fluoroscopy table, because it does not require a room-to room transfer of the patient with the catheter left cannulated. DSA detection for any spinal lesions, neoplastic or vascular ones, is always better assisted by 3D CTA with the IVR-CT/angio system (IVR-CTA). PMID- 22223524 TI - [Usefulness of endovascular treatment for delayed massive epistaxis following endoscopic endonasal transsphenoidal surgery: a case report]. AB - We report here a case of massive nasal bleeding from the sphenopalatine artery three weeks after endonasal transsphenoidal surgery. This 66-year-old male suffered from massive nasal bleeding with the status of hypovolemic shock. Under general anesthesia, an emergent angiography revealed an extravasation from the sphenopalatine artery. Trans-arterial embolization using coil and n-butyl cyanoacrylate (NBCA) was performed following the diagnostic angiography. Complete occlusion of the injured artery was achieved. The patient showed good recovery from general anesthesia. Delayed nasal bleeding after endonasal transsphenoidal surgery is a rare but important complication. The sphenopalatine artery and its branch are located in the hidden inferior lateral corner of the sphenoid sinus and may be injured during enlargement of the sphenoid opening. When massive delayed nasal bleeding follows transsphenoidal surgery and damage of the internal carotid artery has been ruled out, endovascular treatment of the external carotid artery should be considered. PMID- 22223525 TI - [Ruptured giant thrombosed aneurysm at the internal carotid artery successfully treated with endovascular internal trapping following emergent balloon occlusion test: a case report]. AB - The authors report a case of ruptured giant thrombosed aneurysm successfully treated with endovascular internal trapping following emergent balloon occlusion test (BOT), and discuss its clinical implications regarding emergent BOT. A 41 year-old female showing massive epistaxis was referred to our institute for the treatment of a giant aneurysm. Computed tomography and digital subtraction angiography revealed a giant thrombosed aneurysm located at the petrous portion of the right internal carotid artery with an erosion of the petrous bone. Emergent BOT was performed under the monitoring of regional oxygen saturation of the brain (rSO2) and stump pressure as well as neurological changes and confirmed tolerance for permanent internal artery occlusion with a little change of rSO2 and stump pressure. Endovascular internal trapping was performed with detachable coils and the postoperative course was uneventful. Magnetic resonance imaging showed a decrease in the size of the aneurysm three month after the treatment, and the aneurysm got organized four years later. For ruptured aneurysms, emergent BOT is sometimes difficult to perform due the neurological deterioration or inability to prepare radioisotope for single photon computed tomography. Nevertheless, monitoring of rSO2 and stump pressure as well as neurological changes can be of help for decision making concerning the treatment strategy. Endovascular treatment following BOT is a feasible and life-saving approach for emergent management of ruptured internal carotid artery aneurysms presented with massive epistaxis. PMID- 22223526 TI - [Operative neurosurgery: personal view and historical backgrounds (9) Moyamoya angiopathy (MMA): past history and status presens]. AB - The second international meeting on the Moyamoya angiopathy (MMA) was held in mid. July 2011 at the children's hospital Zurich by Frau PD Dr.Khan and Prof.Meuli. On this occasion I was asked to give a survey of this disease, so the following points were presented and discussed: 1. Who was the person who discovered this disease. 2. How has the Research Committee of the Ministry of Health and Welfare, Japan (RCMHWJ) contributed to clarify the epidemiology, etiology, pathophysiology and treatments. 3. What is the current situation in foreign countries especially Euroamerican to date on these topics. 4. How the treatment technique developed and who did the initial revascularization procedures for the first. 5. Update of the disease. 1. Established view; discovery of the disease by Tekeuchi and Shimizu in 1955 could have been called somewhat into question as they described neither abnormal vasculature nor transdural anastomosis. Kudo who described "spontaneous occlusion of the circle of Willis" more precisely, but seemed to have thought that the occlusion site of the internal carotid artery (ICA) is around the origin of the ophthalmic artery. Suzuki and Takaku who coined the name Moyamoya disease (MMD) in 1969 and described 6 stages of progression on the basis of observation on 20 cases. 2. The RCMHWJ founded in 1977 has contributed to clarifying the epidemiology, pathophysiology, treatment and etiology by interdisciplinary cooperative study having some epoch making events especially; (1)by setting the guide lines diagnostic criteria of the disease at the end of 1970, (2)applying MRI and MRA at the beginning of 1990 for the diagnosis instead of angiography used until then. (3)By finding and focusing, therefore, on the cases of asymptomatic or oligosymptomatic presentation around the middle of 2000, which have almost doubled or tripled in incidence and/or prevalence and also changed the age distribution with the higher peak for adult cases. Achievements of research for the etiology and pathophysiology by genetics and molecular biology have enabled the discovery of basic FGF and other cytokines-angiogenetic factors and recently the genetic linkage site 17q25.3 in relation to the familiar incidence. Pathological studies verified by molecular biological methods have indicated that the vascular occluding process with intimal proliferation with thrombus formation does not occur only at the carotid fork originally researched intensively, but also at more distal parts of the cerebral arteries which could be verified with the help of molecular biology. 3. Occurrence but less incidence of the disease in the Euroamerican countries had already been noticed at the beginning of 1970 and its reason has been researched and discussed intensively in relation also to the etiology of the disease. 4. The first extracranial-intracranial (EC-IC) bypass surgery for a case of cerebral ischemia of the disease might have been carried out by Prof.Yasargil and Prof.Reichman independently around the end of 1972. The indirect revascularization methods such as EMS, EDAS are now combined with or without EC-IC bypass to augment cerebral blood flow (CBF) of the hemodynamically compromised territory not only of the MCA, but also of the ACA and PCA. The big disadvantage of indirect revascularization might be the large size of the craniotomy necessitated for the purpose, which would decrease CBF of the brain surface. The author is doing multiple bypass procedures (bilateral EC-IC bypass plus STA-ACA bypass) in one session in accordance with the findings of CBF examination with small craniotomies. Prevention of rebleeding by revascularization is still under study but its results should be scrutinized on the basis of various etiologies and sites of the bleeding. 5. Besides some increase of epidemiological knowledge of asymptomatic or oligosymptomatic cases and of etiological molecular biological and genetic linkage studies, clinically, the mechanism of contralateral ischemia in patients in whom one side is operated upon or/and hyperperfusion after revascularization and its prevention seems to be one of main topics in recent journals. PMID- 22223527 TI - Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) reduces cell survival, homing, and colonization in lung cancer bone metastasis. AB - PURPOSE: We investigated the role of the collagen-binding receptor discoidin domain receptor-1 (DDR1) in the initiation and development of bone metastasis. EXPERIMENTAL DESIGN: We conducted immunohistochemical analyses in a cohort of 83 lung cancer specimens and examined phosphorylation status in a panel of human lung cancer cell lines. Adhesion, chemotaxis, invasiveness, metalloproteolytic, osteoclastogenic, and apoptotic assays were conducted in DDR1-silenced cells. In vivo, metastatic osseous homing and colonization were assessed in a murine model of metastasis. RESULTS: DDR1 was expressed in a panel of human lung cancer cell lines, and high DDR1 levels in human lung tumors were associated with poor survival. Knockdown (shDDR1) cells displayed unaltered growth kinetics in vitro and in vivo. In contrast, shDDR1 cells showed reduced invasiveness in collagen matrices and increased apoptosis in basal conditions and induced apoptosis in vitro. More importantly, conditioned media of DDR1-knockdown cells decreased osteoclastogenic activity in vitro. Consequently, in a model of tumor metastasis to bone, lack of DDR1 showed decreased metastatic activity associated with reduced tumor burden and osteolytic lesions. These effects were consistent with a substantial reduction in the number of cells reaching the bone compartment. Moreover, intratibial injection of shDDR1 cells significantly decreased bone tumor burden, suggesting impaired colonization ability that was highly dependent on the bone microenvironment. CONCLUSIONS: Disruption of DDR1 hampers tumor cell survival, leading to impaired early tumor-bone engagement during skeletal homing. Furthermore, inhibition of DDR1 crucially alters bone colonization. We suggest that DDR1 represents a novel therapeutic target involved in bone metastasis. PMID- 22223529 TI - Results of a phase 1 study of AME-133v (LY2469298), an Fc-engineered humanized monoclonal anti-CD20 antibody, in FcgammaRIIIa-genotyped patients with previously treated follicular lymphoma. AB - PURPOSE: AME-133v is a humanized monoclonal antibody engineered to have increased affinity to CD20 and mediate antibody-dependent cell-mediated cytotoxicity (ADCC) better than rituximab. Safety, pharmacokinetics, and efficacy were assessed in a phase 1/2 trial in patients with previously treated follicular lymphoma (FL). PATIENTS AND METHODS: AME-133v was characterized in vitro by ADCC and cell binding assays. A phase 1 study was conducted in which 23 previously treated patients with FL were assigned sequentially to one of five dose-escalation cohorts of AME-133v at 2, 7.5, 30, 100, or 375 mg/m(2) weekly * 4 doses. RESULTS: AME-133v showed a 13- to 20-fold greater binding affinity for CD20 and was 5- to 7-fold more potent than rituximab in ADCC assays. Cell binding assays showed AME 133v and rituximab competed for an overlapping epitope on the CD20 antigen, and AME-133v inhibited binding of biotinylated rituximab to CD20 in a concentration dependent manner. AME-133v was well tolerated by patients and common related adverse events included chills and fatigue. One patient experienced a dose limiting toxicity of neutropenia. AME-133v showed nonlinear pharmocokinetics with properties similar to rituximab. Selective reduction of B cells during and after AME-133v treatment was shown by flow cytometry of peripheral blood. A partial or complete response was observed in 5 of 23 (22%) patients and the median progression-free survival was 25.4 weeks. CONCLUSIONS: AME-133v was safe and well tolerated at the doses tested. AME-133v showed encouraging results as an anti CD20 therapy in heavily pretreated FL patients with the less favorable FcgammaRIIIa F-carrier genotype. PMID- 22223528 TI - Phase I study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma. AB - PURPOSE: This phase I clinical trial was conducted to determine the safety, efficacy, and molecular effects of sorafenib with temsirolimus in patients with advanced melanoma. PATIENTS AND METHODS: Patients with stage IV or unresectable or recurrent stage III melanoma and Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. Sorafenib was given orally once or twice daily and temsirolimus was given i.v. weekly, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per Response Evaluation Criteria in Solid Tumors criteria. Consenting patients with accessible tumors underwent optional tumor biopsies before treatment and after the second infusion of temsirolimus. Tumor biopsies were analyzed for activating mutations in BRAF and NRAS, and for expression of P-extracellular signal-regulated kinase (P-ERK) and P-S6 proteins. RESULTS: A total of 25 patients were accrued to the study. The maximum tolerated doses were sorafenib 400 mg every morning and 200 mg every evening and temsirolimus 25 mg i.v. weekly. Dose-limiting toxicities included thrombocytopenia, hand-foot syndrome, serum transaminase elevation, and hypertriglyceridemia. There were no complete or partial responses with the combination; 10 patients achieved stabilization of disease as their best response. The median progression-free survival was 2.1 months. Matching pretreatment and day 15 tumor biopsies showed marked inhibition of P-S6 with treatment in 3 of 4 evaluable patients, but minimal inhibition of P-ERK. CONCLUSIONS: Combination therapy with sorafenib and temsirolimus resulted in significant toxicity at higher dose levels, failed to achieve any clinical responses in genetically unselected patient population, and did not inhibit P ERK. PMID- 22223531 TI - Formation of melamium adducts by pyrolysis of thiourea or melamine/NH4 Cl mixtures. AB - Pyrolysis of prominent precursor compounds for the synthesis of carbon nitride type materials (e.g., melamine, thiourea) have been studied in detail. Molecular adducts containing monoprotonated melamium C(6)N(11)H(10)(+) and melaminium HC(3)N(3)(NH(2))(3)(+) ions, respectively, have been identified as intermediates. The adduct C(6)N(11)H(10)Cl.0.5NH(4)Cl was obtained by the reaction of melamine C(3)N(3)(NH(2))(3) with NH(4)Cl at 450 degrees C. During the pyrolysis of thiourea, guanidinium thiocyanate was initially formed and subsequently the melamium thiocyanate melamine adduct C(6)N(11)H(10)SCN.2C(3)N(3)(NH(2))(3) was isolated at 300 degrees C. A second melaminium thiocyanate melamine adduct with the formula HC(3)N(3)(NH(2))(3)SCN.2C(3)N(3)(NH(2))(3) represents an intermediary reaction product that is best accessible at low pressures. The crystal structures of the compounds were solved by single-crystal XRD. Unequivocal proton localization at the C(6)N(11)H(10)(+) ion was established. A typical intramolecular and interannular hydrogen bridge and other characteristic hydrogen bonding motifs were identified. Additionally, the adducts were investigated by solid-state NMR spectroscopy. Our study provides detailed insight into the thermal condensation of thiourea by identifying and characterizing key intermediates involved in the condensation process leading to carbon nitride type materials. Furthermore, factors promoting the formation of melamium adduct phases over melem are discussed. PMID- 22223530 TI - Proximal tubular secretion of creatinine by organic cation transporter OCT2 in cancer patients. AB - PURPOSE: Knowledge of transporters responsible for the renal secretion of creatinine is key to a proper interpretation of serum creatinine and/or creatinine clearance as markers of renal function in cancer patients receiving chemotherapeutic agents. EXPERIMENTAL DESIGN: Creatinine transport was studied in transfected HEK293 cells in vitro and in wild-type mice and age-matched organic cation transporter 1 and 2-deficient [Oct1/2(-/-)] mice ex vivo and in vivo. Clinical pharmacogenetic and transport inhibition studies were done in two separate cohorts of cancer patients. RESULTS: Compared with wild-type mice, creatinine clearance was significantly impaired in Oct1/2(-/-) mice. Furthermore, creatinine inhibited organic cation transport in freshly isolated proximal tubules from wild-type mice and humans, but not in those from Oct1/2(-/-) mice. In a genetic association analysis (n = 590), several polymorphisms around the OCT2/SLC22A2 gene locus, including rs2504954 (P = 0.000873), were significantly associated with age-adjusted creatinine levels. Furthermore, in cancer patients (n = 68), the OCT2 substrate cisplatin caused an acute elevation of serum creatinine (P = 0.0083), consistent with inhibition of an elimination pathway. CONCLUSIONS: Collectively, this study shows that OCT2 plays a decisive role in the renal secretion of creatinine. This process can be inhibited by OCT2 substrates, which impair the usefulness of creatinine as a marker of renal function. PMID- 22223532 TI - Fetal thoracoamniotic shunting for large macrocystic congenital cystic adenomatoid malformations of the lung. AB - OBJECTIVE: To evaluate fetal thoracoamniotic shunting for isolated large macrocystic congenital cystic adenomatoid malformations (CCAM) of the lung. METHODS: This was a retrospective study of 11 fetuses with macrocystic CCAM who underwent thoracoamniotic shunting. This procedure was offered if fetal hydrops or signs of evolving hydrops (such as ascites or polyhydramnios) were present, or when there were very large lesions or lesions rapidly increasing in size. If there were multiple large cysts within the lesion, a single shunt was used, aiming to traverse several cysts. RESULTS: Shunts were inserted at a mean gestational age of 24.6 (range, 17-32) weeks. Marked mediastinal shift was present in all cases. Six fetuses were hydropic and, of the remaining five, one had severe polyhydramnios, three had lesions that were rapidly increasing in size and one had a very large lesion at initial presentation. In total, four cases had polyhydramnios. Shunting one cyst always decompressed the entire lesion and hydrops and/or polyhydramnios resolved in all surviving fetuses. One hydropic fetus that underwent the procedure at 17 weeks died 1 day later. The shunt dislodged in one case and the lesion did not re-expand. No mother went into labor or had ruptured membranes before 35.6 weeks. Mean gestational age at delivery was 38.2 weeks (n = 10). All pregnancies were delivered vaginally, with no maternal complications. All newborns had uneventful lobectomies, and pathology confirmed CCAM in all cases. CONCLUSION: Fetal thoracoamniotic shunting for large macrocystic CCAM is associated with favorable outcome in most cases, and should be considered in severe cases even before hydrops develops. PMID- 22223534 TI - Conjugated polymers for light-activated antifungal activity. AB - A cationic polythiophene-porphyrin (PTP) dyad is shown to exhibit efficient light activated antifungal activity. Higher singlet oxygen (1O2) generation efficiency can be attained from PTP upon photoexcitation due to the light-harvesting properties of the polymer backbone and efficient energy transfer from the polythiophene to the porphyrin units. PTP can be used for treating fungal infections in lower doses of irradiation light and polymer concentration. PMID- 22223535 TI - Concordance with guideline recommendations: previous and more recent nonsteroidal anti-inflammatory drug prescriptions in Quebec, Canada. AB - BACKGROUND: Clinical practice guidelines for appropriate nonsteroidal anti inflammatory drug (NSAID) utilisation focus on preventing NSAID-related gastrointestinal (GI), cardiovascular (CV), congestive heart failure (CHF) and renal adverse events. We compared concordance of NSAID prescriptions with clinical practice guideline recommendations in Quebec, pre and post rofecoxib withdrawal from market. METHODS: Data were obtained from the Quebec Health Insurance Agency (RAMQ). All prescriptions for celecoxib and traditional NSAIDs (tNSAIDs) dispensed to patients >=50 years of age were evaluated for concordance with clinical practice guidelines. Prescriptions were stratified by time period (pre and post rofecoxib withdrawal) and, GI, CV, CHF and renal risk factors at the dispensing date. Gastro-protective agent (GPA) co-prescriptions were also evaluated. RESULTS: We assessed 1,966,793 celecoxib and 1,743,481 tNSAIDs prescriptions. Of celecoxib prescriptions, 87.2% and 86.5% were appropriate in the post- and pre-periods, respectively, compared to 72.6% and 70.1% of tNSAIDs prescriptions, respectively. In logistic regression, 'appropriateness' of celecoxib prescriptions increased with age, rheumatoid arthritis and osteoarthritis (OA), and was higher in the post- versus pre-period (odds ratio 1.22, 95% confidence interval 1.18-1.26); it was lower in women and in patients with higher income. 'Appropriateness' of tNSAID prescriptions decreased in the post-period (0.92, 0.89-0.95), was lower in older persons and those with OA, and higher in women and in higher income patients. Of tNSAID prescriptions that should have received a GPA co-prescription, only 45.6% did. CONCLUSION: Concordance with guideline recommendations increased for celecoxib and decreased for tNSAIDs after rofecoxib withdrawal; GPA co-prescription with tNSAIDs remained suboptimal. PMID- 22223533 TI - Heligmosomoides polygyrus abrogates antigen-specific gut injury in a murine model of inflammatory bowel disease. AB - BACKGROUND: Developing countries have a low incidence of inflammatory bowel disease (IBD), perhaps prevented by the high prevalence of helminth infections and other alterations in intestinal flora and fauna. Helminth infections prevent colitis in various murine models of IBD. IBD may be driven by an aberrant immune response to luminal antigen(s). METHODS: We developed a murine model of IBD in which gut injury was induced by a specific antigen to better simulate the IBD disease process and to determine if helminth infections could abolish gut injury induced by an orally administered antigen. The model features pan-enterocolitis triggered by feeding ovalbumin (OVA). RESULTS: The intestinal inflammation is antigen-specific and generates interleukin (IL)-17 and interferon-gamma (IFN gamma), but not IL-4. Full expression of the disease required T cells with defective capacity to make IL-10 and treatment with a noninjurious, low dose of a nonsteroidal antiinflammatory drug. Exposure to Heligmosomoides polygyrus abrogated this antigen-induced gut injury. H. polygyrus colonization induced Foxp3(+) T regulatory cells (Tregs) and mucosal production of IL-10 from non-T cells. Lamina propria mononuclear cells from H. polygyrus-infected mice released less IL-17 and IFN-gamma constitutively and when stimulated with OVA or anti CD3/CD28 monoclonal antibodies. CONCLUSIONS: We developed a murine IBD model featuring antigen-specific enterocolitis and demonstrate for the first time that gut inflammation induced by an antigen could be abrogated by H. polygyrus infection. Protection was associated with suppressed IL-17 and IFN-gamma production, induction of Foxp3(+) Tregs, and elevated secretion of non-T-cell derived IL-10, all of which could be part of the protective processes. PMID- 22223536 TI - Endoscopic resection of an anterior skull-base Schwannoma. AB - Sinonasal Schwannomas represent less than 4% of all head and neck Schwannomas. These neural sheath tumors arise from the ophthalmic and maxillary divisions of the trigeminal nerve, as well as autonomic nerves from sympathetic fibers of the carotid plexus and parasympathetic fibers of the sphenopalatine ganglion. Patients commonly present with nonspecific symptoms such as nasal obstruction, epistaxis, and anosmia. Nasal endoscopy usually reveals a unilateral polypoid mass. Diagnostic imaging with computed tomography (CT) and magnetic resonance (MR) is typically nonspecific. Diagnosis may be delayed due to the masquerade of common sinonasal conditions, such as allergic rhinitis and chronic rhinosinusitis. We report a case involving a 51-year-old male with an anterior skull-base Schwannoma that was excised endoscopically. Clinical features, imaging characteristics, histopathology, and treatment of sinonasal Schwannomas are discussed. PMID- 22223538 TI - To the Editors of IUBMB Life: Correspondence concerning an alleged erratum in a review on the genetic code. PMID- 22223537 TI - 15-Deoxyspergualin hinders physical interaction between basic residues of transit peptide in PfENR and Hsp70-1. AB - The apicoplast of Plasmodium harbors several metabolic pathways. The enzymes required to perform these reactions are all nuclearly encoded and apicoplast targeted (NEAT) proteins. Plasmodium falciparum Enoyl-ACP Reductase (PfENR) is one such NEAT protein. The NEAT proteins have a transit peptide which is required for crossing the membranes of apicoplast. We studied the importance of basic residues like Arginine and Lysine within the transit peptide. Previous studies have suggested that all basic residues are essential for apicoplast trafficking. In this study, we demonstrate that only some of these residues are essential (K44, R48, K51, and R52), whereas others are dispensable (R40, K42, and K49). On mutating these specific residues, PfENR is not imported into the apicoplast and is mislocalized to the cytoplasm. We also demonstrate that these residues are also crucial for interaction with Hsp70-1, implying that interactions of Lysine 44, Arginine 48, Lysine 51, and Arginine 52 of the transit peptide with PfHsp70-1 are required for apicoplast trafficking. 15-Deoxyspergualin, which has earlier been proposed to interact with EEVD motif of PfHsp70-1 hinders the physical interaction between these cationic residues of PfENR and Hsp70-1. Hence, we propose that in the transport competent state of NEAT proteins some specific positively charged amino acids in the transit peptide interact with PfHsp70-1, and this interaction is essential for apicoplast targeting. PMID- 22223540 TI - Reaction of a 6-dimethylaminopentafulvene with the Mes2PCH2CH2B(C6F5)2 frustrated Lewis pair. AB - The frustrated Lewis pair Mes(2)PCH(2)CH(2)B(C(6)F(5))(2) reacts readily with 6 dimethylamino-6-methylfulvene at room temperature to yield the trans-1 [B(C(6)F(5))(2)]-2-[CH(2)CH(2)PMes(2)] disubstituted fulvene derivative 9 that features an internal N-B contact. Thermolysis (80 degrees C in toluene) results in a complete isomerization to the respective 1-[B(C(6)F(5))(2)]-3 [CH(2)CH(2)PMes(2)] isomer 10. Both compounds were characterized by using X-ray diffraction. A reaction scheme is formulated to rationalize the specific formation of these compounds, involving a retro-hydroboration/hydroboration sequence. The reaction of the 6-dimethylaminofulvene with HB(C(6)F(5))(2) yielded the corresponding parent compound 13 that was also characterized by X-ray diffraction. PMID- 22223543 TI - Value of three-dimensional hysterosalpingo-contrast sonography with SonoVue in the assessment of tubal patency. AB - OBJECTIVE: To investigate the accuracy of transvaginal three-dimensional hysterosalpingo-contrast sonography using SonoVue (3D SonoVue-HyCoSy) in the assessment of Fallopian tubal patency. METHODS: We recruited 75 infertile patients undergoing 3D SonoVue-HyCoSy before standard diagnostic laparoscopy with chromotubation (lap and dye). Tubal patency was assessed by automated 3D coded contrast imaging (3D SonoVue-HyCoSy), and the findings were compared with the results of lap and dye. RESULTS: For detecting tubal patency among the 150 Fallopian tubes assessed, 3D SonoVue-HyCoSy had a sensitivity of 93.5%, specificity of 86.3%, positive and negative predictive values of 87.8% and 92.6%, respectively, and diagnostic accuracy of 90.0%. The test-positive rates of 3D SonoVue-HyCoSy vs lap and dye were not significantly different (82/150 vs 77/150, P > 0.05). CONCLUSION: 3D SonoVue-HyCoSy should be considered clinically valuable as a practical, non-invasive, primary investigatory tool for evaluating tubal patency. PMID- 22223545 TI - Optical identification of single- and few-layer MoS2 sheets. AB - A simple approach is developed to identify the layer number of 2D MoS2 sheets. By using an optical imaging method combined with image analysis software, a high contrast image of the MoS2 sheets can be extracted from the red (R) channel of the color optical microscopy image. The value of the intensity difference in the grayscale image of the R channel between MoS2 sheets (1-3 layers) and the SiO2 substrate can be used to identify the layer number of the sheet. PMID- 22223546 TI - Screening for CGG repeat expansion in the FMR1 gene by melting curve analysis of combined 5' and 3' direct triplet-primed PCRs. AB - BACKGROUND: CGG repeat expansions in the FMR1 (fragile X mental retardation 1) gene are associated with fragile X syndrome, fragile X-associated tremor/ataxia syndrome, and fragile X-associated primary ovarian insufficiency. We evaluated the use of melting curve analysis (MCA) of triplet-primed PCR (TP-PCR) assays as a rapid screening tool for the positive identification of expanded FMR1 alleles in men and women. METHODS: Both 5'- and 3'-weighted direct TP-PCRs (dTP-PCRs) were evaluated on 29 cell line-derived DNA samples and 44 blinded clinical samples. The presence of expansions was identified by the melting curve profiles generated automatically through MCA on the LightCycler 480 Real-Time PCR System. All samples were also analyzed by capillary electrophoresis to confirm the identities of the PCR fragments that gave rise to the observed melt peak profiles. RESULTS: The presence of expanded alleles in samples from both males and females produced melt peak profiles that were distinct from those of individuals with the normal allelic form. In the blinded test, positive and negative calls for the presence of an expanded allele corroborated with previously determined genotype classifications for all samples. CONCLUSIONS: The approach of dTP-PCR plus MCA offers a single-step strategy with high diagnostic sensitivity and specificity for rapid screening detection of FMR1 CGG repeat expansions, regardless of sex. The combined use of 5'- and 3'-weighted dTP-PCR assays minimizes the incidence of false-negative results arising from repeat flanking deletions. PMID- 22223542 TI - Implications of protein post-translational modifications in IBD. AB - In recent years our understanding of the pathogenesis of inflammatory bowel disease (IBD) has greatly increased. Hallmarks of IBD include loss of intestinal barrier function, increased cytokine production, and failed resolution of tissue damage. Lasting treatments are still lacking and, therefore, a better understanding of the underlying molecular mechanisms is necessary to design novel therapeutic approaches. Apart from transcriptional and posttranscriptional regulation of relevant genes, mammals have evolved a complex and efficient series of mechanisms to rapidly modify newly made proteins for the purposes of signaling and adaptation. These posttranslational protein modifications include, among others, phosphorylation, hydroxylation, neddylation, and cytokine cleavage by the inflammasome. This review focuses on our current understanding of posttranslational protein modifications with a particular focus on their relevance to IBD pathogenesis. PMID- 22223544 TI - An event-based approach for comparing the performance of methods for prospective medical product monitoring. AB - BACKGROUND: Prospective medical product monitoring is intended to alert stakeholders about whether and when safety problems are identifiable in longitudinal electronic healthcare data. Little attention has been given to how to compare methods in this setting. PURPOSE: To explore aspects of prospective monitoring that should be considered when comparing method performance and to develop a metric that explicitly accounts for these considerations. METHODS: We reviewed existing metrics and propose an event-based approach that classifies exposed outcomes according to whether a prior alert was generated. RESULTS: In comparing performance of methods for prospective monitoring, three factors must be considered: (1) accuracy in alerting; (2) timeliness of alerting; and (3) the trade-offs between the costs of false negative and false positive alerting. Traditional scenario-based measures of accuracy, such as sensitivity and specificity, which classify only at the end of monitoring, fail to appreciate timeliness of alerting and impose fixed tradeoffs between false positive versus false negative consequences. We provide an expression that summarizes event-based sensitivity (the proportion of exposed events that occur after alerting among all exposed events in scenarios with true safety issues) and event-based specificity (the proportion of exposed events that occur in the absence of alerting among all exposed events in scenarios with no true safety issues) by taking an average weighted by relative costs of false positive and false negative alerting. CONCLUSIONS: The proposed approach explicitly accounts for accuracy in alerting, timeliness in alerting, and the trade-offs between the costs of false negative and false positive alerting. PMID- 22223547 TI - Effects of activating transcription factor 4 deficiency on carbohydrate and lipid metabolism in mammals. AB - It has been shown that the mammalian activating transcription factor 4 (ATF4) is involved in many different physiological events, such as eye development, stress response, learning, and memory. However, several recent studies have demonstrated that ATF4 also plays an important role in the regulation of lipid and glucose metabolism, energy homeostasis, insulin secretion, and sensitivity, suggesting that ATF4 is a master regulator of metabolism. This review summarizes the most recent progress in the understanding of the novel roles of ATF4 in the regulation of metabolism. PMID- 22223548 TI - New Cu-based catalysts supported on TiO2 films for Ullmann S(N)Ar-type C-O coupling reactions. AB - New routes for the preparation of highly active TiO(2)-supported Cu and CuZn catalysts have been developed for C-O coupling reactions. Slurries of a titania precursor were dip-coated onto glass beads to obtain either structured mesoporous or non-porous titania thin films. The Cu and CuZn nanoparticles, synthesized using a reduction by solvent method, were deposited onto calcined films to obtain a Cu loading of 2 wt%. The catalysts were characterized by inductively coupled plasma (ICP) spectroscopy, temperature-programmed oxidation/reduction (TPO/TPR) techniques, (63)Cu nuclear magnetic resonance (NMR) spectroscopy, X-ray diffraction (XRD), scanning and transmission electron microscopy (S/TEM-EDX) and X-ray photo-electron spectroscopy (XPS). The activity and stability of the catalysts obtained have been studied in the C-O Ullmann coupling of 4 chloropyridine and potassium phenolate. The titania-supported nanoparticles retained catalyst activity for up to 12 h. However, catalyst deactivation was observed for longer operation times due to oxidation of the Cu nanoparticles. The oxidation rate could be significantly reduced over the CuZn/TiO(2) catalytic films due to the presence of Zn. The 4-phenoxypyridine yield was 64% on the Cu/nonporous TiO(2) at 120 degrees C. The highest product yield of 84% was obtained on the Cu/mesoporous TiO(2) at 140 degrees C, corresponding to an initial reaction rate of 104 mmol g(cat) (-1) s(-1). The activation energy on the Cu/mesoporous TiO(2) catalyst was found to be (144+/-5) kJ mol(-1), which is close to the value obtained for the reaction over unsupported CuZn nanoparticles (123+/-3 kJ mol(-1)) and almost twice the value observed over the catalysts deposited onto the non-porous TiO(2) support (75+/-2 kJ mol(-1)). PMID- 22223549 TI - Interreader agreement in determining monosodium urate deposition using musculoskeletal ultrasound: comment on the article by Howard et al. PMID- 22223550 TI - Growth and ordering of Ni(II) diphenylporphyrin monolayers on Ag(111) and Ag/Si(111) studied by STM and LEED. AB - The room temperature self-assembly and ordering of (5,15 diphenylporphyrinato)nickel(II) (NiDPP) on the Ag(111) and Ag/Si(111)-(?3 * ?3)R30 degrees surfaces have been investigated using scanning tunnelling microscopy and low-energy electron diffraction. The self-assembled structures and lattice parameters of the NiDPP monolayer are shown to be extremely dependent on the reactivity of the substrate, and probable molecular binding sites are proposed. The NiDPP overlayer on Ag(111) grows from the substrate step edges, which results in a single-domain structure. This close-packed structure has an oblique unit cell and consists of molecular rows. The molecules in adjacent rows are rotated by approximately 17 degrees with respect to each other. In turn, the NiDPP molecules form three equivalent domains on the Ag/Si(111)-(?3 * ?3)R30 degrees surface, which follow the three-fold symmetry of the substrate. The molecules adopt one of three equivalent orientations on the surface, acting as nucleation sites for these domains, due to the stronger molecule-substrate interaction compared to the case of the Ag(111). The results are explained in terms of the substrate reactivity and the lattice mismatch between the substrate and the molecular overlayer. PMID- 22223551 TI - Reflex contraction of the levator ani in women symptomatic for pelvic floor disorders. AB - OBJECTIVE: Stress urinary incontinence (SUI) is a common health problem in women. Reflex activation of muscular pelvic floor structures may play a role in preserving continence. In this study we aimed to analyze reflex pelvic floor activity on coughing in women seen for urodynamic testing. METHODS: In a retrospective cohort study we analyzed the data sets of 191 women who attended a tertiary referral service for multichannel urodynamic testing and four dimensional pelvic floor ultrasound scan between May 2009 and February 2010. Coughs were registered on volume ultrasound at a minimum of 16 Hz and analyzed by postprocessing at a later date, the operator being blinded against all clinical data. RESULTS: Of 175 analyzable cough volume datasets, a levator reflex was seen in 138 (79%), and clitoral reflex movement in 160 (91%). On multivariable analysis there was a significant relationship between urodynamic stress incontinence (USI) and the absence of a levator reflex (P = 0.045), and a negative relationship with the magnitude of such a reflex (P = 0.046). Reflex timing was not associated with SUI or USI. CONCLUSION: Reflex contraction of the levator ani can be observed on translabial ultrasound during sudden increases in intra-abdominal pressure. These reflex contractions are common, even in women with symptoms and signs of pelvic floor dysfunction. The observation of a levator reflex on coughing, and its magnitude, show a weak inverse association with the presence of USI. PMID- 22223552 TI - Importance of nanoparticle size in colorimetric and SERS-based multimodal trace detection of Ni(II) ions with functional gold nanoparticles. AB - Colorimetric detection of analytes using gold nanoparticles along with surface enhanced Raman spectroscopy (SERS) are areas of intense research activity since they both offer sensing of very low concentrations of target species. Multimodal detection promotes the simultaneous detection of a sample by a combination of different techniques; consequently, surface chemistry design in the development of multimodal nanosensors is important for rapid and sensitive evaluation of the analytes by diverse analytical methods. Herein it is shown that nanoparticle size plays an important role in the design of functional nanoparticles for colorimetric and SERS-based sensing applications, allowing controlled nanoparticle assembly and tunable sensor response. The design and preparation of robust nanoparticle systems and their assembly is reported for trace detection of Ni(II) ions as a model system in an aqueous solution. The combination of covalently attached nitrilotriacetic acid moieties along with the L-carnosine dipeptide on the nanoparticle surface represents a highly sensitive platform for rapid and selective detection of Ni(II) ions. This systematic study demonstrates that significantly lower detection limits can be achieved by finely tuning the assembly of gold nanoparticles of different core sizes. The results clearly demonstrate the feasibility and usefulness of a multimodal approach. PMID- 22223553 TI - Regional variations in medical spending and utilization: a longitudinal analysis of US Medicare population. AB - One of the perceived symptoms of US Medicare inefficiency is the existence of the dramatic variation in spending and utilization in different areas of the country. This study uses the Continuous Medicare History Sample, a large longitudinal 5% sample of all Medicare beneficiaries from 1974 to 2003, to study the issue. We show that the spending and utilization disparities are significant at the aggregate state level. More importantly, the variation shows signs of narrowing over time, particularly in the earlier years of the sample period and in some cases following major reforms. However, it remains significant even after an array of demographic, demand and supply side factors are controlled for. PMID- 22223554 TI - Public and private health-care financing with alternate public rationing rules. AB - We develop a model to analyze parallel public and private health-care financing under two alternative public sector rationing rules: needs-based rationing and random rationing. Individuals vary in income and severity of illness. There is a limited supply of health-care resources used to treat individuals, causing some individuals to go untreated. Insurers (both public and private) must bid to obtain the necessary health-care resources to treat their beneficiaries. Given individuals' willingnesses-to-pay for private insurance are increasing in income, the introduction of private insurance diverts treatment from relatively poor to relatively rich individuals. Further, the impact of introducing parallel private insurance depends on the rationing mechanism in the public sector. We show that the private health insurance market is smaller when the public sector rations according to need than when allocation is random. PMID- 22223555 TI - Scope insensitivity in contingent valuation studies of health care services: should we ask twice? AB - The main purpose of the present study was to test for outcome scope insensitivity. Respondents were initially asked to value one of two severe health states by way of a time-trade-off (TTO) exercise. Subsequent to the TTO exercise all respondents were asked to value an intervention, which offered a reduction in risk of falling into the health state they had evaluated. All respondents were subsequent to this initial CV exercise asked to value the same risk reduction, but in this case the outcome was death. Although our study passes the internal scope test, there is not a high degree of sensitivity to outcome. As many as 68% of respondents stated an identical maximum WTP in first and second CV valuation exercise implying that they value the interventions equally despite the fact that the health state presented in the initial CV question was deemed far better than death according to the TTO responses given by the same respondents. In contrast, the external scope test (comparison of response to initial CV across study arms) fared much better. PMID- 22223556 TI - A modified measure of health care disparities applied to birth weight disparities and subsequent mortality. AB - We describe how a modified Gini index serves as an improved method of estimating health care disparities. The method, although general, is applied to an example of birth weight disparities and to their effect on subsequent mortality. The method provides the between-group results obtainable from current methods (i.e. how Hispanics generally fare relative to non-Hispanic Whites) but adds measures of within-group disparities (i.e. which specific Hispanics experience the greatest disparate treatment). Our application to birth weights and receipt of prenatal care, which may provide an upper bound because of omitted variables, shows that the time-of-birth disparities are associated with increased infant mortality within the first year of life. PMID- 22223557 TI - Inheritances, health and death. AB - We examine how wealth shocks, in the form of inheritances, affect the mortality rates, health status and health behaviors of older adults, using data from eight waves of the Health and Retirement Survey. Our main finding is that bequests do not have substantial effects on health, although improvements in quality-of-life are possible. This absence occurs despite increases in out-of-pocket spending on healthcare and in the utilization of medical services, especially discretionary and non-lifesaving types such as dental care. Nor can we find a convincing indication of changes in lifestyles that offset the benefits of increased medical care. Inheritances are associated with higher alcohol consumption, but with no change in smoking or exercise and a possible decrease in obesity. PMID- 22223558 TI - Discrete choice experiments in health economics: a review of the literature. AB - Discrete choice experiments (DCEs) have become a commonly used instrument in health economics. This paper updates a review of published papers between 1990 and 2000 for the years 2001-2008. Based on this previous review, and a number of other key review papers, focus is given to three issues: experimental design; estimation procedures; and validity of responses. Consideration is also given to how DCEs are applied and reported. We identified 114 DCEs, covering a wide range of policy questions. Applications took place in a broader range of health-care systems, and there has been a move to incorporating fewer attributes, more choices and interview-based surveys. There has also been a shift towards statistically more efficient designs and flexible econometric models. The reporting of monetary values continues to be popular, the use of utility scores has not gained popularity, and there has been an increasing use of odds ratios and probabilities. The latter are likely to be useful at the policy level to investigate take-up and acceptability of new interventions. Incorporation of interactions terms in the design and analysis of DCEs, explanations of risk, tests of external validity and incorporation of DCE results into a decision making framework remain important areas for future research. PMID- 22223559 TI - Labor adjustment in the Japanese health care industry: some empirical evidence. AB - This paper examines the labor adjustment costs in the health care industry. Using Japanese data, we find that the cost of hiring new health care workers is the largest component of labor adjustment costs in the health care industry. Hence, it is difficult for employers in this industry to immediately increase the number of workers since this employment adjustment is extremely expensive. PMID- 22223560 TI - Socioeconomic status and health outcomes in a developing country. AB - Although the relationship between socioeconomic status (SES) and health is well documented for developed countries, less evidence has been presented for developing countries. The aim of this paper is to analyse this relationship at the household level for Fiji, a developing country in the South Pacific, using original household survey data. To allow for the endogeneity of SES status in the household health production function, we utilize a simultaneous equation approach where estimates are achieved by full information maximum likelihood. By restricting our sample to one, relatively small island, and including area and district hospital effects, physical geography effects are unpacked from income effects. We measure SES, as permanent income which is constructed using principal components analysis. An alternative specification considers transitory household income. We find that a 1% increase in wealth (our measure of permanent income) would lead to a 15% decrease in the probability of an incapacitating illness occurring intra-household. Although the presence of a strong relationship indicates that relatively small improvements in SES status can significantly improve health at the household level, it is argued that the design of appropriate policy would also require an understanding of the various mechanisms through which the relationship operates. PMID- 22223561 TI - Missing data in trial-based cost-effectiveness analysis: the current state of play. AB - Randomised controlled trial (RCT)-based cost-effectiveness analyses, which are prone to missing data, are increasingly used in healthcare technology assessment. This has highlighted the need for appropriate methodological approaches to the handling of missing data. This paper reviews missing data methodology used in RCT based cost-effectiveness analyses since 2003. Complete case analysis, which may lead to inappropriate conclusions, is still the most popular approach and its use has increased with time. The degree of missing data in cost-effectiveness analyses was often poorly reported and the methodology was often unclear. Reporting of missing data sensitivity analyses would improve article transparency. PMID- 22223562 TI - Social capital and self-rated health in Argentina. AB - The potential link between social capital and health suggests important pathways by which health may be improved. We examine this relationship using a unique data set from Argentina. This national survey allows us to determine whether the relationships between social capital and health that have been found in the US and Europe also apply to countries in South America (Argentina is the second largest country in South America with a population of approximately 40 million). We estimate a causal effect of individual-level social capital on health using a measure of informal social interactions as our measure of social capital. Using information about access to public transportation as instrumental variables, we find that both men and women with higher levels of social capital report better health. PMID- 22223563 TI - Synthesis and luminescence properties of lanthanide complexes with a new tripodal ligand featuring N-thenylsalicylamide arms. AB - To explore the relationship between the structure of the ligands and the luminescent properties of the lanthanide complexes, luminescent lanthanide complexes of a new tripodal ligand, featuring N-thenylsalicylamide arms, were synthesized and characterized by elemental analysis, IR and TGA measurements. Photophysical properties of the complexes were studied by means of UV - visible absorption and steady-state luminescence spectroscopy. The results of UV - vis spectra indicate that metal binding does not disturb the electronic structure of the ligand. Excited-state luminescence lifetimes and quantum yields of the complexes were determined. The photoluminescence analysis suggested that there is an efficient ligand - Ln(III) energy transfer for the Tb(III) complex, and the ligand is an efficient 'antenna' for Tb(III). From a more general perspective, the results demonstrated the potential application of the lanthanide complex as luminescent materials in material chemistry. PMID- 22223564 TI - Spin polarization and magnetoresistance through a ferromagnetic barrier in bilayer graphene. AB - We study spin dependent transport through a magnetic bilayer graphene nanojunction configured as a two-dimensional normal/ferromagnetic/normal structure where the gate voltage is applied on the layers of ferromagnetic graphene. Based on the four-band Hamiltonian, conductance is calculated by using the Landauer-Buttiker formula at zero temperature. For a parallel configuration of the ferromagnetic layers of bilayer graphene, the energy band structure is metallic and spin polarization reaches its maximum value close to the resonant states, while for an antiparallel configuration the nanojunction behaves as a semiconductor and there is no spin filtering. As a result, a huge magnetoresistance is achievable by altering the configurations of ferromagnetic graphene around the band gap. PMID- 22223566 TI - Fecal calprotectin concentration predicts outcome in inflammatory bowel disease after induction therapy with TNFalpha blocking agents. AB - BACKGROUND: Fecal calprotectin (FC) concentration is a useful surrogate marker for mucosal healing (MH) during tumor necrosis factor alpha (TNFalpha)-blocking therapy for inflammatory bowel disease (IBD). Our aim was to evaluate whether a normal FC after induction therapy with TNFalpha antagonist predicts the outcome of IBD patients during maintenance therapy. METHODS: Sixty IBD patients (34 Crohn's disease [CD], 26 ulcerative colitis [UC]), treated with TNFalpha antagonists, either infliximab (n = 42) or adalimumab (n = 18), and having a documented FC level at baseline and after induction therapy were included. Disease activity was evaluated by partial Mayo score without endoscopy or Harvey Bradshaw index at baseline, after induction, and at 12 months during maintenance therapy. RESULTS: After induction, FC was normalized (<= 100 MUg/g) in 31 patients (52%, median 42 MUg/g, range 0-97), whereas the level remained elevated in 29 patients (48%, median 424 MUg/g, range 116-5859). At ~12 months, 26/31 (84%, 18 CD, 8 UC) of the patients with normal FC after induction were in clinical remission, whereas only 11/29 (38%, 9 CD, 2 UC) of those with an elevated (>= 100 MUg/g) postinduction FC were in clinical remission, P < 0.0001. After induction therapy with TNFalpha antagonists, a cutoff concentration of 139 MUg/g for FC had a sensitivity of 72% and a specificity of 80% to predict a risk of clinically active disease after 1 year. CONCLUSIONS: A normal FC after induction therapy with TNFalpha antagonists predicts sustained clinical remission in the majority of patients on scheduled therapy with active luminal disease. PMID- 22223567 TI - Administration of high doses of copper to capuchin monkeys does not cause liver damage but induces transcriptional activation of hepatic proliferative responses. AB - Liver cells respond to copper loading upregulating protective mechanisms. However, to date, except for liver content, there are no good indicators that identify individuals with excess liver copper. We hypothesized that administering high doses of copper to young (5.5 mg Cu . kg-1 . d-1) and adult (7.5 mg Cu . kg 1 . d-1) capuchin monkeys would induce detectable liver damage. Study groups included adult monkeys (2 females, 2 males) 3-3.5 y old at enrollment treated with copper for 36 mo (ACu); age-matched controls (1 female, 3 males) that did not receive additional copper (AC); young monkeys (2 female, 2 males) treated from birth with copper for 36 mo (YCu); and young age-matched controls (2 female, 2 males) that did not receive additional copper (YC). We periodically assessed clinical, blood biochemical, and liver histological indicators and at 36 mo the hepatic mRNA abundance of MT2a, APP, DMT1, CTR1, HGF, TGFbeta, and NFkappaBeta only in adult monkeys. After 36 mo, the liver copper concentration was 4-5 times greater in treated monkeys relative to controls. All monkeys remained healthy with normal routine serum biochemical indices and there was no evidence of liver tissue damage. Relative mRNA abundance of HGF, TGFbeta and NFkappaB was significantly greater in ACu than in AC monkeys. In conclusion, capuchin monkeys exposed to copper at doses up to 50 times the current upper level enhanced expression of genes related to inflammation and injury without clinical, blood biochemical, or histological evidence of liver damage. PMID- 22223568 TI - Factors associated with sugar-sweetened beverage intake among United States high school students. AB - This cross-sectional study examined associations of demographic characteristics, weight status, availability of school vending machines, and behavioral factors with sugar-sweetened beverage (SSB) intake, both overall and by type of SSB, among a nationally representative sample of high school students. The 2010 National Youth Physical Activity and Nutrition Study data for 11,209 students (grades 9-12) were used. SSB intake was based on intake of 4 nondiet beverages [soda, other (i.e., fruit-flavored drinks, sweetened coffee/tea drinks, or flavored milk), sports drinks, and energy drinks]. Nationwide, 64.9% of high school students drank SSB >=1 time/d, 35.6% drank SSB >=2 times/d, and 22.2% drank SSB >=3 times/d. The most commonly consumed SSB was regular soda. Factors associated with a greater odds for high SSB intake (>=3 times/d) were male gender [OR = 1.66 (95% CI = 1.41,1.95); P < 0.05], being non-Hispanic black [OR = 1.87 (95% CI = 1.52, 2.29); P < 0.05], eating at fast-food restaurants 1-2 d/wk or eating there >=3 d/wk [OR = 1.25 (95% CI = 1.05, 1.50); P < 0.05 and OR = 2.94 (95% CI = 2.31, 3.75); P < 0.05, respectively] and watching television >2 h/d [OR = 1.70 (95% CI = 1.44, 2.01); P < 0.05]. Non-Hispanic other/multiracial [OR = 0.67 (95% CI = 0.47, 0.95); P < 0.05] and being physically active >=60 min/d on <5 d/wk were associated with a lower odds for high SSB intake [OR = 0.85 (95% CI = 0.76, 0.95); P < 0.05]. Weight status was not associated with SSB intake. Differences in predictors by type of SSB were small. Our findings of significant associations of high SSB intake with frequent fast-food restaurant use and sedentary behaviors may be used to tailor intervention efforts to reduce SSB intake among high-risk populations. PMID- 22223569 TI - The glycemic response does not reflect the in vivo starch digestibility of fiber rich wheat products in healthy men. AB - Starchy food products differ in the rate of starch digestion, which can affect their metabolic impact. In this study, we examined how the in vivo starch digestibility is reflected by the glycemic response, because this response is often used to predict starch digestibility. Ten healthy male volunteers [age 21 +/- 0.5 y, BMI 23 +/- 0.6 kg/m2 (mean +/- SEM)] participated in a cross-over study, receiving three different meals: pasta with normal wheat bran (PA) and bread with normal (CB) or purple wheat bran (PBB). Purple wheat bran was added in an attempt to decrease the rate of starch digestion. The meals were enriched in 13C and the dual isotope technique was applied to calculate the rate of appearance of exogenous glucose (RaE). The 13C-isotopic enrichment of glucose in plasma was measured with GC/combustion/isotope ratio MS (IRMS) and liquid chromatography/IRMS. Both IRMS techniques gave similar results. Plasma glucose concentrations [2-h incremental AUC (iAUC)] did not differ between the test meals. The RaE was similar after consumption of CB and PBB, showing that purple wheat bran in bread does not affect in vivo starch digestibility. However, the iAUC of RaE after men consumed PA was less than after they consumed CB (P < 0.0001) despite the similar glucose response. To conclude, the glycemic response does not always reflect the in vivo starch digestibility. This could have implications for intervention studies in which the glycemic response is used to characterize test products. PMID- 22223570 TI - Lactobacillus rhamnosus GG and Bifidobacterium animalis MB5 induce intestinal but not systemic antigen-specific hyporesponsiveness in ovalbumin-immunized rats. AB - Probiotics may modulate the host immune response by mechanisms not yet fully understood. We evaluated the modulation of intestinal and systemic antigen specific immune response by Lactobacillus rhamnosus GG (LGG) or Bifidobacterium animalis MB5 in tolerized and immunized rats. Three groups of rats received orally LGG, B. animalis, or PBS (control) for 28 d. Each group was divided into two subgroups of tolerized or immunized rats receiving orally ovalbumin (OVA; 7 mg) or PBS on d 7, 9, and 11. All rats were immunized with OVA (300 MUg) on d 14 and 21. In tolerized rats, the OVA-induced proliferative response of mesenteric lymph nodes (MLN) and spleen cells did not differ from control, indicating that the two probiotics maintained the tolerance. LGG and B. animalis in immunized rats reduced the OVA-induced proliferative response in MLN (P < 0.01) but not in spleen, whereas the proliferative response to anti-CD3 and concanavalin A of MLN and spleen cells as well as the delayed-type hypersensitivity reaction were not affected by probiotic treatment, indicating OVA-specific hyporesponsiveness restricted to intestinal immunity. This hyporesponsiveness was associated with CD4+CD25+Foxp3+ T cell expansion (P < 0.01) and increased IL-10 and TGFbeta after LGG (P < 0.05), and increased apoptosis after B. animalis (P < 0.001) in MLN. In conclusion, we report a novel activity of LGG and B. animalis in inducing OVA specific hyporesponsiveness in MLN of OVA-immunized rats that can be useful for a therapeutic strategy to prevent undesirable reactions to immunogenic antigens in the gut. PMID- 22223571 TI - Dietary plasma proteins modulate the adaptive immune response in mice with acute lung inflammation. AB - We examined the effects of oral plasma protein supplements on the pulmonary adaptive immune response in mice challenged with intranasal LPS. C57BL/6 mice were fed a control diet or a diet supplemented with plasma proteins [spray-dried plasma (SDP) 80 g/kg] or with an Ig concentrate [(IC) 20 g/kg] from postnatal d 19 (weaning) until d 34. Mice were challenged with PBS or LPS from Escherichia coli at d 33 and killed 24 h later for leukocyte analyses or at d 34 and killed 6 h later for cytokine determination. LPS induced the activation of T helper (Th) lymphocytes in lung and blood and this response was reduced by SDP and IC (P < 0.05). In both tissues, LPS increased the Th1 and Th2 subpopulations and this effect was inhibited by the two plasma protein supplements (P < 0.05). The LPS challenge increased the expression of all the cytokines studied (P < 0.01). SDP and IC reduced the expression of IFNgamma, IL-5, IL-12p40, IL-12p70, IL-13, and IL-17 in both tissues, whereas they increased the percentage of regulatory Th lymphocytes in lung, even in PBS-treated mice (P < 0.05). LPS reduced the concentration of mature TGFbeta1 (P < 0.05) in the lung but did not modify the expression of IL-10. Mice exposed to LPS and supplemented with SDP or IC showed an increased expression of the anti-inflammatory cytokine IL-10 (P < 0.05). Moreover, the two supplements increased the concentration of IL-10 in intestinal mucosa (P < 0.05). Our results show that plasma supplementation reduces the immune response that characterizes the acute lung inflammation syndrome. PMID- 22223572 TI - Generation and acculturation status are associated with dietary intake and body weight in Mexican American adolescents. AB - Mexican American children are disproportionately affected by obesity. Data on how the acculturation process influences diet and body weight among adolescents are limited. We used the data from the 1999-2004 NHANES, restricting to 2286 Mexican American children between 12 and 19 y old. Acculturation was measured by generation status and language preference. Diet was assessed using 24-h diet recall. Multiple linear, Tobit, logistic, and quantile regression models were used. We found, after adjusting for socio-demographic factors, health, dietary intake, physical activity, and sedentary behaviors compared to the first generation, second and third generations had greater odds of overweight and obesity. Adolescents in the second generation had higher BMI Z-scores than adolescents in the first and third generations. Both second and third generation adolescents consumed less fruit, whole fruit, vegetables, grains, and meats but more sweetened beverages, whole grains, saturated fat, sodium, oil, and energy from discretionary foods. Higher language acculturation was associated with poorer diet and greater body weight. Our findings suggest that Mexican American adolescents face challenges in terms of poorer diet and excessive weight gain associated with their immigration experience. PMID- 22223573 TI - Long-term dietary potential renal acid load during adolescence is prospectively associated with indices of nonalcoholic fatty liver disease in young women. AB - Nonalcoholic fatty liver disease (NAFLD), frequently already present in young subjects, has been linked to reduced growth hormone levels and signaling. Similar hormonal changes occur during metabolic acidosis (MA), which may thus contribute to an increased NAFLD risk. Because subclinical MA can be diet induced, we aimed to examine whether a higher diet-dependent acid load during adolescence is prospectively associated with several currently used NAFLD surrogates in young adulthood. Dietary acidity during adolescence (boys:10-15 y, girls: 9-14 y) was calculated as potential renal acid load (PRAL) from at least three 3-d weighed dietary records according to a published algorithm considering dietary protein and minerals in 145 healthy participants. Routine measurements derived from blood analysis and anthropometric data in participants' young adulthood (18-25 y) were used to determine the NAFLD surrogates alanine-aminotransferase (ALT), hepatic steatosis index (HSI), and fatty liver index (FLI). Sex-stratified linear regression models, adjusted for dietary fiber, saturated fat, protein, and adolescent BMI SD scores, were run with PRAL as the independent variable. Dietary PRAL during puberty was positively associated with ALT (P = 0.02), HSI (P = 0.002), and FLI (P = 0.005) in adult females but not males. Females with an adolescent dietary acid load in the highest tertile had 3.5, 4.4, and 4.5 higher values of ALT, HSI, and FLI as adults, respectively, compared to females with the lowest PRAL. The present findings suggest that higher dietary acidity in adolescence may be prospectively associated with hepatic lipid accumulation in females. Whether this relationship is due to the higher proton load or rather represents an unhealthy dietary pattern requires further investigation. PMID- 22223574 TI - Estimation of the 5-methyltetrahydrofolate apparent volume of distribution in humans. AB - The fractional absorption of a stable isotope-labeled folate dose can be estimated from the subsequent short-term temporal changes in the concentration of labeled L-5-methyltetrahydrofolate (L-5-methyl-THF) in plasma using mathematical modeling. However, the model is dependent on the use of an accurate value for the apparent volume of distribution of L-5-methyl-THF. Previous studies that estimated the apparent volume of distribution of L-5-methyl-THF used large (nonphysiological) doses of unlabeled folates that are not found to any great extent in the circulatory system. The current study estimates the apparent volume of distribution at steady state in 16 healthy humans aged 18-65 y after an i.v. dose (440 nmol) of a stable isotope-labeled version of the naturally circulating plasma folate, L-5-methyl-THF. Blood was collected from 2 min to 2 h postinjection and plasma assayed by specific and sensitive liquid chromatography tandem MS. The apparent volume of distribution for L-5-methyl-THF was 32.0 +/- 11.6 L (mean +/- SD; 392 +/- 110 mL/kg bodyweight). There was a positive association with volunteer body weight (r = 0.64; P = 0.010), which allowed a simple linear equation to be developed relating apparent volume of distribution to body weight. This has important implications for predicting apparent absorption of labeled folates in future bioavailability studies. PMID- 22223575 TI - Validation of an in vitro digestive system for studying macronutrient decomposition in humans. AB - The digestive process transforms nutrients and bioactive compounds contained in food to physiologically active compounds. In vitro digestion systems have proven to be powerful tools for understanding and monitoring the complex transformation processes that take place during digestion. Moreover, the investigation of the physiological effects of certain nutrients demands an in vitro digestive process that is close to human physiology. In this study, human digestion was simulated with a 3-step in vitro process that was validated in depth by choosing pasteurized milk as an example of a complex food matrix. The evolution and decomposition of the macronutrients was followed over the entire digestive process to the level of intestinal enterocyte action, using protein and peptide analysis by SDS-PAGE, reversed-phase HPLC, size exclusion HPLC, and liquid chromatography-MS. The mean peptide size after in vitro digestion of pasteurized milk was 5-6 amino acids (AA). Interestingly, mostly essential AA (93.6%) were released during in vitro milk digestion, a significantly different relative distribution compared to the total essential AA concentration of bovine milk (44.5%). All TG were degraded to FFA and monoacylglycerols. Herein, we present a human in vitro digestion model validated for its ability to degrade the macronutrients of dairy products comparable to physiological ranges. It is suited to be used in combination with a human intestinal cell culture system, allowing ex vivo bioavailability measurements and assessment of the bioactive properties of food components. PMID- 22223576 TI - Longitudinal changes in BMI in older adults are associated with meat consumption differentially, by type of meat consumed. AB - Hypotheses regarding the role of meat consumption in body weight modulation are contradictory. Prospective studies on an association between meat consumption and BMI change are limited. We assessed the association between meat consumption and change in BMI over time in 3902 men and women aged 55-69 y from the Netherlands Cohort Study. Dietary intake was estimated at baseline using a FFQ. BMI was ascertained through baseline self-reported height (1986) and weight (1986, 1992, and 2000). Analyses were based on sex-specific categories of daily total fresh meat, red meat, beef, pork, minced meat, chicken, processed meat, and fish consumption at baseline. Linear mixed effect modeling adjusted for confounders was used to assess longitudinal associations. Significant cross-sectional differences in BMI between quintiles of total meat intake were observed (P-trend < 0.01; both sexes). No association between total fresh meat consumption and prospective BMI change was observed in men (BMI change highest vs. lowest quintile after 14 y: -0.06 kg/m2; P = 0.75) and women (BMI change: 0.26 kg/m2; P = 0.20). Men with the highest intake of beef experienced a significantly lower increase in BMI after 6 and 14 y than those with the lowest intake (BMI change after 14 y 0.60 kg/m2). After 14 y, a significantly higher increase in BMI was associated with higher intakes of pork in women (BMI change highest vs. lowest quintile: 0.47 kg/m2) and chicken in both sexes (BMI change highest vs. lowest category in both men and women: 0.36 kg/m2). The results remained similar when stratifying on median baseline BMI, and age-stratified analyses yielded mixed results. Differential BMI change effects were observed for several subtypes of meat. However, total meat consumption, or factors directly related to total meat intake, was not strongly associated with weight change during the 14-y prospective follow-up in this elderly population. PMID- 22223577 TI - Quantifying resistant starch using novel, in vivo methodology and the energetic utilization of fermented starch in pigs. AB - To quantify the energy value of fermentable starch, 10 groups of 14 pigs were assigned to one of two dietary treatments comprising diets containing 45% of either pregelatinized (P) or retrograded (R) corn starch. In both diets, a contrast in natural 13C enrichment between the starch and nonstarch components of the diet was created to partition between enzymatic digestion and fermentation of the corn starch. Energy and protein retention were measured using indirect calorimetry after adapting the pigs to the diets for 3 wk. Fecal 13C enrichment was higher in the R-fed pigs (P < 0.001) and 43% of the R resisted enzymatic digestion. Energy retained as protein was unaffected and energy retained as fat was 29% lower than in P-fed pigs (P < 0.01). Prior to the morning meal, end products of fermentation substantially contributed to substrate oxidation in the R-fed pigs. During the 3-4 h following both meals, heat production was higher (P < 0.05) in P-fed pigs, but this was not preferentially fueled by glucose from corn starch. Digestible energy intake, metabolizable energy intake, and energy retention were reduced (P < 0.05) in R-fed pigs compared with P-fed pigs by 92, 54, and 33 kJ/(kg0.75 . d), respectively. Therefore, the energy values of fermented resistant starch were 53, 73, and 83% of the digestible, metabolizable, and net energy values of enzymatically degradable starch, respectively. Creating a contrast in natural 13C enrichment between starch and nonstarch dietary components provides a promising, noninvasive, in vivo method for estimating the proportion of dietary starch fermented in the gastrointestinal tract. PMID- 22223578 TI - Tomato-based food products are related to clinically modest improvements in selected coronary biomarkers in women. AB - Few epidemiologic studies have examined the potential cardiovascular mechanisms of tomato-based food products, the primary dietary source of lycopene. We examined the cross-sectional association between tomato-based food product intake and coronary biomarkers in the Women's Health Study. Tomato-based food products (tomatoes, tomato juice, tomato sauce, pizza) were summed from a semiquantitative FFQ and multiple risk factors ascertained. Plasma from baseline blood samples were assayed for lipids, lipoproteins, hemoglobin A1c, C-reactive protein, fibrinogen, soluble intracellular adhesion molecule-1, and creatinine. A total of 27,261 women aged >=45 y who were free of cardiovascular disease and cancer provided relevant data for this study. Tomato-based food product intake was modest, with 84% of women consuming <1 serving/d, but those with greater intake had healthier lifestyle and dietary habits. Women consuming >=10 compared with <1.5 servings/wk of tomato-based food products had significant but clinically modest improvements in total cholesterol (TC) (5.38 vs. 5.51 mmol/L; P = 0.029), the TC:HDL cholesterol ratio (4.08 vs. 4.22; P = 0.046), and hemoglobin A1c (5.02 vs. 5.13%; P < 0.001) in multivariable models. Considering clinical cutpoints, women consuming >=10 compared with <1.5 servings/wk were 31% (95% CI = 6%, 50%), 40% (95% CI = 13%, 59%), and 66% (95% CI = 20%, 86%) less likely to have elevated TC (>=6.21 mmol/L), LDL cholesterol (>=4.14 mmol/L), and hemoglobin A1c (>=6%), respectively. Other coronary biomarkers were unassociated with tomato-based food products. In conclusion, women consuming >=10 compared with <1.5 servings/wk of tomato-based food products had clinically modest but significant improvements in TC, the TC:HDL cholesterol ratio, and hemoglobin A1c but not other coronary biomarkers. PMID- 22223579 TI - Oleate metabolism in pig enterocytes is characterized by an increased oxidation rate in the presence of a high esterification rate within two days after birth. AB - Oleate (OLE) is the principle fatty acid (FA) in mammalian colostrum, but its role in the energy supply in enterocytes after birth remains unknown. We investigated the metabolic fate of OLE in pig enterocytes at birth (d0) and after 2 d of suckling (d2). Cellular TG and phospholipids (PL) and FA composition were analyzed. Metabolic end-products of [1-14C]OLE were measured in enterocyte incubations. We characterized intestinal carnitine palmitoyltransferase 1 (CPT1), the key enzyme of mitochondrial FA oxidation. The TG content was 6.6-fold higher in enterocytes from pigs on d 2 than in those obtained on d 0, whereas the PL content did not differ. The level of OLE in TG and PL increased from 15 and 11% of total FA, respectively, in enterocytes from newborn piglets to 30 and 17%, respectively, in those from d2 pigs. The capacity for OLE utilization was 2.8 fold greater in d2 than in d0 pig enterocytes. The oxidation and esterification rates were enhanced in enterocytes from piglets on d 2 compared to those obtained on d 0, by 4- and 2.6-fold, respectively. The predominant OLE fate was the esterification pathway, representing >85% of OLE metabolized in both groups. The limited OLE oxidation observed at d 2 may result from the presence of a highly malonyl-CoA-sensitive CPT1A, because the half maximal inhibitory concentration for malonyl-CoA was 162 +/- 25 nmol/L. This study highlighted the high esterification capacity for OLE in the newborn pig intestine, which may preserve this major colostrum FA for delivery to other tissues. PMID- 22223580 TI - Prebiotic fiber increases hepatic acetyl CoA carboxylase phosphorylation and suppresses glucose-dependent insulinotropic polypeptide secretion more effectively when used with metformin in obese rats. AB - Independently, metformin (MET) and the prebiotic, oligofructose (OFS), have been shown to increase glucagon-like peptide (GLP-1) secretion. Our objective was to determine whether using OFS as an adjunct with MET augments GLP-1 secretion in obese rats. Male, diet-induced obese Sprague Dawley rats were randomized to: 1) high-fat/-sucrose diet [HFHS; control (C); 20% fat, 50% sucrose wt:wt]; 2) HFHS+10% OFS (OFS); 3) HFHS + MET [300 mg/kg/d (MET)]; 4) HFHS+10% OFS+MET (OFS+MET). Body composition, glycemia, satiety hormones, and mechanisms related to dipeptidyl peptidase 4 (DPP4) activity in plasma, hepatic AMP-activated protein kinase (AMPK; Western blots), and gut microbiota (qPCR) were examined. Direct effects of MET and SCFA were examined in human enteroendocrine cells. The interaction between OFS and MET affected fat mass, hepatic TG, secretion of glucose-dependent insulinotropic polypeptide (GIP) and leptin, and AMPKalpha2 mRNA and phosphorylated acetyl CoA carboxylase (pACC) levels (P < 0.05). Combined, OFS and MET reduced GIP secretion to a greater extent than either treatment alone (P < 0.05). The hepatic pACC level was increased by OFS+MET by at least 50% above all other treatments, which did not differ from each other (P < 0.05). OFS decreased plasma DPP4 activity (P < 0.001). Cecal Bifidobacteria (P < 0.001) were markedly increased and C. leptum decreased (P < 0.001) with OFS consumption. In human enteroendocrine cells, the interaction between MET and SCFA affected GLP-1 secretion (P < 0.04) but was not associated with higher GLP-1 than the highest individual doses. In conclusion, the combined actions of OFS and MET were associated with important interaction effects that have the potential to improve metabolic outcomes associated with obesity. PMID- 22223581 TI - Blauth II thumb hypoplasia: a management algorithm for the unstable metacarpophalangeal joint. AB - Blauth Type II thumb hypoplasia is defined by first web space narrowing, deficiency of thenar musculature, and instability of the metacarpophalangeal joint (MCPJ). This instability can be uni-axial (type IIA) or multi-axial (type IIB). The aim of this study was to assess the results of treating type II thumb hypoplasia using an algorithm based on the type of instability present. Cases of uni-axial MCPJ laxity (type IIA) underwent stabilization as part of a flexor digitorum superficialis opposition transfer. Type IIB cases with multi-axial instability were treated with an MCPJ chondrodesis and an abductor digit minimi transfer for opposition. First web space release was achieved using a z-plasty approach in all patients. An analysis was carried out of all cases of type II thumb hypoplasia treated by the senior author within the setting of a tertiary referral children's hospital over a 9 year period. Using our management algorithm, equivalent functional results were seen in each subgroup in terms of first web space release, MCPJ stabilization, and opposition. PMID- 22223582 TI - Patient outcomes following wrist ganglion excision surgery. AB - We present patient outcomes following surgical excision of primary wrist ganglia over a 5 year period. Patients (48 of 59; 81%) responded to a questionnaire by post or telephone, with a mean time to follow-up of 44 (range 21-77) months. There was a statistically significant reduction in all reported symptoms, including pain, paraesthesia, weakness, stiffness, and cosmesis. The recurrence rate was 8%. In total, 98% of patients were satisfied or very satisfied with treatment. Surgical excision of primary wrist ganglia may have advantages over aspiration and reassurance alone, particularly in reducing recurrence and hastening resolution of symptoms. PMID- 22223583 TI - A technique to reconstruct the deep transverse metacarpal ligament. PMID- 22223584 TI - Thumb carpometacarpal osteoarthritis: trapeziectomy versus pyrocarbon interposition implant (Pi2) arthroplasty. AB - We retrospectively compared the short-term outcomes of 18 thumbs that had a trapeziectomy and 18 that had a pyrocarbon interposition implant (Pi2) arthroplasty in 33 patients. We measured the Disability of the Arm, Shoulder, and Hand (DASH) and Short Form 36 (SF-36) scores at a mean of 20 months. Pain severity was assessed using a visual analogue scale (VAS), and level of patient satisfaction was assessed using a 5-point scale. The mean DASH scores at follow up were 27 for those that had a trapeziectomy and 35 for those that had a Pi2 arthroplasty (p = 0.001). There was no difference in the VAS for pain, SF-36 scores, or other parameters assessed. Six out of 18 (33%) thumbs in the Pi2 group had multiple operations, usually for dislocation or subluxation of the implant. The early results of Pi2 arthroplasty show a high complication rate compared with trapeziectomy and no identifiable benefit. PMID- 22223585 TI - Conversion of methane into C1 oxygenates by deep-UV photolysis on solid surfaces: influence of the nature of the solid and optimization of photolysis conditions. AB - Deep-UV photolysis (either 165 or 185 nm) of surface hydroxy groups leads to homolytic O-H bond-cleavage with the generation of oxyl radicals that can initiate the room-temperature radical-chain methane activation. Whilst in the absence of oxygen, radical coupling reactions to give low-molecular-weight alkanes are observed in the gas phase, the presence of some oxygen quenches these radicals and increases the selectivity towards C1 oxygenates (methanol, formaldehyde, and formic acid species). The nature of the solid influences the efficiency of the photochemical process and the distribution between products in the gas and solid phases. Using Beta-, delaminated ITQ2 and ITQ6, and medium-pore ZSM5 zeolites, mesoporous MCM41 silicates, and non-porous TiO(2), we observed that confinement and porosity increased the proportion of C1 oxygenates adsorbed onto the solid and reduced the contribution of the gas-phase products. In addition, the presence of aluminum in the zeolite framework, which is responsible for the generation of acid sites, increased overoxidation of methanol and methoxy groups into formaldehyde and formic acids. For a given amount of methane and unchanged photolysis conditions, the conversion increased with the amount of the solid used as photocatalyst. In this way, methane conversions of up to 7% were achieved for the 185 nm photolysis of methane for 1 h with a 76 MJ mol(-1) energy consumption. PMID- 22223586 TI - Polar behaviour induced by lithium in potassium tantalate ceramics. AB - Polar behaviour in K(1-x)Li(x)TaO(3) ceramics with x = 0:02, 0.05 and 0.10, processed by the conventional solid state method, is studied by Raman spectroscopy and thermally stimulated depolarization current (TSDC) techniques between 10 and 290 K. The TO1 mode of KTaO(3) is revealed to harden in the whole temperature range and to split in the low-temperature range by Li doping. One splitting is observed for x = 0:02 and two consequent splittings are detected for x = 0:05 and 0.10. The temperatures, where TO1 mode splitting occurs, are found to correspond to those of the peaks of TSDC, and hence to the onset of the electric polarization. Such behaviour provides evidence for the order-disorder ferroelectric phase transition induced in KTaO(3) by lithium doping, which emerges from deformations of the cubic phase developed on cooling either in one (for x = 0:02) or two steps (for x = 0:05 and 0.10). PMID- 22223587 TI - Prospective evaluation of the IOTA logistic regression model LR2 for the diagnosis of ovarian cancer. AB - OBJECTIVES: To assess the accuracy of the IOTA logistic regression model LR2 for the diagnosis of ovarian cancer. METHODS: This was a prospective single-center study of women with an ultrasound diagnosis of an adnexal tumor. They were all examined by a single Level-II ultrasound operator, who had received training in the systematic examination of ovarian tumors in accordance with the IOTA guidelines. In all women the likelihood of the adnexal lesion being malignant was calculated using the IOTA LR2 model. All women underwent surgery within 120 days of ultrasound examination and the ultrasound findings were compared with operative findings and the final histological diagnosis. RESULTS: One hundred and twenty-four women were included in the final analysis. The mean age was 53.2 (range, 20-91) years and 61/124 (49.2%) women were postmenopausal. 66/124 (53.2%) women had malignant lesions on postoperative histological examination. The IOTA LR2 model had a sensitivity of 97.0% (95% CI, 89.5-99.6%) and a specificity of 69.0% (95% CI, 55.5-80.5%). The area under the receiver-operating characteristics curve was 0.93 (SE, 0.022; 95% CI, 0.89-0.97), which was not significantly different from 0.92 (SE, 0.018) reported in the original study (P > 0.05). CONCLUSION: When evaluated prospectively, the accuracy of the IOTA LR2 model was similar to that reported in the original study. PMID- 22223588 TI - Fluorescent and colorimetric probes for mercury(II): tunable structures of electron donor and pi-conjugated bridge. AB - A new series of intramolecular-charge-transfer (ICT) molecules (compounds 1, 2, and 3) were synthesized by attaching various electron-donating thiophenes groups to a triphenylamine backbone with an aldehyde group as the electron acceptor. Based on the protection reaction between ethanethiol and aldehyde, the corresponding dithioacetals (compounds S1, S2, and S3) were prepared to serve as novel colorimetric and fluorescent chemosensors for Hg(2+) ions. Also, compound S1 was further utilized to construct the chemical-reaction-based conjugated polymer probe (PS1) towards Hg(2+) ions. In the presence of as little as 10 nM Hg(2+), compound PS1 displayed an apparent change in the fluorescent intensity. The sensing processes were revealed to be mediated by ICT, as confirmed by time dependent DFT calculations. Furthermore, compound S1 was successfully applied to microscopic imaging for the detection of Hg(2+) in HeLa cells with ratiometric fluorescent methods. PMID- 22223589 TI - An automated microscale platform for evaluation and optimization of oxidative bioconversion processes. AB - In this work an integrated robotic platform has been used for the development of a fully automated microscale process sequence comprising fermentation and bioconversion using E. coli TOP10 [pQR210] expressing cyclohexanone monooxygenase (CHMO). Ninety six-Deep Square Well (96-DSW) microtiter plates were used for microbial culture and enzyme-catalyzed conversion, where plate preparation, reagent addition, and sampling were all carried out without manual intervention. The adoption of automated robotic procedures has enabled the rapid collection of kinetic data for whole process optimization at the microscale. This high throughput approach enabled a range of amino acid sources for media formulation and well fill volumes to be investigated highlighting when nutritional limitation and oxygen limitations took place. The automated process sequence has been applied to test six CHMO substrates including norcamphor and cycloheptanone all of which to the best of our knowledge have yet to be tested with E. coli TOP10 [pQR210]. Substrate specificity and product selectivity were effectively demonstrated and compared to both the natural substrate cyclohexanone and the model substrate bicyclo[3.2.0]hept-2-en-6-one used to demonstrate asymmetric synthesis. The results obtained using the developed process sequence could be reproduced at 75 L scale when a matched oxygen transfer coefficient k(L) a approach was used. The study demonstrates how automated microscale processing enables the rapid collection of kinetic quantitative data in a robust manner with clear implications for accelerating bioprocess development, optimization, and scale-up. PMID- 22223590 TI - Chemiluminescence behaviour of CdTe-potassium permanganate enhanced by sodium hexametaphosphate and sensitized sensing of L-ascorbic acid. AB - A highly sensitive flow-injection chemiluminescence (FIA-CL) method based on the CdTe nanocrystals and potassium permanganate chemiluminescence system was developed for the determination of L-ascorbic acid. It was found that sodium hexametaphosphate (SP), as an enhancer, could increase the chemiluminescence (CL) emission from the redox reaction of CdTe quantum dots with potassium permanganate in near-neutral pH conditions. L-ascorbic acid is suggested as a sensitive enhancer for use in the above energy-transfer excitation process. Under optimal conditions, the calibration graph of emission intensity against logarithmic l ascorbic acid concentration was linear in the range 1.0 * 10(-9)-5.0 * 10(-6) mol/L, with a correlation coefficient of 0.9969 and relative standard deviation (RSD) of 2.3% (n = 7) at 5.0 * 10(-7) mol/L. The method was successfully used to determine L-ascorbic acid in vitamin C tablets. The possible mechanism of the chemiluminescence in the system is also discussed. PMID- 22223591 TI - Single-molecule conductance of pi-conjugated rotaxane: new method for measuring stipulated electric conductance of pi-conjugated molecular wire using STM break junction. AB - An electronic conductance with small fluctuations, which is stipulated in single molecule junctions, is necessary for the precise control of single-molecule devices. However, the suppression of conductance fluctuations in conventional molecular junctions is intrinsically difficult because the fluctuations are related to the contact fluctuations and molecular motion. In the present study involving experimental and theoretical investigations, it is found that covering a single pi-conjugated wire with an alpha-cyclodextrin molecule is a promising technique for suppressing conductance fluctuations. The conductance histogram of the covered molecular junction measured with the scanning tunneling microscope break-junction technique shows that the conductance peak for the covered junction is sharper than that of the uncovered junction. The covering technique thus has two prominent effects: the suppression of intramolecular motion, and the elimination of intermolecular interactions. Theoretical calculations of electronic conductance clearly support these experimental observations. PMID- 22223592 TI - SWITCHing anti-TNF for nonclinical reasons? Think again! PMID- 22223593 TI - Differences in length of stay for hip replacement between public hospitals, specialised treatment centres and private providers: selection or efficiency? AB - We investigate differences in patients' length of stay between National Health Service (NHS) public hospitals, specialised public treatment centres and private treatment centres that provide elective (non-emergency) hip replacement to publicly funded patients. We find that the specialised public treatment centres and private treatment centres have, on average, respectively 18% and 40% shorter length of stay compared with NHS public hospitals, even after controlling for differences in age, gender, number and type of diagnoses, deprivation and regional variation. Therefore, we interpret such differences as because of efficiency as opposed to selection of less complex patients. Quantile regression suggests that the proportional differences between different provider types are larger at the higher conditional quantiles of length of stay. PMID- 22223595 TI - Sequential antiretroviral adherence measurement using electronic bottle cap monitors in a cohort of HIV-infected adults. AB - Most studies employing electronic bottle monitors to measure antiretroviral adherence are limited to 24 weeks of duration, providing a snapshot of adherence from a treatment course that may be lifelong. The stability of these measures in individual patients over time has not been previously described. We measured antiretroviral adherence using Medication Event Monitoring System (MEMS) caps in a patient cohort in 2004 and 2005 and repeated the measurement in 2008 and 2009. Forty-eight participants completed both monitoring periods. Mean adherence rates in the first and second periods were 74.2% and 68.9%, respectively. Adherence rates from the 2 periods for individual participants were highly correlated (Spearman rho = .66, P < .001). PMID- 22223596 TI - Untargeted metabolic quantitative trait loci analyses reveal a relationship between primary metabolism and potato tuber quality. AB - Recent advances in -omics technologies such as transcriptomics, metabolomics, and proteomics along with genotypic profiling have permitted dissection of the genetics of complex traits represented by molecular phenotypes in nonmodel species. To identify the genetic factors underlying variation in primary metabolism in potato (Solanum tuberosum), we have profiled primary metabolite content in a diploid potato mapping population, derived from crosses between S. tuberosum and wild relatives, using gas chromatography-time of flight-mass spectrometry. In total, 139 polar metabolites were detected, of which we identified metabolite quantitative trait loci for approximately 72% of the detected compounds. In order to obtain an insight into the relationships between metabolic traits and classical phenotypic traits, we also analyzed statistical associations between them. The combined analysis of genetic information through quantitative trait locus coincidence and the application of statistical learning methods provide information on putative indicators associated with the alterations in metabolic networks that affect complex phenotypic traits. PMID- 22223597 TI - Evolution of magnetic properties in the normal spinel solid solution Mg(1 x)Cu(x)Cr2O4. AB - We examine the evolution of magnetic properties in the normal spinel oxides Mg(1 x)Cu(x)Cr2O4 using magnetization and heat capacity measurements. The end-member compounds of the solid solution series have been studied in some detail because of their very interesting magnetic behavior. MgCr2O4 is a highly frustrated system that undergoes a first-order structural transition at its antiferromagnetic ordering temperature. CuCr2O4 is tetragonal at room temperature as a result of Jahn-Teller active tetrahedral Cu2+ and undergoes a magnetic transition at 135 K. Substitution of magnetic cations for diamagnetic Mg2+ on the tetrahedral A site in the compositional series Mg(1-x)Cu(x)Cr2O4 dramatically affects magnetic behavior. In the composition range 0 <= x <= ~0.3, the compounds are antiferromagnetic. A sharp peak observed at 12.5 K in the heat capacity of MgCr2O4 corresponding to a magnetically driven first-order structural transition is suppressed even for small x. Uncompensated magnetism--with open magnetization loops--develops for samples in the x range ~0.43 <= x <= 1. Multiple magnetic ordering temperatures and large coercive fields emerge in the intermediate composition range 0.43 <= x <= 0.47. The Neel temperature increases with increasing x across the series while the value of the Curie-Weiss Theta(CW) decreases. A magnetic temperature-composition phase diagram of the solid solution series is presented. PMID- 22223598 TI - Could antispasmodic drug reduce pain during hysterosalpingo-contrast sonography (HyCoSy) in infertile patients? A randomized double-blind clinical trial. AB - OBJECTIVE: To assess the effectiveness of an antispasmodic drug, hyoscine-N butylbromide, in reducing pain during hysterosalpingo-contrast sonography (HyCoSy). METHODS: Eight hundred and sixteen patients undergoing HyCoSy were randomized to receive 10 mg hyoscine-N-butylbromide (n = 408) or placebo (n = 408) per os, 30 min before the procedure, in a double-blind randomized controlled trial. Immediately after the procedure, the patient was asked to describe any pain experienced in comparison with pain usually suffered during the menstrual cycle, and the operator assigned a pain score between 0 and 4 as follows: 0 (no reaction or discomfort), 1 (slight pain, less than menstrual pain), 2 (moderate pain, exceeding menstrual cramps but no vasovagal reaction), 3 (vasovagal reaction or pain requiring observation in a hospital) and 4 (vasovagal reaction or pain requiring resuscitation). The primary aim was to estimate the difference in pain score, considered as a categorical value, between the active arm of the trial and the control group. The secondary aim was to evaluate if pain is related to tubal patency. RESULTS: There was no difference in pain score between the hyoscine-N-butylbromide group and the placebo group (P = 0.807). There was a negative correlation between pain and tubal patency, regardless of treatment group (P < 0.0001). CONCLUSIONS: Administration of 10 mg antispasmodic drug hyoscine-N-butylbromide does not reduce pain in patients undergoing HyCoSy. PMID- 22223600 TI - Novel insights in transport mechanisms and kinetics of phenylacetic acid and penicillin-G in Penicillium chrysogenum. AB - Although penicillin-G (PenG) production by the fungus Penicillium chrysogenum is a well-studied process, little is known about the mechanisms of transport of the precursor phenylacetic acid (PAA) and the product PenG over the cell membrane. To obtain more insight in the nature of these mechanisms, in vivo stimulus response experiments were performed with PAA and PenG in chemostat cultures of P. chrysogenum at time scales of seconds to minutes. The results indicated that PAA is able to enter the cell by passive diffusion of the undissociated acid at a high rate, but is at the same time actively excreted, possibly by an ATP-binding cassette transporter. This results in a futile cycle, dissipating a significant amount of metabolic energy, which was confirmed by increased rates of substrate and oxygen consumption, and carbon dioxide production. To estimate the kinetic properties of passive import and active export of PAA over the cell membrane, a dynamic mathematical model was constructed. With this model, a good description of the dynamic data could be obtained. Also, PenG was found to be rapidly taken up by the cells upon extracellular addition, indicating that PenG transport is reversible. The measured concentration gradient of PenG over the cell membrane corresponded well with facilitated transport. Also, for PenG transport, a dynamic model was constructed and validated with experimental data. The outcome of the model simulations was in agreement with the presence of a facilitated transport system for PenG. PMID- 22223599 TI - Identification of novel microRNAs in Xenopus laevis metaphase II arrested eggs. AB - Using a combination of deep sequencing and bioinformatics approach, we for the first time identify miRNAs and their relative abundance in mature, metaphase II arrested eggs in Xenopus laevis. We characterize 115 miRNAs that have been described either in Xenopus tropicalis (85), X. laevis (9), or other vertebrate species (21) that also map to known Xenopus pre-miRNAs and to the X. tropicalis genome. In addition, 72 new X. laevis putative candidate miRNAs are identified based on mapping to X. tropicalis genome within regions that have the propensity to form hairpin loops. These data expand on the availability of genetic information in X. laevis and identify target miRNAs for future functional studies. PMID- 22223601 TI - Flow injection-chemiluminescence determination of acyclovir. AB - The chemiluminescence (CL) reaction of acyclovir (ACV)-potassium permanganate, with formaldehyde as an enhancer, was investigated by the flow-injection system, and a new method is reported for the determination of ACV on the basis of the reaction. The method is rapid, effective and simple for the determination of acyclovir in the range 0.2-80 mg/L, with a limit of detection of 0.06 mg/L (3 S:N), a relative standard deviation (RSD) of 3.7% for the determination of 1.0 mg/L acyclovir solution in 11 repeated measurements. The method has been applied to the determination of acyclovir in pharmaceuticals, with satisfactory results. The possible reaction mechanism is also discussed briefly. PMID- 22223602 TI - Self-fluorescence of chemically crosslinked MRI nanoprobes to enable multimodal imaging of therapeutic cells. AB - Old chemistry for novel materials: Self-fluorescent high-relaxivity T(2)-weighted magnetic resonance imaging (MRI) contrast agents are produced. They are a novel type of MR/optical dual-modality in vivo imaging nanoprobe using glutaraldehyde crosslinking chemistry, and they are used to label and monitor therapeutic cells both in vitro and in vivo. PMID- 22223603 TI - A "clickable" styryl dye for fluorescent DNA labeling by excitonic and energy transfer interactions. PMID- 22223604 TI - A new concept for glycosyltransferase inhibitors: nonionic mimics of the nucleotide donor of the human blood group B galactosyltransferase. AB - Glycosyltransferases play an important role in the formation of oligosaccharides and glycoconjugates. To find suitable and selective inhibitors for this class of enzymes is still challenging. Here, we describe a novel concept that allows the design of inhibitors based on the structure of the donor substrate binding pocket. As a first step we describe the design, synthesis and analysis of inhibitors of the human blood group B galactosyltransferase (GTB). This enzyme served as a model system to study the concept, which can be used for easy access of glycosyltransferase inhibitors in general. In silico docking of bicyclic heteroaromatic ligands to GTB and experimental verification of binding affinities by saturation transfer difference NMR (STD NMR) spectroscopy gave 9-N-pentityl uric acid derivatives as non-ionic mimics of UDP. Two derivatives were synthesized and showed inhibitory activity for GTB as determined by competitive STD NMR experiments and by a radiolabeled enzyme assay. PMID- 22223605 TI - An evaluation of the UK Food Standards Agency's salt campaign. AB - Excessive salt intake is linked to cardiovascular disease and several other health problems around the world. The UK Food Standards Agency initiated a campaign at the end of 2004 to reduce salt intake in the population. There is disagreement over whether the campaign was effective in curbing salt intake or not. We provide fresh evidence on the impact of the campaign, by using data on spot urinary sodium readings and socio-demographic variables from the Health Survey for England over 2003-2007 and combining it with food price information from the Expenditure and Food Survey. Aggregating the data into a pseudo-panel, we estimate fixed effects models to examine the trend in salt intake over the period and to deduce the heterogeneous effects of the policy on the intake of socio-demographic groups. Our results are consistent with a previous hypothesis that the campaign reduced salt intakes by approximately 10%. The impact is shown to be stronger among women than among men. Older cohorts of men show a larger response to the salt campaign compared to younger cohorts, while among women, younger cohorts respond more strongly than older cohorts. PMID- 22223606 TI - Causes of alternative pathway dysregulation in dense deposit disease. AB - BACKGROUND AND OBJECTIVES: This study was designed to investigate the causes of alternative pathway dysregulation in a cohort of patients with dense deposit disease (DDD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Thirty-two patients with biopsy-proven DDD underwent screening for C3 nephritic factors (C3Nefs), factor H autoantibodies (FHAAs), factor B autoantibodies (FBAAs), and genetic variants in CFH. C3Nefs were detected by: ELISA, C3 convertase surface assay (C3CSA), C3CSA with properdin (C3CSAP), two-dimensional immunoelectrophoresis (2DIEP), and immunofixation electrophoresis (IFE). FHAAs and FBAAs were detected by ELISA, and CFH variants were identified by Sanger sequencing. RESULTS: Twenty five patients (78%) were positive for C3Nefs. Three C3Nef-positive patients were also positive for FBAAs and one of these patients additionally carried two novel missense variants in CFH. Of the seven C3Nef-negative patients, one patient was positive for FHAAs and two patients carried CFH variants that may be causally related to their DDD phenotype. C3CASP was the most sensitive C3Nef-detection assay. C3CASP and IFE are complementary because C3CSAP measures the stabilizing properties of C3Nefs, whereas IFE measures their expected consequence-breakdown of C3b. CONCLUSIONS: A test panel that includes C3CSAP, IFE, FHAAs, FBAAs, and genetic testing for CFH variants will identify a probable cause for alternative pathway dysregulation in approximately 90% of DDD patients. Dysregulation is most frequently due to C3Nefs, although some patients test positive for FHAAs, FBAAs, and CFH mutations. Defining the pathophysiology of DDD should facilitate the development of mechanism-directed therapies. PMID- 22223607 TI - Efficacy and safety of paricalcitol therapy for chronic kidney disease: a meta analysis. AB - BACKGROUND AND OBJECTIVES: Observational data indicate that newer vitamin D compounds such as paricalcitol can suppress serum intact parathyroid hormone (iPTH) and reduce proteinuria in patients with CKD. To systematically evaluate the efficacy and safety of paricalcitol for CKD, we conducted a meta-analysis of the published randomized controlled trials (RCTs). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: MEDLINE, Embase, the Cochrane Library, and article reference lists were searched for RCTs that compared paricalcitol with placebo in the treatment of patients with stage 2-5 CKD. The quality of the studies was evaluated using the Jadad method. The results are summarized as risk ratios (RRs) for dichotomous outcomes or mean differences for continuous outcomes. RESULTS: Nine studies (832 patients) were included. Compared with placebo, paricalcitol suppressed serum iPTH (RR, 6.37; 95% confidence interval [95% CI], 4.64-8.74; P<0.001) and reduced proteinuria (RR, 1.68; 95% CI, 1.25-2.25; P<0.001). Compared with the control group, the RR for hypercalcemia associated with paricalcitol use was 2.25 (95% CI, 0.81-6.26; P=0.12). Patients receiving paricalcitol therapy did not have an increased risk of endocrine system and cardiovascular system adverse effects (RR, 1.07; 95% CI, 0.84-1.36; P=0.58). CONCLUSIONS: We confirm that paricalcitol suppresses iPTH and lowers proteinuria in patients with stage 2-5 CKD without an increased risk of adverse events. A trend toward increased hypercalcemia did not reach statistical significance, but may be clinically relevant. A randomized trial is needed to determine if paricalcitol affects the development of ESRD or mortality. PMID- 22223609 TI - Racial and ethnic disparities in end stage renal disease: access failure. PMID- 22223610 TI - Clinical features and outcomes of IgA nephropathy with nephrotic syndrome. AB - BACKGROUND AND OBJECTIVES: Nephrotic syndrome (NS) is a rare manifestation of IgA nephropathy (IgAN). Clinical characteristics and long-term outcomes of this condition have not yet been explored. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A multicenter observational study was conducted between January 2000 and September 2010 in 1076 patients with biopsy-proven IgAN from four medical centers in Korea. The primary outcome was a doubling of the baseline serum creatinine concentration. RESULTS: Of the 1076 patients, 100 (10.2%) presented with NS; complete remission (CR), partial remission (PR), and no response (NR) occurred in 48 (48%), 32 (32%), and 20 (20%) patients, respectively. During the median follow-up of 45.2 months, 24 patients (24%) in the NS group reached the primary endpoint compared with 63 (7.1%) in the non-NS group (P<0.001). The risk of reaching the primary endpoint was significantly higher in the PR (P=0.04) and NR groups (P<0.001) than in the CR group. Among patients with NS, 24 (24%) underwent spontaneous remission (SR). SR occurred more frequently in female patients and in patients with serum creatinine levels <=1.2 mg/dl and a >50% decrease in proteinuria within 3 months after NS onset. None of the patients with SR reached the primary endpoint and they had fewer relapses during follow-up. CONCLUSIONS: This study demonstrated that the prognosis of NS in IgAN was not favorable unless PR or CR was achieved. In addition, SR was more common than expected, particularly in patients with preserved kidney function and spontaneous decrease in proteinuria shortly after NS onset. PMID- 22223608 TI - Characteristics and outcomes of children with primary oxalosis requiring renal replacement therapy. AB - BACKGROUND AND OBJECTIVES: Primary hyperoxaluria (PH) as a cause of ESRD in children is believed to have poor outcomes. Data on management and outcomes of these children remain scarce. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study included patients aged <19 years who started renal replacement therapy (RRT) between 1979 and 2009 from 31 countries providing data to a large European registry. RESULTS: Of 9247 incident patients receiving RRT, 100 patients had PH. PH children were significantly younger than non-PH children at the start of RRT. The median age at RRT of PH children decreased from 9.8 years in 1979-1989 to 1.5 years in 2000-2009. Survival was 86%, 79%, and 76% among PH patients at 1, 3, and 5 years after the start of RRT, compared with 97%, 94%, and 92% in non-PH patients, resulting in a three-fold increased risk of death over non-PH patients. PH and non-PH patient survival improved over time. Sixty-eight PH children received a first kidney (n=13) or liver-kidney transplantation (n=55). Although the comparison was hampered by the lower number of kidney transplantations primarily derived from the earlier era of RRT, kidney graft survival in PH patients was 82%, 79%, and 76% at 1, 3, and 5 years for liver-kidney transplantation and 46%, 28%, and 14% at 1, 3, and 5 years for kidney transplantation alone, compared with 95%, 90%, and 85% in non-PH patients. CONCLUSIONS: The outcomes of PH children with ESRD are still poorer than in non PH children but have substantially improved over time. PMID- 22223611 TI - Factor I autoantibodies in patients with atypical hemolytic uremic syndrome: disease-associated or an epiphenomenon? AB - BACKGROUND AND OBJECTIVES: Atypical hemolytic uremic syndrome is a disease associated with mutations in the genes encoding the complement regulators factors H and I. In addition, factor H autoantibodies have been reported in ~10% of patients with atypical hemolytic uremic syndrome. This study searched for the presence of factor I autoantibodies in atypical hemolytic uremic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study screened 175 atypical hemolytic uremic syndrome patients for factor I autoantibodies using ELISA with confirmatory Western blotting. Functional studies using purified immunoglobulin from one patient were subsequently undertaken. RESULTS: Factor I autoantibodies were detected in three patients. In one patient with a high titer of autoantibody, the titer was tracked over time and was found to have no association with disease activity. This study found evidence of an immune complex of antibody and factor I in this patient, but purified IgG, isolated from current serum samples, had only a minor effect on fluid phase and cell surface complement regulation. Genetic analysis of the three patients with factor I autoantibodies revealed that they had two copies of the genes encoding factor H-related proteins 1 and 3 and therefore, did not have a deletion commonly associated with factor H autoantibodies in atypical hemolytic uremic syndrome. Two patients, however, had functionally significant mutations in complement factor H. CONCLUSIONS: These findings reinforce the concept of multiple concurrent risk factors being associated with atypical hemolytic uremic syndrome but question whether autoantibodies per se predispose to atypical hemolytic uremic syndrome. PMID- 22223612 TI - Obesity and mortality risk among younger dialysis patients. AB - BACKGROUND AND OBJECTIVES: Many studies show that obesity in dialysis patients is not strongly associated with mortality but not whether this modest association is constant over age. This study investigated the extent to which the relation of body mass index (BMI) and mortality differs between younger and older dialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Adult dialysis patients were prospectively followed from their first dialysis treatment for 7 years or until death or transplantation. Patients were stratified by age (<65 or >=65 years) and baseline BMI (<20, 20-24 [reference], 25-29, and >=30 kg/m(2)). RESULTS: The study sample included 984 patients younger than 65 years and 765 patients 65 years or older; cumulative survival proportions at end of follow-up were 50% and 16%. Age-standardized mortality rate was 1.7 times higher in obese younger patients than those with normal BMI, corresponding to an excess rate of 5.2 deaths/100 patient-years. Mortality rates were almost equal between obese older patients and those with normal BMI. Excess rates of younger and older patients with low compared with normal BMI were 8.7 and 1.1 deaths/100 patient years. After adjustment for age, sex, smoking, comorbidity, and treatment modality, hazard ratios by increasing BMI were 2.00, 1, 0.95, and 1.57 for younger patients and 1.07, 1, 0.88, and 0.91 for older patients, implying that obesity is a 1.7-fold (95% confidence interval, 1.1- to 2.9-fold) stronger risk factor in younger than older patients. CONCLUSIONS: In contrast to older dialysis patients, younger patients with low or very high BMI had a substantially elevated risk for death. PMID- 22223613 TI - Pharmacokinetics of ampicillin/sulbactam in critically ill patients with acute kidney injury undergoing extended dialysis. AB - BACKGROUND AND OBJECTIVES: The fixed antibacterial combination of ampicillin and sulbactam is frequently used for various infections. Intact kidneys eliminate approximately 71% of ampicillin and 78% of sulbactam. Patients on thrice-weekly low-flux hemodialysis exhibit an ampicillin t(1/2) of 2.3 hours on and 17.4 hours off dialysis. Despite its frequent use in intensive care units, there are no available dosing recommendations for patients with AKI undergoing renal replacement therapy. The aims of this study were to evaluate the pharmacokinetics of ampicillin/sulbactam in critically ill patients with AKI undergoing extended dialysis (ED) and to establish a dosing recommendation for this treatment method. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twelve critically ill patients with anuric AKI being treated with ED were enrolled in a prospective, open-label, observational pharmacokinetic study. Pharmacokinetics after a single dose of ampicillin/sulbactam (2 g/1 g) was obtained in 12 patients. Multiple-dose pharmacokinetics after 4 days of twice-daily ampicillin/sulbactam (2 g/1 g) was obtained in three patients. RESULTS: The mean dialyzer clearance for ampicillin/sulbactam was 80.1 +/- 7.7/83.3 +/- 12.1 ml/min. The t(1/2) of ampicillin and sulbactam in patients with AKI undergoing ED were 2.8 +/- 0.8 hours and 3.5 +/- 1.5 hours, respectively. There was no significant accumulation using a twice-daily dosage of 2 g/1 g ampicillin/sulbactam. CONCLUSIONS: Our data suggest that in patients treated with ED using a high-flux dialyzer (polysulphone, 1.3 m(2); blood and dialysate flow, 160 ml/min; treatment time, 480 minutes), a twice-daily dosing schedule of at least 2 g/1 g ampicillin/sulbactam, with one dose given after ED, should be used to avoid underdosing. PMID- 22223614 TI - Solar-assisted hemodialysis. AB - BACKGROUND AND OBJECTIVES: Hemodialysis resource use-especially water and power, smarter processing and reuse of postdialysis waste, and improved ecosensitive building design, insulation, and space use-all need much closer attention. Regarding power, as supply diminishes and costs rise, alternative power augmentation for dialysis services becomes attractive. The first 12 months of a solar-assisted dialysis program in southeastern Australia is reported. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A 24-m(2), 3-kWh rated solar array and inverter-total cost of A$16,219-has solar-assisted the dialysis-related power needs of a four-chair home hemodialysis training service. All array-created, grid donated power and all grid-drawn power to the four hemodialysis machines and minireverse osmosis plant pairings are separately metered. After the grid-drawn and array-generated kilowatt hours have been billed and reimbursed at their respective commercial rates, financial viability, including capital repayment, can be assessed. RESULTS: From July of 2010 to July of 2011, the four combined equipment pairings used 4166.5 kWh, 9% more than the array-generated 3811.0 kWh. Power consumption at 26.7 c/kWh cost A$1145.79. Array-generated power reimbursements at 23.5 c/kWh were A$895.59. Power costs were, thus, reduced by 76.5%. As new reimbursement rates (60 c/kWh) take effect, system reimbursements will more than double, allowing both free power and potential capital pay down over 7.7 years. With expected array life of ~30 years, free power and an income stream should accrue in the second and third operative decades. CONCLUSIONS: Solar-assisted power is feasible and cost-effective. Dialysis services should assess their local solar conditions and determine whether this ecosensitive power option might suit their circumstance. PMID- 22223615 TI - The living kidney donor evaluation: focus on renal issues. AB - Living kidney donor evaluations and follow-up have previously been addressed mostly by transplant physicians and surgeons. However, this area is significantly informed by basic principles of renal physiology and is of increasing clinical interest to general nephrologists. The general nephrology community is increasingly involved in evaluating the suitability of potential donors and in following them after donation when questions are raised about low GFR, hypertension, and other renal concerns. This article focuses on some of the most central and common issues that arise in evaluating potential donors and attempts to provide guidance on the basis of our review of the living donor literature, extrapolations from the general nephrology literature, and our own clinical experience. PMID- 22223616 TI - Thoracic hyperkyphosis: a survey of Australian physiotherapists. AB - BACKGROUND: Age-related thoracic hyperkyphosis can lead to poor health outcomes including pain and dysfunction. Physiotherapists are fundamentally involved in the assessment and treatment of this problem but there is no published data that details assessment and treatment strategies or the attitudes of practitioners with respect to hyperkyphosis. PURPOSE: The purpose of the study is to ascertain current physiotherapy practice for, and attitudes to, the assessment and treatment of thoracic hyperkyphosis in Australia. METHOD: A stratified random sample (N = 468) of Australian physiotherapists in all states and territories working in hospitals, outpatient clinics and community clinics were sent an anonymous cross-sectional postal survey. The survey had six sections identifying clinical profile, prevalence, measurement strategy, treatment frequency, treatment strategy and evidence source. RESULTS: A response rate of 47% with anonymity preserved was achieved. The majority of respondents had a musculoskeletal practice profile (75%). Seventy-eight per cent encountered hyperkyphosis at least weekly, and three treatment sessions were most commonly given (35%). Visual inspection was almost universally used to assess the degree of hyperkyphosis (98%), and for 64% it was their only measurement tool. Postural re-education was the most common treatment strategy (90%) but the range of treatments reported was diverse. The primary source of evidence used by the majority of respondents was their undergraduate education, and there was concern expressed that physiotherapists lack good evidence upon which to make therapeutic decisions about hyperkyphosis. CONCLUSIONS: Thoracic hyperkyphosis is commonly encountered by physiotherapists. Measurement of treatment efficacy is highly subjective, and the treatment modalities employed are diverse. Many physiotherapists based their management of hyperkyphosis on their undergraduate education alone. PMID- 22223617 TI - Ab initio study of the electronic and magnetic properties of Sr(2 x)La(x)Fe(1+y/2)Mo(1-y/2)O6 double perovskites. AB - Using the first-principles full potential linearized augmented plane wave method, the electronic structure of Sr(2-x)La(x)Fe(1+y/2)Mo(1-y/2)O6 (SLFMO) double perovskite systems is investigated for x = 1/2 and 1 and for y = +1 and -1. Substituting Sr atoms by La atoms allows one to tune the electrons added into the minority spin band and enhances the half-metal feature--according to the rigid band shift model--even if the magnetization decreases with increasing La concentration. By taking into account the chemical disorder on the Fe and Mo sites, resulting from the introduction of La as shown experimentally, it is shown (i) that a supplemental magnetization reduction occurs because the magnetic moment on the Fe antisite is opposite to the one on the Fe regular sites and (ii) that the half-metal feature is preserved in SLFMO for x = 1/2 and 1 contrary to the case for SFMO. Finally, because surface or interface Fe deficiency should have a more limited impact on the spin polarization than for SFMO, SLFMO/SrTiO3 multilayers are investigated in order to confirm this prediction by determining the spin polarization at the interface, which is found to remain high. PMID- 22223618 TI - Does baseline fatigue influence treatment response to reboxetine or citalopram in depression? An open label randomized controlled trial. AB - It has been suggested that antidepressants that increase noradrenergic transmission should be better than serotonergic antidepressants at treating fatigue in depression. We conducted a secondary analysis of an RCT in which patients with depression were randomly assigned to reboxetine (a noradrenaline reuptake inhibitor [NARI]) or citalopram (a selective serotonin reuptake inhibitor [SSRI]). We investigated the difference between citalopram and reboxetine in treating the symptom of fatigue in depression, and also in treating depression with high levels of baseline fatigue. We found no difference between citalopram and reboxetine in terms of improvement in fatigue at six weeks (0.11, 95% confidence interval (-0.28, 0.49); p = 0.59:), or at 12 weeks. Using the Beck Depression Inventory at 12 weeks as the outcome measure, we found some evidence in support of our hypothesis that reboxetine is more effective than citalopram in treating depression in those with high baseline fatigue (interaction term: -2.87, 95% confidence interval (-5.15, -0.60); p = 0.01). We conclude that there is no evidence of any difference between reboxetine and citalopram in their efficacy in treating fatigue as a symptom of depression, but that reboxetine may be more effective in treating depression with high levels of fatigue. Fatigue might be useful in the prediction of response to NARIs or SSRIs. PMID- 22223619 TI - Synthesis and characterizations of iso-luminol-functionalized, tadpole-shaped, gold nanomaterials. AB - Iso-luminol functionalized gold nanomaterials were synthesized in high yield by a simple seeding approach, using the chemiluminescent reagent iso-luminol as reductant in the presence of HAuCl(4), AgNO(3) and cetyltrimethylammonium bromide (CTAB). The morphology of as-prepared gold nanoparticles was characterized by transmission electron microscopy and UV-vis spectroscopy, showing that gold nanotadpoles (AuNTps) were obtained. Subsequent experiments revealed that the amounts of seed colloids and AgNO(3) and the concentrations of iso-luminol and CTAB in the growth solution play critical roles in the formation of well-shaped AuNTps. The surface state of AuNTps was characterized by UV-vis spectroscopy and fluorescence spectroscopy, indicating that iso-luminol and its oxidation product, 4-aminophthalate, coexisted on the surface of AuNTps. The CL behaviour was studied by static injection CL experiments, demonstrating that AuNTps were of CL activity. Finally, the growth mechanism of AuNTps was also discussed. PMID- 22223621 TI - Simultaneous purification and site-specific modification of pyrroline-carboxy lysine proteins. AB - Sticky residue: Pyrroline-carboxy-lysine (Pcl) can be readily incorporated into proteins expressed in E. coli and mammalian cells by using the pyrrolysyl tRNA/tRNA synthetase pair. Pcl can be used as a single amino acid purification tag and can be site-specifically modified with functional probes during the elution process. PMID- 22223622 TI - The field of proteomics continues to expand. PMID- 22223620 TI - Dynamic expression of Tbx2 subfamily genes in development of the mouse reproductive system. AB - BACKGROUND: Tbx2, Tbx3, Tbx4, and Tbx5, members of the Tbx2 subfamily of T-box transcription factor genes, are important for many aspects of embryonic development and mutations in some human TBX2 subfamily genes cause developmental syndromes. In addition, TBX2 and TBX3 are overexpressed in a variety of cancers, including reproductive system cancers. This study characterizes the expression of Tbx2 subfamily genes during development of the reproductive system. RESULTS: We show that these genes are expressed in both the internal and external reproductive systems. Tbx2 is expressed in gonads and genital ducts, the Wolffian and Mullerian ducts, while Tbx3 is only expressed in genital ducts. Tbx4 is expressed in embryonic and postnatal germ cells. All four genes are expressed in mesenchyme in external genitalia, with Tbx3 and Tbx5 expression in the epithelium as well. CONCLUSION: This study lays the foundation for investigation of functional requirements for Tbx2 subfamily genes in development of the mammalian reproductive system. PMID- 22223624 TI - Searching for partners. AB - A combination of the EMARS reaction and the application of mass spectrometry based proteomics techniques promises to permit cell-surface molecular clustering to be analyzed under physiological conditions [Jiang et al., Proteomics 2012, 12, 54-62]. It is very likely that this approach will provide new insights into a wide range of research areas directed at understanding the cell-surface interactome. PMID- 22223629 TI - Two different packing arrangements of antiparallel polyalanine. PMID- 22223630 TI - Direct graphene growth on Co3O4(111) by molecular beam epitaxy. AB - Direct growth of graphene on Co(3)O(4)(111) at 1000 K was achieved by molecular beam epitaxy from a graphite source. Auger spectroscopy shows a characteristic sp(2) carbon lineshape, at average carbon coverages from 0.4 to 3 ML. Low energy electron diffraction (LEED) indicates (111) ordering of the sp(2) carbon film with a lattice constant of 2.5(+/-0.1) A characteristic of graphene. Sixfold symmetry of the graphene diffraction spots is observed at 0.4, 1 and 3 ML. The LEED data also indicate an average domain size of ~1800 A, and show an incommensurate interface with the Co(3)O(4)(111) substrate, where the latter exhibits a lattice constant of 2.8(+/-0.1) A. Core level photoemission shows a characteristically asymmetric C(1s) feature, with the expected pi to pi* satellite feature, but with a binding energy for the 3 ML film of 284.9(+/-0.1) eV, indicative of substantial graphene-to-oxide charge transfer. Spectroscopic ellipsometry data demonstrate broad similarity with graphene samples physically transferred to SiO(2) or grown on SiC substrates, but with the pi to pi* absorption blue-shifted, consistent with charge transfer to the substrate. The ability to grow graphene directly on magnetically and electrically polarizable substrates opens new opportunities for industrial scale development of charge- and spin-based devices. PMID- 22223631 TI - A practical quantification of blood glucose production due to high-level chronic stress. AB - Blood glucose (BG) is the primary metabolic fuel for, among others, cancer cell progression, cardiovascular disease and inflammation. Stress is an important contributor to the amount of BG produced especially by the liver. In this paper, we attempt to quantify the BG production due to chronic (in the order of weeks) high-level psychological stress in a manner that a lay person will understand. Three independent approaches were used. The first approach was based on a literature survey of stress hormone data from healthy individuals and its subsequent mathematical manipulation. The next approach was a deductive process where BG levels could be deduced from published stress data of large cardiovascular clinical trials. The third approach used empirical BG data and a BG simulation model. The three different methods produced an average BG increase of 2.2-fold above basal for high levels of stress over a period of more than a day. The standard deviation normalized to the average value was 4.5%. PMID- 22223632 TI - Ab initio molecular dynamics study of water oxidation reaction pathways in mono Ru catalysts. AB - Ab initio molecular dynamics simulations with an adaptive biasing potential are carried out to study the reaction path in mononuclear Ru catalysts for water oxidation of the type [(Ar)Ru(X)(bpy)](+) with different aromatic ligands (Ar). The critical step of the O-O bond formation in the catalytic cycle starting from the [(Ar)Ru(O)(bpy)](2+) intermediate is analyzed in detail. It is shown that an explicit inclusion of the solvent environment is essential for a realistic description of the reaction path. Clear evidence is presented for a concerted reaction in which the O-O bond formation is quickly followed by a proton transfer leading to a Ru-OOH intermediate and a hydronium ion. An alternative path in which the approaching water first coordinates to the metal centre is also investigated, and it is found to induce a structural instability of the catalyst with the breaking of the aromatic ligand coordination bond. PMID- 22223636 TI - A qualitative study of herbal medicine use in the Ukraine: implications for US pharmacy practice. AB - INTRODUCTION: Half of nearly all new immigrants in the United States come from only 10 countries, including the Ukraine. Immigrants bring facets of their culture to their new country; therefore, it is important for health care providers to have an appreciation and understanding of cultural differences in regard to the use of herbal medicine. OBJECTIVES: To determine health care provider and patient preferences for herbal versus synthetic medications, health care provider didactic training in pharmacognosy and trends in herbal medication use in the Ukraine. METHODS: Ten health care providers, pharmacists and physicians, were interviewed to determine their views on herbal medicine use in Ukraine using semistructured in-depth face-to-face interviews. RESULTS: Ukrainian practitioners and patients viewed herbal medicines as safer than synthetic drugs, appropriate and preferable for use in chronic and preventative programs. Synthetic drugs were viewed as more desirable for use in the acute setting. Preference for synthetic versus herbal medication was not price driven. CONCLUSIONS: The inclusion of pharmacognosy training in the US pharmacy curricula is recommended to facilitate US health care professional's ability to provide pharmaceutical care both to new US immigrants and to the increasing number of US citizens utilizing herbal medications. PMID- 22223637 TI - Malin regulates Wnt signaling pathway through degradation of dishevelled2. AB - Using yeast-two hybrid screening followed by co-immunoprecipitation assay, we have found that the Lafora disease ubiquitin ligase malin interacts with dishevelled2, a key mediator of Wnt signaling pathway. Overexpression of malin enhances the degradation of dishevelled2 and inhibits Wnt signaling, which is evident from the down-regulation of beta-catenin target genes and the decrease in beta-catenin-mediated transcriptional activity. Partial knockdown of malin significantly increases the level of dishevelled2 and up-regulates Wnt signaling. Several malin mutants are found to be ineffective in degrading dishevelled2 and regulating the Wnt pathway. We have also found that malin enhances K48- and K63 linked ubiquitination of dishevelled2 that could lead to its degradation through both proteasome and autophagy. Altogether, our results indicate that malin regulates Wnt signaling pathway through the degradation of dishevelled2 and suggest possible deregulation of Wnt signaling in Lafora disease. PMID- 22223638 TI - Intronic promoter drives the BORIS-regulated expression of FerT in colon carcinoma cells. AB - Fer is an intracellular tyrosine kinase that accumulates in most mammalian tissues. A truncated variant of Fer, FerT, is uniquely detected in spermatogenic cells and is absent from normal somatic tissues. Here, we show that in addition to Fer, FerT also accumulates in CC cells and in metastases derived from colorectal tumors, but not in normal human cells. Thus, FerT is a new member of the CTA protein family. Transcription of the ferT gene in CC cells was found to be driven by an intronic promoter residing in intron 10 of the fer gene and to be regulated by another CTA, the Brother of the Regulator of Imprinted Sites (BORIS) transcription factor. BORIS binds to the ferT promoter and down-regulation of BORIS significantly decreases the expression of ferT in CC cells. Accumulation of the ferT RNA was also regulated by the DNA methylation status and paralleled the expression profile of the boris transcript. Accordingly, the intronic ferT promoter was found to be hypomethylated in cancer cells expressing the FerT protein, by comparison with non-expressers. Collectively, we show here that FerT is a new CTA whose accumulation in CC cells, commonly considered low CTA expressers, is controlled by a novel transcription regulatory mechanism. PMID- 22223639 TI - Cdk5 protein inhibition and Abeta42 increase BACE1 protein level in primary neurons by a post-transcriptional mechanism: implications of CDK5 as a therapeutic target for Alzheimer disease. AB - The beta-secretase enzyme BACE1 initiates production of the amyloid-beta (Abeta) peptide that comprises plaques in Alzheimer disease (AD) brain. BACE1 levels are increased in AD, potentially accelerating Abeta generation, but the mechanisms of BACE1 elevation are not fully understood. Cdk5/p25 has been implicated in neurodegeneration and BACE1 regulation, suggesting therapeutic Cdk5 inhibition for AD. In addition, caspase 3 has been implicated in BACE1 elevation. Here, we show that the Cdk5 level and p25:p35 ratio were elevated and correlated with BACE1 level in brains of AD patients and 5XFAD transgenic mice. Mouse primary cortical neurons treated with Abeta42 oligomers had increased BACE1 level and p25:p35 ratio. Surprisingly, the Abeta42-induced BACE1 elevation was not blocked by Cdk5 inhibitors CP68130 and roscovitine, and instead the BACE1 level was increased greater than with Abeta42 treatment alone. Moreover, Cdk5 inhibitors alone elevated BACE1 in a time- and dose-dependent manner that coincided with increased caspase 3 cleavage and decreased Cdk5 level. Caspase 3 inhibitor benzyloxycarbonyl-VAD failed to prevent the Abeta42-induced BACE1 increase. Further experiments suggested that the Abeta42-induced BACE1 elevation was the result of a post-transcriptional mechanism. We conclude that Abeta42 may increase the BACE1 level independently of either Cdk5 or caspase 3 and that Cdk5 inhibition for AD may cause BACE1 elevation, a potentially negative therapeutic outcome. PMID- 22223641 TI - The molecular chaperone gp96/GRP94 interacts with Toll-like receptors and integrins via its C-terminal hydrophobic domain. AB - The structural basis for molecular chaperones to discern misfolded proteins has long been an enigma. As the endoplasmic reticulum paralogue of the cytosolic HSP90, gp96 (GRP94, HSP90b1) is an essential molecular chaperone for Toll-like receptors (TLRs) and integrins. However, little is known about its client-binding domain (CBD). Herein, we provide genetic and biochemical evidence to definitively demonstrate that a C-terminal loop structure, formed by residues 652-678, is the critical region of CBD for both TLRs and integrins. Deletion of this region affects neither the intrinsic ATPase activity nor the overall conformation of gp96. However, without it, the chaperoning function of gp96 collapses. We also find a critical Met pair (Met(658)-Met(662)) for the folding of integrins but not TLRs. Moreover, we find that the TLR binding to gp96 is also dependent on the C terminal dimerization domain but not the N-terminal ATP-binding pocket of gp96. Our study has unveiled surprisingly the exquisite specificity of gp96 in substrate binding and suggests a manipulation of its CBD as an alternative strategy for targeted therapy of a variety of diseases. PMID- 22223640 TI - Structural insights into apoptotic DNA degradation by CED-3 protease suppressor-6 (CPS-6) from Caenorhabditis elegans. AB - Endonuclease G (EndoG) is a mitochondrial protein that traverses to the nucleus and participates in chromosomal DNA degradation during apoptosis in yeast, worms, flies, and mammals. However, it remains unclear how EndoG binds and digests DNA. Here we show that the Caenorhabditis elegans CPS-6, a homolog of EndoG, is a homodimeric Mg(2+)-dependent nuclease, binding preferentially to G-tract DNA in the optimum low salt buffer at pH 7. The crystal structure of CPS-6 was determined at 1.8 A resolution, revealing a mixed alphabeta topology with the two betabetaalpha-metal finger nuclease motifs located distantly at the two sides of the dimeric enzyme. A structural model of the CPS-6-DNA complex suggested a positively charged DNA-binding groove near the Mg(2+)-bound active site. Mutations of four aromatic and basic residues: Phe(122), Arg(146), Arg(156), and Phe(166), in the protein-DNA interface significantly reduced the DNA binding and cleavage activity of CPS-6, confirming that these residues are critical for CPS-6 DNA interactions. In vivo transformation rescue experiments further showed that the reduced DNase activity of CPS-6 mutants was positively correlated with its diminished cell killing activity in C. elegans. Taken together, these biochemical, structural, mutagenesis, and in vivo data reveal a molecular basis of how CPS-6 binds and hydrolyzes DNA to promote cell death. PMID- 22223642 TI - G Protein-coupled receptor kinase 5 is localized to centrosomes and regulates cell cycle progression. AB - G protein-coupled receptor kinases (GRKs) are important regulators of G protein coupled receptor function and mediate receptor desensitization, internalization, and signaling. While GRKs also interact with and/or phosphorylate many other proteins and modify their function, relatively little is known about the cellular localization of endogenous GRKs. Here we report that GRK5 co-localizes with gamma tubulin, centrin, and pericentrin in centrosomes. The centrosomal localization of GRK5 is observed predominantly at interphase and although its localization is not dependent on microtubules, it can mediate microtubule nucleation of centrosomes. Knockdown of GRK5 expression leads to G2/M arrest, characterized by a prolonged G2 phase, which can be rescued by expression of wild type but not catalytically inactive GRK5. This G2/M arrest appears to be due to increased expression of p53, reduced activity of aurora A kinase and a subsequent delay in the activation of polo-like kinase 1. Overall, these studies demonstrate that GRK5 is localized in the centrosome and regulates microtubule nucleation and normal cell cycle progression. PMID- 22223643 TI - Association of novel domain in active site of archaic hyperthermophilic maltogenic amylase from Staphylothermus marinus. AB - Staphylothermus marinus maltogenic amylase (SMMA) is a novel extreme thermophile maltogenic amylase with an optimal temperature of 100 degrees C, which hydrolyzes alpha-(1-4)-glycosyl linkages in cyclodextrins and in linear malto oligosaccharides. This enzyme has a long N-terminal extension that is conserved among archaic hyperthermophilic amylases but is not found in other hydrolyzing enzymes from the glycoside hydrolase 13 family. The SMMA crystal structure revealed that the N-terminal extension forms an N' domain that is similar to carbohydrate-binding module 48, with the strand-loop-strand region forming a part of the substrate binding pocket with several aromatic residues, including Phe-95, Phe-96, and Tyr-99. A structural comparison with conventional cyclodextrin hydrolyzing enzymes revealed a striking resemblance between the SMMA N' domain position and the dimeric N domain position in bacterial enzymes. This result suggests that extremophilic archaea that live at high temperatures may have adopted a novel domain arrangement that combines all of the substrate binding components within a monomeric subunit. The SMMA structure provides a molecular basis for the functional properties that are unique to hyperthermophile maltogenic amylases from archaea and that distinguish SMMA from moderate thermophilic or mesophilic bacterial enzymes. PMID- 22223644 TI - Contactin-associated protein 1 (Caspr1) regulates the traffic and synaptic content of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. AB - Glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type mediate fast excitatory synaptic transmission in the CNS. Synaptic strength is modulated by AMPA receptor binding partners, which regulate receptor synaptic targeting and functional properties. We identify Contactin associated protein 1 (Caspr1) as an AMPA receptor interactor. Caspr1 is present in synapses and interacts with AMPA receptors in brain synaptic fractions. Coexpression of Caspr1 with GluA1 increases the amplitude of glutamate-evoked currents. Caspr1 overexpression in hippocampal neurons increases the number and size of synaptic GluA1 clusters, whereas knockdown of Caspr1 decreases the intensity of synaptic GluA1 clusters. Hence, Caspr1 is a regulator of the trafficking of AMPA receptors to synapses. PMID- 22223645 TI - Kinome-wide selectivity profiling of ATP-competitive mammalian target of rapamycin (mTOR) inhibitors and characterization of their binding kinetics. AB - An intensive recent effort to develop ATP-competitive mTOR inhibitors has resulted in several potent and selective molecules such as Torin1, PP242, KU63794, and WYE354. These inhibitors are being widely used as pharmacological probes of mTOR-dependent biology. To determine the potency and specificity of these agents, we have undertaken a systematic kinome-wide effort to profile their selectivity and potency using chemical proteomics and assays for enzymatic activity, protein binding, and disruption of cellular signaling. Enzymatic and cellular assays revealed that all four compounds are potent inhibitors of mTORC1 and mTORC2, with Torin1 exhibiting ~20-fold greater potency for inhibition of Thr 389 phosphorylation on S6 kinases (EC(50) = 2 nM) relative to other inhibitors. In vitro biochemical profiling at 10 MUM revealed binding of PP242 to numerous kinases, although WYE354 and KU63794 bound only to p38 kinases and PI3K isoforms and Torin1 to ataxia telangiectasia mutated, ATM and Rad3-related protein, and DNA-PK. Analysis of these protein targets in cellular assays did not reveal any off-target activities for Torin1, WYE354, and KU63794 at concentrations below 1 MUM but did show that PP242 efficiently inhibited the RET receptor (EC(50), 42 nM) and JAK1/2/3 kinases (EC(50), 780 nM). In addition, Torin1 displayed unusually slow kinetics for inhibition of the mTORC1/2 complex, a property likely to contribute to the pharmacology of this inhibitor. Our results demonstrated that, with the exception of PP242, available ATP-competitive compounds are highly selective mTOR inhibitors when applied to cells at concentrations below 1 MUM and that the compounds may represent a starting point for medicinal chemistry efforts aimed at developing inhibitors of other PI3K kinase-related kinases. PMID- 22223646 TI - Cdc6 protein activates p27KIP1-bound Cdk2 protein only after the bound p27 protein undergoes C-terminal phosphorylation. AB - In mammalian cells Cdk2 activity during the G(1)-S transition is mainly controlled by p27(KIP1). Although the amount and subcellular localization of p27 influence Cdk2 activity, how Cdk2 activity is regulated during this phase transition still remains virtually unknown. Here we report an entirely new mechanism for this regulation. Cdc6 the AAA+ ATPase, known to assemble prereplicative complexes on chromosomal replication origins and activate p21(CIP1)-bound Cdk2, also activated p27-bound Cdk2 in its ATPase and cyclin binding motif-dependent manner but only after the p27 bound to the Cdk2 was phosphorylated at the C terminus. ROCK, which mediates a signal for cell anchorage to the extracellular matrix and activates the mTORC1 cascade as well as controls cytoskeleton assembly, was partly responsible for C-terminal phosphorylation of the p27. In vitro reconstitution demonstrated ROCK (Rho associated kinase)-mediated phosphorylation of Cdk2-bound p27 at the C terminus and subsequent activation of the Cdk2 by Cdc6. PMID- 22223647 TI - Nuclear factor-kappaB (NF-kappaB) inhibitory protein IkappaBbeta determines apoptotic cell death following exposure to oxidative stress. AB - The transcription factor NF-kappaB regulates the cellular response to inflammatory and oxidant stress. Although many studies have evaluated NF-kappaB activity following exposure to oxidative stress, the role of the IkappaB family of inhibitory proteins in modulating this activity remains unclear. Specifically, the function of IkappaBbeta in mediating the cellular response to oxidative stress has not been evaluated. We hypothesized that blocking oxidative stress induced NF-kappaB signaling through IkappaBbeta would prevent apoptotic cell death. Using IkappaBbeta knock-in mice (AKBI), in which the IkappaBalpha gene is replaced with the IkappaBbeta cDNA, we show that IkappaBbeta overexpression prevented oxidative stress-induced apoptotic cell death. This was associated with retention of NF-kappaB subunits in the nucleus and maintenance of NF-kappaB activity. Furthermore, the up-regulation of pro-apoptotic genes in WT murine embryonic fibroblasts (MEFs) exposed to serum starvation was abrogated in AKBI MEFs. Inhibition of apoptosis was observed in WT MEFs overexpressing IkappaBbeta with simultaneous IkappaBalpha knockdown, whereas IkappaBbeta overexpression alone did not produce this effect. These findings represent a necessary but not sufficient role of IkappaBbeta in preventing oxidant stress-induced cell death. PMID- 22223648 TI - Dimeric alpha-cobratoxin X-ray structure: localization of intermolecular disulfides and possible mode of binding to nicotinic acetylcholine receptors. AB - In Naja kaouthia cobra venom, we have earlier discovered a covalent dimeric form of alpha-cobratoxin (alphaCT-alphaCT) with two intermolecular disulfides, but we could not determine their positions. Here, we report the alphaCT-alphaCT crystal structure at 1.94 A where intermolecular disulfides are identified between Cys(3) in one protomer and Cys(20) of the second, and vice versa. All remaining intramolecular disulfides, including the additional bridge between Cys(26) and Cys(30) in the central loops II, have the same positions as in monomeric alpha cobratoxin. The three-finger fold is essentially preserved in each protomer, but the arrangement of the alphaCT-alphaCT dimer differs from those of noncovalent crystallographic dimers of three-finger toxins (TFT) or from the kappa bungarotoxin solution structure. Selective reduction of Cys(26)-Cys(30) in one protomer does not affect the activity against the alpha7 nicotinic acetylcholine receptor (nAChR), whereas its reduction in both protomers almost prevents alpha7 nAChR recognition. On the contrary, reduction of one or both Cys(26)-Cys(30) disulfides in alphaCT-alphaCT considerably potentiates inhibition of the alpha3beta2 nAChR by the toxin. The heteromeric dimer of alpha-cobratoxin and cytotoxin has an activity similar to that of alphaCT-alphaCT against the alpha7 nAChR and is more active against alpha3beta2 nAChRs. Our results demonstrate that at least one Cys(26)-Cys(30) disulfide in covalent TFT dimers, similar to the monomeric TFTs, is essential for their recognition by alpha7 nAChR, although it is less important for interaction of covalent TFT dimers with the alpha3beta2 nAChR. PMID- 22223649 TI - Cell division cycle 7 is a novel regulator of transforming growth factor-beta induced smooth muscle cell differentiation. AB - Smooth muscle cell (SMC) differentiation and proliferation occur simultaneously during embryonic development. The underlying mechanisms especially common factors regulating both processes, however, remain largely unknown. The present study has identified cell division cycle 7 (Cdc7) as one of the factors mediating both the proliferation and SMC differentiation. TGF-beta induces Cdc7 expression and phosphorylation in the initial phase of SMC differentiation of pluripotent mesenchymal C3H10T1/2 cells. Cdc7 specific inhibitor or shRNA knockdown suppresses TGF-beta-induced expression of SMC early markers including alpha-SMA, SM22alpha, and calponin. Cdc7 overexpression, on the other hand, enhances SMC marker expression. Cdc7 function in inducing SMC differentiation is independent of Dumbbell former 4 or Dbf4, the catalytic subunit of Cdc7 critical for cell proliferation, suggesting that Cdc7 mediates SMC differentiation through a mechanism distinct from cell proliferation. Cdc7 regulates SMC differentiation via activating SMC marker gene transcription. Knockdown of Cdc7 by shRNA inhibits SMC marker gene promoter activities. Mechanistically, Cdc7 interacts with Smad3 to induce SMC differentiation. Smad3 is required for Cdc7 function in inducing SMC promoter activities and marker gene expression. Likewise, Cdc7 enhances Smad3 binding to SMC marker promoter via supporting Smad3 nuclear retention and physically interacting with Smad3. Taken together, our studies have demonstrated a novel role of Cdc7 in SMC differentiation. PMID- 22223651 TI - The signaling protein CD38 is essential for early embryonic development. AB - CD38 is a multifunctional protein possessing ADP-ribosyl cyclase activity responsible for both the synthesis and the degradation of several Ca(2+) mobilizing second messengers. Although a variety of functions have been ascribed to CD38, such as immune responses, insulin secretion, and social behavior in adults, nothing is known of its role during embryonic development when Ca(2+) signals feature prominently. Here, we report the identification and functional expression of CD38 from Xenopus laevis, a key model organism for the study of vertebrate development. We show that CD38 expression and endogenous ADP-ribosyl cyclase activity are developmentally regulated during cellular differentiation. Chemical or molecular inhibition of CD38 abolished ADP-ribosyl cyclase activity and disrupted elongation of the anterior-posterior axis and differentiation of skeletal muscle, culminating in embryonic death. Our data uncover a previously unknown role for CD38 as an essential regulator of embryonic development. PMID- 22223650 TI - Lipolysis response to endoplasmic reticulum stress in adipose cells. AB - In obesity and diabetes, adipocytes show significant endoplasmic reticulum (ER) stress, which triggers a series of responses. This study aimed to investigate the lipolysis response to ER stress in rat adipocytes. Thapsigargin, tunicamycin, and brefeldin A, which induce ER stress through different pathways, efficiently activated a time-dependent lipolytic reaction. The lipolytic effect of ER stress occurred with elevated cAMP production and protein kinase A (PKA) activity. Inhibition of PKA reduced PKA phosphosubstrates and attenuated the lipolysis. Although both ERK1/2 and JNK are activated during ER stress, lipolysis is partially suppressed by inhibiting ERK1/2 but not JNK and p38 MAPK and PKC. Thus, ER stress induces lipolysis by activating cAMP/PKA and ERK1/2. In the downstream lipolytic cascade, phosphorylation of lipid droplet-associated protein perilipin was significantly promoted during ER stress but attenuated on PKA inhibition. Furthermore, ER stress stimuli did not alter the levels of hormone-sensitive lipase and adipose triglyceride lipase but caused Ser-563 and Ser-660 phosphorylation of hormone-sensitive lipase and moderately elevated its translocation from the cytosol to lipid droplets. Accompanying these changes, total activity of cellular lipases was promoted to confer the lipolysis. These findings suggest a novel pathway of the lipolysis response to ER stress in adipocytes. This lipolytic activation may be an adaptive response that regulates energy homeostasis but with sustained ER stress challenge could contribute to lipotoxicity, dyslipidemia, and insulin resistance because of persistently accelerated free fatty acid efflux from adipocytes to the bloodstream and other tissues. PMID- 22223652 TI - Receptor tyrosine kinase Ephb6 regulates vascular smooth muscle contractility and modulates blood pressure in concert with sex hormones. AB - Eph kinases constitute the largest receptor tyrosine kinase family, and their ligands, ephrins (Efns), are also cell surface molecules. Our study is the first to assess the role of Ephb6 in blood pressure (BP) regulation. We observed that EphB6 and all three of its Efnb ligands were expressed on vascular smooth muscle cells (VSMC) in mice. We discovered that small arteries from castrated Ephb6 gene KO males showed increased contractility, RhoA activation, and constitutive myosin light chain phosphorylation ex vivo compared with their WT counterparts. Consistent with this finding, castrated Ephb6 KO mice presented heightened BP compared with castrated WT controls. In vitro experiments in VSMC revealed that cross-linking Efnbs but not Ephb6 resulted in reduced VSMC contractions, suggesting that reverse signaling through Efnbs was responsible for the observed BP phenotype. The reverse signaling was mediated by an adaptor protein Grip1. Additional experiments demonstrated decreased 24-h urine catecholamines in male Ephb6 KO mice, probably as a compensatory feedback mechanism to keep their BP in the normal range. After castration, however, such compensation was abolished in Ephb6 KO mice and was likely the reason why BP increased overtly in these animals. It suggests that Ephb6 has a target in the nervous/endocrine system in addition to VSMC, regulating a testosterone-dependent catecholamine compensatory mechanism. Our study discloses that Ephs and Efns, in concert with testosterone, play a critical role in regulating small artery contractility and BP. PMID- 22223653 TI - Induction of DNA damage signaling upon Rift Valley fever virus infection results in cell cycle arrest and increased viral replication. AB - Rift Valley fever virus (RVFV) is a highly pathogenic arthropod-borne virus infecting a wide range of vertebrate hosts. Of particular interest is the nonstructural NSs protein, which forms large filamentous fibril bundles in the nucleus. Past studies have shown NSs to be a multifaceted protein important for virulence through modulation of the interferon response as well acting as a general inhibitor of transcription. Here we investigated the regulation of the DNA damage signaling cascades by RVFV infection and found virally inducted phosphorylation of the classical DNA damage signaling proteins, ataxia telangiectasia mutated (ATM) (Ser-1981), Chk.2 (Thr-68), H2A.X (Ser-139), and p53 (Ser-15). In contrast, ataxia-telangiectasia mutated and Rad3-related kinase (ATR) (Ser-428) phosphorylation was decreased following RVFV infection. Importantly, both the attenuated vaccine strain MP12 and the fully virulent strain ZH548 showed strong parallels in their up-regulation of the ATM arm of the DNA damage response and in the down-regulation of the ATR pathway. The increase in DNA damage signaling proteins did not result from gross DNA damage as no increase in DNA damage was observed following infection. Rather the DNA damage signaling was found to be dependent on the viral protein NSs, as an NSs mutant virus was not found to induce the equivalent signaling pathways. RVFV MP12 infected cells also displayed an S phase arrest that was found to be dependent on NSs expression. Use of ATM and Chk.2 inhibitors resulted in a marked decrease in S phase arrest as well as viral production. These results indicate that RVFV NSs induces DNA damage signaling pathways that are beneficial for viral replication. PMID- 22223656 TI - Crystal structures of (Mg1-x,Fe(x))SiO3 postperovskite at high pressures. AB - X-ray diffraction experiments on postperovskite (ppv) with compositions (Mg(0.9)Fe(0.1))SiO(3) and (Mg(0.6)Fe(0.4))SiO(3) at Earth core-mantle boundary pressures reveal different crystal structures. The former adopts the CaIrO(3) type structure with space group Cmcm, whereas the latter crystallizes in a structure with the Pmcm (Pmma) space group. The latter has a significantly higher density (rho = 6.119(1) g/cm(3)) than the former (rho = 5.694(8) g/cm(3)) due to both the larger amount of iron and the smaller ionic radius of Fe(2+) as a result of an electronic spin transition observed by X-ray emission spectroscopy (XES). The smaller ionic radius for low-spin compared to high-spin Fe(2+) also leads to an ordered cation distribution in the M1 and M2 crystallographic sites of the higher density ppv structure. Rietveld structure refinement indicates that approximately 70% of the total Fe(2+) in that phase occupies the M2 site. XES results indicate a loss of 70% of the unpaired electronic spins consistent with a low spin M2 site and high spin M1 site. First-principles calculations of the magnetic ordering confirm that Pmcm with a two-site model is energetically more favorable at high pressure, and predict that the ordered structure is anisotropic in its electrical and elastic properties. These results suggest that interpretations of seismic structure in the deep mantle need to treat a broader range of mineral structures than previously considered. PMID- 22223655 TI - Na(V)1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms. AB - Na(V)1.1 is the primary voltage-gated Na(+) channel in several classes of GABAergic interneurons, and its reduced activity leads to reduced excitability and decreased GABAergic tone. Here, we show that Na(V)1.1 channels are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus. Mice carrying a heterozygous loss of function mutation in the Scn1a gene (Scn1a(+/-)), which encodes the pore-forming alpha-subunit of the Na(V)1.1 channel, have longer circadian period than WT mice and lack light-induced phase shifts. In contrast, Scn1a(+/-) mice have exaggerated light-induced negative-masking behavior and normal electroretinogram, suggesting an intact retina light response. Scn1a(+/-) mice show normal light induction of c-Fos and mPer1 mRNA in ventral SCN but impaired gene expression responses in dorsal SCN. Electrical stimulation of the optic chiasm elicits reduced calcium transients and impaired ventro-dorsal communication in SCN neurons from Scn1a(+/-) mice, and this communication is barely detectable in the homozygous gene KO (Scn1a(-/-)). Enhancement of GABAergic transmission with tiagabine plus clonazepam partially rescues the effects of deletion of Na(V)1.1 on circadian period and phase shifting. Our report demonstrates that a specific voltage-gated Na(+) channel and its associated impairment of SCN interneuronal communication lead to major deficits in the function of the master circadian pacemaker. Heterozygous loss of Na(V)1.1 channels is the underlying cause for severe myoclonic epilepsy of infancy; the circadian deficits that we report may contribute to sleep disorders in severe myoclonic epilepsy of infancy patients. PMID- 22223659 TI - Forkhead transcription factor FoxA1 regulates sweat secretion through Bestrophin 2 anion channel and Na-K-Cl cotransporter 1. AB - Body temperature is maintained in a narrow range in mammals, primarily controlled by sweating. In humans, the dynamic thermoregulatory organ, comprised of 2-4 million sweat glands distributed over the body, can secrete up to 4 L of sweat per day, thereby making it possible to withstand high temperatures and endure prolonged physical stress (e.g., long-distance running). The genetic basis for sweat gland function, however, is largely unknown. We find that the forkhead transcription factor, FoxA1, is required to generate mouse sweating capacity. Despite continued sweat gland morphogenesis, ablation of FoxA1 in mice results in absolute anihidrosis (lack of sweating). This inability to sweat is accompanied by down-regulation of the Na-K-Cl cotransporter 1 (Nkcc1) and the Ca(2+) activated anion channel Bestrophin 2 (Best2), as well as glycoprotein accumulation in gland lumens and ducts. Furthermore, Best2-deficient mice display comparable anhidrosis and glycoprotein accumulation. These findings link earlier observations that both sodium/potassium/chloride exchange and Ca(2+) are required for sweat production. FoxA1 is inferred to regulate two corresponding features of sweat secretion. One feature, via Best2, catalyzes a bicarbonate gradient that could help to drive calcium-associated ionic transport; the other, requiring Nkcc1, facilitates monovalent ion exchange into sweat. These mechanistic components can be pharmaceutical targets to defend against hyperthermia and alleviate defective thermoregulation in the elderly, and may provide a model relevant to more complex secretory processes. PMID- 22223660 TI - 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma. AB - 14-3-3 proteins are ubiquitously expressed regulators of various cellular functions, including proliferation, metabolism, and differentiation, and altered 14-3-3 expression is associated with development and progression of cancer. We report a transforming 14-3-3 oncoprotein, which we identified through conventional cytogenetics and whole-transcriptome sequencing analysis as a highly recurrent genetic mechanism in a clinically aggressive form of uterine sarcoma: high-grade endometrial stromal sarcoma (ESS). The 14-3-3 oncoprotein results from a t(10;17) genomic rearrangement, leading to fusion between 14-3-3epsilon (YWHAE) and either of two nearly identical FAM22 family members (FAM22A or FAM22B). Expression of YWHAE-FAM22 fusion oncoproteins was demonstrated by immunoblot in t(10;17)-bearing frozen tumor and cell line samples. YWHAE-FAM22 fusion gene knockdowns were performed with shRNAs and siRNAs targeting various FAM22A exons in an t(10;17)-bearing ESS cell line (ESS1): Fusion protein expression was inhibited, with corresponding reduction in cell growth and migration. YWHAE-FAM22 maintains a structurally and functionally intact 14-3-3epsilon (YWHAE) protein binding domain, which is directed to the nucleus by a FAM22 nuclear localization sequence. In contrast to classic ESS, harboring JAZF1 genetic fusions, YWHAE FAM22 ESS display high-grade histologic features, a distinct gene-expression profile, and a more aggressive clinical course. Fluorescence in situ hybridization analysis demonstrated absolute specificity of YWHAE-FAM22A/B genetic rearrangement for high-grade ESS, with no fusions detected in other uterine and nonuterine mesenchymal tumors (55 tumor types, n = 827). These discoveries reveal diagnostically and therapeutically relevant models for characterizing aberrant 14-3-3 oncogenic functions. PMID- 22223661 TI - Distinct influences of peptide-MHC quality and quantity on in vivo T-cell responses. AB - The strength of T-cell receptor (TCR) stimulation and subsequent T-cell response depend on a combination of peptide-major histocompatibility complex (pMHC) density and potency. By comparing two different pMHC at doses yielding similar proliferation in vivo, we have highlighted unexpected differences in the qualitative and quantitative effects of TCR ligand. Measurements of cytokine sensitivity and two-photon imaging of T cell-dendritic cell (T-DC) interactions reveal discrimination between comparably weak stimuli resulting from either decreased pMHC potency or pMHC density. In addition, TCR-induced genes in broad gene expression profiles segregate into two groups: one that responds to cumulative TCR signal and another that responds to pMHC quality, independent of quantity. These observations suggest that models of TCR ligand discrimination must account for disparate sensitivity of downstream responses to specific influences of pMHC potency. PMID- 22223662 TI - The mystery of missing heritability: Genetic interactions create phantom heritability. AB - Human genetics has been haunted by the mystery of "missing heritability" of common traits. Although studies have discovered >1,200 variants associated with common diseases and traits, these variants typically appear to explain only a minority of the heritability. The proportion of heritability explained by a set of variants is the ratio of (i) the heritability due to these variants (numerator), estimated directly from their observed effects, to (ii) the total heritability (denominator), inferred indirectly from population data. The prevailing view has been that the explanation for missing heritability lies in the numerator--that is, in as-yet undiscovered variants. While many variants surely remain to be found, we show here that a substantial portion of missing heritability could arise from overestimation of the denominator, creating "phantom heritability." Specifically, (i) estimates of total heritability implicitly assume the trait involves no genetic interactions (epistasis) among loci; (ii) this assumption is not justified, because models with interactions are also consistent with observable data; and (iii) under such models, the total heritability may be much smaller and thus the proportion of heritability explained much larger. For example, 80% of the currently missing heritability for Crohn's disease could be due to genetic interactions, if the disease involves interaction among three pathways. In short, missing heritability need not directly correspond to missing variants, because current estimates of total heritability may be significantly inflated by genetic interactions. Finally, we describe a method for estimating heritability from isolated populations that is not inflated by genetic interactions. PMID- 22223664 TI - Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/beta-catenin signaling. AB - Tissue inhibitor of metalloproteinases 1 (TIMP-1) is a matrix metalloproteinase (MMP)-independent regulator of growth and apoptosis in various cell types. The receptors and signaling pathways that are involved in the growth factor activities of TIMP-1, however, remain controversial. RNA interference of TIMP-1 has revealed that endogenous TIMP-1 suppresses the proliferation, metabolic activity, and osteogenic differentiation capacity of human mesenchymal stem cells (hMSCs). The knockdown of TIMP-1 in hMSCs activated the Wnt/beta-catenin signaling pathway as indicated by the increased stability and nuclear localization of beta-catenin in TIMP-1-deficient hMSCs. Moreover, TIMP-1 knockdown cells exhibited enhanced beta-catenin transcriptional activity, determined by Wnt/beta-catenin target gene expression analysis and a luciferase based beta-catenin-activated reporter assay. An analysis of a mutant form of TIMP 1 that cannot inhibit MMP indicated that the effect of TIMP-1 on beta-catenin signaling is MMP independent. Furthermore, the binding of CD63 to TIMP-1 on the surface of hMSCs is essential for the TIMP-1-mediated effects on Wnt/beta-catenin signaling. An array analysis of microRNAs (miRNAs) and transfection studies with specific miRNA inhibitors and mimics showed that let-7f miRNA is crucial for the regulation of beta-catenin activity and osteogenic differentiation by TIMP-1. Let 7f was up-regulated in TIMP-1-depleted hMSCs and demonstrably reduced axin 2, an antagonist of beta-catenin stability. Our results demonstrate that TIMP-1 is a direct regulator of hMSC functions and reveal a regulatory network in which let 7f modulates Wnt/beta-catenin activity. PMID- 22223663 TI - Compensatory functions of histone deacetylase 1 (HDAC1) and HDAC2 regulate transcription and apoptosis during mouse oocyte development. AB - Dramatic changes in chromatin structure and histone modification occur during oocyte growth, as well as a global cessation of transcription. The role of histone modifications in these processes is poorly understood. We report the effect of conditionally deleting Hdac1 and Hdac2 on oocyte development. Deleting either gene has little or no effect on oocyte development, whereas deleting both genes results in follicle development arrest at the secondary follicle stage. This developmental arrest is accompanied by substantial perturbation of the transcriptome and a global reduction in transcription even though histone acetylation is markedly increased. There is no apparent change in histone repressive marks, but there is a pronounced decrease in histone H3K4 methylation, an activating mark. The decrease in H3K4 methylation is likely a result of increased expression of Kdm5b because RNAi-mediated targeting of Kdm5b in double mutant oocytes results in an increase in H3K4 methylation. An increase in TRP53 acetylation also occurs in mutant oocytes and may contribute to the observed increased incidence of apoptosis. Taken together, these results suggest seminal roles of acetylation of histone and nonhistone proteins in oocyte development. PMID- 22223665 TI - Polyelectrolyte complex materials consisting of antibacterial and cell-supporting layers. AB - The characterization of a polyelectrolyte complex material comprised of two biopolymers, a chitosan upper layer and a gellan gum under layer, is reported. It is shown that the upper layer of chitosan with incorporated levofloxacin displays an antibacterial activity, while the under layer of a gellan gum/TiO(2) composite supports the growth of fibroblastic cells. PMID- 22223666 TI - Thiamine in nutrition therapy. AB - Clinicians involved with nutrition therapy traditionally concentrated on macronutrients and have generally neglected the importance of micronutrients, both vitamins and trace elements. Micronutrients, which work in unison, are important for fundamental biological processes and enzymatic reactions, and deficiencies may lead to disastrous consequences. This review concentrates on vitamin B(1), or thiamine. Alcoholism is not the only risk factor for thiamine deficiency, and thiamine deficiency is often not suspected in seemingly well nourished or even overnourished patients. Deficiency of thiamine has historically been described as beriberi but may often be seen in current-day practice, manifesting as neurologic abnormalities, mental changes, congestive heart failure, unexplained metabolic acidosis, and so on. This review explains the importance of thiamine in nutrition therapy and offers practical tips on prevention and management of deficiency states. PMID- 22223667 TI - Difficulties in applying pure Kohn-Sham density functional theory electronic structure methods to protein molecules. AB - Self-consistency-based Kohn-Sham density functional theory (KS-DFT) electronic structure calculations with Gaussian basis sets are reported for a set of 17 protein-like molecules with geometries obtained from the Protein Data Bank. It is found that in many cases such calculations do not converge due to vanishing HOMO LUMO gaps. A sequence of polyproline I helix molecules is also studied and it is found that self-consistency calculations using pure functionals fail to converge for helices longer than six proline units. Since the computed gap is strongly correlated to the fraction of Hartree-Fock exchange, test calculations using both pure and hybrid density functionals are reported. The tested methods include the pure functionals BLYP, PBE and LDA, as well as Hartree-Fock and the hybrid functionals BHandHLYP, B3LYP and PBE0. The effect of including solvent molecules in the calculations is studied, and it is found that the inclusion of explicit solvent molecules around the protein fragment in many cases gives a larger gap, but that convergence problems due to vanishing gaps still occur in calculations with pure functionals. In order to achieve converged results, some modeling of the charge distribution of solvent water molecules outside the electronic structure calculation is needed. Representing solvent water molecules by a simple point charge distribution is found to give non-vanishing HOMO-LUMO gaps for the tested protein-like systems also for pure functionals. PMID- 22223668 TI - Definitions, attitudes, and management practices in relation to diarrhea during enteral nutrition: a survey of patients, nurses, and dietitians. AB - BACKGROUND: Diarrhea is a common complication in patients receiving enteral nutrition (EN), and understanding this problem among patients and healthcare professionals is required. The aim of the study was to investigate patients', nurses', and dietitians' definitions of diarrhea during EN, the attitudes of nurses and patients toward it, and the management practices of nurses and dietitians in response to diarrhea during EN. METHODS: Twenty-two patients receiving EN, 57 nurses, and 33 dietitians were recruited and interviewed in a cross-sectional study, using a questionnaire that had been developed following an extensive literature review and pretested for clarity. RESULTS: The ratings assigned by the 3 groups differed significantly for all the characteristics used to define diarrhea: frequency (P = .006), quantity (P < .001), consistency (P = .003), color (P < .001), odor (P < .001), and incontinence (P < .001). Patients gave incontinence the highest rank when defining diarrhea, whereas the healthcare professionals gave fecal consistency and frequency the highest ranks. Patients and nurses rated the unpleasantness of each characteristic of diarrhea during EN differently, with patients rating incontinence and fecal frequency and nurses rating odor and changing the patients' underwear as the most unpleasant characteristics. Nurses and dietitians differed in the frequency with which they adopted various strategies to manage patients who developed diarrhea during EN. CONCLUSIONS: Patients have different definitions and attitudes toward diarrhea during EN from those of nurses and dietitians. Patients' perceptions need to be understood and respected by healthcare professionals to improve patient-centered care. PMID- 22223669 TI - Micronutrients and inflammatory bowel disease. PMID- 22223670 TI - A giant retroperitoneal mass. PMID- 22223671 TI - Sternoclavicular joint septic arthritis and osteomyelitis caused by Aggregatibacter aphrophilus. PMID- 22223672 TI - Facial swelling and somnolence in a patient with cancer. PMID- 22223673 TI - Silicosis with splenic involvement. PMID- 22223674 TI - Amyloid diseases of the heart: current and future therapies. AB - Amyloid diseases in man are caused by as many as 23 different pre-cursor proteins already described. Cardiologists predominantly encounter three main types of amyloidosis that affect the heart: light chain (AL) amyloidosis, senile systemic amyloidosis (SSA) and hereditary amyloidosis, most commonly caused by a mutant form of transthyretin. In the third world, secondary amyloid (AA) is more prevalent, due to chronic infections and inadequately treated inflammatory conditions. Much less common, are the non-transthyretin variants, including mutations of fibrinogen, the apolipoproteins apoA1 and apoA2 and gelsolin. These rarer types do not usually cause significant cardiac compromise. Occurring worldwide, later in life and of less clinical significance, isolated atrial amyloid (IAA) also involves the heart. Heart involvement by amyloid often has devastating consequences. Clinical outcome depends on amyloid type, the extent of systemic involvement and the treatment options available. An exact determination of amyloid type is critical to appropriate therapy. In this review we describe the different approaches required to treat this spectrum of amyloid cardiomyopathies. PMID- 22223676 TI - A taste of TGFbeta in Tuscany. AB - The recent FASEB Summer Research Conference entitled 'The TGFbeta Superfamily: Signaling in Development and Disease' was held in August, 2011 in the spectacular setting of Il Ciocco, Lucca, amidst the olive trees in Tuscany, Italy. The organizers assembled an amazing forum, which included 53 speakers and 67 poster presentations from laboratories around the world, to showcase recent advances made in our understanding of the transforming growth factor-beta (TGFbeta) signaling pathway. PMID- 22223675 TI - Cilia in vertebrate development and disease. AB - Through the combined study of model organisms, cell biology, cell signaling and medical genetics we have significantly increased our understanding of the structure and functions of the vertebrate cilium. This ancient organelle has now emerged as a crucial component of certain signaling and sensory perception pathways in both developmental and homeostatic contexts. Here, we provide a snapshot of the structure, function and distribution of the vertebrate cilium and of the pathologies that are associated with its dysfunction. PMID- 22223677 TI - Regulation of DNA replication during development. AB - As development unfolds, DNA replication is not only coordinated with cell proliferation, but is regulated uniquely in specific cell types and organs. This differential regulation of DNA synthesis requires crosstalk between DNA replication and differentiation. This dynamic aspect of DNA replication is highlighted by the finding that the distribution of replication origins varies between differentiated cell types and changes with differentiation. Moreover, differential DNA replication in some cell types can lead to increases or decreases in gene copy number along chromosomes. This review highlights the recent advances and technologies that have provided us with new insights into the developmental regulation of DNA replication. PMID- 22223679 TI - Drosophila aPKC is required for mitotic spindle orientation during symmetric division of epithelial cells. AB - Epithelial cells mostly orient the spindle along the plane of the epithelium (planar orientation) for mitosis to produce two identical daughter cells. The correct orientation of the spindle relies on the interaction between cortical polarity components and astral microtubules. Recent studies in mammalian tissue culture cells suggest that the apically localised atypical protein kinase C (aPKC) is important for the planar orientation of the mitotic spindle in dividing epithelial cells. Yet, in chicken neuroepithelial cells, aPKC is not required in vivo for spindle orientation, and it has been proposed that the polarization cues vary between different epithelial cell types and/or developmental processes. In order to investigate whether Drosophila aPKC is required for spindle orientation during symmetric division of epithelial cells, we took advantage of a previously isolated temperature-sensitive allele of aPKC. We showed that Drosophila aPKC is required in vivo for spindle planar orientation and apical exclusion of Pins (Raps). This suggests that the cortical cues necessary for spindle orientation are not only conserved between Drosophila and mammalian cells, but are also similar to those required for spindle apicobasal orientation during asymmetric cell division. PMID- 22223678 TI - p57(KIP2) regulates radial glia and intermediate precursor cell cycle dynamics and lower layer neurogenesis in developing cerebral cortex. AB - During cerebral cortex development, precise control of precursor cell cycle length and cell cycle exit is required for balanced precursor pool expansion and layer-specific neurogenesis. Here, we defined the roles of cyclin-dependent kinase inhibitor (CKI) p57(KIP2), an important regulator of G1 phase, using deletion mutant mice. Mutant mice displayed macroencephaly associated with cortical hyperplasia during late embryogenesis and postnatal development. Embryonically, proliferation of radial glial cells (RGC) and intermediate precursors (IPC) was increased, expanding both populations, with greater effect on IPCs. Furthermore, cell cycle re-entry was increased during early corticogenesis, whereas cell cycle exit was augmented at middle stage. Consequently, neurogenesis was reduced early, whereas it was enhanced during later development. In agreement, the timetable of early neurogenesis, indicated by birthdating analysis, was delayed. Cell cycle dynamics analyses in mutants indicated that p57(KIP2) regulates cell cycle length in both RGCs and IPCs. By contrast, related CKI p27(KIP1) controlled IPC proliferation exclusively. Furthermore, p57(KIP2) deficiency markedly increased RGC and IPC divisions at E14.5, whereas p27(KIP1) increased IPC proliferation at E16.5. Consequently, loss of p57(KIP2) increased primarily layer 5-6 neuron production, whereas loss of p27(KIP1) increased neurons specifically in layers 2-5. In conclusion, our observations suggest that p57(KIP2) and p27(KIP1) control neuronal output for distinct cortical layers by regulating different stages of precursor proliferation, and support a model in which IPCs contribute to both lower and upper layer neuron generation. PMID- 22223680 TI - Midbrain-hindbrain boundary patterning and morphogenesis are regulated by diverse grainy head-like 2-dependent pathways. AB - The isthmic organiser located at the midbrain-hindbrain boundary (MHB) is the crucial developmental signalling centre responsible for patterning mesencephalic and metencephalic regions of the vertebrate brain. Formation and maintenance of the MHB is characterised by a hierarchical program of gene expression initiated by fibroblast growth factor 8 (Fgf8), coupled with cellular morphogenesis, culminating in the formation of the tectal-isthmo-cerebellar structures. Here, we show in zebrafish that one orthologue of the transcription factor grainy head like 2 (Grhl2), zebrafish grhl2b plays a central role in both MHB maintenance and folding by regulating two distinct, non-linear pathways. Loss of grhl2b expression induces neural apoptosis and extinction of MHB markers, which are rescued by re-expression of engrailed 2a (eng2a), an evolutionarily conserved target of the Grhl family. Co-injection of sub-phenotypic doses of grhl2b and eng2a morpholinos reproduces the apoptosis and MHB marker loss, but fails to substantially disrupt formation of the isthmic constriction. By contrast, a novel direct grhl2b target, spec1, identified by phylogenetic analysis and confirmed by ChIP, functionally cooperates with grhl2b to induce MHB morphogenesis, but plays no role in apoptosis or maintenance of MHB markers. Collectively, these data show that MHB maintenance and morphogenesis are dissociable events regulated by grhl2b through diverse transcriptional targets. PMID- 22223681 TI - CycA is involved in the control of endoreplication dynamics in the Drosophila bristle lineage. AB - Endocycles, which are characterised by repeated rounds of DNA replication without intervening mitosis, are involved in developmental processes associated with an increase in metabolic cell activity and are part of terminal differentiation. Endocycles are currently viewed as a restriction of the canonical cell cycle. As such, mitotic cyclins have been omitted from the endocycle mechanism and their role in this process has not been specifically analysed. In order to study such a role, we focused on CycA, which has been described to function exclusively during mitosis in Drosophila. Using developing mechanosensory organs as model system and PCNA::GFP to follow endocycle dynamics, we show that (1) CycA proteins accumulate during the last period of endoreplication, (2) both CycA loss and gain of function induce changes in endoreplication dynamics and reduce the number of endocycles, and (3) heterochromatin localisation of ORC2, a member of the Pre-RC complex, depends on CycA. These results show for the first time that CycA is involved in endocycle dynamics in Drosophila. As such, CycA controls the final ploidy that cells reached during terminal differentiation. Furthermore, our data suggest that the control of endocycles by CycA involves the subnuclear relocalisation of pre-RC complex members. Our work therefore sheds new light on the mechanism underlying endocycles, implicating a process that involves remodelling of the entire cell cycle network rather than simply a restriction of the canonical cell cycle. PMID- 22223682 TI - DAZL is essential for stress granule formation implicated in germ cell survival upon heat stress. AB - Mammalian male germ cells should be maintained below body temperature for proper development. Here, we investigated how male germ cells respond to heat stress. A short exposure of mouse testes to core body temperature induced phosphorylation of eIF2alpha and the formation of stress granules (SGs) in male germ cells. We observed that DAZL, a germ cell-specific translational regulator, was translocated to SGs upon heat stress. Furthermore, SG assembly activity was significantly diminished in the early male germ cells of Dazl-knockout mice. The DAZL-containing SGs played a protective role against heat stress-induced apoptosis by the sequestration of specific signaling molecules, such as RACK1, and the subsequent blockage of the apoptotic MAPK pathway. Based on these results, we propose that DAZL is an essential component of the SGs, which prevent male germ cells from undergoing apoptosis upon heat stress. PMID- 22223684 TI - Nano-plasmonic antennas in the near infrared regime. AB - Plasmonic nano-antennas constitute a central research topic in current science and engineering with an enormous variety of potential applications. Here we review the recent progress in the niche of plasmonic nano-antennas operating in the near infrared part of the spectrum which is important for a variety of applications. Tuning of the resonance into the near infrared regime is emphasized in the perspectives of fabrication, measurement, modeling, and analytical treatments, concentrating on the vast recent achievements in these areas. PMID- 22223683 TI - The extracellular loops of Smoothened play a regulatory role in control of Hedgehog pathway activation. AB - The Hedgehog (Hh) signaling pathway plays an instructional role during development, and is frequently activated in cancer. Ligand-induced pathway activation requires signaling by the transmembrane protein Smoothened (Smo), a member of the G-protein-coupled receptor (GPCR) superfamily. The extracellular (EC) loops of canonical GPCRs harbor cysteine residues that engage in disulfide bonds, affecting active and inactive signaling states through regulating receptor conformation, dimerization and/or ligand binding. Although a functional importance for cysteines localized to the N-terminal extracellular cysteine-rich domain has been described, a functional role for a set of conserved cysteines in the EC loops of Smo has not yet been established. In this study, we mutated each of the conserved EC cysteines, and tested for effects on Hh signal transduction. Cysteine mutagenesis reveals that previously uncharacterized functional roles exist for Smo EC1 and EC2. We provide in vitro and in vivo evidence that EC1 cysteine mutation induces significant Hh-independent Smo signaling, triggering a level of pathway activation similar to that of a maximal Hh response in Drosophila and mammalian systems. Furthermore, we show that a single amino acid change in EC2 attenuates Hh-induced Smo signaling, whereas deletion of the central region of EC2 renders Smo fully active, suggesting that the conformation of EC2 is crucial for regulated Smo activity. Taken together, these findings are consistent with loop cysteines engaging in disulfide bonds that facilitate a Smo conformation that is silent in the absence of Hh, but can transition to a fully active state in response to ligand. PMID- 22223685 TI - Impact of stance phase microprocessor-controlled knee prosthesis on ramp negotiation and community walking function in K2 level transfemoral amputees. AB - BACKGROUND: Microprocessor controlled prosthetic knees (MPK) offer opportunities for improved walking stability and function, but some devices' swing phase features may exceed needs of users with invariable cadence. One MPK offers computerized control of only stance (C-Leg Compact). OBJECTIVE: To assess Medicare Functional Classification Level K2 walkers' ramp negotiation performance, function and balance while using a non-MPK (NMPK) compared to the C Leg Compact. STUDY DESIGN: Crossover. METHODS: Gait while ascending and descending a ramp (stride characteristics, kinematics, electromyography) and function were assessed in participant's existing NMPK and again in the C-Leg Compact following accommodation. RESULTS: Ramp ascent and descent were markedly faster in the C-Leg Compact compared to the NMPK (p <= 0.006), owing to increases in stride length (p <= 0.020) and cadence (p <= 0.020). Residual limb peak knee flexion and ankle dorsiflexion were significantly greater (12.9 degrees and 4.9 degrees more, respectively) during single limb support while using the C-Leg Compact to descend ramps. Electromyography (mean, peak) did not differ significantly between prosthesis. Function improved in the C-Leg Compact as evidenced by a significantly faster Timed Up and Go and higher functional questionnaire scores. CONCLUSIONS: Transfemoral K2 walkers exhibited significantly improved function and balance while using the stance-phase only MPK compared to their traditional NMPK. PMID- 22223687 TI - Trophoblast development. AB - This review summarises current knowledge about the specification, commitment and maintenance of the trophoblast lineage in mice and cattle. Results from gene expression studies, in vivo loss-of-function models and in vitro systems using trophoblast and embryonic stem cells have been assimilated into a model seeking to explain trophoblast ontogeny via gene regulatory networks. While trophoblast differentiation is quite distinct between cattle and mice, as would be expected from their different modes of implantation, recent studies have demonstrated that differences arise much earlier during trophoblast development. PMID- 22223688 TI - Effects of ubiquitin C-terminal hydrolase L1 deficiency on mouse ova. AB - Maternal proteins are rapidly degraded by the ubiquitin-proteasome system during oocyte maturation in mice. Ubiquitin C-terminal hydrolase L1 (UCHL1) is highly and specifically expressed in mouse ova and is involved in the polyspermy block. However, the role of UCHL1 in the underlying mechanism of polyspermy block is poorly understood. To address this issue, we performed a comprehensive proteomic analysis to identify maternal proteins that were relevant to the role of UCHL1 in mouse ova using UCHL1-deficient gad. Furthermore, we assessed morphological features in gad mouse ova using transmission electron microscopy. NACHT, LRR, and PYD domain-containing (NALP) family proteins and endoplasmic reticulum (ER) chaperones were identified by proteomic analysis. We also found that the 'maternal antigen that embryos require' (NLRP5 (MATER)) protein level increased significantly in gad mouse ova compared with that in wild-type mice. In an ultrastructural study, gad mouse ova contained less ER in the cortex than in wild type mice. These results provide new insights into the role of UCHL1 in the mechanism of polyspermy block in mouse ova. PMID- 22223686 TI - Reproductive consequences of developmental phytoestrogen exposure. AB - Phytoestrogens, estrogenic compounds derived from plants, are ubiquitous in human and animal diets. These chemicals are generally much less potent than estradiol but act via similar mechanisms. The most common source of phytoestrogen exposure to humans is soybean-derived foods that are rich in the isoflavones genistein and daidzein. These isoflavones are also found at relatively high levels in soy-based infant formulas. Phytoestrogens have been promoted as healthy alternatives to synthetic estrogens and are found in many dietary supplements. The aim of this review is to examine the evidence that phytoestrogen exposure, particularly in the developmentally sensitive periods of life, has consequences for future reproductive health. PMID- 22223691 TI - Development of microsatellite markers for Cinnamomum camphora (Lauraceae). AB - PREMISE OF THE STUDY: Cinnamomum camphora is an evergreen tree distributed in southern Japan, Taiwan, and southeastern China. Because of its vast utilization and cultivation, the natural distribution area of this species has been controversial. METHODS AND RESULTS: I isolated and characterized 22 microsatellite loci in C. camphora. Levels of polymorphism were evaluated in 104 adult trees from three populations in Japan: Meiji Jingu (Shinto Shrine), Kajiya Plantation, and Manazuru Peninsula. The mean number of alleles per locus ranged from 4.1 to 8.0 among populations. The mean observed and expected heterozygosities per population ranged from 0.53 to 0.60 and 0.55 to 0.68, respectively. CONCLUSIONS: All of 22 loci showed a clear and strong single band for each allele, and revealed a useful degree of polymorphism. The microsatellite markers described here will be useful to study the history, population dynamics, mating system, and genetic structure of C. camphora. PMID- 22223689 TI - A new Oligocene Calocedrus from South China and its implications for transpacific floristic exchanges. AB - PREMISE OF THE STUDY: Calocedrus is among the genera with a typical eastern Asian western North American disjunct distribution today. The origin of its modern distribution pattern can be better understood by examining its fossil record. METHODS: The present article reports for the first time a new fossil species of this genus based on compressed material from the Oligocene Ningming Formation of Guangxi, South China, in its present major distribution area in eastern Asia. KEY RESULTS: Calocedrus huashanensis sp. nov. is most similar to the two extant eastern Asian species, C. macrolepis and C. formosana, in gross morphology of foliage shoots and bears a close resemblance to the latter in cuticle structure. It shows a general similarity to the North American fossil representatives of the genus in alternately branched foliage shoots but is clearly different from the European Paleogene species characterized by oppositely branched leafy shoots. CONCLUSIONS: This discovery provides new evidence for the floristic exchange of this genus between eastern Asia and North America before the Oligocene (most likely in the Eocene), presumably via the Bering land bridge. The flattened leafy shoots and dimorphic leaves with thin cuticle, open stomatal pits, and shallowly sunken guard cells of the present fossils suggest a rather humid climate during the Oligocene in the Ningming area, South China. PMID- 22223692 TI - The value of pleural lavage cytology examined during surgery for primary lung cancer. AB - OBJECTIVES: The pleural invasion (PL) score is a useful prognostic indicator in lung cancer. However, in many cases, the cancer may exfoliate itself into the pleural cavity and may progress to a malignant pleural effusion without invading the parietal pleura. This stage is not currently evaluated, but it is detectable by means of the pleural lavage cytology (PLC). However, PLC's contribution to TNM staging has not yet been clarified. The purpose of this investigation was to demonstrate the usefulness of PLC in the precise staging of patients with such an occult pleural dissemination. METHODS: A total of 3231 patients who were included in a multi-institutional database were studied retrospectively. PLC was performed by washing the thoracic cavity with a small amount of physiological saline immediately after opening the thoracic cavity during lung cancer surgery. RESULTS: The incidence of positive PLC findings was 4.58%. In comparison with the negative group, the survival curves were significantly worse (P < 0.001) and the incidence of recurrence with pleuritis carcinomatosa was significantly higher (P < 0.001). According to the subset analysis, the survival difference was prominent in earlier stage groups and lower PL score groups. The positive findings were confirmed to be a significantly poor prognostic indicator (P = 0.016) by multivariate analysis using the Cox proportional hazard model (Cox analysis). However, integration of the positive findings with the PL score was attempted for the convenience of TNM staging. To find the accurate PL score for positive PLC findings, the Cox analysis was re-estimated using the PL score upgraded stepwise. The most reliable model with the highest score for the likelihood ratio chi(2) statistic was obtained by scoring positive findings as PL3. So, it was considered to be the most reliable conversion. CONCLUSIONS: Examining PLC in clinical practice is useful for detecting occult pleural dissemination before the appearance of a malignant pleural effusion. Evidence of positive findings should be treated as supplemental information to the precise diagnosis of TNM staging. Scoring positive PLC findings as PL3 (=T3) was appropriate. PMID- 22223694 TI - Sizing the annulus for transcatheter aortic valve implantation: more than a simple measure? PMID- 22223693 TI - Sleeve lobectomy after induction chemoradiotherapy. AB - OBJECTIVES: The effect of induction chemoradiotherapy (CRT) on bronchial anastomoses remains uncertain. This prospective study aimed to assess the impact of neoadjuvant CRT on mortality, morbidity and survival following circular sleeve lobectomy (SL). METHODS: All consecutive patients undergoing SL between June 2005 and December 2010 were prospectively included. Clinico-demographic variables were sex, age, clinical and pathologic TNM staging, comorbidities, pulmonary function, SL type, complications, neoadjuvant CRT and mortality. RESULTS: Of 79 patients, who underwent SL during this period, 53 (67%) patients were directly assigned to surgery and 26 (33%) patients had pre-induction treatment for N2 pathologically confirmed. Induction treatment (CRT) was based on platinum-based chemotherapy and radiation (range 45-60 Gy). Twenty-one (80%) patients of the CRT group achieved a complete mediastinal pathological response. Mortality occurred in only three cases in the non-CRT [bronchovascular fistula, pulmonary artery thrombosis (reoperation and pneumonectomy and exitus due to pneumonia) and ADRS]. There were no differences with respect to complication rate between the non-CRT and CRT patients (33 versus 37%, P > 0.05), and overall 5-year survival was 69 and 33%, respectively (P = 0.017). Overall survival in the subgroup of CRT patients with mediastinal complete response after induction resulted significantly worse than the non-CRT group (43 versus 69%, P < 0.01). The rate of distant metastases was similar in both groups and only one patient experienced local recurrence. CONCLUSIONS: Neoadjuvant CRT does not increase surgical morbidity, anastomotic complications or mortality in SL. Complete mediastinal response after induction therapy overcomes a significant independent prognostic factor for better survival. Although SL following induction CRT carries a good prognosis, the long term results shows significantly lower survival compared with SL without induction CTR. In addition, patients who had complete pathological responses have a better prognosis than non-responders. SL appears to be safe and reliable after neoadjuvant concurrent CRT and can be considered the primary surgical option to save the complications related to pneumonectomy in central tumours. PMID- 22223696 TI - Gallbladder herniation after minimally invasive cardiothoracic surgery. PMID- 22223695 TI - Can three-dimensional echocardiography accurately predict complexity of mitral valve repair? AB - OBJECTIVE: Feasibility of mitral repair is a key factor in the decision to operate for mitral regurgitation. Repair feasibility is highly dependent on surgical experience and repair complexity. We sought an objective means of predicting complexity of repair using three-dimensional (3D) transoesophageal echocardiography. METHODS: In a cohort of 786 patients who underwent mitral valve surgery between 2007 and 2010, 3D transoesophageal echocardiography was performed in 66 patients with mitral regurgitation prior to the institution of cardiopulmonary bypass. The surgeon reviewed the 2D echocardiographic images for all patients pre-operatively, but did not view the 3D echocardiographic quantitative data or volumetric analysis until after surgery. Repairs involving no or a single-segment leaflet resection, sliding-plasty, cleft closure, chordal or commissural repair techniques were classed as standard repairs. Complex repairs were defined as those involving bileaflet repair techniques, requiring multiple resections or patch augmentation. Disease aetiology included Barlow's disease (n = 18), fibroelastic deficiency (n = 22), ischaemic (n = 5), endocarditis (n = 5), rheumatic (n = 2) and dilated cardiomyopathy (n = 2). RESULTS: No patient required mitral replacement or had more than mild mitral regurgitation on pre-discharge echocardiography. Anterior and posterior leaflet areas, annular circumference, anterior and posterior leaflet angles, prolapse and tenting heights and volumes were most strongly predictive of repair complexity. As 21 of the 22 patients with bileaflet pathology and multisegment prolapse were complex repairs, we sought to develop a model predicting repair complexity in the remaining patients. The most predictive model with a c-statistic of 0.91 included three predictors: multisegment pathology, prolapsing height and posterior leaflet angle. After bootstrap validation, the revised c-statistic was 0.88. CONCLUSIONS: 3D transoesophageal echocardiography provides an objective means of predicting mitral repair complexity in mitral regurgitation due to a range of aetiology. PMID- 22223698 TI - Successful reoperation of the valveless calcified right atrium to right ventricle conduit in an adult patient with tricuspid atresia after Fontan procedure. AB - A 31-year old woman with tricuspid atresia, after Bjork Fontan modification and reoperation due to homograft narrowing, was evaluated because of progressive exercise intolerance; she was planning a pregnancy. The right atrium (RA) to right ventricle (RV) homograft narrowing and calcification with significant reversal flow were found. Successful reoperation was performed-calcified conduit was excised and extracardiac pulmonary homograft tipped with vascular prosthesis was implanted between the RA and the RV. PMID- 22223697 TI - Immune response to bovine pericardium implanted into alpha1,3 galactosyltransferase knockout mice: feasibility as an animal model for testing efficacy of anticalcification treatments of xenografts. AB - OBJECTIVES: Glutaraldehyde (GA)-fixed xenografts are prone to calcification after implantation in humans and there is evidence that immune reaction to the Galalpha1,3-Galbeta1,4GlcNAc-R (alpha-Gal) antigen may play a part in this process. The objectives of this study were to evaluate the immune response of alpha1,3-galactosyltransferase knockout (alpha-Gal KO) mice to bovine pericardium and to evaluate the effect of various anticalcification treatments on bovine pericardium using mouse subcutaneous implantation model. METHODS: Bovine pericardial tissues were divided into eight groups according to the method of anticalcification treatments. Prepared tissues were subcutaneously implanted into the alpha-Gal KO and wild-type mice for 2 months, and anti-alpha-Gal antibodies were measured at 2 weeks and 2 months after implantation. Explanted tissues were examined by immunohistochemistry and calcium contents of the explanted tissues were measured. RESULTS: Titres of IgM and IgG antibodies in the alpha-Gal KO mice increased significantly according to the duration of implantation, whereas titres of IgM and IgG antibodies in the wild-type mice increased until 2 weeks after implantation without further increase thereafter. Titres of IgG antibodies measured at 2 months after implantation were significantly higher in the alpha Gal KO mice than in the wild-type mice. Immunohistochemistry revealed macrophages surrounding the pericardial tissues irrespective of the mouse type into which the tissues implanted, whereas T-cells could only be observed in the tissues implanted into the alpha-Gal KO mice. Except the high-concentration GA-treated group, calcium contents of anticalcification-treated groups were all significantly lower or tended to be lower than that of the control group, irrespective of the mouse type. Calcium contents of the control group were significantly higher in the alpha-Gal KO mice than in the wild-type mice. CONCLUSIONS: Bovine pericardium implanted into the alpha-Gal KO mice caused significant increase in anti-alpha-Gal antibodies, showed some histologic evidences of chronic rejection and revealed a potential toward more calcification. These findings suggest a possible role of immune response in calcification of xenografts. High-concentration GA fixation alone did not prove to be an effective anticalcification treatment in mouse subcutaneous implantation model. alpha-Gal KO mouse subcutaneous implantation model might be a feasible animal model for testing efficacy of anticalcification treatments incorporating immunologic approach. PMID- 22223699 TI - Application of triple-branched stent graft for Stanford type A aortic dissection: potential risks. AB - OBJECTIVES: A new surgical technique named triple-branched stent graft was developed and reported to have excellent clinical results for Stanford type A aortic dissection. However, we found some potential risks, in our experience, of this technique. We compared this technique with total arch replacement combined with stented elephant trunk implantation in patients with acute Stanford type A dissection. METHODS: Thirty-eight patients with acute Stanford type A aortic dissection underwent surgical treatment from January to November 2010. These patients were divided into two groups: patients with total arch replacement combined with stented elephant trunk implantation (Group A, n = 22) and those with ascending aorta replacement combined with open placement of triple-branched stent graft (Group B, n = 16). RESULTS: In-hospital mortality was not different in the two groups (9.1 and 6.25%, respectively). Cardiopulmonary bypass, aortic cross-clamp, circulation arrest, selective cerebral perfusion and low-body arrest times were shorter in Group B. Mechanical ventilation support, duration of intensive care unit (ICU) stay and hospitalization time were not different in the two groups. The incidence of postoperative stent graft-related complications was significantly higher in Group B. Actuarial survival rates and freedom from reoperation during the follow-up did not differ in the two groups. CONCLUSIONS: The triple-branched stent graft technique truly has some advantages in simplifying the procedure and reducing the surgical time. However, this technique has some potential risks such as postoperative stent graft shifting or kinking, which may cause occlusion, aortic disruption and malperfusion syndrome. Long-term follow-up and further multicentre clinical trials are necessary to verify their use in this setting and the design of the grafts and surgical procedure should be further refined to reduce the incidence of stent graft complications. PMID- 22223700 TI - Which metastasis management allows long-term survival of synchronous solitary M1b non-small cell lung cancer? AB - OBJECTIVES; Patients with extrathoracic synchronous solitary metastasis and non small cell lung cancer (NSCLC) are rare. The effectiveness of both tumour sites resection is difficult to evaluate because of the high variability among clinical studies. We reviewed our experience regarding the management and prognosis of these patients. METHODS: The charts of 4668 patients who underwent lung cancer surgery from 1983 to 2006 were retrospectively reviewed. We analysed the epidemiology, treatment, pathology and prognostic characteristics of those with extrathoracic synchronous solitary metastasis amenable to lung cancer surgery on a curative intend. RESULTS: There were 94 patients (sex ratio M/F 3.2/1, mean age 56 years). Surgery included pneumonectomy (n = 27), lobectomy (n = 65) and exploratory thoracotomy (n = 2). Pathology revealed adenocarcinomas (n = 57), squamous cell carcinoma (n = 20), large cell carcinoma (n = 14) and other NSCLC histology (n = 3). Lymphatic extension was N0 (n = 46), N1 (n = 17) and N2 (n = 31). Metastasis involved the brain (n = 57), adrenal gland (n = 12), bone (n = 14), liver (n = 5) and skin (n = 6). Sixty-nine metastases were resected. Five year survival rate was 16% (median 13 months). Induction therapy, adenocarcinoma, N0 staging and lobectomy were criteria of better prognosis, but metastasis resection was not. CONCLUSIONS: These results suggest that extrathoracic synchronous solitary metastasis of pN0 adenocarcinoma may achieve long-term survival in the case of lung resection with or without metastasis resection. This pattern may reflect a specific tumour biology whose solitary metastasis benefits both from surgical or non-surgical treatment. PMID- 22223701 TI - Increased frequency of the DI genotype of the angiotensin-I converting enzyme and association of the II genotype with insulin resistance in polycystic ovary syndrome. AB - OBJECTIVE: The polycystic ovary syndrome (PCOS) is a common and complex disease with unclear pattern of inheritance, characterized by an androgen excess, while hyperinsulinemia and insulin resistance (IR) are common features of the syndrome. The angiotensin I converting enzyme (ACE) insertion (I)/deletion (D) gene polymorphism was proved to be involved in many pathophysiological conditions, including hypertension and IR. DESIGN: The purpose of this study was to evaluate the involvement of the ACE gene polymorphism in the pathogenesis of PCOS. METHODS: In a case-control association study involving 801 PCOS women and 266 healthy controls, hormonal determinations and ACE polymorphism genotyping were performed. The PCOS women were classified into three groups: Group A presented biochemical hyperandrogenism, combined with anovulation and polycystic ovarian morphology; Group B, clinical hyperandrogenism combined with anovulation and polycystic ovarian morphology; and Group C, chronic anovulation and polycystic ovarian morphology. RESULTS: A significant increase in the frequency of the DI genotype of the ACE polymorphism was detected in PCOS women as a whole (P=0.035), in PCOS Group A (P=0.039) and Group B (P=0.010), while there was no difference in Group C (P=0.939). Significant difference was also observed in hyperandrogenic PCOS women as a whole (Group A+B) (P=0.017). The II genotype was positively correlated with HOMA-IR and QUICKI and with fasting insulin and glucose/insulin ratio in these groups. CONCLUSIONS: The association study of the ACE I/D polymorphism in PCOS women demonstrates an increase in the DI genotype incidence and an association of the II genotype with IR. PMID- 22223702 TI - Inositol administration reduces oxidative stress in erythrocytes of patients with polycystic ovary syndrome. AB - OBJECTIVE: Possibly due to a deficiency of insulin mediators, polycystic ovary syndrome (PCOS) is often associated with insulin resistance (IR) and hyperinsulinemia, likely responsible for an elevated production of reactive oxygen species. We investigated oxidative-related alterations in erythrocytes and anti-inflammatory effects of inositol in women with PCOS before and after treatment with myo-inositol (MYO). METHODS: Twenty-six normal-weight PCOS patients were investigated before and after MYO administration (1200 mg/day for 12 weeks; n=18) or placebo (n=8) by evaluating serum testosterone, serum androstenedione, fasting serum insulin, fasting serum glucose, insulin area under the curve (AUC), and glucose AUC after oral glucose tolerance test and homeostasis model of assessment-IR. In erythrocytes, band 3 tyrosine phosphorylation (Tyr-P) level, glutathione (GSH) content, and glutathionylated proteins (GSSP) were also assessed. RESULTS: Data show that PCOS patients' erythrocytes underwent oxidative stress as indicated by band 3 Tyr-P values, reduced cytosolic GSH content, and increased membrane protein glutathionylation. MYO treatment significantly improved metabolic and biochemical parameters. Significant reductions were found in IR and serum values of androstenedione and testosterone. A significant association between band 3 Tyr-P levels and insulin AUC was found at baseline but disappeared after MYO treatment, while a correlation between band 3 Tyr-P and testosterone levels was detected both before and after MYO treatment. CONCLUSIONS: PCOS patients suffer from a systemic inflammatory status that induces erythrocyte membrane alterations. Treatment with MYO is effective in reducing hormonal, metabolic, and oxidative abnormalities in PCOS patients by improving IR. PMID- 22223703 TI - EF/SSc overlap syndrome and aplastic anaemia resistant to immunosuppressive therapy. PMID- 22223704 TI - Comparison of radiographic scoring methods in a cohort of RA patients treated with anti-TNF therapy. AB - OBJECTIVE: To compare the ability of the simple erosion narrowing score (SENS) to classify radiographic progression relative to the Sharp/van der Heijde score (SHS) in a prospective cohort of anti-TNF-treated RA patients. METHODS: Radiographs of the hands, wrists and feet of patients enrolled in a pharmacovigilance programme are performed every 2 years. These radiographs were read in chronological order by three rheumatologists and scored using the SHS. SENS scores were derived from the SHS. Additionally, one rheumatologist scored the radiographs using the SENS method only. Patients with radiographic progression in excess of the smallest detectable change were classified as progressors. The probability of agreement and kappa-value between the SHS and SENS methods for determining progression was calculated. RESULTS: A sample of 25 patients was selected from the database. The annualized mean (s.d.) change in SHS score was 6.61 U (7.48 U) and in SENS score was 2.27 U (2.17 U). Five patients were classified as progressors using SHS and seven using SENS, with a probability of agreement of 84% (kappa = 0.565). CONCLUSION: The SENS method captures radiographic progression reliably compared with the more detailed SHS method. SENS is suitable for application in clinical practice or in observational cohorts. PMID- 22223705 TI - The impact of cardiopulmonary manifestations on the mortality of SSc: a systematic review and meta-analysis of observational studies. AB - OBJECTIVES: Internal organ involvement reduces the life expectancy of SSc patients. Cardiopulmonary manifestations are currently the primary cause of death. We aimed to perform a systematic review and meta-analysis to define more precise effect estimates of different cardiopulmonary manifestations and to verify trends in the mortality of SSc. METHODS: A systematic literature search was performed to identify relevant cohort studies. Reports analyzing the role of the organ manifestations in mortality or analysing survival compared with the control population were included. The outcome parameters were pooled with the random-effect model via generic inverse-variance weighting in conventional and cumulative meta-analysis. RESULTS: Eighteen studies comprising a total of 12, 829 patients qualified. The reported causes of death were as follows: 19.7% cardiac, 16.8% interstitial pulmonary disease, 13.1% pulmonary hypertension and 13.8% renal disease. The risk of death was significantly increased in patients with cardiac involvement [hazard ratio (HR) 3.15], with pulmonary interstitial disease (HR 2.58), with pulmonary hypertension (HR 3.50) and with renal manifestations (HR 2.76). A trend for survival improvement (R2)= 0.4295, P = 0.04) was found, and the difference in survival between the diffuse and limited scleroderma subgroups was diminishing (R2)= 0.4119. P = 0.02). CONCLUSION: Meta-analysis of observational studies indicates a trend for improvement over the last decades in which the life expectancy of SSc patients approaches that of the general population. A decreasing tendency in the survival differences between the limited and diffuse SSc subgroups was also verified. Internal organ involvements have similarly unfavourable predictive impact on survival. PMID- 22223706 TI - Efficacy and tolerance of infliximab in refractory Takayasu arteritis: French multicentre study. AB - OBJECTIVE: To analyse the efficacy and tolerance of infliximab in refractory Takayasu arteritis (TA). METHODS: French multicentre retrospective study that included patients with TA. Clinical disease activity was defined as new vascular and/or constitutional signs. RESULTS: Fifteen patients with TA [median age 41 (range 17-61) years; 13 women] were included. At initiation of infliximab therapy, 14 patients were treated with CSs [prednisone; median dose 20 (range 5 35) mg/day], MTX (n = 7) or AZA (n = 4). Infliximab was used at median 5 (range 3 5) mg/kg at a median of every 6 (range 4-8) weeks. A partial or good overall response was noted in 13 (87%) of the 15 cases, 10 (77%) of the 13 cases and 8 (73%) of the 11 cases at 3, 6 and 12 months, respectively. Clinical and biological activities significantly decreased within 3 months (from 11 at baseline to 4 patients at 12 months; P < 0.05), and similarly for CS dose [from median 20 (range 5-35) mg/day at baseline to median 6 (range 2.5-30) mg/day at 12 months; P < 0.05]. Only one patient was still steroid-dependent at 12 months (vs 8 cases before infliximab). CRP regressed from a median 30 (range 4-70) mg/l to 5 (range 0-57) mg/l and 6 (0-50) mg/l at 3 and 6 months, respectively (P < 0.05). Side effects were two infusion-related reactions, one pulmonary tuberculosis, one severe bacterial infection and EBV reactivation. CONCLUSION: This study confirms the interest of infliximab in terms of clinical and biological response, as well as the steroid-sparing effect in TA. PMID- 22223707 TI - Goal-directed therapy for RA in routine practice is associated with improved function in patients with disease duration up to 15 years. PMID- 22223708 TI - A comparison of self-reported analgesic use and detection of urinary ibuprofen and acetaminophen metabolites by means of metabonomics: the INTERMAP Study. AB - Information on dietary supplements, medications, and other xenobiotics in epidemiologic surveys is usually obtained from questionnaires and is subject to recall and reporting biases. The authors used metabolite data obtained from hydrogen-1 (or proton) nuclear magnetic resonance ((1)H NMR) analysis of human urine specimens from the International Study of Macro-/Micro-Nutrients and Blood Pressure (INTERMAP Study) to validate self-reported analgesic use. Metabolic profiling of two 24-hour urine specimens per individual was carried out for 4,630 participants aged 40-59 years from 17 population samples in Japan, China, the United Kingdom, and the United States (data collection, 1996-1999). (1)H NMR detected acetaminophen and ibuprofen use was low (~4%) among East Asian population samples and higher (>16%) in Western population samples. In a comparison of self-reported acetaminophen and ibuprofen use with (1)H NMR detected acetaminophen and ibuprofen metabolites among 496 participants from Chicago, Illinois, and Belfast, Northern Ireland, the overall rate of concordance was 81%-84%; the rate of underreporting was 15%-17%; and the rate of underdetection was approximately 1%. Comparison of self-reported unspecified analgesic use with (1)H NMR-detected acetaminophen and ibuprofen metabolites among 2,660 Western INTERMAP participants revealed similar levels of concordance and underreporting. Screening for urinary metabolites of acetaminophen and ibuprofen improved the accuracy of exposure information. This approach has the potential to reduce recall bias and other biases in epidemiologic studies for a range of substances, including pharmaceuticals, dietary supplements, and foods. PMID- 22223709 TI - Racial and geographic factors in the incidence of Legg-Calve-Perthes' disease: a systematic review. AB - Legg-Calve-Perthes' disease (Perthes' disease) is a childhood osteonecrosis of the hip for which the disease determinants are poorly understood. In this review, the authors identify studies of Perthes' disease incidence published up to December 2010 and make denominator populations comparable in order to allow meaningful between-study evaluation. Incidence rates and confidence intervals were determined, and, where appropriate, denominator populations were obtained from national statistical offices. Poisson regression was used to determine the influence of race and geography. The review included 21 studies that described 27 populations in 16 countries, with 124 million person-years of observation. The annual incidence among children under age 15 years ranged from 0.2 per 100,000 to 19.1 per 100,000. Race was a key determinant, with East Asians being least affected and whites most affected, though data were insufficient to consider incidence among blacks (for South Asians vs. East Asians, incidence rate ratio = 2.9, 95% confidence interval (CI): 2.4, 3.5; for whites vs. East Asians, incidence rate ratio = 8.8, 95% CI: 8.2, 9.6). Latitude was a strong predictor of disease, even after adjustment for race. Each 10 degrees increase in latitude was associated with an incidence increase of 1.44 (95% CI: 1.30, 1.58) times. While much of the international variation appears to be a function of race, latitude demonstrates a strong association. This observation may offer new epidemiologic insights into the determinants of Perthes' disease. PMID- 22223711 TI - Is childhood asthma associated with educational level and longest-held occupation? AB - Children with asthma can experience chronic morbidity that may interfere with education and career progression. The authors investigated retrospectively whether a history of childhood asthma is associated with educational level and longest-held occupation, by gender. Cross-sectional analysis included a nationally representative sample of 10,452 adults aged >=20 years who participated in the US National Health and Nutrition Examination Survey (2001 2004). Logistic regression was used to assess associations between a childhood asthma history and educational level, employment, and longest-held occupation. An estimated 6.9% of men and 5.8% of women had a childhood-asthma history. Persons with a childhood-asthma history tended to have a higher educational level than those with no asthma history. Among those who ever worked, and after adjustment for age and race/ethnicity, men with a childhood-asthma history were more likely to work in health-diagnosing occupations, other professional occupations, and as cooks; women with a childhood-asthma history were more likely to work in management-related, entertainment-related, and health service occupations. Compared with those with no asthma history, persons with a childhood-asthma history tended to achieve a higher educational level and, if they worked, were more likely to work in particular occupations. PMID- 22223712 TI - Inequalities in body mass index and smoking behavior in 70 countries: evidence for a social transition in chronic disease risk. AB - Despite the growing burden of chronic disease globally, few studies have examined the socioeconomic patterning of risk across countries. The authors examined differences in the social patterning of body mass index (BMI) and current smoking by urbanicity among 70 countries from the 2002-2003 World Health Surveys. Age adjusted, gender-stratified ordinary least squares and logistic regression analyses were conducted in each country to assess the relation between education and BMI or smoking. Meta-analytic techniques were used to assess heterogeneity between countries in the education-risk factor relations. Meta-regression was used to determine whether the heterogeneity could be explained by country-level urbanicity. In the least urban countries, persons with higher education had a higher BMI, while the opposite pattern was seen in the most urban countries, with this pattern being especially pronounced among women. In contrast, smoking was consistently concentrated among persons of lower education among all men and among women in the least urban countries. For women in the most urban countries, higher education was associated with higher odds of smoking, although there was substantial variability in this relation. These results highlight a global trend toward an increasing burden of chronic disease risk among persons of lower socioeconomic position as countries become more urban. PMID- 22223710 TI - Bias in observational studies of prevalent users: lessons for comparative effectiveness research from a meta-analysis of statins. AB - Randomized clinical trials (RCTs) are usually the preferred strategy with which to generate evidence of comparative effectiveness, but conducting an RCT is not always feasible. Though observational studies and RCTs often provide comparable estimates, the questioning of observational analyses has recently intensified because of randomized-observational discrepancies regarding the effect of postmenopausal hormone replacement therapy on coronary heart disease. Reanalyses of observational data that excluded prevalent users of hormone replacement therapy led to attenuated discrepancies, which begs the question of whether exclusion of prevalent users should be generally recommended. In the current study, the authors evaluated the effect of excluding prevalent users of statins in a meta-analysis of observational studies of persons with cardiovascular disease. The pooled, multivariate-adjusted mortality hazard ratio for statin use was 0.77 (95% confidence interval (CI): 0.65, 0.91) in 4 studies that compared incident users with nonusers, 0.70 (95% CI: 0.64, 0.78) in 13 studies that compared a combination of prevalent and incident users with nonusers, and 0.54 (95% CI: 0.45, 0.66) in 13 studies that compared prevalent users with nonusers. The corresponding hazard ratio from 18 RCTs was 0.84 (95% CI: 0.77, 0.91). It appears that the greater the proportion of prevalent statin users in observational studies, the larger the discrepancy between observational and randomized estimates. PMID- 22223713 TI - Emergency department crowding. AB - BACKGROUND: Emergency department (ED) crowding is a significant international problem. There is increasing overseas research into this field. In the UK, the focus has been on waiting times in EDs, and on the government's 4 h standard, rather than on crowding itself. AIMS: To examine the causes and effects of ED crowding, along with solutions. To consider whether the 4 h standard has had an effect on ED crowding in the UK. METHODS: A structured literature review on ED crowding. RESULTS: The evidence base largely consists of retrospective or descriptive studies (65% combined) from North America and Australasia (89% combined). Measurement of crowding is not well developed, and the lack of a gold standard additionally limits the quality of research. The main cause of crowding is access block, because of high levels of hospital occupancy. Crowding carries a number of adverse consequences for patients and staff. Many solutions are described, but with weak evidence behind them. Most of these focus on interventions in the ED, despite the fact that the main causes lie outside. Solutions aimed at achieving the 4 h standard may mitigate crowding. CONCLUSION: The extent of ED crowding in the UK is unknown. The problem is probably mitigated by process standards such as the 4 h standard. The causes and effects of crowding are likely to be the same as overseas, but there is little research to validate this. The best solutions are not known. PMID- 22223714 TI - Thigh muscle injuries in youth soccer: predictors of recovery. AB - BACKGROUND: Participation in soccer at younger ages with attendant risk of muscle injury is increasing. PURPOSE: To delineate patterns of thigh muscle injury and predictors of recovery in male youth soccer academy players. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: Forty-one English Premiership soccer academy squads (all male, aged 8-16 years) over a 5-year period comprising 12 306 player seasons were studied prospectively for pattern, mechanism, and outcome after thigh muscle injury. Event analysis was used to identify independent predictors of slow recovery. RESULTS: A total of 1288 injuries were recorded representing an incidence (mean [SD]) of 0.42 (0.24) per thousand hours of training with a mean annual incidence of 0.52. Midfield players received the most injuries, followed by defense and attack positions. The quadriceps muscle group was most likely to be injured. There were 345 reinjuries (27%). Median time off for a primary injury was 13 days (interquartile range, 7-22 days) and 12 days (7-21 days) following a reinjury. Risk of such injury increased as the game progressed toward the end of the first half period (P = .028), and this risk persisted throughout the entire second half. There were 2 peaks of incidence (January and September). The percentage of the total for hamstring, adductor, and quadriceps injuries did not significantly change with player age. However, the proportion of injuries that were severe increased with age of player (t = 3.72, P = .010). Poor prognostic factors for recovery were hamstring injuries (z = 2.182, P = .029), contact injury (z = -3.137, P = .002), and older age (z = -2.2298, P = .022). CONCLUSION: The risk for prolonged recovery from thigh muscle injury was found to increase with age of the player and contact mechanism. The risk of injury increased toward the end of the first half, and this risk persisted throughout the second half. Delayed recovery was significantly associated with a hamstring muscle injury, first injury, and contact mechanism. This study, for the first time, allows identification of youth male soccer players at high-risk for prolonged symptoms after thigh muscle injury. PMID- 22223715 TI - Clinical correlates of immediate success and outcome at 1-year follow-up of real world cardioversion of atrial fibrillation: the Euro Heart Survey. AB - AIMS: In atrial fibrillation (AF) cardioversion is the cornerstone of the rhythm management strategy despite the lack of contemporary data on acute and long-term success. We aim to describe present-day cardioversion of AF and identify characteristics associated with immediate and long-term outcome. METHODS AND RESULTS: Based on the 5333 AF patients enrolled in the multi-centre prospective Euro Heart Survey on AF we selected the 1801 patients undergoing cardioversion at enrolment. Sinus rhythm (SR) was restored in 630 of 712 (88%), 458 of 643 (71%), and 333 of 446 (75%) (P< 0.001) of the electrical (ECV), intravenous (ivCCV), and oral (oCCV) chemical cardioversions, respectively, at the cost of few (4.2%) major complications. In multivariate analysis, absence of chronic obstructive pulmonary disease (COPD) (P< 0.001), presence of paroxysmal AF (PAF) (P= 0.013), and use of biphasic waveform (P= 0.018) were predictors of successful ECV. For ivCCV PAF (P< 0.001), absence of valvular heart disease (P= 0.004), and heart failure (P= 0.009), the presence of hypertension (P= 0.018) and coronary artery disease (P= 0.007) were predictive. Success of oCCV was driven by PAF (P< 0.001) and a smaller left atrial dimension (P= 0.001). At 1-year follow-up 893 of 1271 (70%) patients were in SR. Multivariate analysis revealed PAF (P< 0.001), shorter total AF history (P< 0.001), continuous use of Class Ic drugs or amiodarone during follow-up (P< 0.001), absence of COPD (P= 0.003), younger age (P= 0.004), and smaller left atrial dimension (P= 0.005) as independent predictors of SR at 1 year follow-up. CONCLUSIONS: Contemporary cardioversion of AF is routinely successfully and safely performed with a high proportion of patients in SR at 1 year follow-up. PMID- 22223716 TI - Effect of subchondral drilling on the microarchitecture of subchondral bone: analysis in a large animal model at 6 months. AB - BACKGROUND: Marrow stimulation techniques such as subchondral drilling are clinically important treatment options for symptomatic small cartilage defects. Little is known about whether they induce deleterious changes in the subchondral bone. HYPOTHESIS: Subchondral drilling induces substantial alterations of the microarchitecture of the subchondral bone that persist for a clinically relevant postoperative period in a preclinical large animal model. STUDY DESIGN: Controlled laboratory study. METHODS: Standardized full-thickness chondral defects in the medial femoral condyles of 19 sheep were treated by subchondral drilling. Six months postoperatively, the formation of cysts and intralesional osteophytes was evaluated. A standardized methodology was developed to segment the ovine subchondral unit into reproducible volumes of interest (VOIs). Indices of bone structure were determined by micro-computed tomography (micro-CT). RESULTS: Analysis of the microarchitecture revealed the absence of zonal stratification in the ovine subarticular spongiosa, permitting an unimpeded and simultaneous analysis of the entire subchondral trabecular network. Subchondral drilling led to the formation of subchondral bone cysts (63%) and intralesional osteophytes (26%). Compared with the adjacent unaffected subchondral bone, drilling induced significant alterations in nearly all parameters for the microarchitecture of the subchondral bone plate and the subarticular spongiosa, most importantly in bone volume, bone surface/volume ratio, trabecular thickness, separation, pattern factor, and bone mineral density (BMD) (all P <= .01). CONCLUSION: The data show that the ovine subchondral bone can be reliably evaluated using micro-CT with standardized VOIs. We report that subchondral drilling deteriorates the microarchitecture both of the subchondral bone plate and subarticular spongiosa and decreases BMD. These results suggest that the entire osteochondral unit is altered after drilling for an extended postoperative period. CLINICAL RELEVANCE: The subchondral bone remains fragile after subchondral drilling for longer durations than previously expected. Further evaluations of structural subchondral bone parameters of patients undergoing marrow stimulation are warranted. PMID- 22223718 TI - Synthesis and characterisation of BaSo4:Eu thermoluminescence phosphor. AB - Polycrystalline powder samples of BaSO(4) doped with Eu(2+) were prepared by solid-state reaction in different reducing atmospheres. Photoluminescence (PL), thermoluminescence (TL), TL kinetic and dosimetric studies have been carried out in this phosphor. The TL glow curve of BaSO(4):Eu(2+) showed only a single peak at 513 K unlike other phosphors and the TL intensity is about three to four times higher than that of CaSO(4):Dy, which is currently used as the radiation dosemeter for personnel monitoring in India. The TL dose response of the phosphor was found to be linear up to the dose range of 10(3) Gy beyond which saturation sets in. PL and TL spectra showed the characteristic emission of Eu(2+) ion. The TL parameters such as trap depth (E) or the energy required to release the electron or hole from the trap, frequency factor (s) and the order of kinetics (b) are determined by different methods such as isothermal decay, initial rise and variable heating rate. PMID- 22223717 TI - What strains the anterior cruciate ligament during a pivot landing? AB - BACKGROUND: The relative contributions of an axial tibial torque and frontal plane moment to anterior cruciate ligament (ACL) strain during pivot landings are unknown. HYPOTHESIS: The peak normalized relative strain in the anteromedial (AM) bundle of the ACL is affected by the direction of the axial tibial torque but not by the direction of the frontal plane moment applied concurrently during a simulated jump landing. STUDY DESIGN: Controlled and descriptive laboratory studies. METHODS: Fifteen adult male knees with pretensioned knee muscle-tendon unit forces were loaded under a simulated pivot landing test. Compression, flexion moment, internal or external tibial torque, and knee varus or valgus moment were simultaneously applied to the distal tibia while recording the 3D knee loads and tibiofemoral kinematics. The AM-ACL relative strain was measured using a 3-mm differential variable reluctance transducer. The results were analyzed using nonparametric Wilcoxon signed-rank tests. A 3D dynamic biomechanical knee model was developed using ADAMS and validated to help interpret the experimental results. RESULTS: The mean (SD) peak AM-ACL relative strain was 192% greater (P < .001) under the internal tibial torque combined with a knee varus or valgus moment (7.0% [3.9%] and 7.0% [4.1%], respectively) than under external tibial torque with the same moments (2.4% [2.5%] and 2.4% [3.2%], respectively). The knee valgus moment augmented the AM-ACL strain due to the slope of the tibial plateau inducing mechanical coupling (ie, internal tibial rotation and knee valgus moment); this augmentation occurred before medial knee joint space opening. CONCLUSION: An internal tibial torque combined with a knee valgus moment is the worst-case ACL loading condition. However, it is the internal tibial torque that primarily causes large ACL strain. CLINICAL RELEVANCE: Limiting the maximum coefficient of friction between the shoe and playing surface should limit the peak internal tibial torque that can be applied to the knee during jump landings, thereby reducing peak ACL strain and the risk for noncontact injury. PMID- 22223719 TI - Verification of some building materials as gamma-ray shields. AB - The shielding properties for gamma rays of a few low Z materials were investigated. The values of the mass attenuation coefficient, equivalent atomic number, effective atomic number, exposure buildup factor and energy absorption buildup factor were calculated and used to estimate the shielding effectiveness of the samples under investigation. It has been observed that the shielding effectiveness of a sample is directly related to its effective atomic number. The shielding character of any sample is a function of the incident photon energy. Good shielding behaviour has been verified in soil samples in the photon energy region of 0.015-0.30 MeV and of dolomite in 3-15 MeV. The results have been shown graphically with more useful conclusions. PMID- 22223720 TI - Estimation of thoron concentration using scintillation cell. AB - Two counting techniques are proposed in this paper to estimate thoron ((220)Rn) concentration using a Lucas scintillation cell. The alpha activity build-up inside the cell is calculated theoretically by using Bateman equations. The first method is having a minimum detection limit of 325 Bq m(-3) and can be used for thoron measurement in thorium-processing plants. In the second method, thoron concentration is calculated using the alpha counts from thoron progenies and is a reference to the first method. The results obtained by these techniques compare well with the double filter method. PMID- 22223721 TI - Survey of the interventional cardiology procedures in Italy. AB - Interventional cardiology procedures are increasing because they offer many advantages to patients compared with other techniques: therefore the Italian National Institution for Insurance against Accidents at Work decided to start a survey for monitoring the state-of-the-art regarding the professionals involved in those procedures. The survey covered six cardiology and medical physics Italian departments. Each centre was asked to record 10 examinations for five types of procedures: coronary angiography (CA), electrophysiology studies (ES), pacemaker implantation (PI), percutaneous transluminal coronary angioplasty (PTCA) and radiofrequency catheter ablation (RA). For each examination all the centres were requested to fill in a questionnaire containing information regarding the operator performing the examination, the patient and the procedure. A total of 290 examinations were recorded: 103 CA, 14 ES, 68 PI, 79 PTCA and 26 RA. As occupational doses are strongly related to patient doses, both patients and operators radiation dose data are reported. Ratios of maximum to minimum mean patient doses across the hospitals surveyed were 2.0, 3.9, 7.0, 1.8 and 1.4 for CA, ES, PI, PTCA and RA, respectively. The calculated rounded mean dose-area product values across all participating hospitals were comparable with other values reported in the literature. In general, specific radiation protection tools were used by all operators performing different procedures in all hospitals. A major issue in this survey was the absence of information about correlation between staff and patient doses in a single procedure: future studies could be more aimed to prospective goals where occupational exposures per procedure are monitored specifically. PMID- 22223722 TI - A new mammography dosimetric phantom. AB - Breast phantoms produced with tissue-equivalent materials are used in an attempt to simulate glandular and adipose tissues, in terms of X-ray attenuation and density. In this work, a set of breast tissue-equivalent phantoms (BTE phantoms) with semicircular shapes of different thicknesses and compositions were produced. Such phantoms may be used in the measurement of the incident air kerma (K(i)) and the mean glandular dose (D(G)) delivered to patients undergoing mammography. To characterise the materials used to produce the phantoms, a series of 17-keV X-ray attenuation coefficient measurements were performed. The carbon-nitrogen-hydrogen elemental composition and the densities of the tissue-equivalent materials were also determined and compared with values available in the literature. Linear attenuation coefficients of 0.724 and 0.923 cm(-1) were determined, respectively, for adipose and glandular tissues. Such values agree with data available in the literature. On the basis of the results obtained in this work, it is suggested that BTE phantoms are used instead of polymethyl methacrylate phantoms to select exposure parameters (kV, mAs and target/filter combination) specific for breast glandularities from 0 to 50 % in the optimisation of doses in mammography. PMID- 22223723 TI - On personal dosimetry for members of the general public in Japan and the medical management of radiation accidents. PMID- 22223725 TI - Medical male circumcision for HIV/AIDS prevention in Uganda - the cost of disposable versus re-usable circumcision kits. AB - We evaluated the cost implications of medical male circumcisions for HIV prevention when performed using re-usable equipment that is sterilized after each use versus using single-use disposal kits. In Uganda, a re-usable circumcision kit results in a net saving of US$7.14-US$12.34 or 46-59%. In resource-limited settings seeking to expand access to medical male circumcision for HIV prevention, substantial cost reductions may be achieved by adopting re-usable circumcision kits. PMID- 22223724 TI - Area dosimetry in the Praid-salt mine. AB - The aim of the paper is to present a special application of the Romanian thermoluminescent dosemeters system, based on the use of the LiF:Mg,Cu,P, commercial GR-200A detectors, for the measurement of the ultra-low-level ambient dose equivalent rate values, situated within the interval of 1-100 nSv h(-1). The paper briefly describes the system and presents in detail the experimental procedure, including the corrections to be applied to the experimental values. The final characterisation of a Romanian salt mine, proposed to be used as an underground accelerator laboratory, is given. The comparison with the previous measurement results in the Slanic Prahova former salt mine and with the results obtained using the gamma-ray spectrometry method validates the results reported in this paper. The conclusion is that the system provides reliable results in the measurement of the ultra-low-level radiation background. PMID- 22223726 TI - The impact of snake bite on household economy in Bangladesh. AB - The present study aims to assess the different types of costs for treatment of snake bite patients, to quantify household economic impact and to understand the coping mechanisms required to cover the costs for snake bite patients in Bangladesh. The patients admitted to four tertiary level hospitals in Bangladesh were interviewed using structured questionnaires including health-care-related expenditures and the way in which the expenditures were covered. Of the snakes which bit the patients, 54.2% were non-venomous, 45.8% were venomous and 42.2% of the patients were given polyvalent antivenom. The total expenditure related to snake bite varies from US$4 (US$1 = Taka 72) to US$2294 with a mean of US$124 and the mean income loss was US$93. Expenditure for venomous snake bite was US$231, which is about seven times higher than non-venomous snake bite (US$34). The treatment imposes a major economic burden on affected families, especially in venomous snake bite cases. PMID- 22223727 TI - Forgotten intrauterine devices presenting with pre- and postmenopausal bleeding: a case series. AB - We present two cases of retained intrauterine contraceptive devices (IUCDs). The first presented with perimenopausal bleeding and dysmenorrhoea and the symptoms were resolved following the removal of an IUCD. The second presented with postmenopausal bleeding and had a Lippes loop in the uterine cavity. The symptoms resolved after the removal of the device. PMID- 22223729 TI - Urotensin-II signaling mechanism in rat coronary artery: role of STIM1 and Orai1 dependent store operated calcium influx in vasoconstriction. AB - OBJECTIVE: Human urotensin-II (UII) is considered the most potentendogenous vasoconstrictor discovered to date, although the precise mechanism activated downstream of its receptor UTS2R in blood vessels remains elusive. The aim of this study was to determine the role of the store operated Ca(2+) entry (SOCE) signaling pathway in UII-induced coronary artery vasoconstriction. METHODS AND RESULTS: We used a combination of isometric tension measurement, Ca(2+) imaging, pharmacology, and molecular approaches to study UII-mediated rat coronary artery vasoconstriction and intracellular Ca(2+) mobilization in coronary smooth muscle cells. We found that UII promoted dose-dependent vasoconstriction and elicited Ca(2+) and Mn(2+) influx, which were sensitive to classical SOCE inhibitors. In addition, knockdown of either STIM1 or Orai1 essentially inhibited UII-mediated SOCE and prevented UII but not high-KCL evoked contraction in transfected coronary artery. Moreover, we found that Ca(2+)-independent phospholipase A(2)beta was involved in UII effects and that is colocalized with STIM1 in different submembrane compartments. Importantly, STIM1 but not Orai1 downregulation inhibits significantly independent phospholipase A(2) activation. Furthermore, lysophosphatidylcholine, an independent phospholipase A(2) product, activated Orai1 but not STIM1-dependent contraction and SOCE. CONCLUSIONS: Here, we demonstrated that different critical players of SOCE signaling pathway are required for UII-induced vasoconstriction of rat coronary artery. PMID- 22223728 TI - Regulatory T-cell response to apolipoprotein B100-derived peptides reduces the development and progression of atherosclerosis in mice. AB - OBJECTIVE: The immunoinflammatory response plays a critical role in the development and progression of atherosclerosis. Recent studies suggested an important role for regulatory T (Treg) cells in the inhibition of disease-related vascular inflammation. We hypothesized that induction of a specific Treg cell response to atherosclerosis-relevant antigens would be an attractive strategy to limit the development and progression of atherosclerosis through the promotion of immune tolerance. METHODS AND RESULTS: Young or old Apoe-/- mice were subcutaneously infused for 2 weeks with either a control ovalbumin (OVA) peptide or with apolipoprotein B100 (ApoB100)-derived peptides without adjuvant. Atherosclerosis development, progression and immunologic status were assessed at 8 weeks after the end of the infusion. Treatment with ApoB100 peptides led to significant reduction of lesion development in young Apoe-/- mice (P=0.001 versus OVA group) and abrogated atherosclerosis progression in old Apoe-/- mice with already established lesions (0% progression in ApoB100 versus 17% in OVA group, P<0.005). Limitation of plaque progression was associated with reduced vascular inflammation and increased collagen content, indicative of plaque stabilization. Infusion of ApoB100 peptides did not alterantibody production but promoted a specific Treg cell response, which was associated with a reduction of both T helper type 1-related and T helper type 2-related cytokines. Interestingly, depletion of CD4+CD25+ Treg cells abrogated ApoB100 peptides-dependent immune modulation and atheroprotection. CONCLUSION: Subcutaneous infusion of adjuvant free ApoB100-derived peptides to Apoe-/- mice reduces atherosclerosis through the induction of a specific Treg cell response. PMID- 22223730 TI - Tissue factor pathway inhibitor blocks angiogenesis via its carboxyl terminus. AB - OBJECTIVE: Tissue factor pathway inhibitor (TFPI) is the primary regulator of the tissue factor (TF) coagulation pathway. As such, TFPI may regulate the proangiogenic effects of TF. TFPI may also affect angiogenesis independently of TF, through sequences within its polybasic carboxyl terminus (TFPI C terminus [TFPIct]). We aimed to determine the effects of TFPI on angiogenesis and the role of TFPIct. METHODS AND RESULTS: Transgenic overexpression of TFPI attenuated angiogenesis in the murine hindlimb ischemia model and an aortic sprout assay. In vitro, TFPI inhibited endothelial cell migration. Peptides within the human TFPIct inhibited endothelial cell cord formation and migration in response to vascular endothelial growth factor (VEGF) 165 but not VEGF121. Furthermore, exposure to human TFPIct inhibited the phosphorylation of VEGF receptor 2 at residue Lys951, a residue known to be critical for endothelial cell migration. Finally, systemic delivery of a murine TFPIct peptide inhibited angiogenesis in the hindlimb model. CONCLUSION: These data demonstrate an inhibitory role for TFPI in angiogenesis that is, in part, mediated through peptides within its carboxyl terminus. In addition to its known role as a TF antagonist, TFPI, via its carboxyl terminus, may regulate angiogenesis by directly blocking VEGF receptor 2 activation and attenuating the migratory capacity of endothelial cells. PMID- 22223732 TI - Gamma-glutamyltransferase, hepatic enzymes, and risk of incident heart failure in older men. AB - OBJECTIVE: The relationship between gamma-glutamyl transferase (GGT) and heart failure (HF) in older adults is unknown. We have examined the relationship between GGT, other markers of hepatic function (alanine aminotransferase, aspartate transaminase, and alkaline phosphatase), and incident HF in older men. METHODS AND RESULTS: This was a prospective study of 3494 men aged 60 to 79 years with no diagnosed HF or myocardial infarction followed up for a mean period of 9 years, in whom there were 168 incident HF cases. Elevated GGT (top quartile, >=38 U/L) was associated with significantly increased risk of incident HF in men aged<70 years but not in men aged>=70 years (test for age-GGT interaction, P<0.0001). The increased risk of HF associated with elevated GGT persisted after adjustment for a wide range of established and novel risk factors for HF, including diabetes, stroke, obesity, systolic blood pressure, atrial fibrillation, lung function, inflammation (C-reactive protein), endothelial dysfunction (von Willebrand factor), leptin, and N terminal pro brain natriuretic peptide (adjusted hazard ratio [95% CI], 1.91 [1.07, 3.42]). Other liver function markers showed no significant associations with HF after similar adjustments. CONCLUSION: Elevated GGT was associated with increased risk of HF in men aged<70 years. Additional studies are now needed to determine the mechanisms responsible. PMID- 22223731 TI - Inhibition of bone morphogenetic protein signaling reduces vascular calcification and atherosclerosis. AB - OBJECTIVE: The expression of bone morphogenetic proteins (BMPs) is enhanced in human atherosclerotic and calcific vascular lesions. Although genetic gain- and loss-of-function experiments in mice have supported a causal role of BMP signaling in atherosclerosis and vascular calcification, it remains uncertain whether BMP signaling might be targeted pharmacologically to ameliorate both of these processes. METHODS AND RESULTS: We tested the impact of pharmacological BMP inhibition on atherosclerosis and calcification in LDL receptor-deficient (LDLR-/ ) mice. LDLR-/- mice fed a high-fat diet developed abundant vascular calcification within 20 weeks. Prolonged treatment of LDLR-/- mice with the small molecule BMP inhibitor LDN-193189 was well-tolerated and potently inhibited development of atheroma, as well as associated vascular inflammation, osteogenic activity, and calcification. Administration of recombinant BMP antagonist ALK3-Fc replicated the antiatherosclerotic and anti-inflammatory effects of LDN-193189. Treatment of human aortic endothelial cells with LDN-193189 or ALK3-Fc abrogated the production of reactive oxygen species induced by oxidized LDL, a known early event in atherogenesis. Unexpectedly, treatment of mice with LDN-193189 lowered LDL serum cholesterol by 35% and markedly decreased hepatosteatosis without inhibiting HMG-CoA reductase activity. Treatment with BMP2 increased, whereas LDN 193189 or ALK3-Fc inhibited apolipoprotein B100 secretion in HepG2 cells, suggesting that BMP signaling contributes to the regulation of cholesterol biosynthesis. CONCLUSION: These results definitively implicate BMP signaling in atherosclerosis and calcification, while uncovering a previously unidentified role for BMP signaling in LDL cholesterol metabolism. BMP inhibition may be helpful in the treatment of atherosclerosis and associated vascular calcification. PMID- 22223734 TI - Socioeconomic status, cardiovascular risk factors, and subclinical atherosclerosis in young adults: the cardiovascular risk in Young Finns Study. AB - OBJECTIVE: The goal of this study was to investigate the extent to which socioeconomic status (SES) in young adults is associated with cardiovascular risk factor levels and carotid intima-media thickness (IMT) and their changes over a 6 year follow-up period. METHODS AND RESULTS: The study population included 1813 subjects participating in the 21- and 27-year follow-ups of the Cardiovascular Risk in Young Finns Study (baseline age 24-39 years in 2001). At baseline, SES (indexed with education) was inversely associated with body mass index (P=0.0002), waist circumference (P<0.0001), glucose (P=0.01), and insulin (P=0.0009) concentrations; inversely associated with alcohol consumption (P=0.02) and cigarette smoking (P<0.0001); and directly associated with high-density lipoprotein cholesterol levels (P=0.05) and physical activity (P=0.006). Higher SES was associated with a smaller 6-year increase in body mass index (P=0.001). Education level and IMT were not associated (P=0.58) at baseline, but an inverse association was observed at follow-up among men (P=0.004). This became nonsignificant after adjustment with conventional risk factors (P=0.11). In all subjects, higher education was associated with a smaller increase in IMT during the follow-up (P=0.002), and this association remained after adjustments for conventional risk factors (P=0.04). CONCLUSION: This study shows that high education in young adults is associated with favorable cardiovascular risk factor profile and 6-year change of risk factors. Most importantly, the progression of carotid atherosclerosis was slower among individuals with higher educational level. PMID- 22223733 TI - Mirtron microRNA-1236 inhibits VEGFR-3 signaling during inflammatory lymphangiogenesis. AB - OBJECTIVE: Vascular endothelial growth factor receptor(VEGFR)-3 is a critical regulator of developmental and adult vasculogenesis and lymphangiogenesis through its interactions with select members of the VEGF family. The goal of this study was to investigate how VEGFR-3 expression is regulated during inflammatory lymphangiogenesis. METHODS AND RESULTS: In this study, we present for the first time evidence that VEGFR-3 can be negatively regulated by a mirtron, hsa-miR-1236 (miR-1236), which is expressed in primary human lymphatic endothelial cells. In human lymphatic endothelial cells, miR-1236 is upregulated in response to IL 1beta, a negative regulator of VEGFR-3. miR-1236 binds the 3' untranslated region of Vegfr3, resulting in translational inhibition. Overexpression of miR-1236 significantly decreased expression of VEGFR-3, but not VEGFR-2, in human lymphatic endothelial cells. Compared to a control miR, overexpression of miR 1236 also led to decreased VEGFR-3 signaling. However, VEGFR-2-specific signaling was not affected. miR-1236 can attenuate human lymphatic endothelial cell migration and tube formation, as well as in vivo lymphangiogenesis. CONCLUSION: Our data suggest that miR-1236 may function as a negative regulator of VEGFR-3 signaling during inflammatory lymphangiogenesis. PMID- 22223735 TI - Report on the inaugural meeting of the International Consortium on Hallucination Research: a clinical and research update and 16 consensus-set goals for future research. AB - This article presents a report on the first meeting of the International Consortium on Hallucination Research, which took place on September 13-14, 2011 at the Institute of Psychiatry, London. The first day of the meeting served to reflect on the current state of knowledge regarding auditory hallucinations in different diagnostic groups, based on the presentations from the phenomenology, cognition, emotion, electrophysiology, neurochemical, neuroimaging, genetics, treatment, and computational modeling working groups. The second day comprised a discussion forum where the most important and urgent questions for future research were identified. The meeting recognized that a lot has been achieved in auditory hallucination research but that much still remains to be done. Here, we outline the top 16 goals for research on auditory hallucinations, which cover topics of conceptual importance, academic and treatment issues, scientific rigor, and cross-disciplinary collaboration. Concerted and coordinated actions will be required to make substantial research progress. PMID- 22223736 TI - The crystal structure of TAL effector PthXo1 bound to its DNA target. AB - DNA recognition by TAL effectors is mediated by tandem repeats, each 33 to 35 residues in length, that specify nucleotides via unique repeat-variable diresidues (RVDs). The crystal structure of PthXo1 bound to its DNA target was determined by high-throughput computational structure prediction and validated by heavy-atom derivatization. Each repeat forms a left-handed, two-helix bundle that presents an RVD-containing loop to the DNA. The repeats self-associate to form a right-handed superhelix wrapped around the DNA major groove. The first RVD residue forms a stabilizing contact with the protein backbone, while the second makes a base-specific contact to the DNA sense strand. Two degenerate amino terminal repeats also interact with the DNA. Containing several RVDs and noncanonical associations, the structure illustrates the basis of TAL effector DNA recognition. PMID- 22223737 TI - Centrosome loss in the evolution of planarians. AB - The centrosome, a cytoplasmic organelle formed by cylinder-shaped centrioles surrounded by a microtubule-organizing matrix, is a hallmark of animal cells. The centrosome is conserved and essential for the development of all animal species described so far. Here, we show that planarians, and possibly other flatworms, lack centrosomes. In planarians, centrioles are only assembled in terminally differentiating ciliated cells through the acentriolar pathway to trigger the assembly of cilia. We identified a large set of conserved proteins required for centriole assembly in animals and note centrosome protein families that are missing from the planarian genome. Our study uncovers the molecular architecture and evolution of the animal centrosome and emphasizes the plasticity of animal cell biology and development. PMID- 22223738 TI - Structural basis for sequence-specific recognition of DNA by TAL effectors. AB - TAL (transcription activator-like) effectors, secreted by phytopathogenic bacteria, recognize host DNA sequences through a central domain of tandem repeats. Each repeat comprises 33 to 35 conserved amino acids and targets a specific base pair by using two hypervariable residues [known as repeat variable diresidues (RVDs)] at positions 12 and 13. Here, we report the crystal structures of an 11.5-repeat TAL effector in both DNA-free and DNA-bound states. Each TAL repeat comprises two helices connected by a short RVD-containing loop. The 11.5 repeats form a right-handed, superhelical structure that tracks along the sense strand of DNA duplex, with RVDs contacting the major groove. The 12th residue stabilizes the RVD loop, whereas the 13th residue makes a base-specific contact. Understanding DNA recognition by TAL effectors may facilitate rational design of DNA-binding proteins with biotechnological applications. PMID- 22223739 TI - RNA editing underlies temperature adaptation in K+ channels from polar octopuses. AB - To operate in the extreme cold, ion channels from psychrophiles must have evolved structural changes to compensate for their thermal environment. A reasonable assumption would be that the underlying adaptations lie within the encoding genes. Here, we show that delayed rectifier K(+) channel genes from an Antarctic and a tropical octopus encode channels that differ at only four positions and display very similar behavior when expressed in Xenopus oocytes. However, the transcribed messenger RNAs are extensively edited, creating functional diversity. One editing site, which recodes an isoleucine to a valine in the channel's pore, greatly accelerates gating kinetics by destabilizing the open state. This site is extensively edited in both Antarctic and Arctic species, but mostly unedited in tropical species. Thus adenosine-to-inosine RNA editing can respond to the physical environment. PMID- 22223740 TI - Activation-induced B cell fates are selected by intracellular stochastic competition. AB - In response to stimulation, B lymphocytes pursue a large number of distinct fates important for immune regulation. Whether each cell's fate is determined by external direction, internal stochastic processes, or directed asymmetric division is unknown. Measurement of times to isotype switch, to develop into a plasmablast, and to divide or to die for thousands of cells indicated that each fate is pursued autonomously and stochastically. As a consequence of competition between these processes, censorship of alternative outcomes predicts intricate correlations that are observed in the data. Stochastic competition can explain how the allocation of a proportion of B cells to each cell fate is achieved. The B cell may exemplify how other complex cell differentiation systems are controlled. PMID- 22223741 TI - Neural control of the circulation: exercise. PMID- 22223742 TI - Building an HIV data mashup using Bio2RDF. AB - We present an update to the Bio2RDF Linked Data Network, which now comprises ~30 billion statements across 30 data sets. Significant changes to the framework include the accommodation of global mirrors, offline data processing and new search and integration services. The utility of this new network of knowledge is illustrated through a Bio2RDF-based mashup with microarray gene expression results and interaction data obtained from the HIV-1, Human Protein Interaction Database (HHPID) with respect to the infection of human macrophages with the human immunodeficiency virus type 1 (HIV-1). PMID- 22223743 TI - The impact of polypharmacy on the health of Canadian seniors. AB - BACKGROUND: Prescription medication use increases with age. Seniors face an increased risk of adverse drug reactions from medications, partly because the kidneys and liver can lose functional ability with increasing age, resulting in the need for changes in dosage. OBJECTIVE: To use population survey data to understand the extent and impact of multiple medication use and adverse drug events among Canadian seniors. METHODS: This study consists of analysis of data from the Canadian Survey of Experiences with Primary Health Care, which was conducted through telephone by Statistics Canada in 2008. These analyses focussed on the 3132 respondents who were >= 65 years of age. RESULTS: Twenty-seven per cent of seniors reported taking five or more medications on a regular basis. Within the past year, 12% of seniors taking five or more medications experienced a side effect that required medical attention compared with 5% of seniors taking only one or two medications. Even when controlling for age and number of chronic conditions, the number of prescription medications was associated with the rate of emergency department use. Less than half of all seniors reported having received medication reviews and having the possible side effects of their prescription medications explained to them by their physician. CONCLUSIONS: Many Canadian seniors have an elevated risk of adverse events due to taking a high number of prescription medications and not having the potential side effects and drug interactions explained to them. There are interventions that can potentially reduce polypharmacy and adverse events, including routine medication reviews. PMID- 22223744 TI - Mutual referral: a survey of GPs in Beijing. AB - BACKGROUND: China has been engaged in the process of reforming its health care system recently. The government has attempted to rebuild the referral system to lower cost and enhance equity of the medical services. OBJECTIVE: This study was undertaken to evaluate the current status of mutual referral pilot programme, perceived factors that affect referral behaviour and changes that would improve the current referral process in Beijing. METHODS: Using a cross-sectional study design, we sent a postal questionnaire to 138 urban district community health service (CHS) centres in Beijing. Questions were chosen from a formal consensus process based on a nominal group technique. RESULTS: One hundred twenty-five of 138 (90.6%) CHS centres responded to the survey. Seventy-six (61.8%) CHS centres reported that the mutual referral system was feasible. Twenty-six (21.1%) CHS centres reported that the mutual referral programme was running smoothly. Uncertainties of diagnosis/management and access to particular medical specialty interest or skills were the two most common factors that were suggested as affecting referral behaviour. The presence of a dedicated department to accept referrals in hospitals and the use of referral guidelines were the most preferred choices as likely to improve the current referral process. CONCLUSIONS: Since a system of gatekeeper role by GPs at CHS organizations has not been established in Beijing, most CHS doctors agree that to ensure the smooth operation of referrals, a dedicated department should be assigned by hospitals to receive referred patients. Official guidelines on referral should be developed, and health authorities should strengthen their supervision of referrals. PMID- 22223745 TI - A method to infer positive selection from marker dynamics in an asexual population. AB - MOTIVATION: The observation of positive selection acting on a mutant indicates that the corresponding mutation has some form of functional relevance. Determining the fitness effects of mutations thus has relevance to many interesting biological questions. One means of identifying beneficial mutations in an asexual population is to observe changes in the frequency of marked subsets of the population. We here describe a method to estimate the establishment times and fitnesses of beneficial mutations from neutral marker frequency data. RESULTS: The method accurately reproduces complex marker frequency trajectories. In simulations for which positive selection is close to 5% per generation, we obtain correlations upwards of 0.91 between correct and inferred haplotype establishment times. Where mutation selection coefficients are exponentially distributed, the inferred distribution of haplotype fitnesses is close to being correct. Applied to data from a bacterial evolution experiment, our method reproduces an observed correlation between evolvability and initial fitness defect. PMID- 22223746 TI - A Bayesian model for time-to-event data with informative censoring. AB - Randomized trials with dropouts or censored data and discrete time-to-event type outcomes are frequently analyzed using the Kaplan-Meier or product limit (PL) estimation method. However, the PL method assumes that the censoring mechanism is noninformative and when this assumption is violated, the inferences may not be valid. We propose an expanded PL method using a Bayesian framework to incorporate informative censoring mechanism and perform sensitivity analysis on estimates of the cumulative incidence curves. The expanded method uses a model, which can be viewed as a pattern mixture model, where odds for having an event during the follow-up interval $$({t}_{k-1},{t}_{k}]$$, conditional on being at risk at $${t}_{k-1}$$, differ across the patterns of missing data. The sensitivity parameters relate the odds of an event, between subjects from a missing-data pattern with the observed subjects for each interval. The large number of the sensitivity parameters is reduced by considering them as random and assumed to follow a log-normal distribution with prespecified mean and variance. Then we vary the mean and variance to explore sensitivity of inferences. The missing at random (MAR) mechanism is a special case of the expanded model, thus allowing exploration of the sensitivity to inferences as departures from the inferences under the MAR assumption. The proposed approach is applied to data from the TRial Of Preventing HYpertension. PMID- 22223747 TI - Localising rectus muscle insertions using high frequency wide-field ultrasound biomicroscopy. AB - AIM: The ultrasound biomicroscope (UBM) can accurately locate an extraocular muscle (EOM) insertion. The authors compared the accuracy of the Sonomed UBM (SUBM), a new 'wide-field ultrasound biomicroscope', with the older model Humphrey UBM (HUBM) in localising EOM insertions and compared their ranges of detection of muscle insertions. METHODS: Prospective, double-masked, observational study of 27 patients undergoing primary (n=40 muscles) or repeat (n=10 muscles) horizontal or vertical rectus muscle surgery. EOM insertional distances were measured with SUBM, and then intraoperatively with callipers. A Bland-Altman analysis and intraclass correlation coefficient were used to compare the SUBM and surgical data. RESULTS: For all muscles, the differences between SUBM and surgery measurements were less than 1.0 mm. The mean of the SUBM insertion distances was 6.67 mm (SD 1.65 mm) versus 6.7 mm (SD 1.6 mm) at surgery. The intraclass correlation coefficient showed 'excellent' correlation between the two sets of data and was higher than that reported with HUBM. The image quality with the SUBM was superior to the HUBM, and its range of field was much larger (14*18 mm vs 5*6 mm). CONCLUSION: The SUBM with its smaller, more manoeuvrable probe handpiece and a wider scanning field was more accurate in detecting muscle insertions compared with HUBM. PMID- 22223748 TI - Ischaemia in the Zinn-Haller circle and glaucomatous optic neuropathy in macaque monkeys. AB - AIMS: To elucidate the morphological features of optic neuropathy in an ischaemic model of glaucoma in macaque monkeys. METHODS: The regional degenerative process was investigated by experimentally occluding the paraoptic branches of the lateral short posterior ciliary artery, that is, the circle of Haller and Zinn, in 11 eyes. Morphological changes in nerve fibres in the lamina cribrosa were evaluated by histopathology, immunocytochemistry and angiography, and the findings were compared with those observed in an aged macaque with spontaneous glaucomatous optic neuropathy. RESULTS: Retinal ganglion cell axons were grouped in bundles and traversed through pores in columns of the lamina cribrosa. The processes of astrocytes extended to the bundles, and capillaries branched in surrounding connective tissue from the circular arterioles. Experimental ischaemia induced time-dependent anoxic deterioration of phosphorylated fibres in the temporal arcuate zone, accompanied by glial proliferation. A monkey with spontaneous visual impairment had nerve fibre loss and gliosis with collagenous proliferation in the temporal hemisphere, suggesting glaucomatous neuropathy. CONCLUSIONS: Circulatory interference in the circle of Haller and Zinn caused time-dependent deterioration in the area where anoxic segmental degeneration is associated with pathogenesis of open-angle glaucoma. PMID- 22223750 TI - Transcranial pulsed magnetic field stimulation facilitates reorganization of abnormal neural circuits and corrects behavioral deficits without disrupting normal connectivity. AB - Although the organization of neuronal circuitry is shaped by activity patterns, the capacity to modify and/or optimize the structure and function of whole projection pathways using external stimuli is poorly defined. We investigate whether neuronal activity induced by pulsed magnetic fields (PMFs) alters brain structure and function. We delivered low-intensity PMFs to the posterior cranium of awake, unrestrained mice (wild-type and ephrin-A2A5(-/-)) that have disorganized retinocollicular circuitry and associated visuomotor deficits. Control groups of each genotype received sham stimulation. Following daily stimulation for 14 d, we measured biochemical, structural (anterograde tracing), and functional (electrophysiology and behavior) changes in the retinocollicular projection. PMFs induced BDNF, GABA, and nNOS expression in the superior colliculus and retina of wild-type and ephrin-A2A5(-/-) mice. Furthermore, in ephrin-A2A5(-/-) mice, PMFs corrected abnormal neuronal responses and selectively removed inaccurate ectopic axon terminals to improve structural and functional organization of their retinocollicular projection and restore normal visual tracking behavior. In contrast, PMFs did not alter the structure or function of the normal projection in wild-type mice. Sham PMF stimulation had no effect on any mice. Thus, PMF-induced biochemical changes are congruent with its capacity to facilitate beneficial reorganization of abnormal neural circuits without disrupting normal connectivity and function. PMID- 22223749 TI - Pivotal role of RanBP9 in integrin-dependent focal adhesion signaling and assembly. AB - Accumulation of the amyloid beta (Abeta) peptide derived from the amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer's disease (AD). We previously reported that the scaffolding protein RanBP9 is markedly increased in AD brains and promotes Abeta generation by scaffolding APP/BACE1/LRP complexes together and accelerating APP endocytosis. Because APP, LRP, and RanBP9 all physically interact with beta-integrins, we investigated whether RanBP9 alters integrin-dependent cell adhesion and focal adhesion signaling. Here, we show that RanBP9 overexpression dramatically disrupts integrin-dependent cell attachment and spreading in NIH3T3 and hippocampus derived HT22 cells, concomitant with strongly decreased Pyk2/paxillin signaling and talin/vinculin localization in focal adhesion complexes. Conversely, RanBP9 knockdown robustly promotes cell attachment, spreading, and focal adhesion signaling and assembly. Cell surface biotinylation and endocytosis assays reveal that RanBP9 overexpression and RanBP9 siRNA potently reduces and increases surface beta1-integrin and LRP by accelerating and inhibiting their endocytosis, respectively. Primary hippocampal neurons derived from RanBP9-transgenic mice also demonstrate severely reduced levels of surface beta1-integrin, LRP, and APP, as well as neurite arborization. Therefore, these data indicate that RanBP9 simultaneously inhibits cell-adhesive processes and enhances Abeta generation by accelerating APP, LRP, and beta1-integrin endocytosis. PMID- 22223751 TI - Primary cilia mediate mechanotransduction through control of ATP-induced Ca2+ signaling in compressed chondrocytes. AB - We investigated the role of the chondrocyte primary cilium in mechanotransduction events related to cartilage extracellular matrix synthesis. We generated conditionally immortalized wild-type (WT) and IFT88(orpk) (ORPK) mutant chondrocytes that lack primary cilia and assessed intracellular Ca(2+) signaling, extracellular matrix synthesis, and ATP release in response to physiologically relevant compressive strains in a 3-dimensional chondrocyte culture system. All conditions were compared to unloaded controls. We found that cilia were required for compression-induced Ca(2+) signaling mediated by ATP release, and an associated up-regulation of aggrecan mRNA and sulfated glycosaminosglycan secretion. However, chondrocyte cilia were not the initial mechanoreceptors, since both WT and ORPK cells showed mechanically induced ATP release. Rather, we found that primary cilia were required for downstream ATP reception, since ORPK cells did not elicit a Ca(2+) response to exogenous ATP even though WT and ORPK cells express similar levels of purine receptors. We suggest that purinergic Ca(2+) signaling may be regulated by polycystin-1, since ORPK cells only expressed the C-terminal tail. This is the first study to demonstrate that primary cilia are essential organelles for cartilage mechanotransduction, as well as identifying a novel role for primary cilia not previously reported in any other cell type, namely cilia-mediated control of ATP reception. PMID- 22223752 TI - A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential. AB - Metabotropic glutamate (mGlu) receptors are promising targets to treat numerous brain disorders. So far, allosteric modulators are the only subtype selective ligands, but pure agonists still have strong therapeutic potential. Here, we aimed at investigating the possibility of developing subtype-selective agonists by extending the glutamate-like structure to hit a nonconsensus binding area. We report the properties of the first mGlu4-selective orthosteric agonist, derived from a virtual screening hit, LSP4-2022 using cell-based assays with recombinant mGlu receptors [EC(50): 0.11 +/- 0.02, 11.6 +/- 1.9, 29.2 +/- 4.2 MUM (n>19) in calcium assays on mGlu4, mGlu7, and mGlu8 receptors, respectively, with no activity at the group I and -II mGlu receptors at 100 MUM]. LSP4-2022 inhibits neurotransmission in cerebellar slices from wild-type but not mGlu4 receptor knockout mice. In vivo, it possesses antiparkinsonian properties after central or systemic administration in a haloperidol-induced catalepsy test, revealing its ability to cross the blood-brain barrier. Site-directed mutagenesis and molecular modeling was used to identify the LSP4-2022 binding site, revealing interaction with both the glutamate binding site and a variable pocket responsible for selectivity. These data reveal new approaches for developing selective, hydrophilic, and brain-penetrant mGlu receptor agonists, offering new possibilities to design original bioactive compounds with therapeutic potential. PMID- 22223753 TI - Met degradation: more than one stone to shoot a receptor down. AB - The receptor tyrosine kinase Met and its high-affinity ligand, the hepatocyte growth factor/scatter factor (HGF/SF), are essential to embryonic development. Deregulation of their signaling is associated with tumorigenesis and metastasis, notably through receptor overexpression. It is thus important to understand the mechanisms controlling Met expression. The ligand-dependent internalization of Met and its subsequent degradation in the lysosomal compartment are well described. This process is known to attenuate downstream Met signaling pathways. Yet internalized Met takes part directly in intracellular signaling by chaperoning signaling factors in the course of its trafficking. Furthermore, recent studies describe various new degradation mechanisms of membrane-anchored Met, involving proteolytic cleavages or association with novel partners. Although all these degradations are ligand-independent, they share, to different extents, some common features with canonical HGF/SF-dependent degradation. Interestingly, activated Met variants display resistance to degradation, suggesting defective degradation is involved in tumorigenesis. Conversely, forced degradation of Met through reinduction of one or more degradation pathways is a promising therapeutic strategy. PMID- 22223754 TI - Epigenetic changes in fetal hypothalamic energy regulating pathways are associated with maternal undernutrition and twinning. AB - Undernutrition during pregnancy is implicated in the programming of offspring for the development of obesity and diabetes. We hypothesized that maternal programming causes epigenetic changes in fetal hypothalamic pathways regulating metabolism. This study used sheep to examine the effect of moderate maternal undernutrition (60 d before to 30 d after mating) and twinning to investigate changes in the key metabolic regulators proopiomelanocortin (POMC) and the glucocorticoid receptor (GR) in fetal hypothalami. Methylation of the fetal hypothalamic POMC promoter was reduced in underfed singleton, fed twin, and underfed twin groups (60, 73, and 63% decrease, respectively). This was associated with reduced DNA methyltransferase activity and altered histone methylation and acetylation. Methylation of the hypothalamic GR promoter was decreased in both twin groups and in maternally underfed singleton fetuses (52, 65, and 55% decrease, respectively). This correlated with changes in histone methylation and acetylation and increased GR mRNA expression in the maternally underfed singleton group. Alterations in GR were hypothalamic specific, with no changes in hippocampi. Unaltered levels of OCT4 promoter methylation indicated gene-specific effects. In conclusion, twinning and periconceptional undernutrition are associated with epigenetic changes in fetal hypothalamic POMC and GR genes, potentially resulting in altered energy balance regulation in the offspring. PMID- 22223755 TI - Origins and evolution of microRNA genes in plant species. AB - MicroRNAs (miRNAs) are among the most important regulatory elements of gene expression in animals and plants. However, their origin and evolutionary dynamics have not been studied systematically. In this paper, we identified putative miRNA genes in 11 plant species using the bioinformatic technique and examined their evolutionary changes. Our homology search indicated that no miRNA gene is currently shared between green algae and land plants. The number of miRNA genes has increased substantially in the land plant lineage, but after the divergence of eudicots and monocots, the number has changed in a lineage-specific manner. We found that miRNA genes have originated mainly by duplication of preexisting miRNA genes or protein-coding genes. Transposable elements also seem to have contributed to the generation of species-specific miRNA genes. The relative importance of these mechanisms in plants is quite different from that in Drosophila species, where the formation of hairpin structures in the genomes seems to be a major source of miRNA genes. This difference in the origin of miRNA genes between plants and Drosophila may be explained by the difference in the binding to target mRNAs between plants and animals. We also found that young miRNA genes are less conserved than old genes in plants as well as in Drosophila species. Yet, nearly half of the gene families in the ancestor of flowering plants have been lost in at least one species examined. This indicates that the repertoires of miRNA genes have changed more dynamically than previously thought during plant evolution. PMID- 22223757 TI - Significance of heparin binding to basic residues in homologous to the amino terminus of hepatoma-derived growth factor and related proteins. AB - Hepatoma-derived growth factor (HDGF) recognizes cell surface heparan sulfate to promote its internalization though binding to its N-terminal HATH (homologous to amino terminus of HDGF) domain. HDGF-related proteins (HRPs) all have the HATH domain in their N terminus. In this study, we report on the commonality of heparin binding in all HRPs with a broad range of heparin-binding affinity: HRP-4 is the strongest binder, and the lens epithelium-derived growth factor shows a relatively weak binding, with binding affinities (K(D)) showing 30-fold difference in magnitude. With the HDGF HATH domain used as a model, residue K19 was the most critical basic residue in molecular recognition and protein internalization, and with its proximal proline-tryptophan-tryptophan-proline motif, coordinated a conformational change when binding to the heparin fragment. Other basic residues, K21, K61, K70, K72 and R79, confer added contribution in binding that the total ionic interaction from these residues represents more than 70% of the binding energy. Because the positive-charged residues are conserved in all HRP HATH domains, heparin binding outside of cells might be of equal importance for all HRPs in mediating downstream signaling; however, distinct effects and/or distribution might be associated with the varying affinities to heparin. PMID- 22223756 TI - Evolutionary dynamics of small RNAs in 27 Escherichia coli and Shigella genomes. AB - Small RNAs (sRNAs) are widespread in bacteria and play critical roles in regulating physiological processes. They are best characterized in Escherichia coli K-12 MG1655, where 83 sRNAs constitute nearly 2% of the gene complement. Most sRNAs act by base pairing with a target mRNA, modulating its translation and/or stability; many of these RNAs share only limited complementarity to their mRNA target, and require the chaperone Hfq to facilitate base pairing. Little is known about the evolutionary dynamics of bacterial sRNAs. Here, we apply phylogenetic and network analyses to investigate the evolutionary processes and principles that govern sRNA gene distribution in 27 E. coli and Shigella genomes. We identify core (encoded in all 27 genomes) and variable sRNAs; more than two thirds of the E. coli K-12 MG1655 sRNAs are core, whereas the others show patterns of presence and absence that are principally due to genetic loss, not duplication or lateral genetic transfer. We present evidence that variable sRNAs are less tightly integrated into cellular genetic regulatory networks than are the core sRNAs, and that Hfq facilitates posttranscriptional cross talk between the E. coli-Shigella core and variable genomes. Finally, we present evidence that more than 80% of genes targeted by Hfq-associated core sRNAs have been transferred within the E. coli-Shigella clade, and that most of these genes have been transferred intact. These results suggest that Hfq and sRNAs help integrate laterally acquired genes into established regulatory networks. PMID- 22223758 TI - Deoxycholic acid impairs glycosylation and fucosylation processes in esophageal epithelial cells. AB - It is generally accepted that esophageal adenocarcinoma arises from a Barrett's metaplastic lesion. Altered glycoprotein expression has been demonstrated in tissue from patients with Barrett's esophagus and esophageal cancer but the mechanisms regarding such changes are unknown. The bile acid deoxycholic acid (DCA) alters many cell signaling pathways and is implicated in esophageal cancer progression. We have demonstrated that DCA disrupts Golgi structure and affects protein secretion and glycosylation processes in cell lines derived from normal squamous epithelium (HET-1A) and Barrett's metaplastic epithelium (QH). Cell surface expression of glycans was identified using carbohydrate-specific probes (wheat germ agglutinate, conconavalin A, peanut agglutinin, lithocholic acid and Ulex europaeus agglutinin) that monitored N-glycosylation, O-glycosylation and core fucosylation in resting and DCA-treated cells. DCA altered intracellular localization and reduced cell surface expression of N-acetyl-D-glucosamine, alpha methyl-mannopyranoside (Man/Glc) and fucose in both cell lines. Furthermore, DCA reduced the expression of epithelial growth factor receptor and E-cadherin in a manner analogous to treatment of cells with the N-glycan biosynthesis inhibitor tunicamycin. This is the first study to identify an altered Golgi structure and glycomic profile in response to DCA in esophageal epithelial cells, a process which could potentially contribute to metaplasia, dysplasia and cancer of the esophagus. PMID- 22223759 TI - Malignant gastrointestinal stromal tumour in the posterior mediastinum. AB - Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract. GISTs are predominant in the stomach and intestine, and rarely occur in the oesophagus. A GIST in the posterior mediastinum usually arises from the oesophagus, but single case of gastric GIST in the posterior mediastinum is reported. We present a case of a posterior mediastinal malignant GIST which was likely of gastric origin. The patient had no recurrence for 5 years after a complete resection. PMID- 22223760 TI - Management of early postoperative coronary artery bypass graft failure. AB - Perioperative graft failure following coronary artery bypass grafting (CABG) may result in acute myocardial ischaemia. Whether acute percutaneous coronary intervention, emergency reoperation or conservative intensive care treatment should be used is currently unknown. Between 2003 and 2009, 39 of the 5598 patients who underwent isolated CABG surgery underwent early postoperative coronary angiography for suspected myocardial ischaemia. Following angiography, two groups were identified: patients who underwent immediately reintervention (group 1); and those treated conservatively (group 2). Primary study endpoints were mortality and postoperative myocardial infarct size. Postoperative coronary angiography revealed early perioperative bypass graft failure in 32 of 39 patients. Acute percutaneous coronary intervention was performed in 15 patients, redo-CABG in 4 patients and conservative treatment in 13 patients. The number of failing bypass grafts were significantly higher in group 1 compared with group 2 (P = 0.0251). A trend toward lower post-procedural peak cardiac troponin T and creatinine phosphokinase serum levels in group 1 was observed (163.0 vs. 206.0 and 4.35 vs. 5.53, respectively) (P = 0.0662 and 0.1648). Early reintervention may limit the extent of myocardial cellular damage compared with conservative medical strategy in patients with myocardial ischaemia due to early graft failure. PMID- 22223761 TI - Role of the common gamma chain in cell cycle progression of human malignant cell lines. AB - The gamma-chain (gammac) is a transducing element shared between several cytokine receptors whose alteration causes X-linked severe combined immunodeficiency. Recently, a direct involvement of gammac in self-sufficient growth in a concentration-dependent manner was described, implying a direct relationship between the amount of the molecule and its role in cell cycle progression. In this study, we evaluate whether gammac expression could interfere in cell cycle progression also in malignant hematopoietic cells. Here, we first report that in the absence of gammac expression, lymphoblastoid B-cell lines (BCLs) die at a higher extent than control cells. This phenomenon is caspase-3 independent and is associated to a decreased expression of the antiapoptotic Bcl-2 family members. By contrast, increased expression of gammac protein directly correlates with spontaneous cell growth in several malignant hematopoietic cell lines. We, also, find that the knockdown of gammac protein through short interfering RNA is able to decrease the cell proliferation rate in these malignancies. Furthermore, an increased expression of all D-type cyclins is found in proliferating neoplastic cells. In addition, a direct correlation between the amount of gammac and cyclins A2 and B1 expression is found. Hence, our data demonstrate that the amount of the gammac is able to influence the transcription of genes involved in cell cycle progression, thus being directly involved in the regulatory control of cell proliferation of malignant hematopoietic cells. PMID- 22223762 TI - Analysis of mice deficient in both REV1 catalytic activity and POLH reveals an unexpected role for POLH in the generation of C to G and G to C transversions during Ig gene hypermutation. AB - Multiple DNA polymerases are involved in the generation of somatic mutations during Ig gene hypermutation. Mice expressing a catalytically inactive REV1 (REV1AA) exhibit reduction of both C to G and G to C transversions and moderate decrease of A/T mutations, whereas DNA polymerase eta (POLH) deficiency causes greatly reduced A/T mutations. To investigate whether REV1 and POLH interact genetically and functionally during Ig gene hypermutation, we established REV1AA Polh(-/-) mice and analyzed Ig gene hypermutation in the germinal center (GC) B cells. REV1AA Polh(-/-) mice were born at the expected ratio and developed normally with no apparent gross abnormalities. B-cell development, maturation, Ig gene class switch and the GC B-cell expansion were not affected in these mice. REV1AA Polh(-/-) B cells also exhibited relatively normal sensitivity to etoposide and ionizing radiation. Analysis of somatic mutations in the J(H)4 intronic region revealed that REV1AA Polh(-/-) mice had a further decrease of overall mutation frequency compared with REV1AA or Polh(-/-) mice, indicating that the double deficiency additively affected the generation of mutations. Remarkably, REV1AA Polh(-/-) mice had nearly absent C to G and G to C transversions, suggesting that POLH is essential for the generation of residual C to G and G to C transversions observed in REV1AA mice. These results reveal genetic interactions between REV1 catalytic activity and POLH and identify an alternative pathway, mediated by non-catalytic REV1 and POLH, in the generation of C to G and G to C transversions. PMID- 22223763 TI - Update in the CNS response to hypoglycemia. AB - Hypoglycemia remains a major clinical issue in the management of people with type 1 and type 2 diabetes. Research in basic science is only beginning to unravel the mechanisms that: 1) underpin the detection of hypoglycemia and initiation of a counterregulatory defense response; and 2) contribute to the development of defective counterregulation in both type 1 and type 2 diabetes, particularly after prior exposure to repeated hypoglycemia. In animal studies, the central nervous system has emerged as key to these processes. However, bench-based research needs to be translated through studies in human subjects as a first step to the future development of clinical intervention. This Update reviews studies published in the last 2 yr that examined the central nervous system effects of hypoglycemia in human subjects, largely through neuroimaging techniques, and compares these data with those obtained from animal studies and the implications for future therapies. Based on these studies, it is increasingly clear that our understanding of how the brain responds and adapts to recurrent hypoglycemia remains very limited. Current therapies have provided little evidence that they can prevent severe hypoglycemia or improve hypoglycemia awareness in type 1 diabetes. There remains an urgent need to increase our understanding of how and why defective counterregulation develops in type 1 diabetes in order for novel therapeutic interventions to be developed and tested. PMID- 22223764 TI - Approach to the adolescent requesting contraception. AB - It is essential to develop contraceptive counseling skills given the potential complications associated with an unplanned pregnancy, especially for adolescents. Multiple factors must be considered when reviewing contraceptive options with an adolescent: maturity, finances, access to care and prescriptions, confidentiality, medical risks and benefits, and contraindications to use of certain hormonal agents. Many adolescents will be concerned about the possibility of weight gain or the development of acne associated with the use of certain contraceptive agents. They are usually unaware of the risks of thrombosis, stroke, or adverse bone health effects. Providers must be able to speak to these issues using an evidence-based approach. PMID- 22223765 TI - Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. AB - OBJECTIVE: The aim was to formulate practice guidelines on the management of hyperglycemia in hospitalized patients in the non-critical care setting. PARTICIPANTS: The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee of The Endocrine Society, six additional experts, and a methodologist. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and e mail communications enabled consensus. Endocrine Society members, American Diabetes Association, American Heart Association, American Association of Diabetes Educators, European Society of Endocrinology, and the Society of Hospital Medicine reviewed and commented on preliminary drafts of this guideline. CONCLUSIONS: Hyperglycemia is a common, serious, and costly health care problem in hospitalized patients. Observational and randomized controlled studies indicate that improvement in glycemic control results in lower rates of hospital complications in general medicine and surgery patients. Implementing a standardized sc insulin order set promoting the use of scheduled basal and nutritional insulin therapy is a key intervention in the inpatient management of diabetes. We provide recommendations for practical, achievable, and safe glycemic targets and describe protocols, procedures, and system improvements required to facilitate the achievement of glycemic goals in patients with hyperglycemia and diabetes admitted in non-critical care settings. PMID- 22223766 TI - Cushing syndrome due to ectopic adrenocorticotropin secretion by oncocytic thyroid nodule. PMID- 22223767 TI - Contraception quandaries: oral contraceptive decisions in the pediatric endocrinology office. PMID- 22223768 TI - Cortisol binding globulin: more than just a carrier? PMID- 22223769 TI - Long-term therapy with growth hormone: bringing sagacity to SAGHE. PMID- 22223775 TI - Patient guide to managing hyperglycemia (high blood sugar) in the hospital. PMID- 22223776 TI - Voices of the next generation. PMID- 22223781 TI - Biosecurity. Will flu papers lead to new research oversight? PMID- 22223782 TI - Biosecurity. In the eye of the storm, two rivals, two strategies. PMID- 22223783 TI - Energy. Laser fusion project alters goals, fueling concern over its strategy. PMID- 22223784 TI - Oceanography. China makes waves with ambitious ocean research plan. PMID- 22223786 TI - U.S. graduate education. Cornell's plans for the Big Apple rely on quality, cash, and dreams. PMID- 22223785 TI - U.S. science. Research remains a favored child in budget decisions. PMID- 22223787 TI - Cancer research. Unraveling the obesity-cancer connection. PMID- 22223788 TI - Cancer research. Cancer prevention with a diabetes pill? PMID- 22223789 TI - Cancer research. Ravenous for glucose. PMID- 22223790 TI - Profile: Kit Parker. Engineering a new line of attack on a signature war injury. PMID- 22223793 TI - Comment on "Nonreciprocal light propagation in a silicon photonic circuit". AB - We show that the structure demonstrated by Feng et al. (Reports, 5 August 2011, p. 729) cannot enable optical isolation because it possesses a symmetric scattering matrix. Moreover, one cannot construct an optical isolator by incorporating this structure into any system as long as the system is linear and time-independent and is described by materials with a scalar dielectric function. PMID- 22223795 TI - Genetics. Variable outcome of mutations. PMID- 22223796 TI - Applied physics. Ohm's law in a quantum world. PMID- 22223797 TI - Plant science. Controlling hormone action by subversion and deception. PMID- 22223798 TI - Applied physics. Plasmonic modes revealed. PMID- 22223799 TI - Retrospective. Lloyd J. Old (1933-2011). PMID- 22223800 TI - PrP antibodies do not trigger mouse hippocampal neuron apoptosis. AB - Intraperitoneal administration of ICSM18 and 35, monoclonal antibodies against prion protein (PrP), has been shown to significantly delay the onset of prion disease in mice, and humanized versions are candidate therapeutics for prion and Alzheimer's diseases. However, a previous report of severe and widespread apoptosis after intracerebral injection of anti-PrP monoclonal antibodies raised concerns about such therapy and led to an influential model of prion neurotoxicity via cross-linking of cell surface PrP by disease-related PrP aggregates. In extensive studies including ICSM18 and 35, fully humanized ICSM18, and the previously reported proapoptotic antibodies, we found no evidence of apoptosis, thereby questioning this model of prion neurotoxicity. PMID- 22223801 TI - Subparticle ultrafast spectrum imaging in 4D electron microscopy. AB - Single-particle imaging of structures has become a powerful methodology in nanoscience and molecular and cell biology. We report the development of subparticle imaging with space, time, and energy resolutions of nanometers, femtoseconds, and millielectron volts, respectively. By using scanning electron probes across optically excited nanoparticles and interfaces, we simultaneously constructed energy-time and space-time maps. Spectrum images were then obtained for the nanoscale dielectric fields, with the energy resolution set by the photon rather than the electron, as demonstrated here with two examples (silver nanoparticles and the metallic copper-vacuum interface). This development thus combines the high spatial resolution of electron microscopy with the high energy resolution of optical techniques and ultrafast temporal response, opening the door to various applications in elemental analysis as well as mapping of interfaces and plasmonics. PMID- 22223802 TI - Ohm's law survives to the atomic scale. AB - As silicon electronics approaches the atomic scale, interconnects and circuitry become comparable in size to the active device components. Maintaining low electrical resistivity at this scale is challenging because of the presence of confining surfaces and interfaces. We report on the fabrication of wires in silicon--only one atom tall and four atoms wide--with exceptionally low resistivity (~0.3 milliohm-centimeters) and the current-carrying capabilities of copper. By embedding phosphorus atoms within a silicon crystal with an average spacing of less than 1 nanometer, we achieved a diameter-independent resistivity, which demonstrates ohmic scaling to the atomic limit. Atomistic tight-binding calculations confirm the metallicity of these atomic-scale wires, which pave the way for single-atom device architectures for both classical and quantum information processing. PMID- 22223803 TI - An exhumation history of continents over billion-year time scales. AB - The continental lithosphere contains the oldest and most stable structures on Earth, where fragments of ancient material have eluded destruction by tectonic and surface processes operating over billions of years. Although present-day erosion of these remnants is slow, a record of how they have uplifted, eroded, and cooled over Earth's history can provide insight into the physical properties of the continents and the forces operating to exhume them over geologic time. We constructed a continuous record of ancient lithosphere cooling with the use of uranium-lead (U-Pb) thermochronology on volcanically exhumed lower crustal fragments. Combining these measurements with thermal and Pb-diffusion models constrains the range of possible erosion histories. Measured U-Pb data are consistent with extremely low erosion rates persisting over time scales approaching the age of the continents themselves. PMID- 22223804 TI - Multiyear prediction of monthly mean Atlantic Meridional Overturning Circulation at 26.5 degrees N. AB - Attempts to predict changes in Atlantic Meridional Overturning Circulation (AMOC) have yielded little success to date. Here, we demonstrate predictability for monthly mean AMOC strength at 26.5 degrees N for up to 4 years in advance. This AMOC predictive skill arises predominantly from the basin-wide upper-mid-ocean geostrophic transport, which in turn can be predicted because we have skill in predicting the upper-ocean zonal density difference. Ensemble forecasts initialized between January 2008 and January 2011 indicate a stable AMOC at 26.5 degrees N until at least 2014, despite a brief wind-induced weakening in 2010. Because AMOC influences many aspects of climate, our results establish AMOC as an important potential carrier of climate predictability. PMID- 22223805 TI - Ancestral developmental potential facilitates parallel evolution in ants. AB - Complex worker caste systems have contributed to the evolutionary success of advanced ant societies; however, little is known about the developmental processes underlying their origin and evolution. We combined hormonal manipulation, gene expression, and phylogenetic analyses with field observations to understand how novel worker subcastes evolve. We uncovered an ancestral developmental potential to produce a "supersoldier" subcaste that has been actualized at least two times independently in the hyperdiverse ant genus Pheidole. This potential has been retained and can be environmentally induced throughout the genus. Therefore, the retention and induction of this potential have facilitated the parallel evolution of supersoldiers through a process known as genetic accommodation. The recurrent induction of ancestral developmental potential may facilitate the adaptive and parallel evolution of phenotypes. PMID- 22223806 TI - Dystroglycan function requires xylosyl- and glucuronyltransferase activities of LARGE. AB - Posttranslational modification of alpha-dystroglycan (alpha-DG) by the like acetylglucosaminyltransferase (LARGE) is required for it to function as an extracellular matrix (ECM) receptor. Mutations in the LARGE gene have been identified in congenital muscular dystrophy patients with brain abnormalities. However, the precise function of LARGE remains unclear. Here we found that LARGE could act as a bifunctional glycosyltransferase, with both xylosyltransferase and glucuronyltransferase activities, which produced repeating units of [-3-xylose alpha1,3-glucuronic acid-beta1-]. This modification allowed alpha-DG to bind laminin-G domain-containing ECM ligands. PMID- 22223807 TI - Langerhans cells facilitate epithelial DNA damage and squamous cell carcinoma. AB - Polyaromatic hydrocarbons (PAHs) are prevalent, potent carcinogens, and 7,12 dimethylbenz[a]anthracene (DMBA) is a model PAH widely used to study tumorigenesis. Mice lacking Langerhans cells (LCs), a signatory epidermal dendritic cell (DC), are protected from cutaneous chemical carcinogenesis, independent of T cell immunity. Investigation of the underlying mechanism revealed that LC-deficient skin was relatively resistant to DMBA-induced DNA damage. LCs efficiently metabolized DMBA to DMBA-trans-3,4-diol, an intermediate proximal to oncogenic Hras mutation, and DMBA-treated LC-deficient skin contained significantly fewer Hras mutations. Moreover, DMBA-trans-3,4-diol application bypassed tumor resistance in LC-deficient mice. Additionally, the genotoxic impact of DMBA on human keratinocytes was significantly increased by prior incubation with human-derived LC. Thus, tissue-associated DC can enhance chemical carcinogenesis via PAH metabolism, highlighting the complex relation between immune cells and carcinogenesis. PMID- 22223810 TI - Diel patterns of leaf and root growth: endogenous rhythmicity or environmental response? AB - Plants are sessile organisms forced to adjust to their surrounding environment. In a single plant the photoautotrophic shoot is exposed to pronounced environmental variations recurring in a day-night 24 h (diel) cycle, whereas the heterotrophic root grows in a temporally less fluctuating environment. The contrasting habitats of shoots and roots are reflected in different diel growth patterns and their responsiveness to environmental stimuli. Differences between diel leaf growth patterns of mono- and dicotyledonous plants correspond to their different organization and placement of growth zones. In monocots, heterotrophic growth zones are organized linearly and protected from the environment by sheaths of older leaves. In contrast, photosynthetically active growth zones of dicot leaves are exposed directly to the environment and show characteristic, species specific diel growth patterns. It is hypothesized that the different exposure to environmental constraints and simultaneously the sink/source status of the growing organs may have induced distinct endogenous control of diel growth patterns in roots and leaves of monocot and dicot plants. Confronted by strong temporal fluctuations in environment, the circadian clock may facilitate robust intrinsic control of leaf growth in dicot plants. PMID- 22223808 TI - The jasmonate pathway mediates salt tolerance in grapevines. AB - Salt stress is a major constraint for many crop plants, such as the moderately salt-sensitive economically important fruit crop grapevine. Plants have evolved different strategies for protection against salinity and drought. Jasmonate signalling is a central element of both biotic and abiotic stress responses. To discriminate stress quality, there must be cross-talk with parallel signal chains. Using two grapevine cell lines differing in salt tolerance, the response of jasmonate ZIM/tify-domain (JAZ/TIFY) proteins (negative regulators of jasmonate signalling), a marker for salt adaptation Na(+)/H(+) EXCHANGER (NHX1), and markers for biotic defence STILBENE SYNTHASE (StSy) and RESVERATROL SYNTHASE (RS) were analysed. It is shown that salt stress signalling shares several events with biotic defence including activity of a gadolinium-sensitive calcium influx channel (monitored by apoplastic alkalinization) and transient induction of JAZ/TIFY transcripts. Exogenous jasmonate can rescue growth in the salt-sensitive cell line. Suppression of jasmonate signalling by phenidone or aspirin blocks the induction of JAZ/TIFY transcripts. The rapid induction of RS and StSy characteristic for biotic defence in grapevine is strongly delayed in response to salt stress. In the salt-tolerant line, NHX1 is induced and the formation of reactive oxygen species, monitored as stress markers in the sensitive cell line, is suppressed. The data are discussed in terms of a model where salt stress signalling acts as a default pathway whose readout is modulated by a parallel signal chain triggered by biotic factors downstream of jasmonate signalling. PMID- 22223809 TI - RBCS1A and RBCS3B, two major members within the Arabidopsis RBCS multigene family, function to yield sufficient Rubisco content for leaf photosynthetic capacity. AB - Ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) small subunit (RBCS) is encoded by a nuclear RBCS multigene family in many plant species. The contribution of the RBCS multigenes to accumulation of Rubisco holoenzyme and photosynthetic characteristics remains unclear. T-DNA insertion mutants of RBCS1A (rbcs1a-1) and RBCS3B (rbcs3b-1) were isolated among the four Arabidopsis RBCS genes, and a double mutant (rbcs1a3b-1) was generated. RBCS1A mRNA was not detected in rbcs1a-1 and rbcs1a3b-1, while the RBCS3B mRNA level was suppressed to ~20% of the wild-type level in rbcs3b-1 and rbcs1a3b-1 leaves. As a result, total RBCS mRNA levels declined to 52, 79, and 23% of the wild-type level in rbcs1a-1, rbcs3b-1, and rbcs1a3b-1, respectively. Rubisco contents showed declines similar to total RBCS mRNA levels, and the ratio of Rubisco-nitrogen to total nitrogen was 62, 78, and 40% of the wild-type level in rbcs1a-1, rbcs3b-1, and rbcs1a3b-1, respectively. The effects of RBCS1A and RBCS3B mutations in rbcs1a3b-1 were clearly additive. The rates of CO(2) assimilation at ambient CO(2) of 40 Pa were reduced with decreased Rubisco contents in the respective mutant leaves. Although the RBCS composition in the Rubisco holoenzyme changed, the CO(2) assimilation rates per unit of Rubisco content were the same irrespective of the genotype. These results clearly indicate that RBCS1A and RBCS3B contribute to accumulation of Rubisco in Arabidopsis leaves and that these genes work additively to yield sufficient Rubisco for photosynthetic capacity. It is also suggested that the RBCS composition in the Rubisco holoenzyme does not affect photosynthesis under the present ambient [CO(2)] conditions. PMID- 22223811 TI - Physiological and proteomic approaches to evaluate the role of sterol binding in elicitin-induced resistance. AB - Cryptogein is a proteinaceous elicitor secreted by Phytophthora cryptogea that can induce resistance to P. parasitica in tobacco plants. On the basis of previous computer modelling experiments, by site-directed mutagenesis a series of cryptogein variants was prepared with altered abilities to bind sterols, phospholipids or both. The sterol binding and phospholipid transfer activities corresponded well with the previously reported structural data. Induction of the synthesis of reactive oxygen species (ROS) in tobacco cells in suspension and proteomic analysis of intercellular fluid changes in tobacco leaves triggered by these mutant proteins were not proportional to their ability to bind or transfer sterols and phospholipids. However, changes in the intercellular proteome corresponded to transcription levels of defence genes and resistance to P. parasitica and structure-prediction of mutants did not reveal any significant changes in protein structure. These results suggest, contrary to previous proposals, that the sterol-binding ability of cryptogein and its mutants, and the associated conformational change in the omega-loop, might not be principal factors in either ROS production or resistance induction. Nevertheless, the results support the importance of the omega-loop for the interaction of the protein with the high affinity binding site on the plasma membrane. PMID- 22223812 TI - Insights into Populus XIP aquaporins: evolutionary expansion, protein functionality, and environmental regulation. AB - A novel category of major intrinsic proteins which share weak similarities with previously identified aquaporin subfamilies was recently identified in land plants, and named X (for unrecognized) intrinsic proteins (XIPs). Because XIPs are still ranked as uncharacterized proteins, their further molecular characterization is required. Herein, a systematic fine-scale analysis of XIP sequences found in flowering plant databases revealed that XIPs are found in at least five groups. The phylogenetic relationship of these five groups with the phylogenetic organization of angiosperms revealed an original pattern of evolution for the XIP subfamily through distinct angiosperm taxon-specific clades. Of all flowering plant having XIPs, the genus Populus encompasses the broadest panel and the highest polymorphism of XIP isoforms, with nine PtXIP sequences distributed within three XIP groups. Comprehensive PtXIP gene expression patterns showed that only two isoforms (PtXIP2;1 and PtXIP3;2) were transcribed in vegetative tissues. However, their patterns are contrasted, PtXIP2;1 was ubiquitously accumulated whereas PtXIP3;2 was predominantly detected in wood and to a lesser extent in roots. Furthermore, only PtXIP2;1 exhibited a differential expression in leaves and stems of drought-, salicylic acid-, or wounding-challenged plants. Unexpectedly, the PtXIPs displayed different abilities to alter water transport upon expression in Xenopus laevis oocytes. PtXIP2;1 and PtXIP3;3 transported water while other PtXIPs did not. PMID- 22223813 TI - Gonorrhoea or chlamydia in a U.S. military HIV-positive cohort. AB - OBJECTIVES: To investigate the epidemiology and risk factors of gonorrhoea (GC) or chlamydia (CT) coinfection in an HIV-positive US military cohort, focusing on the time after participants' knowledge of HIV diagnosis. METHODS: The authors analysed data from 4461 participants enrolled in the U.S. Military Natural History Study cohort for GC or CT infection >=6 months after their HIV-positive test. RESULTS: During a mean follow-up of 7.08 years, 482 (11%) participants acquired a GC or CT infection. Of these, 283 (6%) acquired a GC infection, 278 (6%) acquired a CT infection and 123 (3%) had multiple GC or CT infections during follow-up. Risk of GC or CT infection was significantly greater in those younger, male, African-American and with a history of GC or CT infection. CONCLUSIONS: Frequent GC and CT diagnoses observed among members of this HIV-positive cohort indicate substantial ongoing risk behaviours that raise concerns for HIV transmission and underscore the need for continued screening to help identify and treat these sexually transmitted infections in this population. PMID- 22223814 TI - Advertisements promoting human papillomavirus vaccine for adolescent boys: does source matter? AB - OBJECTIVES: Many parents recall hearing of human papillomavirus (HPV) vaccine through drug company advertisements. This study sought to examine whether parents accurately recall the source (ie, sponsor) of advertisements promoting HPV vaccine and the impact of drug company advertisements. METHODS: A U.S. national sample of 544 parents of adolescent boys aged 11-17 participated in an online between-subjects experiment. Parents viewed an advertisement encouraging HPV vaccination for boys with a logo from a randomly assigned source. Parents rated trust, likability and motivation for vaccination while viewing the advertisement and later indicated who they believed sponsored it. RESULTS: Nearly half (43%) of parents who viewed a hypothetical advertisement containing a logo incorrectly identified the advertisement source. More parents correctly identified the source of drug company advertisements than advertisement from other sources (62% vs. 25%, OR 4.93, 95% CI 3.26 to 7.46). The majority of parents who saw a logo-free advertisement believed a drug company created it (60%). Among parents who correctly identified the advertisement source, drug company advertisements decreased motivation to vaccinate their sons, an association mediated by reduced liking of and trust in the advertisements. CONCLUSIONS: Parents were more accurate in identifying drug company advertisements, primarily because they tended to assume any advertisement was from a drug company. Public health organisations may need to take special measures to ensure their messages are not perceived as sponsored by drug companies. PMID- 22223815 TI - A hospital's adoption of information technology is associated with altered risks of hospital-acquired venous thromboembolism. AB - The objective was to examine the relationship between hospital adoption of information technology (IT) and hospital-acquired venous thromboembolism (VTE). Inpatients aged 65 years and older who were discharged from hospitals in California, Florida, and New York were analyzed. A cross-sectional study design was used to perform secondary data analyses. The association between implementing IT applications (ie, electronic clinical documentation, electronic lab orders, medication orders written electronically) in the patients' hospitals (independent variables) and hospital-acquired VTE (the dependent variable) were studied using a hierarchical logistic model. Electronic clinical documentation was associated with lower odds of hospital-acquired VTE (odds ratio [OR] = 0.835, P < .001). An even larger reduction in the odds was found among patients of hospitals that implemented electronic lab orders (OR = 0.627, P < .001). However, the implementation of electronic medication orders did not show such an association. PMID- 22223816 TI - M(yeloma)IXing up T maintenance. PMID- 22223817 TI - Two genes, tipifarnib, and AML. PMID- 22223818 TI - The Serenity Prayer for acute GVHD. PMID- 22223819 TI - A pilot randomized trial of adjuvant rituximab or placebo for nonsplenectomized patients with immune thrombocytopenia. AB - The benefit of adding rituximab to standard treatment in nonsplenectomized patients with primary immune thrombocytopenia (ITP) is uncertain. We performed a pilot randomized trial to determine the feasibility of recruitment, protocol adherence, and blinding of a larger trial of rituximab versus placebo; and to evaluate the potential efficacy of adjuvant rituximab in ITP. Nonsplenectomized adults with newly diagnosed or relapsed ITP who were receiving standard ITP therapy for a platelet count below 30 * 10(9)/L were randomly allocated to receive 4 weekly infusions of 375 mg/m(2) rituximab or saline placebo. Sixty patients were recruited over 46 months, which was slower than anticipated. Protocol adherence and follow-up targets were achieved, and blinding was successful for research staff but not for patients. After 6 months, there was no difference between rituximab and placebo groups for the composite outcome of any platelet count below 50 * 10(9)/L, significant bleeding or rescue treatment once standard treatment was stopped (21/32 [65.6%] vs 21/26 [80.8%]; relative risk = 0.81, 95% confidence intervals, 0.59%-1.11%). Timely accrual poses a challenge to the conduct of a large randomized trial of rituximab for presplenectomy ITP. No difference in the frequency of the composite outcome was observed in this pilot trial (registered at www.clinicaltrials.gov NCT00372892). PMID- 22223822 TI - Rituximab decreases the risk of lymphoma in patients with HIV-associated multicentric Castleman disease. AB - HIV-associated multicentric Castleman disease (MCD) is associated with a high risk of developing non-Hodgkin lymphoma (NHL). Rituximab is effective in HIV-MCD, but its impact on NHL incidence remains unknown. From a single-center prospective cohort, 113 patients were identified with a diagnosis of HIV-MCD for the present study. To compare the incidence of NHL between patients who had received a rituximab-based treatment (R+ group) and those who had not (R- group), data were analyzed before and after matching on propensity scores and after multiple imputation. The mean follow-up was 4.2 years. In the R- group (n = 65), 17 patients developed NHL (incidence, 69.6 of 1000 person years). In the R+ group (n = 48), only 1 patient developed NHL (incidence, 4.2 of 1000 person years). Based on the propensity score-matching method, a significant decrease in the incidence of NHL was observed in patients who had been treated with rituximab (hazard ratio, 0.09; 95% confidence interval, 0.01-0.70). Ten Kaposi sarcoma (KS) exacerbations and 1 newly diagnosed KS were observed in 9 patients after rituximab therapy. Rituximab was associated with an 11-fold lower risk of developing lymphoma. KS exacerbation was the most challenging adverse event after rituximab therapy. PMID- 22223821 TI - Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. AB - Current factor VIII (FVIII) products display a half-life (t(1/2)) of ~ 8-12 hours, requiring frequent intravenous injections for prophylaxis and treatment of patients with hemophilia A. rFVIIIFc is a recombinant fusion protein composed of a single molecule of FVIII covalently linked to the Fc domain of human IgG(1) to extend circulating rFVIII t(1/2). This first-in-human study in previously treated subjects with severe hemophilia A investigated safety and pharmacokinetics of rFVIIIFc. Sixteen subjects received a single dose of rFVIII at 25 or 65 IU/kg followed by an equal dose of rFVIIIFc. Most adverse events were unrelated to study drug. None of the study subjects developed anti-rFVIIIFc antibodies or inhibitors. Across dose levels, compared with rFVIII, rFVIIIFc showed 1.54- to 1.70-fold longer elimination t(1/2), 1.49- to 1.56-fold lower clearance, and 1.48 to 1.56-fold higher total systemic exposure. rFVIII and rFVIIIFc had comparable dose-dependent peak plasma concentrations and recoveries. Time to 1% FVIII activity above baseline was ~ 1.53- to 1.68-fold longer than rFVIII across dose levels. Each subject showed prolonged exposure to rFVIIIFc relative to rFVIII. Thus, rFVIIIFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia A. This trial was registered at www.clinicaltrials.gov as NCT01027377. PMID- 22223823 TI - Targeting hedgehog in hematologic malignancy. AB - The Hedgehog pathway is a critical mediator of embryonic patterning and organ development, including hematopoiesis. It influences stem cell fate, differentiation, proliferation, and apoptosis in responsive tissues. In adult organisms, hedgehog pathway activity is required for aspects of tissue maintenance and regeneration; however, there is increasing awareness that abnormal hedgehog signaling is associated with malignancy. Hedgehog signaling is critical for early hematopoietic development, but there is controversy over its role in normal hematopoiesis in adult organisms where it may be dispensable. Conversely, hedgehog signaling appears to be an important survival and proliferation signal for a spectrum of hematologic malignancies. Furthermore, hedgehog signaling may be critical for the maintenance and expansion of leukemic stem cells and therefore provides a possible mechanism to selectively target these primitive cell subpopulations, which are resistant to conventional chemotherapy. Indeed, phase 1 clinical trials of hedgehog pathway inhibitors are currently underway to test this hypothesis in myeloid leukemias. This review covers: (1) the hedgehog pathway and its role in normal and malignant hematopoiesis, (2) the recent development of clinical grade small molecule inhibitors of the pathway, and (3) the potential utility of hedgehog pathway inhibition as a therapeutic strategy in hemato-oncology. PMID- 22223820 TI - Negative effects of GM-CSF signaling in a murine model of t(8;21)-induced leukemia. AB - The t(8;21)(q22;q22) is common in adult acute myeloid leukemia (AML). The RUNX1 ETO fusion protein that is expressed by this translocation is poorly leukemogenic and requires additional mutations for transformation. Loss of sex chromosome (LOS) is frequently observed in t(8;21) AML. In the present study, to evaluate whether LOS cooperates with t(8;21) in leukemogenesis, we first used a retroviral transduction/transplantation model to express RUNX1-ETO in hematopoietic cells from XO mice. The low frequency of leukemia in these mice suggests that the potentially critical gene for suppression of t(8;21) leukemia in humans is not conserved on mouse sex chromosomes. The gene encoding the GM-CSF receptor alpha subunit (CSF2RA) is located on X and Y chromosomes in humans but on chromosome 19 in mice. GM-CSF promotes myeloid cell survival, proliferation, and differentiation. To determine whether GM-CSF signaling affects RUNX1-ETO leukemogenesis, hematopoietic stem/progenitor cells that lack GM-CSF signaling were used to express RUNX1-ETO and transplanted into lethally irradiated mice, and a high penetrance of AML was observed in recipients. Furthermore, GM-CSF reduced the replating ability of RUNX1-ETO-expressing cells. These results suggest a possible tumor-suppressor role of GM-CSF in RUNX1-ETO leukemia. Loss of the CSF2RA gene may be a critical mutation explaining the high incidence of LOS associated with the t(8;21)(q22;q22) translocation. PMID- 22223824 TI - Characterization and discovery of novel miRNAs and moRNAs in JAK2V617F-mutated SET2 cells. AB - To gain insights into a possible role of microRNAs in myeloproliferative neoplasms, we performed short RNA massive sequencing and extensive bioinformatic analysis in the JAK2V617F-mutated SET2 cell line. Overall, 652 known mature miRNAs were detected, of which 21 were highly expressed, thus being responsible of most of miRNA-mediated gene repression. microRNA putative targets were enriched in specific signaling pathways, providing information about cell activities under massive posttranscriptional regulation. The majority of miRNAs were mixtures of sequence variants, called isomiRs, mainly because of alternative, noncanonical processing of hairpin precursors. We also identified 78 novel miRNAs (miRNA*) derived from known hairpin precursors. Both major and minor (*) forms of miRNAs were expressed concurrently from half of expressed hairpins, highlighting the relevance of miRNA* and the complexity of strand selection bias regulation. Finally, we discovered that SET2 cells express a number of miRNA offset RNAs (moRNAs), short RNAs derived from genomic regions flanking mature miRNAs. We provide novel data about the possible origin of moRNAs, although their functional role remains to be elucidated. Overall, this study shed light on the complexity of microRNA-mediated gene regulation in SET2 cells and represents the basis for future studies in JAK2V617F-mutated cellular models. PMID- 22223825 TI - Fludarabine and rituximab for relapsed or refractory hairy cell leukemia. AB - The purine analogs, pentostatin and cladribine, induce high remission rates when used as first-line monotherapy for hairy cell leukemia (HCL); however, patients continue to relapse. Re-treatment with the same or alternate purine analog produces lower response rates and a shorter duration of response. Fludarabine is another purine analog widely used in indolent lymphoid cancers, often in combination with rituximab, but there are few reports of its use in HCL. We identified 15 patients treated in British Columbia with fludarabine and rituximab (FR) from 2004 to 2010 for relapsed/refractory HCL after first-line cladribine (n = 3) or after multiple lines of therapy (n = 12). All patients with available response data responded to FR. With median follow-up of 35 months, 14 patients remain progression-free, whereas 1 patient has developed progressive leukemia and died. Five-year progression-free and overall survivals are 89% and 83%, respectively. FR is a safe and effective therapeutic option for relapsed/refractory HCL. PMID- 22223826 TI - Annexin II interactions with the annexin II receptor enhance multiple myeloma cell adhesion and growth in the bone marrow microenvironment. AB - Multiple myeloma (MM) is an incurable B-cell malignancy in which the marrow microenvironment plays a critical role in our inability to cure MM. Marrow stromal cells in the microenvironment support homing, lodging, and growth of MM cells through activation of multiple signaling pathways in both MM and stromal cells. Recently, we identified annexin II (AXII) as a previously unknown factor produced by stromal cells and osteoclasts (OCL) that is involved in OCL formation, HSC and prostate cancer (PCa) homing to the BM as well as mobilization of HSC and PCa cells. AXII expressed on stromal cells supports PCa cell lodgment via the AXII receptor (AXIIR) on PCa cells, but the role of AXII and AXIIR in MM is unknown. In this study, we show that MM cells express AXIIR, that stromal/osteoblast-derived AXII facilitates adhesion of MM cells to stromal cells via AXIIR, and OCL-derived AXII enhances MM cell growth. Finally, we demonstrate that AXII activates the ERK1/2 and AKT pathways in MM cells to enhance MM cell growth. These results demonstrate that AXII and AXIIR play important roles in MM and that targeting the AXII/AXIIR axis may be a novel therapeutic approach for MM. PMID- 22223828 TI - Timing of onset of cognitive decline: results from Whitehall II prospective cohort study. AB - OBJECTIVES: To estimate 10 year decline in cognitive function from longitudinal data in a middle aged cohort and to examine whether age cohorts can be compared with cross sectional data to infer the effect of age on cognitive decline. DESIGN: Prospective cohort study. At study inception in 1985-8, there were 10,308 participants, representing a recruitment rate of 73%. SETTING: Civil service departments in London, United Kingdom. PARTICIPANTS: 5198 men and 2192 women, aged 45-70 at the beginning of cognitive testing in 1997-9. MAIN OUTCOME MEASURE: Tests of memory, reasoning, vocabulary, and phonemic and semantic fluency, assessed three times over 10 years. RESULTS: All cognitive scores, except vocabulary, declined in all five age categories (age 45-49, 50-54, 55-59, 60-64, and 65-70 at baseline), with evidence of faster decline in older people. In men, the 10 year decline, shown as change/range of test * 100, in reasoning was -3.6% (95% confidence interval -4.1% to -3.0%) in those aged 45-49 at baseline and 9.6% (-10.6% to -8.6%) in those aged 65-70. In women, the corresponding decline was -3.6% (-4.6% to -2.7%) and -7.4% (-9.1% to -5.7%). Comparisons of longitudinal and cross sectional effects of age suggest that the latter overestimate decline in women because of cohort differences in education. For example, in women aged 45-49 the longitudinal analysis showed reasoning to have declined by -3.6% (-4.5% to -2.8%) but the cross sectional effects suggested a decline of -11.4% (-14.0% to -8.9%). CONCLUSIONS: Cognitive decline is already evident in middle age (age 45-49). PMID- 22223827 TI - Induction of autophagy is essential for monocyte-macrophage differentiation. AB - Monocytes are programmed to undergo apoptosis in the absence of stimulation. Stimuli that promote monocyte-macrophage differentiation not only cause cellular changes, but also prevent the default apoptosis of monocytes. In the present study, we demonstrate that autophagy is induced when monocytes are triggered to differentiate and that the induction of autophagy is pivotal for the survival and differentiation of monocytes. We also show that inhibition of autophagy results in apoptosis of cells that are engaged in differentiation. We found that the differentiation signal releases Beclin1 from Bcl-2 by activating JNK and blocks Atg5 cleavage, both of which are critical for the induction of autophagy. Preventing autophagy induction hampers differentiation and cytokine production; therefore, autophagy is an important transition from monocyte apoptosis to differentiation. PMID- 22223829 TI - How early can cognitive decline be detected? PMID- 22223830 TI - Proposals to increase the motorway speed limit by 10 mph. PMID- 22223831 TI - Skin camouflage. PMID- 22223832 TI - Multiple myeloma. PMID- 22223833 TI - Individual managers are liable for record discrimination award as well as trust. PMID- 22223835 TI - Spanish woman becomes pregnant through ovarian tissue transplantation. PMID- 22223834 TI - Tic disorders. PMID- 22223836 TI - Let doctors help terminally ill patients to die, says commission. PMID- 22223837 TI - Reactions of Norwegian children with severe egg allergy to an egg-containing influenza A (H1N1) vaccine: a retrospective audit. AB - Design Retrospective audit. Setting Secondary paediatric outpatient clinic, Tromso, Norway. Participants The participants were 80 (62.5% boys and 37.5% girls) children and adolescents with a diagnosed egg allergy who had to be on an egg-free diet and be unable to eat any food containing any amount of egg, including egg-containing baked goods, without an allergic reaction to egg protein. We also included patients who were sensitised to egg but had never been exposed to egg or egg-containing baked goods and were on an egg-free diet. Other atopic diseases among the study participants were also registered. Intervention The vaccination took place from November to December 2009. The patients were vaccinated with a monovalent influenza A (H1N1) vaccine that had an ovalbumin content <0.33 MUg/ml. They were divided into two groups, receiving the vaccine either as a single dose or as a fractionated dose. Patients were selected for the fractionated dose because of their prior reaction to egg or because they never had been exposed to egg. Primary outcome There were no serious adverse reactions to the vaccine; only one mild adverse reaction and two possible adverse reactions. Results Patients ranged in age from 10 months to 16.5 years. Thirty eight (48%) patients received a fractionated dose. Sixty-three (79%) had one or more atopic disease apart from egg allergy. With regard to atopy, serum specific IgE levels or skin prick test, there were no significant differences between the groups receiving the vaccine as a fractionated or as a single dose. Conclusions The study confirmed that patients allergic to egg can be safely vaccinated with a regular influenza vaccine containing <0.333 MUg/ml ovalbumin, even if these patients had displayed previous anaphylactic reactions to egg and had been diagnosed with concurrent atopic diseases. PMID- 22223838 TI - The relationship between age of coital debut and HIV seroprevalence among women in Durban, South Africa: a cohort study. AB - Objectives To investigate the impact of early sexual debut on HIV seroprevalence and incidence rates among a cohort of women. Design Prospective study. Setting KwaZulu-Natal, South Africa. Participants A total of 3492 sexually active women who consented to screen a HIV prevention trial during September 2002 to September 2005; a total of 1485 of them were followed for approximately 24 months. Primary and secondary outcome measures HIV seroprevalence among those who were screened for the trial and HIV seroconversion among those who seroconverted during the study. Results Lowest quintiles of age at sexual debut, less than high school education, a higher number of lifetime sexual partners and lack of cohabitation, being diagnosed as having herpes simplex virus 2 and other sexually transmitted infections were all significantly associated with prevalent HIV infection in multivariate analysis. During follow-up, 148 (6.8 per 100 person-years, 95% CI 5.8 to 8.0) women seroconverted. Highest seroconversion rate was observed among women who had reported to have had sex 15 years or younger (12.0 per 100 person years, 95% CI 8.0 to 18.0). Overall, impact of risk factors considered in this study was associated with considerable potential reductions in HIV prevalence and incidence rates (population attributable risk: 85%, 95% CI 84% to 87% and population attributable risk: 77%, 95% CI 72% to 82%, respectively). Conclusions The association of HIV status with younger age at sexual debut may likely due to an increased number of lifetime partners. This increase could result from longer duration of sexual life. Prevention of HIV infection should include efforts to delay age at first sex in young women. Trial registration number NCT00121459. PMID- 22223839 TI - Knowledge, attitudes and preferences regarding genetic testing for smoking cessation. A cross-sectional survey among Dutch smokers. AB - Objectives Recent research strongly suggests that genetic variation influences smokers' ability to stop. Therefore, the use of (pharmaco) genetic testing may increase cessation rates. This study aims to assess the intention of smokers concerning undergoing genetic testing for smoking cessation and their knowledge, attitudes and preferences about this subject. Design Online cross-sectional survey. Setting Database internet research company of which every inhabitant of the Netherlands of >=12 years with an email address and capable of understanding Dutch can become a member. Participants 587 of 711 Dutch smokers aged >=18 years, daily smokers for >=5 years and smoke on average >=10 cigarettes/day (response rate=83%). Primary and secondary outcome measures Smokers' knowledge, attitudes and preferences and their intention to undergo genetic testing for smoking cessation. Results Knowledge on the influence of genetic factors in smoking addiction and cessation was found to be low. Smokers underestimated their chances of having a genetic predisposition and the influence of this on smoking cessation. Participants perceived few disadvantages, some advantages and showed moderate self-efficacy towards undergoing a genetic test and dealing with the results. Smokers were mildly interested in receiving information and participating in genetic testing, especially when offered by their general practitioner (GP). Conclusions For successful implementation of genetic testing for smoking in general practice, several issues should be addressed, such as the knowledge on smoking cessation, genetics and genetic testing (including advantages and disadvantages) and the influence of genetics on smoking addiction and cessation. Furthermore, smokers allocate their GPs a crucial role in the provision of information and the delivery of a genetic test for smoking; however, it is unclear whether GPs will be able and willing to take on this role. PMID- 22223840 TI - A cost-effectiveness analysis of an in-hospital clinical pharmacist service. AB - Objective A randomised controlled study performed from 2007 to 2008 showed beneficial effects of a composite clinical pharmacist service as regards a simple health status instrument. The present study aimed to evaluate if the intervention was cost-effective when evaluated in a decision-theoretic model. Design A piggyback cost-effectiveness analysis from the healthcare perspective. Setting Two internal medicine wards at Sahlgrenska University Hospital, Goteborg, Sweden. Participants Of 345 patients (61% women; median age: 82 years; 181 control and 164 intervention patients), 240 patients (62% women, 82 years; 124 control and 116 intervention patients) had EuroQol-5 dimensions (EQ-5D) utility scores at baseline and at 6-month follow-up. Outcome measures Costs during a 6-month follow-up period in all patients and incremental cost-effectiveness ratio per quality-adjusted life-year (QALY) in patients with EQ-5D utility scores. Inpatient and outpatient care was extracted from the VEGA database. Drug costs were extracted from the Swedish Prescribed Drug Register. A probabilistic analysis was performed to characterise uncertainty in the cost-effectiveness model. Results No significant difference in costs between the randomisation groups was found; the mean total costs per individual+/-SD, intervention costs included, were ?10 748+/-13 799 (intervention patients) and ?10 344+/-14 728 (control patients) (p=0.79). For patients in the cost-effectiveness analysis, the corresponding costs were ?10 912+/-13 999 and ?9290+/-12 885. Intervention patients gained an additional 0.0051 QALYs (unadjusted) and 0.0035 QALYs (adjusted for baseline EQ-5D utility score). These figures result in an incremental cost-effectiveness ratio of ?316 243 per unadjusted QALY and ?463 371 per adjusted QALY. The probabilistic uncertainty analysis revealed that, at a willingness-to-pay of ?50 000/QALY, the probability that the intervention was cost-effective was approximately 0.2. Conclusions The present study reveals that an intervention designed like this one is probably not cost-effective. The study thus illustrates that the complexity of healthcare requires thorough health economics evaluations rather than simplistic interpretation of data. PMID- 22223841 TI - Breast cancer survival and season of surgery: an ecological open cohort study. AB - Background Vitamin D has been suggested to influence the incidence and prognosis of breast cancer, and studies have found better overall survival (OS) after diagnosis for breast cancer in summer-autumn, where the vitamin D level are expected to be highest. Objective To compare the prognostic outcome for early breast cancer patients operated at different seasons of the year. Design Open population-based cohort study. Setting Danish women operated 1978-2010. Cases 79 658 adjusted for age at surgery, period of surgery, tumour size, axillary lymph node status and hormone receptor status. Statistical analysis The association between OS and season of surgery was analysed by Cox proportional hazards regression models, at survival periods 0-1, 0-2, 0-5 and 0-10 years after surgery. A two-sided p value <0.05 was considered statistical significant. Results Only after adjustment for prognostic factors that may be influenced by vitamin D, 1-year survival was close to significantly associated season of surgery. 2, 5 and 10 years after surgery, the association between OS and season of surgery was not significant. Limitations Season is a surrogate measure of vitamin D. Conclusions The authors found no evidence of a seasonal variation in the survival after surgery for early breast cancer. Lack of seasonal variation in this study does not necessarily mean that vitamin D is of no importance for the outcome for breast cancer patients. PMID- 22223842 TI - Randomised controlled trial evaluating the efficacy of wrap therapy for wound healing acceleration in patients with NPUAP stage II and III pressure ulcer. AB - Objectives To evaluate if 'wrap therapy' using food wraps, which is widely used in Japanese clinical sites, is not inferior when compared to guideline adhesion treatments. Design Multicentre, prospective, randomised, open, blinded endpoint clinical trial. Setting 15 hospitals in Japan. Patients 66 older patients with new National Pressure Ulcer Advisory Panel stage II or III pressure ulcers. Interventions Of these 66 patients, 31 were divided into the conventional treatment guidelines group and 35 into the wrap therapy group. Main outcome measures The primary end point was the period until the pressure ulcers were cured. The secondary end point was a comparison of the speed of change in the Pressure Ulcer Scale for Healing score. Results 64 of the 66 patients were analysed. The estimated mean period until healing was 57.5 days (95% CI 45.2 to 69.8) in the control group as opposed to 59.8 days (95% CI 49.7 to 69.9) in the wrap therapy group. By the extent of pressure ulcer infiltration, the mean period until healing was 16.0 days (95% CI 8.1 to 23.9) in the control group as opposed to 18.8 days (95% CI 10.3 to 27.2) in the wrap therapy group with National Pressure Ulcer Advisory Panel stage II ulcers, and 71.8 days (95% CI 61.4 to 82.3) as opposed to 63.2 days (95% CI 53.0 to 73.4), respectively, with stage III ulcers. There is no statistical significance in difference in Pressure Ulcer Scale for Healing scores. Conclusions It might be possible to consider wrap therapy as an alternative choice in primary care settings as a simple and inexpensive dressing care. Clinical Trial registration UMIN Clinical Trials Registry UMIN000002658. Summary protocol is available on https://upload.umin.ac.jp/cgi bin/ctr/ctr.cgi?function=brows&action=brows&type=detail&recptno=R000003235&admin= &language=J. PMID- 22223843 TI - Hearing in 44-45 year olds with m.1555A>G, a genetic mutation predisposing to aminoglycoside-induced deafness: a population based cohort study. AB - Background The mitochondrial DNA mutation m.1555A>G predisposes to permanent idiosyncratic aminoglycoside-induced deafness that is independent of dose. Research suggests that in some families, m.1555A>G may cause non-syndromic deafness, without aminoglycoside exposure, as well as reduced hearing thresholds with age (age-related hearing loss). Objectives To determine whether adults with m.1555A>G have impaired hearing, a factor that would inform the cost-benefit argument for genetic testing prior to aminoglycoside administration. Design Population-based cohort study. Setting UK. Participants Individuals from the British 1958 birth cohort. Measurements Hearing thresholds at 1 and 4 kHz at age 44-45 years; m.1555A>G genotyping. Results 19 of 7350 individuals successfully genotyped had the m.1555A>G mutation, giving a prevalence of 0.26% (95% CI 0.14% to 0.38%) or 1 in 385 (95% CI 1 in 714 to 1 in 263). There was no significant difference in hearing thresholds between those with and without the mutation. Single-nucleotide polymorphism analysis indicated that the mutation has arisen on a number of different mitochondrial haplogroups. Limitations No data were collected on aminoglycoside exposure. For three subjects, hearing thresholds could not be predicted because information required for modelling was missing. Conclusions In this cohort, hearing in those with m.1555A>G is not significantly different from the general population and appears to be preserved at least until 44-45 years of age. Unbiased ascertainment of mutation carriers provides no evidence that this mutation alone causes non-syndromic hearing impairment in the UK. The findings lend weight to arguments for genetic testing for this mutation prior to aminoglycoside administration, as hearing in susceptible individuals is expected to be preserved well into adult life. Since global use of aminoglycosides is likely to increase, development of a rapid test is a priority. PMID- 22223845 TI - Monosodium glutamate-induced diabetic mice are susceptible to azoxymethane induced colon tumorigenesis. AB - Obese people and diabetic patients are known to be high risk of colorectal cancer (CRC), suggesting need of a new preclinical animal model, by which to extensively study the diverse mechanisms, therapy and prevention. The present study aimed to determine whether experimental obese and diabetic mice produced by monosodium glutamate (MSG) treatment are susceptible to azoxymethane (AOM)-induced colon tumorigenesis using early biomarkers, aberrant crypts foci (ACF) and beta-catenin accumulated crypts (BCACs), of colorectal carcinogenesis. Male Crj:CD-1 (ICR) newborns were daily given four subcutaneous injections of MSG (2 mg/g body wt) to induce diabetes and obesity. They were then given four intraperitoneal injections of AOM (15 mg/kg body wt) or saline (0.1 ml saline/10 g body wt). Ten weeks after the last injection of AOM, the MSG-AOM mice had a significant increase in the multiplicity of BCAC (13.83 +/- 7.44, P < 0.002), but not ACF (78.00 +/- 11.20), when compare to the Saline-AOM mice (5.45 +/- 1.86 of BCAC and 69.27 +/- 8.06 of ACF). Serum biochemical profile of the MSG-treated mice with or without AOM showed hyperinsulinemia, hypercholesteremia and hyperglycemia. The mRNA expression of insulin-like growth factor-1 receptor (IGF-1R, P<0.01) was increased in the MSG-AOM mice, when compared with the mice given AOM alone. IGF 1R was immunohistochemically expressed in the BCAC, but not ACF, in the AOM treated mice. Our findings suggest that the MSG mice are highly susceptible to AOM-induced colorectal carcinogenesis, suggesting potential utility of our MSG AOM mice for further investigation of the possible underlying events that affect the positive association between obese/diabetes and CRC. PMID- 22223844 TI - Hyperpolarized (13)C spectroscopy detects early changes in tumor vasculature and metabolism after VEGF neutralization. AB - No clinically validated biomarkers exist to image tumor responses to antiangiogenic therapy. Here, we report the utility of hyperpolarized (13)C magnetic resonance spectroscopy (MRS) to detect the early effects of anti-VEGF therapy. In two colorectal cancer xenograft models, displaying differential sensitivity to VEGF blockade, we compared hyperpolarized MRS with measurements of tumor perfusion using dynamic contrast agent-enhanced (DCE)-MRI and tumor cellularity using diffusion-weighted MRI of the apparent diffusion coefficient (ADC) of tissue water. In tumors sensitive to anti-VEGF therapy, (13)C flux between hyperpolarized [1-(13)C]pyruvate and [1-(13)C]lactate decreased after anti-VEGF therapy and correlated with reduced perfusion. Production of [1,4 (13)C(2)]malate from hyperpolarized [1,4-(13)C(2)]fumarate increased in parallel with tumor cell necrosis, preceding any change in tumor ADC. In contrast, tumors that were less sensitive to anti-VEGF therapy showed an increase in (13)C flux from hyperpolarized [1-(13)C]pyruvate and an increase in uptake of a gadolinium contrast agent, whereas tumor ADC decreased. Increased label flux could be explained by vascular normalization after VEGF blockade, increasing delivery of hyperpolarized [1-(13)C]pyruvate as observed. Despite the minimal response of these tumors to treatment, with only a minor increase in necrosis observed histologically, production of [1,4-(13)C(2)]malate from hyperpolarized [1,4 (13)C(2)]fumarate in therapy-resistant tumors also increased. Together, our findings show that hyperpolarized (13)C MRS detects early responses to anti-VEGF therapy, including vascular normalization or vascular destruction and cell death. PMID- 22223846 TI - Hypoxia-inducible factor-1alpha inhibition by a pyrrolopyrazine metabolite of oltipraz as a consequence of microRNAs 199a-5p and 20a induction. AB - Oltipraz, a cancer chemopreventive agent, has antitumor and antiangiogenic effects. In animal models and clinical studies, a considerable amount of oltipraz is metabolized to pyrrolopyrazines, including M2, 7-methyl-6,8 bis(methylthio)pyrrolo[1,2-a]pyrazine; M3, 7-methyl-8-(methylsulfinyl)-6 (methylthio)pyrrolo[1,2-a]pyrazine and M4, 7-methyl-6,8 bis(methylsulfinyl)pyrrolo[1,2-a]pyrazine. In view of the role of hypoxia inducible factor-1 (HIF-1) alpha in tumor growth and angiogenesis, this study investigated whether pyrrolopyrazine metabolites of oltipraz inhibit HIF-1alpha induction, and if so, what the molecular basis is. M2 treatment inhibited the induction of HIF-1alpha by a variety of stimuli including insulin, hypoxia, CoCl(2) and hydrogen peroxide in HCT116 cells, whereas M3 or M4 failed to do so. Consistently, M2 prevented HIF-1alpha target gene induction. Moreover, it inhibited cancer cell invasion and migration. M2 caused no change in the expression of HIF-1alpha transcript but increased the levels of precursor forms of microRNAs (miRNAs) 199a-5p and 20a, but not those of primary forms, indicating facilitation of the maturation process of the miRNAs by M2. Increased levels of the miRNAs contributed to HIF-1alpha repression, as shown by the results of experiments using mimics. Consistently, M2 treatment inhibited de novo synthesis of HIF-1alpha, as supported by decreased incorporation of [(35)S]-methionine into HIF-1alpha with no changes in its ubiquitination or degradation. 7-Ethyl-6,8 bis(methylthio)pyrrolo[1,2-a]pyrazine, a synthetic analog of M2, had a similar inhibitory effect. In conclusion, M2 with pyrrolopyrazine structure and its 7 ethyl congenor have the ability to prevent the induction of HIF-1alpha, which may result from the inhibition of HIF-1alpha de novo synthesis, as mediated by the induction of miR-199a-5p and miR-20a. PMID- 22223847 TI - The tumor-suppressor gene Nkx2.8 suppresses bladder cancer proliferation through upregulation of FOXO3a and inhibition of the MEK/ERK signaling pathway. AB - Invasive bladder cancer is a lethal disease for which effective prognostic markers as well as potential therapy targets are still lacking. Nkx2.8 (Nk2 homeobox 8), a novel member of the NK-2 gene family, was reported to play an important role in the development and progression of human cancer. Herein, we reported that Nkx2.8 was markedly reduced in bladder cancer tissues compared with matched adjacent normal urothelial tissues. Nkx2.8 levels were inversely correlated with advanced T classification, N classification, tumor multiplicity, high proliferation index (Ki-67) and poor survival of patients. Furthermore, we found that overexpression of Nkx2.8 in bladder cancer cells significantly inhibited cell proliferation in vitro and in vivo, whereas silencing Nkx2.8 dramatically enhanced cell proliferation. Moreover, we demonstrated that overexpression of Nkx2.8 resulted in G(1)/S phase arrest, accompanied by upregulation of p27(Kip1), downregulation of cyclin D1 and p-FOXO3a and inhibition of MEK/ERK pathway activity. Meanwhile, silencing Nkx2.8 led to acceleration of G(1)/S transition, downregulation of p27(Kip1), upregulation of cyclin D1 and p-FOXO3a and increase of MEK/ERK pathway activity. These findings suggest that Nkx2.8 plays a potential tumor suppressor role in bladder cancer progression and represents a valuable clinical prognostic marker of this disease. PMID- 22223848 TI - Loss of the platelet activating factor receptor in mice augments PMA-induced inflammation and cutaneous chemical carcinogenesis. AB - Although platelet-activating factor (PAF) is a well-known acute inflammatory mediator, little is known regarding the role of PAF in chronic inflammation. Phorbol esters are known to stimulate PAF production. Moreover, the ability of repeated applications of phorbol esters to induce a sustained inflammatory response is crucial to their tumorigenic activity. We therefore examined whether PAF acts as a mediator of phorbol ester-induced inflammation and tumorigenesis. While PAF receptor knockout mice (PAFR(-/-)) showed an expected but modest reduction in the acute inflammatory response to phorbol 12-myristate 13-acetate (PMA), these mice exhibited a surprising increase in inflammation following chronic PMA application. This increased inflammation was documented by a number of findings that included: increased skin thickness, increased myeloperoxidase activity and expression and increased expression of known inflammatory mediators. Interestingly, vehicle-treated PAFR(-/-) mice also exhibited modest increases in levels of inflammatory markers. This suggests that the platelet activating factor receptor (PAFR) acts to suppress chronic inflammation in response to other stimuli, such as barrier disruption. The idea that chronic PAFR activation is anti-inflammatory was documented by repetitive topical PAFR agonist administration that resulted in reduced myeloperoxidase activity in skin. We next utilized a 7,12-dimethylbenz(a)anthracene/PMA carcinogenesis protocol to demonstrate that PAFR(-/-) mice exhibit significantly increased tumor formation and malignant progression compared with wild-type control mice. These studies provide evidence for two important, unexpected and possibly interrelated pathological roles for the PAFR: first, the PAFR acts to suppress PMA-induced chronic inflammation; secondly, the PAFR acts to suppress neoplastic development in response to chemical carcinogens. PMID- 22223849 TI - DJ-1 promotes invasion and metastasis of pancreatic cancer cells by activating SRC/ERK/uPA. AB - A major hallmark of pancreatic ductal adenocarcinoma (PDAC) is extensive local tumor invasion and early systemic dissemination. DJ-1 has been shown to prevent cell death via the Akt pathway, thereby playing an important role in cancer progression and Parkinson's disease development. Here, we investigated the role of DJ-1 in tumor invasion and metastasis of pancreatic cancer and showed that DJ 1 is upregulated in 68.5% of pancreatic cancer specimens, correlated with tumor stage and predictive of short overall survival. Knockdown of DJ-1 expression in two PDAC cell lines reduced cell migration and invasion potential in vitro and inhibited metastasis in vivo. Knockdown of DJ-1 led to cytoskeleton disruption and diminished urokinase plasminogen activator (uPA) activity and expression, without affecting plasminogen activator inhibitor-1 and uPA receptor (uPAR) expression. All these effects were reversed by restoration of DJ-1 expression. In determining the pathway through which DJ-1 regulated cell migration and invasion, DJ-1 was found not to regulate Akt phosphorylation. Rather, it promoted extracellular signal-regulated kinase (ERK) and SRC phosphorylation. Inhibition of the ERK pathway in PDAC mimicked the effects of DJ-1 on cell migration, invasion, actin cytoskeleton and uPA/uPAR system and abolished the effects on promoting PDAC cell invasion and migration. These data represent the first identification of an important function of DJ-1, which is to regulate the invasion and metastasis properties of PDAC through the ERK/uPA cascade. PMID- 22223850 TI - Comment on "B cell depletion enhances T regulatory cell activity essential in the suppression of arthritis". PMID- 22223852 TI - Are you upset? Distinct roles for orbitofrontal and lateral prefrontal cortex in detecting and distinguishing facial expressions of emotion. AB - Navigating our complex social world requires effective processing of subtle emotional signals, such as those conveyed by facial expressions. Failure to do so may underlie some of the disabling social-emotional deficits common in a range of neuropsychiatric and neurological conditions. Prefrontal cortex (PFC) has long been implicated in these processes, but the particular contributions of subregions within PFC remain unclear. We used a sensitive facial emotion rating task in patients with focal lesions to different regions within PFC to identify distinct contributions of 2 prefrontal regions to recognizing emotions from facial expressions. A combination of region-of-interest and voxel-based lesion symptom mapping established that damage to ventromedial PFC impaired the detection of subtle facial expressions of emotion. Such patients had difficulty distinguishing emotional from neutral expressions. In contrast, patients with left ventrolateral PFC were able to detect the presence of emotional signals but had difficulty discriminating between specific emotions. These effects were regionally specific: Dorsomedial prefrontal damage had no effect on either aspect of emotion recognition. These findings suggest that separable processes relying critically on distinct regions within PFC responsible, on the one hand, for detecting emotional signals from facial expressions and, on the other, for correctly classifying such signals. PMID- 22223851 TI - Kruppel-like factors in lymphocyte biology. AB - The Kruppel-like factor family of transcription factors plays an important role in differentiation, function, and homeostasis of many cell types. While their role in lymphocytes is still being determined, it is clear that these factors influence processes as varied as lymphocyte quiescence, trafficking, differentiation, and function. This review will present an overview of how these factors operate and coordinate with each other in lymphocyte regulation. PMID- 22223853 TI - Multimodal MRI analysis of the corpus callosum reveals white matter differences in presymptomatic and early Huntington's disease. AB - Recent magnetic resonance imaging (MRI) studies suggest that abnormalities in Huntington's disease (HD) extend to white matter (WM) tracts in early HD and even in presymptomatic stages. Thus, changes of the corpus callosum (CC) may reflect various aspects of HD pathogenesis. We recruited 17 HD patients, 17 pre-HD subjects, and 34 healthy age-matched controls. Three-dimensional anatomical MRI and diffusion tensor images of the brain were acquired on a 3T scanner. Combining region-of-interest analyses, voxel-based morphometry, and tract-based spatial statistics, we investigated callosal thickness, WM density, fractional anisotropy, and radial and axial diffusivities. Compared with controls, pre-HD subjects showed reductions of the isthmus, likely due to myelin damage. Compared with pre-HD subjects, HD patients showed reductions of isthmus and body, with axonal damage confined to the body. Compared with controls, HD patients had significantly decreased callosal measures in extended regions across almost the entire CC. At this disease stage, both myelin and axonal damage are detectable. Supplementary multiple regression analyses revealed that WM reduction density in the isthmus as well as Disease Burden scores allowed to predict the "HD development" index. While callosal changes seem to proceed in a posterior-to anterior direction as the diseases progresses, this observation requires validation in future longitudinal investigations. PMID- 22223854 TI - Common polymorphisms in the PKP3-SIGIRR-TMEM16J gene region are associated with susceptibility to tuberculosis. AB - BACKGROUND: Tuberculosis has been associated with genetic variation in host immunity. We hypothesized that single-nucleotide polymorphisms (SNPs) in SIGIRR, a negative regulator of Toll-like receptor/IL-1R signaling, are associated with susceptibility to tuberculosis. METHODS: We used a case-population study design in Vietnam with cases that had either tuberculous meningitis or pulmonary tuberculosis. We genotyped 6 SNPs in the SIGIRR gene region (including the adjacent genes PKP3 and TMEM16J) in a discovery cohort of 352 patients with tuberculosis and 382 controls. Significant associations were genotyped in a validation cohort (339 patients with tuberculosis, 376 controls). RESULTS: Three SNPs (rs10902158, rs7105848, rs7111432) were associated with tuberculosis in discovery and validation cohorts. The polymorphisms were associated with both tuberculous meningitis and pulmonary tuberculosis and were strongest with a recessive genetic model (odds ratios, 1.5-1.6; P = .0006-.001). Coinheritance of these polymorphisms with previously identified risk alleles in Toll-like receptor 2 and TIRAP was associated with an additive risk of tuberculosis susceptibility. CONCLUSIONS: These results demonstrate a strong association of SNPs in the PKP3 SIGIRR-TMEM16J gene region and tuberculosis in discovery and validation cohorts. To our knowledge, these are the first associations of polymorphisms in this region with any disease. PMID- 22223855 TI - Evaluation of HIV protease inhibitor use and the risk of sudden death or nonhemorrhagic stroke. AB - Concerns have arisen about possible effects of protease inhibitors (PIs) on cardiac conductivity. We found no significant association between current or recent PI exposure and sudden death or nonhemorrhagic stroke (adjusted rate ratio, 1.22; 95% confidence interval, .95-1.57), whereas cumulative exposure to PIs was associated with an increased risk (adjusted rate ratio, 1.06 per year of exposure; 95% confidence interval, 1.01-1.11). PMID- 22223856 TI - Human genetic susceptibility to tuberculosis: time for a bottom-up approach? PMID- 22223857 TI - Protective antigen antibody augments hemodynamic support in anthrax lethal toxin shock in canines. AB - BACKGROUND: Anthrax-associated shock is closely linked to lethal toxin (LT) release and is highly lethal despite conventional hemodynamic support. We investigated whether protective antigen-directed monoclonal antibody (PA-mAb) treatment further augments titrated hemodynamic support. METHODS AND RESULTS: Forty sedated, mechanically ventilated, instrumented canines challenged with anthrax LT were assigned to no treatment (controls), hemodynamic support alone (protocol-titrated fluids and norepinephrine), PA-mAb alone (administered at start of LT infusion [0 hours] or 9 or 12 hours later), or both, and observed for 96 hours. Although all 8 controls died, 2 of 8 animals receiving hemodynamic support alone survived (median survival times 65 vs 85 hours, respectively; P = .03). PA-mAb alone at 0 hour improved survival (5 of 5 animals survived), but efficacy decreased progressively with delayed treatment (9 hours, 2 of 3 survived; 12 hours, 0 of 4 survived) (P = .004 comparing survival across treatment times). However, combined treatment increased survival irrespective of PA-mAb administration time (0 hours, 4 of 5 animals; 9 hours, 3 of 3 animals; and 12 hours, 4 of 5 animals survived) (P = .95 comparing treatment times). Compared to hemodynamic support alone, when combined over PA-mAb treatment times (0, 9, and 12 hours), combination therapy produced higher survival (P = .008), central venous pressures, and left ventricular ejection fractions, and lower heart rates, norepinephrine requirements and fluid retention (P <= .03). CONCLUSIONS: PA-mAb may augment conventional hemodynamic support during anthrax LT-associated shock. PMID- 22223858 TI - Functional organ preservation for laryngeal cancer: past, present and future. AB - OBJECTIVE: Management of laryngeal cancer has focused on improving survival while preserving function. Over the past 20 years, the trends have shifted from surgery to chemoradiotherapy and presently we are facing various challenges. It is imperative to re-examine what has happened and what can be done. METHODS: Review of the literature along with our experience in the management of functional organ preservation for laryngeal cancer. RESULTS: There was an increasing use of chemoradiotherapy with a decreasing use of surgery. Inappropriate patient selection along with inability to properly apply salvage surgeries have been presumed to be responsible for survival deterioration in laryngeal cancer. Reports concerning late adverse events after chemoradiotherapy are also increasing. Reconfirmation of the multidisciplinary team approach is imperative. Transoral laser microsurgery can be used for early laryngeal cancer and, in some experienced institutes, for advanced-stage cancers. Supracricoid laryngectomy demonstrated satisfactory oncologic and functional outcomes, based on our experience. CONCLUSIONS: Treatment selection for larynx preservation should not merely be decided by guidelines but considering each patient's individual condition. Head and neck surgeons are encouraged to take reasonable risks in performing salvage larynx preservation surgery when it is the only option to save a functioning larynx. PMID- 22223859 TI - Epoxyeicosatrienoic acids protect rat hearts against tumor necrosis factor-alpha induced injury. AB - Epoxyeicosatrienoic acids (EET), the primary arachidonic acid metabolites of cytochrome P450 2J (CYP2J) epoxygenases, possess potent vasodilatory, anti inflammatory, antiapoptotic, and mitogenic effects. To date, little is known about the role of CYP2J2 and EETs in tumor necrosis factor (TNF)-alpha-induced cardiac injury. We utilized cell culture and in vivo models to examine the effects of exogenously applied EETs or CYP2J2 overexpression on TNF-alpha-induced cardiac apoptosis and cardiac dysfunction. In neonatal rat cardiomyocytes, TNF alpha-induced apoptosis was markedly attenuated by EETs or CYP2J2 overexpression, leading to significantly improved cell survival. Further studies showed that TNF alpha decreased expression of the antiapoptotic proteins Bcl-2 and Bcl-xL, decreased IkappaBalpha and PPARgamma, and also inhibited PI3K-dependent Akt and EGFR signaling. Both EETs and CYP2J2 overexpression reversed the effects of TNF alpha on these pathways. Furthermore, overexpression of CYP2J2 in rats prevented the decline in cardiac function that is normally observed in TNF-alpha-challenged animals. These results demonstrate that EETs or CYP2J2 overexpression can prevent TNF-alpha-induced cardiac cell injury and cardiac dysfunction by inhibiting apoptosis, reducing inflammation, and enhancing PPARgamma expression. Targeting the CYP2J2 epoxygenase pathway may represent a novel approach to mitigate cardiac injury in diseases such as heart failure, where increased TNF-alpha levels are known to occur. PMID- 22223862 TI - "Proton therapy in an era of cost containment". PMID- 22223860 TI - Unusual binding of ursodeoxycholic acid to ileal bile acid binding protein: role in activation of FXRalpha. AB - Ursodeoxycholic acid (UDCA, ursodiol) is used to prevent damage to the liver in patients with primary biliary cirrhosis. The drug also prevents the progression of colorectal cancer and the recurrence of high-grade colonic dysplasia. However, the molecular mechanism by which UDCA elicits its beneficial effects is not entirely understood. The aim of this study was to determine whether ileal bile acid binding protein (IBABP) has a role in mediating the effects of UDCA. We find that UDCA binds to a single site on IBABP and increases the affinity for major human bile acids at a second binding site. As UDCA occupies one of the bile acid binding sites on IBABP, it reduces the cooperative binding that is often observed for the major human bile acids. Furthermore, IBABP is necessary for the full activation of farnesoid X receptor alpha (FXRalpha) by bile acids, including UDCA. These observations suggest that IBABP may have a role in mediating some of the intestinal effects of UDCA. PMID- 22223863 TI - JNCCN reaches 10. PMID- 22223861 TI - Loss of liver FA binding protein significantly alters hepatocyte plasma membrane microdomains. AB - Although lipid-rich microdomains of hepatocyte plasma membranes serve as the major scaffolding regions for cholesterol transport proteins important in cholesterol disposition, little is known regarding intracellular factors regulating cholesterol distribution therein. On the basis of its ability to bind cholesterol and alter hepatic cholesterol accumulation, the cytosolic liver type FA binding protein (L-FABP) was hypothesized to be a candidate protein regulating these microdomains. Compared with wild-type hepatocyte plasma membranes, L-FABP gene ablation significantly increased the proportion of cholesterol-rich microdomains. Lack of L-FABP selectively increased cholesterol, phospholipid (especially phosphatidylcholine), and branched-chain FA accumulation in the cholesterol-rich microdomains. These cholesterol-rich microdomains are important, owing to enrichment therein of significant amounts of key transport proteins involved in uptake of cholesterol [SR-B1, ABCA-1, P-glycoprotein (P-gp), sterol carrier binding protein (SCP-2)], FA transport protein (FATP), and glucose transporters 1 and 2 (GLUT1, GLUT2) insulin receptor. L-FABP gene ablation enhanced the concentration of SCP-2, SR-B1, FATP4, and GLUT1 in the cholesterol poor microdomains, with functional implications in HDL-mediated uptake and efflux of cholesterol. Thus L-FABP gene ablation significantly impacted the proportion of cholesterol-rich versus -poor microdomains in the hepatocyte plasma membrane and altered the distribution of lipids and proteins involved in cholesterol uptake therein. PMID- 22223864 TI - JNCCN at 10. PMID- 22223865 TI - By the pricking of my thumbs, something wicked this way comes: sporadic cancers versus eponymous hereditary cancer predisposition syndromes. AB - Advances in cancer genomics have led to the recognition of a growing number of high-penetrance single-gene cancer predisposition syndromes. Frequently, the suspicion for a hereditary syndrome is raised by a strongly positive family history. However, other features, such as younger-than-usual age at diagnosis and rare histology should also prompt consideration of a genetic syndrome. Common malignancies frequently show a positive family history without an eponymous syndrome being recognized. This article reports on a case with an unusual constellation of malignancies with distinctive pathologies, which raised suspicion for an eponymous cancer pre-disposition syndrome. Absent a positive family history, a de novo mutation-an alteration in a gene that is present for the first time in a family member as a result of a mutation in a germ cell of one of the parents or in the fertilized ovum-was suspected. The authors discuss indications for genetic counseling and testing, limitations, and the evidence that supports the recommendations as formulated by working groups and the NCCN. Most frequently, these recommendations are reasonable statements based on the natural history of the disease, but without population-based studies for many rare syndromes, the actual penetrance, variable expressivity, and actual associated cancer risk are unknown. PMID- 22223866 TI - Value-based insurance design: aligning incentives, benefits, and evidence in oncology. AB - When everyone is required to pay the same out-of-pocket amount for oncology services for which benefits depend on patient characteristics and clinical indication, there is enormous potential for both under- and overutilization. Unlike most current health plan designs, the value-based insurance design (V-BID) explicitly acknowledges and responds to patient heterogeneity across the entire continuum of cancer care. By adding "clinical nuance" to benefit design, V-BID encourages the use of services when the clinical benefits exceed the cost, and likewise discourages the use of services when the benefits do not justify the expenditure. This manuscript further describes the concept of V-BID, creates a framework for its development in oncology, and outlines how this concept aligns with ongoing research, care delivery, and payment reform initiatives. PMID- 22223867 TI - Malignant pleural mesothelioma. PMID- 22223869 TI - Current concepts in the evaluation and treatment of patients with diffuse malignant peritoneal mesothelioma. AB - Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and ultimately fatal cancer that was first recognized and described a century ago. It is a diffuse primary malignant condition arising from the mesothelial lining of the peritoneum, and its natural history is hallmarked by a propensity to progress almost exclusively within the abdominal cavity throughout the entire course of disease. Patients afflicted with DMPM most commonly present with nonspecific abdominal symptoms that lead to diagnosis when the condition is relatively advanced. Historically, median overall survival for patients with DMPM without treatment is very short, averaging 6 months. Systemic chemotherapy using pemetrexed and cisplatin has an overall response rate of approximately 25% and a median overall survival of approximately 1 year. Many institutional reports have shown that in selected patients, operative cytoreduction and hyperthermic intraoperative peritoneal chemotherapy using cisplatin or mitomycin C is associated with long-term survival. Recent studies on the molecular biology of DMPM have yielded new insights relating to the potentially important role of the phosphatidylinositol 3-kinase/mammalian target of rapamycin and epidermal growth factor receptor pathways in this disease, which may translate into new therapeutic options for patients with DMPM. PMID- 22223868 TI - Novel therapies in phase II and III trials for malignant pleural mesothelioma. AB - Mesothelioma is a rare malignancy of the pleura with limited therapeutic options. Despite the desperate need to develop better treatment for this disease, the rarity of the tumor type creates formidable challenges in clinical research. Nonetheless, several novel agents are under investigation. Most efforts are directed toward improving standard first-line therapy with pemetrexed and cisplatin, or developing effective second-line treatments. Several classes of drugs are being explored, including those that impact DNA transcription, cell cycle progression, angiogenesis, and immune tolerance. This article describes several ongoing or recently completed phase II and III trials using novel agents vorinostat, everolimus, CBP501, MORAb-009, NGR-hTNF, WT1 vaccine, bevacizumab, cediranib, and thalidomide. PMID- 22223870 TI - Chronic myelogenous leukemia. PMID- 22223871 TI - How to choose frontline therapy for chronic myelogenous leukemia: so many drugs, not so many patients. AB - With the development of tyrosine kinase inhibitors (TKIs), the management and outlook for patients with chronic myelogenous leukemia (CML) have completely changed over the past 10 years. Imatinib was the first TKI approved to treat CML in the chronic phase. After their initial approval as second-line agents, dasatinib and nilotinib were compared with imatinib in the first-line setting in 2 randomized trials. Both trials showed that therapeutic milestones (complete cytogenetic remission and major molecular remission) occurred earlier with these newer agents, leading to their approval for the treatment of newly diagnosed CML. Therefore, 3 different TKIs are now available for treating CML. Long-term follow up of patients treated with imatinib shows that the attainment of therapeutic milestones by 12 months of therapy leads to better long-term outcomes. Most patients who experience disease progression on imatinib do so within the first 3 years of therapy. Therefore, one can argue that dasatinib or nilotinib should be chosen to treat patients with newly diagnosed CML. However, these agents do not have the long-term track record of imatinib. This article summarizes the published data and reviews the rationale in choosing the appropriate TKI for first-line treatment of CML in the chronic phase. PMID- 22223872 TI - Practical monitoring of chronic myelogenous leukemia: when to change treatment. AB - In patients with chronic myelogenous leukemia (CML) treated at diagnosis with the standard therapy consisting of imatinib, 400 mg once daily, the failure to achieve a complete cytogenetic response (CCyR) within 12 months from the start of therapy has been shown to be associated with an increased risk of progression and an overall inferior survival. Experts of the European LeukemiaNet and NCCN have indicated what degrees of hematologic, cytogenetic, and molecular responses should be expected at definite time points for patients with CML to have the highest probability of experiencing the final optimal response, defined as the achievement of at least a complete hematologic response with a minor cytogenetic response after 3 months; at least a partial cytogenetic response after 6 months; at least a CCyR after 12 months; and a major molecular response after 18 months of therapy. The last opportunity for a CCyR has been established at 18 months. Because the residual probability of attaining a CCyR is reduced for patients who do not experience a complete hematologic response by 3 months, any cytogenetic response by 6 months, or a major cytogenetic response by 12 months, these conditions are considered treatment failures. At this point, a change in therapy is highly recommended, such as second-line treatment with the second-generation tyrosine kinase inhibitors nilotinib or dasatinib and, in specific situations, a stem cell transplant. The loss of any grade of previously achieved cytogenetic response at any time point is also considered an imatinib failure demanding a change of therapy. Finally, intermediate gradations of response exist between optimal response and failure in which, although not totally compromised, the possibilities of achieving an optimal response later are decreased. The best therapeutic strategies to be followed in these intermediate situations, called suboptimal responses, have not been clearly established and are still under clinical investigation, but for the moment, a change of therapy is not required. PMID- 22223873 TI - Health care reform and its implications for the academic cancer center. PMID- 22223875 TI - Multiple factors influence glomerular albumin permeability in rats. AB - Different laboratories recently reported incongruous results describing the quantification of albumin filtration using two-photon microscopy. We investigated the factors that influence the glomerular sieving coefficient for albumin (GSC(A)) in an effort to explain these discordant reports and to develop standard operating procedures for determining GSC(A). Multiple factors influenced GSC(A), including the kidney depth of image acquisition (10-20 MUm was appropriate), the selection of fluorophore (probes emitting longer wavelengths were superior), the selection of plasma regions for fluorescence measurements, the size and molecular dispersion characteristics of dextran polymers if used, dietary status, and the genetic strain of rat. Fasting reduced the GSC(A) in Simonsen Munich Wistar rats from 0.035+/-0.005 to 0.016+/-0.004 (P<0.01). Fromter Munich Wistar rats had a much lower GSC(A) in both the fed and the fasted states. Finally, we documented extensive albumin transcytosis with vesicular and tubular delivery to and fusion with the basolateral membrane in S1 proximal tubule cells. In summary, these results help explain the previously conflicting microscopy and micropuncture data describing albumin filtration and highlight the dynamic nature of glomerular albumin permeability. PMID- 22223876 TI - It is chloride depletion alkalosis, not contraction alkalosis. AB - Maintenance of metabolic alkalosis generated by chloride depletion is often attributed to volume contraction. In balance and clearance studies in rats and humans, we showed that chloride repletion in the face of persisting alkali loading, volume contraction, and potassium and sodium depletion completely corrects alkalosis by a renal mechanism. Nephron segment studies strongly suggest the corrective response is orchestrated in the collecting duct, which has several transporters integral to acid-base regulation, the most important of which is pendrin, a luminal Cl/HCO(3)(-) exchanger. Chloride depletion alkalosis should replace the notion of contraction alkalosis. PMID- 22223877 TI - Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathy. AB - TGF-beta1 upregulates microRNA-192 (miR-192) in cultured glomerular mesangial cells and in glomeruli from diabetic mice. miR-192 not only increases collagen expression by targeting the E-box repressors Zeb1/2 but also modulates other renal miRNAs, suggesting that it may be a therapeutic target for diabetic nephropathy. We evaluated the efficacy of a locked nucleic acid (LNA)-modified inhibitor of miR-192, designated LNA-anti-miR-192, in mouse models of diabetic nephropathy. LNA-anti-miR-192 significantly reduced levels of miR-192, but not miR-194, in kidneys of both normal and streptozotocin-induced diabetic mice. In the kidneys of diabetic mice, inhibition of miR-192 significantly increased Zeb1/2 and decreased gene expression of collagen, TGF-beta, and fibronectin; immunostaining confirmed the downregulation of these mediators of renal fibrosis. Furthermore, LNA-anti-miR-192 attenuated proteinuria in these diabetic mice. In summary, the specific reduction of renal miR-192 decreases renal fibrosis and improves proteinuria, lending support for the possibility of an anti-miRNA-based translational approach to the treatment of diabetic nephropathy. PMID- 22223878 TI - Radiosynthesis and characterization of 11C-GSK215083 as a PET radioligand for the 5-HT6 receptor. AB - The development of a PET radioligand for imaging 5-hydroxytryptamine (5-HT) 6 receptors in the brain would, for the first time, enable in vivo imaging of this target along with assessment of its involvement in disease pathophysiology. In addition, such a tool would assist in the development of novel drugs targeting the 5-HT6 receptor. METHODS: On the basis of in vitro data, GSK215083 was identified as a promising 5-HT6 radioligand candidate and was radiolabeled with (11)C via methylation. The in vivo properties of (11)C-GSK215083 were evaluated first in pigs (to investigate brain penetration and specific binding), second in nonhuman primates (to confirm brain penetration, specific binding, selectivity, and kinetics), and third in human subjects (to confirm brain penetration and biodistribution). RESULTS: (11)C-GSK215083 readily entered the brain in all 3 species, leading to a heterogeneous distribution (striatum > cortex > cerebellum) consistent with reported 5-HT6 receptor densities and distribution determined by tissue-section autoradiography in preclinical species and humans. In vivo saturation studies using escalating doses of GSK215083 in primates demonstrated saturable, dose-dependent binding to the 5-HT6 receptor in the striatum. Importantly, (11)C-GSK215083 also exhibited affinity for the 5-HT2A receptor; however, given the differential localization of these 2 receptors in the central nervous system, the discrete 5-HT6 binding properties of this radioligand were able to be determined. CONCLUSION: These data demonstrate the utility of (11)C GSK215083 as a promising PET radioligand for probing the 5-HT6 receptor in vivo in both preclinical and clinical species. PMID- 22223880 TI - Positive charges on the translocating polypeptide chain arrest movement through the translocon. AB - Polypeptide chains synthesized by membrane-bound ribosomes are translocated through, and integrated into, the endoplasmic reticulum (ER) membrane by means of the protein translocation channel, the translocon. Positive charges on the nascent chain determine the orientation of the hydrophobic segment as it is inserted into the translocon and enhance the stop-translocation of translocating hydrophobic segments. Here we show that positive charges temporarily arrested ongoing polypeptide chain movement through the ER translocon by electrostatic interaction, even in the absence of a hydrophobic segment. The C-terminus of the polypeptide chain was elongated during the arrest, and then the full-length polypeptide chain moved through the translocon. The translocation-arrested polypeptide was not anchored to the membrane and the charges were on the cytoplasmic side of the membrane. The arrest effect was prevented by negatively charged residues inserted into the positive-charge cluster, and it was also suppressed by high salt conditions. We propose that positive charges are independent translocation regulators that are more active than previously believed. PMID- 22223879 TI - Cell metabolism affects selective vulnerability in PINK1-associated Parkinson's disease. AB - Mitochondrial dysfunction plays a primary role in the pathogenesis of Parkinson's disease (PD), particularly in autosomal recessive forms of the disease caused by mutations encoding PINK1. Although mitochondrial pathology can be demonstrated in many cell types, it is neurons that bear the brunt of cell death in PD. We studied the mitochondrial physiology of neurons and muscle cells with loss of function of the nuclear encoded mitochondrial protein PINK1. PINK1 is widely expressed in many types of tissues, but deficiency selectively induces death in neurons. We report here that the same genetic defect results in opposing phenotypes in different cell types, depending on the metabolic properties of the cell. Thus, PINK1-deficient myocytes exhibit high basal mitochondrial membrane potential (Deltapsim), whereas PINK1-deficient neurons have been shown to exhibit a low Deltapsim. PINK1 deficiency induces impaired respiration in both cell types, with a concomitant increase in glycolytic activity. We demonstrate that the high glycolytic capacity in myocytes compared with neurons enables them to produce more ATP and, therefore, compensates for the metabolic defects induced by PINK1 deficiency. Furthermore, the high Deltapsim generated in PINK1 knockout (KO) muscle mitochondria enables them to buffer cytosolic Ca(2+) fluxes, rendering them resistant to Ca(2+) stress effectively. Conversely, PINK1 KO neurons were previously shown to develop mitochondrial Ca(2+) overload and Ca(2+) induced mitochondrial depolarisation. Prevention of Ca(2+) dysregulation in myocytes might therefore account for the sparing of these cells in PD. PMID- 22223881 TI - MAL/MRTF-A controls migration of non-invasive cells by upregulation of cytoskeleton-associated proteins. AB - Monomeric actin regulates gene expression through serum response factor (SRF) by inhibiting its transcriptional coactivator myocardin-related transcription factor (MAL/MRTF). Many affected genes encode cytoskeletal components. We have analysed the migratory effects of actin-MAL signalling and of new target genes in non invasive highly adherent cells. Expression of active MAL impaired migration of both fibroblasts and epithelial cells, whereas dominant-negative constructs and partial knockdown of MAL/MRTF enhanced motility. Knockdown of three newly characterised G-actin-regulated MAL targets, integrin alpha5, plakophilin 2 (Pkp2) and FHL1, enhanced cell migration. All three were upregulated by external stimulation through actin-MAL-SRF signalling, and MAL and SRF were inducibly recruited to cis-regulatory elements of the integrin alpha5 and Pkp2 genes. Finally, the reduced migration of epithelial cells stably expressing MAL was partially reversed by knockdown of Pkp2 and FHL1. We conclude that the actin-MAL pathway promotes adhesive gene expression, including integrin alpha5, Pkp2 and FHL1, and that this is anti-motile for non-invasive cells harbouring high basal activity. PMID- 22223882 TI - Regulation of an RNA granule during spermatogenesis: acetylation of MVH in the chromatoid body of germ cells. AB - During mammalian spermatogenesis, the mouse VASA homolog (MVH; also known as DDX4), a germ-cell-specific DEAD-box type RNA-binding protein, localizes in a germline-specific RNA granule termed the chromatoid body (CB). Genetic analyses have revealed that MVH is essential for progression through spermatogenesis, although the molecular mechanisms of its function remain elusive. We found that the acetyltransferase Hat1, and its cofactor, p46, are specifically colocalized with MVH in the CB and acetylate MVH at Lys405, leading to inactivation of its RNA-binding activity. Notably, the acetylation is developmentally regulated, paralleling the temporally regulated colocalization of Hat1 and p46 in the CB. We have identified 858 mRNAs as MVH targets, a large proportion of which correspond to previously known translationally arrested genes. Importantly, eIF4B mRNA, a target of MVH, is selectively released from the MVH-ribonucleoprotein (RNP) complex when MVH is acetylated, paralleling an increase in eIF4B protein. These findings reveal a previously unknown signaling pathway that links acetylation to RNA processing in the control of spermatogenesis. PMID- 22223884 TI - The p65 subunit of NF-kappaB and PARP1 assist Snail1 in activating fibronectin transcription. AB - Snail1 is a transcriptional repressor of E-cadherin that triggers epithelial mesenchymal transition (EMT). Here, we report assisted Snail1 interaction with the promoter of a typical mesenchymal gene, fibronectin (FN1), both in epithelial cells undergoing EMT and in fibroblasts. Together with Snail1, the p65 subunit of NF-kappaB and PARP1 bound to the FN1 promoter. We detected nuclear interaction of these proteins and demonstrated the requirement of all three for FN1 transcription. Moreover, other genes involved in cell movement mimic FN1 expression induced by Snail1 or TGF-beta1 treatment and recruit p65NF-kappaB and Snail1 to their promoters. The molecular cooperation between Snail1 and NF-kappaB in transcription activation provides a new insight into how Snail1 can modulate a variety of cell programs. PMID- 22223883 TI - The induction of a nucleoplasmic reticulum by prelamin A accumulation requires CTP:phosphocholine cytidylyltransferase-alpha. AB - Farnesylated prelamin A accumulates when the final endoproteolytic maturation of the protein fails to occur and causes a dysmorphic nuclear phenotype; however, the morphology and mechanisms of biogenesis of these changes remain unclear. We show here that acute prelamin A accumulation after reduction in the activity of the ZMPSTE24 endoprotease by short interfering RNA knockdown, results in the generation of a complex nucleoplasmic reticulum that depends for its formation on the enzyme CTP:phosphocholine-cytidylyltransferase-alpha (CCT-alpha, also known as choline-phosphate cytidylyltransferase A). This structure can form during interphase, confirming that it is independent of mitosis and therefore not a consequence of disordered nuclear envelope assembly. Serial-section dual-axis electron tomography reveals that these invaginations can take two forms: one in which the inner nuclear membrane infolds alone with an inter membrane space interior, and the other in which an invagination of both nuclear membranes occurs, enclosing a cytoplasmic core. Both types of invagination can co-exist in one nucleus and both are frequently studded with nuclear pore complexes (NPC), which reduces NPC abundance on the nuclear surface. PMID- 22223885 TI - Communication-based assessment of developmental age for young children with developmental disabilities. AB - PURPOSE: In this study, the authors compared a multiple-domain strategy for assessing developmental age of young children with developmental disabilities who were at risk for long-term reliance on augmentative and alternative communication (AAC) with a communication-based strategy composed of receptive language and communication indices that may be less affected by physically challenging tasks than traditional developmental age scores. METHOD: Participants were 42 children (age 9-27 months) with developmental disabilities and who were at risk for long term reliance on AAC. Children were assessed longitudinally in their homes at 3 occasions over 18 months using multiple-domain and communication-based measures. Confirmatory factor analysis examined dimensionality across the measures, and age equivalence scores under each strategy were compared, where possible. RESULTS: The communication-based latent factor of developmental age demonstrated good reliability and was almost perfectly correlated with the multiple-domain latent factor. However, the mean age-equivalence score of the communication-based assessment significantly exceeded that of the multiple-domain assessment by 5.3 months across ages. CONCLUSIONS: Clinicians working with young children with developmental disabilities should consider a communication-based approach as an alternative developmental age assessment strategy for characterizing children's capabilities, identifying challenges, and developing interventions. A communication-based developmental age estimation is sufficiently reliable and may result in more valid inferences about developmental age for children whose developmental or cognitive age scores may otherwise be limited by their physical capabilities. PMID- 22223886 TI - The processing and interpretation of verb phrase ellipsis constructions by children at normal and slowed speech rates. AB - PURPOSE: To examine children's comprehension of verb phrase (VP) ellipsis constructions in light of their automatic, online structural processing abilities and conscious, metalinguistic reflective skill. METHOD: Forty-two children ages 5 through 12 years listened to VP ellipsis constructions involving the strict/sloppy ambiguity (e.g., "The janitor untangled himself from the rope and the fireman in the elementary school did too after the accident.") in which the ellipsis phrase ("did too") had 2 interpretations: (a) strict ("untangled the janitor") and (b) sloppy ("untangled the fireman"). We examined these sentences at a normal speech rate with an online cross-modal picture priming task (n = 14) and an offline sentence-picture matching task (n = 11). Both tasks were also given with slowed speech input (n = 17). RESULTS: Children showed priming for both the strict and sloppy interpretations at a normal speech rate but only for the strict interpretation with slowed input. Offline, children displayed an adultlike preference for the sloppy interpretation with normal-rate input but a divergent pattern with slowed speech. CONCLUSIONS: Our results suggest that children and adults rely on a hybrid syntax-discourse model for the online comprehension and offline interpretation of VP ellipsis constructions. This model incorporates a temporally sensitive syntactic process of VP reconstruction (disrupted with slow input) and a temporally protracted discourse effect attributed to parallelism (preserved with slow input). PMID- 22223887 TI - Phonological awareness and print knowledge of preschool children with cochlear implants. AB - PURPOSE: To determine whether preschool-age children with cochlear implants have age-appropriate phonological awareness and print knowledge and to examine the relationships of these skills with related speech and language abilities. METHOD: The sample comprised 24 children with cochlear implants (CIs) and 23 peers with normal hearing (NH), ages 36 to 60 months. Children's print knowledge, phonological awareness, language, speech production, and speech perception abilities were assessed. RESULTS: For phonological awareness, the CI group's mean score fell within one standard deviation of the Test of Preschool Early Literacy's (Lonigan, Wagner, Torgesen, & Rashotte, 2007) normative sample mean but was more than one standard deviation below the NH group mean. The CI group's performance did not differ significantly from that of the NH group for print knowledge. For the CI group, phonological awareness and print knowledge were significantly correlated with language, speech production, and speech perception. Together these predictor variables accounted for 34% of variance in the CI group's phonological awareness but no significant variance in their print knowledge. CONCLUSIONS: Children with CIs have the potential to develop age appropriate early literacy skills by preschool age but are likely to lag behind their NH peers in phonological awareness. Intervention programs serving these children should target these skills with instruction and by facilitating speech and language development. PMID- 22223888 TI - The Speech Intelligibility Index and the pure-tone average as predictors of lexical ability in children fit with hearing AIDS. AB - PURPOSE: To determine whether a clinically obtainable measure of audibility, the aided Speech Intelligibility Index (SII; American National Standards Institute, 2007), is more sensitive than the pure-tone average (PTA) at predicting the lexical abilities of children who wear hearing aids (CHA). METHOD: School-age CHA and age-matched children with normal hearing (CNH) repeated words and nonwords, learned novel words, and completed a standardized receptive vocabulary test. Analyses of covariance allowed comparison of the 2 groups. For CHA, regression analyses determined whether SII held predictive value over and beyond PTA. RESULTS: CHA demonstrated poorer performance than CNH on tests of word and nonword repetition and receptive vocabulary. Groups did not differ on word learning. Aided SII was a stronger predictor of word and nonword repetition and receptive vocabulary than PTA. After accounting for PTA, aided SII remained a significant predictor of nonword repetition and receptive vocabulary. CONCLUSIONS: Despite wearing hearing aids, CHA performed more poorly on 3 of 4 lexical measures. Individual differences among CHA were predicted by aided SII. Unlike PTA, aided SII incorporates hearing aid amplification characteristics and speech-frequency weightings and may provide a more valid estimate of the child's access to and ability to learn from auditory input in real-world environments. PMID- 22223889 TI - A kinematic description of the temporal characteristics of jaw motion for early chewing: preliminary findings. AB - PURPOSE: The purpose of this investigation was to describe age- and consistency related changes in the temporal characteristics of chewing in typically developing children between the ages of 4 and 35 months and adults using high resolution optically based motion capture technology. METHOD: Data were collected from 60 participants (48 children, 12 adults) across 5 age ranges (beginners, 7 months, 12 months, 35 months, and adults); each age group included 12 participants. Three different food consistencies were trialed as appropriate. The data were analyzed to assess changes in chewing rate, chewing sequence duration, and estimated number of chewing cycles. RESULTS: The results revealed both age- and consistency-related changes in chewing rate, sequence duration, and estimated number of chewing cycles, with consistency differences affecting masticatory timing in children as young as 7 months of age. Chewing rate varied as a function of age and consistency, and chewing sequence duration was shorter for adults than for children regardless of consistency type. In addition, the results from the estimated number of chewing cycles measure suggest that chewing effectiveness increased with age; this measure was also dependent on consistency type. CONCLUSIONS: The findings suggest that the different temporal chewing variables follow distinct developmental trajectories and are consistency dependent in children as young as 7 months of age. Clinical implications are detailed. PMID- 22223890 TI - Speech perception with music maskers by cochlear implant users and normal-hearing listeners. AB - PURPOSE: The goal of this study was to investigate how the spectral and temporal properties in background music may interfere with cochlear implant (CI) and normal-hearing listeners' (NH) speech understanding. METHOD: Speech-recognition thresholds (SRTs) were adaptively measured in 11 CI and 9 NH subjects. CI subjects were tested while using their clinical processors; NH subjects were tested while listening to unprocessed audio. Speech was presented with different music maskers (excerpts from musical pieces) and with steady, speech-shaped noise. To estimate the contributions of energetic and informational masking, SRTs were also measured in "music-shaped noise" and in music-shaped noise modulated by the music temporal envelopes. RESULTS: NH performance was much better than CI performance. For both subject groups, SRTs were much lower with the music-related maskers than with speech-shaped noise. SRTs were strongly predicted by the amount of energetic masking in the music maskers. Unlike CI users, NH listeners obtained release from masking with envelope and fine structure cues in the modulated noise and music maskers. CONCLUSIONS: Although speech understanding was greatly limited by energetic masking in both subject groups, CI performance worsened as more spectrotemporal complexity was added to the maskers, most likely due to poor spectral resolution. PMID- 22223891 TI - Predicting later language outcomes from the Language Use Inventory. AB - PURPOSE: To examine the predictive validity of the Language Use Inventory (LUI), a parent report of language use by children 18-47 months old (O'Neill, 2009). METHOD: 348 children whose parents had completed the LUI were reassessed at 5-6 years old with standardized, norm-referenced language measures and parent report of developmental history. The relationship between scores on the LUI and later measures was examined through correlation, binary classification, and receiver operating characteristic curve analysis. RESULTS: For children aged 24-47 months at the time of LUI completion, LUI scores correlated significantly with language measure scores. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were also calculated for 4 cutoff scores on the LUI, including -1.64 SD, a score that maximized sensitivity to 81% and specificity to 93%. For children aged 18-23 months at the time of LUI completion, specificity and NPV were high, but sensitivity and PPV were lower than desirable. CONCLUSIONS: The results provide initial support for the LUI's predictive validity, particularly for children 24-47 months, and suggest the LUI can serve as an indicator of later language outcomes in referred populations. The results compare favorably to findings for other early child-language measures. PMID- 22223892 TI - Children's verbal working memory: role of processing complexity in predicting spoken sentence comprehension. AB - PURPOSE: This study investigated the role of processing complexity of verbal working memory tasks in predicting spoken sentence comprehension in typically developing children. Of interest was whether simple and more complex working memory tasks have similar or different power in predicting sentence comprehension. METHOD: Sixty-five children (6- to 12-year-olds) completed a verbal working memory (listening) span task that varied in syntactic processing difficulty (simple sentences representing a "simple working memory task," complex sentences representing a "complex working memory task") and a standardized sentence comprehension test. RESULTS: Word recall on the simple and complex working memory tasks correlated with each other. Both memory tasks also correlated with children's sentence comprehension. Regression analyses showed that the simple working memory task remained a significant predictor of comprehension even after accounting for variance associated with age and performance on the complex working memory task. CONCLUSIONS: Results were interpreted to suggest that relative to more complex verbal working memory tasks, simple tasks are more robust predictors of children's sentence comprehension because they represent a basic yet robust index of working memory that sufficiently captures controlled attentional focus. PMID- 22223893 TI - Nonword repetition: the relative contributions of phonological short-term memory and phonological representations in children with language and reading impairment. AB - PURPOSE: This study investigates the relative contributions of phonological short term memory and phonological representations to nonword repetition (NWR). This was evaluated in children with specific language impairment (SLI) and/or reading impairment (RI); it was also studied from a developmental perspective by comparing 2 groups of typically developing (TD) children who differed in age. METHOD: NWR, digit span, vocabulary, and word and nonword discrimination were tested in 2 groups of TD children: one group matched on chronological age (CA TD group: n = 41, mean age = 7;8 [months;years]), and one language age-matched control group (LA TD group: n = 16, mean age = 5;8). Also, 10 children with SLI, 14 children with RI, and 23 children with SLI and RI (hereafter, SLI + RI) participated and were matched to the age of the CA TD group. RESULTS: For the TD children, NWR was predicted by discrimination, digit span, and age. The interaction between discrimination ability and age was also significant. Children with SLI + RI were significantly impaired on NWR compared with all other groups. A regression analysis, including the CA TD group and the children with SLI and/or RI, showed that digit span, discrimination ability, and group (SLI + RI) contributed significantly to NWR. CONCLUSIONS: Phonological short-term memory and phonological representations both significantly contribute to NWR. The predictive strength of the quality of phonological representations changes during development. PMID- 22223894 TI - Talker differences in clear and conversational speech: vowel intelligibility for older adults with hearing loss. AB - PURPOSE: To establish the range of talker variability for vowel intelligibility in clear versus conversational speech for older adults with hearing loss and to determine whether talkers who produced a clear speech benefit for young listeners with normal hearing also did so for older adults with hearing loss. METHOD: Clear and conversational vowels in /bVd/ context produced by 41 talkers were presented in noise for identification by 40 older (ages 65-87 years) adults with sloping sensorineural hearing loss. RESULTS: Vowel intelligibility within each speaking style and the size of the clear speech benefit varied widely among talkers. The clear speech benefit was equivalent to that enjoyed by young listeners with normal hearing in an earlier study. Most talkers who had produced a clear speech benefit for young listeners with normal hearing also did so for the older listeners with hearing loss in the present study. However, effects of talker gender differed between listeners with normal hearing and listeners with hearing loss. CONCLUSION: The clear speech vowel intelligibility benefit generated for listeners with hearing loss varied considerably among talkers. Most talkers who produced a clear speech benefit for normal-hearing listeners also produced a benefit for listeners with hearing loss. PMID- 22223896 TI - Sedation in Intensive Care Unit patients: Assessment and awareness. PMID- 22223897 TI - Chirality and anaesthetic drugs: A review and an update. AB - Many molecules can exist as right-handed and left-handed forms that are non superimposable mirror images of each other. They are known as enantiomers or substances of opposite shape. Such compounds are also said to be chiral (Greek chiros meaning 'hand'). Such chiral molecules are of great relevance to anaesthetic theory and practice. This review summarizes the basic concepts, pharmacokinetic and pharmacodynamic aspects of chirality, and some specific examples of their application in anaesthesia, along with recent advances to elucidate the anaesthetic mechanisms. Chirality is relevant to anaesthesia, simply because more than half of the synthetic agents used in anaesthesia practice are chiral drugs. Almost all these synthetic chiral drugs are administered as racemic mixture, rather than as single pure enantiomers. These mixtures are not drug formulations containing two or more therapeutic substances, but combination of isomeric substances, with the therapeutic activity residing mainly in one of the enantiomer. The other enantiomer can have undesirable properties, have different therapeutic activities or be pharmacologically inert. Specific examples of application of chirality in anaesthetic drugs include inhalational general anaesthetics (e.g. isoflurane), intravenous anaesthetics (e.g. etomidate, thiopentone), neuromuscular blocking agents (e.g. cisatracurium), local anaesthetics (e.g. ropivacaine and levobupivacaine) and other agents (e.g. levosimendan, dexmedetomidine, L-cysteine). In the recent advances, chirality study has not only helped new drug development as mentioned above, but has also contributed in a more profound way to the understanding of the mechanism of anaesthesia and anaesthetic drugs. PMID- 22223895 TI - Comparative large scale characterization of plant versus mammal proteins reveals similar and idiosyncratic N-alpha-acetylation features. AB - N-terminal modifications play a major role in the fate of proteins in terms of activity, stability, or subcellular compartmentalization. Such modifications remain poorly described and badly characterized in proteomic studies, and only a few comparison studies among organisms have been made available so far. Recent advances in the field now allow the enrichment and selection of N-terminal peptides in the course of proteome-wide mass spectrometry analyses. These targeted approaches unravel as a result the extent and nature of the protein N terminal modifications. Here, we aimed at studying such modifications in the model plant Arabidopsis thaliana to compare these results with those obtained from a human sample analyzed in parallel. We applied large scale analysis to compile robust conclusions on both data sets. Our data show strong convergence of the characterized modifications especially for protein N-terminal methionine excision, co-translational N-alpha-acetylation, or N-myristoylation between animal and plant kingdoms. Because of the convergence of both the substrates and the N-alpha-acetylation machinery, it was possible to identify the N acetyltransferases involved in such modifications for a small number of model plants. Finally, a high proportion of nuclear-encoded chloroplast proteins feature post-translational N-alpha-acetylation of the mature protein after removal of the transit peptide. Unlike animals, plants feature in a dedicated pathway for post-translational acetylation of organelle-targeted proteins. The corresponding machinery is yet to be discovered. PMID- 22223898 TI - Awareness of bispectral index monitoring system among the critical care nursing personnel in a tertiary care hospital of India. AB - BACKGROUND: Bispectral index monitoring system (BIS) is one of the several systems used to measure the effects of anaesthetic and sedative drugs on the brain and to track changes in the patient's level of sedation and hypnosis. BIS monitoring provides information clinically relevant to the adjustment of dosages of sedating medication. It can help the nursing personnel in preventing under- and over sedation among intensive care unit (ICU) patients. OBJECTIVE: The present study was conducted to assess the knowledge of nursing personnel working in the ICU regarding BIS. METHODS: Fifty-four subjects participated in the study. A structured questionnaire was developed to assess the knowledge of the nursing personnel regarding BIS. Focus group discussions were held among the nursing personnel to know their views regarding BIS. RESULTS: Mean age (years) of the subjects was 30.7+/-7.19 (21-47) years, with a female preponderance. Although the use of BIS in ICU is not common, majority (94.44%) were aware of BIS and its purpose. 79.62% of the subjects knew about its implication in patient care. The mean knowledge score of the subjects was 11.87+/-2.43 (maximum score being 15). CONCLUSION: There exists an awareness among the critical care nursing staff in our institution regarding BIS and its clinical implications. Its use in the critical care setting may benefit the patients in terms of providing optimal sedation. PMID- 22223899 TI - The effects of N-acetylcysteine on hepatic function during isoflurane anaesthesia for laparoscopic surgery patients. AB - INTRODUCTION: Although most general anaesthesia procedures are performed without any complications, volatile agents may have adverse effects on various living systems. This study aims to compare the antioxidant effects of isoflurane and N acetylcysteine (NAC) on liver function. METHODS: Forty-one patients in the ASA I II risk groups, who were scheduled to undergo gynaecologic laparoscopy, were randomly divided into two groups: The placebo (group P, n=21) and the NAC group (group N, n=20). In both groups, anaesthesia was maintained with 1-2% isoflurane in 50% Oxygen-50% N(2)O at 6 l/min, also administered by inhalation. Venous blood samples were obtained before anaesthesia induction, and then in the postoperative 1(st) hour and at the 24(th) hour. The samples were centrifuged and serum levels of glutathione S-transferase (GST), malondialdehyde (MDA), aspartate amino transferase (AST), alanine amino transferase (ALT), lactate dehydrogenase (LDH), gamma glutamyltranspeptidase (GGT), prothrombin time (PT), activated partial thromboplastin time (aPTT) and international normalised ratio were determined. RESULTS: GST levels were significantly higher in group N than in group P in the postoperative 1(st) hour. Postoperative values of GST in the two groups were higher when compared to preoperative values (P<0.05). When postoperative levels were compared with preoperative levels, the postoperative MDA levels of group N were significantly higher (P<0.05). Levels of AST, ALT, GGT and LDH in both groups revealed significant decreases at the postoperative 1(st) hour and postoperative 24(th) hour compared to preoperative values (P<0.05, P<0.001). PT values were significantly higher in both groups in the postoperative 1(st) hour and 24(th) hour (P<0.05, P<0.001), although there were no differences in aPTT levels. CONCLUSION: Our results showed that liver functions were well preserved with administration of NAC during anaesthesia with isoflurane. Isoflurane with NAC has lesser effect on liver function tests compared to isoflurane alone. PMID- 22223900 TI - Changes in intraocular pressure following administration of suxamethonium and endotracheal intubation: Influence of dexmedetomidine premedication. AB - BACKGROUND: Use of suxamethonium is associated with an increase in intraocular pressure (IOP) and may be harmful for patients with penetrating eye injuries. The purpose of our study was to observe the efficacy of dexmedetomidine for prevention of rise in IOP associated with the administration of suxamethonium and endotracheal intubation. METHODS: Sixty-six American Society of Anaesthesiologists I or II patients undergoing general anaesthesia for non ophthalmic surgery were included in this randomized, prospective, clinical study. Patients were allocated into three groups to receive 0.4 MUg/kg dexmedetomidine (group D4), 0.6 MUg/kg dexmedetomidine (group D6) or normal saline (group C) over a period of 10 min before induction. IOP, heart rate and mean arterial pressure were recorded before and after the premedication, after induction, after suxamethonium injection and after endotracheal intubation. RESULTS: Fall in IOP was observed following administration of dexmedetomidine. IOP increased in all three groups after suxamethonium injection and endotracheal intubation, but it never crossed the baseline value in group D4 as well as in group D6. Fall in mean arterial pressure was noticed after dexmedetomidine infusion, especially in the D6 group. CONCLUSION: Dexmedetomidine (0.6 MUg/kg as well as 0.4 MUg/kg body weight) effectively prevents rise of IOP associated with administration of suxamethonium and endotracheal intubation. However, dexmedetomidine 0.6 MUg/kg may cause significant hypotension. Thus, dexmedetomidine 0.4 MUg/kg may be preferred for prevention of rise in IOP. PMID- 22223901 TI - A comparative study of infusions of phenylephrine, ephedrine and phenylephrine plus ephedrine on maternal haemodynamics in elective caesarean section. AB - INTRODUCTION: This randomized double blind study was started with an objective of management of spinal anaesthesia-induced hypotension in elective caesarean section by combining two commonly used vasopressors - ephedrine and phenylephrine in half of their usual doses with an expectation of reducing their foetomaternal side effects. METHODS: One hundred and thirty two patients were randomized into three groups to receive either 100 MUg/ml phenylephrine (group-P, n=31) or 3 MUg/ml ephedrine (group-E, n=33) or 50 mg phenylephrine plus 1.5 mg ephedrine/ml (group-PE, n=29). Immediately after spinal injection the study solution was started prophylactically in every patient at the rate of 40 ml/h. A predefined algorithm was used to adjust the infusion rate according to the systolic blood pressure (SBP). RESULTS: Mean fall of SBP was significantly more in group-E than group-P (P=0.009) and group-PE (P=0.013). This was not significantly different when compared between group-P and group-PE (P=0.9). Episodes of hypotension and tachycardia were more in group-E than the other two groups. Statistically significant tachycardia was seen in Group-E than that in other two groups. Incidence of bradycardia and hypertension did not differ significantly among the groups. Maternal nausea and Apgar score were also comparable in three groups. CONCLUSION: Current study claims that prophylactic phenylephrine 100 mg/ml is a better choice than ephedrine (3 mg/ml) or 50 mcg phenylephrine plus 1.5 mg ephedrine/ml in prevention of spinal anaesthesia-induced hypotension in elective caesarean section. Combination of two drugs in half the usual dose has no added advantage over phenylephrine, but this is better than ephedrine alone. PMID- 22223902 TI - Paravertebral block can be an alternative to unilateral spinal anaesthesia for inguinal hernia repair. AB - BACKGROUND: Inguinal hernia repair can be performed under satisfactory anaesthetic conditions using general, regional and peripheral nerve block anaesthesia. Unilateral spinal anaesthesia provides optimal anaesthesia, with stable haemodynamics and minimal adverse events. The paravertebral block, being segmental in nature, can be expected to produce some advantages regarding haemodynamic stability and early ambulation and may be a viable alternative. METHODS: Fifty-four consenting male patients posted for inguinal hernia repair were randomized into two groups, to receive either the two-segment paravertebral block (group-P, n=26) at T10 and L1 or unilateral spinal anaesthesia (group-S, n=28), respectively. The time to ambulation (primary outcome), time to the first analgesic, total rescue analgesic consumption in the first 24-hour period and adverse events were noted. RESULTS: Block performance time and time to reach surgical anaesthesia were significantly higher in the patients of group-P (P<0.001). Time to ambulation was significantly shorter in group-P compared to group-S (P<0.001), while postoperative sensory block was prolonged in patients of group-S; P<0.001. A significantly higher number of patients could bypass the recovery room in group-P compared to group-S, (45% versus 0%, respectively, P<0.001). No statistically significant difference in adverse outcomes was recorded. CONCLUSION: Both the paravertebral block and unilateral spinal anaesthesia are effective anaesthetic techniques for uncomplicated inguinal hernia repair. However, the paravertebral block can be an attractive alternative as it provides early ambulation and prolonged postoperative analgesia with minimal adverse events. PMID- 22223903 TI - Effect of tranexamic acid on blood loss and transfusion requirement in total knee replacement in the Indian population: A case series. AB - CONTEXT: Total knee replacement (TKR) is often carried out using a tourniquet to minimize intraoperative blood loss. However, its application enhances local fibrinolysis, resulting in excessive blood loss during the post-operative period. Fibrinolytic profile varies in different regions and races. Tranexamic acid has been shown to reduce post-operative blood loss and the need for transfusion in TKR. However, there is paucity of literature from the Indian population and the efficacy of the agent has not been tested in Indian patients undergoing TKR. AIMS: Effect of tranexamic acid on blood loss in TKR surgery in the Indian population. SETTING AND DESIGN: In this double-blinded study, 40 patients undergoing unilateral TKR were randomly divided into two groups. METHODS: All patients were conducted under spinal anaesthesia using injection bupivacaine 0.5% heavy 12-15 mg. The treatment group received 10 mg/kg tranexamic acid, intravenous (IV), half an hour before deflation of the tourniquet, with a second dose of 2 mg/kg administered 3 hours after the first dose. The exact protocol was followed for the placebo group, except that normal saline was used instead of tranexamic acid. Blood loss, blood transfusion details and change in haemoglobin levels were noted. STATISTICAL ANALYSIS: Student's paired 't' test was used in statistical analysis. RESULTS: The mean post-operative blood loss in the tranexamic acid group was 272.5+/-122.5 ml (mean+/-SD), and 685+/-118.2 ml in the placebo group (P<0.001). The total blood loss was lower in the tranexamic acid group than in the placebo group (427.6 ml vs. 911.6 ml; P<0.001). The absolute number of blood transfusions and the number of patients who required transfusions were lower in the tranexamic acid group than in the placebo group. None of the patients had any side or adverse effect. CONCLUSIONS: Tranexamic acid significantly decreases post-operative blood loss and reduces the need for blood transfusion in patients undergoing TKR. PMID- 22223904 TI - Incidence of bacteremia at the time of ICU admission and its impact on outcome. AB - CONTEXT: Blood culture is routinely taken at the time of admission to the intensive care unit (ICU) for patients suspected to have infection. We undertook this study to determine the incidence of bacteremia at the time of ICU admission and to assess its impact on the outcome. METHODS: Retrospective cohort study from all the admissions in ICU, in whom blood cultures sent at the time of admission were analyzed. Data regarding patient demographics, probable source of infection, previous antibiotic use and ICU course was recorded. Severity of illness on admission was assessed by acute physiology and chronic health evaluation II score. STATISTICAL ANALYSIS: Qualitative data were analyzed using Chi-square or Fisher Exact test and quantitative data were analyzed using Student's t-test. Primary outcome measure was ICU mortality. RESULTS: Of 567 patients, 42% patients were on antibiotics. Sixty-four percent of the patients were direct ICU admission from casualty, 10.76% were from wards and 6.17% from other ICUs, and 19.05% were transfers from other hospitals. Blood cultures were positive in 10.6% patients. Mortality was significantly higher in patients with positive blood cultures (45% vs. 13.6%; P=0.000). On univariate analysis, only previous antibiotic use was statistically associated with higher mortality (P=0.011). Bacteremic patients who were already on antibiotics had a significantly higher mortality (OR 12.9, 95% CI: 1.6-100). CONCLUSIONS: Blood cultures may be positive in only minority of the patients with suspected infection admitted to ICU. Nevertheless, the prognosis of those patients with positive blood culture is worse, especially if culture is positive in spite of the patient being on antibiotics. PMID- 22223906 TI - Anaesthetic management of a child with congenital afibrinogenemia - A rare inherited coagulation disorder. AB - Congenital afibrinogenemia is a very rare autosomal recessive disorder, results from mutation that affects plasma fibrinogen concentration. It is frequently associated with bleeding diathesis of varying severity. We describe the case of a 10-year-old child diagnosed of congenital afibrinogenemia who presented to hospital with subperiosteal haematoma and was posted for incision and drainage. Replacement therapy is the mainstay of treatment of bleeding episodes in this patient and plasma-derived fibrinogen concentrate is the agent of choice. Cryoprecipitate and fresh frozen plasma are alternative treatments. Appropriate amount of cryoprecipitate were transfused pre-operatively to the child. Individuals with congenital afibrinogenemia should be managed by a comprehensive bleeding disorder care team experienced in diagnosing and managing inherited bleeding disorders. Anaesthesiologist, surgeons and haematologist should work like a unit to manage the surgical emergencies. PMID- 22223905 TI - Applicability of different scoring systems in outcome prediction of patients with mixed drug poisoning-induced coma. AB - BACKGROUND: Mixed drugs poisoning (MDP) is common in the emergency departments. Because of the limited number of intensive care unit beds, recognition of risk factors to divide the patients into different survival groups is necessary. Poisoning due to ingestion of different medications may have additive or antagonistic effects on different parameters included in the scoring systems; therefore, the aim of the study was to compare applicability of the different scoring systems in outcomes prediction of patients admitted with MDP-induced coma. METHODS: This prospective, observational study included 93 patients with MDP-induced coma. Clinical and laboratory data conforming to the Acute Physiology and Chronic Health Evaluation (APACHE II), Modified APACHE II Score (MAS), Mainz Emergency Evaluation Scores (MEES) and Glasgow Coma Scale (GCS) were recorded for all patients on admission (time(0)) and 24 h later (time(24)). The outcome was recorded in two categories: Survived with or without complication and non survived. Discrimination was evaluated using receiver operating characteristic (ROC) curves and area under the ROC curve (AUC). RESULTS: The mortality rate was 9.7%. Mean of each scoring system was statistically significant between time(0) and time(24) in the survivors. However, it was not significant in non-survivors. Discrimination was excellent for GCS(24) (0.90+/-0.05), APACHE II(24) (0.89+/ 0.01), MAS(24) (0.86+/-0.10), and APACHE II(0) (0.83+/-0.11) AUC. CONCLUSION: The GCS(24), APACHE II(24), MAS(24), and APACHE II(0) scoring systems seem to predict the outcome in comatose patients due to MDP more accurately. GCS and MAS may have superiority over the others in being easy to perform and not requiring laboratory data. PMID- 22223907 TI - Prolonged postoperative desaturation in a child with Down syndrome and atrial septal defect. AB - We report prolonged desaturation in a child with Down syndrome (DS) and atrial septal defect due to undiagnosed interstitial lung disease. An 18-month-old child with DS was scheduled for bilateral lens aspiration for cataract. The child had atrial septal defect and hypothyroidism. He also had delayed milestones and hypotonia with episodes of recurrent respiratory tract infection necessitating repeated hospitalization. Preoperative evaluation was unremarkable. General anaesthesia and controlled ventilation using proseal laryngeal mask airway was instituted. He had uneventful intraoperative period. In the postoperative period, the child had desaturation 1 hour after surgery on discontinuation of oxygen supplementation by face mask, which improved with oxygen therapy. Supplemental oxygen via face mask was continued and weaned off over several days. On further evaluation, the child was diagnosed as having interstitial lung disease. He improved and discharged from the hospital 15 days after the surgery with room air saturation of 90%. PMID- 22223908 TI - Postoperative acute anisocoria and old traumatic brain injury. AB - Anisocoria is an uncommon entity in general postoperative intensive care. We present a case of a 45-year-old man suffering from severe acute pancreatitis with a past history of traumatic brain injury (TBI), who developed hypertension, bradycardia and anisocoria soon after re-exploration surgery under general anaesthesia. Computed tomography showed no new lesion. Measures directed towards reducing intracranial pressure resulted in amelioration in about 12h. The possible role of old TBI in the causation of anisocoria during general anaesthesia and resuscitation has been explored in this report. PMID- 22223909 TI - Anaesthetic management for emergency caesarean section in a patient with an untreated recently diagnosed phaeochromocytoma. AB - Phaeochromocytoma is a rare cause of hypertension during pregnancy with potentially fatal consequences. If not detected and treated early in pregnancy, it is catastrophic for both the mother and the baby. Management requires close co ordination between the obstetrician, anaesthesiologist, paediatrician and the endocrinologist. Perioperative management for an emergency caesarean section in a parturient with untreated phaeochromocytoma is an anaesthetic challenge and no standard recommendations have been reported till date. In this case report, we present anaesthetic management in such a case with successful maternal and foetal outcome. PMID- 22223910 TI - Anaesthetic management for caesarean section in a case of previously operated with residual pituitary tumour. AB - Successful anaesthetic management for caesarean section in a case with previous pituitary tumour resection, with residual tumour, is reported. The pituitary gland undergoes global hyperplasia during pregnancy. Functional pituitary tumours may exhibit symptomatic enlargement during pregnancy. Growth hormone secreting tumour is associated with acromegaly which has associated anaesthetic implications of difficult airway, systemic hypertension, and diabetes and electrolyte imbalance. Intracranial space occupying lesions can increase intra cranial pressure and compromise cerebral perfusion or cause herniation. We report management of this case. PMID- 22223911 TI - Emergency anaesthetic management of a severely anaemic, chronic schizophrenic patient with history of neuroleptic malignant syndrome. AB - Administering anaesthesia to a patient with chronic schizophrenia is a challenge due to the increased risk of various perioperative complications. Neuroleptic agents are highly effective drugs used for the treatment of psychiatric disorders, but are rarely associated with neuroleptic malignant syndrome (NMS). Here, we describe the successful anaesthetic management of a patient of chronic schizophrenia with past history of NMS who presented in emergency with active bleeding per rectum and haemoglobin of 3 gm%. PMID- 22223912 TI - Cystic hygroma: A difficult airway and its anaesthetic implications. AB - A 2-month-old child presented with gross and huge swelling on the left side of the neck with difficulty in feeding. It was diagnosed to be cystic hygroma and a decision was made to excise the swelling to enable the child thrive better. Difficult intubation was anticipated and the child was intubated with inhalation induction. The intra-operative period was smooth and the tumour was excised completely. Post-operatively, it was decided to ventilate the child because of airway difficulties. PMID- 22223913 TI - Catastrophic complication - Bezold-Jarisch reflex: Case series. PMID- 22223914 TI - Mortality in hydatidiform mole: Should we blame thyroid? PMID- 22223915 TI - A rare complication of epidural anaesthesia a case report with brief review of literature. PMID- 22223916 TI - Anaphylaxis with midazolam - Our experience. PMID- 22223917 TI - Late and acute reaction to iohexol, refractory to treatment. PMID- 22223918 TI - Acute normovolaemic haemodilution and autotransfusion in neurosurgical patients. PMID- 22223919 TI - Burn injury by displacement of electrocautery plate. PMID- 22223920 TI - A case of breakage of LMA Supreme on its first use. PMID- 22223921 TI - Bronchial blocker for one-lung ventilation: An unanticipated complication. PMID- 22223922 TI - Airway obstruction by round worm in mechanically ventilated patient: An unusual cause. PMID- 22223923 TI - Dangerous sedation in an obese patient. PMID- 22223925 TI - Prosody and Syntax in Sign Languages. PMID- 22223924 TI - Civic Returns to Higher Education: A Note on Heterogeneous Effects. AB - American educational leaders and philosophers have long valued schooling for its role in preparing the nation's youth to be civically engaged citizens. Numerous studies have found a positive relationship between education and subsequent civic participation. However, little is known about possible variation in effects by selection into higher education, a critical omission considering education's expressed role as a key mechanism for integrating disadvantaged individuals into civic life. I disaggregate effects and examine whether civic returns to higher education are largest for disadvantaged low likelihood or advantaged high likelihood college goers. I find evidence for significant effect heterogeneity: civic returns to college are greatest among individuals who have a low likelihood for college completion. Returns decrease as the propensity for college increases. PMID- 22223926 TI - THE PARADOX OF SIGN LANGUAGE MORPHOLOGY. AB - Sign languages have two strikingly different kinds of morphological structure: sequential and simultaneous. The simultaneous morphology of two unrelated sign languages, American and Israeli Sign Language, is very similar and is largely inflectional, while what little sequential morphology we have found differs significantly and is derivational. We show that at least two pervasive types of inflectional morphology, verb agreement and classifier constructions, are iconically grounded in spatiotemporal cognition, while the sequential patterns can be traced to normal historical development. We attribute the paucity of sequential morphology in sign languages to their youth. This research both brings sign languages much closer to spoken languages in their morphological structure and shows how the medium of communication contributes to the structure of languages. PMID- 22223927 TI - The gradual emergence of phonological form in a new language. AB - The division of linguistic structure into a meaningless (phonological) level and a meaningful level of morphemes and words is considered a basic design feature of human language. Although established sign languages, like spoken languages, have been shown to be characterized by this bifurcation, no information has been available about the way in which such structure arises. We report here on a newly emerging sign language, Al-Sayyid Bedouin Sign Language, which functions as a full language but in which a phonological level of structure has not yet emerged. Early indications of formal regularities provide clues to the way in which phonological structure may develop over time. PMID- 22223928 TI - High Hostility Among Smokers Predicts Slower Recognition of Positive Facial Emotion. AB - High levels of trait hostility are associated with wide-ranging interpersonal deficits and heightened physiological response to social stressors. These deficits may be attributable in part to individual differences in the perception of social cues. The present study evaluated the ability to recognize facial emotion among 48 high hostile (HH) and 48 low hostile (LH) smokers and whether experimentally-manipulated acute nicotine deprivation moderated relations between hostility and facial emotion recognition. A computer program presented series of pictures of faces that morphed from a neutral emotion into increasing intensities of happiness, sadness, fear, or anger, and participants were asked to identify the emotion displayed as quickly as possible. Results indicated that HH smokers, relative to LH smokers, required a significantly greater intensity of emotion expression to recognize happiness. No differences were found for other emotions across HH and LH individuals, nor did nicotine deprivation moderate relations between hostility and emotion recognition. This is the first study to show that HH individuals are slower to recognize happy facial expressions and that this occurs regardless of recent tobacco abstinence. Difficulty recognizing happiness in others may impact the degree to which HH individuals are able to identify social approach signals and to receive social reinforcement. PMID- 22223929 TI - Multi-energy CT based on a prior rank, intensity and sparsity model (PRISM). AB - We propose a compressive sensing approach for multi-energy computed tomography (CT), namely the prior rank, intensity and sparsity model (PRISM). To further compress the multi-energy image for allowing the reconstruction with fewer CT data and less radiation dose, the PRISM models a multi-energy image as the superposition of a low-rank matrix and a sparse matrix (with row dimension in space and column dimension in energy), where the low-rank matrix corresponds to the stationary background over energy that has a low matrix rank, and the sparse matrix represents the rest of distinct spectral features that are often sparse. Distinct from previous methods, the PRISM utilizes the generalized rank, e.g., the matrix rank of tight-frame transform of a multi-energy image, which offers a way to characterize the multi-level and multi-filtered image coherence across the energy spectrum. Besides, the energy-dependent intensity information can be incorporated into the PRISM in terms of the spectral curves for base materials, with which the restoration of the multi-energy image becomes the reconstruction of the energy-independent material composition matrix. In other words, the PRISM utilizes prior knowledge on the generalized rank and sparsity of a multi-energy image, and intensity/spectral characteristics of base materials. Furthermore, we develop an accurate and fast split Bregman method for the PRISM and demonstrate the superior performance of the PRISM relative to several competing methods in simulations. PMID- 22223930 TI - DEEP-differential evolution entirely parallel method for gene regulatory networks. AB - The Differential Evolution Entirely Parallel (DEEP) method is applied to the biological data fitting problem. We introduce a new migration scheme, in which the best member of the branch substitutes the oldest member of the next branch that provides a high speed of the algorithm convergence. We analyze the performance and efficiency of the developed algorithm on a test problem of finding the regulatory interactions within the network of gap genes that control the development of early Drosophila embryo. The parameters of a set of nonlinear differential equations are determined by minimizing the total error between the model behavior and experimental observations. The age of the individuum is defined by the number of iterations this individuum survived without changes. We used a ring topology for the network of computational nodes. The computer codes are available upon request. PMID- 22223931 TI - Tough decisions. PMID- 22223933 TI - Case report: Isolated unilateral pulmonary vein atresia diagnosed on 128-slice multidetector CT. AB - Unilateral pulmonary venous atresia is an uncommon entity that is generally believed to be congenital. Most patients present in infancy or childhood with recurrent chest infections or hemoptysis. Pulmonary angiography is usually used for definitive diagnosis. However, the current multislice CT scanners may obviate the need for pulmonary angiography. We report two cases diagnosed using 128-slice CT angiography. On the CT angiography images both these cases demonstrated absent pulmonary veins on the affected side, with a small pulmonary artery and prominent bronchial or other systemic arterial supply. PMID- 22223932 TI - Pictorial essay: Allergic bronchopulmonary aspergillosis. AB - Allergic bronchopulmonary aspergillosis (ABPA) is the best-known allergic manifestation of Aspergillus-related hypersensitivity pulmonary disorders. Most patients present with poorly controlled asthma, and the diagnosis can be made on the basis of a combination of clinical, immunological, and radiological findings. The chest radiographic findings are generally nonspecific, although the manifestations of mucoid impaction of the bronchi suggest a diagnosis of ABPA. High-resolution CT scan (HRCT) of the chest has replaced bronchography as the initial investigation of choice in ABPA. HRCT of the chest can be normal in almost one-third of the patients, and at this stage it is referred to as serologic ABPA (ABPA-S). The importance of central bronchiectasis (CB) as a specific finding in ABPA is debatable, as almost 40% of the lobes are involved by peripheral bronchiectasis. High-attenuation mucus (HAM), encountered in 20% of patients with ABPA, is pathognomonic of ABPA. ABPA should be classified based on the presence or absence of HAM as ABPA-S (mild), ABPA-CB (moderate), and ABPA-CB HAM (severe), as this classification not only reflects immunological severity but also predicts the risk of recurrent relapses. PMID- 22223934 TI - Bilateral hypoplasia of the internal carotid artery. AB - Agenesis and hypoplasia of the internal carotid artery (ICA) are rare congenital anomalies, occurring in less than 0.01% of the population. We report a rare case of bilateral hypoplasia of the ICA in a patient with post-traumatic subarachnoid hemorrhage. We describe the embryological development of the cerebral vasculature and present a review of literature. PMID- 22223935 TI - MRI findings in cranial eumycetoma. AB - Cranial eumycetoma (CE) due to direct inoculation of Madurella grisea into the scalp is extremely rare. We describe a case of CE caused by direct inoculation of M. grisea with the characteristic MRI findings of the "dot-in-circle" sign and a conglomeration of multiple, extremely hypointense "dots." PMID- 22223936 TI - Case report: Dot-in-circle sign - An MRI and USG sign for "Madura foot". AB - Mycetoma is a chronic granulomatous disease that is more common in tropical than in temperate regions. Early diagnosis is important due to the therapeutic implications. Although biopsy and microbiological culture provide definitive diagnosis, they are time-consuming procedures and may not be able to provide a definite diagnosis in cases of fastidious organisms. The "dot-in-circle" sign has recently been proposed as a highly specific magnetic resonance imaging (MRI) and ultrasonography (USG) sign of mycetoma, which may allow a noninvasive as well as early diagnosis. We present a case of histologically proven mycetoma that demonstrated this sign. PMID- 22223937 TI - Technical note: Real-time sonoelastography evaluation of Achilles tendon. AB - Sonoelastography (SE) is a new USG-based technique that is being used to assess the elasticity and pliability of various tissues and lesions. We evaluated normal and abnormal Achilles tendons and correlated SE findings with those of high resolution USG. This article briefly discusses the principle and technique of sonoelastography and the variations in elasticity and pliability between normal and abnormal Achilles tendons. PMID- 22223938 TI - Presacral hibernoma: Radiologic-pathologic correlation. AB - Hibernoma is a rare benign tumor of brown fat origin. It is found in locations where brown adipose tissue is present in the fetus. These locations include the neck, axilla, thorax, and extremities. Retroperitoneal hibernoma is an extremely rare site of presentation. We present a rare case of presacral hibernoma. Preoperative embolization of this highly vascular tumor was performed. To the best of our knowledge, this is the first reported case of a presacral hibernoma in the English literature. PMID- 22223939 TI - Lesions in the external auditory canal. AB - The external auditory canal is an S- shaped osseo-cartilaginous structure that extends from the auricle to the tympanic membrane. Congenital, inflammatory, neoplastic, and traumatic lesions can affect the EAC. High-resolution CT is well suited for the evaluation of the temporal bone, which has a complex anatomy with multiple small structures. In this study, we describe the various lesions affecting the EAC. PMID- 22223940 TI - Ultrasonography with color Doppler and power Doppler in the diagnosis of periapical lesions. AB - AIM: To evaluate the efficacy of ultrasonography (USG) with color Doppler and power Doppler applications over conventional radiography in the diagnosis of periapical lesions. MATERIALS AND METHODS: Thirty patients having inflammatory periapical lesions of the maxillary or mandibular anterior teeth and requiring endodontic surgery were selected for inclusion in this study. All patients consented to participate in the study. We used conventional periapical radiographs as well as USG with color Doppler and power Doppler for the diagnosis of these lesions. Their diagnostic performances were compared against histopathologic examination. All data were compared and statistically analyzed. RESULTS: USG examination with color Doppler and power Doppler identified 29 (19 cysts and 10 granulomas) of 30 periapical lesions accurately, with a sensitivity of 100% for cysts and 90.91% for granulomas and a specificity of 90.91% for cysts and 100% for granulomas. In comparison, conventional intraoral radiography identified only 21 lesions (sensitivity of 78.9% for cysts and 45.4% for granulomas and specificity of 45.4% for cysts and 78.9% for granulomas). There was definite correlation between the echotexture of the lesions and the histopathological features except in one case. CONCLUSIONS: USG imaging with color Doppler and power Doppler is superior to conventional intraoral radiographic methods for diagnosing the nature of periapical lesions in the anterior jaws. This study reveals the potential of USG examination in the study of other jaw lesions. PMID- 22223941 TI - Case Report: Acute tuberculous laryngitis presenting as acute epiglottitis. AB - The incidence of laryngeal tuberculosis (TB), which had dropped dramatically after the institution of modern anti-TB chemotherapy, has shown recent reemergence. It is important to be aware of its possibility, especially as it can present with nonspecific upper airway symptoms and a frequent lack of constitutional manifestations. We report such a case presenting as acute epiglottitis, with diffuse involvement of the supraglottic larynx associated with reactivation lung TB. PMID- 22223942 TI - Case report: Periorbital intraosseous hemangiomas. AB - Hemangiomas are hamartomatous proliferation of vessels. Intraosseous hemangiomas of the facial bones are rare and most commonly involve the zygoma, maxilla, mandible, and the nasal bones. A "sunburst" pattern is a typical appearance on CT scan and MRI and therefore a biopsy is not always necessary. Surgery is usually performed in symptomatic cases. The authors describe five typical periorbital intraosseous hemangiomas with a brief review of literature. PMID- 22223943 TI - Measurement of hepatic venous pressure gradient revisited: Catheter wedge vs balloon wedge techniques. AB - AIMS: To evaluate the accuracy of measurement of hepatic venous pressure gradient by catheter wedge as compared to balloon wedge (the gold standard). MATERIALS AND METHODS: Forty-five patients having a clinical diagnosis of intrahepatic portal hypertension were subjected to the two different types of pressure measurements (catheter wedge and balloon wedge) during transjugular liver biopsy under fluoroscopic guidance. STATISTICAL ANALYSIS: Spearman's rank correlation coefficient, Bland-Altman plot for agreement, and single measure intraclass correlation were used for analysis of data. RESULTS: There was a close correlation between the results obtained by both the techniques, with highly significant concordance (P < 0.0001). Hepatic venous pressure gradients as measured by the catheter wedge technique were either equal to or less than those obtained by the balloon wedge technique. CONCLUSIONS: The difference in hepatic venous pressure gradients measured by the two techniques is insignificant. PMID- 22223944 TI - Decision making in the treatment of peripheral arterial disease - A single institution comparative study using information from color doppler and digital subtraction angiogram studies. AB - BACKGROUND: Numerous studies have compared the accuracy of color Doppler (CD) with that of digital subtraction angiography (DSA) in the diagnosis of peripheral arterial disease (PAD). However, only a few have looked at the influence of these diagnostic tests on the treatment decision in PAD. AIM: This study evaluated the differences in treatment decisions that were based on CD and with those based on DSA findings. METHODS AND MATERIALS: Findings from CD and DSA studies obtained in 40 patients were entered on line diagrams by two radiologists working separately. These were randomized and sent to three experienced clinicians - two vascular surgeons and one interventional radiologist. The treatment decisions of the clinicians based on each proforma were collected and analyzed to look for the degree of agreement between Doppler-based and DSA-based decisions. RESULTS: There was fair to moderate agreement between CD-based and DSA-based decisions for all three clinicians, with some improvement in agreement with the addition of clinical data. The vascular surgeons showed better agreement with each other on treatment decisions compared to the interventional radiologist who showed a fair to-moderate level of agreement with the vascular surgeons, which did not significantly change with the addition of clinical data. CONCLUSION: There is a fair to moderate agreement between treatment decisions based on CD findings and those based on DSA findings. We conclude that CD along with clinical data is sufficient to make decisions in the treatment of PAD. PMID- 22223945 TI - Management of empyema of gallbladder with percutaneous cholecysto-duodenal stenting in a case of hilar cholangiocarcinoma treated with common bile duct metallic stenting. AB - Empyema of the gallbladder develops when the gallbladder neck is obstructed in the presence of infection, preventing pus from draining via the cystic duct. Treatment options include cholecystectomy or, in patients with comorbidities, drainage via percutaneous cholecystostomy, later followed by cholecystectomy. Here, we describe a 59-year-old man who presented with complaints of recurrent hiccups and was found to have cholangiocarcinoma causing obstruction to cystic duct drainage. The patient was managed successfully by percutaneous transhepatic cholecysto-duodenal self-expandable covered metal stent. PMID- 22223946 TI - Differential diagnosis of breast lesions using ultrasound elastography. AB - CONTEXT: The recent introduction of elastography has increased the specificity of USG and enabled early diagnosis of breast cancer. Quantitative elastography, especially with strain ratio (SR) index, improves diagnostic accuracy and decreased number of biopsies. AIMS: The purpose of this study was to assess the role of USG elastography in the differential diagnosis of breast lesions. SETTINGS AND DESIGN: This prospective study was conducted in the University of Medicine and Pharmacy Research Centre of Craiova. MATERIALS AND METHODS: Fifty eight patients diagnosed with breast lesions between January 2009 and January 2010 were included in this prospective study. All the patients were examined in the supine position, and the B-mode USG image was displayed alongside the elastography strain image. For obtaining the elastography images we used a EUS Hitachi EUB 8500 ultrasound system with a 6.5-MHz linear probe. The elastography strain images were scored according to the Tsukuba elasticity score. STATISTICAL ANALYSIS: We performed receiver operator characteristic (ROC) analysis for assessment of the role of USG elastography in the diagnosis of breast lesions. RESULTS: We obtained a sensitivity of 86.7% and a specificity of 92.9% for elasticity score and a sensitivity of 93.3% and a specificity of 92.9% for SR (when a cutoff point of 3.67 was used). There was very good correlation between SR and elasticity score (Spearman coefficient of 0.911). CONCLUSIONS: Elastography is a fast, simple method that can complement conventional USG examination. This method has the lowest cost/efficiency ratio and it is also the most noninvasive and accessible imaging method, with an accuracy comparable to MRI. PMID- 22223948 TI - Use of 3D CISS as part of a routine protocol for the evaluation of intracranial granulomas. PMID- 22223947 TI - Case report: Calcifying fibrous tumor presenting as an asymptomatic pelvic mass. AB - Calcifying fibrous tumor (CFT) is a rare benign mesenchymal tumor most commonly found in the soft tissues of the extremities and pleura. It is characterized by hyalinized collagenous fibrous tissue, with bland spindle cells, psammomatous or dystrophic calcifications, and focal lymphoplasmacytic infiltrate. CFT of the gastrointestinal tract is exceedingly uncommon. We report a case of CFT arising from the small intestine and associated mesentery; this case was identified incidentally in an otherwise healthy 45-year-old man. PMID- 22223949 TI - Occupational health practice: Need of the hour - training and accreditation. PMID- 22223950 TI - Occupational risk assessment of paint industry workers. AB - BACKGROUND: Thousands of chemical compounds are used in paint products, like pigments, extenders, binders, additives, and solvents (toluene, xylene, ketones, alcohols, esters, and glycol ethers). Paint manufacture workers are potentially exposed to the chemicals present in paint products although the patterns and levels of exposure to individual agents may differ from those of painters. The aim of the present study was to evaluate genome damage induced in peripheral blood lymphocytes and oral mucosa cells of paint industry workers. MATERIALS AND METHODS: Genotoxicity was evaluated using the alkaline Comet assay in blood lymphocytes and oral mucosa cells, and the Micronucleus test in oral mucosa cells. For the micronucleus test in exfoliated buccal cells, no significant difference was detected between the control and paint industry workers. RESULTS: The Comet assay in epithelia buccal cells showed that the damage index (DI) and damage frequency (DF) observed in the exposed group were significantly higher relative to the control group (P<=0.05). In the same way, the Comet assay data in peripheral blood leukocytes showed that both analysis parameters (DI and DF) were significantly greater than that for the control group (P<=0.05). CONCLUSIONS: Chronic occupational exposure to paints may lead to a slightly increased risk of genetic damage among paint industry workers. PMID- 22223952 TI - Adaptation cost of diarrhea and malaria in 2030 for India. AB - BACKGROUND: Climate change is significant and an emerging threat to public health. The climate change-related health consequences of diarrheal diseases and malaria are projected to pose the largest risks to future populations. This study provides an initial estimate of the cost of intervention to cope with the health impacts of climate change in 2030 on diarrhea and malaria for India. MATERIALS AND METHODS: The costs of treating diarrheal diseases and malaria in 2030 were estimated under three climate scenarios using: (1) the current numbers of cases; (2) the projected relative risks of these diseases in 2030; and (3) current treatment costs. The analysis assumed that the number of annual cases and costs of treatment would remain constant. There was limited consideration for population growth and socioeconomic development. RESULTS: Underscenario assuming emissions reduction resulting in stabilization at 750 ppm CO(2) equivalent in 2210, the costs of treating diarrheal diseases and malaria were estimated to be between Rs. 3648 lakhs and Rs. 7787 lakhs. The Mitigation scenario results in fewer cases and lower investment needs than the BAU scenario. For the middle scenario, the annual needs are about Rs. 1036 lakhs per year, lower from Rs. 4684 lakhs down to Rs. 3648 lakhs. Should the high scenario occur, the annual investment needs are about Rs. 3901 lakhs lower from the BAU to the Mitigation scenario. CONCLUSION: The adaptation and mitigation can reduce sensitivity to climate change. The case for making public expenditures is strong on economic and moral grounds because the costs without interventions are much higher if we consider the relative risk of these diseases. PMID- 22223951 TI - Musculoskeletal pain and its associated risk factors in residents of National Capital Region. AB - BACKGROUND: Musculoskeletal (MS) pain is responsible for poor quality of life and decreased productivity. Objective information about the burden of musculoskeletal disorders among the general community in India is scanty, and the few reports that exist are based on a small sample size. MATERIALS AND METHODS: This paper examines the issue of MS pain and its associated risk factors in a cross sectional study of 2086 subjects from National Capital Region (NCR). RESULTS: Overall prevalence of MS pain was found to be 25.9%. Pain was found to be more frequent among females (31.3%) as compared with males (20.9%). Significant association of pain in joints/limbs/knee/lower legs with obesity (OR = 2.1, P < 0.001) and high body fat (OR = 2.2, P < 0.001) was established. More than 50% of the subjects complained of backache. CONCLUSIONS: Our findings confirm that MS pain is a significant burden of disease among the residents of NCR. Women and subjects doing heavy work load, like agriculture and dairy farming, constitute the chief demographic groups. It is high time that a policy is framed to reduce this load of sickness. PMID- 22223953 TI - Smoking ban and indoor air quality in restaurants in Mumbai, India. AB - BACKGROUND: Second-hand smoke contains several toxic chemicals that are known to pollute the air and harm people's health. In India, smoking in public places has been prohibited since October 2008 as a way to reduce second-hand smoke (SHS) exposure. The purpose of the present study was to assess the implementation of smoke-free policies and its impact on indoor air quality by measuring the PM(2.5) levels in bars and restaurants, restaurants, country liquor bars, hookah restaurants and pubs in Mumbai. MATERIALS AND METHODS: Air quality measurements at 50 venues were conducted by using a "SIDEPAK(TM) AM510 Personal Aerosol Monitor" during April to May 2009. Average concentration of PM(2.5) (MUg/m(3)) particles was calculated separately for each venue. RESULTS: Smoking was observed in 36% of the surveyed venues during an hour of data collection. The PM(2.5) levels ranged from 16.97 to 1101.76 MUg/m(3). The average level of PM(2.5) among non-smoking venues was 97.19 MUg/m(3) and among smoking venues was 363.04 MUg/m(3). CONCLUSION: Considerable scope for improvement in implementation of smoke-free policies exists. The PM(2.5) levels were exceedingly high in venues where smoking was observed. PMID- 22223954 TI - Environmental health impact assessment of National Aluminum Company, Orissa. AB - Environmental Health Impact Assessment of industries is an important tool help decision-makers make choices about alternatives and improvements to prevent disease/injury and to actively promote health around industrial sites. A rapid environmental health hazard and vulnerability assessment of National Aluminum Company was undertaken in the villages in the vicinity plant in Angul region of Orissa. Aluminum smelter plant was known to discharge hundreds of tones of fluoride in to the environment contaminating the ecosystem around the plant. The present Environmental health impact assessment was carried out in 2005-06 at the request of officials from Government of Orissa. The findings showed adverse effects on human, veterinary and ecological health. Human health effects manifestations included dental and skeletal fluorosis. Veternary health effects were manifested through skeletal fluorosis. Ecological adverse effects were manifested by damage to paddy fields and crop yield. PMID- 22223955 TI - Some initiatives for promoting environmental sanitation in India. PMID- 22223956 TI - We are what we breathe! PMID- 22223957 TI - Is removal of clavicle plate after fracture union necessary? AB - PURPOSE: To review whether clavicle plates should be removed after union of the fracture. MATERIALS AND METHODS: 48 patients with middle third clavicle fractures treated by plating were assessed with UCLA shoulder rating and Oxford shoulder scores. RESULTS: At an average follow up of 13 months,96% of 27 patients with plates out recommended its removal. 86% of 21 patients with plates in were happy to keep them. CONCLUSIONS: We recommend leaving clavicle plates in unless requested by the patient. LEVEL OF EVIDENCE: IV-retrospective study. PMID- 22223958 TI - The frequency of subscapularis tears in arthroscopic rotator cuff repairs: A retrospective study comparing magnetic resonance imaging and arthroscopic findings. AB - PURPOSE: With the advent of arthroscopic shoulder surgery the comprehension and description of rotator cuff tears have strongly evolved. Subscapularis tears are difficult to recognize and are underestimated. Our purpose is to report our observations concerning the relative frequency of subscapularis tears in patients undergoing arthroscopic rotator cuff repair and to compare the arthroscopic observations with the magnetic resonance imaging (MRI) findings. MATERIALS AND METHODS: Retrospective cohort study including all patients undergoing arthroscopic rotator cuff repair was performed between March 2006 and March 2009 at our institution. Preoperative MRI findings, intraoperative arthroscopic findings, and details of surgical intervention were collected using medical charts. RESULTS: We reviewed the medical charts of a total of 348 consecutive arthroscopic rotator cuff repairs. There were 311 supraspinatus tears (89%), 48 infraspinatus tears (14%), and 129 subscapularis tears (37%). MRI sensitivity and specificity were respectively 0.25 and 0.98 for subscapularis tendon tears, 0.67 and 1.0 for supraspinatus tears and 0.5 and 0.99 for infraspinatus tears. CONCLUSION: Subscapularis tears are frequent lesions and usually appear concomitantly with supra or infraspinatus lesions. We propose a classification of subscapularis tendon tears, based on our observations of the pathoanatomy of the tears. While concordance with MRI results are good for the supraspinatus, MRI often fails to diagnose the presence of subscapularis tears and infraspinatus tears. PMID- 22223959 TI - Latissimus dorsi tendon transfers for rotator cuff deficiency. AB - PURPOSE: Latissimus dorsi tendon transfers are increasingly being used around the shoulder. We aim to assess any improvement in pain and function following a latissimus dorsi tendon transfer for massive, irreparable postero-superior cuff deficiency. MATERIALS AND METHODS: At our institution, between 1996 and 2009, 38 latissimus dorsi tendon transfer procedures were performed. Sixteen of these were for massive irreparable rotator cuff deficiency associated with pain and impaired function. All patients were evaluated by means of interview or postal questionnaire and case note review. Pain and function were assessed using the Stanmore percentage of normal shoulder assessment (SPONSA) score, visual analogue scale and Oxford Shoulder Score. Forward elevation was also assessed and a significant improvement was thought to correlate with the success of the procedure at stabilizing the humeral head upon elevation. RESULTS: Mean follow-up time was 70 months. There was a significant reduction in pain on the visual analogue scale from 6.4 to 3.4 (P < 0.05), an improved SPONSA score from 32.5 to 57.5 (P < 0.05), and an improved Oxford Shoulder Score from 40.75 to 29.6 (P < 0.05). Forward elevation improved from 40 degrees preoperatively to 75 degrees postoperatively (P < 0.05). CONCLUSION: Our results add to the body of evidence that latissimus dorsi tendon transfers for irreparable postero-superior cuff deficiency in selected patients reduce pain and improve shoulder function in the medium term. LEVEL OF EVIDENCE: Level 4. PMID- 22223960 TI - Distal clavicle osteolysis following fixation with a synthetic ligament. AB - We present a case of distal clavicle osteolysis following treatment of a chronic acromioclavicular joint dislocation with a synthetic ligament. The relevant literature is reviewed and discussed. PMID- 22223961 TI - Combining of small fragment screws and large fragment plates for open reduction and internal fixation of periprosthetic humeral fractures. AB - Operative treatment of periprosthetic humeral fractures in elderly patients with osteoporotic bone requires a stable fixations technique. The combination of 3.5 cortical screws with washers in a 4.5 Arbeitsgemeinschaft fur Osteosynthesefragen, Limited-contact dynamic compression plate or Locking plate, allows a stable periprosthetic fixation with the small 3.5 screws and 4.5 screws above and below the prosthesis, respectively. This combination is a cost effective technique to treat periprosthetic humeral fractures. PMID- 22223962 TI - Human hair - an evolutionary relic? PMID- 22223963 TI - Meeting report: the 15 annual meeting of The European Hair Research Society. PMID- 22223964 TI - 16 annual meeting of The European Hair Research Society, Barcelona. PMID- 22223965 TI - "Free full text articles": where to search for them? AB - References form the backbone of any medical literature. Presently, because of high inflation, it is very difficult for any library/organization/college to purchase all journals. The condition is even worse for an individual person, such as private practitioners. The solution lies in the free availability of full-text articles. Here, the authors share their experiences about the accessibility of free full-text articles. PMID- 22223966 TI - Extensive alopecia areata: not necessarily recalcitrant to therapy! AB - BACKGROUND: Extensive alopecia areata includes alopecia universalis, alopecia totalis, ophiasis and patients having more than 50% scalp involvement. Alopecia universalis (AU) and totalis (AT) are considered to be resistant to single modalities of treatment. Our study highlights the efficacy and safety of combination therapy in extensive alopecia areata. AIM: To evaluate the efficacy and safety of a combination treatment with oral bethametasone mini-pulse, topical minoxidil and short contact anthralin in long-standing, treatment-resistant, extensive alopecia areata. MATERIALS AND METHODS: Fifteen patients aged 7 to 45 years with extensive, treatment-resistant alopecia areata (AU: 7; AT: 1; ophiasis: 4; patients with more than 50% scalp involvement: 3) were treated with betamethasone oral mini-pulse (0.1 mg per kg body weight per dose on two consecutive days per week) along with short contact anthralin (1.15%) and 2-5% minoxidil lotion daily, till response. The response was assessed by the severity of alopecia tool (SALT) score. Cosmetic response was defined as regrowth obviating the need of a wig. Failure of treatment was defined as no growth or vellus hair on the scalp. RESULTS: Out of eight patients with AU/AT, two attained cosmetic response as early as three months, two at six months and one had partial response. Cosmetic response was attained in all four patients with ophiasis and all three patients with more than 50% scalp involvement at six months. All responders maintained their response without systemic steroids beyond 12 months. Among a total of twelve responders (80%), two with AU showed a mild relapse and were effectively treated with intralesional steroids. Side effects to therapy were mild and reversible. CONCLUSION: A combination therapy of oral steroid minipulse with topical anthralin and minoxidil acts synergistically, being effective as well as safe in treatment-resistant, extensive, long-standing alopecia areata. PMID- 22223967 TI - The role of bimatoprost eyelash gel in chemotherapy-induced madarosis: an analysis of efficacy and safety. AB - OBJECTIVES: Breast cancer patients suffer from madarosis (loss of eyelashes) due to chemotherapy side effects. An effective treatment or prevention for alopecia or madarosis induced by chemotherapy is not available. Potential drug side effects of bimatoprost solution include increased eyelash length, darkness, and number. A formulation of bimatoprost which maximizes eyelash enhancement and minimizes intraocular and systemic side effects has not been reported. MATERIALS AND METHODS: An Institutional Review Board (IRB) and Investigational New Drug (IND) approved, randomized, single-blinded, prospective, internally controlled trial compared bimatoprost eyelash gel in relation to eyelash enhancement of madarosis patients. Forty eyelids of 20 chemotherapy-treated breast cancer patients were randomized to treatment or control (fellow eyelid). Both patient and surgeon (blindly) evaluated bimatoprost gel's effectiveness in improving eyelash appearance at baseline and at monthly intervals. RESULTS: The median follow-up time was 3 months (range 1-4). There was a significant difference between treated and fellow eyelash length during month 2 [1.00 mm (P=0.004)] and month 3 [1.00 mm, P=0.02)], in eyelash pigment [month 1 (2.5, P=0.04); month 2 (2, P=0.0009); month 3 (3, P=0.06)] and thickness [month 2 (2, P=0.002); month 3 (3, P=0.01)]. There was an improvement in the patient satisfaction scale from baseline 16 (median, range 7-21) to 26 (median, range 17-33, P=0.002) at last follow-up. CONCLUSIONS: Bimatoprost eyelash gel appears promising for chemotherapy-induced madarosis. Patients may find the effects restorative and cosmetically enhancing. PMID- 22223969 TI - Practicality in using diphenyl cyclo propenone for alopecia areata. AB - Diphenyl cyclo propenone (DPCP) is used as a topical immunomodulator in alopecia areata. It is a potent allergen. The process of procuring, dilution and application limits its wider use. This short communication aims to make the DPCP application easy to use. PMID- 22223968 TI - Treatment of pseudofolliculitis in trichotillomania improves outcome. AB - Trichotillomania is an impulse-control disorder. The underlying psychiatric comorbidity or functional impairment is well recognized by clinicians. Patients with trichotillomania pull their scalp hairs, resulting in damaged, distorted hair follicles, and broken hair shafts within the skin. The local irritation and inflammation resulting from reaction to the broken, impacted hair shafts and malaligned regrowing hair can lead to pseudofolliculitis, much the same as a patient who waxes or shaves her legs gets itchy papules of pseudofolliculitis. Pseudofolliculitis becomes an organic reason for scalp itch and discomfort, and contributes further to the vicious cycle of itch and scratching in trichotillomania. This phenomenon has not been well documented. Treatment of trichotillomania would be more effective if the pseudofolliculitis component is addressed. We describe a series of patients with trichotillomania and pseudofolliculitis. These patients improved after topical steroid therapy, topical or oral antibiotics. Hair regrowth was also visibly better, with patients reporting improvement of symptoms of itch. All these patients were not placed on antidepressants nor antipsychotics. PMID- 22223970 TI - Low-grade malignant proliferating pilar tumor simulating a squamous-cell carcinoma in an elderly female: a case report and immunohistochemical study. AB - A 65-year-old lady presented with an ulcerated lesion over the occipital region of nine-year duration, an incisional biopsy of which was reported as squamous cell carcinoma. A wide local excision was performed and the tissue was sent for histopathological examination which revealed a low-grade malignant pilar tumor. Focal invasion and atypia were noted. Immunohistochemical (IHC) analysis revealed positivity for CD34 and calretinin immunomarkers favoring outer root sheath origin. Ki67 immunostains revealed a relatively low immunoreactivity indicating the low-grade nature of the tumor; however, p53 immunostain showed strong diffuse nuclear staining confirming the malignant nature of the tumor. Proliferating pilartumors (PPT) are rare tumors and less than 100 well-documented cases of malignant PPT have been reported so far in the literature. These tumors have been recently classified into benign, low- and high-grade malignant tumors and statistically significant difference was found in their biological behavior. However, we propose that IHC can be of immense value in assisting the subtyping of the tumor, so that the behavior and role of adjuvant therapy can be validated in future studies. PMID- 22223971 TI - An unusual case report of rapunzel syndrome trichobezoar in a 3-year-old boy. AB - Rapunzel Syndrome is a rare trichobezoar, involving strands of swallowed hair extending as a tail through the duodenum, beyond the stomach. Trichobezoar usually occur in patients with history of trichotillomania, characterized by compulsive behavioral disorder of pulling own hairs, combined with trichophagia that consists of ingesting that hairs. It typically occurs in stomach and rarely affects the small intestine. Trichobezoars are more common in adolescent females. Common presentation is gastrointestinal tract obstruction with nausea and vomiting, gut perforation, acute pancreatic necrosis, obstructive jaundice, hypochromic anemia, vitamin B12 deficiency, weight loss, an abdominal mass, or other serious problems. Intestinal obstruction due to trichobezoar is extremely rare. We are here reporting a large trichobezoar in a 3-year-old male child who presented to the emergency department with thread protruding from mouth with no sign of hair loss on body. PMID- 22223972 TI - Trichorrhexis nodosa with nail dystrophy: diagnosis by dermoscopy. AB - A 25-year-old male, born of non-consanguineous marriage presented with complaints of sparse and thin hairs over scalp and dystrophy of nails since childhood. This case highlights the association of trichorrhexis nodosa with nail dystrophy and the use of trichoscopy as a noninvasive method for diagnosis of hair disorders. PMID- 22223973 TI - Silvery hair syndrome in two cousins: Chediak-Higashi syndrome vs Griscelli syndrome, with rare associations. AB - Silvery hair is a rare clinical manifestation which is a common presentation in a group of rare syndromes which usually present in the pediatric age group together termed as "silvery hair syndrome," consisting of Chediak-Higashi syndrome (CHS), Griscelli syndrome (GS), and Elejalde disease. CHS is a rare autosomal recessive disorder. It is characterized by mild pigment dilution (partial oculocutaneous albinism), silvery blond hair, severe phagocytic immunodeficiency, bleeding tendencies, recurrent pyogenic infections, progressive sensory or motor neurological defects. GS is also a rare autosomal recessive disorder characterized by reduced skin pigmentation, often regarded as partial albinism and silvery grey hair combined with immunodeficiency. To make correct diagnosis and to differentiate between CHS and GS, it requires light microscopic examination of skin and hair shafts, immunological and peripheral blood smear evaluation. They have been reported to be associated with some common clinical association as a part of the syndrome due to pigmentary delusion, neurological dysfunction, and severe life-threatening infections due to neutrophil phagocytosis dysfunction. There are reports of few rare associations and varied presentations and variable mean survival age. We report two cases with common presentation of silvery hair but varied systemic and clinical manifestations and survival in two cousin brothers from the same family. PMID- 22223974 TI - Atrichia with papular lesions. AB - Atrichia with papular lesions (APL) is a rare autosomal recessive form of irreversible alopecia with onset at few months of age with papular keratin cysts over the body. It is associated with mutation in the Zinc finger domain of the human hairless gene on chromosome region 8p12. An eleven-year-old male presented with extensive alopecia starting at six months of age refractory to the treatment along with keratotic papules on the face and trunk. Biopsy from a papule showed mid-dermal keratin cysts and from the scalp showed few vellus follicles with no terminal hairs. The diagnosis of APL was made based upon the criteria proposed. Vitamin D-dependent rickets was ruled out as it has similar clinical presentation. Accurate diagnosis of APL is required to avoid unnecessary treatment to the patient as it is commonly misdiagnosed as alopecia universalis and treated with systemic steroids. PMID- 22223975 TI - Nevoid hypertrichosis: case report with review of the literature. AB - Nevoid hypertrichosis is a rare entity characterized by circumscribed patches of terminal hair. It is associated with many cutaneous and extra-cutaneous abnormalities. In our case, a single circumscribed patch of terminal hair growth was present without any underlying or associated cutaneous or systemic abnormalities. PMID- 22223976 TI - Bubble hair and other acquired hair shaft anomalies due to hot ironing on wet hair. AB - Bubble hair is an acquired hair shaft abnormality characterized by multiple airfilled spaces within the hair shaft. It is a result of thermal injury. We report a classic case of 22-year-old female who complained of dry brittle hair of two-week duration. Patient had used hot iron on wet hair twice to straighten hair. Hair microscopy was diagnostic and showed multiple air-filled spaces within the hair shaft. PMID- 22223977 TI - Hair casts or pseudonits. AB - Hair casts or pseudonits are thin, elongated, cylindrical concretions that encircle the hair shaft and can be easily dislodged. A case of pseudonits in a 9 year-old girl is reported. Though not unusual, false diagnoses are common. PMID- 22223978 TI - Elevated yellow nodule over the scalp in a middle-aged man. PMID- 22223979 TI - Hair follicle stem cells: a new arena. PMID- 22223980 TI - Hard facts about loose stools - massive alopecia in Gloriosa superba poisoning. PMID- 22223981 TI - Stories that hair can tell. PMID- 22223982 TI - Optical detection of hairs. PMID- 22223983 TI - An effect of bimatoprost: adverse for some, therapeutic for others. PMID- 22223984 TI - A summary on researches on Thai natural products for treatment of pediculosis. PMID- 22223985 TI - Hair - a yardstick for diabetes. PMID- 22223986 TI - Trichology concern and the present nuclear accident crisis. PMID- 22223987 TI - 'Tracing elements' in hair. PMID- 22223988 TI - Forearm pilomatricoma with extensive ossification. PMID- 22223989 TI - State of the globe: many challenges of the multifaceted leprosy. PMID- 22223991 TI - Erratum: ERRATUM. AB - [This corrects the article on p. 312 in vol. 3, PMID: 21887072.]. PMID- 22223990 TI - Hunting in the Rainforest and Mayaro Virus Infection: An emerging Alphavirus in Ecuador. AB - OBJECTIVES: The objectives of this report were to document the potential presence of Mayaro virus infection in Ecuador and to examine potential risk factors for Mayaro virus infection among the personnel of a military garrison in the Amazonian rainforest. MATERIALS AND METHODS: The study population consisted of the personnel of a garrison located in the Ecuadorian Amazonian rainforest. The cross-sectional study employed interviews and seroepidemiological methods. Humoral immune response to Mayaro virus infection was assessed by evaluating IgM- and IgG-specific antibodies using ELISA. RESULTS: Of 338 subjects studied, 174 were from the Coastal zone of Ecuador, 73 from Andean zone, and 91 were native to the Amazonian rainforest. Seroprevalence of Mayaro virus infection was more than 20 times higher among Amazonian natives (46%) than among subjects born in other areas (2%). CONCLUSIONS: Age and hunting in the rainforest were significant predictors of Mayaro virus infection overall and among Amazonian natives. The results provide the first demonstration of the potential presence of Mayaro virus infection in Ecuador and a systematic evaluation of risk factors for the transmission of this alphavirus. The large difference in prevalence rates between Amazonian natives and other groups and between older and younger natives suggest that Mayaro virus is endemic and enzootic in the rainforest, with sporadic outbreaks that determine differences in risk between birth cohorts of natives. Deep forest hunting may selectively expose native men, descendants of the Shuar and Huaronai ethnic groups, to the arthropod vectors of Mayaro virus in areas close to primate reservoirs. PMID- 22223992 TI - Improving diagnosis of trichomonas vaginalis infection in resource limited health care settings in sri lanka. AB - OBJECTIVE: This study was designed to compare diagnosis of trichomoniasis by culture, wet smear examination, and Giemsa stain. A modified technique was used to transport and prepare the specimen to ensure parasite viability prior to Giemsa staining. MATERIALS AND METHODS: A clinic-based prospective study was carried out in association with the National STD/AIDS Control Programme over a period of 18 months. Three swabs were collected from the posterior fornix of 346 newly registered female patients for diagnosis of trichomoniasis. A wet smear was prepared using the first swab. The second swab was placed in 5 mL of 0.9% saline with three drops of 5% glucose at room temperature and centrifuged twice at a low speed prior to preparation of a Giemsa stained smear. The third swab was for culture. The three tests were performed independently. The specificity and sensitivity of the wet smear and Giemsa stain were compared to culture. RESULTS: With culture, the prevalence of trichomoniasis was 6.9% (95% CI: 4.1-9.3%). The Giemsa-stained smear was found to be highly sensitive (100%, 95% CI: 86.2-100%) and specific (99.69%, 95% CI: 98.26-99.95%) compared to culture. The wet smear was less sensitive (95.83%, 95% CI: 79.76-99.26%) but equally specific (100%, 95% CI: 98.82-100%). CONCLUSION: In developing countries, facilities for using culture are limited and wet smear examination in the field is also difficult due to the immediate need for laboratory facilities. Our study demonstrated that, in this setting, using a transport medium prior to Giemsa staining is a feasible alternative, with a high-diagnostic yield. PMID- 22223993 TI - Etiological study of Fever of unknown origin in patients admitted to medicine ward of a teaching hospital of eastern India. AB - BACKGROUND: In a developing country, infectious disease remains the most important cause of fever, but the noncommunicable diseases, like malignancy, are fast becoming important differential diagnoses. An important clinical problem is the cases labeled as fever of unknown origin (FUO), which often evade diagnosis. OBJECTIVE: The present study was undertaken to find the cause of FUO in a tertiary care hospital of eastern India. MATERIALS AND METHODS: This is a prospective study of inpatients, with regard to both clinical signs and investigations. RESULTS: The main diagnosis in the end was tuberculosis, closely followed by hematological malignancy. A substantial number of cases remained undiagnosed despite all investigations. The provisional diagnosis matched with the final in around two thirds of the cases. While for younger patients leukemia was a significant diagnosis, for older ones, extra-pulmonary tuberculosis was a main concern. INTERPRETATION: In India, infectious disease still remains the most important cause of fever. Thus the initial investigations should always include tests for that purpose in a case of FUO. CONCLUSION: Geographic variations and local infection profiles should always be considered when investigating a case of FUO. However, some of the cases always elude diagnosis, although the patients may respond to empirical therapy. PMID- 22223994 TI - Socio-demographic Characteristics of Adults Screened for Human Immunodeficiency Virus Infection in Ahoada-East Local Government Area in the Niger Delta of Nigeria. AB - BACKGROUND: Human immunodeficiency virus (HIV), the pathogen responsible for the acquired immunodeficiency syndrome and the most significant emerging infectious disease is causing health, social, and developmental problems to mankind. AIMS, SETTING AND DESIGN: This is a cross-sectional study to evaluate the socio demographic characteristics of adults screened for HIV infection in Ahoada Community in Rivers State in the Niger Delta of Nigeria. MATERIALS AND METHODS: HIV antibodies were detected using "Determine" (Abbott Laboratories, Japan), Start-Pak (Chembio Diagnostics, USA) and SD Bioline HIV-1/2 kits (Standard Diagnostics, Korea). All test procedures were carried out according to the manufacturers' instructions. Subjects included 152) consecutively recruited adults consisting of 955 females and 566 males aged 18-54 years with a mean age of 36.25+/-7.02 years. STATISTICAL ANALYSIS: Data were entered and analyzed using statistical package SPSS version 9. A P-value <=0.05 were considered statistically significant in all statistical comparisms. RESULTS AND CONCLUSION: Out of a total of 1521 persons screened for HIV infection, 162 persons tested positive for HIV (10.6%). HIV infection was higher among females (10.9%) compared to males (10.1%) and in the 25-34 and 45-60 years age groups (11.1%) (P= 0.08). HIV-1 was the predominant subtype (74%) compared to 26% for dual HIV-1 and 2. This study indicates the urgent need for both government and non-governmental organizations to intensify awareness campaign programme to reduce the spread of the HIV infection in the area with emphasis on behavioral change and economic empowerment of the people as well as provision of universal access to antiretroviral therapy for those with HIV infection. PMID- 22223995 TI - Utility of Gastric Lavage for Diagnosis of Tuberculosis in Patients who are Unable to Expectorate Sputum. AB - BACKGROUND: There are number of patients who are unable to expectorate sputum specimens. In this study, we used gastric lavage (GL) test for diagnosis of tuberculosis (TB) in patients who were unable to produce sputum. MATERIALS AND METHODS: Patients who were unable to produce sputum specimens were included in the study to confirm TB disease. Gastric lavage sampling was performed and sent for acid fast bacillus smear and culture under special laboratory conditions and sterilized methods. Further bronchoscopy for broncho-alveolar lavage was done on patients with negative GL smear results. Drug susceptibility tests were performed on 48 GL culture positive cases. RESULTS: Eighty-five patients were included in the study; who were hospitalized at our referral center for suspected TB. GL smears were reported to be positive in 37 cases (66.07%) and culture in 85.7%. The total number of smear and culture-positive cases in this study was 48 (85.7%). Forty cases (87%) of drug-sensitive, 1 case (2.2%) of isoniazid and rifampin-resistant TB (multi-drug resistant; MDR), and 5 cases of resistant to one drug were detected. There have not been observed any complications after the GL method. CONCLUSION: It seems that regarding the high number of positive GL cultures (85.7%), GL can be effective for diagnosis of patients who have suspicious tuberculosis symptoms and are unable to produce sputum especially in resource limited areas. PMID- 22223996 TI - Presenting experience of managing abdominal tuberculosis at a tertiary care hospital in India. AB - BACKGROUND: Abdominal tuberculosis remains the great mimic despite years of experience and awareness. Reliable epidemiological data on abdominal tuberculosis are lacking in India. OBJECTIVES: To define the most suggestive clinical features of abdominal tuberculosis, to evaluate the usefulness of the normally available investigations, and the response of anti-tuberculous drugs. STUDY DESIGN: Retrospective study. MATERIALS AND METHODS: Out of 110 patients attending our hospital between July 2000 and June 2002, with clinical suspicion of abdominal tuberculosis, 46 patients had confirmed abdominal tuberculosis. Their clinico radiological and cyto / histopathological profiles, side effects of anti tuberculous drugs, and the outcome of the treatment were analyzed. RESULTS: Weight loss, abdominal pain, and bowel disturbances were the most common symptoms. Anemia and under- nutrition, abdominal tenderness, ascites, and hepato / splenomegaly were the most common findings. Chest radiography showed active or healed tuberculous focus in 16. Ultrasonography revealed abdominal lymphadenopathy, ascites, and mass lesions in 26, 12, and four patients, respectively. Barium examination showed abnormality in eight patients out of 18, among whom it was performed. An ascitic fluid study done in 12 patients showed high adenosine deaminase in all, and positive acid fast bacilli in one. Laparoscopic peritoneal biopsy was done in18 patients, and 13 showed tuberculous granuloma. Treatment success was achieved in 38 patients with anti-tuberculous drugs. Most patients tolerated the anti-tuberculous drugs well. CONCLUSION: With good clinical examination and appropriate investigations definitive diagnosis of abdominal tuberculosis can be reached in a significant number of patients. Strongly suggestive clinical and laboratory data are also indications for anti tuberculous therapy in an endemic country like India. Anti-tuberculous drugs are well tolerated and highly effective. PMID- 22223997 TI - Actinomyces and nocardia infections in chronic granulomatous disease. AB - OBJECTIVE: Chronic granulomatous disease (CGD) is an inherited disorder of the Nicotinamide adenine dinucleotide phosphate reduced oxidase complex characterized by recurrent bacterial and fungal infections. Disseminated infection by combination of opportunistic agents is being increasingly reported in CGD patients. We presented in the retrospective review of medical records, the etiology, presentation, clinical characteristics the infections detected, predisposing condition and outcome of nocardiosis and actinomycosis involved in a group of pediatric patients diagnosed with CGD. MATERIALS AND METHODS: The clinical presentation of CGD-related infections was reviewed retrospectively from the medical records of all 12 patients with CGD. We studied respectively 12 patients between 2001 and 2008, and we analyzed two pediatric patients with CGD who acquired Nocardia and Actinomyces infections, and their clinical and microbiological characteristics were described. The material for investigations was collected from scrapings, crusts, pus from subcutaneous abscesses or exudation from sinus tracts, surgical debridement, and biopsy specimens. The microbiological diagnosis was determined by biochemical tests, histology, microscopy, and culture of clinical samples. RESULTS: The medical records of 12 diagnosed CGD patients with suspected nocardiosis or actinomycosis were reviewed. One patient was diagnosed with actinomycosis and one patient with nocardiosis. Patients consisted of seven males and five females with ranging ages of 3 to 18 years. Nocardiosis and actinomycosis isolated in the two patients were confirmed by histology and culture methods. Neutrophil oxidative burst were absent (NBT=0) in both patients. The most common manifestations of CGD due to fungal infections, actinomycosis, and nocardiosis were osteomyelitis (42.8%), pulmonary infections (28.6%), lymphadenopathy (14.3%), and skin involvement (14.3%) during their illness. CONCLUSION: Nocardiosis and actinomycosis in children indicate the need for evaluation for an underlying immunological deficiency. Early diagnosis remains critical for decreased morbidity and occasional mortality. Physicians caring for patients with CGD should maintain a high index of suspicion for nocardiosis and actinomycosis especially if work up for TB and fungal infections are negative. PMID- 22223998 TI - Comparison of DNA Extraction Protocols for Mycobacterium Tuberculosis in Diagnosis of Tuberculous Meningitis by Real-time Polymerase Chain Reaction. AB - BACKGROUND: Several nucleic acid amplification techniques are available for detection of Mycobacterium tuberculosis (MTB) in pulmonary and extrapulmonary samples, but insufficient data are available on the diagnostic utility of these techniques in tubercular meningitis where bacilli load is less. The success of final amplification and detection of nucleic acid depends on successful extraction of DNA from the organism. AIMS: We performed this study to compare four methods of extraction of MTB DNA from cerebrospinal fluid (CSF) samples so as to select one method of DNA extraction for amplification of nucleic acid from clinical samples. MATERIALS AND METHODS: Four methods of extracting MTB DNA from CSF samples for testing by real-time polymerase chain reaction (PCR) were compared: QIAGEN(R) protocol for DNA purification using QIAamp spin procedure (manual), AMPLICOR(R) respiratory specimen preparation kit, MagNA Pure(R) kit extraction, combined manual DNA extraction with automated extraction by MagNA Pure(R). Real-time PCR was performed on COBAS TaqMan 48 Analyzer(R) with known positive and negative controls. RESULTS: The detection limit for the combined manual and MagNA Pure(R) extraction protocol was found to be 100 copies of MTB DNA per reaction as against 1,000 copies of MTB DNA per reaction by the QIAGEN(R), AMPLICOR(R), and the MagNA Pure(R) extraction protocol. CONCLUSION: The real-time PCR assay employing the combination of manual extraction steps with MagNA Pure(R) extraction protocol for extraction of MTB DNA proved to be better than other extraction methods in analytical sensitivity, but could not detect less than 10(2) bacilli /ml. PMID- 22223999 TI - Determination of antifungal susceptibility patterns among the clinical isolates of Candida species. AB - CONTEXT: Candida species are opportunistic yeasts that cause infections ranging from simple dermatosis to potentially life-threatening fungemia. The emergence of resistance to antifungal drugs has been increased in the past two decades. AIM: the present study we determined to find out the susceptibility profiles of clinical isolates of Candida species against four antifungal drugs, including amphotericin B, ketoconazole, fluconazole and itraconazole. MATERIALS AND METHODS: Antifungal susceptibility testing of the yeasts was done in accordance with the proposed guidelines for antifungal disk diffusion susceptibility testing of yeasts based on the CLSI document M44-A. RESULTS: A total of 206 yeast isolates were assessed. Among the evaluated Candida species, the highest rates of resistance to ketoconazole were seen in Candida glabrata (16.6%) and Candida albicans (3.2%). Susceptibility and intermediate response to fluconazole were seen in 96.6% and 3.4% of the Candida isolates, respectively. A total of 19 (9.2%) yeast isolates showed petite phenomenon including 11 C. glabrata, 3 C. albicans, 2 Candida dubliniensis and one isolate of each Candida krusei and Candida parapsilosis. CONCLUSION: The high number of petite mutation in the isolated yeasts should be seriously considered since it may be one of the reasons of antifungal treatment failure. PMID- 22224000 TI - Epidemiological investigation of an outbreak of acute diarrheal disease: a shoe leather epidemiology. AB - BACKGROUND: Health care problems faced by migrant construction workers are always neglected. Fifteen patients were admitted with the complaints of loose motion and pain in the abdomen from a labor settlement at a construction site near our city. Three stool samples revealed darting motility. OBJECTIVES: To find out more number of cases, the source of infection and to recommend necessary actions to control the outbreak. STUDY DESIGN: A cross-sectional epidemiological study. MATERIALS AND METHODS: Pre-tested, pre-designed epidemiological case sheet was used. Sanitary survey and assessment of ecological correlation was also done. Stool samples of all the admitted patients and seven water samples from the site were collected for laboratory analysis. RESULTS: Out of 99 inhabitants, 69 were suffering from the same complaints. Male sufferers were more in number. The age groups affected prominently were 1-4 years and 15-44 years. Peculiar epidemic curve with one peak was noted down. There was a history of heavy rains 2 days before the complaints had started. The construction site was situated on the plateau. The source of the water - dug well - was situated on a slope. The water from the site while moving along the slope was getting mixed into the well. Considering the person, time, place distribution and the peculiar symptoms, presumptive diagnosis of outbreak (point source) of acute gastroenteritis was made. The well water was thought to be the source of infection. Three stool samples and three water samples including the sample from drinking well water grew Vibrio cholerae O1. These results support an earlier hypothesis. The timely interventions were done. CONCLUSION: The impending outbreak can be brought under control with the rapid and simple field epidemiological investigation (shoe leather epidemiology). PMID- 22224001 TI - Trends in Peptic Ulcer Disease and the Identification of Helicobacter Pylori as a Causative Organism: Population-based Estimates from the US Nationwide Inpatient Sample. AB - BACKGROUND: Peptic ulcer disease can lead to serious complications including massive hemorrhage or bowel perforation. The modern treatment of peptic ulcer disease has transitioned from the control of gastric acid secretion to include antibiotic therapy in light of the identification of Helicobacter pylori as a causative infectious organism. We sought to determine trends related to this discovery by using a national database. MATERIALS AND METHODS: Patient discharges with peptic ulcer disease and associated sequelae were queried from the Nationwide Inpatient Sample, 1993 to 2007, under the auspices of a data user agreement. To account for the Nationwide Inpatient Sample weighting schema, design-adjusted analyses were used. Standard error was calculated using SUDAAN software (Research Triangle International, NC, USA). RESULTS: Decreases in the incidences of gastrointestinal perforation, gastrointestinal hemorrhage, and surgical procedures most specific to peptic ulcer disease were statistically significant over the study period [range of P value (two tailed) = 0.000 - 0.00353; significant at P < 0.001 to < 0.01]. The incidence of H. pylori rose dramatically, peaking at an estimated 97,823 cases in 1998 [SE = 3155; 95% CI = 6,184]. Since that time it has decreased and then stabilized. CONCLUSIONS: The identification of H. pylori as the causative agent in the majority of peptic ulcer disease has revolutionized the understanding and management of the disease. Medical conditions and surgical procedures associated with end-stage peptic ulcer disease have significantly decreased according to analysis of selected index categories. Resident physician education objectives may need to be modified in light of these trends. REVIEW CRITERIA: We reviewed patients with peptic ulcer disease. The database used was the Nationwide Inpatient Sample, 1993 to 2007. MESSAGE FOR THE CLINIC: Medical therapy has resulted in decreased morbidity from H. pylori infection as it is the causative agent in the majority of peptic ulcer disease. Aggressive screening and treatment of this infection will lead to further reduction in morbidity. PMID- 22224002 TI - Studying PPTCT Services, Interventions, Coverage and Utilization in India. AB - BACKGROUND AND OBJECTIVES: Risk of vertical transmission (largest source of HIV in children) reduces from 33% to 3% with effective PPTCT interventions. NACP III has got an objective of testing all pregnant women for earliest linkage with PMTCT. Study was carried out to find out PPTCT service coverage, drop-outs, interventions efficacy with other determinants. MATERIALS AND METHODS: At ICTCs, registered ANCs are counseled and tested for HIV. HIV+ve ANCs are linked to services and followed-up for institutional delivery, sdNVP, nutrition and children testing. HIV+ve ANCs since 2004 subsequently delivered till December 2009 and their exposed children in PPTCT-VSGH constituted study cohort. RESULTS: 29281 ANCs registered, 69.7% were counseled pre-test, 100% of them tested, 94.9% were counseled post-test. 60.5% were detected in 3(rd) trimester. CD4 testing was carried out in 71.6% HIV+ve ANCs. 81 ANCs were detected HIV+ve inclusive of 11 unregistered cases. 72 pregnancy outcomes reported institutionally, 77.6% were caesarian sections. Out of 59 live births, 56 sdNVP-MB-Pair were given. 88.1% children were traced till 18 months, 76.3% of live births were alive, 40.7% of live births were tested. 1 was found HIV+ve with history of adherence to all prescribed PPTCT guidelines. CONCLUSIONS: PMTCT services - counseling and testing should be provided to all ANCs. EDD-based tracking, institutional deliveries, postnatal counseling to be encouraged along with complete MB pair coverage, capacity building of concerned staff regarding delivery of HIV+ve ANCs and exposed children tracking. PMID- 22224003 TI - A Comparative Study of the Quality of Life, Knowledge, Attitude and Belief About Leprosy Disease Among Leprosy Patients and Community Members in Shantivan Leprosy Rehabilitation centre, Nere, Maharashtra, India. AB - BACKGROUND: Leprosy a chronic infectious affliction, is a communicable disease that posses a risk of permanent and progressive disability. The associated visible deformities and disabilities have contributed to the stigma and discrimination experienced by leprosy patients, even among those who have been cured. AIMS AND OBJECTIVES: 1) To assess the knowledge, attitude and belief about leprosy in leprosy patients compared with community members. 2) To find the perceived stigma among leprosy patients. 3). To evaluate the quality of life in leprosy patients as compared to community members using WHO Quality of Life assessment questionaire (WHOQOL- BREF). MATERIALS AND METHODS: A cross sectional study was conducted at Leprosy Rehabilitation Centre, Shantivan, Nere in Panvel Taluka, district Raigad from October - December 2009. A pre-designed and pre structured questionaire was used to evaluate knowledge, attitude and perceived stigma among leprosy patients and community members. WHO Quality of life questionaire (WHOQOL-BREF) was used to assess quality of life in leprosy patients and controls. Data analysis was done with the help of SPSS package. RESULT: Among the cases and control, 43.13% of cases were aware that leprosy is an infectious disease compared to 20.69% of control. 68.62% of cases had knowledge of hypopigmented patches being a symptom of leprosy compared to the 25.86% in control. There was overall high level of awareness about disease, symptoms, transmission and curability in leprosy patients as compared to control. Among control group, 43.10% of population said that they would not like food to be served by leprosy patients as compared to 13.73% in study group. It was seen that the discrimination was much higher in female leprosy patients as compared to male leprosy patients. The mean quality of life scores for cases was significantly lower than those for control group in physical and psychological domain but not in the social relationship and environmental domain. The mean quality of life scores for male cases were lower in each domain as compared to male control group but the difference was not significant except in the physical and enviornmental domain. The mean quality of life scores for female cases were lower in each domain as compared to female control group and the difference was not significant except in the psychological domain. CONCLUSIONS: There was a significant difference in physical domain in male leprosy patients and psychological domain in female leprosy patients as compared with their respective gender controls. The leprosy patients were more aware about the infectious nature of the disease, symptoms, transmission, and curability than the control group. A negative attitude was seen towards the leprosy patients in the society. PMID- 22224005 TI - Brucellosis, presenting with guillain-barre syndrome. AB - Brucellosis is an infectious disease caused by gram-negative bacteria of the genus Brucella. Involvement of the gastrointestinal, hepatobilliary, and skeletal systems has been reported frequently in the literature. Involvement of the nervous system is relatively uncommon and has been reported in only 3%-25% of cases of generalized brucellosis. Guillain-Barre syndrome is a prototypical postinfectious autoimmune disease. We report a case of Guillain-Barre syndrome in a 26-year-old woman as an uncommon presentation of neurobrucellosis. PMID- 22224004 TI - Urinary tract infections and asymptomatic bacteriuria in renal transplant recipients. AB - Asymptomatic bacteriuria and urinary tract infection are common complications after kidney transplantation. In this population, if urinary tract infection occurred in the first six months post procedure, it carries a grave impact on both graft and patient survival. Renal transplant recipients with urinary tract infection are often clinically asymptomatic as a consequence of immunosuppression. Urinary tract infection, however, may progress to acute pyelonephritis, bacteremia and the full blown picture of urosepsis. PubMed and Cochrane databases were searched. The purpose of this review is to discuss the screening and treatment of urinary tract infection and asymptomatic bacteriuria in renal transplant recipients and to evaluate the guidelines on the basis of a review of published evidence. PMID- 22224006 TI - Chrysomya bezziana oral myiasis. AB - Myiasis is an opportunistic infestation of human and vertebrate animals with dipterous larvae. Oral myiasis is a rare condition associated with poor oral hygiene, mental disability, halitosis and other conditions. We present a case report of an adult mentally challenged woman with extensive necrotic oral lesion burrowing into the hard palate through which three live maggots (larvae) were seen emerging out. The larvae were removed using forceps and the patient was treated with oral ivermectin. The maggots were identified as larvae of the Chrysomya bezziana fly. PMID- 22224007 TI - A Rare Case of Pancreatic Abscess due to Candida Tropicalis. AB - Candida albicans is found frequently as a commensal organism in the gastrointestinal tract. Despite this, it is rarely found in pancreatic abscesses, there being only a few cases in the literature and in most of these cases the significance of Candida spp. as a pathogen was not initially recognized at the time of diagnosis. In most of the earlier reported pancreatitis associated with candida, C. albicans was the commonest isolate. We report the case of a patient in whom computed tomography was used initially to diagnose a pancreatic abscess, aspiration of which showed growth of Candida tropicalis and Escherichia coli on culture. The patient was started on amphotericin B and imipenem, but the condition of the patient deteriorated, for which the patient underwent surgical necrosectomy and continued treatment with imipenem and amphotericin B led to the satisfactory recovery of the patient. PMID- 22224008 TI - Hemophagocytic syndrome in classic dengue Fever. AB - A 24-year-old previously healthy girl presented with persistent fever, headache, and jaundice. Rapid-test anti-dengue virus IgM antibody was positive but anti dengue IgG was nonreactive, which is suggestive of primary dengue infection. There was clinical deterioration during empiric antibiotic and symptomatic therapy. Bone marrow examination demonstrated the presence of hemophagocytosis. Diagnosis of dengue fever with virus-associated hemophagocytic syndrome was made according to the diagnostic criteria of the HLH 2004 protocol of the Histiocyte Society. The patient recovered with corticosteroid therapy. A review of literature revealed only a handful of case reports that showed the evidence that this syndrome is caused by dengue virus. Our patient is an interesting case of hemophagocytic syndrome associated with classic dengue fever and contributes an additional case to the existing literature on this topic. This case highlights the need for increased awareness even in infections not typically associated with hemophagocytic syndrome. PMID- 22224009 TI - Bilateral Breast Abscesses due to Salmonella Enterica Serotype Typhi. AB - Focal infection is an uncommon complication of Salmonella septicemia, particularly in immunocompetent patients. The localization of Salmonella infection to breast tissue is regarded as a rare event. We report a case of bilateral breast abscesses due to Salmonellaenterica serotype Typhi in a nonlactating female and highlight the fact that Salmonella spp. should be included in differential diagnosis of abscesses in individuals coming from endemic areas with the history of recent typhoid fever and should be treated accordingly. PMID- 22224010 TI - Safety of Air Travel in H1N1-positive Patient with Hydropneumothorax. PMID- 22224011 TI - "To use or not to use"- dilemma of developing countries in introducing new vaccines. PMID- 22224012 TI - As is our Pathology, So is our Practice. PMID- 22224013 TI - Biopsy pathology in uveitis. AB - Uveitis is fraught with speculations and suppositions with regard to its etiology, progress and prognosis. In several clinical scenarios what may be perceived as due to a systemic infection may actually not be so and the underlying etiology may be an autoimmune process. Investigations in uveitis are sometimes the key in identification and management. Invasive techniques could be of immense value in narrowing down the etiology and help in identifying the cause. This article updates one on the invasive techniques used in biopsy such as anterior chamber paracentesis, vitreous tap and diagnostic vitrectomy, iris and ciliary body biopsy, choroidal and retinochoroidal biopsy and fine needle aspiration biopsy (FNAB). In populations where certain infections are endemic, the clinical scenario does not always respect a known presentation and the use of biopsy is resorted to as a sure way of confirming the etiology. Biopsies have a role in diagnosis of several inflammatory and infectious conditions in the eye and are pivotal in diagnosis in several dilemmas such as intraocular tumors and in inflammations. Appropriate and timely use of biopsy in uveitis could enhance the diagnosis and provide insight into the etiology, thus enabling precise management. PMID- 22224014 TI - Update in pathological diagnosis of orbital infections and inflammations. AB - Orbital infections and inflammations include a broad spectrum of orbital diseases that can be idiopathic, infectious, from primary or secondary inflammatory processes. Being able to properly diagnose and manage these orbital diseases in a timely manner can avoid permanent vision loss and possibly save a patient's life. When clinicians are faced with such patients, quite often the exact diagnosis cannot be made just based on clinical examination, various laboratory tests and imaging are needed. Moreover, orbital biopsies with histopathological analyses are often required, especially for the atypical cases. Thus, it is important for the clinicians to be familiar with the pathological features and characteristics of these orbital diseases. This review provides a comprehensive update on the clinical and pathological diagnosis of these orbital infections and inflammations. PMID- 22224015 TI - Update on pathologic diagnosis of corneal infections and inflammations. AB - One of the most frequent types of corneal specimen that we received in our pathology laboratory is an excised corneal tissue following keratoplasty. Several of these cases are due to corneal infections or the sequelae, like corneal scar. Advances in the histological and molecular diagnosis of corneal infections and inflammations have resulted in rapid and accurate diagnosis of the infectious agent and in the overall understanding of the mechanisms in inflammatory diseases of the cornea. This review provides an update of histopathological findings in various corneal infections and inflammations. PMID- 22224017 TI - Combined Viscocanalostomy-Trabeculectomy for management of Advanced Glaucoma - A Comparative Study of the Contralateral Eye: A Pilot Study. AB - PURPOSE: To compare combined viscocanalostomy-trabeculectomy (VISCO-TRAB) to trabeculectomy (TRAB) for the management of advanced glaucoma. MATERIALS AND METHODS: The study cohort comprised of 18 subjects with bilateral advanced glaucoma who underwent VISCO-TRAB surgery (VISCO-TRAB group) in the right eye and TRAB (TRAB group) in the left eye. VISCO-TRAB constituted lamellar scleral flap, deep scleral flap dissection with deroofing of Schlemm's canal (SC), viscodilation of SC, penetrating trabeculectomy, peripheral iridectomy, and tight flap closure. All eyes received subconjunctival mitomycin. Success criteria included intraocular pressure (IOP) < 14 mmHg or > 30% lowering of IOP with no devastating complications. A P value less than 0.05 was considered statistically significant. RESULTS: Mean IOP was significantly lower after VISCO-TRAB compared to TRAB at 1 week and 3 months postoperatively (P<0.05). No eyes lost more than two lines of Snellen acuity. There were more hypotony-related complications after TRAB than VISCO-TRAB surgery. Target IOP was achieved in 83.3% in the VISCO-TRAB group compared to 55.6% in the TRAB group. CONCLUSION: Combined VISCO-TRAB is effective in reducing IOP to the target level for advanced glaucoma with lower postoperative complications. PMID- 22224018 TI - Oral propranolol for the treatment of periorbital infantile hemangioma: a preliminary report from oman. AB - PURPOSE: To investigate the efficacy and safety of oral propranolol in the management of periorbital infantile hemangioma in four subjects. MATERIALS AND METHODS: Consecutive patients who presented with periorbital capillary hemangioma with vision-threatening lesions were prospectively enrolled in this study between January 2009 and October 2010. All subjects underwent treatment with 2 mg/kg/day oral propranolol. All subjects underwent ocular, systemic, and radiologic evaluations before treatment and at periodic intervals after starting therapy. Side effects from therapy were also evaluated. RESULTS: Four subjects, between 3 months and 19 months of age, with periorbital hemangioma were enrolled in this study. Two subjects had been previously treated with oral corticosteroids with unsatisfactory response. All subjects had severe ptosis, with the potential for deprivation amblyopia. Three subjects had orbital involvement. After hospital admission, oral propranolol was initiated in all subjects under monitoring by a pediatric cardiologist. Subsequent therapy was performed with periodic out patient monitoring. All subjects had excellent response to treatment, with regression of periorbital and orbital hemangioma. There were no side effects from therapy. CONCLUSIONS: Oral propranolol for periorbital hemangioma was effective in all the four subjects. Oral propranolol may be appropriate for patients who are nonresponsive to intralesional or systemic steroids. In patients with significant orbital involvement and lesions causing vision-threatening complications, oral propranolol can be the primary therapy. PMID- 22224016 TI - Femtosecond laser-assisted cataract surgery: a current review. AB - To evaluate the safety, efficacy, advantages, and limitations of femtosecond laser-assisted cataract surgery through a review of the literature. A PubMed search was conducted using topic-appropriate keywords to screen and select articles. Initial research has shown appropriate safety and efficacy of femtosecond laser-assisted cataract surgery, with improvements in anterior capsulotomy, phacofragmentation, and corneal incision. Limitations of these studies include small sample size and short-term follow-up. Cost-benefit analysis has not yet been addressed. Preliminary data for femtosecond laser-assisted cataract surgery shows appropriate safety and efficacy, and possible advantage over conventional cataract surgery. Questions to eventually be answered include comparisons of long-term postoperative complication rates-including infection and visual outcomes-and analysis of contraindications and financial feasibility. PMID- 22224019 TI - Serendipity, the humble case report and modern health science challenges. PMID- 22224020 TI - Oestrus ovis as a Cause of Red Eye in Aljabal Algharbi, Libya. AB - PURPOSE: To study the common presenting signs of external ophthalmomyiasis caused by Oestrus ovis larvae in Aljabal Algharbi province, Libya. MATERIALS AND METHODS: A prospective non- comparative study was conducted from September 2009 to July 2010 at the Gharian outpatient clinic, Gharian, Aljabal Algharbi, Libya. The common presenting features of patients with external ophthalmomyiasis and data on the organism that caused the disease were collected. RESULTS: Twenty one cases diagnosed with external ophthalmomyiasis were recorded. There were fourteen males (66.67%) and seven females (33.33%) in the cohort. The mean age was 14.29 +/- 3.46 years (range, 8 years to 22 years: males; 13.39 +/- 3.03 years and females; 16.67 +/- 3.75 years). The main complaint was redness (100.00%), itching (71.43%) and tearing (57.14%). Twelve patients (57.14%) were from rural areas and 9 patients (42.9%) were from urban areas. The causative organism was found to be first instar of Oestrus ovis larvae. CONCLUSION: External ophthalmomyiasis caused by Oestrus ovis can cause red eye in patients from Aljabal Algharbi, Libya and requires careful examination to ensure early diagnosis and proper treatment. PMID- 22224022 TI - Primary orbital liposarcoma: histopathologic report of two cases. AB - Liposarcoma is a malignant tumor of adipose tissue. Considered the most common soft tissue sarcoma in adults, orbital liposarcoma is extremely rare. Most cases of orbital liposarcoma are primary and rarely metastatic. We report two cases of primary orbital liposarcoma with clinical presentation, radiologic studies (available for one case), and detailed histopathologic features. A brief review of primary orbital liposarcoma is also presented. PMID- 22224023 TI - Histopathologic findings in two cases with history of intrastromal corneal ring segments insertion. AB - Intrastromal corneal ring segments (INTACS) implantation for mild myopia or keratoconus is simple and effective in most cases. Rarely, major complications can occur due to implantation. In this case report, we present two examples of possible intraoperative and postoperative complications of INTACS. The first case had histopathologic documentation of Descemet's membrane perforation as an intraoperative complication and the second case had accumulation of foamy histiocytes along the lamellar channels which has not been previously reported. These complications suggest further study is required on the long term effect of INTACS implantation on corneal tissue. PMID- 22224021 TI - Photodynamic therapy of symptomatic choroidal nevi. AB - PURPOSE: To evaluate the role of photodynamic therapy (PDT) for patients with symptomatic choroidal nevi involving the fovea or located near the fovea with subretinal fluid extending to the fovea. MATERIALS AND METHODS: Retrospective review of five patients who underwent PDT for choroidal nevi at two separate centers in Ankara and Barcelona. RESULTS: The mean initial logMAR visual acuity was 0.5 (range: 0 to 1.5). The mean largest tumor base diameter was 3.2 mm (range: 2.1-4.5 mm) and the mean tumor thickness was 1.1 mm (range: 0.7-1.6 mm). The mean number of PDT sessions was 1.6 (range:1-3). The mean final tumor thickness was 1.0 mm (range: 0-1.6 mm) at a mean follow-up of 19 months (range: 12-32 months). The mean final logMAR visual acuity was 0.4 (range: 0-1.5). Subfoveal fluid disappeared or decreased significantly in 4 of 5 eyes (80%) after PDT. CONCLUSIONS: PDT led to resolution of subretinal fluid with preservation of visual acuity in many symptomatic choroidal nevi in this study. Careful case selection is important as PDT of indeterminate pigmented tumors may delay the diagnosis and treatment of an early choroidal melanoma and thereby increase the risk for metastasis. PMID- 22224024 TI - Susac's Syndrome in a 27-Year-Old Female. AB - A 27-year-old woman was referred by the neurologist for ophthalmic examination. She had a history of headache, visual loss in her right eye, four-limb paresthesia, and behavioral changes over the previous 10 months. The patient complained of tinnitus and hearing loss for two weeks. The patient was initially diagnosed with multiple sclerosis, but auditory and retinal involvement (small branch retinal artery occlusion in fluorescein angiography) raised the possibility of Susac's syndrome. PMID- 22224025 TI - Orbital rosai-dorfman disease in a five-year-old boy. AB - Rosai-Dorfman disease (RDD) is characterized by histiocytic proliferation and massive cervical lymphadenopathy, although some patients have extra-nodal involvement. We report a case of extranodal RDD in a five-year-old child, initially misdiagnosed as orbital inflammatory disease and treated with oral steroids. A subsequent orbital biopsy three years later confirmed the diagnosis of Rosai Dorfman disease. PMID- 22224026 TI - Lacrimal gland fistula after upper eyelid blepharoplasty. AB - To report the first case of lacrimal gland fistula after upper eyelid blepharoplasty for blepharochalasis. Standard upper blepharoplasty and the hooding excision were performed in a female with blepharochalasis. The patient developed a fistulous tract with tearing from the incision few days after hooding excision. Fistula excision and lacrimal gland repositioning were performed. There were no complications after the repositioning procedure (6 months follow up). Prolapsed lacrimal gland and fistula formation can occur after upper blepharoplasty hooding excision. PMID- 22224027 TI - Lacrimal glands: size does matter! AB - A 40-year-old woman presented with vague headaches and blurred vision. Contrast enhanced magnetic resonance imaging of the brain revealed bilaterally symmetrical diffuse enlargement of the lacrimal glands. A fine needle biopsy of the lacrimal gland was consistent with sarcoidosis. Although, isolated lacrimal gland involvement is rare, it may be the initial clinical presentation of sarcoidosis, as seen in this patient. Imaging plays a vital role in these unsuspected cases and careful evaluation of the lacrimal glands with dedicated thin section, fat suppressed, axial and coronal orbital imaging, may help identify a pathological cause and avoid a delay in diagnosis. PMID- 22224028 TI - Surgical treatment and histopathology of a symptomatic free-floating primary pigment epithelial iris cyst in the anterior vitreous. AB - We report the surgical removal of an iris pigment epithelial cyst that was floating freely in the posterior chamber of an 18-month-old child. The reason for surgical removal was disturbance in near vision secondary to the movement of the cyst across the visual axis. Visual disturbance secondary to a unilateral anterior vitreous iris cyst at this age is a rare presentation and, to the best of our knowledge, has not been reported previously as an indication for surgery. We performed histopathological study of the cyst aspirate to determine its contents and its possible origin. PMID- 22224029 TI - Different patterns of orbital roof involvement by cholesterol granuloma. AB - Two patients presented with cholesterol granuloma (CG), with completely different patterns of orbital roof involvement. One patient had a large intraorbital cystic CG, whereas the other had a very large intraosseous CG of the frontal bone. The presentation of CG with variable orbital roof involvement highlights the importance of being aware of the clinical characteristics and the imaging features of CG. PMID- 22224030 TI - Visual Disturbance as the first Symptom of Chronic Myeloid Leukemia. AB - Chronic myeloid leukemia (CML) is a well-studied entity and advances made in diagnosis and treatment have improved the disease outcome. Patients with ophthalmic manifestation of CML have been reported to have lower 5-year survival rates. Hence, recognizing the early fundus changes may improve outcome by allowing earlier diagnosis and treatment. We report a case of a previously healthy 30-year-old Myanmarese male, who presented with a minor visual disturbance, complaining of seeing a 'black dot' in his left visual field for the past 1 week. Fundoscopic examination revealed bilateral retinal blot hemorrhages, white-centered hemorrhage, and preretinal hemorrhage over the left fovea. The full blood count and peripheral blood film were abnormal, and bone marrow biopsy confirmed the diagnosis of CML. Cytoreduction therapy was promptly commenced and his symptoms resolved, with improvement in visual acuity. No complications were recorded at 1-year follow-up. PMID- 22224031 TI - Formulation and evaluation of cephalexin extended release matrix tablets using 3 factorial design. AB - The aim of the present investigation was to prepare extended release film coated matrix tablets of cephalexin using binary mixture of two grades of hydrophilic polymer, hydroxypropyl methyl cellulose (HPMC), by direct compression method. Results of the preliminary trials indicated that the polymers used have significant release retarding effect on the formulation. To study the effect of concentration of polymers on drug release from matrix tablets, 3(2) full factorial design was applied. The concentration of HPMC K15M and HPMC 15cps were used as independent variables, while percentage drug release was selected as dependent variable. The dissolution data were fitted into zero-order, first order, Higuchi and Korsemeyer-Peppas models to identify the pharmacokinetics and mechanism of drug release. Comparative study of dissolution profile of final batch F3 with market preparation (Sporidex AF 375) was done by similarity factor (f(2)) determination and it was concluded that final formulation F3 (10% HPMC K15M, 17.5% HPMC 15cps) shows good similarity with the market product. The results of the accelerated stability study of final formulation F3 for 1 month revealed that storage conditions were not found to have made any significant changes in final formulation F3. The release of cephalexin was prolonged for 6 h by using polymer combinations of HPMC and a twice daily matrix tablet was formulated. PMID- 22224032 TI - Preparation and characterization of pioglitazone cyclodextrin inclusion complexes. AB - Pioglitazone, a class II Biopharmaceutical Classification System drug having poor water solubility and slow dissolution rate may have a negative impact on its subtherapeutic plasma drug levels leading to therapeutic failure. In order to improve its water solubility and thus dissolution, cyclodextrin complexation technique was followed. The phase solubility studies were carried using three different types of cyclodextrins viz., beta, methyl-beta and gamma-cyclodextrins. The Gibbs free energy was calculated in order to determine ease of the complexation. Binary systems of pioglitazone with cyclodextrins were prepared by kneading method and spray drying method. The phase solubility profiles with all the three cyclodextrins were classified as A(L)-type, indicating the formation of 1:1 stoichiometric inclusion complexes. The complexation capability of cyclodextrins with pioglitazone increased in the order of methyl-beta > beta > gamma-cyclodextrin. The Gibbs free energy was found to be in the order gamma > methyl-beta > beta cyclodextrin. Characterization of inclusion complexes was done by solubility studies, in vitro dissolution studies, Fourier transformation infrared spectroscopy, scanning electron microscopy, differential scanning calorimetry and X-ray powder diffractometry studies. Inclusion complexes exhibited higher rates of dissolution than the corresponding physical mixtures and pure drug. Greater solubility was observed with spray-dried methyl-beta cyclodextrin complexes (2.29 +/- 0.001 mg/ml) in comparison to the kneaded methyl beta cyclodextrin complexes (1.584 +/- 0.053 mg/ml) and pure drug (0.0714 +/- 0.0018 mg/ml). PMID- 22224033 TI - Formulation and optimization of mucoadhesive nanodrug delivery system of acyclovir. AB - Acyclovir is an antiviral drug used for the treatment of herpes simplex virus infections, with an oral bioavailability of only 10-20% [limiting absorption in gastrointestinal tract to duodenum and jejunum] and half-life of about 3 h, and is soluble only at acidic pH (pKa 2.27). Mucoadhesive polymeric nanodrug delivery systems of acyclovir have been designed and optimized using 2(3) full factorial design. Poly (lactic-co-glycolic acid) (PLGA) (50:50) was used as the polymer along with polycarbophil (Noveon AA-1) as the mucoadhesive polymer and pluronic F68 as the stabilizer. From the preliminary trials, the constraints for independent variables X(1) (amount of PLGA), X(2) (amount of pluronic F68) and X(3) (amount of polycarbophil) have been fixed. The dependent variables that were selected for study were particle size (Y(1)), % drug entrapment (Y(2)) and % drug release in 12 h (Y(3)). The derived polynomial equations were verified by check point formulation. The application of factorial design gave a statistically systematic approach for the formulation and optimization of nanoparticles with the desired particle size, % drug release and high entrapment efficiency. Drug: Polymer ratio and concentration of stabilizer were found to influence the particle size and entrapment efficiency of acyclovir-loaded PLGA nanoparticles. The release was found to follow Fickian as well as non-Fickian diffusion mechanism with zero-order drug release for all batches. In vitro intestinal mucoadhesion of nanoparticles increased with increasing concentration of polycarbophil. These preliminary results indicate that acyclovir-loaded mucoadhesive PLGA nanoparticles could be effective in sustaining drug release for a prolonged period. PMID- 22224034 TI - Antimicrobial activity of the extract of stem bark of diplotropis ferruginea benth. AB - This is the first report about the antibacterial activity of Diplotropis ferruginea Benth. In this study, the ethanol extract of D. ferruginea was tested for its antimicrobial activity against strains gram-positive and gram-negative. In order to determine the minimal inhibitory concentration, assays were carried out by micro dilution method. The extract was screened for antimicrobial activity, and it showed antibacterial activity against Escherichia coli and Pseudomonas aeruginosa. PMID- 22224036 TI - Cardioprotective Effects of Lagenaria siceraria Fruit Juice on Isoproterenol induced Myocardial Infarction in Wistar Rats: A Biochemical and Histoarchitecture Study. AB - The present study was designed to evaluate the cardioprotective effects of Lagenaria siceraria fruit juice in isoproterenol-induced myocardial infarction. Rats injected with isoproterenol (200 mg/kg, s.c.) showed a significant increase in the levels of serum uric acid, tissue Na(++) and Ca(++) ions and membrane bound Ca(+2)-ATPase activity. A significant decrease in the levels of serum protein, tissue K(+) ion, vitamin E level, and the activities of Na(+)/K(+) ATPase and mg(+2)-ATPase was observed. Isoproterenol injected rats also showed a significant increase in the intensity of lactate dehydrogenase isoenzyme and histopathologic alterations in the heart. Treatment with L. siceraria fruit juice (400 mg/kg/day, p.o.) for 30 days and administration of isoproterenol on 29(th) and 30(th) days showed a protective effect on altered biochemical and histopathologic changes. These findings indicate the cardioprotective effect of L. siceraria fruit juice in isoproterenol-induced myocardial infarction in rats. PMID- 22224035 TI - Litsea deccanensis ameliorates myocardial infarction in wistar rats: evidence from biochemical and histological studies. AB - The present study was designed to evaluate the cardioprotective effects of methanolic extract of Litsea deccanensis (MELD) against isoproterenol-induced myocardial infarction in rats by studying cardiac markers, lipid peroxidation, lipid profile, and histological changes. Male Wistar rats were treated orally with MELD (100 and 200 mg/kg) daily for a period of 21 days. After 21 days of pretreatment, isoproterenol (100 mg/kg) was injected subcutaneously to rats at an interval of 24 h for 2 days to induce myocardial infarction. Isoproterenol induced rats showed significant (P < 0.05) increase in the levels of serum creatine kinase, lactate dehydrogenase, thiobarbituric acid reactive substances, and lipid hydro peroxides. The serum lipid levels were altered in the isoproterenol-induced myocardial infarcted rats. The histopathological findings of the myocardial tissue evidenced myocardial damage in isoproterenol-induced rats. The oral pretreatment with MELD restored the pathological alterations in the isoproterenol-induced myocardial infarcted rats. The MELD pretreatment significantly reduced the levels of biochemical markers, lipid peroxidation and regulated the lipid profile of the antioxidant system in the isoproterenol induced rats. An inhibited myocardial necrosis was evidenced by the histopathological findings in MELD pretreated isoproterenol-induced rats. Our study shows that oral pretreatment with MELD prevents isoproterenol-induced oxidative stress in myocardial infarction. The presence of phenolic acid and flavonoid contents were confirmed by preliminary phytochemical tests. The reducing power and free radical scavenging activities of the MELD may be the possible reason for it pharmacological actions. PMID- 22224038 TI - Synthesis, characterization and biological activity studies of 1,3,4-oxadiazole analogs. AB - The reaction of p-bromoanilino acetohydrazide(II) with aromatic aldehydes in alcohol yielded 2-[4-bromo aniline] N-substituted benzylidine hydrazides (IIIa IIIj), which in presence of yellow mercuric oxide and iodine in DMF, yielded corresponding 4-bromo[(N-5-substituted 1,3,4 oxadiazole-2 -yl)methyl]aniline (IVa IVj). Structures of the compounds synthesized were confirmed by IR, (1)HNMR and MASS spectroscopic analysis. The newly synthesized compounds were screened for antibacterial, antifungal and anti-inflammatory activities. Some of the compounds showed remarkable antibacterial, antifungal and anti-inflammatory activities. PMID- 22224037 TI - Oxidative stress induced by fluoroquinolones on treatment for complicated urinary tract infections in Indian patients. AB - The aim of the study is to examine the oxidative stress in patients on fluoroquinolones (ciprofloxacin, levofloxacin, gatifloxacin) therapy for complicated urinary tract infections and to correlate with plasma concentrations at different time intervals. Superoxide dismutase (SOD), glutathione, plasma antioxidant status and lipid peroxides were evaluated in 52 patients on different dosage regimens up to 5 days. There is significant and gradual elevation of lipid peroxide levels in patients on ciprofloxacin (3.6 +/- 0.34 nmol/ml to 6.2 +/- 0.94 nmol/ml) and levofloxacin (3.5 +/- 0.84 nmol/ml to 5.1 +/- 0.28 nmol/ml) dosage regimen but not with gatifloxacin (3.5 +/- 0.84 nmol/ml to 3.74 +/- 0.17 nmol.ml). There was substantial depletion in both SOD and glutathione levels particularly with ciprofloxacin. On the 5(th) day of treatment, plasma antioxidant status decreased by 77.6% %, 50.5%, 7.56% for ciprofloxacin, levofloxacin and gatifloxacin respectively. In conclusion ciprofloxacin and levofloxacin induce more reactive oxygen species that lead to cell damage than gatifloxacin irrespective of their concentrations in patient population. PMID- 22224039 TI - High performance liquid chromatographic fluorescence detection method for the quantification of rivastigmine in rat plasma and brain: application to preclinical pharmacokinetic studies in rats. AB - A highly sensitive and selective high performance liquid chromatographic fluorescence detection method has been developed and validated for the quantification of rivastigmine in rat plasma and brain. Protein precipitation and one-step liquid-liquid extraction techniques were utilized for the extraction of RSM from brain and plasma, respectively, along with an internal standard. The chromatographic separation was achieved with a column inertsil ODS-3V and a mobile phase consisting of ammonium acetate buffer (20 mM, pH 4.5) and acetonitrile (76:24, v/v) delivered at a flow rate of 1 ml/min. The lower limit of quantitation for the developed method was 10 ng/mL for both matrices. The method was found to be accurate and reproducible and was successfully used to quantify levels of RSM in plasma and brain following intravenous administration of RSM in rats. PMID- 22224040 TI - Pharmacokinetic evaluation of Paclitaxel in South Indian cancer patients: a prospective study. AB - Paclitaxel is a promising drug in the treatment of different solid tumors. It exhibits nonlinear pharmacokinetics, particularly when administered as a constant rate infusion for shorter duration (e.g., 3 h). Because of the nonlinearity, relatively small changes in dose may lead to large changes in peak plasma concentration and total drug exposure. The study was conducted to evaluate the pharmacokinetics of different doses of paclitaxel administered intravenously as an infusion. A prospective study was conducted in 23 cancer patients aged between 28 and 74 years, treated with paclitaxel (130, 200, 230, and 260 mg/m(2)) over 3 h as constant rate infusion. Plasma samples were collected from all patients at 0, 1, and 3 h and for five patients at 5 and 13 h and paclitaxel concentrations were determined using high-performance liquid chromatography method. The overall mean clearance was found to be 47.5847 +/- 142.028 l/h; the mean volume of distribution was 142.028 +/- 73.438 l; mean elimination rate constant was 0.336 +/- 0.002/h; mean half-life was 2.086 +/- 0.009 h; mean area under the curve (AUC) was 5.5917 +/- 2.707 mg/ml*h; and the mean of mean residence time was 2.980 +/- 0.0131 h. Paclitaxel showed nonlinear kinetics and the pharmacokinetic parameters calculated were similar to those quoted in the literature. The peak plasma concentration at 130 mg dose level was 2 MU/ml, but an increase in dose was not associated with proportional increase in plasma concentration. No significant difference was found between pharmacokinetic parameters such as clearance, volume of distribution, and AUC at different dose levels. PMID- 22224041 TI - Drug-drug interactions in hospitalized cardiac patients. AB - Drug-drug interactions (DDIs) are defined as two or more drugs interacting in such a manner that the effectiveness or toxicity of one or more drugs is altered. DDI in patients receiving multidrug therapy is a major concern. The aim of the present study was to assess the incidence and risk factors of DDIs in patients admitted in cardiology unit of a teaching hospital. A prospective, observational study was carried out for a period of 3 months (April-July 2009). During the study period, a total of 600 prescriptions were analyzed and it was found that 88 patients had at least one DDI. The percentage of DDIs was higher in females compared to males (56.82% vs. 43.18%). DDIs were observed more in the age group of 60 years and above (57.96). Patients with more than 10 prescribed drugs developed DDIs more frequently [58 (65.91%)]. Heparin [55 (62.25%)] and aspirin [42 (47.72%)] were the most common drugs responsible for DDIs. Bleeding was the commonest clinical consequence [76 (86.63%)] found in this study population. On assessment of severity of DDIs, majority of the cases were classified as moderate in severity (61.36%). Aging, female gender and increase in concurrent medications were found to be associated with increased DDIs. Patients having these risk factors can be actively monitored during their stay in the cardiology department to identify DDIs. PMID- 22224042 TI - Pharmacy education in India: strategies for a better future. AB - In this world of specialization and globalization the pharmacy education in India is suffering from serious backdrops and flaws. There is an urgent need to initiate an academic exercise aimed at attaining revamping of curriculum, keeping in pace with current and emerging trends in the field of pharmacy. Unfortunately all these years, enough emphasis was not laid on strengthening the components of Community Pharmacy, Hospital and Clinical pharmacy, while designing curriculum at diploma and degree levels of teaching. The curriculum followed by almost all universities in India are no were up to the world standards and students are still getting the 20-30 yrs older compounding practical exposure in labs during the graduation level. The article emphasises the concept of innovation ecosystems and quality management. Application of TQM to the educational system improves the present situation. The counseling system which serves to be the gateway of the students for entry into the profession should be brought under the scanner. Introducing specializations at the graduation level will result in professional expertise and excellence. Education is a customer focused industry and every student should be capable of evaluating themselves for continuously improving their quality and professionalism. Teacher focused mastery learning should give away to student focused smart learning. An educational institution should provide the student with a stress-free atmosphere for learning and developing his intellectual capabilities. Every college should have a counseling centre to address the problems of students in their academic and personal life. An emphasis on the concept of quality teacher is included. Revival of the pharmacy education in India is the need of the hour which in turn will pave the way for the up gradation of the pharmacy profession in the country. PMID- 22224043 TI - Buyouts of Indian pharmaceutical companies by multinational pharmaceutical companies: an issue of concern. PMID- 22224044 TI - Assessment of antioxidant potentials of free and bound phenolics of Hemidesmus indicus (L) R.Br against oxidative damage. AB - BACKGROUND: Hemidesmus indicus R.Br. is a twining shrub commonly found in India, which was known to have wide pharmacological actions. 2-hydroxy-4-methoxy-benzoic acid (HMBA) and a number of pregnane glycosides were believed to be responsible for its various bioactivities. Until now, there are no reports regarding the antioxidant properties of phenolics from H. indicus OBJECTIVE: To establish the role of phenolics in the properties of H.indicus. MATERIALS AND METHODS: Hemidesmus free phenolic fraction (HDFP) and Hemidesmus bound phenolic fraction (HDBP) have been isolated from H. indicus, and the antioxidant activity was evaluated for inhibition of lipid peroxidation, DNA protection, free radical scavenging (FRS), reducing power and cytoprotective activities. RESULTS: HDFP and HDBP exhibited potent inhibition of lipid peroxidation (IC(50) - 19.5 +/-0.5 and 21.7 +/-0.5 MUg gallic acid equivalent - GAE/mL), FRS (IC(50) - 7 +/- 0.2 and 8.6 +/- 0.2 MUgGAE/mL), reducing power (110.3 +/- 2 and 33.5 +/- 1 U/g) and red blood cell protection (14.8 +/- 0.4 and 14.5 +/- 0.5 mg GAE/mL). HDFP is constituted by gallic (18%), caffeic (17%), ferulic acids (16%) and HDBP by syringic acid (35%) as major phenolic acids. Besides, both HDFP and HDBP contained significant levels of HMBA; in HDFP (10%) and HDBP (57%), respectively. Results indicated a 34-and 27-folds better contribution to the antioxidant activity by HDFP and HDBP, respectively, than that of HMBA. CONCLUSION: Potent antioxidant activities of phenolics may be one of the mechanisms by which H.indicus is effective against several health disorders as encountered in traditional medicines. PMID- 22224045 TI - Indigenous anti-ulcer activity of Musa sapientum on peptic ulcer. AB - BACKGROUND: Peptic ulcer disease (PUD), encompassing gastric and duodenal ulcers is the most prevalent gastrointestinal disorder. The pathophysiology of PUD involves an imbalance between offensive factors like acid, pepsin and defensive factors like nitric oxide and growth factors. The clinical evaluation of antiulcer drugs showed tolerance, incidence of relapses and side-effects that make their efficacy arguable. An indigenous drug like Musa sapientum possessing fewer side-effects is the major thrust area of present day research, aiming at a better and safer approach for the management of PUD. MATERIAL AND METHODS: The unripe plantain bananas (Musa sapientum) were shade-dried, powdered and used for phytochemical analysis and as antiulcer drug. In our present study Group I rats served as control and were treated with saline, Group II was indomethacin-induced ulcerated rats, Group III received aqueous extract of Musa sapientum along with indomethacin and Group IV received esomeprazole along with indomethacin for 21 days. The anti-ulcerogenic activity was investigated by performing hematological, mucosal, antioxidant profile in comparison with the standard drug esomeprazole. RESULTS: Our findings from High - Performance Thin Layer Chromatography (HPTLC) analysis showed that Musa sapientum has an active compound a monomeric flavonoid (leucocyanidin) with anti-ulcerogenic activity. Results were expressed as mean +/ SD. All our results are in congruous with the results of standard drug esomeprazole. CONCLUSION: It could be clearly concluded that administration of the aqueous extract of Musa sapientum at the dose used in this study tends to ameliorate ulcers. Its use in indigenous medicine should be scientifically scrutinized with further research. PMID- 22224046 TI - Cardioprotective effects of gallic acid in diabetes-induced myocardial dysfunction in rats. AB - BACKGROUND: Normalization of hyperglycemia, hyperlipidemia, and oxidative stress is an important objective in preventing diabetes-induced cardiac dysfunction. OBJECTIVE: This study was undertaken to examine the effects of gallic acid in myocardial dysfunctions associated with type-1 diabetes. MATERIALS AND METHODS: Diabetes was induced by single intravenous injection of streptozotocin (STZ, 50 mg/kg i.v.). Gallic acid was administered daily at three different doses (100, 50, and 25 mg/kg p.o.) for 8 weeks at the end of which blood samples were collected and analyzed for various biochemical parameters. RESULTS: Injection of STZ produced significant loss of body weight (BW), polyphagia, polydypsia, hyperglycemia, hypoinsulinemia, hyperlipidemia, hypertension, bradycardia, and myocardial functional alterations. Treatment with gallic acid significantly lowered fasting glucose, the AUC(glucose) level in a dose-dependent manner; however, the insulin level was not increased significantly at same the dose and prevented loss of BW, polyphagia, and polydypsia in diabetic rats. It also prevented STZ-induced hyperlipidemia, hypertension, bradycardia, structural alterations in cardiac tissue such as increase in force of contraction, left ventricular weight to body weight ratio, collagen content, protein content, serum lactate dehydrogenase, and creatinine kinase levels in a dose-dependent manner. Further, treatment also produced reduction in lipid peroxidation and increase in antioxidant parameters in heart of diabetic rats. CONCLUSION: The results of this study suggest that gallic acid to be beneficial for the treatment of myocardial damage associated with type-1 diabetes. PMID- 22224047 TI - Acetylcholine and memory-enhancing activity of Ficus racemosa bark. AB - BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in dementia and enhancement of acetylcholine (Ach) levels in brain using acetylcholinesterase inhibitors is one of the most important approaches for the treatment of AD. METHODS: In this study, aqueous extract of Ficus racemosa Linn. (Moraceae) bark having anti-inflammatory, antioxidant, and anticholinesterase activity was evaluated for its ability to enhance Ach levels, and to ascertain its antidementia activity in rats. This work was carried out under the assumption that the F. racemosa extract may show combination of actions which could be beneficial in the treatment of AD, such as neuroprotection, attributed to antioxidant and anti-infl ammatory property and may elevate levels of Ach like Ficus hispida extract reported earlier. RESULTS: Administration of the extract at two levels viz., 250 and 500 mg/kg signifi cantly raised (P <= 0.05) Ach levels in hippocampi of rats compared to control. The percentage enhancement in Ach levels was found to be 22% and 38%, respectively. Further, the extract at both dosage levels elicited signifi cant reduction (P <= 0.05) in transfer latency on elevated plus-maze, which was used as an exteroceptive behavioral model to evaluate memory in rats. CONCLUSION: It is inferred that it would be worthwhile to explore the potential of F. racemosa in the management of Alzheimer disease. PMID- 22224048 TI - Protective effects of goldenseal (Hydrastis canadensis L.) on acetaminophen induced hepatotoxicity through inhibition of CYP2E1 in rats. AB - BACKGROUND: Goldenseal (Hydrastis canadensis L.) inhibits various cytochrome P450 (CYP) isoforms such as CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A in vitro. High doses of acetaminophen (APAP) generate the highly reactive intermediate, N-acetyl p-benzoquinone imine (NAPQI), catalyzed mainly by CYP2E1. The aim of this study was to investigate the hepatoprotective effects of orally administrated goldenseal against APAP-induced acute liver failure (ALF) via inhibition of CYP2E1. MATERIALS AND METHODS: Male Wistar rats were treated orally with goldenseal (300 and 1000 mg/kg) 2, 18, and 26 h before and 6 h after oral APAP (400 mg/kg) administration. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities as well as serum APAP concentration were evaluated. RESULTS: Goldenseal extract inhibited CYP1A2, CYP2D6, CYP2E1, and CYP3A activity, and the inhibitory effect on CYP2E1 was the strongest (IC(50) 4.32 MUg/mL). Treatment with goldenseal (300 mg/kg) significantly attenuated the APAP-induced increase in serum AST and ALT, and the hepatoprotective effect of goldenseal was stronger than that of silymarin (200 mg/kg). Moreover, serum APAP concentration was increased by goldenseal treatment, presumably as a result of the inhibitory effect of goldenseal on the metabolism of APAP to NAPQI. CONCLUSION: These results suggest that goldenseal ameliorates APAP-induced ALF and that this protection can likely be attributed to the inhibition of CYP2E1 activity, which generates the highly reactive intermediate of APAP. PMID- 22224049 TI - Screening of radical scavenging activity and polyphenol content of Bulgarian plant species. AB - BACKGROUND: Discovery of new plant species with antioxidant properties is a priority of many research teams. Most of the species included in this study are unstudied for antioxidant properties, but they are taxonomically related to reference plants with well-documented antioxidant activity. MATERIALS AND METHODS: Free radical scavenging activity of plant extracts was evaluated using a 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. An aluminum chloride colorimetric method was used for flavonoid determination. The amount of phenolic compounds in the extracts was estimated by using the Folin-Ciocalteu reagent. RESULTS: As a result of screening, it was found that the significant antioxidant properties possess several unstudied until now plant species (Veronica bellidioides L., V. kellereri Deg. et Urm, V. vindobonensis (M. Fisher) M. Fisher, V. beccabunga L., V. rhodopaea L., V. austriaca (Velen.) Degen., Clinopodium vulgare L., Stachysrecta L., Clematis vitalba L., and Xeranthemum annum L.). The antioxidant potential of the new species is comparable to that of reference medicinal plants. CONCLUSIONS: The existing data presented here provide new information for antioxidant potential of plant species that have not been traditionally used as medicinal plants. PMID- 22224050 TI - Effects of the oral administration of nonpolar extract from Ardisia squamulosa Presl (Myrsinaceae) leaves on spermatogenesis in rats. AB - BACKGROUND: Several Ardisia species have been found to possess numerous bioactivities but their reproductive toxicity has been poorly explored. In the present study, the effects of the leaf hexane extract of Philippine indigenous Ardisia squamulosa on epididymal sperm count, %viability and %aberration of sperms and weights of seminal vesicle, cauda epididymis, and testes in addition to the weights of liver, kidney, and body were evaluated. METHODS: The extracts at daily dose levels of 1, 10, and 100 mg/Kg BW in 10% polysorbate-80 in corn oil were administered by gavage for 8 successive days to 8-10 weeks old male SD rats and sacrificed after 9 days. Daily body weights and final organ weights were measured. Sperm from the cauda epididymis was extracted and measured according standard sperm parameters (sperm count, morphology, viability and membrane integrity). RESULTS: Significant findings were the decline of left epididymal sperm count to testis weight ratio and increase in %sperm morphological aberration from both cauda epididymis obtained with the 10 mg/Kg BW dose. CONCLUSION: The hexane extract from Ardisia squamulosa had significant effect on sperm count but with negligible effect on sperm morphology and viability. PMID- 22224052 TI - A search for mosquito larvicidal compounds by blocking the sterol carrying protein, AeSCP-2, through computational screening and docking strategies. PMID- 22224051 TI - Antioxidant and antibacterial properties of green, black, and herbal teas of Camellia sinensis. AB - BACKGROUND: The role of non-polymeric phenolic (NP) and polymeric tannin (PT) constituents in the antioxidant and antibacterial properties of six brands of green, black, and herbal teas of Camellia sinensis were investigated. MATERIALS AND METHODS: Total phenolic content (TPC) and ascorbic acid equivalent antioxidant capacity (AEAC) were assessed using the Folin-Ciocalteu and 2,2 diphenyl-1-picrylhydrazyl (DPPH) assays, respectively. Minimum inhibitory dose (MID) against Gram-positive Micrococcus luteus, Staphylococcus aureus, and Bacillus cereus, and Gram-negative. Escherichia coli, Salmonella typhi, and Pseudomonas aeruginosa was assessed using the disc-diffusion method. Teas were extracted with hot water successively three times for one hour each time. The extracts were fractionated using Sephadex LH-20 column chromatography to obtain the NP and PT constituents. RESULTS: Extraction yields ranged from 12 to 23%. Yields of NP fractions (70-81%) were much higher than those of PT fractions (1 11%), suggesting that the former are the major tea components. Ranking of antioxidant properties of extracts was green tea>black tea>herbal tea. For all six teas, antioxidant properties of PT fractions were significantly higher than extracts and NP fractions. Extracts and fractions of all six teas showed no activity against the three Gram-negative bacteria. Green teas inhibited all three Gram-positive bacteria with S. aureus being the least susceptible. Black and herbal teas inhibited the growth of M. luteus and B. cereus, but not S. aureus. The most potent were the PT fractions of Boh Cameron Highlands and Ho Yan Hor with MID of 0.01 and 0.03 mg/disc against M. luteus. CONCLUSION: Results suggested that NP constituents are major contributors to the antioxidant and antibacterial properties of teas of C. sinensis. Although PT constituents have stronger antioxidant and antibacterial properties, they constitute only a minor component of the teas. PMID- 22224053 TI - Pharmacognosy Research: The future looks very promising. PMID- 22224054 TI - A computational perspective of molecular interactions through virtual screening, pharmacokinetic and dynamic prediction on ribosome toxin A chain and inhibitors of Ricinus communis. AB - BACKGROUND: Ricin is considered to be one of the most deadly toxins and gained its favor as a bioweapon that has a serious social and biological impact, due to its widespread nature and abundant availability. The hazardous effects of this toxin in human being are seen in almost all parts of the organ system. The severe consequences of the toxin necessitate the need for developing potential inhibitors that can effectively block its interaction with the host system. MATERIALS AND METHODS: In order to identify potential inhibitors that can effectively block ricin, we employed various computational approaches. In this work, we computationally screened and analyzed 66 analogs and further tested their ADME/T profiles. From the kinetic and toxicity studies we selected six analogs that possessed appropriate pharmacokinetic and dynamic property. We have also performed a computational docking of these analogs with the target. RESULTS: On the basis of the dock scores and hydrogen bond interactions we have identified analog 64 to be the best interacting molecule. Molecule 64 seems to have stable interaction with the residues Tyr80, Arg180, and Val81. The pharmacophore feature that describes the key functional features of a molecule was also studied and presented. CONCLUSION: The pharmacophore features of the drugs provided suggests the key functional groups that can aid in the design and synthesis of more potential inhibitors. PMID- 22224055 TI - GC-MS analysis of phytocomponents in the ethanol extract of Polygonum chinense L. AB - BACKGROUND: The presence of diverse secondary metabolites has been reported from species of the genus Polygonum. However, there has been not much information available on phytochemical components and biological activity in the whole plant ethanol extract of Polygonum chinense L. OBJECTIVE: This study was designed to determine the phytocomponents in the whole plant ethanol extract of P. chinense. MATERIALS AND METHODS: GC-MS analysis of the whole plant ethanol extract of P. chinense was performed using a Perkin-Elmer GC Clarus 500 system comprising an AOC-20i auto-sampler and a gas chromatograph interfaced to a mass spectrometer (GC-MS). RESULTS: This investigation was carried out to determine the possible chemical components from P. chinense by GC-MS. This analysis revealed that the ethanol extract of P. chinense (whole plant) contained mainly a triterpene compound-squalene (47.01%), and a plasticizer compound-1,2-benzenedicarboxylic acid, mono[2-ethylhexyl]ester (40.30%). All identified compounds were, generally, reported as having antimicrobial activity. In addition, the squalene compound also having anti-cancer, anti-oxidant, anti-tumor, chemo-preventive, pesticidal and sun-screen properties, while the plasticizer compound -1,2 benzenedicarboxylic acid, mono[2-ethylhexyl] ester reported to have anti-oxidant and anti-inflammatory properties. No activity was reported in the alcoholic compound-4-hexene-1-ol, 5-methyl-2-(1-methylethanyl)-acetate-(R)-. CONCLUSIONS: From the results, it is evident that P. chinense contains various bioactive compounds and is recommended as a plant of phytopharmaceutical importance. PMID- 22224056 TI - Black tea (Camellia sinensis) decoction shows immunomodulatory properties on an experimental animal model and in human peripheral mononuclear cells. AB - BACKGROUND: Black tea (Camellia sinensis) has been used as a daily beverage for time immemorial. Immunomodulatory effects of tea are recognized as it stimulates the proliferation of cultured human peripheral blood mononuclear cells. Anti inflammatory effects of tea have also been depicted in the available literature. Therefore, we designed this study to examine the potential immunemodulatory and anti-inflammatory activities of black tea in a rat model and in human peripheral mononuclear cells. AIMS: The purpose of the study was to determine (1) evaluation of anti-inflammatory effects of black tea on rats, (2) evaluation of immunemodulator effects of black tea on rats, and (3) evaluation of immunemodulator effects of black tea on human peripheral mononuclear cells. MATERIALS AND METHODS: Black tea decoction (10% and 20%) was prepared. Acute anti inflammatory activity of tea decoction was evaluated using carrageenan and dextran whereas chronic anti-inflammatory (Immunomodulatory) effects were evaluated in a complete Freunds' adjuvant-induced arthritis model. Immunostimulatory role was evaluated in cultured human (in vitro) peripheral mononuclear cells (T-lymphocytes) by using methyl thioazolyl tetrazolium (MTT) and Trypan blue assay. STUDY DESIGN: An experimental study was designed. RESULTS: Black tea decoction (10% and 20%) strength has shown significant anti inflammatory effects (64.8% and 77% reduction, respectively), on carrageenan induced acute inflammatory models (rat paw edema) which can be comparable with the standard drug indomethacin (89.1%). In a chronic anti-inflammatory model, black tea decoction (10% and 20%) has shown significant suppressive effects on rat paw edema (38.56% and 69.53%) observed on 21(st) day. Lymphoproliferative action of tea was evaluated on human peripheral mononuclear cells using an MTT assay where the number of living cells were expressed in terms of optical density at 570 nm. An experiment has shown that black tea increases the maximum number of T-lymphocytes at 72 h with a maximum strength of 20%. Maximum number of viable cells (T-lymphocytes) was observed with black tea at 20% strength at 72 h. The results were expressed as mean +/- SD, and the significance was evaluated by Student's t-test versus control, with P < 0.05 implying significance. CONCLUSIONS: Taken together, our data indicate that black tea has potential anti inflammatory and immunomodulatory action and this corroborates with the current trend of tea being promoted as a 'health drink'. PMID- 22224058 TI - Dichlorvos and lindane induced oxidative stress in rat brain: Protective effects of ginger. AB - BACKGROUND: Dichlorvos and lindane pesticide causes toxicity in animals including humans. Ginger (Zingiber officinale) is widely used as a culinary medicine in the Ayurvedic system of medicine, possessing a number of pharmacological properties. OBJECTIVE: This study was designed to assess ameliorating effects of ginger juice in dichlorvos and lindane induced neurotoxicity in wistar rats. MATERIALS AND METHODS: Dichlorvos (8.8 mg/kg bw) and lindane (8.8 mg/kg bw) were orally administered alone as well as in combination to adult male and female wistar rats for 14 days followed by the post-treatment of ginger juice (100 mg/kg bw) for 14 days. Lipid peroxidation (LPO), reduced glutathione (GSH), and activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR), quinine reductase (QR), and protein level were measured to evaluate the toxicity of these pesticides in brain. RESULTS: Dichlorvos and lindane administration alone and in combination increased LPO and decreased the GSH level, SOD, CAT, GPx, GST, GR, QR activity, and protein. Oxidative stress due to abnormal production of reactive oxygen species (ROS) is believed to be involved in the toxicities induced by these pesticides. Post-treatment of ginger juice decreased LPO and increased the level of GSH, SOD, CAT, GPx, GST, GR, QR activity and protein in the brain of rats. CONCLUSIONS: The results indicated that dichlorovos and lindane induced tissue damage was ameliorated by ginger juice. PMID- 22224057 TI - Antidepressant-like effects of young green barley leaf (Hordeum vulgare L.) in the mouse forced swimming test. AB - BACKGROUND: Young green barley leaf is one of the richest sources of antioxidants and has been widely consumed for health management in Japan. In this study, we examined whether oral administration of young green barley leaf has an antidepressant effect on the forced swimming test in mice. MATERIALS AND METHODS: Mice were individually forced to swim in an open cylindrical container, one hour after oral administration of young green barley leaf (400 or 1000 mg / kg) or imipramine (100 mg / kg). Expression of mRNA for nerve growth factor (NGF), brain derived neurotrophic factor, and glucocorticoid receptor in the brain was analyzed using real-time quantitative polymerase chain reaction (PCR). RESULTS: There was a significant antidepressant-like effect in the forced swimming test; both 400 and 1000 mg / kg young green barley leaves, as well as the positive control imipramine (100 mg / kg), reduced the immobility duration compared to the vehicle group. The expression of mRNA for NGF detected in the hippocampus immediately after the last swimming test was higher than that in the non-swimming group (Nil). Oral administration of imipramine suppressed this increase to the level of the Nil group. Young green barley leaf (400 and 1000 mg / kg) also showed a moderate decrease in the expression of mRNA for NGF, in a dose-dependent manner. CONCLUSION: Oral administration of young green barley leaf is able to produce an antidepressant-like effect in the forced swimming test. Consequently it is possible that the antidepressant-like effects of the young green barley leaf are, at least in part, mediated by an inhibition of the increase in the hippocampus levels of NGF. PMID- 22224059 TI - Effect of Butea monosperma Lam. leaves and bark extracts on blood glucose in streptozotocin-induced severely diabetic rats. AB - BACKGROUND: Diabetes mellitus is a chronic metabolic disorder that has significant impact on the health, quality of life and life expectancy, as well as on the health care system. Butea monosperma Lam. Kuntze (Fabaceae), commonly known as palash, is widely used in the treatment of various diseases and disorders including diabetes. MATERIALS AND METHODS: The present study was planned to evaluate the antidiabetic effect of aqueous extracts of B. monosperma leaves and bark in streptozotocin-induced severely diabetic rats. The animals were divided into four groups, with each consisting of six rats, viz. control, diabetic control, leaf extract-treated and bark extract-treated groups. Treatment was continued for 6 weeks. The biochemical estimations included blood glucose and serum insulin levels. Histopathology of pancreas was also performed. RESULTS: The results indicated that both leaf and bark extracts of B. monosperma produced insignificant antihyperglycemic activity. The leaf and bark extracts reduced blood glucose to an extent of 28% and 11%, respectively. It was also evidenced that both leaf and bark extracts did not increase insulin synthesis or secretion and did not improve pancreatic architecture as reflected by the histopathologic studies. CONCLUSIONS: The findings of the study emphasize that B. monosperma does not possess significant antidiabetic activity in severe experimental diabetes at the dosage tested. PMID- 22224060 TI - Antibacterial activity and the histopathological study of crude extracts and isolated tecomine from Tecoma stans Bignoniaceae in Iraq. AB - BACKGROUND: Tecoma stans (Bignoniaceae) is a central and south American tree used for the control of diabetes, also known as Yellow Elder, it was collected from the gardens of Al-Jadria in Iraq. MATERIALS AND METHODS: One of the main reported alkaloidal constituents, tecomine, was isolated and confirmed by spectral analysis. The bacteriological assay for different plant leaves extracts; aqueous, ethanolic, and isolated tecomine were conducted to evaluate the antibacterial effect against gram-negative and gram-positive bacteria. RESULTS: Whole alcoholic and aqueous extract exhibited the antibacterial activity and isolated tecomine. Histopathological evaluation was demonstrated on the liver, spleen, and pancreas of the BALB/c mice given the whole alcoholic and aqueous extract that showed no significant changes in the organ texture. CONCLUSION: Biochemical analysis of the serum obtained showed decrease in the glucose level in the mice treated with plant extract at the most two higher concentrations used with no change in the cholesterol and triglyceride level. PMID- 22224061 TI - Moringa oleifera Lam.: Protease activity against blood coagulation cascade. AB - BACKGROUND: The present study evaluated the protease activity of aqueous extracts of Moringa oleifera (Moringaceae) leaf (MOL) and root (MOR). MATERIALS AND METHODS: Protease activity was assayed using casein, human plasma clot and human fibrinogen as substrates. RESULTS: Caseinolytic activity of MOL was significantly higher (P <= 0.05) than that of MOR. Similar observations were found in case of human plasma clot hydrolyzing activity, wherein MOL caused significantly higher (P <= 0.05) plasma clot hydrolysis than MOR. Zymographic techniques were used to detect proteolytic enzymes following electrophoretic separation in gels. Further, both the extracts exhibited significant procoagulant activity as reflected by a significant decrease (P <= 0.05) in recalcification time, accompanied by fibrinogenolytic and fibrinolytic activities; clotting time was decreased from 180 +/- 10 sec to 119 +/- 8 sec and 143 +/- 10 sec by MOL and MOR, respectively, at a concentration of 2.5 mg/mL. Fibrinogenolytic (human fibrinogen) and fibrinolytic activity (human plasma clot) was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), plate method and colorimetric method. Zymographic profile indicated that both the extracts exerted their procoagulant activity by selectively hydrolyzing Aalpha and Bbeta subunits of fibrinogen to form fibrin clot, thereby exhibiting fibrinogenolytic activity. However, prolonged incubation resulted in degradation of the formed fibrin clot, suggesting fibrinolytic like activity. CONCLUSIONS: These findings support the traditional usage of M. oleifera extracts for wound healing. PMID- 22224062 TI - Hepatoprotective effect of poly herbal formulation against various hepatotoxic agents in rats. AB - BACKGROUND: Individually Andrographis paniculata Nees. (Acanthaceae), Phyllanthus niruri Linn.(Euphorbiaceae) and Phyllanthus emblica Linn. single plant extracts have been reported to have hepatoprotective activity. However, literature survey shows that no sufficient scientific data has been publish on pharmacological evaluation of these plants in combined form. METHOD: Hepatoprotective activity of the polyherbal hepatoprotaective formulation (PHF)-containing spray-dried aqueous extracts of Andrographis paniculata Nees. (Acanthaceae), Phyllanthus niruri Linn. (Euphorbiaceae) and Phyllanthus emblica Linn. (Euphorbiaceae), was screened against paracetamol, carbon tetrachloride (CCl(4)), and ethanol-induced hepatic damage in rats. PHF was evaluated by measuring levels of serum marker enzymes like SGOT, SGPT, ALP, direct bilirubin (DB), and lactate dehydrogenase (LDH). The histological studies were also studied support the biochemical parameters. Silymarin was used as standard drug. RESULTS: Administration of PHF (100 and 200 mg/kg p.o.) significantly inhibited paracetamol, CCl(4) and ethanol-induced elevation levels of SGPT, SGOT, ALP, DB and LDH. A comparative histopathological study of liver exhibited almost normal architecture as compared to toxicant group. CONCLUSION: Results suggests that the hepatoprotective effects of PHF might be useful for liver protection due to combined action of all plant extracts along with their phytoconstituents. PMID- 22224063 TI - Antihyperglycemic and antioxidative effects of the hydro-methanolic extract of the seeds of Caesalpinia bonduc on streptozotocin-induced diabetes in male albino rats. AB - BACKGROUND: No satisfactory effective treatment is available yet to cure diabetes mellitus. Though, synthetic drugs are used but there are several drawbacks. The attributed antihyperglycemic effects of many traditional plants are due to their ability for the management of diabetes mellitus. MATERIALS AND METHODS: A hydromethanolic extract was administered orally at a dose of 250 mg/kg of body weight per day for 21 days. Its effects on the fasting blood glucose (FBG) level, activities of key carbohydrate metabolic enzymes like hexokinase, glucose-6 phosphatase, and glucose-6-phosphate dehydrogenase, and antioxidant enzymes like catalase and superoxide dismutase along with the effect on the lipid peroxidation level in hepatic tissues were measured. Glycogen levels were also assessed in hepatic and skeletal muscles and some toxicity parameters, such as serum glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, and alkaline phosphates activities were measured. RESULTS: Treatment of the hydromethanolic extract of the seeds of Caesalpinia bonduc resulted in a significant (P < 0.05) recovery in the activities of carbohydrate metabolic enzymes along with correction in FBG and glycogen levels as compared with the untreated diabetic group. The extract also resulted in a significant (P < 0.05) recovery in the activities of toxicity assessment enzyme parameters. Activities of antioxidant enzymes like catalase and superoxide dismutase along with the lipid peroxidation levels were also recovered significantly (P < 0.05) after the treatment of the extract. The corrective effects produced by the extract were compared with the standard antidiabetic drug, glibenclamide. CONCLUSION: Our findings provide that the extract shows possible antihyperglycemic and antioxidative activities. PMID- 22224065 TI - The importance of measuring growth in response to intervention models: Testing a core assumption. AB - A core assumption of response to instruction or intervention (RTI) models is the importance of measuring growth in achievement over time in response to effective instruction or intervention. Many RTI models actively monitor growth for identifying individuals who need different levels of intervention. A large-scale (N=23,438), two-year longitudinal study of first grade children was carried out to compare the predictive validity of measures of achievement status, growth in achievement, and their combination for predicting future reading achievement. The results indicate that under typical conditions, measures of growth do not make a contribution to prediction that is independent of measures of achievement status. These results question the validity of a core assumption of RTI models. PMID- 22224064 TI - Identification of the protease inhibitor miraziridine A in the Red sea sponge Theonella swinhoei. AB - BACKGROUND: Miraziridine A, a natural peptide isolated from a marine sponge, is a potent cathepsin B inhibitor with a second-order rate constant of 1.5 * 10(4) M( 1) s(-1). In the present study, miraziridine A was isolated from the Red Sea sponge Theonella swinhoei on the basis of chromatographic and spectrometric techniques. We conclude that T. swinhoei from the Red Sea represents an alternative source of the aziridinylpeptide miraziridine A to the previously identified Theonella mirabilis from Japan. We confirmed that the metabolite is produced by marine sponges from different geographical locations. CONTEXT: Marine sponges have been proven to be a rich source of secondary metabolites exhibiting a huge diversity of biological activities, including antimicrobial, antitumor and immunomodulatory activities. Theonella species (order Lithistida, Demospongiae) have been shown to be a source of anti-protease and anti-HIV secondary metabolites. AIMS: To identify the protease inhibitor mirazirine A in the marine sponge Theonella swinhoei. MATERIAL AND METHODS: The marine sponge Theonella swinhoei was collected by SCUBA diving in the Red Sea in Eilat (Israel). Sponge material was lyophilized and further extracted successively with cyclohexane, dichloromethane and methanol to obtain three crude extracts. LC-MS analysis was performed to confirm the presence of Miraziridine A in the dichloromethane fraction. RESULTS: In the present study, miraziridine A was isolated from the Red Sea sponge T. swinhoei on the basis of chromatographic and spectrophotometric techniques. CONCLUSIONS: We conclude that T. swinhoei from the Red Sea represents an alternative source of the aziridinylpeptide miraziridine A to the previously identified Theonella mirabilis from Japan. PMID- 22224066 TI - Crack and Cocaine Use among Adolescents in Psychiatric Treatment: Associations with HIV Risk. AB - Crack and cocaine use among adults has been associated with co-occurring psychiatric disorders as well as other drug use and unprotected sex. However, this issue is relatively unstudied in adolescents. This study collected data from 282 adolescents (mean age=14.9 years) treated in intensive psychiatric treatment settings to understand the relationship between crack/cocaine use and HIV risk. Thirteen percent of youth reported ever using crack or cocaine. Use was not associated with age, gender, race/ethnicity or SES. After controlling for known factors that influence unprotected sex, the odds that those with a history of crack/cocaine use engaged in inconsistent condom use was six times greater than that for those youth who did not ever use. Thus, crack/cocaine use is prevalent even among younger adolescents with psychiatric disorders who are not in drug treatment. Its use is associated with high rates of sexual and other risk behaviors. A history of use should alert clinicians to a wide variety of possible behavioral risks. These results can also inform future adolescent HIV prevention intervention development. PMID- 22224067 TI - The Association of Family and Peer Factors with Tobacco, Alcohol, and Marijuana Use Among Chilean adolescents in Neighborhood Context. AB - Research on adolescent use of substances has long sought to understand the family factors that may be associated with use of different substances such as alcohol, tobacco and marijuana. However, scant attention has been focused on these questions in Latin American contexts, despite growing concerns about substance use among Latin American youth. Using data from a sample of 866 Chilean youth, we examined the relationship of family and neighborhood factors with youth substance abuse. We found that in a Latin American context access to substances is an important predictor of use, but that neighborhood effects differ for marijuana use as opposed to cigarettes or alcohol. Age of youth, family and peer relationships, and gender all play significant roles of substance use.The study findings provide additional evidence that the use of substances is complex whereby individual, family, and community influences must be considered jointly to prevent or reduce substance use among adolescents. PMID- 22224068 TI - Adrenal ganglioneuroma with multifocal retroperitoneal extension: a challenging diagnosis. AB - A ganglioneuroma (GN) is the rarest and most benign of the neuroblastic tumors and originates from neural crest cells wherever sympathetic nervous tissue exists, such as in the retroperitoneum and adrenal gland. The diagnosis can be very challenging, given the rarity and asymptomatic presentation of this neoplasia, and can be achieved only by means of histological evaluation. Although benign, a few cases of metastatic GNs have been reported in the literature. The prognosis, however, seems to be excellent after surgical resection. We describe a rare case of multifocal retroperitoneal GN, diagnosed incidentally in a 46-year old woman, with para-aortic and adrenal localizations. After intraoperative pathological diagnosis was made, complete excision of all the visible masses was performed. The postoperative period was uneventful and she was recurrence free 3 months after surgery. To our knowledge, this is the first case report of a multifocal retroperitoneal GN. Among the broad differential diagnoses of adrenal incidentalomas, an adrenal location of neuroblastic tumors should not be forgotten. PMID- 22224069 TI - Rapid treatment of leukostasis in leukemic mantle cell lymphoma using therapeutic leukapheresis: a case report. AB - We describe a case of severe leukocytosis caused by leukemic mantle cell lymphoma (MCL), complicated by leukostasis with myocardial infarction in which leukapheresis was used in the initial management. A 73-year-old male presented to the emergency department because of fatigue and thoracic pain. Blood count revealed 630 * 10(9)/L WBC (white blood cells). The electrocardiogram showed ST elevation with an increase of troponin and creatinine kinase. The diagnosis was ST-elevation myocardial infarction (STEMI) induced and complicated by leukostasis. Immunophenotyping, morphology, cytogenetic and fluorescence-in-situ hybridization analysis revealed the diagnosis of a blastoid variant of MCL. To remove leukocytes rapidly, leukapheresis was performed in the intensive care unit. Based on the differential blood count with 95% blasts, which were assigned to the lymphocyte population by the automatic hematology analyzer, leukapheresis procedures were then performed with the mononuclear cell standard program on the Spectra cell separator. The patient was treated with daily leukapheresis for 3 days. The WBC count decreased to 174 * 10(9)/L after the third leukapheresis, with a 72% reduction. After the second apheresis, treatment with vincristine, cyclophosphamide, and prednisolone was started. The patient fully recovered in the further course of the treatment. To the best of our knowledge, this is the first report on blastoid MCL with leukostasis associated with a STEMI that was successfully treated by leukapheresis. Effective harvest of circulating lymphoma cells by leukapheresis requires adaptation of instrument settings based on the results of the differential blood count prior to apheresis. PMID- 22224070 TI - Rubin H. Flocks and colloidal gold treatments for prostate cancer. AB - In the early 1950s, Rubin H. Flocks of the University of Iowa began to treat prostate cancer patients with colloidal gold (Au(198)) therapy, evolving his technique over nearly 25 years in 1515 patients. We reviewed the long-term outcomes of Flocks' prostate cancer patients as compared to those patients treated by other methods at the University of Iowa before Flocks' chairmanship. We reviewed archived patient records, Flocks' published data, and long-term survival data from the Iowa Tumor Registry to determine short- and long-term outcomes of Flocks' work with colloidal gold. We also reviewed the literature of Flocks' time to compare his outcomes against those of his contemporaries. The use of colloidal gold, either as primary or adjunctive therapy, provided short- and long-term survival benefit for the majority of Flocks' patients as compared to historical treatment options (p < 0.001). Flocks' use of colloidal gold for the treatment of locally advanced prostate cancer offered short- and long-term survival benefits compared to other contemporary treatments. PMID- 22224071 TI - Current status of human adipose-derived stem cells: differentiation into hepatocyte-like cells. AB - The shortage of human organ donors and the low cell quality of available liver tissues represent major obstacles for the clinical application of orthotropic liver transplantation and hepatocyte transplantation, respectively. Therefore, worldwide research groups are investigating alternative extrahepatic cell sources. Recent in vitro studies have demonstrated that mesenchymal stem cells (MSCs) from various sources, including human bone marrow, adipose tissue, and umbilical cord, can be differentiated into hepatocyte-like cells when appropriate conditions are used. In particular, interest exists for human adipose-derived stems cells (hASCs) as an attractive cell source for generating hepatocyte-like cells. The hASCs are multipotent MSCs that reside in adipose tissue, with the ability to self-renew and differentiate into multiple cell lineages. Moreover, these cells can secrete multiple growth factors and cytokines that exert beneficial effects on organ or tissue injury. In this review, we will not only present recent data regarding hASC biology, their isolation, and differentiation capability towards hepatocytes, but also the potential application of hASC derived hepatocytes to study drug toxicity. Additionally, this review will discuss the therapeutic potential of hASCs as undifferentiated cells in liver regeneration. PMID- 22224072 TI - Comparison between carotid artery wall thickness measured by multidetector row computed tomography angiography and intimae-media thickness measured by sonography. AB - The increased thickness of the carotid wall >1 mm is a significant predictor of coronary and cerebrovascular diseases. The purpose of our study was to assess the agreement between multidetector row computed tomography angiography (MDCTA) in measuring carotid artery wall thickness (CAWT) and color Doppler ultrasound (CD US) in measuring intimae-media thickness (IMT). Eighty-nine patients (aged 35-81) were prospectively analyzed using a 64-detector MDCTA and a CD-US scanner. Continuous data were described as the mean value +/- standard deviation, and were compared using the Mann-Whitney U test. A p value <0.05 was considered significant. Bland-Altman statistics were employed to measure the agreement between MDCTA and CD-US. CAWT ranged from 0.62 to 1.60 mm, with a mean value of 1.09 mm. IMT ranged from 0.60 to 1.55 mm, with a mean value of 1.06 mm. We observed an excellent agreement between CD-US and MDCTA in the evaluation of the common carotid artery thickness, with a bias between methods of 0.029 mm (which is a highly statistically important difference of absolute values [t = 43.289; p < 0.01] obtained by paired T test), and limits of agreement from 0.04 to 0.104. Pearson correlation coefficient was 0.9997 (95% CI 0.9996-0.9998; p < 0.01). We conclude that there is an excellent correlation between CAWT and IMT measurements obtained with the MDCTA and CD-US. PMID- 22224073 TI - Complete duplication of collecting system in a horseshoe kidney presenting with recurrent urinary tract infections: report of an exceedingly rare congenital anomaly and review of literature. AB - We report the fifth case in the English literature of a horseshoe kidney with a complete ureteral duplication. Our case is unique in that the previous four cases occurred in the presence of a ureterocele, whereas our patient lacked this anomaly. Further, our patient was managed conservatively, whereas the previous four patients were managed with surgery. PMID- 22224074 TI - Immune response to hepatitis B vaccine in patients with chronic kidney disease. PMID- 22224075 TI - Guidelines for the detection of a common source of hepatitis B virus infections. PMID- 22224076 TI - Chronic hepatitis B: management challenges in resource-poor countries. AB - Sylvester Chuks Nwokediuko, Department of Medicine, University of Nigeria Teaching Hospital, Ituku OzallaChronic infection with hepatitis B virus (HBV) is a global public health problem because of its worldwide distribution and its potential to cause sequelae. HBV is most prevalent in China, South East Asia, sub Saharan Africa, and the Amazon basin of South America where health care resources are most limited. Numerous challenges exist for effective management of chronic HBV infection, particularly in resource-limited regions. These challenges include lack of accurate prevalence data, absence of a surveillance program, and poor political will of governments in resource-poor countries to enforce effective measures to control the disease. There is a lack of understanding regarding HBV infec-tion by both the general public and health care providers. A better understanding of the pathogenesis and treatment of this condition is necessary. The acute shortage of trained medical manpower necessary for accurate diagnosis and treatment of chronic hepati-tis B (CHB) in resource-poor countries is a formidable challenge. The condition is com-plicated by the continuing efflux of medical graduates from low-income economies to richer countries. The most critical problem in the management of CHB is the high cost of laboratory tests and drugs. Drugs are also not readily available. Other challenges in the manage ment of CHB include stigmatization of patients, co-infection with other viruses, lack of management guidelines, and absence of an effective patient referral system. To address these challenges, governments of resource-poor nations must be committed to budg-etary allocation for the implementation of health programs. It is necessary to provide awareness campaigns, health education, proper screening of blood and blood products for transfusion, active screening, intensification of existing childhood immunization, technical and financial assistance from wealthier nations, and implementation of the recommendations outlined in the Global Hepatitis Policy (2010). PMID- 22224077 TI - Obesity and air pollution: global risk factors for pediatric non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is becoming as an important health problem in the pediatric age group. In addition to the well-documented role of obesity on the fatty changes in liver, there is a growing body of evidence about the role of environmental factors, such as smoking and air pollution, in NAFLD. Given that excess body fat and exposure to air pollutants is accompanied by systemic low-grade inflammation, oxidative stress, as well as alterations in insulin/insulin-like growth factor and insulin resistance, all of which are etiological factors related to NAFLD, an escalating trend in the incidence of pediatric NAFLD can be expected in the near future. This review focuses on the current knowledge regarding the epidemiology, diagnosis and pathogenesis of pediatric NAFLD. The review also highlights the importance of studying the underlying mechanisms of pediatric NAFLD and the need for broadening efforts in prevention and control of the main risk factors. The two main universal risk factors for N LD, obesity and air pollution, have broad adverse health effects, and reducing their prevalence will help abate the serious health problems associated with pediatric NAFLD. PMID- 22224078 TI - Identification and characterization of novel small-molecule inhibitors against hepatitis delta virus replication by using docking strategies. AB - BACKGROUND: The small delta antigen protein of hepatitis delta virus (HDV) has been shown to be important for replication of the virus and essential for the viral life cycle. Therefore, it may be an appropriate target for designing biological experiments for drug development to identify the potential inhibitors of hepatitis D. OBJECTIVES: To identify a novel molecule as possible drug candidate for the treatment of Hepatitis D. MATERIALS AND METHODS: In the present study, a computational approach was used for the identification of novel small molecule inhibitors against HDV replication using docking studies. An Autodock tool was used for docking and identifying the active binding sites in target proteins. The Lipinski filter and preADMET program were also used for determining the pharmacokinetic properties in order to filter out potential ligand molecules to restrain virus replication. RESULTS: Our results suggest that pyridinone (3 [(4,7-dichloro-1,3-benzoxazol-2-yl) methylamino]-5-ethyl-6-methyl-pyridin-2(1H) one) is a validated potential inhibitor of HDV replication and could be as a novel antiviral drug for the treatment of hepatitis D. COUNCLUSIONS: We have identified a novel antiviral drug by using innovative computational approaches. The results provide a basis to experimentally develop into drug which can be used for the treatment of delta hepatitis. PMID- 22224079 TI - Alteration in cellular immunity after chronic hepatitis B deteriorated into severe hepatitis and its significance. AB - BACKGROUND: It is difficult to predict what type of chronic hepatitis B (CHB) progresses to chronic severe hepatitis B. OBJECTIVES: This study aimed to observe changes in the HBV-specific and -nonspecific cellmediated immune responses after CHB deteriorates into severe hepatic disease and explore the significance of such changes. PATIENTS AND METHODS: This study aimed to observe changes in the HBV specific and -nonspecific cell-mediated immune responses after CHB deteriorates into severe hepatic disease and explore the significance of such changes. RESULTS: In 49 of 255 CHB patients (19.22%), the disease developed into chronic severe hepatitis (early stage) an average of 10.06 +/- 1.73 days after admission. CD4+ and NK cells levels in Group A were lower after progression into severe hepatitis than on the second day of admission (baseline) (P < 0.01). CD8+ cells and nonspecific CTL levels in Group A were higher after progression than at baseline (P < 0.01), and latter was higher than in Group B at baseline (P < 0.01); the levels of CD8+ cells and nonspecific CTLs in Group A after progression were significantly higher than those of Group B 10 days after admission (P < 0.01). There were no significant differences in HBV-specific CTL levels in Group A before and after progression to severe hepatitis (P > 0.05). CONCLUSIONS: Our results suggest that the immunological pathogenesis of chronic severe hepatitis B is related to significant rises in CD8+ and nonspecific CTL levels and that such increases predict that the disease will deteriorate into severe hepatitis. PMID- 22224080 TI - Efficacy of HBV vaccination in various stages of chronic kidney disease: is earlier better? AB - BACKGROUND: Despite improvement in hepatitis B infection prevention through national vaccination programs, implementation of compulsory and thorough blood donor screening, and reduction of transfusion numbers due to erythropoietin administration,hepatitis B remains a major concern in hemodialysis (HD) centers [1]. Compared to aresponse rate of over 90% in the normal population, only 50 to 60% of those with endstage renal disease (ESRD) achieve protective antibody levels following immunization against hepatitis B [2][3]. Various strategies have been developed to overcome the low seroconversion rate in ESRD patients, including co-administering zinc, gamma-interferon,thymopentin, interleukin-2, and levamisole as immunostimulants or adjuvants [3][4],changing the injection mode (intradermal versus intramuscular), or doubling the vaccine dose [5]. OBJECTIVES: Previous studies demonstrated that renal failure patients benefit from HBV vaccination; however, not all studies have demonstrated this. Therefore, we compared the rates of seroconversion (hepatitis B surface antibody [HBsAb] titer > 10 IU/mL) in patients at various stages of chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2) who received HBV vaccination. PATIENTS AND METHODS: A total of 167 patients in 3 different stages of CKD were vaccinated against HBV. Each patient received the vaccine according to a standardized vaccination schedule consisting of 40 MUg of the recombinant vaccine "Engerix" at 0, 1, and 6 months.Eight to 12 weeks after the last dose of vaccination, anti-HBsAb levels were measured. RESULTS: Mean age and eGFR were 57.4 +/- 16.5 years and 26.7 +/- 14.7 mL/min/1.73 m2, respectively.The overall seroconversion rate was 78%. Although a significant correlation between HBsAb titer and eGFR (r = 0.265, P = 0.001) was observed, in the multivariate analysis using age, CKD stage, diabetes mellitus, and gender as independent variables,the degree of renal function did not significantly contribute to seroconversion. In contrast,higher age (> 60 years) showed a significant negative correlation to seroconversion (odds ratio = 0.22; P = 0.004). CONCLOUSIONS: CKD patients of advanced age should be vaccinated against HBV. Although higher eGFR was not associated with improved seroconversion, the persistence of seroconversion was not evaluated; future studies should be conducted to develop recommendations for earlier or later vaccination. PMID- 22224081 TI - Expression characteristics of hypoxia-inducible factor-1alpha and its clinical values in diagnosis and prognosis of hepatocellular carcinoma. AB - BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) is a ubiquitously expressed oxygen regulated transcription factor composed of alpha and beta subunits. HIF-1 activates the transcription of various genes including those involved in the formation and metastatic growth of hepatocellular carcinoma (HCC). OBJECTIVES: To investigate the levels of hepatic and circulating HIF-1alpha expression in a range of patients with liver disease in order to determine how it can be used in the diagnosis of HCC and in establishing prognosis. PATIENTS AND METHODS: Total RNA was extracted from a self-controlled HCC and paracancerous specimen. HIF 1alpha mRNA was amplified by nested RT-PCR and confirmed by sequencing. Tissue HIF-1alpha was analyzed by immunohistochemistry. The levels of HIF-1alpha, vascular endothelial growth factor (VEGF), and angiopoietin-2 (Ang-2) expression in the sera of 220 patients with liver disease were quantitatively detected by ELISA. RESULTS: The positive staining of liver HIF-1alpha was brown and granule like and was mainly present in the cytoplasm, with lower levels in the nucleus of hepatocytes. Its incidence was 80% in HCC cells and 100% in paracancerous tissues, with no significant difference in HIF-1alpha expression in relation to tumor number, degree of differentiation, or hepatitis B surface antigen (HBsAg) positivity, but with some correlation between HIF-1alpha and tumor size. HIF 1alpha expression was detected in the sera of HCC patients at a significantly higher level than in cases of benign liver disease, with pathological characteristics associated with the levels of circulating VEGF and Ang-2 expression, the size of the tumor, and the level of extrahepatic metastasis, but not with patients' gender, age, or alpha-fetoprotein (AFP) levels. CONCLUSIONS: Hepatic HIF-1alpha expression is associated with the development and prognosis of HCC, and circulating HIF-1alpha level is a useful marker for HCC diagnosis and prognosis. PMID- 22224082 TI - Do prior contraceptive methods impact maternal carriage in patients with hepatitis B? AB - BACKGROUND: Hepatitis B virus (HBV) infection is highly endemic in many Asian countries. OBJECTIVES: We examined whether prior contraceptive methods and sexual behavioral factors impact maternal HBV carriage in an obstetric population. PATIENTS AND METHODS: For this study, pregnant women were considered to be representative of the sexually active and fertile female population. Contraceptive methods used prior to the index pregnancy were examined in 1283 pregnant Chinese women attending an antenatal clinic using a self-administered questionnaire, and correlated with the maternal HBV status determined using routine antenatal screening. RESULTS: In our study, 111 (8.7%) women were infected with HBV and there was no difference in the incidence of male condom usage between HBV-positive (88.3%) and HBV-negative (83.5%) women. No contraceptive method was associated with a reduced incidence of maternal HBV carriage, except for coitus interruptus. In multivariate analysis, only multiparity (adjusted odds ratio [aOR], 1.62) and more than 1 sexual partner (aOR, 1.57) were independent factors associated with maternal HBV carriage. CONCLUSIONS: Contraceptive use played only a minimal role in preventing sexual transmission of HBV infection within the sexually active female population in an endemic area. PMID- 22224083 TI - Frequency and mutation patterns of resistance in patients with chronic hepatitis B infection treated with nucleos(t)ide analogs in add-on and switch strategies. AB - BACKGROUND: Treatment for chronic hepatitis B (CHB) has improved over the last 10 years mainly due to the development of effective oral antiviral agents [nucleoside/nucleotide analogs (NUCs)]. OBJECTIVES: The aim of the present study is to identify the frequency and major patterns of resistance to the hepatitis B virus (HBV) in a Turkish population of CHB patients treated with NUCs using add on and switch therapy strategies. PATIENTS AND METHODS: The investigation involved a total of 194 patients (88 were treated using add-on therapy, and 106 were treated using switch therapy). We analyzed the HBV polymerase gene by amplification and direct sequencing procedures. RESULTS: Primary drug-resistance mutations were detected in 84 patients (43%; 42 in add-on therapy, and 42 in switch therapy) taking lamivudine (LAM), 10 patients (5%; 6 in add-on therapy, and 4 in switch therapy) taking entecavir (ETV), and 16 patients (8%; 8 in add-on therapy, and 8 in switch therapy) taking adefovir (ADV). The most common LAM and ETV resistance mutations were rtM204I/V, rtL180M and rtT184A/I/S, respectively, while rtA181T/V and rtN236T substitutions were the most frequently observed ADV resistance mutations. CONCLUSIONS: Patients with CHB who developed NUC resistance were managed using 2 different rescue strategies. The frequency and mutation pattern of resistance were similar in patients treated with add-on and switch strategies. These findings may be helpful in the management of rescue strategies in LAM-resistant patients. PMID- 22224084 TI - Hepatic failure related to itraconazole use successfully treated by corticosteroids. AB - BACKGROUND: Itraconazole is believed to carry a low risk of hepatic toxicity owing to its low affinity for the human P-450 enzyme. Therefore, hepatic failure caused by itraconazole is exceedingly rare. OBJECTIVES: We report the case of a 46-year-old woman who developed hepatic failure related to itraconazole that was administered for the treatment of onychomycosis. Her condition deteriorated after withdrawal of the drug, followed solely by supportive care initially. CASE REPORT: Treatment with corticosteroids was started 10 days after her admission, and her condition gradually improved. Unfortunately, her condition worsened when the dosage of corticosteroids was abruptly decreased. Ultimately, her condition improved with appropriate adjustments of corticosteroid dosage. DISCUSSION: We conclude that corticosteroid therapy may be effective for itraconazole-induced hepatitis, especially in those patients who do not respond to conservative treatment. Notably, any decrease in the dosage should be performed with caution. We also recommend that close monitoring of liver function is mandatory during the use of itraconazole. PMID- 22224085 TI - Nucleic acid testing for the detection of HBV DNA. PMID- 22224087 TI - New hepatitis B vaccine schedule for children with celiac disease. PMID- 22224088 TI - Hepatitis E virus infection in macaca mulatta. PMID- 22224089 TI - A modeling study of aldehyde inhibitors of human cathepsin K using partial least squares method. AB - Quantitative relationships between molecular structure of forty eight aldehyde compounds with their known Cathepsin K inhibitory effects were discovered by partial least squares (PLS) method. Evaluation of a test set of 10 compounds with the developed PLS model revealed that this model is reliable with a good predictability. Since the QSAR study was performed on the basis of theoretical descriptors calculated completely from the molecular structures, the proposed model could potentially provide useful information about the activity of the studied compounds. Various tests and criteria such as leave-one-out cross validation, leave-many-out cross validation, and also criteria suggested by Tropsha were employed to examine the predictability and robustness of the developed model. PMID- 22224090 TI - Bioactivity-guided isolation of spasmolytic components of Pycnocycla spinosa Decne ex Boiss. AB - Hydroalcoholic extract of Pycnocycla spinosa has spasmolytic effect in vitro and antidiarrhoeal action in vivo. The aim of this research was to separate fractions of total hydroalcoholic extract of P. spinosa guided by their spasmolytic activity. Aerial parts of P. spinosa were extracted with ethanol. The concentrated extract was subjected to column chromatography and thin layer chromatography. Initially four fractions were obtained (F1, F2, F3, and F4) and their spasmolytic activities were determined on ileum contraction induced by KCl (80 mM). The more active fraction was subjected to further isolation and tested to find its most active components. The active component was phytochemically characterized using phytochemical methods including ultraviolet and infrared spectroscopy. Hydroalcoholic extract of P. spinosa (10-320 MUg/ml) in a concentration dependent manner inhibited ileum contraction with the IC(50) value of 47 +/- 8.1 MUg/ml (mean +/- S.E.M., n=6). Fraction F2 was the most potent inhibitor of ileum contraction (IC(50)= 3.4 +/- 0.33 MUg/ml). From five sub fractions separated from fraction F2 (F2a, F2b, F2c, F2d, and F2e, respectively), F2c was a more active component with the IC(50) value of 2.6 +/- 0.27 MUg/ml. The primary results of target fraction (F2c) showed sugar moiety in its structure or in one of its components. In this research we have isolated pharmacological active fraction which is most likely responsible for antispasmodic action of P. spinosa hydroalcoholic extract. PMID- 22224092 TI - Synthesis of some new tricyclic 4(3H)-quinazolinone derivatives. AB - Quinazolinones are interesting molecules with a wide range of biological activities. We prepared a number of quinazolinone derivatives by the condensation of 5-bromo- or 5-nitro-substituted anthranilic acids with chloro-acyl chlorides. Anthranilic acid derivatives were treated with either 3-chloro-propionyl chloride or 4-chloro-butyryl chloride to yield the corresponding N-acyl-anthranilic acids. The resultants were reacted with acetic anhydride to afford the benzoxazinone intermediates, which upon condensation with elected amines in either DMF or ethanol gave the corresponding tricyclic 4(3H)-quinazolinone derivatives. It was found that reactions in DMF produced higher yields. PMID- 22224091 TI - Optimization of the expression of reteplase in Escherichia coli. AB - Reteplase is a segment of tissue plasminogen activator used for the removal of thrombi in blood vessels. In the present study the cloned reteplase gene was used for its expression in competent E. coli. The recombinant plasmid, pET15b/reteplase (rpET-BL21), was transformed into competent E. coli strain BL21 (DE3) cells. Overnight culture of the transformed bacteria was induced by the addition of isopropylthio-beta-Dgalactoside (IPTG) to the final concentrations of 0.25, 0.5, 1 and 1.5 mM. Also, the effects of different temperatures(25, 30, 37 and 39 degrees C), shaking speeds (100, 170 and 190 rpm), and various glucose concentrations (0.25, 0.5, 0.75 and 1 mM) on the expression of reteplase were examined. Samples were analyzed by SDS-PAGE. Maximum amount of protein production was obtained by the addition of 1 mM IPTG at 37 degrees C, 100 rpm of shaking speed in the absence of glucose. PMID- 22224093 TI - A Lack of tolerance to the anxiolytic action of Echium amoenum. AB - The anxiolytic effect of the flower of Echium. amoenum was shown in several experimental studies in mice. The present study was aimed to determine whether tolerance develops to anxiolytic action of E. amoenum in mice. NMRI male mice were injected intraperitoneal with hydroalcoholic extract (12.5, 25 and 50 mg/kg) or saline once each day (8 am) for period of 7 days and then tested on light/dark box model. Anxiolytic effect was determined by light/dark box and elevated plus maze. According to the results, hydroalcohoic extract of E. amoenum when given both acutely and chronically (7 days) at 25 and 50 mg/kg, significantly increased the time in the illuminated zone. The number of transitions in the light/dark apparatus, however, was not significantly altered by the tested doses of the plant. Diazepam at 0.5 and 1 mg/kg produced anxiolytic effect in both model of anxiety, namely, the light/dark box and elevated plus-maze. No tolerance was developed to the anxiolytic effect of E. amoenum extract after 7 days of treatment. Our results suggest that one week treatment with extract of the E. amoenum does not produce tolerance to its anxiolytic action. Longer period of treatment using implant procedure is probably necessary to cause molecular changes in order to induce tolerance. PMID- 22224094 TI - Development and validation of a rapid HPLC method for simultaneous analysis of budesonide and its novel synthesized hemiesters in colon specific formulations. AB - A simple and reliable reversed-phase high performance liquid chromatographic (HPLC) method was developed, validated and applied for determination of budesonide and its novel synthesized hemiesters in colon specific formulations and dissolution media. The method was employed on a MU-Bondapak C(18) column (250 mm * 4.6 mm, 5 MUm) at ambient temperature. The mobile phase consisted of acetonitrile: monobasic potassium phosphate containing orthophosphoric acid (55:45, pH 3.2) at a flow rate of 1 ml/min. The UV detection wavelength was set at 244 nm and 50 MUL of sample was injected into the HPLC system. Dexamethasone was used as the internal standard. The retention times for internal standard and budesonide were 4.5 and 7.2 min, respectively. The method was linear in the concentration range of 1-20 MUg/ml of budesonide (R(2)>0.999). Limit of detection and limit of quantitation were 0.05 and 0.5 MUg/ml, respectively. The method presented the requisite accuracy, selectivity, sensitivity and precision and showed good resolution for separation of the drug and related derivatives in the presence of excipients. The proposed method was successfully used for analysis of the drug and its derivatives in dissolution media and oral colon specific formulations prepared in our laboratory with enough reproducibility. PMID- 22224095 TI - Synthesis and biological evaluation of bidentate 3-hydroxypyridin-4-ones iron chelating agents. AB - A series of 3-hydroxypyridin-4-one derivatives (HPOs) were synthesized and their partition coefficient values (K(part)) were determined. The cytotoxic effects of these iron chelators against Hela cancer cells were also evaluated. The IC(50) of HPOs was determined using MTT assay. Among these ligands, compound 4e (K(part)=5.02) with an IC(50) of 30 MUM and 4f (K(part)=0.1) with an IC(50) of 700 MUM showed the lowest and highest IC(50)s, respectively. In conclusion, the introduction of a more hydrophobic functional group (such as butyl in compound 4e) on the nitrogen of pyridinone ring resulted in higher cytotoxic activity of ligands. PMID- 22224096 TI - Antinociceptive study of extracts of Platanus orientalis leaves in mice. AB - Platanus orientalis L. (Platanaceae) is a medicinal tree used in Iranian folklore and traditional medicine as a pain and inflammation reliever. In this study, the polyphenolic and total extract of P. orientalis leaves were prepared and their antinociceptive effects were studied in mice using the acetic acid-induced writhing, formalin and light tail flick tests. Both hydroalcoholic and polyphenolic extracts of P. orientalis at a dose of 2 g/kg significantly (P<0.05) reduced acetic acid-induced abdominal writhes. These extracts were also effective in suppression of formalin-induced pain behavior but they did not show any significant analgesia in light tail flick test. It is concluded that P. orientalis extracts have moderate analgesic effect and further studies are needed to elucidate the mechanism and active constituents. PMID- 22224097 TI - Situation of children's rights in Isfahan city. AB - BACKGROUND: Taking care of children makes them happy, lively and healthy, and it makes the society healthy. Children's rights have been discussed for years and the United Nation General Assembly has two conventions to prevent children abuse, the Minimum Age Convention of 1973 and the Convention on the Rights of the Child on 1989 However, in spite of these international agreements, the statistics show that the cases of children abuse increased from 749 cases in 1960 to one million cases in 1995 in the Western countries Islamic republic of IRAN agreed this international agreement in 1993. This study investigated the nature, structure and process of children's right in the city of Isfahan. METHODS: The study is qualitative, using Content Analysis. The purpose of the study is to discover children's right nature, and to describe the existing condition. Sampling method was purposive (or judgmental) and continued until data collection was completed. Sample consisted of 43 children, parents and teachers or trainers. Data were collected by observing schools and other public communities and also by interviews which were recorded, transcribed, reviewed and coded in three steps using qualitative research methods, Thematic Analysis, to extract the main conception. RESULTS: The findings of observations and interviews classified in 260 codes and then joined together again to extract the main concepts and categories related to children's rights. This step lead to 12 categories and in the third step, four major categories including psychological and personality, physical, economic and cultural factors were extracted. CONCLUSIONS: Based on the findings of this study, it is recommended that parents, teachers and other significant figures in the children's life should receive education on the children's rights and needs in various fields to become capable of developing policies and plans in this regard. PMID- 22224098 TI - The impact of group therapy training on social communications of Afghan immigrants. AB - BACKGROUND: Mental training considers sharing of mental health care information as the primary objective. The secondary objectives include facilitating dialogue about feelings such as isolation, sadness, labeling, loneliness and possible strategies for confronting with these feelings. Group therapy trainings have supportive functioning in accepting the environment so that the members are able to be part of the indigenous groups. However, no study has been ever done on the impact of this educational method on the communication problems of this group. This study aimed to determine the impact of group therapy training on the communication problems of Afghan immigrants. METHODS: This was a clinical trial study. Eighty-eight Afghan men were investigated. Sampling method was simple sampling method. Thereafter, the study subjects were divided randomly into two groups of test and control based on the inclusion criteria. Data collection tool was a self-made questionnaire about the social problems. For analyzing the data, software SPSS, independent t-test and paired t-test were used. RESULTS: Reviewing the data indicated lower mean score of the social problems after implementing the group therapy training in social communication compared with before implementing the group therapy training. Paired t-test showed a significant difference between mean scores of the social communication problems before and after the implementation of group therapy training. CONCLUSIONS: Given the effectiveness of the intervention, group therapy training on social problems in social communication of Afghan immigrants is recommended. This program should be part of continuous education and training of the Afghan immigrants. PMID- 22224099 TI - Evaluation of validity of midwifery special courses in Isfahan University of Medical Sciences. AB - BACKGROUND: The aim of training midwifery student is to increase scientific and practical abilities in trainees in order to present caring health services. Then, the evaluation tools of these abilities have great importance. This study tried to evaluate the content validity, criterion validity and base validity of academic exams. METHODS: This cross-sectional research was an evaluated type that has been done on 18 special theoretical courses of midwifery in 2 semesters in 2007-2008. The data gathered by checklists. The data about questionnaire and the result of analyzing exam questions (final and midterm) were compiled by 2 educating experts of medical education and 2 experts for each course. The data analyzed by SPSS software. For determining the base validity, spearman correlation test and for presenting descriptive results, distribution tables were applied. RESULTS: The evaluation of 1013 questions showed that in 18 courses, in 61.18% of exams, more than 90% of questions had content validity and in 28.27% of exams, in more than 90% of questions, criterion validity had been considered. The results showed that in 92.38% of questions, content validity and in 80.45% of questions, criterion validity was considered. 11 courses out of 18 courses had base validity. CONCLUSIONS: This survey showed that content validity of the exam questions in midwifery special theoretical courses was in favorable levels. But, the criterion validity of exam questions was far away from the ideal level. Then, education in each session can help the teachers achieve their exam purposes. PMID- 22224100 TI - Factors contributing to medication errors in Jordan: a nursing perspective. AB - BACKGROUND: Significant efforts have been directed to understand medication errors in recent years. Therefore, this study was conducted to determine the factors contributing to medication errors and related areas for improvement, as perceived by nurses. METHODS: Two hundred registered nurses were asked to complete a questionnaire which asked them to identify types, stages and issues perceived as contributing factors to medication errors. RESULTS: Out of 200 delivered questionnaire, a total of 126 of registered nurses responded or completed the questionnaire representing a 63% response rate. The leading types of medication errors were wrong patient (26.2%) and wrong dosage (26.2%). The highest level of medication errors were 48.4%, 31.7% and 11.1% related to nurses, physicians and pharmacists, respectively. In addition, the leading causes of medication errors were due to heavy workload (41.4%) and new staff (20.6%). CONCLUSIONS: A wide range of factors perceived as contributing factors of medication errors were identified. These results provide valuable information that could be used to improve the medication system in Jordan. PMID- 22224101 TI - The effects of nursing discharge plan (post-discharge education and follow-up) on self-care ability in patients with chronic schizophrenia hospitalized in Razi psychiatric Center. AB - BACKGROUND: Schizophrenia is a debilitating psychotic disorder that affects patients' personality, career-related and social functioning. Patients stop medications after discharge or inpatient care, when they feel relatively recovered. Most patients do not know that they are sick and they need medication for recovery due to lack of information and cognitive impairment, which makes them incompetent for self-care. A well designed discharge plan with disease management, prevention cares and education along with follow-up can significantly improve patients and decrease the health care costs; because it helps them take care of themselves and maintain a certain level of health. This study aimed to determine the effect of discharge, education and follow-up program on self-care abilities of patients with chronic schizophrenia. METHODS: This was a quasi experimental study, using a hospital based accessible sampling method. Participants included 60 schizophrenic patients who were randomly divided into two groups of intervention and control (30 patients in each group). After their symptoms were relatively controlled, the intervention group received a service of post-discharge program and home-care for 6 months. Data were collected before, and one month after education up to 6 month after discharge, using a demographic data questionnaire and a researcher-made questionnaire for self-care. Validity and reliability of instruments were approved by content validity and test-retest, respectively. Also, ethical approval for this study was obtained from the University of Social Welfare and Rehabilitation Science. RESULTS: There was a significant difference between the self-care abilities after intervention (from month 1 to month 6) in the intervention group compared with the controls. It means that conducting a discharge plan, education and follow-up increased the self-care abilities of the participants in the intervention group compared with themselves and control group members. CONCLUSIONS: Educating patients and their families and follow-up cares after discharge along with medications led to independency, self-care improvement and cognitive and social functioning of schizophrenic patients. PMID- 22224102 TI - The association between antenatal anxiety and fear of childbirth in nulliparous women: a prospective study. AB - BACKGROUND: This study aimed to examine the association of state and trait anxiety with fear of childbirth to explore whether there was any support for the hypothesis that state and trait anxiety are risk factors for the fear of childbirth or not. METHODS: In this prospective study, 156 pregnant women referred to the health centers of Qom. The study samples selected using simple random sampling method. Anxiety and fear of the childbirth in nulliparous women were measured using Spielberger's state-trait anxiety inventory and childbirth attitudes questionnaire (CAQ) at gestational age of 28 and 38 weeks respectively. The data were analyzed using Pearson correlation, t-test, logistic regression and software SPSS(16). RESULTS: Pearson correlation test indicated a positive and statistically significant association between fear of childbirth scores and state and trait anxiety (p < 0.05). Logistic regression analysis showed that state and trait anxiety at gestational age of week 28(th) increased the risk of fear of childbirth (odds ratio [OR] 2.7, 95% confidence interval [CI] 1.69-4.35) (p = 0.03) ([OR] 2.8, 95% [CI] 1.17-6.80) (p = 0.02) respectively. It also indicated that state and trait anxiety increased the risk of fear of childbirth at gestational age of week 38(th) ([OR] 2.7, 95% [CI] 1.03-6.80) and ([OR] 5.4, 95% [CI] 1.75-16.76) (p = 0.04) (p = 0.003) respectively. CONCLUSIONS: The results support this possibility that state and trait anxiety could be considered as risk factors for the fear of childbirth. Hence, considering other included biological and medical factors, measurement and control of psychological factors in pregnancy is recommended. PMID- 22224103 TI - The effects of regular breathing exercise and making bubbles on the pain of catheter insertion in school age children. AB - BACKGROUND: Treatment procedures are the most common sources of pain in children. Children with chronic diseases such as thalassemia experience many pains during painful procedures including at times of diagnosis, treatment and control of their disease. Several methods have been reported to reduce pain. Clinical professionals usually use distraction techniques to reduce pain. However, there is no agreement between them that which distraction technique is better for reducing pain. The aim of this study was omparing the effects of regular breathing exercise and making bubbles on the pain of catheter insertion in school age children. METHODS: This was a clinical trial on 60 children in the age range of 6 to 12 years, who were suffering from thalassemia and had a file in the Center for Thalassemia. Participants were randomly divided into two groups of experiment and control. Bubble making was performed for the first group and regular breathing exercise was performed for the second group. Data were collected using a demographic questionnaire, a scale for pediatric pain behavioral symptoms and Numeric Pain Rating Scale. Data were analyzed using descriptive (frequency, mean and standard deviation) and inferential statistics (ANOVA, Kruskal Wallis, and Mann Whitney U tests and Spearman correlation). RESULTS: The mean pain score based on the numerical scale was 5.60 +/- 3.13 in the control group, 1.60 +/- 1.75 in the bubble-making group and 1.85 +/- 1.42 in the breathing exercise group. The mean score of behavioral pain symptoms was 3.80 +/- 2.80 in the control group, 1.15 +/- 1.13 in the bubble-making group, and 0.96 +/- 0.75 in the breathing exercise group. Results showed a significant difference in the mean pain scores (based on numeric scale and pain behavior scale) between the control group and other groups after the injection, but the difference in the mean pain scores between the two groups of experiment after the injection was not significant. CONCLUSIONS: According to the results of this study, both distraction methods of regular breathing exercise and bubble-making can reduce the pain of catheter insertion in children and since there was no difference between their effects, they can be used based on the individual child's interest. PMID- 22224104 TI - Experiences of patients with multiple sclerosis from group counseling. AB - BACKGROUND: Group counseling is one of the most important methods in somatic and psychological rehabilitation of the multiple sclerosis (M.S.) patients. Knowing these patients' experiences, feelings, believes and emotion based on learning in group is necessary to indicate the importance of group discussion on quality of life of the patients. This study was done to achieve experiences of M.S. patients from group training. METHODS: This was a qualitative study using phenomenological method. The samples were selected using purposeful sampling. Ten patients from M.S. society who had passed group training were included in the study. The group training was done through seven sessions weekly and voluntarily. The participants were interviewed using in-depth interview. The average time of each interview was between 30-50 minutes which has been recorded digitally and moved to a compact disc to transcribe and analysis. RESULTS: The data analyzed using 7-step Colaizzi method. The data were transformed into 158 codes, 12 sub-concepts and 4 main concepts including emotional consequences, communication, quality of life and needs. CONCLUSIONS: M.S can lead to multiple problems in patients such as somatic, behavioral, emotional and social disorders. Group psychotherapy is one of the methods which can decrease these problems and improve rehabilitation of the patients. Group discussion helps patients to overcome adverse feelings, behaviors and thoughts and guides them to move in a meaningful life. It also can improve quality of life and mental health of the patients. PMID- 22224105 TI - Evaluation of midwifery students' competency in providing intrauterine device services using objective structured clinical examination. AB - BACKGROUND: Delivering IUD services is one of the important competencies that midwifery students must obtain during academic period. As Objective Structured Clinical Examination (OSCE) can be reasonably reliable, valid and objective method for clinical skills assessment, this study was conducted to assess midwifery students' skill in delivering intrauterine device (IUD) services using a clinical examination and their satisfaction from the OSCE. METHODS: All of the 62 eligible Bachelor of Science midwifery students of Mashhad University of Medical Sciences participated in a ten-station OSCE about delivering IUD services for 50 minutes in 2006. Students performed technical skills or interacted with standard patients in 6 stations and in 4 stations they answered to the related questions. Students' performance in 6 stations was rated by observer or standard patients using validated checklists. Students' level of satisfaction and also their experience of participating in OSCE examination were gathered. RESULTS: Performance of 98.2% of students was poor. On average, the students gained 49% of total score in counseling and screening, 35.7% in inserting the IUD, 40% in IUD removal and 24.4% in management of IUD side effect. Eighty percent of students rated their satisfaction from the OSCE high and very high. Students reported the OSCE as an enjoying examination experience. CONCLUSIONS: Students' skill in delivering IUD services was lower than expected level that shows the need to change the current teaching methods. OSCE is a valid evaluation method which provides valuable information which cannot be obtained by more traditional assessment modalities. Based on the finding of this study a workshop program on providing IUD services for midwifery students and family planning providers should be prepared. PMID- 22224106 TI - Differences in episiotomy technique between midwives and midwifery and medical students. AB - BACKGROUND: Episiotomy is the incision of perineum made to facilitate childbirth. Here are the two types of episiotomy: median and mediolateral. Considering the important role of incision characteristics such as length, angle and distance of initiation point from midperineum line in prevention of perineal rupture and reduction of further complications, this study investigated the comparison episiotomy in midwives and midwifery and medical students in maternity ward of hospitals of Mashhad University of Medical Sciences. METHODS: In this descriptive cross-sectional study, 127 midwives and midwifery and medical students completed the novel validated pictorial questionnaire. The length of episiotomy drawn, the distance from the sagittal plane at which the episiotomy was begun, and the angle of the episiotomy from the sagittal plane were evaluated. RESULTS: Median length of the episiotomy from the midline was 2.89 +/- 0.95 cm. Episiotomies drawn by midwives more angled than those drawn by students (P = 0.04) and median distance of the episiotomy from the midline in episiotomies drawn by students were significantly more than those drawn by midwives (P = 0.0001). CONCLUSIONS: This study demonstrated some differences in the episiotomy practice by midwives and midwifery and medical students. The differences demonstrated could predispose mothers to a greater risk of anal sphincter injuries and subsequence complications in child birth. PMID- 22224107 TI - Spiritual well-being of patients with multiple sclerosis. AB - BACKGROUND: Spiritual well-being is one of the fundamental concepts in chronic diseases which create meaning and purpose in life and is an important approach in promoting general health and quality of life. This study performed to determine the level of spiritual health and its dimensions in patients with multiple sclerosis (MS). METHODS: 236 members of Iranian MS Society were volunteered to participate in a descriptive co-relational study. Spiritual well-being was evaluated by The Spiritual Well-Being Scale (SWBS) questionnaires in two religious and Existential dimensions. Descriptive statistics, ANOVA, t-test and Pearson correlation coefficient were used to analyse the data. RESULTS: The majority of patients (% 97.9) showed moderate spiritual well-being (mean score = 74.3, SD= 8.90). Although Existential well-being (mean score = 40.3, SD= 5.51) was higher than religious well- being (mean score = 33.9, SD= 4.88). A significant relationship was seen between economic status and the spiritual well being. CONCLUSIONS: The results emphasize on the necessity of spiritual well being as an effective factor on different aspects of these patients' life. This key point is useful and even necessary to be considered to design programs of care and cure for these patients in a country (like Iran) with cultural and religious beliefs. On the other hand, patients' economic status should be considered. PMID- 22224108 TI - Continuous exclusive breastfeeding and some related factors in the selected hospitals of Isfahan. AB - BACKGROUND: Exclusive nutrition with breastfeeding is the health provider of the infant and mothers and its continuing would provide more advantages. Exclusive nutrition on different communities is affected by different factors. This study aimed to determine continuous exclusive breastfeeding and some of the related factors. METHODS: This was a descriptive-analysis prospective study. The study population included all the breastfed mothers admitted in the obstetrics wards of the selected hospitals. Selecting the hospitals also was done randomly. Data collection tools included a questionnaire completed by 291 mothers. To obtain the data about breastfeeding duration, mothers were phone called at the first and sixth postpartum months. The collected data were analyzed using descriptive and analytical statistics and software SPSS. RESULTS: Estimation of mean and standard deviation of exclusive breastfeeding duration at the first and sixth months after the delivery, respectively, were 3.86 (0.55) and 23.67 (6.63) weeks. One month after the delivery, 93.1%, 6.2% and 0.7% of the mothers, respectively, had exclusive breastfeeding, breastfeeding with formula milk or other ingredients and discontinuation of breastfeeding; 6 months after the delivery, these values changed to 86.3, 12 and 1.7%, respectively. The most frequent period of breastfeeding discontinuation (6.9%) was related to 1-4 weeks. The results indicated that statistically there was a significant correlation between breastfeeding duration and age and the birth hospital. While the results of the study showed no association between breastfeeding duration and number of the children, duration of marriage, educational level and mothers' occupation. CONCLUSIONS: The findings of the present study represented a high continuous exclusive breastfeeding which perhaps was due to applied baby-friendly hospitals strategies. Furthermore, to prevent from discontinuation of exclusive breastfeeding, knowing the discontinuation time and its related factors, particularly the first four postpartum weeks, can increase the knowledge of the health staff about counseling and education. PMID- 22224109 TI - The effect of sodium and ultra filtration profile combination and cold dialysate on hypotension during hemodialysis and its symptoms. AB - BACKGROUND: One of the most prevalent side effects of hemodialysis is intradialytic hypotension and its symptoms. Using sodium profiles 3 and ultra filtration profile 3 and cold dialysate are the ways to overcome this problem. Since none of these methods could control this complication lonely, this study was done to investigate the effect of combination of two methods on intradialytic hypotension. METHODS: This study was a cross over clinical trial in which 24 patients experienced intradialytic hypotension frequently, underwent three different methods of treatments during 9 successive hemodialysis sessions, group 1 used sodium profile 3 and ultra filtration profile 3, group 2 underwent hemodialysis with cold dialysate, and group 3received combination of both methods. Blood pressure was controlled before, during (3 times) and after hemodialysis. Data were analyzed via SPSS version 15, using x(2) and ANOVA test. RESULTS: Findings showed that although there was no significant difference considering intradialytic hypotension and its symptoms in two groups of sodium profile 3 and ultra filtration profile 3 and cold dialysate and the combination group (p > 0.05), but there was a significant difference considering the mean of blood pressure in three groups (p < 0.05). In combination group, drop of systolic and diastolic blood pressure was less than groups using each of methods. CONCLUSIONS: Concerning the decreased rate of hypotension using combination method, nurses can use this method to decrease intradialytic hypotension and help the patients undergo hemodialysis for enough time and improve their quality of life. PMID- 22224110 TI - The relationship between students' study habits, happiness and depression. AB - BACKGROUND: One of the important requirements for cultural, social and even economic development is having a book-loving nation. In order to achieve this, there is a need for purposeful and continuous programming. The purpose of this research was to determine the relationship between students' study habits, happiness and depression in Isfahan University of Medical Science. METHODS: This research was a kind of descriptive and correlation survey. Statistical population included all MSc and PhD students in the second semester of the Isfahan University of Medical Science (263 students). In this research, stratified and random sampling was used in which a sample of 100 students was selected. Data collection instruments were Beck Depression Inventory (BDI), Oxford Happiness Inventory and a researcher-made questionnaire to determine the amount of students' study. Validity of this questionnaires was determined by structure and content related validity and its reliability was calculated by Cronbach's alpha coefficient for the first (r = 0.94), second (r = 0.91) and third (r = 0.85) questionnaire. Analysis of research findings was done through descriptive and inferential statistics. RESULTS: Findings showed that 68.8 percent of students study less than 5 hours and only 2.5 percent of students study more than 10 hours. 65 percent of students had high amount of happiness and 35 percent had medium amount of happiness. In 60 percent of students there was no symptom of depression and 7.5 had depression symptoms. Also, there was no significant relationship between happiness and studying but there was a significant and negative relationship between studying and depression and happiness and depression. CONCLUSIONS: The amount of study and tendency for reading are among the most important indices of human growth in terms of potential abilities for achieving a perfect human life and to prevent one-dimensional thinking. Thus, finding ways to encourage students to study is considered essential to achieve a healthy and developed society. PMID- 22224111 TI - The effect of using maternal care log book on pregnancy outcome in clients referred to private gynecologists and midwives offices. AB - BACKGROUND: One of the important health indicators in every society is maternal and neonatal health status. Provision of the best prenatal care can reduce mortality rate in these two susceptible groups. This study focused on the effect of maternal care log book on pregnancy outcome. METHODS: This was a clinical trial and 180 samples were randomly selected from the mothers referred to private offices of gynecologists and midwives and were divided into two groups of case and control. The outcome of pregnancy was determined by prenatal care log books in the case group and with pregnancy card in the control group. The data were collected using quality of life questionnaire and a pregnancy complications questionnaire. Descriptive and analytical statistical methods (Fisher's exact test, independent t-test and chi-square test) were used to analyze the data. RESULTS: The results demonstrated a significant difference between case and control groups concerning normal vaginal delivery (p = 0.01), preterm labor (p = 0.015) and postpartum infection (p = 0.012). The result of quality of life in physical and mental domains and especially in mental domains was better in the case group than in the control group (p = 0.026 in physical and mental dimensions and (p = 0.02 in mental dimensions). This difference was lower in physical dimensions alone (p = 0.049). However, there was no significant difference between the case and control groups in terms of preeclampsia, intrauterine growth retardation and intrauterine fetal death. CONCLUSIONS: As found out by the results, using maternal log book of mothers cares due to its comprehensive care items was more effective than simple maternal cards used by gynecologists and midwives. This can bring about better prenatal care and detected pregnancy complications. PMID- 22224112 TI - Comparison of head nurses and practicing nurses in nurse competence assessment. AB - BACKGROUND: Nurses play a crucial role in patient-care. Therefore, assessing nurses' clinical competence is essential to achieve qualified and safe care. The aim of this study was to determine and compare the competence assessments made by head nurses and practicing nurses in a university hospital in Iran in 2009. METHODS: A cross-sectional survey was conducted to make comparisons of both self assessment of nurse competence as well as assessment made by their respective head nurses working in a university hospital setting in Iran. The instrument employed for data collection was Nurse Competence Scale (NCS), whose reliability and validity have been previously confirmed. The clinical competence of the nurses in 73 skills under 7 categories was determined based on a Visual Analogue Scale (VAS) (0 to 100). They were also asked to indicate the extent to which their competence was actually used in clinical practice on a four-point scale of Likert. The data was analyzed through descriptive and inferential statistics. RESULTS: Comparison of self-assessment (87.03 +/- 10.03) and the assessment done by head nurses (80.15 +/- 15.54) showed a significant difference but no precise differences were found between the assessment methods for the frequency of using these competencies. CONCLUSIONS: The results of this study indicated no consensus between the nurses owns assessment and their head nurse assessment. Therefore, it is necessary to use a combination of nurses' competence assessment methods in order to reach a more valid and precise conclusion. PMID- 22224113 TI - A comparative study on effect of e-learning and instructor-led methods on nurses' documentation competency. AB - BACKGROUND: Accurate recording of the nursing care indicates the care performance and its quality, so that, any failure in documentation can be a reason for inadequate patient care. Therefore, improving nurses' skills in this field using effective educational methods is of high importance. Since traditional teaching methods are not suitable for communities with rapid knowledge expansion and constant changes, e-learning methods can be a viable alternative. To show the importance of e-learning methods on nurses' care reporting skills, this study was performed to compare the e-learning methods with the traditional instructor-led methods. METHODS: This was a quasi-experimental study aimed to compare the effect of two teaching methods (e-learning and lecture) on nursing documentation and examine the differences in acquiring competency on documentation between nurses who participated in the e-learning (n = 30) and nurses in a lecture group (n = 31). RESULTS: The results of the present study indicated that statistically there was no significant difference between the two groups. The findings also revealed that statistically there was no significant correlation between the two groups toward demographic variables. However, we believe that due to benefits of e learning against traditional instructor-led method, and according to their equal effect on nurses' documentation competency, it can be a qualified substitute for traditional instructor-led method. CONCLUSIONS: E-learning as a student-centered method as well as lecture method equally promote competency of the nurses on documentation. Therefore, e-learning can be used to facilitate the implementation of nursing educational programs. PMID- 22224114 TI - The process of major depressive disorder (MDD) in women referred to the health centers. AB - BACKGROUND: Major depressive disorder is one of the most widespread psychological problems in the world. The feelings of a person who is affected by this condition is boring. This article aimed to shed light on the experiences of women with major depressive disorder. METHODS: A qualitative approach with thematic analysis design has been used to describe the studied phenomenon as experienced by the participants. RESULTS: Analysis of 92 codes from 12 interviewed participants brought about 4 main themes including loss, inappropriate marital life, cognitive errors, and economic condition. CONCLUSIONS: This study revealed main concerns of the participants through their life and suggested that psychotherapists should be more sensitive to these aspects of their depress patients' experiences. PMID- 22224115 TI - Clinical learning environment in viewpoint of nursing students in Tabriz University of Medical Sciences. AB - BACKGROUND: Clinical learning environment (CLE) is an important factor in clinical education of nursing students. The CLE of nursing students has been less studied in Iran. Therefore, the aim of present study was to investigate the viewpoints of nursing students in Tabriz nursing faculty regarding CLE. METHODS: In this descriptive study, 133 nursing students participated. For data collection the CLE inventory was used that assesses six aspects including personalization, cooperation, task orientation, innovation, satisfaction with clinical education, and satisfaction with clinical instructors. The score ranged from 46 to 184 and scores below 115 were considered as a negative. RESULTS: The average score of viewpoint regarding CLE was 108.4 (12.7) and 93.2% of students had a negative viewpoint about CLE. CONCLUSIONS: Educational authorities should have special attention to the quality of CLE of nursing students. PMID- 22224117 TI - Welcome to the JOCB Bulletin. PMID- 22224116 TI - What health professionals should know about the health effects of air pollution and climate change on children and pregnant mothers. AB - BACKGROUND: Health professionals face the adverse health effects of climate change and air pollution in their practices. This review underscores the effects of these environmental factors on maternal and children's health, as the most vulnerable groups to climate change and air pollution. METHODS: We reviewed electronic databases for a search of the literature to find relevant studies published in English from 1990 to 2011. RESULTS: Environmental factors, notably climate change and air pollution influence children's health before conception and continue during pregnancy, childhood, and adolescence. Experts have suggested that such health hazards may represent the greatest public health challenge that humanity has faced. The accumulation of greenhouse gases such as carbon dioxide, primarily from burning fossil fuels, results in warming which has an impact on air pollution particularly on levels of ozone and particulates. Heat-related health effects include increased rates of pregnancy complications, pre-eclampsia, eclampsia, low birth weight, renal effects, vector-borne diseases as malaria and dengue, increased diarrheal and respiratory disease, food insecurity, decreased quality of foods (notably grains), malnutrition, water scarcity, exposures to toxic chemicals, worsened poverty, natural disasters and population displacement. Air pollution has many adverse health effects for mothers and children. In addition to short-term effects like premature labour, intrauterine growth retardation, neonatal and infant mortality rate, malignancies (notably leukaemia and Hodgkin lymphoma), respiratory diseases, allergic disorders and anaemia, exposure to criteria air pollutants from early life might be associated with increase in stress oxidative, inflammation and endothelial dysfunction which in turn might have long-term effects on chronic non-communicable diseases. CONCLUSIONS: Health professionals have an exclusive capability to help prevent and reduce the harmful effects of environmental factors for high-risk groups, and should consider this capacity in their usual practice. PMID- 22224118 TI - Rapid Sequence Intubation from the Patient's Perspective. AB - INTRODUCTION: This study assesses the efficacy of the rapid sequence intubation (RSI) protocol in preventing patient recollection of resuscitative events and patient discomfort during intubation, as subjectively determined by the patient. METHODS: This was a prospective study of all patients intubated at Los Angeles County, University of Southern California Medical Center from July 2009 to January 2010. Extubated patients were interviewed using a standard questionnaire and data collection tool. RESULTS: Of 211 airway codes, 201 were excluded due to death before extubation, transfer, or persistent vegetative state, leaving 10 awake, alert subjects who were interviewed regarding their recollection of the RSI and resuscitation. Five had recollection of the event. Most patients recalling RSI described the event as painful or uncomfortable despite receiving the recommended doses of sedation/induction agents. CONCLUSION: In this cohort of 10 patients intubated using typical agents, 5 remembered some details of their intubation and 2 described pain that was 10/10 on a verbal pain scale. Further work is indicated to ensure that the medications used during this procedure provide the appropriate sedation and amnesia. PMID- 22224119 TI - Impending Airway Compromise due to Cystic Hygroma. AB - We report on a 3-month-old infant, who arrived in the pediatric emergency department (ED) with a cervical cystic hygroma causing an impending compromise of the airway. We recognize that such a lesion can rapidly progress, and the judicious use of imaging in the ED may help to avoid airway compromise and possibly fatal complications. PMID- 22224120 TI - Quincke's Disease. PMID- 22224121 TI - Myositis ossificans. PMID- 22224122 TI - Nonconvulsive status epilepticus in hepatic encephalopathy. AB - We discuss a case of a 64-year-old male with a history of liver failure presenting with altered mental status, initially diagnosed with hepatic encephalopathy but ultimately diagnosed with nonconvulsive status epilepticus (NCSE) by electroencephalogram (EEG). NCSE is a difficult diagnosis to make, given no clear consensus on diagnostic criteria. Especially in the intensive care unit setting of persistent altered mental status with no clear etiology, NCSE must be considered in the differential diagnosis, as the consequences of delayed diagnosis and treatment can be substantial. EEG can be useful in the evaluation of patients with hepatic encephalopathy who have persistently altered levels of consciousness despite optimal medical management. PMID- 22224123 TI - Antibiotic prescribing practices of emergency physicians and patient expectations for uncomplicated lacerations. AB - INTRODUCTION: Prophylactic antibiotics have not been found to have a benefit in the setting of uncomplicated lacerations. We evaluated the proportion of patients with uncomplicated lacerations who are prescribed prophylactic antibiotics in the emergency department (ED), factors that physicians considered when prescribing antibiotics, and factors associated with patient satisfaction. METHODS: Adults and children presenting to 10 academic EDs with acute lacerations were enrolled. Enrolled patients were interviewed before and after their physician encounter in the ED and 2 weeks later. Physicians were interviewed in the ED after the patient encounter about factors that influenced their management decisions, including their perceptions of patients' expectations. We included patients with uncomplicated lacerations (without contamination, infection, bone, tendon, or joint involvement) for analysis. RESULTS: Of 436 patients enrolled, 260 had uncomplicated lacerations, and of these, 55 (21%) were treated with antibiotics in the ED or by prescription. Physicians were more likely to use antibiotics when the wound was more than 8 hours old, involved a puncture or amputation, and when the patient lacked medical insurance. A treatment course of 7 days or greater was given to 24 of 45 patients (53%) receiving outpatient prescriptions. Patient satisfaction was not associated with antibiotic use. CONCLUSION: Antibiotics were used for about one fifth of ED patients with uncomplicated lacerations despite a lack of evidence for efficacy. PMID- 22224124 TI - Comparison of three aspirin formulations in human volunteers. AB - INTRODUCTION: The treatment of acute coronary syndrome (ACS) includes the administration of aspirin. Current guidelines recommend chewing aspirin tablets to increase absorption. While this is intuitive, there are scant data supporting this recommendation. The purpose of this study is to assess which of 3 different aspirin formulations is most rapidly absorbed after ingestion. METHODS: A prospective, open-label, 3-way crossover volunteer study at a tertiary university medical center with human subjects 18 years or older. Fasted subjects were randomly assigned to receive aspirin 1,950 mg as (1) solid aspirin tablets swallowed whole, (2) solid aspirin tablet chewed then swallowed, or (3) a chewable aspirin formulation chewed and swallowed. Serum salicylate measurements were obtained over a period of 180 minutes. Pharmacokinetic parameters were determined. RESULTS: Thirteen males and 1 female completed all 3 arms of study. Peak serum salicylate concentrations were seen at 180 minutes in all groups. Mean peaks were 10.4, 11.3, and 12.2 mg/dL in groups 1, 2, and 3, respectively. Mean area under the time concentration was 1,153, 1,401, and 1,743 mg-min/dL in groups 1, 2, and 3, respectively. No measurable salicylate concentrations were seen in 6 subjects in group 1 at 60 minutes as compared to 1 subject in group 2. All subjects in group 3 had measurable levels at 45 minutes. There were no adverse effects in any of the subjects during the study period. CONCLUSION: Our data demonstrate that the chewable aspirin formulation achieved the most rapid rate of absorption. In addition, the chewable formulation absorption was more complete than the other formulations at 180 minutes. These data suggest that in the treatment of ACS, a chewable aspirin formulation may be preferable to solid tablet aspirin, either chewed or swallowed. PMID- 22224126 TI - Tattoos and piercings: a review for the emergency physician. AB - Tattoos and piercings are increasingly part of everyday life for large sections of the population, and more emergency physicians are seeing these body modifications (BM) adorn their patients. In this review we elucidate the most common forms of these BMs, we describe how they may affect both the physical and psychological health of the patient undergoing treatment, and also try to educate around any potential pitfalls in treating associated complications. PMID- 22224125 TI - Reversal of warfarin-induced hemorrhage in the emergency department. AB - Warfarin, an oral vitamin K antagonist, is used to prevent arterial and venous thromboembolism in patients suffering from a multitude of diseases. In 2004, 31 million warfarin prescriptions were dispensed in the United States. Warfarin inhibits the activation of the vitamin K-dependent clotting factors (Factors II, VII, IX, and X) and regulatory proteins (proteins C, S, and Z). It is one of the leading drugs implicated in emergency room visits for adverse drug reactions. Annually the frequency of bleeding complications associated with overanticoagulation is 15% to 20%, with fatal bleeds measuring as high as 1% to 3%. The most effective method of warfarin reversal involves the use of Four Factor Prothrombin Complex Concentrate (PCC), which is widely used throughout Europe but is unavailable in the United States. The current therapies available to emergency room physicians in the United States are fresh frozen plasma, recombinant Factor VIIa (rFVIIa), Factor Eight Inhibitory Bypassing Activity, or Three Factor PCC concomitantly administered with vitamin K. We review the advantages and disadvantages of these therapies and recommend Three Factor PCC with small doses of rFVIIa and with vitamin K in life-threatening situations if Four Factor PCC is unavailable. PMID- 22224127 TI - Propofol and Etomidate are Safe for Deep Sedation in the Emergency Department. AB - This study describes deep sedations performed for painful procedures completed in the emergency department at an academic tertiary care hospital during an 18-month period. One hundred consecutive cases were retrospectively reviewed to describe indications, complications, procedural lengths, medication dosing, and safety of these sedations. Propofol and etomidate were the preferred agents. We found that there were relatively few complications (10%), with only 2 of these (2%) being major complications. All complications were brief and did not adversely affect patient outcomes. This data further demonstrate the safety profile of deep sedation medications in the hands of emergency physicians trained in sedation and advanced airway techniques. PMID- 22224128 TI - Ileus and small bowel obstruction in an emergency department observation unit: are there outcome predictors? AB - INTRODUCTION: The purpose of our study was to describe the evaluation and outcome of patients with ileus and bowel obstruction admitted to an emergency department (ED) observation unit (OU) and to identify predictors of successful management for such patients. METHODS: We performed a retrospective chart review of 129 patients admitted to a university-affiliated, urban, tertiary hospital ED OU from January 1999 through November 2004. Inclusion criteria were all adult patients admitted to the OU with an ED diagnosis of ileus, partial small bowel obstruction, or small bowel obstruction, and electronic medical records available for review. The following variables were examined: ED diagnosis, history of similar admission, number of prior abdominal surgeries, surgery in the month before, administration of opioid analgesia at any time after presentation, radiographs demonstrating air-fluid levels or dilated loops of small bowel, hypokalemia, use of nasogastric decompression, and surgical consultation. RESULTS: Treatment failure, defined as hospital admission from the OU, occurred in 65 (50.4%) of 129 patients. Only the use of a nasogastric tube was associated with OU failure (21% discharged versus 79% requiring admission, P = 0.0004; odds ratio, 5.294; confidence interval, 1.982-14.14). CONCLUSION: Half of the patients admitted to our ED OU with ileus or varying degrees of small bowel obstruction required hospital admission. The requirement of a nasogastric tube in such patients was associated with a greater rate of observation unit failure. PMID- 22224129 TI - Prehospital 12-Lead Electrocardiogram within 60 Minutes Differentiates Proximal versus Nonproximal Left Anterior Descending Artery Myocardial Infarction. AB - INTRODUCTION: Acute anterior myocardial infarctions caused by proximal left anterior descending (LAD) artery occlusions are associated with a higher morbidity and mortality. Early identification of high-risk patients via the 12 lead electrocardiogram (ECG) could assist physicians and emergency response teams in providing early and aggressive care for patients with anterior ST-elevation myocardial infarctions (STEMI). Approximately 25% of US hospitals have primary percutaneous coronary intervention (PCI) capability for the treatment of acute myocardial infarctions. Given the paucity of hospitals capable of PCI, early identification of more severe myocardial infarction may prompt emergency medical service routing of these patients to PCI-capable hospitals. We sought to determine if the 12 lead ECG is capable of predicting proximal LAD artery occlusions. METHODS: In a retrospective, post-hoc analysis of the Pre-Hospital Administration of Thrombolytic Therapy with Urgent Culprit Artery Revascularization pilot trial, we compared the ECG findings of proximal and nonproximal LAD occlusions for patients who had undergone an ECG within 180 minutes of symptom onset. RESULTS: In this study, 72 patients had anterior STEMIs, with ECGs performed within 180 minutes of symptom onset. In patients who had undergone ECGs within 60 minutes (n = 35), the mean sum of ST elevation (STE) in leads V1 through V6 plus ST depression (STD) in leads II, III, and aVF was 19.2 mm for proximal LAD occlusions and 11.7 mm for nonproximal LAD occlusions (P = 0.007). A sum STE in V1 through V6 plus STD in II, III, and aVF of at least 17.5 mm had a sensitivity of 52.3%, specificity of 92.9%, positive predictive value of 91.7%, and negative predictive value of 56.5% for proximal LAD occlusions. When the ECG was performed more than 60 minutes after symptom onset (n = 37), there was no significant difference in ST-segment deviation between the 2 groups. CONCLUSION: The sum STE (V1-V6) and STD (II, III, aVF) on a 12-lead ECG can be used to predict proximal LAD occlusions if performed within the first hour of symptom onset. This should be considered a high-risk finding and may prompt prehospital direction of such patients to PCI-capable hospitals. PMID- 22224131 TI - Course of untreated high blood pressure in the emergency department. AB - INTRODUCTION: No clear understanding exists about the course of a patient's blood pressure (BP) during an emergency department (ED) visit. Prior investigations have demonstrated that BP can be reduced by removing patients from treatment areas or by placing patients supine and observing them for several hours. However, modern EDs are chaotic and noisy places where patients and their families wait for long periods in an unfamiliar environment. We sought to determine the stability of repeated BP measurements in the ED environment. METHODS: A prospective study was performed at an urban ED. Research assistants trained and certified in BP measurement obtained sequential manual BPs and heart rates on a convenience sample of 76 patients, beginning with the patient arrival in the ED. Patients were observed through their stay for up to 2 hours, and BP was measured at 10-minute intervals. Data analysis with SAS PROC MIXED (SAS Institute, Cary, North Carolina) for regression models with correlated data determined the shape of the curve as BP changed over time. Patients were grouped on the basis of their presenting BP as normal (less than 140/90), elevated (140 160/90-100), or severely elevated (greater than 160/100) for the regression analysis. RESULTS: A statistically significant downward trend in systolic and diastolic BP was observed only for those patients presenting with severely elevated BPs (ie, greater than 160/100). CONCLUSION: We demonstrate a statistically significant decline in systolic and diastolic BP over time spent in the ED only for patients with severely elevated presenting BPs. PMID- 22224130 TI - Cardiac complications in acute ischemic stroke. AB - INTRODUCTION: To characterize cardiac complications in acute ischemic stroke (AIS) patients admitted from an urban emergency department (ED). METHODS: Retrospective cross-sectional study evaluating AIS patients admitted from the ED within 24 hours of symptom onset who also had an echocardiogram performed within 72 hours of admission. RESULTS: Two hundred AIS patients were identified with an overall in-hospital mortality rate of 8% (n = 16). In our cohort, 57 (28.5%) of 200 had an ejection fraction less than 50%, 35 (20.4%) of 171 had ischemic changes on electrocardiogram (ECG), 18 (10.5%) of 171 presented in active atrial fibrillation, 21 (13.0%) of 161 had serum troponin elevation, and 2 (1.1%) of 184 survivors had potentially lethal arrhythmias on telemetry monitoring. Subgroup analysis revealed higher in-hospital mortality rates among those with systolic dysfunction (15.8% versus 4.9%; P = 0.0180), troponin elevation (38.1% versus 3.4%; P < 0.0001), atrial fibrillation on ECG (33.3% versus 3.8%; P = 0.0003), and ischemic changes on ECG (17.1% versus 6.1%; P = 0.0398) compared with those without. CONCLUSION: A proportion of AIS patients may have cardiac complications. Systolic dysfunction, troponin elevation, atrial fibrillation, or ischemic changes on ECG may be associated with higher in-hospital mortality rates. These findings support the adjunctive role of cardiac-monitoring strategies in the acute presentation of AIS. PMID- 22224133 TI - "Playboy bunny" sign of congestive heart failure. AB - In emergency, ultrasound has been widely used as a noninvasive and effective examination to evaluate congestive heart failure. We highlight "Playboy Bunny" sign as a reliable marker and an important clue to the diagnosis of passive hepatic congestion, caused by congestive heart failure. PMID- 22224132 TI - Vascular pedicle width on chest radiograph as a measure of volume overload: meta analysis. AB - INTRODUCTION: Vascular pedicle width (VPW), a measurement obtained from a chest radiograph (CR), is thought to be an indicator of circulating blood volume. To date there are only a handful of studies that demonstrate a correlation between high VPW and volume overload, each utilizing different VPW values and CR techniques. Our objective was to determine a mean VPW measurement from erect and supine CRs and to determine whether VPW correlates with volume overload. METHODS: MEDLINE database, Web of Science, and the Cochrane Central Register of Controlled Trials were searched electronically for relevant articles. References from the original and review publications selected electronically were manually searched for additional relevant articles. Two investigators independently reviewed relevant articles for inclusion criteria and data extraction. Mean VPW measurements from both supine and erect CRs and their correlation with volume overload were calculated. RESULTS: Data from 8 studies with a total of 363 subjects were included, resulting in mean VPW measurements of 71 mm (95% confidence interval [CI] 64.9-77.3) and 62 mm (95% CI 49.3-75.1) for supine and erect CRs, respectively. The correlation coefficients for volume overload and VPW were 0.81 (95% CI 0.74-0.86) for both CR techniques and 0.81 (95% CI 0.72-0.87) for supine CR and 0.80 (95% CI 0.69-0.87) for erect CR, respectively. CONCLUSION: There is a clinical and statistical correlation between VPW and volume overload. VPW may be used to evaluate the volume status of a patient regardless of the CR technique used. PMID- 22224135 TI - Can emergency medicine residents reliably use the internet to answer clinical questions? AB - INTRODUCTION: The study objective was to determine the accuracy of answers to clinical questions by emergency medicine (EM) residents conducting Internet searches by using Google. Emergency physicians commonly turn to outside resources to answer clinical questions that arise in the emergency department (ED). Internet access in the ED has supplanted textbooks for references because it is perceived as being more up to date. Although Google is the most widely used general Internet search engine, it is not medically oriented and merely provides links to other sources. Users must judge the reliability of the information obtained on the links. We frequently observed EM faculty and residents using Google rather than medicine-specific databases to seek answers to clinical questions. METHODS: Two EM faculties developed a clinically oriented test for residents to take without the use of any outside aid. They were instructed to answer each question only if they were confident enough of their answer to implement it in a patient-care situation. Questions marked as unsure or answered incorrectly were used to construct a second test for each subject. On the second test, they were instructed to use Google as a resource to find links that contained answers. RESULTS: Thirty-three residents participated. The means for the initial test were 32% correct, 28% incorrect, and 40% unsure. On the Google test, the mean for correct answers was 59%; 33% of answers were incorrect and 8% were unsure. CONCLUSION: EM residents' ability to answer clinical questions correctly by using Web sites from Google searches was poor. More concerning was that unsure answers decreased, whereas incorrect answers increased. The Internet appears to have given the residents a false sense of security in their answers. Innovations, such as Internet access in the ED, should be studied carefully before being accepted as reliable tools for teaching clinical decision making. PMID- 22224134 TI - Pharmaceutical sponsorship bias influences thrombolytic literature in acute ischemic stroke. AB - BACKGROUND: The efficacy of thrombolytic therapy for acute ischemic stroke remains controversial in emergency medicine and has not been fully endorsed by either the American College of Emergency Physicians or the American Academy of emergency medicine. A growing recognition exists of the influence of pharmaceutical sponsorship on the reported findings of published clinical trials. Sponsorship bias has been suggested as a potential criticism of the literature and guidelines favoring thrombolytic therapy. OBJECTIVE: The objective of this study is to review the most influential literature regarding thrombolytic therapy for acute ischemic stroke and document the presence or absence of pharmaceutical sponsorship. METHODS: A publication-citation analysis was performed to identify the most frequently cited articles pertaining to thrombolytic therapy for acute ischemic stroke. Identified articles were reviewed for disclosures of pharmaceutical funding. RESULTS: Of the 20 most-cited articles pertaining to thrombolytic therapy for acute stroke, 17 (85%) disclosed pharmaceutical sponsorship. These disclosures range from general sponsorship to direct employment of authors by pharmaceutical companies. CONCLUSION: An overwhelming predominance of the most influential literature regarding thrombolytic therapy for acute ischemic stroke is susceptible to sponsorship bias. This potential bias may provide a basis for physician concern regarding the efficacy and safety of thrombolytic therapy. Further, large, independent, placebo-controlled studies may be required to guide therapy and professional guidelines definitively for acute ischemic stroke. PMID- 22224136 TI - Completeness and accuracy of emergency medical information on the web: update 2008. AB - INTRODUCTION: Reliable and accurate Web-based health information is extremely valuable when applied to emergency medical diagnoses. With this update we seek to build upon on the 2004 study by determining whether the completeness and accuracy of emergency medical information available online has improved over time. METHODS: The top 15 healthcare information sites, as determined by internet traffic, were reviewed between February 4, 2008, and February 29, 2008. Standard checklists were created from information provided by American Stroke Association, American Heart Association, National Institutes of Health, and American College of Emergency Physicians to evaluate medical content on each of the Web sites for 4 common emergency department diagnoses: myocardial infarct, stroke, influenza, and febrile child. Each Web site was evaluated for descriptive information, completeness, and accuracy. Data were sorted for total medical checklist items, certification and credentialing, and medical items by topic. RESULTS: Three of the 15 sites were excluded because of a lack of medical information on the selected topics. Completeness of sites ranged from 46% to 80% of total checklist items found. The median percentage of items found was 72. Two sites, MSN Health and Yahoo!Health, contained the greatest amount of medical information, with 98 of 123 checklist items found for each site. All Web sites but 1, Healthology.com, contained greater than 50% of aggregated checklist items, and the majority (ie, 7 of 12) contained greater than 70%. Healthology.com was the least complete Web site, containing 57 of 123 items. No significant correlation was found between credentialing and completeness of site (correlation coefficient = -0.385) or credentialing and site popularity (correlation coefficient = 0.184). CONCLUSION: This study indicates that the completeness and accuracy of online emergency medical information available to the general public has improved over the past 6 years. Overall, health Web sites studied contained greater than 70% of aggregated medical information on 4 common emergency department diagnoses, and 4 sites examined advanced from 2002 to 2008. PMID- 22224137 TI - Simulation in medical student education: survey of clerkship directors in emergency medicine. AB - INTRODUCTION: The objective of this study is to identify (1) the current role of simulation in medical student emergency medicine (EM) education; (2) the challenges to initiating and sustaining simulation-based programs; and (3) educational advances to meet these challenges. METHODS: We solicited members of the Clerkship Directors in Emergency Medicine (CDEM) e-mail list to complete a Web-based survey addressing the use of simulation in both EM clerkships and preclinical EM curricula. Survey elements addressed the nature of the undergraduate EM clerkship and utilization of simulation, types of technology, and barriers to increased use in each setting. RESULTS: CDEM members representing 60 EM programs on the list (80%) responded. Sixty-seven percent of EM clerkships are in the fourth year of medical school only and 45% are required. Fewer than 25% of clerkship core curriculum hours incorporate simulation. The simulation modalities used most frequently were high-fidelity models (79%), task trainers (55%), and low-fidelity models (30%). Respondents identified limited faculty time (88.7%) and clerkship hours (47.2%) as the main barriers to implementing simulation training in EM clerkships. Financial resources, faculty time, and the volume of students were the main barriers to additional simulation in preclinical years. CONCLUSION: A focused, stepwise application of simulation to medical student EM curricula can help optimize the ratio of student benefit to faculty time. Limited time in the curriculum can be addressed by replacing existing material with simulation-based modules for those subjects better suited to simulation. Faculty can use hybrid approaches in the preclinical years to combine simulation with classroom settings for either small or large groups to more actively engage learners while minimizing identified barriers. PMID- 22224138 TI - Simulation in medical school education: review for emergency medicine. AB - Medical education is rapidly evolving. With the paradigm shift to small-group didactic sessions and focus on clinically oriented case-based scenarios, simulation training has provided educators a novel way to deliver medical education in the 21st century. The field continues to expand in scope and practice and is being incorporated into medical school clerkship education, and specifically in emergency medicine (EM). The use of medical simulation in graduate medical education is well documented. Our aim in this article is to perform a retrospective review of the current literature, studying simulation use in EM medical student clerkships. Studies have demonstrated the effectiveness of simulation in teaching basic science, clinical knowledge, procedural skills, teamwork, and communication skills. As simulation becomes increasingly prevalent in medical school curricula, more studies are needed to assess whether simulation training improves patient-related outcomes. PMID- 22224139 TI - Comparison of Metallic Foreign-Body Removal between Dynamic Ultrasound and Static Radiography in a Pigs' Feet Model. AB - INTRODUCTION: We compared the immediate cosmetic outcome of metallic foreign-body removal by emergency medicine (EM) residents with ultrasound guidance and conventional radiography. METHODS: This single-blinded, randomized, crossover study evaluated the ability of EM residents to remove metallic pins embedded in pigs' feet. Before the experiment, we embedded 1.5-cm metallic pins into numbered pigs' feet. We randomly assigned 14 EM residents to use either ultrasound or radiography to help remove the foreign body. Residents had minimal ultrasound experience. After a brief lecture, we provided residents with a scalpel, laceration kit, a bedside portable ultrasound machine, nipple markers, paper clips, a dedicated radiograph technician, and radiograph machine 20 feet away. After removal, 3 board-certified emergency physicians, who were blinded to the study group, evaluated the soft-tissue model by using a standardized form. They recorded incision length and cosmetic appearance on the Visual Analog Scale. RESULTS: In total, 28 foreign bodies were removed. No significant difference in the time of removal (P = 0.12), cosmetic appearance (P = 0.96), or incision length (P = 0.76) was found. CONCLUSION: This study showed no difference between bedside ultrasound and radiography in assisting EM residents with metallic foreign-body removal from soft tissue. No significant difference was found in removal time or cosmetic outcome when comparing ultrasound with radiography. PMID- 22224140 TI - Implications and approach to incidental findings in live ultrasound models. AB - INTRODUCTION: Incidental findings during ultrasound examinations occur frequently with live models in training sessions. Because of the broad scope of training sessions available, the ethics and guidelines of dealing with incidental findings in live models need to be discussed. METHODS: We provide a case of an endovaginal ultrasound that had significant unexpected findings. RESULTS: This report demonstrates an important finding uncovered during an endovaginal modeling session. CONCLUSION: Models should be notified beforehand of the possibility of an incidental finding, informed about it, made aware of potential associated costs, referred to another physician for follow-up, and provided a copy of the scans. A secure copy of the ultrasound scan should be stored for future reference. PMID- 22224141 TI - Ultrasound-guided peripheral intravenous access in the emergency department: patient-centered survey. AB - INTRODUCTION: To assess characteristics, satisfaction, and disposition of emergency department (ED) patients who successfully received ultrasound (US) guided peripheral intravenous (IV) access. METHODS: This is a prospective observational study among ED patients who successfully received US-guided peripheral IV access by ED technicians. Nineteen ED technicians were taught to use US guidance to obtain IV access. Training sessions consisted of didactic instruction and hands-on practice. The US guidance for IV access was limited to patients with difficult access. After successfully receiving an US-guided peripheral IV, patients were approached by research assistants who administered a 10-question survey. Disposition information was collected after the conclusion of the ED visit by accessing patients' electronic medical record. RESULTS: In total, 146 surveys were completed in patients successfully receiving US-guided IVs. Patients reported an average satisfaction with the procedure of 9.2 of 10. Forty two percent of patients had a body mass index (BMI) of greater than 30, and 17.8% had a BMI of more than 35. Sixty-two percent reported a history of central venous catheter placement. This patient population averaged 3 ED visits per year in the past year. Fifty-three percent of the patients were admitted. CONCLUSION: Patients requiring US-guided IVs in our ED are discharged home at the conclusion of their ED visit about half of the time. These patients reported high rates of both difficult IV access and central venous catheter placement in the past. Patient satisfaction with US-guided IVs was very high. These data support the continued use of US-guided peripheral IVs in this patient population. PMID- 22224142 TI - Incidental identification of right atrial mass using bedside ultrasound: cardiac angiosarcoma. AB - BACKGROUND: Emergency ultrasound is now used in both community and academic hospitals for rapid diagnosis and treatment of life-threatening conditions. Bedside emergency echocardiography can rapidly identify significant pathology such as pericardial effusions and tamponade, right ventricle dilatation due to pulmonary embolism, and cardiac hypokinesis, and aid in the diagnosis and management of patients in emergency department (ED). CASE REPORT: A 41-year-old man presented twice to the ED with history of abdominal pain and was diagnosed with primary cardiac angiosarcoma with point-of-care ultrasound. CONCLUSION: This case is illustrative of how bedside cardiac ultrasound in the ED can dramatically change a patient's hospital course. PMID- 22224143 TI - Bedside ultrasound diagnosis of acalculous cholecystitis from epstein-barr virus. AB - Acalculous cholecystitis is thought to occur in patients with a severe systemic illness or during long periods of intravenous nutrition. We discuss a case of acalculous cholecystitis secondary to Epstein-Barr virus detected by bedside ultrasound. We hope to alert clinicians who are actively using bedside ultrasound of an important, yet not commonly discussed, association. [West J Emerg Med. 2011;12(4): PMID- 22224144 TI - Assessment of a chief complaint-based curriculum for resident education in geriatric emergency medicine. AB - INTRODUCTION: We hypothesized that a geriatric chief complaint-based didactic curriculum would improve resident documentation of elderly patient care in the emergency department (ED). METHODS: A geriatric chief complaint curriculum addressing the 3 most common chief complaints-abdominal pain, weakness, and falls was developed and presented. A pre- and postcurriculum implementation chart review assessed resident documentation of the 5 components of geriatric ED care: 1) differential diagnosis/patient evaluation considering atypical presentations, 2) determination of baseline function, 3) chronic care facility/caregiver communication, 4) cognitive assessment, and 5) assessment of polypharmacy. A single reviewer assessed 5 pre- and 5 postimplementation charts for each of 18 residents included in the study. We calculated 95% confidence and determined that statistical significance was determined by a 2-tailed z test for 2 proportions, with statistical significance at 0.003 by Bonferroni correction. RESULTS: For falls, resident documentation improved significantly for 1 of 5 measures. For abdominal pain, 2 of 5 components improved. For weakness, 3 of 5 components improved. CONCLUSION: A geriatric chief complaint-based curriculum improved emergency medicine resident documentation for the care of elderly patients in the ED compared with a non-age-specific chief complaint-based curriculum. PMID- 22224146 TI - Blunt abdominal trauma patients are at very low risk for intra-abdominal injury after emergency department observation. AB - INTRODUCTION: Patients are commonly admitted to the hospital for observation following blunt abdominal trauma (BAT), despite initially negative emergency department (ED) evaluations. With the current use of screening technology, such as computed tomography (CT) of the abdomen and pelvis, ultrasound, and laboratory evaluations, it is unclear which patients require observation. The objective of this study was to determine the prevalence of intra-abdominal injury (IAI) and death in hemodynamically normal and stable BAT patients with initially negative ED evaluations admitted to an ED observation unit and to define a low-risk subgroup of patients and assess whether they may be discharged without abdominal/pelvic CT or observation. METHODS: This was a retrospective cohort study performed at an urban level 1 trauma center and included all BAT patients admitted to an ED observation unit as part of a BAT key clinical pathway. All were observed for at least 8 hours as part of the key clinical pathway, and only minors and pregnant women were excluded. Outcomes included the presence of IAI or death during a 40-month follow-up period. Prior to data collection, low-risk criteria were defined as no intoxication, no hypotension or tachycardia, no abdominal pain or tenderness, no hematuria, and no distracting injury. To be considered low risk, patients needed to meet all low-risk criteria. RESULTS: Of the 1,169 patients included over the 2-year study period, 29% received a CT of the abdomen and pelvis, 6% were admitted to the hospital from the observation unit for further management, 0.4% (95% confidence interval [CI], 0.1%-1%) were diagnosed with IAI, and 0% (95% CI, 0%-0.3%) died. Patients had a median combined ED and observation length of stay of 9.5 hours. Of the 237 (20%) patients who met low-risk criteria, 7% had a CT of the abdomen and pelvis and 0% (95% CI, 0%-1.5%) were diagnosed with IAI or died. CONCLUSION: Most BAT patients who have initially negative ED evaluations are at low risk for IAI but still require some combination of observation and CT. A subgroup of BAT patients may be safely discharged without CT or observation after the initial evaluation. PMID- 22224145 TI - Physician and nurse acceptance of technicians to screen for geriatric syndromes in the emergency department. AB - INTRODUCTION: The objective of this study was to evaluate emergency medicine physician and nurse acceptance of nonnurse, nonphysician screening for geriatric syndromes. METHODS: This was a single-center emergency department (ED) survey of physicians and nurses after an 8-month project. Geriatric technicians were paid medical student research assistants evaluating consenting ED patients older than 65 years for cognitive dysfunction, fall risk, or functional decline. The primary objective of this anonymous survey was to evaluate ED nurse and physician perceptions about the geriatric screener feasibility and barriers to implementation. In addition, as a secondary objective, respondents reported ongoing geriatric screening efforts independent of the research screeners. RESULTS: The survey was completed by 72% of physicians and 33% of nurses. Most nurses and physicians identified geriatric technicians as beneficial to patients without impeding ED throughput. Fewer than 25% of physicians routinely screen for any geriatric syndromes. Nurses evaluated for fall risk significantly more often than physicians, but no other significant differences were noted in ongoing screening efforts. CONCLUSION: Dedicated geriatric technicians are perceived by nurses and physicians as beneficial to patients with the potential to improve patient safety and clinical outcomes. Most nurses and physicians are not currently screening for any geriatric syndromes. PMID- 22224147 TI - Oral and tympanic membrane temperatures are inaccurate to identify Fever in emergency department adults. AB - INTRODUCTION: Identifying fever can influence management of the emergency department (ED) patient, including diagnostic testing, treatment, and disposition. We set out to determine how well oral and tympanic membrane (TM) temperatures compared with rectal measurements. METHODS: A convenience sample of consecutively adult ED patients had oral, TM, and rectal temperatures performed within several minutes of each other. Descriptive statistics, Bland-Altman agreement matrices with 95% confidence interval (CI), and measures of test performance, including sensitivity, specificity, predictive values, and interval likelihood ratios were performed. RESULTS: A total of 457 patients were enrolled with an average age of 64 years (standard deviation: 19 years). Mean temperatures were: oral (98.3 degrees F), TM (99.6 degrees F), and rectal (99.4 degrees F). The mean difference in rectal and oral temperatures was 1.1 degrees F, although there was considerable lack of agreement between oral and rectal temperatures, with the oral temperature as much as 2.91 degrees F lower or 0.74 degrees F higher than the rectal measurement (95% CI). Although the difference in mean temperature between right TM and rectal temperature was only 0.22 degrees F, the right TM was lower than rectal by up to 1.61 degrees F or greater by up to 2.05 degrees F (95% CI). Test performance varied as the positive predictive value of the oral temperature was 97% and for tympanic temperature was 55% (relative to a rectal temperature of 100.4 degrees F or higher). Comparative findings differed even at temperatures considered in the normal range; among patients with an oral temperature of 98.0 to 98.9, 38% (25/65) were found to have a rectal temperature of 100.4 or higher, while among patients with a TM of 98.0 to 98.9, only 7% (10/134) were found to have a rectal temperature of 100.4 or higher. CONCLUSION: The oral and tympanic temperature readings are not equivalent to rectal thermometry readings. Oral thermometry frequently underestimates the temperature relative to rectal readings, and TM values can either under- or overestimate the rectal temperature. The clinician needs to be aware of the varying relationship between oral, TM, and rectal temperatures when interpreting readings. PMID- 22224148 TI - Food protein-induced enterocolitis syndrome as a cause for infant hypotension. AB - Infants with food protein-induced enterocolitis syndrome (FPIES) may present to the emergency department (ED) with vomiting and hypotension. A previously healthy, 5-month-old male presented with vomiting and hypotension 2 to 3 hours after eating squash. The patient was resuscitated with intravenous fluids, antibiotics, and admitted for presumed sepsis. No source of infection was ever found and the patient was discharged. The patient returned 8 days later with the same symptoms after eating sweet potatoes; the diagnosis of FPIES was made during this admission. Two additional ED visits occurred requiring hydration after new food exposure. FPIES should be considered in infants presenting with gastrointestinal complaints and hypotension. A dietary history, including if a new food has been introduced in the last few hours, may help facilitate earlier recognition of the syndrome. PMID- 22224149 TI - Torsion of undescended testis in a 14-month-old child refusing to bear weight. AB - In this report, we discuss a case of a 14-month-old male presenting in the emergency department with refusal to bear weight on his left leg. Plain radiographic studies revealed no evidence of effusion, fracture, or dislocation. Laboratory studies were significant for an elevated white blood cell count, erythrocyte sedimentation rate, and C-reactive protein. Further studies included unremarkable ultrasound of the left hip and normal magnetic resonance imaging (MRI) of both hips. An incidental finding on MRI was a left inguinal mass concerning an incarcerated hernia. Ultrasound of this mass demonstrated a left undescended testis within the inguinal canal and possible incarcerated paratesticular inguinal hernia. The final pathologic diagnosis of a torsed gangrenous left testicle within the inguinal canal was confirmed during surgery. PMID- 22224150 TI - Os odontoideum: rare cervical lesion. AB - We report the case of a 22-year-old Marine who presented to the emergency department, after a martial arts exercise, with transient weakness and numbness in all extremities. Computed tomography cervical spine radiographs revealed os odontoideum. Lateral flexion-extension radiographs identified atlanto-axillary instability. This abnormality is rare and can be career ending for military members who do not undergo surgical fusion. PMID- 22224151 TI - A rare isolated trapezoid fracture. PMID- 22224152 TI - Unusual cause of chest pain on radiograph. AB - Although pneumomediastinum (PM) is a cause of chest pain, which can be diagnosed on a plain chest radiograph, emergency physicians frequently miss the diagnosis. As follows a description of findings of PM on a chest radiograph. PMID- 22224153 TI - Continuous diaphragm sign. PMID- 22224154 TI - Radiographic evidence of osteomyelitis. PMID- 22224155 TI - In-training practice patterns of combined emergency medicine/internal medicine residents, 2003-2007. AB - INTRODUCTION: This study seeks to evaluate the practice patterns of current combined emergency medicine/internal medicine (EM/IM) residents during their training and compare them to the typical practice patterns of EM/IM graduates. We further seek to characterize how these current residents perceive the EM/IM physician's niche. METHODS: This is a multi-institution, cross-sectional, survey based cohort study. Between June 2008 and July 2008, all 112 residents of the 11 EM/IM programs listed by the Accreditation Council for Graduate Medical Education were contacted and asked to complete a survey concerning plans for certification, fellowship, and practice setting. RESULTS: The adjusted response rate was 71%. All respondents anticipated certifying in both specialties, with 47% intending to pursue fellowships. Most residents (97%) allotted time to both EM and IM, with a median time of 70% and 30%, respectively. Concerning academic medicine, 81% indicated intent to practice academic medicine, and 96% planned to allocate at least 10% of their future time to a university/academic setting. In evaluating satisfaction, 94% were (1) satisfied with their residency choice, (2) believed that a combined residency will advance their career, and (3) would repeat a combined residency if given the opportunity. CONCLUSION: Current EM/IM residents were very content with their training and the overwhelming majority of residents plan to devote time to the practice of academic medicine. Relative to the practice patterns previously observed in EM/IM graduates, the current residents are more inclined toward pursuing fellowships and practicing both specialties. PMID- 22224156 TI - Feedback in the emergency medicine clerkship. AB - OBJECTIVE: Feedback is a technique used in medical education to help develop and improve clinical skills. A comprehensive review article specifically intended for the emergency medicine (EM) educator is lacking, and it is the intent of this article to provide the reader with an in-depth, up-to-date, and evidence-based review of feedback in the context of the EM clerkship. METHODS: The review article is organized in a progressive manner, beginning with the definition of feedback, the importance of feedback in medical education, the obstacles limiting the effective delivery of feedback, and the techniques to overcome these obstacles then follows. The article concludes with practical recommendations to implement feedback in the EM clerkship. To advance the literature on feedback, the concept of receiving feedback is introduced. RESULTS: The published literature regarding feedback is limited but generally supportive of its importance and effectiveness. Obstacles in the way of feedback include time constraints, lack of direct observation, and fear of negative emotional responses from students. Feedback should be timely, expected, focused, based on first-hand data, and limited to behaviors that are remediable. Faculty development and course structure can improve feedback in the EM clerkship. Teaching students to receive feedback is a novel educational technique that can improve the feedback process. CONCLUSION: Feedback is an important educational technique necessary to improve clinical skills. Feedback can be delivered effectively in the EM clerkship. PMID- 22224158 TI - Cutaneous conditions leading to dermatology consultations in the emergency department. AB - INTRODUCTION: We established the most common cutaneous diseases that received dermatology consultation in the adult emergency department (ED) and identified differentiating clinical characteristics of dermatoses that required hospital admission. METHODS: A retrospective chart review of 204 patients presenting to the ED who received dermatology consultations at Los Angeles County/University of Southern California Medical Center, an urban tertiary care teaching hospital. RESULTS: Of all patients, 18% were admitted to an inpatient unit primarily for their cutaneous disease, whereas 82% were not. Of nonadmitted patients, the most commonly diagnosed conditions were eczematous dermatitis not otherwise specified (8.9%), scabies (7.2%), contact dermatitis (6.6%), cutaneous drug eruption (6.0%), psoriasis vulgaris (4.2%), and basal cell carcinoma (3.6%). Of patients admitted for their dermatoses, the most highly prevalent conditions were erythema multiforme major/Stevens-Johnson syndrome (22%), pemphigus vulgaris (14%), and severe cutaneous drug eruption (11%). When compared with those of nonadmitted patients, admitted skin conditions were more likely to be generalized (92% vs 72%; P = 0.0104), acute in onset (<1 month duration) (81% vs 51%; P = 0.0005), painful (41% vs 15%; P = 0.0009), blistering (41% vs 7.8%; P < 0.0001), and ulcerated or eroded (46% vs 7.8%; P < 0.0001). They were more likely to involve the mucosa (54% vs 7.2%; P < 0.0001) and less likely to be pruritic (35% vs 58%; P = 0.0169). CONCLUSION: We have described a cohort of patients receiving dermatologic consultation in the ED of a large urban teaching hospital. These data identify high-risk features of more severe skin disease and may be used to refine curricula in both emergency and nonemergency cutaneous disorders for emergency physicians. PMID- 22224157 TI - Advanced topics in emergency medicine: curriculum development and initial evaluation. AB - BACKGROUND: Emergency medicine (EM) is a young specialty and only recently has a recommended medical student curriculum been developed. Currently, many schools do not require students to complete a mandatory clerkship in EM, and if one is required, it is typically an overview of the specialty. OBJECTIVES: We developed a 10-month longitudinal elective to teach subject matter and skills in EM to fourth-year medical students interested in the specialty. Our goal was producing EM residents with the knowledge and skills to excel at the onset of their residency. We hoped to prove that students participating in this rigorous 10 month longitudinal EM elective would feel well prepared for residency. METHODS: We studied the program with an end-of-the-year, Internet-based, comprehensive course evaluation completed by each participant of the first 2 years of the course. Graduates rated each of the course components by using a 5-point Likert format from "strongly disagree" to "strongly agree," either in terms of whether the component was beneficial to them or whether the course expectations were appropriate, or their perceptions related to the course. RESULTS: Graduates of this elective have reported feeling well prepared to start residency. The resident-led teaching shifts, Advanced Pediatric Life Support certification, Grand Rounds presentations, Advanced Cardiovascular Life Support proficiency testing, and ultrasound component, were found to be beneficial by all students. CONCLUSIONS: Our faculty believes that participating students will be better prepared for an EM residency than those students just completing a 1-month clerkship. Our data, although limited, lead us to believe that a longitudinal, immersion-type experience assists fourth-year medical students in preparation for residency. PMID- 22224159 TI - Erythema gyratum repens: a rare paraneoplastic rash. AB - Erythema gyratum repens (EGR) is a rare and characteristic, paraneoplastic rash associated with a variety of malignancies, most notably lung, esophageal, and breast cancers. This case report details the appearance, epidemiology, diagnosis, and treatment of EGR. Prompt identification of EGR is essential, as the rash often precedes the diagnosis of malignancy by several months. Urgent patient referral to evaluate for malignancy is crucial, as this may lead to decreased morbidity and mortality. PMID- 22224160 TI - Drug rash with eosinophilia and systemic symptoms: two emergency department cases. AB - Drug rash with eosinophilia and systemic symptoms (DRESS) is a rare, severe adverse drug event that appears with a generalized rash, fevers, and dysfunction of 1 or more organ systems. We describe 2 patients (1 adult and 1 pediatric) seen in the emergency department with DRESS, and review the clinical presentations, potential complications, and management of DRESS. Although rare, it can be associated with significant morbidity, including liver failure and death, and should be considered in the differential diagnosis of patients with diffuse rash and systemic symptoms. PMID- 22224161 TI - A desert rash. AB - A 29-year-old man presented to the emergency department (ED) with a rash across his chest and abdomen. The rash began 2 hours before his arrival and was initially pruritic, but subsequently became painful. The patient also complained of acute onset of aching pain in both hips and his left arm. He denied associated chest pain or dyspnea, and had no paresthesias or disequilibrium. Routine laboratory studies and chest radiograph were normal. Earlier in the day, the patient had completed a dive to 235 feet in depth in Lake Mead, Nevada, but reported a very controlled ascent with appropriate decompression stops. Two days earlier, he had completed a dive to 315 feet in Lake Mead without any problems. PMID- 22224162 TI - Pacemaker limitation of tachycardia in hypovolemic shock. AB - A 49-year-old white man was admitted to the emergency department with nausea and diarrhea of 11 hours duration. He had experienced crampy abdominal pain as well. He reported that his stools had been dark and malodorous. He had no prior history of gastrointestinal disorders, nor travel, unusual oral or liquid intake. There was a remote history of alcohol abuse, but no hepatitis or cirrhosis. Recent alcohol intake was denied by the patient. He had no medical allergies. His past medical history was pertinent for a history of hypertension, congestive heart failure, and a dual chamber pacemaker insertion. There was no history of diabetes mellitus, smoking, or myocardial infarction. Medications included lisinopril, a small dose of aspirin daily, and thyroid supplement. Family history was negative for cardiomyopathy, sudden cardiac death, gastric or duodenal ulcers, colon cancer, or any congenital abnormalities. PMID- 22224163 TI - Cardiac arrest from postpartum spontaneous coronary artery dissection. AB - We present the case of a 32-year-old woman who presented to the emergency department with a witnessed cardiac arrest. She was otherwise healthy with no cardiac risk factors and had undergone an uneventful repeated cesarean section 3 days priorly. The patient underwent defibrillation, out of ventricular fibrillation to a perfusing sinus rhythm, and was taken to the catheterization laboratory where coronary angiography findings showed spontaneous dissection of the left anterior descending artery. The patient received a total of 6 stents during her hospital stay and was eventually discharged in good condition. Spontaneous coronary artery dissection is a rare entity with a predilection for pregnant or postpartum women. Early diagnosis and treatment are key for survival, and when identified early, mortality rate is reduced. PMID- 22224164 TI - Acute Aortic Dissection in Third Trimester Pregnancy without Risk Factors. AB - Spontaneous aortic dissection in pregnancy is rare and life threatening for both the mother and the fetus. Most commonly, it is associated with connective tissue disorders, cardiac valve variants, or trauma. We present the case of a 23-year old previously healthy woman, 36 weeks pregnant with a syncopal episode after dyspnea and vomiting. She subsequently developed cardiac arrest and underwent aggressive resuscitation, emergent thoracotomy, and cesarean delivery without recovery. On autopsy, she was found to have an aortic dissection of the ascending aorta. This case is presented to raise awareness and review the literature and the clinical approach to critical care for pregnant patients. PMID- 22224165 TI - Pylephlebitis: an uncommon complication of intra-abdominal infection. AB - We present a case of pylephlebitis, which is an infective suppurative thrombosis of the portal vein. Pylephlebitis is an uncommon complication of intra-abdominal infections and carries with it significant morbidity and mortality. PMID- 22224166 TI - Fracture dislocation c6 to c7: importance of adequate radiographs. PMID- 22224167 TI - Pericardial cyst: unexpected finding on a chest radiograph. PMID- 22224168 TI - Severe open ankle sprain. PMID- 22224169 TI - Footwear and Falls in the Home Among Older Individuals in the MOBILIZE Boston Study. AB - BACKGROUND: Whether certain types of footwear, such as slippers, socks without shoes, and going barefoot, increase the risk for falls among the elderly is uncertain. Our purpose was to examine the relationship between footwear and falls within the home in MOBILIZE Boston, a prospective cohort study of falls etiology among non-institutionalized women and men, mainly aged 70 years and older, from the Boston MA, USA area. METHODS: The 765 participants were from households randomly selected from town lists. They were followed for a median of 27.5 months. At baseline, participants were administered a questionnaire that included questions on footwear usually worn, and were given a comprehensive examination that included measurement of many risk factors for falls. During follow-up participants were asked to record each day whether they had fallen; those reporting falls were asked about their footwear when they fell. RESULTS: At the time of in-home falls, 51.9% of people were barefoot, wearing socks without shoes, or wearing slippers; 10.1% of people reported that their usual footwear was one of these types. Among those who fell in their own home, the adjusted odds ratio for a serious injury among those who were shoeless or wearing slippers compared to those who were wearing other shoes at the time of the fall was 2.27 (95% confidence interval 1.21-4.24). CONCLUSIONS: It may be advisable for older individuals to wear shoes in their home whenever possible to minimize the risk of falling. Further research is needed to identify optimal footwear for falls prevention. PMID- 22224170 TI - Hepatogenic differentiation of mesenchymal stem cells induced by insulin like growth factor-I. AB - AIM: To improve hepatic differentiation of human mesenchymal stem cell (MSC) using insulin growth factor 1 (IGF-I), which has important role in liver development, hepatocyte differentiation and function. METHODS: Bone marrow of healthy donors was aspirated from the iliac crest. The adherent cells expanded rapidly and were maintained with periodic passages until a relatively homogeneous population was established. The identification of these cells was carried out by immunophenotype analysis and differentiation potential into osteocytes and adipocytes. To effectively induce hepatic differentiation, we designed a protocol based on a combination of IGF-I and liver specific factors (hepatocyte growth factor, oncostatin M and dexamethasone). Morphological features, hepatic functions and cytological staining were assessed to evaluate transdifferentiation of human marrow-derived MSCs. RESULTS: Flow cytometric analysis and the differentiation potential into osteoblasts and adipocytes showed that more than 90% of human MSCs which were isolated and expanded were positive by specific markers and functional tests. Morphological assessment and evaluation of glycogen storage, albumin and alpha-feto protein expression, as well as albumin and urea secretion revealed a statistically significant difference between the experimental groups and control. CONCLUSION: In vitro differentiated MSCs using IGF-I were able to display advanced liver metabolic functions, supporting the possibility of developing them as potential alternatives to primary hepatocytes. PMID- 22224171 TI - Rationale and techniques of cytoreductive surgery and peritoneal chemohyperthermia. AB - The evolution of loco-regional treatments has occurred in the last two decades and has deeply changed the natural history of primitive and secondary peritoneal surface malignancies. Several phase II-III studies have proved the effectiveness of the combination of cytoreductive surgery with peritoneal chemohyperthermia. Cytoreductive surgery allows the reduction of the neoplastic mass and increases tumoral chemosensitivity. The development of chemohyperthermia finds its origins in the necessity to exceed the limits of intraperitoneal chemotherapy performed in normothermia. It permits a continuous high concentration gradient of chemotherapeutic drugs between the peritoneal cavity and the plasma compartment to and a more uniform distribution throughout the abdominal cavity compared to systemic administration. PMID- 22224172 TI - Predictive role of XRCC5/XRCC6 genotypes in digestive system cancers. AB - Cancers are a worldwide concern; oral, esophageal and gastrointestinal cancers represent important causes of cancer-related mortality and contribute to a significant burden of human health. The DNA repair systems are the genome caretakers, playing a critical role in the initiation and progression of cancers. However, the association between the genomic variations of DNA repair genes and cancer susceptibility is not well understood. This review focuses on the polymorphic genotypes of the non-homologous end-joining DNA repair system, highlighting the role of two genes of this pathway, XRCC5 and XRCC6, in the susceptibility to digestive system cancers and discussing their potential contributions to personalized medicine. PMID- 22224174 TI - Superior mesenteric artery syndrome in a patient with Charcot Marie Tooth disease. AB - The extrinsic compression of the third part of the duodenum as it passes through the aorto-mesenteric angle is known as the superior mesenteric artery syndrome (SMAS). This syndrome is a rare mechanical cause of upper intestinal obstruction, with a reported incidence of between 0.2% and 0.78%. Clinical manifestations of SMAS may be chronic or acute; chronic symptoms include intermittent gastric pain, fullness and occasional episodes of postprandial vomiting, while acute symptoms include incoercible vomiting, oral intolerance, mainly epigastric abdominal distension and abdominal pain. Surgery is recommended only when initial conservative treatment fails. Here, we report what appears to be the third published case of SMAS associated with hereditary motor and sensory neuropathy or Charcot Marie Tooth disease. PMID- 22224175 TI - Solid-pseudopapillary pancreatic tumor, mimicking submucosal tumor of the stomach: A case report. AB - Solid-pseudopapillary tumors of the pancreas (SPTs) are comparatively rare and have low malignancy, with a predilection for young women. Diagnosis is difficult when a SPT develops in a boundary region with other organs. Here, we report a 42 year old woman with a SPT of the pancreas mimicking a submucosal tumor of the stomach on imaging. She was admitted to our hospital complaining of abdominal pain. We suspected a submucosal tumor of the stomach from the findings of endoscopy, endoscopic ultrasonography and abdominal computed tomography. However, angiography showed that some of the tumor vessels arose from the pancreas. Intraoperative findings revealed the tumor originated from the pancreas. Therefore, distal pancreatectomy was performed. The pathological diagnosis was SPT of the pancreas. PMID- 22224173 TI - Current state of surgical treatment of liver metastases from colorectal cancer. AB - Hepatic resection is the procedure of choice for curative treatment of colorectal liver metastases (CLM). Objectives of surgical strategy are low intraoperative blood loss, short liver ischemic times and minor postoperative morbidity and mortality. Blood loss is an independent predictor of mortality and compromises, in common with postoperative complications, long-term outcome after hepatectomy for CLM. The type of liver resection has no impact on the outcome of patients with CLM; wedge resections are not inferior to anatomical resections in terms of tumor clearance, pattern of recurrence or survival. Despite the lack of proof of survival benefit, routine lymphadenectomy has been advocated, allowing the detection of microscopic lymph node metastases and with prognostic value. In experienced hands, minimally invasive liver surgery is safe with acceptable morbidity and mortality and oncological results comparable to open hepatic surgery, but with reduced blood loss and earlier recovery. The European Colorectal Metastases Treatment Group recommended treating up front with chemotherapy for patients with both resectable and unresectable CLM. However, neoadjuvant chemotherapy can induce damage to the remnant liver, dependent on the number of chemotherapy cycles. Therefore, in our opinion, preoperative chemotherapy should be reserved for patients whose CLM are marginally resectable or unresectable. A meta analysis of randomized trials dealing with perioperative chemotherapy for the treatment of resectable CLM demonstrated a benefit of systemic chemotherapy but did not answer the question of whether a neoadjuvant or adjuvant approach should be preferred. Analysis of the literature demonstrates that the results of specialized centers cannot be attained in the reality of comprehensive patient care. Reasons behind the commonly poorer results seen in cancer networks as compared with literature-based data are, on the one hand, geographical disparities in access to specialized surgical and medical care. On the other hand, a selection bias in the reports of the literature may be assumed. Studies of surgical resection for CLM derive almost exclusively from case series generally drawn from large academic centers where patient selection or surgical expertise is superior to what is found in many communities. Therefore, we may conclude that the comprehensive propagation of the standards outlined in this paper constitutes a major task in the near future to reduce the variations in survival of patients with CLM. PMID- 22224176 TI - Chest neoplasms with infectious etiologies. AB - A wide spectrum of thoracic tumors have known or suspected viral etiologies. Oncogenic viruses can be classified by the type of genomic material they contain. Neoplastic conditions found to have viral etiologies include post-transplant lymphoproliferative disease, lymphoid granulomatosis, Kaposi's sarcoma, Castleman's disease, recurrent respiratory papillomatosis, lung cancer, malignant mesothelioma, leukemia and lymphomas. Viruses involved in these conditions include Epstein-Barr virus, human herpes virus 8, human papillomavirus, Simian virus 40, human immunodeficiency virus, and Human T-lymphotropic virus. Imaging findings, epidemiology and mechanism of transmission for these diseases are reviewed in detail to gain a more thorough appreciation of disease pathophysiology for the chest radiologist. PMID- 22224177 TI - Multidetector computed tomography imaging of congenital anomalies of major airways: A pictorial essay. AB - Congenital airway anomalies can be asymptomatic or may cause severe respiratory distress requiring immediate treatment. These anomalies can present early in life, or may be just incidental findings. It is important to recognize these entities to realize their clinical significance and to avoid false diagnosis. In this article, the various congenital airway anomalies and their imaging features by multidetector computed tomography (MDCT) are reviewed in order of occurrence during the embryological timeline. This pictorial essay reviews the various distinct congenital airway lesions and their MDCT manifestations. It also provides insight into the embryological basis of the congenital airway lesions encountered. PMID- 22224179 TI - Working time directive in an all female specialty. PMID- 22224178 TI - Image of tumor metastasis and inflammatory lymph node enlargement by contrast enhanced ultrasonography. AB - AIM: To compare the difference between tumor-induced lymph node enlargement and inflammation-induced lymph node enlargement by contrast-enhanced ultrasonography and pathological findings. METHODS: A model of tumor-induced lymph node metastasis was prepared by embedding a VX2 tumor into the hind paws of white rabbits. A model of inflammation-induced enlargement was prepared by injecting a suspension of Escherichia coli into separate hind paws of white rabbits. Then, a solution of SonazoidTM (GE Healthcare, Oslo, Norway) was injected subcutaneously in the proximity of the lesion followed by contrast-enhanced ultrasonography of the enlarged popliteal lymph nodes. RESULTS: In the contrast-enhanced ultrasonography of the tumor-induced metastasis model, the sentinel lymph node was imaged. An area of filling defect was observed in that enlarged lymph node. In the histology examination, the area of filling defect corresponded to the metastatic lesion of the tumor. Contrast-enhanced ultrasonography of the model on inflammation-induced lymph node enlargement, and that of the acute inflammation model performed 3-7 d later, revealed dense staining that was comparatively uniform. The pathological findings showed acute lymphadenitis mainly due to infiltration of inflammatory cells. Contrast-enhanced ultrasonography that was performed 28 d post-infection in the acute inflammation model showed speckled staining. Inflammation-induced cell infiltration and fiberization, which are findings of chronic lymphadenitis, were seen in the pathological findings. CONCLUSION: Sentinel lymph node imaging was made possible by subcutaneous injection of SonazoidTM. Contrast-enhanced ultrasonography was suggested to be useful in differentiating tumor-induced enlargement and inflammation-induced enlargement of lymph nodes. PMID- 22224181 TI - An Investigation into Perioperative Antibiotic Use during Lower Segment Caesarean Sections (LSCS) in Four Hospitals in Oman. AB - OBJECTIVES: This investigation aims to assess the current practice of antibiotic prophylaxis and its use in various types of surgery in Oman. METHODS: A retrospective sample of 510 patients from four major hospitals were studied for the use of antibiotics in lower segment caesarean section (LSCS) surgeries. RESULTS: There was a great diversity in the regimes from each hospital and only one had written guidelines. Although cephalosporin was used in the majority of cases, there was little consistency in the generation prescribed with second generation cefuroxime being the most popular (47% of all cases). The majority of cases also had metronidazole added. In one hospital, ampicillin was the prophylactic of choice and was routinely combined with oral amoxicillin. There were very few cases where only a single dose was given with most receiving at least 3 doses. In one extreme case, most patients received five days of prophylaxis with a 3rd gen-eration cephalosporin. CONCLUSION: It appears that protocols for antibiotic prophylaxis have developed in an ad hoc fashion over time. It was found that none of the studied hospitals followed the Ministry of Health antibiotic guidelines, nor were they using any international standard or recommendation. Based on the available infection rates, a consistent policy with written guidelines appears to lead to the best outcomes for patients. PMID- 22224182 TI - Safety of induction of labor with vaginal prostaglandins (e2) in grandmultipara. AB - OBJECTIVES: The aim of this study is to determine safety of induction of labor with vaginal Prostaglandins (E2) in Grand Multipara. METHODS: Prostaglandin E2 was used in the form of vaginal tablets or gel in post fornix for induction as per protocol. Maternal and fetal data collected included age, parity, and indication of induction, bishops score, total dose of PGE2 used & complications of induction of labor. The data was collected and analyzed using Epi info - 6. RESULTS: 50% cases were induced for past dates, the ceasarean rate was high in the induction group (19.5%) compared to the control (12.5%) OR 1.69 RR 1.37(95% CI-1.07-1.75) difference was statistically significant. Adverse neonatal outcome was found to be similar in both groups. Special Care Baby Unit (SCBU) admissions were 19 in the induction group and 21 in the control group, which was not statistically significant. No severe maternal complications were observed such as infection or uterine rupture. CONCLUSION: As there were no adverse events in the study, it may be safe to use vaginal PGE2 as method of choice for induction of labour in grand mutipara. However, RCT for further validation of these findings is recommended. PMID- 22224180 TI - Atherosclerosis and physical activity. AB - Atherosclerosis and coronary heart disease have been considered as major health problem worldwide. Abnormalities in lipids and lipoprotein metabolism and impairment of endothelial function have been implicated as the main contributing factors in atherosclerosis and its progression. Physical activity has been recognized as a preventive measure for atherosclerosis. PMID- 22224183 TI - The Role of Calcium Correction during Normal Pregnancy at Third Trimester in Mosul. AB - OBJECTIVES: To assess calcium status in healthy pregnant women during limited sun exposure time in winter, and to demonstrate the possible effect of serum albumin alterations on serum total calcium level and the role of albumin adjusted calcium concentration. METHODS: Subjects enrolled in the study included 160 apparently healthy women divided equally into four groups (I - IV), group I was considered as the control group, composed of non-pregnant women. Groups II-IV were composed of pregnant women in the first, second and third trimesters respectively. Semiquantitative urine protein determination and measurement of serum total calcium, ionized calcium, albumin, phosphorous and creatinine with calculation of corrected calcium were performed in all groups. The results were statistically evaluated by standard statistical methods. RESULTS: There was no significant difference in serum ionized calcium, corrected calcium and phosphorous during pregnancy. However, there was a significant reduction of serum total calcium, albumin and creatinine in pregnant women at second and third trimesters. In each group, a significant positive correlation was observed between total calcium with corrected and ionized calcium. CONCLUSION: In healthy pregnant women even during limited sun exposure time in winter, there was no need for calcium supplementation in spite of the continuous and progressive reduction of serum measured total calcium during the second and third trimesters due to dilutional hypoalbuminemia. During pregnancy, measured calcium is parallel to both corrected and ionized calcium and since there was no significant difference between measured and corrected calcium, therefore, measured calcium is a useful test in assessing calcium status and suggests the need to establish a reference range for pregnant women. PMID- 22224184 TI - Level control of asthma patients in chest specialist clinics. AB - OBJECTIVES: This survey aims to assess the current levels of asthma control as reported by patients attending chest specialist clinic by using the Asthma Control Test (ACT) questionnaire. METHODS: Current levels of asthma control were assessed using the ACT questionnaire, and a brief instrument developed to assess asthma control in a clinical setting. 141 (100 females) patients aged 13 years and above were recruited from the chest clinic of Royal hospital, a tertiary hospital in the Sultanate of Oman. The ACT questionnaire was administered only from the second visit. RESULTS: The result showed that 61% of patients scored between "20 and 25" (well controlled), 17.7% of the patients scored between "15 and 19" (not well controlled), and the rest 21.3% scored between "5 and 14" (poorly controlled). More than 50% of the patients reported that their asthma had an impact in work, school or home Nocturnal symptoms were reported by 66% and the use of rescue medications by 70%. Patient perception of asthma control did not match their symptom severity as more than 65% considered their asthma controlled despite the fact that their symptoms limited their daily activities and disturbed their sleep. CONCLUSION: The current level of asthma control among the study patients falls far short of the goals for long-term asthma management and patients' perception of asthma control is different from their actual asthma control. PMID- 22224185 TI - Modelling Factors Causing Mortality in Oesophageal VaricesPatients in King Abdul Aziz University Hospital. AB - OBJECTIVES: The objective of this study is to reach a model defining factors precipitating short survival in patients with oesophageal varices and improving the understanding of such factors. Models would help to prioritize the clinical goals and intervention for saving the lives of patients. METHODS: Retrospective analysis of all patients admitted to King Abdul Aziz University Hospital who had been diagnosed with oesophageal varices. The patients' demographics, disease history, physical examination, viral infections, parasitic infections, blood pictures, cancer biomarkers, liver enzymes and bleeding details were collected, tested for correlation with mortality to formulate a model. RESULTS: A total of 148 patients were included in this study. 37 clinical variables were studied only 15 factors were found to have a statistical significance. These factors were PT (RC=0.17338 P-value 0.00011), APTT (RC=0.07916, P-value 0.00002), haemoglobin level (RC=-0.44748, P-value <0.0001), WBC (RC = 0.22255, P-value 0.00001), serum albumin level (RC=-0.12953, P-value 0.00001), serum creatinine (RC=0.01483, P value 0.00002), at least one incidence of encephalopathy (RC=1.80500, P-value 0.00014), total bilirubin (RC=0.01371, P-value 0.00016), direct bilirubin (RC=0.01298, P-value 0.00357, serum AST (RC=0.00914, P-value 0.00462), presence of at least bleeding event (RC=1.03373, P-value 0.00613), ascites grade I (RC= 1.57435, P-value 0.00967), SBP (RC=1.47216, P-value 0.01581), platelets count (RC=0.00398, P-value 0.03476) and oesophageal varices (RC = -1.42139, P-value 0.03673). Only 5 factors were likely to affect the mortality status. These factors were encephalopathy, spontaneous SBP, bleeding, ascites and grade of oesophageal varices. Six models were then formulated. CONCLUSION: These models should be retested in larger study groups to test their reliability in order to use them as surrogate end point in future clinical studies. PMID- 22224186 TI - Quality of Life in Cancer Patients undergoing Chemotherapy. AB - OBJECTIVES: The objective of this study is to describe the quality of life (QoL) in cancer patients with solid tumors and at different chemotherapy (CT) cycles. METHODS: A total of 200 cancer patients were included. With some modification, the European Organization for Research and Treatment of Cancer QoL Questionnaire (EORTC QLQ-C30) was used to measure QoL in the student patients. RESULTS: There was no correlation between the QoL and variables such as age, sex, marital status, duration of disease, economic conditions, and occupational function. Furthermore, no correlation was found between QoL and the patients' educational level (literate or illiterate). Nevertheless, a significant difference was found between the level of QoL in patients with <= 2 CT cycles and/or with 3-5 cycles (p< 0.001). CONCLUSION: This study suggests that encouraging cancer patients to complete a CT course plays an important role in the treatment outcome and the QoL in cancer patients undergoing CT. PMID- 22224187 TI - Clinical findings and prevalence of helicobacter pylori in patients with gastritis B in Al-basrah governorate. AB - OBJECTIVES: To detect the prevalence of H. pylori in patients with gastritis B. METHODS: This study involved 58 patients (group A) with gastritis B attending the Al-Sadder teaching hospital from January to November 2008. 120 of family's patients (group B) and normal 20 people, 10 males 10 females (group C) were taken as controls for presence of H. pylori infection in general population. Endoscopy was carried for all patients to diagnose gastritis B. Urease, ELISA test, and culturing on Columbia agar used to detect the presence of H. pylori in these patients RESULTS: Fifty-eight patients; 30 males (51.7%) and 28 females (48.3%) were infected with gastritis B. The results showed that 81% of the patients gave positive results of serum IgG anti body. CONCLUSION: The results showed that for screening and determining the clinical features of gastritis B, at least two methods for H. pylori are required to give positive result at the same time for the same patient, in order to identify an infected patient with from H. pylori. PMID- 22224188 TI - Factors contributing to school failure among school children in very fast developing Arabian Society. AB - OBJECTIVES: Education is one of the main foundations for the child's development and also for national human resource development. Failure at school and grade retention is a serious concern among children, and their parents. The characteristics of school failure in Qatar have not been studied earlier. The aim of this study is to assess the presence of social, psychological, health and school related factors that cause school failure. METHODS: All students who had failed their grades and had to be retained and repeat the year from 35 randomly selected schools of all grades elementary, intermediate and high school were included in this study for academic years from 2003 to 2008. Each student was individually interviewed by a well-trained school social worker. RESULTS: The study was performed on a total 699 children who were classified as school failures. Social reasons include living with one parent 26.9%, parental divorce (27%) parents showing no interest in their child's education and school system (41.6%), low income (19.3%), and smoking (19.6%). Frequent absence from school was a result in 33.3%; incomplete homework (45.9%) and teachers identified 63.7% of students to be hyperactive, inattentive and disruptive in classroom. Most frequent psychological disorders include examination phobia (68.8%), anxiety (49.4%), anger (32.5%), fear (43.2%) and learning disability (37.9%). The most prevalent health disorders included visual disorders (23.5%), asthma (14.9%), anemia (15.2%), and hearing deficiency (8.2%). CONCLUSION: Psychological and health related factors were found to be more prevalent in students who failed a grade in school. The primary care pediatrician can play a key role by identifying students at high risk and providing early intervention. PMID- 22224189 TI - Encysted hydrocele of cord in an adult misdiagnosed as irreducible hernia: a case report. AB - A number of pathologies can present as groin swellings in adults.Among these, encysted hydrocele of the cord presenting as swelling in an adult is a rare. A case of encysted hydrocele of cord in 36 year old male mimicking as as an irreducible hernia is reported. The diagnosis of hydrocele was made intraoperatively. An excision of the sac was performed. PMID- 22224190 TI - A case report of Basal Ganglia calcification - a rare finding of hypoparathyroidism. AB - Physiological intracranial calcification occurs in about 0.3-1.5% of cases. It is asymptomatic and detected incidentally by neuroimaging. Pathological basal ganglia calcification is due to various causes, such as: metabolic disorders, infectious and genetic diseases. Hypoparathyroidism and pseudohypoparathyroidism are the most common causes of pathological basal ganglia calcification. Besides tetany and seizures this condition is presented by parkinsonism and dementia. Such parkinsonism does not respond to drugs containing levodopa. Infections (toxoplasmosis, rubella, cytomegalovirus, cysticercosis, AIDS) give multiple and asymmetric intracranial calcification. Inherited and neurodegenerative diseases cause symmetrical, bilateral basal ganglia calcification which is not related to metabolic disorders. Since adequate treatment of hypoparathyroidism may lead to marked clinical improvement, serum concentration of calcium, phosphorus, and parathyroid hormone (PTH) is suggested to be determined in all individuals with calcification of the basal ganglia to rule out hypoparathyroidism. PMID- 22224191 TI - Infection Associated with Hemophagocytic Lymphohisticytosis triggered by nosocomial Infection. AB - Hemophagocytic lymphohistiocytosis (HLH) can occur as primary idiopathic syndrome or secondary to neoplastic, infection or autoimmune processes. It is characterized by the proliferation of histiocytes with phagocytosis of formed elements of blood. Clinical manifestations include signs and symptoms of immune activation and pancytopenia. This report presents a child with infection associated with HLH trigged by Acinetobacter baumannii sepsis. Multidrug resistant Acinetobacter, an emergent nosocomial pathogen but so far in the literature, it has not been reported to cause HLH. PMID- 22224192 TI - Ocular sebaceous carcinoma, the great masquerader. PMID- 22224193 TI - An Under-recognized Complication: Diabetic Myonecrosis. PMID- 22224194 TI - Epidemiology of activated protein C resistance and factor v leiden mutation in the mediterranean region. AB - Venous thromboembolic disorders (VTE) are serious disorders with high morbidity and mortality rates. Many genetic and acquired risk factors were identified to cause VTE. The most common genetic risk factor is Factor V Leiden mutation (FVL). FVL was found in high percentage of populations of Caucasian origin but was almost absent in non-Caucasians. It was also reported in populations living in North Africa and the Middle East. This review article briefly explains FVL and how it causes VTE, the distribution of FVL worldwide, and then it elaborates on the epidemiology of FVL in the Mediterranean Region and how this brought speculations that FVL might have originated in the Eastern Mediterranean area. PMID- 22224196 TI - In favor of controlling proven, but not probable, causes of cancer. PMID- 22224197 TI - Special Issue Honoring Jacek Klinowski for his scientific contributions to the field of Solid State NMR in Materials Science. PMID- 22224198 TI - This Special Focus Issue on "Bioanalytical Mass Spectrometry" is dedicated to David Muddiman. PMID- 22224199 TI - Special Focus Issue in honor of Marvin L. Vestal, recipient of the 2010 Award for a Distinguished Contribution in Mass Spectrometry. PMID- 22224200 TI - Antibiotic resistance in Europe: the ?62 million question. PMID- 22224201 TI - Proceedings of the Aegean Conference '3rd Crossroads between Innate and Adaptive Immunity', September 27-October 2, 2009, Crete, Greece. PMID- 22224202 TI - Special issue: Migration, aging, and health in honor of Dr. Charles (Chuck) F. Longino. PMID- 22224195 TI - Epigenetics in Developmental Disorder: ADHD and Endophenotypes. AB - Heterogeneity in attention-deficit/hyperactivity disorder (ADHD), with complex interactive operations of genetic and environmental factors, is expressed in a variety of disorder manifestations: severity, co-morbidities of symptoms, and the effects of genes on phenotypes. Neurodevelopmental influences of genomic imprinting have set the stage for the structural-physiological variations that modulate the cognitive, affective, and pathophysiological domains of ADHD. The relative contributions of genetic and environmental factors provide rapidly proliferating insights into the developmental trajectory of the condition, both structurally and functionally. Parent-of-origin effects seem to support the notion that genetic risks for disease process debut often interact with the social environment, i.e., the parental environment in infants and young children. The notion of endophenotypes, markers of an underlying liability to the disorder, may facilitate detection of genetic risks relative to a complex clinical disorder. Simple genetic association has proven insufficient to explain the spectrum of ADHD. At a primary level of analysis, the consideration of epigenetic regulation of brain signalling mechanisms, dopamine, serotonin, and noradrenaline is examined. Neurotrophic factors that participate in the neurogenesis, survival, and functional maintenance of brain systems, are involved in neuroplasticity alterations underlying brain disorders, and are implicated in the genetic predisposition to ADHD, but not obviously, nor in a simple or straightforward fashion. In the context of intervention, genetic linkage studies of ADHD pharmacological intervention have demonstrated that associations have fitted the "drug response phenotype," rather than the disorder diagnosis. Despite conflicting evidence for the existence, or not, of genetic associations between disorder diagnosis and genes regulating the structure and function of neurotransmitters and brain-derived neurotrophic factor (BDNF), associations between symptoms-profiles endophenotypes and single nucleotide polymorphisms appear reassuring. PMID- 22224204 TI - Retraction notice to "Particle-associated polycyclic aromatic hydrocarbons near power plants as determined by large volume injection - GC/MS, Chemosphere 80 (2010) 235-240". PMID- 22224203 TI - Equine disease surveillance: quarterly summary. PMID- 22224206 TI - Progressive weakness in a 12-year-old boy. PMID- 22224205 TI - Multiple basal ganglia lesions in an immunocompetent patient. PMID- 22224207 TI - John K. Critser: In Memoriam. PMID- 22224209 TI - Response to Letter to Editor by Dr. J. C. Wolf on "Analysis of unbiased histopathology data from rodent toxicity studies (or, are these groups different enough to ascribe it to treatment?)". PMID- 22224211 TI - Structural variation in the mouse genome. PMID- 22224210 TI - Genomic variation in the mouse. PMID- 22224212 TI - Chest X-ray quiz. PMID- 22224213 TI - [Urological screening program for patients with hereditary nonpolyposis colorectal cancer]. PMID- 22224214 TI - [Occupational medicine is political]. PMID- 22224215 TI - [Use of antibiotics]. PMID- 22224216 TI - [Territorial communities and villagers in France in the 17th and 18th centuries]. PMID- 22224217 TI - [Enclosures, advances in agriculture, and the rural population in Great Britain in the 17th and 18th centuries]. PMID- 22224218 TI - [Between survival and profit: types of agricultural production in regions of small-scale agriculture in France in the 17th and 18th centuries]. PMID- 22224219 TI - [Jean Bochart de Champigny (1561-1630)]. PMID- 22224221 TI - [The land question in France and England, ca. 1600 to 1800]. PMID- 22224222 TI - [The seigniorial class, the land, and the peasants, 17th-18th centuries]. PMID- 22224224 TI - [The revolutionary government, land, and the rural community, 1793-95]. PMID- 22224226 TI - [Candies for Figaro's daughter, or Beaumarchais and nursing mothers]. PMID- 22224227 TI - [The beginnings of the Council of the Order of Physicians in the Basses Pyrenees]. PMID- 22224228 TI - [Parish registers and civil archives: a source for the history of the valley of Baretous, 17th-19th centuries]. PMID- 22224229 TI - [The "ghost ships" on the eve of World War II]. PMID- 22224230 TI - Charles S. Kleinman, MD, 1946-2011. PMID- 22224232 TI - [The "passportization" of the Soviet Far Eastern population, 1933-34]. PMID- 22224231 TI - [The irresistible rise of the farmers of Ile-de-France: social dynamic or "success story"?]. PMID- 22224233 TI - [Were there any technological innovations in agriculture before the 19th century?]. PMID- 22224234 TI - [Humanitarian action and political power: the involvement of Lille physicians in the 19th century]. PMID- 22224235 TI - [Learning from the French: science and the second British Empire, 1780-1830]. PMID- 22224236 TI - [Colonial cartography and the ordering of populations in French colonial Africa during the first half of the 20th century]. PMID- 22224237 TI - [Prognostic aspects of intima-media complex in patients with discirculatory encephalopathy and ischemic heart disease]. AB - Different clinical/instrumental traits and factors of cardiovascular risk in stroke patients of different ages and able-bodied patients with discirculatory encephalopathy are compared. The frequency of some risk factors was even greater in more younger patients compared to older ones while the frequency of enlarged intima-media complex as a parameter of vascular remodeling was similar in both groups. Effects of different risk factors in the aspect of vascular remodeling were evaluated with regression analysis using odds-ratio with 95% confidence interval. The family history of cardiovascular disease with the early age at onset and visceral obesity are the most significant predictors of stroke, their contribution to the vascular remodeling is comparable to that in diabetes mellitus. PMID- 22224238 TI - [Characteristics of ischemic stroke in patients with congenital anomalies of the circle of Willis]. AB - The study included 76 patients with ischemic stroke in the carotid system (56 patients) and in the vertebrobasilar system (20 patients). The magnetic resonance angiography (MRA) revealed congenital anomalies of Willis circle in 31 patients. These anomalies were stratified as follows: back trifurcation of the internal carotid artery (ICA) (19 patients), anterior trifurcation of the ICA (4 patients), the combination of anterior trifurcation of the one of ICA and posterior trifurcation of the other ICA (4 patients), double back trifurcation of ICA (2 patients), the normal structure of the circle of Willis (45 patients). Patients with anomalies of the circle of Willis scored significantly higher on the Neurological deficit scale NIH-NINDS. Despite the lack of significant differences in the size of lesions in 2 groups, the foci in patients with the abnormalities of the circle of Willis were frequently localized in adjacent blood supply zones. The signs of vascular encephalopathy were seen as well. The data obtained suggest that the presence of anomalies in the circle of Willis is a risk factor, together with in the additional adversities, including iatrogenic factor, for the development of hemodynamic ischemic stroke. PMID- 22224239 TI - [The heart rate variability in the acute lacunar cerebral infarct]. AB - Clinical-electrophysiological investigation has been performed in 30 patients with acute lacunar cerebral infarct. Patients with atrial fibrillation, severe extrasystole weren't included to the study. The control group includes 7 health volunteers. EKG registration within 5 minutes with time domain, frequency domain analysis have been made. Brain attack on the type of lacunar IS associates with evident HRV disturbances. Centralization of the heart rate autonomic control, caused by suprasegmental part of the vegetative nervous system hyperactivity occurs against a background relative sympaticothonia and decrease of parasympathetic nervous system. In case of right carotid stroke there is significant lowering of standard deviation of the RR intervals (p=0,024), triangular index (p<0,001), total power (p=0,016), increase of mode of the histogram distribution of RR intervals (p=0,002) and the proportion derived by the number of RR intervals, that match the value of mode (p=0,001). PMID- 22224240 TI - [Androgenic deficit and its treatment in stroke male patients with diabetes mellitus type II]. AB - We have studied 154 men (mean age 61,4+/-4,1 years) with the first hemispheric ischemic stroke. Clinical and laboratory studies have revealed the androgenic deficit in 66,3%, with its frequency higher in patients with diabetes mellitus type II (50 and 26,3%, respectively). Forty-two men with diabetes mellitus type II and acquired androgenic deficit received replacing treatment with testosterone undecanoate in dose 1000 mg intramuscular. The treatment was started one week after the development of stroke, the next injections were given after 6 weeks and then every 12 weeks during 2 years. The control group included 30 males who did not receive androgens. After 2 years from the beginning of treatment, there were the decrease in clinical severity of androgenic deficit, the increase of total and free testosterone levels, and muscle power in the main group compared to the controls. Body mass index, glicated hemoglobin, cholesterol, triglycerides, low density lipoproteins have decreased as well. Secondary stroke has developed in 3 (7,1%) patients of the main group and in 5 (16,6%) controls; 12 (28,6%) patients returned to work in the main group compared to 2 (6,6%) in the control group. The treatment with androgens has a positive effect on risk factors of secondary ischemic stroke. It is an effective method for improvement of social adaptation of men survived after the stroke. PMID- 22224241 TI - [Clinical-electrophysiological characteristics of the cognitive sphere in patients in the acute period of the first cerebral ischemic stroke]. AB - A neuropsychological and neurophysiological study using computed EEG was carried out in 31 stroke patients who did not have a cognitive impairment according to MMSE. Thirty age-matched patients with the same risk factors without a history of stroke were included into the control group. The examination of the control group was performed only once. The examination of stroke patients was performed on days 1, 7 and 21. It was shown that cognitive neurodynamic disturbances (memory disorders and the visual memory decrease) and bioelectrical brain activity disturbances (the decrease in a- and beta band activities and the increase of theta-band power) occurred from the first day and lasted during the acute stroke period even after the improvement of neurological status. PMID- 22224242 TI - [Clinical and laboratory assessment of indicators of oxidative status in the cerebrospinal fluid of patients with ischemic stroke]. AB - The objective of the present study was to estimate parameters of oxidative status in the cerebrospinal fluid in the course of ischemic stroke and in the prediction of recovery of neurological functions. Concentration of superoxide dismutase (SOD) as a marker of antioxidant adaptation, the secondary lipid peroxidation products reacting with thiobarbituric acid (PRTBA), cyclic guanosine monophosphate (cGMP) as an indirect product of NO generation, and N acetylneuraminic acid (NANA) as a marker of destruction of neuronal membranes were studied. One hundred and fifty patients with hemispheric ischemic stroke admitted to a hospital during the first 12 h after stroke were examined. It has been shown that the development of cerebral infarction is accompanied by increased concentrations of oxidative stress markers. Progressive ischemic stroke was characterized by the significantly prolonged increase in PRTBA, cGMP, NANA to the third day from the first symptoms of disease while regressive course was accompanied by the lack of higher production of TBKRP, cGMP, NANA to the third day of disease. The decrease in concentrations of factors of brain damage (PRTBA, cGMP, NANA) in the cerebrospinal fluid, along with the increasing role of processes of antioxidant adaptation, expressed in the growth of SOD concentrations, can be considered as a criterion for the prediction of recovery of disturbed neurologic function to the 21th day of disease. PMID- 22224243 TI - [The use of neuromidin in patients with minor ischemic stroke]. AB - Efficacy of neuromidin was studied in 62 patients with a small ischemic stroke and cognitive disorders. Patients of the main group received neuromidin as an add on to basic treatment and patients of the comparison group received only basic treatment (antiaggregant, antihypertensive, cardiac and antidiabetic drugs with the exclusion of nootropic and psychotropic medications). The decrease of subjective complaints, improvement of memory, attention, abstract and practical reasoning assessed by neuropsychological tests were seen in 32 patients of the main group after the end of treatment course. Neuromidin did not cause side effects and was well tolerated. The long use of this led to the reduction of cognitive impairment, a predictor of vascular dementia. PMID- 22224244 TI - [Comparative aspects of using neuroprotectors in the management of patients with ischemic stroke]. AB - Comparative efficacy of neuroprotective preparations: actovegin, cerebrolysin and ceraxon was studied in 73 patients in the most acute phase of ischemic stroke. A control group included 33 patients in the most acute phase of ischemic stroke who received only basic treatment without neuroprotectors. Patient's state was assessed with the NIHSS, the original scale of E.I. Gusev and V.I. Skvortsova and the Barthel index. Ceraxon in daily dosage 2 g and cerebrolysin in daily dosage 10 ml during 10 days after the development of ischemic stroke led to the significantly better regression of neurological symptoms to the 21st day of disease compared to the control group. Barthel index scores did not differ in the groups studied. PMID- 22224245 TI - [The use of stabilizing platforms in the correction of atactic disorders in patients with vertebrobasilar stroke]. AB - Results of the treatment of atactic gait and balance disorders in post-stroke patients are presented. A method of neurorehabilitation using stabilizing platforms based on the excluding ankle joint postural strategy and support square is proposed. The efficacy of this method assessed by the computerized stabilometry and functional balance scale was comparable with the results of the generally accepted computerized dynamic posturography with visual biofeedback. PMID- 22224246 TI - [The methodological approach to the group formation of pharmacological drugs for the primary prevention of ischemic stroke]. AB - The paper is devoted to the development of a drug list, so called "marker baskets", which can be recommended for the primary prevention of ischemic stroke in patients with high cardio-vascular risk. The authors reviewed various combinations of pharmacological drugs with similar treatment effects and different availability of prices. PMID- 22224247 TI - [The analysis of risk factors for acute stroke in Dagestan]. AB - Results of the first epidemiologic survey of cerebral stroke in Dagestan carried out in 2009 using a method of population register are presented. Arterial hypertension was on the first place (98.5%) among risk factors. Other risk factors were determined as follows: cardiac diseases (24.2%), cardiac fibrillation (14.5%), lipid profile dysfunction (10.6%), smoking (8.7%), diabetes mellitus (8.6%), stress (7.5%), history of myocardial infarction (3.6%). PMID- 22224248 TI - [Experimental hemorrhagic stroke: the effect of the peptide preparation cortexin in the formation of Hb-NO-complexes and other blood paramagnetic centers]. AB - Using electronic paramagnetic resonance (EPR), we studied the effect of the peptide cortexin on the content of hemoglobin nitrozyl complexes (Hb-NO complexes) and other paramagnetic centers (transferrin, methemoglobin) in the blood of rats of Krushynsky-Molodkina line in the experimental hemorrhagic stroke induced by acoustic stress. After the acoustic exposure, the level of Hb-NO complexes have increased by more than 6 times. The intensity of the EPR signal of the plasma peptide transferrin increased by 1,5 times. The level of blood methemoglobin was also elevated, though not significantly, after the acoustic stress. Cortexin substantially reduces the formation of Hb-NO-complexes and, therefore, the level of nitride oxide while the contents of transferrin and methemoglobin remain intact. PMID- 22224249 TI - [Cerebral angiospasm in subarachnoid hemorrhages]. AB - Publications on the prevalence and causes of subarachnoid hemorrhages (SAH) and one of the most frequent their complications, cerebral vasospasm (CV), are reviewed. The issues of the pathogenesis and pathophysiology of CV in SAH are covered, basic methods of its clinical and paraclinical verification are described. The authors reviewed the reasons of the discrepancy between clinically significant and angiographic vasoconstrictive reactions. The angiographic criteria of ranking angiospasm by the degree of its severity are described. Strengths and limitations of current methods of detection CV and its combinations are reviewed. The special attention is drawn to ultrasound criteria that allow to confirm the presence of CV and evaluate its severity, the reasons of present interpretative and factological inconsistencies are analyzed. The conclusions based on the literature reviewed are presented. PMID- 22224250 TI - [Stroke in elderly patients]. AB - Stroke is a disease predominantly of elderly people. Three-quarters of strokes occur after age 65 years, while age has a great influence on the outcomes of stroke. Stroke risk factors and mechanisms of ischemic cerebral damage are different in older and younger patients. Elderly patients have a severe course of stroke. Emergency diagnosis and active intensive treatment of stroke with antioxidants and neuroprotectors improve the outcome of this disease in the old age. The special focus is on the use of complex energy corrector cytoflavin that increases brain tolerance to ischemia in elderly patients with stroke. Particular attention should be paid to primary and secondary stroke prevention after 65 years of age. PMID- 22224251 TI - [A new concept of nutrition in treatment of burn injury: from nutrition support to nutrition therapy]. AB - For many years, the major concerns in the treatment of a major burn injury have always been shock resuscitation, infection control, and wound treatment, while nutrition has been considered as a subordinate concern. The concept of nutrition in the treatment of a major burn has been recognized as "nutrition support", only with the purpose of restraining negative nitrogen balance through administration of energy and protein, in order to prevent malnutrition in patients with severe burn. In recent 10 years, however, increasing evidences have showed that optimal nutritional management could improve the outcome of severe burn patients. Now it is recognized that nutrition is not only to provide exogenous nutrients to improve nutritional status of the patients, but also to regulate cell metabolism, enhance cell activity, maintain and uphold the structure and function of the gastrointestinal mucosa, thus to improve patient's outcome. Therefore, the term of "nutrition support"seems to be far from comprehensiveness to reflect the purpose and the aim of this important treatment strategy. Medical literatures especially those in nutritional guidelines have begun to use the term of "nutrition therapy" instead of "nutrition support", which typifies the changes in nutritional concept, aim, means, and clinical evaluation. The aim of nutrition has changed from simply "providing nutritional substrate and improving nutritional status of patients" to "regulating cell metabolism, maintaining organ structure and function, and ultimately improving outcome of patient". Meanwhile, nutritional means has been more consummate, including special nutrients, hormones, and growth factors, in addition to use of conventional nutrients, in order to enhance therapeutic effect of nutrition in treatment of massive burn injury. Burn nutrition is no longer confined to maintenance of positive nitrogen balance, it should also consider the regulation of cell activity, metabolic status, immune and organ function. The purpose of the article is to analyze and discuss the important issues concerning nutrition therapy in treatment of burn injury, including risk screening, optimal energy supply and ratio of different nutritional ingredients, the choice of special nutrient, as well as the determination of optimal time for giving various nutritional supplements. PMID- 22224252 TI - [Regulatory effect of glucagon-like peptide-1 on cell proliferation of skeletal myoblast strain L6 and its possible signal mechanism]. AB - OBJECTIVE: To study the regulatory effect of glucagon-like peptide-1 (GLP-1) on cell proliferation of skeletal myoblast strain L6 and its possible signal mechanism. METHODS: L6 cells cultured in DMEM high glucose culture medium containing 10% FBS were divided into control group (C, without addition), GLP-1 group (G, added with 10 nmol/L GLP-1), PI3K inhibitor group (W, added with 50 nmol/L PI3K specific inhibitor wortmannin), and GLP-1 + PI3K inhibitor group (GW, added with 10 nmol/L GLP-1 and 50 nmol/L wortmannin) according to the random number table. Cell proliferation activity was detected with MTT assay at post culture hour (PCH) 24, 48, 72 (denoted as absorbance value). At PCH 24, the change in cell cycle was evaluated with flow cytometer, the expression level of proliferating cell nuclear antigen (PCNA) was determined with immunohistochemical staining, the protein levels of phosphorylated PI3K (p-PI3K) and p-Akt were determined with Western blotting. Data were processed with multi-group analysis of variance. RESULTS: (1) The cell proliferation activity at PCH 48, 72 in G group was respectively 0.660 +/- 0.120, 0.870 +/- 0.240, all significantly higher than those in C group (0.530 +/- 0.060, 0.700 +/- 0.100, with F value respectively 5.46, 5.90, P < 0.05 or P < 0.01). The cell proliferation activity in W group at each time point was lower than that in C group. The cell proliferation activity in GW group at PCH 48, 72 was respectively 0.510 +/- 0.080, 0.740 +/- 0.160, all lower than those in G group (with F value respectively 5.46, 5.90, P < 0.05 or P < 0.01). (2) The percentage of S phase cell in G group at PCH 24 [(15.7 +/- 0.4)%] was significantly higher than that in C group [(13.6 +/- 0.6)%] and GW group [(10.1 +/- 0.6)%], while that in W group [(6.8 +/- 1.2)%] was lower than that in C group (with F values all equal to 15.39, P values all below 0.01). (3) PCNA level in G group at PCH 24 [(51.24 +/- 1.18)%] was markedly higher than that in C group [(36.72 +/- 1.56)%] and GW group [(25.90 +/- 1.22)%], and while in W group [(21.70 +/- 0.09)%] was lower than that in C group (with F values equal to 783.80, P values all below 0.05). (4) The protein level of p-Akt in G group at PCH 24 was significantly higher than that in the other 3 groups, while that in W group was lower than that in C group (with F values equal to 94.43, P values all below 0.01). There was no obvious difference in protein level of p-PI3K at PCH 24 among G, GW, and C groups ( F = 20.94, P > 0.05). The protein level of p-PI3K at PCH 24 in W group was lower than that in C group (F = 20.94, P < 0.05). CONCLUSIONS: GLP-1 can promote cell proliferation of skeletal myoblast by accelerating the progression of cell cycle and increasing the synthesis of DNA, which can be attributed to PI3K/Akt signal pathway. PMID- 22224253 TI - [Influence of rhubarb on gastrointestinal motility and intestinal mucosal barrier in patients with severe burn]. AB - OBJECTIVE: To observe the influence of rhubarb on gastrointestinal motility and intestinal mucosal barrier in patients with severe burn. METHODS: Thirty patients with severe burn admitted to our burn wards within 48 hours after burn injury from December 2009 to December 2010 were divided into therapeutic group (T, treated with 10 g rhubarb by nasal feeding and 5 g L-glutamine by oral administration beginning from 6 hours after admission, three times per day, and also given enteral nutrition beginning from 24 hours after admission, n = 16) and control group (C, received the same treatment as used in T group but without rhubarb, n = 14) according to the random number table. Gastrointestinal function indexes including restoration of bowel sound within 24 hours, abdominal distension, tolerance to enteral nutrition, and defecation were observed after treatment. The serum samples were harvested on post burn day (PBD) 3, 7, 14 for determination of the levels of gastrin (GAS) by radioimmunoassay, motilin (MTL) by enzyme-linked immunosorbent assay, diamine oxidase (DAO) by enzyme spectrophotometry, and endotoxin (ET) by kinetic turbidimetric assay with TAL. Data were processed with t test and chi-square test. RESULTS: Compared with those in C group, the numbers of patients with restoration of bowel sound within 24 hours and tolerance to enteral nutrition in T group were increased (with chi2 value respectively 5.01, 4.84, P values all below 0.05), the number of patients with abdominal distension was decreased (chi2 = 4.84, P = 0.025). Compared with those of C group, defecation time was earlier, number of bowel movement was increased with soft feces in patients of T group. The serum levels of GAS in T group on PBD 3, 7, 14 [ (92 +/- 26), (95 +/- 16), (98 +/- 18) ng/L] were significantly higher than those in C group [(80 +/- 15), (75 +/- 17), (79 +/- 13) ng/L, with t value respectively 15.352, 22.951, 19.263, P values all below 0.01]. The serum levels of MTL in T group on PBD 3, 7, 14 [(246 +/- 80), (299 +/- 76), (300 +/- 100) ng/L] were significantly higher than those in C group [(189 +/- 44), (203 +/- 64), (200 +/- 67) ng/L, with t value respectively 14.173, 19.294, 26.298, P values all below 0.01]. The serum levels of ET in T group on PBD 3, 7, 14 [(0.398 +/- 0.035), (0.373 +/- 0.005), (0.238 +/- 0.019) EU/mL] were significantly lower than those in C group [(0.493 +/- 0.043), (0.501 +/- 0.045), (0.423 +/- 0.099) EU/mL, with t value respectively 6.213, 9.153, 15.134, P < 0.05 or P < 0.01]. The serum levels of DAO in T group on PBD 3, 7 [ (3.0 +/- 0.4), (2.9 +/- 0.5) U/mL] were significantly lower than those in C group [(3.9 +/- 0.5), (3.6 +/- 0.6) U/mL, with t value respectively 3.982, 4.236, P values all below 0.05], and there was no obvious difference between T and C groups on PBD 14 (t = 1.762, P > 0.05). CONCLUSIONS: Rhubarb can protect intestinal mucosal barrier in patients with severe burn through increasing secretion of gastrointestinal hormones and promoting restoration of gastrointestinal motility. PMID- 22224254 TI - [Effects of intestinal trefoil factor combined with mucin on immune function of burn serum treated intestinal epithelial cells]. AB - OBJECTIVE: To observe the effect of intestinal trefoil factor (ITF) combined with mucin on immune function of intestinal epithelial cells (IEC) after being treated with burn rat serum. METHODS: The rat IEC-6 cell lines were divided into control group (C, cultured in DEME medium containing 10% calf serum), burn control group (BC, cultured in DEME medium containing 10% burn rat serum), burn serum + ITF group (B + I, cultured in DEME medium containing 10% burn rat serum and 25 microg/mL ITF), burn serum + mucin group (B + M, cultured in DEME medium containing 10% burn rat serum and 250 microg/mL mucin), and burn serum + ITF + mucin group (B + I + M, cultured in DEME medium containing 10% burn rat serum, 25 microg/mL ITF, and 250 microg/mL mucin) according to the random number table. Meanwhile, 200 microL suspension of E. coli with density of 1 x 10(8) CFU/mL was added to each culture. At post culture minute (PCM) 15, 30 and post culture hour (PCH) 1, 2, 3, the number of bacteria adherent to IEC-6 was counted after Wright Giemsa staining, and cell survival rate was calculated after trypan blue staining, with 20 samples in each group at each time point. (2) Other samples of IEC-6 cells without addition of E. coli were divided into BC, B + I, B + M, and B + I + M groups with the same treatment as above. The supernatant contents of IL 6, IL-8, and TNF-alpha were determined by radioimmunoassay at PCH 3, 6, 12, 24, 48, with 6 samples in each group at each time point. Data were processed with t test. RESULTS: (1) Compared with that in C group, count of adherent bacteria to IEC-6 in BC group at each time point was significantly increased (with t values from 2.947 to 8.149, P values all below 0.01). Compared with those in BC group, the counts in B + I, B + M, B + I + M groups at the major time points were significantly decreased (with t values from -4.733 to -2.180, P < 0.05 or P < 0.01). (2) Compared with that in C group, cell survival rate in BC group at each time point was obviously lowered (with t values from -4.126 to -2.363, P values all below 0.05). Cell survival rates in B + I and B + M groups at some time points were significantly elevated as compared with those in BC group (with t values from 2.120 to 3.423, P < 0.05 or P < 0.01). Cell survival rate in B + I + M group at PCM 15 and PCH 3 was respectively (96.7 +/- 2.4)% and (84.0 +/- 6.7)%, which was respectively higher than that in B + I and B + M groups [(94.5 +/- 3.1)%, t = 2.507, P < 0.05; (77.1 +/- 8.2)%, t = 2.934, P < 0.01]. (3) The contents of TNF-alpha in supernatant of B + I + M group at PCH 6, 12, 24, 48 were significantly lower than those in the other 3 groups (with t values from -6. 914 to -2.889, P < 0.05 or P < 0.01). The contents of IL-6 in supernatant of B + I + M group at some time points were significantly lower than those in the other 3 groups (with t values from -7. 657 to -2.580, P < 0.05 or P < 0.01). The contents of IL-8 in supernatant of B + I + M group at PCH 6, 12, 24, 48 were significantly lower than those in BC and B + M groups (with t values from - 8.802 to - 3.640, P values all below 0.01), and those in B + I + M group at PCH 12, 24 were lower than those in B + I group (with t value respectively -2.786, -2.740, P value all below 0.05). CONCLUSIONS: ITF can maintain immune function and homeostasis of IEC, prevent bacterial adherence, decrease cell death rate, and reduce release of inflammatory mediators. The effect can be strengthened with addition of mucin. PMID- 22224255 TI - [Effects of intestinal trefoil factor combined with mucin on ability of proliferation and migration of intestinal epithelial cells after being treated by rat burn serum]. AB - OBJECTIVE: To observe the effect of intestinal trefoil factor (ITF) combined with mucin on the ability of proliferation and migration of intestinal epithelial cells (IEC) after being treated by burn rat serum. METHODS: The rat IEC-6 cell lines were subcultured and divided into control group (C, cultured with DMEM medium containing 10% calf serum), burn serum group (BS, cultured with DMEM medium containing 10% burn rat serum), burn serum + ITF group (B + I, cultured with DMEM medium containing 10% burn rat serum and 25 microg/mL ITF), burn serum + mucin group (B + M, cultured with DMEM medium containing 10% burn rat serum and 250 microg/mL mucin), and burn serum + ITF + mucin group (B + I + M, cultured with DMEM medium containing 10% burn rat serum, 25 microg/mL ITF, and 250 microg/mL mucin) according to the random number table. Cells were counted on post culture day (PCD) 0, 1, 2, 3, 4, reflecting cell proliferation ability. Cell migration distance was measured at post scratch hour (PSH) 12, 24, 36, 48, 72. Then, cells of each group were placed in upper compartment of Transwell chamber while the corresponding medium was respectively added into lower compartment of Transwell chamber. Cells in lower compartment of Transwell chamber were counted at post culture hour (PCH) 4, 6, 8, 10, 12, reflecting cytomorphosis ability. Data were processed with t test. RESULTS: (1) Cell proliferation ability. The cell numbers in BS group on PCD 0, 1, 2, 3, 4 were significantly less than those in C group (with t values from -16.569 to -2.613, P < 0.05 or P < 0.01). The cell number showed no statistical difference between B + I and BS groups, and between B + M and BS groups at each time point (with t values respectively from 0.037 to 0.740 and 0.116 to 0.429, P values all above 0.05). The cell number in B + I + M group on PCD 2 was respectively larger than that in BS group (t = 6.484, P < 0.01) and B + I group ( t = 3.838, P < 0.01). (2) Cell migration distance in BS group at PSH 12, 24, 36, 48, 72 was significantly shorter than that in C group (with t values from -37.594 to -6.727, P values all below 0.01). There was no obvious difference in cell migration distance between BS and B + M groups at each time point (with t values from 0.055 to 0.589, P values all above 0.05). Cell migration distance in B + I group at PSH 12, 24, 36 was respectively (47 +/- 6), (126 +/- 13), (170 +/- 11) microm, all longer than those in BS group [(42 +/- 7), (98 +/- 14), (154 +/- 22) microm, with t values from 2.230 to 4.817, P < 0.05 or P < 0.01]. Cell migration distance in BS group at PSH 12, 24, 36, 48, 72 and B + I group at PSH 12, 24, 36, 48 was respectively shorter than that in B + I + M group (with t values respectively from 2.982 to 7.390 and 2.707 to 2.918, P < 0.05 or P < 0.01). (3) Cytomorphosis ability. Compared with those of C group, cell counts in lower compartment of BS group at PCH 4, 6, 8, 10, 12 were significantly decreased (with t values from -23.965 to -6.436, P values all below 0.01). Cell count in lower compartment of BS group at PCH 4, 6, 8, 10, 12 was respectively less than that of B + I group (with t values from 3.650 to 10.028, P values all below 0.01) and similar to that of B + M group (with t values from 0.199 to 0.797, P values all above 0.05). Cell counts in lower compartment of B + I + M group at PCH 4, 6, 8, 10, 12 were significantly larger than those of BS group (with t values from 4.313 to 15.100, P values all below 0.01). Cell count in lower compartment of B + I + M group at PCH 10 (328 +/- 47) and PCH 12 (465 +/ 37) was respectively larger than that in B + I group (277 +/- 25, 353 +/- 34, with t value respectively 3.051, 6.945, P values all below 0.01). CONCLUSIONS: ITF can improve cytomorphosis ability for promoting cell migration with limited effect on cell proliferation, which can be enhanced with addition of mucin. The main mechanism of ITF in maintaining intestinal mucosal barrier may be attributed to acceleration of cell migration. PMID- 22224256 TI - [Modulatory effect of insulin on scalded rat serum-induced apoptosis of skeletal myoblast]. AB - OBJECTIVE: To study the modulatory effect of insulin on apoptosis of skeletal myoblast (L6 cells) by serum of scalded rat and its mechanism. METHODS: L6 cells cultured with DMEM medium containing 10% FBS were divided into control (C, added with 20% normal rat serum), serum from rat with scald injury (S, added with 20% serum from scalded rat), insulin (I, added with 20% normal rat serum and 100 nmol/L insulin), and serum of scalded rat + insulin (SI, added with 20% serum of scalded rat + 100 nmol/L insulin) groups according to the random number table. After being cultured for 48 hours, apoptosis was observed with Hoechst 33258 staining and its number counted, annexin V -FITC/PI double-labeling method was used to assess apoptosis rate, the protein levels of phosphorylated (p-) Akt, p PI3K, Bax, Bcl-2, and active caspase-3 were determined by Western blotting. Data were processed with grouped or paired t test. RESULTS: (1) The amount of apoptosis with typical morphological change in S group [(59.6 +/- 3.9) per visual field] was more than that in C, I, and SI groups [(4.9 +/- 2.6), (5.5 +/- 2.1), (19.7 +/- 2.3) per visual field, with t value respectively 28.53, 29.86, 21.53, P values all below 0.01]. (2) Apoptotic rate in S group was (18.5 +/- 1.8)%, which was markedly higher than that in C, I, and SI groups [(1.1 +/- 0.6)%, (1.5 +/- 0.3)%, (7.8 +/- 0.6)%, with t value respectively 22.41, 22.83, 13.92, P values all below 0.01]. (3) Compared with those in C group, the protein levels of Bax and active caspase-3 in S group were up-regulated (1.12 +/- 0.63 vs. 0.16 +/- 0.03, 2.15 +/- 0.51 vs. 0.21 +/- 0.03, with t value respectively 3.80, 10.69, P values all below 0.01), the protein level of p-Akt was lowered (0.20 +/- 0.03 vs. 0.42 +/- 0.07, t = -8.46, P < 0.01), and the protein levels of p-PI3K and Bcl-2 showed no statistical difference (0.19 +/- 0.03 vs. 0.26 +/- 0.09, 0.17 +/- 0.03 vs. 0.28 +/- 0.07, with t value respectively -2.73, - 1.14, P values all above 0.05). The protein levels of Bax (0.40 +/- 0.14) and active caspase-3 (0.83 +/- 0.18) in SI group were lowered (t = -3.23, P < 0.05; t = 6.66, P < 0.01) and the protein levels of p-Akt, Bcl-2, and p-PI3K in SI group were elevated (0.39 +/- 0.10, 0.78 +/- 0.03, 0.47 +/- 0.12, with t value respectively 4.07, 18.71, 5.05, P < 0.05 or P < 0.01) as compared with those in S group. CONCLUSIONS: Serum from scalded rat can induce apoptosis in skeletal myoblast, and the effect can be inhibited by insulin through PI3K/Akt signal pathway. PMID- 22224257 TI - [Influence of omega-3 polyunsaturated fatty acids on inflammation-related parameters in lung tissue of rats with severe scald]. AB - OBJECTIVE: To study the effect of omega-3 polyunsaturated fatty acids (omega-3 PUFA) on inflammation in lung tissue of rats with severe scald and its mechanism. METHODS: Seventy-two adult SD rats were divided into sham scald group (SS, n = 8), treatment group 1 (T1, n = 32), treatment group 2 (T2, n = 32) according to the random number table. Rats in T1 group and T2 group were inflicted with 30% TBSA full-thickness scald, and then they were respectively injected with 100 g/L omega-3 PUFA (1 mL/kg) and 200 g/L long-chain fatty acid (2 mL/kg) via tail vein within 5 minutes after burn. The above two fatty acids with equivalent calories were continuously injected for 10 days (once a day). On post burn day (PBD) 1, 4, 7, and 10, serum level of TNF-alpha and level of macrophage inflammatory protein 1alpha (MIP-lalpha) in lung homogenate of T1 and T2 groups were detected, the levels of NF-kappaBp65 and macrophage migration inhibitory factor (MIF) in lung tissue of T1 and T2 groups were observed with immunohistochemical staining (recorded as score). Above-mentioned parameters were also determined in SS group. Data were processed with t test. RESULTS: The levels of 4 parameters in T1 and T2 groups on PBD 1, 4, 7, 10 were higher than those in SS group (with t values from 3.411 to 8.782, P values all below 0.01), and those in T1 group on PBD 4, 7, 10 were lower than those in T2 group (with t values from 2. 321 to 2.785, P values all below 0.05). The serum level of TNF-alpha and levels of MIP-1alpha, NF kappaBp65, and MIF in lung tissue in SS group was respectively (0.96 +/- 0.32) ng/mL, (76 +/- 16) pg/mL, 0.24 +/- 0.03, 1.31 +/- 0.03, and those in T1 and T2 groups all peaked on PBD 7 [(2.43 +/- 0.32) ng/mL, (210 +/- 56) pg/mL, 4.23 +/- 2.15, 4.69 +/- 1.83; (3.15 +/- 0.54) ng/mL, (274 +/- 64) pg/mL, 5.15 +/- 2.31, 5.37 +/- 2.16]. CONCLUSIONS: Omega-3 PUFA can effectively reduce serum level of TNF-alpha and levels of MIP-1alpha, NF-kappaBp65, and MIF in lung tissue of rats with severe scald, showing that it has a protective effect against injury of lung tissue. PMID- 22224258 TI - [Epidemiological investigation of burn inpatients in 6 hospitals of Hainan province: a retrospective analysis in 8 years]. AB - OBJECTIVE: To analyze epidemiological characteristics of burn inpatients in Hainan province over 8 years. METHODS: Six thousand and ninety-nine burn patients admitted to 6 hospitals of Hainan province from January 2002 to December 2009 were enrolled in the study. The clinical data of these patients were analyzed retrospectively, including age, gender, injury cause, wound position, burn area, ailment prior to admission, admission time, medical insurance, length of hospital stay, and mortality rate, relationship among inpatient distribution, admission time, and ambient temperature at the time of admission. Data were processed with SPSS 13.0 software. RESULTS: There were more burn male patients than female, with ratio of 2.1: 1.0. Most patients were younger than 13 years (57.2%, 3488/6099). The most common burn area was smaller than or equal to 10% TBSA (67.4%, 4108/6099), and the fewest patients had burn areas of over 50% TBSA (2.0%, 121/6099). The main causative agents were hot liquid and flame, accounting for 71.5% (4358/6099), 17.9% (1092/6099), respectively. Most patients had injuries of more than two body areas (60.7%, 3705/6099), and lower extremity injury (17.1%, 1042/6099) was predominant in wound of single body area. Among 703 cases who had other ailments prior to admission (11.5%), the highest rate of prior ailments was found in patients older than 60 years (18.5%, 48/260), it was lowest in children younger than 1 year (8.0%, 32/398). The length of hospital stay was 1 to 375 day, and the admission time was 10 minutes to 90 days after burn. Total mortality rate was 0.4% (26 cases). The number of inpatients aged from 19 to 59 was obviously higher in months with high ambient temperature (from June to August), and for inpatients younger than 13 years the incidence of burn injury showed no obvious seasonal change. The inpatients who had medical insurance accounted for 10.9% (66/603) to 19.5% (121/619) from 2002 to 2005, which increased to 46.0% (372/808) in 2007 and 79.1% (869/1098) in 2009. CONCLUSIONS: For burn inpatients in Hainan province, the main injury cause of burn injury is hot liquid, the number of burn adults aged from 19 to 59 seems to increase in months with high ambient temperature, while the incidence of burn in children showed no obvious seasonal change. The number of inpatients and those with medical insurance showed a tendency of increase from 2005 to 2009 in Hainan province. PMID- 22224259 TI - [Rheological changes of leukocytes in mesentery capillary of rats with transcranial high-voltage electrical burn and the therapeutic effects of ulinastatin]. AB - OBJECTIVE: To study the influence of transcranial high-voltage electrical burn (HEB) on rheological changes of leukocytes in mesentery capillary in rats and the therapeutic effects of ulinastatin. METHODS: Forty-five SD rats were divided into control (C), electrical burns (EB), and ulinastatin treatment (UT) groups according to the random number table, with 15 rats in each group. Model of HEB was reproduced in rats of EB and UT groups with voltage regulator and experimental transformer, and then rats in EB group was intraperitoneally injected with 2 mL isotonic saline while rats in UT group was intraperitoneally injected with 2 mL ulinastatin (2 x 10(4) U/kg). Rats in C group received sham burn with the same treatment as used in EB group but without electric current. Rheological changes of leukocytes in mesentery capillary were observed with Bradford microscope at 15 minutes before HEB and 5 minutes, 1, 2, 4, 8 hour (s) after HEB (PHM or PHH), including counting the number of rolling leukocytes, leukocytes rolling speed, the number of leukocytes adherent to mesentery capillary, total leukocyte-endothelium contact time (TLECT). Data were processed with t test. RESULTS: (1) The number of rolling leukocytes from PHM 5 to PHH 8 was increased in EB group and UT group as compared with that at 15 minutes before HEB, especially at PHM 5 [(51.4 +/- 3.2), (24.6 +/- 1.9) cells/min, respectively] which were higher than that in C group [( 1.1 +/- 0.7) cells/min, with t value respectively 59.28, 44.99, P values all below 0.05]. The number in UT group at each time point after burn was less than those in EB group, especially at PHM 5 (t = 27.97, P < 0.05). (2) Compared with that at 15 minutes before HEB, the rolling speed of leukocytes from PHM 5 to PHH 8 was slow in EB group and UT group, especially at PHM 5 [(90 +/- 9), (175 +/- 13) microm/s, respectively] which were slower than that in C group [(277 +/- 12) microm/s, with t value respectively 47.97, 21.59, P values all below 0.05]. The rolling speed in UT group from PHM 5 to PHH 8 was faster than that in EB group, especially at PHM 5 (t = 20.55, P < 0.05). (3) Compared with that at 15 minutes before HEB, the number of leukocytes per 100 micrometer capillary from PHM 5 to PHH 8 was increased in EB group and UT group, especially at PHM 5 (23.27 +/- 3.20, 5.80 +/- 1.61, respectively) which were higher than that in C group (0, with t value respectively 28.16, 13.95, P values all below 0.05). The number of adhered leukocytes in UT group at each time point after burn was less than that in EB group, especially at PHM 5 ( t = 18.89, P < 0.05). (4) Compared with that at 15 minutes before HEB, TLECT from PHM 5 to PHH 8 was increased in EB group and UT group, especially at PHM 5 [(14.45 +/- 1.99), (3.66 +/- 0.96) s/min, respectively] which were longer than that in C group (0 s/min, with t value respectively 28.12, 14.77, P values all below 0.05). TLECT in UT group from PHM 5 to PHH 8 was shorter than that in EB group, especially at PHM 5 (t = 18.91, P < 0.05). (5) No rolling leukocyte or wall-adherent leukocyte was found in blood flow of arterioles or capillaries of rats in three groups at each time point. CONCLUSIONS: Transcranial HEB can lead to abnormal rheological changes of leukocytes in mesentery capillary in rats, and the changes can be ameliorated by ulinastatin. PMID- 22224261 TI - A new diacylated labdane diterpenoid from Andrographis wightiana. AB - A new acylated labdane diterpenoid, 14-deoxy-3,19-diacetyl-11,12 didehydroandrographolide (1), together with three known labdane diterpenoids, wightionolide (2), andrographolide (3) and neoandrographolide (4), and three known flavones, echioidinin (5), skullcapflavone I 2'-methyl ether (6) and echioidin (7), were isolated from the whole plant of Andrographis wightiana. The structure of compound 1 was elucidated by 1D and extensive 2D-NMR spectral studies. PMID- 22224260 TI - Antifungal activity of plumericin and isoplumericin. AB - This study evaluated the in vitro antifungal activity of the chloroform extract of Plumeria bicolor and its phytoconstituents plumericin and isoplumericin against Candida species and Cryptococcus neoformans by measuring the Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC). Plumericin's consistently high activity against Candida albicans, C. krusei, C. glabrata, C. tropicalis and Cryptococcus neoformans was more potent than isoplumericin and the standard antifungal drug nystatin suggesting its potential as a drug candidate for candidiasis and cryptococcosis. PMID- 22224262 TI - Triterpenoid acids and lactones from the leaves of Fadogia tetraquetra var. tetraquetra (Rubiaceae). AB - Four triterpenoids isolated from the leaves of Fadogia tetraquetra var. tetraquetra, 3beta-hydroxy-11alpha, 12alpha-epoxyoleanan-28,13beta-olide (1), 3beta-hydroxyurs-11-en-28,13beta-olide (2), oleanolic acid (3), and ursolic acid (4), were evaluated for their antiviral and antibacterial properties. Compound 4 showed potent activity against the Semliki Forest virus with an IC50 of 14.7 microM, but was also found to be significantly cytotoxic (68% reduction in cell viability after 24 hours exposure at 50 microM) towards baby hamster kidney (BHK21) host cells. A viability assay on the mammalian human hepatocellular carcinoma (Huh-7) cell line showed no significant effects on intracellular ATP content after 48 hours exposure to compounds 1-4 at this concentration. Compound 4 also inhibited Staphylococcus aureus (MIC 12.5 microM), but was inactive against Enterobacter aerogenes, Escherichia coli, and Pseudomonas aeruginosa. Compounds 1-3 were inactive against all tested bacterial strains at 50 microM concentration. PMID- 22224263 TI - Isolation of friedelin from black condensate of cork. AB - Black condensates (BC) are wastes of the insulation corkboard industry that contain several valuable chemicals, including friedelin, a terpene exhibiting biological activity. Herein, we report a straightforward procedure to extract friedelin from BC. Using this procedure, we were able to extract friedelin with yields between 0.4% and 2.9% and to further purify it obtaining purities from 77.0% to 99.3% (HPLC). The initial BC (2 batches), extracted raw product and purified friedelin were analyzed using FTIR. The extraction yields and purities were found to be directly related to the intensity of the carbonyl vibration at 1713 cm(-1) in the FTIR spectrum of the used BC batch. Therefore, these spectra can be used to screen and select BC batches suitable for friedelin extraction. PMID- 22224264 TI - Novel microbial transformation of resibufogenin by Absidia coerules. AB - Resibufogenin is one of the major active components of the Chinese medicine ChanSu. In this paper, microbial transformation of resibufogenin by Absidia coerules AS 3.3382 was investigated and five metabolites were isolated and identified as 5beta-hydroxy-resibufogenin (2), 3-epi-resibufogenin (3), 3alpha hydroxy-15-oxo-14alphaH-bufa-20, 22-dienolide (4), 3alpha,14alpha,15beta trihydroxy-bufa-20, 22-dienolide (5) and 3-epi-15beta-hydroxy-bufalin (6). Among them, 4-6 are novel compounds, and compound 3 is a major transformed product. The cytotoxicities of the compounds against Bel-7402 and Hela cells were investigated, and our result suggested that 14,15-OH configuration was directly related to the cytotoxicities of bufadienolides. PMID- 22224265 TI - Antidiabetic activity of Terminalia sericea constituents. AB - Diabetes mellitus is an endocrine disorder that affects more than 100 million people worldwide. South African plants namely Terminalia sericea, Euclea natalensis, Warbugia salutaris, Aloe ferox, Artemisia afra, Sclerocarya birrea, Spirostachys africana and Psidium guajava were investigated for their in vitro alpha-glucosidase and alpha-amylase properties, and antioxidant activities. Terminalia sericea stem bark extract showed the best results against alpha glucosidase and alpha-amylase enzymes. Bioassay-guided fractionation of an acetone extract of T. sericea stem bark led to the isolation of four known compounds namely beta-sitosterol (1), beta-sitosterol-3-acetate (2), lupeol (3), and stigma-4-ene-3-one (4), in addition to two inseparable sets of mixtures of isomers [epicatechin-catechin (M1), and gallocatechin-epigallocatechin (M2). 1 and 3 showed the best inhibitory activity on alpha-glucosidase (IC50:54.5 and 66.5 microM). Bio-evaluation of the inhibitory activity of the purified compounds on alpha-amylase showed that 3 and 1 exhibited IC50 values of 140.7 and 216.02 microM, respectively against alpha-amylase. Compounds 2, M1, 3 and M2 were found to be non-toxic to Vero cells. This study is the first to report alpha glucosidase and alpha-amylase activity of M1, M2, 2 and 4 isolated from T. sericea, which validated the traditional use of the bark of T. sericea for diabetes in South Africa. PMID- 22224266 TI - X-ray crystallographic study of ranaconitine. AB - The crystal structure of natural diterpenoid alkaloid ranaconitine isolated from Aconitum sinomontanum Nakai has been determined by single crystal X-ray diffraction analysis. The crystal presents a monoclinic system, space group C2 with Z = 4, unit cell dimensions a = 30.972(19) angstrom, b = 7.688(5) angstrom, and c = 19.632(12) angstrom. Moreover, the intermolecular O-H...O hydrogen bonds and weak pi-pi interactions play a critical role in expanding the dimensionality. PMID- 22224267 TI - Obscurine: a new cyclostachine acid derivative from Beilschmiedia obscura. AB - From the methylene chloride extract of the stem bark of Beilschmiedia obscura, a new cyclostachine derivative, obscurine (1), has been isolated, together with six known compounds. The structure of compound 1 was established by spectroscopic methods, including 1- and 2-dimensional NMR techniques. PMID- 22224268 TI - Alkaloids from Papaver coreanum. AB - The alkaloid pattern of the endemic plant Papaver coreanum Nakai (Papaveraceae) was determined for the first time. Eight alkaloids could be identified by LC/ESI MS/MS and high-resolution mass spectrometry. Among them, protopine and allocryptopine represent the main components. Besides norsanguinarine, sanguinarine, dihydrosanguinarine, oxysanguinarine, lincangenine, and cryptopine, some other trace alkaloids were found whose structures remain unknown. PMID- 22224269 TI - Isolation, structure elucidation, and biological activity of a new alkaloid from Zanthoxylum rhetsa. AB - Several biologically active alkaloids (1-4, 6), including a new quinazoline-6 carboxylic acid (1), were isolated from the medicinal plant Zanthoxylum rhetsa, an evergreen tree, native to subtropical areas. Whereas the pharmacological properties of the plant extract and single constituents have been widely tested, we now show that all of the metabolites have antialgal activities, all but 6 are antibacterial, and 6 and the reduction product 5 (derived from 4) are also antifungal. PMID- 22224270 TI - Amplexicine, an antioxidant flavan-3-ol from Polygonum amplexicaule. AB - Bioassay guided fractionation of an ethanolic extract of Polygonum amplexicaule D. Don led to the isolation of amplexicine, a new flavan-3-ol (1), along with khellactone (2). The structure of the isolates was established by UV, IR, HRESI/MS and NMR, including 1D and 2D experiments. Compound 1 exhibited considerable antioxidant activity in a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging assay. PMID- 22224271 TI - A new flavonoid glycoside from Vaccaria hispanica. AB - A profiling analysis for the methanol extract of the seeds of Vaccaria hispanica (Mill.) Rauschert was performed using a HPLC-ESI-MS technique. Five compounds were identified according to their retention times, UV spectroscopic and MS features, and by comparison with literature data. Among them, a new flavonoid glycoside, named vaccarin H, was isolated and the structure determined by spectral and chemical analysis as isovitexin 2"-O-alpha-L-arabinopyranosyl-4'-O (6""-O-dihydroferuloyl)-3-beta-glucopyranoside. PMID- 22224272 TI - Flavonoids from Algerian endemic Centaurea microcarpa and their chemotaxonomical significance. AB - Six flavonoids, namely 6-methoxykaempferol (1), 6-methoxykaempferol 7-O-glucoside (2), kaempferol 7-O-glucoside (3), 6-methoxyluteolin (4), patuletin 7-O-glucoside (5), and hispidulin 7-O-glucoside (6), were isolated from a n-butanolic fraction of Centaurea microcarpa Coss et Dur. flowers. This work describes for the first time the phytochemical composition of this endemic Algerian plant. PMID- 22224273 TI - On-line (HPLC-NMR) and off-line phytochemical profiling of the Australian plant, Lasiopetalum macrophyllum. AB - On-line (HPLC-NMR) and off-line (HPLC, NMR and MS) methodologies were used to profile the constituents present in the crude extract of Lasiopetalum macrophyllum. On-flow and stop-flow HPLC-NMR supported the presence of trans tiliroside and permitted partial identification of cis-tiliroside and 4'-methoxy trans-tiliroside. Off-line isolation led to the unequivocal identification of four flavanoid glycosides including a new structural derivative, 4'-methoxy-cis tiliroside. This is the first report of flavonoid glycosides occurring in this plant genus. In addition, a number of structure revisions have been proposed for previously reported flavonoid glycosides that were incorrectly assigned. PMID- 22224274 TI - Chemical fingerprint analysis of phenolics of Albizia chinensis based on ultra performance LC-electrospray ionization-quadrupole time-of-flight mass spectrometry and antioxidant activity. AB - Albizia species have been shown to have anti-inflammatory and anti-allergic properties. However, efficient analytical methods for identification of their active constituents are still lacking. Ultra-performance liquid chromatography coupled with electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS) was used to study the phenolic composition of the ethanolic extracts of different parts (flowers, leaves, pods and bark) of A. chinensis. In addition, the antioxidant activity of the ethanolic extracts was evaluated by the 1,1-diphenyl-2-picryl hydrazyl (DPPH) free-radical and 2,2'-azino-bis(3 ethylbenzthiazoline-6-sulfonic acid (ABTS) radical cation scavenging methods. Four compounds were isolated from the ethanolic extract of the flowers and characterized by 1H and 13C NMR spectroscopy as quercetin-3-O-rhamnoside, quercetin, quercetin-3-O-arabinofuranoside, and myricetin-3-O-rhamnoside. Separation and quantification of the phenolics was accomplished using a reversed phase BEH C18 column with the mobile phase of methanol-water (0.05% formic acid), and detection wavelengths of 360 and 254 nm. PMID- 22224275 TI - Application to classification of mulberry leaves using multivariate analysis of proton NMR metabolomic data. AB - Recently, NMR-based metabolomic analysis has been used to acquire information based on differentiation among biological samples. In the present study, we examined whether multivariate analysis was able to be applied to natural products and/or material field. Each extraction of 24 leaf samples, divided into six locations from the tip of the stem in each of four strains, was analyzed by pattern recognition methods, known as Principal Component Analysis (PCA) and Soft Independent Modeling of Class Analogy (SIMCA). Twenty-four extracts from mulberry leaf showed independent spectra by 1H NMR. The separation of leaf extraction data due to the difference at six locations was achieved in the PCA score plot as correlation PC1 (86.1%) and PC3 (4.6%) and showed two loading plots, suggesting classification by leaf position as an independent variable in the loading plot. Moreover, the difference among six locations clarified the seven highest discrimination powers by the SIMCA method. Meanwhile, the PCA score plot obtained classification by the variety of mulberry strains with three loading plots, but the SIMCA method did not give a peak by classification. PMID- 22224276 TI - Phenolic constituents of Knautia arvensis aerial parts. AB - A new C-6 flavone glycoside (6), together with seven known compounds, cryptochlorogenic acid (1), chlorogenic acid (2), 2-O-trans-caffeoylhydrocitric acid (3), isovitexin 7-beta-D-glucopyranoside (4), 7,4'-dihydroxy-5 methoxyflavone-6-C-beta-D-glucopyranoside (5), 3,5-O-dicaffeoylquinic acid (7) and 4,5-O-dicaffeoylquinic acid (8), were isolated from the aerial parts of Knautia arvensis. Their structures were elucidated by extensive spectroscopic methods including 1D- (1H, 13C and TOCSY) and 2D-NMR (DQF-COSY, HSQC, HMBC) experiments, as well as ESIMS analysis. Compounds 1, 3-5 and 8 are reported for the first time in Knautia arvensis. PMID- 22224277 TI - New acylated anthocyanins and other flavonoids from the red flowers of Clematis cultivars. AB - Six new acylated cyanidin glycosides, cyanidin 3-O-beta-(2''-E caffeoylglucopyranosyl)-(1 --> 2)-O-beta-galactopyranoside (1), cyanidin 3-O-beta (2''-E-caffeoylglucopyranosyl)-(1 --> 2)-O-beta-(6''-malonylgalactopyranoside) (2), cyanidin 3-O-beta-(2''-E-caffeoylglucopyranosyl)-(1 --> 2)-O-beta-(6'' succinylgalactopyranoside) (3), cyanidin 3-O-beta-(2''-E-caffeoylglucopyranosyl) (1 --> 2)-O-beta-galactopyranoside-3''- O-beta-glucuronopyranoside (4), cyanidin 3-O-beta-(2''-E-caffeoylglucopyranosyl)-(1 --> 2)-O-beta-(6'' malonylgalactopyranoside)-3'-O-beta-glucuronopyranoside (5), and cyanidin 3-O beta-(2'-E-feruloylglucopyranosyl)-(1 --> 2)-O-beta-(6''-malonylgalactoside)-3' O-beta-glucuronopyranoside (6), were isolated from the red flowers of two Clematis cultivars, 'Niobe'and 'Madame Julia Correvon'. The chemical structures of the isolated anthocyanins were determined by UV, LC-MS, HPLC, TLC, characterization of hydrolysates, and 1H and 13C NMR spectroscopy, including H-H COSY, C-H COSY, HMBC, HMQC and NOESY. The last three anthocyanins were widely distributed in 37 red flower Clematis cultivars. On the other hand, the first three compounds were found only in two cultivars. Five known flavonol glycosides, kaempferol 3-O-glucoside, kaempferol 3-O-rutinoside, quercetin 3-O-galactoside, quercetin 3-O-glucoside and quercetin 3-O-rutinoside, were isolated from the flowers of'Madame Julia Correvon'. PMID- 22224278 TI - Prenylated isoflavonoids from Rhynchosia edulis. AB - Four new prenylated isoflavones, rhynedulins A-C (1-3) and rhynedulinal (4), were isolated by bioassay-guided fractionation of the dichloromethane bark extract of Rhynchosia edulis. Five previously described compounds, scandenal, ulexin B, cajanone, cajanin, and cyclochandalone, were also isolated. These isoflavonoids showed weak inhibitory activity towards rhodesain, the major cathepsin-L like protease in Trypanosoma brucei. They also have weak antiproliferative activity towards MCF-7 cells. PMID- 22224279 TI - Antiparasitic and antimicrobial isoflavanquinones from Abrus schimperi. AB - The EtOH extract of Abrus schimperi (Fabaceae), collected in Kenya, demonstrated significant activity against Leishmania donovani promastigotes with IC50 value of 3.6 microg/mL. Bioassay-guided fractionation of CHCl3 fraction using Centrifugal Preparative TLC afforded two antiparasitic isoflavanquinones, namely amorphaquinone (1) and pendulone (2). They displayed IC50 values of 0.63 microg/mL and 0.43 microg/mL, respectively, against L. donovani promastigotes. Both the compounds were also evaluated against L. donovani axenic amastigotes and amastigotes in THPI macrophage cultures. In addition, compounds 1 and 2 showed antiplasmodial activity against Plasmodium falciparum D6 and W2 strains, while 2 displayed antibacterial activity against Staphylococcus aureus and methicillin resistant S. aureus (each IC50 1.44 microg/mL). The 1H and 13C data of 1, not fully assigned previously, were unambiguously assigned using 1D and 2D NMR HMBC and HMQC experiments. In addition, the absolute stereochemistry of the isolated compounds 1 and 2 was revised as C-(3S) based on Circular Dichroism experiments. This appears to be the first report of amorphaquinone (1) and pendulone (2) from the genus Abrus. PMID- 22224280 TI - Two new rotenoids from Boerhavia repens. AB - Two new rotenoids, boerharotenoids A (1) and B (2), and four known compounds, boeravinone (3), 5,7,3'-trihydroxycoumaronochromone (4), boeravinone F (5), and eupalitin-3-O-beta-D-galactopyranoside (6), have been isolated from Boerhavia repens and their structures established by spectroscopic (1D and 2D NMR) and mass spectrometric comparison with literature values. PMID- 22224281 TI - A comparison of the diastereoisomers, silybin A and silybin B, on the induction of apoptosis in K562 cells. AB - Two diastereoisomers of silybin, silybin A and silybin B, were separated from silymarin by HPLC in our previous study. The present study assessed the effects of the diastereoisomers on cell apoptosis, and compared these with their mixture, silybin, in human chronic myeloid leukemia K562 cells. Both isomers showed stronger effects on cell growth inhibition and apoptosis induction than silybin. Compared with silybin B, silybin A showed higher effects on the production of intracellular reactive oxygen species and Ca2+. These results suggest that silybin A and silybin B have similar potency on apoptosis induction with different oxidative effects. Antagonistic effects may exist between silybin A and silybin B, partially through ROS production and Ca2+ increase. PMID- 22224282 TI - Effects of pH, sample size, and solvent partitioning on recovery of soluble phenolic acids and isoflavonoids in leaves and stems of red clover (Trifolium pratense cv. Kenland). AB - Several extraction parameters were tested to determine optimal conditions for extracting phenolics from leaves and stems of red clover (Trifolium pratense L. cv. Kenland), with the goal of using extracts in bioassays and in assessment of phenolic profiles. HPLC-UV profiles were compared before and after partitioning a methanolic extract of soluble phenolics with ethyl acetate-ethyl ether (1:1, v/v). The effect of extract pH on the partitioning of phenolics into the ethyl acetate-ethyl ether (EtOAc-Et2O) phase was evaluated, and several tissue weights were extracted to determine a minimum amount that could be extracted without loss of information. HPLC profiles of soluble phenolics were similar in the methanolic extracts and the partitioned EtOAc-Et2O extracts. However, recoveries in unpartitioned extracts were 2- to 4-fold greater than in the acidified, partitioned extracts. Also, recovery was considerably affected by the pH to which extracts were adjusted prior to partitioning. In extracts acidified to pH 2, recoveries were 2- to 7-fold higher than in extracts partitioned at pH 6. In extracts prepared from 250, 120, or 60 mg of tissue, peak areas of methanolic extracts were directly proportional to the amount of tissue extracted. PMID- 22224283 TI - Arbutin derivatives from the seeds of Madhuca latifolia. AB - A new arbutin derivative, madhuglucoside (1), along with three known arbutin derivatives were isolated from the seeds of Madhuca latifolia in addition to seven other known constituents. Their structures were established on the basis of spectral analysis. Compounds 1a, 2a and 3a were obtained in a pure state after acetylation of the mother fraction and characterized as their acetyl derivatives. PMID- 22224285 TI - Cytotoxic activity and cell cycle analysis of hexahydrocurcumin on SW 480 human colorectal cancer cells. AB - The cytotoxicity of hexahydrocurcumin and its effect on the cell cycle in human colorectal cancer cells SW480 has been studied for the first time. The compound, extracted from Zingiber officinale, was shown to be cytotoxic to colorectal cancer cells. Treatment of SW480 cells with hexahydrocurcumin (100 microM) resulted in a massive accumulation of the cells in the G1/G0 phase of the cell cycle. The cytotoxic effect of hexahydrocurcumin may prove useful in cancer prevention. PMID- 22224284 TI - Quinic acids from Aster caucasicus and from transgenic callus expressing a beta amyrin synthase. AB - Several different classes of secondary metabolites, including flavonoids, triterpenoid saponins and quinic acid derivatives, are found in Aster spp. (Fam. Asteraceae). Several Aster compounds revealed biological as well as pharmacological activities. In this work, a phytochemical investigation of A. caucasicus evidenced the presence of quinic acid derivatives, as well as the absence of triterpene saponins. To combine in one species the production of different phytochemicals, including triterpenes, an Agrobacterium-mediated transformation of A. caucasicus was set up to introduce A. sedifolius beta-amyrin synthase (AsOXA1)-encoding gene under the control of the constitutive promoter CaMV35S. The quali-quantitative analysis of transgenic calli with ectopic expression of AsOXA1 showed, in one sample, a negligible amount of triterpene saponins combined with higher amount of quinic acid derivatives as compared with the wild type callus. PMID- 22224286 TI - Does the combination of resveratrol with Al (III) and Zn (II) improve its antioxidant activity? AB - This communication describes the in situ combination of Al(III) and Zn(II) with resveratrol, and evaluation of the antioxidant power of the novel species via DPPH* assay. The formation of the complexes in aqueous medium was verified by Job's method, using fluorescence spectroscopy. The metal/ligand stoichiometry for the Zn(II)/resveratrol complex was found to be 1:2 and, for the Al(III)/resveratrol complex two preferential species were formed with 1:1 and 3:1 stoichiometries. The compounds were also studied by 1H and 13C NMR spectroscopy. Their antioxidant activity, evaluated by a scavenging assay using DPPH* (1,1 diphenyl-2-picrylhydrazyl), demonstrated that the combined species are more effective free radical scavengers than free resveratrol. The electrochemical behavior of the complexes revealed the occurrence of irreversible oxidation processes, which take place at a lower potential than that observed with free resveratrol. These results indicate that metallic complexes of this natural product have a higher antioxidant power than resveratrol alone. PMID- 22224287 TI - Photosensitization mechanisms of triplet excited state beta-lapachone. A density functional theory study. AB - Beta-Lapachone is a natural product with multiple pharmacological activities and mechanistic studies indicated that reactive oxygen species (ROS) generated by beta-lapachone play significant roles in its pharmacological actions. As photosensitization is an important ROS-generating pathway, in the present work, the photosensitization mechanisms of beta-lapachone are explored on the basis of density functional theory estimated triplet excited state characters. Starting from triplet excited state beta-lapachone, the possible generating pathways of 1O2 and O2*- are elucidated and the solvent effects on the photosensitizing reactions are also discussed. PMID- 22224288 TI - AFLP marking and polymorphism among progenies of Gymnema sylvestre: an important medicinal plant of India. AB - The level of polymorphism among twelve selected progenies of Gymnema sylvestre was investigated through AFLP markers by multiplexing PCR reactions using 64 (8x8) primer combinations. Fourteen primer combinations were selected as the most suitable combination for G. sylvestre. Analysis of the 12 progenies with these 14 primer pairs produced 1689 fragments of which 972 (57.5%) were polymorphic and 485 (28.7%) were unique to a particular genotype. The number of fragments produced by individual primer pairs was in the range of 55 to 225. Out of these, polymorphic fragments were in the range of 34 (E-ACC/M-CAC) to 157 (E-AGG/M-CAG) and unique bands observed were 8 (E-ACC / M-CAC) to 69 (E-AGG/M-CAC). Different primer combinations detected different levels of polymorphism, ranging from 33% (E-AGG/ M-CAC) to 69.8% (E-AGG/ M-CAC). From the observations, it appears that the primer combinations E-AGG/M-CAC, E-AGG/CTG, E-AGG/CAG and E-ACA/CAT were the most informative for the detection of polymorphism among the progenies compared with others, since they produced a high number of unique fragments. The similarity coefficient ranged from 0.212 to 0.731. High similarity was observed between progeny S8 and S9 (73%) and high divergence between progenies S3 and S11. Among the selected progeny, S9 was found to be the most similar to the parent (63%), while genotype S11 was the most distant (36.9%). PMID- 22224289 TI - Antioxidant activity of protein hydrolysates from aqueous extract of velvet antler (Cervus elaphus) as influenced by molecular weight and enzymes. AB - The crude protein hydrolysates from aqueous extract of velvet antler (AEVA) were prepared by simulated gastrointestinal digestion (SGI, pepsin-pancreatin) using pancreatin-pepsin, alcalase and neutrase. The resulting hydrolysates were separated by sequential ultrafiltration into four fractions. The antioxidant activities of peptide fractions were evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, ferric reducing antioxidant power (FRAP), 2,2' azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging and Fe(2+)-chelating assays. Results showed that the hydrolysate prepared by SGI had a low degree of hydrolysis, which was significantly improved with altered proteases, such as pancreatin-pepsin and alcalase. Antioxidant activities of peptide fractions varied with molecular weight (MW) and the enzyme used. Generally, low-MW peptide fractions had higher ABTS radical scavenging activity and Fe(2+)-chelating ability, and high-MW peptide fractions were more effective in DPPH radical scavenging activity and reducing power. PMID- 22224291 TI - In vitro antiprotozoal activity of extracts of five Turkish Lamiaceae species. AB - The in vitro antiprotozoal activities of crude methanolic extracts from the aerial parts of five Lamiaceae plants (Salvia tomentosa, S. sclarea, S. dichroantha, Nepeta nuda subsp. nuda and Marrubium astracanicum subsp. macrodon) were evaluated against four parasitic protozoa, i.e. Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani and Plasmodium falciparum. The cytotoxic potentials of the extracts on L6 cells were also evaluated. Melarsoprol, benznidazole, miltefosine, chloroquine and podophyllotoxin were used as reference drugs. All crude MeOH extracts showed antiprotozoal potential against at least three parasites, so they were dispersed in water and partitioned against n-hexane and chloroform to yield three subextracts that were screened in the same test systems. The n-hexane extract of N. nuda was the most active against T. brucei rhodesiense while the CHCl3 extracts of S. tomentosa and S. dichroantha showed significant activity against L. donovani. All organic extracts displayed in vitro antimalarial and moderate trypanocidal activities against T. cruzi with the n-hexane extract of S. sclarea being the most active against the latter. The extracts displayed low or no cytotoxicity towards mammalian L6 cells. PMID- 22224290 TI - Effects of Sideritis euboea (Lamiaceae) aqueous extract on IL-6, OPG and RANKL secretion by osteoblasts. AB - The water extract obtained from the aerial parts of Sideritis euboea (Lamiaceae), which is known in Greece as 'mountain tea', was investigated by determining the in vitro effect of this extract on the IL-6, OPG and RANKL secretion by osteoblasts, three important molecules in osteoblast-osteoclast interplay. The results showed that this extract reduced significantly the secretion of IL-6 by KS-483 osteoblasts, while it also suppressed RANKL secretion, with both effects being dose-dependent and more potent at the higher concentrations tested (50, 100 microg/mL). We further determined the chemical profile of the extract by applying an analytical U-HPLC-DAD-ESI-MS/MS method using the high resolution hybrid LTQ Orbitrap Discovery spectrometer. An ESI source in negative mode was employed. The analysis indicated that the water extract of S. euboea is rich in flavonoid glycosides, and phenylpropanoid glycosides. PMID- 22224292 TI - Antimicrobial investigation of Linum usitatissimum for the treatment of acne. AB - Light petroleum, dichloromethane and methanolic extracts of Linum usitatissimum were investigated using GC/MS. The main components of three sequential extracts were methyl linolenate (11.9-33.9%) and methyl linoleate (3.4-9.1%). Components possessing antimicrobial activity against acne causing bacteria, namely alpha linolenic acid (7.0 -7.1%), alpha-terpinene (1.7-3.1%), terpinen-4-ol (1.3-4.6%), 4-cymene (1.6-7.1%) and alpha-pinene (1.1%), were found in varying amounts. Antimicrobial screening indicated that the light petroleum extract was more active against aerobic and anaerobic test strains with a MIC value of 1.25 mg/mL and a MBC of 2.5 mg/mL against S. aureus and P. acnes. A MIC of 2.5 mg/mL was observed against S. epidermidis. PMID- 22224293 TI - Chemical and biological diversity in fourteen selections of four Ocimum species. AB - Biomass, essential oil yield, essential oil composition diversity, and antibacterial and antifungal activities of 14 selections of 4 Ocimum species [Ocimum basilicum L. (selections: T1-T10), O. gratissimum L. (selections: T11 T12), O. tenuiflorum L.f., syn. O. sanctum L. (selection: T13) and O. kilimandscharicum Baker ex. Guerke (selection: T14)] were investigated. O. basilicum selections T9 (methyl chavicol: 87.0%) and T10 {(Z)- and (E)-methyl cinnamate: 69.1%} produced higher biomass (67.8 and 56.7 t/ha) and oil (203.4 and 141.7 kg/ha) yields relative to 8 (T1-T8) linalool (up to 58.9%), or methyl chavicol (up to 61.8%) rich selections. O. gratissimum selection T12 (eugenol: 84.1%, 254.6 kg/ha oil yield) was significantly superior to T11 (62.1% eugenol and 18.4% camphor). O. tenuiflorum (T13, methyl eugenol: 72.5%) and O. kilimandscharicum (T14, camphor: 51.7%) produced 171.7 and 96.2 kg/ha essential oil, respectively. The essential oils exhibited broad spectrum antibacterial (against 5 Gram-positive and 7 Gram-negative bacteria) and antifungal (against 10 fungi) activities. The bacterial species Bacillus subtilis, Staphylococcus aureus, Streptococcus mutans, and Enterococcus faecalis, and the fungal species Epidermophyton floccosum, Microsporum gypseum, and Sporothrix schenckii were more sensitive to the essential oils. PMID- 22224294 TI - Environmental effect on essential oil composition of Aloysia citriodora from Corrientes (Argentina). AB - Lemon verbena (Aloysia citriodora Palau) is indigenous to South America and was introduced into Europe. It is cultivated mainly due to the lemon-like aroma emitted from its leaves, which are utilized for the preparation of herbal tea reputed to have antispasmodic, antipyretic, sedative and digestive properties. In this work we introduce the enantiomeric distribution of sabinene and limonene by bidimensional gas chromatography (chiral GC-GC) as a genuine quantitative parameter in order to improve the knowledge so far available on A. citriodora oil. Multivariate analysis afforded information on the similarities and differences of wild and cultivated A. citriodora populations during different seasons in the same environmental conditions. The results indicated that it was possible to discard the environmental and seasonal effect on the chemical composition of A. citriodora for wild and cultivated materials belonging to the same genetic origin. PMID- 22224295 TI - Essential oil of three Uvaria species from Ivory Coast. AB - Different parts of Uvaria ovata (Dunals) A, U. anonoides Baker f. and U. tortilis A. Chev were collected from Ivory Coast, in Toumodi (center), Agboville (south east) and Sikensi (south), respectively. The essential oils, obtained by hydrodistillation using a Clevenger-type apparatus, were investigated by CG and CG/MS. The proportion of the chromatographed constituents identified varied from 92.5% to 98.5%. For U. ovata, the root bark oil comprised mainly camphene (10.2%), beta-pinene (10.1%), epi-alpha-cadinol (13.2%) and intermedeol (9.7%), while the oil of the stem bark was dominated by epi-alpha-cadinol (27.3%), intermedeol (11.9%) and benzyl benzoate (13.4%). The oil of the leaves showed beta-caryophyllene (15.6%), germacrene D (24.2%) and benzyl benzoate (18.3%) as the most abundant constituents. The leaf oil of U. anonoides was rich in 2,5 dimethoxy-p-cymene (15.5%), bicyclogermacrene (21.3%) and benzyl benzoate (8.7%), while, gamma-terpinene (31.7%), beta-caryophyllene (23.9%) and germacrene D (15.8%) constituted the main components of the stem bark oil of U. tortilis. PMID- 22224296 TI - Composition of the essential oil of Origanum tyttanthum from Tajikistan. AB - Origanum tyttanthum Gontsch. was collected from two different sites in south central Tajikistan. The essential oils were obtained by hydrodistillation and analyzed by gas chromatography-mass spectrometry. A total of 52 compounds were identified representing 99.0-100% of total oil compositions. The major components of Origanum tyttanthum Gontsch. oil were carvacrol (34.3-59.2%), thymol (10.8 46.4%), p-cymene (0.7-7.3%), beta-thujone (1.9-4.1%), piperitenone oxide (0.1 3.8%), gamma-terpinene (0.3-3.5%), cis-piperitone epoxide (0.8-3.3%), carvacrol acetate (0.4-2.4%), menthone (0.6-2.1%) and borneol (1.0-2.3%). PMID- 22224297 TI - Volatiles of French ferns and "fougere" scent in perfumery. AB - Six French ferns were investigated for volatile organic compounds (VOC) by GC-MS using organic solvent extraction. Seventy-seven VOC biosynthesized from the shikimic, lipidic and terpenic pathways, including isoprenoid derivatives, were identified from these putative natural resources. Asplenium trichomanes subsp. trichomanes contained mainly polyketides with an oily or waxy odor. (E)-2-Hexenal and (Z)-3-hexenol, responsible for the "green odor", were found in high contents in Polystichum setiferum, Dryopteris dilatata and Phegopteris connectilis. In the last, 7.4% of coumarin with a cut hay scent was highlighted from the volatile fraction. (E)-3-Hexenoic acid and (E)-2-hexenoic acid, both with herbal and fruity notes, were identified in Gymnocarpium dryopteris and Pteridium aquilinum. 1-Octen-3-ol, well-known for its mushroom-like odor, was abundant in all analyzed French ferns. While the "fougere" fragrance is claimed by the perfumers to be a fantasy scent, coumarin, (E)-2-hexenal, (Z)-3-hexenol and 1-octen-3-ol are the main odorous components of the perfumes belonging to the fougere accord family. This suggests that the fougere scent from the perfumers' imagination is a natural fragrance. PMID- 22224298 TI - Volatile constituents of two species of Protium from the Atlantic rainforest in the state of Pernambuco, Brazil. AB - The chemical composition of the essential oils from Protium giganteum and P. aracouchine was determined, for the first time, using GC-MS analysis. From the oil of P. giganteum, 32 components were identified, representing 93.9% of the oil, and from P. aracouchine, 29 components, representing 97.8% of the oil. Among the compounds identified in the P. giganteum oil, 93.6% were sesquiterpenes, with beta-caryophyllene (26.0 +/- 0.8%), globulol (9.3 +/- 0.2%), alpha-cadinol (7.0 +/- 0.5%), alpha-humulene (6.4 +/- 0.1%) and germacrene D (6.2 +/- 0.3%) as the major components. Among the 29 compounds identified in the P. aracouchine oil, 95.9% were sesquiterpenes as well, with spathulenol (31.8 +/- 1.6%), alpha-cis bergamotene (8.8 +/- 0.2%) and viridiflorol (9.7 +/- 0.7%) as the major components. PMID- 22224299 TI - Volatile constituents of two Hypericum species from Tunisia. AB - The chemical composition of the essential oils obtained by hydrodistillation from the aerial parts of the Tunisian Hypericum perforatum and H. ericoides ssp. roberti was elucidated by a combination of GC and GC-MS analyses. The main constituents of the oil of H. perforatum were alpha-pinene (11.8%), alpha ylangene (10.4%), germacrene-D (9.5%), n-octane (6.5%) and alpha-selinene (5.9%). The oil of H. ericoides ssp. roberti exhibited a higher amount of aliphatic and branched hydrocarbons and the main constituents were n-octane (29.1%), alpha pinene (10.9%), pulegone (7.7%) and acetophenone (7%). Both qualitative and quantitative differences were observed between the studied oils. This chemical variability seems likely to result from the genetic variability, since samples of both species were collected at the same location and processed under the same conditions. PMID- 22224300 TI - Chemical composition and possible in vitro antigermination activity of three Hypericum essential oils. AB - The essential oils of Hypericum perforatum, H. perfoliatum and H. hircinum, growing in Southern Italy, were analyzed by GC and GC/MS. In the three oils, 111 compounds in all were identified: 53 for the oil of H. hircinum (93.7% of the total oil), 55 for H. perforatum (96.5% of the total oil) and 63 for H. perfoliatum (98.7% of the total oil). The major fraction of the essential oils of H. perforatum and H. hircinum was represented by sesquiterpene hydrocarbons, while the monoterpene alpha-pinene, and the phenol thymol were the most abundant compounds in the essential oil of H. perfoliatum. The oils were evaluated for their potential in vitro phytotoxic activity against germination and early radicle elongation of Raphanus sativus and Lepidium sativum. The germination of this latter was significantly inhibited by the essential oil of H. hircinum, at the highest doses tested, whereas radicle elongation of garden cress was significantly inhibited by the essential oils of H. perfoliatum and H. hircinum. The radicle elongation of radish was inhibited by the essential oil of H. hircinum to a major extent and by H. perforatum and perfoliatum in a minor measure. PMID- 22224301 TI - Antioxidant, antimicrobial activities and fatty acid components of flower, leaf, stem and seed of Hypericum scabrum. AB - The hexane extracts of flower, leaf, stem, and seed of Hypericum scabrum, which were collected from northwestern Iran, were obtained by extraction in a Soxhlet apparatus. The fatty acids were converted to methyl esters and determined by gas chromatography/flame ionization detector (GC/FID) and gas chromatography/mass spectrometry (GC/MS) systems. The hexane extract from the flower, leaf, stem, and seed contained 39.1%, 43.2%, 29.0%, and 37.6% of omega-3 fatty acids, respectively. The other main components of the flower extract were tetracosane (12.2%) and palmitic acid (9.3%), and that of the leaf extract was palmitic acid (7.4%). The stem and seed extracts contained bis(2-ethylhexyl)phthalate (18.7% and 35.7%), nonacosane (11.7% and 3.9%) and linoleic acid (6.5% and 6.9%) as major components. The hexane extracts of different parts from H. scabrum represent an important source of omega-3 fatty acids in several Hypericum species. The antioxidant activity of all hexane extracts was evaluated by the 2,2 diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method. The results indicate that hexane extracts from different parts of H. scabrum possess considerable antioxidant activity. The highest radical scavenging activity was detected in seed, which had an IC50 = 165 microg/mL. The antimicrobial activity of the extracts of those samples were determined against seven Gram-positive and Gram negative bacteria (Bacillus subtilis, Enterococcus faecalis, Staphylococcus aureus, S. epidermidis, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae), as well as three fungi (Candida albicans, Saccharomyces cerevisiae, and Aspergillus niger). The bioassay showed that the oil exhibited moderate antimicrobial activity. This study reveals that the all parts of this plant are attractive sources of fatty acid components, especially the essential ones, as well as of effective natural antioxidants. PMID- 22224302 TI - Composition of three essential oils, and their mammalian cell toxicity and antimycobacterial activity against drug resistant-tuberculosis and nontuberculous mycobacteria strains. AB - Tuberculosis (TB) is the most ancient epidemic disease in the world and a serious opportunistic disease in HIV/AIDS patients. The increase in multidrug resistant Mycobacterium tuberculosis (MDR-TB, XDR-TB) demands the search for novel antimycobacterial drugs. Essential oils (EOs) have been widely used in medicine and some EOs and their major components have been shown to be active against M. tuberculosis. The aim of this work was to evaluate the antimycobacterial and cell toxicity activities of three EOs derived from Salvia aratocensis, Turnera diffusa and Lippia americana, aromatics plants collected in Colombia. The EOs were isolated by hydrodistillation and analyzed by GC/MS techniques. The EOs were tested against 15 Mycobacterium spp using a colorimetric macrodilution method and against mammalian Vero and THP-1 cells by MTT. The activity was expressed as minimal concentration in microg/mL that inhibits growth, and the concentration that is cytotoxic for 50 or 90% of the cells (CC50 and CC90). The major components were epi-alpha-cadinol (20.1%) and 1,10-di-epi-cubenol (14.2%) for Salvia aratocensis; drima-7,9(11)-diene (22.9%) and viridiflorene (6.6%) for Turnera diffusa; and germacrene D (15.4%) and trans-beta- caryophyllene (11.3%) for Lippia americana. The most active EO was obtained from S. aratocensis, with MIC values below 125 microg mL(-1) for M. tuberculosis Beijing genotype strains, and 200 to 500 microg mL(-1) for nontuberculous mycobacterial strains. The EOs were either partially or non toxic to Vero and THP-1 mammalian cells with CC50 values from 30 to > 100 microg mL(-1), and a CC90 > 100 microg mL(-1). The EOs obtained from the three aromatic Colombian plants are an important source of potential compounds against TB. Future studies using the major EO components are recommended. PMID- 22224303 TI - Antimicrobial and antioxidant activities of the flower essential oil of Halimodendron halodendron. AB - The essential oil obtained by hydro-distillation from the flowers of Halimondendron halodendron (Leguminosae) was analyzed for its chemical composition by gas chromatography-mass spectrometry (GC-MS). Undecane (16.4%), dodecane (15.3%), tridecane (12.5%), decane (8.2%), 6,10,14-trimethyl-pentadecan 2-one (6.3%), methyl palmitate (6.0%), methyl linolenate (4.1%) and ethylcyclohexane (4.1%) were the major compounds of the thirty-five identified components of the oil. The essential oil was shown to have a broad spectrum of antimicrobial activity with MIC values ranging from 100 to 250 microg/mL, and IC50 values from 40.4 to 193.8 microg/mL. The oil also showed strong antioxidant activity, with an especially high metal chelating capacity of ferrous ions with an IC50 value of 7.4 microg/mL on ferrozine-Fe2+ complex formation. PMID- 22224304 TI - Composition and antimicrobial activity of the leaf and twig oils of Litsea acutivena from Taiwan. AB - The chemical composition, and antimicrobial and anti-wood-decay fungal activities of the essential oils isolated from the leaves and twigs of Litsea acutivena of Taiwan were investigated. The essential oils from the fresh leaves and twigs were isolated using hydrodistillation in a Clevenger-type apparatus, and characterized by GC-FID and GC-MS. Ninety-five and fifty-two compounds were identified in the leaf and twig oils, respectively. The main components of the leaf oil were gamma patchoulene (11.0%), delta-cadinene (6.3%), trans-muurola-3,5-diene (5.9%), and beta-selinene (5.3%), whereas the main components of the twig oil were tau cadinol (13.1%), beta-selinene (9.6%), trans-beta-ocimene (6.2%) and alpha cadinol (7.7%). Bioactivity studies demonstrated that twig oil had excellent antimicrobial and anti-wood-decay fungal activities, superior to those of the leaf oil. For the antimicrobial and anti-wood-decay fungal activities of the twig oil, the active compounds were determined to be tau-cadinol and alpha-cadinol. PMID- 22224305 TI - Chemical composition and antimicrobial activity of the volatile oil from Fusarium tricinctum, the endophytic fungus in Paris polyphylla var. yunnanensis. AB - The volatile oil, obtained by hydro-distillation from Fusarium tricinctum, the endophytic fungus isolated from Paris polyphylla var. yunnanensis, was analyzed by gas chromatography-mass spectrometry (GC-MS). trans-1,2,3,3a,4,7a-Hexahydro-7a methyl-5H-inden-5-one (73.1%), 2-methylene-4,8,8-trimethyl-4-vinyl bicyclo [5.2.0] nonane (12.0%), and 2,6-dimethyl-6-(4-methyl-3-pentenyl) bicyclo [3.1.1] hept-2-ene (4.5%) were the major compounds of the 15 identified components accounting for 95.4% of the volatile oil. The antimicrobial activity of the volatile oil was assayed against eight bacteria and two fungi. The minimum inhibitory concentration (MIC) values of the volatile oil against the test bacteria ranged from 25 to 45 microg/mL. The MIC values against the fungi Candida albicans and Magnaporthe oryzae were 100 and 225 microg/mL, respectively. The mean inhibitory concentration (IC50) values of the volatile oil against the test bacteria ranged from 17.8 to 31.6 microg/mL, and those of the volatile oil against C. albicans and M. oryzae were 84.3 and 204.3 microg/mL, respectively. PMID- 22224306 TI - Antifungal activity of essential oil from Asteriscus graveolens against postharvest phytopathogenic fungi in apples. AB - The essential oils of the aerial parts of Asteriscus graveolens have been studied using GC and GC-MS. Twenty-eight compounds were identified in the essential oil amounting to 94.9% of the total oil. The aerial part oils showed similar chromatographic profiles and were characterized by having a high content of oxygenated sesquiterpenes with 6-oxocyclonerolidol (66.7% +/- 5.5) and 6 hydroxycyclonerolidol (8.8% +/-1.2) as the major components. The antifungal effect of the essential oil from A. graveolens leaves was evaluated in vitro against three phytopathogenic fungi of apples (Alternaria sp., Penicillium expansum, and Rhizopus stolonifer). The results suggest that this essential oil has fungicidal properties towards Alternaria sp. from direct contact assay at 0.2% (v/v) and to P. expansum from vapor assay tests at 80 microL. PMID- 22224307 TI - Interspecies comparison of chemical composition and anxiolytic-like effects of lavender oils upon inhalation. AB - Essential oils have traditionally been used for decades to alleviate the symptoms of various mental problems. In terms of anxiolytic-like properties, lavender oil is probably the most commonly used and best-studied essential oil. Although there is compositional variance among the oils extracted from different origins, there have been few studies performed to date to investigate how these differences affect the expression of anxiolytic-like activity. This paper discusses the interspecies differences and contributions of the main constituents in the expression of anxiolytic-like effects upon inhalation, as assessed in mice by the elevated-plus maze test, by comparing the essential oils from six different species of Lavandula. The results showed qualitative and quantitative variations in the tested oils, which results in significant differences in their anxiolytic like activities. Our findings also suggest that linalyl acetate (LA) works synergistically with linalool (LO) and that the presence of both LA and LO is essential for the whole oil to work as an inhaled anti-anxiety agent. PMID- 22224308 TI - Essential oils from the Hyptis genus--a review (1909-2009). AB - Several species belonging to the Hyptis (Lamiaceae) genus represent an important source of bioactive constituents, which are reputed for their wide range of antimicrobial, anticancer and insecticidal activities. The volatile oils obtained from various parts of the Hyptis plants were found to be primarily composed of mono- and sesquiterpenes. Significant differences were observed in the percentage compositions of the major components, which allowed for differentiation among the species. Based on the dominant constituents, phylogenetic relationships were found to be common among some species: 1,8-cineole (H. fruticosa, H. goyazensis, H. martiusii and H. suaveolens); beta-caryophyllene (H. marrubioides, H. pectinata, H. spicigera and H. suaveolens); eugenol (H. recurvata and H. suaveolens); gamma-cadinene (H. glomerata and H. ovalifolia); p-cymene (H. mutabilis and H. pectinata); alpha-pinene (H. crenata and H. emoryi). The monoterpenes, alpha-pinene and p-cymene were detected at various concentrations in all the Hyptis oils investigated. This paper reviews the essential oil compositions of eighteen Hyptis plant species studied in various parts of the world covering the publications of 100 years (1909 to 2009) after the first article appeared in the literature. PMID- 22224310 TI - Congenital mastoid cholesteatoma: case series, definition, surgical key points, and literature review. AB - OBJECTIVES: We evaluate 3 new cases of congenital cholesteatoma confined to the mastoid process, and compare them with cases presented in the literature in order to better define this rare lesion. METHODS: We performed a retrospective chart analysis of all congenital cholesteatomas treated surgically in a tertiary referral and skull base center. We performed a complete analysis (history, radiologic, and surgical) of all patients with congenital cholesteatoma confined to the mastoid process; we then performed a literature review and compared our findings with the presented cases. RESULTS: The results of preoperative imaging were in line with the surgical findings. The most important surgical issue in this type of lesion was the management of the sigmoid sinus and the jugular bulb. Half of the cases previously reported in the literature appeared not to fulfill the definition criteria of a congenital cholesteatoma of the mastoid process. CONCLUSIONS: Congenital cholesteatoma confined to the mastoid process is a rare lesion, and is even more exceptional upon critical review of the literature. Symptoms are often lacking or nonspecific, and although cases have a congenital origin, the diagnosis often is not made until adulthood. A combined congenital cholesteatoma group with middle ear and mastoid features seems to fill in the gap in the definition. Management of the sigmoid sinus and the jugular bulb is the most demanding surgical key point. PMID- 22224309 TI - Management of plastic bronchitis in a child with mild intermittent asthma. AB - OBJECTIVES: We describe the clinical presentation of a 7 1/2-year-old boy with a history of mild intermittent asthma who presented with left lung collapse and was found to have plastic bronchitis. METHODS: We reviewed the patient chart and imaging results and performed a literature review of plastic bronchitis and its management. RESULTS: Bronchoscopy in our patient demonstrated a large white, friable, cast-like material that obstructed the entire left main stem bronchus and could not be easily suctioned. The cast was removed in a piecemeal fashion by means of serial rigid bronchoscopy over a 6-month period with use of both optical forceps and flexible suction catheters. Microscopic examination of the cast-like material showed a predominance of eosinophils along with neutrophils encased in proteinaceous material. CONCLUSIONS: Plastic bronchitis in children is a rare condition that can mimic foreign body aspiration and can be associated with underlying pulmonary inflammatory disorders or cardiovascular disease. Aggressive bronchoscopic management of the airway obstruction and medical management of the underlying disease process are important for the successful treatment of plastic bronchitis. PMID- 22224311 TI - Microbiology of acute and chronic maxillary sinusitis in smokers and nonsmokers. AB - OBJECTIVES: We evaluated the microbiology of sinus aspirates of smokers and nonsmokers with acute and chronic maxillary sinusitis. METHODS: Cultures were obtained from 458 patients, 244 (87 smokers and 157 nonsmokers) of whom had acute maxillary sinusitis and 214 (84 smokers and 130 nonsmokers) of whom had chronic maxillary sinusitis, between 2001 and 2007. RESULTS: A greater number of Staphylococcus aureus, methicillin-resistant S aureus (MRSA), and beta-lactamase producing bacteria (BLPB) were found in the 87 smokers with acute sinusitis than in the nonsmokers with acute sinusitis (p < 0.005, p < 0.025, and p < 0.05, respectively). A greater number of these organisms were found in the 84 smokers with chronic sinusitis than in the nonsmokers (p < 0.01, p < 0.025, and p < 0.001, respectively). Eighty-five BLPB isolates were recovered from 73 patients (30%) with acute sinusitis. These included Moraxella catarrhalis, S aureus, Haemophilus influenzae, Prevotella spp, and Fusobacterium spp; 40 BLPB isolates were found in smokers, and 45 in nonsmokers (p < 0.05). One hundred twenty-five BLPB isolates were recovered from 91 patients (43%) with chronic sinusitis, including M catarrhalis, Bacteroides fragilis group, S aureus, H influenzae, Prevotella spp, and Fusobacterium spp; 69 BLPB isolates were found in smokers, and 56 in nonsmokers (p < 0.001). Antimicrobial therapy had been administered in the past month to 130 patients (28%; 60 smokers and 70 nonsmokers; p <0.025). Both MRSA and BLPB were isolated more often from these individuals (p < 0.025). However, the higher isolation rates of MRSA and BLPB in smokers were independent of previous antimicrobial therapy. CONCLUSIONS: These data illustrate a greater frequency of isolation of S aureus, MRSA, and BLPB in patients with acute and chronic sinusitis who smoke. PMID- 22224312 TI - Light and electron microscopic observation of regenerated fungiform taste buds in patients with recovered taste function after severing chorda tympani nerve. AB - OBJECTIVES: The aim of this study was to evaluate the mean number of regenerated fungiform taste buds per papilla and perform light and electron microscopic observation of taste buds in patients with recovered taste function after severing the chorda tympani nerve during middle ear surgery. METHODS: We performed a biopsy on the fungiform papillae (FP) in the midlateral region of the dorsal surface of the tongue from 5 control volunteers (33 total FP) and from 7 and 5 patients with and without taste recovery (34 and 29 FP, respectively) 3 years 6 months to 18 years after surgery. The specimens were observed by light and transmission electron microscopy. The taste function was evaluated by electrogustometry. RESULTS: The mean number of taste buds in the FP of patients with completely recovered taste function was significantly smaller (1.9 +/- 1.4 per papilla; p < 0.01) than that of the control subjects (3.8 +/- 2.2 per papilla). By transmission electron microscopy, 4 distinct types of cell (type I, II, III, and basal cells) were identified in the regenerated taste buds. Nerve fibers and nerve terminals were also found in the taste buds. CONCLUSIONS: It was clarified that taste buds containing taste cells and nerve endings do regenerate in the FP of patients with recovered taste function. PMID- 22224313 TI - Chronic pharyngitis is associated with severe acidic laryngopharyngeal reflux in patients with Reinke's edema. AB - OBJECTIVES: We evaluated the association between pathological acidic laryngopharyngeal reflux (LPR) events and chronic pharyngitis in patients with Reinke's edema. METHODS: We performed a prospective controlled study in 20 consecutive patients with Reinke's edema without pathological acidic LPR events (group A) and 40 consecutive patients with Reinke's edema with both clinical symptoms and 24-hour pH-metry suggesting acidic LPR (group B). The severity of acidic LPR was assessed by use of the Reflux Finding Score (RFS), the Reflux Symptom Index (RSI), and dual antimony probe 24-hour pH-metry. The patients were evaluated for the presence of chronic pharyngitis by clinical examination and biopsy specimens taken from the posterior pharyngeal wall. The Chi2 test was used to compare the groups for the presence of pharyngitis. In group B, the RSI, the RFS, and the total duration and number of acidic LPR events on 24-hour pH-metry were compared between patients with and without concomitant pharyngitis by use of the Mann-Whitney test. RESULTS: Five patients of group A and 20 patients of group B had chronic pharyngitis. Therefore, more patients with Reinke's edema and clinical signs of LPR tended to have chronic pharyngitis than did those with Reinke's edema and no clinical signs of LPR, but the difference was not statistically significant (p = 0.064; odds ratio, 3.0; 95% confidence interval, 0.9 to 9.8). Among group B patients, those with pharyngitis had significantly more acidic LPR events (p < 0.001) and a greater exposure time to gastric fluid (p = 0.008) than did those without pharyngitis. Their RFS and RSI did not differ significantly (p = 0.692 and p = 0.914, respectively). CONCLUSIONS: Only in the subgroup of patients with Reinke's edema and LPR was there a statistically significant correlation between the pH probe results and the incidence of clinical pharyngitis. Awareness should increase among physicians about addressing chronic pharyngitis in therapy for acidic LPR and/or Reinke's edema. PMID- 22224314 TI - Benchmarks for the durations of ambulatory surgical procedures in otolaryngology. AB - OBJECTIVES: I undertook to determine benchmarks and variability for the surgical times associated with ambulatory otolaryngological procedures in the United States. METHODS: I examined the 2006 release of the National Survey of Ambulatory Surgery and extracted all cases of otolaryngological surgery in which one, and only one, otolaryngological procedure was performed. The mean surgical times and operating room times were determined for each procedure that met reliability criteria for their estimates. A secondary analysis was computed for tonsillectomy and for tonsillectomy plus adenoidectomy according to a patient age of greater than 12 years. RESULTS: An estimated 1.68 +/- 0.23 million otolaryngological procedures were analyzed as solitary procedures, including 507,000 cases of myringotomy with ventilation tube placement, 136,000 cases of tonsillectomy, and 429,000 cases of tonsillectomy plus adenoidectomy. The mean (+/- SE) surgical times were 8.0 +/- 0.5, 23.9 +/- 1.8, and 20.3 +/- 0.8 minutes, respectively. The total operating room times were 17.6 +/- 0.9, 48.2 +/- 2.0, and 40.7 +/- 1.1 minutes, respectively. Septoplasty with turbinectomy was the most common rhinologic procedure performed (48,000 cases analyzed) and had surgical and operating room times of 49.6 +/- 4.78 and 79.8 +/- 5.8 minutes, respectively. The surgical times for tonsillectomy and tonsillectomy plus adenoidectomy did not differ significantly in magnitude according to standard age cutoffs, although the operating room time was slightly (11.7 minutes) longer for tonsillectomy in patients more than 12 years of age (p = 0.034). CONCLUSIONS: The surgical times for the performance of the most common otolaryngological ambulatory procedures are remarkably consistent in the United States. Given the volume and consistency of these surgical procedures, they are ideal candidates for studies of cost and efficiency. PMID- 22224315 TI - Nasal packing with strips of cured pork as treatment for uncontrollable epistaxis in a patient with Glanzmann thrombasthenia. AB - OBJECTIVES: Glanzmann thrombasthenia is a rare disorder of platelet function that may result in life-threatening hemorrhage, particularly from the nasal vaults. Various medical therapies (such as recombinant factor VII, antifibrinolytic agents, and blood transfusions) and surgical therapies (such as nasal packing, electrocautery, laser coagulation, septoplasty, and embolization) have been described with various degrees of success. METHODS: We present a unique case report of a 4-year-old child with known Glanzmann thrombasthenia and two separate episodes of life-threatening epistaxis that were treated successfully by nasal packing with strips of cured pork because of special circumstances. RESULTS: Cured salted pork crafted as a nasal tampon and packed within the nasal vaults successfully stopped nasal hemorrhage promptly, effectively, and without sequelae. In both applications, the patient had complete cessation of nasal bleeding within 24 hours, and was discharged within 72 hours after treatment. CONCLUSIONS: To our knowledge, this represents the first description of nasal packing with strips of cured pork for treatment of life-threatening hemorrhage in a patient with Glanzmann thrombasthenia. PMID- 22224316 TI - Protective effect of systemic administration of erythropoietin on auditory brain stem response and compound action potential thresholds in an animal model of cochlear implantation. AB - OBJECTIVES: An animal model of cochlear implantation has been developed, and the hearing threshold was evaluated after different surgical procedures. The effect of perioperative systemic administration of erythropoietin on the hearing loss induced by cochlear implantation was tested. METHODS: Twenty-nine guinea pigs with normal hearing underwent implantation of a 254-microm-diameter array through a cochleostomy. The effects on hearing of cochleostomy and transient and long term array implantation (21 days) were assessed by testing of the auditory brain stem responses and compound action potentials. Eleven implanted animals received intraperitoneal administration of erythropoietin. Selected computed tomographic scans and cochlear histologic studies were performed 1 month after implantation to confirm proper placement of the array. The erythropoietin concentration at the time of surgery was assessed in samples of perilymph, cerebrospinal fluid, and blood. RESULTS: The cochleostomy and transient array insertion had no effect on hearing thresholds. Long-term array implantation induced a stable decrease of hearing threshold (30 dB), a decrease that was reduced by 12 dB in erythropoietin treated animals. The erythropoietin-treated animals had better hearing preservation at higher frequencies. Fibrosis surrounding the array was seen in both groups. CONCLUSIONS: The hearing loss observed was probably due to the presence of the array in the cochlea. The intraperitoneal injection of erythropoietin improved the hearing threshold shift induced by implantation. PMID- 22224317 TI - Pathologic effects of external-beam irradiation on human vocal folds. AB - OBJECTIVES: We sought to better characterize pathologic changes that occur in the human vocal fold after radiotherapy for head and neck cancer. METHODS: In a blinded, controlled study of archived tissue, we evaluated postirradiation salvage laryngectomy vocal fold tissue without evidence of malignant disease. Clinical and demographic patient data were collected. In a blinded fashion, irradiated tissue was compared to nonirradiated, benign control tissue. Histomorphometric analysis was used to assess muscle and collagen organization, superficial lamina propria (SLP) and vocal ligament thickness, vocalis muscle fiber area, collagen content, and hyaluronic acid content. Immunohistochemical analysis was used to assess the content of type I collagen, type IV collagen, vimentin, fibronectin, alpha-smooth muscle actin, matrix metalloproteinase 9, and laminin. RESULTS: Twenty irradiated vocal folds were evaluated and compared to control specimens. Collagen and muscle disorganization was noted in the irradiated specimens. The SLP and vocal ligament thicknesses and the mean muscle fiber diameters did not differ significantly. The SLP fibronectin and the vocalis muscle and SLP collagen content were significantly increased in the irradiated vocal folds, and the SLP collagen content increased significantly with time between irradiation and resection. The laminin content of irradiated vocalis muscles was significantly decreased. CONCLUSIONS: Radiotherapy results in significant vocal fold tissue changes. Having more precisely defined these changes, we plan continued investigation seeking targeted preventive and therapeutic interventions for improved vocal quality following radiotherapy. PMID- 22224318 TI - Neuronal mechanisms underlying the laryngeal adductor reflex. AB - OBJECTIVES: Electromyographic studies of the laryngeal adductor reflex, glottal closure occurring in response to laryngeal stimulation, have demonstrated an early ipsilateral response (R1) and a late bilateral response (R2). To better define the physiologic properties of these responses, we recorded responses from expiratory laryngeal motoneurons (ELMs) in rats during stimulation of the superior laryngeal nerve (SLN). METHODS: Single unit extracellular recordings were obtained from 5 ELMs, identified by their antidromic responses to recurrent laryngeal nerve stimulation and postinspiratory firing pattern, in 4 Sprague Dawley rats. RESULTS: Unilateral stimulation of the SLN (at 20 Hz) stopped both phrenic nerve inspiratory activity and ELM postinspiratory activity. However, the ELMs displayed robust tonic firing, consisting of non-respiratory burst activity and single action potentials. The single action potentials were identified as short-latency ones (5 to 10 ms) activated by ipsilateral SLN stimulation, with an occurrence rate of 90%, and long-latency ones (20 to 50 ms) activated by bilateral SLN stimulation, with occurrence rates of 47% on the ipsilateral side and 58% on the contralateral side. CONCLUSIONS: The R1 response appears to be the result of the short-latency action potentials, orthodromically activated by ipsilateral stimulation of the SLN. The R2 response is likely to be a result of the long-latency action potentials that can be recorded from ELMs on both sides. PMID- 22224319 TI - Quantity and three-dimensional position of the recurrent and superior laryngeal nerve lower motor neurons in a rat model. AB - OBJECTIVES: We sought to elucidate the 3-dimensional position and quantify the lower motor neurons (LMNs) of the recurrent laryngeal nerve (RLN) and the superior laryngeal nerve (SLN) in a rat model. Quantification and mapping of these neurons will enhance the usefulness of the rat model in the study of reinnervation following trauma to these nerves. METHODS: Female Sprague-Dawley rats underwent microsurgical transection of the RLN, the SLN, or both the RLN and SLN or sham surgery. After transection, either Fluoro-Ruby (FR) or Fluoro-Gold (FG) was applied to the proximal nerve stumps. The brain stems were harvested, sectioned, and examined for fluorolabeling. The LMNs were quantified, and their 3 dimensional position within the nucleus ambiguus was mapped. RESULTS: Labeling of the RLN was consistent regardless of the labeling agent used. A mean of 243 LMNs was documented for the RLN. The SLN labeling with FR was consistent and showed a mean of 117 LMNs; however, FG proved to be highly variable in labeling the SLN. The SLN LMNs lie rostral and ventral to those of the RLN. In the sham surgical condition, FG was noted to contaminate adjacent tissues--in particular, in the region of the SLN. CONCLUSIONS: Fluorolabeling is an effective tool to locate and quantify the LMNs of the RLN and SLN. The LMN positions and counts were consistent when FR was used in labeling of either the RLN or the SLN. Fluoro Gold, however, because of its tendency to contaminate surrounding structures, can only be used to label the RLN. Also, as previously reported, the SLN LMNs lie rostral and ventral to those of the RLN. This information results in further clarification of a rat model of RLN injury that may be used to investigate the effects of neurotrophic factors on RLN reinnervation. PMID- 22224320 TI - Total ankle replacement in obese patients: component stability, weight change, and functional outcome in 118 consecutive patients. AB - BACKGROUND: Obesity is a growing problem in Europe and the United States. While obesity has been linked to poor outcomes after total knee or hip replacement, there are no data addressing outcomes in obese patients who underwent total ankle replacement (TAR). METHODS: This retrospective chart review included 118 patients (123 ankles) with a minimum body mass index (BMI) of 30 kg/m2 who underwent TAR between May 2000 and June 2008. There were 61 male (51.7%) and 57 female (48.3%) patients with a mean age of 59.8 +/- 11.6 years (range, 25.4 to 85.0). All patients were evaluated pre- and postoperatively (mean followup 67.7 +/- 27.0 months; range, 29 to 126). Radiological outcomes were assessed using standardized weightbearing radiographs. Clinical outcomes were assessed using the visual analogue scale (VAS) and American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot scale. RESULTS: There were nine intraoperative complications. All patients experienced significant pain relief (VAS change from 7.0 +/- 1.7 to 1.4 +/- 1.1, p < 0.001) and functional improvement (AOFAS score change from 35.4 +/- 14.9 to 75.4 +/- 9.6, p < 0.001; total ROM change from 26.9 +/- 13.7 to 35.3 +/- 8.1 degrees, p < 0.001). BMI measured preoperatively, and at 1 and 2 years postoperatively was 32.9 +/- 2.5 (range, 30.0 to 40.0) kg/m2, 32.4 +/- 2.4 (range, 28.6 to 41.0) kg/m2, and 32.2 +/- 2.4 (range, 28.6 to 40.5) kg/m2, respectively. Gender had a significant effect on weight loss, but not age or postoperative sports activity. Revision surgery was performed in six patients, resulting in a 6-year survivorship of 93%. CONCLUSION: Our findings confirm that TAR gives significant pain relief and functional improvement. In this study, the survivorship of the prosthesis components was comparable to the results obtained in non-obese patients. PMID- 22224321 TI - Long-term results following Keller resection arthroplasty for hallux rigidus. AB - BACKGROUND: We assessed the long-term results following Keller resection arthroplasty for the treatment of hallux rigidus. We then compared them with alternative surgical methods like cheilectomy, arthrodesis and joint replacement. METHODS: Eighty-seven cases of Keller resection arthroplasty for hallux rigidus were reviewed with mean followup of 23 years. Their mean age at time of surgery was 50 years. Analysis included personal clinical evaluation with the AOFAS Hallux Score, quality-of-life assessment using the SF-36, radiographic assessment, pedobarographic evaluation and analysis of the patients' charts to detect any postoperative complications. RESULTS: At the time of followup only five (5%) feet had undergone revision surgery. For all other cases we calculated a mean AOFAS score of 83 points. Sixty-nine of 73 unrevised patients (94%) would opt for this operation again under the same circumstances. SF-36 parameters showed age related normal values. Pedobarographic assessment revealed only moderate weightbearing alterations. Our long-term results compare favorably with published results following arthrodesis, cheilectomy or joint replacement for the treatment of painful hallux rigidus. Clinical results and subjective assessments were very good and complication rates were low compared to competing methods. CONCLUSION: Keller resection arthroplasty remains a valuable surgical option for the treatment of advanced stages of hallux rigidus with high patient satisfaction, moderate weightbearing alterations and comparable low complication rate in our experience. PMID- 22224322 TI - Medium- to long-term outcome of ankle arthrodesis. AB - BACKGROUND: Despite improvement in outcome after ankle arthroplasty, fusion of the ankle joint is still considered the gold standard. A matter of concern is deterioration of clinical outcome as a result of loss of motion and advancing degeneration of adjacent joints. We performed a long-term study to address these topics. METHODS: Between 1990 and 2005 a total of 121 ankle arthrodeses were performed at our institute. Thirty-five cases were excluded because of simultaneous subtalar arthrodesis. Ten had died and ten were lost to followup. Six had a bilateral ankle arthrodeses, leaving 60 patients (66 ankles) eligible for followup. There were 40 males and 26 females with a mean age at surgery of 47 years. In 60 ankles, fusion was obtained using a two-incision, three-screw technique. All patients were assessed using validated questionnaires and clinical rating systems: Short Form 36 (SF-36), American Orthopaedic Foot and Ankle Society (AOFAS) Ankle and Hindfoot scale, Foot and Ankle Ability Measure (FAAM) and a subjective satisfaction rating. Radiological progression of osteoarthritis of the adjacent joints was assessed. RESULTS: Fusion was achieved in 91% after primary surgery. In six patients rearthrodesis was needed to obtain fusion. The mean SF-36 score was 63 (SD, 22) for the physical component scale and 81 (SD, 15) for the mental component scale. The mean FAAM score was 69 (SD, 17) and the mean AOFAS Ankle Hindfoot score was 67 (SD, 12). Ninety-one percent were satisfied with their clinical result. Infection occurred once. No other serious adverse events were encountered. In all contiguous joints significant progression of arthritis was appreciated. CONCLUSION: Ankle arthrodesis using a two-incision, three-screw technique was a reliable and safe technique for the treatment of end stage osteoarthritis of the ankle. It resulted in a good functional outcome at a mean followup of 9 years. Progressive osteoarthritis of the contiguous joints was clearly appreciated but the functional and clinical importance of these findings remains unclear. PMID- 22224323 TI - Incidence of osteochondral lesions of the talus in the United States military. AB - BACKGROUND: Osteochondral lesion of the talus (OCLT) is frequently described as an uncommon diagnosis; however, little is known of its incidence. In light of increased awareness combined with the continued evolution of radiologic and treatment modalities, more attention has been given to this diagnosis. Serving a young, athletic population with unique occupational requirements, we have perceived an increase in the diagnosis of OCLTs. The goal of this study was to determine the incidence of OCLTs in an active duty military population, as well as demographic risk factors for OCLTs. METHODS: We performed a query of the Defense Medical Epidemiology Database (DMED) of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for OCLTs which in the Armed Forces Health Longitudinal Technology Application (AHLTA) system is uniquely assigned the code 732.5. An overall injury incidence was calculated, in addition to multivariate analysis to determine independent risk factors among the following demographic considerations: gender, race, rank, branch of military service, and age. Year of diagnosis was also considered. RESULTS: The overall incidence rate for the 10-year period (1999 to 2008) was 27 OCLTs per 100,000 person-years. Significant demographic risk factors were female gender, white race, enlisted rank, service in the Army and Marines, and age greater than 20 years. Incidence rate was 16 per 100,000 in 2002, with steady annual increases resulting in an incidence rate of 56 per 100,000 person-years in 2008, corresponding to the years of active involvement in global combat operations. CONCLUSION: The incidence of OCLTs in the active duty military population was higher with female gender, white race, enlisted rank, increased age, and Army or Marine service. PMID- 22224324 TI - Open reduction with internal fixation versus limited internal fixation and external fixation for high grade pilon fractures (OTA type 43C). AB - BACKGROUND: The optimal treatment for high energy pilon fractures is controversial. Good clinical and functional results have been reported with traditional open reduction techniques and minimally invasive techniques utilizing external fixation (EF). The purpose of this study was to critically evaluate clinical, radiographic and functional outcomes following high-energy fractures of the tibial plafond. METHODS: Between 2000 and 2006, 62 patients who were diagnosed with 63 Type 43C pilon fractures were treated surgically by a single surgeon and retrospectively reviewed. Twenty-seven patients were treated with a hinged bridging external fixator (EF) with supplemental limited internal fixation and 35 were treated with open reduction and internal fixation (ORIF) utilizing traditional small fragment plates and screws. Out of the 62 patients, a total of 46 patients were available for review. Charts and radiographs were reviewed and a Short Musculoskeletal Function Assessment (SMFA) questionnaire was administered by a trained interviewer. Seventy-four percent of both the ex-fix patients and ORIF patients were available for followup with a mean of 18 and 22 months, respectively. Results were compared using student's T-tests. RESULTS: There were no differences between the cohorts with respect to mechanism of injury, presence of an open wound and age. Functional outcomes were similar between the two groups based on the American Orthopaedic Foot and Ankle Society (AOFAS) score and the "function" index of the SMFA. The overall complication and union rates were similar between the two groups. CONCLUSION: Both ORIF and EF appear to be comparable for treatment of OTA type 43C (pilon) fractures with regard to final range of ankle motion, development of arthritis and hindfoot scores. PMID- 22224325 TI - Intraoperative incidence of hallux valgus interphalangeus following basilar first metatarsal osteotomy and distal soft tissue realignment. AB - BACKGROUND: The premise of this study was that after the correction of hallux metatarsophalangeal pronation, the intraoperative interphalangeal angle (HIA) increases significantly, and that an additional Akin osteotomy (AO) is often needed. Therefore, the purpose of this study was to evaluate whether HIAs in hallux valgus (HV) feet were underestimated, and to assess the need for AO during HV correction. METHOD: This study was conducted on 54 feet with moderate to severe HV treated from June 2007 to December 2008. HIAs and medial sesamoid subluxations (MSS) were measured initially and intraoperatively after a distal soft tissue procedure (DSTP) and proximal chevron metatarsal osteotomy (PCMO). An intraoperative technique was used to evaluate the incongruency of the metatarsophalangeal joint (MTPJ) to determine the need for additional AO. RESULTS: After performing DSTP and PCMO, HIAs significantly increased from an average of 9 to 13.3 degrees and MSS reduced from average grade 2.5 to 0.5 (p < 0.05). AO was added in 44 (81%) feet. After an average followup of 13.2 months in Akin group, average VAS pain score decreased from 5.7 to 1.2 and average AOFAS score increased from 57.8 to 90.2 (p < 0.05). Final hallux MTPJ dorsiflexion in the Akin group was significantly larger than in the without-Akin group (p < 0.05). CONCLUSION: Average HIA significantly increased after DSTP and PCMO for moderate to severe HV necessitating additional AO, to achieve ideal HV correction and, to preserve MTPJ motion. PMID- 22224326 TI - Complex primary arthrodesis of the first metatarsophalangeal joint after bone loss. AB - BACKGROUND: Complications associated with a failed Keller procedure or joint replacement include bone loss and shortening of the first ray. We treated failed Keller resection arthroplasty and joint replacement arthroplasty cases with metatarsophalangeal joint arthrodesis, using an interpositional tricortical autograft from the iliac crest and a low-profile titanium plate. METHODS: This was a retrospective case note review of the patients treated by four consultant surgeons in a university teaching hospital. A Keller procedure was considered to have failed when patients presented with a short, painful great toe with valgus cock-up deformity. Prosthetic joint replacements were considered to have failed based on the clinico-radiological loosening with associated pain. Metatarsophalangeal joint arthrodesis was carried out using an interpositional tricortical bone autograft and a titanium plate. Patients were assessed for resolution of pain, clinical and radiological evidence of fusion and complications. Ten operated feet in nine female patients, with a mean age of 55.9 (range, 37.8 to 80.2) years were followed for a mean of 12.6 (range, 6 to 26) months. Six patients presented with failed prosthetic joint replacements and four with failed Keller arthroplasty. RESULTS: Full clinicoradiological union was achieved in nine of the ten patients as judged by an independent consultant musculo-skeletal radiologist. Four patients needed removal of implants, one for infection, two for prominent hardware and one for implant failure. Eight of the ten patients were satisfied with the relief of pain. CONCLUSION: Failed arthroplasty or Keller procedure is a difficult problem to manage. We recommend complex primary arthrodesis with an interpositional iliac crest autograft and a low profile plate as a salvage procedure. PMID- 22224327 TI - Hammer toe correction using an absorbable pin. AB - BACKGROUND: Fixed flexion deformity of the proximal interphalangeal joint with or without hyperextension of the metatarsaophalangeal joint, hammertoe, is one of the most common foot deformities. Many surgical options have been recommended including the use of a more flexible PDS Orthosorb absorbable pin for fixation. The authors, using the PDS pin technique, reported some coronal angulations with painful soft corns requiring surgical correction. A new proximal interphalangeal joint arthrodesis procedure for hammer toe deformities utilizing a stiffer poly L lactate 2-mm absorbable pin for internal fixation is presented. METHODS: Forty seven toe procedures were done on 29 patients followed for an average of 18 (range, 10 to 36) months. Final evaluation included: physical exam, X-rays, MRI scan, AOFAS score, and a patient satisfaction survey. RESULTS: Utilization of the stiffer poly-L-lactate absorbable pin resulted in minimal coronal angulations, no soft corns, high fusion rates and patient satisfaction. CONCLUSION: The stiffer poly-L-lactate absorbable pin technique in this study was found to be superior to the published results using other methods of fixation including the more flexible PDS absorbable pin. PMID- 22224328 TI - Supramalleolar osteotomy using circular external fixation with six-axis deformity correction of the distal tibia. AB - BACKGROUND: Supramalleolar osteotomy using circular external fixation with six axis deformity correction is a rarely reported treatment method particularly well suited for complex multidimensional deformities of the adult ankle. The purpose of this study was to assess the accuracy of deformity correction and change in functional status using this technique. METHODS: We present a retrospective review of 52 patients who underwent supramalleolar osteotomy with application of the Taylor Spatial Frame (Smith & Nephew, Memphis, TN). Mean age was 44 (range, 18 to 79) years. The primary outcome was change in preoperative to postoperative distal tibial joint orientation angles. Coronal and sagittal plane joint orientation angles were measured for all 52 enrolled patients. The secondary outcome was change in AOFAS scores which were available for 31 patients. RESULTS: Twenty-two patients had oblique plane deformities. The mean time in frame was 4 (range, 2 to 11) months, and patients were followed for a mean of 14 months after frame removal. All aggregate postoperative distal tibial angles underwent a significant improvement (p < 0.05) and were within 0 degrees to 4 degrees of normal in the various deformity groups. Average preoperative AOFAS score was 40 (range, 12 to 67) and average postoperative AOFAS score was 71 (range, 34 to 97; p < 0.001). Complications included two patients with nonunions at the osteotomy site that healed with further treatment. Three patients went on to have ankle fusion. CONCLUSION: We feel that supramalleolar osteotomy using circular external fixation with six-axis deformity correction was an effective method for correction of distal tibial deformities in the adult population, particularly for those patients with complex oblique-plane deformities, associated rotational deformity, a compromised soft tissue envelope, or a prior history of infection. PMID- 22224329 TI - Accuracy of plain radiographs versus 3D analysis of ankle stress test. AB - BACKGROUND: Radiographic stress testing using both the anterior drawer (AD) and talar tilt (TT) technique is a widely accepted means of assessing ankle instability. The purpose of this study was to investigate the accuracy of plain film radiography in measuring translation of the talus during the AD test and the rotation of the talus during TT stress testing. In addition to determining the true accuracy of radiologic assessment in two planes, our goal was to further define instability in the sagittal, coronal and transverse planes. METHODS: Twenty lower extremity specimens were placed in a Telos ankle stress apparatus, and respective lateral and AP radiographs were taken during simulated AD and TT testing. Positional measurements were calculated from the films. Next, a three dimensional tracking system was used to calculate these displacements. The anterior talofibular ligament and calcaneofibular ligament were sectioned to simulate an unstable ankle, followed by repeat measurement using both methods. Movement calculated using the three dimensional system was compared to that of plain radiographs using a paired t-test. RESULTS: Mean positional changes determined by plain film radiographs were found to be significantly lower than those calculated by the three-dimensional system in both AD and TT tests in the intact and sectioned states (p < 0.001). CONCLUSION: Radiographic stress testing assessment of ankle instability appears to be much less accurate than previously believed. CLINICAL RELEVANCE: Compared to values calculated with the 3D system, radiographic measurements may underestimate the true magnitude of TT and AD changes which could influence clinical decision making. PMID- 22224330 TI - Finite element analysis of nonanatomic tenodesis reconstruction methods of combined anterior talofibular ligament and calcaneofibular ligament deficiency. AB - BACKGROUND: Nonanatomic tenodesis reconstruction procedures have been used for lateral ankle ligament reconstruction. However, there has been no comparison of Watson-Jones, Evans, and Chrisman-Snook procedures with respect to biomechanical characteristics such as kinematics, ligaments and grafts stresses using finite element analysis. METHODS: A three-dimensional finite element model of the ankle including seven bony structures, cartilage and nine principal ligaments surrounding the ankle joint complex was developed and validated. In addition to the intact model, combined anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL) deficient, Watson-Jones reconstruction, Evans reconstruction and Chrisman-Snook reconstruction models were simulated. Then, the forces in the ligaments and grafts and the kinematics of the talus and calcaneus were predicted for an inversion or internal torque of 1.7 Nom and an anterior drawer stress of 150 N through the range of ankle motion. RESULTS: All three operations were able to improve the stability of the ankle, but the effectiveness of each procedure was dependent on the direction of the stress applied and the position of the ankle in dorsiflexion-plantarflexion. CONCLUSION: This study showed that the Watson-Jones procedure has advantages with regard to anterior and rotational stabilities as well as ligaments and grafts stresses in comparison with other nonanatomic tenodesis reconstruction methods. CLINICAL RELEVANCE: The knowledge of stress inside the ligaments and reconstructed grafts could help to better understand the biomechanical behavior of the reconstructed joint. PMID- 22224331 TI - Dislocation of the proximal and distal tibiofibular syndesmotic complex without associated fracture: case report. PMID- 22224332 TI - Strong tendon repair using SLLS technique for traumatic disruption of tibialis anterior tendon and extensor hallucis longus tendon to enable early rehabilitation after surgery. PMID- 22224333 TI - Counselling mothers of babies with the sickle cell trait: to be or not to be. PMID- 22224334 TI - Study of promoter and structural gene sequence of whiB7 in MDR and XDR forms of Mycobacterium tuberculosis. AB - Resistance phenomenon in M tuberculosis is mainly based on decreased permeability of the bacterial envelope and function of effluent pumps. The regulatory gene of the whiB7 transcription determines drug resistance in these bacteria. Increases in WhiB7 protein activity induce transcription of resistance genes leading to intrinsic multidrug resistance. The aim of this work was to evaluate the whiB7 gene sequence in susceptible, MDR and XDR clinical isolates of M tuberculosis in order to further design an inhibitor. Thirty-three clinical isolates of MTB identified as susceptible, MDR and XDR-TB were investigated by PCR for sequencing of the entire promoter (429 bp), structural gene (279 bp) and the end of the upstream gene uvrD (265 bp). No differences were detected in the sequences of the structural gene in susceptible and MDR with XDR isolates and all of them terminated at TGA as stop codon. Examination of sequence profiles of the promoter part of whiB7 by several sets of primers proved that there were no differences between sequence of susceptible, MDR and XDR isolates by type strain (H37Rr). Furthermore, the structure of WhiB7 protein was studied in achieved sequences from clinical isolates. We found that the promoter and structural gene of whiB7 are highly conservative in clinical susceptible and resistant isolates. It is a key finding that would assist in the design of an inhibitor for the WhiB7 protein in all clinical forms in further studies. PMID- 22224335 TI - DNA release and uptake associated with the development of pleomorphic cells in mammalian skin autotransplants. AB - OBJECTIVE: Although several in vitro studies have demonstrated active release of DNA by living cells, there is still doubt. There are no such in vivo studies (1). The following experiment is an in vivo study to determine whether DNA release and uptake by cells and tissues occur and can be related to normal growth and differentiation, abnormal growth and cancer METHODS: Epidermal and full-thickness ear-skin grafts were separately autotransplanted into two groups of mice. In a second group, host mice were labelled with tritiated thymidine and autografted separately, with unlabelled epidermal and full-thickness ear-skin grafts. Animals were sacrificed regularly in both cases. RESULTS: Full thickness grafts revealed cysts in 15 out of 16 grafts, with well-differentiated squamous epidermis, DNA labelling of dermalfibroblasts and no DNA labelling of epidermal cells. Epidermal grafts revealed cysts in six out of 20 grafts, with epidermal cells variable in shape and arrangement; some appeared normal but others were two to four times larger, forming solid nests of cells. In some grafts, there were spindle-shaped pleomorphic cells loosely interconnected. DNA labelling was observed in occasional epidermal cell. Two lung adenocarcinomas were found. CONCLUSION: These results suggest active release of DNA by host cells and DNA uptake by grafted cells. This phenomenon and the differential uptake of DNA labelling of epidermal and dermal cells in the epidermal and full-thickness grafts suggest an association with abnormal, even pleomorphic epidermal cell behaviour due to the interference of dermal/epidermal interacting factors. PMID- 22224336 TI - Possible molecular mechanism of promotion of repair of acute Achilles tendon rupture by low intensity-pulsed ultrasound treatment in a rat model. AB - OBJECTIVE: This study investigated the effect of Low Intensity-pulsed Ultrasound (LIPUS) on the repair process of ruptured Achilles tendon using a rat model and also examined the regulation of a biological molecule that may contribute to this in vivo and in vitro. METHODS: To investigate the effect of LIPUS and its biological mechanism of promoting Achilles tendon repair after acute injury, ninety-eight male Sprague-Dawley (SD) rats (mean body weight, 258 +/- 9.8 g) aged 12 weeks were used in this study. To create the model, the Achilles tendon attachment site and musculotendinous junction were ruptured under direct vision. The leg on one side was exposed to LIPUS (frequency at 1.5 MHz, the repetition cycle at 1.0 kHz, the burst width at 200 msec and the power output at 45 mW/cm2), for 20 minutes daily with a 0.7 mm diameter probe. RESULTS: Low Intensity-pulsed Ultrasound treatment accelerated the repair of the Achilles tendon compared to the untreated group, judged by electron microscopy. Both cyclo-oxygenase (COX)-2* and EP4* expressions were over-expressed in the LIPUS treated group in the inflammatory period, and TGFbeta1* expression was markedly induced in LIPUS treated groups followed by collagen I* and II* expression in the repair and reconstitution process. CONCLUSION: These findings suggest that LIPUS is potentially able to accelerate the repair of acute ruptured Achilles tendon in several ways: by exaggerating inflammation by inducing COX-2 and EP4 and reconstituting tissue by inducing TGFbeta1 followed by collagen I and III. (*: p < 0.05, **: 0.001). PMID- 22224337 TI - Adherence to antiretroviral therapy by people accessing services from non governmental HIV support organisations in three Caribbean countries. AB - OBJECTIVE: To identify factors associated with antiretroviral therapy (ART) adherence in order to guide the development of strategies to improve the situation. DESIGN AND METHODS: A cross-sectional survey was conducted with people living with HIV (PLHIV) who receive services from non-governmental organisations affiliated to the Caribbean Regional Network of People Living with HIV/AIDS (CRN+) in Antigua and Barbuda, Grenada and Trinidad and Tobago. PLHIV from CRN+, traced potential participants, administered informed consent procedures and carried out structured interviews. The main outcome measure was 95% to 100% adherence over the previous seven days. Multiple logistic regression was conducted to identify associations with demographic characteristics, psychological status, health and support service use, sexual behaviour and substance abuse. RESULTS: Of 394 respondents, 69.5% were currently taking ART. Of these, 70.1% took 95% to 100% of their prescribed pills. One in 20 took more pills than prescribed, all of whom were prescribed fewer or equal to the median pill number. Factors independently associated with adherence were use of a counselling service (OR 3.20; 95% CI 1.55, 6.61), revelation of HIV status without consent (OR 2.31; 95% CI 1.13, 4.74), alcohol consumption (OR 0.47; 95% CI 0.23, 0.96) and side effects (OR 0.32; 95% CI 0.15, 0.68). Drug resistance to ART was reported by 6% of users. CONCLUSION: Improvements in ART adherence may be achieved by counselling, focussed attention to alcohol users and developing drugs with reduced side effects. Such measures are critical to maintain PLHIV quality of life gains and prevent the proliferation of drug resistant HIV strains. PMID- 22224338 TI - Sociodemographic and behavioural characteristics of youth reporting HIV testing in three Caribbean countries. AB - OBJECTIVES: Human Immunodeficiency Virus (HIV) testing is the gateway to treatment and care of HIV infection, however little is known about the HIV testing behaviours among Caribbean youth. The objective of this study was to determine the prevalence of HIV testing and to examine associations of HIV testing with sociodemographic characteristics and risk behaviours. METHODS: Data were used from nationally representative surveys in three Caribbean countries: Guyana AIDS Indicator Survey 2005-2006; Haiti Demographic and Health Survey 2005 2006 and the Dominican Republic Demographic and Health Survey 2007. Youth 15-24 years who had ever heard of AIDS and ever had sex were selected, yielding samples of 875 in Guyana, 4199 in Haiti and 12 418 in the Dominican Republic. Bivariate tests were conducted to examine the associations between sociodemographic characteristics, risk behaviours and being tested for HIV. RESULTS: The proportion of youth reporting HIV testing ranged from 17% in Haiti to 48% in the Dominican Republic. About 54% of youth in Haiti and less than one-third in the Dominican Republic initiated HIV testing. A greater proportion of females than males had ever tested in each country, ranging from 68% in Guyana to 82% in Haiti. Higher rates of HIV testing were observed among ever married youth and among youth with 2-4 lifetime sexual partners. CONCLUSIONS: Males, rural and never married youth were less likely to be tested. Outreach at individual and community levels and public health messages targeting these youth should be implemented. There is also a need to mainstream gender into the design of programmes aimed at increasing uptake of HIV testing. Programmes which assist youth in accurately assessing their risk behaviours are also required to improve HIV testing. PMID- 22224339 TI - Propofol sedation in patients undergoing colonoscopy in Jamaica. AB - BACKGROUND: Propofol sedation is increasingly used for colonoscopy and may be associated with increased satisfaction and efficiency in diagnostic and therapeutic endoscopy. However propofol has a relatively narrow therapeutic window as it frequently produces deep sedation, and can precipitate respiratory depression. AIM: To determine the efficacy, safety and patient satisfaction with propofol sedation in patients undergoing colonoscopy at the University Hospital of the West Indies (UHWI). METHODS: Patients undergoing outpatient colonoscopy at the UHWI who were sedated with propofol were studied. Boluses of 10 - 20 mg of propofol at intervals of 2 - 5 minutes, as needed for adequate sedation, were administered after initial induction. Continuous monitoring of the pulse rate, and oxygen saturation were performed and the blood pressure checked every 2 - 5 minutes. All patients received supplemental oxygen (4 L/min). The following observations were recorded: the endoscopist recorded the ease of the procedure, the anaesthetist recorded the comfort of the patient throughout the procedure and at the time of discharge, and the patient stated the degree of satisfaction with the procedure. Any unusual events were recorded. RESULTS: Sixty consecutive patients sedated with propofol were studied. There were 28 (46.7%) males, with a mean age of 58.3 years and 32 (53.3%) females, with mean age of 59.5 years. Most were normal healthy patients (56.6%). Comorbid illnesses were present in 43.4%, with hypertension being most common (23.3%). All patients were classified as ASA class 1 and 2. The average dose of propofol used was 180 mg (range 50 - 355 mg). The mean duration of colonoscopy was 19.5 minutes. The mean recovery period (able to stand) was 29.6 minutes. There were no documented cases of significant hypotension, bradycardia, or hypoxaemia during the procedure. Transient apnoeic episodes during the initial stages of sedation occurred in 12 (20%) patients. The majority of patients (91.7%) rated the experience as being extremely good or excellent. The majority could not recall the actual colonoscopy and there were minimal subjective reports of nausea or discomfort during the procedure. CONCLUSIONS: Propofol sedation was associated with quick recovery and excellent satisfaction by patients and is a suitable alternative for sedation for colonoscopy in Jamaica. PMID- 22224340 TI - Upper gastrointestinal bleeding: a Jamaican perspective. AB - BACKGROUND: Upper gastrointestinal bleeding (UGIB) remains one of the most common clinical life-threatening emergencies which is associated with a high morbidity, mortality and medical care costs. OBJECTIVES: This study reviews the clinical features, management and outcomes of patients with UGIB seen at the University Hospital of the West Indies (UHWI), Jamaica, between January 2006 and December 2008. METHODS: Patients with UGIB admitted to the medical wards of the UHWI, Jamaica, between January 2006 and December 2008 were reviewed. Consecutive patients admitted with a confirmed diagnosis of UGIB were selected for analysis. Data collected included age, gender presenting complaints, risk factors, clinical features and management. Endoscopic findings, treatment and outcomes were also reviewed. RESULTS: There were 104 patients, with a mean age of 55 years, admitted with UGIB. There were significantly more men than women (73 vs 31). Retching and vomiting were the most common presenting complaints followed by melaena and haemetemesis. Non-steroidal anti-inflammatory drug use was present in 28% of patients. Overall, 80% of patients had upper GI endoscopy (EGD) and 40% were done within 24 hours of admission. The median time for performing EGD was 24 hours (mean 46 hours). The leading causes of UGIB were duodenal ulcer (28%), erosive gastritis (20%) and gastric ulcer (13%). Proton pump inhibitors (PPI) were given to 95 (91%) patients intravenously. Blood transfusion was given to 40% of patients. The mortality was 5.7%, rebleeding occured in 4.8% of patients and 5% underwent surgery. The average duration of hospital stay was 6.6 days. CONCLUSION: Upper gastrointestinal bleeding was more common in men of middle age in this study. Proton pump inhibitors were used in most patients. The overall mortality of 5.7% is similar to other series. Early EGD and use of endoscopic therapy may lead to a decrease in mortality in high risk patients. PMID- 22224341 TI - Satisfaction with pharmacy services and its relationships with the control of selected chronic diseases. AB - OBJECTIVE: To assess the level of satisfaction with pharmacy services and whether satisfaction/dissatisfaction had any effect on two common chronic diseases. Proper control of chronic diseases requires a management regime which includes promotive, preventive, curative and rehabilitative services through primary, secondary and tertiary preventive intervention measures and a wide range of support services. METHODS: A cross-sectional descriptive study with both quantitative and qualitative components was designed to collect data from among all diabetic and hypertensive patients (n = 150) attending 3 health centres in the parish of St Thomas on the days that data were being collected. The questionnaires were interviewer administered. Qualitative data were obtained from focus group discussions which explored themes related to the objectives. RESULTS: Though there was overall satisfaction with the pharmacy services studied, the level of control of the two diseases was unsatisfactory. There was no relationship between hypertension control and satisfaction with pharmacy services while the relationship with diabetes mellitus control was limited to a very weak negative association with the rating of the pharmacists' instructions on how to take the prescribed medications. CONCLUSION: "Satisfactory Pharmacy Services" could be improved by the employment of additional staff improvement in how drugs are stocked, greater availability of generic drugs and more utilization of health cards. PMID- 22224342 TI - Five-year follow-up of patients treated with imatinib mesylate for chronic myeloid leukaemia in Trinidad and Tobago. AB - OBJECTIVE: Data on the use of Imatinib (IM) in developing countries remain limited. A retrospective study was done to assess the efficacy and toxicity of IM in treating chronic myeloid leukaemia (CML) in Trinidad and Tobago. METHODS: Patients in all phases of CML who started IM therapy between February 2001 and February 2004 were included. All had received other previous therapy. They were assessed for haematological, cytogenetic and molecular response, overall survival (OS), event free survival (EFS) and adverse effects (AE). RESULTS: Twenty-five patients were followed-up for a median 61 months. At initiation of IM, 18 were in the chronic phase (CP), 3 in accelerated phase (AP), 3 in blast crisis (BC) and one in myelofibrotic transformation (MF). Overall, 96% of patients achieved complete haematological remission (CHR). Among CP patients, 67% attained a major cytogenetic response (MCR) and 44% a complete cytogenetic response (CCR). Overall survival and event free survival in the CP group were 82% and 76% respectively. Overall survival for advanced phase patients was 14% at 61 months. The adverse effects of IM were the same as previously described and generally tolerable. No patient opted to discontinue IM because of side effects. CONCLUSION: After 5 years of follow-up, IM was found to induce favourable and durable survival responses with an acceptable side effect profile in CP-CML patients who had received prior treatment with alternative agents. PMID- 22224343 TI - Therapeutic results of the modified Cadenat procedure for acromioclavicular joint separations compared with the modified Dewar procedure. AB - AIM AND BACKGROUND: The surgical treatment for acromioclavicular joint dislocations is recommended for Rockwood's classification types 4, 5 and 6. In this study we evaluate the therapeutic results of the modified Cadenat procedure on type 5 acromioclavicular joint dislocation, and report on a comparative study of the modified Dewar procedure also on type 5 acromioclavicular joint dislocation. SUBJECTS AND METHODS: The modified Cadenat procedure was performed on 73 patients (66 males and 7 females, group C). The mean age at the time of the surgery was 35.4 years. On the other hand, the modified Dewar procedure was performed on 55 patients (51 males and 4 females, group D). The mean age at the time of the surgery was 34.5 years. RESULTS: The mean therapeutic results were 28.2 points in group C and 27.3 in group D according to the UCLA scoring system. In group C, the subluxation that represented less than 5 mm superior translation of the clavicle, occurred only in 18 of 73 patients. Meanwhile, in group D, the subluxation that represented less than 5 mm, occurred only in 14; that which represented 5 to 10 mm was in seven patients, and the complete dislocation occurred in three patients. Also, the occurrence of osteoarthritic changes in the acromioclavicular joint was nine patients in group C and 20 in group D, respectively. CONCLUSION: The modified Cadenat procedure could provide satisfactory therapeutic results and avoid postoperative failure of reduction compared to the modified Dewar procedure. However the modified Cadenat procedure does not aim to restore the anatomical coracoclavicular ligaments. It is believed that anatomic restoration of both coracoclavicular ligaments could best restore the function of the acromioclavicular joint. PMID- 22224344 TI - Effects of contraceptives on serum trace elements, calcium and phosphorus levels. AB - BACKGROUND: Women on different contraceptive methods have been linked with the development of various diseases and possible changes in serum trace elements and vitamins of women on contraceptives have been postulated. Therefore, the relationship between contraceptive use and trace elements needs to be investigated. METHODS: This is a cross-sectional randomized study. After informed consent was obtained, blood samples were collected from a total of 100 women of child-bearing age on different contraceptive methods: 50 on oral contraceptives, 25 on injectables and another 25 on intra-uterine device. Blood samples were also collected from another 50 age-matched non-contraceptive users to serve as control. Serum was analysed using atomic absorption spectrophotometer for zinc, copper manganese, iron, selenium, cadmium, lead and magnesium while colorimetric method was used for phosphorus and calcium. Body mass index (BMI) was calculated as weight in kilogram/height in meter squared. Results obtained from laboratory analysis and anthropometric measurements were analysed using computer SPSS package. RESULTS: The mean serum zinc, selenium, phosphorus and magnesium levels obtained from subjects on contraceptives were significantly lower (p < 0.01, p < 0.05, p < 0.05 and p < 0.05 respectively) than those of the control group. However, the mean serum copper iron, calcium and cadmium levels were significantly higher (p < 0.05) in participants on contraceptive when compared with the control group. Manganese and lead levels were similar in participants and control groups. Correlation analysis shows significant association between some trace elements and the duration of contraception and body mass index of the participants. CONCLUSION: The study showed and confirmed reduced levels of trace elements in women on contraceptives. The reduction is proportional to the duration of contraceptive use. PMID- 22224345 TI - Body mass index and prostate specific antigen levels in Jamaican men. AB - OBJECTIVE: To investigate the relationship between body mass index (BMI) and prostate specific antigen (PSA) levels in Jamaican men. METHODS: Men, 40-79 years old, attending public and private urology clinics in Kingston, Jamaica were recruited to a case-control study on the role of dietary and lifestyle factors on prostate cancer. Trained interviewers administered questionnaires and measured weight and height using standardized techniques. Blood samples for PSA were measured at a central laboratory using a micro-particle enzyme immunoassay method. Prostate biopsy was used to confirm prostate cancer. Multivariable linear regression was used to examine the relationship between BMI and PSA separately in the cases and controls. RESULTS: Data from 501 men (233 cases and 263 controls) were assessed. Thirty-five per cent of subjects were overweight and 13% were obese. Among cases, the median PSA was 35.3 ng/dL in normal weight, 26.1 ng/dL in overweight and 14.5 ng/dL in obese men (p = 0.02). For controls, median PSA was 2.0 ng/dL in normal weight, 1.3 ng/dL in overweight and 1.1ng/dl in obese men (p = 0.01). Among cases, BMI was negatively associated with PSA (B(SE) per 5 kg/m2 (BMI difference = -0.51 (0.13); p < 0.01) and remained significant after adjustment for age, sexual activity, smoking, use of statins and tumour grade. For controls, the BMI was also inversely related to the PSA (B(SE) per 5 kg/m2 difference -0.17 (0.07)) but the effect became of borderline significance after adjusting for age. CONCLUSIONS: Prostate specific antigen was inversely related to body mass index in Jamaican men with prostate cancer. Clinicians should consider this association when interpreting PSA results. PMID- 22224346 TI - Health status and health-seeking behaviour of Jamaican men fifty-five years and over. AB - OBJECTIVE: The Caribbean including Jamaica is undergoing rapid population ageing with implications for health service planning and delivery. Such planning should take into account gender differentials. This study describes and analyses the health status and health-seeking behaviour of men 55 years and over in Jamaica. METHOD: A quantitative cross-sectional survey employing cluster sampling techniques was utilized to recruit 2000 men, 55 years and older in the parish of St Catherine, Jamaica. A 126-item questionnaire was administered and standard instruments utilized to assess functional status. RESULTS: Respondents (74%) rated their health status as excellent/good. Few men were highly dependent with regard to Activities of Daily Living with incontinence being a major concern. Medication management and shopping were the major Instrumental Activities of Daily Living domains where assistance was needed. Depression was associated with non-involvement in community/social organizations and not being in physical contact with their children. Major health conditions reported were cancers (16%), kidney/bladder conditions (12.7%), hypertension (9.2%) diabetes (6.5%) and prostate problems (7.3%). Most men (67.6%) had not visited a health provider in the year prior to the survey; 17.1% had been hospitalized after age 55 years. Only 35% of men ever had a prostate check/examination and 8.2% of men eligible for drug benefits under the Jamaica Drugs for the Elderly Programme registered for that programme. CONCLUSION: There is need to focus on older men's health and ensure that primary prevention and early interventions reach middle-aged and older men while improving health literacy. Taking programmes to 'where men are" is suggested--the bars, race track and sports events. Gender and age-specific research should reduce gender disparities in health among older persons in Jamaica. PMID- 22224347 TI - Specificity of vascular reactivity and altered response in experimental malaria. AB - OBJECTIVE: Adherence of erythrocytes infected with Plasmodium falciparum (P falciparum) to microvascular endothelial cells (sequestration) is considered to play an important role in parasite virulence and pathogenesis. In this study, we have examined the possibility that there is altered vascular reactivity due to the direct interaction between the parasitized erythrocytes and vascular endothelial cells and that it could be tissue specific. METHOD: Ring preparations of blood vessels from the rabbit carotid and rat aorta were studied using standard organ bath techniques. Dose response curves for phenylephrine (PE) and acetylcholine (Ach)-induced relaxation were constructed in rings pre-contracted with PE. RESULTS: Incubation of rat aortic rings with parasitized blood resulted in a significant (p < 0.05) increase in maximum contractile response to phenylephrine in the rat aortic rings but there was no effect on the rabbit carotid artery. The dose-response curve showed a significant (p < 0.05) left-ward shift following the addition of parasitized blood. Parasitised blood had no effect on baseline in both tissues. Following exposure to parasitized blood, the magnitude of Ach-induced relaxation responses reduced significantly (p < 0.05) in rat aortic rings and (p < 0.05) in rabbit carotid rings; relaxations to acetylcholine was more pronounced in the aortic compared to the carotid rings. CONCLUSIONS: Malaria altered vascular reactivity through an endothelium-dependent mechanism. The regulation of vascular tone by various vasoactive agents following exposure to malaria parasites might be altered in a vessel-specific manner. This may contribute to or exacerbate the abnormal haemodynamics observed in the microcirculation of numerous vascular beds in malaria. PMID- 22224349 TI - Peutz-Jeghers syndrome. AB - Peutz-Jeghers Syndrome (PJS) is an autosomal dominant colonic polyposis syndrome. It is a rare condition but is of importance because of the risk of gastrointestinal as well as extraintestinal malignancies and the high penetrance in the family linkage. There has been no report of this condition in the Caribbean. We report a 32-year old male who presents with a history of rectal bleeding on a background history of having colonic polyps. Colonoscopy revealed multiple large colonic polyps with partial obstruction in the descending colon. The histology revealed hamartomatous Peutz-Jeghers polyps. Peutz-Jeghers Syndrome is an important consideration in a young patient with colonic polyps. PMID- 22224348 TI - Comparative study of osteoblastic activity of same implants (Endopore) in the immediate extraction site utilizing single photon emission computerized tomography: peri-implant autogeneous bone grafting with GTR versus no peri implant bone grafting--experimental study in pig model. AB - The study was designed to exploit the single photon emission computerized tomography (SPECT) to compare osteoblastic activity of two implant systems: an Endopore implant (Beaded implants) placed immediately into an extraction socket in conjunction with peri-implant autogenous grafting supplemented with a guided tissue regeneration (GTR) technique, and an Endopore implant placed immediately into the extraction socket without peri-implant grafting and GTR. Endopore implants of the same size (12 mm x 4.1 mm INT-Hex) were placed in fresh extraction sockets in the canine-tooth region of the pigs jaw. The implant on the right side had peri-implant bone grafting utilizing autogenous bone together with cytoplast resorbable GTR membrane, whilst the implant on the left side received no peri-implant bone grafting. Osteoblastic activity was evaluated 81 days (11 weeks and 4 days) post implantation using the SPECT imaging technique. The SPECT imaging revealed more osteoblastic activity on the side with peri-implant bone grafting as compared with the site without peri-implant bone grafting. The result suggests that peri-implant bone grafting with GTR around the immediate implant showed more osteoblastic activity and thus enhanced osseointegration when compared with the implant without bone grafting and GTR. Bone grafting and GTR should be encouraged as a standard procedure with dental implants. PMID- 22224350 TI - Non-operative management of non-destructive extra-peritoneal rectal injury. AB - This is a case report of extra-peritoneal rectal injury, secondary to a gunshot, that was managed non-operatively. A 57-year old male presented with a single gunshot to the right buttock and had blood per rectum. Extra-peritoneal rectal injuries were seen on proctoscopy and he had no genitourinary injury. He was managed successfully without rectal injury repair orfaecal stream diversion. PMID- 22224351 TI - A severe laryngeal angioedema reaction from cefadroxil in a patient with no known allergies to penicillins. AB - We report a life-threatening anaphylactic reaction to cefadroxil in a 60-year old female with no previous history of allergies to penicillins. Cefadroxil is a first-generation cephalosporin and anaphylactic reactions to it in patients with no previous history of penicillin allergy are very rare. Since cefadroxil is a commonly prescribed antibiotic for both adults and children in the Caribbean, an appropriate level of caution should be exercised in its use even with no reported history of previous allergies to the penicillin class of medications. PMID- 22224352 TI - Parotid actinomycosis mimicking metastatic lymphadenopathy. AB - We present a patient with actinomycosis of the parotid, as confirmed by histology, and discuss the challenges involved when clinical and radiological findings are highly indicative of metastatic malignancy. Early treatment with antibiotics is indicated infungating or infected masses and exclusion of malignancy by histology is often needed. PMID- 22224353 TI - Abdominal scar endometriosis after caesarean section: report of five cases. AB - Scar endometriosis is an under-appreciated or misdiagnosed phenomenon in general surgery and may eventually be more common than reflected in the literature. We herein report five cases of scar endometriosis that were treated in our surgical department one to five years after Caesarean section. Scar endometriosis should be considered when the symptoms are present in a cyclic manner mostly after gynaecological operations and worsening during menstruation. Diagnosis is mainly based upon a high index ofsuspicion. The treatment of choice is surgical resection. PMID- 22224354 TI - Primary renal synovial sarcoma--a case report. AB - Renal synovial sarcoma is a recently reported neoplasm rarely seen. We report a case of primary renal synovial sarcoma. The signs and symptoms are similar to any primary renal tumour diagnosis is clinically difficult through general survey or multiple imaging modalities and requires specific molecular and genetic testing. Surgical resection and ifosfamide-based chemotherapy are the mainstay of management. The prognosis can be poor. Physicians should be aware that synovial sarcoma is one of the possibilities of malignancy in the kidney. PMID- 22224355 TI - Transient cortical blindness post angiography--a case report. AB - A 56-year old female reported having had a fall two weeks prior to presentation. Computed Tomography (CT) scan showed an acute right-sided convexity subdural haematoma. A computed tomography angiogram revealed no vascular anomaly. One hour post procedure she had bilateral cortical blindness. Her vision subsequently was fully restored. A diagnosis of transient cortical blindness was made. Transient cortical blindness is a rare but recognized complication ofintra-arterial injection of iodinated contrast agents. PMID- 22224356 TI - The Haitian earthquake crisis: the first responders' perspective. AB - A catastrophic earthquake of the magnitude of 7 on the Richter scale hit Haiti's capital Port-au-Prince on Tuesday January 12, 2010 at a focal depth of 13 km or 8.1 miles. Four days after, a joint Ministry of Health (Jamaica)/Jamaica Medical Doctor Association (JMDA) initiated CARICOM (Caribbean Community) endeavour entered Haiti to establish a system whereby medical help could be offered to the Haitian populace. Two hospital sites were established (one for life-saving surgeries, the other for limb reconstructions), clinic facilities for walk-in wounded and other related cases, and mobile clinic services (called the Train of Hope). Within 48 hours, a total of 43 operations were performed (26 major 17 minor). Within eight days, a total of 1229-1249 patients were seen in all the facilities established. This included a total of 106 operations (64 major 42 minor). There were a total of 21 life-saving amputations. PMID- 22224357 TI - Decriminalization of marijuana: is this a realistic public mental health policy for Jamaica? AB - Marijuana has potential benefits and adverse effects. Despite its popularity in Jamaica, decriminalization may not be possible given the international and regional obligations of Jamaica. PMID- 22224358 TI - Malignant neoplasms in one city in Japan: based on a study of trends. PMID- 22224359 TI - A report summarizing measures formulated to prevent aspiration pneumonia. PMID- 22224360 TI - Adenocarcinoma of the colon: an uncommon cause of adult colonic intussusception. PMID- 22224361 TI - Future proposals in light of the current status of suicide prevention measures for the young and middle-aged in Japan. PMID- 22224362 TI - Primary splenic hydatid cyst in a young boy--an uncommon entity. PMID- 22224363 TI - Materials for sustained and controlled release of nutrients and molecules to support plant growth. AB - Controlled release fertilizers (CRFs) are a branch of materials that are designed to improve the soil release kinetics of chemical fertilizers to address problems stemming losses from runoff or other factors. Current CRFs are used but only in a limited market due to relatively high costs and doubts about their abilities to result in higher yields and increased profitability for agricultural businesses. New technologies are emerging that promise to improve the efficacy of CRFs to add additional functionality and reduce cost to make CRFs a more viable alternative to traditional chemical fertilizer treatment. CRFs that offer ways of reducing air and water pollution from fertilizer treatments, improving the ability of plants to access required nutrients, improving water retention to increase drought resistance, and reducing the amount of fertilizer needed to provide maximum crop yields are under development. A wide variety of different strategies are being considered to tackle this problem, and each approach offers different advantages and drawbacks. Agricultural industries will soon be forced to move toward more efficient and sustainable practices to respond to increasing fertilizer cost and desire for sustainable growing practices. CRFs have the potential to solve many problems in agriculture and help enable this shift while maintaining profitability. PMID- 22224365 TI - Chemical understanding of carbide cluster metallofullerenes: a case study on Sc2C2@C2v(5)-C80 with complete X-ray crystallographic characterizations. AB - Little is known about the chemical properties of carbide cluster metallofullerenes (CCMFs). Here we report the photochemical reaction of a newly assigned CCMF Sc(2)C(2)@C(2v)(5)-C(80) with 2-adamantane-2,3-[3H]-diazirine (AdN(2), 1), which provides a carbene reagent under irradiation. Five monoadduct isomers (2a-2e), with respective abundances of 20%, 40%, 25%, 5%, and 10%, were isolated and characterized with a combination of experimental techniques including unambiguous single-crystal X-ray crystallography. Results show that the two Sc atoms of the bent Sc(2)C(2) cluster tend to move in most cases, whereas the C(2)-unit is almost fixed. Accordingly, it is difficult to explain the addition patterns by considering the strain and charge density on the cage with a fixed cluster, and thus a moving cluster may account for the addition patterns. These results show that the situation of CCMFs is more complicated than those in other metallofullerenes. Furthermore, a thermal isomerization process from 2b to 2c was observed, confirming that the most abundant isomer 2b is a kinetically favored adduct. Finally, it is revealed that the electronic and electrochemical properties of pristine Sc(2)C(2)@C(2v)(5)-C(80) have been markedly altered by exohedral modification. PMID- 22224366 TI - Deflected capillary force lithography. AB - Herein we introduce a novel strategy based on capillary force lithography (CFL) to fabricate asymmetric polymeric ring structures by applying both shear and nomal forces to a poly(dimethylsiloxane) stamp. The mechanism for the formation of asymmetric rings is caused by the deflection of cylindrical PDMS pillars due to the shear load, which is therefore termed deflected CFL (dCFL). The asymmetric polymeric rings could be readily transferred to an underlying gold layer to generate split ring structures with tunable opening angles. Asymmetric structures based upon trigular and square-shaped pillars were also fabricated. These elements were formed into periodic arrays over surface areas as large as 1 cm(2) and may have optical and electromagnetic applications. PMID- 22224368 TI - Neuroprotective effects of citrus flavonoids. AB - Recent attention has been given to the influence of dietary factors on health and mental well-being. Oxidative stress is associated with many diseases including neurodegenerative disorders. Dietary flavonoids exert cardioprotective, chemopreventive, and neuroprotective effects. The biological activities of flavonoids have been attributed to their antioxidant, anti-inflammatory, and signaling properties. A clear understanding of the mechanisms of action, as either antioxidants or signaling molecules, is crucial for the application of flavonoids as interventions in neurodegeneration and as brain foods. Citrus flavonoids exert little adverse effect and have low or no cytotoxicity to healthy, normal cells. The main citrus flavonoids can also traverse the blood brain barrier; hence, they are promising candidates for intervention in neurodegeneration and as constituents in brain foods. In this review, we discuss the bioactivity, multiple neuroprotection mechanisms, and antioxidant and signaling properties of citrus flavonoids. Receptor-mediated neuroprotective actions and parallel signaling pathways are also explored. Finally, the induction of cellular defense proteins against oxidative stress and neurotoxicity by hesperetin, a main and widespread citrus flavonoid, are also discussed. It is suggested that citrus fruits, which are rich in abundant sources of hesperetin and other flavonoids, are promising for the development of general food-based neuroprotection and brain foods. PMID- 22224369 TI - Gas-phase synthesis and structure of monomeric ZnOH: a model species for metalloenzymes and catalytic surfaces. AB - Monomeric ZnOH has been studied for the first time using millimeter and microwave gas-phase spectroscopy. ZnOH is important in surface processes and at the active site of the enzyme carbonic anhydrase. In the millimeter-wave direct-absorption experiments, ZnOH was synthesized by reacting zinc vapor, produced in a Broida type oven, with water. In the Fourier-transform microwave measurements, ZnOH was produced in a supersonic jet expansion of CH(3)OH and zinc vapor, created by laser ablation. Multiple rotational transitions of six ZnOH isotopologues in their X(2)A' ground states were measured over the frequency range of 22-482 GHz, and splittings due to fine and hyperfine structure were resolved. An asymmetric top pattern was observed in the spectra, showing that ZnOH is bent, indicative of covalent bonding. From these data, spectroscopic constants and an accurate structure were determined. The Zn-O bond length was found to be similar to that in carbonic anhydrase and other model enzyme systems. PMID- 22224401 TI - Preparation and characterization of imidacloprid lignin-polyethylene glycol matrices coated with ethylcellulose. AB - Imidacloprid, a systemic insecticide that has a water solubility of 610 mg L(-1), has been formulated in lignin-polyethylene glycol matrices by a melting process. This formulation was coated in a Wurster type fluidized-bed equipment using ethylcellulose and dibutyl sebacate. Imidacloprid has been entrapped, with an entrapment efficiency higher than 87% in all cases. Thermogravimetric analysis, differential scanning calorimetry, and Fourier transformed infrared spectroscopy studies indicate the stability and compatibility of polymers and imidacloprid. Scanning electron microscopy images show a homogeneous film of ethylcellulose in coated formulations. From T(50) values (the time taken for 50% of the active ingredient to be released into water), the release rate of imidacloprid is controlled by changing the thickness of the coating film and modifying its surface properties by adding a plasticizer. T(50) values, ranging from 3.02 to 168.6 h, allow supplying the appropriate amount of imidacloprid in each specific agronomic practice to increase the efficiency of this bioactive material and minimize the risk of environmental pollution. PMID- 22224402 TI - Classification of difference between inhibition constants of an inhibitor to facilitate identifying the inhibition type. AB - To identify the common inhibition types, the putative decision system is unsatisfactory. In a new decision system, Michaelis-Menten constants and maximal reaction rates were plotted versus inhibitor concentrations for deriving K(ik) and K(iv) as the inhibition constants, respectively; their difference was quantified as the ratio of the larger one to the smaller one. Such ratios below 2.0 suggested uncompetitive inhibitors, over 5.0 suggested noncompetitive or competitive inhibitors, and from 2.0 to 5.0 suggested mixed inhibitors. By the new decision system, (i) the simulation recovery of uncompetitive inhibitors under CVs of 2% or 5% was improved by four times, but that of competitive or noncompetitive inhibitors was improved slightly; (ii) the recovery of L phenylalanine as an uncompetitive inhibitor of intestinal alkaline phosphatase reached 38%, while the putative decision system lost all; the recovery of xanthine as a competitive inhibitor of uricase was improved slightly. Therefore, the new decision system was better. PMID- 22224403 TI - Hydraulic conductance of leaves correlates with leaf lifespan: implications for lifetime carbon gain. AB - Previous research suggests that the lifetime carbon gain of a leaf is constrained by a tradeoff between metabolism and longevity. The biophysical reasons underlying this tradeoff are not fully understood. We used a photosynthesis-leaf water balance model to evaluate biophysical constraints on carbon gain. Leaf hydraulic conductance (K(Leaf)), carbon isotope discrimination (Delta(13)C), leaf mass per unit area (LMA) and the driving force for water transport from stem to leaf (DeltaPsi(Stem-Leaf)) were characterized for leaves spanning three orders of magnitude in surface area and two orders of magnitude in lifespan. We observed positive isometric scaling between K(Leaf) and leaf area but no relationship between Delta(13)C and leaf area. Leaf lifespan and LMA had minimal effect on K(Leaf) per unit leaf area, but a negative correlation exists among LMA, lifespan, and K(Leaf) per unit dry mass. During periods of leaf water loss, DeltaPsi(Stem-Leaf) was relatively constant. We show for the first time that K(Leaf, mass), an index of the carbon cost associated with water use, is negatively correlated with lifespan. This highlights the importance of characterizing K(Leaf, mass) and suggests a tradeoff between resource investment in liquid phase processes and structural rigidity. PMID- 22224404 TI - Tumor classification of six common cancer types based on proteomic profiling by MALDI imaging. AB - In clinical diagnostics, it is of outmost importance to correctly identify the source of a metastatic tumor, especially if no apparent primary tumor is present. Tissue-based proteomics might allow correct tumor classification. As a result, we performed MALDI imaging to generate proteomic signatures for different tumors. These signatures were used to classify common cancer types. At first, a cohort comprised of tissue samples from six adenocarcinoma entities located at different organ sites (esophagus, breast, colon, liver, stomach, thyroid gland, n = 171) was classified using two algorithms for a training and test set. For the test set, Support Vector Machine and Random Forest yielded overall accuracies of 82.74 and 81.18%, respectively. Then, colon cancer liver metastasis samples (n = 19) were introduced into the classification. The liver metastasis samples could be discriminated with high accuracy from primary tumors of colon cancer and hepatocellular carcinoma. Additionally, colon cancer liver metastasis samples could be successfully classified by using colon cancer primary tumor samples for the training of the classifier. These findings demonstrate that MALDI imaging derived proteomic classifiers can discriminate between different tumor types at different organ sites and in the same site. PMID- 22224405 TI - South American spider mites: new hosts and localities. AB - In order to contribute to taxonomic information on Tetranychid mites (Acari: Tetranychidae) in South America, surveys were conducted in Brazil (15 States and the Federal District) and Uruguay (one Department); 550 samples of 120 plant species were collected. Tetranychid mite infestations were confirmed in 204 samples, and 22 species belonging to seven genera of the Bryobiinae and Tetranychinae subfamilies were identified on 58 different host plants. Thirty-six new plant hosts were found in Brazil, South America, and worldwide for the following species: Eutetranychus banksi (McGregor); Mononychellus tanajoa (Bondar); Oligonychus anonae Paschoal; O. mangiferus (Rahman and Sapra); Tetranychus bastosi Tuttle, Baker and Sales; T. desertorum Banks, 1900 , T. evansi Baker and Pritchard; T. ludeni Zacher; T. mexicanus (McGregor); T. neocaledonicus Andre; and T. urticae Koch. Four new localities in Brazil were reported for Eotetranychus tremae De Leon; O. anonae; Panonychus ulmi (Koch); and T. gloveri Baker and Pritchard. PMID- 22224406 TI - Stabilisation of walking by intrinsic muscle properties revealed in a three dimensional muscle-driven simulation. AB - A fundamental question in movement science is how humans perform stable movements in the presence of disturbances such as contact with objects. It remains unclear how the nervous system, with delayed responses to disturbances, maintains the stability of complex movements. We hypothesised that intrinsic muscle properties (i.e. the force-length-velocity properties of muscle fibres and tendon elasticity) may help stabilise human walking by responding instantaneously to a disturbance and providing forces that help maintain the movement trajectory. To investigate this issue, we generated a 3D muscle-driven simulation of walking and analysed the changes in the simulation's motion when a disturbance was applied to models with and without intrinsic muscle properties. Removing the intrinsic properties reduced the stability; this was true when the disturbing force was applied at a variety of times and in different directions. Thus, intrinsic muscle properties play a unique role in stabilising walking, complementing the delayed response of the central nervous system. PMID- 22224407 TI - Protein secondary structure prediction with SPARROW. AB - A first step toward predicting the structure of a protein is to determine its secondary structure. The secondary structure information is generally used as starting point to solve protein crystal structures. In the present study, a machine learning approach based on a complete set of two-class scoring functions was used. Such functions discriminate between two specific structural classes or between a single specific class and the rest. The approach uses a hierarchical scheme of scoring functions and a neural network. The parameters are determined by optimizing the recall of learning data. Quality control is performed by predicting separate independent test data. A first set of scoring functions is trained to correlate the secondary structures of residues with profiles of sequence windows of width 15, centered at these residues. The sequence profiles are obtained by multiple sequence alignment with PSI-BLAST. A second set of scoring functions is trained to correlate the secondary structures of the center residues with the secondary structures of all other residues in the sequence windows used in the first step. Finally, a neural network is trained using the results from the second set of scoring functions as input to make a decision on the secondary structure class of the residue in the center of the sequence window. Here, we consider the three-class problem of helix, strand, and other secondary structures. The corresponding prediction scheme "SPARROW" was trained with the ASTRAL40 database, which contains protein domain structures with less than 40% sequence identity. The secondary structures were determined with DSSP. In a loose assignment, the helix class contains all DSSP helix types (alpha, 3 10, pi), the strand class contains beta-strand and beta-bridge, and the third class contains the other structures. In a tight assignment, the helix and strand classes contain only alpha-helix and beta-strand classes, respectively. A 10-fold cross validation showed less than 0.8% deviation in the fraction of correct structure assignments between true prediction and recall of data used for training. Using sequences of 140,000 residues as a test data set, 80.46% +/- 0.35% of secondary structures are predicted correctly in the loose assignment, a prediction performance, which is very close to the best results in the field. Most applications are done with the loose assignment. However, the tight assignment yields 2.25% better prediction performance. With each individual prediction, we also provide a confidence measure providing the probability that the prediction is correct. The SPARROW software can be used and downloaded on the Web page http://agknapp.chemie.fu-berlin.de/sparrow/ . PMID- 22224408 TI - Full-length HLA-DPB1 diversity in multiple alleles of individuals from Caucasian, Black, or Oriental origin. AB - Despite DP antigens have been shown to be stimulators of the mixed lymphocyte reaction, human leukocyte antigen-DPB1 is not considered in the matching criteria for hematopoietic stem cell transplantation (HSCT). The role of DPB1 matching in HSCT remains inconclusive because of contradictory findings in different studies. The concept of permissible and non-permissible mismatches might clarify these contradictory results. Although several groups have attempted to identify immunogenic epitopes in exon 2 to establish permissive and non-permissive allele groups, the direct correlation between individual exon 2 amino acids and epitopes with DPB1 immunogenicity is still not evident. We hypothesize that polymorphism within the entire molecule, including polymorphic variability in different ethnic groups, is crucial to unravel the function of DPB1 polymorphism. Using an RNA based approach, we sequenced all frequent and available non-frequent DPB1 alleles full length from 148 samples representing 28 different DPB1 alleles from either Black, Caucasian, or Oriental origin. We identified various DPB1 alleles with, in addition to the exon 2 polymorphism, polymorphisms in exons 1, 3, 4, and 5. Based on this polymorphism outside exon 2, we defined one new allele. Two alleles with identical exon 2 polymorphism but differing outside exon 2 were identified in individuals of different ethnic groups. As T cell binding is not restricted to the polymorphic groove and polymorphism in the beta2 domain of the DP molecule affects CD4 interaction, full-length polymorphism should be considered to determine immunogenicity. Eventually, this knowledge will provide new insights in the classification of DPB1 polymorphism and more importantly will add new perspectives to the concept of permissiveness in transplantation. PMID- 22224410 TI - Proteinase production in Pseudomonas fluorescens ON2 is affected by carbon sources and allows surface-attached but not planktonic cells to utilize protein for growth in lake water. AB - Proteins may be an important carbon and nitrogen source to bacteria in aquatic habitats, yet knowledge on the actual utilization of this substrate by proteolytic bacteria is scarce. In this study, Pseudomonas fluorescens ON2 produced an alkaline proteinase (AprX) during growth, and there was no evidence for cell density-regulated or starvation-induced proteinase production. Proteinase was produced in the absence of an organic nitrogen source, and citrate had a negative while glucose had a positive effect on the production. Hence, P. fluorescens ON2 seems to exploit protein sources by expressing the proteinase during growth unless a preferred carbon source such as citrate is present. Lake water model systems were subsequently used to investigate the ability of proteolytic vs. nonproteolytic ON2 strains to utilize protein for growth at moderate cell densities. Only cells forming surface-attached microcolonies were able to utilize this resource, while planktonic cells were not. Our experiments are the first to experimentally support models predicting that production of extracellular enzymes in dilute environments may be a waste of resources, whereas it represents a favorable feeding strategy in organic matrices such as detritus, microcolonies, or biofilm. PMID- 22224411 TI - Task-shifting to community health workers: evaluation of the performance of a peer-led model in an antiretroviral program in Uganda. AB - Task shifting to community health workers (CHW) has received recognition. We examined the performance of community antiretroviral therapy and tuberculosis treatment supporters (CATTS) in scaling up antiretroviral therapy (ART) in Reach Out, a community-based ART program in Uganda. Retrospective data on home visits made by CATTS were analyzed to examine the CATTS ability to perform home visits to patients based on the model's standard procedures. Qualitative interviews conducted with 347 randomly selected patients and 47 CATTS explored their satisfaction with the model. The CATTS ability to follow-up with patients worsened from patients requiring daily, weekly, monthly, to three-monthly home visits. Only 26% and 15% of them correctly home visited patients with drug side effects and a missed clinic appointment, respectively. Additionally, 83% visited stable pre-ART and ART patients (96%) more frequently than required. Six hundred eighty of the 3650 (18%) patients were lost to follow-up (LTFU) during the study period. The mean number of patients LTFU per CATTS was 40.5. Male (p = 0.005), worked for longer durations (p = 0.02), and had lower education (p = 0.005). An increased number of patients (p = 0.01) were associated with increased LTFU. Ninety-two percent of the CATTS felt the model could be improved by reducing the workload. CATTS who were HIV positive, female, not residing in the same village as their patients, more educated, married, on ART, and spent less time with the patients were rated better by their patients. The Reach-Out CHW model is labor intensive. Triaged home visits could improve performance and allow CATTS time to focus on patients requiring more intensive follow-up. PMID- 22224412 TI - Role of ruthenium oxidation states in ligand-to-ligand charge transfer processes. AB - We describe in this paper the properties of [Ru(II/III)(bpy)(2)ClL](+1/+2) and [Ru(II/III)(bpy)(2)L(2)](+2/+3). L = ditolyl-3-pyridylamine (dt3pya) is a redox active ligand related to triarylamines, which is very similar to 3-aminopyridine except for the reversible redox behavior. The monosubstituted complex shows a metal-to-ligand charge-transfer (MLCT) at 502 nm, and reversible waves in acetonitrile at E(0)(Ru(III/II)) = 1.07 V, E(0)(L(+/0)) = 1.46 V (NHE). The disubstituted complex shows an MLCT at 461 nm, a photorelease of dt3pya with quantum yield of 0.11 at 473 nm, and two reversible one-electron overlapped waves at 1.39 V associated with one of the ligands (1.37 V) and Ru(III/II) (1.41 V). Further oxidation of the second ligand at 1.80 V forms a 2,2'-bipiridine derivative, in an irreversible reaction similar to dimerization of triphenylamine to yield tetraphenylbenzidine. In the dioxidized state, the spectroelectrochemistry of the disubstituted complex shows a ligand-to-ligand charge transfer at 1425 nm, with a transition moment of 1.25 A and an effective two-state coupling of 1200 cm(-1). No charge transfer between ligands was observed when Ru was in a 2+ oxidation state. We propose that a superexchange process would be involved in ligand-metal-ligand charge transfer, when ligands and metals are engaged in complementary pi interactions, as in metal-ligand-metal complexes. Best orbital matching occurs when metallic donor fragments are combined with acceptor ligands and vice versa. In our case, Ru(III) bridge (an acceptor) and two dt3pya (donors, one of them being oxidized) made the complex a Robin-Day Class II system, while the Ru(II) bridge (a donor, reduced) was not able to couple two dt3pya (also donors, one oxidized). PMID- 22224414 TI - Nurses' perceptions of and participation in continuing nursing education: results from a study of psychiatric hospital nurses in Bahrain. AB - BACKGROUND: Although many psychiatric hospital nurses in Bahrain attend at least one continuing nursing education (CNE) activity per year, many others do not. This study explored these nurses' perceptions of CNE and factors that promote or hinder participation in CNE activities. METHODS: A descriptive design was used to gather data from a convenience sample of 200 nurses working at the psychiatric hospital in Bahrain. RESULTS: Nurses believed that CNE improved the quality of patient care and patient outcomes, increased nurses' knowledge and skills, and kept them current with advances in nursing. Participation in CNE was hindered by unavailability of CNE activities related to psychiatric nursing. CONCLUSION: The majority of nurses had positive perceptions of CNE. Their participation was hindered by unavailability of CNE activities related to psychiatric nursing. Those responsible for planning continuing education in Bahrain should consider these findings when planning future CNE activities. PMID- 22224415 TI - Membrane permeation of testosterone from either solutions, particle dispersions, or particle-stabilized emulsions. AB - We derive a unified model that accounts for the variation in extent and rate of membrane permeation by a permeating species with the type of donor compartment formulation (aqueous and oil solutions, particle dispersions, and oil-in-water and water-in-oil emulsions stabilized by particles) initially containing the permeant. The model is also applicable to either closed-loop or open-flow configurations of the receiver compartment of the permeation cell. Predictions of the model are compared with measured extents and rates of permeation of testosterone across an 80 MUm thick polydimethylsiloxane (PDMS) membrane from donor compartments initially containing testosterone dissolved in either aqueous or isopropylmyristate (IPM) solutions, aqueous or IPM dispersions of silica nanoparticles or IPM-in-water or water-in-IPM emulsions stabilized by silica nanoparticles. Using a single set of input parameters, the model successfully accounts for the wide variations in permeation behavior observed for the different donor formulation types with either closed-loop or open flow configurations of the permeation cell receiver compartment. PMID- 22224416 TI - Adenosine-5'-triphosphate up-regulates proliferation of human cardiac fibroblasts. AB - BACKGROUND AND PURPOSE: ATP is a potent signalling molecule that regulates biological activities including increasing or decreasing proliferation in different types of cells. The aim of the present study was to investigate how ATP regulates the proliferation of human cardiac fibroblasts. EXPERIMENTAL APPROACH: Reverse transcription (RT)-PCR, Western blot analysis, cell proliferation and migration assays were employed to investigate the effects of ATP on human adult ventricular fibroblasts. KEY RESULTS: ATP increased cell proliferation in a concentration-dependent manner. Similarly, the P2X receptor agonist alpha,beta methylene ATP and P2Y receptor agonist ATP-gammaS also up-regulated cell proliferation. The P2 receptor antagonists suramin and reactive blue-2 prevented the ATP-induced increase in proliferation and RT-PCR and Western blot analysis revealed that mRNAs of P2X(4/7) and P2Y(2) are abundant in cardiac fibroblasts. ATP increased phosphorylated PKB (Akt) and ERK1/2 levels; an effect antagonized by suramin, reactive blue-2, the PI3-kinase inhibitor, wortmannin, PKB inhibitor, API-2, and MAPK inhibitor, PD98059. These kinase inhibitors also prevented the ATP-induced increase in proliferation. In addition, ATP enhanced the progression of cells from the G0/G1 phase to the S phase by increasing the expression of proteins for cyclin D1 and cyclin E. Silencing the P2X(4/7) and P2Y(2) receptors with siRNA targeting the corresponding receptor diminished ATP stimulated proliferation and migration of the cardiac fibroblasts. CONCLUSION AND IMPLICATION: ATP activates P2X(4/7) and P2Y(2) receptors and up-regulates the proliferation of human cardiac fibroblasts by promoting cell cycling progression. It also increases the migration of these cells. These effects of ATP may be involved in cardiac remodelling of injured hearts. PMID- 22224417 TI - Enzymatic transamination of D-kynurenine generates kynurenic acid in rat and human brain. AB - In the mammalian brain, the alpha7 nicotinic and NMDA receptor antagonist kynurenic acid is synthesized by irreversible enzymatic transamination of the tryptophan metabolite l-kynurenine. d-kynurenine, too, serves as a bioprecursor of kynurenic acid in several organs including the brain, but the conversion is reportedly catalyzed through oxidative deamination by d-amino acid oxidase. Using brain and liver tissue homogenates from rats and humans, and conventional incubation conditions for kynurenine aminotransferases, we show here that kynurenic acid production from d-kynurenine, like the more efficient kynurenic acid synthesis from l-kynurenine, is blocked by the aminotransferase inhibitor amino-oxyacetic acid. In vivo, focal application of 100 MUM d-kynurenine by reverse microdialysis led to a steady rise in extracellular kynurenic acid in the rat striatum, causing a 4-fold elevation after 2 h. Attesting to functional significance, this increase was accompanied by a 36% reduction in extracellular dopamine. Both of these effects were duplicated by perfusion of 2 MUM l kynurenine. Co-infusion of amino-oxyacetic acid (2 mM) significantly attenuated the in vivo effects of d-kynurenine and essentially eliminated the effects of l kynurenine. Thus, enzymatic transamination accounts in part for kynurenic acid synthesis from d-kynurenine in the brain. These results are discussed with regard to implications for brain physiology and pathology. PMID- 22224418 TI - In vitro fermentation of arabinoxylan oligosaccharides and low molecular mass arabinoxylans with different structural properties from wheat (Triticum aestivum L.) bran and psyllium (Plantago ovata Forsk) seed husk. AB - Ball milling was used for producing complex arabinoxylan oligosaccharides (AXOS) and low molecular mass arabinoxylans (AX) from wheat bran, pericarp-enriched wheat bran, and psyllium seed husk. The arabinose to xylose ratio of the samples produced varied between 0.14 and 0.92, and their average degree of polymerization (avDP) ranged between 42 and 300. Their fermentation for 48 h in an in vitro system using human colon suspensions was compared to enzymatically produced wheat bran AXOS with an arabinose to xylose ratio of 0.22 and 0.34 and an avDP of 4 and 40, respectively. Degrees of AXOS fermentation ranged from 28% to 50% and were lower for the higher arabinose to xylose ratio and/or higher avDP materials. Arabinose to xylose ratios of the unfermented fractions exceeded those of their fermented counterparts, indicating that molecules less substituted with arabinose were preferably fermented. Xylanase, arabinofuranosidase, and xylosidase activities increased with incubation time. Enzyme activities in the samples containing psyllium seed husk AX or psyllium seed husk AXOS were generally higher than those in the wheat bran AXOS preparations. Fermentation gave rise to unbranched short-chain fatty acids. Concentrations of acetic, propionic, and butyric acids increased to 1.9-2.6, 1.9-2.8, and 1.3-2.0 times their initial values, respectively, after 24 h incubation. Results show that the human intestinal microbiota can at least partially use complex AXOS and low molecular mass AX. The tested materials are thus interesting physiologically active carbohydrates. PMID- 22224420 TI - Magnesium-antimony liquid metal battery for stationary energy storage. AB - Batteries are an attractive option for grid-scale energy storage applications because of their small footprint and flexible siting. A high-temperature (700 degrees C) magnesium-antimony (Mg||Sb) liquid metal battery comprising a negative electrode of Mg, a molten salt electrolyte (MgCl(2)-KCl-NaCl), and a positive electrode of Sb is proposed and characterized. Because of the immiscibility of the contiguous salt and metal phases, they stratify by density into three distinct layers. Cells were cycled at rates ranging from 50 to 200 mA/cm(2) and demonstrated up to 69% DC-DC energy efficiency. The self-segregating nature of the battery components and the use of low-cost materials results in a promising technology for stationary energy storage applications. PMID- 22224421 TI - Analytical model of the three-dimensional plasmonic ruler. AB - An electrostatic eigenmode method that describes the coupling between plasmonic nanoparticles is used to model the optical resonances of the 3D plasmonic ruler. The model provides a mathematical description of the ruler that enables us to identify the key resonance in the scattering spectrum that encodes the location of the central nanorod. The model demonstrates excellent agreement with experimentally measured spectra. We show that the spectra can uniquely encode the horizontal and vertical displacements of the central nanorod. From an understanding of the spatial dependence of the plasmonic coupling between the nanorods, we devise a method for estimating the position of the central nanorod and apply this to experimental data. Our method paves the way toward the use of high-resolution spectra from 3D plasmonic oligomers for structural analysis of single entities such as complex macromolecules, DNA scaffolds, proteins, and peptides. PMID- 22224424 TI - Distribution and organoleptic impact of ethyl 2-hydroxy-4-methylpentanoate enantiomers in wine. AB - The enantiomers of ethyl 2-hydroxy-4-methylpentanoate (ethyl dl-leucate) were assayed in several wines using chiral gas chromatography (gamma-cyclodextrin). Analyses of 55 commercial wines from various vintages and origins revealed different distributions. Generally, white wines presented only the R form, whereas red wines contained both enantiomers, in various ratios according to aging. The highest levels of the S form were found in the oldest samples. The R/S average enantiomeric ratio of this compound in red wine was approximately 95:5 with an average total concentration of ~400 MUg/L. The olfactory threshold of R ethyl 2-hydroxy-4-methylpentanoate (126 MUg/L) in hydroalcoholic solution was almost twice that of the S form (55 MUg/L). The olfactory threshold of a mixture of R- and S-ethyl 2-hydroxy-4-ethylpentanoate (95:5, m/m) in hydroalcoholic solution was 51 MUg/L, suggesting that both enantiomeric forms contribute to perception of this compound in wine, resulting in a synergistic effect. Both enantiomers have quite similar aromatic nuances. Sensory analysis was employed to demonstrate a synergistic effect of this ethyl ester on the perception of fruity aromas in wine: in hydroalcoholic solution supplemented with R- or S-ethyl 2 hydroxy-4-methylpentanoate or a mixture of the R and S forms (95:5, m/m) at their average concentrations in red wines, fruity character was perceived at concentrations 2.2, 4.5, and 2.5 times lower, respectively, than in hydroalcoholic solution alone. Sensory profiles of aromatic reconstitutions, using HPLC fruity fractions, highlighted the contribution of this compound to blackberry fruit and fresh fruit descriptors. PMID- 22224425 TI - pi-Hydrogen bonding wins over conventional hydrogen bonding interaction: a jet cooled study of indole...furan heterodimer. AB - In this study, we have explored the conformational landscape of the indole...furan dimer in a supersonic jet by using resonant two-photon ionization (R2PI) and IR-UV double-resonance spectroscopic techniques combined with dispersion-corrected density functional theory (DFT) calculations. Only one conformer of the dimer has been observed in the experiment. DFT/B97-D level calculation shows that N-H...pi hydrogen-bonded conformer (T') is energetically more stable than the N-H...O hydrogen-bonded conformer (HB). Natural bond orbital (NBO) calculation also shows that the hydrogen-bonding interaction in the HB conformer is very weak. Finally, the structure of the observed dimer has been determined to be tilted T-shaped N-H...pi hydrogen-bonded (T') from very excellent agreement between experimental and theoretical N-H stretch frequency. The most significant finding of this study is the first-time observation of a N H...pi bound conformer of a dimer, which wins over a conventional hydrogen-bonded conformer of the dimer. PMID- 22224423 TI - Sgf29p facilitates the recruitment of TATA box binding protein but does not alter SAGA's global structural integrity in vivo. AB - Although Sgf29p has been biochemically implicated as a component of SAGA (Spt-Ada Gcn5 acetyltransferase), its precise mechanism of action in transcription is not clearly understood in vivo. Here, using a formaldehyde-based in vivo cross linking and chromatin immunoprecipitation (ChIP) assay in conjunction with transcriptional and mutational analyses, we show that Sgf29p along with other SAGA components is recruited to the upstream activating sequence (UAS) of a SAGA regulated gene, GAL1, in an activation domain-dependent manner. However, Sgf29p does not alter the recruitment of Spt20p that maintains the overall structural and functional integrity of SAGA. The recruitment of other SAGA components such as TAF10p, TAF12p, and Ubp8p to the GAL1 UAS is also not altered in the absence of Sgf29p. Interestingly, we find that the recruitment of TBP (TATA box binding protein that nucleates the assembly of general transcription factors to form the preinitiation complex for transcriptional initiation) to the core promoter of GAL1 is weakened in Deltasgf29. Likewise, Sgf29p also enhances the recruitment of TBP to other SAGA-regulated promoters. Such weakening of recruitment of TBP to these promoters subsequently decreases the level of transcription. Taken together, these results support the idea that SAGA-associated Sgf29p facilitates the recruitment of TBP (and hence transcription) without altering the global structural integrity of SAGA in vivo. PMID- 22224428 TI - Prediction and experimental evaluation of soil sorption by natural hormones and hormone mimics. AB - Surface runoff from manure-fertilized fields is a significant source of endocrine disrupting compounds (EDCs) in the environment. Sorption by soils may play a major role in the environmental fate of manure-borne EDCs, including 17alpha- and 17beta-estradiol (17alpha-E2 and 17beta-E2), estrone (E1), melengestrol acetate (MGA), 17alpha- and 17beta-trenbolone (17alpha-TB and 17beta-TB), trendione (TND), and zeranol (alpha-ZAL). As a measure of sorption behavior, the organic carbon-normalized partition coefficients (K(OC)) of 17beta-E2, E1, MGA, and alpha ZAL were experimentally determined for three agricultural soils with initial EDC concentrations spanning from ~0.01 to >1 MUM. Sorption isotherms were linear for most solute-soil combinations. Measured K(OC) values were compared to those predicted using a suite of single-parameter and polyparameter linear free energy relationships (sp- and pp-LFERs). Sp-LFER models were based on experimentally determined octanol-water partition coefficients (K(OW)), whereas pp-LFER solute descriptors were calculated indirectly from experimentally determined solvent water partition coefficients or the program ABSOLV. Log K(OC) predictions by sp LFERs were closest to the experimentally determined values, whereas pp-LFER predictions varied considerably due to uncertainties in both solute and sorbent descriptors determined by ABSOLV or estimates using the partition coefficient approach. PMID- 22224431 TI - Pyridine analogues of the antimetastatic Ru(III) complex NAMI-A targeting non covalent interactions with albumin. AB - A series of pyridine-based derivatives of the antimetastatic Ru(III) complex imidazolium [trans-RuCl(4)(1H-imidazole)(DMSO-S)] (NAMI-A) have been synthesized along with their sodium-ion compensated analogues. These compounds have been characterized by X-ray crystallography, electron paramagnetic resonance (EPR), NMR, and electrochemistry, with the goal of probing their noncovalent interactions with human serum albumin (hsA). EPR studies show that the choice of imidazolium ligands and compensating ions does not strongly influence the rates of ligand exchange processes in aqueous buffer solutions. By contrast, the rate of formation and persistence of interactions of the complexes with hsA is found to be strongly dependent on the properties of the axial ligands. The stability of noncovalent binding is shown to correlate with the anticipated ability of the various pyridine ligands to interact with the hydrophobic binding domains of hsA. These interactions prevent the oligomerization of the complexes in solution and limit the rate of covalent binding to albumin amino acid side chains. Electrochemical studies demonstrate relatively high reduction potentials for these complexes, leading to the formation of Ru(II) species in aqueous solutions containing biological reducing agents, such as ascorbate. However, EPR measurements indicate that while noncovalent interactions with hsA do not prevent reduction, covalent binding produces persistent mononuclear Ru(III) species under these conditions. PMID- 22224432 TI - Patterned polymeric multilayered assemblies through hydrogen bonding and metal coordination. AB - Patterned polymeric multilayered assemblies were formed using a combination of metal coordination and hydrogen bonding interactions. We proved that the hydrogen bonding interaction between diamidopyridine and thymine can be employed for polymeric multilayer assemblies. We then combined this strategy along with a second supramolecular interaction, metal coordination. These interactions proved to be orthogonal to one another on the surface, making each discrete region individually responsive to external stimuli. PMID- 22224429 TI - Annotator: postprocessing software for generating function-based signatures from quantitative mass spectrometry. AB - Mass spectrometry is used to investigate global changes in protein abundance in cell lysates. Increasingly powerful methods of data collection have emerged over the past decade, but this has left researchers with the task of sifting through mountains of data for biologically significant results. Often, the end result is a list of proteins with no obvious quantitative relationships to define the larger context of changes in cell behavior. Researchers are often forced to perform a manual analysis from this list or to fall back on a range of disparate tools, which can hinder the communication of results and their reproducibility. To address these methodological problems, we developed Annotator, an application that filters validated mass spectrometry data and applies a battery of standardized heuristic and statistical tests to determine significance. To address systems-level interpretations, we incorporated UniProt and Gene Ontology keywords as statistical units of analysis, yielding quantitative information about changes in abundance for an entire functional category. This provides a consistent and quantitative method for formulating conclusions about cellular behavior, independent of network models or standard enrichment analyses. Annotator allows for "bottom-up" annotations that are based on experimental data and not inferred by comparison to external or hypothetical models. Annotator was developed as an independent postprocessing platform that runs on all common operating systems, thereby providing a useful tool for establishing the inherently dynamic nature of functional annotations, which depend on results from ongoing proteomic experiments. Annotator is available for download at http://people.cs.uchicago.edu/~tyler/annotator/annotator_desktop_0.1.tar.gz . PMID- 22224433 TI - The nest growth of the neotropical mound-building termite, Cornitermes cumulans: a micromorphological analysis. AB - The nests of Cornitermes cumulans K. (Isoptera: Termitidae), a very common termite in South American grasslands, display notable morphological transformations during the development of the colony. Young colonies inhabit small subterranean nests that develop into large, conspicuous, epigean mounds, inhabited by very populous colonies. Those macromorphological transformations are accompanied by micromorphological changes occurring gradually in the nest walls. The micromorphological changes during nest development described in the present study expand on previous macromorphological descriptions by explaining the re organization of the soil components during nest growth. In subterranean nests, walls are composed of piles of lensshaped aggregates of soil material, each one surrounded by a thin organic coating. As the nest grows, mound walls are constructed by disassembling this first lenticular structure and rearranging the materials in a new fabric, where sand grains are loosely distributed among soil microaggregates of organic matter and clay. This is also a temporary construction, because the walls of large nests are composed of a porous mass of sands densely cemented with organic matter and clay in the mound, and a compact mass of the same components in the floor. PMID- 22224435 TI - Plasmon blockade in nanostructured graphene. AB - Among the many extraordinary properties of graphene, its optical response allows one to easily tune its interaction with nearby molecules via electrostatic doping. The large confinement displayed by plasmons in graphene nanodisks makes it possible to reach the strong-coupling regime with a nearby quantum emitter, such as a quantum dot or a molecule. In this limit, the quantum emitter can introduce a significant plasmon-plasmon interaction, which gives rise to a plasmon blockade effect. This produces, in turn, strongly nonlinear absorption cross sections and modified statistics of the bosonic plasmon mode. We characterize these phenomena by studying the equal-time second-order correlation function g((2))(0), which plunges below a value of 1, thus revealing the existence of nonclassical plasmon states. The plasmon-emitter coupling, and therefore the plasmon blockade, can be efficiently controlled by tuning the doping level of the graphene nanodisks. The proposed system emerges as a new promising platform to realize quantum plasmonic devices capable of commuting optical signals at the single-photon/plasmon level. PMID- 22224434 TI - Preparation and comparative release characteristics of three anthocyanin encapsulation systems. AB - Bilberries (Vaccinium myrtillus L.) and their major polyphenolic constituents, anthocyanins, have preventive activities inter alia against colon cancer and inflammatory bowel diseases. However, anthocyanins are sensitive to environmental conditions; thus their bioavailability in the gastrointestinal tract is an important determinant of their in vivo activity. In the study reported here, the potential benefits of encapsulating an anthocyanin rich bilberry extract (BE) on anthocyanin stability were investigated. Nonencapsulated BE and three different BE loaded microcapsule systems were incubated in simulated gastric fluid (SGF) and fed state simulated intestinal fluid (FeSSIF). After exposure to these media, released anthocyanins were identified and quantified by HPLC with UV/Vis detection. Although a rapid release of anthocyanins was observed within the first 20 min, encapsulation of anthocyanins doubled the amount of available anthocyanins after 150 min of incubation. These results illustrate the ability of encapsulation to inhibit early degradation of anthocyanins in the intestinal system. PMID- 22224436 TI - Electrical phenomena of soft particles. A soft step function model. AB - Simple analytic expressions are derived for the electrophoretic mobility of a soft particle consisting of the hard particle core covered with an ion-penetrable surface layer of polyelectrolyte for the case where the electric potential is low. The effect of the distribution of the polymer segments is taken into account by modeling the surface layer as a soft step function with the inhomogeneous distribution width delta. It is shown that the electrophoretic mobility becomes lower than that for the hard step function model and that the maximum deviation of the soft step function model from the hard step function model, which is a function of lambdadelta (where 1/lambda is the softness parameter) and kappa/lambda (where kappa is the Debye-Huckel parameter), is 2.7% at lambdadelta = 0.1, 5.1% at lambdadelta = 0.2, and 11% at lambdadelta = 0.5. In the limit of very high electrolyte concentrations, the obtained mobility expression tends to the result derived from the conventional hard step function model. In addition, an analytic expression for the interaction energy between two similar soft plates is derived on the basis of the present soft step function model. The magnitude of the interaction energy is shown to decrease by a factor 1/(1 + kappadelta)(2). Approximate analytic expressions for the interaction energies between two similar soft spheres and between two similar soft cylinders are also derived with the help of Derjaguin's approximation. PMID- 22224437 TI - New insights on regulation of LMTK2, a membrane kinase integrating pathways central to neurodegeneration. PMID- 22224438 TI - Effects of the food additive sulfite on nitrite-dependent nitric oxide production under conditions simulating the mixture of saliva and gastric juice. AB - The food additive sulfite is mixed with saliva, which contains nitrite, in the oral cavity, and the mixture is mixed with gastric juice in the stomach. In the stomach, salivary nitrite can be transformed to nitric oxide (NO). In this study, the effects of sulfite on nitrite-dependent NO production were investigated using acidified saliva (pH 2.6) and acidic buffer solutions (pH 2.0). Sulfite enhanced NO production in acidified saliva and acidic buffer solutions, and the enhancement increased with the increase in sulfite concentration from 0 to 0.1 mM, whereas suppressed NO production and the suppression increased as the concentration was increased over 0.2 mM. The enhancement was due to the increase in reaction rate between nitrous acid and nitrososulfonate (ONSO(3)(-)) that was formed by the reaction of nitrous acid with hydrogen sulfite, and the suppression was due to the increase in hydrogen sulfite-dependent consumption rate of ONSO(3)(-). A salivary component SCN(-) (1 mM) enhanced and suppressed NO production induced by 1 mM nitrite when sulfite concentrations were lower and higher than 1 mM, respectively. ONSO(3)(-) formed from hydrogen sulfite and nitrosyl thiocyanate (ONSCN), which was produced by the reaction of nitrous acid with SCN(-), seemed to contribute to the enhancement and suppression. NO production induced by nitrite/ascorbic acid systems was suppressed by sulfite, and the suppressive effects were decreased by SCN(-), whereas sulfite-induced suppression of NO production in nitrite/rutin systems was increased by SCN(-). During reactions of nitrite with sulfite in the presence and absence of SCN(-), oxygen was taken up. The oxygen uptake is discussed to be due to autoxidation of NO and radical chain reactions initiated by hydrogen sulfite radicals. The results of the present study suggest that sulfite can enhance and suppress nitrite-dependent NO production. It is discussed that radicals including hydrogen sulfite radicals can be formed through the reactions of nitrite and sulfite in the stomach. PMID- 22224439 TI - Bone tissue engineering: current strategies and techniques--part II: Cell types. AB - Bone repair and regeneration is a dynamic process that involves a complex interplay between the (1) ground substance; (2) cells; and (3) milieu. Each constituent is integral to the final product, but it is often helpful to consider each component individually. While bone tissue engineering has capitalized on a number of breakthrough technologies, one of the most valued advancements is the incorporation of mesenchymal stem cells (SCs) into bone tissue engineering applications. With this new idea, however, came new found problems of guiding SC differentiation. Moreover, investigators are still working to understand which SCs source produces optimal bone formation in vitro and in vivo. Bone marrow derived mesenchymal SCs and adipose-derived SCs have been researched most extensively, but other SC sources, including dental pulp, blood, umbilical cord blood, epithelial cells reprogrammed to become induced pluripotent SCs, among others, are being investigated. In Part II of this review series, we discuss the variety of cell types (e.g., osteocytes, osteoblasts, osteoclasts, chondrocytes, mesenchymal SCs, and vasculogenic cells) important in bone tissue engineering. PMID- 22224440 TI - Activation of cardiac M3 muscarinic acetylcholine receptors has cardioprotective effects against ischaemia-induced arrhythmias. AB - Increasing evidence indicates the important roles of M(3) muscarinic acetylcholine receptors (M(3) mAChR) in the regulation and maintenance of cardiac function and heart disease. In the present study, we investigated whether the M(3) mAChR mediates the cardioprotection against ischaemia-induced arrhythmias and the mechanisms involved. Myocardial ischaemia was established in Wistar rats by occlusion of the left anterior descending coronary artery. Rats were treated with choline chloride (an M(3) mAChR agonist; 10 mg/kg, i.v.) 10 min before occlusion. In addition, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; 0.12 MUg/kg, i.v.) was administered 5 min before choline in the 4-DAMP-treated group. Ischaemia-induced arrhythmias were evaluated in each group for a period of 1 h after occlusion. After 24 h occlusion, protein and mRNA levels of L-type Ca(2+) channels and the Na(+) /Ca(2+) exchanger (NCX) were determined. Ischaemia-induced arrhythmias following coronary artery occlusion were diminished by choline and this effect was reversed in the 4-DAMP-treated group. In vitro, the effects of myocardial ischaemia were simulated by incubating isolated ventricular cardiomyocytes with Tyrode's solution (pH 6.8). Intracellular Ca(2+) overload was confirmed and this was decreased by choline. Furthermore, choline reduced the L-type Ca(2+) current (I(C) (a,) (L) ) compared with cardiomyocytes incubated in Tyrode's solution (pH 6.8) alone. Choline reduced the 'ischaemia'-induced upregulated expression of L-type Ca(2+) channels and NCX at both the protein and mRNA level. Based on these results, choline has an obvious protective effect against ischaemia-induced arrhythmias that is mediated via activation of cardiac M(3) mAChR, which reduces Ca(2+) overload mediated by L-type Ca(2+) channels and the NCX. PMID- 22224442 TI - Absorption and excretion of 14C-perfluorooctanoic acid (PFOA) in Angus cattle (Bos taurus). AB - Perfluoroalkyl substances (PFASs), such as perfluorooctanoic acid (PFOA), are environmentally persistent industrial chemicals often found in biosolids. Application of these biosolids to pastures raises concern about the accumulation of PFOA in the edible tissues of food animals. Because data on the absorption, distribution, metabolism, and excretion (ADME) of PFOA in cattle were unavailable, a study was conducted to determine pharmacokinetic parameters following a single oral exposure (1 mg/kg body weight of (14)C-PFOA) in four Lowline Angus steers. Radiocarbon was quantified in blood, urine, and feces for 28 days and in tissues at the time of slaughter (28 days) by liquid scintillation counting (LSC) or by combustion analysis with LSC with confirmation by liquid chromatography-tandem mass spectrometry (LC-MS/MS). (14)C-PFOA was completely absorbed and excreted (100.7 +/- 3.3% recovery) in the urine within 9 days of dosing. The plasma elimination half-life was 19.2 +/- 3.3 h. No (14)C-PFOA derived radioactivity was detected in edible tissues. Although PFOA was rapidly absorbed, it was also rapidly excreted by steers and did not persist in edible tissues, suggesting meat from cattle exposed to an acute dose of PFOA is unlikely to be a major source of exposure to humans. PMID- 22224444 TI - Perioperative inflammatory response and protein S-100beta concentrations - relationship with post-operative cognitive dysfunction in elderly patients. AB - BACKGROUND: One major concern in about one third of elder patients after total hip-replacement surgery is post-operative cognitive dysfunction (POCD). Previous studies have suggested that cognitive impairment is accompanied with changes in serum S-100beta protein (S-100beta) and inflammatory markers. Thus, the aim of the current study was to investigate the value of serum S-100beta and interleukin(IL)-1beta, IL-6, tumour necrosis factor-alpha (TNF-alpha), and C reactive protein (CRP) in reflecting POCD after total hip-replacement surgery. METHODS: Forty-two elderly patients were enrolled, and 37 patients completed the follow-up. Serum S-100beta protein and IL-1beta, IL-6, TNF-alpha, and CRP were determined pre-operatively, as well as 1 h and 6 h post-operatively. Neuropsychological tests were performed pre-operatively, as well as on day 1, 3, and 7 post-operatively. RESULTS: Seventeen (45.9%, 17/37) patients developed POCD 1 day after surgery, and three (8.1%, 3/37) developed POCD 7 days after surgery. [Correction added after publication 7 February 2012: in the preceding sentence (54.1%, 17/37) was corrected to (45.9%, 17/37)]. Patients with POCD 1 day after surgery had significantly higher serum levels of IL-6 at 6 h (135 +/- 32 pg/ml vs. 91 +/- 29 pg/ml, P < 0.05) and S-100beta at 1 h (1872 +/- 385 pg/ml vs. 1289 +/- 143 pg/ml, P < 0.05. No significant post-operative change was detected in levels of TNF-alpha, IL-1, or CRP. CONCLUSION: The serum levels of pro inflammatory marker IL-6 and S-100beta protein increased after total hip replacement in elderly patients, and such increase may serve as predicting parameters for the occurrence of POCD. PMID- 22224443 TI - Quaternary ammonium oxidative demethylation: X-ray crystallographic, resonance Raman, and UV-visible spectroscopic analysis of a Rieske-type demethylase. AB - Herein, the structure resulting from in situ turnover in a chemically challenging quaternary ammonium oxidative demethylation reaction was captured via crystallographic analysis and analyzed via single-crystal spectroscopy. Crystal structures were determined for the Rieske-type monooxygenase, stachydrine demethylase, in the unliganded state (at 1.6 A resolution) and in the product complex (at 2.2 A resolution). The ligand complex was obtained from enzyme aerobically cocrystallized with the substrate stachydrine (N,N-dimethylproline). The ligand electron density in the complex was interpreted as proline, generated within the active site at 100 K by the absorption of X-ray photon energy and two consecutive demethylation cycles. The oxidation state of the Rieske iron-sulfur cluster was characterized by UV-visible spectroscopy throughout X-ray data collection in conjunction with resonance Raman spectra collected before and after diffraction data. Shifts in the absorption band wavelength and intensity as a function of absorbed X-ray dose demonstrated that the Rieske center was reduced by solvated electrons generated by X-ray photons; the kinetics of the reduction process differed dramatically for the liganded complex compared to unliganded demethylase, which may correspond to the observed turnover in the crystal. PMID- 22224445 TI - Structure-based discovery of a novel inhibitor targeting the beta-catenin/Tcf4 interaction. AB - Overactivation or overexpression of beta-catenin in the Wnt (wingless) signaling pathway plays an important role in tumorigenesis. Interaction of beta-catenin with T-cell factor (Tcf) DNA binding proteins is a key step in the activation of the proliferative genes in response to upstream signals of this Wnt/beta-catenin pathway. Recently, we identified a new small molecule inhibitor, named BC21 (C(32)H(36)Cl(2)Cu(2)N(2)O(2)), which effectively inhibits the binding of beta catenin with Tcf4-derived peptide and suppresses beta-catenin/Tcf4 driven reporter gene activity. This inhibitor decreases the viability of beta-catenin overexpressing HCT116 colon cancer cells that harbor the beta-catenin mutation, and more significantly, it inhibits the clonogenic activity of these cells. Down regulation of c-Myc and cyclin D1 expression, the two important effectors of the Wnt/beta-catenin signaling, is confirmed by treating HCT116 cells with BC21. This compound represents a new and modifiable potential anticancer candidate that targets beta-catenin/Tcf-4 interaction. PMID- 22224446 TI - Is RNA editing implicated in group II intron survival in the angiosperm mitochondrial genome? AB - Introns may be considered as optional because they are removed from mRNA molecules, but introns are fairly preserved for unknown reasons. Previously, the mitochondrial rps3 gene of sugar beet ( Beta vulgaris L., Caryophyllales) was shown to represent a unique example of an intron loss. We have determined the distribution of the rps3 intron in 19 Caryophyllalean species. The intron was absent from the Amaranthaceae and the Achatocarpaceae. In the Caryophyllaceae, Dianthus japonicus rps3 was pseudogenized, but the intronic sequence was retained. Intact intron-bearing rps3 copies were cloned from Portulaca grandiflora and Myrtillocactus geometrizans , members of the sister clade of the Amaranthaceae-Achatocarpaceae-Caryophyllaceae clade. Most of the C-to-U RNA editing sites in P. grandiflora and M. geometrizans rps3 transcripts were homologous in the two species, as well as in the sugar beet rps3, which, unlike the other 12 rps3 transcripts, lacks editing in the exonic regions around the intron. Provided that the loss of editing preceded the loss of rps3 intron, it appears conceivable that a requirement for editing could have prevented the loss of group II introns retained in angiosperm mitochondrial genomes. This interpretation is an alternative to the conventional one that views the loss of editing as a mere trace of RNA-mediated gene conversion. PMID- 22224447 TI - Nectar yeasts of two southern Spanish plants: the roles of immigration and physiological traits in community assembly. AB - Recent studies have shown that dense yeast populations often occurring in floral nectar are numerically dominated by a few species from the flower-insect interface specialized genus Metschnikowia, while generalist yeast species commonly occurring on leaf surfaces, soil, freshwater, and air were rarely isolated from nectar samples. This study was designed to understand the main factors responsible for the assembly of nectar yeast communities, by combining field experiments with laboratory tests characterizing the physiological abilities of all yeast species forming the pool of potential colonizers for two Spanish flowering plants (Digitalis obscura and Atropa baetica). Yeast frequency and species richness were assessed in external sources (bee glossae, air, plant phylloplane) as well as in pollinator rewards (pollen, nectar). Yeasts were most frequent in external sources (air, flower-visiting insects), less so in the proximate floral environment (phylloplane), and least in pollen and nectar. Nectar communities appeared to be considerably impoverished versions of those in insect glossae and phylloplane. Nectar, pollen, and insect yeast assemblages differed in physiological characteristics from those in other substrates. Nectarivorous Metschnikowia were not more resistant than other yeast species to plant secondary compounds and high sugar concentrations typical of nectar, but their higher growth rates may be decisive for their dominance in ephemeral nectar communities. PMID- 22224448 TI - Selective IGT decision-making impairment in a patient with juvenile Parkinson's disease and pathological gambling: a role for dopaminergic therapy? AB - The orbitofrontal cortex and the dopaminergic system are structures involved in managing impulsivity and sensibility to reinforcements, and both are typically impaired in Parkinson's disease (PD). Also, l-DOPA treatment can contribute to the development of the 'Dopamine Dysregulation Syndrome', a syndrome that can influence the patients' personality and lead to risk-taking behaviors. In this study, we describe the case of a 42-year-old woman (LT) affected by juvenile PD, treated with both l-DOPA and dopamine agonists, who showed a sudden onset of pathological gambling (PG), as the only neuropsychiatric symptom. We assessed LT with a full neuropsychological battery and the Iowa Gambling Task (IGT), in order to describe her specific failure in decision making. LT's performance on the IGT is compared with that of 15 non-demented PD patients under therapy with dopamine agonists and no behavioral dysregulations and with that of 16 age- and education matched healthy subjects. Results showed fully preserved memory, executive functions, and reasoning abilities for LT, but a remarkable and stable impairment in the IGT. Performance of LT on the IGT is significantly lower than that of both control groups. This case shows, for the first time, that high cognitive functioning and preserved executive functions are no guarantee for advantageous decision making, and that the onset of PG is consistent with selective orbitofrontal disruption and side-effects of dopamine agonist therapy. It is also showed that the IGT is a useful neuropsychological device to detect specific risk taking behaviors, which compromise functioning in real life. PMID- 22224450 TI - Plant nitrogen assimilation and use efficiency. AB - Crop productivity relies heavily on nitrogen (N) fertilization. Production and application of N fertilizers consume huge amounts of energy, and excess is detrimental to the environment; therefore, increasing plant N use efficiency (NUE) is essential for the development of sustainable agriculture. Plant NUE is inherently complex, as each step-including N uptake, translocation, assimilation, and remobilization-is governed by multiple interacting genetic and environmental factors. The limiting factors in plant metabolism for maximizing NUE are different at high and low N supplies, indicating great potential for improving the NUE of current cultivars, which were bred in well-fertilized soil. Decreasing environmental losses and increasing the productivity of crop-acquired N requires the coordination of carbohydrate and N metabolism to give high yields. Increasing both the grain and N harvest index to drive N acquisition and utilization are important approaches for breeding future high-NUE cultivars. PMID- 22224451 TI - Growth control and cell wall signaling in plants. AB - Plant cell walls have the remarkable property of combining extreme tensile strength with extensibility. The maintenance of such an exoskeleton creates nontrivial challenges for the plant cell: How can it control cell wall assembly and remodeling during growth while maintaining mechanical integrity? How can it deal with cell wall damage inflicted by herbivores, pathogens, or abiotic stresses? These processes likely require mechanisms to keep the cell informed about the status of the cell wall. In yeast, a cell wall integrity (CWI) signaling pathway has been described in great detail; in plants, the existence of CWI signaling has been demonstrated, but little is known about the signaling pathways involved. In this review, we first describe cell wall-related processes that may require or can be targets of CWI signaling and then discuss our current understanding of CWI signaling pathways and future prospects in this emerging field of plant biology. PMID- 22224453 TI - Asymmetrical N4,N9-diacyl spermines: SAR studies of nonviral lipopolyamine vectors for efficient siRNA delivery with silencing of EGFP reporter gene. AB - Our aim is to study the effects of varying the two acyl moieties in synthesized N(4),N(9)-diacyl spermines on siRNA formulations and their delivery efficiency in cell lines. Six novel asymmetrical lipopolyamines, [N(4)-cholesteryloxy-3 carbonyl-N(9)-oleoyl-, N(4)-decanoyl-N(9)-oleoyl-, N(4)-decanoyl-N(9)-stearoyl-, N(4)-lithocholoyl-N(9)-oleoyl-, N(4)-myristoleoyl-N(9)-myristoyl-, and N(4) oleoyl-N(9)-stearoyl]-1,12-diamino-4,9-diazadodecane, were assessed for their abilities to bind to siRNA, studied using a RiboGreen intercalation assay, and to form nanoparticles. Their siRNA delivery efficiencies were quantified in FEK4 primary skin cells and in an immortalized cancer cell line (HtTA) using a fluorescein-tagged siRNA, and compared with formulations of N(4),N(9)-dioleoyl 1,12-diamino-4,9-diazadodecane and of a leading transfecting agent, TransIT-TKO. Transfection was measured in terms of siRNA delivery and silencing of EGFP reporter gene in HeLa cells. By incorporating two different acyl moieties, changing their length and oxidation level in a controlled manner, we show efficient fluorescein-tagged siRNA formulation, delivery, and knock-down of EGFP reporter gene. N(4)-Oleoyl-N(9)-stearoyl spermine and N(4)-myristoleoyl-N(9) myristoyl spermine are effective siRNA delivery vectors typically resulting in 89% cell delivery and gene silencing to 34% in the presence of serum, comparable with the results obtained with TransIT-TKO; adding a second lipid chain is better than incorporating a steroid moiety. PMID- 22224452 TI - Early embryogenesis in flowering plants: setting up the basic body pattern. AB - Early embryogenesis is the critical developmental phase during which the basic features of the plant body are established: the apical-basal axis of polarity, different tissue layers, and both the root pole and the shoot pole. Polarization of the zygote correlates with the generation of apical and basal (embryonic and extraembryonic) cell fates. Whereas mechanisms of zygote polarization are still largely unknown, distinct expression domains of WOX family transcription factors as well as directional auxin transport and local auxin response are known to be involved in early apical-basal patterning. Radial patterning of tissue layers appears to be mediated by cell-cell communication involving both peptide signaling and transcription factor movement. Although the initiation of the shoot pole is still unclear, the apical organization of the embryo depends on both the proper establishment of transcription factor expression domains and, for cotyledon initiation, upward auxin flow in the protoderm. Here we focus on the essential patterning processes, drawing mainly on data from Arabidopsis thaliana and also including relevant data from other species if available. PMID- 22224454 TI - Species-specific effect of UV-B radiation on the temporal pattern of leaf growth. AB - Recent molecular and physiological studies have demonstrated that ultraviolet-B radiation (UV-B) can affect some of the processes involved in leaf growth, but the phases of leaf growth affected have not been clearly delimited. We used functional growth analysis to assess the effects of UV-B radiation on the time course of leaf growth in seedlings of two birch species (Betula pendula and Betula pubescens). Our aim was to identify the phase(s) of leaf development affected by UV-B radiation. In a greenhouse study, 1-year-old birch seedlings were subjected to three daily doses of supplemental UV-B radiation treatments (UV B+) and no UV-B radiation controls (UV-B-). Leaf growth measurements every 2 days were complemented by assessment of other functional traits over a 4-week period at the start of the growing season. Using fitted curves, we were able to determine that the rate of leaf expansion was slowed by the UV-B+ treatment in leaves of B. pendula because of a slower maximum leaf growth rate compared with plants under the UV-B- controls, but that compensation toward the end of the period of expansion negated this difference when leaves reached their final size. UV-B+ had little effect on the rate of B. pubescens leaf growth despite a larger reduction in leaf final size due to UV-B+ than occurred in B. pendula leaves. In conclusion, effective regulation ameliorated the effects of UV-B radiation on leaf and seedling growth in B. pendula, whereas in B. pubescens, reductions in leaf final size under UV-B+ were consistent with a slightly reduced rate of height growth. PMID- 22224456 TI - 1,1-Diamino-2,2-dintroethene (FOX-7) in copper and nickel diamine complexes and copper FOX-7. AB - 1,1-Diamino-2,2-dinitroethene (FOX-7) reacts readily with copper nitrate in an aqueous solution of potassium hydroxide to form pea green Cu(FOX)(2)(H(2)O)(2) (5). FOX-7 complexes of copper and nickel supported by a variety of diamines including Cu(en)(2)(FOX)(2)(H(2)O) (1), Cu(pn)(2)(FOX)(2) (2), Cu(bipy)(FOX)(2)(H(2)O)(4) (3a), Cu(bipy)(2)(FOX)(2)(H(2)O)(2.5) (3b), Cu(bipy)(FOX)(2)(DMSO)(2).2DMSO (3c), Cu(phen)(3)(FOX)(2)(H(2)O)(3) (4), (Ni)(2)(phen)(6)(FOX)(4)(NO(3))(3)(H(2)O)(2) (6), and Ni(bipy)(3)(FOX)(2)(H(2)O)(4) (7a) were obtained via metathesis reactions with potassium-FOX (K-FOX). Surprisingly FOX-7, in the presence of Ni(II) and bipyridyl in a mixed solvent of methanol and dimethyl sulfoxide, gave a chelated FOX carbamate anion resulting in the compound Ni(bipy)(2)(FOX-CO(2)).(DMSO) (7b). All metal salts were characterized by infrared, elemental analysis, and differential scanning calorimetry (DSC). Single-crystal X-ray diffraction structures were obtained for compounds 1, 2, 3c, 6, and 7b. PMID- 22224457 TI - Renin activates PI3K-Akt-eNOS signalling through the angiotensin AT1 and Mas receptors to modulate central blood pressure control in the nucleus tractus solitarii. AB - BACKGROUND AND PURPOSE: The renin-angiotensin system (RAS) is critical for the control of blood pressure by the CNS. Recently, direct renin inhibitors were approved as antihypertensive agents. However, the signalling mechanism of renin, which regulates blood pressure in the nucleus tractus solitarii (NTS) remains unclear. Here we have investigated the signalling pathways involved in renin mediated blood pressure regulation, at the NTS. EXPERIMENTAL APPROACH: Depressor responses to renin microinjected into the NTS of Wistar-Kyoto rats were elicited in the absence and presence of the endothelial nitric oxide synthase (eNOS) specific inhibitor, N(5)-(-iminoethyl)-L-ornithine, Akt inhibitor IV and LY294002, a PI3K inhibitor and GP antagonist-2A [G(q) inhibitor]. Lisinopril (angiotensin converting enzyme inhibitor), losartan, valsartan (angiotensin AT(1) receptor antagonists), D-Ala7-Ang-(1-7) (angiotensin-(1-7) receptor antagonist) were used to study the involvement of RAS on renin-induced depressor effects. KEY RESULTS: Microinjection of renin into the NTS produced a prominent depressor effect and increased NO production. Pretreatment with G(q) -PI3K-Akt-eNOS pathway specific inhibitors significantly attenuated the depressor response evoked by renin. Immunoblotting and immunohistochemical studies further showed that inhibition of PI3K significantly blocked renin-induced eNOS-Ser 117 and Akt Ser473 phosphorylation in situ. In addition, pre-treatment of the NTS with RAS inhibitors attenuated the vasodepressor effects evoked by renin. Microinjection of renin also increased Ras activation in the NTS. CONCLUSIONS AND IMPLICATIONS: Taken together, these results suggest renin modulated blood pressure at the NTS by AT1 and Mas receptor-mediated activation of G(q) and Ras to evoke PI3K-Akt eNOS signalling. PMID- 22224460 TI - Lateral etching of core-shell Au@Metal nanorods to metal-tipped au nanorods with improved catalytic activity. AB - Selective growth/etching of hybrid materials is very important for the rational synthesis of hierarchical structures and precise modulation of their physical properties. Here, the lateral etching of the core-shell Au@Ag nanorods is achieved by FeCl(3) at room temperature, producing a number of dumbbell-like Ag tipped Au nanorods. This selective etching at the side of the core-shell nanorods is attributed to the increased reactivity of the side facets, due to less surface passivation of cetyltrimethylammonium bromide. The similar synthetic strategy has also been demonstrated to be successful for the Pd-tipped Au nanorods that have not been reported before, indicating the great potential of this selective etching. The Ag-tipped Au nanorods are examined as a catalyst for the reduction of p-nitrophenol at room temperature. The Ag-tipped Au nanorods exhibit a higher catalytic activity than Au nanorods and core-shell Au@Ag nanorods, which could be attributed to the electronic effect and the unique structure in the Ag-tipped Au nanorods. PMID- 22224459 TI - Development of an enzyme-linked immunosorbent assay (ELISA) for residue analysis of the fungicide azoxystrobin in agricultural products. AB - A direct competitive enzyme-linked immunosorbent assay (dc-ELISA) was developed for residue analysis of azoxystrobin in garden crops, for which the maximum residue limits (MRLs) are 0.5-50 mg/kg in Japan. For hapten synthesis, an ethyl carboxyl group was introduced to the 4-position of the 2-cyanophenoxy group in azoxystrobin, and its cyano group was changed to a methyl group. An anti azoxystrobin monoclonal antibody was prepared from mice immunized with hapten keyhole limpet hemocyanin conjugate. The dc-ELISA using prepared antibody showed 50-250-fold higher sensitivity compared to the MRLs. The working range of the dc ELISA was 10-200 ng/mL. The dc-ELISA showed high specificity to azoxystrobin. When methanol extracts from nine kinds of garden crops spiked with azoxystrobin ranging near the MRLs were analyzed, the determined results by the dc-ELISA agreed well with the results of their controls. In addition, azoxystrobin spiked in garden crops homogenates was satisfactorily extracted by methanol solution and easily analyzed. The recovery rate of dc-ELISA was 96-109% and correlated well with the results obtained by HPLC analysis. PMID- 22224461 TI - Viscosity dependence of intra- and intermolecular Diels-Alder reactions. AB - The kinetics of the bimolecular Diels-Alder reaction between anthracene-9 carbinol and N-ethyl maleimide have been studied in a series of pyridinium-based ionic liquids with the tetrafluoroborate ([BF(4)](-)) and the bis(trifluorosulfonimide) ([NTf(2)](-)) anions and the viscosity dependence of the rate constants have been compared with the results for the intramolecular Diels-Alder reaction of (E)-1-phenyl-4-[2-(3-methyl-2-butenyloxy)benzylidene]-5 pyrazolone. The comparison leads to the surprising observation that the intermolecular reaction is less susceptible to viscosity variations of the ionic liquids as compared to the intramolecular reaction. The observed similarities and differences emphasize the complicated nature of solvent friction on the kinetics of cycloaddition reactions. The results are explained by considering the bimolecular and intramolecular processes as cases of translational and rotational diffusion, respectively. Plausible indicators of microviscosity consistent with the kinetic data for the Diels-Alder reactions are briefly discussed along with the constraints involved in designing a general microviscosity scale. PMID- 22224462 TI - Interpersonal development, stability, and change in early adulthood. AB - The goal of this research was to explore the development of the interpersonal system mapped by the interpersonal circumplex in early adulthood (ages 18-22). This study uses the Longitudinal Study of Personality Disorders sample (N = 250; 53% female). Participants completed the Revised Interpersonal Adjective Scales (Wiggins, Trapnell, & Phillips, 1988) in their freshman, sophomore, and senior years of college. Estimates of structural, rank-order, mean, individual, and ipsative stability were calculated for the broad interpersonal dimensions of Dominance and Affiliation and also the lower order octant scales. Additionally, the interpersonal profile parameters of differentiation and prototypicality were calculated at each wave and explored longitudinally and also used as predictors of interpersonal stability. We found excellent structural and high rank-order and ipsative stability in the interpersonal scales over this time period. Mean increases on the Affiliation axis, but not on the Dominace axis, were found to mask differential rates of change among the octant scales, along with significant individual variation in the rates of change. Interpersonal differentiation and prototypicality were related to higher stability in overall interpersonal style. Results point to evidence of both stability and nuanced change, illuminating some of the features of the structural variables that can be derived from interpersonal circumplex profiles. PMID- 22224463 TI - High-antioxidant potatoes: acute in vivo antioxidant source and hypotensive agent in humans after supplementation to hypertensive subjects. AB - Potatoes have the highest daily per capita consumption of all vegetables in the U.S. diet. Pigmented potatoes contain high concentrations of antioxidants, including phenolic acids, anthocyanins, and carotenoids. In a single-dose study six to eight microwaved potatoes with skins or a comparable amount of refined starch as cooked biscuits was given to eight normal fasting subjects; repeated samples of blood were taken over an 8 h period. Plasma antioxidant capacity was measured by ferric reducing antioxidant power (FRAP). A 24 h urine was taken before and after each regimen. Urine antioxidant capacity due to polyphenol was measured by Folin reagent after correction for nonphenolic interferences with a solid phase (Polyclar) procedure. Potato caused an increase in plasma and urine antioxidant capacity, whereas refined potato starch caused a decrease in both; that is, it acted as a pro-oxidant. In a crossover study 18 hypertensive subjects with an average BMI of 29 were given either six to eight small microwaved purple potatoes twice daily or no potatoes for 4 weeks and then given the other regimen for another 4 weeks. There was no significant effect of potato on fasting plasma glucose, lipids, or HbA1c. There was no significant body weight increase. Diastolic blood pressure significantly decreased 4.3%, a 4 mm reduction. Systolic blood pressure decreased 3.5%, a 5 mm reduction. This blood pressure drop occurred despite the fact that 14 of 18 subjects were taking antihypertensive drugs. This is the first study to investigate the effect of potatoes on blood pressure. Thus, purple potatoes are an effective hypotensive agent and lower the risk of heart disease and stroke in hypertensive subjects without weight gain. PMID- 22224467 TI - Environmental conditions influence allometric patterns in the blow fly, Chrysomya albiceps. AB - The objective of this research was to study variations in allometry of body characters in females and males of two populations of blow flies, Chrysomya albiceps (Wiedemann) (Diptera: Calliphoridae), under different environmental conditions to establish patterns of morphological variation. Body size of both males and females in the experimental population was significantly higher than in the individuals of the natural population, indicating an important influence of food on body size. All genitalic and non-genitalic characters in males and females of the two populations showed a trend towards negative allometry rather than isometry. Allometric patterns were modified in both sexes and between populations. The data show generally larger allometric slopes in females than in males. We confirmed that the environmental conditions have an important effect on allometric patterns and body size. PMID- 22224470 TI - Treatment of adult short bowel syndrome patients with teduglutide. AB - INTRODUCTION: Parenteral support is lifesaving in short bowel syndrome patients with intestinal failure (SBS-IF), who are unable to compensate for their malabsorption by metabolic or pharmacologic adaptation. Mutually, the symptoms of SBS-IF and the inconveniences and complications in relation to parenteral support may cause impairment of the quality of life of SBS-IF patients. Conventional treatments include dietary manipulations, oral rehydration solutions, antidiarrheal and antisecretory treatments. However, the evidence base for these interventions is limited, and treatments improving structural and functional integrity of the remaining intestine are desired. Teduglutide , an analog of glucagon-like peptide 2, improves intestinal rehabilitation by promoting mucosal growth and possibly by inhibiting gastric emptying and secretion, which in turn reduces intestinal losses and promotes intestinal absorption. AREAS COVERED: This paper reviews the following findings: in a 3-week, Phase II balance study, teduglutide reduced diarrhea by ~ 700 g/day and fecal energy losses by ~ 0.8 MJ/day, and in a randomized, placebo-controlled, 24-week, Phase III study, corresponding reductions in the need for parenteral support were obtained. EXPERT OPINION: Teduglutide seems to be safe and well-tolerated and demonstrates restoration of structural and functional integrity of the remaining intestine with significant intestinotrophic and proabsorptive effects, facilitating a reduction in diarrhea and an equivalent reduction in the need for parenteral support in SBS-IF patients. PMID- 22224469 TI - Structural and biophysical insights into the ligand-free Pitx2 homeodomain and a ring dermoid of the cornea inducing homeodomain mutant. AB - The homeodomain-containing transcription factor Pitx2 (pituitary homeobox protein 2) is present in many developing embryonic tissues, including the heart. Its homeodomain is responsible for the recognition and binding to target DNA sequences and thus constitutes a major functional unit in the Pitx2 protein. Nuclear magnetic resonance techniques were employed to determine the solution structure of the native Pitx2 homeodomain and a R24H mutant that causes autosomal dominantly inherited ring dermoid of the cornea syndrome. The structures reveal that both isoforms possess the canonical homeodomain fold. However, the R24H mutation results in a 2-fold increase in DNA binding affinity and a 5 degrees C decrease in thermal stability, while changing the dynamic environment of the homeodomain only locally. When introduced into full-length Pitx2c, the mutation results in an only 25% loss of transactivation activity. Our data correlate well with clinical observations suggesting a milder deficiency for the R24H mutation compared to those of other Pitx2 homeodomain mutations. PMID- 22224472 TI - Thiol, disulfide, and trisulfide complexes of Ru porphyrins: potential models for iron-sulfur bonds in heme proteins. AB - Thirty-two Ru(porp)L(2) complexes have been synthesized, where porp = the dianion of meso-tetramesitylporphyrin (TMP) or meso-tetrakis(4-methylphenyl)porphyrin (H(2)T-pMe-PP), and L = a thiol, a sulfide, a disulfide, or a trisulfide. Species studied were with RSH [R = Me, Et, (n)Pr, (i)Pr, (t)Bu, Bn (benzyl), and Ph], RSR (R = Me, Bn), RSSR (R = Me, Et, (n)Pr, Bn) and MeSS(t)Bu, and RSSSR (R = Me, Bn). All the species except two, which were the isolated Ru(T-pMe-PP)((t)BuSH)(2) and Ru(TMP)(MeSSMe)(2), were characterized in situ. The disulfide complex was characterized by X-ray analysis. (1)H NMR data for the coordinated thiols are the first reported within metalloporphyrin systems, and are especially informative because of the upfield shifts of the axial sulfur-containing ligands due to the porphyrin pi-ring current effect, which is also present in the di- and trisulfide species. The disulfide in the solid state structure of Ru(TMP)(MeSSMe)(2) is eta(1)(end-on) coordinated, the first example of such bonding in a nontethered, acyclic dialkyl disulfide; (1)H-(1)H EXSY NMR data in solution show that the species undergoes 1,2-S-metallotropic shifts. Stepwise formation of the bis(disulfide) complex from Ru(TMP)(MeCN)(2) in solution occurs with a cooperativity effect, resembling behavior of Fe(II)-porphyrin systems where crystal field effects dominate, but ligand trans-effects are more likely in the Ru system. The eta(1)(end-on) coordination mode is also favored for the trisulfide ligand. Discussed also are the remarkable linear correlations that exist between the ring-current shielding shifts for the axial ligand C(1) protons of Ru(porp)(RS(x)R)(2) and x (the number of S atoms). The Introduction briefly reviews literature on Ru- and Fe porphyrins (including heme proteins) with sulfur containing ligands or substrates, and relationships between our findings and this literature are discussed throughout the paper. PMID- 22224473 TI - QSPR-based estimation of the half-lives for polychlorinated biphenyl congeners. AB - In this study, the depuration half-lives of 62 polychlorinated biphenyl (PCB) congeners in juvenile rainbow trout (Oncorhynchus mykiss) were estimated from their structural features based on QSPR methodology. A genetic algorithm (GA) was applied as a variable subset selection strategy and QSPR models established upon multiple linear regression (MLR), multilayer perceptron neural network (MLP NN) and support vector regression (SVR) procedures. Robustness and predictive stability of the constructed models were evaluated through internal and external validation methods. The high numerical values of [Formula: see text] and [Formula: see text], and low RMSE in the case of the MLP NN model, confirm the supremacy of this model as well as nonlinear dependency of molecular structural features to the PCB congeners half-lives. In the best developed QSPR model the following four descriptors are used; lopping centric index (Lop), mean topological charge index of order 1 (JGI1), Geary autocorrelation lag-8/weighted by atomic Sanderson electronegativities (GATS8e) and highest eigenvalue of Burden matrix/weighted by atomic masses (BEHm3). Analysis of the descriptors involved in these models revealed that 2D molecular structural features, compactness and electronegativities are the main factors contributing to the half-lives of PCBs. The structural information presented in this work can be used for further evaluation of half-lives of PCBs and other similar structural compounds in the environment. PMID- 22224468 TI - Tissue engineering and regenerative strategies to replicate biocomplexity of vascular elastic matrix assembly. AB - Cardiovascular tissues exhibit architecturally complex extracellular matrices, of which the elastic matrix forms a major component. The elastic matrix critically maintains native structural configurations of vascular tissues, determines their ability to recoil after stretch, and regulates cell signaling pathways involved in morphogenesis, injury response, and inflammation via biomechanical transduction. The ability to tissue engineer vascular replacements that incorporate elastic matrix superstructures unique to cardiac and vascular tissues is thus important to maintaining vascular homeostasis. However, the vascular elastic matrix is particularly difficult to tissue engineer due to the inherently poor ability of adult vascular cells to synthesize elastin precursors and organize them into mature structures in a manner that replicates the biocomplexity of elastic matrix assembly during development. This review discusses current tissue engineering materials (e.g., growth factors and scaffolds) and methods (e.g., dynamic stretch and contact guidance) used to promote cellular synthesis and assembly of elastic matrix superstructures, and the limitations of these approaches when applied to smooth muscle cells, the primary elastin-generating cell type in vascular tissues. The potential application of these methods for in situ regeneration of disrupted elastic matrix at sites of proteolytic vascular disease (e.g., abdominal aortic aneurysms) is also discussed. Finally, the review describes the potential utility of alternative cell types to elastic tissue engineering and regenerative matrix repair. Future progress in the field is contingent on developing a thorough understanding of developmental elastogenesis and then mimicking the spatiotemporal changes in the cellular microenvironment that occur during that phase. This will enable us to tissue engineer clinically applicable elastic vascular tissue replacements and to develop elastogenic therapies to restore homeostasis in de-elasticized vessels. PMID- 22224474 TI - The uptake of recombinant glucocerebrosidases by blood monocytes from type 1 Gaucher disease patients is variable. PMID- 22224475 TI - Moderators of the synchrony of change between decreasing depression severity and disability. AB - OBJECTIVE: To identify moderators of synchrony of change between depression severity and disability. METHOD: From a large cohort study with 2 years of follow up, patients with major depressive disorder at baseline who decreased at least 25% in depression severity after 2 years (n = 245) were selected. We measured overall and domain-specific disability at baseline, and at 1- and 2-year follow up. Possible moderators, among which several demographic, clinical, personality, and contextual factors, were measured at baseline. We used linear mixed models to analyze the data. RESULTS: Decrease in depression severity correlated strongly with reductions of overall disability (r = 0.54). Synchrony of change for the disability domains ranged from 0.13 for self-care to 0.47 for participation. From the possible moderators, only age and work stress moderated the association between change in depression severity and disability, with stronger synchrony of change among younger patients and patients who experienced moderate work stress. CONCLUSION: Strong synchrony of change exists between depression severity and disability. Perhaps, because of the strength of this synchrony, few contextual characteristics moderated the association. Clinicians should be aware of the risk of slower or incomplete functional recovery in older people and those without a job or those experiencing low work stress. PMID- 22224476 TI - Yeast and yeast-like fungi associated with dry indehiscent fruits of Nothofagus nervosa in Patagonia, Argentina. AB - Nothofagus nervosa (Rauli) is a native tree species that yields valuable timber. It was overexploited in the past and is currently included in domestication and conservation programs. Several research programs have focused on the characterization of epiphytic microorganisms because it has been demonstrated that they can affect plant-pathogen interactions and/or promote plant growth. Although the microbial ecology of leaves has been well studied, less is known about microorganisms occurring on seeds and noncommercial fruits. In this work, we analyzed the yeast and yeast-like fungi present on N. nervosa fruits destined for the propagation of this species, as well as the effects of fruit preservation and seed dormancy-breaking processes on fungal diversity. Morphological and molecular methods were used, and differences between fungal communities were analyzed using a similarity index. A total of 171 isolates corresponding to 17 species were recovered, most of which belong to the phylum Ascomycota. The majority of the species develop mycelia, produce pigments and mycosporines, and these adaptation strategies are discussed. It was observed that the preservation process considerably reduced yeast and yeast-like fungal diversity. This is the first study concerning microbial communities associated with this ecologically and economically important species, and the information presented is relevant to domestication programs. PMID- 22224477 TI - Speciation and monitoring test for inorganic arsenic in white rice flour. AB - A monitoring test for arsenic species in white rice flour was developed and applied to flours made from 20 samples of polished rice collected from locations all over Japan. The arsenic species in white rice flour made from five samples each of four types of rice were analyzed by HPLC-ICP-MS after a heat-assisted aqueous extraction. The total arsenic and major and minor element concentrations in the white rice flours were measured by ICP-MS and ICP-OES after microwave assisted digestion. 91 +/- 1% of the arsenic in the flours was extractable. Concentrations of arsenite [As(III)], arsenate [As(V)], and dimethylarsinic acid (DMAA) were closely positively correlated with the total arsenic concentrations. The total arsenic concentration in flours made from rice collected around Japan was 0.15 +/- 0.07 mg kg(-1) (highest, 0.32 mg kg(-1)), which is very low. It was thus confirmed that the white rice flour samples collected in this experiment were not suffered from noticeable As contamination. PMID- 22224479 TI - Effect of polysaccharides on the gelatinization properties of cornstarch dispersions. AB - Konjac glucomannan (KG, neutral), carboxymethylcellulose (CMC, negatively charged), and chitosan (positively charged) were added to cornstarch dispersions to study the effect of polysaccharide-starch interactions on starch gelatinization properties. Pasting and retrogradation properties were measured with a rheometer and DSC. Swelling properties of the starch granules were determined by solubility index, swelling power, and particle size distribution. Depending on the nature of the different polysaccharides, viscosities of cornstarch dispersions were affected differently. The particle size distributions were not influenced by the addition of any of the polysaccharides. Swelling results showed that the KG and CMC molecules interacted with the released or partly released amylose in the cornstarch dispersions. This was correlated with the short-term retrogradation of the starch pastes being retarded by the additions of KG and CMC. However, the chitosan molecules appeared not to associate with the amylose, so the retrogradation of the chitosan-cornstarch dispersions was not retarded. PMID- 22224480 TI - The lace plant: a novel model system to study plant proteases during developmental programmed cell death in vivo. AB - Programmed cell death (PCD) plays a major role in plant development and defense throughout the plant kingdom. Within animal systems, it is well accepted that caspases play a major role in the PCD process, although no true caspases have yet to be identified in plants. Despite this, vast amounts of evidence suggest the existence of caspase-like proteases in plants. The lace plant (Aponogeton madagascariensis) forms perforations in a predictable pattern between longitudinal and transverse veins over its entire leaf surface via PCD. Due to the thin nature of the leaf, allowing for long-term live cell imaging, a perfected method for sterile culture, as well as the feasibility of pharmacological experiments, the lace plant provides an excellent model to study developmental PCD. In this review, we report the suitability of the lace plant as a novel organism to study proteases in vivo during developmentally regulated cell death. PMID- 22224482 TI - Neurofunctional assessment in a stroke patient with musical hallucinations. AB - We reported a case of an elderly female patient affected by musical hallucinations (MHs) as the unique symptom of a right temporal ischemic stroke. A functional magnetic resonance imaging examination was performed in the patient and in five age- and sex-matched normal controls (NC) to detect the complex neural substrate subserving MHs in such a context. Although an activation pattern involving the primary auditory cortex and the temporal associative areas bilaterally was found in the patient and NC, a significant increased activation mostly located in right temporal cortex (in the ischemic area), was observed in the patient. Further functional neuroimaging studies should be performed to detect the complex neural pathways underlying MHs and to find out differences between these hallucinations and real music perception. PMID- 22224483 TI - BDDCS class prediction for new molecular entities. AB - The Biopharmaceutics Drug Disposition Classification System (BDDCS) was successfully employed for predicting drug-drug interactions (DDIs) with respect to drug metabolizing enzymes (DMEs), drug transporters and their interplay. The major assumption of BDDCS is that the extent of metabolism (EoM) predicts high versus low intestinal permeability rate, and vice versa, at least when uptake transporters or paracellular transport is not involved. We recently published a collection of over 900 marketed drugs classified for BDDCS. We suggest that a reliable model for predicting BDDCS class, integrated with in vitro assays, could anticipate disposition and potential DDIs of new molecular entities (NMEs). Here we describe a computational procedure for predicting BDDCS class from molecular structures. The model was trained on a set of 300 oral drugs, and validated on an external set of 379 oral drugs, using 17 descriptors calculated or derived from the VolSurf+ software. For each molecule, a probability of BDDCS class membership was given, based on predicted EoM, FDA solubility (FDAS) and their confidence scores. The accuracy in predicting FDAS was 78% in training and 77% in validation, while for EoM prediction the accuracy was 82% in training and 79% in external validation. The actual BDDCS class corresponded to the highest ranked calculated class for 55% of the validation molecules, and it was within the top two ranked more than 92% of the time. The unbalanced stratification of the data set did not affect the prediction, which showed highest accuracy in predicting classes 2 and 3 with respect to the most populated class 1. For class 4 drugs a general lack of predictability was observed. A linear discriminant analysis (LDA) confirming the degree of accuracy for the prediction of the different BDDCS classes is tied to the structure of the data set. This model could routinely be used in early drug discovery to prioritize in vitro tests for NMEs (e.g., affinity to transporters, intestinal metabolism, intestinal absorption and plasma protein binding). We further applied the BDDCS prediction model on a large set of medicinal chemistry compounds (over 30,000 chemicals). Based on this application, we suggest that solubility, and not permeability, is the major difference between NMEs and drugs. We anticipate that the forecast of BDDCS categories in early drug discovery may lead to a significant R&D cost reduction. PMID- 22224484 TI - Distinct photophysics of the isomers of B18H22 explained. AB - The photophysics of the two isomers of octadecaborane(22), anti- and syn B(18)H(22), have been studied by UV-vis spectroscopic techniques and theoretical computational methods. In air-saturated hexane, anti-B(18)H(22) shows fluorescence with a high quantum yield, Phi(F) = 0.97, and singlet oxygen O(2)((1)Delta(g)) production (Phi(Delta) ~ 0.008). Conversely, isomer syn B(18)H(22) shows no measurable fluorescence, instead displaying much faster, picosecond nonradiative decay of excited singlet states. Computed potential energy hypersurfaces (PEHs) for both isomers rationalize these data, pointing to a deep S(1) minimum for anti-B(18)H(22) and a conical intersection (CI) between its S(0) and S(1) states that lies 0.51 eV higher in energy. Such an energy barrier to nonradiative relaxation is not present in the PEH of syn-B(18)H(22), and the system therefore has sufficient initial energy on excitation to reach the (S(0)/S(1)) CI and to then decay to the ground state without fluorescence. The computational analysis of the geometries at stationary points along the PEH of both isomers shows that the determining factor for the dissimilar photophysics of anti- and syn-B(18)H(22) may be due to the significant differences in the geometrical rearrangements at their respective conical intersections. Thus, the syn isomer shows one very large, B-B elongation of 1.2 A from 1.8 A in the ground state to 3.0 A at the CI, whereas the anti isomer shows smaller elongations (below 1 A) in several B-B connectivities at its (S(0)/S(1))(CI). The absorbed energy in S(1) for the anti-B(18)H(22) is therefore redistributed vibrationally into several regions of the molecule rather than almost completely into a single vibrational mode as in the case for the syn isomer. The consequent prolonged S(1) lifetime for the anti isomer allows for relaxation via fluorescence. PMID- 22224486 TI - Atopic dermatitis: recent findings and insights. PMID- 22224487 TI - Comorbid infections of pediatric inflammatory skin diseases. PMID- 22224485 TI - Caffeic acid phenethyl ester protects nigral dopaminergic neurons via dual mechanisms involving haem oxygenase-1 and brain-derived neurotrophic factor. AB - BACKGROUND AND PURPOSE: Caffeic acid phenethyl ester (CAPE) is a component of honey bee propolis that can induce expression of haem oxygenase-1 (HO-1). Because HO-1 induction has been suggested to protect dopaminergic neurons in the substantia nigra, we examined the effect of CAPE in experimental models of dopaminergic neurodegeneration. EXPERIMENTAL APPROACH: Neuroprotective effect of CAPE was investigated in rat organotypic midbrain slice cultures and in vivo, using a mouse model of dopaminergic neurodegeneration induced by intranigral injection of LPS and intrastriatal injection of 6-hydroxydopamine. KEY RESULTS: CAPE protected dopaminergic neurons in slice cultures from IFN-gamma/LPS-induced injury. The effect of CAPE was inhibited by zinc protoporphyrin IX, an HO-1 inhibitor, and by neutralizing antibody against brain-derived neurotrophic factor (BDNF). A p38 MAPK inhibitor SB203580 prevented activation of NF-E2-related factor 2, attenuated increased expression of HO-1 and BDNF, and blocked the neuroprotective actions of CAPE. In the LPS-injected mouse model, daily intraperitoneal administration of CAPE protected dopaminergic neurons, up regulated HO-1 and BDNF, and reduced the increase of activated microglia/macrophages. Neuroprotective effects of CAPE against LPS-induced injury was prevented by zinc protoporphyrin IX or anti-BDNF antibody. CAPE protected dopaminergic neurons and alleviated methamphetamine-induced rotational behaviour also in 6-hydroxydopamine hemiparkinsonian mice. CONCLUSION AND IMPLICATIONS: CAPE is a novel type of neuroprotective agent whose actions are mediated by both HO-1 and BDNF. These findings may provide novel clues to develop neuroprotective agents for treatment of neurodegenerative disorders. PMID- 22224488 TI - Management of pediatric psoriasis. PMID- 22224489 TI - Bright futures and NHLBI integrated pediatric cardiovascular health guidelines. PMID- 22224491 TI - Skin fragility and blistering secondary to imatinib. PMID- 22224492 TI - Accumulation mechanism of gamma-aminobutyric acid in tomatoes (Solanum lycopersicum L.) under low O2 with and without CO2. AB - The storage of ripe tomatoes in low-O(2) conditions with and without CO(2) promotes gamma-aminobutyric acid (GABA) accumulation. The activities of glutamate decarboxylase (GAD) and alpha-ketoglutarate-dependent GABA transaminase (GABA-TK) were higher and lower, respectively, following storage under hypoxic (2.4 or 3.5% O(2)) or adjusted aerobic (11% O(2)) conditions compared to the activities in air for 7 days at 25 degrees C. GAD activity was consistent with the expression level of mRNA for GAD. The GABA concentration in tomatoes stored under hypoxic conditions and adjusted aerobic conditions was 60-90% higher than that when they are stored in air on the same day. These results demonstrate that upregulation of GAD activity and downregulation of GABA-TK activity cause GABA accumulation in tomatoes stored under low-O(2) conditions. Meanwhile, the effect of CO(2) on GABA accumulation is probably minimal. PMID- 22224493 TI - Anthocyanin-rich acai (Euterpe oleracea Mart.) fruit pulp fractions attenuate inflammatory stress signaling in mouse brain BV-2 microglial cells. AB - Age-related diseases of the brain compromise memory, learning, and movement and are directly linked with increases in oxidative stress and inflammation. Previous research has shown that supplementation with berries can modulate signaling in primary hippocampal neurons or BV-2 mouse microglial cells. Because of their high polyphenolic content, fruit pulp fractions of acai ( Euterpe oleracea Mart.) were explored for their protective effect on BV-2 mouse microglial cells. Freeze dried acai pulp was fractionated using solvents with different polarities and analyzed using HPLC for major anthocyanins and other phenolics. Fractions extracted using methanol (MEOH) and ethanol (ETOH) were particularly rich in anthocyanins such as cyanidin, delphinidin, malvidin, pelargonidin, and peonidin, whereas the fraction extracted using acetone (ACE) was rich in other phenolics such as catechin, ferulic acid, quercetin, resveratrol, and synergic and vanillic acids. Studies were conducted to investigate the mitigating effects of acai pulp extracts on lipopolysaccharide (LPS, 100 ng/mL) induced oxidative stress and inflammation; treatment of BV-2 cells with acai fractions resulted in significant (p < 0.05) decreases in nitrite production, accompanied by a reduction in inducible nitric oxide synthase (iNOS) expression. The inhibition pattern was emulated with the ferulic acid content among the fractions. The protection of microglial cells by acai pulp extracts, particularly that of MEOH, ETOH, and ACE fractions, was also accompanied by a significant concentration-dependent reduction in cyclooxygenase-2 (COX-2), p38 mitogen-activated protein kinase (p38 MAPK), tumor necrosis factor-alpha (TNFalpha), and nuclear factor kappaB (NF kappaB). The current study offers valuable insights into the protective effects of acai pulp fractions on brain cells, which could have implications for improved cognitive and motor functions. PMID- 22224496 TI - Electronic properties of nanodiamond decorated graphene. AB - The electronic properties of graphene sheets decorated with nanodiamond (ND) particles have been investigated. The chemical fusion of ND to the graphene lattice creates pockets of local defects with robust interfacial bonding. At the ND-bonded regions, the atoms of graphene lattice follow sp(3)-like bonding, and such regions play the role of conduction bottlenecks for the percolating sp(2) graphene network. The low-temperature charge transport reveals an insulating behavior for the disordered system associated with Anderson localization for the charge carriers in graphene. A large negative magnetoresistance is observed in this insulating regime, and its origin is discussed in the context of magnetic correlations of the localized charge carriers with local magnetic domains and extrinsic metal impurities associated with the ND. PMID- 22224495 TI - Foraging range of honey bees, Apis mellifera, in alfalfa seed production fields. AB - A study was conducted in 2006 and 2007 designed to examine the foraging range of honey bees, Apis mellifera (Hymenoptera: Apidae), in a 15.2 km(2) area dominated by a 128.9 ha glyphosate-resistant Roundup Ready(r) alfalfa seed production field and several non-Roundup Ready alfalfa seed production fields (totaling 120.2 ha). Each year, honey bee self-marking devices were placed on 112 selected honey bee colonies originating from nine different apiary locations. The foraging bees exiting each apiary location were uniquely marked so that the apiary of origin and the distance traveled by the marked (field-collected) bees into each of the alfalfa fields could be pinpointed. Honey bee self-marking devices were installed on 14.4 and 11.2% of the total hives located within the research area in 2006 and 2007, respectively. The frequency of field-collected bees possessing a distinct mark was similar, averaging 14.0% in 2006 and 12.6% in 2007. A grand total of 12,266 bees were collected from the various alfalfa fields on seven sampling dates over the course of the study. The distances traveled by marked bees ranged from a minimum of 45 m to a maximum of 5983 m. On average, marked bees were recovered ~ 800 m from their apiary of origin and the recovery rate of marked bees decreased exponentially as the distance from the apiary of origin increased. Ultimately, these data will be used to identify the extent of pollen-mediated gene flow from Roundup Ready to conventional alfalfa. PMID- 22224497 TI - Prolonged-release oxycodone/naloxone in the treatment of neuropathic pain - results from a large observational study. AB - OBJECTIVES: Opioids have shown consistent efficacy in neuropathic pain, but opioid-induced bowel dysfunction is a relevant problem. In controlled clinical trials, a fixed-dose combination of prolonged-release (PR) oxycodone/PR naloxone was superior to oxycodone alone in bowel function, while providing effective analgesia. The present report is an analysis of its efficacy and safety in a subgroup of patients with severe chronic neuropathic pain who were treated in a large observational study under real-life conditions. RESEARCH DESIGN AND METHODS: Dosed according to pain severity, 1488 patients with chronic severe neuropathic pain received PR oxycodone/PR naloxone for up to 4 weeks. Variables included pain severity, patient-reported bowel function (Bowel Function Index; BFI) and quality of life. RESULTS: During treatment with PR oxycodone/PR naloxone, mean pain intensity decreased in opioid-naive and opioid-pretreated patients. After 4 weeks on treatment, mean BFI scores were reduced from 41.6 +/- 31.6 at the initiation visit to 16.5 +/- 19.6 (p < 0.001), reflecting normal bowel function. Quality of life was improved by 47%. CONCLUSIONS: Treatment of severe neuropathic pain with PR oxycodone/PR naloxone provided effective analgesia with the added benefit of favorable effects on bowel function and quality of life. PMID- 22224499 TI - False prolongation of the activated partial thromboplastin time (aPTT) in inflammatory patients: interference of C-reactive protein. PMID- 22224501 TI - In silico toxicity prediction by support vector machine and SMILES representation based string kernel. AB - There is a great need to assess the harmful effects or toxicities of chemicals to which man is exposed. In the present paper, the simplified molecular input line entry specification (SMILES) representation-based string kernel, together with the state-of-the-art support vector machine (SVM) algorithm, were used to classify the toxicity of chemicals from the US Environmental Protection Agency Distributed Structure-Searchable Toxicity (DSSTox) database network. In this method, the molecular structure can be directly encoded by a series of SMILES substrings that represent the presence of some chemical elements and different kinds of chemical bonds (double, triple and stereochemistry) in the molecules. Thus, SMILES string kernel can accurately and directly measure the similarities of molecules by a series of local information hidden in the molecules. Two model validation approaches, five-fold cross-validation and independent validation set, were used for assessing the predictive capability of our developed models. The results obtained indicate that SVM based on the SMILES string kernel can be regarded as a very promising and alternative modelling approach for potential toxicity prediction of chemicals. PMID- 22224500 TI - Environmental DNA-encoded antibiotics fasamycins A and B inhibit FabF in type II fatty acid biosynthesis. AB - In a recent study of polyketide biosynthetic gene clusters cloned directly from soil, we isolated two antibiotics, fasamycins A and B, which showed activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. To identify the target of the fasamycins, mutants with elevated fasamycin A minimum inhibitory concentrations were selected from a wild type culture of E. faecalis OG1RF. Next-generation sequencing of these mutants, in conjunction with in vitro biochemical assays, showed that the fasamycins inhibit FabF of type II fatty acid biosynthesis (FASII). Candidate gene overexpression studies also showed that fasamycin resistance is conferred by fabF overexpression. On the basis of comparisons with known FASII inhibitors and in silico docking studies, the chloro-gem-dimethyl-anthracenone substructure seen in the fasamycins is predicted to represent a naturally occurring FabF-specific antibiotic pharmacophore. Optimization of this pharmacophore should yield FabF specific antibiotics with increased potencies and differing spectra of activity. This study demonstrates that culture-independent antibiotic discovery methods have the potential to provide access to novel metabolites with modes of action that differ from those of antibiotics currently in clinical use. PMID- 22224502 TI - Comparative analysis of cyanobacteria in the rhizosphere and as endosymbionts of cycads in drought-affected soils. AB - Does the diversity of cyanobacteria in the cycad rhizosphere relate to the cyanobiont species found in the coralloid roots of these ancient plants? The aim of this study was to identify the diversity of soil cyanobacteria occurring in the immediate vicinity of 22 colonized coralloid roots belonging to members of the cycad genera: Macrozamia, Lepidozamia, Bowenia and Cycas. The majority of coralloid roots were sampled at depths > 10 cm below the soil surface. A total of 32 cyanobacterial isolates were cultured and their 16S rRNA gene partially sequenced. Phylogenetic analysis revealed nine operational taxonomic units of soil cyanobacteria comprising 30 Nostoc spp., a Tolypothrix sp. and a Leptolyngbya sp. Microscopy indicated that all isolates were unialgal and confirmed their genus identity. Rhizospheric diversity was compared to existing data on cyanobionts isolated at the same time from the cycad coralloid root. The same isolate was present in both the cycad coralloid root and rhizosphere at only six sites. Phylogenetic evidence indicates that most rhizosphere isolates were distinct from root cyanobionts. This weak relationship between the soil cyanobacteria and cycad cyanobionts might indicate that changes in the soil community composition are due to environmental factors. PMID- 22224503 TI - Balancing the pharmacokinetics and pharmacodynamics of interferon-alpha2b and human serum albumin fusion protein by proteolytic or reductive cleavage increases its in vivo therapeutic efficacy. AB - Human serum albumin (HSA) fusion (Albufusion) technology has evolved to be a general strategy to increase the in vivo half-lives of therapeutic proteins. However, because of the steric hindrance effect of HSA, conventional Albufusion technology improves the pharmacokinetics (PK) at the cost of pharmacodynamics (PD). To achieve balanced PK and PD of interferon-alpha2b (IFN-alpha2b) and HSA fusion protein, protease cleavage sites or disulfide linkage that enabled releasing of intact IFN-alpha2b with full activity was introduced between these two moieties. Nonreleasable and releasable fusion proteins showed similar cell surface receptor binding affinities; however, releasable fusion proteins exhibited release efficiency proportional increase of in vitro antiviral and antiproliferative activities. The release rate also had a profound impact on the in vivo pharmaceutical properties of fusion proteins. Releasable fusion proteins with intermediate release rate had the most balanced PK and PD, which translated into improved therapeutic efficacy in the HT29 human colon cancer xenograft model. Releasable Albufusion (rAlbufusion) allows tailored design of the PK/PD profile and greatly extends the utility of conventional Albufusion technology. PMID- 22224504 TI - Risk factors for postoperative complications after fast-track abdominal hysterectomy. AB - BACKGROUND: Fast-track regimen has been shown to reduce postoperative complications in gastrointestinal surgery. AIMS: We investigated the incidence and type of postoperative complications and associated risk factors after benign abdominal hysterectomy undertaken in a fast-track program. METHODS: A prospective longitudinal cohort study. In five Swedish hospitals, a cohort of 162 women, ASA 1-2, undergoing abdominal hysterectomy in a fast-track program was prospectively studied. Surgery was performed under spinal or general anaesthesia. The fast track concept was standardised with discharge criteria and a restricted intravenous fluid regimen. Complications were systematically registered during the five-week follow-up period. Risk factors for complications were analysed using multiple logistic regression models. RESULTS: Forty-one (25.3%) developed postoperative complications, mainly infection and wound healing complications. The majority of the complications developed after discharge and were treated in the outpatient clinics. Four women (2.5%) were readmitted to hospital. Substantial risk factors for postoperative complications were obesity (OR 8.83), prior laparotomy (OR 2.92) and relative increase in body weight on the first postoperative day (OR 1.52). CONCLUSIONS: Minor infection and wound healing complications seem to be common in healthy women undergoing abdominal hysterectomy in a fast-track program. Obesity is an important risk factor also in fast-track abdominal hysterectomy. A modest increase in postoperative relative weight gain during the first postoperative day seemed to increase the risk of postoperative complications. This factor merits further study. Randomised studies are necessary to determine the impact of fast-track program and perioperative fluid regimens on postoperative complications. PMID- 22224505 TI - Fully delocalized (ethynyl)(vinyl)phenylene bridged triruthenium complexes in up to five different oxidation states. AB - Triruthenium [(dppe)(2)Ru{-C=C-1,4-C(6)H(2)-2,5-R(2)-CH?CH RuCl(CO)(P(i)Pr(3))(2)}(2)](n+) (4a, R = H; 4b, R = OMe) containing unsymmetrical (ethynyl)(vinyl)phenylene bridging ligands and displaying five well-separated redox states (n = 0-4) are compared to their bis(alkynyl)ruthenium precursors (dppe)(2)Ru{-C=C-1,4-C(6)H(2)-2,5-R(2)-C=CR'} (2a,b: R' = TMS; 3a,b: R' = H) and their symmetrically substituted bimetallic congeners, complexes {Cl(dppe)(2)Ru}(2){MU-C=C-1,4-C(6)H(2)-2,5-R(2)-C=C} (A(a), R = H; A(b), R = OMe) and {RuCl(CO)(P(i)Pr(3))(2)}(2){MU-CH?CH-1,4-C(6)H(2)-2,5-R(2)-CH?CH} (V(a), R = H; V(b), R = OMe) as well as the mixed (ethynyl)(vinyl)phenylene bridged [Cl(dppe)(2)Ru-C=C-1,4-C(6)H(4)-CH?CH-RuCl(CO)(P(i)Pr(3))(2)] (M(a)). Successive one-electron transfer steps were studied by means of cyclic voltammetry, EPR and UV-vis-NIR-IR spectroelectrochemistry. These studies show that the first oxidation mainly involves the central bis(alkynyl) ruthenium moiety with only limited effects on the appended vinyl ruthenium moieties. The second to fourth oxidations (n = 2, 3, 4) involve the entire carbon-rich conjugated path of the molecule with an increased charge uniformly distributed between the two arms of the molecules, including the terminal vinyl ruthenium sites. In order to assess the charge distribution, we judiciously use (13)CO labeled analogues to distinguish stretching vibrations due to the acetylide triple bonds and the intense and charge-sensitive Ru(CO) IR probe in different oxidation states. The comparison between complex pairs 4a,b(n+) (n = 0-3), A(a,b)(n+) and V(a,b)(n+) (n = 0-2) serves to elucidate the effect of the methoxy donor substituents on the redox and spectroscopic properties of these systems in their various oxidation states and on the metal/ligand contributions to their frontier orbitals. PMID- 22224506 TI - Phytochelatin synthase: of a protease a peptide polymerase made. AB - Of the mechanisms known to protect vascular plants and some algae, fungi and invertebrates from the toxic effects of non-essential heavy metals such as As, Cd or Hg, one of the most sophisticated is the enzyme-catalyzed synthesis of phytochelatins (PCs). PCs, (gamma-Glu-Cys)(n) Gly polymers, which serve as high affinity, thiol-rich cellular chelators and contribute to the detoxification of heavy metal ions, are derived from glutathione (GSH; gamma-Glu-Cys-Gly) and related thiols in a reaction catalyzed by phytochelatin synthases (PC synthases, EC 2.3.2.15). Using the enzyme from Arabidopsis thaliana (AtPCS1) as a model, the reasoning and experiments behind the conclusion that PC synthases are novel papain-like Cys protease superfamily members are presented. The status of S substituted GSH derivatives as generic PC synthase substrates and the sufficiency of the N-terminal domain of the enzyme from eukaryotic and its half-size equivalents from prokaryotic sources, for net PC synthesis and deglycylation of GSH and its derivatives, respectively, are emphasized. The question of the common need or needs met by PC synthases and their homologs is discussed. Of the schemes proposed to account for the combined protease and peptide polymerase capabilities of the eukaryotic enzymes vs the limited protease capabilities of the prokaryotic enzymes, two that will be considered are the storage and homeostasis of essential heavy metals in eukaryotes and the metabolism of S-substituted GSH derivatives in both eukaryotes and prokaryotes. PMID- 22224507 TI - Breastfeeding attitudes among couples planning exclusive breastfeeding or mixed feeding. AB - OBJECTIVES: The goals of the study were to describe maternal and paternal attitudes toward breastfeeding among couples planning exclusive breastfeeding and those planning mixed feeding and to compare maternal predictions of paternal attitudes with actual paternal attitudes. METHODS: Expectant parents with the intention to breastfeed were recruited from outpatient clinics. During the third trimester of pregnancy, mothers and fathers independently completed a demographic questionnaire and a breastfeeding attitude survey. In addition, mothers were asked to predict fathers' attitudes. RESULTS: Seventy-one subjects completed all study requirements: 56 planned to exclusively breastfeed, and 15 planned to mix feed. The majority of subjects were white, educated beyond high school, and married. Expectant parents planning to exclusively breastfeed were significantly more likely to report higher paternal age (p=0.019), higher maternal age (p=0.006), and higher maternal education (p=0.023) than those planning to mix feed. Among fathers, those planning exclusive breastfeeding expressed more favorable attitudes related to naturalness (p=0.009) and closeness (p=0.036) than their mixed-feeding peers. Compared with mothers planning mixed feeding, those planning exclusive breastfeeding indicated more favorable attitudes related to naturalness (p=0.006) and respect for breastfeeding women (p=0.005). Overall, mothers reported more favorable attitudes toward breastfeeding than fathers in several areas, including disease protection (p=0.004), respect for breastfeeding women (p=0.043), and naturalness (p=0.011). The mother's predictions were less favorable than the father's actual attitudes in the areas of purpose of breasts (p=0.007), respect (p=0.049), and closeness (p=0.024). CONCLUSIONS: Results suggest expectant parents who plan to mix feed may be fundamentally different from those planning to exclusively breastfeed. There is a continued need to identify factors that influence the prenatal decision to mix feed and to develop strategies that promote exclusive breastfeeding in this population. PMID- 22224508 TI - Management of deficient lactation in Switzerland and Canada: a survey of midwives' current practices. PMID- 22224509 TI - Normative data in women aged 85 and older: verbal fluency, digit span, and the CVLT-II short form. AB - Individuals aged 85 years and above (i.e., the oldest old) represent the fastest growing segment of the US population and are at increased risk of developing dementia. This represents an important challenge for the clinical neuropsychologist, as the extant normative data on neuropsychological measures remain relatively limited for this age group. Therefore the aim of the present study was to characterize the performance effects of age and education in a large, well-characterized sample of women between the ages of 85 and 95 years on the California Verbal Learning Test-II (CVLT-II) Short Form (Delis, Kramer, Kaplan, & Ober, 2000), verbal fluency tasks, and the WAIS-III Digit Span Test (Wechsler, 1997 ). In order to minimize the likelihood that women with an incipient neurodegenerative process were included in the final normative sample, we applied regression-based change scores to identify and exclude women who evidenced a statistically significant decline on a global cognitive screening measure over a 20-year interval. The results of our analysis indicate varying influence of age and education on these measures and we provide tables with descriptive statistics stratified by both age and education. Findings from the present normative study are discussed within the context of "robust" longitudinal normative data. PMID- 22224510 TI - Model study of the enzymatic modification of natural extracts: peroxidase-based removal of eugenol from rose essential oil. AB - A protocol based on the use of horseradish peroxidase (HRP) is proposed for the removal of allergenic eugenol from rose essential oil without loss of the organoleptic quality and with a good conservation of the chemical composition. For the first time, an enzyme-based strategy is proposed for essential oils treatment and opens new opportunities in the detoxification of natural extracts used in perfumery and cosmetics. Our results on eugenol in rose essential oil constitute a first step toward the development of efficient and mild processes for the removal of more toxic compounds of natural extracts. PMID- 22224541 TI - Characterization of degradable polyelectrolyte multilayers fabricated using DNA and a fluorescently-labeled poly(beta-amino ester): shedding light on the role of the cationic polymer in promoting surface-mediated gene delivery. AB - Polyelectrolyte multilayers (PEMs) fabricated from cationic polymers and DNA have been investigated broadly as materials for surface-mediated DNA delivery. One attractive aspect of this "multilayered" approach is the potential to exploit the presence of cationic polymer "layers" in these films to deliver DNA to cells more effectively. Past studies demonstrate that these films can promote transgene expression in vitro and in vivo, but significant questions remain regarding roles that the cationic polymers could play in promoting the internalization and processing of DNA. Here, we report physicochemical and in vitro cell-based characterization of DNA-containing PEMs fabricated using fluorescently end labeled derivatives of a degradable polycation (polymer 1) used in past studies of surface-mediated transfection. This approach permitted simultaneous characterization of polymer and DNA in solution and in cells using fluorescence based techniques, and provided information about the locations and behaviors of polymer 1 that could not be obtained using other methods. LSCM and flow cytometry experiments revealed that polymer 1 and DNA released from film-coated objects were both internalized extensively by cells and that they were colocalized to a significant extent inside cells (e.g., ~58% of DNA was colocalized with polymer). Fluorescence anisotropy measurements of solutions containing partially eroded films were also consistent with the presence of aggregates of polymer 1 and DNA in solution (e.g., after release from surfaces, but prior to internalization by cells). Our results support the view that polymer 1, which is incorporated into these materials as "layers" rather than as part of optimized, preformed "polyplexes", can act to promote or enhance surface-mediated DNA delivery. More broadly, our results suggest opportunities to improve the delivery properties of DNA-containing PEMs by incorporation of additional "layers" of other conventional cationic polymers designed to address specific intracellular barriers to transfection, such as endosomal escape, more effectively. PMID- 22224542 TI - Justice sensitivity and forgiveness in close interpersonal relationships: the mediating role of mistrustful, legitimizing, and pro-relationship cognitions. AB - The purpose of the present investigation was to explore and better understand the relationship between justice sensitivity from a victim's perspective (JS-victim) and interpersonal forgiveness. In particular, we aimed to identify the cognitive mechanisms mediating this relationship and test the moderating influence of post transgression perpetrator behavior. We used data from a questionnaire study employing a Swiss community sample (N = 450) and 2 scenario-based studies employing German online samples, in the context of romantic (N = 242) and friendship relationships (N = 974). We consistently found JS-victim to be negatively related to dispositional (Study 1) and situational forgiveness (Studies 2 and 3). Study 2 demonstrated the relationship between JS-victim and reduced forgiveness to be partly mediated by mistrustful interpretations of the partner's post-transgression behavior. In Study 3, cognitions legitimizing one's own antisocial reactions and a lack of pro-relationship cognitions were identified as further mediators. These variables mediated the negative effect of JS-victim on forgiveness largely independent of whether the friend perpetrator displayed reconciliatory behavior or not. Findings suggest that the cognitive mechanisms mediating victim-sensitive individuals' unforgiveness could barely be neutralized. Future research should investigate their malleability in light of qualitatively different perpetrator behaviors as well as their broader relational implications. PMID- 22224543 TI - Oil powders and gels from particle-stabilized emulsions. AB - We report on the use of silica particle-stabilized oil-in-water emulsions as a template for the preparation of oil powders and gels obtained in a single step by either slow or rapid evaporation of water using freeze-drying or spray-drying, respectively. Using olive oil and partially hydrophobic fumed silica nanoparticles, an oil powder containing nearly 90 wt % oil can be formed by spray drying, which shows no sign of oil leakage over several months. Upon slow evaporation of water by freeze-drying, a transparent oil gel with oil content as high as 98 wt % can be formed, in which the silica particles form a space-filling network thickening the oil. Comparisons are made throughout with a typical surfactant-stabilized emulsion which does not produce oil powders or gels. PMID- 22224544 TI - Examination of parental effect on the progeny diapause by reciprocal cross test in the cabbage beetle, Colaphellus bowringi. AB - The cabbage beetle, Colaphellus bowringi Baly (Coleoptera: Chrysomelidae), a serious pest of crucifers in China, undergoes summer or winter diapause in the soil as an adult. In the present study, the incidence of diapause were measured in reciprocal crosses between a high-diapause strain (HD strain) and a laboratory selected nondiapausing strain (ND strain) under different photoperiods and temperatures, to explore parental influences on the progeny diapause. Sensitivity to photoperiod in the selected nondiapausing strain was nearly eliminated at 25 degrees C, whereas sensitivity to temperature of the selected nondiapausing strain was retained under continuous darkness at 20 and 22 degrees C. Reciprocal crosses between the HD strain and the ND strain showed that the incidence of diapause in the progeny was always intermediate to that of the parents under different photoperiods and temperatures, suggesting that diapause induction was determined by both female and male parents. There was a significant effect of temperature; temperature interacted with reciprocal cross on diapause induction, whereas no significant effect of reciprocal cross was demonstrated. The incidence of diapause in ?(ND) * ?(HD) was the same as in ?(HD) * ?(ND) under continuous darkness at 18 degrees C (100%) and 26 degrees C (0%), but the former was higher than that in ?(HD) * ?(ND) under continuous darkness at 22 degrees C, suggesting that female parent does not exhibit strong influence on the diapause response to temperature. There was a significant effect of photoperiod and reciprocal cross on diapause induction, whereas no significant interactive effect on diapause induction was demonstrated. Incidence of diapause in ?(HD) * ?(ND) was always higher than in ?(ND) * ?(HD) at 25 degrees C and 12:12 L:D, 14:10 L:D, and 16:8 L:D, suggesting a strong maternal influence on the diapause response to photoperiod, though a significant difference was observed only at 14:10 L:D. Our results support the idea that diapause induction is determined by both female and male parents. However, results also indicated that a strong maternal influence on diapause was exhibited only in response to photoperiod. PMID- 22224546 TI - Differential effects of grape ( Vitis vinifera ) skin polyphenolics on human platelet aggregation and low-density lipoprotein oxidation. AB - Antioxidant and antiplatelet properties of grape products are thought to be responsible for observed antiatherosclerotic effects. Diverse classes of phenolics are derived from the seed and skin (GSK) of grapes. The relative contributions of the classes of phenolics to observed properties of grape products are unknown. In this paper, GSK fractions were used to examine effects on platelet aggregation, low-density lipoprotein (LDL) oxidation in vitro, and relative binding of phenolics to LDL. GSK was separated into six fractions (fractions 1-6), and primary phenolics were characterized using high-performance liquid chromatography and matrix-assisted laser desorption/ionization time-of flight mass spectrometry. Fractions 4, 5, and 6, enriched in polygalloyl polyflavan-3-ols (PGPFs) with 3-6, 4-8, and 6-15 degrees of polymerization, respectively, inhibited platelet aggregation. Fractions 1-3, containing various amounts of oligosaccharides, hydroxycinnamic acids, anthocyanins, flavanols, and low molecular weight PGPFs, significantly increased platelet aggregation. Fractions 4-6 were most effective in binding LDL and inhibiting LDL oxidation. Fractions 5 and 6 exhibited the greatest inhibition of platelet aggregation and LDL oxidation, suggesting that polymeric PGPFs are responsible for the beneficial effects of grape products. Conversely, phenolics in fractions 1-3 may reduce the net biological potency of the grape products and have undesirable effects on cardiovascular disease risk factors. PMID- 22224547 TI - Infants' developing understanding of social gaze. AB - Young infants are sensitive to self-directed social actions, but do they appreciate the intentional, target-directed nature of such behaviors? The authors addressed this question by investigating infants' understanding of social gaze in third-party interactions (N = 104). Ten-month-old infants discriminated between 2 people in mutual versus averted gaze, and expected a person to look at her social partner during conversation. In contrast, 9-month-old infants showed neither ability, even when provided with information that highlighted the gazer's social goals. These results indicate considerable improvement in infants' abilities to analyze the social gaze of others toward the end of their 1st year, which may relate to their appreciation of gaze as both a social and goal-directed action. PMID- 22224549 TI - Facile ultrasonic synthesis of CoO quantum dot/graphene nanosheet composites with high lithium storage capacity. AB - In this paper, we report a facile ultrasonic method to synthesize well-dispersed CoO quantum dots (3-8 nm) on graphene nanosheets at room temperature by employing Co(4)(CO)(12) as cobalt precursor. The prepared CoO/graphene composites displayed high performance as an anode material for lithium-ion battery, such as high reversible lithium storage capacity (1592 mAh g(-1) after 50 cycles), high Coulombic efficiency (over 95%), excellent cycling stability, and high rate capability (1008 mAh g(-1) with a total retention of 77.6% after 50 cycles at a current density of 1000 mA g(-1), dramatically increased from the initial 50 mA g(-1)). The extraordinary performance arises from the structure advantages of the composites: the nanosized CoO quantum dots with high dispersity on conductive graphene substrates supply not only large quantity of accessible active sites for lithium-ion insertion but also good conductivity and short diffusion length for lithium ions, which are beneficial for high capacity and rate capability. Meanwhile, the isolated CoO quantum dots anchored tightly on the graphene nanosheets can effectively circumvent the volume expansion/contraction associated with lithium insertion/extraction during discharge/charge processes, which is good for high capacity as well as cycling stability. Moreover, regarding the anomalous behavior of capacity increase with cycles (activation effect) observed, we proposed a tentative hypothesis stressing the competition between the conductivity increase and the amorphorization of the composite electrodes during cycling in determining the trends of the capacity, in the hope to gain a fuller understanding of the inner working of the novel nanostructured electrode-based lithium-ion batteries. PMID- 22224548 TI - Osteoblastic/cementoblastic and neural differentiation of dental stem cells and their applications to tissue engineering and regenerative medicine. AB - Recently, dental stem and progenitor cells have been harvested from periodontal tissues such as dental pulp, periodontal ligament, follicle, and papilla. These cells have received extensive attention in the field of tissue engineering and regenerative medicine due to their accessibility and multilineage differentiation capacity. These dental stem and progenitor cells are known to be derived from ectomesenchymal origin formed during tooth development. A great deal of research has been accomplished for directing osteoblastic/cementoblastic differentiation and neural differentiation from dental stem cells. To differentiate dental stem cells for use in tissue engineering and regenerative medicine, there needs to be efficient in vitro differentiation toward the osteoblastic/cementoblastic and neural lineage with well-defined and proficient protocols. This would reduce the likelihood of spontaneous differentiation into divergent lineages and increase the available cell source. This review focuses on the multilineage differentiation capacity, especially into osteoblastic/cementoblastic lineage and neural lineages, of dental stem cells such as dental pulp stem cells (DPSC), dental follicle stem cells (DFSC), periodontal ligament stem cells (PDLSC), and dental papilla stem cells (DPPSC). It also covers various experimental strategies that could be used to direct lineage-specific differentiation, and their potential applications in tissue engineering and regenerative medicine. PMID- 22224550 TI - Endogenous enzymes, heat, and pH affect flavone profiles in parsley (Petroselinum crispum var. neapolitanum) and celery (Apium graveolens) during juice processing. AB - Flavones are abundant in parsley and celery and possess unique anti-inflammatory properties in vitro and in animal models. However, their bioavailability and bioactivity depend in part on the conjugation of sugars and other functional groups to the flavone core. The effects of juice extraction, acidification, thermal processing, and endogenous enzymes on flavone glycoside profile and concentration in both parsley and celery were investigated. Parsley yielded 72% juice with 64% of the total flavones extracted, whereas celery yielded 79% juice with 56% of flavones extracted. Fresh parsley juice averaged 281 mg flavones/100 g and fresh celery juice, 28.5 mg/100 g. Flavones in steamed parsley and celery were predominantly malonyl apiosylglucoside conjugates, whereas those in fresh samples were primarily apiosylglucoside conjugates; this was apparently the result of endogenous malonyl esterases. Acidification and thermal processing of celery converted flavone apiosylglucosides to flavone glucosides, which may affect the intestinal absorption and metabolism of these compounds. PMID- 22224552 TI - The early settlers: intestinal microbiology in early life. AB - The human intestinal microbiota forms an integral part of normal human physiology, and disturbances of the normal gut microbiology have been implicated in many health and disease issues. Because newborns are essentially sterile, their microbiota must establish and develop from the very first days of life. The first colonizers play an important role in the development of the ecosystem and may impact the long-term composition and activity of the microbiota. These first settlers obviously develop and proliferate dependent on host characteristics and diet, but other factors can also significantly contribute to this vital biological process. Considering the importance of the microbiota for the human immune, metabolic, and neurological systems, it is important to understand the dynamics and driving determinants of this development. This review gives a global overview of our current understanding of the different factors impacting the intestinal microbiology in early life. PMID- 22224551 TI - Non-caloric sweeteners, sweetness modulators, and sweetener enhancers. AB - For a new sweetness technology to realize strong commercial success, it must be safe, exhibit good taste quality, be sufficiently soluble and stable in food and beverage systems, and be cost effective and patentable. Assessments of the commercial promise of eight synthetic and eight natural non-caloric sweeteners are made relevant to these metrics. High-potency (HP) non-caloric sweeteners, both synthetic and natural, are generally limited in taste quality by (a) low maximal sweetness response, (b) "off" tastes, (c) slow-onset sweet tastes that linger, and (d) sweet tastes that adapt or desensitize the gustatory system. Formulation approaches to address these limitations are discussed. Enhancement of the normal sucrose sensory response by action of a sweetener receptor positive allosteric modulator (PAM) has been achieved with very significant calorie reduction and with retention of the taste quality of sucrose. Research on PAM discovery over the past decade is summarized. PMID- 22224554 TI - Health claims in Europe: probiotics and prebiotics as case examples. AB - Health claims regarding foods imply a relationship between a specific food and maintenance of good health, or that food can reduce the risk of disease. Health claim legislation in the European Union sets out from the concept of consumer protection. Health claim assessment focuses on defining given foods, assessing their health relationship, and evaluating relevant studies with an emphasis on controlled human intervention research. Challenges include the focus of claims on healthy populations, although most intervention studies have been conducted among patients. A further problem attends the risk reduction claim, which requires changes in generally accepted biomarkers reflecting the risk of disease. Scientific assessment and guidance documents direct the development of health claims both in Europe and elsewhere. Experience from completed assessments should make it possible to provide consumers with reliable claims to help them make healthier choices and develop lifestyles supporting long-term well-being. PMID- 22224553 TI - Biochemical basis for functional ingredient design from fruits. AB - Functional food ingredients (nutraceuticals) in fruits range from small molecular components, such as the secondary plant products, to macromolecular entities, e.g., pectin and cellulose, that provide several health benefits. In fruits, the most visible functional ingredients are the color components anthocyanins and carotenoids. In addition, several other secondary plant products, including terpenes, show health beneficial activities. A common feature of several functional ingredients is their antioxidant function. For example, reactive oxygen species (ROS) can be oxidized and stabilized by flavonoid components, and the flavonoid radical can undergo electron rearrangement stabilizing the flavonoid radical. Compounds that possess an orthodihydroxy or quinone structure can interact with cellular proteins in the Keap1/Nrf2/ARE pathway to activate the gene transcription of antioxidant enzymes. Carotenoids and flavonoids can also exert their action by modulating the signal transduction and gene expression within the cell. Recent results suggest that these activities are primarily responsible for the health benefits associated with the consumption of fruits and vegetables. PMID- 22224555 TI - Challenges for the delivery of long-chain n-3 fatty acids in functional foods. AB - Extensive research has shown that increased consumption of long-chain omega-3 polyunsaturated fatty acids (n-3 LCPUFAs), namely alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), may lower the risk of chronic diseases, such as heart disease, cancer, and arthritis. Given that Western diets are deficient in n-3 LCPUFAs, enrichment of food products is seen as an alternative for increasing the intake of these fatty acids. However, because of the high instability of these fatty acids to oxidative deterioration, enrichment of foods with n-3 LCPUFAs has been technically challenging. This review provides an overview of different technical approaches that have been taken to overcome oxidation-related problems. This review also looks at the challenges faced by health organizations, food manufacturers, and food scientists for the delivery of long-chain n-3 fatty acids in functional foods. PMID- 22224556 TI - CRISPR: new horizons in phage resistance and strain identification. AB - Bacteria have been widely used as starter cultures in the food industry, notably for the fermentation of milk into dairy products such as cheese and yogurt. Lactic acid bacteria used in food manufacturing, such as lactobacilli, lactococci, streptococci, Leuconostoc, pediococci, and bifidobacteria, are selectively formulated based on functional characteristics that provide idiosyncratic flavor and texture attributes, as well as their ability to withstand processing and manufacturing conditions. Unfortunately, given frequent viral exposure in industrial environments, starter culture selection and development rely on defense systems that provide resistance against bacteriophage predation, including restriction-modification, abortive infection, and recently discovered CRISPRs (clustered regularly interspaced short palindromic repeats). CRISPRs, together with CRISPR-associated genes (cas), form the CRISPR/Cas immune system, which provides adaptive immunity against phages and invasive genetic elements. The immunization process is based on the incorporation of short DNA sequences from virulent phages into the CRISPR locus. Subsequently, CRISPR transcripts are processed into small interfering RNAs that guide a multifunctional protein complex to recognize and cleave matching foreign DNA. Hypervariable CRISPR loci provide insights into the phage and host population dynamics, and new avenues for enhanced phage resistance and genetic typing and tagging of industrial strains. PMID- 22224557 TI - Wheat gluten functionality as a quality determinant in cereal-based food products. AB - The unique properties of wheat reside primarily in its gluten-forming storage proteins. Their intrinsic viscoelastic behavior is responsible for the characteristics of different wheat-based foods and for the use of wheat gluten proteins in different food products. Wheat-based food processing generally develops and sets the gluten protein network. Heat-induced gluten aggregation proceeds through cross-linking within and between its protein fractions. Prominent reactions include sulfhydryl (SH) oxidation and SH-disulfide (SS) interchange, which lead to SS cross-links. Other covalent bonds are also formed. Gluten functionality can be (bio-) chemically impacted. We focus on bread making, in which gluten proteins contribute to dough properties, bread loaf volume, and structure, and on pasta production, in which gluten proteins generate the desired cooking quality. Furthermore, it is speculated that the structure and texture of soft wheat products are also, at least to some degree, shaped by the heat-induced changes in the gluten protein fraction. PMID- 22224559 TI - Allele and genotype frequencies of CYP3A4, CYP2C19, and CYP2D6 in Han, Uighur, Hui, and Mongolian Chinese populations. AB - PURPOSE: This study was carried out to estimate the allele and genotype frequencies of common variants in the CYP3A4, CYP2C19, and CYP2D6 in the Han, Uighur, Hui, and Mongolian Chinese populations and compare genetic polymorphisms difference between the Han and minority Chinese ethnicities. METHODS: We evaluated 672 unrelated, healthy Chinese volunteers (Han: 136; Uighur: 214; Hui: 164; Mongolian: 158). Genomic DNA was extracted from peripheral leukocytes and genotyped for CYP3A4*18, CYP2C19*2, *3, and CYP2D6*10 by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The allele frequencies of CYP3A4*18 in the Han, Uighur, Hui, and Mongolian Chinese population were 18.4%, 14.0%, 19.2%, and 20.3%, respectively; the allele frequencies of CYP2C19*2 were 38.6%, 32.5%, 49.4%, and 41.5%, respectively; the allele frequencies of CYP2C19*3 were 5.2%, 2.1%, 5.2%, and 4.4%, respectively; and the allele frequencies of CYP2D6*10 were 57.4%, 22.4%, 39.7%, and 46.5%, respectively. CONCLUSION: The results showed that there was no significant ethnic difference in the distribution of CYP3A4*18 and CYP2C19*3 genotypes in the Han, Uighur, Hui, and Mongolian Chinese populations. For CYP2C19*2, the Han were not significantly different from the Uighur, Hui, or Mongolian; however, the Uighur were significantly lower than the Hui and the Mongolian, and the Mongolian were significantly lower than the Hui. For CYP2D6*10, the Mongolian were not significantly different from the Han and the Hui. However, the Uighur were significantly lower than the other three. Our findings confirm the existence of interethnic differences in the CYP2C9, CYP2C19, and CYP2D6 alleles and genotype frequencies in the Han, Uighur, Hui, and Mongolian Chinese populations. PMID- 22224560 TI - The Online Parent Information and Support project, meeting parents' information and support needs for home-based management of childhood chronic kidney disease: research protocol. AB - AIM: This article is a report of a protocol for studying the development and evaluation of an online parent information and support package for home-based care of children with chronic kidney disease stages 3-5. The study is funded by a National Institute of Health Research, Research for Patient Benefit Grant awarded (December 2010). Approval to undetake the study was obtained from the Department of Health National Research Ethics Service (June 2011). BACKGROUND: Children with chronic kidney disease require skilled, home-based care by parents, supported by professionals. Parents have identified a need for continuously available online resources to supplement professional support, and structured resources tailored to parents' needs are highlighted by policy makers as key to optimizing care; yet, online resource provision is patchy with little evidence base. METHODS: Using mixed methods, we will (i) conduct parent/child/young person/professional/patient and parent volunteer focus groups to explore views on existing resources, (ii) collaboratively define gaps in provision, identify desirable components, develop/test resources and conduct a feasibility randomized controlled trial, and (iii) of usual professional support versus usual support supplemented by the package. Eighty parents of children with chronic kidney disease will be randomized. Primary outcomes will assess parents' self-efficacy and views of resources, using standardized measures at entry and 24 weeks, and semi-structured interviews at 24 weeks. We will finalize trial components for a later definitive trial. DISCUSSION: By working collaboratively, we will derive a detailed insight into parents' information and support needs and experiences of using the package, and should see improved parental self-efficacy. PMID- 22224561 TI - Improving survival in patients with transformed B cell non Hodgkin lymphoma: consolidation with 90Yttrium ibritumomab tiuxetan-BEAM and autologous stem cell transplantation. PMID- 22224562 TI - Molecular determinants of AcrB-mediated bacterial efflux implications for drug discovery. PMID- 22224563 TI - Microbial diversity of eolian dust sources from saline lake sediments and biological soil crusts in arid Southern Australia. AB - While microbial communities of aerosols have been examined, little is known about their sources. Nutrient composition and microbial communities of potential dust sources, saline lake sediments (SLS) and adjacent biological soil crusts (BSC), from Southern Australia were determined and compared with a previously analyzed dust sample. Multivariate analyses of fingerprinting profiles indicated that the bacterial communities of SLS and BSC were different, and these differences were mainly explained by salinity. Nutrient concentrations varied among the sites but could not explain the differences in microbial diversity patterns. Comparison of microbial communities with dust samples showed that deflation selects against filamentous cyanobacteria, such as the Nostocales group. This could be attributed to the firm attachment of cyanobacterial filaments to soil particles and/or because deflation occurs mainly in disturbed BSC, where cyanobacterial diversity is often low. Other bacterial groups, such as Actinobacteria and the spore forming Firmicutes, were found in both dust and its sources. While Firmicutes related sequences were mostly detected in the SLS bacterial communities (10% of total sequences), the actinobacterial sequences were retrieved from both (11 13%). In conclusion, the potential dust sources examined here show highly diverse bacterial communities and contain nutrients that can be transported with aerosols. The obtained fingerprinting and sequencing data may enable back tracking of dust plumes and their microorganisms. PMID- 22224564 TI - The fires of life. AB - This retrospective recounts the hunt for the mechanism of mitochondrial ATP synthesis, the early days of research on mitochondrial formation, and some of the colorful personalities dominating these often dramatic and emotional efforts. The narrative is set against the backdrop of postwar Austria and Germany and the stream of young scientists who had to leave their countries to receive postdoctoral training abroad. Many of them--including the author--chose the laboratory of a scientist their country had expelled a few decades before. The article concludes with some thoughts on the uniqueness of U.S. research universities and a brief account of the struggles to revive science in Europe. PMID- 22224578 TI - Extracranial and intracranial complications of otitis media: 22-year clinical experience and analysis. AB - CONCLUSION: The morbidity of the complications has had a decreased tendency in recent decades, but the category of the complications was rather diverse. There are still many serious complications that require our attention. Surgery is still the most important treatment option. OBJECTIVE: To investigate otogenic extracranial and intracranial complications in patients with acute and chronic otitis media. METHODS: A retrospective study investigated 285 patients with extracranial and intracranial complications among the 2346 inpatients with acute or chronic otitis media with or without cholesteatoma admitted to the Department of Otolaryngology, AnHui Medical University Hospital between 1987 and 2008. RESULTS: In the 285 patients with cranial complications, 253 had a single complication, 29 had two complications, and 3 had more than two complications. Intracranial complications included meningitis (16 cases), brain abscess (42 cases), sigmoid sinus involvement (29 cases), extradural abscess (8 cases), subdural abscess (1 case), and hydrocephalus (2 cases). Extracranial complications included labyrinthitis (90 cases), mastoid abscess (79 cases), facial paralysis (47 cases), Bezold abscess (5 cases), and apicitis pyramidalis (1 case). In all, 267 patients were cured or improved without recurrence. Five patients died from complications, of whom four died of cerebral hernia and one died of multiple abscesses. PMID- 22224579 TI - Fruit ripening in Vitis vinifera: light intensity before and not during ripening determines the concentration of 2-methoxy-3-isobutylpyrazine in Cabernet Sauvignon berries. AB - The roles of light and temperature in the accumulation of the vegetal impact compound 2-methoxy-3-isobutylpyrazine (MIBP) in grape (Vitis vinifera L.) berries were determined. Individual clusters were exposed to various light intensities using neutral density shade cloth before ripening, during ripening or throughout the season in three growing seasons. A recently developed method using headspace solid-phase microextraction combined with GC-MS in the selected ion-monitoring mode was employed to measure MIBP in berries. Berry MIBP concentration increased subsequent to berry set, reached a maximum prior to onset of ripening, and then decreased thereafter until harvest. Complete shading of clusters increased the concentration of MIBP more than 100% compared to unshaded controls in 2 out of 3 years. Light increasingly inhibited MIBP concentrations up to 25-50% of ambient light intensities (1500 umol photons m(-2) s(-1) ). However, only changes in light intensity before ripening had any effect on MIBP accumulation or final MIBP concentration. Analyses of weather data showed that the 1 year in which shading was ineffective was unusually warm, warm early in the season, and had more hot days and higher early season degree days than the other 2 years. In controlled environment experiments, warm growth conditions reduced MIBP concentrations in fruit about as much as light exposure reduced MIBP concentrations in the field experiments. The results indicate that both light and temperature significantly affect MIBP in harvested fruit, but that the light environment during ripening does not significantly affect MIBP concentrations in the berries at harvest. PMID- 22224580 TI - Highly porous 4,8-connected metal-organic frameworks: synthesis, characterization, and hydrogen uptake. AB - A series of highly porous 4,8-connected isoreticular MOFs of the scu topology [Cu(4)(L(1))(H(2)O)(4)].20DEF, [Cu(4)(L(2))(H(2)O)(4)].16DMF.5H(2)O, and [Cu(4)(L(3))(H(2)O)(4)].14DMF (L(1)-L(3) are (R)-1,1'-binaphthyl-derived octacarboxylate bridging ligands) were synthesized and characterized by single crystal X-ray crystallography. Although the frameworks exhibit some distortion during the solvent removal process, the high-connectivity nature of the building blocks helps in stabilizing the frameworks, leading to high surface areas (S(BET) = 1189-2448 m(2)/g) and significant hydrogen uptake of up to 1.8 wt % (77 K, 1 atm). PMID- 22224582 TI - Electrical and thermal conduction in atomic layer deposition nanobridges down to 7 nm thickness. AB - While the literature is rich with data for the electrical behavior of nanotransistors based on semiconductor nanowires and carbon nanotubes, few data are available for ultrascaled metal interconnects that will be demanded by these devices. Atomic layer deposition (ALD), which uses a sequence of self-limiting surface reactions to achieve high-quality nanolayers, provides an unique opportunity to study the limits of electrical and thermal conduction in metal interconnects. This work measures and interprets the electrical and thermal conductivities of free-standing platinum films of thickness 7.3, 9.8, and 12.1 nm in the temperature range from 50 to 320 K. Conductivity data for the 7.3 nm bridge are reduced by 77.8% (electrical) and 66.3% (thermal) compared to bulk values due to electron scattering at material and grain boundaries. The measurement results indicate that the contribution of phonon conduction is significant in the total thermal conductivity of the ALD films. PMID- 22224584 TI - cDNA cloning and expression pattern of homolog of alpha subunit of platelet activating factor acetylhydrolase Ib from the Chinese oak silkworm, Antheraea pernyi. AB - Platelet-activating factor acetylhydrolase (PAF-AH) is an enzyme that catalyzes the hydrolysis of platelet-activating factor (PAF). A homolog of alpha subunit of PAF-AH(Ib) from Antheraea pernyi (Guerin-Meneville) (Lepidoptera: Saturniidae) (ApPAFAHIbalpha) was isolated and characterized. The obtained cDNA sequence was 1843 base pairs (bp) long with an open reading frame (ORE) of 678 bp encoding 225 amino acids. The predicted amino acid sequence shared several conserved features of PAF-AHs of other organisms, and revealed 88, 60, and 46% identity with the homologues of Bombyx mori, Drosophila melanogaster, and Homo sapiens, respectively. Phylogenetic analysis indicated that lepidopteran PAFAHIbalphas including ApPAFAHIbalpha might be a new member of the PAF-AHs family of insects. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed that the ApPAFAHIbalpha gene was transcribed at four developmental stages and expressed in all tissues tested. PMID- 22224586 TI - Simultaneous quantitation of 2-acetyl-4-tetrahydroxybutylimidazole, 2- and 4 methylimidazoles, and 5-hydroxymethylfurfural in beverages by ultrahigh performance liquid chromatography-tandem mass spectrometry. AB - An ultrahigh-performance liquid chromatography (UHPLC) tandem mass spectrometric (MS/MS) method was developed for the simultaneous quantification of 2-acetyl-4 tetrahydroxybutylimidazole (THI), 2- and 4-methylimidazoles (2-MI and 4-MI), and 5-hydroxymethylfurfural (HMF) in beverage samples. A C30 reversed-phase column was used in this method, providing sufficient retention and total resolution for all targeted analytes, with an MS/MS instrument operated in selected reaction monitoring (SRM) mode for sensitive and selective detection using isotope-labeled 4-methyl-d(3)-imidazole (4-MI-d(3)) as the internal standard (IS). This method demonstrates lower limit of quantification (LLOQ) at 1 ng/mL and coefficient of determination (r(2)) >0.999 for each analyte with a calibration range established from 1 to 500 ng/mL. This method also demonstrates excellent quantification accuracy (84.6-105% at 5 ng/mL, n = 7), precision (RSD < 7% at 5 ng/mL, n = 7), and recovery (88.8-99.5% at 10, 100, and 200 ng/mL, n = 3). Seventeen carbonated beverage samples were tested (n = 2) in this study including 13 dark-colored beverage samples with different flavors and varieties and 4 light-colored beverage samples. Three target analytes were quantified in these samples with concentrations in the range from 284 to 644 ng/mL for 4-MI and from 706 to 4940 ng/mL for HMF. THI was detected in only one sample at 6.35 ng/mL. PMID- 22224587 TI - Flexible FET-type VEGF aptasensor based on nitrogen-doped graphene converted from conducting polymer. AB - Graphene-based field-effect transistors (FETs) have been developed rapidly and are currently considered as an alternative for postsilicon electronics. In this study, polypyrrole-converted nitrogen-doped few-layer graphene (PPy-NDFLG) was grown on Cu substrate by chemical vapor deposition combined with vapor deposition polymerization and then transferred onto a flexible substrate. Furthermore, antivascular endothelial growth factor (VEGF) RNA aptamer conjugated PPy-NDFLG was integrated into a liquid-ion gated FET geometry to fabricate a high performance VEGF aptamer-based sensor. Field-induced high sensitivity was observed for the analyte-binding events, eventually leading to the recognition of the target molecules at an unprecedentedly low concentration (100 fM). Additionally, the aptasensor had excellent reusability, mechanical bendability, and durability in the flexible process. The developed methodology describes, for the first time, the fabrication of N-doped graphene using conducting polymers including heteroatoms in their structures as the carbonization precursor and demonstrates its use in a high-performance, flexible FET-type aptasensor to detect vascular endothelial growth factor as a cancer biomarker. PMID- 22224588 TI - Effect of high-pressure processing and milk on the anthocyanin composition and antioxidant capacity of strawberry-based beverages. AB - The present study investigated processing strategies and matrix effects on the antioxidant capacity (AC) and polyphenols (PP) content of fruit-based beverages: (1) strawberry powder (Str) + dairy, D-Str; (2) Str + water, ND-Str; (3) dairy + no Str, D-NStr. Beverages were subjected to high-temperature-short-time (HTST) and high-pressure processing (HPP). AC and PP were measured before and after processing and after a 5 week shelf-life study. Unprocessed D-Str had significantly lower AC compared to unprocessed ND-Str. Significant reductions in AC were apparent in HTST- compared to HPP-processed beverages (up to 600 MPa). PP content was significantly reduced in D-Str compared to ND-Str and in response to HPP and HTST in all beverages. After storage (5 weeks), AC and PP were reduced in all beverages compared to unprocessed and week 0 processed beverages. These findings indicate potentially negative effects of milk and processing on AC and PP of fruit-based beverages. PMID- 22224590 TI - A mesofluidics-based test platform for systematic development of scaffolds for in situ cardiovascular tissue engineering. AB - Recently, in situ tissue engineering has emerged as a new approach to obtain autologous, living replacement tissues with off-the-shelf availability. The method is based on the use of an instructive biodegradable scaffold that is capable of repopulation with host cells in situ and subsequent tissue formation. This approach imposes high demands on scaffold properties. For cardiovascular grafts, the repopulation with endogenous cells from the circulation is further hypothesized to be influenced by the hemodynamic environment of the scaffold. To systematically study the effect of scaffold properties on the response of circulating cells, we aimed to develop a mesofluidics-based in vitro test platform that enables on-stage investigation of the interaction of circulating cells with three-dimensional (3D) synthetic scaffolds under physiologic hemodynamic conditions. The test platform consists of a custom-developed cross flow chamber that houses small-scale 3D scaffolds. The cross-flow chamber is incorporated into a flow-loop to drive a cell suspension along the scaffold with physiological wall shear stress and perfusion pressure. The fluidics system is validated numerically and experimentally using a computational fluid dynamics model and real-time microbead tracing studies, demonstrating a fully developed flow profile with a homogeneous shear stress distribution over the scaffold. Wall shear stresses and pressure can be controlled independently, well within the target physiological range (0-8 Pa and 0-100 mmHg, respectively). Bench-top evaluation is performed using electrospun poly(E-caprolactone) scaffolds with varying fiber diameter, exposed to a suspension of human peripheral blood mononuclear cells in pulsatile flow for 72 h. Cell adhesion and infiltration are monitored using time-lapsed confocal laser scanning microscopy. In conclusion, we have successfully developed a mesofluidics platform to study cell-scaffold interactions under hemodynamic conditions in vitro. This platform not only enables us to systematically screen and develop potential scaffolds for future in situ cardiovascular tissue engineering approaches, but also acts as a tool to further elucidate processes as observed in vivo. PMID- 22224589 TI - Factor VIII light chain contains a binding site for factor X that contributes to the catalytic efficiency of factor Xase. AB - Factor (F) VIII functions as a cofactor in FXase, markedly accelerating the rate of FIXa-catalyzed activation of FX. Earlier work identified a FX-binding site having MUM affinity within the COOH-terminal region of the FVIIIa A1 subunit. In the present study, surface plasmon resonance (SPR), ELISA-based binding assays, and chemical cross-linking were employed to assess an interaction between FX and the FVIII light chain (A3C1C2 domains). SPR and ELISA-based assays showed that FVIII LC bound to immobilized FX (K(d) = 165 and 370 nM, respectively). Furthermore, active site-modified activated protein C (DEGR-APC) effectively competed with FX in binding FVIII LC (apparent K(i) = 82.7 nM). Western blotting revealed that the APC-catalyzed cleavage rate at Arg(336) was inhibited by FX in a concentration-dependent manner. A synthetic peptide comprising FVIII residues 2007-2016 representing a portion of an APC-binding site blocked the interaction of FX and FVIII LC (apparent K(i) = 152 MUM) and directly bound to FX (K(d) = 7.7 MUM) as judged by SPR and chemical cross-linking. Ala-scanning mutagenesis of this sequence revealed that the A3C1C2 subunit derived from FVIII variants Thr2012Ala and Phe2014Ala showed 1.5- and 1.8-fold increases in K(d) for FX, whereas this value using the A3C1C2 subunit from a Thr2012Ala/Leu2013Ala/Phe2014Ala triple mutant was increased >4-fold. FXase formed using this LC triple mutant demonstrated an ~4-fold increase in the K(m) for FX. These results identify a relatively high affinity and functional FX site within the FVIIIa A3C1C2 subunit and show a contribution of residues Thr2012 and Phe2014 to this interaction. PMID- 22224592 TI - Automatic diagnosis of mammographic abnormalities based on hybrid features with learning classifier. AB - Breast cancer screening is currently performed by mammography, which is limited by overlying anatomy and dense breast tissue. Computer-aided detection (CAD) systems can serve as a double reader to improve radiologist performance. In this paper, we have applied a novel approach to segmentation of suspicious region by mammogram and classification based on hybrid features with learning classifier. We formulated differentiation of lesion from normal tissue as a supervised learning problem, and applied this learning method to develop the classification algorithm. The algorithm has been verified with 164 mammograms in the mini Mammographic Image Analysis Society database. The experimental results show that the detection method has a sensitivity of 94.5% at 0.26 false positives per image. The efficiency of algorithm is measured using free receiver operating characteristics curve and the results are highlighted. We conclude that CAD technology with learning classifier has the potential to help radiologists with the task of discriminating between lesion and normal tissues. PMID- 22224593 TI - Donation intentions for cancer genetics research among African Americans. AB - AIMS: Scientific agencies rely on individuals to donate their DNA to support research on chronic conditions that disproportionately affect African Americans; however, donation is variable in this population. The purpose of this study was to identify sociodemographic characteristics, health care variables, and cultural values having significant independent associations with intentions to donate blood or saliva samples for cancer genetics research among African American adults. METHOD: Cross-sectional survey of donation intentions. RESULTS: The majority of respondents (73%) were willing to donate a biological sample for cancer genetics research. The results of the multivariate regression model found that respondents who received care at a facility other than a doctor's office (e.g., community center) were about five times more likely to be willing to donate a sample for cancer genetics research (odds ratio [OR]=5.28, 95% confidence interval [CI]=1.16-24.12, p=0.03); whereas, greater levels of religiosity (OR=0.09, 95% CI=0.01-0.75, p=0.02) and present temporal orientation (OR=0.23, 95% CI=0.06-0.79, p=0.02) were associated with a lower likelihood of donating a sample. CONCLUSION: Efforts to enhance donation of biological samples for cancer genetics research may need to target diverse clinical sites for recruitment. Additionally, recruitment materials may need to address cultural values related to religiosity and present temporal orientation. PMID- 22224594 TI - Discovery and structure-activity relationship of potent and selective covalent inhibitors of transglutaminase 2 for Huntington's disease. AB - Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington's disease (HD); specifically, TG2 is up-regulated in the brains of HD patients and in animal models of the disease. Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. The suitability of the compounds as in vitro tools to elucidate the biology of TG2 was demonstrated through mode of inhibition studies, characterization of druglike properties, and inhibition profiles in a cell lysate assay. PMID- 22224595 TI - Response of sediment microbial community structure in a freshwater reservoir to manipulations in oxygen availability. AB - Hypolimnetic oxygenation systems (HOx) are being increasingly used in freshwater reservoirs to elevate dissolved oxygen levels in the hypolimnion and suppress sediment-water fluxes of soluble metals (e.g. Fe and Mn) which are often microbially mediated. We assessed changes in sediment microbial community structure and corresponding biogeochemical cycling on a reservoir-wide scale as a function of HOx operations. Sediment microbial biomass as quantified by DNA concentration was increased in regions most influenced by the HOx. Following an initial decrease in biomass in the upper sediment while oxygen concentrations were low, biomass typically increased at all depths as the 4-month-long oxygenation season progressed. A distinct shift in microbial community structure was only observed at the end of the season in the upper sediment near the HOx. While this shift was correlated to HOx-enhanced oxygen availability, increased TOC levels and precipitation of Fe- and Mn-oxides, abiotic controls on Fe and Mn cycling, and/or the adaptability of many bacteria to variations in prevailing electron acceptors may explain the delayed response and the comparatively limited changes at other locations. While the sediment microbial community proved remarkably resistant to relatively short-term changes in HOx operations, HOx induced variation in microbial structure, biomass, and activity was observed after a full season of oxygenation. PMID- 22224596 TI - Clinical significance of coagulation studies in predicting response to activated recombinant Factor VII in cardiac surgery patients. PMID- 22224598 TI - Allostery and the Monod-Wyman-Changeux model after 50 years. AB - The Monod-Wyman-Changeux (MWC) model was conceived in 1965 to account for the signal transduction and cooperative properties of bacterial regulatory enzymes and hemoglobin. It was soon extended to pharmacological receptors for neurotransmitters and other macromolecular entities involved in intracellular and intercellular communications. Five decades later, the two main hypotheses of the model are reexamined on the basis of a variety of regulatory proteins with known X-ray structures: (a) Regulatory proteins possess an oligomeric structure with symmetry properties, and (b) the allosteric interactions between topographically distinct sites are mediated by a conformational transition established between a few preestablished states with conservation of symmetry and ligand-directed conformational selection. Several well-documented examples are adequately represented by the MWC model, yet a few possible exceptions are noted. New questions are raised concerning the dynamics of the allosteric transitions and more complex supramolecular ensembles. PMID- 22224600 TI - Disulfide bonding in protein biophysics. AB - It has been known for many decades that cell surface, soluble-secreted, and extracellular matrix proteins are generally rich in disulfide bonds, but only more recently has the functional diversity of disulfide bonding in extracellular proteins been appreciated. In addition to the classic mechanisms by which disulfide bonds enhance protein thermodynamic stability, disulfides in certain configurations contribute particular mechanical properties to proteins that sense and respond to tensile forces. Disulfides may help warp protein folds for the evolution of new functions, or they may fasten aggregation-prone flaps of polypeptide to protein surfaces to prevent fibrilization or oligomerization. Disulfides can also be used to package and secure macromolecular cargo for intercellular transport. A series of case studies illustrating diverse biophysical roles of disulfide bonding are reviewed, with a focus on proteins functioning in the extracellular environment. PMID- 22224601 TI - Mechanisms of Sec61/SecY-mediated protein translocation across membranes. AB - The Sec61 or SecY channel, a universally conserved protein-conducting channel, translocates proteins across and integrates proteins into the eukaryotic endoplasmic reticulum (ER) membrane and the prokaryotic plasma membrane. Depending on channel-binding partners, polypeptides are moved by different mechanisms. In cotranslational translocation, the ribosome feeds the polypeptide chain directly into the channel. In posttranslational translocation, a ratcheting mechanism is used by the ER-lumenal chaperone BiP in eukaryotes, and a pushing mechanism is utilized by the SecA ATPase in bacteria. In prokaryotes, posttranslational translocation is facilitated through the function of the SecD/F protein. Recent structural and biochemical data show how the channel opens during translocation, translocates soluble proteins, releases hydrophobic segments of membrane proteins into the lipid phase, and maintains the barrier for small molecules. PMID- 22224619 TI - Specificity of jumping to conclusions and attributional biases: a comparison between patients with schizophrenia, depression, and anorexia nervosa. AB - INTRODUCTION: The knowledge of the specificity of cognitive biases in psychiatric disorders is important in order to develop disorder-specific cognitive models and therapies. This cross-sectional study aimed to investigate the specificity of jumping to conclusions (JTC) and attributional biases (AB) for patients with schizophrenia. METHODS: Twenty patients with paranoid schizophrenia were compared with patients with depression (n=20) and with anorexia nervosa (n=15) and nonclinical controls (n=55). All participants were administered a modified version of the beads task (JTC), a revised German version of the Internal, Personal, and Situational Attributions Questionnaire (AB), and several symptom and neurocognitive measures. RESULTS: The proportion of patients with JTC bias in the schizophrenia group was, at the descriptive level, higher than in the depression and the anorexia groups. Regarding AB, the schizophrenia group showed a significantly stronger externalising but not personalising bias than the clinical control groups. Neither JTC nor attributional biases were significantly associated with delusions in general or persecutory delusion. CONCLUSIONS: We found evidence for the specificity of an externalising bias for paranoid schizophrenia. Concerning JTC bias the evidence was less clear. Whether the modification of those biases through psychological interventions would have an effect on psychopathology should be investigated in the context of clinical trials. PMID- 22224620 TI - Effect of modification of the NI artificial diet on the biological fitness parameters of mass reared western tarnished plant bug, Lygus hesperus. AB - The NI artificial diet is the only known successful diet for mass rearing the western tarnished plant bug, Lygus hesperus Knight (Hemiptera: Miridae). This diet has been used for more than a decade. However, because it contains cooked chicken egg, and thus requires laborious preparation (Cohen 2000), this diet is difficult to use. Three modifications (D1, D2, D3) of the NI diet were investigated in hopes of developing a more easily prepared diet that avoids the cooked egg and improves mass fitness parameters of L. hesperus. The modified D3 diet, containing autoclaved chicken egg yolk based component, had the highest egg/cage/day production (13120 +/- 812 SE). This was significantly greater than diets D1, containing autoclaved dry chicken egg yolk based component (9027 +/- 811 SE), D2, containing autoclaved chicken egg white based component (8311 +/- 628 SE), and NI, which contained autoclaved chicken egg yolk + cooked egg diet (7890 +/- 761 SE). Significant differences were observed in the weights of all developmental stages except for eggs and first instar nymphs. Higher rates of fertility, hatchability, and low mortality in nymphs during the first instar were also obtained in the modified D3 diet. The results clearly indicated that the D3 diet provided an opportunity to significantly reduce rearing cost by avoiding time-consuming issues with preparation of a cooked egg diet. This should result in an increase in production capacity and a reduction in production costs. PMID- 22224599 TI - Prokaryotic diacylglycerol kinase and undecaprenol kinase. AB - Prokaryotic diacylglycerol kinase (DAGK) and undecaprenol kinase (UDPK) are the lone members of a family of multispan membrane enzymes that are very small, lack relationships to any other family of proteins-including water soluble kinases-and exhibit an unusual structure and active site architecture. Escherichia coli DAGK plays an important role in recycling diacylglycerol produced as a by-product of biosynthesis of molecules located in the periplasmic space. UDPK seems to play an analogous role in gram-positive bacteria, where its importance is evident because UDPK is essential for biofilm formation by the oral pathogen Streptococcus mutans. DAGK has also long served as a model system for studies of membrane protein biocatalysis, folding, stability, and structure. This review explores our current understanding of the microbial physiology, enzymology, structural biology, and folding of the prokaryotic DAGK family, which is based on over 40 years of studies. PMID- 22224622 TI - Percolation effects in supercapacitors with thin, transparent carbon nanotube electrodes. AB - We have explored the effects of percolation on the properties of supercapacitors with thin nanotube networks as electrodes. We find the equivalent series resistance, R(ESR), and volumetric capacitance, C(V), to be thickness independent for relatively thick electrodes. However, once the electrode thickness falls below a threshold thickness (~100 nm for R(ESR) and ~20 nm for C(V)), the properties of the electrode become thickness dependent. We show the thickness dependence of both R(ESR) and C(V) to be consistent with percolation theory. While this is expected for R(ESR), that the capacitance follows a percolation scaling law is not. This occurs because, for sparse networks, the capacitance is proportional to the fraction of nanotubes connected to the main network. This fraction, in turn, follows a percolation scaling law. This allows us to understand and quantify the limitations on the achievable capacitance for transparent supercapacitors. We find that supercapacitors with thickness independent R(ESR) and C(V) occupy a well-defined region of the Ragone plot. However, supercapacitors whose electrodes are limited by percolation occupy a long tail to lower values of energy and power density. For example, replacing electrodes with transparency of T = 80% with thinner networks displaying T = 97% will result in a 20-fold reduction of both power and energy density. PMID- 22224623 TI - Prevalence of anti-dengue immunoglobulin G antibodies among American Red Cross blood donors in Puerto Rico, 2006. AB - BACKGROUND: Dengue is endemic in Puerto Rico and causes periodic outbreaks involving thousands of persons. Seroprevalence studies among blood donors can provide useful data on the immune status of the adult population. The objective of this study was to determine the prevalence of anti-dengue immunoglobulin (Ig)G antibodies in a random sample of blood donors to the American Red Cross (ARC) in Puerto Rico. STUDY DESIGN AND METHODS: Three-hundred randomly selected blood donations collected by the ARC from February 1 to March 31, 2006, were tested using an anti-dengue IgG enzyme-linked immunosorbent assay. One-third of the positive specimens were randomly selected and tested by a microneutralization test (MNT) to determine the serotypes of previous dengue infections. RESULTS: Most (84%) blood donors were male, and the mean age was 44.6 years (range, 18-80 years). The prevalence (95% confidence interval) of anti-dengue IgG antibodies was 92% (89%-95%). Of the 92 specimens tested by the MNT, reactivity to all four dengue serotypes was observed and 96% were secondary infections. The predominant serotype with the highest neutralization titers, as identified by at least a fourfold higher titer compared to any other serotype tested, was identified in 32 specimens; the most common predominant serotypes identified by the MNT were DENV 3 and DENV-2 (63%). Recent infection with DENV-1 was detected but, in 2005, routine surveillance did not detect any cases of this serotype. CONCLUSION: Supplementary serologic testing of donated blood can potentially provide information on the silent circulation or introduction of dengue serotypes. PMID- 22224624 TI - Quantitative bioluminometric method for DNA-based species/varietal identification in food authenticity assessment. AB - A method is reported for species quantification by exploiting single-nucleotide polymorphisms (SNPs). These single-base changes in DNA are particularly useful because they enable discrimination of closely related species and/or varieties. As a model, quantitative authentication studies were performed on coffee. These involved the determination of the percentage of Arabica and Robusta species based on a SNP in the chloroplastic trnL(UAA)-trnF(GAA) intraspacer region. Following polymerase chain reaction (PCR), the Robusta-specific and Arabica-specific fragments were subjected to 15 min extension reactions by DNA polymerase using species-specific primers carrying oligo(dA) tags. Biotin was incorporated into the extended strands. The products were captured in streptavidin-coated microtiter wells and quantified by using oligo(dT)-conjugated photoprotein aequorin. Aequorin was measured within 3 s via its characteristic flash-type bioluminescent reaction that was triggered by the addition of Ca(2+). Because of the close resemblance between the two DNA fragments, during PCR one species serves as an internal standard for the other. The percentage of the total luminescence signal obtained from a certain species was linearly related to the percent content of the sample with respect to this species. The method is accurate and reproducible. The microtiter well-based assay configuration allows high sample throughput and facilitates greatly the automation. PMID- 22224625 TI - Cytotoxic dehydromonacolins from red yeast rice. AB - Two new dehydromonacolins (1 and 3), together with nine known monacolins (4-12), were isolated from red yeast rice. Compounds 4-6 were isolated from a natural resource for the first time. Their structures were elucidated by means of NMR and mass spectroscopic analyses. The structure of dehydromonacolin N (1) was further confirmed by its semisynthesis from monacolin K (lovastatin) (11). Dehydromonacolin J (2), an intermediate in the semisynthesis of 1, was obtained as a new dehydromonacolin. The structure of dehydromonacolin L (3) was also confirmed by an elimination reaction of monacolin L (12). Compound 1, possessing a C2 side chain, is unprecedented in the natural monacolin family and exhibited moderate cytotoxic activity against Hep G2, Caco-2, and MCF-7 cancer cell lines. Dehydromonacolin K (8) demonstrated the most potent cytotoxicity to all three of these cell lines. The structure-activity relationship of natural and synthesized monacolins was discussed. This is the first report on the cytotoxic effects of dehydromonacolins. PMID- 22224626 TI - How are personality judgments made? A cognitive model of reference group effects, personality scale responses, and behavioral reactions. AB - This article suggests that personality judgments are wholly relative, being the outcome of a comparison of a given individual to a reference group of others. The underlying comparison processes are the same as those used to judge psychophysical stimuli (as outlined by range frequency theory and decision by sampling accounts). Five experimental studies show that the same person's personality is rated differently depending on how his or her behavior (a) ranks within a reference group and (b) falls within the overall range of behavior shown by other reference group members. Results were invariant across stimulus type and response options (7-point Likert scale, 990-point allocation task, or dichotomous choice). Simulated occupational scenarios led participants to give different sized bonuses and employ different people as a function of context. Future research should note that personality judgments (as in self-report personality scales) only represent perceived standing relative to others or alternatively should measure personality through behavior or biological reactivity. Personality judgments cannot be used to compare different populations when the population participants have different reference groups (as in cross-cultural research). PMID- 22224628 TI - Modeling stem/progenitor cell-induced neovascularization and oxygenation around solid implants. AB - Tissue engineering constructs and other solid implants with biomedical applications, such as drug delivery devices or bioartificial organs, need oxygen (O(2)) to function properly. To understand better the vascular integration of such devices, we recently developed a novel model sensor containing O(2) sensitive crystals, consisting of a polymeric capsule limited by a nanoporous filter. The sensor was implanted in mice with hydrogel alone (control) or hydrogel embedded with mouse CD117/c-kit+ bone marrow progenitor cells in order to stimulate peri-implant neovascularization. The sensor provided local partial O(2) pressure (pO(2)) using noninvasive electron paramagnetic resonance signal measurements. A consistently higher level of peri-implant oxygenation was observed in the cell-treatment case than in the control over a 10-week period. To provide a mechanistic explanation of these experimental observations, we present in this article a mathematical model, formulated as a system of coupled partial differential equations, that simulates peri-implant vascularization. In the control case, vascularization is considered to be the result of a foreign body reaction, while in the cell-treatment case, adipogenesis in response to paracrine stimuli produced by the stem cells is assumed to induce neovascularization. The model is validated by fitting numerical predictions of local pO(2) to measurements from the implanted sensor. The model is then used to investigate further the potential for using stem cell treatment to enhance the vascular integration of biomedical implants. We thus demonstrate how mathematical modeling combined with experimentation can be used to infer how vasculature develops around biomedical implants in control and stem cell-treated cases. PMID- 22224629 TI - DNA repair genes in Parkinson's disease. AB - AIMS: There is a growing interest in the understanding of a possible role of DNA repair systems in ageing and neurodegenerative diseases after DNA damage is observed in the brain of individuals affected by neurodegenerative diseases. In the light of these findings, we investigated whether DNA repair gene polymorphisms (XRCC1 Arg399Gln, XRCC3 Thr241Met XPD Lys751Gln, XPG Asp1104His, APE1 Asp148Glu, and HOGG1 Ser326Cys) account for an increased risk of Parkinson's disease (PD). METHODS: The present analyses are based on 60 case subjects with PD and 108 unrelated healthy controls. Genotyping of DNA repair gene polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: We, for the first time, demonstrated the positive association of APE1, XRCC1, and XRCC3 DNA repair gene variants with PD risk. In our study, the frequencies of Glu/Glu genotype in APE1, Gln+ genotype of XRCC1, and Thr+ genotype of XRCC3 are higher in patients than in controls (p=0.028, p=0.002 and p=0.046, respectively). CONCLUSIONS: In conclusion, our findings have suggested that APE1, XRCC1, and XRCC3 genetic variants may be a risk factor by increasing oxidative stress that might cause the loss of dopaminergic cells in the substantiata nigra and locus caeruleus, leading to abnormal signal transmittion, and ultimately, the development of PD. In addition, generation of reactive oxygen species from dopamine might affect the other DNA repair pathway proteins that we did not examine in the current study. Further studies with larger sample groups are necessary to clarify the role of DNA repair genes and the development of PD. PMID- 22224630 TI - Identification of novel mutations in LMNA associated with familial forms of dilated cardiomyopathy. AB - The lamin A/C proteins are major structural and functional components of the nuclear lamina. Mutations identified in LMNA encoding lamin A/C belong to the most frequently described causes for inherited forms of dilated cardiomyopathy (DCM). To elucidate the clinical characteristics of LMNA mutation carriers we performed genetic analysis of LMNA in 20 unrelated patients with DCM and cardiac conduction disease. In six small nuclear families heterozygous mutations in LMNA were identified. Two missense mutations led to the substitution of highly conserved amino acid residues within the rod domain of lamin A/C and four not-yet described nonsense mutations cause the formation of predicted truncated lamin A/C missing parts of the tail domain. DCM was the most prominent clinical characteristic of the affected family members with a high degree of involvement of conduction system defects and less often accompanied by muscular dystrophy. The cardiac phenotype of the affected family members was severe and progressive with age, indicating the necessity for a genetic testing for LMNA mutations in patients with familial DCM and early onset of conduction disorders. PMID- 22224631 TI - -765 G->C and -1195 A->G promoter variants of the cyclooxygenase-2 gene decrease the risk for preeclampsia. AB - Cyclooxygenase-2 (COX-2) is the inducible isoenzyme of COX that leads to increased production of prostaglandins and thromboxane, the mediators of inflammation. Controversial data regarding COX levels or activities in the placentas of women with preeclampsia have led us to examine whether a single nucleotide polymorphism (SNP) in the COX-2 gene is associated with the onset of preeclampsia. Two polymorphisms in the promoter region of COX-2 gene were examined by the polymerase chain reaction and restriction fragment length polymorphism in 128 controls and 74 preeclamptic patients. Genotype distribution and allelic frequencies for -765G->C polymorphism of COX-2 gene were significantly different between patients and controls (p=0.000 and p=0.042, respectively). The odds ratio (OR) for preeclampsia risk associated to the -765G allelic variant was 4.07 (95% confidence interval [CI]: 0.89-18.56). The AA genotype of the -1195 A->G variant was present at a significantly higher frequency among all preeclamptic subjects (p=0.000 chi(2): 13.4, OR: 3.44, 95% CI: 1.74-6.77). A moderate linkage was observed between the -765G and -1195A variants (D(0): 0.201; r(2): 0.003). These findings suggest that SNPs, -765G->C and -1195 A->G, on the promoter region of COX-2 gene may reduce the risk of preeclampsia, possibly by affecting the rate of gene expression. PMID- 22224632 TI - Mapping of microsatellite instability in endoscopic normal colon. AB - Genomic instability in colorectal cancer (CRC) occurs as either microsatellite instability (MSI) or chromosomal instability. The present study was aimed at examining the MSI for the MLH1 and MSH2 genes in normal colon and polyps, if detected. Four segments of the colon were sampled in 102 subjects during colonoscopy. DNA samples were analyzed for the MSI status according to the Bethesda consensus panel. Family history of any type of cancer or for colon cancer was present in 44.8% and 9.4% of the individuals, respectively. Forty eight percent of individuals were microsatellite stable for all five markers at all locations, 20% had low MSI status (MSI-L), and 32% had high MSI status (MSI H). The frequencies of MSI markers differed significantly from each other (p=0.003). The most frequent positive marker was D17S250. This is the first study which revealed that MSI is present in endoscopically normal-looking colon of normal individuals and, more frequently, in individuals with family histories of CRC. The detection of very early-stage CRC is possible by MSI analysis of DNA mismatch repair genes in colon tissues. This study has revealed crucial information for the use of molecular tests in CRC screening, such as high frequencies of MSI in endoscopically normal colon, which might cause false positivity. PMID- 22224633 TI - Validation of a screening tool for the rapid and reliable detection of CGG trinucleotide repeat expansions in FMR1. AB - AIMS: Most individuals with intellectual disability and/or autism are tested for Fragile X syndrome at some point in their lifetime. Greater than 99% of individuals with Fragile X have an expanded CGG trinucleotide repeat motif in the promoter region of the FMR1 gene, and diagnostic testing involves determining the size of the CGG repeat as well as methylation status when an expansion is present. RESULTS: Using a previously described triplet repeat-primed polymerase chain reaction, we have performed additional validation studies using two cohorts with previous diagnostic testing results available for comparison purposes. The first cohort (n=88) consisted of both males and females and had a high percentage of abnormal samples, while the second cohort (n=624) consisted of only females and was not enriched for expansion mutations. Data from each cohort were completely concordant with the results previously obtained during the course of diagnostic testing. CONCLUSIONS: This study further demonstrates the utility of using laboratory-developed triplet repeat-primed FMR1 testing in a clinical setting. PMID- 22224634 TI - Colorectal cancer survivors' interest in genetic testing for hereditary cancer: implications for universal tumor screening. AB - AIMS: Benefits of universal tumor screening for Lynch syndrome (LS), the most common form of hereditary colorectal cancer (CRC), will be realized only if patients are interested in genetic counseling and testing. This study explores interest in genetic testing for hereditary CRC among CRC patients who have never received genetic counseling or testing. METHODS: Using results from a cross sectional survey of CRC patients (n=91) at varying categories of risk for hereditary CRC, bivariate and multivariable analyses were conducted to compare positive and negative attitudinal beliefs regarding genetic testing, risk perceptions, demographics, and tumor stage of those who were interested in genetic testing (n=61) and those who were not interested or were not sure (n=30). RESULTS: Although significant at the bivariate level, gender, perceived relative risk of hereditary cancer, employment status, and belief that genetic testing would help in preparing for the future were not significantly related to interest in genetic testing when controlling for all other variables in a logistic regression model. The two factors that remained significant include a single-item question measuring the belief that genetic testing is warranted based on personal/family history and a positive attitudinal scale regarding the utility of genetic testing in medical decision making and cancer prevention. CONCLUSION: Results have potential implications for policies regarding universal tumor screening for LS. PMID- 22224636 TI - Modelling porous structures by penalty approach in the extended finite element method. AB - In this study, a methodology for studying porous structures was proposed. The extended finite element method (XFEM) in conjunction with a penalty approach was used to model the porous structures. The holes were considered to have very small Young's modulus, thus they could be treated as inclusions in a matrix. The level set method was applied to describe the internal boundaries of the holes. Various porous structures were investigated. A practical example of the porous structures, which was the microstructure of a trabecular bone, was examined to show the capability of the proposed methodology. The aim of the study was to demonstrate that various complicated porous structures can be modelled efficiently by the XFEM without any major modification to the existing formula. PMID- 22224635 TI - Inflammatory bowel disease: susceptibility and disease heterogeneity revealed by human leukocyte antigen genotyping. AB - This study aimed to investigate the association between HLA DR/DQ and inflammatory bowel diseases (IBD) in Tunisian patients and to determine the relationship between HLA DR/DQ alleles with the clinical disease patterns. DNA typing of human leukocyte antigen (HLA) genes was performed in 70 ulcerative colitis (UC) patients, 40 Crohn's disease (CD) patients, and 123 healthy controls (HC) using a polymerase chain reaction sequence specific primer technique. Data were analyzed using Cochran-Mantel-Haenszel test and binary logistic regression. Compared with HC, IBD patients showed an increased frequency of the homozygous DRB1*07 genotype. This positive association was maintained when UC and CD were separately compared to HC. In UC patients, DQB1*03:02 was predictive of colonic extension whereas DRB1*13 and DQB1*03:01 were associated limited disease localization (left-sided colitis and proctitis). The DRB1*15 allele increased in patients with extraintestinal manifestations. In CD, female patients showed an increased frequency of DRB1*13, DRB1*15, and DQB1*06 alleles and DRB1*13-DQB1*06 haplotype, whereas a significant increase of DRB1*07, DQB1*02 alleles, and DRB1*07-DQB1*02 haplotype was noted in male patients. These results show a significant association of the homozygous HLA-DRB1*07 genotype with UC and CD and of several HLA DR/DQ alleles and haplotypes with the clinical phenotypes of these diseases in Tunisian patients. Because of limited statistical power, our study findings are subject to further investigation. PMID- 22224639 TI - Interionic interactions in imidazolic ionic liquids probed by soft X-ray absorption spectroscopy. AB - This work investigates pure ionic liquids (ILs) derived from an imidazolium ring with different carbonic chains and halides or bis(trifluoromethanesulfonilimide) (TFSI(-)) as anions, using X-ray absorption near edge spectroscopy (XANES) at different energies (N, S, O, F, and Cl edges) to probe the interionic interactions. XANES data show that the interaction with the anion is weaker when the cation is an imidazolium than when the salt is formed by smaller cations, as lithium, independently of the length of the carbonic chain attached to the imidazolium cation. The results also show that, for all studied ILs, it is not observed any influence of the anion on the XANES spectra of the cation, nor the opposite. 1-Methylimidazolium with Cl(-), a small and strongly coordinating anion, presents in the N K XANES spectrum a splitting of the band corresponding to nitrogen in the imidazolic ring, indicating two different chemical environments. For this cation with TFSI(-), on the contrary, this splitting was not observed, showing that the anion has a weaker interaction with the imidazolic ring, even without a lateral carbonic chain. PMID- 22224638 TI - Surprising spectra of root-associated fungi in submerged aquatic plants. AB - Similarly to plants from terrestrial ecosystems, aquatic species harbour wide spectra of root-associated fungi (RAF). However, comparably less is known about fungal diversity in submerged roots. We assessed the incidence and diversity of RAF in submerged aquatic plants using microscopy, culture-dependent and culture independent techniques. We studied RAF of five submerged isoetid species collected in four oligotrophic freshwater lakes in Norway. Levels of dark septate endophytes (DSE) colonization differed among the lakes and were positively related to the organic matter content and negatively related to pH. In total, we identified 41 fungal OTUs using culture-dependent and culture-independent techniques, belonging to Mucoromycotina, Chytridiomycota, Glomeromycota, Ascomycota as well as Basidiomycota. Sequences corresponding to aquatic hyphomycetes (e.g. Nectria lugdunensis, Tetracladium furcatum and Varicosporium elodeae) were obtained. Eight arbuscular mycorrhizal taxa belonging to the orders Archaeosporales, Diversisporales and Glomerales were also detected. However, the vast majority of the fungal species detected (e.g. Ceratobasidium sp., Cryptosporiopsis rhizophila, Leptodontidium orchidicola, and Tuber sp.) have previously been known only from roots of terrestrial plants. The abundance and phylogenetic distribution of mycorrhizal as well as nonmycorrhizal fungi in the roots of submerged plants have reshaped our views on the fungal diversity in aquatic environment. PMID- 22224640 TI - Update on the development of antagonists of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). From lead optimization to clinical proof of-concept in asthma and allergic rhinitis. PMID- 22224641 TI - Uncoordinated regulation of atrial natriuretic factor and brain natriuretic peptide in lipopolysaccharide-treated rats. AB - We investigated the expression and secretion of the natriuretic peptides (NPs) ANF and BNP in lipopolysaccharide (LPS)-induced sepsis and its association with cytokines and other biologically active substances. LPS treatment increased plasma levels of ANF and BNP. The latter increase was larger than the increase in plasma ANF. LPS also increased cardiac content and gene expression of BNP but not of ANF. LPS treatment significantly increased gene expression cytokines, chemokines and proteases, which significantly correlated with BNP gene expression. SB203580, a p38 MAP kinase inhibitor, inhibited the elevation of BNP in plasma. The present work suggests that during inflammation, BNP gene expression and secretion is uniquely related to changes in gene expression in the absence of hemodynamic changes and hence differentiates ANF and BNP as biomarkers of cardiac disease. PMID- 22224653 TI - Early relapse and refractory disease remain risk factors in the anthracycline and autologous transplant era for patients with relapsed/refractory classical Hodgkin lymphoma: a single centre intention-to-treat analysis. AB - An intention-to-treat (ITT) analysis was performed in 103 unselected patients with relapsed/refractory classical Hodgkin lymphoma (CHL) comparing early relapse (<12 months) or failure of first-line therapy (ER/FTF) with late relapses (LR). Seventy one percentage proceeded to high-dose therapy/autologous stem cell rescue (HDT/ASCR) following salvage treatment. By ITT, 5-year overall survival (OS) was 50% for ER/FTF compared to 73% for LR patients (P = 0.012). However OS was equivalent for both groups if salvage treatment response was adequate to proceed to HDT/ASCR. ER/FTF patients remain a high-risk group largely due to a failure of salvage therapy: a point at which novel interventions could impact survival. PMID- 22224654 TI - Dynamics of redox processes in ionic liquids and their interplay for discriminative electrochemical sensing. AB - Motivated by the use of ionic liquids (ILs) as green replacers of traditional electrolytes, a mechanistic study has been systematically conducted to comprehend various design principles responsible for electrochemical profiling of redox active species in ILs. The full spectrum of properties associated with ILs is exploited to assess the viability of this platform, thus revealing the correlation between the redox properties and the physiochemical parameters of the species involved. This includes the evaluation of (1) the variation of redox responses toward analytes with similar molecular structures or functionalities of ILs, (2) the influence in terms of physical criteria of the system such as viscosity and conductivity as well as chemical structure of ILs, and (3) the sustainability in harsh conditions (high temperature or humidity) and interferences. The principle is exemplified via trinitrotoluene (TNT) and dinitrotoluene (DNT) with inherent redox activity as analytes and IL membranes as solvents and electrolytes using glassy carbon (GC) electrodes. A discrete response pattern is generated that is analyzed through linear discriminant analysis (LDA) leading to 100% classification accuracy even for the mixture of analytes. Quantitative analysis through square wave voltammetry (SWV) gave rise to the detection limits in liquid phase of 190 and 230 nM for TNT and DNT, respectively, with a linear range up to 100 MUM. Gas-phase analysis shows strong redox signals for the estimated concentrations of 0.27 and 2.05 ppm in the gas phase for TNT and DNT, respectively, highlighting that ILs adopt a role as a preconcentrator to add on sensitivity with enhanced selectivity coming from their physiochemical diversity, thus addressing the major concerns usually referred to most sensor systems. PMID- 22224655 TI - Overall-mouth disinfection by photodynamic therapy using curcumin. AB - BACKGROUND DATA: Photodynamic therapy is a technique that involves the activation of photosensitizers by light in the presence of tissue oxygen, resulting in the production of reactive radicals capable of inducing cell death. OBJECTIVE: The present study assessed the overall susceptibility of pathogens of salivary flora to photodynamic therapy after sensitization with curcumin and exposure to blue light at 450 nm. METHODS: A randomized trial was executed with 13 adult volunteers. Three different groups were analyzed: L-D- (no light, no drug; control group), L-D+ (treated only with the drug; curcumin group) and L+D+ (treated with drug and light; photodynamic therapy group). Non-stimulated saliva samples were collected for bacterial counts at baseline and after the experimental phase, and adverse events experienced were recorded. Serial dilutions were performed, and the resulting samples were cultured on blood agar plates in microaerophilic conditions. The number of colony-forming units was then determined. RESULTS: There was a considerable difference between the two experimental groups with regard to effectiveness of bacterial reduction. In the L D+ group, the bacterial decline was considerably smaller (9%) than in the L+D+ group, with a 68% decrease in bacteria. A statistically significant reduction in the bacterial population was observed only in the photodynamic therapy group (p<0.05). CONCLUSIONS: Photodynamic therapy was found to be effective in the reduction of salivary microorganisms. No significant reduction was found for the group in which only curcumin was used, proving the absence of dark toxicity of the drug. This work shows that overall disinfection of the mouth can be done with a simple procedure involving photodynamic action. PMID- 22224658 TI - On African Eupsilobiinae (Coleoptera: Endomychidae) with descriptions of a new genus and species. AB - Species of the South African genus Microxenus Wollaston are revised. Microxenus laticollis Wollaston is redescribed, and M. muelleri sp. nov. and M. krugeri sp. nov. are described. Natalinus gen. nov. and its single included species, N. klimaszewskii sp. nov. are described. All of these taxa are diagnosed and illustrated, and a key to the species of Microxenus is presented. Female genitalia of newly described species are discussed in terms of monophyly of Eupsilobiinae. Zoogeographical and biological data of African Eupsilobiinae are summarized. PMID- 22224659 TI - Controlled polymerization and self-assembly of halogen-bridged diruthenium complexes in organic media and their dielectrophoretic alignment. AB - Lipophilic paddlewheel biruthenium complexes [Ru(2)(MU-O(2)CR)(3)X](n) (O(2)CR = 3,4,5-tridodecyloxybenzoate, X = Cl, I) self-assemble in organic media to form halogen-bridged coordination polymers. The polymerization is accompanied by spectral changes in pi(RuO,Ru(2)) -> pi*(Ru(2)) and pi(axial ligand) -> pi*(Ru(2)) absorption bands. These polymeric complexes form lyotropic liquid crystals in n-decane at concentrations above ~100 unit mM. The bridging halogen axial ligands (X = Cl or I) exert significant influences on their electronic structures and self-assembling characteristics: the chloride-bridged polymers give hexagonally aligned ordered columnar structure (columnar hexagonal phase, Col(h)), whereas the iodide-bridged polymers form less ordered columnar nematic (Col(n)) phase, as revealed by small-angle X-ray diffraction measurements. Chloro bridged coordination polymers dispersed in n-decane are thermally intact even at the elevated temperature of 70 degrees C. In contrast, iodo-bridged polymers show reversible dissociation and reassembly phenomena depending on temperature. These halogen-bridged coordination polymers show unidirectional alignment upon applying alternating current (ac) electric field as investigated by crossed polarizing optical microscopy and scanning electron microscopy. The unidirectionally oriented columns of chloro-bridged polymers are accumulated upon repetitive application of the ac voltage, whereas iodo-bridged coordination polymers show faster and reversible alignment changes in response to turning on and-off the electric field. The controlled self-assembly of electronically conjugated linear complexes provide a potential platform to design electric field responsive nanomaterials. PMID- 22224660 TI - In situ tissue engineering using magnetically guided three-dimensional cell patterning. AB - Manipulation of cell patterns in three dimensions in a manner that mimics natural tissue organization and function is critical for cell biological studies and likely essential for successfully regenerating tissues--especially cells with high physiological demands, such as those of the heart, liver, lungs, and articular cartilage.(1, 2) In the present study, we report on the feasibility of arranging iron oxide-labeled cells in three-dimensional hydrogels using magnetic fields. By manipulating the strength, shape, and orientation of the magnetic field and using crosslinking gradients in hydrogels, multi-directional cell arrangements can be produced in vitro and even directly in situ. We show that these ferromagnetic particles are nontoxic between 0.1 and 10 mg/mL; certain species of particles can permit or even enhance tissue formation, and these particles can be tracked using magnetic resonance imaging. Taken together, this approach can be adapted for studying basic biological processes in vitro, for general tissue engineering approaches, and for producing organized repair tissues directly in situ. PMID- 22224661 TI - Nematicidal activity of (E,E)-2,4-decadienal and (E)-2-decenal from Ailanthus altissima against Meloidogyne javanica. AB - Methanol extracts of various plant parts of Ailanthus altissima were tested against the root knot nematode Meloidogyne javanica . Extracts of bark (ABE), wood (AWE), roots (ARE), and leaves (ALE) from A. altissima were investigated against freshly hatched second-stage juveniles (J(2)). AWE was the most active extract, with EC(50/3d) of 58.9 mg/L, while ALE, ARE, and ABE did not show nematicidal activity. The chemical composition of the extracts of A. altissima was determined by gas chromatography-mass spectrometry, and (E,E)-2,4-decadienal, (E)-2-undecenal, (E)-2-decenal, hexanal, nonanal, and furfural were the most prominent constituents. (E,E)-2,4-Decadienal, (E)-2-decenal, and furfural showed the highest nematicidal activity against M. javanica , with EC(50/1d) = 11.7, 20.43, and 21.79 mg/L, respectively, while the other compounds were inactive at the concentrations tested. The results obtained showed that AWE and its constituents (E,E)-2,4-decadienal and (E)-2-decenal could be considered as potent botanical nematicidal agents. PMID- 22224662 TI - Effects of the FeII/CuII interaction on copper aging enhancement and pentachlorophenol reductive transformation in paddy soil. AB - The present study investigated copper aging and pentachlorophenol (PCP) reductive transformation under the effects of the Fe(II)/Cu(II) interaction in paddy soil in south China. Kinetic measurements demonstrated that the PCP reductive transformation rate (k) could be promoted in the presence of no more than 0.375 mM Cu(II) and inhibited in the presence of no less than 0.5 mM Cu(II). The highest k value in the presence of 0.25 mM Cu(II) corresponds to the lowest redox potential (E(p)) value of active Fe species. The increasing trend in E(p) of the active Fe species is consistent with the declining trend in the k value of PCP reduction and vice versa. Dissolved Cu(II) is gradually transformed into immobilized Cu species during PCP reduction, which indicates that Cu aging is enhanced by the Fe(II)/Cu(II) interaction. These findings improve our general understanding of the Fe(II)/Cu(II) interaction on soil iron redox chemistry for polychlorinated pesticide detoxification and heavy metal immobilization. PMID- 22224663 TI - Knowledge translation: who needs to know what research tells us? PMID- 22224665 TI - Issues in diagnosis of children with developmental coordination disorder. PMID- 22224664 TI - Environmental stress, evolution, and the COMT Val158Met SNP. PMID- 22224666 TI - Hand function in children with an upper brachial plexus birth injury. PMID- 22224667 TI - GM2 gangliosidosis: the prototype of lysosomal storage disorders. PMID- 22224668 TI - Reliability and responsiveness of the Movement Assessment Battery for Children Second Edition Test in children with developmental coordination disorder. AB - AIM: To examine the internal consistency, test-retest reliability, and responsiveness of the Movement Assessment Battery for Children-Second Edition (MABC-2) Test for children with developmental coordination disorder (DCD). METHOD: One hundred and forty-four Taiwanese children with DCD aged 6 to 12 years (87 males, 57 females) were tested on three separate occasions: two baseline measurements with a 20-day interval before the intervention, and a follow-up measurement after 6 months of rehabilitation. The therapists rated the performance of children in school-related physical tasks at baseline and after intervention. RESULTS: Internal consistency for the MABC-2 Test was alpha = 0.90. Test-retest reliability for the total score was excellent, with an intraclass correlation coefficient of 0.97. A small to medium magnitude of treatment effect was captured by the MABC-2 Test. The minimal detectable change (MDC) was 0.28 points whereas the minimal important difference (MID) values were from 2.36 to 2.50. All subscales except balance showed acceptable validity in differentiating groups of children whose physical performance had improved or remained stable. INTERPRETATION: The MABC-2 Test is a reliable and valid measure to assess motor competence in children with DCD. The MID and MDC scores provide the reference point for clinical decision-making in managing the individual child. PMID- 22224669 TI - Nutritional rehabilitation increases the resting energy expenditure of malnourished children with severe cerebral palsy. AB - AIM: The aim of this study was to measure resting energy expenditure (REE) and energy intake in children with quadriplegic cerebral palsy (CP), to relate these to anthropometric measurements, and to determine the influence of nutritional rehabilitation on REE. METHODS: Fifty-six children (20 females, 36 males; age range 3y 11mo-18y; mean age 10y; SD 3y 11mo) with CP (Gross Motor Function Classification System level V) participated in this cross-sectional study. Children were excluded if they had a known metabolic disorder, genetic syndrome, or chromosomal abnormality. Thirty-three of the children were tube fed and 23 were fed orally. A comparison group comprised 111 (42 females, 69 males) healthy children who had undergone anthropometric and REE measurements and were of similar age to the children with CP (4-19y). REE was measured by indirect calorimetry and energy intake was determined from weighed food records. RESULTS: The REE in the children with CP was low (79.5%) compared with that predicted and highly variable (SD 38.4%). Fat-free mass was the strongest predictor of REE, accounting for 27% of the variation. Energy intake as a percentage of REE in was greatly overestimated in oral-fed children with CP (293%). In a subset of children with CP (n=14), an increased energy intake by gastrostomy tube feeding resulted in an increase in REE from 70.0% to 101.9% of that predicted. INTERPRETATION: The REE of children with CP is low and variable and is not strongly related to any one anthropometric measurement. Food records in oral-fed children with CP are of little value owing to their inaccuracy. This study provided support for the hypothesis that the low REE found in malnourished children with CP is partly due to a low energy intake. PMID- 22224671 TI - 4-Shogaol, an active constituent of dietary ginger, inhibits metastasis of MDA-MB 231 human breast adenocarcinoma cells by decreasing the repression of NF kappaB/Snail on RKIP. AB - 4-Shogaol is one of the phytoconstituents isolated from dried red ginger, which is commercially available to consumers. Some active constituents from ginger have been found to have anti-inflammatory and antioxidant effects, but studies on 4 shogaol have been relatively rare. This is the first report describing the antimetastasis activities of 4-shogaol and the possible mechanisms. This study determined that 4-shogaol inhibits the migration and invasion of MDA-MB-231 and causes mesenchymal-epithelial transition (MET). In addition, 4-shogaol suppresses the activation of NF-kappaB and cell migration and invasion induced by TNF-alpha. Furthermore, 4-shogaol has been shown to inhibit the phosphorylation of IkappaB and the translocation of NF-kappaB/Snail in MDA-MB-231. This study shows that RKIP, an inhibitory molecule of IKK, is up-regulated after 4-shogaol treatment and prolongs the inhibitory effects of 4-shogaol. Inhibition of RKIP by shRNA transfection significantly decreases the inhibitory effect of 4-shogaol on the NF kappaB/Snail pathway, together with cell migration and invasion, whereas overexpression of Snail suppresses 4-shogaol-mediated metastasis inhibition and E cadherin upregulation. Finally, the animal model revealed that 4-shogaol effectively inhibits metastasis of MDA-MB-231 in mice. This study demonstrates that 4-shogaol may be a novel anticancer agent for the the treatment of metastasis in breast cancer. PMID- 22224672 TI - Predicting law enforcement officer job performance with the Personality Assessment Inventory. AB - This study examined the descriptive and predictive characteristics of the Personality Assessment Inventory (PAI; Morey, 1991) in a sample of 85 law enforcement officer candidates. Descriptive results indicate that mean PAI full scale and subscale scores are consistently lower than normative community sample scores, with some exceptions noted typically associated with defensive responding. Predictive validity was examined by relating PAI full-scale and subscale scores to supervisor ratings in the areas of job performance, integrity problems, and abuse of disability status. Modest correlations were observed for all domains; however, predictive validity was moderated by defensive response style, with greater predictive validity observed among less defensive responders. These results suggest that the PAI's full scales and subscales are able to predict law enforcement officers' performance, but their utility is appreciably improved when taken in the context of indicators of defensive responding. PMID- 22224673 TI - New and emerging disease modifying therapies for multiple sclerosis. AB - Several disease-modifying drugs (DMDs) are currently approved for the treatment of multiple sclerosis (MS). Recently, there has been increased identification and development of potential new treatments that may modulate the MS disease process, including oral therapies. Many of the newly approved MS therapies, as well as those in ongoing clinical trials, have the advantage of improved efficacy and/or being oral and more convenient, as compared to conventional injectable first-line MS therapies. However, many of these new and emerging MS treatments are known to be associated with serious adverse events, some of which may be potentially life threatening. Of additional concern, there is limited experience and long-term safety data for many of these drugs, and thus the true potential for complications associated with these agents remains ambiguous. With an anticipated explosion in the artillery of available MS therapies in the near future, neurologists will need to carefully weigh drug efficacy, convenience, safety, and tolerability when making therapeutic decisions. In this review, we describe the known mechanisms of action, efficacy, and side-effect profiles of new and emerging MS DMDs. PMID- 22224674 TI - Bending and pressurisation test of the human aortic arch: experiments, modelling and simulation of a patient-specific case. AB - This work presents experiments, modelling and simulation aimed at describing the mechanical behaviour of the human aortic arch during the bending and pressurisation test. The main motivation is to describe the material response of this artery when it is subjected to large quasi-static deformations in three different stages: bending, axial stretching and internal pressurisation. The sample corresponds to a young artery without cardiovascular pathologies. The pressure levels are within the normal and hypertension physiological ranges. The two principal findings of this work are firstly, the material characterisation performed via tensile test measurements that serve to derive the material parameters of a hyperelastic isotropic constitutive model and, secondly, the assessment of these material parameters in the simulation of the bending and pressurisation test. Overall, the reported material characterisation was found to provide a realistic description of the mechanical behaviour of the aortic arch under severe complex loading conditions considered in the bending and pressurisation test. PMID- 22224676 TI - Ordered assemblies of triangular-shaped molecules with strongly interacting vertices: phase diagrams for honeycomb and zigzag structures on triangular lattice. AB - The model for ordering of triangular-shaped molecules with strongly interacting vertices is proposed and solved by the Monte Carlo method. The model accounts for three main intermolecular interactions and three states (two main orientations and a vacancy state) of a molecule on triangular lattice, the situation which is encountered in self-assembly of TMA molecules characterized by strongly directional H-bonding. Distinguishing the main "tip-to-tip" interaction, we calculate the phase diagrams for the honeycomb and frustrated honeycomb structures and demonstrate how these structures shrink and vanish with gradual increase of two other ("side-to-side" and "tip-to-side") interactions. We study the effect of frustration on the phase diagram, since the frustrated phase is obtained at the Ising limit of the model. We also demonstrate how the inclusion of longer-range interactions leads to substitution of the frustrated phase by the zigzag structure. Finally, we obtain the phase diagram with two experimentally found TMA structures (honeycomb and zigzag) and discuss the conditions of their existence by comparison with the experimental results. PMID- 22224699 TI - Interactions between an arbuscular mycorrhizal fungus and a soil microbial community mediating litter decomposition. AB - We investigated arbuscular mycorrhizal fungi (AMF) alteration of microbial mediation of litter decomposition. AMF (Glomus hoi) were either allowed access to or excluded from Plantago lanceolata L. root litter embedded in soil; litter was labeled with either (13) C only or (13) C and (15) N. Plant N uptake was significantly increased if AMF accessed the litter, and (15) N analysis of the plant material indicated that 2-3% of plant N originated from litter. Succession of the soil community mediating decomposition was assessed by phospholipid fatty acids (PLFA) combined with (13) C-PLFA. During the first 21 days of decomposition, saprotrophic fungi and Gram-negative bacteria were the dominant consumers of litter C. As decomposition progressed however, (13) C content of the fungal biomarkers declined substantially, and Gram-negative and Gram-positive bacteria became the primary reservoirs of labeled litter C. The putative PLFA marker for AMF (16:1omega5c) originated primarily from non-AMF sources. In AMF invaded root litter, Gram-negative, Gram-positive, and 16:1omega5c markers became less (13) C-enriched relative to their counterparts in non-AMF-invaded microcosms during active decomposition. These patterns of (13) C: (12) C enrichment may result from AMF supply of (12) C from the plant to the decomposing soil microbial community; such C inputs could alter the microbial mediation of litter decomposition. PMID- 22224701 TI - Extensivity of energy and electronic and vibrational structure methods for crystals. AB - A pedagogical proof is presented for the extensivity of energies of metallic and nonmetallic crystals that proceeds by elucidating the asymptotic distance dependence of the effective chemical interactions: kinetic, Coulomb, exchange, and correlation. On this basis, a guideline for the size-consistent design of electronic and vibrational methods is proposed. This guideline underscores the significance of the distinct use of the intermediate and standard normalization of wave functions for extensive and intensive quantities, includes the extensive and intensive diagram theorems as the unambiguous criteria for determining size consistency of a method for extensive and intensive quantities, and introduces the extensive-intensive consistency theorem, which stipulates the precise balance between the determinant spaces reached by extensive and intensive operators. Electronic and vibrational methods for crystals are reviewed that are inspired by these formal analyses or developed in accordance with the guideline. PMID- 22224700 TI - Omission of in vivo T-cell depletion promotes rapid expansion of naive CD4+ cord blood lymphocytes and restores adaptive immunity within 2 months after unrelated cord blood transplant. AB - Umbilical cord blood transplant (UCBT) is associated with impaired early immune reconstitution. This might be explained by a lower T-cell dose infused, the naivety of cord blood T-cells and the use of in vivo T-cell depletion. We studied the pattern of early immune reconstitution and the clinical outcome of children undergoing unrelated UCBT when in vivo T-cell depletion was omitted. Thirty children affected by malignancies (46%) or immunodeficiencies (54%) underwent an unrelated UCBT. Prospective assessment of immune reconstitution and clinical outcome was performed. We observed an unprecedented CD4(+) T-cell reconstitution, with a median cell count at 30 and 60 d post UCBT of 0.3 * 10(9) /l and 0.56 * 10(9) /l, respectively. Early T-cell expansion was thymic-independent, with a rapid shift from naive to central memory phenotype and early regulatory T-cell recovery. Viral infections were frequent (63%) but resolved rapidly in most cases and virus-specific T-lymphocytes were detected within 2 months post-UCBT. Acute graft-versus-host disease (GvHD) was frequent (grade II = 34%, grade III-IV = 16%) but steroid responsive, and the incidence of chronic GvHD was low (14%). The omission of in vivo T-cell depletion promotes a unique thymic-independent CD4(+) T-cell reconstitution after unrelated UCBT in children. We postulate that this relates to the specific immunological and ontological qualities of fetal-derived lymphocytes. PMID- 22224702 TI - Environmental chemistry at vapor/water interfaces: insights from vibrational sum frequency generation spectroscopy. AB - The chemistry that occurs at surfaces has been an intense area of study for many years owing to its complexity and importance in describing a wide range of physical phenomena. The vapor/water interface is particularly interesting from an environmental chemistry perspective as this surface plays host to a wide range of chemistries that influence atmospheric and geochemical interactions. The application of vibrational sum frequency generation (VSFG), an inherently surface specific, even-order nonlinear optical spectroscopy, enables the direct interrogation of various vapor/aqueous interfaces to elucidate the behavior and reaction of chemical species within the surface regime. In this review we discuss the application of VSFG to the study of a variety of atmospherically important systems at the vapor/aqueous interface. Chemical systems presented include inorganic ionic solutions prevalent in aqueous marine aerosols, small molecular solutes, and long-chain fatty acids relevant to fat-coated aerosols. The ability of VSFG to probe both the organization and reactions that may occur for these systems is highlighted. A future perspective toward the application of VSFG to the study of environmental interfaces is also provided. PMID- 22224703 TI - Singlet nuclear magnetic resonance. AB - Nuclear singlet states may have lifetimes that are much longer than the conventional relaxation time of nuclear spin magnetization. This review covers how these states may be generated, observed, and exploited in solution nuclear magnetic resonance (NMR). Potential applications include the study of slow molecular processes, the elucidation of molecular geometry, and the transport of hyperpolarized nuclear spin order. PMID- 22224704 TI - Single-molecule surface-enhanced Raman spectroscopy. AB - A general overview of the field of single-molecule (SM) surface-enhanced Raman spectroscopy (SERS) as it stands today is provided. After years of debates on the basic aspects of SM-SERS, the technique is emerging as a well-established subfield of spectroscopy and SERS. SM-SERS is allowing the observation of subtle spectroscopic phenomena that were not hitherto accessible. Examples of the latter are natural isotopic substitutions in single molecules, observation of the true homogeneous broadening of Raman peaks, Raman excitation profiles of individual molecules, and SM electrochemistry. With background examples of the contributions produced by our group, properly interleaved with results by other practitioners in the field, we present some of the latest developments and promising new leads in this new field of spectroscopy. PMID- 22224705 TI - Freeze-dried heart valve scaffolds. AB - In this study, structure and biomechanical properties of freeze-dried decellularized porcine pulmonary heart valves were investigated. Heart valves were dissected from porcine hearts. The tissues were decellularized and separated in three groups: (1) without lyoprotectant, (2) with 5% sucrose, and (3) with a mixture of 2.5% sucrose and 2.5% hydroxyl ethylene starch (HES), and then underwent freeze-drying. Freeze-drying in the absence of lyoprotectants caused an overall more disintegrated appearance of the histological architecture of the porcine valves, especially between the fibrosa and the ventricularis layers. Freeze-dried tissues with lyoprotectants have a looser network of collagen and elastic fibers with bigger pore sizes. Tissue freeze-dried in the absence of lyoprotecants had the largest pore sizes, whereas the tissue freeze-dried in the presence of protectants showed pores of intermediate sizes between the decellularized tissue and the unprotected freeze-dried samples. Tissue freeze dried with sucrose alone displayed less porosity than tissue freeze-dried with the sucrose/HES mixture, whereas no significant differences in biomechanical properties were observed. Decellularization decreased the elastic modulus of artery tissue. The elastic modulus of freeze-dried tissue without protectants resembled that of decellularized tissue. The elastic modulus values of freeze dried tissue stabilized by lyoprotectants were greater than those of decellularized tissue, but similar to those of native tissue. PMID- 22224707 TI - 'More of a leg to stand on': views and usage of the Mental Capacity Act 2005 among staff of local Alzheimer's Society and carer organisations. AB - OBJECTIVES: The Mental Capacity Act (MCA) 2005 was implemented in 2007 in England and Wales. It offers new opportunities for people to plan for any future loss of capacity and provides a framework for decision-making on behalf of people lacking capacity. This article explores the challenges staff in local voluntary organisations focusing on dementia and carers face when they offer information and advice connected to possible loss of decision-making capacity to people with dementia and carers. METHOD: A set of 17 qualitative interviews were undertaken with a purposively sampled voluntary sector staff in London in 2008-09. Framework analysis was used to delineate themes in the transcripts and identified themes were included in the iteratively developed coding framework. RESULTS: Interviews revealed that voluntary sector staff generally perceived the Act as largely benefiting people with dementia in the exercise of their rights. They also thought that carers would benefit from the Act's provisions, whilst their own involvement in advice, information-giving and referral to other sources of expertise in relation to the MCA differed according to their role and confidence. Voluntary sector staff's capability and interest in using the MCA vary; there should be no presumption of detailed knowledge, and resources relevant to the MCA might be need to be coordinated more effectively by this sector. CONCLUSION: Ongoing training, local coordination and auditing seem warranted. These could encompass the new safeguarding provisions of the MCA which may need to be highlighted as part of the welcome extension of rights conferred by the MCA. PMID- 22224708 TI - Effects of roasting on the antioxidant status and phenolic profiles of commercial Turkish hazelnut varieties (Corylus avellana L.). AB - The effect of roasting on the antioxidant status and phenolic profiles of seven commercial Turkish hazelnut varieties (namely, Cakildak, Fosa, Karafindik, Mincane, Palaz, Sivri, and Tombul) was assessed. Samples were examined for their total phenolics, oxygen radical absorbance capacity (ORAC) values, condensed tannins, and phenolic acids (free and bound forms). Significant losses (p < 0.05) in total phenolics (~66.3%), ORAC values (~41.6%), condensed tannins (~75.2), and phenolic acids (~42.7) were noted when the hazelnuts were roasted. Some variations both between and within natural and roasted hazelnuts were observed (p < 0.05). Phenolic acids were mainly found in the bound form. Gallic, protocatechuic, p-coumaric, and ferulic + sinapic acids were present in all hazelnut varieties, albeit to different extents, and the first two were dominant. Mincane, in roasted form, had the highest total phenolics, ORAC values, condensed tannins, and phenolic acids. This was due to the presence of some skin in roasted Mincane. No skin was left in all other varieties upon roasting. The present work suggests that roasting results in a significant loss in the antioxidant status and phenolic profiles because of the removal of the skin, which is a rich source of phenolics. It is highly recommended to consume natural hazelnut instead of the roasted counterpart to take advantage of all of the functional benefits of this nut. PMID- 22224706 TI - Multiple mediators of the relations between caregiving stress and depressive symptoms. AB - OBJECTIVE: This study tested a model for explaining how stress is associated with depressive symptoms in a sample of spouse caregivers of patients with Alzheimer's disease. It was hypothesized that more depressive symptoms would be significantly correlated with both 'primary' caregiver stressors (i.e., care recipient problem behaviors) and 'secondary' stress (i.e., role overload), but that this relationship would be significantly mediated by four variables: (1) personal mastery, (2) coping self-efficacy, (3) activity restriction, and (4) avoidance coping. METHOD: We used an asymptotic and resampling strategy for simultaneously testing multiple mediators of the stress-to-depressive symptoms pathway. RESULTS: Greater stress was significantly related to more depressive symptoms. Increased stress was also associated with reduced personal mastery and self-efficacy, as well as increased activity restriction and avoidance coping. Finally, these four mediators accounted for a significant amount of the relationship between stress and depressive symptoms. DISCUSSION: These results suggest multiple pathways by which both primary and secondary caregiver stresses may be associated with increased depressive symptoms, and may argue for multiple treatment targets for caregiver interventions. PMID- 22224710 TI - Structure-activity relationship study of opiorphin, a human dual ectopeptidase inhibitor with antinociceptive properties. AB - Toward developing new potential analgesics, this first structure-activity relationship study of opiorphin (H-Gln-Arg-Phe-Ser-Arg-OH), a human peptide inhibiting enkephalin degradation, was performed. A systematic Ala scanning proved that Phe(3) is a key residue for neprilysin and aminopeptidase N (AP-N) ectoenkephalinase inhibition. A series of Phe(3)-halogenated analogues revealed that halogen bonding based optimization strategies are not applicable to this residue. Additional substituted Phe(3) derivatives showed that replacing l-Phe(3) for d-Phe(3) increased the AP-N inhibition potency by 1 order of magnitude. NMR studies and molecular mechanics calculations indicated that the improved potency may be due to CH-pi stacking interactions between the aromatic ring of d-Phe(3) and the Hgamma protons of Arg(2). This structural motif is not possible for the native opiorphin and may be useful for the design of further potent and metabolically stable analogues. PMID- 22224711 TI - Vacuolar glyphosate-sequestration correlates with glyphosate resistance in ryegrass (Lolium spp.) from Australia, South America, and Europe: a 31P NMR investigation. AB - Lolium spp., ryegrass, variants from Australia, Brazil, Chile, and Italy showing differing levels of glyphosate resistance were examined by (31)P NMR. Extents of glyphosate (i) resistance (LD(50)), (ii) inhibition of 5-enopyruvyl-shikimate-3 phosphate synthase (EPSPS) activity (IC(50)), and (iii) translocation were quantified for glyphosate-resistant (GR) and glyphosate-sensitive (GS) Lolium multiflorum Lam. variants from Chile and Brazil. For comparison, LD(50) and IC(50) data for Lolium rigidum Gaudin variants from Italy were also analyzed. All variants showed similar cellular uptake of glyphosate by (31)P NMR. All GR variants showed glyphosate sequestration within the cell vacuole, whereas there was minimal or no vacuole sequestration in the GS variants. The extent of vacuole sequestration correlated qualitatively with the level of resistance. Previous (31)P NMR studies of horseweed ( Conyza canadensis (L.) Cronquist) revealed that glyphosate sequestration imparted glyphosate resistance. Data presented herein suggest that glyphosate vacuolar sequestration is strongly contributing, if not the major contributing, resistance mechanism in ryegrass as well. PMID- 22224714 TI - A 16-year-old boy with leg swelling. PMID- 22224712 TI - Exploring the value of apoB48 as a marker for atherosclerosis in clinical practice. AB - BACKGROUND: Postprandial accumulation of atherogenic remnants has been described in patients with type 2 diabetes mellitus (T2DM), familial combined hyperlipidaemia (FCH), familial hypercholesterolaemia (FH) and coronary artery disease (CAD). Scarce data are available on fasting plasma apolipoprotein (apo) B48 levels in relation to these conditions and atherosclerosis. DESIGN: Treated patients with FCH (18), FH (20), T2DM (26), CAD (65), T2DM with CAD (T2DM/CAD) (28) and 33 healthy controls were included. Intima-media thickness (IMT) measurements were carried out to investigate subclinical atherosclerosis. RESULTS: LDL-C and total apoB were lowest in patients with T2DM/CAD owing to the more frequent use of lipid-lowering medication. Fasting plasma apoB48 was elevated in patients with FCH (11.38 +/- 1.50 mg/L) and T2DM/CAD (9.65 +/- 1.14 mg/L) compared with the other groups (anova, P < 0.01). CAD patients (8.09 +/- 0.57 mg/L) had higher apoB48 levels than controls (5.74 +/- 0.55 mg/L) and FH patients (5.40 +/- 0.51 mg/L) (P = 0.02). IMT was highest in subjects with T2DM/CAD (0.77 +/- 0.03 mm) (P < 0.01). The lowest IMT was measured in controls (0.56 +/- 0.02 mm) and FCH patients (0.60 +/- 0.03 mm). In the total group, the best association for apoB48 was found with fasting triglyceride (Pearson's r = 0.72, P < 0.001). In the subjects not using statins (n = 74), the best correlation was found with IMT (r = 0.52; P < 0.001), whereas total apoB was not associated with IMT (r = 0.20, P = 0.12). CONCLUSIONS: ApoB48 concentrations are highest in patients with FCH and in atherosclerotic subjects with T2DM. In patients not using statins, the surrogate atherosclerosis marker IMT correlates best with apoB48, suggesting that fasting apoB48 may help to detect subjects at risk. PMID- 22224715 TI - A 16-year-old girl with chronic intermittent abdominal pain. PMID- 22224716 TI - Ankyloglossia: when frenectomy is the right choice. PMID- 22224717 TI - Pediatric dermatology. PMID- 22224718 TI - Effects of sugar-sweetened beverages on children. PMID- 22224719 TI - History and development of Haemophilus influenzae type b vaccine. PMID- 22224720 TI - A conversation with Larry K. Pickering, MD, FAAP, FIDSA. Interview by Stanford T. Shulman. PMID- 22224722 TI - One-step preparation of uniform cane-ball shaped water-swellable microgels containing poly(N-vinyl formamide). AB - In this study we report the preparation of a new family of core-shell microgels that are water-swellable and have a morphology that is controllable by particle composition. Here, nearly monodisperse core-shell PNVF-xGMA [poly(N vinylformamide-co-glycidyl methacrylate)] particles (where x is the weight fraction of GMA used) were prepared via nonaqueous dispersion (NAD) polymerization in one step. The shells were PGMA-rich and were cross-linked by reaction of epoxide groups (from GMA) with amide groups (from NVF). The core of the particles was PNVF-rich. A bifunctional cross-linking monomer was not required to prepare these new microgels. The particles had a remarkable "cane ball"-like morphology with interconnected ridges, and this could be controlled by the value for x. The particle size was tunable over the range 0.8-1.8 MUm. Alkaline hydrolysis was used to hydrolyze the PNVF segments to poly(vinylamine), PVAM. The high swelling pressure of the cationic cores caused shell fragmentation and release of some of the core polymer when the hydrolyzed particles were dispersed in pure water. The extent to which this occurred was controllable by x. Remarkably, the PGMA-rich shells could be detached from the hydrolyzed particles by dispersion in water followed by drying. The hydrolyzed PNVF-0.4GMA particles contained both positively and negatively charged regions and the dispersions appeared to exhibit charge-patch aggregation at low ionic strengths. The new cross-linking strategy used here to prepare the PNVF-xGMA particles should be generally applicable for amide-containing monomers and may enable the preparation of a range of new water-swellable microgels. PMID- 22224723 TI - Examining the factor structure of the Hare Self-Report Psychopathy Scale. AB - The 64-item Hare Self-Report Psychopathy Scale (Hare SRP; Paulhus, Neumann, & Hare, in press ) is the most recent revision of the SRP, which has undergone numerous iterations. Little research has been conducted with this new edition; therefore, the goal of this study was to elucidate the factor structure as well as the criterion-related, convergent, and discriminant validity of the measure in a large sample of college students (N = 602). Confirmatory factor analyses revealed that the best fitting model was the original 4-factor model proposed by the authors of the Hare SRP (compared to a 1-factor, 2-factor, and 4-factor random model). The 4-factor model revealed superior fit for the data relative to the other alternative models. In addition, we elaborated on the psychometric properties of this 4-factor model in this sample. The Hare SRP total and factor scores evidenced good internal reliability as well as promising criterion related, convergent, and discriminant validity in terms of predicting scores on conceptually relevant external criteria. Implications for theory and future research are discussed. PMID- 22224724 TI - Regional annulus fibre orientations used as a tool for the calibration of lumbar intervertebral disc finite element models. AB - The collagen network of the annulus fibrosus largely controls the functional biomechanics of the lumbar intervertebral discs (IVDs). Quantitative anatomical examinations have shown bundle orientation patterns, possibly coming from regional adaptations of the annulus mechanics. This study aimed to show that the regional differences in annulus mechanical behaviour could be reproduced by considering only fibre orientation changes. Using the finite element method, a lumbar annulus was modelled as a poro-hyperelastic material in which fibres were represented by a direction-dependent strain energy density term. Fibre orientations were calibrated to reproduce the annulus tensile behaviours measured for four different regions: posterior outer, anterior outer, posterior inner and anterior inner. The back-calculated fibre angles and regional patterns as well as the global disc behaviour were comparable with anatomical descriptions reported in the literature. It was concluded that annulus fibre variations might be an effective tool to calibrate lumbar spine IVD and segment models. PMID- 22224725 TI - Large-scale cubic InN nanocrystals by a combined solution- and vapor-phase method under silica confinement. AB - Large-scale cubic InN nanocrystals were synthesized by a combined solution- and vapor-phase method under silica confinement. Nearly monodisperse cubic InN nanocrystals with uniform spherical shape were dispersed stably in various organic solvents after removal of the silica shells. The average size of InN nanocrystals is 5.7 +/- 0.6 nm. Powder X-ray diffraction results indicate that the InN nanocrystals are of high crystallinity with a cubic phase. X-ray photoelectron spectroscopy and energy-dispersive spectroscopy confirm that the nanocrystals are composed of In and N elements. The InN nanocrystals exhibit infrared photoluminescence at room temperature, with a peak energy of ~0.62 eV, which is smaller than that of high-quality wurtzite InN (~0.65-0.7 eV) and is in agreement with theoretical calculations. The small emission peak energy of InN nanocrystals, as compared to other low-cost solution or vapor methods, reveals the superior crystalline quality of our samples, with low or negligible defect density. This work will significantly promote InN-based applications in IR optoelectronic device and biology. PMID- 22224728 TI - The addition of rituximab reduces the incidence of secondary central nervous system involvement in patients with diffuse large B-cell lymphoma. PMID- 22224746 TI - Choosing the right assessment for the right purpose. PMID- 22224726 TI - Mechanisms of immunosenescence: lessons from models of accelerated immune aging. AB - With increasing age, the ability of the adaptive immune system to respond to vaccines and to protect from infection declines. In parallel, the production of inflammatory mediators increases. While cross-sectional studies have been successful in defining age-dependent immunological phenotypes, studies of accelerated immune aging in human subpopulations have been instrumental in obtaining mechanistic insights. The immune system depends on its regenerative capacity; however, the T cell repertoire, once established, is relatively robust to aging and only decompensates when additionally stressed. Such stressors include chronic infections such as CMV and HIV, even when viral replication is controlled, and autoimmune diseases. Reduced regenerative capacity, chronic immune activation in the absence of cell exhaustion, T cell memory inflation, and accumulation of highly potent effector T cells in these patients synergize to develop an immune phenotype that is characteristic of the elderly. Studies of accelerated immune aging in autoimmune diseases have identified an unexpected link to chronic DNA damage responses that are known to be important in aging, but so far had not been implicated in immune aging. PMID- 22224747 TI - Hierarchical integration of agency and communion: a study of influential moral figures. AB - The purpose of this research is to (a) identify which of recent history's influential figures did and which did not personify moral excellence, and (b) to examine the motives that drove these individuals along such divergent paths. In Study 1, 102 social scientists evaluated the moral qualities of influential figures from Time Magazine's lists. In Study 2, we selected the 15 top ranking of these figures to comprise a moral exemplar group and the bottom 15 to comprise a comparison group of similarly influential people. We measured the motivational aspects of their personality (agency and communion) by content-analyzing extant speeches and interviews. Moral exemplars exhibited the hierarchical integration of agency and communion by treating agentic motives as a means to an end of communal motives. Comparison subjects, by contrast, personified unmitigated agency by treating motives of agency as both a means to an end and an end unto itself. These results imply that both the strength and structure of a person's motives account for moral behavior. PMID- 22224749 TI - Self-diffusion of ions in Nafion-117 membrane having mixed ionic composition. AB - The self-diffusion coefficients (SDCs) of Na(+), Cs(+), and Ba(2+) have been determined in Nafion-117 membrane having mixed cationic compositions. Membranes with different proportions of Na(+)-Cs(+), Cs(+)-Ba(2+), Na(+)-Ba(2+), and Ag(+) Ba(2+) cations have been prepared by equilibrating with solutions containing different ratios of these cations. The SDCs of the cations (D(Na), D(Cs), D(Ba)) and the ionic compositions of the membrane have been determined using a radiotracer method. For the Na-Cs and Cs-Ba systems, the SDCs of the cations have been found to be independent of the ionic compositions of the membrane. In the case of the Na-Ba system, D(Na) does not change with ionic composition, while D(Ba) has been found to be strongly dependent on the ionic composition of the membrane and decreases continuously with increasing Na(+) content in the membrane. Similar results have also been obtained for D(Ba) in the case of the Ag Ba system. The specific conductivities (kappa(imp)) of the membrane in mixed cationic forms have also been obtained from ac impedance measurement and compared with that (kappa(cal)) calculated from the SDC data. For the Na-Ba system, the increment of kappa(imp) with increase in the Na(+) content of the membrane has been found to be parabolic, whereas for the Na-Cs system the increment is linear. The reason behind the different behaviors for different types of ionic systems has been qualitatively explained based on different transport pathways of the cations in the membrane. PMID- 22224750 TI - Geomicrobiology of extremely acidic subsurface environments. AB - Extreme acidophiles (microorganisms with pH optima of < 3) can colonize and exploit subterranean environments, such as abandoned metal sulfide mines, that have the potential for developing widespread or isolated pockets of acidity. Although acidophiles can utilize a wide range of electron donors, inorganic materials (reduced sulfur, ferrous iron, and possibly hydrogen) are often the most abundant sources of energy for acidophiles in the subsurface. The diversity and interactions of acidophilic microbial communities in two abandoned sulfide mineral mines (in Iron Mountain, California, and the Harz mountains in Germany) and a sulfidic cave (Frasissi, Italy) are reviewed. In addition, the contrasting geomicrobiology of two abandoned sulfide mineral mines in north Wales is described. Both are extremely acidic (pH~2) and low-temperature (8-9 degrees C) sites, but one (Cae Coch) is essentially a dry mine with isolated pockets of water, while the other (Mynydd Parys) contains a vast underground lake that was partially drained several years ago. The microbial communities in these two mines exhibit different relative abundances and often different species of archaea and bacteria. Wooden pit props, submerged in the underground lake, act as a slow release source of organic carbon in the subterranean Mynydd Parys lake, supporting a microbial community that is more enriched with heterotrophic microorganisms. PMID- 22224751 TI - Three-dimensional image quantification as a new morphometry method for tissue engineering. AB - Morphological analysis is an essential step in verifying the success of a tissue engineering strategy where the presence of a desired cellular phenotype must be determined. While morphometry has transitioned from observational grading to computational quantification, established quantitative methods eliminate information by relying on two-dimensional (2D) analysis to describe three dimensional (3D) niches. In this study, we demonstrate the validity and utility of 3D morphological quantification using two common angiogenesis assays in our fibrin-based in vitro model: (1) the microcarrier bead assay with human mesenchymal stem cells and (2) the rat aortic ring outgrowth assay. The quantification method is based on collecting and segmenting fluorescent confocal z-stacks into 3D models with 3D Slicer, an open-source magnetic resonance imaging/computed tomography analysis program. Data from 3D models are then processed into biologically relevant metrics in MATLAB for statistical analysis. Metrics include descriptive parameters such as vascular network length, volume, number of network segments, and degree of network branching. Our results indicate that 2D measures are significantly different than their 3D counterparts unless the vascular network exhibits anisotropic growth along the plane of imaging. Additionally, the statistical outcomes of 3D morphological quantification agreed with our initial qualitative observations among different test groups. This novel quantification approach generates more spatially accurate and objective measures, representing an important step toward improving the reliability of morphological comparisons. PMID- 22224752 TI - Accumulation of weathered p,p'-DDTs in grafted watermelon. AB - The grafting of melon plants onto cucurbit rootstocks is a common commercial practice in many parts of the world. However, certain cucurbits have been shown to accumulate large quantities of weathered persistent organic pollutants from the soil, and the potential contamination of grafted produce has not been thoroughly evaluated. Large pot and field experiments were conducted to assess the effect of grafting on accumulation of weathered DDX (the sum of p,p'-DDT, p,p'-DDD, and p,p'-DDE) from soils. Intact squash (Cucurbita maxima * moschata) and watermelon (Citrullus lanatus), their homografts, and compatible heterografts were grown in pots containing soil with weathered DDX at 1480-1760 ng/g soil or under field conditions in soil at 150-300 ng/g DDX. Movement of DDX through the soil-plant system was investigated by determining contaminant levels in the bulk soil and in the xylem sap, roots, stems, leaves, and fruit of the grafted and nongrafted plants. In all plants, the highest DDX concentrations were detected in the roots, followed by decreasing amounts in the stems, leaves, and fruit. Dry weight concentrations of DDX in the roots ranged from 7900 ng/g (intact watermelon) to 30100 ng/g (heterografted watermelon) in the pot study and from 650 ng/g (intact watermelon) to 2430 ng/g (homografted squash) in the field experiment. Grafting watermelon onto squash rootstock significantly increased contaminant uptake into the melon shoot system. In the pot and field studies, the highest stem DDX content was measured in heterografted watermelon at 1220 and 244 ng/g, respectively; these values are 140 and 19 times greater than contaminant concentrations in the intact watermelon, respectively. The xylem sap DDX concentrations of pot-grown plants were greatest in the heterografted watermelon (6.10 MUg/L). The DDX contents of the leaves and fruit of watermelon heterografts were 3-12 and 0.53-8.25 ng/g, respectively, indicating that although the heterografted watermelon accumulated greater pollutant levels, the resulting contamination is not likely a food safety concern. PMID- 22224754 TI - Racial/ethnic differences in prevalence and correlates of binge drinking among older adults. AB - OBJECTIVES: This study examines how the prevalence and correlates of binge drinking among older adults vary by race/ethnicity. METHODS: Drawn from the 2007 California Health Interview Survey, adults aged 60 and older (n = 18,772) were selected. Binge drinking was measured dichotomously based on whether individuals reported consuming five or more drinks in a single day (four or more for females) in the previous year. Prevalence rates for binge drinking in the past year were calculated by race/ethnicity. A hierarchical logistic regression analysis was conducted using binge drinking in the past year as the dependent variable. RESULTS: Significant racial/ethnic differences were found in prevalence rates: the presence of binge drinking was most common among non-Hispanic Whites (11.9%), followed by Latinos (10.8%), American Indian/Alaska Natives (9.8%), Blacks (8.0%), and Asians (4.2%). Being a current smoker was found to be the strongest predictor of binge drinking and significant main effects were also found for being Black, being Asian, younger age, being male, being unemployed, having a higher poverty threshold, having better self-rated health, and having more psychological distress. Significant interactions between race/ethnicity and age, sex, employment status, educational attainment, smoking status, and self-rated health were found. These findings indicate that certain correlates of binge drinking vary significantly by race/ethnicity among older adults. CONCLUSIONS: Apparent racial/ethnic differences existed in the prevalence and correlates of binge drinking among older adults. Identification of more racial/ethnic specific predictors may be important for the development of racial/ethnic appropriate intervention programs. PMID- 22224755 TI - Editors' introduction to the addendum to efficacy of music therapy based on cycles of sessions: a randomized control trial. PMID- 22224756 TI - Addendum to 'Efficacy of music therapy treatment based on cycles of sessions: a randomised controlled trial' (Raglio et al., 2010). AB - OBJECTIVES: The aim of this paper is to provide further detail about the results of a randomised controlled study published in this journal (Raglio et al., 2010, 14, 900-904), in which we assessed the efficacy of music therapy (MT) on the behavioural disturbances in people with moderate-severe dementia. METHODS: Sixty patients were randomly assigned to the experimental (MT and standard care) and control group (standard care only). The experimental group received three cycles of 12 MT sessions each, three times a week. Each cycle of treatment was followed by one month of washout period, while the standard care activities continued over time. RESULTS: The impact of the treatment (12 MT sessions) was reliable on NPI global scores, as the interaction Time by Group was significant (F(1,49) = 4.09, p = 0.049). After the end of the treatment the NPI global scores of the experimental and control groups tended to become similar, as both groups worsened (Time effect: F(1,48) = 4.67, p = 0.014) and the difference between them disappeared (F < 1). Interaction Time by Group was not significant. CONCLUSIONS: The study confirms that active MT determines a positive response and can amplify and strengthen the efficacy of therapeutic interventions towards people with dementia. PMID- 22224757 TI - Prevention of liver fibrosis and liver reconstitution of DMN-treated rat liver by transplanted EPCs. AB - BACKGROUND: Using the dimethylnitrosamine (DMN) rat model of induced fibrosis, we investigated whether transfer of in vitro-expanded endothelial progenitor cells (EPCs) could reconstitute liver tissue and protect against liver fibrosis. MATERIALS AND METHODS: Low-density, adherent, rat bone marrow-derived mononuclear cells were cultured for one week in medium supporting the growth of chemokine (C-X-C motif) receptor 4 (CXCR4)-positive EPCs that were used for transplantation. Test rats were treated with weekly intraperitoneal injections of DMN over a period of 4 weeks. During that period, the rats were also transplanted weekly with in vivo-expanded EPCs. RESULTS: Transplanted CXCR4-positive expanded EPCs entered around the portal tracts, fibrous septa and hepatic sinusoids, locations at which stromal cell-derived factor 1 (SDF-1), a ligand attracting CXCR4-positive cells, was expressed nearby. In EPC-transplanted rats, we observed suppression of liver fibrogenesis, reduced deposition of type I collagen and fibronectin, fewer alpha-smooth muscle actin-positive cells and lower expression of transforming growth factor (TGF)-beta. The expression of growth factors promoting hepatic regeneration (hepatocyte growth factor, transforming growth factor-alpha (TGF-alpha), epidermal growth factor and vascular endothelial growth factor) was significantly increased in EPC transplanted rats, resulting in hepatocyte proliferation. Immunohistochemical analyses of eNOS and isolectin B4 demonstrated that the livers of EPC transplanted animals had markedly increased vascular density, suggesting reconstitution of sinusoidal blood vessels with endothelium. Liver function tests of transaminase, total bilirubin, total protein and albumin demonstrated that normal levels were maintained in EPC-transplanted rats. CONCLUSIONS: EPC transplantation effectively promotes the remodelling of tissues damaged by liver fibrosis; it can also reconstitute sinusoids in chronic liver injury. PMID- 22224758 TI - Use of near-infrared spectroscopy for fast fraud detection in seafood: application to the authentication of wild European sea bass (Dicentrarchus labrax). AB - The possibility of using near-infrared spectroscopy (NIRS) for the authentication of wild European sea bass ( Dicentrarchus labrax ) was investigated in this study. Three different chemometric techniques to process the NIR spectra were developed, and their ability to discriminate between wild and farmed sea bass samples was evaluated. One approach used spectral information to directly build the discrimination model in a latent variable space; the second approach first used wavelets to transform the spectral information and subsequently derived the discrimination model using the transformed spectra; in the third approach a cascaded arrangement was proposed whereby very limited chemical information was first estimated from spectra using a regression model, and this estimated information was then used to build the discrimination model in a latent variable space. All techniques showed that NIRS can be used to reliably discriminate between wild and farmed sea bass, achieving the same classification performance as classification methods that use chemical properties and morphometric traits. However, compared to methods based on chemical analysis, NIRS-based classification methods do not require reagents and are simpler, faster, more economical, and environmentally safer. All proposed techniques indicated that the most predictive spectral regions were those related to the absorbance of groups CH, CH(2), CH(3), and H(2)O, which are related to fat, fatty acids, and water content. PMID- 22224759 TI - A facile method for preparing sticky, hydrophobic polymer surfaces. AB - Textured surfaces consisting of nanometer- to micrometer-sized lightly sulfonated polystyrene ionomer (SPS) particles were prepared by rapid evaporation of the solvent from a dilute polymer solution-cast onto silica. The particle textured ionomer surfaces were prepared by either spin-coating or solution-casting ionomer solutions at controlled evaporation rates. The effects of the solvent used to spin-coat the film, the molecular weight of the ionomer, and the rate of solvent evaporation on the surface morphology of cast films were investigated. The surface morphologies were consistent with a spinodal decomposition mechanism, where the surface first existed as a percolated-like structure and then ripened into droplets if molecular mobility was retained for sufficient time. The SPS particles or particle aggregates were robust and resisted separation from the surface even after annealing at 120 degrees C for 1 week. The water contact angles on as-prepared surfaces were relatively low, ~90 degrees , due to the polar groups in the ionomer, but when the surface was modified by chemical vapor deposition of 1H,1H,2H,2H-perfluorooctyltrichlorosilane, the surface contact angles increased to ~109 degrees on smooth surfaces and up to ~140 degrees on the textured surfaces. Although the surfaces were hydrophobic, the contact angle hysteresis was relatively high and water droplets stuck to these surfaces even when the surface was turned upside down. PMID- 22224760 TI - Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. AB - T helper cell differentiation occurs in the context of the extracellular cytokine milieu evoked by diverse microbes and other pathogenic stimuli along with T cell receptor stimulation. The culmination of these signals results in specification of T helper lineages, which occurs through the combinatorial action of multiple transcription factors that establish distinctive transcriptomes. In this manner, inducible, but constitutively active, master regulators work in conjunction with factors such as the signal transducer and activator of transcriptions (STATs) that sense the extracellular environment. The acquisition of a distinctive transcriptome also depends on chromatin modifications that impact key cis elements as well as the changes in global genomic organization. Thus, signal transduction and epigenetics are linked in these processes of differentiation. In this review, recent advances in understanding T helper lineage specification and deciphering the action of transcription factors are summarized with emphasis on comprehensive views of the dynamic T cell epigenome. PMID- 22224761 TI - Cancer and inflammation: an old intuition with rapidly evolving new concepts. AB - Recent scientific advances have contributed much to the dissection of the complex molecular and cellular pathways involved in the connection between cancer and inflammation. The evidence for this connection in humans is based on the association between infection or chronic sterile inflammation and cancer. The decreased incidence of tumors in individuals who have used nonsteroidal anti inflammatory drugs is supportive of a role for inflammation in cancer susceptibility. The increased incidence of tumors in overweight patients points to a role for adipose tissue inflammation and energy metabolism in cancer. Energy metabolism, obesity, and genetic instability are regulated in part by the relationship of the organism with commensal bacteria that affect inflammation with both local and systemic effects. Different aspects of inflammation appear to regulate all phases of malignant disease, including susceptibility, initiation, progression, dissemination, morbidity, and mortality. PMID- 22224762 TI - Induced CD4+Foxp3+ regulatory T cells in immune tolerance. AB - Regulatory T lymphocytes are essential to maintain homeostasis of the immune system, limiting the magnitude of effector responses and allowing the establishment of immunological tolerance. Two main types of regulatory T cells have been identified--natural and induced (or adaptive)-and both play significant roles in tuning down effector immune responses. Adaptive CD4(+)Foxp3(+) regulatory T (iTreg) cells develop outside the thymus under a variety of conditions. These include not only antigen presentation under subimmunogenic or noninflammatory conditions, but also chronic inflammation and infections. We speculate that the different origin of iTreg cells (noninflammatory versus inflammatory) results in distinct properties, including their stability. iTreg cells are also generated during homeostasis of the gut and in cancer, although some cancers also favor expansion of natural regulatory T (nTreg) cells. Here we review how iTreg cells develop and how they participate in immunological tolerance, contrasting, when possible, iTreg cells with nTreg cells. PMID- 22224763 TI - Innate lymphoid cells: emerging insights in development, lineage relationships, and function. AB - Innate lymphoid cells (ILCs) are immune cells that lack a specific antigen receptor yet can produce an array of effector cytokines that in variety match that of T helper cell subsets. ILCs function in lymphoid organogenesis, tissue remodeling, antimicrobial immunity, and inflammation, particularly at barrier surfaces. Their ability to promptly respond to insults inflicted by stress causing microbes strongly suggests that ILCs are critical in first-line immunological defenses. Here, we review current data on developmental requirements, lineage relationships, and effector functions of two families of ILCs: (a) Rorgammat-expressing cells involved in lymphoid tissue formation, mucosal immunity, and inflammation and (b) type 2 ILCs that are important for helminth immunity. We also discuss the potential roles of ILCs in the pathology of immune-mediated inflammatory and infectious diseases including allergy. PMID- 22224767 TI - Pathogenesis of human B cell lymphomas. AB - The mechanisms that drive normal B cell differentiation and activation are frequently subverted by B cell lymphomas for their unlimited growth and survival. B cells are particularly prone to malignant transformation because the machinery used for antibody diversification can cause chromosomal translocations and oncogenic mutations. The advent of functional and structural genomics has greatly accelerated our understanding of oncogenic mechanisms in lymphomagenesis. The signaling pathways that normal B cells utilize to sense antigens are frequently derailed in B cell malignancies, leading to constitutive activation of prosurvival pathways. These malignancies co-opt transcriptional regulatory systems that characterize their normal B cell counterparts and frequently alter epigenetic regulators of chromatin structure and gene expression. These mechanistic insights are ushering in an era of targeted therapies for these cancers based on the principles of pathogenesis. PMID- 22224764 TI - The microbiome in infectious disease and inflammation. AB - The mammalian alimentary tract harbors hundreds of species of commensal microorganisms (microbiota) that intimately interact with the host and provide it with genetic, metabolic, and immunological attributes. Recent reports have indicated that the microbiota composition and its collective genomes (microbiome) are major factors in predetermining the type and robustness of mucosal immune responses. In this review, we discuss the recent advances in our understanding of host-microbiota interactions and their effect on the health and disease susceptibility of the host. PMID- 22224765 TI - Monogenic autoimmunity. AB - Monogenic autoimmune syndromes provide a rare yet powerful glimpse into the fundamental mechanisms of immunologic tolerance. Such syndromes reveal not only the contribution of an individual breakpoint in tolerance but also patterns in the pathogenesis of autoimmunity. Disturbances in innate immunity, a system built for ubiquitous sensing of danger signals, tend to generate systemic autoimmunity. For example, defects in the clearance of self-antigens and chronic stimulation of type 1 interferons lead to the systemic autoimmunity seen in C1q deficiency, SPENCDI, and AGS. In contrast, disturbances of adaptive immunity, which is built for antigen specificity, tend to produce organ-specific autoimmunity. Thus, the loss of lymphocyte homeostasis, whether through defects in apoptosis, suppression, or negative selection, leads to organ-specific autoimmunity in ALPS, IPEX, and APS1. We discuss the unique mechanisms of disease in these prominent syndromes as well as how they contribute to the spectrum of organ-specific or systemic autoimmunity. The continued study of rare variants in autoimmune disease will inform future investigations and treatments directed at rare and common autoimmune diseases alike. PMID- 22224766 TI - Signaling by myeloid C-type lectin receptors in immunity and homeostasis. AB - Myeloid cells are key drivers of physiological responses to pathogen invasion or tissue damage. Members of the C-type lectin receptor (CLR) family stand out among the specialized receptors utilized by myeloid cells to orchestrate these responses. CLR ligands include carbohydrate, protein, and lipid components of both pathogens and self, which variably trigger endocytic, phagocytic, proinflammatory, or anti-inflammatory reactions. These varied outcomes rely on a versatile system for CLR signaling that includes tyrosine-based motifs that recruit kinases, phosphatases, or endocytic adaptors as well as nontyrosine-based signals that modulate the activation of other pathways or couple to the uptake machinery. Here, we review the signaling properties of myeloid CLRs and how they impact the role of myeloid cells in innate and adaptive immunity. PMID- 22224768 TI - Reflex principles of immunological homeostasis. AB - The reasoning that neural reflexes maintain homeostasis in other body organs, and that the immune system is innervated, prompted a search for neural circuits that regulate innate and adaptive immunity. This elucidated the inflammatory reflex, a prototypical reflex circuit that maintains immunological homeostasis. Molecular products of infection or injury activate sensory neurons traveling to the brainstem in the vagus nerve. The arrival of these incoming signals generates action potentials that travel from the brainstem to the spleen and other organs. This culminates in T cell release of acetylcholine, which interacts with alpha7 nicotinic acetylcholine receptors (alpha7 nAChR) on immunocompetent cells to inhibit cytokine release in macrophages. Herein is reviewed the neurophysiological basis of reflexes that provide stability to the immune system, the neural- and receptor-dependent mechanisms, and the potential opportunities for developing novel therapeutic devices and drugs that target neural pathways to treat inflammatory diseases. PMID- 22224770 TI - Tolerance of infections. AB - A host has two methods to defend against pathogens: It can clear the pathogens or reduce their impact on health in other ways. The first, resistance, is well studied. Study of the second, which ecologists call tolerance, is in its infancy. Tolerance measures the dose response curve of a host's health in reaction to a pathogen and can be studied in a simple quantitative manner. Such studies hold promise because they point to methods of treating infections that put evolutionary pressures on microbes different from antibiotics and vaccines. Studies of tolerance will provide an improved foundation to describe our interactions with all microbes: pathogenic, commensal, and mutualistic. One obvious mechanism affecting tolerance is the intensity of an immune response; an overly exuberant immune response can cause collateral damage through immune effectors and because of the energy allocated away from other physiological functions. There are potentially many other tolerance mechanisms, and here we systematically describe tolerance using a variety of animal systems. PMID- 22224769 TI - Siglecs and immune regulation. AB - Sialic acid-binding Ig-like lectins, or Siglecs, vary in their specificity for sialic acid-containing ligands and are mainly expressed by cells of the immune system. Many Siglecs are inhibitory receptors expressed in innate immune cells that regulate inflammation mediated by damage-associated and pathogen-associated molecular patterns (DAMPs and PAMPs). This family also includes molecules involved in adhesion and phagocytosis and receptors that can associate with the ITAM-containing DAP12 adaptor. Siglecs contribute to the inhibition of immune cells both by binding to cis ligands (expressed in the same cells) and by responding to pathogen-derived sialoglycoconjugates. They can help maintain tolerance in B lymphocytes, modulate the activation of conventional and plasmacytoid dendritic cells, and contribute to the regulation of T cell function both directly and indirectly. Siglecs modulate immune responses, influencing almost every cell in the immune system, and are of relevance both in health and disease. PMID- 22224771 TI - Chromatin topology and the regulation of antigen receptor assembly. AB - During an organism's ontogeny and in the adult, each B and T lymphocyte generates a unique antigen receptor, thereby creating the organism's ability to respond to a vast number of different antigens. The antigen receptor loci are organized into distinct regions that contain multiple variable (V), diversity (D), and/or joining (J) and constant (C) coding elements that are scattered across large genomic regions. In this review, we discuss the epigenetic modifications that take place in the different antigen receptor loci, the chromatin structure adopted by the antigen receptor loci to allow recombination of elements separated by large genomic distances, and the relationship between epigenetics and chromatin structure and how they relate to the generation of antigen receptor diversity. PMID- 22224772 TI - Germinal centers. AB - Germinal centers (GCs) were described more than 125 years ago as compartments within secondary lymphoid organs that contained mitotic cells. Since then, it has become clear that this structure is the site of B cell clonal expansion, somatic hypermutation, and affinity-based selection, the combination of which results in the production of high-affinity antibodies. Decades of anatomical and functional studies have led to an overall model of how the GC reaction and affinity-based selection operate. More recently, the introduction of intravital imaging into the GC field has opened the door to direct investigation of certain key dynamic features of this microanatomic structure, sparking renewed interest in the relationship between cell movement and affinity maturation. We review these and other recent advances in our understanding of GCs, focusing on cellular dynamics and on the mechanism of selection of high-affinity B cells. PMID- 22224773 TI - microRNA regulation of inflammatory responses. AB - The mammalian inflammatory response is a rapid and complex physiological reaction to noxious stimuli including microbial pathogens. Although inflammation plays a valuable role in combating infection, its dysregulation often occurs in people and can cause a variety of pathologies, ranging from chronic inflammation, to autoimmunity, to cancer. In recent years, our understanding of both the cellular and molecular networks that regulate inflammation has improved dramatically. Although much of the focus has been on the study of protein regulators of inflammation, recent evidence also points to a critical role for a specific class of noncoding RNAs, called microRNAs (miRNAs), in managing certain features of the inflammatory process. In this review, we discuss recent advances in our understanding of miRNAs and their connection to inflammatory responses. Additionally, we consider the link between perturbations in miRNA levels and the onset of human inflammatory diseases. PMID- 22224774 TI - Neutrophil function: from mechanisms to disease. AB - Neutrophils are the most abundant white blood cells in circulation, and patients with congenital neutrophil deficiencies suffer from severe infections that are often fatal, underscoring the importance of these cells in immune defense. In spite of neutrophils' relevance in immunity, research on these cells has been hampered by their experimentally intractable nature. Here, we present a survey of basic neutrophil biology, with an emphasis on examples that highlight the function of neutrophils not only as professional killers, but also as instructors of the immune system in the context of infection and inflammatory disease. We focus on emerging issues in the field of neutrophil biology, address questions in this area that remain unanswered, and critically examine the experimental basis for common assumptions found in neutrophil literature. PMID- 22224776 TI - Immune regulatory function of B cells. AB - B cells are regarded for their capacity to produce antibody. However, recent advances in B cell biology have capitalized on old findings and demonstrated that B cells also release a broad variety of cytokines. As with T helper cells, B cells can be classified into subsets according to the cytokine milieu that they produce. One functional B cell subset, regulatory B cells (Bregs), has recently been shown to contribute to the maintenance of the fine equilibrium required for tolerance. Bregs restrain the excessive inflammatory responses that occur during autoimmune diseases or that can be caused by unresolved infections. Pivotal to Breg function is interleukin-10 (IL-10), which inhibits proinflammatory cytokines and supports regulatory T cell differentiation. This review reports and discusses the factors that are important for Breg differentiation and for their effector function in both mouse and human. PMID- 22224775 TI - VLR-based adaptive immunity. AB - Lampreys and hagfish are primitive jawless vertebrates capable of mounting specific immune responses. Lampreys possess different types of lymphocytes, akin to T and B cells of jawed vertebrates, that clonally express somatically diversified antigen receptors termed variable lymphocyte receptors (VLRs), which are composed of tandem arrays of leucine-rich repeats. The VLRs appear to be diversified by a gene conversion mechanism involving lineage-specific cytosine deaminases. VLRA is expressed on the surface of T-like lymphocytes; B-like lymphocytes express and secrete VLRB as a multivalent protein. VLRC is expressed by a distinct lymphocyte lineage. VLRA-expressing cells appear to develop in a thymus-like tissue at the tip of gill filaments, and VLRB-expressing cells develop in hematopoietic tissues. Reciprocal expression patterns of evolutionarily conserved interleukins and chemokines possibly underlie cell-cell interactions during an immune response. The discovery of VLRs in agnathans illuminates the origins of adaptive immunity in early vertebrates. PMID- 22224777 TI - Lung dendritic cells in respiratory viral infection and asthma: from protection to immunopathology. AB - Lung dendritic cells (DCs) bridge innate and adaptive immunity, and depending on context, they also induce a Th1, Th2, or Th17 response to optimally clear infectious threats. Conversely, lung DCs can also mount maladaptive Th2 immune responses to harmless allergens and, in this way, contribute to immunopathology. It is now clear that the various aspects of DC biology can be understood only if we take into account the functional specializations of different DC subsets that are present in the lung in homeostasis or are attracted to the lung as part of the inflammatory response to inhaled noxious stimuli. Lung DCs are heavily influenced by the nearby epithelial cells, and a model is emerging whereby direct communication between DCs and epithelial cells determines the outcome of the pulmonary immune response. Here, we have approached DC biology from the perspective of viral infection and allergy to illustrate these emerging concepts. PMID- 22224778 TI - The response to and repair of RAG-mediated DNA double-strand breaks. AB - Developing lymphocytes must assemble antigen receptor genes encoding the B cell and T cell receptors. This process is executed by the V(D)J recombination reaction, which can be divided into DNA cleavage and DNA joining steps. The former is carried out by a lymphocyte-specific RAG endonuclease, which mediates DNA cleavage at two recombining gene segments and their flanking RAG recognition sequences. RAG cleavage generates four broken DNA ends that are repaired by nonhomologous end joining forming coding and signal joints. On rare occasions, these DNA ends may join aberrantly forming chromosomal lesions such as translocations, deletions and inversions that have the potential to cause cellular transformation and lymphoid tumors. We discuss the activation of DNA damage responses by RAG-induced DSBs focusing on the component pathways that promote their normal repair and guard against their aberrant resolution. Moreover, we discuss how this DNA damage response impacts processes important for lymphocyte development. PMID- 22224779 TI - Microbial translocation across the GI tract. AB - The lumen of the gastrointestinal (GI) tract is home to an enormous quantity of different bacterial species, our microbiota, that thrive in an often symbiotic relationship with the host. Given that the healthy host must regulate contact between the microbiota and its immune system to avoid overwhelming systemic immune activation, humans have evolved several mechanisms to attenuate systemic microbial translocation (MT) and its consequences. However, several diseases are associated with the failure of one or more of these mechanisms, with consequent immune activation and deleterious effects on health. Here, we discuss the mechanisms underlying MT, diseases associated with MT, and therapeutic interventions that aim to decrease it. PMID- 22224783 TI - Recanalization with subsequent near-total occlusion of an internal carotid artery aneurysm after immediate thrombotic occlusion using a flow-diverting stent. AB - A flow-diverting stent is placed in the parent artery to reduce blood flow in the aneurysm sac to facilitate progressive thrombosis and neointimal remodeling while maintaining outflow in the side branches and perforators. All international multicenter registries have reported on the progressive occlusion of aneurysms with time and have implied that an occluded aneurysm would not recanalize given the protective effect of the altered hemodynamics. Recanalization of an occluded aneurysm after placement of a flow-diverting stent has not been reported in the literature. The authors here describe a case of aneurysm recanalization after immediate thrombotic occlusion of the aneurysm with a flow-diverting stent. A 46 year-old male chronic smoker with chronic hypertension and hypercholesterolemia had a recurrent internal carotid artery aneurysm 1 year after embolization. Immediate thrombotic occlusion of the aneurysm and cessation of blood flow to the posterior communicating artery (PCoA) occurred immediately after activating a flow-diverting stent, with corresponding ischemic complications. However, 3 months after insertion of the stent, follow-up MR angiography showed recanalization of the aneurysm as well as of the PCoA. Additional angiography studies at 6 months showed near-total occlusion of the aneurysm with the restoration of blood flow to the PCoA. PMID- 22224784 TI - Transnasal excerebration surgery in ancient Egypt. AB - Ancient Egyptians were pioneers in many fields, including medicine and surgery. Our modern knowledge of anatomy, pathology, and surgical techniques stems from discoveries and observations made by Egyptian physicians and embalmers. In the realm of neurosurgery, ancient Egyptians were the first to elucidate cerebral and cranial anatomy, the first to describe evidence for the role of the spinal cord in the transmission of information from the brain to the extremities, and the first to invent surgical techniques such as trepanning and stitching. In addition, the transnasal approach to skull base and intracranial structures was first devised by Egyptian embalmers to excerebrate the cranial vault during mummification. In this historical vignette, the authors examine paleoradiological and other evidence from ancient Egyptian skulls and mummies of all periods, from the Old Kingdom to Greco-Roman Egypt, to shed light on the development of transnasal surgery in this ancient civilization. The authors confirm earlier observations concerning the laterality of this technique, suggesting that ancient Egyptian excerebration techniques penetrated the skull base mostly on the left side. They also suggest that the original technique used to access the skull base in ancient Egypt was a transethmoidal one, which later evolved to follow a transsphenoidal route similar to the one used today to gain access to pituitary lesions. PMID- 22224780 TI - Adaptive immunity to fungi. AB - Only a handful of the more than 100,000 fungal species on our planet cause disease in humans, yet the number of life-threatening fungal infections in patients has recently skyrocketed as a result of advances in medical care that often suppress immunity intensely. This emerging crisis has created pressing needs to clarify immune defense mechanisms against fungi, with the ultimate goal of therapeutic applications. Herein, we describe recent insights in understanding the mammalian immune defenses deployed against pathogenic fungi. The review focuses on adaptive immune responses to the major medically important fungi and emphasizes how dendritic cells and subsets in various anatomic compartments respond to fungi, recognize their molecular patterns, and signal responses that nurture and shape the differentiation of T cell subsets and B cells. Also emphasized is how the latter deploy effector and regulatory mechanisms that eliminate these nasty invaders while also constraining collateral damage to vital tissue. PMID- 22224785 TI - Reduction of catheter-associated urinary tract infections among patients in a neurological intensive care unit: a single institution's success. AB - OBJECT: To date, there has been a shortage of evidence-based quality improvement initiatives that have shown positive outcomes in the neurosurgical patient population. A single-institution prospective intervention trial with continuous feedback was conducted to investigate the implementation of a urinary tract infection (UTI) prevention bundle to decrease the catheter-associated UTI rate. METHODS: All patients admitted to the adult neurological intensive care unit (neuro ICU) during a 30-month period were included. The study consisted of two 1 month preintervention observation periods (approximately 1200 catheter days) followed by a 30-month intervention phase (20,394 catheter days). A comprehensive evidence-based UTI bundle encompassing avoidance of catheter insertion, maintenance of sterility, product standardization, and early catheter removal was enacted. RESULTS: The urinary catheter utilization rate dropped from 100% to 73.3% during the intervention phase (p < 0.0001) without any increase in the rate of sacral decubitus ulcers or other skin breakdown. The rate of catheter associated UTI was also significantly reduced from 13.3 to 4.0 infections per 1000 catheter days (p < 0.001). There was a linear relationship between the decreased quarterly catheter utilization rate and the decreased catheter associated UTI rate (r(2) = 0.79, p < 0.0001). CONCLUSIONS: This single-center prospective study demonstrated that a comprehensive UTI prevention bundle along with a continuous quality improvement program can significantly reduce the duration of urinary catheterization and rate of catheter-associated UTI in a neuro ICU. PMID- 22224786 TI - Trigeminal neuralgia caused by a fibrous ring around the nerve. AB - Trigeminal neuralgia is usually caused by compression of the nerve by vessels or a tumor. The authors report a case of trigeminal neuralgia not caused by vessel/tumor compression but by a constricting fibrous band around the trigeminal nerve. A 26-year-old man presented with typical trigeminal neuralgia. Although a gradient echo MR imaging demonstrated no offending vessel or a tumor, the patient agreed to undergo exploratory surgery. Intraoperatively, there were no vessels that could be the cause of the neuralgia; instead, the trigeminal nerve was constricted near the root entry zone. After the fiber was cautiously cut, the nerve expanded slightly. The neuralgia resolved without any neurological deficit, and the postoperative course was uneventful. A fibrous band around the trigeminal nerve can cause trigeminal neuralgia. When the symptom is typical and gradient echo MR imaging shows constriction of the trigeminal nerve, surgery is recommended to release the constricted the trigeminal nerve. PMID- 22224781 TI - Regulatory T cells: mechanisms of differentiation and function. AB - The immune system has evolved to mount an effective defense against pathogens and to minimize deleterious immune-mediated inflammation caused by commensal microorganisms, immune responses against self and environmental antigens, and metabolic inflammatory disorders. Regulatory T (Treg) cell-mediated suppression serves as a vital mechanism of negative regulation of immune-mediated inflammation and features prominently in autoimmune and autoinflammatory disorders, allergy, acute and chronic infections, cancer, and metabolic inflammation. The discovery that Foxp3 is the transcription factor that specifies the Treg cell lineage facilitated recent progress in understanding the biology of regulatory T cells. In this review, we discuss cellular and molecular mechanisms in the differentiation and function of these cells. PMID- 22224787 TI - Patency of the ophthalmic artery after flow diversion treatment of paraclinoid aneurysms. AB - OBJECT: In this study the authors determined the patency rate of the ophthalmic artery (OphA) after placement of 1 or more flow diversion devices across the arterial inlet for treatment of proximal internal carotid artery (ICA) aneurysms, and correlated possible risk factors for OphA occlusion. METHODS: Nineteen consecutive patients were identified (mean age 53.9 years, range 23-74 years, all female) who were treated for 20 ICA aneurysms. In all patients a Pipeline Embolization Device (PED) was placed across the ostium of the OphA while treating the target aneurysm. Flow through the OphA after PED placement was determined by immediate angiography as well as follow-up angiograms (mean 8.7 months), compared with the baseline study. Potential risk factors for OphA occlusion, including age, immediate angiographic flow through the ophthalmic branch, status of flow within the aneurysm after placement of PEDs, whether the ophthalmic branch originated from the aneurysm dome, and number of PEDs placed across the ophthalmic branch inlet were correlated with patency rate. RESULTS: Patients were treated with 1-3 PEDs (3 aneurysms treated with placement of 1 PED, 12 with 2 PEDs, and 5 with 3 PEDs). In 17 (85%) of 20 treated aneurysms, no changes in the OphA flow were noted immediately after placement of the device. Two (10%) of 20 patients had delayed antegrade filling immediately following PED placement and 1 patient (5%) had retrograde flow from collaterals to the OphA immediately after placement of the device. One patient (5%) experienced delayed asymptomatic ICA occlusion; this patient was excluded from analysis at follow-up. At follow-up the OphA remained patent with normal antegrade flow in 13 (68%) of 19 patients, patent but with slow antegrade flow in 2 patients (11%), and was occluded in 4 patients (21%). No visual changes or clinical symptoms developed in patients with OphA flow compromise. The mean number of PEDs in the patients with occluded OphAs or change in flow at angiographic follow-up was 2.4 (SEM 0.2) compared with 1.9 (SEM 0.18) in the patients with no change in OphA flow (p = 0.09). There was no significant difference between the patients with occluded OphAs compared with nonoccluded branches based on patient age, immediate angiographic flow through the ophthalmic branch, status of flow through the aneurysm after placement of PEDs, whether the ophthalmic branch originated from the aneurysm dome, or number of PEDs placed across the ophthalmic branch inlet. CONCLUSIONS: Approximately one quarter of OphAs will undergo proximal thrombosis when covered with flow diversion devices. Even though these events were well-tolerated clinically, our findings suggest that coverage of branch arteries that have adequate collateral circulation may lead to spontaneous occlusion of those branches. PMID- 22224788 TI - Endoscopic endonasal approach to cholesterol granulomas of the petrous apex: a series of 17 patients: clinical article. AB - OBJECT: The aim of this study was to report the results in a consecutive series of patients who had undergone an endoscopic endonasal approach (EEA) for drainage of a petrous apex cholesterol granuloma (CG). METHODS: Seventeen cases with a confirmed diagnosis of petrous apex CG were identified from a database of more than 1600 patients who had undergone an EEA to skull base lesions at the authors' institution in the period from 1998 to 2011. Clinical outcomes were reviewed and compared with those in previous studies of open approaches. RESULTS: Nine patients underwent a transclival approach and 8 patients underwent a combined transclival and infrapetrous approach. A Silastic stent was used in 11 patients (65%), a miniflap in 4 (24%), and a simple marsupialization of the cyst in 3 (18%). All symptomatic patients had partial or complete improvement of their symptoms postoperatively and at the follow-up (mean follow-up 20 months, range 3 67 months). Complications developed in 3 patients (18%) including epistaxis, chronic serous otitis media, eye dryness, and a transient sixth cranial nerve palsy. Two patients (12%) had a symptomatic recurrence of the cyst requiring repeat endoscopic endonasal drainage. There were no instances of internal carotid artery injuries, CSF leaks, or new hearing loss. The mean postoperative hospital stay was 2 days (range 0.7-4.6 days). These results were comparable with those in previous studies of open approaches to petrous apex CGs. There was a strong correlation between the size of the cyst and the type of approach chosen (Rpb [point biserial correlation coefficient] = +0.67, p = 0.003359) and a very strong correlation between the degree of medial extension (defined by the V-angle) and the choice of approach (Rpb = +0.81, p < 0.0001). Based on these observations, the authors developed an algorithm for guiding the choice of the most appropriate route of drainage. CONCLUSIONS: The EEA is a safe and effective alternative to traditional open approaches to petrous apex CGs. PMID- 22224789 TI - Severe disability. PMID- 22224790 TI - Incidence and causes of perioperative mortality after primary surgery for intracranial tumors: a national, population-based study. AB - OBJECT: Surgical mortality is a frequent outcome measure in studies of volume outcome relationships, and the Agency for Healthcare Research and Quality has endorsed surgical mortality after craniotomies as an Inpatient Quality Indicator. Still, the frequency and causes of 30-day mortality after neurosurgical procedures have not been much explored. The authors sought to study the frequency and possible causes of death following primary intracranial tumor operations. They also sought to explore a possible predictive value of perioperative mortality rates from neurosurgical centers in relation to long-term survival. METHODS: Using population-based data from the Norwegian cancer registry, the authors identified 15,918 primary operations for primary CNS tumors treated in Norway in the period from August 1955 through December 2008. Patients were followed up until death, emigration, or September 2009. Causes of mortality as indicated on death certificates were studied. Factors associated with an increased risk of perioperative death were identified. RESULTS: The overall risk of perioperative death after first-time surgery for primary intracranial tumors is currently 2.2% and has decreased over the last decades. An age >= 70 years and histopathological entities with poor long-term prognoses are risk factors. Overlapping lesions are also associated with excess risk, indicating that lesion size or multifocality may matter. The overall risk of perioperative death is also higher in biopsy cases than in resection cases. Perioperative mortality rates of the 4 Norwegian neurosurgical centers were not predictive of their respective long-term survival rates. CONCLUSIONS: Although considered surgically related if they occur within the first 30 days of surgery, most early postoperative deaths can happen independent of the handiwork of the operating surgeon or anesthesiologist. Overall prognosis of the disease seems to be a strong predictor of perioperative death-perhaps not surprisingly since the 30-day mortality rate is merely the intonation of the Kaplan-Meier curve. Both referral and treatment policies at a neurosurgical center will therefore markedly affect such early outcomes, but early deaths may not necessarily reflect overall quality of care or long-term results. The low incidence of perioperative death in intracranial tumor surgery also greatly limits the statistical power in comparative analyses, such as between published patient series or between centers and certainly between surgeons. Therefore the authors question the value of perioperative mortality rates as a quality indicator in modern neurosurgery for tumors. PMID- 22224791 TI - Editorial: urinary tract infection. PMID- 22224792 TI - Perioperative mortality. PMID- 22224793 TI - Automated pelvic anatomical coordinate system is reproducible for determination of anterior pelvic plane. AB - Most of computer-assisted planning systems need to determine the anatomical axis based on the anterior pelvic plane (APP). We analysed that our new system is more reproducible for determination of APP than previous methods. A pelvic model bone and two subjects suffering from hip osteoarthritis were evaluated. Multidetector row computed tomography (MDCT) images were scanned with various rotations by MDCT scanner. The pelvic rotation was calibrated using silhouette images. APP was determined by an optimisation technique. The values of variation of APP caused by pelvic rotation were analysed with statistical analysis. APP determination with calibration and optimisation was most reproducible.The values of variance of APP were within 0.05 degrees in model bone and 0.2 degrees even in patient pelvis. Furthermore, the values of variance of APP with calibration/optimisation were significantly lower in comparison without calibration/optimisation. Both calibration and optimisation are actually required for determination of APP. This system could contribute to the evaluation of hip joint kinematics and computer assisted surgery. PMID- 22224794 TI - Primary immunodeficiencies in India: a perspective. AB - Although primary immunodeficiency diseases (PIDs) were first reported in India in the 1970s, those diagnoses were based predominantly on clinical presentations very limited immunological analyses were performed. Therefore, the validity of many early reports of PIDs may be questionable. However, in the last 10-15 years, diagnoses of PIDs have been based on flow cytometric analysis and, in a few cases, by mutational analysis. In India, PIDs in adults are markedly underreported. We present data from two major centers where diagnosis of PID has been focused primarily in children. We highlight some of the limitations and challenges in the diagnosis and therapy of PID, and more recent efforts to establish PID Centers of Excellence and a national PID registry in India. PMID- 22224796 TI - Acute splenic sequestration crisis in sickle cell disease: cohort study of 190 paediatric patients. AB - Acute splenic sequestration crisis (ASSC) is an unpredictable life-threatening complication of sickle cell disease (SCD) in infants. Here, our objective was to update available clinical information on ASSC. We retrospectively studied the 190 patients who were diagnosed at birth with SS or Sbeta(0) in the Paris conurbation between 2000 and 2009 and who experienced ASSC. They had 437 ASSC episodes (0.06/patient-year). Median age at the first episode was 1.4 years (0.1-7) and 67% of patients had more than one episode. Age was the only factor predicting recurrence: the risk was lower when the first episode occurred after 2 years versus before 1 year of age (hazard ratio, 0.60; 95% confidence interval, 0.41 0.88; P=0.025). A concomitant clinical event was found in 57% of episodes. The mortality rate was 0.53%. The treatment consisted in watchful waiting without prophylactic blood transfusions or splenectomy in 103 (54%) patients and in a blood transfusion programme in 55 (29%) patients. Overall, splenectomy was performed in 71 (37%) patients, at a median age of 4.5 years (range, 1.9-9.4). In conclusion, aggressive treatment may be warranted in patients experiencing ASSC before 2 years of age. Randomized controlled trials are needed to define the best treatment modalities. PMID- 22224814 TI - Tomatidine, a tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in apoE-deficient mice by inhibiting acyl-CoA:cholesterol acyl-transferase (ACAT). AB - It was previously revealed that esculeoside A, a new glycoalkaloid, and esculeogenin A, a new aglycon of esculeoside A, contained in ripe tomato ameliorate atherosclerosis in apoE-deficent mice. This study examined whether tomatidine, the aglycone of tomatine, which is a major tomato glycoalkaloid, also shows similar inhibitory effects on cholesterol ester (CE) accumulation in human monocyte-derived macrophages (HMDM) and atherogenesis in apoE-deficient mice. Tomatidine significantly inhibited the CE accumulation induced by acetylated LDL in HMDM in a dose-dependent manner. Tomatidine also inhibited CE formation in Chinese hamster ovary cells overexpressing acyl-CoA:cholesterol acyl-transferase (ACAT)-1 or ACAT-2, suggesting that tomatidine suppresses both ACAT-1 and ACAT-2 activities. Furthermore, the oral administration of tomatidine to apoE-deficient mice significantly reduced levels of serum cholesterol, LDL-cholesterol, and areas of atherosclerotic lesions. The study provides the first evidence that tomatidine significantly suppresses the activity of ACAT and leads to reduction of atherogenesis. PMID- 22224815 TI - The value of diagnostic whole-body scanning and serum thyroglobulin in the presence of elevated serum thyrotropin during follow-up of anti-thyroglobulin antibody-positive patients with differentiated thyroid carcinoma who appeared to be free of disease after total thyroidectomy and radioactive iodine ablation. AB - BACKGROUND: In the presence of anti-thyroglobulin antibodies (TgAb), serum thyroglobulin (Tg) might be underestimated. Therefore, the American Thyroid Association does not recommend serum Tg after thyroid hormone withdrawal or recombinant human thyrotropin administration (stimulated Tg) and diagnostic whole body scanning (DxWBS) in TgAb-positive patients who have serum Tg values while on thyroxine (Tg-on-T4) of <1 ng/mL. The objective of this study was to determine, in patients with differentiated thyroid cancer (DTC) who appeared to be free of disease after surgery and ablative treatment, but who had positive serum TgAb, the value of performing DxWBS and obtaining serum Tg under stimulated Tg conditions. METHODS: There were 121 women and 15 men in the study. By selection criteria, all of them had total thyroidectomy with apparent complete tumor resection, remnant ablation with (131)I (1.1-5.5 GBq), and a post-(131)I therapy WBS that were negative for ectopic (131)I uptake. On assessment 8-12 months after (131)I ablation, their clinical exam needed to be normal, their Tg-on-T4 needed to be <1 ng/mL, and the test for TgAb needed to be positive. Stimulated Tg, neck ultrasound (US), and DxWBS were obtained from all patients. Patients with stimulated Tg >1 ng/mL without disease on US and DxWBS were evaluated by other imaging methods. RESULTS: In 10 (7.3%) patients, stimulated Tg was >1 ng/mL. The DxWBS revealed metastases in two of these patients, and other imaging methods showed disease in three others. Stimulated Tg was <1 ng/mL in 126 patients. DxWBS revealed metastases in three of these patients, and US detected lymph node metastases in four with a negative DxWBS. Tg stimulation combined with DxWBS revealed evidence for disease in 13 (9.5%) patients. When excluding patients with a positive US, DxWBS revealed metastases in four patients, and stimulated Tg of >1 ng/mL led to detection of persistent disease by other imaging methods in two more patients. CONCLUSIONS: Performing stimulated Tg and DxWBS at the same time seems to be useful after initial therapy in DTC patients with TgAb who do not otherwise appear to have persistent disease, even when US is negative. PMID- 22224816 TI - Psychometric evaluation of Patient Scar Assessment Questionnaire following thyroid and parathyroid surgery. AB - BACKGROUND: The Patient Scar Assessment Questionnaire (PSAQ) was constructed to evaluate the effect of any surgical therapy with a linear scar. This study aims to demonstrate reliability and validity of Appearance and Consciousness subscales of PSAQ in patients who underwent thyroidectomy or parathyroidectomy. METHODS: Patients who underwent a thyroidectomy or parathyroidectomy between 2000 and 2010 were administered the aforementioned subscales of the PSAQ. Each subscale was separately evaluated for its psychometric performance according to established criteria. Acceptability, reliability, and internal validity analysis were conducted. RESULTS: There were 696 patients (mean age=51.6 years) who participated in this study. Cronbach's alpha acceptable levels were demonstrated for the Appearance (alpha=0.79) and Consciousness (alpha=0.85) subscales. Reliability was also supported for the Appearance (Intraclass Correlation Coefficient [ICC]=0.79) and Consciousness subscales (ICC=0.81) by performing test retest reliability analysis. Individual subscale items' correlations with all subscale scores were acceptable for the Appearance (0.31 to 0.78) and Consciousness (0.23 to 0.81) subscales. Internal validity was supported by evaluating correlations between the global assessment item of each subscale and both summary subscale scores (Appearance: 0.42 to 0.72, Consciousness: 0.66 to 0.67). CONCLUSIONS: The Appearance and Consciousness subscales of the PSAQ are both reliable and valid for the assessment of a linear scar following thyroid or parathyroid surgery, independent of the minimally invasive approach being used. PMID- 22224817 TI - A large-scale population-based analysis of common genetic variation in the thyroid hormone receptor alpha locus and bone. PMID- 22224818 TI - The prevalence and features of thyroid pyramidal lobes as assessed by computed tomography. AB - BACKGROUND: The pyramidal lobe is an accessory lobe of the thyroid gland. The prevalence of the pyramidal lobe in thyroid glands and its features have been studied in autopsy series but there is little information regarding its parameters in patients or normal subjects. The purpose of the current study was to assess the frequency, location, and size of the pyramidal lobe using computed tomography (CT) of the neck. METHODS: From January to December 2010, 327 patients who underwent neck CT for trauma, thyroid cancer, pharyngolaryngeal malignancy, a palpable neck mass, cervical lymphadenopathy, and vocal cord paralysis were enrolled in the study. Their neck CTs were retrospectively analyzed by a single radiologist. Small pyramidal lobes (<9 mm) were not included in the study. RESULTS: A pyramidal lobe was present in 41.3% (135/327) of the patients; some pyramidal lobes showed complete separation from the thyroid gland (12.6%, 17/135). There was no difference in the frequency of pyramidal lobe detection by gender (p>0.05, Fisher's exact test). The pyramidal lobe predominantly originated from the left thyroid gland in 54.1% (73/135) of patients. There were two patients in whom the pyramidal lobe was located bilaterally (one case from both the right and left sides of the thyroid gland and one case from the left side and midline of the thyroid gland). The average length and volume of the pyramidal lobes were 25.0 mm and 129.4 mm(3), respectively. The upper margin of the pyramidal lobe was most commonly located at the level of the thyroid cartilage. CONCLUSION: The prevalence of the pyramidal lobe in the left lobe of the thyroid gland is somewhat greater than 50% using the criteria employed in this study. Neck CT is useful for detecting the presence, size, configuration, and location of the pyramidal lobe. PMID- 22224819 TI - Common genetic variants in sex hormone pathway genes and papillary thyroid cancer risk. AB - BACKGROUND: Hormonal differences are hypothesized to contribute to the approximately >=2-fold higher thyroid cancer incidence rates among women compared with men worldwide. Although thyroid cancer cells express estrogen receptors and estrogen has a proliferative effect on papillary thyroid cancer (PTC) cells in vitro, epidemiologic studies have not found clear associations between thyroid cancer and female hormonal factors. We hypothesized that polymorphic variation in hormone pathway genes is associated with the risk of developing papillary thyroid cancer. METHODS: We evaluated the association between PTC and 1151 tag single nucleotide polymorphisms (SNPs) in 58 candidate gene regions involved in sex hormone synthesis and metabolism, gonadotropins, and prolactin in a case-control study of 344 PTC cases and 452 controls, frequency matched on age and sex. Odds ratios and p-values for the linear trend for the association between each SNP genotype and PTC risk were estimated using unconditional logistic regression. SNPs in the same gene region or pathway were aggregated using adaptive rank truncated product methods to obtain gene region-specific or pathway-specific p values. To account for multiple comparisons, we applied the false discovery rate method. RESULTS: Seven SNPs had p-values for linear trend <0.01, including four in the CYP19A1 gene, but none of the SNPs remained significant after correction for multiple comparisons. Results were similar when restricting the dataset to women. p-values for examined gene regions and for all genes combined were >=0.09. CONCLUSIONS: Based on these results, SNPs in selected hormone pathway genes do not appear to be strongly related to PTC risk. This observation is in accord with the lack of consistent associations between hormonal factors and PTC risk in epidemiologic studies. PMID- 22224820 TI - Role of [(18)F]-fluorodeoxy-D-glucose positron emission tomography and computed tomography in the early detection of persistent/recurrent thyroid carcinoma in intermediate-to-high risk patients following initial radioactive iodine ablation therapy. AB - BACKGROUND: Positron emission tomography/computed tomography (PET/CT) scan has a role in the surveillance of patients with a history of thyroid carcinoma. Its efficacy after remnant ablation as far as detecting persistent or recurrent thyroid carcinoma before other surveillance methods is not known, however. In intermediate-to-high risk thyroid carcinoma patients we studied whether PET/CT scan, performed 6-12 months after the first remnant ablation, could provide more information than ultrasonography (US) and thyrotropin-stimulated serum thyroglobulin (Tg) determination with diagnostic whole-body scan (DxWBS). METHODS: We studied 71 subjects with differentiated thyroid cancer (DTC) who were intermediate-to-high risk for persistent/recurrent disease and who had received PET/CT scan, US, and DxWBS simultaneously with stimulated Tg levels 6-12 months after remnant ablation. To evaluate the diagnostic efficacy of PET/CT scan, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were calculated. RESULTS: Ten subjects (14%) had persistent/recurrent disease detected 6-12 months after remnant ablation. Persistence/recurrence was detected in nine (12.7%) of these patients by conventional methods, including US and DxWBS, along with stimulated Tg levels. The remaining case was detected solely by a PET/CT scan, which showed a mediastinal prevascular lesion; this was confirmed by a therapeutic WBS after additional radioiodine therapy. Among the six patients whose PET/CT scan showed positive results, five had persistent/recurrent disease. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of PET/CT scan for detecting persistent/recurrent thyroid carcinoma were 50%, 98.4%, 83.3%, 92.3%, and 91.5%, respectively. CONCLUSION: In intermediate-to high risk patients with DTC seen 6-12 months after their first remnant ablation, there is almost no complementary role for adding a PET/CT scan to conventional follow-up methods, an US and a DxWBS simultaneously with stimulated Tg levels. PMID- 22224821 TI - Mucoepidermoid carcinoma of the thyroid: a report of three cases and postulated histogenesis. AB - BACKGROUND: Primary mucoepidermoid carcinoma (MEC) of the thyroid is a rare clinical and pathological entity that accounts for <0.5% of all thyroid malignancies. Although the histogenesis has been controversial, most investigators now favor it as arising from either metaplasia of thyroid follicular epithelium or heterologous de-differentiation from papillary thyroid carcinoma (PTC). We report three cases of thyroid MEC found in continuity with, and clearly arising from de-differentiation of, well-differentiated thyroid carcinomas (WDTCs). PATIENT FINDINGS AND SUMMARY: The cases presented here included two women (aged 22 and 52) and one man (aged 58). One of these cases arose in conjunction with PTC, one with follicular thyroid carcinoma (FTC), and one with Hurthle cell carcinoma (HCC). In all three cases, there was a gradual transition in morphology between the areas of typical WDTC and the areas showing MEC differentiation. In addition, immunohistochemistry demonstrated a gradual loss of thyroid specific markers (thyroid transcription factor-1, thyroglobulin) mirroring the change in morphology. CONCLUSION: We conclude that thyroid MEC can arise from metaplastic de-differentiation of WDTC, including FTC or HCC in addition to PTC. Currently, we recommend that after excision, each of the WDTC and MEC components of these tumors be treated with targeted adjuvant therapies, which may involve radioactive-iodine ablation, thyrotropin suppression, and external beam radiotherapy. PMID- 22224822 TI - Does temporal contiguity moderate contingency learning in a speeded performance task? AB - In four experiments, we varied the time between the onset of distracting nonwords and target colour words in a word-word version of the colour-word contingency learning paradigm. Contingencies were created by pairing a distractor nonword more often with one target colour word than with other colour words. A contingency effect corresponds to faster responses to the target colour word on high-contingency trials (i.e., distractor nonword followed by the target colour word with which it appears most often) than on low-contingency trials (i.e., distractor nonword followed by a target colour word with which it appears only occasionally). Roughly equivalent-sized contingency effects were found at stimulus-onset asynchronies (SOAs) of 50, 250, and 450 ms in Experiment 1, and 50, 500, and 1,000 ms in Experiment 2. In Experiment 3, a contingency effect was observed at SOAs of -50, -200, and -350 ms. In Experiment 4, interstimulus interval (ISI) was varied along with SOA, and learning was equivalent for 200-, 700-, and 1,200-ms SOAs. Together, these experiments suggest that the distracting stimulus does not need to be presented in close temporal contiguity with the response to induce learning. Relations to past research on causal judgement and implications for further contingency learning research are discussed. PMID- 22224823 TI - Nanoparticle-enhanced surface plasmon resonance detection of proteins at attomolar concentrations: comparing different nanoparticle shapes and sizes. AB - The application of biofunctionalized nanoparticles possessing various shapes and sizes for the enhanced surface plasmon resonance (SPR) detection of a protein biomarker at attomolar concentrations is described. Three different gold nanoparticle shapes (cubic cages, rods and quasi-spherical) with each possessing at least one dimension in the 40-50 nm range were systematically compared. Each nanoparticle (NP) was covalently functionalized with an antibody (anti-thrombin) and used as part of a sandwich assay in conjunction with a Au SPR chip modified with a DNA-aptamer probe specific to thrombin. The concentration of each NP antibody conjugate solution was first optimized prior to establishing that the quasi-spherical nanoparticles resulted in the greatest enhancement in sensitivity with the detection of thrombin at concentrations as low as 1 aM. When nanorod and nanocage antibody conjugates were instead used, the minimum target concentrations detected were 10 aM (rods) and 1 fM (cages). This is a significant improvement (>10(3)) on previous NP-enhanced SPR studies utilizing smaller (~15 nm) gold NP conjugates and is attributed to the functionalization of both the NP and chip surfaces resulting in low nonspecific adsorption as well as a combination of density increases and plasmonic coupling inducing large shifts in the local refractive index at the chip surface upon nanoparticle adsorption. PMID- 22224825 TI - Formation of early and advanced Maillard reaction products correlates to the ripening of cheese. AB - The present study deals with the characterization of the ripening of cheese. A traditional German acid curd cheese was ripened under defined conditions at elevated temperature, and protein and amino acid modifications were investigated. Degree of proteolysis and analysis of early [Amadori compound furosine (6)] and advanced [N(epsilon)-carboxymethyllysine (4), N(epsilon)-carboxyethyllysine (5)] Maillard reaction products confirmed the maturation to proceed from the rind to the core of the cheese. Whereas 6 was decreased, 4 and 5 increased over time. Deeper insight into the Maillard reaction during the ripening of cheese was achieved by the determination of selected alpha-dicarbonyl compounds. Especially methylglyoxal (2) showed a characteristic behavior during storage of the acid curd cheese. Decrease of this reactive structure was directly correlated to the formation of 5. To extend the results of experimental ripening to commercial cheeses, different aged Gouda types were investigated. Maturation times of the samples ranged from 6 to 8 weeks (young) to more than 1 year (aged). Again, increase of 5 and decrease of 2 were able to describe the ripening of this rennet coagulated cheese. Therefore, both chemical parameters are potent markers to characterize the degree of maturation, independent of coagulation. PMID- 22224827 TI - Engineering empty space between Si nanoparticles for lithium-ion battery anodes. AB - Silicon is a promising high-capacity anode material for lithium-ion batteries yet attaining long cycle life remains a significant challenge due to pulverization of the silicon and unstable solid-electrolyte interphase (SEI) formation during the electrochemical cycles. Despite significant advances in nanostructured Si electrodes, challenges including short cycle life and scalability hinder its widespread implementation. To address these challenges, we engineered an empty space between Si nanoparticles by encapsulating them in hollow carbon tubes. The synthesis process used low-cost Si nanoparticles and electrospinning methods, both of which can be easily scaled. The empty space around the Si nanoparticles allowed the electrode to successfully overcome these problems Our anode demonstrated a high gravimetric capacity (~1000 mAh/g based on the total mass) and long cycle life (200 cycles with 90% capacity retention). PMID- 22224828 TI - Cold-storage potential of four yellow-fleshed peach cultivars defined by their volatile compounds emissions, standard quality parameters, and consumer acceptance. AB - 'Early Rich', 'Royal Glory', 'Sweet Dream(cov)', and 'Elegant Lady' peaches were stored at -0.5 degrees C for up to 40 days and then subjected to ripening at 20 degrees C for up to 3 days. Firmness, soluble solids content (SSC), titratable acidity (TA), color, consumer acceptance, and volatile compounds were then determined. The observed physicochemical changes included a significant decrease in firmness during both storage and commercialization periods. In contrast, the SSC, TA, and color remained constant during storage. Ten days of cold storage produced the highest total volatile emissions and the greatest consumer acceptance for 'Elegant Lady' and 'Sweet Dream(cov)', whereas similar results were obtained after 40 and 20 days for 'Royal Glory' and 'Early Rich', respectively. Volatile compounds that most consistently exhibited a positive correlation with consumer acceptance were dependent on the cultivar. PMID- 22224829 TI - eNOS [Glu298Asp] polymorphism, erectile function and ocular pressure in type 2 diabetes. AB - BACKGROUND: Imbalance in nitric oxide (NO), an atheroprotective vasodilator, is associated with endothelial dysfunction, cardiovascular diseases (CVD) and diabetic complications. Various endothelial NO synthase (eNOS) polymorphisms may affect NO bioavailability, thereby promoting adverse cardiovascular milieu. MATERIALS AND METHODS: To analyze glucose homeostasis, cardiometabolic phenotype, and micro- and macroangiopathies associated with eNOS G894T gene polymorphism in type 2 diabetes (T2DM). 210 T2DM outpatients (mean age (1SD) 70 (12); diabetes duration 19 (9) years; males:females 64:36%; metabolic syndrome 87%) had insulin sensitivity and b-cell function modelled with HOMA, alongside routine laboratory and endothelin measurements. RESULTS: GG, GT and TT genotypes represented 48% (n = 100), 39% (n = 83) and 13% (n = 27). Overall microangiopathy (retinopathy, neuropathy and/or nephropathy) was present in 74%, and overall macroangiopathy (CAD, PAD and/or TIA/stroke) in 45%. The TT genotype did not translate into a more severe vascular phenotype, as TT patients carrying the proposed risk genotype did not suffer a higher rate of micro- and macrovascular complications. On the other hand, erectile dysfunction, present in 60% of males (n = 135), was much more prevalent in TT males: 57% [GG & GT] vs. 93% in TT (p 0.0088). Ocular hypertension/glaucoma frequency (18% of the whole group) was also markedly different, albeit in opposing directions, between eNOS G894T gene polymorphism subgroups: 21% [GG & GT] vs. 0% prevalence (TT; p 0.0057). CONCLUSIONS: eNOS G894T gene polymorphism in homozygous TT carriers translates into opposing effects on erectile function (detrimental) and ocular hypertension/glaucoma (protective) in T2DM, without affecting glucose homeostasis determinants or the presence of micro- and macrovascular complications. PMID- 22224830 TI - Describing two-photon absorptivity of fluorescent proteins with a new vibronic coupling mechanism. AB - Fluorescent proteins (FPs) are widely used in two-photon microscopy as genetically encoded probes. Understanding the physical basics of their two-photon absorption (2PA) properties is therefore crucial for creation of two-photon brighter mutants. On the other hand, it can give us better insight into molecular interactions of the FP chromophore with a complex protein environment. It is known that, compared to the one-photon absorption spectrum, where the pure electronic transition is the strongest, the 2PA spectrum of a number of FPs is dominated by a vibronic transition. The physical mechanism of such intensity redistribution is not understood. Here, we present a new physical model that explains this effect through the "Herzberg-Teller"-type vibronic coupling of the difference between the permanent dipole moments in the ground and excited states (DeltaMU) to the bond-length-alternating coordinate. This model also enables us to quantitatively describe a large variability of the 2PA peak intensity in a series of red FPs with the same chromophore through the interference between the "Herzberg-Teller" and Franck-Condon terms. PMID- 22224831 TI - High abundance of ammonia-oxidizing archaea in acidified subtropical forest soils in southern China after long-term N deposition. AB - Nitrification has been believed to be performed only by autotrophic ammonia oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB) until the recent discovery of ammonia-oxidizing archaea (AOA). Meanwhile, it has been questioned whether AOB are significantly responsible for NH(3) oxidation in acidic forest soils. Here, we investigated nitrifying communities and their activity in highly acidified soils of three subtropical forests in southern China that had received chronic high atmospheric N deposition. Nitrifying communities were analyzed using PCR- and culture (most probable number)-based approaches. Nitrification activity was analyzed by measuring gross soil nitrification rates using a (15) N isotope dilution technique. AOB were not detected in the three forest soils: neither via PCR of 16S rRNA and ammonia monooxygenase (amoA) genes nor via culture-based approaches. In contrast, an extraordinary abundance of the putative archaeal amoA was detected (3.2 * 10(8) -1.2 * 10(9) g soil(-1) ). Moreover, this abundance was correlated with gross soil nitrification rates. This indicates that amoA possessing archaea rather than bacteria were predominantly responsible for nitrification of the soils. Furthermore, sequences of the genus Nitrospira, a dominant group of soil NOB, were detected. Thus, nitrification of acidified subtropical forest soils in southern China could be performed by a combination of AOA and NOB. PMID- 22224832 TI - Pharmacokinetics of standard dose regimens of rifampicin in patients with pulmonary tuberculosis in Pakistan. AB - BACKGROUND: This clinical study investigated the pharmacokinetics of standard doses of rifampicin (RMP; 450 and 600 mg) in pulmonary tuberculosis (TB) patients in the context of its high sterilizing potential and the increased frequency of multidrug-resistant TB in Pakistan. The objective of this study was to determine the sufficiency or inadequacy of peak plasma levels of RMP in pulmonary TB patients after the administration of standard doses. METHODS: Twenty adult patients with newly diagnosed pulmonary TB consented to participate in the study. Blood sampling for pharmacokinetic assessment of RMP was done after at least 14 days of regular daily treatment to ensure steady state. Plasma concentrations of RMP were determined by a validated high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detection. RESULTS: The peak plasma concentration of RMP at 2 h was subtherapeutic, i.e. 3.76 +/- 1.23 mg/l (range 1.80-6.62), in all of our patients. Out of 20 patients, 13 (65%), had 2-h plasma concentrations below 4 mg/l. CONCLUSIONS: This study reports evidence of suboptimal RMP concentrations in a small group of Pakistani TB patients and highlights the need for larger clinical studies to identify possible reasons and consequences of low RMP levels in terms of treatment outcomes. Quality control problems in local drug preparations used widely among TB patients in Pakistan need to be addressed as a matter of urgency. PMID- 22224833 TI - A protein-polymer hybrid mediated by DNA. AB - Protein-polymer hybrids (PPHs) represent an important and rapidly expanding class of biomaterials. Typically in these hybrids the linkage between the protein and the polymer is covalent. Here we describe a straightforward approach to a noncovalent PPH that is mediated by DNA. Although noncovalent, the DNA-mediated approach affords the highly specific pairing and assembly properties of DNA. To obtain the protein-DNA conjugate for assembly of the PPH, we report here the first direct copper catalyzed azide-alkyne cycloaddition-based protein-DNA conjugation. This significantly simplifies access to protein-DNA conjugates. The protein-DNA conjugate and partner polymer-DNA conjugate are readily assembled through annealing of the cDNA strands to obtain the PPH, the assembly of which was confirmed via dynamic light scattering and fluorescence spectroscopy. PMID- 22224834 TI - Default mode network activity and connectivity in psychopathology. AB - Neuropsychiatric disorders are associated with abnormal function of the default mode network (DMN), a distributed network of brain regions more active during rest than during performance of many attention-demanding tasks and characterized by a high degree of functional connectivity (i.e., temporal correlations between brain regions). Functional magnetic resonance imaging studies have revealed that the DMN in the healthy brain is associated with stimulus-independent thought and self-reflection and that greater suppression of the DMN is associated with better performance on attention-demanding tasks. In schizophrenia and depression, the DMN is often found to be hyperactivated and hyperconnected. In schizophrenia this may relate to overly intensive self-reference and impairments in attention and working memory. In depression, DMN hyperactivity may be related to negative rumination. These findings are considered in terms of what is known about psychological functions supported by the DMN, and alteration of the DMN in other neuropsychiatric disorders. PMID- 22224835 TI - Cognition in the vegetative state. AB - Awake but not aware: This puzzling dissociation of the two central elements of consciousness defines the vegetative state. Traditionally, this condition has been believed to imply a brain with preserved hypothalamic and brainstem autonomic functions but with no capacity for cortical cognitive processes. As is discussed in this review, over a 20-year span neuroimaging techniques have clearly demonstrated that this characterization of patients in a vegetative state is incorrect. Contrary to the initial belief, the "vegetative" brain can retain several high-level aspects of cognitive functions, across sensory modalities, including language processing and learning dynamics. Nonetheless, the residual cognitive functions observed in vegetative patients might reflect intact but functionally disconnected cortical modules that do not give rise to the subjective feeling of phenomenological awareness. PMID- 22224837 TI - Prediction and prevention of psychosis in youth at clinical high risk. AB - Most individuals with schizophrenia retrospectively report a prodromal period characterized by increasing problems in thinking, feeling, and behaving. However, it is less clear how many individuals who display prodromal symptoms will subsequently develop a psychotic illness. Thus, a precondition for early intervention in psychosis is the accurate detection of those who may be at true risk of developing a psychotic illness. The aim of this article is to review current work addressing prediction and prevention in the prodrome to psychosis. First, we describe research efforts to develop and test operational criteria for prospectively assessing psychosis liability over time. Second, the clinical, functional, and biological features of the prodrome are presented, along with a discussion of the variables most frequently associated with psychosis onset. Next, treatment studies are reviewed. The review concludes with a framework for future early identification and treatment studies. PMID- 22224836 TI - Coping with chronic illness in childhood and adolescence. AB - Chronic illnesses and medical conditions present millions of children and adolescents with significant stress that is associated with risk for emotional and behavioral problems and interferes with adherence to treatment regimens. We review research on the role of child and adolescent coping with stress as an important feature of the process of adaptation to illness. Recent findings support a control-based model of coping that includes primary control or active coping (efforts to act on the source of stress or one's emotions), secondary control or accommodative coping (efforts to adapt to the source of stress), and disengagement or passive coping (efforts to avoid or deny the stressor). Evidence suggests the efficacy of secondary control coping in successful adaptation to chronic illness in children and adolescents, disengagement coping is associated with poorer adjustment, and findings for primary control coping are mixed. Avenues for future research are highlighted. PMID- 22224839 TI - Obesity and public policy. AB - There is a pressing need to reduce both the prevalence and impact of obesity. This review begins with a discussion of the roles of treatment and prevention. Two overriding issues, weight bias and the addictive nature of food, are covered because of their importance not only to the individuals affected but also to public policy. We then cover promising policy areas in which changes can be implemented to support healthy behaviors: school policy, food marketing, food labeling and packaging, and taxes on unhealthy foods. The roles of the food industry and federal, state, and local governments are also discussed. PMID- 22224840 TI - Crushing or splitting medications: unrecognized hazards. AB - Given the high use and the cost of medications in the current economy, one way older adults may save money on prescription costs is to split some of their medications in half. However, not all oral medications can be split. Splitting inappropriate medications such as extended-release tablets can be harmful and in some instances very dangerous. In addition to splitting medications, older adults who have difficulty swallowing pills may resort to crushing the medication for ease of administration. This option is also problematic and potentially harmful if the medication is not intended to be crushed. Clinicians managing the care of older adults need to discuss medication administration, clarify the dosing schedule, and clearly indicate the route of administration. Patients should be cautioned not to split or crush a medication without checking with the health care provider or pharmacist. PMID- 22224838 TI - A "SMART" design for building individualized treatment sequences. AB - Interventions often involve a sequence of decisions. For example, clinicians frequently adapt the intervention to an individual's outcomes. Altering the intensity and type of intervention over time is crucial for many reasons, such as to obtain improvement if the individual is not responding or to reduce costs and burden when intensive treatment is no longer necessary. Adaptive interventions utilize individual variables (severity, preferences) to adapt the intervention and then dynamically utilize individual outcomes (response to treatment, adherence) to readapt the intervention. The Sequential Multiple Assignment Randomized Trial (SMART) provides high-quality data that can be used to construct adaptive interventions. We review the SMART and highlight its advantages in constructing and revising adaptive interventions as compared to alternative experimental designs. Selected examples of SMART studies are described and compared. A data analysis method is provided and illustrated using data from the Extending Treatment Effectiveness of Naltrexone SMART study. PMID- 22224841 TI - Blunt thoracic injury in older adults: application of Haddon's phase-factor matrix model. AB - Blunt thoracic injury (BTI) in older adults can lead to grave illness, permanent disability, and even death. Using Haddon's phase-factor matrix model, this article examines the phenomenon of BTI in older adults. Preventive, diagnostic, and treatment interventions are discussed from the perspective of the pre-event, event, and post-event phases. Relevant physiological and pathophysiological changes regarding senescence and injury are reviewed, as are the common mechanisms of blunt trauma and anatomic injury patterns seen in older adults. Considerations for clinical interventions and future research are also presented. PMID- 22224843 TI - A forward incremental prestressing method with application to inverse parameter estimations and eye-specific simulations of posterior scleral shells. AB - Numerical simulations or inverse numerical analyses of individual eyes or eye segments are often based on an eye-specific geometry obtained from in vivo medical images such as computed tomography (CT) scans or from in vitro 3D digitiser scans. These eye-specific geometries are usually measured while the eye is subjected to internal pressure. Due to the nonlinear stiffening of the collagen fibril network in the eye, numerical incorporation of the pre-existing stress/strain state may be essential for realistic eye-specific computational simulations. Existing prestressing methods either compute accurate predictions of the prestressed state or guarantee a unique solution. In this contribution, a forward incremental prestressing method is presented which unifies the advantages of the existing approaches by providing accurate and unique predictions of the pre-existing stress/strain state at the true measured geometry. The impact of prestressing is investigated on (i) the inverse constitutive parameter identification of a synthetic sclera inflation test and (ii) an eye-specific simulation that estimates the realistic mechanical response of a pre-loaded posterior monkey scleral shell. Evaluation of the pre-existing stress/strain state in the inverse analysis had a significant impact on the reproducibility of the constitutive parameters but may be estimated based on an approximative approach. The eye-specific simulation of one monkey eye shows that prestressing is required for accurate displacement and stress/strain predictions. The numerical results revealed an increasing error in displacement, strain and stress predictions with increasing pre-existing pressure load when the pre-stress/strain state is disregarded. Disregarding the prestress may lead to a significant underestimation of the strain/stress environment in the sclera and overestimation in the lamina cribrosa. PMID- 22224844 TI - Gender differences in response to deployment among military healthcare providers in Afghanistan and Iraq. AB - BACKGROUND: Despite their growing numbers in the United States military, little has been published on healthcare providers (HCP) or female service members from conflicts in Afghanistan and Iraq. The purpose of this secondary analysis of data from the 2005 Department of Defense (DoD) Survey of Health Related Behaviors Among Active Duty Military Personnel was to determine gender differences in reaction to the impact of operational stress in deployed military healthcare providers. METHODS: The unweighted study sample selected for this data analysis included results from female and male active duty military personnel over the age of 18 years (n=16,146) deployed at least once to Operation Enduring Freedom (OEF) or Operation Iraqi Freedom (OIF) within the past 3 years (n=1,425), for a final sample consisting of either officer (healthcare officer) or enlisted (healthcare specialist) personnel (n=455) (weighted n=23,440). Indices of psychologic distress and social relations were explored and compared. RESULTS: Enlisted female HCPs were more likely to be African American (42.3%) and single (63.0%) and represented the greater percentage with significant psychologic difficulties, as shown by serious psychologic distress endorsement (11.3%) and positive screen results for depression (32.2%). More harmful drinking patterns (Alcohol Use Disorders Identifications Test [AUDIT] score 8-15) were found in more female HCPs (enlisted 61.8%, officers 76.4%) compared with males (enlisted 41.1%, officers 67.1%). CONCLUSIONS: Female HCPs serving in the current military conflicts are reporting significant psychologic distress that may adversely impact their performance within the military, in theaters of operations, and in their lives at home. Implications for clinical care of female service members and veterans of current wars are addressed. PMID- 22224845 TI - Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and therapy results. AB - Patients with chronic lymphocytic leukaemia (CLL) whose tumour cells harbour a 17p deletion (17p-) are universally considered to have a poor prognosis. The deletion can be detected at diagnosis or during the evolution of the disease, particularly in patients who have received chemotherapy. We sought to evaluate the natural history of patients with 17p- CLL, identify predictive factors within this prognostic subgroup, and evaluate the results of different therapeutic approaches. Data from 294 patients with 17p- CLL followed up at 20 different institutions was retrospectively collected and analysed. Median age was 68 (range 27-98) years at the time of fluorescence in situ hybridization analysis. After 17p- documentation, 52% received treatment, achieving an overall response rate of 50%. Median overall survival was 41 months, and was significantly shorter in patients with elevated beta(2)-microglobulin concentration (P < 0.001), B symptoms (P = 0.016), higher percentage of cells with deletion (P < 0.001), and acquired deletions (P = 0.012). These findings suggest that patients with 17p- CLL have a variable prognosis that can be refined using simple clinical and laboratory features, including 17p- clone size, beta2-microglobulin concentration, presence of B symptoms and type of deletion (de novo versus acquired). PMID- 22224847 TI - Environmentalism as a context for expressing identity and generativity: patterns among activists and uninvolved youth and midlife adults. AB - Previous qualitative studies have identified themes of generativity and identity development in the interviews of environmental activists (Chan, 2009; Horwitz, 1996), suggesting their importance as motives for environmental behavior. The purpose of our study was to extend this work by identifying positive relationships between identity maturity, generativity, and environmentalism using quantitative methodologies. To explore these relationships, we designed quasi experimental and correlational studies. We recruited 54 environmental activists and 56 comparison individuals, half of whom were youth (mean age = 22 years) and the other half midlife adults (mean age = 43 years). Sixty-three percent of our sample was female. Participants completed several environmental, generativity, and identity questionnaires. We found that activists and comparison individuals differed on the identity maturity, generativity, and environmental measures overall. Further, greater identity maturity and generativity were associated with higher environmental engagement. And generativity was found to mediate the relation between identity maturity and environmentalism. Our findings suggest that engaging in generative behaviors may be an important part of the process in forming an environmental identity and engaging in environmental actions. PMID- 22224848 TI - Isolation and characterization of a phenolic antioxidant from the Pacific oyster (Crassostrea gigas). AB - Using an oxygen radical absorbance capacity (ORAC) assay, antioxidant activity was detected in the ethanol extract of the Pacific oyster, which was purified by sequential extraction with organic solvents. The ethyl acetate fraction showed the strongest antioxidant activity and was further purified, yielding a single compound [as assessed by thin-layer chromatography (TLC) and reverse-phase high performance liquid chromatography (HPLC)]. This compound was identified as 3,5 dihydroxy-4-methoxybenzyl alcohol on the basis of (1)H and (13)C nuclear magnetic resonance (NMR), heteronuclear multiple-bond correlation (HMBC), and electrospray ionization-mass spectrometry (ESI-MS) spectral analyses, a conclusion that was confirmed by chemical synthesis. The concentration of the compound was 6.7 mg/100 g of whole oyster meat wet weight. This amphiphilic antioxidant retarded the copper-mediated oxidation of low-density lipoproteins (LDLs) and the generation of thiobarbituric acid reactive substances. Furthermore, the compound showed substantial antioxidant activity using the ORAC and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays compared to natural antioxidants. Although the same compound was previously found in brown algae, its presence in other organisms and antioxidant activity are reported here for the first time. PMID- 22224850 TI - An electron-transfer path through an extended disulfide relay system: the case of the redox protein ALR. AB - The oxidative folding mechanism in the intermembrane space of human mitochondria underpins a disulfide relay system consisting of the import receptor Mia40 and the homodimeric FAD-dependent thiol oxidase ALR. The flavoprotein ALR receives two electrons per subunit from Mia40, which are then donated through one-electron reactions to two cytochrome c molecules, thus mediating a switch from two electron to one-electron transfer. We dissect here the mechanism of the electron flux within ALR, characterizing at the atomic level the ALR intermediates that allow electrons to rapidly flow to cytochrome c. The intermediate critical for the electron-transfer process implies the formation of a specific inter-subunit disulfide which exclusively allows electron flow from Mia40 to FAD. This finding allows us to present a complete model for the electron-transfer pathway in ALR. PMID- 22224852 TI - Nonesterified fatty acid determination for functional lipidomics: comprehensive ultrahigh performance liquid chromatography-tandem mass spectrometry quantitation, qualification, and parameter prediction. AB - Despite their central importance for lipid metabolism, straightforward quantitative methods for determination of nonesterified fatty acid (NEFA) species are still missing. The protocol presented here provides unbiased quantitation of plasma NEFA species by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Simple deproteination of plasma in organic solvent solution yields high accuracy, including both the unbound and initially protein-bound fractions, while avoiding interferences from hydrolysis of esterified fatty acids from other lipid classes. Sample preparation is fast and nonexpensive, hence well suited for automation and high-throughput applications. Separation of isotopologic NEFA is achieved using ultrahigh-performance liquid chromatography (UPLC) coupled to triple quadrupole LC-MS/MS detection. In combination with automated liquid handling, total assay time per sample is less than 15 min. The analytical spectrum extends beyond readily available NEFA standard compounds by a regression model predicting all the relevant analytical parameters (retention time, ion path settings, and response factor) of NEFA species based on chain length and number of double bonds. Detection of 50 NEFA species and accurate quantification of 36 NEFA species in human plasma is described, the highest numbers ever reported for a LC MS application. Accuracy and precision are within widely accepted limits. The use of qualifier ions supports unequivocal analyte verification. PMID- 22224854 TI - Impact of high-fat and high-carbohydrate diets on liver metabolism studied in a rat model with a systems biology approach. AB - The aim of the present study was to investigate the use of an integrated metabolomics and proteomics approach in the elucidation of diet-induced effects on hepatic metabolism in a rat model. Nuclear magnetic resonance (NMR)-based metabolomics of liver extracts revealed a pronounced effect of a high-fat diet on the hepatic betaine content, whereas a carbohydrate-rich diet induced increases in hepatic glucose. In addition, the metabolomic investigations revealed that the high-fat diet was associated with increased hepatic lipid levels, which was not evident with the carbohydrate-rich diet. The proteomic investigations revealed strong high-fat diet effects on the expression of 186 proteins in the liver including malate dehydrogenase. Comparison of malate dehydrogenase expression determined by proteomics and NMR metabolite profiles revealed correlations between malate dehydrogenase and lactate, glucose, and glutamine/glutamate signals, thereby demonstrating a diet-induced regulation that was evident at both proteomic and metabolomic levels. PMID- 22224855 TI - Context-specific control in the single-prime negative-priming procedure. AB - The current paper examines the applicability of the context-specific control principle to the probe selection dependence of negative-priming effects using the single-prime procedure. In a series of experiments, we highlight the applicability of the context-specific control principle, first by illustrating a key result that implicates the role of context-specific control and challenges the contextual similarity principle. Following this, we show the importance of distinct probe contexts in the single-prime negative-priming procedure and report a novel finding that illustrates a learning effect that can occur within an experimental session. Finally, we test the relation of our novel learning effect to a related learning proposal offered by Frings and Wentura (2006), and we demonstrate that the learning involved in context-specific control is not dependent on contingency learning. Overall, the patterns of results highlight the role of context-sensitive memory in controlling how current perception and action are integrated with prior experience. PMID- 22224857 TI - Transport/magnetotransport of high-performance graphene transistors on organic molecule-functionalized substrates. AB - In this article, we present the transport and magnetotransport of high-quality graphene transistors on conventional SiO(2)/Si substrates by modification with organic molecule octadecyltrichlorosilane (OTS) self-assembled monolayers (SAMs). Graphene devices on OTS SAM-functionalized substrates with high carrier mobility, low intrinsic doping, suppressed carrier scattering, and reduced thermal activation of resistivity at room temperature were observed. Most interestingly, the remarkable magnetotransport of graphene devices with pronounced quantum Hall effect, strong Shubnikov-de Haas oscillations, a nonzero Berry's phase, and a short carrier scattering time also confirms the high quality of graphene on this ultrasmooth organic SAM-modified platform. The high-performance graphene transistors on the solution-processable OTS SAM-functionalized SiO(2)/Si substrates are promising for the future development of large-area and low-cost fabrications of graphene-based nanoelectronics. PMID- 22224858 TI - A configurational approach to the relationship between high-performance work practices and frontline health care worker outcomes. AB - OBJECTIVE: To identify high-performance work practices (HPWP) associated with high frontline health care worker (FLW) job satisfaction and perceived quality of care. METHODS: Cross-sectional survey data from 661 FLWs in 13 large health care employers were collected between 2007 and 2008 and analyzed using both regression and fuzzy-set qualitative comparative analysis. PRINCIPAL FINDINGS: Supervisor support and team-based work practices were identified as necessary for high job satisfaction and high quality of care but not sufficient to achieve these outcomes unless implemented in tandem with other HPWP. Several configurations of HPWP were associated with either high job satisfaction or high quality of care. However, only one configuration of HPWP was sufficient for both: the combination of supervisor support, performance-based incentives, team-based work, and flexible work. These findings were consistent even after controlling for FLW demographics and employer type. Additional research is needed to clarify whether HPWP have differential effects on quality of care in direct care versus administrative workers. CONCLUSIONS: High-performance work practices that integrate FLWs in health care teams and provide FLWs with opportunities for participative decision making can positively influence job satisfaction and perceived quality of care, but only when implemented as bundles of complementary policies and practices. PMID- 22224859 TI - Dried-bonito aroma components enhance salivary hemodynamic responses to broth tastes detected by near-infrared spectroscopy. AB - To elucidate the effects of aroma from dried bonito (katsuo-bushi) on broth tastes caused by the central integration of flavor, optical imaging of salivary hemodynamic responses was conducted using near-infrared spectroscopy (NIRS). A reconstituted dried bonito flavored broth produced a significantly larger hemodynamic response than the odorless broth taste solutions for 5 of the 10 panelists, who felt that the combination of the aroma with the tastes was congruent. In the remaining 5 panelists who felt the combination incongruent, the flavored broth did not cause the enhancement of response. Moreover, when the odor active smoky parts were removed from the flavoring, the reconstituted flavoring did not enhance the response in the former five panelists. These results indicate that NIRS offers a sensitive method to detect the effect of specific congruent aroma components from dried-bonito broth on the taste-related salivary hemodynamic responses, dependent on the perceptual experience of the combination of aromas and tastes. PMID- 22224861 TI - Probing the interaction of human serum albumin with ciprofloxacin in the presence of silver nanoparticles of three sizes: multispectroscopic and zeta potential investigation. AB - The binding of ciprofloxacin to human serum albumin (HSA) in the presence and absence of silver nanoparticles of three sizes was investigated for the first time. For this purpose fluorescence spectroscopy, circular dichroism, UV-vis spectroscopy, and zeta potential techniques were employed under physiological conditions. The titration results indicated that ciprofloxacin quenched the fluorescence intensity of HSA through a static mechanism, but in the presence of Ag nanoparticles of sizes I and II there were two different kinds of interaction behavior. Results of circular dichroism indicated that the secondary structure of HSA was modified with increasing ciprofloxacin concentration. A comparison between resonance light scattering of binary and ternary systems allowed us to estimate the effect of silver nanoparticles on the initial formation and aggregation of ciprofloxacin with HSA. The zeta-potential results suggested induced conformational changes on HSA, thus confirming the experimental and theoretical results. PMID- 22224860 TI - In situ identification of carboxymethyl cellulose-digesting bacteria in the rumen of cattle fed alfalfa or triticale. AB - A method was developed and used to arrest and stain reducing sugars (glucose) produced by bacteria with cell-surface-associated carboxymethyl cellulase (CMCase) and endoglucanase activities (CMC bacteria) in the rumen of cows fed alfalfa or triticale. Precipitation of silver oxide on the surface of individual cells was observed using cellulolytic bacterial pure cultures with known CMCase activity and rumen mixed cultures. The CMC bacteria in the liquid and solid fractions of the rumen digesta were identified using fluorescence in situ hybridization (FISH) with currently available and newly designed oligonucleotide probes. The CMC bacteria contributed between 8.2% and 10.1% to the total bacterial cell numbers. Most of the CMC bacteria (75.2-78.5%) could be identified by FISH probing. The known cellulolytic populations Ruminococcus flavefaciens, R. albus, and Fibrobacter succinogenes constituted 44.5-53.1% of the total. Other CMC bacteria identified hybridized with the probe Clo549 (11.2-23.0%) targeting members of an uncharacterized genus in Clostridia, the probe Inc852 (8.9-10.7%) targeting members of the family Incertae Sedis III and unclassified Clostridiales, and the probe But1243 (< 1%) designed against members of genus Butyrivibrio. Different forage feeds had no marked effects on the percentage abundances of these identified CMC bacteria. All appeared to be involved in cellulose degradation in the rumen of cows fed either alfalfa or triticale. PMID- 22224862 TI - The present and future of biologically inspired adhesive interfaces and materials. AB - The natural world provides many examples of robust, permanent adhesive platforms. Synthetic adhesive interfaces and materials inspired by mussels of genus Mytulis have been extensively applied, and it is expected that characterization and adaptation of several other biological adhesive strategies will follow the Mytilus edulis model. These candidate species will be introduced, along with a discussion of the adhesive behaviors that make them attractive for synthetic adaptation. While significant progress has been made in the development of biologically inspired adhesive interfaces and materials, persistent questions, current challenges, and emergent areas of research will be also be discussed. PMID- 22224864 TI - Does routine gynecological surgery contribute to an early menopause? PMID- 22224863 TI - Thermal plasticity in life-history traits in the polymorphic blue-tailed damselfly, Ischnura elegans: no differences between female morphs. AB - Female polymorphism is observed in various animal species, but is particularly common in damselflies. The maintenance of this polymorphism has traditionally been explained from frequency and density dependent sexual conflict, however, the role of abiotic factors has recently attracted more interest. Here, the role of ambient temperature in shaping life-history was investigated for the three female morphs of Ischnura elegans (Vander Linden) (Zygoptera: Coenagrionidae). Eggs were obtained from the three mature female morphs for two populations in the Netherlands. Using a split-brood design, eggs of both populations were divided between a cold and a warm treatment group in the laboratory, and egg survival and hatching time were measured. Significant thermal plasticity was found in both hatching time and egg survival between both temperature treatments. However, individuals born to mothers belonging to different colour morphs did not differ in their response to temperature treatment. Independent of colour morph, clear differences in both life-history traits between the populations were found, suggesting local adaptation. Specifically, individuals from one population hatched faster but had lower egg survival in both thermal regimes. The selection force establishing fast hatching could be (facultative) bivoltinism in one of the populations compared to univoltinism in the other. This would be in line with the more southern (and more coastal) location of the presumed bivoltine population and the inverse relation between voltinism and latitude known from earlier studies. However, other natural selection forces, e.g. deterioration of the aquatic habitat, may also drive fast hatching. PMID- 22224865 TI - Computational simulation modelling of bioreactor configurations for regenerating human bladder. AB - The objective of this study was to investigate a bioreactor suitable for human bladder regeneration. Simulations were performed using the computational fluid dynamic tools. The thickness of the bladder scaffold was 3 mm, similar to the human bladder, and overall hold-up volume within the spherical shape scaffold was 755 ml. All simulations were performed using (i) Brinkman equation on porous regions using the properties of 1% chitosan-1% gelatin structures, (ii) Michaelis Menten type rate law nutrient consumption for smooth muscle cells (SMCs) and (iii) Mackie-Meares relationship for determining effective diffusivities. Steady state simulations were performed using flow rates from 0.5 to 5 ml/min. Two different inlet shapes: (i) straight entry at the centre (Design 1) and (ii) entry with an expansion (Design 2) were simulated to evaluate shear stress distribution. Also, mimicking bladder shape of two inlets (Design 3) was tested. Design 2 provided the uniform shear stress at the inlet and nutrient distribution, which was further investigated for the effect of scaffold locations within the reactor: (i) attached with a 3-mm open channel (Design 2-A), (ii) flow through with no open channel (Design 2-B) and (iii) porous structure suspended in the middle with 1.5-mm open channel on either side (Design 2-C). In Design 2-A and 2-C, fluid flow occurred by diffusion dominant mechanisms. Furthermore, the designed bioreactor is suitable for increased cell density of SMCs. These results showed that increasing the flow rate is necessary due to the decreased permeability at cell densities similar to the human bladder. PMID- 22224867 TI - Myeloid neoplasm with rearrangement of PDGFRA, but with no significant eosinophilia: should we broaden the World Health Organization definition of the entity? PMID- 22224870 TI - Production of volatile organic compounds by mycobacteria. AB - The need for improved rapid diagnostic tests for tuberculosis disease has prompted interest in the volatile organic compounds (VOCs) emitted by Mycobacterium tuberculosis complex bacteria. We have investigated VOCs emitted by Mycobacterium bovis BCG grown on Lowenstein-Jensen media using selected ion flow tube mass spectrometry and thermal desorption-gas chromatography-mass spectrometry. Compounds observed included dimethyl sulphide, 3-methyl-1-butanol, 2-methyl-1-propanol, butanone, 2-methyl-1-butanol, methyl 2-methylbutanoate, 2 phenylethanol and hydrogen sulphide. Changes in levels of acetaldehyde, methanol and ammonia were also observed. The compounds identified are not unique to M. bovis BCG, and further studies are needed to validate their diagnostic value. Investigations using an ultra-rapid gas chromatograph with a surface acoustic wave sensor (zNose) demonstrated the presence of 2-phenylethanol (PEA) in the headspace of cultures of M. bovis BCG and Mycobacterium smegmatis, when grown on Lowenstein-Jensen supplemented with glycerol. PEA is a reversible inhibitor of DNA synthesis. It is used during selective isolation of gram-positive bacteria and may also be used to inhibit mycobacterial growth. PEA production was observed to be dependent on growth of mycobacteria. Further study is required to elucidate the metabolic pathways involved and assess whether this compound is produced during in vivo growth of mycobacteria. PMID- 22224871 TI - Formulation of the Total Western Diet (TWD) as a basal diet for rodent cancer studies. AB - Rodent cancer studies typically use defined diets with nutrient profiles optimized for rodent health. However, a defined rodent diet that represents typical American nutrition in all aspects, including calorie sources and macro- and micronutrient composition, is not yet available. Thus, a nutrient density approach was used to formulate the new Total Western Diet (TWD) based on NHANES data for macro- and micronutrient intakes. The TWD has fewer calories from protein and carbohydrate sources and twice that from fat as compared to the AIN 93 diet. The new diet contains more saturated and monounsaturated fats, less polyunsaturated fat, fewer complex carbohydrates, and twice the level of simple sugars. The TWD includes less calcium, copper, folate, thiamin, and vitamins B6, B12, D, and E, but much more sodium. This newly devised diet that better represents typical American nutrition will be highly useful for studies employing animal models of human disease, including cancer. PMID- 22224873 TI - Postacquisition mass resolution improvement in time-of-flight secondary ion mass spectrometry. AB - Good mass resolution can be difficult to achieve in time-of-flight secondary ion mass spectrometry (TOF-SIMS) when the analysis area is large or when the surface being analyzed is rough. In most cases, a significant improvement in mass resolution can be achieved by postacquisition processing of raw data. Methods are presented in which spectra are extracted from smaller regions within the original analysis area, recalibrated, and selectively summed to produce spectra with higher mass resolution than the original. No hardware modifications or specialized instrument tuning are required. The methods can be extended to convert the original raw file into a new raw file containing high mass resolution data. To our knowledge, this is the first report of conversion of a low mass resolution raw file into a high mass resolution raw file using only the data contained within the low mass resolution raw file. These methods are applicable to any material but are expected to be particularly useful in analysis of difficult samples such as fibers, powders, and freeze-dried biological specimens. PMID- 22224872 TI - Serological survey of exposure to Erysipelothrix rhusiopathiae in poultry in New Zealand. AB - AIMS: To estimate the seroprevalence of antibodies to Erysipelothrix rhusiopathiae in chickens in New Zealand, and to estimate the effect of housing type, geographical location and age on seroprevalence. METHODS: A cross-sectional serological survey of a convenience sample of 545 broiler, breeder, and layer chickens in 55 flocks was conducted in 2010-2011. Birds were aged 5-83 weeks; housing types were free-range, shed, caged, and unknown; and flocks were located in the Auckland, Manawatu, North Canterbury, Otago, Taranaki, Waikato, and Wairarapa regions of New Zealand. An ELISA was used to measure antibodies to E. rhusiopathiae. Samples with an optical density reading >= 1.50 were considered to be positive. Logistic regression analysis was used to model the effect of housing type, geographical location and flock age on the prevalence of samples positive for antibodies to E. rhusiopathiae. RESULTS: The overall prevalence of samples with antibodies to E. rhusiopathiae was 39.8 (95% CI=35.68-44.06)% for the 545 samples, and 46/55 (84%) farms that were tested had at least one positive sample. Mean seroprevalence for types of housing was 44.2 (95% CI=37.79-50.70)% for free range (n=240 birds), 23.7 (95% CI=17.83-30.38)% for shed (n=190), 73 (95% CI=56 86)% for caged (n=37) and 50 (95% CI=38-62)% for unknown (n=78). The disease was present in all seven geographical locations from which samples were obtained for this study. Seroprevalence increased with increasing age of birds (p<0.001); for birds <= 12 weeks of age it was 2 (95% CI=0.3-8)% (n=91), 13-24 weeks 29.1 (95% CI=23.34-35.46)% (n=230), 25-36 weeks 47 (95% CI=32-64)% (n=40), 37-48 weeks 75 (95% CI=51-91)% (n=20), >48 weeks 63.8 (95% CI=54.78-72.12)% (n=127). Neither housing type nor geographical location had a significant effect on the likelihood of samples being positive for antibodies to E. rhusiopathiae. CONCLUSIONS: The results of this study suggest the prevalence of erysipelas under New Zealand field conditions may be higher than expected and that the disease is significantly associated with increasing age. Housing type and geographical location appear to be unrelated to seroprevalence. CLINICAL RELEVANCE: Further study of the epidemiology of E. rhusiopathiae in chickens in New Zealand should be considered in order to minimise the extent of birds' exposure to the organism. These findings will assist in the design of further studies. PMID- 22224874 TI - Stability of white wine proteins: combined effect of pH, ionic strength, and temperature on their aggregation. AB - Protein haze development in white wines is an unacceptable visual defect attributed to slow protein unfolding and aggregation. It is favored by wine exposure to excessive temperatures but can also develop in properly stored wines. In this study, the combined impact of pH (2.5-4.0), ionic strength (0.02-0.15 M), and temperature (25, 40, and 70 degrees C) on wine protein stability was investigated. The results showed three classes of proteins with low conformational stability involved in aggregation at room temperature: beta glucanases, chitinases, and some thaumatin-like protein isoforms (22-24 kDa). Unexpectedly, at 25 degrees C, maximum instability was observed at the lower pH, far from the protein isoelectric point. Increasing temperatures led to a shift of the maximum haze at higher pH. These different behaviors could be explained by the opposite impact of pH on intramolecular (conformational stability) and intermolecular (colloidal stability) electrostatic interactions. The present results highlight that wine pH and ionic strength play a determinant part in aggregation mechanisms, aggregate characteristics, and final haze. PMID- 22224875 TI - The hurrider I go the behinder I get: the deteriorating international ranking of U.S. health status. AB - The health of societies can be measured by a range of mortality indicators, and comparisons of national parameters with those of other societies can be symbolic of health status and progress. Over the past century, health outcomes have been steadily improving almost everywhere in the world, but the rates of improvements have varied. In the 1950s, the United States, having among the lowest mortality and other indicators of good health, ranked well among nations. Since then, the United States has not seen the scale of improvements in health outcomes enjoyed by most other developed countries, despite spending increasing amounts of its economy on health care services. Trends in personal health-related behaviors are only part of the explanation. Structural factors related to inequality and conditions of early life are important reasons for the relative stagnation in health. Reversing this relative decline would require a major national coordinated long-term effort to expose the problem and create the political will to address it. PMID- 22224876 TI - Health inequalities: trends, progress, and policy. AB - Health inequalities, which have been well documented for decades, have more recently become policy targets in developed countries. This review describes time trends in health inequalities (by sex, race/ethnicity, and socioeconomic status), commitments to reduce health inequalities, and progress made to eliminate health inequalities in the United States, United Kingdom, and other OECD countries. Time trend data in the United States indicate a narrowing of the gap between the best- and worst-off groups in some health indicators, such as life expectancy, but a widening of the gap in others, such as diabetes prevalence. Similarly, time-trend data in the United Kingdom indicate a narrowing of the gap between the best- and worst-off groups in some indicators, such as hypertension prevalence, whereas the gap between social classes has increased for life expectancy. More research and better methods are needed to measure precisely the relationships between stated policy goals and observed trends in health inequalities. PMID- 22224877 TI - Community-based approaches to controlling childhood asthma. AB - The prevalence and burden of childhood asthma remain high and are increasing. Asthma hot spot neighborhoods around the country face particular challenges in controlling the effects of the condition. Increasing attention is being paid to developing interventions that recognize the child and family as the primary managers of disease and to introducing assistance that reaches beyond the clinical care setting into the places where families live and work. A range of types of community-focused interventions has been assessed in the past decade in schools, homes, and community health clinics, and programs using electronic media and phone links have been evaluated. Stronger evidence for all these approaches is needed. However, school-based programs and community coalitions designed to bring about policy and systems changes show particular promise for achieving sustainable improvements in asthma control. Research is needed that emphasizes comparisons among proven asthma control interventions, translation of effective approaches to new settings and communities, and institutionalization of effective strategies. PMID- 22224878 TI - Preventability of cancer: the relative contributions of biologic and social and physical environmental determinants of cancer mortality. AB - Whereas models of cancer disparities and variation in cancer burden within population groups now specify multiple levels of action from biologic processes to individual risk factors and social and physical contextual factors, approaches to estimating the preventable proportion of cancer use more traditional direct models often from single exposures to cancer at specific organ sites. These approaches are reviewed, and the strengths and limitations are presented. The need for additional multilevel data and approaches to estimation of preventability are identified. International or regional variation in cancer may offer the most integrated exposure assessment over the life course. For the four leading cancers, which account for 50% of incidence and mortality, biologic, social, and physical environments play differing roles in etiology and potential prevention. Better understanding of the interactions and contributions across these levels will help refine prevention strategies. PMID- 22224879 TI - Conceptual approaches to the study of health disparities. AB - Scientific and policy interest in health disparities, defined as systematic, plausibly avoidable health differences adversely affecting socially disadvantaged groups, has increased markedly over the past few decades. Like other research, research in health disparities is strongly influenced by the underlying conceptual model of the hypothetical causes of disparities. Conceptual models are important and a major source of debate because multiple types of factors and processes may be involved in generating disparities, because different disciplines emphasize different types of factors, and because the conceptual model often drives what is studied, how results are interpreted, and which interventions are identified as most promising. This article reviews common conceptual approaches to health disparities including the genetic model, the fundamental cause model, the pathways model, and the interaction model. Strengths and limitations of the approaches are highlighted. The article concludes by outlining key elements and implications of an integrative systems-based conceptual model. PMID- 22224880 TI - Public health and the epidemic of incarceration. AB - An unprecedented number of Americans have been incarcerated in the past generation. In addition, arrests are concentrated in low-income, predominantly nonwhite communities where people are more likely to be medically underserved. As a result, rates of physical and mental illnesses are far higher among prison and jail inmates than among the general public. We review the health profiles of the incarcerated; health care in correctional facilities; and incarceration's repercussions for public health in the communities to which inmates return upon release. The review concludes with recommendations that public health and medical practitioners capitalize on the public health opportunities provided by correctional settings to reach medically underserved communities, while simultaneously advocating for fundamental system change to reduce unnecessary incarceration. PMID- 22224882 TI - Speed limits, enforcement, and health consequences. AB - This review summarizes current knowledge regarding the effects of speed limit enforcement on public health. Speed limits are commonly used around the world to regulate the maximum speed at which motor vehicles can be operated on public roads. Speed limits are statutory, and violations of them are normally sanctioned by means of fixed penalties (traffic tickets) or, in the event of serious violations, suspension of the driver's license and imposition of prison sentences. Speed limit violations are widespread in all countries for which statistics can be found. Speeding contributes more to the risk of traffic injury than do other risk factors for which estimates of population-attributable risk are available. Traffic speed strongly influences impact speed in crashes and therefore has major implications for public health. PMID- 22224883 TI - Policies for healthier communities: historical, legal, and practical elements of the obesity prevention movement. AB - The U.S. population is facing an obesity crisis wrought with severe health and economic costs. Because social and environmental factors have a powerful influence over lifestyle choices, a national obesity prevention strategy must involve population-based interventions targeted at the places where people live, study, work, shop, and play. This means that policy, in addition to personal responsibility, must be part of the solution. This article first describes the emergence of and theory behind the obesity prevention movement. It then explains how government at all levels is empowered to develop obesity prevention policy. Finally, it explores eight attributes of a promising state or local obesity prevention policy and sets the obesity prevention movement in the context of a larger movement to promote healthy communities and prevent chronic disease. PMID- 22224881 TI - Toward a systems approach to enteric pathogen transmission: from individual independence to community interdependence. AB - Diarrheal disease is still a major cause of mortality and morbidity worldwide; thus a large body of research has been produced describing its risks. We review more than four decades of literature on diarrheal disease epidemiology. These studies detail a progression in the conceptual understanding of transmission of enteric pathogens and demonstrate that diarrheal disease is caused by many interdependent pathways. However, arguments by diarrheal disease researchers in favor of attending to interaction and interdependencies have only recently yielded more formal systems-level approaches. Therefore, interdependence has not yet been highlighted in significant new research initiatives or policy decisions. We argue for a systems-level framework that will contextualize transmission and inform prevention and control efforts so that they can integrate transmission pathways. These systems approaches should be employed to account for community effects (i.e., interactions among individuals and/or households). PMID- 22224884 TI - From small area variations to accountable care organizations: how health services research can inform policy. AB - Much of health services research seeks to inform particular policy choices and is best characterized as policy-driven research. The reverse, research-driven policy, occurs when studies alter how people perceive reality, which eventually leads to new policy. An example of the latter is nearly four decades of work by John Wennberg and colleagues. Observing variations in practice across small geographic areas led to the notion that some care is preference sensitive, whereas other care is supply constrained. For the former, patient, rather than physician, preferences should be honored, after acquiring and effectively communicating the best available information on the benefits and risks of treatment options. Finding that areas with high use of services have no better quality or outcomes than do areas with lower use led to the notion of accountable care organizations (ACOs). Eventually, both patient engagement and ACOs were written into the Affordable Care Act of 2010. PMID- 22224886 TI - Suicide mortality in the United States: the importance of attending to method in understanding population-level disparities in the burden of suicide. AB - Suicide mortality varies widely across age, sex, race, and geography, far more than does mortality from the leading causes of natural death. Unlike the tight correlation between cancer mortality and the incidence of cancer, suicide mortality is only modestly correlated with the incidence of suicidal acts and other established risk factors for suicidal behavior, such as major psychiatric disorders. An implication of this modest correlation is that the proportion of all suicidal acts that prove fatal (the case fatality ratio) must account for a substantial portion of the (nonrandom) variation observed in suicide mortality. In the United States, the case fatality ratio is strongly related to the availability of household firearms. Findings from ecologic and individual-level studies conducted over the past two decades illustrate the importance of accounting for the availability of highly lethal suicide methods in efforts to understand (and ultimately reduce) disparities in suicide mortality across populations. PMID- 22224885 TI - Systems science methods in public health: dynamics, networks, and agents. AB - Complex systems abound in public health. Complex systems are made up of heterogeneous elements that interact with one another, have emergent properties that are not explained by understanding the individual elements of the system, persist over time, and adapt to changing circumstances. Public health is starting to use results from systems science studies to shape practice and policy, for example in preparing for global pandemics. However, systems science study designs and analytic methods remain underutilized and are not widely featured in public health curricula or training. In this review we present an argument for the utility of systems science methods in public health, introduce three important systems science methods (system dynamics, network analysis, and agent-based modeling), and provide three case studies in which these methods have been used to answer important public health science questions in the areas of infectious disease, tobacco control, and obesity. PMID- 22224887 TI - Future challenges to protecting public health from drinking-water contaminants. AB - Over the past several decades, human health protection for chemical contaminants in drinking water has been accomplished by development of chemical-specific standards. This approach alone is not feasible to address current issues of the occurrence of multiple contaminants in drinking water, some of which have little health effects information, and water scarcity. In this article, we describe the current chemical-specific paradigm for regulating chemicals in drinking water and discuss some potential additional approaches currently being explored to focus more on sustaining quality water for specific purposes. Also discussed are strategies being explored by the federal government to screen more efficiently the toxicity of large numbers of chemicals to prioritize further intensive testing. Water reuse and water treatment are described as sustainable measures for managing water resources for potable uses as well as other uses such as irrigation. PMID- 22224888 TI - Quitlines and nicotine replacement for smoking cessation: do we need to change policy? AB - In the past 20 years, public health initiatives on smoking cessation have increased substantially. Randomized trials indicate that pharmaceutical cessation aids can increase success by 50% among heavier smokers who seek help, and use of these aids has increased markedly. Quitlines provide a portal through which smokers can seek assistance to quit and are promoted by tobacco control programs. Randomized trials have demonstrated that telephone coaching following a quitline call can also increase quitting, and a combination of quitlines, pharmaceutical aids and physician monitoring can help heavier smokers to quit. While quit attempts have increased, widespread dissemination of these aids has not improved population success rates. Pharmaceutical marketing strategies may have reduced expectations of the difficulty of quitting, reducing success per attempt. Some policies actively discourage unassisted smoking cessation despite the documented high success rates of this approach. There is an urgent need to revisit public policy on smoking cessation. PMID- 22224889 TI - Economic evaluation of pharmaco- and behavioral therapies for smoking cessation: a critical and systematic review of empirical research. AB - Economic evaluations are an important tool to improve our understanding of the costs and effects of health care services and to create sustainable health care systems. This article critically assesses empirical evidence from economic evaluations of pharmaco- and behavioral therapies for smoking cessation. A comprehensive literature review of PubMed and the British National Health Service Economic Evaluation Database was conducted. The search identified 15 articles on nicotine-based pharmacotherapies, 12 articles on nonnicotine based pharmacotherapies, no articles on selegiline, and 10 articles on brief counseling for smoking cessation treatment. Results show that both pharmaco- and behavioral therapies for smoking cessation are cost-effective or even cost-saving. The review highlights several shortcomings in methodology and a lack of standardization of current economic evaluations. Efforts to improve methodology will help make future studies more comparable and increase the evidence base so that such evaluations can be more useful to public health practitioners and policy makers. PMID- 22224890 TI - Disparities in infant mortality and effective, equitable care: are infants suffering from benign neglect? AB - Quality care for infant mortality disparity elimination requires services that improve health status at both the individual and the population level. We examine disparity reduction due to effective care and ask the following question: Has clinical care ameliorated factors that make some populations more likely to have higher rates of infant mortality compared with other populations? Disparities in postneonatal mortality due to birth defects have emerged for non-Hispanic black and Hispanic infants. Surfactant and antenatal steroid therapy have been accompanied by growing disparities in respiratory distress syndrome mortality for black infants. Progesterone therapy has not reduced early preterm birth, the major contributor to mortality disparities among non-Hispanic black and Puerto Rican infants. The Back to Sleep campaign has minimally reduced SIDS disparities among American Indian/Alaska Native infants, but it has not reduced disparities among non-Hispanic black infants. In general, clinical care is not equitable and contributes to increasing disparities. PMID- 22224891 TI - The methods of comparative effectiveness research. AB - This review describes methods used in comparative effectiveness research (CER). The aim of CER is to improve decisions that affect medical care at the levels of both policy and the individual. The key elements of CER are (a) head-to-head comparisons of active treatments, (b) study populations typical of day-to-day clinical practice, and (c) a focus on evidence to inform care tailored to the characteristics of individual patients. These requirements will stress the principal methods of CER: observational research, randomized trials, and decision analysis. Observational studies are especially vulnerable because they use data that directly reflect the decisions made in usual practice. CER will challenge researchers and policy makers to think deeply about how to extract more actionable information from the vast enterprise of the daily practice of medicine. Fortunately, the methods are largely applicable to research in the public health system, which should therefore benefit from the intense interest in CER. PMID- 22224892 TI - Clinical care and health disparities. AB - Health disparities, also known as health inequities, are systematic and potentially remediable differences in one or more aspects of health across population groups defined socially, economically, demographically, or geographically. This topic has been the subject of research stretching back at least decades. Reports and studies have delved into how inequities develop in different societies and, with particular regard to health services, in access to and financing of health systems. In this review, we consider empirical studies from the United States and elsewhere, and we focus on how one aspect of health systems, clinical care, contributes to maintaining systematic differences in health across population groups characterized by social disadvantage. We consider inequities in clinical care and the policies that influence them. We develop a framework for considering the structural and behavioral components of clinical care and review the existing literature for evidence that is likely to be generalizable across health systems over time. Starting with the assumption that health services, as one aspect of social services, ought to enhance equity in health care, we conclude with a discussion of threats to that role and what might be done about them. PMID- 22224893 TI - Unintentional injuries: magnitude, prevention, and control. AB - The World Health Organization estimates injuries accounted for more than 5 million deaths in 2004, significantly impacting the global burden of disease. Nearly 3.9 million of these deaths were due to unintentional injury, a cause also responsible for more than 138 million disability-adjusted life years (DALYs) lost in the same year. More than 90% of the DALYs lost occur in low- and middle-income countries (LMICs), highlighting the disproportionate burden that injuries place on developing countries. This article examines the health and social impact of injury, injury data availability, and injury prevention interventions. By proposing initiatives to minimize the magnitude of death and disability due to unintentional injuries, particularly in LMICs, this review serves as a call to action for further investment in injury surveillance, prevention interventions, and health systems strengthening. PMID- 22224894 TI - The medicalization of chronic disease and costs. AB - U.S. health care spending has increased dramatically in the past several decades, consuming 17.6% percent ($2.6 trillion) of GDP in 2010. Although historical spending drivers do not account for this recent increase, two major changes in population health--the rise in obesity and obesity-related chronic disease- provide a likely explanation. This article reviews the contribution that rising treated obesity-related chronic disease prevalence and its associated treatment (spending per treated case) has made to the growth in health care spending. We discuss trends in the clinical incidence of obesity and chronic disease as well as timely advancements in disease detection, treatment, and management. Evidence shows that rising obesity rates are influencing spending largely by increasing the treated prevalence of obesity-related chronic disease. Therefore, preventing individuals from becoming treated cases in the first place is one key way that our country can cut health care spending moving forward. PMID- 22224895 TI - Health disparities research in global perspective: new insights and new directions. AB - This commentary introduces this volume's symposium on "Comparative Approaches to Reducing Health Disparities." Disparities in the health of socially and economically disadvantaged compared with more advantaged populations are observed worldwide. The lack of progress in addressing these disparities compels a continuing search for new ideas and evidence about potential solutions as well as efforts to understand when and where these solutions work and how they work. The symposium consists of five in-depth reviews led by established scholars who approach the topic from their different disciplinary and topical perspectives. Taken together, these reviews point out the conceptual and methodological opportunities for generating more effective disparities research within biomedical, public health, and health services approaches, the value of also applying theory and methods from disciplines such as political science and economics to health disparities research, and insights to be gained from comparisons of how disparities occur and are remedied in different societies. PMID- 22224899 TI - Polyphenol content of plasma and litter after the oral administration of green tea and tea polyphenols in chickens. AB - Metabolic profiles of broiler chickens were examined after the ingestion of green tea, tea polyphenols, and (-)-epigallocatechin-3-gallate (EGCG). Solid-phase extraction of serum and litters yielded free catechins and their metabolites, which were then identified and quantified by liquid chromatography-tandem mass spectrometry. In plasma samples, (-)-gallocatechin, (+)-catechin, and EGCG were detected in the green tea group; pyrogallol acid, (epi)catechin-O-sulfate, 4'-O methyl-(epi)gallocatechin-O-glucuronide, and (epi)catechin-3'-O-glucuronide were detected in the tea polyphenols group; and EGCG, (-)-gallocatechin gallate (GCG), and 4'-O-methyl-(epi)gallocatechin-O-glucuronides were detected in the EGCG group. In litters, gallic acid, EGCG, GCG, and ECG were detected in the green tea and tea polyphenols groups; EGCG and ECG were detected in the EGCG group. The conjugated metabolites, 4'-O-methyl-(epi)gallocatechin-O-glucuronide, (epi)catechin-3'-glucuronide, and 4'-O-methyl-(epi)catechin-O-sulfate, were identified in the green tea group; 4'-O-methyl-(epi)catechin-O-sulfate and 4'-O methyl-(epi)gallocatechin-O-sulfate were identified in the tea polyphenols group; only 4'-O-methyl-(epi)gallocatechin-O-sulfate was detected in the EGCG group. The excretion of tea catechins was 95.8, 87.7, and 97.7% for the green tea, tea polyphenols, and EGCG groups, respectively. PMID- 22224900 TI - The gene encoding the alternative thymidylate synthase ThyX is regulated by sigma factor SigB in Corynebacterium glutamicum ATCC 13032. AB - Both ThyA and ThyX proteins catalyze the transfer of the methyl group from methylenetetrahydrofolate (CH(2) H(4) -folate) to dUMP, forming dTMP. To estimate the relative steady state expression levels of ThyA and ThyX, Western blot analysis was performed using ThyA or ThyX antiserum on total protein from the wild-type, DeltathyX, and thyX-complemented strains of Corynebacterium glutamicum. The level of ThyA decreased gradually during the stationary growth phase but that of ThyX was maintained steadily. Whereas the expression level of ThyA in a DeltasigB strain was comparable to that of the wild-type, the level of ThyX was significantly diminished in the deletion mutant and was restored to that of the wild-type in the complemented strain, indicating that the level of ThyX was regulated by SigB. Growth of the C. glutamicum DeltasigB strain was dependent upon coupling activity of dihydrofolate reductase (DHFR) with ThyA for the synthesis of thymidine, and thus showed sensitivity to the inhibition of DHFR by the experimental inhibitor, WR99210-HCl. These results suggested that the relative levels of ThyA and ThyX differ in response to different growth phases and that SigB is necessary for maintenance of the level of ThyX during transition into the stationary growth phase. PMID- 22224901 TI - Heterozygosity maintains developmental stability of sternopleural bristles in Drosophila subobscura interpopulation hybrids. AB - Interpopulation hybridization can lead to outbreeding depression within affected populations due to breakdown of coadapted gene complexes or heterosis in hybrid populations. One of the principal methods commonly used to estimate the level of developmental instability (DI) is fluctuating asymmetry (FA). We used three genetically differentiated Drosophila subobscura populations according to inversion polymorphism analysis and measured the variability of sternopleural bristle number and change in FA across generations P, F1, and F2 between intra- and interpopulation hybrids of D. subobscura. The mean variability of sternopleural bristle number in intra- and interpopulation hybrids of D. subobscura across generations cannot determine whether the changes at the level of developmental homeostasis are due exclusively to genomic coadaptation or to heterozygosity. Phenotypic variance (V(p)) and FA of sternopleural bristle number was higher in interpopulation than in intrapopulation hybrids across generations. F1 hybrids were more developmentally stable compared to each parental population in both intra- and interpopulation hybrids. The most probable mechanism providing developmental homeostasis is heterozygote or hybrid superiority, also called overdominace. However, V(p) was higher and FA lower in the F2 generation when compared to F1, due mainly to crossing-over in the formation of F2. PMID- 22224903 TI - Medication problems occurring at hospital discharge among older adults with heart failure. AB - Medication reconciliation problems are common among older adults at hospital discharge and lead to adverse events. The purpose of this study was to examine the rates and types of medication reconciliation problems among older adults hospitalized for acute episodes of heart failure who were discharged home. This secondary analysis of data generated from a transitional care intervention included 198 hospital discharge medical records, representing 162 patients. A retrospective chart review comparing medication lists between hospital discharge summaries and patient discharge instructions was completed to identify medication reconciliation problems. Most hospital discharges (71.2%) had at least one type of reconciliation problem and frequently involved a high-risk medication (76.6%). Discrepancies were the most common problem (58.9%), followed by incomplete discharge summaries (52.5%) and partial patient discharge instructions (48.9%). More attention needs to be given to the quality of discharge instructions, and the problem of vague phrases (e.g., "take as directed") can be addressed by adding it to "do not use" lists to promote safer transitions in care. PMID- 22224902 TI - The role of matched controls in building an evidence base for hospital-avoidance schemes: a retrospective evaluation. AB - OBJECTIVE: To test whether two hospital-avoidance interventions altered rates of hospital use: "intermediate care" and "integrated care teams." DATA SOURCES/STUDY SETTING: Linked administrative data for England covering the period 2004 to 2009. STUDY DESIGN: This study was commissioned after the interventions had been in place for several years. We developed a method based on retrospective analysis of person-level data comparing health care use of participants with that of prognostically matched controls. DATA COLLECTION/EXTRACTION METHODS: Individuals were linked to administrative datasets through a trusted intermediary and a unique patient identifier. PRINCIPAL FINDINGS: Participants who received the intermediate care intervention showed higher rates of unscheduled hospital admission than matched controls, whereas recipients of the integrated care team intervention showed no difference. Both intervention groups showed higher rates of mortality than did their matched controls. CONCLUSIONS: These are potentially powerful techniques for assessing impacts on hospital activity. Neither intervention reduced admission rates. Although our analysis of hospital utilization controlled for a wide range of observable characteristics, the difference in mortality rates suggests that some residual confounding is likely. Evaluation is constrained when performed retrospectively, and careful interpretation is needed. PMID- 22224904 TI - End-of-life care for rural-dwelling older adults and their primary family caregivers. AB - Older adults dying from chronic illness in rural areas are understudied and of concern because of their limited access to health services. The purpose of this qualitative descriptive study was to describe the perspectives of primary family caregivers regarding experiences with formal and informal care at the end of life for dying older adults in one rural, agricultural county. Semi-structured interviews were conducted with 23 caregivers following the death of an older relative. Major themes that emerged from the data were the benefits and challenges associated with care services. Benefits included neighbors, friends, and other volunteers who offered household help and provided respite care. Challenges included limited resources for continuity of care, geographical service boundaries, and lack of knowledge about end-of-life care by paid caregivers. Further research that addresses the perspective of rural service providers is needed to better understand the benefits and challenges of end-of life care in this setting. PMID- 22224905 TI - Fluorescent nanoparticle adhesion assay: a novel method for surface pKa determination of self-assembled monolayers on silicon surfaces. AB - Since the computer industry enables us to generate smaller and smaller structures, silicon surface chemistry is becoming increasingly important for (bio )analytical and biological applications. For controlling the binding of charged biomacromolecules such as DNA and proteins on modified silicon surfaces, the surface pK(a) is an important factor. Here we present a fluorescent nanoparticle adhesion assay as a novel method to determine the surface pK(a) of silicon surfaces modified with weak acids or bases. This method is based upon electrostatic interactions between the modified silicon surface and fluorescent nanoparticles with an opposite charge. Silicon slides were modified with 3 aminopropyltriethoxysilane (APTES) and were further derivatized with succinic anhydride. Layer thickness of these surfaces was determined by ellipsometry. After incubating the surfaces with an amine-reactive fluorescent dye, fluorescence microscopy revealed that the silicon surfaces were successfully modified with amine- and carboxyl-groups. Two surface pK(a) values were found for APTES surfaces by the fluorescent nanoparticle adhesion assay. The first surface pK(a) (6.55 +/- 0.73) was comparable with the surface pK(a) obtained by contact angle titration (7.3 +/- 0.8), and the second surface pK(a) (9.94 +/- 0.19) was only found by using the fluorescent nanoparticle adhesion assay. The surface pK(a) of the carboxyl-modified surface by the fluorescent nanoparticle adhesion assay (4.37 +/- 0.59) did not significantly differ from that found by contact angle titration (5.7 +/- 1.4). In conclusion, we have developed a novel method to determine the surface pK(a) of modified silicon surfaces: the fluorescent nanoparticle adhesion assay. This method may provide a useful tool for designing pH-dependent electrostatic protein and particle binding/release and to design surfaces with a pH-dependent surface charge for (bio-)analytical lab-on-a-chip devices or drug delivery purposes. PMID- 22224906 TI - Pronounced hydrogen bonding giving rise to apparent probe hyperpolarity in ionic liquid mixtures with 2,2,2-trifluoroethanol. AB - The fascinating and attractive features of ionic liquids (ILs) can be considerably expanded by mixing with suitable cosolvents, opening their versatility beyond the pure materials. We show here that mixtures of the IL 1 butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF6]) and 2,2,2 trifluoroethanol (TFE) display the intriguing phenomenon of hyperpolarity, examples of which are notably sparse in the literature. From the perspective of the E(T)(N) polarity scale and Kamlet-Taft parameters for hydrogen bond acidity (alpha) and basicity (beta), the polarity of this mixture exceeds that of either neat component. Fluorescent molecular probes capable of engaging in hydrogen bonds (e.g., 2-(p-toluidino)naphthalene-6-sulfonate, TNS; 6-propionyl-2 (dimethylamino)naphthalene, PRODAN) also exhibit this curious behavior. The choice of IL anion appears to be essential as hyperpolarity is not observed for mixtures of TFE with ILs containing anions other than hexafluorophosphate. The complex solute-solvent and solvent-solvent interactions present in the [bmim][PF6] + TFE mixture were further elucidated using infrared absorbance, dynamic viscometry, and density measurements. These results are discussed in terms of Coulombic interactions, disruption of TFE multimers, formation of hyperanion preference aggregates, and "free" [bmim]+. It is our intent that these results open the door for computational exploration of related solvent mixtures while inspiring practical questions, such as whether such systems might offer the potential for stabilization of highly charged transition states or ionic clusters during (nano)synthesis. PMID- 22224909 TI - Personality and relationship quality during the transition from high school to early adulthood. AB - The post-high school transition period is believed to be associated with considerable changes in social networks, yet longitudinal studies documenting these changes are scarce. To address this gap, the current research explored 3 relevant issues. First, changes in participants' relationship characteristics during the transition from high school were examined. Second, the roles of personality traits as antecedents of these changes were studied. Third, the association between change in relationship characteristics and personality during the transition was explored. A sample of over 2,000 German emerging adults, surveyed before leaving school and then 2 years after the transition from high school, was assessed on personality traits and a multidimensional assessment of the quality of their relationships. Findings indicated that participants experienced mostly positive changes in relationship quality during the transition from high school and that antecedent personality at school was an important predictor of the nature of this change. Finally, change in relationship quality was found to be associated with personality change during the post-school transition. Findings indicated that personality traits may influence transition success and that change in relationships during this transition may influence personality development. The implications of the research for post-school transition success are discussed. PMID- 22224911 TI - Metabolism of the insecticide metofluthrin in cabbage (Brassica oleracea). AB - The metabolic fate of metofluthrin [2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (E,Z)-(1R,3R)-2,2-dimethyl-3-(prop-1-enyl)cyclopropanecarboxylate] separately labeled with (14)C at the carbonyl carbon and the alpha-position of the 4 methoxymethylbenzyl ring was studied in cabbage ( Brassica oleracea ). An acetonitrile solution of (14)C-metofluthrin at 431 g ai ha(-1) was once applied topically to cabbage leaves at head-forming stage, and the plants were grown for up to 14 days. Each isomer of metofluthrin applied onto the leaf surface rapidly volatilized into the air and was scarcely translocated to the untreated portion. On the leaf surface, metofluthrin was primarily degraded through ozonolysis of the propenyl side chain to produce the secondary ozonide, which further decomposed to the corresponding aldehyde and carboxylic acid derivatives. In the leaf tissues, the 1R-trans-Z isomer was mainly metabolized to its dihydrodiol derivative probably via an epoxy intermediate followed by saccharide conjugation in parallel with the ester cleavage, whereas no specific metabolite was dominant for the 1R-trans-E isomer. Isomerization of metofluthrin at the cyclopropyl ring was negligible for both isomers. In this study, the chemical structure of each secondary ozonide derivative was fully elucidated by the various modes of liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy together with cochromatography with the synthetic standard, and their cis/trans configuration was examined by the nuclear Overhauser effect (NOE) difference NMR spectrum. PMID- 22224913 TI - The influence of different magnitudes and methods of applying preload on fusion and disc replacement constructs in the lumbar spine: a finite element analysis. AB - In a finite element (FE) analysis of the lumbar spine, different preload application methods that are used in biomechanical studies may yield diverging results. To investigate how the biomechanical behaviour of a spinal implant is affected by the method of applying the preload, hybrid-controlled FE analysis was used to evaluate the biomechanical behaviour of the lumbar spine under different preload application methods. The FE models of anterior lumbar interbody fusion (ALIF) and artificial disc replacement (ADR) were tested under three different loading conditions: a 150 N pressure preload (PP) and 150 and 400 N follower loads (FLs). This study analysed the resulting range of motion (ROM), facet contact force (FCF), inlay contact pressure (ICP) and stress distribution of adjacent discs. The FE results indicated that the ROM of both surgical constructs was related to the preload application method and magnitude; differences in the ROM were within 7% for the ALIF model and 32% for the ADR model. Following the application of the FL and after increasing the FL magnitude, the FCF of the ADR model gradually increased, reaching 45% at the implanted level in torsion. The maximum ICP gradually decreased by 34.1% in torsion and 28.4% in lateral bending. This study concluded that the preload magnitude and application method affect the biomechanical behaviour of the lumbar spine. For the ADR, remarkable alteration was observed while increasing the FL magnitude, particularly in the ROM, FCF and ICP. However, for the ALIF, PP and FL methods had no remarkable alteration in terms of ROM and adjacent disc stress. PMID- 22224914 TI - Multidimensional protein identification technology-selected reaction monitoring improving detection and quantification for protein biomarker studies. AB - The targeted analysis of proteins in complex biological samples is best achieved using selected reaction monitoring (SRM). To maximize the sensitivity of this approach, sample fractionation or enrichment is still required, particularly to detect less abundant proteins in clinically relevant biofluids. Here, we report the development of multidimensional protein identification technology (MudPIT) SRM, taking advantage of the robust online strong cation exchange chromatography for tryptic peptide fractionation and combining it with the multiplexed, quantitative attributes of SRM. The classical MudPIT method has been modified with an in-line strategy to introduce reference peptides onto the analytical column to enable quantitation at each salt step. Applying the MudPIT-SRM approach to profile abundant plasma proteins, we demonstrated mean increases in peak areas of almost 90% compared to conventional SRM. MudPIT-SRM analyses of low abundant proteins present in human wound fluid exudates similarly demonstrated increased peak areas and enabled the detection of proteins which were below the lower limit of detection when analyzed by conventional SRM. The MudPIT-SRM method is relatively facile to conduct and offers performance advantages to enhance sensitivity for biomarker studies. PMID- 22224915 TI - No-wash protein labeling with designed fluorogenic probes and application to real time pulse-chase analysis. AB - Small molecule labeling techniques for cellular proteins under physiological conditions are very promising for revealing new biological functions. We developed a no-wash fluorogenic labeling system by exploiting fluorescence resonance energy transfer (FRET)-based fluorescein-cephalosporin-azopyridinium probes and a mutant beta-lactamase tag. Fast quencher elimination, hydrophilicity, and high resistance against autodegradation were achieved by rational refinement of the structure. By applying the probe to real-time pulse chase analysis, the trafficking of epidermal growth factor receptors between cell surface and intracellular region was imaged. In addition, membrane-permeable derivatization of the probe enabled no-wash fluorogenic labeling of intracellular proteins. PMID- 22224916 TI - Synthesis of thiophenylalanine-containing peptides via Cu(I)-mediated cross coupling. AB - Aryl thiolates have unique reactive, redox, electronic, and spectroscopic properties. A practical approach to synthesize peptides containing thiophenylalanine has been developed via a novel Cu(I)-mediated cross-coupling reaction between thiolacetic acid and iodophenylalanine-containing peptides in the solid phase. This approach is compatible with all canonical proteinogenic functional groups, providing general access to aryl thiolates in peptides. Peptides containing thiophenylalanine (pK(a) 6.4) were readily elaborated to contain methyl, allyl, and nitrobenzyl thioethers, disulfides, sulfoxides, sulfones, or sulfonates. PMID- 22224918 TI - Hypoglycemic health benefits of D-psicose. AB - Diabetes is an emerging health problem worldwide. The incidence of type 2 diabetes has dramatically increased and is expected to increase more rapidly in the future. Most patients with type 2 diabetes suffer from obesity and diabetes related complications, including cardiovascular disease and hepatic steatosis. It has been proposed that simple sugar consumption is one of the major risk factors in the development of diabetes. Hence, the replacement of sugars with a low glycemic response would be an effective strategy to prevent type 2 diabetes. Accumulating evidence demonstrates that D-psicose, which has 70% the sweetness of sucrose and no calories, is a functional sugar exerting several health benefits preventing the development of diabetes. Although D-psicose presents in small amounts in natural products, a recent new technique using biocatalyst sources enables large-scale D-psicose production. More importantly, several clinical and animal studies demonstrated that D-psicose has hypoglycemic, hypolipidemic, and antioxidant activities, which make it an ideal candidate for preventing diabetes and related health concerns. This review will summarize the protective effects of D-psicose against type 2 diabetes and its complications, suggesting its potential benefits as a sucrose substitute. PMID- 22224919 TI - ACTN3 R577X polymorphism and performance phenotypes in young Chinese male soldiers. AB - Alpha-actinin-3 (ACTN3) is absent in 18% of healthy Caucasian individuals owing to homozygosity for a premature stop codon (X) at amino acid 577 (rs1815739). Previous studies have shown a strong association between ACTN3 genotype and human athletic performance. In a study of 452 young Chinese male soldiers, we examined the distribution of ACTN3 genotypes and alleles and analysed the association between ACTN3 genotypes and athletic performance. We found that the frequencies of the ACTN3 R577X genotype (RR 39.8%, RX 43.4%, and XX 16.8%) and R577X allele (R 61.5%, X 38.5%) in young Chinese males were not significantly different from those in Caucasians. We only observed a significant association (P = 0.025) between ACTN3 R577X genotypes and grip strength. Participants with the XX genotype displayed significantly lower handgrip strength than individuals with the RR genotype (P = 0.021), but the difference between XX and RX means (P = 0.258) and that between RR and RX means (P = 0.42) was not significant. We did not observe a strong association between the ACTN3 R577X genotypes and sprint phenotypes or endurance phenotypes. In conclusion, our results indicate that the ACTN3 R577X polymorphism is most strongly associated with grip strength in young Chinese male soldiers. PMID- 22224920 TI - Purification of a novel angiotensin I-converting enzyme (ACE) inhibitory peptide with an antihypertensive effect from loach (Misgurnus anguillicaudatus). AB - To isolate and characterize novel angiotensin I-converting enzyme (ACE) inhibitory peptide from loach (Misgurnus anguillicaudatus), six proteases, pepsin, alpha-chymotrypsin, bromelain, papain, alcalase, and Neutrase, were used to hydrolyze loach protein. The hydrolysate (LPH) generated by bromelain [ratio of enzyme to substrate, 3:1000 (w/w)] was found to have the highest ACE inhibitory activity (IC(50), 613.2 +/- 8.3 MUg/mL). Therefore, it was treated by ultrafiltration to afford fraction of LPH-IV (MW < 2.5 kDa) with an IC(50) of 231.2 +/- 3.8 MUg/mL, having higher activity than the other fractions. Then, LPH IV was isolated and purified by consecutive purification steps of gel filtration chromatography and reverse-phase high-performance liquid chromatography to afford a purified peptide with an IC(50) of 18.2 +/- 0.9 MUg/mL, an increase of 33.7 fold in ACE inhibitory activity as compared with that of LPH. The purified peptide was identified as Ala-His-Leu-Leu (452 Da) by Q-TOF mass spectrometry and amino acid analyzer. An antihypertensive effect in spontaneously hypertensive rats revealed that oral administration of LPH-IV could decrease systolic blood pressure significantly. PMID- 22224921 TI - Characterization of the adherence properties of human Lactobacilli strains to be used as vaginal probiotics. AB - In the present work, the adhesion of 43 human lactobacilli isolates to mucin has been studied. The most adherent strains were selected, and their capacities to adhere to three epithelial cell lines were studied. All intestinal strains and one vaginal isolate adhered to HT-29 cells. The latter was the most adherent to Caco-2 cells, although two of the intestinal isolates were also highly adherent. Moreover, five of the eight strains strongly adhered to HeLa cells. The binding of an Actinomyces neuii clinical isolate to HeLa cells was enhanced by two of the lactobacilli and by their secreted proteins, while those of another two strains almost abolished it. None of the strains were able to interfere with the adhesion of Candida albicans to HeLa cells. The components of the extracellular proteome of all strains were identified by MALDI-TOF/MS. Among them, a collagen-binding A precursor and aggregation-promoting factor-like proteins are suggested to participate on adhesion to Caco-2 and HeLa cells, respectively. In this way, several proteins with LysM domains might explain the ability of some bacterial supernatants to block A. neuii adhesion to HeLa cell cultures. Finally, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) could explain the good adhesion of some strains to mucin. PMID- 22224922 TI - Circulating tumour cells in disseminated malignant melanoma. PMID- 22224923 TI - Clients' and therapists' perceptions of intrasessional connection: an analogue study of change over time, predictor variables, and level of consensus. AB - Clients' and therapists' within-session experiences of relational connection were investigated using an analogue design. Eighty "therapist-client" dyads rated, on a minute-by-minute basis, their levels of connection to the other over a 20 minute counselling session. Therapists' and clients' feelings of connection increased over time with a negatively accelerating curve. Clients experienced a greater increase in feelings of connection with therapists that they perceived as less anxious; while older therapists, and therapists who believed they were perceived as more agreeable, experienced a deeper connection. Clients' and therapists' perception of connection were significantly associated, with a median within-dyad correlation of .76. PMID- 22224924 TI - How habitat change and rainfall affect dung beetle diversity in Caatinga, a Brazilian semi-arid ecosystem. AB - The aim of the present study was to evaluate how dung beetle communities respond to both environment and rainfall in the Caatinga, a semi-arid ecosystem in northeastern Brazil. The communities were sampled monthly from May 2006 to April 2007 using pitfall traps baited with human feces in two environments denominated "land use area" and "undisturbed area." Abundance and species richness were compared between the two environments and two seasons (dry and wet season) using a generalized linear model with a Poisson error distribution. Diversity was compared between the two environments (land use area and undisturbed area) and seasons (dry and wet) using the Two-Way ANOVA test. Non-metric multidimensional scaling was performed on the resemblance matrix of Bray-Curtis distances (with 1000 random restarts) to determine whether disturbance affected the abundance and species composition of the dung beetle communities. Spearman's correlation coefficient was used to determine whether rainfall was correlated with abundance and species richness. A total of 1097 specimens belonging to 13 species were collected. The most abundant and frequent species was Dichotomius geminatus Arrow (Coleoptera: Scarabaeidae). The environment exerted an influence over abundance. Abundance and diversity were affected by season, with an increase in abundance at the beginning of the wet season. The correlation coefficient values were high and significant for abundance and species richness, which were both correlated to rainfall. In conclusion, the restriction of species to some environments demonstrates the need to preserve these areas in order to avoid possible local extinction. Therefore, in extremely seasonable environments, such as the Caatinga, seasonal variation strongly affects dung beetle communities. PMID- 22224925 TI - Trichinella spiralis-secreted products modulate DC functionality and expand regulatory T cells in vitro. AB - Helminths and their products can suppress the host immune response which may benefit parasite survival. Trichinella spiralis can establish chronic infections in a wide range of mammalian hosts including humans and mice. Here, we aim at studying the effect of T. spiralis muscle larvae excretory/secretory products (TspES) on the functionality of DC and T cell activation. We found that TspES suppress in vitro DC maturation induced by both S- and R-form lipopolysaccharide(LPS) from enterobacteria. Using different toll-like receptor (TLR) agonists, we show that the suppressive effect of TspES on DC maturation is restricted to TLR4. These helminth products also interfere with the expression of several genes related to the TLR-mediated signal transduction pathways. To investigate the effect of TspES on T cell activation, we used splenocytes derived from OVA-TCR transgenic D011.10 that were incubated with OVA and TspES-pulsed DC. Results indicate that the presence of TspES resulted in the expansion of CD4(+) CD25(+) Foxp3+ T cells. These regulatory T (Treg) cells were shown to have suppressive activity and to produce TGF-beta. Together these results suggest that T. spiralis secretion products can suppress DC maturation and induce the expansion of functional Treg cells in vitro. PMID- 22224926 TI - Investigation of optical nonlinearities and transient dynamics in a stilbenzene derivative. AB - The temporal properties of nonlinear absorption of a stilbenzene derivative have been investigated by time-resolved pump-probe techniques with picosecond laser pulses at the wavelength of 532 nm. With the help of an additional nanosecond and picosecond open-aperture Z-scan technique, numerical simulations based on a new five-energy level model are used to interpret the experimental results, and the nonlinear optical parameters of this new compound are determined. The five-energy level model is described by two-photon absorption (TPA) excited from ground-state induced excited-state absorption (ESA) including singlet ESA and triplet ESA. Under the nanosecond pulse excitation, a TPA excited from the triplet excited state contributes to the nonlinear absorption, and the value of the TPA is found to be 1 order of magnitude larger than those usually found for TPA excited from the ground state. PMID- 22224927 TI - Wicking and spreading of water droplets on nanotubes. AB - Recently, there has been intensive research on the use of nanotechnology to improve the wettability of solid surfaces. It is well-known that nanostructures can improve the wettability of a surface, and this is a very important safety consideration in regard to the occurrence of boiling crises during two-phase heat transfer, especially in the operation of nuclear power plant systems. Accordingly, there is considerable interest in wetting phenomena on nanostructures in the field of nuclear heat transfer. Much of the latest research on liquid absorption on a surface with nanostructures indicates that liquid spreading is generated by capillary wicking. However, there has been comparatively little research on how capillary forces affect liquid spreading on a surface with nanotubes. In this paper, we present a visualization of liquid spreading on a zircaloy surface with nanotubes, and establish a simple quantitative method for measuring the amount of water absorbed by the nanotubes. We successfully describe liquid spreading on a two-dimensional surface via one dimensional analysis. As a result, we are able to postulate a relationship between liquid spreading and capillary wicking in the nanotubes. PMID- 22224928 TI - Grape antioxidant dietary fiber stimulates Lactobacillus growth in rat cecum. AB - The digesta is a highly active biological system where epithelial cells, microbiota, nondigestible dietary components, and a large number of metabolic products interact. The gut microbiota can be modulated by both endogenous and exogenous substrates. Undigested dietary residues are substrates for colonic microbiota and may influence gut microbial ecology. The objective of this work was to study the capacity of grape antioxidant dietary fiber (GADF), which is rich in polyphenols, to modify the bacterial profile in the cecum of rats. Male adult Wistar rats were fed for 4 wk with diets containing either cellulose or GADF as dietary fiber. The effect of GADF on bacterial growth was evaluated in vitro and on the cecal microbiota of rats using quantitative real time polymerase chain reaction (RT-PCR). The results showed that GADF intake stimulates proliferation of Lactobacillus and slightly affects the composition of Bifidobacterium species. GADF was also found to have a stimulative effect on Lactobacillus reuteri and Lactobacillus acidophilus in vitro. These findings suggest that the consumption of a diet rich in plant foods with high dietary fiber and polyphenol content may enhance the gastrointestinal health of the host through microbiota modulation. PRACTICAL APPLICATION: Grape antioxidant fiber combines nutritional and physiological properties of dietary fiber and natural antioxidants from grapes. Grape antioxidant fiber could be used as an ingredient for functional foods and as a dietary supplement to increase the intake of dietary fiber and bioactive compounds. PMID- 22224931 TI - Stilbene levels in grape cane of different cultivars in southern Chile: determination by HPLC-DAD-MS/MS method. AB - Health benefits of trans-resveratrol and other stilbenes in grapes, must, and wine have been pointed out by numerous authors. Less attention has been paid to the presence of stilbene derivatives in viticultural residues, such as grape canes. The present work reports the first results of a systematic study of stilbene levels in different grape varieties and cultivation areas in Chile, to evaluate their potential as an alternative source of bioactive stilbenes. In all cane samples, the predominant stilbene is trans-resveratrol, followed by epsilon viniferin and piceatannol. In canes of Pinot noir up to 5590 +/- 172 mg kg(-1) of trans-resveratrol and up to 6915 +/- 175 mg kg(-1) of total stilbenes were detected. The observed concentrations of stilbenes in canes of Pinot noir from southern Chile until now are higher than those reported previously for this red variety. However, the highest concentration of total stilbenes observed in the analyzed samples was in the canes of white variety Gewurztraminer with 7857 +/- 498 mg kg(-1). Preliminary results indicate that these levels can evolve if canes are left for some months on the vineyard after pruning, observing an increase during the first 2 months and a decrease after this period. PMID- 22224930 TI - The triglyceride paradox in people of African descent. AB - Even though insulin resistance, cardiovascular disease (CVD), and type 2 diabetes (T2D) are associated with hypertriglyceridemia, blacks with these conditions usually have normal triglyceride (TG) levels. This is often called a lipid paradox. More precisely, it is a "TG paradox." The pathways that lead to hypertriglyceridemia have been intensively explored. Yet, the pathways that allow TG levels to be normal in the presence of insulin resistance have received little attention and this is problematic. Tests designed for the early detection of insulin-resistant conditions often use elevated TG levels as a diagnostic criterion. However, insulin resistance, CVD, and T2D are not usually associated with hypertriglyceridemia in people of African descent; therefore, the widespread use of TG levels to predict these conditions needs re-evaluation. This review focuses on black-white differences in: (1) the lipid profile across North America, Europe, and Africa; (2) the efficacy of TG-based screening tests, specifically the metabolic syndrome and its two abbreviated versions, the hypertriglycerdemic waist and TG/high-density lipoprotein cholesterol (HDL-C) ratio; and (3) the mechanisms that allow TG to be normal even in the presence of insulin resistance. Overall, a broader understanding of how TG physiology varies by race could lead to better diagnostic tests and improved health outcomes. PMID- 22224932 TI - An insidious skin rash without itch. AB - A 74-year-old female with a 5-year medical history of breast infiltrating lobular carcinoma was admitted to our Rehabilitation Unit ward for left hemiparesis secondary to neurosurgical removal of frontal and right parietal metastatic lesions. After the intervention, prophylactic treatment with the antiepileptic diphenylhydantoin 100 mg/tid was started. On 38th day of drug administration an erythema without itch appeared in jugular and parasternal region and absent in the clothing covered areas, suggesting a contact dermatitis. Next day, the erythema extended to the neck with poorly delineated red plaques. During the following 4 days the patient presented oral stomatitis with fetid breath, atypical targetoid and erythematous confluenced macules. The clinical picture rapidly worsened with vesiculate, bullate lesions and frank skin erosions. The patient was sent to a Dermatology Burn Unit where a therapy with corticosteroids, antibiotics, fluids, albumin and immunoglobulins was administrated. Complete clinical resolution was observed after 1 month without long-term sequelae. Toxic epidermal necrolysis (TEN) is a rare (incidence about 0.01%) adverse drug reaction related to idiosyncratic mechanism, burdened by a mortality rate ranging from 3.2 to 90%. In our patient, TEN covered 63% of body surface, a condition associated with a death risk of 58.3% according to the specific severity illness scale SCORTEN. The disease onset may be insidious, and it could appear as a skin rash without itch; the cutaneous manifestations appear quite lately, then the disease quickly progresses. Early recognition of the disease, especially in oncologic patients, is critical for effective management of this condition in terms of mortality reduction. PMID- 22224933 TI - 'Ivory wave' toxicity in recreational drug users; integration of clinical and poisons information services to manage legal high poisoning. AB - BACKGROUND: Novel psychoactive substances or 'legal highs' can be defined as psychoactive substances that have been developed to avoid existing drug control measures. Consistency of name, but with change in the content of the product, may cause harm. This could result in clusters of users being poisoned and developing unexpected physical and psychiatric symptoms. We describe such an event and the clinical phenotypes of a cluster of patients poisoned with a novel psychoactive substance in 'ivory wave' and analyze data from the National Poisons Information Service (NPIS) to estimate use across the United Kingdom. In addition, the likely active ingredient in this cluster of 'ivory wave' poisonings was identified. METHODS: An analysis of consecutive patients attending the Royal Infirmary of Edinburgh emergency department in July and August 2010 with self-reported 'ivory wave' use was performed. Over a similar time frame, poisons enquiries regarding 'ivory wave' to the UK NPIS, by telephone and via the internet-based TOXBASE((r)) poisons database ( www.toxbase.org ), were analyzed. A sample of 'ivory wave' powder and biological fluids from poisoned patients were investigated to determine the active ingredient. RESULTS: Thirty four emergency attendances due to 'ivory wave' toxicity were identified. The mean +/- SD (range) age was 28.6 +/ 7.8 (16-44) years. Patients demonstrated a toxidrome which lasted several days, characterized by tachycardia (65%), tachypnoea (76%), dystonia (18%), rhabdomyolysis (96%), leucocytosis (57%), agitation (62%), hallucinations (50%), insomnia (32%) and paranoia (21%). Enquiries to NPIS suggest that 'ivory wave' poisoning occurred throughout the United Kingdom. A sample of 'ivory wave' powder was analyzed and found to contain desoxypipradrol, which was also identified in biological fluids from 4 out of 5 patients tested. DISCUSSION: A cluster of cases presenting after use of a novel psychoactive substance was identified in Edinburgh and desoxypipradrol was identified as the likely cause. It was associated with prolonged psychiatric symptoms as a key feature. This chemical was regulated in response to the wider UK outbreak, which NPIS data suggest was geographically widespread but probably short lived. CONCLUSION: Novel psychoactive substances can produce significant toxicity and data from poisons centres may be used to indirectly detect new 'legal highs' that are causing clinical toxicity. PMID- 22224936 TI - Highly sensitive detection of protein with aptamer-based target-triggering two stage amplification. AB - Highly sensitive detection of proteins is essential to biomedical research as well as clinical diagnosis. However, so far most detection methods rely on antibody-based assays and are usually laborious and time-consuming with poor sensitivity. Here, we develop a simple and sensitive method for the detection of a biomarker protein, platelet-derived growth factor BB (PDGF-BB), based on aptamer-based target-triggering two-stage amplification. With the involvement of an aptamer-based probe and an exponential amplification reaction (EXPAR) template, our method combines strand displacement amplification (SDA) and EXPAR, transforming the probe conformational change induced by target binding into two stage amplification and distinct fluorescence signal. This detection method exhibits excellent specificity and high sensitivity with a detection limit of 9.04 * 10(-13) M and a detection range of more than 5 orders of magnitude, which is comparable with or even superior to most currently used approaches for PDGF-BB detection. Moreover, this detection method has significant advantages of isothermal conditions required, simple and rapid without multiple separation and washing steps, low-cost without the need of any labeled DNA probes. Furthermore, this method might be extended to sensitive detection of a variety of biomolecules whose aptamers undergo similar conformational changes. PMID- 22224937 TI - Cartesian stiffness for wrist joints: analysis on the Lie group of 3D rotations and geometric approximation for experimental evaluation. AB - This paper is concerned with the analysis and the numerical evaluation from experimental measurements of the static, Cartesian stiffness of wrist joints, in particular the human wrist. The primary aim is to extend from Euclidean spaces to so(3), the group of rigid body rotations, previous methods for assessing the end point stiffness of the human arm, typically performed via a robotic manipulandum. As a first step, the geometric definition of Cartesian stiffness from current literature is specialised to the group so(3). Emphasis is placed on the choice of the unique, natural, affine connection on so(3) which guarantees symmetry of the stiffness matrix in presence of conservative fields for any configuration, also out of equilibrium. As the main contribution of this study, a coordinate independent approximation based on the geometric notion of geodesics is proposed which provides a working equation for evaluating stiffness directly from experimental measurements. Finally, a graphical representation of the stiffness is discussed which extends the ellipse method often used for end-point stiffness visualisation and which is suitable to compare stiffness matrices evaluated at different configurations. PMID- 22224938 TI - Relative tendency of carbonyl compounds to form enamines. AB - Equilibria between carbonyl compounds and their enamines (from O-TBDPS-derived prolinol) have been examined by NMR spectroscopy in DMSO-d(6). By comparing the exchange reactions between pairs (enamine A + carbonyl B -> carbonyl A + enamine B), a quite general scale of the tendency of carbonyl groups to form enamines has been established. Aldehydes quickly give enamines that are relatively more stable than those of ketones, but there are exceptions to this expected rule; for example, 1,3-dihydroxyacetone acetals or 3,5-dioxacyclohexanones (2-phenyl-1,3 dioxan-5-one and 2,2-dimethyl-1,3-dioxan-5-one) show a greater tendency to afford enamines than many alpha-substituted aldehydes. PMID- 22224939 TI - Development of zein nanoparticles coated with carboxymethyl chitosan for encapsulation and controlled release of vitamin D3. AB - In this study, zein nanoparticles coated with carboxymethyl chitosan (CMCS) were prepared to encapsulate vitamin D3 (VD3). VD3 was first encapsulated into zein nanoparticles using a low-energy phase separation method and coated with CMCS simultaneously. Then, calcium was added to cross-link CMCS to achieve thicker and denser coatings. The nanoparticles with CMCS coatings had a spherical structure with particle size from 86 to 200 nm. The encapsulation efficiency was greatly improved to 87.9% after CMCS coating, compared with 52.2% for that using zein as a single encapsulant. The physicochemical properties were characterized by differential scanning calorimetry and Fourier transform infrared spectroscopy. Nanoparticles with coatings provided better controlled release of VD3 in both PBS medium and simulated gastrointestinal tract. Photostability against UV light was significantly improved after encapsulation. Encapsulation of hydrophobic nutrients in zein nanoparticles with CMCS coatings is a promising approach to enhance chemical stability and controlled release property. PMID- 22224942 TI - Orientational dynamics of room temperature ionic liquid/water mixtures: water induced structure. AB - Optical heterodyne detected optical Kerr effect (OHD-OKE) measurements on a series of 1-alkyl-3-methylimidazolium tetrafluoroborate room-temperature ionic liquids (RTILs) as a function of chain length and water concentration are presented. The pure RTIL reorientational dynamics are identical in form to those of other molecular liquids studied previously by OHD-OKE (two power laws followed by a single exponential decay at long times), but are much slower at room temperature. In contrast, the addition of water to the longer alkyl chain RTILs causes the emergence of a long time biexponential orientational anisotropy decay. Such distinctly biexponential decays have not been seen previously in OHD-OKE experiments on any type of liquid and are analyzed here using a wobbling-in-a cone model. The slow component for the longer chain RTILs does not obey the Debye Stokes-Einstein (DSE) equation across the range of solutions, and thus we attribute it to slow cation reorientational diffusion caused by a stiffening of cation alkyl tail-tail associations. The fast component of the decay is assigned to the motions (wobbling) of the tethered imidazolium head groups. The wobbling in-a-cone analysis provides estimates of the range of angles sampled by the imidazolium head group prior to the long time scale complete orientational randomization. The heterogeneous dynamics and non-DSE behavior observed here should have a significant effect on reaction rates in RTIL/water cosolvent mixtures. PMID- 22224944 TI - Roasting process of coffee beans as studied by nuclear magnetic resonance: time course of changes in composition. AB - In this paper, we report a (1)H and (13)C nuclear magnetic resonance (NMR)-based comprehensive analysis of coffee bean extracts of different degrees of roast. The roasting process of coffee bean extracts was chemically characterized using detailed signal assignment information coupled with multivariate data analysis. A total of 30 NMR-visible components of coffee bean extracts were monitored simultaneously as a function of the roasting duration. During roasting, components such as sucrose and chlorogenic acids were degraded and components such as quinic acids, N-methylpyridinium, and water-soluble polysaccharides were formed. Caffeine and myo-inositol were relatively thermally stable. Multivariate data analysis indicated that some components such as sucrose, chlorogenic acids, quinic acids, and polysaccharides could serve as chemical markers during coffee bean roasting. The present composition-based quality analysis provides an excellent holistic method and suggests useful chemical markers to control and characterize the coffee-roasting process. PMID- 22224945 TI - Excretory-secretory products of Giardia lamblia induce interleukin-8 production in human colonic cells via activation of p38, ERK1/2, NF-kappaB and AP-1. AB - Giardia lamblia, a pathogen causing diarrhoeal outbreaks, is interesting how it triggers immune response in the human epithelial cells. This study defined the crucial roles of signalling components involved in G. lamblia-induced cytokine production in human epithelial cells. Incubation of the gastrointestinal cell line HT-29 with G. lamblia GS trophozoites triggered production of interleukin (IL)-1beta, IL-8 and tumour necrosis factor (TNF)-alpha. IL-8 production was not significantly decreased by physically separating the HT-29 cells and G. lamblia GS trophozoites. Indeed, treatment of HT-29 with G. lamblia excretory-secretory products (ESP) induced IL-8 production. Electrophoretic mobility gel shift and transfection assays using mutagenized IL-8 promoter reporter plasmids indicated that IL-8 production by G. lamblia ESP occurs through activation of two transcriptional factors, nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1) in HT-29 cells. In addition, activation of two mitogen-activated protein kinases (MAPKs), p38 and ERK1/2, was also detected in the HT-29 cells stimulated with G. lamblia ESP. Selective inhibition of these MAPKs resulted in decreased production of ESP-induced IL-8. These results indicate that activation of p38, ERK1/2 MAPK, NF-kappaB and AP-1 comprises the signalling pathway responsible for IL-8 production by G. lamblia ESP. PMID- 22224946 TI - An asymmetric Ugi three-component reaction induced by chiral cyclic imines: synthesis of morpholin- or piperazine-keto-carboxamide derivatives. AB - A series of chiral 5,6-dihydro-1,4-oxazin-2-one substrates, as preformed cyclic aldimines and ketoimines, were employed to develop a new asymmetric Ugi three component reaction for the first time. The Ugi reaction of the imines, isocyanides, and carboxylic acids opens an efficient access to novel morpholin-2 one-3-carboxamide compounds. The chiral imines showed promising stereoinduction for the new chiral center of the Ugi products, and predominant trans-isomers were obtained in the most cases. Addition of some Lewis acids or proton acids could improve the diastereoselectivity further but usually led to a drop in total yield. The Ugi-3CR could be extended to the stereoselective synthesis of ketopiperazine-2-carboxamide derivatives. PMID- 22224940 TI - Prospects for primary stroke prevention in children with sickle cell anaemia. AB - This review will focus on the strengths and limitations associated with the current standard of care for primary prevention of ischaemic strokes in children with sickle cell anaemia (SCA) - transcranial Doppler ultrasound (TCD) screening followed by regular blood transfusion therapy when TCD measurement is above a threshold defined by a randomized clinical trial (RCT). The theoretical basis for potential alternative strategies for primary prevention of neurological injury in SCA is also discussed. These strategies will include, but will not be limited to: immunizations to prevent bacterial infections, particularly in low income countries; management of elevated blood pressure; and targeted strategies to increase baseline haemoglobin levels with therapies such as hyroxycarbamide or potentially definitive haematopoietic stem cell transplant. PMID- 22224947 TI - Processing speed and visuospatial executive function predict visual working memory ability in older adults. AB - BACKGROUND/STUDY CONTEXT: Visual working memory (VWM) has been shown to be particularly age sensitive. Determining which measures share variance with this cognitive ability in older adults may help to elucidate the key factors underlying the effects of aging. METHODS: Predictors of VWM (measured by a modified Visual Patterns Test) were investigated in a subsample (N = 44, mean age = 73) of older adults from the Lothian Birth Cohort 1936 (LBC1936; Deary et al., 2007 , BMC Geriatrics, 7, 28). Childhood intelligence (Moray House Test) and contemporaneous measures of processing speed (four-choice reaction time), executive function (verbal fluency; block design), and spatial working memory (backward spatial span), were assessed as potential predictors. RESULTS: All contemporaneous measures except verbal fluency were significantly associated with VWM, and processing speed had the largest effect size (r = -.53, p < .001). In linear regression analysis, even after adjusting for childhood intelligence, processing speed and the executive measure associated with visuospatial organization accounted for 35% of the variance in VWM. CONCLUSION: Processing speed may affect VWM performance in older adults via speed of encoding and/or rate of rehearsal, while executive resources specifically associated with visuospatial material are also important. PMID- 22224948 TI - Aging and interference in story recall. AB - BACKGROUND/STUDY CONTEXT: According to inhibitory deficit theory, older adults should be more impaired by visual distractors than younger adults when reading texts. Studies using a multiple-choice recognition test to examine age differences in the impairment of text comprehension due to distractor words yielded inconsistent results. METHODS: In the present study, younger participants and older participants were required to read short texts comprising unrelated, related, or no distractor words. Visual acuity was equated between groups. Text recall was assessed using a gist-based propositional scoring procedure. RESULTS: There were pronounced age differences in reading with distraction. Older adults were slowed down more than younger adults by the presence of distractor words when reading. Furthermore, older adults' story recall was clearly impaired by the presence of distractor material, whereas younger adults' recall performance was not. In addition, older adults were more likely to make intrusion errors. CONCLUSION: Consistent with inhibitory deficit theory, the findings suggest that older adults were less able than younger adults to establish a correct mental representation of the target text when distractors were present. Furthermore, older adults were more likely than younger adults to build up incorrect memory representations that comprise distractor concepts. Thus, there are pronounced age differences in the impairment of text comprehension by distracting information. PMID- 22224949 TI - Age differences in the effects of experimenter-instructed versus self-generated strategy use. AB - Background/Study Context: Interactive imagery is superior to rote repetition as an encoding strategy for paired associate (PA) recall. Younger and older individuals often rate these strategies as equally effective before they gain experience using each strategy. The present study investigated how experimenter supervised and participant-chosen strategy experience affected younger and older adults' knowledge about the effectiveness of these two strategies. METHODS: Ninety-nine younger (M = 19.0 years, SD = 1.4) and 90 older adults (M = 70.4 years, SD = 5.2) participated in the experiment. In learning a first PA list participants were either instructed to use imagery or repetition to study specific items (supervised) or could choose their own strategies (unsupervised). All participants were unsupervised on a second PA list to evaluate whether strategy experience affected strategy knowledge, strategy use, and PA recall. RESULTS: Both instruction groups learned about the superiority of imagery use through task experience, downgrading repetition ratings and upgrading imagery ratings on the second list. However, older adults showed less knowledge updating than did younger adults. Previously supervised younger adults increased their imagery use, improving PA recall; older adults maintained a higher level of repetition use. CONCLUSION: Older adults update knowledge of the differential effectiveness of the rote and imagery strategies, but to a lesser degree than younger adults. Older adults manifest an inertial tendency to continue using the repetition strategy even though they have learned that it is inferior to interactive imagery. PMID- 22224950 TI - Age-related differences in typical intellectual engagement between young and old adults. AB - BACKGROUND/STUDY CONTEXT: Typical intellectual engagement has been postulated as a trait-like construct that can explain interindividual differences in the extent of engaging in cognitively challenging tasks. Although formulated within the framework of cognitive development, the developmental aspects of typical intellectual engagement itself have not been studied yet. METHODS: Three hundred thirty-four participants from the Zurich Longitudinal Study on Cognitive Aging (73 years on average, ranging from 60 to 85) and 468 graduate students (21 years on average, ranging from 18 to 25) were administered a self-rating scale on typical intellectual engagement. Structural equation modeling was used to study differences in factor means, differences in factor variances, and differences in factor covariances between the two groups. RESULTS: Significant mean-level differences between age groups exhibit both decline and increase in old age. An increase in factor variances was shown in the old. Factor correlations were higher in old age compared to young adults. CONCLUSION: Both higher and lower mean levels in the old group imply that typical intellectual engagement is a variable that contributes incremental information compared to well-known measures of basic personality traits. Larger variances in the old imply greater heterogeneity in the old sample, which fits into literature on fan-spread phenomenon. Higher factor covariances in the old imply dedifferentiation of typical intellectual engagement in the old. PMID- 22224951 TI - Aging and random task switching: the role of endogenous versus exogenous task selection. AB - BACKGROUND/STUDY CONTEXT: Task switching research typically emphasizes two robust shifting effects between competing tasks: mixing costs (MCs), which indicate less efficient performance in mixed-task versus single-task conditions, and switch costs (SCs), which reflect differences between switch trials and repetition trials within mixed-task conditions. The current study examined age-related MC and SC influenced by the method of task selection in two procedures. METHODS: Twenty-six young adults, 18 to 21 years of age (M = 18.4, SD = 1.1), and 25 older adults, 74 to 87 years of age (M = 80.3, SD = 5.4), participated as part of the Cognition, Health, and Aging Project (CHAP). Younger and older adults' performed cued and voluntary task switching, requiring a random sequence of task changes, placing demands on externally versus internally directed processes. RESULTS: Results indicated that SCs were not disproportionately larger for older adults during an exogenous switching condition, but large age differences in MCs were present beyond the degree predicted by differences in baseline speed. In an endogenous switching condition, small age differences were present both for MCs and SCs, although further age differences were evident in older adults' reduced switch rates. CONCLUSION: These findings suggest that older adults are substantially slower at updating repeated task sets during exogenous switching, but partially counter these effects by adopting a more persistent within-set mode of processing during endogenous switching. PMID- 22224952 TI - Minimal age-related deficits in task switching, inhibition, and oculomotor control. AB - BACKGROUND/STUDY CONTEXT: We are often required to carry out complex tasks in changing, context-dependent ways. This task switching requires the rapid realignment of attention to task constraints and may be age sensitive. METHODS: Three experiments, two in which eye movements were recorded, were conducted to assess age-related differences in task switching and inhibitory control. Observers carried out a Same-Different task and Go-No Go task in single and mixed blocks of trials. RESULTS: Other than Experiment 1, although switch costs were observed, they were not larger for older adults compared to younger adults. Furthermore, eye movement and false alarm data demonstrated little evidence of age-related decline in inhibitory and oculomotor control. CONCLUSIONS: A major implication is that, at least when two tasks involve different stimuli and unique responses, older adults are no more likely than younger adults to show task switching costs or inhibition deficit. PMID- 22224953 TI - Follicular spicules associated with Propionibacterium acnes with response to erythromycin: Lack of evidence for the species? PMID- 22224954 TI - Nanoscale characterization of zein self-assembly. AB - Zein, a major protein of corn, is rich in alpha-helical structure. It has an amphiphilic character and is capable of self-assembly. Zein can self-assemble into various mesostructures that may find applications in food, agricultural, and biomedical engineering. Understanding the mechanism of zein self-assembly at the nanoscale is important for further development of zein structures. In this work, high-resolution transmission electron microscopy (TEM) images revealed nanosize zein stripes, rings, and discs containing a 0.35 nm periodicity, which is characteristic of beta-sheet. TEM images were interpreted in terms of the transformation of original alpha-helices into beta-sheet conformation after evaporation-induced self-assembly (EISA). The presence of beta-sheet was also detected by circular dichroism (CD) spectroscopy. Zein beta-sheets self-assembled into stripes, which curled into rings. Rings formed discs and eventually spheres. The formation of zein nanostructures was believed to be the result of beta-sheet orientation, alignment, and packing. PMID- 22224956 TI - Contribution of sarcoplasmic proteins to myofibrillar proteins gelation. AB - Surimi, a refined protein extract, is produced by solubilizing myofibrillar proteins during the comminuting and salting stages of manufacturing. The resulting paste gels on heating to produce kamaboko or a range of analog shellfish such as crab claw, filament sticks, fish mushroom, and so on. The myosin molecule is the major myofibrillar protein in gelation. It is believed that washing steps during the traditional surimi process play an important role in enhancing the gel properties of the resultant kamaboko by removing water soluble (sarcoplasmic, Sp-P) proteins. By contrast, some researchers claim that retaining Sp-P or adding it into the surimi gel network not only does not interfere with the action of myofibrillar proteins during the sol-gel transition step but also improves the gel characteristics of the resultant kamaboko. It seems that retention of Sp-P or their addition into raw surimi does enhance the textural properties of kamaboko gel perhaps by functioning as a proteinase inhibitor, particularly against trypsin and trypsin-like proteinases but this depends on the type of applied surimi process. Among different types of Sp-P, it has been claimed that some proteins such as endogenous transglutaminase (TGase) play a more important role than other Sp-P in bond formation, by catalyzing the cross-linking of myosin heavy chain (MHC) molecules during low-temperature setting of surimi, resulting a more elastic kamaboko gel. PMID- 22224957 TI - Does Tribolium brevicornis cuticular chemistry deter cannibalism and predation of pupae? AB - The cuticular hydrocarbons of insects are species-specific and often function as semiochemicals. The activity of Tribolium brevicornis cuticular hydrocarbons as feeding deterrents that ostensibly function to prevent pupal cannibalism and predation was evaluated. The cuticular hydrocarbons of T. brevicornis pupae were characterized and flour disk bioassays conducted with individual and combined extract components incorporated into artificial diets on which Tribolium adults fed for six days. Feeding by T. brevicornis and T. castaneum on flour disks containing cuticular extracts of T. brevicornis pupae resulted in reduced consumption and weight loss relative to feeding on control flour disks. In both cases, feeding deterrence indices exceeded 80% suggesting that T. brevicornis cuticular hydrocarbons could function to deter cannibalism and predation of pupae by larvae and adult beetles. Sixteen different cuticular hydrocarbons were identified in T. brevicornis pupal extracts. Eight of the commercially available linear alkanes were tested individually in feeding trials with eight Tribolium species. One compound (C28) significantly reduced the amount of food consumed by three species compared to control disks, whereas the compounds C25, C26, and C27 elicited increased feeding in some species. Four other compounds had no effect on consumption for any species. When four hydrocarbon mixtures were tested for synergistic deterrence on T. brevicornis and T. castaneum, none significantly influenced consumption. Our results indicate that the cuticular chemistry of T. brevicornis pupae could serve to deter predation by conspecific and congeneric beetles. PMID- 22224958 TI - Integrating plasmonic nanoparticles with TiO2 photonic crystal for enhancement of visible-light-driven photocatalysis. AB - Aimed at enhancing photocatalysis through intensifying light harvesting, a new photocatalyst was fabricated by infiltrating Au nanoparticles into TiO(2) photonic crystals (TiO(2) PC/Au NPs). Scanning electron microscopy (SEM) and transmission electron microscope (TEM) images showed that the Au NPs with average diameter around 15 nm were dispersed uniformly into the porous TiO(2) material. The results of the transmittance spectra demonstrated that the light absorption by Au NPs was amplified after they were infiltrated into TiO(2) 240, which was fabricated from 240 nm polystyrene spheres. In the photocatalytic experiments of 2,4-dichlorophenol degradation under visible light (lambda > 420 nm) irradiation, the kinetic constant using TiO(2) 240/Au NPs was 2.3 fold larger than that using TiO(2) nanocrystalline/Au NPs (TiO(2) NC/Au NPs). The excellent photocatalysis benefited from the cooperatively enhanced light harvesting owing to the localized surface plasmon resonance of Au NPs, which extended the light response spectra and the photonic effect of the TiO(2) 240 which intensified the plasmonic absorption by Au NPs. The hydroxyl radicals originated from the electroreduction of dissolved oxygen with photogenerated electrons via chain reactions were the main reactive oxygen species responsible for the pollutant degradation. PMID- 22224959 TI - Toward a more humane and peaceful world. PMID- 22224960 TI - Investigating the evidence for the effectiveness of risk assessment in mental health care. AB - Risk assessment pervades mental health care policy, practice, and legislation. This paper aims to establish the research evidence for the effectiveness of a risk assessment approach in mental health. A search was conducted of the professional literature on risk assessment in mental health, specifically seeking any research on the effectiveness of risk assessment in reducing risk of harm to self or others. The search found limited research on the effectiveness of risk assessment. "Structured professional judgment" possibly reduces aggression risk but there is no evidence that risk assessment is effective in relation to self harm or suicide reduction. The implications for practice are discussed and alternatives to a risk assessment approach are considered. PMID- 22224961 TI - Motivational interviewing: addressing ambivalence to improve medication adherence in patients with bipolar disorder. AB - Poor adherence to psychotropic medication is a significant issue for patients with bipolar disorder. The effectiveness of medication treatment is limited by high rates of medication non-adherence among this population. Motivational Interviewing is an evidence-based intervention that has been efficacious in promoting behavioral health regimens and treatment recommendations, including medication adherence. By using a patient-centered approach, Motivational Interviewing has been shown to enhance patients' insight and attitudes toward treatment. This article aims to describe to mental health nurses how to use Motivational Interviewing with bipolar patients to address ambivalence and improve adherence to psychotropic medication regimens. PMID- 22224962 TI - Occupational stress, social support, and quality of life among Jordanian mental health nurses. AB - Occupational stress affects physical and mental health of mental health nurses. This study measured levels of occupational stress and identified the variables that are associated with occupational stress among Jordanian mental health nurses. A descriptive design was conducted, using self-report questionnaires and demographic characteristics. Data were collected from 181 mental health nurses who were recruited from all mental health settings in Jordan. Jordanian mental health nurses showed high levels of occupational stress regarding "client-related difficulties," "lack of resources," and "workload." The highest level of social support as indicated by these Jordanian mental health nurses was from a spouse/partner followed by colleagues. Regarding quality of life (QOL), physical health scores were higher than mental health scores. Occupational stress correlated significantly and negatively with QOL-physical scores, QOL-mental scores, and social support scores, and correlated positively with being physically assaulted, verbally assaulted, and the respondent having the intention to leave his or her current job. Social support, QOL-mental scores, verbal assault, ward type, and intention to leave the current job were the best predictors of occupational stress among Jordanian mental health nurses. Mental health nurses are under significant occupational stress levels; therefore, comprehensive interventions aimed at minimizing the risk of occupational stress and improving social support and quality of life among mental health nurses are needed. PMID- 22224963 TI - A suggested revision of the Community Oriented Program Environmental Scale (COPES) for measuring the psychosocial environment of supported housing facilities for persons with psychiatric disabilities. AB - The aim of the present study is to address issues of construct validity and reliability of a revised short version of the COPES instrument to measure the psychosocial environment of supported housing facilities for persons with psychiatric disabilities. The results revealed that the division into subscales is not sufficiently reliable for use in measuring the psychosocial environment, although the three higher order dimensions can possibly be used for the descriptive and comparative purposes. A factor analysis based on the revised short version generated new factor solutions, differing from the COPES subscales, but with sufficient psychometric properties. PMID- 22224964 TI - Ways of coping in survivors of suicide. AB - The purpose of this pilot study was to describe ways in which survivors cope after a death by suicide of a family member or significant other and to explore the psychometric properties of the Ways of Coping Questionnaire (WoCQ). An examination of inter-item correlations indicated that subscales were unidimensional and reliabilities ranged from alpha = .57 to alpha = .82. Construct validity was established by correlating the WoCQ subscales with other established instruments. Females used Seeking Social Support and Positive Reappraisal significantly more than males (p < .05). Interventions to enhance positive coping strategies may assist future survivors in managing the death of a significant other by suicide. PMID- 22224965 TI - Developmental and ethnic issues experienced by emerging adult African American women related to developing a mature love relationship. AB - This qualitative study explored perspectives of emerging adult African American women on the development of mature love relationships. Inductive analysis of focus group interviews, conducted with a purposive sample of 31 African American women, yielded themes related to relationship goals and characteristics, and interpersonal and societal challenges to finding the right partner and developing a mature love relationship. Core categories that emerged from analysis of the discussions were (1) age and relationship goal differences within the emerging adult group, (2) mature love relationship goals and characteristics, (3) interpersonal obstacles to finding the right partner, and (4) societal obstacles to finding the right partner. Two approaches-black womanist/feminist thought (Collins, 2000 ; Walker, 1983 ) and relationship maturity theory (Paul & White, 1990 )-were then combined to explain the influence of historic and contemporary interpersonal and societal factors on developmental and ethnic issues that challenge positive gender identity formation, hasten intimacy maturity, and hinder the development of mature love relationships among emerging adult African American women. For these women, premature responsibility, especially early caregiver burden, was related to the early development of intimacy capacity and the desire for a mature love relationship, to be protected, and to have someone to help carry the load. Interracial dating, negative stereotypic images of African American women, and even positive images of enduring black love relationships posed difficult challenges to positive identity formation and intimacy maturity. A primary challenge was to counteract negative stereotypic images, so that they could develop their own self-identities as women and as relationship partners. PMID- 22224966 TI - Stressors related to depression among elderly Korean immigrants. AB - While depression in the elderly is well documented, little is known about depression in specific groups of immigrant elderly. In this study, 160 elderly Korean immigrants completed measures of depression, stressful life events, acculturative stress, family relationships, social support, and demographic variables. Findings revealed that income, acculturative stress, and living place were significant predictors of depression. As income declined, depression increased; living with one's adult children was associated with less depression; depression increased in concert with acculturative stress. These findings suggest that maintaining family relationships may be a key factor in preventing and/or lessening depression in elderly Korean immigrants. PMID- 22224967 TI - Reflections on trust and self-disclosure. PMID- 22224968 TI - Culturally competent nursing care of the Muslim patient. PMID- 22224973 TI - Extractive electrospray ionization mass spectrometry-enhanced sensitivity using an ion funnel. AB - Electrodynamic ion funnel interfaces for electrospray ionization (ESI) have shown to enhance the sensitivity of measurements by more than 2 orders of magnitude in the intermediate pressure region of the instrument (1-30 Torr). In this study, we use an ion funnel at ambient pressure to enhance the sensitivity of extractive electrospray ionization (EESI) by spraying directly into the ion funnel. EESI is a powerful ionization technique that is capable of handling complex matrixes that may contain dozens of compounds. Our results using atenolol, salbutamol, and cocaine as test compounds show that we can improve the limit of detection for these compounds by more than 3 orders of magnitude compared to standard EESI experiments. PMID- 22224971 TI - Xanthigen suppresses preadipocyte differentiation and adipogenesis through down regulation of PPARgamma and C/EBPs and modulation of SIRT-1, AMPK, and FoxO pathways. AB - Xanthigen is a source of punicic acid and fucoxanthin derived from pomegranate seed and brown seaweed, respectively with recognized triacylglycerol-lowering effects in humans, yet the mechanism remains to be fully elucidated. The present study investigated the inhibitory effects of Xanthigen, fucoxanthin, and punicic acid (70% in pomegranate seed oil) on the differentiation of 3T3-L1 preadipocytes. Xanthigen potently and dose-dependently suppressed accumulation of lipid droplets in adipocytes compared to its individual components, fucoxanthin and pomegranate seed oil. Western blot analysis revealed that Xanthigen markedly down-regulated the protein levels of key adipogenesis transcription factors peroxisome proliferator-activated receptor (PPAR)gamma, CCAAT/enhancer binding protein (C/EBP) beta, and C/EBPdelta as well as a key enzyme involved in adipogenesis, fatty acid synthase (FAS). Xanthigen up-regulated the NAD(+) dependent histone deacetylases (SIRT1) and activated AMP-activated protein kinase (AMPK) signaling in differentiated 3T3-L1 adipocytes. In addition, Xanthigen may also stimulate insulin trigger signaling and result in Akt-dependent phosphorylation of forkhead/winged helix O (FoxO)1 and FoxO3a. These results indicate that Xanthigen suppresses adipocyte differentiation and lipid accumulation through multiple mechanisms and may have applications for the treatment of obesity. PMID- 22224974 TI - The endothelial cell line bEnd.3 maintains human pluripotent stem cells. AB - Endothelial cells line blood vessels and coordinate many aspects of vascular biology. More recent work has shown that endothelial cells provide a key niche in vivo for neural stem cells. In vitro, endothelial cells secrete a factor that expands neural stem cells while inhibiting their differentiation. Here, we show that a transformed mouse endothelial cell line (bEnd.3) maintains human pluripotent stem cells in an undifferentiated state. bEnd.3 cells have a practical advantage over mouse embryonic fibroblasts for pluripotent stem cell maintenance since they can be expanded in vitro and engineered to express genes of interest. We demonstrate this capability by producing fluorescent and drug resistant feeder cells. Further, we show that bEnd.3 secretes an activity that maintains human embryonic stem cells without direct contact. PMID- 22224975 TI - Envy divides the two faces of narcissism. AB - In this article, we test psychodynamic assumptions about envy and narcissism by examining malicious envy in the context of narcissistic grandiosity and vulnerability. In Study 1, students (N = 192) and community adults (N = 161) completed trait measures of narcissism, envy, and schadenfreude. In Study 2 (N = 121), participants relived an episode of envy, and cognitive-affective components of envy were examined in the context of both self- and informant reports of their envy and narcissism. In Study 3 (N = 69), narcissism was linked to reports of envy covertly induced in the laboratory. Vulnerable narcissism was strongly and consistently related to dispositional envy and schadenfreude (Studies 1-2), as well as to all cognitive-affective components of envy (Study 2). Furthermore, it facilitated envy and schadenfreude toward a high-status peer (Study 3). Grandiose narcissism was slightly negatively related to dispositional envy (Studies 1-2), and it did not predict informant reports of envy or cognitive-affective components of the emotion (Study 2). Finally, it did not exacerbate envy, hostility, or resentment toward a high-status peer (Study 3). The results suggest envy is a central emotion in the lives of those with narcissistic vulnerability and imply that envy should be reconsidered as a symptom accompanying grandiose features in the diagnosis of narcissistic personality disorder. PMID- 22224977 TI - An optimisation approach to multiprobe cryosurgery planning. AB - In cryosurgery operations, tumoural cells are killed by means of a freezing procedure realised with the insertion of cryoprobes in the diseased tissue. Cryosurgery planning aims at establishing the best values for operation parameters like number and position of the probes or temperature and duration of the freezing process. Here, we present an application of ant colony optimisation (ACO) to cryosurgery planning, whereby the ACO cost function is computed by numerically solving several direct Stefan problems in biological tissues. The method is validated in the case of a 2D phantom of a prostate cross section. PMID- 22224978 TI - Monoclonal B-cell lymphocytosis is closely related to chronic lymphocytic leukaemia and may be better classified as early-stage CLL. AB - The World Health Organization classification uses a cut-off point of 5.0 * 10(9)/l cells with a chronic lymphocytic leukaemia (CLL)-phenotype in peripheral blood to discriminate between monoclonal B-lymphocytosis (MBL) and B-CLL. This study analysed 298 MBL patients by multi-parameter flow cytometry, chromosome banding analysis (CBA)/fluorescence in situ hybridization (FISH), and IGHV mutation status and compared them with 356 CLL patients. In MBL, CBA more frequently revealed a normal karyotype and FISH identified less frequently del(6q), del(13q) (as sole alterations), and del(17)(p13). Within the MBL cohort, a shorter time to treatment (TTT) was found for ZAP-70-positivity, 14q32/IGH translocations (CBA), del(11)(q22.3) (FISH) and unmutated IGHV status. Higher CD38 and ZAP-70 expression, del(11)(q22.3) (FISH), trisomy 12 (FISH), and 14q32/IGH-translocations (CBA) were correlated with a shorter TTT in the combined cohort (MBL + CLL); a sole del(13)(q14) (FISH) correlated with longer TTT. Regarding overall survival, unmutated IGHV status and 'other' alterations (CBA) had an adverse impact. There was no correlation between the concentration of CLL cells and TTT or overall survival. Multivariate analysis confirmed a negative impact on TTT for del(11)(q22.3)/ATM, trisomy 12 (both by FISH), and 14q32/IGH translocations by CBA. These data emphasize a close relationship between MBL and CLL regarding clinically relevant parameters and provide no evidence to strictly separate these entities by a distinct threshold of clonal B-cells. PMID- 22224979 TI - Trans-arterial coil embolization of the internal carotid artery in standing horses. AB - OBJECTIVES: To develop transarterial coil embolization (TACE) for occlusion of the internal carotid artery (ICA), in normal standing horses, and to evaluate it use for prevention of hemorrhage in horses with guttural pouch mycosis (GPM). STUDY DESIGN: Prospective study. ANIMALS: Normal horses (n = 8) and 5 with GPM. METHODS: Horses had TACE of the ICA in standing position under fluoroscopic guidance. Four normal horses were euthanatized 2 weeks after TACE for morphologic assessment and 4 were followed for 6 months. The 5 clinically affected horses were evaluated for long-term (10-12 months) success rate and complications. RESULTS: No complications related to the TACE were noted. Up to 30 mL warmed meglumine ioxithalamate was injected and well tolerated. Standing angiography confirmed complete occlusion of all vessels, and coils were positioned as intended; the procedure did not alter local hemodynamics. At 2 weeks, maturing to mature continuous thrombi was seen at the site of the coils. Two clinically affected horses died at day 3 and 12 after surgery from other problems. In the 3 surviving horses, mycotic lesions completely resolved without additional treatment. CONCLUSIONS: TACE under fluoroscopic guidance in standing horses provided a safe, minimally invasive, and effective method for ICA occlusion and should be recommended for individuals at risk of general anesthesia. Residual neurologic deficits are a common sequela, but they do not reflect a treatment failure. PMID- 22225003 TI - Antioxidant activity-guided fractionation of blue wheat (UC66049 Triticum aestivum L.). AB - Antioxidant activity-guided fractionation based on three in vitro antioxidant assays (Folin-Ciocalteu, TEAC, and leucomethylene blue assays) was used to identify major antioxidants in blue wheat (UC66049 Triticum aestivum L.). After consecutive extractions with solvents of various polarities and multiple chromatographic fractionations, several potent antioxidants were identified by NMR spectroscopy and mass spectrometry. Anthocyanins (delphinidin-3-glucoside, delphinidin-3-rutinoside, cyanidin-3-glucoside, and cyanidin-3-rutinoside), tryptophan, and a novel phenolic trisaccharide (beta-D-glucopyranosyl-(1->6)-beta D-glucopyranosyl-(1->6)-(4-hydroxy-3-methoxyphenyl)-beta-D-glucopyranoside) were the most active water-extractable constituents. However, anthocyanins were found to be major contributors to the overall blue wheat antioxidant activity only when the extraction steps were performed under acidic conditions. Alkylresorcinols were among the most active antioxidants extractable with 80% ethanol in the TEAC assay. However, this may be due to a color change instead of a bleaching of the ABTS radical. Ferulic acid was found to be the major antioxidant in alkaline cell wall hydrolysates. The contents of the most active antioxidants were determined. PMID- 22225005 TI - Lignans from the root of Rhodiola crenulata. AB - Rhodiola crenulata L. is an important species in genus Rhodiola widely used as a health food to reinforce immunity, improve memory and learning, scavenge active oxygen species, and relieve altitude sickness. Eleven new lignans and a new benzonitrile compound, crenulatanoside A, were isolated from the roots of R. crenulata L. along with 25 known compounds, including 12 lignans. The structures of these compounds were elucidated by spectroscopic data and chemical evidence. Among them, compounds 1-4 and 5-7 were determined to be optical isomers of two 8 O-4' neolignan glycosides. Compounds 8-11 were aryl tetralin type lignans, and compounds 12 and 13 were dihydrobenzofuran neolignans. All of the isolated compounds were evaluated for their inhibitory activity against alpha-glucosidase. From the data obtained, compound 37 showed strong inhibitory activity against alpha-glucosidase with an IC(50) value of 96.8 MUM. PMID- 22225006 TI - Electron attachment to the cytosine-centered DNA single strands: does base stacking matter? AB - Electron attachment to the trimer of nucleotide, dGpdCpdG, has been investigated by a quantum mechanical approach at a reliable level of theory. The study of the electron attached dGpdCpdG species demonstrates that cytosine contained DNA single strands have a strong tendency to capture low-energy electrons and to form electronically stable cytosine-centered radical anions. The comparative study of the model molecules pdCpdG and dGpdCp reveals that base stacking has little contribution to the adiabatic electron affinity (AEA) of cytosine in DNA single strands. Additionally, the base-base stacking does not affect the vertical detachment energy (VDE) of the cytosine-centered radicals. Intrastrand H-bonding is found to be critical in increasing the values of the AEA and VDE. However, base-base stacking is revealed to be important in enlarging the vertical electron affinity (VEA) of cytosine. The electron attachment to the cytosine moiety intensifies the intrastrand H-bonding between the neighboring G and C bases. This process disrupts the base-base stacking interaction in the radical anion of dGpdCpdG. PMID- 22225007 TI - An expression for the radiation force exerted by an acoustic beam with arbitrary wavefront (L). AB - Most studies investigating the acoustic radiation force upon a target are based on symmetry considerations between the object and the incident beam. Even so, this symmetry condition is not always fulfilled in several cases. An expression for the radiation force is obtained as a function of the beam-shape and the scattering coefficients of an incident wave and the object, respectively. The expression for the radiation force caused by a plane wave on a rigid sphere is used to validate the formula. This method represents a theoretical advance permitting different interpretations and predictions concerned to the acoustic radiation force phenomenon. PMID- 22225008 TI - An exact method of regularity analysis for auditory brainstem neurons (L). AB - The standard regularity analysis for spike trains in cochlear nucleus neurons evoked by tonebursts first proposed by Bourk is widely used, primarily as one of the criteria for classification of such neurons. It is shown that this procedure does not estimate quite what it is supposed to, and introduces unnecessary noise to its results due to its use of bins. Instead the desired quantities (mean and coefficient of variation of the lengths of all inter-spike intervals in progress as a function of time since stimulus onset) can all be exactly calculated directly from the spike train without the need for data binning. The implications for classification and other studies are discussed. PMID- 22225009 TI - Phase velocities and attenuations of shear, Lamb, and Rayleigh waves in plate like tissues submerged in a fluid (L). AB - In the past several decades, the fields of ultrasound and magnetic resonance elastography have shown promising results in noninvasive estimates of mechanical properties of soft tissues. These techniques often rely on measuring shear wave velocity due to an external or internal source of force and relating the velocity to viscoelasticity of the tissue. The mathematical relationship between the measured velocity and material properties of the myocardial wall, arteries, and other organs with non-negligible boundary conditions is often complicated and computationally expensive. A simple relationship between the Lamb-Rayleigh dispersion and the shear wave dispersion is derived for both the velocity and attenuation. The relationship shows that the shear wave velocity is around 20% higher than the Lamb-Rayleigh velocity and that the shear wave attenuation is about 20% lower than the Lamb-Rayleigh attenuation. Results of numerical simulations in the frequency range 0-500 Hz are presented. PMID- 22225010 TI - Evaluation of the effective speed of sound in phononic crystals by the monodromy matrix method (L). AB - A scheme for evaluating the effective quasistatic speed of sound c in two- and three-dimensional periodic materials is reported. The approach uses a monodromy matrix operator to enable direct integration in one of the coordinates and exponentially fast convergence in others. As a result, the solution for c has a more closed form than previous formulas. It significantly improves the efficiency and accuracy of evaluating c for high-contrast composites as demonstrated by a two-dimensional scalar-wave example with extreme behavior. PMID- 22225011 TI - Observation of traveling thermoacoustic shock waves (L). AB - Shock waves were explored in the thermoacoustic spontaneous gas oscillations occurring in a gas column with a steep temperature gradient. The results show that a periodic shock occurs in the traveling wave mode in a looped tube but not in the standing wave mode in a resonator. Measurements of the harmonic components of the acoustic intensity reveal a clear difference between them. The temperature gradient acts as an acoustic energy source for the harmonic components of the shock wave in the traveling wave mode but as an acoustic energy sink of the second harmonic in the standing wave mode. PMID- 22225012 TI - Influence of pitch, timbre and timing cues on melodic contour identification with a competing masker (L). AB - Pitch, timbre, and/or timing cues may be used to stream and segregate competing musical melodies and instruments. In this study, melodic contour identification was measured in cochlear implant (CI) and normal-hearing (NH) listeners, with and without a competing masker; timing, pitch, and timbre cues were varied between the masker and target contour. NH performance was near-perfect across different conditions. CI performance was significantly poorer than that of NH listeners. While some CI subjects were able to use or combine timing, pitch and/or timbre cues, most were not, reflecting poor segregation due to poor spectral resolution. PMID- 22225013 TI - Localization of a small change in a multiple scattering environment without modeling of the actual medium. AB - A method to actively localize a small perturbation in a multiple scattering medium using a collection of remote acoustic sensors is presented. The approach requires only minimal modeling and no knowledge of the scatterer distribution and properties of the scattering medium and the perturbation. The medium is ensonified before and after a perturbation is introduced. The coherent difference between the measured signals then reveals all field components that have interacted with the perturbation. A simple single scatter filter (that ignores the presence of the medium scatterers) is matched to the earliest change of the coherent difference to localize the perturbation. Using a multi-source/receiver laboratory setup in air, the technique has been successfully tested with experimental data at frequencies varying from 30 to 60 kHz (wavelength ranging from 0.5 to 1 cm) for cm-scale scatterers in a scattering medium with a size two to five times bigger than its transport mean free path. PMID- 22225014 TI - Impact of attenuation on guided mode wavenumber measurement in axial transmission on bone mimicking plates. AB - Robust signal processing methods adapted to clinical measurements of guided modes are required to assess bone properties such as cortical thickness and porosity. Recently, an approach based on the singular value decomposition (SVD) of multidimensional signals recorded with an axial transmission array of emitters and receivers has been proposed for materials with negligible absorption, see Minonzio et al. [J. Acoust. Soc. Am. 127, 2913-2919 (2010)]. In presence of absorption, the ability to extract guided mode degrades. The objective of the present study is to extend the method to the case of absorbing media, considering attenuated plane waves (complex wavenumber). The guided mode wavenumber extraction is enhanced and the order of magnitude of the attenuation of the guided mode is estimated. Experiments have been carried out on 2 mm thick plates in the 0.2-2 MHz bandwidth. Two materials are inspected: polymethylacrylate (PMMA) (isotropic with absorption) and artificial composite bones (Sawbones, Pacific Research Laboratory Inc, Vashon, WA) which is a transverse isotropic absorbing medium. Bulk wave velocities and bulk attenuation have been evaluated from transmission measurements. These values were used to compute theoretical Lamb mode wavenumbers which are consistent with the experimental ones obtained with the SVD-based approach. PMID- 22225015 TI - Nonlinear elastodynamics in micro-inhomogeneous solids observed by head-wave based dynamic acoustoelastic testing. AB - Dynamic acoustoelastic testing provides a more complete insight into the acoustic nonlinearity exhibited by micro-inhomogeneous media like granular and cracked materials. This method consists of measuring time of flight and energy modulations of pulsed ultrasonic waves induced by a low-frequency standing wave. Here pulsed ultrasonic head waves were employed to assess elastic and dissipative nonlinearities in a region near the surface of a solid. Synchronization of the ultrasound pulse sequence with the low-frequency excitation provided instantaneous variations in the elastic modulus and the attenuation as functions of the instantaneous low-frequency strain. Weak quadratic elastic nonlinearity and no dissipative nonlinearity were detected in duralumin. In limestone, distinction between tensile and compressive behaviors revealed an asymmetry in the acoustic nonlinearity and hysteresis in both the elastic modulus and the attenuation variations. Measured nonlinear acoustical parameters are in good agreement with values obtained by different techniques. Reversible acoustically induced conditioning modified the acoustic nonlinearity both quantitatively and qualitatively. It reduced tension-compression asymmetry, suggesting a nonequilibrium modification of the sources of acoustic nonlinearity. Additionally to the metrology of the acoustic nonlinearity, head wave based dynamic acoustoelastic testing may be a useful tool to monitor changes in the microstructure or the accumulation of damage in solids. PMID- 22225016 TI - Improved prediction of the turbulence-shear contribution to wind noise pressure spectra. AB - In previous research [Raspet et al., J. Acoust. Soc. Am. 123(3), 1260-1269 (2008)], predictions of the low frequency turbulence-turbulence and turbulence mean shear interaction pressure spectra measured by a large wind screen were developed and compared to the spectra measured using large spherical wind screens in the flow. The predictions and measurements agreed well except at very low frequencies where the turbulence-mean shear contribution dominated the turbulence turbulence interaction pressure. In this region the predicted turbulence-mean shear interaction pressure did not show consistent agreement with microphone measurements. The predicted levels were often much larger than the measured results. This paper applies methods developed to predict the turbulence-shear interaction pressure measured at the ground [Yu et al., J. Acoust. Soc. Am. 129(2), 622-632 (2011)] to improve the prediction of the turbulence-shear interaction pressure above the ground surface by incorporating a realistic wind velocity profile and realistic turbulence anisotropy. The revised prediction of the turbulence-shear interaction pressure spectra compares favorably with wind screen microphone measurements in large wind screens at low frequency. PMID- 22225017 TI - Random focusing of nonlinear acoustic N-waves in fully developed turbulence: laboratory scale experiment. AB - A laboratory experiment was conducted to study the propagation of short duration (25 MUs) and high amplitude (1000 Pa) acoustic N-waves in turbulent flow. Turbulent flows with a root-mean-square value of the fluctuating velocity up to 4 m/s were generated using a bidimensional nozzle (140 * 1600 mm(2)). Energy spectra of velocity fluctuations were measured and found in good agreement with the modified von Karman spectrum for fully developed turbulence. Spherical N waves were generated by an electric spark source. Distorted waves were measured by four 3 mm diameter microphones placed beyond the turbulent jet. The presence of turbulence resulted in random focusing of the pulse; more than a threefold increase of peak pressures was occasionally observed. Statistics of the acoustic field parameters were evaluated as functions of the propagation distance and the level of turbulence fluctuations. It is shown that random inhomogeneities decrease the mean peak positive pressure up to 30% at 2 m from the source, double the mean rise time, and cause the arrival time about 0.3% earlier than that for corresponding conditions in still air. Probability distributions of the pressure amplitude possess autosimilarity properties with respect to the level of turbulence fluctuations. PMID- 22225018 TI - Incorporating source directionality into outdoor sound propagation calculations. AB - Many outdoor sound sources, such as aircraft or ground vehicles, exhibit directional radiation patterns. However, long-range sound propagation algorithms are usually formulated for omnidirectional point sources. This paper describes two methods for incorporating directional sources into long-range sound propagation algorithms. The first is the equivalent source method (ESM), which determines a compact distribution of omnidirectional point sources reproducing a given directivity pattern in the far field. This method can be used with any propagation algorithm because it explicitly reconstructs a source function as a set of point sources with certain amplitudes and positions. The second is a directional starter method (DSM), which is developed specifically for the parabolic equation (PE) algorithms. This method derives narrow- or wide-angle directional starter fields, corresponding to a given source directivity pattern, without reconstructing the equivalent source distribution. Although the ESM can also be used for the PE, the DSM is simpler and can be more convenient, especially if the sound propagation is calculated only for one or a few azimuthal directions. While these two methods are found to produce generally distinct starter fields, they nonetheless yield identical directivity patterns. PMID- 22225019 TI - Model-based seafloor characterization employing multi-beam angular backscatter data--a comparative study with dual-frequency single beam. AB - Sediment geoacoustic inversion results are estimated employing a multi-beam (MB) echo-sounding system operable at 95 kHz. To characterize the western continental shelf of India (off Goa) seafloor, MB backscatter signals were acquired along with grab sediment samples. The substrate type and roughness of the site were estimated using the composite roughness scattering model with the measured backscatter values. The seafloor parameters, namely mean grain size (M(phi)); roughness spectrum strength (w(2)) and exponent (gamma(2)); and sediment volume parameter (sigma(2)), for coarse and fine grain sediments are estimated by employing the MB system. These parameters have also been estimated at two other frequencies (33 and 210 kHz) and are compared to the ground truth data to provide sufficient support in validating the model results and increasing the understanding of the shelf seafloor processes. Distinct interclass separations between the sediment provinces are evident from the estimated mean grain size M(phi) and water-sediment interface roughness w(2). The seafloor parameters for coarse and fine grain sediments derived from the 95 kHz MB data are consistent with the sediment sample data as well as with the inversion results obtained using backscatter data at 33 and 210 kHz from the same locations. PMID- 22225020 TI - Coherent averaging of the passive fathometer response using short correlation time. AB - The passive fathometer algorithm was applied to data from two drifting array experiments in the Mediterranean, Boundary 2003 and 2004. The passive fathometer response was computed with correlation times from 0.34 to 90 s and, for correlation times less than a few seconds, the observed signal-to-noise ratio (SNR) agrees with a 1D model of SNR of the passive fathometer response in an ideal waveguide. In the 2004 experiment, the fathometer response showed the array depth varied periodically with an amplitude of 1 m and a period of 7 s consistent with wave driven motion of the array. This introduced a destructive interference, which prevents the SNR growing with increasing correlation time. A peak-tracking algorithm applied to the fathometer response of experimental data was used to remove this motion allowing the coherent passive fathometer response to be averaged over several minutes without destructive interference. Multirate adaptive beamforming, using 90 s correlation time to form adaptive steer vectors which were applied to 0.34 s data snapshots, increases the SNR of the passive fathometer response. PMID- 22225021 TI - Where the ocean influences the impulse response and its effect on synchronous changes of acoustic travel time. AB - In 1983, sounds at 133 Hz, 0.06 s resolution were transmitted in the Pacific for five days at 2 min intervals over 3709 km between bottom-mounted instruments maintained with atomic clocks. In 1989, a technique was developed to measure changes in acoustic travel time with an accuracy of 135 microseconds at 2 min intervals for selected windows of travel time within the impulse response. The data have short-lived 1 to 10 ms oscillations of travel time with periods less than a few days. Excluding tidal effects, different windows exhibited significant synchronized changes in travel time for periods shorter than 10 h. In the 1980s, this phenomenon was not understood because internal waves have correlation lengths of a few kilometers which are smaller than the way sound was thought to sample the ocean along well-separated and distinct rays corresponding to different windows. The paradox's resolution comes from modern theories that replace the ray-picture with finite wavelength representations that predict sound can be influenced in the upper ocean over horizontal scales such as 20 km or more. Thus, different windows are influenced by the same short-scale fluctuations of sound speed. This conclusion is supported by the data and numerical simulations of the impulse response. PMID- 22225022 TI - Vocal characteristics of pygmy blue whales and their change over time. AB - Vocal characteristics of pygmy blue whales of the eastern Indian Ocean population were analyzed using data from a hydroacoustic station deployed off Cape Leeuwin in Western Australia as part of the Comprehensive Nuclear-Test-Ban Treaty monitoring network, from two acoustic observatories of the Australian Integrated Marine Observing System, and from individual sea noise loggers deployed in the Perth Canyon. These data have been collected from 2002 to 2010, inclusively. It is shown that the themes of pygmy blue whale songs consist of ether three or two repeating tonal sounds with harmonics. The most intense sound of the tonal theme was estimated to correspond to a source level of 179 +/- 2 dB re 1 MUPa at 1 m measured for 120 calls from seven different animals. Short-duration calls of impulsive downswept sound from pygmy blue whales were weaker with the source level estimated to vary between 168 to 176 dB. A gradual decrease in the call frequency with a mean rate estimated to be 0.35 +/- 0.3 Hz/year was observed over nine years in the frequency of the third harmonic of tonal sound 2 in the whale song theme, which corresponds to a negative trend of about 0.12 Hz/year in the call fundamental frequency. PMID- 22225024 TI - Generalized optical theorems for the reconstruction of Green's function of an inhomogeneous elastic medium. AB - This paper investigates the reconstruction of elastic Green's function from the cross-correlation of waves excited by random noise in the context of scattering theory. Using a general operator equation-the resolvent formula-Green's function reconstruction is established when the noise sources satisfy an equipartition condition. In an inhomogeneous medium, the operator formalism leads to generalized forms of optical theorem involving the off-shell T-matrix of elastic waves, which describes scattering in the near-field. The role of temporal absorption in the formulation of the theorem is discussed. Previously established symmetry and reciprocity relations involving the on-shell T-matrix are recovered in the usual far-field and infinitesimal absorption limits. The theory is applied to a point scattering model for elastic waves. The T-matrix of the point scatterer incorporating all recurrent scattering loops is obtained by a regularization procedure. The physical significance of the point scatterer is discussed. In particular this model satisfies the off-shell version of the generalized optical theorem. The link between equipartition and Green's function reconstruction in a scattering medium is discussed. PMID- 22225023 TI - A threatened beluga (Delphinapterus leucas) population in the traffic lane: vessel-generated noise characteristics of the Saguenay-St. Lawrence Marine Park, Canada. AB - The threatened resident beluga population of the St. Lawrence Estuary shares the Saguenay-St. Lawrence Marine Park with significant anthropogenic noise sources, including marine commercial traffic and a well-established, vessel-based whale watching industry. Frequency-dependent (FD) weighting was used to approximate beluga hearing sensitivity to determine how noise exposure varied in time and space at six sites of high beluga summer residency. The relative contribution of each source to acoustic habitat degradation was estimated by measuring noise levels throughout the summer and noise signatures of typical vessel classes with respect to traffic volume and sound propagation characteristics. Rigid-hulled inflatable boats were the dominant noise source with respect to estimated beluga hearing sensitivity in the studied habitats due to their high occurrence and proximity, high correlation with site-specific FD-weighted sound levels, and the dominance of mid-frequencies (0.3-23 kHz) in their noise signatures. Median C weighted sound pressure level (SPL(RMS)) had a range of 19 dB re 1 MUPa between the noisiest and quietest sites. Broadband SPL(RMS) exceeded 120 dB re 1 MUPa 8 32% of the time depending on the site. Impacts of these noise levels on St. Lawrence beluga will depend on exposure recurrence and individual responsiveness. PMID- 22225025 TI - Effect of laser beam incidence angle on the thermoelastic generation in semi transparent materials. AB - When a laser beam is absorbed in a semi-transparent material, a volume acoustic source is created owing to penetration of the laser beam inside the material and to thermoelastic transduction. Many experimental and theoretical studies have been conducted to better understand this ultrasound generation process with normal laser light incidence on the material surface. The purpose of this paper is to analyze the effects of the asymmetry caused by oblique incidence of a laser line source on the generation of acoustic waves in semi-transparent isotropic materials. Experiments on a glass plate demonstrate that such an obliquely incident laser light strongly affects bulk acoustic waves generation. Compressional and shear waves are enhanced and the loss of symmetry of the acoustic source causes asymmetrical behavior of the acoustic waves. Surprisingly, compressional-wave amplitude decreases whereas shear-wave amplitude increases in the region where the electromagnetic energy is refracted. This feature is explained by semi-analytical calculations. PMID- 22225026 TI - An analytical-numerical method for determining the mechanical response of a condenser microphone. AB - The paper is based on determining the reaction pressure on the diaphragm of a condenser microphone by integrating numerically the frequency domain Stokes system describing the velocity and the pressure in the air domain beneath the diaphragm. Afterwards, the membrane displacement can be obtained analytically or numerically. The method is general and can be applied to any geometry of the backplate holes, slits, and backchamber. As examples, the method is applied to the Bruel & Kjaer (B&K) 4134 1/2-inch microphone determining the mechanical sensitivity and the mechano-thermal noise for a domain of frequencies and also the displacement field of the membrane for two specified frequencies. These elements compare well with the measured values published in the literature. Also a new design, completely micromachined (including the backvolume) of the B&K micro-electro-mechanical systems (MEM) 1/4-inch measurement microphone is proposed. It is shown that its mechanical performances are very similar to those of the B&K MEMS measurement microphone. PMID- 22225027 TI - A transport model and numerical simulation of the high-frequency dynamics of three-dimensional beam trusses. AB - The theory of microlocal analysis shows that the energy density associated with the high-frequency vibrations of a three-dimensional Timoshenko beam satisfies a Liouville-type transport equation. In the present application, the material of the beam is assumed to be isotropic. Its parameters are allowed to vary along the beam axis at length scales much larger than the wavelength of the high-frequency waves traveling in it. Moreover, the curvature and torsion of the beam are accounted for. The first part of the paper focuses on the derivation of the transport model for a single three-dimensional beam. In order to extend this model to beam trusses, the reflection/transmission phenomena of the energy fluxes at junctions of beams are described by power flow reflection/transmission operators in a subsequent part. For numerical simulations, a discontinuous Galerkin finite element method is used on account of the discontinuities of the energy density field at the junctions. Thus, a complete mechanical-numerical modeling of the linear transient dynamics of beam trusses is proposed. It is illustrated by numerical examples highlighting some remarkable features of high frequency vibrations: The onset of a diffusive regime characterized by energy equipartition rules at late times. Energy diffusion is prompted by the multiple reflection/transmission of waves at the junctions, with possible mode (polarization) conversions. This is the regime applicable to the statistical energy analysis of structural acoustics systems. The main purpose of this research is to develop an effective strategy to simulate and predict the transient response of beam trusses impacted by acoustic or mechanical shocks. PMID- 22225028 TI - Subjective ratings of whole-body vibration for single- and multi-axis motion. AB - Real-world whole-body vibration exposures comprise motion in fore-aft, lateral, and vertical directions simultaneously. There can also be components of roll, pitch, and yaw. If evaluating vibration with respect to human response, most investigators will use methods defined in ISO 2631-1. This uses frequency weightings that were originally derived from laboratory studies of the subjective responses to vibration in one direction at a time. This paper describes experiments that were carried out using a 6 degree-of-freedom vibration simulator to validate the applicability of ISO 2631-1 in multi-axis environments. Fifteen subjects were exposed to 87 stimuli comprising single-axis, dual-axis, and tri axial random vibration, to which they were required to produce subjective ratings. It is shown that in this study the root-sum-of-squares method of summation of subjective ratings in individual axes was an adequate technique for prediction of subjective rating of multi-axis vibration. Better agreement between objective and subjective measures of vibration was obtained for unweighted vibration than for frequency weighted signals. The best agreement for this study was achieved when axis multiplying factors were set at 2.2 and 2.4 for x- and y axis vibration, respectively. Different values could be appropriate for other postures, seats, and vibration conditions and should be determined in future studies. PMID- 22225029 TI - Measurement of viscoelastic properties from the vibration of a compliantly supported beam. AB - A laboratory method is presented by which the viscoelastic properties of compliant materials are measured over a wide frequency range. The test setup utilizes a flexible beam clamped at one end and excited by a shaker at the free end. A small specimen of a compliant material is positioned to support the beam near its midpoint. The deformation from gravity is minimized since the specimen is not loaded by an attached mass. Forced vibration responses measured at two locations along the beam are used to derive a transfer function from which the dynamic properties of compliant materials are directly determined by use of a theoretical procedure investigating the effects of specimen stiffness on the propagation of flexural waves. Sensitivity of the measured properties to experimental uncertainties is investigated. Young's moduli and associated loss factors are determined for compliant materials ranging from low-density closed cell foams to high-density damping materials. The method is validated by comparing the measured viscoelastic properties to those from an alternative dynamic test method. PMID- 22225030 TI - Acoustic insertion loss due to two dimensional periodic arrays of circular cylinders parallel to a nearby surface. AB - The acoustical performances of regular arrays of cylindrical elements, with their axes aligned and parallel to a ground plane, have been investigated through predictions and laboratory experiments. Semi-analytical predictions based on multiple scattering theory and numerical simulations based on a boundary element formulation have been made. Measurements have been made in an anechoic chamber using arrays of (a) cylindrical acoustically-rigid scatterers (PVC pipes) and (b) thin elastic shells. Insertion loss (IL) spectra due to the arrays have been measured without and with ground planes for several receiver heights. Data and predictions have been compared. The minima in the excess attenuation spectrum i.e., attenuation maxima due to the ground alone resulting from destructive interference between direct and ground-reflected sound waves, tend to have an adverse influence on the band gaps (BG) related to a periodic array in the free field when these two effects coincide. On the other hand, the presence of rigid ground may result in an IL for an array near the ground similar to or, in the case of the first BG, greater than that resulting from a double array, equivalent to the original array plus its ground plane mirror image, in the free field. PMID- 22225032 TI - Noise in an intensive care unit. AB - Patients and staff in hospitals are exposed to a complex sound environment with rather high noise levels. In intensive care units, the main noise sources are hospital staff on duty and medical equipment, which generates both operating noise and acoustic alarms. Although noise in most cases is produced during activities for the purpose of saving life, noise can induce significant changes in the depth and quality of sleep and negatively affect health in general. Results of a survey of hospital staff are presented, as well as measurements in two German hospital wards: a standard two-bed room and a special intermediate care unit (IMC-Unit), each in a different intensive care unit (ICU). Sound pressure data were collected over a 48 hour period and converted into different levels (L(AFeq), L(AFmax) L(AFmin), L(AF 5%)), as well as a rating level L(Ar), which is used to take tonality and impulsiveness into account. An analysis of the survey and the measured data, together with a comparison of thresholds of national and international regulations and standards describe the acoustic situation and its likely noise effects on staff and patients. PMID- 22225031 TI - A comparison between exposure-response relationships for wind turbine annoyance and annoyance due to other noise sources. AB - Surveys have shown that noise from wind turbines is perceived as annoying by a proportion of residents living in their vicinity, apparently at much lower noise levels than those inducing annoyance due to other environmental sources. The aim of the present study was to derive the exposure-response relationship between wind turbine noise exposure in L(den) and the expected percentage annoyed residents and to compare it to previously established relationships for industrial noise and transportation noise. In addition, the influence of several individual and situational factors was assessed. On the basis of available data from two surveys in Sweden (N=341, N=754) and one survey in the Netherlands (N=725), a relationship was derived for annoyance indoors and for annoyance outdoors at the dwelling. In comparison to other sources of environmental noise, annoyance due to wind turbine noise was found at relatively low noise exposure levels. Furthermore, annoyance was lower among residents who received economical benefit from wind turbines and higher among residents for whom the wind turbine was visible from the dwelling. Age and noise sensitivity had similar effects on annoyance to those found in research on annoyance by other sources. PMID- 22225033 TI - Non-auditory factors affecting urban soundscape evaluation. AB - The aim of this study is to characterize urban spaces, which combine landscape, acoustics, and lighting, and to investigate people's perceptions of urban soundscapes through quantitative and qualitative analyses. A general questionnaire survey and soundwalk were performed to investigate soundscape perception in urban spaces. Non-auditory factors (visual image, day lighting, and olfactory perceptions), as well as acoustic comfort, were selected as the main contexts that affect soundscape perception, and context preferences and overall impressions were evaluated using an 11-point numerical scale. For qualitative analysis, a semantic differential test was performed in the form of a social survey, and subjects were also asked to describe their impressions during a soundwalk. The results showed that urban soundscapes can be characterized by soundmarks, and soundscape perceptions are dominated by acoustic comfort, visual images, and day lighting, whereas reverberance in urban spaces does not yield consistent preference judgments. It is posited that the subjective evaluation of reverberance can be replaced by physical measurements. The categories extracted from the qualitative analysis revealed that spatial impressions such as openness and density emerged as some of the contexts of soundscape perception. PMID- 22225034 TI - Enhancing the absorption coefficient of a backed rigid frame porous layer by embedding circular periodic inclusions. AB - The acoustic properties of a porous sheet of medium static air flow resistivity (around 10,000 N m s(-4)), in which a periodic set of circular inclusions is embedded and which is backed by a rigid plate, are investigated. The inclusions and porous skeleton are assumed motionless. Such a structure behaves like a multi component diffraction grating. Numerical results show that this structure presents a quasi-total (close to unity) absorption peak below the quarter wavelength resonance of the porous sheet in absence of inclusions. This result is explained by the excitation of a complex trapped mode. When more than one inclusion per spatial period is considered, additional quasi-total absorption peaks are observed. The numerical results, as calculated with the help of the mode-matching method described in this paper, agree with those calculated using a finite element method. PMID- 22225035 TI - Estimating the direct-to-reverberant energy ratio from the coherence between coincident pressure and particle velocity. AB - An analytical expression for the relationship between the direct-to-reverberant energy ratio (DRR) and the coherence estimation function between coincident pressure and particle velocity component is derived. The analytical solution is first validated with simulated room impulse responses and then used to estimate the DRR in five octave bands for several receiver positions measured in a total of 11 rooms of vastly different sizes and acoustic characteristics. The accuracy is evaluated by comparison with the DRR estimated directly from the room impulse response. The difference is typically 5 dB. For two rooms, the variation of the DRR estimate with source-to-receiver position is also shown. The method is blind in the sense that it is virtually independent of the signal generated by a single sound source. PMID- 22225036 TI - Design and evaluation of an aeroacoustic wind tunnel for measurement of axial flow fans. AB - An anechoic wind tunnel dedicated to fan self-noise studies has been designed and constructed at the von Karman Institute The multi-chamber, mass flow driven design allows for all fan performance characteristics, aerodynamic quantities (e.g., wake turbulence measurements), and acoustic properties to be assessed in the same facility with the same conditions. The acoustic chamber performance is assessed using the optimum reference method and found to be within the ISO 3745 standards down to 150 Hz for pure tone and broadband source mechanisms. The additional influence of installation effects of an aerodynamic inlet was found to create a scattered sound field only near the source location, while still providing good anechoic results at more distant sound pressure measurement positions. It was found to have inflow properties, span-wise uniformity, and low turbulence intensity, consistent with those desired for fan self-noise studies. PMID- 22225037 TI - Multi-carrier synthetic aperture communication in shallow water: experimental results. AB - Orthogonal frequency division multiplexing (OFDM) communications in the presence of motion is investigated using data collected from the Kauai Acomms MURI 2008 (KAM08) experiment, conducted off the western side of Kauai, Hawaii, in June-July 2008. The experiment involved a vertical array moored in 106 m deep shallow water and a source towed at a speed of 3 knots at ranges between 600 m and 6 km. In order to attain reliable communications with only a single receive element, a synthetic aperture approach is applied. After combining multiple transmissions, an error-free reception is achieved with a low-density parity-check code, confirming the feasibility of coherent synthetic aperture communications using OFDM. PMID- 22225038 TI - Observer-based beamforming algorithm for acoustic array signal processing. AB - In the field of noise identification with microphone arrays, conventional delay and-sum (DAS) beamforming is the most popular signal processing technique. However, acoustic imaging results that are generated by DAS beamforming are easily influenced by background noise, particularly for in situ wind tunnel tests. Even when arithmetic averaging is used to statistically remove the interference from the background noise, the results are far from perfect because the interference from the coherent background noise is still present. In addition, DAS beamforming based on arithmetic averaging fails to deliver real time computational capability. An observer-based approach is introduced in this paper. This so-called observer-based beamforming method has a recursive form similar to the state observer in classical control theory, thus holds a real-time computational capability. In addition, coherent background noise can be gradually rejected in iterations. Theoretical derivations of the observer-based beamforming algorithm are carefully developed in this paper. Two numerical simulations demonstrate the good coherent background noise rejection and real-time computational capability of the observer-based beamforming, which therefore can be regarded as an attractive algorithm for acoustic array signal processing. PMID- 22225039 TI - The effect of nearby bubbles on array gain. AB - The coherent processing of signals from multiple hydrophones in an array offers improvements in angular resolution and signal-to-noise ratio. When the array is steered in a particular direction, the signals arriving from that direction are added in phase, and any signals arriving from other directions are not. Array gain (AG) is a measure of how much the signal arriving from the steering direction is amplified relative to signals arriving from all other directions. The subject of this paper is the manner in which the AG of an acoustic array operating in water that contains air bubbles is affected by scattering from nearby bubbles. The effects of bubbles on acoustic attenuation and dispersion are considered separately from their effects on AG. Acoustic measurements made in bubbly water using the AB Wood tank at the Institute of Sound and Vibration Research, University of Southampton, in June 2008 show that as bubble density increases, relative phase shifts in individual hydrophone signals increase and signal correlation among the hydrophones is reduced. A theory and numerical simulation linking bubble density at the hydrophone to the AG is in good agreement with the measurements up to the point where multiple scattering becomes important. PMID- 22225040 TI - Comparison of the measured and theoretical performance of a broadband circular microphone array. AB - The design and construction of a circular microphone array (CMA) that has a wide frequency range suitable for human hearing is presented. The design of the CMA was achieved using a technique based on simulated directivity index (DI) curves. The simulated DI curves encapsulate the critical microphone array performance limitations: spatial aliasing, measurement noise, and microphone placement errors. This paper demonstrates how the non-regularized DI curves for a given beamforming order clearly define the bandwidth of operation, in other words, the frequency band for which the beamformer has relatively constant and maximum directivity. Detailed and comprehensive experimental data that characterizes the CMA beamformer are also presented. PMID- 22225041 TI - Acoustic quasi-holographic images of scattering by vertical cylinders from one dimensional bistatic scans. AB - When synthetic aperture sonar (SAS) is used to image elastic targets in water, subtle features can be present in the images associated with the dynamical response of the target being viewed. In an effort to improve the understanding of such responses, as well as to explore alternative image processing methods, a laboratory-based system was developed in which targets were illuminated by a transient acoustic source, and bistatic responses were recorded by scanning a hydrophone along a rail system. Images were constructed using a relatively conventional bistatic SAS algorithm and were compared with images based on supersonic holography. The holographic method is a simplification of one previously used to view the time evolution of a target's response [Hefner and Marston, ARLO 2, 55-60 (2001)]. In the holographic method, the space-time evolution of the scattering was used to construct a two-dimensional image with cross range and time as coordinates. Various features for vertically hung cylindrical targets were interpreted using high frequency ray theory. This includes contributions from guided surface elastic waves, as well as transmitted wave features and specular reflection. PMID- 22225042 TI - Vibration responses of the organ of Corti and the tectorial membrane to electrical stimulation. AB - Coupling of somatic electromechanical force from the outer hair cells (OHCs) into the organ of Corti is investigated by measuring transverse vibration patterns of the organ of Cori and tectorial membrane (TM) in response to intracochlear electrical stimulation. Measurement places at the organ of Corti extend from the inner sulcus cells to Hensen's cells and at the lower (and upper) surface of the TM from the inner sulcus to the OHC region. These locations are in the neighborhood of where electromechanical force is coupled into (1) the mechanoelectrical transducers of the stereocilia and (2) fluids of the organ of Corti. Experiments are conducted in the first, second, and third cochlear turns of an in vitro preparation of the adult guinea pig cochlea. Vibration measurements are made at functionally relevant stimulus frequencies (0.48-68 kHz) and response amplitudes (<15 nm). The experiments provide phase relations between the different structures, which, dependent on frequency range and longitudinal cochlear position, include in-phase transverse motions of the TM, counterphasic transverse motions between the inner hair cell and OHCs, as well as traveling wave motion of Hensen's cells in the radial direction. Mechanics of sound processing in the cochlea are discussed based on these phase relationships. PMID- 22225043 TI - Inverse solution of ear-canal area function from reflectance. AB - A number of acoustical applications require the transformation of acoustical quantities, such as impedance and pressure that are measured at the entrance of the ear canal, to quantities at the eardrum. This transformation often requires knowledge of the shape of the ear canal. Previous attempts to measure ear-canal area functions were either invasive, non-reproducible, or could only measure the area function up to a point mid-way along the canal. A method to determine the area function of the ear canal from measurements of acoustic impedance at the entrance of the ear canal is described. The method is based on a solution to the inverse problem in which measurements of impedance are used to calculate reflectance, which is then used to determine the area function of the canal. The mean ear-canal area function determined using this method is similar to mean ear canal area functions measured by other researchers using different techniques. The advantage of the proposed method over previous methods is that it is non- invasive, fast, and reproducible. PMID- 22225044 TI - Further assessment of forward pressure level for in situ calibration. AB - Quantifying ear-canal sound level in forward pressure has been suggested as a more accurate and practical alternative to sound pressure level (SPL) calibrations used in clinical settings. The mathematical isolation of forward (and reverse) pressure requires defining the Thevenin-equivalent impedance and pressure of the sound source and characteristic impedance of the load; however, the extent to which inaccuracies in characterizing the source and/or load impact forward pressure level (FPL) calibrations has not been specifically evaluated. This study examined how commercially available probe tips and estimates of characteristic impedance impact the calculation of forward and reverse pressure in a number of test cavities with dimensions chosen to reflect human ear-canal dimensions. Results demonstrate that FPL calibration, which has already been shown to be more accurate than in situ SPL calibration, can be improved particularly around standing-wave null frequencies by refining estimates of characteristic impedance. Better estimates allow FPL to be accurately calculated at least through 10 kHz using a variety of probe tips in test cavities of different sizes, suggesting that FPL calibration can be performed in ear canals of all sizes. Additionally, FPL calibration appears a reasonable option when quantifying the levels of extended high-frequency (10-18 kHz) stimuli. PMID- 22225045 TI - Cascades of two-pole-two-zero asymmetric resonators are good models of peripheral auditory function. AB - A cascade of two-pole-two-zero filter stages is a good model of the auditory periphery in two distinct ways. First, in the form of the pole-zero filter cascade, it acts as an auditory filter model that provides an excellent fit to data on human detection of tones in masking noise, with fewer fitting parameters than previously reported filter models such as the roex and gammachirp models. Second, when extended to the form of the cascade of asymmetric resonators with fast-acting compression, it serves as an efficient front-end filterbank for machine-hearing applications, including dynamic nonlinear effects such as fast wide-dynamic-range compression. In their underlying linear approximations, these filters are described by their poles and zeros, that is, by rational transfer functions, which makes them simple to implement in analog or digital domains. Other advantages in these models derive from the close connection of the filter cascade architecture to wave propagation in the cochlea. These models also reflect the automatic-gain-control function of the auditory system and can maintain approximately constant impulse-response zero-crossing times as the level dependent parameters change. PMID- 22225046 TI - Spectral loudness summation of nonsimultaneous tone pulses. AB - The level of broadband signals is usually lower than that of equally loud narrow band signals. This effect, referred to as spectral loudness summation, is commonly measured for broadband signals where all frequency components are presented simultaneously. The present study investigated to what extent spectral loudness summation also occurs for nonsimultaneously presented frequency components. Spectral loudness summation was measured in normal-hearing listeners with an adaptive forced-choice procedure for sequences of short tone pulses with varying frequencies, randomly chosen from a set of five frequencies. In addition, spectral loudness summation was measured for the simultaneous presentation of all five frequencies. The comparison stimulus consisted of tone pulses with the same frequency for all tone pulses of the sequence and the same repetition rate and overall duration as the test signal. The pulse duration was 10, 20, 50, or 100 ms and the inter-pulse interval ranged from 0 to 390 ms. In general, a considerable nonsimultaneous spectral loudness summation was found for short pulse durations and inter-pulse intervals, but a residual effect was also observed for the largest inter-pulse interval. The data are discussed in the light of repetition rate dependent spectral loudness summation and effects of persistence of specific loudness after tone-pulse offset. PMID- 22225047 TI - The effect of carrier level on tuning in amplitude-modulation masking. AB - The effect of carrier level on tuning in modulation masking was investigated for noise and tonal carriers. Bandwidths of the modulation filters, estimated from the masked detection thresholds using an envelope power spectrum model, were independent of level for the noise carrier but seemed to decrease with increasing level for the tonal carrier. However, the apparently sharper tuning could be explained by increased modulation sensitivity and modulation dynamic range with increasing level rather than improved modulation-frequency selectivity. Consistent with this interpretation, the addition of a high-pass noise with a level adjusted to maintain the same threshold for the detection of the signal modulation for each carrier level used eliminated the effect of level on tuning. Overall, modulation filters estimated from psychophysical data do not depend on level in contrast to the modulation transfer functions obtained from neural recordings in the inferior colliculus in physiological studies. The results highlight differences between the characteristics of modulation processing obtained from neural data and perception. The discrepancies indicate the need for further investigation into physiological correlates of tuning in modulation processing. PMID- 22225048 TI - Contextual effects in the identification of nonspeech auditory patterns. AB - This study investigated the benefit of a priori cues in a masked nonspeech pattern identification experiment. Targets were narrowband sequences of tone bursts forming six easily identifiable frequency patterns selected randomly on each trial. The frequency band containing the target was randomized. Maskers were also narrowband sequences of tone bursts chosen randomly on every trial. Targets and maskers were presented monaurally in mutually exclusive frequency bands, producing large amounts of informational masking. Cuing the masker produced a significant improvement in performance, while holding the target frequency band constant provided no benefit. The cue providing the greatest benefit was a copy of the masker presented ipsilaterally before the target-plus-masker. The masker cue presented contralaterally, and a notched-noise cue produced smaller benefits. One possible mechanism underlying these findings is auditory "enhancement" in which the neural response to the target is increased relative to the masker by differential prior stimulation of the target and masker frequency regions. A second possible mechanism provides a benefit to performance by comparing the spectrotemporal correspondence of the cue and target-plus-masker and is effective for either ipsilateral or contralateral cue presentation. These effects improve identification performance by emphasizing spectral contrasts in sequences or streams of sounds. PMID- 22225049 TI - Dynamic-range compression affects the lateral position of sounds. AB - Dynamic-range compression acting independently at each ear in a bilateral hearing aid or cochlear-implant fitting can alter interaural level differences (ILDs) potentially affecting spatial perception. The influence of compression on the lateral position of sounds was studied in normal-hearing listeners using virtual acoustic stimuli. In a lateralization task, listeners indicated the leftmost and rightmost extents of the auditory event and reported whether they heard (1) a single, stationary image, (2) a moving/gradually broadening image, or (3) a split image. Fast-acting compression significantly affected the perceived position of high-pass sounds. For sounds with abrupt onsets and offsets, compression shifted the entire image to a more central position. For sounds containing gradual onsets and offsets, including speech, compression increased the occurrence of moving and split images by up to 57 percentage points and increased the perceived lateral extent of the auditory event. The severity of the effects was reduced when undisturbed low-frequency binaural cues were made available. At high frequencies, listeners gave increased weight to ILDs relative to interaural time differences carried in the envelope when compression caused ILDs to change dynamically at low rates, although individual differences were apparent. Specific conditions are identified in which compression is likely to affect spatial perception. PMID- 22225050 TI - Detection of pulse trains in the electrically stimulated cochlea: effects of cochlear health. AB - Perception of electrical stimuli varies widely across users of cochlear implants and across stimulation sites in individual users. It is commonly assumed that the ability of subjects to detect and discriminate electrical signals is dependent, in part, on conditions in the implanted cochlea, but evidence supporting that hypothesis is sparse. The objective of this study was to define specific relationships between the survival of tissues near the implanted electrodes and the functional responses to electrical stimulation of those electrodes. Psychophysical and neurophysiological procedures were used to assess stimulus detection as a function of pulse rate under the various degrees of cochlear pathology. Cochlear morphology, assessed post-mortem, ranged from near-normal numbers of hair cells, peripheral processes and spiral ganglion cells, to complete absence of hair cells and peripheral processes and small numbers of surviving spiral ganglion cells. The psychophysical and neurophysiological studies indicated that slopes and levels of the threshold versus pulse rate functions reflected multipulse integration throughout the 200 ms pulse train with an additional contribution of interactions between adjacent pulses at high pulse rates. The amount of multipulse integration was correlated with the health of the implanted cochlea with implications for perception of more complex prosthetic stimuli. PMID- 22225052 TI - What affects the presence versus absence of schwa and its duration: a corpus analysis of French connected speech. AB - This study presents an analysis of over 4000 tokens of words produced as variants with and without schwa in a French corpus of radio-broadcasted speech. In order to determine which of the many variables mentioned in the literature influence variant choice, 17 predictors were tested in the same analysis. Only five of these variables appeared to condition variant choice. The question of the processing stage, or locus, of this alternation process is also addressed in a comparison of the variables that predict variant choice with the variables that predict the acoustic duration of schwa in variants with schwa. Only two variables predicting variant choice also predict schwa duration. The limited overlap between the predictors for variant choice and for schwa duration, combined with the nature of these variables, suggest that the variants without schwa do not result from a phonetic process of reduction; that is, they are not the endpoint of gradient schwa shortening. Rather, these variants are generated early in the production process, either during phonological encoding or word-form retrieval. These results, based on naturally produced speech, provide a useful complement to on-line production experiments using artificial speech tasks. PMID- 22225051 TI - Production of contrast between sibilant fricatives by children with cochlear implants. AB - Speech production by children with cochlear implants (CIs) is generally less intelligible and less accurate on a phonemic level than that of normally hearing children. Research has reported that children with CIs produce less acoustic contrast between phonemes than normally hearing children, but these studies have included correct and incorrect productions. The present study compared the extent of contrast between correct productions of /s/ and /?/ by children with CIs and two comparison groups: (1) normally hearing children of the same chronological age as the children with CIs and (2) normally hearing children with the same duration of auditory experience. Spectral peaks and means were calculated from the frication noise of productions of /s/ and /?/. Results showed that the children with CIs produced less contrast between /s/ and /?/ than normally hearing children of the same chronological age and normally hearing children with the same duration of auditory experience due to production of /s/ with spectral peaks and means at lower frequencies. The results indicate that there may be differences between the speech sounds produced by children with CIs and their normally hearing peers even for sounds that adults judge as correct. PMID- 22225053 TI - Analysis of the effects of physical task stress on the speech signal. AB - Physical task stress is known to affect the fundamental frequency and other measurements of the speech signal. A corpus of physical task stress speech is analyzed using a spectrum F-ratio and frame score distribution divergences. The measurements differ between phone classes, and are greater for vowels and nasals than for plosives and fricatives. In further analysis, frame score distribution divergences are used to measure the spectral dissimilarity between neutral and physical task stress speech. Frame scores are the log likelihood ratios between Gaussian mixture models (GMMs) of physical task stress and of neutral speech. Mel frequency cepstral coefficients are used as the acoustic feature inputs to the GMMs. A Laplacian distribution is fitted to the frame scores for each of ten phone classes, and the symmetric Kullback-Leibler divergence is employed to measure the change in distribution from neutral to physical task stress. The results suggest that the spectral dissimilarity is greatest for the second level of a four level exertion measurement, and that spectral dissimilarity is greater for nasal phones than for plosives and fricatives. Further, the results suggest that different phone classes are affected differently by physical task stress. PMID- 22225054 TI - Investigating acoustic correlates of human vocal fold vibratory phase asymmetry through modeling and laryngeal high-speed videoendoscopy. AB - Vocal fold vibratory asymmetry is often associated with inefficient sound production through its impact on source spectral tilt. This association is investigated in both a computational voice production model and a group of 47 human subjects. The model provides indirect control over the degree of left-right phase asymmetry within a nonlinear source-filter framework, and high-speed videoendoscopy provides in vivo measures of vocal fold vibratory asymmetry. Source spectral tilt measures are estimated from the inverse-filtered spectrum of the simulated and recorded radiated acoustic pressure. As expected, model simulations indicate that increasing left-right phase asymmetry induces steeper spectral tilt. Subject data, however, reveal that none of the vibratory asymmetry measures correlates with spectral tilt measures. Probing further into physiological correlates of spectral tilt that might be affected by asymmetry, the glottal area waveform is parameterized to obtain measures of the open phase (open/plateau quotient) and closing phase (speed/closing quotient). Subjects' left-right phase asymmetry exhibits low, but statistically significant, correlations with speed quotient (r=0.45) and closing quotient (r=-0.39). Results call for future studies into the effect of asymmetric vocal fold vibration on glottal airflow and the associated impact on voice source spectral properties and vocal efficiency. PMID- 22225055 TI - Restraining mechanisms in regulating glottal closure during phonation. AB - Recent experimental studies showed that isotropic vocal fold models were often blown wide apart and thus not able to maintain adductory position, resulting in voice production with noticeable breathy quality. This study showed that the capability of the vocal fold to resist deformation against airflow and maintain adductory position can be improved by stiffening the body-layer stiffness or increasing the anterior-posterior tension of the vocal folds, which presumably can be achieved through the contraction of the thyroarytenoid (TA) and cricothyroid (CT) muscles, respectively. Experiments in both physical models and excised larynges showed that, when these restraining mechanisms were activated, the vocal folds were better able to maintain effective adduction, resulting in voice production with much clearer quality and reduced breathiness. In humans, one or more restraining mechanisms may be activated at different levels to accommodate the varying degree of restraining required under different voice conditions. PMID- 22225056 TI - Bidirectional clear speech perception benefit for native and high-proficiency non native talkers and listeners: intelligibility and accentedness. AB - This study investigated how native language background interacts with speaking style adaptations in determining levels of speech intelligibility. The aim was to explore whether native and high proficiency non-native listeners benefit similarly from native and non-native clear speech adjustments. The sentence-in noise perception results revealed that fluent non-native listeners gained a large clear speech benefit from native clear speech modifications. Furthermore, proficient non-native talkers in this study implemented conversational-to-clear speaking style modifications in their second language (L2) that resulted in significant intelligibility gain for both native and non-native listeners. The results of the accentedness ratings obtained for native and non-native conversational and clear speech sentences showed that while intelligibility was improved, the presence of foreign accent remained constant in both speaking styles. This suggests that objective intelligibility and subjective accentedness are two independent dimensions of non-native speech. Overall, these results provide strong evidence that greater experience in L2 processing leads to improved intelligibility in both production and perception domains. These results also demonstrated that speaking style adaptations along with less signal distortion can contribute significantly towards successful native and non-native interactions. PMID- 22225057 TI - Adaptive bandwidth measurements of importance functions for speech intelligibility prediction. AB - The Articulation Index (AI) and Speech Intelligibility Index (SII) predict intelligibility scores from measurements of speech and hearing parameters. One component in the prediction is the "importance function," a weighting function that characterizes contributions of particular spectral regions of speech to speech intelligibility. Previous work with SII predictions for hearing-impaired subjects suggests that prediction accuracy might improve if importance functions for individual subjects were available. Unfortunately, previous importance function measurements have required extensive intelligibility testing with groups of subjects, using speech processed by various fixed-bandwidth low-pass and high pass filters. A more efficient approach appropriate to individual subjects is desired. The purpose of this study was to evaluate the feasibility of measuring importance functions for individual subjects with adaptive-bandwidth filters. In two experiments, ten subjects with normal-hearing listened to vowel-consonant vowel (VCV) nonsense words processed by low-pass and high-pass filters whose bandwidths were varied adaptively to produce specified performance levels in accordance with the transformed up-down rules of Levitt [(1971). J. Acoust. Soc. Am. 49, 467-477]. Local linear psychometric functions were fit to resulting data and used to generate an importance function for VCV words. Results indicate that the adaptive method is reliable and efficient, and produces importance function data consistent with that of the corresponding AI/SII importance function. PMID- 22225058 TI - Relative contribution of target and masker temporal fine structure to the unmasking of consonants in noise. AB - The present study assessed the relative contribution of the "target" and "masker" temporal fine structure (TFS) when identifying consonants. Accordingly, the TFS of the target and that of the masker were manipulated simultaneously or independently. A 30 band vocoder was used to replace the original TFS of the stimuli with tones. Four masker types were used. They included a speech-shaped noise, a speech-shaped noise modulated by a speech envelope, a sentence, or a sentence played backward. When the TFS of the target and that of the masker were disrupted simultaneously, consonant recognition dropped significantly compared to the unprocessed condition for all masker types, except the speech-shaped noise. Disruption of only the target TFS led to a significant drop in performance with all masker types. In contrast, disruption of only the masker TFS had no effect on recognition. Overall, the present data are consistent with previous work showing that TFS information plays a significant role in speech recognition in noise, especially when the noise fluctuates over time. However, the present study indicates that listeners rely primarily on TFS information in the target and that the nature of the masker TFS has a very limited influence on the outcome of the unmasking process. PMID- 22225059 TI - Effects of cross-language voice training on speech perception: whose familiar voices are more intelligible? AB - Previous research has shown that familiarity with a talker's voice can improve linguistic processing (herein, "Familiar Talker Advantage"), but this benefit is constrained by the context in which the talker's voice is familiar. The current study examined how familiarity affects intelligibility by manipulating the type of talker information available to listeners. One group of listeners learned to identify bilingual talkers' voices from English words, where they learned language-specific talker information. A second group of listeners learned the same talkers from German words, and thus only learned language-independent talker information. After voice training, both groups of listeners completed a word recognition task with English words produced by both familiar and unfamiliar talkers. Results revealed that English-trained listeners perceived more phonemes correct for familiar than unfamiliar talkers, while German-trained listeners did not show improved intelligibility for familiar talkers. The absence of a processing advantage in speech intelligibility for the German-trained listeners demonstrates limitations on the Familiar Talker Advantage, which crucially depends on the language context in which the talkers' voices were learned; knowledge of how a talker produces linguistically relevant contrasts in a particular language is necessary to increase speech intelligibility for words produced by familiar talkers. PMID- 22225060 TI - Perception of intonation in Mandarin Chinese. AB - There is a tendency across languages to use a rising pitch contour to convey question intonation and a falling pitch contour to convey a statement. In a lexical tone language such as Mandarin Chinese, rising and falling pitch contours are also used to differentiate lexical meaning. How, then, does the multiplexing of the F(0) channel affect the perception of question and statement intonation in a lexical tone language? This study investigated the effects of lexical tones and focus on the perception of intonation in Mandarin Chinese. The results show that lexical tones and focus impact the perception of sentence intonation. Question intonation was easier for native speakers to identify on a sentence with a final falling tone and more difficult to identify on a sentence with a final rising tone, suggesting that tone identification intervenes in the mapping of F(0) contours to intonational categories and that tone and intonation interact at the phonological level. In contrast, there is no evidence that the interaction between focus and intonation goes beyond the psychoacoustic level. The results provide insights that will be useful for further research on tone and intonation interactions in both acoustic modeling studies and neurobiological studies. PMID- 22225061 TI - Audibility-based predictions of speech recognition for children and adults with normal hearing. AB - This study investigated the relationship between audibility and predictions of speech recognition for children and adults with normal hearing. The Speech Intelligibility Index (SII) is used to quantify the audibility of speech signals and can be applied to transfer functions to predict speech recognition scores. Although the SII is used clinically with children, relatively few studies have evaluated SII predictions of children's speech recognition directly. Children have required more audibility than adults to reach maximum levels of speech understanding in previous studies. Furthermore, children may require greater bandwidth than adults for optimal speech understanding, which could influence frequency-importance functions used to calculate the SII. Speech recognition was measured for 116 children and 19 adults with normal hearing. Stimulus bandwidth and background noise level were varied systematically in order to evaluate speech recognition as predicted by the SII and derive frequency-importance functions for children and adults. Results suggested that children required greater audibility to reach the same level of speech understanding as adults. However, differences in performance between adults and children did not vary across frequency bands. PMID- 22225063 TI - Fine-grained pitch processing of music and speech in congenital amusia. AB - Congenital amusia is a lifelong disorder of music processing that has been ascribed to impaired pitch perception and memory. The present study tested a large group of amusics (n=17) and provided evidence that their pitch deficit affects pitch processing in speech to a lesser extent: Fine-grained pitch discrimination was better in spoken syllables than in acoustically matched tones. Unlike amusics, control participants performed fine-grained pitch discrimination better for musical material than for verbal material. These findings suggest that pitch extraction can be influenced by the nature of the material (music vs speech), and that amusics' pitch deficit is not restricted to musical material, but extends to segmented speech events. PMID- 22225062 TI - Statistical bias in the assessment of binaural benefit relative to the better ear. AB - The comparison of measured binaural performance with the better of two monaural measures (one from each ear) may lead to underestimated binaural benefit due to statistical sampling bias that favors the monaural condition. The mathematical basis of such bias is reviewed and applied to speech reception thresholds measured in 32 bilateral cochlear implant (CI) users for coincident and spatially separated speech and noise. It is shown that the bias increases with test-retest variation and is maximal for uncorrelated samples of identical underlying performance in each ear. When measured differences between ears were assumed to reflect actual underlying performance differences, the bias averaged across the CI users was about 0.2 dB for coincident target and noise, and 0.1 dB for spatially separated conditions. An upper-bound estimate of the bias, based on the assumption that both ears have the same underlying performance and observed differences were due to test-retest variation, was about 0.7 dB regardless of noise location. To the extent that the test-retest variation in these data is comparable to other studies, the results indicate that binaural benefits in bilateral cochlear implant users are not substantially underestimated (on for average) when binaural performance is compared with the better ear in each listening configuration. PMID- 22225064 TI - Absolute pitch correlates with high performance on interval naming tasks. AB - Absolute pitch, the rare ability to identify or produce a musical tone without a reference tone, has been shown to be advantageous in some musical tasks; however, its relevance in musical contexts primarily involving relative pitch has been questioned. To explore this issue, 36 trained musicians-18 absolute pitch possessors and 18 non-possessors with equivalent age of onset and duration of musical training-were tested on interval naming tasks requiring only relative pitch. The intervals to be named were either ascending or descending with separation ranging from 1 to 12 semitones and equally involved all 12 pitch classes. Three different conditions were employed; these used brief sine waves, piano tones, and piano tones preceded by a V7-I chord cadence so as to establish a tonal context. The possession of absolute pitch was strongly correlated with enhanced performance on all these tests of relative pitch. Furthermore, no evidence was found that this absolute pitch avantage depended on key, interval size, or musical context. PMID- 22225065 TI - The violin bow: taper, camber and flexibility. AB - An analytic, small-deflection, simplified model of the modern violin bow is introduced to describe the bending profiles and related strengths of an initially straight, uniform cross-section, stick as a function of bow hair tension. A number of illustrative bending profiles (cambers) of the bow are considered, which demonstrate the strong dependence of the flexibility of the bow on longitudinal forces across the ends of the bent stick. Such forces are shown to be comparable in strength to critical buckling loads causing excessive sideways buckling unless the stick is very straight. Non-linear, large deformation, finite element computations extend the analysis to bow hair tensions comparable with and above the critical buckling strength of the straight stick. The geometric model assumes an expression for the taper of Tourte bows introduced by Vuillaume, which is re-examined and generalized to describe violin, viola and cello bows. A comparison is made with recently published measurements of the taper and bending profiles of a particularly fine bow by Kittel. PMID- 22225066 TI - Model and experimental analysis of oblique incident ultrasound in a tissue layer using doublet mechanics theory. AB - The fundamental framework of doublet mechanics (DM) is used to analyze high frequency ultrasound wave propagation in materials with discrete microstructure. Ultrasonic reflection coefficients were measured from a thin layer of tissue embedded between two glass substrates at oblique incidence. Theoretical calculations for the reflection coefficients of a multi-layered system at oblique angles are performed using both DM theory and the classical continuum mechanics theory (CCM). For example, at the frequency of 10 MHz at incident angle 8 degrees in sample with 30 MUm thickness, the discrepancy in the magnitude of the reflection coefficient between experimental results and theoretical prediction is 15.8% for DM but 79.0% for CCM; similar results at other frequencies and incident angle in the samples with 30 and 60 MUm thickness have also been obtained, which demonstrates that the DM theory can better describe the wave propagation in tissue. The influence of the incident angles and tissue thickness are also discussed in this paper. PMID- 22225067 TI - Estimating material viscoelastic properties based on surface wave measurements: a comparison of techniques and modeling assumptions. AB - Previous studies of the first author and others have focused on low audible frequency (<1 kHz) shear and surface wave motion in and on a viscoelastic material comprised of or representative of soft biological tissue. A specific case considered has been surface (Rayleigh) wave motion caused by a circular disk located on the surface and oscillating normal to it. Different approaches to identifying the type and coefficients of a viscoelastic model of the material based on these measurements have been proposed. One approach has been to optimize coefficients in an assumed viscoelastic model type to match measurements of the frequency-dependent Rayleigh wave speed. Another approach has been to optimize coefficients in an assumed viscoelastic model type to match the complex-valued frequency response function (FRF) between the excitation location and points at known radial distances from it. In the present article, the relative merits of these approaches are explored theoretically, computationally, and experimentally. It is concluded that matching the complex-valued FRF may provide a better estimate of the viscoelastic model type and parameter values; though, as the studies herein show, there are inherent limitations to identifying viscoelastic properties based on surface wave measurements. PMID- 22225069 TI - Vocalization control in Mongolian gerbils (Meriones unguiculatus) during locomotion behavior. AB - The vocalization behavior of Mongolian gerbils, a model animal of auditory physiology, was examined. A pair of gerbils was placed in a chamber, and their species-specific vocalizations and locomotive behaviors were recorded and analyzed. Two types of calls were predominantly produced: high-frequency upward frequency-modulated (HU-FM) calls and low-frequency multi-harmonic frequency modulated (LM-FM) calls. Emission rates of HU-FM calls significantly decreased as the distance between the two gerbils increased, and playback of simulated HU-FM calls increased the emission rates. Acoustic analysis of HU-FM calls showed that the calls exhibited a stereotypic spectro-temporal structure including a fixed inter-onset interval (100-175 ms) and that individual differences in the frequency could convey the body size of the callers. The timing of HU-FM calls was highly synchronized with jump movements when an animal vocalized while jumping, suggesting the existence of tight locomotor-vocal coupling. Conversely, LM-FM calls were observed only when the gerbils tactilely contacted with each other while fighting over a food. These results suggest that Mongolian gerbils change the rates of call emissions and call types (e.g., LM-FM or HU-FM calls) in response to changes in visual and possibly tactile and auditory information. The functions of both calls are discussed in terms of their acoustic structures. PMID- 22225068 TI - Ultrasonic backscatter coefficient quantitative estimates from high-concentration Chinese Hamster Ovary cell pellet biophantoms. AB - Previous work estimated the ultrasonic backscatter coefficient (BSC) from low concentration (volume density <3%) Chinese Hamster Ovary (CHO, 6.7-MUm cell radius) cell pellets. This study extends the work to higher cell concentrations (volume densities: 9.6% to 63%). At low concentration, BSC magnitude is proportional to the cell concentration and BSC frequency dependency is independent of cell concentration. At high cell concentration, BSC magnitude is not proportional to cell concentration and BSC frequency dependency is dependent on cell concentration. This transition occurs when the volume density reaches between 10% and 30%. Under high cell concentration conditions, the BSC magnitude increases slower than proportionally with the number density at low frequencies (ka<1), as observed by others. However, what is new is that the BSC magnitude can increase either slower or faster than proportionally with number density at high frequencies (ka>1). The concentric sphere model least squares estimates show a decrease in estimated cell radius with number density, suggesting that the concentric spheres model is becoming less applicable as concentration increases because the estimated cell radius becomes smaller than that measured. The critical volume density, starting from when the model becomes less applicable, is estimated to be between 10% and 30% cell volume density. PMID- 22225070 TI - Acoustic source separation for the detection of coronary artery sounds. AB - Coronary artery disease (CAD) is the leading cause of death in the United States, being responsible for more than 20% of all deaths in the country. This is in large part due to the difficulty of diagnostic screening for CAD. Phonoangiography seeks to detect CAD via the acoustic signature associated with turbulent flow near an abnormally constricted, or stenosed, region. However, the usefulness of the technique is severely hindered by the low strength of the CAD signal compared to the background noise within the chest. In this work, acoustic finite element analysis (FEA) was performed on physiologically accurate chest geometries to demonstrate the feasibility of an original acoustic source separation methodology for isolating coronary sounds. This approach is based upon pseudoinversion of mixing matrices determined through a combination of experiment and computation. This allows calculation of the sound emitted by the coronary arteries based upon measurements of the acoustic velocity on the chest surface. This work demonstrates the feasibility of such a technique computationally and examines the vulnerability of the proposed approach to measurement errors. PMID- 22225129 TI - Asymmetric glottal jet deflection: differences of two- and three-dimensional models. AB - Flow is studied through a channel with an oscillating orifice mimicking the motion of the glottal-gap during phonation. Simulations with prescribed flow and wall-motion are carried out for different orifice geometries, a 2D slit-like and a 3D lens-like one. Although the jet emerges from a symmetric orifice a significant deflection occurs in case of the slit-like geometry, contrary to the 3D lens-like one. The results demonstrate the dependency of jet entrainment and vortex dynamics on the orifice geometry and the interpretation of asymmetric jet deflection with regard to the relevance of the Coanda effect in the process of human phonation. PMID- 22225130 TI - A connectionist study on the role of pitch in infant-directed speech. AB - Infant-directed speech (IDS) is believed to facilitate language learning. However, the benefit may be either due to clearer acoustic correlates to linguistic structures, or simply increased attention from infants induced by IDS exaggerated prosody. This study investigated the pure effect of IDS pitch on lexical tone learning, with attentional/affective factors removed by using artificial neural networks. Following training with the pitch of Mandarin tones in IDS versus adult-directed speech, the networks yielded equal tonal categorization for both registers. IDS pitch produced no additional linguistic support. IDS pitch appears to strictly play the non-linguistic role of attention/affect, which may indirectly benefit learning. PMID- 22225131 TI - Design and implementation of a shielded underwater vector sensor for laboratory environments. AB - Underwater acoustic vector sensors, for measuring acoustic intensity, are typically used in open water where electromagnetic interference (EMI) is generally not a contributor to overall background noise. However, vector sensors are also useful in a laboratory setting where EMI can be a limiting factor at low frequencies. An underwater vector sensor is designed and built with specific care for EMI immunity. The sensor, and associated signal processing, is shown to reduce background noise at EMI frequencies by 10-50 dB and 10-20 dB across the entire frequency bandwidth, as compared to an identical unshielded vector sensor. PMID- 22225132 TI - Low latency localization of multiple sound sources in reverberant environments. AB - Sound source localization algorithms determine the physical position of a sound source in respect to a listener. For practical applications, a localization algorithm design has to take into account real world conditions like multiple active sources, reverberation, and noise. The application can impose additional constraints on the algorithm, e.g., a requirement for low latency. This work defines the most important constraints for practical applications, introduces an algorithm, which tries to fulfill all requirements as good as possible, and compares it to state-of-the-art sound source localization approaches. PMID- 22225133 TI - Correlations of group velocity, phase velocity, and dispersion with bone density in bovine trabecular bone. AB - The present study investigated the correlations of the group velocity, the phase velocity, and the velocity dispersion with the apparent bone density in bovine trabecular bone in vitro. The phase velocity exhibited the negative dispersion, consistent with the behavior in human trabecular bone. The group and the phase velocities were found to increase with increasing apparent bone density, respectively, exhibiting similar high correlations of r=0.94 and 0.96. The negative dispersion rate exhibited a decreasing dependence on the apparent bone density, with a significant correlation of r=-0.86. PMID- 22225134 TI - Experimental verification of subwavelength acoustic focusing using a near-field array of closely spaced elements. AB - A linear array of closely spaced sound transducers is presented that can produce a subwavelength-focused intensity profile at a distance of a quarter wavelength. This work is related to research on super-resolution using metamaterials in both the acoustic and optical domains. It is designed using the principle of shifted beams, a near-field antenna array theory developed for the subwavelength focusing of electromagnetic waves. Once the spatial sound pattern is characterized for each source, the optimal weights for a minimum beam width can be calculated. An experiment operating at 4 kHz was able to successfully construct a super-focused beam. PMID- 22225135 TI - Communication: Manipulating the singlet-triplet equilibrium in organic biradical materials. AB - We investigated the tunability of the singlet-triplet equilibrium population in the organic biradical 1,4-phenylenedinitrene via magneto-optical spectroscopy. A rich magnetochromic response occurs because applied field increases the concentration of the triplet state species, which has a unique optical signature by comparison with the singlet biradical and the precursor molecule. A Curie-like analysis of the magneto-optical properties allows us to extract the spin gap, which is smaller than previously supposed. These measurements establish the value of local-probe photophysical techniques for magnetic property determination in open-shell systems such as biradicals where a traditional electron paramagnetic resonance Curie law analysis has intrinsic limitations. PMID- 22225136 TI - Communication: Spectroscopic phase and lineshapes in high-resolution broadband sum frequency vibrational spectroscopy: resolving interfacial inhomogeneities of "identical" molecular groups. AB - The ability to achieve sub-wavenumber resolution (0.6 cm(-1)) and a large signal to-noise ratio in high-resolution broadband sum-frequency generation vibrational spectroscopy (HR-BB-SFG-VS) allows for the detailed SFG spectral lineshapes to be used in the unambiguous determination of fine spectral features. Changes in the structural spectroscopic phase in SFG-VS as a function of beam polarization and experimental geometry proved to be instrumental in the identification of an unexpected 2.78 +/- 0.07 cm(-1) spectral splitting for the two methyl groups at the vapor/dimethyl sulfoxide (DMSO, (CH(3))(2)SO) liquid interface as well as in the determination of their orientational angles. PMID- 22225137 TI - Communication: The reason why +c ZnO surface is less stable than -c ZnO surface: first-principles calculation. AB - It has been experimentally shown that an O(-c)-polar ZnO surface is more stable than a Zn(+c)-polar surface in H(2) ambient. We applied first-principles calculations to investigating the polarity dependence on the stability at the electronic level. The calculations revealed that the -c surface terminated with H atom was stable maintaining a wurtzite structure, whereas the +c surface was unstable due to the change of coordination numbers of Zn at the topmost surface from four (wurtzite) to six (rock salt). This causes the generation of O(2) molecules, resulting in instability at the +c surface. PMID- 22225138 TI - Localization scheme for relativistic spinors. AB - A new method to determine localized complex-valued one-electron functions in the occupied space is presented. The approach allows the calculation of localized orbitals regardless of their structure and of the entries in the spinor coefficient matrix, i.e., one-, two-, and four-component Kramers-restricted or unrestricted one-electron functions with real or complex expansion coefficients. The method is applicable to localization schemes that maximize (or minimize) a functional of the occupied spinors and that use a localization operator for which a matrix representation is available. The approach relies on the approximate joint diagonalization (AJD) of several Hermitian (symmetric) matrices which is utilized in electronic signal processing. The use of AJD in this approach has the advantage that it allows a reformulation of the localization criterion on an iterative 2 * 2 pair rotating basis in an analytical closed form which has not yet been described in the literature for multi-component (complex-valued) spinors. For the one-component case, the approach delivers the same Foster-Boys or Pipek-Mezey localized orbitals that one obtains from standard quantum chemical software, whereas in the multi-component case complex-valued spinors satisfying the selected localization criterion are obtained. These localized spinors allow the formulation of local correlation methods in a multi-component relativistic framework, which was not yet available. As an example, several heavy and super heavy element systems are calculated using a Kramers-restricted self-consistent field and relativistic two-component pseudopotentials in order to investigate the effect of spin-orbit coupling on localization. PMID- 22225139 TI - Unambiguous optimization of effective potentials in finite basis sets. AB - The optimization of effective potentials is of interest in density-functional theory (DFT) in two closely related contexts. First, the evaluation of the functional derivative of orbital-dependent exchange-correlation functionals requires the application of optimized effective potential methods. Second, the optimization of the effective local potential that yields a given electron density is important both for the development of improved approximate functionals and for the practical application of embedding schemes based on DFT. However, in all cases this optimization turns into an ill-posed problem if a finite basis set is introduced for the Kohn-Sham orbitals. So far, this problem has not been solved satisfactorily. Here, a new approach to overcome the ill-posed nature of such finite-basis set methods is presented for the optimization of the effective local potential that yields a given electron density. This new scheme can be applied with orbital basis sets of reasonable size and makes it possible to vary the basis sets for the orbitals and for the potential independently, while providing an unambiguous potential that systematically approaches the numerical reference. PMID- 22225140 TI - Exact on-lattice stochastic reaction-diffusion simulations using partial propensity methods. AB - Stochastic reaction-diffusion systems frequently exhibit behavior that is not predicted by deterministic simulation models. Stochastic simulation methods, however, are computationally expensive. We present a more efficient stochastic reaction-diffusion simulation algorithm that samples realizations from the exact solution of the reaction-diffusion master equation. The present algorithm, called partial-propensity stochastic reaction-diffusion (PSRD) method, uses an on lattice discretization of the reaction-diffusion system and relies on partial propensity methods for computational efficiency. We describe the algorithm in detail, provide a theoretical analysis of its computational cost, and demonstrate its computational performance in benchmarks. We then illustrate the application of PSRD to two- and three-dimensional pattern-forming Gray-Scott systems, highlighting the role of intrinsic noise in these systems. PMID- 22225141 TI - Analytic second derivatives for the spin-free exact two-component theory. AB - The formulation and implementation of the spin-free (SF) exact two-component (X2c) theory at the one-electron level (SFX2c-1e) is extended in the present work to the analytic evaluation of second derivatives of the energy. In the X2c-1e scheme, the four-component one-electron Dirac Hamiltonian is block diagonalized in its matrix representation and the resulting "electrons-only" two-component Hamiltonian is then used together with untransformed two-electron interactions. The derivatives of the two-component Hamiltonian can thus be obtained by means of simple manipulations of the parent four-component Hamiltonian integrals and derivative integrals. The SF version of X2c-1e can furthermore exploit available nonrelativistic quantum-chemical codes in a straightforward manner. As a first application of analytic SFX2c-1e second derivatives, we report a systematic study of the equilibrium geometry and vibrational frequencies for the bent ground state of the copper hydroxide (CuOH) molecule. Scalar-relativistic, electron correlation, and basis-set effects on these properties are carefully assessed. PMID- 22225142 TI - Computing the energy of a water molecule using multideterminants: a simple, efficient algorithm. AB - Quantum Monte Carlo (QMC) methods such as variational Monte Carlo and fixed node diffusion Monte Carlo depend heavily on the quality of the trial wave function. Although Slater-Jastrow wave functions are the most commonly used variational ansatz in electronic structure, more sophisticated wave functions are critical to ascertaining new physics. One such wave function is the multi-Slater-Jastrow wave function which consists of a Jastrow function multiplied by the sum of Slater determinants. In this paper we describe a method for working with these wave functions in QMC codes that is easy to implement, efficient both in computational speed as well as memory, and easily parallelized. The computational cost scales quadratically with particle number making this scaling no worse than the single determinant case and linear with the total number of excitations. Additionally, we implement this method and use it to compute the ground state energy of a water molecule. PMID- 22225143 TI - Rigorous formulation of two-parameter double-hybrid density-functionals. AB - A two-parameter extension of the density-scaled double hybrid approach of Sharkas et al. [J. Chem. Phys. 134, 064113 (2011)] is presented. It is based on the explicit treatment of a fraction of multideterminantal exact exchange. The connection with conventional double hybrids is made when neglecting density scaling in the correlation functional as well as second-order corrections to the density. In this context, the fraction a(c) of second-order Moller-Plesset (MP2) correlation energy is not necessarily equal to the square of the fraction a(x) of Hartree-Fock exchange. More specifically, it is shown that a(c)<=a(x)(2), a condition that conventional semi-empirical double hybrids actually fulfill. In addition, a new procedure for calculating the orbitals, which has a better justification than the one routinely used, is proposed. Referred to as lambda(1) variant, the corresponding double hybrid approximation has been tested on a small set consisting of H(2), N(2), Be(2), Mg(2), and Ar(2). Three conventional double hybrids (B2-PLYP, B2GP-PLYP, and PBE0-DH) have been considered. Potential curves obtained with lambda(1)- and regular double hybrids can, in some cases, differ significantly. In particular, for the weakly bound dimers, the lambda(1) variants bind systematically more than the regular ones, which is an improvement in many but not all cases. Including density scaling in the correlation functionals may of course change the results significantly. Moreover, optimized effective potentials based on a partially-interacting system could also be used to generate proper orbitals. Work is currently in progress in those directions. PMID- 22225144 TI - A novel method to describe the interaction pressure between charged plates with application of the weighted correlation approach. AB - Based on the Euler-Lagrange equation for ion density distribution in an inhomogeneous, charged, and hard-sphere fluid, a novel method is proposed to determine the interaction pressure between charged plates. The resulting expression is a sum of distinct physical contributions to the pressure, which involves different contributions to the single-particle direct correlation function. It can, therefore, be conveniently used in any density functional approach to facilitate analysis of the pressure components. In this study, the so called fundamental measure theory (FMT)/weighted correlation approach (WCA) approach is applied to estimate both the hard-sphere and the electric residual contributions to the single-particle direct correlation function, upon the calculation of the ionic density profiles between charged plates. The results, against the Monte Carlo simulations, show that the FMT/WCA approach is superior to the typical FMT/mean spherical approximation approach of the density functional theory in predicting the interaction pressure between charged plates immersed in an electrolyte solution upon various conditions in the primitive model. The FMT/WCA approach can well capture the fine features of the pressure separation dependence, to reproduce not only the shoulder shape and the weak attractions in monovalent electrolytes but also the strongly oscillatory behavior of pressure in divalent electrolytes where pronounced attractions are observed. In addition, it is found that the FMT/WCA approach even has an advantage over the anisotropic, hyper-netted chain approach in that it agrees with the Monte Carlo results to a very good extent with, however, much less computational effort. PMID- 22225145 TI - Anisotropy effect on global minimum structures of clusters: two-center Lennard Jones model. AB - Using a two-center Lennard-Jones (2CLJ) model, the simplest anisotropic case, we investigated how anisotropy affects global minimum structures of clusters and obtained some interesting results. The anisotropy parameter, R, is defined as the ratio of the bond length of 2CLJ dimer to the LJ equilibrium pair separation, where a larger R value means higher anisotropy. For low R values, the structures resemble those of the Lennard-Jones atomic clusters. However, as the pairwise interaction becomes more anisotropic, the "magic numbers" change, and several novel cluster patterns emerge as particularly stable structures, and the global minima change from icosahedral, to polyicosahedral and to novel irregular structures. Moreover, increasing the anisotropy effectively softens the 2CLJ potential. Given the general importance of the LJ cluster as a simple model cluster, 2CLJ model can provide a straightforward and useful analysis of the effect of molecular shape on the structures of clusters. PMID- 22225146 TI - On a relationship between molecular polarizability and partial molar volume in water. AB - We reveal a universal relationship between molecular polarizability (a single molecule property) and partial molar volume in water that is an ensemble property characterizing solute-solvent systems. Since both of these quantities are of the key importance to describe solvation behavior of dissolved molecular species in aqueous solutions, the obtained relationship should have a high impact in chemistry, pharmaceutical, and life sciences as well as in environments. We demonstrated that the obtained relationship between the partial molar volume in water and the molecular polarizability has in general a non-homogeneous character. We performed a detailed analysis of this relationship on a set of ~200 organic molecules from various chemical classes and revealed its fine well organized structure. We found that this structure strongly depends on the chemical nature of the solutes and can be rationalized in terms of specific solute-solvent interactions. Efficiency and universality of the proposed approach was demonstrated on an external test set containing several dozens of polyfunctional and druglike molecules. PMID- 22225147 TI - Quantum entanglement between electronic and vibrational degrees of freedom in molecules. AB - We consider the quantum entanglement of the electronic and vibrational degrees of freedom in molecules with tendencies towards double welled potentials. In these bipartite systems, the von Neumann entropy of the reduced density matrix is used to quantify the electron-vibration entanglement for the lowest two vibronic wavefunctions obtained from a model Hamiltonian based on coupled harmonic diabatic potential-energy surfaces. Significant entanglement is found only in the region in which the ground vibronic state contains a density profile that is bimodal (i.e., contains two separate local maxima). However, in this region two distinct types of density and entanglement profiles are found: one type arises purely from the degeneracy of energy levels in the two potential wells and is destroyed by slight asymmetry, while the other arises through strong interactions between the diabatic levels of each well and is relatively insensitive to asymmetry. These two distinct types are termed fragile degeneracy-induced entanglement and persistent entanglement, respectively. Six classic molecular systems describable by two diabatic states are considered: ammonia, benzene, BNB, pyridine excited triplet states, the Creutz-Taube ion, and the radical cation of the "special pair" of chlorophylls involved in photosynthesis. These chemically diverse systems are all treated using the same general formalism and the nature of the entanglement that they embody is elucidated. PMID- 22225148 TI - An algebraic operator approach to electronic structure. AB - In this paper, we introduce an algebraic approach to electronic structure calculations. Our approach constructs a Jordan algebra based on the second quantized electronic Hamiltonian. From the structure factor of this algebra, we show that we can calculate the energy of the ground electronic state of the Hamiltonian operator. We apply our method to several generalized Hubbard models and show that we can usually obtain a significant fraction of the correlation energy for low-to-moderate values of the electronic repulsion parameter while still retaining the O(L(3)) scaling of the Hartree-Fock algorithm. This surprising result, along with several other observations, suggests that our algebraic approach represents a new paradigm for electronic structure calculations which opens up many new directions for research. PMID- 22225149 TI - Efficient electron dynamics with the planewave-based real-time time-dependent density functional theory: absorption spectra, vibronic electronic spectra, and coupled electron-nucleus dynamics. AB - The electron dynamics with complex third-order Suzuki-Trotter propagator (ST(3)) has been implemented into a planewave (PW) based density functional theory program, and several applications including linear absorption spectra and coupled electron-nucleus dynamics have been calculated. Since the ST(3) reduces the number of Fourier transforms to less than half compared to the fourth-order Suzuki-Trotter propagator (ST(4)), more than twice faster calculations are possible by exploiting the ST(3). We analyzed numerical errors of both the ST(3) and the ST(4) in the presence/absence of an external field for several molecules such as Al(2), N(2), and C(2)H(4). We obtained that the ST(3) gives the same order of numerical errors (10(-5) Ry after 100 fs) as the ST(4). Also, the time evolution of dipole moments, hence the absorption spectrum, is equivalent for both ST(3) and ST(4). As applications, the linear absorption spectrum for an ethylene molecule was studied. From the density difference analysis, we showed that the absorption peaks at 6.10 eV and 7.65 eV correspond to the pi -> 4a(g) and pi -> pi* excitation bands, respectively. We also investigated the molecular vibrational effect to the absorption spectra of an ethylene molecule and the dynamics of a hydrogen molecule after the sigma -> sigma* transition by formulating coupled electron-nucleus dynamics within the Ehrenfest regime. The trajectory of nuclei follows the excited state potential energy curve exactly. PMID- 22225150 TI - High-resolution Fourier-transform extreme ultraviolet photoabsorption spectroscopy of 14N15N. AB - The first comprehensive high-resolution photoabsorption spectrum of (14)N(15)N has been recorded using the Fourier-transform spectrometer attached to the Desirs beamline at the Soleil synchrotron. Observations are made in the extreme ultraviolet and span 100 000-109 000 cm(-1) (100-91.7 nm). The observed absorption lines have been assigned to 25 bands and reduced to a set of transition energies, f values, and linewidths. This analysis has verified the predictions of a theoretical model of N(2) that simulates its photoabsorption and photodissociation cross section by solution of an isotopomer independent formulation of the coupled-channel Schrodinger equation. The mass dependence of predissociation linewidths and oscillator strengths is clearly evident and many local perturbations of transition energies, strengths, and widths within individual rotational series have been observed. PMID- 22225151 TI - Multiphoton dissociative ionization of tert-pentyl bromide near 265 nm. AB - We report on the photodissociation dynamics of tert-pentyl bromide near 265 nm investigated by time-sliced velocity map imaging. The speed and angular distributions have been analyzed for both the ground-state Br((2)P(3/2)) atom (denoted Br) and the spin-orbit excited-state Br((2)P(1/2)) atom (denoted Br*). The speed distributions of Br and Br* atoms are all found to consist of three Gaussian components, which correlate to three independent dissociation pathways on the excited potential energy surfaces: (1) the high translational energy (E(T)) component from the prompt dissociation along the C-Br stretching mode, (2) the middle E(T) component from the repulsive mode along the C-Br stretching coupled with some bending motions, and (3) the low E(T) component from the repulsive mode along the C-Br stretching coupled with more bending motions. More interestingly, we have also observed the tert-C(5)H(11)(+) ions in 263-267 nm. The near-zero kinetic energy distributions extracted from the three tert C(5)H(11)(+) images near 265 nm show the typical characteristics that are attributable to multiphoton dissociative ionization, suggesting the existence of a neutral superexcited state of the parent tert-pentyl bromide molecule. The contribution of bromine atoms formed in this dissociative ionization channel adds in the total relative distribution of low E(T) component in the Br*(Br) formation channel, which reasonably explains the abnormal distributions observed in between the middle and low E(T) components in the Br*(Br) formation channel. PMID- 22225152 TI - Ab initio calculations of the electronic states of AsH2 including dissociation characteristics. AB - Multireference configuration interaction calculations have been carried out for low-lying electronic states of AsH(2). Bending potentials for the ten lowest states of AsH(2) are obtained in C(2v) symmetry for As-H distances fixed at the the ground state equilibrium value of 2.845 a(0), as well as for the minimum energy path constrained to R(1) = R(2). The calculated equilibrium geometries for the X(2)B(1) ground state and the A(2)A(1) excited state agree very well with the previous experimental and theoretical results, whereas the data for the higher lying states are obtained for the first time. Asymmetric potential energy surface (PES) cuts (at R(1) = 2.845 a(0), theta = 90.7 degrees ) and two-dimensional (2D) PESs for the lowest three states are also new. The calculated ab initio data are used for analysis of possible AsH(2) photodissociation channels and predissociation effects. It is shown that the A(2)A(1)-X(2)B(1) transition dipole moment decreases with increasing bending angle, which influences the intensity distribution in the A(0,0,0)->X emission spectrum (v(2)'' bending series), shifting its maximum to smaller v(2)'' quantum numbers. PMID- 22225153 TI - Rotational and vibrational energy transfer in vibrationally excited acetylene at energies near 6560 cm(-1). AB - Collisional energy transfer kinetics of vibrationally excited acetylene has been examined for states with internal energies near 6560 cm(-1). Total population removal rate constants were determined for selected rotational levels of the (1,0,1,0(0),0(0)) and (0,1,1,2(0),0(0)) states. Values in the range of (10-18) * 10(-10) cm(3) s(-1) were obtained. Measurements of state-to-state rotational energy transfer rate constants were also carried out for these states. The rotational energy transfer kinetics was found to be consistent with simple energy gap models for the transfer probabilities. Vibrational transfer out of the (0,1,1,2(0),0(0)) state accounted for no more than 16% of the total removal process. Transfer from (1,0,1,0(0),0(0)) to the u-symmetry (0,2,0,3(1),1(-1)), (0,1,1,2(0),0(0)), and (1,1,0,1(1),1(-1)) states was observed. Applying the principle of detailed balance to these data indicated that vibrational transfer to (1,0,1,0(0),0(0)) accounted for ~0.1% of the population loss from (0,2,0,3(1),1(-1)) or (0,1,1,2(0),0(0)), and 3% of the loss from (1,1,0,1(1),1( 1)). Relative rotational transfer probabilities were obtained for transfer to the g-symmetry (1,1,0,2(0),0(0))/(0,0,2,0(0),0(0)) dyad. These results are related to recent studies of optically pumped acetylene lasers. PMID- 22225154 TI - HNO3-NHx, H2SO4-NHx, CH(O)OH-NHx, and CH3C(O)OH-NHx complexes and their role in the formation of condensation nuclei. AB - The formation of sulfuric acid (H(2)SO(4)), nitric acid (HNO(3)), acetic acid (CH(3)C(O)OH), and formic acid (HC(O))H) complexes with ammonia (NH(3)), amidogen radical (NH(2)), and imidogen radical (NH) was studied using natural bond orbital calculations. The equilibrium structures, binding energies, and harmonic frequencies were calculated for each acid-NH(x) complex using hybrid density functional (B3LYP) and second-order Moller-Plesset perturbation approximation methods with the 6-311++G(3df,3pd) basis set. The results presented here suggest that the effect of NH(2) on the formation of new condensation nuclei will be similar to that of NH(3), but to a lesser degree and confined primarily to complexes with H(2)SO(4) and HNO(3). The NH radical is not expected to play a significant role in the formation of new atmospheric condensation nuclei. PMID- 22225155 TI - Zero kinetic energy photoelectron spectroscopy of jet cooled benzo[a]pyrene from resonantly enhanced multiphoton ionization. AB - We report zero kinetic energy (ZEKE) photoelectron spectroscopy of benzo[a]pyrene (BaP) via resonantly enhanced multiphoton ionization (REMPI). Our analysis concentrates on the vibrational modes of the first excited state (S(1)) and those of the ground cationic state (D(0)). Similar to pyrene, another peri-condensed polycyclic aromatic hydrocarbon we have investigated, the first two electronically excited states of BaP exhibit extensive configuration interactions. However, the two electronic states are of the same symmetry, hence vibronic coupling does not introduce any out-of-plane modes in the REMPI spectrum, and Franck-Condon analysis is qualitatively satisfactory. The ZEKE spectra from the in-plane modes observed in the REMPI spectrum demonstrate strong propensity in preserving the vibrational excitation of the intermediate state. Although several additional bands in combination with the vibrational mode of the intermediate state are identifiable, they are much lower in intensity. This observation implies that the molecular structure of BaP has a tremendous capability to accommodate changes in charge density. All observed bands of the cation are IR active, establishing the role of ZEKE spectroscopy in mapping out far infrared bands for astrophysical applications. PMID- 22225156 TI - Long-range interactions between like homonuclear alkali metal diatoms. AB - Long-range electrostatic and van der Waals coefficients up to terms of order R( 8) have been evaluated by the sum over states method using ab initio and time dependent density functional theory. We employ several widely used density functionals and systematically investigate the convergence of the calculated results with basis set size. Static electric moments and polarizabilities up to octopole order are also calculated. We present values for Li(2) through K(2) which are in good agreement with existing values, in addition to new results for Rb(2) and Cs(2). Interaction potential curves calculated from these results are shown to agree well with high level ab initio theory. Preliminary results are reported that demonstrate the applicability of the method to larger alkali clusters. PMID- 22225157 TI - The ab initio ground-state potential energy function of beryllium monohydride, BeH. AB - The accurate ground-state potential energy function of beryllium monohydride, BeH, has been determined from large-scale ab initio calculations using the multi reference averaged coupled-pair functional (MR-ACPF) method in conjunction with the correlation-consistent core-valence basis sets up to septuple-zeta quality. The effects of electron correlation beyond the MR-ACPF level of approximation were taken into account. The scalar relativistic and adiabatic (the diagonal correction) effects, as well as some of the nonadiabatic effects, were also discussed. The vibration-rotation energy levels of three isotopologues, BeH, BeD, and BeT, were predicted to sub-cm(-1) accuracy. PMID- 22225158 TI - Theoretical characterization of intermolecular vibrational states through the multi-configuration time dependent Hartree approach: the He2,3ICl clusters. AB - Benchmark, full-dimensional calculations on the ground and excited vibrational states for the tetra-, and penta-atomic weakly bound He(2,3)ICl complexes are reported. The representation of the potential energy surfaces includes three-body HeICl potentials parameterized to coupled-cluster singles, doubles, and perturbative triples ab initio data. These terms are important in accurately describing the interactions of such highly floppy systems. The corresponding 6D/9D computations are performed with the multi-configuration time dependent Hartree method, using natural potential fits, and a mode combination scheme to optimize the computational effort in the improved relaxation calculations. For these complexes several low-lying vibrational states are computed, and their binding energies and radial/angular probability density distributions are obtained. We found various isomers which are assigned to different structural models related with combinations of the triatomic isomers, like linear, T-shaped, and antilinear ones. Comparison of these results with recent experimental data is presented, and the quantitative deviations found with respect to the experiment are discussed. PMID- 22225159 TI - Accurate ab initio quartic force fields of cyclic and bent HC2N isomers. AB - Highly correlated ab initio quartic force fields (QFFs) are used to calculate the equilibrium structures and predict the spectroscopic parameters of three HC(2)N isomers. Specifically, the ground state quasilinear triplet and the lowest cyclic and bent singlet isomers are included in the present study. Extensive treatment of correlation effects were included using the singles and doubles coupled cluster method that includes a perturbational estimate of the effects of connected triple excitations, denoted as CCSD(T). Dunning's correlation consistent basis sets cc-pVXZ, X = 3,4,5, were used, and a three-point formula for extrapolation to the one-particle basis set limit was used. Core-correlation and scalar relativistic corrections were also included to yield highly accurate QFFs. The QFFs were used together with second-order perturbation theory (PT) (with proper treatment of Fermi resonances) and variational methods to solve the nuclear Schrodinger equation. The quasilinear nature of the triplet isomer is problematic, and it is concluded that a QFF is not adequate to describe properly all of the fundamental vibrational frequencies and spectroscopic constants (though some constants not dependent on the bending motion are well reproduced by PT). On the other hand, this procedure (a QFF together with either PT or variational methods) leads to highly accurate fundamental vibrational frequencies and spectroscopic constants for the cyclic and bent singlet isomers of HC(2)N. All three isomers possess significant dipole moments, 3.05 D, 3.06 D, and 1.71 D, for the quasilinear triplet, the cyclic singlet, and the bent singlet isomers, respectively. It is concluded that the spectroscopic constants determined for the cyclic and bent singlet isomers are the most accurate available, and it is hoped that these will be useful in the interpretation of high-resolution astronomical observations or laboratory experiments. PMID- 22225160 TI - Nitrogen nucleation in a cryogenic supersonic nozzle. AB - We follow the vapor-liquid phase transition of N(2) in a cryogenic supersonic nozzle apparatus using static pressure measurements. Under our operating conditions, condensation always occurs well below the triple point. Mean field kinetic nucleation theory (MKNT) does a better job of predicting the conditions corresponding to the estimated maximum nucleation rates, J(max) = 10(17+/-1) cm( 3) s(-1), than two variants of classical nucleation theory. Combining the current results with the nucleation pulse chamber measurements of Iland et al. [J. Chem. Phys. 130, 114508-1 (2009)], we use nucleation theorems to estimate the critical cluster properties. Both the theories overestimate the size of the critical cluster, but MKNT does a good job of estimating the excess internal energy of the clusters. PMID- 22225161 TI - Superhalogen properties of CumCln clusters: theory and experiment. AB - Using a combination of density functional theory and anion photoelectron spectroscopy experiment, we have studied the structure and electronic properties of CuCl(n)(-) (n = 1-5) and Cu(2)Cl(n)(-) (n = 2-5) clusters. Prominent peaks in the mass spectrum of these clusters occurring at n = 2, 3, and 4 in CuCl(n)(-) and at n = 3, 4, and 5 in Cu(2)Cl(n)(-) are shown to be associated with the large electron affinities of their neutral clusters that far exceed the value of Cl. While CuCl(n) (n >= 2) clusters are conventional superhalogens with a metal atom at the core surrounded by halogen atoms, Cu(2)Cl(n) (n >= 3) clusters are also superhalogens but with (CuCl)(2) forming the core. The good agreement between our calculated and measured electron affinities and vertical detachment energies confirm not only the calculated geometries of these superhalogens but also our interpretation of their electronic structure and relative stability. PMID- 22225162 TI - Vibrationally averaged post Born-Oppenheimer isotopic dipole moment calculations approaching spectroscopic accuracy. AB - We report an upgrade of the Dalton code to include post Born-Oppenheimer nuclear mass corrections in the calculations of (ro-)vibrational averages of molecular properties. These corrections are necessary to achieve an accuracy of 10(-4) debye in the calculations of isotopic dipole moments. Calculations on the self consistent field level present this accuracy, while numerical instabilities compromise correlated calculations. Applications to HD, ethane, and ethylene isotopologues are implemented, all of them approaching the experimental values. PMID- 22225163 TI - Monte Carlo computer simulations and electron microscopy of colloidal cluster formation via emulsion droplet evaporation. AB - We consider a theoretical model for a binary mixture of colloidal particles and spherical emulsion droplets. The hard sphere colloids interact via additional short-ranged attraction and long-ranged repulsion. The droplet-colloid interaction is an attractive well at the droplet surface, which induces the Pickering effect. The droplet-droplet interaction is a hard-core interaction. The droplets shrink in time, which models the evaporation of the dispersed (oil) phase, and we use Monte Carlo simulations for the dynamics. In the experiments, polystyrene particles were assembled using toluene droplets as templates. The arrangement of the particles on the surface of the droplets was analyzed with cryogenic field emission scanning electron microscopy. Before evaporation of the oil, the particle distribution on the droplet surface was found to be disordered in experiments, and the simulations reproduce this effect. After complete evaporation, ordered colloidal clusters are formed that are stable against thermal fluctuations. Both in the simulations and with field emission scanning electron microscopy, we find stable packings that range from doublets, triplets, and tetrahedra to complex polyhedra of colloids. The simulated cluster structures and size distribution agree well with the experimental results. We also simulate hierarchical assembly in a mixture of tetrahedral clusters and droplets, and find supercluster structures with morphologies that are more complex than those of clusters of single particles. PMID- 22225164 TI - Experimental evidences for molecular origin of low-Q peak in neutron/x-ray scattering of 1-alkyl-3-methylimidazolium bis(trifluoromethanesulfonyl)amide ionic liquids. AB - Short- and long-range liquid structures of [C(n)mIm(+)][TFSA(-)] with n = 2, 4, 6, 8, 10, and 12 have been studied by high-energy x-ray diffraction (HEXRD) and small-angle neutron scattering (SANS) experiments with the aid of MD simulations. Observed x-ray structure factor, S(Q), for the ionic liquids with the alkyl-chain length n > 6 exhibited a characteristic peak in the low-Q range of 0.2-0.4 A(-1), indicating the heterogeneity of their ionic liquids. SANS profiles I(H)(Q) and I(D)(Q) for the normal and the alkyl group deuterated ionic liquids, respectively, showed significant peaks for n = 10 and 12 without no form factor component for large spherical or spheroidal aggregates like micelles in solution. The peaks for n = 10 and 12 evidently disappeared in the difference SANS profiles DeltaI(Q) [=I(D)(Q) - I(H)(Q)], although that for n = 12 slightly remained. This suggests that the long-range correlations originated from the alkyl groups hardly contribute to the low-Q peak intensity in SANS. To reveal molecular origin of the low-Q peak, we introduce here a new function; x-ray structure factor intensity at a given Q as a function of r, S(Q) (peak)(r). The S(Q) (peak)(r) function suggests that the observed low-Q peak intensity depending on n is originated from liquid structures at two r-region of 5-8 and 8-15 A for all ionic liquids examined except for n = 12. Atomistic MD simulations are consistent with the HEXRD and SANS experiments, and then we discussed the relationship between both variations of low-Q peak and real-space structure with lengthening the alkyl group of the C(n)mIm. PMID- 22225165 TI - Insights in quantum dynamical effects in the infrared spectroscopy of liquid water from a semiclassical study with an ab initio-based flexible and polarizable force field. AB - The dynamical properties of liquid water play an important role in many processes in nature. In this paper, we focus on the infrared (IR) absorption spectrum of liquid water based on the linearized semiclassical initial value representation (LSC-IVR) with the local Gaussian approximation (LGA) [J. Liu and W. H. Miller, J. Chem. Phys. 131, 074113 (2009)] and an ab initio based, flexible, polarizable Thole-type model (TTM3-F) [G. S. Fanourgakis and S. S. Xantheas, J. Chem. Phys. 128, 074506 (2008)]. Although the LSC-IVR (LGA) gives the exact result for the isolated three-dimensional shifted harmonic stretching model, it yields a blueshifted peak position for the more realistic anharmonic stretching potential. By using the short-time information of the LSC-IVR correlation function; however, it is shown how one can obtain more accurate results for the position of the stretching peak. Due to the physical decay in the condensed phase system, the LSC IVR (LGA) is a good and practical approximate quantum approach for the IR spectrum of liquid water. The present results offer valuable insight into future attempts to improve the accuracy of the TTM3-F potential or other ab initio-based models in reproducing the IR spectrum of liquid water. PMID- 22225166 TI - Kinetics of azobenzene nitrene oxidation by molecular oxygen in glassy propylene carbonate. AB - The kinetics of azobenzene nitrene oxidation by molecular oxygen dissolved in a matrix was studied in glassy propylene carbonate. The reaction was carried out in excess oxygen within its concentration range 0.008 to 0.048 M. The oxidation kinetics, controlled by oxygen diffusion, is not described by the exponential function. A specific reaction rate decreases in the course of the process. The higher the oxygen concentration in the matrix, the sharper is the decrease in the reaction rate. It is shown that at all concentrations, the oxidation kinetics is described in the framework of the model of heterogeneous matrix with a characteristic size of heterogeneities of 1.5 nm and a dispersion of the activation energy of oxygen molecule jump of 4 kJ/mol. The reaction radius is about 0.5 nm. PMID- 22225167 TI - A molecular dynamics study of water nucleation using the TIP4P/2005 model. AB - Extensive molecular dynamics simulations were conducted using the TIP4P/2005 water model of Abascal and Vega [J. Chem. Phys. 123, 234505 (2005)] to investigate its condensation from supersaturated vapor to liquid at 330 K. The mean first passage time method [J. Wedekind, R. Strey, and D. Reguera, J. Chem. Phys. 126, 134103 (2007); L. S. Bartell and D. T. Wu, 125, 194503 (2006)] was used to analyze the influence of finite size effects, thermostats, and charged species on the nucleation dynamics. We find that the Nose-Hoover thermostat and the one proposed by Bussi et al. [J. Chem. Phys. 126, 014101 (2007)] give essentially the same averages. We identify the maximum thermostat coupling time to guarantee proper thermostating for these simulations. The presence of charged species has a dramatic impact on the dynamics, inducing a marked change towards a pure growth regime, which highlights the importance of ions in the formation of liquid droplets in the atmosphere. It was found a small but noticeable sign preference at intermediate cluster sizes (between 5 and 30 water molecules) corresponding mostly to the formation of the second solvation shell around the ion. The TIP4P/2005 water model predicts that anions induce faster formation of water clusters than cations of the same magnitude of charge. PMID- 22225168 TI - Numerically exact, time-dependent treatment of vibrationally coupled electron transport in single-molecule junctions. AB - The multilayer multiconfiguration time-dependent Hartree (ML-MCTDH) theory within second quantization representation of the Fock space, a novel numerically exact methodology to treat many-body quantum dynamics for systems containing identical particles, is applied to study the effect of vibrational motion on electron transport in a generic model for single-molecule junctions. The results demonstrate the importance of electronic-vibrational coupling for the transport characteristics. For situations where the energy of the bridge state is located close to the Fermi energy, the simulations show the time-dependent formation of a polaron state that results in a pronounced suppression of the current corresponding to the phenomenon of phonon blockade. We show that this phenomenon cannot be explained solely by the polaron shift of the energy but requires methods that incorporate the dynamical effect of the vibrations on the transport. The accurate results obtained with the ML-MCTDH in this parameter regime are compared to results of nonequilibrium Green's function theory. PMID- 22225169 TI - Slow dynamics in a liquid crystal: 1H and 19F NMR relaxometry. AB - Spin-lattice relaxation rates (R(1H) and R(1F)) of two nuclear species ((1)H and (19)F) are measured at different temperatures in the isotropic phase of a liquid crystal (4(')-butoxy-3(')-fluoro-4-isothiocyanatotolane-4OFTOL), over a wide range of Larmor frequency (10 kHz-50 MHz). Their dispersion profiles are found to be qualitatively very different, and the R(1F) in particular shows significant dispersion (varying over two orders of magnitude) in the entire isotropic range, unlike R(1H). The proton spin-lattice relaxation, as has been established, is mediated by time modulation of magnetic dipolar interactions with other protons (case of like spins), and the discernable dispersion in the mid-frequency range, observed as the isotropic to nematic transition is approached on cooling, is indicative of the critical slowing of the time fluctuations of the nematic order. Significant dispersion seen in the R(1F) extending to very low frequencies suggests a distinctly different relaxation path which is exclusively sensitive to the ultra slow modes apparently present in the system. We find that under the conditions of our experiment at low Zeeman fields, spin-rotation coupling of the fluorine with the molecular angular momentum is the dominant mechanism, and the observed dispersion is thus attributed to the presence of slow torques experienced by the molecules, arising clearly from collective modes. Following the arguments advanced to explain similar slow processes inferred from earlier detailed ESR measurements in liquid crystals, we propose that slowly relaxing local structures representing such dynamic processes could be the likely underlying mechanism providing the necessary slow molecular angular momentum correlations to manifest as the observed low frequency dispersion. We also find that the effects of the onset of cross-relaxation between the two nuclear species when their resonance lines start overlapping at very low Larmor frequencies (below ~400 kHz), provide an additional relaxation contribution. PMID- 22225170 TI - The role of the isothermal bulk modulus in the molecular dynamics of super-cooled liquids. AB - Elastic models imply that the energy expended for a flow event in ultra-viscous matter coincides with the elastic work required for deforming and re-arranging the environment of the moving entity. This is quite promising for explaining the strong non-Arrhenius behavior of dynamic quantities of fragile super-cooled liquids. We argue that the activation volume obtained from dielectric relaxation and light-scattering experiments for super-cooled liquids should scale with the Gibbs free energy of activation, with a proportionality constant determined by the isothermal bulk modulus and its pressure derivative, as described by an earlier thermodynamic elastic model. For certain super-cooled liquids the bulk compression transpiring in the local environment, as governed by the isothermal bulk modulus, play a significant role in the reorientational dynamics, with far field density fluctuations and volume changes avoided by shear deformation. PMID- 22225171 TI - Quantum decoherence and quasi-equilibrium in open quantum systems with few degrees of freedom: application to 1H NMR of nematic liquid crystals. AB - Explanation of decoherence and quasi-equilibrium in systems with few degrees of freedom demands a deep theoretical analysis that considers the observed system as an open quantum system. In this work, we study the problem of decoherence of an observed system of quantum interacting particles, coupled to a quantum lattice. Our strategy is based on treating the environment and the system-environment Hamiltonians fully quantum mechanically, which yields a representation of the time evolution operator useful for disentangling the different time scales underlying in the observed system dynamics. To describe the possible different stages of the dynamics of the observed system, we introduce quantum mechanical definitions of essentially isolated, essentially adiabatic, and thermal-contact system-environment interactions. This general approach is then applied to the study of decoherence and quasi-equilibrium in proton nuclear magnetic resonance ((1)H NMR) of nematic liquid crystals. A summary of the original results of this work is as follows. We calculate the decoherence function and apply it to describe the evolution of a coherent spin state, induced by the coupling with the molecular environment, in absence of spin-lattice relaxation. By assuming quantum energy conserving or non-demolition interactions, we identify an intermediate time scale, between those controlled by self-interactions and thermalization, where coherence decays irreversibly. This treatment is also adequate for explaining the buildup of quasi-equilibrium of the proton spin system, via the process we called eigen-selectivity. By analyzing a hypothetical time reversal experiment, we identify two sources of coherence loss which are of a very different nature and give rise to distinct time scales of the spin dynamics: (a) reversible or adiabatic quantum decoherence and (b) irreversible or essentially adiabatic quantum decoherence. Local irreversibility arises as a consequence of the uncertainty introduced by the coupling with an infinite quantum environment. The reversible part can be represented by a semiclassical model, similar to standard line-shape adiabatic models. By exploiting the separation existing between the time scales of the spin coherences and the irreversible decoherence, we present a novel technique to obtain the orientational molecular distribution function for a nematic liquid crystal. The procedure is based on the comparison of the observed coherence time evolution and numerical calculation under the adiabatic quantum decoherence approach. As an example, it is used the experimental free induction decay from a nematic PAA(d6) sample to extract such an orientational distribution. This is the first theoretical description of the experimental liquid crystal NMR signal in the time domain. On the contrary, the irreversible decoherence is intrinsically full-quantum mechanical, as it is governed by the commutation properties of the environment and the spin-lattice Hamiltonians. Consistently, it depends on the molecular correlation in a decisive way, since it vanishes under a mean-field model for the molecular dynamics. The results of this work can contribute to the understanding of the open question of the applicability of the spin-temperature concept in spin systems with few degrees of freedom. PMID- 22225172 TI - Mechanisms of the rotational dynamics of C70 in C70-cubane heteromolecular crystals. AB - Fullerenes and cubane (C(8)H(8)) can be arranged to form heteromolecular crystals that exhibit interesting crystal phases. Experimental measurements indicate a rotor-stator phase for C(60)-cubane crystals in which the C(60) molecules rotate freely whereas cubane molecules are essentially static. A similar phase is found for C(70)-cubane crystals but, due to C(70)'s asymmetry, hindered rotations can be observed in specific crystal phases. Details of the rotational dynamics of the fullerenes in these heteromolecular crystals are difficult to be completely assessed by experiments. To this end, we have performed classical molecular dynamics simulations of C(70)-cubane crystals to investigate the behavior of C(70) fullerenes and cubanes in the face-centered cubic and body-centered tetragonal crystallographic phases. Our simulations show that, in the cubic phase, C(70) molecules are allowed to freely rotate whereas cubanes act as molecular bearings. In the tetragonal phase, the cubane molecules also remain practically fixed and the rotation of C(70) fullerenes becomes hindered. In this phase, C(70) molecules rotate around the fivefold axis, which in turn precesses about the c crystallographic direction of the unit cell. Details regarding the dynamics (e.g., energy barriers, reorientational relaxation processes, and phonon libration coupling) of the C(70) molecules in both crystal phases are discussed. In general, our results agree with previous experimental findings for C(70) cubane crystals. PMID- 22225173 TI - Energy relaxation of intermolecular motions in supercooled water and ice: a molecular dynamics study. AB - We investigate the energy relaxation of intermolecular motions in liquid water at temperatures ranging from 220 K to 300 K and in ice at 220 K using molecular dynamics simulations. We employ the recently developed frequency resolved transient kinetic energy analysis, which provides detailed information on energy relaxation in condensed phases like two-color pump-probe spectroscopy. It is shown that the energy cascading in liquid water is characterized by four processes. The temperature dependences of the earlier three processes, the rotational-rotational, rotational-translational, and translational-translational energy transfers, are explained in terms of the density of states of the intermolecular motions. The last process is the slow energy transfer arising from the transitions between potential energy basins caused by the excitation of the low frequency translational motion. This process is absent in ice because the hydrogen bond network rearrangement, which accompanies the interbasin transitions in liquid water, cannot take place in the solid phase. We find that the last process in supercooled water is well approximated by a stretched exponential function. The stretching parameter, beta, decreases from 1 to 0.72 with decreasing temperature. This result indicates that the dynamics of liquid water becomes heterogeneous at lower temperatures. PMID- 22225174 TI - An activated scheme for resonance energy transfer in conjugated materials. AB - Energy transfer mechanism in conjugated materials has been demonstrated with an activated expression, which is equivalent to Fermi's golden rule. Spectral overlap integrals obtained from simulated spectra of model chromophores agree very well with the results obtained with the activated formula. Although this approach works best for chromophores with spectral profiles resembling a Gaussian distribution, the activated expression formula also performs quite well for chromophores with vibronically resolved spectra. Activation energies for exciton hopping can also be predicted using a phonon coupled exciton relaxation scheme. The accuracy of predictions with this new approach is quite attractive and hence should allow practical applications. PMID- 22225176 TI - A two-dimensional-reference interaction site model theory for solvation structure near solid-liquid interface. AB - We develop a new equation to describe solvation structure near solid-liquid interface at the atomic-level. The developed equation focuses on anisotropy of solvation structure near the interface by using two-dimensional density distribution of solvent along two directions, one of which is perpendicular to the interface and the other is parallel to the interface. As a first application of the equation, we treat a system where a solid modeled by an atomistic wall is immersed in solvent water. The preferential adsorption position of water molecules and the change of water orientation by charging the wall are discussed. PMID- 22225175 TI - Thermal fluctuations in shape, thickness, and molecular orientation in lipid bilayers. AB - We present a unified continuum-level model for bilayer energetics that includes the effects of bending, compression, lipid orientation (tilting relative to the monolayer surface normal), and microscopic noise (protrusions). Expressions for thermal fluctuation amplitudes of several physical quantities are derived. These predictions are shown to be in good agreement with molecular simulations. PMID- 22225177 TI - Hybrid density functional/molecular mechanics studies on activated adsorption of oxygen on zeolite supported gold monomer. AB - Density functional theory calculations on oxygen adsorption over gas phase and faujasite supported Au monomer has been studied using hybrid quantum mechanics/molecular mechanics method, surface integrated molecular orbital molecular mechanics implemented in GAMESS package. Three different oxidation states of Au (0, +1, +3) and three different adsorption modes viz., top, bridge, and dissociative adsorption of oxygen have been considered in our calculations. Redshift in the nu(O-O) value from that in gas phase O(2) indicates activation of O(2) upon adsorption over faujasite supported gold monomer. The activation of O(2) is an important step in the catalytic oxidation of CO. The presence of adsorbed O(2) increases the interaction of the Au monomer with the faujasite support. In faujasite supported cationic Au monomer, O(2) preferably remains bridge bonded to Au rather than being dissociated. PMID- 22225178 TI - Structure, electronic, and optical properties of TiO2 atomic clusters: an ab initio study. AB - Atomic clusters of TiO(2) are modeled by means of state-of-the-art techniques to characterize their structural, electronic and optical properties. We combine ab initio molecular dynamics, static density functional theory, time-dependent density functional theory, and many body techniques, to provide a deep and comprehensive characterization of these systems. TiO(2) clusters can be considered as the starting seeds for the synthesis of larger nanostructures, which are of technological interest in photocatalysis and photovoltaics. In this work, we prove that clusters with anatase symmetry are energetically stable and can be considered as the starting seeds to growth much larger and complex nanostructures. The electronic gap of these inorganic molecules is investigated, and shown to be larger than the optical gap by almost 4 eV. Therefore, strong excitonic effects appear in these systems, much more than in the corresponding bulk phase. Moreover, the use of various levels of theory demonstrates that charge transfer effects play an important role under photon absorption, and therefore the use of adiabatic functionals in time dependent density functional theory has to be carefully evaluated. PMID- 22225179 TI - Density functional theory simulations of amorphous high-kappa oxides on a compound semiconductor alloy: a-Al2O3/InGaAs(100)-(4*2), a-HfO2/InGaAs(100) (4*2), and a-ZrO2/InGaAs(100)-(4*2). AB - The structural properties of a-Al(2)O(3)/In(0.5)Ga(0.5)As, a HfO(2)/In(0.5)Ga(0.5)As, and a-ZrO(2)/In(0.5)Ga(0.5)As interfaces were investigated by density-functional theory (DFT) molecular dynamics (MD) simulations. Realistic amorphous a-Al(2)O(3), a-HfO(2), and a-ZrO(2) samples were generated using a hybrid classical-DFT MD "melt-and-quench" approach and tested against the experimental properties. For each stack type, two systems with different initial oxide cuts at the interfaces were investigated. All stacks were free of midgap states, but some had band-edge states which decreased the bandgaps by 0%-40%. The band-edge states were mainly produced by deformation, intermixing, and bond-breaking, thereby creating improperly bonded semiconductor atoms. The interfaces were dominated by metal-As and O-In/Ga bonds which passivated the clean surface dangling bonds. The valence band-edge states were mainly localized at improperly bonded As atoms, while conduction band-edge states were mainly localized at improperly bonded In and Ga atoms. The DFT-MD simulations show that electronically passive interfaces can be formed between high-kappa oxides dielectrics and InGaAs if the processing does not induce defects because on a short time scale the interface spontaneously forms electrically passive bonds as opposed to bonds with midgap states. PMID- 22225180 TI - The tensile strengths of heterogeneous interfaces: a comparison of static and dynamic first-principles calculations. AB - First-principles molecular dynamics (FPMD) simulations and static quantum chemical (QC) calculations are used to evaluate the tensile strengths, sigma(c), of interfaces consisting of (0001) surfaces of alpha-Al(2)O(3) separated by small organic species. The evaluation of sigma(c) with FPMD was achieved by performing simulations in which the simulation cell was extending in a direction normal to the fracture plane until rupture of the interface occurred. The static QC calculations employed an approach which treated fracture of the interface as a competition between uniform extension of the simulation cell and crack formation at the rupture site, which is analogous to that used in the construction of universal binding energy relationships. The results showed that the static QC calculations accurately reproduced the FPMD simulations with respect to tensile strength and the cell extension at which rupture occurred, provided that the rupture site employed in the static calculations matched the site at which rupture occurred during the FPMD simulations. A simple strategy for identifying the rupture site, even in complex systems containing many potential rupture sites, is proposed. Overall, the work extends the calculation of tensile strengths with static QC methods to highly heterogeneous interfaces, thus providing a computationally efficient alternative to demanding FPMD simulations for this purpose. PMID- 22225181 TI - Adsorption mechanisms of isoxazole and oxazole on Si(100)-2 * 1 surface: Si-N dative bond addition vs. [4+2] cycloaddition. AB - The surface reaction pathways of isoxazole and oxazole on Si(100)-2 * 1 surface were theoretically investigated. They both form a weakly bound Si-N dative bond adduct on Si(100)-2 * 1 surface. In the case of isoxazole, the barrierlessly formed Si-N adduct is the most important surface product, that cannot be easily converted into other species. On the other hand, a facile concerted [4+2](CC) cycloaddition without involving the initial Si-N dative bond adduct was also found in the case of oxazole adsorption. The existence of Diels-Alder reactions is attributed to the particular arrangement of the two heteroatoms of oxazole in such a way that the two Si-C sigma-bonds can be formed in a [4+2] fashion. In short, the unique geometric arrangements and electronegativity of these similar heteroatomic molecules yielded distinctively different surface reaction characteristics. PMID- 22225182 TI - On the adsorption and formation of Pt dimers on the CeO2(111) surface. AB - The direct adsorption of Pt(2) dimers on CeO(2)(111) and their formation from isolated adsorbed Pt atoms have been studied using periodic slab model calculations based on density functional theory and including the so-called on site Hubbard parameter (GGA + U). In the most stable configuration Pt(2) is found to be almost parallel to the surface; the electronic ground state is closed shell and there is no evidence of charge transfer towards or from the surface. The formation of Pt(2) from two single adsorbed Pt atoms involves a rather small energy barrier of ~0.10 eV only. On the contrary, dissociation of adsorbed Pt(2) requires to overcome a considerable barrier of ~1.43 eV. This indicates that once Pt(2) is formed it will remain on the surface, thus likely triggering the growth of larger supported Pt particles. PMID- 22225183 TI - Phase behavior of lyotropic rigid-chain polymer liquid crystal studied by dissipative particle dynamics. AB - The phase behavior of lyotropic rigid-chain liquid crystal polymer was studied by dissipative particle dynamics (DPD) with variations of the solution concentration and temperature. A chain of fused DPD particles was used to represent each mesogenic polymer backbone surrounded with the strongly interacted solvent molecules. The free solvent molecules were modeled as independent DPD particles, where each particle includes a lump of solvent molecules with the volume roughly equal to the solvated polymer segment. The simulation shows that smectic-B (S(B)), smectic-A (S(A)), nematic (N), and isotropic (I) phases exist within certain regions in the temperature and concentration parameter space. The temperature-dependent S(B)/S(A), S(A)/N, and N/I phase transitions occur in the high concentration range. In the intermediate concentration range, the simulation shows coexistence of the anisotropic phases and isotropic phase, where the anisotropic phases can be the S(B), S(A), or N phases. Mole fraction and compositions of the coexisted phases are determined from the simulation, which indicates that concentration of rigid rods in isotropic phase increases as the temperature increases. By fitting the orientational distribution function of the systems, the biphasic coexistence is further confirmed. From the parameter alpha obtained for the simulation, the distribution of the rigid rods in the two coexistence phases is quantitatively evaluated. By using model and simulation methods developed in this work, the phase diagrams of the lyotropic rigid-chain polymer liquid crystal are obtained. Incorporating the solvent particles in the DPD simulation is critical to predict the phase coexistence and obtain the phase diagrams. PMID- 22225184 TI - Free energy of alternating two-component polymer brushes on cylindrical templates. AB - We use computer simulations to investigate the stability of a two-component polymer brush de-mixing on a curved template into phases of different morphological properties. It has been previously shown via molecular dynamics simulations that immiscible chains having different length and anchored to a cylindrical template will phase separate into stripes of different widths oriented perpendicularly to the cylindrical axis. We calculate free energy differences for a variety of stripe widths, and extract simple relationships between the sizes of the two polymers, N(1) and N(2), and the free energy dependence on the stripe width. We explain these relationships using simple physical arguments based upon previous theoretical work on the free energy of polymer brushes. PMID- 22225185 TI - Collapse kinetics of vibrated granular chains. AB - The kinetics of the collapse of the coil state into condensed states is studied with vibrated granular chain composed of N metal beads partially immersed in water. The radius of gyration of the chain, R(g) is measured. For short chains (N < 140), disk-like condensed state is formed and R(g) decreases with time such that the function DeltaR(g)(2) (= R(g)(2) - R(g)(2)(infinity)) = A e(-t/tau), where the relaxation time tau follows a power-law dependence on the chain length N with an exponent gamma = 1.9 +/- 0.2. For the chains with length N >= 300, rod like clusters are observed during the initial stage of collapse and R(g)(2) = R(g)(2)(0) - Bt(beta), with beta = 0.6 +/- 0.1. In the coarsening stage, the exponential dependence of DeltaR(g)(2) on time still holds, however, the relaxation time tau fluctuates and has no simple dependence on N. Furthermore, the time dependence of the averaged radius of gyration of the individual clusters, R(g,cl) can be described by the theory of Lifshitz and Slyozov. A peak in the structure function of long chains is observed in the initial stage of the collapse transition. The collapse transition in the bead chains is a first order phase transition. However, features of the spinodal decomposition are also observed. PMID- 22225187 TI - First passage time distribution of chaperone driven polymer translocation through a nanopore: homopolymer and heteropolymer cases. AB - Combining the advection-diffusion equation approach with Monte Carlo simulations we study chaperone driven polymer translocation of a stiff polymer through a nanopore. We demonstrate that the probability density function of first passage times across the pore depends solely on the Peclet number, a dimensionless parameter comparing drift strength and diffusivity. Moreover it is shown that the characteristic exponent in the power-law dependence of the translocation time on the chain length, a function of the chaperone-polymer binding energy, the chaperone concentration, and the chain length, is also effectively determined by the Peclet number. We investigate the effect of the chaperone size on the translocation process. In particular, for large chaperone size, the translocation progress and the mean waiting time as function of the reaction coordinate exhibit pronounced sawtooth-shapes. The effects of a heterogeneous polymer sequence on the translocation dynamics is studied in terms of the translocation velocity, the probability distribution for the translocation progress, and the monomer waiting times. PMID- 22225186 TI - Cotranscriptional folding kinetics of ribonucleic acid secondary structures. AB - We develop a systematic helix-based computational method to predict RNA folding kinetics during transcription. In our method, the transcription is modeled as stepwise process, where each step is the transcription of a nucleotide. For each step, the kinetics algorithm predicts the population kinetics, transition pathways, folding intermediates, and the transcriptional folding products. The folding pathways, rate constants, and the conformational populations for cotranscription folding show contrastingly different features than the refolding kinetics for a fully transcribed chain. The competition between the transcription speed and rate constants for the transitions between the different nascent structures determines the RNA folding pathway and the end product of folding. For example, fast transcription favors the formation of branch-like structures than rod-like structures and chain elongation in the folding process may reduce the probability of the formation of misfolded structures. Furthermore, good theory experiment agreements suggest that our method may provide a reliable tool for quantitative prediction for cotranscriptional RNA folding, including the kinetics for the population distribution for the whole conformational ensemble. PMID- 22225188 TI - Preferential solvation of lysozyme in water/ethanol mixtures. AB - We provide a quantitative description of the solvation properties of lysozyme in water/ethanol mixtures, which has been obtained by a simultaneous analysis of small-angle neutron scattering and differential scanning calorimetry experiments. All data sets were analyzed by an original method, which integrates the exchange equilibrium model between water and ethanol molecules at the protein surface and activity coefficients data of water/ethanol binary mixtures. As a result, the preferential binding of ethanol molecules at the protein surface was obtained for both native and thermal unfolded protein states. Excess solvation numbers reveal a critical point at ethanol molar fraction ~0.06, corresponding to the triggering of the hydrophobic clustering of alcohol molecules detected in water/ethanol binary mixtures. PMID- 22225190 TI - Note: Accurate ab initio predictions of ionization energies of propargyl and allyl radicals: revisited. PMID- 22225189 TI - Conformational fluctuations of a protein-DNA complex and the structure and ordering of water around it. AB - Protein-DNA binding is an important process responsible for the regulation of genetic activities in living organisms. The most crucial issue in this problem is how the protein recognizes the DNA and identifies its target base sequences. Water molecules present around the protein and DNA are also expected to play an important role in mediating the recognition process and controlling the structure of the complex. We have performed atomistic molecular dynamics simulations of an aqueous solution of the protein-DNA complex formed between the DNA binding domain of human TRF1 protein and a telomeric DNA. The conformational fluctuations of the protein and DNA and the microscopic structure and ordering of water around them in the complex have been explored. In agreement with experimental studies, the calculations reveal conformational immobilization of the terminal segments of the protein on complexation. Importantly, it is discovered that both structural adaptations of the protein and DNA, and the subsequent correlation between them to bind, contribute to the net entropy loss associated with the complex formation. Further, it is found that water molecules around the DNA are more structured with significantly higher density and ordering than that around the protein in the complex. PMID- 22225191 TI - Perspective: Photopyroelectric effects and pyroelectric measurements: "Invited review article: Photopyroelectric calorimeter for the simultaneous thermal, optical, and structural characterization of samples over phase transitions" [Rev. Sci. Instrum. 82, 121101 (2011)]. PMID- 22225192 TI - Invited review article: Photopyroelectric calorimeter for the simultaneous thermal, optical, and structural characterization of samples over phase transitions. AB - The study of thermophysical properties is of great importance in several scientific fields. Among them, the heat capacity, for example, is related to the microscopic structure of condensed matter and plays an important role in monitoring the changes in the energy content of a system. Calorimetric techniques are thus of fundamental importance for characterizing physical systems, particularly in the vicinity of phase transitions where energy fluctuations can play an important role. In this work, the ability of the Photopyroelctric calorimetry to study the versus temperature behaviour of the specific heat and of the other thermal parameters in the vicinity of phase transitions is outlined. The working principle, the theoretical basis, the experimental configurations, and the advantages of this technique, with respect to the more conventional ones, have been described and discussed in detail. The integrations in the calorimetric setup giving the possibility to perform, simultaneously with the calorimetric studies, complementary kind of characterizations of optical, structural, and electrical properties are also described. A review of the results obtained with this technique, in all its possible configurations, for the high temperature resolution studies of the thermal parameters over several kinds of phase transitions occurring in different systems is presented and discussed. PMID- 22225193 TI - Junction temperature measurement of light emitting diode by electroluminescence. AB - Junction temperature (JT) is a key parameter of the performance and lifetime of light emitting diodes (LEDs). In this paper, a mobile instrument system has been developed for the non-contact measurement of JTs of LED under LabVIEW control. The electroluminescence (EL) peak shift of the LED is explored to measure the JT. Commercially available high power blue LEDs are measured. A linear relation between emission peak shift and JT is found. The accuracy of the JT is about 1 degrees C determined by the precision of the emission peak shift, +/-0.03 nm, at 3sigma standard deviation for blue LED. Using this system, on-line temperature rise curves of LED lamps are determined. PMID- 22225194 TI - Scanning absorption nanoscopy with supercontinuum light sources based on photonic crystal fiber. AB - We have experimentally demonstrated a scanning absorption nanoscopy system combining a near-field scanning optical microscope with an absorption spectroscope using supercontinuum radiation generated by coupling a mode-locked Ti:sapphire pulse laser to a nonlinear photonic crystal fiber as a light source. For the performance test of the system, the absorption spectrum and near-field absorption image of Rhodamine 6G were observed. As this system allows us to investigate the absorption properties and distribution of materials with high spatial resolution, it is expected to be effectively applied in various research areas. PMID- 22225195 TI - Measurement of axial neutral density profiles in a microwave discharge ion thruster by laser absorption spectroscopy with optical fiber probes. AB - In order to reveal the physical processes taking place within the "MU10" microwave discharge ion thruster, internal plasma diagnosis is indispensable. However, the ability of metallic probes to access microwave plasmas biased at a high voltage is limited from the standpoints of the disturbance created in the electric field and electrical isolation. In this study, the axial density profiles of excited neutral xenon were successfully measured under ion beam acceleration by using a novel laser absorption spectroscopy system. The target of the measurement was metastable Xe I 5p(5)((2)P(0) (3/2))6s[3/2](0) (2) which absorbed a wavelength of 823.16 nm. Signals from laser absorption spectroscopy that swept a single-mode optical fiber probe along the line of sight were differentiated and converted into axial number densities of the metastable neutral particles in the plasma source. These measurements revealed a 10(18) m( 3) order of metastable neutral particles situated in the waveguide, which caused two different modes during the operation of the MU10 thruster. This paper reports a novel spectroscopic measurement system with axial resolution for microwave plasma sources utilizing optical fiber probes. PMID- 22225196 TI - High coherent bi-chromatic laser with gigahertz splitting produced by the high diffraction orders of acousto-optic modulator used for coherent population trapping experiments. AB - To prepare the coherent population trapping (CPT) states with rubidium and cesium, the commonly used atoms in CPT studies, a coherent bi-chromatic light field with frequency difference of several GHz is a basic requirement. With a 200 MHz center frequency acousto-optic modulator (AOM), we have realized bi-chromatic laser fields with several GHz frequency splits through high diffraction orders. We have experimentally studied the coherence between two frequency components of a bi-chromatic laser beam, which is composed of +/-6 orders with frequency split of 3 GHz diffracted from the same laser beam, and the measured residual phase noise is Deltaphi(2)<0.019 rad(2). The bi-chromatic laser fields were used to prepare CPT states with (85)Rb and (87)Rb atoms, and high contrast CPT signals were obtained. For CPT states preparation, our study result shows that it is a feasible approach to generate the bi-chromatic light field with larger frequency splits through high diffraction orders of AOM. PMID- 22225197 TI - Apparatus for laser-assisted electron scattering in femtosecond intense laser fields. AB - An apparatus for observation of laser-assisted electron scattering (LAES) in femtosecond intense laser fields was developed. The unique apparatus has three essential components, i.e., a photocathode-type ultrashort pulsed-electron gun, a toroidal-type electron energy analyzer enabling simultaneous detection of energy and angular distributions of scattered electrons with high efficiency, and a high repetition-rate data acquisition system combined with a high power 5 kHz Ti:sapphire laser system. These advantages make extremely weak femtosecond-LAES signals distinguishable from the huge elastic scattering signals. A precise method for securing a spatial overlap between three beams, that is, an atomic beam, an electron beam, and a laser beam, and synchronization between the electron and laser pulses is described. As a demonstration of this apparatus, an electron energy spectrum of the LAES signals with 1.4 * 10(12) W/cm(2), 795 nm, 50 fs laser pulses was observed, and the detection limit and further improvements of the apparatus are examined. PMID- 22225198 TI - Versatile multispectral microscope based on light emitting diodes. AB - We describe the development of a novel multispectral microscope, based on light emitting diodes, capable of acquiring megapixel images in thirteen spectral bands from the ultraviolet to the near infrared. The system captures images and spectra in transmittance, reflectance, and scattering modes. We present as examples of applications ground truth measurements for remote sensing and parasitology diagnostics. The system is a general purpose scientific instrument that could be used to develop dedicated simplified instruments with optimal bands and mode selection. PMID- 22225199 TI - Multimode laser beam analyzer instrument using electrically programmable optics. AB - Presented is a novel design of a multimode laser beam analyzer using a digital micromirror device (DMD) and an electronically controlled variable focus lens (ECVFL) that serve as the digital and analog agile optics, respectively. The proposed analyzer is a broadband laser characterization instrument that uses the agile optics to smartly direct light to the required point photodetectors to enable beam measurements of minimum beam waist size, minimum waist location, divergence, and the beam propagation parameter M(2). Experimental results successfully demonstrate these measurements for a 500 mW multimode test laser beam with a wavelength of 532 nm. The minimum beam waist, divergence, and M(2) experimental results for the test laser are found to be 257.61 MUm, 2.103 mrad, 1.600 and 326.67 MUm, 2.682 mrad, 2.587 for the vertical and horizontal directions, respectively. These measurements are compared to a traditional scan method and the results of the beam waist are found to be within error tolerance of the demonstrated instrument. PMID- 22225200 TI - Pulsed laser noise analysis and pump-probe signal detection with a data acquisition card. AB - A photodiode and data acquisition card whose sampling clock is synchronized to the repetition rate of a laser are used to measure the energy of each laser pulse. Simple analysis of the data yields the noise spectrum from very low frequencies up to half the repetition rate and quantifies the pulse energy distribution. When two photodiodes for balanced detection are used in combination with an optical modulator, the technique is capable of detecting very weak pump probe signals (DeltaI/I(0) ~ 10(-5) at 1 kHz), with a sensitivity that is competitive with a lock-in amplifier. Detection with the data acquisition card is versatile and offers many advantages including full quantification of noise during each stage of signal processing, arbitrary digital filtering in silico after data collection is complete, direct readout of percent signal modulation, and easy adaptation for fast scanning of delay between pump and probe. PMID- 22225201 TI - Time-resolved soft x-ray absorption setup using multi-bunch operation modes at synchrotrons. AB - Here, we report on a novel experimental apparatus for performing time-resolved soft x-ray absorption spectroscopy in the sub-ns time scale using non-hybrid multi-bunch mode synchrotron radiation. The present setup is based on a variable repetition rate Ti:sapphire laser (pump pulse) synchronized with the ~500 MHz x ray synchrotron radiation bunches and on a detection system that discriminates and singles out the significant x-ray photon pulses by means of a custom made photon counting unit. The whole setup has been validated by measuring the time evolution of the L(3) absorption edge during the melting and the solidification of a Ge single crystal irradiated by an intense ultrafast laser pulse. These results pave the way for performing synchrotron time-resolved experiments in the sub-ns time domain with variable repetition rate exploiting the full flux of the synchrotron radiation. PMID- 22225202 TI - Long-term frequency stabilization system for external cavity diode laser based on mode boundary detection. AB - We have realized a long-term frequency stabilization system for external cavity diode laser (ECDL) based on mode boundary detection method. In this system, the saturated absorption spectroscopy was used. The current and the grating of the ECDL were controlled by a computer-based feedback control system. By checking if there are mode boundaries in the spectrum, the control system determined how to adjust current to avoid mode hopping. This procedure was executed periodically to ensure the long-term stabilization of ECDL in the absence of mode hops. This diode laser system with non-antireflection coating had operated in the condition of long-term mode-hop-free stabilization for almost 400 h, which is a significant improvement of ECDL frequency stabilization system. PMID- 22225203 TI - Dual beat-frequencies laser Doppler interferometer. AB - A dual beat-frequencies laser Doppler interferometer which can measure high speed back and forth motion is proposed and demonstrated. In this interferometer, the two frequencies, f(1) and f(2), emitted by a Zeeman laser are introduced into the signal beams. They are changed to f(1)' and f(2)' by Doppler shift f(Doppler), which is proportional to the velocity of the object. The use of the two beat signals of |f(1)' - f(2)| and |f(1) - f(2)'| appearing at two photodetectors enables to measure the velocity over the limitation v(c) = lambda(f(1) - f(2))/2. PMID- 22225204 TI - Feedback-controlled laser fabrication of micromirror substrates. AB - Short (40-200 MUs) single focused CO(2) laser pulses of energy ?100 MUJ were used to fabricate high quality concave micromirror templates on silica and fluoride glass. The ablated features have diameters of ~20-100 MUm and average root-mean square (RMS) surface microroughness near their center of less than 0.2 nm. Temporally monitoring the fabrication process revealed that it proceeds on a time scale shorter than the laser pulse duration. We implement a fast feedback control loop (~20 kHz bandwidth) based on the light emitted by the sample that ensures an RMS size dispersion of less than 5% in arrays on chips or in individually fabricated features on an optical fiber tip, a significant improvement over previous approaches using longer pulses and open loop operation. PMID- 22225205 TI - Limitations of the terahertz photomixer. AB - In the paper, Fourier transform has been used for calculations of a refractive index of dielectric samples measured in the terahertz photomixer arrangement. We considered measurement limitations caused by a sampling frequency and a photomixer bandwidth. PMID- 22225206 TI - Optic-microwave mixing velocimeter for superhigh velocity measurement. AB - The phenomenon that a light beam reflected off a moving object experiences a Doppler shift in its frequency underlies practical interferometric techniques for remote velocity measurements, such as velocity interferometer system for any reflector (VISAR), displacement interferometer system for any reflector (DISAR), and photonic Doppler velocimetry (PDV). While VISAR velocimeters are often bewildered by the fringe loss upon high-acceleration dynamic process diagnosis, the optic-fiber velocimeters such as DISAR and PDV, on the other hand, are puzzled by high velocity measurement over 10 km/s, due to the demand for the high bandwidth digitizer. Here, we describe a new optic-microwave mixing velocimeter (OMV) for super-high velocity measurements. By using currently available commercial microwave products, we have constructed a simple, compact, and reliable OMV device, and have successfully obtained, with a digitizer of bandwidth 6 GH only, the precise velocity history of an aluminum flyer plate being accelerated up to 11.2 km/s in a three stage gas-gun experiment. PMID- 22225207 TI - Mapping the magnetic field vector in a fountain clock. AB - We show how the mapping of the magnetic field vector components can be achieved in a fountain clock by measuring the Larmor transition frequency in atoms that are used as a spatial probe. We control two vector components of the magnetic field and apply audio frequency magnetic pulses to localize and measure the field vector through Zeeman spectroscopy. PMID- 22225208 TI - Frequency discriminators for the characterization of narrow-spectrum heterodyne beat signals: application to the measurement of a sub-hertz carrier-envelope offset beat in an optical frequency comb. AB - We describe a radio-frequency (RF) discriminator, or frequency-to-voltage converter, based on a voltage-controlled oscillator phase-locked to the signal under test, which has been developed to analyze the frequency noise properties of an RF signal, e.g., a heterodyne optical beat signal between two lasers or between a laser and an optical frequency comb. We present a detailed characterization of the properties of this discriminator and we compare it to three other commercially available discriminators. Owing to its large linear frequency range of 7 MHz, its bandwidth of 200 kHz and its noise floor below 0.01 Hz(2)/Hz in a significant part of the spectrum, our frequency discriminator is able to fully characterize the frequency noise of a beat signal with a linewidth ranging from a couple of megahertz down to a few hertz. As an example of application, we present measurements of the frequency noise of the carrier envelope offset beat in a low-noise optical frequency comb. PMID- 22225209 TI - High-precision soft x-ray polarimeter at Diamond Light Source. AB - The development and performance of a high-precision polarimeter for the polarization analysis in the soft x-ray region is presented. This versatile, high vacuum compatible instrument is supported on a hexapod to simplify the alignment with a resolution less than 5 MUrad, and can be moved with its own independent control system easily between different beamlines and synchrotron facilities. The polarimeter can also be used for the characterization of reflection and transmission properties of optical elements. A W/B(4)C multilayer phase retarder was used to characterize the polarization state up to 1200 eV. A fast and accurate alignment procedure was developed, and complete polarization analysis of the APPLE II undulator at 712 eV has been performed. PMID- 22225210 TI - Influence of frequency tuning and double-frequency heating on ions extracted from an electron cyclotron resonance ion source. AB - The electromagnetic field within the plasma chamber of an electron cyclotron resonance ion source (ECRIS) and the properties of the plasma waves affect the plasma properties and ion beam production. We have experimentally investigated the "frequency tuning effect" and "double frequency heating" on the CAPRICE ECRIS device. A traveling wave tube amplifier, two microwave sweep generators, and a dedicated experimental set-up were used to carry out experiments in the 12.5-16.5 GHz frequency range. During the frequency sweeps the evolution of the intensity and shape of the extracted argon beam were measured together with the microwave reflection coefficient. A range of different ion source parameter settings was used. Here we describe these experiments and the resultant improved understanding of these operational modes of the ECR ion source. PMID- 22225211 TI - Characterization of plasma ion source utilizing anode spot with positively biased electrode for stable and high-current ion beam extraction. AB - The operating conditions of a rf plasma ion source utilizing a positively biased electrode have been investigated to develop a stably operating, high-current ion source. Ion beam characteristics such as currents and energies are measured and compared with bias currents by varying the bias voltages on the electrode immersed in the ambient rf plasma. Current-voltage curves of the bias electrode and photographs confirm that a small and dense plasma, so-called anode spot, is formed near an extraction aperture and plays a key role to enhance the performance of the plasma ion source. The ion beam currents from the anode spot are observed to be maximized at the optimum bias voltage near the knee of the characteristic current-voltage curve of the anode spot. Increased potential barrier to obstruct beam extraction is the reason for the reduction of the ion beam current in spite of the increased bias current indicating the density of the anode spot. The optimum bias voltage is measured to be lower at higher operating pressure, which is favorable for stable operation without severe sputtering damage on the electrode. The ion beam current can be further enhanced by increasing the power for the ambient plasma without increasing the bias voltage. In the same manner, noble gases with higher atomic number as a feedstock gas are preferable for extracting higher beam current more stably. Therefore, performance of the plasma ion source with a positively biased electrode can be enhanced by controlling the operating conditions of the anode spot in various manners. PMID- 22225212 TI - A novel scaling law relating the geometrical dimensions of a photocathode radio frequency gun to its radio frequency properties. AB - Developing a photocathode RF gun with the desired RF properties of the pi-mode, such as field balance (e(b)) ~1, resonant frequency f(pi) = 2856 MHz, and waveguide-to-cavity coupling coefficient beta(pi) ~1, requires precise tuning of the resonant frequencies of the independent full- and half-cells (f(f) and f(h)), and of the waveguide-to-full-cell coupling coefficient (beta(f)). While contemporary electromagnetic codes and precision machining capability have made it possible to design and tune independent cells of a photocathode RF gun for desired RF properties, thereby eliminating the need for tuning, access to such computational resources and quality of machining is not very widespread. Therefore, many such structures require tuning after machining by employing conventional tuning techniques that are iterative in nature. Any procedure that improves understanding of the tuning process and consequently reduces the number of iterations and the associated risks in tuning a photocathode gun would, therefore, be useful. In this paper, we discuss a method devised by us to tune a photocathode RF gun for desired RF properties under operating conditions. We develop and employ a simple scaling law that accounts for inter-dependence between frequency of independent cells and waveguide-to-cavity coupling coefficient, and the effect of brazing clearance for joining of the two cells. The method has been employed to successfully develop multiple 1.6 cell BNL/SLAC/UCLA type S-band photocathode RF guns with the desired RF properties, without the need to tune them by a tiresome cut-and-measure process. Our analysis also provides a physical insight into how the geometrical dimensions affect the RF properties of the photo-cathode RF gun. PMID- 22225213 TI - Variable dual-frequency electrostatic wave launcher for plasma applications. AB - A variable tuning system is presented for launching two electrostatic waves concurrently in a magnetized plasma. The purpose of this system is to satisfy the wave launching requirements for plasma applications where maximal power must be coupled into two carefully tuned electrostatic waves while minimizing erosion to the launching antenna. Two parallel LC traps with fixed inductors and variable capacitors are used to provide an impedance match between a two-wave source and a loop antenna placed outside the plasma. Equivalent circuit analysis is then employed to derive an analytical expression for the normalized, average magnetic flux density produced by the antenna in this system as a function of capacitance and frequency. It is found with this metric that the wave launcher can couple to electrostatic modes at two variable frequencies concurrently while attenuating noise from the source signal at undesired frequencies. An example based on an experiment for plasma heating with two electrostatic waves is used to demonstrate a procedure for tailoring the wave launcher to accommodate the frequency range and flux densities of a specific two-wave application. This example is also used to illustrate a method based on averaging over wave frequencies for evaluating the overall efficacy of the system. The wave launcher is shown to be particularly effective for the illustrative example--generating magnetic flux densities in excess of 50% of the ideal case at two variable frequencies concurrently--with a high adaptability to a number of plasma dynamics and heating applications. PMID- 22225214 TI - Simple method of determining plasma impedance of streamer discharge in atmospheric air. AB - For atmospheric streamer discharges using a lightning impulse generator, we demonstrate a method of determining the plasma impedance in a streamer region by analyzing the periodic attenuated discharge waveforms having high-frequency components. When the streamer region in the plasma can be treated as an equivalent series circuit model including resistance and inductance elements, the regression waveforms obtained by reducing and smoothing the discharge waveforms are analyzed in the equivalent circuit. We found that the streamer resistance increased exponentially with time after the discharge, whereas the streamer inductance and series impedance were constant at 4.0 Omega for longer than the first period of the discharge waveforms. Moreover, the slope of the regression curve increases more rapidly for the positive streamer resistance than for the negative resistance. Finally, the absolute values of the streamer impedance versus time were 3.3-19 Omega and 3.5-9.0 Omega for positive and negative discharges, respectively. PMID- 22225215 TI - A novel zirconium Kalpha imager for high energy density physics research. AB - We report on the development and characterization of a zirconium Kalpha imager for high energy density physics research. The imager consists of a spherically bent quartz crystal operating at 15.7 keV photon energy. We compare the performance of the imager in terms of integrated reflectivity (R(int)) and temperature dependent collection efficiency (eta(Te)) to that of the widely used Cu Kalpha imager. Our collisional-radiative simulations show that the new imager can be reliably used up to 250 eV plasma temperature. Monte Carlo simulations show that for a 25 MUm thick tracer layer of zirconium, the contribution to Kalpha production from photo-pumping is only 2%. We present, for the first time, 2D spatially resolved images of zirconium plasmas generated by a high intensity short pulse laser interacting with Zr solid targets. PMID- 22225216 TI - A magnetically driven reciprocating probe for tokamak scrape-off layer measurements. AB - A new in situ reciprocating probe system has been developed to provide scrape-off layer measurements in the Tore Supra tokamak. The probe motion is provided by the rotation of an energized coil in the tokamak magnetic field. Simple analytic approximations to the exact numerical model were used to identify the important parameters that govern the dynamics of the system, and optimize the coil geometry, the electrical circuit, and the stiffness of the retaining spring. The linear speed of the probe is directly proportional to the current induced by the coil's rotation; its integral gives the coil position, providing a means to implement real-time feedback control of the probe motion. Two probes were recently mounted on a movable outboard antenna protection limiter in Tore Supra and provided automatic measurements during the 2011 experimental campaign. PMID- 22225217 TI - Study of self-generated magnetic fields in laser produced plasmas using a three channel polaro-interferometer. AB - Self-generated magnetic fields produced in laser plasmas at moderate laser intensities have been measured using a three-channel polaro-interferometer. The main elements of this device are two birefringent calcite wedges placed between two crossed polarizers. Using this device, the spatial profiles of (a) the rotation angle (polarometry), (b) the electron density (interferometry), and (c) the transmitted probe beam intensity (shadowgraphy) are recorded simultaneously using a digital camera with a large format CCD in a single laser shot. Magnetic fields of 2-4 MG had been estimated in aluminum plasma at laser intensities ~10(13) W/cm(2). It is also possible to use this device in other configurations to get time resolved information. PMID- 22225218 TI - A 24 keV liquid-metal-jet x-ray source for biomedical applications. AB - We present a high-brightness 24-keV electron-impact microfocus x-ray source based on continuous operation of a heated liquid-indium/gallium-jet anode. The 30-70 W electron beam is magnetically focused onto the jet, producing a circular 7-13 MUm full width half maximum x-ray spot. The measured spectral brightness at the 24.2 keV In K(alpha) line is 3 * 10(9) photons/(s * mm(2) * mrad(2) * 0.1% BW) at 30 W electron-beam power. The high photon energy compared to existing liquid-metal-jet sources increases the penetration depth and allows imaging of thicker samples. The applicability of the source in the biomedical field is demonstrated by high resolution imaging of a mammography phantom and a phase-contrast angiography phantom. PMID- 22225219 TI - Fabrication of nanoscale patterns in lithium fluoride crystal using a 13.5 nm Schwarzschild objective and a laser produced plasma source. AB - Lithium fluoride (LiF) crystal is a radiation sensitive material widely used as EUV and soft x-ray detector. The LiF-based detector has high resolution, in principle limited by the point defect size, large field of view, and wide dynamic range. Using LiF crystal as an imaging detector, a resolution of 900 nm was achieved by a projection imaging of test meshes with a Schwarzschild objective operating at 13.5 nm. In addition, by imaging of a pinhole illuminated by the plasma, an EUV spot of 1.5 MUm diameter in the image plane of the objective was generated, which accomplished direct writing of color centers with resolution of 800 nm. In order to avoid sample damage and contamination due to the influence of huge debris flux produced by the plasma source, a spherical normal-incidence condenser was used to collect EUV radiation. Together with a description of experimental results, the development of the Schwarzschild objective, the influence of condenser on energy density and the alignment of the imaging system are also reported. PMID- 22225220 TI - Compact ultra-fast vertical nanopositioner for improving scanning probe microscope scan speed. AB - The mechanical design of a high-bandwidth, short-range vertical positioning stage is described for integration with a commercial scanning probe microscope (SPM) for dual-stage actuation to significantly improve scanning performance. The vertical motion of the sample platform is driven by a stiff and compact piezo stack actuator and guided by a novel circular flexure to minimize undesirable mechanical resonances that can limit the performance of the vertical feedback control loop. Finite element analysis is performed to study the key issues that affect performance. To relax the need for properly securing the stage to a working surface, such as a laboratory workbench, an inertial cancellation scheme is utilized. The measured dominant unloaded mechanical resonance of a prototype stage is above 150 kHz and the travel range is approximately 1.56 MUm. The high bandwidth stage is experimentally evaluated with a basic commercial SPM, and results show over 25-times improvement in the scanning performance. PMID- 22225221 TI - A combined scanning tunneling microscope-atomic layer deposition tool. AB - We have built a combined scanning tunneling microscope-atomic layer deposition (STM-ALD) tool that performs in situ imaging of deposition. It operates from room temperature up to 200 degrees C, and at pressures from 1 * 10(-6) Torr to 1 * 10(-2) Torr. The STM-ALD system has a complete passive vibration isolation system that counteracts both seismic and acoustic excitations. The instrument can be used as an observation tool to monitor the initial growth phases of ALD in situ, as well as a nanofabrication tool by applying an electric field with the tip to laterally pattern deposition. In this paper, we describe the design of the tool and demonstrate its capability for atomic resolution STM imaging, atomic layer deposition, and the combination of the two techniques for in situ characterization of deposition. PMID- 22225222 TI - Airtight container for the transfer of atmosphere-sensitive materials into vacuum operated characterization instruments. AB - This paper describes the design and operation of a simple airtight container devised to facilitate the transfer of atmosphere-sensitive samples from a glovebox to the vacuum chamber of an analytical instrument such as a scanning electron microscope. The use of this device for characterizing the microstructure of highly hygroscopic strontium iodide ceramics by scanning electron microscopy is illustrated as an application example. PMID- 22225223 TI - Developments of scanning probe microscopy with stress/strain fields. AB - An innovative stress/strain fields scanning probe microscopy in ultra high vacuum (UHV) environments is developed for the first time. This system includes scanning tunneling microscope (STM) and noncontact atomic force microscope (NC-AFM). Two piezo-resistive AFM cantilever probes and STM probes used in this system can move freely in XYZ directions. The nonoptical frequency shift detection of the AFM probe makes the system compact enough to be set in the UHV chambers. The samples can be bent by an anvil driven by a step motor to induce stress and strain on their surface. With a direct current (dc) power source, the sample can be observed at room and high temperatures. A long focus microscope and a monitor are used to observe the samples and the operation of STM and AFM. Silicon(111) surface in room temperature and silicon(001) surface in high temperature with stress were investigated to check the performance of the scanning probe microscope. PMID- 22225224 TI - Scanning properties of a resonant fiber-optic piezoelectric scanner. AB - We develop a resonant fiber-optic scanner using four piezoelectric elements arranged as a square tube, which is efficient to manufacture and drive. Using coupled-field model based on finite element method, scanning properties of the scanner, including vibration mode, resonant frequency, and scanning range, are numerically studied. We also physically measure the effects of geometry sizes and drive signals on the scanning properties, thus providing a foundation for general purpose designs. A scanner adopted in a prototype of imaging system, with a diameter of ~2 mm and driven by a voltage of 10 V (peak to peak), demonstrates the scanning performance by obtaining an image of resolution target bars. The proposed fiber-optic scanner can be applied to micro-endoscopy that requires two dimensional scanning of fibers. PMID- 22225225 TI - Ultra-flat coplanar electrodes for controlled electrical contact of molecular films. AB - Reliable measurement of electrical charge transport in molecular layers is a delicate task that requires establishing contacts with electrodes without perturbing the molecular structure of the film. We show how this can be achieved by means of novel device consisting of ultra-flat electrodes separated by insulating material to support the molecular film. We show the fabrication process of these electrodes using a replica technique where gold electrodes are embedded in a silicon oxide film deposited on the angstrom-level flat surface of a silicon wafer. Importantly, the co-planarity of the electrode and oxide areas of the substrate was in the sub-nanometer range. We illustrate the capabilities of the system by mapping the distribution of electrical transport pathways in molecular thin films of self-assembled oligothiophene derivatives using conductive atomic force microscopy. In comparison with traditional bottom contact non-coplanar electrodes, the films deposited on our electrodes exhibited contact resistances lower by a factor of 40 than that of the similar but non-coplanar electrodes. PMID- 22225226 TI - Experimental measurements within a phase change metallurgical reactor. AB - The measurement of solidification front evolution is essential for the optimization and control of many important metallurgical processes. However, this measurement is tedious, imprecise, and time consuming. More generally, industry needs reliable instruments for the thermal characterization of phase change reactors. This paper enables researchers with means and instruments to study the thermal behavior of processes involving the transformation of phase change materials up to 1000 degrees C. In this work, an original experimental setup is described to analyze the behavior of two high temperature phase change materials: zinc and molten salts. In particular, it is possible to evaluate the 2D solid solidification front evolution with time. The measurements done with zinc show the presence of two thermal regimes. A solidification rate of 20 mm h(-1) is measured with two different approaches: thermocouples and a mechanical probe. Finally, an infrared camera is also used to make the link between the external thermal behavior and the solidification front evolution inside the reactor. When implemented within an inverse numerical method, the use of this instrument as a new external sensor looks promising. PMID- 22225227 TI - A mirror based polar magneto-optical Kerr effect spectroscopy arrangement. AB - An arrangement is described for performing magneto-optical Kerr effect (MOKE) spectroscopy in polar geometry with a conventional C-frame or H-frame type electromagnet. It uses an additional mirror which eliminates the need for an electromagnet pole piece with an axial hole and allows for easy switching between polar MOKE geometry and longitudinal or transverse MOKE geometries. A theoretical analysis of the photo-elastic modulation based detection scheme shows that the mirror causes a strong mixing of signals corresponding to Kerr rotation and ellipticity. The influence of the mirror is experimentally demonstrated and a procedure is given to correct for it. MOKE spectrum of nickel films obtained using this arrangement is shown to match with reports in the literature. PMID- 22225228 TI - An electron energy loss spectrometer designed for studies of electronic energy losses and spin waves in the large momentum regime. AB - Based on 143 degrees electrostatic deflectors we have realized a new spectrometer for electron energy loss spectroscopy which is particularly suitable for studies on surface spin waves and other low energy electronic energy losses. Contrary to previous designs high resolution is maintained even for diffuse inelastic scattering due to a specific management of the angular aberrations in combination with an angle aperture. The performance of the instrument is demonstrated with high resolution energy loss spectra of surface spin waves on a cobalt film deposited on the Cu(100) surface. PMID- 22225229 TI - Determination of energy scales in few-electron double quantum dots. AB - The capacitive couplings between gate-defined quantum dots and their gates vary considerably as a function of applied gate voltages. The conversion between gate voltages and the relevant energy scales is usually performed in a regime of rather symmetric dot-lead tunnel couplings strong enough to allow direct transport measurements. Unfortunately, this standard procedure fails for weak and possibly asymmetric tunnel couplings, often the case in realistic devices. We have developed methods to determine the gate voltage to energy conversion accurately in the different regimes of dot-lead tunnel couplings and demonstrate strong variations of the conversion factors. Our concepts can easily be extended to triple quantum dots or even larger arrays. PMID- 22225230 TI - Simple spark erosion device based on optical disk or hard disk drive actuators. AB - We present the design of a compact electric discharge device incorporating hard disk or optical disk drive actuators. It is simple enough to be assembled in the absence of a mechanical workshop. The electronic circuit allows the adjustment of current, voltage, and discharge power. The system has been tested with organic dielectric liquids and deionized water and spark conditions; dynamic properties and machining characteristics were investigated. This device can be used to shape materials or to produce powdered samples with low material loss and minimal liquid consumption. PMID- 22225231 TI - Epitaxial Ag wires with a single grain boundary for electromigration. AB - Test structures for electromigration with defined grain boundary configurations can be fabricated using focused ion beam (FIB). We present a novel approach of combining epitaxial growth of Ag islands with FIB milling. Depending on the growth parameters, bi-crystalline Ag islands can be grown on Si(111) surfaces and can be structured into wires by FIB. To avoid doping effects of the used Ga FIB, silicon on insulator (SOI) substrates are used. By cutting through the device layer of the SOI substrate with deep trenches, the Ag wire can be electrically separated from the rest of the substrate. In this way, Ag wires with one isolated grain boundary of arbitrary direction can be assembled. Using scanning electron microscopy we demonstrate the feasibility of our approach. PMID- 22225232 TI - A gain and bandwidth enhanced transimpedance preamplifier for Fourier-transform ion cyclotron resonance mass spectrometry. AB - The nature of the ion signal from a 12-T Fourier-transform ion cyclotron resonance mass spectrometer and the electronic noise were studied to further understand the electronic detection limit. At minimal cost, a new transimpedance preamplifier was designed, computer simulated, built, and tested. The preamplifier design pushes the electronic signal-to-noise performance at room temperature to the limit, because of its enhanced tolerance of the capacitance of the detection device, lower intrinsic noise, and larger flat mid-band gain (input current noise spectral density of around 1 pA/?Hz when the transimpedance is about 85 dBOmega). The designed preamplifier has a bandwidth of ~3 kHz to 10 MHz, which corresponds to the mass-to-charge ratio, m/z, of approximately 18 to 61 k at 12 T. The transimpedance and the bandwidth can be easily adjusted by changing the value of passive components. The feedback limitation of the circuit is discussed. With the maximum possible transimpedance of 5.3 MOmega when using an 0402 surface mount resistor, the preamplifier was estimated to be able to detect ~110 charges in a single scan. PMID- 22225233 TI - Airfoil sampling of a pulsed Laval beam with tunable vacuum ultraviolet synchrotron ionization quadrupole mass spectrometry: application to low temperature kinetics and product detection. AB - A new pulsed Laval nozzle apparatus with vacuum ultraviolet (VUV) synchrotron photoionization quadrupole mass spectrometry is constructed to study low temperature radical-neutral chemical reactions of importance for modeling the atmosphere of Titan and the outer planets. A design for the sampling geometry of a pulsed Laval nozzle expansion has been developed that operates successfully for the determination of rate coefficients by time-resolved mass spectrometry. The new concept employs airfoil sampling of the collimated expansion with excellent sampling throughput. Time-resolved profiles of the high Mach number gas flow obtained by photoionization signals show that perturbation of the collimated expansion by the airfoil is negligible. The reaction of C(2)H with C(2)H(2) is studied at 70 K as a proof-of-principle result for both low-temperature rate coefficient measurements and product identification based on the photoionization spectrum of the reaction product versus VUV photon energy. This approach can be used to provide new insights into reaction mechanisms occurring at kinetic rates close to the collision-determined limit. PMID- 22225234 TI - Carbon fiber reinforced polymer dimensional stability investigations for use on the laser interferometer space antenna mission telescope. AB - The laser interferometer space antenna (LISA) is a mission designed to detect low frequency gravitational waves. In order for LISA to succeed in its goal of direct measurement of gravitational waves, many subsystems must work together to measure the distance between proof masses on adjacent spacecraft. One such subsystem, the telescope, plays a critical role as it is the laser transmission and reception link between spacecraft. Not only must the material that makes up the telescope support structure be strong, stiff, and light, but it must have a dimensional stability of better than 1 pm Hz(-1/2) at 3 mHz and the distance between the primary and the secondary mirrors must change by less than 2.5 MUm over the mission lifetime. Carbon fiber reinforced polymer is the current baseline material; however, it has not been tested to the pico meter level as required by the LISA mission. In this paper, we present dimensional stability results, outgassing effects occurring in the cavity and discuss its feasibility for use as the telescope spacer for the LISA spacecraft. PMID- 22225235 TI - Study on electrodynamic sensor of multi-modality system for multiphase flow measurement. AB - Accurate measurement of multiphase flows, including gas/solids, gas/liquid, and liquid/liquid flows, is still challenging. In principle, electrical capacitance tomography (ECT) can be used to measure the concentration of solids in a gas/solids flow and the liquid (e.g., oil) fraction in a gas/liquid flow, if the liquid is non-conductive. Electrical resistance tomography (ERT) can be used to measure a gas/liquid flow, if the liquid is conductive. It has been attempted to use a dual-modality ECT/ERT system to measure both the concentration profile and the velocity profile by pixel-based cross correlation. However, this approach is not realistic because of the dynamic characteristics and the complexity of multiphase flows and the difficulties in determining the velocities by cross correlation. In this paper, the issues with dual modality ECT/ERT and the difficulties with pixel-based cross correlation will be discussed. A new adaptive multi-modality (ECT, ERT and electro-dynamic) sensor, which can be used to measure a gas/solids or gas/liquid flow, will be described. Especially, some details of the electrodynamic sensor of multi-modality system such as sensing electrodes optimum design, electrostatic charge amplifier, and signal processing will be discussed. Initial experimental results will be given. PMID- 22225236 TI - A high-sensitive static vector magnetometer based on two vibrating coils. AB - A static vector magnetometer based on two-dimensional (2D) vibrating coils actuated by a piezoelectric cantilever is presented. Two individual sensing coils are orthogonally fastened at the tip of cantilever and piezoelectric sheets are used to excite the cantilever bending. Due to off-axis coupler on the tip, the cantilever generates bending and twisting vibrations simultaneously on their corresponding resonant frequencies, realizing the 2D rotating vibrations of the coils. According to Faraday-Lenz Law, output voltages are induced from the coils. They are amplified by a pre-amplifier circuit, decoupled by a phase-sensitive detector, and finally used to calculate the vector of magnetic field at the coil location. The coil head of a prototype magnetometer possesses a dc sensitivity of around 10 MUV/Gs with a good linearity in the measuring range from 0 to 16 MUT. The corresponding noise level is about 13.1 nT in the bandwidth from 0.01 Hz to 1 Hz. PMID- 22225237 TI - Efficient heating with a controlled microwave field. AB - To uncover the intriguing non-thermal microwave effect, an experiment was conducted using an amplifier rather than an oscillator as the radiation source, which was injected into an applicator with strong electromagnetic field enhancement. The characteristics of the applicator are discussed and the enhancement of the microwave field is illustrated and explained. Thermal distribution is simulated based on the calculated microwave field profile. It was demonstrated that the proposed system heated a SiC susceptor to a temperature of 637 degrees C with the input power of 60 W. The reasons for such an efficient heating are discussed. PMID- 22225238 TI - Ultrafast electrical measurements of polarization dynamics in ferroelectric thin film capacitors. AB - We have developed a new approach to measure fast electrical signals during polarization switching in ferroelectric thin-film capacitors. This article describes a simple method for probing transient currents and voltages in a broad range of time scales from microseconds to hundreds of picoseconds. In order to test our approach, we probed polarization dynamics in commercial PbZr(0.2)Ti(0.8)O(3) ferroelectric capacitors in which the measured switching time was as fast as 1.7 ns. PMID- 22225239 TI - Prognostic monitoring of aircraft wiring using electrical capacitive tomography. AB - Electrical capacitive tomography (ECT) has been used to monitor sections of aircraft wiring, as a tool for prognostic analysis. To apply the principles of ECT across a cross section of only 4 mm, modification of the basic circuit was required. Additionally, a more novel method of placing the necessary electrodes was needed, this being accomplished by etching them from flexible copper sheeting and wrapping them inside the perimeter of an enclosure. Results showed that at this small scale, it was possible to determine the position of a wire-under-test inside the 4 mm diameter enclosure to about 0.1 mm, and that by measuring capacitance between pairs, it was also possible to determine whether or not the insulation of wire passed between the electrodes was damaged. With more than one wire-under-test present, it was possible to determine whether or not damage was present, and if so, which wire was damaged. By detecting insulation damage in this way, ECT has proven to be a useful tool in prognostic monitoring, helping faults to be found before they become safety-critical onboard an aircraft. PMID- 22225240 TI - Photoacoustic technique for simultaneous measurements of thermal effusivity and absorptivity of pigments in liquid solution. AB - A photoacoustic (PA) methodology, in the transmission configuration, for simultaneous measurements of thermal effusivity and molar absorption coefficient (absorptivity) for pigments in liquid solution is introduced. The analytical treatment involves a self-normalization procedure for the PA signal, as a function of the modulation frequency, for a strong absorbing material in the thermally thin regime, when the light travels across the sample under study. Two fitted parameters are obtained from the analysis of the self-normalized PA amplitude and phase, one of them proportional to the sample's optical absorption coefficient and from which, taking it for a series of samples at different concentrations, the pigment's absorptivity in liquid solution can be measured, the other one yields the sample's thermal effusivity. Methylene blue's absorptivity in distilled water was measured with this methodology at 658 nm, finding good agreement with the corresponding one reported in the literature. PMID- 22225241 TI - Prediction of atomic force microscope probe dynamics through the receptance coupling method. AB - The increased growth in the use of tip-based sensing, manipulations, and fabrication of devices in atomic force microscopy (AFM) necessitates the accurate prediction of the dynamic behavior of the AFM probe. The chip holder, to which the micro-sensing device is attached, and the rest of the AFM system can affect the overall dynamics of the probe. In order to consider these boundary effects, we propose a novel receptance coupling method to mathematically combine the dynamics of the AFM setup and probe, based on the equilibrium and compatibility conditions at the joint. Once the frequency response functions of displacement over force at the tool tip are obtained, the dynamic interaction forces between the tip and the sample in nanoscale can be determined by measuring the probe tip displacement. PMID- 22225242 TI - Torsional bridge setup for the characterization of integrated circuits and microsensors under mechanical shear stress. AB - We present a torsional bridge setup for the electro-mechanical characterization of devices integrated in the surface of silicon beams under mechanical in-plane shear stress. It is based on the application of a torsional moment to the longitudinal axis of the silicon beams, which results in a homogeneous in-plane shear stress in the beam surface. The safely applicable shear stresses span the range of +/-50 MPa. Thanks to a specially designed clamping mechanism, the unintended normal stress typically stays below 2.5% of the applied shear stress. An analytical model is presented to compute the induced shear stress. Numerical computations verify the analytical results and show that the homogeneity of the shear stress is very high on the beam surface in the region of interest. Measurements with piezoresistive microsensors fabricated using a complementary metal-oxide-semiconductor process show an excellent agreement with both the computational results and comparative measurements performed on a four-point bending bridge. The electrical connection to the silicon beam is performed with standard bond wires. This ensures that minimal forces are applied to the beam by the electrical interconnection to the external instrumentation and that devices with arbitrary bond pad layout can be inserted into the setup. PMID- 22225243 TI - Preliminary characterization of a low-powered microwave induced flame plasma for direct organic solvent nebulization. AB - A low powered (<90 W) microwave-induced plasma has been generated at atmospheric pressure by using a Beenakker cavity, a laboratory constructed torch, and a gas mixture of argon (400 ml/min), hydrogen (100 ml/min), and air (130 ml/min). This plasma has an excitation temperature of 3300-3500 K, electron number density of 7 * 10(14) cm(-3), and easily accepts direct methanol and ethanol introduction with a 1 ml/min solution nebulization rate. Detection limits (3sigma) obtained from the atomic emission signals of Li, Sr, and Cr in water are 15, 120, and 290 ng/ml, respectively. Similarly, detection limits for the metals in methanol are 15, 120, and 260 ng/ml, respectively, and in ethanol they are 25, 360, and 330 ng/ml, respectively. The linear dynamic range is greater than three orders of magnitude. PMID- 22225244 TI - Fabrication of large scale nanostructures based on a modified atomic force microscope nanomechanical machining system. AB - The atomic force microscope (AFM) tip-based nanomechanical machining has been demonstrated to be a powerful tool for fabricating complex 2D/3D nanostructures. But the machining scale is very small, which holds back this technique severely. How to enlarge the machining scale is always a major concern for the researches. In the present study, a modified AFM tip-based nanomechanical machining system is established through combination of a high precision X-Y stage with the moving range of 100 mm * 100 mm and a commercial AFM in order to enlarge the machining scale. It is found that the tracing property of the AFM system is feasible for large scale machining by controlling the constant normal load. Effects of the machining parameters including the machining direction and the tip geometry on the uniform machined depth with a large scale are evaluated. Consequently, a new tip trace and an increasing load scheme are presented to achieve a uniform machined depth. Finally, a polymer nanoline array with the dimensions of 1 mm * 0.7 mm, the line density of 1000 lines/mm and the average machined depth of 150 nm, and a 20 * 20 polymer square holes array with the scale of 380 MUm * 380 MUm and the average machined depth of 250 nm are machined successfully. The uniform of the machined depths for all the nanostructures is acceptable. Therefore, it is verified that the AFM tip-based nanomechanical machining method can be used to machine millimeter scale nanostructures. PMID- 22225245 TI - Simple alignment technique for polarisation maintaining fibres. AB - We describe a simple technique for rapid alignment of input state of polarisation with respect to the preferred axis of polarisation maintaining fibres. In this technique a combination of a half-wave and a quarter-wave plate is used to turn the polarisation of incoming beam and to compensate for stress-induced perturbation of polarisation states in a laid-out fibre, respectively. The angular alignment technique is tested with temperature excursion on the fibre. The technique is easy to implement, affordable, and gives quick and accurate alignment. PMID- 22225246 TI - Development of an x-ray diffraction camera used in magnetic fields up to 10 T. AB - A high-field x-ray diffraction (HF-XRD) camera was developed to observe structural changes of magnetic materials in magnetic fields up to 10 T. The instrument mainly consists of a Debye-Scherrer-type camera with a diameter of 80.1 mm, a 10-T cryocooled superconducting magnet with a 100-mm room-temperature bore, an x-ray source, a power supply, and a chiller for the x-ray source. An x ray detector (image plate) in the HF-XRD camera can be taken out and inserted into the magnet without changing the sample position. The performance of the instrument was tested by measuring the HF-XRD for silicon and ferromagnetic MnBi powders. A change of x-ray diffraction pattern was observed due to the magnetic orientation of MnBi, showing that the instrument is useful for studying field induced orientation processes and structural properties of field-controlled materials. PMID- 22225247 TI - Single x-ray transmission system for bone mineral density determination. AB - Bones are the support of the body. They are composed of many inorganic compounds and other organic materials that all together can be used to determine the mineral density of the bones. The bone mineral density is a measure index that is widely used as an indicator of the health of the bone. A typical manner to evaluate the quality of the bone is a densitometry study; a dual x-ray absorptiometry system based study that has been widely used to assess the mineral density of some animals' bones. However, despite the success stories of utilizing these systems in many different applications, it is a very expensive method that requires frequent calibration processes to work properly. Moreover, its usage in small species applications (e.g., rodents) has not been quite demonstrated yet. Following this argument, it is suggested that there is a need for an instrument that would perform such a task in a more reliable and economical manner. Therefore, in this paper we explore the possibility to develop a new, affordable, and reliable single x-ray absorptiometry system. The method consists of utilizing a single x-ray source, an x-ray image sensor, and a computer platform that all together, as a whole, will allow us to calculate the mineral density of the bone. Utilizing an x-ray transmission theory modified through a version of the Lambert Beer law equation, a law that expresses the relationship among the energy absorbed, the thickness, and the absorption coefficient of the sample at the x rays wavelength to calculate the mineral density of the bone can be advantageous. Having determined the parameter equation that defines the ratio of the pixels in radiographies and the bone mineral density [measured in mass per unit of area (g/cm(2))], we demonstrated the utility of our novel methodology by calculating the mineral density of Wistar rats' femur bones. PMID- 22225248 TI - Improved measurement for volatile particles: vapor-particle separator design and laboratory tests. AB - Sampling and measurement of volatile particles is a challenging task. It has been hampered by lack of a reliable technique capable of accurately capturing the phase-partition process of the pollutants without generating bias and artifacts in the data. The objective of this research is to design a new vapor-particle separation technique for performing the phase separation on-line (the sampling aspect), which, simultaneously, enables characterization of the vapors and particles. The new vapor-particle separator (VPS) consists of a thin metallic microporous membrane for (1) extraction of vapor molecules that are thermally desorbed from the condensed particulate phases and (2) collection of the vapors for subsequent chemical analysis. We evaluated this new separator using synthetic particles made of nonvolatile and or semi-volatile chemicals, and reported the laboratory test results in this paper. The laboratory particle test results showed reasonably high particle transmission efficiency across all particle sizes. The thermal dynamics of nanoparticles was succinctly observed on-line. The results successfully demonstrated the ability of VPS to separate particles and vapors thus enabling a faithful observation of the thermal behavior. We believe the new technology will make a great contribution to the measurement of volatile particles. PMID- 22225249 TI - Measurement of momentum transfer due to adhesive forces: on-ground testing of in space body injection into geodesic motion. AB - In the frame of many scientific space missions, a massive free-falling object is required to mark a geodesic trajectory, i.e., to follow inside a spacecraft an orbit that is determined only by the planetary gravity field. The achievement of high-purity geodesic trajectories sets tight design constraints on the reference sensor that hosts and controls the reference body. Among these, a mechanism may be required to cage the reference body during the spacecraft launch and to inject it into the geodesic trajectory once on-orbit. The separation of the body from the injection mechanism must be realized against the action of adhesion forces, and in the worst case this is performed dynamically, relying on the body's inertia through a quick retraction of the holding finger(s). Unfortunately, this manoeuvre may not avoid transferring some momentum to the body, which may affect or even jeopardize the subsequent spacecraft control if the residual velocity is too large. The transferred momentum measurement facility (TMMF) was developed to reproduce representative conditions of the in-flight dynamic injection and to measure the transferred momentum to the released test mass. In this paper, we describe the design and development of the TMMF together with the achieved measurement performance. PMID- 22225250 TI - Tip-tilt mirror suspension: beam steering for advanced laser interferometer gravitational wave observatory sensing and control signals. AB - We describe the design of a small optic suspension system, referred to as the tip tilt mirror suspension, used to isolate selected small optics for the interferometer sensing and control beams in the advanced LIGO gravitational wave detectors. The suspended optics are isolated in all 6 degrees of freedom, with eigenmode frequencies between 1.3 Hz and 10 Hz. The suspended optic has voice coil actuators which provide an angular range of +/-4 mrad in the pitch and yaw degrees of freedom. PMID- 22225251 TI - Higher order parametric excitation modes for spaceborne quadrupole mass spectrometers. AB - This paper describes a technique to significantly improve upon the mass peak shape and mass resolution of spaceborne quadrupole mass spectrometers (QMSs) through higher order auxiliary excitation of the quadrupole field. Using a novel multiresonant tank circuit, additional frequency components can be used to drive modulating voltages on the quadrupole rods in a practical manner, suitable for both improved commercial applications and spaceflight instruments. Auxiliary excitation at frequencies near twice that of the fundamental quadrupole RF frequency provides the advantages of previously studied parametric excitation techniques, but with the added benefit of increased sensed excitation amplitude dynamic range and the ability to operate voltage scan lines through the center of upper stability islands. Using a field programmable gate array, the amplitudes and frequencies of all QMS signals are digitally generated and managed, providing a robust and stable voltage control system. These techniques are experimentally verified through an interface with a commercial Pfeiffer QMG422 quadrupole rod system. When operating through the center of a stability island formed from higher order auxiliary excitation, approximately 50% and 400% improvements in 1% mass resolution and peak stability were measured, respectively, when compared with traditional QMS operation. Although tested with a circular rod system, the presented techniques have the potential to improve the performance of both circular and hyperbolic rod geometry QMS sensors. PMID- 22225252 TI - Nanohertz frequency determination for the gravity probe B high frequency superconducting quantum interference device signal. AB - In this paper, we present a method to measure the frequency and the frequency change rate of a digital signal. This method consists of three consecutive algorithms: frequency interpolation, phase differencing, and a third algorithm specifically designed and tested by the authors. The succession of these three algorithms allowed a 5 parts in 10(10) resolution in frequency determination. The algorithm developed by the authors can be applied to a sampled scalar signal such that a model linking the harmonics of its main frequency to the underlying physical phenomenon is available. This method was developed in the framework of the gravity probe B (GP-B) mission. It was applied to the high frequency (HF) component of GP-B's superconducting quantum interference device signal, whose main frequency f(z) is close to the spin frequency of the gyroscopes used in the experiment. A 30 nHz resolution in signal frequency and a 0.1 pHz/s resolution in its decay rate were achieved out of a succession of 1.86 s-long stretches of signal sampled at 2200 Hz. This paper describes the underlying theory of the frequency measurement method as well as its application to GP-B's HF science signal. PMID- 22225253 TI - Pressure-driven capillary viscometer: fundamental challenges in transient flow viscometry. AB - We describe an unsteady pressure-driven capillary viscometer, in which the liquid under test is forced through a capillary tube by compressed-air pressure. The principle of operation involves measurement of the driving pressure versus time that decays progressively as the fluid flows and covers continuously a broad shear rate range in a single measurement. The viscosity is determined by curve fitting of the experimental data to the explicit expression for the transient pressure as a function of time. A laboratory bench test shows the validity of the theoretical approach for viscosity determination of both Newtonian and non Newtonian liquids. PMID- 22225254 TI - Development of a new dynamic gas flow-control system in the pressure range of 1 Pa-133 Pa. AB - A new flow-control system (FCS-705) has been developed at Korea Research Institute of Standards and Science. The system is intended for calibration of vacuum gauges in the pressure range of 1 Pa-133 Pa by comparison method. This paper describes some basic characteristics of the system including; (1) the design and construction of the system, (2) the generation of stable pressures in the chamber, (3) achieving high upstream pressure limit by installing a short duct in the by-pass pumping line, and (4) investigation of the gas flow regimes within the short duct. PMID- 22225255 TI - A method for fine positioning of diagnostic packages in inertial confinement fusion experiments. AB - A method based on binocular vision servoing for positioning of a diagnostic package in inertial confinement fusion (ICF) experiments is presented. The general diagnostic instrument manipulator will provide precision three dimension positioning and alignment-to-target capability in ICF experiments. In this work, we focus on the final precise automatic positioning with a binocular vision system. A three dimension image projection vector (IPV), which has an almost linear relationship with the target position in 3D space under the condition of weak perspective, is introduced to extract target position information from binocular image. The difference of the IPV between the current image and the desired image will be used as the input of servo controller. A differential motion model was found for the hybrid manipulator with three degrees of freedom. With this model and the said IPV, the servo strategy will be dramatically simplified compare with general image based visual servo in which the image Jacobian matrix needs estimated online. The experiment result implies that the locating accuracy of the manipulator is less than two pixels. This method can also be used in micromanipulation visual servo field. PMID- 22225256 TI - Note: Phase-locked loop with a voltage controlled oscillator based on a liquid crystal cell as variable capacitance. AB - A phase-locked loop is demonstrated using a twisted-nematic liquid crystal cell as a capacitance that can be varied as a function of applied voltage. The system is formed by a phase detector, a low-pass filter, as well as a voltage controlled oscillator including such variable capacitance. A theoretical study is proposed and experimentally validated. Capture and locked ranges of hundreds of kHz have been obtained for the configuration used in this circuit. An application as frequency demodulator using a practical implementation of this circuit has been demonstrated. PMID- 22225257 TI - Note: Intensity control of a phase-shift based laser scanner for reducing distance errors caused by varying surface reflectivity. AB - In the phase-shift measurement method, the distance traveled by light can be obtained on the basis of the phase difference between the reference signal and the measured signal. When a different colored object is measured, the intensity of the measured signal varies greatly, even at the same distance, which causes a different phase delay owing to the wide dynamic range input into the signal processing circuit. In this study, an intensity control method is proposed to solve this phase delay problem. PMID- 22225258 TI - Note: Higher resolution Brillouin spectroscopy by offset stabilization of a tandem Fabry-Perot interferometer. AB - A simple modification to a Sandercock-type tandem Fabry-Perot interferometer is demonstrated. By adding an independent reference laser with temperature tunability, narrow Brillouin lines that are tens GHz shifted from the Rayleigh line can be recorded with much higher frequency resolution than in the original system. PMID- 22225259 TI - Note: Optimization of piezoresistive response of pure carbon nanotubes networks as in-plane strain sensors. AB - The use of carbon nanotubes (CNT) for the application in in-plane strain detection is promising. In recent years, in-plane strain sensors constructed from CNT networks have been developed; however, few studied optimization of these sensors. In this paper, a study of the optimization of pure CNT networks in terms of piezoresistive response is reported. The so-called pure CNT networks are CNT networks free of surfactants. The performances of piezoresistive response are gauge factor (GF) and linearity. The variables are the number of layers of networks, concentration of CNT solution, and length of sonication time. As a result, the study concluded an optimal pure CNT networks sensor (GF: 2.59, linearity 0.98) with ten layers of networks, 0.8 mg/ml concentration, and 2 h of sonication time. PMID- 22225260 TI - Note: Temperature derivative of the refractive index of binary mixtures measured by using a new thermodiffusion cell. AB - A thermodiffusion cell is developed for performing Soret experiments on binary mixtures at high pressure and in the presence of a porous medium. The cell is validated by performing experiments at atmospheric pressure. The experiments are performed by applying different temperature gradients to binary mixtures in order to determine their thermal contrast factor. These measurements provide a first demonstration of the good reproducibility of this kind of measurements upon calibration. PMID- 22225261 TI - Note: Integration of trapped ion mobility spectrometry with mass spectrometry. AB - The integration of a trapped ion mobility spectrometer (TIMS) with a mass spectrometer (MS) for complementary fast, gas-phase mobility separation prior to mass analysis (TIMS-MS) is described. The ion transmission and mobility separation are discussed as a function of the ion source condition, bath gas velocity, analysis scan speed, RF ion confinement, and downstream ion optical conditions. TIMS mobility resolution depends on the analysis scan speed and the bath gas velocity, with the unique advantage that the IMS separation can be easily tuned from high speed (~25 ms) for rapid analysis to slower scans for higher mobility resolution (R > 80). PMID- 22225262 TI - Note: Automated maskless micro-multidomain photoalignment. AB - We present a fully automated maskless exposure system for the fabrication of microscopic orientational surface alignment patterns. The maskless system allows us to fabricate arbitrary surface patterns over a 2 mm * 2 mm area with a resolution of 2.2 MUm. A confocal autofocus system insures accurate and repeatable focus. Microscopic orientational surface patterns have been demonstrated to exhibit a variety of novel functionalities, such as surface alignment multi-stability. PMID- 22225263 TI - Note: Investigation of atom transfer using a red-detuned push beam in a double magneto-optical trap setup. AB - We present our results on transfer of cold (87)Rb atoms from a vapor cell magneto optical trap to ultrahigh vacuum magneto-optical trap (UHV-MOT) using a red detuned continuous wave push beam in a double-magneto-optical trap setup. We find that use of retro-reflected red-detuned push laser beam results in higher number in UHV-MOT than the number obtained without retro-reflection of push beam. PMID- 22225264 TI - Note: Signal conditioning of a hot-film anemometer for a periodic flow rate monitoring system. AB - A flow monitoring system based on a constant temperature hot-film anemometer is presented. The device has been designed to monitor a dispensing process of extremely low quantities of adhesive material. The monitoring device presented in this paper is useful in industrial applications where exact flow speed tracking is not needed, but reliability and tolerance to parameters variability are essential. During the design of the device, problems related to the physical characteristic of the calorimetric sensor, in particular its thermal capacitance, and to the periodic nature of the monitored flow have been taken into account and suitable solutions have been implemented. The schematic representation of the monitoring device together with the experimental results obtained by monitoring fluids with different physical characteristics are presented. PMID- 22225269 TI - Point/Counterpoint. Medical Physics residency programs in nonacademic facilities should affiliate themselves with a university-based program. PMID- 22225270 TI - Fast time-of-flight camera based surface registration for radiotherapy patient positioning. AB - PURPOSE: This work introduces a rigid registration framework for patient positioning in radiotherapy, based on real-time surface acquisition by a time-of flight (ToF) camera. Dynamic properties of the system are also investigated for future gating/tracking strategies. METHODS: A novel preregistration algorithm, based on translation and rotation-invariant features representing surface structures, was developed. Using these features, corresponding three-dimensional points were computed in order to determine initial registration parameters. These parameters became a robust input to an accelerated version of the iterative closest point (ICP) algorithm for the fine-tuning of the registration result. Distance calibration and Kalman filtering were used to compensate for ToF-camera dependent noise. Additionally, the advantage of using the feature based preregistration over an "ICP only" strategy was evaluated, as well as the robustness of the rigid-transformation-based method to deformation. RESULTS: The proposed surface registration method was validated using phantom data. A mean target registration error (TRE) for translations and rotations of 1.62 +/- 1.08 mm and 0.07 degrees +/- 0.05 degrees , respectively, was achieved. There was a temporal delay of about 65 ms in the registration output, which can be seen as negligible considering the dynamics of biological systems. Feature based preregistration allowed for accurate and robust registrations even at very large initial displacements. Deformations affected the accuracy of the results, necessitating particular care in cases of deformed surfaces. CONCLUSIONS: The proposed solution is able to solve surface registration problems with an accuracy suitable for radiotherapy cases where external surfaces offer primary or complementary information to patient positioning. The system shows promising dynamic properties for its use in gating/tracking applications. The overall system is competitive with commonly-used surface registration technologies. Its main benefit is the usage of a cost-effective off-the-shelf technology for surface acquisition. Further strategies to improve the registration accuracy are under development. PMID- 22225271 TI - A forward bias method for lag correction of an a-Si flat panel detector. AB - PURPOSE: Digital a-Si flat panel (FP) x-ray detectors can exhibit detector lag, or residual signal, of several percent that can cause ghosting in projection images or severe shading artifacts, known as the radar artifact, in cone-beam computed tomography (CBCT) reconstructions. A major contributor to detector lag is believed to be defect states, or traps, in the a-Si layer of the FP. Software methods to characterize and correct for the detector lag exist, but they may make assumptions such as system linearity and time invariance, which may not be true. The purpose of this work is to investigate a new hardware based method to reduce lag in an a-Si FP and to evaluate its effectiveness at removing shading artifacts in CBCT reconstructions. The feasibility of a novel, partially hardware based solution is also examined. METHODS: The proposed hardware solution for lag reduction requires only a minor change to the FP. For pulsed irradiation, the proposed method inserts a new operation step between the readout and data collection stages. During this new stage the photodiode is operated in a forward bias mode, which fills the defect states with charge. A Varian 4030CB panel was modified to allow for operation in the forward bias mode. The contrast of residual lag ghosts was measured for lag frames 2 and 100 after irradiation ceased for standard and forward bias modes. Detector step response, lag, SNR, modulation transfer function (MTF), and detective quantum efficiency (DQE) measurements were made with standard and forward bias firmware. CBCT data of pelvic and head phantoms were also collected. RESULTS: Overall, the 2nd and 100th detector lag frame residual signals were reduced 70%-88% using the new method. SNR, MTF, and DQE measurements show a small decrease in collected signal and a small increase in noise. The forward bias hardware successfully reduced the radar artifact in the CBCT reconstruction of the pelvic and head phantoms by 48%-81%. CONCLUSIONS: Overall, the forward bias method has been found to greatly reduce detector lag ghosts in projection data and the radar artifact in CBCT reconstructions. The method is limited to improvements of the a-Si photodiode response only. A future hybrid mode may overcome any limitations of this method. PMID- 22225272 TI - Computer-aided detection of clustered microcalcifications in digital breast tomosynthesis: a 3D approach. AB - PURPOSE: To design a computer-aided detection (CADe) system for clustered microcalcifications in reconstructed digital breast tomosynthesis (DBT) volumes and to perform a preliminary evaluation of the CADe system. METHODS: IRB approval and informed consent were obtained in this study. A data set of two-view DBT of 72 breasts containing microcalcification clusters was collected from 72 subjects who were scheduled to undergo breast biopsy. Based on tissue sampling results, 17 cases had breast cancer and 55 were benign. A separate data set of two-view DBT of 38 breasts free of clustered microcalcifications from 38 subjects was collected to independently estimate the number of false-positives (FPs) generated by the CADe system. A radiologist experienced in breast imaging marked the biopsied cluster of microcalcifications with a 3D bounding box using all available clinical and imaging information. A CADe system was designed to detect microcalcification clusters in the reconstructed volume. The system consisted of prescreening, clustering, and false-positive reduction stages. In the prescreening stage, the conspicuity of microcalcification-like objects was increased by an enhancement-modulated 3D calcification response function. An iterative thresholding and 3D object growing method was used to detect cluster seed objects, which were used as potential centers of microcalcification clusters. In the cluster detection stage, microcalcification candidates were identified using a second iterative thresholding procedure, which was applied to the signal-to-noise ratio (SNR) enhanced image voxels with a positive calcification response. Starting with each cluster seed object as the initial cluster center, a dynamic clustering algorithm formed a cluster candidate by including microcalcification candidates within a 3D neighborhood of the cluster seed object that satisfied the clustering criteria. The number, size, and SNR of the microcalcifications in a cluster candidate and the cluster shape were used to reduce the number of FPs. RESULTS: The prescreening stage detected a cluster seed object in 94% of the biopsied microcalcification clusters at a threshold of 100 cluster seed objects per DBT volume. After clustering, the detection sensitivity was 90% at 15 marks per DBT volume. After FP reduction, at 85% sensitivity, the average number of FPs estimated using the data set containing microcalcification clusters was 3.8 per DBT volume, and that estimated using the data set free of microcalcification clusters was 3.4. The detection performance for malignant microcalcification clusters was superior to that for benign clusters. CONCLUSIONS: Our study indicates the feasibility of the 3D approach to the detection of clustered microcalcifications in DBT and that the newly designed enhancement-modulated 3D calcification response function is promising for prescreening. Further work is needed to assess the generalizability of our approach and to improve its performance. PMID- 22225273 TI - Monte Carlo linear accelerator simulation of megavoltage photon beams: independent determination of initial beam parameters. AB - PURPOSE: To individually benchmark the incident electron parameters in a Monte Carlo model of an Elekta linear accelerator operating at 6 and 15 MV. The main objective is to establish a simplified but still precise benchmarking procedure that allows accurate dose calculations of advanced treatment techniques. METHODS: The EGSnrc Monte Carlo user codes BEAMnrc and DOSXYZnrc are used for photon beam simulations and dose calculations, respectively. A 5 * 5 cm(2) field is used to determine both the incident electron energy and the electron radial intensity. First, the electron energy is adjusted to match the calculated depth dose to the measured one. Second, the electron radial intensity is adjusted to make the calculated dose profile in the penumbrae region match the penumbrae measured by GafChromic EBT film. Finally, the mean angular spread of the incident electron beam is determined by matching calculated and measured cross-field profiles of large fields. The beam parameters are verified for various field sizes and shapes. RESULTS: The penumbrae measurements revealed a non-circular electron radial intensity distribution for the 6 MV beam, while a circular electron radial intensity distribution could best describe the 15 MV beam. These electron radial intensity distributions, given as the standard deviation of a Gaussian distribution, were found to be 0.25 mm (in-plane) and 1.0 mm (cross-plane) for the 6 MV beam and 0.5 mm (both in-plane and cross-plane) for the 15 MV beam. Introducing a small mean angular spread of the incident electron beam has a considerable impact on the lateral dose profiles of large fields. The mean angular spread was found to be 0.7 degrees and 0.5 degrees for the 6 and 15 MV beams, respectively. CONCLUSIONS: The incident electron beam parameters in a Monte Carlo model of a linear accelerator could be precisely and independently determined by the benchmarking procedure proposed. As the dose distribution in the penumbra region is insensitive to moderate changes in electron energy and angular spread, accurate penumbra measurements is feasible for benchmarking the electron radial intensity distribution. This parameter is particularly important for accurate dosimetry of mlc-shaped fields and small fields. PMID- 22225274 TI - Dosimetric investigation of breath-hold intensity-modulated radiotherapy for pancreatic cancer. AB - PURPOSE: To experimentally investigate the effects of variations in respiratory motion during breath-holding (BH) at end-exhalation (EE) on intensity-modulated radiotherapy (BH-IMRT) dose distribution using a motor-driven base, films, and an ionization chamber. METHODS: Measurements were performed on a linear accelerator, which has a 120-leaf independently moving multileaf collimator with 5-mm leaf width at the isocenter for the 20-cm central field. Polystyrene phantoms with dimensions of 40 * 40 * 10 cm were set on a motor-driven base. All gantry angles of seven IMRT plans (a total of 35 fields) were changed to zero, and doses were then delivered to a film placed at a depth of 4 cm and an ionization chamber at a depth of 5 cm in the phantom with a dose rate of 600 MU/min under the following conditions: pulsation from the abdominal aorta and baseline drift with speeds of 0.2 mm/s (BD(0.2mm/s)) and 0.4 mm/s (BD(0.4mm/s)). As a reference for comparison, doses were also delivered to the chamber and film under stationary conditions. RESULTS: In chamber measurements, means +/- standard deviations of the dose deviations between stationary and moving conditions were -0.52% +/- 1.03% (range: -3.41-1.05%), -0.07% +/- 1.21% (range: -1.88-4.31%), and 0.03% +/- 1.70% (range: 2.70-6.41%) for pulsation, BD(0.2mm/s), and BD(0.4mm/s), respectively. The gamma passing rate ranged from 99.5% to 100.0%, even with the criterion of 2%/1 mm for pulsation pattern. In the case of BD(0.4mm/s), the gamma passing rate for four of 35 fields (11.4%) did not reach 90% with a criterion of 3%/3 mm. The differences in gamma passing rate between BD(0.2mm/s) and BD(0.4mm/s) were statistically significant for each criterion. Taking gamma passing rates of > 90% as acceptable with a criterion of 3%/3 mm, large differences were observed in the gamma passing rate between the baseline drift of <=5 mm and that of >5 mm (minimum gamma passing rate: 92.0% vs 82.7%; p < 0.01). CONCLUSIONS: This study suggested that the baseline drift of >5 mm should be avoided in the BH-IMRT. PMID- 22225275 TI - A voxel-based finite element model for the prediction of bladder deformation. AB - PURPOSE: A finite element (FE) bladder model was previously developed to predict bladder deformation caused by bladder filling change. However, two factors prevent a wide application of FE models: (1) the labor required to construct a FE model with high quality mesh and (2) long computation time needed to construct the FE model and solve the FE equations. In this work, we address these issues by constructing a low-resolution voxel-based FE bladder model directly from the binary segmentation images and compare the accuracy and computational efficiency of the voxel-based model used to simulate bladder deformation with those of a classical FE model with a tetrahedral mesh. METHODS: For ten healthy volunteers, a series of MRI scans of the pelvic region was recorded at regular intervals of 10 min over 1 h. For this series of scans, the bladder volume gradually increased while rectal volume remained constant. All pelvic structures were defined from a reference image for each volunteer, including bladder wall, small bowel, prostate (male), uterus (female), rectum, pelvic bone, spine, and the rest of the body. Four separate FE models were constructed from these structures: one with a tetrahedral mesh (used in previous study), one with a uniform hexahedral mesh, one with a nonuniform hexahedral mesh, and one with a low-resolution nonuniform hexahedral mesh. Appropriate material properties were assigned to all structures and uniform pressure was applied to the inner bladder wall to simulate bladder deformation from urine inflow. Performance of the hexahedral meshes was evaluated against the performance of the standard tetrahedral mesh by comparing the accuracy of bladder shape prediction and computational efficiency. RESULTS: FE model with a hexahedral mesh can be quickly and automatically constructed. No substantial differences were observed between the simulation results of the tetrahedral mesh and hexahedral meshes (<1% difference in mean dice similarity coefficient to manual contours and <0.02 cm difference in mean standard deviation of residual errors). The average equation solving time (without manual intervention) for the first two types of hexahedral meshes increased to 2.3 h and 2.6 h compared to the 1.1 h needed for the tetrahedral mesh, however, the low resolution nonuniform hexahedral mesh dramatically decreased the equation solving time to 3 min without reducing accuracy. CONCLUSIONS: Voxel-based mesh generation allows fast, automatic, and robust creation of finite element bladder models directly from binary segmentation images without user intervention. Even the low resolution voxel-based hexahedral mesh yields comparable accuracy in bladder shape prediction and more than 20 times faster in computational speed compared to the tetrahedral mesh. This approach makes it more feasible and accessible to apply FE method to model bladder deformation in adaptive radiotherapy. PMID- 22225277 TI - Evaluation of the accuracy of 3DVH software estimates of dose to virtual ion chamber and film in composite IMRT QA. AB - PURPOSE: A novel patient-specific intensity modulated radiation therapy (IMRT) QA system, 3DVH software and mapcheck 2, purports to be able to use diode array measured beam doses and the patient's DICOM RT plan, structure set, and dose files to predict the delivered 3D dose distribution in the patient for comparison to the treatment planning system (TPS) calculated doses. In this study, the composite dose to an ion chamber and film in phantom predicted by the 3DVH and mapcheck 2 system is compared to the actual measured chamber and film doses. If validated in this context, then 3DVH can be used to perform an equivalent dose analysis as that obtained with film dosimetry and ion chamber-based composite IMRT QA. This is important for those losing their ability to perform film dosimetry for true composite IMRT QA and provides a measure of confidence in the accuracy of 3DVH 3D dose calculations which may replace phantom-based IMRT QA. METHODS: The dosimetric results from 15 consecutive patient-specific IMRT QA tests performed by composite field irradiation of ion chamber and EDR2 film in a solid water phantom were compared to the predicted doses for those virtual detectors based on the calculated 3D dose by the 3DVH software using mapcheck 2 measured doses of each beam within each plan. For each of the 15 cases, immediately after performing the ion chamber plus film measurements, the mapcheck 2 was used to measure the dose for each beam of the plan. The dose to the volume of the virtual ion chamber and the dose distribution in the plane of the virtual film calculated by the 3DVH software was extracted. The ratio of the measured to 3DVH or eclipse-predicted ion chamber doses was calculated. The same plane in the phantom measured using film and calculated with eclipse was exported from 3DVH and the 2D gamma metric was used to compare the relationship between the film doses and the eclipse or 3DVH predicted planar doses. Also, the 3D gamma value was calculated in the 3DVH software which compares the eclipse dose to the 3DVH predicted dose distribution. For the 2D and 3D gamma metrics, 2% dose and 2 mm distance to agreement (DTA) were used. In addition, a simple dose difference was performed using either a 2% or 3% dose difference tolerance. RESULTS: The mean ratio +/- standard deviation of the measured vs 3DVH or vs eclipse-predicted dose to the ion chamber was 1.013 +/- 0.015 and 1.003 +/- 0.012, respectively. For 3DVH vs eclipse, the mean percentage of pixels failing the 3D gamma metric was 1.2% +/- 1.4% while the failure rate for the 2D gamma metric was 1.1% +/- 0.9%. When either 3DVH or eclipse was compared to EDR2 film, the gamma failure rate was 2.3% +/- 2.0% and 1.6% +/- 1.7%, respectively. Mean dose difference failures were 9%-27% +/- 5%-15% for 2 or 3% dose difference tolerances, depending on the combination of systems tested. No statistically significant differences were found for any of the planar dosimetric comparisons. CONCLUSIONS: 3DVH + mapcheck 2 predicts the same absolute dose, the percent of pixels failing the gamma metric, and the percent of pixels failing 2% or 3% dose difference tolerance tests as one would have obtained had one made measurements in solid water phantom using an ion chamber and coronal film instead of a diode array. This is also a necessary although not sufficient condition for validation of the accuracy of 3DVH predictions of the 3D dose using beam-by-beam measurements. PMID- 22225276 TI - Prior image constrained compressed sensing: implementation and performance evaluation. AB - PURPOSE: Prior image constrained compressed sensing (PICCS) is an image reconstruction framework which incorporates an often available prior image into the compressed sensing objective function. The images are reconstructed using an optimization procedure. In this paper, several alternative unconstrained minimization methods are used to implement PICCS. The purpose is to study and compare the performance of each implementation, as well as to evaluate the performance of the PICCS objective function with respect to image quality. METHODS: Six different minimization methods are investigated with respect to convergence speed and reconstruction accuracy. These minimization methods include the steepest descent (SD) method and the conjugate gradient (CG) method. These algorithms require a line search to be performed. Thus, for each minimization algorithm, two line searching algorithms are evaluated: a backtracking (BT) line search and a fast Newton-Raphson (NR) line search. The relative root mean square error is used to evaluate the reconstruction accuracy. The algorithm that offers the best convergence speed is used to study the performance of PICCS with respect to the prior image parameter alpha and the data consistency parameter lambda. PICCS is studied in terms of reconstruction accuracy, low-contrast spatial resolution, and noise characteristics. A numerical phantom was simulated and an animal model was scanned using a multirow detector computed tomography (CT) scanner to yield the projection datasets used in this study. RESULTS: For lambda within a broad range, the CG method with Fletcher-Reeves formula and NR line search offers the fastest convergence for an equal level of reconstruction accuracy. Using this minimization method, the reconstruction accuracy of PICCS was studied with respect to variations in alpha and lambda. When the number of view angles is varied between 107, 80, 64, 40, 20, and 16, the relative root mean square error reaches a minimum value for alpha ~ 0.5. For values of alpha near the optimal value, the spatial resolution of the reconstructed image remains relatively constant and the noise texture is very similar to that of the prior image, which was reconstructed using the filtered backprojection (FBP) algorithm. CONCLUSIONS: Regarding the performance of the minimization methods, the nonlinear CG method with NR line search yields the best convergence speed. Regarding the performance of the PICCS image reconstruction, three main conclusions can be reached. (1) The performance of PICCS is optimal when the weighting parameter of the prior image parameter is selected to be near alpha = 0.5. (2) The spatial resolution measured for static objects in images reconstructed using PICCS from undersampled datasets is not degraded with respect to the fully-sampled reconstruction for alpha near its optimal value. (3) The noise texture of PICCS reconstructions is similar to that of the prior image, which was reconstructed using the conventional FBP method. PMID- 22225278 TI - Implementation of EPID transit dosimetry based on a through-air dosimetry algorithm. AB - PURPOSE: A method to perform transit dosimetry with an electronic portal imaging device (EPID) by extending the commercial implementation of a published through air portal dose image (PDI) prediction algorithm Van Esch et al. [Radiother. Oncol. 71, 223-234 (2004)] is proposed and validated. A detailed characterization of the attenuation, scattering, and EPID response behind objects in the beam path is used to convert through-air PDIs into transit PDIs. METHODS: The EPID detector response beyond a range of water equivalent thicknesses (0-35 cm) and field sizes (3*3 to 22.2*29.6 cm(2)) was analyzed. A constant air gap between the phantom exit surface and the EPID was utilized. A model was constructed that accounts for the beam's attenuation along the central axis, the presence of phantom scattered radiation, the detector's energy dependent response, and the difference in EPID off-axis pixel response relative to the central pixel. The efficacy of the algorithm was verified by comparing predicted and measured PDIs for IMRT fields delivered through phantoms of increasing complexity. RESULTS: The expression that converts a through-air PDI to a transit PDI is dependent on the object's thickness, the irradiated field size, and the EPID pixel position. Monte Carlo derived narrow-beam linear attenuation coefficients are used to model the decrease in primary fluence incident upon the EPID due to the object's presence in the beam. This term is multiplied by a factor that accounts for the broad beam scatter geometry of the linac-phantom-EPID system and the detector's response to the incident beam quality. A 2D Gaussian function that models the nonuniformity of pixel response across the EPID detector plane is developed. For algorithmic verification, 49 IMRT fields were repeatedly delivered to homogeneous slab phantoms in 5 cm increments. Over the entire set of measurements, the average area passing a 3%/3mm gamma criteria slowly decreased from 98% for no material in the beam to 96.7% for 35 cm of material in the beam. The same 49 fields were delivered to a heterogeneous slab phantom and on average, 97.1% of the pixels passed the gamma criteria. Finally, a total of 33 IMRT fields were delivered to the anthropomorphic phantom and on average, 98.1% of the pixels passed. The likelihood of good matches was independent of anatomical site. CONCLUSIONS: A prediction of the transit PDI behind a phantom or patient can be created for the purposes of treatment verification via an extension of the Van Esch through-air PDI algorithm. The results of the verification measurements through phantoms indicate that further investigation through patients during their treatments is warranted. PMID- 22225279 TI - Novel needle cutting edge geometry for end-cut biopsy. AB - PURPOSE: To introduce and determine the biopsy length performance of the novel enhanced cutting edge (ECE) needle tip design, which contains high inclination angles that allow for more efficient tissue cutting. METHODS: ECE and regular two plane symmetric needle tip's biopsy performance and cutting force are compared over a series of needle insertion experiments into bovine liver under varying levels of internal needle vacuum. An earlier developed needle tip force model is also applied. From these experiments and force model, the effect of needle tip geometry and vacuum on biopsy performance and force is studied. RESULTS: Biopsy sample length is on average 22%, 30%, and 49% longer for ECE needles compared to that of regular needles for the internal pressures of 0, -33.9, and -67.7 kPa, respectively. For ECE needles the vacuum level of -67.7 kPa produces on average biopsy lengths that are 41%, 31%, 29%, 45%, and 42% longer compared to no vacuum for two-plane needle tip bevel angles of 10 degrees , 15 degrees , 20 degrees , 25 degrees , and 30 degrees , respectively. The force results show the ECE needle can be inserted with less initial insertion force than the regular two-plane needle for needles where the needle tip is fully contacting the tissue upon insertion. Vacuum is also showed to help lower insertion forces. CONCLUSIONS: The novel ECE needle tip design outperforms the regular two-plane symmetric needle by yielding longer biopsy samples and lower insertion forces, thereby demonstrating the benefits of needle geometries that contain higher inclination angles. The use of vacuum further improves the ECE needle tip biopsy sample length and lowers insertion forces. PMID- 22225280 TI - Position detection accuracy of a novel linac-mounted intrafractional x-ray imaging system. AB - PURPOSE: The authors have developed a system that monitors intrafractional target motion perpendicular to the treatment beam with the aid of radioopaque markers by means of separating kV image and megavoltage (MV) treatment field on a single flat-panel detector. METHODS: They equipped a research Siemens Artiste linear accelerator (linac) with a 41 * 41 cm(2) a-Si flat-panel detector underneath the treatment head. The in-line geometry allows kV (imaging) and MV (treatment) beams to share closely aligned beam axes. The kV source, usually mounted directly across from the flat-panel imager, was retracted toward the gantry by 13 cm to intentionally misalign kV and MV beams, resulting in a geometric separation of MV treatment field and kV image on the detector. Two consecutive images acquired within 140 ms (the first with MV-only and the second with kV and MV signal) were subtracted to generate a kV-only image. The images were then analyzed "online" with an automated threshold-based marker detection algorithm. They employed a 3D and a 4D phantom equipped with either a single radioopaque marker or three Calypso beacons to mimic respiratory motion. Measured room positions were either cross-referenced with a phantom voltage signal (single marker) or the Calypso system. The accuracy of the back-projection (from detected marker positions into room coordinates) was verified by a simulation study. RESULTS: A phantom study has demonstrated that the imaging framework is capable of automatically detecting marker positions and sending this information to the tracking tool at an update rate of 7.14 Hz. The system latency is 86.9 +/- 1.0 ms for single marker detection in the absence of MV radiation. In the presence of a circular MV field of 5 cm diameter, the latency is 87.1 +/- 0.9 ms. The total RMS position detection accuracy is 0.20 mm (without MV radiation) and 0.23 mm (with MV). CONCLUSIONS: Based on the evaluated motion patterns and MV field size, the positional accuracy and system latency indicate that this system is suitable for real-time adaptive applications. PMID- 22225281 TI - Development and commissioning of a Monte Carlo photon beam model for the forthcoming clinical trials in microbeam radiation therapy. AB - PURPOSE: A new radiotherapy technique, named microbeam radiation therapy (MRT), is under development at the ID17 Biomedical Beamline of the European Synchrotron Radiation Facility (ESRF). This innovative method is based on the fact that normal tissue can withstand high radiation doses in small volumes without any significant damage. The promising results obtained in the preclinical studies have paved the way to forthcoming clinical trials, which are currently in preparation. Highly accurate dose calculations at the treatment planning stage are required in this context. The aims of this study are the development and experimental benchmarking of a photon beam source model, which will be the core of the future MRT treatment planning system (TPS). METHODS: The ID17 x-ray source was modeled by the synchrotron ray tracing code SHADOW. The Monte Carlo (MC) simulation code PENELOPE/PENEASY was employed to transport the photon beam from the source to the patient position through all the beamline components. The phase space state variables of the particles reaching the patient position were used as an input to generate a photon beam model. Computed dose distributions in a homogeneous media were experimentally verified by using Gafchromic((r)) films in a solid-water phantom. Benchmarking was split into two phases. First, the lateral dose profiles and the percentage depth-dose (PDD) curves in the broad beam configuration were considered. The acceptability criteria for radiotherapy dose computations recommended by international protocols such as the Technical Reports Series 430 (TRS 430) of the International Atomic Energy Agency (IAEA) were used. Second, the analogous dosimetric magnitudes in MRT irradiations, i.e., PDD of the central microbeam and the corresponding peak-to-valley dose ratios (PVDR) were evaluated and compared with MC calculations. RESULTS: A full characterization of the ID17 Biomedical Beamline (ESRF) synchrotron x-ray source and the development of an accurate photon beam model were achieved in this work. Calculated and experimental dose distributions agreed to within the recommended acceptability criteria described in international codes of practice (TRS 430) for broad beam irradiations. The overall deviation in low gradient areas amounted to 2%-3%. The maximum distance-to-agreement in high gradient regions was lower than 0.7 mm. MC calculations also reproduced MRT experimental results within uncertainty bars. These results validate the photon beam model for its use in MRT radiation therapy calculations. CONCLUSIONS: The first MC synchrotron photon beam model for MRT irradiations that reproduces experimental dose distributions in homogeneous media has been developed. This beam model will constitute an essential component of the TPS calculation engine for patient dose computation in forthcoming MRT clinical trials. PMID- 22225282 TI - A theoretical comparison of x-ray angiographic image quality using energy dependent and conventional subtraction methods. AB - PURPOSE: X-ray digital subtraction angiography (DSA) is widely used for vascular imaging. However, the need to subtract a mask image can result in motion artifacts and compromised image quality. The current interest in energy-resolving photon-counting (EPC) detectors offers the promise of eliminating motion artifacts and other advanced applications using a single exposure. The authors describe a method of assessing the iodine signal-to-noise ratio (SNR) that may be achieved with energy-resolved angiography (ERA) to enable a direct comparison with other approaches including DSA and dual-energy angiography for the same patient exposure. METHODS: A linearized noise-propagation approach, combined with linear expressions of dual-energy and energy-resolved imaging, is used to describe the iodine SNR. The results were validated by a Monte Carlo calculation for all three approaches and compared visually for dual-energy and DSA imaging using a simple angiographic phantom with a CsI-based flat-panel detector. RESULTS: The linearized SNR calculations show excellent agreement with Monte Carlo results. While dual-energy methods require an increased tube heat load of 2* to 4* compared to DSA, and photon-counting detectors are not yet ready for angiographic imaging, the available iodine SNR for both methods as tested is within 10% of that of conventional DSA for the same patient exposure over a wide range of patient thicknesses and iodine concentrations. CONCLUSIONS: While the energy-based methods are not necessarily optimized and further improvements are likely, the linearized noise-propagation analysis provides the theoretical framework of a level playing field for optimization studies and comparison with conventional DSA. It is concluded that both dual-energy and photon-counting approaches have the potential to provide similar angiographic image quality to DSA. PMID- 22225283 TI - TomoTherapy MLC verification using exit detector data. AB - PURPOSE: Treatment delivery verification (DV) is important in the field of intensity modulated radiation therapy (IMRT). While IMRT and image guided radiation therapy (IGRT), allow us to create more conformal plans and enables the use of tighter margins, an erroneously executed plan can have detrimental effects on the treatment outcome. The purpose of this study is to develop a DV technique to verify TomoTherapy's multileaf collimator (MLC) using the onboard mega-voltage CT detectors. METHODS: The proposed DV method uses temporal changes in the MVCT detector signal to predict actual leaf open times delivered on the treatment machine. Penumbra and scattered radiation effects may produce confounding results when determining leaf open times from the raw detector data. To reduce the impact of the effects, an iterative, Richardson-Lucy (R-L) deconvolution algorithm is applied. Optical sensors installed on each MLC leaf are used to verify the accuracy of the DV technique. The robustness of the DV technique is examined by introducing different attenuation materials in the beam. Additionally, the DV technique has been used to investigate several clinical plans which failed to pass delivery quality assurance (DQA) and was successful in identifying MLC timing discrepancies as the root cause. RESULTS: The leaf open time extracted from the exit detector showed good agreement with the optical sensors under a variety of conditions. Detector-measured leaf open times agreed with optical sensor data to within 0.2 ms, and 99% of the results agreed within 8.5 ms. These results changed little when attenuation was added in the beam. For the clinical plans failing DQA, the dose calculated from reconstructed leaf open times played an instrumental role in discovering the root-cause of the problem. Throughout the retrospective study, it is found that the reconstructed dose always agrees with measured doses to within 1%. CONCLUSIONS: The exit detectors in the TomoTherapy treatment systems can provide valuable information about MLC behavior during delivery. A technique to estimate the TomoTherapy binary MLC leaf open time from exit detector signals is described. This technique is shown to be both robust and accurate for delivery verification. PMID- 22225284 TI - Antiscatter grids in mobile C-arm cone-beam CT: effect on image quality and dose. AB - PURPOSE: X-ray scatter is a major detriment to image quality in cone-beam CT (CBCT). Existing geometries exhibit strong differences in scatter susceptibility with more compact geometries, e.g., dental or musculoskeletal, benefiting from antiscatter grids, whereas in more extended geometries, e.g., IGRT, grid use carries tradeoffs in image quality per unit dose. This work assesses the tradeoffs in dose and image quality for grids applied in the context of low-dose CBCT on a mobile C-arm for image-guided surgery. METHODS: Studies were performed on a mobile C-arm equipped with a flat-panel detector for high-quality CBCT. Antiscatter grids of grid ratio (GR) 6:1-12:1, 40 lp/cm, were tested in "body" surgery, i.e., spine, using protocols for bone and soft-tissue visibility in the thoracic and abdominal spine. Studies focused on grid orientation, CT number accuracy, image noise, and contrast-to-noise ratio (CNR) in quantitative phantoms at constant dose. RESULTS: There was no effect of grid orientation on possible gridline artifacts, given accurate angle-dependent gain calibration. Incorrect calibration was found to result in gridline shadows in the projection data that imparted high-frequency artifacts in 3D reconstructions. Increasing GR reduced errors in CT number from 31%, thorax, and 37%, abdomen, for gridless operation to 2% and 10%, respectively, with a 12:1 grid, while image noise increased by up to 70%. The CNR of high-contrast objects was largely unaffected by grids, but low contrast soft-tissues suffered reduction in CNR, 2%-65%, across the investigated GR at constant dose. CONCLUSIONS: While grids improved CT number accuracy, soft tissue CNR was reduced due to attenuation of primary radiation. CNR could be restored by increasing dose by factors of ~1.6-2.5 depending on GR, e.g., increase from 4.6 mGy for the thorax and 12.5 mGy for the abdomen without antiscatter grids to approximately 12 mGy and 30 mGy, respectively, with a high GR grid. However, increasing the dose poses a significant impediment to repeat intraoperative CBCT and can cause the cumulative intraoperative dose to exceed that of a single diagnostic CT scan. This places the mobile C-arm in the category of extended CBCT geometries with sufficient air gap for which the tradeoffs between CNR and dose typically do not favor incorporation of an antiscatter grid. PMID- 22225285 TI - Dose calculation software for helical tomotherapy, utilizing patient CT data to calculate an independent three-dimensional dose cube. AB - PURPOSE: Treatment plans for the TomoTherapy unit are produced with a planning system that is integral to the unit. The authors have produced an independent dose calculation system, to enable plans to be recalculated in three dimensions, using the patient's CT data. METHODS: Software has been written using MATLAB. The DICOM-RT plan object is used to determine the treatment parameters used, including the treatment sinogram. Each projection of the sinogram is segmented and used to calculate dose at multiple calculation points in a three-dimensional grid using tables of measured beam data. A fast ray-trace algorithm is used to determine effective depth for each projection angle at each calculation point. Calculations were performed on a standard desktop personal computer, with a 2.6 GHz Pentium, running Windows XP. RESULTS: The time to perform a calculation, for 3375 points averaged 1 min 23 s for prostate plans and 3 min 40 s for head and neck plans. The mean dose within the 50% isodose was calculated and compared with the predictions of the TomoTherapy planning system. When the modified CT (which includes the TomoTherapy couch) was used, the mean difference for ten prostate patients, was -0.4% (range -0.9% to +0.3%). With the original CT (which included the CT couch), the mean difference was -1.0% (range -1.7% to 0.0%). The number of points agreeing with a gamma 3%/3 mm averaged 99.2% with the modified CT, 96.3% with the original CT. For ten head and neck patients, for the modified and original CT, respectively, the mean difference was +1.1% (range -0.4% to +3.1%) and 1.1% (range -0.4% to +3.0%) with 94.4% and 95.4% passing a gamma 4%/4 mm. The ability of the program to detect a variety of simulated errors has been tested. CONCLUSIONS: By using the patient's CT data, the independent dose calculation performs checks that are not performed by a measurement in a cylindrical phantom. This enables it to be used either as an additional check or to replace phantom measurements for some patients. The software has potential to be used in any application where one wishes to model changes to patient conditions. PMID- 22225286 TI - 3D shape-dependent thinning method for trabecular bone characterization. AB - PURPOSE: Curve and surface thinning are widely-used skeletonization techniques for modeling objects in three dimensions. In the case of trabecular bone analysis, however, neither curve nor surface thinning is really efficient since the internal geometry of the object is usually composed of both rod and plate shapes. The purpose of this paper is to propose an original method called hybrid skeleton which better matches the geometry of the data compared to curve and surface skeletons. In the hybrid skeleton algorithm, 1D curves represent rod shaped zones whereas 2D surfaces represent plate-shaped elements. METHODS: The proposed hybrid skeleton algorithm is based on a combination of three methods. (1) A new variant of the method proposed by Bonnassie et al. for the classification of voxels as belonging to plate-like or rod-like structures, where the medial axis (MA) algorithm is replaced by a fast and connected skeletonization algorithm. In addition, the reversibility of the MA algorithm is replaced by an isotropic region-growth method to spread the rod and plate labels back to the original object. (2) A well chosen surface thinning method applied on the plate voxels set. (3) A well chosen curve skeleton thinning method applied on the rod voxels set. The efficiency and the robustness of the proposed algorithm were evaluated using synthesis test vectors. A clinical study was led on micro-CT (computed tomography) images of two different populations of osteoarthritic and osteoporotic trabecular bone samples. The morphological and topological characteristics of the two populations were evaluated using the proposed hybrid skeleton as well as the classification algorithm. RESULTS: When evaluated on test vectors and compared to Bonnassie's algorithm, the proposed classification algorithm gives a slightly better rate of classification. The hybrid skeleton preserves the shape information of the processed objects. Interesting morphological and topological features as well as volumetric ones were extracted from the skeleton and from the classified volumes, respectively. The extracted features enable the two populations of osteoarthritic and osteoporotic trabecular bone samples to be distinguished. CONCLUSIONS: Compared to curve-based or surface based skeletons, the hybrid skeleton better matches the geometry of the data. Each rod is represented by a one-voxel-thick arc and each plate is represented by a one-voxel-thick surface. The hybrid skeleton as well as the proposed classification algorithm introduce relevant parameters linked to the presence of plates in the trabecular bone data, showing that rods and plates contain independent information about trabeculae. The hybrid skeleton offers a new opportunity for precise studies of porous media such as trabecular bone. PMID- 22225287 TI - An MR image-guided, voxel-based partial volume correction method for PET images. AB - PURPOSE: Partial volume effect in positron emission tomography (PET) can cause incorrect quantification of radiopharmaceutical uptake in functional imaging. A PET partial volume correction method is presented to attenuate partial volume blurring and to yield voxel-based corrected PET images. METHODS: By modeling partial volume effect as a convolution of point spread function of the PET scanner, the reconstructed PET images are corrected by iterative deconvolution with an edge-preserving smoothness constraint. The constraint is constructed to restore discontinuities extracted from coregistered MR images but maintains the smoothness in radioactivity distribution. The correction is implemented in a Bayesian deconvolution framework and is solved by a conjugate gradient method. The performance of the method was compared with the geometric transfer matrix (GTM) method on a simulated dataset. The method was evaluated on synthesized brain FDG-PET data and phantom MRI-PET experiments. RESULTS: The true PET activity of objects with a size of greater than the full-width at half maximum of the point spread function has been effectively restored in the simulated data. The partial volume correction method is quantitatively comparable to the GTM method. For synthesized FDG-PET with true activity 0 MUci/cc for cerebrospinal fluid (CSF), 228 MUci/cc for white matter (WM), and 621 MUci/cc for gray matter (GM), the method has improved the radioactivity quantification from 186 +/- 16 MUci/cc to 30 +/- 7 MUci/cc in CSF, 317 +/- 15 MUci/cc to 236 +/- 10 MUci/cc for WM, 438 +/- 4 MUci/cc to 592 +/- 5 MUci/cc for GM. Both visual and quantitative assessments show improvement of partial volume correction in the synthesized and phantom experiments. CONCLUSIONS: The partial volume correction method improves the quantification of PET images. The method is comparable to the GTM method but does not need MR image segmentation or prior tracer distribution information. The voxel-based method can be particularly useful for combined PET/MRI studies. PMID- 22225289 TI - Aperture superposition dose model versus pencil beam superposition dose model for a finite size Cobalt-60 source for tomotherapy deliveries. AB - PURPOSE: The finite size pencil beam (FSPB) superposition method is a commonly used dose calculation method in intensity modulated radiation therapy (IMRT). The FSPB model assumes that dose for a broad intensity modulated beam can be calculated by superposition of dose from small, pencil-like beams. However, this model is limited to point-like radiation sources and is not valid for finite size sources, such as a Cobalt-60 (Co-60) source of 2 cm diameter. In this paper, the authors present results that show the limitation of this model and propose an alternative model, namely the aperture superposition (AS) model, to calculate photon dose for intensity modulated beams arising from finite size radiation sources. METHODS: The AS model is based on adding beam apertures rather than pencil beams. Each aperture is defined as a series of adjacently opened leaves of a multileaf collimator with no closed leaves in between them. The apertures are calculated using the EGSnrc Monte Carlo program. The accuracy of the AS model was tested for dose calculations of fan beams, as encountered in tomotherapy treatment plans. The results were compared with the FSPB model and GafChromic film measurements. The measurements and simulations were performed for a clinical Theratronics T780C Co-60 unit with MIMiC binary multileaf collimator mounted on it. RESULTS: The comparisons between the AS model and film measurements show agreement better than 1.5% in the high dose regions and 3.7% in the low dose regions. On the contrary, film measurement comparisons to the FSPB model show that the FSPB model underestimates the dose by up to 7% for small field sizes such as 2 * 2 cm(2) and 20% for larger field sizes such as 20 * 2 cm(2). CONCLUSIONS: The results presented in this paper indicate that the AS model provides better accuracy than the FSPB model when calculating dose for fan beams from large radiation sources. The implementation of this model to the current treatment planning systems has the scope of advancing Co-60 based IMRT and tomotherapy. PMID- 22225288 TI - A method for deriving a 4D-interpolated balanced planning target for mobile tumor radiotherapy. AB - PURPOSE: Tumor control and normal tissue toxicity are strongly correlated to the tumor and normal tissue volumes receiving high prescribed dose levels in the course of radiotherapy. Planning target definition is, therefore, crucial to ensure favorable clinical outcomes. This is especially important for stereotactic body radiation therapy of lung cancers, characterized by high fractional doses and steep dose gradients. The shift in recent years from population-based to patient-specific treatment margins, as facilitated by the emergence of 4D medical imaging capabilities, is a major improvement. The commonly used motion encompassing, or internal-target volume (ITV), target definition approach provides a high likelihood of coverage for the mobile tumor but inevitably exposes healthy tissue to high prescribed dose levels. The goal of this work was to generate an interpolated balanced planning target that takes into account both tumor coverage and normal tissue sparing from high prescribed dose levels, thereby improving on the ITV approach. METHODS: For each 4DCT dataset, 4D deformable image registration was used to derive two bounding targets, namely, a 4D-intersection and a 4D-composite target which minimized normal tissue exposure to high prescribed dose levels and maximized tumor coverage, respectively. Through definition of an "effective overlap volume histogram" the authors derived an "interpolated balanced planning target" intended to balance normal tissue sparing from prescribed doses with tumor coverage. To demonstrate the dosimetric efficacy of the interpolated balanced planning target, the authors performed 4D treatment planning based on deformable image registration of 4D-CT data for five previously treated lung cancer patients. Two 4D plans were generated per patient, one based on the interpolated balanced planning target and the other based on the conventional ITV target. Plans were compared for tumor coverage and the degree of normal tissue sparing resulting from the new approach was quantified. RESULTS: Analysis of the 4D dose distributions from all five patients showed that while achieving tumor coverage comparable to the ITV approach, the new planning target definition resulted in reductions of lung V(10), V(20), and V(30) of 6.3% +/- 1.7%, 10.6% +/- 3.9%, and 12.9% +/- 5.5%, respectively, as well as reductions in mean lung dose, mean dose to the GTV-ring and mean heart dose of 8.8% +/- 2.5%, 7.2% +/- 2.5%, and 10.6% +/- 3.6%, respectively. CONCLUSIONS: The authors have developed a simple and systematic approach to generate a 4D-interpolated balanced planning target volume that implicitly incorporates the dynamics of respiratory organ motion without requiring 4D-dose computation or optimization. Preliminary results based on 4D-CT data of five previously treated lung patients showed that this new planning target approach may improve normal tissue sparing without sacrificing tumor coverage. PMID- 22225290 TI - A strategy to decrease partial scan reconstruction artifacts in myocardial perfusion CT: phantom and in vivo evaluation. AB - PURPOSE: Partial scan reconstruction (PSR) artifacts are present in myocardial perfusion imaging using dynamic multidetector computed tomography (MDCT). PSR artifacts appear as temporal CT number variations due to inconsistencies in the angular data range used to reconstruct images and compromise the quantitative value of myocardial perfusion when using MDCT. The purpose of this work is to present and evaluate a technique termed targeted spatial frequency filtration (TSFF) to reduce CT number variations due to PSR when applied to myocardial perfusion imaging using MDCT. METHODS: The TSFF algorithm requires acquiring enough X-ray projections to reconstruct both partial (pi + fan angle alpha) and full (2pi) scans. Then, using spatial linear filters, the TSFF-corrected image data are created by superimposing the low spatial frequency content of the full scan reconstruction (containing no PSR artifacts, but having low spatial resolution and worse temporal resolution) with the high spatial frequency content of the partial scan reconstruction (containing high spatial frequencies and better temporal resolution). The TSFF method was evaluated both in a static anthropomorphic thoracic phantom and using an in vivo porcine model and compared with a previously validated reference standard technique that avoids PSR artifacts by pacing the animal heart in synchrony with the gantry rotation. CT number variations were quantified by measuring the range and standard deviation of CT numbers in selected regions of interest (ROIs) over time. Myocardial perfusion parameters such as blood volume (BV), mean transit time (MTT), and blood flow (BF) were quantified and compared in the in vivo study. RESULTS: Phantom experiments demonstrated that TSFF reduced PSR artifacts by as much as tenfold, depending on the location of the ROI. For the in vivo experiments, the TSFF-corrected data showed two- to threefold decrease in CT number variations. Also, after TSFF, the perfusion parameters had an average difference of 13.1% (range 4.5%-25.6%) relative to the reference method, in contrast to an average difference of 31.8% (range 0.3%-54.0%) between the non-TSFF processed data with the reference method. CONCLUSIONS: TSFF demonstrated consistent reduction in CT number variations due to PSR using controlled phantom and in vivo experiments. TSFF-corrected data provided quantitative measures of perfusion (BV, MTT, and BF) with better agreement to a reference method compared to noncorrected data. Practical implementation of TSFF is expected to incur in an additional radiation exposure of 14%, when tube current is modulated to 20% of its maximum, to complete the needed full scan reconstruction. PMID- 22225291 TI - A generalized linear-quadratic model incorporating reciprocal time pattern of radiation damage repair. AB - PURPOSE: It has been conventionally assumed that the repair rate for sublethal damage (SLD) remains constant during the entire radiation course. However, increasing evidence from animal studies suggest that this may not the case. Rather, it appears that the repair rate for radiation-induced SLD slows down with increasing time. Such a slowdown in repair would suggest that the exponential repair pattern would not necessarily accurately predict repair process. As a result, the purpose of this study was to investigate a new generalized linear quadratic (LQ) model incorporating a repair pattern with reciprocal time. The new formulas were tested with published experimental data. METHODS: The LQ model has been widely used in radiation therapy, and the parameter G in the surviving fraction represents the repair process of sublethal damage with T(r) as the repair half-time. When a reciprocal pattern of repair process was adopted, a closed form of G was derived analytically for arbitrary radiation schemes. The published animal data adopted to test the reciprocal formulas. RESULTS: A generalized LQ model to describe the repair process in a reciprocal pattern was obtained. Subsequently, formulas for special cases were derived from this general form. The reciprocal model showed a better fit to the animal data than the exponential model, particularly for the ED50 data (reduced chi(2) (min) of 2.0 vs 4.3, p = 0.11 vs 0.006), with the following gLQ parameters: alpha/beta = 2.6-4.8 Gy, T(r) = 3.2-3.9 h for rat feet skin, and alpha/beta = 0.9 Gy, T(r) = 1.1 h for rat spinal cord. CONCLUSIONS: These results of repair process following a reciprocal time suggest that the generalized LQ model incorporating the reciprocal time of sublethal damage repair shows a better fit than the exponential repair model. These formulas can be used to analyze the experimental and clinical data, where a slowing-down repair process appears during the course of radiation therapy. PMID- 22225292 TI - Dosimetric characteristics and quality control tests for the collimator sectors of the Leksell Gamma Knife((r)) Perfexion(TM). AB - PURPOSE: The purpose of this study was to evaluate the dosimetric characteristics of each sector of the Leksell Gamma Knife Perfexion (LGK PFX) and to develop tests that can be done for the routine quality assurance checks of the sectors of the LGK PFX. METHODS: The following tests were performed to evaluate the dosimetric characteristics of the sectors: (1) Flash-radiation dose for the 16 mm collimator, (2) transit-radiation dose for the 8 and 4 mm collimators, (3) sector leakage within the radiation cavity and, (4) sector output uniformity. In these tests, the Elekta ABS phantom was used. A micropoint ion-chamber Exradin A16 was placed at the center of the phantom for all measurements. RESULTS: With the version 8.0 of the control software of the MCU in the LGK PFX, the average flash radiation dose per sector for the 16 mm collimator was measured to be 0.423 +/- 0.003 cGy, and the average transit-radiation dose per sector for the 8 and 4 mm collimators was measured to be 0.169 +/- 0.0009 and 0.147 +/- 0.020 cGy, respectively. The calibration dose rate on the day of measurements was 280.8 cGy/min. Here, the authors have introduced a new concept of "equivalent-time duration" (ETD) to represent the time duration, during which the flash-radiation or the transit-radiation dose is delivered. The ETD is a quotient of the measured dose of the flash-radiation or the transit-radiation and the respective calibrated dose rate for the 16, 8, or 4 mm collimator. The ETD constancy is an indicator of the constancy of the sector movements. The average value of ETD per sector was measured to be 724 +/- 6, 313 +/- 2, and 311 +/- 45 ms for the 16, 8, and 4 mm collimators, respectively. During monthly spot checks, the authors have been measuring the total ETD for the flash-radiation when all eight sectors are open with the 16 mm collimator. The average value of the total ETD of the last 40 consecutive months was measured to be 642 +/- 10 ms. This number is a useful quality parameter for the LGK PFX, which can be used to establish the base-line performance of the collimators of the LGK PFX. The reader is alerted that with the newly introduced version 9.0 of the control software of the MCU in the LGK PFX, the flash-radiation and the transit-radiation doses have become practically zero due to the fact that the treatment time is now corrected to compensate for these radiation doses. The sector output uniformity for the 16, 8, and 4 mm collimators was determined to be 98.9%, 97.3%, and 96.6%, respectively. The total leakage radiation with in the radiation cavity from all sectors was measured to be 0.17% of the dose output for the 16 mm collimator. CONCLUSIONS: Our measurements show that the dosimetric characteristics of all sectors of the LGK PFX are satisfactory. The authors recommend that the sector performance of the LGK PFX be determined initially at the time of installation of the LGK PFX and thereafter, at least annually. Similarly, our recommendation is that the total flash-radiation dose for the 16 mm collimator and the corresponding ETD value be measured on a monthly basis. Should any change in the sector movement occur, it will be revealed by the sector performance and the measurement of ETD. PMID- 22225293 TI - Biological-based optimization and volumetric modulated arc therapy delivery for stereotactic body radiation therapy. AB - PURPOSE: To describe biological-based optimization and Monte Carlo (MC) dose calculation-based treatment planning for volumetric modulated arc therapy (VMAT) delivery of stereotactic body radiation therapy (SBRT) in lung, liver, and prostate patients. METHODS: Optimization strategies and VMAT planning parameters using a biological-based optimization MC planning system were analyzed for 24 SBRT patients. Patients received a median dose of 45 Gy [range, 34-54 Gy] for lung tumors in 1-5 fxs and a median dose of 52 Gy [range, 48-60 Gy] for liver tumors in 3-6 fxs. Prostate patients received a fractional dose of 10 Gy in 5 fxs. Biological-cost functions were used for plan optimization, and its dosimetric quality was evaluated using the conformity index (CI), the conformation number (CN), the ratio of the volume receiving 50% of the prescription dose over the planning target volume (Rx/PTV50). The quality and efficiency of the delivery were assessed according to measured quality assurance (QA) passing rates and delivery times. For each disease site, one patient was replanned using physical cost function and compared to the corresponding biological plan. RESULTS: Median CI, CN, and Rx/PTV50 for all 24 patients were 1.13 (1.02-1.28), 0.79 (0.70-0.88), and 5.3 (3.1-10.8), respectively. The median delivery rate for all patients was 410 MU/min with a maximum possible rate of 480 MU/min (85%). Median QA passing rate was 96.7%, and it did not significantly vary with the tumor site. CONCLUSIONS: VMAT delivery of SBRT plans optimized using biological-motivated cost-functions result in highly conformal dose distributions. Plans offer shorter treatment-time benefits and provide efficient dose delivery without compromising the plan conformity for tumors in the prostate, lung, and liver, thereby improving patient comfort and clinical throughput. The short delivery times minimize the risk of patient setup and intrafraction motion errors often associated with long SBRT treatment delivery times. PMID- 22225294 TI - Characterization of ultrasound elevation beamwidth artifacts for prostate brachytherapy needle insertion. AB - PURPOSE: Ultrasound elevation beamwidth leads to image artifacts and uncertainties in localizing objects (such as a surgical needle) in ultrasound images. The authors examined the clinical significance of errors caused by elevation beamwidth artifacts and imaging parameters in needle insertion procedures. METHODS: Beveled prostate brachytherapy needles were inserted through all holes of a grid template under real-time transrectal ultrasound (TRUS) guidance. The needle tip position as indicated by the TRUS image was compared to their observed physical location. A new device was developed to measure the ultrasound elevation beamwidth. RESULTS: Imaging parameters of the TRUS scanner have direct impact on the localization error ranging from 0.5 up to 4 mm. The smallest localization error was observed laterally close to the center of the grid template and axially within the beam's focal zone. Largest localization error occurs laterally around both sides of the grid template and axially within the beam's far field. The authors also found that the localization errors vary with both lateral and elevation offsets. CONCLUSIONS: The authors found properly adjusting the TRUS imaging settings to lower the ultrasound gain and power effectively minimized the appearance of elevation beamwidth artifacts and in turn reduced the localization errors of the needle tip. PMID- 22225295 TI - The development and experimental evaluation of a simple analytical model for the TPR in the build-up region of megavoltage photon beams. AB - PURPOSE: The purpose of this work was to develop a simple analytical model for the tissue phantom ratio (TPR) in the build-up region of megavoltage photon beams and to experimentally evaluate the model under a variety of clinically relevant field configurations. METHODS: Considering electron contamination and primary photons as the main components of the absorbed dose in the build-up region, an analytic expression for the TPR was derived. The electron contamination component was addressed with a biexponential function; the primary photon component was treated as nonlocal energy transport, i.e., assuming the energy deposited by secondary electrons can be described by a biexponential mode similar to that of contaminating electrons. The model contains five independent constants, which were fitted experimentally. The accuracy of the model was evaluated by comparing its results with in-phantom measurements taken on square, rectangular, irregular, and wedged fields, for 6 and 15 MV photon beams on a GE-Saturne 41 accelerator. More specifically, the accuracy of the model was quantified using the gamma index with 2% dose and 2 mm spatial tolerances as described by Low et al. [Med. Phys. 25, 656-661 (1998)]. RESULTS: For square cerrobende blocked fields, the maximum recorded gamma indices were 0.42 and 0.54 for 6 and 15 MV beams, respectively. For "I" shaped fields, the corresponding maxima were 0.64 and 0.52, respectively, while for "cross" shaped fields they were 0.42 and 0.76. For rectangular 10 * 30 cm fields, the corresponding maxima were 0.32 and 0.42, and for 7 * 20 cm fields, they were 0.70 and 0.35, respectively. For square 10 * 10 cm and 15 * 15 cm fields with an acrylic tray, the maxima were 0.57 and 0.45 for 6 MV and 0.32 and 0.77 for 15 MV beams, respectively. For a 10 * 10 cm 60 degrees wedged field, the maxima were 0.53 and 0.33 for 6 and 15 MV beams, respectively. In all examined cases of irregular, rectangular, square (with and without tray), and wedged fields, the gamma index was less than unity. Thus, the model correctly predicted TPR in all cases, using the defined criteria. CONCLUSIONS: A simple analytical model for the TPR in the build-up region was developed and evaluated experimentally. The model's predicted TPR values were compared with physical measurements for irregular, square (with and without tray), rectangular, and wedged fields, for 6 and 15 MV photon beams. In every case examined, the results of the model agreed with the experimental measurements based on specific quantitative agreement criteria. The model appears useful for predicting the TPR in the build-up region of megavoltage beams for different types of fields, in different configurations. PMID- 22225296 TI - The readout thickness versus the measured thickness for a range of screen film mammography and full-field digital mammography units. AB - PURPOSE: To establish a simple method to determine breast readout accuracy on mammography units. METHODS: A thickness measuring device (TMD) was used in conjunction with a breast phantom. This phantom had compression characteristics similar to human female breast tissue. The phantom was compressed, and the thickness was measured using TMD and mammography unit readout. Measurements were performed on a range of screen film mammography (SFM) and full-field digital mammography (FFDM) units (8 units in total; 6 different models/manufacturers) for two different sized paddles and two different compression forces (60 and 100 N). RESULTS: The difference between machine readout and TMD for the breast area, when applying 100 N compression force, for nonflexible paddles was largest for GE Senographe DMR+ (24 cm * 30 cm paddle: +14.3%). For flexible paddles the largest difference occurred for Hologic Lorad Selenia (18 cm * 24 cm paddle: +26.0%). CONCLUSIONS: None of the units assessed were found to have perfect correlation between measured and readout thickness. TMD measures and thickness readouts were different for the duplicate units from two different models/manufacturers. PMID- 22225297 TI - On the dosimetric effect and reduction of inverse consistency and transitivity errors in deformable image registration for dose accumulation. AB - PURPOSE: Deformable image registration (DIR) is necessary for accurate dose accumulation between multiple radiotherapy image sets. DIR algorithms can suffer from inverse and transitivity inconsistencies. When using deformation vector fields (DVFs) that exhibit inverse-inconsistency and are nontransitive, dose accumulation on a given image set via different image pathways will lead to different accumulated doses. The purpose of this study was to investigate the dosimetric effect of and propose a postprocessing solution to reduce inverse consistency and transitivity errors. METHODS: Four MVCT images and four phases of a lung 4DCT, each with an associated calculated dose, were selected for analysis. DVFs between all four images in each data set were created using the Fast Symmetric Demons algorithm. Dose was accumulated on the fourth image in each set using DIR via two different image pathways. The two accumulated doses on the fourth image were compared. The inverse consistency and transitivity errors in the DVFs were then reduced. The dose accumulation was repeated using the processed DVFs, the results of which were compared with the accumulated dose from the original DVFs. To evaluate the influence of the postprocessing technique on DVF accuracy, the original and processed DVF accuracy was evaluated on the lung 4DCT data on which anatomical landmarks had been identified by an expert. RESULTS: Dose accumulation to the same image via different image pathways resulted in two different accumulated dose results. After the inverse consistency errors were reduced, the difference between the accumulated doses diminished. The difference was further reduced after reducing the transitivity errors. The postprocessing technique had minimal effect on the accuracy of the DVF for the lung 4DCT images. CONCLUSIONS: This study shows that inverse consistency and transitivity errors in DIR have a significant dosimetric effect in dose accumulation; Depending on the image pathway taken to accumulate the dose, different results may be obtained. A postprocessing technique that reduces inverse consistency and transitivity error is presented, which allows for consistent dose accumulation regardless of the image pathway followed. PMID- 22225298 TI - Verification of dose distribution for volumetric modulated arc therapy total marrow irradiation in a humanlike phantom. AB - PURPOSE: Volumetric modulated arc therapy (VMAT) treatment planning studies have been reported to provide good target coverage and organs at risk (OARs) sparing in total marrow irradiation (TMI). A comprehensive dosimetric study simulating the clinical situation as close as possible is a norm in radiotherapy before a technique can be used to treat a patient. Without such a study, it would be difficult to make a reliable and safe clinical transition especially with a technique as complicated as VMAT-TMI. To this end, the dosimetric feasibility of VMAT-TMI technique in terms of treatment planning, delivery efficiency, and the most importantly three dimensional dose distribution accuracy was investigated in this study. The VMAT-TMI dose distribution inside a humanlike Rando phantom was measured and compared to the dose calculated using RapidArc especially in the field junctions and the inhomogeneous tissues including the lungs, which is the dose-limiting organ in TMI. METHODS: Three subplans with a total of nine arcs were used to treat the planning target volume (PTV), which was determined as all the bones plus the 3 mm margin. Thermoluminescent detectors (TLDs) were placed at 39 positions throughout the phantom. The measured TLD doses were compared to the calculated plan doses. Planar dose for each arc was verified using mapcheck. RESULTS: TLD readings demonstrated accurate dose delivery, with a median dose difference of 0.5% (range: -4.3% and 6.6%) from the calculated dose in the junctions and in the inhomogeneous medium including the lungs. CONCLUSIONS: The results from this study suggest that RapidArc VMAT technique is dosimetrically accurate, safe, and efficient in delivering TMI within clinically acceptable time frame. PMID- 22225299 TI - Use of weekly 4DCT-based ventilation maps to quantify changes in lung function for patients undergoing radiation therapy. AB - PURPOSE: A method has been proposed to calculate ventilation maps from four dimensional computed tomography (4DCT) images. Weekly 4DCT data were acquired throughout the course of radiation therapy for patients with lung cancer. The purpose of our work was to use ventilation maps calculated from weekly 4DCT data to study how ventilation changed throughout radiation therapy. METHODS: Quantitative maps representing ventilation were generated for six patients. Deformable registration was used to link corresponding lung volume elements between the inhale and exhale phases of the 4DCT dataset. Following spatial registration, corresponding Hounsfield units were input into a density-change based model for quantifying the local ventilation. The ventilation data for all weeks were registered to the pretreatment ventilation image set. We quantitatively analyzed the data by defining regions of interest (ROIs) according to dose (V(20)) and lung lobe and by tracking the weekly ventilation of each ROI throughout treatment. The slope of the linear fit to the weekly ventilation data was used to evaluate the change in ventilation throughout treatment. A positive slope indicated an increase in ventilation, a negative slope indicated a decrease in ventilation, and a slope of 0 indicated no change. The dose ROI ventilation and slope data were used to study how ventilation changed throughout treatment as a function of dose. The lung lobe ROI ventilation data were used to study the impact of the presence of tumor on pretreatment ventilation. In addition, the lobe ROI data were used to study the impact of tumor reduction on ventilation change throughout treatment. RESULTS: Using the dose ROI data, we found that three patients had an increase in weekly ventilation as a function of dose (slopes of 1.1, 1.4, and 1.5) and three patients had no change or a slight decrease in ventilation as a function of dose (slopes of 0.3, -0.6, -0.5). Visually, pretreatment ventilation appeared to be lower in the lobes that contained tumor. Pretreatment ventilation was 39% for lobes that contained tumor and 54% for lobes that did not contain tumor. The difference in ventilation between the two groups was statistically significant (p = 0.017). When the weekly lobe ventilation data were qualitatively observed, two distinct patterns emerged. When the tumor volume in a lobe was reduced, ventilation increased in the lobe. When the tumor volume was not reduced, the ventilation distribution did not change. The average slope of the group of lobes that contained tumors that shrank was 1.18, while the average slope of the group that did not contain tumors (or contained tumors that did not shrink) was -0.32. The slopes for the two groups were significantly different (p = 0.014). CONCLUSIONS: We did not find a consistent pattern of ventilation change as a function of radiation dose. Pretreatment ventilation was significantly lower for lobes that contained tumor, due to occlusion of the central airway. The weekly lobe ventilation data indicated that when tumor volume shrinks, ventilation increases, and when the thoracic anatomy is not visibly changed, ventilation is likely to remain unchanged. PMID- 22225300 TI - Attenuation, scattering, and absorption of ultrasound in the skull bone. AB - PURPOSE: Measured values of ultrasound attenuation in bone represent a combination of different loss mechanisms. As a wave is transmitted from a fluid into bone, reflections occur at the interface. In the bone, mode conversion occurs between longitudinal and shear modes and the mechanical wave is scattered by its complex internal microstructure. Finally, part of the wave energy is absorbed by the bone and converted into heat. Due to the complexity of the wave propagation and the difficulty in performing measurements that are capable of separating the various loss mechanisms, there are currently no estimates of the absorption in bone. The aim of this paper is, thus, to quantify the attenuation, scattering, and thermal absorption in bone. METHODS: An attenuating model of wave propagation in bone is established and used to develop a three-dimensional finite difference time domain numerical algorithm. Hydrophone and optical heterodyne interferometer measurements of the acoustic field as well as a x-ray microtomography of the bone sample are used to drive the simulations and to measure the attenuation. The acoustic measurements are performed concurrently with an infrared camera that can measure the temperature elevation during insonication. A link between the temperature and the absorption via a three dimensional thermal simulation is then used to quantify the absorption coefficients for longitudinal and shear waves in cortical bone. RESULTS: We demonstrate that only a small part of the attenuation is due to absorption in bone and that the majority of the attenuation is due to reflection, scattering, and mode conversion. In the nine samples of a human used for the study, the absorption time constant for cortical bone was determined to be 1.04 MUs +/- 28%. This corresponds to a longitudinal absorption of 2.7 dB/cm and a shear absorption of 5.4 dB/cm. The experimentally measured attenuation across the approximately 8 mm thick samples was 13.3 +/- 0.97 dB/cm. CONCLUSIONS: This first measurement of ultrasound absorption in bone can be used to estimate the amount of heat deposition based on knowledge of the acoustic field. PMID- 22225301 TI - Spatiotemporal Monte Carlo transport methods in x-ray semiconductor detectors: application to pulse-height spectroscopy in a-Se. AB - PURPOSE: The authors describe a detailed Monte Carlo (MC) method for the coupled transport of ionizing particles and charge carriers in amorphous selenium (a-Se) semiconductor x-ray detectors, and model the effect of statistical variations on the detected signal. METHODS: A detailed transport code was developed for modeling the signal formation process in semiconductor x-ray detectors. The charge transport routines include three-dimensional spatial and temporal models of electron-hole pair transport taking into account recombination and trapping. Many electron-hole pairs are created simultaneously in bursts from energy deposition events. Carrier transport processes include drift due to external field and Coulombic interactions, and diffusion due to Brownian motion. RESULTS: Pulse-height spectra (PHS) have been simulated with different transport conditions for a range of monoenergetic incident x-ray energies and mammography radiation beam qualities. Two methods for calculating Swank factors from simulated PHS are shown, one using the entire PHS distribution, and the other using the photopeak. The latter ignores contributions from Compton scattering and K-fluorescence. Comparisons differ by approximately 2% between experimental measurements and simulations. CONCLUSIONS: The a-Se x-ray detector PHS responses simulated in this work include three-dimensional spatial and temporal transport of electron-hole pairs. These PHS were used to calculate the Swank factor and compare it with experimental measurements. The Swank factor was shown to be a function of x-ray energy and applied electric field. Trapping and recombination models are all shown to affect the Swank factor. PMID- 22225302 TI - Characteristics of x-ray beams in two commercial multidetector computed tomography simulators: Monte Carlo simulations. AB - PURPOSE: As multidetector computed tomography (MDCT) scanning is routinely performed for treatment planning in radiation oncology, understanding the characteristics of the MDCT x-ray beam is essential to accurately estimate patient dose. The purpose of this study is to characterize the x-ray beams of two commercial MDCT simulators widely used in radiation oncology by Monte Carlo (MC) simulations. METHODS: X-ray tube systems of two wide bore MDCT scanners (GE LightSpeed RT 4 and Philips Brilliance Big Bore) were modeled in the BEAMNRC/EGSNRC MC system. All the tube components were modeled from targets to bowtie filters. To validate our MC models, the authors measured half-value layers (HVL) using aluminum sheets and multifunctional radiation detectors and compared them to those obtained from MC simulations for 120 kVp beams. The authors also compared x-ray spectra obtained from MC simulation to the data provided by manufacturers. Additionally, lateral/axial beam profiles were measured in-air using radiochromic films and compared to the MC results. To understand the scatter effect, the authors also derived the scatter-to-primary energy fluence ratio (SPR) profiles and calculated the total SPR for each CT system with the CT dose index (CTDI) head and body phantoms using the BEAMNRC system. RESULTS: The authors found that the HVL, x-ray spectrum and beam profiles of the MC simulations agreed well with the manufacturer-specified data within 1%-10% on average for both scanners. The total SPR were ranged from 7.8 to 13.7% for the head phantom and from 10.7 to 18.9% for the body phantom. CONCLUSIONS: The authors demonstrate the full MC simulations of two commercial MDCT simulators to characterize their x-ray beams. This study may be useful to establish a patient specific dosimetry for the MDCT systems. PMID- 22225304 TI - Evaluating dosimetric accuracy of flattening filter free compensator-based IMRT: measurements with diode arrays. AB - PURPOSE: Compensator-based IMRT coupled with the high dose rate flattening filter free (FFF) beams offers an intriguing possibility of delivering an intensity modulated radiation field in just a few seconds. As a first step, the authors evaluate the dosimetric accuracy of the treatment planning system (TPS) FFF beam model with compensators. METHODS: A 6 MV FFF beam from a TrueBeam accelerator (Varian Medical Systems, Palo Alto CA) was modeled in PINNACLE TPS (v. 9.0, Philips Radiation Oncology, Fitchburg WI). Flat brass slabs from 0.3 to 7 cm thick and an 18 degrees brass wedge were used to adjust the beam model. A 2D (MAPCHECK) and 3D (ARCCHECK) diode arrays (Sun Nuclear Corp, Melbourne FL), were investigated for use with the compensator FFF beams. Corrections for diode sensitivity caused by the spectral changes in the beam were introduced. Four compensator plans based on the AAPM TG-119 report were developed. A composite ion chamber measurement, beam by beam MAPCHECK measurements, and a composite ARCCHECK measurement were performed. The array results were analyzed with the same thresholds as in TG-119 report-3%/3 mm with global dose normalization-as well as with the more stringent combinations of the gamma analysis criteria. RESULTS: The FFF beam shows a greater variation of the effective attenuation coefficient with brass thickness due to the prevalence of the low energy photons compared to the conventional 6X beam. As a result, a compromise had to be made while trying to achieve dose agreement for a combination of field sizes, brass thicknesses, and measurement depths (>=5 cm in water). An agreement of measured and calculated dose to within 1% was observed for brass thicknesses up to 2 cm. For the 3 cm slab, an error of up to 2.8% was noted for the field sizes above 10 * 10 cm(2), and up to 3.8% for the 5 * 5 cm(2) field. Both diode arrays exhibit a substantial sensitivity drop as the compensator thickness increases, reaching 10% for a 7 cm brass slab. A simple correction based on the brass thickness along the ray was introduced to counteract this effect. Pooled for five profiles, the average ratio of uncorrected and corrected MAPCHECK to ion chamber readings are 0.966 and 1.008, respectively. With the proper correction, all MAPCHECK measurement to calculation comparisons exhibit 100% gamma(3%/3 mm) passing rates with global dose-error normalization. For the TG-119-type plans, the average gamma(2%/2 mm) passing rate with local normalization is 94% (range 87.8%-98.3%). The lower ARCCHECK gamma-analysis passing rates (corrected for diode sensitivity) are predictable based on the observed PDD discrepancies. However, with the 3%/3 mm thresholds and global normalization, the average gamma-analysis passing rate is 96.4% (range 89.9%-100%). CONCLUSIONS: MAPCHECK analysis demonstrates high passing rates with the stringent gamma(2%/2 mm) and local normalization criteria combination. The geometry of the ARCCHECK array creates a stress test for the FFF TPS model because of the shallow depth of the entrance diodes and large air cavity. Hence, the ARCCHECK gamma-analysis passing rates are lower than with the MAPCHECK, while still on par with TG-119. PMID- 22225303 TI - Localization accuracy from automatic and semi-automatic rigid registration of locally-advanced lung cancer targets during image-guided radiation therapy. AB - PURPOSE: To evaluate localization accuracy resulting from rigid registration of locally-advanced lung cancer targets using fully automatic and semi-automatic protocols for image-guided radiation therapy. METHODS: Seventeen lung cancer patients, fourteen also presenting with involved lymph nodes, received computed tomography (CT) scans once per week throughout treatment under active breathing control. A physician contoured both lung and lymph node targets for all weekly scans. Various automatic and semi-automatic rigid registration techniques were then performed for both individual and simultaneous alignments of the primary gross tumor volume (GTV(P)) and involved lymph nodes (GTV(LN)) to simulate the localization process in image-guided radiation therapy. Techniques included "standard" (direct registration of weekly images to a planning CT), "seeded" (manual prealignment of targets to guide standard registration), "transitive based" (alignment of pretreatment and planning CTs through one or more intermediate images), and "rereferenced" (designation of a new reference image for registration). Localization error (LE) was assessed as the residual centroid and border distances between targets from planning and weekly CTs after registration. RESULTS: Initial bony alignment resulted in centroid LE of 7.3 +/- 5.4 mm and 5.4 +/- 3.4 mm for the GTV(P) and GTV(LN), respectively. Compared to bony alignment, transitive-based and seeded registrations significantly reduced GTV(P) centroid LE to 4.7 +/- 3.7 mm (p = 0.011) and 4.3 +/- 2.5 mm (p < 1 * 10( 3)), respectively, but the smallest GTV(P) LE of 2.4 +/- 2.1 mm was provided by rereferenced registration (p < 1 * 10(-6)). Standard registration significantly reduced GTV(LN) centroid LE to 3.2 +/- 2.5 mm (p < 1 * 10(-3)) compared to bony alignment, with little additional gain offered by the other registration techniques. For simultaneous target alignment, centroid LE as low as 3.9 +/- 2.7 mm and 3.8 +/- 2.3 mm were achieved for the GTV(P) and GTV(LN), respectively, using rereferenced registration. CONCLUSIONS: Target shape, volume, and configuration changes during radiation therapy limited the accuracy of standard rigid registration for image-guided localization in locally-advanced lung cancer. Significant error reductions were possible using other rigid registration techniques, with LE approaching the lower limit imposed by interfraction target variability throughout treatment. PMID- 22225305 TI - Hierarchical alignment of breast DCE-MR images by groupwise registration and robust feature matching. AB - PURPOSE: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) shows high sensitivity in detecting breast cancer. However, its performance could be affected by patient motion during the imaging. To overcome this problem, it is necessary to correct patient motion by deformable registration, before using the DCE-MRI to detect breast cancer. However, deformable registration of DCE-MR images is challenging due to the dramatic contrast change over time (especially between the precontrast and postcontrast images). Most existing methods typically register each postcontrast image onto the precontrast image independently, without considering the dynamic contrast change after agent uptake. This could lead to the inconsistency among the aligned postcontrast images in the precontrast image space, which will eventually result in worse performance in cancer detection. In this paper, the authors present a novel hierarchical registration framework to address this problem. METHODS: First, the authors propose a hierarchical registration framework to deploy the groupwise registration for simultaneous registration of all postcontrast images onto their group-mean image and further aligning the group-mean image of postcontrast images onto the precontrast image space for final alignment of all precontrast and postcontrast images. In this way, the postcontrast images (with similar intensity patterns) can be jointly aligned onto the precontrast image for increasing their overall consistency after registration. Second, in order to improve the registration between the precontrast image and the group-mean image of the postcontrast images, the authors propose using the contrast-invariant attribute vectors to guide the robust feature matching during the registration. RESULTS: Our proposed hierarchical registration framework has been comprehensively evaluated and compared with affine registration and widely used deformable registration methods in both pairwise and groupwise registration formulation. The experimental results on both real and simulated images show that our method can obtain not only more accurate but also more consistent registration results than any of all other registration algorithms. CONCLUSIONS: The authors have proposed a novel groupwise registration method to achieve accurate and consistent alignment for breast DCE-MR images. In the future, the authors will further evaluate our proposed method with more clinical datasets. PMID- 22225306 TI - In aqua vivo EPID dosimetry. AB - PURPOSE: At the Netherlands Cancer Institute--Antoni van Leeuwenhoek Hospital in vivo dosimetry using an electronic portal imaging device (EPID) has been implemented for almost all high-energy photon treatments of cancer with curative intent. Lung cancer treatments were initially excluded, because the original back projection dose-reconstruction algorithm uses water-based scatter-correction kernels and therefore does not account for tissue inhomogeneities accurately. The aim of this study was to test a new method, in aqua vivo EPID dosimetry, for fast dose verification of lung cancer irradiations during actual patient treatment. METHODS: The key feature of our method is the dose reconstruction in the patient from EPID images, obtained during the actual treatment, whereby the images have been converted to a situation as if the patient consisted entirely of water; hence, the method is termed in aqua vivo. This is done by multiplying the measured in vivo EPID image with the ratio of two digitally reconstructed transmission images for the unit-density and inhomogeneous tissue situation. For dose verification, a comparison is made with the calculated dose distribution with the inhomogeneity correction switched off. IMRT treatment verification is performed for each beam in 2D using a 2D gamma evaluation, while for the verification of volumetric-modulated arc therapy (VMAT) treatments in 3D a 3D gamma evaluation is applied using the same parameters (3%, 3 mm). The method was tested using two inhomogeneous phantoms simulating a tumor in lung and measuring its sensitivity for patient positioning errors. Subsequently five IMRT and five VMAT clinical lung cancer treatments were investigated, using both the conventional back-projection algorithm and the in aqua vivo method. The verification results of the in aqua vivo method were statistically analyzed for 751 lung cancer patients treated with IMRT and 50 lung cancer patients treated with VMAT. RESULTS: The improvements by applying the in aqua vivo approach are considerable. The percentage of gamma values <=1 increased on average from 66.2% to 93.1% and from 43.6% to 97.5% for the IMRT and VMAT cases, respectively. The corresponding mean gamma value decreased from 0.99 to 0.43 for the IMRT cases and from 1.71 to 0.40 for the VMAT cases, which is similar to the accepted clinical values for the verification of IMRT treatments of prostate, rectum, and head-and neck cancers. The deviation between the reconstructed and planned dose at the isocenter diminished on average from 5.3% to 0.5% for the VMAT patients and was almost the same, within 1%, for the IMRT cases. The in aqua vivo verification results for IMRT and VMAT treatments of a large group of patients had a mean gamma of approximately 0.5, a percentage of gamma values <=1 larger than 89%, and a difference of the isocenter dose value less than 1%. CONCLUSIONS: With the in aqua vivo approach for the verification of lung cancer treatments (IMRT and VMAT), we can achieve results with the same accuracy as obtained during in vivo EPID dosimetry of sites without large inhomogeneities. PMID- 22225307 TI - Carotid artery recognition system: a comparison of three automated paradigms for ultrasound images. AB - PURPOSE: The development of completely automated techniques for arterial wall segmentation and intima-media thickness measurement requires the recognition of the artery in the image frame. Conceptually, automated techniques can be thought of as the combination of two cascaded stages: artery recognition and wall segmentation. In this paper, the authors show three carotid artery recognition systems (CARS) that are fully automated. METHODS: The first technique is based on a first-order derivative Gaussian edge analysis (CARSgd). The second method is based on an integrated approach (CARSia) that combines image feature extraction, fitting, and classification. The third strategy is based on signal analysis (CARSsa). The output of all the three paradigms provide tracing of the far adventitial (AD(F)). The authors validated CARSgd, CARSia, and CARSsa on a dataset of 365 longitudinal B-Mode carotid images, acquired by different sonographers. Performance evaluation of the carotid recognition process was done in three ways: (1) visual inspection by experts; (2) by measuring the Hausdorff distance (HD) between the automatic far adventitial (AD(F)) and the manually traced AD(F), and (3) by measuring the HD between AD(F) and the lumen-intima (GT(LI)) and media-adventitia (GT(MA)) borders of the arterial walls. RESULTS: The average HD between AD(F) and the manual AD(F) was 1.53 +/- 1.51 mm for CARSgd, 1.82 +/- 3.08 mm for CARSia, and 2.56 +/- 2.89 mm for CARSsa. The average HD between GT(LI) and AD(F) for CARSgd, CARSia, and CARSsa were 2.16 +/- 1.16 mm, 2.71 +/- 2.89 mm, and 2.66 +/- 1.52 mm, respectively. The average HD between AD(F) and GT(MA) for CARSgd, CARSia, and CARSsa were 1.54 +/- 1.19 mm, 1.86 +/- 2.66 mm, and 1.95 +/- 1.64 mm, respectively. Considering a maximum distance of 50 pixels (about 3 mm), CARSgd showed an identification accuracy of 100%, CARSia of 92%, and CARSsa of 96%. These identification accuracies were confirmed by visual inspection. All the three systems work on MATLAB, Windows OS, and on a PC based cross platform medical application written in Java called ATHEROEDGETM with 1 s per image. CONCLUSIONS: CARSgd showed very accurate AD(F) profiles coupled with a low computational burden and without the need for specific tuning. It can be thought of as a reference technique for carotid localization, to be used in automated intima-media thickness measurement strategies. PMID- 22225308 TI - Gold nanoparticle-aided brachytherapy with vascular dose painting: estimation of dose enhancement to the tumor endothelial cell nucleus. AB - PURPOSE: Theoretical microdosimetry at the subcellular level is employed in this study to estimate the dose enhancement to tumor endothelial cell nuclei, caused by radiation-induced photo/Auger electrons originating from gold nanoparticles (AuNPs) targeting the tumor endothelium, during brachytherapy. METHODS: A tumor vascular endothelial cell (EC) is modeled as a slab of 2 MUm (thickness) * 10 MUm (length) * 10 MUm (width). The EC contains a nucleus of 5 MUm diameter and thickness of 0.5-1 MUm, corresponding to nucleus size 5%-10% of cellular volume, respectively. Analytic calculations based on the electron energy loss formula of Cole were carried out to estimate the dose enhancement to the nucleus caused by photo/Auger electrons from AuNPs attached to the exterior surface of the EC. The nucleus dose enhancement factor (nDEF), representing the ratio of the dose to the nucleus with and without the presence of gold nanoparticles was calculated for different AuNP local concentrations. The investigated concentration range considers the potential for significantly higher local concentration near the EC due to preferential accumulation of AuNP in the tumor vasculature. Four brachytherapy sources: I-125, Pd-103, Yb-169, and 50 kVp x-rays were investigated. RESULTS: For nucleus size of 10% of the cellular volume and AuNP concentrations ranging from 7 to 140 mg/g, brachytherapy sources Pd-103, I-125, 50 kVp, and Yb-169 yielded nDEF values of 5.6-73, 4.8-58.3, 4.7-56.6, and 3.2 25.8, respectively. Meanwhile, for nucleus size 5% of the cellular volume in the same concentration range, Pd-103, I-125, 50 kVp, and Yb-169 yielded nDEF values of 6.9-79.2, 5.1-63.2, 5.0-61.5, and 3.3-28.3, respectively. CONCLUSIONS: The results predict that a substantial dose boost to the nucleus of endothelial cells can be achieved by applying tumor vasculature-targeted AuNPs in combination with brachytherapy. Such vascular dose boosts could induce tumor vascular shutdown, prompting extensive tumor cell death. PMID- 22225309 TI - Accuracy of electromagnetic tracking with a prototype field generator in an interventional OR setting. AB - PURPOSE: The authors have studied the accuracy and robustness of a prototype electromagnetic window field generator (WFG) in an interventional radiology suite with a robotic C-arm. The overall purpose is the development of guidance systems combining real-time imaging with tracking of flexible instruments for bronchoscopy, laparoscopic ultrasound, endoluminal surgery, endovascular therapy, and spinal surgery. METHODS: The WFG has a torus shape, which facilitates x-ray imaging through its centre. The authors compared the performance of the WFG to that of a standard field generator (SFG) under the influence of the C-arm. Both accuracy and robustness measurements were performed with the C-arm in different positions and poses. RESULTS: The system was deemed robust for both field generators, but the accuracy was notably influenced as the C-arm was moved into the electromagnetic field. The SFG provided a smaller root-mean-square position error but was more influenced by the C-arm than the WFG. The WFG also produced smaller maximum and variance of the error. CONCLUSIONS: Electromagnetic (EM) tracking with the new WFG during C-arm based fluoroscopy guidance seems to be a step forward, and with a correction scheme implemented it should be feasible. PMID- 22225310 TI - Dose homogeneity specification for reference dosimetry of nonstandard fields. AB - PURPOSE: To investigate the sensitivity of the plan-class specific correction factor to dose distributions in composite nonstandard field dosimetry. METHODS: A cylindrical water-filled PMMA phantom was constructed at the center of which reference absorbed dose could be measured. Ten different TomoTherapy((r))-based IMRT fields were created on the CT images of the phantom. The dose distribution for each IMRT field was estimated at the position of a radiation detector or ionization chamber. The dose in each IMRT field normalized to that in a reference 10 * 10 cm(2) field was measured using a PTW micro liquid ion chamber. Based on the new dosimetry formalism, a plan-class specific correction factor k(Q(pcsr),Q) (f(pcsr),f(ref)) for each field was measured for two Farmer-type chambers, Exradin A12 and NE2571, as well as for a smaller Exradin A1SL chamber. The dependence of the measured correction factor on parameters characterizing dose distribution was analyzed. RESULTS: Uncertainty on the plan-class specific correction factor measurement was in the range of 0.3%-0.5% and 0.3%-0.8% for the Farmer-type chambers and the Exradin A1SL, respectively. When the heterogeneity of the central region of the target volume was less than 5%, the correction factor did not differ from unity by more than 0.7% for the three air-filled ionization chambers. For more heterogeneous dose deliveries, the correction factor differed from unity by up to 2.4% for the Farmer-type chambers. For the Exradin A1SL, the correction factor was closer to unity due to the reduced effect of dose gradients, while it was highly variable in different IMRT fields because of a more significant impact of positioning uncertainties on the response of this chamber. CONCLUSIONS: The authors have shown that a plan-class specific correction factor can be specified as a function of plan evaluation parameters especially for Farmer-type chambers. This work provides a recipe based on quantifying dose distribution to accurately select air-filled ionization chamber correction factors for nonstandard fields. PMID- 22225311 TI - Monte Carlo modeling and simulations of the High Definition (HD120) micro MLC and validation against measurements for a 6 MV beam. AB - PURPOSE: The most recent Varian((r)) micro multileaf collimator (MLC), the High Definition (HD120) MLC, was modeled using the BEAMNRC Monte Carlo code. This model was incorporated into a Varian medical linear accelerator, for a 6 MV beam, in static and dynamic mode. The model was validated by comparing simulated profiles with measurements. METHODS: The Varian((r)) Trilogy((r)) (2300C/D) accelerator model was accurately implemented using the state-of-the-art Monte Carlo simulation program BEAMNRC and validated against off-axis and depth dose profiles measured using ionization chambers, by adjusting the energy and the full width at half maximum (FWHM) of the initial electron beam. The HD120 MLC was modeled by developing a new BEAMNRC component module (CM), designated HDMLC, adapting the available DYNVMLC CM and incorporating the specific characteristics of this new micro MLC. The leaf dimensions were provided by the manufacturer. The geometry was visualized by tracing particles through the CM and recording their position when a leaf boundary is crossed. The leaf material density and abutting air gap between leaves were adjusted in order to obtain a good agreement between the simulated leakage profiles and EBT2 film measurements performed in a solid water phantom. To validate the HDMLC implementation, additional MLC static patterns were also simulated and compared to additional measurements. Furthermore, the ability to simulate dynamic MLC fields was implemented in the HDMLC CM. The simulation results of these fields were compared with EBT2 film measurements performed in a solid water phantom. RESULTS: Overall, the discrepancies, with and without MLC, between the opened field simulations and the measurements using ionization chambers in a water phantom, for the off-axis profiles are below 2% and in depth-dose profiles are below 2% after the maximum dose depth and below 4% in the build-up region. On the conditions of these simulations, this tungsten-based MLC has a density of 18.7 g cm(- 3) and an overall leakage of about 1.1 +/- 0.03%. The discrepancies between the film measured and simulated closed and blocked fields are below 2% and 8%, respectively. Other measurements were performed for alternated leaf patterns and the agreement is satisfactory (to within 4%). The dynamic mode for this MLC was implemented and the discrepancies between film measurements and simulations are within 4%. CONCLUSIONS: The Varian((r)) Trilogy((r)) (2300 C/D) linear accelerator including the HD120 MLC was successfully modeled and simulated using the Monte Carlo BEAMNRC code by developing an independent CM, the HDMLC CM, either in static and dynamic modes. PMID- 22225312 TI - Multicontrast x-ray computed tomography imaging using Talbot-Lau interferometry without phase stepping. AB - PURPOSE: The purpose of this work is to demonstrate that multicontrast computed tomography (CT) imaging can be performed using a Talbot-Lau interferometer without phase stepping, thus allowing for an acquisition scheme like that used for standard absorption CT. METHODS: Rather than using phase stepping to extract refraction, small-angle scattering (SAS), and absorption signals, the two gratings of a Talbot-Lau interferometer were rotated slightly to generate a moire pattern on the detector. A Fourier analysis of the moire pattern was performed to obtain separate projection images of each of the three contrast signals, all from the same single-shot of x-ray exposure. After the signals were extracted from the detector data for all view angles, image reconstruction was performed to obtain absorption, refraction, and SAS CT images. A physical phantom was scanned to validate the proposed data acquisition method. The results were compared with a phantom scan using the standard phase stepping approach. RESULTS: The reconstruction of each contrast mechanism produced the expected results. Signal levels and contrasts match those obtained using the phase stepping technique. CONCLUSIONS: Absorption, refraction, and SAS CT imaging can be achieved using the Talbot-Lau interferometer without the additional overhead of long scan time and phase stepping. PMID- 22225313 TI - Dosimetric performance and array assessment of plastic scintillation detectors for stereotactic radiosurgery quality assurance. AB - PURPOSE: To compare the performance of plastic scintillation detectors (PSD) for quality assurance (QA) in stereotactic radiosurgery conditions to a microion chamber (IC), Gafchromic EBT2 films, 60 008 shielded photon diode (SD) and unshielded diodes (UD), and assess a new 2D crosshair array prototype adapted to small field dosimetry. METHODS: The PSD consists of a 1 mm diameter by 1 mm long scintillating fiber (BCF-60, Saint-Gobain, Inc.) coupled to a polymethyl methacrylate optical fiber (Eska premier, Mitsubishi Rayon Co., Ltd., Tokyo, Japan). Output factors (S(c,p)) for apertures used in radiosurgery ranging from 4 to 40 mm in diameter have been measured. The PSD crosshair array (PSDCA) is a water equivalent device made up of 49 PSDs contained in a 1.63 cm radius area. Dose profiles measurements were taken for radiosurgery fields using the PSDCA and were compared to other dosimeters. Moreover, a typical stereotactic radiosurgery treatment using four noncoplanar arcs was delivered on a spherical phantom in which UD, IC, or PSD was placed. Using the Xknife planning system (Integra Radionics Burlington, MA), 15 Gy was prescribed at the isocenter, where each detector was positioned. RESULTS: Output Factors measured by the PSD have a mean difference of 1.3% with Gafchromic EBT2 when normalized to a 10 * 10 cm(2) field, and 1.0% when compared with UD measurements normalized to the 35 mm diameter cone. Dose profiles taken with the PSD crosshair array agreed with other single detectors dose profiles in spite of the presence of the 49 PSDs. Gamma values comparing 1D dose profiles obtained with PSD crosshair array with Gafchromic EBT2 and UD measured profiles shows 98.3% and 100.0%, respectively, of detector passing the gamma acceptance criteria of 0.3 mm and 2%. The dose measured by the PSD for a complete stereotactic radiosurgery treatment is comparable to the planned dose corrected for its SD-based S(c,p) within 1.4% and 0.7% for 5 and 35 mm diameter cone, respectively. Furthermore, volume averaging of the IC can be observed for the 5 mm aperture where it differs by as much as 9.1% compared to the PSD measurement. The angular dependency of the UD is also observed, unveiled by an under-response around 2.5% of both 5 and 35 mm apertures. CONCLUSIONS: Output Factors and dose profiles measurements performed, respectively, with the PSD and the PSDCA were in agreement with those obtained with the UD and EBT2 films. For stereotactic radiosurgery treatment verification, the PSD gives accurate results compared to the planning system and the IC once the latter is corrected to compensate for the averaging effect of the IC. The PSD provides precise results when used as a single detector or in a dense array, resulting in a great potential for stereotactic radiosurgery QA measurements. PMID- 22225315 TI - An efficient inverse radiotherapy planning method for VMAT using quadratic programming optimization. AB - PURPOSE: The purpose of this study is to investigate the feasibility of an inverse planning optimization approach for the Volumetric Modulated Arc Therapy (VMAT) based on quadratic programming and the projection method. The performance of this method is evaluated against a reference commercial planning system (eclipse(TM) for rapidarc(TM)) for clinically relevant cases. METHODS: The inverse problem is posed in terms of a linear combination of basis functions representing arclet dose contributions and their respective linear coefficients as degrees of freedom. MLC motion is decomposed into basic motion patterns in an intuitive manner leading to a system of equations with a relatively small number of equations and unknowns. These equations are solved using quadratic programming under certain limiting physical conditions for the solution, such as the avoidance of negative dose during optimization and Monitor Unit reduction. The modeling by the projection method assures a unique treatment plan with beneficial properties, such as the explicit relation between organ weightings and the final dose distribution. Clinical cases studied include prostate and spine treatments. The optimized plans are evaluated by comparing isodose lines, DVH profiles for target and normal organs, and Monitor Units to those obtained by the clinical treatment planning system eclipse(TM). RESULTS: The resulting dose distributions for a prostate (with rectum and bladder as organs at risk), and for a spine case (with kidneys, liver, lung and heart as organs at risk) are presented. Overall, the results indicate that similar plan qualities for quadratic programming (QP) and rapidarc(TM) could be achieved at significantly more efficient computational and planning effort using QP. Additionally, results for the quasimodo phantom [Bohsung et al., "IMRT treatment planning: A comparative inter-system and inter centre planning exercise of the estro quasimodo group," Radiother. Oncol. 76(3), 354-361 (2005)] are presented as an example for an extreme concave case. CONCLUSION: Quadratic programming is an alternative approach for inverse planning which generates clinically satisfying plans in comparison to the clinical system and constitutes an efficient optimization process characterized by uniqueness and reproducibility of the solution. PMID- 22225314 TI - Motion-compensated estimation of delivered dose during external beam radiation therapy: implementation in Philips' Pinnacle(3) treatment planning system. AB - PURPOSE: Recent research efforts investigating dose escalation techniques for three-dimensional conformal radiation therapy (3D CRT) and intensity modulated radiation therapy (IMRT) have demonstrated great benefit when high-dose hypofractionated treatment schemes are implemented. The use of these paradigms emphasizes the importance of smaller treatment margins to avoid high dose to surrounding normal tissue or organs at risk (OARs). However, tighter margins may lead to underdosage of the target due to the presence of organ motion. It is important to characterize organ motion and possibly account for it during treatment delivery. The need for real-time localization of dynamic targets has encouraged the use and development of more continuous motion monitoring systems such as kilo-voltage/fluoroscopic imaging, electromagnetic tracking, and optical monitoring systems. METHODS: This paper presents the implementation of an algorithm to quantify translational and rotational interfractional and intrafractional prostate motion and compute the dosimetric effects of these motion patterns. The estimated delivered dose is compared with the static plan dose to evaluate the success of delivering the plan in the presence of prostate motion. The method is implemented on a commercial treatment planning system (Pinnacle(3), Philips Radiation Oncology Systems, Philips Healthcare) and is termed delivered dose investigational tool (DiDIT). The DiDIT implementation in Pinnacle(3) is validated by comparisons with previously published results. Finally, different workflows are discussed with respect to the potential use of this tool in clinical treatment planning. RESULTS: The DiDIT dose estimation process took approximately 5-20 min (depending on the number of fractions analyzed) on a Pinnacle(3) 9.100 research version running on a Dell M90 system (Dell, Inc., Round Rock, TX, USA) equipped with an Intel Core 2 Duo processor (Intel Corporation, Santa Clara, CA, USA). The DiDIT implementation in Pinnacle(3) was found to be in agreement with previously published results, on the basis of the percent dose difference (PDD). This metric was also utilized to compare plan dose versus delivered dose, for prostate targets in three clinically acceptable treatment plans. CONCLUSIONS: This paper presents results from the implementation of an algorithm on a commercially available treatment planning system that quantifies the dosimetric effects of interfractional and intrafractional motion in external beam radiation therapy (EBRT) of prostate cancer. The implementation of this algorithm within a commercial treatment planning system such as Pinnacle(3) enables easy deployment in the existing clinical workflow. The results of the PDD tests validate the implementation of the DiDIT algorithm in Pinnacle(3), in comparison with previously published results. PMID- 22225316 TI - Numerical prediction of frequency dependent 3D maps of mechanical index thresholds in ultrasonic brain therapy. AB - PURPOSE: Therapeutic ultrasound has been used in the brain for thrombolysis and high intensity focused ultrasound (HIFU) therapy. A low-frequency clinical study of sonothrombolysis, called the transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia (TRUMBI), has revealed an increased incidence of hemorrhage, which may have been caused by cavitation. The goal of this study is to determine if there is a comparable risk of generating cavitation during HIFU brain therapy at different frequencies. METHODS: Two approaches are used to transmit acoustic energy through the skull to the brain: low-frequency ultrasound, with a wavelength that is larger than the skull thickness, and high frequency ultrasound, that is sensitive to aberrations and must use corrective techniques. At high frequency, the mechanical index (MI) is lower, which translates to a higher cavitation threshold. In addition to the nonfocused geometry of the 300 kHz sonothrombolysis treatment device, two types of focused therapeutic transducers were modeled: a low frequency 220 kHz transducer and a 1 MHz transducer that required aberration correction with a time-reversal approach, representing the lowest and highest frequencies currently used. The acoustic field was modeled with a finite difference fullwave acoustic code developed for large scale computations, that is, capable of simulating the entire brain volume. Various MI thresholds and device geometries were considered to determine the regions of the brain that have an increased probability of cavitation events. RESULTS: For an equivalent energy deposition rate, it is shown that at a low frequency there is a significant volume of the brain that is above the MI thresholds. At a high frequency, the volume is over 3 orders of magnitude smaller, and it is entirely confined to a compact focal spot. CONCLUSIONS: The significant frequency dependence of the volumes with an increased probability of cavitation can be attributed to two factors: First, the volume encompassed by the focal region depends on the cube of the frequency. Second, the heat deposition increases with frequency. In conclusion, according to these simulations, the acoustic environment during HIFU brain therapy at 1 MHz is not conducive to a high probability of cavitation in extended regions of the brain. PMID- 22225317 TI - High-quality multiple T(2)(*) contrast MR images from low-quality multi-echo images using temporal-domain denoising methods. AB - PURPOSE: The aim of this study was to develop an effective postprocessing method to increase the signal-to-noise ratio in successive multi-echo magnetic resonance (MR) images acquired at multiple time points and generate high-quality multiple T(2)(*) contrast images from low-quality multi-echo images. METHODS: Successive multi-echo MR images were acquired at multiple time points using a multigradient recalled echo sequence at 3T and rearranged so that each pixel in the images had its own decay signal in the temporal-domain. Two different denonising approaches were implemented in the temporal-domain: (1) In a filtering approach, conventional low-pass filter, median filter, and anisotropic diffusion filter were applied to the decay signals to reduce random noise; (2) In a model-based approach, a non-negative least squares algorithm was applied for fitting to MR relaxation model for decay signals. Numerical simulations and in vivo experiments were conducted. The denoised images were compared to each other by visual inspection and analysis of mean square error (MSE) and contrast-to-noise ratio (CNR) on several regions of interest. RESULTS: Our proposed method suppressed noise in each multi-echo images without introducing spatial artifacts. This was a natural consequence of the proposed denoising process, which was performed in the temporal-domain and did not use any cross-pixel operation. MSEs decreased by a factor of 5.4-7.9 and CNRs increased by a factor of 5 in simulation studies. The results were consistent with the in vivo findings. Random noise in the images was effectively reduced and high-quality multiple T(2)(*) contrast images were obtained. CONCLUSIONS: This study demonstrated that denoising methods in the temporal-domain can effectively suppress noise in the spatial domain, and increase signal-to-noise ratio (SNR) for each image of different T(2)(*) weights at multiple time points, resulting in multiple high-quality T(2)(*) contrast images. PMID- 22225318 TI - An H(infinity) approach for elasticity properties reconstruction. AB - PURPOSE: Quantification of object elasticity properties has significant technical implications as well as important practical applications, such as medical disease diagnosis. In general, given noisy measurements on the kinematic states of the objects from imaging data, the aim is to recover the elasticity parameters for assumed material constitutive models of the objects. The implementation is complicated caused by the large dimensionality of the parameters. METHODS: Various versions of the least-square (LS) methods have been widely used, which, however, do not perform well under reasonably realistic levels of disturbances. Another popular strategy, based on the extended Kalman filter (EKF), is also far from optimal and subject to divergence if either the initializations are poor or the noises are not Gaussian. In this paper, the authors propose a robust system identification paradigm for the quantitative analysis of object elasticity. It is derived and extended from the H(infinity) filtering principles and is particularly powerful for real-world situations where the types and levels of the disturbances are unknown. RESULTS: Using synthetic data, the authors investigate the sensitivity of the strategies toward different types (Gaussian and Poisson) and levels of noises, as well as various initializations. The experimental results show consistently superior performance of the proposed method over the LS and EKF algorithms in reliably identifying object elastic modulus distributions. CONCLUSIONS: Results from phase contrast imaging data of canine hearts and human MRI data are also presented, which demonstrate the power of the framework. PMID- 22225319 TI - A convolution model for obtaining the response of an ionization chamber in static non standard fields. AB - PURPOSE: This work contains an alternative methodology for obtaining correction factors for ionization chamber (IC) dosimetry of small fields and composite fields such as IMRT. The method is based on the convolution/superposition (C/S) of an IC response function (RF) with the dose distribution in a certain plane which includes chamber position. This method is an alternative to the full Monte Carlo (MC) approach that has been used previously by many authors for the same objective. METHODS: The readout of an IC at a point inside a phantom irradiated by a certain beam can be obtained as the convolution of the dose spatial distribution caused by the beam and the IC two-dimensional RF. The proposed methodology has been applied successfully to predict the response of a PTW 30013 IC when measuring different nonreference fields, namely: output factors of 6 MV small fields, beam profiles of cobalt 60 narrow fields and 6 MV radiosurgery segments. The two-dimensional RF of a PTW 30013 IC was obtained by MC simulation of the absorbed dose to cavity air when the IC was scanned by a 0.6 * 0.6 mm(2) cross section parallel pencil beam at low depth in a water phantom. For each of the cases studied, the results of the IC direct measurement were compared with the corresponding obtained by the C/S method. RESULTS: For all of the cases studied, the agreement between the IC direct measurement and the IC calculated response was excellent (better than 1.5%). CONCLUSIONS: This method could be implemented in TPS in order to calculate dosimetry correction factors when an experimental IMRT treatment verification with in-phantom ionization chamber is performed. The miss-response of the IC due to the nonreference conditions could be quickly corrected by this method rather than employing MC derived correction factors. This method can be considered as an alternative to the plan-class associated correction factors proposed recently as part of an IAEA work group on nonstandard field dosimetry. PMID- 22225320 TI - GateCTTM surface tracking system for respiratory signal reconstruction in 4DCT imaging. AB - PURPOSE: To assess the temporal and spatial accuracy of the GateCTTM system (VisionRT, London, UK), a recently released respiratory tracking system for 4DCT, under both ideal and nonideal respiratory conditions. METHODS: Three experiments were performed by benchmarking and comparing its results with the ground-truth input data and those generated by the widely used Varian RPMTM system (Real-time Position Management, Varian, Palo Alto, CA). The first experiment used 10 sinusoidal breathing patterns (constant amplitude and frequency using sin(6)omegat), 10 "consistent" patient breathing patterns, and 10 "sporadic" patient breathing patterns. Motion was simulated with the quasarTM Programmable Respiratory Motion Platform (MODUS, London, Canada) as the surrogate. The GateCTTM and RPMTM systems were used to track the breathing patterns. The data from both systems were then analyzed in the Fourier domain, to evaluate temporal/phase accuracy, using the Pearson's correlation coefficient (PCC). The analysis correlated the ground-truth input data against the GateCTTM and RPMTM tracking results, respectively. The second experiment used 10 ideal sinusoidal breathing patterns, five of period 2.0 s, and five of period 5.0 s, with varying abdominal amplitudes found in clinical cases (peak-to-peak range: 1.67-10 mm) to test the sensitivity of the system to reconstruct various range of motion. And, the third experiment used 12 consecutive clinical patients to track the abdominal motion simultaneously by the GateCTTM and RPMTM systems. The baseline of the tracking results from both the two systems was analyzed via the mean-position estimate (MPE) calculations. All experiments were tracked for at least 120 s. RESULTS: In the first experiment, the average PCC values (+/-SD) of all thirty breathing patterns were 0.9995 +/- 0.00035 and 0.9994 +/- 0.00041 for the GateCTTM and the RPMTM system, respectively. These nearly identical results demonstrated similar temporal/phase tracking accuracy for the two systems. The results in the second experiment, however, revealed a pattern for the GateCTTM system in which the uncertainty of its mean-position tracking increased as the amplitude of the breathing pattern decreased. For example, a non-negligible baseline drift of up to 29.3% with respect to the peak-to-peak amplitude of 1.67 mm was observed. On the contrary, the RPMTM system displayed a more consistent recording of amplitudes over time with the greatest drift being <7.7%. The third experiment confirmed these findings in the clinical setting. Consistent decrease in PCC values due to the increase in artificial amplitude drifts, as the breathing amplitude decreased, was found. The lowest PCC value was 0.7239 for a patient with 1.57-mm peak-to-peak amplitude. CONCLUSIONS: The GateCTTM system revealed its consistency in temporal/phase tracking but had limitations in accurately tracking the absolute abdominal positions, thus suggesting its appropriateness for phase-sorting of 4DCT rather than amplitude-sorting. In contrast, the RPMTM system demonstrated stable respiratory signal tracking in all ranges and accurately both in phase and amplitude, and is a robust system to use for both phase-sorting and amplitude-sorting techniques. The impact of the observed mean-position drift in the GateCTTM system on the resulting 4DCT image quality, in amplitude-sorting, needs further investigation. PMID- 22225321 TI - Automatic vessel lumen segmentation and stent strut detection in intravascular optical coherence tomography. AB - PURPOSE: Optical coherence tomography (OCT) is a catheter-based imaging method that employs near-infrared light to produce high-resolution cross-sectional intravascular images. The authors propose a segmentation technique for automatic lumen area extraction and stent strut detection in intravascular OCT images for the purpose of quantitative analysis of neointimal hyperplasia (NIH). METHODS: A clinical dataset of frequency-domain OCT scans of the human femoral artery was analyzed. First, a segmentation method based on the Markov random field (MRF) model was employed for lumen area identification. Second, textural and edge information derived from local intensity distribution and continuous wavelet transform (CWT) analysis were integrated to extract the inner luminal contour. Finally, the stent strut positions were detected via the introduction of each strut wavelet response across scales into a feature extraction and classification scheme in order to optimize the strut position detection. RESULTS: The inner lumen contour and the position of stent strut were extracted with very high accuracy. Compared with manual segmentation by an expert vascular physician the automatic segmentation had an average overlap value of 0.937 +/- 0.045 for all OCT images included in the study. The strut detection accuracy had an area under the curve (AUC) value of 0.95, together with sensitivity and specificity average values of 0.91 and 0.96, respectively. CONCLUSIONS: A robust automatic segmentation technique integrating textural and edge information for vessel lumen border extraction and strut detection in intravascular OCT images was designed and presented. The proposed algorithm may be employed for automated quantitative morphological analysis of in-stent neointimal hyperplasia. PMID- 22225322 TI - A new multi-object image thresholding method based on correlation between object class uncertainty and intensity gradient. AB - PURPOSE: Image thresholding and gradient analysis have remained popular image preprocessing tools for several decades due to the simplicity and straight forwardness of their definitions. Also, optimum selection of threshold and gradient strength values are hidden steps in many advanced medical imaging algorithms. A reliable method for threshold optimization may be a crucial step toward automation of several medical image based applications. Most automatic thresholding and gradient selection methods reported in literature primarily focus on image histograms ignoring a significant amount of information embedded in the spatial distribution of intensity values forming visible features in an image. Here, we present a new method that simultaneously optimizes both threshold and gradient values for different object interfaces in an image that is based on unification of information from both the histogram and spatial image features; also, the method works for unknown number of object regions. METHODS: A new energy function is formulated by combining the object class uncertainty measure, a histogram-based feature, of each pixel with its image gradient measure, a spatial contextual feature in an image. The energy function is designed to measure the overall compliance of the theoretical premise that, in a probabilistic sense, image intensities with high class uncertainty are associated with high image gradients. Finally, it is expressed as a function of threshold and gradient parameters and optimum combinations of these parameters are sought by locating pits and valleys on the energy surface. A major strength of the algorithm lies in the fact that it does not require the number of object regions in an image to be predefined. RESULTS: The method has been applied on several medical image datasets and it has successfully determined both threshold and gradient parameters for different object interfaces even when some of the thresholds are almost impossible to locate in the histogram. Both accuracy and reproducibility of the method have been examined on several medical image datasets including repeat scan 3D multidetector computed tomography (CT) images of cadaveric ankles specimens. Also, the new method has been qualitatively and quantitatively compared with Otsu's method along with three other algorithms based on minimum error thresholding, maximum segmented image information and minimization of homogeneity- and uncertainty-based energy and the results have demonstrated superiority of the new method. CONCLUSIONS: We have developed a new automatic threshold and gradient strength selection algorithm by combining class uncertainty and spatial image gradient features. The performance of the method has been examined in terms of accuracy and reproducibility and the results found are better as compared to several popular automatic threshold selection methods. PMID- 22225323 TI - CT-PET weighted image fusion for separately scanned whole body rat. AB - PURPOSE: The limited resolution and lack of spatial information in positron emission tomography (PET) images require the complementary anatomic information from the computed tomography (CT) and/or magnetic resonance imaging (MRI). Therefore, multimodality image fusion techniques such as PET/CT are critical in mapping the functional images to structural images and thus facilitate the interpretation of PET studies. In our experimental situation, the CT and PET images are acquired in separate scanners at different times and the inherent differences in the imaging protocols produce significant nonrigid changes between the two acquisitions in addition to dissimilar image characteristics. The registration conditions are also poor because CT images have artifacts due to the limitation of current scanning settings, while PET images are very blurry (in transmission-PET) and have vague anatomical structure boundaries (in emission PET). METHODS: The authors present a new method for whole body small animal multimodal registration. In particular, the authors register whole body rat CT image and PET images using a weighted demons algorithm. The authors use both the transmission-PET and the emission-PET images in the registration process emphasizing particular regions of the moving transmission-PET image using the emission-PET image. After a rigid transformation and a histogram matching between the CT and the transmission-PET images, the authors deformably register the transmission-PET image to the CT image with weights based on the intensity normalized emission-PET image. For the deformable registration process, the authors develop a weighted demons registration method that can give preferences to particular regions of the input image using a weight image. RESULTS: The authors validate the results with nine rat image sets using the M-Hausdorff distance (M-HD) similarity measure with different outlier-suppression parameters (OSP). In comparison with standard methods such as the regular demons and the normalized mutual information (NMI)-based nonrigid free-form deformation (FFD) registration, the proposed weighted demons registration method shows average M-HD errors: 3.99 +/- 1.37 (OSP = 10), 5.04 +/- 1.59 (OSP = 20) and 5.92 +/- 1.61 (OSP = infinity) with statistical significance (p < 0.0003) respectively, while NMI based nonrigid FFD has average M-HD errors: 5.74 +/- 1.73 (OSP = 10), 7.40 +/- 7.84 (OSP = 20) and 9.83 +/- 4.13 (OSP = infinity), and the regular demons has average M-HD errors: 6.79 +/- 0.83 (OSP = 10), 9.19 +/- 2.39 (OSP = 20) and 11.63 +/- 3.99 (OSP = infinity), respectively. In addition to M-HD comparisons, the visual comparisons on the faint-edged region between the CT and the aligned PET images also show the encouraging improvements over the other methods. CONCLUSIONS: In the whole body multimodal registration between CT and PET images, the utilization of both the transmission-PET and the emission-PET images in the registration process by emphasizing particular regions of the transmission-PET image using an emission-PET image is effective. This method holds promise for other image fusion applications where multiple (more than two) input images should be registered into a single informative image. PMID- 22225324 TI - Dynamic cone beam CT angiography of carotid and cerebral arteries using canine model. AB - PURPOSE: This research is designed to develop and evaluate a flat-panel detector based dynamic cone beam CT system for dynamic angiography imaging, which is able to provide both dynamic functional information and dynamic anatomic information from one multirevolution cone beam CT scan. METHODS: A dynamic cone beam CT scan acquired projections over four revolutions within a time window of 40 s after contrast agent injection through a femoral vein to cover the entire wash-in and wash-out phases. A dynamic cone beam CT reconstruction algorithm was utilized and a novel recovery method was developed to correct the time-enhancement curve of contrast flow. From the same data set, both projection-based subtraction and reconstruction-based subtraction approaches were utilized and compared to remove the background tissues and visualize the 3D vascular structure to provide the dynamic anatomic information. RESULTS: Through computer simulations, the new recovery algorithm for dynamic time-enhancement curves was optimized and showed excellent accuracy to recover the actual contrast flow. Canine model experiments also indicated that the recovered time-enhancement curves from dynamic cone beam CT imaging agreed well with that of an IV-digital subtraction angiography (DSA) study. The dynamic vascular structures reconstructed using both projection-based subtraction and reconstruction-based subtraction were almost identical as the differences between them were comparable to the background noise level. At the enhancement peak, all the major carotid and cerebral arteries and the Circle of Willis could be clearly observed. CONCLUSIONS: The proposed dynamic cone beam CT approach can accurately recover the actual contrast flow, and dynamic anatomic imaging can be obtained with high isotropic 3D resolution. This approach is promising for diagnosis and treatment planning of vascular diseases and strokes. PMID- 22225325 TI - An anthropomorphic polyvinyl alcohol brain phantom based on Colin27 for use in multimodal imaging. AB - PURPOSE: In this paper, the method for the creation of an anatomically and mechanically realistic brain phantom from polyvinyl alcohol cryogel (PVA-C) is proposed for validation of image processing methods such as segmentation, reconstruction, registration, and denoising. PVA-C is material widely used in medical imaging phantoms because of its mechanical similarities to soft tissues. METHODS: The phantom was cast in a mold designed using the left hemisphere of the Colin27 brain dataset [C. Holmes et al., "Enhancement of MR images using registration for signal averaging," J. Comput. Assist. Tomogr. 22(2), 324 (1998)]. Marker spheres and inflatable catheters were also implanted to enable good registration comparisons and to simulate tissue deformation, respectively. RESULTS: The phantom contained deep sulci, a complete insular region, and an anatomically accurate left ventricle. It was found to provide good contrast in triple modality imaging, consisting of computed tomography, ultrasound, and magnetic resonance imaging. Multiple sets of multimodal data were acquired from this phantom. CONCLUSIONS: The methods for building the anatomically accurate, multimodality phantom were described in this work. All multimodal data are made available freely to the image processing community (http://pvabrain.inria.fr). We believe the phantom images could allow for the validation and further aid in the development of novel medical image processing techniques. PMID- 22225326 TI - Response to "comment on 'in-patient to isocenter KERMA ratios in CT'" [Med. Phys. 38, 5362-5369 (2010)]. PMID- 22225330 TI - Editorial: honoring Janis Bennett. PMID- 22225331 TI - Introduction: eighth annual Gallery of Nonlinear Images (Dallas, Texas, 2011). PMID- 22225332 TI - Four-dimensional structural dynamics of sheared collagen networks. PMID- 22225334 TI - Mathematical genealogy and department prestige. PMID- 22225333 TI - Tracking the Brownian diffusion of a colloidal tetrahedral cluster. PMID- 22225336 TI - Local action, global impact: forcing nonperiodicity with a single structural unit. PMID- 22225335 TI - Linear shear in a model granular system. PMID- 22225337 TI - How granular materials jam in a hopper. PMID- 22225338 TI - Vibrational resonance in excitable neuronal systems. AB - In this paper, we investigate the effect of a high-frequency driving on the dynamical response of excitable neuronal systems to a subthreshold low-frequency signal by numerical simulation. We demonstrate the occurrence of vibrational resonance in spatially extended neuronal networks. Different network topologies from single small-world networks to modular networks of small-world subnetworks are considered. It is shown that an optimal amplitude of high-frequency driving enhances the response of neuron populations to a low-frequency signal. This effect of vibrational resonance of neuronal systems depends extensively on the network structure and parameters, such as the coupling strength between neurons, network size, and rewiring probability of single small-world networks, as well as the number of links between different subnetworks and the number of subnetworks in the modular networks. All these parameters play a key role in determining the ability of the network to enhance the outreach of the localized subthreshold low frequency signal. Considering that two-frequency signals are ubiquity in brain dynamics, we expect the presented results could have important implications for the weak signal detection and information propagation across neuronal systems. PMID- 22225339 TI - Dual-lag synchronization between coupled chaotic lasers due to path-delay interference. AB - We study experimentally the synchronization dynamics of two semiconductor lasers coupled unidirectionally via two different delayed paths. The emitter laser operates in a chaotic regime characterized by low-frequency fluctuations due to optical feedback and induces a synchronized dynamical activity in the receiver laser, which operates in the continuous-wave regime when uncoupled. Different delays in the two coupling paths lead to the coexistence of two time lags in the synchronized dynamics of the oscillators. This dual-lag synchronization degrades the average synchronization quality of the system of coupled lasers and hinders the transmission of information between them. Numerical simulation results agree with the experimental observations, and allow us to explore this phenomenon in a wide parameter range, and quantify the degree of signal transmission degradation caused by this chaotic path-delay interference. PMID- 22225340 TI - Center manifold reduction for large populations of globally coupled phase oscillators. AB - A bifurcation theory for a system of globally coupled phase oscillators is developed based on the theory of rigged Hilbert spaces. It is shown that there exists a finite-dimensional center manifold on a space of generalized functions. The dynamics on the manifold is derived for any coupling functions. When the coupling function is sin theta, a bifurcation diagram conjectured by Kuramoto is rigorously obtained. When it is not sin theta, a new type of bifurcation phenomenon is found due to the discontinuity of the projection operator to the center subspace. PMID- 22225341 TI - Lyapunov exponents for multi-parameter tent and logistic maps. AB - The behaviour of logistic and tent maps is studied in cases where the control parameter is dependent on iteration number. Analytic results for global Lyapunov exponent are presented in the case of the tent map and numerical results are presented in the case of the logistic map. In the case of a tent map with N control parameters, the fraction of parameter space for which the global Lyapunov exponent is positive is calculated. The case of bi-parameter maps of period N are investigated. PMID- 22225342 TI - Plykin type attractor in electronic device simulated in MULTISIM. AB - An electronic device is suggested representing a non-autonomous dynamical system with hyperbolic chaotic attractor of Plykin type in the stroboscopic map, and the results of its simulation with software package NI MULTISIM are considered in comparison with numerical integration of the underlying differential equations. A main practical advantage of electronic devices of this kind is their structural stability that means insensitivity of the chaotic dynamics in respect to variations of functions and parameters of elements constituting the system as well as to interferences and noises. PMID- 22225343 TI - Understanding the complexity of the Levy-walk nature of human mobility with a multi-scale cost/benefit model. AB - Probability distributions of human displacements have been fit with exponentially truncated Levy flights or fat tailed Pareto inverse power law probability distributions. Thus, people usually stay within a given location (for example, the city of residence), but with a non-vanishing frequency they visit nearby or far locations too. Herein, we show that an important empirical distribution of human displacements (range: from 1 to 1000 km) can be well fit by three consecutive Pareto distributions with simple integer exponents equal to 1, 2, and (>) 3. These three exponents correspond to three displacement range zones of about 1 km ?Deltar?10 km, 10 km ?Deltar?300 km, and 300 km ?Deltar?1000 km, respectively. These three zones can be geographically and physically well determined as displacements within a city, visits to nearby cities that may occur within just one-day trips, and visit to far locations that may require multi-days trips. The incremental integer values of the three exponents can be easily explained with a three-scale mobility cost/benefit model for human displacements based on simple geometrical constrains. Essentially, people would divide the space into three major regions (close, medium, and far distances) and would assume that the travel benefits are randomly/uniformly distributed mostly only within specific urban-like areas. The three displacement distribution zones appear to be characterized by an integer (1, 2, or >3) inverse power exponent because of the specific number (1, 2, or >3) of cost mechanisms (each of which is proportional to the displacement length). The distributions in the first two zones would be associated to Pareto distributions with exponent beta = 1 and beta = 2 because of simple geometrical statistical considerations due to the a priori assumption that most benefits are searched in the urban area of the city of residence or in the urban area of specific nearby cities. We also show, by using independent records of human mobility, that the proposed model predicts the statistical properties of human mobility below 1 km ranges, where people just walk. In the latter case, the threshold between zone 1 and zone 2 may be around 100-200 m and, perhaps, may have been evolutionary determined by the natural human high resolution visual range, which characterizes an area of interest where the benefits are assumed to be randomly and uniformly distributed. This rich and suggestive interpretation of human mobility may characterize other complex random walk phenomena that may also be described by a N-piece fit Pareto distributions with increasing integer exponents. This study also suggests that distribution functions used to fit experimental probability distributions must be carefully chosen for not improperly obscuring the physics underlying a phenomenon. PMID- 22225344 TI - Linear matrix inequality criteria for robust synchronization of uncertain fractional-order chaotic systems. AB - This paper is devoted to synchronization of uncertain fractional-order chaotic systems with fractional-order alpha: 0 < alpha < 1 and 1 <= alpha < 2, respectively. On the basis of the stability theory of fractional-order differential system and the observer-based robust control, two sufficient and necessary conditions for synchronizing uncertain fractional-order chaotic systems with parameter perturbations are presented in terms of linear matrix inequality, which is an efficient method and could be easily solved by the toolbox of MATLAB. Finally, fractional-order uncertain chaotic Lu system with fractional-order alpha = 0.95 and fractional-order uncertain chaotic Lorenz system with fractional-order alpha = 1.05 are taken as numerical examples to show the validity and feasibility of the proposed method. PMID- 22225345 TI - Combinatorial games with a pass: a dynamical systems approach. AB - By treating combinatorial games as dynamical systems, we are able to address a longstanding open question in combinatorial game theory, namely, how the introduction of a "pass" move into a game affects its behavior. We consider two well known combinatorial games, 3-pile Nim and 3-row Chomp. In the case of Nim, we observe that the introduction of the pass dramatically alters the game's underlying structure, rendering it considerably more complex, while for Chomp, the pass move is found to have relatively minimal impact. We show how these results can be understood by recasting these games as dynamical systems describable by dynamical recursion relations. From these recursion relations, we are able to identify underlying structural connections between these "games with passes" and a recently introduced class of "generic (perturbed) games." This connection, together with a (non-rigorous) numerical stability analysis, allows one to understand and predict the effect of a pass on a game. PMID- 22225346 TI - Multiple coherence resonance induced by time-periodic coupling in stochastic Hodgkin-Huxley neuronal networks. AB - In this paper, we study the effect of time-periodic coupling strength (TPCS) on the spiking coherence of Newman-Watts small-world networks of stochastic Hodgkin Huxley (HH) neurons and investigate the relations between the coupling strength and channel noise when coherence resonance (CR) occurs. It is found that, when the amplitude of TPCS is varied, the spiking induced by channel noise can exhibit CR and coherence bi-resonance (CBR), and the CR moves to a smaller patch area (bigger channel noise) when the amplitude increases; when the frequency of TPCS is varied, the intrinsic spiking can exhibit CBR and multiple CR, and the CR always occurs when the frequency is equal to or multiple of the spiking period, manifesting as the locking between the frequencies of the intrinsic spiking and the coupling strength. These results show that TPCS can greatly enhance and optimize the intrinsic spiking coherence, and favors the spiking with bigger channel noise to exhibit CR. This implies that, compared to constant coupling strength, TPCS may play a more efficient role for improving the time precision of the information processing in stochastic neuronal networks. PMID- 22225347 TI - Noise reduction by recycling dynamically coupled time series. AB - We say that several scalar time series are dynamically coupled if they record the values of measurements of the state variables of the same smooth dynamical system. We show that much of the information lost due to measurement noise in a target time series can be recovered with a noise reduction algorithm by crossing the time series with another time series with which it is dynamically coupled. The method is particularly useful for reduction of measurement noise in short length time series with high uncertainties. PMID- 22225348 TI - Adaptive tuning of feedback gain in time-delayed feedback control. AB - We demonstrate that time-delayed feedback control can be improved by adaptively tuning the feedback gain. This adaptive controller is applied to the stabilization of an unstable fixed point and an unstable periodic orbit embedded in a chaotic attractor. The adaptation algorithm is constructed using the speed gradient method of control theory. Our computer simulations show that the adaptation algorithm can find an appropriate value of the feedback gain for single and multiple delays. Furthermore, we show that our method is robust to noise and different initial conditions. PMID- 22225349 TI - Fractal descriptors in the Fourier domain applied to color texture analysis. AB - The present work proposes the development of a novel method to provide descriptors for colored texture images. The method consists of two steps. First, we apply a linear transform in the color space of the image aiming at highlighting spatial structuring relations among the color of pixels. Second, we apply a multiscale approach to the calculus of fractal dimension based on Fourier transform. From this multiscale operation, we extract the descriptors that are used to discriminate the texture represented in digital images. The accuracy of the method is verified in the classification of two color texture datasets, by comparing the performance of the proposed technique to other classical and state of-the-art methods for color texture analysis. The results showed an advantage of almost 3% of the proposed technique over the second best approach. PMID- 22225350 TI - Melnikov's criteria, parametric control of chaos, and stationary chaos occurrence in systems with asymmetric potential subjected to multiscale type excitation. AB - We consider the problems of chaos and parametric control in nonlinear systems under an asymmetric potential subjected to a multiscale type excitation. The lower bound line for horseshoes chaos is analyzed using the Melnikov's criterion for a transition to permanent or transient nonperiodic motions, complement by the fractal or regular shape of the basin of attraction. Numerical simulations based on the basins of attraction, bifurcation diagrams, Poincare sections, Lyapunov exponents, and phase portraits are used to show how stationary dissipative chaos occurs in the system. Our attention is focussed on the effects of the asymmetric potential term and the driven frequency. It is shown that the threshold amplitude ?gamma(c)? of the excitation decreases for small values of the driven frequency omega and increases for large values of omega. This threshold value decreases with the asymmetric parameter alpha and becomes constant for sufficiently large values of alpha. gamma(c) has its maximum value for asymmetric load in comparison with the symmetric load. Finally, we apply the Melnikov theorem to the controlled system to explore the gain control parameter dependencies. PMID- 22225351 TI - Combination synchronization of three classic chaotic systems using active backstepping design. AB - In this paper, an active backstepping design is proposed to achieve combination synchronization between three different chaotic systems: Lorenz system, Chen's system, and Lu system. The proposed method is a systematic design approach and consists in a recursive procedure that interlaces the choice of a Lyapunov function with the design of active control. Numerical simulations are shown to verify the feasibility and effectiveness of the proposed control technique. PMID- 22225352 TI - Enhancement and weakening of stochastic resonance for a coupled system. AB - In the paper, we investigate the phenomenon of stochastic resonance of a system with finite locally coupled linear elements driven by multiplicative dichotomous noise and temporal periodic signal. It is shown that, for some suitably selected values of the parameters, with increasing the size of the system or the coupling among the nearest elements, the stochastic resonance phenomenon can be enhanced; while for some other suitably selected parameters' values, with the increase of the size or the coupling, the phenomenon of stochastic resonance can be weakened. Our results can provide some useful insights for the investigation of the stochastic resonance phenomenon of the systems with locally (or globally) coupled finite (or infinite) elements. PMID- 22225353 TI - Finding communities in weighted networks through synchronization. AB - Community detection in weighted networks is an important challenge. In this paper, we introduce a local weight ratio scheme for identifying the community structures of weighted networks within the context of the Kuramoto model by taking into account weights of links. The proposed scheme takes full advantage of the information of the link density among vertices and the closeness of relations between each vertex and its neighbors. By means of this scheme, we explore the connection between community structures and dynamic time scales of synchronization. Moreover, we can also unravel the hierarchical structures of weighted networks with a well-defined connectivity pattern by the synchronization process. The performance of the proposed method is evaluated on both computer generated benchmark graphs and real-world networks. PMID- 22225354 TI - On stochastic stabilization of the Kelvin-Helmholtz instability by three-wave resonant interaction. AB - An analytical investigation of the effect of three-wave resonant interactions with the linearly unstable wave is proposed. We consider the waves in the Kelvin Helmholtz model, consisting of two fluid layers with different densities and velocities. We suppose that the velocity shear is weakly supercritical, the instability is of the algebraic type, i.e., the amplitude of the unstable wave grows linearly, and the instability occurs within the framework of a single mode. The amplitudes of two other waves taking part in the nonlinear interaction are assumed to be stable. The initial amplitudes of these waves are supposed to be small in comparison with the initial amplitude of the unstable wave. We present an analysis of the system of amplitude equations derived for this case using JWKB method. As a result, we obtain equations that couple solutions pre- and post passing the singular point, i.e., the point where the amplitude of the unstable wave has a local minimum. These equations give us the transformation rule of a parameter that characterizes the phase shift between fast and slow waves and defines the behavior of the system. This parameter is constant between two singular points and varies by chance at a singular point. As long as it stays positive, the amplitude of the wave remains limited and performs stochastic oscillations. If this parameter passes over zero, then we leave the region of stabilization and turn out in the region, where the amplitude grows infinitely. Accordingly, the transition to the region of instability happens stochastically. However, if the time interval, when the amplitude remains bounded, is large enough, the proposed scenario can be treated as a partial stabilization of instability. PMID- 22225355 TI - Unexpected light behaviour in periodic segmented waveguides. AB - In this article, it is shown that multimode periodic segmented waveguides (PSW) are versatile optical systems in which properties of wave chaos can be highlighted. Numerical wave analysis reveals that structures of quantum phase space of PSW are similar to Poincare sections which display a mixed phase space where stability islands are surrounded by a chaotic sea. Then, unexpected light behavior can occur such as, input gaussian beams do not diverge during the propagation in a highly multimode waveguide. PMID- 22225356 TI - Synaptic plasticity modulates autonomous transitions between waking and sleep states: insights from a Morris-Lecar model. AB - The transitions between waking and sleep states are characterized by considerable changes in neuronal firing. During waking, neurons fire tonically at irregular intervals and a desynchronized activity is observed at the electroencephalogram. This activity becomes synchronized with slow wave sleep onset when neurons start to oscillate between periods of firing (up-states) and periods of silence (down states). Recently, it has been proposed that the connections between neurons undergo potentiation during waking, whereas they weaken during slow wave sleep. Here, we propose a dynamical model to describe basic features of the autonomous transitions between such states. We consider a network of coupled neurons in which the strength of the interactions is modulated by synaptic long term potentiation and depression, according to the spike time-dependent plasticity rule (STDP). The model shows that the enhancement of synaptic strength between neurons occurring in waking increases the propensity of the network to synchronize and, conversely, desynchronization appears when the strength of the connections become weaker. Both transitions appear spontaneously, but the transition from sleep to waking required a slight modification of the STDP rule with the introduction of a mechanism which becomes active during sleep and changes the proportion between potentiation and depression in accordance with biological data. At the neuron level, transitions from desynchronization to synchronization and vice versa can be described as a bifurcation between two different states, whose dynamical regime is modulated by synaptic strengths, thus suggesting that transition from a state to an another can be determined by quantitative differences between potentiation and depression. PMID- 22225357 TI - Jumps of adiabatic invariant at the separatrix of a degenerate saddle point. AB - We consider a slow-fast Hamiltonian system with two degrees of freedom. One degree of freedom corresponds to slow variables, and the other one corresponds to fast variables. A characteristic ratio of the rates of change of slow and fast variables is a small parameter kappa. For every fixed value of the slow variables, in the phase portrait of the fast variables there are a saddle point and separatrices passing through it. When the slow variables change, phase points may cross the separatrices. The action variable of the fast motion is an adiabatic invariant of the full system as long as a trajectory is far from the separatrices: value of the adiabatic invariant is conserved with an accuracy of order of kappa on time intervals of order of 1/kappa. A passage through a narrow neighborhood of the separatrices results in a jump of the adiabatic invariant. We consider a case when the saddle point is degenerate. We derive an asymptotic formula for the jump of the adiabatic invariant which turns out to be a value of order of kappa(3/4) (in the case of a non-degenarate saddle point a similar jump is known to be a value of order of kappa). Accumulation of these jumps after many consecutive separatrix crossings leads to the "diffusion" of the adiabatic invariant and chaotic dynamics. We verify the analytical expression for the jump of the adiabatic invariant by numerical simulations. We discuss application of the obtained results to the description of charged particle dynamics in the Earth magnetosphere. PMID- 22225358 TI - Nonlinear systems identification by combining regression with bootstrap resampling. AB - A new parameter estimation method for nonlinear systems from time series data is proposed. For the purpose of unbiased estimation, we employ the idea of bootstrap method on regression problems. Our method can be applied into even short and noisy data and is expected to give us a robust estimation. Some benchmarks of estimating chaotic models show its practical applicability. We also try to apply this method to analysis for intermittent hormonal therapy for prostate cancer by using a mathematical model and real clinical data. PMID- 22225359 TI - Shrimp-shape domains in a dissipative kicked rotator. AB - Some dynamical properties for a dissipative kicked rotator are studied. Our results show that when dissipation is taken into account a drastic change happens in the structure of the phase space in the sense that the mixed structure is modified and attracting fixed points and chaotic attractors are observed. A detailed numerical investigation in a two-dimensional parameter space based on the behavior of the Lyapunov exponent is considered. Our results show the existence of infinite self-similar shrimp-shaped structures corresponding to periodic attractors, embedded in a large region corresponding to the chaotic regime. PMID- 22225360 TI - Mapping the Arnold web with a graphic processing unit. AB - The Arnold diffusion constitutes a dynamical phenomenon which may occur in the phase space of a non-integrable Hamiltonian system whenever the number of the system degrees of freedom is M >= 3. The diffusion is mediated by a web-like structure of resonance channels, which penetrates the phase space and allows the system to explore the whole energy shell. The Arnold diffusion is a slow process; consequently, the mapping of the web presents a very time-consuming task. We demonstrate that the exploration of the Arnold web by use of a graphic processing unit-supercomputer can result in distinct speedups of two orders of magnitude as compared with standard CPU-based simulations. PMID- 22225361 TI - Relating the sequential dynamics of excitatory neural networks to synaptic cellular automata. AB - We have developed a new approach for the description of sequential dynamics of excitatory neural networks. Our approach is based on the dynamics of synapses possessing the short-term plasticity property. We suggest a model of such synapses in the form of a second-order system of nonlinear ODEs. In the framework of the model two types of responses are realized-the fast and the slow ones. Under some relations between their timescales a cellular automaton (CA) on the graph of connections is constructed. Such a CA has only a finite number of attractors and all of them are periodic orbits. The attractors of the CA determine the regimes of sequential dynamics of the original neural network, i.e., itineraries along the network and the times of successive firing of neurons in the form of bunches of spikes. We illustrate our approach on the example of a Morris-Lecar neural network. PMID- 22225362 TI - Chaotic phase synchronization in a modular neuronal network of small-world subnetworks. AB - We investigate the onset of chaotic phase synchronization of bursting oscillators in a modular neuronal network of small-world subnetworks. A transition to mutual phase synchronization takes place on the bursting time scale of coupled oscillators, while on the spiking time scale, they behave asynchronously. It is shown that this bursting synchronization transition can be induced not only by the variations of inter- and intra-coupling strengths but also by changing the probability of random links between different subnetworks. We also analyze the effect of external chaotic phase synchronization of bursting behavior in this clustered network by an external time-periodic signal applied to a single neuron. Simulation results demonstrate a frequency locking tongue in the driving parameter plane, where bursting synchronization is maintained, even with the external driving. The width of this synchronization region increases with the signal amplitude and the number of driven neurons but decreases rapidly with the network size. Considering that the synchronization of bursting neurons is thought to play a key role in some pathological conditions, the presented results could have important implications for the role of externally applied driving signal in controlling bursting activity in neuronal ensembles. PMID- 22225363 TI - Applying snapback repellers in resource budget models. AB - In Satake's generalized resource budget model of ecology, which was modified from Isagi's resource budget model, Satake and Iwasa illustrated, by computing the positive Lyapunov exponent, that if the depletion coefficient is greater than one, then the system is chaotic. However, a positive Lyapunov exponent implies only sensitivity in Devaney's chaos. Therefore, this work presents mathematical viewpoints and numerical analysis on Satake's generalized resource budget model to rigorously prove that the generalized resource budget model is chaotic in Devaney's sense by using the snapback repeller theory and the topological entropy theory. Moreover, this work also investigates that there is a significant difference between the behaviors of positive odd depletion coefficients and positive even depletion coefficients under numerical computations. PMID- 22225364 TI - The two-stage dynamics in the Fermi-Pasta-Ulam problem: from regular to diffusive behavior. AB - A numerical and analytical study of the relaxation to equilibrium of both the Fermi-Pasta-Ulam (FPU) alpha-model and the integrable Toda model, when the fundamental mode is initially excited, is reported. We show that the dynamics of both systems is almost identical on the short term, when the energies of the initially unexcited modes grow in geometric progression with time, through a secular avalanche process. At the end of this first stage of the dynamics, the time-averaged modal energy spectrum of the Toda system stabilizes to its final profile, well described, at low energy, by the spectrum of a q-breather. The Toda equilibrium state is clearly shown to describe well the long-living quasi-state of the FPU system. On the long term, the modal energy spectrum of the FPU system slowly detaches from the Toda one by a diffusive-like rising of the tail modes, and eventually reaches the equilibrium flat shape. We find a simple law describing the growth of tail modes, which enables us to estimate the time-scale to equipartition of the FPU system, even when, at small energies, it becomes unobservable. PMID- 22225365 TI - Output-feedback lag-synchronization of time-delayed chaotic systems in the presence of external disturbances subjected to input nonlinearity. AB - In this paper, an adaptive output error feedback control scheme is proposed for the lag-synchronization of two time-delayed chaotic systems in the presence of channel time-delay, external disturbances and input nonlinearity. Using the Lyapunov theory, stability of the proposed adaptive controller is proved. Lyapunov-Krasovskii approach is used to deal with the existence of time-delay in the system dynamics. Finally, two numerical simulations are presented to illustrate the effectiveness of the developed method. PMID- 22225366 TI - Detecting the topologies of complex networks with stochastic perturbations. AB - How to recover the underlying connection topology of a complex network from observed time series of a component variable of each node subject to random perturbations is studied. A new technique termed Piecewise Granger Causality is proposed. The validity of the new approach is illustrated with two FitzHugh Nagumo neurobiological networks by only observing the membrane potential of each neuron, where the neurons are coupled linearly and nonlinearly, respectively. Comparison with the traditional Granger causality test is performed, and it is found that the new approach outperforms the traditional one. The impact of the network coupling strength and the noise intensity, as well as the data length of each partition of the time series, is further analyzed in detail. Finally, an application to a network composed of coupled chaotic Rossler systems is provided for further validation of the new method. PMID- 22225367 TI - Variability of contact process in complex networks. AB - We study numerically how the structures of distinct networks influence the epidemic dynamics in contact process. We first find that the variability difference between homogeneous and heterogeneous networks is very narrow, although the heterogeneous structures can induce the lighter prevalence. Contrary to non-community networks, strong community structures can cause the secondary outbreak of prevalence and two peaks of variability appeared. Especially in the local community, the extraordinarily large variability in early stage of the outbreak makes the prediction of epidemic spreading hard. Importantly, the bridgeness plays a significant role in the predictability, meaning the further distance of the initial seed to the bridgeness, the less accurate the predictability is. Also, we investigate the effect of different disease reaction mechanisms on variability, and find that the different reaction mechanisms will result in the distinct variabilities at the end of epidemic spreading. PMID- 22225368 TI - Optimal pinning synchronization on directed complex network. AB - In this paper, pinning synchronization on directed network was considered. By analyzing, some general synchronization criteria on directed network were established. And then, we verified it on directed globally coupled network, directed scale-free network, and directed small-world network, respectively. The pinning nodes were selected, respectively, according to order of in-degrees and out-degrees. Through comparing and analyzing simulations, the optimal pinning scheme was found, and a practical principle was induced finally. PMID- 22225369 TI - Effects of thermal gradients on the intensity of vortices generated in a cylindrical annulus. AB - This paper shows the influence of horizontal and vertical temperature gradients on the intensity of vertical vortices, qualitatively similar to dust devils, generated by a convective instability in a cylindrical annulus non-homogeneously heated. The behavior of the vortices formed is studied, showing that the increase of the temperature gradients intensifies the strength of the vortical structures developed and vice versa, small horizontal and vertical temperature gradients lead to weaker vortices or even make them disappear. Consequently, the intensity of the vortices can be controlled thermally by cooling or heating adequately the bottom boundary. PMID- 22225370 TI - Fractal structures in two-metal electrodeposition systems I: Pb and Zn. AB - Pattern formation in two-metal electrochemical deposition has been scarcely explored in the chemical literature. In this paper, we report new experiments on zinc-lead fractal co-deposition. Electrodeposits are grown in special cells at a fixed large value of the zinc ion concentration, while that of the lead ion is increased gradually. A very wide diversity of morphologies are obtained and classified. Most of the deposited domains are almost exclusively Pb or Zn. But certain regions originating at the base cathode, ranging from a short grass alley to dense, grown-up bushes or shrubs, manifest a combined Pb-Zn composition. Composition is determined using scanning electron microscopy/energy dispersive x ray measurements as well atomic absorption spectroscopy. Pb domains are characterized by shiny leaf-like and dense deposits as well as flowers with round, balloon-like corollas. The Zn zones display a greater variety of morphologies such as thick trunks and thin and fine branching, in addition to minute "cigar flower" structures. The various morphologies are analyzed and classified from the viewpoint of fractal nature, characterized by the box-count fractal dimension. Finally, macroscopic spatial alternation between two different characteristic morphologies is observed under certain conditions. PMID- 22225371 TI - Robust adaptive synchronization for a general class of uncertain chaotic systems with application to Chua's circuit. AB - The synchronization problem for a general class of uncertain chaotic systems is addressed. The underlying systems may be perturbed by unknown time-varying parameters, unstructured uncertainties, and external disturbances. Meanwhile, the time-varying parameters and disturbances are neither required to be periodic nor to have known bounds. Assuming the disturbances are L(2) signals, an adaptive control incorporated with H(infinity) control technique is employed to construct a robust adaptive synchronization algorithm. Then, removing such assumption, a novel adaptive-based method is developed to achieve the goal of synchronization. In order to demonstrate the effectiveness of the proposed algorithms, such methods are applied to solve the synchronization problem of uncertain chaotic Chua's circuits. PMID- 22225372 TI - Modeling of relay helix functional dynamics and feasibility of experimental verification by neutron scattering. AB - Cellular long-range transport involves motor proteins (MPs) (especially, kinesin and myosin) which contain a so-called relay helix. Its motion is of crucial importance to the conversion of chemical energy released in ATP hydrolysis into the coordinated mechanical movement of the entire motor protein. In this paper, we propose two combined nonlinear mechanisms for this particular functional activity and suggest the application of neutron scattering assays to experimentally determine the incoherent dynamic structure factor S(q,omega). We argue that this type of experiment is not only feasible but it could offer significant insights into the mechanism of MP function at a molecular level. PMID- 22225373 TI - Eikonal-based initiation of fibrillatory activity in thin-walled cardiac propagation models. AB - Reentrant arrhythmias can be simulated in electrophysiological models of electrical impulse propagation governed by a reaction-diffusion system. To facilitate the initiation of a large number of independent episodes of simulated arrhythmias with controllable level of complexity, a new approach is proposed for thin-walled geometries in which depolarization wave dynamics is essentially two dimensional. Points representing phase singularities are first randomly distributed over the epicardial surface and are assigned a topological charge (direction of rotation). A qualitatively-correct phase map is then reconstructed on the whole surface by interpolation. The eikonal-diffusion equation is used to iteratively regularize the phase map based on a priori information on wavefront propagation. An initial condition for the reaction-diffusion model is created from the resulting phase map with multiple functional/anatomical reentries. Results in an atrial model demonstrate the ability to generate statistical realizations of the same dynamics and to vary the level of complexity measured by the number of phase singularities. A library of 100 simulations with an average number of phase singularities ranging from 1 to 10 is created. An extension to volumetric patient-specific atrial models including fiber orientation and a fast conducting system is presented to illustrate possible applications. PMID- 22225374 TI - Exponential cluster synchronization of impulsive delayed genetic oscillators with external disturbances. AB - This paper investigates the problem of the exponential cluster synchronization of coupled impulsive genetic oscillators with external disturbances and communication delay. Based on the Kronecker product, some new cluster synchronization criteria for coupled impulsive genetic oscillators with attenuation level are derived. The derived results are related to the impulsive strength, and the derived results also indicate that the maximal allowable bound of time delay is inversely proportional to the decay rate, the decay rate is proportional to the couple strength, the maximal allowable bound of time delay is proportional to attenuation level, and the attenuation level is inversely proportional to the couple strength. Moreover, the case when the feedback have different self-delay is also investigated. Finally, numerical examples are given to illustrate the effectiveness of the derived results. PMID- 22225375 TI - Introduction to Focus Issue: nonlinear and stochastic physics in biology. AB - Frank Moss was a leading figure in the study of nonlinear and stochastic processes in biological systems. His work, particularly in the area of stochastic resonance, has been highly influential to the interdisciplinary scientific community. This Focus Issue pays tribute to Moss with articles that describe the most recent advances in the field he helped to create. In this Introduction, we review Moss's seminal scientific contributions and introduce the articles that make up this Focus Issue. PMID- 22225376 TI - Stochastic resonance on a modular neuronal network of small-world subnetworks with a subthreshold pacemaker. AB - We study the phenomenon of stochastic resonance on a modular neuronal network consisting of several small-world subnetworks with a subthreshold periodic pacemaker. Numerical results show that the correlation between the pacemaker frequency and the dynamical response of the network is resonantly dependent on the intensity of additive spatiotemporal noise. This effect of pacemaker-driven stochastic resonance of the system depends extensively on the local and the global network structure, such as the intra- and inter-coupling strengths, rewiring probability of individual small-world subnetwork, the number of links between different subnetworks, and the number of subnetworks. All these parameters play a key role in determining the ability of the network to enhance the noise-induced outreach of the localized subthreshold pacemaker, and only they bounded to a rather sharp interval of values warrant the emergence of the pronounced stochastic resonance phenomenon. Considering the rather important role of pacemakers in real-life, the presented results could have important implications for many biological processes that rely on an effective pacemaker for their proper functioning. PMID- 22225377 TI - Brownian motors and stochastic resonance. AB - We study the transport properties for a walker on a ratchet potential. The walker consists of two particles coupled by a bistable potential that allow the interchange of the order of the particles while moving through a one-dimensional asymmetric periodic ratchet potential. We consider the stochastic dynamics of the walker on a ratchet with an external periodic forcing, in the overdamped case. The coupling of the two particles corresponds to a single effective particle, describing the internal degree of freedom, in a bistable potential. This double well potential is subjected to both a periodic forcing and noise and therefore is able to provide a realization of the phenomenon of stochastic resonance. The main result is that there is an optimal amount of noise where the amplitude of the periodic response of the system is maximum, a signal of stochastic resonance, and that precisely for this optimal noise, the average velocity of the walker is maximal, implying a strong link between stochastic resonance and the ratchet effect. PMID- 22225378 TI - Nonlinear dynamics of skin potentials in the electrosensory paddlefish. AB - It is known that steady skin potentials are present in fishes due to chloride pumps in the gills and in the skin. We have found previously that these skin potentials can fluctuate and oscillate in the electrosensory paddlefish. Here we show that larger, discharge like potentials can be triggered by applying external electric fields in the water surrounding the fish. These resemble action potentials in nerve cells, but have a longer time scale. Like action potentials, these discharges travel laterally in the skin. They start at the tip of the rostrum and propagate caudally to the tip of the gill covers. They follow the all or-nothing rule and need some refractory period before they can be evoked again. This is the first time that such discharges, so strikingly similar to action potentials, have been described at the level of a whole organism. PMID- 22225380 TI - Synchronization analysis of voltage-sensitive dye imaging during focal seizures in the rat neocortex. AB - Seizures are often assumed to result from an excess of synchronized neural activity. However, various recent studies have suggested that this is not necessarily the case. We investigate synchronization during focal neocortical seizures induced by injection of 4-aminopyridine (4AP) in the rat neocortex in vivo. Neocortical activity is monitored by field potential recording and by the fluorescence of the voltage-sensitive dye RH-1691. After removal of artifacts, the voltage-sensitive dye (VSD) signal is analyzed using the nonlinear dynamics based technique of stochastic phase synchronization in order to determine the degree of synchronization within the neocortex during the development and spread of each seizure event. Results show a large, statistically significant increase in synchronization during seizure activity. Synchrony is typically greater between closer pixel pairs during a seizure event; the entire seizure region is synchronized almost exactly in phase. This study represents, to our knowledge, the first application of synchronization analysis methods to mammalian VSD imaging in vivo. Our observations indicate a clear increase in synchronization in this model of focal neocortical seizures across a large area of the neocortex; a sharp increase in synchronization during seizure events was observed in all 37 seizures imaged. The results are consistent with a recent computational study which simulates the effect of 4AP in a neocortical neuron model. PMID- 22225381 TI - Coherence depression in stochastic excitable systems with two-frequency forcing. AB - We study the response of two generic neuron models, the leaky integrate-and-fire (LIF) model and the leaky integrate-and-fire model with dynamic threshold (LIFDT) (i.e., with memory) to a stimulus consisting of two sinusoidal drives with incommensurate frequency, an amplitude modulation ("envelope") noise and a relatively weak additive noise. Spectral and coherence analysis of responses to such naturalistic stimuli reveals how the LIFDT model exhibits better correlation between modulation and spike train even in the presence of both noises. However, a resonance-induced synchrony, occurring when the beat frequency between the sinusoids is close to the intrinsic neuronal firing rate, decreases the coherence in the dynamic threshold case. Under suprathreshold conditions, the modulation noise simultaneously decreases the linear spectral coherence between the spikes and the whole stimulus, as well as between spikes and the stimulus envelope. Our study shows that the coefficient of variation of the envelope fluctuations is positively correlated with the degree of coherence depression. As the coherence function quantifies the linear information transmission, our findings indicate that under certain conditions, a transmission loss results when an excitable system with adaptive properties encodes a beat with frequency in the vicinity of its mean firing rate. PMID- 22225379 TI - Sensory coding in oscillatory electroreceptors of paddlefish. AB - Coherence and information theoretic analyses were applied to quantitate the response properties and the encoding of time-varying stimuli in paddlefish electroreceptors (ERs), studied in vivo. External electrical stimuli were Gaussian noise waveforms of varied frequency band and strength, including naturalistic waveforms derived from zooplankton prey. Our coherence analyses elucidated the role of internal oscillations and transduction processes in shaping the 0.5-20 Hz best frequency tuning of these electroreceptors, to match the electrical signals emitted by zooplankton prey. Stimulus-response coherence fell off above approximately 20 Hz, apparently due to intrinsic limits of transduction, but was detectable up to 40-50 Hz. Aligned with this upper fall off was a narrow band of intense internal noise at ~25 Hz, due to prominent membrane potential oscillations in cells of sensory epithelia, which caused a narrow deadband of external insensitivity. Using coherence analysis, we showed that more than 76% of naturalistic stimuli of weak strength, ~1 MUV/cm, was linearly encoded into an afferent spike train, which transmitted information at a rate of ~30 bits/s. Stimulus transfer to afferent spike timing became essentially nonlinear as the stimulus strength was increased to induce bursting firing. Strong stimuli, as from nearby zooplankton prey, acted to synchronize the bursting responses of afferents, including across populations of electroreceptors, providing a plausible mechanism for reliable information transfer to higher-order neurons through noisy synapses. PMID- 22225382 TI - Testing resonating vector strength: auditory system, electric fish, and noise. AB - Quite often a response to some input with a specific frequency nu(?) can be described through a sequence of discrete events. Here, we study the synchrony vector, whose length stands for the vector strength, and in doing so focus on neuronal response in terms of spike times. The latter are supposed to be given by experiment. Instead of singling out the stimulus frequency nu(?) we study the synchrony vector as a function of the real frequency variable nu. Its length turns out to be a resonating vector strength in that it shows clear maxima in the neighborhood of nu(?) and multiples thereof, hence, allowing an easy way of determining response frequencies. We study this "resonating" vector strength for two concrete but rather different cases, viz., a specific midbrain neuron in the auditory system of cat and a primary detector neuron belonging to the electric sense of the wave-type electric fish Apteronotus leptorhynchus. We show that the resonating vector strength always performs a clear resonance correlated with the phase locking that it quantifies. We analyze the influence of noise and demonstrate how well the resonance associated with maximal vector strength indicates the dominant stimulus frequency. Furthermore, we exhibit how one can obtain a specific phase associated with, for instance, a delay in auditory analysis. PMID- 22225383 TI - Noise-induced precursors of tonic-to-bursting transitions in hypothalamic neurons and in a conductance-based model. AB - The dynamics of neurons is characterized by a variety of different spiking patterns in response to external stimuli. One of the most important transitions in neuronal response patterns is the transition from tonic firing to burst discharges, i.e., when the neuronal activity changes from single spikes to the grouping of spikes. An increased number of interspike-interval sequences of specific temporal correlations was detected in anticipation of temperature induced tonic-to-bursting transitions in both, experimental impulse recordings from hypothalamic brain slices and numerical simulations of a stochastic model. Analysis of the modelling data elucidates that the appearance of such patterns can be related to particular system dynamics in the vicinity of the period doubling bifurcation. It leads to a nonlinear response on de- and hyperpolarizing perturbations introduced by noise. This explains why such particular patterns can be found as reliable precursors of the neurons' transition to burst discharges. PMID- 22225384 TI - Temperature-dependent stochastic dynamics of the Huber-Braun neuron model. AB - The response of a four-dimensional mammalian cold receptor model to different implementations of noise is studied across a wide temperature range. It is observed that for noisy activation kinetics, the parameter range decomposes into two regions in which the system reacts qualitatively completely different to small perturbations through noise, and these regions are separated by a homoclinic bifurcation. Noise implemented as an additional current yields a substantially different system response at low temperature values, while the response at high temperatures is comparable to activation-kinetic noise. We elucidate how this phenomenon can be understood in terms of state space dynamics and gives quantitative results on the statistics of interspike interval distributions across the relevant parameter range. PMID- 22225385 TI - Variability of spatio-temporal patterns in non-homogeneous rings of spiking neurons. AB - We show that a ring of unidirectionally delay-coupled spiking neurons may possess a multitude of stable spiking patterns and provide a constructive algorithm for generating a desired spiking pattern. More specifically, for a given time periodic pattern, in which each neuron fires once within the pattern period at a predefined time moment, we provide the coupling delays and/or coupling strengths leading to this particular pattern. The considered homogeneous networks demonstrate a great multistability of various travelling time- and space-periodic waves which can propagate either along the direction of coupling or in opposite direction. Such a multistability significantly enhances the variability of possible spatio-temporal patterns and potentially increases the coding capability of oscillatory neuronal loops. We illustrate our results using FitzHugh-Nagumo neurons interacting via excitatory chemical synapses as well as limit-cycle oscillators. PMID- 22225386 TI - Vulnerability to paroxysmal oscillations in delayed neural networks: a basis for nocturnal frontal lobe epilepsy? AB - Resonance can occur in bistable dynamical systems due to the interplay between noise and delay (tau) in the absence of a periodic input. We investigate resonance in a two-neuron model with mutual time-delayed inhibitory feedback. For appropriate choices of the parameters and inputs three fixed-point attractors co exist: two are stable and one is unstable. In the absence of noise, delay-induced transient oscillations (referred to herein as DITOs) arise whenever the initial function is tuned sufficiently close to the unstable fixed-point. In the presence of noisy perturbations, DITOs arise spontaneously. Since the correlation time for the stationary dynamics is ~tau, we approximated a higher order Markov process by a three-state Markov chain model by rescaling time as t -> 2stau, identifying the states based on whether the sub-intervals were completely confined to one basin of attraction (the two stable attractors) or straddled the separatrix, and then determining the transition probability matrix empirically. The resultant Markov chain model captured the switching behaviors including the statistical properties of the DITOs. Our observations indicate that time-delayed and noisy bistable dynamical systems are prone to generate DITOs as switches between the two attractors occur. Bistable systems arise transiently in situations when one attractor is gradually replaced by another. This may explain, for example, why seizures in certain epileptic syndromes tend to occur as sleep stages change. PMID- 22225387 TI - Synchronization of multi-frequency noise-induced oscillations. AB - Using a model system of FitzHugh-Nagumo type in the excitable regime, the similarity between synchronization of self-sustained and noise-induced oscillations is studied for the case of more than one main frequency in the spectrum. It is shown that this excitable system undergoes the same frequency lockings as a self-sustained quasiperiodic oscillator. The presence of noise induced both stable and unstable limit cycles and tori, as well as their tangential bifurcations, are discussed. As the FitzHugh-Nagumo oscillator represents one of the basic neural models, the obtained results are of high importance for neuroscience. PMID- 22225388 TI - Sensitivity analysis of stochastic attractors and noise-induced transitions for population model with Allee effect. AB - We study a stochastically forced predator-prey model with Allee effect. In the deterministic case, this model exhibits non-trivial stable equilibrium or limit cycle corresponding to the coexistence of both species. Computational methods based on the stochastic sensitivity functions technique are suggested for the analysis of the dispersion of random states in stochastic attractors. Our method allows to construct confidence domains and estimate the threshold value of the intensity for noise generating a transition from the coexistence to the extinction. PMID- 22225389 TI - Huygens (and others) revisited. AB - We develop a generic iterative map model of coupled oscillators based on simple physical processes common to many such systems. The model allows us to understand, from a unified perspective, the range of different outcomes reported for experiments by Huygens and modern realizations of his two coupled clocks. PMID- 22225390 TI - Energetics of stochastic resonance. AB - In this paper, we discuss the motion of a Brownian particle in a double-well potential driven by a periodic force in terms of energies delivered by the periodic and the noise forces and energy dissipated into the viscous environment. It is shown that, while the power delivered by the periodic force to the Brownian particle is controlled by the strength of the noise, the power delivered by the noise itself is independent of the amplitude and frequency of the periodic force. The implications of this result for the mechanism of stochastic resonance in an equilibrium system is that it is not energy from the noise force which enhances a small periodic force, but rather an increase of energy delivered by the periodic force, regulated by the strength of the noise. We further re-evaluate the frequency dependence of stochastic resonance in terms of energetic terms including efficiency. PMID- 22225391 TI - Active particles with broken symmetry. AB - We discuss and analyze the driving a polar active particle with a head-tail asymmetry based on the dynamics of an internal motor variable driven by an energy depot and a broken symmetry of friction with respect to the internal degree of freedom. We show that such a driving may be advantageous for driving large masses with small energy uptake from the environment and exhibits interesting properties such as resonance-driven optimal propulsion. PMID- 22225392 TI - Biased Brownian motion in extremely corrugated tubes. AB - Biased Brownian motion of point-size particles in a three-dimensional tube with varying cross-section is investigated. In the fashion of our recent work, Martens et al. [Phys. Rev. E 83, 051135 (2011)] we employ an asymptotic analysis to the stationary probability density in a geometric parameter of the tube geometry. We demonstrate that the leading order term is equivalent to the Fick-Jacobs approximation. Expression for the higher order corrections to the probability density is derived. Using this expansion orders, we obtain that in the diffusion dominated regime the average particle current equals the zeroth order Fick-Jacobs result corrected by a factor including the corrugation of the tube geometry. In particular, we demonstrate that this estimate is more accurate for extremely corrugated geometries compared with the common applied method using a spatially dependent diffusion coefficient D(x, f) which substitutes the constant diffusion coefficient in the common Fick-Jacobs equation. The analytic findings are corroborated with the finite element calculation of a sinusoidal-shaped tube. PMID- 22225393 TI - Surface area of the domain visited by a spherical Brownian particle. AB - A spatial domain swept out by a spherical particle, whose center follows a Wiener trajectory, is referred to as a Wiener sausage. The present study focuses on the surface area of the Wiener sausage. Using intuitive arguments we derive the mean and variance of the surface area, as well as the asymptotic behavior of its probability density in the limits when the area tends to zero and infinity. PMID- 22225394 TI - Unstable periodic orbits and noise in chaos computing. AB - Different methods to utilize the rich library of patterns and behaviors of a chaotic system have been proposed for doing computation or communication. Since a chaotic system is intrinsically unstable and its nearby orbits diverge exponentially from each other, special attention needs to be paid to the robustness against noise of chaos-based approaches to computation. In this paper unstable periodic orbits, which form the skeleton of any chaotic system, are employed to build a model for the chaotic system to measure the sensitivity of each orbit to noise, and to select the orbits whose symbolic representations are relatively robust against the existence of noise. Furthermore, since unstable periodic orbits are extractable from time series, periodic orbit-based models can be extracted from time series too. Chaos computing can be and has been implemented on different platforms, including biological systems. In biology noise is always present; as a result having a clear model for the effects of noise on any given biological implementation has profound importance. Also, since in biology it is hard to obtain exact dynamical equations of the system under study, the time series techniques we introduce here are of critical importance. PMID- 22225395 TI - Logical stochastic resonance with correlated internal and external noises in a synthetic biological logic block. AB - Following the advent of synthetic biology, several gene networks have been engineered to emulate digital devices, with the ability to program cells for different applications. In this work, we adapt the concept of logical stochastic resonance to a synthetic gene network derived from a bacteriophage lambda. The intriguing results of this study show that it is possible to build a biological logic block that can emulate or switch from the AND to the OR gate functionalities through externally tuning the system parameters. Moreover, this behavior and the robustness of the logic gate are underpinned by the presence of an optimal amount of random fluctuations. We extend our earlier work in this field, by taking into account the effects of correlated external (additive) and internal (multiplicative or state-dependent) noise. Results obtained through analytical calculations as well as numerical simulations are presented. PMID- 22225396 TI - Key role of time-delay and connection topology in shaping the dynamics of noisy genetic regulatory networks. AB - This paper focuses on a paced genetic regulatory small-world network with time delayed coupling. How the dynamical behaviors including temporal resonance and spatial synchronization evolve under the influence of time-delay and connection topology is explored through numerical simulations. We reveal the phenomenon of delay-induced resonance when the network topology is fixed. For a fixed time delay, temporal resonance is shown to be degraded by increasing the rewiring probability of the network. On the other hand, for small rewiring probability, temporal resonance can be enhanced by an appropriately tuned small delay but degraded by a large delay, while conversely, temporal resonance is always reduced by time-delay for large rewiring probability. Finally, an optimal spatial synchrony is detected by a proper combination of time-delay and connection topology. PMID- 22225397 TI - A common repressor pool results in indeterminacy of extrinsic noise. AB - For just over a decade, stochastic gene expression has been the focus of many experimental and theoretical studies. It is now widely accepted that noise in gene expression can be decomposed into extrinsic and intrinsic components, which have orthogonal contributions to the total noise. Intrinsic noise stems from the random occurrence of biochemical reactions and is inherent to gene expression. Extrinsic noise originates from fluctuations in the concentrations of regulatory components or random transitions in the cell's state and is imposed to the gene of interest by the intra- and extra-cellular environment. The basic assumption has been that extrinsic noise acts as a pure input on the gene of interest, which exerts no feedback on the extrinsic noise source. Thus, multiple copies of a gene would be uniformly influenced by an extrinsic noise source. Here, we report that this assumption falls short when multiple genes share a common pool of a regulatory molecule. Due to the competitive utilization of the molecules existing in this pool, genes are no longer uniformly influenced by the extrinsic noise source. Rather, they exert negative regulation on each other and thus extrinsic noise cannot be determined by the currently established method. PMID- 22225398 TI - Comment on "Sil'nikov chaos of the Liu system" [Chaos 18, 013113 (2008)]. AB - In the referenced paper, the authors use the undetermined coefficient method to prove analytically the existence of homoclinic and heteroclinic orbits in a Lorenz-like system. If the proof was correct, the existence of horseshoe chaos would be guaranteed via the Sil'nikov criterion. However, we hereby show that their demonstration is incorrect for two reasons. On the one hand, they wrongly use a symmetry the Lorenz-like system exhibits. On the other hand, they try to find structurally unstable global bifurcations by means of a series that is uniformly convergent in an open set of the parameter space: this would imply that the dynamical object they have found is structurally stable. PMID- 22225399 TI - Flow resistance of samplers for personal monitoring in work areas and requirements for sampling pump performance. PMID- 22225400 TI - Dietary influences on nonexercise physical activity and energy expenditure in C57BL/6J mice. AB - It is well established that the lack of physical activity can lead to weight gain or obesity. However, there is limited information on influences of diet components on physical activity. Thus the purpose of this study was to investigate the role of major dietary components on energy expenditure by affecting nonexercise physical activity in C57BL/6J mice. All mice were assigned to 1 of the following 4 dietary groups based on their body weight and baseline physical activity; low fat/normal protein, high fat/normal protein, low fat/low protein, or low fat/high protein. After 3 mo, the highest weight gain was observed in animals fed with high-fat/normal-protein diet, and the caloric intake was significantly lower in low-fat/high-protein diet-fed mice compared to other groups. However, there were no significant changes in nonexercise physical activity during experimental periods in all groups. The respiratory quotient and energy expenditure were not significantly different among the dietary groups. These findings suggest that diet-induced obesity is not explainable by levels of physical activity and energy expenditure. PRACTICAL APPLICATION: The understanding the link between diet and nonexercise physical activity would provide important knowledge that will potentially assist appropriate food choices to control obesity and its related health problems. PMID- 22225401 TI - Probing the radialene-character in triplesalophen ligands by spectroscopic and structural analysis. AB - The triplesalen ligand system based on three salen-like coordination environments bridged by a common phloroglucinol ring has been designed and successfully applied for the rational synthesis of single-molecule magnets from two trinuclear triplesalen complexes and one hexacyanometallate by supramolecular recognition. In order to optimize this system with respect to magnetic anisotropy, the triplesalophen ligand system has been identified, which should allow for the synthesis of nonanuclear complexes composed of two trinuclear triple-salophen complexes and three connecting units. Herein, the convergent synthesis of the triplesalophen ligand system is described, which differs fom the divergent strategy for the triplesalen ligand system. The molecular and elecrtronic structures of the triplesalophen ligands H(6)baron(R) (R = Me, Cl, Br) have been established by single-crystal X-ray diffraction, NMR, FTIR, and UV-vis spectroscopies. These complementary methods allowed the assignment of the central compartment not to be in the O-protonated tautomer but in the N-protonated tautomer with the prevalence of a keto-enamine resonance description, which resembles a heteroradialene. Furthermore, the comparison with the mononucleating unsymmetrical salophen reference ligand H(2)carl(Cl) and with compounds from the literature provides unique signatures for the appearance of the heteroradialene motif not only in NMR spectra and structural parameters but also in IR and UV-vis spectra. These signatures form the basis for the interpretation and understanding of the electronic structures of transition metal complexes with the triplesalophen ligand system. PMID- 22225403 TI - Future emissions and atmospheric fate of HFC-1234yf from mobile air conditioners in Europe. AB - HFC-1234yf (2,3,3,3-tetrafluoropropene) is under discussion for replacing HFC 134a (1,1,1,2-tetrafluoroethane) as a cooling agent in mobile air conditioners (MACs) in the European vehicle fleet. Some HFC-1234yf will be released into the atmosphere, where it is almost completely transformed to the persistent trifluoroacetic acid (TFA). Future emissions of HFC-1234yf after a complete conversion of the European vehicle fleet were assessed. Taking current day leakage rates and predicted vehicle numbers for the year 2020 into account, European total HFC-1234yf emissions from MACs were predicted to range between 11.0 and 19.2 Gg yr(-1). Resulting TFA deposition rates and rainwater concentrations over Europe were assessed with two Lagrangian chemistry transport models. Mean European summer-time TFA mixing ratios of about 0.15 ppt (high emission scenario) will surpass previously measured levels in background air in Germany and Switzerland by more than a factor of 10. Mean deposition rates (wet + dry) of TFA were estimated to be 0.65-0.76 kg km(-2) yr(-1), with a maxium of ~2.0 kg km(-2) yr(-1) occurring in Northern Italy. About 30-40% of the European HFC-1234yf emissions were deposited as TFA within Europe, while the remaining fraction was exported toward the Atlantic Ocean, Central Asia, Northern, and Tropical Africa. Largest annual mean TFA concentrations in rainwater were simulated over the Mediterranean and Northern Africa, reaching up to 2500 ng L( 1), while maxima over the continent of about 2000 ng L(-1) occurred in the Czech Republic and Southern Germany. These highest annual mean concentrations are at least 60 times lower than previously determined to be a safe level for the most sensitive aquatic life-forms. Rainwater concentrations during individual rain events would still be 1 order of magnitude lower than the no effect level. To verify these results future occasional sampling of TFA in the atmospheric environment should be considered. If future HFC-1234yf emissions surpass amounts used here studies of TFA accumulation in endorheic basins and other sensitive areas should be aspired. PMID- 22225405 TI - Ingestion of proteoglycan fraction from shark cartilage increases serum inhibitory activity against matrix metalloproteinase-9 and suppresses development of N-nitrosobis(2-oxopropyl)amine-induced pancreatic duct carcinogenesis in hamster. AB - A water extract of shark cartilage was fractionated into acidic and basic fractions by preparative isoelectric focusing on the basis of the amphoteric nature of samples. The acidic fraction was further fractionated into ethanol soluble and -precipitate fractions. After the carcinogenesis treatment using N nitrosobis(2-oxopropyl)amine, hamsters received a diet containing each fraction or purified chondroichin sulfate to give 0.4% (w/w) for 50 days. Only administration of the acidic ethanol-precipitate-fraction-containing diet significantly increased serum inhibitory activity against matrix metalloproteinase (MMP)-9 and reduced the number of adenocarcinomas in the pancreatic duct. The active fraction predominantly consisted of chondroichin sulfate-containing proteoglycan. However, the purified chondroichin sulfate had no significant activity. These results suggest that the protein moiety of the proteoglycan might be involved in the increase of serum inhibitory activity against MMP-9 and suppression of pancreatic carcinogenesis in hamster. PMID- 22225406 TI - Screening strains of the mulberry silkworm, Bombyx mori, for thermotolerance. AB - A tropical climate prevails in most of the sericultural areas in India, where temperature increases during the summer lead to adverse effects on temperate bivoltine silkworm rearing and cause crop losses. Screening for thermotolerance in the silkworm, Bombyxmori L. (Lepidoptera: Bombycidae) is an essential prerequisite for the development of thermotolerant breeds/hybrids. In the current study, the aim was to identify potential bivoltine silkworm strains specific for tolerance to high temperature. The third day of fifth stage silkworm larvae of bivoltine strains were subjected to high temperature of 36 +/- 1 degrees C with RH of 50 +/- 5 % for six hours (10:00-16:00) every day until spinning for three consecutive generations. Highly significant differences were found among all genetic traits of bivoltine silkworm strains in the treated groups. Three groups of silkworm resulted including susceptible, moderately tolerant, and tolerant by utilizing pupation rate or survival rate with thermal stress as the index for thermotolerance. Furthermore, based on the overall silkworm rearing performance of nine quantitative genetic traits such as larval weight, cocoon yield by number and weight, pupation, single cocoon and shell weight, shell ratio, filament length and denier, three bivoltine silkworm strains, BD2-S, SOF-BR and BO(2) were developed as having the potential for thermotolerance. The data from the present study enhance knowledge for the development of thermo tolerant silkworm breeds/ hybrids and their effective commercial utilization in the sericulture industry. PMID- 22225408 TI - Electrochemically controlled assembly and logic gates operations of gold nanoparticle arrays. AB - The reversible assembly of beta-cyclodextrin-functionalized gold NPs (beta-CD Au NPs) is studied on mixed self-assembled monolayer (SAM), formed by coadsorption of redox-active ferrocenylalkylthiols and n-alkanethiols on gold surfaces. The surface coverage and spatial distribution of the beta-CD Au NPs monolayer on the gold substrate are tuned by the self-assembled monolayer composition. The binding and release of beta-CD Au NPs to and from the SAMs modified surface are followed by surface plasmon resonance (SPR) spectroscopy. The redox state of the tethered ferrocene in binary SAMs controls the formation of the supramolecular interaction between ferrocene moieties and beta-CD-capped Au NPs. As a result, the potential induced uptake and release of beta-CD Au NPs to and from the surface is accomplished. The competitive binding of beta-CD Au NPs with guest molecules in solution shifted the equilibrium of the complexation-decomplexation process involving the supramolecular interaction with the Fc-functionalized surface. The dual controlled assembly of beta-CD Au NPs on the surface enabled to use two stimuli as inputs for logic gate activation; the coupling between the localized surface plasmon, associated with the Au NP, and the surface plasmon wave, associated with the thin metal surface, is implemented as readout signal for "AND" logic gate operations. PMID- 22225407 TI - The role of mycelium production and a MAPK-mediated immune response in the C. elegans-Fusarium model system. AB - Fusariosis is an emerging infectious complication of immune deficiency, but models to study this infection are lacking. The use of the soil nematode Caenorhabditis elegans as a model host to study the pathogenesis of Fusarium spp. was investigated. We observed that Fusarium conidia consumed by C. elegans can cause a lethal infection and result in more than 90% killing of the host within 120 hours, and the nematode had a significantly longer survival when challenged with Fusarium proliferatum compared to other species. Interestingly, mycelium production appears to be a major contributor in nematode killing in this model system, and C. elegans mutant strains with the immune response genes, tir-1 (encoding a protein containing a TIR domain that functions upstream of PMK-1) and pmk-1 (the homolog of the mammalian p38 MAPK) lived significantly shorter when challenged with Fusarium compared to the wild type strain. Furthermore, we used the C. elegans model to assess the efficacy and toxicity of various compounds against Fusarium. We demonstrated that amphotericin B, voriconazole, mancozeb, and phenyl mercury acetate significantly prolonged the survival of Fusarium infected C. elegans, although mancozeb was toxic at higher concentrations. In conclusion, we describe a new model system for the study of Fusarium pathogenesis and evolutionarily preserved host responses to this important fungal pathogen. PMID- 22225409 TI - Proangiogenic soluble factors from amniotic fluid stem cells mediate the recruitment of endothelial progenitors in a model of ischemic fasciocutaneous flap. AB - Skin flaps are routinely used in surgery for the functional and cosmetic repair of wounds or disfiguring scars. The recent concept of therapeutic angiogenesis has emerged as an attractive approach to overcome the problem of blood supply deficiency, often resulting in the flap grafting failure. In the present study, we embedded a gelatin membrane with amniotic fluid stem cells (AFSC) derived conditioned media (ACM) to topically deliver angiogenic growth factors and cytokines into a rat model of ischemic full-thickness skin flap elevated in the epigastric region. AFSC secretome triggered the endogenous repair by the recruitment of endothelial progenitor cells. We studied the vascular perfusion rate, the vessel distribution, and the survival of ACM-treated flaps. In detail, the ischemic sectors of ACM-treated flaps showed at day 7 a perfusion level 50% higher than the preoperation baseline. The ensuing necrosis development was delayed and the histology analysis showed a normal arrangement of epidermal and dermal structures and a high density of vessels in subcutaneous tissues. Further, we found that ACM recruited CD31+/VEGFR2+ and CD31+/CD34+ cells into the ischemic subcutaneous tissues and that the isolated progenitors were capable to form clusters of von Willebrand factor-positive cells in culture. We propose ACM as a cell-free cocktail of chemokines and growth factors to be adopted for clinical applications. PMID- 22225412 TI - S-Nitrosated human serum albumin dimer is not only a novel anti-tumor drug but also a potentiator for anti-tumor drugs with augmented EPR effects. AB - Macromolecules have been developed as carriers of low-molecular-weight drugs in drug delivery systems (DDS) to improve their pharmacokinetic profile or to promote their uptake in tumor tissue via enhanced permeability and retention (EPR) effects. In the present study, recombinant human serum albumin dimer (AL Dimer), which was designed by linking two human serum albumin (HSA) molecules with the amino acid linker (GGGGS)(2), significantly accumulated in tumor tissue even more than HSA Monomer (AL-Monomer) and appearing to have good retention in circulating blood in murine colon 26 (C26) tumor-bearing mice. Moreover, we developed S-nitrosated AL-Dimer (SNO-AL-Dimer) as a novel DDS compound containing AL-Dimer as a carrier, and nitric oxide (NO) as (i) an anticancer therapeutic drug/cell death inducer and (ii) an enhancer of the EPR effect. We observed that SNO-AL-Dimer treatment induced apoptosis of C26 tumor cells in vitro, depending on the concentration of NO. In in vivo experiments, SNO-AL-Dimer was found to specifically deliver large amounts of cytotoxic NO into tumor tissue but not into normal organs in C26 tumor-bearing mice as compared with control (untreated tumor bearing mice) and SNO-AL-Monomer-treated mice. Intriguingly, S-nitrosation improved the uptake of AL-Dimer in tumor tissue through augmenting the EPR effect. These data suggest that SNO-AL-Dimer behaves not only as an anticancer therapeutic drug, but also as a potentiator of the EPR effect. Therefore, SNO-AL Dimer would be a very appealing carrier for utilization of the EPR effect in future development of cancer therapeutics. PMID- 22225415 TI - Determination of expander apparatus displacements and contact pressures on the mucosa using FEM modelling considering mandibular asymmetries. AB - This paper presents a method for prediction of forces and displacements in the expansion screw of a modified mandibular Schwarz appliance and the contact pressure distributions on the mucosa during malocclusions treatment. A 3D finite element biomechanical model of the complete mandible-mucosa-apparatus set was built using computerised tomographic images of a patient's mandible and constructive solid geometry by computer software. An iterative procedure was developed to handle a boundary condition that takes into account the mandibular asymmetries. The results showed asymmetries in the contact pressure distributions that indicated with precision the patient's malocclusion diagnosis. In vivo measurements of contact pressure using piezoelectric sensors agreed with the computational results. It was shown that the left and right ends of the expansion screw move differently with respect to the patient mandible, even though the expansion screw has an opening mechanism to ensure equal stretching at both ends. The contact pressures between the apparatus and the mucosa vary linearly with applied forces, which can simplify the analysis of the biomechanical behaviour of the expander mandible apparatus. The biomechanical modelling proposed in this paper can be a useful tool to improve malocclusions treatment, safely avoiding the use of forces acting on live structures beyond the biological tolerance, which could result in traumatic effects. PMID- 22225414 TI - Citrus juice extraction systems: effect on chemical composition and antioxidant activity of clementine juice. AB - Clementines are especially appreciated for their delicious flavor, and recent years have seen a great increase in the consumption of clementine juice. In previous decades, antioxidant compounds have received particular attention because of widely demonstrated beneficial health effects. In this work, the organoleptic, volatile flavor, and antioxidant quality of clementine juice were studied with regard to the influence on them by different juice extraction systems: plug inside fruit and rotating cylinders. The results showed that juice extracted by the former method presented higher yields and hesperidin content, which was related to higher antioxidant activity, demonstrated by ORAC and LDL assays. The organoleptic quality was not affected by the processing technique, whereas there were significant differences in the chemical flavor profile. There are important differences in chemical and functional quality between juice extraction techniques, which must be taken into account when employing processing systems to produce high-quality products. PMID- 22225417 TI - Effects of crystallization temperature of poly(vinylidene fluoride) on crystal modification and phase transition of poly(butylene adipate) in their blends: a novel approach for polymorphic control. AB - Effects of the isothermal crystallization temperatures of poly(vinylidene fluoride), T(IC,PVDF), on polymorphic crystalline structure, phase transition, fractional crystallization, and enzymatic degradation of poly(butylene adipate) (PBA) in crystalline/crystalline blends have been investigated. The crystal modifications of PBA can be regulated by T(IC,PVDF). Lower T(IC,PVDF) (e.g., 80 degrees C) facilitates the formation of PBA alpha crystals in both the isothermal and nonisothermal melt crystallizations and also favors the beta-to-alpha phase transition of PBA upon annealing at elevated temperatures. This might be attributable to the decreased equilibrium melting temperature of PBA when T(IC,PVDF) is decreased. Higher T(IC,PVDF) is favorable for the fractional crystallization of PBA, which tends to segregate in the interlamellar regions of the PVDF matrix under these conditions. PBA shows faster enzymatic degradation in the blends with a lower T(IC,PVDF) than those with a higher T(IC,PVDF), attributable to the preferential formation of alpha crystals at a lower T(IC,PVDF). This study provides a new method to control the crystal modification and physical properties of polymorphic polymers in their blend systems. PMID- 22225419 TI - Bile acid malabsorption in patients with graft-versus-host disease of the gastrointestinal tract. PMID- 22225420 TI - Chemical compositions of the essential oils of the aerial parts of Chamaemelum mixtum (L.) Alloni. AB - The chemical compositions of the aerial parts essential oils of Chamaemelum mixtum (L.) Alloni from Corsica and Sardinia were investigated employing gas chromatography and gas chromatography-mass spectrometry (GC-MS). The structure of (Z)-heptadeca-9,16-dien-7-one, a natural compound not previously described, was elucidated by GC-MS (electron impact and chemical ionization) and one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy. The variation in C. mixtum essential oil was studied, and statistical analysis showed the clustering of oil samples into three groups according to the amount of oxygenated compounds; these groups correlated to the harvest area. The strong biological activity of the oxygenated fraction (minimum inhibitory concentration of <0.1 mg/mL) of the Corsican oil against Candida albicans , Citrobacter frendii , Enterococcus faecalis , Escherichia coli , Klebsiella pneumoniae , Listeria monocytogenes , and Staphyllococcus aureus can be attributed to the presence of irregular monoterpene alcohols and (Z)-heptadeca-9,16-dien-7-one. PMID- 22225421 TI - Osteomyelitis of the patella in eight foals. AB - OBJECTIVE: To describe the characteristics of osteomyelitis lesions of the patella and to report short- and long-term outcome after treatment in 8 foals. STUDY DESIGN: Retrospective case series. ANIMALS: Foals (n = 8). METHODS: Medical records (2003-2007) and radiographs of foals that had osteomyelitis of the patella were reviewed. Inclusion criteria included clinical, radiographic, and surgical findings consistent with osteomyelitis of the patella, and a long-term follow-up of >15 months. Information acquired included signalment, hematologic and serum biochemical profile results, clinical and radiographic signs, surgical technique and perioperative treatment. Follow-up radiographs were evaluated and outcome was determined from veterinary examination, race records, and telephone questionnaire. RESULTS: Six foals survived long term (15 months-4 years); all had intralesional and systemic antimicrobial therapy, along with synovial lavage and antimicrobial medication. All were sound and achieved either yearling sales (n=3), show hunter or racing (2). Two foals died in the short term from renal failure and suppurative peritonitis secondary to cecal perforation, 1 remaining lame with suppurative osteonecrosis confirmed at necropsy. This foal was not administered intralesional antimicrobial therapy. CONCLUSIONS: Prompt medical and surgical therapy for osteomyelitis of the patella can result in a good prognosis for soundness and a potential athletic career. Concurrent septicemia or other systemic perinatal disease can result in prolonged therapy and delayed recovery. PMID- 22225422 TI - Antioxidant capacities and total polyphenol contents of hydro-ethanolic extract of phytococktail from trans-Himalaya. AB - The aim of this study was to evaluate the in vitro antioxidant potential of hydro ethanolic extract of a novel phytococktail comprising of sea buckthorn, apricot, and Rhodiola (SAR) from trans-Himalaya. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) activity of the extract increased in a dose-dependent manner (upto 0.1 mg/mL), and was found to be about 38% of that of ascorbic acid at 0.1 mg/mL. The hydro ethanolic extract of SAR also scavenged the ABTS(.+) radical generated by ABTS/potassium persulfate (PPS) system and was found to be about 62% of that of ascorbic acid at 0.1 mg/ mL. The total antioxidant power of the extract was determined by ferric reducing antioxidant power (FRAP) assay. Total phenolic content was found to be 1.28016 * 10(-3) mol gallic acid equivalent (GAE)/g extract. Total flavonoid and flavonol contents were estimated to be 2.5970 * 10( 4) mol and 4.87 * 10(-4) mol quercetin equivalent/g extract, respectively. The hydro-ethanolic extract of this phytococktail indicated presence of essential phytoconstituents of polyphenols, flavonoids, flavonols, and ascorbic acid, which contributed significantly to its antioxidant capacity. The combination of the 3 plants may well support their use in traditional medicine to combat oxidative stress and high-altitude sickness. PMID- 22225423 TI - Spotted fever group Rickettsia in Yunnan Province, China. AB - Information about spotted fever group (SFG) rickettsiae in southern China remains sparse. A specific and sensitive real-time PCR assay for detection of SFG rickettsiae was established and used to detect the prevalence rate of SFG rickettsiae in Yunnan Province, China. The limit of detection (LOD) of our real time PCR was 200 copies per reaction, which is more sensitive than the previously developed nested PCR assays for Rickettsia. We tested 265 blood samples (127 goats, 78 dogs, and 60 cattle) collected from Yunnan Province using the real-time PCR assay and revealed that the prevalence of SFG rickettsiae among dogs, cattle, and goats were 14.10%, 23.33%, and 24.41%, respectively. The SFG rickettsiae detected in animals in Yunnan Province were classified into two genotypes: a unique group that is different from all known SFG rickettsiae species, and R. heilongjiangensis. PMID- 22225424 TI - Multifocal cutaneous ORF virus infection in goats in the Amazon region, Brazil. AB - Orf virus is the etiological agent of contagious ecthyma, a severe exanthematic disease that affects small ruminants. Orf virus is zoonosis that is associated with occupational contact with infected animals in human disease. Clinically, contagious ecthyma is characterized by the appearance of vesicles, pustules, ulcers, and papillomatous proliferative lesions on the skin of the lips and nostrils. Here we describe a case of lethal cutaneous multifocal Orf virus infection in goats in the Amazon region of Brazil. Exanthematic lesions were collected and epidemiological and clinical data were obtained. Orf virus was detected using PCR amplification of the whole B2L, VIR, and VEGF open reading frame. Phylogenetic analysis revealed that this virus clustered together with the Orf virus samples isolated during classical contagious ecthyma. The present work is the first to report a severe proliferative Orf virus case in South America. PMID- 22225425 TI - Tula virus infections in the Eurasian water vole in Central Europe. AB - Recent reports of novel hantaviruses in shrews and moles and the detection of rodent-borne hantaviruses in different rodent species raise important questions about their host range and specificity, evolution, and host adaptation. Tula virus (TULV), a European hantavirus, is believed to be slightly or non-pathogenic in humans and was initially detected in the common vole Microtus arvalis, the East European vole M. levis (formerly rossiaemeridionalis), and subsequently in other Microtus species. Here we report the first multiple RT-PCR detection and sequence analyses of TULV in the Eurasian water vole Arvicola amphibius from different regions in Germany and Switzerland. Additional novel TULV S-, M-, and L segment sequences were obtained from M. arvalis and M. agrestis trapped in Germany at sites close to trapping sites of TULV-RT-PCR-positive water voles. Serological investigations using a recombinant TULV nucleocapsid protein revealed the presence of TULV-reactive antibodies in RT-PCR-positive and a few RT-PCR negative water voles. Phylogenetic analyses revealed a geographical clustering of the novel S-, M-, and L-segment sequences from A. amphibius with those of M. arvalis- and M. agrestis-derived TULV lineages, and may suggest multiple TULV spillover or a potential host switch to A. amphibius. Future longitudinal studies of sympatric Microtus and Arvicola populations and experimental infection studies have to prove the potential of A. amphibius as an additional TULV reservoir host. PMID- 22225426 TI - Engineering of a tyrosol-producing pathway, utilizing simple sugar and the central metabolic tyrosine, in Escherichia coli. AB - Metabolic engineering was applied to the development of Escherichia coli capable of synthesizing tyrosol (2-(4-hydroxyphenyl)ethanol), an attractive phenolic compound with great industrial value, from glucose, a renewable carbon source. In this strain, tyrosine, which was supplied not only from the culture medium but also from the central metabolism, was converted into tyrosol via three steps: decarboxylation, amine oxidation, and reduction. The engineered strain synthesized both tyrosol and 4-hydroxyphenylacetate (4HPA), but disruption of the endogenous phenylacetaldehyde dehydrogenase gene shut off 4HPA production and improved the production of tyrosol as a sole product. The engineered mutant strain was capable of producing 0.5 mM tyrosol from 1% (w/v) glucose during a 48 h shake flask cultivation. PMID- 22225427 TI - Unique stoichiometric representation for computational thermochemistry. AB - Evaluation of the enthalpy of formation of species via quantum chemical methods, as well as the evaluation of their performance, is mainly based on single reaction schemes, i.e., reaction schemes that involve a minimal number of reference species where minimal means that, if a reference species is omitted, there is no way to write a balanced reaction scheme involving the remaining species. When the number of reference species exceeds the minimal number, the main problem of computational thermochemistry is inevitably becoming an optimization problem. In this communication we present an exact and unique solution of the optimization problem in computational thermochemistry along with a stoichiometric interpretation of the solution. Namely, we prove that the optimization problem may be identically solved by enumerating a finite and unique set of reactions referred to as group additivity (GA) response reactions (RERs). PMID- 22225428 TI - Visualization of mixing processes in a heterogeneous sand box aquifer. AB - Mixing is increasingly recognized as a critical process for understanding and modeling reactive transport. Yet, mixing is hard to characterize because it depends nonlinearly on concentrations. Visualization of optical tracers in the laboratory at high spatial and temporal resolution can help advance the study of mixing processes. The solute distribution is obtained by analyzing the relationship between pixel intensity and tracer concentration. The problem with such techniques is that grain borders, light fluctuations, and nonuniform brightness contribute to produce noisy images of concentrations that cannot be directly used to estimate mixing at the local scale. We present a nonparametric regression methodology to visualize local values of mixing from noisy images of optical tracers that minimizes smoothing in the direction of concentration gradients. This is achieved by weighting pixel data along concentration isolines. The methodology is used to provide a full visualization of mixing dynamics in a tracer experiment performed in a reconstructed aquifer consisting of two materials with contrasting hydraulic properties. The experiment reveals that mixing is largest at the contact area of regions with different permeability. Also, the temporal evolutions of mixing and dilution rates are significantly different. The mixing rate is more persistent than the dilution rate during tracer invasion, and the opposite is true during flushing, which helps in understanding the complementary nature of these two measures. PMID- 22225430 TI - New record for the coffee berry borer, Hypothenemus hampei, in Hawaii. AB - The coffee berry borer, Hypothenemus hampei (Ferrari) (Coleoptera: Curculionidae) is endemic to Africa and is the most devastating pest of coffee worldwide. The female bores a hole in the coffee berry and deposits her eggs inside. Upon hatching, larvae feed on the seeds, thus reducing both quality and yields of the marketable product. The coffee berry borer was found in the district of Kona on the island of Hawaii in August 2010 and appears to be restricted to that area. PMID- 22225432 TI - Challenging 50 years of established views on Ugi reaction: a theoretical approach. AB - The Ugi reaction is one of the most famous multicomponent couplings, and its efficiency is still explained by the original mechanism suggested by Ugi in the 60s. This article aims to present a thorough theoretical study of this reaction. It describes how the imine is activated and how the new stereogenic center is formed. Our calculations strongly suggest alternatives to some commonly accepted features, such as the reversibility of the intermediate steps, and temper the nature of the driving force of the reaction. PMID- 22225431 TI - Screening for elder mistreatment in dental and medical clinics. AB - OBJECTIVE: Elder mistreatment (EM) is a potentially fatal and largely unrecognised problem in the United States. The purpose of this study was to determine the prevalence of EM in busy clinics and specifically, we report on the feasibility of screening for EM as well as the appropriate instrumentation for screening. BACKGROUND: Prevalence estimates for elder mistreatment vary, but recent data from a national sample of community-residing adults over 60 years of age indicate that 11.4% of older adults report some form of elder mistreatment. There is a paucity of research related to screening in dental and medical clinics to understand the prevalence in such practice settings. METHODS: A cross sectional study was conducted from January 2008 to March 2009. We enrolled 241 patients at two clinics: a medical clinic (n = 102) and dental clinics (n = 139). A mini-mental status exam was conducted with a minimum of 18 or better for inclusion. An elder mistreatment screen was next used [elder assessment instrument (EAI-R) for medical and Hwalek-Sengstock elder abuse screening test (HS-EAST) for dental]. RESULTS: For the 241 patients, we were able to compare data from the EAI-R with the HS-EAST. This pilot work demonstrates the feasibility of screening for EM in busy clinics since we documented patient enrolment of 20% in the medical clinics and 66% in dental clinics. Patients are willing to answer extremely-sensitive questions related to elder mistreatment and are also willing to use computer technology for interviewing. CONCLUSION: Dental and medical clinics are important practice venues to screen for elder mistreatment. PMID- 22225433 TI - How self-determination theory can assist our understanding of the teaching and learning processes in medical education. AMEE guide No. 59. AB - Self-determination Theory (SDT), designed by Edward Deci and Richard Ryan, serves among the current major motivational theories in psychology. SDT research has been conducted in many areas, among which are education and health care, but its applications in medical education are rare. The potential of SDT to help understand processes in medical education justifies this Guide. SDT is explained in seven principles, one of which is the distinction of three innate psychological needs of human beings: for competence, for autonomy and for relatedness. Further, SDT elaborates how humans tend to internalise regulation of behaviour that initially has been external, in order to develop autonomous, self determined behaviour. Implications of SDT for medical education are discussed with reference to preparation and selection, curriculum structure, classroom teaching, assessments and examinations, self-directed learning, clinical teaching, students as teachers and researchers, continuing professional development, faculty development and stress among trainees. PMID- 22225434 TI - How we developed a bioethics theme in an undergraduate medical curriculum. AB - The 5-year undergraduate medical curriculum at Aga Khan University integrates basic sciences with clinical and community health sciences. Multimodal strategies of teaching and learning, with an emphasis on problem-based learning, are utilized to equip students with knowledge, skills, behaviours, attitudes and values necessary for a high-calibre medical graduate. Bioethics teaching was introduced in the medical curriculum in 1988 and has since undergone several changes. In 2009, a multidisciplinary voluntary group began review of undergraduate bioethics teaching and invested over 350 man-hours in curricular revision. This involved formulating terminal objectives, delineating specific objectives and identifying instructional methodologies and assessment strategies appropriate for the contents of each objective. Innovative strategies were specially devised to work within the time constraints of the existing medical curriculum and importantly, to increase student interest and engagement. The new bioethics curriculum is designed to be comprehensive and robust, and strives to develop graduates who, in addition to being technically skilled and competent, are well-versed in the history and philosophy of ethics and bioethics and are ethical in their thinking and practice, especially in the context of a developing country like Pakistan where health indicators are among the worst in the region, and clinical practices are not effectively regulated to ensure quality of care. PMID- 22225435 TI - Twelve tips to stimulate intrinsic motivation in students through autonomy supportive classroom teaching derived from self-determination theory. AB - BACKGROUND: Self-determination theory (SDT) of motivations distinguishes between intrinsic and extrinsic motivations. Intrinsic motivation is observed when one engages in an activity out of genuine interest and is truly self-determined. Intrinsic motivation is the desired type of motivation for study as it is associated with deep learning, better performance and positive well-being in comparison to extrinsic motivation. It is dependent on the fulfilment of three basic psychological needs described by SDT. These are the needs for autonomy, competence and relatedness. According to SDT, autonomy-supportive teaching is important, because it makes students feel autonomous and competent in their learning and also supported (relatedness) by their teachers. AIM: The concept of autonomy-supportive teaching is relevant to medical education, but less known. Through this article, we aim to make this concept understood and practically used by medical teachers. METHODS: We used SDT literature as a basis to formulate these 12 tips. RESULTS: We present 12 practical tips derived from SDT, for teachers in health professions, on how to engage in autonomy-supportive teaching behaviours in order to stimulate intrinsic motivation in their students. CONCLUSION: These tips demonstrate that it is not difficult to engage in autonomy supportive teaching behaviour. It can be learned through practice and self reflection on teaching practices. PMID- 22225436 TI - Collaborative group work: effects of group size and assignment structure on learning gain, student satisfaction and perceived participation. AB - BACKGROUND: Collaborative group sessions in Nijmegen include 15 students who work all together on a group assignment. Sometimes, the group is split-up in three and every subgroup elaborates a part of the assignment. At the end, they peer-teach each other. It is believed that the split-up enhances participation and therefore learning gain. AIMS: To establish the effect of group size and structure of the assignment on the perceived participation, the satisfaction and learning gain of collaborative group sessions. METHODS: In this study, 27 groups of 15 students were equally divided into: A-group: all 15 students working on the complete assignment. B-group: subgroups of 5 students working on the complete assignment. C-group: subgroups of 5 students working on a smaller part, and peer-teaching each other at the end of the group session. All students took a pre-test, a post test and a follow-up test and completed a questionnaire. Questionnaires were analyzed with a one-way analysis of variance (ANOVA) and post hoc by multiple comparisons. Learning gain was analyzed using a repeated measures ANOVA. RESULTS: A group size effect is observed in favor of working in subgroups. Perceived participation of the students differs between A and B (p <= 0.001) and between A and C (p <= 0.001), but not between B and C. Also, an assignment effect is found in favor of the smaller assignment combined with peer-teaching. The students' satisfaction differs between A and C (p <= 0.003) and between B and C (p <= 0.001), but not between A and B. The C-group also shows higher test results (p <= 0.043). CONCLUSIONS: The students prefer smaller groups as well as smaller assignments including peer-teaching. A possible larger learning gain of this format needs to be re-investigated. PMID- 22225437 TI - How Italian students learn to become physicians: a qualitative study of the hidden curriculum. AB - BACKGROUND: A great deal of what medical students learn in terms of behaviors, values, and attitudes related to their profession is conveyed by the hidden curriculum. AIM: To explore the messages conveyed by the hidden curriculum as perceived by third-year students of the Milan School of Medicine, Italy, following their first clinical internship. METHOD: Three group interviews were conducted. Students were asked to reflect on values, attitudes, and implicit rules they noticed during their internship experiences. Verbatim transcripts of the group interviews were analyzed through content analysis using Nvivo8. RESULTS: Of the 81 students, 57 (70%) participated in the group interviews. Six themes were identified within the hidden curriculum: Physicians reassure and protect patients; power differential between physicians and patients; variable respect for patients; disease-centered medicine; respect for hierarchies; and delegation of patients' emotional needs to nurses. CONCLUSIONS: Our findings suggest that the hidden curriculum has a strong cultural component. In our students' experience, the hidden curriculum conveyed a paternalistic model of physician-patient relationships. Some of the messages conveyed by the actual hidden curriculum may compromise the standards formally taught in medical schools about doctor-patient relationships. Organizational culture change and student empowerment could be fostered to counteract the negative effects of the hidden curriculum. PMID- 22225438 TI - Effect of feedback from standardized patients on medical students' performance and perceptions of the neurological examination. AB - BACKGROUND: Feedback can have a powerful influence on the performance of learners, and has traditionally been provided by faculty. AIM: This study set out to explore whether feedback from a standardized patient (SP) can improve students' performance of the neurological examination. METHODS: A randomized controlled design was used with final year medical students. The control group did not receive any feedback. The intervention groups received either written feedback or a combination of written and verbal feedback. A written test was given prior to the intervention to assess comparability of the three groups. Pretest and post-test scores on the neurological examination were compared. Attitudinal questionnaires were administered at the time of the posttest, and 6 months later. RESULTS: Students receiving feedback from the SPs had significantly greater scores on the posttest than the control group. In the intervention groups, students receiving both verbal and written feedback scored significantly higher than those who received only written feedback. More positive perceptions of learning outcomes and the value of SP feedback were noted in the intervention groups. CONCLUSION: SP feedback was associated with a significant increase in student scores on the neurological examination, as well as more favorable perceptions of the experience. PMID- 22225439 TI - Use of an expert concept map as an advance organizer to improve understanding of respiratory failure. AB - BACKGROUND: Helping novices transition toward expertise requires "meaningful" learning. Advance organizers are educational tools which help connect prior knowledge with new information, a critical step in making learning meaningful. Concept maps visually represent knowledge organization and can serve as advance organizers enabling deeper and more meaningful learning while enhancing knowledge integration. AIM: To compare respiratory failure understanding of resident physicians instructed, using an expert concept map advance organizer with learners receiving traditional didactic teaching. METHODS: Residents were randomized by month of service to receive either a control lecture or a session using an expert concept map as an advanced organizer. Participants completed three concept maps; pre-education (CM1), immediately post-education (CM2), and 1 week later (CM3). Concept maps were scored using a standardized structural scoring method. RESULTS: Forty-six pediatric residents (23 control and 23 experimental) participated. To account for repeated measures within subjects, the generalized estimating equations method compared concept map improvement between groups. The experimental group improved significantly more than controls (CM1-CM2 CM3 p = 0.001; CM1-CM2 p = 0.001; and CM1-CM3 p = 0.017). CONCLUSIONS: Using an expert concept map as an advance organizer improves knowledge organization and integration while offering a tool to enhance deeper understanding of medical knowledge among resident physicians. PMID- 22225440 TI - The use of simulated patients in medical education: Guide supplement 42.1- viewpoint. PMID- 22225441 TI - Portfolios for assessment and learning: Guide supplement 45.1--viewpoint. PMID- 22225442 TI - Effective small group learning: Guide supplement 48.1--viewpoint. PMID- 22225443 TI - eMedical Teacher. PMID- 22225446 TI - Effective multilevel teaching techniques on attending rounds: a pilot survey and systematic review of the literature. AB - BACKGROUND: While numerous authors acknowledge the challenge of teaching simultaneously to medical students, interns, and residents, few offer specific advice on how to meet that challenge, and none have studied which techniques are most effective. AIMS: The purpose of this study was to determine whether multilevel teaching is challenging for attendings, whether trainees feel that teaching on rounds is appropriate to their level, and to define multilevel teaching techniques. METHODS: We surveyed attendings and trainees on the internal medicine services at two academic medical centers. RESULTS: Attendings were divided about whether teaching to multiple levels posed a challenge. Trainees reported that the teaching they received was usually appropriate to their level of training. The most effective techniques for multilevel teaching were Broadening (asking "what if" questions), Targeting (directing questions at specific team members), and Novelty (teaching newly published information), while the least effective were techniques that taught advanced material unfamiliar to most or all of the team. A systematic literature review yielded no studies that focused on multilevel teaching techniques. CONCLUSIONS: This article is the first to define and evaluate specific techniques for multilevel instruction in a medical setting and identifies certain techniques as more effective at engaging multiple levels of learners simultaneously. PMID- 22225447 TI - Influence of study approaches on academic outcomes during pre-clinical medical education. AB - BACKGROUND: Different approaches to study lead to differing academic outcomes. Deep and strategic approaches have been linked to academic success while surface approaches lead to poorer understandings. AIMS: This study sought to characterize how the approaches to study used by medical students impacted their academic success as measured by three outcomes: cumulative grades at the end of the first year, cumulative grades at the end of the second year, and performance on a medical licensing examination. METHODS: The approaches and study skills inventory for students was administered to medical students to determine their predominant study approach (deep, strategic, superficial) at the beginning of their first year, end of first year, and end of second year. Each group's mean performance on each outcome measure was compared by ANOVA to find significant differences. RESULTS: For all three outcome measures, strategic approaches to study were associated with high performance while surface approaches with a poor one. Deep approaches were most popular at all times and were largely associated with adequate performance. CONCLUSIONS: Deep approaches to study are sufficient for success in the current paradigm of medical education but strategic ones may offer a selective advantage to those who use them. Surface approaches to study must be discouraged by instructors through deliberate course design. PMID- 22225448 TI - "Being-in-role": A teaching innovation to enhance empathic communication skills in medical students. AB - BACKGROUND: The communication of empathy is key in physician-patient interactions. We introduced drama training in "How to act-in-role" to medical students and evaluated the effect of this. METHODS: A quasi-experimental design was employed, with 72 students in the control and 77 students in the intervention group. The students' empathy scores were obtained using the Jefferson Scale of Physician Empathy (JSPE) during the introductory course. Both groups received tutorials in motivational interviewing and brief intervention skills. The students in the intervention group also received training in "How to act-in role". The JSPE was repeated for both groups. The students subsequently undertook observed structured clinical examinations (OSCE). Both tutors and students evaluated the student's OSCE performance as well as their motivational interviewing skills using the Behavior Change Counseling Index (BECCI). RESULTS: Our findings show that while the students in both groups did not significantly differ in baseline empathy scores, the intervention group reported significantly higher empathy scores post-intervention. The intervention group also received significantly higher tutor ratings for their motivational interviewing (BECCI score) and overall OSCE performances. In conclusion, the teaching innovation "How to act-in-role" was effective not only in increasing medical students' self reported empathy but also their competence in consultation skills. PMID- 22225449 TI - Engagement and opportunity in clinical learning: findings from a case study in primary care. AB - BACKGROUND: This article explores in a primary care setting how clinical learning occurs across a range of professional groups and levels of learner experience, both undergraduate and postgraduate. AIM: To explore how clinical learning occurs in a primary care workplace from a socio-cultural perspective. METHOD: A single case study approach using interview data from 33 participants and strengthened through direct and indirect observations and documentary evidence. RESULTS: Clinical learning occurs through engagement and opportunity. Engagement in learning appeared to be developed through four elements: recognition, respect, relevance and emotion. Opportunity includes the availability of patient encounters (made meaningful through the immediacy of hearing patient narratives de novo and the authenticity arising from the social context of illness) and the ability to learn with peers and professional colleagues. CONCLUSION: These findings support and develop existing literature on learning in other clinical settings. They are consistent with socio-cultural theories of learning, but develop this literature within the context of clinical education. Engagement and learning occurred in transient learners in the absence of prolonged participation, belonging or a clear trajectory of learning. The study offers evidence from multiple learner perspectives as to how the learning environment might be enhanced in all educational settings. PMID- 22225450 TI - Development of a modified Cohen method of standard setting. AB - BACKGROUND: A new 'Cohen' approach to standard setting was recently described where the pass mark is calculated as 60% of the score of the student at the 95th percentile, after correcting for guessing. AIM: This article considers how two potential criticisms of the Cohen method can be addressed and proposes a modified version, with the assumptions tested using local data. METHODS: The modified version removes the correction for guessing and uses the score of the 90th, rather than the 95th percentile student as the reference point, based on the cumulative density functions for 32 modules from one medical school; and incorporates an indirect criterion-referenced passing standard by changing the 60% multiplier to the ratio of the cut score to the score of the student at the 90th percentile on exams that have been standard set using modified Angoff. RESULTS: The assumption that the performance of the 90th percentile student is consistent over time holds for multiple choice questions. Applying the modified Cohen method to the 32 modules generally reduced the variation in failure rate across modules, compared to a fixed pass mark of 50%. CONCLUSION: The results suggest that the modified Cohen method holds much promise as an economical approach to standard setting. PMID- 22225451 TI - Evidence for validity of a survey to measure the learning environment for professionalism. AB - BACKGROUND: With the emphasis on professionalism in academic health settings, including recently added accreditation requirements for US medical schools, there is a need for a valid and feasible method to assess the learning environment for professionalism. AIM: This article describes the development and investigation of the validity of a brief measure, the learning environment for professionalism (LEP) survey, designed to assess medical student perceptions of professionalism among residents and faculty during clinical rotations. METHOD: Two successive cohorts of third-year medical students completed the 22-item LEP survey at the conclusion of clerkship rotations, providing a total of 902 responses for scale reliability and principal components factor analysis, as well as assessment of changes in scores over time and correlations with a related clerkship evaluation item. RESULTS: The internal structure of the LEP survey was consistent with intended goals to assess both positive and negative professionalism behaviors. Acceptable internal consistency, sensitivity to change over time, and positive relationships between LEP scores and a concurrent measure of professionalism were observed. CONCLUSIONS: Use of the instrument could help identify clinical learning environments for professionalism that represent either best practices or areas in need of improvement, assess the impact of professionalism initiatives, and help satisfy accreditation requirements. PMID- 22225452 TI - Alternating skills training and clerkships to ease the transition from preclinical to clinical training. AB - BACKGROUND: The transition from preclinical to clinical training is perceived as stressful with a high workload being the main difficulty. To ease this transition, we implemented a dual learning year, where just-in-time skills training and clerkships alternated. AIMS: To examine the effect of the dual learning year on students' stress and perceptions of workload and skills level, and to compare these data with a baseline measurement from a curriculum in which skills training was provided in advance of clerkships. METHOD: During the first Master year, students completed four rotations in which 5 weeks of skills training and 5-week clerkships alternated. In the second clerkship week of each rotation, students (n = 476) completed questionnaires measuring their experienced workload, perceived skills level and stress. Analysis of variance was used for trend analysis and to determine differences with the baseline measurement (n = 83). RESULTS: During the dual learning year, 'experienced workload' decreased (F(1,471) = 9.408, p < 0.01), 'perceived skills level' increased (F(1,471) = 94.202, p < 0.001) and stress decreased (F(1,471) = 3.309, p < 0.10). 'Experienced workload' was lower (F(5,553) = 7.599, p < 0.001) and 'perceived skills level' was comparable to the baseline measurement. CONCLUSIONS: Compared to the baseline measurement and the results of earlier studies on transition difficulties, alternating just-in-time skills training and clerkships seem to ease the transition from preclinical to clinical training. PMID- 22225453 TI - Teaching strategies used by internal medicine residents on the wards. AB - BACKGROUND: Residents serve as teachers to interns and students in most internal medicine residency programs. AIM: The purpose of our study is to explore what internal medicine residents perceive as effective teaching strategies in the inpatient setting and to formulate a guideline for preparing residents to lead their ward teams. METHODS: Housestaff identified as excellent teaching residents were recruited from a large internal medicine residency program. Focus groups were formed and interviews were conducted using open-ended questions. Transcripts of the interviews were reviewed, analyzed, and compared for accuracy by two investigators. The transcripts were then coded to categorize data into similar subjects from which recurrent themes in resident teaching were identified. RESULTS: Twenty-two residents participated in four focus group interviews held in 2008. We identified five principal themes for effective teaching by residents: (T)aking advantage of teaching opportunities, (E)mpowering learners, (A)ssuming the role of leader, (C)reating a learning environment, and (H)abituating the practice of teaching. CONCLUSION: Strategies for effective teaching by residents exist. The TEACH mnemonic is a resident-identified method of instruction. Use of this tool could enable residency programs to create instructional curricula to prepare their residents and interns to take on the roles of team leaders and teachers. PMID- 22225455 TI - Modified spin-coating technique to achieve directional colloidal crystallization. AB - Fabricating large single crystals with colloidal spheres as building blocks is challenging and of competitive interest. Spin-coating of colloids offers a robust technique, which is highly reproducible in obtaining colloidal crystals even at fast dynamical regimes; however, these crystals are intrinsically polycrystalline due to the axial symmetry of spin-coating. We report a new method that applies a nonuniform electric field during the spin-coating process. By arranging the field direction to be stationary in the rotating frame, we are able to break the axial symmetry and to orient the colloids along one predefined direction. By regulating the applied field strength, we demonstrate local control over the orientation of the crystallites, and thus, the orientation is determined by the applied field strength. PMID- 22225456 TI - Study of plasmid-mediated extended-spectrum beta-lactamase-producing strains of enterobacteriaceae, isolated from diabetic foot infections in a North Indian tertiary-care hospital. AB - AIM: This study evaluated the incidence and factors responsible for plasmid mediated extended-spectrum beta-lactamase (ESBL) infection among patients with diabetic foot ulcer (DFU). SUBJECTS AND METHODS: A prospective study was conducted on 162 DFU inpatients treated in a multidisciplinary-based diabetes and endocrinology center at Jawaharlal Nehru Medical College of Aligarh Muslim University, Aligarh, India, during the period of December 2008-March 2011. Detailed history and patient's profile, grade of DFU, co-morbidities and complications, laboratory data, and final outcome were collected. Standard methods were used for culture identification, sensitivity testing, and ESBL detection. Polymerase chain reaction for bla genes was performed, and the risk factors for bla gene positivity were determined by univariate analysis with 95% confidence interval. RESULTS: In total, 127 (78.3%) Enterobacteriaceae members were isolated. The most common isolate was Escherichia coli (71; 55.9%), followed by Klebsiella sp. (33; 25.9%) and Proteus sp. (13; 10.2%). By phenotypic methods, 67.8% were ESBL producers. In the molecular detection of ESBLs, 81.9% were found to be positive for the bla gene, of which bla(CTX-M) showed 81.8% positivity, followed by bla(TEM) (50%) and bla(SHV) (46.9%). In a univariate analysis, bla gene-positive status was associated with low-density lipoprotein-cholesterol (>100 mg/dL) (P<0.004, odds ratio 13.4, relative risk 8.65) and triglycerides (>200 mg/dL) (P<0.003, odds ratio 6.5, relative risk 4.11). CONCLUSION: ESBL constitutes a major threat to currently available beta-lactam therapy, leading to complications in DFUs. Aminoglycosides, cephalosporin, and beta-lactam inhibitor drugs would probably be more appropriate empirical agents after establishing the patient's history of previous antibiotic use. The detection of ESBL should be done on a routine basis. PMID- 22225459 TI - Dipstick test for DNA-based food authentication. Application to coffee authenticity assessment. AB - This paper reports DNA-based food authenticity assays, in which species identification is accomplished by the naked eye without the need of specialized instruments. Strongly colored nanoparticles (gold nanoparticles) are employed as reporters that enable visual detection. Furthermore, detection is performed in a low-cost, disposable, dipstick-type device that incorporates the required reagents in dry form, thereby avoiding multiple pipetting and incubation steps. Due to its simplicity, the method does not require highly qualified personnel. The procedure comprises the following steps: (i) PCR amplification of the DNA segment that flanks the unique SNP (species marker); (ii) a 15 min extension reaction in which DNA polymerase extends an allele-specific primer only if it is perfectly complementary with the target sequence; (iii) detection of the products of the extension reaction within a few minutes by the naked eye employing the dipstick. No purification is required prior to application of the extension products to the dipstick. The method is general and requires only a unique DNA sequence for species discrimination. The only instrument needed is a conventional thermocycler for PCR, which is common equipment in every DNA laboratory. As a model, the method was applied to the discrimination of Coffea robusta and arabica species in coffee authenticity assessment. As low as 5% of Robusta coffee can be detected in the presence of Arabica coffee. PMID- 22225458 TI - Efficient derivation and genetic modifications of human pluripotent stem cells on engineered human feeder cell lines. AB - Derivation of pluripotent stem cells (iPSCs) induced from somatic cell types and the subsequent genetic modifications of disease-specific or patient-specific iPSCs are crucial steps in their applications for disease modeling as well as future cell and gene therapies. Conventional procedures of these processes require co-culture with primary mouse embryonic fibroblasts (MEFs) to support self-renewal and clonal growth of human iPSCs as well as embryonic stem cells (ESCs). However, the variability of MEF quality affects the efficiencies of all these steps. Furthermore, animal sourced feeders may hinder the clinical applications of human stem cells. In order to overcome these hurdles, we established immortalized human feeder cell lines by stably expressing human telomerase reverse transcriptase, Wnt3a, and drug resistance genes in adult mesenchymal stem cells. Here, we show that these immortalized human feeders support efficient derivation of virus-free, integration-free human iPSCs and long term expansion of human iPSCs and ESCs. Moreover, the drug-resistance feature of these feeders also supports nonviral gene transfer and expression at a high efficiency, mediated by piggyBac DNA transposition. Importantly, these human feeders exhibit superior ability over MEFs in supporting homologous recombination mediated gene targeting in human iPSCs, allowing us to efficiently target a transgene into the AAVS1 safe harbor locus in recently derived integration-free iPSCs. Our results have great implications in disease modeling and translational applications of human iPSCs, as these engineered human cell lines provide a more efficient tool for genetic modifications and a safer alternative for supporting self-renewal of human iPSCs and ESCs. PMID- 22225461 TI - Surgical treatment of severe pulmonic stenosis under cardiopulmonary bypass in small dogs. AB - OBJECTIVES: The aim of this study was to report the long-term outcome of the surgical palliation of pulmonic stenosis in dogs. METHODS: The subjects comprised three female and six male dogs, mean (+/-sd) age: 23 (+/-25) months, mean (+/-sd) weight: 3.4 (+/-2.1) kg, diagnosed with severe pulmonic stenosis and right ventricular hypertrophy, with an average preoperative pressure gradient of 153 (+/-43) mmHg on echocardiography. RESULTS: The pressure overload with severe pulmonic stenosis was reduced by valvotomy, i.e., open pulmonary valve commissurotomy, with/without biomembrane patch grafting, under cardiopulmonary bypass. The postoperative pressure gradient at 1 to 7 days was significantly decreased to 65 (+/-39) mmHg (P<0.05). The reduced pressure gradient was maintained at 58 (+/-38) mmHg at final follow-up. CLINICAL SIGNIFICANCE: Open valvotomy, pulmonary valve commissurotomy and biomembrane patch grafting were effective in reducing obstruction in severe pulmonic stenosis in dogs. PMID- 22225463 TI - Efficacy and safety of deracoxib for control of postoperative pain and inflammation associated with soft tissue surgery in dogs. AB - OBJECTIVE: To investigate the effectiveness and safety of deracoxib (Deramaxx(r)) administered at a dose of 1-2 mg/kg/day for 3 days for control of postoperative pain and inflammation associated with soft tissue surgery in dogs. STUDY DESIGN: Prospective, randomized, blinded, placebo-controlled, multi-center clinical study. ANIMALS: Dogs (n = 34). METHODS: Dogs undergoing soft tissue surgeries were randomly assigned to receive either deracoxib (n = 18) or placebo (n = 16) as a preoperative treatment and again once daily for 2 additional days after surgery unless removed from the study. Dogs were evaluated before surgery and again postsurgically at predetermined times using the Glasgow Composite Pain Scale (GCPS). All dogs were allowed to receive another pain medication (except nonsteroidal anti-inflammatory drugs [NSAIDs] or corticosteroids) as postsurgical pain intervention if the dog scored >=6 on the GCPS or was in obvious discomfort. Dogs receiving pain intervention were considered treatment failures and were removed from the study. RESULTS: Two of 16 dogs treated with deracoxib were rescued compared with 9 of 16 dogs receiving placebo (P = .0091). In addition, deracoxib treated dogs had numerically lower GCPS scores. CONCLUSIONS: Results suggest perioperative administration of deracoxib to dogs at 1-2 mg/kg/day for 3 days significantly improves analgesia in the postoperative surgical period after soft tissue surgery. Placebo dogs not rescued after painful procedures highlight the need for refinement of current pain assessment tools. PMID- 22225464 TI - Mechanistic study of the synthesis of CdSe nanocrystals: release of selenium. AB - We outline a reaction pathway for the cleavage of the P?Se bond in trialkylphosphine selenide during the synthesis of CdSe nanocrystals. The reaction between cadmium carboxylate and trimethylphosphine selenide in the presence of an alcohol produces alkoxytrimethylphosphonium (2). Control experiments and density functional theory calculations suggested that the cleavage of the P?Se bond is initiated by nucleophilic attack of carboxylate on a Cd(2+)-activated phosphine selenide to produce an acyloxytrialkylphosphonium intermediate (1), which is converted to 2 in the presence of an alcohol. PMID- 22225465 TI - New phenolic compounds hydrothermally extracted from the olive oil byproduct alperujo and their antioxidative activities. AB - The application of a novel process based on the hydrothermal treatment of olive oil waste (alperujo) led to a final liquid phase that contained a high concentration of simple phenolic compounds. This study evaluated the effects of time (15-90 min) on the composition of the phenolic compounds isolated at a fixed temperature of 160 degrees C. Phenolic compounds were extracted with ethyl acetate. Both qualitative and quantitative HPLC analyses of the extracts showed variation of the concentrations of phenolic compounds with time. In addition, new phenols that were not present in the untreated control have been characterized. The antioxidant activities of different phenolic extracts was measured by various assays conducted in vitro: antiradical capacity (using DPPH and ABTS radicals), ferric reducing power (P(R)), inhibition of primary and secondary oxidation in lipid systems, and other tests, such as inhibition of tyrosinase activity. The results show that the phenolic extracts inhibited oxidation in aqueous and lipid systems to a significantly greater extent than the untreated control, and they performed as well as or better than vitamin E in this capacity. PMID- 22225466 TI - Reactivity and biological properties of a series of cytotoxic PtI2(amine)2 complexes, either cis or trans configured. AB - Six diiodido-diamine platinum(II) complexes, either cis or trans configured, were prepared, differing only in the nature of the amine ligand (isopropylamine, dimethylamine, or methylamine), and their antiproliferative properties were evaluated against a panel of human tumor cell lines. Both series of complexes manifested pronounced cytotoxic effects, with the trans isomers being, generally, more effective than their cis counterparts. Cell cycle analysis revealed different modes of action for these new Pt(II) complexes with respect to cisplatin. The reactivity of these platinum compounds with a number of biomolecules, including cytochrome c, two sulfur containing modified amino acids, 9-ethylguanine, and a single strand oligonucleotide, was analyzed in depth by mass spectrometry and NMR spectroscopy. Interestingly, significant differences in the reactivity of the investigated compounds toward the various model biomolecules were observed: in particular we observed that trans complexes preferentially release their iodide ligands upon biomolecule binding, while the cis isomers may release the amine ligands with retention of iodides. Such differences in reactivity may have important mechanistic implications and a relevant impact on the respective pharmacological profiles. PMID- 22225467 TI - Development of a method for the quantitation of chloro-, bromo-, and iodoacetic acids in alcoholic beverages. AB - Chloroacetic, bromoacetic, and iodoacetic acids can be found in alcoholic beverages when they are used as preservatives/stabilizers or as disinfectants. As they are toxic components, their addition is not permitted under European Union and U.S. regulations. To date, no sensitive methods are available, and those proposed are very laborious. This paper describes a sensitive and straightforward method for the determination of the three monohalogenated acetic acids (m-HAAs) in wines and beers using static headspace extraction coupled with gas chromatography-mass spectrometry. Prior to extraction, the target analytes were esterified to increase their volatility, and all parameters related to the extraction/methylation process were optimized to achieve high efficiency (>90%). The study examined the influence both of the ethanol concentration on the headspace partitioning and of the primary acids present in wine on the derivatization reaction of the m-HAAs. The proposed method allows the determination of these compounds at microgram per liter levels in alcoholic beverages. PMID- 22225468 TI - A method to minimise error in 2D-DLT reconstruction of non-planar markers filmed with a moving camera. AB - This article describes a method that allows estimating, with the 2D version of the direct linear transformation (DLT), the actual 2D coordinates of a point when the latter is not strictly in the calibration plane. Markers placed in vertical line, above, below and in the centre of a horizontal calibration plane were filmed by a moving camera. Without correction, strong errors (up to 64.5%) were noticed for markers out of the calibration plane. After correction, calculated coordinates were consistent with actual values (error < 0.55%). The method was then applied to slip distance measurement, using a marker fixed on the hoof of a horse trotting on a calibrated track while being followed with a camera. The correction effect represented 6.6% of slip distance. Combined with the 2D-DLT transformation, the proposed corrective method allows an accurate measurement of slip distances, for high-speed outdoor locomotion analysis, using a moving camera. PMID- 22225469 TI - Effect of water-soluble fraction from lysozyme-treated Enterococcus faecalis FK 23 on mortality caused by influenza A virus in mice. AB - To maintain homeostasis of the immune system is considered important for the prevention of influenza A virus infection. Aberrant systemic inflammation is frequently induced by influenza A virus infection, and the severity of the symptoms is associated with pathogenicity of the virus. Lactic acid bacteria are known to have a positive effect in maintaining the immune system. Furthermore, preparations of a lactic acid bacteria strain, Enterococcus faecalis FK-23 (FK 23), have been reported to exert preferable homeostatic effects on immune diseases such as allergic rhinitis and early asthmatic responses. In this study, we examined the efficacy of the water-soluble fraction of lysed and heat-treated FK-23 (SLFK) against a lethal influenza A virus challenge. Mice were orally administered SLFK from day -7 to day 20, and intranasally infected with influenza virus A/Puerto Rico/8/34 (H1N1) at 10(3) PFU on day 0. The survival rate of SLFK administered mice after influenza A virus infection was significantly improved compared with that of control mice. In addition, the mRNA expression level of the anti-inflammatory cytokine interleukin-10 (IL-10) in lung tissues was enhanced by the oral administration of SLFK after influenza A virus infection. These observations suggest that the oral administration of SLFK exerts a protective effect against influenza virus infection through the activation of the anti inflammatory response. PMID- 22225470 TI - Association of a TANK gene polymorphism with outcomes of hepatitis B virus infection in a Chinese Han population. AB - The host genetic compound plays a vital role in determining clinical outcomes of hepatitis B virus (HBV) infection. The tumor necrosis factor receptor-associated factor family member-associated nuclear factor-kappaB (NF-kappaB) activator (TANK) takes part in the tumor necrosis factor-alpha (TNF-alpha)-mediated NF kappaB signaling pathway and the interferon (IFN)-induction pathways that have relevance to HBV-related liver disease. In this report, we explored whether the intronic polymorphism rs3820998 of the TANK gene was associated with outcomes of HBV infection by binary logistic regression analysis. A total of 1305 unrelated Han Chinese patients recruited from Wuhan, including 180 acute-on-chronic hepatitis B liver failure (ACLF-HBV) patients, 331 HBV-related liver cirrhosis (LC) patients, 308 HBV-related hepatocellular carcinoma (HCC) patients, and 486 asymptomatic HBV carriers (AsC) were genotyped using the TaqMan probe method. Logistic analysis revealed that the single-nucleotide polymorphism (SNP) rs3820998 was significantly associated with susceptibility to ACLF-HBV (dominant model, OR 0.643, 95% CI 0.428,0.964, p=0.033; additive model, OR 0.640, 95% CI 0.414,0.990, p=0.045), and LC (recessive model, OR 0.398, 95% CI 0.164,0.966, p=0.042; additive model, OR 0.379, 95% CI 0.155,0.928, p=0.034). These results indicate that the G > T variant is a protective factor in the development of ACLF HBV and LC, and that the SNP rs3820998 in the TANK gene may play a role in mediating susceptibility to ACLF-HBV and LC in a Chinese Han population. PMID- 22225471 TI - Immune responses to mucosal vaccination by the recombinant A1 and N proteins of infectious bronchitis virus. AB - Infectious bronchitis virus (IBV) is prevented primarily by the use of live attenuated vaccines, which are known to have a limited strain range of protection. Alternative vaccines against the emerging new virus strains can improve control of the disease. The aim of this study was to evaluate the immunogenic potential of two recombinant viral proteins, when administered by eyedrop, without the assistance of a vector. The recombinant S1 (rS1) and N (rN) proteins of the M41 strain expressed in E. coli were tested, and the live attenuated vaccine H120 was used as a positive control. Protection was evaluated by re-isolation of virus from tracheas of vaccinated chickens after challenge with strain M41. After three immunizations, rS1 glycoprotein induced 40% protection, while vaccination with rN provided no protection. Vaccination with rS1, rN, or H120 induced a cellular immune response as demonstrated by in vitro ChIFN-gamma production by splenocytes of vaccinated birds. Vaccination with H120, and to a lesser extent rS1, induced HI and virus-specific IgG antibody production. These findings indicate that recombinant viral proteins administered through the mucosal route can evoke an immune response without the assistance of a vector. PMID- 22225472 TI - Cavity-enhanced measurements of hydrogen peroxide absorption cross sections from 353 to 410 nm. AB - We report near-ultraviolet and visible absorption cross sections of hydrogen peroxide (H(2)O(2)) using incoherent broad-band cavity-enhanced absorption spectroscopy (IBBCEAS), a recently developed, high-sensitivity technique. The measurements reported here span the range of 353-410 nm and extend published electronic absorption cross sections by 60 nm to absorption cross sections below 1 * 10(-23) cm(2) molecule(-1). We have calculated photolysis rate constants for H(2)O(2) in the lower troposphere at a range of solar zenith angles by combining the new measurements with previously reported data at wavelengths shorter than 350 nm. We predict that photolysis at wavelengths longer than those included in the current JPL recommendation may account for up to 28% of the total hydroxyl radical (OH) production from H(2)O(2) photolysis under some conditions. Loss of H(2)O(2) via photolysis may be of the same order of magnitude as reaction with OH and dry deposition in the lower atmosphere; these processes have very different impacts on HO(x) loss and regeneration. PMID- 22225473 TI - Effect of elicitor spray at different reproductive stages on saponin content of soybean. AB - The beneficial health effects of soybeans may be enhanced by increasing bioactive compounds including soyasaponins (ssp). The objective of this study is to elucidate the effect of elicitors sprayed on Ozark variety soybeans, on ssp content. Different concentrations of elicitors, ethyl acetate (EA) and methyl jasmonate (MJ), were sprayed at 4 different growth stages (1-bloom, 2-pod development, 3-seed development, and 4-seed maturity). Seeds were ground, defatted, ssp was extracted and identified and quantified with HPLC. Elicitor and growth stage had an effect on betag and betaa contents of soybeans compared with control (P < 0.05). Elicitor had an effect on total ssp content (P < 0.001) and alphag and gammag content of soybeans compared with control (P < 0.05). Total ssp content of EA 0.05 M, MJ 0.001 M, and 0.005 M sprayed soybeans were higher than EA 0.001 M, which is higher than control (P < 0.05; 3.62, 3.56, 3.56, 3.29, and 2.98 MUmol/g soybean, respectively). The overall effect of elicitor on total ssp content was not dependent on growth stage, however, elicitors sprayed at growth stages 1, 2, and 3 showed differences among elicitor applied soybeans. Elicitors applied at growth stage 4 did not have any effect on total ssp content compared to control. Elicitors EA 0.05 M, MJ 0.001, and 0.005 M can be applied on any growth stage to increase total saponin content of soybean variety Ozark. Higher saponin content may improve the beneficial health effects of soybean consumption. PMID- 22225474 TI - Undetectable molecular residual disease after omacetaxine and nilotinib combination therapy in an imatinib-resistant chronic myeloid leukaemia patient harbouring the BCR-ABL1 T315I gatekeeper mutation. PMID- 22225475 TI - TiO2-photocatalytic reduction of pentavalent and trivalent arsenic: production of elemental arsenic and arsine. AB - Heterogeneous photocatalytic reduction of As(V) and As(III) at different concentrations over TiO(2) under UV light in deoxygenated aqueous suspensions is described. For the first time, As(0) was unambiguously identified together with arsine (AsH(3)) as reaction products. As(V) reduction requires the presence of an electron donor (methanol in the present case) and takes place through the hydroxymethyl radical formed from methanol oxidation by holes or hydroxyl radicals. On the contrary, As(III) reduction takes place through direct reduction by the TiO(2)-conduction band electrons. Detailed mechanisms for the photocatalytic processes are proposed. Although reduction to solid As(0) is convenient for purposes of As removal from water as a deposit on TiO(2), attention must be paid to formation of AsH(3), one of the most toxic forms of As, and strategies for AsH(3) treatment should be considered. PMID- 22225476 TI - Male genital mutilation in the high-mountain goblin spider, Unicorn catleyi. AB - Male genital mutilation is a common mechanism by which males reduce sperm competition by plugging female insemination ducts with different parts of its own genital system. This behavior is frequent in many spider families but is uncommon in Haplogynae. The reproductive biology of Dysderoidea is not well studied and the data is fragmentary; male genital mutilation has been reported only for one species of Oonopidae. This study provides evidence of male genital mutilation in Unicorn catleyi Platnick and Brescovit (Araneae: Oonopidae). Pieces of the embolus were found in the female posterior receptaculum. This behavior is a strategy used by the males in order to guarantee their paternity and not for escape from female attacks as has been reported for other species of Araneae, since cannibalism is unlikely in this species. The presence of embolus in the posterior receptaculum suggests this is the first place where sperm is received. The similarity of the female genitalia of U. catleyi to those of Orsolobidae, along with sclerotization of the seminal duct in the male copulatory bulb that is also present in Orchestina, Xiombarg, and Orsolobidae, provide strong evidence of the basal position of this genus in the family Oonopidae. PMID- 22225478 TI - Relationship between oral impacts on daily performance and chewing ability among independent elders residing in Daejeon City, Korea. AB - OBJECTIVE: The aim of this study was to assess the association between oral health-related quality of life (OHRQoL) measured by the oral impacts on daily performances (OIDP) inventory and chewing ability. METHODS: The cluster sampling method was used to select a sample of 634 socially active independent community dwelling elders. An oral examination was conducted and a questionnaire was implemented. After bivariate comparisons, a multivariable two-level logistic model was developed for the dichotomous OIDP indicator using the generalised linear mixed model. RESULTS: The mean age of the participants was 74 years and 56.6% were women. Eight percent were edentulous, and the mean number of teeth was 17.7. Overall, 39.3% of participants had one or more oral impacts on daily performance. Elders with chewing ability of 0-49, 50-74 and 75-99% were approximately 120, 20 and seven times more likely to have oral impacts compared with those with full chewing ability, respectively. Elders reporting their oral health as 'fair' or 'better' were 68% less likely to have oral impacts than those with poor or very poor self-reported oral health. CONCLUSION: Among independent elders, amelioration of chewing ability including delivery of appropriate prosthodontic care might independently contribute to improving OHRQoL of elders by improving their physical, psychological and social wellbeing. PMID- 22225479 TI - Adaptation to stroke using a model of successful aging. AB - The process of adaptation to the physical and psychosocial consequences after stroke is a major challenge for many individuals affected. The aim of this study was to examine if stroke patients within 1 month of admission (n = 153) and followed up at 1 year (n = 107) engage in selection, optimization, and compensation (SOC) adaptive strategies and the relationship of these strategies with functional ability, health-related quality of life (HRQOL) and depression 1 year later. Adaptive strategies were measured using a 15-item SOC questionnaire. Internal and external resources were assessed including recovery locus of control, stroke severity, and socio-demographics. Outcome measures were the Stroke Specific Quality of Life Questionnaire (SS-QoL), the Nottingham Extended Activities of Daily Living Scale and the Depression Subscale of the Hospital Anxiety and Depression Scale. Findings indicated that stroke patients engaged in the use of SOC strategies but the use of these strategies were not predictive of HRQOL, functional ability or depression 1 year after stroke. The use of SOC strategies were not age specific and were consistent over time, with the exception of the compensation subscale. Results indicate that SOC strategies may potentially be used in response to loss regulation after stroke and that an individual's initial HRQOL functional ability, levels of depression and socio economic status that are important factors in determining outcome 1 year after stroke. A stroke-specific measure of SOC may be warranted in order to detect significant differences in determining outcomes for a stroke population. PMID- 22225480 TI - Influence of mesoporosity on lithium-ion storage capacity and rate performance of nanostructured TiO2(B). AB - Here, we present the Li(+) insertion behavior of mesoporous ordered TiO(2)(B) nanoparticles (meso-TiO(2)(B)). Using presynthesized 4 nm TiO(2)(B) nanoparticles as building blocks and a commercially available ethylene glycol-propylene glycol block copolymer (P123) as a structure-directing agent, we were able to produce mesoporous structures of high-purity TiO(2)(B) with nanocrystallinity and mesopore channels ranging from 10 to 20 nm in diameter. We compared the Li(+) insertion properties of nontemplated TiO(2)(B) nanoparticles (nano-TiO(2)(B)) to meso-TiO(2)(B) via voltammetry and galvanostatic cycling and found significant increases in overall Li(+) insertion capacity for the latter. While nano TiO(2)(B) and meso-TiO(2)(B) both show surface charging (pseudocapacitive) Li(+) insertion behavior, meso-TiO(2)(B) exhibits a higher overall capacity especially at high charge rates. We attribute this effect to higher electrode/electrolyte contact area as well as the improved electron and ion transport in meso TiO(2)(B). In this study, we have demonstrated the influence of both nanostructuring and mesoporosity on Li(+) insertion behavior by rationally controlling the overall architecture of the TiO(2)(B) materials. PMID- 22225481 TI - High-efficiency inverted polymer solar cells with double interlayer. AB - We have studied the performance of normal and inverted bulk-heterojunction solar cells with an active layer composed of a blend of poly[(4,4'-bis(2 ethylhexyl)dithieno[3,2-b:2',3'-d]silole)-2,6-diyl-alt-(2,1,3-benzothiadiazole) 4,7-diyl] (PDTS-BTD) and {6,6}-phenyl-C71 butyric acid methyl ester (PC(71)BM). For inverted cells, a thin layer of ZnO nanoparticles and MoO(3) were used as interlayers for the bottom cathode and the top anode respectively. To enhance the device performance, a thin film of 4,4',4"-tris[N-(3-methylphenyl)-N phenylamino]triphenylamine (MTDATA) was used along with MoO(3) as an anode interlayer to improve the hole extraction from the photoactive layer to the anode. The inverted polymer solar cells with double interlayer exhibit a higher power conversion efficiency of 6.45% compared to the conventional cell of 4.91% due to efficient charge extraction and favorable vertical morphology of active layer blend. Our ultraviolet photoemission spectroscopy results indicate that the formation of band bending due to interlayer leads to the enhancement in hole extraction. PMID- 22225483 TI - Efficacy of whole body vibration exercise in older people: a systematic review. AB - PURPOSE: The aim of this study was to perform a systematic review of the literature on whole body vibration programs in older population and a meta analysis of randomized controlled clinical trials. METHOD: A search was conducted in MEDLINE, EMBASE, CENTRAL, CINAHL and PsychINFO databases. We included randomized controlled trials evaluating the efficacy and safety of whole body vibration training in older populations compared to conventional exercise or control groups that assessed balance, muscle strength, falls, bone mineral density and adverse events. RESULTS: Sixteen trials met the inclusion criteria. Comparing the vibration and the control group, we found that vibration significantly improved knee muscle isometric strength (18.30 Nm, 95% CI 7.95 28.65), muscle power (10.44 W, 95% CI 2.85-18.03) and balance control (Tinetti test: 4.5 points, 95% CI 0.95-8.11). Comparison with a conventional exercise showed that the only significant difference was bone mineral density in the femoral neck (0.04 g/cm(-2), 95% CI 0.02-0.07). There were no serious complications in most of studies. CONCLUSION: Whole body vibration training may improve strength, power and balance in comparison with a control group, although these effects are not apparent when compared with a group that does conventional exercise. PMID- 22225484 TI - The anatomical relationship of the diaphragm to the thoracolumbar junction during the minimally invasive lateral extracoelomic (retropleural/retroperitoneal) approach. AB - OBJECT: The thoracolumbar junction (T11-L2) poses an anatomical dilemma, given the presence of the lower rib cage and the diaphragm when performing anterolateral approaches. To circumvent dealing with the diaphragm, a minimally invasive lateral extracoelomic approach has been used to approach the thoracolumbar junction by mobilizing the diaphragm anteriorly. No anatomical studies have described the attachments of the diaphragm and their surgical significance during the lateral approach to the thoracolumbar spine. The objective of this study is to describe the anatomical relationship of the diaphragm in reference to the minimally invasive lateral approach to the thoracolumbar spine and its surgical significance. METHODS: Nine adult fresh frozen cadaveric specimens were dissected and studied (18 sides). All specimens were placed in the lateral decubitus position, similar to the surgical technique, for the dissections. The relationship between the retroperitoneum, retropleural space, diaphragm, and thoracolumbar spine was analyzed in reference to the minimally invasive lateral approach. Special attention was given to the attachments of the diaphragm and their relationship to the ribs during the early stages of the approach. RESULTS: All 18 sides were successfully dissected, analyzed, and photographed. The diaphragm is a musculotendinous sheet extending between the thoracic and abdominal cavities. Its attachments can be divided into 3 main categories: 1) sternal or anterior, 2) costal or lateral, and 3) lumbar or posterior. These attachments are described in detail, with specific reference to the lateral approach. When performing the minimally invasive lateral extracoelomic approach to the thoracolumbar spine, the lateral and posterior attachments must be identified and dissected to successfully mobilize the diaphragm anteriorly. CONCLUSIONS: The diaphragm has multiple attachments that can be categorized as anterior, lateral, and posterior. In reference to the minimally invasive lateral extracoelomic approach to the thoracolumbar junction, the surgically significant attachments are primarily to the 12th rib and transverse process of L-1. PMID- 22225485 TI - Spinal arteriovenous malformation associated with spinal metameric syndrome: a treatable cause of long-term paraplegia? AB - Cutaneomeningospinal angiomatosis, or Cobb syndrome, is a rare metameric developmental disorder presenting as an extradural-intradural vascular malformation that involves bone, muscle, skin, spinal cord, and nerve roots. A 14-year-old girl with a red nevus involving the T6-9 dermatomes on the left side of her back presented with a 5-year history of bowel and bladder incontinence, paraplegia, and lower-extremity sensory loss. Magnetic resonance imaging demonstrated a hemangioma in the T-8 and T-9 vertebral bodies and a spinal cord AVM nidus extending from T-6 to T-9. The AVM was successfully embolized and the patient regained lower-extremity strength, ambulation, and normal sphincter functions after 5 years of having been wheelchair bound. The authors report the restoration of ambulation after endovascular embolization of a large spinal AVM in a patient with long-standing paraplegia due to Cobb syndrome. PMID- 22225486 TI - Postvertebroplasty instability. AB - Vertebroplasty provides excellent pain relief and functional restoration for osteoporotic fractures. Short-term complications such as cement leak and embolism are well described. Incident fractures are the only well-reported long-term complications. The authors describe the cases of 5 patients who presented with back pain caused by instability or worsening neurological status 13 months (range 8-17 months) after vertebroplasty. They further classify this postvertebroplasty instability into intervertebral instability and intravertebral instability, depending on the apex of abnormal mobility. One patient presented with cement migration and progressive collapse of the augmented vertebral body. Another patient presented with an additional fracture. Both cases were classified as intravertebral instability. The cases of 3 other patients presenting with adjacent endplate erosion, vacuum disc phenomenon, and bridging osteophyte formation were classified as having intervertebral instability. Long-term effect of cements on the augmented vertebral body and adjacent endplates and discs is a cause for concern. Vertebroplasty acts as a mechanical stabilizer and provides structural support but does not bring about union. Micromotion has been shown to persist for years after vertebroplasty. This study describes persistent instability after vertebroplasty in a series of 5 cases. The authors propose that postvertebroplasty instability occurs due to collapse of soft osteoporotic bone and endplates around cement. All 3 cases of intervertebral instability were associated with an intradiscal cement leak. With increased longevity and higher functional demands of the geriatric population, the durability of this "rock (cement) between cushions (of osteoporotic bone)" arrangement (as seen in vertebroplasty) will be increasingly challenged. PMID- 22225487 TI - Primary telangiectatic osteosarcoma of the cervical spine. AB - Telangiectatic osteosarcoma (TOS) is one of the 8 subtypes of osteosarcoma that infrequently affects the spine. The radiopathological features of TOS overlap with those of more benign entities, most commonly the aneurysmal bone cyst), and therefore is a significant diagnostic challenge. It is a rare but well-described entity in the thoracolumbar and sacral spine, and to the authors' knowledge has not been previously reported in the cervical spine. The authors report the case of a 15-year-old boy who presented with a 6-month history of neck pain and torticollis. He underwent preoperative glue embolization followed by a staged subtotal C-5 spondylectomy and posterior fusion for a C-5 vertebral body lytic expansile lesion. Histopathological examination showed the lesion to be TOS. The surgery was followed by adjuvant radiation and chemotherapy with a favorable outcome at the 1-year follow-up. This report reiterates that TOS is an important differential diagnosis for aneurysmal bone cyst and giant-cell tumor of the spine, as its biological behavior and clinical outcome differ from those of these more benign lesions, which it mimics. PMID- 22225488 TI - Vertebral compression fracture risk after stereotactic body radiotherapy for spinal metastases. AB - OBJECT: The aim of this study was to identify potential risk factors for and determine the rate of vertebral compression fracture (VCF) after intensity modulated, near-simultaneous, CT image-guided stereotactic body radiotherapy (SBRT) for spinal metastases. METHODS: The study group consisted of 123 vertebral bodies (VBs) in 93 patients enrolled in prospective protocols for metastatic disease. Data from these patients were retrospectively analyzed. Stereotactic body radiotherapy consisted of 1, 3, or 5 fractions for overall median doses of 18, 27, and 30 Gy, respectively. Magnetic resonance imaging studies, obtained at baseline and at each follow-up, were evaluated for VCFs, tumor involvement, and radiographic progression. Self-reported average pain levels were scored based on the 11-point (0-10) Brief Pain Inventory both at baseline and at follow-up. Obesity was defined as a body mass index >= 30. RESULTS: The median imaging follow-up was 14.9 months (range 1-71 months). Twenty-five new or progressing fractures (20%) were identified, and the median time to progression was 3 months after SBRT. The most common histologies included renal cancer (36 VBs, 10 fractures, 10 tumor progressions), breast cancer (20 VBs, 0 fractures, 5 tumor progressions), thyroid cancer (14 VBs, 1 fracture, 2 tumor progressions), non small cell lung cancer (13 VBs, 3 fractures, 3 tumor progressions), and sarcoma (9 VBs, 2 fractures, 2 tumor progressions). Fifteen VBs were treated with kyphoplasty or vertebroplasty after SBRT, with 5 procedures done for preexisting VCFs. Tumor progression was noted in 32 locations (26%) with 5 months' median time to progression. At the time of noted fracture progression there was a trend toward higher average pain scores but no significant change in the median value. Univariate logistic regression showed that an age > 55 years (HR 6.05, 95% CI 2.1 17.47), a preexisting fracture (HR 5.05, 95% CI 1.94-13.16), baseline pain and narcotic use before SBRT (pain: HR 1.31, 95% CI 1.06-1.62; narcotic: HR 2.98, 95% CI 1.17-7.56) and after SBRT (pain: HR 1.34, 95% CI 1.06-1.70; narcotic: HR 3.63, 95% CI 1.41-9.29) were statistically significant predictors of fracture progression. On multivariate analysis an age > 55 years (HR 10.66, 95% CI 2.81 40.36), a preexisting fracture (HR 9.17, 95% CI 2.31-36.43), and baseline pain (HR 1.41, 95% CI 1.05-1.9) were found to be significant risks, whereas obesity (HR 0.02, 95% CI 0-0.2) was protective. CONCLUSIONS: Stereotactic body radiotherapy is associated with a significant risk (20%) of VCF. Risk factors for VCF include an age > 55 years, a preexisting fracture, and baseline pain. These risk factors may aid in the selection of which spinal SBRT patients should be considered for prophylactic vertebral stabilization or augmentation procedures. Clinical trial registration no.: NCT00508443. PMID- 22225489 TI - The impact of segmental and en bloc derotation maneuvers on scoliosis correction and rib prominence in adolescent idiopathic scoliosis. AB - OBJECT: Idiopathic scoliosis is a pathological process influencing the spinal column in 3 dimensions. Initial surgical treatment focused primarily on correction in the coronal plane, and with improved instrumentation, increasing attention has targeted balancing the sagittal profile. Newer surgical techniques now permit operative corrective forces to also directly address axial rotation. Although several technical variations of direct vertebral body derotation (DVBD) have been devised, no studies have compared outcomes from the differing techniques. The purpose of this study was to describe and compare the differences between segmental and en bloc DVBD. METHODS: A large prospectively collected database was queried for patients with adolescent idiopathic scoliosis (AIS) who underwent posterior spinal fusion and for whom there was a minimum of 2 years of follow-up. In all patients some type of DVBD maneuver was performed (segmental, en bloc, or both). Any patients with concurrent thoracoplasties were excluded. RESULTS: The authors identified 188 patients, of whom 120 underwent segmental derotation, 17 en bloc derotation, and 51 both. No significant radiographic or clinical differences existed among the groups preoperatively. The mean preoperative thoracic curve in the entire cohort was 53.1 degrees +/- 14.1 degrees and the mean thoracic rib prominence was 14.0 degrees +/- 5.5 degrees , whereas the respective postoperative values were 19.3 degrees +/- 8.3 degrees and 7.2 degrees +/- 4.0 degrees . No significant difference was identified between the various techniques postoperatively, either. However, when comparing intraoperative variables, significant differences were found for operative duration (p = 0.0001), estimated blood loss (p = 0.0081), and volume of blood transfusions (p = 0.041). CONCLUSIONS: Although each surgical technique of DBVD may have theoretical benefits and risks, no apparent difference in outcomes was observed between techniques. The concurrent use of both techniques was associated with increased blood loss and operative duration without any appreciable benefit. The surgeon should adopt the derotation technique with which he or she is most comfortable, but concurrent use of both does not appear to improve results. PMID- 22225490 TI - Local autograft retrieval from a cervical vertebral body: biomechanical consequences. AB - OBJECT: To avoid the cost of bone graft substitutes and the morbidity of iliac crest bone graft retrieval, locally harvested vertebral body bone has been used to fill interbody cages. When marginal hypertrophic osteophytes are used, there is little impact on the adjacent vertebrae, but when cancellous bone is removed from the central part of the vertebral body, it is not clear how significantly this procedure weakens the vertebra. The objective of this study was to investigate the immediate mechanical response of the cervical spine after removing bone from the central vertebral body. METHODS: Fourteen cervical functional spinal units (FSUs) (mean age 73.3 years, range 63-90 years) were used. For each FSU, bone mineral density (BMD) was determined using lateral-view dual-energy x-ray absorptiometry studies. The FSUs were assigned to 1 of 2 groups (test group or control group) with an equal distribution of BMD. All specimens received a cage placed into the cleaned disc space. The specimens from the test group had a 5-mm-diameter bone plug removed from the vertebral bodies superior and inferior to the cage-fitted disc. The specimens were loaded in flexion compression until failure via an eccentric compressive force at 0.25 mm/second. RESULTS: The yield compression strength was 1149 +/- 523 N for the test group and 1647 +/- 962 N for the control group (p = 0.25). The ultimate compression strength was 1699 +/- 498 N for the test group and 2450 N +/- 835 N for the control group (p = 0.06). Force at 4 mm displacement was 1064 N for the test group and 1574 N for the control group (p = 0.15). Displacement at yield compression strength was 4.4 mm for the test group and 4.2 mm for the control group (p = 0.78). There was no significant intergroup difference for any of the studied parameters. CONCLUSIONS: There does not appear to be a significant early biomechanical weakening of adjacent vertebrae caused by aforementioned technique of local bone harvest. PMID- 22225491 TI - Long-term effect of phytoestrogens from Curcuma comosa Roxb. on vascular relaxation in ovariectomized rats. AB - Phytoestrogens have been implicated as promising therapeutic agents to treat the vascular impairment seen in menopausal women. The present study investigated the long-term effects of phytoestrogens from Curcuma comosa Roxb. on vascular relaxation of isolated thoracic aorta from ovariectomized (OVX) rats. Treatment of OVX rats for 12 weeks with C. comosa powder, hexane extract, and a novel phytoestrogen, diarylheptanoid-D3, [(3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol] prevented impairment of the endothelium-dependent relaxation response to acetylcholine in OVX, but not the endothelium-denude aortic ring relaxation in response to sodium nitroprusside. These data suggest that the vascular relaxation effect of C. comosa is mediated via endothelial cells. Treatment with D3 also increased endothelial nitric oxide synthase (eNOS) and estrogen receptor-alpha (ERalpha) protein expression in the aorta of OVX rats and suppressed elevated tumor necrosis factor-alpha (TNF-alpha) expression in OVX aortic rings. These results indicate that C. comosa treatment prevents impairment of vascular relaxation in estrogen-deficient animals via the ER-eNOS pathway as well as through its ability to promote an anti-inflammatory response. PMID- 22225492 TI - wbeT sequence typing and IS1004 profiling of Vibrio cholerae isolates. AB - AIMS: To investigate the molecular basis for serotype variation in Vibrio cholerae O1 and the genetic relatedness amongst different serotypes isolated from 2004 to 2008 in Iran. METHODS AND RESULTS: Despite the presence of all three serotypes of V.cholerae O1 (Ogawa, Inaba and Hikojima) in Iran in the last decade, the Inaba strains have been the dominated serotype. Sequence analysis of wbeT determined only a single substitution of G for A at position 295 in all Inaba strains resulting in a replacement of serine to proline. No difference was found in the copy numbers and profile of IS1004 between the classical and El Tor V. cholerae O1 strains, supporting the clonality amongst the isolates obtained over 5 years in Iran. In addition, Southern blots of HpaII-digested chromosomal DNAs of our Ogawa and Inaba isolates showed the presence of an incomplete copy of IS1004 for all isolates. CONCLUSIONS: IS1004 profiling can be a reliable method for analysis of clonal dissemination of V. cholerae. The results indicated that specific point mutation at a particular position within the wbeT of V. cholerae O1 strains in Iran may occur which, in turn, may result in serotype switching. SIGNIFICANCE AND IMPACT OF THE STUDY: Understanding the molecular basis for serotype conversion of V. cholerae and their genetic relatedness could give insights for the incoming cholera epidemic prediction and control. PMID- 22225494 TI - Distribution and persistence of topical clotrimazole after sinus infusion in normal canine cadavers. AB - OBJECTIVES: To determine the in vitro persistence of clotrimazole 1% cream in the canine frontal sinus and to evaluate the distribution of clotrimazole solution over the sino-nasal mucosa using a previously described surgical treatment protocol for canine nasal aspergillosis. METHODS: Two canine skulls were used to monitor the persistence of clotrimazole cream in the lateral frontal sinus at 37 degrees C. The distribution of irrigation solution around the frontal sinus compartments and nasal cavity was determined using six canine cadaver heads by trephining either the lateral or both the lateral and rostral compartments of the frontal sinus. Stain was added to the sinus irrigation solution before visually inspecting the sagittally sectioned heads. RESULTS: Clotrimazole cream persisted in the frontal sinus for at least 96 hours. The nasal cavity mucosa was completely stained in 8 of 12 sides and almost completely stained in the remaining 4 of 12 sides. Flushing irrigation solution through the lateral compartment of the frontal sinus resulted in inadequate staining of the rostral compartment but medicating both the lateral and rostral compartments resulted in complete coating of all frontal sinus mucosa in eight of eight sides. CLINICAL SIGNIFICANCE: Clotrimazole cream has the potential to be retained in the frontal sinus for several days and is distributed effectively in normal canine cadavers. Medicating both the rostral and lateral compartments of the frontal sinus may be indicated in some clinical cases. PMID- 22225496 TI - Peptides derived from atlantic salmon skin gelatin as dipeptidyl-peptidase IV inhibitors. AB - The dipeptidyl-peptidase IV (DPP-IV)-inhibitory activity of peptides derived from Atlantic salmon skin gelatin hydrolyzed by alcalase (ALA), bromelain (BRO), and Flavourzyme (FLA) was determined. The FLA hydrolysate with the enzyme/substrate ratio of 6% showed the greatest DPP-IV-inhibitory activity. The hydrolysate was fractionated by ultrafiltration with 1 and 2.5 kDa cutoff membranes, and the <1 kDa fraction had the highest DPP-IV-inhibitory activity with an IC(50) value of 1.35 mg/mL. The F-1 fraction further isolated by HPLC showed the IC(50) value against DPP-IV of 57.3 MUg/mL, and the peptide sequences were identified as Gly Pro-Ala-Glu (372.4 Da) and Gly-Pro-Gly-Ala (300.4 Da). The synthetic peptides showed dose-dependent inhibition effects on DPP-IV with IC(50) values of 49.6 and 41.9 MUM, respectively. The results suggest that the peptides derived from Atlantic salmon skin gelatin would be beneficial ingredients for functional foods or pharmaceuticals against type 2 diabetes. PMID- 22225495 TI - Metabotyping of long-lived mice using 1H NMR spectroscopy. AB - Significant advances in understanding aging have been achieved through studying model organisms with extended healthy lifespans. Employing 1H NMR spectroscopy, we characterized the plasma metabolic phenotype (metabotype) of three long-lived murine models: 30% dietary restricted (DR), insulin receptor substrate 1 null (Irs1-/-), and Ames dwarf (Prop1df/df). A panel of metabolic differences were generated for each model relative to their controls, and subsequently, the three long-lived models were compared to one another. Concentrations of mobile very low density lipoproteins, trimethylamine, and choline were significantly decreased in the plasma of all three models. Metabolites including glucose, choline, glycerophosphocholine, and various lipids were significantly reduced, while acetoacetate, d-3-hydroxybutyrate and trimethylamine-N-oxide levels were increased in DR compared to ad libitum fed controls. Plasma lipids and glycerophosphocholine were also decreased in Irs1-/- mice compared to controls, as were methionine and citrate. In contrast, high density lipoproteins and glycerophosphocholine were increased in Ames dwarf mice, as were methionine and citrate. Pairwise comparisons indicated that differences existed between the metabotypes of the different long-lived mice models. Irs1-/- mice, for example, had elevated glucose, acetate, acetone, and creatine but lower methionine relative to DR mice and Ames dwarfs. Our study identified several potential candidate biomarkers directionally altered across all three models that may be predictive of longevity but also identified differences in the metabolic signatures. This comparative approach suggests that the metabolic networks underlying lifespan extension may not be exactly the same for each model of longevity and is consistent with multifactorial control of the aging process. PMID- 22225497 TI - Copper(II)-binding ability of stereoisomeric cis- and trans-2 aminocyclohexanecarboxylic acid-L-phenylalanine dipeptides. A combined CW/pulsed EPR and DFT study. AB - With the aim of an improved understanding of the metal-complexation properties of alicyclic beta-amino acid stereoisomers, and their peptides, the complex equilibria and modes of coordination with copper(II) of L-phenylalanine (F) derivatives of cis/trans-2-aminocyclohexanecarboxylic acid (c/tACHC), i.e. the dipeptides F-c/tACHC and c/tACHC-F, were investigated by a combination of CW and pulsed EPR methods. For the interpretation of the experimental data, DFT quantum chemical calculations were carried out. Simulation of a pH-dependent series of room-temperature CW-EPR spectra revealed the presence of EPR-active complexes ([Cu(aqua)](2+), [CuL](+), [CuLH(-1)], [CuLH(-2)](-), and [CuL(2)H(-1)](-)), and an EPR-inactive species ([Cu(2)L(2)H(-3)](-)) in aqueous solutions for all studied cases. [CuLH](2+) was included in the equilibrium model for the c/tACHC-F copper(II) systems, and [CuL(2)], together with two coordination isomers of [CuL(2)H(-1)](-), were also identified in the F-tACHC-copper(II) system. Comparison of the complexation properties of the diastereomeric ligand pair F (1S,2R)-ACHC and F-(1R,2S)-ACHC did not reveal significant differences. Considerably lower formation constants were obtained for the trans than for the cis isomers for both the F-c/tACHC and the c/tACHC-F pairs in the case of [CuLH( 1)] involving tridentate coordination by the amino, the deprotonated peptide, and the carboxylate groups. A detailed structural analysis by pulsed EPR methods and DFT calculations indicated that there was no significant destabilization for the complexes of the trans isomers. The lower stability of their complexes was explained by the limitation that only the conformer with donor groups in equatorial-equatorial ring positions can bind to copper(II), whereas both equatorial-axial conformers of the cis isomers are capable of binding. From a consideration of the proton couplings obtained with X-band (1)H HYSCORE, (2)H exchange experiments, and DFT, the thermodynamically most stable cyclohexane ring conformer was assigned for all four [CuLH(-1)] complexes. For the F-cACHC case, the conformer did not match the most stable conformer of the free ligand. PMID- 22225498 TI - Survival after surgery for tracheal collapse and the effect of intrathoracic collapse on survival. AB - OBJECTIVES: To determine (1) long-term survival of dogs with tracheal collapse (TC) receiving cervical extraluminal prosthetic rings (ELR) and (2) whether intrathoracic collapse effects long-term survival of dogs receiving ELR. STUDY DESIGN: Retrospective case series. ANIMALS: Dogs (n = 33) with TC that had ELR. METHODS: Medical records (July 2002-July 2008) were searched for TC dogs treated with ELR. Age, breed, gender, location of TC, and age at follow-up (death or censor) were recorded. Kaplan-Meier survival curves were generated. RESULTS: Of 114 TC dogs, 33 had ELR. Breeds and gender were consistent with previous reports; mean (+/-SD) age at presentation was 6.3+/-2.6 years. TC was categorized as cervical or cervical and intrathoracic. All dogs had cervical TC and 15 had concurrent intrathoracic collapse; 8 of these had collapse of mainstem bronchi. Median survival time was >2500 days (median not reached) for cervical TC alone and 1500 days for cervical and intrathoracic TC with no difference in median survival time between groups (P = .26). CONCLUSION: Dogs with TC have a median survival time of 1680 days (4.6 years) after ELR and no differences were seen when dogs had intrathoracic collapse. Intrathoracic collapse does not exclude a dog from receiving ELR. PMID- 22225499 TI - Tuning the photoresponse in organic field-effect transistors. AB - We report on the fabrication of solution-processed organic phototransistors (OPTs) based on perylenebis(dicarboximide)s (PDIs). We found that the responsivity to the photoillumination depends on the transistor's channel length and that it can be tuned by varying the device geometry. The analysis of different morphologies of the active semiconducting layer revealed that single PDI fibers exhibit the higher photoresponse when compared to more poorly organized films. The highest responsivity value of 4.08 +/- 1.65 * 10(5) A/W was achieved on a multifiber-based OPT. These findings represent a step forward toward the use of organic based phototransistors as photosensors. PMID- 22225500 TI - Artefact-reduced kinematics measurement using a geometric finger model with mixture-prior particle filtering. AB - It is challenging to measure the finger's kinematics of underlying bones in vivo. This paper presents a new method of finger kinematics measurement, using a geometric finger model and several markers deliberately stuck on skin surface. Using a multiple-view camera system, the optimal motion parameters of finger model were estimated using the proposed mixture-prior particle filtering. This prior, consisting of model and marker information, avoids generating improper particles for achieving near real-time performance. This method was validated using a planar fluoroscopy system that worked simultaneously with photographic system. Ten male subjects with asymptomatic hands were investigated in experiments. The results showed that the kinematic parameters could be estimated more accurately by the proposed method than by using only markers. There was 20 40% reduction in skin artefacts achieved for finger flexion/extension. Thus, this profile system can be developed as a tool of reliable kinematics measurement with good applicability for hand rehabilitation. PMID- 22225501 TI - The utility of pharmacokinetic-pharmacodynamic modeling in the discovery and optimization of selective S1P(1) agonists. AB - Sphingosine-1-phosphate (S1P(1)) receptor agonists such as Fingolimod (FTY-720) are a novel class of immunomodulators that have clinical utility in the treatment of remitting relapsing multiples sclerosis. This class of compound act by inducing peripheral lymphopenia. Using an integrated pharmacokinetic/pharmacodynamic (PK-PD) approach based on an in vivo rat model, novel S1P(1) agonists were identified with a predicted more rapid rate of reversibility of lymphocyte reduction in human compared to Fingolimod. The in vivo potency of 15 compounds based on PK-PD modelling of the rat lymphocyte reduction model was correlated with in vitro measures of potency at the S1P(1) receptor using beta arrestin recruitment and G-protein signalling. A structurally novel S1P(1) agonist was identified and predictions of human pharmacokinetics and clinical dose are presented. PMID- 22225502 TI - Cloning and functional expression of an acidophilic beta-mannanase gene (Anman5A) from Aspergillus niger LW-1 in Pichia pastoris. AB - A cDNA fragment of the Anman5A, a gene that encodes an acidophilic beta-mannanase of Aspergillus niger LW-1 (abbreviated as AnMan5A), was cloned and functionally expressed in Pichia pastoris . Homology alignment of amino acid sequences verified that the AnMan5A belongs to the glycoside hydrolase (GH) family 5. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) assay demonstrated that the recombinant AnMan5A (reAnMan5A), a N-glycosylated protein with an apparent molecular weight of 52.0 kDa, was secreted into the medium. The highest reAnMan5A activity expressed by one P. pastoris transformant, labeled as GSAnMan4-12, reached 29.0 units/mL. The purified reAnMan5A displayed the highest activity at pH 3.5 and 70 degrees C. It was stable at a pH range of 3.0 7.0 and at a temperature of 60 degrees C or below. Its activity was not significantly affected by an array of metal ions and ethylenediaminetetraacetic acid (EDTA). The K(m) and V(max) of the reAnMan5A, toward locust bean gum, were 1.10 mg/mL and 266.7 units/mg, respectively. PMID- 22225503 TI - Effect of cooking on radiation-induced chemical markers in beef and pork during storage. AB - Raw and cooked beef and pork loins were irradiated at 0 or 5 kGy. The radiation induced marker compounds, such as hydrocarbons, 2-alkylcyclobutanones (2-ACBs), and sulfur volatiles, were determined after 0 and 6 mo of frozen storage. Two hydrocarbons (8-heptadecene [C(17:1)] and 6,9-heptadecadiene [C(17:2)]) and two 2 ACBs (2-dodecylcyclobutanone [2-DCB] and 2-tetradecylcyclobutanone [2-TCB]) were detected only in irradiated raw and cooked meats. Although precooked irradiated meats produced more hydrocarbons and 2-ACBs than the irradiated cooked ones, the amounts of individual hydrocarbons and 2-ACBs, such as 8-heptadecene, 6,9 heptadecadiene, 2-DCB, and 2-TCB, were sufficient enough to detect whether the meat was irradiated or not. Dimethyl disulfide and dimethyl trisulfide were also determined only in irradiated meats but dimethyl trisulfide disappeared after 6 mo of frozen storage under oxygen-permeable packaging conditions. The results indicated that 8-heptadecene, 6,9-heptadecadiene, 2-DCB, 2-TCB, and dimethyl disulfide, even though they were decreased with storage, could be used as marker compounds for the detection of irradiated beef and pork regardless of cooking under the frozen conditions for 6 mo. PRACTICAL APPLICATION: Radiation-induced chemical changes such as specific hydrocarbons, 2-ACBs, and sulfur volatiles may be used as potential identification markers by regulatory authorities to confirm irradiation history of frozen stored raw or cooked beef and pork. PMID- 22225504 TI - Low-energy isomer identification, structural evolution, and magnetic properties in manganese-doped gold clusters MnAu(n) (n = 1-16). AB - The size-dependent electronic, structural, and magnetic properties of Mn-doped gold clusters have been systematically investigated by using relativistic all electron density functional theory with generalized gradient approximation. A number of new isomers are obtained for neutral MnAu(n) (n = 1-16) clusters to probe the structural evolution. The two-dimensional (2D) to three-dimensional (3D) transition occurs in the size range n = 7-10 with manifest structure competitions. From size n = 13 to n = 16, the MnAu(n) prefers a gold cage structure with Mn atom locating at the center. The relative stabilities of the ground-state MnAu(n) clusters show a pronounced odd-even oscillation with the number of Au atoms. The magnetic moments of MnAu(n) clusters vary from 3 MU(B) to 6 MU(B) with the different cluster size, suggesting that nonmagnetic Au(n) clusters can serve as a flexible host to tailor the dopant's magnetism, which has potential applications in new nanomaterials with tunable magnetic properties. PMID- 22225505 TI - Impact of aggregate size and structure on the photocatalytic properties of TiO2 and ZnO nanoparticles. AB - Aggregation of photocatalytic semiconductors was determined to reduce the generation of free hydroxyl radicals in aqueous suspensions in a fashion dependent on aggregate size and structure. Static light scattering measurements were used to follow temporal changes in the fractal dimension of aggregating TiO(2) and ZnO nanoparticles. At length scales comparable to nanoparticle size, the structure of aggregated TiO(2) nanoparticles was independent of particle stability and the associated aggregation rate, consistent with the fused nature of TiO(2) primary particles in the initial suspension. In contrast, ZnO aggregates were characterized by smaller fractal dimensions when ionic strength, and the resulting aggregation rate, were increased. The photocatalytic activity of ZnO and TiO(2) in generating free hydroxyl radicals varied with aggregate structure and size, consistent with theory that predicts reduced reactivity as aggregates become larger and more dense. PMID- 22225506 TI - The withdrawal of Activated Protein C from the use in patients with severe sepsis and DIC [Amendment to the BCSH guideline on disseminated intravascular coagulation]. PMID- 22225507 TI - Parasitism by the endoparasitoid, Cotesia flavipes induces cellular immunosuppression and enhances susceptibility of the sugar cane borer, Diatraea saccharalis to Bacillus thuringiensis. AB - Cotesia flavipes Cameron (Hymenoptera: Braconidae), is a gregarious larval endoparasitoid of the sugarcane borer, Diatraea saccharalis Fabricius (Lepidoptera: Crambidae). The aim of this research was to analyze cellular immunosuppression of D. saccharalis parasitized by C. flavipes in terms of encapsulation, melanization, and hemocyte nodule formation. The encapsulation assay was done 1 and 6 days after parasitoid oviposition. In addition, the susceptibility of parasitized and nonparasitzed larvae to Bacillus thuringiensis HD 73 strain was assessed. 3, 12, and 24 h after bead injection; the percentages of encapsulation were significantly higher in unparasitized larvae compared to larvae parasitized 1 and 6 days after oviposition. Interestingly, there was a significant reduction in numbers of beads encapsulated at 1 day after oviposition compared to 6 days, and unparasitized larvae. The percentage of melanized beads decreased significantly in parasitized larvae compared to control. There was a reduction in the number of nodules in parasitized larvae compared to unparasitized controls. Larvae that were injected with polyndavirus 24 h before beads were injected showed significantly reduced encapsulation responses relative to control larvae. The D. saccharalis parasitized by C. flavipes exhibited higher susceptibility to B. thuringiensis. These results suggest that parasitization induced host immunosuppression, and the immunosuppression factors could impair the defense capacity against microbial pathogens--causing an increase in pathogen susceptibility. PMID- 22225510 TI - Behavior regulation and mood predict social functioning among healthy young adults. AB - Impulsive behavior is thought to lead to both positive and negative psychosocial outcomes. However, little is known about the potential consequences of subclinical expressions of behavior dysregulation on everyday functioning. To examine this relationship, global social functioning was measured in 89 healthy, young adults who also completed the Degraded Stimulus Continuous Performance Test, Color-Word Interference Test, Barratt Impulsiveness Scale, 11th Edition, and Behavior Rating Inventory of Executive Functioning-Adult. Better self reported executive functioning and mood were significant independent predictors of higher social functioning, even in a sample of healthy adults. The results of this study may serve as a foundation for comparison with clinical populations who demonstrate greater behavior dysregulation and mood instability. PMID- 22225509 TI - Effect of the addition of silanated silica on the mechanical properties of microwave heat-cured acrylic resin. AB - OBJECTIVES: The purpose of this study was to evaluate the flexural strength and Vickers hardness of a microwave energy heat-cured acrylic resin by adding different concentrations of silane surface-treated nanoparticle silica. METHODS: Acrylic resin specimens with dimensions of 65 * 10 * 2.5 mm were formed and divided into five experimental groups (n = 10) according to the silica concentration added to the acrylic resin mass (weight %) prior to polymerisation : G1, without silica; G2, 0.1% silica; G3, 0.5% silica; G4, 1.0% silica; and G5, 5.0% silica. The specimens were submitted to a three-point flexural strength test and to the Vickers hardness test (HVN). The data obtained were statistically analysed by anova and the Tukey test (alpha = 0.05). RESULTS: Regarding flexural strength, G5 differed from the other experimental groups (G1, G2, G3 and G4) presenting the lowest mean, while G4 presented a significantly higher mean, with the exception of group G3. Regarding Vickers hardness, a decrease in values was observed, in which G1 presented the highest hardness compared with the other experimental groups. CONCLUSION: Incorporating surface-treated silica resulted in direct benefits in the flexural strength of the acrylic resin activated by microwave energy; however, similar results were not achieved for hardness. PMID- 22225511 TI - Calculations on noncovalent interactions and databases of benchmark interaction energies. AB - Although covalent interactions determine the primary structure of a molecule, the noncovalent interactions are responsible for the tertiary and quaternary structure of a molecule and create the fascinating world of the 3D architectures of biomacromolecules. For example, the double helical structure of DNA is of fundamental importance for the function of DNA: it allows it to store and transfer genetic information. To fulfill this role, the structure is rigid to maintain the double helix with a proper positioning of the complementary base, and floppy to allow for its opening. Very strong covalent interactions cannot fulfill both of these criteria, but noncovalent interactions, which are about 2 orders of magnitude weaker, can. This Account highlights the recent advances in the field of the design of novel wave function theory (WFT) methods applicable to noncovalent complexes ranging in size from less than 100 atoms, for which highly accurate ab initio methods are available, up to extended ones (several thousands atoms), which are the domain of semiempirical QM (SQM) methods. Accurate interaction energies for noncovalent complexes are generated by the coupled cluster technique, taking single- and double-electron excitations iteratively and triple-electron excitation perturbatively with a complete basis set description (CCSD(T)/CBS). The procedure provides interaction energies with high accuracy (error less than 1 kcal/mol). Because the method is computationally demanding, its application is limited to complexes smaller than 30 atoms. But researchers would also like to use computational methods to determine these interaction energies accurately for larger biological and nanoscale structures. Standard QM methods such as MP2, MP3, CCSD, or DFT fail to describe various types of noncovalent systems (H-bonded, stacked, dispersion-controlled, etc.) with comparable accuracy. Therefore, novel methods are needed that have been parametrized toward noncovalent interactions, and existing benchmark data sets represent an important tool for the development of new methods providing reliable characteristics of noncovalent clusters. Our laboratory developed the first suitable data set of CCSD(T)/CBS interaction energies and geometries of various noncovalent complexes, called S22. Since its publication in 2006, it has frequently been applied in parametrization and/or verification of various wave function and density functional techniques. During the intense use of this data set, several inconsistencies emerged, such as the insufficient accuracy of the CCSD(T) correction term or its unbalanced character, which has triggered the introduction of a new, broader, and more accurate data set called the S66 data set. It contains not only 66 CCSD(T)/CBS interaction energies determined in the equilibrium geometries but also 1056 interaction energies calculated at the same level for nonequilibrium geometries. The S22 and S66 data sets have been used for the verification of various WFT methods, and the lowest RMSE (S66, in kcal/mol) was found for the recently introduced SCS-MI-CCSD/CBS (0.08), MP2.5/CBS (0.16), MP2.X/6-31G* (0.27), and SCS-MI-MP2/CBS (0.38) methods. Because of their computational economy, the MP2.5 and MP2.X/6-31G* methods can be recommended for highly accurate calculations of large complexes with up to 100 atoms. The evaluation of SQM methods was based only on the S22 data set, and because some of these methods have been parametrized toward the same data set, the respective results should be taken with caution. For really extended complexes such as protein-ligand systems, only the SMQ methods are applicable. After adding the corrections to the dispersion energy and H-bonding, several methods exhibit surprisingly low RMSE (even below 0.5 kcal/mol). Among the various SMQ methods, the PM6-DH2 can be recommended because of its computational efficiency and it can be used for optimization (which is not the case for other SQM methods). The PM6 DH2 is the base of our novel scoring function used in in silico drug design. PMID- 22225512 TI - Synchrotron FTIR microscopy of Langmuir-Blodgett monolayers and polyelectrolyte multilayers at the solid-solid interface. AB - Synchrotron FTIR microscopy has been used to probe the structure of model boundary lubricant layers confined at the solid-solid interface. The combination of high brightness of the IR source and a novel contact geometry that uses a hemispherical internal reflection element as the means for light delivery has enabled the detection of <2.5 nm thin monolayer lubricant layers in the solid solid contact, in addition to allowing for spectral acquisition from specific regions of the contact. Spectra of hydration water from within a confined polyelectrolyte multilayer film have also been acquired, highlighting the altered hydrogen bonding environment within the polymer layer. PMID- 22225513 TI - Inhibitory effects of melatonin on the lipopolysaccharide-induced CC chemokine expression in BV2 murine microglial cells are mediated by suppression of Akt induced NF-kappaB and STAT/GAS activity. AB - Melatonin influences sleep and circadian rhythm, and it has anti-inflammatory functions. However, the mechanism of its anti-inflammatory roles is not well understood. In our studies, we show that melatonin blocked lipopolysaccharide (LPS)-induced CCL2 (monocyte chemotactic protein-1; MCP-1), CCL5 (Regulated upon Activation, Normal T-cell Expressed, and Secreted), and CCL9 (macrophage inflammatory protein-1gamma) chemokine mRNA expression in BV2 murine microglial cells. Melatonin markedly inhibited LPS-induced Akt phosphorylation and NF-kappaB activation. Furthermore, melatonin inhibited LPS-induced STAT1/3 phosphorylation and interferon-gamma activated sequence (GAS)-driven transcriptional activity. Interestingly, these effects were not associated with reactive oxygen species scavenging effects of melatonin or melatonin receptor signal pathways. Taken together, our results suggested that melatonin has anti-inflammatory functions through down-regulation of chemokine expression by inhibition of NF-kappaB and STAT/GAS activation in LPS-stimulated BV2 murine microglial cell line. PMID- 22225514 TI - The personalized medicine revolution: getting it right for children. PMID- 22225515 TI - A detailed 3D finite element analysis of the peeling behaviour of a gecko spatula. AB - This paper presents a detailed finite element analysis of the adhesion of a gecko spatula. The gecko spatulae form the tips of the gecko foot hairs that transfer the adhesional and frictional forces between substrate and foot. The analysis is based on a parameterised description of the 3D geometry of the spatula that only requires 12 parameters. The adhesion is described by a nonlinear computational contact formulation that accounts for the van der Waals interaction between spatula and substrate. The spatula adhesion model is implemented using an enriched contact finite element formulation recently developed by the first author. The finite element model is then used to simulate the peeling behaviour of the gecko spatula under applied vertical and rotational loading for various model parameters. Variations of the material stiffness, adhesional strength and range, stiction, spatula size and spatula inclination are considered to account for the natural variation of spatula properties. The study demonstrates that the spatula can function over a wide range of conditions. The computed pull-off forces are in agreement with experimental results reported in the literature. The study also examines the energy required for the spatula pull-off. The proposed model is ideal to study the influence of substrate roughness on the spatula adhesion, as is finally demonstrated. PMID- 22225517 TI - Review article: probiotics for the treatment of irritable bowel syndrome--focus on lactic acid bacteria. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a poorly understood, yet highly prevalent functional gastrointestinal disorder (FGID). The withdrawal, due to adverse events, of a number of pharmacological agents that were approved for the treatment of IBS has left a therapeutic vacuum for patients suffering from the disorder. AIM: To review, summarise and critically evaluate current knowledge of lactic acid bacteria (LAB) used to treat IBS. METHODS: We assessed a comprehensive range of relevant literature from Pubmed, Medline and online sources based on our definition of LAB which included both typical and atypical species, covering Lactobacilli, Bifidobacteria, Enterococci, Streptococci and Bacilli. RESULTS: Of the 42 trials evaluated examining the efficacy of LAB in IBS, 34 reported beneficial effects in at least one of the endpoints or symptoms examined, albeit with tremendous variation in both the magnitude of effect and the choice of outcome under consideration. However, numerous concerns have been expressed over deficits of trial design and execution relating to strain selection, optimum dosage, mode of action, safety and long-term tolerability in a disorder that can persist throughout the lifetime of affected individuals. CONCLUSIONS: Progress in the field will require an improved understanding of how the microbiota impacts on health and disease, adequately powered long-term multicentre trials and the embracing of bench to bedside approaches. Recent incremental advances suggest these areas are being addressed and that the future holds much promise for the use of lactic acid bacteria in the treatment of irritable bowel syndrome. PMID- 22225516 TI - Identity of the exchangeable sulfur-containing ligand at the Mo(V) center of R160Q human sulfite oxidase. AB - In our previous study of the fatal R160Q mutant of human sulfite oxidase (hSO) at low pH (Astashkin et al. J. Am. Chem. Soc.2008, 130, 8471-8480), a new Mo(V) species, denoted "species 1", was observed at low pH values. Species 1 was ascribed to a six-coordinate Mo(V) center with an exchangeable terminal oxo ligand and an equatorial sulfate group on the basis of pulsed EPR spectroscopy and (33)S and (17)O labeling. Here we report new results for species 1 of R160Q, based on substitution of the sulfur-containing ligand by a phosphate group, pulsed EPR spectroscopy in K(a)- and W-bands, and extensive density functional theory (DFT) calculations applied to large, more realistic molecular models of the enzyme active site. The combined results unambiguously show that species 1 has an equatorial sulfite as the only exchangeable ligand. The two types of (17)O signals that are observed arise from the coordinated and remote oxygen atoms of the sulfite ligand. A typical five-coordinate Mo(V) site is compatible with the observed and calculated EPR parameters. PMID- 22225518 TI - The Candida glabrata adhesin Epa1p causes adhesion, phagocytosis, and cytokine secretion by innate immune cells. AB - While Candida albicans is the most significant fungal pathogen for humans, Candida glabrata accounts for an increasing number of infections. Little is known about how C. glabrata interacts with the innate immune system, the first line of defense against such organisms. The C. glabrata adhesin Epa1p was previously shown to bind mammalian epithelial cells. We hypothesized that Epa1p mediates unique, nonopsonic binding to macrophages, leading to induction of immune responses. We found that Epa1p mediated adhesion by both C. glabrata (Cg) and transformed Saccharomyces cerevisiae (Sc(EPA1) ) to human macrophage-like cells, including Thp1 and U937 lines, and donor PBMCs. Adhesion was distinct from described mechanisms such as Dectin-1. Epa1p expression was necessary and sufficient for S. cerevisiae binding and phagocytosis, the latter of which was actin-mediated. Sc(EPA1) induced inflammatory cytokine production (IL-8 and TNF alpha) by human PBMC-derived macrophages. Despite expressing Epa1p and binding to macrophages, Cg avoided phagocytosis and cytokine induction. In contrast to human results, in murine cell models (RAW264.7, J774A.1, and C57BL/6-derived cells), Epa1p-mediated binding was only revealed after blocking the Dectin-1 system. Recognition of Epa1p represents a novel mechanism by which human innate immune cells bind fungi, and for Sc(EPA1) results in phagocytosis and subsequent cytokine production. PMID- 22225519 TI - GSTM1, GSTT1 and GSTP1 gene polymorphism in polymorphous light eruption. AB - BACKGROUND: Polymorphous light eruption (PLE) is the most common chronic and idiopathic photodermatosis. PLE is assumed to represent an immunological hypersensitivity reaction to a radiation-induced cutaneous antigen involving reactive oxygen species (ROS) on the basis of a genetic predisposition. Among others, cellular protection against ROS is provided by glutathione S-transferases (GSTs). Different variants of the GST enzymes may influence the activity and efficiency of detoxification and biotransformation of unknown UV-induced skin antigens and other factors that may play an important role in the pathogenesis of PLE. METHODS: In this study the relationship between isoenzymes of the GST genes GSTM1, GSTT1 and GSTP1 and possible protective or predisposing effects on PLE was examined in 29 patients and 144 controls. Diagnosis of PLE was based on the presence of characteristic clinical features. RESULTS: No association between the functional polymorphisms of the GST gene family and PLE was found. Prevalence of certain GST isoenzymes or polymorphisms in patients with PLE did not differ from healthy controls. CONCLUSION: Our data do not support prevalence of GST isoenzymes or polymorphisms as a protective effect against PLE. Especially a higher carrier frequency of GSTP1 Val(105) as a protective factor against PLE which has been published before could not be proved. The GST genotypes GSTM1, GSTT1 and GSTP1 (including SNPs) seem to have no relevant association with PLE. PMID- 22225520 TI - Truffle brule: an efficient fungal life strategy. AB - The terms 'brule' and 'burnt' are used to describe vegetation-devoid areas of the ground around a range of woody plants interacting with certain truffle species. Increasing interest is currently focused on a systematic search for and study of volatile organic compounds (VOCs) emitted by truffles in the course of their life cycle. These metabolites are now recognized as biochemicals with an important impact on burnt formation. Based on current molecular approaches, Tuber melanosporum is emerging as an aggressive colonizer of the brule, dominant in competition with indigenous brule-associated organisms, suppressing their richness and biodiversity. There is compelling evidence that mycelia, mycorrhizae, and fruiting bodies of brule-forming truffles have evolved diffusible metabolites for their survival, typically characterized as having harmful effects on weeds, impairing seed germination, altering root morphogenesis and plant hormonal balance, or inhibiting the native rhizospheric microflora regularly associated with the brule. These effects can be widely interpreted as allelopathic phenomena, and the brule may thus be regarded as a promising opportunity to study truffle allelopathy. Considering the outstanding success of the genome analysis in T. melanosporum, we are facing a very difficult task to proceed from the molecular to the ecological level. PMID- 22225522 TI - Comparison of trigeminal and spinal modulation of pain and nociception. AB - Modulation of pain and nociception by noxious counterstimulation, also called "diffuse noxious inhibitory controls" or DNIC-like effect, is often used in studies of pain disorders. It can be elicited in the trigeminal and spinal innervation areas, but no study has previously compared effects in both innervation areas. Therefore, we performed a study comparing DNIC-like effects on the nociceptive flexion reflex (NFR) and the nociceptive blink reflex as well as the respective pain sensations. In 50 healthy volunteers, the blink reflex elicited with a concentric electrode and the NFR were recorded before and after immersion of the contralateral hand in cold water. Responses were recorded as the subjective pain sensation and the reflex size. The cold water immersion of the contralateral hand elicited a reduction of both subjective pain sensation and reflex amplitude following the stimulation of both reflexes. However, there were no strong correlations between the individual reductions of both subjective pain sensation and reflex amplitude for both reflexes, and neither when results of the two reflexes were compared with each other. The dissociation between DNIC-like effects on pain and on nociception, which had been found previously already for the NFR, implies that both effects need to be studied separately. PMID- 22225523 TI - Liver transplantation for hepatitis C from donation after cardiac death donors: an analysis of OPTN/UNOS data. AB - Donation after cardiac death (DCD) liver transplantation is increasing largely because of a shortage of organs. However, there are almost no data that have specifically assessed the impact of using DCD livers for HCV patients. We retrospectively studied adult primary DCD liver transplantation (630 HCV, 1164 non-HCV) and 54 129 donation after brain death (DBD) liver transplantation between 2002 and 2009 using the UNOS/OPTN database. With donation after brain death (DBD) livers, HCV recipients had significantly inferior graft survival compared to non-HCV recipients (p < 0.0001). Contrary to DBD donors, DCD livers used in HCV patients showed no difference in graft survival compared to non-HCV patients (p = 0.5170). Cox models showed DCD livers and HCV disease had poorer graft survival (HR = 1.80 and 1.28, p < 0.0001, respectively). However, the hazard ratio of DCD and HCV interaction was 0.80 (p = 0.02) and these results suggest that DCD livers on HCV disease do not fare worse than DCD livers on non HCV disease. The graft survival of recent years (2006-2009) was significantly better than that in former years (2002-2005) (p = 0.0482). In conclusion, DCD liver transplantation for HCV disease showed satisfactory outcomes. DCD liver transplantation can be valuable option for HCV related end-stage liver disease. PMID- 22225525 TI - Demonstration of ligand decoration, and ligand-induced perturbation, of G quadruplexes in a plasmid using atomic force microscopy. AB - G-Quadruplexes are nucleic acid secondary structures consisting of a planar arrangement of four guanine residues. Potential G-quadruplex-forming sequences are widely distributed throughout the genome. Significantly, they are present in telomeres and are enriched in gene promoters and first introns, raising the possibility that perturbation of G-quadruplex stability might have therapeutic potential, for example in the treatment of cancer. Ligands that interact selectively with G-quadruplexes include both proteins and small molecules, although the interactions between ligands and their G-quadruplex targets have been monitored using indirect methods. In addition, the G-quadruplex targets have often been short DNA fragments. Here, we have used atomic force microscopy imaging to examine directly at the single-molecule level the interaction of ligands with G-quadruplexes generated during transcription of a plasmid containing a G-rich insert. We show that the structures produced during transcription are decorated specifically by the single-chain antibody HF1 and by the nuclear protein PARP-1, both of which are known to recognize G-quadruplexes. Our results provide clear structural evidence of G-quadruplex formation in a transcription-dependent case and demonstrate directly how small-molecule stabilizers and destabilizers can manipulate these structures in a biochemically functional system. PMID- 22225526 TI - Multinuclear solid-state nuclear magnetic resonance and density functional theory characterization of interaction tensors in taurine. AB - A variety of experimental solid-state nuclear magnetic resonance (NMR) techniques has been used to characterize each of the elements in 2-aminoethane sulfonic acid (taurine). A combination of (15)N cross-polarization magic angle spinning (CPMAS), (14)N ultrawideline, and (14)N overtone experiments enabled a determination of the relative orientation of the nitrogen electric field gradient and chemical shift tensors. (17)O spectra recorded from an isotopically enriched taurine sample at multiple magnetic fields allowed the three nonequivalent oxygen sites to be distinguished, and NMR parameters calculated from a neutron diffraction structure using density functional theory allowed the assignment of the (17)O parameters to the correct crystallographic sites. This is the first time that a complete set of (17)O NMR tensors are reported for a sulfonate group. In combination with (1)H and (13)C MAS spectra, as well as a previously reported (33)S NMR study, this provides a very broad set of NMR data for this relatively simple organic molecule, making it a potentially useful structure on which to test DFT calculation methods (particularly for the quadrupolar nuclei (14)N, (17)O, and (33)S) or NMR crystallography approaches. PMID- 22225527 TI - Frequency of CDH1 germline mutations in gastric carcinoma coming from high- and low-risk areas: metanalysis and systematic review of the literature. AB - BACKGROUND: The frequency of E-cadherin germline mutations in countries with different incidence rates for gastric carcinoma has not been well established. The goal of this study was to assess the worldwide frequency of CDH1 germline mutations in gastric cancers coming from low- and high-risk areas. METHODS: English articles using MEDLINE access (from 1998 to 2011). Search terms included CDH1, E-cadherin, germline mutation, gastric cancer, hereditary, familial and diffuse histotype.The study included all E-cadherin germline mutations identified in gastric cancer patients; somatic mutations and germline mutations reported in other tumors were excluded.The method of this study was scheduled in accordance with the "PRISMA statement for reporting systematic reviews and meta-analyses". Countries were classified as low- or middle/high risk-areas for gastric carcinoma incidence. Statistical analysis was performed to correlate the CDH1 mutation frequency with gastric cancer incidence areas. RESULTS: A total of 122 E-cadherin germline mutations have been identified; the majority (87.5%) occurred in gastric cancers coming from low-risk areas. In high-risk areas, we identified 16 mutations in which missense mutations were predominant. (68.8%). We verified a significant association between the mutation frequency and the gastric cancer risk area (p < 0.001: overall identified mutations in low- vs. middle/high-risk areas). CONCLUSIONS: E-cadherin genetic screenings performed in low-risk areas for gastric cancer identified a higher frequency of CDH1 germline mutations. This data could open new approaches in the gastric cancer prevention test; before proposing a proband candidate for the CDH1 genetic screening, geographic variability, alongside the family history should be considered. PMID- 22225529 TI - Naturally occurring contamination in the Mancos Shale. AB - Some uranium mill tailings disposal cells were constructed on dark-gray shale of the Upper Cretaceous Mancos Shale. Shale of this formation contains contaminants similar to those in mill tailings. To establish the contributions derived from the Mancos, we sampled 51 locations in Colorado, New Mexico, and Utah. Many of the groundwater samples were saline with nitrate, selenium, and uranium concentrations commonly exceeding 250, 000, 1000, and 200 MUg/L, respectively. Higher concentrations were limited to groundwater associated with shale beds, but were not correlated with geographic area, stratigraphic position, or source of water. The elevated concentrations suggest that naturally occurring contamination should be considered when evaluating groundwater cleanup levels. At several locations, seep water was yellow or red, caused in part by dissolved organic carbon concentrations up to 280 mg/L. Most seeps had (234)U to (238)U activity ratios greater than 2, indicating preferential leaching of (234)U. Seeps were slightly enriched in (18)O relative to the meteoric water line, indicating limited evaporation. Conceptually, major ion chemical reactions are dominated by calcite dissolution following proton release from pyrite oxidation and subsequent exchange by calcium for sodium residing on clay mineral exchange sites. Contaminants are likely released from organic matter and mineral surfaces during weathering. PMID- 22225528 TI - Bimetallic effects on ethylene polymerization in the presence of amines: inhibition of the deactivation by Lewis bases. AB - Dinickel complexes supported by terphenyl ligands appended with phenoxy and imine donors were synthesized. Full substitution of the central arene blocks rotation around the aryl-aryl bond and allows for the isolation of atropisomers. The reported complexes perform ethylene polymerization in the presence of amines. The inhibiting effect of polar additives is up to 250 times lower for the syn isomer than the anti isomer. Comparisons with mononuclear systems indicate that the proximity of the metal centers leads to the observed inhibitory effect on the deactivation of the catalysts. PMID- 22225530 TI - Efficiency, behavior, and clinical properties of superelastic NiTi versus multistranded stainless steel wires: a prospective clinical trial. AB - OBJECTIVE: To investigate efficiency, behavior, and properties of superelastic NiTi vs multistranded stainless steel wires in Begg and preadjusted edgewise appliance (PEA) under moderate to severe crowding conditions. MATERIAL AND METHODS: Ninety-six participants (48 male, 48 female), aged 12-18 years old (mean age = 15.2 +/- 1.95), with moderate (<= 6 mm; mean = 5.3 +/- 0.48) to severe (> 6 mm; mean = 7.9 +/- 0.66) initial crowding were distributed into four groups: superelastic NiTi PEA (n = 24), superelastic NiTi Begg (n = 24), multistranded (coaxial) stainless steel PEA (n = 25), and multistranded (coaxial) stainless steel Begg (n = 23). In this study, 0.16-inch superelastic (austenitic active) NiTi and 0.175-inch multistranded (six stranded, coaxial) stainless steel wires were used in a 0.022-inch slot (Roth prescription) PEA and Begg appliance with a follow-up of six weeks. RESULTS: Analysis of variance revealed no significant difference in reduction of crowding between superelastic NiTi PEA and multistranded (coaxial) stainless steel PEA groups, but reduction in crowding was significantly greater in the superelastic NiTi Begg group compared with the multistranded (coaxial) stainless steel Begg group with F (3, 44) = 8.896, P < .001, and effect size (omega) 0.57 in moderate crowding and F (3, 44) = 122.341, P < .001, and effect size (omega) 0.93 in severe crowding. Linear regression demonstrated significant (P < .05) positive correlation between amount of initial crowding and reduction in crowding in all groups except the multistranded (coaxial) stainless steel Begg group, wherein a negative correlation did exist. CONCLUSION: Superelastic NiTi performed significantly better than multistranded (coaxial) stainless steel wire in the Begg appliance. However, in PEA, there was no significant difference. PMID- 22225532 TI - Nuclear and chloroplast DNA phylogeography reveals vicariance among European populations of the model species for the study of metal tolerance, Arabidopsis halleri (Brassicaceae). AB - Arabidopsis halleri is a pseudometallophyte involved in numerous molecular studies of the adaptation to anthropogenic metal stress. In order to test the representativeness of genetic accessions commonly used in these studies, we investigated the A. halleri population genetic structure in Europe. Microsatellite and nucleotide polymorphisms from the nuclear and chloroplast genomes, respectively, were used to genotype 65 populations scattered over Europe. The large-scale population structure was characterized by a significant phylogeographic signal between two major genetic units. The localization of the phylogeographic break was assumed to result from vicariance between large populations isolated in southern and central Europe, on either side of ice sheets covering the Alps during the Quaternary ice ages. Genetic isolation was shown to be maintained in western Europe by the high summits of the Alps, whereas admixture was detected in the Carpathians. Considering the phylogeographic literature, our results suggest a distinct phylogeographic pattern for European species occurring in both mountain and lowland habitats. Considering the evolution of metal adaptation in A. halleri, it appears that recent adaptations to anthropogenic metal stress that have occurred within either phylogeographic unit should be regarded as independent events that potentially have involved the evolution of a variety of genetic mechanisms. PMID- 22225534 TI - Sensitive determination of barbiturates in biological matrix by capillary electrophoresis using online large-volume sample stacking. AB - In China, some forensic cases are caused by barbiturates. Thus, the determination of trace level barbiturates in body fluid is important for the poisoning investigation. In this study, an online large-volume sample stacking (LVSS) with polarity switching in capillary electrophoresis (CE) was applied for the sensitive determination of barbiturates. This technique involves injecting a large volume of sample into a capillary and removing the sample matrix plug out of the capillary by reversing the polarity. Quantitation limit obtained was 0.048, 0.057, 0.039, and 0.015 MUg/mL for secobarbital, amobarbital, barbital, and phenobarbital (signal-to-noise ratio = 9). By using LVSS, the stacking was simply achieved at 171.7-, 169.7-, 202.7-, and 169.1-fold for the above four barbiturates. The relative standard deviation values of intraday and interday were <2.11% and 4.69%, respectively. Recoveries were ranged from 83.7 to 105.2%. Finally, the trace analysis method was applied to the analysis of real forensic specimens and has achieved satisfactory results. PMID- 22225533 TI - Altered synaptic marker abundance in the hippocampal stratum oriens of Ts65Dn mice is associated with exuberant expression of versican. AB - DS (Down syndrome), resulting from trisomy of chromosome 21, is the most common cause of genetic mental retardation; however, the molecular mechanisms underlying the cognitive deficits are poorly understood. Growing data indicate that changes in abundance or type of CSPGs (chondroitin sulfate proteoglycans) in the ECM (extracellular matrix) can influence synaptic structure and plasticity. The purpose of this study was to identify changes in synaptic structure in the hippocampus in a model of DS, the Ts65Dn mouse, and to determine the relationship to proteoglycan abundance and/or cleavage and cognitive disability. We measured synaptic proteins by ELISA and changes in lectican expression and processing in the hippocampus of young and old Ts65Dn mice and LMCs (littermate controls). In young (5 months old) Ts65Dn hippocampal extracts, we found a significant increase in the postsynaptic protein PSD-95 (postsynaptic density 95) compared with LMCs. In aged (20 months old) Ts65Dn hippocampus, this increase was localized to hippocampal stratum oriens extracts compared with LMCs. Aged Ts65Dn mice exhibited impaired hippocampal-dependent spatial learning and memory in the RAWM (radial-arm water maze) and a marked increase in levels of the lectican versican V2 in stratum oriens that correlated with the number of errors made in the final RAWM block. Ts65Dn stratum oriens PNNs (perineuronal nets), an extension of the ECM enveloping mostly inhibitory interneurons, were dispersed over a larger area compared with LMC mice. Taken together, these data suggest a possible association with alterations in the ECM and inhibitory neurotransmission in the Ts65Dn hippocampus which could contribute to cognitive deficits. PMID- 22225535 TI - Synthesis of a gamma-lactam library via formal cycloaddition of imines and substituted succinic anhydrides. AB - Formal cycloaddition reactions between imines and cyclic anhydrides serve as starting point for the synthesis of diverse libraries of small molecules. The synthesis of succinic anhydrides substituted with electron-withdrawing groups is facilitated by new mild conditions for alkylation of aryl-substituted acetyl esters with ethyl bromoacetate. These anhydrides are then used in formal cycloaddition reactions with imines to produce gamma-lactams. 2-Fluoro-5 nitrophenylsuccinic anhydride reacts efficiently with imines to provide lactams that are further diversified by conversion of the nitro group to either an aniline and an azide for subsequent reactions with acylating agents and alkynes, respectively. The synthesis of cyanosuccinic anhydride is reported for the first time, and the use of this compound in reactions with imines and subsequent functionalization of the resultant lactams is demonstrated. PMID- 22225536 TI - Differential SERS activity of gold and silver nanostructures enabled by adsorbed poly(vinylpyrrolidone). AB - We report that poly(vinylpyrrolidone) (PVP), a common stabilizer of colloidal dispersions of noble metal nanostructures, has a dramatic effect on their surface enhanced Raman scattering (SERS) activity and enables highly selective SERS detection of analytes of various type and charge. Nanostructures studied include PVP-stabilized Au-Ag nanoshells synthesized by galvanic exchange reaction of citrate-reduced Ag nanoparticles (NPs), as well as solid citrate-reduced Ag and Au NPs, both before and after stabilization with PVP. All nanostructures were characterized in terms of their size, surface plasmon resonance wavelength, surface charge, and chemical composition. While the SERS activities of the parent citrate-reduced Ag and Au NPs are similar for rhodamine 6G (R6G) and 1,2-bis(4 pyridyl)ethylene (BPE) at various pH values, PVP-stabilized nanostructures demonstrate large differences in SERS enhancement factors (EFs) between these analytes depending on their chemical nature and protonation state. At pH values higher than BPE's pK(a2) of 5.65, where the analyte is largely unprotonated, the PVP-coated Au-Ag nanoshells showed a high SERS EF of >10(8). In contrast, SERS EFs were 10(3)- to 10(5)-fold lower for the protonated form of BPE at lower pH values, or for the usually highly SERS-active cationic R6G. The differential SERS activity of PVP-stabilized nanostructures is a result of discriminatory binding of analytes within-adsorbed PVP monolayer and a subsequent increase of analyte concentration at the nanostructure surface. Our experimental and theoretical quantum chemical calculations show that BPE binding with PVP-stabilized Au-Ag nanoshells is stronger when the analyte is in its unprotonated form as compared to its cationic, protonated form at a lower pH. PMID- 22225537 TI - The role of symbiont genetic distance and potential adaptability in host preference towards Pseudonocardia symbionts in Acromyrmex leaf-cutting ants. AB - Fungus-growing ants display symbiont preference in behavioral assays, both towards the fungus they cultivate for food and Actinobacteria they maintain on their cuticle for antibiotic production against parasites. These Actinobacteria, genus Pseudonocardia Henssen (Pseudonocardiacea: Actinomycetales), help defend the ants' fungal mutualist from specialized parasites. In Acromyrmex Mayr (Hymenoptera: Formicidae) leaf-cutting ants, individual colonies maintain either a single or a few strains of Pseudonocardia, and the symbiont is primarily vertically transmitted between generations by colony-founding queens. A recent report found that Acromyrmex workers are able to differentiate between their native Pseudonocardia strain and non-native strains isolated from sympatric or allopatric Acromyrmex species, and show preference for their native strain. Here we explore worker preference when presented with two non-native strains, elucidating the role of genetic distance on preference between strains and Pseudonocardia origin. Our findings suggest that ants tend to prefer bacteria more closely related to their native bacterium and that genetic similarity is probably more important than whether symbionts are ant-associated or free-living. Preliminary findings suggest that when continued exposure to a novel Pseudonocardia strain occurs, ant symbiont preference is potentially adaptable, with colonies apparently being able to alter symbiont preference over time. These findings are discussed in relation to the role of adaptive recognition, potential ecological flexibility in symbiont preference, and more broadly, in relation to self versus non-self recognition. PMID- 22225539 TI - Mean platelet volume: comparison of three analysers towards standardization of platelet morphological phenotype. AB - INTRODUCTION: The aim of this study was to show variability in the measurement of the mean platelet volume (MPV) depending on the instrument used. METHODS: This prospective analysis was carried out to measure MPV with three instruments, in 30 healthy controls and 113 hospital patients. RESULTS: Firstly, for values in the normal range, the values obtained with the Siemens Advia((r)) 2120 are lower than those given by the Beckman Coulter LH750((r)) (-0.89), which are in turn lower than those obtained with the Sysmex XE-2100D((r)) (-1.11), which represents a 20 25% variation in the measurement. These results emphasize the lack of universal external calibration for MPV analysis and thus make any intercentre comparison of MPV impossible unless the automated haematology analyser used is indicated. Secondly, we stress the differences in behaviour of the instruments in the presence of abnormally large platelets, i.e. an underestimate of the platelet count and the MPV may be provided because instruments using impedance technology may fail to take into account these platelets, but they rightly flag them. CONCLUSION: To harmonize our procedures, we propose definitions of platelet size (normal size, macroplatelets and giant platelets) based on the coordinated interpretation of the MPV, the distribution of platelet volume and the morphological appearance. PMID- 22225538 TI - The evolving science of detection of 'blood doping'. AB - Blood doping practices in sports have been around for at least half a century and will likely remain for several years to come. The main reason for the various forms of blood doping to be common is that they are easy to perform, and the effects on exercise performance are gigantic. Yet another reason for blood doping to be a popular illicit practice is that detection is difficult. For autologous blood transfusions, for example, no direct test exists, and the direct testing of misuse with recombinant human erythropoietin (rhEpo) has proven very difficult despite a test exists. Future blood doping practice will likely include the stabilization of the transcription factor hypoxia-inducible factor which leads to an increased endogenous erythropoietin synthesis. It seems unrealistic to develop specific test against such drugs (and the copies hereof originating from illegal laboratories). In an attempt to detect and limit blood doping, the World Anti Doping Agency (WADA) has launched the Athlete Biological Passport where indirect markers for all types of blood doping are evaluated on an individual level. The approach seemed promising, but a recent publication demonstrates the system to be incapable of detecting even a single subject as 'suspicious' while treated with rhEpo for 10-12 weeks. Sad to say, the hope that the 2012 London Olympics should be cleaner in regard to blood doping seems faint. We propose that WADA strengthens the quality and capacities of the National Anti-Doping Agencies and that they work more efficiently with the international sports federations in an attempt to limit blood doping. PMID- 22225540 TI - MAP-mediated nuclear delivery of a cargo protein. AB - Radiolabeled cytochrome c (Cyt c), either as a free protein or as cell penetrating peptide (CPP)-conjugates, was tested for cellular uptake and nuclear transport in Human embryonic kidney 293 (HEK293) cells and HeLa cells. Conjugation of Cyt c with either the amphipathic peptide model amphipathic peptide (MAP) or the cationic peptide oligoarginine via a disulfide linkage significantly increased the total internalization and nuclear localization of Cyt c in both cell lines, though to a greater extent following conjugation with MAP. The nuclear localization was also evaluated qualitatively by confocal laser scanning microscopy (CLSM). CLSM images depicted high amounts of colocalization of fluorescently labeled Cyt c-MAP and the nucleus in HEK293 cells. In addition, prevention of disulfide reduction at the cell surface, or comparison of reducible disulfide or non-reducible thioether MAP-conjugates, showed that maintenance of an intact conjugate using a stable linkage enhanced MAP-mediated nuclear delivery. Furthermore, nuclear transport of the MAP-cargo conjugate appears to be dependent on vesicle fusion events following internalization via endocytosis. The findings presented in this report demonstrate the MAP-mediated transport of a small protein such as Cyt c into the nuclear compartment, which can be used to improve current CPP-cargo delivery of macromolecules with nuclear biological functions. PMID- 22225541 TI - Melatonin promotes embryonic development and reduces reactive oxygen species in vitrified mouse 2-cell embryos. AB - Two-cell embryos of mouse were vitrified by the open-pulled straw (OPS) method. The vitrified embryos were warmed and introduced into M16 medium for culture that contains melatonin at different concentrations (10(-3), 10(-5), 10(-7), 10(-9), 10(-11) m). This process caused reactive oxygen species (ROS) formation and jeopardized the development of the embryos. Melatonin, at different concentrations, significantly suppresses ROS production and promotes embryonic development in vitrified embryos compared with untreated ones. The mechanistic studies indicated that the beneficial effects of melatonin on vitrified 2-cell embryos of mouse were melatonin receptor (MT1 and MT2) independent. The direct free radical scavenging activity, the enhancement of endogenous glutathione levels, and the anti-apoptotic capacity of melatonin may account for its protective effects on vitrified embryonic development. PMID- 22225542 TI - In vitro pharmacokinetic characterization of mulberroside A, the main polyhydroxylated stilbene in mulberry (Morus alba L.), and its bacterial metabolite oxyresveratrol in traditional oral use. AB - Mulberroside A (MulA) is one of the main bioactive constituents in mulberry (Morus alba L.). This study examined the determining factors for previously reported oral pharmacokinetic profiles of MulA and its bacterial metabolite oxyresveratrol (OXY) on in vitro models. When incubated anaerobically with intestinal bacteria, MulA underwent rapid deglycosylation and generated two monoglucosides and its aglycone OXY sequentially. MulA exhibited a poor permeability and predominantly traversed Caco-2 cells via passive diffusion; yet, the permeation of OXY across Caco-2 cells was much more rapid and involved efflux (both p-glycoprotein and MRPs)-mediated mechanisms. Moreover, OXY underwent extensive hepatic glucuronidation; yet, the parent MulA was kept intact in liver subcellular preparations. There was insignificant species difference in intestinal bacterial conversion of MulA and the extent of OXY hepatic glucuronidation between humans and rats, while OXY exhibited a distinct positional preference of glucuronidation in the two species. Overall, these findings revealed a key role of intestinal bacterial conversion in absorption and systemic exposure of MulA and its resultant bacterial metabolite OXY in oral route in humans and rats and warranted further investigational emphasis on OXY and its hepatic metabolites for understanding the benefits of mulberry. PMID- 22225543 TI - Development and validation of a subject-specific finite element model of a human clavicle. AB - This study aimed to develop and validate a finite element (FE) model of a human clavicle which can predict the structural response and bone fractures under both axial compression and anterior-posterior three-point bending loads. Quasi-static non-injurious axial compression and three-point bending tests were first conducted on a male clavicle followed by a dynamic three-point bending test to fracture. Then, two types of FE models of the clavicle were developed using bone material properties which were set to vary with the computed tomography image density of the bone. A volumetric solid FE model comprised solely of hexahedral elements was first developed. A solid-shell FE model was then created which modelled the trabecular bone as hexahedral elements and the cortical bone as quadrilateral shell elements. Finally, simulations were carried out using these models to evaluate the influence of variations in cortical thickness, mesh density, bone material properties and modelling approach on the biomechanical responses of the clavicle, compared with experimental data. The FE results indicate that the inclusion of density-based bone material properties can provide a more accurate reproduction of the force-displacement response and bone fracture timing than a model with uniform bone material properties. Inclusion of a variable cortical thickness distribution also slightly improves the ability of the model to predict the experimental response. The methods developed in this study will be useful for creating subject-specific FE models to better understand the biomechanics and injury mechanism of the clavicle. PMID- 22225544 TI - Randomised clinical trial: efficacy of Lactobacillus paracasei-enriched artichokes in the treatment of patients with functional constipation--a double blind, controlled, crossover study. AB - BACKGROUND: The role of probiotics in the management of constipation is uncertain. AIMS: To evaluate the effects of probiotic-enriched artichokes on treatment preference, symptom profile and short-chain fatty acid (SCFA) production in constipated subjects when compared with ordinary artichokes. METHODS: Twenty constipated patients (3M/17F; 38.8 +/- 14.4 years) were studied using a double-blind method and a computer-generated randomisation list. Each patient consumed 180 g per day of ordinary artichokes or artichokes enriched with Lactobacillus paracasei IMPC 2.1 for 15 days (daily dose of 2 * 10(10) CFU). Relief of symptoms was evaluated using a visual analogue scale. The stool consistency and symptom profile of patients were investigated using the Bristol stool form chart and the Gastrointestinal Symptom Rating Scale questionnaire (GSRS). SCFA production in faecal samples was evaluated using HPLC. RESULTS: Eighty per cent of patients preferred probiotic-enriched artichokes to ordinary ones (P = 0.011). Satisfactory relief of symptoms was significantly higher (P = 0.0014) during the probiotic-enriched artichoke period. Bristol chart cluster scores were significantly higher (3.3 +/- 1.2, 2.9 +/- 1.3 2.2 +/- 1.2, baseline, ordinary artichokes and probiotic-enriched ones, respectively; P = 0.009) and GSRS constipation was significantly lower (13.9 +/- 0.9, 10.2 +/- 0.8, 8.3 +/- 0.9; P = 0.032) in the probiotic group compared with the baseline. As for SCFA production, propionic acid was significantly higher (2.2 +/- 1.4, 2.1 +/- 1.53, 1.5 +/- 1.2; P = 0.035) in the probiotic group compared with baseline. CONCLUSION: This trial shows a positive effect on symptoms in constipated patients after intake of probiotic-enriched artichokes. PMID- 22225546 TI - Patient preferences for psoriasis treatments: impact of treatment experience. AB - BACKGROUND: Patient preferences for psoriasis treatments can impact treatment satisfaction and adherence and may therefore influence clinical outcome. OBJECTIVE: To assess the impact of treatment experience (satisfaction with current treatment, number of prior visits, disease duration, number of preceding therapies and currently prescribed treatment modalities) on treatment preferences. METHODS: A computer-based conjoint analysis experiment was conducted to analyse preferences of patients with moderate or severe psoriasis (n = 163) treated at a German University Medical Center for outcome (probability, magnitude and duration of benefit; probability, severity and reversibility of side effects) and process attributes (location, frequency, duration, delivery method, individual cost) of psoriasis treatments. Relative importance scores (RIS) were calculated for each attribute and compared using anova, post hoc test and multivariate regression analysis. RESULTS: Participants with longer disease duration attached significantly greater importance to duration of benefit (beta = 0.206, P = 0.018), whereas participants on oral therapy were more concerned about magnitude of benefit by trend (beta = 0.218, P = 0.058). Participants receiving injectables not only set higher value to probability of benefit (RIS = 32.80 vs. 21.89, P = 0.025) but also to treatment location (RIS = 44.74 vs. 23.03, P = 0.011), delivery method (RIS = 43.75 vs. 19.29, P = 0.019), treatment frequency (RIS = 31.24 vs. 16.89, P = 0.005) and duration (RIS = 32.54 vs. 16.57, P = 0.003) when compared with others. Treatment satisfaction was significantly higher in participants on infusions or injections compared with those on phototherapy and mere topical therapy. CONCLUSIONS: Treatment preferences may change over time course and with treatment experience. Participants on injectables attach great importance to efficiency and convenience of therapies, and are highly satisfied with their treatment. PMID- 22225545 TI - Host cell species-specific effect of cyclosporine A on simian immunodeficiency virus replication. AB - BACKGROUND: An understanding of host cell factors that affect viral replication contributes to elucidation of the mechanism for determination of viral tropism. Cyclophilin A (CypA), a peptidyl-prolyl cis-trans isomerase (PPIase), is a host factor essential for efficient replication of human immunodeficiency virus type 1 (HIV-1) in human cells. However, the role of cyclophilins in simian immunodeficiency virus (SIV) replication has not been determined. In the present study, we examined the effect of cyclosporine A (CsA), a PPIase inhibitor, on SIV replication. RESULTS: SIV replication in human CEM-SS T cells was not inhibited but rather enhanced by treatment with CsA, which inhibited HIV-1 replication. CsA treatment of target human cells enhanced an early step of SIV replication. CypA overexpression enhanced the early phase of HIV-1 but not SIV replication, while CypA knock-down resulted in suppression of HIV-1 but not SIV replication in CEM SS cells, partially explaining different sensitivities of HIV-1 and SIV replication to CsA treatment. In contrast, CsA treatment inhibited SIV replication in macaque T cells; CsA treatment of either virus producer or target cells resulted in suppression of SIV replication. SIV infection was enhanced by CypA overexpression in macaque target cells. CONCLUSIONS: CsA treatment enhanced SIV replication in human T cells but abrogated SIV replication in macaque T cells, implying a host cell species-specific effect of CsA on SIV replication. Further analyses indicated a positive effect of CypA on SIV infection into macaque but not into human T cells. These results suggest possible contribution of CypA to the determination of SIV tropism. PMID- 22225549 TI - Effect of phenotypic switching on the biological properties and susceptibility to chlorhexidine in Candida krusei ATCC 14243. AB - Phenotypic switching is characterized as a virulence factor of Candida spp. This study was carried out to evaluate the phenotypic switching ability of C. krusei ATCC 14243 and to determine its effect on the biological properties, adherence capacity and susceptibility towards chlorhexidine digluconate (CHX). To induce switched generations C. krusei was cultured under nitrogen-depleted growth conditions by adding phloxine B. These phenotypically switched colonies were designated as the 1st generation. Subsequent sub-culturing was performed to produce the 2nd, 3rd and 4th switched generations. The recovery of the 3rd generation was the highest at 85.7% while that of the 4th generation was lower at 70.8%, and the recovery of the 1st and 2nd generations gradually reduced to 46.6% and 36.4%, respectively. All generations of C. krusei were susceptible towards CHX. The unswitched C. krusei was the most susceptible but the least adherent to coated hard surfaces. The 2nd generation was the least susceptible, but with the highest adherent ability. The minimum inhibition concentration and minimal fungicidal concentration of C. krusei of all generations were determined at 0.4 mg mL(-1) . These observations suggest that the switching activity of C. krusei induces changes to its biological properties and susceptibility towards CHX. PMID- 22225547 TI - Exploring mixed microbial community functioning: recent advances in metaproteomics. AB - System approaches to elucidate ecosystem functioning constitute an emerging area of research within microbial ecology. Such approaches aim at investigating all levels of biological information (DNA, RNA, proteins and metabolites) to capture the functional interactions occurring in a given ecosystem and track down characteristics that could not be accessed by the study of isolated components. In this context, the study of the proteins collectively expressed by all the microorganisms present within an ecosystem (metaproteomics) is not only crucial but can also provide insights into microbial functionality. Overall, the success of metaproteomics is closely linked to metagenomics, and with the exponential increase in the availability of metagenome sequences, this field of research is starting to experience generation of an overwhelming amount of data, which requires systematic analysis. Metaproteomics has been employed in very diverse environments, and this review discusses the recent advances achieved in the context of human biology, soil, marine and freshwater environments as well as natural and bioengineered systems. PMID- 22225548 TI - Association between being African-American, serum urate levels and the risk of developing hyperuricemia: findings from the Coronary Artery Risk Development in Young Adults cohort. AB - INTRODUCTION: Findings that African-American race/ethnicity is associated with higher concentrations of serum urate have not been adjusted for possible confounding factors or have not explored this question as a primary outcome. We tested this hypothesis in a bi-racial cohort of younger African-American and white men and women. METHODS: Data from 5,049 participants at the Coronary Artery Risk Development in Young Adults (CARDIA) cohort baseline (1985 to 1986) and follow-up for up to 20 years of individuals without hyperuricemia (defined as a serum urate of 6.8 mg/dL or more) at baseline were utilized. We determined associations between race, serum urate and the development of hyperuricemia in sex-specific cross-sectional and longitudinal analyses. Confounding factors examined included: age at enrollment, body mass index, development of hypertension, glomerular filtration rate, medication use, diet and alcohol intake and menopausal symptoms in women. RESULTS: Referent to whites, African-American men and women had significantly lower concentrations of serum urate at baseline. African-American men had an essentially equal risk of developing incident hyperuricemia during follow-up compared with white men (multivariable adjusted HR = 1.12 (0.88 to 1.40)). African-American women developed a significantly increased risk of hyperuricemia when compared to white women (HR = 2.31 (1.34 to 3.99)). CONCLUSIONS: Young African-American men and women had lower concentrations of serum urate than whites. During longitudinal follow-up, African American women had a significantly increased risk of developing hyperuricemia when compared with white women, a difference that was not observed in men. Differences in production of serum urate or a more rapid decline in fractional excretion of serum urate are potential, albeit still unproven, explanations for these findings in African-American women. PMID- 22225551 TI - Vascularized composite allotransplantation research: the emerging field. PMID- 22225552 TI - Prediabetes in patients treated with antipsychotic drugs. AB - BACKGROUND: In 2010, the American Diabetes Association (ADA) proposed that individuals with fasting glucose level of 100-125 mg/dL (5.6-6.9 mmol/L) or glucose level of 140-199 mg/dL (7.8-11.0 mmol/L) 2 hours after a 75-g oral glucose tolerance test or hemoglobin A(1c) 5.7%-6.4% be classified as prediabetic, indicating increased risk for the emergence of diabetes mellitus. At the same time, the ADA formulated guidelines for the use of metformin for the treatment of prediabetes. OBJECTIVE: To determine the prevalence of prediabetes in a cohort of psychiatrically ill adults receiving antipsychotics and to compare the clinical and metabolic features of prediabetic patients with those of patients with normal glucose tolerance and those with diabetes mellitus. METHOD: The 2010 ADA criteria were applied to a large, consecutive, single-site European cohort of 783 adult psychiatric inpatients (mean age: 37.6 years) without a history of diabetes who were receiving antipsychotics. All patients in this cross sectional study underwent measurement of body mass index (BMI), waist circumference, oral glucose tolerance test, and fasting insulin and lipids from November 2003 through July 2007. RESULTS: 413 patients (52.8%) had normal glucose tolerance, 290 (37.0%) had prediabetes, and 80 (10.2%) had diabetes mellitus. The fasting glucose and/or hemoglobin A(1c) criteria were met by 89.7% of prediabetic patients. A statistically significant intergroup gradient from normal glucose tolerance to prediabetes and from prediabetes to diabetes mellitus was observed for waist circumference, triglycerides, fasting insulin levels, and frequency of metabolic syndrome (P = .02 to P < .0001). Only 19/290 prediabetic patients (6.6%) met the 2010 ADA criteria for treatment with metformin. CONCLUSIONS: Prediabetes is highly prevalent in adults treated with antipsychotic drugs and correlates with markers of increased intraabdominal adiposity, enhanced lipolysis, and insulin resistance. Criteria for using metformin to prevent the emergence of diabetes mellitus may need to be revised for this population. PMID- 22225553 TI - Secular changes in height, body weight, body mass index and pubertal development in male children and adolescents in Krakow, Poland. AB - This study examined the secular changes in height, body weight, body mass index and pubertal development in male children and adolescents in Krakow (Poland) over the past 80 years, with an emphasis on the last decade (2000-2010). The survey of the population of Krakow is a continuation of observations conducted in that area for many years. The analysis aims to determine whether in the last decade Krakow still witnessed the secular trend, and what form the trend took. The body height and weight, and body mass index (BMI), of 1862 boys aged 3.5-18.5 years were analysed, against the background of a survey series from the years 1938 (N = 1801), 1971 (N = 2045), 1983 (N = 3124) and 2000 (N = 2328). The mean body height, in almost all age categories, was greater than in the past; however the final height over the last decade remained the same. The mean values of body weight and BMI increased, especially in the last decade. Also, an acceleration of puberty in boys was observed. The last 10 years saw an over 3-month decrease in the age of initial appearance of pubic hair in boys. In conclusion, the last decade saw cessation of the growing taller trend: maximum body height stabilized at approximately 179 cm, but weight and BMI increased. Also, a distinct acceleration of puberty was noticed. Lack of height increase, at the same time as weight gain and puberty acceleration, indicate a progressing developmental disharmony. PMID- 22225555 TI - Experimental studies in air medical research. AB - This article is the 18th in a multipart series designed to assist readers, particularly novices, in the area of clinical research. This article is focused on the process of developing a new research project. It provides tools to help those involved in beginning their own research projects. PMID- 22225556 TI - Blast lung injury in a 20-year-old man after a home explosion. AB - A large family home exploded after a propane leak ignited. Initial reports from the scene noted that 11 people were injured, with many sustaining critical injuries. Immediately, multiple helicopter emergency medical services aircraft were dispatched to respond to the scene, and ground emergency medical services (EMS) providers were en route. Of the five aircraft requested, only two were available to respond; one aircraft was out for maintenance, and two others were committed to other missions. PMID- 22225557 TI - The smoking gun: patient confidentiality. PMID- 22225561 TI - Hypoxia symptoms during altitude training in professional Iranian fighter pilots. AB - INTRODUCTION: Susceptibility to hypoxia is influenced by a multitude of factors, including fatigue, physical activity, illnesses, ambient temperature, rate of ascent, destination altitude, medications, and alcohol. Anecdotally, several reports have been made regarding changes in the form of hypoxia presentation in Iranian fighter pilots in the absence of these factors. This study focused specifically on the effect of pilot age on susceptibility to hypoxia and its initial presentation. We assumed that a pilot's age may increase his susceptibility to hypoxia and consequently reduce the amount of time it takes for hypoxia to present. Because our literature review did not reveal any previous study addressing the possible relationship between age and susceptibility to hypoxia, the purpose of this study is to address and clarify this relationship. METHOD: In this retrospective study, we collected information from Iranian fighter pilots (n = 30) through an anonymous questionnaire in 2000. The form of hypoxia presentation of each subject was evaluated during five altitude chamber training (ACT) sessions that were conducted routinely from 1972 to 1984. To enhance the accuracy of the study's results, confounding factors such as prior hypoxia experience in an ACT session have been taken into consideration. RESULTS: The results revealed a statistically significant relationship between age and a change in the form of hypoxia presentation in our subjects. Increased age reduced the amount of time before the first individual hypoxia symptom appeared (P < .000002). Although having previous hypoxia experience may help pilots to recognize their symptoms earlier, its effect was not statistically significant (P < .18). A few changes in the nature of individual symptoms were observed; however, we did not find a meaningful statistical correlation between pilot age and change in the nature of symptoms. CONCLUSION: Susceptibility ot hypoxia increases with pilot age. PMID- 22225562 TI - Propofol infusion for the retrieval of the acutely psychotic patient. AB - Transporting acutely psychotic patients is hazardous because of the risks they present to themselves, escorting staff, and aircraft. Various strategies have been proposed, usually involving combinations of sedating drugs and physical restraint. Thus far, none guarantees safe retrieval while completely mitigating risks. This case proposes the use of propofol as an alternative to more traditionally used agents. An infusion facilitated the uneventful and safe retrieval of a patient who had demonstrated resistance and tolerance to other drugs. Discussion is also presented on the potential utility of propofol for the retrieval of acutely psychotic patients. PMID- 22225563 TI - Medical flight crew perceived work-related musculoskeletal symptoms and related characteristics. AB - INTRODUCTION: Flight crews who provide stabilization and care for patients during air medical flights represent a specialty group, with unique safety, physical environment, and weather concerns, as well as patient care challenges. The purpose of this study was to identify the self-reported prevalence, location, and severity (frequency, duration, and intensity) of perceived work-related musculoskeletal symptoms and associated characteristics among flight crews, and to correlate any age-related differences between participants. METHOD: This study used a descriptive, cross-sectional survey design. An internet-based questionnaire was made available through a link from the Flightweb.com listserv to Survey Monkey. A convenience sample of 462 flight crewmembers responded. RESULTS: Significant differences were found by age group for two of four musculoskeletal symptoms (frequency and duration were significantly different by age group). Those 39 and older had a greater proportion of having been previously diagnosed with arthritis or osteoporosis (2chi = 8.503, P = .004). CONCLUSION: Age-related differences were believed to be a factor that contributed to more musculoskeletal complaints for older flight crewmembers; however, the data from this study only partially support that hypothesis. Flight crewmembers face a number of unique challenges that require maintaining physical strength and endurance. PMID- 22225564 TI - Myocardial infarction complicated by ventricular septal rupture. AB - Transporting patients with an ST segment elevation myocardial infarction (STEMI) is a fairly common practice for most critical care transport teams. When a STEMI is complicated by ventricular septal rupture, the care can become more challenging, especially if the rupture is not yet diagnosed. This article describes such a transport and reviews the pathophysiology of the process along with treatment options. PMID- 22225565 TI - Hypertrophic pyloric stenosis: it can take your breath away. PMID- 22225567 TI - Pollinators cause stronger selection than herbivores on floral traits in Lobelia cardinalis (Lobeliaceae). AB - Measures of selection on floral traits in flowering plants are often motivated by the assumption that pollinators cause selection. Flowering plants experience selection from other sources, including herbivores, which may enhance or oppose selection by pollinators. Surprisingly, few studies have examined selection from multiple sources on the same traits. We quantified pollinator-mediated selection on six floral traits of Lobelia cardinalis by comparing selection in naturally and supplementally (hand-) pollinated plants. Directional, quadratic and correlational selection gradients as well as total directional and quadratic selection differentials were examined. We used path analysis to examine how three herbivores--slugs, weevils and caterpillars--affected the relationship between floral traits and fitness. We detected stronger total selection on four traits and correlational selection (gamma(ij)) on three trait combinations in the natural pollination treatment, indicating that pollinators caused selection on these traits. Weak but statistically significant selection was caused by weevil larvae on stem diameter and anther-nectary distance, and by slugs on median flower date. In this study, pollinators imposed stronger selection than herbivores on floral traits in L. cardinalis. In general, the degree of pollen limitation and rate of herbivory are expected to influence the relative strength of selection caused by pollinators or herbivores. PMID- 22225568 TI - Click chemistry facilitates formation of reporter ions and simplified synthesis of amine-reactive multiplexed isobaric tags for protein quantification. AB - We report the development of novel reagents for cell-level protein quantification, referred to as Caltech isobaric tags (CITs), which offer several advantages in comparison with other isobaric tags (e.g., iTRAQ and TMT). Click chemistry, copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), is applied to generate a gas-phase cleavable linker suitable for the formation of reporter ions. Upon collisional activation, the 1,2,3-triazole ring constructed by CuAAC participates in a nucleophilic displacement reaction forming a six-membered ring and releasing a stable cationic reporter ion. To investigate its utility in peptide mass spectrometry, the energetics of the observed fragmentation pathway are examined by density functional theory. When this functional group is covalently attached to a target peptide, it is found that the nucleophilic displacement occurs in competition with formation of b- and y-type backbone fragment ions regardless of the amino acid side chains present in the parent bioconjugate, confirming that calculated reaction energetics of reporter ion formation are similar to those of backbone fragmentations. Based on these results, we apply this selective fragmentation pathway for the development of CIT reagents. For demonstration purposes, duplex CIT reagent is prepared using a single isotope-coded precursor, allyl-d(5)-bromide, with reporter ions appearing at m/z 164 and 169. Isotope-coded allyl azides for the construction of the reporter ion group can be prepared from halogenated alkyl groups which are also employed for the mass balance group via N-alkylation, reducing the cost and effort for synthesis of isobaric pairs. Owing to their modular designs, an unlimited number of isobaric combinations of CIT reagents are, in principle, possible. The reporter ion mass can be easily tuned to avoid overlapping with common peptide MS/MS fragments as well as the low mass cutoff problems inherent in ion trap mass spectrometers. The applicability of the CIT reagent is tested with several model systems involving protein mixtures and cellular systems. PMID- 22225569 TI - 3-Iodothyronamine: a modulator of the hypothalamus-pancreas-thyroid axes in mice. AB - BACKGROUND AND PURPOSE Preclinical pharmacology of 3-iodothyronamine (T1AM), an endogenous derivative of thyroid hormones, indicates that it is a rapid modulator of rodent metabolism and behaviour. Since T1AM undergoes rapid enzymatic degradation, particularly by MAO, we hypothesized that the effects of T1AM might be altered by inhibition of MAO. EXPERIMENTAL APPROACH We investigated the effects of injecting T1AM (i.c.v.) on (i) feeding behaviour, hyperglycaemia and plasma levels of thyroid hormones and (ii) T1AM systemic bioavailability, in overnight fasted mice, under control conditions and after pretreatment with the MAO inhibitor clorgyline. T1AM (1.3, 6.6, 13, 20 and 26 ug.kg(-1) ) or vehicle were injected i.c.v. in fasted male mice not pretreated or pretreated i.p. with clorgyline (2.5 mg.kg(-1) ). Glycaemia was measured by a glucorefractometer, plasma triiodothyronine (fT3) by a chemiluminescent immunometric assay, c-fos activation immunohistochemically and plasma T1AM by HPLC coupled to tandem-MS. KEY RESULTS T1AM, 1.3 ug.kg(-1) , produced a hypophagic effect (-24% vs. control) and reduced c-fos activation. This dose showed systemic bioavailability (0.12% of injected dose), raised plasma glucose levels and reduced peripheral insulin sensitivity (-33% vs. control) and plasma fT3 levels. These effects were not linearly related to the dose injected. Clorgyline pretreatment strongly increased the systemic bioavailability of T1AM and prevented the hyperglycaemia and reduction in fT3 induced by T1AM. CONCLUSIONS AND IMPLICATIONS T1AM induces central and peripheral effects including hyperglycaemia and a reduction in plasma fT3 levels in fasted mice. These effects critically depend on the concentration of T1AM or its metabolites in target organs. PMID- 22225570 TI - An astrocyte-specific enhancer of the aquaporin-4 gene functions through a consensus sequence of POU transcription factors in concert with multiple upstream elements. AB - Aquaporin-4, a predominant water channel in the brain, is specifically expressed in astrocyte endfeet and plays a central role in water homeostasis, neuronal activity, and cell migration in the brain. It has two dominant isoforms called M1 and M23, whose mRNA is driven by distinct promoters located upstream of exons 0 and 1 of the aquaporin-4 gene, respectively. To identify cis-acting elements responsible for the astrocyte-specific transcription of M1 mRNA, the promoter activity of the 5'-flanking region upstream of exon 0 in primary cultured mouse astrocytes was examined by luciferase assay, and sequences, where nuclear factors bind, were identified by electrophoretic mobility shift assay. An astrocyte specific activity enhancing transcription from the M1 promoter was observed within ~2 kb from the transcriptional start sites of M1 mRNA. At least five elements clustered within the 286-bp region were found to function as a novel astrocyte-specific enhancer. Among the five elements, a consensus sequence of Pit 1/Oct/Unc-86 (POU) transcription factors was indispensable to the astrocyte specific enhancer since disruption of the POU motif completely abolished the enhancer activity in astrocytes. However, the POU motif alone had little activity, indicating the requirement for cooperation with other upstream elements to exert full enhancer activity. PMID- 22225572 TI - Validation of the Health of the Nation Outcome Scales as a routine measure of outcome in early intervention programmes. AB - AIM: So far, no study has assessed the validity of the Health of the Nation Outcome Scales (HoNOS) in patients enrolled in early intervention programmes, nor has any study evaluated the validity of the HoNOS in people at ultra high-risk (UHR) of psychosis. This study set out to assess the validity and reliability of the HoNOS as a measure of outcome in the patients enrolled in an early intervention programme. METHODS: The concurrent, discriminant and predictive validity, and the reliability of the HoNOS as a measure of outcome in an early intervention programe were assessed in 87 first-episode psychosis (FEP) patients, and in 81 patients at UHR of psychosis. RESULTS: Reliability indexes were good in the FEP sample, and less good in the UHR sample. HoNOS total scores differentiated between FEP and UHR patients, and the HoNOS subscales proved able to assess a specific profile of symptoms in the two samples, demonstrating a helpful adjunctive measure of health status without complete overlap with other scales. Sensitivity to change was also very good, again with differences between FEP and UHR patients. HoNOS scores at intake did not predict failure to attain remission in FEP patients. There were too few cases of transition to psychosis (n = 2) to assess predictive validity of HoNOS in the UHR sample. CONCLUSION: HoNOS possesses satisfactory sensitivity and validity to be used in the routine assessment in early intervention programmes. PMID- 22225571 TI - Learning novel words: detail and vulnerability of initial representations for children with specific language impairment and typically developing peers. AB - This study examines the phonological representations that children with specific language impairment (SLI) and typically developing peers (TD) have during the initial process of word learning. The goals of this study were to determine if children with SLI attended to different components of words than peers, and whether they were more vulnerable to interference than peers. Forty 7- and 8-year old children, half with SLI, took part in a fast mapping, word learning task. In addition to producing the word, there was a mispronunciation detection task that included mispronunciations of the target word in the initial position, final position or that modified the word's syllable structure. Children with SLI showed a different learning profile than peers, demonstrating stronger representations of the word-initial phonemes, but less information about word-final phonemes. They were more prone to interference overall, but especially from word-final foils. Children with SLI did not demonstrate less-defined phonological representations, but did attend to different features than TD children, perhaps in an attempt to compensate for problems learning longer words. The greatest weakness of children with SLI appears to be their susceptibility to interference, particularly for word-final information. LEARNING OUTCOMES: Readers will be able to: (1) explain what children attend to when learning new words; (2) state the pattern of recognition and production performance for both children with SLI and their typical language peers; and (3) identify specific parts of novel words that are most susceptible to interference in children with SLI. PMID- 22225573 TI - Accurate prediction of cardiorespiratory fitness using cycle ergometry in minimally disabled persons with relapsing-remitting multiple sclerosis. AB - OBJECTIVE: To examine the accuracy of predicting peak oxygen consumption (VO(2peak)) primarily from peak work rate (WR(peak)) recorded during a maximal, incremental exercise test on a cycle ergometer among persons with relapsing remitting multiple sclerosis (RRMS) who had minimal disability. DESIGN: Cross sectional study. SETTING: Clinical research laboratory. PARTICIPANTS: Women with RRMS (n=32) and sex-, age-, height-, and weight-matched healthy controls (n=16) completed an incremental exercise test on a cycle ergometer to volitional termination. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Measured and predicted VO(2peak) and WR(peak). RESULTS: There were strong, statistically significant associations between measured and predicted VO(2peak) in the overall sample (R(2)=.89, standard error of the estimate=127.4 mL/min) and subsamples with (R(2)=.89, standard error of the estimate=131.3 mL/min) and without (R(2)=.85, standard error of the estimate=126.8 mL/min) multiple sclerosis (MS) based on the linear regression analyses. Based on the 95% confidence limits for worst-case errors, the equation predicted VO(2peak) within 10% of its true value in 95 of every 100 subjects with MS. CONCLUSIONS: Peak VO(2) can be accurately predicted in persons with RRMS who have minimal disability as it is in controls by using established equations and WR(peak) recorded from a maximal, incremental exercise test on a cycle ergometer. PMID- 22225574 TI - Early serum HBsAg level as a strong predictor of sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. AB - BACKGROUND: The roles remain unclear of early on-treatment quantitative serum HBsAg and hepatitis B virus (HBV) DNA levels in the prediction of a sustained response (SR) to peginterferon alfa-2a therapy in HBeAg-negative chronic hepatitis B (CHB) patients infected with genotype B or C. AIMS: To determine their roles in HBeAg-negative CHB patients infected with genotype B or C. METHODS: Sixty-one patients were treated with peginterferon alfa-2a for 48 weeks. Serum HBsAg levels were quantified using the Abbott Architect HBsAg QT assay throughout treatment. Multiple regression analyses were performed to identify independent predictors of SR. RESULTS: Nineteen patients (31%) achieved SR with serum HBV DNA levels <312 copies/mL at 24 weeks post-treatment. Serum HBsAg levels at 12 (OR 31.9; 95% CI 4.8-209.6; P = 0.0003) and 24 weeks of therapy (OR 8.8; 95% CI 2.0-38.0; P = 0.0035), and HBV DNA levels at baseline (OR 7.0; 95% CI 1.3-36.2; P = 0.0203), 12 (OR 7.9; 95% CI 1.2-48.4; P = 0.0249) and 24 weeks of therapy (OR 22.3; 95% CI 2.2-224.0; P = 0.0083) were early independent predictors of SR. A serum HBsAg cut-off of 150 IU/mL at week 12 had an AUC, sensitivity, specificity and positive and negative predictive values of 0.75, 63%, 95%, 86% and 85% with respect to predicting SR respectively. CONCLUSIONS: A quantitative serum HBsAg level at 12 weeks of therapy can be used for the early prediction of SR to peginterferon therapy in HBeAg-negative CHB patients infected with genotype B or C. PMID- 22225575 TI - Melatonin sensitizes human hepatoma cells to endoplasmic reticulum stress-induced apoptosis. AB - Endoplasmic reticulum stress-mediated cell apoptosis is implicated in the development of cancer. Melatonin induces apoptosis in hepatocellular carcinoma (HCC) in experimental studies, but the effects of melatonin on endoplasmic reticulum (ER) stress-induced apoptosis in HCC have not been tested. Differences in ER stress-induced apoptosis in human hepatoma cells and normal human hepatocyte were investigated by exposure to tunicamycin (ER stress inducer). Significant differences were observed in the rate of apoptosis between HepG2 cells (hepatoma cells) and HL-7702 cells (normal human hepatocyte cells). The expression of cyclooxygenase-2 (COX-2) was increased in HepG2 cells but not in HL 7702 cells. Furthermore, down-regulation of COX-2 expression using the COX-2 inhibitor, celecoxib, increased tunicamycin-induced apoptosis concomitant with the up-regulation of pro-apoptotic transcription factor CHOP (GADD153) and down regulation of B-cell lymphoma 2/Bcl-2-associated X protein (Bcl-2/Bax) ratio, suggesting that inhibition of COX-2 sensitized human hepatoma cells to ER stress induced apoptosis. Interestingly, co-treatment with tunicamycin and melatonin also decreased the expression of COX-2 and significantly increased the rate of apoptosis by elevating the levels of CHOP and reducing the Bcl-2/Bax ratio. These results demonstrate that melatonin sensitizes human hepatoma cells to ER stress induced apoptosis by down-regulating COX-2 expression, increasing the levels of CHOP and decreasing the Bcl-2/Bax ratio. PMID- 22225576 TI - Inhibitory properties of ibuprofen and its amide analogues towards the hydrolysis and cyclooxygenation of the endocannabinoid anandamide. AB - A dual-action cyclooxygenase (COX)-fatty acid amide hydrolase (FAAH) inhibitor may have therapeutic usefulness as an analgesic, but a key issue is finding the right balance of inhibitory effects. This can be done by the design of compounds exhibiting different FAAH/COX-inhibitory potencies. In the present study, eight ibuprofen analogues were investigated. Ibuprofen (1), 2-(4-Isobutylphenyl)-N-(2 (3-methylpyridin-2-ylamino)-2-oxoethyl)propanamide (9) and N-(3-methylpyridin-2 yl)-2-(4'-isobutylphenyl)propionamide (2) inhibited FAAH with IC(50) values of 134, 3.6 and 0.52 uM respectively. The corresponding values for COX-1 were ~29, ~50 and ~60 uM, respectively. Using arachidonic acid as substrate, the compounds were weak inhibitors of COX-2. However, when anandamide was used as COX-2 substrate, potency increased, with approximate IC(50) values of ~6, ~10 and ~19 uM, respectively. Compound 2 was confirmed to be active in vivo in a murine model of visceral nociception, but the effects of the compound were not blocked by CB receptor antagonists. PMID- 22225578 TI - Long-term genomic improvement - new challenges for population genetics. PMID- 22225577 TI - Yearly transitions of disability profiles in older people living at home. AB - PURPOSE: Planning home services for older people requires extensive knowledge about the progression of disabilities. Disability-based case-mix classifications identify meaningful groups of older people; yet transitions between profiles are mostly unknown. METHODS: Disability was assessed annually over four years with the Functional Autonomy Measurement System (SMAF) in 1410 older people at risk of functional decline aged 75 and over and living at home. The SMAF generates a case mix classification of 14 Iso-SMAF profiles with progressive mean disability levels. Transitions made by older people were analyzed using a continuous-time, multi-state Markov model to estimate the probabilities of annual transitions into and out of each profile as well as the mean sojourn time in each profile. RESULTS: The probability of staying in a profile tended to decrease as profile severity increased. For profiles 5 and above, recovery to mild profiles 1, 2 and 3 was low, while annual probabilities of death and institutionalization were high (>0.10). The lower disability profiles (1 and 2) evidenced a mean profile sojourn time of over two years, contrary to sojourn times of 18 months or less with the other profiles. CONCLUSIONS: The probabilities are identifiable, indicating that a disability-based classification can characterize progression in older people. Since the required resources and costs are known for each profile, these probabilities are very helpful in planning home services for elderly populations. PMID- 22225579 TI - Evaluation of a multi-line broiler chicken population using a single-step genomic evaluation procedure. AB - Effects on prediction of analysing a multi-line chicken population as one line were evaluated. Body weight records were provided by Cobb-Vantress for two lines of broiler chickens. Phenotypic records for 183 695 and 164 149 broilers and genotypic records for 3195 and 3001 broilers were available for each line. Lines were combined to create a multi-line population and analysed using a single-step procedure combining the additive relationship matrix and the genomic relationship matrix (G). G was scaled using allele frequencies from each line, the multi-line population, or 0.5. When allele frequencies were calculated from each line, distributions of diagonal elements were bimodal. When allele frequencies were calculated from the multi-line population, the distribution of diagonal elements had one peak. When allele frequency 0.5 was used, the distribution was bimodal. Genomic estimated breeding values (GEBVs) were predicted using each allele frequency. GEBVs differed with allele frequency but had >= 0.99 correlations with GEBVs predicted with correct allele frequencies. Means of each line and differences in mean between the lines differed based on allele frequencies. Assumed allele frequencies have little impact on ranking within line but larger impact on ranking across lines. G may be used to evaluate multiple populations simultaneously but must be adjusted to obtain properly scaled estimates when population structure is unknown. PMID- 22225580 TI - Test-day somatic cell score, fat-to-protein ratio and milk yield as indicator traits for sub-clinical mastitis in dairy cattle. AB - Test-day (TD) records of milk, fat-to-protein ratio (F:P) and somatic cell score (SCS) of first-lactation Canadian Holstein cows were analysed by a three-trait finite mixture random regression model, with the purpose of revealing hidden structures in the data owing to putative, sub-clinical mastitis. Different distributions of the data were allowed in 30 intervals of days in milk (DIM), covering the lactation from 5 to 305 days. Bayesian analysis with Gibbs sampling was used for model inferences. Estimated proportion of TD records originated from cows infected with mastitis was 0.66 in DIM from 5 to 15 and averaged 0.2 in the remaining part of lactation. Data from healthy and mastitic cows exhibited markedly different distributions, with respect to both average value and the variance, across all parts of lactation. Heterogeneity of distributions for infected cows was also apparent in different DIM intervals. Cows with mastitis were characterized by smaller milk yield (down to -5 kg) and larger F:P (up to 0.13) and SCS (up to 1.3) compared with healthy contemporaries. Differences in averages between healthy and infected cows for F:P were the most profound at the beginning of lactation, when a dairy cow suffers the strongest energy deficit and is therefore more prone to mammary infection. Residual variances for data from infected cows were substantially larger than for the other mixture components. Fat-to-protein ratio had a significant genetic component, with estimates of heritability that were larger or comparable with milk yield, and was not strongly correlated with milk and SCS on both genetic and environmental scales. Daily milk, F:P and SCS are easily available from milk-recording data for most breeding schemes in dairy cattle. Fat-to-protein ratio can potentially be a valuable addition to SCS and milk yield as an indicator trait for selection against mastitis. PMID- 22225581 TI - Trends of the genetic connectedness measures among Nelore beef cattle herds. AB - Validity of comparisons between expected breeding values obtained from best linear unbiased prediction procedures in genetic evaluations is dependent on genetic connectedness among herds. Different cattle breeding programmes have their own particular features that distinguish their database structure and can affect connectedness. Thus, the evolution of these programmes can also alter the connectedness measures. This study analysed the evolution of the genetic connectedness measures among Brazilian Nelore cattle herds from 1999 to 2008, using the French Criterion of Admission to the group of Connected Herds (CACO) method, based on coefficients of determination (CD) of contrasts. Genetic connectedness levels were analysed by using simple and multiple regression analyses on herd descriptors to understand their relationship and their temporal trends from the 1999-2003 to the 2004-2008 period. The results showed a high level of genetic connectedness, with CACO estimates higher than 0.4 for the majority of them. Evaluation of the last 5-year period showed only a small increase in average CACO measures compared with the first 5 years, from 0.77 to 0.80. The percentage of herds with CACO estimates lower than 0.7 decreased from 27.5% in the first period to 16.2% in the last one. The connectedness measures were correlated with percentage of progeny from connecting sires, and the artificial insemination spread among Brazilian herds in recent years. But changes in connectedness levels were shown to be more complex, and their complete explanation cannot consider only herd descriptors. They involve more comprehensive changes in the relationship matrix, which can be only fully expressed by the CD of contrasts. PMID- 22225582 TI - Accuracy of pastoralists' memory-based kinship assignment of Ankole cattle: a microsatellite DNA analysis. AB - This study aimed to estimate the level of relatedness within Ankole cattle herds using autosomal microsatellite markers and to assess the accuracy of relationship assignment based on farmers' memory. Eight cattle populations (four from each of two counties in Mbarara district in Uganda) were studied. Cattle in each population shared varying degrees of relatedness (first-, second- and third degree relatives and unrelated individuals). Only memory-based kinship assignments which farmers knew with some confidence were tested in this experiment. DNA isolated from the blood of a subsample of 304 animals was analysed using 19 microsatellite markers. Average within population relatedness coefficients ranged from 0.010 +/- 0.005 (Nshaara) to 0.067 +/- 0.004 (Tayebwa). An exclusion probability of 99.9% was observed for both sire-offspring and dam offspring relationships using the entire panel of 19 markers. Confidence from likelihood tests performed on 292 dyads showed that first-degree relatives were more easily correctly assigned by farmers than second-degree ones (p < 0.01), which were also easier to assign than third-degree relatives (p < 0.01). Accuracy of kinship assignment by the farmers was 91.9% +/- 5.0 for dam-offspring dyads, 85.5% +/- 3.4 for sire-offspring dyads, 75.6% +/- 12.3 for half-sib and 60.0% +/- 5.0 for grand dam-grand offspring dyads. Herd size, number of dyads assigned and length of time spent by the herder with their cattle population did not correlate with error in memorizing relationships. However, herd size strongly correlated with number of dyads assigned by the herder (r = 0.967, p < 0.001). Overall, we conclude that memorized records of pastoralists can be used to trace relationships and for pedigree reconstruction within Ankole cattle populations, but with the awareness that herd size constrains the number of kinship assignments remembered by the farmer. PMID- 22225583 TI - Effects of integrated genetic evaluations for Icelandic horses on predictive ability, accuracy and selection bias. AB - The genetic evaluation of Icelandic horses is currently based on results from breeding field tests of riding ability and conformation. The effect of integrating competition traits and/or test status into the genetic evaluation was studied concerning estimation bias, predictive ability, accuracy, correlations between breeding values and ranking of sires. Breeding field test data included 19 954 records from horses assessed in 11 countries during 1994-2008. Competition data included 44 160 records from 7687 horses competing in Iceland and Sweden in 1998-2008. Test status was defined as attendance of horses born in Iceland at breeding field tests and/or in competition. Overall, there were trivial differences between different genetic evaluation models regarding estimation bias and predictive ability. Very strong correlations were estimated between breeding values for combined indexes of conformation, riding ability and total score from different models. Higher accuracy was achieved for most of the traits when competition traits and/or test status were added to the model. Sires ranked differently when the new traits were added to the genetic evaluation model. It was concluded that competition traits should be integrated into the genetic evaluation. Further analyses on genetic parameters for test status and its relationship with the other traits are needed for future inclusion of test status in the genetic evaluation. PMID- 22225584 TI - Estimation of genetic parameters and response to selection for a continuous trait subject to culling before testing. AB - The consequences of assuming a zero environmental covariance between a binary trait 'test-status' and a continuous trait on the estimates of genetic parameters by restricted maximum likelihood and Gibbs sampling and on response from genetic selection when the true environmental covariance deviates from zero were studied. Data were simulated for two traits (one that culling was based on and a continuous trait) using the following true parameters, on the underlying scale: h2 = 0.4; r(A) = 0.5; r(E) = 0.5, 0.0 or -0.5. The selection on the continuous trait was applied to five subsequent generations where 25 sires and 500 dams produced 1500 offspring per generation. Mass selection was applied in the analysis of the effect on estimation of genetic parameters. Estimated breeding values were used in the study of the effect of genetic selection on response and accuracy. The culling frequency was either 0.5 or 0.8 within each generation. Each of 10 replicates included 7500 records on 'test-status' and 9600 animals in the pedigree file. Results from bivariate analysis showed unbiased estimates of variance components and genetic parameters when true r(E) = 0.0. For r(E) = 0.5, variance components (13-19% bias) and especially (50-80%) were underestimated for the continuous trait, while heritability estimates were unbiased. For r(E) = 0.5, heritability estimates of test-status were unbiased, while genetic variance and heritability of the continuous trait together with were overestimated (25 50%). The bias was larger for the higher culling frequency. Culling always reduced genetic progress from selection, but the genetic progress was found to be robust to the use of wrong parameter values of the true environmental correlation between test-status and the continuous trait. Use of a bivariate linear-linear model reduced bias in genetic evaluations, when data were subject to culling. PMID- 22225585 TI - Estimation of genetic parameters for hip dysplasia in Czech Labrador Retrievers. AB - The objective of this study was to estimate the genetic parameters, genetic trends and breeding values using linear model (LM) and threshold model (TM) for the development of hip dysplasia (HD) in Labrador Retrievers in the Czech Republic (n = 3151). The right and left hip joints were evaluated separately using the Federation Cynologique Internationale scoring system. Four linear and four TMs were tested for the correct estimation of genetic parameters. All the tested models utilized fixed effects of sex, assessor, year of birth, regression of age at evaluation, random direct genetic effects and the effect of the animals' permanent environments. The models differed in the inclusion of the following effects: fixed effects of regression of inbreeding coefficient, random maternal effect and random effect of the maternal permanent environment. Compared to the TM, the LM provided lower coefficients of direct (0.25-0.29 versus 0.26 0.35) and maternal heritability (0.01-0.02 versus 0.03-0.05), repeatability (0.76 0.77 versus 0.78-0.83) and of the correlation between direct and maternal effects (-0.55 to -0.21 versus -0.80 to -0.27). In the tested models, no statistical significance was found for fixed regression of inbreeding coefficients or for the random effect of the permanent maternal environment. In spite of the similarity of the LM and TM results, the TM is recommended as the more suitable model for estimating genetic parameters and subsequent breeding values for HD in Labrador Retrievers in the Czech Republic. PMID- 22225586 TI - Polymorphisms in genes of the somatotrophic axis are independently associated with milk production, udder health, survival and animal size in Holstein-Friesian dairy cattle. AB - The somatotrophic axis consisting of pituitary-derived growth hormone and circulating insulin-like growth factor 1 has been well established as key regulators of animal health, metabolism, lactation, fertility, body composition and growth rate. The aim of this study was to simultaneously quantify the associations between SNPs in candidate genes of the somatotrophic axis (i.e., IGF 1, GH1 and GHR) with performance traits in Holstein-Friesian (HF) dairy cattle. Both novel SNPs identified previously by this group alongside other published SNPs within these genes were analysed for associations with performance in dairy cattle. Multiple regression analyses regressing genetic merit of up to 848 HF sires on novel SNPs (n = 76) and published SNPs (n = 33) were undertaken using weighted animal mixed linear models. Twenty-three SNPs were significantly associated with at least one of 18 traits analysed and involved in milk production, udder health, fertility and growth. Eight traits including milk fat composition, carcass conformation, stature, chest width, body depth, rump width, carcass and cull cow weight were independently associated with SNPs in two genes. Furthermore, for several traits including milk fat yield, somatic cell count, survival and carcass fat, SNPs in all three genes were independently associated with performance. Milk fat yield and carcass fat showed the highest number of independent associations across all three genes with five SNPs associated with both traits. The cumulative effects of the favourable alleles of all five SNPs across GH1, GHR and IGF-1 result in an increase of 5.9 kg and 28.6 units of milk fat and carcass fat, respectively. Cow survival was associated with a single SNP in each of the three genes with a cumulative allele effect of 1.5%. Independent effects of polymorphisms in GH1, GHR and IGF-1 reinforce the central role of the somatotrophic axis on animal development and performance. PMID- 22225587 TI - Drift across the Atlantic: genetic differentiation and population structure in Brazilian and Portuguese native goat breeds. AB - Brazilian goat breeds are believed to derive mainly from animals brought by Portuguese settlers since the 16th century. We used microsatellite markers in a sample of 436 animals to study genetic variability and differentiation of the six Portuguese (PT) and six Brazilian (BR) goat breeds currently recognized in the two countries. These breeds were also compared with an outgroup represented by a sample of Alpine (ALP) goats. The effective number of alleles and allelic richness were slightly higher in PT than in BR breeds. The global F(ST) was nearly 0.11 when PT and BR breeds were considered, with a mean pairwise F(ST) of about 0.03 among PT breeds, 0.07 among BR breeds and 0.15 between PT and BR breeds. The dendrogram illustrating relationships between populations and the correspondence analysis indicate the existence of two very distinct clusters, corresponding to the countries of origin of the breeds studied, which are nearly equidistant from the Alpine outgroup. The analysis with structure confirmed the separation between PT and BR breeds but suggests that some BR breeds, especially Grauna and Caninde, may share a common ancestry with PT breeds. The divergence observed between PT and BR breeds may result from founder effects and genetic drift but could also reflect the introduction in Brazil of goats originating from other regions, e.g., West Africa. PMID- 22225589 TI - In vitro inhibition of monkeypox virus production and spread by Interferon-beta. AB - BACKGROUND: The Orthopoxvirus genus contains numerous virus species that are capable of causing disease in humans, including variola virus (the etiological agent of smallpox), monkeypox virus, cowpox virus, and vaccinia virus (the prototypical member of the genus). Monkeypox is a zoonotic disease that is endemic in the Democratic Republic of the Congo and is characterized by systemic lesion development and prominent lymphadenopathy. Like variola virus, monkeypox virus is a high priority pathogen for therapeutic development due to its potential to cause serious disease with significant health impacts after zoonotic, accidental, or deliberate introduction into a naive population. RESULTS: The purpose of this study was to investigate the prophylactic and therapeutic potential of interferon-beta (IFN-beta) for use against monkeypox virus. We found that treatment with human IFN-beta results in a significant decrease in monkeypox virus production and spread in vitro. IFN-beta substantially inhibited monkeypox virus when introduced 6-8 h post infection, revealing its potential for use as a therapeutic. IFN-beta induced the expression of the antiviral protein MxA in infected cells, and constitutive expression of MxA was shown to inhibit monkeypox virus infection. CONCLUSIONS: Our results demonstrate the successful inhibition of monkeypox virus using human IFN-beta and suggest that IFN-beta could potentially serve as a novel safe therapeutic for human monkeypox disease. PMID- 22225590 TI - Impact of complex NOTCH1 mutations on survival in paediatric T-cell leukaemia. AB - BACKGROUND: Molecular alterations occur frequently in T-ALL and the potential impact of those abnormalities on outcome is still controversial. The current study aimed to test whether NOTCH1 mutations and additional molecular abnormalities would impact T-ALL outcome in a series of 138 T-ALL paediatric cases. METHODS: T-ALL subtypes, status of SIL-TAL1 fusion, ectopic expression of TLX3, and mutations in FBXW7, KRAS, PTEN and NOTCH1 were assessed as overall survival (OS) and event-free survival (EFS) prognostic factors. OS and EFS were determined using the Kaplan-Meier method and compared using the log-rank test. RESULTS: The frequencies of mutations were 43.5% for NOTCH1, while FBXW7, KRAS and PTEN exhibited frequencies of 19.1%, 9.5% and 9.4%, respectively. In 78.3% of cases, the coexistence of NOTCH1 mutations and other molecular alterations was observed. In multivariate analysis no statistical association was revealed between NOTCH1 mutations and any other variable analyzed. The mean length of the follow-up was 68.4 months and the OS was 50.7%. SIL-TAL1 was identified as an adverse prognostic factor. NOTCH1 mutation status was not associated with outcome, while the presence of NOTCH1 complex mutations (indels) were associated with a longer overall survival (p = 0.031) than point mutations. CONCLUSION: NOTCH1 mutations alone or in combination with FBXW7 did not impact T-ALL prognosis. Nevertheless, complex NOTCH1 mutations appear to have a positive impact on OS and the SIL-TAL1 fusion was validated as a negative prognostic marker in our series of T-ALL. PMID- 22225592 TI - Attention to body mass index by child psychiatry providers when prescribing second-generation antipsychotic medication to children: a survey study using a clinical vignette. AB - AIM: We sought to determine whether weight and body mass index measurement were taken into consideration when prescribing second-generation antipsychotic (SGA) medication to a child. METHODS: Two hundred clinicians were surveyed using a hypothetical clinical case vignette at a child psychopharmacology, postgraduate medical education course. The vignette described an overweight 10-year-old boy who was about to be prescribed an SGA medication to control psychotic symptoms. The reference to the patient's being 'overweight' was purposefully included to determine if providers would assess the patient's risk of morbidity from the metabolic side effects of the SGAs at the time of prescribing. RESULTS: Only 7.0% of prescribers listed either 'body mass index' or a combination of 'height' and 'weight' as part of their next treatment steps for an overweight child before prescribing an SGA. CONCLUSIONS: These results suggest the need for education as to the importance of body mass index monitoring when prescribing second generation antipsychotic medications to children. PMID- 22225593 TI - When mothers are better than fathers.... PMID- 22225591 TI - Involvement of Nav 1.8 sodium ion channels in the transduction of mechanical pain in a rodent model of osteoarthritis. AB - INTRODUCTION: A subgroup of voltage gated sodium channels including Nav1.8 are exclusively expressed on small diameter primary afferent neurons and are therefore believed to be integral to the neurotransmission of nociceptive pain. The present study examined whether local application of A-803467, a selective blocker of the Nav 1.8 sodium channel, can reduce nociceptive transmission from the joint in a rodent model of osteoarthritis (OA). METHODS: OA-like changes were induced in male Wistar rats by an intra-articular injection of 3 mg sodium monoiodoacetate (MIA). Joint nociception was measured at day 14 by recording electrophysiologically from knee joint primary afferents in response to non noxious and noxious rotation of the joint both before and following close intra arterial injection of A-803467. The effect of Nav1.8 blockade on joint pain perception and secondary allodynia were determined in MIA treated animals by hindlimb incapacitance and von Frey hair algesiometry respectively. RESULTS: A 803467 significantly reduced the firing rate of joint afferents during noxious rotation of the joint but had no effect during non-noxious rotation. In the pain studies, peripheral injection of A-803467 into OA knees attenuated hindlimb incapacitance and secondary allodynia. CONCLUSIONS: These studies show for the first time that the Nav1.8 sodium channel is part of the molecular machinery involved in mechanotransduction of joint pain. Targeting the Nav1.8 sodium channel on joint nociceptors could therefore be useful for the treatment of OA pain, avoiding the unwanted side effects of non-selective nerve blocks. PMID- 22225594 TI - Ultrasonically assisted evaluation of the impact of atherosclerotic plaque on the pulse pressure wave propagation: a clinical feasibility study. AB - The purpose of this work was to evaluate ultrasound modality as a non-invasive tool for determination of impact of the degree of the atherosclerotic plaque located in human internal carotid arteries on the values of the parameters of the pulse wave. Specifically, the applicability of the method to such arteries as brachial, common, and internal carotid was examined. The method developed is based on analysis of two characteristic parameters: the value of the mean reflection coefficient modulus |Gamma|(a) of the blood pressure wave and time delay Deltat between the forward (travelling) and backward (reflected) blood pressure waves. The blood pressure wave was determined from ultrasound measurements of the artery's inner (internal) diameter, using the custom made wall tracking system (WTS) operating at 6.75 MHz. Clinical data were obtained from the carotid arteries measurements of 70 human subjects. These included the control group of 30 healthy individuals along with the patients diagnosed with the stenosis of the internal carotid artery (ICA) ranging from 20% to 99% or with the ICA occlusion. The results indicate that with increasing level of stenosis of the ICA the value of the mean reflection coefficient measured in the common carotid artery, significantly increases from |Gamma|(a)=0.45 for healthy individuals to |Gamma|(a)=0.61 for patients with stenosis level of 90-99%, or ICA occlusion. Similarly, the time delay Deltat decreases from 52 ms to 25 ms for the respective groups. The method described holds promise that it might be clinically useful as a non-invasive tool for localization of distal severe artery narrowing, which can assist in identifying early stages of atherosclerosis especially in regions, which are inaccessible for the ultrasound probe (e.g. carotid sinus or middle cerebral artery). PMID- 22225595 TI - Simultaneous measurement of the phase and group velocities of Lamb waves in a laser-generation based imaging method. AB - This paper describes a novel approach to the simultaneous measurement of the phase and group velocities of Lamb waves based on images of their propagation. The laser-generation based imaging method was first introduced to obtain images of Lamb wave propagation. The time series of snapshot images is used to make a position-time diagram, and the velocities can be estimated based on the slopes of the position curves. Thus, the phase and group velocities can be obtained by measuring the phase advance and energy flow of the Lamb wave, respectively. Details of the principle of simultaneous measurement are presented herein. Experimental verification was also performed in the range of 0.2-3.0 MHz-mm using aluminum plates. The average errors between experiment and theory in the phase and group velocities were 3.31% and 5.68%, respectively. PMID- 22225596 TI - Enucleation after fusion and activation enhances the development of reconstructed bovine embryos. AB - Effects of enucleation timing on enucleation rates, development and methylation levels of reconstructed bovine embryos were investigated. However, the enucleation rate of reconstructed embryos produced by the enucleation before fusion and activation (EBFA) was higher than that by the enucleation after fusion and activation (EAFA) procedure (80.7% vs. 59.1%, P<0.05). The blastocyst rate of reconstructed embryos cloned with ear fibroblasts in EBFA group was reduced (P<0.05) in comparison with that of EAFA group (24.6% vs. 34.4%). Two out of 11 recipients were pregnant and gave birth to two viable calves after transfer of 20 reconstructed EBFA embryos. Two out of seven recipients were pregnant and also gave birth to two calves, with one surviving, after transfer of 12 reconstructed embryos produced by EAFA procedure. Finally, the methylation level of satellite I gene of donor cells (69.8%) and reconstructed embryos in EBFA group (64.7%) were similar, which were both higher (P<0.05) than that of the reconstructed embryos in EAFA group (44.4%). The methylation level of satellite I gene of the reconstructed embryos in the IVF embryos (31.9%) was lower (P<0.05) than those in all other treatments. In conclusion, the reconstructed bovine embryos produced by the EAFA procedure revealed a better developmental competence with a lower methylation rate of satellite I gene than those produced by the EBFA procedure. PMID- 22225597 TI - Nonunion rate of first metatarsal-phalangeal joint arthrodesis for end-stage hallux rigidus with crossed titanium flexible intramedullary nails and dorsal static staple with immediate weight-bearing. AB - Myriad forms of fixation have been proposed for arthrodesis of the first metatarsal-phalangeal joint (MTPJ). Regardless of the fixation type, nonunion of the arthrodesis site has been purported to be a common complication. We performed a retrospective review of all patients undergoing arthrodesis of the first MTPJ for end-stage hallux rigidus with 2 crossed flexible titanium intramedullary nails and a dorsal static 10-mm titanium staple followed by immediate protected weight-bearing. The inclusion criteria were as follows: the exact internal fixation technique described was employed for end-stage hallux rigidus of the first MTPJ only; preoperative and at least 6 weeks of postoperative weight bearing radiographs were available; weight-bearing was initiated on the operative foot immediately in a protective shoe; the patient was followed for at least 6 months postoperatively; any complication was documented; and bilateral surgery was not done in the same setting. A total of 42 female patients (51 feet) with a mean age +/- SD of 69.4 +/- 9.2 years met the inclusion criteria. Complications resulting from technical error during insertion of the crossed titanium flexible intramedullary nails occurred in 3 feet (5.9%), but none led to nonunion or revision surgery. One delayed union (2%) occurred but it ultimately united. The incidence of nonunion after arthrodesis of the first MTPJ consisting of 2 crossed flexible titanium intramedullary nails and a dorsal static 10-mm titanium staple for end-stage hallux rigidus in an exclusively female population was lower than the historic mean for most other fixation techniques. However, methodologically sound prospective cohort studies that focus on the use of isolated arthrodesis of the first MTPJ for end-stage hallux rigidus in both male and female patients are still needed, as are comparisons of the presented technique with other modern osteosynthesis techniques. PMID- 22225598 TI - Nutritional status of adolescents in the context of the Moroccan nutritional transition: the role of parental education. AB - In Morocco, the beginning of the nutritional transition is closely linked to social and economic transformations and changes in behaviour and traditional lifestyles. The objective of this study is to describe the current pattern of food consumption and the nutritional status of adolescents in the province of Ouarzazate and its association with parents' educational level. The sample comprises 327 high school students from Ouarzazate: 135 (41.3%) boys and 192 (58.7%) girls (age range 15-20 years). For both boys and girls, the results show lower height and BMI z-scores than the WHO reference values. Adolescents whose parents have a low educational level have lower height/age and BMI/age z-scores than those whose fathers have a high educational level. No differences are observed in total daily energy intake depending on fathers' educational level, but the energy provided by lipids is higher in adolescents whose fathers have a high educational background. The quality of fats consumed (MUFA+PUFA/SFA) is better among those boys whose fathers have low education, but no differences are observed for girls. The process of nutritional transition is not uniform in the sample, but depends on the socioeconomic characteristics of population groups, which include, among others, accessibility of certain food, differences in habits and lifestyles related to energy expenditure, and higher prevalence of overweight and obesity in more favoured groups. PMID- 22225599 TI - Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. AB - OBJECTIVE: Mounting evidence suggests that inflammation is involved in the pathogenesis of schizophrenia. This evidence implies that anti-inflammatory agents are potentially useful therapeutic strategies in schizophrenia. This article quantitatively summarizes the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) to augment antipsychotic treatment to reduce schizophrenia symptom severity. DATA SOURCES: An electronic search was performed using MEDLINE, Embase, the National Institutes of Health Web site clinicaltrials.gov, Cochrane Schizophrenia Group entries in PsiTri, and the Cochrane Database of Systematic Reviews. The following basic search terms were used: schizophrenia, nonsteroidal anti-inflammatory drug, and NSAID together with the name of each specific NSAID (ibuprofen, diclofenac, naproxen sodium, and acetylsalicylic acid). We applied no year or language restrictions. STUDY SELECTION: Studies were selected if they met the following inclusion criteria: (1) randomized, double-blind, placebo controlled trials regarding augmentation of antipsychotic medication with an NSAID, (2) patients included had a diagnosis of a schizophrenia spectrum disorder according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, and (3) studies reported sufficient information to compute common effect size statistics, or corresponding authors could supply these data upon request. DATA EXTRACTION: The primary outcome measure was the mean change in total score on the Positive and Negative Syndrome Scale (PANSS). Secondary outcome measures included positive and negative symptom subscores of the PANSS. RESULTS: We could include 5 double-blind, randomized, placebo-controlled trials, reporting on 264 patients. Four studies applied celecoxib, and 1 used acetylsalicylic acid. We found a mean effect size of 0.43, which was significant at P = .02 in favor of NSAIDs on total symptom severity. For positive symptom severity, the mean standardized difference was 0.34 (P = .02). For severity of negative symptoms the mean standardized difference was 0.26 (P = .03). CONCLUSIONS: These results suggest that NSAID augmentation could be a potentially useful strategy to reduce symptom severity in schizophrenia. As these are the first studies on a relatively new strategy and the included sample size is modest, these results should be interpreted with caution. However, augmentation with acetylsalicylic acid may have the additional benefit of reducing cardiac and cancer mortality in schizophrenia. We therefore believe that application of NSAIDs in schizophrenia deserves further investigation as augmentation of antipsychotic treatment and reducing comorbid somatic diseases. PMID- 22225600 TI - Intralocus sexual conflict and offspring sex ratio. AB - Males and females frequently have different fitness optima for shared traits, and as a result, genotypes that are high fitness as males are low fitness as females, and vice versa. When this occurs, biasing of offspring sex-ratio to reduce the production of the lower-fitness sex would be advantageous, so that for example, broods produced by high-fitness females should contain fewer sons. We tested for offspring sex-ratio biasing consistent with these predictions in broad-horned flour beetles. We found that in both wild-type beetles and populations subject to artificial selection for high- and low-fitness males, offspring sex ratios were biased in the predicted direction: low-fitness females produced an excess of sons, whereas high-fitness females produced an excess of daughters. Thus, these beetles are able to adaptively bias sex ratio and recoup indirect fitness benefits of mate choice. PMID- 22225601 TI - Sex affects immunity. AB - Sex based differences in immune responses, affecting both the innate and adaptive immune responses, contribute to differences in the pathogenesis of infectious diseases in males and females, the response to viral vaccines and the prevalence of autoimmune diseases. Indeed, females have a lower burden of bacterial, viral and parasitic infections, most evident during their reproductive years. Conversely, females have a higher prevalence of a number of autoimmune diseases, including Sjogren's syndrome, systemic lupus erythematosus (SLE), scleroderma, rheumatoid arthritis (RA) and multiple sclerosis (MS). These observations suggest that gonadal hormones may have a role in this sex differential. The fundamental differences in the immune systems of males and females are attributed not only to differences in sex hormones, but are related to X chromosome gene contributions and the effects of environmental factors. A comprehensive understanding of the role that sex plays in the immune response is required for therapeutic intervention strategies against infections and the development of appropriate and effective therapies for autoimmune diseases for both males and females. This review will focus on the differences between male and female immune responses in terms of innate and adaptive immunity, and the effects of sex hormones in SLE, MS and RA. PMID- 22225602 TI - Loss of T cell microRNA provides systemic protection against autoimmune pathology in mice. AB - With an increasing number of studies demonstrating alterations in T cell microRNA expression during autoimmune disease, modulation of the T cell microRNA network is considered a potential therapeutic strategy. Due to the complex and often opposing interactions of individual microRNA, prioritization of therapeutic targets first requires dissecting the dominant effects of the T cell microRNA network. Initial results utilizing a unidirectional screen suggested that the tolerogenic functions were dominant, with spontaneous colitis resulting from T cell-specific excision of Dicer. Here we performed a bidirectional screen for microRNA function by removing Dicer from the T cells of both wildtype mice and Transforming Growth Factor beta (TGFbeta) receptor-deficient mice. This allowed the impact of microRNA loss on T cell activation, effector T cell differentiation and autoimmune pathology to be systematically assessed. This bidirectional screen revealed a dominant immunogenic function for T cell microRNA, with potent suppression of T cell activation, IFNgamma production and autoimmune pathology in all targeted organs except the colon, where Dicer-dependent microRNA demonstrated a dominant tolerogenic function. These results reverse the original conclusions of microRNA function in T cells by revealing a systemic pro-autoimmune function. PMID- 22225603 TI - FT-IR and Raman spectroscopic and quantum chemical investigations of some metal halide complexes of 1-phenylpiperazine. AB - New metal halide complexes in the form of M(pp)(2)Cl(2) (where pp=1 phenylpiperazine and M=Pd or Hg) have been prepared for the first time and their FT-IR and FT-Raman spectra are reported in the region of 4000-10 cm(-1) and 4000 50 cm(-1), respectively. The optimized geometric parameters, normal mode frequencies and corresponding vibrational assignments of the present compounds are theoretically examined by means of B3LYP hybrid density functional theory (DFT) method together with Lanl2dz basis set. Furthermore, reliable vibrational assignments made on the basis of potential energy distribution (PED) were calculated and the thermodynamics functions, the highest occupied and the lowest unoccupied molecular orbitals (HOMO and LUMO) of these compounds have been predicted. According to the results, theoretical values have been successfully compared against experimental data. PMID- 22225604 TI - Synthesis, structural, optical and thermal studies of an organic nonlinear optical 4-aminopyridinium maleate single crystal. AB - Synthesis and growth of a novel organic nonlinear optical (NLO) crystal of 4 aminopyridinium maleate (4APM) in larger size by the slow evaporation solution growth technique are reported. Single crystal and powder X-ray diffraction analyses reveal that 4APM crystallizes in monoclinic system with space group P2(1) with cell parameters a=8.140(4)A, b=5.457(5)A, c=10.926(10)A and volume=481.4(7)A(3). The grown crystal has been characterized by Fourier transform infrared and UV-visible spectral analyses. Thermogravimetric analysis (TGA) and differential thermal analysis (DTA) have been carried out to study its thermal properties. Dielectric measurements have been carried out to study the distribution of charges within the crystal. The mechanical strength of the crystal has been studied by using Vickers' microhardness test. The etching studies have been carried out on the grown crystal. The Kurtz and Perry powder SHG technique confirms the NLO property of the grown crystal and the SHG efficiency of 4APM was found to be 4.8 times greater than that of KDP crystal. PMID- 22225605 TI - Experimental, quantum chemical and natural bond orbital investigations of N-(2,4 dimethylphenyl)-2,2-dichloroacetamide and N-(3,5-dimethylphenyl)-2,2 dichloroacetamide. AB - N-(2,4-Dimethylphenyl)-2,2-dichloroacetamide (24DMPA) and N-(3,5-dimethylphenyl) 2,2-dichloroacetamide (35DMPA) of the configuration X(y)C(6)H(5-y)NHCO-CHCl(2) (where, X=CH(3) and y=2) were synthesised and an extensive spectroscopic investigations have been carried out. The ab initio and DFT studies were carried out with 6-31G** and cc-pVDZ basis sets to determine the structural, thermodynamical and vibrational characteristics of the compounds and also to understand the steric influence of methyl groups on the characteristic frequencies of amide (-CONH-) group. The most stable conformer has been determined by PES scan. Normal co-ordinate analysis has been carried out in an effort to provide mixing of the fundamental modes with the help of potential energy distribution (PED). The energies of the frontier molecular orbitals have been determined. Complete NBO analysis was also carried out to find out the intramolecular electronic interactions and their stabilisation energy. All the computed values are well agreed with the experimental data. PMID- 22225606 TI - Molecular spectroscopic study for suggested mechanism of chrome tanned leather. AB - Collagen represents the structural protein of the extracellular matrix, which gives strength of hides and/or skin under tanning process. Chrome tan is the most important tanning agent all over the world. The methods for production of leather evolved over several centuries as art and engineering with little understanding of the underlying science. The present work is devoted to suggest the most probable mechanistic action of chrome tan on hide proteins. First the affect of Cr upon hide protein is indicated by the studied mechanical properties. Then the spectroscopic characterization of the hide protein as well as chrome tanned leather was carried out with Horizontal Attenuated Total Reflection (HATR) FT-IR. The obtained results indicate how the chromium can attached with the active sites of collagen. Molecular modeling confirms that chromium can react with amino as well as carboxylate groups. Four schemes were obtained to describe the possible interactions of chrome tan with hide proteins. PMID- 22225607 TI - A comprehensive approach to the design of ethanol supply chains including carbon trading effects. AB - The optimal design of biofuels production systems is a key component in the analysis of the environmental and economic performance of new sustainable transport systems. In this paper a general mixed integer linear programming modelling framework is developed to assess the design and planning of a multi period and multi-echelon bioethanol upstream supply chain under market uncertainty. The optimisation design process of biofuels production systems aims at selecting the best biomass and technologies options among several alternatives according to economic and environmental (global warming potential) performance. A key feature in the proposed approach is the acknowledgement of an economic value to the overall GHG emissions, which is implemented through an emissions allowances trading scheme. The future Italian biomass-based ethanol production is adopted as a case study. Results show the effectiveness of the model as a decision making-tool to steer long-term decisions and investments. PMID- 22225608 TI - Biotransformation of methyl-beta-D-glucopyranoside to higher chain alkyl glucosides by cell bound beta-glucosidase of Pichia etchellsii. AB - In the present study, we have investigated the use of Pichia etchellsii whole cells for synthesis of long-chain alkyl glucosides. Methyl-beta-d-glucopyranoside (MG) was used in reaction with fatty alcohols, n-hexanol, n-octanol, n-decanol and n-dodecanol to synthesize the respective alkyl glucosides. The initial reaction conditions were first optimized at 2.5 ml scale for synthesis of octyl glucoside (OG) and were 8% water content, 100mM MG and 6h of reaction time and this resulted in ~ 53% yield. A maximum transglucosylation/hydrolysis ratio of 2.79 was obtained at 100mM MG favoring high product yield. Based on the optimized conditions, a reactor was operated at 50 ml level which resulted in ~ 60% conversion of MG to OG. A simple high performance liquid chromatography method was developed for quantitation of higher chain glucosides using a refractive index detector. A maximum of 27% and 13% yield was obtained for decyl-, and dodecyl-beta-d-glucopyranoside, respectively. PMID- 22225609 TI - Electro-extractive fermentation for efficient biohydrogen production. AB - Electrodialysis, an electrochemical membrane technique, was found to prolong and enhance the production of biohydrogen and purified organic acids via the anaerobic fermentation of glucose by Escherichia coli. Through the design of a model electrodialysis medium using cationic buffer, pH was precisely controlled electrokinetically, i.e. by the regulated extraction of acidic products with coulombic efficiencies of organic acid recovery in the range 50-70% maintained over continuous 30-day experiments. Contrary to previous reports, E. coli produced H(2) after aerobic growth in minimal medium without inducers and with a mixture of organic acids dominated by butyrate. The selective separation of organic acids from fermentation provides a potential nitrogen-free carbon source for further biohydrogen production in a parallel photofermentation. A parallel study incorporated this fermentation system into an integrated biohydrogen refinery (IBR) for the conversion of organic waste to hydrogen and energy. PMID- 22225610 TI - Reversal of the inhibitory effect of light and high temperature on germination of Phacelia tanacetifolia seeds by melatonin. AB - Possible role of melatonin in the germination of negatively photoblastic and thermosensitive seeds of Phacelia tanacetifolia Benth was studied. Final germination percentage (FGP) was determined in the presence or absence of light at various temperatures, ranging from 0 to 40 degrees C. The highest FGP was determined as 48.7% and 92% at temperature of 15 degrees C in the presence and absence of light, respectively. Seeds were primed with 1% KNO(3) containing various concentrations (0.3, 1, 6, 12, 30, 60, or 90 MUM) of melatonin for 2 days at 15 degrees C in darkness. Primed seeds were germinated at an inhibitory temperature of 30 degrees C, and results were compared to those occurring at the optimum temperature of 15 degrees C under both light and no light conditions. Melatonin incorporated into priming medium significantly reversed the inhibitory effects of light and high temperature. Germination was elevated from 2.5% to 52% of FGP for seeds primed in the presence of 6 MUM melatonin in darkness at 30 degrees C, while 1 MUM melatonin had the highest FGP (21.0%) in the presence of light at 30 degrees C. The highest FGP (47.5%) was obtained from seeds primed in the presence of 0.3 MUM melatonin under the light condition at 15 degrees C, while untreated seeds had 1.5% of FGP. The fastest seed germination was determined from seeds primed in the presence of 0.3 MUM melatonin (G(50) = 0.56 days) at 15 degrees C in darkness. The possible roles of melatonin in promoting germination parameters of photo- and thermosensitive seed germination are discussed. PMID- 22225611 TI - [Tumor necrosis factor alpha and melfalan-based hyperthermic isolated limb perfusion in locally advanced extremity soft tissue sarcomas and melanomas]. AB - INTRODUCTION: The aim of the study is to evaluate the limb salvage rate achieved by treating locally advanced extremity sarcoma and melanoma by hyperthermic isolated limb perfusion with melphalan and TNF-alpha (ILP-MT). MATERIAL AND METHODS: A retrospective study was conducted on patients suffering from locally advanced soft tissue sarcoma and melanoma of the limb and treated by means of ILP MT between November 2001 and February 2010. The response rate, toxicity, complications, disease free intervals, overall survival and limb salvage rate were evaluated. RESULTS: A total of 30 patients (19 females and 11 males) with a median age of 60 years (14-82) were treated by this technique. The overall response rate was 93.4% (complete, 46.7%; partial 46.7%); the mean follow-up was 23 months. The median duration of response was 5 months (0-62), The median overall survival was 13.5 months (range 1 - 62). Limb salvage rate was 86.7%. Eleven patients are currently alive (5 without disease, 2 with residual disease on treatment, 2 with local progression and 2 with systemic progression). CONCLUSION: With the use of ILP-MT we have avoided the amputation of 26 limbs affected by locally advanced sarcoma or melanoma. ILP-MT is feasible and safe in a multidisciplinary environment. PMID- 22225613 TI - Chimeric primates: embryonic stem cells need not apply. AB - In this issue, Tachibana et al. report the generation of the first chimeras from a nonhuman primate, the rhesus monkey. Unlike mice, rhesus chimeras fail to form when embryonic stem cells are injected into blastocysts. Instead, chimera formation is achieved by aggregation of several four-cell embryos. PMID- 22225612 TI - Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. AB - Identification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer therapy. PMID- 22225614 TI - Generation of chimeric rhesus monkeys. AB - Totipotent cells in early embryos are progenitors of all stem cells and are capable of developing into a whole organism, including extraembryonic tissues such as placenta. Pluripotent cells in the inner cell mass (ICM) are the descendants of totipotent cells and can differentiate into any cell type of a body except extraembryonic tissues. The ability to contribute to chimeric animals upon reintroduction into host embryos is the key feature of murine totipotent and pluripotent cells. Here, we demonstrate that rhesus monkey embryonic stem cells (ESCs) and isolated ICMs fail to incorporate into host embryos and develop into chimeras. However, chimeric offspring were produced following aggregation of totipotent cells of the four-cell embryos. These results provide insights into the species-specific nature of primate embryos and suggest that a chimera assay using pluripotent cells may not be feasible. PMID- 22225615 TI - Fibroblast progenitor cells are recruited into the myocardium prior to the development of myocardial fibrosis. AB - Using an established model of myocardial hypertrophy and fibrosis after angiotensin II (AngII) infusion, our aim was to characterize the early cellular element involved in the development of myocardial fibrosis in detail. Male Lewis rats were infused with saline or AngII (0.7 mg/kg per day) for up to seven days. Collagen deposition and cellular infiltration were identified by histology stains. Infiltrating cells were grown in vitro and examined by flow cytometry and immunostaining. Chemokine expression was measured using qRT-PCR. AngII infusion resulted in multifocal myocardial cellular infiltration (peak at three days) that preceded collagen deposition. Monocyte chemotactic protein (MCP)-1 transcripts peaked after one day of AngII exposure. Using a triple-labelling technique, the infiltrating cells were found to express markers of leucocyte (ED1(+)), mesenchymal [alpha-smooth muscle actin (SMA)(+)] and haematopeotic progenitor cells (CD133(+)) suggesting a fibroblast progenitor phenotype. In vitro, ED1(+)/SMA(+)/CD133(+) cells were isolated and grown from AngII-exposed animals. Comparatively few cells were cultured from untreated control hearts, and they were found to be ED1(-)/SMA(+)/CD133(-). We provide evidence that myocardial ECM deposition is preceded by infiltration into the myocardium by cells that express a combination of haematopoietic (ED1, CD133) and mesenchymal (SMA) cell markers, which is a characteristic of the phenotype of fibroblast precursor cells, termed fibrocytes. This suggests that fibrocytes rather than (as is often presumed) leucocytes may have effector functions in the initiation of myocardial fibrosis. PMID- 22225616 TI - Platelet-derived growth factor receptor alpha-positive cells in the tunica muscularis of human colon. AB - An obstacle to understanding motor pathologies of the gastrointestinal (GI) tract is that the physiology of some of the cellular components of the gut wall is not understood. Morphologists identified fibroblast-like cells in the tunica muscularis many years ago, but little is known about these interstitial cells because of inadequate techniques to identify these cells. Recent findings have shown that fibroblast-like cells express platelet-derived growth factor receptor alpha (PDGFRalpha) in mice and that antibodies for these receptors can be used to label the cells. We used immunohistochemical techniques to study the phenotype and intercellular relationships of fibroblast-like cells in the human colon. Fibroblast-like cells are labelled specifically with antibodies to PDGFRalpha and widely distributed through the tunica muscularis of human colon. These cells form discrete networks in the region of the myenteric plexus and within the circular and longitudinal muscle layers. Platelet-derived growth factor receptor alpha(+) cells are distinct from c-Kit(+) interstitial cells of Cajal and closely associated with varicose processes of neurons expressing substance P (excitatory motor neurons) or neuronal nitric oxide synthase (nNOS) (inhibitory motor neurons). Platelet-derived growth factor receptor alpha(+) cells express small conductance Ca(2+)-activated K(+) channels (SK3), which are likely to mediate purinergic neural regulation of colonic muscles. Our data suggest that PDGFRalpha(+) cells may have an important role in transducing inputs from enteric motor neurons. This study identifies reagents and techniques that will allow investigation of this class of interstitial cells and help develop an understanding of the role of PDGFRalpha(+) cells in the human GI tract in health and disease. PMID- 22225617 TI - Prevalence of the metabolic syndrome among children from six cities of China. AB - BACKGROUND: Metabolic syndrome (MetS) in childhood can increase the risk of cardiovascular disease, diabetes mellitus and dyslipidemia in adulthood, which is of increasing concern in transitional and advanced economies. The aim of the current study was to explore the prevalence of MetS among children from six cities of China. METHODS: A total of 8,764 children (4,495 boys, 4,269 girls) aged 7-11 years were randomly selected from 6 cities of China. MetS was mainly defined by the criteria proposed by International Diabetes Federation (IDF). RESULTS: The overall prevalence of MetS for children older than 10 years was 0.8% by IDF definition. Obese children had significantly higher MetS prevalence compared with their counterparts with overweight (6.6% vs. 0.9%, p < 0.01) and normal weight (6.6% vs. 0.05%, p < 0.01). The prevalence of abdominal obesity, high triglycerides, low high density lipoprotein cholesterol, hypertension and high glucose among obese children was 93.4%, 16.5%, 14.3%, 7.3% and 4.0%, respectively, which significantly higher than those among overweight children (37.0%, 6.1%, 10.0%, 4.2%, and 3.3%, respectively) and among normal weight children (1.2%, 3.3%, 4.0%, 1.7% and 2.5%, respectively). The proportion of children with at least one, two, and three items of the metabolic abnormalities were 25.0%, 5.4% and 0.9%, respectively. Metabolic abnormalities were also present in children under 10 years of age. CONCLUSIONS: The early onset of MetS among children and relatively high proportions of children with at least one or two metabolic abnormalities in cities of China can increase the risk of developing MetS. It implies the necessity to take effective actions to control and prevent the rapid development of obesity among children in developing countries, especial those undergoing transition to a Western lifestyle. PMID- 22225618 TI - Antiviral activity of the EB peptide against zoonotic poxviruses. AB - BACKGROUND: The EB peptide is a 20-mer that was previously shown to have broad spectrum in vitro activity against several unrelated viruses, including highly pathogenic avian influenza, herpes simplex virus type I, and vaccinia, the prototypic orthopoxvirus. To expand on this work, we evaluated EB for in vitro activity against the zoonotic orthopoxviruses cowpox and monkeypox and for in vivo activity in mice against vaccinia and cowpox. FINDINGS: In yield reduction assays, EB had an EC50 of 26.7 MUM against cowpox and 4.4 MUM against monkeypox. The EC50 for plaque reduction was 26.3 MUM against cowpox and 48.6 MUM against monkeypox. A scrambled peptide had no inhibitory activity against either virus. EB inhibited cowpox in vitro by disrupting virus entry, as evidenced by a reduction of the release of virus cores into the cytoplasm. Monkeypox was also inhibited in vitro by EB, but at the attachment stage of infection. EB showed protective activity in mice infected intranasally with vaccinia when co administered with the virus, but had no effect when administered prophylactically one day prior to infection or therapeutically one day post-infection. EB had no in vivo activity against cowpox in mice. CONCLUSIONS: While EB did demonstrate some in vivo efficacy against vaccinia in mice, the limited conditions under which it was effective against vaccinia and lack of activity against cowpox suggest EB may be more useful for studying orthopoxvirus entry and attachment in vitro than as a therapeutic against orthopoxviruses in vivo. PMID- 22225619 TI - Caregiver causal attributions in youth psychosis. AB - AIM: Caregiver causal attributions influence patient and caregiver reactions to psychosis. The current study describes common caregiver causal attributions about psychosis onset in youth, including a subset of first-episode psychosis patients, and the patient and caregiver characteristics that influence these attributions. It also examines if caregiver views are affected by contact with youth mental health services. METHODS: Fifty-one caregivers of 50 youth patients with a diagnosed Diagnostic and statistical manual of mental disorders, fourth edition (DSM-IV) psychotic disorder were interviewed about their causal attributions. Patient and caregiver demographic and clinical predictors were also collected. RESULTS: Caregivers most highly endorsed substance use, genetics, negative peer influences and school stress as individual causes. These findings were consistent across the total sample. Principal components analysis derived three causal categories. Caregivers most frequently endorsed a biological and substance use lifestyle causal category, followed by psychological vulnerability and stress reactivity causal categories. There was evidence that caregiver and patient factors, as well as contact with youth mental health services, influenced the causal attributions caregivers made about the onset of psychosis. CONCLUSION: Caregivers of youth with psychosis are making causal attributions that are consistent with current aetiological theories of psychosis in youth. The study showed that caregivers are particularly cognizant of genetic and substance use factors in the development and maintenance of psychosis. However, youth mental health services may need to particularly focus on increasing caregiver understanding of the dynamics of stress factors as symptoms, and not causes, of psychosis early in the illness course. PMID- 22225621 TI - Good news regarding race and kidney transplant access in America. PMID- 22225620 TI - Safety, pharmacokinetics, and biologic activity of pateclizumab, a novel monoclonal antibody targeting lymphotoxin alpha: results of a phase I randomized, placebo-controlled trial. AB - INTRODUCTION: Pateclizumab (MLTA3698A) is a humanized mAb against lymphotoxin alpha (LTalpha), a transiently expressed cytokine on activated B and T cells (Th1, Th17), which are implicated in rheumatoid arthritis (RA) pathogenesis. This study was conducted to assess the safety, tolerability, < NOTE: For clarity and per AMA/S-W Style, please restore the use of Oxford/serial commas (ie: David likes vanilla, strawberry, and chocolate ice cream) throughout. and biologic activity of single and multiple doses of intravenous (IV) or subcutaneous (SC) pateclizumab in RA patients. METHODS: The single ascending dose (SAD) phase in patients with stable RA consisted of six cohorts (4:1 active:placebo at 0.3 mg/kg IV, 1.0 mg/kg IV, 1.0 mg/kg SC, 3.0 mg/kg IV, 3.0 mg/kg SC, and 5.0 mg/kg IV; n = 5/cohort). In the multiple ascending dose (MAD) phase, patients with prespecified RA disease activity received three doses of pateclizumab or placebo (4:1) every 2 weeks (1.0 mg/kg SC, n = 10; 3.0 mg/kg SC, n = 20; or 5.0 mg/kg IV, n = 5). Safety and tolerability were assessed throughout, and clinical activity was determined after three doses (Week 6). RESULTS: We observed no serious adverse events (AEs) or dose-limiting toxicities, and the majority of AEs were mild to moderate. The pharmacokinetic profiles were linear, and clearance was independent of dose. Reductions in levels of serum CXCL13 were observed, supporting the biologic activity of pateclizumab on the LTalpha pathway. Patients receiving pateclizumab in the 3.0 mg/kg MAD group (3.0 mg/kg SC) demonstrated ACR20, ACR50, and ACR70 response rates at week 6 of 75%, 56% and 25%, respectively, compared with 57%, 29%, and 0% in the placebo group. The median Disease Activity Score in 28 joints, C-reactive protein, reduction was 28% for pateclizumab, versus 8.4% for placebo. CONCLUSIONS: Pateclizumabwas generally well-tolerated in RA patients. Preliminary evidence of clinical activity was observed in active RA patients at the dose level targeted for clinical effect. PMID- 22225622 TI - Factors affecting sex ratio at birth in Croatia 1998-2008. AB - This investigation aims to contribute to the existing literature on demographic and ecological factors affecting the sex ratio at birth, by analysing the births in Croatia from 1998 to 2008. Data from birth certificates for all Croatian births for the investigated period (n=420,256) were used to establish the link between parental ages, birth order, region of birth, parental occupation and parental education level, and sex of the child. The chi2 test and t-test were used to assess the significance of each of the factors, along with multiple logistic regression to control for possible confounding effects. The results suggest that a joint higher age of both parents significantly lowers the sex ratio at birth. There is also a regional variation in sex ratio at birth, the lowest value being in Central Croatia and the highest in the City of Zagreb. Changes in the reproductive physiology of older parents are most probably responsible for the lower sex ratio, although the limited sample size warns against widespread generalizations. The causes of the regional variation in sex ratio at birth are most likely the different regional levels of obesity and physical inactivity. PMID- 22225623 TI - Abundance of microbial genes associated with nitrogen cycling as indices of biogeochemical process rates across a vegetation gradient in Alaska. AB - Nitrification and denitrification processes are crucial to plant nutrient availability, eutrophication and greenhouse gas production both locally and globally. Unravelling the major environmental predictors for nitrification and denitrification is thus pivotal in order to understand and model environmental nitrogen (N) cycling. Here, we sampled five plant community types characteristic of interior Alaska, including black spruce, bog birch, tussock grass and two fens. We assessed abundance of functional genes affiliated with nitrification (bacterial and archaeal amoA) and denitrification (nirK/S and nosZ) using qPCR, soil characteristics, potential nitrification and denitrification rates (PNR and PDR) and gross mineralization rates. The main chemical and biological predictors for PNR and PDR were assigned through path analysis. The potential N cycling rates varied dramatically between sites, from some of the highest (in fens) to some of the lowest (in black spruce) measured globally. Based on path analysis, functional gene abundances were the most important variables to predict potential rates. PNR was best explained by bacterial amoA gene abundance followed by ammonium content, whereas PDR was best explained directly by nosZ gene abundance and indirectly by nirK/S gene abundance and nitrate. Hence, functional gene abundance is a valuable index that integrates recent environmental history and recent process activity, and therefore is a good predictor of potential rates. The results of this study contribute to our understanding of the relative importance of different biological and chemical factors in driving the potential for nitrification and denitrification across terrestrial ecosystems. PMID- 22225624 TI - Comparison of women with confirmed versus presumably misdiagnosed bipolar disorder. AB - OBJECTIVE: Because bipolar disorder can be difficult to diagnose, we compared characteristics of women with confirmed versus presumably misdiagnosed bipolar disorder. METHOD: This cohort study was conducted from July 2005 to January 2010 in the outpatient clinic of the Emory Women's Mental Health Program, Atlanta, Georgia. Young adult women (mean age = 32 years) who were either pregnant or planning to conceive and who reported having previous clinical diagnoses of bipolar disorder completed 2 independent diagnostic assessments: the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) and an evaluation by a perinatal mood-disorder expert who was masked to the SCID findings. We compared clinical characteristics of women with confirmed versus presumably misdiagnosed bipolar disorder by bivariate testing followed by multivariate logistic regression modeling. RESULTS: Of 199 participants, 141 (70.9%) had confirmed DSM IV bipolar disorder on the basis of concordant assessments, 23 (11.6%) were considered misdiagnosed, and 35 (17.6%) who had discordant diagnostic assessments were excluded from further analysis. Multivariate modeling indicated that confirmed bipolar disorder was associated with a history of antidepressant associated mania/hypomania (OR = 13.30; 95% CI, 3.32-53.20; P = .0003), psychotic symptoms (OR = 12.40; 95% CI, 2.14-71.10; P = .005), and sustained euthymia during mood-stabilizer treatment (OR = 4.53; 95% CI, 1.32-15.60; P = .02); presumably misdiagnosed bipolar disorder was associated with childhood physical abuse (OR = 8.73; 95% CI, 2.33-32.70; P = .001) and comorbid obsessive-compulsive disorder (OR = 7.26; 95% CI, 1.86-28.30; P = .004). CONCLUSIONS: Several clinical factors found to distinguish women with confirmed versus presumably misdiagnosed bipolar disorder may help to refine clinical diagnosis. PMID- 22225625 TI - Monitoring melatonin and its isomer in Vitis vinifera cv. Malbec by UHPLC-MS/MS from grape to bottle. AB - Several studies have shown the presence of melatonin and related compounds in grapes and wines. The latter provides evidence of the possibility to enhance the nutraceutical properties of premium wines. However, there are many external factors that can influence the levels of this indolamine in grape and wines. In this study, the monitoring of melatonin and its tentatively identified isomer was carried out during the entire winemaking process in Vitis vinifera cv. Malbec by ultra high-performance liquid chromatography-tandem mass spectrometry. Laboratory and pilot studies were carried out to elucidate the role of grape, yeasts, and tryptophan in the evolution of the indolamines during the fermentation process. Melatonin was detected in grape extract within the range 120-160 ng/g while its isomer was found in musts and finished wines. Our results demonstrate that Saccaromyces cervisiae plays a decisive role in contributing to the content of melatonin and its isomer in wine. PMID- 22225627 TI - A cross-sectional survey of prevalence and correlates of suicidal ideation and suicide attempts among prisoners in New South Wales, Australia. AB - BACKGROUND: We aimed to estimate the prevalence of suicidal ideation and suicide attempt among prisoners in New South Wales, Australia; and, among prisoners reporting suicidal ideation, to identify factors associated with suicide attempt. METHODS: A cross-sectional design was used. Participants were a random, stratified sample of 996 inmates who completed a telephone survey. The estimated population prevalence of suicidal ideation and suicide attempt were calculated and differences by sex and Aboriginality were tested using chi2 tests. Correlates of suicidal ideation and suicide attempt were tested using logistic regression. RESULTS: One-third of inmates reported lifetime suicidal ideation and one-fifth had attempted suicide. Women and Aboriginal participants were significantly more likely than men and non-Aboriginal participants, respectively, to report attempting suicide. Correlates of suicidal ideation included violent offending, traumatic brain injury, depression, self-harm, and psychiatric hospitalisation. Univariate correlates of suicide attempt among ideators were childhood out-of home care, parental incarceration and psychiatric hospitalization; however, none of these remained significant in a multivariate model. CONCLUSIONS: Suicidal ideation and attempts are highly prevalent among prisoners compared to the general community. Assessment of suicide risk is a critical task for mental health clinicians in prisons. Attention should be given to ensuring assessments are gender- and culturally sensitive. Indicators of mental illness may not be accurate predictors of suicide attempt. Indicators of childhood trauma appear to be particularly relevant to risk of suicide attempt among prisoners and should be given attention as part of risk assessments. PMID- 22225626 TI - Dose-dependent functional benefit of human cardiosphere transplantation in mice with acute myocardial infarction. AB - Despite mounting pre-clinical and clinical evidence of the beneficial effects of cell-based therapy, optimal cell dosing and delivery approaches have not been identified. Cardiospheres are self-assembling three-dimensional (3D) microtissues formed by cardiac stem cells and supporting cell types. The ability of cardiospheres to augment cardiac function has been demonstrated in animal models of ischemic cardiomyopathy. In this study, we studied the dose dependence of the benefits of human cardiospheres, delivered via intramyocardial injection, upon cardiac function and ventricular remodelling in SCID mice with acute myocardial infarction. Four doses of cardiospheres were used: 1 * 10(4), 5 * 10(4), 1 * 10(5) and 5 * 10(5) (expressed as number of plated cardiosphere-forming cells). Acute (24 hr) cell retention rates in all groups were similar. Functional assessment and quantitative heart morphometry indicated benefit from higher cell doses (>=5 * 10(4)) in terms of ejection fraction, infarct size and capillary density. Histological analysis indicated that the dose-dependent benefit was primarily because of indirect effects of transplanted cells. The results provide scalable data on cardiosphere dosing for intramyocardial injection. PMID- 22225628 TI - Can a targeted psychological intervention be effective for young people following a first manic episode? Results from an 18-month pilot study. AB - AIM: There is a scarce literature describing psychological interventions for a young, first-episode cohort who have experienced psychotic mania. This study aimed to assess whether a manualized psychological intervention could be effective in reducing symptomatology and relapse, and improve functional outcome in this population. METHODS: The study was an open-label design, drawn from a larger pharmacotherapy trial. All participants in the pharmacotherapy trial were offered a manualized psychological intervention in addition to case management. Inclusion in the psychotherapy group was based on participant's choice, and on completion of four or more of the eight modules offered. All clinical files were audited to ensure accuracy of group allocation. Forty young people aged 15 to 25 years old who had experienced a manic episode with psychotic features were recruited into the study, with 20 people in the combined treatment as usual plus psychotherapy group (P+TAU), and an equal number of matched control participants who received treatment as usual (TAU) within the same service. All participants were prescribed antipsychotic and mood-stabilizing medication. Symptomatic, functional and relapse measures were taken both at baseline and at 18-month follow-up. RESULTS: Manic symptoms improved significantly for both groups, with no differences between groups. Depression scores and overall symptom severity were significantly lower in the P + TAU group. No differences were evident between groups with regard to numbers or type of relapse. The P + TAU group had significantly better social and occupational functioning after 18 months. CONCLUSION: This study suggests that a manualized psychological intervention targeted to a first-episode population can be effective in reducing depression and overall symptom severity, and can improve functional outcome following a first episode of psychotic mania. PMID- 22225629 TI - Further evidence for a male-selective genetic association of synapse-associated protein 97 (SAP97) gene with schizophrenia. AB - BACKGROUND: The synapse-associated protein 97 gene (SAP97) encodes a regulatory scaffold protein for the localization of L-alpha-amino-3-hydroxy-5-methyl-4 isoxazole propionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) type glutamate receptors. We have recently demonstrated nominally significant associations between SAP97 gene and schizophrenia among Japanese males. The present study aimed to replicate these findings using an independent and larger sample. METHODS: We investigated seven SAP97 single nucleotide polymorphisms (SNPs) that displayed a significant association with schizophrenia in our preceding study in an independent Japanese population consisting of a total of 393 unrelated patients with schizophrenia (232 males and 161 females) and 393 unrelated control subjects (211 males and 182 females). RESULTS: The SNP rs9843659 showed a significant genotypic association with male patients in a recessive model (p = 0.037). The analysis of the combined data from the current and prior studies also demonstrated a significant association of this SNP (p = 0.0039). The meta-analysis for the allele frequency covering the two studies yielded an odds ratio of 1.38. CONCLUSIONS: The present study replicated the previously reported male-selective genetic association between the SAP97 polymorphism and schizophrenia. These findings further support the possible involvement of the SAP97 gene variation in the susceptibility to schizophrenia in males and in the genetic basis for sex differences in the disorder. PMID- 22225631 TI - Apolipoprotein E influences melatonin biosynthesis by regulating NAT and MAOA expression in C6 cells. AB - Previous studies have demonstrated that apolipoprotein E (ApoE) genotype and melatonin are closely associated with Alzheimer's disease (AD). However, the relationship between ApoE genotype and melatonin remains unclear. Recently, we reported that cultured rat cortical astrocytes and glioma C6 cells synthesize melatonin. In the current study, we investigated the effect of ApoE genotype on melatonin biosynthesis. C6 cells with stable expression of ApoE isoforms (ApoE 2, 3 and 4) were established. A higher level of melatonin was demonstrated in cultured ApoE4-C6 cells than that in ApoE3-C6 cells. In addition, we found that N acetyltransferase (NAT) protein level was up-regulated in ApoE4-C6 cells compared with ApoE3-C6 cells. Further study suggested that mRNA expression of monoamine oxidase A (MAOA) and monoamine oxidase B (MAOB) decreased in ApoE4-C6 cells. In conclusion, the increased melatonin level in ApoE4-C6 cells results from up regulation of NAT expression, a key enzyme for melatonin synthesis, and down regulation of MAOA and MAOB expression, the metabolic enzyme for its precursor serotonin. PMID- 22225630 TI - Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4. AB - INTRODUCTION: Osteoarthritis (OA) is a degenerative disease characterized by cartilage breakdown in the synovial joints. The presence of low-grade inflammation in OA joints is receiving increasing attention, with synovitis shown to be present even in the early stages of the disease. How the synovial inflammation arises is unclear, but proteins in the synovial fluid of affected joints could conceivably contribute. We therefore surveyed the proteins present in OA synovial fluid and assessed their immunostimulatory properties. METHODS: We used mass spectrometry to survey the proteins present in the synovial fluid of patients with knee OA. We used a multiplex bead-based immunoassay to measure levels of inflammatory cytokines in serum and synovial fluid from patients with knee OA and from patients with rheumatoid arthritis (RA), as well as in sera from healthy individuals. Significant differences in cytokine levels between groups were determined by significance analysis of microarrays, and relations were determined by unsupervised hierarchic clustering. To assess the immunostimulatory properties of a subset of the identified proteins, we tested the proteins' ability to induce the production of inflammatory cytokines by macrophages. For proteins found to be stimulatory, the macrophage stimulation assays were repeated by using Toll-like receptor 4 (TLR4)-deficient macrophages. RESULTS: We identified 108 proteins in OA synovial fluid, including plasma proteins, serine protease inhibitors, proteins indicative of cartilage turnover, and proteins involved in inflammation and immunity. Multiplex cytokine analysis revealed that levels of several inflammatory cytokines were significantly higher in OA sera than in normal sera, and levels of inflammatory cytokines in synovial fluid and serum were, as expected, higher in RA samples than in OA samples. As much as 36% of the proteins identified in OA synovial fluid were plasma proteins. Testing a subset of these plasma proteins in macrophage stimulation assays, we found that Gc-globulin, alpha1-microglobulin, and alpha2-macroglobulin can signal via TLR4 to induce macrophage production of inflammatory cytokines implicated in OA. CONCLUSIONS: Our findings suggest that plasma proteins present in OA synovial fluid, whether through exudation from plasma or production by synovial tissues, could contribute to low-grade inflammation in OA by functioning as so-called damage-associated molecular patterns in the synovial joint. PMID- 22225632 TI - The polyhydroxyalkanoate metabolism controls carbon and energy spillage in Pseudomonas putida. AB - The synthesis and degradation of polyhydroxyalkanoates (PHAs), the storage polymer of many bacteria, is linked to the operation of central carbon metabolism. To rationalize the impact of PHA accumulation on central carbon metabolism of the prototype bacterium Pseudomonas putida, we have revisited PHA production in quantitative physiology experiments in the wild-type strain vs. a PHA negative mutant growing under low nitrogen conditions. When octanoic acid was used as PHA precursor and as carbon and energy source, we have detected higher intracellular flux via acetyl-CoA in the mutant strain than in the wild type, which correlates with the stimulation of the TCA cycle and glyoxylate shunt observed on the transcriptional level. The mutant defective in carbon and energy storage spills the additional resources, releasing CO(2) instead of generating biomass. Hence, P. putida operates the metabolic network to optimally exploit available resources and channels excess carbon and energy to storage via PHA, without compromising growth. These findings demonstrate that the PHA metabolism plays a critical role in synchronizing global metabolism to availability of resources in PHA-producing microorganisms. PMID- 22225633 TI - Design and synthesis of boronic acid inhibitors of endothelial lipase. AB - Endothelial lipase (EL) and lipoprotein lipase (LPL) are homologous lipases that act on plasma lipoproteins. EL is predominantly a phospholipase and appears to be a key regulator of plasma HDL-C. LPL is mainly a triglyceride lipase regulating (V)LDL levels. The existing biological data indicate that inhibitors selective for EL over LPL should have anti-atherogenic activity, mainly through increasing plasma HDL-C levels. We report here the synthesis of alkyl, aryl, or acyl substituted phenylboronic acids that inhibit EL. Many of the inhibitors evaluated proved to be nearly equally potent against both EL and LPL, but several exhibited moderate to good selectivity for EL. PMID- 22225634 TI - Cinobufacini induced MDA-MB-231 cell apoptosis-associated cell cycle arrest and cytoskeleton function. AB - Cinobufacini is a traditional Chinese anti-tumor drug and widely used in clinic experiences. But little is known about its effect on the cells. In this study, the effects of cinobufacini on breast cancer MDA-MB-231 cell were evaluated by CCK-8 assay, and the data showed cinobufacini could inhibit the MDA-MB-231 cells growth effectively in dose-dependent and time-dependent manners. Cell apoptosis and cell cycle were detected by flow cytometry analysis. After the cells being treated with 50 MUg/mL cinobufacini for 48 h, the early apoptosis percentage (20.45 +/- 1.46%) is much higher than the normal group (7.73 +/- 1.21%). The cell cycle data indicated that cinobufacini caused a cell cycle arrest at S phase. What's more, cinobufacini can affect the disruption of cytoskeleton, and these alterations changed the cell-surface ultrastructure and the cell morphology which were detected by atomic force microscopy (AFM) at nanoscale level. It indicated that the cell membrane structure and cytoskeleton networks were destroyed and the cell tails were narrowed after the cell being treated with cinobufacini. The present study is to provide valuable new insights to understand the mechanism of the drug in anti-tumor process. Furthermore, the knowledge concerning the signaling of cell cycle is potentially important to clinical utility. PMID- 22225635 TI - Synthesis and biological evaluation of benzo[d]imidazole derivatives as potential anti-cancer agents. AB - We herein report the synthesis, biological activity and structure-activity relationship of derivatives of 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole and benzo[d]imidazole. A lead compound 6o demonstrates potent anti-proliferative activity and the ability to induce cancer cell apoptosis. PMID- 22225636 TI - The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a beta secretase inhibitor. AB - (2)-Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. A number of studies have demonstrated EGCG has the possibility for delaying the onset or retarding the progression of Alzheimer's disease (AD) and indicated EGCG possess inhibition of beta-secretase activity. We utilized homogeneous time resolved fluorescence assay with a substrate Eu-CEVNLDAEFK-Qsy7 to screen beta secretase inhibitor in a cell-free system and AlphaLISA assay in cell system. The results first showed that EGCG had significant inhibition of beta-secretase activity with IC(50) value of 7.57 * 10(-7)M in screening assay, but then we found EGCG had significant fluorescence-quenching effect in confirming assay, this indicates EGCG has the false positive beta-secretase inhibitory activity. Furthermore, the followed AlphaLISA assay based on cell showed EGCG did not reduce the beta-amyloid 1-40 secretion in HuAPPswe/HuBACE1 Chinese hamster ovary cell without affecting cell viability. Therefore our findings indicate EGCG do not inhibit beta-secretase cleavage activity. Overall this study illustrates that EGCG is not a beta-secretase inhibitor based on the compelling data. This provides further support that the choice of complementary assay format or technology is a critical factor in molecular screening and drug development for improving the hit-finding capability and efficiency. PMID- 22225637 TI - New bisabolane sesquiterpenoids from a marine-derived fungus Aspergillus sp. isolated from the sponge Xestospongia testudinaria. AB - Three new phenolic bisabolane sesquiterpenoid dimers, disydonols A-C (1-3), and one known compound (S)-(+)-sydonol (4) were isolated from the fermentation broth of a marine-derived fungus Aspergillus sp., which was isolated from the sponge Xestospongia testudinaria collected from the South China Sea. Their structures were elucidated on the basis of comprehensive spectral analysis including 1D and 2D NMR spectra and HR-ESI-MS. These compounds were evaluated for cytotoxic activity against HepG-2 and Caski human tumour cell lines. Among them, compounds 1 and 3 exhibited cytotoxicity against the two cell lines. PMID- 22225638 TI - A scaffold hopping approach to identify novel monoamine oxidase B inhibitors. AB - Monoamine oxidase B (MAO-B) inhibitors are used to treat Parkinson's disease. In this study, we searched for novel MAO-B inhibitors using a scaffold hopping approach based on our experience with the thiazolidinedione (TZD) class of compounds as MAO-B inhibitors. Several novel compounds were identified, with potencies in the low nanomolar and low micromolar range. We also found that derivatives of the natural product sulfuretin are potent MAO-A and MAO-B inhibitors. PMID- 22225639 TI - Synthesis of 3-phenylsulfonylmethyl cyclohexylaminobenzamide-derived antagonists of CC chemokine receptor 2 (CCR2). AB - We report the synthesis of 3-phenylsulfonylmethyl cyclohexylaminobenzamides (4) as CCR2 inhibitors for the potential treatment of inflammatory diseases. Several of the compounds display nanomolar binding affinity for CCR2. The in vitro structure-activity relationships of 4 are described, and are also reconciled with those from the related 2-phenylsulfonylmethyl series. PMID- 22225640 TI - Development of an efficient method for phosphorodiamidate bond formation by using inorganic salts. AB - Phosphorodiamidate morpholino oligonucleotides (PMOs) have been extensively applied in antisense strategies for gene regulation because of their high stability in serum and low toxicity. However, chain elongation of PMOs requires long reaction time because few efficient methods have been developed for the formation of phosphorodiamidate bonds. In this Letter, we examined the effect of various additives to improve the reaction efficiency for formation of the phosphorodiamidate bond in the synthesis of PMOs. The addition of certain inorganic salts to the reaction media was found to be more effective. Particularly, lithium bromide was the most effective reagent and led to considerable acceleration (ca. 10-fold improvement). PMID- 22225641 TI - Substituents at the naphthalene C3 position of (-)-Cercosporamide derivatives significantly affect the maximal efficacy as PPARgamma partial agonists. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a potential drug target for treating type 2 diabetes. The selective PPARgamma modulators (SPPARMs), which partially activate the PPARgamma transcriptional activity, are considered to improve the plasma glucose level with attenuated PPARgamma related adverse effects. However, the relationships between desired pharmacological profiles and ligand specific PPARgamma transcriptional profiles have been unclear. And there is also little knowledge of how to control ligand specific PPARgamma transcriptional profiles. Herein, we present synthesis of novel derivatives containing substituent at naphthalene C3 position of compound 1. The novel derivatives showed various maximal efficacies as PPARgamma partial agonist. PMID- 22225642 TI - Mechanistic studies on the flavin:NADH reductase (PrnF) from Pseudomonas fluorescens involved in arylamine oxygenation. AB - We report the mechanistic studies of a FAD:NADH reductase (PrnF) involved in arylamine oxygenation. PrnF catalyzes the reduction of FAD via a sequential ordered bi-bi mechanism with NADH as the first substrate to bind and FADH(2) as the first product to be released. The residues Asp145 and His146 are proposed as catalytic acid/base residues for PrnF based on pH profile and molecular dynamics simulation studies. These studies provide the first detailed account of the mechanism of the flavin reductase involved in arylamine oxygenation. PMID- 22225644 TI - Lymph node staging in colorectal cancer: revisiting the benchmark of at least 12 lymph nodes in R0 resection. PMID- 22225643 TI - Community-based educational intervention to limit the dissemination of community associated methicillin-resistant Staphylococcus aureus in Northern Saskatchewan, Canada. AB - BACKGROUND: Surveillance examining the incidence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) was conducted over 8 years beginning in 2001 in three health regions covering the northern half of Saskatchewan. The annual rate of individuals reported with CA-MRSA infection in these regions dramatically increased from 8.2 per 10,000 population in 2001 (range to 4.4-10.1 per 10,000) to 168.1 per 10,000 in 2006 (range 43.4-230.9 per 10,000). To address this issue, a team of community members, healthcare professionals, educators and research scientists formed a team called "the Northern Antibiotic Resistance Partnership" (NARP) to develop physician, patient, community, and school based educational materials in an attempt to limit the spread of CA-MRSA. METHODS: Posters, radio broadcasts, community slide presentations, physician treatment algorithms, patient pamphlets, and school educational programs Do Bugs Need Drugs http://www.dobugsneeddrugs.org and Germs Away http://www.germsaway.ca were provided to targeted northern communities experiencing high rates of infections. RESULTS: Following implementation of this program, the rates of MRSA infections in the targeted communities have decreased nearly two-fold (242.8 to 129.3 infections/10,000 population) from 2006 to 2008. Through pre-and post-educational intervention surveys, this decrease in MRSA infections coincided with an increase in knowledge related to appropriate antimicrobial usage and hand washing in these communities. CONCLUSION: These educational materials are all freely available http://www.narp.ca and will hopefully aid in increasing awareness of the importance of proper antimicrobial usage and hygiene in diminishing the spread of S. aureus and other infectious diseases in other communities. PMID- 22225645 TI - Nanoparticle migration and delivery of Paclitaxel to regional lymph nodes in a large animal model. AB - BACKGROUND: The aim of this study was to demonstrate feasibility of migration and in situ chemotherapy delivery to regional lymph nodes (LN) in a large animal model using an expansile polymer nanoparticle (eNP) delivery system. STUDY DESIGN: Dual-labeled 50-nm and 100-nm eNP were prepared by encapsulating an IR 813 near-infrared (NIR) fluorescent dye within coumarin-conjugated expansile polymer nanoparticles (NIR-C-eNP). NIR imaging and fluorescent microscopy were used to identify intralymphatic migration of NIR-nanoparticles to draining inguinal or mesenteric LN after injection in swine hind legs or intestine. Nanoparticle-mediated intranodal delivery of chemotherapy was subsequently assessed with Oregon Green paclitaxel-loaded NIR-eNP (NIR-OGpax-eNP). RESULTS: NIR imaging demonstrated direct lymphatic migration of 50-nm, but not 100-nm, NIR C-eNP and NIR-OGpax-eNP to the draining regional LNs after intradermal injection in the hind leg or subserosal injection in intestine. Fluorescent microscopy demonstrated that IR-813 used for NIR real-time trafficking colocalized with both the coumarin-labeled polymer and paclitaxel chemotherapy and was identified within the subcapsular spaces of the draining LNs. These studies verify nodal migration of both nanoparticle and encapsulated payload, and confirm the feasibility of focusing chemotherapy delivery directly to regional nodes. CONCLUSIONS: Regionally-targeted intranodal chemotherapy can be delivered to draining LNs for both skin and solid organs using 50-nm paclitaxel-loaded eNP. PMID- 22225646 TI - Improving access to care: breast surgeons, the gatekeepers to breast reconstruction. AB - BACKGROUND: Fewer than half of patients undergo reconstruction after breast cancer treatment, despite its quality of life benefits. Earlier studies demonstrated that most general surgeons do not discuss reconstructive options with patients. The aim of this study was to examine the likelihood of reconstruction within a cohort of mastectomy patients and compare rates of reconstruction between those referred and not referred for plastic surgery evaluation. STUDY DESIGN: Retrospective review of the records of 471 consecutive patients between the ages of 19 and 94 years who underwent mastectomy between 2003 and 2007. Variables evaluated were age, body mass index, diabetes, laterality (unilateral vs bilateral), TNM staging, history of radiation, smoking history, insurance type, and race. RESULTS: Of 471 patients, 313 were referred for consultation with a plastic surgeon and 158 were not; 91.7% of those referred were reconstructed and 100% of those not referred were not reconstructed. The 2 groups differed considerably in terms of age (mean age 61.84 years in the nonreferred group vs 51.83 years in the referred group), body mass index (25.9 in referred group, 27 in nonreferred group), diabetes (15% in nonreferred group vs 3.5% in referred group), and laterality (14% of nonreferred group underwent bilateral mastectomies vs 26% of those referred). The groups did not differ significantly in terms of race or tobacco use. Those with private insurance were more likely to be reconstructed, but no independent effect of insurance type was seen on multivariate analysis. CONCLUSIONS: The breast surgeon's decision to refer a patient for reconstruction significantly affects whether the patient will receive breast reconstruction. Factors that appear to influence the referral decision are age, diabetes, body mass index, and laterality of mastectomy (bilateral more than unilateral). PMID- 22225647 TI - An online spaced-education game to teach and assess residents: a multi institutional prospective trial. AB - BACKGROUND: While games are frequently used in resident education, there is little evidence supporting their efficacy. We investigated whether a spaced education (SE) game can be both a reliable and valid method of assessing residents' knowledge and an effective means of teaching core content. STUDY DESIGN: The SE game consisted of 100 validated multiple-choice questions and explanations on core urology content. Residents were sent 2 questions each day via email. Adaptive game mechanics re-sent the questions in 2 or 6 weeks if answered incorrectly and correctly, respectively. Questions expired if not answered on time (appointment dynamic). Residents retired questions by answering each correctly twice in a row (progression dynamic). Competition was fostered by posting relative performance among residents. Main outcomes measures were baseline scores (percentage of questions answered correctly on initial presentation) and completion scores (percentage of questions retired). RESULTS: Nine hundred thirty-one US and Canadian residents enrolled in the 45-week trial. Cronbach alpha reliability for the SE baseline scores was 0.87. Baseline scores (median 62%, interquartile range [IQR] 17%) correlated with scores on the 2008 American Urological Association in-service examination (ISE08), 2009 American Board of Urology qualifying examination (QE09), and ISE09 (r = 0.76, 0.46, and 0.64, respectively; all p < 0.001). Baseline scores varied by sex, country, medical degree, and year of training (all p <= 0.001). Completion scores (median 100%, IQR 2%) correlated with ISE08 and ISE09 scores (r = 0.35, p < 0.001 for both). Seventy-two percent of enrollees (667 of 931) requested to participate in future SE games. CONCLUSIONS: An SE game is a reliable and valid means to assess residents' knowledge and is a well-accepted method by which residents can master core content. PMID- 22225648 TI - Long-term impact of liver transplantation on respiratory function and nutritional status in children and adults with cystic fibrosis. AB - Early liver transplant (LT) has been advocated for patients with cystic fibrosis liver disease (CFLD) and evidence of deterioration in nutritional state and respiratory function to prevent further decline. However, the impact of single LT on long-term respiratory function and nutritional status has not been adequately addressed. We performed a retrospective analysis of the outcomes of 40 (21 adult/19 pediatric) patients with CFLD transplanted between 1987 and 2009 with median follow-up of 47.8 months (range 4-180). One and five-year actuarial survival rates were 85%/64% for adult and 90%/85% for pediatric LT cohorts, respectively. Lung function remained stable until 4 years (FEV(1) % predicted; pretransplant 48.4% vs. 45.9%, 4 years posttransplant) but declined by 5 years (42.4%). Up to 4 years posttransplant mean annual decline in FEV(1) % was lower (0.74%; p = 0.04) compared with the predicted 3% annual decline in CF patients with comorbidity including diabetes. Number of courses of intravenous antibiotics was reduced following LT, from 3.9/year pretransplant to 1.1/year, 5 years posttransplant. Body mass index was preserved posttransplant; 18.0 kg/m(2) (range 15-24.3) pretransplant versus 19.6 kg/m(2) (range 16.4-22.7) 5 years posttransplant. In conclusion, LT is an effective treatment for selected patients with cirrhosis due to CFLD, stabilizing aspects of long-term lung function and preserving nutritional status. PMID- 22225650 TI - Unmasking of presynaptic cutaneous HFOs burst by DBS lead recordings. PMID- 22225649 TI - MicroRNA control of myelopoiesis and the differentiation block in acute myeloid leukaemia. AB - In the relatively short period of time since their discovery, microRNAs have been shown to control many important cellular functions such as cell differentiation, growth, proliferation and apoptosis. In addition, microRNAs have been demonstrated as key drivers of many malignancies and can function as either tumour suppressors or oncogenes. The haematopoietic system is not outside the realm of microRNA control with microRNAs controlling aspects of stem cell and progenitor self-renewal and differentiation, with many, if not all, haematological disorders associated with aberrant microRNA expression and function. In this review, we focus on the current understanding of microRNA control of haematopoiesis and detail the evidence for the contribution and clinical relevance of aberrant microRNA function to the characteristic block of differentiation in acute myeloid leukaemia. PMID- 22225651 TI - Semiautomatic quantification of spiking in patients with continuous spikes and waves in sleep: sensitivity to settings and correspondence to visual assessment. AB - OBJECTIVE: To define the optimal analysis protocol for semiautomatic quantification of spike index (SI) in continuous spikes and waves in sleep (CSWS). METHODS: Ten overnight EEGs (nine patients) with abundant spiking were used to quantify SI with a previously published semiautomatic quantification based on spike detection with BESA software. We studied (i) dependency of SI on maximal interspike interval (maxISI) defining the continuous discharge, (ii) sensitivity of SI to variations in the spike search protocol, and (iii) stability of SI over time. Finally, the semiautomatic method was compared with the quantification based on visual scoring by two neurophysiologists. RESULTS: MaxISI of 3s appeared to yield the best combination of sensitivity and stability in SI quantification. The SI of the first hour of sleep did not differ significantly from the SI of the whole night. Mean error of the semiautomatic method compared to visual scoring was only seven percentage units. CONCLUSIONS: Semiautomatic quantification of SI functions well with maxISI of 3s, and the first hour of sleep represents the whole night SI with a clinically relevant accuracy. SIGNIFICANCE: This method opens a possibility for objective quantification of near-continuous epileptiform spiking during sleep, and it supports the use of shorter epochs for quantitative assessment of CSWS. PMID- 22225652 TI - Breast cancer risk factors in Queensland women attending population-based mammography screening. AB - OBJECTIVE: To investigate the prevalence of established modifiable and non modifiable risk factors associated with breast cancer in Queensland (Australia) women. STUDY DESIGN: Cross-sectional prevalence study of 9792 women (58% of women sent the questionnaire) attending BreastScreen Queensland Screening and Assessment Services between November 2008 and February 2009. Prevalence and 95% confidence intervals were calculated for each risk factor, stratified by age group (45-49 years, 50-59 years, 60-69 years, >=70 years). MAIN OUTCOME MEASURES: First-degree family history (FH) of breast cancer (mother, sister, daughter), reproductive history, behavioural factors, co-morbidities, use of hormone replacement therapy (HRT) and alternatives, and socio-demographic factors. RESULTS: The prevalence of first-degree FH of breast cancer was 16% and a previous diagnosis of breast cancer was 3.5%; both are considered major risk factors for breast cancer. The prevalence of modifiable breast cancer risk factors of moderate risk were: current HRT use (12%), HRT use within the past 5 years (7%), overweight [body mass index 25-29] (33%) or obesity [BMI>30] (27%), alcohol consumption [>=11 drinks/week] (10%), sedentary behaviour (70%), and low fruit (34%) and vegetable consumption (69%). These risk factors tended to be higher in younger women (45-49 years) compared to older women (>50 years). CONCLUSION: Prevalence of risk factors in Queensland women were largely consistent with other Australian and international studies. Hormone therapy use is lower than previously reported estimates in Australia and internationally. The comparatively high prevalence of modifiable lifestyle factors which have been shown to be moderately associated with breast cancer are potential targets for reducing the public health burden of breast cancer. PMID- 22225653 TI - Escape-echo bigeminy. AB - Escape-capture bigeminy is a well-known arrhythmia characterized by group beating of a junctional beat followed by a conducted sinus beat. We report a variant of this arrangement where a junctional beat gives rise to a retrograde P wave, which is then conducted back to the ventricles producing a hitherto undescribed combination (escape-echo bigeminy) resembling escape-capture bigeminy. The clinical significance of escape-echo bigeminy appears similar to that of classic escape-capture bigeminy. PMID- 22225655 TI - North Korea--who will help? PMID- 22225654 TI - Translational research and experimental medicine in 2012. PMID- 22225656 TI - Addiction--a global problem with no global solution. PMID- 22225658 TI - Louisa Degenhardt: hooked on addiction research. PMID- 22225659 TI - An open letter to Michael Ball, Chief Executive of Hospira Pharmaceuticals. PMID- 22225660 TI - The new decade of vaccines. PMID- 22225662 TI - The new decade of vaccines. PMID- 22225664 TI - Global burden of disease in young people aged 10-24 years. PMID- 22225665 TI - The new decade of vaccines. PMID- 22225667 TI - Misleading information concerning the University of Helsinki. PMID- 22225668 TI - The NHS IT project: more than just a bad dream. PMID- 22225669 TI - Global burden of disease in young people aged 10-24 years. PMID- 22225670 TI - The unobtainable placebo: control of independent clinical research by industry? PMID- 22225671 TI - Extent of illicit drug use and dependence, and their contribution to the global burden of disease. AB - This paper summarises data for the prevalence, correlates, and probable adverse health consequences of problem use of amphetamines, cannabis, cocaine, and opioids. We discuss findings from systematic reviews of the prevalence of illicit drug use and dependence, remission from dependence, and mortality in illicit drug users, and evidence for acute and chronic effects of illicit drug use. We outline the regional and global distribution of use and estimated health burden from illicit drugs. These distributions are likely to be underestimates because they have not included all adverse outcomes of drug use and exclude those of cannabis- the mostly widely used illicit drug. In high-income countries, illicit drug use contributes less to the burden of disease than does tobacco but a substantial proportion of that due to alcohol. The major adverse health effects of cannabis use are dependence and probably psychotic disorders and other mental disorders. The health-related harms of cannabis use differ from those of amphetamine, cocaine, and opioid use, in that cannabis contributes little to mortality. Intelligent policy responses to drug problems need better data for the prevalence of different types of illicit drug use and the harms that their use causes globally. This need is especially urgent in high-income countries with substantial rates of illicit drug use and in low-income and middle-income countries close to illicit drug production areas. PMID- 22225672 TI - Drug policy and the public good: evidence for effective interventions. AB - Debates about which policy initiatives can prevent or reduce the damage that illicit drugs cause to the public good are rarely informed by scientific evidence. Fortunately, evidence-based interventions are increasingly being identified that are capable of making drugs less available, reducing violence in drug markets, lessening misuse of legal pharmaceuticals, preventing drug use initiation in young people, and reducing drug use and its consequences in established drug users. We review relevant evidence and outline the likely effects of fuller implementation of existing interventions. The reasoning behind the final decisions for action might be of a non-scientific nature, focused more on what the public and policy-makers deem of value. Nevertheless, important opportunities exist for science to inform these deliberations and guide the selection of policies that maximise the public good. PMID- 22225673 TI - How well do international drug conventions protect public health? AB - The Single Convention on Narcotic Drugs in 1961 aimed to eliminate the illicit production and non-medical use of cannabis, cocaine, and opioids, an aim later extended to many pharmaceutical drugs. Over the past 50 years international drug treaties have neither prevented the globalisation of the illicit production and non-medical use of these drugs, nor, outside of developed countries, made these drugs adequately available for medical use. The system has also arguably worsened the human health and wellbeing of drug users by increasing the number of drug users imprisoned, discouraging effective countermeasures to the spread of HIV by injecting drug users, and creating an environment conducive to the violation of drug users' human rights. The international system has belatedly accepted measures to reduce the harm from injecting drug use, but national attempts to reduce penalties for drug use while complying with the treaties have often increased the number of drug users involved with the criminal justice system. The international treaties have also constrained national policy experimentation because they require nation states to criminalise drug use. The adoption of national policies that are more aligned with the risks of different drugs and the effectiveness of controls will require the amendment of existing treaties, the formulation of new treaties, or withdrawal of states from existing treaties and re-accession with reservations. PMID- 22225674 TI - 'Animal-type' melanoma of the scalp with satellitosis and positive sentinel nodes in a 4-year-old child: case report and review of the literature. AB - BACKGROUND: Although showing a rapidly rising incidence, paediatric melanoma is relatively rare, accounting for 1-4% of all cases of melanoma and for 1-3% of all paediatric malignancies. The overall survival rate in paediatric patients seems to be similar to that recorded in adults. 'Animal-type' melanoma (ATM) is a rare melanoma subtype, occurring both in childhood and in adults, that shows a close histological resemblance to the heavily pigmented melanocytic tumours observed in grey and white horses. CASE PRESENTATION: We present a case of ATM of the scalp with satellitosis and two positive sentinel nodes in a 4-year-old male child. No other tumour deposits were found in the subsequent regional lymphadenectomy; the patient has been tumour free for 30 months. CONCLUSIONS: We treated our case of ATM in a child as the other types of paediatric melanoma, therefore as an adult melanoma. ATM is generally considered a neoplasm with an indolent course, that occasionally shows an aggressive behaviour, and patient deaths of ATM have been reported. Due to the rarity of ATM, further studies are needed to better define the biological behaviour of this particular melanoma subtype and the therapeutic and follow-up strategies. PMID- 22225675 TI - Effectiveness of type A botulinum toxins for aesthetic indications and their relative economic impact. AB - BACKGROUND: It is accepted that the three commercially available type A botulinum toxins (BoNT-As) are different, their units of potency are not interchangeable and no fixed dose conversion ratio exists between them. To date, there is no clear evidence demonstrating the superiority of one toxin over another clinically. OBJECTIVE: The study aims to identify evidence confirming the equivocal efficacy of the formulations and to justify that attention can therefore be reasonably turned to their differing costs as a means of aiding choice of treatment. This is achieved via the development of the cost calculator presented herein, to enable direct economic comparisons to be made between the three commercially available BoNT-A formulations licensed for aesthetic indications in the UK. METHODS: An online literature search using PubMed was undertaken and the latest available information on the cost for each BoNT-A treatment was accessed via the British National Formulary (BNF). Predicated on the evidence review, a cost calculator was developed which takes into account for the glabella: the number of treatments needed per patient with each product over a year and the number of treatments available with differing dilutions of each vial of each product over a year. A range of cost prices can also be introduced allowing a direct cost-comparison to be made for treating the glabella of a set number of patients over a year between different products. RESULTS: Azzalure((r)) (abobotulinumtoxinA) was the most cost-effective in almost all scenarios tested, whilst Vistabel((r)) (onabotulinumtoxinA) was the least cost-effective. Of the two products with published non-inferiority with respect to each other, onabotulinumtoxinA and Bocouture((r)) (incobotulinumtoxinA), incobotulinumtoxinA offered a lower overall cost to treat the glabella of the same number of patients when compared with Vistabel. CONCLUSION: In most scenarios, BoNT-A treatment with abobotulinumtoxinA will result in significant annual cost savings when compared with treatment with onabotulinumtoxinA or incobotulinumtoxinA. PMID- 22225676 TI - Variants within the GABA transaminase (ABAT) gene region are associated with somatosensory evoked EEG potentials in families at high risk for affective disorders. AB - BACKGROUND: Depression frequently co-occurs with somatization, and somatic complaints have been reported as a vulnerability marker for affective disorders observable before disease onset. Somatization is thought to result from an increased attention to somatic sensations, which should be reflected in long latency somatosensory evoked electroencephalogram (EEG) potentials (SSEPs) at the physiological level. Previous studies revealed that SSEPs are altered in depressed patients and suggested late SSEP components as vulnerability markers for affective disorders. Neurotransmitters such as serotonin, gamma-aminobutyric acid (GABA) and the neuropeptide substance P may play an important role for both affective disorders and somatosensory processing. Method We investigated the associations between SSEPs and polymorphisms within candidate genes of the serotonergic, GABAergic as well as the substance P system in subjects at high risk for affective disorders. The sample was composed of high-risk families participating in the Munich Vulnerability Study and genetic association analyses were calculated using qfam (family-based association tests for quantitative traits) implemented in PLINK 1.05. RESULTS: We observed significant associations (false discovery rate <0.05) withstanding correction for multiple testing between late SSEP components (response strength 170-370 ms after stimulation) and four single nucleotide polymorphisms within the GABA transaminase (ABAT) gene region coding for a protein responsible for GABA degradation. No effects were found with the classical disease trait approach, suggesting SSEP marker specificity of the observed associations. CONCLUSIONS: Our findings point to a possible role of ABAT gene-regulated GABA catabolism for an altered processing of somatosensory stimuli as a potential vulnerability marker for affective disorders. PMID- 22225677 TI - Suicidal risk factors in bipolar I and II disorder patients. AB - BACKGROUND: Suicidal risks may be similar in bipolar I and II disorders, but predictive risk factors are not well established for each disorder type or across cultures. METHOD: Accordingly, we compared selected demographic and clinical factors for long-term association with nonlethal suicidal acts or ideation in 290 DSM-IV bipolar I (n = 204) and II (n = 86) disorder patients followed for a mean of 9.3 years at the University of Barcelona, using preliminary bivariate comparisons followed by multivariate logistic regression modeling. RESULTS: Rates of suicidal ideation (41.5%) and acts (19.7%) were similarly prevalent with bipolar I and II disorders and somewhat more common among women. Factors significantly and independently associated with suicidal acts were determined by multivariate modeling and ranked in order of their strength of association: suicidal ideation, more mixed episodes, Axis II comorbidity, female sex, more antidepressant trials, rapid cycling, predominant lifetime depression, having been hospitalized, older onset, and longer delay of diagnosis. Suicidal ideation was associated with suicidal acts, more antidepressant trials, predominant depressions, more mixed-episodes/year, depressive first-lifetime episodes, electroconvulsive therapy use, delay of bipolar disorder diagnosis, unemployment, melancholic features, Axis II disorders, rapid cycling, and more depressions per year. Risk factors selectively associated with suicidal risk, overall, included more mixed-states per year and melancholic features, whereas hospitalization, unemployment, and predominantly depressive recurrences were more characteristic of diagnostic subtypes. CONCLUSIONS: Suicidal risk-factors found to be independent of bipolar disorder diagnostic subtype included mixed-states, melancholic depressive features, and more antidepressant trials. PMID- 22225678 TI - Subpopulation distribution of motile sperm relative to activation medium in steelhead (Oncorhynchus mykiss). AB - In the present study, steelhead sperm were activated in artificial tap water, ovarian fluid, activating saline, or in combinations of these media, and motility characteristics were determined using computer-assisted sperm analysis. Motility characteristics of individual sperm were then assessed to test the hypothesis that motile sperm are distributed among discrete subpopulations and that their distribution is influenced by the activation medium. Analysis with k-means clustering detected three discrete motile sperm subpopulations in steelhead semen, regardless of the activation medium. Based on multivariate analysis of variance, proportions of these subpopulations did not differ between sperm activated with ovarian fluid and activating saline, or any combination of these two media. However, subpopulation distributions for sperm activated with either ovarian fluid or activating saline were influenced by the level of dilution of these media in artificial tap water. There was an increase in the number of sperm in high velocity (curvilinear), high straightness, and high wobble subpopulation with increased levels of ovarian fluid or activating saline. The change in sperm motility characteristics with a change in activation medium may play a role in normal fertilization, as discharged sperm pass from seminal plasma and water through ovarian fluid en route to the egg. PMID- 22225679 TI - The dynamics of sperm DNA stability in Asian elephant (Elephas maximus) spermatozoa before and after cryopreservation. AB - The purpose of this study was to investigate the occurrence of sperm DNA fragmentation in Asian elephant (Elephas maximus) spermatozoa at various processing stages before and after cryopreservation. Five semen samples from four elephants were assessed at four different stages during processing; after (1) collection and reextension in TEST-egg yolk; (2) cooling to 5 degrees C; (3) equilibration for 1 h with glycerol; (4) thawing. An experimental approach was adopted that allowed comparisons of DNA fragmentation rates developed after the various processing stages. For this, spermatozoa were incubated in TEST-yolk media at 37 degrees C for 0, 4, 8, 24 and 48 h, and sperm DNA fragmentation rates were estimated using an elephant-specific Halosperm procedure. Incubation at 37 degrees C induced a rapid increase in DNA fragmentation, and significant differences between males were observed. The overall rate of increase over 4 h was estimated at about 5% per hour, and no significant changes to this rate were observed at the different processing stages, even, including the post-thaw samples. As semen quality of the five ejaculates was relatively poor, the basic semen parameter data were compared with nine different samples collected 11 mo earlier to see whether the tested samples were atypical or representative of the population, As there was no significant difference between the two sets of samples, it is believed that the samples tested for DNA stability were not unusually sensitive. These results suggest that Asian elephant spermatozoa are more susceptible to DNA fragmentation than spermatozoa of other mammals. PMID- 22225680 TI - The influence of genital tract status in postpartum period on the subsequent reproductive performance in high producing dairy cows. AB - The aim of the present study was to characterize the early postpartum period in clinically healthy dairy cows by ultrasonography (US), endometrial cytology (EC), and white blood cell counts, and determine possible relationships between postpartum findings and subsequent reproductive performance. Fifty-three dairy cows were examined on Days 15 to 21 (Visit 1), 22 to 28 (Visit 2), and 29 to 35 (Visit 3) postpartum. The clinical examination included: examination of vaginal fluid, EC, transrectal palpation and ultrasonography of the genital tract (cervical diameter, endometrial thickness, presence of a corpus luteum [CL] or intrauterine fluid [IUF] and its echogenicity). Luteal activity (presence of a CL in a single visit), return to cyclicity (presence of a CL in 2 consecutive visits), and conception rate at 70 and 120 days postpartum were considered as the dependent variables in four consecutive binary logistic regression analyses. Factors affecting leukocyte counts were established by general linear model (GLM) repeated measures analysis of variance. Based on the odds ratio (OR), the likelihood of luteal activity was higher in multiparous than primiparous cows (OR = 3.75) and tended to diminish in cows showing increased endometrial thickness in Visit 1 (V1) (OR = 0.06). The likelihood of returning to cyclicity decreased for each centimeter increase in cervical diameter in V1 (OR = 0.14) and that of conception on Day 70 was lower in cows showing the presence of echogenic or anechogenic IUF in V1 (OR = 0.09 or OR = 0.13, respectively) compared with cows lacking IUF. Effects of parity and IUF were observed on neutrophil counts. Positive EC results were unrelated to the cumulative conception rate at 70 and 120 days in milk, whereas cows returning a positive EC result in V1 showed a greater likelihood of increased endometrial thickness. In conclusion, measuring cervical diameter, endometrial thickness, and detecting the echogenicity of IUF by ultrasonography from Days 15 to 21 postpartum in clinically normal cows is an appropriate tool to predict subsequent reproductive performance. Vaginal examination and transrectal palpation alone did not emerge as valuable predictors. PMID- 22225681 TI - Comparison of two techniques for the morphometry study on gilthead seabream (Sparus aurata) spermatozoa and evaluation of changes induced by cryopreservation. AB - The development of powerful software has made possible spermatozoa morphology studies. However, some problems have emerged in relation to protocol standardization to compare results from different laboratories. This study was carried out to compare two techniques commonly used (staining vs phase contrast technique) for the morphometry study of gilthead sea bream spermatozoa using an integrated sperm analysis system (ISAS). Spermatozoa morphometry values were significantly affected by the technique used, and phase contrast technique was found to be the more accurate method, showing lower coefficients of variation on spermatozoa morphometry parameters measurements. Moreover, it has been shown that cryopreservation process produces damage in gilthead sea bream spermatozoa, causing negative effects in sperm parameters as spermatozoa morphometry (a decrease in cell volume), motility (from 95 to 68% motile cells) and viability (from 95 to 87% of live cells), being the addition of freezing medium containing cryoprotectant (DMSO) an important factor that caused the morphometry changes. PMID- 22225682 TI - Lacking expression of paternally-expressed gene confirms the failure of syngamy after intracytoplasmic sperm injection in swamp buffalo (Bubalus bubalis). AB - The objectives were to: (1) examine the efficiency of intracytoplasmic sperm injection (ICSI) technique, with or without chemical activation of in vitro matured buffalo oocytes, on sperm head decondensation; and (2) compare the subsequent development of embryos after activation of ICSI (ICSI (+) activation group) and sham injection (Sham (+) activation group) oocytes (embryos obtained by in vitro fertilization of IVM oocytes served as a control group). Pronuclear formation rates in ICSI (+) activation and Sham (+) activation groups were higher than that of ICSI without activation (P < 0.05). However, because 90.9% of presumptive zygotes in ICSI (+) activation group demonstrated pronuclear formation with an intact sperm head, we inferred that most were parthenotes. Neither developmental competence (morula and blastocyst formation rates) nor mean total cell number of blastocysts was significantly different among ICSI (+) activation, Sham (+) activation, and IVF groups. To clarify whether blastocysts were derived from syngamy or parthenogenesis, expression of Nnat, a paternally expressed gene in blastocysts derived from IVF, ICSI and oocyte activation without sperm or sham injection was additionally examined using reverse transcription polymerase chain reaction (RT-PCR). Expression of Nnat mRNA was not detected in ICSI (+) activation blastocysts, indicating failure of male genome activation. Although blastocyst development after ICSI combined with chemical activation was similar to IVF oocytes, these blastocysts were generated by parthenogenesis, due to failure of male pronucleus formation. PMID- 22225683 TI - The influence of 9-cis-retinoic acid on nuclear and cytoplasmic maturation and gene expression in canine oocytes during in vitro maturation. AB - Retinoids have important roles in regulation of oocyte nuclear and cytoplasmic maturation. The present study investigated the effects of a retinoid metabolite on nuclear maturation, cytoplasmic maturation, and gene expression in canine oocytes during in vitro maturation (IVM). Cumulus-oocyte complexes (COCs) were harvested from ovaries by slicing. Only oocytes that were >120 MUm in diameter, with a homogeneous dark cytoplasm and three or more layers of compact cumulus cells were used. Varying concentrations of 9-cis retinoic acid (9-cis-RA; 0, 5, 50, and 500 nm) were included in the maturation medium, and the following were measured: (i) oocyte nuclear maturation after culture for 48 h; (ii) cytoplasmic granular migration by labeling of oocytes with fluorescein isothiocyanate labeled lectins; and (iii) relative expression of genes related to apoptosis (BAX and BclII) in cumulus cells detached from oocytes, by semiquantitative reverse transcriptase-polymerase chain reaction. After 48 h culture with IVM, the highest percentage of oocytes that had developed to the metaphase II (MII) stage were in the 5 nm 9-cis-RA treatment group (18.3 +/- 2.5%; P < 0.05). Complete granular migration was observed in oocytes matured with 5 nm 9-cis-RA, consistent with a commensurate gain in developmental competence. Treatment with 5 nm 9-cis-RA had no effect on BclII gene expression, but downregulated BAX expression. In conclusion, since 5 nm 9-cis-RA was beneficial to nuclear and cytoplasmic maturation of canine oocytes, we inferred an important role for 9-cis-RA during IVM. PMID- 22225684 TI - Cervical expression of hyaluronan synthases varies with the stage of the estrous cycle in the ewe. AB - The natural cervical relaxation which occurs at estrus in the ewe may be initiated by binding of hyaluronan (HA) to its receptor CD44. Indeed, we have previously shown that HA content and fragment size in the ovine cervix varies with the stage of the estrous cycle. Despite the importance of cervical relaxation in promoting sperm transport and facilitating the possible development of transcervical artificial insemination (AI), the mechanisms coordinating these changes in HA content remain to be defined. Hyaluronan synthases (HAS) 1, 2, and 3 regulate HA biosynthesis and herein, we describe the changing pattern of HAS isoform expression during the estrous cycle to determine whether this may underpin HA-mediated changes in relaxation of the ovine cervix. Accordingly, cervices were collected from 24 cyclic sheep (n = 8 / group) at the luteal, pre luteinizing hormone (LH) and post-LH surge stages. Protein and mRNA expression for HAS 1, 2 and 3 was determined in five different tissue layers (epithelium, subepithelial stroma, and longitudinal, circular and transverse muscle) of the vaginal, mid and uterine regions of each cervix by immunohistochemistry and in situ hybridization, respectively. HA synthases were expressed in all the tissue layers and regions of the cervix, and the pattern of expression was similar for mRNA and protein. HAS1 protein and mRNA expression was significantly (P <= 0.05) higher at the pre-LH surge stage, while HAS 2 and 3 protein and mRNA expression was significantly (P <= 0.001) higher at the luteal stage. Overall, both HAS protein and mRNA expression was significantly (P <= 0.001) higher in the epithelial layer and the vaginal region. These findings are in accordance with our previous results and explain the differences observed in the HA content and differing HA fragment size at different stages of the estrous cycle. PMID- 22225685 TI - Comparison of heat transfer in liquid and slush nitrogen by numerical simulation of cooling rates for French straws used for sperm cryopreservation. AB - Slush nitrogen (SN(2)) is a mixture of solid nitrogen and liquid nitrogen, with an average temperature of -207 degrees C. To investigate whether plunging a French plastic straw (commonly used for sperm cryopreservation) in SN(2) substantially increases cooling rates with respect to liquid nitrogen (LN(2)), a numerical simulation of the heat conduction equation with convective boundary condition was used to predict cooling rates. Calculations performed using heat transfer coefficients in the range of film boiling confirmed the main benefit of plunging a straw in slush over LN(2) did not arise from their temperature difference (-207 vs. -196 degrees C), but rather from an increase in the external heat transfer coefficient. Numerical simulations using high heat transfer (h) coefficients (assumed to prevail in SN(2)) suggested that plunging in SN(2) would increase cooling rates of French straw. This increase of cooling rates was attributed to a less or null film boiling responsible for low heat transfer coefficients in liquid nitrogen when the straw is placed in the solid liquid mixture or slush. In addition, predicted cooling rates of French straws in SN(2) tended to level-off for high h values, suggesting heat transfer was dictated by heat conduction within the liquid filled plastic straw. PMID- 22225686 TI - Effect of corticotherapy on proteomics of endometrial fluid from mares susceptible to persistent postbreeding endometritis. AB - The objective was to determine the effects of corticotherapy, in the presence and absence of uterine inflammation, on proteomics of endometrial fluid from mares susceptible to endometritis. In 11 mares, estrus was induced seven times with 5 mg PGF(2alpha) given at 14-day intervals. The first estrus was a control (no treatment). During the third estrus, mares received glucocorticoid (GC) treatment (20 mg isoflupredone acetate) every 12 h, for three consecutive days. The fifth estrus was the Infected treatment (intrauterine infusion of 1 * 10(9) colony forming unit/mL Streptococcus equi subspecies zooepidemicus). Finally, the seventh was a combination of GC + Infected treatment (infusion of bacteria 24 h after the first GC treatment). At 12 h after the end of each treatment, uterine samples were collected and submitted to two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) for protein separation and mass spectrometry. Both GC treatment and uterine lumen infection induced proteomic alterations in the endometrial fluid of susceptible mares, characterized by an increase, decrease, or both in the relative optic density and/or frequency of inflammatory acute phase proteins (APP), with major alterations occurring when corticotherapy was applied in the presence of an infectious process. Corticotherapy in the presence of infection increased alpha(1)-antitrypsin (AAT), transthyretin (TT), and actin, but reduced immunoglobulin G, whereas intrauterine infection increased haptoglobin (Hp) and apolipoprotein A-1 (ApoA-1) and decreased transferrin (TF). Infection reduced levels of alpha(1)-antitrypsin and transthyretin, whereas corticotherapy in the presence of infection increased their frequency. We concluded that GC influenced the immune response, not only as suppressors, but also as enhancers of local defense mechanisms, through an immunomodulatory action. Short-term corticotherapy could be beneficial for treatment of uterine infectious processes in the mare. PMID- 22225687 TI - Boar sperm thawing practices: the number of straws does matter. AB - The number of straws thawed has been largely neglected in reports of boar sperm cryopreservation. Whereas previous studies confirm the effect of sperm concentration on function and survival of thawed boar spermatozoa, it is still unknown whether, for a same concentration, total number of sperm in the thawing solution affects its mechanics. The present trial sought to define good boar sperm thawing practices by checking if a minimal number of straws as well as the percentage of air volume in the thawing tube should be stated or not to decrease variability from one trial to another. In a first assay, three tubes with different numbers of thawed straws were compared in terms of motility and membrane integrity: control (C, four straws), T1.1 (two straws), and T1.2 (one straw). In a second parallel assay, the sperm motility was evaluated when one straw was thawed in a tube containing 86.67% of air volume (T2.1), and when the tube contained < 1% air volume (T2.2). In all treatments the final concentration of sperm in Beltsville thawing solution (BTS) was 1:3 (v:v) and quality parameters were assessed 4 h after thawing. Results showed the number of straws does affect motility parameters but not the membrane integrity, whereas less air volume in the tube nonsignificantly minimizes data deviation among replicates. In conclusion, it is recommended the use of four straws at 1:3 (v:v) to maintain motility records in boar sperm thawing practices as well as to be provided with vials that fit the sperm volume. PMID- 22225688 TI - Influence of day of postpartum breeding on pregnancy rate, pregnancy loss rate, and foaling rate in Thoroughbred mares. AB - Records (years 2005-2007) were analyzed from a Thoroughbred stud farm in central Kentucky. Data from all breeding cycles of foaling mares were tabulated (3184 cycles of 2003 foaling mares bred between 7 and 163 days postpartum). A multiple logistic regression model employing Bayesian statistics was used to adjust for factors that significantly affected outcome; odds ratios (ORs) for pregnancy rate, pregnancy loss rate, and foaling rate were determined to examine the influence of day of postpartum breeding on these parameters. Mares bred before Day 22 (Day 0 = day of foaling) postpartum had a decreased OR for becoming pregnant (P < 0.05); the median OR for becoming pregnant (1.00) was not reached until Day 46 postpartum. Mares bred before Day 13 postpartum had an increased OR for pregnancy loss (P < 0.05). The median OR for pregnancy loss did not decline below 1.00 until Day 78 postpartum. Mares bred before Day 20 postpartum had a decreased OR for producing a foal (P < 0.05). The median OR for producing a foal (1.00) was not reached until Day 75 postpartum. We concluded that fertility (in terms of a higher OR for becoming pregnant and a lower OR for pregnancy loss, resulting in a higher OR for producing a foal) continued to improve in Thoroughbred mares for approximately 2.5 mo postpartum. These findings are of importance to management strategies directed at early postpartum breeding, and explain some of the reported drift in subsequent foaling dates of Thoroughbred mares, despite management practices that employ early postpartum breeding. PMID- 22225689 TI - Automatic evaluation of ram sperm morphometry. AB - This study was designed to develop a new method based on fluorescence microscopy and image analysis for the automatic assessment of sperm morphometry and to study separately the effect of drying and fixation on the parameters of head sperm morphometry in the ram. The study was divided into two experiments. In the first experiment, ejaculates from 25 adult males were collected using an artificial vagina, diluted and divided into four sample aliquots. The first was labeled directly with Hoechst 33342 (FRESH), and the others were processed as smears. Between smears, one group was directly labeled with Hoechst after air drying (DRIED), and the other were fixed either with glutaraldehyde (GLUT), or with methanol (MET), and labeled with Hoechst afterward. Digital images of the fluorescence-labeled sperm were recorded with a digital camera, and sperm heads were automatically captured and analyzed using the ImageJ program. The method used allowed a fast and automatic selection of most sperm heads for a given image with high precision. There was a general trend toward significant decrease in head length, width, area and perimeter of air-dried sperm compared with fresh sperm. On average, this decrease was of 4.1% in length, 4.3% in width, 9.1% in area, and 2.8% in perimeter. Between semen smears, fixation with glutaraldehyde significantly increased head sperm dimensions. The smears fixed with glutaraldehyde method is recommended for a more practical use than with fresh samples, providing better quality images than the other methods, and because the morphometric results obtained were more similar to the FRESH group than those of the DRIED and MET. In the second experiment, ejaculates from adult males were used to compare the sperm head morphometric results obtained with the new method developed (using the GLUT treatment as reference) with a more conventional CASMA method (semen smears stained with Hemacolor and processed with the ISAS commercial software, HEM). The GLUT method allowed the analysis of 100% of sperm, whereas only 93% of sperm could be analyzed using HEM. Spermatozoa displayed a bigger size when processed with HEM than with GLUT method in all primary sperm head morphometric parameters. A significant correlation was observed between the two methods used in this experiment for all morphometric size parameters. The new method developed allows automatic determination of sperm head morphometry in a reduced time, which facilitates its use in routine semen analysis. It was concluded that the automation of sperm morphometry is feasible using fluorescence microscopy and image analysis and that the effect of drying and fixation was less important than previously stated. PMID- 22225690 TI - Nitric oxide in the bovine oviduct: influence on contractile activity and nitric oxide synthase isoforms localization. AB - The oviducts of 64 Holstein cows in luteal (early I, early II and late) and follicular phases were evaluated to determine the protein expression and mRNA transcription of different nitric oxide synthase isoforms (eNOS, iNOS, nNOS) as well as the effect of nitric oxide (NO) on spontaneous contractility in vitro. The expression patterns of nitric oxide synthase (NOS) isoforms in isthmus and ampulla (n = 6 for each phase) were determined by immunohistochemistry, reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot analysis. In the contractility studies, longitudinal and circular isolated strips of isthmus and ampulla (n = 10 for each phase) of oviducts located ipsilateral to the luteal structure or preovulatory follicle were treated as follows: a) L-arginine, an endogenous NO donor (10(-8) to 10(-3)m), b) N(omega)-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor (10(-5)m) and L-arginine (10(-3)m), c) methylene blue (MB), an inhibitor of soluble guanylate (10(-5)m) and L-arginine (10(-3)m) and d) sodium nitroprusside (SNP), an exogenous NO donor (10(-8) to 10(-4)m). Immunohistochemical evaluation revealed that endothelial NOS (eNOS) expression detected in epithelial layer of isthmus and ampulla was strong in early I luteal phase, moderate in follicular phase and weak in other phases. Neuronal NOS (nNOS) immunoreactivity was strong in isthmus and moderate in ampulla, and staining of nerve fibers was observed mostly in early I luteal and follicular phases. All eNOS, nNOS and inducible NOS (iNOS) isoforms were detected by RT-PCR. eNOS and iNOS proteins were evident, whereas nNOS was undetectable by Western blot analysis in the tissue examined. L-arginine applied alone or after L-NAME did not alter or increase the contractile tension of the strips in most tissues examined. However, L-arginine applied after MB increased contractile tension in the strips of ampulla and longitudinal isthmus from early I luteal phase and circular isthmus from follicular phase but decreased it in isthmus from early II luteal phase. SNP differentially modulated oviductal contraction depending on the type of muscular strips and period examined. These results showed the estrous phase dependent changes related to endogenous NO system which might be of physiological importance to the oviduct for secretory and ciliary functions involved in gametes and embryo(s) transportation. PMID- 22225691 TI - Effect of cryopreservation on sperm parameters, lipid peroxidation and antioxidant enzymes activity in fowl semen. AB - The aim of the present study was to determine the influence of chicken semen cryopreservation on sperm parameters, lipid peroxidation and antioxidant enzymes activities. Pooled semen from 10 Black Minorca roosters was used in the study. Semen samples were subjected to cryopreservation using the "pellet" method and dimethylacetamide (DMA) as a cryoprotectant. In the fresh and the frozen-thawed semen sperm membrane integrity (SYBR-14/propidium iodide (PI)), acrosomal damage (PNA-Alexa Fluor((r))488) and mitochondrial activity (Rhodamine 123) were assessed using flow cytometry. Malondialdehyde (MDA) concentration, catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were determined in sperm cells and seminal plasma by spectrophotometry. All sperm characteristics evaluated using flow cytometry were affected by cryopreservation. After freezing-thawing, there was significant (P < 0.01) reduction in sperm membrane integrity, sperm acrosome integrity and mitochondrial activity. Following cryopreservation, MDA concentration significantly increased in chicken seminal plasma and spermatozoa (P < 0.01, P < 0.05). The CAT activity in seminal plasma significantly decreased (P < 0.05), while intracellular activity of this enzyme did not significantly change in frozen-thawed semen. In seminal plasma of frozen-thawed semen the significant increase (P < 0.01) in GPx activity was detected. Whereas GPx activity in spermatozoa remained statistically unchanged after thawing. The SOD activity significantly increased (P < 0.01) in cryopreserved seminal plasma with simultaneous decrease (P < 0.01) of its activity in cells. In conclusion, this is probably the first report describing the level of antioxidant enzymes in frozen-thawed avian semen. The present study showed that the activity of CAT, GPx and SOD in chicken semen was affected by cryopreservation, what increased the intensity of lipid peroxidation (LPO). Catalase appeared to play an important role in the sperm antioxidant defense strategy at cryopreservation since, opposite to SOD and GPx, its content was clearly reduced by the cryopreservation process. Change in the antioxidant defense status of the chicken spermatozoa and surrounding seminal plasma might affect the semen quality and sperm fertilizing ability. PMID- 22225692 TI - Changes in sperm parameters of sex-reversed female rainbow trout during spawning season in relation to sperm parameters of normal males. AB - The production of all-female populations has important economic benefits in commercial rainbow trout aquaculture. The procedure commonly implemented to produce all-female stocks centers on the sex reversal of rainbow trout females via the administration of androgens in the early developmental stages, followed by the egg fertilization of normal females with semen from sex-reversed females (srf). However, there is no information regarding the quality of semen from srf rainbow trout throughout the spawning season. This information is critical because the quality of srf semen is highly variable. The aim of the study was to determine the changes in the semen parameters of srf rainbow trout throughout the duration of the spawning season. Sperm concentration, sperm motility parameters, and the biochemical parameters of seminal plasma (protein concentration, antitrypsin activity, osmolality, and lactate dehydrogenase activity) from srf were monitored during the spawning season and compared with normal male rainbow trout. The observed values of sperm, protein concentration, antitrypsin activity, osmolality, and lactate dehydrogenase activity of seminal plasma were all higher in comparison with normal males. Semen from srf was therefore characterized by a lower sperm motility during each period of the spawning season, in comparison with normal males, approximately 1.8, 1.5, and 1.7 times, respectively for the beginning, middle, and end of the spawning season. The percentage of sperm motility from srf and normal males were affected by the spawning season in the same way, as the highest values in the middle of the spawning season demonstrate (60% and 91% for srf and normal males, respectively). Spermatozoa of srf are characterized by a lower speed and a more curvilinear trajectory of movement as compared with that of normal males. The patterns of changes during the spawning season in sperm concentration, sperm motility parameters, as well as osmolality, and lactate dehydrogenase activity of the seminal plasma of srf were different in comparison with normal males. Our results could be important for fish breeders in regard to the spawning control of srf rainbow trout, as well as for the development of short- and long-term sperm storage procedures. PMID- 22225693 TI - Effect of growth rate from 6 to 16 months of age on sexual development and reproductive function in beef bulls. AB - Sexual development and reproductive function were studied in 22 Angus * Charolais and 17 Angus bulls from 6 to 16 mo of age. Associations of average daily gain (ADG) and body weight with ages at puberty and at maturity (satisfactory semen quality), scrotal circumference, paired-testes volume and weight, testicular vascular cone diameter and fat thickness, scrotal temperature, sperm production and morphology, and testicular histology, were determined. There were no significant correlations between cumulative average daily gain and any of the end points investigated. Body weight at various ages was negatively correlated with ages at puberty and maturity in Angus * Charolais bulls, positively correlated with paired-testes weight in Angus * Charolais and Angus bulls, and positively correlated with seminiferous tubule volume in Angus bulls (P < 0.05). Semen quality improved gradually with age and the interval between puberty and maturity (mean +/- SD; 309.4 +/- 29.7 and 357 +/- 42 days of age) was approximately 50 days. Age, weight, scrotal circumference, and paired-testes volume were all good predictors of pubertal and mature status, with moderate to high sensitivity and specificity (71.6% to 92.4%). In summary, growth rate between 6 and 16 mo of age did not affect sexual development and reproductive function in beef bulls. However, greater body weight at various ages was associated with reduced age at puberty and maturity, and with larger testes at 16 mo of age, indicating that improved nutrition might be beneficial, but only when offered before 6 mo of age. Average daily gains of approximately 1 to 1.6 kg/day did not result in excessive fat accumulation in the scrotum, increased scrotal temperature, or reduction in sperm production and semen quality, and could be considered "safe" targets for growing beef bulls. PMID- 22225694 TI - The inseminating bull and plasma pregnancy-associated glycoprotein (PAG) levels were related to peripheral leukocyte counts during the late pregnancy/early postpartum period in high-producing dairy cows. AB - It has been established that the immunologic and endocrine status of the peripartum dairy cow determines the animal's subsequent productive and reproductive performance. Thus, at parturition reduced immune functions of peripheral blood polymorphonuclear cells (PMN) has been observed after a peak in pregnancy-associated glycoproteins (PAGs), and, more recently, the inseminating bull was linked to plasma levels of bovine PAGs in pregnant Holstein-Friesian dairy cows. The present study sought to determine whether changes in leukocyte counts during the peripartum period, indicative of the animal's immune status, could be related to the inseminating bull and to PAG levels. Ninety-six clinically healthy, single pregnant cows in a commercial dairy herd were selected. Four samples were collected before parturition (on gestation Days 220 226, 234-240, 248-254, and 262-268) and two samples after parturition (on Days 14 21, and 28-34 postpartum) to analyze total and differential blood cell counts. Based on GLM analysis procedures of variance for repeated measures, the inseminating bull was found to affect counts of total leukocytes and lymphocytes (P < 0.001; between-subject effects) throughout the peripartum period. In addition, cows with high plasma PAG levels (> 900 ng/ml) on Day 262-268 of gestation had higher numbers of total leukocytes and neutrophils throughout the peripartum (P < 0.001; between-subject effects). Young animals (<= 1 lactation) had higher total leukocyte and lymphocyte counts than older cows (2 or more lactations) throughout the study period. These results reveal a clear relationship between the inseminating bull or plasma PAG levels and peripheral leukocyte counts during the peripartum period in dairy cows. PMID- 22225695 TI - Variations of chromatin, tubulin and actin structures in primate oocytes arrested during in vitro maturation and fertilization--what is this telling us about the relationships between cytoskeletal and chromatin meiotic defects? AB - A nonhuman primate model was applied to investigate the relationships between variations in the organization of microtubules, microfilaments, and chromatin in metaphase I and metaphase II oocytes. Marmoset oocytes were subjected to in vitro maturation and coincubation with sperm. Oocytes which failed to cleave were investigated for chromatin, tubulin, and actin using Hoechst 33258, fluorescein isothiocyanate (FITC)-labeled alpha-tubulin antibody and rhodamine-labeled phalloidin, respectively. Spindles were categorized according to size, shape and microtubule organization: normal, large, multipolar, disorganized, absent spindle, and spindles with broad poles. Actin caps were categorized as: normal, small, split, and disorganized. Chromosomal condensation and alignment were described as normal or abnormal. Improper chromosomal condensation was associated with both abnormal microfilament and microtubule arrangement. This was further associated with abnormal actin organization, disorientation and late stabilization of microtubules, but not related to abnormal organization of spindle poles. Chromosomal misalignment was associated with disorientation and late stabilization of tubulin, but not to broad spindle pole. Additionally, abnormal actin polarization appeared not to be related to abnormal spindle poles. The model system presented in this study could be used as an experimental platform for studying the contribution of different factors to the exactness of late meiotic events in primate oocytes. The present study provides basic information on spindle, chromosome, and actin normal and abnormal organization, which can be observed in in vitro matured, but failed to cleave primate oocytes. PMID- 22225696 TI - The effects of bovine necrotic vulvo-vaginitis on reproductive and production performance of Israeli 1st calf heifers. AB - Bovine necrotic vulvovaginitis (BNVV) is a syndrome unique to Israel characterized by necrotic lesion in the caudal vagina mainly in first calf heifers after calving, associated with Porphyromonas levii. The objectives of this study were to analyze the impact of BNVV on reproductive performance, milk production and survival in the heard of first calf dairy heifers in affected farms, and to verify if the effects of BNVV are severity-dependent. For assessment of the severity level a scale of 4 degrees was formed, and cows were scored 4 to 6 d after calving. Data were obtained from two dairy farms during 2006-07, consisting of 603 lactations. The incidence and the severity of BNVV declined between 2006 and 2007, and severe BNVV tended to be more prevalent in the summer. The odds to conceive in the first artificial insemination of BNVV cow tended to be lower than healthy cows (OR = 0.676, P = 0.052). Cows with BNVV had longer empty period (145.8 d vs. 135.1 d of healthy cows, P = 0.031), but only severe BNVV had a negative effect on the odds of the cow to be empty at 150 d in milk (DIM) (OR = 2.05, P = 0.052). Severe BNVV also affected the mean survival time to conception (155.9 d vs. 142.3 d, P = 0.042). All BNVV severity degrees had a negative effect on milk production. The effect on milk production was not limited only to the beginning of the lactation, cows with BNVV produced 338.1 kg milk less than healthy cows (P = 0.016) in 305 d corrected lactation. The effect on milk production was not severity depended. No effect on survival time in the herd was demonstrated. PMID- 22225697 TI - Effects of the dialectical behavioral therapy-mindfulness module on attention in patients with borderline personality disorder. AB - It is known that patients with borderline personality disorder (BPD) show attention deficits and impulsivity. The main aim of this study was to explore the effects of Dialectical Behavioral Therapy-Mindfulness training (DBT-M), used as an adjunct to general psychiatric management (GPM), on attention variables in patients diagnosed with BPD. A second objective was to assess the relation of mindfulness formal practice on clinical variables. A sample of 60 patients with BPD was recruited. Forty of them were allocated to GPM + DBT-M treatment and the other 20 received GPM alone. At the termination of the mindfulness training, DBT M + GPM group showed a significant improvement on commissions, hit reaction time, detectability scores from the CPT-II neuropsychological test, and also on the composite scores of inattention and impulsivity. Further, the more minutes of mindfulness practice were correlated to greater improvement in general psychiatric symptoms and affective symptomatology, but not in CPT-II measures. This is probably the first study so far assessing the effects of this single DBT module in patients with BPD. The results suggest a positive effect of such intervention on attention and impulsivity variables. PMID- 22225698 TI - Free-running disorder in a sighted adolescent. PMID- 22225699 TI - A cost-effectiveness analysis of provider interventions to improve health worker practice in providing treatment for uncomplicated malaria in Cameroon: a study protocol for a randomized controlled trial. AB - BACKGROUND: Governments and donors all over Africa are searching for sustainable, affordable and cost-effective ways to improve the quality of malaria case management. Widespread deficiencies have been reported in the prescribing and counselling practices of health care providers treating febrile patients in both public and private health facilities. Cameroon is no exception with low levels of adherence to national guidelines, the frequent selection of non-recommended antimalarials and the use of incorrect dosages. This study evaluates the effectiveness and cost-effectiveness of introducing two different provider training packages, alongside rapid diagnostic tests (RDTs), designed to equip providers with the knowledge and practical skills needed to effectively diagnose and treat febrile patients. The overall aim is to target antimalarial treatment better and to facilitate optimal use of malaria treatment guidelines. METHODS/DESIGN: A 3-arm stratified, cluster randomized trial will be conducted to assess whether introducing RDTs with provider training (basic or enhanced) is more cost-effective than current practice without RDTs, and whether there is a difference in the cost effectiveness of the provider training interventions. The primary outcome is the proportion of patients attending facilities that report a fever or suspected malaria and receive treatment according to malaria guidelines. This will be measured by surveying patients (or caregivers) as they exit public and mission health facilities. Cost-effectiveness will be presented in terms of the primary outcome and a range of secondary outcomes, including changes in provider knowledge. Costs will be estimated from a societal and provider perspective using standard economic evaluation methodologies. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00981877. PMID- 22225700 TI - Abiotic stress-inducible receptor-like kinases negatively control ABA signaling in Arabidopsis. AB - Membrane-anchored receptor-like protein kinases (RLKs) recognize extracellular signals at the cell surface and activate the downstream signaling pathway by phosphorylating specific target proteins. We analyzed a receptor-like cytosolic kinase (RLCK) gene, ARCK1, whose expression was induced by abiotic stress. ARCK1 belongs to the cysteine-rich repeat (CRR) RLK sub-family and encodes a cytosolic protein kinase. The arck1 mutant showed higher sensitivity than the wild-type to ABA and osmotic stress during the post-germinative growth phase. CRK36, an abiotic stress-inducible RLK belonging to the CRR RLK sub-family, was screened as a potential interacting factor with ARCK1 by co-expression analyses and a yeast two-hybrid system. CRK36 physically interacted with ARCK1 in plant cells, and the kinase domain of CRK36 phosphorylated ARCK1 in vitro. We generated CRK36 RNAi transgenic plants, and found that transgenic plants with suppressed CRK36 expression showed higher sensitivity than arck1-2 to ABA and osmotic stress during the post-germinative growth phase. Microarray analysis using CRK36 RNAi plants revealed that suppression of CRK36 up-regulates several ABA-responsive genes, such as LEA genes, oleosin, ABI4 and ABI5. These results suggest that CRK36 and ARCK1 form a complex and negatively control ABA and osmotic stress signal transduction. PMID- 22225701 TI - The impact of diabetes prevention on labour force participation and income of older Australians: an economic study. AB - BACKGROUND: Globally, diabetes is estimated to affect 246 million people and is increasing. In Australia diabetes has been made a national health priority. While the direct costs of treating diabetes are substantial, and rising, the indirect costs are considered greater. There is evidence that interventions to prevent diabetes are effective, and cost-effective, but the impact on labour force participation and income has not been assessed. In this study we quantify the potential impact of implementing a diabetes prevention program, using screening and either metformin or a lifestyle intervention on individual economic outcomes of pre-diabetic Australians aged 45-64. METHODS: The output of an epidemiological microsimulation model of the reduction in prevalence of diabetes from a lifestyle or metformin intervention, and another microsimulation model, Health&WealthMOD, of health and the associated impacts on labour force participation, personal income, savings, government revenue and expenditure were used to quantify the estimated outcomes of the two interventions. RESULTS: An additional 753 person years in the labour force would have been achieved from 1993 to 2003 for the male cohort aged 60-64 years in 2003, if a lifestyle intervention had been introduced in 1983; with 890 person years for the equivalent female group. The impact on labour force participation was lower for the metformin intervention, and increased with age for both interventions. The male cohort aged 60-64 years in 2003 would have earned an additional $30 million in income with the metformin intervention, and the equivalent female cohort would have earned an additional $25 million. If the lifestyle intervention was introduced, the same male and female cohorts would have earned an additional $34 million and $28 million respectively from 1993 to 2003. For the individuals involved, on average, males would have earned an additional $44,600 per year and females an additional $31,800 per year, if they had continued to work as a result of preventing diabetes. CONCLUSIONS: In addition to improved health and wellbeing, considerable benefits to individuals, in terms of both additional working years and increased personal income, could be made by introducing either a lifestyle or metformin intervention to prevent diabetes. PMID- 22225702 TI - First report on development of quantitative interspecies structure carcinogenicity relationship models and exploring discriminatory features for rodent carcinogenicity of diverse organic chemicals using OECD guidelines. AB - Different regulatory agencies in food and drug administration and environmental protection worldwide are employing quantitative structure-activity relationship (QSAR) models to fill the data gaps related with properties of chemicals affecting the environment and human health. Carcinogenicity is a toxicity endpoint of major concern in recent times. Interspecies toxicity correlations may provide a tool for estimating sensitivity towards toxic chemical exposure with known levels of uncertainty for a diversity of wildlife species. In this background, we have developed quantitative interspecies structure-carcinogenicity correlation models for rat and mouse [rodent species according to the Organization for Economic Cooperation and Development (OECD) guidelines] based on the carcinogenic potential of 166 organic chemicals with wide diversity of molecular structures, spanning a large number of chemical classes and biological mechanisms. All the developed models have been assessed according to the OECD principles for the validation of QSAR models. Consensus predictions for carcinogenicity of the individual compounds are presented here for any one species when the data for the other species are available. Informative illustrations of the contributing structural fragments of chemicals which are responsible for specific carcinogenicity endpoints are identified by the developed models. The models have also been used to predict mouse carcinogenicities of 247 organic chemicals (for which rat carcinogenicities are present) and rat carcinogenicities of 150 chemicals (for which mouse carcinogenicities are present). Discriminatory features for rat and mouse carcinogenicity values have also been explored. PMID- 22225703 TI - Determination of C(5)-C(12) perfluoroalkyl carboxylic acids in river water samples in the Czech Republic by GC-MS after SPE preconcentration. AB - A method employing solid phase extraction followed by gas chromatography-mass spectrometry with negative chemical ionization has been developed for determination of ultratrace concentrations of perfluoroalkyl carboxylic acids in river water. The effects of the experimental parameters, such as the pH, additions of NaCl and an ion-pairing agent (tetraethylammonium bromide) and the kind of the elution agent, on the efficiency of the test acid extraction have been studied. The analyte extraction recoveries and the limits of detection and determination have been found. The method developed has been tested on determinations of perfluoroalkyl carboxylic acids in the waters of the two largest Czech rivers, Vltava and Labe (Elbe). The best extraction results have been attained without any alteration of the sample pH, with an addition of tetrabutylammonium bromide (a concentration of 50 MUg mL(-1) in the sample) and using methanol as the elution agent. Under these conditions, the recoveries of the test acids in the spiked real samples are within ranges from 60% to 104% and 53% to 111% for analyte concentration levels of 1.40 ng mL(-1) and 0.14 ng mL( 1), respectively, depending on the lengths of the perfluorinated chains of the acids. In general, the recovery decreases with increasing length of this chain. The method developed exhibits very low limits of detection and determination and the results are fully comparable with those obtained when using more expensive HPLC-MS/MS instrumentation. Typical values amount to tenths to tens of pg mL(-1) and units to one hundred pg mL(-1) for the limits of detection and determination, respectively; the measuring sensitivity increases with increasing length of the analyte chain. The analyzes of real samples from the Vltava and Elbe rivers have demonstrated that the results obtained are similar to the values published for contamination of the Elbe and other rivers in western and central Europe. The concentrations determined are of the order of units to tens of pg mL(-1) and the C(8)-C(10) acids occur most often. PMID- 22225704 TI - Cr(VI) uptake mechanism of Bacillus cereus. AB - In this study, we investigated the Cr(VI) uptake mechanism in an indigenous Cr(VI)-tolerant bacterial strain -Bacillus cereus through batch and microscopic experiments. We found that both the cells and the supernatant collected from B. cereus cultivation could reduce Cr(VI). The valence state analysis revealed the complete transformation from Cr(VI) into Cr(III) by living B. cereus. Further X ray absorption fine structure and Fourier transform infrared analyses showed that the reduced Cr(III) was coordinated with carboxyl and amido functional groups from either the cells or supernatant. Scanning electron microscopy and atomic force microscopy observation showed that noticeable Cr(III) precipitates were accumulated on bacterial surfaces. However, Cr(III) could also be detected in bacterial inner portions by using transmission electron microscopy thin section analysis coupled with energy dispersive X-ray spectroscopy. Through quantitative analysis of chromium distribution, we determined the binding ratio of Cr(III) in supernatant, cell debris and cytoplasm as 22%, 54% and 24%, respectively. Finally, we further discussed the role of bacterium-origin soluble organic molecules to the remediation of Cr(VI) pollutants. PMID- 22225705 TI - Predator cues and an herbicide affect activity and emigration in an agrobiont wolf spider. AB - Animals use chemical cues for signaling between species. However, anthropogenic chemicals might interrupt this natural chemical information flow, with potential impacts on predator-prey interactions. Our goal was to explore how Buccaneer(r) Plus, a common herbicide similar to Round-up(r) (active ingredient glyphosate), affected the interactions between intraguild predators. The wolf spider Pardosa milvina (Hentz, 1844) is numerically dominant in agricultural systems across the eastern United States, and often falls prey to or competes with the larger wolf spider, Hogna helluo (Walckenaer, 1837) and/or the carabid beetle, Scarites quadriceps (Chaudoir, 1843). We tested the effects of chemical cues from these intraguild predators and exposure to herbicide on the activity, emigration, and survival of P. milvina using a full-factorial laboratory experiment. Both predator cues and herbicide led to a decrease in movement by P. milvina. However, although H. helluo cues alone decreased movement, S. quadriceps cues only decreased movement when combined with herbicide. These results indicate that predation risk and herbicide application likely interact in complex ways to affect the movement of a major arthropod predator in agricultural systems, and thus may have complex effects on the food web. PMID- 22225706 TI - Radioactivity and heavy metal concentrations of some commercial fish species consumed in the Black Sea Region of Turkey. AB - Marine fish is an important daily diet item for the people of Turkey. The Black Sea Region of Turkey was contaminated by the Chernobyl accident in 1986, a comprehensive study was planned and carried out to determine the radioactivity levels ((226)Ra, (232)Th, (40)K and (137)Cs) and heavy metal concentrations (As, Mn, Fe, Cr, Ni, Zn, Cu and Pb) in four of the most common fish species: Engraulis encrasicholus (anchovy), Oncorhynchus mykiss (trout), Trachurus mediterranus (bluefin) and Merlangius merlangus (whiting) samples collected from eight stations in the Black Sea Region of Turkey during 2010. The dose due to consumption of fish by the public was estimated and it was shown that this dose imposes no threat to human healthy. The concentrations of heavy metal are below the daily intake recommended by the international organizations. PMID- 22225707 TI - Methyl chloride emissions from halophyte leaf litter: dependence on temperature and chloride content. AB - Methyl chloride (CH(3)Cl) is the most abundant natural chlorine containing compound in the atmosphere, and responsible for a significant fraction of stratospheric ozone destruction. Understanding the global CH(3)Cl budget is therefore of great importance. However, the strength of the individual sources and sinks is still uncertain. Leaf litter is a potentially important source of methyl chloride, but factors controlling the emissions are unclear. This study investigated CH(3)Cl emissions from leaf litter of twelve halophyte species. The emissions were not due to biological activity, and emission rates varied between halophyte species up to two orders of magnitude. For all species, the CH(3)Cl emission rates increased with temperature following the Arrhenius relation. Activation energies were similar for all investigated plant species, indicating that even though emissions vary largely between plant species, their response to changing temperatures is similar. The chloride and methoxyl group contents of the leaf litter samples were determined, but those parameters were not significantly correlated to the CH(3)Cl emission rate. PMID- 22225708 TI - Molecular mechanism for cadmium-induced anthocyanin accumulation in Azolla imbricata. AB - Anthocyanins inducibly synthesized by Cd treatment showed high antioxidant activity and might be involved in internal detoxification mechanisms of Azolla imbricata against Cd toxicity. In order to understand anthocyanin biosynthesis mechanism during Cd stress, the cDNAs encoding chalcone synthase (CHS) and dihydroflavonol reductase (DFR), two key enzymes in the anthocyanin synthesis pathway, were isolated from A. imbricata. Deduced amino acid sequences of the cDNAs showed high homology to the sequences from other plants. Expression of AiDFR, and to a lesser extent AiCHS, was significantly induced in Cd treatment plant in comparison with the control. CHS and DFR enzymatic activities showed similar pattern changes with these genes expression during Cd stress. These results strongly indicate that Cd induced anthocyanin accumulation is probably mediated by up-regulation of structural genes including CHS and DFR, which might further increase the activities of enzymes encoded by these structural genes that control the anthocyanin biosynthetic steps. PMID- 22225709 TI - Pacing transmural scar tissue reduces left ventricle reverse remodeling after cardiac resynchronization therapy. AB - BACKGROUND: In patients with ischemic heart failure undergoing cardiac resynchronization therapy (CRT) the underlying myocardial substrate at the left ventricle (LV) pacing site may affect CRT response. However, the effect of delivering the pacing stimulus remote, adjacent to or over LV transmural scar tissue (TST) identified by echocardiography is still unknown. METHODS: First, 35 patients with healed myocardial infarction (57 +/- 11 years) were prospectically studied to demonstrate the capability of echocardiographic end-diastolic wall thickness (EDWT) to identify LV-TST as defined by delayed enhancement magnetic resonance imaging (DE-MRI). Subsequently, in 136 patients (65 +/- 10 years) who underwent CRT, EDWT was retrospectively evaluated at baseline. The LV catheter placement was defined over, adjacent to and remote from TST if pacing was delivered at a scarred segment, at a site 1 segment adjacent to or remote from scarred segments. CRT response was defined as LV end-systolic volume (ESV) decrease by at least 10% after 6 months. RESULTS: A EDWT <= 5mm identified TST at DE-MRI with 92% sensitivity and 96% specificity. In the 76 CRT responders, less overall and posterolateral TST segments and more segments paced remote from TST areas were found. At the multivariate regression analysis, the number of TST segments and scar/pacing relationship showed a significant association with CRT response. CONCLUSIONS: In addition to LV global scar burden, CRT response relates also to the myocardial substrate underlying pacing site as evaluated by standard echocardiography. This information may expand the role of echocardiography to guide pacing site avoiding pacing at TST areas. PMID- 22225710 TI - Local breast cancer recurrence after mastectomy and immediate breast reconstruction for invasive cancer: a meta-analysis. AB - BACKGROUND: The main priorities in the surgical treatment of patients with breast cancer are to achieve cure, local control and prevent recurrence. It is increasingly important to address quality of life and self-image with women undergoing surgical intervention for breast cancer. There is a lack of consensus as to the oncologic safety of immediate breast reconstruction (IBR). The purpose of this paper is to systematically review the literature and compare the frequency of recurrence in patients with and without IBR following mastectomy for breast cancer. METHODS: Two independent investigators searched PubMed, Embase, and the Cochrane database using predefined search terms. After application of inclusion and exclusion criteria, 10 articles remained. Each article was assessed for quality. Relevant data was collected including recurrence rates, cancer stage, type of mastectomy and reconstruction, adjuvant treatments, and duration of follow-up. RESULTS: Inter-rater reliability was good at 74% (95% CI: 0, 93%). There was no evidence of study heterogeneity (p for Q-statistic=0.34 and I(2)=12%). The OR ratio for recurrence of breast cancer for mastectomy with IBR as compared to mastectomy alone was 0.98 (95% CI: 0.62, 1.54). CONCLUSION: This meta-analysis demonstrated no evidence for increased frequency of local breast cancer recurrence with IBR compared with mastectomy alone. PMID- 22225711 TI - Effect of dietary patterns differing in carbohydrate and fat content on blood lipid and glucose profiles based on weight-loss success of breast-cancer survivors. AB - INTRODUCTION: Healthy body weight is an important factor for prevention of breast cancer recurrence. Yet, weight loss and weight gain are not currently included in clinical-practice guidelines for posttreatment of breast cancer. The work reported addresses one of the questions that must be considered in recommending weight loss to patients: does it matter what diet plan is used, a question of particular importance because breast cancer treatment can increase risk for cardiovascular disease. METHODS: Women who completed treatment for breast cancer were enrolled in a nonrandomized, controlled study investigating effects of weight loss achieved by using two dietary patterns at the extremes of macronutrient composition, although both diet arms were equivalent in protein: high fat, low carbohydrate versus low fat, high carbohydrate. A nonintervention group served as the control arm; women were assigned to intervention arms based on dietary preferences. During the 6-month weight-loss program, which was menu and recipe defined, participants had monthly clinical visits at which anthropometric data were collected and fasting blood was obtained for safety monitoring for plasma lipid profiles and fasting glucose. Results from 142 participants are reported. RESULTS: Adverse effects on fasting blood lipids or glucose were not observed in either dietary arm. A decrease in fasting glucose was observed with progressive weight loss and was greater in participants who lost more weight, but the effect was not statistically significant, even though it was observed across both diet groups (P = 0.21). Beneficial effects of weight loss on cholesterol (4.7%; P = 0.001), triglycerides (21.8%; P = 0.01), and low density lipoprotein (LDL) cholesterol (5.8%; P = 0.06) were observed in both groups. For cholesterol (P = 0.07) and LDL cholesterol (P = 0.13), greater reduction trends were seen on the low-fat diet pattern; whereas, for triglycerides (P = 0.01) and high-density lipoprotein (HDL) cholesterol (P = 0.08), a decrease or increase, respectively, was greater on the low-carbohydrate diet pattern. CONCLUSIONS: Because an individual's dietary preferences can affect dietary adherence and weight-loss success, the lack of evidence of a negative effect of dietary pattern on biomarkers associated with cardiovascular risk is an important consideration in the development of breast cancer practice guidelines for physicians who recommend that their patients lose weight. Whether dietary pattern affects biomarkers that predict long-term survival is a primary question in this ongoing clinical trial. PMID- 22225713 TI - Budget cuts in the USA: a short-term win? PMID- 22225715 TI - Further progress in HER2-directed therapy. PMID- 22225716 TI - Analysis of media reporting of The Lancet Oncology Commission. PMID- 22225717 TI - Drivers of the cost of cancer care. PMID- 22225718 TI - Cancer care after the National Health Service reforms. PMID- 22225719 TI - Shark cartilage: has the popularisation of science failed? PMID- 22225720 TI - Affordable cancer care. PMID- 22225721 TI - What price cure? PMID- 22225722 TI - Chemotherapy for colorectal cancer. PMID- 22225723 TI - Regulatory T cells in melanoma: the final hurdle towards effective immunotherapy? AB - Immunotherapy studies in patients with melanoma have reported success in the expansion of tumour-specific effector T cells in vivo, but even in the presence of substantial numbers of functional T cells circulating in the blood, favourable clinical outcomes are scarce. This failure to induce robust clinical responses might be related to tumour-induced immune evasion, rendering the host tolerant to melanoma antigens. Immunosuppression in the tumour microenvironment mediated by regulatory T cells (Treg) is a dominant mechanism of tumour immune escape and is a major hurdle for tumour immunotherapy. Accumulation of Treg in melanoma is frequently recorded and the ratio of CD8-positive T cells versus Treg in the tumour microenvironment is predictive for survival of patients with melanoma. Hence, depletion of Treg seems to be a promising strategy for the enhancement of melanoma-specific immunity. Indeed, murine studies have shown that Treg depletion greatly increases the efficacy of immunotherapy. But despite the success of some strategies in depletion of Treg in patients, overall clinical efficacy has been disappointing. The lack of Treg specificity of the Treg depleting strategies applied so far imply that well-designed studies into dosage, timing, and administration regimens with more specific agents are urgently needed. Depletion of functional Treg from the tumour microenvironment as part of multifaceted immunotherapeutic treatments is a major challenge to induce clinically relevant immune responses against melanomas. PMID- 22225725 TI - Breast-cancer stem cells-beyond semantics. AB - Intratumoral heterogeneity in breast cancer is well documented. Although the mechanisms leading to this heterogeneity are not understood, a subpopulation of cancer cells, cancer stem cells (CSCs), that have some phenotypic similarities with adult tissue stem cells, has been suggested to contribute to tumour heterogeneity. It has been postulated that these CSCs are dormant, and by virtue of their low proliferative activity and ability to exclude intracellular toxins, are resistant to chemotherapy and radiation therapy. These cells were initially isolated based on the presence of markers such as CD44, CD24, and ALDH1, with further characterisation using mammosphere assay and transplantation into immunodeficient mice. The CSC hypothesis raises several theoretical and practical questions. Does cancer arise in normal mammary stem cells or do some malignant cells acquire a CSC phenotype through clonal evolution? Are CSCs in different molecular (intrinsic) subtypes of breast cancer similar, or do they have distinct properties based on the subtype? Does the CSC phenotype reflect plasticity or the dynamic nature of a few cancer cells? How do these cells acquire invasive behaviour, as they go through epithelial-to-mesenchymal transition and then revert to epithelial phenotype at sites of metastasis in response to tumour microenvironmental and metastasis site-specific cues? It is increasingly recognised that the methods and assays used for identifying CSCs have substantial limitations; does this negate the entire concept? In this Personal View, we argue that the CSC phenotype represents an aggressive clone that survives in an adverse environment through constant evolution and integration of various hallmarks of cancer. This evolution could involve acquiring mutations that permit asymmetric and symmetric division, converting the host immune attack to its own advantage, and plasticity to adapt to sites of metastasis through reversible change in adhesion molecules. We also argue that the cell-type origin of cancer could affect the rate at which CSCs develop in a tumour, with an eventual effect on disease outcome. PMID- 22225726 TI - Impact of ventricular contrast medium attenuation on the accuracy of left and right ventricular function analysis at cardiac multi detector-row CT compared with cardiac MRI. AB - RATIONALE AND OBJECTIVES: The aim of this study was to investigate the impact of ventricular contrast medium attenuation on the accuracy of left ventricular (LV) and right ventricular (RV) function analysis on coronary computed tomographic angiographic (CCTA) imaging compared to cardiac magnetic resonance imaging (CMR). MATERIALS AND METHODS: Thirty patients (mean age, 61.9 +/- 11.2 years; 14 men) underwent CCTA imaging and CMR. For both the right and left ventricles, end diastolic volume (EDV), end-systolic volume (ESV), and stroke volume (SV) were computed using multiphase image reconstruction of CCTA data. The accuracy of CCTA imaging was determined by subtracting CCTA measurements from CMR measurements. The accuracy of CCTA imaging was then correlated with the level of LV and RV contrast medium attenuation using regression analysis. RESULTS: In the right ventricle, there was strong correlation between the accuracy of CCTA functional assessment of EDV (R(2) = 0.78, P < .001), ESV (R(2) = 0.36, P < .001), and SV (R(2) = 0.75, P < .001) and the level of RV contrast medium attenuation. In studies with lower RV enhancement (<176 Hounsfield units; n = 15), the mean CCTA deviations of EDV, ESV, and SV from CMR measurements were 43.6 +/- 17.4, 11.2 +/- 9.64, and 35.1 +/- 11.5 mL, respectively. In studies with higher RV attenuation (>176 Hounsfield units; n = 15), these values were 13.6 +/- 10, 8.0 +/- 5.28, and 13 +/- 4.96 mL, respectively. In the left ventricle, there was weak correlation between functional CCTA accuracy and LV attenuation (mean, 358.31 +/- 68.71 Hounsfield units), and there was excellent correlation with CMR for LV EDV (R(2) = 0.86, P < .001), ESV (R(2) = 0.85, P < .001), and SV (R(2) = 0.51, P < .001). CONCLUSIONS: If computed tomographic evaluation of RV function is desired, attention should be paid to the contrast injection protocol, because the accuracy of RV function analysis depends on the level of contrast medium attenuation. The high contrast medium attenuation that is typically achieved in the left ventricle routinely enables highly accurate measurements compared to CMR. PMID- 22225727 TI - Exposure creep in computed radiography: a longitudinal study. AB - PURPOSE: Exposure creep is the gradual increase in x-ray exposures over time that results in increased radiation dose to the patient. It has been theorized as being a phenomenon that results from the wide-exposure latitude of computed radiography (CR) and direct/indirect digital radiography (DR). This project evaluates radiographic exposures over 43 months to determine if exposure creep exists and if measures can be applied to halt or reverse exposure creep trends. METHODS: Exposure indices were initially recorded over 29 months between August 2007 and December 2009 from the intensive and critical care unit (ICCU) and the emergency department (ED) departments where manual CR exposures were used. The data from this period were then assessed and the exposure indexes (EI) values from the radiographic images were compared to the radiology department criteria of EI values between 1400 to 1800 as being in the optimal exposure range. EI values below this were considered underexposed and over this as overexposed. An intervention was required to be used in ICCU and implemented in January 2010 to halt a noted trend of overexposure. The EI value for each chest x-ray (CXR) was recorded in the patients' ICCU records and was to be used by radiologic technologists/radiographers in determine exposure factors in subsequent CXR. After the intervention, EI values were recorded and evaluated for an additional 15 months between February 2010 and March 2011. RESULTS: Between August 2007 and December 2009, 17,678 ICCU CXR images and 69,327 ED x-ray examinations were evaluated for over- and underexposure. A trend was noted in ICCU that showed a significant increase (P = .023) in EI values from the beginning to the end of the evaluation. No such trend was seen in the ED EI values (P = .120). After the intervention in ICCU, the overexposure trend was halted. CONCLUSIONS: Exposure creep has been show to exist. It is surmised that this occurs where judgment to determine the correct radiographic exposure factors is needed when taking into account a large range of patient sizes. It has also been shown that providing radiologic technologists/radiographers with previous EI values for the same x-ray examination can halt a trend of exposure creep. PMID- 22225728 TI - Genomic and functional analysis of Vibrio phage SIO-2 reveals novel insights into ecology and evolution of marine siphoviruses. AB - We report on a genomic and functional analysis of a novel marine siphovirus, the Vibrio phage SIO-2. This phage is lytic for related Vibrio species of great ecological interest including the broadly antagonistic bacterium Vibrio sp. SWAT3 as well as notable members of the Harveyi clade (V.harveyi ATTC BAA-1116 and V.campbellii ATCC 25920). Vibrio phage SIO-2 has a circularly permuted genome of 80598 bp, which displays unusual features. This genome is larger than that of most known siphoviruses and only 38 of the 116 predicted proteins had homologues in databases. Another divergence is manifest by the origin of core genes, most of which share robust similarities with unrelated viruses and bacteria spanning a wide range of phyla. These core genes are arranged in the same order as in most bacteriophages but they are unusually interspaced at two places with insertions of DNA comprising a high density of uncharacterized genes. The acquisition of these DNA inserts is associated with morphological variation of SIO-2 capsid, which assembles as a large (80 nm) shell with a novel T=12 symmetry. These atypical structural features confer on SIO-2 a remarkable stability to a variety of physical, chemical and environmental factors. Given this high level of functional and genomic novelty, SIO-2 emerges as a model of considerable interest in ecological and evolutionary studies. PMID- 22225729 TI - Impact of BDNF Val66Met and 5-HTTLPR polymorphism variants on neural substrates related to sadness and executive function. AB - The brain-derived neurotrophic factor (BDNF) Val(66) Met allelic variation is linked to both the occurrence of mood disorders and antidepressant response. These findings are not universally observed, and the mechanism by which this variation results in increased risk for mood disorders is unclear. One possible explanation is an epistatic relationship with other neurotransmitter genes associated with depression risk, such as the serotonin-transporter-linked promotor region (5-HTTLPR). Further, it is unclear how the coexistence of the BDNF Met and 5-HTTLPR S variants affects the function of the affective and cognitive control systems. To address this question, we conducted a functional magnetic resonance imaging (fMRI) study in 38 older adults (20 healthy and 18 remitted from major depressive disorder). Subjects performed an emotional oddball task during the fMRI scan and provided blood samples for genotyping. Our analyses examined the relationship between genotypes and brain activation to sad distractors and attentional targets. We found that 5-HTTLPR S allele carriers exhibited stronger activation in the amygdala in response to sad distractors, whereas BDNF Met carriers exhibited increased activation to sad stimuli but decreased activation to attentional targets in the dorsolateral prefrontal and dorsomedial prefrontal cortices. In addition, subjects with both the S allele and Met allele genes exhibited increased activation to sad stimuli in the subgenual cingulate and posterior cingulate. Our results indicate that the Met allele alone or in combination with 5-HTTLPR S allele may increase reactivity to sad stimuli, which might represent a neural mechanism underlying increased depression vulnerability. PMID- 22225730 TI - Prevalence of psychotic symptoms in childhood and adolescence: a systematic review and meta-analysis of population-based studies. AB - BACKGROUND: Psychotic symptoms occur more frequently in the general population than psychotic disorder and index risk for psychopathology. Multiple studies have reported on the prevalence of these symptoms using self-report questionnaires or clinical interviews but there is a lack of consensus about the prevalence of psychotic symptoms among children and adolescents. METHOD: We conducted a systematic review of all published literature on psychotic symptom prevalence in two age groups, children aged 9-12 years and adolescents aged 13-18 years, searching through electronic databases PubMed, Ovid Medline, PsycINFO and EMBASE up to June 2011, and extracted prevalence rates. RESULTS: We identified 19 population studies that reported on psychotic symptom prevalence among children and adolescents. The median prevalence of psychotic symptoms was 17% among children aged 9-12 years and 7.5% among adolescents aged 13-18 years. CONCLUSIONS: Psychotic symptoms are relatively common in young people, especially in childhood. Prevalence is higher in younger (9-12 years) compared to older (13 18 years) children. PMID- 22225731 TI - Nursing students' satisfaction with supervision from preceptors and teachers during clinical practice. AB - The last two decades have seen widespread changes in nursing education. The clinical environment remains important for the development of nursing students' confidence in and fulfillment of intended learning outcomes. Preceptors and university teachers are an invaluable resource in preparing students for the reality of their professional roles. The current study examined Norwegian nursing students' perceptions of preceptors' and university teachers' supervision. Participants were invited to complete a version of the Nursing Facilitator Clinical Questionnaire (NFCQ) after the completion of their latest clinical practice periods. Three hundred and eighty students representing all three years of education completed the questionnaire. Data were analyzed with descriptive and inferential statistics. It was found that students highly valued teachers' and preceptors' supervision, although teachers' supervision was rated somewhat more highly. Fulfillment of learning outcomes for clinical practice was also rated highly, and the teachers' supervision was estimated, to some extent, more highly than the preceptors' supervision in this respect. The study underlines that, in addition to the estimation of satisfaction with supervision, it is important to relate supervision to the intended learning outcomes, which can be seen as a realization of that which students should know. PMID- 22225732 TI - Utilising the Hand Model to promote a culturally safe environment for international nursing students. AB - The rising number of international students studying outside their own country poses challenges for nursing education. Numbers are predicted to grow and economic factors are placing increasing pressure on tertiary institutions to accept these students. In adapting to a foreign learning environment international students must not only adapt to the academic culture but also to the social cultural context. The most significant acculturation issues for students are English as a second language, differences in education pedagogy and social integration and connectedness. Students studying in New Zealand need to work with Maori, the indigenous people, and assimilate and practice the unique aspects of cultural safety, which has evolved in nursing as part of the response to the principles underpinning the Treaty of Waitangi. The Hand Model offers the potential to support international nursing students in a culturally safe manner across all aspects of acculturation including those aspects of cultural safety unique to New Zealand. The model was originally developed by Lou Jurlina, a nursing teacher, to assist her to teach cultural safety and support her students in practising cultural safety in nursing. The thumb, represents 'awareness', with the other four digits signifying 'connection', 'communication', 'negotiation' and 'advocacy' respectively. Each digit is connected to the palm where the ultimate evaluation of The Hand Model in promoting cultural safety culminates in the clasping and shaking of hands: the moment of shared meaning. It promotes a sense of self worth and identity in students and a safe environment in which they can learn. PMID- 22225735 TI - [Can drug-induced rashes constitute epidemics?]. PMID- 22225736 TI - [Complications associated with injectable hyaluronic acid]. PMID- 22225737 TI - [Acquired ichthyosis and haematological malignancies: five cases]. AB - BACKGROUND: Acquired ichthyosis is a rare condition that can reveal an unsuspected haematological malignancy, thus allowing early diagnosis and management. If ichthyosis regresses under treatment for the haematological disorder, its recurrence reflects a turning point in the course of the disease and implies worsening of the prognosis. PATIENTS AND METHODS: The patients were examined at a joint dermatology/haematology consultation. The diagnosis of ichthyosis was based on clinical examination alone with no patients undergoing skin biopsy. RESULTS: Our series included three men and two women aged 38 to 65 years consulting for a variety of reasons including asthenia, anaemia and adenopathy. Ichthyosis occurred 2 to 9 months after the initial symptoms of the blood disease. Lesions consisted of diffuse brown scales. The disease was associated with lymphadenopathy and biological inflammatory syndrome. Two patients were presenting non-Hodgkin lymphoma, one had Hodgkin's disease, one had chronic myeloid leukaemia in progression and one had an undifferentiated lymphomatous process. Treatment was based on chemotherapy and emollients. The ichthyosis progressed in step with the underlying malignancy in all cases, with regression being complete in three cases, partial in one case and absent in one case. DISCUSSION: In rare cases, acquired ichthyosis reveals systemic disease, and may be of infectious, endocrine or drug origin; it may also be idiopathic. However, it is most often a paraneoplastic syndrome with cutaneous expression encountered during haematological malignancies. Because of the variety of causative blood dyscrasias, ichthyosis cannot be used to guide their diagnosis, although it remains a reliable monitoring tool. CONCLUSION: Acquired ichthyosis should prompt the clinician to search for a neoplastic condition, primarily a haematological disorder, guided by other associated signs, given that in our study, skin lesions generally appear to precede signs of the blood disease. PMID- 22225739 TI - [Folliculosebaceous cystic hamartoma: anatomo-clinical study]. AB - BACKGROUND: Folliculosebaceous cystic hamartoma (FSCH) is a relatively recently described malformation with follicular and sebaceous components and a particular type of stroma with adipocytes. We conducted an anatomo-clinical study in order to clarify the clinical and histological characteristics of FSCH. MATERIALS AND METHODS: We included all cases of FSCH diagnosed between 1985 and February 2011 at our dermatopathology laboratory. Clinical information was obtained from medical records and requests for histological examination. RESULTS: We studied 25 cases of FSCH in 25 patients of mean age 51 years. The sex ratio was 1.3. The mean disease duration was 9 years. Lesions were described mainly as flesh colored, occasionally pedunculated nodules and were found primarily on the face (60%). The diagnosis of FSCH had never been mentioned by the clinician. Histological examination revealed in all cases one or more follicular cystic structures surrounded by sebaceous glands in a stroma containing adipocytes. A number of variants were identified, such as the presence of a mucinous stroma, a neuroid component with protein S 100 expression, and rudimentary hair follicles in adjacent dermis. One case involved a proliferating cyst while another was on the scalp in the area of pre-existing radiodermatitis. Only one relapse was noted, 5 years after the initial excision. DISCUSSION: FSCH is a benign, underdiagnosed lesion, localized on the face, particularly on the nose. It is dome-shaped or pedunculated and grows slowly. Differential diagnoses include nevus lipomatosus superficialis and "sebaceous" trichofolliculoma. FSCH can be readily identified by the presence of adipocytes and a fibrous stroma. One case was unique in its appearance of a large pedunculated nodule with a proliferating cyst. Prior to the invidualization of this entity, such cases were interpreted as nevus lipomatosus superficialis or "sebaceous" trichofolliculoma, although their histological appearance was inconsistent with such a diagnosis. PMID- 22225738 TI - [Six cases of spring DRESS]. AB - BACKGROUND: An association between herpes virus reactivations and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is accepted. We report six cases of DRESS with viral reactivation occurring within a single 1-month period. We attempted to find a common factor for these six cases and carried out clinical and virological examinations. Before and after this "epidemic", the mean number of cases of DRESS seen at the same centre was one per quarter, making the occurrence of six cases within a single month all the more remarkable and prompting us to seek an explanation. PATIENTS AND METHODS: All six patients had taken a partly causative medication from different drug classes three to six weeks prior to the start of symptoms and herpes virus was detected in the blood of all of these subjects at the time of DRESS onset (four reactivations and two primary infections), and one patient subsequently displayed herpetic meningoencephalitis 95 days after the initial episode, associated with recurrence of DRESS. DISCUSSION: There was no common denominator among these six DRESS patients in terms of either drug class or reactivation of a particular type of herpes virus, which raises the possibility of a single unidentified environmental agent. DRESS does not appear fully explainable in terms of a cellular response to drug antigens but seems rather to result from complex interactions between the drug-induced immune response, viral reactivation and antiviral immune response. Several investigators have reported sequential reactivation of herpes viruses in DRESS. A viral epidemic could thus cause a "DRESS epidemic" in patients on medication. CONCLUSION: These cases point to the possible existence of a shared initial environmental factor (infectious or not) that favours reactivation of herpes viruses and induces DRESS in patients on medication. Before and after this "DRESS epidemic", about one patient each quarter was admitted to hospital for DRESS. PMID- 22225740 TI - [New developments in Sezary syndrome]. AB - Sezary syndrome (SS) represents 3% of cutaneous T-cell lymphomas (CTCL). It is an aggressive epidermotropic CTCL with a 5-year survival rate of 24%. According to EORTC (European organization for research and treatment of cancer), SS is defined by erythroderma, diffuse lymphadenopathy, atypical T lymphocytes (>1000/mm(3)), and the presence of a major blood, cutaneous and nodal T cell clone. A specific marker for atypical tumoral T lymphocytes known as Sezary cells was identified in 2001, namely KIR3DL2 (CD158k) receptor, which allows more specific diagnosis of SS; levels of this marker are highly correlated with the clinical course of the disease. In therapeutic terms, clinical trials are being conducted on new molecules that point towards an improved prognosis for this disease. We propose a review of Sezary syndrome, which is currently the subject of scientific papers concerning both physiopathology and therapeutics, with new prospects of targeted therapy. PMID- 22225741 TI - [Bilateral elastofibroma dorsi]. AB - BACKGROUND: Elastofibroma dorsi (EFD) is a rare form of benign soft-tissue tumour that is almost always located at the lower pole of the scapula, deep to the serratus anterior muscle. There are few reports in the dermatological literature since it rarely develops in skin or subcutaneous tissue. CASE REPORT: We present the case of a 59-year-old man with bilateral elastofibroma dorsi. Physical examination showed two bilateral scapular masses, better visualized in abduction or antepulsion. They were firm, painless, mobile, covered by normal skin, and measured 40/35 mm on the right and 50/55 mm on the left. Ultrasound of soft tissue and a chest CT scan showed two heterogeneous masses (tissue and fat) within the serratus anterior muscle measuring 30/15 mm on the right and 60/19 mm on the left. Histopathological study of a deep biopsy done on the right helped to confirm the diagnosis of EFD. Tumour resection was done on the right. DISCUSSION: Elastofibroma dorsi is an uncommon, benign, non-encapsulated pseudo-tumour occurring in connective tissue of the infrascapular region of elderly patients. Another mass must be sought in all cases in the corresponding contralateral site since this form of tumour is often bilateral. CONCLUSION: EFD must be considered in the differential diagnosis of shoulder masses in elderly patients. PMID- 22225742 TI - [Haemophagocytic syndrome as a complication of acute pancreatitis during systemic lupus erythematosus]. AB - BACKGROUND: Acute pancreatitis and haemophagocytic syndrome (HS) are rarely seen in systemic lupus erythematosus (SLE). PATIENTS AND METHODS: We report the case of a young female patient without any noteworthy prior history, who was hospitalised for abdominal pain associated with acute pancreatitis possibly related to SLE with associated haemophagocytic syndrome. DISCUSSION: Screening for cutaneous symptoms of lupus in patients with pancreatitis can help avoid diagnostic errors. PMID- 22225743 TI - [Syringotropic cutaneous T-cell lymphoma mimicking dermatomycosis]. AB - INTRODUCTION: Cutaneous syringotropic T-cell lymphoma is a rare form of lymphoma. We report a case involving a misleading cutaneous presentation on the sole of the foot. PATIENTS AND METHODS: A 55-year-old woman presented discrete coalescent papules on her left foot, having an anhidrotic appearance, for which a number of antifungal treatments had been given without success. The skin biopsy revealed CD4+ T lymphocytic dermal infiltrate, mainly near the sweat glands, with syringotropism. The diagnosis of syringotropic T-cell lymphoma was reinforced by the presence of dominant cutaneous T-lymphocyte clone in the skin biopsy. Staging tests were negative. Treatment was initiated with an extremely potent (class IV) dermal corticosteroid. DISCUSSION: Syringotropic T-cell lymphoma is an extremely rare form of cutaneous lymphoma similar in presentation to mycosis fungoides, characterised by the mainly perisudoral and syringotropic nature of the lymphocytic infiltrate. The value of this case report lies in the extremely mild nature of the misleading skin lesions, which could only be diagnosed through biopsy. Treatment for this condition is not as yet codified due to the extremely low number of cases reported in the literature. PMID- 22225744 TI - [Extensive Dowling-Degos disease following long term PUVA therapy]. AB - BACKGROUND: Dowling-Degos disease is a rare and benign inherited dermatosis. PATIENTS AND METHODS: A 53-year-old woman presented with generalized histologically confirmed Dowling-Degos disease revealed 8 years after psoralen photochemotherapy (PUVA) for psoriasis. This presentation was special in terms of its considerable spread as well as the absence of comedone-like and punctate scars. DISCUSSION: Dowling-Degos disease is a reticulate pigmentary disorder of the flexures associating prominent comedone-like lesions and pitted scars. Diagnosis is based on clinical and histopathological examination, which allows this entity to be differentiated from other reticulate pigmentary disorders. A literature review failed to provide any indication that PUVA therapy either aggravates or reveals Dowling-Degos disease, a finding which we feel merits mention. PMID- 22225745 TI - [Atypical papular mucinosis with initial histological findings evocative of granuloma annulare]. AB - BACKGROUND: Papular mucinosis is characterized by primary reticular dermal mucin deposition in the absence of any thyroid abnormalities. There is extensive clinical variety in this disease, from benign localized forms to generalized forms, on occasion lethal. The current classification was established in 1991 in order to allow identification of these generalized forms of the disease and help ensure a better therapeutic approach. We report the case of a patient with atypical papular mucinosis having initial histological features consistent with granuloma annulare. PATIENTS AND METHODS: A 55-year-old man consulted for a papular eruption of the hands. A diagnosis of granuloma annulare was initially made because of misleading histological findings. However, the eruption spread to the inner thighs and the hypogastric area despite dermocorticoid therapy. Laboratory evaluation showed a monoclonal gammopathy. Further biopsies revealed diffuse dermal mucin deposits. We finally concluded on atypical localized papular mucinosis. DISCUSSION: Papular mucinosis is a rare disease and its physiopathology remains to be elucidated. The diagnostic criteria are sometimes inadequate, and its classification includes both atypical and intermediate forms. Our case belongs to the latter class because of its extensive and unusual topography, and its association with a monoclonal gammopathy. Although granuloma annulare is not a classical differential diagnosis, two other cases with similar histological findings have already been published. PMID- 22225733 TI - Central coordination as an alternative for local coordination in a multicenter randomized controlled trial: the FAITH trial experience. AB - BACKGROUND: Surgeons in the Netherlands, Canada and the US participate in the FAITH trial (Fixation using Alternative Implants for the Treatment of Hip fractures). Dutch sites are managed and visited by a financed central trial coordinator, whereas most Canadian and US sites have local study coordinators and receive per patient payment. This study was aimed to assess how these different trial management strategies affected trial performance. METHODS: Details related to obtaining ethics approval, time to trial start-up, inclusion, and percentage completed follow-ups were collected for each trial site and compared. Pre-trial screening data were compared with actual inclusion rates. RESULTS: Median trial start-up ranged from 41 days (P25-P75 10-139) in the Netherlands to 232 days (P25 P75 98-423) in Canada (p = 0.027). The inclusion rate was highest in the Netherlands; median 1.03 patients (P25-P75 0.43-2.21) per site per month, representing 34.4% of the total eligible population. It was lowest in Canada; 0.14 inclusions (P25-P75 0.00-0.28), representing 3.9% of eligible patients (p < 0.001). The percentage completed follow-ups was 83% for Canadian and Dutch sites and 70% for US sites (p = 0.217). CONCLUSIONS: In this trial, a central financed trial coordinator to manage all trial related tasks in participating sites resulted in better trial progression and a similar follow-up. It is therefore a suitable alternative for appointing these tasks to local research assistants. The central coordinator approach can enable smaller regional hospitals to participate in multicenter randomized controlled trials. Circumstances such as available budget, sample size, and geographical area should however be taken into account when choosing a management strategy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00761813. PMID- 22225747 TI - [Lichen sclerosus]. PMID- 22225746 TI - [Facial angioedema following hyaluronic acid injection]. PMID- 22225748 TI - [Subungual keratoacanthoma]. PMID- 22225749 TI - [Kaposi's sarcoma]. PMID- 22225750 TI - [Adermatoglyphia or "immigration delay disease": the role of mutations in the SMARCAD1 gene]. PMID- 22225751 TI - [Adverse effect of hypodermoclysis: an unusual clinical presentation]. PMID- 22225752 TI - [Congenital lower lip pits]. PMID- 22225753 TI - [Lime, beer and phytophotodermatitis]. PMID- 22225754 TI - [Note the irritant effect of Emla(r) cream potentially leading to diagnostic errors]. PMID- 22225755 TI - The effectiveness and cost of single and multi-factorial cardiovascular risk factor modification to guideline targets in type 2 diabetes. AB - AIMS: Cardiovascular disease is the main cause of morbidity and mortality in type 2 diabetes (T2DM), at huge cost to the NHS. We investigated the potential effect on population cardiovascular risk and associated costs of single and multi factorial intervention, to target levels, in individuals with T2DM. METHODS: Baseline population means and proportions for cardiovascular risk factors were calculated for 159 patients with T2DM from 3 general practices. Predicted 10year cardiovascular risk, and associated costs were calculated using the LIP2687 risk calculator, based on Framingham and UKPDS equations. Systolic blood pressure, HbA(1C), total cholesterol and HDL-cholesterol were altered to NICE and SIGN target levels and the model run again. The difference in outcomes was observed. RESULTS: 45%, 76% and 38% of patients met NICE targets for cholesterol, systolic blood pressure and HbA1c, respectively. As expected, comparing the two guidelines, fewer patients met the 'stricter' targets (P=0.0001). Treatment-to target produced no significant difference in cardiovascular risk or costs, although greater reductions in outcomes were seen with multi-factorial intervention. CONCLUSION: This small study suggests that intervention in only those patients with the highest cardiovascular risk brings little reduction in population cardiovascular risk and associated health costs. Multi-factorial intervention in all patients with T2DM, regardless of baseline values, is likely to bring greater reductions. This raises the question as to whether the current emphasis on treatment to target should be modified to encourage multi-factorial intervention in all patients with T2DM, even those with baseline values below target levels. PMID- 22225756 TI - Advances in mesenchymal stem cell research in sepsis. AB - BACKGROUND: Sepsis remains a source of morbidity and mortality in the postoperative patient despite appropriate resuscitative and antimicrobial approaches. Recent research has focused upon additional interventions such as exogenous cell-based therapy. Mesenchymal stem cells (MSCs) exhibit multiple beneficial properties through their capacity for homing, attenuating the inflammatory response, modulating immune cells, and promoting tissue healing. Recent animal trials have provided evidence that MSCs may be useful therapeutic adjuncts. MATERIALS AND METHODS: A directed search of recent medical literature was performed utilizing PubMed to examine the pathophysiology of sepsis, mechanisms of mesenchymal stem cell interaction with host cells, sepsis animal models, and recent trials utilizing stem cells in sepsis. RESULTS: MSCs continue to show promise in the treatment of sepsis by their intrinsic ability to home to injured tissue, secrete paracrine signals to limit systemic and local inflammation, decrease apoptosis in threatened tissues, stimulate neoangiogenesis, activate resident stem cells, beneficially modulate immune cells, and exhibit direct antimicrobial activity. These effects are associated with reduced organ dysfunction and improved survival in animal models. CONCLUSION: Research utilizing animal models of sepsis has provided a greater understanding of the beneficial properties of MSCs. Their capacity to home to sites of injury and use paracrine mechanisms to change the local environment to ultimately improve organ function and survival make MSCs attractive in the treatment of sepsis. Future studies are needed to further evaluate the complex interactions between MSCs and host tissues. PMID- 22225757 TI - Iron chelation afforded cardioprotection against H2O2-induced H9C2 cell injury: application of novel 3-hydroxy pyridine-4-one derivatives. PMID- 22225758 TI - Predictors for in-hospital peak glycemia in STEMI patients without previously known diabetes. PMID- 22225759 TI - Electrocardiographic abnormalities and risk of complete atrioventricular block. PMID- 22225760 TI - Combined use of exercise electrocardiography, coronary calcium score and cardiac CT angiography for the prediction of major cardiovascular events in patients presenting with stable chest pain. AB - BACKGROUND: The usual diagnostic work-up of chest pain patients includes clinical risk profiling and exercise-ECG, possibly followed by additional tests. Recently cardiac computed tomographic angiography (CCTA) has been employed. We evaluated the prognostic value of the combined use of exercise-ECG and CCTA for the development of cardiovascular endpoints. METHODS: In 283 patients (143 male, mean age 54 +/- 10 years) with intermediate pre-test probability for coronary artery disease presenting with stable chest pain, exercise-ECG, CCTA and calcium score were performed. Patients were followed-up for combined endpoint of acute coronary syndrome (ACS) and revascularization. RESULTS: After a median follow-up of 769 days (interquartile range 644-1007), 6 ACS and 9 revascularizations were recorded. A positive exercise-ECG predicted for the combined endpoint, [hazard ratio (HR) 5.14 (95% confidence interval (CI) 1.64-16.13), p=0.005], as well as a positive calcium score [HR 4.59 (95% CI 1.30-16.28), p=0.02] and a >= 50% stenosis on CCTA [HR 45.82 (95% CI 6.02-348.54), p<0.001]. ROC-analysis showed an area under the curve (AUC) of 0.79 (95% CI 0.67-0.90) for exercise-ECG, which increased significantly when CCTA was added: 0.91 (95% CI; 0.86-0.97; p=0.006). Multivariable Cox regression showed exercise-ECG predicted independently [HR 3.6, (95% CI 1.1-11.2), p=0.03], as well as CCTA [HR 31.4 (95% CI 4.0-246.6), p=0.001], but not calcium score [HR 0.6 (95% CI 0.2-2.3), p=0.5]. CONCLUSIONS: The combined subsequent use of exercise-ECG for functional information and CCTA for anatomical information provides a high diagnostic yield in stable chest pain patients with an intermediate pre-test probability for coronary artery disease. PMID- 22225761 TI - Association of Marfan syndrome and bicuspid aortic valve: frequency and outcome. PMID- 22225762 TI - Tako-tsubo cardiomyopathy following an allergic asthma attack after cephalosporin administration. PMID- 22225763 TI - Objective assessment of internal stress in children during dental treatment by analysis of autonomic nervous activity. AB - AIMS: The aim of this study was to assess the internal stress of children during dental treatment based on autonomic nerve activity and facial muscle activity. METHODS: We recorded the electrocardiogram of children during the treatment of composite resin restoration and analysed autonomic nerve activity by means of power spectral analysis of heart rate variability. Simultaneously, electromyography (EMG) activity of the corrugator muscle was recorded in children during dental treatment, and the relationship between sympathetic nerve activity and corrugator EMG activity was analysed. RESULTS: In all subjects, the mean sympathetic nerve activity was significantly higher during oral examination and after treatment compared with pre-treatment. Depending on the sympathetic nerve responses to the other treatment procedures, the subjects could be classified into two groups: the stress group and the nonstress group. Sympathetic nerve activity was significantly higher during infiltration anaesthesia and cavity preparation compared with pre-treatment activity in the stress group, whereas it was consistently lower than the pre-treatment levels during most treatment procedures in the nonstress group. The mean amplitudes of the averaged corrugator muscle EMG during dental treatment did not differ between the stress and nonstress groups. CONCLUSION: The present results suggest that the measurement of autonomic nervous activity, especially sympathetic nervous activity, is quite useful in assessing the internal stress of children, even when no expressed sign of unease are present during dental treatment. PMID- 22225764 TI - Collaborative study for the establishment of the second international standard for vancomycin. AB - An international collaborative study has been organised by the European Directorate for the Quality of Medicines & HealthCare (EDQM) to establish the World Health Organization (WHO) 2nd International Standard (IS) for Vancomycin. Twelve laboratories from 10 different countries participated. The potency of the candidate material, a freeze-dried preparation, was estimated by microbiological assays with sensitive micro-organisms. As the stocks of the 1st IS for Vancomycin had been completely depleted, in order to ensure continuity between consecutive batches of the WHO IS, the European Pharmacopoeia Chemical Reference Standard (CRS) for Vancomycin batch 2 was used as a standard. It had been calibrated in a large international collaborative study against the WHO 1st IS for Vancomycin. Based on the results of the study, the 2nd IS for Vancomycin was adopted at the meeting of the WHO Expert Committee on Biological Standardisation (ECBS) in 2010 with an assigned antimicrobiological activity of 109,700 IU per vial. The 2nd IS for Vancomycin is available from the EDQM. PMID- 22225765 TI - New BRP for human plasma calibrated for coagulation factors V, VIII, XI and XIII collaborative study for establishment of batches 1 and 2. AB - A human plasma reference preparation in International Units (IU) must be used in each potency assay of the human coagulation factors V, VIII and XI in human plasma pooled and treated for virus inactivation, according to the European Pharmacopoeia (Ph. Eur.) monograph 1646 and general chapters 2.7.4 and 2.7.22 respectively, and in the potency assay of human coagulation factor XIII in fibrin sealant kits, according to Ph. Eur. monograph 0903. International reference standards for all of these factors are now established, however, regional reference standards were not available for the required routine use. It was therefore proposed by European OMCLs and manufacturers to establish a European reference preparation, and it was the goal of this study to accomplish that. Two candidate biological reference preparations (BRPs), separate lyophilisation lots of the same normal human plasma bulk material, were calibrated against the International Standards (ISs) for human coagulation factors V, VIII, XI and XIII. Twelve European laboratories including OMCLs and manufacturers participated. The candidate material was tested against the ISs in 4 separate assays for each factor using the methods described in the relevant Ph. Eur. monographs and general chapters. No discernable difference was noted between the activities of the 2 candidates. They were shown to be suitable for their intended use and it was recommended to assign to both batches a potency of 0.73 IU/mL for factor V, 0.74 IU/mL for factor VIII, 0.59 IU/mL for factor XI and 0.79 IU/mL for factor XIII. Candidate batch B is proposed to be used first as lot 1, followed upon its depletion by candidate batch A (lot 2). The BRP batches will be monitored regularly for potency throughout their lifetime. EDQM BRP batches 1 and 2 of coagulation factors V, VIII, XI and XIII plasma were formally adopted by the Ph. Eur. Commission at their session in June 2011. PMID- 22225766 TI - Biological indicators, tools to verify the effect of sterilisation processes - position paper prepared on behalf of group 1 (biological methods and statistical analysis). AB - Biological indicators (BIs) are test systems containing viable microorganisms (usually spores of bacteria) providing a defined challenge to a specified sterilisation process. General chapter 5.1.2 of the European Pharmacopoeia [1] (Ph. Eur.) sets specifications for BIs and gives some guidance for their use. As shown in this text, the approach followed by Ph. Eur. as well as by ISO standards is outdated and could create nowadays some confusion among the users of the pharmacopoeia. It is the objective of this paper to provide the theoretical background of BIs as tools for the design and qualification of reliable moist heat sterilisation processes. The principles laid down in this article will form the basis of a future draft on a revised chapter on BIs in Pharmeuropa. PMID- 22225767 TI - Determination of water content by capillary gas chromatography coupled with thermal conductivity detection. AB - This article presents some experience obtained by applying capillary gas chromatography coupled with thermal conductivity detection (GC/TCD) to the determination of water in substances for pharmaceutical use. This technique represents a useful, orthogonal tool complementary to water determination methods based on volumetric or coulometric titration. It can also represent an alternative technique when such titrations are not applicable. This article presents the preliminary results obtained in a number of case studies where a GC/TCD procedure was applied in comparison with pharmacopoeial methods to substances with different water contents. PMID- 22225768 TI - Preface: The neurobiology of syntax. PMID- 22225769 TI - Measuring passive myocardial stiffness in Drosophila melanogaster to investigate diastolic dysfunction. AB - Aging is marked by a decline in LV diastolic function, which encompasses abnormalities in diastolic relaxation, chamber filling and/or passive myocardial stiffness. Genetic tractability and short life span make Drosophila melanogaster an ideal organism to study the effects of aging on heart function, including senescent-associated changes in gene expression and in passive myocardial stiffness. However, use of the Drosophila heart tube to probe deterioration of diastolic performance is subject to at least two challenges: the extent of genetic homology to mammals and the ability to resolve mechanical properties of the bilayered fly heart, which consists of a ventral muscle layer that covers the contractile cardiomyocytes. Here, we argue for widespread use of Drosophila as a novel myocardial aging model by (1) describing diastolic dysfunction in flies, (2) discussing how critical pathways involved in dysfunction are conserved across species and (3) demonstrating the advantage of an atomic force microscopy-based analysis method to measure stiffness of the multilayered Drosophila heart tube versus isolated myocytes from other model systems. By using powerful Drosophila genetic tools, we aim to efficiently alter changes observed in factors that contribute to diastolic dysfunction to understand how one might improve diastolic performance at advanced ages in humans. PMID- 22225770 TI - Duplication of CXC chemokine genes on chromosome 4q13 in a melanoma-prone family. AB - Copy number variations (CNVs) have been shown to contribute substantially to disease susceptibility in several inherited diseases including cancer. We conducted a genome-wide search for CNVs in blood-derived DNA from 79 individuals (62 melanoma patients and 17 spouse controls) of 30 high-risk melanoma-prone families without known segregating mutations using genome-wide comparative genomic hybridization (CGH) tiling arrays. We identified a duplicated region on chromosome 4q13 in germline DNA of all melanoma patients in a melanoma-prone family with three affected siblings. We confirmed the duplication using quantitative PCR and a custom-made CGH array design spanning the 4q13 region. The duplicated region contains 10 genes, most of which encode CXC chemokines. Among them, CXCL1 (melanoma growth-stimulating activity alpha) and IL8 (interleukin 8) have been shown to stimulate melanoma growth in vitro and in vivo. Our data suggest that the alteration of CXC chemokine genes may confer susceptibility to melanoma. PMID- 22225771 TI - Inhibition of return and schizophrenia: a meta-analysis. AB - Inhibition of return (IOR) is a phenomenon that involves inhibited or delayed orienting to previously cued locations in favor of attending to novel locations. To date, research on IOR in patients with schizophrenia has generated mixed, and seemingly conflicting, results. Some researchers report patients with schizophrenia exhibit blunted or delayed IOR, while other researchers report normal IOR, in terms of time course and magnitude. This meta-analysis summarizes the literature that has employed an IOR task in patients with schizophrenia and with controls while focusing upon a procedural feature, the use of a cue back to fixation, between the cue and target that is known to be important when executive control has been hampered in non-clinical populations. Fifteen experiments were located yielding a total sample of 362 patients with schizophrenia or schizoaffective disorder and 285 controls. Using a meta-analytic approach, results of the present analyses show that patients with schizophrenia demonstrate delayed IOR in the single cue procedure. In the cue back to fixation procedure, the time course of IOR among patients is more consistent with that of controls. Differences in measured IOR between patients with schizophrenia and controls are largely related to a deficit in endogenous disengagement of attention. PMID- 22225772 TI - Cross-sectional survey of antimicrobial prescribing patterns in UK small animal veterinary practice. AB - The increase in the prevalence of antimicrobial resistance has resulted in both human and veterinary antimicrobial use coming under increased scrutiny. The aim of this study was to characterise antimicrobial prescribing patterns in small animal veterinary practices in the UK. A cross-sectional survey of UK small animal veterinarians was undertaken. A postal questionnaire to evaluate antimicrobial prescribing habits was sent to 900 clinicians. Data were collected on the clinicians, their practices and their sources of information regarding antimicrobials and their use. Respondents were asked if they would prescribe antimicrobials to animals described in four clinical scenarios, and, if so, to provide details of the prescription(s). Questionnaires were completed by 51% of the veterinarians. Only 3.5% of clinicians reported that their practice had an antimicrobial use policy. Penicillins were most commonly prescribed in three clinical scenarios, and 1st generation cephalosporins were most commonly prescribed in a scenario about canine pyoderma. In one scenario, fluoroquinolones and 3rd generation cephalosporins accounted for 10% and 13% of prescriptions respectively. Five percent of all prescriptions were under the recommended dose and 20% were over the recommended dose. Overall, 2.3% of prescriptions were not licensed for use in dogs or cats in the UK. Associations between the use of various antimicrobial drugs and independent variables were analysed using multivariable logistic regression models. Off-license prescriptions and inaccurate dosing of antimicrobials by small-animal clinicians in the UK appears to occur. Antimicrobial use guidelines are rare in small animal practice. The introduction of such guidelines has been shown to lead to more appropriate use of antimicrobials and is therefore recommended. PMID- 22225773 TI - A capture-recapture analysis in a challenging environment: assessing the epidemiological situation of foot-and-mouth disease in Cambodia. AB - We performed a two-source capture-recapture analysis for estimating the true number of villages that experienced clinical cases of foot-and-mouth disease (FMD) in 2009 in Svay Rieng province, Cambodia, and assessing the completeness of the official case-reporting procedure. As a first source, we used the 2009 official dataset made up of the 15 FMD-infected villages that were reported to the provincial authorities, and enlarged this list by assuming that all the villages located at less than 4 km from one of these villages also experienced clinical cases in 2009. In addition, we created a retrospective detection protocol using participatory tools cross-checked against a serological survey that detected 13 infected villages. The capture-recapture analysis of these two detection sources led us to the conclusion that 315 (CI(95%) 117-514) villages experienced clinical cases of foot-and-mouth disease in Svay Rieng province in 2009, corresponding to a village-level annual prevalence rate of 0.46 (CI(95%) 0.17-0.74). The official reporting rate to provincial authorities could therefore be evaluated at 0.05 (CI(95%) 0.03-0.13). An analysis of the sensitivity of the estimation of the number of cases to the radius used for enlargement of Source 1 was performed, indicating its low influence. This study clearly highlights the highly enzootic situation of Cambodia regarding foot-and-mouth disease and the substantial underreporting of clinically affected villages to veterinary authorities. We propose explanations for this low notification rate, stress the importance of accurate reporting procedures and, finally, discuss the potential of capture-recapture techniques as a tool for the quantitative evaluation of animal disease surveillance systems. PMID- 22225774 TI - Construction and transformation of a Thermotoga-E. coli shuttle vector. AB - BACKGROUND: Thermotoga spp. are attractive candidates for producing biohydrogen, green chemicals, and thermostable enzymes. They may also serve as model systems for understanding life sustainability under hyperthermophilic conditions. A lack of genetic tools has hampered the investigation and application of these organisms. This study aims to develop a genetic transfer system for Thermotoga spp. RESULTS: Methods for preparing and handling Thermotoga solid cultures under aerobic conditions were optimized. A plating efficiency of ~50% was achieved when the bacterial cells were embedded in 0.3% Gelrite. A Thermotoga-E. coli shuttle vector pDH10 was constructed using pRQ7, a cryptic mini-plasmid found in T. sp. RQ7. Plasmid pDH10 was introduced to T. maritima and T. sp. RQ7 by electroporation and liposome-mediated transformation. Transformants were isolated, and the transformed kanamycin resistance gene (kan) was detected from the plasmid DNA extracts of the recombinant strains by PCR and was confirmed by restriction digestions. The transformed DNA was stably maintained in both Thermotoga and E. coli even without the selective pressure. CONCLUSIONS: Thermotoga are transformable by multiple means. Recombinant Thermotoga strains have been isolated for the first time. A heterologous kan gene is functionally expressed and stably maintained in Thermotoga. PMID- 22225776 TI - Silencing of homeobox B9 is associated with down-regulation of CD56 and extrathyroidal extension of tumor in papillary thyroid carcinoma. AB - Papillary thyroid carcinoma is the most common type of thyroid malignancy, and CD56, a neural cell adhesion molecule, is typically down-regulated in almost all cases of papillary thyroid carcinoma. Homeobox B9 is a transcription factor, belongs to the products of the homeobox transcription factor gene family, and has been known to regulate transcription of CD56 and to promote tumorigenicity and metastasis in some malignancies. In this study, we investigated the expression and relation of homeobox B9 to reduced expression of CD56 in papillary thyroid carcinomas and also a relationship between their expression and clinicopathologic parameters. Therefore, we performed CD56 and homeobox B9 immunohistochemical staining on 72 papillary thyroid carcinomas and Western blotting on 31 papillary thyroid carcinomas. CD56 protein staining revealed that it was reduced or absent in 65 papillary thyroid carcinomas (90.3%) and was related to silencing of homeobox B9 (77.8%) (P = .003). The loss of homeobox B9 expression was associated with extrathyroidal extension (P = .002), pathologic stage of tumor (P = .01), and age older than 45 years (P = .032). However, the CD56 staining did not reveal any significant relationship with clinicopathologic features (P > .05). In conclusion, reduced expression of CD56 is associated with homeobox B9 in papillary thyroid carcinomas. Furthermore, silencing of homeobox B9 is more common in older age and is linked to extrathyroidal extension and advanced pathologic stage of papillary thyroid carcinoma. PMID- 22225775 TI - Dynamics of eye-position signals in the dorsal visual system. AB - BACKGROUND: Many visual areas of the primate brain contain signals related to the current position of the eyes in the orbit. These cortical eye-position signals are thought to underlie the transformation of retinal input-which changes with every eye movement-into a stable representation of visual space. For this coding scheme to work, such signals would need to be updated fast enough to keep up with the eye during normal exploratory behavior. We examined the dynamics of cortical eye-position signals in four dorsal visual areas of the macaque brain: the lateral and ventral intraparietal areas (LIP; VIP), the middle temporal area (MT), and the medial-superior temporal area (MST). We recorded extracellular activity of single neurons while the animal performed sequences of fixations and saccades in darkness. RESULTS: The data show that eye-position signals are updated predictively, such that the representation shifts in the direction of a saccade prior to (<100 ms) the actual eye movement. Despite this early start, eye position signals remain inaccurate until shortly after (10-150 ms) the eye movement. By using simulated behavioral experiments, we show that this brief misrepresentation of eye position provides a neural explanation for the psychophysical phenomenon of perisaccadic mislocalization, in which observers misperceive the positions of visual targets flashed around the time of saccadic eye movements. CONCLUSIONS: Together, these results suggest that eye-position signals in the dorsal visual system are updated rapidly across eye movements and play a direct role in perceptual localization, even when they are erroneous. PMID- 22225777 TI - Oral extragonadal yolk sac tumor in a patient with Aicardi syndrome: putative origin and differential diagnosis. AB - We report, for the first time, a primary oral presentation of a germ cell yolk sac tumor in a 4-year-old girl with Aicardi syndrome. The diagnosis, differential diagnosis, and histogenesis are discussed. PMID- 22225779 TI - Wuwhs 2012. PMID- 22225783 TI - Interpersonal sensitivity in the at-risk mental state for psychosis. AB - BACKGROUND: Interpersonal sensitivity is a personality trait described as excessive awareness of both the behaviour and feelings of others. Although interpersonal sensitivity has been found to be one of the vulnerability factors to depression, there has been little interest in its relationship with the prodromal phase of psychosis. The aims of this study were to examine the level of interpersonal sensitivity in a sample of individuals with an at-risk mental state (ARMS) for psychosis and its relationship with other psychopathological features. METHOD: Sixty-two individuals with an ARMS for psychosis and 39 control participants completed a series of self-report questionnaires, including the Interpersonal Sensitivity Measure (IPSM), the Prodromal Questionnaire (PQ), the Ways of Coping Questionnaire (WCQ) and the Depression and Anxiety Stress Scale (DASS). RESULTS: Individuals with an ARMS reported higher interpersonal sensitivity compared to controls. Associations between interpersonal sensitivity, positive psychotic symptoms (i.e. paranoid ideation), avoidant coping and symptoms of depression, anxiety and stress were also found. CONCLUSIONS: This study suggests that being 'hypersensitive' to interpersonal interactions is a psychological feature of the putatively prodromal phase of psychosis. The relationship between interpersonal sensitivity, attenuated positive psychotic symptoms, avoidant coping and negative emotional states may contribute to long term deficits in social functioning. We illustrate the importance, when assessing a young client with a possible ARMS, of examining more subtle and subjective symptoms in addition to attenuated positive symptoms. PMID- 22225778 TI - Alterations in tumor necrosis factor signaling pathways are associated with cytotoxicity and resistance to taxanes: a study in isogenic resistant tumor cells. AB - INTRODUCTION: The taxanes paclitaxel and docetaxel are widely used in the treatment of breast, ovarian, and other cancers. Although their cytotoxicity has been attributed to cell-cycle arrest through stabilization of microtubules, the mechanisms by which tumor cells die remains unclear. Paclitaxel has been shown to induce soluble tumor necrosis factor alpha (sTNF-alpha) production in macrophages, but the involvement of TNF production in taxane cytotoxicity or resistance in tumor cells has not been established. Our study aimed to correlate alterations in the TNF pathway with taxane cytotoxicity and the acquisition of taxane resistance. METHODS: MCF-7 cells or isogenic drug-resistant variants (developed by selection for surviving cells in increasing concentrations of paclitaxel or docetaxel) were assessed for sTNF-alpha production in the absence or presence of taxanes by enzyme-linked immunosorbent assay (ELISA) and for sensitivity to docetaxel or sTNF-alpha by using a clonogenic assay (in the absence or presence of TNFR1 or TNFR2 neutralizing antibodies). Nuclear factor (NF)-kappaB activity was also measured with ELISA, whereas gene-expression changes associated with docetaxel resistance in MCF-7 and A2780 cells were determined with microarray analysis and quantitative reverse transcription polymerase chain reaction (RTqPCR). RESULTS: MCF-7 and A2780 cells increased production of sTNF-alpha in the presence of taxanes, whereas docetaxel-resistant variants of MCF-7 produced high levels of sTNF-alpha, although only within a particular drug-concentration threshold (between 3 and 45 nM). Increased production of sTNF-alpha was NF-kappaB dependent and correlated with decreased sensitivity to sTNF-alpha, decreased levels of TNFR1, and increased survival through TNFR2 and NF-kappaB activation. The NF-kappaB inhibitor SN-50 reestablished sensitivity to docetaxel in docetaxel-resistant MCF-7 cells. Gene expression analysis of wild-type and docetaxel-resistant MCF-7, MDA-MB-231, and A2780 cells identified changes in the expression of TNF-alpha-related genes consistent with reduced TNF-induced cytotoxicity and activation of NF-kappaB survival pathways. CONCLUSIONS: We report for the first time that taxanes can promote dose-dependent sTNF-alpha production in tumor cells at clinically relevant concentrations, which can contribute to their cytotoxicity. Defects in the TNF cytotoxicity pathway or activation of TNF-dependent NF-kappaB survival genes may, in contrast, contribute to taxane resistance in tumor cells. These findings may be of strong clinical significance. PMID- 22225784 TI - Identification of Rv0535 as methylthioadenosine phosphorylase from Mycobacterium tuberculosis. AB - 5'-methylthioadenosine (MTA) is a natural purine that is metabolized by methylthioadenosine phosphorylase (MTAP, E.C 2.4.2.28) in Eukarya and Archaea but generally not in bacteria. In this work, Rv0535, which has been annotated as a probable MTAP in Mycobacterium tuberculosis, was expressed in and purified from Escherichia coli BL21 (DE3). The purified protein displayed properties of a phosphorylase and MTA was the preferred substrate. Adenosine and S-adenosyl-l homocysteine were poor substrates and no activity was detected with 5' methylthioinosine, the other natural purines, or the natural pyrimidines. Kinetic analysis of M. tuberculosis MTAP showed that the K(m) value for MTA was 9 MUM. Rv0535 was estimated as a 30 kDa protein on a denaturing SDS-PAGE gel, which agreed with the molecular mass predicted by its gene sequence. Using gel filtration chromatography, the native molecular mass of the enzyme was determined to be 60 +/- 4 kDa, and thus indicated that M. tuberculosis MTAP is a dimer. Differences in active site between mycobacterial and human MTAPs were identified by homology modeling based on the crystal of the human enzyme. A complete structure-activity relationship analysis could identify differences in substrate specificity between the two enzymes to aid in the development of purine-based, anti-tuberculosis drugs. PMID- 22225785 TI - The microbial ecology of anaerobic cellulose degradation in municipal waste landfill sites: evidence of a role for fibrobacters. AB - Cellulose is reputedly the most abundant organic polymer in the biosphere, yet despite the fundamental role of cellulolytic microorganisms in global carbon cycling and as potential sources of novel enzymes for biotechnology, their identity and ecology is not well established. Cellulose is a major component of landfill waste and its degradation is therefore a key feature of the anaerobic microbial decomposition process. Here, we targeted a number of taxa containing known cellulolytic anaerobes (members of the bacterial genus Fibrobacter, lineages of Clostridium clusters I, III, IV and XIV, and anaerobic fungi of the Neocallimastigales) in landfill leachate and colonized cellulose 'baits' via PCR and quantitative PCR (qPCR). Fibrobacter spp. and Clostridium clusters III, IV and XIV were detected in almost all leachate samples and cluster III and XIV clostridia were the most abundant (1-6% and 1-17% of total bacterial 16S rRNA gene copies respectively). Two landfill leachate microcosms were constructed to specifically assess those microbial communities that colonize and degrade cellulose substrates in situ. Scanning electron microscopy (SEM) of colonized cotton revealed extensive cellulose degradation in one microcosm, and Fibrobacter spp. and Clostridium cluster III represented 29% and 17%, respectively, of total bacterial 16S rRNA gene copies in the biofilm. Visible cellulose degradation was not observed in the second microcosm, and this correlated with negligible relative abundances of Clostridium cluster III and Fibrobacter spp. (<= 0.1%), providing the first evidence that the novel fibrobacters recently detected in landfill sites and other non-gut environments colonize and degrade cellulose substrates in situ. PMID- 22225787 TI - Cross-national survey of winter and summer patterns of mood seasonality: a comparison between Italy and India. AB - The aim of this study was to compare winter and summer patterns of mood seasonality in university students living at different latitudes: Bologna, 44 degrees N (Italy), and Kalyani, 22 degrees N (India). To assess the mood seasonality, the Seasonal Pattern Assessment Questionnaire was administered to 1370 university students (808 females, 562 males; 862 Italians, 508 Indians), ranging in age between 18 and 28 years. A significantly higher Global Seasonality Score was observed in females than males as well as in Italians than Indians. The estimated rates of summer seasonal affective disorder (SAD) and summer subsyndromal SAD were higher in Indians, whereas Italians reported higher percentage of winter SAD and winter subsyndromal SAD. The present findings are discussed in relation to the different environmental features between the 2 countries: high summer temperature in India and short winter photoperiod along with its great excursion over the year in Italy. PMID- 22225786 TI - Stromal micropapillary component as a novel unfavorable prognostic factor of lung adenocarcinoma. AB - BACKGROUND: Pulmonary adenocarcinomas with a micropapillary component having small papillary tufts and lacking a central fibrovascular core are thought to result in poor prognosis. However, the component consists of tumor cells often floating within alveolar spaces (aerogenous micropapillary component [AMPC]) rather than invading fibrotic stroma observed in other organs like breast (stromal invasive micropapillary component [SMPC]). We previously observed cases of lung adenocarcinoma with predominant SMPC that was associated with micropapillary growth of tumors in fibrotic stroma observed in other organs. We evaluated the incidence and clinicopathological characteristics of SMPC in lung adenocarcinoma cases. PATIENTS AND METHODS: We investigated the clinicopathological characteristics and prognostic significance of SMPC in lung adenocarcinoma cases by reviewing 559 patients who had undergone surgical resection. We examined the SMPC by performing immunohistochemical analysis with 17 antibodies and by genetic analysis with epidermal growth factor receptor (EGFR) and KRAS mutations. RESULTS: SMPC-positive (SMPC(+)) tumors were observed in 19 cases (3.4%). The presence of SMPC was significantly associated with tumor size, advanced-stage disease, lymph node metastasis, pleural invasion, lymphatic invasion, and vascular invasion. Patients with SMPC(+) tumors had significantly poorer outcomes than those with SMPC-negative tumors. Multivariate analysis revealed that SMPC was a significant independent prognostic factor of lung adenocarcinoma, especially for disease-free survival of pathological stage I patients (p = 0.035). SMPC showed significantly higher expression of E-cadherin and lower expression of CD44 than the corresponding expression levels shown by AMPC and showed lower surfactant apoprotein A and phospho-c-Met expression level than corresponding expression levels shown by tumor cell components without a micropapillary component. Fourteen cases with SMPC(+) tumors (74%) showed EGFR mutations, and none of them showed KRAS mutations. CONCLUSIONS: SMPC(+) tumors are rare, but they may be associated with a poor prognosis and have different phenotypic and genotypic characteristics from those of AMPC(+) tumors. PMID- 22225788 TI - Relationship of alexithymia and dissociation with severity of borderline personality features in male substance-dependent inpatients. AB - The aim of this study was to evaluate possible interactions between severity of borderline personality features (BPFs), dissociative experiences, and alexithymia among substance-dependent men while controlling for their current age, depression, and anxiety. Participants were 200 substance-dependent men consecutively admitted to a dependency treatment unit. The Borderline Personality Inventory, the Toronto Alexithymia Scale, the Dissociative Experiences Scale, the Beck Depression Inventory, and the Spielberger State-Trait Anxiety Inventory were administered to all participants. Severity of negative affect, alexithymia, dissociative experiences, and BPF were correlated with each other. Being younger, severity of dissociative experiences, difficulty in identifying feelings, depression, and trait anxiety predicted the severity of BPF in linear regression analysis. These findings suggest that alexithymia and dissociative experiences may be a way of coping with depression and chronic anxiety, but they also seem to be related to the severity of BPF independent of the negative affect and from each other. PMID- 22225789 TI - Caries prevalence associated with Streptococcus mutans and Streptococcus sobrinus in Japanese schoolchildren. AB - BACKGROUND: Streptococcus mutans and Streptococcus sobrinus are known to be associated with dental caries in humans. AIM: We used a polymerase chain reaction method to detect S. mutans and S. sobrinus in 128 Japanese schoolchildren and then compared their presence with the dental caries experience. DESIGN: Plaque samples were collected from all erupted tooth sites with a sterile toothbrush, and dental examinations were performed to determine the numbers of decayed and filled teeth in primary (dft) and permanent (DFT) dentition using the WHO caries diagnostic criteria. Fisher's PLSD test was employed to compare caries scores between combinations of the detected bacteria. RESULTS: Streptococcus mutans and S. sobrinus were present in 38.3% and 68.0%, respectively, whereas 14.8% were positive for S. mutans alone, 44.5% for S. sobrinus alone, and 23.5% for both S. mutans and S. sobrinus, with 17.2% negative for both. The DFT, dft, and total (DFT + dft) scores for subjects positive for both S. mutans and S. sobrinus were significantly higher than those positive for S. mutans alone (P < 0.05, in triplicate). CONCLUSION: These results suggest that schoolchildren harbouring both S. mutans and S. sobrinus have a significant higher dental caries experience in both permanent and primary teeth as compared to those with S. mutans alone. PMID- 22225790 TI - Propriospinal myoclonus associated with gluten sensitivity in a young woman. AB - Propriospinal myoclonus (PSM) is a rare movement disorder characterized by involuntary axial jerks originating from muscles innervated by multiple spinal segments. Most cases of PSM are idiopathic. Gluten sensitivity is a multisystemic autoimmune condition which may be associated with various neurological disorders, most commonly peripheral neuropathy and cerebellar ataxia. We report a case of a young woman who developed PSM in the setting of gluten sensitivity, indicating that gluten sensitivity should be considered in the differential diagnosis of PSM such that a gluten challenge test may prove diagnostically useful. PMID- 22225791 TI - Ionizing radiation regulates the expression of AMP-activated protein kinase (AMPK) in epithelial cancer cells: modulation of cellular signals regulating cell cycle and survival. AB - PURPOSE: To analyze the (i) expression of AMPK in a variety of epithelial cancer cells, (ii) regulation of AMPK subunit expression by ionizing radiation (IR) and (iii) impact of AMPK on signaling pathways regulating cell cycle and survival. METHODS AND MATERIALS: Human lung, prostate, and breast normal and cancer cells were treated with 0 or 8 Gy IR and mRNA and protein levels of AMPK were evaluated by RT-PCR and immunoblotting 24 or 48 h later. Untreated and radiated wild type (WT) and AMPKalpha(-/-) mouse embryonic fibroblasts (MEFs) were analyzed by immunoblotting using total- and phosphorylation-specific antibodies. Histone H2Ax was examined by fluorescence microscopy. The cell cycle and survival of WT and AMPKalpha(-/-) MEFs was also evaluated following 8 Gy by IR. RESULTS: AMPK subunits were found widely expressed in normal and cancer epithelial cells. IR increased subunit protein levels and stimulated gene transcription in cancer cells. AMPKalpha(-/-)-MEFs showed enhanced basal total levels of ATM and phosphorylation of its substrates histone H2Ax, but inhibited response of these markers and of checkpoint kinase Chk2 phosphorylation to IR. AMPKalpha(-/-)-MEFs showed increased basal levels of p53 and cyclin-dependent kinase inhibitors p21(cip1), but lack of response of both genes to IR. These cells had increased basal levels and activation of the Akt-mTOR-p70(S6K)/4-EBP1 signalling pathway. IR increased Akt, p70(S6K) and 4-EBP1 phosphorylation in WT-MEFs, but this was reduced in AMPKalpha(-/-)-MEFs. AMPKalpha(-/-)-MEFs failed to arrest at the G2-M checkpoint after IR and showed a trend for radio-resistance in proliferation assays. CONCLUSIONS: AMPK is widely expressed in human normal and cancer epithelial cells and its gene transcription, protein levels, and enzymatic activity is stimulated by IR. Work with AMPKalpha knockout cells suggests that AMPK (i) may mediate a suppressive regulation on basal expression and activity of ATM and its downstream effector pathways Chk2/p53-p21(cip1) and Akt-mTOR, (ii) facilitates the normal response of these pathways to IR and, (iii) mediates the IR-induced G2-M checkpoint. PMID- 22225792 TI - Micro- and macrorheology of jellyfish extracellular matrix. AB - Mechanical properties of the extracellular matrix (ECM) play a key role in tissue organization and morphogenesis. Rheological properties of jellyfish ECM (mesoglea) were measured in vivo at the cellular scale by passive microrheology techniques: microbeads were injected in jellyfish ECM and their Brownian motion was recorded to determine the mechanical properties of the surrounding medium. Microrheology results were compared with macrorheological measurements performed with a shear rheometer on slices of jellyfish mesoglea. We found that the ECM behaved as a viscoelastic gel at the macroscopic scale and as a much softer and heterogeneous viscoelastic structure at the microscopic scale. The fibrous architecture of the mesoglea, as observed by differential interference contrast and scanning electron microscopy, was in accord with these scale-dependent mechanical properties. Furthermore, the evolution of the mechanical properties of the ECM during aging was investigated by measuring microrheological properties at different jellyfish sizes. We measured that the ECM in adult jellyfish was locally stiffer than in juvenile ones. We argue that this stiffening is a consequence of local aggregations of fibers occurring gradually during aging of the jellyfish mesoglea and is enhanced by repetitive muscular contractions of the jellyfish. PMID- 22225793 TI - Blood clot formation under flow: the importance of factor XI depends strongly on platelet count. AB - A previously validated mathematical model of intravascular platelet deposition and tissue factor (TF)-initiated coagulation under flow is extended and used to assess the influence on thrombin production of the activation of factor XI (fXI) by thrombin and of the activation of factor IX (fIX) by fXIa. It is found that the importance of the thrombin-fXIa-fIXa feedback loop to robust thrombin production depends on the concentration of platelets in the blood near the injury. At a near-wall platelet concentration of ~250,000/MUL, typical in vessels in which the shear rate is <200 s(-1), thrombin activation of fXI makes a significant difference only at low densities of exposed TF. If the near-wall platelet concentration is significantly higher than this, either because of a higher systemic platelet count or because of the redistribution of platelets toward the vessel walls at high shear rates, then thrombin activation of fXI makes a major difference even for relatively high densities of exposed TF. The model predicts that the effect of a severe fXI deficiency depends on the platelet count, and that fXI becomes more important at high platelet counts. PMID- 22225795 TI - Extracting surface activation time from the optically recorded action potential in three-dimensional myocardium. AB - Optical mapping has become an indispensible tool for studying cardiac electrical activity. However, due to the three-dimensional nature of the optical signal, the optical upstroke is significantly longer than the electrical upstroke. This raises the issue of how to accurately determine the activation time on the epicardial surface. The purpose of this study was to establish a link between the optical upstroke and exact surface activation time using computer simulations, with subsequent validation by a combination of microelectrode recordings and optical mapping experiments. To simulate wave propagation and associated optical signals, we used a hybrid electro-optical model. We found that the time of the surface electrical activation (t(E)) within the accuracy of our simulations coincided with the maximal slope of the optical upstroke (t(F)*) for a broad range of optical attenuation lengths. This was not the case when the activation time was determined at 50% amplitude (t(F50)) of the optical upstroke. The validation experiments were conducted in isolated Langendorff-perfused rat hearts and coronary-perfused pig left ventricles stained with either di-4-ANEPPS or the near-infrared dye di-4-ANBDQBS. We found that t(F)* was a more accurate measure of t(E) than was t(F50) in all experimental settings tested (P = 0.0002). Using t(F)* instead of t(F50) produced the most significant improvement in measurements of the conduction anisotropy and the transmural conduction time in pig ventricles. PMID- 22225794 TI - Stability and multiattractor dynamics of a toggle switch based on a two-stage model of stochastic gene expression. AB - A toggle switch consists of two genes that mutually repress each other. This regulatory motif is active during cell differentiation and is thought to act as a memory device, being able to choose and maintain cell fate decisions. Commonly, this switch has been modeled in a deterministic framework where transcription and translation are lumped together. In this description, bistability occurs for transcription factor cooperativity, whereas autoactivation leads to a tristable system with an additional undecided state. In this contribution, we study the stability and dynamics of a two-stage gene expression switch within a probabilistic framework inspired by the properties of the Pu/Gata toggle switch in myeloid progenitor cells. We focus on low mRNA numbers, high protein abundance, and monomeric transcription-factor binding. Contrary to the expectation from a deterministic description, this switch shows complex multiattractor dynamics without autoactivation and cooperativity. Most importantly, the four attractors of the system, which only emerge in a probabilistic two-stage description, can be identified with committed and primed states in cell differentiation. To begin, we study the dynamics of the system and infer the mechanisms that move the system between attractors using both the quasipotential and the probability flux of the system. Next, we show that the residence times of the system in one of the committed attractors are geometrically distributed. We derive an analytical expression for the parameter of the geometric distribution, therefore completely describing the statistics of the switching process and elucidate the influence of the system parameters on the residence time. Moreover, we find that the mean residence time increases linearly with the mean protein level. This scaling also holds for a one-stage scenario and for autoactivation. Finally, we study the implications of this distribution for the stability of a switch and discuss the influence of the stability on a specific cell differentiation mechanism. Our model explains lineage priming and proposes the need of either high protein numbers or long-term modifications such as chromatin remodeling to achieve stable cell fate decisions. Notably, we present a system with high protein abundance that nevertheless requires a probabilistic description to exhibit multistability, complex switching dynamics, and lineage priming. PMID- 22225796 TI - Protein translocation through Tom40: kinetics of peptide release. AB - Mitochondrial proteins are almost exclusively imported into mitochondria from the cytosol in an unfolded or partially folded conformation. Regardless of whether they are destined for the outer or inner membrane, the intermembrane space, or the matrix, proteins begin the importation process by crossing the mitochondrial outer membrane via a specialized protein import machinery whose main component is the Tom40 channel. High-resolution ion conductance measurements through the Tom40 channel in the presence of the mitochondrial presequence peptide pF(1)beta revealed the kinetics of peptide binding. Here we show that the rates for association k(on) and dissociation k(off) strongly depend on the applied transmembrane voltage. Both kinetic constants increase with an increase in the applied voltage. The increase of k(off) with voltage provides strong evidence of peptide translocation. This allows us to distinguish quantitatively between substrate blocking and permeation. PMID- 22225797 TI - A novel phase of compressed bilayers that models the prestalk transition state of membrane fusion. AB - The force model of protein-mediated membrane fusion hypothesizes that fusion is driven by mechanical forces exerted on the membranes, but many details are unknown. Here, we investigated by x-ray diffraction the consequence of applying compressive force on a stack of membranes against the hydration barrier. We found that as the osmotic pressure increased, the lamellar phase transformed first to a new phase of tetragonal lattice (T-phase) over a narrow range of relative humidity, and then to a phase of rhombohedral lattice. The unit cell structure changed from parallel bilayers to a bent configuration with a point contact between adjacent bilayers and then to the stalk hemifusion configuration. The T phase is discussed as a possible transition state in the membrane merging pathway of fusion. We estimate the work required to form the T-phase and the subsequent hemifusion-stalk-resembling R-phase. The work for the formation of a stalk is compatible with the energy estimated to be released by several SNARE complexes. PMID- 22225799 TI - Force spectroscopy reveals the effect of different ions in the nanomechanical behavior of phospholipid model membranes: the case of potassium cation. AB - How do metal cations affect the stability and structure of phospholipid bilayers? What role does ion binding play in the insertion of proteins and the overall mechanical stability of biological membranes? Investigators have used different theoretical and microscopic approaches to study the mechanical properties of lipid bilayers. Although they are crucial for such studies, molecular-dynamics simulations cannot yet span the complexity of biological membranes. In addition, there are still some experimental difficulties when it comes to testing the ion binding to lipid bilayers in an accurate way. Hence, there is a need to establish a new approach from the perspective of the nanometric scale, where most of the specific molecular phenomena take place. Atomic force microscopy has become an essential tool for examining the structure and behavior of lipid bilayers. In this work, we used force spectroscopy to quantitatively characterize nanomechanical resistance as a function of the electrolyte composition by means of a reliable molecular fingerprint that reveals itself as a repetitive jump in the approaching force curve. By systematically probing a set of bilayers of different composition immersed in electrolytes composed of a variety of monovalent and divalent metal cations, we were able to obtain a wealth of information showing that each ion makes an independent and important contribution to the gross mechanical resistance and its plastic properties. This work addresses the need to assess the effects of different ions on the structure of phospholipid membranes, and opens new avenues for characterizing the (nano)mechanical stability of membranes. PMID- 22225798 TI - Lipid-protein interactions alter line tensions and domain size distributions in lung surfactant monolayers. AB - The size distribution of domains in phase-separated lung surfactant monolayers influences monolayer viscoelasticity and compressibility which, in turn, influence monolayer collapse and set the compression at which the minimum surface tension is reached. The surfactant-specific protein SP-B decreases the mean domain size and polydispersity as shown by fluorescence microscopy. From the images, the line tension and dipole density difference are determined by comparing the measured size distributions with a theory derived by minimizing the free energy associated with the domain energy and mixing entropy. We find that SP B increases the line tension, dipole density difference, and the compressibility modulus at surface pressures up to the squeeze-out pressure. The increase in line tension due to SP-B indicates the protein avoids domain boundaries due to its solubility in the more fluid regions of the film. PMID- 22225800 TI - Two-component coarse-grained molecular-dynamics model for the human erythrocyte membrane. AB - We present a two-component coarse-grained molecular-dynamics model for simulating the erythrocyte membrane. The proposed model possesses the key feature of combing the lipid bilayer and the erythrocyte cytoskeleton, thus showing both the fluidic behavior of the lipid bilayer and the elastic properties of the erythrocyte cytoskeleton. In this model, three types of coarse-grained particles are introduced to represent clusters of lipid molecules, actin junctions, and band-3 complexes, respectively. The proposed model facilitates simulations that span large length scales (approximately micrometers) and timescales (approximately milliseconds). By tuning the interaction potential parameters, we were able to control the diffusivity and bending rigidity of the membrane model. We studied the membrane under shearing and found that at a low shear strain rate, the developed shear stress was due mainly to the spectrin network, whereas the viscosity of the lipid bilayer contributed to the resulting shear stress at higher strain rates. In addition, we investigated the effects of a reduced spectrin network connectivity on the shear modulus of the membrane. PMID- 22225801 TI - Quantitative analysis of the nanopore translocation dynamics of simple structured polynucleotides. AB - Nanopore translocation experiments are increasingly applied to probe the secondary structures of RNA and DNA molecules. Here, we report two vital steps toward establishing nanopore translocation as a tool for the systematic and quantitative analysis of polynucleotide folding: 1), Using alpha-hemolysin pores and a diverse set of different DNA hairpins, we demonstrate that backward nanopore force spectroscopy is particularly well suited for quantitative analysis. In contrast to forward translocation from the vestibule side of the pore, backward translocation times do not appear to be significantly affected by pore-DNA interactions. 2), We develop and verify experimentally a versatile mesoscopic theoretical framework for the quantitative analysis of translocation experiments with structured polynucleotides. The underlying model is based on sequence-dependent free energy landscapes constructed using the known thermodynamic parameters for polynucleotide basepairing. This approach limits the adjustable parameters to a small set of sequence-independent parameters. After parameter calibration, the theoretical model predicts the translocation dynamics of new sequences. These predictions can be leveraged to generate a baseline expectation even for more complicated structures where the assumptions underlying the one-dimensional free energy landscape may no longer be satisfied. Taken together, backward translocation through alpha-hemolysin pores combined with mesoscopic theoretical modeling is a promising approach for label-free single molecule analysis of DNA and RNA folding. PMID- 22225802 TI - Bandpass filtering of DNA elastic modes using confinement and tension. AB - During a variety of biological and technological processes, biopolymers are simultaneously subject to both confinement and external forces. Although significant efforts have gone into understanding the physics of polymers that are only confined, or only under tension, little work has been done to explore the effects of the interplay of force and confinement. Here, we study the combined effects of stretching and confinement on a polymer's configurational freedom. We measure the elastic response of long double-stranded DNA molecules that are partially confined to thin, nanofabricated slits. We account for the data through a model in which the DNA's short-wavelength transverse elastic modes are cut off by applied force and the DNA's bending stiffness, whereas long-wavelength modes are cut off by confinement. Thus, we show that confinement and stretching combine to permit tunable bandpass filtering of the elastic modes of long polymers. PMID- 22225803 TI - A kinetic zipper model with intrachain interactions applied to nucleic acid hairpin folding kinetics. AB - Single-stranded DNA and RNA hairpin structures with 4-10 nucleotides (nt) in the loop and 5-8 basepairs (bp) in the stem fold on 10-100 MUs timescale. In contrast, theoretical estimate of first contact time of two ends of an ideal semiflexible polymer of similar lengths (with persistence length ~2-nt) is 10-100 ns. We propose that this three-orders-of-magnitude difference between these two timescales is a result of roughness in the folding free energy surface arising from intrachain interactions. We present a statistical mechanical model that explicitly includes all misfolded microstates with nonnative Watson-Crick (WC) and non-WC contacts. Rates of interconversion between different microstates are described in terms of two adjustable parameters: the strength of the non-WC interactions (DeltaG(nWC)) and the rate at which a basepair is formed adjacent to an existing basepair (k(bp)(+)). The model accurately reproduces the temperature and loop-length dependence of the measured relaxation rates in temperature-jump studies of a 7-bp stem, single-stranded DNA hairpin with 4-20-nt-long poly(dT) loops, with DeltaG(nWC) ~ -2.4 kcal/mol and k(bp)(+) >= (1 ns)(-1), in 100 mM NaCl. Thus, our model provides a microscopic interpretation of the slow hairpin folding times as well as an estimate of the strength of intrachain interactions. PMID- 22225804 TI - Molecular dynamics simulation of shear- and stretch-induced dissociation of P selectin/PSGL-1 complex. AB - By mediating the tethering and rolling of leukocytes on vascular surfaces, the interactions between P-selectin and the P-selectin glycoprotein ligand 1 (PSGL-1) play crucial roles during inflammation cascade. Tensile stretch produced by rolling leukocytes and shear stress exerted by blood flow constitute the two types of mechanical forces that act on the P-selectin/PSGL-1 bond. These forces modulate not only dissociation kinetics of this bond, but also the leukocyte adhesion dynamics. However, the respective contribution of the two forces to bond dissociation and to the corresponding microstructural bases remains unclear. To mimic the mechanical microenvironment, we developed two molecular dynamics approaches; namely, an approach involving the shear flow field with a controlled velocity gradient, and the track dragging approach with a defined trajectory. With each approach or with both combined, we investigate the microstructural evolution and dissociation kinetics of the P-LE/SGP-3 construct, which is the smallest functional unit of the P-selectin/PSGL-1 complex. The results demonstrate that both shear flow and tensile stretch play important roles in the collapse of the construct and that, before bond dissociation, the former causes more destruction of domains within the construct than the latter. Dissociation of the P-LE/SGP-3 construct features intramolecular destruction of the epidermal growth-factor (EGF) domain and the breaking of hydrogen-bond clusters at the P selectin-lectin/EGF interface. Thus, to better understand how mechanics impacts the dissociation kinetics of the P-selectin/PSGL-1 complex, we propose herein two approaches to mimic its physiological mechanical environment. PMID- 22225805 TI - Pressure-accelerated dissociation of amyloid fibrils in wild-type hen lysozyme. AB - The dynamics of amyloid fibrils, including their formation and dissociation, could be of vital importance in life. We studied the kinetics of dissociation of the amyloid fibrils from wild-type hen lysozyme at 25 degrees C in vitro as a function of pressure using Trp fluorescence as a probe. Upon 100-fold dilution of 8 mg ml(-1) fibril solution in 80 mM NaCl, pH 2.2, no immediate change occurred in Trp fluorescence, but at pressures of 50-450 MPa the fluorescence intensity decreased rapidly with time (k(obs) = 0.00193 min(-1) at 0.1 MPa, 0.0348 min(-1) at 400 MPa). This phenomenon is attributable to the pressure-accelerated dissociation of amyloid fibrils into monomeric hen lysozyme. From the pressure dependence of the rates, which reaches a plateau at ~450 MPa, we determined the activation volume DeltaV(0?) = -32.9 +/- 1.7 ml mol(monomer)(-1) and the activation compressibility Deltakappa(?) = -0.0075 +/- 0.0006 ml mol(monomer)(-1) bar(-1) for the dissociation reaction. The negative DeltaV(0?) and Deltakappa(?) values are consistent with the notion that the amyloid fibril from wild-type hen lysozyme is in a high-volume and high-compressibility state, and the transition state for dissociation is coupled with a partial hydration of the fibril. PMID- 22225806 TI - Role of channel lysines and the "push through a one-way valve" mechanism of the viral DNA packaging motor. AB - Linear double-stranded DNA (dsDNA) viruses package their genomes into preformed protein shells via nanomotors using ATP as an energy source. The central hub of the bacteriophage phi29 DNA-packaging motor contains a 3.6-nm channel for dsDNA to enter during packaging and to exit during infection. The negatively charged interior channel wall is decorated with a total of 48 positively charged lysine residues displayed as four 12-lysine rings from the 12 gp10 subunits that enclose the channel. The standard notion derived from many models is that these uniquely arranged, positively charged rings play active roles in DNA translocation through the channel. In this study, we tested this prevailing view by examining the effect of mutating these basic lysines to alanines, and assessing the impact of altering the pH environment. Unexpectedly, mutating these basic lysine residues or changing the pH to 4 or 10, which could alter the charge of lysines, did not measurably impair DNA translocation or affect the one-way traffic property of the channel. The results support our recent findings regarding the dsDNA packaging mechanism known as the "push through a one-way valve". PMID- 22225807 TI - NMR solution structure of rat abeta(1-16): toward understanding the mechanism of rats' resistance to Alzheimer's disease. AB - In an attempt to reveal the mechanism of rats' resistance to Alzheimer's disease, we determined the structure of the metal-binding domain 1-16 of rat beta-amyloid (rat Abeta(1-16)) in solution in the absence and presence of zinc ions. A zinc induced dimerization of the domain was detected. The zinc coordination site was found to involve residues His-6 and His-14 of both peptide chains. We used experimental restraints obtained from analyses of NMR and isothermal titration calorimetry data to perform structure calculations. The calculations employed an explicit water environment and a simulated annealing molecular-dynamics protocol followed by quantum-mechanical/molecular-mechanical optimization. We found that the C-tails of the two polypeptide chains of the rat Abeta(1-16) dimer are oriented in opposite directions to each other, which hinders the assembly of rat Abeta dimers into oligomeric aggregates. Thus, the differences in the structure of zinc-binding sites of human and rat Abeta(1-16), their ability to form regular cross-monomer bonds, and the orientation of their hydrophobic C-tails could be responsible for the resistance of rats to Alzheimer's disease. PMID- 22225808 TI - Discrete molecular dynamics distinguishes nativelike binding poses from decoys in difficult targets. AB - Virtual screening is one of the major tools used in computer-aided drug discovery. In structure-based virtual screening, the scoring function is critical to identifying the correct docking pose and accurately predicting the binding affinities of compounds. However, the performance of existing scoring functions has been shown to be uneven for different targets, and some important drug targets have proven especially challenging. In these targets, scoring functions cannot accurately identify the native or near-native binding pose of the ligand from among decoy poses, which affects both the accuracy of the binding affinity prediction and the ability of virtual screening to identify true binders in chemical libraries. Here, we present an approach to discriminating native poses from decoys in difficult targets for which several scoring functions failed to correctly identify the native pose. Our approach employs Discrete Molecular Dynamics simulations to incorporate protein-ligand dynamics and the entropic effects of binding. We analyze a collection of poses generated by docking and find that the residence time of the ligand in the native and nativelike binding poses is distinctly longer than that in decoy poses. This finding suggests that molecular simulations offer a unique approach to distinguishing the native (or nativelike) binding pose from decoy poses that cannot be distinguished using scoring functions that evaluate static structures. The success of our method emphasizes the importance of protein-ligand dynamics in the accurate determination of the binding pose, an aspect that is not addressed in typical docking and scoring protocols. PMID- 22225809 TI - The Role of Gln61 in HRas GTP hydrolysis: a quantum mechanics/molecular mechanics study. AB - Activation of the water molecule involved in GTP hydrolysis within the HRas.RasGAP system is analyzed using a tailored approach based on hybrid quantum mechanics/molecular mechanics (QM/MM) simulation. A new path emerges: transfer of a proton from the attacking water molecule to a second water molecule, then a different proton is transferred from this second water molecule to the GTP. Gln(61) will stabilize the transient OH(-) and H(3)O(+) molecules thus generated. This newly proposed mechanism was generated by using, for the first time to our knowledge, the entire HRas-RasGAP protein complex in a QM/MM simulation context. It also offers a rational explanation for previous experimental results regarding the decrease of GTPase rate found in the HRas Q61A mutant and the increase exhibited by the HRas Q61E mutant. PMID- 22225810 TI - Energy landscape of the prion protein helix 1 probed by metadynamics and NMR. AB - The characterization of the structural dynamics of proteins, including those that present a substantial degree of disorder, is currently a major scientific challenge. These dynamics are biologically relevant and govern the majority of functional and pathological processes. We exploited a combination of enhanced molecular simulations of metadynamics and NMR measurements to study heterogeneous states of proteins and peptides. In this way, we determined the structural ensemble and free-energy landscape of the highly dynamic helix 1 of the prion protein (PrP-H1), whose misfolding and aggregation are intimately connected to a group of neurodegenerative disorders known as transmissible spongiform encephalopathies. Our combined approach allowed us to dissect the factors that govern the conformational states of PrP-H1 in solution, and the implications of these factors for prion protein misfolding and aggregation. The results underline the importance of adopting novel integrated approaches that take advantage of experiments and theory to achieve a comprehensive characterization of the structure and dynamics of biological macromolecules. PMID- 22225811 TI - alpha-alpha Cross-links increase fibrin fiber elasticity and stiffness. AB - Fibrin fibers, which are ~100 nm in diameter, are the major structural component of a blood clot. The mechanical properties of single fibrin fibers determine the behavior of a blood clot and, thus, have a critical influence on heart attacks, strokes, and embolisms. Cross-linking is thought to fortify blood clots; though, the role of alpha-alpha cross-links in fibrin fiber assembly and their effect on the mechanical properties of single fibrin fibers are poorly understood. To address this knowledge gap, we used a combined fluorescence and atomic force microscope technique to determine the stiffness (modulus), extensibility, and elasticity of individual, uncross-linked, exclusively alpha-alpha cross-linked (gammaQ398N/Q399N/K406R fibrinogen variant), and completely cross-linked fibrin fibers. Exclusive alpha-alpha cross-linking results in 2.5* stiffer and 1.5* more elastic fibers, whereas full cross-linking results in 3.75* stiffer, 1.2* more elastic, but 1.2* less extensible fibers, as compared to uncross-linked fibers. On the basis of these results and data from the literature, we propose a model in which the alpha-C region plays a significant role in inter- and intralinking of fibrin molecules and protofibrils, endowing fibrin fibers with increased stiffness and elasticity. PMID- 22225812 TI - Distribution of sialic acids on mucins and gels: a defense mechanism. AB - Moist mucosal epithelial interfaces that are exposed to external environments are dominated by sugar epitopes, some of which (e.g., sialic acids) are involved in host defense. In this study, we determined the abundance and distribution of two sialic acids to assess differences in their availability to an exogenous probe in isolated mucins and mucous gels. We used atomic force microscopy to obtain force maps of human preocular mucous and purified ocular mucins by probing and locating the interactions between tip-tethered lectins Maackia amurensis and Sambucus nigra and their respective receptors, alpha-2,3 and alpha-2,6 N-acetylneuraminic (sialic) acids. The rupture force distributions were not affected by neighboring sugar-bearing molecules. Energy contours for both lectin-sugar bonds were fitted to a two-barrier model, suggesting a conformational change before dissociation. In contrast to data from purified mucin molecules, the preocular gels presented numerous large clusters (19,000 +/- 4000 nm(2)) of alpha-2,6 sialic acids, but very few small clusters (2000 +/- 500 nm(2)) of alpha-2,3 epitopes. This indicates that mucins, which are rich in alpha-2,3 sialic acids, are only partially exposed at the surface of the mucous gel. Microorganisms that recognize alpha-2,3 sialic acids will encounter only isolated ligands, and the adhesion of other microorganisms will be enhanced by large islands of neighboring alpha-2,6 sialic acids. We have unveiled an additional level of mucosal surface heterogeneity, specifically in the distribution of pro- and antiadhesive sialic acids that protect underlying epithelia from viruses and bacteria. PMID- 22225813 TI - Direct measurement of the mechanical properties of lipid phases in supported bilayers. AB - Biological membranes define not only the cell boundaries but any compartment within the cell. To some extent, the functionality of membranes is related to the elastic properties of the lipid bilayer and the mechanical and hydrophobic matching with functional membrane proteins. Supported lipid bilayers (SLBs) are valid biomimetic systems for the study of membrane biophysical properties. Here, we acquired high-resolution topographic and quantitative mechanics data of phase separated SLBs using a recent atomic force microscopy (AFM) imaging mode based on force measurements. This technique allows us to quantitatively map at high resolution the mechanical differences of lipid phases at different loading forces. We have applied this approach to evaluate the contribution of the underlying hard support in the determination of the elastic properties of SLBs and to determine the adequate indentation range for obtaining reliable elastic moduli values. At ~200 pN, elastic forces dominated the force-indentation response and the sample deformation was <20% of the bilayer thickness, at which the contribution of the support was found to be negligible. The obtained Young's modulus (E) of 19.3 MPa and 28.1 MPa allowed us to estimate the area stretch modulus (k(A)) as 106 pN/nm and 199 pN/nm and the bending stiffness (k(c)) as 18 k(B)T and 57 k(B)T for the liquid and gel phases, respectively. PMID- 22225815 TI - Foot-and-mouth disease in pigs: current epidemiological situation and control methods. AB - Foot-and-mouth disease (FMD) is the paradigm of a transboundary animal disease. Beyond any doubt, it is the most serious challenge for livestock's health. Official Veterinary Services from free countries invest considerable amount of money to prevent its introduction, whereas those from endemic countries invest most of their resources in the control of the disease. A very important volume of scientific production is developed every year in different aspects of FMD, and for that reason, the current knowledge makes the diagnosis of the disease easier to a great extent. However, FMD is still endemic in about two-thirds of the countries, and periodically re-emergent in several countries. This paper is a review of recent publications, focusing mainly on control measures and current world epidemiological situation, emphasizing primarily pigs. PMID- 22225816 TI - A 'biopsychosocial' model for recovery: a grounded theory study of families' journeys after a Paediatric Intensive Care Admission. AB - Paediatric intensive care has a significant impact on the children and families who experience it. This effect continues post-discharge as the family attempt to recover from their ordeal. This article begins with an exploration of what makes a Paediatric Intensive Care Unit (PICU) admission potentially so traumatising and then examines current models for recovery which exist in the literature. These remain sparse and do not provide a coherent model for recovery after PICU. This paper therefore presents research which aimed to develop a model to understand the recovery journey for families. Children who had been PICU patients and their parents were interviewed and the transcripts analysed using grounded theory. Participants highlighted the importance of physical, psychological and social recovery and these have been integrated into a biopsychosocial model of recovery. Finding and accepting a 'new normal' were the culmination of this biopsychosocial journey. This paper concludes that an integrated approach to recovery is necessary and makes some recommendations for further research and clinical practice. PMID- 22225814 TI - Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomised, open-label, cross-over trials. AB - BACKGROUND: Skin and mucosal herpes simplex virus type 2 (HSV-2) shedding predominantly occurs in short subclinical episodes. We assessed whether standard dose or high-dose antiviral therapy reduces the frequency of such shedding. METHODS: HSV-2-seropositive, HIV-seronegative people were enrolled at the University of Washington Virology Research Clinic (WA, USA). We did three separate but complementary open-label cross-over studies comparing no medication with aciclovir 400 mg twice daily (standard-dose aciclovir), valaciclovir 500 mg daily (standard-dose valaciclovir) with aciclovir 800 mg three times daily (high dose aciclovir), and standard-dose valaciclovir with valaciclovir 1 g three times daily (high-dose valaciclovir). The allocation sequence was generated by a random number generator. Study drugs were supplied in identical, numbered, sealed boxes. Study periods lasted 4-7 weeks, separated by 1 week wash-out. Participants collected genital swabs four times daily for quantitative HSV DNA PCR. Clinical data were masked from laboratory personnel. The primary endpoint was within person comparison of shedding rate in each study group. Analysis was per protocol. The trials are registered at ClinicalTrials.gov (NCT00362297, NCT00723229, NCT01346475). RESULTS: Of 113 participants randomised, 90 were eligible for analysis of the primary endpoint. Participants collected 23 605 swabs; 1272 (5.4%) were HSV-positive. The frequency of HSV shedding was significantly higher in the no medication group (n=384, 18.1% of swabs) than in the standard-dose aciclovir group (25, 1.2%; incidence rate ratio [IRR] 0.05, 95% CI 0.03-0.08). High-dose aciclovir was associated with less shedding than standard-dose valaciclovir (198 [4.2%] vs 209 [4.5%]; IRR 0.79, 95% CI 0.63 1.00). Shedding was less frequent in the high-dose valaciclovir group than in the standard-dose valaciclovir group (164 [3.3%] vs 292 [5.8%]; 0.54, 0.44-0.66). The number of episodes per person-year did not differ significantly for standard-dose valaciclovir (22.6) versus high-dose aciclovir (20.2; p=0.54), and standard-dose valaciclovir (14.9) versus high-dose valaciclovir (16.5; p=0.34), but did for no medication (28.7) and standard-dose aciclovir (10.0; p=0.001). Median episode duration was longer for no medication than for standard-dose aciclovir (13 h vs 7 h; p=0.01) and for standard-dose valaciclovir than for high-dose valaciclovir (10 h vs 7 h; p=0.03), but did not differ significantly between standard-dose valaciclovir and high-dose aciclovir (8 h vs 8 h; p=0.23). Likewise, maximum log(10) copies of HSV detected per mL was higher for no medication than for standard dose aciclovir (3.3 vs 2.9; p=0.02), and for standard-dose valaciclovir than for high-dose valaciclovir (2.5 vs 3.0; p=0.001), but no significant difference was recorded for standard-dose valaciclovir versus high-dose aciclovir (2.7 vs 2.8; p=0.66). 80% of episodes were subclinical in all study groups. Except for a higher frequency of headaches with high-dose valaciclovir (n=13, 30%) than with other regimens, all regimens were well tolerated. INTERPRETATION: Short bursts of subclinical genital HSV reactivation are frequent, even during high-dose antiherpes therapy, and probably account for continued transmission of HSV during suppressive antiviral therapy. More potent antiviral therapy is needed to eliminate HSV transmission. FUNDING: NIH. Valaciclovir was provided for trial 3 for free by GlaxoSmithKline. PMID- 22225817 TI - Experiences of inner strength in critically ill patients--a hermeneutical approach. AB - Becoming critically ill and in need of ventilator treatment is a considerable burden. Fear and anxiety are natural reactions and it is not uncommon for patients to experience hopelessness, withdrawal and depression. In situations like these the possession of inner strength can be of vital importance. OBJECTIVES: To gain knowledge on what factors contribute to inner strength in critically ill patients cared for in an intensive care unit. The depth interviews were conducted with six former ventilator-treated patients aged 60-72years. SETTING: The informants were recruited through the ICU at an urban hospital in Norway. RESEARCH METHODOLOGY/DESIGN: The study has an exploratory and descriptive design. A hermeneutic approach was used to interpret the data, in which Kvale's self-perception, critical common sense and theoretical levels were applied. RESULTS: The study clearly demonstrates that there are certain factors that promote the inner strength of patients undergoing ventilator treatment. These are: "To have the support of next of kin", "The wish to go on living", "To be seen" and "Signs of progress". Amongst these patients it appears that the presence of one's next of kin has prime significance in promoting inner strength. PMID- 22225818 TI - Can Chlorella pyrenoidosa be a bioindicator for hazardous solid waste detoxification? AB - Four kinds of solid waste residue (SWR, S1 to S4) from different stages in a sequential detoxification process were chosen. The biotoxicity of the leachates from S1 to S4 was tested by Chlorella pyrenoidosa. The growth inhibition, the chlorophyll a (chla) and chlorophyll b (chlb) concentrations, and the ultrastructural morphology of cells of C. pyrenoidosa were studied. It shows that the growth inhibition of C. pyrenoidosa significantly increased with increasing leachate concentration when exposed to the leachates from S1, S2, S3, and S4, respectively. It well reflects the toxicity difference of leachate from SWR at different treatment stages, namely S1>S2>S3>S4. Correspondingly, the chla and chlb concentrations of C. pyrenoidosa increased gradually as SWR was treated deeply. Leachate disrupted chlorophyll synthesis and inhibited cell growth. The changing of the ultrastructural morphology of cells under different leachate exposures, such as volume of chloroplasts and quantity of thylakoids reducing, confirmed the toxicity decrease of leachates from different stages. C. pyrenoidosa is a good bioindicator for hazardous solid waste detoxification. The EC(50) at difference scenarios also suggests that it was feasible to estimate ecological toxicity of leachates to C. pyrenoidosa after exposure times of 72h. C. pyrenoidosa can be introduced to evaluate the effect of hazardous solid waste disposal by biotoxicity assessment. PMID- 22225819 TI - Effects of nitrogen deposition on carbon sequestration in Chinese fir forest ecosystems. AB - Nitrogen deposition and its ecological effects on forest ecosystems have received global attention. We used the ecosystem model FORECAST to assess the effects of nitrogen deposition on carbon sequestration in Chinese fir planted forests in SE China. This topic is important as China is intensifying its reforestation efforts to increase forest carbon sequestration for combating climate change impacts, using Chinese fir as the most important plantation species. A series of scenarios including seven N deposition levels (1, 5, 10, 20, 30, 40 and 50kg ha(-1)y(-1)), three management regime (rotation lengths of 15, 30 and 50 years) and two site qualities (nutrient poor and fertile sites) were defined for the simulations. Our results showed that N deposition increased carbon sequestration in Chinese fir forests, but the efficiency of the increasing effect is reduced as N deposition levels increase. When N deposition levels exceeded 20-30kg ha(-1)y(-1), the incremental effects of N deposition on forest C pools were marginal. This suggests that N deposition levels above 20-30kg ha(-1)y(-1) could lead to N saturation in Chinese fir forest soils. Any additional amounts of N input from deposition would likely be leached out. Total above-ground C was more sensitive to N deposition than to rotation length and site quality. It was also estimated that the contributions of N deposition to C sequestration in all Chinese fir forests in South-East China are 7.4*10(6)MgCy(-1) under the current N deposition levels (5 to 10kg ha(-1)y(-1)) and could reach up to 16*10(6)MgCy(-1) if N deposition continues increasing and reaches levels of 7.5 to 15kg N ha(-1)y(-1). PMID- 22225820 TI - Methoxylated polybrominated diphenyl ethers (MeO-PBDEs) are major contributors to the persistent organobromine load in sub-Arctic and Arctic marine mammals, 1986 2009. AB - A selection of MeO-BDE and BDE congeners were analyzed in pooled blubber samples of pilot whale (Globicephala melas), ringed seal (Phoca hispida), minke whale (Balaenoptera acutorostrata), fin whale (Balaenoptera physalus), harbor porpoise (Phocoena phocoena), hooded seal (Cystophora cristata), and Atlantic white-sided dolphin (Lagenorhynchus acutus), covering a time period of more than 20 years (1986-2009). The analytes were extracted and cleaned-up using open column extraction and multi-layer silica gel column chromatography. The analysis was performed using both low resolution and high resolution GC-MS. MeO-PBDE concentrations relative to total PBDE concentrations varied greatly between sampling periods and species. The highest MeO-PBDE levels were found in the toothed whale species pilot whale and white-sided dolphin, often exceeding the concentration of the most abundant PBDE, BDE-47. The lowest MeO-PBDE levels were found in fin whales and ringed seals. The main MeO-BDE congeners were 6-MeO-BDE47 and 2'-MeO-BDE68. A weak correlation only between BDE47 and its methoxylated analog 6-MeO-BDE47 was found and is indicative of a natural source for MeO-PBDEs. PMID- 22225821 TI - Decreased birth weight in relation to maternal urinary trichloroacetic acid levels. AB - BACKGROUND: The effect of exposure to disinfection by-products (DBPs) during pregnancy on newborn's birth weight has been commonly described in animal studies. However, epidemiological evidence was not consistent. OBJECTIVES: To investigate the relationship between exposure to DBPs and newborn's birth weight in a Chinese population, we conducted a cross-sectional study in Wuhan, China. METHODS: A total number of 398 women who had given birth to a live singleton with a gestational age between 37 to 42 weeks were recruited from a local hospital between November 2008 and May 2009. Basic information for all mothers and newborns was obtained from clinic birth records. Among these subjects, 180 women also gave further information including maternal medical history, social status and water-use behaviors by a face-to-face interview. Urinary creatinine (Cr) adjusted trichloroacetic (TCAA) was used as an exposure biomarker. RESULTS: No statically significant results were found in the linear regression for both 398 participants and 180 participants who finished questionnaires. However, both the crude and adjusted results showed that the mean birth weight of the subjects in the third and top quartiles of Cr-adjusted urinary TCAA concentrations was decreased compared with those in the lowest quartile. Subjects in the top quartiles had the lowest mean birth weight compared to those in other quartiles. In addition, a weak correlation was observed among 82 subjects between drinking water ingestion and urinary Cr-adjusted TCAA (r=0.23, P=0.04). CONCLUSION: Our findings suggested that elevated exposure to DBPs may affect fetal growth. The effect of exposure to DBPs during pregnancy on birth weight still warrants further investigations. PMID- 22225822 TI - Risk-benefit evaluation of fish from Chinese markets: nutrients and contaminants in 24 fish species from five big cities and related assessment for human health. AB - The risks and benefits of fish from markets in Chinese cities have not previously been fully evaluated. In the present study, 24 common fish species with more than 400 individual samples were collected from markets from five big Chinese cities in 2007. The main nutrients and contaminants were measured and the risk-benefit was evaluated based on recommended nutrient intakes and risk level criteria set by relevant authorities. The comprehensive effects of nutrients and contaminants in marine oily fish were also evaluated using the data of two related human dietary intervention trials performed in dyslipidemic Chinese men and women in 2008 and 2010, respectively. The results showed that concentrations of contaminants analyzed including DDT, PCB(7), arsenic and cadmium were much lower than their corresponding maximum limits with the exception of the mercury concentration in common carp. Concentrations of POPs and n-3 LCPUFA, mainly EPA and DHA, were positively associated with the lipid content of the fish. With a daily intake of 80-100g marine oily fish, the persistent organic pollutants in fish would not counteract the beneficial effects of n-3 LCPUFA in reducing cardiovascular disease (CVD) risk markers. Marine oily fish provided more effective protection against CVD than lean fish, particularly for the dyslipidemic populations. The risk-benefit assessment based on the present daily aquatic product intake in Chinese urban residents (44.9 and 62.3g for the average values for all cities and big cities, respectively) indicated that fish, particularly marine oily fish, can be regularly consumed to achieve optimal nutritional benefits from n-3 LCPUFA, without causing significant contaminant related health risks. However, the potential health threat from contaminants in fish should still be emphasized for the populations consuming large quantities of fish, particularly wild fish. PMID- 22225823 TI - Expanding perceptions of subsistence fish consumption: evidence of high commercial fish consumption and dietary mercury exposure in an urban coastal community. AB - Through collaborative partnerships established between current researchers and The Moton Community House (a local community center), African American women (ages 16-49yrs) from the Southeast Community of Newport News, Virginia, USA were surveyed to assess the reproducibility and consistency of fish consumption patterns (ingestion rates, exposure frequencies, weight, and fish consumption rates) derived from a community-specific fish consumption survey. Women were also surveyed to assess the reliability of the survey responses, and to estimate daily mercury intake. Fish consumption patterns were reproducible and the survey responses were reliable. Comparison between years revealed that fish consumption patterns remained consistent over time. In addition, the high fish consumption rate estimated in 2008 (147.8g/day; 95% CI: 117.6-185.8g/day) was confirmed with a rate (134.9g/day; 95% CI: 88-207g/day) not materially different and still considerably higher than mean fish consumption rates reported for U.S. women. Daily mercury intake rates were estimated using consumption data from 2008 and three consumption scenarios (canned white, canned light, and no tuna) due to confirmed differences in mercury concentration between canned white and light tuna. Arithmetic mean daily mercury intake rates were 0.284MUg/kg bw/day (95% CI: 0.229-0.340MUg/kg bw/day) using canned white tuna, 0.212MUg/kg bw/day (95% CI: 0.165-0.259MUg/kg bw/day) using light tuna, and 0.197MUg/kg bw/day (95% CI: 0.151 0.243MUg/kg bw/day) using no tuna. Approximately 58%-73% of the daily mercury intake rates for African American women in the Southeast Community exceeded US EPA's oral reference dose (RfD) of 0.10MUg/kg bw/day for mercury. In addition, 2% of the rates exceeded a level (1.00MUg/kg bw/day) documented to produce adverse health effects. Past and current investigations confirmed that even though women in this community were not subsistence fishers, they are subsistence fish consumers. PMID- 22225824 TI - Mercury photolytic transformation affected by low-molecular-weight natural organics in water. AB - Mechanisms by which dissolved organic matter (DOM) mediates the photochemical reduction of Hg(II) in aquatic ecosystems are not fully understood, owing to the heterogeneous nature and complex structural properties of DOM. In this work, naturally occurring aromatic compounds including salicylic, 4-hydrobenzoic, anthranilic, 4-aminobenzoic, and phthalic acid were systematically studied as surrogates for DOM in order to gain an improved mechanistic understanding of these compounds in the photoreduction of Hg(II) in water. We show that the photoreduction rates of Hg(II) are influenced not only by the substituent functional groups such as -OH, -NH(2) and -COOH on the benzene ring, but also the positioning of these functional groups on the ring structure. The Hg(II) photoreduction rate decreases in the order anthranilic acid>salicylic acid>phthalic acid according to the presence of the -NH(2), -OH, -COOH functional groups on benzoic acid. The substitution position of the functional groups affects reduction rates in the order anthranilic acid>4-aminobenzoic acid and salicylic acid>4-hydroxybenzoic acid. Reduction rates correlate strongly with ultraviolet (UV) absorption of these compounds and their concentrations, suggesting that the formation of organic free radicals during photolysis of these compounds is responsible for Hg(II) photoreduction. These results provide insight into the role of low-molecular-weight organic compounds and possibly DOM in Hg photoredox transformation and may thus have important implications for understanding Hg geochemical cycling in the environment. PMID- 22225825 TI - 4D imaging and quantification of pore structure modifications inside natural building stones by means of high resolution X-ray CT. AB - Weathering processes have been studied in detail for many natural building stones. The most commonly used analytical techniques in these studies are thin section petrography, SEM, XRD and XRF. Most of these techniques are valuable for chemical and mineralogical analysis of the weathering patterns. However, to obtain crucial quantitative information on structural evolutions like porosity changes and growth of weathering crusts in function of time, non-destructive techniques become necessary. In this study, a Belgian historical calcareous sandstone, the Lede stone, was exposed to gaseous SO(2) under wet surface conditions according to the European Standard NBN EN 13919 (2003). Before, during and after the strong acid test, high resolution X-ray tomography has been performed to visualize gypsum crust formation to yield a better insight into the effects of gaseous SO(2) on the pore modification in 3D. The tomographic scans were taken at the Centre for X-ray Tomography at Ghent University (UGCT). With the aid of image analysis, partial porosity changes were calculated in different stadia of the process. Increasing porosity has been observed visually and quantitatively below the new superficial formed layer of gypsum crystals. In some cases micro-cracks and dissolution zones were detected on the grain boundaries of quartz. By using Morpho+, an in-house developed image analysis program, radial porosity, partial porosity, ratio of open and closed porosity and equivalent diameter of individual pore structures have been calculated. The results obtained in this study are promising for a better understanding of gypsum weathering mechanisms, porosity changes and patterns on natural building stones in four dimensions. PMID- 22225826 TI - The impacts of low-cost treatment options upon scale formation potential in remote communities reliant on hard groundwaters. A case study: Northern Territory, Australia. AB - The majority of small, remote communities within the Northern Territory (NT) in Central Australia are reliant on groundwater as their primary supply of domestic, potable water. Saturation indices for a variety of relevant minerals were calculated using available thermodynamic speciation codes on collected groundwater data across the NT. These saturation indices were used to assess the theoretical formation of problematic mineral-scale, which manifests itself by forming stubborn coatings on domestic appliances and fixtures. The results of this research show that 63% of the measured sites within the NT have the potential to form calcium carbonate (CaCO(3)) scale, increasing to 91% in arid, central regions. The data also suggests that all groundwaters are over-saturated with respect to amorphous calcium-bridged ferric-silica polymers, based on the crystalline mineral index (Ca(3)Fe(2)Si(3)O(12)), although the quantitative impact of this scale is limited by low iron concentrations. An assessment of possible low-cost/low-technology management options was made, including; lowering the temperature of hot-water systems, diluting groundwater with rainwater and modifying the pH of the source water. Source water pH modification (generally a reduction to pH 7.0) was shown to clearly alleviate potential carbonate-based scale formation, over and above the other two options, albeit at a greater technical and capital expense. Although low-cost/low-technology treatment options are unlikely to remove severe scale-related issues, their place in small, remote communities with minor scale problems should be investigated further, owing to the social, technical and capital barriers involved with installing advanced treatment plants (e.g. reverse osmosis) in such locations. PMID- 22225828 TI - Detection of collagen VII autoantibodies to NC1 and NC2 domains of collagen VII by ELISA in suspected epidermolysis bullosa acquisita and bullous lupus erythematosus patients. PMID- 22225827 TI - Breed, age and gender distribution of dogs with chronic hepatitis in the United Kingdom. AB - Standardised histological criteria are now available for the diagnosis of canine chronic hepatitis (CH). CH is common in dogs, but no studies have reported breed, age and gender distributions in the United Kingdom (UK). The objective of this study was to determine which breeds had an increased risk for developing CH in the UK and to report the age and gender distribution for those breeds. The databases of six veterinary histopathology laboratories were searched for cases with a histological diagnosis of CH according to standardised criteria. The breed, age and gender of dogs was recorded and compared to a control population to calculate the odds ratio and 95% confidence intervals for developing CH. A total of 551 cases of CH were identified, consisting of 61 breeds. Nineteen breeds were represented by five or more cases. Breeds with an increased risk for developing CH included the American cocker spaniel, Cairn terrier, Dalmatian, Dobermann pinscher, English cocker spaniel, English springer spaniel, Great Dane, Labrador retriever and Samoyed. The median age at diagnosis for all breeds with CH was 8 years (range 7 months to 16 years). Dalmatians, Dobermann pinschers and English springer spaniels with CH were significantly younger than Cairn terriers, English cocker spaniels and Labrador retrievers with CH. Females were over represented when all cases were examined together. In conclusion, several breeds in the UK have an increased risk of CH, some of which have not been previously reported. PMID- 22225830 TI - The role of the prostatic vasculature as a landmark for nerve sparing during robot-assisted radical prostatectomy. AB - BACKGROUND: Macroscopic landmarks are lacking to identify the cavernosal nerves (CNs) during radical prostatectomy. The prostatic and capsular arteries run along the lateral border of the prostate and could help identify the location of the CNs during robot-assisted radical prostatectomy (RARP). OBJECTIVE: Describe the visual cues that have helped us achieve consistent nerve sparing (NS) during RARP, placing special emphasis on the usefulness of the prostatic vasculature (PV). DESIGN, SETTING, AND PARTICIPANTS: Retrospective video analysis of 133 consecutive patients who underwent RARP in a single institution between January and February 2011. SURGICAL PROCEDURE: NS was performed using a retrograde, antegrade, or combined approach. MEASUREMENTS: A landmark artery (LA) was identified running on the lateral border of the prostate corresponding to either a prostatic or capsular artery. NS was classified as either medial or lateral to the LA. The area of residual nerve tissue on surgical specimens was measured to compare the amount of NS between the groups. RESULTS AND LIMITATIONS: We could identify an LA in 73.3% (195 of 266) of the operated sides. The area of residual nerve tissue was significantly different whether the NS was performed medial (between the LA and the prostate) or lateral to the LA (between the LA and pelvic side wall): median (interquartile range) of 0 (0-3) mm2 versus14 (9-25) mm2; p<0.001, respectively. CONCLUSIONS: The PV is an identifiable landmark during NS. Fine tailoring on the medial border of an LA can consistently result in a complete or almost complete NS, whereas performing the NS on its lateral border results in several degrees of incomplete NS. PMID- 22225832 TI - Different potassium channels are involved in relaxation of rat renal artery induced by P1075. AB - The ATP-sensitive K(+) channels opener (K(ATP)CO), P1075 [N-cyano-N'-(1,1 dimethylpropyl)-N"-3-pyridylguanidine], has been shown to cause relaxation of various isolated animal and human blood vessels by opening of vascular smooth muscle ATP-sensitive K(+) (K(ATP)) channels. In addition to the well-known effect on the opening of K(ATP) channels, it has been reported that vasorelaxation induced by some of the K(ATP)COs includes some other K(+) channel subtypes. Given that there is still no information on other types of K(+) channels possibly involved in the mechanism of relaxation induced by P1075, this study was designed to examine the effects of P1075 on the rat renal artery with endothelium and with denuded endothelium and to define the contribution of different K(+) channel subtypes in the P1075 action on this blood vessel. Our results show that P1075 induced a concentration-dependent relaxation of rat renal artery rings pre contracted by phenylephrine. Glibenclamide, a selective K(ATP) channels inhibitor, partly antagonized the relaxation of rat renal artery induced by P1075. Tetraethylammonium (TEA), a non-selective inhibitor of Ca(2+)-activated K(+) channels, as well as iberiotoxin, a most selective blocker of large conductance Ca(2+) -activated K(+) (BK(Ca)) channels, did not abolish the effect of P1075 on rat renal artery. In contrast, a non-selective blocker of voltage gated K(+) (K(V)) channels, 4-aminopyridine (4-AP), as well as margatoxin, a potent inhibitor of K(V)1.3 channels, caused partial inhibition of the P1075 induced relaxation of rat renal artery. In addition, in this study, P1075 relaxed contractions induced by 20 mM K(+) , but had no effect on contractions induced by 80 mM K(+). Our results showed that P1075 induced strong endothelium-independent relaxation of rat renal artery. It seems that K(ATP), 4-AP- and margatoxin sensitive K(+) channels located in vascular smooth muscle mediated the relaxation of rat renal artery induced by P1075. PMID- 22225833 TI - Effect of milk protein glycation and gastrointestinal digestion on the growth of bifidobacteria and lactic acid bacteria. AB - In this paper, beta-lactoglobulin (beta-Lg) and sodium caseinate (SC) have been glycated via Maillard reaction with galactose and lactose and, subsequently, the effect of glycoconjugates hydrolyzed under simulated gastrointestinal digestion on the growth of pure culture of Lactobacillus, Streptococcus and Bifidobacterium has been investigated. Glycopeptides were added to the growth media as the sole carbon source. None of the bacterial strains was able to grow in hydrolysates of native and control heated beta-Lg and SC. However, glycopeptides were fermented, in different degree, by Lactobacillus and Bifidobacterium and hardly any effect was detected on the growth of Streptococcus. Digested beta-Lg glycoconjugates showed a strain-dependent effect whereas growth profiles of bacteria when hydrolysates of SC glycoconjugates were used as substrates were very similar, regardless of the strain. A general preference towards peptides from beta-Lg/SC glycated with galactose, particularly at the state of the reaction in which the highest content in the Amadori compound tagatosyl-lysine is present, was observed. SC glycoconjugates were quickly fermented by some strains, promoting their growth in a greater extent than beta-Lg complexes or even glucose. Therefore, from the results obtained in this work it can be concluded that conjugation of both milk proteins with galactose and lactose via the Maillard reaction could be an efficient method to obtain novel food ingredients with a potential prebiotic character. PMID- 22225834 TI - Generic and oral quality of life is affected by oral mucosal diseases. AB - BACKGROUND: The generic and oral health-related quality of life (QoL) has provided opportunity for investigation of the interrelations among generic health, oral health, and related outcomes. The purpose of this study was to identify the generic and oral QoL in the patients with oral mucosal disease (OMD). METHODS: Five hundred and thirty-eight OMDs were recruited in this study. The instruments applied were Chinese version of the 36-item short form health survey (SF-36) and the short-form of Oral Health Impact Profile (OHIP-14). RESULTS: The mean score of sum OHIP-14 was significantly higher in the patients with OMD (10.81 +/- 9.01) compared with those in the healthy subjects (HS) (6.55 +/- 6.73) (p < 0.001, Mann-Whitney U test). 56.51% of the OMD patients and 12.94% of the HS reported at least one oral negative impact (p < 0.001, Chi-square test). The overall mean score of SF-36 was significantly lower in the patients with OMD (74.54 +/- 12.77) compared with those in the HS (77.97 +/- 12.39) (p = 0.021, t-test). CONCLUSIONS: Administration of specific and generic questionnaires of QoL can provide us a detailed picture of the impact of OMDs on patients, and both generic and oral QoL were impaired in the patients with OMD. PMID- 22225829 TI - Rhabdomyosarcomas: an overview on the experimental animal models. AB - Rhabdomyosarcomas (RMS) are aggressive childhood soft-tissue malignancies deriving from mesenchymal progenitors that are committed to muscle-specific lineages. Despite the histopathological signatures associated with three main histological variants, termed embryonal, alveolar and pleomorphic, a plethora of genetic and molecular changes are recognized in RMS. Over the years, exposure to carcinogens or ionizing radiations and gene-targeting approaches in vivo have greatly contributed to disclose some of the mechanisms underlying RMS onset. In this review, we describe the principal distinct features associated with RMS variants and focus on the current available experimental animal models to point out the molecular determinants cooperating with RMS development and progression. PMID- 22225835 TI - IL-10-generated tolerogenic dendritic cells are optimal for functional regulatory T cell induction--a comparative study of human clinical-applicable DC. AB - Tolerogenic dendritic cells (tDC) are a promising tool for specific cellular therapy to induce immunological tolerance in transplantation and autoimmunity. To date, most described tDC methods have not been converted into clinically applicable protocols and systematic comparison of required functional characteristics, i.e. migration and functional regulatory T cell (Treg) induction, is lacking. We compare clinical-grade tDC generated with vitamin D(3), IL-10, dexamethasone, TGFbeta or rapamycin. For good migratory capacity and a stable phenotype, additional maturation of tDC was required. Maturation with a cocktail of TNFalpha, IL-1beta and PGE(2) induced optimal migration. Importantly, all tDC showed a stable phenotype under pro-inflammatory conditions. Especially IL-10 DC showed most powerful tolerogenic characteristics with high IL-10 production and low T cell activation. Moreover, in a functional suppression assay only IL-10 DC induced Treg that strongly suppressed T cell reactivity. Thus, clinical-grade IL-10 DC show functional characteristics that make them best suited for tolerance-inducing therapies. PMID- 22225837 TI - Positional velar fronting: an updated articulatory account. AB - This study develops the hypothesis that the child-specific phenomenon of positional velar fronting can be modeled as the product of phonologically encoded articulatory limitations unique to immature speakers. Children have difficulty executing discrete tongue movements, preferring to move the tongue and jaw as a single unit. This predisposes the child to produce undifferentiated linguopalatal contact, neutralizing the coronal-velar contrast. Adopting a phonetically sensitive model of phonology, I propose that children's difficulty with discrete tongue movement can be encoded in a violable constraint, Move.as-Unit. The positional nature of fronting reflects the fact that discrete lingual movement is penalized more heavily in the motorically challenging context of a larger gesture. This analysis is supported with a longitudinal study of one child (3 ; 9 to 4 ; 4) whose fronting was conditioned by both segmental and prosodic factors. Adopting Move.as-Unit in a Harmonic Grammar framework makes it possible to reframe disparate-seeming conditioning factors as a unified grammatical system. PMID- 22225836 TI - Prognostic value of proliferation assay in the luminal, HER2-positive, and triple negative biologic classes of breast cancer. AB - INTRODUCTION: Although the prognostic significance of proliferation in early invasive breast cancer has been recognized for a long time, recent gene expression profiling studies have reemphasized its biologic and prognostic value and the potential application of its assessment in routine practice, particularly to define prognostic subgroups of luminal/hormone receptor-positive (HR+) tumors. This study aimed to assess the prognostic value of a proliferation assay by using Ki-67 immunohistochemistry as compared with mitotic count scores. METHOD: Proliferation was assessed by using Ki-67 labeling index (Ki-67LI) and mitotic scores in a large (n = 1,550) and well-characterized series of clinically annotated primary operable invasive breast cancer with long-term follow-up. Tumors were phenotyped based on their IHC profiles into luminal/HR+, HER2+, and triple-negative (TN) classes. We used a split-sample development and validation approach to determine the optimal Ki-67LI cut-offs. RESULTS: The optimal cut points of Ki-67LI were 10% and 50% for the luminal class. Both Ki7LI and MS were able to split luminal tumors into subgroups with significantly variable outcomes, independent of other variables. Neither mitotic count scores nor Ki-67LI was associated with outcome in the HER2+ or the TN classes. CONCLUSIONS: Assessment of proliferation by using Ki-67LI and MS can distinguish subgroups of patients within luminal/hormone receptor-positive breast cancer significantly different in clinical outcomes. Overall, both Ki-67 LI and mitotic-count scores showed comparable results. The method described could provide a cost-effective method for prognostic subclassification of luminal/hormone receptor-positive breast cancer in routine clinical practice. PMID- 22225838 TI - Effect of challenge of pigs previously immunised with inactivated vaccines containing homologous and heterologous Mycoplasma hyopneumoniae strains. AB - BACKGROUND: Mycoplasma hyopneumoniae is the primary cause of enzootic pneumonia in pigs. Although vaccination is an important control tool, the results observed under field conditions are variable. This may be due to antigenic differences between the strains circulating in pig herds and the vaccine strain. This study compared the protective efficacy of four bacterins against challenge infection with a highly virulent field strain of M. hyopneumoniae. Seventy eight, one-week old piglets were randomly assigned to five treatment groups (A, B, C, D, E), 14 piglets each, and a negative control group (F) consisting of 8 piglets. All pigs were injected at 1 (D7) and 4 weeks of age (D28), with 2 ml of either a placebo or a bacterin based on selected M. hyopneumoniae strains, namely A (F7.2C), B (F20.1L), C (B2V1W20 1A-F), D (J strain), E (placebo; positive control), F (placebo; negative control). At D56, all pigs except those of group F were challenged intratracheally with 7 ml culture medium containing 107 CCU/ml of M. hyopneumoniae strain F7.2C. All pigs were euthanized and necropsied at D84. The severity of coughing and pneumonia lesions were the main parameters. Immunofluorescence (IF) testing, nested PCR testing of bronchoalveolar lavage (BAL) fluid and serology for M. hyopneumoniae were also performed. RESULTS: The different bacterins only slightly improved clinical symptoms (average 0.38 in vaccinated groups vs. 0.45 in group E) and histopathological lung lesions (average 3.20 in vaccinated groups vs. 3.45 in group E), but did not improve macroscopic lung lesions (score 4.30 vs. 4.03 in group E). None of the vaccines was significantly and/or consistently better or worse than the other ones. All bacterins evoked a serological response in the vaccinated animals. All pigs, except those from group F, were positive with nPCR in BAL fluid at D84. CONCLUSION: The bacterins did not induce a clear overall protection against challenge infection, and there were no significant differences in protective efficacy between bacterins containing homologous and heterologous M. hyopneumoniae strains. Further research is necessary to better characterize the antigens involved in protection and to elucidate the protective immunity responses following M. hyopneumoniae vaccination and/or infection. PMID- 22225839 TI - ARHP's Annual Reproductive Health Clinical Conference: a laboratory for innovative provider education that can lead to real practice change. AB - For reproductive health professionals, a combination of clinical and social science, presented in a variety of credible, interactive formats and featuring some type of mentoring and longer-term evaluation and follow-up, provides the richest platform for learning. There is growing support in the literature for this approach to improve clinician knowledge, competence and practice. ARHP is incorporating new educational platforms for all of its programs, including the annual Reproductive Health Clinical Conference. ARHP leaders plan to continue in depth evaluation and experimentation to work toward improved provider performance and the best possible patient outcomes. There is a strong need for more research to inform this promising area, but we are on the right track. PMID- 22225840 TI - A Bridge for postpartum women to Standard Days Method(r): I. Developing the Bridge. AB - BACKGROUND: A new fertility-awareness-based Bridge was developed for postpartum women starting with their first postpartum menses and until they are eligible to use the Standard Days Method(r). This article describes the development of the Bridge and theoretical efficacy. STUDY DESIGN: Analysis of a preexisting data set collected in 1986-1990 was performed. Seventy-three breastfeeding women in Australia, Britain and Canada were followed starting 42 days postpartum until they had at least two potentially fertile cycles. We used these data to calculate the theoretical probability of pregnancy from intercourse on different days of the cycle relative to ovulation for postpartum women following the instructions of the Bridge. RESULTS: The fertility-awareness-based family-planning Bridge is theoretically effective for postpartum women until they reestablish cycle regularity and can start using the Standard Days Method. CONCLUSION: The Bridge can potentially be effective for postpartum women until they are eligible to use the Standard Days Method. Results from an efficacy study of the Bridge are described in a companion article. PMID- 22225841 TI - Telephone follow-up and self-performed urine pregnancy testing after early medical abortion: a service evaluation. AB - INTRODUCTION: Telephone follow-up with a self-performed low-sensitivity urine pregnancy (LSUP) test was introduced at the Royal Infirmary of Edinburgh, Scotland, as an alternative to routine ultrasonography for confirming successful abortion at 2 weeks following early medical abortion (<9 weeks' gestation). Women who screened 'positive' at telephone follow-up on the basis of ongoing pregnancy symptoms, scant bleeding or LSUP test result subsequently attended the clinic for a confirmatory ultrasound. METHODS: A service evaluation was conducted of the first 8 months of telephone follow-up consisting of a review of the numbers choosing this method of follow-up, the proportion successfully contacted and the efficacy for detecting ongoing pregnancies. In the last 3 months of the study, women were surveyed about their satisfaction with this method of follow-up. RESULTS: Opting for telephone follow-up were 476 out of 619 women (77%). Four women (1%) attended the clinic before telephone follow-up because of pain or bleeding. A total of 410 (87%) of the remaining 472 women were successfully contacted by telephone. Sixty women (15%) screened 'positive', three of whom had ongoing pregnancies, and one woman falsely screened 'negative'. The sensitivity of the telephone follow-up was 75% [95% confidence interval (CI) 30.1-95.4], and specificity was 86% (95% CI 82.2-89). The negative predictive value was 99.7% (95% CI 98.4-99.9), and positive predictive value was 5% (95% CI 1.7-13.7). All women surveyed (n=75) would recommend telephone follow-up to a friend. CONCLUSION: A telephone follow-up and an LSUP test at 2 weeks are effective for detecting ongoing pregnancy, have good follow-up rates and are popular choices for women. PMID- 22225842 TI - A Bridge for postpartum women to Standard Days Method(r): II. Efficacy study. AB - BACKGROUND: In a companion article, we described the development of a new fertility-awareness-based Bridge for postpartum women starting with their first postpartum menses and until they are eligible to use the Standard Days Method(r). This article presents the results of an efficacy trial to test the Bridge. STUDY DESIGN: This was a prospective, nonrandomized, multicenter study following 157 women for up to 9 months. Participants were aged 18-39 years, had menstruated at least once since their baby was born, and wished to avoid or delay pregnancy using a fertility-awareness-based approach. Acceptability and correct use were examined. Life table pregnancy rates were calculated to assess method effectiveness. RESULTS: The typical-use failure rate is 11.2 for 6 months of Bridge use. CONCLUSION: The Bridge can offer significant protection from pregnancy for postpartum women who prefer using a fertility-awareness-based approach to avoiding pregnancy but are not yet eligible to use the Standard Days Method. Counseling should emphasize the importance of following the Bridge guidelines for it to be effective. PMID- 22225843 TI - Effects of parity and gestational age on second-trimester induction-abortion interval in combination with osmotic dilators and gemeprost. AB - BACKGROUND: The true prognostic factors for induced medical abortion are unknown. We sought to investigate the effects of a patient's obstetric parameters on the induction-abortion interval in second-trimester medical abortion. STUDY DESIGN: We studied 216 consecutive women. Pregnancy was terminated with cervical preparation using osmotic dilators followed by 1 mg vaginal gemeprost administered every 3 h for a maximum of five doses in the first 24 h. All variables are expressed in categorical form (parity, gestational age, maternal age and body mass index) and analyzed by the Cox proportional hazards model. RESULTS: Parity >= 3 was associated with a shorter duration of the induction abortion interval (adjusted hazards ratio 1.96; 95% confidence interval 1.13 3.40). A gestational age >= 16 weeks was associated with a longer duration of the induction-abortion interval (0.71; 0.52-0.98). No significant association was found in maternal age and body mass index. CONCLUSIONS: In combination with osmotic dilators and gemeprost, gestational age and parity are independent factors that affected the induction to abortion interval of second-trimester medical abortion. PMID- 22225844 TI - The origin and ecological significance of multiple branches for histidine utilization in Pseudomonas aeruginosa PAO1. AB - Pseudomonas proliferate in a wide spectrum of harsh and variable environments. In many of these environments, amino acids, such as histidine, are a valuable source of carbon, nitrogen and energy. Here, we demonstrate that the histidine uptake and utilization (hut) pathway of Pseudomonas aeruginosa PAO1 contains two branches from the intermediate formiminoglutamate to the product glutamate. Genetic analysis revealed that the four-step route is dispensable as long as the five-step route is present (and vice versa). Mutants with deletions of either the four-step (HutE) or five-step (HutFG) branches were competed against each other and the wild-type strain to test the hypothesis of ecological redundancy; that is, that the presence of two pathways confers no benefit beyond that delivered by the individual pathways. Fitness assays performed under several environmental conditions led us to reject this hypothesis; the four-step pathway can provide an advantage when histidine is the sole carbon source. An IclR-type regulator (HutR) was identified that regulates the four-step pathway. Comparison of sequenced genomes revealed that P.aeruginosa strains and P.fluorescens Pf-5 have branched hut pathways. Phylogenetic analyses suggests that the gene encoding formiminoglutamase (hutE) was acquired by horizontal gene transfer from a Ralstonia-like ancestor. Potential barriers to inter-species transfer of the hutRE module were explored by transferring it from P.aeruginosa PAO1 to P.fluorescens SBW25. Transfer of the operon conferred the ability to utilize histidine via the four-step pathway in a single step, but the fitness cost of acquiring this new operon was found to be environment dependent. PMID- 22225845 TI - Evaluation of medical students' expectations for multimedia teaching materials: Illustration by an original method using the evaluation of a web site on cardiovascular rehabilitation. AB - INTRODUCTION: Different multimedia tools have been developed to help medical students prepare for the National Ranking Examination (NRE), rendering their choice quite difficult. No study has specifically evaluated students' expectations regarding these materials. OBJECTIVES: To learn how medical students in Dijon assessed a website dedicated to cardiovascular rehabilitation, and collecting their suggestions in order to meet their expectations and the goals of second cycle medical studies. METHODS: Eighteen second-cyle students were evaluated in a semi-directed manner and in ecological situation, a website specifically designed for the national curricula on cardiovascular rehabilitation for obtaining the Diploma of Specialty Studies (DES) for physical medicine and rehabilitation (PM&R) residents. Students also had to fill out a pretest and a posttest (5 MCQs). RESULTS: The overall quality of the site was deemed satisfactory (65.6 +/- 7.7 points/100). Medical information was considered better than non-medical data and site's design (respectively 84.8 +/- 8.1, 61.1 +/- 20 and 64.4 +/- 14.9/100). Students found the site useful in terms of understanding the items related to cardiovascular rehabilitation, although they judged it not completely in line with the NRE goals. The average score increased significantly between the pre-and post-test (6.8 +/- 0.8 vs. 5 +/- 1.5/8, p<0.05). CONCLUSION: This site appears to be significantly useful for short-term knowledge improvement, but only partially meeting the expectations of second-cycle students. It seems relevant to study further possibilities for customizing and providing summarized learning for the NRE. These elements could serve as building grounds for the future version of this website. PMID- 22225846 TI - Tooth bioengineering leads the next generation of dentistry. AB - BACKGROUND: As a result of numerous rapid and exciting developments in tissue engineering technology, scientists are able to regenerate a fully functional tooth in animal models, from a bioengineered tooth germ. Advances in technology, together with our understanding of the mechanisms of tooth development and studies dealing with dentally derived stem cells, have led to significant progress in the field of tooth regeneration. AIM AND DESIGN: This review focuses on some of the recent advances in tooth bioengineering technology, the signalling pathways in tooth development, and in dental stem cell biology. These factors are highlighted in respect of our current knowledge of tooth regeneration. RESULTS AND CONCLUSION: An understanding of these new approaches in tooth regeneration should help to prepare clinicians to use this new and somewhat revolutionary therapy while also enabling them to partake in future clinical trials. Tooth bioengineering promises to be at the forefront of the next generation of dental treatments. PMID- 22225847 TI - Raman spectroscopy and laser desorption mass spectrometry for minimal destructive forensic analysis of black and color inkjet printed documents. AB - Inkjet ink analysis is the best way to discriminate between printed documents, or even though more difficult, to connect an inkjet printed document with a brand or model of printers. Raman spectroscopy and laser desorption mass spectrometry (LDMS) have been demonstrated as powerful tools for dyes and pigments analysis, which are ink components. The aim of this work is to evaluate the aforementioned techniques for inkjet inks analysis in terms of discriminating power, information quality, and nondestructive capability. So, we investigated 10 different inkjet ink cartridges (primary colors and black), 7 from the HP manufacturer and one each from Epson, Canon and Lexmark. This paper demonstrates the capabilities of three methods: Raman spectroscopy, LDMS and MALDI-MS. Raman spectroscopy, as it is preferable to try the nondestructive approach first, is successfully adapted to the analysis of color printed documents in most cases. For analysis of color inkjet inks by LDMS, we show that a MALDI matrix (9-aminoacridine, 9AA) is needed to desorb and to ionize dyes from most inkjet inks (except Epson inks). Therefore, a method was developed to apply the 9AA MALDI matrix directly onto the piece of paper while avoiding analyte spreading. The obtained mass spectra are very discriminating and lead to information about ink additives and paper compositions. Discrimination of black inkjet printed documents is more difficult because of the common use of carbon black as the principal pigment. We show for the first time the possibility to discriminate between two black-printed documents coming from different, as well as from the same, manufacturers. Mass spectra recorded from black inks in positive ion mode LDMS detect polyethylene glycol polymers which have characteristic mass distributions and end groups. Moreover, software has been developed for rapid and objective comparison of the low mass range of these positive mode LDMS spectra which have characteristic unknown peaks. PMID- 22225848 TI - Presynaptic inhibition of gamma-aminobutyric acid release in the bed nucleus of the stria terminalis by kappa opioid receptor signaling. AB - BACKGROUND: The kappa opioid receptor (KOR) and its endogenous agonist, the neuropeptide dynorphin, are a critical component of the central stress system. Both dynorphin and KOR are expressed in the bed nucleus of the stria terminalis (BNST), a brain region associated with anxiety and stress. This suggests that KOR activation in this region may play a role in the regulation of emotional behaviors. To date, however, there has been no investigation of the ability of KOR to modulate synaptic transmission in the BNST. METHODS: We used whole-cell patch-clamp recordings from acutely prepared mouse brain slices to examine the actions of KOR on inhibitory transmission in the BNST. Additionally, we used neurochemical and pathway-specific optogenetic manipulations to selectively stimulate gamma-aminobutyric acid (GABA)ergic fibers from the central nucleus of the amygdala (CeA) to the BNST. RESULTS: We found that activation of KOR reduced GABAergic transmission through a presynaptic mechanism. Furthermore, we examined the signal transduction pathways that mediate this inhibition and provide the first functional information implicating extracellular signal-regulated kinase in KOR-mediated presynaptic modulation. Moreover, we found that at KOR signaling robustly reduced inhibitory synaptic transmission in the CeA to BNST pathway. CONCLUSIONS: Together, these results demonstrate that KOR provides important inhibitory control over presynaptic GABAergic signaling within the BNST and provides the first direct functional demonstration of KOR-sensitive long-range GABAergic connections between the CeA and the BNST. PMID- 22225850 TI - The minimal clinically important difference for the Gait Profile Score. AB - The minimally clinically important difference (MCID) is an important concept for interpreting the results of clinical research. This paper proposes a rationale for defining an MCID for the Gait Profile Score (GPS) based on an analysis of the difference in median GPS for children classified at different levels of the Functional Assessment Questionnaire. A strong linear correlation between median score and FAQ level was found. An MCID of 1.6 degrees is therefore suggested, reflecting the mean difference between adjacent FAQ levels. Comparison of this value with (i) the standard deviation of GPS from typically developing children (1.4 degrees ) and (ii) the percentage of the difference between the median GPS for each FAQ level and that for typically developing children offers further support to suggest that 1.6 degrees is an appropriate figure. PMID- 22225849 TI - Comparison of the effects of estradiol and progesterone on serotonergic function. AB - BACKGROUND: Ovarian hormones may contribute to the vulnerability to depression, as well as to the response to antidepressants (ADs). Previously, we reported that acute systemic treatment with estradiol or progesterone blocked the ability of the selective serotonin reuptake inhibitor, fluvoxamine, to inhibit serotonin transporter function in ovariectomized rats. In this study, behavioral consequences, as well as receptor mechanisms underlying these hormonal effects, were investigated. METHODS: Using the forced swimming test, the acute effect of estradiol and/or progesterone on fluvoxamine's AD-like effects was investigated. Using in vivo chronoamperometry, the effect of local application of estradiol or progesterone into the hippocampus of ovariectomized rats on serotonin (5-HT) clearance, as well as on the ability of fluvoxamine to slow 5-HT clearance, were investigated. RESULTS: The decreased immobility and increased swimming caused by fluvoxamine in the forced swimming test was blocked in rats treated with estradiol and/or progesterone. Local application of estradiol, but not progesterone, slowed 5-HT clearance and both hormones blocked the ability of fluvoxamine to slow 5-HT clearance. Use of hormone receptor agonists and antagonists, revealed that the effects of estradiol are mediated by activation of membrane, as well as nuclear estrogen receptors (ER). The AD-like effect of estradiol involved ER beta and G-protein coupled receptor 30, whereas its blockade of fluvoxamine's effects was ER alpha-mediated. The effects of progesterone occurred solely by activation of intracellular progesterone receptors. CONCLUSIONS: Targeting of ER beta or G-protein coupled receptor 30 might reveal a strategy to permit beneficial effects of estrogen without its deleterious effect on selective serotonin reuptake inhibitor efficacy. PMID- 22225851 TI - Compensatory balance reactions during forward and backward walking on a treadmill. AB - Previous work suggests that balance perturbations to the body opposing the direction of progression during walking lead to larger amplitude corrective reactions than perturbations concurrent with walking direction. To test this hypothesis, subjects received forward and backward perturbations applied to the pelvis through a padded harness, while walking forwards or backwards on a treadmill. Contrary to our hypothesis, the greatest responses were associated with backward perturbations regardless of the direction of walking. PMID- 22225852 TI - The effects of word length, articulation, oral-motor movement, and lexicality on gait: a pilot study. AB - Previous research has suggested that articulatory demands are important predictors of the impact of dual-task interference on spatial-temporal parameters of gait. In this study, we evaluated the effects of word length, oral-motor movement, articulation, and lexicality, within a verbal task, on a continuous gait task. Fifteen healthy young women participated in a study in which two word lengths (monosyllabic and bisyllabic) were crossed with four levels of secondary task complexity (no dual-task, non-speech movement, spoken non-word, and spoken word). Spatial and temporal parameters of gait were measured using a 23' instrumented carpet. Results indicated a significant multivariate main effect for task type, F(15, 120)=3.07, that explained 71.1% of the demonstrated variability in gait. Univariate analyses of this main effect revealed statistically significant effects for velocity, step time, swing time, and stance time, but no statistically significant effect for step length. Post hoc analyses suggested that dual-task interference produced significant changes in the parameters of gait, but that this interference was not significantly greater with non-words as compared to the non-speech movement condition, nor was it significantly greater with words as compared to non-words. The results of this systematic deconstruction of a simple verbal task suggest that the motor component of a secondary speech task may produce the largest amount of interference within a dual-task interference paradigm. PMID- 22225853 TI - A linear soft tissue artefact model for human movement analysis: proof of concept using in vivo data. AB - We investigated the accuracy of a linear soft tissue artefact (STA) model in human movement analysis. Simultaneously recorded bone-mounted pin and skin marker data for the thigh and shank during walking, cutting and hopping were used to measure and model the motion of the skin marker clusters within anatomical reference frames (ARFs). This linear model allows skin marker movements relative to the underlying bone contrary to a rigid-body assumption. The linear model parameters were computed through a principal component analysis, which revealed that 95% of the variance of the STA motion for the thigh was contained in the first four principal components for all three tasks and all subjects. For the shank, 95% of the variance was contained in the first four principal components during walking and cutting and first five during hopping. For the thigh, the maximum residual artefact was reduced from 27.0mm to 5.1mm (walking), 22.7 mm to 3.0mm (cutting) and 16.2mm to 3.5mm (hopping) compared to a rigid-body assumption. Similar reductions were observed for the shank: 24.2mm to 1.9 mm (walking), 20.3mm to 1.9 mm (cutting) and 14.7 mm to 1.8mm (hopping). A geometric analysis of the first four principal components revealed that, within the ARFs, marker cluster STA is governed by rigid-body translations and rotations rather than deformations. The challenge remains, however, in finding the linear model parameters without bone pin data, but this investigation shows that relatively few parameters in a linear model are required to model the vast majority of the STA movements. PMID- 22225854 TI - Direction specific preserved limits of stability in early progressive supranuclear palsy: a dynamic posturographic study. AB - OBJECTIVES: To quantitatively detect the nature of balance impairment in patients with progressive supranuclear palsy (PSP) using dynamic posturography. METHODS: Twenty clinically diagnosed PSP patients (8 women, 12 men; age: 62.1 +/- 7.7 years; duration: 2.6 +/- 1.3 years) and 20 healthy controls were studied. All subjects were right side dominant. They were evaluated by dynamic posturography (Biodex, USA). The measurements included (i) balance indices: ability to control balance in all directions (overall balance index, OBI), front to back (anterior posterior index, API) and side-to-side (medio-lateral index, MLI), and (ii) the limits of stability (LOS) in 8 directions: forward (FW), backward (BW), right (RT), left (LT), forward-right (FW-RT), forward-left (FW-LT), backward-right (BW RT) and backward-left (BW-LT). RESULTS: Compared to controls, patients showed significantly higher OBI (p<0.001), API (p=0.003) and MLI (p<0.001), implying impaired balance. The total LOS score was significantly lower (implying poor stability) in PSP than in controls (18.3 +/- 7.3 vs. 28.4 +/- 8.5, p<0.001). Patients took significantly longer time to complete LOS test (262.7 +/- 33.0 s vs. 135.4 +/- 20.6 s, p<0.001). Direction-wise analysis showed that PSP patients had significantly lower LOS scores in FW, BW, RT, FW-RT, BW-RT and BW-LT directions compared to controls. However the scores in LT and FW-LT did not differ significantly. CONCLUSIONS: PSP patients showed impaired balance indices and decreased overall LOS compared to controls. Though LOS is affected in PSP, the scores in the left (non-dominant side) and forward-left (non-dominant forward diagonal) directions were preserved. PMID- 22225855 TI - Emerging and re-emerging swine viruses. AB - In the past two decades or so, a number of viruses have emerged in the global swine population. Some, such as porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2), cause economically important diseases in pigs, whereas others such as porcine torque teno virus (TTV), now known as Torque teno sus virus (TTSuV), porcine bocavirus (PBoV) and related novel parvoviruses, porcine kobuvirus, porcine toroviruses (PToV) and porcine lymphotropic herpesviruses (PLHV), are mostly subclinical in swine herds. Although some emerging swine viruses such as swine hepatitis E virus (swine HEV), porcine endogenous retrovirus (PERV) and porcine sapovirus (porcine SaV) may have a limited clinical implication in swine health, they do pose a potential public health concern in humans due to zoonotic (swine HEV) or potential zoonotic (porcine SaV) and xenozoonotic (PERV, PLHV) risks. Other emerging viruses such as Nipah virus, Bungowannah virus and Menangle virus not only cause diseases in pigs but some also pose important zoonotic threat to humans. This article focuses on emerging and re-emerging swine viruses that have a limited or uncertain clinical and economic impact on pig health. The transmission, epidemiology and pathogenic potential of these viruses are discussed. In addition, the two economically important emerging viruses, PRRSV and PCV2, are also briefly discussed to identify important knowledge gaps. PMID- 22225856 TI - Critical role of factors II and X during coumarin anticoagulation and their combined measurement with a new Fiix-prothrombin time. AB - Vitamin K antagonists (VKA) are monitored with prothrombin time (PT) based assays that are equally sensitive to reductions in factors II, VII or X. We compared the effect of vitamin K dependent (VKD) coagulation factors on PT and also on rotational thromboelastometric (ROTEM) parameters. The PT was equally sensitive to reductions in factors II, VII or X but ROTEM parameters correlated poorly with the PT in anticoagulated patients' plasmas. ROTEM parameters were more affected by mild and moderate reductions in FII or FX than by FVII or FIX which had little influence except at very low coagulant activity. We developed a modified PT that was sensitive only to reductions in factors II and X. The Fiix-PT (Fiix-INR) correlated well with PT (INR) but the Fiix-INR fluctuated less than the INR in an anticoagulated patient reflecting its insensitivity to FVII. The ROTEM results suggest that mild to moderate reductions in factors II or X are more important during clot formation than factors VII or IX. Reductions in FII and X may better reflect anticoagulation with VKA than FVII or IX. The new Fiix-PT may more accurately reflect the degree of therapeutic anticoagulation in patients treated with VKA than the current PT which is subject to a confounding variation caused by FVII. PMID- 22225857 TI - Pioglitazone inhibits platelet function and potentiates the effects of aspirin: a prospective observation study. AB - BACKGROUND: Thiazolidinediones (TZDs) are agonists of PPARgamma and exert beneficial metabolic effects in patients with diabetes. They may also affect platelet function. OBJECTIVES: To characterize potential platelet inhibitory effect of pioglitazone alone and in the presence of aspirin. METHODS: 20 normal and 20 diabetic subjects were enrolled in a prospective study. On day 1, a blood sample was obtained at baseline and a second one after ingestion of 30mg of pioglitazone. PRP was prepared and platelet aggregation and release were evaluated using ADP, collagen and arachidonic acid as agonists. Subjects returned at 6-9days later after ingesting a single 81mg dose of aspirin and a third blood sample was obtained. The subjects then again ingested 30mg of pioglitazone and a fourth and final blood sample was obtained. Platelet aggregation and release were measured. PRP was incubated with thrombin to activate platelets, and the serum was separated and assayed for thromboxane B2, TGFbeta and CD40L RESULTS: Pioglitazone alone did not affect aggregation with arachidonic acid. However, following ingestion of both aspirin and pioglitazone aggregation was significantly decreased compared to aspirin alone (P<0.0001). Pioglitazone also potentiated aspirin-induced inhibition of ATP release using either arachidonic acid or collagen. Following pioglitazone alone, TXB(2) release was 32,719+/ 3,585pg/ml which was significantly reduced compared to baseline (42,075+/-4,479, P=0.0004). Pioglitazone also potentiated the inhibition of TXB(2) release by aspirin. CONCLUSION: Pioglitazone inhibits platelet function and potentiates the inhibitory effects of aspirin. PMID- 22225858 TI - Concomitant use of medication with antiplatelet effects in patients receiving either rivaroxaban or enoxaparin after total hip or knee arthroplasty. AB - INTRODUCTION: The RECORD programme compared oral rivaroxaban with enoxaparin for prevention of venous thromboembolism after elective total hip or knee replacement. This analysis compared the safety of concomitant use of specified medications with rivaroxaban and enoxaparin by evaluating postoperative bleeding rates from the pooled RECORD1-4 data. MATERIALS AND METHODS: The co-medications were non-steroidal anti-inflammatory drugs and platelet function inhibitors, including acetylsalicylic acid (no dose restriction). The endpoints evaluated were the composite of major and non-major clinically relevant bleeding and any bleeding occurring after first oral study drug intake. The time relative to surgery was stratified into three time periods: day 1-3, day 4-7 and after day 7. Relative bleeding rate ratios for co-medication use versus non-use were derived using stratified Mantel-Haenszel methods and compared between rivaroxaban and enoxaparin groups. RESULTS: Co-medication use with rivaroxaban or enoxaparin resulted in non-significant increases in bleeding events. Respective rate ratios were not significantly different between rivaroxaban and enoxaparin for all bleeding endpoints with concomitant use of non-steroidal anti-inflammatory drugs (any bleeding, 1.22 vs 1.22; major and non-major clinically relevant bleeding, 1.28 vs 0.90) and with concomitant use of platelet function inhibitors/acetylsalicylic acid (any bleeding, 1.32 vs 1.40; major and non-major clinically relevant bleeding, 1.11 vs 1.13). CONCLUSIONS: This explorative analysis indicates that there is no significant increase in bleeding risk for rivaroxaban compared with enoxaparin when co-administered with non-steroidal anti inflammatory drugs or acetylsalicylic acid, although, because of low usage, the experience with platelet function inhibitors (except acetylsalicylic acid) was limited. PMID- 22225859 TI - Childhood chronic inflammatory demyelinating polyneuroradiculopathy--three cases and a review of the literature. AB - BACKGROUND: Chronic inflammatory demyelinating polyneuroradiculopathy (CIDP) is an autoimmune disease of the peripheral nervous system, causing demyelination and even axonal degeneration. In children, abnormal gait as a first sign of muscle weakness is a frequent reason to seek medical attention. Diagnosis is made on the basis of clinical characteristics, electromyography and nerve conduction studies, and elevated protein in cerebrospinal fluid. AIMS: We present three new cases of CIDP. The literature was reviewed in order to obtain more information on presentation, outcome and treatment strategies world-wide. RESULTS: The course of disease can be relapsing-remitting or chronic-progressive. From case series it is known that first-line immunotherapy (intravenously administered immunoglobulin, corticosteroids or plasmapheresis) is initially of benefit in most children with CIDP. There is little evidence, however, on second-line therapies as azathioprine, cyclosporine A, mycophenolate mofetil, methothrexate, cyclophosphamide and IFN alpha. Although the outcome of children with CIDP is generally regarded to be good, disease related disability can be severe. CONCLUSION: Childhood CIDP is rare. In general and in comparison to adults, children tend to have a more acute progressive onset, with more severe symptoms. Showing a higher tendency towards a relapsing-remitting course, children often show a better and faster improvement after therapy, and a more favorable outcome. Swift recognition of CIDP and empiric start of treatment are considered important to avoid potentially irreversible axonal damage and associated disability. Response to first-line therapies is usually favorable, however recommendations regarding the choice of second-line therapy can only be made on the basis of current practice described in case reports. Safety and efficacy data are insufficient. The cases described show that trial and error are often involved in finding an optimal treatment strategy, especially in those patients refractory to first-line treatment or with a prolonged course. Clinical experience with immunomodulatory treatment is paramount when treating children with CIDP. PMID- 22225860 TI - Age, sex and NK1 receptors in the human brain -- a positron emission tomography study with [11C]GR205171. AB - The substance P/neurokinin 1 (SP/NK1) system has been implicated in the processing of negative affect. Its role seems complex and findings from animal studies have not been easily translated to humans. Brain imaging studies on NK1 receptor distribution in humans have revealed an abundance of receptors in cortical, striatal and subcortical areas, including the amygdala. A reduction in NK1 receptors with increasing age has been reported in frontal, temporal, and parietal cortices, as well as in hippocampal areas. Also, a previous study suggests sex differences in cortical and subcortical areas, with women displaying fewer NK1 receptors. The present PET study explored NK1 receptor availability in men (n=9) and women (n=9) matched for age varying between 20 and 50years using the highly specific NK1 receptor antagonist [11C]GR205171 and a reference tissue model with cerebellum as the reference region. Age by sex interactions in the amygdala and the temporal cortex reflected a lower NK1 receptor availability with increasing age in men, but not in women. A general age-related decline in NK1 receptor availability was evident in the frontal, temporal, and occipital cortices, as well as in the brainstem, caudate nucleus, and thalamus. Women had lower NK1 receptor availability in the thalamus. The observed pattern of NK1 receptor distribution in the brain might have functional significance for brain related disorders showing age- and sex-related differences in prevalence. PMID- 22225862 TI - Quantitative, molecular and growth analyses of Ulva microscopic propagules in the coastal sediment of Jiangsu province where green tides initially occurred. AB - From 2007 to 2011, large-scale green tides formed by unattached filamentous alga, Ulva prolifera in Ulva linza-procera-prolifera complex, have initially occurred in Jiangsu coasts of China. The real niche or the substrate(s) on which U. prolifera attaches before it starts to float is still under debate. However, great numbers of Ulva propagules would be supposed to exist in the microscopic, overwintering stage for the next spring's bloom in coastal environments. This study was designed to confirm the above prediction and investigate abundance, species composition and growth characteristics of Ulva propagules in the sediments. Quantification result showed that Ulva propagules widely distributed in the sediments and the abundance of these isolates did not change much over a 3 month testing period at low temperature in darkness. Molecular data based on three DNA markers revealed that four Ulva species existed in the sediments, among which green-tide forming alga, U. prolifera, was included. Elevated levels of temperature, irradiance as well as nutrients in seawater greatly facilitated recovery and growth of propagules. Results of this investigation indicated the possibility of microscopic propagules turning directly into floating biomass in season when temperature, irradiance and nutrients together meet the required levels in questioned coastal water area. PMID- 22225861 TI - Macro- and meiofaunal community features in the critical environmental system of a tourist harbour (Rapallo, Ligurian Sea, NW Mediterranean). AB - Two samplings were carried out in a tourist harbour, during low and high touristic activity periods, to study the macro- and meiofaunal communities in relation to the environmental features. A multivariate analysis showed close relationships: the maritime traffic disturbance and the food quality and availability drive the spatial differences of the assemblages, dividing the area into three sub-areas: the area near the Boate torrent that empties into the harbour, the harbour proper, and the external area (just outside the harbour). Macro- and meiofauna showed notably different temporal trends, indicating competition for the resources and the higher sensitivity of the macrofauna to environmental pressures. The macrofauna strongly decreased as a response to heavier harbour activities, with increasing turbidity also affecting the external station outside the harbour. Finally, comparing the macrofaunal communities to those sampled in the same area 10 years before, we found that their abundance, richness and biomass had notably decreased, highlighting the worsening of the harbour environment due to the increased organic load and turbidity. PMID- 22225863 TI - Outcomes of intravenous thrombolytic therapy for acute ischemic stroke with an integrated acute stroke referral network: initial experience of a community-based hospital in a developing country. AB - Some of the literature encourages the use of intravenous (IV) thrombolytic therapy for acute ischemic stroke (AIS) in centers with no previous experience with this therapy. The benefits of an acute stroke referral network for IV thrombolytic therapy remain controversial, however. We present outcomes of IV thrombolytic therapy for AIS with an integrated acute stroke referral network at an institution with no previous experience in stroke thrombolysis and compare the results with previously published data. A total of 458 patients with AIS or transient ischemic attack (TIA), referred from a hospital in the acute stroke referral network or walk-ins, admitted to the stroke unit of Thammasat Hospital between October 2007 and January 2009 (16 months) were prospectively assessed. The main outcome measures were IV thrombolytic treatment rate, initial National Institutes of Health Stroke Scale (NIHSS) score, door-to-needle time, onset-to treatment time (OTT), intracerebral hemorrhage, and morbidity and mortality at 3 months after onset. A total of 100 patients (59 from hospitals in the stroke referral network) received IV recombinant tissue plasminogen activator (rt-PA) therapy (21% of the admissions with AIS and TIA); 41% of the patients referred from a hospital in the network received IV rt-PA. The median NIHSS score before thrombolysis was 15 (range, 3-34). Mean door-to-needle time was 54 minutes (range, 15-125 minutes), and mean OTT was 160 minutes (range, 60-270 minutes). There were 13 asymptomatic intracerebral hemorrhages and 2 symptomatic intracerebral hemorrhages (1 fatal). By 3 months, 42 patients had achieved excellent recovery (modified Rankin Scale score of 0-1), and 14 had died. These outcomes are comparable to data from the National Institute of Neurological Disorders and Stroke and previous studies of IV rt-PA therapy in Thailand. Our findings indicate that integrating an acute stroke referral network into IV thrombolytic therapy for AIS in a community-based setting is safe and feasible and should help increase the rate of thrombolytic therapy. Previously inexperienced community-based centers can reproduce the experience and outcome measures reported by clinical trials and in the landmark literature of IV thrombolytic therapy in patients with stroke. PMID- 22225864 TI - Mortality and cost of pneumonia after stroke for different risk groups. AB - An evidenced-based approach to detecting and treating dysphagia needs to be informed by the costs and risks associated with pneumonia. In this study, the cost of pneumonia during hospitalization after stroke and the effect of pneumonia on mortality were estimated. The effect of pneumonia on mortality and costs for different levels of risk were analyzed as well. The data come from the 2005 and 2006 Nationwide Inpatient Sample. Regression models, including the propensity for pneumonia, were used to estimate the in-hospital mortality-associated pneumonia, as well as the marginal cost of pneumonia on the hospitalization. A stratified analysis based on quintile of propensity for pneumonia was also undertaken. There were 183,976 hospitalizations for stroke in the sample. The adjusted relative risk of death associated with pneumonia was 2.0 (95% confidence interval [CI], 1.9-2.1). The average marginal cost of pneumonia on the hospitalization was $27,633 (95% CI, $27,078-$27,988). The quintile of hospitalizations with the highest propensity for pneumonia had the highest average marginal cost associated with pneumonia and the lowest adjusted relative risk of death. There was an inverse relationship between adjusted relative risk of death and propensity for pneumonia. The data indicate that pneumonia after stroke is associated with higher mortality and hospitalization costs. Patients with the lowest risk for pneumonia have the highest risk for death associated with pneumonia. Screening is important at all levels of risk. PMID- 22225865 TI - Recurrence of embolic stroke during intravenous thrombolysis. AB - An 81-year-old man with atrial fibrillation presented with embolic stroke in the right middle cerebral artery. During intravenous thrombolysis, he became comatose and developed a recurrent embolism in the top of the basilar artery. Intra arterial mechanical disruption of the embolus failed to recanalize. Laboratory studies on admission demonstrated thrombocytosis, but echocardiography performed after thrombolysis did not identify an embolic source, including mural thrombi. PMID- 22225867 TI - Treating obesity like a tumor. AB - Expanding adipose tissue in obesity requires a great deal of angiogenesis to support increasing volumes of tissue. A growing body of evidence indicates that inhibiting these blood vessels can result in substantial weight loss, and now this has been demonstrated in nonhuman primates. PMID- 22225866 TI - A fibronectin-fibrinogen-tropoelastin coating reduces smooth muscle cell growth but improves endothelial cell function. AB - Reendothelialization of the stent surface after percutaneous coronary intervention (PCI) is known to be an important determinant of clinical outcome. We compared the effects of biological stent coatings, fibronectin, fibrinogen and tropoelastin, on human umbilical vein endothelial cell (HUVEC) and vascular smooth muscle cell (VSMC) characteristics. Umbilical cord arterial segments were cultured on coated surfaces and VSMC outgrowth (indicating proliferation and migration) was measured after 12 days. mRNA was isolated from HUVEC and VSMC cultured on these coatings and gene expression was profiled by QPCR. Procoagulant properties of HUVEC were determined by an indirect chromogenic assay which detects tissue factor activity. The varying stent coatings influence VSMC outgrowth: 31.2 +/- 4.0 mm(2) on fibronectin, 1.6 +/- 0.3 mm(2) on tropoelastin and 8.1 +/- 1.5 mm(2) on a mixture of fibronectin/fibrinogen/tropoelastin, although HUVEC migration remains unaffected. Culturing HUVEC on tropoelastin induces increased expression of VCAM-1 (13.1 +/- 4.4 pg/ml), ICAM-1 (5.1 +/- 1.3 pg/ml) and IL-8 (11.6 +/- 3.1 pg/ml) compared to fibronectin (0.7 +/- 0.2, 0.8 +/ 0.2, 2.3 +/- 0.5 pg/ml, respectively), although expression levels on fibronectin/fibrinogen/tropoelastin remain unaltered. No significant differences in VCAM-1, ICAM-1 and IL-8 mRNA expression are found in VSMC. Finally, HUVEC cultured on tropoelastin display a fivefold increased tissue factor activity (511.6 +/- 26.7%), compared to cells cultured on fibronectin (100 +/- 3.9%) or fibronectin/fibrinogen/tropoelastin (76.3 +/- 25.0%). These results indicate that tropoelastin inhibits VSMC migration but leads to increased inflammatory and procoagulant markers on endothelial cells. Fibronectin/fibrinogen/tropoelastin inhibits VSMCs while compensating the inflammatory and procoagulant effects. These data suggest that coating a mixture of fibronectin/fibrinogen/tropoelastin on a stent may promote reendothelialization, while keeping unfavourable processes such as restenosis and procoagulant activity limited. PMID- 22225868 TI - Reactive oxygen species resulting from mitochondrial mutation diminishes stem and progenitor cell function. AB - While age-dependent stem cell decline is widely recognized as being a key component of organismal aging, the underlying mechanisms remain elusive. In this issue of Cell Metabolism, Suomalainen and colleagues provide evidence that mitochondrial mutation and associated reactive oxygen species can adversely impact tissue-specific stem and progenitor cell function. PMID- 22225869 TI - Power surge: supporting cells "fuel" cancer cell mitochondria. AB - An emerging paradigm in tumor metabolism is that catabolism in host cells "fuels" the anabolic growth of cancer cells via energy transfer. A study in Nature Medicine (Nieman et al., 2011) supports this; they show that triglyceride catabolism in adipocytes drives ovarian cancer metastasis by providing fatty acids as mitochondrial fuels. PMID- 22225870 TI - Transgenerational inheritance of longevity: epigenetic mysteries abound. AB - Transgenerational inheritance of epigenetic characteristics in plants has been reported, whereas nongenetic persistence of complex phenotypes in animals is controversial. A recent report by Anne Brunet and colleagues describes a fascinating example of persistence across generations of extended life span in worm and explores whether epigenetic mechanisms account for the longevity. PMID- 22225871 TI - IL-6 muscles in on the gut and pancreas to enhance insulin secretion. AB - The role of the cytokine interleukin-6 (IL-6) in metabolic homeostasis is the subject of conjecture. Recent work in Nature Medicine (Ellingsgaard et al., 2011) demonstrates that IL-6 released from skeletal muscle during exercise mediates crosstalk between insulin-sensitive tissues, intestinal L cells, and pancreatic islets to adapt to changes in insulin demand. PMID- 22225872 TI - The inflammasome puts obesity in the danger zone. AB - Obesity-induced inflammation is an important contributor to the induction of insulin resistance. Recently, the cytokine interleukin-1beta (IL-1beta) has emerged as a prominent instigator of the proinflammatory response in obesity. Several studies over the last year have subsequently deciphered the molecular mechanisms responsible for IL-1beta activation in adipose tissue, liver, and macrophages and demonstrated a central role of the processing enzyme caspase-1 and of the protein complex leading to its activation called the inflammasome. These data suggest that activation of the inflammasome represents a crucial step in the road from obesity to insulin resistance and type 2 diabetes. PMID- 22225873 TI - Metabolic disease drug discovery- "hitting the target" is easier said than done. AB - Despite the advent of new drug classes, the global epidemic of cardiometabolic disease has not abated. Continuing unmet medical needs remain a major driver for new research. Drug discovery approaches in this field have mirrored industry trends, leading to a recent increase in the number of molecules entering development. However, worrisome trends and newer hurdles are also apparent. The history of two newer drug classes-glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors-illustrates both progress and challenges. Future success requires that researchers learn from these experiences and continue to explore and apply new technology platforms and research paradigms. PMID- 22225874 TI - Srf-dependent paracrine signals produced by myofibers control satellite cell mediated skeletal muscle hypertrophy. AB - Adult skeletal muscles adapt their fiber size to workload. We show that serum response factor (Srf) is required for satellite cell-mediated hypertrophic muscle growth. Deletion of Srf from myofibers and not satellite cells blunts overload induced hypertrophy, and impairs satellite cell proliferation and recruitment to pre-existing fibers. We reveal a gene network in which Srf within myofibers modulates interleukin-6 and cyclooxygenase-2/interleukin-4 expressions and therefore exerts a paracrine control of satellite cell functions. In Srf-deleted muscles, in vivo overexpression of interleukin-6 is sufficient to restore satellite cell proliferation but not satellite cell fusion and overall growth. In contrast cyclooxygenase-2/interleukin-4 overexpression rescue satellite cell recruitment and muscle growth without affecting satellite cell proliferation, identifying altered fusion as the limiting cellular event. These findings unravel a role for Srf in the translation of mechanical cues applied to myofibers into paracrine signals, which in turn will modulate satellite cell functions and support muscle growth. PMID- 22225875 TI - PGRN is a key adipokine mediating high fat diet-induced insulin resistance and obesity through IL-6 in adipose tissue. AB - Adipose tissue secretes adipokines that mediate insulin resistance, a characteristic feature of obesity and type 2 diabetes. By differential proteome analysis of cellular models of insulin resistance, we identified progranulin (PGRN) as an adipokine induced by TNF-alpha and dexamethasone. PGRN in blood and adipose tissues was markedly increased in obese mouse models and was normalized with treatment of pioglitazone, an insulin-sensitizing agent. Ablation of PGRN (Grn(-/-)) prevented mice from high fat diet (HFD)-induced insulin resistance, adipocyte hypertrophy, and obesity. Grn deficiency blocked elevation of IL-6, an inflammatory cytokine, induced by HFD in blood and adipose tissues. Insulin resistance induced by chronic administration of PGRN was suppressed by neutralizing IL-6 in vivo. Thus, PGRN is a key adipokine that mediates HFD induced insulin resistance and obesity through production of IL-6 in adipose tissue, and may be a promising therapeutic target for obesity. PMID- 22225876 TI - p53-induced adipose tissue inflammation is critically involved in the development of insulin resistance in heart failure. AB - Several clinical studies have shown that insulin resistance is prevalent among patients with heart failure, but the underlying mechanisms have not been fully elucidated. Here, we report a mechanism of insulin resistance associated with heart failure that involves upregulation of p53 in adipose tissue. We found that pressure overload markedly upregulated p53 expression in adipose tissue along with an increase of adipose tissue inflammation. Chronic pressure overload accelerated lipolysis in adipose tissue. In the presence of pressure overload, inhibition of lipolysis by sympathetic denervation significantly downregulated adipose p53 expression and inflammation, thereby improving insulin resistance. Likewise, disruption of p53 activation in adipose tissue attenuated inflammation and improved insulin resistance but also ameliorated cardiac dysfunction induced by chronic pressure overload. These results indicate that chronic pressure overload upregulates adipose tissue p53 by promoting lipolysis via the sympathetic nervous system, leading to an inflammatory response of adipose tissue and insulin resistance. PMID- 22225877 TI - Acetylation negatively regulates glycogen phosphorylase by recruiting protein phosphatase 1. AB - Glycogen phosphorylase (GP) catalyzes the rate-limiting step in glycogen catabolism and plays a key role in maintaining cellular and organismal glucose homeostasis. GP is the first protein whose function was discovered to be regulated by reversible protein phosphorylation, which is controlled by phosphorylase kinase (PhK) and protein phosphatase 1 (PP1). Here we report that lysine acetylation negatively regulates GP activity by both inhibiting enzyme activity directly and promoting dephosphorylation. Acetylation of GP Lys(470) enhances its interaction with the PP1 substrate-targeting subunit, G(L), and PP1, thereby promoting GP dephosphorylation and inactivation. We show that GP acetylation is stimulated by glucose and insulin and inhibited by glucagon. Our results provide molecular insights into the intricate regulation of the classical GP and a functional crosstalk between protein acetylation and phosphorylation. PMID- 22225878 TI - Lysosome-related organelles in intestinal cells are a zinc storage site in C. elegans. AB - Zinc is an essential trace element involved in many biological processes and human diseases. Because zinc deficiency and excess are deleterious, animals require homeostatic mechanisms to maintain zinc levels in response to dietary fluctuations. Here, we demonstrate that lysosome-related organelles in intestinal cells of C. elegans, called gut granules, function as the major site of zinc storage. Zinc storage in gut granules promotes detoxification and subsequent mobilization, linking cellular and organismal zinc metabolism. The cation diffusion facilitator protein CDF-2 plays a critical role in this process by transporting zinc into gut granules. In response to high dietary zinc, gut granules displayed structural changes characterized by a bilobed morphology with asymmetric distributions of zinc and molecular markers. We defined a genetic pathway that mediates the formation of bilobed morphology. These findings elucidate mechanisms of zinc storage, detoxification, and mobilization in C. elegans and may be relevant to other animals. PMID- 22225879 TI - Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. AB - Somatic stem cell (SSC) dysfunction is typical for different progeroid phenotypes in mice with genomic DNA repair defects. MtDNA mutagenesis in mice with defective Polg exonuclease activity also leads to progeroid symptoms, by an unknown mechanism. We found that Polg-Mutator mice had neural (NSC) and hematopoietic progenitor (HPC) dysfunction already from embryogenesis. NSC self-renewal was decreased in vitro, and quiescent NSC amounts were reduced in vivo. HPCs showed abnormal lineage differentiation leading to anemia and lymphopenia. N-acetyl-L cysteine treatment rescued both NSC and HPC abnormalities, suggesting that subtle ROS/redox changes, induced by mtDNA mutagenesis, modulate SSC function. Our results show that mtDNA mutagenesis affected SSC function early but manifested as respiratory chain deficiency in nondividing tissues in old age. Deletor mice, having mtDNA deletions in postmitotic cells and no progeria, had normal SSCs. We propose that SSC compartment is sensitive to mtDNA mutagenesis, and that mitochondrial dysfunction in SSCs can underlie progeroid manifestations. PMID- 22225881 TI - Motor excitability evaluation in developmental stuttering: a transcranial magnetic stimulation study. AB - INTRODUCTION: Developmental stuttering (DS) is viewed as a motor speech-specific disorder, although several lines of research suggest that DS is a symptom of a broader motor disorder. We investigated corticospinal excitability in adult DS and normal speakers. METHODS: Transcranial magnetic stimulation (TMS) was administered over left/right hand representation of the motor cortex while recording motor evoked potentials (MEPs) from the contralateral first dorsal interosseous (FDI) muscle. Resting, active motor thresholds, silent period threshold and duration were measured. A stimulus-response curve at resting was also obtained to evaluate MEP amplitudes. RESULTS: Lower corticospinal responses in the left hemisphere of DS were found, as indicated by a reduction of peak-to peak MEP amplitudes compared to normal speakers. CONCLUSIONS: This provides further evidence that DS may be a general motor deficit that also involves motor non-speech-related structures. Moreover, our results confirm that DS may be related to left hemisphere hypoactivation and/or lower left hemisphere dominance. The present data and protocol may be useful for diagnosis of subtypes of DS that may benefit from pharmacological treatment by targeting the general level of cortical excitability. PMID- 22225880 TI - Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. AB - Because MYC plays a causal role in many human cancers, including those with hypoxic and nutrient-poor tumor microenvironments, we have determined the metabolic responses of a MYC-inducible human Burkitt lymphoma model P493 cell line to aerobic and hypoxic conditions, and to glucose deprivation, using stable isotope-resolved metabolomics. Using [U-(13)C]-glucose as the tracer, both glucose consumption and lactate production were increased by MYC expression and hypoxia. Using [U-(13)C,(15)N]-glutamine as the tracer, glutamine import and metabolism through the TCA cycle persisted under hypoxia, and glutamine contributed significantly to citrate carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and citrate were significantly increased. Their (13)C-labeling patterns demonstrate an alternative energy-generating glutaminolysis pathway involving a glucose-independent TCA cycle. The essential role of glutamine metabolism in cell survival and proliferation under hypoxia and glucose deficiency makes them susceptible to the glutaminase inhibitor BPTES and hence could be targeted for cancer therapy. PMID- 22225882 TI - Landmark sequencing and route knowledge: an fMRI study. AB - INTRODUCTION: The ability to navigate in a familiar environment mainly relies on route knowledge, that is, a mental representation of relevant locations along a way, sequenced according to a navigational goal. Despite the clear ecological validity of this issue, route navigation and route knowledge have been scarcely investigated and little is known about the neural and cognitive bases of this navigational strategy. Using functional magnetic resonance imaging (fMRI) we tested the validity of the predictions based on the main cognitive models of spatial knowledge acquisition about route-based navigation. METHODS: An order judgment task was used with two conditions (route and activity). Subjects were required to detect potential mismatches between a current sensory input and expectations deriving from route and activity knowledge. RESULTS: A medial occipto-temporal (e.g., lingual gyrus, calcarine cortex, fusiform gyrus, parahippocampal cortex) network was found activated during the route task, whereas a temporo-parietal (temporo-parietal junction) and frontal (e.g., Broca's area) network was related to the activity task. CONCLUSIONS: Functional data are congruent with cognitive models of route-based navigation. The route task activated areas related to both landmark identity and landmark order. Data are discussed in view of route-based navigation models. PMID- 22225883 TI - The basic sciences as preparation for clinical learning. PMID- 22225884 TI - Facilitating small groups: how to encourage student learning. AB - BACKGROUND: Many clinicians are involved in medical education, with small group teaching (SGT) forming a significant part of their work. Most facilitate these sessions by experience and common sense: less than one-third of them have received formal training in SGT. CONTEXT: Evidence suggests small group productivity depends on good facilitation rather than on topic knowledge. Applying the fundamental concepts of SGT will lead to improvements in the quality of clinicians' teaching and in student learning. Good SGT creates the perfect environment for learning and discussion, without the need for didactic teaching. SGT emphasises the role of students in sharing and discussing their ideas in a safe learning environment, without domination by the tutor. INNOVATION: This article provides clinicians with basic requirements for effective session design and planning, explains how to encourage student participation, how to manage students as a group, how to manage student learning, and how to recognise and deal with problems. IMPLICATIONS: Active facilitation and group management is the key to success in SGT, and consequently better learning outcomes. Improving the facilitation skills of clinical teachers makes teaching more effective, stimulating, and enjoyable for both tutors and students. PMID- 22225885 TI - Medical students talking to hospice patients. AB - BACKGROUND: All newly qualified doctors will look after patients in the last stages of life. CONTEXT: This article is a review of the literature regarding medical students learning from hospice patients, focusing on practical concerns of relevance to those involved in organising or conducting medical student teaching. INNOVATION: Medical students have increasing opportunities to learn about palliative care from talking to patients in a hospice. This resource is not fully utilised, in part because of concerns about patient and student welfare. These concerns are not supported by current research findings, including a qualitative interview study of patients and staff. IMPLICATIONS: We would encourage course coordinators to use opportunities for medical students to talk to hospice patients in order to enhance the education of medical students. PMID- 22225886 TI - Speed supervision. AB - BACKGROUND: Over the last few years the London Deanery has offered workshops in supervision skills for clinical teachers. In response to the concern that supervision conversations are time consuming, we devised an exercise to promote the ability to carry out a small piece of supervision that can nudge forwards an issue in a short time (10 minutes or less): speed supervision. CONTEXT: The workshops are part of the faculty development programme for clinical and educational supervisors in primary and secondary care at the London Deanery. The workshops teach a question-based approach to help the supervisee reflect and shift their perspective. INNOVATION: Offering advice is often not the most time efficient way to help someone towards the solution for an issue. We chose to introduce an approach that could help a supervisee think differently about an issue in a brief period of time. Helping a supervisee to make a small piece of progress in their thinking can in turn lead to future changes. Supervisors are encouraged to explore values and context as well as technical and scientific aspects. IMPLICATIONS: Even during a brief period of supervision, asking questions rather than reaching for the familiar solution may be surprisingly satisfying for both supervisee and supervisor alike. The skills can be applied to professional and personal dilemmas and situations. PMID- 22225887 TI - High fidelity trainee simulation to improve trainer performance. AB - BACKGROUND: Using trained actors to simulate trainee doctors in difficulty is a cost-effective communication skills teaching tool that can be enhanced by techniques that are familiar to hi-fidelity electronic simulation. Simulation has two broad strands: the first exchanges the patient for an actor in the clinical encounter, and the second introduces some form of technology to the encounter. The strand concerning actors is well developed, and generally focuses on 'the consultation'. Where simulation draws on technology, the spectrum is broad: it may be relatively low-tech, for example computer-based scenarios to test prescribing, through to more high-tech approaches to learning practical skills using sophisticated manikins that replicate patient signs and symptoms. Over the years simulation has radically changed medical training, and is set to continue to do so in the future. CONTEXT: Actors have been used for many years to contribute to the training and assessment of medical students, specialty trainees and established doctors. Their role to date has largely been limited to playing patients in scenarios. INNOVATION: This innovation in communication skills teaching seeks to draw on both strands of simulation. It sees actors playing general practice (GP) trainees to enhance the continuing professional development of established GP trainers, in contrast to the more usual use of actors playing patients. It also makes use of the control mechanisms afforded by technological simulation in fine-tuning role-play scenarios. IMPLICATIONS: By using actors, the scenarios can be played up or down in order to challenge participants and maximise their learning. More research is needed to develop this approach further in other medical education contexts. PMID- 22225888 TI - Problem-based learning: a review of the educational and psychological theory. AB - BACKGROUND: Problem-based learning (PBL) is a teaching method where the use of clinical problems is the starting point for learning, and it is through the process of working through these problems that students acquire the knowledge and skills required to be a doctor. CONTEXT: Many advantages of PBL over traditional curricula have been proposed. On reviewing the evidence on the results of PBL curricula for producing better doctors, students tend to perform either a little better or a little worse in examinations. In this article the educational and psychological theories supporting PBL are described. IMPLICATIONS: There is a wealth of theory underpinning the use of PBL to teach clinical medicine, despite disappointing results. Future research should concentrate on the reasons behind this uncoupling of theory and outcomes. PMID- 22225889 TI - Interprofessional education in practice. AB - BACKGROUND: Undergraduate interprofessional education (IPE) is perceived by many in health and social care education to reduce barriers between the professions. In Aberdeen there has been an IPE programme with Robert Gordon University and University of Aberdeen, and 10 health and social care courses since 2003. The steering groups reported to the Scottish Government in 2008. It was recommended that IPE should be extended from classroom-based learning experiences to practice based learning experiences. METHODS: Replicating the same methodology, this study aimed to ascertain attitudinal change experienced by students undertaking IPE in clinical practice. Small groups in theatre and primary care were the pilot placement areas. The study design was a joint venture between the IPE research team and members of the clinical team. IPE activities were created for the specialities using adult learning and patient-centred approaches. RESULTS: Thirty eight students from medicine, nursing and pharmacy were involved in the studies, and completed readiness for interprofessional learning scale (RIPLS) questionnaires before and after the course activity. There were 29 valid responses, showing a strong level of agreement for 14 out of 19 questions. The studies suggest that the IPE activities implemented had positive effects on the students' perceptions of interprofessional working. DISCUSSION: The implications are that IPE does not require large classroom-based activities to be successful. The study was successful in achieving its aims and learning outcomes for students in the two locations. It demonstrated that students can leave university better prepared for practice. There is a need for a rigorous longitudinal study to ensure tomorrow's health and social care workforce demonstrate graduate attributes in interprofessional working. PMID- 22225890 TI - Teaching professionalism through virtual means. AB - OBJECTIVES: Virtual patients are used across a variety of clinical disciplines for both teaching and assessment, but are they an appropriate environment in which to develop professional skills? This study aimed to evaluate students' perceived effectiveness of an online interactive virtual patient developed to augment a personal professional development curriculum, and to identify factors that would maximise the associated educational benefits. METHODS: Student focus group discussions were conducted to explore students' views on the usefulness and acceptability of the virtual patient as an educational tool to teach professionalism, and to identify factors for improvement. A thematic content analysis was used to capture content and synthesise the range of opinions expressed. RESULTS: Overall there was a positive response to the virtual patient. The students recognised the need to teach and assess professionalism throughout their curriculum, and viewed the virtual patient as a potentially engaging and valuable addition to their curriculum. We identified factors for improvement to guide the development of future virtual patients. CONCLUSION: It is possible to improve approaches to teaching and learning professionalism by exploring students' views on innovative teaching developments designed to augment personal professional development curricula. PMID- 22225891 TI - A study of innovative patient safety education. AB - BACKGROUND: Medical error continues to significantly harm patients, notwithstanding the continued efforts to improve the situation over the past decade. We report a pilot project using high-fidelity simulation to integrate the World Health Organisation (WHO) patient safety curriculum into undergraduate medical education. METHODS: From the literature on avoidable medical error we developed a series of authentic clinical scenarios using a Clinical Skills Lab (CSL) and simulated patients to produce a high-fidelity simulated ward environment. The clinical challenges embody common day-to-day encounters experienced by newly graduated doctors. After participating, final-year medical students were given time to reflect on the experience, given feedback and completed a quantitative evaluation. RESULTS: Twenty final-year medical students completed the scenarios, and gave written feedback using a Likert scale (ranging from 1, strongly disagree, to 7, strongly agree). The responses showed 18 students agreed or strongly agreed that the session was valuable, all 20 would recommend the session to peers and 18 would be interested in attending further sessions. The students gave more mixed views of faculty feedback: 13 agreed or strongly agreed that this was useful, five were undecided and two were undecided or disagreed. CONCLUSION: With the caveats of a small sample size, first experience of high-fidelity simulation, the 'halo' effect in the evaluation, and with possible omissions from our evaluation, the students reported predominantly positively on the experience. We believe that the use of high-fidelity simulation in patient safety is a promising, safe and low-cost curricular development in undergraduate medical education. It is transferable worldwide and has the potential to improve patient safety outcomes by reducing medical error. PMID- 22225892 TI - Improving patient safety: lessons from rock climbing. AB - BACKGROUND: How to improve patient safety remains an intractable problem, despite large investment and some successes. CONTEXT: Academics have argued that the root of the problem is a lack of a comprehensive 'safety culture' in hospitals. Other safety-critical industries such as commercial aviation invest heavily in staff training to develop such a culture, but comparable programmes are almost entirely absent from the health care sector. INNOVATION: In rock climbing and many other dangerous activities, the 'buddy system' is used to ensure that safety systems are adhered to despite adverse circumstances. This system involves two or more people using simple checks and clear communication to prevent problems causing harm. Using this system as an example could provide a simple, original and entertaining way of introducing medical students to the idea that human factors are central to ensuring patient safety. IMPLICATIONS: Teaching the buddy system may improve understanding and acceptance of other patient safety initiatives, and could also be used by junior doctors as a tool to improve the safety of their practice. PMID- 22225893 TI - Pre-prescribing: a safe way to learn at work? AB - BACKGROUND: The General Medical Council mandates that UK medical graduates must be able to 'prescribe drugs safely, effectively and economically'. However, data from three UK medical schools show that graduates are poorly prepared for prescribing, and a recent study detected a prescribing error rate of 8.4 per cent amongst foundation year 1 doctors. CONTEXT: This study took place in the National Health Service (NHS) Fife where, in common with all health boards in the UK, medical students are not permitted to prescribe. University of Edinburgh final year medical student volunteers took part in the study. INNOVATION: Medical, pharmacy and nursing staff collaborated to design and implement a controlled process (pre-prescribing) that allows medical students to write instructions on in-patient drug charts, and requires a doctor's countersignature before drugs are dispensed. Key features of the pre-prescribing protocol include fluorescent stickers for drug charts, bookmark aide-memoires to guide countersigning and ward based information sheets. Twelve final-year medical students wrote 586 pre prescriptions, and no adverse events were reported. IMPLICATIONS: This study demonstrates the successful small-scale implementation of pre-prescribing. Initial data regarding the safety of the process is positive, but further evaluation is required to reassure all that the risk of adverse events is minimal. The project is to be expanded throughout South East Scotland with a view to all units providing the opportunity for pre-prescribing during the first student assistantships in March 2012. The longer-term goal is to set-up safe processes that will support medical students undertaking pre-prescribing throughout most of their final year. PMID- 22225894 TI - A novel 3D stereoscopic anatomy tutorial. AB - BACKGROUND: Advancement in technology is an important driver for the evolution of the medical curriculum. With continued criticism of medical students' knowledge of anatomy, further investigation into adjuncts for anatomy teaching seems appropriate. This project sought to create an interactive 3D stereoscopic tutorial to bridge the teaching of anatomy and pathology. METHODS: Anonymised computed tomography (CT) scans were collected of a normal aorta and a ruptured abdominal aortic aneurysm. These scans were rendered into 3D stereoscopic images using open-source software. These images were then annotated with interactive labels and buttons to access information on normal aortic anatomy and the clinical details of abdominal aortic aneurysms. A total of 183 first-year medical students viewed the tutorial, and 160 gave feedback (87%). RESULTS: The students found the 3D system aided their understanding of anatomy and pathology (93 versus 3%), and provided an advantage when compared with current anatomy classes (93 versus 1%). The students highlighted the musculoskeletal system and cerebral vasculature as areas for future 3D visualisation. Of the responders, 96 per cent felt that the curriculum would benefit from further 3D stereoscopic anatomy/pathology tutorials. DISCUSSION: This technology has the exciting potential to use the radiographic libraries in hospitals for medical education. The computer software, however, has some limitations at present. It is not able to effectively distinguish between tissues of similar densities. Furthermore, not all tissues are amenable to CT scanning of a high enough resolution for presentation. Despite these limitations, the software continues to advance and is capable of producing very high quality anatomy images. PMID- 22225895 TI - Learning biomedical ethics in the clinical context. PMID- 22225896 TI - Feedback delivery as a peer-tutor. PMID- 22225897 TI - It's all sleight of hand. PMID- 22225902 TI - The preoperative assessment clinic: the Keele experience. PMID- 22225903 TI - Desmosomal proteins and microRNAs-markers for hybrid tumors (verrucous carcinoma with foci of squamous cell carcinoma). PMID- 22225904 TI - Are elastic stain and specialty sign out necessary to evaluate pleural invasion in lung cancers? AB - The seventh edition of American Joint Committee on Cancer (AJCC) staging system assigns lung cancers with visceral pleural invasion in the tumor size of 3 cm or less than 3 cm as T2 and without pleural invasion as T1. However, it may be difficult to distinguish with certainty between PL0 (no pleural invasion) and PL1 (extends through the elastic layer) on routine hematoxylin and eosin (H&E) stain. In this study, 25 cases of peripherally located lung adenocarcinoma were retrieved from the surgical pathology archives at the Asan Medical Center from May through June 2009. One representative H&E-stained slide was selected from each case and circulated to 31 pathology trainees and board-certified pathologists at Asan Medical Center who evaluated presence or absence of pleural invasion on H&E-stained slides. Elastic stain was used to determine the final status of pleural invasion for each case. The concordance rate of all pathologists with elastic stain results was, overall, 60.5%. The concordance rate of 2 lung specialists was 64%, better than the remaining faculty (54.7%). Fellows' and residents' evaluations were slightly more concordant than those of faculty responses (faculty overall, 56.4%; fellows, 62%; residents, 63.6%), but this difference was not statistically significant (P = .228). Our results confirm that pleural invasion status is difficult to discern with certainty on H&E stained sections alone. Therefore, we recommend the routine use of elastic stain in evaluation of pleural invasion in all peripherally located lung cancers. Furthermore, our study indicates that subspecialty sign out may be preferable in evaluation of pleural invasion status. PMID- 22225905 TI - Microcalcifications of the breast: a mammographic-histologic correlation study using a newly designed Path/Rad Tissue Tray. AB - The introduction of screening mammography has brought about a greater knowledge of early breast cancer characteristics. These improvements have led to a reduction in size of suspicious lesions and a shift from surgical to image-guided core needle biopsies (CNBs). Establishing correlation between histologic and imaging findings is required for accurate diagnosis. Currently, there are no standardized multidisciplinary protocols for evaluating such lesions. We correlated histologic and radiologic findings in mammographically detectable calcified lesions in CNBs using specially designed Path/Rad Tissue Trays (patent pending, University of Kansas). Evidence of calcification was analyzed in 440 with and without the use of tissue trays. After mammographic identification of the lesion, CNBs are harvested, placed in tissue trays, and x-rayed to confirm sampling of the lesion. Images of CNBs with calcifications are marked by the radiologists and sent to the pathologist along with the biopsies. Trays with CNBs are then placed into cassettes and sent to the laboratory where they are embedded without disturbing orientation. Identification and localization of targeted microcalcifications were accomplished by radiologists and pathologists in 68 of 71 cases when using the tissue trays compared with 292 of 369 without tissue trays. Confirmation of microcalcifications was accomplished after deeper sectioning into tissue blocks from discordant cases. In conclusion, a systematic approach is recommended to standardize reporting of calcifications. The use of Path/Rad Tissue Trays has created a level of concordance between pathologists and radiologists that previously did no exist. It improved diagnostic reliability, encouraged communication between pathologists and radiologists, and minimized false diagnoses and/or delays in cancer diagnosis. PMID- 22225906 TI - Evidence that GTP-binding domain but not catalytic domain of transglutaminase 2 is essential for epithelial-to-mesenchymal transition in mammary epithelial cells. AB - INTRODUCTION: The expression of proinflammatory protein tissue transglutaminase 2 (TG2) is frequently upregulated in multiple cancer cell types. However, the exact role of TG2 in cancer cells is not well-understood. We recently initiated studies to determine the significance of TG2 in cancer cells and observed that sustained expression of TG2 resulted in epithelial-to-mesenchymal transition (EMT) and promoted cancer stem cell (CSC) traits in mammary epithelial cells. These results suggested that TG2 could serve as a promising therapeutic target for overcoming chemoresistance and inhibiting metastatic spread of cancer cells. METHODS: Using various mutant constructs, we analyzed the activity of TG2 that is essential for promoting the EMT-CSC phenotype. RESULTS: Our results suggest that catalytically inactive TG2 (TG2-C277S) is as effective as wild-type TG2 (TG2-WT) in inducing the EMT-CSC in mammary epithelial cells. In contrast, overexpression of a GTP binding-deficient mutant (TG2-R580A) was completely incompetent in this regard. Moreover, TG2-dependent activation of the proinflammatory transcription factor NF kappaB is deemed essential for promoting the EMT-CSC phenotype in mammary epithelial cells. CONCLUSIONS: Our results suggest that the transamidation activity of TG2 is not essential for promoting its oncogenic functions and provide a strong rationale for developing small-molecule inhibitors to block GTP binding pockets of TG2. Such inhibitors may have great potential for inhibiting the TG2-regulated pathways, reversing drug resistance and inhibiting the metastasis of cancer cells. PMID- 22225907 TI - Transfer of gangliosides across the human placenta. AB - OBJECTIVES: Gangliosides are structural and functional glycosphingolipids, considered to have important roles in neuronal development in fetal and neonatal development and in memory formation. In this report, we have investigated the ability of bovine milk-derived gangliosides GM3 and GD3 to cross the human placenta. STUDY DESIGN: We have employed the ex-vivo model of dually-perfused isolated human placental lobules. RESULTS: There was significant uptake of both GD3 and GM3 from the maternal perfusate. There was significant increase of GM3 in the fetal side and a non-statistically significant trend for GD3 to increase on the fetal side. CONCLUSIONS: Hence an apparent preference for GM3 release into fetal circulation. We suggest that gangliosides consumed by the mother enter her circulation, can be transferred across the placenta and may be available to the developing fetus for building neural connections. PMID- 22225908 TI - Crim1 has an essential role in glycogen trophoblast cell and sinusoidal trophoblast giant cell development in the placenta. AB - Normal placental development and function is essential for fetal growth of eutherian mammals. Mutational studies have shown that numerous growth factors are required for placental development and differentiation of placental lineages. Here, using a gene-trap mutant mouse line, Crim1(KST264), we show that Crim1 is essential for murine placental development. Crim1 is a developmentally expressed, trans-membrane regulator of growth factor activity. Crim1(KST264/KST264) mutant placentae displayed hypoplasia from 13.5 dpc, and altered structure from 15.5 dpc, including alterations in cell number in both the junctional and labyrinth zones. Using the reporter gene from the Crim1(KST264) allele, we found that Crim1 is expressed in multiple cell types of the placenta, including strong expression in the spongiotrophoblast cells of the junctional zone. In the junctional zone of Crim1(KST264/KST264) placentae, there was an increase in the glycogen trophoblast cells adjacent to the spongiotrophoblast cells. In the labyrinth zone, we found a decrease in the density of sinusoidal-trophoblast giant cells. Our findings show that Crim1 is required for placental development, and is necessary for the proper differentiation of sinusoidal-trophoblast giant cells and glycogen trophoblast cells. PMID- 22225909 TI - A survey of issues of ethnicity and culture in nursing homes in an English region: nurse managers' perspectives. AB - AIMS: This survey explored issues of ethnicity and culture in nursing homes in one English region. BACKGROUND: The older black and minority ethnic population in the UK is increasing, and this is the first detailed study of numbers of black and minority ethnic residents in nursing homes and of managers' perceptions of their abilities to respond to residents' needs. DESIGN: Mixed methods. METHODS: Date were collected in 2008. A postal survey was sent to all nursing homes in the region. A sub-sample of managers participated in semi-structured telephone interviews. RESULTS: A hundred and one homes responded to the survey, and 13 managers were interviewed. One-third of homes had black and minority ethnic residents, and 95% had staff from these groups. Managers' underlying philosophies of care were to treat each resident individually and not by category. It was felt that individualised care plans resulted in residents' needs being met appropriately. Culturally sensitive care delivery varied. Some homes had established systems that were responsive to residents' diversity, while others responded to the needs of black and minority ethnic residents on an 'as-required' basis. Managers' identified advantages in having staff from diverse backgrounds, although prejudice from residents towards staff emerged as a theme and managers' responses varied. Staff training in the provision of appropriate end-of-life care was identified as a need. CONCLUSION: Black and minority ethnic residents form a small but growing minority of nursing home residents. Predicted increases in this resident group mean that managers must consider the delivery of culturally sensitive services. Future research is needed to explore the perspectives of black and minority ethnic residents. RELEVANCE TO CLINICAL PRACTICE: Nursing homes in England are increasingly diverse communities, and staff training needs must be addressed to promote quality care for all residents. PMID- 22225910 TI - Suitability and limitations of portion-specific abattoir data as part of an early warning system for emerging diseases of swine in Ontario. AB - BACKGROUND: Abattoir data have the potential to provide information for geospatial disease surveillance applications, but the quality of the data and utility for detecting disease outbreaks is not well understood. The objectives of this study were to 1) identify non-disease factors that may bias these data for disease surveillance and 2) determine if major disease events that took place during the study period would be captured using multi-level modelling and scan statistics. We analyzed data collected at all provincially-inspected abattoirs in Ontario, Canada during 2001-2007. During these years there were outbreaks of porcine circovirus-associated disease (PCVAD), porcine reproductive and respiratory syndrome (PRRS) and swine influenza that produced widespread disease within the province. Negative binomial models with random intercepts for abattoir, to account for repeated measurements within abattoirs, were created. The relationships between partial carcass condemnation rates for pneumonia and nephritis with year, season, agricultural region, stock price, and abattoir processing capacity were explored. The utility of the spatial scan statistic for detecting clusters of high partial carcass condemnation rates in space, time, and space-time was investigated. RESULTS: Non-disease factors that were found to be associated with lung and kidney condemnation rates included abattoir processing capacity, agricultural region and season. Yearly trends in predicted condemnation rates varied by agricultural region, and temporal patterns were different for both types of condemnations. Some clusters of high condemnation rates of kidneys with nephritis in time and space-time preceded the timeframe during which case clusters were detected using traditional laboratory data. Yearly kidney condemnation rates related to nephritis lesions in eastern Ontario were most consistent with the trends that were expected in relation to the documented disease outbreaks. Yearly lung condemnation rates did not correspond with the timeframes during which major respiratory disease outbreaks took place. CONCLUSIONS: This study demonstrated that a number of abattoir-related factors require consideration when using abattoir data for quantitative disease surveillance. Data pertaining to lungs condemned for pneumonia did not provide useful information for predicting disease events, while partial carcass condemnations of nephritis were most consistent with expected trends. Techniques that adjust for non-disease factors should be considered when applying cluster detection methods to abattoir data. PMID- 22225911 TI - Mixed Giardia duodenalis assemblage infections in children and adults in South India. AB - The assemblages of Giardia duodenalis in 25 children with and 25 children without diarrhoea and 24 adults with gastrointestinal symptoms in South India were determined. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) targeting the glutamate dehydrogenase (gdh), beta-giardin and triosephosphate isomerase (tpi) genes was used. The tpi PCR was the most sensitive and detected G. duodenalis in all 74 microscopy-positive samples, while gdh and beta-giardin PCR were positive in 62.2% and 56.8% of the samples. Assemblage B was predominant in both children and adults (82.4%) followed by assemblage AII (9.4%); assemblage AI was not detected. Infections with both assemblages A and B (detected by tpi PCR-RFLP) were seen exclusively in children and the mixed assemblage BIII and BIV (detected by gdh PCR-RFLP) was more common in children than adults (P=0.058). PMID- 22225912 TI - Algal delta15N values detect a wastewater effluent plume in nearshore and offshore surface waters and three-dimensionally model the plume across a coral reef on Maui, Hawai'i, USA. AB - The coral reef at Kahekili, Maui is located ~300 m south of the Lahaina Wastewater Reclamation Facility which uses four Class V injection wells to dispose of 3-5 million gallons of wastewater effluent daily. Prior research documented that the wastewater effluent percolates into the nearshore region of Kahekili. To determine if the wastewater effluent was detectable in the surface waters offshore, we used algal bioassays from the nearshore region to 100 m offshore and throughout the water column from the surface to the benthos. These algal bioassays documented that significantly more wastewater effluent was detected in the surface rather than the benthic waters and allowed us to generate a three-dimensional model of the wastewater plume in the Kahekili coastal region. Samples located over freshwater seeps had the highest delta(15)N values (~30 350/00) and the effluent was detected in surface samples 500 m south and 100 m offshore of the freshwater seeps (~8-110/00). PMID- 22225913 TI - Organotin compounds in seawater and Mytilus galloprovincialis mussels along the Croatian Adriatic Coast. AB - In this work, data on the level of organotin compounds (OTCs) in seawater and mussels collected along the entire Croatian Adriatic Coast are presented. The samples were collected in 2009 and 2010 at 48 locations representing different levels of maritime activities, including marinas, ports and reference sites. Butyltins (BuTs) were found in all analyzed samples, representing >97% of OTCs, and ranged from 0.46 to 27.98 ng Sn L(-1) in seawater and from <6 to 1675 ng Sn g(-1) in mussels. The results indicate a recent input of TBT, with the highest concentrations of BuTs found in the marinas. It appears that the Adriatic coast is still polluted with TBT despite the fact that TBT-containing antifouling paints have been banned in Croatia since 2008. It is questionable how much TBT pollution decreased since 2005, when a high incidence of imposex was established in the same area. PMID- 22225914 TI - Aspects of the digestive gland cells of the mussel Mytilus galloprovincialis, in relation to lysosomal enzymes, lipofuscin presence and shell size: contribution in the assessment of marine pollution biomarkers. AB - The present study investigates the histochemical localization of N-acetyl-beta hexozaminidase (Hex), acid phosphatase (AcP) and beta-glucuronidase (beta-Gus) in the digestive gland of mussels Mytilus galloprovincialis, as well as the clarification of suitable enzyme for biomarkers' application dealing with lysosomes. The results show more intense and homogenous localization of Hex, in relation to AcP and beta-Gus and, thus, Hex histochemistry is supported as more suitable procedure for the evaluation of "lysosomal membrane stability" and "morphometrical alterations of lysosomes". The affection of lipofuscin granules on lysosomal enzymes' activity is also discussed. Additionally, the present study examines the response of small- and large-sized mussels M. galloprovincialis by assessing the "lysosomal membrane stability", "morphometrical alterations of lysosomes", "lysosomal response index (LRI)" and "structural epithelial changes in digestive tubules". The results indicate appreciable alterations of the above parameters in large-sized mussels, supporting their greater influence by the environmental factors, in relation to small-sized ones. PMID- 22225915 TI - Design, synthesis, biological evaluation, and comparative Cox1 and Cox2 docking of p-substituted benzylidenamino phenyl esters of ibuprofenic and mefenamic acids. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently associated with gastric mucosal and renal adverse reactions, related to inhibition of cyclooxygenase1 (Cox1) in tissues where prostaglandins exert physiological effects. This led us to develop a set of ibuprofenic acid and mefenamic acid esters, namely: 4-((4-substituted benzylidene)amino)phenyl 2-(4 isobutylphenyl)propanoate and 4-((4-substituted benzylidene)amino)phenyl 2-((2,4 dimethylphenyl)amino)benzoate analogs, which were synthesized by condensation of the corresponding acids with Schiff's bases [4-(4-substituted benzylideneamino)phenols] involving dicyclohexyl carbodiimmide (DCC) as mild dehydrating agent. The main objective is to reduce the GIT toxicity associated with acute and chronic NSAIDs use. Anti-inflammatory, analgesic as well as ulcerogenic activities of the prepared esters were evaluated in vivo and compared with that of ibuprofen as reference standard in all screenings, involving the carrageenan induced paw oedema model and hot plate method. Most of the synthesized esters showed remarkable analgesic and anti-inflammatory activities. Interestingly, all of the compounds were found to be non-ulcerogenic under the tested conditions. This evidence have suggested that modification of the carboxyl function of representative NSAIDs results in retained or enhanced anti inflammatory and analgesic activities with reduced ulcerogenic potential. Additionally, a comparative AutoDock study into Cox 1 and Cox2 has been done involving both of rigid and flexible docking for potential selectivity of our compounds within different Cox enzymes and to find out the binding orientation of these novel esters into their binding site. Some of the newly prepared aforementioned compounds showed considerable more Cox2 over Cox1 binding affinities by flexible docking better than rigid one. PMID- 22225916 TI - A photochemical approach for controlled drug release in targeted drug delivery. AB - Photochemistry provides a unique mechanism that enables the active control of drug release in cancer-targeting drug delivery. This study investigates the light mediated release of methotrexate, an anticancer drug, using a photocleavable linker strategy based on o-nitrobenzyl protection. We evaluated two types of the o-nitrobenzyl-linked methotrexate for the drug release study and further extended the study to a fifth-generation poly(amidoamine) dendrimer carrier covalently conjugated with methotrexate via the o-nitrobenzyl linker. We performed the drug release studies by using a combination of three standard analytical methods that include UV/vis spectrometry, (1)H NMR spectroscopy, and anal. HPLC. This article reports that methotrexate is released by the photochemical mechanism in an actively controlled manner. The rate of the drug release varies in response to multiple control parameters, including linker design, light wavelength, exposure time, and the pH of the medium where the drug release occurs. PMID- 22225917 TI - Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802). AB - Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, especially non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl 11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains and identified highly selective, orally active and potent ALK inhibitor CH5424802 (18a) as the clinical candidate. PMID- 22225918 TI - Micro-dissecting the pathogenesis and immune response of PRRSV infection paves the way for more efficient PRRSV vaccines. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is the most important infectious pathogen in pigs worldwide nowadays. Due to its genetic drift and increasing power to escape from immunity, PRRSV becomes more and more difficult to control. Based on a better knowledge of PRRSV, its interaction with the host cell, the macrophage, its pathogenesis and the immunity against this virus, new vaccines can now be constructed. This research-based development of new generation vaccines will allow swine industry to face the devastating consequences of PRRSV infections in the future. The present review summarizes the present knowledge on the pathogenesis, the immune response and the research-based vaccine development. PMID- 22225919 TI - Factors associated with treatment of women with osteoporosis or osteopenia from a national survey. AB - BACKGROUND: Health outcomes could be improved if women at high risk for osteoporotic fracture were matched to effective treatment. This study determined the extent to which treatment for osteoporosis/osteopenia corresponded to the presence of specific risk factors for osteoporotic fracture. METHODS: This retrospective analysis of the United States 2007 National Health and Wellness Survey included women age >= 40 years who reported having a diagnosis of osteoporosis (69% of 3276) or osteopenia (31% of 3276). Patients were stratified by whether they were or were not taking prescription treatment for osteoporosis/osteopenia. Using 34 patient characteristics as covariates, logistic regression was used to determine factors associated with treatment. RESULTS: Current prescription treatment was reported by 1800 of 3276 (54.9%) women with osteoporosis/osteopenia. The following factors were associated with receiving prescription treatment: patient-reported diagnosis of osteoporosis (versus osteopenia); previous bone mineral density test; >= 2 fractures since age 50; older age; lower body mass index; better physical functioning; postmenopausal status; family history of osteoporosis; fewer comorbidities; prescription insurance coverage; higher total prescription count; higher ratio of prescription costs to monthly income; higher income; single status; previous visit to a rheumatologist or gynecologist; and 1 or 2 outpatient visits to healthcare provider (vs. none) in the prior 6 months. Glucocorticoid, tobacco, and daily alcohol use were risk factors for fracture that were not associated with treatment. CONCLUSIONS: There is a mismatch between those women who could benefit from treatment for osteoporosis and those who are actually treated. For example, self-reported use of glucocorticoids, tobacco, and alcohol were not associated with prescription treatment of osteoporosis. Other clinical and socioeconomic factors were associated with treatment (e.g. prescription drug coverage and higher income) or not (e.g. comorbid osteoarthritis and anxiety) and could be opportunities to improve care. PMID- 22225920 TI - Plasma antioxidant capacity is reduced in Asperger syndrome. AB - Recent evidence suggests that children with autism have impaired detoxification capacity and may suffer from chronic oxidative stress. To our knowledge, there has been no study focusing on oxidative metabolism specifically in Asperger syndrome (a milder form of autism) or comparing this metabolism with other psychiatric disorders. In this study, total antioxidant status (TAOS), non enzymatic (glutathione and homocysteine) and enzymatic (catalase, superoxide dismutase, and glutathione peroxidase) antioxidants, and lipid peroxidation were measured in plasma or erythrocyte lysates in a group of adolescent patients with Asperger syndrome, a group of adolescents with a first episode of psychosis, and a group of healthy controls at baseline and at 8-12 weeks. TAOS was also analyzed at 1 year. TAOS was reduced in Asperger individuals compared with healthy controls and psychosis patients, after covarying by age and antipsychotic treatment. This reduced antioxidant capacity did not depend on any of the individual antioxidant variables measured. Psychosis patients had increased homocysteine levels in plasma and decreased copper and ceruloplasmin at baseline. In conclusion, Asperger patients seem to have chronic low detoxifying capacity. No impaired detoxifying capacity was found in the first-episode psychosis group in the first year of illness. PMID- 22225921 TI - Acute ethanol treatment reduces blood-brain barrier dysfunction following ischemia/reperfusion injury. AB - BACKGROUND AND PURPOSE: Ethanol has been shown to provide neuroprotective effects, but the precise mechanisms by which these effects occur have yet to be investigated. In this study, we investigate blood-brain barrier (BBB) and edema level changes in association with expression of matrix metalloproteinases (MMP-2 and MMP-9) and aquaporins (AQP-4 and AQP-9) in ethanol treated rats following middle cerebral artery (MCA) occlusion. METHODS: An ischemic stroke model was generated by occlusion of the right MCA for 2h in male Sprague-Dawley rats (n=72). Edema levels and BBB integrity following the ischemic event were studied by quantification of brain water content and extravasation of Evans blue following 24 and 48h of reperfusion, respectively. Expression of the proteins MMP 2 and MMP-9, as well as AQP-4 and AQP-9, were determined by Western blot analysis 3 and 24h after reperfusion. RESULTS: Treatment with ethanol significantly reduced brain edema (P<0.01) and BBB dysfunction (P<0.05) when compared to the saline-treated control groups. The upregulation of MMP-2 and MMP-9, as well as AQP-4 and AQP-9, following ischemia/reperfusion, was significantly reduced in ethanol-treated groups (P<0.05). CONCLUSIONS: Ethanol ameliorates brain edema and BBB disruption after stroke, in association with a reduction in the expression of MMPs and AQPs. These results provide clues to ethanol's neuroprotective properties. PMID- 22225922 TI - Focal EEG abnormalities might reflect neuropathological characteristics of pervasive developmental disorder and attention-deficit/hyperactivity disorder. AB - Neurophysiological characteristics in electroencephalograms (EEG) were investigated for patients with pervasive developmental disorder (PDD) and for patients with attention-deficit/hyperactivity disorder (AD/HD). This study examined 64 PDD children and 22 AD/HD children with no history of epilepsy or progressive neurological or psychiatric disorder. We used multivariate analysis to compare EEG abnormalities, clinical symptoms, and intelligence levels between PDD and AD/AD patient groups. Paroxysmal discharges at the frontopolar-frontal (Fp-F) brain regions and background EEG abnormalities tended to be detected preferentially in the PDD group, although paroxysmal discharges at central temporal (C-T) regions tended to be detected preferentially in the AD/HD group. The paroxysmal discharges observed in patients expressing persistence and impulsivity are apparently localized respectively in the Fp-F and C-T regions. A combination of EEG abnormalities, including background EEG abnormalities and paroxysmal discharges at Fp-F and C-T regions, might be useful diagnostic hallmarks to distinguish PDD with AD/HD from AD/HD alone using a logistic regression model. The dysfunction of specific brain areas associated with EEG abnormalities might explain characteristics of clinical symptoms observed in PDD and AD/HD patients. PMID- 22225923 TI - Posterior resection for childhood lesional epilepsy: neuropsychological evolution. AB - The aim of this study was to provide information on the neuropsychological evolution of children with symptomatic epilepsy who have undergone surgical resection of posterior (occipitoparietal) lesions. Twelve children with epilepsy with parietal and/or occipital lesions were enrolled in the study and followed after surgical resection: full clinical and epileptic examinations were performed before and after surgery, as was a neuropsychological study of both general and specific cognitive abilities. Epilepsy evolution was generally good (Engel classification IA in nine cases) with persistent selective neurological impairments (eye field defects, sensory unilateral spatial neglect) in some cases, consistent with the lesion site. Neuropsychological defects before surgery in the absence of refractory epilepsy were minimal with a normal global cognitive competence; yet, the relatively low performance scores with some impairment of specific cognitive skills were strictly correlated with defects in visual perceptive skills in both right- and left-sided lesions. Surgery seems to have improved performance abilities, whereas other abnormal specific skills did not change with the exception of working memory that in some cases was defective before surgery and normalized after lesion removal. Our study in this particular cohort of children with epileptogenic occipitoparietal lesions thus confirmed a trend toward a benign epileptic and neurodevelopmental outcome after surgical resection of the lesion. PMID- 22225924 TI - The effect of age, movement direction, and target size on the maximum speed of targeted COP movements in healthy women. AB - Rapid center of pressure (COP) movements are often required to avoid falls. Little is known about the effect of age on rapid and accurate volitional COP movements. We hypothesized that COP movements to a target would be slower and exhibit more submovements in older versus younger adults, particularly in posterior versus anterior movements. Healthy older (N=12, mean age=76 years) and young women (N=13, mean age=23 years) performed anterior and posterior lean movements while standing on a force plate, and were instructed to move their COP 'as fast and as accurately as possible' using visual feedback. The results showed that rapid posterior COP movements were slower and had an increased number of submovements and ratio of peak-to-average velocity, in comparison to anterior movements (p<.005). Moreover, older compared to younger adults were 27% slower and utilized nearly twice as many compensatory submovements (p<.005), particularly when moving posteriorly (p<.05). Older women also had higher ratios of peak-to-average COP velocity than young (p<.05). Thus, despite moving more slowly, older women needed to take more frequent submovements to maintain COP accuracy, particularly posteriorly, thereby providing evidence of a compensatory strategy that may be used for preventing backward falls. PMID- 22225926 TI - When opinions differ: gridlock, parallel universes, and moral insanity. PMID- 22225925 TI - Raf-1 levels determine the migration rate of primary endometrial stromal cells of patients with endometriosis. AB - Endometriosis is a disease characterized by the localization of endometrial tissue outside the uterine cavity. The differences observed in migration of human endometrial stromal cells (hESC) obtained from patients with endometriosis versus healthy controls were proposed to correlate with the abnormal activation of Raf 1/ROCKII signalling pathway. To evaluate the mechanism by which Raf-1 regulates cytoskeleton reorganization and motility, we used primary eutopic (Eu-, n = 16) and ectopic (Ec-, n = 8; isolated from ovarian cysts) hESC of patients with endometriosis and endometriosis-free controls (Co-hESC, n = 14). Raf-1 siRNA knockdown in Co- and Eu-hESC resulted in contraction and decreased migration versus siRNA controls. This phenotype was reversed following the re-expression of Raf-1 in these cells. Lowest Raf-1 levels in Ec-hESC were associated with hyperactivated ROCKII and ezrin/radixin/moesin (E/R/M), impaired migration and a contracted phenotype similar to Raf-1 knockdown in Co- and Eu-hESC. We further show that the mechanism by which Raf-1 mediates migration in hESC includes direct myosin light chain phosphatase (MYPT1) phosphorylation and regulation of the levels of E/R/M, paxillin, MYPT1 and myosin light chain (MLC) phosphorylation indirectly via the hyperactivation of ROCKII kinase. Furthermore, we suggest that in contrast to Co-and Eu-hESC, where the cellular Raf-1 levels regulate the rate of migration, the low cellular Raf-1 content in Ec-hESC, might ensure their restricted migration by preserving the contracted cellular phenotype. In conclusion, our findings suggest that cellular levels of Raf-1 adjust the threshold of hESC migration in endometriosis. PMID- 22225928 TI - The perfect storm, the rise of localism, and its effects on national wellness. PMID- 22225929 TI - Effect of pranayama (breathing exercise) on arrhythmias in the human heart. AB - BACKGROUND: Cardiac arrhythmias, especially ventricular tachyarrhythmias are an important public health problem. QT dispersion (QTd), defined as the difference between maximal and minimal QT intervals, reflects the regional inhomogeneity of ventricular repolarization dispersion and may mark the presence of malignant ventricular arrhythmias. PURPOSE: To determine the effects of Pranayama (breathing exercise) on QTd in patients with arrhythmia. PATIENTS: Fifteen patients with arrhythmia and ejection fractions <40% (mean = 28 +/- 9%) who were on a stable medical regimen. DESIGN AND INTERVENTION: Standardized 12-lead surface ECGs were obtained at the beginning and end of the Pranayama session, and QT and JT intervals were measured manually and corrected for heart rate by using Bazett's formula. QTd, heart rate-corrected QTd (QTc-d), JT dispersion (JTd), and heart ratecorrected JTd (JTc-d) were measured in at least eight ECG leads in each patient. RESULTS: Following the Pranayama session, patients with arrhythmia had only slight improvements in exercise capacity (results were not significant). However, these patients had marked improvements in QTd (71 +/- 11 to 59 +/- 17 ms; P < .02), QTc-d (82 +/- 28 to 63 +/- 17 ms; P < .01), JTd (76 +/- 19 to 57 +/ 18 ms; P < .002), and JTc-d (84 +/- 23 to 61 +/- 18 ms; P < .001) following the Pranayama session. CONCLUSION: These data indicate that Pranayama significantly reduces the indices of ventricular repolarization dispersion in patients with arrhythmia. Further studies are needed to evaluate how effectively this reduction in ventricular repolarization dispersion decreases the risk of malignant ventricular arrhythmias and sudden death in patients with arrhythmia. PMID- 22225930 TI - Symbolic diseases and "mindbody" co-emergence. A challenge for psychoneuroimmunology. AB - Physical diseases that appear to be symbolic somatic representations of patients' personal meanings or individual 'stories' continue to be reported in the medical literature. The identification of a symbolic disease requires a clinical focus upon a patient's highly individual and nuanced meanings largely rendered invisible by the usual methodologies of clinical and research medicine, which has no coherent model for understanding symbolic disease. Therefore, a model is proposed of co-emergence of physicality and subjectivity, body and mind, disease and meaning, disease and symbol, which does provide a coherent basis for understanding symbolic disease. The 'mindbody' co-emergence model avoids mind and body dualism, assumes unbroken continuity between internal body processes and external interpersonal meanings and influences, and asserts that disease-related 'internal' bodily changes and collateral external interpersonal and environmental fluxes are mutually contingent and crucial to the development of the disease. The co-emergence model is discussed specifically in relation to psychoneuroimmunology, but it has exciting clinical and research implications for the whole of medicine. PMID- 22225931 TI - Vedic principles of therapy. AB - This paper introduces Vedic principles of therapy as a holistic integration of healing and human development. The most integrative aspect is a "consciousness based" approach in which the bottom line of the mind is consciousness itself, accessed by transcending mental activity to its simplest ground state. This directly contrasts with "unconscious-based" approaches that hold the basis of conscious mind is the unconscious, such as analytic, humanistic, and cognitive behavioral approaches. Although not presented as a specific therapeutic approach, interventions associated with this Vedic approach have extensive support in the applied research literature. A brief review of experimental research toward a general model of mind-and cutting-edge developments in quantum physics toward nonlocal mind-shows a convergence on the ancient Vedic model of mind. Comparisons with contemporary therapies further show that the simplicity, subtlety, and holistic nature of the Vedic approach represent a significant advance over approaches which have overlooked the fundamental ground state of the mind. PMID- 22225932 TI - A qualitative exploration of the impact of yoga on breast cancer survivors with aromatase inhibitor-associated arthralgias. AB - RESEARCH QUESTION: Arthralgia affects postmenopausal breast cancer survivors (BCS) receiving aromatase inhibitors (AI), which may result in reduced function and long-term well-being. This is an exploratory, qualitative investigation of BCS who participated in a yoga-based program to understand impact on joint pain and various aspects of quality of life (QOL) through a yoga program. THEORETICAL FRAMEWORK: Social cognitive theory was used and provided the foundation for developing a yoga intervention through sources of efficacy information: (1) performance accomplishment, (2) structured experience, (3) verbal support from instructor and group, and (4) physical feedback. METHODOLOGY: Ten postmenopausal women with stage I-III breast cancer and AI associated arthralgia (AIAA) received yoga twice a week for eight weeks for 90 minutes and were instructed to continue in a home-based yoga program. We used social cognitive theory (SCT) to structure a yoga intervention as an ongoing physical activity to manage joint pain and function. Participants completed journal reflections on their experience and received weekly phone calls. ANALYSIS: Data was collected and analyzed using qualitative methods. Member checks were completed and emergent themes were explored and agreed upon by the research team to ensure reliability and validity of data. Several emergent themes were discovered: Empowerment: Importance of Camaraderie, Community, and Sharing; Pain Relief; Increased Physical Fitness (Energy, Flexibility, and Function); Relieved Stress/Anxiety and Transferability of Yoga through Breathing. These themes were identified through instructor observation, participant observation, and weekly phone call documentation. INTERPRETATION: Participants experienced an eight-week yoga intervention as an effective physical activity and support group that fostered various improvements in quality of life (QOL) and reduction in AIAA. Participants were highly motivated to improve physical fitness levels and reduce pain. This study revealed benefits from alternative forms of exercise such as yoga to provide a structure, which is transferable in other situations. Information, structured physical guidance in yoga postures, support, and feedback are necessary to foster physical activity for BCS experiencing pain. IMPLICATIONS FOR CANCER SURVIVORS: Results of this qualitative analysis indicate that interventions to support BCS with AIAA are warranted. Yoga appears to positively impact these side effects of hormonal therapies. Additional research would aid in the development of other interventions. PMID- 22225933 TI - Living with type 2 diabetes mellitus in a modern Mexican city and opting for phytotherapy. PMID- 22225934 TI - Integrative Mental Health (IMH): paradigm, research, and clinical practice. AB - This paper provides an overview of the rapidly evolving paradigm of "Integrative Mental Health (IMH)." The paradigm of contemporary biomedical psychiatry and its contrast to non-allopathic systems of medicine is initially reviewed, followed by an exploration of the emerging paradigm of IMH, which aims to reconcile the bio psycho-socio-spiritual model with evidence-based methods from traditional healing practices. IMH is rapidly transforming conventional understandings of mental illness and has significant positive implications for the day-to-day practice of mental health care. IMH incorporates mainstream interventions such as pharmacologic treatments, psychotherapy, and psychosocial interventions, as well as alternative therapies such as acupuncture, herbal and nutritional medicine, dietary modification, meditation, etc. Two recent international conferences in Europe and the United States show that interest in integrative mental health care is growing rapidly. In response, the International Network of Integrative Mental Health (INIMH: www.INIMH.org) was established in 2010 with the objective of creating an international network of clinicians, researchers, and public health advocates to advance a global agenda for research, education, and clinical practice of evidence-based integrative mental health care. The paper concludes with a discussion of emerging opportunities for research in IMH, and an exploration of potential clinical applications of integrative mental health care. PMID- 22225935 TI - The case for commons health care. PMID- 22225937 TI - Evidence informed practice as the catalyst for culture change in CAM. PMID- 22225938 TI - Variation in transport explains polymorphism of histidine and urocanate utilization in a natural Pseudomonas population. AB - Phenotypic variation is a fundamental requirement for evolution by natural selection. While evidence of phenotypic variation in natural populations abounds, its genetic basis is rarely understood. Here we report variation in the ability of plant-colonizing Pseudomonas to utilize histidine, and its derivative, urocanate, as sole sources of carbon and nitrogen. From a population of 164 phyllosphere-colonizing Pseudomonas strains, 77% were able to utilize both histidine and urocanate (His(+) , Uro(+) ) as growth substrates, whereas the remainder could utilize histidine, but not urocanate (His(+) , Uro(-) ), or vice versa (His(-) , Uro(+) ). An in silico analysis of the hut locus, which determines capacity to utilize both histidine and urocanate, from genome sequenced Pseudomonas strains, showed significant variation in the number of putative transporters. To identify transporter genes specific for histidine and urocanate, we focused on a single genotype of Pseudomonas fluorescens, strain SBW25, which is capable of utilizing both substrates. Site-directed mutagenesis, combined with [(3) H]histidine transport assays, shows that hutT(u) encodes a urocanate-specific transporter; hutT(h) encodes the major high-affinity histidine transporter; and hutXWV encodes an ABC-type transporter that plays a minor role in histidine uptake. Introduction of cloned copies of hutT(h) and hutT(u) from SBW25 into strains incapable of utilizing either histidine, or urocanate, complemented the defect, demonstrating a lack of functional transporters in these strains. Taken together our data show that variation in transport systems, and not in metabolic genes, explains a naturally occurring phenotypic polymorphism. PMID- 22225940 TI - Ca2+ signaling and exocytosis in pituitary corticotropes. AB - The secretion of adrenocorticotrophin (ACTH) from corticotropes is a key component in the endocrine response to stress. The resting potential of corticotropes is set by the basal activities of TWIK-related K(+) (TREK)-1 channel. Corticotrophin-releasing hormone (CRH), the major ACTH secretagogue, closes the background TREK-1 channels via the cAMP-dependent pathway, resulting in depolarization and a sustained rise in cytosolic [Ca(2+)] ([Ca(2+)](i)). By contrast, arginine vasopressin and norepinephrine evoke Ca(2+) release from the inositol trisphosphate (IP(3))-sensitive store, resulting in the activation of small conductance Ca(2+)-activated K(+) channels and hyperpolarization. Following [Ca(2+)](i) rise, cytosolic Ca(2+) is taken into the mitochondria via the uniporter. Mitochondrial inhibition slows the decay of the Ca(2+) signal and enhances the depolarization-triggered exocytotic response. Both voltage-gated Ca(2+) channel activation and intracellular Ca(2+) release generate spatial Ca(2+) gradients near the exocytic sites such that the local [Ca(2+)] is ~3-fold higher than the average [Ca(2+)](i). The stimulation of mitochondrial metabolism during the agonist-induced Ca(2+) signal and the robust endocytosis following stimulated exocytosis enable corticotropes to maintain sustained secretion during the diurnal ACTH surge. Arachidonic acid (AA) which is generated during CRH stimulation activates TREK-1 channels and causes hyperpolarization. Thus, corticotropes may regulate ACTH release via an autocrine feedback mechanism. PMID- 22225941 TI - Surface modification of magnetite nanoparticles using gluconic acid and their application in immobilized lipase. AB - Superparamagnetic magnetite nanoparticles (SMN) were surface-modified with gluconic acid (GLA) to improve their hydrophilicity and bio-affinity. Gluconic acid was successfully coated on the surface of magnetite nanoparticles and characterized using Fourier transform infrared spectroscopy (FT-IR). With water soluble carbodiimide (EDC) as the coupling reagent, lipase was successfully immobilized onto the hydroxyl-functionalized magnetic nanoparticles. The immobilized lipase had better resistance to temperature and pH inactivation in comparison to the free form and hence widened the reaction pH and temperature range. Thermostability and storage stability of the enzyme improved upon covalent immobilization. Immobilized lipase showed higher activity after recycling when compared to the free one and could be recovered by magnetic separation. PMID- 22225939 TI - Mannose-binding lectin genotype and serum levels in patients with chronic and allergic pulmonary aspergillosis. AB - Several studies suggest mannose-binding lectin (MBL) deficiency is associated with various manifestations of aspergillosis. MBL serum levels and function are genetically determined, but levels rise during inflammation. We address the relative frequency of deficient genotypes, the relationship between serum level and genotype and both age and disease manifestations in patients with chronic pulmonary (CPA) and allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS). DNA was extracted from blood samples, and MBL2 genotyping was performed using the INNO-LiPA MBL2 kit. Serum MBL concentrations were determined using ELISA. One hundred and eight patients were evaluated, 70 (65%) with CPA, 38 (35%) with allergic disease (ABPA, SAFS or undefined) and 13 (12%) had both CPA and ABPA. The mean MBL serum level was 1849 MUg L(-1) and did not differ between groups. Forty subjects (37%) had exon 1 genotypes producing nonfunctional MBL (A/B, A/C, A/D and O/O), a frequency not different from published normal controls. A/A subjects with CPA had higher levels (2981 MUg L(-1)) compared with allergic A/A subjects (2202 MUg L(-1)) (pc0.012). No single haplotype, genotype or allele was significantly related to any aspergillosis phenotype. Worse breathlessness was associated with higher MBL levels among A/A subjects (P = 0.009) and conversely nonfunctional genotypes. Mean MBL values were higher in those with an Medical Research Council (MRC) breathlessness score of 5 compared with those with and MRC score of 1 (P = 0.023). A/A allergic subjects (n = 27) in this study were ~ 11 years younger than allergic A/O subjects (n = 11, P = 0.02). Subjects with worse respiratory status or more severe CPA had higher MBL serum levels (P = 0.023; P = 0.034). Bronchiectasis was not associated with MBL levels in CPA or allergic aspergillosis. MBL genotype and serum level modulate progression of aspergillosis. PMID- 22225942 TI - Characteristics and cytocompatibility of biodegradable polymer film on magnesium by spin coating. AB - In recent years, magnesium and its alloys have been investigated as biodegradable metallic materials in cardiovascular stents and bone implants. However, rapid corrosion rate in the early stage of the degradation process greatly influences the cytocompatibility and hinters their application. In this research, biodegradable polymer films are prepared under same coating condition by spin coating in order to improve the early corrosion resistance and cytocompatibility of Mg. The results present that uniform, nonporous, amorphous PLLA and semi crystalline PCL films are coated on Mg. PLLA film shows better adhesion strength to Mg substrate than that of PCL film. For both PLLA and PCL, low molecular weight (LMW) film is thinner and exhibits better adhesion strength than high molecular weight (HMW) one. SaOS-2 cells show significantly good attachment and high growth on the polymer-coated Mg, demonstrating that all the polymer films can significantly improve the cytocompatibility in the 7-day incubation. The pH measurement of the immersion medium and the quantification of released Mg(2+) during the cell culture clearly indicate that the corrosion resistance of Mg substrate is improved by the polymer films to different extents. It can be concluded that both PLLA and PCL films are promising protective coatings for improving the initial corrosion resistance and cytocompatibility. PMID- 22225943 TI - Synthesis and characterization of chitosan and grape polyphenols stabilized palladium nanoparticles and their antibacterial activity. AB - Based on enhanced effectiveness, the new age drugs are nanoparticles of polymers, metals or ceramics, which can combat conditions like cancer and fight human pathogens like bacteria. In this present study we aimed for a green approach to synthesize palladium nanoparticles by reducing palladium chloride salts with nontoxic and biodegradable polymeric chitosan and grape polyphenols and confirmed by FTIR, TEM, SEM and UV-spectroscopy. We also extended our study to show the efficacy of the grape and chitosan impregnated palladium nanoparticles as an antibacterial agent against Escherichia coli. Antibacterial assays were carried out with a representative gram-negative bacterium, E. coli and a gram-positive bacterium, Staphylococcus aureus. Commendable efforts have been made to explore this property using electron microscopy, which has revealed size dependent interaction of palladium nanoparticles conjugates with bacteria by disrupting cell membranes and the leakage of cytoplasm. Therefore, the observed results imply that grape and chitosan-based nano palladium conjugates prepared in our present system are promising candidates for a wide range of biomedical and general applications. PMID- 22225944 TI - Intracellular biosynthesis of superparamagnetic 2-lines ferri-hydrite nanoparticles using Euglena gracilis microalgae. AB - The intracellular biosynthesis of superparamagnetic (blocking temperature 5.6K) 2 lines ferrihydrite (Fh2L) nanoparticles was observed within living Euglena gracilis microalgae. PMID- 22225945 TI - Increased adsorption of histidine-tagged proteins onto tissue culture polystyrene. AB - In this study we compare histidine-tagged and native proteins with regards to adsorption properties. We observe significantly increased adsorption of proteins with an incorporated polyhistidine amino acid motif (HIS-tag) onto tissue culture polystyrene (TCPS) compared to similar proteins without a HIS-tag. The effect is not observed on polystyrene (PS). Adsorption experiments have been performed at physiological pH (7.4) and the effect was only observed for the investigated proteins that have pI values below or around 7.4. Competitive adsorption experiments with imidazole and ethylenediaminetetraacetic acid (EDTA), as well as adsorption performed at different pH and ionic strength indicates that the high adsorption is caused by electrostatic interaction between negatively charged carboxylate groups on the TCPS surface and positively charged histidine residues in the proteins. Pre-adsorption of bovine serum albumin (BSA) does not decrease the adsorption of HIS-tagged proteins onto TCPS. Our findings identify a potential problem in using HIS-tagged signalling molecule in assays with cells cultured on TCPS, since the concentration of the molecule in solution might be affected and this could critically influence the assay outcome. PMID- 22225946 TI - A comparison of student and faculty perceptions of clinical post-conference learning environment. AB - The purpose of this study was to repeat a study by Letizia and Jennrich that described and compared perceptions of the clinical post-conference learning environment of undergraduate baccalaureate student nurses (BSN) and faculty. The Clinical Post-Conference Learning Environment Survey (CPCLES) was sent electronically to all traditional and accelerated BSN students and faculty; 178 usable responses were returned. Both faculty and students perceived the environmental characteristics captured by the CPCLES were important, but were used less than expected (p<0.025). No differences were found between faculty and students in perceptions of importance and actual use of the post-conference learning environment. Results showed highest scores for the subscale Teacher Support for both faculty and students. Lowest scores were received for Innovation. The results suggest the important role faculty has in supporting students' efforts to understand and find meaning in clinical experiences. Post conference learning experiences could be enriched by faculty efforts to increase active learning strategies and innovative experiences. Further research is needed to determine effectiveness of new approaches to the post-conference in facilitating clinical reasoning among student nurses, and promote students' ability to provide safe, high-quality care. PMID- 22225947 TI - Service user involvement--addressing the crisis in confidence in healthcare. PMID- 22225948 TI - Nursing students' experiences of assessment by the Swedish National Clinical Final Examination. AB - The Swedish National Clinical Final Examination (NCFE) was established in 2007 in order to examine nursing students' clinical competence upon completing their Bachelor's degree in nursing. The NCFE constitutes an innovative method of examination, divided into two parts: a written and bedside test. The aim of this study was to evaluate nursing students' experiences of being assessed by means of the NCFE, in order to obtain information that could be used to improve the examination. A survey was conducted using a questionnaire with open-ended questions concerning the written and the bedside part of the NCFE. The answers from 577 third-year nursing students were analysed using content analysis. The nursing students regarded the NCFE as promoting further learning and as an important means of quality assurance. Its comprehensive nature was perceived to tie the education together and contributed to the students' awareness of their own clinical competence. The strengths of the NCFE especially highlighted were its high degree of objectivity and the fact that it took place in a natural setting. However, the students felt that the NCFE did not cover the entire nursing programme and that it caused stress. It thus appears to be important to reconsider the written theoretical part of the examination and to standardise the bedside part. PMID- 22225949 TI - Neurogenesis in the central olfactory pathway of adult decapod crustaceans: development of the neurogenic niche in the brains of procambarid crayfish. AB - BACKGROUND: In the decapod crustacean brain, neurogenesis persists throughout the animal's life. After embryogenesis, the central olfactory pathway integrates newborn olfactory local and projection interneurons that replace old neurons or expand the existing population. In crayfish, these neurons are the descendants of precursor cells residing in a neurogenic niche. In this paper, the development of the niche was documented by monitoring proliferating cells with S-phase-specific markers combined with immunohistochemical, dye-injection and pulse-chase experiments. RESULTS: Between the end of embryogenesis and throughout the first post-embryonic stage (POI), a defined transverse band of mitotically active cells (which we will term 'the deutocerebral proliferative system' (DPS) appears. Just prior to hatching and in parallel with the formation of the DPS, the anlagen of the niche appears, closely associated with the vasculature. When the hatchling molts to the second post-embryonic stage (POII), the DPS differentiates into the lateral (LPZ) and medial (MPZ) proliferative zones. The LPZ and MPZ are characterized by a high number of mitotically active cells from the beginning of post-embryonic life; in contrast, the developing niche contains only very few dividing cells, a characteristic that persists in the adult organism. CONCLUSIONS: Our data suggest that the LPZ and MPZ are largely responsible for the production of new neurons in the early post-embryonic stages, and that the neurogenic niche in the beginning plays a subordinate role. However, as the neuroblasts in the proliferation zones disappear during early post-embryonic life, the neuronal precursors in the niche gradually become the dominant and only mechanism for the generation of new neurons in the adult brain. PMID- 22225950 TI - Breast cancer incidence and case fatality among 4.7 million women in relation to social and ethnic background: a population-based cohort study. AB - INTRODUCTION: Incidence of breast cancer is increasing around the world and it is still the leading cause of cancer mortality in low- and middle-income countries. We utilized Swedish nationwide registers to study breast cancer incidence and case fatality to disentangle the effect of socioeconomic position (SEP) and immigration from the trends in native Swedes. METHODS: A nation-wide cohort of women in Sweden was followed between 1961 and 2007 and incidence rate ratio (IRR) and hazard ratio (HR) with 95% confidence intervals (CIs) were estimated using Poisson and Cox proportional regression models, respectively. RESULTS: Incidence continued to increase; however, it remained lower among immigrants (IRR = 0.88, 95% CI = 0.86 to 0.90) but not among immigrants' daughters (IRR = 0.97, 95% CI = 0.94 to 1.01) compared to native Swedes. Case fatality decreased over the last decades and was similar in native Swedes and immigrants. However, case fatality was significantly 14% higher if cancer was diagnosed after age 50 and 20% higher if cancer was diagnosed in the most recent years among immigrants compared with native Swedes. Women with the highest SEP had significantly 20% to 30% higher incidence but had 30% to 40% lower case fatality compared with women with the lowest SEP irrespective of country of birth. Age at immigration and duration of residence significantly modified the incidence and case fatality. CONCLUSIONS: Disparities found in case fatality among immigrants by age, duration of residence, age at immigration and country of birth emphasize the importance of targeting interventions on women that are not likely to attend screenings or are not likely to adhere to the therapy suggested by physicians. The lower risk of breast cancer among immigrant women calls for more knowledge about how the lifestyle factors in these women differ from those with high risk, so that preventative measures may be implemented. PMID- 22225951 TI - The redefinition of the familialist home care model in France: the complex formalization of care through cash payment. AB - This article investigates the impact of policy measures on the organisation of home-based care for older people in France, by examining the balance between formal and informal care and the redefinition of the initial familialist model. It focuses on the specific cash for care scheme (the Allocation personnalisee d'autonomie - Personalised allowance for autonomy) which is at the core of the French home-based care policy. The author argues that in a redefined context of 'welfare mix', the French public strategy for supporting home-based care in France is articulated around two major objectives, which can appear contradictory. It aims to formalise a professional care sector, with respect to the employment policy while allowing the development of new forms of informal care, which cannot be considered to be formal employment. The data collection is two-fold. Firstly, a detailed analysis was made of different policy documents and public reports, together with a systematic review of existing studies. Secondly, statistical analysis on home-based care resources were collected, which was not easy, as home-care services for older people in France are part of a larger sector of activity, 'personal services' (services a la personne). The article exposes three main findings. First, it highlights the complexity of the formalisation process related to the introduction of the French care allowance and demonstrates that formalisation, which facilitates the recognition of care as work, does not necessarily mean professionalisation. Second, it outlines the diversity of the resources available: heterogeneous professional care, semi formal forms of care work with the possibility to employ a relative and informal family care. Finally, the analysis outlines the importance of the regulation of cash payments on the reshaping of formal and informal care and comments on its impact on the redefinition of informal caring activities. PMID- 22225952 TI - Accuracy of estimation of time-intervals in psychogeriatric outpatients. AB - BACKGROUND: Accuracy of estimation of time-intervals has received marginal attention in psychogeriatrics. We examined presumed differences in this time measure in participants with dementia (PWD) versus participants without dementia (PWoutD), further subdivided into specific diagnoses and performance subgroups. We also studied its demographic, clinical, and cognitive correlates and predictors. A diagnostic role was hypothesized. METHODS: Forty-three individuals (27 PWD: 16 dementia of the Alzheimer's type (DAT), 11 vascular dementia (VaD); 16 PWoutD: 10 major depressive disorder (MDD), 6 normal) were interviewed with the Cambridge Examination for Mental Disorders of the Elderly - Revised (CAMDEX R) that permits the registration of this time measure. Demographic, clinical, and cognitive data were obtained. RESULTS: Neither absolute accuracy of estimation of duration of interview nor its transformed logarithm were significantly different between PWD and PWoutD, or between DAT and VaD participants. MDD participants performed significantly poorer than normal and did not differ from PWD, and the PWD relatively better performing subgroup. The logarithm of absolute accuracy of estimation correlated with some clinical and cognitive variables. Only a measure of depression and of impaired judgment could significantly predict it. CONCLUSIONS: The absolute accuracy of estimation of time-intervals did not differ between the major groups and the main diagnoses subgroups. It was associated with a variety of clinical and cognitive measures, and was predicted by the composite constructs of depression and impaired judgment. The diagnostic value of this measure in the psychogeriatric clinic is questionable, and limited to "worried" well individuals. PMID- 22225953 TI - Distribution and morphometric studies of flagellar sensilla in Emphorini bees (Hymenoptera, Apoidea). AB - The tribe Emphorini is a group of pollen-collecting solitary bees with a geographical distribution restricted to the western hemisphere. Most of the Emphorini bees collect Page 10 linepollen from a few specific plant families and display specialized behaviors for constructing their nests. Insect sensilla are the basic structural and functional units of cuticle receptors, serving mainly mechano- and chemo-receptor functions. The external morphology of the antennal sensilla has been well characterized in species of different families of Apoidea, however there is scarce information about this issue in solitary bees of the family Apidae. For a better understanding of the association between the external sensory system and several types of behaviors which emerged along the evolutionary history of bees, it is important to characterize the antennal receptors in several representative species of this tribe. The distribution of the antennal sensilla on the dorsal flagella of 18 taxa was studied in insects of both sexes, using light and scanning electron microscopy. There were six types of sensilla and setae on the antennae, which were identified as sensilla placodea, trichodea, basiconica, coeloconica, coelocapitular and ampullacea. The sensilla trichodea were classified into subtypes, A, B, C-D. Sensilla subtype A were the most abundant sensilla and were distributed over the entire antennae, while sensilla placodea and sensilla trichodea type B, showed a restricted distribution on specific areas of the flagella. We have recognized four patterns of spatial distribution of setae on dorsal flagella. Species having setae on the distal part of the flagellomeres tended to contain a low density of sensilla trichodea type A. Females showed a higher number of sensilla subtypes B and C-D than males; instead sensilla trichodea A were more abundant in males. No significant difference was found in the number of sensilla placodea, ampullacea, coeloconica and coelocapitular. Sensilla basiconica were found only in females. Our results showed that gustative and tactile sensilla were more abundant in female bees, as well as, olfactory receptors predominate in the antennal system of males. The possible coevolution of flagellar sensilla in males and females of solitary bees is discussed in light of previous reports. Patterns of distribution of setae determine the relative abundance of the types of sensilla in the flagellum. PMID- 22225954 TI - Oxysterol sulfation by cytosolic sulfotransferase suppresses liver X receptor/sterol regulatory element binding protein-1c signaling pathway and reduces serum and hepatic lipids in mouse models of nonalcoholic fatty liver disease. AB - Cytosolic sulfotransferase (SULT2B1b) catalyzes oxysterol sulfation. 5-Cholesten 3beta-25-diol-3-sulfate (25HC3S), one product of this reaction, decreases intracellular lipids in vitro by suppressing liver X receptor/sterol regulatory element binding protein (SREBP)-1c signaling, with regulatory properties opposite to those of its precursor 25-hydroxycholesterol. Upregulation of SULT2B1b may be an effective strategy to treat hyperlipidemia and hepatic steatosis. The objective of the study was to explore the effect and mechanism of oxysterol sulfation by SULT2B1b on lipid metabolism in vivo. C57BL/6 and LDLR(-/-) mice were fed with high-cholesterol diet or high-fat diet for 10 weeks and infected with adenovirus encoding SULT2B1b. SULT2B1b expressions in different tissues were determined by immunohistochemistry and Western blot. Sulfated oxysterols in liver were analyzed by high-pressure liquid chromatography. Serum and hepatic lipid levels were determined by kit reagents and hematoxylin and eosin staining. Gene expressions were determined by real-time reverse transcriptase polymerase chain reaction and Western Blot. Following infection, SULT2B1b was successfully overexpressed in the liver, aorta, and lung tissues, but not in the heart or kidney. SULT2B1b overexpression, combined with administration of 25 hydroxycholesterol, significantly increased the formation of 25HC3S in liver tissue and significantly decreased serum and hepatic lipid levels, including triglycerides, total cholesterol, free cholesterol, and free fatty acids, as compared with controls in both C57BL/6 and LDLR(-/-) mice. Gene expression analysis showed that increases in SULT2B1b expression were accompanied by reduction in key regulators and enzymes involved in lipid metabolism, including liver X receptor alpha, SREBP-1, SREBP-2, acetyl-CoA carboxylase-1, and fatty acid synthase. These findings support the hypothesis that 25HC3S is an important endogenous regulator of lipid biosynthesis. PMID- 22225956 TI - Apolipoprotein E predicts incident cardiovascular disease risk in women but not in men with concurrently high levels of high-density lipoprotein cholesterol and C-reactive protein. AB - Although there is great interest in the notion that dysfunctional transformation of high-density lipoprotein (HDL) facilitates development of atherosclerosis and cardiovascular disease (CVD), few studies in human populations directly address this issue. As apolipoprotein E (apoE) is a constituent of HDL thought to be important for HDL antiatherogenic function, we sought to assess the role of apoE in CVD risk in subjects likely to display dysfunctional transformation of HDL. Association of apoE levels with incident CVD risk was investigated using Cox multivariable proportional hazards modeling. Analyses were performed in subgroups of women and men likely to display dysfunctional transformation of HDL deriving from previous subgroup identification based upon defining characteristics of concurrently high levels of HDL cholesterol and systemic inflammation as reflected by high C-reactive protein levels. Results revealed apoE levels (dichotomized as highest quartile vs combined 3 lowest quartiles) as predicting subgroup risk in women (hazard ratio, 4.52; 95% confidence interval, 1.07-19.12; P = .040) but not in men. Further sex differences were manifested in terms of the relationship of apoE levels with age. Analysis revealed positive correlation of apoE levels with age in women (r = 0.47, P < .0001) but not in men (r = 0.04, P = .43). Apolipoprotein E levels predict incident CVD risk in women with high levels of HDL cholesterol and C-reactive protein but not in men. Future studies should be oriented toward investigations of apoE as related to multiplicity of HDL functionality and toward assessment of potential roles for apoE in dysfunctional transformation of HDL. PMID- 22225955 TI - Correction of metabolic abnormalities in a rodent model of obesity, metabolic syndrome, and type 2 diabetes mellitus by inhibitors of hepatic protein kinase C iota. AB - Excessive activity of hepatic atypical protein kinase (aPKC) is proposed to play a critical role in mediating lipid and carbohydrate abnormalities in obesity, the metabolic syndrome, and type 2 diabetes mellitus. In previous studies of rodent models of obesity and type 2 diabetes mellitus, adenoviral-mediated expression of kinase-inactive aPKC rapidly reversed or markedly improved most if not all metabolic abnormalities. Here, we examined effects of 2 newly developed small molecule PKC-iota/lambda inhibitors. We used the mouse model of heterozygous muscle-specific knockout of PKC-lambda, in which partial deficiency of muscle PKC lambda impairs glucose transport in muscle and thereby causes glucose intolerance and hyperinsulinemia, which, via hepatic aPKC activation, leads to abdominal obesity, hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia. One inhibitor, 1H-imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4 [(phosphonooxy)methyl]cyclopentyl-[1R-(1a,2b,3b,4a)], binds to the substrate binding site of PKC-lambda/iota, but not other PKCs. The other inhibitor, aurothiomalate, binds to cysteine residues in the PB1-binding domains of aPKC lambda/iota/zeta and inhibits scaffolding. Treatment with either inhibitor for 7 days inhibited aPKC, but not Akt, in liver and concomitantly improved insulin signaling to Akt and aPKC in muscle and adipocytes. Moreover, both inhibitors diminished excessive expression of hepatic, aPKC-dependent lipogenic, proinflammatory, and gluconeogenic factors; and this was accompanied by reversal or marked improvements in hyperglycemia, hyperinsulinemia, abdominal obesity, hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia. Our findings highlight the pathogenetic importance of insulin signaling to hepatic PKC-iota in obesity, the metabolic syndrome, and type 2 diabetes mellitus and suggest that 1H imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4 [(phosphonooxy)methyl]cyclopentyl-[1R-(1a,2b,3b,4a)] and aurothiomalate or similar agents that selectively inhibit hepatic aPKC may be useful treatments. PMID- 22225957 TI - Effects of PKF275-055, a dipeptidyl peptidase-4 inhibitor, on the development of atherosclerotic lesions in apolipoprotein E-null mice. AB - We recently discovered that glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide can both prevent the development of atherosclerosis in apolipoprotein E-null (Apoe(-/-)) mice. In the present study, we attempted to extend these findings to orally administered dipeptidyl peptidase (DPP)-4 inhibitor. Seventeen-week-old Apoe(-/-) mice fed an atherogenic diet were administered a DPP-4 inhibitor, vildagliptin analogue (PKF275-055 [PKF], 100 um/[kg d]), in drinking water over a period of 4 weeks. Aortic atherosclerosis and oxidized low-density lipoprotein-induced foam cell formation were determined. Orally administered PKF increased plasma levels of active glucagon-like peptide-1 by 3.5-fold, increased total glucose-dependent insulinotropic polypeptide levels by 2-fold, reduced body weight by 13%, and reduced plasma cholesterol levels by 30%. Compared with drinking water controls, PKF significantly suppressed total aortic atherosclerotic lesions, atheromatous plaque in the aortic root, and macrophage accumulation in the aortic wall by 30% to 40% (P < .001). None of these changes were associated with the PKF-induced reductions in body weight and plasma cholesterol levels. Foam cell formation was suppressed by 40% in the exudate peritoneal macrophages obtained from the PKF-treated mice. The DPP-4 inhibitor prevents the development of atherosclerotic lesions by suppressing macrophage foam cell formation. PMID- 22225959 TI - Kidney damage during organ recovery in donation after circulatory death donors: data from UK National Transplant Database. AB - During the last 10 years, kidneys recovered/transplanted from donors after circulatory death (DCD) have significantly increased. To optimize their use, there has been an urgent need to minimize both warm and cold ischemia, which often necessitates more rapid removal. To compare the rates of kidney injury during procurement from DCD and donors after brain death (DBD) organ donors. A total of 13 260 kidney procurements were performed in the United Kingdom over a 10-year period (2000-2010). Injuries occurred in 903 procedures (7.1%). Twelve thousand three hundred seventy-two (93.3%) kidneys were recovered from DBD donors and 888 (6.7%) from DCD donors. The rates of kidney injury were significantly higher when recovered from DCD donors (11.4% vs. 6.8%, p < 0.001). Capsular, ureteric and vascular injuries were all significantly more frequent (p = 0.002, p < 0.001 and p = 0.017, respectively). Discard because of injury was more common after DCD donation (p = 0.002). Multivariate analysis demonstrated procurement injuries were significantly associated with DCD donors (p = 0.035) and increased donor age (<0.001) and donor body mass index (BMI; 0.001), donor male gender (p = 0.001) and no liver donation (0.009). We conclude that procurement from DCD donors leads to higher rates of injury to the kidney and are more likely to be discarded. PMID- 22225958 TI - The serum concentration of allograft inflammatory factor-1 is correlated with metabolic parameters in healthy subjects. AB - Obesity is associated with low-grade chronic inflammation characterized by inflamed adipose tissue with increased infiltration of macrophages. The aim of this study was to investigate the correlations between the serum concentration of allograft inflammatory factor-1 (AIF-1), which is a marker of activated macrophages, and metabolic parameters. The serum AIF-1 concentrations were measured in 303 healthy subjects (163 men and 140 women). We then evaluated the relationships between the serum AIF-1 concentrations and metabolic parameters, including fasting plasma glucose levels, serum lipid concentration, uric acid concentration, and waist circumference. The serum AIF-1 concentrations positively correlated with levels of fasting plasma glucose (r = 0.159, P =.0056), hemoglobin A(1c) (r = 0.169, P = .0032), triglycerides (r = 0.137, P = .0172), and uric acid (r = 0.146, P = .0108) and with waist circumference (r = 0.221, P = .0001) and body mass index (r = 0.185, P = .0012), whereas the serum AIF-1 concentrations inversely correlated with high-density lipoprotein cholesterol level (r = -0.178, P = .0019). Stepwise multiple regression analysis demonstrated that hemoglobin A(1c) level (beta = .133, F = 5.490, P < .05) and waist circumference (beta = .197, F = 11.954, P < .05) were independent predictors of the serum AIF-1 concentrations. The serum AIF-1 concentrations correlated with clinical and biochemical metabolic parameters. Allograft inflammatory factor-1 may be a significant predictor of activated macrophages as well as cardiovascular disease in humans. PMID- 22225960 TI - Prevalence of undiagnosed diabetes mellitus and cardiovascular risk factors in Hong Kong professional drivers. AB - AIMS: To investigate the prevalence of undiagnosed diabetes mellitus (DM) and cardiovascular risk factors among professional drivers in Hong Kong. METHODS: Chinese professional drivers with no history of DM were invited to complete a questionnaire on their health status, followed by taking their body measurements, fasting blood glucose (FG) and lipids. 75g OGTT were performed when FG>=5.6 to <7.0mmol/L. RESULTS: Of these 3376 drivers (male 92.6%, mean age 50.9+/-7.6 years), the prevalence of undiagnosed DM, prediabetes, and metabolic syndrome was 8.1% (272/3376, 95% CI 7.1-9.0%), 10.0% (337/3376, 95% CI 9.0-11.0%) and 26.8% (904/3376, 95% CI 25.3-28.3%) respectively, while the corresponding WHO Standard Population age-standardized prevalence was 7.8%, 9.0% and 24.7% respectively. Many of them were obese (51.2%), had hypertension (57.0%) and high cholesterol (58.7%), and a third had hypertriglyceridaemia (34.9%) and low HDL-cholesterol (29.3%). Their median working hours were 60.0 (IQR 14)h. Majority had exercise <1h/week (56.0%) and ate out >=6times/week (54.9%). CONCLUSIONS: Hong Kong professional drivers have higher prevalence of undiagnosed DM, cardiovascular risk factors and metabolic syndrome than the general population. Therefore, health care measures targeting against them should be taken to prevent and detect DM and cardiovascular diseases. PMID- 22225961 TI - How to read a pathology report of a bone tumor. AB - The interpretation of a biopsy specimen involving bone is one of the most challenging feats for a pathologist, as it is often difficult to distinguish between benign or reactive lesions and malignant tumors on microscopic analysis. Therefore, correlation with the clinical data and imaging is essential and sometimes it is only the evolution of certain characteristics over time or information garnered from molecular analysis that can provide an accurate diagnosis. The pathology report is critical in that it will define subsequent patient management; its wording must precisely reflect those elements that are known with certainty and those that are diagnostic hypotheses. It must be systematic, thorough, and complete and should not be limited to a simple conclusion. The pathologist must first ensure the completeness and correct transcription of the information provided with the specimen, then describe and analyze the histology as well as the quality and representative nature of the sample (as they relate to the radiographic findings and preliminary/final diagnoses), and finally, compare what is seen under the microscope with the assessment made by the radiologist and/or surgeon. This analysis helps to identify difficult cases requiring further consultation between the radiologist and pathologist. There are multiple reasons for misinterpretation of a pathology report. An important and largely underestimated reason is varied interpretations of terms used by the pathologist. Standardized pathology reports with concise phrases as well as multidisciplinary meetings may limit errors and should be encouraged for optimal diagnostic accuracy. PMID- 22225962 TI - Congestive hepatopathy. PMID- 22225963 TI - Hereditary intraductal papillary mucinous neoplasm of the pancreas. AB - Intraductal papillary mucinous neoplasm (IPMN) is a rare pancreatic tumor defined as intraductal mucin-producting neoplasm with tall, columnar, mucin-containing epithelium. IPMN have already been described in association with inherited genetic disorder including familial adenomatous polyposis and Peutz-Jeghers syndrome. However, there is no reported description of familial history of IPMN. We reported in this case-report IPMN in the first-degree relatives without familial history of colorectal polyposis or previous extra-pancreatic cancer. The rarety of IPMN suggests that the coexistence of this tumor in two first-degree relatives is probably due to a genetic inherited factor that remains to be elucidated. PMID- 22225964 TI - Allele frequency of inosine triphosphate pyrophosphatase (ITPA) and thiopurine-S methyl transferase (TPMT) genes in the Tunisian population. AB - AIM: The aim of this study was to determine the frequencies of TPMT and ITPA polymorphisms in Crohn's disease patients of Tunisian origin and to compare them with allele frequencies previously reported in other populations of various ethnic origins. METHODS: ITPA (c.94C>A and IVS2+21A>C) and TPMT (c.238G>C, c.460G>A and c.719A>G) mutations and genotypes were assessed in 208 Tunisian subjects (78 males/130 females) by polymerase chain reaction-restriction fragment length polymorphism and allele-specific-PCR methods. RESULTS: Genotyping of ITPA revealed frequencies of 6% and 7.9% for c.94C>A and IVS2+21A>C, respectively. Accordingly, deficient or diminished ITPA phenotype can be predicted to concern 2.4% of Tunisians. The observed frequencies of the c. 238G>C, c.460G>A and c.719A>G TPMT polymorphisms were 0, 0.24 and 1.44%, respectively. CONCLUSION: This study provides the first analysis of TPMT and ITPA mutant allele frequency in individuals of Tunisian origin. Unlike in Caucasians, TPMT*3C which harbours the c.719A>G polymorphism appears to be the most common mutant allele in Tunisians. In contrast, ITPA mutant allele frequency distribution appears to be similar to that observed in Caucasians. PMID- 22225965 TI - Effects of paliperidone extended release on the symptoms and functioning of schizophrenia. AB - BACKGROUND: We aimed to explore relations between symptomatic remission and functionality evaluation in schizophrenia patients treated with paliperidone extended-release (ER), as seen in a normal day-to-day practice, using flexible dosing regimens of paliperidone ER. We explored symptomatic remission rate in patients treated with flexibly dosed paliperidone ER by 8 items of Positive and Negative Syndrome Scale (PANSS) and change of Personal and Social Performance (PSP) scale. METHOD: This was a 12-week multicenter, open-label, prospective clinical study conducted in in-patient and out-patient populations. Flexible dosing in the range 3-12 mg/day was used throughout the study. All subjects attended clinic visits on weeks 0, 4, 8, and 12 as usual clinical practice for the 12-week observation period. Data were summarized with respect to demographic and baseline characteristics, efficacy measurement with PANSS scale, PSP, and social functioning score, and safety observations. Descriptive statistics were performed to identify the retention rate at each visit as well as the symptomatic remission rate. Summary statistics of average doses the subjects received were based on all subjects participating in the study. RESULTS: A total of 480 patients were enrolled. Among them, 426 patients (88.8%) had evaluation at week 4 and 350 (72.9%) completed the 12-week evaluation. Patients with at least moderate severity of schizophrenia were evaluated as "mild" or better on PANSS scale by all 8 items after 12 weeks of treatment with paliperidone ER. There was significant improvement in patients' functionality as measured by PSP improvement and score changes. Concerning the other efficacy parameters, PANSS total scale, PSP total scale, and social functioning total scale at the end of study all indicated statistically significant improvement by comparison with baseline. The safety profile also demonstrated that paliperidone ER was well-tolerated without clinically significant changes after treatment administration. CONCLUSIONS: Although the short-term nature of this study may limit the potential for assessing improvements in function, it is noteworthy that in the present short term study significant improvements in patient personal and social functioning with paliperidone ER treatment were observed, as assessed by PSP scale. TRIAL REGISTRATION: Clinical Trials. PAL-TWN-MA3. PMID- 22225966 TI - Centre-embedded structures are a by-product of associative learning and working memory constraints: evidence from baboons (Papio Papio). AB - Influential theories have claimed that the ability for recursion forms the computational core of human language faculty distinguishing our communication system from that of other animals (Hauser, Chomsky, & Fitch, 2002). In the present study, we consider an alternative view on recursion by studying the contribution of associative and working memory processes. After an intensive paired-associate training with visual shapes, we observed that baboons spontaneously ordered their responses in keeping with a recursive, centre embedded structure. This result suggests that the human ability for recursion might partly if not entirely originate from fundamental processing constraints already present in nonhuman primates and that the critical distinction between animal communication and human language should more likely be found in working memory capacities than in an ability to produce recursive structures per se. PMID- 22225967 TI - African swine fever: an epidemiological update. AB - African swine fever (ASF) is one of the most important swine diseases, mainly because of its significant sanitary and socioeconomic consequences. This review gives an update on the epidemiology of the disease and reviews key issues and strategies to improve control of the disease and promote its eradication. Several characteristics of ASF virus (ASFV) make its control and eradication difficult, including the absence of available vaccines, marked virus resistance in infected material and contaminated animal products, and a complex epidemiology and transmission involving tick reservoir virus interactions. The incidence of ASF has not only increased on the African continent over the last 15 years, so that it now affects West African countries, Mauritius and Madagascar, but it has also reached new areas, such as the Caucasus region in 2007. In fact, the rapid spread of the disease on the European continent and the uncontrolled situation in the Russian Federation places all countries at great risk as a result of intense global trade. The proximity of some affected areas to the European Union (EU) borders (<150 km) has increased concerns about the potential economic consequences of an ASF incursion into the EU pig sector. Establishing effective surveillance, control and eradication programmes that implicate all actors (veterinarians, farmers, and policy makers) is essential for controlling ASF. African swine fever -free countries should be aware of the potential risk of ASF incursion and implement risk reduction measures such as trade controls and other sanitary measures. This review will discuss lessons learnt so far about ASF control, current challenges to its control and future studies needed to support global efforts at prevention and control. PMID- 22225968 TI - How do I empathize with you? Let me count the ways: relations between facets of pain-related empathy. AB - This study examined the extent to which components of empathy (ie, empathic accuracy, empathic tendencies, and empathic responses) were correlated within the context of chronic pain couples. Additionally, the interrelationships between these empathy variables and spouse responses to pain were investigated. Participants were 57 couples in which at least 1 spouse reported chronic musculoskeletal pain. Each couple participated in a videotaped interaction about the impact of pain in their lives together, after which they completed an empathic accuracy procedure. The interactions were coded for the spouse's use of empathic responses. Couples also completed surveys about pain severity, pain interference, empathic tendencies, marital satisfaction, and perceived spousal responses (ie, solicitous and punishing responses) to pain. Spousal empathic responses and empathic accuracy were not related to one another nor were they related to spousal empathic tendencies, or solicitous spouse responses. Spousal punishing responses were negatively related to empathic responses. The association between solicitousness and empathic responses was moderated by spousal marital satisfaction. The findings suggest that there are not clear associations among these empathy variables. The results also indicate that the climate in which solicitousness is provided may influence the extent to which spouses display empathic responses. PERSPECTIVE: The findings have implications for models of pain empathy and suggest that future research is needed to understand relations between aspects of empathy. Moreover, interventions aimed at addressing the empathic climate in which support is delivered may help spouses more empathically and effectively communicate with and assist partners with pain management. PMID- 22225970 TI - Membrane protein structure and function. PMID- 22225969 TI - The perception of pain in others: how gender, race, and age influence pain expectations. AB - Sex, race/ethnic, and age differences in pain have been reported in clinical and experimental research. Gender role expectations have partly explained the variability in sex differences in pain, and the Gender Role Expectations of Pain questionnaire (GREP) was developed to measure sex-related stereotypic attributions about pain. It is hypothesized that similar expectations exist for age- and race-related pain decisions. This study investigated new measures of race/ethnic- and age-related stereotypic attributions of pain sensitivity and willingness to report pain, and examined the psychometric properties of a modified GREP. Participants completed the Race/Ethnicity Expectations of Pain questionnaire, Age Expectations of Pain questionnaire, and modified GREP. Results revealed a 3-factor solution to the race/ethnicity questionnaire and a 2-factor solution to the age questionnaire, consistent with theoretical construction of the items. Results revealed a 4-factor solution to the modified GREP that differed from the original GREP and theoretical construction of the items. Participants' pain-related stereotypic attributions differed across racial/ethnic, age, and gender groups. These findings provide psychometric support for the measures examined herein and suggest that stereotypic attributions of pain in others differ across demographic categories. Future work can refine the measures and examine whether select demographic variables influence pain perception, assessment, and/or treatment. PERSPECTIVE: The findings suggest that one's expectations of the pain experience of another person are influenced by the stereotypes one has about different genders, races, and ages. The 3 pain expectation measures investigated in the current study could be used in future work examining biases in pain assessment and treatment. PMID- 22225971 TI - An unusual case of hearing loss in a patient with neurofibromatosis type 1. PMID- 22225972 TI - Posterior reversible encephalopathy syndrome and oral methotrexate. PMID- 22225973 TI - Visual outcome after fronto-temporo-orbito-zygomatic approach combined with early extradural and intradural optic nerve decompression in tuberculum and diaphragma sellae meningiomas. AB - OBJECT: The surgical challenge of the treatment of tuberculum (TSMs) and diaphragma sellae meningiomas (DSMs) is to preserve or improve the visual function. Extradural and intradural optic nerve decompression should reduce surgical trauma of the nerve achieving a good visual result. METHODS: We reported 37 consecutive TSMs and DSMs operated through fronto-temporo-orbito-zygomatic approach with extradural unroofing of the optical canal and early intradural incision of the dural sheath. Visual data were recorded measuring the visual impairment score (VIS), the visual acuity (VA), the visual field (VF) and the postoperative improvement. RESULTS: A good visual outcome (VIS improved or unchanged) was obtained in 97.2% of patients (35/36). The evaluation of 72 eyes showed a good outcome (VA and VF unchanged or improved) in 98.6% (71/72 eyes). The degree of preoperative VA and VF impairment was the only factor correlating with the postoperative improvement of VA (P<.001 and P=.018) and VF defect (P<.001). Worsening of visual function occurred in 1/37 patient (2.7%). CONCLUSION: Using this surgical technique we achieved a high improvement rate of visual defects and a low frequency of worsening. PMID- 22225974 TI - Parametric effects of syntactic-semantic conflict in Broca's area during sentence processing. AB - The hypothesized role of Broca's area in sentence processing ranges from domain general executive function to domain-specific computation that is specific to certain syntactic structures. We examined this issue by manipulating syntactic structure and conflict between syntactic and semantic cues in a sentence processing task. Functional neuroimaging revealed that activation within several Broca's area regions of interest reflected the parametric variation in syntactic semantic conflict. These results suggest that Broca's area supports sentence processing by mediating between multiple incompatible constraints on sentence interpretation, consistent with this area's well-known role in conflict resolution in other linguistic and non-linguistic tasks. PMID- 22225975 TI - Basin-scale patterns in the abundance of SAR11 subclades, marine Actinobacteria (OM1), members of the Roseobacter clade and OCS116 in the South Atlantic. AB - Bacterioplankton are major biogeochemical agents responsible for mediating the flux of dissolved organic matter (DOM) and subsequent cycling of nutrients in the oceans. Most information about the composition of bacterioplankton communities has come from studies along well-defined biogeochemical gradients in the northern hemisphere. This study extends observations of spatial and temporal dynamics for SAR11, Actinobacteria and OCS116 in the North Atlantic by demonstrating distinct spatial variability in the abundance and distribution of these and other lineages across the South Atlantic gyre and in the Benguela upwelling system. We identified shifts in SAR11, Actinobacteria, OCS116, SAR86, SAR116 and members of the Roseobacter clade along basin-scale gradients in nutrients, chlorophyll and dissolved organic carbon (DOC). Distinct SAR11 subclades dominated the western and eastern regions of the gyre, and Actinobacteria, OCS116 and members of the Roseobacter lineages were most abundant at the deep chlorophyll maxima. SAR86 and SAR116 accounted for a significant fraction of coastal and open ocean communities, respectively, and members of the gamma sulfur oxidizer (GSO) clade persisted in the Benguela upwelling system. These data suggest that distinct communities are partitioned along basin-scale biogeochemical gradients, that SAR11 community structure varies across the gyre and that Actinobacteria, OCS116, and members of the Roseobacter clade are closely associated with phytoplankton in the gyre. PMID- 22225976 TI - Hydrogen-rich saline attenuates lung ischemia-reperfusion injury in rabbits. AB - BACKGROUND: Hydrogen gas, an antioxidant agent, was found to protect against cerebral and myocardial ischemia-reperfusion (I/R) injury. In the present study, we investigated the effect of hydrogen-rich saline (HRS) on the I/R-induced lung injury. METHODS: Left lung of male New Zealand White rabbits rendered normothermic ischemia for 60 min and reperfused for up to 240 min. Treated animals received intraperitoneal injection of 5 mL/kg HRS or the same volume of normal saline 10 min before the start of reperfusion. Blood and lung tissue samples were obtained for blood gas and biochemical analyses. The tissues obtained from lower lobe of left lung were used for histologic examination. RESULTS: After 240 min of reperfusion, intraperitoneal administration of HRS increased PaO2/FiO2 ratio and superoxide dismutase activities, and decreased malondialdehyde contents, proinflammatory cytokines expression, and myeloperoxidase activities, along with reduced wet/dry ratio and histologic injury scores (P < 0.05 versus I/R group). CONCLUSIONS: These results suggest that intraperitoneal administration of HRS before reperfusion protects the lung from I/R injury. The protective effect seems to be closely related to regulating oxidative damage and antioxidant enzyme activities and neutrophil infiltration. PMID- 22225977 TI - Gastric emptying is delayed in transgastric NOTES: a randomized study in swine. AB - AIM: The aim of this study was to evaluate the restoration of gastrointestinal motility after NOTES using capsule endoscopy (CE). MATERIALS AND METHODS: Twenty adult Yorkshire pigs were randomly assigned to four groups: transgastric NOTES (gNOTES), transrectal NOTES (rNOTES), transvaginal NOTES (vNOTES), and laparoscopy (LAP). At the end of a 30-min peritoneoscopy with identification of seven predetermined organs, an array of eight receivers and the recorder were attached to the abdominal wall. The CE was delivered into the antrum with the help of an endoscope and a polypectomy snare. Animals were kept alive for 14 d. RESULTS: Median time for surgery was longer in gNOTES (56 min, range 47-63) and vNOTES (54 min, range 44-79) than in LAP (32 min, range 32-33; P < 0.05 and P < 0.01) and in rNOTES (45.5 min, range 33-56) (P = ns). This increase was related to a larger incision and longer closure times. Images from the CE were successfully retrieved in 19 cases. The CE was retained in the stomach in all animals in gNOTES (459 min; range 360-600), but only in one animal in rNOTES and vNOTES and in none in the LAP group. Failure of passage of the CE beyond the stomach was associated with gNOTES and longer closure of the incision. Animals in the gNOTES group gained less weight than the others and this change was statistical significant when compared with vNOTES animals (1.7 kg, range -1.98 to 4.5 versus 8.4 kg, range 5.8 to 11.45; P < 0.01). CONCLUSION: Gastric emptying is delayed after gNOTES peritoneoscopy compared with rNOTES, vNOTES, and LAP and this effect is associated with less weight gain. PMID- 22225978 TI - Preoperative CD4 count or CD4/CD8 ratio as a useful indicator for postoperative sepsis in HIV-infected patients undergoing abdominal operations. AB - BACKGROUND: CD4 count or CD4/CD8 ratio has been found to be a valuable marker of disease progression in HIV and AIDS. Our objective was to evaluate preoperative CD4 count or CD4/CD8 ratio as a useful indicator for postoperative sepsis in HIV infected patients undergoing abdominal operations. METHODS: Retrospective analysis of 35 HIV-infected patients (four females, 31 males) undergoing abdominal operations. All patients were divided into postoperative sepsis group (A) and non-sepsis group (B). Demographic and clinical information were entered into a database and included: type of surgical procedure, age, peripheral blood cells, plasma albumin, CD4 counts, and CD4/CD8 ratios. Furthermore, we stratified and compared the incidence of postoperative sepsis according to the preoperative CD4 counts with breakpoint value of 200 cells/MUL and preoperative CD4/CD8 ratios with breakpoint value of 0.15. RESULTS: Overall postoperative sepsis morbidity in our study was 51.43% (18/35). In sepsis group, the mean preoperative and postoperative CD4 counts, CD4/CD8 ratios, and postoperative platelet count were found significantly lower, respectively, than those in non-sepsis group (P < 0.05). The incidence of postoperative sepsis in the patients with preoperative CD4 counts <= 200 cells/MUL was markedly higher than those with CD4 counts > 200 cells/MUL (83.3% versus 17.65%; P = 0.000). Likewise, the incidence of postoperative sepsis in the patients with preoperative CD4/CD8 ratios <= 0.15 was dramatically higher than those with CD4/CD8 ratios > 0.15 (90% versus 36%; P = 0.007). CONCLUSIONS: Our preliminary study showed that HIV-infected patients with preoperative CD4 count <= 200 cells/MUL or CD4/CD8 ratio <= 0.15 had overall higher postoperative sepsis morbidity. Preoperative CD4 count or CD4/CD8 ratio may be used as a useful indicator for postoperative sepsis in HIV-infected patients undergoing abdominal operations. PMID- 22225979 TI - Assessment of screening colonoscopy competency in colon and rectal surgery fellows: a single institution experience. AB - BACKGROUND: The American Board of Surgery and the American Board of Colorectal Surgery requirements for certification include 80 and 140 colonoscopic procedures, respectively. However, little data support the attainment of colonoscopic competency. The aim of this retrospective study is to report the colonoscopy learning experience for colorectal surgery fellows at a single high volume training program. MATERIAL AND METHODS: A prospective database recorded the experience of six colorectal fellows over two consecutive academic years. Univariate, moving average curves, and change point analysis were used to assess learning curve trends over time. Screening colonoscopy competency was defined by a significant reduction in total procedure time and 80% cecal intubation rate within 35 min. RESULTS: From 2004 to 2006, a total of 2904 screening colonoscopies were performed, including 1498 (52%) by fellows (mean 249 procedures per fellow). The mean procedure time for fellows was 30.2 +/- 15 min. Procedure time decreased significantly up to 120 procedures but not thereafter. Overall, fellows' total procedure time decreased by 7.6 min over the course of the year (P < 0.0001); 66% of fellows were able to complete 80% of the procedure in 40 min in the last 2 mo of training. The combined learning curve of all the fellows and the change point analysis showed a significant change occurs at 94 procedures. Using the moving average curve, we have shown 114 procedures are needed to achieve 80% completion rate in 35 min in majority of the fellows. CONCLUSIONS: Colorectal surgery fellows were observed to achieve screening colonoscopy competency approximately between 94 and 114 procedures. In the era of working time restrictions, prospective documentation of individual trainee performance may allow tailored training based on observed competency. PMID- 22225980 TI - The role of the A2a receptor agonist, regadenoson, in modulating hepatic artery flow in the porcine small-for-size liver graft. AB - BACKGROUND: Hepatic artery vasoconstriction plays a major role in the pathophysiology of the small-for-size (SFS) liver graft injury and is reversed by adenosine. The A2a adenosine receptor (AR) has been suggested to be one of the key receptors that modulate hepatic hemodynamic changes. The aim of the study is to define the effects of the A2a AR agonist, regadenoson, in modulating hepatic artery flow (HAF) in SFS liver grafts of a porcine model. METHODS: Seven female recipient pigs (66-70 kg) receiving 20% liver grafts were treated with regadenoson, 0.1 ug/kg/min starting on POD1 (n = 7). Results were compared with those with untreated 20% liver grafts (n= 8). The recipients were observed for 14 d. Hepatic artery flow (HAF) and portal vein flow (PVF) were recorded. Liver biopsies and serum samples were also taken at the designed time points through postoperative day (POD)14. RESULTS: Dose-response curves of regadenoson established 0.1 ug/kg/min as the most effective dose of regadenoson for maintaining an increase in HAF. No adverse effects were seen with regadenoson infusion. HAF immediately increased by up to 2.2-fold after regadenoson infusion. The levels of daily average of HAF and percentage of HAF in total liver blood flow were 34.5% and 41.8%, respectively, higher in the regadenoson group than in the untreated group. Histologic scores of hepatic artery spasm and bile duct necrosis were significantly lower in the regadenoson group than in the untreated group (P = 0.01 and 0.04, respectively). The complication rates of hepatic artery thrombosis and gastrointestinal bleeding were lower in the regadenoson group than in the untreated group (0/7, 0% versus 2/8, 25% and 0/7, 0% versus 2/8 and 25%, respectively). The 14-d survival rates were 4/7 (57.1 %) in regadenoson group compared with 2/8 (25%) in the untreated group. CONCLUSION: Adenosine A2a AR agonist, regadenoson, increases HAF in the recipients of SFS grafts with modest improvements in outcome. PMID- 22225982 TI - Molecular typing of Vibrio parahaemolyticus isolates from the middle-east coastline of China. AB - The occurrence of outbreaks of Vibrio parahaemolyticus gastroenteritis in China highlights the need for strain characterization and subtyping of this pathogenic species. A total of 56 epidemiologically-unrelated strains of V. parahaemolyticus were isolated from clinical samples, seafood and various environmental sites in the middle-east coastline of China from 2006 to 2008. The isolates were characterized using four molecular typing methods, including ribotyping, enterobacterial repetitive intergenic consensus sequence PCR (ERIC-PCR), pulsed field gel electrophoresis (PFGE), and sequence analysis of the gyrB gene. Genetic profiles of cluster analysis from these molecular typing tests clearly showed that there were differences in potential pathogenicity among isolates from seafood and its environments. Genetic characterization of two isolates (F13 and QS2) that originated from seafood demonstrated that they were potentially pathogenic. Discriminatory indices of four typing methods for the 56 V. parahaemolyticus isolates were differentiated by Simpson's Index of Diversity. The discriminatory index of ERIC-PCR typing was maximal (D=0.942), while that of sequence analysis of the gyrB gene was minimal (D=0.702). The discriminatory ability was greatly enhanced (D=0.966) when ERIC-PCR was coupled with sequence analysis of the gyrB gene. These results suggest that ERIC-PCR combined with sequence analysis of gyrB gene may be a reliable, rapid typing strategy for V. parahaemolyticus strains. PMID- 22225983 TI - Resistance of pathogenic bacteria on the surface of stainless steel depending on attachment form and efficacy of chemical sanitizers. AB - Various bacteria including food spoilage bacteria and pathogens can form biofilms on different food processing surfaces, leading to potential food contamination or spoilage. Therefore, the survival of foodborne pathogens (Escherichia coli O157:H7, Listeria monocytogenes, Salmonella typhimurium, Staphylococcus aureus, Cronobacter sakazakii) in different forms (adhered cells, biofilm producing in TSB, biofilm producing at RH 100%) on the surface of stainless steel and stored at various relative humidities (RH 23%, 43%, 68%, 85%, and 100%) at room temperature for 5 days was investigated in this study. Additionally, the efficacy of chemical sanitizers (chlorine-based and alcohol-based commercial sanitizers) on inhibiting various types of biofilms of E. coli O157:H7 and S. aureus on the surface of stainless steel was investigated. The number of pathogens on the surface of stainless steel in TSB stored at 25 degrees C for 7 days or RH 100% at 25 degrees C for 7 days was significantly increased and resulted in the increase of 3 log(10) CFU/coupon after 1 day, and these levels were maintained for 7 days. When stainless steel coupons were stored at 25 degrees C for 5 days, the number of pathogens on the surface of stainless steel was significantly reduced after storage at RH 23%, 43%, 68%, and 85%, but not at 100%. When the bacteria formed biofilms on the surface of stainless steel in TSB after 6 days, the results were similar to those of the attached form. However, levels of S. aureus and C. sakazakii biofilms were more slowly reduced after storage at RH 23%, 43%, 68%, and 85% for 5 days than were those of the other pathogens. Formation of biofilms stored at RH 100% for 5 days displayed the highest levels of resistance to inactivation. Treatment with the alcohol sanitizer was very effective at inactivating attached pathogens or biofilms on the surface of stainless steel. Reduction levels of alcohol sanitizer treatment ranged from 1.91 to 4.77 log and from 4.35 to 5.35 log CFU/coupon in E. coli O157:H7 and S. aureus, respectively. From these results, the survival of pathogens contaminating the surfaces of food processing substrates such as stainless steel varied depending on RH and attachment form. Also, alcohol-based sanitizers can be used as a potential method to remove microbial contamination on the surfaces of utensils, cooking equipment, and other related substrates regardless of the microbial attached form. PMID- 22225984 TI - Cloning, characterization, expression and antifungal activity of an alkaline serine protease of Aureobasidium pullulans PL5 involved in the biological control of postharvest pathogens. AB - An alkaline protease gene was amplified from genomic DNA and cDNA of the antagonistic yeast-like fungus Aureobasidium pullulans PL5, a biocontrol agent effective against Monilinia laxa on stone fruit and Botrytis cinerea and Penicillium expansum on pome fruits. An open reading frame of 1248 bp encoding a 415-amino acid (aa) protein with a calculated molecular weight (M(r)) of 42.9 kDa and an isoelectric point (pI) of 4.5 was characterized. The cDNAALP5 gene had an 18-amino acid signal peptide, one N-gylcosylation, one histidine active site, and one serine active site. The ALP5 gene with a M(r) of 1351 bp contained two introns. One intron was of 54 bp, while the other was of 50 bp. Protein BLAST and phylogenetic tree analysis of the deduced amino sequences from the cDNAALP5 gene showed that the encoded protein had 100% homology to a protease enzyme (ALP2) of a sea strain of A. pullulans, suggesting that the protein ALP5 was an alkaline serine protease. Expression of ALP5 in Escherichia coli BL21 (DE3), followed by identification with Western-blotting, purification with Ni-NTA and analysis of enzymatic activity, yielded an homogeneous recombinant ALP5 which hydrolysed the substrate casein and inhibited the mycelial growth of the pathogens. At its optimal pH of 10.0 and reaction temperature of 50 degrees C, the recombinant protease exhibited the highest activity towards the substrate casein, though the highest stability was at lower temperatures and pH between 7.0 and 9.0. This study provided the direct evidence that extracellular proteases secreted by the antagonist A. pullulans PL5 played a role in the biocontrol activities against some postharvest pathogens of apple and peach. PMID- 22225985 TI - A comparison of the effects of E-beam irradiation and heat treatment on the variability of Bacillus cereus inactivation and lag phase duration of surviving cells. AB - The effects of electron beam irradiation and heat treatments on the variability of inactivation of Bacillus cereus spores (CECT 131/ATCC 10876) and of the lag phase of single surviving cells have been studied. In general, dispersion in the number of survivors increased as the stress became more intense. A polynomial relationship was derived between the coefficient of variation of the survivor number and the inactivation achieved. Heat treatments caused wider distributions than irradiation for the same substrate and for a similar degree of microbial inactivation. Increasing the intensity of the inactivation treatment lengthened the lag phase of survivors and increased its variability. Comparison of lag phases of heated and irradiated spores did not show any clear relationship. Heating did not affect the specific growth rate of surviving cells, whereas irradiation lowered the maximum specific growth rate in proportion to the dose applied. These results suggest that the shelf life of irradiated foods is longer than that of heated foods. PMID- 22225986 TI - Detection of two HLA-B*27 alleles, B*27:25 and B*27:86, in two Taiwanese blood donors by sequence-based typing. AB - We report here two HLA-B*27 alleles, B*27:86 and B*27:25, found in two Taiwanese blood donors. The new sequence of B*27:86 is identical to B*27:04:01 in exons 2 and 3, except at nucleotide 602 (A -> G) in exon 3. The nucleotide change caused an amino acid substitution from E to G at amino acid residue 177. The sequence of B*27:25 is identical to B*27:04:01 in exons 2, 3, 4, 5, 6 and 7 except at nucleotides 538, 539, 559 and 560 in exon 4. The nucleotide changes caused amino acid substitutions from L to W and from E to L at residues 156 and 163, respectively. The generation of B*27:86 was probably resulted by a point mutation while the generation of B*27:25 may have been derived from a sequence recombination event between B*46:01:01 and B*27:04:01. The probable HLA-A, -B and -DRB1 haplotypes in association with B*27:86 and B*27:25 may be deduced as A*11:53-B*27:86-DRB1*12 and A*11:01-B*27:25-DRB1*04:05, respectively. PMID- 22225987 TI - Nesfatin-1, a unique regulatory neuropeptide of the brain. AB - Nesfatin-1, a newly discovered NUCB2-derived satiety neuropeptide is expressed in several neurons of forebrain, hindbrain, brainstem and spinal cord. This novel anorexigenic substance seems to play an important role in hypothalamic pathways regulating food intake and energy homeostasis. Nesfatin-1 immunoreactive cells are detectable in arcuate (ARC), paraventricular (PVN) and supraoptic nuclei (SON), where the peptide is colocalized with POMC/CART, NPY, oxytocin and vasopressin. The nesfatin-1 molecule interacts with a G-protein coupled receptor and its cytophysiological effect depends on inhibitory hyperpolarization of NPY/AgRP neurons in ARC and melanocortin signaling in PVN. Administration of nesfatin-1 significantly inhibits consumatory behavior and decreases weight gain in experimental animals. These recent findings suggest the evidence for nesfatin 1 involvement in other important brain functions such as reproduction, sleep, cognition and anxiety- or stress-related responses. The neuroprotective and antiapoptotic properties of nesfatin-1 were also reported. From the clinical viewpoint it should be noteworthy, that the serum concentration of nesfatin-1 may be a sensitive marker of epileptic seizures. However, the details of nesfatin-1 physiology ought to be clarified, and it may be considered suitable in the future, as a potential drug in the pharmacotherapy of obesity, especially in patients treated with antipsychotics and antidepressants. On the other hand, some putative nesfatin-1 antagonists may improve eating disorders. PMID- 22225990 TI - Can mechanism help explain insect host choice? AB - Evolutionary theory predicts that herbivorous insects should lay eggs on plants in a way that reflects the suitability of each plant species for larval development. Empirical studies, however, often fail to find any relationship between an adult insect's choice of host-plant and offspring fitness, and in such cases, it is generally assumed that other 'missing' factors (e.g. predation, host plant abundance, learning and adult feeding sites) must be contributing to overall host suitability. Here, I consider an alternative theory - that a fitness cost inherent in the olfactory mechanism could constrain the evolution of insect host selection. I begin by reviewing current knowledge of odour processing in the insect antennal lobe with the aid of a simple schematic: the aim being to explain the workings of this mechanism to scientists who do not have prior knowledge in this field. I then use the schematic to explore how an insect's perception of host and non-host odours is governed by a set of processing rules, or algorithm. Under the assumptions of this mechanistic view, the perception of every plant odour is interrelated, and seemingly bad host choices can still arise as part of an overall adaptive behavioural strategy. I discuss how an understanding of mechanism can improve the interpretation of theoretical and empirical studies in insect behaviour and evolution. PMID- 22225988 TI - Hypoxia-inducible factor 1alpha promotes primary tumor growth and tumor initiating cell activity in breast cancer. AB - INTRODUCTION: Overexpression of the oxygen-responsive transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha) correlates with poor prognosis in breast cancer patients. The mouse mammary tumor virus polyoma virus middle T (MMTV-PyMT) mouse is a widely utilized preclinical mouse model that resembles human luminal breast cancer and is highly metastatic. Prior studies in which the PyMT model was used demonstrated that HIF-1alpha is essential to promoting carcinoma onset and lung metastasis, although no differences in primary tumor end point size were observed. Using a refined model system, we investigated whether HIF-1alpha is directly implicated in the regulation of tumor-initiating cells (TICs) in breast cancer. METHODS: Mammary tumor epithelial cells were created from MMTV-PyMT mice harboring conditional alleles of Hif1a, followed by transduction ex vivo with either adenovirus beta-galactosidase or adenovirus Cre to generate wild-type (WT) and HIF-1alpha-null (KO) cells, respectively. The impact of HIF-1alpha deletion on tumor-initiating potential was investigated using tumorsphere assays, limiting dilution transplantation and gene expression analysis. RESULTS: Efficient deletion of HIF-1alpha reduced primary tumor growth and suppressed lung metastases, prolonging survival. Loss of HIF-1alpha led to reduced expression of markers of the basal lineage (K5/K14) in cells and tumors and of multiple genes involved in the epithelial-to-mesenchymal transition. HIF 1alpha also enhanced tumorsphere formation at normoxia and hypoxia. Decreased expression of several genes in the Notch pathway as well as Vegf and Prominin-1 (CD133)was observed in response to Hif1a deletion. Immunohistochemistry confirmed that CD133 expression was reduced in KO cells and in tumorspheres. Tumorsphere formation was enhanced in CD133hi versus CD133neg cells sorted from PyMT tumors. Limiting dilution transplantation of WT and KO tumor cells into immunocompetent recipients revealed > 30-fold enrichment of TICs in WT cells. CONCLUSION: These results demonstrate that HIF-1alpha plays a key role in promoting primary mammary tumor growth and metastasis, in part through regulation of TICs. HIF-1alpha regulates expression of several members of the Notch pathway, CD133 and markers of the basal lineage in mammary tumors. Our results suggest that CD133, which has not been profiled extensively in breast cancer, may be a useful marker of TICs in the PyMT mouse model. These data reveal for the first time that HIF-1alpha directly regulates breast TIC activity in vivo. PMID- 22225991 TI - Use of astronomy filters in fluorescence microscopy. AB - Monochrome astronomy filters are well suited for use as excitation or suppression filters in fluorescence microscopy. Because of their particular optical design, such filters can be combined with standard halogen light sources for excitation in many fluorescent probes. In this "low energy excitation," photobleaching (fading) or other irritations of native specimens are avoided. Photomicrographs can be taken from living motile fluorescent specimens also with a flash so that fluorescence images can be created free from indistinctness caused by movement. Special filter cubes or dichroic mirrors are not needed for our method. By use of suitable astronomy filters, fluorescence microscopy can be carried out with standard laboratory microscopes equipped with condensers for bright-field (BF) and dark-field (DF) illumination in transmitted light. In BF excitation, the background brightness can be modulated in tiny steps up to dark or black. Moreover, standard industry microscopes fitted with a vertical illuminator for examinations of opaque probes in DF or BF illumination based on incident light (wafer inspections, for instance) can also be used for excitation in epi illumination when adequate astronomy filters are inserted as excitatory and suppression filters in the illuminating and imaging light path. In all variants, transmission bands can be modulated by transmission shift. PMID- 22225989 TI - Systems analysis of the transcriptional response of human ileocecal epithelial cells to Clostridium difficile toxins and effects on cell cycle control. AB - BACKGROUND: Toxins A and B (TcdA and TcdB) are Clostridium difficile's principal virulence factors, yet the pathways by which they lead to inflammation and severe diarrhea remain unclear. Also, the relative role of either toxin during infection and the differences in their effects across cell lines is still poorly understood. To better understand their effects in a susceptible cell line, we analyzed the transciptome-wide gene expression response of human ileocecal epithelial cells (HCT-8) after 2, 6, and 24 hr of toxin exposure. RESULTS: We show that toxins elicit very similar changes in the gene expression of HCT-8 cells, with the TcdB response occurring sooner. The high similarity suggests differences between toxins are due to events beyond transcription of a single cell-type and that their relative potencies during infection may depend on differential effects across cell types within the intestine. We next performed an enrichment analysis to determine biological functions associated with changes in transcription. Differentially expressed genes were associated with response to external stimuli and apoptotic mechanisms and, at 24 hr, were predominately associated with cell-cycle control and DNA replication. To validate our systems approach, we subsequently verified a novel G1/S and known G2/M cell-cycle block and increased apoptosis as predicted from our enrichment analysis. CONCLUSIONS: This study shows a successful example of a workflow deriving novel biological insight from transcriptome-wide gene expression. Importantly, we do not find any significant difference between TcdA and TcdB besides potency or kinetics. The role of each toxin in the inhibition of cell growth and proliferation, an important function of cells in the intestinal epithelium, is characterized. PMID- 22225992 TI - Evaluation of uncertainty and detection limits in 210Pb and 210Po measurement in water by alpha spectrometry using 210Po spontaneous deposition onto a silver disk. AB - An easy and accurate method for the determination of (210)Pb and (210)Po in water using (210)Po spontaneous deposition onto a silver disk is proposed and assessed for its detection capabilities according to the ISO Guide for the expression of uncertainty in measurement (GUM) and ISO Standard 11929-7 concerning the evaluation of the characteristic limits for ionizing radiation measurements. The method makes no assumption on the initial values of the activity concentrations of (210)Pb, (210)Bi and (210)Po in the sample to be analyzed, and is based on the alpha spectrometric measurement of (210)Po in two different aliquots: the first one measured five weeks after the sampling date to ensure radioactive equilibrium between (210)Pb and (210)Bi and the second after a sufficient time for the ingrowth of (210)Po from (210)Pb to be significant. As shown, for a recommended time interval of seven months between (210)Po measurements, the applicability of the proposed method is limited to water samples with a (226)Ra to (210)Pb activity ratio C(Ra)/C(Pb) <= 4, as usual in natural waters. Using sample and background counting times of 24h and 240 h, respectively, the detection limit of the activity concentration of each radionuclide at the sampling time for a 1L sample typically varies between 0.7 and 16 mBq L(-1) for (210)Pb in water samples with an initial activity of (210)Po in the range 0-200 mBq L(-1), and between 0.6 and 8.5 mBq L(-1) for (210)Po in water samples with an initial activity of (210)Pb in the same range. PMID- 22225993 TI - Mannan-binding lectin mediates renal ischemia/reperfusion injury independent of complement activation. AB - Ischemia/reperfusion injury (IRI) remains a major problem in renal transplantation. Clinical studies have identified that high serum levels of Mannan-binding lectin (MBL), the initiator of the lectin pathway of complement activation, are associated with inferior renal allograft survival. Using a rat model, we identified an entirely novel role for MBL in mediating renal IRI. Therapeutic inhibition of MBL was protective against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. Following reperfusion, exposure of tubular epithelial cells to circulation-derived MBL resulted in internalization of MBL followed by the rapid induction of tubular epithelial cell death. Interestingly, this MBL mediated tubular injury was completely independent of complement activation since attenuation of complement activation was not protective against renal IRI. Our identification that MBL-mediated cell death precedes complement activation strongly suggests that exposure of epithelial cells to MBL immediately following reperfusion is the primary culprit of tubular injury. In addition, also human tubular epithelial cells in vitro were shown to be susceptible to the cytotoxic effect of human MBL. Taken together, these data reveal a crucial role for MBL in the early pathophysiology of renal IRI and identify MBL as a novel therapeutic target in kidney transplantation. PMID- 22225994 TI - Bifidobacterium reuteri sp. nov., Bifidobacterium callitrichos sp. nov., Bifidobacterium saguini sp. nov., Bifidobacterium stellenboschense sp. nov. and Bifidobacterium biavatii sp. nov. isolated from faeces of common marmoset (Callithrix jacchus) and red-handed tamarin (Saguinus midas). AB - Five strains of bifidobacteria were isolated from faeces of a common marmoset (Callithrix jacchus) and a red-handed tamarin (Saguinus midas). The five isolates clustered inside the phylogenetic group of the genus Bifidobacterium but did not show high sequence similarities between the isolates and to known species in the genus by phylogenetic analysis based on 16S rRNA gene sequences. Sequence analyses of dnaJ1 and hsp60 also indicated their independent phylogenetic positions to each other in the Bifidobacterium cluster. DNA G+C contents of the species ranged from 57.3 to 66.3 mol%, which is within the values recorded for Bifidobacterium species. All isolates showed fructose-6-phosphate phosphoketolase activity. Based on the data provided, the five isolates represent five novel species, for which the names Bifidobacterium reuteri sp. nov. (type strain: AFB22 1(T) = JCM 17295(T) = DSM 23975(T)), Bifidobacterium callitrichos sp. nov. (type strain: AFB22-5(T) = JCM 17296(T) = DSM 23973(T)), Bifidobacterium saguini sp. nov. (type strain: AFB23-1(T) = JCM 17297(T) = DSM 23967(T)), Bifidobacterium stellenboschense sp. nov. (type strain: AFB23-3(T) = JCM 17298(T) = DSM 23968(T)) and Bifidobacterium biavatii sp. nov. (type strain: AFB23-4(T) = JCM 17299(T) = DSM 23969(T)) are proposed. PMID- 22225995 TI - Detection of bovine papillomavirus types, co-infection and a putative new BPV11 subtype in cattle. AB - The aim of this study was to evaluate the presence of different types of Bovine papillomavirus (BPV) in cattle skin lesions and to identify new viral types in Brazil. A total of 72 skin lesions were analysed from 66 different bovines by PCR using degenerate and specific primers, and subsequent sequencing. Sequencing quality was determined using Staden package with Phred 30. Similarity analysis was performed with BioEdit and BLAST programs to verify the identity with known BPV types. Phylogenetic analysis was carried out using Maximum Likelihood method with TIM3 + G as nucleotide substitution model in PAUP*, and 1000 non-parametric bootstrap replicates. Analyses revealed the presence of ten different types of BPV in the samples, with the exception of BPV7. The presence of co-infections was very high as almost all samples (89%) were co-infected. A putative new BPV11 subtype was also found in lesions from different animals. These results add significant knowledge about the prevalence and diversity of BPV infection in Brazilian cattle, which could be used in future studies aiming at the development of more specific treatment and diagnostic methods. PMID- 22225996 TI - Quantified statements are recalled as generics: evidence from preschool children and adults. AB - Generics are sentences such as "ravens are black" and "tigers are striped", which express generalizations concerning kinds. Quantified statements such as "all tigers are striped" or "most ravens are black" also express generalizations, but unlike generics, they specify how many members of the kind have the property in question. Recently, some theorists have proposed that generics express cognitively fundamental/default generalizations, and that quantified statements in contrast express cognitively more sophisticated generalizations (Gelman, 2010; Leslie, 2008). If this hypothesis is correct, then quantified statements may be remembered as generics. This paper presents four studies with 136 preschool children and 118 adults, demonstrating that adults and preschoolers alike tend to recall quantified statements as generics, thus supporting the hypothesis that generics express cognitively default generalizations. PMID- 22225998 TI - Secondary analyses in cardiovascular clinical trials - statistical and other considerations. Introduction. PMID- 22225997 TI - The effect of household heads training about the use of treated bed nets on the burden of malaria and anaemia in under-five children: a cluster randomized trial in Ethiopia. AB - BACKGROUND: Long-lasting insecticide-treated bed nets (LLITN) have demonstrated a significant effect in reducing malaria-related morbidity and mortality. However, barriers on the utilization of LLITN have hampered the desired outcomes. The aim of this study was to assess the effect of community empowerment on the burden of malaria and anaemia in under-five children in Ethiopia. METHODS: A cluster randomized trial was done in 22 (11 intervention and 11 control) villages in south-west Ethiopia. The intervention consisted of tailored training of household heads about the proper use of LLITN and community network system. The burden of malaria and anaemia in under-five children was determined through mass blood investigation at baseline, six and 12 months of the project period. Cases of malaria and anaemia were treated based on the national protocol. The burden of malaria and anaemia between the intervention and control villages was compared using the complex logistic regression model by taking into account the clustering effect. Eight Focus group discussions were conducted to complement the quantitative findings. RESULTS: A total of 2,105 household heads received the intervention and the prevalence of malaria and anaemia was assessed among 2410, 2037 and 2612 under-five children at baseline, six and 12 months of the project period respectively. During the high transmission/epidemic season, children in the intervention arm were less likely to have malaria as compared to children in the control arm (OR = 0.42; 95%CI: 0.32, 0.57). Symptomatic malaria also steadily declined in the intervention villages compared to the control villages in the follow up periods. Children in the intervention arm were less likely to be anaemic compared to those in the control arm both at the high (OR = 0.84; 95%CI: 0.71, 0.99)) and low (OR = 0.73; 95%CI: 0.60, 0.89) transmission seasons. CONCLUSION: Training of household heads on the utilization of LLITN significantly reduces the burden of malaria in under-five children. The Ministry of Health of Ethiopia in collaboration with other partners should design similar strategies in high-risk areas to control malaria in Ethiopia. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000035022. PMID- 22225999 TI - Approaches to data analyses of clinical trials. AB - There are two types of data analyses of randomized clinical trials (RCTs). The primary analyses are pre-specified in the protocol and the findings form the basis for recommendations and clinical decisions. They typically adhere to the intention-to-treat principle. Secondary analyses are supplemental and of various sorts. Although some may be pre-specified, many are not. We encourage the use of the rich sources of data from large RCTs for these secondary purposes. Depending on the kinds of secondary analyses, whether they are pre-specified, and whether intention-to-treat analysis is used, the results range from being quite conclusive to being hypothesis generating. In this article we answer four questions related to secondary analysis with emphasis on sharing of data primarily from NIH-sponsored trials: Who has access to this information? What questions can be asked? What are the requirements? What are the common challenges? PMID- 22226000 TI - Secondary analysis of clinical trials--a cautionary note. AB - There is concern in published reports and reviews that patients are being harmed or denied effective treatment by the use of questionable results from secondary analyses of data from clinical trials. A well-reported secondary analysis must make clear to the reader the uncertainty of the result--so clear, in fact, that it should be an obvious part of the conclusions that implementation should await confirmation as the primary outcome in an adequately powered trial. Those who write, review and publish these reports have a responsibility to ensure that reports accurately describe the sources of uncertainty, explain complex methods and their weaknesses with clarity, and convince readers to require better evidence before changing their practice. PMID- 22226001 TI - Rudiments of subgroup analyses. AB - Subgroup analysis in a clinical trial is the evaluation of the effect of a randomly allocated intervention within only a fraction of the patients in the entire research cohort. This article provides several examples of the use of subgroup analysis, discusses some of the interpretative difficulties that occur during the assessment of the effect of therapy within subgroups, and provides a summary of recent recommendations on reporting subgroup analyses in the literature. Although subgroup analyses can provide new, provocative, and sometimes clinically relevant findings, this group of evaluations must be handled with extreme care. PMID- 22226002 TI - Surrogate end points in secondary analyses of cardiovascular trials. AB - A surrogate end point is one that is used as a substitute for a clinical end point of more direct interest, usually for reasons of practicality, and that is expected to predict clinical benefit. Surrogate end points play a critical role in the advancement of all medical research, and cardiovascular (CV) research in particular. However, the relationship between a surrogate end point and its clinical end point is usually complex, and there are many examples where results based on surrogates have proved to be misleading. Secondary analyses of existing clinical trial data are likely to involve surrogate end points, if only because clinical end points will have been extensively studied as part of the primary analysis of a trial large enough to collect useful clinical end point data. Validation of a surrogate end point is a laudable goal for a secondary analysis of a large clinical end point trial (or meta-analysis of multiple smaller trials), and the result may be an important new tool for further study of a class of compounds in a particular disease context. Secondary analyses using surrogate end points may also provide new insight into disease or treatment mechanism, but as with any surrogate end point analysis, the results can mislead, and the existing literature is heavy on application and light on methodology. Surrogate end points often substitute efficiency for clarity, and while many interesting and potentially informative secondary analyses of CV trials will involve surrogates, results are likely to be ambiguous and should be interpreted with care. PMID- 22226003 TI - Economic analysis of secondary trial data. AB - Clinical trials may furnish data to conduct economic analyses. An economic analysis requires us to identify all opportunity costs associated with the intervention over the time horizon chosen for the analysis and enumerate the improvements in benefits from the intervention of interest. We review the basic steps used when performing economic studies based on secondary analysis of data from clinical trials using examples from myocardial infarction studies. Different types of economic analyses and the potential contributions of Markov modeling are described. Issues of measuring quality of life, patient utilities, cost of care, and potential sources of cost data are reviewed. The interpretation of incremental cost-effectiveness ratios is discussed and economic benchmarks for defining good and poor value interventions are provided. PMID- 22226004 TI - Comparison of the global statistical test and composite outcome for secondary analyses of multiple coronary heart disease outcomes. AB - Multiple outcomes (or multiple endpoints), such as mortality and recurrent myocardial infarction, are increasingly common in clinical trials and are often of interest in secondary analyses. Traditionally, a clinical trial protocol is built around a single event as its primary outcome, with several secondary outcomes specified, the analyses for which lack the same level of power. To accommodate all the relevant outcomes and to increase the power of the comparison in trials evaluating the efficacy of treatments for coronary heart disease, investigators often chose to construct a composite outcome. The more conventional composite outcome fails to account for the relative importance and the relationship (correlation) among its components. The purpose of this work is to demonstrate the usefulness of the Global Statistical Test, which considers the correlation between multiple outcomes, as an alternative strategy for these situations and to demonstrate its effect on hypothesis testing and power analysis issues in comparison with the traditional composite outcome analysis. Data from the cardiovascular clinical trial Systolic Hypertension in the Elderly Population are used as an example. PMID- 22226005 TI - The high-risk myocardial infarction database initiative. AB - Coronary artery disease and myocardial infarction represent a major cause of morbidity and mortality. Four randomized, controlled, double-blind clinical trials--VALIANT, EPHESUS, OPTIMAAL, and CAPRICORN evaluated pharmacologic intervention in a total of 28,771 high-risk patients following acute MI complicated with signs of heart failure or evidence of left ventricular dysfunction. The demographic profiles of the 4 study cohorts were similar. The High-Risk MI Database Initiative constructed a common database by merging the data captured by these 4 large trials. The merged data set did not contain the randomized study treatment, so no comparisons could be made between the agents investigated. A total of more than 17,600 subjects experienced a cardiovascular end point. Approximately 5100 deaths occurred, and more than 15,700 subjects experienced a hospitalization. The primary objectives of this initiative were to use this large database to define more precisely the prognostic profile of this high-risk population, to perform rigorous, adequately-sized, subset analyses, to provide epidemiologic information and event rate estimation based on baseline demographics. The methodological challenges and limitations of such an analyses are discussed. It is proposed that some thoughtful foresight and planning could enable us to use the large number of clinical events that accrue during randomized clinical trials to address questions of scientific and clinical interest. PMID- 22226006 TI - Observational epidemiology within randomized clinical trials: getting a lot for (almost) nothing. AB - Randomized clinical trials (RCTs) are considered the gold standard approach to establish relationships between exposures/treatments and outcomes. Analyses that examine the association between the randomized factor and outcomes are "protected by randomization" from potential confounding factors. Despite limitations largely arising from the lack of generalizability of findings, RCTs offer a rich environment to assess associations between other factors and outcomes which are by definition observational epidemiological studies. Herein we discuss the limitations of these analyses, but also the opportunities that arise from the use of observational epidemiological assessments that can be performed: 1) between factors assessed prior to randomization, 2) analyses of longitudinal outcomes both in the cohort all together, and among subjects randomized to placebo treatment, and 3) analyses of "associated" series of patients (such as non randomized registries or screenees for the RCT). While these assessments of associations are not protected by randomization, with proper planning these assessments within the RCT framework can be done in a powerful and effective manner. PMID- 22226007 TI - Expanding the benefits of implantable cardioverter-defibrillator therapy: "is less more"? AB - Implantable cardioverter-defibrillator (ICD) therapy improves survival in patients with significant left ventricular systolic dysfunction. Although this lifesaving therapy has many benefits, inappropriate ICD shocks may increase morbidity and mortality. With rates of inappropriate therapy quoted as high as 35% at 3 years after device implantation, numerous strategies have been evaluated to decrease the overall incidence of inappropriate therapy. Changes in programming algorithms, which allow for longer detection windows for rhythm analysis, extended the use of antitachycardia pacing, and improved supraventricular tachycardia discriminators, hold promise for decreasing inappropriate ICD therapy. In this review, we discuss the data summarizing the adverse effects of ICD shocks on outcomes, clinical trial-based programming algorithms to decrease inappropriate shocks, and the expanded role of antitachycardia pacing in ventricular arrhythmia management. PMID- 22226008 TI - Weight changes and their predictors amongst 11 140 patients with type 2 diabetes in the ADVANCE trial. AB - AIMS: To determine the baseline characteristics and glucose-lowering therapies associated with weight change among patients with type 2 diabetes. METHODS: Eleven thousand one hundred and forty participants in the ADVANCE trial were randomly assigned to an intensive [aiming for a haemoglobin A1c (HbA1c) <=6.5%] or a standard blood glucose-control strategy. Weight was measured at baseline and every 6 months over a median follow-up of 5 years. Multivariable linear regression and linear-mixed effect models were used to examine predictors of weight change. RESULTS: The mean difference in weight between the intensive and standard glucose-control arm during follow-up was 0.75 kg (95% CI: 0.56-0.94), p value <0.001. The mean weight decreased by 0.70 kg (95% CI: 0.53-0.87), p < 0.001 by the end of follow-up in the standard arm but remained stable in the intensive arm, with a non-significant gain of 0.16 kg (95% CI: -0.02 to 0.34), p = 0.075. Baseline factors associated with weight gain were younger age, higher HbA1c, Caucasian ethnicity and number of glucose-lowering medications. Treatment combinations including insulin [3.22 kg (95% CI: 2.92-3.52)] and thiazolidinediones [3.06 kg (95% CI: 2.69-3.43)] were associated with the greatest weight gain while treatment combinations including sulphonylureas were associated with less weight gain [0.71 kg (95%CI: 0.39-1.03)]. CONCLUSIONS: Intensive glucose-control regimens are not necessarily associated with substantial weight gain. Patient characteristic associated with weight change were age, ethnicity, smoking and HbA1c. The main treatment strategies predicting weight gain were the use of insulin and thiazolidinediones. PMID- 22226009 TI - Release of metronidazole from electrospun poly(L-lactide-co-D/L-lactide) fibers for local periodontitis treatment. AB - OBJECTIVES: We aimed to achieve detailed biomaterials characterization of a drug delivery system for local periodontitis treatment based on electrospun metronidazole-loaded resorbable polylactide (PLA) fibers. METHODS: PLA fibers loaded with 0.1-40% (w/w) MNA were electrospun and were characterized by SEM and DSC. HPLC techniques were used to analyze the release profiles of metronidazole (MNA) from these fibers. The antibacterial efficacy was determined by measuring inhibition zones of drug-containing aliquots from the same electrospun fiber mats in an agar diffusion test. Three pathogenic periodontal bacterial strains: Fusobacterium nucleatum, Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis were studied. Cytotoxicity testing was performed with human gingival fibroblasts by: (i) counting viable cells via live/dead staining methods and (ii) by exposing cells directly onto the surface of MNA-loaded fibers. RESULTS: MNA concentration influenced fiber diameters and thus w/w surface areas: diameter being minimal and area maximal at 20% MNA. HPLC showed that these 20% MNA fibers had the fastest initial MNA release. From the third day, MNA release was slower and nearly linear with time. All fiber mats released 32-48% of their total drug content within the first 7 days. Aliquots of media taken from the fiber mats inhibited the growth of all three bacterial strains. MNA released up to the 28th day from fiber mats containing 40% MNA significantly decreased the viability of F. nucleatum and P. gingivalis and up to the 2nd day also for the resistant A. actinomycetemcomitans. All of the investigated fibers and aliquots showed excellent cytocompatibility. SIGNIFICANCE: This study shows that MNA-loaded electrospun fiber mats represent an interesting class of resorbable drug delivery systems. Sustained drug release properties and cytocompatibility suggest their potential clinical applicability for the treatment of periodontal diseases. PMID- 22226010 TI - Writing errors in ALS related to loss of neuronal integrity in the anterior cingulate gyrus. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor neuron and various cognitive deficits including writing errors. (11)C-flumazenil (FMZ), the positron emission tomography (PET) GABA(A) receptor ligand, is a marker of cortical dysfunction. The objective of this study was to investigate the relationship between cognitive deficits and loss of neuronal integrity in ALS patients using (11)C-FMZ PET. Ten patients with ALS underwent both neuropsychological tests and (11)C-FMZ-PET. The binding potential (BP) of FMZ was calculated from (11)C-FMZ PET images. There were no significant correlations between the BP and most test scores except for the writing error index (WEI), which was measured by the modified Western Aphasia Battery - VB (WAB IVB) test. The severity of writing error was associated with loss of neuronal integrity in the bilateral anterior cingulate gyrus with mild right predominance (n=9; x=4 mm, y=36 mm, z=4 mm, Z=5.1). The results showed that writing errors in our patients with ALS were related to dysfunction in the anterior cingulate gyrus. PMID- 22226012 TI - Happy 10th birthday. PMID- 22226013 TI - [Relationship between precariousness, social coverage, and vaccine coverage: survey among children consulting in pediatric emergency departments in France]. AB - Poor children are more susceptible to infectious diseases. Routine medical follow up is infrequent in these patients, sometimes resulting in immunization delays. The aim of this study was to correlate a number of socioeconomic factors related to poverty with vaccination coverage in children visiting a pediatric emergency ward. PATIENTS AND METHODS: Previous routine vaccinations and various socioeconomic features were prospectively recorded for children aged 9 months to 7 years visiting two public pediatric emergency departments in Marseilles (southern France) from 2009 to 2010. RESULTS: Three hundred and seventy-five children were included. Vaccination coverage was 87% for diphtheria, tetanus, poliomyelitis, Haemophilus influenzae type b infections and pertussis, 69% for tuberculosis (Bacillus Calmette-Guerin), 77% for measles, mumps and rubella, 74% for pneumococcal infections (conjugate vaccine), and 55% for hepatitis B. Socioeconomic factors related to poverty were significantly associated with delays in immunizations. Children not attending school (OR=2.5), having parents who were not fluent in French (OR=5.7), living in caravans or squatting (OR=11.5), or being recipients of the national medical assistance for foreigners (OR=12.8) had significant delays with diphtheria, tetanus, and poliomyelitis vaccines. The measles-mumps-rubella vaccine was also delayed in homeless children (OR=3.4). Children who were recipients of the national medical assistance for citizens were better vaccinated against tuberculosis and hepatitis B. CONCLUSION: Poor children living in southern France had significant delays in their routine immunizations, resulting in gaps in their protection. Every medical visit, even those conducted in an emergency ward, should identify children with immunization delays and offer a catch-up schedule if necessary. PMID- 22226015 TI - 1-Benzyl-1,2,3,4-tetrahydro-beta-carboline as channel blocker of N-methyl-D aspartate receptors. AB - N-methyl-d-aspartate (NMDA) receptors belong to the family of ligand-gated ion channels and are important for synaptic plasticity and memory function. The NMDA receptor consists of a voltage-dependent channel permeable to Ca(2+) and Na(+) . In Alzheimer's disease, neuronal degeneration is thought to cause an excessive release of glutamate to the extracellular space, which may in turn mediate prolonged stimulation of the NMDA receptor complex and, as a consequence, excessive calcium influx into neuronal cells, leading to subsequent cell death. This process is called glutamate-induced excitotoxicity, and its inhibition may present an effective antidementive therapy. We found that 1-benzyl-1,2,3,4 tetrahydro-beta-carboline (1a) blocked NMDA receptor-mediated, glutamate-induced excitotoxicity with an IC(50) value of 27.4 MUm, whereas the closely related 1 phenyl-1,2,3,4-tetrahydro-beta-carboline (1b) had no effect. The binding modes of the reported compounds were studied by in silico docking simulations. We demonstrate that compounds (S)-1a and (R)-1a, but not (S)-1b and (R)-1b, have the same characteristics of potent NMDA receptor blockers, because they establish the main interactions inside the vestibule region of the receptor described previously for the high-affinity NMDA receptor blocker, MK-801. PMID- 22226014 TI - [Cow's milk protein allergy through human milk]. AB - Cow's milk protein allergy (CMPA) is the first allergy that affects infants. In this population, the incidence rate reaches 7.5%. The multiplicity and aspecificity of the symptoms makes its diagnosis sometimes complicated, especially in the delayed type (gastrointestinal, dermatological, and cutaneous). CMPA symptoms can develop in exclusively breastfed infants with an incidence rate of 0.5%. It, therefore, raises questions about sensitization to cow's milk proteins through breast milk. Transfer of native bovine proteins such as beta lactoglobulin into the breast milk is controversial: some authors have found bovine proteins in human milk but others point to cross-reactivity between human milk proteins and cow's milk proteins. However, it seems that a small percentage of dietary proteins can resist digestion and become potentially allergenic. Moreover, some authors suspect the transfer of some of these dietary proteins from the maternal bloodstream to breast milk, but the mechanisms governing sensitization are still being studied. Theoretically, CMPA diagnosis is based on clinical observations, prick-test or patch-test results, and cow's milk-specific IgE antibody concentration. A positive food challenge test usually confirms the diagnosis. No laboratory test is available to make a certain diagnosis, but the detection of eosinophil cationic protein (ECP) in the mother's milk, for example, seems to be advantageous since it is linked to CMA. Excluding cow's milk from the mother's diet is the only cure when she still wants to breastfeed. Usually, cow's milk proteins are reintroduced after 6 months of exclusion. Indeed, the prognosis for infants is very good: 80% acquire a tolerance before the age of 3 or 4 years. Mothers should not avoid dairy products during pregnancy and breastfeeding as preventive measures against allergy. PMID- 22226016 TI - Cytogenetic findings in benign and malignant oral tumors - the role of autologous human plasma. AB - The present study examined the possible use of autologous human plasma (AHP) to improve the in vitro culture for cytogenetics of benign and malignant oral tumor cells. The effect of AHP on the growth of a variety of benign and malignant head and neck tumor cells was studied by inverted microscope and cytogenetic analysis. Minced tumor biopsies of cases of hemangioma (HM), lipoma (LP), central giant cell granuloma (GC), pleomorphic adenoma (PA), schwannoma (SW), oral squamous cell carcinoma (SCC), Ewing sarcoma (ES), Merkel cell carcinoma (MCC) and adenoid cystic carcinoma (ACC), were cultured in medium supplemented with either AHP, allogeneic pooled human plasma (PHP), or fetal calf serum (FCS). More fibroblasts were seen in the FCS supplemented cultures, while in HP or PHP culture medium, more epithelial-like tumor cells were noted. The karyotypes of HM, LP, GC and PA were normal in all 3 different mediums. Cytogenetic analysis of SW and SCC revealed random numerical changes in all cultures. However, in AHP cultures a clone bearing translocation was found in SW t(2;13). In the SCC cultures one tumor had t(12;14) and the other t(3;21) translocations. Complex karyotype was found in all kinds of cultures in ES, MCC and ACC. AHP by itself does not cause chromosomal aberrations but may improve the ability to find chromosomal aberrations in some tumors over medium containing FCS. The spectrum of oral tumors where AHP can improve the cytogenetic analyses should be further studied on a greater number of tumors. PMID- 22226017 TI - Re: Herd MK, Anand R, Brennan PA. Use of propofol emulsion for intraoperative lubrication of oral and maxillofacial surgical instruments [Br. J. Oral Maxillofac. Surg. 49 (2011) 666-667]. PMID- 22226018 TI - Elacytarabine, a novel 5'-elaidic acid derivative of cytarabine, and idarubicin combination is active in refractory acute myeloid leukemia. PMID- 22226019 TI - RT-PCR diagnosis of recurrent rearrangements in pediatric acute lymphoblastic leukemia in Argentina. AB - The present study was performed to establish the prevalence of the recurrent fusion transcripts in Argentinean pediatric patients with acute lymphoblastic leukemia (ALL). A total of 380 newly diagnosed children (including 50 infants and 44 T-ALL) were screened by RT-PCR; the incidence of recurrent rearrangements was: ETV6-RUNX1, 12.9%; TCF3-PBX1, 5.0%; BCR-ABL1, 1.6%; and MLL rearrangements, 10.5%. STIL-TAL1 was detected in 22.7% of T-ALL cases. In B-ALL cases, the pEFS was significantly influenced by the presence of genetic alterations. RT-PCR studies improved patients' stratification and also the overall outcome of children treated in a pediatric hospital from a developing country. PMID- 22226020 TI - No evidence for association of inherited variation in genes involved in mitosis and percent mammographic density. AB - INTRODUCTION: Increased mammographic breast density is one of the strongest risk factors for breast cancer. While two-thirds of the variation in mammographic density appears to be genetically influenced, few variants have been identified. We examined the association of inherited variation in genes from pathways that mediate cell division with percent mammographic density (PMD) adjusted for age, body mass index (BMI) and postmenopausal hormones, in two studies of healthy postmenopausal women. METHODS: We investigated 2,058 single nucleotide polymorphisms (SNPs) in 378 genes involved in regulation of mitosis for associations with adjusted PMD among 484 unaffected postmenopausal controls (without breast cancer) from the Mayo Clinic Breast Cancer Study (MCBCS) and replicated the findings in postmenopausal controls (n = 726) from the Singapore and Sweden Breast Cancer Study (SASBAC) study. PMD was assessed in both studies by a computer-thresholding method (Cumulus) and linear regression approaches were used to assess the association of SNPs and PMD, adjusted for age, BMI and postmenopausal hormones. A P-value threshold of 4.2 * 10-5 based on a Bonferroni correction of effective number of independent tests was used for statistical significance. Further, a pathway-level analysis was conducted of all 378 genes using the self-contained gene-set analysis method GLOSSI. RESULTS: A variant in PRPF4, rs10733604, was significantly associated with adjusted PMD in the MCBCS (P = 2.7 * 10-7), otherwise, no single SNP was associated with PMD. Additionally, the pathway analysis provided no evidence of enrichment in the number of associations observed between SNPs in the mitotic genes and PMD (P = 0.60). We evaluated rs10733604 (PRPF4), and 73 other SNPs at P < 0.05 from 51 genes in the SASBAC study. There was no evidence of an association of rs10733604 (PRPF4) with adjusted PMD in SASBAC (P = 0.23). There were, however, consistent associations (P < 0.05) of variants at the putative locus, LOC375190, Aurora B kinase (AURKB), and Mini-chromosome maintenance complex component 3 (MCM3) with adjusted PMD, although these were not statistically significant. CONCLUSIONS: Our findings do not support a role of inherited variation in genes involved in regulation of cell division and adjusted percent mammographic density in postmenopausal women. PMID- 22226021 TI - 64Cu-NO2A-RGD-Glu-6-Ahx-BBN(7-14)NH2: a heterodimeric targeting vector for positron emission tomography imaging of prostate cancer. AB - INTRODUCTION: The present study describes the design and development of a new heterodimeric RGD-bombesin (BBN) agonist peptide ligand for dual receptor targeting of the form (64)Cu-NO2A-RGD-Glu-6-Ahx-BBN(7-14)NH(2) in which Cu-64=a positron emitting radiometal; NO2A=1,4,7-triazacyclononane-1,4-diacetic acid; Glu=glutamic acid; 6-Ahx=6-aminohexanoic acid; RGD=the amino acid sequence [Arg Gly-Asp], a nonregulatory peptide that has been used extensively to target alpha(v)beta(3) receptors up-regulated on tumor cells and neovasculature; and BBN(7-14)NH(2)=Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH(2), an agonist analogue of bombesin peptide for specific targeting of the gastrin-releasing peptide receptor (GRPr). METHODS: RGD-Glu-6-Ahx-BBN(7-14)NH(2) was manually coupled with NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), and the resulting conjugate was labeled with (64)Cu to yield (64)Cu-NO2A-RGD-Glu-6-Ahx-BBN(7-14)NH(2). Purification was achieved via reversed-phase high-performance liquid chromatography and characterization confirmed by electrospray ionization-mass spectrometry. RESULTS: Competitive displacement binding assays displayed single digit nanomolar IC(50) values showing very high binding affinities toward the GRPr for the new heterodimeric peptide analogues. In vivo biodistribution studies showed high uptake and retention of tumor-associated radioactivity in PC-3 tumor bearing rodent models with little accumulation and retention in nontarget tissues. The radiolabeled conjugate also exhibited rapid urinary excretion and high tumor-to-background ratios. Micro-positron emission tomography (microPET) molecular imaging investigations produced high-quality, high-contrast images in PC-3 tumor-bearing mice 15 h postinjection. CONCLUSIONS: Based on microPET imaging experiments that show high-quality, high-contrast images with virtually no residual gastrointestinal radioactivity, this new heterodimeric RGD-BBN conjugate can be considered as a promising PET tracer candidate for the diagnosis of GRPr-positive tumors in human patients. PMID- 22226022 TI - Synthesis and preliminary evaluation of [18F]-labeled 2-oxoquinoline derivatives for PET imaging of cannabinoid CB2 receptor. AB - INTRODUCTION: The cannabinoid receptor type 2 (CB(2)) is an important target for development of drugs and imaging agents for diseases, such as neuroinflammation, neurodegeneration and cancer. Recently, we reported synthesis and results of in vitro receptor binding of a focused library of fluorinated 2-oxoquinoline derivatives as CB(2) receptor ligands. Some of the compounds demonstrated to be good CB(2)-specific ligands with Ki values in the nanomolar to subnanomolar concentrations; therefore, we pursued the development of their (18)F-labeled analogues that should be useful for positron emission tomography (PET) imaging of CB(2) receptor expression. Here, we report the radiosynthesis of two (18)F labeled 2-oxoquinoline derivatives and the preliminary in vitro and ex vivo evaluation of one compound as a CB(2)-specific radioligand. METHODS: 4 [(18)F]fluorobenzyl amine [(18)F]-3 was prepared by radiofluorination of 4-cyano N,N,N-trimethylanilinium triflate salt followed by reduction with LiAlH(4) and then coupled with acid chlorides 11 and 12 to afford [(18)F]-13 and [(18)F]-14. In vitro CB(2) receptor binding assay was performed using U87 cells transduced with CB(2) and CB(1) receptor. Ex vivo autoradiography was performed with [(18)F] 14 on spleen and on CB(2)- and CB(1)-expressing and wild-type U87 subcutaneous tumors grown in mice. RESULTS: The radiochemical yields of [(18)F]-13 and [(18)F] 14 were 10%-15.0% with an average of 12% (n=10); radiochemical purity was >99% with specific activity 1200 mCi/MUmol. The dissociation constant Kd for [(18)F] 14 was 3.4 nM. Ex vivo autoradiography showed accumulation of [(18)F]-14 in the CB(2)-expressing tumor. CONCLUSION: Two new [(18)F]-labeled CB(2) ligands have been synthesized. Compound [(18)F]-14 appears to be a potential PET imaging agent for the assessment of CB(2) receptor expression; however, poor solubility restrain its use in vivo. PMID- 22226023 TI - Synthesis and preclinical evaluation of [11C]D617, a metabolite of (R) [11C]verapamil. AB - OBJECTIVES: (R)-[(11)C]verapamil is widely used as a positron emission tomography (PET) tracer to evaluate P-glycoprotein (P-gp) functionality at the blood-brain barrier in man. A disadvantage of (R)-[(11)C]verapamil is the fact that its main metabolite, [(11)C]D617, also enters the brain. For quantitative analysis of (R) [(11)C]verapamil data, it has been assumed that the cerebral kinetics of (R) [(11)C]verapamil and [(11)C]D617 are the same. The aim of the present study was to investigate whether the cerebral kinetics of (R)-[(11)C]verapamil and [(11)C]D617 are indeed similar and, if so, whether [(11)C]D617 itself could serve as an alternative PET tracer for P-gp. METHODS: [(11)C]D617 was synthesized and its ex vivo biodistribution was investigated in male rats at four time points following intravenous administration of [(11)C]D617 (50 MBq) without (n=4) or with (n=4) pretreatment with the P-gp inhibitor tariquidar (15 mg.kg(-1), intraperitoneally). Brain distribution was further assessed using consecutive PET scans (n=8) before and after pretreatment with tariquidar (15 mg.kg(-1), intravenously), as well as metabolite analysis (n=4). RESULTS: The precursor for the radiosynthesis of [(11)C]D617, 5-amino-2-(3,4-dimethoxy-phenyl)-2-isopropyl pentanitrile (desmethyl D617), was synthesized in 41% overall yield. [(11)C]D617 was synthesized in 58%-77% decay-corrected yield with a radiochemical purity of >=99%. The homogeneously distributed cerebral volume of distribution (V(T)) of [(11)C]D617 was 1.1, and this increased 2.4-fold after tariquidar pretreatment. CONCLUSION: V(T) of [(11)C]D617 was comparable to that of (R)-[(11)C]verapamil, but its increase after tariquidar pretreatment was substantially lower. Hence, (R)-[(11)C]verapamil and [(11)C]D617 do not show similar brain kinetics after inhibition of P-gp with tariquidar. PMID- 22226025 TI - Preclinical studies of potential amyloid binding PET/SPECT ligands in Alzheimer's disease. AB - Visualizing the neuropathological hallmarks amyloid plaques and neurofibrillary tangles of Alzheimer's disease in vivo using positron emission tomography (PET) or single photon emission computed tomography will be of great value in diagnosing the individual patient and will also help in our understanding of the disease. The successful introduction of [(11)C]PIB as a PET tracer for the amyloid plaques less than 10 years ago started an intensive research, and numerous new compounds for use in molecular imaging of the amyloid plaques have been developed. The candidates are based on dyes like thioflavin T, Congo red and chrysamine G, but also on other types such as benzoxazoles, curcumin and stilbenes. In the present review, we present methods of the radiochemistry and preclinical evaluation as well as the main properties of some of these compounds. PMID- 22226024 TI - Synthesis, radiolabeling, biodistribution and fluorescent imaging of histidine coupled hematoporphyrin. AB - INTRODUCTION: Hematoporphyrin (Hp) and hematoporphyrin derivatives (HpDs) have been widely used as photosensitizers in photodynamic therapy (PDT). Radiolabeling of HpDs is helpful for preclinical and clinical studies of PDT. METHODS: The histidine-coupled hematoporphyrin (His-Hp) was synthesized and radiolabeled with [(99m)Tc(CO)(3)(H(2)O)(3)](+). Biodistribution of the radioligand and fluorescent imaging of His-Hp in mice bearing S180 tumor were investigated. RESULTS: [(99m)Tc(CO)(3)](+)-labeled His-Hp was electrically neutral, hydrophilic and stable. The biodistribution of the radioligand in S180 tumor-bearing mice was similar with that of nonlabeled HpD in the literature. The uptake of His-Hp in tumors and livers was confirmed by fluorescent imaging. CONCLUSIONS: The complex [(99m)Tc(CO)(3)](+)-His-Hp might be suitable for in vivo dose evaluation of HpD in PDT. PMID- 22226026 TI - An automated module for the separation and purification of cyclotron-produced 99mTcO4-. AB - INTRODUCTION: The shortage of reactor-produced molybdenum-99 ((99)Mo, t(1/2)=66 h) has renewed interest in alternative production methods of its daughter isotope, technetium-99m ((99m)Tc, t(1/2)=6.02 h). While adsorption chromatography serves as a mechanism for selective elution of sodium pertechnetate from technetium generators, this method of purification is not sufficient for many alternative production methods. Several ion-separation/solid phase extraction chromatography methods are known, yet none have been demonstrated on cyclotron produced [(99m)Tc]TcO(4)(-). Herein we describe the design, manufacture and optimization of a remotely operated module for the purification of sodium pertechnetate from a bulk solution of molybdate. METHODS: The automated purification module was designed to separate [(99m)Tc]TcO(4)(-) using either Dowex 1x8 or an Aqueous Biphasic Extraction Chromatography (ABEC) resin. (100)Mo composite targets were irradiated with 18.5 MeV protons for 10 MUA.h using an ASCI TR19 cyclotron. Once purified, the radiopharmaceutical quality of (99m)TcO(4)(-) isolated from each process (Dowex and/or ABEC) was established by assaying for molybdate breakthrough, alumina levels and, in the case of the Dowex approach, residual organics. RESULTS: The separation processes are efficient (75% for Dowex, 90% for ABEC) and complete in less than 30 min. Overall, up to 2.1 GBq of (99m)Tc was produced using the (100)Mo(p,2n)(99m)Tc transformation, processed using the separation module and subjected to a detailed chemical and radionuclidic analysis. Due to its expense and limited availability, (100)MoO(4)(2-) was recovered in >90% yield using a precipitation/filtration/lyophilization approach. CONCLUSIONS: Na[(99m)Tc]TcO(4) was produced using a medical cyclotron, recovered using an automated purification module and found to exceed all established quality control parameters. PMID- 22226028 TI - Evidence-based pharmacotherapy of obsessive-compulsive disorder. AB - Pharmacological strategies for the treatment of obsessive-compulsive disorder (OCD) continue to develop apace but deficiencies remain. We present an updated literature review of the evidence supporting available strategies. We aim to answer key questions including: (1) What are the first-line treatments? (2) Does pharmacotherapy improve health-related quality of life? (3) How do we evaluate clinical response and relapse? (4) How long should treatment continue? (5) Can we predict treatment outcomes? (6) What is the management of treatment-refractory OCD? Selective serotonin reuptake inhibitors (SSRIs) remain the pharmacological treatment of choice for most patients and are associated with improved health related quality of life. However, discontinuation is associated with relapse and loss of quality of life, implying treatment should continue long term. A substantial minority of patients fail to respond to SSRI. Such patients may respond to strategies such as dose elevation or adjunctive antipsychotic, although long-term trials validating the effectiveness and tolerability of these strategies are relatively lacking. Newer compounds targeting other neurotransmitter systems, such as glutamate, are undergoing evaluation. PMID- 22226027 TI - Guidelines for information about therapy experiments: a proposal on best practice for recording experimental data on cancer therapy. AB - BACKGROUND: Biology, biomedicine and healthcare have become data-driven enterprises, where scientists and clinicians need to generate, access, validate, interpret and integrate different kinds of experimental and patient-related data. Thus, recording and reporting of data in a systematic and unambiguous fashion is crucial to allow aggregation and re-use of data. This paper reviews the benefits of existing biomedical data standards and focuses on key elements to record experiments for therapy development. Specifically, we describe the experiments performed in molecular, cellular, animal and clinical models. We also provide an example set of elements for a therapy tested in a phase I clinical trial. FINDINGS: We introduce the Guidelines for Information About Therapy Experiments (GIATE), a minimum information checklist creating a consistent framework to transparently report the purpose, methods and results of the therapeutic experiments. A discussion on the scope, design and structure of the guidelines is presented, together with a description of the intended audience. We also present complementary resources such as a classification scheme, and two alternative ways of creating GIATE information: an electronic lab notebook and a simple spreadsheet-based format. Finally, we use GIATE to record the details of the phase I clinical trial of CHT-25 for patients with refractory lymphomas. The benefits of using GIATE for this experiment are discussed. CONCLUSIONS: While data standards are being developed to facilitate data sharing and integration in various aspects of experimental medicine, such as genomics and clinical data, no previous work focused on therapy development. We propose a checklist for therapy experiments and demonstrate its use in the 131Iodine labeled CHT-25 chimeric antibody cancer therapy. As future work, we will expand the set of GIATE tools to continue to encourage its use by cancer researchers, and we will engineer an ontology to annotate GIATE elements and facilitate unambiguous interpretation and data integration. PMID- 22226029 TI - Potentially modifiable pre-, peri-, and postdeployment characteristics associated with deployment-related posttraumatic stress disorder among ohio army national guard soldiers. AB - PURPOSE: To evaluate potentially modifiable deployment characteristics-- predeployment preparedness, unit support during deployment, and postdeployment support-that may be associated with deployment-related posttraumatic stress disorder (PTSD). METHODS: We recruited a sample of 2616 Ohio Army National Guard (OHARNG) soldiers and conducted structured interviews to assess traumatic event exposure and PTSD related to the soldiers' most recent deployment, consistent with DSM-IV criteria. We assessed preparedness, unit support, and postdeployment support by using multimeasure scales adapted from the Deployment Risk and Resilience Survey. RESULTS: The prevalence of deployment-related PTSD was 9.6%. In adjusted logistic models, high levels of all three deployment characteristics (compared with low) were independently associated with lower odds of PTSD. When we evaluated the influence of combinations of deployment characteristics on the development of PTSD, we found that postdeployment support was an essential factor in the prevention of PTSD. CONCLUSIONS: Results show that factors throughout the life course of deployment-in particular, postdeployment support-may influence the development of PTSD. These results suggest that the development of suitable postdeployment support opportunities may be centrally important in mitigating the psychological consequences of war. PMID- 22226030 TI - Estimated effects of potential interventions to prevent decreases in self-rated health among breast cancer survivors. AB - PURPOSE: To estimate the effect of hypothetical changes in modifiable predictors on the incidence of fair-to-poor self-rated health (SRH) in breast cancer survivors. METHODS: In 2007-2008, we interviewed 832 breast cancer survivors 1 year after diagnosis (baseline) and 1 year later. First, multivariable logistic regression models estimated the association between the predictors (sociodemographic factors, access to medical care, comorbid conditions, psychosocial factors, perceived neighborhood conditions, cancer-related behaviors, clinical factors) and SRH. Second, we estimated the probabilities of fair-to-poor SRH for values of the predictors for each breast cancer survivor. Third, we estimated the population-wide effect of potential changes in modifiable predictors on the incidence of fair-to-poor SRH. RESULTS: A total of 7.6% of participants (92.4% white; mean age, 58.0 years) whose SRH was rated good-to excellent at baseline reported fair-to-poor SRH 1 year later. The largest potential reduction in incidence of fair-to-poor SRH could be obtained by eliminating surgical side effects (27.8% reduction) and comorbidity (21.8% reduction) and by engaging in any physical activity (19.6% reduction). CONCLUSIONS: A significant portion of the decline in SRH can be avoided by reducing surgical side effects, preventing comorbidity, and improving physical activity with the use of evidence-based strategies. PMID- 22226031 TI - Socioeconomic inequalities in the morbidity and mortality of acute coronary events in Finland: 1988 to 2002. AB - PURPOSE: To examine the changes in socioeconomic disparities in the incidence of coronary heart disease (CHD) and mortality in Finland and to analyze the effects of the severe economic recession of the early 1990s on these disparities. METHODS: The population-based FINAMI Myocardial Infarction (MI) register recorded all suspected MI events among men and women ages 35 to 99 years in four geographical areas of Finland. Record linkage with the files of Statistics Finland provided us with detailed information on the indicators of socioeconomic status (SES; income, education, and profession). Rates were expressed per 100,000 inhabitants of each socioeconomic group per year and age-standardized to the European standard population. Poisson regression was used for analyzing rate ratios and time trends of coronary events in different socioeconomic groups. RESULTS: The mortality rate ratio of coronary events among 35- to 64 year-old men was 5.21 (95% confidence interval, 4.23-6.41) when the lowest income sixth to the highest income sixth were compared. Among women, the respective rate ratio was 11.13 (5.77-21.45). Significant differences in the incidence and 28-day mortality by SES were seen also in the older age groups. Some socioeconomic differences were found in the proportions of patients receiving thrombolysis or undergoing early revascularization. No substantial changes were observed in inequalities between the socioeconomic groups during the study period. CONCLUSIONS: The excess CHD morbidity and mortality among persons with lower SES is still considerable in Finland, but the economic recession did not widen the differences. PMID- 22226032 TI - Use of leg length to height ratio to assess the risk of childhood overweight and obesity: results from a longitudinal cohort study. AB - PURPOSE: To determine whether leg-length to height ratio (LLHR) measured in children can be used to assess overweight and obese status 3 years later. METHODS: A total of 1166 children from South Ontario, Canada, were assessed in grade five and again in grade eight were included in this analysis. On the basis of LLHR gender-specific quartile cutoffs in grade five, children were categorized into four groups (Q1[low]-Q4). Gender and age specific cutoffs of body mass index were used to categorize children as overweight/obese or normal weight in grade eight. Multiple logistic regression models were used to examine the overweight/obesity risk association with LLHR. RESULTS: In comparing those in Q1 of LLHR, we found the odds ratios (OR, 95% confidence interval) of overweight/obese for those in the Q2-Q4 were 0.60 (0.29-1.21), 0.43 (0.21-0.89), and 0.32 (0.15-0.70) for boys and 0.77 (0.36-1.64), 0.60 (0.28-1.29), and 0.27 (0.12-0.62) for girls, respectively. The overweight/obesity risk association with LLHR remains after removing those who were considered overweight/obese at grade five. CONCLUSIONS: LLHR is associated with risk of childhood overweight/obesity. Further studies are warranted to investigate the role of LLHR on development of obesity. PMID- 22226034 TI - Trait-dependent diversification and the impact of palaeontological data on evolutionary hypothesis testing in New World ratsnakes (tribe Lampropeltini). AB - For studies investigating trait evolution, there are at least two important questions. First, have traits under consideration influenced cladogenesis and extinction in the group? Second, how do fossil data alter inferences about trait evolution or diversification-rate dynamics? However, relatively few studies have assessed these questions. Here, we use recently developed methods to test for trait-dependent diversification in the New World colubrid snake tribe Lampropeltini. We also integrate data from fossil taxa into phylogenetic estimation of evolutionary parameters using a simple Monte Carlo randomization test. These analyses suggest that ecological conditions in temperate regions are tied to higher rates of cladogenesis, but that body size is not related to diversification in the group. We also find that the inclusion of fossil taxa alters absolute estimates of size and the rate of size evolution, but not the overall pattern of ecomorphological diversification, as well as estimates of evolutionary rates, particularly extinction. PMID- 22226033 TI - Estimating the health effects of exposure to multi-pollutant mixture. AB - PURPOSE: Air pollution constitutes a major public health concern because of its ubiquity and of its potential health impact. Because individuals are exposed to many air pollutants at once that are highly correlated with each other, there is a need to consider the multi-pollutant exposure phenomenon. The characteristics of multiple pollutants that make statistical analysis of health-related effects of air pollution complex include the high correlation between pollutants prevents the use of standard statistical methods, the potential existence of interaction between pollutants, the common measurement errors, the importance of the number of pollutants to consider, and the potential nonlinear relationship between exposure and health. METHODS: We made a review of statistical methods either used in the literature to study the effect of multiple pollutants or identified as potentially applicable to this problem. We reported the results of investigations that applied such methods. RESULTS: Eighteen publications have investigated the multi-pollutant effects, 5 on indoor pollution, 10 on outdoor pollution, and 3 on statistical methodology with application on outdoor pollution. Some other publications have only addressed statistical methodology. CONCLUSIONS: The use of Hierarchical Bayesian approach, dimension reduction methods, clustering, recursive partitioning, and logic regression are some potential methods described. Methods that provide figures for risk assessments should be put forward in public health decisions. PMID- 22226035 TI - Diterpenoids from Euphorbia neriifolia. AB - Nine diterpenoids were isolated from the stems of Euphorbia neriifolia Linn. with their structures established by 1D and 2D NMR techniques. Relative stereochemistries were determined by ROESY, and single-crystal X-ray experiments. PMID- 22226036 TI - A single amino acid determines the site of deprotonation in the active center of sesquiterpene synthases SbTPS1 and SbTPS2 from Sorghum bicolor. AB - The multitude of terpene carbon skeletons found in nature is formed by enzymes known as terpene synthases (TPSs). These proteins are often multiproduct enzymes converting a single prenyl diphosphate substrate into a mixture of terpene products. The recently identified sesquiterpene synthases SbTPS1 and SbTPS2 from Sorghum bicolor produce terpene blends containing the same products, but in different proportions. A single amino acid in the active site was reported to determine the different product specificities of SbTPS1 and SbTPS2. In this study we examined the reaction mechanism of the Sorghum TPSs. Feeding experiments with deuterium-labeled substrates and chiral analysis of the enzyme products zingiberene, beta-sesquiphellandrene and beta-bisabolene revealed that the reactions catalyzed by both enzymes proceeded via (S)-nerolidyl diphosphate and the cyclic (6S)-bisabol-7-yl and (6R)-bisabol-1-yl cation intermediates. The site of deprotonation of the final cation was shown to be the only catalytic difference between SbTPS1 and SbTPS2. Docking of the (6R)-bisabol-1-yl cation into structural models of SbTPS1 and SbTPS2 indicated a potential role of initially cleaved pyrophosphate group as a proton acceptor. PMID- 22226037 TI - Metabolic and gene expression changes triggered by nitrogen deprivation in the photoautotrophically grown microalgae Chlamydomonas reinhardtii and Coccomyxa sp. C-169. AB - Microalgae are emerging as suitable feedstocks for renewable biofuel production. Characterizing the metabolic pathways involved in the biosynthesis of energy-rich compounds, such as lipids and carbohydrates, and the environmental factors influencing their accumulation is necessary to realize the full potential of these organisms as energy resources. The model green alga Chlamydomonas reinhardtii accumulates significant amounts of triacylglycerols (TAGs) under nitrogen starvation or salt stress in medium containing acetate. However, since cultivation of microalgae for biofuel production may need to rely on sunlight as the main source of energy for biomass synthesis, metabolic and gene expression changes occurring in Chlamydomonas and Coccomyxa subjected to nitrogen deprivation were examined under strictly photoautotrophic conditions. Interestingly, nutrient depletion triggered a similar pattern of early synthesis of starch followed by substantial TAG accumulation in both of these fairly divergent green microalgae. A marked decrease in chlorophyll and protein contents was also observed, including reduction in ribosomal polypeptides and some key enzymes for CO2 assimilation like ribulose-1,5-bisphosphate carboxylase/oxygenase. These results suggest that turnover of nitrogen-rich compounds such as proteins may provide carbon/energy for TAG biosynthesis in the nutrient deprived cells. In Chlamydomonas, several genes coding for diacylglycerol:acyl-CoA acyltransferases, catalyzing the acylation of diacylglycerol to TAG, displayed increased transcript abundance under nitrogen depletion but, counterintuitively, genes encoding enzymes for de novo fatty acid synthesis, such as 3-ketoacyl-ACP synthase I, were down-regulated. Understanding the interdependence of these anabolic and catabolic processes and their regulation may allow the engineering of algal strains with improved capacity to convert their biomass into useful biofuel precursors. PMID- 22226038 TI - Oxygenated compounds from the bioconversion of isostevic acid and their inhibition of TNF-alpha and COX-2 expressions in LPS-stimulated RAW 264.7 cells. AB - Fourteen oxygenated compounds were isolated from the preparative-scale biotransformation of isostevic acid (ent-beyeran-19-oic acid). Incubation of it with Aspergillus niger BCRC 32720 produced eight metabolites, four with Bacillus megaterium ATCC 14581, and another four with Mortierella isabellina ATCC 38063. In addition to their structural elucidation by NMR spectroscopy and HRMS, structures of four of these were further confirmed by X-ray diffraction studies. Real-time reverse transcription PCR analysis found that 15 of these compounds displayed significant in vitro anti-inflammatory activity in lipopolysaccharide stimulated RAW 264.7 macrophages by reducing the levels of both TNF-alpha and COX 2 mRNA relative to control cells stimulated by LPS alone. The activity of one metabolite was similar to that of dexamethasone in inhibiting the expression of TNF-alpha mRNA, while all test compounds except two of them were more potent than dexamethasone in inhibiting the expression of the COX-2 mRNA. PMID- 22226039 TI - Racial disparities in pediatric access to kidney transplantation: does socioeconomic status play a role? AB - Racial disparities persist in access to renal transplantation in the United States, but the degree to which patient and neighborhood socioeconomic status (SES) impacts racial disparities in deceased donor renal transplantation access has not been examined in the pediatric and adolescent end-stage renal disease (ESRD) population. We examined the interplay of race and SES in a population based cohort of all incident pediatric ESRD patients <21 years from the United States Renal Data System from 2000 to 2008, followed through September 2009. Of 8452 patients included, 30.8% were black, 27.6% white-Hispanic, 44.3% female and 28.0% lived in poor neighborhoods. A total of 63.4% of the study population was placed on the waiting list and 32.5% received a deceased donor transplant. Racial disparities persisted in transplant even after adjustment for SES, where minorities were less likely to receive a transplant compared to whites, and this disparity was more pronounced among patients 18-20 years. Disparities in access to the waiting list were mitigated in Hispanic patients with private health insurance. Our study suggests that racial disparities in transplant access worsen as pediatric patients transition into young adulthood, and that SES does not explain all of the racial differences in access to kidney transplantation. PMID- 22226040 TI - Development of chromatographic methods for the determination of genotoxic impurities in cloperastine fendizoate. AB - The classification of an impurity of a drug substance as genotoxic means that the "threshold of toxicological concern" (TTC) value of 1.5 MUg/day intake, considered to be associated with an acceptable risk, should be the admissible limit in the raw material and that leads to new analytical challenges. In this study, reliable chromatographic methods were developed and applied as limit tests for the control of three genotoxic impurities (GTIs) in cloperastine fendizoate, drug widely used as an antitussive active pharmaceutical ingredient (API). In particular, GC-MS was applied to the determination of one alkyl halide (2 chloroethanol, 2-CE), while HPLC-DAD was selected for the analysis of two sulfonate esters (methyl p-toluenesulfonate, MPTS, and 2-chloroethyl p toluenesulfonate, CEPTS). Regarding GC-MS, strong anion-exchange (SAX)-SPE was applied to remove fendizoate from the sample solutions, due its low volatility and its high amount in the raw material. The GC-MS analysis was performed on a Factor Four VF-23 ms capillary column (30 m * 0.25 mm I.D., film thickness 0.25 MUm, Varian). Single ion-monitoring (SIM) detection mode was set at m/z 80. In the case of HPLC-DAD, a suitable optimization of the chromatographic conditions was carried out in order to obtain a good separation of the impurity peaks from the drug substance peaks. The optimized method utilizes a SymmetryShield RP(8) column (250 mm * 4.6 mm, 5 MUm, Waters) kept at 50 degrees C, with phosphate buffer (pH 3.0; 10 mM)-methanol (containing 10% ACN) (45:55, v/v) as the mobile phase, at the flow-rate of 1.7 mL/min and UV detection at 227 nm. The required sensitivity level was achieved by injecting 80 MUL of sample solution, purified from fendizoate by SAX-SPE, followed by a 1:1 (v/v) dilution of the SPE eluate with water. For both GC-MS and HPLC-DAD, the method validation was performed in relation to specificity and limit of detection (LOD), as required by ICH guidelines in relation to limit assays. The developed methods were successfully applied for the determination of GTIs in five different batches of cloperastine fendizoate. In all the analyzed batches, the three target GTIs were below the concentration limit. PMID- 22226041 TI - Development of an UPLC-MS/MS method for the determination of antibiotic ertapenem on dried blood spots. AB - Ertapenem (Invanz) is a newly developed carbapenem beta-lactam antimicrobial agent. The drug usage in pediatric age needs an accurate drug monitoring for effective patient management. The aim of this study was to evaluate the use of dried blood spot (DBS) specimens to measure ertapenem concentration during treatment. The analysis was performed by UPLC-MS/MS operating in multiple reaction monitoring (MRM) mode. The calibration curve in matrix was linear in the concentration range of 0.5-100 mg/L with correlation coefficient value higher than 0.997. Performance parameters of this method like lower limit of detection (LLOD, 0.2 mg/L), lower limit of quantification (LLOQ, 0.5 mg/L), matrix effect (20%), intra- and inter-day imprecision (CV within than 15%) and accuracy (between 94 and 155%) of drug concentrations have been evaluated. The drug stability at different temperatures was tested for one month, to evaluate the risks of sample delivery at different climatic conditions. The reported method allows now ertapenem analysis and offers many advantages for patients including the possibility of collecting samples at home. This new assay is both precise and accurate and is especially suitable for therapeutic drug monitoring and pharmacokinetic studies in neonates in whom obtaining larger blood samples is not convenient or possible. PMID- 22226042 TI - Mechanistic study on degradation of azelnidipine solution under radical initiator based oxidative conditions. AB - We identified four degradants (Dg-A, Dg-B, Dg-C, Dg-D) of azelnidipine to be generated under radical initiator-based oxidative conditions and proposed the mechanistic pathway for their formation. 2,2'-Azobisisobutyronitrile was used as a radical initiator. There appeared to be two major pathways in the oxidation of the 1,4-dihydropyridine moiety. One was initiated by hydrogen abstraction from the C-4 position of the dihydropyridine ring, followed by hydrogen abstraction from the N-1 position, leading to aromatization of the dihydropyridine ring and Dg-A generation. The other was initiated by hydrogen abstraction from the N-1 position of the dihydropyridine ring followed by oxidation and hydrolysis to yield Dg-B. Furthermore, Dg-B was subjected to hydrolysis to generate Dg-C and Dg D. It has been revealed that the rate of the Dg-B degradation was predominantly governed by the water content of the solvent used. Water participation in Dg-B degradation was proved by monitoring the incorporation of heavy oxygen atom ((18)O) into the structure with LC-MS, in which the experiment was carried out in a medium prepared with heavy oxygen water to label (18)O during the hydrolysis. PMID- 22226043 TI - Estrogen receptor alpha deletion enhances the metastatic phenotype of Ron overexpressing mammary tumors in mice. AB - BACKGROUND: The receptor tyrosine kinase family includes many transmembrane proteins with diverse physiological and pathophysiological functions. The involvement of tyrosine kinase signaling in promoting a more aggressive tumor phenotype within the context of chemotherapeutic evasion is gaining recognition. The Ron receptor is a tyrosine kinase receptor that has been implicated in the progression of breast cancer and evasion of tamoxifen therapy. RESULTS: Here, we report that Ron expression is correlated with in situ, estrogen receptor alpha (ERalpha)-positive tumors, and is higher in breast tumors following neoadjuvant tamoxifen therapy. We also demonstrate that the majority of mammary tumors isolated from transgenic mice with mammary specific-Ron overexpression (MMTV-Ron mice), exhibit appreciable ER expression. Moreover, genetic-ablation of ERalpha, in the context of Ron overexpression, leads to delayed mammary tumor initiation and growth, but also results in an increased metastasis. CONCLUSIONS: Ron receptor overexpression is associated with ERalpha-positive human and murine breast tumors. In addition, loss of ERalpha on a Ron overexpressing background in mice leads to the development of breast tumors which grow slower but which exhibit more metastasis and suggests that targeting of ERalpha, as in the case of tamoxifen therapy, may reduce the growth of Ron overexpressing breast cancers but may cause these tumors to be more metastatic. PMID- 22226044 TI - Real-time recognition of patient intentions from sequences of pressure maps using artificial neural networks. AB - OBJECTIVE: In this paper we address the problem of recognising the movement intentions of patients restricted to a medical bed. The developed recognition system will be used to implement a natural human-machine interface to move a medical bed by means of the slight movements of patients with reduced mobility. METHODS AND MATERIAL: Our proposal uses pressure map sequences as input and presents a novel system based on artificial neural networks to recognise the movement intentions. The system analyses each pressure map in real-time and classifies the raw information into output classes which represent these intentions. The complexity of the recognition problem is high because of the multiple body characteristics and distinct ways of communicating intentions. To address this problem, a complete processing chain was developed consisting of image processing algorithms, a knowledge extraction process, and a multilayer perceptron (MLP) classification model. RESULTS: Different configurations of the MLP have been investigated and quantitatively compared. The accuracy of our approach is high, obtaining an accuracy of 87%. The model was compared with five well-known classification paradigms. The performance of a reduced model, obtained by through feature selection algorithms, was found to be better and less time consuming than the original model. The whole proposal has been validated with real patients in pre-clinical tests using the final medical bed prototype. CONCLUSIONS: The proposed approach produced very promising results, outperforming existing classification approaches. The excellent behaviour of the recognition system will enable its use in controlling the movements of the bed, in several degrees of freedom, by the patient with his/her own body. PMID- 22226045 TI - Group B streptococcal disease in infants. PMID- 22226046 TI - Herpes simplex virus: a new era? PMID- 22226047 TI - Group B streptococcal disease in infants aged younger than 3 months: systematic review and meta-analysis. AB - BACKGROUND: Despite widespread use of intrapartum antibiotic prophylaxis, group B streptococcus remains a leading cause of morbidity and mortality in infants in Europe, the Americas, and Australia. However, estimates of disease burden in many countries outside of these regions is not available. We aimed to examine the current global burden of invasive disease and the serotype distribution of group B streptococcus isolates. METHODS: We searched Medline, Embase, and Wholis databases for studies on invasive early-onset (day 0-6) and late-onset (day 7-89) group B streptococcal disease. Eligible studies were those that described incidence, deaths, or serotypes. We also reviewed reference lists and contacted experts to seek unpublished data and data missed by our search. Random effects meta-analysis was used to pool data. FINDINGS: 74 studies met the inclusion criteria; 56 studies reported incidence, 29 case fatality, and 19 serotype distribution. An additional search for studies that reported serotype distribution from Jan 1, 1980, yielded a total of 38 articles. Only five low income countries were represented in the review and contributed 5% weight to the meta-analysis. 47 (69%) studies reported use of any intrapartum antibiotic prophylaxis. Substantial heterogeneity existed between studies. Mean incidence of group B streptococcus in infants aged 0-89 days was 0.53 per 1000 livebirths (95% CI 0.44-0.62) and the mean case fatality ratio was 9.6% (95% CI 7.5-11.8). Incidence of early-onset group B streptococcus (0.43 per 1000 livebirths [95% CI 0.37-0.49]) and case fatality (12.1%, [6.2-18.3]) were two-times higher than late onset disease. Serotype III (48.9%) was the most frequently identified serotype in all regions with available data followed by serotypes Ia (22.9%), Ib (7.0%), II (6.2%), and V (9.1%). Studies that reported use of any intrapartum antibiotic prophylaxis were associated with lower incidence of early-onset group B streptococcus (0.23 per 1000 livebirths [95% CI 0.13-0.59]) than studies in which patients did not use prophylaxis (0.75 per 1000 livebirths [0.58-0.89]). INTERPRETATION: More high-quality studies are needed to accurately estimate the global burden of group B streptococcus, especially in low-income countries. A conjugate vaccine incorporating five serotypes (Ia, Ib, II, III, V) could prevent most global group B streptococcal disease. FUNDING: Child Epidemiology Reference Group (CHERG), WHO. PMID- 22226048 TI - Developing a drug library for smart pumps in a pediatric intensive care unit. AB - BACKGROUND: The most serious medication errors occur during intravenous administration. The potential consequences are more serious the more critical and younger the patient. Smart pumps can help to prevent infusion-related programming errors, thanks to associated dose-limiting software known as "drug library". Drug libraries alert the user if pre-determined high dosage limits are exceeded or if entry is below pre-determined low dosage limits. OBJECTIVE: To describe the process for developing a specific drug library for a pediatric intensive care unit (PICU) and the key factors for preventing programming errors. METHODS AND MATERIALS: The study was performed by a multidisciplinary team consisting of a clinical pharmacist, a PICU pediatrician, and the chief nurse of the unit. The process of developing the drug library lasted seven months. A literature review was carried out to determine standard concentrations and accurate limits for intravenous administration of high-risk drugs. Alaris((r)) syringe pumps and Guardrails((r)) CQI v4.1 Event Reporter software were used. RESULTS: Several manufacturers offer smart pump technology. Users should be aware of differences in features, such as definition of parameters and associations between them, definition of safety limits, organization of the drug library, and data use. Our infusion pump technology covered 108 drugs. Compliance with the drug library was 85% and nurses' acceptance of the drug library was high as 94% would recommend implementation of this technology in other units. After nine months of implementation, several potentially harmful infusion-related programming errors were intercepted. CONCLUSIONS: Drug libraries are specifically designed for a particular hospital unit, and may condition the success in implementing this technology. Implementation of smart pumps proved effective in intercepting infusion-related programming errors after nine months of implementation in a PICU. PMID- 22226049 TI - Transmembrane domain Nrg1 mutant mice show altered susceptibility to the neurobehavioural actions of repeated THC exposure in adolescence. AB - Heavy cannabis abuse increases the risk of developing schizophrenia. Adolescents appear particularly vulnerable to the development of psychosis-like symptoms after cannabis use. To test whether the schizophrenia candidate gene neuregulin 1 (NRG1) modulates the effects of cannabinoids in adolescence, we tested male adolescent heterozygous transmembrane domain Nrg1 mutant (Nrg1 TM HET) mice and wild type-like littermates (WT) for their neurobehavioural response to repeated Delta(9)-tetrahydrocannabinol (THC, 10 mg/kg i.p. for 21 d starting on post-natal day 31). During treatment and 48 h after treatment withdrawal, we assessed several behavioural parameters relevant to schizophrenia. After behavioural testing we measured autoradiographic CB(1), 5-HT(2A) and NMDA receptor binding. The hyperlocomotor phenotype typical of Nrg1 mutants emerged after drug withdrawal and was more pronounced in vehicle than THC-treated Nrg1 TM HET mice. All mice were equally sensitive to THC-induced suppression of locomotion. However, mutant mice appeared protected against inhibiting effects of repeated THC on investigative social behaviours. Neither THC nor Nrg1 genotype altered prepulse inhibition. Repeated adolescent THC promoted differential effects on CB(1) and 5-HT(2A) receptor binding in the substantia nigra and insular cortex respectively, decreasing binding in WT while increasing it in Nrg1 TM HET mice. THC also selectively affected 5-HT(2A) receptor binding in several other regions in WT mice, whereas NMDA receptor binding was only affected in mutant mice. Overall, Nrg1 mutation does not appear to increase the induction of psychotomimetic symptoms by repeated adolescent THC exposure but may attenuate some of its actions on social behaviour and schizophrenia-relevant neurotransmitter receptor profiles. PMID- 22226050 TI - Transmission of influenza A virus in pigs. AB - Influenza A virus infections cause respiratory disease in pigs and are a risk to public health. The pig plays an important role in influenza ecology because of its ability to support replication of influenza viruses from avian, swine and human species. Influenza A virus is widespread in pigs worldwide, and influenza A virus interspecies transmission has been documented in many events. Influenza A virus is mostly transmitted through direct pig-to-pig contact and aerosols although other indirect routes of transmission may also exist. Several factors contribute to differences in the transmission dynamics within populations including among others vaccination, pig flow, animal movement and animal introduction which highlights the complexity of influenza A transmission in pigs. In addition, pigs can serve as a reservoir of influenza A viruses for other pigs and other species and understanding mechanisms of transmission within pigs and from pigs to other species and vice versa is crucial. In this paper, we review the current understanding of influenza virus transmission in pigs. We highlight the ubiquity of influenza A virus in the pig population and the widespread distribution of pandemic H1N1 virus worldwide while emphasizing an understanding of the routes of transmission and factors that contribute to virus spread and dissemination within and between pig populations. In addition, we describe transmission events between pigs and other species including people. Understanding transmission is crucial for designing effective control strategies and for making well-informed recommendations for surveillance. PMID- 22226051 TI - Decapping of long noncoding RNAs regulates inducible genes. AB - Decapping represents a critical control point in regulating expression of protein coding genes. Here, we demonstrate that decapping also modulates expression of long noncoding RNAs (lncRNAs). Specifically, levels of >100 lncRNAs in yeast are controlled by decapping and are degraded by a pathway that occurs independent of decapping regulators. We find many lncRNAs degraded by DCP2 are expressed proximal to inducible genes. Of these, we show several genes required for galactose utilization are associated with lncRNAs that have expression patterns inversely correlated with their mRNA counterpart. Moreover, decapping of these lncRNAs is critical for rapid and robust induction of GAL gene expression. Failure to destabilize a lncRNA known to exert repressive histone modifications results in perpetuation of a repressive chromatin state that contributes to reduced plasticity of gene activation. We propose that decapping and lncRNA degradation serve a vital role in transcriptional regulation specifically at inducible genes. PMID- 22226052 TI - Investigating uptake of water-dispersible CdSe/ZnS quantum dot nanoparticles by Arabidopsis thaliana plants. AB - Interest on the environmental impacts of engineered nanomaterials has rapidly increased over the past years because it is expected that these materials will eventually be released into the environment. The present work investigates the potential root uptake of water-dispersible CdSe/ZnS quantum dots (QDs) by the model plant species, Arabidopsis thaliana. Experiments revealed that Arabidopsis exposed to QDs that are dispersed in Hoagland's solution for 1-7 days did not internalize intact QDs. Analysis of Cd and Se concentrations in roots and leaves by inductively-coupled plasma mass spectrometry indicated that Cd and Se from QD treated plants were not translocated into the leaves, and remained in the root system of Arabidopsis. Furthermore, fluorescence microscopy showed strong evidence that the QDs were generally on the outside surfaces of the roots, where the amount of QDs adsorbed is dependent on the stability of the QDs in suspension. Despite no evidence of nanoparticle internalization, the ratio of reduced glutathione levels (GSH) relative to the oxidized glutathione (GSSG) in plants decreased when plants were exposed to QD dispersions containing humic acids, suggesting that QDs caused oxidative stress on the plant at this condition. PMID- 22226053 TI - Liraglutide: short-lived effect on gastric emptying -- long lasting effects on body weight. AB - AIM: Previous studies with the novel once daily glucagon-like peptide-1 (GLP-1) analogue liraglutide and the GLP-1 receptor agonist exenatide have revealed profound insulinotrophic and antidiabetic effects, but also potent effects on gastric emptying (GE) and long-term and lasting reductions in body weight. In this study, we examined the acute and chronic effects of two different GLP-1 analogues with different pharmacokinetic profiles on GE, food intake and body weight. METHODS: On the basis of a series of dose-finding studies, the doses of exenatide and liraglutide with similar acute anorectic effects were identified. GE was assessed using a standard acetaminophen release assay. After the acute test, rats were dosed bi-daily for 14 days in which period food intake and body weight was monitored. On day 14, the GE rate was reassessed. RESULTS: While both compounds exerted robust acute reductions in GE, the effect was markedly diminished following 14 days of dosing with liraglutide. In contrast, exenatide treated rats still displayed a profound reduction in GE at the 14-day time-point. Both compounds exerted similar effects on body weight. CONCLUSION: The data suggest that the 'gastric inhibitory' GLP-1 receptors in rats are subject to desensitization/tachyphylaxis but that this effect is dependent on full 24-h exposure as obtained by liraglutide. The body weight-lowering effects of GLP-1 receptor stimulation are not subject to desensitization. These data indicate that regulation of appetite signals in the brain, and not GE, is the main mechanism for liraglutide-induced weight loss. PMID- 22226054 TI - Hyperinsulinemia enhances c-Myc-mediated mammary tumor development and advances metastatic progression to the lung in a mouse model of type 2 diabetes. AB - INTRODUCTION: Hyperinsulinemia, which is common in early type 2 diabetes (T2D) as a result of the chronically insulin-resistant state, has now been identified as a specific factor which can worsen breast cancer prognosis. In breast cancer, a high rate of mortality persists due to the emergence of pulmonary metastases. METHODS: Using a hyperinsulinemic mouse model (MKR+/+) and the metastatic, c-Myc transformed mammary carcinoma cell line Mvt1, we investigated how high systemic insulin levels would affect the progression of orthotopically inoculated primary mammary tumors to lung metastases. RESULTS: We found that orthotopically injected Mvt1 cells gave rise to larger mammary tumors and to a significantly higher mean number of pulmonary macrometastases in hyperinsulinemic mice over a period of six weeks (hyperinsulinemic, 19.4 +/- 2.7 vs. control, 4.0 +/- 1.3). When Mvt1 mediated mammary tumors were allowed to develop and metastasize for approximately two weeks and were then surgically removed, hyperinsulinemic mice demonstrated a significantly higher number of lung metastases after a four-week period (hyperinsulinemic, 25.1 +/- 4.6 vs. control, 7.4 +/- 0.42). Similarly, when Mvt1 cells were injected intravenously, hyperinsulinemic mice demonstrated a significantly higher metastatic burden in the lung than controls after a three week period (hyperinsulinemic, 6.0 +/- 1.63 vs. control, 1.5 +/- 0.68). Analysis of Mvt1 cells both in vitro and in vivo revealed a significant up-regulation of the transcription factor c-Myc under hyperinsulinemic conditions, suggesting that hyperinsulinemia may promote c-Myc signaling in breast cancer. Furthermore, insulin-lowering therapy using the beta-adrenergic receptor agonist CL-316243 reduced metastatic burden in hyperinsulinemic mice to control levels. CONCLUSIONS: Hyperinsulinemia in a mouse model promotes breast cancer metastasis to the lung. Therapies to reduce insulin levels in hyperinsulinemic patients suffering from breast cancer could lessen the likelihood of metastatic progression. PMID- 22226055 TI - Towards the eradication of hepatitis B in Taiwan. AB - Viral hepatitides are important public health problems in humans. The etiologic agents were not identified until 1965, when Baruch S. Blumberg found the relationship of Australia antigen to serum hepatitis. The antigen was found to be the surface antigen of the hepatitis B virus (HBV). This observation launched a new era in the diagnosis, prevention and treatment of hepatitis B. Over 15-20 years, the natural history of HBV infection was elucidated, and more importantly, an effective vaccine became available. The routes of transmission were also made clear, rendering effective interruption of the transmission possible. The vaccine together with effective interruption of the transmission contributed greatly to the control of HBV infection. However, these measures do very little for those who have already been chronically infected. Fortunately, specific therapies against chronic hepatitis B started to appear about 10-15 years before, and the treatments have improved substantially in the last few years. Although far from perfect, effective means to treat those who are chronically infected now exist. In Taiwan, acute and chronic liver diseases were rampant as early as the beginning of the last century. Studies around 1975, showed an extremely high prevalence of chronic hepatitis B infection in the general population (15-20%), and 80-90% of the chronic liver diseases and hepatocellular carcinoma were caused by chronic infection with the HBV. This important health problem caught the attention of the government in the late 1970s, and a government-sponsored control program was finalized in 1981. Accordingly, a mass vaccination program against hepatitis B, primarily aiming at immunizing newborn infants, was launched on July 1, 1984. Twenty years after implementation of the program, the hepatitis B carrier rate in children covered by the program decreased by 85%, from ~ 15% to <1%. Most importantly, the deadly sequela of hepatocellular carcinoma in the vaccinees was also found to decrease in parallel. This is the first time that a human cancer was prevented by vaccination. Despite the success, there are still some who were born after implementation of the program but were not prevented from developing chronic hepatitis B infection and hepatocellular carcinoma. Non compliance to the vaccination schedule, breakthrough infection and intrauterine infection are the causes of the failure. At present, we have effective measures for immunizing susceptible individuals, interrupting the routes of transmission and treating the chronically infected. The time for considering the elimination or even the eradication of HBV infection has come. This is especially true for countries where hepatitis B infection is not endemic. Nevertheless, with the admirable results achieved in the past, Taiwan should also think about elimination/eradication of hepatitis B, even though it will certainly be much more difficult than in the non-endemic countries. In exploring the possibility of eliminating/eradicating hepatitis B in Taiwan, we reviewed the epidemiology of hepatitis B, and analyzed the problems that remain to be tackled in Taiwan. We hope that Taiwan can take further steps towards the elimination or eradication of hepatitis B. PMID- 22226056 TI - Effects of different biomaterials: comparing the bladder smooth muscle cells on waterborne polyurethane or poly-lactic-co-glycolic acid membranes. AB - Tissue engineering materials have often been used to repair bladder damage caused by conditions, such as infection, resection, inflammation, and trauma. However, the concept of generating a functional urinary bladder using autologous cells obtained from a biopsy specimen combined with a biomaterial scaffold remains a challenge. Previously, we presented a new method for synthesizing a biocompatible, mechanically sound, nontoxic, and cross-linked waterborne polyurethane (WBPU) as a potential material for bladder regeneration. Here, we further evaluated the response of bladder smooth muscle cells (BSMCs) seeded on WBPU membranes in comparison with the gold standard biomaterial, poly-lactic-co glycolic acid. Specifically, we observed the BSMC attachment, proliferation, and alpha-actin distribution at 1 day, 3 days, and 5 days after membrane seeding. We found that significantly more cells attached and proliferated on the WBPU membranes after 3 days and 5 days of culture, and the cells exhibited greater organization and a wider distribution of alpha-actin compared with BSMCs cultured on poly-lactic-co-glycolic acid membranes. These preliminary data offer promise for the use of WBPU biomaterials in bladder tissue engineering. PMID- 22226057 TI - The presence of oxidized low-density lipoprotein and inducible nitric oxide synthase expression in renal damage after intestinal ischemia reperfusion. AB - Intestinal ischemia/reperfusion (I/R) is a complex phenomenon that causes destruction of both local and remote tissues. The objective of this study was to investigate the possible participation of oxidized low-density lipoproteins (oxLDLs) and inducible nitric oxide synthase (iNOS) expression in renal tissue damage after intestinal I/R. The superior mesenteric artery was blocked for 30 minutes, followed by 24 hours of reperfusion. At the end of the reperfusion period, renal tissues were removed; the presence of oxLDL, superoxide dismutase enzyme activity, malondialdehyde levels, and iNOS expression were evaluated. I/R resulted in positive oxLDL staining in renal tissue. Compared with control rats, tissue from the I/R group showed significantly higher malondialdehyde levels and lower superoxide dismutase enzyme activity. Strong and diffuse iNOS expression was present in the I/R group. Our findings support the hypothesis that I/R of intestinal tissue results in oxidative and nitrosative stress and enhances lipid peroxidation in the end organ. These data show that oxLDL accumulates in rat renal tissue after intestinal I/R. Antioxidant strategies may provide organ protection in patients with reperfusion injury, at least by affecting interactions with free radicals, nitric oxide, and oxLDL. This study demonstrates for the first time that oxLDL may play a role in renal tissue damage after intestinal I/R. Antioxidant strategies may be beneficial for protection from reperfusion injury. PMID- 22226058 TI - Clinical relevance of the risk factors for coronary artery lesions in Kawasaki disease. AB - We aimed to investigate which factors are associated with coronary artery lesions (CALs) during the acute and chronic stages in Taiwanese children with Kawasaki disease (KD). A total of 216 children with KD were enrolled. Clinical and laboratory data were obtained for each child within 7 days of illness. The patients were classified into KD children without acute CALs (n=135) and those with acute CALs (n=81) according to echocardiography data at Week 2 after treatment. Then, KD children with acute CALs were further divided into those without chronic CALs (n=55) and with chronic CALs (n=26) according to annual echocardiography data. During acute stage of KD, neutrophil count (<54%) [odds ratio (OR)=0.44, p=0.041]; second dose of intravenous immunoglobulin (IVIG) treatment (OR=5.01, p=0.009); and platelet count (<=400,000) (OR=0.42, p=0.006) were correlated with the risk of acute CALs. During chronic stage of KD, age (12 60 months) (OR=0.25, p=0.042); first dose of IVIG treatment (OR=0.12, p=0.005); and band count (>=3%) (OR=3.51, p=0.032) were correlated with the risk of chronic CALs. Our results suggest that the effects of neutrophil count, doses of IVIG treatment, and platelet count on CALs in acute KD are important. Age, doses of IVIG treatment, and band count are related to the persistence of CALs in chronic stage of KD. PMID- 22226059 TI - Cementless large-head metal-on-metal total hip arthroplasty in patients younger than 60 years--a multicenter early result. AB - Large-head metal-on-metal total hip arthroplasty has the theoretical advantages of less wear and better range of motion than traditional polyethylene bearings and seems to be a better choice for young and active patients. We conducted a retrospective study and reported the early results of using such prostheses in 59 patients (70 hips) with a mean age of 43.1 years (range, 23-59 years) at the time of surgery. Osteonecrosis of the femoral head accounted for most diagnoses. Harris Hip Scores and hip range of motion both significantly improved (p<0.001) at an average follow-up of 32.6 months (range, 24-48 months). Only one intraoperative calcar fissure was encountered, and it was fixated by cerclage wiring; there was no infection, dislocation, or osteolysis around either the cup or the stem at the latest follow-up. A postoperative gap in the acetabular component was noted in 24 hips, with a mean depth of 1.11 mm, but this was not correlated with the functional score (p=0.291). Transient thigh pain, which resolved after 6 months, was observed in six patients but was not related to either the postoperative gap or cup inclination (p=1.000 and p=0.664, respectively). All patients resumed their original jobs and recreational activities with little discomfort. Thus far, large-head metal-on-metal total hip arthroplasty has shown excellent early results. The long-term results and the effects of metal debris and potentially elevated serum metal ion levels require further observation. PMID- 22226061 TI - Development of the child abuse and neglect reporting self-efficacy questionnaire for nurses. AB - Taiwan nurses are mandated to report known or suspected child abuse and neglect (CAN), and self-efficacy is known to have an important influence on professional behaviors. The aim of this study was to develop and test the CAN reporting self efficacy (CANRSE) scale as a measure of nurses' self-efficacy to report CAN. A sample of 496 nurses from Southern Taiwanese hospitals used the CANRSE scale. The psychometric evaluation of the scale included content validity, exploratory and confirmatory factor analyses, convergent validity, as well as Cronbach's alpha and test-retest reliability. Satisfactory internal consistency (Cronbach's alpha = 0.92) and test-retest reliability were demonstrated. Confirmatory factor analysis supported the proposed models as having acceptable model fit. Exploratory factor analysis and regression analyses showed that the CANRSE scale had good construct validity and criterion-related validity, respectively. Convergent validity was tested using the general self-efficacy scale and was found to be satisfactory (r = 0.53). The results indicate the CANRSE is reliable and valid, and further testing of its predictive validity is recommended. It can be used to examine the influence of professional self-efficacy in recognizing and reporting CAN cases and to evaluate the impact of training programs aimed at improving CAN reporting. PMID- 22226060 TI - Development of a home-based telehealthcare model for improving the effectiveness of the chronic care of stroke patients. AB - This study describes the development of an information technology (IT)-mediated home-based healthcare model designed to improve the effectiveness of caring for stroke patients who require chronic, home care. This model was evaluated at Kaohsiung Medical Hospital in Taiwan between 2005 and 2008; 84 newly diagnosed stroke patients diagnosed as the chronic covalence stage were enrolled for preliminary testing of this model. These patients required 24-hour in-home monitoring of their health status and emergency call service. Over the course of the study, 15 emergency transfers were carried out, and the acute stroke patients were sent to the emergency care within 26 minutes, on average. This system helped physicians, patients, and their families to more efficiently detect the occurrence of recurrent stroke. In addition, we found a statistically significant finding (p < 0.001) that daily blood pressure (BP) monitoring increased from 45.5% in the initial month of the study to 76% after 3-10 months of intervention. Meanwhile, the proportion of patients with an abnormal BP rate decreased from 20.5% in the initial month of the study to 10.9% after 3-10 months of intervention. This suggests that this model helped to improve patient behavior and their ability to care for themselves. This is the first study to develop an IT-mediated, home-based healthcare model in Taiwan. This model integrates both healthcare and clinical services and is capable of enhancing the effectiveness of the care provided to patients with chronic diseases, especially those in situations where self-care is essential for disease management. PMID- 22226062 TI - Polyarthritis as a prewarning sign of occult lung cancer. AB - Cancer polyarthritis is an uncommon, paraneoplastic manifestation of some solid and hematological malignancies. Herein, we report the case of a 55-year-old woman who recently experienced polyarthritis for 2 months. On admission, the patient developed cough, expectoration, and fever. According to the clinical manifestations and the findings in radiological examinations and sputum cultures, pneumonia was considered. No evidence of lung cancer was noted by repeated computed tomography scan of lung, single bronchoscopy, or computed tomography guided lung biopsy. Ultimately, the second bronchoscopy with biopsy was carried out, and lung adenocarcinoma was confirmed by pathological examination. Symptoms of polyarthritis starting 2 months before the symptoms of her lung cancer in the present case leads us to believe that polyarthritis may be a manifestation of paraneoplastic syndrome. Arthritis resolved after anticancer therapy. Our report indicates that polyarthritis of unknown cause may be suspected as a manifestation of malignancies. PMID- 22226063 TI - Basaloid follicular hamartoma: a case report and review of the literature. AB - Basaloid follicular hamartoma (BFH) is a rare, benign, skin adnexal tumor. Several clinical patterns have been reported, but they all share the same histopathological features. BFH may be hereditary or nonhereditary and can be accompanied by systemic diseases. Microscopic examination of BFH shows branching cords and anastomosing strands of basaloid cells in a loose, fibrous stroma. The most important pathological differential diagnosis is infundibulocystic basal cell carcinoma. These two lesions must be differentiated carefully based on clinical presentation and histopathological picture, and even molecular studies may be needed. We present a report of a 78-year-old woman with a solitary, asymptomatic, slow-growing skin tumor on her left scalp. No associated systemic disorders were found. On the basis of an excisional biopsy performed on the tumor, a pathological diagnosis of sporadic BFH was made. PMID- 22226064 TI - Microdebrider-assisted endoscopic excision for congenital laryngeal cysts in infants. PMID- 22226066 TI - [Ablation profiles in refractive surgery. Part 1: in search of excellence]. AB - PURPOSE: To provide an overview of the clinical results of various ablation profiles and discuss their technical characteristics and limitations. MATERIALS AND METHODS: Literature review. RESULTS: With the emergence of wavefront technology, new photoablation profiles have been developed, allowing for customization of refractive treatments and reduction of nocturnal visual symptoms, which adversely affect the reputation of refractive surgery. Over the past decade, several comparative studies have been published in the literature aiming to demonstrate either the superiority of wavefront-guided correction over conventional, or one laser platform over another. However, has an ideal treatment algorithm really emerged from these studies? Does one ablation profile clearly demonstrate superiority over another, in terms of visual performance? CONCLUSION: Despite technological advances as well as improved visual results for custom versus conventional photoablation, the promise of excellence in visual performance has not been achieved with these various technologies. The concept of an individualized eye model has emerged recently, based on an optical ray tracing algorithm, and could theoretically provide an ideal ablation profile, thus fulfilling the promise of "supernormal vision". PMID- 22226067 TI - Expanded role of cytopathology in breast cancer diagnosis, therapy and research: the impact of fine needle aspiration biopsy and imprint cytology. PMID- 22226068 TI - A model of knowledge acquisition in early stage breast cancer patients. AB - To meaningfully participate in the decision-making regarding a newly diagnosed breast cancer, a patient must acquire new knowledge. We describe a model of knowledge acquisition that can provide a framework for exploring the process and types of knowledge that breast cancer patients gain following their diagnosis. The four types of knowledge presented in this model-authoritative, technical, embodied, and traditional-are described and potential sources discussed. An understanding of knowledge acquisition in early stage breast cancer patients can provide healthcare practitioners with an important framework for optimizing decision-making in this population. PMID- 22226069 TI - Screening mammography in men with BRCA mutations: is there a role? AB - Male breast cancer is rare, with an estimated incidence of 1.08 per 100,000 men, and a death rate less than one third of that. However, the incidence of breast cancer in men with the BRCA2 mutation is significantly higher, 7.1% before age 70 (Evans et al., J Med Genet. 2010; 47:710). Due to the low incidence of male breast carcinoma, and even lower incidence of male BRCA2 positive breast cancers, clear screening guidelines for patients at risk for male for breast cancer have not been established. We report a case of male breast carcinoma in a patient with the BRCA2 mutation detected by screening mammography, and review the literature regarding screening mammography in men. PMID- 22226070 TI - Conformational preferences of proline derivatives incorporated into vasopressin analogues: NMR and molecular modelling studies. AB - In this study, arginine vasopressin analogues modified with proline derivatives - indoline-2-carboxylic acid (Ica), (2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2 carboxylic acid (Nmp), (2S,4S)-4-aminopyroglutamic acid (APy) and (2R,4S)-4 aminopyroglutamic acid, (Apy) - were examined using NMR spectroscopy and molecular modelling methods. The results have shown that Ica is involved in the formation of the cis peptide bond. Moreover, it reduces to a great extent the conformational flexibility of the peptide. In turn, incorporation of (2S,4R)-Nmp stabilizes the backbone conformation, which is heavily influenced by the pyrrolidine ring. However, the aromatic part of the Nmp side chain exhibits a high degree of conformational freedom. With analogues IV and V, introduction of the 4-aminopyroglumatic acid reduces locally conformational space of the peptides, but it also results in weaker interactions with the dodecylphosphocholine/sodium dodecyl sulphate micelle. Admittedly, both analogues are adsorbed on the micelle's surface but they do not penetrate into its core. With analogue V, the interactions between the peptide and the micelle seem to be so weak that conformational equilibrium is established between different bound states. PMID- 22226071 TI - De novo identification of viral pathogens from cell culture hologenomes. AB - BACKGROUND: Fast, specific identification and surveillance of pathogens is the cornerstone of any outbreak response system, especially in the case of emerging infectious diseases and viral epidemics. This process is generally tedious and time-consuming thus making it ineffective in traditional settings. The added complexity in these situations is the non-availability of pure isolates of pathogens as they are present as mixed genomes or hologenomes. Next-generation sequencing approaches offer an attractive solution in this scenario as it provides adequate depth of sequencing at fast and affordable costs, apart from making it possible to decipher complex interactions between genomes at a scale that was not possible before. The widespread application of next-generation sequencing in this field has been limited by the non-availability of an efficient computational pipeline to systematically analyze data to delineate pathogen genomes from mixed population of genomes or hologenomes. FINDINGS: We applied next-generation sequencing on a sample containing mixed population of genomes from an epidemic with appropriate processing and enrichment. The data was analyzed using an extensive computational pipeline involving mapping to reference genome sets and de-novo assembly. In depth analysis of the data generated revealed the presence of sequences corresponding to Japanese encephalitis virus. The genome of the virus was also independently de-novo assembled. The presence of the virus was in addition, verified using standard molecular biology techniques. CONCLUSIONS: Our approach can accurately identify causative pathogens from cell culture hologenome samples containing mixed population of genomes and in principle can be applied to patient hologenome samples without any background information. This methodology could be widely applied to identify and isolate pathogen genomes and understand their genomic variability during outbreaks. PMID- 22226072 TI - Profile of anti-Leishmania antibodies related to clinical picture in canine visceral leishmaniasis. AB - This research investigated the profile of anti-Leishmania antibodies in different clinical forms of canine visceral leishmaniasis (CVL). Naturally infected dogs were divided into two groups: subclinical dogs (SD, n=10) and clinical dogs (CD, n=68). Non-infected dogs (ND, n=7) comprised the negative control group. The humoral response was evaluated by the profile of total IgG, IgG1, IgG2, IgM, IgA and IgE, determined by ELISA. Infected animals showed increased levels of total IgG, IgA and IgE in addition to IgG1 and IgG2 in groups SD and CD, when compared with group ND. Furthermore, it was observed that IgG2 and IgM were correlated with symptomatology, while total IgG, IgG1 and IgA were negatively correlated and IgE showed no correlation. It follows that serum levels of IgG2 anti-Leishmania are correlated with typical clinical signs of disease. Furthermore the determination of specific anti-Leishmania antibodies could be an important tool in monitoring CVL clinical picture. PMID- 22226073 TI - Characterization of shiga toxin producing (STEC) and enteropathogenic Escherichia coli (EPEC) in raw yak (Poephagus grunniens) milk and milk products. AB - Thirty-one shiga toxin-producing (STEC) and 6 enteropathogenic Escherichia coli (EPEC) were isolated from 87 raw yak milk and 63 'churpi' samples. Of 18 stx(1) positive isolates (48.6%), 14 carried stx(1c) (77.7%). Subtyping of 28 stx(2) positive isolates (75.7%) revealed the presence of stx(2c) (9, 32.1%), stx(2d) (3, 10.7%), stx(2e) (1, 3.57%) and stx(2f) (3, 10.7%) variants. Furthermore, intimin (eaeA), enterohaemolysin (ehxA), autoagglutinating adhesin (saa), iha (adherence conferring protein), efa1 (EHEC factor for adherence), bundle forming pilli (bfpA) and toxB (type III secreted protein encoded on LEE Island, similar to toxin B of Clostridium difficile) genes were detected in 14, 16, 12, 4, 3, 2 and 2 isolates, respectively. Univariate and multivariate analysis depicted that both stx(1) and stx(2) or their variants were more likely to occur in isolates from Arunachal Pradesh (p<0.04) rather than Sikkim. Dendogram constructed on the basis of RAPD and ERIC PCR profile distributed the STEC and EPEC isolates in separate clusters irrespective of their sources and serotypes. The STEC and EPEC isolates exhibited resistance against erythromycin, amikacin, azithromycin, amoxicillin, ampicillin+cloxacillin, cephalothin, furazolidone, gentamicin, kanamycin, streptomycin and tetracycline. This is the first ever report on occurrence and characterization of STEC and EPEC isolated from yak milk and milk products. PMID- 22226074 TI - The effect of clavicle malunion on shoulder biomechanics; a computational study. AB - BACKGROUND: Clavicle malunion affects the biomechanics of the shoulder joint. The purpose of this study is to establish the abduction, flexion, and internal (medial) rotation biomechanics of the shoulder after clavicle malunion. METHODS: A computational study was performed utilizing a three-dimensional, validated computational model of the upper extremity. Sequential shortening of the clavicle up to 20% was simulated. Muscle forces, moment arms, and moments were calculated for the surrounding musculature through a range of flexion, abduction, and internal rotation during the simulated shortening. FINDINGS: Shortening of the clavicle decreases the shoulder elevation moments of the upper extremity muscles during abduction. Internal rotation moments are also decreased with shortening. Flexion moments were affected less through physiologic range of motion. The observed effects are due to a combination of changes in moment arms of the individual muscles as well as a decrease in the force generating capacity of the muscles. Additionally, shortening of the clavicle increases coronal angulation of the clavicle at the sternoclavicular joint. INTERPRETATION: Shortening causes a decrease in the moment generating capacity as well as the total force generating capacity of the shoulder girdle muscles. The clinical significance of these computational results, which are consistent with recent clinical studies, is validation of the proposed functional deficit caused by clavicle malunion. PMID- 22226075 TI - The contribution of quasi-joint stiffness of the ankle joint to gait in patients with hemiparesis. AB - BACKGROUND: The role of ankle joint stiffness during gait in patients with hemiparesis has not been clarified. The purpose of this study was to determine the contribution of quasi-joint stiffness of the ankle joint to spatiotemporal and kinetic parameters regarding gait in patients with hemiparesis due to brain tumor or stroke and healthy individuals. METHODS: Spatiotemporal and kinetic parameters regarding gait in twelve patients with hemiparesis due to brain tumor or stroke and nine healthy individuals were measured with a 3-dimensional motion analysis system. Quasi-joint stiffness was calculated from the slope of the linear regression of the moment-angle curve of the ankle joint during the second rocker. FINDINGS: There was no significant difference in quasi-joint stiffness among both sides of patients and the right side of controls. Quasi-joint stiffness on the paretic side of patients with hemiparesis positively correlated with maximal ankle power (r=0.73, P<0.01) and gait speed (r=0.66, P<0.05). In contrast, quasi-joint stiffness in controls negatively correlated with maximal ankle power (r=-0.73, P<0.05) and gait speed (r=-0.76, P<0.05). INTERPRETATION: Our findings suggested that ankle power during gait might be generated by increasing quasi-joint stiffness in patients with hemiparesis. In contrast, healthy individuals might decrease quasi-joint stiffness to avoid deceleration of forward tilt of the tibia. Our findings might be useful for selecting treatment for increased ankle stiffness due to contracture and spasticity in patients with hemiparesis. PMID- 22226076 TI - Changes in patellofemoral joint contact pressures caused by vastus medialis muscle weakness. AB - BACKGROUND: Patellofemoral joint pain is a common knee disorder, but its underlying causes remain unknown. One proposed mechanism is an imbalance in force in the knee extensor muscles. Specifically, the vastus medialis and vastus lateralis are thought to play a crucial role in proper patellar tracking, and weakness in vastus medialis is thought to lead to a lateral shift in the patella causing increased contact pressures and pain. The purpose of this study was to create an animal model of vastus medialis weakness and to test the effect of this weakness on patellofemoral contact pressures. METHODS: Experiments were performed using New Zealand white rabbits (mass 4.9-7.7 kg, n=12). Loading of the patellofemoral joint was produced by femoral nerve stimulation of the knee extensor muscles. Knee extensor imbalance was produced by vastus medialis ablation. Fuji pressure sensitive film was used to record contact area, shape and pressures for maximal and sub-maximal, matched-force contractions at knee angles of 30 degrees , 60 degrees , and 90 degrees . FINDINGS: Patellofemoral peak pressures, average pressures, contact areas and contact shapes were the same across all loading conditions for matched-force contractions before and after elimination of vastus medialis. INTERPRETATION: We conclude that vastus medialis weakness does not cause changes in patellofemoral contact pressures. Since the muscular and knee joint geometry in rabbits and humans is similar, we question the idea of vastus medialis weakness as a cause of patellar mal-tracking and patellofemoral joint pain. PMID- 22226077 TI - Prognostic markers: data misinterpretation often leads to overoptimistic conclusions. PMID- 22226078 TI - Real time presence of a microbiologist in a multidisciplinary diabetes foot clinic. AB - Multidisciplinary foot-care teams (MDFT) are recommended in the management of severe diabetic foot disease [1]. However, even though infection is often the dominant immediate risk, it is rare to have real time input from a microbiologist. We highlight the value of a microbiologist as a MDFT member. PMID- 22226079 TI - Practical steps for establishing ocular plaque therapy in developing countries. AB - INTRODUCTION: Retinoblastoma and uveal melanoma are the most common ocular tumors in children and adults, respectively. Enucleation and external beam radiation therapy are integral in the management of ocular tumors. However, these tumors could also be treated effectively by plaque therapy, which has the potential of preserving the globe and maintaining vision. METHODS AND MATERIALS: We reviewed our experience with the introduction of this technique to our center. Furthermore, we highlighted the critical role of a specialized multidisciplinary team in the successful implementation of this procedure. DISCUSSION: This review represents a detailed report addressing the practical steps for successfully establishing plaque therapy in developing countries. RESULTS: Plaque therapy was successfully implemented at our center in 1.5 years. Integration with an advanced cancer center is crucial for the correct transfer of this complex technology. CONCLUSION: Complex brachytherapy procedures could be successfully established and implemented in developing countries. PMID- 22226080 TI - Dosimetry comparison between TG-43 and Monte Carlo calculations using the Freiburg flap for skin high-dose-rate brachytherapy. AB - PURPOSE: The purpose of this work was to evaluate whether the delivered dose to the skin surface and at the prescription depth when using a Freiburg flap applicator is in agreement with the one predicted by the treatment planning system (TPS) using the TG-43 dose-calculation formalism. METHODS AND MATERIALS: Monte Carlo (MC) simulations and radiochromic film measurements have been performed to obtain dose distributions with the source located at the center of one of the spheres and between two spheres. Primary and scatter dose contributions were evaluated to understand the role played by the scatter component. A standard treatment plan was generated using MC- and TG-43-based TPS applying the superposition principle. RESULTS: The MC model has been validated by performing additional simulations in the same conditions but transforming air and Freiburg flap materials into water to match TG-43 parameters. Both dose distributions differ less than 1%. Scatter defect compared with TG-43 data is up to 15% when the source is located at the center of the sphere and up to 25% when the source is between two spheres. Maximum deviations between TPS- and MC-based distributions are of 5%. CONCLUSIONS: The deviations in the TG-43-based dose distributions for a standard treatment plan with respect to the MC dose distribution calculated taking into account the composition and shape of the applicator and the surrounding air are lower than 5%. Therefore, this study supports the validity of the TPS used in clinical practice. PMID- 22226081 TI - Centennial records of lead contamination in northern Atlantic bivalves (Arctica islandica). AB - In the study, we establish centennial records of anthropogenic lead pollution at different locations in the North Atlantic (Iceland, USA, and Europe) by means of lead deposited in shells of the long-lived bivalve Arctica islandica. Due to local oceanographic and geological conditions we conclude that the lead concentrations in the Icelandic shell reflect natural influxes of lead into Icelandic waters. In comparison, the lead profile of the US shell is clearly driven by anthropogenic lead emissions transported from the continent to the ocean by westerly surface winds. Lead concentrations in the European North Sea shell, in contrast, are dominantly driven by local lead sources resulting in a much less conspicuous 1970s gasoline lead peak. In conclusion, the lead profiles of the three shells are driven by different influxes of lead, and yet, all support the applicability of Pb/Ca analyses of A. islandica shells to reconstruct location specific anthropogenic lead pollution. PMID- 22226082 TI - Manual correction of semi-automatic three-dimensional echocardiography is needed for right ventricular assessment in adults; validation with cardiac magnetic resonance. AB - BACKGROUND: Three-dimensional echocardiography (3DE) and semi-automatic right ventricular delineation has been proposed as an appropriate method for right ventricle (RV) evaluation. We aimed to examine how manual correction of semi automatic delineation influences the accuracy of 3DE for RV volumes and function in a clinical adult setting using cardiac magnetic resonance (CMR) as the reference method. We also examined the feasibility of RV visualization with 3DE. METHODS: 62 non-selected patients were examined with 3DE (Sonos 7500 and iE33) and with CMR (1.5T). Endocardial RV contours of 3DE-images were semi automatically assessed and manually corrected in all patients. End-diastolic (EDV), end-systolic (ESV) volumes, stroke volume (SV) and ejection fraction (EF) were computed. RESULTS: 53 patients (85%) had 3DE-images feasible for examination. Correlation coefficients and Bland Altman biases between 3DE with manual correction and CMR were r = 0.78, -22 +/- 27 mL for EDV, r = 0.83, -7 +/- 16 mL for ESV, r = 0.60, -12 +/- 18 mL for SV and r = 0.60, -2 +/- 8% for EF (p < 0.001 for all r-values). Without manual correction r-values were 0.77, 0.77, 0.70 and 0.49 for EDV, ESV, SV and EF, respectively (p < 0.001 for all r-values) and biases were larger for EDV, SV and EF (-32 +/- 26 mL, -21 +/- 15 mL and - 6 +/- 9%, p <= 0.01 for all) compared to manual correction. CONCLUSION: Manual correction of the 3DE semi-automatic RV delineation decreases the bias and is needed for acceptable clinical accuracy. 3DE is highly feasible for visualizing the RV in an adult clinical setting. PMID- 22226083 TI - Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1. AB - The molecular basis for primary hereditary hypertriglyceridemia has been identified in fewer than 5% of cases. Investigation of monogenic dyslipidemias has the potential to expose key metabolic pathways. We describe a hitherto unreported disease in ten individuals manifesting as moderate to severe transient childhood hypertriglyceridemia and fatty liver followed by hepatic fibrosis and the identification of the mutated gene responsible for this condition. We performed SNP array-based homozygosity mapping and found a single large continuous segment of homozygosity on chromosomal region 12q13.12. The candidate region contained 35 genes that are listed in Online Mendelian Inheritance in Man (OMIM) and 27 other genes. We performed candidate gene sequencing and screened both clinically affected individuals (children and adults with hypertriglyceridemia) and also a healthy cohort for mutations in GPD1, which encodes glycerol-3-phosphate dehydrogenase 1. Mutation analysis revealed a homozygous splicing mutation, c.361-1G>C, which resulted in an aberrantly spliced mRNA in the ten affected individuals. This mutation is predicted to result in a truncated protein lacking essential conserved residues, including a functional site responsible for initial substrate recognition. Functional consequences of the mutation were evaluated by measuring intracellular concentrations of cholesterol and triglyceride as well as triglyceride secretion in HepG2 (hepatocellular carcinoma) human cells lines overexpressing normal and mutant GPD1 cDNA. Overexpression of mutant GPD1 in HepG2 cells, in comparison to overexpression of wild-type GPD1, resulted in increased secretion of triglycerides (p = 0.01). This finding supports the pathogenicity of the identified mutation. PMID- 22226084 TI - ABCB6 mutations cause ocular coloboma. AB - Ocular coloboma is a developmental defect of the eye and is due to abnormal or incomplete closure of the optic fissure. This disorder displays genetic and clinical heterogeneity. Using a positional cloning approach, we identified a mutation in the ATP-binding cassette (ABC) transporter ABCB6 in a Chinese family affected by autosomal-dominant coloboma. The Leu811Val mutation was identified in seven affected members of the family and was absent in six unaffected members from three generations. A LOD score of 3.2 at theta = 0 was calculated for the mutation identified in this family. Sequence analysis was performed on the ABCB6 exons from 116 sporadic cases of microphthalmia with coloboma (MAC), isolated coloboma, and aniridia, and an additional mutation (A57T) was identified in three patients with MAC. These two mutations were not present in the ethnically matched control populations. Immunostaining of transiently transfected, Myc-tagged ABCB6 in retinal pigment epithelial (RPE) cells showed that it localized to the endoplasmic reticulum and Golgi apparatus of RPE cells. RT-PCR of ABCB6 mRNA in human cell lines and tissue indicated that ABCB6 is expressed in the retinae and RPE cells. Using zebrafish, we show that abcb6 is expressed in the eye and CNS. Morpholino knockdown of abcb6 in zebrafish produces a phenotype characteristic of coloboma and replicates the clinical phenotype observed in our index cases. The knockdown phenotype can be corrected with coinjection of the wild-type, but not mutant, ABCB6 mRNA, suggesting that the phenotypes observed in zebrafish are due to insufficient abcb6 function. Our results demonstrate that ABCB6 mutations cause ocular coloboma. PMID- 22226085 TI - Synthesis, structure, DNA-binding properties and antioxidant activity of a nickel(II) complex with bis(N-allylbenzimidazol-2-ylmethyl)benzylamine. AB - A V-shape ligand bis(N-allylbenzimidazol-2-ylmethyl)benzylamine (babb) and its nickel complex, [Ni(babb)(2)](pic)(2) (pic=picrate), have been synthesized and characterized by physico-chemical and spectroscopic methods. Single-crystal X-ray revealed that the coordination sphere around Ni(II) is distorted octahedral with a N(6) ligand set, in which six nitrogen atoms were afforded by two tridentate ligand babb. The DNA-binding properties of the free ligand babb and Ni(II) complex have been investigated by electronic absorption, fluorescence, and viscosity measurements. The results suggest that babb and Ni(II) complex both bind to DNA via an intercalative binding mode, and the affinity for DNA is more strong in case of Ni(II) complex when compared with babb. The intrinsic binding constants (K(b)) of the Ni(II) complex and ligand with DNA were 3.65*10(4) M(-1) and 2.26*10(3) M(-1), respectively. Additionally, Ni(II) complex also exhibited potential antioxidant properties in vitro studies. PMID- 22226086 TI - Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. AB - AIM: Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that is being investigated for the treatment of type 2 diabetes mellitus (T2DM). METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, 28-day study conducted at two sites, in 29 subjects with T2DM not optimally controlled on insulin and up to one oral antihyperglycaemic agent. Subjects were treated with canagliflozin 100 mg QD or 300 mg twice daily (BID) or placebo. Safety, tolerability, pharmacokinetic characteristics and pharmacodynamic effects of canagliflozin were examined. Glucose malabsorption following a 75-g oral glucose challenge was also examined. RESULTS: Canagliflozin pharmacokinetics were dose dependent, and the elimination half-life ranged from 12 to 15 h. After 28 days, the renal threshold for glucose excretion was reduced; urinary glucose excretion was increased; and A1C, fasting plasma glucose and body weight decreased in subjects administered canagliflozin (A1C reductions: 0.19% with placebo, 0.73% with 100 mg QD, 0.92% with 300 mg BID; body weight changes: 0.03 kg increase with placebo, 0.73 kg reduction with 100 mg QD, 1.19 kg reduction with 300 mg BID). Glucose malabsorption was not observed with canagliflozin treatment. There were no deaths, serious adverse events or severe hypoglycaemic episodes. The incidence of adverse events was similar across groups. There were no clinically meaningful changes in routine laboratory safety tests, vital signs or electrocardiograms. CONCLUSION: In subjects receiving insulin and oral antihyperglycaemic therapy, canagliflozin was well tolerated without evidence for glucose malabsorption, had pharmacokinetic characteristics consistent with once-daily dosing, and improved glycaemic control. PMID- 22226087 TI - Comparative meta-analysis of adefovir dipivoxil monotherapy and combination therapy of adefovir dipivoxil and lamivudine for lamivudine-resistant chronic hepatitis B. AB - OBJECTIVES: The aim of the current study was to compare the effectiveness of adefovir dipivoxil (ADV) monotherapy with that of combination ADV and lamivudine (LAM) therapy in the treatment of LAM-resistant chronic hepatitis B (CHB). METHODS: Publications on the effectiveness of ADV monotherapy versus the combination of ADV and LAM therapy for the treatment of LAM-resistant CHB were identified by a search (up to year 2010) of the PubMed, HealthStar, ScienceDirect, and VIP databases. Biochemical response data (alanine aminotransferase normalization rate) and virological response data (serum hepatitis B virus DNA undetectable rate) were extracted and combined to obtain an integrated result. RESULTS: The literature search yielded 11 articles, six of which reported randomized controlled trials; the remaining five reported prospective cohort studies. The summary odds ratio (OR) values of the biochemical response at 3, 6, 12, and >12 months were 1.60 (p=0.06), 1.30 (p=0.18), 1.77 (p=0.008), and 3.35 (p<0.00001), respectively. The summary OR values of the virological response at 3, 6, 12, and >12 months were 1.46 (p=0.21), 1.68 (p=0.04), 1.16 (p=0.54), and 1.87 (p=0.01), respectively. CONCLUSIONS: The effectiveness of the combination therapy was not obviously predominant over the monotherapy in short duration therapies; however, the combination therapy had a great advantage over monotherapy in both biochemical and virological response when the therapy duration was prolonged to >12 months. PMID- 22226088 TI - Risk factors associated with bovine tuberculosis and molecular characterization of Mycobacterium bovis strains in urban settings in Niger. AB - A retrospective and a longitudinal survey were carried out at the abattoir of Niamey. Results showed a highly significant difference in suspected tuberculosis (TB) gross lesions among different animal species (P < 0.0001). The proportion of carcasses with TB-like lesions was 0.19% among cattle, 0.11% among camels, 0.001% among sheep and 0.0006% among goats. In cattle, cows are significantly more affected than the other categories (P < 0.001). Also in cattle, TB-like lesions are mostly localized in the lungs (92.77%) followed by the lymph nodes (50.87%) and the liver (32.40%). The prevalence of gross lesions compatible with bovine TB (BTB) is strongly influenced by the season (P < 0.0001), is closely correlated with the origin of the animals (P < 0.001) and has a negative impact on the weight of affected animals (P < 0.0001). Sixty-two samples of suspected TB gross lesions were subject to microbiological analysis and molecular typing of strains. Mycobacterium bovis was identified in 18 animals showing five different spoligotypes, belonging to type 'African 1' previously identified in Central and West Africa. In addition, a profile (SB1982) not previously reported distinguished by the absence of spacers 3, 4, 9, 16, 22, 30 and 39-43 has been characterized in this study. To assess risk factors for BTB transmission, a questionnaire on animal husbandry practices, food habits, and clinical signs of TB in animals and humans was submitted to the heads of 1131 randomly selected households. The main risk factors identified are consumption of unpasteurized milk (91%) and lack of hygiene within households (32-74%). Clinical signs that could be attributed to TB were also reported both in humans and in animals of the households. PMID- 22226089 TI - The antidepressant hyperforin increases the phosphorylation of CREB and the expression of TrkB in a tissue-specific manner. AB - Hyperforin is one of the main bioactive compounds that underlie the antidepressant actions of the medicinal plant Hypericum perforatum (St. John's wort). However, the effects of a chronic hyperforin treatment on brain cells remains to be fully addressed. The following study was undertaken to further advance our understanding of the biological effects of this plant extract on neurons. Special attention was given to its impact on the brain-derived neurotrophic factor (BDNF) receptor TrkB and on adult hippocampal neurogenesis since they appear central to the mechanisms of action of antidepressants. The consequences of a chronic hyperforin treatment were investigated on cortical neurons in culture and on the brain of adult mice treated for 4 wk with a daily injection (i.p.) of hyperforin (4 mg/kg). Its effects on the expression of the cyclic adenosine monophosphate response element-binding protein (CREB), phospho CREB (p-CREB), TrkB and phospho-TrkB (p-TrkB) were analysed by Western blot experiments and its impact on adult hippocampal neurogenesis was also investigated. Hyperforin stimulated the expression of TRPC6 channels and TrkB via SKF-96365-sensitive channels controlling a downstream signalling cascade involving Ca(2+), protein kinase A, CREB and p-CREB. In vivo, hyperforin augmented the expression of TrkB in the cortex but not in the hippocampus where hippocampal neurogenesis remained unchanged. In conclusion, this plant extract acts on the cortical BDNF/TrkB pathway leaving adult hippocampal neurogenesis unaffected. This study provides new insights on the neuronal responses controlled by hyperforin. We propose that the cortex is an important brain structure targeted by hyperforin. PMID- 22226090 TI - Whole blood thromboelastometry: another Knight at the Roundtable? AB - Thromboelastography and thromboelastometry represent viscoelastic diagnostic methodologies with promising application to diseases of altered coagulation. Their use in trauma-induced coagulopathy as a means of assessing the real-time status of the patient's functional coagulation profile in addition to its impact on effective and appropriate use of blood product support has been gaining acceptance among trauma surgeons, anesthesiologists, and transfusion medicine specialists. However, the ability of viscoelastic testing to augment or supplant conventional coagulation testing for the diagnosis and management of trauma induced coagulopathy remains controversial. Many of these issues pertain to the differences in methodology, instrumentation, logic, accessibility, ease of use, operator variability, and the method's relationship to patient care, blood product use, cost, and conventional testing algorithms. PMID- 22226091 TI - The 2012 education supplement on hematopoietic cell transplantation. PMID- 22226092 TI - Complications of transplant for nonmalignant disorders: autoimmune cytopenias, opportunistic infections, and PTLD. PMID- 22226093 TI - Anti-T cell antibodies as part of the preparative regimen in hematopoietic cell transplantation--a debate. PMID- 22226095 TI - Supportive care of hematopoietic cell transplant patients. AB - Hematopoietic cell transplant survivors face a number of challenges including low energy and stamina, "chemo-brain" and emotional distress, and late effects that can compromise functioning or lead to early mortality. This session will review the most recent interventions and recommendations to avoid or mitigate these complications. PMID- 22226094 TI - Clinical applications for biomarkers of acute and chronic graft-versus-host disease. AB - Acute and chronic graft-versus-host disease (aGVHD, cGVHD) are serious complications of allogeneic hematopoietic cell transplantation. The complex pathophysiology of these disease processes is associated with immune system activation, the release of cytokines and chemokines, and alterations in cell populations. The blood levels of specific protein and cellular levels in patients with GVHD have correlated with the development, diagnosis, and prognosis of GVHD. Here, we review the most promising biomarkers for aGVHD and cGVHD with clinical relevance. The utility of GVHD biomarkers in clinical care of allogeneic hematopoietic cell transplantation recipients needs to be proven through clinical trials, and potential approaches to trial design are discussed. PMID- 22226097 TI - Novel therapies and their integration into allogeneic stem cell transplant for chronic lymphocytic leukemia. AB - Over the past decade, numerous advances have been made in elucidating the biology of and improving treatment for chronic lymphocytic leukemia (CLL). These studies have led to identification of select CLL patient groups that generally have short survival dating from time of treatment or initial disease relapse who benefit from more aggressive therapeutic interventions. Allogeneic transplantation represents the only potentially curative option for CLL, but fully ablative regimens applied in the past have been associated with significant morbidity and mortality. Reduced-intensity preparative regimens has made application of allogeneic transplant to CLL patients much more feasible and increased the number of patients proceeding to this modality. Arising from this has been establishment of guidelines where allogeneic stem cell transplantation should be considered in CLL. Introduction of new targeted therapies with less morbidity, which can produce durable remissions has the potential to redefine where transplantation is initiated in CLL. This review briefly summarizes the field of allogeneic stem cell transplant in CLL and the interface of new therapeutics with this modality. PMID- 22226096 TI - Emerging therapies in hematopoietic stem cell transplantation. AB - Despite improvements to hematopoietic stem cell transplantation over the past several decades, further advances are necessary to achieve: improved control of toxicities like graft-versus-host disease; enhanced immunologic reconstitution posttransplantation; and reduction in relapse risk via enhancement of graft versus-tumor responses. Achieving these disparate hematopoietic stem cell transplantation goals will likely require the introduction of novel therapeutic agents to the current armamentarium. In this article, we outline preclinical and early-phase clinical data indicating the potential of proteasome-inhibitor therapy (bortezomib), hypomethylating agent therapy (azacytidine), and histone deacetylase-inhibitor therapy (vorinostat) to help improve hematopoietic stem cell transplantation outcomes. PMID- 22226098 TI - Subsequent malignant neoplasms after hematopoietic cell transplantation. PMID- 22226100 TI - Back to the future: mismatched unrelated donor, haploidentical related donor, or unrelated umbilical cord blood transplantation? PMID- 22226099 TI - Applications of next-generation sequencing to blood and marrow transplantation. AB - Since the advent of next-generation sequencing (NGS) in 2005, there has been an explosion of published studies employing the technology to tackle previously intractable questions in many disparate biological fields. This has been coupled with technology development that has occurred at a remarkable pace. This review discusses the potential impact of this new technology on the field of blood and marrow stem cell transplantation. Hematologic malignancies have been among the forefront of those cancers whose genomes have been the subject of NGS. Hence, these studies have opened novel areas of biology that can be exploited for prognostic, diagnostic, and therapeutic means. Because of the unprecedented depth, resolution and accuracy achievable by NGS, this technology is well-suited for providing detailed information on the diversity of receptors that govern antigen recognition; this approach has the potential to contribute important insights into understanding the biologic effects of transplantation. Finally, the ability to perform comprehensive tumor sequencing provides a systematic approach to the discovery of genetic alterations that can encode peptides with restricted tumor expression, and hence serve as potential target antigens of graft-versus leukemia responses. Altogether, this increasingly affordable technology will undoubtedly impact the future practice and care of patients with hematologic malignancies. PMID- 22226101 TI - Hematopoietic cell transplantation for nonmalignant disorders. AB - Hereditary disorders that trace their origin to the hematopoietic stem cell have been targeted for allogeneic therapy and were among the first human diseases cured by successful hematopoietic cell transplantation (HCT). More recently, the possibility of treating nonhematopoietic hereditary disorders in which engraftment of hematopoietic cells might ameliorate tissue damage in target organs has also been investigated with encouraging results. As in the malignant hematological disorders, transplantation results have improved over the past 3 decades as a consequence of more refined donor selection and patient risk stratification with modifications to the conditioning regimen. The application of these principles is described in this update about HCT for hereditary marrow failure syndromes and hemoglobin disorders. In addition, a novel indication of HCT for epidermolysis bullosa is presented. Together, these representative disorders illustrate the potential for an expanding role of HCT for nonmalignant disorders. PMID- 22226102 TI - GVHD prevention: an ounce is better than a pound. PMID- 22226103 TI - HIV-1 and hematopoietic stem cell transplantation. PMID- 22226104 TI - Autologous hematopoietic stem cell transplantation for autoimmune disease--is it now ready for prime time? AB - Current systemic therapies are rarely curative for patients with severe life threatening forms of autoimmune disease (AID). During the past 15 years, autologous hematopoietic stem cell transplantation (HCT) has been demonstrated to cure some patients with severe AID refractory to all other available therapies, and thus AID has become an emerging indication for cell therapy. The sustained clinical effects after autologous HCT are better explained by qualitative change in the reconstituted immune repertoire rather than transient depletion of immune cells. Since 1996, more than 1300 AID patients have been registered by the European Group for Blood and Marrow Transplantation (EBMT) and almost 500 patients by the Center for International Blood and Marrow Transplant Research (CIBMTR). Autologous HCT is most commonly performed for patients with multiple sclerosis (MS) or systemic sclerosis (SSc). Systemic lupus, Crohn's disease, type I diabetes, and juvenile idiopathic arthritis are other common indications. Allogeneic transplants are still considered too toxic for use in AID, except for cases of immune cytopenia. Although biologic therapies have been effective at controlling the manifestations of the disease, they require continuous administration, thus raising questions about their increasing costs, morbidity, and mortality related to prolonged therapy. Perhaps it is a reasonable time to ask, "Is autologous HCT for severe AID now ready for prime time?" Yet, the paucity of controlled studies, the short-term toxicities, and the upcoming availability of second-generation biologic and targeted immunotherapies argues that perhaps HCT for AID should be still limited to clinical trials. In this article, we focus on the results of autologous HCT for MS and SSc because these are the two most commonly transplanted diseases. The promising data that is emerging may establish these diseases as standard indications for HCT. PMID- 22226105 TI - Understanding chronic GVHD from different angles. PMID- 22226106 TI - Radiation disasters: role of the BMT team. AB - Bone marrow transplant (BMT) teams do not generally consider themselves to be emergency responders. But the bone marrow is the most radiosensitive organ in the body, and early changes in peripheral blood counts remain the best indicator of major total-body radiation exposures. Following a mass casualty incident, such as that occasioned by a nuclear detonation, BMT teams should expect that they will be called upon for their expertise in managing severe myelosuppression. Numerous resources, including the Radiation Injury Treatment Network, are available to assist BMT teams in planning for such a role. PMID- 22226107 TI - Tolerance after solid organ and hematopoietic cell transplantation. PMID- 22226108 TI - NK cells--from bench to clinic. AB - After decades of mouse and human research, we now know that natural killer (NK) cells have unique properties including memory. Although initially described as major histocompatibility complex (MHC) unrestricted killers, NK cells have several families of receptors that directly recognize MHC including Ly49 receptors in the mouse and killer immunoglobulin-like receptors (KIR) in humans. The strength of this signal is determined by polymorphisms in NK cell inhibitory receptor genes and their MHC ligands inherited on different chromosomes. Inhibitory receptors protect "self"-expressing normal tissue from being killed by NK cells and protecting against autoimmunity. Therefore, for NK cells to kill and produce cytokines, they must encounter activating receptor ligands in the context of "missing self" that occurs with some viral infections and malignant transformation. The second property of inhibitory receptors is to educate or license NK cells to acquire function. This is best demonstrated in the mouse and in humans by enhanced function on self-inhibitory receptor-expressing NK cells when in a host expressing cognate ligate. In contrast, NK cells without inhibitory receptors or with nonself-inhibitory receptors are relatively hyporesponsive. The basic biology of NK cells in response to cytokines, education, and viruses will translate into strategies to manipulate NK cells for therapeutic purposes. PMID- 22226110 TI - Transplantation for AML in children. PMID- 22226111 TI - From biology to clinical practice: aging and hematopoietic cell transplantation. PMID- 22226109 TI - Autologous stem cell transplantation and multiple myeloma cancer stem cells. AB - It is well established that high-dose therapy (HDT) combined with autologous stem cell transplantation (ASCT) produces superior response rates and progression-free survival compared with conventional chemotherapy in patients with multiple myeloma (MM). Accordingly, MM currently represents the most common indication for ASCT. Despite these clinical improvements, the impact of ASCT on overall survival is unclear because the vast majority of patients eventually experience disease relapse and progression. The continual risk of relapse suggests that malignant cells resistant to HDT possess the clonogenic growth potential to mediate tumor regrowth, and in several diseases cancer stem cells (CSCs) have been identified that are both highly tumorigenic and resistant to standard anticancer approaches. Putative CSCs have been identified in MM, and their characterization may lead to the development of novel maintenance strategies that inhibit the production of new tumor cells, prevent disease relapse, and improve overall survival. PMID- 22226112 TI - Fibrotic and sclerotic manifestations of chronic graft-versus-host disease. PMID- 22226113 TI - Reduced-intensity conditioning (RIC) in children with nonmalignant disorders (NMD) undergoing unrelated donor umbilical cord blood transplantation (UCBT). PMID- 22226115 TI - Monitoring and prevention of relapse after allogeneic hematopoietic cell transplantation for myeloid malignancies. AB - Acute myeloid leukemia and myelodysplastic syndromes are the most common indications for allogeneic hematopoietic cell transplantation. Although this treatment can be curative, even in advanced disease, treatment failure is commonly manifested by relapse of disease, for which treatment is successful in only a minority of patients. There is a necessity for new strategies for prevention of posttransplantation relapse through early disease detection and intervention in order to improve patient outcomes. Detection of minimal residual disease in posttransplantation surveillance is felt to be a necessary component of any strategy. In chronic myeloid leukemia, assessment of the BCR-ABL1 load by quantitative real-time PCR provides an optimal guideline for posttransplantation therapeutic decisions, but in patients with acute myeloid leukemia or myelodysplastic syndromes, the situation is more complex because of the genetic heterogeneity of these disorders. Past strategies for relapse prevention have focused on use of donor lymphocyte infusions with variable success. Peritransplantation and maintenance therapies (eg, azacitidine) are under current investigation. This review summarizes the current status of minimal residual disease monitoring and prevention strategies for both pediatric and adult patients with myeloid malignancies in the transplantation setting and discusses perspectives for further improvement. PMID- 22226114 TI - The IL-17 differentiation pathway and its role in transplant outcome. AB - The limitations of allogeneic transplantation are graft-versus-host disease (both acute and chronic), infection, and relapse. Acute GVHD has traditionally been thought of as a Th1-mediated disease with inflammatory cytokines (eg, interferon [IFN]-gamma and tumor necrosis factor [TNF]) and cellular cytolysis mediating apoptotic target tissue damage in skin, gut, and liver. Chronic GVHD has not fit neatly into either Th1 or Th2 (eg, IL-4, IL-13) paradigms. Increasingly, the Th17 pathway of differentiation has been shown to play important roles in acute and chronic GVHD (aGVHD, cGVHD), particularly in relation to skin and lung disease. Here we discuss the IL-17 pathway of T cell differentiation and the accumulating evidence suggesting it represents an important new target for the control of deleterious alloimmune responses. PMID- 22226116 TI - Nonpharmacologic treatment of chronic graft-versus-host disease in children and adolescents. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many children with life-threatening diseases. One of the most significant long-term complications of transplantation is chronic graft-versus-host disease (cGVHD). Although the rates of cGVHD after HSCT are lower in the pediatric population than in adults, cGVHD remains a significant cause of morbidity and mortality. Medicines used to prevent and treat cGVHD remain unsatisfactory, with protracted use of immune suppression necessary and high rates of first-line treatment failure. Efforts to improve salvage treatment are urgently required. Nonpharmacologic strategies attempt to modulate the cellular inflammation response and possibly allow reduction or cessation of immunosuppressive drugs. Mesenchymal stromal cells (MSC) have been shown in vitro to mediate a wide variety of immune responses. MSC have been used in the prophylaxis of acute GVHD (aGVHD) and for the treatment of established steroid refractory aGVHD and, more recently, in the management of cGVHD. Extracorporeal photochemotherapy (ECP) has shown promising efficacy in graft-versus-host disease, and may allow a significant reduction in the use of systemic steroids and other immunosuppressants, reducing long-term morbidity and mortality. The accumulated experience shows ECP to be well tolerated, with no clinically significant side effects. PMID- 22226117 TI - Clinical trials In BMT: ensuring that rare diseases and rarer therapies are well done. PMID- 22226118 TI - Follicular lymphoma: prognostic factors, conventional therapies, and hematopoietic cell transplantation. PMID- 22226120 TI - Risky dopamine. PMID- 22226119 TI - Neuroblastoma: issues in transplantation. PMID- 22226121 TI - GR-owing up stressed: implications for anxiety and addiction. PMID- 22226122 TI - Synthesis and hypolipidemic activity of novel 2-(4-(2-amino-6-(4-substituted phenyl) pyrimidin-4-yl)-2-substituted phenoxy) acetic acid derivatives. AB - A novel series of 2-(4-(2-amino-6-(4-substituted phenyl) pyrimidin-4-yl)-2 substituted phenoxy) acetic acid derivatives were efficiently synthesized. The synthesized compounds were evaluated for their in vivo hypolipidemic activity, using high-fat-diet-induced hyperlipidemia in rats. Some of these compounds showed significant antihyperlipidemic activity. PMID- 22226123 TI - IL-4 regulates chemokine CCL26 in keratinocytes through the Jak1, 2/Stat6 signal transduction pathway: Implication for atopic dermatitis. AB - Atopic dermatitis (AD), a chronic, pruritic, inflammatory skin disease, is histopathologically characterized by epidermal hyperplasia and infiltration of T cells, mast cells, and eosinophils. Clinical study and basic research have established that IL-4 plays an important role in the pathogenesis of AD. In this report, using HaCat cells, we show that CCL26, a chemokine for eosinophils, is up regulated by IL-4 at both the mRNA and protein levels. IL-4 also enhances CCL26 promoter activity. Serial 5' deletion of the promoter and mutagenesis study reveal that the proximal Stat site is the key response element for IL-4 regulation of CCL26. Although IL-4 increases phosphorylation of both Stat3 and Stat6, it only activates Stat6 as shown by dominant negative studies. In addition, we found that IL-4 induces Stat6 nuclear translocation and stimulates phosphorylation of Jak1 and Jak2 but not Tyk2. IL-4 up-regulation of CCL26 can be suppressed by Jak inhibitors in a dose-dependent manner. Taken together, results of this investigation reveal that IL-4 signals through the Jak1, 2/Stat6 pathway in keratinocytes to stimulate CCL26 expression and this may provide an explanation for the pathogenesis of AD. PMID- 22226124 TI - Uptake and depuration of pharmaceuticals in aquatic invertebrates. AB - The uptake and depuration of a range of pharmaceuticals in the freshwater shrimp (Gammarus pulex) and the water boatman (Notonecta glauca) was studied. For one compound, studies were also done using the freshwater snail Planobarius corneus. In G. pulex, bioconcentration factors (BCFs) ranged from 4.6 to 185,900 and increased in the order moclobemide < 5-fluoruracil < carbamazepine < diazepam < carvedilol < fluoxetine. In N. glauca BCFs ranged from 0.1 to 1.6 and increased in the order 5-fluorouracil < carbamazepine < moclobemide < diazepam < fluoxetine < carvedilol. For P. corneus, the BCF for carvedilol was 57.3. The differences in degree of uptake across the three organisms may be due to differences in mode of respiration, behaviour and the pH of the test system. BCFs of the pharmaceuticals for each organism were correlated to the pH-corrected liposome-water partition coefficient of the pharmaceuticals. PMID- 22226125 TI - My child is unique; the pharmacokinetics are universal. AB - The pharmacokinetic (PK) parameters that are important for dosing (e.g., clearance and volume) are well known. They are used in universal mathematical formulae that describe the time course of drug concentration. Additional formulae can be used to describe major covariate effects in children, such as size and maturation. PK parameters describing the time-concentration profile of a drug after administration are those for a typical individual in a population. These parameters are associated with variability. Further, any one individual may not be typical of the population studied. While size and maturation are two important considerations in children and assist with dosing estimation, there are also a number of additional PK covariates (e.g., organ function, disease, drug interactions, pharmacogenetics), and identifying these sources of variability allows us to individualize drug dose. Pharmacology is not simply an application of PK, and determinants of drug dose also require an understanding of the variability associated with pharmacodynamic response and a balancing of beneficial effects against unwanted effects. Each child is unique in this respect. PMID- 22226126 TI - Ventilator-associated pneumonia due to meticillin-resistant Staphylococcus aureus: risk factors and outcome in a large general hospital. AB - BACKGROUND: Data about risk factors and impact on outcome of methicillin resistant S. aureus (MRSA) in unselected patients with ventilator-associated pneumonia (VAP) are limited. AIM: To assess predisposing factors and outcome of VAP due to MRSA in a large teaching institution. METHODS: Prospective study carried out over four years in the three adult ICUs of our hospital. Patients with MRSA-VAP were compared with those with bacterial VAP due to other microorganisms. FINDINGS: Overall, 474 episodes of bacterial VAP were collected. Significant differences between MRSA-VAP (111) and VAP due to other microorganisms (363) were found for median age (68 vs. 62 years), median APACHE II score (12 vs. 11), neurosurgery (5.4% vs. 13.8%), abdominal surgery (35% vs. 19%), prior treatment with any antibiotic (82.9% vs. 64.5%) and with imipenem (24% vs. 11%) at present admission before VAP, and pleural effusion (12% vs. 5%). Multivariate analysis adjusted for confounding factors showed that higher APACHE II score, prior treatment with any antibiotic and pleural effusion were independent risk factors for MRSA. As for treatment and outcome, the differences between MRSA-VAP and other VAP were inadequate empiric treatment (70% vs. 53%), median cost of antibiotics per episode (?974 vs. ?726), and in-hospital mortality (60% vs. 47%). At multivariate analysis, however, MRSA was not found to be an independent risk factor for mortality. CONCLUSION: MRSA is a common cause of VAP. Underlying conditions predispose to its high mortality. PMID- 22226127 TI - Ultrasound Guided Needle Aspiration versus Surgical Drainage in the management of breast abscesses: a Ugandan experience. AB - BACKGROUND: Despite breast abscess becoming less common in developed countries, it has remained one of the leading causes of morbidity in women in developing countries. A randomized controlled trial was conducted at Mulago hospital complex in Kampala Uganda to establish whether ultrasound guided needle aspiration is a feasible alternative treatment option for breast abscesses. RESULTS: A total of 65 females with breast abscess were analyzed, of these 33 patients were randomized into the ultrasound guided needle aspiration and 32 patients in the Incision and drainage arm. The mean age was 23.12, most of them were lactating (66.2%), primipararous (44.6%) with peripheral abscesses (73.8%) located in the upper lateral quadrant (56%).The mean breast size was 3.49 cm. The two groups were comparably in demographic characteristic and breast abscess size. Survival analysis showed no difference in breast abscess healing rate between the two groups (Log rank 0.24 df 1 and P = 0.63). Incision and drainage was found to be more costly than ultrasound guided aspiration (cost effective ratio of 2.85). CONCLUSION: Ultrasound guided needle aspiration is therefore a feasible and cost effective treatment option for both lactating and non lactating breast abscesses with a diameter up to 5 cm by ultrasound in an immune competent patient. PMID- 22226128 TI - Need for oversight and standardization of HIV screening for living organ donors. PMID- 22226130 TI - ENA, supporting emergency nurses on the front lines in 2012. PMID- 22226129 TI - Integrated residency training pathways of the future: diagnostic radiology, nuclear radiology, nuclear medicine, and molecular imaging. AB - Following up on the recommendations of the ACR/SNM Task Force on Nuclear Medicine Training, the respective leaderships convened Task Force II. Its charge is to develop realistic residency training pathways integrating diagnostic radiology, nuclear radiology, nuclear medicine, and molecular imaging. The diagnostic radiology participants offer these "pathways of the future" that are built on a foundation of training in diagnostic radiology. It is hoped that these pathways will ensure that the traditional and emerging clinical, educational, and research domains of nuclear radiology, nuclear medicine, and molecular imaging will be sustained and will indeed flourish in the decades to come. PMID- 22226131 TI - New year, new challenges, new opportunities. PMID- 22226132 TI - Hemolysis of coagulation specimens: a comparative study of intravenous draw methods. AB - INTRODUCTION: Hemolysis of blood samples creates significant delays in the treatment and disposition of patients in the emergency department. The purpose of this study was to compare the hemolysis rates of coagulation blood samples obtained during insertion of an intravenous (IV) catheter without (group 1) or with (group 2) extension tubing connected to the IV catheter hub. A secondary purpose of this study was to determine whether the investigators could predict whether a coagulation sample was hemolyzed based on visual observation during the specimen withdrawal process. METHODS: A prospective, 2-group randomized comparative design was used to determine which method of blood collection for coagulation specimens provided the lowest hemolysis rate. This study was conducted in an urban level I emergency department averaging 58,000 visits per year. The sample consisted of 121 adult ED patients randomly assigned to 1 of the 2 groups. Data collectors were trained in the 2 methods of coagulation sample collection and followed a strict protocol. The clinical laboratory used a standardized color-coded scale to determine hemolysis. RESULTS: Pearson chi(2) analysis was used to test for differences between all nominal variables. The level of significance for all tests was P < .05. There was no significant difference in hemolysis rates between the groups by use of chi(2) analysis (P = .84). Nurses were significantly more likely to predict that a sample was hemolyzed when it was not and to think that it was not hemolyzed when in fact it was (P < .001). DISCUSSION: High hemolysis rates occurred equally when coagulation blood samples were drawn via a peripheral IV catheter either at the hub or through extension tubing. Emergency nurse investigators could not accurately predict by visualization whether a coagulation sample was hemolyzed at the time of blood withdrawal. Venipuncture as the preferred method of blood draw is an industry recommendation. This method has been shown in prior experimental studies to reduce hemolysis rates to less than 4%. Therefore, if hemolysis rates are a concern, one should consider obtaining blood whenever possible through a venipuncture rather than through an IV catheter. Replication studies are needed to determine whether the findings of this study can be generalized to the larger population. PMID- 22226133 TI - Perceptions of participating emergency nurses regarding an ED seasonal influenza vaccination program. AB - INTRODUCTION: Numerous professional organizations have recommended that emergency departments provide influenza vaccine to patients. However, no study has reported on the perceptions of participating emergency nurses regarding ED influenza vaccination programs. METHODS: We conducted an anonymous Web-based survey to assess the post-participation perceptions of emergency nurses regarding an ED influenza vaccination protocol. The vaccination protocol occurred at an urban, academic emergency department and was designed to be performed by emergency nurses without added staffing resources by using ED Electronic Medical Record technology. Data from the Web-based survey were analyzed using descriptive statistics and chi(2) analysis to assess significant associations of where emergency nurses believed the protocol was time inefficient. RESULTS: The ED influenza vaccination protocol was in effect from October 1-25, 2009, with 3091 eligible ED visits and 613 patients receiving ED seasonal influenza vaccination. Fifty-eight of 59 participating emergency nurses (98%) responded to the survey. Significant findings were that 59% of responding emergency nurses found the protocol too time consuming and believed it was inappropriate in the ED setting. Responding emergency nurses reported that protocol efficiency could be improved by adding staff, simplifying screening and vaccination documentation requirements, and improving vaccine supply and stocking procedures in the emergency department. CONCLUSION: A majority of surveyed emergency nurses who had participated in an ED influenza vaccination program reported that the protocol was too time consuming and inappropriate for the ED setting. Surveyed emergency nurses expressed the opinion that such protocols required added staff, simplified patient consent/vaccination documentation requirements, and improved vaccine supply and stocking processes. PMID- 22226134 TI - Outcomes of implementing rapid triage in the pediatric emergency department. AB - INTRODUCTION: Efficiency and effectiveness are often used as quality indicators in emergency departments. With an aim to improve patient throughput and departmental efficiency while decreasing left-without-being-seen (LWBS) rates, this two-group, pre-intervention, post-intervention study in a pediatric emergency department evaluated the outcomes of implementing rapid triage on arrival-to-triage time, fast track utilization, and LWBS. METHODS: We implemented rapid triage assessment integrating the Emergency Severity Index and fast track guidelines in our pediatric emergency department. Arrival-to-triage times were tracked for 1 month before and after the intervention (N = 13,910 patient visits) by recording the time the patient arrived in the department and time triage assessment was complete. Fast track utilization and LWBS rates were measured for all patients sequentially included in pre-intervention (n = 60,373) and post intervention (n = 67,939) groups for 10 months. RESULTS: After the intervention, patients experienced a significant decrease in arrival-to-triage times compared with the pre-intervention group (P < .001), with most patients (88.3%) being triaged in less than 10 minutes after the intervention. Following implementation of fast track guidelines, patients were 14% more likely to be triaged to fast track compared with pre-intervention patients (odds ratio [OR] = 1.14, 95% confidence interval [CI] = 1.11-1.67). Additionally, patients with the lowest acuity were nearly 50% more likely to be triaged to fast track compared with pre intervention patients (OR = 1.48, 95% CI = 1.35-1.63). Although LWBS rates were insignificant, overall acuity level of this group was lower in the post intervention group. DISCUSSION: Although LWBS rates did not decrease with the intervention, implementation of a rapid triage system and fast track guidelines reduced arrival-to-triage times and decreased acuity in the LWBS population. Implementing rapid triage and fast track guidelines can affect nurse-sensitive patient outcomes related to safety and care delivery in a pediatric emergency department. PMID- 22226135 TI - A 35-year-old man with back pain and saddle anesthesia. PMID- 22226136 TI - Allergic reaction or adverse drug effect: correctly classifying vancomycin induced hypersensitivity reactions. PMID- 22226137 TI - Project helping hands unites with Bolivian leaders. PMID- 22226138 TI - Sexual assault forensic examiners' training and assessment using simulation technology. AB - INTRODUCTION: More than 190,000 sexual assaults involving persons aged 12 years or older occur annually in the United States. For these victims, a forensic examination is the first step in the process to justice. Assessment and treatment of victims, as well as the meticulous collection and documentation of evidence, are vital for a strong case. Providing timely services 24/7 by qualified professionals can be taxing on schedules and budgets. Using in-house resources to cross-train ED personnel, we developed a program that introduced novice forensic examiners to common clinical scenarios encountered in the treatment of victims and provided a framework for the evaluation and management of each case. METHODS: Seventeen ED personnel attended statewide sexual assault nurse examination training and participated in four simulation scenarios and debriefings. Pre-tests and post-tests were administered, and a checklist was used to assess competence in performing examinations independently. RESULTS: The majority of participants achieved competence (>=85% on the checklist) with their first case and had statistically significant gains in knowledge between pre-test and post-test (pre test mean score [+/-SE] of 69.1 +/- 1.7 vs. post-test mean score of 84.4 +/- 2.6, P < .001). Course evaluations were favorable, with a mean score of 91.3%. DISCUSSION: Our results validated the use of simulation technology and in-house resources for cross-training in a sexual assault forensic examination program, together with a checklist to assess competence in performing examinations independently. Benefits of having a sexual assault forensic examination program in the emergency department are standardized and timely care for victims, as well as enhanced evidence collection and increased reporting and prosecution of crimes. PMID- 22226140 TI - Cold and heat waves in the United States. AB - Extreme cold and heat waves, characterized by a number of cold or hot days in succession, place a strain on people's cardiovascular and respiratory systems. The increase in deaths due to these waves may be greater than that predicted by extreme temperatures alone. We examined cold and heat waves in 99 US cities for 14 years (1987-2000) and investigated how the risk of death depended on the temperature threshold used to define a wave, and a wave's timing, duration and intensity. We defined cold and heat waves using temperatures above and below cold and heat thresholds for two or more days. We tried five cold thresholds using the first to fifth percentiles of temperature, and five heat thresholds using the 95 99 percentiles. The extra wave effects were estimated using a two-stage model to ensure that their effects were estimated after removing the general effects of temperature. The increases in deaths associated with cold waves were generally small and not statistically significant, and there was even evidence of a decreased risk during the coldest waves. Heat waves generally increased the risk of death, particularly for the hottest heat threshold. Cold waves of a colder intensity or longer duration were not more dangerous. Cold waves earlier in the cool season were more dangerous, as were heat waves earlier in the warm season. In general there was no increased risk of death during cold waves above the known increased risk associated with cold temperatures. Cold or heat waves earlier in the cool or warm season may be more dangerous because of a build up in the susceptible pool or a lack of preparedness for extreme temperatures. PMID- 22226139 TI - In vitro and in vivo double-enhanced suicide gene therapy mediated by generation 5 polyamidoamine dendrimers for PC-3 cell line. AB - BACKGROUND: One of the most frequently used and efficient suicide gene therapies for prostate cancer is HSV-TK/GCV system, but its application has been limited due to lack of favorable gene vector and the reduction of "bystander effect". We investigated the effect of a novel combination of HSV-TK/GCV fused with Cx43 and gemcitabine using non-viral vector generation 5 polyamidoamine dendrimers (G5 PAMAM-D) on PC-3 cells. METHODS: RT-PCR and Western blot were used to detect TK and Cx43 expression. Cell viability and proliferation were measured by using MTT assay. Cell apoptosis was detected with double-staining of Annexin V-FITC and propidium iodide (PI) by flow cytometry. Nude mice models were established to evaluate the therapeutic effect in vivo. RESULTS: G5-PAMAM-D efficiently delivered recombinant plasmids into PC-3 cells and HSV-TK and Cx43 could be expressed successfully. With gemcitabine, G5-PAMAM-D mediated HSV-TK and Cx43 expression effectively inhibited prostate cancer PC-3 cell proliferation, leading to more cellular apoptosis and inhibiting PC-3 tumor growth in nude mice models. CONCLUSIONS: This study illustrates that this new suicide gene system mediated by G5-PAMAM-D is effective in decreasing PC-3 cell proliferation and inducing cell apoptosis, and inhibiting tumor growth in vivo. In a word, our study could provide a potential approach for gene therapy of prostate cancer. PMID- 22226142 TI - Implementation of a service for physicians' consultation and information in euthanasia requests in Belgium. AB - AIM: To study the implementation of LEIF, the consultation service which provides access to specially trained physicians to act as the legally required second physician in requests for euthanasia in Flanders and Brussels, Belgium, the use of which has been to shown to be beneficial to the careful practice of euthanasia. METHOD: A representative sample of 3006 Belgian physicians from the area where LEIF is active received a questionnaire investigating their attitude and practice regarding euthanasia, asking about their knowledge of LEIF, their attitude towards the service, their use of the service and their intentions regarding its future use. FINDINGS: Seventy-eight per cent of physicians knew about the existence of the organization, 90% felt supported by the idea of being able to consult a LEIF physician and 90% intended to use LEIF in the future. Only 35% of those who had received a euthanasia request since LEIF became active had made use of LEIF. Awareness, use and intended use of LEIF were lower among specific groups of physicians (e.g. specialists). Positive attitudes towards consultation and training were positively associated with future use of LEIF. CONCLUSION: Implementation can be considered successful but LEIF should continue promoting its services as widely as possible, with specific attention paid to specialists. PMID- 22226141 TI - Stakeholder involvement in expensive drug recommendation decisions: an international perspective. AB - OBJECTIVES: To describe stakeholder involvement in the priority setting and appeals processes across five drug reimbursement recommendation committees. METHODS: We conducted qualitative case studies of how five independent drug advisory committees from Canada, Israel, England and Wales, Australia, and the USA made funding decisions for six expensive drugs. Interviews with 48 informants were conducted with committee members, patient groups, and industry representatives. RESULTS: Different stakeholders were allowed, in varying degrees, to participate in the formal mechanisms for revisions and appeals of decisions. Participants identified a number of stakeholder groups who were already involved in the process, as well as stakeholders whom they believed should be included in the decision-making process. CONCLUSIONS: A central component of a legitimate and fair priority setting process is to make priority setting explicit and to involve both pertinent values and stakeholders in decision-making. Study participants believed that the involvement of multiple stakeholder groups within the deliberative and appeals/revisions processes would contribute to a fair and legitimate drug reimbursement process. PMID- 22226143 TI - Outcomes of cytoreduction with hyperthermic intraperitoneal chemotherapy: our experience at a midwest community hospital. AB - BACKGROUND: Most cytoreduction with hyperthermic intraperitoneal chemotherapy procedures are performed at academic tertiary referral centers with numerous surgical oncology faculty. The objective of this study was to review the postoperative morbidity and mortality data of our institution, a large community hospital. METHODS: This was a retrospective cohort study of patients who underwent cytoreduction with hyperthermic intraperitoneal chemotherapy at a single institution. Two surgical oncologists performed all the procedures between May 2005 and June 2011. RESULTS: We retrospectively analyzed 57 patients. The most common pathology being treated was pseudomyxoma peritonei (34 of 57; 59.6%), followed by colorectal cancer (9 of 57; 15.8%). Other types of cancer included peritoneal mesothelioma and gastric adenocarcinoma. The average surgery time was 6.9 hours. Approximately 51% of patients suffered grade 3 or 4 morbidity and there were no perioperative mortalities. CONCLUSIONS: Cytoreduction with hyperthermic intraperitoneal chemotherapy can be performed at our institution with comparable outcomes as academic referral centers. PMID- 22226144 TI - Acute prognosis of critically ill patients with secondary peritonitis: the impact of the number of surgical revisions, and of the duration of surgical therapy. AB - BACKGROUND: Duration of surgical therapy and the number of surgical revisions performed to control the focus may be important prognostic variables. Association of such time-dependent therapies with survival, however, has not yet been studied. METHODS: We analyzed survival times of adult patients (n = 283) who were suffering from secondary peritonitis and associated organ failure. Cox-type additive hazard regression models were used to analyze associations of surgical variables with survival time. RESULTS: Seventy-two patients (25.4%) survived the period of excess mortality after intensive care unit admission. A total of 79.5% of the 283 patients required one or more surgical revisions. Besides the underlying disease and disease severity at intensive care unit admission, there was a nonlinear smoothed association between a poorer outcome and the duration of surgical therapy, and the number of surgical revisions. For the latter, hazard ratios increased sharply between 1 and 5 revisions, and remained largely constant later on. CONCLUSIONS: In critically ill patients with peritonitis, a long therapy and the necessity for a high number of reoperations is related inversely to acute survival. PMID- 22226145 TI - Does interference with the renin-angiotensin system protect against diabetes? Evidence and mechanisms. AB - Agents interfering with the renin-angiotensin system (RAS) were consistently shown to lower the incidence of type 2 diabetes mellitus (T2DM), as compared to other antihypertensive drugs, in hypertensive high-risk populations. The mechanisms underlying this protective effect of RAS blockade using angiotensin converting enzyme inhibitors or angiotensin-receptor blockers on glucose metabolism are not fully understood. In this article, we will review the evidence from randomized controlled trials and discuss the proposed mechanisms as to how RAS interference may delay the onset of T2DM. In particular, as T2DM is characterized by beta-cell dysfunction and obesity-related insulin resistance, we address the mechanisms that underlie RAS blockade-induced improvement in beta cell function and insulin sensitivity. PMID- 22226146 TI - Translocation of calcium-permeable TRPV2 channel to the podosome: Its role in the regulation of podosome assembly. AB - The present study was conducted to investigate localization and function of TRPV2 channel in a mouse macrophage cell line, TtT/M87. We infected an adenovirus vector encoding TRPV2 tagged with c-Myc in the extracellular domain. Immunoreactivity of c-Myc epitope exposed to the cell surface formed a ring structure, which was colocalized with markers of the podosome, namely beta integrin, paxillin and Pyk2. The ring structure was also observed in TRPV2-GFP expressing cells using total internal reflection fluorescent microscopy. Addition of formyl-Met-Leu-Phe (fMLP) increased the number of podosome and increased the intensity of the TRPV2 signal associated with the podosome. Measurement of subplasmalenmal free calcium concentration ([Ca(2+)](pm)) revealed that [Ca(2+)](pm) was elevated around the podosome. fMLP further increased [Ca(2+)](pm) in this region, which was abolished by a TRPV2 inhibitor ruthenium red. Phosphorylated Pyk2 was detected in fMLP-treated cells, and knockdown of TRPV2 reduced the expression of phospho-Pyk2. Introduction of dominant-negative Pyk2 or knockdown of TRPV2 increased the number of podosome. Conversely, elevation of [Ca(2+)](pm) by the addition of ionomycin reduced the number of podosome. These results indicate that TRPV2 is localized abundantly in the podosome and increases [Ca(2+)](pm) by the podosome. The elevation of [Ca(2+)](pm) is critical to regulate assembly of the podosome. PMID- 22226147 TI - The juvenile myoclonic epilepsy-related protein EFHC1 interacts with the redox sensitive TRPM2 channel linked to cell death. AB - The transient receptor potential M2 channel (TRPM2) is the Ca(2+)-permeable cation channel controlled by cellular redox status via beta-NAD(+) and ADP-ribose (ADPR). TRPM2 activity has been reported to underlie susceptibility to cell death and biological processes such as inflammatory cell migration and insulin secretion. However, little is known about the intracellular mechanisms that regulate oxidative stress-induced cell death via TRPM2. We report here a molecular and functional interaction between the TRPM2 channel and EF-hand motif containing protein EFHC1, whose mutation causes juvenile myoclonic epilepsy (JME) via mechanisms including neuronal apoptosis. In situ hybridization analysis demonstrates TRPM2 and EFHC1 are coexpressed in hippocampal neurons and ventricle cells, while immunoprecipitation analysis demonstrates physical interaction of the N- and C-terminal cytoplasmic regions of TRPM2 with the EFHC1 protein. Coexpression of EFHC1 significantly potentiates hydrogen peroxide (H(2)O(2))- and ADPR-induced Ca(2+) responses and cationic currents via recombinant TRPM2 in HEK293 cells. Furthermore, EFHC1 enhances TRPM2-conferred susceptibility of HEK293 cells to H(2)O(2)-induced cell death, which is reversed by JME mutations. These results reveal a positive regulatory action of EFHC1 on TRPM2 activity, suggesting that TRPM2 contributes to the expression of JME phenotypes by mediating disruptive effects of JME mutations of EFHC1 on biological processes including cell death. PMID- 22226148 TI - Endoplasmic reticulum stress mediating downregulated StAR and 3-beta-HSD and low plasma testosterone caused by hypoxia is attenuated by CPU86017-RS and nifedipine. AB - BACKGROUND: Hypoxia exposure initiates low serum testosterone levels that could be attributed to downregulated androgen biosynthesizing genes such as StAR (steroidogenic acute regulatory protein) and 3-beta-HSD (3-beta-hydroxysteroid dehydrogenase) in the testis. It was hypothesized that these abnormalities in the testis by hypoxia are associated with oxidative stress and an increase in chaperones of endoplasmic reticulum stress (ER stress) and ER stress could be modulated by a reduction in calcium influx. Therefore, we verify that if an application of CPU86017-RS (simplified as RS, a derivative to berberine) could alleviate the ER stress and depressed gene expressions of StAR and 3-beta-HSD, and low plasma testosterone in hypoxic rats, these were compared with those of nifedipine. METHODS: Adult male Sprague-Dawley rats were randomly divided into control, hypoxia for 28 days, and hypoxia treated (mg/kg, p.o.) during the last 14 days with nifedipine (Nif, 10) and three doses of RS (20, 40, 80), and normal rats treated with RS isomer (80). Serum testosterone (T) and luteinizing hormone (LH) were measured. The testicular expressions of biomarkers including StAR, 3 beta-HSD, immunoglobulin heavy chain binding protein (Bip), double-strand RNA activated protein kinase-like ER kinase (PERK) and pro-apoptotic transcription factor C/EBP homologous protein (CHOP) were measured. RESULTS: In hypoxic rats, serum testosterone levels decreased and mRNA and protein expressions of the testosterone biosynthesis related genes, StAR and 3-beta-HSD were downregulated. These changes were linked to an increase in oxidants and upregulated ER stress chaperones: Bip, PERK, CHOP and distorted histological structure of the seminiferous tubules in the testis. These abnormalities were attenuated significantly by CPU86017-RS and nifedipine. CONCLUSION: Downregulated StAR and 3 beta-HSD significantly contribute to low testosterone in hypoxic rats and is associated with ER stress which mediates testis damage caused by oxygen deprivation. CPU86017-RS is potential in ameliorating hypoxia-induced testicular injuries, possibly by its calcium antagonist effects on the testis. PMID- 22226149 TI - Skin telocytes. AB - A distinctive stromal cell-type, the telocyte (TC), has recently been described to send specific long prolongations (telopodes) alternating thin segments (podomers) with dilations (podoms). Even though one would expect TCs to be identified in various stromal tissues, there were not yet reported evidence of skin TCs. We aimed to check for the presence of TCs in human skin dermis. Transmission electron microscopy revealed the presence in dermis of TCs projecting specific telopodes. Skin TCs were closely related to or contacting fibroblasts, mast cells, adipocytes, and connective fiber bundles (collagenous and elastic). As it appears, skin TCs exist and are related to other stromal cells. The structural association of TCs to elastic fibers deserves further investigation. PMID- 22226150 TI - Characteristic of galaninergic components of the enteric nervous system in the cancer invasion of human large intestine. AB - BACKGROUND: This study presents changes that take place in galanin (GAL) containing components of the enteric nervous system in patients with colorectal carcinoma. The main goal of our study was to investigate the morphological and biochemical characteristics of the GAL-ergic neurons and nerve fibers in the cancer-affected part of the colon and to compare results to the unchanged part of the intestine. MATERIAL AND METHODS: The study was performed on tissue samples collected from 15 patients (9 women and 6 men). The material was collected during surgery, i.e., resection of the anterior sigmoid colon and anterior amputation of the rectum, from patients in good general condition, without any other significant disease. Immunohistochemistry and ELISA were used to study, respectively, the distribution of neurons and nerve fibers containing GAL and concentration of this neuropeptide in the human large intestine during the colorectal cancer infiltration. RESULTS: Morphological examinations have revealed that a statistically significantly higher percentage of GAL+ neurons (46%) was observed in the pathologically changed myenteric plexuses as compared to the unchanged part of the intestine (35%). No changes were observed in the density of GAL+ nerve fibers in the submucosal and myenteric plexuses. Biochemical examinations performed with the ELISA revealed that the average GAL content in the cancer tissues was 9.38 ng/g versus 12.27 ng/g in the morphologically unchanged tissues (the difference was statistically significant). CONCLUSIONS: The results indicate the continuous presence of GAL-ergic innervation in the immediate vicinity of the cancer invasion, which may be attributed to increased contraction of the affected part of intestine. PMID- 22226151 TI - Probiotics for severe trauma patients. AB - Probiotics are live micro-organisms with a health promoting effect. Because of their immunomodulating capacity as well as improvement of gut barrier function, probiotics have the capacity to prevent infectious complications in a variety of clinical settings. Now selected probiotics show potential for improving the clinical outcome of severe trauma patients. PMID- 22226152 TI - Pathogenicity of Eimeria praecox alone or associated with Eimeria acervulina in experimentally infected broiler chickens. AB - Eimeria praecox and Eimeria acervulina are two species of coccidia parasites infecting chickens, which develop in the duodenum. The purpose of this study was to evaluate the pathogenicity of E. praecox and to study interactions of this coccidium with E. acervulina. The results showed that the pathogenicity of E. praecox was related to the infective dose, and that its impact on individual weight and weight gain was significant from the lowest administered dose: 5000 oocysts per bird. No morbidity was observed, even with the highest infective dose, but faecal consistency alteration was higher with increasing infective doses. No consistent lesion was observed. When E. praecox was associated with E. acervulina with a low infective dose, performance deterioration seemed to be an additional effect of the two species. However, in the case of heavy infections, signs worsened along with duration of negative impact on growth, compared to a mono-infection. PMID- 22226153 TI - Worms in smallholder livestock systems: technologies and practices that make a difference. AB - Australian scientists, in partnership with Asian, African and Pacific nations have longstanding interests in applied research on helminth parasite control. Many technologies and practices have been successfully developed to control the parasite problems of smallholder and emerging farmers. This wide range extends from simple herbal remedies to complex, integrated use of chemicals, feeding and breeding. In many cases widespread adoption has been limited by lack of technical support, poor access to input markets and lack of incentives for poorer farmers to seek out and pay for innovations. A further new approach may be required that encompasses the wider production and market environment. The biological, social and economic context of each 'emerging farming system' is different and the matching of technologies to each system requires sound understanding of farmer needs and requirements. Thus, it is essential that farmers, extension workers, and scientists jointly decide what technologies to try, what results mean and, if successful, how to sustain their use. In one Asian example a range of technologies were considered for pig, large ruminant and goat production and parasite control through a participatory process which was also used to agree on what determines sustainability beyond testing. The criteria use to screen technologies and practices were (a) continued availability of inputs including dewormers, (b) dependence on related innovations (e.g. weaning or fencing) and (c) degree of community organisation required (e.g. control of breeding or communal grazing). On this basis deworming with chemicals, especially for Toxacara infection in cattle and buffalo calves following on from supplementary feeding with forages were the most feasible entry points. Further interventions were dependent on changes to the production system, including the introduction of weaning and controlled breeding. Further, the incentives for these production changes could not exist without improved market access and market signals for improved weight and condition. Examples such as this point to the need for stronger multidisciplinary and participatory approaches to parasite control. PMID- 22226154 TI - Intralesional interferon-alpha for conjunctival mucosa-associated lymphoid tissue lymphoma: long-term results. AB - OBJECTIVE: To report the long-term therapeutic results for patients with conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma who were treated with intralesional injections of interferon-alpha (IFN-alpha). DESIGN: Prospective, nonrandomized, interventional case series. PARTICIPANTS: Twenty eyes of 16 patients with histologically proven conjunctival MALT lymphoma in the absence of systemic disease. METHODS: Patients were given 1,500,000 international units (IU) of IFN-alpha (Roferon-A; Roche s.p.a., Milano, Italy) subconjunctivally inside the lesion 3 times weekly for 4 weeks. If there was even a minimal response, a further cycle of 1,000,000 IU 3 times weekly for 4 weeks was administered. MAIN OUTCOME MEASURES: Patients were followed up clinically using slit-lamp examination to determine evidence of tumor disappearance or recurrence. In 10 eyes, an incisional biopsy was performed 6 months after therapy to verify the histologic absence of the lesion. RESULTS: A complete response was obtained in 15 eyes (75%) at the end of first cycle treatment, and in 5 eyes (25%) after further cycles. Seventeen eyes (85%) showed no local recurrence after a median follow-up of 65 months (range, 15-136 months). Three eyes (15%) demonstrated recurrence at variable points after treatment. One patient with stage IIA lymphoma exhibited systemic lymphoma progression. CONCLUSIONS: Local immunotherapy with IFN-alpha seems to be an effective and lasting treatment method and provides an alternative to radiotherapy for conjunctival MALT lymphomas. Very few transient side effects were detected. PMID- 22226155 TI - Prevalence of malignancies among U.S. male patients with haemophilia: a review of the Haemophilia Surveillance System. AB - The prevalence of malignancies in US male patients with haemophilia, with or without concomitant viral infections, remains unknown. To estimate the prevalence of malignancy in US male patients with haemophilia. We investigated the prevalence of malignancies among male patients with haemophilia using data from a six-state haemophilia surveillance project. Case patients with malignancies were identified using International Classification of Diseases, 9th Revision, Clinical Modification codes abstracted from hospital records and death certificates during the surveillance period. Cancer prevalence rates were calculated for each year during the surveillance and compared with age- and race-specific prevalence rates among the U.S. male population obtained from the Surveillance, Epidemiology and End Results (SEER) Program. A total of 7 cases of leukaemia, 23 cases of lymphoma and 56 classifiable solid malignancies were identified among 3510 case patients during a total of 15,330 annual data abstraction collections. The rates of leukaemia, lymphoma and liver cancer among case patients were significantly higher than the rates among U.S. males as judged by prevalence ratios of 3.1 [95% confidence interval (CI) = 1.4-7.0] and 2.9 (95% CI =1.8-4.6), respectively. In contrast, the prevalence ratio of prostate cancer was lower than expected at 0.49 (95% CI = 0.31-0.77). Overall the prevalence of most cancers among case patients was similar to that of the U.S. male population. However, patients with haemophilia who have unexplained symptoms should be evaluated for malignancy. PMID- 22226156 TI - Disability, participation, and subjective wellbeing among older couples. AB - This paper investigates the link between disability and subjective wellbeing, using data from the 2009 Disability and Use of Time supplement to the Panel Study of Income Dynamics, the longest running national panel study in the United States. Disability is construed broadly to include both the presence of any physical, cognitive, or sensory impairment or activity limitation and also the severity of underlying impairments. Subjective wellbeing is measured using two distinct approaches: reports of life satisfaction and of moment-to-moment wellbeing-both positive and negative-on the previous day. The latter, collected through 24-h time diaries, also offers for the first time the ability to explore the role of participation in particular kinds of activities linking disability to subjective wellbeing. The analytic sample included married persons ages 60 and older and their spouses (n = 751 married individuals) who completed 1498 diaries. Several new findings emerged: no matter what the measure of wellbeing, older married adults with disability report worse subjective wellbeing than those without, and neither different demographic and socioeconomic profiles nor differences in participation fully account for these disparities. Influences of disability on global life satisfaction and episodic reports of happiness were relatively small and of comparable size. However, notably sizeable differences were identified in the cumulative number of pleasant minutes experienced yesterday by disability status - on the order of 71 fewer minutes on average for those with a disability of average severity. Differences appear to be more strongly linked to somatic symptoms of pain and feeling tired than to differential intensity of experiencing happiness, sadness, frustration, or worry. We also found limited support for the notion that participation partially mediates the relationship between disability and global, but not episodic, subjective wellbeing. PMID- 22226157 TI - United States--challenges of economic and demographic trends. PMID- 22226158 TI - Interfacing the neural system to restore deficient functions: from theoretical studies to neuroprothesis design. AB - Electrical stimulation is a valuable technical solution to treat severe deficiencies related to nervous system. It is particularly interesting when no medical treatment exists as for cardiac deficiencies, deafness, blindness or complete paralysis. However, activating excitable cells such as neurons or muscle fibers to recover functions remains a difficult scientific and technological challenge. Indeed, both the function to restore and the way to activate selectively the desired target are not fully understood. The article describes how both theoretical studies based on experiments, and technological developments based on electrophysiology knowledge may help in the development of highly effective solutions. Existing systems such as pacemakers and cochlear implants proved that the recovered functions are of great quality leading to increase of quality of life and autonomy of the patients. However, the challenge for movement restoration is still in front of researchers, developers and clinical teams. The described method is the way we choose to face fundamental and tremendous scientific questions in order to provide disabled people with extended autonomy. PMID- 22226159 TI - [Cellular aspects of aging in the pineal gland of the shrew, Crocidura russula]. AB - The Greater White-toothed shrew Crocidura russula is short-lived species and the phase of senescence is greatly elongated in captivity. The loss of rhythmicity of biological functions that accompanies its aging is also well documented. C. russula is thus an excellent model to test the effects of aging on biological clocks. Melatonin is a key hormone in the synchronization of behaviors, metabolisms and physiological regulations with environmental factors. In the present work we want to know if the loss of rhythmicity and the reduced melatonin levels registered by the second year of life in this species could be associated to modified ultrastructural features of the pineal parenchyma, site of melatonin synthesis. Transmission electron microscopy (TEM) analysis of young (1-4 months) and old (25-28 months) shrew's pineals show that in older individuals, the parenchyma undergoes alterations affecting mainly nucleus, mitochondria and endoplasmic reticulum cisternae, with increased numbers of dense bodies and the formation of many concretions as well as a depletion of secretory products. These changes suggest a process of slowing pinealocytes metabolism which could explain the gradual reduction of melatonin levels registered during aging in C. russula. PMID- 22226160 TI - Larvicidal activity of extracts from Artemisia species against Culex pipiens L. mosquito: comparing endemic versus ubiquist species for effectiveness. AB - The larvicidal activity of ethanolic leaf extracts from two Artemisia species, Artemisia campestris var. glutinosa and A. molinieri, on mosquito Culex pipiens Linnaeus (Diptera, Culicidae) larvae was investigated. Since A. molinieri is a rare and protected species confined to temporary ponds of Southern France, its toxic activity may help to value this species and to finance its conservation. A. molinieri extracts showed a higher larvicidal activity (from 50 ppm (K=9.488, DDL=4, P<0.001)) than those from A. campestris var glutinosa (from 500 ppm (K=9.488, DDL=4, P<0.01)) after 48 h of exposure. Calculated lethal concentrations, after 48 h of exposure, (LC(50)) were low, 9091 and 9898 ppm for A. molinieri and A. campestris var. glutinosa extracts, respectively, but using a non-pollutant solvent (ethanol). However, A. molinieri may be valued as an environmentally friendly biocide and developing its culture may be of interest for both pesticide activity and conservation purpose. PMID- 22226161 TI - Seed germination responses to varying environmental conditions and provenances in Crucianella maritima L., a threatened coastal species. AB - Seed germination (effects of light, temperature, NaCl and KNO(3)) of the coastal endangered species Crucianella maritima was investigated by testing seeds from three different populations. Data were analyzed by means of Generalized Linear Mixed Model (GLMM). The principal results showed that germination of C. maritima seeds was characterized by photoinhibition, absence of primary dormancy and salt induced secondary dormancy, with no need for high nutrient availability (KNO(3)). Intraspecific differences in germination pattern emerged, apparently due to a different seed mass. These results show important germination traits of C. maritima which should be taken into account in possible reintroduction attempts aimed at restoring threatened populations of this species. PMID- 22226162 TI - Pattern and timing of diversification of Cetartiodactyla (Mammalia, Laurasiatheria), as revealed by a comprehensive analysis of mitochondrial genomes. AB - The order Cetartiodactyla includes cetaceans (whales, dolphins and porpoises) that are found in all oceans and seas, as well as in some rivers, and artiodactyls (ruminants, pigs, peccaries, hippos, camels and llamas) that are present on all continents, except Antarctica and until recent invasions, Australia. There are currently 332 recognized cetartiodactyl species, which are classified into 132 genera and 22 families. Most phylogenetic studies have focused on deep relationships, and no comprehensive time-calibrated tree for the group has been published yet. In this study, 128 new complete mitochondrial genomes of Cetartiodactyla were sequenced and aligned with those extracted from nucleotide databases. Our alignment includes 14,902 unambiguously aligned nucleotide characters for 210 taxa, representing 183 species, 107 genera, and all cetartiodactyl families. Our mtDNA data produced a statistically robust tree, which is largely consistent with previous classifications. However, a few taxa were found to be para- or polyphyletic, including the family Balaenopteridae, as well as several genera and species. Accordingly, we propose several taxonomic changes in order to render the classification compatible with our molecular phylogeny. In some cases, the results can be interpreted as possible taxonomic misidentification or evidence for mtDNA introgression. The existence of three new cryptic species of Ruminantia should therefore be confirmed by further analyses using nuclear data. We estimate divergence times using Bayesian relaxed molecular clock models. The deepest nodes appeared very sensitive to prior assumptions leading to unreliable estimates, primarily because of the misleading effects of rate heterogeneity, saturation and divergent outgroups. In addition, we detected that Whippomorpha contains slow-evolving taxa, such as large whales and hippos, as well as fast-evolving taxa, such as river dolphins. Our results nevertheless indicate that the evolutionary history of cetartiodactyls was punctuated by four main phases of rapid radiation during the Cenozoic era: the sudden occurrence of the three extant lineages within Cetartiodactyla (Cetruminantia, Suina and Tylopoda); the basal diversification of Cetacea during the Early Oligocene; and two radiations that involve Cetacea and Pecora, one at the Oligocene/Miocene boundary and the other in the Middle Miocene. In addition, we show that the high species diversity now observed in the families Bovidae and Cervidae accumulated mainly during the Late Miocene and Plio-Pleistocene. PMID- 22226163 TI - Genetics and taxonomy of Chilean smooth-shelled mussels, Mytilus spp. (Bivalvia: Mytilidae). AB - It has been previously established that native smooth-shelled mussels in southern South America possess close evolutionary affinities with Northern-Hemisphere Mytilus edulis L. 1758 (McDonald et al. (1991) [5]). This result has since been challenged by authors claiming that Chilean mussels should be considered a local subspecies of M. galloprovincialis Lmk. 1819. Moreover, morphological, physiological, ecotoxicological and molecular genetic studies on Chilean smooth shelled mussels still frequently refer to 'M. chilensis' Hupe 1854, even though the previous discovery of alien M. galloprovincialis and considerable heterogeneity in shell morphology among samples collected along the Chilean shores raise concerns that different Mytilus spp. species might have been included under 'M. chilensis'. Here we reviewed the molecular and morphological data available on smooth-shelled mussels from Chile in an attempt to clarify both their genetic composition and their taxonomic status. Using multivariate analysis on sample*allozyme-frequency matrices, we confirmed the widespread occurrence of the Southern-Hemisphere form of M. edulis along the shores from the North Patagonia region of Chile to the southern tip of the South American continent. The populations sampled in southern central Chile showed some evidence of slight introgression from Southern-Hemisphere M. galloprovincialis. Morphological characterization of a sample from Dichato in southern central Chile was consistent with its previous genetic identification as Mediterranean M. galloprovincialis. The occurrence of Southern-Hemisphere M. galloprovincialis in Punta Arenas at the southern tip of the South American continent was also reported. Southern-Hemisphere M. edulis, including native Chilean smooth-shelled Mytilus, should be assigned subspecific rank and named M. edulis platensis d'Orbigny 1846. PMID- 22226164 TI - Morphometric identification of individuals when there are more shape variables than reference specimens: a case study in Galapagos tortoises. AB - Molecular biology techniques are useful for taxonomic assignment, but they are not always accessible and can be expensive and time consuming to perform. Morphological methods to identify the origin of individuals could be valuable if they can be performed rapidly, accurately, and with minimal resources. In order to correctly assign the origin of individuals from two distinct tortoise lineages, we studied here the accuracy of shape statistics depending on the inclusion of different numbers of shape components. Misleading assignment may occur if an optimal balance between the number of shape variables and the number of sampled individuals is not respected, especially when more variables than specimens are available. Assignment of museum samples of unknown origin suggests that they mostly belong to only one of the two lineages. PMID- 22226165 TI - Diversity and ecological characteristics of vascular flora in Mediterranean temporary pools. AB - Vascular flora of Mediterranean temporary pools has been studied with the aims to define its diversity and to individuate the ecological characteristics of the different plant groups associated with this relevant and endangered habitat type. Overall, 246 species were found of which 108 were terrestrial, 57 generalist of aquatic or wet habitats and 81 typical of temporary water and strongly linked to temporary pools. The results suggest that: (i) vascular flora associated with Sardinian Mediterranean temporary pools is rich and diversified; (ii) rare ferns are better represented than previously reported; (iii) plant species are generally heliophilous and acidophilous, specialized temporary pool species mainly differing from the unspecialized ones in relationship to their soil moisture requirements; (iv) these habitats are particularly important for maintaining regional freshwater biodiversity. PMID- 22226166 TI - Proposition for a protocol for anatomical studies on collection specimens by magnetic resonance imaging. AB - Magnetic resonance imaging (MRI) examinations for anatomical studies on collection specimens are becoming more and more frequent. As the presence of metallic objects within the specimens can disturb the acquisition of images and damage both specimens and materials, a simple protocol using radiographs is here proposed to detect these objects in collection specimens before conducting an MRI examination. PMID- 22226167 TI - A second species of Vietbocap Lourenco & Pham, 2010 (Scorpiones: Pseudochactidae) from Vietnam. AB - A second species of scorpion belonging to the family Pseudochactidae and to the genus Vietbocap is described from two specimens collected in the Thien Duong cave, which belongs to the Vom cave system, in the Phong Nha - Ke Bang National Park, Quang Binh Province, Vietnam. Like the previously described species of Vietbocap, the new species is also a true troglobitic element, the second known for the family Pseudochactidae. This represents the fourth known record of a pseudochactid, and the second from Vietnam. PMID- 22226168 TI - Excessive axial plaque redistribution during coronary stent implantation confirmed by intravascular ultrasound. AB - We report a case of excessive axial plaque redistribution leading to luminal narrowing at the reference segment confirmed by serial intravascular ultrasound during coronary stent implantation. PMID- 22226169 TI - Radial artery spasm during transradial cardiac catheterization and percutaneous coronary intervention: incidence, predisposing factors, prevention, and management. AB - Transradial cardiac catheterization and percutaneous coronary intervention are increasingly being performed worldwide in elective and emergency procedures, with many centers adopting the transradial route as their first choice of arterial access. One of the most common complications encountered during transradial procedures is radial artery spasm. This article reviews the current literature on the incidence, predisposing factors, preventive, and treatment measures for radial artery spasm. PMID- 22226170 TI - Impact of vascular approach (transradial vs. transfemoral) on the efficacy of thrombus aspiration in acute myocardial infarction patients. AB - BACKGROUND: Manual thrombus aspiration improves the efficacy of percutaneous coronary interventions (PCIs) in ST-elevation acute myocardial infarction (STEMI). The transradial approach (TRA) is an emerging vascular approach for PCI but is associated with specific technical requirements. As data on the combination of thrombus aspiration and TRA are scarce, we sought to assess the feasibility of TRA manual thrombus aspiration in STEMI patients. METHODS: All consecutive patients treated with manual thrombectomy for acute STEMI in three Italian hospitals were considered. Patients were divided according to the vascular approach into two groups: TRA and transfemoral (TFA). Two primary end points were defined: thrombectomy feasibility (ability to cross the occlusion with the device) and thrombectomy efficacy (absolute thrombus score reduction after device crossing). RESULTS: From January 2008 to December 2009, 303 patients were included: 151 patients (63+/-13 years) were treated through TFA, and 152 patients (61+/-12 years, P=.25) were treated through TRA. There were no significant differences in thrombectomy feasibility (75% in the TRA compared to 74.8% in the TFA group, P=.97) or in thrombectomy efficacy (2.6+/-.8 for TRA and 2.9+/-2 for TFA, P=.15). In both groups, there was a significant reduction in thrombus score after manual thrombus aspiration. Angiographically evident distal embolization after device crossing was low and observed in seven cases (5%) either for TFA and TRA (P=.99). CONCLUSIONS: The present study suggests that, in the setting of acute STEMI, manual thrombus aspiration through TRA is feasible, and its efficacy is comparable to the TFA. PMID- 22226171 TI - Clinical and silent stroke following aortic valve surgery and transcatheter aortic valve implantation. AB - Transcatheter aortic valve implantation (TAVI) has been introduced as an alternative to conventional surgery for high-risk patients with aortic stenosis. A recently published randomized clinical trial demonstrated reduction of mortality in high-risk or inoperable patients when compared to medical treatment or balloon aortic valvuloplasty. Despite this evidence of superiority, the rate of TAVI complications is high, and perhaps the most devastating of the nonfatal complications is cerebral injury. This review will compare the incidence of stroke and "silent" cerebral injury after surgical aortic valve replacement and after TAVI and will discuss mechanisms that can lead to cerebral injury during these procedures and subsequently how to prevent this with new protection devices. PMID- 22226172 TI - Copy number variation in Williams-Beuren syndrome: suitable diagnostic strategy for developing countries. AB - BACKGROUND: Williams-Beuren syndrome (WBS; OMIM 194050) is caused by a hemizygous contiguous gene microdeletion at 7q11.23. Supravalvular aortic stenosis (SVAS), mental retardation, and overfriendliness comprise typical symptoms of WBS. Although fluorescence in situ hybridization (FISH) is considered the gold standard technique, the microsatellite DNA markers and multiplex ligation dependent probe amplification (MLPA) could be used for to confirm the diagnosis of WBS. RESULTS: We have evaluated a total cohort of 88 patients with a suspicion clinical diagnosis of WBS using a collection of five markers (D7S1870, D7S489, D7S613, D7S2476, and D7S489_A) and a commercial MLPA kit (P029). The microdeletion was present in 64 (72.7%) patients and absent in 24 (27.3%) patients. The parental origin of deletion was maternal in 36 of 64 patients (56.3%) paternal in 28 of 64 patients (43.7%). The deletion size was 1.55 Mb in 57 of 64 patients (89.1%) and 1.84 Mb in 7 of 64 patients (10.9%). The results were concordant using both techniques, except for four patients whose microsatellite markers were uninformative. There were no clinical differences in relation to either the size or parental origin of the deletion. CONCLUSION: MLPA was considered a faster and more economical method in a single assay, whereas the microsatellite markers could determine both the size and parental origin of the deletion in WBS. The microsatellite marker and MLPA techniques are effective in deletion detection in WBS, and both methods provide a useful diagnostic strategy mainly for developing countries. PMID- 22226173 TI - A mouse model of CMV transmission following kidney transplantation. AB - Reactivation of latent CMV in transplant recipients remains a significant infectious complication of transplantation. Investigation of the cellular and molecular mechanisms by which reactivation occurs has been hampered by the lack of appropriate animal models. Here, we show that transplantation of kidneys latently infected with murine cytomegalovirus (MCMV) into NOD.Cg-Prkdc(scid) IL2rg(tm1Wjl) /Szj mice results in reactivation of latent virus in the kidney, resulting in a disseminated primary infection of the recipient. This model will be useful in elucidating mechanisms of MCMV reactivation, including the roles of injury and of spontaneous reactivation, and in testing new therapies for treatment and prevention of CMV reactivation and disease. PMID- 22226174 TI - A prospective, multicenter study of pharmacist activities resulting in medication error interception in the emergency department. AB - STUDY OBJECTIVE: The primary objective of this study is to determine the activities of pharmacists that lead to medication error interception in the emergency department (ED). METHODS: This was a prospective, multicenter cohort study conducted in 4 geographically diverse academic and community EDs in the United States. Each site had clinical pharmacy services. Pharmacists at each site recorded their medication error interceptions for 250 hours of cumulative time when present in the ED (1,000 hours total for all 4 sites). Items recorded included the activities of the pharmacist that led to medication error interception, type of orders, phase of medication use process, and type of error. Independent evaluators reviewed all medication errors. Descriptive analyses were performed for all variables. RESULTS: A total of 16,446 patients presented to the EDs during the study, resulting in 364 confirmed medication error interceptions by pharmacists. The pharmacists' activities that led to medication error interception were as follows: involvement in consultative activities (n=187; 51.4%), review of medication orders (n=127; 34.9%), and other (n=50; 13.7%). The types of orders resulting in medication error interceptions were written or computerized orders (n=198; 54.4%), verbal orders (n=119; 32.7%), and other (n=47; 12.9%). Most medication error interceptions occurred during the prescribing phase of the medication use process (n=300; 82.4%) and the most common type of error was wrong dose (n=161; 44.2%). CONCLUSION: Pharmacists' review of written or computerized medication orders accounts for only a third of medication error interceptions. Most medication error interceptions occur during consultative activities. PMID- 22226175 TI - Ethylene glycol elimination kinetics and outcomes in patients managed without hemodialysis. AB - STUDY OBJECTIVE: Ethylene glycol remains an important toxic cause of metabolic acidosis and acute renal failure. Traditionally, inhibition of alcohol dehydrogenase along with hemodialysis has been used for treatment. Because of reported long elimination half-life of ethylene glycol during alcohol dehydrogenase inhibition, hemodialysis has been used in patients who are otherwise doing well to clear ethylene glycol. We study ethylene glycol elimination kinetics in patients treated with fomepizole, but without hemodialysis. METHODS: This was a retrospective, multicenter cohort study of patients older than 15 years who were treated at one of 3 medical centers during an 8-year period. Inclusion criteria were peak serum ethylene glycol concentration greater than 20 mg/dL, lack of renal failure on admission, treatment with fomepizole but without hemodialysis, and availability of serial serum ethylene glycol concentrations, allowing calculation of elimination half life. The primary outcome variable was ethylene glycol elimination half-life; mortality and onset of renal failure were secondary outcome variables. RESULTS: During the study period, 85 patients were treated for ethylene glycol toxicity, of whom 40 met inclusion criteria. The mean serum ethylene glycol elimination half-life was 14.2 hours (SD=3.7 hours; 95% confidence interval 13.1 to 15.3 hours). One patient presented with metabolic acidosis on admission and developed mild transient renal insufficiency but did not require hemodialysis. No patient died. CONCLUSION: The mean elimination half-life of ethylene glycol in this population was shorter than previously reported without hemodialysis, and this select group of patients did well without enhanced elimination by hemodialysis. PMID- 22226176 TI - Cellular epigenetic stability and cancer. AB - When a cell divides, it must not only accurately duplicate its genome, but also restore its previous levels of gene expression. The information determining gene expression is often not directly encoded in the DNA and is hence termed 'epigenetic'. The molecular basis of epigenetic memory remains a subject of intense debate, but is likely to arise from the collaboration of several mechanisms, including histone post-translational modifications, transcription factors, DNA methylation and noncoding RNAs. In this article, we look at how these mechanisms interact to generate robust epigenetic states. We then consider recent observations that mitotic inheritance of stable gene expression can be compromised by interruption of DNA replication. We discuss how these data may provide direct evidence for a central role for histone modifications in transcriptional memory and how they could potentially provide an explanation for the some of the widespread alterations in transcription seen in cancer cells. PMID- 22226177 TI - Recombinant H2 relaxin inhibits apoptosis and induces cell proliferation in cultured leiomyoma cells without affecting those in cultured normal myometrial cells. AB - OBJECTIVE: To evaluate the effects of human relaxin on proliferation and apoptosis in cultured human uterine leiomyoma cells and normal myometrial cells. DESIGN: In vitro experiment. SETTING: Research laboratory at Kobe University Graduate School of Medicine. PATIENT(S): Nine patients undergoing hysterectomy for uterine leiomyoma. INTERVENTION(S): Cultured leiomyoma cells and normal myometrial cells were treated with human recombinant (rH2) relaxin. MAIN OUTCOME MEASURE(S): Human relaxin receptor LGR7 expressions in cultured leiomyoma cells and myometrial cells were evaluated by immunocytochemical staining. Cell proliferation, proliferating cell nuclear antigen-positive rate, and TUNEL positive rate were assessed by MTS assay, immunocytochemistry, and TUNEL assay, respectively. Caspase-3 expression was evaluated by Western blot analysis. RESULT(S): LGR7 expression was observed both in cultured human leiomyoma cells and myometrial cells. Compared with untreated control cultures, treatment with rH2 relaxin increased the number of viable cultured leiomyoma cells and the proliferating cell nuclear antigen-positive rate in those cells but not in myometrial cells. Moreover, treatment with rH2 relaxin decreased the TUNEL positive rate in cultured leiomyoma cells but not in myometrial cells. Similarly, Western blot analysis revealed that treatment with rH2 relaxin decreased the expression of caspase-3 in cultured leiomyoma cells but not in myometrial cells. CONCLUSION(S): These results suggest that rH2 relaxin selectively inhibits apoptosis by down-regulating caspse-3 expression and induces proliferation in cultured human leiomyoma cells without affecting apoptosis or proliferation in normal myometrial cells. PMID- 22226178 TI - Pattern of distant recurrence according to the molecular subtypes in Korean women with breast cancer. AB - BACKGROUND: Distant recurrence is one of the most important risk factors in overall survival, and distant recurrence is related to a complex biologic interaction of seed and soil factors. The aim of the study was to investigate the association between the molecular subtypes and patterns of distant recurrence in patients with breast cancer. METHODS: In an investigation of 313 women with breast cancer who underwent surgery from 1994 and 2000, the expressions of estrogen and progestrone receptor (ER/PR), and human epithelial receptor-2 (HER2) were evaluated. The subtypes were defined as luminal-A, luminal-HER2, HER2 enriched, and triple negative breast cancer (TNBC) according to ER, PR, and HER2 status. RESULTS: Bone was the most common site of distant recurrence. The incidence of first distant recurrence site was significantly different among the subtypes. Brain metastasis was more frequent in the luminal-HER2 and TNBC subtypes. In subgroup analysis, overall survival in patients with distant recurrence after 24 months after surgery was significantly different among the subtypes. CONCLUSIONS: Organ-specific metastasis may depend on the molecular subtype of breast cancer. Tailored strategies against distant metastasis concerning the molecular subtypes in breast cancer may be considered. PMID- 22226179 TI - Expression of cytoskeleton and energetic metabolism-related proteins at human abdominal aortic aneurysm sites. AB - OBJECTIVE: The purpose of this study was to evaluate the expression of proteins related to cytoskeleton and energetic metabolism at abdominal aortic aneurysm (AAA) sites using proteomics. Several remodeling-related mechanisms have been associated with AAA formation but less is known about the expression of proteins associated with cytoskeleton and energetic metabolism in AAAs. METHODS: AAA samples (6.73 +/- 0.40 cm size) were obtained from 13 patients during elective aneurysm repair. Control abdominal aortic samples were obtained from 12 organ donors. Proteins were analyzed using two-dimensional electrophoresis and mass spectrometry. RESULTS: The expression of filamin was increased in the AAA site compared to control abdominal aortic samples while microfibril-associated glycoprotein-4 isotype 1, annexin A5 isotype 1, and annexin A2 were reduced compared with control abdominal aortic samples. Reduction in expression level of energetic metabolism-associated proteins such as triosephosphate isomerase, glyceraldehyde 3-phosphate dehydrogenase, and cytosolic aldehyde dehydrogenase was also observed in AAAs compared to controls. Reduction of triosephosphate isomerase expression was also observed by Western blot, which was accompanied by diminished triosephosphate isomerase activity. At the AAA site, pyruvate dehydrogenase expression was reduced and the content of both lactate and pyruvate was increased with respect to controls without changes in lactate dehydrogenase activity. CONCLUSIONS: The present results suggest that an anaerobic metabolic state may be favored further to reduce the expression of cytoskeleton-related proteins. The better knowledge of molecular mechanism involved in AAAs may favor development of new clinical strategies. PMID- 22226180 TI - Intermediate-term outcome of carotid endarterectomy with bovine pericardial patch closure compared with Dacron patch and primary closure. AB - OBJECTIVE: Multiple studies have established that patch angioplasty following carotid endarterectomy (CEA) reduces the risk of subsequent stroke and restenosis compared with primary closure. Previous reports have also demonstrated bovine pericardium to be associated with similar rates of postoperative complications and restenosis compared with other patch materials. Due to favorable handling and sonographic properties, bovine pericardium has become increasingly popular as a patch option in recent years. However, the intermediate- and long-term performance of this material remains incompletely defined. Through a retrospective analysis of our carotid endarterectomy experience, we sought to compare the bleeding, infection, and pseudoaneurysm rates with bovine pericardium patch closure to those with Dacron patch and primary closure. In this study, 1331 primary carotid endarterectomies performed in our institution between 1996 and 2008 were grouped according to the method of arteriotomy closure: primary closure (PC) (216, 16.3%), Dacron patch angioplasty (DPA) (642, 48.2%), and bovine pericardial patch angioplasty (BPA) (457, 34.3%). Demographic variable and postoperative outcome measures collected real-time via a designated database manager were assessed by univariate and multivariate analysis. RESULTS: Mean follow-up for the entire cohort was 46.1 months. There were no statistically significant differences in rates of postoperative wound infection, hematoma, pseudoaneurysm formation, or 30-day stroke or 30-day mortality among the three groups. Combined 30-day stroke and death was significantly lower in the PC cohort (0.5% vs 2.3% DPA vs 2.4% BPA; P = .94, BPA vs DPA; P = .001, BPA vs PC; P = .001, DPA vs PC), while 5-year restenosis after both DPA (2.0% +/- 0.6%) and BPA (1.1% +/- 0.6%) was significantly lower compared with PC (5.2% +/- 1.6%) (P = .03, DPA vs PC; P = .008, BPA vs PC; P = .14, BPA vs DPA). Five-year survival following BPA (77.9% +/- 3.6%) was significantly improved compared with PC (66.9% +/- 3.5%) and DPA (60.8% +/- 2.1%) in univariate analysis (P = .24, DPA vs PC; P = .01, BPA vs PC; P = .03, BPA vs DPA), with statin use (P = .004) and male gender (P = .05) being positive predictors of enhanced survival on multivariate analysis. CONCLUSIONS: This single-institution, retrospective review represents the largest reported experience with BPA after CEA to date and is the only report comparing outcomes after BPA to PC or to DPA. Our experience further demonstrates that patch angioplasty is protective against restenosis after CEA compared with PC. Equivalent rates of perioperative bleeding, infection, and pseudoaneurysm formation were seen with each closure strategy in this study. PMID- 22226181 TI - Loss of lymphatic vessels and regional lipid accumulation is associated with great saphenous vein incompetence. AB - OBJECTIVE: Recent studies suggest that biologic changes in the vein wall associated with varicose veins (VVs) occur not only in valvular tissue but also in nonvalvular regions. We previously used imaging mass spectrometry (IMS) to determine the distribution of lipid molecules in incompetent valve tissue. In this study, we used IMS to analyze incompetent great saphenous veins (GSVs) in patients with varicose vein (VV) to assess the distribution of lipid molecules. METHODS: We obtained GSV tissue from 38 VV patients (50 limbs) who underwent GSV stripping. For the control veins (CV), we obtained GSV samples from 10 patients undergoing infrainguinal bypass with reversed GSV grafting for peripheral artery occlusive disease (10 limbs). Conventional and immunofluorescence staining were performed for histopathologic examination. The total lipid content in the homogenized vein tissue was determined. The localization of each lipid molecule in the vein wall was assessed by IMS. RESULTS: The histologic examination showed the VV walls were significantly thicker than the CV walls, and only the VV adventitia was positive for lipid staining. The VV wall had higher concentrations of phospholipids and triglycerides than the CV wall. IMS revealed an abnormal accumulation of lysophosphatidylcholine (LPC; 1-acyl 16:0) and phosphatidylcholine (diacyl 16:0/20:4) in the VV intima and media. Triglyceride was found only in VV adventitia. The number of lymphatic vessels, as measured by staining with D2-40, a lymphatic vessel-specific marker, was significantly lower in the VV adventitia than in the CV adventitia. Lymphatic vessel reduction may be associated with insufficient lymphatic drainage in the VV adventitia causing histologic changes in VV tissue. CONCLUSIONS: The accumulation of LPC (1-acyl 16:0) and PC (diacyl 16:0/20:4) in the VV intima and media may be associated with chronic inflammation, leading to VV tissue degeneration. Furthermore, insufficient lipid drainage by lymphatic vessel may be responsible for accumulation of lipid molecules and subsequent vein wall degeneration. PMID- 22226182 TI - A comparative study of the bell-bottom technique vs hypogastric exclusion for the treatment of aneurysmal extension to the iliac bifurcation. AB - INTRODUCTION: A significant proportion of patients undergoing endovascular aneurysm repair (EVAR) have common iliac artery aneurysms (CIAA). Aneurysmal involvement at the iliac bifurcation potentially undermines long-term durability. METHODS: Patients with CIAA who underwent EVAR were identified in two teaching hospitals. Bell-bottom technique (BBT; iliac limb >=20 mm) or internal iliac artery embolization and limb extension to the external iliac artery (IIE + EE) were used. Outcome between these two approaches was compared. RESULTS: We identified 185 patients. Indication for EVAR included asymptomatic abdominal aortic aneurysm (AAA) in 157, symptomatic or ruptured aneurysm in 19, and CIAA in nine. Mean AAA diameter was 59 mm. Among 260 large CIAAs that were treated, BBT was used to treat 166 CIAA limbs, and 94 limbs underwent IIE + EE. Total reintervention rates were 11% for BBT (n = 19) and 19.1% for IIE + EE (n = 18; P = .149). Rates of reintervention for type Ib or III endoleak were 4% for BBT (n = 7) and 4% for IIE + EE (n = 4; P > .99). The difference in limb patency rates was not significant. The 30-day mortality rate was 1%. Median follow-up was 22 months. Complications did not differ significantly between the two groups; however, the combined incidence of perioperative complications and reinterventions was higher in the IIE + EE group (49% vs 22%; P = .002). CONCLUSIONS: The combined incidence of perioperative complications and reinterventions is significantly higher with IIE + EE than with BBT; therefore, when feasible, BBT is desirable. PMID- 22226183 TI - The impact of adjunctive iliac stenting on femoral-femoral bypass in contemporary practice. AB - OBJECTIVES: Most reports of femoral-femoral bypass (FFB) were published before the era of endovascular intervention. This study examines the utilization and impact of adjunctive endovascular intervention on FFB in contemporary practice. METHODS: We reviewed 253 FFB performed in 247 patients between 1984 and 2010. Primary endpoints, including graft patency, primary-assisted patency, limb salvage, and survival, were assessed using Kaplan-Meier life-table analysis. Univariate and multivariate analyses were performed to determine predictors of primary endpoints. RESULTS: The indication for FFB included claudication (27%; n = 69) and critical limb ischemia (72%; n = 184). Forty-eight patients (19%) were treated urgently for acute ischemia. Mean follow-up was 5.6 +/- 5.5 years. Over the study interval, adjunctive iliac percutaneous transluminal angioplasty (PTA)/stent placement increased significantly from 0% to 54% (P trend < .001), while the rate of axillofemoral bypass or no inflow procedure decreased from 100% to 46% (P trend < .001). Despite increased utilization, iliac PTA/stenting was associated with decreased 5-year primary graft patency of 44% compared with 74% for axillofemoral bypass patients and 71% in patients with no adjunctive inflow procedure (P = .004). Patients with inflow iliac PTA/stents also had diminished 5 year assisted primary patency of 61% compared with 85% for axillofemoral bypass patients and 87% in patients without inflow revascularization (P = .002). Adjunctive iliac PTA/stenting did not impact limb salvage or overall survival. Five-year primary patency among claudicants and critical leg ischemia patients was 65% and 68%, respectively. CONCLUSIONS: The incidence of iliac PTA/stent placement in conjunction with FFB has increased significantly over time in contemporary practice. Reliance on iliac stent placement for FFB inflow is paradoxically associated with both diminished primary and assisted primary graft patency when compared with historical controls. These findings highlight the importance of patient selection and inflow consideration when performing FFB. PMID- 22226184 TI - Paclitaxel coating of the luminal surface of hemodialysis grafts with effective suppression of neointimal hyperplasia. AB - OBJECTIVES: Paclitaxel coating of hemodialysis grafts is effective in suppressing neointimal hyperplasia in the graft and vascular anastomosis sites. However, paclitaxel can have unwanted effects on the surrounding tissues. To reduce such problems, we developed a method to coat the drug only on the luminal surface of the graft, with little loading on the outer surface. METHODS: A peristaltic pump and a double-solvent (water and acetone) system were used to achieve an inner coating of paclitaxel. At the ratio of 90% acetone, paclitaxel was homogeneously coated only on the luminal surface of the graft without changing the physical properties. To determine its effect, grafts were implanted between the common carotid artery and the external jugular vein in pigs using uncoated control grafts (n = 6) and low-dose (n = 6, 0.22 MUg/mm(2)) and high-dose (n = 6, 0.69 MUg/mm(2)) paclitaxel inner-coated grafts. Cross-sections of graft-venous anastomoses were analyzed histomorphometrically 6 weeks after placement to measure the patency rate, percentage of luminal stenosis, and neointimal area. RESULTS: No signs of infection or bacterial contamination were observed in the paclitaxel inner-coated groups. Only one of the six control grafts was patent, but all of the paclitaxel-coated grafts were patent, with little neointima. The mean +/- standard error values of percentage luminal stenosis were 75.7% +/- 12.7% (control), 17.5% +/- 3.1% (low dose), and 19.7% +/- 3.0% (high dose). The values for the neointimal area (in mm(2)) were 8.77 +/- 1.66 (control), 3.53 +/- 0.73 (lose dose), and 4.24 +/- 0.99 (high dose). Compared with the control group, paclitaxel inner-coated vascular grafts significantly suppressed neointimal hyperplasia (low dose, P = .001; high dose, P = .002). Myofibroblast proliferation and migration into the graft interstices confirmed the firm attachment of the implanted graft to the surrounding tissue. CONCLUSIONS: Paclitaxel coating on the inner luminal surface of vascular grafts was effective in suppressing neointimal hyperplasia, with little inhibition of myofibroblast infiltration within the graft wall. PMID- 22226187 TI - Failed superficial femoral artery intervention for advanced infrainguinal occlusive disease has a significant negative impact on limb salvage. AB - OBJECTIVE: Endovascular treatment of superficial femoral artery (SFA) lesions is a well-established practice. The repercussions of failed SFA interventions are unclear. Our goal was to review the efficacy of SFA stenting and define negative effects of its failure. METHODS: A retrospective chart review was conducted from January 2007 to January 2010 that identified 42 limbs in 39 patients that underwent SFA stenting. Follow-up ankle-brachial index and a duplex ultrasound scan was performed at routine intervals. RESULTS: Mean patient age was 68 years (range, 43-88 years); there were 22 men (56%) and 17 women (44%). Intervention indication was claudication in 15 patients (36%), rest pain in seven patients (17%), and tissue loss in 19 patients (45%). There were 15 patients (36%) with TransAtlantic Inter-Society Consensus (TASC) A, nine patients (21%) with TASC B, five patients (12%) with TASC C, and 13 patients (31%) with TASC D lesions. The majority of lesions intervened on were the first attempt at revascularization. Three stents (7.7%) occluded within 30 days. One-year primary, primary-assisted, and secondary patency rates were 24%, 44%, and 51%, respectively. Limb salvage was 93% during follow-up. Seventeen interventions failed (40%) at 1 year. Of these, seven patients (41%) developed claudication, seven patients (41%) developed ischemic rest pain, and three patients (18%) were asymptomatic. During follow-up, three patients (7.7%) required bypass and three patients (7.7%) major amputation, one after failed bypass. All limbs requiring bypass or amputation had TASC C/D lesions. Thirty-day and 1-year mortality was 2.6% and 10.3%, respectively. CONCLUSIONS: Interventions performed for TASC C/D lesions are more likely to fail and more likely to lead to bypass or amputation. Interventions performed for TASC C/D lesions that fail have a negative impact on limb salvage. This should be considered when performing stenting of advanced SFA lesions. PMID- 22226188 TI - Placement of a retrievable inferior vena cava filter for deep venous thrombosis in term pregnancy. AB - OBJECTIVE: Venous thromboembolism is a significant cause of morbidity and death in pregnant women. Retrievable vena cava filters were placed right before labor as prophylaxis for peripartum pulmonary embolism. We reviewed the experience of caval filter placement and retrieval in term pregnancy in this study. METHODS: We reviewed 15 patients with deep venous thrombosis (DVT) of the lower extremity who underwent OptEase (Cordis Corp, New Brunswick, NJ) retrievable vena cava filter placement. DVT was diagnosed by clinical symptoms and Doppler ultrasound imaging. Subcutaneous low-molecular-weight heparin was eased 12 hours before cesarean delivery and restarted 12 hours after delivery. The caval filters were placed suprarenally from the jugular approach and retrieved from the femoral approach. RESULTS: The filters were successfully placed in all patients on the day of cesarean delivery. No placement-related complications occurred. The caval filter was left in situ as a permanent device in one patient because the captured thrombus within the filter was not eliminated after the thrombolytic therapy. Filters in other 14 patients were retrieved successfully, without difficulty, including in one patient after complete lysis of captured thrombus by the thrombolytic therapy. Oral warfarin therapy was recommended for at least 3 months after hospital discharge, and for at least 6 months in the patient with a caval filter left in situ. All patients were examined by Doppler ultrasound imaging during the follow-up. None presented with symptomatic pulmonary embolism or filter-related complications. CONCLUSIONS: OptEase retrievable vena cava filter placement and retrieval in term pregnant patients with extensive DVT of the lower extremities is safe, effective, and feasible. The results in our study may justify prophylactic filter placement use right before labor. PMID- 22226189 TI - Trends in management of abdominal aortic aneurysms. AB - OBJECTIVE: The purpose of this study was to evaluate patients undergoing elective repair of infrarenal abdominal aortic aneurysms (AAAs) and the longitudinal trends in surgical management (open repair vs endovascular aneurysm repair [EVAR]), factors associated with the choice of surgical technique, and differences in the rate of in-hospital mortality at a single large-volume Canadian center. METHODS: This retrospective cohort study used data from a prospectively collected vascular surgery database and reviewed all patients undergoing elective repair of an infrarenal AAA over a recent 10-year period (June 2000-May 2010). Information was reviewed regarding surgical techniques, patient demographics, and short-term outcomes. Subsequent analysis included univariate statistics and multivariable logistic regression with data presented as odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 1942 patients underwent elective AAA repair over this 10-year study period, 1067 (54.9%) via open repair and 875 (45.1%) via EVAR. The proportion of patients undergoing EVAR was significantly higher in the latter half of the study period compared to the first half (55.8% vs 33.9%; P < .01). Older patients (75 vs 71; P < .01) and those with higher American Society of Anesthesiologists classifications (P < .01) were more likely to receive endovascular repair than open repair. The overall in-hospital mortality rate in the entire cohort was low (2.3% for EVAR and 3.9% for open repair), and after multivariable logistic regression and adjustment for preoperative factors, in-hospital mortality was significantly higher in patients with open AAA repair (OR, 1.8; 95% CI, 1.04 3.13; P = .04). CONCLUSIONS: This 10-year analysis shows a significant shift toward an endovascular approach in the repair of infrarenal AAAs at our Canadian center. Similar to other jurisdictions, higher risk and older patients are more likely to be treated with an endovascular repair resulting in a survival advantage in these patients compared to standard open repair. PMID- 22226190 TI - Pharmacological maintenance of protein homeostasis could postpone age-related disease. AB - Over the last 10 years, various screens of small molecules have been conducted to find long sought interventions in aging. Most of these studies were performed in invertebrates but the demonstration of pharmacological lifespan extension in the mouse has created considerable excitement. Since aging is a common risk factor for several chronic diseases, there is a reasonable expectation that some compounds capable of extending lifespan will be useful for preventing a range of age-related diseases. One of the potential targets is protein aggregation which is associated with several age-related diseases. Genetic studies have long indicated that protein homeostasis is a critical component of longevity but recently a series of chemicals have been identified in the nematode Caenorhabditis elegans that lead to the maintenance of the homeostatic network and extend lifespan. Herein we review these interventions in C. elegans and consider the potential of improving health by enhancing protein homeostasis. PMID- 22226191 TI - The PFA-100 (r) does not predict delta-granule platelet storage pool deficiencies. AB - There are no published reports investigating the ability of the platelet function analyzer (PFA-100((r)) ) to detect the presence of delta-granule platelet storage pool deficiencies (delta-PSPD), a common mild bleeding disorder. Prior studies of the PFA-100((r)) and congenital platelet disorders have been limited by small numbers of patients with a variety of disorders. We examined PFA-100((r)) results in a large paediatric patient population diagnosed specifically with delta-PSPD, and determined the relationship between PFA-100((r)) and platelet electron microscopy (the gold standard for diagnosis). This study is a retrospective review of patients <19 years of age diagnosed with delta-PSPD at Nationwide Children's Hospital from 2008 to 2010. To examine the correlation between PFA 100((r)) and average number of granules per platelet we used Spearman's Rho as a non-parametric measure of dependence. A total of 105 patients diagnosed with delta-PSPD were included, of which 99 patients underwent PFA-100((r)) testing. Of those tested 46% had at least one abnormal closure time, whereas 16% had abnormal results for both cartridges. We found no statistical correlation between C-EPI closure time and average number of granules per platelet (rho= -0.0095, P-value = 0.9328), nor between C-ADP closure time and the average number of granules (rho = 0.0315, P-value = 0.7798). The PFA-100((r)), a widely used screening test for suspected bleeding disorders, did not correlate with presence or severity of delta-PSPD as determined by platelet electron microscopy. When evaluating patients with suspected bleeding disorders, PFA-100((r)) alone cannot be used to rule out the presence of a delta-PSPD. PMID- 22226192 TI - A comparison study on feature selection of DNA structural properties for promoter prediction. AB - BACKGROUND: Promoter prediction is an integrant step for understanding gene regulation and annotating genomes. Traditional promoter analysis is mainly based on sequence compositional features. Recently, many kinds of structural features have been employed in promoter prediction. However, considering the high dimensionality and overfitting problems, it is unfeasible to utilize all available features for promoter prediction. Thus it is necessary to choose some appropriate features for the prediction task. RESULTS: This paper conducts an extensive comparison study on feature selection of DNA structural properties for promoter prediction. Firstly, to examine whether promoters possess some special structures, we carry out a systematical comparison among the profiles of thirteen structural features on promoter and non-promoter sequences. Secondly, we investigate the correlations between these structural features and promoter sequences. Thirdly, both filter and wrapper methods are utilized to select appropriate feature subsets from thirteen different kinds of structural features for promoter prediction, and the predictive power of the selected feature subsets is evaluated. Finally, we compare the prediction performance of the feature subsets selected in this paper with nine existing promoter prediction approaches. CONCLUSIONS: Experimental results show that the structural features are differentially correlated to promoters. Specifically, DNA-bending stiffness, DNA denaturation and energy-related features are highly correlated with promoters. The predictive power for promoter sequences differentiates greatly among different structural features. Selecting the relevant features can significantly improve the accuracy of promoter prediction. PMID- 22226193 TI - Nanobiotechnologies for the detection and reduction of pathogens. AB - Advances in the manipulation of nanomaterials has permitted the development of nanobiotechnology with enhanced sensitivities and improved response times. Low levels of infection of the major pathogens require the need for sensitive detection platforms and the properties of nanomaterials make them suitable for the development of assays with enhanced sensitivity, improved response time and increased portability. Nanobiotechnologies focusing on the key requirements of signal amplification and pre-concentration for the development of sensitive assays for food-borne pathogen detection in food matrices will be described and evaluated. The potential that exists for the use of nanomaterials as antimicrobial agents will also be examined. PMID- 22226194 TI - Efficient xylose fermentation by the brown rot fungus Neolentinus lepideus. AB - The efficient production of bioethanol on an industrial scale requires the use of renewable lignocellulosic biomass as a starting material. A limiting factor in developing efficient processes is identifying microorganisms that are able to effectively ferment xylose, the major pentose sugar found in hemicellulose, and break down carbohydrate polymers without pre-treatment steps. Here, a basidiomycete brown rot fungus was isolated as a new biocatalyst with unprecedented fermentability, as it was capable of converting not only the 6 carbon sugars constituting cellulose, but also the major 5-carbon sugar xylose in hemicelluloses, to ethanol. The fungus was identified as Neolentinus lepideus and was capable of assimilating and fermenting xylose to ethanol in yields of 0.30, 0.33, and 0.34 g of ethanol per g of xylose consumed under aerobic, oxygen limited, and anaerobic conditions, respectively. A small amount of xylitol was detected as the major by-product of xylose metabolism. N. lepideus produced ethanol from glucose, mannose, galactose, cellobiose, maltose, and lactose with yields ranging from 0.34 to 0.38 g ethanol per g sugar consumed, and also exhibited relatively favorable conversion of non-pretreated starch, xylan, and wheat bran. These results suggest that N. lepideus is a promising candidate for cost-effective and environmentally friendly ethanol production from lignocellulosic biomass. To our knowledge, this is the first report on efficient ethanol fermentation from various carbohydrates, including xylose, by a naturally occurring brown rot fungus. PMID- 22226195 TI - A method for rapid screening of ketone biotransformations: detection of whole cell Baeyer-Villiger monooxygenase activity. AB - A method for screening of ketone biotransformations was developed and applied to the identification of Baeyer-Villiger monooxygenase (BVMO) activity. The method was based on the formation of a purple coloured product on reaction between an enolizable ketone and 3,5-dinitrobenzoic acid in an alkaline solution. Absorbance of the colour decreased with the size of the cycloketone ring. Stoichiometric ratio between cycloketone and 3,5-dinitrobenzoic acid was 1:1 at maximum absorbance. The method was applied for monitoring the consumption of cyclohexanone by bacteria under aerobic conditions, and was found to be potentially useful for both screening assays and quantitative measurements of BVMO activity. Compared to other existing methods, this method is faster, cheaper and amenable for whole cell assays. PMID- 22226196 TI - Characterization of potential elastase inhibitor-peptides regulated by a molecular switch for wound dressings applications. AB - Elastase plays an important role in wound healing process, degrading damaged tissue and allowing complete tissue recovery. The levels of human neutrophil elastase (HNE) are usually controlled by endogenous inhibitors. However, in the presence of high levels of elastase, like the ones present in chronic wounds, the inhibitors cannot overcome this overproduction and the enzyme starts to degrade the surrounding healthy tissue. In this work we report the development of a molecular switch to control the elastase activity in the exudate of non-healing chronic wounds. A peptide library was generated and screened in a microarray format for protein kinase-mediated phosphorylation. Two peptides were identified as casein kinase Idelta (CKI) substrates: KRCCPDTCGIKCL and its analogous peptide KRMMPDTMGIKML, with cysteine residues replaced by methionine residues. These peptides were studied in solution, both in the phosphorylated and non phosphorylated forms as potential inhibitors for elastase. The obtained results show that the reversible process of phosphorylation/dephosphorylation results in differential inhibitory activity of the peptides. Thus the reversible process of phosphorylation/dephosphorylation can be used as a kind of molecular switch to control elastase activity. Degradation studies reveal that both the inhibitor peptides and CKI are degraded by elastase. These results envisage the safe utilisation of these inhibitor-peptides together with CKI in the formulation of wound dressings. PMID- 22226197 TI - Engineered NADH-dependent GRE2 from Saccharomyces cerevisiae by directed enzyme evolution enhances HMF reduction using additional cofactor NADPH. AB - Furfural and 5-hydroxymethylfurfural (HMF) are inhibitors generated by lignocellulosic biomass pretreatment such as dilute acid hydrolysis that inhibit microbial growth and interfere with subsequent fermentation. It is possible to in situ detoxify these inhibitory compounds by aldehyde reductions using tolerant Saccharomyces cerevisiae. YOL151W (GRE2) is a commonly recognized up-regulated gene expressed under stress conditions that encodes reductase activities toward furfural and HMF using cofactor NADH. Applying a directed enzyme evolution approach, we altered the genetic code of GRE2 yielding two mutants with amino acid substitutions of Gln261 to Arg261 and Phe283 to Leu283; and Ile107 to Val107, Gln261 to Arg261, and Val285 to Asp285 for strain Y62-C11 and Y62-G6, respectively. Clones of these mutants showed faster growth rates and were able to establish viable cultures under 30 mM HMF challenges when compared with a wild type GRE2 clone when inoculated into synthetic medium containing this inhibitor. Compared with the wild type control, crude cell extracts of the two mutants showed 3- to 4-fold and 3- to 9-fold increased specific enzyme activity using NADH toward HMF and furfural reduction, respectively. While retaining its aldehyde reductase activities using the cofactor NADH, mutant Y62-G6 displayed significantly greater reductase activities using NADPH as the cofactor with 13- and 15-fold increase toward furfural and HMF, respectively, as measured by its partially purified protein. Using reverse engineering and site directed mutagenesis methods, we were able to confirm that the amino acid substitution of the Asp285 is responsible for the increased aldehyde reductase activities by utilizing the additional cofactor NADPH. PMID- 22226198 TI - Expression and characterization of an endo-1,4-beta-galactanase from Emericella nidulans in Pichia pastoris for enzymatic design of potentially prebiotic oligosaccharides from potato galactans. AB - Potato pulp is a high-volume side-stream from industrial potato starch manufacturing. Enzymatically solubilized beta-1,4-galactan-rich potato pulp polysaccharides of molecular weights >100 kDa (SPPP) are highly bifidogenic in human fecal sample fermentations in vitro. The objective of the present study was to use potato beta-1,4-galactan and the SPPP as substrates for enzymatic production of potentially prebiotic compounds of lower and narrower molecular weight. A novel endo-1,4-beta-galactanase from Emericella nidulans (anamorph Aspergillus nidulans), GH family 53, was produced in a recombinant Pichia pastoris strain. The enzyme was purified by Cu(2+) affinity chromatography and its optimal reaction conditions were determined to pH 5 and 49 degrees C via a statistical experimental design. The specific activity of the E. nidulans enzyme expressed in P. pastoris was similar to that of an endo-1,4-beta-galactanase from Aspergillus niger used as benchmark. The E. nidulans enzyme expressed in P. pastoris generated a spectrum poly- and oligo-saccharides which were fractionated by membrane filtration. The potential growth promoting properties of each fraction were evaluated by growth of beneficial gut microbes and pathogenic bacteria. All the galactan- and SPPP-derived products promoted the growth of probiotic strains of Bifidobacterium longum and Lactobacillus acidophilus and generally did not support the propagation of Clostridium perfringens in single culture fermentations. Notably the growth of B. longum was significantly higher (p<0.05) or at least as good on galactan- and SPPP-derived products as fructooligosaccharides (FOS). Except in one case these products did not support the growth of the pathogen Cl. perfringens to any significant extent. PMID- 22226199 TI - Photocrosslinked bovine serum albumin hydrogels with partial retention of esterase activity. AB - Novel biohybrid hydrogels based on bovine serum albumin (BSA) were synthesized by one-pot photopolymerization of chemically modified protein in the presence of N,N'-methylenebisacrylamide (MBA) as cross-linking agent under mild conditions. Two batches of methacrylated albumins were prepared by treating the protein with different amounts of methacrylic anhydride (MAN) and the degree of substitution (DS) of primary amines was quantified via trinitrobenzesulfonic acid (TNBS) colorimetric assay. Hydrogels readily formed when a diluted buffered solution of the modified protein and MBA was exposed to LW-UV in the presence of 1-[4-(2 hydroxyethoxy)phenyl]-2-hydroxy-2-methyl-1-propan-1-one (Irgacure 2959) as the radical initiator. In contrast, no hydrogel was obtained in the absence of a polymerizable BSA, nor when the cross-linker, the radical initiator or UV light exposure was excluded from the reaction, suggesting the critical importance of the combined conditions for hydrogel formation. Hydrogels were characterized via scanning electron microscopy (SEM) and the swelling ratios were monitored at different pHs. The esterolytic activity of the novel biohybrid materials was quantitatively investigated via UV-vis spectroscopy by measuring the release of para-nitrophenol upon incubation with para-nitrophenyl acetate (p-NPA) substrate. The effect of the addition of acrylic acid co-monomer and of the monomer concentration in the catalytic activity and in the swelling behavior was also examined. Finally, the reusability of the materials following one round of catalysis was evaluated. PMID- 22226200 TI - Coenzyme Q(10) production by immobilized Sphingomonas sp. ZUTE03 via a conversion extraction coupled process in a three-phase fluidized bed reactor. AB - A three-phase fluidized bed reactor (TPFBR) was designed to evaluate the potential of CoQ(10) production by gel-entrapped Sphingomonas sp. ZUTE03 via a conversion-extract coupled process. In the reactor, the CoQ(10) yield reached 46.99 mg/L after 8 h of conversion; a high-level yield of about 45 mg/L was maintained even after 15 repetitions (8 h/batch). To fully utilize the residual precursor (para-hydroxybenzoic acid, PHB) in the aqueous phase, the organic phase was replaced with new solution containing 70 mg/L solanesol for each 8 h batch. The CoQ(10) yield of each batch was maintained at a level of about 43 mg/L until the PHB ran out. When solid solanesol was fed to the organic phase for every 8 h batch, CoQ(10) could accumulate and reach a yield of 171.52 mg/L. When solid solanesol and PHB were fed to the conversion system after every 8 h batch, the CoQ(10) yield reached 441.65 mg/L in the organic phase after 20 repetitions, suggesting that the conversion-extract coupled process could enhance CoQ(10) production in the TPFBR. PMID- 22226201 TI - Two-step oxidation of glycerol to glyceric acid catalyzed by the Phanerochaete chrysosporium glyoxal oxidase. AB - Glyoxal oxidase of P. chrysosporium is a radical copper oxidase that catalyzes oxidation of aldehydes to carboxylic acids coupled to dioxygen reduction to H(2)O(2). In addition to known substrates, glycerol is also found to be a substrate for glyoxal oxidase. During enzyme turnover, glyoxal oxidase undergoes a reversible inactivation, probably caused by loss of the active site free radical, resulting in short-lasting enzyme activities and undetectable substrate conversions. Enzyme activity could be extended by including two additional enzymes, horseradish peroxidase and catalase, in addition to a redox chemical activator, such as Mn(III) (or Mn(II)+H(2)O(2)) or hexachloroiridate. Using this three-enzyme system glycerol was converted in glyceric acid in a two-step reaction, with glyceraldehyde as intermediate. A possible operation mechanism is proposed in which the three enzymes would work coordinately allowing to maintain a sustained glyoxal oxidase activity. In the course of its catalytic cycle, glyoxal oxidase alternates between two functional and interconvertible reduced and oxidized forms resulting from a two-electron transfer process. However, glyoxal oxidase can also undergo an one-electron reduction to a catalytically inactive form lacking the active site free radical. Horseradish peroxidase could use glyoxal oxidase-generated H(2)O(2) to oxidize Mn(II) to Mn(III) which, in turn, would reoxidize and reactivate the inactive form of glyoxal oxidase. Catalase would remove the excess of H(2)O(2) generated during the reaction. In spite of the improvement achieved using the three-enzyme system, glyoxal oxidase inactivation still occurred, which resulted in low substrate conversions. Possible causes of inactivation, including end-product inhibition, are discussed. PMID- 22226202 TI - Cyclodextrin glycosyltransferase encoded by a gene of Paenibacillus azotofixans YUPP-5 exhibited a new function to hydrolyze polysaccharides with beta-1,4 linkage. AB - The bacteria with hydrolysis activity to glucomannan were isolated from the rhizosphere of Amorphophallus konjac through enrichment cultivation. One strain with strong activity in degrading glucomannan was identified preliminarily as Paenibacillus azotofixans YUPP-5 according to the sequence analysis of 16S rDNA. This strain is able to hydrolyze many polysaccharide with beta-1,4 linkage, including glucomannan, galactomannan, xylan, carboxymethyl cellulose, and chitin. One hydrolytic enzyme band of approximately 70 kDa was examined from the supernatants of YUPP-5 by using zymogram with mixture polysaccharides as substrate. The encoding gene had an open reading frame of 2157 bp, which deduced cyclodextrin glycosyltransferase (CGTase), including 718 amino acids with a signal peptide in the N-terminal region. When the gene was expressed in Escherichia coli BL21, the recombinant CGTase exhibited strong activity in degrading polysaccharides with beta-1,4 linkage, and in forming cyclodextrin by using carboxymethyl cellulose as substrate. This CGTase exhibited some new functions. Finally, the hydrolytic oligosaccharides from galactomannan or glucomannan were detected by thin layer chromatography. Pentasaccharide, tetrasaccharide, trisaccharide, and disaccharide could be examined as reaction time went on. PMID- 22226203 TI - Synthesis and characterization of Ag nanoparticles@Polyethylene fibers under ultrasound irradiation. AB - The polyethylene fibers containing Ag nanoparticles were prepared through the chemical reduction under ultrasound irradiation. The effect of reducing reagent, power of ultrasound irradiation, reaction time and temperature in growth of the nanometric Ag were studied. Particle sizes and morphology of nanoparticle are depending on power of ultrasound irradiation. Results show a decrease in the particles size as increasing power of ultrasound irradiation. Also, an increase in temperature led to increase of particle size. The polyethylene fibers containing Ag nanoparticles were characterized with powder X-ray diffraction (XRD) and scanning electron microscopy (SEM). PMID- 22226204 TI - Tim-3, a negative regulator of anti-tumor immunity. AB - T cell immunoglobulin-3 (Tim-3) was identified nearly 10 years ago as a negative regulator of IFN-gamma-secreting CD4(+) T helper 1 and CD8(+) T cytotoxic 1 cells. Tim-3 is now classed with other inhibitory receptors, such as cytotoxic lymphocyte antigen-4 and programmed death-1 that are commonly referred to as immune checkpoint molecules. Recent studies have highlighted Tim-3 as an important player in the CD8(+) T cell exhaustion that takes place in chronic immune conditions such as chronic viral infection and cancer in both humans and experimental models. In addition to its role in exhausted T cells, recent data suggest that Tim-3 can further influence cancer outcome through its action on myeloid cells and cancer stem cells. PMID- 22226206 TI - [Atypical glandular cells of undetermined significance (agus) which entity?]. AB - OBJECTIVE: The aim of this study was to determine the incidence and evolution of the atypical glandular cells of undetermined significance (AGUS) without associated lesions identified on cervical Pap smear. MATERIAL AND METHODS: Retrospective study concerning 33.923 cervicovaginal smears performed in the Cytopathology Department of the Coimbra University Hospital (H.U.C.) between January 1995 an December 1997. AGUS diagnosis, isolated or associated with other lesions, was made in 716 cases. Four hundred fourty-four of them were refered to patiens of the H.U.C. Ginecology Department. One hundred seventy-seven cases were classified as AGUS alone; 62 related to the Ginecology Department where follow-up was performed within a period from 3 to 36 months. This study concerns exclusively AGUS patients without associated lesions (N=62). RESULTS: Sixty two cases of isolated AGUS were studied; the incidence was 0,52% and the average age 44,7 +/-11,7 [19-75] years old. Follow-up, performed between 3 and 36 months, revealed: isolated cervical smears (N=9), cervical smears and endocervical curettage (N=15), cervical smears with colposcopy and directed biopsy and/or endocervical curettage (N=11), cervical smears and colposcopy (N=19). Total histerectomy was performed in 8 cases by other reasons. Cervical smears were normal in 91,2 % of the cases (N=62). Histologic examination of surgical samples refering to total histerectomy, cervix biopsies was normal in 14 cases (38,9%), revealed cronic cervicitis in 14 cases, LSIL in 7 cases and endocervical polyps in one case. CONCLUSION: In spite of the reduced data of the study, the results point to no need to an agressive therapeutical approach at AGUS diagnosis in Pap smears. PMID- 22226205 TI - Plasma neutrophil gelatinase-associated lipocalin for the prediction of acute kidney injury in acute heart failure. AB - INTRODUCTION: The accurate prediction of acute kidney injury (AKI) in patients with acute heart failure (AHF) is an unmet clinical need. Neutrophil gelatinase associated lipocalin (NGAL) is a novel sensitive and specific marker of AKI. METHODS: A total of 207 consecutive patients presenting to the emergency department with AHF were enrolled. Plasma NGAL was measured in a blinded fashion at presentation and serially thereafter. The potential of plasma NGAL levels to predict AKI was assessed as the primary endpoint. We defined AKI according to the AKI Network classification. RESULTS: Overall 60 patients (29%) experienced AKI. These patients were more likely to suffer from pre-existing chronic cardiac or kidney disease. At presentation, creatinine (median 140 (interquartile range (IQR), 91 to 203) umol/L versus 97 (76 to 132) umol/L, P<0.01) and NGAL (114.5 (IQR, 67.1 to 201.5) ng/ml versus 74.5 (60 to 113.9) ng/ml, P<0.01) levels were significantly higher in AKI compared to non-AKI patients. The prognostic accuracy for measurements obtained at presentation, as quantified by the area under the receiver operating characteristic curve was mediocre and comparable for the two markers (creatinine 0.69; 95%CI 0.59 to 0.79 versus NGAL 0.67; 95%CI 0.57 to 0.77). Serial measurements of NGAL did not further increase the prognostic accuracy for AKI. Creatinine, but not NGAL, remained an independent predictor of AKI (hazard ratio (HR) 1.12; 95%CI 1.00 to 1.25; P=0.04) in multivariable regression analysis. CONCLUSIONS: Plasma NGAL levels do not adequately predict AKI in patients with AHF. PMID- 22226207 TI - [Presence of the double pfmdr1 mutation 86Tyr and 1246 Tyr in clones of a chloroquine-resistant west African isolate of Plasmodium falciparum]. AB - Isolates of Plasmodium falciparum from three areas of West Africa were recovered from cryopreservation and their chloroquine-sensitivity were determined in vitro. Of the 90 samples studied, 60 were from Guinea-Bissau (30Resistant/30Sensitive), 15 were from S. Tome and Principe (11Resistant/4Sensitive) and 15 were from Angola (11Resistant/4Sensitive). All the isolates were sensitive to mefloquine. Using the polymerase chain reaction/restriction fragment length polymorphism technique (PCR/RFLP) it was possible to detect two mutations in the pfmdr1 gene, often associated with chloroquine-resistance. 66% of the samples from Guine Bissau showed a correlation with chloroquine-resistance while 73% of the samples from Sao Tome and Angola altogether had the 86Tyr mutation. The present study on West African isolates and clones showed, for the first time, the presence of a double point mutation in the pfmdr1 gene one being found, up to now, only in South America isolates of Plasmodium falciparum. PMID- 22226208 TI - [Presence of pyrimethamine and cycloguanil resistance genotype in West Africa? Evidence of a single mutation 59Arg in the dhfr gene of Plasmodium falciparum]. AB - In 3 different geographical areas of West Africa (Guinea-Bissau, S. Tome e Principe and Angola) where chloroquine activity against P. falciparum seems to have decreased, the choice for prevention and/or treatment of malaria is often based on second line drugs such as Fansidar(r) (pyrimethamine/sulphadoxine). Little is known about the genetic basis of dhfr-ts gene mutations from parasites from these areas. In this study a PCR/RFLP methodology was used to screen 33 field isolates, without intervening steps of in vitro culture, for the pyrimethamine and cycloguanil sensitive/resistant genotype of P. falciparum. Analysis of the digested fragments revealed a prevalence of a Ser108 to Asn108 change in 63.63% of the samples tested. PMID- 22226209 TI - [Stroke in young adults]. AB - INTRODUCTION: Stroke in young adults is not as uncommon as one might expect and often present a diagnostic challenge. Our purpose was to determinate the incidence and causes of stroke in young adults admitted to our hospital. METHODS: retrospective study of all patients aged 18-45 years (36,9+/-7,4 years), admitted to our hospital from January 1998 to December 1999, with the diagnosis of stroke. A data sheet considering clinical profile, past medical history, investigation, stroke classification and cause and early clinical outcome, was filled according to clinical register. RESULTS: During the study period 751 patients were admitted with stroke, 581 (77,3%) with ischemic stroke and 170 (22,7%) with haemorrhage. Forty-five were young adults (6%). Thirty-five had ischemic stroke (77,8%), with a mean age of 37 years; the stroke was in the anterior circulation in 44%. In 94% of the patients risk factors for atherosclerotic vascular disease were identified. Ischemic stroke was classified, according to NINDS, in: atherosclerotic occlusive disease (28,6%), lacuna (14,3%), fibrodysplasia/arterial dissection (11,4%) cardioembolism (11,4%), undetermined (25,7%) and unknown (8,6%), because of early death or abandon. Ten patients were admitted with haemorrhage, with a mean age of 32 years, hypertension was the cause in 50%, altered vascular anatomy (arteriovenous malformation, aneurysm, angioma) in 40% and 10% were of unknown aetiology (early death). Mortality rate in the first week was 11,4% in ischemic stroke and 30% in haemorrhage. From the 45 patients admitted to this study, 85,7% were discharged with autonomy, 28% needed to continue physical rehabilitation. CONCLUSIONS: Stroke is an important pathology in the young adults accounting for 6% of all patients admitted with this diagnosis. In our population, atherosclerosis was responsable for an important percentage of cases, probably in association with the high incidence of risk factors for atherosclerotic vascular disease founded. We would like to stress once more the high importance of primary prevention, specially in this young group of patients. PMID- 22226210 TI - [Molecular characterisation of a kindred with MEN2A and clinical implications]. AB - INTRODUCTION: MEN2A is an autossomal dominant cancer syndrome characterised by the presence of medullary thyroid cancer, pheochromocytoma and primary hyperparathyroidism. Germline mutations of the RET protooncogene constitute the molecular defect and can be identified in affected individuals. Genetic screening of family members at risk allows early diagnosis and preventive measures before the appearance of the disease. We present a family with several members affected with MEN2A, their molecular characterisation and the clinical implications of genetic testing. POPULATION AND METHODS: We studied 18 members distributed among three generations of a family of which four members were clinically affected with MEN2A and cutaneous lichen amyloidosis. RET gene mutations were screened for in affected individuals and their offspring by PCR-RFLP techniques. RESULTS: Genetic testing revealed a point mutation at codon 634 (TGC>TGG), in the heterozygous state, in all affected individuals. The same mutation was also found in a five years old asymptomatic child which after total thyroidectomy showed to have multifocal medullary thyroid carcinoma. DISCUSSION: Genetic screening is the most suitable method for pre-symptomatic diagnosis of MEN2A allowing an efficient and early identification of individuals who will later develop the disease. These can be monitored more closely and be submitted to a prophylactic thyroidectomy before the appearance of medullary thyroid carcinoma. The ideal moment for this intervention is still under discussion although the results of this study suggest that it should be undertaken before the age of five. PMID- 22226211 TI - [Prevalence of type 1 diabetes mellitus in Portugal, 1995-1999: cohort of young men]. AB - We designed a study to assess the prevalence of type 1 diabetes mellitus among the Portuguese population. The study was based on a cohort of young Portuguese men inspected at the different recruitment Centres of the Portuguese Armed Forces in 1995 and 1999. We found a prevalence of 1.28 and 1.58 cases per 1,000 young men aged 20 (median), in 1995 and 1999, respectively. As far as the geographical distribution of this population was concerned, the recruitment centres (RC) with highest prevalence of diabetes in 1995 were that of Oporto, Evora and Lisboa. In 1999, highest prevalence was in Evora, Faro and Lisbon. The greatest increase was found at the RCs in Faro, Evora and Vila Real. Although the regional asymmetries are not very significant, they point to a higher prevalence in the southern region and in the urban areas of Lisbon and Oporto. PMID- 22226212 TI - [Prophylaxis of RhD isoimmunization: a proposal of management]. AB - Isoimmunisation RhD has an important perinatal morbidity and mortality. Since prophylaxis was introduced in the sixties, the incidence of haemolytic disease of the newborn has decreased. When administred in due time and in the right dosage anti-D immunoglobulin can prevent sensibilization. Nevertheless new cases continue to occur, underlying the need for an urgent improvement of our conduct. The purpose of this review is to provide an overview of the pathology of RhD isoimmunization and of aspects involved in its prophylaxis. PMID- 22226213 TI - [Berger disease: therapeutic algorithm proposal and chronic renal failure predictive factors]. AB - Berger disease is described as a glomerulonephritis by anti-IgA and anti-IgG immune complexes and it has become the most common form of glomerulonephritis, affecting up to 1,3% of the population, most often affecting young adult males. Berger disease etiopathogenesis is still unknown, being well recognized its temporal associations with bacterial and viral infections, as well with genetic factors which lead some authors to suggest the existence of a founder effect. Characteristically IgA nephropathy presents intermittent macroscopic hematuria following mucosal infections, nonnephrotic proteinuria and persistent microscopic hematuria. A renal biopsy should be performed in patients in whom this diagnosis is suspected, particularly if there is persistent proteinuria. IgA nephropathy was initially considered a benign disease, but long term follow up studies have shown the course to be slowly progressive with up to 50% of the patients developing terminal renal failure. The authors propose themselves a therapeutic algoritm, as well as clinical indicators of evolutive course. PMID- 22226214 TI - [Of medicine and arts: the poet, he and the other]. AB - The poet Mario de Sa-Carneiro, who commited suicide in Paris, in 1916, had had an appointment with the neurologist Egas Moniz, in Lisbon, two years before. After listenning to what he had to say, Moniz tells him that he identifies his symptons, curiously, with expressions of a poem he had read in the literary magazin Orfeu. This magazin wanted, in a provocative way, to announce a literature that was breaking with the past. Sa-Carneiro told him that he was the author of the poem. On reading it, Egas Moniz, had suspected that his author was a squizofrenic. In this article the literary and poetical work of Sa-Carneiro is analised, identifying it, as a whole, with the demonstrations that depict squizofrenia. PMID- 22226215 TI - [Granulosa cell tumor and pregnancy]. AB - Ovary tumor and pregnancy is a rare and serious condition with an unexpected outcome as it can interfere with the course of pregnancy. The authors report a case of a large juvenile granulosa cell tumor diagnosed at 33 weeks of pregnancy during a routine ultrasonographic examination. Pain, nausea and vomiting at the 35th week brought the suspicion of torsion. PMID- 22226216 TI - [Adrenergic beta-agonist intoxication]. AB - The authors describe two clinical cases (father and daughter), observed in the Hospital Urgency with distal tremors, anxiety, palpitations, nausea, headaches and dizziness, two hours after ingestion of cow liver. They also had leucocytosis (with neutrophylia), hypokalemia and hyperglycaemia. After treatment with potassium i.v. and propranolol, the symptoms disappeared. The symptoms recurred at home because the patients didn't take the prescribed medication and persisted for five days, with spontaneous disappearance. The serum of both patients revealed the presence of clenbuterol (65 hg/ml - father and 58 hg/ml - daughter). The animal's liver had a concentration of 1,42 mg/kg. Clenbuterol is a beta adrenergic agonist with low specificity, with some veterinary indications. However, this substance has been illegally used as a growth's promotor. We intend to alert doctors for this problem, particularly those that work in the Urgency. PMID- 22226217 TI - [Spondylodiscitis]. AB - The authors present a clinical case of a female child, aged 23 months, previously healthy that 24 hours after falling down started to refuse walking and complained about back pain. She never had fever. She felt better with nonsteroidal antiinflammatory drugs, restarting the symptoms, two days after therapy suppression. At admission on hospital she presented inability to flex the lower back and loss of lumbar lordosis, being normal the remaining physical examination. There was a raise of erythrocyte sedimentation rate (ESR) and a radiological narrowing of the L1/L2 inter-vertebral disc space, a compatible image of spondylodiscitis in the MRI. Several diagnosis hipothesis have been considered, being infectious spondylodiscitis the most probable. We instituted tuberculosis therapeutic during one year and intravenous ceftriaxone for tree weeks followed by oral acetil cefuroxime (tree weeks). The spine has been immobilized with spine support. At four months disease and two months therapy, a Oerskovia xanthineolytica was isolated by intervertebral needle biopsy. A good clinical and radiological evolution has been observed. The authors stress the importance of MRI and intervertebral needle biopsy in the diagnosis of spondylodiscitis. It is also enhanced the use of MRI and ESR in the monitoring of response to the treatment. PMID- 22226218 TI - [Phenotypic evolution in adrenoleukodystrophy]. AB - The X-linked adrenoleukodystrophy (ALD) is a genetic disease, caused by a defect mapped to Xq28. It is characterised by progressive demyelination of the cerebral white matter and adrenal insufficiency. The most important change that occurs is the accumulation of very long chain fatty acids (VLCFAs). The authors describe a patient whom the initial phenotype was Addison disease only (AO). With 21 years old he developed neurological complaints and the electrophysiological and neuroradiological studies performed, confirmed the phenotypic change from AO to pure Adrenomyeloneuropathy. Less than 2 years later, the clinical condition worsened and the magnetic resonance performed confirmed cerebral involvement by the disease. The authors point out the need to determine the levels of VLCFAs in all men with adrenal insufficiency. They also put much emphasis on the endocrinology and neurology following of any patient with ALD because of the possibility of a phenotypic change to occur. PMID- 22226219 TI - [Catastrophic primary antiphospholipid syndrome]. AB - Catastrophic antiphospholipid syndrome develops in a minority of patients with antiphospholipid syndrome, and is characterized by acute thrombotic microvasculopathy with multiorganic involvement (three or more organs). The aetiology is unknown, the diagnosis is complex, and the treatment is empiric, mortality may approach 50%. The authors present a clinical case of catastrophic antiphospholipid syndrome, diagnosed in a patient with abdominal pain and severe respiratory failure. PMID- 22226220 TI - [Drug induced lupus]. AB - A case of acute ischemia of the right inferior limb after anti-tuberculous therapy in a 42-Year old woman is reported. This complication was confirmed by artheriography and the investigation revealed vasculitis and anti-histone antibodies. Drug-induced lupus was then diagnosed. A brief review about this subject is also made. PMID- 22226221 TI - Structural and biochemical characteristics of various white adipose tissue depots. AB - It is now widely accepted that white adipose tissue (WAT) is not merely a fuel storage organ, but also a key component of metabolic homoeostatic mechanisms. Apart from its major role in lipid and glucose metabolism, adipose tissue is also involved in a wide array of other biological processes. The hormones and adipokines, as well as other biologically active agents released from fat cells, affect many physiological and pathological processes. WAT is neither uniform nor inflexible because it undergoes constant remodelling, adapting the size and number of adipocytes to changes in nutrients' availability and hormonal milieu. Fat depots from different areas of the body display distinct structural and functional properties and have disparate roles in pathology. The two major types of WAT are visceral fat, localized within the abdominal cavity and mediastinum, and subcutaneous fat in the hypodermis. Visceral obesity correlates with increased risk of insulin resistance and cardiovascular diseases, while increase of subcutaneous fat is associated with favourable plasma lipid profiles. Visceral adipocytes show higher lipogenic and lipolytic activities and produce more pro inflammatory cytokines, while subcutaneous adipocytes are the main source of leptin and adiponectin. Moreover, adipose tissue associated with skeletal muscles (intramyocellular and intermuscular fat) and with the epicardium is believed to provide fuels for skeletal and cardiac muscle contraction. However, increased mass of either epicardial or intermuscular adipose tissue correlates with cardiovascular risk, while the presence of the intramyocellular fat is a risk factor for the development of insulin resistance. This review summarizes results of mainly human studies related to the differential characteristics of various WAT depots. PMID- 22226222 TI - Post-burn hypertrophic scars are characterized by high levels of IL-1beta mRNA and protein and TNF-alpha type I receptors. AB - Post-burn hypertrophic scars are characterized by increased collagen synthesis and hyperplasia, and may be associated with erythema, pain, dysesthesia, pruritus, and skin border elevation. Although the etiopathogenesis of hypertrophic scarring remains unclear, proinflammatory and profibrogenic cytokines are known to play an important role in general skin dysfunction. This study assessed mRNA expression, proteins, and type I receptors of tumor necrosis factor-alpha (TNF-alpha) and interleukin 1-beta (IL-1beta) in normal skin, normotrophic and post-burn hypertrophic scars. Skin biopsies were obtained from 10 hypertrophic and 9 normotrophic scars, and 4 normal skin sites. Only post-burn scars covering more than 10% of the body were included. Ex vivo histopathological analysis evaluated scar maturity, in situ hybridization assessed mRNA expression, and cytokine protein and cytokine/cell colocalization were performed using single and double-label immunohistochemistry, respectively. IL-1beta is overexpressed in hypertrophic scars at the post-transcriptional level, associated primarily with keratinocytes and CD1a(+) cells. Type I receptors for TNF-alpha are overexpressed in blood vessels of hypertrophic scars. The coordinated overexpression of IL-1beta and TNF-alpha type I receptor may maintain the fibrogenic phenotypes of hypertrophic scars, even those in "remission". PMID- 22226224 TI - Cardamonin exerts potent activity against multiple myeloma through blockade of NF kappaB pathway in vitro. AB - NF-kappaB plays a major role in the pathology of multiple myeloma. Here, we intended to investigate the regulating effect of cardamonin on NF-kappaB in myeloma cells. We found for the first time that cardamonin suppressed viability and induced apoptosis of myeloma cells. Cardamonin activated caspase-3 and PARP and suppressed the expression of various anti-apoptotic proteins. We discovered that NF-kappaB was repressed by cardamonin through suppression of IKK expression and IkappaBalpha phosphorylation. Furthermore, the expression of NF-kappaB regulated gene products ICAM-1, COX-2 and VEGF was down-regulated by cardamonin. These results suggest that cardamonin blocks NF-kappaB pathway in human multiple myeloma cells. PMID- 22226223 TI - A framework for the youth with type 1 diabetes during the emerging adulthood transition. AB - Emerging adulthood, a developmental period from late adolescence to the late twenties, is a critical transition for youths with type 1 diabetes. This article proposes a framework for emerging adults with diabetes during this transitional time, integrating theoretical writings on transitions and emerging adulthood with empirical findings from younger adolescents with diabetes, about whom more is known. Key health, developmental, and behavioral outcomes are proposed, as well as key influential personal and environmental characteristics. Influential transitional events for this age group are also discussed relative to these outcomes and to personal and environmental characteristics. This framework provides a guide for longitudinal studies on the transition to young adulthood among emerging adults with type 1 diabetes. Identifying key times and influential factors will provide information for designing future effective interventions to improve glycemic control and quality of life for these youths as they transition to adulthood. PMID- 22226225 TI - Associations between EBV serostatus and organ transplant type in PTLD risk: an analysis of the SRTR National Registry Data in the United States. AB - In a prior multiorgan transplant database study, recipient Epstein-Barr virus (EBV) seronegativity was not associated with increased risk for posttransplant lymphoproliferative disorders (PTLD) in liver transplants (LTX), at variance with prior single center reports and with data from kidney and heart transplants (KTX and HTX). The Scientific Registry of Transplant Recipients (SRTR) in the United States is the only other registry with data on the required variables for comparison.Our study set comprised 112 756 KTX (580 PTLDs; 0.51%), 13 937 HTX (140 PTLDs; 1.0%) and 40 437 LTX (383 PTLDs; 0.95%) performed January 2003 onward. The unadjusted hazard ratio (HR) for PTLD if recipient EBV seronegative was 5.005 for KTX, 6.528 for HTX and 2.615 for LTX (p < 0.001 for all). In models adjusted for multiple covariates, the adjusted HR was 3.583 (p < 0.001) for KTX, 4.037 (p < 0.001) for HTX, 1.479 (p = 0.03) for LTX. Interaction models using EBV seropositive KTX as reference group showed significantly higher risk for all other EBV seronegative organ transplant groups and also for EBV seropositive LTX (AHR 2.053, p < 0.0001).Recipient EBV seronegativity is still significantly associated with risk for PTLD in LTX, though less so because of higher baseline risk in the EBV seropositive LTX group. PMID- 22226226 TI - Modeling causes of death: an integrated approach using CODEm. AB - BACKGROUND: Data on causes of death by age and sex are a critical input into health decision-making. Priority setting in public health should be informed not only by the current magnitude of health problems but by trends in them. However, cause of death data are often not available or are subject to substantial problems of comparability. We propose five general principles for cause of death model development, validation, and reporting. METHODS: We detail a specific implementation of these principles that is embodied in an analytical tool - the Cause of Death Ensemble model (CODEm) - which explores a large variety of possible models to estimate trends in causes of death. Possible models are identified using a covariate selection algorithm that yields many plausible combinations of covariates, which are then run through four model classes. The model classes include mixed effects linear models and spatial-temporal Gaussian Process Regression models for cause fractions and death rates. All models for each cause of death are then assessed using out-of-sample predictive validity and combined into an ensemble with optimal out-of-sample predictive performance. RESULTS: Ensemble models for cause of death estimation outperform any single component model in tests of root mean square error, frequency of predicting correct temporal trends, and achieving 95% coverage of the prediction interval. We present detailed results for CODEm applied to maternal mortality and summary results for several other causes of death, including cardiovascular disease and several cancers. CONCLUSIONS: CODEm produces better estimates of cause of death trends than previous methods and is less susceptible to bias in model specification. We demonstrate the utility of CODEm for the estimation of several major causes of death. PMID- 22226228 TI - Cord blood hematopoietic stem cell transplantation in an adolescent with haemophilia. PMID- 22226227 TI - Adenoid cystic carcinoma of the head and neck. AB - PURPOSE: To report our experience using radiotherapy alone or combined with surgery to treat adenoid cystic carcinoma of the head and neck. MATERIALS AND METHODS: Radiotherapy alone or combined with surgery was used to treat 120 previously untreated patients with adenoid cystic carcinoma (ACC) of the head and neck from August 1966 to March 2008. Patients were treated with curative intent. American Joint Committee on Cancer stage distribution was,T0 (n = 1), T1 (n = 26), T2 (n = 25), T3 (n = 14), T4 (n = 54), N0 (n = 113), N1 (n = 2), N2a (n = 1), N2b (n = 2), and N2c (n = 2). Treatment included surgery with postoperative radiotherapy (n = 71), radiotherapy alone (n = 46), and preoperative radiotherapy and surgery (n = 3). Incidental and clinical perineural invasion was found in 41 (34%) and 35 (29%) patients, respectively. Median follow-up was 8.6 and 11.6 years overall and among living patients, respectively. RESULTS: The 10-year overall, cause-specific, and distant metastasis-free survival rates, respectively, were as follows: radiotherapy alone, 37%, 46%, and 76%; surgery and radiotherapy, 57%, 71%, and 62%; and overall, 50%. The 10-year local control rates were as follows: radiotherapy alone, 36%; surgery and radiotherapy, 84%; and overall, 65%. The 10-year neck control rates were as follows: elective nodal irradiation (ENI), 98%; no ENI, 89%; and overall, 95%. CONCLUSIONS: Surgery and adjuvant radiotherapy offer the best chance for cure for patients with resectable adenoid cystic carcinomas of the head and neck. Some patients with advanced, incompletely resectable disease can be cured with radiotherapy alone. ENI should be considered for primary sites located in lymphatic-rich regions. PMID- 22226229 TI - Patent blue staining as a method to improve lymph node detection in rectal cancer following neoadjuvant treatment. AB - INTRODUCTION: Lymph node involvement is one of the most important prognostic factors in rectal cancer. After neoadjuvant treatment the number of retrieved lymph nodes is often reported to be low which impairs reliable tumour staging. This study examines the effect of patent blue staining on the number of harvested lymph nodes and evaluates whether a higher number of retrieved lymph nodes is of prognostic significance. PATIENTS AND METHODS: Between March 2007 and December 2010, 295 consecutive patients with locally advanced rectal cancer following neoadjuvant treatment were included. Specimens were either not stained (NB), injected with patent blue into the mesorectum (MB) or directly into the inferior mesenteric artery (AB). Data were retrieved from a prospective database. RESULTS: The number of evaluated lymph nodes was significantly higher in the stained specimens: mean 6.8 in the NB group (n=89), 11.5 in the MB group (n=86) and 17.4 in the AB group (n=106) (p<0.001). The percentage of patients with a minimum of 12 lymph nodes increased from 15.5% (NB) to 44.2% (MB) to 74.5% (AB) (p<0.001). The three-year cancer specific survival for the lymph node ratio (LNR) was 95% (0), 94.4% (0.01-0.1), 80.1% (0.11-0.4) and 63.7% (0.41-1). CONCLUSION: The use of patent blue in patients who underwent rectal cancer surgery after neoadjuvant treatment significantly enhanced lymph node harvest. Injection into the inferior mesenteric artery was most effective. This relatively simple and generally applicable method can help to improve lymph node detection which lowers the LNR and allows adequate tumour staging. PMID- 22226230 TI - Colorectal neoplasia in PSC-IBD patients: are times changing? PMID- 22226231 TI - Susceptibility to spontaneous bacterial peritonitis--are genetics the future? PMID- 22226232 TI - Movement quantification in epileptic seizures: a feasibility study for a new 3D approach. AB - Movement quantification of the human body is presently used for analyzing deficits resulting from Central Nervous System (CNS) pathologies or exploring the insights of the human motor system behaviour. Following our previous work on 2D movement quantification of epileptic seizures, we now present a feasibility study for a newly developed 3D technique. In order to validate this new 3D approach we made a comparison with the previous method. Both techniques were tested in two different datasets: a simple motor execution performed by a volunteer and a complex motor motion induced by a real epileptic seizure. The results obtained showed, as expected, the superior robustness and precision of the 3D approach but also confirmed the validity of the 2D method, given certain constraints. We conclude that the newly developed 3D system will highly improve our capacity of pursuing the clinical research on quantitative characterization of seizure semiology to support epilepsy diagnosis. PMID- 22226233 TI - The axillary/subclavian artery access route for transcatheter aortic valve replacement: a systematic review of the literature. AB - A primary predictor for success with catheter-based treatment of structural heart disease is having safe remote access to the heart. The devices for transcatheter aortic valve replacement require large-bore access, but many patients with severe aortic stenosis also have iliofemoral disease or relative contraindications to transapical access. In such situations, the leading alternative vascular access site has been the axillary or subclavian artery. This approach has been used with increasing frequency, and as these new devices become more readily available, it is anticipated that the experience will grow. Literature on the use of this access site for transcatheter aortic valve replacement is reviewed to highlight the current understanding about safety of this approach. PMID- 22226234 TI - Left atrial expansion index for predicting atrial fibrillation and in-hospital mortality after coronary artery bypass graft surgery. AB - BACKGROUND: Atrial fibrillation (AF), a common complication after coronary artery bypass graft surgery (CABG), is associated with prolonged hospital stay. This prospective study assessed the accuracy of left atrial parameters and additional preoperative characteristics for predicting post-CABG AF and in-hospital mortality. METHODS: A total of 197 patients without hemodynamic-significant valvular problems, who received isolated CABG, were enrolled. Echocardiography was performed before CABG. RESULTS: Compared with patients without post-CABG AF, those with post-CABG AF were older (71 vs 64 years, p<0.0001), had a higher incidence of CABG during index hospitalization of acute myocardial infarction and preoperative respiratory failure requiring ventilator support, lower left ventricular ejection fraction (0.41 vs 0.48, p<0.0001), lower left atrial expansion index (52.2% vs 93.3%, p<0.0001), and higher left ventricular filling pressure (24.2 vs 19.1 mm Hg, p<0.0001). Multivariate analysis of preoperative variables showed that independent predictors of AF included age (odds ratio [OR], 1.064; 95% confidence interval [CI], 1.022 to 1.107 per 1-year increase; p 0.002), maximal indexed left atrial volume (OR, 1.026; 95% CI, 1.002 to 1.051 per 1 mL/m2 increase; p 0.037) and left atrial expansion index (OR, 0.981; 95% CI, 0.962 to 0.998 per 1% increase; p 0.029). The left atrial expansion index was also significantly associated with in-hospital mortality (OR, 0.982; 95% CI, 0.951 to 0.996 per 1% increase; p 0.042). Incidence of post-CABG AF in patients with left atrial expansion index less than 120% progressively increased as left atrial expansion index decreased. CONCLUSIONS: Left atrial expansion index independently predicts post-CABG AF and in-hospital mortality. PMID- 22226235 TI - Acute kidney injury is associated with higher morbidity and resource utilization in pediatric patients undergoing heart surgery. AB - BACKGROUND: The RIFLE (risk, injury, failure, loss, and end-stage renal disease) classification system was developed to standardize the definition of acute kidney injury (AKI) in adults. We hypothesized that AKI was associated with increased mortality and morbidity. METHODS: Acute kidney injury was defined as a decrease in the amount of estimated creatinine clearance based on pediatric-modified RIFLE (pRIFLE) criteria. Using propensity score analysis, 325 patients who had AKI were matched to 325 patients who did not have AKI from a database of 1,510 consecutive pediatric patients who underwent cardiac surgery between January 2004 and December 2008 at a single center. The association between AKI and outcome was analyzed after propensity score matching of perioperative variables. RESULTS: Four hundred eighty-one patients (31.9%) had AKI according to the RIFLE categories. Of those 1,510, 173 (11.5%) reached pRIFLE criteria for risk; 26 (1.7%) reached the criteria for injury; and 282 (18.7%) reached the criteria for failure. Fifty-five patients (3.6%) died. The 2 matched groups were well balanced in terms of measured perioperative variables. Mortality rate was 5.2% in the AKI and 2.5% in the matched control group (p=0.09). Occurrence of low cardiac output syndrome (p=0.002), need for dialysis (p<0.001), and infection (p=0.03) were significantly higher, and duration of mechanical ventilation (p<0.001) and length of intensive care unit stay (p<0.001) were significantly longer compared with the matched control group. CONCLUSIONS: Acute kidney injury was independently associated with an increased occurrence of postoperative complications but not with mortality after pediatric cardiac surgery. PMID- 22226238 TI - Twelve-hour daytime observation of voiding pattern in newborns <4 weeks of age. AB - AIM: To investigate the voiding pattern in <4-week-old newborns by 12-h daytime observation periods. METHODS: Twenty-one healthy 1- to 28-day-old newborns were included (10 full term, 11 preterm). The 12-h free voiding parameters, including voiding frequency (VF), voiding volume (VV), post-voiding residual volumes (PRV) and status at voiding (awake/sleep), were recorded at day 1, 4, 7, 14 and 28 after birth. RESULTS: Voiding was recorded 778 times. VF increased in the full term and preterm newborns between day 4 and 7, decreased in preterms between day 14 and 28, but remained higher than in the full terms. VV increased twice in full terms and once in preterms during 28 days and PRV fluctuated. In contrast, VV was higher in the full term than in the preterms at days 4, 7, 14 and 28. PRV was higher at days 4 and 28. Interrupted voiding was less frequent in the full term than in the preterms. CONCLUSION: Voiding pattern in the preterms differed in many ways from that of the full-term newborns. Frequent interrupted and incomplete voiding pattern in the preterm newborns indicates a disrupted coordination of the detrusor-sphincter and a delayed maturation of the neural micturition centre. PMID- 22226237 TI - Early initiation of low-dose corticosteroid therapy in the management of septic shock: a retrospective observational study. AB - INTRODUCTION: The use of low-dose steroid therapy in the management of septic shock has been extensively studied. However, the association between the timing of low-dose steroid therapy and the outcome has not been evaluated. Therefore, we evaluated whether early initiation of low-dose steroid therapy is associated with mortality in patients with septic shock. METHODS: We retrospectively analyzed the clinical data of 178 patients who received low-dose corticosteroid therapy for septic shock between January 2008 and December 2009. Time-dependent Cox regression models were used to adjust for potential confounding factors in the association between the time to initiation of low-dose corticosteroid therapy and in-hospital mortality. RESULTS: The study population consisted of 107 men and 71 women with a median age of 66 (interquartile range, 54 to 71) years. The 28-day mortality was 44% and low-dose corticosteroid therapy was initiated within a median of 8.5 (3.8 to 19.1) hours after onset of septic shock-related hypotension. Median time to initiation of low-dose corticosteroid therapy was significantly shorter in survivors than in non-survivors (6.5 hours versus 10.4 hours; P=0.0135). The mortality rates increased significantly with increasing quintiles of time to initiation of low-dose corticosteroid therapy (P=0.0107 for trend). Other factors associated with 28-day mortality were higher Simplified Acute Physiology Score (SAPS) 3 (P<0.0001) and Sequential Organ Failure Assessment (SOFA) scores (P=0.0007), dose of vasopressor at the time of initiation of low-dose corticosteroid therapy (P<0.0001), need for mechanical ventilation (P=0.0001) and renal replacement therapy (P<0.0001), while the impaired adrenal reserve did not affect 28-day mortality (81% versus 82%; P=0.8679). After adjusting for potential confounding factors, the time to initiation of low-dose corticosteroid therapy was still significantly associated with 28-day mortality (adjusted odds ratio (OR) 1.025, 95% confidence interval (CI) 1.007 to 1.044, P=0.0075). The early therapy group (administered within 6 hours after the onset of septic shock, n=66) had a 37% lower mortality rate than the late therapy group (administered more than 6 hours after the onset of septic shock, n=112) (32% versus 51%, P=0.0132). CONCLUSIONS: Early initiation of low dose corticosteroid therapy was significantly associated with decreased mortality. PMID- 22226236 TI - Cilia functions in development. AB - Recent advances in developmental genetics and human disease gene cloning have highlighted the essential roles played by cilia in developmental cell fate decisions, left-right asymmetry, and the pathology of human congenital disorders. Hedgehog signaling in sensory cilia illustrates the importance of trafficking receptors to the cilia membrane (Patched and Smoothened) and the concept of cilia 'gatekeepers' that restrict entry and egress of cilia proteins (Suppressor of fused: Gli complexes). Cilia-driven fluid flow in the embryonic node highlights the role of motile cilia in both generation and detection of mechanical signals in development. In this brief review I select examples of recent studies that have clarified and consolidated our understanding of the role of cilia in development. PMID- 22226240 TI - Real world evaluation of three models of NHS smoking cessation service in England. AB - BACKGROUND: NHS Stop Smoking Services provide various options for support and counselling. Most services have evolved to suit local needs without any retrospective evaluation of their efficiency.Three local service evaluations were carried out at Bournemouth & Poole Teaching Primary Care Trust (PCT) (PCT1), NHS South East Essex (PCT2) and NHS Warwickshire (PCT3) to describe the structure and outcomes associated with different services. RESULT: Standardised interviews with key personnel in addition to analysis of data from 400 clients accessing the service after 1st April 2008 in each PCT. The PCTs varied in geography, population size and quit rate (47%-63%). Services were delivered by PCT-led specialist teams (PCT1), community-based healthcare providers (PCT3) and a combination of the two (PCT2) with varying resources and interventions in each.Group support resulted in the highest quit rates (64.3% for closed groups v 42.6% for one-to-one support (PCT1)). Quit rates were higher for PCT (75.0%) v GP (62.0%) and pharmacist-delivered care (41.0%) where all existed in the same model (PCT2). The most-prescribed therapy was NRT (55.8%-65.0%), followed by varenicline (24.5%-34.3%), counselling alone (6.0%-7.8%) and bupropion (2.0% 4.0%). CONCLUSION: The results suggest that service structure, method of support, healthcare professional involved and pharmacotherapy all play a role in a successful quit. Services must be tailored to support individual needs with patient choice and access to varied services being key factors. PMID- 22226241 TI - Systemic treatment of advanced pancreatic cancer. AB - Pancreatic cancer belongs to the most malignant gastrointestinal cancers and, in its advanced stage, remains a deadly disease for nearly all affected patients. Treatment of metastatic adenocarcinoma of the pancreas not only involves chemotherapy and targeted therapy, but also requires attention to accompanying comorbidities as well as frequently intensive supportive treatment and psychosocial support. Gemcitabine-based combinations with fluoropyrimidines and platin analogs have essentially failed to provide a substantial prolongation of survival and may constitute a treatment option only in patients with a good performance status. Among targeted therapies, only the EGFR tyrosine kinase inhibitor erlotinib has shown activity which is marginal in the overall population, but clinically relevant in patients developing skin rash. New avenues of polychemotherapy are presently explored since the gemcitabine-free FOLFIRINOX regimen (infusional 5-fluorouracil/folinic acid plus irinotecan and oxaliplatin) was shown to be markedly superior to gemcitabine in selected good-performance patients. Pancreatic cancer is notably characterized as a hypovascular tumor rich in desmoplastic stromal tissue. An innovative approach to treatment therefore focuses on peritumoral fibroblasts and aims to induce a depletion of the stroma either by inhibition of the hedgehog pathway or by targeting SPARC (secreted protein acidic and rich in cysteine) via application of albumin-bound paclitaxel. PMID- 22226239 TI - RNA-Seq and molecular docking reveal multi-level pesticide resistance in the bed bug. AB - BACKGROUND: Bed bugs (Cimex lectularius) are hematophagous nocturnal parasites of humans that have attained high impact status due to their worldwide resurgence. The sudden and rampant resurgence of C. lectularius has been attributed to numerous factors including frequent international travel, narrower pest management practices, and insecticide resistance. RESULTS: We performed a next generation RNA sequencing (RNA-Seq) experiment to find differentially expressed genes between pesticide-resistant (PR) and pesticide-susceptible (PS) strains of C. lectularius. A reference transcriptome database of 51,492 expressed sequence tags (ESTs) was created by combining the databases derived from de novo assembled mRNA-Seq tags (30,404 ESTs) and our previous 454 pyrosequenced database (21,088 ESTs). The two-way GLMseq analysis revealed ~15,000 highly significant differentially expressed ESTs between the PR and PS strains. Among the top 5,000 differentially expressed ESTs, 109 putative defense genes (cuticular proteins, cytochrome P450s, antioxidant genes, ABC transporters, glutathione S transferases, carboxylesterases and acetyl cholinesterase) involved in penetration resistance and metabolic resistance were identified. Tissue and development-specific expression of P450 CYP3 clan members showed high mRNA levels in the cuticle, Malpighian tubules, and midgut; and in early instar nymphs, respectively. Lastly, molecular modeling and docking of a candidate cytochrome P450 (CYP397A1V2) revealed the flexibility of the deduced protein to metabolize a broad range of insecticide substrates including DDT, deltamethrin, permethrin, and imidacloprid. CONCLUSIONS: We developed significant molecular resources for C. lectularius putatively involved in metabolic resistance as well as those participating in other modes of insecticide resistance. RNA-Seq profiles of PR strains combined with tissue-specific profiles and molecular docking revealed multi-level insecticide resistance in C. lectularius. Future research that is targeted towards RNA interference (RNAi) on the identified metabolic targets such as cytochrome P450s and cuticular proteins could lay the foundation for a better understanding of the genetic basis of insecticide resistance in C. lectularius. PMID- 22226242 TI - Optimizing radioimmunoconjugate delivery in the treatment of solid tumor. AB - Radioimmunotherapy (RIT) is a therapeutic modality which delivers alpha, beta or Auger emitters directly to targeted cancer cells. It has the advantage of regressing tumors while reducing non-targeted toxicities with the help of the targeting antibody. RIT applications relate to hematologic malignancies and now extend to solid tumors. Therapeutic efficacy of solid tumor RIT was limited by the inadequate penetration of radioimmunoconjugate (RIC). This paper reviews the properties of tumor vasculature abnormalities, the mechanisms of RIC penetration into solid tumors and strategies to enhance RIC delivery to facilitate RIT in reaching its full potential as a systemic cancer therapy. PMID- 22226243 TI - Phenotyping drug disposition in oncology. AB - Efficacy and toxicity of anticancer agents are highly variable between patients and variation in drug disposition is thought to be an important determinant. Genetics, physiology, and environment all are underlying factors contributing to this variation. Phenotyping drug metabolizing enzymes and drug transporters by using in vivo probes is a method that can be used to individualize drug therapy. This review discusses drug disposition of anticancer agents and the potential of phenotyping probes for phase I, II metabolic enzymes, and drug transporters in oncology. PMID- 22226244 TI - Complexation of cytochrome c with calixarenes incorporated into the lipid vesicles and supported membranes. AB - We studied the interaction of cytochrome c (cyt c) with specific calixarenes (CX) incorporated into the large unilamellar vesicles (LUV) composed of dimyristoylphosphatidylcholine (DMPC) or supported lipid membranes (sBLM) and compared this with not specific adsorption of cyt c to the LUV containing DMPC and anionic phosphatidic acid (PA) or sBLM composed of a mixture of DMPC and dimyristoylphosphatidic acid (DMPA). We showed that with increasing concentration of CX the average size of LUV increased and zeta potential become more negative as it is suggested from dynamic light scattering experiments. For PA containing LUV the increase in vesicle diameter was less expressed, but zeta potential decreased similarly like that of LUV contained CX. Cyt c did not affect significantly the LUV size, but reduced the negative zeta potential both for CX and PA containing vesicles. Electrochemical impedance spectroscopy allowed us to determine binding of cyt c to sBLM contained CX or DMPA. In both cases we observed decrease of charge transfer resistance with increasing cyt c concentration. The analysis of binding process suggests that the main driving force for interaction of cyt c with sBLM is the negative surface charge. PMID- 22226245 TI - Structural characterization of tetranortriterpenes from Pseudrocedrela kotschyi and Trichilia emetica and study of their activity towards the chaperone Hsp90. AB - Investigation of roots extracts Pseudrocedrela kotschyi and Trichilia emetica led to identification of 5 limonoid derivatives, Kotschyins D-H, and 11 known compounds. Their structures were elucidated by extensive 1D and 2D NMR experiments in conjunction with mass spectrometry. A surface plasmon resonance (SPR) approach was adopted to screen their Hsp90 binding capability and kotschyin D showed a significant affinity for the chaperone. Therefore, the characterization of the biological activity of kotschyin D by means of a panel of chemical and biological approaches, including limited proteolysis, molecular docking and biochemical and cellular assays, was performed. Our result indicated this compound as a type of client selective Hsp90 inhibitor, directly binding to the middle domain of the protein and possibly preventing its interaction with the activator of Hsp90 ATPase 1 (Aha1). PMID- 22226246 TI - Oxidation of dehydroascorbic acid and 2,3-diketogulonate under plant apoplastic conditions. AB - The rate of L-ascorbate catabolism in plants often correlates positively with the rate of cell expansion. The reason for this correlation is difficult to explore because of our incomplete knowledge of ascorbate catabolism pathways. These involve enzymic and/or non-enzymic oxidation to dehydroascorbic acid (DHA), which may then be hydrolysed to 2,3-diketogulonate (DKG). Both DHA and DKG were susceptible to further oxidation under conditions of pH and H2O2 concentration comparable with the plant apoplast. The kinetics of their oxidation and the identity of some of the products have been investigated here. DHA, whether added in pure form or generated in situ by ascorbate oxidation, was oxidised non enzymically to yield, almost simultaneously, a monoanion (cyclic-oxalyl threonate; cOxT) and a dianion (oxalyl-threonate; OxT). The monoanion was resistant to periodate oxidation, showing that it was not oxalic threonic anhydride. The OxT population was shown to be an interconverting mixture of 3-OxT and 4-OxT, differing in pK(a). The 3-OxT appeared to be formed earlier than 4 OxT, but the latter predominated at equilibrium. DKG was oxidised by H2O2 to two partially characterised products, one of which was itself further oxidised by H2O2 to yield threonate. The possible occurrence of these reactions in the apoplast in vivo and the biological roles of vitamin C catabolites are discussed. PMID- 22226247 TI - Improving the safety of blood glucose monitoring. PMID- 22226248 TI - A controlled study of the effectiveness of an adaptive closed-loop algorithm to minimize corticosteroid-induced stress hyperglycemia in type 1 diabetes. AB - To be effective in type 1 diabetes, algorithms must be able to limit hyperglycemic excursions resulting from medical and emotional stress. We tested an algorithm that estimates insulin sensitivity at regular intervals and continually adjusts gain factors of a fading memory proportional-derivative (FMPD) algorithm. In order to assess whether the algorithm could appropriately adapt and limit the degree of hyperglycemia, we administered oral hydrocortisone repeatedly to create insulin resistance. We compared this indirect adaptive proportional-derivative (APD) algorithm to the FMPD algorithm, which used fixed gain parameters. Each subject with type 1 diabetes (n = 14) was studied on two occasions, each for 33 h. The APD algorithm consistently identified a fall in insulin sensitivity after hydrocortisone. The gain factors and insulin infusion rates were appropriately increased, leading to satisfactory glycemic control after adaptation (premeal glucose on day 2, 148 +/- 6 mg/dl). After sufficient time was allowed for adaptation, the late postprandial glucose increment was significantly lower than when measured shortly after the onset of the steroid effect. In addition, during the controlled comparison, glycemia was significantly lower with the APD algorithm than with the FMPD algorithm. No increase in hypoglycemic frequency was found in the APD-only arm. An afferent system of duplicate amperometric sensors demonstrated a high degree of accuracy; the mean absolute relative difference of the sensor used to control the algorithm was 9.6 +/- 0.5%. We conclude that an adaptive algorithm that frequently estimates insulin sensitivity and adjusts gain factors is capable of minimizing corticosteroid-induced stress hyperglycemia. PMID- 22226250 TI - Exercise in closed-loop control: a major hurdle. AB - BACKGROUND: People with type 1 diabetes mellitus (T1DM) are at risk for exercise induced hypoglycemia. Prevention of such hypoglycemia in a closed-loop setting is a major challenge. Markers for automated detection of physical activity could be heart rate (HR) and body acceleration counts (AC). Correlations between HR, AC, and glucose concentrations before and after moderate intensity exercise were examined in T1DM patients during open- loop control. METHOD: Eleven T1DM subjects treated with an insulin pump performed moderate intensity exercise of 30 min. Glucose profiles, insulin concentrations, HR, and acceleration were measured. RESULTS: Mean (range) glucose decrease during exercise was 1.4 (0 to 3.3) mmol/liter. The mean increase in HR was 45.2 beats per minutes (15 to 106 bpm). Mean increase in AC was 18,000 (3,000 to 25,000). No correlations were seen between the glucose drop and HR or AC. A trend was observed between the increase in HR and increase in AC. CONCLUSION: Moderate intensity exercise resulted in increased HR and body AC while it decreased glucose concentrations but, in this real-time setting, no association could be demonstrated between the glucose decrease and increase in HR or AC. PMID- 22226249 TI - Continuous glucose monitoring considerations for the development of a closed-loop artificial pancreas system. AB - BACKGROUND: Commercialization of a closed-loop artificial pancreas system that employs continuous subcutaneous insulin infusion and interstitial fluid glucose sensing has been encumbered by state-of-the-art technology. Continuous glucose monitoring (CGM) devices with improved accuracy could significantly advance development efforts. However, the current accuracy of CGM devices might be adequate for closed-loop control. METHODS: The influence that known CGM limitations have on closed-loop control was investigated by integrating sources of sensor inaccuracy with the University of Virginia Padova Diabetes simulator. Non-glucose interference, physiological time lag and sensor error measurements, selected from 83 EnliteTM glucose sensor recordings with the Guardian(r) REAL Time system, were used to modulate simulated plasma glucose signals. The effect of sensor accuracy on closed-loop controller performance was evaluated in silico, and contrasted with closed-loop clinical studies during the nocturnal control period. RESULTS: Based on n = 2472 reference points, a mean sensor error of 14% with physiological time lags of 3.28 +/- 4.62 min (max 13.2 min) was calculated for simulation. Sensor bias reduced time in target for both simulation and clinical experiments. In simulation, additive error increased time <70 mg/dl and >180 mg/dl by 0.2% and 5.6%, respectively. In-clinic, the greatest low blood glucose index values (max = 5.9) corresponded to sensor performance. CONCLUSION: Sensors have sufficient accuracy for closed-loop control, however, algorithms are necessary to effectively calibrate and detect erroneous calibrations and failing sensors. Clinical closed-loop data suggest that control with a higher target of 140 mg/dl during the nocturnal period could significantly reduce the risk for hypoglycemia. PMID- 22226251 TI - Closed-loop insulin delivery utilizing pole placement to compensate for delays in subcutaneous insulin delivery. AB - BACKGROUND: We have previously used insulin feedback (IFB) as a component of a closed-loop algorithm emulating the beta cell. This was based on the observation that insulin secretion is inhibited by insulin concentration. We show here that the effect of IFB is to make a closed-loop system behave as if delays in the insulin pharmacokinetic (PK)/pharmacodynamic (PD) response are reduced. We examine whether the mechanism can be used to compensate for delays in the subcutaneous PK/PD insulin response. METHOD: Closed-loop insulin delivery was performed in seven diabetic dogs using a proportional-integral-derivative model of the beta cell modified by model-predicted IFB. The level of IFB was set using pole placement. Meal responses were obtained on three occasions: without IFB (NONE), reference IFB (REF), and 2xREF, with experiments performed in random order. The ability of the insulin model to predict insulin concentration was evaluated by correlation with the measured profile and results reported as R(2). The ability of IFB to improve the meal response was evaluated by comparing peak and nadir postprandial glucose and area under the curve (AUC; repeated measures analysis of variance with post hoc test for linear trend). RESULTS: Insulin concentration was well predicted by the model (median R(2) = 0.87, 0.79, and 0.90 for NONE, REF, and 2xREF, respectively). Peak postprandial glucose (294 +/- 15, 243 +/- 21, and 247 +/- 16 mg/dl) and AUC (518.2 +/- 36.13, 353.5 +/- 45.04, and 280.3 +/- 39.37 mg/dl . min) decreased with increasing IFB (p < .05, linear trend). Nadir glucose was not affected by IFB (76 +/- 5.4, 68 +/- 7.3, and 72 +/- 4.3 mg/dl; p = .63). CONCLUSIONS: Insulin feedback provides an effective mechanism to compensate for delay in the insulin PK/PD profile. PMID- 22226252 TI - Meta-analysis of overnight closed-loop randomized studies in children and adults with type 1 diabetes: the Cambridge cohort. AB - AIM: We reviewed the safety and efficacy of overnight closed-loop insulin delivery compared with conventional continuous subcutaneous insulin infusion (CSII) in two distinct age groups with type 1 diabetes mellitus (T1DM), young people aged 5 to 18 years and adults, combining data of previously published randomized studies. METHODS: We evaluated four randomized crossover studies in 17 children and adolescents [13.4 +/- 3.6 years; mean +/- standard deviation (SD)] and 24 adults (37.5 +/- 9.1 years) on 45 closed-loop (intervention) and 45 CSII (control) visits. Each subject attended for two overnight study visits, using either closed-loop or conventional pump therapy, in random order. In each age group, studies were designed to mimic realistic likely scenarios. In the children and adolescent studies, closed loop was used following a standard evening meal and following 40 min of moderate-intensity exercise. In the adult studies, closed loop was commenced following a 60 g carbohydrate meal or a 100 g carbohydrate meal accompanied by alcohol. The primary outcome measure was time for which plasma glucose was within target range (3.91-8.0 mmol/liter). RESULTS: Overnight closed loop increased the time in target plasma glucose in both young (from 40% to 60%, p = .002) and adults (from 50% to 76%, p < .001) compared with conventional CSII. Combined analysis showed an increase from 43% to 71% with closed loop (p < .001). Additionally, closed loop reduced the time spent below 3.91 mmol/liter and above 8.0 mmol/liter, from 4.1% to 2.1% (p = .01) and 33% to 20% (p = .03), respectively. Glycemic variability, as measured by the SD of plasma glucose, was lower during closed loop compared with CSII (1.5 versus 2.1 mmol/liter, p = .007). CONCLUSIONS: Overnight closed loop may improve glycemic control and reduce nocturnal hypoglycemia in both young people and adults with T1DM. PMID- 22226253 TI - AP@home: a novel European approach to bring the artificial pancreas home. AB - The development of an artificial pancreas (AP) made huge strides from 2006 to 2008 and a large number of activities are going on in this area of research. Until now, most AP systems under development were tested only under highly controlled conditions. The aim of our project, funded by the European Union, is to develop an AP system to such a level that it can be studied under daily life conditions at the home of patients with diabetes (hence AP@home). Based on a subcutaneous-subcutaneous closed-loop strategy (i.e., glucose sensing and insulin infusion in the subcutaneous tissue), two different approaches will be taken to achieve this aim: a two-port AP system and a single-port AP system. The two-port AP system will use off-the-shelf-components for the glucose sensor and insulin pump in combination with closed-loop algorithms generated in Europe. As to the single-port AP system, two different innovative single-port systems will be developed; in this case, continuous glucose monitoring and insulin infusion will take place via a single catheter. The first clinical trials with the two-port AP system under controlled clinical conditions have started and good progress has been made in the development of the single-port AP systems. We believe that our consortium of 12 European partners, which builds on existing achievements and close cooperation between academic centers and industry, can contribute substantially to the development of an AP system that can be used by patients in daily life. PMID- 22226254 TI - Safe glycemic management during closed-loop treatment of type 1 diabetes: the role of glucagon, use of multiple sensors, and compensation for stress hyperglycemia. AB - Patients with type 1 diabetes mellitus (T1DM) must make frequent decisions and lifestyle adjustments in order to manage their disorder. Automated treatment would reduce the need for these self-management decisions and reduce the risk for long-term complications. Investigators in the field of closed-loop glycemic control systems are now moving from inpatient to outpatient testing of such systems. As outpatient systems are developed, the element of safety increases in importance. One such concern is the risk for hypoglycemia, due in part to the delayed onset and prolonged action duration of currently available subcutaneous insulin preparations. We found that, as compared to an insulin-only closed-loop system, a system that also delivers glucagon when needed led to substantially less hypoglycemia. Though the capability of glucagon delivery would mandate the need for a second hormone chamber, glucagon in small doses is tolerated very well. People with T1DM often develop hyperglycemia from emotional stress or medical stress. Automated closed-loop systems should be able to detect such changes in insulin sensitivity and adapt insulin delivery accordingly. We recently verified the adaptability of a model-based closed-loop system in which the gain factors that govern a proportional-integral-derivative-like system are adjusted according to frequently measured insulin sensitivity. Automated systems can be tested by physical exercise to increase glucose uptake and insulin sensitivity or by administering corticosteroids to reduce insulin sensitivity. Another source of risk in closed-loop systems is suboptimal performance of amperometric glucose sensors. Inaccuracy can result from calibration error, biofouling, and current drift. We found that concurrent use of more than one sensor typically leads to better sensor accuracy than use of a single sensor. For example, using the average of two sensors substantially reduces the proportion of large sensor errors. The use of more than two allows the use of voting algorithms, which can temporarily exclude a sensor whose signal is outlying. Elements such as the use of glucagon to minimize hypoglycemia, adaptation to changes in insulin sensitivity, and sensor redundancy will likely increase safety during outpatient use of closed-loop glycemic control systems. PMID- 22226255 TI - Bringing the artificial pancreas home: telemedicine aspects. AB - The design and implementation of telemedicine systems able to support the artificial pancreas need careful choices to cope with technological requirements while preserving performance and decision support capabilities. This article addresses the issue of designing a general architecture for the telemedicine components of an artificial pancreas and illustrates a viable solution that is able to deal with different use cases and is amenable to support mobile-health implementations. The goal is to enforce interoperability among the components of the architecture and guarantee maximum flexibility for the ensuing implementations. Thus, the design stresses modularity and separation of concerns along with adoption of clearly defined protocols for interconnecting the necessary components. This accounts for the implementation of integrated telemedicine systems suitable as short-term monitoring devices for supporting validation of closed-loop algorithms as well as devices meant to provide a lifelong tighter control on the patient state once the artificial pancreas has become the preferred treatment for patients with diabetes. PMID- 22226256 TI - Closed-loop glucose control: psychological and behavioral considerations. AB - Since 2000, the diabetes community has witnessed tremendous technological advances that have revolutionized diabetes management. Currently, closed-loop glucose control (CLC) systems, which link continuous subcutaneous insulin infusion and continuous glucose monitoring, are the newest, cutting edge technology aimed at reducing glycemic variability and improving daily management of diabetes. Although advances in knowledge and technology in the treatment of diabetes have improved exponentially, adherence to diabetes regimens remains complex and often difficult to predict. Human factors, such as patient perceptions and behavioral self-regulation, are central to adherence to prescribed regimens, as well as to adoption and utilization of diabetes technology, and they will continue to be crucial as diabetes management evolves. Thus, the aims of this article are three-fold: (1) to review psychological and behavioral factors that have influenced adoption and utilization of past technologies, (2) to examine three theoretical frameworks that may help in conceptualizing relevant patient factors in diabetes management, and (3) to propose patient-selection factors that will likely affect future CLC systems. PMID- 22226257 TI - "Never events": hepatitis B outbreaks and patient notifications resulting from unsafe practices during assisted monitoring of blood glucose, 2009-2010. AB - INTRODUCTION: Despite sustained public health efforts to publicize the risk of hepatitis B virus (HBV) infection outbreaks during assisted monitoring of blood glucose (AMBG), outbreaks continue to occur. Here, we highlight several outbreaks and patient notifications due to AMBG, discuss prevention initiatives, and highlight gaps that remain. METHODS: We reviewed available data and information from investigations of health care-associated HBV infection outbreaks and patient notification events associated with AMBG in the United States between 2009 and 2010. RESULTS: Four HBV infection outbreaks were reported, all in assisted living facilities. Common infection control breaches included use of reusable finger stick devices, which are intended for personal use, on multiple persons; use of BG meters for more than one person without cleaning and disinfection between each use; and comingling of contaminated and clean equipment and supplies. Twenty-nine (88%) of the 33 residents who acquired acute HBV infection as part of these outbreaks received AMBG. Compared with those who did not, residents undergoing AMBG had significantly increased risk of acquiring acute HBV infection (relative risk: 27.7, 95% confidence interval: 10.3 to 74.4). During two patient notifications, approximately 320 persons were recommended to undergo bloodborne pathogen testing after being placed at risk for exposure to another person's blood when personal-use multilancet finger stick devices were selected for use on multiple persons. CONCLUSIONS: Misperception on the risk for bloodborne pathogen transmission and confusion regarding selection and appropriate use of BG monitoring devices for AMBG remain a problem. In addition to public health outreach and infection control recommendations, clear labeling, packaging, instructions for device use, and appropriate device marketing will assist in infection prevention efforts. PMID- 22226258 TI - Generic safety requirements for developing safe insulin pump software. AB - BACKGROUND: The authors previously introduced a highly abstract generic insulin infusion pump (GIIP) model that identified common features and hazards shared by most insulin pumps on the market. The aim of this article is to extend our previous work on the GIIP model by articulating safety requirements that address the identified GIIP hazards. These safety requirements can be validated by manufacturers, and may ultimately serve as a safety reference for insulin pump software. Together, these two publications can serve as a basis for discussing insulin pump safety in the diabetes community. METHODS: In our previous work, we established a generic insulin pump architecture that abstracts functions common to many insulin pumps currently on the market and near-future pump designs. We then carried out a preliminary hazard analysis based on this architecture that included consultations with many domain experts. Further consultation with domain experts resulted in the safety requirements used in the modeling work presented in this article. RESULTS: Generic safety requirements for the GIIP model are presented, as appropriate, in parameterized format to accommodate clinical practices or specific insulin pump criteria important to safe device performance. CONCLUSIONS: We believe that there is considerable value in having the diabetes, academic, and manufacturing communities consider and discuss these generic safety requirements. We hope that the communities will extend and revise them, make them more representative and comprehensive, experiment with them, and use them as a means for assessing the safety of insulin pump software designs. One potential use of these requirements is to integrate them into model-based engineering (MBE) software development methods. We believe, based on our experiences, that implementing safety requirements using MBE methods holds promise in reducing design/implementation flaws in insulin pump development and evolutionary processes, therefore improving overall safety of insulin pump software. PMID- 22226259 TI - Glucose control in Mayo Clinic intensive care units. AB - BACKGROUND: Safe and effective glucose control in the intensive care unit (ICU) continues to be actively pursued. Large clinical trials have examined the safety and efficacy of insulin infusion protocols in medical and surgical ICUs. We report experiences of a single-center standardized nurse-driven insulin infusion protocol in three ICUs in an observational quality-improvement study. METHOD: We analyzed the hourly point-of-care arterial blood glucose obtained during ICU insulin infusion protocol (protocol A) with a glucose target of 80-130 mg/dl in medical and surgical ICUs in February 2009. Following Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study results, the protocol was amended (protocol B) to achieve target glucose of 110-150 mg/dl. The performance of protocol B was assessed in the ICUs in May 2010 and compared with protocol A with respect to glucose concentrations and rates of severe (<40 mg/dl) and moderate (40-60 mg/dl) hypoglycemia. RESULTS: With protocol A, in medical (n = 44) and surgical (n = 164) ICUs taken together, median glucose was 119 mg/dl, with severe and moderate hypoglycemia rates 1.4% (3/208) and 7.7% (16/208), respectively, which were significantly lower than those reported by the NICE-SUGAR and the Leuven studies. With protocol B, in medical (n = 44) and surgical (n = 167) ICUs taken together, median glucose was 132 mg/dl, with severe and moderate hypoglycemia of 0 % (0/211) and 0.5% (1/211), respectively. CONCLUSION: The current ICU insulin infusion protocol (protocol B) reduces severe and moderate hypoglycemia without compromising glucose control when compared with protocol A. This could potentially impact patient-important outcomes. PMID- 22226260 TI - An analysis of the usability of inpatient insulin ordering in three computerized provider order entry systems. AB - BACKGROUND: Insulin is a highly scrutinized drug in hospitals since it is both frequently used and high risk. As the insulin ordering process makes a transition from pen and paper to computerized provider order entry (CPOE) systems, the effective design of these systems becomes critical. There are fundamental usability principles in the field of human-computer interaction design, which help make interfaces that are effective, efficient, and satisfying. To our knowledge, there has not been a study that specifically looks at how these principles have been applied in the design of insulin orders in a CPOE system. METHOD: We analyzed the usability of inpatient insulin ordering in three widely deployed CPOE systems-two commercially marketed systems and the U.S. Department of Veterans Affairs VistA Computerized Patient Record System. We performed a usability analysis using aspects of three different methods. Our first goal was to note each instance where a usability principle was either upheld or not upheld. Our second goal was to discover ways in which CPOE designers could exploit usability principles to make insulin ordering safer and more intuitive in the future. RESULTS: Commonly encountered usability principles included constraints, obviousness/self-evidence, natural mapping, feedback, and affordance. The three systems varied in their adherence to these principles, and each system had varying strengths and weaknesses. CONCLUSION: Adherence to usability principles is important when building a CPOE system, yet designers observe them to varying degrees. A well-designed CPOE interface allows a clinician to focus more of his or her mental energy on clinical decisions rather than on deciphering the system itself. In the future, intelligent design of CPOE insulin orders can be used to help optimize and modernize management of hyperglycemia in the hospital. PMID- 22226261 TI - Hemoglobin A1c testing in an emergency department. AB - BACKGROUND: Emergency department (ED) visits for hyperglycemia are common and costly. Enhanced strategies for recognizing and managing patients with diabetes in the ED are needed. Hemoglobin A1c (A1C) testing is typically used to assess level of glycemic control in the 2-3 months preceding an office visit. In this article, we report on potential roles for point-of-care (POC) A1C testing in the ED for patients presenting with uncontrolled hyperglycemia. METHODS: We enrolled patients presenting to an urban tertiary care hospital ED with blood glucose (BG) >= 200 mg/dl who were otherwise stable for discharge (n = 86) in a prospective, nonrandomized pilot study. Antihyperglycemic medication management, survival skills diabetes self-management education, and health system navigation were provided. Followup visits took place at 24-72 hours and at 2 and 4 weeks. Point of-care A1C testing was performed at baseline and at 2 weeks. Baseline A1C results were used by the ED physician and the educator to inform the patient of likely preadmission glycemic classification, and the potential role that the (diabetes mellitus) DM medication regimen assigned in the ED had in enabling overall progress in glycemic control at 2 weeks post-ED initiation of treatment. RESULTS: At baseline, 50% of POC A1C values were >13%. Mean BG fell from 356 +/- 110 mg/dl to 183 +/- 103 mg/dl at 4 weeks (average decrease of 173.5 g/dl, p < 0.001). Mean A1C fell by 0.4%, from 12.0 +/- 1.5% to 11.6 +/- 1.6% at 2 weeks, p = 0.048. There were zero instances of day 1 hypoglycemia and overall hypoglycemia rates were low (1.3%). CONCLUSIONS: Point-of-care A1C testing in the ED helped inform both the provider and the patient of likely prior glycemic status, including unrecognized or uncontrolled type 2 diabetes, and allowed emphasis of the importance of timely diabetes self-management education and medication management in preventing acute and chronic complications. Followup POC A1C testing at 2 weeks was used to confirm early improvement in glycemic control postintervention. PMID- 22226262 TI - The effect of an instant hand sanitizer on blood glucose monitoring results. AB - BACKGROUND: People with diabetes mellitus are instructed to clean their skin prior to self-monitoring of blood glucose to remove any dirt or food residue that might affect the reading. Alcohol-based hand sanitizers have become popular when soap and water are not available. The aim of this study was to determine whether a hand sanitizer is compatible with glucose meter testing and effective for the removal of exogenous glucose. METHODS: We enrolled 34 nonfasting subjects [14 male/20 female, mean ages 45 (standard deviation, 9.4)] years, 2 with diagnosed diabetes/32 without known diabetes]. Laboratory personnel prepared four separate fingers on one hand of each subject by (1) cleaning the second finger with soap and water and towel drying (i.e., control finger), (2) cleaning the third finger with an alcohol-based hand sanitizer, (3) coating the fourth finger with cola and allowing it to air dry, and (4) coating the fifth finger with cola and then cleaning it with the instant hand sanitizer after the cola had dried. Finger sticks were performed on each prepared finger and blood glucose was measured. Several in vitro studies were also performed to investigate the effectiveness of the hand sanitizer for removal of exogenous glucose.z RESULTS: Mean blood glucose values from fingers cleaned with instant hand sanitizer did not differ significantly from the control finger (p = .07 and .08, respectively) and resulted in 100% accurate results. Blood glucose data from the fourth (cola coated) finger were substantially higher on average compared with the other finger conditions, but glucose data from the fifth finger (cola-coated then cleaned with hand sanitizer) was similar to the control finger. The data from in vitro experiments showed that the hand sanitizer did not adversely affect glucose meter results, but when an exogenous glucose interference was present, the effectiveness of the hand sanitizer on glucose bias (range: 6% to 212%) depended on the surface area and degree of dilution. CONCLUSIONS: In our study, use of an instant hand sanitizer was compatible with the results of a blood glucose monitor and did not affect finger stick blood glucose results. However, depending on surface area, hand sanitizers may not be adequate for cleaning the skin prior to glucose meter testing. PMID- 22226263 TI - Evaluation of different disinfectants on the performance of an on-meter dosed amperometric glucose-oxidase-based glucose meter. AB - BACKGROUND: Off-meter dosed photometric glucose-oxidase-based glucose meters have been reported to be susceptible to interference by hydrogen-peroxide-based disinfecting agents. The objective of this study was to determine if a single application of hydrogen-peroxide-containing Accel(r) wipe to disinfect an on meter dosed amperometric glucose-oxidase-based glucose meter will influence its performance. METHOD: The performance of five on-meter dosed amperometric glucose oxidase-based glucose meters was determined before and after disinfecting the devices with a single application of either CaviWipes(r) (14.3% isopropanol and 0.23% diisobutyl-phenoxy-ethoxyethyl dimethyl benzyl ammonium chloride) or Accel (0.5% hydrogen peroxide) wipes. Replicate glucose measurements were conducted before disinfecting the devices, immediately after disinfecting, and then 1 and 2 min postdisinfecting, with measurements in triplicate. Analysis was sequentially completed for five different meters. Results were analyzed by a two-way analysis of variance (Analyze-it software). RESULTS: No clinical (<0.3 mmol/liter) or statistical differences (p > .05) in glucose concentration were detected when the on-meter dosed amperometric glucose-oxidase-based glucose meters were disinfected with either CaviWipes or Accel wipes and measured immediately or 1 or 2 min postdisinfecting. No clinically significant difference in glucose concentration was detected between meters (<0.3 mmol/liter). CONCLUSION: The on-meter dosed glucose oxidase amperometric-based glucose meters are not analytically susceptible to interference by a single application of hydrogen-peroxide containing Accel disinfectant wipes. PMID- 22226264 TI - Disinfected so it is safe and works. AB - There has been an upsurge in interest in monitoring the cleanliness of the health care environment as it relates to disease transmission. Cleaning and disinfecting practices are nothing new in health care facilities. However, continued development of analytical medical products such as point-of-care devices or, as in this review, glucose meters, has created potential risks to patients on a number of levels. Examples are (1) inappropriate disinfection of glucose meters so that the risk of disease transmission is increased and (2) cleaning agents potentially affecting glucose reading accuracy. Cleaning and disinfection recommendations have become available to address these issues. In this issue of Journal of Diabetes Science and Technology, Sarmaga and colleagues discuss the impact of a disinfecting agent on results generated from a particular device, which suggests that not all equipment are created equal and not all practices/products used to clean and disinfect are the same. It appears that more interaction must take place between vendors of these technologies as well as vendors of cleaning/disinfecting agents and the end users who will be performing all the requisite tasks to ensure a high quality product as well as care. PMID- 22226265 TI - Basic performance of an enzymatic method for glycated albumin and reference range determination. AB - BACKGROUND: Glycated albumin (GA) is a medium-term glycemic control marker of diabetes and may be more sensitive to changes in plasma glucose than hemoglobin A1c. We studied where and how many fructosyl groups bind to albumin, and which glycation sites are measured by the enzymatic method for GA. We also studied the basic performance of the enzymatic method for GA. METHODS: Glycated albumin was measured using an enzymatic method (Lucica(r)GA-L, Asahi Kasei Pharma) on a biochemical autoanalyzer. Molecular weights of purified GA and nonglycated albumin were measured by a mass spectrometry system. Two hundred one healthy volunteers with normal results of oral glucose tolerance testing were recruited to determine the reference range in Americans. RESULTS: The present method measured only glycated amino acids from albumin in serum protein. We estimate that the number of glycated amino acids measured by this method was approximately two per molecule of albumin. The general performance (sensitivity, specificity, reproducibility, linearity, interference) of the method was good. The reference range of GA% in Americans with normal glucose tolerance was determined to be 11.9 15.8% (mean +/- 2 standard deviations). Significant differences were not observed between the sexes; however, race differences were observed (higher levels in blacks relative to whites). CONCLUSIONS: The method was specific for measuring glycated amino acids in albumin and had good basic performance characteristics. The reference range in Americans was 11.9-15.8%. This method may be a useful indicator for diabetes control. PMID- 22226266 TI - Usefulness of glycated albumin assay for diabetes monitoring. AB - In this issue of Journal of Diabetes Science and Technology, Kohzuma and colleagues describe a method for measuring glycated amino acids in albumin from serum samples. This method may be useful as an alternative to hemoglobin A1c in monitoring patients with diabetes in certain situations, e.g., diabetes patients with chronic renal failure. Because there are drawbacks of each analyte for measuring glycemic status, it is important to be able to clearly define what is being measured and determine what factors might interfere with each type of measurement. Once the utility of glycated albumin measurement is clearly defined and its use is accepted for diabetes care, standardization may be warranted. PMID- 22226267 TI - The ASPIRE study: design and methods of an in-clinic crossover trial on the efficacy of automatic insulin pump suspension in exercise-induced hypoglycemia. AB - BACKGROUND: The Paradigm(r)VeoTM System includes a low glucose suspend (LGS) feature which suspends insulin delivery when a prespecified glucose threshold setting is reached by the associated continuous glucose monitoring (CGM) sensor. The ASPIRE (Automation to Simulate Pancreatic Insulin REsponse) study is a multicenter, in-clinic, randomized, crossover study to examine the efficacy of LGS in exercise-induced hypoglycemia. METHODS: Insulin-pump users underwent two separate exercise sessions, one with the LGS feature set to suspend insulin (LGS on) when the CGM-detected glucose concentration was <= 70 mg/dl and one with the LGS feature off. Exercise sessions were conducted after an overnight fast and with initial plasma glucose level as measured by the YSI 2300 STAT Plus glucose analyzer (YSI) of 100-140 mg/dl. Subjects exercised until their YSI value fell to <= 85 mg/dl; subsequent YSI values <70 mg/dl were recorded for up to 4 h to measure the duration and nadir of hypoglycemia. The protocol required that subjects with YSI values <50 or >300 mg/dl were rescued with carbohydrates or insulin, respectively, based on the provider's recommendation. The primary end point was comparison of duration and severity of hypoglycemia between LGS-on and LGS-off sessions. Secondary end points included areas under the glucose concentration curve, CGM sensor accuracy, and last YSI glucose. Device- and procedure-related adverse events and serious adverse events were recorded. RESULTS: Fifty adults and teenagers (17-58 years) with type 1 diabetes were randomized. Study completion is expected in November 2011. PMID- 22226268 TI - Effect on glycemic control by short- and long-term use of continuous glucose monitoring in clinical practice. AB - BACKGROUND: In Sweden, patients with diabetes mellitus frequently receive short term (<3 months) continuous glucose monitoring (CGM) to study glucose patterns or long-term CGM to treat poor glycemic control or severe hypoglycemia. The effects of CGM on glycemic control in clinical practice in relation to indication and duration of use has not been completely studied. METHODS: Patients with diabetes, among which 99% were diagnosed as type 1, receiving CGM at 10 outpatient clinics in Sweden were studied retrospectively. Long-term use of CGM was defined as >= 3 months use of CGM and short-term as <3 months. A control group matched on start date and date of latest value 3 months after the start was selected for both long and short-term groups. RESULTS: In 34 long-term users of CGM, over a mean follow up of 1.1 years, the adjusted mean difference of hemoglobin A1c (HbA1c) compared with controls (n = 408) was -0.76 (95% confidence interval -1.17; -0.33, p < .001). Long-term users with indications for high HbA1c (n = 15) had a reduction of 1.2% in HbA1c from 10.1 to 8.9% (p = .003), whereas patients with hypoglycemia as their indication (n = 16) decreased by 0.3% (p = .17). Nonsevere hypoglycemic events decreased in long-term users within the same follow-up period (p = .004). Short-term users showed no statistically significant improvement in HbA1c compared with controls at 1.1 years (n = 41), p = .85 or at 2.6 years (n = 43), p = .19. CONCLUSION: Long-term CGM use was associated with improved glycemic control in clinical practice and a reduction in nonsevere hypoglycemic events, whereas short-term use had no effect on HbA1c. The effect on glycemic control varied by indication. PMID- 22226269 TI - Needle with a novel attachment versus conventional screw-thread needles: a preference and ease-of-use test among children and adolescents with diabetes. AB - BACKGROUND: This usability test investigated the overall preference and usability of the novel NovoTwist(r) insulin pen needle versus conventional screw-thread needles, when used with Next Generation FlexPen(r), in children and adolescents with diabetes. METHODS: This was an open-label, randomized, crossover usability test in children and adolescents with type 1 diabetes who administered insulin with an insulin pen. Test needles were NovoTwist and the participant's current screw-thread needle (or NovoFine(r) needle). Following instruction, participants attached the needle to Next Generation FlexPen, made an injection into a foam cushion, and detached the needle. This procedure was conducted three times with both needles in a random order. Responses to 13 questions on user experience with each needle (including overall preference, ease of attachment/detachment of needle/cap, handling, learning, confidence in attachment, and convenience of use) were subsequently recorded on a six-point rating scale (1 = very difficult; 6 = very easy). RESULTS: Fifteen children aged >= 6 to <= 12 years and 15 adolescents aged >= 13 to <= 17 years participated in the test. A significantly higher proportion of children and adolescents (77%) indicated that they would prefer to use NovoTwist compared with screw-thread needles (p = .005). NovoTwist was preferred by most children and adolescents for overall ease of use (77%; p = .005), for ease of attachment (87%; p < .001) and detachment (83%; p < .001), and as the most appropriate needle to handle for daily injections (73%; p = .016). The mean rating for confidence in correct needle attachment was not significantly different between the two needle types. Seven out of eight parents of children who required assistance for their daily insulin injections stated that they would be "very likely" to allow their child to attach NovoTwist. CONCLUSIONS: These factors may promote confidence in this needle, and thus in self-injecting, among younger patients and their parents. PMID- 22226270 TI - Analysis of the NovoTwist pen needle in comparison with conventional screw-thread needles. AB - Administration of insulin via a pen device may be advantageous over a vial and syringe system. Hofman and colleagues introduce a new insulin pen needle, the NovoTwist, to simplify injections to a small group of children and adolescents. Their overall preferences and evaluation of the handling of the needle are reported in the study. This new needle has the potential to ease administration of insulin via a pen device that may increase both the use of a pen device and adherence to insulin therapy. PMID- 22226271 TI - Activation of polymorphonuclear leukocytes by candidate biomaterials for an implantable glucose sensor. AB - BACKGROUND: Continuous monitoring of glucose by implantable microfabricated devices offers key advantages over current transcutaneous glucose sensors that limit usability due to their obtrusive nature and risk of infection. A successful sensory implant should be biocompatible and retain long-lasting function. Polymorphonuclear leukocytes (PMN) play a key role in the inflammatory system by releasing enzymes, cytokines, and reactive oxygen species, typically as a response to complement activation. The aim of this study was to perform an in vitro analysis of PMN activation as a marker for biocompatibility of materials and to evaluate the role of complement in the activation of PMN. METHODS: Fifteen candidate materials of an implantable glucose sensor were incubated in lepirudin anticoagulated whole blood. The cluster of differentiation molecule 11b (CD11b) expression on PMN was analyzed with flow cytometry and the myeloperoxidase (MPO) concentration in plasma was analyzed with enzyme-linked immunosorbent assay. Complement activation was prevented by the C3 inhibitor compstatin or the C5 inhibitor eculizumab. RESULTS: Three of the biomaterials (cellulose ester, polyamide reverse osmosis membrane, and polyamide thin film membrane), all belonging to the membrane group, induced a substantial and significant increase in CD11b expression and MPO release. The changes were virtually identical for these two markers. Inhibition of complement with compstatin or eculizumab reduced the CD11b expression and MPO release dose dependently and in most cases back to baseline. The other 12 materials did not induce significant PMN activation. CONCLUSION: Three of the 15 candidate materials triggered PMN activation in a complement-dependent manner and should therefore be avoided for implementation in implantable microsensors. PMID- 22226272 TI - A spectrum of dynamic insulin sensitivity test protocols. AB - BACKGROUND: Numerous tests have been developed to estimate insulin sensitivity (SI). However, most of the established tests are either too expensive for widespread application or do not yield reliable results. The dynamic insulin sensitivity and secretion test (DISST) uses assays of glucose, insulin, and C peptide from nine samples to quantify SI and endogenous insulin secretion (UN) at a comparatively low cost. The quick dynamic insulin sensitivity test has shown that the DISST SI values are robust to significant assay omissions. METHODS: Eight DISST-based variations of the nine-sample assay regimen are proposed to investigate the effects of assay omission within the DISST-based framework. SI and UN were identified using the fully-sampled DISST and data from 218 nine sample tests undertaken in 74 female individuals with elevated diabetes risk. This same data was then used with appropriate assay omissions to identify SI and UN with the eight DISST-based assay variations. RESULTS: Median intraprocedure proportional difference between SI values from fully-sampled DISST and the DISST based variants was in the range of -17.9 to 7.8%. Correlations were in the range of r = 0.71 to 0.92 with the highest correlations between variants with the greatest commonality with the nine-sample DISST. Metrics of UN correlated relatively well between tests when C-peptide was assayed (r = 0.72 to 1) but were sometimes not well estimated when samples were not assayed for C-peptide (r = 0.14 to 0.75). CONCLUSIONS: The DISST-based spectrum offers a series of tests with very distinct compromises of information yield, accuracy, assay cost, and clinical intensity. Thus, the spectrum of tests has the potential to enable researchers to better allocate funds by selecting an optimal test configuration for their particular application. PMID- 22226273 TI - Novel methodology to determine the accuracy of the OmniPod insulin pump: a key component of the artificial pancreas system. AB - BACKGROUND: This article describes two novel and easy approaches for assessing the accuracy of insulin pumps as implemented within the artificial pancreas system. The approaches are illustrated by data testing the OmniPod Insulin Management System at its lowest delivery volume (0.05 U) and at doses of 0.1, 0.2, 1, and 6U. METHOD: In method 1, a pipette, digital microscope, and imaging software were used to measure average bolus delivery on a linear scale for multiple volumes. In method 2, a digital microscope and imaging software were used to measure the volume of a spherical bolus of 0.05 U of insulin. RESULTS: Bench testing results using the two novel methods demonstrated that the OmniPod is extremely accurate, with a relative error ranging from -0.90% to +0.96% for all measured doses (0.05, 0.1, 0.2, 1, and 6 U). In method 1, at target bolus dose of 0.05 U, the mean delivered dose (+/- standard deviation) was 0.0497 +/- 0.003 U, 0.099 +/- 0.005 U at 0.1 U, 0.2 +/- <1e-5 U at 0.2 U, 1.001 +/- 0.018 U at 1 U, and 6.03 +/- 0.04 U at 6 U. In method 2, at target bolus dose of 0.5 ml, the mean delivered dose for both OmniPods was 0.505 +/- 0.014. CONCLUSIONS: Both methods confirmed a high degree of accuracy for the OmniPod insulin pump. These techniques can be used to estimate delivery volume in other infusion pumps as well. PMID- 22226274 TI - Analysis of novel methods to determine the accuracy of the OmniPod insulin pump: a key component of the artificial pancreas system. AB - In this issue of Journal of Diabetes Science and Technology, Zisser and collegues describe two inexpensive methods for accurate measurement of dosage delivered by OmniPod insulin pump. The first method is based on imaging a meniscus movement in a micro-pipette and using simple image analysis; the second relies on using a digital microscope to measure the volume of a dispensed droplet while it is still attached to the cannula tip. Both methods produce accurate measurements for doses >0.2 U, and the latter method is especially appropriate for doses <0.2 U, with accuracies down to 0.9%. PMID- 22226275 TI - Pancreatic polypeptide administration enhances insulin sensitivity and reduces the insulin requirement of patients on insulin pump therapy. AB - INTRODUCTION: The effects of pancreatic polypeptide (PP) infusion were examined in patients on insulin pump therapy to determine whether PP administration can reduce insulin requirements in patients with type 1 diabetes mellitus (T1DM) or type 3c diabetes mellitus (T3cDM; pancreatogenic). METHODS: Ten subjects with long-standing T1DM (n = 7) or T3cDM (n = 3) on insulin pump treatment received a 72 h subcutaneous infusion of 2 pmol/kg/min bovine PP or saline by portable infusion pump in a single-blinded, randomized, crossover design. RESULTS: Pancreatic polypeptide infusion raised plasma PP levels to 450-700 pmol/liter. Daily insulin infusion requirements (I) fell from 48 +/- 6.9 to 40 +/- 7.5 U on day 2 (p < .05) and from 46 +/- 7.7 to 37 +/- 6.6 U on day 3 (p < .05) of PP infusion compared with saline. Corrected for average blood glucose concentration (G), I/G fell in 10/10 subjects during the second 24 h period and in 7/10 subjects during the third 24 h period; sensitivity to insulin, calculated as 1/(I/G), increased 45% +/- 12% on day 2 (p < .01) and 34% +/- 14% on day 3 (p < .05) of PP infusion. Pancreatic polypeptide responses to a test meal were compared with the change in insulin infusion requirements in 5 subjects; the reduction in insulin requirements seen during PP infusion correlated with the degree of baseline PP deficiency (p < .002). CONCLUSIONS: A concurrent subcutaneous infusion of PP enhances insulin sensitivity and reduces insulin requirements in patients with long-standing T1DM and T3cDM on insulin pump therapy. The benefit of PP infusion correlated with the degree of PP deficiency. PMID- 22226277 TI - Data-mining technologies for diabetes: a systematic review. AB - BACKGROUND: The objective of this study is to conduct a systematic review of applications of data-mining techniques in the field of diabetes research. METHOD: We searched the MEDLINE database through PubMed. We initially identified 31 articles by the search, and selected 17 articles representing various data-mining methods used for diabetes research. Our main interest was to identify research goals, diabetes types, data sets, data-mining methods, data-mining software and technologies, and outcomes. RESULTS: The applications of data-mining techniques in the selected articles were useful for extracting valuable knowledge and generating new hypothesis for further scientific research/experimentation and improving health care for diabetes patients. The results could be used for both scientific research and real-life practice to improve the quality of health care diabetes patients. CONCLUSIONS: Data mining has played an important role in diabetes research. Data mining would be a valuable asset for diabetes researchers because it can unearth hidden knowledge from a huge amount of diabetes-related data. We believe that data mining can significantly help diabetes research and ultimately improve the quality of health care for diabetes patients. PMID- 22226276 TI - Consensus report: the current role of self-monitoring of blood glucose in non insulin-treated type 2 diabetes. AB - The Coalition for Clinical Research--Self-Monitoring of Blood Glucose Scientific Board convened a meeting in San Francisco, CA, July 20-21, 2011, to discuss the current practice of self-monitoring of blood glucose (SMBG) in non-insulin treated (NIT) type 2 diabetes mellitus (T2DM). Twelve physician panel members from academia, practice, and government attended this meeting. These experts came from the United States, Brazil, Canada, France, Germany, Italy, and the United Kingdom. In addition, three consultants from Australia, Germany, and the United States contributed to the group's final report. This coalition was organized by Diabetes Technology Society. Self-monitoring of blood glucose was studied from eight perspectives related to patients with NIT T2DM: (1) epidemiological studies; (2) randomized controlled trials (RCT)s and meta-analyses; (3) targets, timing, and frequency of SMBG use; (4) incidence and role of SMBG in preventing hypoglycemia with single-drug regimens and combination regimens consisting of antihyperglycemic agents other than secretagogues and insulin; (5) comparison of SMBG with continuous glucose monitoring; (6) technological capabilities and limitations of SMBG; (7) barriers to appropriate use of SMBG; and (8) methods and end points for appropriate future clinical trials. The panel emphasized recent studies, which reflect the current approach for applying this intervention. Among the participants there was consensus that: SMBG is an established practice for patients with NIT T2DM, and to be most effective, it should be performed in a structured format where information obtained from this measurement is used to guide treatment; New, high-quality efficacy data from RCTs have demonstrated efficacy of SMBG in NIT T2DM in trials reported since 2008; Both patients and health care professionals require education on how to respond to the data for SMBG to be effective; and Additional well-defined studies are needed to assess the benefits and costs of SMBG with end points not limited to hemoglobin A1c. PMID- 22226278 TI - A review of the security of insulin pump infusion systems. AB - Insulin therapy has enabled patients with diabetes to maintain blood glucose control to lead healthier lives. Today, rather than injecting insulin manually using syringes, a patient can use a device such as an insulin pump to deliver insulin programmatically. This allows for more granular insulin delivery while attaining blood glucose control. Insulin pump system features have increasingly benefited patients, but the complexity of the resulting system has grown in parallel. As a result, security breaches that can negatively affect patient health are now possible. Rather than focus on the security of a single device, we concentrate on protecting the security of the entire system. In this article, we describe the security issues as they pertain to an insulin pump system that includes an embedded system of components, which include the insulin pump, continuous glucose management system, blood glucose monitor, and other associated devices (e.g., a mobile phone or personal computer). We detail not only the growing wireless communication threat in each system component, but also describe additional threats to the system (e.g., availability and integrity). Our goal is to help create a trustworthy infusion pump system that will ultimately strengthen pump safety, and we describe mitigating solutions to address identified security issues. PMID- 22226279 TI - What can we learn from patient-reported outcomes of insulin pen devices? AB - Although a variety of effective treatment options are available for patients with type 1 or type 2 diabetes, many patients in the United States have difficulty reaching their glycemic goals. Patient adherence to insulin therapy, which often involves self-administered subcutaneous injections of insulin using either a vial and syringe or an insulin pen device, is often poor. Various factors associated with the type of injection device have been shown to influence the rate of patient adherence to insulin therapy. This article reviews patient-reported outcome (PRO) evidence from pediatric and adult studies that compared insulin pen devices with vial and syringe use. In a majority of these cases, patients preferred the pen devices over vial and syringe, stating advantages such as ease of use, convenience, greater confidence in their ability to properly administer the drug, and a greater perceived social acceptance. The pens were considered less painful than syringes and were associated with less needle fear. In addition, PRO evidence has directed pen technology design, leading to development of more advanced insulin pen devices. By appreciating the correlation between adherence to insulin regimens and a patient's device preference, clinicians can make improved treatment recommendations to facilitate achievement and maintenance of glycemic targets. PMID- 22226281 TI - Actionable self-monitoring of blood glucose: redefining the role for patients using multiple daily injection therapy. AB - Self-monitoring of blood glucose (SMBG) values is an accepted requirement for patients with diabetes using multiple daily injections of insulin. Nevertheless, for many patients, the full value of SMBG has yet to be realized due to a number of factors that contribute to patients not taking appropriate action based on the achieved result. The reasons for this are complex but are related to the burden imposed by performing the tests, the need for complex numerical calculations, and the demand for undertaking this activity multiple times each day. In the near future, SMBG devices are likely to include technological innovations that are aimed at overcoming these barriers, offering "actionable" SMBG for patients using insulin. These innovations should include technologies that will allow customization and individualization based upon specific therapy regimens. PMID- 22226280 TI - Is there a relationship between mean blood glucose and glycated hemoglobin? AB - Measurement of hemoglobin A1c (HbA1c) is considered the gold standard for monitoring chronic glycemia of diabetes patients. Hemoglobin A1c indicates an average of blood glucose levels over the past 3 months. Its close association with the risk for the development of long-term complications is well established. However, HbA1c does not inform patients about blood glucose values on a daily basis; therefore, frequent measurements of blood glucose levels are necessary for the day-to-day management of diabetes. Clinicians understand what HbA1c means and how it relates to glucose, but this is not the case with patients. Therefore, the translation of the HbA1c results into something more familiar to patients seemed a necessity. The scope of this article is to review the literature to search for enough scientific evidence to support the idea of a close relationship between HbA1c and mean blood glucose (MBG), and to justify the translation of HbA1c into something that reflects the MBG. Most studies confirm a close relationship between HbA1c and MBG, although different studies result in different linear equations. Factors affecting this relationship may limit the usefulness and applicability of a unique mathematical equation to all diabetes populations. PMID- 22226282 TI - Diabetic foot ulcers and vascular insufficiency: our population has changed, but our methods have not. AB - Diabetic foot complications are increasing in prevalence worldwide. Care and attention to these complications have improved greatly. Many advanced therapies are now being investigated or taken through final stages of clinical studies worldwide. However, the data upon which assumptions regarding morbidity, healing, and mortality have been based are grossly outdated. The purpose of this brief article is to report on current data regarding neuropathic and neuroischemic wounds and to propose that the latter category of advanced-stage diabetic foot wound may now be emerging as the most commonly encountered lesion in the developed world. Unfortunately, it is still systematically excluded from most clinical study criteria. Additionally, just as in the care of cancer, we call for therapy of these advanced-stage diabetic foot ulcers to be managed in similarly interdisciplinary centers where patients may have access to potentially beneficial clinical trials. PMID- 22226284 TI - Precision, accuracy, and user acceptance of the OneTouch SelectSimple blood glucose monitoring system. AB - BACKGROUND: The OneTouch(r) SelectSimpleTM blood glucose monitoring system (BGMS) is a device for self-monitoring of blood glucose designed for ease of use. Alarms alert subjects to low [20-69 mg/dl (1.1-3.8 mmol/liter)], high [180-239 mg/dl (9.9-13.2 mmol/liter)], and very high [240-600 mg/dl (13.3-33.1 mmol/liter)] blood glucose readings. METHODS: Repeatability in blood and intermediate precision with aqueous controls were examined using blood from one donor adjusted to different glucose concentrations, and tested with 10 meters and 1 test-strip lot. System accuracy was evaluated with blood samples from 100 diabetes patients tested on 3 test-strip lots, compared with a reference system (YSI 2300 STAT). To test user accuracy, patients (n = 156) and health care professionals (HCPs) tested subject blood with the SelectSimple twice. Health care professionals evaluated subject BGMS technique after a 3-5 day home-testing period. Users evaluated the instructions for use and responded to a user acceptance questionnaire. RESULTS: In repeatability and intermediate precision testing, the SelectSimple BGMS had a coefficient of variation of <= 5% or standard deviation of <= 5 mg/dl. In the clinical accuracy study, 100% of measurements <75 mg/dl (4.2 mmol/liter) were within +/- 15 mg/dl (0.8 mmol/liter) of reference value, and 99.6% of measurements >= 75 mg/dl (4.2 mmol/liter) were within +/-20%. Patients were able to use the BGMS appropriately and evaluated it as easy to use. Acceptance of the SelectSimple BGMS was within predefined limits. CONCLUSIONS: In these studies, the SelectSimple BGMS met all criteria for precision, system, and user accuracy, was easy to use, and was well accepted by patients. PMID- 22226283 TI - Intensive control of diabetes in the hospital: why, how, and what is in the future? AB - Intensive management of diabetes is identified as a critical component of inpatient care. However, the fundamental question that remains is whether controlling glycemia in noncritically ill diabetes patients at the lower end of the current guidelines improves outcomes of hospitalization, long-term outcomes of the primary condition, and long-term outcomes of diabetes compared with average glycemia greater than 180 mg/dl. A group of clinical investigators- Planning Research in Inpatient Diabetes (PRIDE)--is preparing randomized controlled trials with the hope of defining optimal glycemic targets for hospitalized patients with diabetes. Given the variety of clinical situations that can occur in the inpatient setting, many medical centers have established dedicated inpatient diabetes teams. There is ample evidence, albeit retrospective, that these teams improve inpatient glucose control and reduce lengths of hospital stays. Using hospitalization as an opportunity to educate patients about diabetes and to optimize their treatment regimen may improve long term outpatient glycemic control. PMID- 22226285 TI - Analysis of the performance of the OneTouch SelectSimple blood glucose monitoring system: why ease of use studies need to be part of accuracy studies. AB - The article entitled "Precision, Accuracy, and User Acceptance of the OneTouch SelectSimple Blood Glucose Monitoring System" by Philis-Tsimikas and colleagues in this issue of Journal of Diabetes Science and Technology demonstrates that the OneTouch(r) SelectSimpleTM glucose meter meets current regulatory expectations for glucose meter performance. These authors describe three studies: precision, accuracy, and ease of use. Accuracy study analysis includes the effects of accuracy and precision. The ease-of-use study was analyzed separately, as recommended by the International Organization for Standardization 15197 glucose standard. The ultimate goal of an evaluation is to estimate the distribution of errors (from any source) that will be experienced in routine use. To accomplish this, ease-of-use results need to be part of the accuracy dataset. PMID- 22226286 TI - Evaluation of the analytical performance of the coulometry-based Optium Omega blood glucose meter. AB - BACKGROUND: The goal of diabetes treatment is maintaining near normoglycemia based on self-monitoring of blood glucose (SMBG). In this study, an evaluation of the analytical performance of the coulometry-based Optium OmegaTM glucose meter designed for SMBG has been carried out. METHODS: The assessment of precision and between-lot variability was based on glucose measurements in ethylene diaminetetraacetic acid venous blood samples. Glucose concentrations measured in 289 fresh capillary blood samples using the Omega glucose meter and the Biosen C_line analyzer were compared. RESULTS: Within-run imprecision coefficient of variation for the lower and higher glucose concentrations amounted to 5.09 and 2.1%, respectively. The relative lot-dependent differences found for the lower and higher glucose concentrations were equal to 6.8 and 2.6%, respectively. The glucose meter error calculated for various concentration ranges amounted from 2.22 to 4.48%. The glucose meter error met the accuracy criteria recommended by the International Organization for Standardization and the American Diabetes Association. The Passing-Bablok agreement test and error grid analysis with 96% of results in zone A indicated good concordance of results, including glucose concentrations below 100 mg/dl. CONCLUSIONS: The evaluated Optium Omega glucose meter fits the analytical requirements for its use in blood glucose monitoring in diabetes patients. PMID- 22226287 TI - Evaluation of the analytical performance of the coulometry-based Optium Omega blood glucose meter: what do such evaluations show? AB - The article entitled "Evaluation of the Analytical Performance of the Coulometry Based Optium Omega Blood Glucose Meter", by Solnica and colleagues in this issue of Journal of Diabetes Science and Technology demonstrates that the Optium Omega blood glucose meter meets the analytical requirements for glucose meter performance and it is stated that the results are clinically useful. The authors studied precision, bias, and reagent lot-to-lot error sources. The ultimate goal of an evaluation is to estimate the distribution of errors (from any source) that will be experienced in routine use. The data collection and analysis methods to achieve this are discussed, as are the standards used to compare the results. Claiming clinical usefulness is almost a boilerplate statement in evaluations but meeting standards does not prove clinical usefulness. PMID- 22226288 TI - Impact of high altitudes on glucose control. PMID- 22226289 TI - Accuracy of dosage volume for halfway doses in the Victoza Pen. PMID- 22226290 TI - An analysis of dosage volume for halfway doses in the Victoza Pen. PMID- 22226291 TI - Comment on "Do different body colors and labels of insulin pens enhance a patient's ability to correctly identify pens for injecting long acting versus short-acting insulins?". PMID- 22226292 TI - Longitudinal changes in psychosocial constructs and physical activity among adults with physical disabilities. AB - BACKGROUND: Given the importance of physical activity (PA) and the low activity levels among adults with physical disabilities, it is important to understand how temporal changes in psychosocial constructs affect PA changes over time. OBJECTIVE/HYPOTHESIS: Examine if changes in the transtheoretical model (TTM) constructs affected changes in PA levels over time. METHODS: One hundred thirty two adults with physical disabilities, such as multiple sclerosis and spinal cord injuries, completed a web-based survey once every 4 months, for a total of 3 time points, to assess the TTM constructs and PA. Six latent growth curve analyses were conducted using Mplus(5) to examine if longitudinal changes in the TTM constructs affected temporal changes in PA levels. RESULTS: All six hypothesized models fit the sample data well (e.g., chi(2) = NS; RMSEA = <.001-.06). In a descending order of significance, the best predictors of the initial levels of PA were the stages of change, the behavioral processes of change, the cognitive processes of change, self-efficacy, and perceived pros. The meaningful predictors of PA changes over time were the initial levels and the slopes of the cognitive processes of change, perceived pros, and the behavioral processes of change. Although the slopes of the stages of change and perceived cons did not have a statistically significant effect on PA changes, their effects approached a medium size (.33 and .38, respectively). CONCLUSIONS: In order to reassure the maintenance of an exercise program, interventionists need to first emphasize cognitive, motivational strategies (cognitive processes of change), such as the importance of PA and positive thoughts about exercise participation as well as exercise benefits (pros) before they implement behavioral strategies (behavioral processes of change), such as social support, goal setting, and self-rewarding. PMID- 22226293 TI - A comparison of autism spectrum disorder DSM-IV criteria and associated features among African American and white children in Philadelphia County. AB - BACKGROUND: Racial differences are documented in the timing and type of autism spectrum disorder (ASD) diagnosis among white and African American children. Differences in clinical presentation by race may contribute to these disparities. This study explores documented differences in core ASD symptoms and associated behavioral features among African American and white children. METHODS: This project is a secondary data analysis from the Pennsylvania Autism and Developmental Disabilities Surveillance Program and utilized methodology that evaluates existing records, reviews, and codes for DSM-IV criteria for ASD and 12 associated behavioral features. The sample comprised 343 children meeting surveillance case definition for ASD, from 3 population-based cohorts of children in Philadelphia County. RESULTS: A higher frequency of white children compared to African American children with ASD have documented DSM-IV criteria of inflexible adherence to nonfunctional routines/rituals (92% vs 81%; p = .005) and persistent preoccupation with parts of objects (67% vs 50%; p = .002). A higher frequency of white children with ASD compared to African American children with ASD have documented abnormal motor development (74% vs 60%; p = .008) and odd responses to sensory stimuli (76% vs 51%; p < .001). There were no significant differences in externalizing behaviors or reciprocal social interaction. CONCLUSIONS: This study suggests differences in the types of ASD symptoms and associated behavioral features exhibited by African American as compared to white children with ASD. Further research is needed to determine if these differences contribute to disparities in the timing or type of ASD diagnosis. PMID- 22226294 TI - Association between parental nativity and autism spectrum disorder among US-born non-Hispanic white and Hispanic children, 2007 National Survey of Children's Health. AB - BACKGROUND: Limited studies suggest the prevalence of autism spectrum disorders (ASD) varies by whether maternal and child birth country are discordant. OBJECTIVE/HYPOTHESIS: We explored associations between ASD and maternal and paternal nativity in a sample of US-born non-Hispanic white (NHW, n = 37,265) and US-born Hispanic (n = 4,690) children in the 2007 National Survey of Children's Health (NSCH). METHODS: We assessed ASD prevalence within race-ethnicity and parental nativity subgroups. Prevalence ratios (aPR), comparing each group to NHW children with 2 US-born parents, were adjusted for child age, sex, and receipt of care in a medical home. Estimates were weighted to reflect US noninstitutionalized children. Standard errors were adjusted to account for the complex sample design. RESULTS: In NHW children with 2 US-born parents, ASD prevalence was 1.19%; estimates were similar for NHW children with a foreign-born mother or father. There was a striking heterogeneity between Hispanic children with 2 US-born versus 2 foreign-born parents (ASD prevalence 2.39% versus 0.31%, p = .05). Even after adjustment, PRs comparing ASD prevalence in Hispanic versus NHW children were vastly different for Hispanic subgroups, suggesting a substantially lower prevalence for Hispanic children with both parents foreign born (aPR 0.2, 95% confidence interval 0.1-0.5) and a higher prevalence for Hispanic children with both parents US-born (aPR 2.0 [0.8-4.6]). CONCLUSIONS: Previous studies comparing ASD prevalence between NHW and Hispanic children based on a composite Hispanic grouping without consideration of parental nativity likely missed important differences between these racial-ethnic groups. Continuing efforts toward improving early identification in Hispanic children are needed. PMID- 22226295 TI - "He only takes those type of patients on certain days": specialty care access for children with special health care needs. AB - BACKGROUND: Expansions to public and private coverage opportunities under the Affordable Care Act and the Children's Health Insurance Program are meant to provide greater access to medical services, particularly for the 10 million US children with special health care needs (CSHCN). OBJECTIVE/HYPOTHESIS: We used qualitative methods to explore the nuanced processes of obtaining access to specialty care for publicly and privately insured CSHCN. METHODS: From May 2009 to February 2010, 30 in-depth qualitative interviews (60-90 minutes in length) were conducted with English-speaking family caregivers of CSHCN covered by public insurance (n = 15), private insurance (n = 6), or both (n = 9) in Cook County, IL. We used purposive quota sampling techniques to recruit parents from a group of 102 respondents from a related telephone survey who agreed to follow-up contact. All audio transcriptions and field notes were entered into Atlas-Ti software and analyzed by the authors through a thematic coding scheme. RESULTS: Respondents varied in their success in obtaining requested specialty care. Several themes emerged that shape access to specialty care for CSHCN in this study: marked differences based upon insurance type, the acuity of a child's health condition, and the presence of language and cultural barriers in scheduling and attending appointments. CONCLUSIONS: Qualitative interviews with families illuminated current perceptions of inequities in access to outpatient specialty care for CSHCN. Such findings generate questions and concerns about parity across public and private coverage systems for vulnerable children and suggest areas for future research and policy consideration for ensuring access to both primary and specialty care. PMID- 22226296 TI - Quality of diabetes care for adults with physical disabilities in Kansas. AB - BACKGROUND: Similar to health disparities found among racial and ethnic minority groups, individuals with physical disabilities experience a greater risk for diabetes than those without disabilities. OBJECTIVE: The purpose of this works was to assess Kansas Medicaid data to determine the quality of diabetic care and the level to which individuals with physical disabilities' prevention and diabetes management needs are being met. METHODS: We selected a continuously eligible cohort of adults (ages 18 and older) with physical disabilities who had diabetes and received medical benefits through Kansas Medicaid. We examined their quality of care measures (screening for HbA1c/glucose, cholesterol, and eye exams; and, primary care visits) in the succeeding year. Using unconditional logistic regression, we assessed the measures for quality of care as they related to demographic variables and comorbid hypertension. RESULTS: Thirty-nine percent of the 9,532 adults with physical disabilities had diabetes. They had the following testing rates: HbA1c, 82.7%; cholesterol, 51.5%; and eye examinations, 86.8%. Females, those with dual eligibility, and those with comorbid hypertension had higher rates for all types of screenings and primary care visits. Those living in MUAs had a higher screening rate for cholesterol. CONCLUSIONS: Adults with physical disabilities supported by Kansas Medicaid received diabetes quality indicator screenings have better diabetes quality of care rates for 3 out of 4 measures than nationally published figures for Medicaid. These findings point to a strong quality of care programs in Kansas for this population; however an imperative next step is to determine how effectively this population is managing their blood sugar levels day-to-day. PMID- 22226297 TI - Availability of physical activity resources in the environment for adults with intellectual disabilities. AB - BACKGROUND: Adults with intellectual disabilities (ID) have high rates of physical inactivity, yet little is known about the prevalence of facilitators and barriers in the built environment contributing to these high rates. OBJECTIVE: To describe the physical activity resources available to adults with ID in both the home and day programs outside of the home. METHODS: Demographic information was collected on a sample of adults with ID. A survey checklist of the physical activity environment at the participants' home and the facility or workplace where the participant spent his/her weekdays was collected by trained research staff. Differences in the prevalence of environmental resources between those living in group homes and those living alone or with family were tested using chi(2) tests. RESULTS: A total of 103 participants had complete demographic and environmental data. Of these, only 37.9% had exercise equipment available, 39.8% had sports equipment, and 15.5% had a bicycle in the home environment. At the facility where the individual attended a day program or where the individual was employed, 55.4 had sports equipment, 50.5% had an outdoor recreation area, 41.8% had an indoor recreation area, and 41.8 had organized physical activities. Those who lived in group homes were more likely to have access to basketball hoops, sports fields, and recreation centers than those who lived alone or with family (p < .01). CONCLUSIONS: Adults with ID have few physical activity environmental resources and opportunities available to them, especially those not living in group homes. Future interventions are needed to increase physical activity opportunities in this underserved population. PMID- 22226298 TI - Disability and home hazards and safety practices in US households. AB - BACKGROUND: Individuals with disabilities have an elevated risk of residential injury. However, the prevalence of home hazards and safety practices among households where an individual with a disability resides is unknown. METHODS: This study examined patterns of home hazards and safety practices among 1003 households across the United States in 2002. RESULTS: Households with at least 1 resident with a disability had a lower prevalence of household hazards than those without a resident with a disability, including living in a 2-story dwelling (34.6% vs 50.7%) and having stairs inside the home (48.1% vs 58.4%). They were more likely to implement fall prevention strategies, such as handrails or grab bars in the bathroom (40.4% vs 21.8%) and mats or nonskid strips in the tub or shower (71.7% vs 61.5%). CONCLUSION: There is room for improvement in safety practices among households where an individual with a disability resides. PMID- 22226299 TI - Enhancing early identification and coordination of intervention services for young children with autism spectrum disorders: report from the Act Early Regional Summit Project. AB - BACKGROUND: Increasing prevalence of autism spectrum disorders (ASD) and the merits of early intervention support the importance of early identification and detection. The Act Early Initiative attempts to address the states' capacity to support this process of early identification and early intervention. OBJECTIVE: The Centers for Disease Control and Prevention (CDC) Health Resources and Services Administration (HRSA) collaborated with the Association of University Centers on Disabilities (AUCD) to develop strategies that will address state capacity for responding to the increasing demand for earlier identification, earlier diagnoses, and coordination of service systems for children with ASDs and other developmental disabilities (DD). METHODS: Act Early regional summits were held to engage stakeholders from the early detection and intervention community including parents, state agencies, provider groups, autism and related disability organizations, and academia. The stakeholders then used the Logic Model to facilitate the teams' planning process. The Logic Model enables teams to understand the strengths and gaps within their state resources and plan specific activities to achieve concrete outcomes. RESULTS: States identified opportunities and challenges in early identification of children with delay. One of the particular challenges identified were low income, rural and non-English speaking populations encountering more challenges than others in accessing diagnosis and early intervention services. CONCLUSIONS: The Summits are a unique model that demonstrates the importance of developing comprehensive state plans to advance the collaboration and coordination of early detection and intervention service systems for children with ASDs and related DDs from all racial, ethnic, geographical, and socioeconomic backgrounds. PMID- 22226300 TI - Discrepancy among Behavioral Risk Factor Surveillance System, Social Security, and functional disability measurement. PMID- 22226301 TI - Melatonin and the metabolic syndrome: a tool for effective therapy in obesity associated abnormalities? AB - The metabolic syndrome (MetS) is a cluster of metabolic abnormalities associated with increased risk for cardiovascular diseases. Apart from its powerful antioxidant properties, the pineal gland hormone melatonin has recently attracted the interest of various investigators as a multifunctional molecule. Melatonin has been shown to have beneficial effects in cardiovascular disorders including ischaemic heart disease and hypertension. However, its role in cardiovascular risk factors including obesity and other related metabolic abnormalities is not yet established, particularly in humans. New emerging data show that melatonin may play an important role in body weight regulation and energy metabolism. This review will address the role of melatonin in the MetS focusing on its effects in obesity, insulin resistance and leptin resistance. The overall findings suggest that melatonin should be exploited as a therapeutic tool to prevent or reverse the harmful effects of obesity and its related metabolic disorders. PMID- 22226302 TI - Donation after cardiac death liver transplant recipients have an increased frequency of acute kidney injury. AB - Donation after cardiac death (DCD) liver transplantation is associated with an increased frequency of hepato-biliary complications. The implications for renal function have not been explored previously. The aims of this single-center study of 88 consecutive DCD liver transplant recipients were (1) to compare renal outcomes with propensity-risk-matched donation after brain death (DBD) patients and (2) in the DCD patients specifically to examine the risk factors for acute kidney injury (AKI; peak creatinine >=2 times baseline) and chronic kidney disease (CKD; eGFR <60 mL/min/1.73 m(2) ). During the immediate postoperative period DCD liver transplantation was associated with an increased incidence of AKI (DCD, 53.4%; DBD 31.8%, p = 0.004). In DCD patients AKI was a risk factor for CKD (p = 0.035) and mortality (p = 0.017). The cumulative incidence of CKD by 3 years post-transplant was 53.7% and 42.1% for DCD and DBD patients, respectively (p = 0.774). Importantly, increasing peak perioperative aspartate aminotransferase, a surrogate marker of hepatic ischemia reperfusion injury, was the only consistent predictor of renal dysfunction after DCD transplantation (AKI, p < 0.001; CKD, p = 0.032). In conclusion, DCD liver transplantation is associated with an increased frequency of AKI. The findings suggest that hepatic ischemia reperfusion injury may play a critical role in the pathogenesis of post transplant renal dysfunction. PMID- 22226304 TI - A robust disturbance reduction scheme for linear small delay systems with disturbances of unknown frequencies. AB - A robust disturbance reduction scheme for linear small delay systems with disturbances of unknown frequencies is presented in this paper. Unlike other methods, the proposed scheme does not require disturbance frequencies to be known. The linear systems modeled in this study are nominally stable and minimum phase systems with relative degree. The control structure is an integration of Astrom's modified Smith predictor and the proposed scheme. The proposed scheme consists of an input disturbance reduction controller (IDRC) and a residual disturbance reduction controller (RDRC). The IDRC using an artificial neural network (ANN) is proposed to reduce unknown load disturbances and modeling uncertainties in stable systems and unstable systems. The ANN can appropriately approximate the product of an inverse time delay and a nonnegative gain in the IDRC. The residual signals including residual disturbances and residual uncertainties are suppressed by the RDRC based on a disturbance observer. Simulation examples are illustrated to show the effectiveness of the proposed robust disturbance reduction scheme for linear delay uncertain systems with periodic or non-periodic unknown load disturbances. PMID- 22226303 TI - Environmental factors producing autoimmune dysregulation--chronic activation of T cells caused by silica exposure. AB - Autoimmune disorders are induced by various environmental and occupational substances. Among the most typical factors involving these substances, it is well known that silica exposure causes not only pulmonary fibrosis known as silicosis, but also induces autoimmune diseases such as rheumatoid arthritis known as Caplan's syndrome, systemic sclerosis, systemic lupus erythematosus, and anti neutrophil cytoplasmic autoantibody (ANCA)-related vasculitis/nephritis. To investigate the immunological effects of silica, a focus on the occurrence of autoimmune dysfunction may clarify these autoimmune diseases and develop effective tools for observing silicosis patients (SIL). In this review, our investigation concerns the autoantibodies found in SIL, alteration of CD95/Fas and related molecules in SIL, case-oriented and in vitro analyses of silica induced activation of responder and regulatory T cells, and supposed mechanisms of reduction of CD4+25+FoxP3+ regulatory T cells (T(reg)) in SIL. Further studies are required to investigate Th17 and the interaction with T(reg) in SIL to understand the cellular and molecular mechanisms of environmental and occupational autoimmune disorders. PMID- 22226305 TI - Enhancing the stability of xylanase from Cellulomonas fimi by cell-surface display on Escherichia coli. AB - AIMS: The cell-surface display of Cex, which encodes xylanase and exoglucanase from Cellulomonas fimi, was constructed on Escherichia coli using PgsA as the anchor protein. Characterization of the cell-surface display of Cex was performed. METHODS AND RESULTS: PgsA was fused to the N-terminus of Cex and six histidines were utilized as spacers between the targeting and anchor proteins. Successful cell-surface display of Cex was demonstrated by Western blot and immunofluorescence analyses on E. coli C41 (DE3). According to the time-course analysis, the xylanase activity of Cex was achieved at 49Ug(-1) dry cell weight after 12 h culture at 37 degrees C. The optimal temperature and pH ranges of the cell-surface displayed protein with whole-cell were broader than the corresponding ranges of the purified form. Further determination of thermostability indicated that the half-life of cell-surface displayed Cex was 1.6 times longer than that of purified Cex at 60 degrees C. CONCLUSIONS: We have successfully developed the cell-surface display of xylanase on E. coli. The cell surface display can enhance the stability of xylanase against changes in temperature and has the potential of becoming a whole-cell biocatalyst for industrial applications, such as biobleaching of paper and production of renewable energy. SIGNIFICANCE AND IMPACT OF THE STUDY: The results demonstrated that the cell-surface display of xylanase embedded in the cell membrane is more stable than that of the purified enzyme. Thus, to improve the stability of heterologous proteins production, cell-surface display using the PgsA anchor protein as a tool can be considered in E. coli. PMID- 22226306 TI - Developing criteria and data to determine best options for expanding the core CODIS loci. AB - BACKGROUND: Recently, the Combined DNA Index System (CODIS) Core Loci Working Group established by the US Federal Bureau of Investigation (FBI) reviewed and recommended changes to the CODIS core loci. The Working Group identified 20 short tandem repeat (STR) loci (composed of the original CODIS core set loci (minus TPOX), four European recommended loci, PentaE, and DYS391) plus the Amelogenin marker as the new core set. Before selecting and finalizing the core loci, some evaluations are needed to provide guidance for the best options of core selection. METHOD: The performance of current and newly proposed CODIS core loci sets were evaluated with simplified analyses for adventitious hit rates in reasonably large datasets under single-source profile comparisons, mixture comparisons and kinship searches, and for international data sharing. Informativeness (for example, match probability, average kinship index (AKI)) and mutation rates of each locus were some of the criteria to consider for loci selection. However, the primary factor was performance with challenged forensic samples. RESULTS: The current battery of loci provided in already validated commercial kits meet the needs for single-source profile comparisons and international data sharing, even with relatively large databases. However, the 13 CODIS core loci are not sufficiently powerful for kinship analyses and searching potential contributors of mixtures in larger databases; 19 or more autosomal STR loci perform better. Y-chromosome STR (Y-STR) loci are very useful to trace paternal lineage, deconvolve female and male mixtures, and resolve inconsistencies with Amelogenin typing. The DYS391 locus is of little theoretical or practical use. Combining five or six Y-chromosome STR loci with existing autosomal STR loci can produce better performance than the same number of autosomal loci for kinship analysis and still yield a sufficiently low match probability for single-source profile comparisons. CONCLUSION: A more comprehensive study should be performed to provide the necessary information to decision makers and stakeholders about the construction of a new set of core loci for CODIS. Finally, selection of loci should be driven by the concept that the needs of casework should be supported by the processes of CODIS (or for that matter any forensic DNA database). PMID- 22226307 TI - Homeopathy for acute otitis media-time for a definitive trial. PMID- 22226308 TI - Atopy and Hering's Law. PMID- 22226309 TI - Randomized controlled pilot study to compare Homeopathy and Conventional therapy in Acute Otitis Media. AB - OBJECTIVE: To compare the effectiveness of Homeopathy and Conventional therapy in Acute Otitis Media (AOM). METHOD: A randomized placebo-controlled parallel group pilot study of homeopathic vs conventional treatment for AOM was conducted in Jaipur, India. Patients were randomized by a computer generated random number list to receive either individualized homeopathic medicines in fifty millesimal (LM) potencies, or conventional treatment including analgesics, antipyretics and anti-inflammatory drugs. Patients who did not improve were prescribed antibiotics at the 3rd day. Outcomes were assessed by the Acute Otitis Media-Severity of Symptoms (AOM-SOS) Scale and Tympanic Membrane Examination over 21 days. RESULTS: 81 patients were included, 80 completed follow-up: 41 for conventional and 40 for homeopathic treatment. In the Conventional group, all 40 (100%) patients were cured, in the Homeopathy group, 38 (95%) patients were cured while 02 (5%) patients were lost to the last two follow-up. By the 3rd day of treatment, 4 patients were cured in Homeopathy group but in Conventional group only one patient was cured. In the Conventional group antibiotics were prescribed in 39 (97.5%), no antibiotics were required in the Homeopathy group. 85% of patients were prescribed six homeopathic medicines. CONCLUSION: Individualized homeopathy is an effective conventional treatment in AOM, there were no significant differences between groups in the main outcome. Symptomatic improvement was quicker in the Homeopathy group, and there was a large difference in antibiotic requirements, favouring homeopathy. Further work on a larger scale should be conducted. PMID- 22226310 TI - Homeopathy in paediatric atopic diseases: long-term results in children with atopic dermatitis. AB - AIM: To study the socio-demographic features, the prescribed remedies and the outcome of atopic diseases in children treated with homeopathy at the Homeopathic Clinic of Lucca (Italy), and the long-term outcome of children suffering from atopic dermatitis (AD) after an approximate 8-year period (range 5-10 years). METHODS: Our data derive from an observational longitudinal study carried out on 213 children (38.6%) with atopic diseases out of 551 children consecutively examined from September 1998 to December 2008. We used the Glasgow Homeopathic Hospital Outcome Score to evaluate the results that were classified on the basis of a Likert scale. RESULTS: Eighty-three (39%) children were affected by asthma, 51 (24%) by allergic rhinoconjunctivitis, 76 (36%) by AD and 3 (1%) by food intolerance. Follow-up patients were 104 (48.8%), and 65 (62.5%) of them reported a major improvement or resolution. The parents of paediatric patients suffering from AD, who had started homeopathic treatment at <4.9 years of age were invited to follow-up assessment 8 years later and 40 children (mean age 12.9) were examined; 28/40 (70%) had a complete disappearance of AD, 12/40 children (30.0%) were still affected by AD; 8/40 (20%) had asthma and 8/40 patients had, or developed, allergic rhinitis. CONCLUSION: These preliminary results seem to confirm a positive therapeutic effect of homeopathy in atopic children. Furthermore, according to the data from the literature paediatric patients treated with homeopathy seem to show a reduced tendency to maintain AD and develop asthma (and allergic rhinitis) in adult age. PMID- 22226311 TI - Prospective observational study of 42 patients with atopic dermatitis treated with homeopathic medicines. AB - BACKGROUND: Atopic dermatitis (AD) is a highly prevalent chronic inflammatory skin disease which usually develops during childhood. Despite being a condition frequently treated with homeopathy, the evidence is still insufficient to define homeopathic treatment's efficacy and the best therapeutic strategies. AIMS: To evaluate the effectiveness of homeopathic treatment of AD in a general homeopathic practice setting. METHODS: Patients spontaneously seeking homeopathic treatment meeting Hanifin and Rajka's criteria were prospectively treated. Severity of disease was evaluated by Rajka and Langeland's score and a set of four Visual Analogue Scales (VAS) evaluating disease severity, itch, general and psychological wellbeing and quality of sleep. Assessed outcomes were: change in AD extension, change in VASs, and a categorical scale for global subjective perception of evolution. RESULTS: Forty two patients were eligible. Twenty-one had other atopic comorbidities and 28 (66.7%) were moderate or severe cases. Sixteen (38.1%) patients dropped out. Significant differences were found comparing first and last consultations in mean percentage (95%CI) of affected skin area, 21.1% (10.9; 31.4) versus 5.5% (1.3; 9.7) respectively, P=0.002, and in the change or the four VASs: [mm (95%CI)] AD 31.1 (20.6; 41.7), P<0.0001; Itch 35.0 (23.6; 46.4), P<0.0001; General wellbeing 11.1 (1.2; 20.9), P<0.0188, and Sleep 17.4 (5.0; 29.8), P<0.0073. Homeopathic aggravations were reported after 29.8% of prescriptions. Twelve individualized homeopathic medicines were prescribed; Sulphur accounted for 60% of cases with good treatment response. CONCLUSIONS: This study suggests that in a general medical practice setting, homeopathic treatment could be regarded as an effective choice for patients with AD. PMID- 22226312 TI - Monitoring improvement in health during homeopathic intervention. Development of an assessment tool based on Hering's Law of Cure: the Hering's Law Assessment Tool (HELAT). AB - INTRODUCTION: Hering's 'Law of Cure' is considered important in homeopathy and thought to predict a positive outcome to treatment. No formal outcome measures are currently available to monitor response to homeopathic treatment on the basis of these assumptions. We describe a simple assessment tool, the Hering's Law Assessment Tool (HELAT) to identify and differentiate patient responses to homeopathic treatment as corresponding to Hering's Law from other symptomatic responses. We describe the development of the tool and assess its face, content and predictive validity. METHOD: The HELAT was initially developed through literature review, discussion between homeopaths and clinical experience. In phase one, the tool was reviewed by three experienced homeopaths to assess face and content validity. In phase two, we tested its predictive validity by hypothesizing that the HELAT total score may predict changes in a clinical response (using standard validated rheumatological outcome, the American College of Rheumatology (ACR)20%) in 32 patients with rheumatoid arthritis receiving homeopathic intervention over 24 weeks as part of a clinical trial. RESULTS: The HELAT was piloted and changed to improve face and content validity and the final version was then employed for phase two as a predictor of outcome. HELAT total score predicted patient's clinical response (ACR20) [B = 1.142, SE = 0.462, P = 0.013] which was independent of practitioner assessing the patients treatment response [B = 1.04, SE = 1.01, P = 0.302]. CONCLUSION: The initial data suggests that the HELAT may hold promise for a potential clinical and research outcome measure in homeopathy. Further work is now needed to formally assess its reliability and validity for potential use in clinical practice and trials. PMID- 22226313 TI - Homeopathic medicines substantially reduce the need for clotting factor concentrates in haemophilia patients: results of a blinded placebo controlled cross over trial. AB - BACKGROUND: Modern management of haemophilia patients is expensive: 90% of expenditure is on clotting factor concentrates. Any intervention which reduces the need for clotting factor concentrates in these patients without compromising the quality of life is of interest. AIMS AND OBJECTIVES: To investigate the effectiveness of individualised homeopathic medicines in reducing the requirement of factor concentrates in haemophilia patients. MATERIALS AND METHODS: In a single blind placebo controlled cross over trial 28 consecutive persons with haemophilia (PWH) with severe (24) or moderately severe (4) disease received standard management with placebo homeopathy for 1 year and active homeopathic treatment in the subsequent year with the same conventional management. There was no wash out period. They received standard managements for any acute emergency during the study period. Development of inhibitor during the study period was a withdrawal criterion. Sample size for the trial was calculated as 24 PWH. Transfusion requirements, bleeding scores, pain scores were evaluated blind by independent experts. Homeopathic medicines were selected by experienced homeopathic physicians depending on clinical condition of the patient. Chi squared and paired t tests were used in statistical analysis. RESULTS: 28 patients were recruited. Homeopathic medicines improved frequency of bleeding, extent of bleeding, blood products consumed and pain scores (P<0.0001). There was also significant improvement in well being. Plasma levels of clotting factors did not change. No patients developed inhibitors during the study there were no dropouts. CONCLUSION: Individualised homeopathic medicines may have an important supportive role in the management of PWH, where blood products and factor concentrates are not easily available. Larger, perhaps multicentric trials are warranted. PMID- 22226314 TI - The impact of the medical speciality in primary health-care problem solving in Belo Horizonte, Brazil: homeopaths versus family doctors: a preliminary quantitative study. AB - INTRODUCTION: This research project examined influence of the doctors' speciality on primary health care (PHC) problem solving in Belo Horizonte (BH) Brazil, comparing homeopathic with family health doctors (FH), from the management's and the patients' viewpoint. In BH, both FH and homeopathic doctors work in PHC. The index of resolvability (IR) is used to compare resolution of problems by doctors. METHODS: The present research compared IR, using official data from the Secretariat of Health and test requests made by the doctors and 482 structured interviews with patients. A total of 217,963 consultations by 14 homeopaths and 67 FH doctors between 1 July 2006 and 30 June 2007 were analysed. RESULTS: The results show significant differences greater problem resolution by homeopaths compared to FH doctors. CONCLUSION: In BH, the medical speciality, homeopathy or FH, has an impact on problem solving, both from the managers' and the patients' point of view. Homeopaths request fewer tests and have better IR compared with FH doctors. Specialisation in homeopathy is an independent positive factor in problem solving at PHC level in BH, Brazil. PMID- 22226315 TI - Running an NHS community homeopathy clinic - 10-year anniversary 2001-2011. AB - An outcome series was conducted over a five-year period of patients attending a community NHS homeopathy clinic in Dorchester, Dorset. 273 new patients were seen. 183 (67%) questionnaires were completed at six months after initial consultation. 44% of patients had been unwell for more than five years; 19% of all patients for more than 15 years. A wide variety of conditions were seen, the largest group with depression, anxiety or grief. For follow-up patients 75-81% indicated an improvement in their symptoms and activity while 58% recorded an improvement in their overall wellbeing. Six months after the initiation of treatment 155 (84.7%) felt an improvement in their condition with 148 (81%) attributing this to homeopathy. Nobody reported deterioration due to homeopathic treatment; conventional drug use was reduced in 46 patients (25%). PMID- 22226316 TI - Effects of Ignatia amara in mouse behavioural models. AB - BACKGROUND: Ignatia amara (Ignatia), a remedy made from the Strychnos ignatii seeds, is used for anxiety-related symptoms, but consistent evidence of its activity in reproducible experimental models is lacking. An investigation was performed in order to assess on mice, by means of emotional response models, the activity of homeopathic Ignatia dilutions/dynamizations. METHODS: Groups of 8 mice of the CD1 albino strain were treated intraperitoneally for 9 days with 0.3ml of five centesimal (C) dilutions/dynamizations of Ignatia (4C, 5C, 7C, 9C and 30C). Control mice were treated with the same hydroalcoholic (0.3%) solution used to dilute the medicines. Diazepam (1mg/kg) was the positive reference drug. Validated test models for locomotion and emotional response, the Open-Field (OF) and the Light-Dark (LD) tests, were employed. Five replications of the same protocol were carried out, in a randomised way using coded drugs/controls. RESULTS: In the OF the general locomotion of mice was slightly decreased by Ignatia 4C, but not by Ignatia 5C, 7C, 9C and 30C, indicating the absence of unspecific motor impairment or sedation by these dilutions/dynamizations. Ignatia and diazepam seemed to decrease the number of urine spots released in the OF during 10min, with borderline significance (P=0.083). In the LD the tested medicine showed anxiolytic-like activity (increase of time spent and distance travelled in the lit area), though to a lesser extent than diazepam. The highest and most significant difference with untreated controls (P<0.01) was observed with the 9C dilution/dynamization. Among the 5 replication experiments, the best drug effects were obtained where the baseline anxiety of mice was higher. CONCLUSIONS: Homeopathic Ignatia dilutions/dynamizations (peak at 9C) modify some emotion-related symptoms in laboratory mice without affecting locomotion. PMID- 22226317 TI - Development of broiler chickens after treatment with thymulin 5cH: a zoo technical approach. AB - Modulation of immune response due to thymulin 5cH has been previously observed. The aim of the present study is to evaluate the development of broiler chickens treated with thymulin 5cH by conventional zoo technical indices, phytohemaglutinin induced inflammation test and histomorphometric analysis of lymphoid organs (thymus, Fabricius bursa and spleen). Animals were divided in two groups: (a) test: birds with free access to thymulin 5cH diluted into the drink water and (b) control: birds with free access to water only, from the 1st to the 42nd day of life. All experimental procedures were done in blind. The results show that thymulin 5cH treated group had increased productivity index compared to control (391.45 versus 261.93) associated with higher viability in the 7th week (p = 0.013), and a possible shunt to B lymphocyte activity. The data suggest that thymulin 5cH could be a viable method to improve productivity in poultry production due to its immune modulation properties. PMID- 22226318 TI - Lymphocyte proliferation stimulated by activated Cebus apella macrophages treated with a complex homeopathic immune response modifiers. AB - INTRODUCTION: Canova is a complex homeopathic medicine that enhances a specific immunologic responses against several exogenous and endogenous conditions. Canova activates macrophages both in vivo and in vitro. AIM AND METHOD: We evaluated the effects of macrophages activated by Canova in vivo and ex vitro in the proliferation of lymphocytes. Canova was used to activate Cebus apella macrophages in vivo or ex vitro with Canova. Lymphocytes were cultured with the macrophage culture medium. The analysis of Canova effects in cultured lymphocytes was performed according to the cell cycle phase using flow cytometry. The Interferon gamma and Interleukin-5 cytokines quantification in these lymphocyte culture media was performed by Enzyme-linked immunosorbent assay (ELISA). RESULTS: We observed that Canova actives macrophages in vivo and ex vitro. The lymphocytes cultured in a supplemented medium with macrophages activated by Canova treatment presented a higher number of proliferation cells than lymphocytes not exposed to macrophages activated by Canova. The Interferon gamma and Interleukin-5 cytokines were only observed in the medium of lymphocytes exposed to macrophages activated by Canova. Thus, Canova has potential as a new adjuvant therapy. PMID- 22226319 TI - Induction and maintenance of anti-influenza antigen-specific nasal secretory IgA levels and serum IgG levels after influenza infection in adults. AB - OBJECTIVES: To determine the induction and changes in anti-influenza virus secretory IgA (s-IgA) levels in nasal washes and serum IgG levels in patients with influenza. METHODS: The study recruited 16 patients with influenza aged 35.6 +/- 9.6 years in 2007/2008 and 2008/2009 seasons. Nasal washes and serum were obtained throughout the first year. Anti-viral s-IgA levels and neutralization activities in nasal washes, and serum anti-viral IgG levels and hemagglutination inhibition (HI) titers were measured. RESULTS: Anti-viral(H1N1) s-IgA to total IgA ratio and neutralizing antibody titer were low in nasal washes of all patients, whereas serum levels of anti-viral IgG and HI titers varied widely at day 1.4 +/- 1.0 postinfection. Both nasal s-IgA and serum IgG levels later increased significantly, reaching peak levels at day 9.6 +/- 3.3 postinfection. The induced nasal s-IgA then returned toward the initial levels within 300 days, although the levels at day 143 +/- 70 were 3.03-fold of the initial. Individual serum IgG levels also returned toward the initial levels within 300 days, although the mean levels remained high probably because of re-infection in a subgroup of patients. Although influenza A (H3N2) was a minor epidemic subtype in both flu seasons, a significant rise in nasal anti-viral (H3N2) s-IgA levels and a slightly increase in serum IgG levels were noted. CONCLUSION: Low levels of nasal anti-viral s-IgA and neutralizing antibody were noted compared with a wide range of serum anti-viral IgG and HI titers at the onset of infection. Elevated s IgA and IgG returned toward the initial levels within 300 days of infection with minor exceptions. PMID- 22226321 TI - Acute and chronic stress induced changes in sensitivity of peripheral inflammatory pathways to the signals of multiple stress systems --2011 Curt Richter Award Winner. AB - Exposure to psychosocial stress has been associated with increasing rates of morbidity in humans and in animal models, but the underlying mechanisms are not completely understood. Major stress responsive systems, such as the hypothalamus pituitary adrenal (HPA) axis and the autonomic nervous system (ANS) are under investigation as underlying pathways, but although acute stress reliably activates these systems, findings of long-term alternations in baseline activity are inconsistent at present. Emerging evidence suggests that stress-related changes in the sensitivity of target systems toward glucocorticoid (GC) regulation, i.e. development of GC resistance, might help explain inflammatory disinhibition and development of disease related to inflammation. More recent findings further show that the autonomic nervous system might play an important role in the regulatory control of the inflammatory cascade. The major argument put forward in this manuscript is that target tissues for stress system modulation, such as the inflammatory cascade, vary in their ability to respond to stress system signaling, and that assessing alterations in this stress signal sensitivity which can be caused by stress or disease processes, might be necessary to understand and explain stress effects on health. This review focuses on the inflammatory system in particular, because anti-inflammatory effects of most stress systems have been documented, but the general assumption might have to be generalized to other target systems. The main conclusion to be made is that reduction in glucocorticoid sensitivity of target tissues is the most consistent finding at present, and that assessing such changes in glucocorticoid sensitivity might be necessary to understand many stress-related changes in physiology. PMID- 22226320 TI - Assessment of distribution and evolution of mechanical dyssynchrony in a porcine model of myocardial infarction by cardiovascular magnetic resonance. AB - BACKGROUND: We sought to investigate the relationship between infarct and dyssynchrony post- myocardial infarct (MI), in a porcine model. Mechanical dyssynchrony post-MI is associated with left ventricular (LV) remodeling and increased mortality. METHODS: Cine, gadolinium-contrast, and tagged cardiovascular magnetic resonance (CMR) were performed pre-MI, 9 +/- 2 days (early post-MI), and 33 +/- 10 days (late post-MI) post-MI in 6 pigs to characterize cardiac morphology, location and extent of MI, and regional mechanics. LV mechanics were assessed by circumferential strain (eC). Electro anatomic mapping (EAM) was performed within 24 hrs of CMR and prior to sacrifice. RESULTS: Mean infarct size was 21 +/- 4% of LV volume with evidence of post-MI remodeling. Global eC significantly decreased post MI (-27 +/- 1.6% vs. -18 +/- 2.5% (early) and -17 +/- 2.7% (late), p < 0.0001) with no significant change in peri-MI and MI segments between early and late time-points. Time to peak strain (TTP) was significantly longer in MI, compared to normal and peri-MI segments, both early (440 +/- 40 ms vs. 329 +/- 40 ms and 332 +/- 36 ms, respectively; p = 0.0002) and late post-MI (442 +/- 63 ms vs. 321 +/- 40 ms and 355 +/- 61 ms, respectively; p = 0.012). The standard deviation of TTP in 16 segments (SD16) significantly increased post-MI: 28 +/- 7 ms to 50 +/- 10 ms (early, p = 0.012) to 54 +/- 19 ms (late, p = 0.004), with no change between early and late post-MI time-points (p = 0.56). TTP was not related to reduction of segmental contractility. EAM revealed late electrical activation and greatly diminished conduction velocity in the infarct (5.7 +/- 2.4 cm/s), when compared to peri infarct (18.7 +/- 10.3 cm/s) and remote myocardium (39 +/- 20.5 cm/s). CONCLUSIONS: Mechanical dyssynchrony occurs early after MI and is the result of delayed electrical and mechanical activation in the infarct. PMID- 22226322 TI - Non-steroidal anti-inflammatory drugs use and risk of upper gastrointestinal adverse events in cirrhotic patients. AB - BACKGROUND/AIMS: The upper gastrointestinal (GI) toxicity associated with non steroidal anti-inflammatory drugs (NSAID) use among cirrhotic patients remains unclear. The objective of this study was to evaluate the risk of upper GI adverse events associated with celecoxib and oral and parenteral non-selective NSAIDs in cirrhotic patients. METHODS: All the patients aged >= 20 years with a diagnosis of cirrhosis hospitalized for variceal bleeding and non-variceal upper GI adverse events (oesophageal, gastric, duodenal ulcer, bleeding; gastritis and duodenitis) in 2006 were identified using ICD-9-CM diagnosis codes from inpatient claims from the Taiwan National Health Insurance Database. In the case-crossover study design, the case period was defined as 1-30 days and the control period as 31-60 days before the date of hospitalization. The information for individual NSAID use was obtained from the outpatient pharmacy prescription database. Adjusted self matched odds ratios (OR) and their 95% confidence intervals (CI) were estimated with a conditional logistic regression model. RESULTS: A total of 4876 cirrhotic patients were included. The adjusted OR (95% CI) was 1.44 (0.89-2.31) for celecoxib, 1.87 (1.66-2.11) for oral non-selective NSAIDs and 1.90 (1.55-2.32) for parenteral NSAIDs overall. Risks were similar for variceal and non-variceal events. Concomitant use of proton pump inhibitors and histamine-2 receptor antagonists tended to decrease the upper GI toxicity associated with non selective NSAIDs and celecoxib. CONCLUSION: The use of nsNSAIDs but not celecoxib was associated with a two-fold increased risk of variceal and non-variceal upper GI events among cirrhotic patients. PMID- 22226323 TI - O-sulfate groups of heparin are critical for inhibition of ecotropic murine leukemia virus infection by heparin. AB - There is increasing evidence that soluble glycosaminoglycans such as heparin can interfere with the infectivity of various viruses, including ecotropic murine leukemia viruses (MLVs). The ecotropic MLV, Friend MLV (F-MLV) and the neuropathogenic variants A8 MLV and PVC-211 MLV, were susceptible to heparin mediated inhibition of infection of NIH 3T3 cells. To investigate the interaction between the envelope glycoprotein (Env) of MLV and heparin, we prepared vesicular stomatitis virus-based pseudotyped viruses carrying the Env of F-, A8, or PVC-211 MLVs. Surface plasmon resonance analyses indicated that the Env of A8 and PVC-211 MLVs had a higher binding activity to heparin than that of F-MLV. We examined the influence of N- or O-sulfation of heparin on binding activity to Env and on the inhibition of the infectivity of MLV and pseudotyped viruses carrying Env. This analysis indicated that the O-sulfate groups of heparin play a major role in determining Env-dependent inhibitory effects. PMID- 22226324 TI - The nucleocapsid protein of measles virus blocks host interferon response. AB - Measles virus (MV) belongs to the genus Morbillivirus of the family Paramyxoviridae. A number of paramyxoviruses inhibit host interferon (IFN) signaling pathways in host immune systems by various mechanisms. Inhibition mechanisms have been described for many paramyxoviruses. Although there are inconsistencies among previous reports concerning MV, it appears that P/V/C proteins interfere with the pathways. In this study, we confirmed the effects of MV P gene products of a wild MV strain on IFN pathways and examined that of other viral proteins on it. Interestingly, we found that N protein acts as an IFN alpha/beta and gamma-antagonist as strong as P gene products. We further investigated the mechanisms of MV-N inhibition, and revealed that MV-N blocks the nuclear import of activated STAT without preventing STAT and Jak activation or STAT degradation, and that the nuclear translocation of MV-N is important for the inhibition. The inhibitory effect of the N protein was observed as a common feature of other morbilliviruses. The results presented in this report suggest that N protein of MV as well as P/V/C proteins is involved in the inhibition of host IFN signaling pathways. PMID- 22226326 TI - Prevalence of non Helicobacter pylori species in patients presenting with dyspepsia. AB - BACKGROUND: Helicobacter species associated with human infection include Helicobacter pylori, Helicobacter heilmannii and Helicobacter felis among others. In this study we determined the prevalence of H. pylori and non-Helicobacter pylori organisms H. felis and H. heilmannii and analyzed the association between coinfection with these organisms and gastric pathology in patients presenting with dyspepsia. Biopsy specimens were obtained from patients with dyspepsia on esophagogastroduodenoscopy (EGD) for rapid urease test, histology and PCR examination for Helicobacter genus specific 16S rDNA, H. pylori phosphoglucosamine mutase (glmM) and urease B (ureB) gene of H. heilmannii and H. felis. Sequencing of PCR products of H. heilmannii and H. felis was done. RESULTS: Two hundred-fifty patients with dyspepsia were enrolled in the study. The mean age was 39 +/- 12 years with males 162(65%). Twenty-six percent (66 out of 250) were exposed to cats or dogs. PCR for Helicobacter genus specific 16S rDNA was positive in 167/250 (67%), H. pylori glmM in 142/250 (57%), H. heilmannii in 17/250 (6%) and H. felis in 10/250 (4%), respectively. All the H. heilmannii and H. felis PCR positive patients were also positive for H. pylori PCR amplification. The occurrence of coinfection of H. pylori and H. heilmannii was 17(6%) and with H. felis was 10(4%), respectively. Only one out of 66 exposed to pets were positive for H. heilmannii and two for H. felis. Histopathology was carried out in 160(64%) of 250 cases. Chronic active inflammation was observed in 53(56%) (p = 0.001) of the patients with H. pylori infection alone as compared to 3(37%) (p = 0.73) coinfected with H. heilmannii and H. pylori and 3(60%) coinfected with H. felis and H. pylori (p = 0.66). Intestinal metaplasia was observed in 3(3%)(p = 1.0) of the patients with H. pylori infection alone as compared to 2(25%) (p = 0.02) coinfected with H. heilmannii and H. pylori and 1(20%) coinfected with H. felis and H. pylori (p = 0.15). CONCLUSION: The prevalence of H. heilmannii and H. felis was low in our patients with dyspepsia. Exposure to pets did not increase the risk of H. heilmannii or H. felis infection. The coinfection of H. pylori with H. heilmannii was seen associated with intestinal metaplasia, however this need further confirmation. PMID- 22226327 TI - Bio-capture of S. Typhimurium from surface water by aptamer for culture-free quantification. AB - In this study, a DNA aptamer was used to bio-capture Salmonella enterica serovar Typhimurium from surface water collected from highly endemic zone prior to culture-free detection through Molecular-Beacon based real-time PCR assay targeting invA gene. The assay could detect S. Typhimurium cells (1 CFU/PCR or 100 CFU/ml) selectively captured by serovar specific DNA aptamer. The observations indicate that all the water samples (n=40) collected from the river Gomti were contaminated by S. Typhimurium (31400-1 * 10(7) CFU/100 ml). The pre analytical step in the form of serovar specific DNA aptamer based bio-capture of the bacterial cell was found to enhance the sensitivity of the florescent probe based real-time PCR assay during detection of S. Typhimurium in environmental samples exhibiting natural PCR inhibitors and high background bacterial flora. The assay could be used for the regular monitoring of surface waters for forecasting and management of non-typhoidal Salmonellosis in south Asia. PMID- 22226328 TI - Bioavailability of lead in contaminated soil depends on the nature of bioreceptor. AB - Long-term lead (Pb) contaminated soils from two lead-zinc smelters and a shooting range, along with freshly spiked control soil, were studied by means of chemical, biological or a physiological method to examine the effect of ageing on Pb bioavailability. The freshly Pb spiked control soil was subjected to an earthworm toxicity test to observe the avoidance and mortality response of the earthworms. Meanwhile, an extractable fraction of Pb on the spiked soil as a result of ageing was examined and further compared with physiologically based in vitro bioaccessibility extraction tests. Their differences in lethal concentration, LC(50), to the earthworm population from spiked soils varied substantially as a function of soil pH. The strong effect of ageing on toxicity was also reflected in the extractability of Pb which was far greater in acidic soil, labelled AC, compared to the alkaline soil, labelled BC. This demonstrates that the bioavailable fraction causing toxicity to earthworms was achieved at a much lower total Pb content for acidic soils relative to alkaline soils. Moreover, the effect of ageing also exhibits that a marked decline in bioavailable Pb results in lowering toxicity. Significant amounts of weight loss in earthworms during an acute toxicity test in long-term contaminated soils at a relatively low Pb concentration suggested that other metal or combined metal toxicity may also play a significant role. This study demonstrates that the soil characteristics and ageing period greatly influence the bioavailable fraction of Pb which is related to the bioreceptor. PMID- 22226329 TI - Exercise training enhances autonomic function after acute myocardial infarction: a randomized controlled study. AB - INTRODUCTION: Heart rate recovery, defined as the fall in heart rate during the first minute after exercise, is an indicator of autonomic function, and has been found to be an independent predictor of mortality after acute myocardial infarction. Exercise training has several well-known benefits in terms of cardiorespiratory fitness, modifiable cardiovascular risk factors and prognosis after acute coronary events. However, there are no randomized controlled studies in the literature evaluating the effects of exercise training per se, controlling for changes in medication and diet, on heart rate recovery. Thus, this study aims to assess the effects of exercise training on autonomic function in coronary artery disease patients recovering from acute myocardial infarction. METHODS: Thirty-eight patients following a first acute myocardial infarction participated in this prospective randomized clinical trial. Patients were randomized into two groups: exercise training or control. The exercise group participated in an 8 week aerobic exercise program, while the control received standard medical care and follow-up. Changes in hemodynamics at rest and at peak exercise (heart rate, systolic and diastolic blood pressure, and rate pressure product), dietary intake, cardiorespiratory fitness, and heart rate recovery were assessed. RESULTS: Medication and diet remained unchanged in both groups during the study period. The exercise-training group improved resting hemodynamics, particularly resting heart rate (from 68.0 +/- 9.2 to 62.6 +/- 8.7 bpm, p=0.030) and systolic blood pressure (from 135 +/- 7.1 to 125.6 +/- 11.3 mm Hg, p=0.012), cardiorespiratory fitness (from 30.8 +/- 7.8 to 33.9 +/- 8.3 ml/min/kg, p=0.016), and heart rate recovery (from 20 +/- 6 to 24 +/- 5 bpm, p=0.007). No significant changes were observed in the control group. CONCLUSIONS: Exercise training improved autonomic function, assessed by heart rate recovery, resting heart rate and systolic blood pressure, in the absence of changes in diet or medication. PMID- 22226330 TI - Effects of domperidone on QTc interval in infants. AB - AIM: To prospectively evaluate the effects of oral domperidone on the QTc interval in infants. METHODS: Infants (0-1 year) with a diagnosis of gastro oesophageal reflux (GOR) disease were included. A 12-lead electrocardiography (ECG) was performed in all infants at baseline and 1 h after the intake of domperidone after 7-14 days; the corrected QTc interval was calculated by one investigator (MV) according to Bazett's formula. RESULTS: Forty-five infants were enrolled in this study. The mean gestational age was of 38.6 weeks (35.5-42.0), and the mean age at the start of domperidone was 75.3 days (19-218 days). No statistically significant difference in corrected QTc was observed between baseline and the second ECG (0.389 +/- 0.02 vs. 0.397 +/- 0.31; p 0.130)). A trend was observed regarding gender: Although there was no difference in QTc change in girls (p 0.622), there was a strong trend in boys (p 0.051). Two infants (both boys) had a clinically significant QTc prolongation (> 460 msec) without symptoms. The Spearman correlation test showed no relation between the QTc change and age (r: -0.05822; p 0.7284). There was no relation between domperidone dosage and QTc change. CONCLUSION: Overall, the group-analysis showed no statistical significant difference in QTc duration induced by domperidone. However, 2/45 (4.4%) infants had a prolonged QTc interval (> 460 msec) induced by domperidone. As a consequence, QTc measurement should be recommended in routine in infants when domperidone is started. PMID- 22226331 TI - How large is the lung recruitability in early acute respiratory distress syndrome: a prospective case series of patients monitored by computed tomography. AB - INTRODUCTION: The benefits of higher positive end expiratory pressure (PEEP) in patients with acute respiratory distress syndrome (ARDS) have been modest, but few studies have fully tested the "open-lung hypothesis". This hypothesis states that most of the collapsed lung tissue observed in ARDS can be reversed at an acceptable clinical cost, potentially resulting in better lung protection, but requiring more intensive maneuvers. The short-/middle-term efficacy of a maximum recruitment strategy (MRS) was recently described in a small physiological study. The present study extends those results, describing a case-series of non-selected patients with early, severe ARDS submitted to MRS and followed until hospital discharge or death. METHODS: MRS guided by thoracic computed tomography (CT) included two parts: a recruitment phase to calculate opening pressures (incremental steps under pressure-controlled ventilation up to maximum inspiratory pressures of 60 cmH2O, at constant driving-pressures of 15 cmH2O); and a PEEP titration phase (decremental PEEP steps from 25 to 10 cmH2O) used to estimate the minimum PEEP to keep lungs open. During all steps, we calculated the size of the non-aerated (-100 to +100 HU) compartment and the recruitability of the lungs (the percent mass of collapsed tissue re-aerated from baseline to maximum PEEP). RESULTS: A total of 51 severe ARDS patients, with a mean age of 50.7 years (84% primary ARDS) was studied. The opening plateau-pressure was 59.6 (+/-5.9 cmH2O), and the mean PEEP titrated after MRS was 24.6 (+/-2.9 cmH2O). Mean PaO2/FiO2 ratio increased from 125 (+/-43) to 300 (+/-103; P<0.0001) after MRS and was sustained above 300 throughout seven days. Non-aerated parenchyma decreased significantly from 53.6% (interquartile range (IQR): 42.5 to 62.4) to 12.7% (IQR: 4.9 to 24.2) (P<0.0001) after MRS. The potentially recruitable lung was estimated at 45% (IQR: 25 to 53). We did not observe major barotrauma or significant clinical complications associated with the maneuver. CONCLUSIONS: MRS could efficiently reverse hypoxemia and most of the collapsed lung tissue during the course of ARDS, compatible with a high lung recruitability in non-selected patients with early, severe ARDS. This strategy should be tested in a prospective randomized clinical trial. PMID- 22226332 TI - The impact of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) on prescribing practices: an analysis of data from a large midwestern state. AB - BACKGROUND: The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) was a series of effectiveness trials. The results of these trials began publication in September 2005. Among other findings, these studies were interpreted to suggest that (1) second-generation antipsychotics might have fewer advantages over first-generation antipsychotics than had been generally thought; (2) among the agents assessed, olanzapine had the best efficacy outcome; and (3) after treatment failure with a second-generation antipsychotic, the most efficacious second-line medication is clozapine. To examine the actual impact on practice of these publications, we looked at change in physician prescribing behavior based on these 3 conclusions before and after publication of CATIE. METHOD: Rates of antipsychotic medication prescriptions to 51,459 patients with an ICD-9 code of 295 for schizophrenia were extracted from a Missouri Medicaid claims database. chi2 Tests were used to compare the rates of prescribing antipsychotic medications before and after each of 3 key CATIE publications (time 1 was September 2005, time 2 was December 2006, and time 3 was April 2006). RESULTS: At all time points, we demonstrated a decrease in prescriptions by all prescribers for olanzapine (P < .0001). One year after time 1, we found an increase in prescriptions by all prescribers for aripiprazole (P < .0001). No statistically significant increases in clozapine prescribing were observed. Also, a small but statistically significant increase was seen in prescriptions of perphenazine (P < .02 at time 3). However, this increase occurred only for prescriptions written by psychiatrists and not other prescribers. CONCLUSIONS: We found some evidence in our sample that the publication of the results from CATIE had a small but statistically significant effect on prescribing habits of psychiatrists but not other physicians in our sample population. However, larger changes occurred in prescribing behavior that were largely unrelated to the CATIE trial. We propose a hypothesis to explain the direction of observed changes. PMID- 22226333 TI - The GAG deletion in Tor1A (DYT1) is a rare cause of complex musician's dystonia. PMID- 22226334 TI - Oit1/Fam3D, a gut-secreted protein displaying nutritional status-dependent regulation. AB - Oncoprotein-induced transcript 1 (Oit1) was previously identified as a dietary fat-induced gene in the small intestine of C57Bl/6J mice. In this study, we further characterized Oit1 and its human ortholog family with sequence similarity 3, member D (Fam3D), on the messenger RNA as well as the protein level. Oit1 and Fam3D were found to be predominantly expressed in the gastrointestinal tract of mice and humans, respectively. Dietary fat induced a clear and acute up regulation of Oit1, especially in the jejunum, whereas fasting led to a reduced gene expression in the small intestine. Regarding protein expression, we found a remarkable pattern of Oit1 along the longitudinal axis of the intestine, a predominant villus-restricted expression in the proximal small intestine and a more pronounced crypt expression in the distal parts of the intestine. Using transfection experiments, we confirmed secretion of the Oit1 protein, as was predicted by a signal peptide sequence. Detection of Oit1 and Fam3D in plasma samples indicated that both proteins are secreted to the basolateral site of enterocytes. Moreover, in human plasma samples, we also found an effect of nutritional status on Fam3D levels, with a postprandial elevation and a reduction after fasting. In conclusion, Oit1 and Fam3D are gut-derived proteins that are expressed and secreted in a nutritional status-dependent manner. PMID- 22226335 TI - Visual feedback of hand trajectory and the development of infant prehension. AB - The purpose of this longitudinal infant study was to investigate the influence of visual information of the hand trajectory in the development of reaching movements in prehension. Ten infants were observed biweekly from the age of 10 weeks to 28 weeks and 1 yr. The reach kinematics were analyzed at age of reach onset, 6 mo and 1 yr of age. The results showed that infants reached for objects earlier when the visual feedback of the hand trajectory and the object were available. However, visual feedback of the hand trajectory did not change the movement speed and smoothness of the reach component at 6 mo and 1 yr of age. Infants reached for the larger object earlier and with higher velocity than for the smaller object. Visual feedback of the hand facilitates the age of reaching onset, but when the reaching movements become sufficiently stable, infants perform equally well with or without visual trajectory feedback of the hand. PMID- 22226336 TI - Epidemiology of posttransplant lymphoproliferative disorders in adult kidney and kidney pancreas recipients: report of the French registry and analysis of subgroups of lymphomas. AB - A registry of posttransplant lymphoproliferative disorders (PTLD) was set up for the entire population of adult kidney transplant recipients in France. Cases of PTLD were prospectively enrolled between January 1, 1998, and December 31, 2007. Ten-year cumulative incidence was analyzed in patients transplanted after January 1, 1989. PTLD risk factors were analyzed in patients transplanted after January 1, 1998 by Cox analysis. Cumulative incidence was 1% after 5 years, 2.1% after 10 years. Multivariate analysis showed that PTLD was significantly associated with: older age of the recipient 47-60 years and >60 years (vs. 33-46 years, adjusted hazard ratio (AHR) = 1.87, CI = 1.22-2.86 and AHR = 2.80, CI = 1.73-4.55, respectively, p < 0.0001), simultaneous kidney-pancreas transplantation (AHR = 2.52, CI = 1.27-5.01 p = 0.008), year of transplant 1998-1999 and 2000-2001 (vs. 2006-2007, AHR = 3.36, CI = 1.64-6.87 and AHR = 3.08, CI = 1.55-6.15, respectively, p = 0.003), EBV mismatch (HR = 5.31, CI = 3.36-8.39, p < 0.001), 5 or 6 HLA mismatches (vs. 0-4, AHR = 1.54, CI = 1.12-2.12, p = 0.008), and induction therapy (AHR = 1.42, CI = 1-2.02, p = 0.05). Analyses of subgroups of PTLD provided new information about PTLD risk factors for early, late, EBV positive and negative, polymorphic, monomorphic, graft and cerebral lymphomas. This nationwide study highlights the increased risk of PTLD as long as 10 years after transplantation and the role of cofactors in modifying PTLD risk, particularly in specific PTLD subgroups. PMID- 22226337 TI - Recommended or mandatory pertussis vaccination policy in developed countries: does the choice matter? AB - OBJECTIVES: To compare universal recommended and compulsory pertussis vaccination strategies in developed countries, and to discuss their effectiveness in terms of the proportion of infants and children who complete their primary course of pertussis vaccine. STUDY DESIGN: Retrospective analysis. METHOD: National pertussis surveillance and vaccination coverage data, official pertussis vaccination recommendations, and medical and epidemiological sources related to the use, safety and efficacy of whole-cell and acellular vaccines were analysed. RESULTS: Similar vaccine coverage rates among children (above 94%) can be achieved at national level regardless of the type of vaccination legislation in place. Mandatory and recommended vaccination strategies appear to be equally effective. CONCLUSIONS: The choice of vaccination strategy is based on the national history of pertussis infection, the safety of available whole-cell vaccines and the willingness of health authorities to introduce acellular vaccines into routine use. The strategies adopted in the UK and the USA are two contrasting examples of immunization policies developed on the basis of different epidemiological backgrounds. They attest to the various associations between the type of pertussis vaccine and the type of universal vaccination strategies that can be undertaken for successful pertussis control. The introduction of a mandatory policy generally takes place during a period of low vaccination coverage, and is vindicated by the need for a rapid increase in immunization uptake. Countries that have already succeeded in implementing sustainable and high rates of uptake with a voluntary approach are expected to recommend pertussis vaccination, considering this to be the most justifiable policy. PMID- 22226338 TI - Giving radioiodine? Think about airport security alarms. AB - An increased sensitivity of airport detectors, a growing number of isotopic tests, and globalization of the society have raised a number of false positive radioactive alarms at airports and public places. This paper presents two new cases of patients who triggered airport security alarms after receiving 740MBq of (131)I for non-toxic goitre and attempts to compare surprisingly limited literature concerning this problem. A 57-year-old man triggered a security alarm at three different airports on the 17th, 28th, and 31st day after radioiodine exposure. Interestingly enough, in the meantime, on the 18th and 22nd day, no radiation was detected in him at the airport where he was twice detained as a source of radiation later on. The second case presents a 45-year-old woman who activated security alarm detectors while crossing a border on her coach trip 28 days after radioiodine administration. PMID- 22226339 TI - Antioxidative responses in roots and shoots of creeping bentgrass under high temperature: effects of nitrogen and cytokinin. AB - It has been previously reported that either nitrogen (N) or cytokinin (CK) applications can alleviate heat stress injury on creeping bentgrass, with some studies reporting enhanced antioxidant metabolism being related to stress protection. The objective of this research was to investigate the simultaneous effects of CK and N on the antioxidant enzyme activity and isoforms of heat stressed creeping bentgrass. 'L-93' creeping bentgrass treated with three rates of CK (trans-zeatin riboside, tZR, 0, 10 and 100MUM, designated by CK0, 10, and 100) and two nitrogen rates (2.5 and 7.5kgNha(-1) biweekly, low and high N) in a complete factorial arrangement was maintained in a 38/28 degrees C (day/night) growth chamber for 28d and then harvested. Grass grown at high N (averaged across CK rates) had higher O(2)(-) production, H(2)O(2) concentration, and malondialdehyde content in roots. The activities of superoxide dismutase (SOD), ascorbate peroxidase (APX), and guaiacol peroxidase (POD) in roots were enhanced 19%, 22%, and 24%, respectively, by high N relative to low N. Twenty-eight days of heat stress resulted in either the development of new isoforms or enhanced isoform intensities of SOD, APX, and POD in roots compared to plant responses prior to heat stress. However, no apparent differences were observed across treatments. Both SOD and POD showed different isoform patterns between roots and shoots, suggesting the function of these isoforms could be tissue specific. Interestingly, no CK effects on these antioxidant parameters were found in this experiment. These results demonstrate the impacts of N on antioxidant metabolism of creeping bentgrass under heat stress with some differences between roots and shoots, but no simultaneous impacts of CK and N. PMID- 22226340 TI - Transcriptional regulator AtET2 is required for the induction of dormancy during late seed development. AB - During the late stages of seed development, the embryo patterning program is completed and maturation is initiated. One of the main events during the maturation phase is the acquisition of dormancy, characterized by the failure of a normally developed seed to germinate precociously. Dormancy is controlled by a complex regulatory mechanism that involves the phytohormone gibberellin (GA) and the transcription factor FUSCA3 (FUS3). Here, we demonstrate the importance of the previously characterized GA regulator EFFECTOR OF TRANSCRIPTION2 (AtET2) for correct seed development. We show that entering the maturation phase, seeds of the et2-1 mutant, which contain a non-functional AtET2 gene, fail to induce dormancy. This correlates well with the observed activity pattern of the AtET2 promoter, which is active in the maturing embryo. AtET2 action during seed development is dependent on a complex interaction with GA and the FUS3 gene, the latter evidenced by the phenotypes of the et2-1 fus3-T double mutant. We show that in vitro expressed AtET2 protein can bind to both linear and supercoiled DNA without any obvious sequence preference. This suggests that, within a larger protein complex, AtET2 might be required for the correct positioning upon the DNA. PMID- 22226341 TI - Molecular identification of a further branched-chain aminotransferase 7 (BCAT7) in tomato plants. AB - Although the branched-chain amino acids (BCAAs) are essential components of the mammalian diet, our current understanding of their metabolism in plants is still limited. It is however well known that the branched-chain amino acid transaminases (BCATs) play a crucial role in both the synthesis and degradation of the BCAAs leucine, isoleucine and valine. We previously characterized the BCAT gene family in tomato, revealing it to be highly diverse in subcellular localization, substrate preference, and expression. Here we performed further characterization of this family and provide evidence for the presence of another member, BCAT7. On mapping the chromosomal location of this enzyme, it was possible to define the exact chromosome map position of the gene. Although in Arabidopsis thaliana the AtBCAT7 has been considered a pseudo-gene, quantitative evaluation of the expression levels of this gene revealed that the expression profile of the BCAT7 in different tissues of tomato (Solanum lycopersicum cv. M82) plants is highly variable with the highest expression found in developed flowers. By using a C-terminal E-GFP gene fusion we demonstrate that the BCAT7 is extraplastidial and in combination with the kinetic characterization of BCAT7 our results suggest that it most likely operates in BCAA degradation in vivo and support our hypothesis of another functional member of BCAT family. The combined data presented are discussed within the context of BCAA metabolism and its functions in higher plants. PMID- 22226342 TI - Cloning and characterization of a sweet potato calmodulin SPCAM that participates in ethephon-mediated leaf senescence, H2O2 elevation and senescence-associated gene expression. AB - In this report a full-length cDNA, SPCAM, was isolated from ethephon-treated mature leaves of sweet potato. SPCAM contained 450 nucleotides (149 amino acids) in its open reading frame, and exhibited high amino acid sequence identities (ca. 76-100%) with several plant calmodulins, including Arabidopsis, carrot, ghost needle weed, pea, potato, soybean, sweet chestnut, and tobacco. Sweet potato SPCAM also contained four putative conserved calmodulin EF-hand motifs, which responded for Ca(2+) binding and cellular signalling. Phylogenetic tree analysis showed that sweet potato SPCAM exhibited closely-related association with Arabidopsis AtCAM7, which functioned as a transcriptional regulator. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that SPCAM gene expression was not significantly increased from L1 immature leaf to L3 mature leaf, however, was remarkably enhanced in L4 early senescent leaf, and then decreased in L5 late senescent leaf. In dark- and ethephon-treated mature leaves, SPCAM expression was significantly increased from 6 to 48h, then decreased gradually until 72h after treatment. Ethephon-mediated leaf senescence, H(2)O(2) elevation, and senescence-associated gene expression, however, was remarkably inhibited by chlorpromazine, a calmodulin inhibitor. Exogenous application of purified calmodulin SPCAM fusion protein reversed the chlorpromazine repression of ethephon-mediated leaf senescence, H(2)O(2) elevation and senescence associated gene expression. Based on these data we conclude that sweet potato SPCAM is an ethephon-inducible calmodulin and its expression is enhanced in natural and induced senescent leaves. Calmodulin SPCAM may play a physiological role in ethephon-mediated leaf senescence, H(2)O(2) elevation and senescence associated gene expression in sweet potato leaves. PMID- 22226343 TI - Inhaled loxapine for agitation revisited: focus on effect sizes from 2 Phase III randomised controlled trials in persons with schizophrenia or bipolar disorder. AB - OBJECTIVE: To describe the efficacy of inhaled loxapine for the treatment of agitation associated with schizophrenia or bipolar disorder using different examples of effect size (ES). DATA SOURCES: Psychopharmacologic Drug Advisory Committee briefing documents as prepared by the product manufacturer and by the US Food and Drug Administration. STUDY SELECTION: Phase III clinical trials. DATA EXTRACTION: Effect size for primary and secondary efficacy outcomes. DATA SYNTHESIS: Two similarly designed Phase III studies were completed with one conducted in patients with agitation associated with schizophrenia and one in patients with agitation associated with bipolar I disorder, manic or mixed episodes. In both studies, onset of anti-agitation effect was observed at 10 min (first time-point measured) for both the 5 mg and 10 mg doses, as evidenced by time to first statistically significant change from baseline on the Positive and Negative Syndrome Scale, Excited Component (PEC) as compared to placebo. Loxapine remained superior to placebo throughout the remainder of the study at all-time points measured. In the schizophrenia study, the ES difference from placebo on the PEC at 2 h was 0.45 for the 5 mg dose and 0.60 for the 10 mg dose (Cohen's d). ES differences for Clinical Global Impressions-Improvement (CGI-I) were similar. Prior to rounding up, the number needed to treat (NNT) for PEC response and CGI-I response vs. placebo were 4.1 and 4.6, respectively, for loxapine 5 mg and 3.2 and 3.2, respectively, for the 10 mg dose. For the outcome of requiring only one dose of study medication and no rescue medication, the NNT vs. placebo for the 5 mg dose was not statistically significant but was statistically significant for the 10 mg dose vs. placebo with a value of 7. When plotting the PEC responders over time NNT becomes more robust as time after dosing elapses, with the 10 mg dose reaching a NNT of 4 by 20 min. For the bipolar disorder study, the ES difference from placebo on the PEC at 2 h was 0.73 for the 5 mg dose and 0.94 for the 10 mg dose. ES differences for the CGI-I were somewhat higher. Prior to rounding up, NNT for response vs. placebo for PEC and CGI-I criteria were 2.9 and 2.6, respectively, for the loxapine 5 mg dose and 2.2 and 2.1, respectively, for the 10 mg dose. For the outcome of requiring only one dose of study medication and no rescue medication, the NNT vs. placebo for the 5 mg dose was 7 and for the 10 mg dose was 3. The NNT difference between 5 mg vs. 10 mg was statistically significant in favour of the 10 mg dose and had a value of 5. When plotting the PEC responders over time NNT becomes more robust as time after dosing elapses, with the 10 mg dose reaching a NNT of 3 by 20 min. Additional information regarding pulmonary safety demonstrated low rates of pulmonary adverse events among those subjects in the efficacy trials, however, in separate Phase I safety studies conducted in persons with asthma and COPD, respiratory symptoms and/or changes in flow parameters were common. CONCLUSIONS: Inhaled loxapine is a non-invasive treatment option for the management of agitation associated with schizophrenia or bipolar disorder. Effect sizes for inhaled loxapine vs. placebo are robust and on par with those observed with intramuscular antipsychotics and benzodiazepines. Onset of action is rapid. The magnitudes of the effect sizes were generally larger for the 10 mg dose vs. the 5 mg dose, and the overall data supports the 10 mg dose as the dominant choice. The efficacy profile of inhaled loxapine will need to be viewed within the context of its pulmonary safety profile. The advisers to the Food and Drug Administration recommended that inhaled loxapine be restricted to a single dose in 24 h and be subject to a Risk Evaluation and Mitigation Strategy programme. PMID- 22226344 TI - Three-year mortality among alcoholic patients after intensive care: a population based cohort study. AB - INTRODUCTION: Alcoholic patients comprise a large proportion of patients in intensive care units (ICUs). However, data are limited on the impact of alcoholism on mortality after intensive care. METHODS: We conducted a cohort study among 16,848 first-time ICU patients between 2001 and 2007 to examine 30 day and 3-year mortality among alcoholic patients. Alcoholic patients with and without complications of alcohol misuse (for example, alcoholic liver disease) were identified from previous hospital contacts for alcoholism-related conditions or redemption of a prescription for alcohol deterrents. Data on medication use, demographics, hospital diagnoses, and comorbidity were obtained from medical databases. We computed 30-day and 3-year mortality and mortality rate ratios (MRRs) by using Cox regression analysis, controlling for covariates. RESULTS: In total, 1,229 (7.3%) ICU patients were current alcoholics. Among alcoholic patients without complications of alcoholism (n=785, 4.7% of the cohort), 30-day mortality was 15.9% compared with 19.7% among nonalcoholic patients. Compared with nonalcoholic patients, the adjusted 30-day MRR was 1.04 (95% confidence interval (CI), 0.87 to 1.25). Three-year mortality was 36.2% compared with 40.9% among nonalcoholic patients, corresponding to an adjusted 3-year MRR of 1.16 (95% CI, 1.03 to 1.31). For alcoholic patients with complications (n=444, 2.6% of the cohort), 30-day mortality was 33.6%, and 3-year mortality was 64.5%, corresponding to adjusted MRRs, with nonalcoholics as the comparator, of 1.64 (95% CI, 1.38 to 1.95) and 1.67 (95% CI, 1.48 to 1.90), respectively. CONCLUSIONS: Alcoholic ICU patients with chronic complications of alcoholism have substantially increased 30-day and 3-year mortality. In contrast, alcoholics without complications have no increased 30-day and only slightly increased 3- year mortality. PMID- 22226345 TI - Untapping the potential of human retinal pigmented epithelial cells. AB - The innate capacity of adult somatic cells has many potential applications in regenerative medicine. In this issue of Cell Stem Cell, Salero et al. (2012) describe an adult retinal stem cell population capable of generating neural and mesenchymal cell lineages. PMID- 22226346 TI - Tales from the crypt: the expanding role of slow cycling intestinal stem cells. AB - Similar to other highly self-renewing tissues, the intestinal epithelium contains both slowly and rapidly cycling progenitor/stem cells, though their relationship has been largely unexplored. Two recent reports in Nature (Tian et al., 2011) and Science (Takeda et al., 2011) shed new light on their dynamic interplay. PMID- 22226347 TI - Cbx proteins help ESCs walk the line between self-renewal and differentiation. AB - The Polycomb repressive complexes (PRC) regulate self-renewal and differentiation in embryonic stem cells (ESCs). In this issue of Cell Stem Cell, Morey et al. (2012) and O'Loghlen et al. (2012) report that dynamic interchange of PRC subunits modulates the balance between self-renewal and lineage commitment in ESCs. PMID- 22226348 TI - Stem cells deployed for bone repair hijacked by T cells. AB - Mesenchymal stem cells (MSCs) are a promising source for bone regeneration. Recently, in Nature Medicine, Liu et al. (2011) reported that host lymphocytes secrete IFN-gamma and TNF-alpha to initiate apoptosis of transplanted MSCs and that aspirin can alleviate these effects to improve bone repair. PMID- 22226349 TI - Limited acquisition of chromosomal aberrations in human adult mesenchymal stromal cells. PMID- 22226351 TI - Stem cell science on the rise in China. AB - China's output in fundamental stem cell research has increased markedly in recent years. Vigorous public investment and infrastructure development have enabled major productivity gains, but challenges in regulation, governance, and the management of clinical expectations must be addressed to ensure scientific quality and sustainable growth. PMID- 22226353 TI - ISSCR: beginning the next chapter. PMID- 22226352 TI - Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. AB - Cardiovascular disease is a leading cause of death worldwide. The limited capability of heart tissue to regenerate has prompted methodological developments for creating de novo cardiomyocytes, both in vitro and in vivo. Beyond uses in cell replacement therapy, patient-specific cardiomyocytes may find applications in drug testing, drug discovery, and disease modeling. Recently, approaches for generating cardiomyocytes have expanded to encompass three major sources of starting cells: human pluripotent stem cells (hPSCs), adult heart-derived cardiac progenitor cells (CPCs), and reprogrammed fibroblasts. We discuss state-of-the art methods for generating de novo cardiomyocytes from hPSCs and reprogrammed fibroblasts, highlighting potential applications and future challenges. PMID- 22226354 TI - MicroRNA regulation of Cbx7 mediates a switch of Polycomb orthologs during ESC differentiation. AB - The Polycomb Group (PcG) of chromatin modifiers regulates pluripotency and differentiation. Mammalian genomes encode multiple homologs of the Polycomb repressive complex 1 (PRC1) components, including five orthologs of the Drosophila Polycomb protein (Cbx2, Cbx4, Cbx6, Cbx7, and Cbx8). We have identified Cbx7 as the primary Polycomb ortholog of PRC1 complexes in embryonic stem cells (ESCs). The expression of Cbx7 is downregulated during ESC differentiation, preceding the upregulation of Cbx2, Cbx4, and Cbx8, which are directly repressed by Cbx7. Ectopic expression of Cbx7 inhibits differentiation and X chromosome inactivation and enhances ESC self-renewal. Conversely, Cbx7 knockdown induces differentiation and derepresses lineage-specific markers. In a functional screen, we identified the miR-125 and miR-181 families as regulators of Cbx7 that are induced during ESC differentiation. Ectopic expression of these miRNAs accelerates ESC differentiation via regulation of Cbx7. These observations establish a critical role for Cbx7 and its regulatory miRNAs in determining pluripotency. PMID- 22226355 TI - Nonoverlapping functions of the Polycomb group Cbx family of proteins in embryonic stem cells. AB - Polycomb group proteins are essential regulators of cell fate decisions during embryogenesis. In mammals, at least five different Cbx proteins (Cbx2, Cbx4, Cbx6, Cbx7, and Cbx8) are known to associate with the core Polycomb repressive complex 1 (PRC1). Here we show that pluripotency and differentiation of mouse embryonic stem cells (ESCs) is regulated by different Cbx-associated PRC1 complexes with unique functions. Maintenance of pluripotency primarily depends on Cbx7, while lineage commitment is orchestrated by Cbx2 and Cbx4. At the molecular level, we have uncovered a Polycomb autoregulatory loop in which Cbx7 represses the expression of prodifferentiation Cbx proteins, thereby maintaining the pluripotent state. We additionally show that the occupancy of Cbx7 on promoters is completely dependent on PRC2 activity but only partially dependent on a functional PRC1 complex. Thus, Cbx proteins confer distinct target selectivity to the PRC1 complex, achieving a balance between the self-renewal and the differentiation of ESCs. PMID- 22226357 TI - Diazepam binding inhibitor promotes progenitor proliferation in the postnatal SVZ by reducing GABA signaling. AB - The subventricular zone (SVZ) of the lateral ventricles is the largest neurogenic niche of the postnatal brain. New SVZ-generated neurons migrate via the rostral migratory stream to the olfactory bulb (OB) where they functionally integrate into preexisting neuronal circuits. Nonsynaptic GABA signaling was previously shown to inhibit SVZ-derived neurogenesis. Here we identify the endogenous protein diazepam binding inhibitor (DBI) as a positive modulator of SVZ postnatal neurogenesis by regulating GABA activity in transit-amplifying cells. We performed DBI loss- and gain-of-function experiments in vivo at the peak of postnatal OB neuron generation in mice and demonstrate that DBI enhances proliferation by preventing SVZ progenitors to exit the cell cycle. Furthermore, we provide evidence that DBI exerts its effect on SVZ progenitors via its octadecaneuropeptide proteolytic product (ODN) by inhibiting GABA-induced currents. Together our data reveal a regulatory mechanism by which DBI counteracts the inhibitory effect of nonsynaptic GABA signaling on subventricular neuronal proliferation. PMID- 22226356 TI - Paracrine TGF-beta signaling counterbalances BMP-mediated repression in hair follicle stem cell activation. AB - Hair follicle (HF) regeneration begins when communication between quiescent epithelial stem cells (SCs) and underlying mesenchymal dermal papillae (DP) generates sufficient activating cues to overcome repressive BMP signals from surrounding niche cells. Here, we uncover a hitherto unrecognized DP transmitter, TGF-beta2, which activates Smad2/3 transiently in HFSCs concomitant with entry into tissue regeneration. This signaling is critical: HFSCs that cannot sense TGF beta exhibit significant delays in HF regeneration, whereas exogenous TGF-beta2 stimulates HFSCs in vivo and in vitro. By engineering TGF-beta- and BMP-reporter mice, we show that TGF-beta2 signaling antagonizes BMP signaling in HFSCs but not through competition for limiting Smad4-coactivator. Rather, our microarray, molecular, and genetic studies unveil Tmeff1 as a direct TGF-beta2/Smad2/3 target gene, expressed by activated HFSCs and physiologically relevant in restricting and lowering BMP thresholds in the niche. Connecting BMP activity to an SC's response to TGF-betas may explain why these signaling factors wield such diverse cellular effects. PMID- 22226358 TI - Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives. AB - The retinal pigment epithelium (RPE) is a monolayer of cells underlying and supporting the neural retina. It begins as a plastic tissue, capable, in some species, of generating lens and retina, but differentiates early in development and remains normally nonproliferative throughout life. Here we show that a subpopulation of adult human RPE cells can be activated in vitro to a self renewing cell, the retinal pigment epithelial stem cell (RPESC) that loses RPE markers, proliferates extensively, and can redifferentiate into stable cobblestone RPE monolayers. Clonal studies demonstrate that RPESCs are multipotent and in defined conditions can generate both neural and mesenchymal progeny. This plasticity may explain human pathologies in which mesenchymal fates are seen in the eye, for example in proliferative vitroretinopathy (PVR) and phthisis bulbi. This study establishes the RPESC as an accessible, human CNS derived multipotent stem cell, useful for the study of fate choice, replacement therapy, and disease modeling. PMID- 22226359 TI - Rejuvenation of regeneration in the aging central nervous system. AB - Remyelination is a regenerative process in the central nervous system (CNS) that produces new myelin sheaths from adult stem cells. The decline in remyelination that occurs with advancing age poses a significant barrier to therapy in the CNS, particularly for long-term demyelinating diseases such as multiple sclerosis (MS). Here we show that remyelination of experimentally induced demyelination is enhanced in old mice exposed to a youthful systemic milieu through heterochronic parabiosis. Restored remyelination in old animals involves recruitment to the repairing lesions of blood-derived monocytes from the young parabiotic partner, and preventing this recruitment partially inhibits rejuvenation of remyelination. These data suggest that enhanced remyelinating activity requires both youthful monocytes and other factors, and that remyelination-enhancing therapies targeting endogenous cells can be effective throughout life. PMID- 22226360 TI - Green tea: a promising natural product in oral health. AB - Green tea is a leading beverage in the Far East for thousands of years; it is regarded for a long time as a health product. Green tea is important source of polyphenol antioxidants. Polyphenols including epigallocatechin 3 gallate (EGCG) constitute the most interesting components in green tea leaves. Green tea has the potential to protect against various malignant, cardiovascular and metabolic diseases. There is a growing body of evidence pointing a beneficial role of green tea and its polyphenols in oral health. Green tea protects against bacterial induced dental caries. Tea polyphenols possess antiviral properties, believed to help in protection from influenza virus. Additionally, green tea polyphenols can abolish halitosis through modification of odorant sulphur components. Oral cavity oxidative stress and inflammation, consequent to cigarette smoking and cigarettes' deleterious compounds nicotine and acrolein, may be reduced in the presence of green tea polyphenols. Generally, green tea defends healthy cells from malignant transformation and locally has the ability to induce apoptosis in oral cancer cells. All together, there is an increasing interest in the health benefits of green tea in the field of oral health. Nonetheless, there is still a need for more clinical and biological studies to support guidelines for green tea intake as part of prevention and treatment of specific oral pathologies. PMID- 22226361 TI - K-lactate and high pressure effects on the safety and quality of restructured hams. AB - The use of K-lactate in combination with new elaboration procedures and high pressure (HP) treatments may help to produce safe, salt-reduced restructured dry cured ham with no sensory defects. The effect of K-lactate addition on the microbiota of restructured hams manufactured with a reduced salt content was evaluated after the resting period (16% weight loss) and at two drying levels (40% and 50% weight loss). Additionally, the effect of high pressure (HP) on the microbiota and sensory characteristics of hams at 50% weight loss was evaluated. K-lactate reduced a(w) and microbiota of processed hams, mainly in the inner parts, and had no effect on color or sensory parameters. HP treatment at 600 MPa provided an additional reduction in the microbiological counts, increased pink color, brightness, hardness and saltiness and reduced pastiness and adhesiveness. PMID- 22226362 TI - The effect of temperature on the activity of MU- and m-calpain and calpastatin during post-mortem storage of porcine longissimus muscle. AB - The experiment was conducted to determine the effect of temperature during post mortem muscle storage on the activity of the calpain system, the myofibril fragmentation and the free calcium concentration. Porcine longissimus muscle were incubated from 2h post-mortem at temperatures of 2, 15, 25 and 30 degrees C and sampling times were at 2, 6, 24, 48 and 120 h post-mortem. After 120 h at 30 degrees C the free calcium concentration increased to 530 MUM from 440 MUM at 2 degrees C. Incubation at temperatures higher than 2 degrees C resulted in the appearance of autolyzed m-calpain activity and a decrease of native m-calpain activity. Native m-calpain decreased more slowly than native MU-calpain, and the autolysis process started later. Myofibril fragmentation increased with storage time and incubation temperature, while calpastatin activity decreased. The study showed that high temperature incubation not only rapidly activated MU-calpain but at higher temperatures and later time points also m-calpain. PMID- 22226363 TI - High pre rigor temperature limits the ageing potential of beef that is not completely overcome by electrical stimulation and muscle restraining. AB - Two simultaneous trials were conducted to determine the effects of electrical input [electrical stunning and stimulation (ES)], wrapping, pre rigor temperature (15 degrees C and 38 degrees C) and different post rigor chilling rates on beef quality using M. longissimus lumborum (n=100). The high pre rigor temperature induced a faster pH decline than ES. The loins at 38 degrees C had significantly greater protein denaturation, more purge and drip loss, higher shear force values and less desmin degradation compared with the loins at 15 degrees C. No difference in sarcomere length was determined between the pre rigor temperatures regardless of ES and wrapping. Different post rigor chilling rates did not play a substantial role in water-holding capacity, proteolysis, or shear force values during ageing. These results suggest that high pre rigor temperature induces temperature-related toughness of muscle due to protein denaturation with subsequent limitation of proteolysis by MU-calpain, regardless of ES and wrapping treatments. PMID- 22226364 TI - Asymptomatic giant coronary aneurysm in an adolescent with Behcet's syndrome. AB - OBJECTIVE: Behcet's is an idiopathic multi-organ syndrome, which may have onset during childhood. Vascular involvement is uncommon, with rarely reported coronary aneurysm formation. We present a case report of a teenager girl who developed recalcitrant life-threatening Behcet's vasculitis, involving both small and large venous and arterial systems including a giant coronary aneurysm. CASE REPORT: De identified data were collected retrospectively in case report format. Although our sixteen year old female with Behcet's vasculitis had resolution of many arterial aneurysms, she had persistent venous thrombosis of large vessels, as well as persistent, giant arterial aneurysms requiring intra-arterial coiling of a lumbar artery and coronary bypass grafting despite intensive immunosuppression including glucocorticoids, cyclophosphamide, infliximab, methotrexate, azathioprine and intravenous immunoglobulin. CONCLUSIONS: Vascular manifestations may be seen in Behcet's syndrome, including asymptomatic coronary aneurysm, which may be refractory to immunosuppression and ultimately require surgical intervention. Increased awareness is essential for prompt diagnosis and management. PMID- 22226365 TI - Heterogeneous reactions of suspended parathion, malathion, and fenthion particles with NO(3) radicals. AB - Organophosphorus pesticides (OPPs) emit into the atmosphere in both gas and particulate phases via spray drift from treatments and post-application emission, but most of their degradations in the atmosphere are not well known. In this study, the heterogeneous reactions of nitrate (NO(3)) radicals with three typical OPPs (parathion, malathion, and fenthion) absorbed on azelaic acid particles are investigated using an online vacuum ultraviolet photoionization aerosol time-of flight mass spectrometer (VUV-ATOFMS). The reaction products observed with the VUV-ATOFMS are identified on the basis of GC/MS analysis of the products in the reaction between NO(3) radicals and the coating of the pesticide. Paraoxon is identified as the only product of parathion; malaoxon and bis(1,2-bis ethoxycarbonylethyl)disulfide as the products of malathion; fenoxon, fenoxon sulfoxide, fenthion sulfoxide, fenoxon sulfone, and fenthion sulfone as the products of fenthion. The degradation rates of parathion, malathion, and fenthion under the experimental conditions are 5.5*10(-3), 5.6*10(-2), and 3.3*10(-2)s( 1), respectively. The pathways of the heterogeneous reactions between the three OPPs and NO(3) radicals are proposed. The experimental results reveal the possible transformations of these OPPs through the oxidation of NO(3) radicals in the atmosphere. PMID- 22226366 TI - Qualitative structure residue relationship analysis in the determination of the maximum residue limit of veterinary drugs. AB - Aim of the present study was an attempt to find a correlation between physicochemical structure of veterinary drugs and the maximum residue limit (MRL) for muscle tissue of food producing animals. Direct correlation and analysis in quintile groups for 52 physicochemical parameters were performed. An internal validation using leave-one-out cross-validation was performed. In the quintile groups, there were 11 arithmetic expressions created for the limited group of individual parameters (13 from 52 analyzed), which showed a significant linear or quadratic correlation between the number of quintile group and the mean value of MRL within the quintile. The results obtained suggest that there is no direct correlation between individual physicochemical parameters and MRL value in muscle tissue; however, such correlation can be determined for arithmetic expressions created on the basis of several physicochemical parameters, using quintile group analysis. PMID- 22226367 TI - Effects of calcium peroxide on arsenic uptake by celery (Apium graveolens L.) grown in arsenic contaminated soil. AB - The ability of calcium peroxide (CaO(2)) to immobilize As of contaminated soil was studied using pot and field experiments. In pot experiment, CaO(2) applied at 2.5 and 5 g kg(-1) significantly increased celery shoot weight and decreased shoot As accumulation, which was ascribed to the formation of stable crystalline Fe and Al oxides bound As and the reduction of labile As fractions in the soil. The labile As fractions were pH dependent and it followed a "V" shaped profile with the change of pH. In field experiment, the dose of CaO(2) application at 750 kg ha(-1) was optimal and at which the celery was found to produce the highest biomass (63.4 Mg ha(-1)) and lowest As concentration (0.43 mg kg(-1)). CaO(2) probably has a promising potential as soil amendment to treat As contaminated soils. PMID- 22226368 TI - Atypical case of Wolfram syndrome revealed through targeted exome sequencing in a patient with suspected mitochondrial disease. AB - BACKGROUND: Mitochondrial diseases comprise a diverse set of clinical disorders that affect multiple organ systems with varying severity and age of onset. Due to their clinical and genetic heterogeneity, these diseases are difficult to diagnose. We have developed a targeted exome sequencing approach to improve our ability to properly diagnose mitochondrial diseases and apply it here to an individual patient. Our method targets mitochondrial DNA (mtDNA) and the exons of 1,600 nuclear genes involved in mitochondrial biology or Mendelian disorders with multi-system phenotypes, thereby allowing for simultaneous evaluation of multiple disease loci. CASE PRESENTATION: Targeted exome sequencing was performed on a patient initially suspected to have a mitochondrial disorder. The patient presented with diabetes mellitus, diffuse brain atrophy, autonomic neuropathy, optic nerve atrophy, and a severe amnestic syndrome. Further work-up revealed multiple heteroplasmic mtDNA deletions as well as profound thiamine deficiency without a clear nutritional cause. Targeted exome sequencing revealed a homozygous c.1672C > T (p.R558C) missense mutation in exon 8 of WFS1 that has previously been reported in a patient with Wolfram syndrome. CONCLUSION: This case demonstrates how clinical application of next-generation sequencing technology can enhance the diagnosis of patients suspected to have rare genetic disorders. Furthermore, the finding of unexplained thiamine deficiency in a patient with Wolfram syndrome suggests a potential link between WFS1 biology and thiamine metabolism that has implications for the clinical management of Wolfram syndrome patients. PMID- 22226369 TI - Increased gene dosage of the Ink4/Arf locus does not attenuate atherosclerosis development in hypercholesterolaemic mice. AB - RATIONALE: Human genome-wide association studies have identified genetic variants in the chromosome 9p21 region that confer increased risk of coronary artery disease and other age-related diseases. These variants are located in a block of high linkage disequilibrium with the neighboring Ink4/Arf tumor-suppressor locus (also named CDKN2A/CDKN2B). Since previous studies suggest an atheroprotective role of the Ink4/Arf locus, here we assessed whether gain-of-function of the encoded genes can be exploited therapeutically to reduce atherosclerosis. METHODS: Generation and characterization of apolipoprotein E-null mice carrying an additional transgenic copy of the entire Ink4/Arf locus (apoE-/-Super Ink4/Arf) that reproduces the normal expression and regulation of the endogenous locus. RESULTS: Although liver and aorta of apoE-/-Super-Ink4/Arf mice only showed a trend towards increased Ink4/Arf transcript levels compared to apoE-/- controls, cultured macrophages with increased Ink4/Arf gene dosage exhibited augmented apoptosis induced by irradiation with ultraviolet light, indicating that low level of transgene overexpression can lead to augmented Ink4/Arf function. However, increased Ink4/Arf gene dosage did not affect atherosclerosis development in different vascular regions of both male and female apoE-/- mice fed either normal or high-fat diet. Increased gene dosage of Ink4/Arf similarly had no effect on atheroma cell composition or collagen content, an index of plaque stability. CONCLUSION: In contrast with previous studies demonstrating cancer resistance in Super-Ink4/Arf mice carrying an additional transgenic copy of the entire Ink4/Arf locus, our results cast doubt on the potential of Ink4/Arf activation as a strategy for the treatment of atherosclerotic disease. PMID- 22226370 TI - IL-21 and Sjogren's syndrome. AB - Treatment of Sjogren's syndrome is almost entirely symptomatic. A lack of true understanding of the underlying immunological pathology of the disease prevents directed therapy. Interleukin-21 (IL-21) is elevated in the serum of patients with this disease and is expressed by the lymphocytes infiltrating the salivary glands. The known functions of IL-21 in facilitating differentiation, proliferation, and survival of both B and T cells mesh well with the findings in Sjogren's syndrome. Demonstration of IL-21 as a fundamental aspect of the pathophysiology of Sjogren's syndrome could lead to the development of anti-IL-21 therapy for this disease. PMID- 22226371 TI - Successful dose finding with sublingual fentanyl tablet: combined results from 2 open-label titration studies. AB - OBJECTIVE: This analysis was conducted to determine the likelihood of identifying an effective dose of fentanyl sublingual tablet during the initial titration phase of 2 clinical trials, to characterize the actual effective dose in patients achieving successful titration, and to examine the relationship between baseline characteristics and likelihood of achieving an effective dose. METHODS: Data were derived from 2 clinical trials (Study 1, n=131; Study 2, n=139) of fentanyl sublingual tablet in patients with cancer-associated breakthrough pain (BTP). Both trials comprised a 2-week titration phase and 12-month maintenance phase. The initial dose was 100 MUg, titrated to an effective dose (producing effective relief of all BTP episodes on 2 consecutive days) of 100 to 800 MUg. RESULTS: A total of 270 patients entered the titration phase. Mean (SD) baseline BTP opioid dose was 25.7 (88.9) mg morphine equivalent, and mean baseline around-the-clock opioid dose was 196.5 (151.6) mg morphine equivalent. Using conservative criteria for determining effective dose, 174 patients (64.4%) were successfully titrated to an effective dose (mean [SD], 498.2 [234.8] MUg). The most frequent (27.6%) effective dose was 800 MUg, and more than 85% of patients required an effective dose >=300 MUg. There were no significant relationships between any baseline characteristics and titration success. CONCLUSION: Despite stringent criteria, 64.4% of patients achieved an effective dose of fentanyl sublingual tablet within the dose range of 100 to 800 MUg. Baseline characteristics were not identified to be associated with the likelihood of successful titration or with the actual effective dose of fentanyl sublingual tablet. PMID- 22226372 TI - Variable stimulation patterns in younger and older thenar muscle. AB - Neuromuscular electrical stimulation (NMES) is typically used with older adults receiving rehabilitation therapies, but little is known about the stimulation patterns that maximize force output and minimize fatigue in this population. The purpose of this study was to apply variable patterns of stimulation to the thenar muscles of the hand in younger and older adults to determine if force production and neuromuscular fatigue effects were similar. Three submaximal stimulation patterns were administered: A 20Hz constant frequency pattern, a pattern that increased from 20 to 40Hz, and a pattern that incorporated two closely spaced (5ms) doublet pulses. The doublet stimulation produced significantly higher average forces and force-time integrals (FTIs) than the constant frequency and increasing frequency patterns in both age groups. Additionally, older adults showed less fatigue than the younger group during isometric contractions performed after the fatiguing stimulation patterns. These results suggest that variable pulse NMES patterns enhance force production in the hand in both younger and older individuals better than constant frequency patterns, which are typically used in clinical applications. Also, greater fatigue resistance to electrical stimulation protocols may exist in the older population; this is critical information for the design and application of NMES rehabilitation regimens used with older adults. PMID- 22226373 TI - High prevalence of thyroid peroxidase antibodies in patients with alopecia areata. PMID- 22226374 TI - Abasic sites linked to dUTP incorporation in DNA are a major cause of spontaneous mutations in absence of base excision repair and Rad17-Mec3-Ddc1 (9-1-1) DNA damage checkpoint clamp in Saccharomyces cerevisiae. AB - In Saccharomyces cerevisiae, inactivation of base excision repair (BER) AP endonucleases (Apn1p and Apn2p) results in constitutive phosphorylation of Rad53p and delay in cell cycle progression at the G2/M transition. These data led us to investigate genetic interactions between Apn1p, Apn2p and DNA damage checkpoint proteins. The results show that mec1 sml1, rad53 sml1 and rad9 is synthetic lethal with apn1 apn2. In contrast, apn1 apn2 rad17, apn1 apn2 ddc1 and apn1 apn2 rad24 triple mutants are viable, although they exhibit a strong Can(R) spontaneous mutator phenotype. In these strains, high Can(R) mutation rate is dependent upon functional uracil DNA N-glycosylase (Ung1p) and mutation spectra are dominated by AT to CG events. The results point to a role for Rad17-Mec3-Ddc1 (9-1-1) checkpoint clamp in the prevention of mutations caused by abasic (AP) sites linked to incorporation of dUTP into DNA followed by the excision of uracil by Ung1p. The antimutator role of the (9-1-1) clamp can either rely on its essential function in the induction of the DNA damage checkpoint or to another function that specifically impacts DNA repair and/or mutagenesis at AP sites. Here, we show that the abrogation of the DNA damage checkpoint is not sufficient to enhance spontaneous mutagenesis in the apn1 apn2 rad9 sml1 quadruple mutant. Spontaneous mutagenesis was also explored in strains deficient in the two major DNA N-glycosylases/AP-lyases (Ntg1p and Ntg2p). Indeed, apn1 apn2 ntg1 ntg2 exhibits a strong Ung1p-dependent Can(R) mutator phenotype with a spectrum enriched in AT to CG, like apn1 apn2 rad17. However, genetic analysis reveals that ntg1 ntg2 and rad17 are not epistatic for spontaneous mutagenesis in apn1 apn2. We conclude that under normal growth conditions, dUTP incorporation into DNA is a major source of AP sites that cause high genetic instability in the absence of BER factors (Apn1p, Apn2p, Ntg1p and Ntg2p) and Rad17-Mec3-Ddc1 (9-1 1) checkpoint clamp in yeast. PMID- 22226376 TI - [Role of imaging techniques in the TNM classification of non-small cell bronchogenic carcinoma]. AB - The Seventh Edition of the TNM Classification for non-small cell bronchogenic carcinomas include a series of changes in the T and M descriptor, in particular a re-classification of malignant pleural and pericardial effusions and of separated tumour nodes, new tumour size cut-off values and sub-divisions of the T1-T2 and M1 categories. We review these corrections that led to the changes in the staging system that affects stages II-III. Furthermore, we describe and illustrate the role of the different imaging techniques in tumour staging (CT, PET, PET-CT and MRI), highlighting their respective indications, advantages and disadvantages, as well their complementary function. PMID- 22226377 TI - [Analysis of left ventricular diastolic function using magnetic resonance imaging]. AB - Heart failure is not always due to an alteration in systolic function, and a diastolic dysfunction could explain many cases of heart failure with a normal systolic function. Diastolic function depends on the left ventricular filling capacity to ensure a normal stroke volume. It is routinely measured with transthoracic echocardiography, as it is an easily accessible non-invasive test. The MRI, using flow sequences, shows good agreement with the echocardiography, analysing the diastolic function in a practical way, by the flow into the mitral valve and pulmonary veins. In this sense, the analysis of diastolic function should be added as part of a routine cardiac MR examination. PMID- 22226375 TI - Factors associated with the persistence and onset of new anxiety disorders in youth with bipolar spectrum disorders. AB - OBJECTIVE: Anxiety disorders are among the most common comorbid conditions in youth with bipolar disorder, but, to our knowledge, no studies examined the course of anxiety disorders in youth and adults with bipolar disorder. METHOD: As part of the Course and Outcome of Bipolar Youth study, 413 youth, ages 7 to 17 years who met criteria for Diagnostic and Statistical Manual, Fourth Edition (DSM IV) bipolar I disorder (n = 244), bipolar II disorder (n = 28), and operationally defined bipolar disorder not otherwise specified (n = 141) were recruited primarily from outpatient clinics. Subjects were followed on average for 5 years using the Longitudinal Interval Follow-Up Evaluation. We examined factors associated with the persistence (> 50% of the follow-up time) and onset of new anxiety disorders in youth with bipolar disorder. RESULTS: Of the 170 youth who had anxiety at intake, 80.6% had an anxiety disorder at any time during the follow-up. Most of the anxiety disorders during the follow-up were of the same type as those present at intake. About 50% of the youth had persistent anxiety, particularly generalized anxiety disorder (GAD). Persistence was associated with multiple anxiety disorders, less follow-up time in euthymia, less conduct disorder, and less treatment with antimanic and antidepressant medications (all P values <= .05). Twenty-five percent of the sample who did not have an anxiety disorder at intake developed new anxiety disorders during follow-up, most commonly GAD. The onset of new anxiety disorders was significantly associated with being female, lower socioeconomic status, presence of attention deficit/hyperactivity disorder and substance use disorder, and more follow-up time with manic or hypomanic symptoms (all P values <= .05) CONCLUSIONS: Anxiety disorders in youth with bipolar disorder tend to persist, and new-onset anxiety disorders developed in a substantial proportion of the sample. Early identification of factors associated with the persistence and onset of new anxiety disorders may enable the development of strategies for treatment and prevention. PMID- 22226379 TI - ApoE4 and late onset depression in Indian population. AB - OBJECTIVE: ApoE4 is a 'risk factor' for cognitive disorders like Alzheimer's dementia, and Late Onset Depression (LOD) is a forerunner of dementia. There is thus a need to study the association between ApoE4 allele and LOD. METHOD: The study assessed the frequency of ApoE4 allele in 31 cases of LOD above the age of 50 years and 31 matched controls. The subjects were assessed on various clinical parameters towards diagnosis. RESULTS: There was a significant association between the ApoE4 allele and LOD in comparison to controls (Odd's ratio=4.7, Confidence Interval=1.12 to 19.79, P=0.035). ApoE4 allele had no association with the age of onset of depression, cognitive functions and severity of LOD. CONCLUSION: Individuals with LOD have a significantly higher frequency of the ApoE4 allele. In other words, elderly in India with an ApoE4 allele have 4.7 times more risk of developing depression in old age. Within LOD group there is no difference between those with and without ApoE4 accordingly in age of onset of depression, cognitive functions and severity of LOD. PMID- 22226378 TI - Epidemiological isolation causing variable mortality in Island populations during the 1918-1920 influenza pandemic. AB - BACKGROUND: During the 1918 pandemic period, influenza-related mortality increased worldwide; however, mortality rates varied widely across locations and demographic subgroups. Islands are isolated epidemiological situations that may elucidate why influenza pandemic mortality rates were so variable in apparently similar populations. OBJECTIVES: Our objectives were to determine and compare the patterns of pandemic influenza mortality on islands. METHODS: We reviewed historical records of mortality associated with the 1918-1920 influenza pandemic in various military and civilian groups on islands. RESULTS AND CONCLUSIONS: Mortality differed more than 50-fold during pandemic-related epidemics on Pacific islands [range: 0.4% (Hawaii) to 22% (Samoa)], and on some islands, mortality sharply varied among demographic subgroups of island residents such as Saipan: Chamorros [12%] and Caroline Islanders [0.4%]. Among soldiers from island populations who had completed initial military training, influenza-related mortality rates were generally low, for example, Puerto Rico (0.7%) and French Polynesia (0.13%). The findings suggest that among island residents, those who had been exposed to multiple, antigenically diverse respiratory pathogens prior to infection with the 1918 pandemic strain (e.g., less isolated) experienced lower mortality. The continuous circulation of antigenically diverse influenza viruses and other respiratory infectious agents makes widespread high mortality during future influenza pandemics unlikely. PMID- 22226380 TI - Type D personality and persistence of depressive symptoms in a German cohort of cardiac patients. AB - BACKGROUND: Depression is associated with a negative prognosis in coronary heart disease and heart failure patients. Type D personality has been shown to predict the persistence of depressive symptoms over 12 months. Data on longer follow-up periods and on the effectiveness of Type D as a screening tool compared to established measures of depressive symptoms are missing. METHODS: Type D personality and depressive mood were assessed with the DS14 and the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) in 679 consecutive cardiac patients (22.2% female, mean age 62.4+/-10.2 years) over a period of 6 years. Latent class and growth mixture models with Type D, comorbidity, age, and sex as covariates were used to model individual depression trajectory classes and to predict trajectories and class membership. Estimates of specificity and sensitivity were calculated for Type D and the HADS-D baseline cut-off point. RESULTS: In a model with four latent classes (mild symptoms, moderate and increasing symptoms, significant but decreasing symptoms, and significant and increasing symptoms), Type D predicted the membership in the class with significant and increasing symptoms (OR=10.94, 4.93, and 3.15). Sensitivity and specificity were 59% and 78% for Type D and 47% and 80% for the HADS-D. LIMITATIONS: Some possible confounders might be missing. With just two measurement points only linear trajectories could be modeled. CONCLUSIONS: Type D personality is a stronger predictor for persistent depressive symptoms than the baseline HADS-D score, but the predictive power seems low for clinical practice. PMID- 22226381 TI - Individual and contextual determinants of blood donation frequency with a focus on clinic accessibility: a case study of Toronto, Canada. AB - The balance between supply and demand of blood products is a question of great interest for the long-term prospects of health care systems. Trends that affect this balance include an aging population and increasingly large immigrant communities with lower donation rates. Blood agencies must implement several strategies to ensure a sustained supply of blood products. A better understanding of the determinants of donation frequency is essential to develop strategies that encourage new and existing donors to donate more frequently. In this study, we investigate the individual and contextual determinants of the decision to donate multiple times, with a particular focus on accessibility to clinics. The case study is the Toronto Census Metropolitan Area. Analysis is based on discrete choice models estimated using the attributes of the geocoded donors and clinics, and Census data for contextual variables. The results indicate that higher levels of accessibility increase the probability of donor return and more frequent donations. PMID- 22226383 TI - Ischemia reperfusion injury: from basic mechanisms to innovative protective strategies. PMID- 22226384 TI - A new method in the diagnosis of reflux esophagitis: confocal laser endomicroscopy. AB - BACKGROUND: The diagnosis of GERD is made by using a combination of clinical symptoms, pH study, endoscopy, and histology. Histologic changes include basal cell hyperplasia and papillary elongation. Confocal laser endomicroscopy (CLE) enables surface and subsurface imaging of living cells in vivo at *1000 magnification and up to 250 MUm below the tissue surface. In the esophagus, the distance between the surface to papillary (S-P) tip can be measured by using CLE. OBJECTIVE: To measure the S-P distance in the esophagus in patients with reflux esophagitis and controls by using CLE and comparing with histologic measurements. DESIGN: Retrospective analysis of a prospective database. SETTING: Endoscopy unit of a tertiary-care children's hospital. PATIENTS: This study involved 7 patients (5 female) with a median age of 7.6 years (range 1.8-15.5 years) and median weight of 23 kg (range 13.2-71 kg) and 16 controls with a median age of 12.0 years (range 2.2-15.3 years) and median weight of 38.2 kg (range 10.7-83 kg). INTERVENTION: S-P distance was measured both by CLE and histology and was corrected for height for both patients and controls and the results compared. MAIN OUTCOME MEASUREMENTS: To determine if there were significant differences in the S-P distance in patients with esophagitis and controls. RESULTS: The median confocal and histologic measurements for S-P distance, corrected for patient height, were 0.19 MUm/cm (range 0.10-0.49 MUm/cm) and 0.58 MUm/cm (range 0.29 0.76 MUm/cm) and for controls were 0.44 MUm/cm (range 0.20-0.93 MUm/cm) and 1.07 MUm/cm (range 0.76-0.1.57 MUm/cm), respectively. LIMITATIONS: Small numbers involved in the study, reliance on only papillary elongation in arriving at a diagnosis. CONCLUSION: Measurement of the S-P distance by CLE will enable real time diagnosis of GERD-related esophagitis during ongoing endoscopy. PMID- 22226382 TI - Adaptive immunity to Anaplasma pathogens and immune dysregulation: implications for bacterial persistence. AB - Anaplasma marginale is an obligate intraerythrocytic bacterium that infects ruminants, and notably causes severe economic losses in cattle worldwide. Anaplasma phagocytophilum infects neutrophils and causes disease in many mammals, including ruminants, dogs, cats, horses, and humans. Both bacteria cause persistent infection - infected cattle never clear A. marginale and A. phagocytophilum can also cause persistent infection in ruminants and other animals for several years. This review describes correlates of the protective immune response to these two pathogens as well as subversion and dysregulation of the immune response following infection that likely contribute to long-term persistence. I also compare the immune dysfunction observed with intraerythrocytic A. marginale to that observed in other models of chronic infection resulting in high antigen loads, including malaria, a disease caused by another intraerythrocytic pathogen. PMID- 22226385 TI - Magnetic pancreaticobiliary stents and retrieval system: obviating the need for repeat endoscopy (with video). AB - BACKGROUND: Plastic stents are routinely placed in the pancreaticobiliary system to facilitate drainage. A second endoscopy is often required for stent removal. We have developed magnetic pancreaticobiliary stents that can be removed by using an external hand-held magnet, thereby obviating the need for a second endoscopy. OBJECTIVE: To develop and test magnetic pancreaticobiliary stents and retrieval system in ex-vivo and in-vivo porcine models. SETTING: Animal laboratory. DESIGN: Benchtop and animal study. ANIMALS: 5 pigs. INTERVENTIONS: Design: Computer simulations determined both the optimal design of cylindrical magnets attached to the distal aspect of existing plastic stents and the optimal design of the external hand-held magnet. Benchtop ex-vivo experiments measured magnetic force to validate the design. In-vivo analysis: In 5 Yorkshire pigs, magnetic stents were deployed into the common bile duct by using a conventional duodenoscope. An external hand-held magnet was applied for stent removal. Stent insertion and removal times were recorded. MAIN OUTCOME MEASUREMENTS: Technical feasibility. RESULTS: Magnetic stents of varying lengths and calibers were successfully created. In ex-vivo testing, the capture distance was 10.0 cm. During in-vivo testing, the magnetic stents were inserted and removed easily. The mean insertion and removal times were 3.2 minutes and 33 seconds, respectively. LIMITATIONS: Animal study, small numbers. CONCLUSIONS: Magnetic pancreaticobiliary stents and associated retrieval system were successfully designed and tested in the acute porcine model. An external, noninvasive means of stent removal potentially obviates the need for a second endoscopy, which could represent a major gain both for patients and in health care savings. PMID- 22226386 TI - Perspectives on the new kidney disease education benefit: early awareness, race and kidney transplant access in a USRDS study. AB - Education services for Stage-IV chronic kidney disease patients were added in 2010 as a Part B covered benefit under the Medicare Improvements for Patients and Providers Act. Desired outcomes include early pursuit of kidney transplantation by more patients and reduction of racial disparities in access to transplantation. During 2005-2007, a United States Renal Data System (USRDS) special study surveyed 1123 patients in a national cohort who had recently started dialysis, identified themselves as black or white, and were reported by their physician as potentially eligible transplant candidates. Patients were asked if kidney transplantation had been discussed with them before they initiated renal replacement therapy, and survey responses were linked with subsequent wait listing and transplant events in USRDS registry files. Kaplan Meier analyses showed a significant association between early transplant awareness and subsequent wait listing. Adjusted Cox models showed a significant race/early transplant awareness interaction, however, with the impact of early awareness on wait listing much stronger for whites. Ongoing support and education about kidney transplantation for patients after dialysis start could help to build on early education and foster greater quality improvement in patient outcomes. PMID- 22226387 TI - [Results of percutaneous radiofrequency ablation of hepatocellular carcinoma in patients with cirrhosis aged 75 years and over]. AB - PURPOSE: The objective of this study was to assess the results and tolerance of radiofrequency ablation in patients with cirrhosis and hepatocellular carcinoma (HCC) older than 75 years. PATIENTS AND METHODS: Over a period of 9 years from January 2001, 235 patients with cirrhosis and 3 or less HCC<=5 cm of diameter were treated by radiofrequency ablation. Among them, 52 patients older than 75 years were selected for this study. RESULTS: The mean age was 79.4+/-3. 5 years. There were 36 males, cirrhosis was classified Child-Pugh class A (n=52) related to alcohol (n=13), HCV infection (n=33), or other causes (n=6). The mean tumour diameter was 32.5+/-10.6 mm, and 14 patients had a multifocal HCC. A complete ablation was obtained in 50/52 patients (96%). No severe complication occurred. The estimated overall survival rates were 62%, 52% and 36% at 3 years, 4 years and 5 years, respectively; it was similar to those observed in patients younger than 75 years. CONCLUSION: In patients with cirrhosis older than 75 years, radiofrequency ablation of 3 or less HCC<=5cm is well tolerated and survivals rates are similar to those of younger patients. PMID- 22226388 TI - [Intravitreal injections: AFSSAPS guide to good practice]. AB - Intravitreal injections are very commonly performed in the daily practice of Ophthalmology and become a leading procedure in the management of age-related macular degeneration, diabetic retinopathy, infectious endophthalmitis or retinitis, uveitis and retinal vein occlusions. Based on the comments of a group of experts, including ophthalmologists, pharmacists and hygienists, the French Agency for the Safety of Health Products (AFSSAPS) edited a guide to good practice of intravitreal injections, revisiting those previously published in 2006. The overall experience accumulated during time is a valuable source of information to determine the most appropriate protocol. Therefore, the simplification of the procedure is reasonably proposed even though safety remains a major issue, in order to avoid complications, especially infections. PMID- 22226389 TI - Aqueous humor contamination during phacoemulsification in a university teaching hospital. AB - PURPOSE: To evaluate the intraoperative contamination of the anterior chamber in eyes undergoing phacoemulsification in a university teaching hospital. DESIGN: Prospective, non-randomized clinical trial. METHODS: This study included 113 eyes of 113 consecutive patients undergoing cataract surgery performed by experienced surgeons and residents. Phacoemulsification was conducted through a scleral tunnel incision or through a corneal incision. The intraocular lens was implanted with an injector. Aqueous fluid was obtained at the end of surgery before viscoelastic removal, with a cannula through the corneal paracentesis. Povidone iodine 10% solution was used to prepare the eyebrow and eyelids and povidone iodine 5% to disinfect the ocular surface. All patients were given a single oral dose of 400mg ofloxacin 2h before surgery. No preoperative antibiotics were administered locally. RESULTS: Anterior chamber fluid aspirates were positive for bacteria in two eyes (1.8%). No eye developed endophthalmitis during the follow up period. DISCUSSION AND CONCLUSION: Low anterior chamber bacterial contamination rates may be achieved under routine phacoemulsification in a teaching hospital practicing careful antisepsis measures. PMID- 22226390 TI - Sclerosing Sertoli cell tumor without expression of typical sex cord stromal tumor markers: case report and literature review. AB - Sertoli cell tumor is a potential histologic mimic of other tumors, such as seminoma due to similar histology and overlapping clinical presentation. Sclerosing Sertoli cell tumor is a rare sex cord stromal tumor variant, with 16 cases reported in the English literature. We present an unusual case of sclerosing Sertoli cell tumor in a 33-year-old Caucasian male, which was negative or weakly reactive using immunohistochemical markers typically positive in Sertoli cell tumors. The tumor was positive for cytokeratin AE1/AE3, CAM 5.2, vimentin, CD56, CK8, synaptophysin and S100, and negative for inhibin, calretinin, WT1, CD99, CD117, CK5/6, CK7, chromogranin A, placental alkaline phosphatase, neuron specific enolase, D2-40, smooth muscle actin, Melan-A, epithelial membrane antigen and carbonic anhydrase IX. This is the second reported case of a Sertoli cell tumor with reactivity limited to neuroendocrine markers and the first such case of the sclerosing variant. A literature review of sclerosing Sertoli cell tumor, including English and non-English literature, is described. Our case highlights that expected immunohistochemical markers may be negative, and awareness of antigenically unreactive tumors is needed to avoid confusion between Sertoli cell tumor and other entities. PMID- 22226391 TI - Residential hazards, high asthma prevalence and multimorbidity among children in Saginaw, Michigan. AB - OBJECTIVES: Comorbidities complicate our understanding of childhood asthma and its risk factors. This study examined the relationships between asthma, self reported burden of disease symptoms and residential hazards in a representative sample of households in Saginaw, Michigan. STUDY DESIGN: A population-based cross sectional survey. METHOD: The study involved 643 households randomly selected from the City of Saginaw (Michigan) with children 12 years of age or younger or pregnant woman. The survey was completed using random digit dialing, Computer Assisted Telephone Interviewing (CATI) method. The audit instrument for residential hazards developed for the study was used to gather information on 71 household hazards organized in eight scales (dimensions): structural scale, moisture/mold scale, electrical scale, ventilation and combustion appliances scale, pest scale, pets scale, fire scale, and lifestyle-associated factors scale. The data were used to calculate an aggregate score of the household hazard index (HHI) for each housing unit. We also collected information on 43 symptoms of diseases likely to be associated with exposure to residential hazards as well as the demographic characteristics for each household. RESULTS: Asthma prevalence rate among the 1206 children was 18.9% with 27.7% of households reporting at least one asthmatic child. The prevalence of health hazards in households of Saginaw was pervasively high with the rate for each of 29 hazards being over 30%. The HHI was found to be a good predictor of health outcomes in homes; the following linear regression equation describes the relationship between childhood asthma and the scores for individual scales of HHI: Number of Asthmatic Children=0.009(Structural)+0.004(Mold) +0 .019(Pests)-0.023(Pets)-0.029(Fire); (r(2)=0.054; p-value<0.001). Children who were living in housing units classified as high risk (top 25% of the HHI score) were found to be disproportionately afflicted with asthma, allergic reaction and burden of symptoms compared to children who lived in low-risk homes. Average number of symptoms in the households was 14+/-10 and the top 25% of the households had over 26 symptoms. Asthma was associated (comorbid) with each of the 40 symptoms (out of the 43) in the inventory scale, and the HHI was found to be a good predictor of the symptom burden (total count of symptoms) in participating households. CONCLUSIONS: Recognition of the large extent of comorbidity in asthmatic children has implications for the way in which this disease should be treated or managed. In addition, the study of comorbidity between asthma and related risk factors may be important in understanding complex exposure-disease relationships which could lead to more effective interventions. PMID- 22226392 TI - An appraisal of management pathologies in the Great Lakes. AB - Recent research has produced broad application of the health concept to regional ecosystems, including the Great Lakes. The attention is warranted, as new and recurring stresses on the health of the Great Lakes undermine our understanding and hinder our ability to manage and restore critical ecological functions. There is widespread agreement that the Great Lakes are presently exhibiting symptoms of extreme stress and potentially irreversible and catastrophic damage. Historical command and control management has resulted simultaneously in environmental benefits to people and a loss of resilience in Great Lakes ecosystems. Surprising system responses often prompt further control, and the continued decline in resilience has been called the pathology of natural resource management. The pathology is also suggested to affect human systems of organization such as management authorities. We use published criteria of institutional pathologies and illustrate their occurrence in the Great Lakes with evidence of non-existent program evaluation, program incompatibility, lack of coordination among programs, authorities that establish and then abandon public participatory initiatives, and inappropriate choice of policy mechanisms or inadequate level of support for an appropriate mechanism (either of which creates disincentives for stakeholders). Learning is an element of resilience, as managed systems are inherently dynamic and our understanding is therefore always incomplete. Policy mechanisms that mimic learning techniques to improve understanding are therefore central to avoiding pathologies in management. But learning (individually or institutionally) can be threatening and very difficult, and its proper conduct necessarily involves a continuous process of feedback, interpretation, and reformulation. Double-loop learning processes that institutionalize learning in policy are recommended, as these will be required to overcome pathologies in management and maintain resilience of the Great Lakes system. PMID- 22226393 TI - Relationships between congener distribution patterns of PCDDs, PCDFs, PCNs, PCBs, PCBzs and PCPhs formed during flue gas cooling. AB - The congener patterns of mono- to octa-chlorinated dibenzo-p-dioxins (PC(1-8)DD), dibenzofurans (PC(1-8)DF), naphthalenes (PC(1-8)N), mono- to deca-chlorinated biphenyls (PC(1-10)B), di- to hexa-chlorinated benzenes (PC(2-6)Bz) and mono- to penta-chlorinated phenols (PC(1-5)Ph) in flue gas samples collected simultaneously at 450 degrees C, 300 degrees C and 200 degrees C in the post combustion zone during waste incineration in a laboratory-scale reactor in a previous study, were in this study evaluated using principal component analysis (PCA). To our knowledge this is the most comprehensive chemical and multivariate analysis to date of the thermal formation of dioxins. The PCA indicated that different formation pathways occur in the temperature regions 450-300 degrees C and 300-200 degrees C, and reflected a chlorination effect of PCDF and PCDD between 450 degrees C and 200 degrees C which could not be discerned or was less pronounced for the other compound groups. Toxic equivalents (TEQs) of PCDDs, PCDFs and PCBs, as well as total TEQ values (TEQ(Total)) were also calculated, and correlations between changes in levels of specific congeners and the TEQs were explored in the PCA. Levels of four HxCDF congeners and 1,2,3,4,8-, 1,2,3,7,8-PeCDF and 2,3,4,7,8-PeCDF showed the strongest correlations with TEQ(Total) (R(2)>=0.9). In addition, levels of 1,2,4-TriCBz correlated strongly with TEQ(Total) (R(2)>0.7), supporting previous reports that it may be a potential indicator of the TEQ. PMID- 22226394 TI - Biochar influences the microbial community structure during manure composting with agricultural wastes. AB - The influence of biochar derived from a hardwood tree (Quercus serrate Murray) on the dynamics of the microbial community during the composting of poultry manure (PM) and cow manure (CM) was evaluated by phospholipid fatty acid analysis (PLFAs). Changes in the PLFA patterns were related to key composting properties (C/N ratio, temperature, and bulk density) as the major drivers of the dynamics of the microbial community. At the beginning of the process, the fungal biomass was significantly greater in PM and CM than in the respective co-composted materials with biochar (PMB and CMB); this difference declined gradually during the process. In contrast, the Gram+ to Gram- ratio was increased by the presence of biochar. After 12 weeks of composting, factor analysis based on the relative abundances of single PLFAs revealed changes in the microbial community structure which depended on the original organic wastes (CM vs PM). PMID- 22226395 TI - Risk assessment of potentially toxic elements in agricultural soils and maize tissues from selected districts in Tanzania. AB - A field survey was conducted to investigate the contamination of potentially toxic elements (PTEs) arsenic (As), lead (Pb), chromium (Cr), and nickel (Ni) in Tanzanian agricultural soils and to evaluate their uptake and translocation in maize as proxy to the safety of maize used for human and animal consumption. Soils and maize tissues were sampled from 40 farms in Tanzania and analyzed using inductively coupled plasma-mass spectrometry in the United Kingdom. The results showed high levels of PTEs in both soils and maize tissues above the recommended limits. Nickel levels of up to 34.4 and 56.9mgkg(-1) respectively were found in some maize shoots and grains from several districts. Also, high Pb levels >0.2mgkg(-1) were found in some grains. The grains and shoots with high levels of Ni and Pb are unfit for human and animal consumption. Concentrations of individual elements in maize tissues and soils did not correlate and showed differences in uptake and translocation. However, Ni showed a more efficient transfer from soils to shoots than As, Pb and Cr. Transfer of Cr and Ni from shoots to grains was higher than other elements, implying that whatever amount is assimilated in maize shoots is efficiently mobilized and transferred to grains. Thus, the study recommended to the public to stop consuming and feeding their animals maize with high levels of PTEs for their safety. PMID- 22226396 TI - A review of the factors causing paralysis in wild birds: Implications for the paralytic syndrome observed in the Baltic Sea. AB - We reviewed paralysis in wild birds with a special focus on the Baltic Sea paralytic syndrome recently described by Balk et al. (2009) by assessing multiple causative factors. The review showed that paralysis may occur in various species and that the aetiology can be divided into biotoxins, nutritional deficiencies, environmental contaminants and infectious diseases. The review also showed that the symptoms are influenced by age, sex and species of the affected individual. It seemed that paralysis may be treated or relieved by e.g. thiamine injections or additives. Due to a lack of extensive diagnostic studies, the potentially negative effects of paralysis at the population level of wild birds remain unsolved. We recommend that when investigating paralysis in wild birds, a holistic study approach including multiple factors are undertaken in order to pinpoint cause-and-effect relationships as well as the potential impacts on wild bird populations including those in the Baltic Sea. PMID- 22226397 TI - Temperature dependence of denitrification in phototrophic river biofilms. AB - Denitrification is an ecosystem service of nitrogen load regulation along the terrestrial-freshwater-marine continuum. The present study documents the short term temperature sensitivity of denitrification enzyme activity in phototrophic river biofilms as a typical microbial assemblage of this continuum. Denitrification measurements were performed using the acetylene inhibition method at four incubation temperatures: 1.1, 12.1, 21.2 and 30.9 degrees C. For this range of temperature, N(2)O production could be fitted to an exponential function of incubation temperature, yielding mean (+/-standard error) activation energy of 1.42 (+/-0.24) eV and Q(10) of 7.0 (+/-1.4). This first quantification of denitrification enzyme activity temperature dependence in phototrophic river biofilms compares with previous studies performed in soils and sediments. This demonstrates the high temperature dependence of denitrification as compared to other community-level metabolisms such as respiration or photosynthesis. This result suggests that global warming can unbalance natural community metabolisms in phototrophic river biofilms and affect their biogeochemical budget. PMID- 22226398 TI - Oxidative degradation of propachlor by ferrous and copper ion activated persulfate. AB - The process of in situ chemical oxidation (ISCO) by persulfate (S(2)O(8)(2-)) can be accelerated by metal ion activation, which more effectively degrades subsurface pollutants by enhancing sulfate radical (SO(4)(-)) generation. This study compared the results of propachlor degradation by Cu(2+) and Fe(2+) activated persulfate and revealed differing degradation kinetics and mechanisms between the two types of activation system. The activation of persulfate by Fe(2+) ions generally resulted in rapid degradation in the early stage, but was accompanied by a dramatic decrease in efficiency due to the rapid depletion of Fe(2+) by the sulfate radicals generated. In contrast, the Cu(2+) activated persulfate had a longer lasting degradation effect and a proportionally greater degradation enhancement at elevated Cu(2+) concentrations. An optimal Fe(2+) concentration should be sought to activate the persulfate, as a high Fe(2+) concentration of 2.5mM or above, as was used in this study, may inhibit propachlor degradation due to the competitive consumption of sulfate radicals by the excess Fe(2+) ions. Higher temperatures (55 degrees C compared with 30 degrees C) resulted in enhanced metal activation, particularly with the Cu(2+) activated system. Furthermore, acidic conditions were found to be more favorable for propachlor degradation by metal activated persulfate. The ecotoxicity of degraded propachlor samples, which was indicated by average well color development (AWCD) for its microbial community activity, was confirmed to be decreased during the degradation processes with these two ions activated persulfate. PMID- 22226399 TI - On the contribution of mean flow and turbulence to city breathability: the case of long streets with tall buildings. AB - This paper analyses the contribution of mean flow and turbulence to city breathability within urban canopy layers under the hypothesis that winds from rural/marine areas are sources of clean air (inhale effect) and main contributors to local-scale pollutant dilution (exhale effect). Using Computational Fluid Dynamics (CFD) simulations, several idealized long streets flanked by tall buildings are investigated for wind flow parallel to the street axis. Aspect ratios (building height/street width) ranging from 2 to 4 and street lengths ranging from neighborhood scales (~1km in full scale) to city scales (~10km in full scale) are analyzed. To assess the inhale effect, the age of air concept is applied to quantify the time taken by a parcel of rural/marine air to reach a reference location within the urban canopy layer. To simulate the exhale effect, removal of pollutants released from a ground level source is considered. Numerical results agree with wind tunnel observations showing that a bulk portion of rural/marine air enters the streets through windward entries, a smaller part of it leaves through street roofs and the remaining fraction blows through the street aiding pollutant dilution. Substantial differences between neighborhood scale and city-scale configurations are found. For neighborhood-scale models, pollutant removal by rural/marine air is mainly associated to mean flow along the streets. Breathability improves in streets flanked by taller buildings since in this case more rural/marine air is captured inside canyons leading to stronger wind along the street. For city-scale models, pollutant removal due to turbulent fluctuations across street roofs competes with that due to mean flows along the street. Breathability improves in streets flanked by lower buildings in which less rural/marine air is driven out and pollutant removal by turbulent fluctuations is more effective. Based on these findings, suggestions for ventilation strategies for urban areas with tall buildings are provided. PMID- 22226400 TI - Real-world role of tricyclic antidepressants in the treatment of fibromyalgia. AB - OBJECTIVE: To examine the real-world role of tricyclic antidepressants (TCAs) in fibromyalgia (FM) treatment. METHODS: Using privately insured U.S. administrative claims data, this study examined TCA use for newly diagnosed FM patients. Patients ages 18 to 64 years with >= 2 FM diagnoses (ICD-9-CM: 729.1) during Q1:2007 to Q1:2009, no previous FM diagnosis, and continuous eligibility for insurance during the year before and after the first FM diagnosis ("study period") were identified as newly diagnosed (N = 10,129). Treatment with TCAs was examined over the first treatment episode (allowing up to a 45-day gap between refills). A sensitivity analysis was performed excluding patients with depression/anxiety diagnoses during the study period. RESULTS: During the study period, 8.9% of patients with FM used TCAs at anytime, 5.0% used TCAs during the year before FM diagnosis, and 7.2% used TCAs during the year after. The mean (median) duration of the first treatment episode was 150 (58) days. During this episode, 84.0% used other medications concomitantly, with 60.3% using analgesics and 39.6% using other antidepressants. Additionally, 60.8% augmented TCA use with other drugs, 61.8% switched to another drug at the end of their TCA episode, and 22.8% discontinued TCAs without switching. Similar patterns were observed for the subset of patients with no depression or anxiety (N = 7,655). DISCUSSION: Research covering 1999 to 2005 using the same methods found that 15.9% of patients with FM used TCAs during the year before FM diagnosis and 20.7% used TCAs during the year after. These findings suggest that TCA use among the patients with FM is uncommon and may be declining in real-world practice. PMID- 22226401 TI - Measurement of beta-amyloid peptides in specific cells using a photo thin-film transistor. AB - The existence of beta-amyloid [Abeta] peptides in the brain has been regarded as the most archetypal biomarker of Alzheimer's disease [AD]. Recently, an early clinical diagnosis has been considered a great importance in identifying people who are at high risk of AD. However, no microscale electronic sensing devices for the detection of Abeta peptides have been developed yet. In this study, we propose an effective method to evaluate a small quantity of Abeta peptides labeled with fluorescein isothiocyanate [FITC] using a photosensitive field effect transistor [p-FET] with an on-chip single-layer optical filter. To accurately evaluate the quantity of Abeta peptides within the cells cultured on the p-FET device, we measured the photocurrents which resulted from the FITC conjugated Abeta peptides expressed from the cells and measured the number of photons of the fluorochrome in the cells using a photomultiplier tube. Thus, we evaluated the correlation between the generated photocurrents and the number of emitted photons. We also evaluated the correlation between the number of emitted photons and the amount of FITC by measuring the FITC volume using AFM. Finally, we estimated the quantity of Abeta peptides of the cells placed on the p-FET sensing area on the basis of the binding ratio between FITC molecules and Abeta peptides. PMID- 22226402 TI - International cohort study of 73 anti-Ku-positive patients: association of p70/p80 anti-Ku antibodies with joint/bone features and differentiation of disease populations by using principal-components analysis. AB - INTRODUCTION: An international cohort study of 73 anti-Ku-positive patients with different connective tissue diseases was conducted to differentiate the anti-Ku positive populations of patients based on their autoantibody profile and clinical signs/symptoms and to establish possible correlations between antibodies against Ku p70 and Ku p80 with autoimmune diseases. METHODS: Sera of anti-Ku-positive patients were collected from six European centers and were all secondarily tested (in the reference center); 73 were confirmed as positive. Anti-Ku antibodies were detected with counter-immunoelectrophoresis (CIE), line immunoassay (LIA), and immunoblot analyses. All clinical and laboratory data were follow-up cumulative data, except for anti-Ku antibodies. Statistical analyses were performed by using R (V 2.12.1). The Fisher Exact test was used to evaluate the association between anti-Ku antibodies and diagnosis, gender, clinical signs, and other observed antibodies. The P values were adjusted for multiple testing. Separation of disease populations based on the presence of antibodies and clinical signs was investigated by principal-components analysis, which was performed by using thr// R's prcomp function with standard parameters. RESULTS: A 16% higher prevalence of anti-Ku p70 was found over anti-Ku p80 antibodies. In 41 (57%) patients, a combination of both was detected. Five (7%) patients, who were CIE and/or LIA anti-Ku positive, were negative for both subsets, as detected with the immunoblot; 31% of the patients had undifferentiated connective tissue disease (UCTD); 29% had systemic sclerosis (SSc); 18% had systemic lupus erythematosus (SLE); 11% had rheumatoid arthritis; 7% had polymyositis; and 3% had Sjogren syndrome. CONCLUSIONS: A significant positive association was found between female patients with anti-Ku p70 and joint/bone features, and a significant negative association was found between female patients with anti-Ku p80 only and joint/bone features (P = 0.05, respectively). By using the first and the third components of the principal-component analysis (PCA) with 29 parameters evaluated, we observed that the anti-Ku-positive population of UCTD patients had overlapping parameters, especially with SLE, as opposed to SSc, which could be helpful in delineating UCTD patients. PMID- 22226403 TI - The impact of different GFR estimating equations on the prevalence of CKD and risk groups in a Southeast Asian cohort using the new KDIGO guidelines. AB - BACKGROUND: Recently, the Kidney Disease: Improving Global Outcomes (KDIGO) group recommended that patients with CKD should be assigned to stages and composite relative risk groups according to GFR (G) and proteinuria (A) criteria. Asians have among the highest rates of ESRD in the world, but establishing the prevalence and prognosis CKD is a problem for Asian populations since there is no consensus on the best GFR estimating (eGFR) equation. We studied the effects of the choice of new Asian and Caucasian eGFR equations on CKD prevalence, stage distribution, and risk categorization using the new KDIGO classification. METHODS: The prevalence of CKD and composite relative risk groups defined by eGFR from with Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI); standard (S) or Chinese(C) MDRD; Japanese CKD-EPI (J-EPI), Thai GFR (T-GFR) equations were compared in a Thai cohort (n = 5526) RESULTS: There was a 7 fold difference in CKD3-5 prevalence between J-EPI and the other Asian eGFR formulae. CKD3-5 prevalence with S-MDRD and CKD-EPI were 2 - 3 folds higher than T-GFR or C-MDRD. The concordance with CKD-EPI to diagnose CKD3-5 was over 90% for T-GFR or C-MDRD, but they only assigned the same CKD stage in 50% of the time. The choice of equation also caused large variations in each composite risk groups especially those with mildly increased risks. Different equations can lead to a reversal of male: female ratios. The variability of different equations is most apparent in older subjects. Stage G3aA1 increased with age and accounted for a large proportion of the differences in CKD3-5 between CKD-EPI, S-MDRD and C-MDRD. CONCLUSIONS: CKD prevalence, sex ratios, and KDIGO composite risk groupings varied widely depending on the equation used. More studies are needed to define the best equation for Asian populations. PMID- 22226404 TI - Critical role of cardiac t-tubule system for the maintenance of contractile function revealed by a 3D integrated model of cardiomyocytes. AB - T-tubules in mammalian ventricular myocytes constitute an elaborate system for coupling membrane depolarization with intracellular Ca(2+) signaling to control cardiac contraction. Deletion of t-tubules (detubulation) has been reported in heart diseases, although the complex nature of the cardiac excitation-contraction (E-C) coupling process makes it difficult to experimentally establish causal relationships between detubulation and cardiac dysfunction. Alternatively, numerical simulations incorporating the t-tubule system have been proposed to elucidate its functional role. However, the majority of models treat the subcellular spaces as lumped compartments, and are thus unable to dissect the impact of morphological changes in t-tubules. We developed a 3D finite element model of cardiomyocytes in which subcellular components including t-tubules, myofibrils, sarcoplasmic reticulum, and mitochondria were modeled and realistically arranged. Based on this framework, physiological E-C coupling was simulated by simultaneously solving the reaction-diffusion equation and the mechanical equilibrium for the mathematical models of electrophysiology and contraction distributed among these subcellular components. We then examined the effect of detubulation in this model by comparing with and without the t-tubule system. This model reproduced the Ca(2+) transients and contraction observed in experimental studies, including the response to beta-adrenergic stimulation, and provided detailed information beyond the limits of experimental approaches. In particular, the analysis of sarcomere dynamics revealed that the asynchronous contraction caused by a large detubulated region can lead to impairment of myocyte contractile efficiency. These data clearly demonstrate the importance of the t-tubule system for the maintenance of contractile function. PMID- 22226405 TI - Influence of stent configuration on cerebral aneurysm fluid dynamics. AB - Embolic coiling is the most popular endovascular treatment available for cerebral aneurysms. Nevertheless, the embolic coiling of wide-neck aneurysms is challenging and, in many cases, ineffective. Use of highly porous stents to support coiling of wide-neck aneurysms has become a common procedure in recent years. Several studies have also demonstrated that high porosity stents alone can significantly alter aneurysmal hemodynamics, but differences among different stent configurations have not been fully characterized. As a result, it is usually unclear which stent configuration is optimal for treatment. In this paper, we present a flow study that elucidates the influence of stent configuration on cerebral aneurysm fluid dynamics in an idealized wide-neck basilar tip aneurysm model. Aneurysmal fluid dynamics for three different stent configurations (half-Y, Y and, cross-bar) were first quantified using particle image velocimetry and then compared. Computational fluid dynamics (CFD) simulations were also conducted for selected stent configurations to facilitate validation and provide more detailed characterizations of the fluid dynamics promoted by different stent configurations. In vitro results showed that the Y stent configuration reduced cross-neck flow most significantly, while the cross bar configuration reduced velocity magnitudes within the aneurysmal sac most significantly. The half-Y configuration led to increased velocity magnitudes within the aneurysmal sac at high parent-vessel flow rates. Experimental results were in strong agreement with CFD simulations. Simulated results indicated that differences in fluid dynamic performance among the different stent configurations can be attributed primarily to protruding struts within the bifurcation region. PMID- 22226406 TI - The transport of wear particles in the prosthetic hip joint: a computational fluid dynamics investigation. AB - The joint fluid mechanics and transport of wear particles in the prosthetic hip joint were analyzed for subluxation and flexion motion using computational fluid dynamics (CFD). The entire joint space including a moving capsule boundary was considered. It was found that particles suspended in the joint space are drawn into the joint gap between prosthesis cup and head during subluxation, which was also documented by Lundberg et al. (2007; Journal of Biomechanics 40, 1676-1685), however, wear particles remain in the joint gap. Wear particles leave the joint gap during flexion and can finally migrate to the proximal boundaries including the acetabular bone, where the particle deposition can cause osteolysis according to the established literature. Thus, the present study supports the theory of polyethylene wear particle induced osteolysis of the acetabular bone as a major factor in the loosening of hip prosthesis cups. PMID- 22226407 TI - Can people with nonsevere major depression benefit from antidepressant medication? AB - BACKGROUND: Several meta- or mega-analyses suggest antidepressant medications should be given only to severely depressed patients. In our experience, mild depression benefits from medication. We reanalyzed 1 clinic's randomized placebo controlled antidepressant studies, limiting analyses to patients with major depressive disorder (MDD) without severe illness, to determine whether nonsevere depression responds to antidepressant medication. DATA SOURCES: Archives of the Depression Evaluation Service outpatient clinic of the New York State Psychiatric Institute were searched for randomized, placebo-controlled antidepressant studies that were conducted between 1977 and 2009 and included patients having MDD and pretreatment Hamilton Depression Rating Scale (HDRS) scores < 23. STUDY SELECTION: Six placebo-controlled studies were found, including 8 active treatment arms and 1,440 patients. 825 patients were randomized and had MDD and an HDRS score < 23. DSM-III, DSM-III-R, or DSM-IV diagnostic criteria contemporary to each study were employed. DATA EXTRACTION: Treatments were compared within study and via a patient-level meta-analysis using analysis of covariance (ANCOVA) of HDRS end point scores adjusted for pretreatment score. The number needed to treat (NNT) was calculated from remission rates (HDRS end point score <= 7), which were compared by chi2. Effect sizes were calculated from change in HDRS scores. Secondary analyses investigated the effect of chronicity and atypical features on treatment response. DATA SYNTHESIS: Three of 6 studies showed significant (P < .001) treatment effects by ANCOVA, and 4 of 6 studies showed significant (P < .04) differences in remission. The NNT ranged from 3 to 8. Effect sizes ranged from -0.04 to 0.8, with 4 of 8 greater than 0.4. The patient-level meta-analysis confirmed these results; neither chronicity nor atypical features significantly affected outcome. Secondary analyses utilizing global ratings and self-report mimicked the main findings. CONCLUSIONS: Several studies demonstrated significant antidepressant efficacy for patients having nonsevere MDD. Efficacy was not trivial, as NNT ranged from 3 to 8, a range accepted by researchers as sufficiently robust to recommend treatment. These findings suggest mild-moderate MDD can benefit from antidepressants, contrary to findings by several other meta- or mega-analyses. PMID- 22226409 TI - Ultra-sensitive electrochemical immunosensor using analyte peptidomimetics selected from phage display peptide libraries. AB - Immunosensors for small analytes have been a great addition to the analytical toolbox due to their high sensitivity and extended analytical range. In these systems the analyte is detected when it competes for binding to the detecting antibody with a tracer compound. In this work we introduce the use of phage particles bearing peptides that mimic the target analyte as surrogates for conventional tracers. As a proof of concept, we developed a magneto electrochemical immunosensor (EI) for the herbicide molinate and compare its performance with conventional formats. Using the same anti-molinate antibody and phage particles bearing a molinate peptidomimetic, the EI performed with an IC(50) of 0.15 ngmL(-1) (linear range from 4.4 * 10(-3) to 10 ngmL(-1)). Compared to the conventional ELISA, the EI was faster (minutes), performed with a much wider linear range, and the detection limit that was 2500-fold lower. The EI produced consistent measurements and could be successfully used to assay river water samples with excellent recoveries. By using the same EI with a conventional tracer, we found that an important contribution to the gain in sensitivity is due to the filamentous structure of the phage (9 * 1000 nm) which works as a multienzymatic tracer, amplifying the competitive reaction. Since phage-borne peptidomimetics can be selected from phage display libraries in a straightforward systematic manner and their production is simple and inexpensive, they can contribute to facilitate the development of ultrasensitive biosensors. PMID- 22226408 TI - A novel Real Time micro PCR based Point-of-Care device for Salmonella detection in human clinical samples. AB - Our POC (Point of Care) device is intended to be a diagnostic tool for routine use in the clinical sector. The validation of the whole procedure, including bacterial genomic DNA isolation and the Real Time detection of Salmonella spp., was conducted on 29 clinical stool samples that had been diagnosed with Salmonella spp. by a routine culture technique. The entire process was achieved in a single microfluidic chip within 35 min. In comparison to the culture reference method that is used in the clinical laboratories, this new device performed well in regards to the analytical parameters of sensitivity, specificity and accuracy. Therefore, the POC device reported in this study proved to be very appropriate for the fully integrated analysis system. To the best of our knowledge, this is the first work to report the sample preparation and followed by Real Time PCR (Polymerase Chain Reaction) on a single 2.5 MUl chamber chip for the detection of Salmonella spp. bacteria in stool samples. PMID- 22226410 TI - Paper-based three-dimensional electrochemical immunodevice based on multi-walled carbon nanotubes functionalized paper for sensitive point-of-care testing. AB - In this study, electrochemical immunoassay was introduced into the recently proposed microfluidic paper-based analytical device (MUPADs). To improve the performance of electrochemical immunoassay on MUPAD for point-of-care testing (POCT), a novel wax-patterned microfluidic paper-based three-dimensional electrochemical device (3D-MUPED) was demonstrated based on the multi-walled carbon nanotubes (MWCNTs) modified MUPAD. Using typical HRP-O-Phenylenediamine H(2)O(2) electrochemical system, a sandwich immunoassay on this 3D-MUPED for sensitive diagnosis of two tumor markers simultaneously in real clinical serum samples was developed with a linear range of 0.001-75.0 UmL(-1) for cancer antigen 125 and 0.05-50.0 ngmL(-1) for carcinoembryonic antigen. In addition, this 3D-MUPED can be easily integrated and combined with the recently emerging paper electronics to further develop simple, sensitive, low-cost, disposable and portable MUPAD for POCT, public health and environmental monitoring in remote regions, developing or developed countries. PMID- 22226411 TI - Highly sensitive electrochemical detection of potential cytotoxicity of CdSe/ZnS quantum dots using neural cell chip. AB - Cell chip was recently developed as a simple and highly sensitive tool for the toxicity assessment of various kinds of chemicals or nano-materials. Here, we report newly discovered potential cytotoxic effects of CdSe/ZnS quantum dots (QDs) on intracellular redox environment of neural cancer cells at very low concentrations which can be only detected by cell chip technology. Green (2.1 nm in diameter) and red (6.3 nm in diameter) QDs capped with cysteamine (CA) or thioglycolic acid (TA) were found to be toxic at 100 MUg/mL when assessed by trypan blue and differential pulse voltammetry (DPV). However, in case of concentration-dependent cytotoxicity, toxic effects of TA-capped QDs on human neural cells were only measured by DPV method when conventional MTT assay did not show toxicity of TA-capped QDs at low concentrations (1-10 MUg/mL). Red-TA QDs and Green-TA QDs were found to decrease electrochemical signals from cells at 10 MUg/mL and 5 MUg/mL, respectively, while cell viability decreased at 100 MUg/mL and 50 MUg/mL when assessed by MTT assay, respectively. The relative decreases of cell viability determined by MTT assay were 15% and 11.9% when cells were treated with 5-50 MUg/mL of Red-TA QDs and 5-30 MUg/mL of Green-TA QDs, respectively. However, DPV signals decreased 37.5% and 39.2% at the same concentration range, respectively. This means that redox environment of cells is more sensitive than other components and can be easily affected by CdSe/ZnS QDs even at low concentrations. Thus, our proposed neural cell chip can be applied to detect potential cytotoxicity of various kinds of molecular imaging agents simply and accurately. PMID- 22226412 TI - Evaluation of EEG based determination of unconsciousness vs. loss of posture in broilers. AB - Evaluation of the loss of consciousness in poultry is an essential component in evaluating bird welfare under a variety of situations and applications. Many current approaches to evaluating loss of consciousness are qualitative and require observation of the bird. This study outlines a quantitative method for determining the point at which a bird loses consciousness. In this study, commercial broilers were individually anesthetized and the brain activity recorded as the bird became unconscious. A wireless EEG transmitter was surgically implanted and the bird anesthetized after a 24-48 h recovery. Each bird was monitored during treatment with isoflurane anesthesia and EEG data was evaluated using a frequency based approach. The alpha/delta (A/D) ratio and loss of posture (LOP) were used to determine the point at which the birds went unconscious. There was no statistically significant difference between time to unconsciousness as measured by A/D ratio or LOP. PMID- 22226413 TI - Effect of acute exacerbations on skeletal muscle strength and physical activity in cystic fibrosis. AB - BACKGROUND: Skeletal muscle weakness is an important complication of chronic respiratory disease. The effect of acute exacerbations on strength in patients with cystic fibrosis is not known. METHODS: Quadriceps (QMVC) and respiratory muscle strength were measured in patients at the time of acute admission, at discharge and one month later. Patients wore an activity monitor during admission and at one month. Convalescent values were compared to the stable clinic population. RESULTS: Data were available for 13 acute admissions and 25 stable CF outpatients. Strength and other parameters including daily step count did not differ significantly between the stable and one month post-admission groups. At admission, QMVC was 16.7 (8.3)% lower than at convalescence, whereas inspiratory muscle strength did not change significantly. Reduction in QMVC did not correlate with activity levels or with markers of systemic inflammation. CONCLUSION: Further research is needed to identify the mechanisms responsible for the reduction in QMVC. PMID- 22226414 TI - Feasibility of using pedometers to measure daily step counts in cystic fibrosis and an assessment of its responsiveness to changes in health state. AB - BACKGROUND: Evaluation of physical activity is integral to the assessment of daily physical function and a potential objective outcome measure for clinical trials. We evaluated the feasibility of using pedometers to measure physical activity in adolescents and adults with cystic fibrosis (CF) and assessed the responsiveness of its measurement to changes in health state. METHODS: Participants were recruited through two CF clinics in Seattle, WA. Subjects were instructed to use their pedometer for at least one ill and two well periods (each lasting 7 days). Step rate was calculated as steps per hour of use. Daily symptoms were also recorded using the CF Respiratory Symptom Diary (CFRSD). Generalized estimating equation linear regression was used to compare mean step rate between health states and by self-reported symptom category. RESULTS: We enrolled 30 CF patients with a mean (+/-SD) age of 22 (+/-7) years and a mean forced expiratory volume in 1s (FEV(1)) of 57% (+/-25%) predicted. The mean period step rate increased from 397 (95% CI 324-497) steps/hour when ill to 534 (95% CI 413-654) steps/hour when well (p=0.015). Pedometer-recorded step rate also correlated with self-reported physical activity items on the CFRSD. CONCLUSION: Step rate measured with a pedometer correlates significantly with changes in health status and self-reported activity, and could be used as an outcome measure in CF. PMID- 22226415 TI - Forced degradation study of thiocolchicoside: characterization of its degradation products. AB - Thiocolchicoside (TCC, N-[1,2-dimethoxy-10-methylsulphanyl-9-oxo-3-(3,4,5 trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy)-5,6,7,9-tetrahydro benzo[a]heptalen-7-yl]-acetamide) was subjected to hydrolytic, oxidative, and photolytic stresses. TCC underwent degradation in acidic, basic, and oxidative conditions, while it was stable toward other stress conditions. The degradation products (DPs) were detected and their separation was achieved on a SGE Wakosil C18RS 5MUm (250*4.6 mm; SGE) column employing a gradient LC-MS method for a total time of analysis of 18 min. The mass fragmentation pathways of both thiocolchicoside and its degradation products were established using LC-MS experiments assigning the structures to the DPs. In particular, five DPs were identified as: D1SO (N-[1,2-dimethoxy-10-methylsulphoxide-9-oxo-3-(3,4,5 trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy)-5,6,7,9-tetrahydro benzo[a]heptalen-7-yl]-acetamide), D1SO(2) (N-[1,2-dimethoxy-10-methylsulphone-9 oxo-3-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy)-5,6,7,9 tetrahydro-benzo[a]heptalen-7-yl]-acetamide), D2 ([1,2-dimethoxy-10 methylsulphanyl-9-oxo-3-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2 yloxy)-5,6,7,9-tetrahydro-benzo[a]heptalen-7-yl]-amine), D3 (N-[1,2-dimethoxy-3 hydroxy-10-methylsulphanyl-9-oxo-5,6,7,9-tetrahydro-benzo[a]heptalen-7-yl] acetamide or 3-O-demethylthiocolchicine), D4 ([1,2-dimethoxy-3-hydroxy-10 methylsulphanyl-9-oxo-5,6,7,9-tetrahydro-benzo[a]heptalen-7-yl]-amine or N deacetyl-3-O-demethylthiocochicine). Moreover, the structures of DPs were confirmed by synthesis of the reference standards which were fully characterized by MS, NMR, IR analyses. Finally a comprehensive degradation scheme of TCC was proposed allowing to outline D1SO and D3 as the indicators of its stability for oxidative and hydrolytic stress conditions. PMID- 22226416 TI - Development and validation of a liquid chromatographic method for purity control of clopidogrel-acetylsalicylic acid in combined oral dosage forms. AB - A reversed phase liquid chromatographic method with UV detection for the simultaneous determination of clopidogrel and acetylsalicylic acid and their related substances in combined oral formulations was developed and validated. Good separation was achieved on a Luna C18 column (150 mm * 4.6 mm, 3 MUm) using gradient elution at a flow rate of 1 mL/min and a column temperature of 35 degrees C. UV detection was performed at 220 nm. The validation was performed according to the ICH guidelines. The method proved to be specific, sensitive (LOQ=0.975 MUg/mL and 0.0384 MUg/mL for clopidogrel and acetylsalicylic acid, respectively), linear in the concentration range from LOQ to 325 MUg/mL for clopidogrel and from LOQ to 650 MUg/mL for acetylsalicylic acid, precise (RSD values for intermediate precision <1%) and accurate with mean recovery values of 100.7% and 100.2% for clopidogrel and acetylsalicylic acid, respectively. Moreover, the solution stability and method robustness were examined. The method gives satisfactory separation of impurities of clopidogrel and acetylsalicylic acid and so it is suitable for quantification of the related substances as well as for the assay of the actives. PMID- 22226417 TI - Use of rapid "rescue" perioperative echocardiography to improve outcomes after hemodynamic instability in noncardiac surgical patients. AB - OBJECTIVE: To investigate if modified "rescue" echocardiography enhanced management during perioperative hemodynamic instability in patients undergoing noncardiac surgery. DESIGN: A retrospective analysis of the medical data. SETTING: Perioperative setting at a single academic medical center. PARTICIPANTS: Thirty-one adult patients undergoing noncardiac surgery who experienced perioperative hemodynamic instability and were evaluated by either transthoracic echocardiography (TTE, n = 9) or transesophageal echocardiography (TEE, n = 22). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Rapid "rescue" echocardiography was performed on each patient looking for a specific cause for the patient's perioperative compromise. Echocardiography results, medical management, surgical management, and patient outcomes were all reviewed from the medical record and the department database. All patients were found to have an explainable diagnosis for the hemodynamic instability on the echocardiographic examination. The most common diagnoses were left-heart dysfunction (n = 16), right-heart dysfunction (n = 9), hypovolemia (n = 5), pulmonary embolus (n = 5), and myocardial ischemia (n = 4). Based on findings at echocardiography, 4 patients (13%) underwent and survived an emergent secondary procedure. All 31 patients recovered during their surgical procedure, and 25 (81%) progressed to hospital discharge. CONCLUSIONS: Both TTE and TEE can play a critical role in the diagnosis and management of perioperative hemodynamic instability. PMID- 22226418 TI - Mitral regurgitation in acute aortic insufficiency. PMID- 22226419 TI - Misplacement of a guidewire into the vertebral vein through the internal jugular vein. PMID- 22226420 TI - Anesthesia apps: overview of current technology and intelligent search techniques. PMID- 22226421 TI - The flow-time waveform predicts respiratory system resistance and compliance. AB - PURPOSE: Knowledge of patients' lung compliance and resistance aids clinical management. We investigated whether these values, readily measured during volume assist-control ventilation (VACV), could also be estimated during pressure assist control ventilation (PACV). METHODS: Data were collected in 12 mechanically ventilated human subjects. During VACV, peak pressure, plateau pressure, end expiratory pressure, tidal volume, and inspiratory flow rate were measured. During PACV, inspiratory pressure, end-expiratory pressure, and tidal volume were recorded. The linear component of the pressure-time waveform was extrapolated to time and flow axes. Using the equation of motion for the respiratory system, assuming a nonlinear resistance, we calculated inspiratory resistance and compliance. During VACV, compliance and inspiratory resistance were calculated in the conventional manner. RESULTS: In ventilated subjects, mean compliance during PACV was 37.06 +/- 15.65 mL/cm H(2)O, and during VACV, 36.93 +/- 12.18 mL/cm H(2)O. Mean inspiratory resistance during PACV was 15.17 +/- 5.14 cm H(2)O/L per second, whereas during VACV, it was 12.50 +/- 2.99 cm H(2)O/L per second. A strong correlation is evident between compliance and inspiratory resistance calculated during PACV vs VACV (r(2) of 0.73 and 0.51, respectively). CONCLUSIONS: During PACV, the inspiratory flow waveform is linear, and its slope contains information regarding inspiratory resistance and compliance. Calculated values correlate with those during VACV. PMID- 22226423 TI - Epidemiology and management of atrial fibrillation in medical and noncardiac surgical adult intensive care unit patients. AB - PURPOSE: The aim of the study was to describe the epidemiology and management of atrial fibrillation (AF) in noncardiac surgery critically ill patients in a retrospective, observational study at 3 mixed medical-surgical, university affiliated intensive care units (ICUs). METHODS: Consecutive patients admitted during a 1-year period with any documentation of AF during ICU stay were identified. Demographic data, risk factors, interventions, and outcomes were collected from the medical record. RESULTS: A total of 3081 patients were admitted during the 1-year study period in which 348 consecutive patients (10.5%) had documented AF. Atrial fibrillation was of new onset in 139 patients (4.5%) and preexisting in 186 patients (6.0%). Hemodynamic instability developed in 37% and 10% of patients with new-onset AF and patients with preexisting AF, respectively. Most (73%) patients with new-onset AF had at least 1 modifiable risk factor. Pharmacologic rhythm conversion was attempted in 76% and 26% of patients with new-onset AF and patients with preexisting AF, respectively. Although initially successful in 87% of new-onset cases, 42% reverted back to AF. Electrical conversion was successful in 7 (27%) of 26 and 0 (0%) of 5 of patients with new-onset AF and patients with preexisting AF, respectively. In total, 18% and 62% of patients with new-onset AF and patients with preexisting AF, respectively, who survived to ICU discharge left the ICU in AF. CONCLUSIONS: Atrial fibrillation is common but transient in most ICU patients. Electrical cardioversion is often unsuccessful, and pharmacologic rhythm conversion is often only transiently effective. Modifiable risk factors are common among these patients. Future studies are needed to address the management of AF in the ICU. PMID- 22226424 TI - Subcutaneous heparin does not increase postoperative complications in neurosurgical patients: An institutional experience. AB - INTRODUCTION: Prophylaxis for venous thromboembolic disease continues to pose a challenging management problem in postoperative neurosurgical patients, particularly those in the intensive care unit (ICU). This study evaluates neurosurgical patients admitted to the surgical ICU (SICU) at a tertiary hospital and compared those who had received subcutaneous unfractionated heparin (SQUFH) to those who did not. This study was conducted to better evaluate if the administration of SQUFH to neurosurgical patients is safe and whether the administration of SQUFH is an independent risk factor for bleeding in this patient population. METHODS: Retrospective analysis was performed on prospectively collected data on all postoperative neurosurgical patients admitted over the course of 11 years to the SICU at Long Island Jewish Medical Center. This study included neurosurgical patients who received SQUFH and those who did not. Data acquired included demographic information, hemodynamic monitoring, pharmacologic interventions, laboratory results, and survival outcomes as well as occurrences of heparin-induced thrombocytopenia and pulmonary embolism. Subcutaneous unfractionated heparin for venous thromboembolic prophylaxis were dosed according to previously established literature based hospital protocols. Data were analyzed by chi(2), Fisher exact test, Mann-Whitney U test, or the product limit method, where appropriate. RESULTS: Five hundred twenty-two neurosurgical patients were included in the study. Two hundred thirteen patients (40.8%) with mean age of 58 years received SQUFH (133 patients received SQUFH within 24 hours of surgery and 80 patients received SQUFH 24 hours postoperatively). Once SQUFH was initiated, it was continued until discharge from the hospital. Three hundred nine patients (59.2%) with mean age 57.8 years received no anticoagulation. In the SQUFH patient population, 72 patients (33.8%) had a diagnosis of subarachnoid hemorrhage compared with 125 patients (40.5%) from the group who had not received anticoagulation. There was no significant difference in ICU length of stay between the groups, 5.8 +/- 5.4 (no deep vein thrombosis prophylaxis), and those receiving SQUFH, 6.7 +/- 6.1 (over 24 hours) and 5.9 +/- 4.8 (over 24 hours). No postoperative hemorrhages were observed (confirmed by computed tomography of the brain) in any of the neurosurgical patients with subarachnoid hemorrhage, intracerebral hemorrhage, or subdural or epidural hemorrhage. No instances of heparin-induced thrombocytopenia (HIT) or pulmonary embolism (PE) were observed. CONCLUSIONS: Administration of SQUFH dosed according to the risk for thromboembolism does not appear to contribute to postoperative hemorrhage in neurosurgical patients. This study supports the concept that the administration of SQUFH is safe in postoperative neurosurgical population. PMID- 22226422 TI - Prehospital amiodarone may increase the incidence of acute respiratory distress syndrome among patients at risk. AB - PURPOSE: Amiodarone has been implicated as a risk factor for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) when used in the hospital. This study aims to estimate whether prehospital amiodarone also increases the risk of ALI/ARDS. MATERIALS: Adult patients admitted to 22 centers with at least 1 risk factor for developing ALI were recruited. In a secondary analysis of this cohort, the prehospital use of amiodarone was documented on admission, and the patients followed for the primary outcome of ALI and secondary outcomes of ARDS, the need for invasive ventilation, and mortality. Dose/duration of amiodarone therapy was not available. Propensity matching was performed to account for imbalances in being assigned to amiodarone. The adjusted risk for ALI/ARDS was then estimated from a conditional logistic regression model of this propensity matched set. RESULTS: Forty of 5584 patients were on amiodarone at the time of hospitalization; of those, 6 developed ALI, with 5 progressing to ARDS. In comparison, 371 patients not on amiodarone developed ALI, with 224 having ARDS. After propensity score matching, the prehospital use of amiodarone was not statistically associated with an increased risk for all ALI (odds ratio [OR], 1.8; 95% confidence interval [CI], 0.7-5.0; P = .25), invasive ventilation (OR, 1.9; 95% CI, 1.0-3.6; P = .059), or in-hospital mortality (OR, 1.2; 95% CI, 0.5 2.9; P = .75); but its use appeared to significantly increase the risk for ARDS (OR 3.8; 95% CI, 1.1-13.1; P = .036). CONCLUSIONS: Prehospital use of amiodarone may independently increase the risk for ARDS in patients who have at least 1 predisposing condition for ALI. PMID- 22226425 TI - Serum neutrophil gelatinase-associated lipocalin in ballistic injuries: a comparison between blast injuries and gunshot wounds. AB - Neutrophil gelatinase-associated lipocalin (NGAL) is part of a functionally diverse family of proteins that generally bind small, hydrophobic ligands. Neutrophil gelatinase-associated lipocalin is expressed in a number of human tissues including gastrointestinal, respiratory, and urinary tracts and tends to rise in response to inflammation. For this reason, we hypothesized that levels of NGAL might be expressed at higher levels after blast injury compared with other ballistic injury. PURPOSE: The purpose of this study is to test the hypothesis that NGAL may be a marker of injury severity in blast injury. MATERIALS: Twenty three combat casualties (13 blast, 10 gunshot wounds) admitted to the multinational role 3 facility in Helmand province were studied. Serum NGAL was measured using a Biosite Triage point-of-care monitor at 5 time points after injury. RESULTS: Neutrophil gelatinase-associated lipocalin rose in both groups of casualties and was significantly predictive of death or renal failure at intensive care unit admission, 12 and 24 hours after injury. CONCLUSIONS: Neutrophil gelatinase-associated lipocalin is not a specific marker of blast injury but is predictive of both renal failure and poor outcome. PMID- 22226426 TI - Porcine Fc gamma RIIb sub-isoforms are generated by alternative splicing. AB - Receptors for the Fc portion of IgG (FcgammaRs) are expressed on various leukocytes and they modulate both humoral and cell-mediated immune responses with different capacities for IgG binding and phagocytosis. Four different types of FcgammaRs, FcgammaRI (CD64), FcgammaRII (CD32), FcgammaRIII (CD16) and FcgammaRIV, have been identified. There are three FcgammaRII isoforms (activating FcgammaRIIa and FcgammaRIIc, and inhibitory FcgammaRIIb) in humans, one isoform (inhibitory FcgammaRIIb) in mice, and two isoforms (inhibitory FcgammaRIIb and activating FcgammaRIIc) in cattle. Two alternativly spliced isoforms of FcgammaRIIb, b1 and b2, have been identified in humans, mice and cattle, however, only two porcine FcgammaRIIb transcripts have been reported. In this study, we report the identification of three new porcine FcgammaRIIb transcript and analyze the sequences of five porcine FcgammaRIIb transcript generated by alternative splicing. The porcine transcript 1 and porcine transcript 2 have a high homology and structural similarity with human b1 and b2, respectively, while there is only one alanine residue difference at the signal peptide region between porcine transcript 1 and transcript 4, as well as porcine transcript 2 and transcript 3. This is the first time that an alternativly spliced isoform of porcine transcript 5 is described in pigs rather than humans or other animals. All the five transcripts have the consensus sequence of an ITIM (ITYSLL) in their cytoplasmic tails. Analysis results indicate that the five transcripts serve as inhibitory receptors and are these sub-isoforms or alternativly spliced isoforms. Immunoglobulin-binding assays show that transcript 1, transcript 2, transcript 3 and transcript 4 have binding activity for IgG immune complexes, whereas transcripts 5 without domain 2 can not bind IgG-complexes. It is now clear that porcine FcgammaRIIb exists as five sub-isoforms at least. These sub-isoforms may individually modulate FcgammaRIIb-mediated immune responses in the porcine immune system. PMID- 22226427 TI - Evaluation of cell population data on the UniCel DxH 800 Coulter Cellular Analysis system as a screening for viral infection in children. AB - INTRODUCTION: The utility of WBC cell population data (CPD) for the differential diagnosis of viral infection from normal control, bacterial infection, and tuberculosis in children was investigated. METHODS: A data set of 602 total whole blood samples were analyzed on the DxH 800 System for complete blood cell count (CBC) with leukocyte differential from children with the following sample breakdown: 77 confirmed diagnoses of viral infections (Epstein-Barr virus; 30, influenza A; 19, rota virus; 11, other viruses;17), 54 normal control, 71 bacterial infection, 17 TB patients, and 383 with various diseases. The mean (MN) and standard deviation (SD) of the volume (V), conductivity (C), five light scatter measurements, and 14 calculated parameters were obtained for the leukocytes. RESULTS: Using a combination of the CBC and CPD parameter values, a decision rule, composed of 21 parameters, for the screening of viral infection in children was developed. Using this decision rule, 74 of 77 (96.1%) viral infections, two of 54 (3.7%) normal samples, one of 17 (5.9%) TB, and six of 71 (8.5%) bacterial infection samples were identified. The sensitivity was 96.1%, and specificity for normal control was 96.3% with an overall specificity of 93.7%. Fifty-nine samples of 383 samples (15.4%) collected from in-patient children with various diseases without confirmation of viral infection were included in this decision rule. CONCLUSION: In conclusion, the implementation of leukocytes CPD parameters can be useful in the detection of viral infection in children. PMID- 22226428 TI - Predator detection and evasion by flying insects. AB - Echolocating bats detect prey using ultrasonic pulses, and many nocturnally flying insects effectively detect and evade these predators through sensitive ultrasonic hearing. Many eared insects can use the intensity of the predator generated ultrasound and the stereotyped progression of bat echolocation pulse rate to assess risk level. Effective responses can vary from gentle turns away from the threat (low risk) to sudden random flight and dives (highest risk). Recent research with eared moths shows that males will balance immediate bat predation risk against reproductive opportunity as judged by the strength and quality of conspecific pheromones present. Ultrasound exposure may, in fact, bias such decisions for up to 24 hours through plasticity in the CNS olfactory system. However, brain processing of ultrasonic stimuli to yield adaptive prey behaviors remains largely unstudied, so possible mechanisms are not known. PMID- 22226429 TI - Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma: proposed diagnostic criteria and therapeutic evaluation. AB - Primary cutaneous aggressive epidermotropic CD8(+) T-cell lymphoma is a rare cytotoxic lymphoma characterized clinically by aggressive behavior and histologically by prominent epidermotropism of atypical CD8(+) lymphocytes. Despite the continuous addition of new case reports, no definite diagnostic criteria have been established, and an optimum treatment is still awaiting. Herein, we study and analyze the different clinical, histopathological, and immunohistochemical features described in the reported cases. Different therapeutic modalities and their impact on the prognosis of the tumor are also evaluated and presented. We propose two sets of diagnostic criteria. The first comprises constant clinical, histopathological, and immunohistochemical features that are always present in every case, and the combination of which is necessary for the diagnosis. The second set helps to avoid missing cases and includes variable features that may be present in some cases, and to which any emerging finding could be added. Although different therapeutic options have been used, either as single agents or in combinations, there is no standard therapy for primary cutaneous aggressive epidermotropic CD8(+) T-cell lymphoma and the tumor still represents a therapeutic challenge with very poor prognosis. PMID- 22226430 TI - A randomized pilot comparative study of topical methyl aminolevulinate photodynamic therapy versus imiquimod 5% versus sequential application of both therapies in immunocompetent patients with actinic keratosis: clinical and histologic outcomes. AB - BACKGROUND: Photodynamic therapy (PDT) and imiquimod are the treatments of choice for actinic keratosis (AK). As they have different mechanisms of action, it seems reasonable to assume that applying both treatments sequentially would be efficacious. OBJECTIVES: We sought to determine which of these therapeutic modalities provides a better clinical and histologic response in patients with AK and whether sequential use of both was more efficacious than each separately. METHODS: Patients were randomly assigned to one treatment group: group 1, PDT only; group 2, imiquimod only; or group 3, sequential use of PDT and imiquimod. The primary outcome measure was complete clinical response. Partial clinical response was defined as a reduction of more than 75% in the initial number of lesions. A complete clinicopathologic response was defined as lack of evidence of AK in the biopsy specimen. RESULTS: In all, 105 patients completed the study (group 1, 40 patients; group 2, 33 patients; group 3, 32 patients). Sequential application of PDT and imiquimod was more efficacious in all the outcome measures. More patients were satisfied with PDT than with the other two modalities (P = .003). No significant differences were observed among the 3 modalities and tolerance to treatment. LIMITATIONS: Only one cycle of imiquimod was administered. The follow-up period was brief. CONCLUSIONS: Sequential application of PDT and imiquimod provides a significantly better clinical and histologic response in the treatment of AK than PDT or imiquimod monotherapy. It also produces less intense local reactions and better tolerance and satisfaction than imiquimod monotherapy. PMID- 22226431 TI - Topical eflornithine hydrochloride improves the effectiveness of standard laser hair removal for treating pseudofolliculitis barbae: a randomized, double blinded, placebo-controlled trial. AB - BACKGROUND: Pseudofolliculitis barbae (PFB) significantly impacts the military population, especially deployed personnel. OBJECTIVE: This study was designed to determine whether the addition of topical eflornithine to hair laser treatment would improve efficacy in treating PFB. METHODS: This was a randomized, double blinded, placebo-controlled, paired (right and left neck) comparison study examining a combination of eflornithine and hair laser versus placebo and hair laser for the treatment of PFB. In all, 27 male patients with clinical PFB were treated with a long-pulsed neodymium:yttrium-aluminum-garnet laser with an energy fluence of 25 to 30 J/cm(2), a pulse duration of 20 to 30 milliseconds, and a 10 mm spot size to the entire bearded neck region. The laser treatment was performed every 4 weeks for a total of 16 weeks. Between laser treatments, patients applied eflornithine and placebo creams twice daily to opposite sides of the bearded neck region. The number of hairs and inflammatory papules were counted bilaterally at each visit. RESULTS: The eflornithine side had a statistically significant decrease in the number of hairs and inflammatory papules compared with the placebo side. At 16 weeks, the eflornithine side had a median hair reduction of 99.5% from baseline (range 48.5%-100.0%), whereas the placebo side had an 85.0% median hair reduction from baseline (range 50.5%-94.5%), P less than .001. LIMITATIONS: Patients were not followed up beyond 16 weeks. CONCLUSION: The addition of topical eflornithine to hair laser treatment decreased hairs and inflammatory papules faster when compared with hair laser therapy alone in the treatment of PFB. PMID- 22226432 TI - Effects of sub-chronic nandrolone administration on hormonal adaptive response to acute stress in rats. AB - Androgenic-anabolic steroid (AAS) misuse has been associated with depression. It has been proposed that stress has a role in depression and that serotonin is involved in both endocrine responses to stress and depressive physiopathology. Although reports demonstrate that AAS chronic administration modifies components of stress-responsive hypothalamic-pituitary-adrenal axis (HPAA), no study has evaluated AAS effect on the response to stressful stimuli. We studied the effects of the subchronic administration (once a day for 14 days in rats) of a supratherapeutical dose of nandrolone decanoate (ND) on HPAA and cortical serotoninergic system response to acute restraint stress (RS). Acute RS produced the following effects: increase in CORT (in blood) and ACTH (both in blood and in pituitary corticotropes), GR depletion in hippocampus and hypothalamus cytosol and GR translocation in hippocampus nuclear fraction, cortical serotonin re uptake stimulation and hippocampus cytosolic ERK2 activation. ND by itself, i.e. in non-stressed rats, did not modify these parameters, except for a decrease of plasma CORT and ACTH levels and an increase in hippocampus cytosolic phospho ERK1/2. On the contrary, in stressed rats ND affected stress-induced plasma ACTH increase and prevented all other above reported stress effects, except the increase in pituitary ACTH positive cell density. Our results show that the prolonged administration of a supratherapeutical dose of ND in rats, albeit did not affect in a notable way HPAA and serotonin transporter activity in the absence of stress, may deregulate the stress-induced hormonal cascade which plays a crucial role in depressive psychopathology. PMID- 22226433 TI - Involvement of stress in the pathogenesis of autoimmune thyroid disease: a prospective study. AB - BACKGROUND: An association between stress and autoimmune thyroid disease (AITD) (especially Graves' hyperthyroidism) has been reported, but all studies so far on this topic have been retrospective. OBJECTIVE: To evaluate prospectively the relationship between stress and (i) de novo occurrence of thyroid antibodies and (ii) development of overt autoimmune hyper-/hypothyroidism. STUDY DESIGN: Two nested case-control studies in a prospective cohort of 790 euthyroid women who were 1st or 2nd degree relatives of AITD patients. Follow-up was five year, with annual assessments including questionnaires on stressful life events, daily hassles, and mood. In study A, cases were subjects who developed TPO-Ab but remained euthyroid during follow-up (called event). In study B, cases were subjects who developed overt hypothyroidism (TSH>5.7 mU/l and FT4<9.3 pmol/l) or overt hyperthyroidism (TSH<0.4 mU/l and FT4>20.1 pmol/l) during follow-up (called event). For each case, two controls were selected, matched for age and duration of follow-up; controls in study A remained TPO-Ab negative, and in study B remained without overt hyper-/hypothyroidism. OUTCOMES: Contrast in questionnaire responses between cases and controls at baseline, at one year prior to the event and at time of event. RESULTS: Exposure to stress was not different between subjects who developed or did not develop TPO-Ab (study A). No differences were observed in stress questionnaires between hyper-/hypothyroid cases and controls at any time point, but hypothyroid cases had less negative feelings than controls at the time of diagnosis (study B). CONCLUSION: The data suggest that stress is not involved in the pathogenesis of AITD. PMID- 22226434 TI - Blood platelet production and morphology. AB - Circulating platelets are highly specialized cells produced by megakaryocytes (Mks) that participate in hemostatic and inflammatory functions. Despite their critical role little is known about the molecular mechanisms involved in their production from megakaryocytes, or about the pathogenesis of platelet disorders. Megakaryopoiesis occurs in a complex microenvironment within the bone marrow. The underlying relationships between Mk maturation and bone marrow components are key factors in this process. Mk interactions with extracellular matrices (ECM) via specific surface receptors control many functions, with chemistry, physical parameters and membrane elasticity as fundamental elements of the processes involved. Alteration of Mk-ECM interactions in the bone marrow environment may lead to pathophysiologic situations, such as myelofibrosis and congenital thrombocytopenia. Searching the mechanisms related to Mks-bone marrow environment interactions, will provide novel insight into fundamental control of Mk function, leading to new concepts in the study of Mk-related disease states and future modes for therapeutic inquiry. PMID- 22226435 TI - Role of apparent diffusion coefficient values and diffusion-weighted magnetic resonance imaging in differentiation between benign and malignant thyroid nodules. AB - OBJECTIVE: The purpose of the study was to differentiate between benign and malignant thyroid nodules using nodule-spinal cord signal intensity and nodule apparent diffusion coefficient (ADC) ratios on diffusion-weighted magnetic resonance imaging (DW-MRI). MATERIALS AND METHODS: Forty-four patients (27 females, 17 males; mean age, 49 years) with nodules who underwent DW-MRI were included in this study. The images were acquired with 0, 50, 400 and 1000 s/mm(2)b values. ADC maps were calculated afterwards. Fine needle aspiration biopsies (FNAB) were performed at the same day with DW-MRI acquisition. The diagnosis in patients where malignity was detected after FNAB was confirmed by histopathologic analysis of the operation material. The signal intensities of the spinal cord and the nodule were measured additionally, over b-1000 diffusion weighted images. Nodule/cord signal intensity (SI) ratios were obtained and the digital values were calculated by dividing to ADC values estimated for each nodule. Statistical analysis was performed. RESULTS: The (nodule SI-cord SI)/nodule ADC ratio is calculated in the DW images, and a statistically significant relationship was found between this ratio and the histopathology of the nodules (P<.001). The ratio was determined as 0.27 in benign and 0.86 in malignant lesions. The result of receiver operating characteristic (ROC) analysis was statistically significant, and the area under curve (100%) was considerably high. The threshold value was calculated as 0.56 according to the ROC analysis. According to this threshold value, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rates for (nodule SI/cord SI)/ADC ratios in differentiating benign from malignant thyroid nodules are calculated as 100%, 97%, 83%, 100%, and 98%, respectively. CONCLUSION: We have found that (nodule/cord SI)/nodule ADC ratio has the highest values for sensitivity and specificity among the tests defined for characterization of nodules. PMID- 22226436 TI - Mucoepidermoid carcinoma of the lung: common findings and unusual appearances on CT. AB - OBJECTIVES: This study aimed to analyze the computed tomographic (CT) various findings of mucoepidermoid carcinoma of the lung and to improve the diagnostic efficacy for such tumor. MATERIALS AND METHODS: Sixteen consecutive patients with mucoepidermoid carcinoma of the lung confirmed by pathology were reviewed retrospectively. All the patients had undergone unenhanced and contrast-enhanced examinations; one of them also had undergone 18F-FDG PET/CT examinations. RESULTS: There were 6 males and 10 females with a mean age of 34.1 years. On CT plain scan, 14 out of 16 cases showed a well-defined endobronchus mass (n=12) or single peripheral nodule (n=2) with obstructive pneumonia or atelectasis (n=4), one case appeared a cavity in the tumor mass, and one presented diffuse circumferential wall thickening. Punctate calcification was observed in four cases (25%). Tumors showed mild (n=4, 25 %), moderate (n=6, 37.5%), and marked (n=6, 37.5%) degrees of contrast enhancement. Two patients had mediastinal lymph node metastasis, and one of them also had bone metastasis. CONCLUSIONS: Mucoepidermoid carcinoma of the lung likely affects young adults. The common findings included a well-defined ovoid or rounded intraluminal mass; and uncommon findings included cavitation, diffuse thickening, or spiculation. Although CT manifestations of it are variable and nonspecific, a well-defined ovoid or lobulated intraluminal or lung peripheral mass with moderate to marked heterogeneous contrast enhancement may suggest the diagnosis of mucoepidermoid carcinoma of the lung. It should be included in the differential diagnosis of regional tumors. PMID- 22226437 TI - Pulmonary metastases from colorectal cancer: imaging findings and growth rates at follow-up CT. AB - The objective of the study was to evaluate the computed tomographic (CT) features and growth rates of pulmonary metastases from colorectal cancer (CRC) on serial CT scans. The study included 17 patients (28 pulmonary metastases) who underwent metastasectomy from CRC. The characteristic CT features include well-defined round or oval nodules in the peripheral or subpleural/fissural lung with frequent feeding vessel sign. The mean tumor volume doubling time was calculated as 160 days. With these growth rates, short-term follow-up (i.e., 5-6 months) would be helpful. PMID- 22226438 TI - Safety and efficacy of image-guided percutaneous biopsies in the diagnosis of gastrointestinal stromal tumors. AB - BACKGROUND: After the invention of effective target agent therapy for gastrointestinal stromal tumors (GISTs), percutaneous biopsies may be indicated for unresectable diseases or before neoadjuvant chemotherapy. The purpose of this study was to evaluate the safety and efficacy of percutaneous biopsies for GISTs. MATERIAL AND METHODS: Fifty-eight procedures of transluminal biopsies or image guided percutaneous biopsies in 49 patients at our Institution from 1999 to 2010 were retrospectively reviewed. RESULT: Twenty-three transluminal biopsies, 20 ultrasonography-guided biopsies, and 15 CT-guided biopsies were performed. Failure rate was higher in the group of transluminal biopsies (17%). There is no major procedure-related complication in patients who underwent percutaneous biopsy. However, life-threatening bleeding after transluminal biopsies happened in two patients. CONCLUSION: Image-guided percutaneous biopsy is a safe and efficient alternative tool for the diagnosis of patients with GISTs. PMID- 22226439 TI - Ileal adenocarcinoma in Crohn's disease: magnetic resonance enterography features. AB - Patients with Crohn's disease are at increased risk for small bowel adenocarcinoma. We report herein two cases of Crohn's disease-related ileal adenocarcinoma, which were investigated by means of magnetic resonance (MR) enterography. Two different patterns were observed. In one case, the tumor presented as long circumferential, asymmetric and heterogeneous thickening of the ileum with visible nodule on free induction echo stimulated acquisition images. In the other case, the malignant lesion presented as a tumor mass of the terminal ileum, extending onto the cecum, and showed restricted diffusion on diffusion weighted MR imaging. In both cases, the tumors were diagnosed preoperatively. Histopathological analysis after surgical resection confirmed T4N1 poorly differentiated mucinous adenocarcinoma of the ileum in association with findings consistent with active in one case and inactive Crohn's disease in the other case. Our observations suggest that MR-enterography may be a useful imaging test for the detection of small bowel adenocarcinoma in patients with Crohn's disease. PMID- 22226440 TI - Diagnostic power of various computed tomography signs in diagnosing acute appendicitis. AB - OBJECTIVE: To review the diagnostic power of various computed tomography (CT) signs in acute appendicitis, in particular those initially classified as inconclusive. MATERIALS AND METHODS: Retrospective review of 100 CT abdomen and pelvis studies with assessment of maximal luminal diameter, wall thickness and cross-sectional diameter of the appendix, periappendiceal inflammatory changes, and presence of appendicolith. RESULTS: All CT signs show statistically significant occurrences in acute appendicitis. Their respective cut-off values with best sensitivity and specificity were calculated. Those from the inconclusive cases were also reviewed. CONCLUSION: Maximal cross-sectional diameter of the appendix is the most powerful parameter. Rest of the CT signs is supportive, especially in cases with inconclusive results. PMID- 22226441 TI - Transmural colonic ischemia: clinical features and computed tomography findings. AB - Our purpose was to describe the computed tomography features of transmural colonic ischemia in correlation with clinical, laboratory and histopathological findings of 14 patients who underwent colectomy (9 female and 5 male; mean age, 68 years). Seven patients died (50%). Transmural necrosis involved the right colon in 10 patients (10/14, or 72%). Eleven patients showed thickened colonic wall (11/14, or 79%), 10 pneumatosis (10/14, or 71%), 5 gas in the portal venous system (5/14, or 36%), and 14 fat stranding (14/14, or 100%). PMID- 22226442 TI - Is it possible to differentiate between hydatid and simple cysts in the liver by means of diffusion-weighted magnetic resonance imaging? AB - OBJECTIVE: Our aim was to evaluate the contribution of diffusion-weighted imaging to the differentiation of hydatid cysts (HCs) from the simple cysts and to the identification of the HC subtypes. MATERIALS AND METHODS: A total of 37 patients were included in this retrospective study. Fifty of these patients had diagnosed liver cysts (28 HCs and 22 simple cysts) of at least 1 cm in size. All of the cysts were examined with sonography and magnetic resonance imaging, and the HCs were classified according to the World Health Organization criteria. RESULTS: Twenty-eight of the total 50 cysts were HCs, and 22 were simple cysts. When the apparent diffusion coefficient (ADC) values of all HCs were compared with the ADC values of the simple cysts, a statistically significant relationship was found (P=.001). The optimal ADC threshold value was established as 2.5 s/mm(2). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy rates were 60%, 95%, 94%, 65% and 76%, respectively. CONCLUSION: Diffusion-weighted imaging-magnetic resonance imaging is a considerably helpful technique for differentiating between HCs and simple cysts and for differentiating between HC subtypes. PMID- 22226443 TI - Evaluation of the screening power of Cognitive Abilities Screening Instrument for probable Alzheimer's disease using voxel-based morphometry. AB - OBJECTIVE: The aim of this study was to compare two screening methods, total score of the Cognitive Abilities Screening Instrument (CASI(T)) and the combined score for the short-term memory and orientation domains (CASI(R)) for screening and grading probable Alzheimer's disease (AD), based on their correlations with voxel-based morphometry (VBM). MATERIALS AND METHODS: Forty-five subjects with probable AD and normal controls underwent magnetic resonance imaging and CASI testing. Their corresponding T1-weighted magnetic resonance images were analyzed using VBM. RESULTS: VBM results showed that in moderate-to-severe AD subgroups, significant whole-brain gray matter loss was detected using both CASI(T) and CASI(R). Significantly more voxels were detected using the CASI(T) compared with the CASI(R) system in mild AD subjects (P<.05). CONCLUSIONS: Based on their correlations with VBM results, there is no significant difference for CASI(R) and CASI(T) for grading moderate-to-severe AD subgroups, and CASI(R) scoring system may be more accurate and effective than the CASI(T) for screening mild AD. PMID- 22226444 TI - Abdominal complications of chemotherapy: findings at computed tomography. AB - Modern chemotherapy may result in an array of complications that can produce computed tomography (CT) findings in the hepatobiliary, gastrointestinal and urinary systems. This article describes the CT findings that may be seen in abdominal complications of contemporary chemotherapy. Knowledge of the varying CT appearances that can be encountered may facilitate both diagnosis and management in such cases. PMID- 22226445 TI - Angiocentric glioma in a 4-year-old boy: imaging characteristics and review of the literature. AB - An angiocentric glioma of the right temporal lobe is presented in a 4-year-old male. Imaging characteristics of this newly codified glial neoplasm are discussed with a review of the literature. PMID- 22226446 TI - 18F-fluorodeoxyglucose uptake and apparent diffusion coefficient in lung schwannoma. AB - Intrapulmonary schwannoma is uncommon and preoperative radiological diagnosis is rare. Described is a schwannoma that developed as a pulmonary hilar nodule in a 38-year-old woman. The nodule showed strong (18)F-fluorodeoxyglucose uptake with a maximum standard uptake value of 5.98 on positron emission tomography and had a high apparent diffusion coefficient (2.5 * 10(3) mm(2)/s) on diffusion-weighted magnetic resonance imaging. Combination of these functional imaging techniques warrants further evaluation in radiological diagnosis of intrapulmonary schwannoma. PMID- 22226447 TI - Right-side paraduodenal hernia: unexplained recurrent abdominal pain. AB - Paraduodenal hernia is a rare congenital malformation. Although it may be an incidental finding at autopsy or at laparotomy, some cases are symptomatic. In such a condition, imaging is mandatory for the diagnosis. In the clinical literature, only a few cases of paraduodenal hernia diagnosed with computed tomography (CT) have been reported. We report two cases of surgically proven right paraduodenal hernia diagnosed preoperatively by multislice helical CT. PMID- 22226448 TI - Reversible uro-lymphatic fistula. AB - Renal lymphatic fistulas are rare and, in most cases, of parasitic origin. We report a case of a reversible uro-lymphatic fistula, which was demonstrated by CT and was felt to be secondary to a radiolucent calculus. PMID- 22226449 TI - Intramural vesicular fat--an uncommon CT finding. AB - We present a case of a 75-year-old male who presented with lower back pain found to have an incidental finding of intramural vesicular fat on an unenhanced computed tomography of the pelvis. This relatively uncommon finding of a normal entity should not be mistaken for other causes of pathology within the urinary bladder. PMID- 22226450 TI - Radiology-pathology conference: primary perinephric and renal extraosseous Ewing's sarcoma. AB - Ewing's sarcoma/primitive neuroectodermal tumor is a rare entity belonging to a family of neoplasms of neuroectodermal origin. These highly aggressive neoplasms overwhelmingly affect children and young adults. A quarter of Ewing's sarcomas occur principally in the soft tissues with primary involvement of the perinephric fat and kidney being exceptionally rare. We present a 38-year-old man with primary Ewing's sarcoma of the perinephric fat and kidney diagnosed 2 years earlier who subsequently developed an infiltrating left renal and perinephric mass. PMID- 22226451 TI - Re: article by Gonoi et al. PMID- 22226452 TI - Immunological characterization and transcription profiling of peripheral blood (PB) monocytes in children with autism spectrum disorders (ASD) and specific polysaccharide antibody deficiency (SPAD): case study. AB - INTRODUCTION: There exists a small subset of children with autism spectrum disorders (ASD) characterized by fluctuating behavioral symptoms and cognitive skills following immune insults. Some of these children also exhibit specific polysaccharide antibody deficiency (SPAD), resulting in frequent infection caused by encapsulated organisms, and they often require supplemental intravenous immunoglobulin (IVIG) (ASD/SPAD). This study assessed whether these ASD/SPAD children have distinct immunological findings in comparison with ASD/non-SPAD or non-ASD/SPAD children. CASE DESCRIPTION: We describe 8 ASD/SPAD children with worsening behavioral symptoms/cognitive skills that are triggered by immune insults. These ASD/SPAD children exhibited delayed type food allergy (5/8), treatment-resistant seizure disorders (4/8), and chronic gastrointestinal (GI) symptoms (5/8) at high frequencies. Control subjects included ASD children without SPAD (N = 39), normal controls (N = 37), and non-ASD children with SPAD (N = 12). DISCUSSION AND EVALUATION: We assessed their innate and adaptive immune responses, by measuring the production of pro-inflammatory and counter-regulatory cytokines by peripheral blood mononuclear cells (PBMCs) in responses to agonists of toll like receptors (TLR), stimuli of innate immunity, and T cell stimulants. Transcription profiling of PB monocytes was also assessed. ASD/SPAD PBMCs produced less proinflammatory cytokines with agonists of TLR7/8 (IL-6, IL-23), TLR2/6 (IL-6), TLR4 (IL-12p40), and without stimuli (IL-1beta, IL-6, and TNF alpha) than normal controls. In addition, cytokine production of ASD/SPAD PBMCs in response to T cell mitogens (IFN-gamma, IL-17, and IL-12p40) and candida antigen (Ag) (IL-10, IL-12p40) were less than normal controls. ASD/non-SPAD PBMDs revealed similar results as normal controls, while non-ASD/SPAD PBMCs revealed lower production of IL-6, IL-10 and IL-23 with a TLR4 agonist. Only common features observed between ASD/SPAD and non-ASD/SPAD children is lower IL-10 production in the absence of stimuli. Transcription profiling of PB monocytes revealed over a 2-fold up (830 and 1250) and down (653 and 1235) regulation of genes in ASD/SPAD children, as compared to normal (N = 26) and ASD/non-SPAD (N = 29) controls, respectively. Enriched gene expression of TGFBR (p < 0.005), Notch (p < 0.01), and EGFR1 (p < 0.02) pathways was found in the ASD/SPAD monocytes as compared to ASD/non-SPAD controls. CONCLUSIONS: The Immunological findings in the ASD/SPAD children who exhibit fluctuating behavioral symptoms and cognitive skills cannot be solely attributed to SPAD. Instead, these findings may be more specific for ASD/SPAD children with the above-described clinical characteristics, indicating a possible role of these immune abnormalities in their neuropsychiatric symptoms. PMID- 22226453 TI - Anterior chest wall inflammation by whole-body magnetic resonance imaging in patients with spondyloarthritis: lack of association between clinical and imaging findings in a cross-sectional study. AB - INTRODUCTION: Inflammatory involvement of the anterior chest wall (ACW) affects the quality of life of patients with spondyloarthritis (SpA), although involvement of the ACW is often neglected on clinical and imaging evaluation. Whole-body (WB) MRI is an imaging method used to assess the ACW in addition to the sacroiliac joints and spine without inconvenience for patients. Our goals in this study were to describe the distribution of ACW inflammation by WB MRI in both early and established SpA and associations between clinical and imaging findings indicative of inflammation. METHODS: The ACWs of 122 consecutive SpA patients (95 with ankylosing spondylitis (AS) and 27 with nonradiographic SpA (nrSpA)) and 75 healthy controls were scanned by sagittal and coronal WB MRI. The MRI scans were scored independently in random order by seven readers blinded to patient identifiers. Active and structural inflammatory lesions of the ACW were recorded on a web-based data entry form. ACW pain by patient self-report, ACW tenderness on physical examination according to the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) and lesions detected by MRI were analyzed descriptively. kappa statistics served to assess the agreement between clinical and imaging findings. RESULTS: ACW pain or tenderness was present in 26% of patients, with little difference between AS and nrSpA patients. Bone marrow edema (BME), erosion and fat infiltration were recorded in 44.3%, 34.4% and 27.0% of SpA patients and in 9.3%, 12.0% and 5.3% of controls, respectively. Lesions found by MRI occurred more frequently in AS patients (BME, erosion and fat infiltration in 49.5%, 36.8% and 33.7%, respectively) than in nrSpA patients (25.9%, 25.9% and 3.7%, respectively). The joint most frequently affected by lesions found on MRI scans was the manubriosternal joint. The kappa values between clinical assessments and MRI inflammation ranged from -0.10 to only 0.33 for both AS and nrSpA patients. CONCLUSIONS: Among SpA patients, 26% had clinical involvement of the ACW. WB MRI signs of ACW inflammation were found in a substantial proportion of patients with AS (49.5%) and nrSpA (25.9%). There was no association between clinical assessments of ACW, including the MASES, and MRI features. PMID- 22226454 TI - A new liquid chromatography-mass spectrometry approach for generic screening and quantitation of potential genotoxic alkylation compounds without derivatization. AB - One of the crucial tasks of pharmaceutical industry is to quantify the potential genotoxic impurities (PGIs) coming from the process of drug production. The European Medicines Agency (EMEA) imposes analytical testing limits in the order of MUg/g, depending on drug dosage and exposure period, that means the need of a sensitive and selective method of analysis. Liquid chromatography coupled to electrospray ionization mass spectrometry (LC-ESI-MS) has been demonstrated as the most versatile approach to detect PGIs in complex matrices. However, time consuming derivatization processes are needed to enhance sensitivity and selectivity, and to overcome matrix effects (ME) that may arise from active pharmaceutical ingredients (APIs) or excipients. We propose the use of the Direct EI LC-MS as an alternative approach to detect and quantify PGIs in drug formulations. The Direct-EI LC-MS interface is based on electron ionization (EI) which is well suited for the detection of low molecular weight compounds of different polarity, without derivatization and with no sign of ME. The method has been successfully applied to the detection of PGIs belonging to the class of alkylation agents. Calibration experiments show satisfactory linearity and precision data. Recoveries in low enriched samples spanned from 55 to 82%, and were not affected by ME. The method limits of detection (LODs), varying from 0.13 to 1.5 MUg/g, were satisfactory for the quantitation of the target PGIs at the level required by regulatory agencies. PMID- 22226455 TI - Fractional coverage metrics based on ecological home range for calculation of the effective peak capacity in comprehensive two-dimensional separations. AB - Optimization of comprehensive two-dimensional separations frequently relies on the assessment of the peak capacity of the system. A correction is required for the fact that many pairs of separation systems are to some degree correlated, and consequently the entire separation space is not chemically accessible to solutes. This correction is essentially a measure of the fraction of separation space area where the solutes may elute. No agreement exists in the literature as to the best form of the spatial coverage factor. In this work, we distinguish between spatial coverage factors that measure the maximum occupiable space, which is characteristic of the separation dimensionality, and the space actually occupied by a particular sample, which is characteristic of the sample dimensionality. It is argued that the former, which we call f(coverage), is important to calculating the peak capacity. We propose five criteria for a good f(coverage) metric and use them to evaluate various area determination methods that are used to measure animal home ranges in ecology. We consider minimum convex hulls, convex hull peels, alpha-hulls, three variations of local hull methods, and a kernel method and compare the results to the intuitively satisfying but subjective Stoll-Gilar method. The most promising methods are evaluated using two experimental LC*LC data sets, one with fixed separation chemistry but variable gradient times, and a second with variable first dimension column chemistry. For the 12 separations in the first data set, in which f(coverage) is expected to be constant, the minimum convex hull is the most precise method (f(coverage)=0.68+/-0.04) that gives similar results to the Stoll-Gilar method (f(coverage)=0.67+/-0.06). The minimum convex hull is proposed as the best method for calculating f(coverage), because it has no adjustable parameters, can be scaled to different retention time normalizations, is easily calculated using available software, and represents the expected area of solute occupation based on a proposed linear free energy formalism. PMID- 22226456 TI - Investigations on the calculation of the third moments of elution peaks. I: Composite signals generated by adding up a mathematical function and experimental noise. AB - Elution peaks were generated by summing up a mathematical function and a previously recorded experimental noise. The first three statistical moments of these peaks were calculated using several data processing methods. The results obtained were analyzed. From this analysis, a method is developed for the calculation with a satisfying accuracy of the third moments of these combined signals. The method is applicable to real chromatographic peaks and makes it possible to determine accurate estimates of their third moments. This approach could be helpful for the investigation of the mass transfer processes in chromatographic columns because the third moment provides direct access to the external mass transfer coefficient. PMID- 22226457 TI - Multidimensional gas chromatography of oxidative degradation products in algae derived fuel oil samples using narrow heartcuts and rapid cycle times. AB - To characterize a fuel's thermal and storage stability an understanding of the process of oxidation and oxidation pathways is essential. Oxidation pathways commence with hydroperoxides which quickly decompose to form a range of alcohols, acids and other oxygen-containing species. In the presence of significant levels of hydrocarbon-based matrix, analysis of these heteroatomic species is difficult. Applying multidimensional gas chromatography with very narrow heart-cut windows (0.20 min) minimizes the number of compounds transferred to the second dimension (2D) column during each heart-cut. Successive heart-cuts every 2.00 min are taken throughout the analytical run, since each heart-cut has a maximum retention on 2D of <2.00 min on the fast elution 2D column. Subsequent analyses involve incrementing or offsetting the heart-cut windows by 0.20 min, so after 10 analyses, a complete coverage of the sample components can be obtained. On the polar 1D and non-polar 2D phase column arrangement, non-polar matrix compounds elute last on the 2D column, and this determines the largest (2t)R; i.e., (2t)R < P(M) to ensure retained components on 2D will not overlap with subsequent heart cuts. Heartcutting is supported by cryotrapping at the start of the 2D column in order to provide significantly better resolution. Good quality MS library match data generally demonstrate the high resolution separation of oxygenates achieved. Whilst 1D GC-MS was unsuccessful in identifying any of the oxygen-containing compounds reported here, good correlation of MS data (with average MS library similarity data) for acids (903), alcohols (909), ketones (941) and aldehydes (938) in the sample is obtained. The method requires ten sequential runs, and this can be accomplished automatically once the events table is set up. However if fewer target compounds are to be transferred, a reduced number of sequential runs can be implemented. PMID- 22226458 TI - Electrowetting-on-dielectric actuation of droplets with capillary electrophoretic zones for off-line mass spectrometric analysis. AB - Present article describes a novel technique based on digital microfluidics that allows collecting fractions of interest after electrophoretic separation and detection for further ESI-MS investigation. In this technique, a mixture is injected into a capillary electrophoresis (CE) apparatus, and microliter droplets are generated at the CE outlet at a frequency high enough to fraction each compound into several droplets, compartmentalizing the CE zones into a sequence of droplets. The droplets are transported from the CE outlet to a storage tube inlet using electrowetting-on-dielectric (EWOD) for droplet actuation. By applying a vacuum at the other end of the storage tube, the droplets form a sequence of plugs separated by air gaps. The plugs stored in the tubing are later analyzed using a standalone spectrometric device. Off-line electrospray ionization mass spectrometry (ESI-MS) was used to characterize the corresponding vitamin and was performed by pumping the segmented plugs directly into a spray emitter tip. The technique could be of interest to laboratories without access to well-equipped facilities (e.g. clean-rooms or lab robots). PMID- 22226459 TI - Matrix-elimination with steam distillation for determination of short-chain fatty acids in hypersaline waters from pre-salt layer by ion-exclusion chromatography. AB - A method for determination of formic, acetic, propionic and butyric acids in hypersaline waters by ion-exclusion chromatography (IEC), using steam distillation to eliminate matrix-interference, was developed. The steam distillation variables such as type of solution to collect the distillate, distillation time and volume of the 50% v/v H2SO4 solution were optimized. The effect of the addition of NaCl different concentrations to the calibration standards on the carboxylic acid recovery was also investigated. Detection limits of 0.2, 0.5, 0.3 and 1.5 mg L-1 were obtained for formic, acetic, propionic and butyric acids, respectively. Produced waters from petroleum reservoirs in the Brazilian pre-salt layer containing about 19% m/v of NaCl were analyzed. Good recoveries (99-108%) were obtained for all acids in spiked produced water samples. PMID- 22226460 TI - Quality by Design: Multidimensional exploration of the design space in high performance liquid chromatography method development for better robustness before validation. AB - Robust HPLC separations lead to fewer analysis failures and better method transfer as well as providing an assurance of quality. This work presents the systematic development of an optimal, robust, fast UHPLC method for the simultaneous assay of two APIs of an eye drop sample and their impurities, in accordance with Quality by Design principles. Chromatography software is employed to effectively generate design spaces (Method Operable Design Regions), which are subsequently employed to determine the final method conditions and to evaluate robustness prior to validation. PMID- 22226461 TI - Iron and protein biofortification of cassava: lessons learned. AB - Over two hundred and fifty million Africans rely on the starchy root crop cassava (Manihot esculenta) as their primary source of calories. Cassava roots, however, have the lowest protein:energy ratio of all the world's major staple crops. Furthermore, a typical cassava-based diet provides less than 10-20% of the required amounts of iron, zinc, vitamin A and vitamin E. The BioCassava Plus program employed modern biotechnologies to improve the health of Africans through development and delivery of novel cassava germplasm with increased nutrient levels. Here we describe the development of molecular strategies and their outcomes to meet minimum daily allowances for protein and iron in cassava based diets. We demonstrate that cyanogens play a central role in cassava nitrogen metabolism and that strategies employed to increase root protein levels result in reduced cyanogen levels in roots. We also demonstrate that enhancing root iron uptake has an impact on the expression of genes that regulate iron homeostasis in multiple tissues. These observations demonstrate the complex metabolic interactions involved in enhancing targeted nutrient levels in plants and identify potential new strategies for further enhancing nutrient levels in cassava. PMID- 22226462 TI - Towards increased crop productivity and quality. PMID- 22226463 TI - Alternative biofuel production in non-natural hosts. AB - Global energy and environmental concerns have stimulated increased efforts in synthesizing petroleum-derived products from renewable resources. Biological production of metabolites for fuel is increasingly becoming a feasible, renewable, environmentally sound alternative. However, many of these chemicals are not highly produced in any known native organism. Here we review the current progress of modifying microorganisms with heterogeneous elements for the production of biofuels. This strategy has been extensively employed in a variety of hosts for the development of production of various alcohols, fatty acids, alkenes and alkanes. PMID- 22226464 TI - Applications of functional gene microarrays for profiling microbial communities. AB - Functional gene arrays (FGAs) have been considered as a specific, sensitive, quantitative, and high throughput metagenomic tool to detect, monitor and characterize microbial communities. Especially GeoChips, the most comprehensive FGAs have been applied to analyze the functional diversity, composition, structure, and metabolic potential or activity of a variety of microbial communities from different habitats, such as aquatic ecosystems, soils, contaminated sites, extreme environments, and bioreactors. FGAs are able to address fundamental questions related to global change, bioremediation, land use, human health, and ecological theories, and link the microbial community structure to environmental properties and ecosystem functioning. This review focuses on applications of FGA technology for profiling microbial communities, including target preparation, hybridization and data processing, and data analysis. We also discuss challenges and future directions of FGA applications. PMID- 22226465 TI - Petersen hernia complicating laparoscopic duodenal switch. PMID- 22226466 TI - Manifold learning for image-based breathing gating in ultrasound and MRI. AB - Respiratory motion is a challenging factor for image acquisition and image-guided procedures in the abdominal and thoracic region. In order to address the issues arising from respiratory motion, it is often necessary to detect the respiratory signal. In this article, we propose a novel, purely image-based retrospective respiratory gating method for ultrasound and MRI. Further, we apply this technique to acquire breathing-affected 4D ultrasound with a wobbler probe and, similarly, to create 4D MR with a slice stacking approach. We achieve the gating with Laplacian eigenmaps, a manifold learning technique, to determine the low dimensional manifold embedded in the high-dimensional image space. Since Laplacian eigenmaps assign to each image frame a coordinate in low-dimensional space by respecting the neighborhood relationship, they are well suited for analyzing the breathing cycle. We perform the image-based gating on several 2D and 3D ultrasound datasets over time, and quantify its very good performance by comparing it to measurements from an external gating system. For MRI, we perform the manifold learning on several datasets for various orientations and positions. We achieve very high correlations by a comparison to an alternative gating with diaphragm tracking. PMID- 22226467 TI - Development and application of a LC-MS/MS method to quantify basal adenosine concentration in human plasma from patients undergoing on-pump CABG surgery. AB - A sensitive and robust LC-MS/MS method was developed to quantify basal adenosine concentrations in human plasma of patients undergoing on-pump coronary artery bypass grafting (CABG) surgery. A strong cation exchange (SCX) monolithic cartridge was used to enrich analyte, improve robustness, and reduce biological complexity. A simple modifier-free mobile phase was employed to improve sensitivity and reproducibility. This method exhibits consistent precision and accuracy, and the RSDs or REs of all the intraday and interday determinations were within 10%. The calibration curve was linear across the examined dynamic range from 1nM to 500nM (r(2)=0.996). LOD and LOQ were determined to be 0.257nM and 0.857nM respectively, while LLOQ was below 10nM. This method was used to monitor changes of adenosine levels in patient plasma drawn intraoperatively during on-pump CABG surgery. The analysis of 84 patients revealed that the mean concentration of adenosine in coronary sinus plasma after cardiopulmonary bypass (CPB) is higher than that in coronary sinus before CPB (p=0.0024; two-tailed t test) and that in radial artery plasma after CPB (p=0.0409; two-tailed t-test). These findings suggest that the equilibrium between adenosine production and elimination has favored the elevation of adenosine basal level during on-pump CABG surgery and the change is specific to heart tissues. Evaluation of adenosine with a sensitive and robust analytical method has important implications on providing consistent results and meaningful insights into adenosine regulation, as well as its steady state and sustained action on the heart. Relating patient characteristics or clinical outcomes with basal adenosine concentration can be used to optimize the CABG-CPB maneuver by regulating adenosine level via pharmacological intervention, and differentiating adenosine's contribution to cardioprotection from other modulatory factors. PMID- 22226468 TI - Elucidating the selectivity of recombinant forms of Aleuria aurantia lectin using weak affinity chromatography. AB - Aberrant glycosylation is connected to several pathological conditions and lectins are useful tools to characterize glycosylated biomarkers. The Aleuria aurantia lectin (AAL) is of special interest since it interacts with all types of fucosylated saccharides. AAL has been expressed in Escherichia coli as a fully functional recombinant protein. Engineered variants of AAL have been developed with the aim of creating monovalent lectins with more homogenous binding characteristics. Four different forms of AAL were studied in the present work: native AAL purified from A. aurantia mushrooms, recombinant AAL dimer, recombinant AAL monomer and recombinant AAL site 2 (S2-AAL). The affinities of these AAL forms toward a number of saccharides were determined with weak affinity chromatography (WAC). Disaccharides with fucose linked alpha1-3 to GlcNAc interacted with higher affinity compared to fucose linked alpha1-6 or alpha1-4 and the obtained dissociation constants (K(d)) were in the range of 10MUM for all AAL forms. Tetra- and pentasaccharides with fucose in alpha1-2, alpha1-3 or alpha1-4 had K(d) values ranging from 0.1 to 7mM while a large alpha1-6 fucosylated oligosaccharide had a K(d) of about 20MUM. The recombinant multivalent AAL forms and native AAL exhibited similar affinities toward all saccharides, but S2-AAL had a lower affinity especially regarding a sialic acid containing fucosylated saccharide. It was demonstrated that WAC is a valuable technique in determining the detailed binding profile of the lectins. Specific advantages with WAC include a low consumption of non-labeled saccharides, possibility to analyze mixtures and a simple procedure using standard HPLC equipment. PMID- 22226469 TI - Determination of gamma-hydroxybutyrate (GHB), beta-hydroxybutyrate (BHB), pregabalin, 1,4-butane-diol (1,4BD) and gamma-butyrolactone (GBL) in whole blood and urine samples by UPLC-MSMS. AB - The demand of high throughput methods for the determination of gamma hydroxybutyrate (GHB) and its precursors gamma-butyrolactone (GBL) and 1,4-butane diol (1,4BD) as well as for pregabalin is increasing. Here we present two analytical methods using ultra-high pressure liquid chromatography (UPLC) and tandem mass spectrometric (MS/MS) detection for the determination of GHB, beta hydroxybutyrate (BHB), pregabalin, 1,4BD and GBL in whole blood and urine. Using the 96-well formate, the whole blood method is a simple high-throughput method suitable for screening of large sample amounts. With an easy sample preparation for urine including only dilution and filtration of the sample, the method is suitable for fast screening of urine samples. Both methods showed acceptable linearity, acceptable limits of detection, and limits of quantification. The within-day and between-day precisions of all analytes were lower than 10% RSD. The analytes were extracted from matrices with recoveries near 100%, and no major matrix effects were observed. Both methods have been used as routine screening analyses of whole blood and urine samples since January 2010. PMID- 22226470 TI - Investigating the change in three dimensional deformity for idiopathic scoliosis using axially loaded MRI. AB - BACKGROUND: Adolescent idiopathic scoliosis is a complex three-dimensional deformity, involving a lateral deformity in the coronal plane and axial rotation of the vertebrae in the transverse plane. Gravitational loading plays an important biomechanical role in governing the coronal deformity, however, less is known about how they influence the axial deformity. This study investigates the change in three-dimensional deformity of a series of scoliosis patients due to compressive axial loading. METHODS: Magnetic resonance imaging scans were obtained and coronal deformity (measured using the coronal Cobb angle) and axial rotations measured for a group of 18 scoliosis patients (Mean major Cobb angle was 43.4 degrees ). Each patient was scanned in an unloaded and loaded condition while compressive loads equivalent to 50% body mass were applied using a custom developed compressive device. FINDINGS: The mean increase in major Cobb angle due to compressive loading was 7.4 degrees (SD 3.5 degrees ). The most axially rotated vertebra was observed at the apex of the structural curve and the largest average intravertebral rotations were observed toward the limits of the coronal deformity. A level-wise comparison showed no significant difference between the average loaded and unloaded vertebral axial rotations (intra-observer error=2.56 degrees ) or intravertebral rotations at each spinal level. INTERPRETATION: This study suggests that the biomechanical effects of axial loading primarily influence the coronal deformity, with no significant change in vertebral axial rotation or intravertebral rotation observed between the unloaded and loaded condition. However, the magnitude of changes in vertebral rotation with compressive loading may have been too small to detect given the resolution of the current technique. PMID- 22226471 TI - Latent tuberculosis seems not to reactivate in multiple sclerosis patients on natalizumab. AB - Current safety recommendations for multiple sclerosis (MS) patients who are considered for natalizumab do not specify how to screen for latent tuberculosis (LTB). Only chest X-ray is recommended as a routine, and follow-up depends on its results. The incidence of TB in Spain is high and the risk of a LTB reactivation due to natalizumab is unknown. Our objective is to describe in our clinical practice if following the current recommendations for the MS population on natalizumab allows identifying patients with a LTB, as well as the risk for TB reactivation. Our study demonstrated that, in our environment, current recommendations are not sensitive enough to identify cases of LTB, though no cases of active TB were observed. Considering the lack of documented active TB cases worldwide among natalizumab patients, we suggest that these safety measures are probably unnecessary, even in countries with a high TB incidence. PMID- 22226472 TI - GEF-H1-RhoA signaling pathway mediates LPS-induced NF-kappaB transactivation and IL-8 synthesis in endothelial cells. AB - Secretion of proinflammatory cytokines by LPS activated endothelial cells contributes substantially to the pathogenesis of sepsis. However, the mechanism involved in this process is not well understood. In the present study, we determined the roles of GEF-H1 (guanine-nucleotide exchange factor-H1)-RhoA signaling in LPS-induced interleukin-8 (IL-8, CXCL8) production in endothelial cells. First, we observed that GEF-H1 expression was upregulated in a dose- and time-dependent manner as consistent with TLR4 (Toll-like receptor 4) expression after LPS stimulation. Afterwards, Clostridium difficile toxin B-10463 (TcdB 10463), an inhibitor of Rho activities, reduced LPS-induced NF-kappaB phosphorylation. Inhibition of GEF-H1 and RhoA expression reduced LPS-induced NF kappaB and p38 phosphorylation. TLR4 knockout blocked LPS-induced activity of RhoA, however, MyD88 knockout did not impair the LPS-induced activity of RhoA. Nevertheless, TLR4 and MyD88 knockout both significantly inhibited transactivation of NF-kappaB. GEF-H1-RhoA and MyD88 both induced significant changes in NF-kappaB transactivation and IL-8 synthesis. Co-inhibition of GEF-H1 RhoA and p38 expression produced similar inhibitory effects on LPS-induced NF kappaB transactivation and IL-8 synthesis as inhibition of p38 expression alone, thus confirming that activation of p38 was essential for the GEF-H1-RhoA signaling pathway to induce NF-kappaB transactivation and IL-8 synthesis. Taken together, these results demonstrate that LPS-induced NF-kappaB activation and IL 8 synthesis in endothelial cells are regulated by the MyD88 pathway and GEF-H1 RhoA pathway. PMID- 22226473 TI - Uncatalysed wet oxidation of D-glucose with hydrogen peroxide and its combination with hydrothermal electrolysis. AB - An increasing interest in biomass as a renewable feedstock for the chemical industry has risen over the last decades, and glucose, the monomer unit of cellulose, has been widely studied as a source material to produce value-added products such as carboxylic acids, mainly gluconic and formic. In this work, the non-catalysed wet oxidation of glucose using hydrogen peroxide has been analysed, obtaining molar yields to gluconic and formic acids up to 15% and 64%, respectively. Glucose conversion was generally between 40 and 50%, reaching over 80% under the highest temperature (200 degrees C). An appropriate choice of temperature can tune product distribution as well as reaction rates. The interaction of the wet oxidation with an electrolytic reaction was also analysed. PMID- 22226474 TI - Synthesis of pH and temperature sensitive, core-shell nano/microgels, by one pot, soap-free emulsion polymerization. AB - The synthesis and properties of thermal/pH-sensitive core-shell copolymer nano/microgels were investigated. The crosslinked core consisted of N isopropylacrylamide (NIPAAm) while the shell was stabilized by poly(ethylene glycol) methyl ether methacrylate (PEGMA) and 2-methacryloyloxybenzoic acid (2MBA) using a "one pot" soapless emulsion polymerization method. Monodisperse particles were produced with average hydrodynamic diameters ranging from 40 to 880 nm, as determined by dynamic light scattering (DLS) in water at 25 degrees C, depending on the synthetic recipe used. The influence of PEGMA and 2MBA content on size and temperature transition at different pH values was studied. Zeta potential measurements and acid-base titration studies demonstrated almost complete incorporation of acid comonomer (2MBA) into the nano/microgels. Two different crosslinkers, a stable and an acid labile, were compared. The crosslinker used has a major influence on the size and charge density of the nano/microgels produced. Microscopic studies confirmed the core-shell morphology of the nano/microgels. PMID- 22226475 TI - Deposition mechanisms of TiO2 nanoparticles in a parallel plate system. AB - In this study, a microscope-based technique was utilized to understand the fundamental mechanisms involved in deposition of TiO(2) nanoparticles (TNPs). Transport and deposition studies were conducted in a parallel plate (PP) flow chamber with TNP labeled with fluorescein isothiocyanate (FITC) for visualization. Attachment of FITC-labeled TNPs on surfaces is a function of a combination of parameters, including ionic strength (IS), pH and flowrate. Significantly higher deposition rates were observed at pH 5 versus pH 7. This is attributed to the conditions being chemically favorable for deposition at pH 5 as compared to pH 7, as predicted by DLVO theory. Additionally, deposition rates at pH 5 were reduced with IS below 10 mM due to the decrease in range of electrostatic attractive forces. Above 10 mM, aggregate size increased, resulting in higher deposition rates. At pH 7, no deposition was observed below 10 mM and above this concentration, deposition increased with IS. The impact of flowrate was also observed, with decreasing flowrate leading to greater deposition due to the reduction in drag force acting on the aggregate (regardless of pH). Comparisons between experimental and theoretical approximations indicate that non DLVO type forces also play a significant role. This combination of observations suggest that the deposition of these model nanoparticles on glass surfaces was controlled by a combination of DLVO and non-DLVO-type forces, shear rate, aggregation state, and gravitational force acting on TNPs. PMID- 22226476 TI - Dignitary medicine: adapting prehospital, preventive, tactical and travel medicine to new populations. AB - Dignitary Protection Medicine (DPM) is a new area of medical expertise that incorporates elements of virtually all medical and surgical specialties, drawing heavily from travel, tactical and expedition medicine. The fundamentals of DPM stem from the experiences of White House, State Department and other physicians who have traveled extensively with dignitaries. Furthermore, increased international travel of business executives and political dignitaries has mandated a need for proficiency in this realm. We sought to define the requisite knowledge base and skill sets that form the foundation of this new area of specialization. PMID- 22226477 TI - Impulsivity is not always associated with student drinking: a moderation study of impulsivity and drinking by positive alcohol expectancies. AB - Student drinking is a major problem on North American campuses and impulsivity is a significant risk factor for heavy drinking. The present study investigates the moderation of the impulsivity-drinking relationship by the expectation that having a drink will lead to positive experiences. Undergraduate drinkers (n=292) completed measures of impulsivity (Barratt Impulsiveness Scale 11; BIS-11), positive drinking expectancies, and alcohol use. Expectancies moderated the relationship between BIS-11 scores and alcohol use. BIS-11 scores were significantly related to typical alcohol quantity, frequency, quantity X frequency, and binge drinking frequency for individuals with average and high levels of positive expectancies, but not for those with few positive expectancies. Implications for interventions targeted at highly impulsive students, using expectancy modification are discussed. PMID- 22226478 TI - Qualification of imaging biomarkers for oncology drug development. AB - Although many imaging biomarkers have been described for cancer research, few are sufficiently robust, reliable and well-characterised to be used as routine tools in clinical cancer research. In particular, biomarkers which show that investigational therapies have reduced tumour cell proliferation, or induced necrotic or apoptotic cell death are not commonly used to support decision-making in drug development, even though such pharmacodynamic effects are common goals of many classes of investigational drugs. Moreover we lack well-qualified biomarkers of propensity to metastasise. The qualification and technical validation of imaging biomarkers poses unique challenges not always encountered when validating biospecimen biomarkers. These include standardisation of acquisition and analysis, imaging-pathology correlation, cross-sectional clinical-biomarker correlations and correlation with outcome. Such work is ideally suited to precompetitive research and public-private partnerships, and this has been recognised within the Innovative Medicines Initiative (IMI), a Joint Undertaking between the European Union and the European Federation of Pharmaceutical Industries and Associations, which has initiated projects in the areas of drug safety, drug efficacy, knowledge management and training. PMID- 22226479 TI - Apparent diffusion coefficient from magnetic resonance imaging as a biomarker in oncology drug development. AB - Magnetic resonance imaging (MRI) can be made sensitive to diffusion of water molecules in biological tissues: this phenomenon can be quantitated to provide a biomarker, the apparent diffusion coefficient (ADC). Over the past decade, evidence has accumulated from numerous clinical and animal studies that ADC is abnormal in tumours; that elevated ADC reflects an elevated non-cellular fraction; and that acute increases in ADC following therapy can indicate that tumour cells have been killed. However there remain substantial challenges in ensuring robust and valid ADC measurements, particularly in multicentre studies in common sites of metastasis such as lung and liver. Moreover, there is uncertainty about how best to select the timing of observation post-therapy to avoid false-negatives, and how to minimise the confounding factors which could decouple drug-induced ADC increase from drug-induced cell kill. In this review we summarise the physical basis of the biomarker, the evidence that it reflects non viable fraction, particularly in extracranial tumours, and suggest a roadmap for validation and qualification. PMID- 22226480 TI - Imaging apoptosis with positron emission tomography: 'bench to bedside' development of the caspase-3/7 specific radiotracer [(18)F]ICMT-11. AB - The capacity to evade apoptosis has been defined as one of the hallmarks of cancer and, thus, effective anti-cancer therapy often induces apoptosis. A biomarker for imaging apoptosis could assist in monitoring the efficacy of a wide range of current and future therapeutics. Despite the potential, there are limited clinical examples of the use of positron emission tomography for imaging of apoptosis. [(18)F]ICMT-11 is a novel reagent designed to non-invasively image caspase-3 activation and, hence, drug-induced apoptosis. Radiochemistry development of [(18)F]ICMT-11 has been undertaken to improve specific radioactivity, reduce content of stable impurities, reduce synthesis time and enable automation for manufacture of multi-patient dose. Due to the promising mechanistic and safety profile of [(18)F]ICMT-11, the radiotracer is transitioning to clinical development and has been selected as a candidate radiotracer by the QuIC-ConCePT consortium for further evaluation in preclinical models and humans. A successful outcome will allow use of the radiotracer as qualified method for evaluating the pharmaceutical industry's next generation therapeutics. PMID- 22226481 TI - Subjective assessment by ultrasound is superior to the risk of malignancy index (RMI) or the risk of ovarian malignancy algorithm (ROMA) in discriminating benign from malignant adnexal masses. AB - PURPOSE: The combination of two tumour markers, CA125 and HE4, in the risk of ovarian malignancy assay (ROMA) has been shown to be successful in classifying patients into those who have a high or low risk of epithelial ovarian cancer. In the present study, the diagnostic accuracy of ROMA was assessed and compared to the diagnostic accuracy of the two most widely used ultrasound methods, namely the risk of malignancy index (RMI) and subjective assessment by ultrasound. METHODS: From August, 2005 to March, 2009, 432 women with a pelvic mass who were scheduled to have surgery were enrolled in a single-centre prospective cohort study. A preoperative ultrasound was performed and preoperative CA125 and HE4 serum levels were measured. Once the final surgical pathology reports were obtained, the diagnostic accuracy and performance indices of ROMA, RMI and subjective assessment were calculated. RESULTS: Of the 432 eligible patients, 374 could be analysed. Subjective assessment had the highest area under the receiver operator characteristic curve (AUC) (0.968, 95%CI:0.945-0.984), followed by the RMI (0.931, 95%CI:0.901-0.955). The subjective assessment and RMI both had significantly higher AUCs than the ROMA (0.893, 95%CI:0.857-0.922; P<0.0001 and P=0.0030, respectively). The pre- and postmenopausal populations generated similar results. CONCLUSION: Although new tumour markers models are promising, they do not contribute significantly to the diagnosis of ovarian cancer. Ultrasound, especially subjective assessment by ultrasound, remains superior in discriminating malignant from benign ovarian masses. PMID- 22226482 TI - Recent advances in understanding the biochemical and molecular mechanism of diabetic retinopathy. AB - One of the major complications in patients with diabetes is diabetic retinopathy (DR), a leading cause of blindness worldwide. It takes several years before any clinical signs of retinopathy appear in diabetic patients, which gives an ample opportunity for scientists to uncover biochemical and molecular mechanism implicated early in the development and progression of the disease. During the past few decades, research progress has been made in investigating the pathophysiology of the disease; however, due to nonavailability of human retinal samples at different stages of the disease and also due to lack of a proper animal model of DR, the exact molecular mechanism has not been elucidated, making therapeutic a difficult task. In this review article, we have discussed a number of diabetes-induced metabolites such as glucose, lipids, amino acids, and other related factors and molecules that are implicated in the pathophysiology of the DR. Furthermore, we have highlighted neurodegeneration and regulation of neurotrophic factors, being recognized as early events that may be involved in the pathology of the disease in the course of DR. An understanding of the biochemical and molecular changes especially early in the diabetic retina may lead to new and effective therapies towards prevention and amelioration of DR, which is important for the millions of individuals who already have or are likely to develop the disease before a cure becomes available. PMID- 22226483 TI - Clinical, biochemical, and immunological characteristics of newly diagnosed nonobese diabetic patients aged 18-45 years in China. AB - BACKGROUND: The purpose was to characterize the clinical, biochemical, and immunological features of newly diagnosed adult-onset nonobese diabetic patients in China. METHODS: Newly diagnosed diabetic patients aged 18-45 years with body mass index<23 kg/m(2) were included. Excluding one mitochondrial diabetes patient, there were 102 diabetic patients enrolled in this study. Clinical and biochemical data were collected and analyzed. Radioimmunoassay was used to detect islet autoantibodies. RESULTS: Among the 102 study participants, 68.6% had type 1 diabetes (T1DM), 20.6% had type 2 diabetes (T2DM), and 10.8% had latent autoimmune diabetes in adults (LADA). About 92% of the T1DM patients presented hyperglycemic symptoms. The corresponding number in T2DM and LADA patients was 13% and 38%, respectively (P<.01). C-peptide in T2DM patients (1.4+/-0.7 ng/ml) was significantly higher than that in T1DM (0.4+/-0.3 ng/ml) and LADA (0.4+/-0.2 ng/ml) patients (P<.01). The prevalence of glutamic acid decarboxylase antibody (GADA) (64.3%) in T1DM patients was higher than that of insulin autoantibody (17.1%) (P<.05). GADA and islet cell antibody (ICA) combination was positive in 75.7% of T1DM patients. CONCLUSION: T1DM patients accounted for majority of the study sample. In addition, the clinical symptoms of T1DM patients were more severe compared with T2DM patients. GADA is the most sensitive autoantibody marker for adult-onset T1DM and LADA. GADA and ICA are the best test combination for adult-onset autoimmune diabetes. Specific types of diabetes should be in mind when diabetes presents itself with special transmission mode or with other extrapancreatic manifestations. PMID- 22226484 TI - Self-efficacy, self-management, and glycemic control in adults with type 2 diabetes mellitus. AB - OBJECTIVE: The objective was to evaluate the relationships between diabetes management self-efficacy and diabetes self-management behaviors and glycemic control. METHODS: A cross-sectional design was used. A convenience sample of 223 subjects with type 2 diabetes, >=25 years old, who sought care at the National Diabetes Center in Amman, Jordan, was enrolled. A structured interview and medical records provided the data. The instruments included a sociodemographic and clinical questionnaire, a diabetes management self-efficacy scale, and a diabetes self-management behaviors scale. Glycosylated hemoglobin was used as an index for glycemic control. The analyses are presented as proportions, means (+/ S.D.), odds ratios, and 95% confidence intervals obtained from logistic regressions. RESULTS: Diet self-efficacy and diet self-management behaviors predicted better glycemic control, whereas insulin use was a statistically significant predictor for poor glycemic control. In addition, subjects with higher self-efficacy reported better self-management behaviors in diet, exercise, blood sugar testing, and taking medication. The findings showed that more than half of the subjects did not have their diabetes under control and that only 42% had attended diabetes education programs. CONCLUSIONS: The majority of subjects did not have their diabetes controlled; their self-efficacy was low, and they had suboptimal self-management behaviors. Therefore, strategies to enhance and promote self-efficacy and self-management behaviors for patients are essential components of diabetes education programs. Furthermore, behavioral counseling and skill-building interventions are critical for the patients to become confident and be able to manage their diabetes. PMID- 22226485 TI - Trends of insulin use among US adults with type 2 diabetes: the Behavioral Risk Factor Surveillance System, 1995-2007. AB - OBJECTIVE: People with type 2 diabetes may need insulin therapy to compensate for their underlying pathogenic abnormalities and to improve glycemic control. We examined trends of insulin use among US adults aged >=40 years with type 2 diabetes. METHODS: We analyzed data from the Behavioral Risk Factor Surveillance System collected annually during 1995-2007. Insulin use was assessed by self report. Log-linear regression analyses with a robust error variance estimator were performed to estimate the prevalence, prevalence ratios, and their 95% confidence intervals. RESULTS: The overall crude and age-standardized proportion of insulin use decreased from 35% and 36% in 1995 to 23% and 22% in 2007, respectively. After adjustments for age, sex, race/ethnicity, education attainment, body mass index, and diabetes duration, the overall prevalence decreased from 33% to 22% (P<.0001 for linear trend). The decreasing rates were similar across sex (P=.23 for interaction between sex and survey year) and race/ethnicity (P=.35 for interaction between race/ethnicity and survey year). CONCLUSION: The proportion of insulin use decreased from 1995 to 2007 among US adults aged >=40 years. Continuing efforts may be needed to properly identify those who may need to initiate and maintain insulin therapy among patients with type 2 diabetes as medically indicated. PMID- 22226486 TI - The combination of carotid and lower extremity ultrasonography increases the detection of atherosclerosis in type 2 diabetes patients. AB - OBJECTIVE: To evaluate the prevalence of atherosclerosis detected by both carotid and lower extremity ultrasonography in hospitalized Chinese type 2 diabetic patients and to examine whether plaque formation in the carotid arteries could be an indicator of generalized atherosclerosis in type 2 diabetes mellitus. METHODS: Totally, 709 hospitalized Chinese type 2 diabetic patients (men 357, women 352) aged from 18 to 88 years were included. Both carotid and lower extremity atherosclerosis were assessed by Doppler ultrasound. Atherosclerosis was defined as the presence of either the carotid or lower extremity plaque in any of the above-mentioned arteries segments. The prevalence of atherosclerosis was calculated, and the risk factors associated with atherosclerosis were evaluated using binary logistic regression. RESULTS: The prevalence of atherosclerosis was 81.23% in male and 77.56% in female type 2 diabetic patients, respectively. There was no significant difference in the prevalence of atherosclerosis in patients between the sexes. The prevalence of atherosclerosis was significantly higher in the lower extremity arteries than in the carotid arteries (73.91% and 44.43%, respectively, P<.001). Atherosclerosis was significantly associated with smoking, age, duration of diabetes, systolic blood pressure, total number of white blood cells, and mean carotid and femoral intima-media thickness (IMT). CONCLUSIONS: The prevalence of atherosclerosis was very high in Chinese inpatients with type 2 diabetes. Carotid atherosclerosis could not be an indicator of generalized atherosclerosis in type 2 diabetes. The combination of carotid and lower extremity ultrasound examination can significantly improve the detection of atherosclerosis in type 2 diabetes. PMID- 22226487 TI - Thirst deficits in aged rats are reversed by dietary omega-3 fatty acid supplementation. AB - During heat waves many elderly individuals die as a consequence of dehydration. This is partially due to deficits in mechanisms controlling thirst. Reduced thirst following dipsogenic stimuli is well documented in aged humans and rodents. Low in vivo long-chain omega-3 fatty acid levels, as can occur in aging, have been shown to alter body fluid and sodium homeostasis. Therefore, the effect of dietary omega-3 fatty acid supplementation on drinking responses in aged rats was examined. Omega-3 fatty acids reversed thirst deficits in aged rats following dehydration and hypertonic stimuli; angiotensin (ANG) II induced drinking was unaffected in aged rats. Plasma atrial natriuretic peptide (ANP) and arginine vasopressin (AVP) were altered with age, but not affected by diet. Aged omega-3 fatty acid deficient animals displayed increased hypothalamic cytosolic phospholipase A(2) (cPLA(2)), cyclooxygenase (COX)-2, and prostaglandin E (PGE) synthase messenger (m)RNA expression, compared with animals that received omega-3 fatty acids. The aged low omega-3 fatty acid fed animals had significantly elevated hypothalamic PGE(2) compared with all other groups. Hypothalamic PGE(2) was negatively correlated with drinking induced by both dehydration and hypertonicity. The results indicate that PGE(2) may be the underlying mechanism of the reduced thirst observed in aging. PMID- 22226488 TI - Neuroprotection provided by dietary restriction in rats is further enhanced by reducing glucocortocoids. AB - Glucocorticoids (GC)--corticosterone (CORT) in rodents and cortisol in primates- are stress-induced hormones secreted by adrenal glands that interact with the hypothalamic pituitary axis. High levels of cortisol in humans are observed in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), as well as in diabetes, post-traumatic stress syndrome, and major depression. Experimental models of diabetes in rats and mice have demonstrated that reduction of CORT reduces learning and memory deficits and attenuates loss of neuronal viability and plasticity. In contrast to the negative associations of elevated GC levels, CORT is moderately elevated in dietary restriction (DR) paradigms which are associated with many healthy anti-aging effects including neuroprotection. We demonstrate here in rats that ablating CORT by adrenalectomy (ADX) with replenishment to relatively low levels (30% below that of controls) prior to the onset of a DR regimen (ADX-DR) followed by central administration of the neurotoxin, kainic acid (KA), significantly attenuates learning deficits in a 14-unit T-maze task. The performance of the ADX-DR KA group did not differ from a control group (CON) that did not receive KA and was fed ad libitum (AL). By contrast, the sham-operated DR (SHAM-DR KA) group, SHAM-AL KA group, and ADX-AL KA group demonstrated poorer learning behavior in this task compared to the CON group. Stereological analysis revealed equivalent DR-induced neuroprotection in the SH-DR KA and ADX-DR KA groups, as measured by cell loss in the CA2/CA3 region of the hippocampus, while substantial cell loss was observed in SH-AL and ADX-AL rats. A separate set of experiments was conducted with similar dietary and surgical treatment conditions but without KA administration to examine markers of neurotrophic activity, brain-derived neurotrophic factor (BDNF), transcriptions factors (pCREB), and chaperone proteins (HSP-70). Under these conditions, we noted elevations in both BDNF and pCREB in ADX DR rats compared to the other groups; whereas, HSP-70, was equivalently elevated in ADX-DR and SH-DR groups and was higher than observed in both SH-AL and ADX-AL groups. These results support findings that DR protects hippocampal neurons against KA-induced cellular insult. However, this neuroprotective effect was further enhanced in rats with a lower than control level of CORT resulting from ADX and maintained by exogenous CORT supplementation. Our results then suggest that DR-induced physiological elevation of GC may have negative functional consequences to DR-induced beneficial effects. These negative effects, however, can be compensated by other DR-produced cellular and molecular protective mechanisms. PMID- 22226489 TI - What predicts cognitive decline in de novo Parkinson's disease? AB - Subtle cognitive impairment can be detected in early Parkinson's disease (PD). In a consecutive series of de novo, drug-naive PD patients, we applied stepwise regression analysis to assess which clinical, neuropsychological, and functional neuroimaging (dopamine transporter [DAT] and perfusion single photon emission computed tomography [SPECT]) characteristics at baseline was predictive of cognitive decline during an average follow-up time of about 4 years. Decline both in executive (R(2) = 0.54; p = 0.0001) and visuospatial (R(2) = 0.56; p = 0.0001) functions was predicted by the couple of Unified Parkinson's Disease Rating Scale (UPDRS)-III score and caudate dopamine transporter (DAT) uptake in the less affected hemisphere (LAH). Verbal memory and language decline was predicted instead by caudate DAT uptake and brain perfusion in a posterior parieto-temporal area of the less affected hemisphere (R(2) = 0.42; p = 0.0005). No significant effect was shown for age, baseline neuropsychological scores, and levodopa equivalent dose at follow-up. The combined use of clinical structured examination and brain functional assessment by means of dual single photon emission computed tomography imaging appears as a powerful approach to predict cognitive decline in de novo PD patients. PMID- 22226490 TI - Association of IL-18 genotype with impaired glucose regulation in Korean women with polycystic ovary syndrome. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women of reproductive age. The pro-inflammatory cytokine, interleukin (IL)-18, is associated with metabolic syndrome, and elevated serum IL-18 levels are related to obesity and insulin resistance in PCOS patients. However, the role of IL-18 in the PCOS remains unclear. So we examined whether or not two functional polymorphisms in the IL-18 gene, -137G>C and +183A>G, are associated with PCOS itself or glucose intolerance in Korean women with PCOS. STUDY DESIGN: The IL-18 genotypes of 126 women with PCOS and 113 controls were determined and their serum levels of lipid and hormone profiles measured. The insulin resistance index was calculated from the glucose and insulin concentrations obtained by oral glucose tolerance tests. RESULTS: There were no statistically significant differences in the distribution of -137 G>C polymorphisms among the women classified according to presence or absence of PCOS and obesity. However, the -137G/G allele was more frequent in the PCOS+impaired glucose regulation (IGR) group than PCOS+normal glucose tolerance group (X(2)=7.637, p(Bonf)=0.022). The PCOS group with only the -137G allele had a significantly increased risk of IGR compared to the PCOS group with the -137C allele (92 vs. 8%, odds ratio=6.325, 95% confidence interval=1.403 28.519). In the PCOS patients, the mean fasting and 2-h post-prandial plasma glucose level of patients with only the -137G allele was significantly higher than those of the patients with the -137C allele (88.87 +/- 9.49 vs. 84.37 +/- 6.19, p=0.002 and 120.07 +/- 34.53 vs. 107.54 +/- 27.13, p=0.038). Only one woman was heterozygous for the +183A>G polymorphism and the other 224 subjects were homozygous for the polymorphism (A/A). CONCLUSION: The IL-18 -137G allele could play a role in the predisposition to glucose intolerance in Korean women with PCOS, and the +183G allele of IL-18 is not associated with the Korean population. PMID- 22226491 TI - Influence of surgeon volume on outcomes with aortic valve replacement. AB - BACKGROUND: A volume-outcome association has been shown for cardiovascular procedures such as coronary artery bypass grafting. The association of a volume outcome relationship for aortic valve replacement procedures, however, has not been clearly defined. We evaluated the influence of surgeon volume on operative outcomes with isolated aortic valve replacement and aortic valve replacement with concomitant coronary artery bypass grafting. METHODS: One thousand six hundred thirty-five patients were identified as having either isolated aortic valve replacement or aortic valve replacement plus coronary artery bypass grafting between January 1, 2000, and December 31, 2009. Patients were divided into three equal terciles using their Society of Thoracic Surgery Predicted Risk of Mortality scores. Data were retrieved on 14 surgeons with complete data records in our Society of Thoracic Surgery database covering a minimum 5-year period (mean, 8.9 +/- 1.5 years; median, 10 years). RESULTS: Clinically significant increases are seen in operative mortality, permanent stroke, renal failure, prolonged ventilation, and hospital and intensive care unit lengths of stay in the high-risk compared with low-risk groups. The low-risk patient group has the smallest observed to expected ratio, less than 50%, whereas in the high-risk group the ratio is greater than 1. Odds ratios demonstrate that as surgeon volume increases, outcomes improve correspondingly (ie, odds ratio <1). In low-risk patients, five of ten major complications demonstrated improved outcomes with increased surgeon volume; in medium and high-risk groups eight of ten were improved. CONCLUSIONS: Surgeon volumes have a significant influence on operative outcomes in high-risk patients undergoing aortic valve replacement or aortic valve replacement with coronary artery bypass grafting. PMID- 22226492 TI - Identifying recipients at high risk for graft failure after heart retransplantation. AB - BACKGROUND: The aim of this study was to identify recipient factors that are associated with a high risk of graft failure after heart retransplantation (HRT). METHODS: The prospectively collected United Network for Organ Sharing registry was used to identify patients undergoing HRT among 24,477 patients who had undergone cardiac transplantation between 1997 and 2009. The primary outcome was graft failure within 1 year of HRT. The impact of 35 recipient variables on the primary outcome was tested in exploratory univariate logistic regression analysis. Those factors found to be significantly associated with graft failure were entered into a multivariable logistic regression model. RESULTS: A total of 671 patients underwent HRT during the study period. Overall, 302 (45%) grafts failed after HRT at a mean follow-up of 4.3+/-3.7 years. Three recipient factors were found to be associated with 1-year graft failure in the multivariate model: older age, increasing serum creatinine, and mechanical ventilation before HRT. Moreover, each decade increase in recipient age was associated with a 20% increase in odds of 1-year graft failure (odds ratio, 1.02; 95% confidence interval, 1.01 to 1.04; p=0.005). Similarly, each 1-mg/dL increase in serum creatinine increased odds of graft failure by 58% (odds ratio, 1.58; 95% confidence interval, 1.27 to 1.97; p<0.001). Patients who were mechanically ventilated had a fourfold higher likelihood of 1-year graft failure (odds ratio, 4.32; 95% confidence interval, 2.28 to 8.18; p<0.001). CONCLUSIONS: The risk of graft failure after HRT increases with an increasing number of significant recipient risk factors, namely older age, increasing serum creatinine, and mechanical ventilation. These risk factors should serve as relative contraindications to HRT, especially when present in combination, given the higher rate of graft failure in these patients. PMID- 22226493 TI - Heparin brand is associated with postsurgical outcomes in children undergoing cardiac surgery. AB - BACKGROUND: We sought to determine whether the use of specific unfractionated heparin brands during cardiopulmonary bypass for pediatric cardiac surgery was associated with differences in postoperative outcomes, especially regarding the incidence of bleeding and thromboembolic complications. METHODS: We compared postoperative outcomes for pediatric cardiac surgeries performed with Hepalean (Organon Teknika) to those performed with PPC heparin (Pharmaceutical Partners of Canada). Differences in clinical outcomes were determined in multivariable logistic and linear regression models adjusted for patients and surgery characteristics. RESULTS: In all, 903 operations were reviewed, 289 (32%) using Hepalean and 614 (68%) using PPC heparin. Patient demographics and surgical variables were comparable between groups. In multivariable regression models, adjusted for patients' characteristics, heparin use and choice of antifibrinolytic agents, the use of PPC heparin was associated with greater use of red blood cell transfusions in the first 48 postoperative hours (estimates +1.6 mL/kg, p<0.001), increased odds of bleeding complications (odds ratio 3.8, p=0.04), thromboembolic complications (odds ratio 4.7, p=0.01), early unplanned reoperation (odds ratio 6.9, p=0.03), longer postoperative intensive care unit stay (estimate +3.2 days, p<0.001), and longer hospital stay (estimate +3.6 days, p<0.001). CONCLUSIONS: Brand of unfractionated heparin used during cardiopulmonary bypass for pediatric cardiac surgery was associated with bleeding complications and clinical outcomes. Different brands of unfractionated heparin should not be considered equivalent without proper validation in formal trials. PMID- 22226494 TI - What predicts long-term survival after heart transplantation? An analysis of 9,400 ten-year survivors. AB - BACKGROUND: This case-control study was conducted to identify factors predictive of 10-year survival after orthotopic heart transplantation (OHT). METHODS: Prospectively collected data from the United Network for Organ Sharing registry were reviewed to identify adult patients undergoing OHT between 1987 and 1999 (N=22,385) who had survived 10 years. Controls were those who had died within 10 years of OHT. Factors associated with 10-year survival were identified with multivariate logistic regression analysis. Lowess smoothing plots were used to identify linear breakpoints in continuous variables, and splines were incorporated when appropriate. RESULTS: There were 9,404 ten-year survivors (42%; mean follow-up, 14.0+/-3.0 years) and 10,373 controls (46%) with a mean survival of 3.7+/-3.3 years post-OHT. Predictors of 10-year survival in the optimal multivariate model were age younger than 55 (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.10 to 1.38; p<0.001), white race (OR, 1.35; 95% CI, 1.17 to 1.56; p<0.001), shorter ischemic time (OR, 1.11; 95% CI, 1.05 to 1.18; p<0.001), younger donor age (OR, 1.01; 95% CI, 1.01 to 1.02; p<0.001), annual center volume of 9 or more (OR, 1.31; 95% CI, 1.17 to 1.47; p<0.001), mechanical ventilation (OR, 0.53; 95% CI, 0.36 to 0.78; p=0.001), and diabetes (OR, 0.67; 95% CI, 0.57 to 0.78; p<0.001). CONCLUSIONS: Age younger than 55 years, annual center volume of 9 or more, white race, shorter ischemic time, and younger donor age improved the likelihood of 10-year survival after OHT. Mechanical ventilation and diabetes reduced this likelihood. These data should serve as a useful guide to long-term prognostication in adult OHT. PMID- 22226495 TI - [46 XX Male syndrome]. PMID- 22226496 TI - [Diabetes mellitus onset in young patient: type 1 diabetes?]. PMID- 22226497 TI - [Thyrotoxic periodic paralysis: an increasingly common complication of hyperthyroidism]. PMID- 22226498 TI - Synthesis of MCM-22 zeolite using rice husk as a silica source under varying temperature conditions. AB - In this study, rice husk, an abundant agricultural byproduct, was utilized as an alternative silica source for the synthesis of MCM-22. The zeolite with high crystalline was synthesized using a three-stage varying-temperature hydrothermal method. The prepared silica and MCM-22 were characterized by X-ray diffraction, scanning electron microscopy, and transmission electron microscopy. The results showed that the duration required for zeolite crystallization was significantly decreased under varying-temperature conditions. The MCM-22 was in the form of thin platelet-like crystals, and no amorphous material existed in the framework of the MCM-22 after calcination and ammonium exchange. Cationic brilliant red 5GN, a basic dye used in the wool and blanket factories for fiber dyeing, was selected as the adsorptive to study the adsorption performance of the MCM-22. Adsorption experiments indicated that the maximum extent of adsorption was obtained at pH of 10, contact time of 60 min, and MCM-22 dose of 1.0 g/L. The adsorption kinetic has been described by first-order and pseudo-second-order models. It was observed that the rate of dye adsorption followed pseudo-second order model. PMID- 22226499 TI - Efficiency of layered double hydroxide nanoparticle-mediated delivery of siRNA is determined by nucleotide sequence. AB - In this paper, we report the novel finding that the cellular delivery efficiency of siRNAs or their mimic double-stranded (ds)DNA using layered double hydroxide (LDH) nanoparticles is dependent upon the nucleotide sequence. Efficacy of LDH mediated delivery of four different siRNAs into cortical neurons and NIH 3T3 cells was found to vary widely (from 6 to 80%, and 2-11%, respectively). Our investigation into the formation of dsDNA-LDH complexes through monitoring the dsDNA:LDH mass ratio at the point of zero charge (PZC) indicated that the degree of intercalation of the individual dsDNA sequences into the LDH nanoparticles varied significantly. The dsDNA:LDH mass ratio at the PZC was found to be dependent on the nucleotide sequence. We further observed that PZC for each sequence was positively related to the extent of LDH-mediated internalization of the equivalent siRNA into neurons and fibroblasts. This novel finding therefore suggests that the mass ratio at the PZC is a useful predictive tool with which to assess the intercalation efficiency of selected siRNA sequences into the LDH interlayer and subsequent internalization into the cell cytoplasm. This finding will allow a more controlled approach to the design of suitable siRNA sequences for LDH-mediated siRNA delivery. PMID- 22226500 TI - Electrokinetic transport through the nanopores in cell membrane during electroporation. AB - In electroporation, applied electric field creates hydrophilic nanopores in a cell membrane that can serve as a pathway for inserting biological samples to the cell. It is highly desirable to understand the ionic transfer and fluid flow through the nanopores in order to control and improve the cell transfection. Because of submicron dimensions, conventional theories of electrokinetics may lose their applicability in such nanopores. In the current study, the Poisson Nernst-Planck equations along with modified Navier-Stokes equations and the continuity equation are solved in order to find electric potential, fluid flow, and ionic concentration through the nanopores. The results show that the electric potential, velocity field, and ionic concentration vary with the size of the nanopores and are different through the nanopores located at the front and backside of the cell membrane. However, on a given side of the cell membrane, angular position of nanopores has fewer influences on liquid flow and ionic transfer. By increasing the radius of the nanopores, the averaged velocity and ionic concentration through the nanopores are increased. It is also shown that, in the presence of electric pulse, electrokinetic effects (electroosmosis and electrophoresis) have significant influences on ionic mass transfer through the nanopores, while the effect of diffusion on ionic mass flux is negligible in comparison with electrokinetics. Increasing the radius of the nanopores intensifies the effect of convection (electroosmosis) in comparison with electrophoresis on ionic flux. PMID- 22226501 TI - Investigation of the physicochemical aspects from natural kaolin to Al-MCM-41 mesoporous materials. AB - Aluminum-containing hexagonally ordered mesoporous silica Al-MCM-41 was synthesized by hydrothermal treatment of leached products produced by pre grinding and subsequent acid leaching of natural kaolin, without addition of silica or aluminum regents. The resulting Al-MCM-41 had a high surface area of 1041 m(2)/g, a pore volume of 0.97 mL/g, and an average pore diameter of 3.7 nm with narrow pore size distribution centered at 2.7 nm. During the synthesis process of Al-MCM-41 from natural kaolin, the evolutions of chemical environments for Si and Al atoms should be emphasized. Wide angle X-ray diffraction (WAXRD), high-resolution transmission electron micrographs (HRTEMs), solid-state magic angle-spinning nuclear magnetic resonance (MAS NMR), Fourier transform infrared spectroscopy (FT-IR) were used to trace the variations of chemical structures. Pretreatment of grinding and subsequent acid leaching acted as an important role in the whole synthesis process. NMR spectroscopy showed that Q(3) structure (Si(SiO)(3)(OH)), condensed Q(4) framework structure (Si(SiO)(4)), also the octahedral and tetrahedral Al existed in the leached sample and Al-MCM-41, with higher chemical contents of Q(4) structure and the octahedral Al in final product Al-MCM-41 than those in the leached sample. A possible mechanism for the formation of Al-MCM-41 from natural kaolin was suggested. PMID- 22226502 TI - Vitamin B12 supplementation improves heart rate variability in healthy elderly Indian subjects. AB - While vitamin B(12) deficiency is global, data in elderly Indians are lacking. The problem in India is likely to be higher because of vegetarianism and malabsorption related to gastro-intestinal parasites. Autonomic dysfunction is known to occur much earlier in pernicious anemia. However, what is not known is whether these changes are reflected in healthy elderly individuals. This study assessed cardiac sympathetic and parasympathetic activity using heart rate variability (HRV) in healthy elderly individuals of low and high vitamin B(12) status and evaluated the effect of vitamin B(12) supplementation in those with low vitamin B(12) status. 140 elderly subjects aged >=60 years were screened; 47 healthy subjects were assessed. They underwent blood sampling, anthropometry, HRV and nerve conduction assessment. Subjects were classified based on vitamin B(12) level (148 pmol/L) into deplete vitamin B(12) and replete vitamin B(12) groups. Elderly subjects with low vitamin B(12) status underwent cyanocobalamin supplementation (100 MUg) for 3 months. Low frequency (LF) HRV in absolute units was significantly lower in the low vitamin B(12) group. Following supplementation, LF HRV in absolute units and total power rose significantly as compared to pre-supplementation values for the entire supplemented group. In conclusion, elderly with lower vitamin B(12) status have reduced low frequency HRV suggestive of sympathetic involvement. Supplementation with vitamin B(12) for 3 months results in a significant increase in low frequency HRV to values comparable with unsupplemented, but vitamin B(12) replete elderly. PMID- 22226503 TI - Calbindin-D28k immunoreactivity in sympathetic ganglionic neurons during development. AB - Expression of CB in the sympathetic ganglia was investigated by immunohistochemistry. The distribution of CB immunoreactivity was studied in the superior cervical ganglion (SCG), stellate ganglion (SG) and celiac ganglion (CG) from rats and cats of different ages (newborn, 10-day-old, 20-day-old, 30-day old, two-month-old, six-month-old). We observed that the percentage of CB immunoreactive (IR) neurons decreased during early postnatal development in rats and cats. In all studied ganglia of both species, the percentage of CB-IR neurons was high in newborn and 10-day-old animals and significantly decreased up to 30 days of life. In rats of all ages, the largest percentage of CB-IR neurons was observed in the SG compared to the SCG and CG. In the cat sympathetic ganglia, the number of CB-IR neurons decreased more rapidly during the first two months of life, and only scattered CB-IR neurons were found in the sympathetic ganglia of two-month-old and six-month-old cats. In cats, the highest percentage of CB-IR neurons was observed in the SG, while the lowest percentage was found in the CG. The difference in size between CB+ and CB- neurons equally changed during development. Finally, the changes in the size and percentages of CB-IR neurons were complete in rats at the first month of life, and in cats at the end of the second month. PMID- 22226504 TI - Changes in the distribution of calbindin D28-k, parvalbumin, and calretinin in the hippocampus of the circling mouse. AB - The circling (cir) mouse strain, a murine model of deafness caused by a spontaneous mutation, exhibits characteristic behaviors of circling and hyperactivity. In an induced-noise paradigm, cir mice display a significant loss in their spatial orientation abilities, and this has been suggested to be due at least in part to changes in calcium homeostasis. Auditory information is transferred from the cochlear nucleus to the hippocampus, where it is processed to modulate motor and sensory activity. Such a pathway could be affected at the cellular level by alterations in neurotransmission, including alterations that involve Ca(2+). However, there have been no studies in a hearing deficit model examining the concomitant molecular alterations in the hippocampus. Thus, in the present study we used immunohistochemistry to compare the distribution of the calcium-binding proteins (CaBPs) calbindin D-28k, parvalbumin, and calretinin in the hippocampi of heterozygous (+/cir), homozygous (cir/cir), and wild-type (+/+) mice. The expression of the CaBPs in various hippocampal subfields appeared to be significantly lower in cir mice (+/- and -/-) than in +/+ mice. Such a decrease in CaBP expression in cir/cir mice would alter calcium homeostasis, which in turn could affect the connection of the tri-synaptic circuit of the hippocampus as well as the cortical region. A decrease in CaBPs and the probable resultant glutamate-mediated excitability could contribute to the functional changes that lead to the characteristic behavioral features of cir mice. PMID- 22226505 TI - CCL2 binding is CCR2 independent in primary adult human astrocytes. AB - Chemokines are low relative molecular mass proteins, which have chemoattractant actions on many cell types. The chemokine, CCL2, has been shown to play a major role in the recruitment of monocytes in central nervous system (CNS) lesions in multiple sclerosis (MS). Since resident astrocytes constitute a major source of chemokine synthesis including CCL2, we were interested to assess the regulation of CCL2 by astrocytes. We showed that CCL2 bound to the cell surface of astrocytes and binding was not modulated by inflammatory conditions. However, CCR2 protein was not detected nor was activation of the classical CCR2 downstream signaling pathways. Recent studies have shown that non-signaling decoy chemokine receptors bind and modulate the expression of chemokines at site of inflammation. Here, we show that the D6 chemokine decoy receptor is constitutively expressed by primary human adult astrocytes at both mRNA and protein level. In addition, CCL3, which binds to D6, but not CCL19, which does not bind to D6, displaced CCL2 binding to astrocytes; indicating that CCL2 may bind to this cell type via the D6 receptor. Our results suggest that CCL2 binding to primary adult human astrocytes is CCR2-independent and is likely to be mediated via the D6 decoy chemokine receptor. Therefore we propose that astrocytes are implicated in both the establishment of chemokine gradients for the migration of leukocytes into and within the CNS and in the regulation of CCL2 levels at inflammatory sites in the CNS. PMID- 22226506 TI - Luteolin enhances cholinergic activities in PC12 cells through ERK1/2 and PI3K/Akt pathways. AB - Luteolin, a 3', 4', 5, 7-tetrahydroxyflavone, is an active compound in Rosmarinus officinalis (Lamiacea), and has been reported to exert several benefits in neuronal cells. However cholinergic-induced activities of luteolin still remain unknown. Neuronal differentiation encompasses an elaborate developmental program which plays a key role in the development of the nervous system. The advent of several cell lines, like PC12 cells, able to differentiate in culture proved to be the turning point for gaining and understanding of molecular neuroscience. In this work, we investigated the ability of luteolin to induce PC12 cell differentiation and its effect on cholinergic activities. Our findings showed that luteolin treatment significantly induced neurite outgrowth extension, enhanced acetylcholinesterase (AChE) activity, known as neuronal differentiation marker, and increased the level of total choline and acetylcholine in PC12 cells. In addition, luteolin persistently, activated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt; while the addition of pharmacological MEK/ERK1/2 inhibitor (U0126) and PI3k/Akt inhibitor (LY294002) attenuated luteolin-induced AChE activity and neurite outgrowth in PC12 cells. The above findings suggest that luteolin induces neurite outgrowth and enhanced cholinergic activities, at least in part, through the activation of ERK1/2 and Akt signaling. PMID- 22226507 TI - Role of medullary GABA signal transduction on parasympathetic reflex vasodilatation in the lower lip. AB - In the orofacial area, noxious stimulation of the orofacial structure in the trigeminal region evokes parasympathetic reflex vasodilatation, which occurs via the trigeminal spinal nucleus (Vsp) and the inferior/superior salivatory nucleus (ISN/SSN). However, the neurotransmitter involved in the inhibitory synaptic inputs within these nuclei has never been described. This parasympathetic reflex vasodilatation is suppressed by GABAergic action of volatile anesthetics, such as isoflurane, sevoflurane, and halothane, suggesting that medullary GABAergic mechanism exerts its inhibitory effect on the parasympathetic reflex via an activation of GABA receptors. The aim of the present study was to determine the role of GABA(A) and GABA(B) receptors in the Vsp and the ISN in regulating the lingual nerve (LN)-evoked parasympathetic reflex vasodilatation in the lower lip. Under urethane anesthesia (1g/kg), change in lower lip blood flow elicited by electrical stimulation of the LN was recorded in cervically vago-sympathectomized rats. Microinjection of GABA (10 MUM; 0.3 MUl/site) into the Vsp or the ISN significantly and reversibly attenuated the LN-evoked parasympathetic reflex vasodilatation. Microinjection of the GABA(A) receptor-selective agonist muscimol (100 MUM; 0.3 MUl/site) or the GABA(B) receptor-selective agonist baclofen (100 MUM; 0.3 MUl/site) into the Vsp or the ISN significantly and irreversibly reduced this reflex vasodilatation, and these effects were attenuated by pretreatment with microinjection of each receptor-selective antagonists [GABA(A) receptor selective antagonist bicuculline methiodide (1mM; 0.3 MUl/site) or GABA(B) receptor selective antagonist CGP-35348 (1mM; 0.3 MUl/site)] into the Vsp or the ISN. Microinjection of these antagonists alone into the Vsp or the ISN had no significant effect on this reflex vasodilatation. In addition, microinjection (0.3 MUl/site) of the mixture of muscimol (100 MUM) and baclofen (100 MUM) into the Vsp or the ISN also significantly reduced this reflex vasodilatation. These results suggest that medullary GABA signal transduction inhibits the parasympathetic reflex vasodilatation in the rat lower lip via GABA(A) and GABA(B) receptors in the Vsp and the ISN. PMID- 22226508 TI - Removal of estrogens in municipal wastewater treatment plants: a Chinese perspective. AB - Great efforts have been made in China to retrofit and upgrade the existing municipal wastewater treatment plants (WWTPs) for enhanced removal of organic substrates and in particular nutrients. However, the removal of trace recalcitrant or hazardous organic chemicals, e.g. steroid estrogens, one group of typical endocrine disrupting chemicals, has long been overlooked. The extensive investigations on estrogen removal rates in global and Chinese WWTPs and the estrogen biodegradation kinetics results in batch laboratory experiments are reviewed in this study. The effects of estrogen initial concentration and nitrifying activated sludge are highlighted. Challenges existing in current estrogen studies are pointed out, which are relevant for researches on fate and behavior of similar down-the-drain chemicals in both Chinese and global WWTPs. PMID- 22226509 TI - Inertia effects on characterization of dynamic response of brain tissue. AB - Modeling and simulation of traumatic brain injury (TBI) resulted from collision or blast loading requires characterization of mechanical response over a wide range of loading rates under valid testing conditions. In this study, mechanical response of fresh bovine brain tissue was studied using the two modified Kolsky bar techniques. Radial deformation behavior of annular specimens, which are typically used to characterize the dynamic uniaxial compressive response of biological tissues, was examined using a modified Kolsky bar and a high speed camera to collect images while the specimen deforms at an axial strain rate of 2000s(-1). The high-speed images revealed inhomogeneous specimen deformation possibly brought about by radial inertia and causing a multi-axial stress state. To acquire valid stress-strain results that can be used to produce constitutive behavior of the soft materials, a novel torsion technique was developed to obtain pure shear response at dynamic loading rates. Experimental results show clear differences in the material response using the two methods. These results indicate that the previously demonstrated annular specimen geometry aimed at reducing inertia induced stress components for high rate soft materials uniaxial compressive testing may still possess a significant component of radial inertia induced radial stress which consequently caused the observed inhomogeneous deformation in brain tissue test samples. PMID- 22226510 TI - Nuclear localization of matrix metalloproteinases. AB - Matrix metalloproteinases (MMPs) were originally identified as matrixin proteases that act in the extracellular matrix. Recent works have uncovered nontraditional roles for MMPs in the extracellular space as well as in the cytosol and nucleus. There is strong evidence that subspecialized and compartmentalized matrixins participate in many physiological and pathological cellular processes, in which they can act as both degradative and regulatory proteases. In this review, we discuss the transcriptional and translational control of matrixin expression, their regulation of intracellular sorting, and the structural basis of activation and inhibition. In particular, we highlight the emerging roles of various matrixin forms in diseases. The activity of matrix metalloproteinases is regulated at several levels, including enzyme activation, inhibition, complex formation and compartmentalization. Most MMPs are secreted and have their function in the extracellular environment. MMPs are also found inside cells, both in the nucleus, cytosol and organelles. The role of intracellular located MMPs is still poorly understood, although recent studies have unraveled some of their functions. The localization, activation and activity of MMPs are regulated by their interactions with other proteins, proteoglycan core proteins and / or their glycosaminoglycan chains, as well as other molecules. Complexes formed between MMPs and various molecules may also include interactions with noncatalytic sites. Such exosites are regions involved in substrate processing, localized outside the active site, and are potential binding sites of specific MMP inhibitors. Knowledge about regulation of MMP activity is essential for understanding various physiological processes and pathogenesis of diseases, as well as for the development of new MMP targeting drugs. PMID- 22226511 TI - Body mass index correlates with waist circumference in school aged Italian children. AB - This study demonstrates the existence of a linear correlation between Body Mass Index (BMI) and waist circumference in Italian school aged children and suggests an indirect method (from weight and height) to estimate waist circumference, whose increase may be indicative for the diagnosis of the metabolic syndrome. PMID- 22226512 TI - Diagnostic value of CT and MRI in the detection of paratracheal lymph node metastasis. AB - The presence of paratracheal lymph node (PTLN) metastasis harbours a worse prognosis. Uniform guidelines on PTLN dissection are missing, mainly because of the value of diagnostic techniques for the detection of PTLN metastasis are not clear. This study is performed to identify CT and MRI criteria for detection of PTLN metastasis. 149 patients who underwent laryngectomy and a PTLN dissection between 1990 and 2010 were included. Patient, tumour, treatment and follow up data were collected. On computed tomography (CT) and magnetic resonance imaging (MRI) different test criteria were examined. Considering PTLN with a maximal axial diameter of >=5 mm as positive predicts PTLN metastasis best: sensitivity and specificity 70% and 36% (CT) and 50% and 71% (MRI). Other risk factors for PTLN metastasis were subglottic extension of the tumour (sensitivity is 45%) and clinical positive neck status (sensitivity is 59%). When at least one of these risk factors was present and the status of PTLN was considered positive, a high sensitivity (90% for CT and 100% for MRI) and a lower specificity (19% for CT and 32% for MRI) was found. If at least one of the risk factors such as subglottic extension, clinical positive neck and PTLN with a maximal axial diameter of >=5 mm is present, sensitivity and negative predictive value for the prediction of PTLN metastasis are high, but the specificity is low. These risk factors can be used to select laryngectomy patients for PTLN dissection. PMID- 22226514 TI - Escape behaviors in insects. AB - Escape behaviors are, by necessity, fast and robust, making them excellent systems with which to study the neural basis of behavior. This is especially true in insects, which have comparatively tractable nervous systems and members who are amenable to manipulation with genetic tools. Recent technical developments in high-speed video reveal that, despite their short duration, insect escape behaviors are more complex than previously appreciated. For example, before initiating an escape jump, a fly performs sophisticated posture and stimulus dependent preparatory leg movements that enable it to jump away from a looming threat. This newfound flexibility raises the question of how the nervous system generates a behavior that is both rapid and flexible. Recordings from the cricket nervous system suggest that synchrony between the activity of specific interneuron pairs may provide a rapid cue for the cricket to detect the direction of an approaching predator and thus which direction it should run. Technical advances make possible wireless recording from neurons while locusts escape from a looming threat, enabling, for the first time, a direct correlation between the activity of multiple neurons and the time-course of an insect escape behavior. PMID- 22226513 TI - The neuroethology of C. elegans escape. AB - Escape behaviors are crucial to survive predator encounters. Touch to the head of Caenorhabditis elegans induces an escape response where the animal rapidly backs away from the stimulus and suppresses foraging head movements. The coordination of head and body movements facilitates escape from predacious fungi that cohabitate with nematodes in organic debris. An appreciation of the natural habitat of laboratory organisms, like C. elegans, enables a comprehensive neuroethological analysis of behavior. In this review we discuss the neuronal mechanisms and the ecological significance of the C. elegans touch response. PMID- 22226515 TI - Audiological signs in pediatric cases with dehiscence of the bony labyrinth caused by a high jugular bulb. AB - Clinical findings were assessed in three pediatric cases of dehiscence of the bony labyrinth caused by a high jugular bulb (HJB). Two children had two dehiscent lesions, which included posterior semicircular canal dehiscence (PSCD) and vestibular aqueduct dehiscence (VAD). One child had VAD alone. Two subjects with PSCD, but not with VAD alone, had mixed hearing loss and showed wave motion of the baseline on tympanometry and acoustic reflex testing, and a reduced response on otoacoustic emission. These findings may reflect jugular venous pulsations transmitted through the PSC and represent characteristics of cases with PSCD caused by HJB. PMID- 22226516 TI - Social marginalization reduces use of ENT physicians in primary care. AB - OBJECTIVE: The aim of this study was to explore the association between social marginalization of the mothers and their children's use of the healthcare system and ear-nose-throat (ENT) physicians in the year 2009 in a region of Denmark. METHODS: A regional register-based cross-sectional study of use of healthcare services among children (n=10,232) of marginalized mothers and children (n=101,582) of non-marginalized mothers in the North Denmark Region. Social marginalization was defined as having received public social benefits for more than 80% of the year. RESULTS: Children with a marginalized mother had more chronic medical diagnoses (OR=1.22, 95% confidence interval 1.17-1.28), they had more frequently been in contact with their general practitioner during the year, and they used the healthcare system more often than children of non-marginalized mothers, except in the case of ENT specialists (OR=0.90, 0.85-0.95), and they had more seldom tympanostomy tubes inserted (OR=0.75, 0.66-0.87). The distance between ENT-clinic and place of residence of the patients had only a small effect on the use of ENT-physician, and only significant in the non-marginalized. CONCLUSIONS: Children of marginalized mothers used the healthcare system more than other children, except in case of ENT-physicians. They had fewer ENT consultations and had less frequently inserted tympanostomy tubes when they attended the surgery. PMID- 22226518 TI - Adjuvant therapy for gastric cancer after D2 gastrectomy. PMID- 22226517 TI - Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. AB - BACKGROUND: D2 gastrectomy is recommended in US and European guidelines, and is preferred in east Asia, for patients with resectable gastric cancer. Adjuvant chemotherapy improves patient outcomes after surgery, but the benefits after a D2 resection have not been extensively investigated in large-scale trials. We investigated the effect on disease-free survival of adjuvant chemotherapy with capecitabine plus oxaliplatin after D2 gastrectomy compared with D2 gastrectomy only in patients with stage II-IIIB gastric cancer. METHODS: The capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) study was an open-label, parallel-group, phase 3, randomised controlled trial undertaken in 37 centres in South Korea, China, and Taiwan. Patients with stage II-IIIB gastric cancer who had had curative D2 gastrectomy were randomly assigned to receive adjuvant chemotherapy of eight 3-week cycles of oral capecitabine (1000 mg/m(2) twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m(2) on day 1 of each cycle) for 6 months or surgery only. Block randomisation was done by a central interactive computerised system, stratified by country and disease stage. Patients, and investigators giving interventions, assessing outcomes, and analysing data were not masked. The primary endpoint was 3 year disease-free survival, analysed by intention to treat. This study reports a prespecified interim efficacy analysis, after which the trial was stopped after a recommendation by the data monitoring committee. The trial is registered at ClinicalTrials.gov (NCT00411229). FINDINGS: 1035 patients were randomised (520 to receive chemotherapy and surgery, 515 surgery only). Median follow-up was 34.2 months (25.4-41.7) in the chemotherapy and surgery group and 34.3 months (25.6 41.9) in the surgery only group. 3 year disease-free survival was 74% (95% CI 69 79) in the chemotherapy and surgery group and 59% (53-64) in the surgery only group (hazard ratio 0.56, 95% CI 0.44-0.72; p<0.0001). Grade 3 or 4 adverse events were reported in 279 of 496 patients (56%) in the chemotherapy and surgery group and in 30 of 478 patients (6%) in the surgery only group. The most common adverse events in the intervention group were nausea (n=326), neutropenia (n=300), and decreased appetite (n=294). INTERPRETATION: Adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a treatment option for patients with operable gastric cancer. FUNDING: F Hoffmann La Roche and Sanofi-Aventis. PMID- 22226519 TI - High-resolution imaging of cellular processes in Caenorhabditis elegans. AB - Differential interference contrast (DIC) imaging of Caenorhabditis elegans embryogenesis led to a Nobel Prize in Physiology or Medicine (Sulston et al., 1983) as did the first use of green fluorescent protein (GFP) in a transgenic C. elegans (Chalfie et al., 1994). Given that C. elegans is free living, does not require exceptional environmental control, and is optically clear, live imaging is a powerful tool in for this model system. Combining genetics with high resolution imaging has continued to make important contributions to many fields. In this chapter, we discuss how certain aspects of high-resolution microscopy are implemented. This is not an exhaustive review of microscopy; it is meant to be a helpful guide and point of reference for some basic concepts in imaging. While these concepts are largely true for all biological imaging, they are chosen as particularly important for C. elegans. PMID- 22226520 TI - Immunofluorescence microscopy. AB - Immunofluorescence microscopy is a powerful technique that is widely used by researchers to assess both the localization and endogenous expression levels of their favorite proteins. The application of this approach to C. elegans, however, requires special methods to overcome the diffusion barrier of a dense, collagen based outer cuticle. This chapter outlines several alternative fixation and permeabilization strategies for overcoming this problem and for producing robust immunohistochemical staining of both whole animals and freeze-fractured samples. In addition, we provide an accounting of widely used antibody reagents available to the research community. We also describe several approaches aimed at reducing non-specific background often associated with immunohistochemical studies. Finally, we discuss a variety of approaches to raise antisera directed against C. elegans antigens. PMID- 22226521 TI - Fluorescent protein methods: strategies and applications. AB - Fluorescent proteins such as the "green fluorescent protein" (GFP) are popular tools in Caenorhabditis elegans, because as genetically encoded markers they are easy to introduce. Furthermore, they can be used in a living animal without the need for extensive sample preparation, because C. elegans is transparent and small enough so that entire animals can be imaged directly. Consequently, fluorescent proteins have emerged as the method of choice to study gene expression in C. elegans and reporter constructs for thousands of genes are currently available. When fused to a protein of interest, fluorescent proteins allow the imaging of its subcellular localization in vivo, offering a powerful alternative to antibody staining techniques. Fluorescent proteins can be employed to label cellular and subcellular structures and as indicators for cell physiological parameters like calcium concentration. Genetic screens relying on fluorescent proteins to visualize anatomical structures and recent progress in automation techniques have tremendously expanded their potential uses. This chapter presents tools and techniques related to the use of fluorescent proteins, discusses their advantages and shortcomings, and provides practical considerations for various applications. PMID- 22226522 TI - Modern electron microscopy methods for C. elegans. AB - From its inception as a model organism 40 years ago, Caenorhabditis elegans was chosen in part for its suitability for study in serial thin sections by electron microscopy. Recent improvements in electron microscopy technology are making this pursuit more reliable and more powerful. In this chapter, we highlight new methods in specimen preparation, imaging, and data analysis. Accurate three dimensional information can now be obtained for the whole animal at all stages, down to the level of individual organelles and the cytoskeleton. PMID- 22226523 TI - Culture and manipulation of embryonic cells. AB - The direct manipulation of embryonic cells is an important tool for addressing key questions in cell and developmental biology. C. elegans is relatively unique among genetic model systems in being amenable to manipulation of embryonic cells. Embryonic cell manipulation has allowed the identification of cell interactions by direct means, and it has been an important technique for dissecting mechanisms by which cell fates are specified, cell divisions are oriented, and morphogenesis is accomplished. Here, we present detailed methods for isolating, manipulating and culturing embryonic cells of C. elegans. PMID- 22226525 TI - Methods in cell biology: analysis of cell polarity in C. elegans embryos. AB - Cell polarity is a fundamental principle guiding development. Early C. elegans embryos contain a diversity of polarized cell types, ranging from asymmetrically dividing stem cells to a polarized epithelium. Over the past two decades, work using C. elegans embryos has led to mechanistic understandings of many aspects of cell polarity establishment, maintenance and propagation. Here we provide basic methods for researchers interested in using C. elegans embryos to study cell polarity, emphasizing the amenability of C. elegans to quantitative molecular analysis. PMID- 22226524 TI - Laser microsurgery in Caenorhabditis elegans. AB - Laser killing of cell nuclei has long been a powerful means of examining the roles of individual cells in C. elegans. Advances in genetics, laser technology, and imaging have further expanded the capabilities and usefulness of laser surgery. Here, we review the implementation and application of currently used methods for target edoptical disruption in C. elegans. PMID- 22226526 TI - Analysis of membrane-bound organelles. AB - This chapter describes methods for studying membrane traffic and organelle biogenesis in Caenorhabditis elegans. These processes have traditionally been studied with yeast or mammalian cells, but C. elegans is emerging as an attractive alternative model system for cell biologists. C. elegans is well known for the ease of manipulation through classic and molecular genetic techniques. In addition, C. elegans is transparent, so fluorescent proteins can be observed in live animals. These properties have aided the development of functional assays for tracking cell biological processes in situ. Localization results obtained with fluorescent proteins can be validated with immunofluorescence and with biochemical methods, such as subcellular fractionation, adapted from methods developed for other organisms. C. elegans thus combines powerful genetics with a range of cell biological techniques to study subcellular processes in a tractable multicellular organism. PMID- 22226527 TI - C. elegans cell cycle analysis. AB - Caenorhabditis elegans is an important system for the study of cell cycle regulation in the context of animal development. One of the most powerful features of C. elegans is the invariant cell lineage in which somatic cells initiate cell division at specific times within the developmental program. The cell lineage is fully known and provides the foundation for the analysis of cell cycle progression at single-cell resolution in a multicellular organism. In this chapter, we describe the different types of cell cycles observed in C. elegans, and provide methods and reagents for the analysis of cell cycle progression as well as specific cell cycle phases. We also provide strategies for the analysis and proper interpretation of cell cycle and checkpoint mutants. PMID- 22226528 TI - Methods for studying programmed cell death in C. elegans. AB - Programmed cell death or apoptosis is a common cell fate during the development of multicellular organisms, including C. elegans. C. elegans has been proven to be an excellent model organism for studies of programmed cell death. Its transparency and the knowledge of its cell lineage, including its invariant life vs. death fate of all cells, allow programmed cell death to be studied in vivo at single cell resolution in a way that no other systems can currently match. This advantage, in combination with sophisticated genetic manipulations, has facilitated the identification and characterization of many genes important for different aspects of programmed cell death. In addition to the ability to observe life and death of cells directly under Nomarski optics or by using fluorescent transgene products in living animals, several methods have been developed to study other aspects of apoptosis. For example, fragmentation of chromosomal DNA and the identity of phagocytic cells that engulf cell corpses can be analyzed using specific staining methods. Proteases and nucleases involved in cell killing and DNA degradation, respectively, can be studied using specific biochemical assays. These cell death assays have been instrumental in elucidating the functions of cell death-related genes and the mechanisms by which they affect cell death. In this chapter, we will review and describe these methods in detail. PMID- 22226529 TI - Methods for studying the DNA damage response in the Caenorhabdatis elegans germ line. AB - In response to genotoxic insults, cells activate DNA damage response pathways that either stimulate transient cell cycle arrest and DNA repair or induce apoptosis. The Caenorhabditis elegans germ line is now well established as a model system to study these processes in a genetically tractable, multicellular organism. Upon treatment with genotoxic agents, premeiotic C. elegans germ cells transiently halt cell cycle progression, whereas meiotic prophase germ cells in the late-pachytene stage undergo apoptosis. Further, accumulation of unrepaired meiotic recombination intermediates can also lead to apoptosis of affected pachytene cells. DNA damage-induced cell death requires key components of the evolutionarily conserved apoptotic machinery. Moreover, both cell cycle arrest and pachytene apoptosis responses depend on conserved DNA damage checkpoint proteins. Genetics- and genomics-based approaches that have demonstrated roles for conserved checkpoint proteins have also begun to uncover novel components of these response pathways. In this chapter, we briefly review the C. elegans DNA damage response field, discuss in detail methods currently used to assay DNA damage responses in C. elegans, and describe the development of new experimental tools that will facilitate a more comprehensive understanding of the DNA damage response. PMID- 22226530 TI - Analysis of aging in Caenorhabditis elegans. AB - This chapter is dedicated to the study of aging in Caenorhabditis elegans (C. elegans). The assays are divided into two sections. In the first section, we describe detailed protocols for performing life span analysis in solid and liquid medium. In the second section, we describe various assays for measuring age related changes. Our laboratory has been involved in several fruitful collaborations with non-C. elegans researchers keen on testing a role for their favorite gene in modulating aging (Carrano et al., 2009; Dong et al., 2007; Raices et al., 2008; Wolff et al., 2006). But even with the guidance of trained worm biologists, this undertaking can be daunting. We hope that this chapter will serve as a worthy compendium for those researchers who may or may not have immediate access to laboratories studying C. elegans. PMID- 22226531 TI - Analyses of C. elegans fat metabolic pathways. AB - In Caenorhabdatis elegans as in other animals, fat regulation reflects the outcome of behavioral, physiological, and metabolic processes. The amenability of C. elegans to experimentation has led to utilization of this organism for elucidating the complex homeostatic mechanisms that underlie energy balance in intact organisms. The optical advantages of C. elegans further offer the possibility of studying cell biological mechanisms of fat uptake, transport, storage, and utilization, perhaps in real time. Here, we discuss the rationale as well as advantages and potential pitfalls of methods used thus far to study metabolism and fat regulation, specifically triglyceride metabolism, in C. elegans. We provide detailed methods for visualization of fat depots in fixed animals using histochemical stains and in live animals by vital dyes. Protocols are provided and discussed for chloroform-based extraction of total lipids from C. elegans homogenates used to assess total triglyceride or phospholipid content by methods such as thin-layer chromatography or used to obtain fatty acid profiles by methods such as gas chromatography/mass spectrometry. Additionally, protocols are provided for the determination of rates of intestinal fatty acid uptake and fatty acid breakdown by beta-oxidation. Finally, we discuss methods for determining rates of de novo fat synthesis and Raman scattering approaches that have recently been employed to investigate C. elegans lipids without reliance on invasive techniques. As the C. elegans fat field is relatively new, we anticipate that the indicated methods will likely be improved upon and expanded as additional researchers enter this field. PMID- 22226532 TI - Electrophysiological methods for Caenorhabditis elegans neurobiology. AB - Patch-clamp electrophysiology is a technique of choice for the biophysical analysis of the function of nerve, muscle, and synapse in Caenorhabditis elegans nematodes. Considerable technical progress has been made in C. elegans electrophysiology in the decade since the initial publication of this technique. Today, most, if not all, electrophysiological studies that can be done in larger animal preparations can also be done in C. elegans. This chapter has two main goals. The first is to present to a broad audience the many techniques available for patch-clamp analysis of neurons, muscles, and synapses in C. elegans. The second is to provide a methodological introduction to the techniques for patch clamping C. elegans neurons and body-wall muscles in vivo, including emerging methods for optogenetic stimulation coupled with postsynaptic recording. We also present samples of the cell-intrinsic and postsynaptic ionic currents that can be measured in C. elegans nerves and muscles. PMID- 22226533 TI - [The future of the Spanish Journal of Geriatrics and Gerontology forever attached to the Spanish Geriatrics and Gerontology Society]. PMID- 22226535 TI - Can sucralfate be effective to protect on peritoneal membrane in patients receiving peritoneal dialysis treatment? PMID- 22226536 TI - Current concepts review: revision rotator cuff repair. AB - Failed rotator cuff repair may be caused by surgical complications, diagnostic errors, technical errors, failure to heal, and traumatic failure. Revision rotator cuff repair is made technically more difficult by poor tissue quality, tissue adhesions, and retained suture and suture anchor material. Historically, open revision rotator cuff repair yields inferior results compared with primary rotator cuff repair; however, more recent studies show 52% to 69% satisfactory results in small-sized or medium-sized tears. Arthroscopic revision rotator cuff repair yields greater than 60% good or excellent results. Poor tissue quality, detachment of the deltoid origin, and multiple previous surgeries are risk factors for poor results in revision rotator cuff repair. PMID- 22226537 TI - Three-year outcome of transvaginal mesh repair for the treatment of pelvic organ prolapse. AB - OBJECTIVE: To evaluate the clinical and urodynamic outcomes of transvaginal mesh repair (TVM) for the treatment of pelvic organ prolapse (POP). STUDY DESIGN: One hundred and twenty-four women with POP stage II to IV were scheduled for a TVM procedure. Preoperative and postoperative assessments included pelvic examination, urodynamic testing, and a personal interview about urinary symptoms using a standard questionnaire. RESULTS: We found a significant improvement at points Aa, Ba, C, Ap, and Bp (P<0.001) except for total vaginal length (P=0.08), and the overall success rate was 93.5% (116/124). Various urinary symptoms improved significantly following TVM (P<0.01). In addition, residual urine, functional urethral length, and the rate of detrusor overactivity, improved significantly after surgery (P<0.05). Apart from vaginal erosion (14/124; 11.3%), the rates of other surgical complications were acceptably low. CONCLUSION: TVM is an effective procedure for the treatment of POP and urinary symptoms, this being possibly related to postoperative release of urethral obstruction. Vaginal erosion is less likely to occur beyond the learning curve. PMID- 22226538 TI - Poland syndrome with Mullerian agenesis: a rare occurrence. PMID- 22226539 TI - Expression and possible role of interleukin-10 receptors in patients with adenomyosis. AB - OBJECTIVE: To investigate the expression and potential roles of interleukin-10 receptor 1 (IL-10R1) and interleukin-10 receptor 2 (IL-10R2) in adenomyosis. STUDY DESIGN: This prospective study examined 33 women with histologically proven adenomyosis and 21 women without adenomyosis who had undergone hysterectomy for non-endometrial pathology. Comparative immunohistochemistry was used to evaluate the expression and localization of IL-10R1 and IL-10R2. Tissue sections were immunostained with goat anti-human interleukin-10 receptor alpha and rabbit anti human interleukin-10 receptor beta antibodies. The presence and localization of IL-10R1 and IL-10R2 were evaluated microscopically throughout the menstrual cycle in eutopic and ectopic endometrial tissues of women with adenomyosis, and the results were compared with those for normal endometrium. RESULTS: IL-10R1 and IL 10R2 were mainly expressed by epithelial cells in both women with adenomyosis and controls. Epithelial expression of IL-10R1 and IL-10R2 was higher in adenomyotic samples than in eutopic endometrium of women with adenomyosis or normal endometrium. Moreover, epithelial expression of IL-10R1 was higher in eutopic endometrium of women with adenomyosis than in normal endometrium. Epithelial expression of IL-10R1 showed cyclic variation in eutopic endometrium of women with adenomyosis and normal endometrium, with elevated expression in secretory phase tissues compared with proliferative-phase tissues. CONCLUSIONS: Intrinsic abnormalities concerning IL-10 and IL-10 receptors may be present in eutopic and ectopic endometria of women with adenomyosis. These findings suggest that IL-10 receptors may be involved in the immunotolerant and/or anti-inflammatory process of adenomyosis. PMID- 22226540 TI - Detergents modify proteinase K resistance of PrP Sc in different transmissible spongiform encephalopathies (TSEs). AB - Prion diseases are diagnosed by the detection of their proteinase K-resistant prion protein fragment (PrP(Sc)). Various biochemical protocols use different detergents for the tissue preparation. We found that the resistance of PrP(Sc) against proteinase K may vary strongly with the detergent used. In our study, we investigated the influence of the most commonly used detergents on eight different TSE agents derived from different species and distinct prion disease forms. For a high throughput we used a membrane adsorption assay to detect small amounts of prion aggregates, as well as Western blotting. Tissue lysates were prepared using DOC, SLS, SDS or Triton X-100 in different concentrations and these were digested with various amounts of proteinase K. Detergents are able to enhance or diminish the detectability of PrP(Sc) after proteinase K digestion. Depending on the kind of detergent, its concentration - but also on the host species that developed the TSE and the disease form or prion type - the detectability of PrP(Sc) can be very different. The results obtained here may be helpful during the development or improvement of a PrP(Sc) detection method and they point towards a detergent effect that can be additionally used for decontamination purposes. A plausible explanation for the detergent effects described in this article could be an interaction with the lipids associated with PrP(Sc) that may stabilize the aggregates. PMID- 22226541 TI - Virus survival in slurry: analysis of the stability of foot-and-mouth disease, classical swine fever, bovine viral diarrhoea and swine influenza viruses. AB - Farm slurry can be highly contaminated with viral pathogens. The survival of these pathogens within slurry is important since this material is often distributed onto farm land either directly or after heat treatment. There is clearly some risk of spreading pathogens in the early stages of an outbreak of disease before it has been recognized. The survival of foot-and-mouth disease virus, classical swine fever virus, bovine viral diarrhoea virus and swine influenza virus, which belong to three different RNA virus families plus porcine parvovirus (a DNA virus) was examined under controlled conditions. For each RNA virus, the virus survival in farm slurry under anaerobic conditions was short (generally <= 1 h) when heated (to 55 degrees C) but each of these viruses could retain infectivity at cool temperatures (5 degrees C) for many weeks. The porcine parvovirus survived considerably longer than each of the RNA viruses under all conditions tested. The implications for disease spread are discussed. PMID- 22226542 TI - Salmonella flagellin enhances mucosal immunity of avian influenza vaccine in chickens. AB - Flagellin, a bioactive Toll-like receptor (TLR) 5 ligand, may trigger the innate immunity that in turn is important for subsequent adaptive immune responses. In the present study, the adjuvant effects of the monomeric and polymeric forms of Salmonella flagellin (mFliC and pFliC, respectively) were examined in specific pathogen free (SPF) chickens immunized intramuscularly (i.m.) or intranasally (i.n.) with formalin-inactivated avian influenza virus (AIV) H5N2 vaccines. Results showed that mFliC cooperating with the 64CpG adjuvant significantly induced influenza-specific antibody titers of plasma IgA in the i.m.-vaccinated animals. The nasal IgA levels in the i.n.-mFliC-coadministrated AIV vaccinated chickens were significantly elevated compared to levels observed in the control group (H5N2 vaccine alone). The pFliC cooperating with the 64CpG adjuvant significantly enhanced cell proliferation of splenocytes in the i.m.-vaccinated animals. TLR3 and TLR5 expressions were activated by flagellin stimulation in vitro and in vivo. These results suggest that flagellin can be used as an adjuvant in an AIV H5N2 vaccine, especially for mucosal immunity. PMID- 22226543 TI - Motivation of extended behaviors by anterior cingulate cortex. AB - Intense research interest over the past decade has yielded diverse and often discrepant theories about the function of anterior cingulate cortex (ACC). In particular, a dichotomy has emerged between neuropsychological theories suggesting a primary role for ACC in motivating or 'energizing' behavior, and neuroimaging-inspired theories emphasizing its contribution to cognitive control and reinforcement learning. To reconcile these views, we propose that ACC supports the selection and maintenance of 'options' - extended, context-specific sequences of behavior directed toward particular goals - that are learned through a process of hierarchical reinforcement learning. This theory accounts for ACC activity in relation to learning and control while simultaneously explaining the effects of ACC damage as disrupting the motivational context supporting the production of goal-directed action sequences. PMID- 22226544 TI - Facile synthesis of acacetin-7-O-beta-D-galactopyranoside. AB - Acacetin-7-O-beta-D-galactopyranoside (1), a natural flavonoid isolated from flower heads of Chrysanthemum morifolium, has been reported to inhibit the replication of HIV in H9 cells. We achieved the total synthesis of compound 1 by employing a one-pot synthesis of the aglycon. The key reactions in this approach include the modified Baker-Venkataraman reaction and regio- and stereoselective O glycosylations. PMID- 22226545 TI - The benefits of an additional worker are task-dependent: assessing low-back injury risks during prefabricated (panelized) wall construction. AB - Team manual material handling is a common practice in residential construction where prefabricated building components (e.g., wall panels) are increasingly used. As part of a larger effort to enable proactive control of ergonomic exposures among workers handling panels, this study explored the effects of additional workers on injury risks during team-based panel erection tasks, specifically by quantifying how injury risks are affected by increasing the number of workers (by one, above the nominal or most common number). Twenty-four participants completed panel erection tasks with and without an additional worker under different panel mass and size conditions. Four risk assessment methods were employed that emphasized the low back. Though including an additional worker generally reduced injury risk across several panel masses and sizes, the magnitude of these benefits varied depending on the specific task and exhibited somewhat high variability within a given task. These results suggest that a simple, generalizable recommendation regarding team-based panel erection tasks is not warranted. Rather, a more systems-level approach accounting for both injury risk and productivity (a strength of panelized wall systems) should be undertaken. PMID- 22226546 TI - Does cytotechnician training influence the accuracy of EUS-guided fine-needle aspiration of pancreatic masses? AB - BACKGROUND/AIM: The presence of on-site cytopathologists improves the diagnostic yield of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of pancreatic masses; however, on-site cytopathologists are not available to all endoscopic units. We hypothesized that experienced cytotechnicians can accurately assess whether an on-site pancreatic mass fine needle aspiration specimen is adequate. The aim of this study was to evaluate the effect of formal cytotechnician training on the diagnostic accuracy of EUS-FNA of pancreatic masses. METHODS: Single-centre, prospective study. The cytotechnician made an on site assessment of specimen adequacy with immediate evaluation of smears over a 12-month period (pre-training period) then over another 12-month period (post training period), with a year's intermediate training when the cytopathologist and the cytotechnician worked together in the room. The gold standard used to establish the final diagnosis was based on a non-equivocal fine needle aspiration biopsy reviewed by the same expert cytopathologist. The main outcome measurements were the cytotechnician diagnostic accuracy before and after the training period. RESULTS: A total of 107 patients were enrolled in the pre-training period. Cytotechnician in-room adequacy was 68.2% (73/107). The diagnostic accuracy was 74.8%. The adequacy for the blind-review pathologist was 93.4% (100/107), significantly higher (p=0.008) than the cytotechnician's results. During the post training period, 95 EUS-FNA were performed and reviewed. Cytotechnician in-room adequacy was 87.4% (83/95). The diagnostic accuracy was 90.5%. The adequacy for the blinded pathologist was 95.8% (91/95), not significantly different from the cytotechnician (p=0.23). CONCLUSIONS: An adequate training period with an expert pathologist significantly improves the cytotechnician skill in terms of judging adequacy and diagnostic accuracy. PMID- 22226547 TI - Novel di-n-butyltin(IV) derivatives: Synthesis, high levels of cytotoxicity in tumor cells and the induction of apoptosis in KB cancer cells. AB - Two classes of dibutyltin(IV) hydroxamates complexes, formulated as the mononuclear mixed-ligand diorganotin(IV) complex [(n)Bu(2)Sn(HL)Cl] a and the tetranuclear [(n)Bu(4)Sn(2)(HL)(2)(L)](2)b were fully characterized. X-ray diffraction analyses were also carried out for the representative complexes [(n)Bu(2)Sn(2,6-F(2)C(6)H(3)C(O)NHO)Cl](4a) and [[(n)Bu(4)Sn(2){3 BrC(6)H(4)C(O)NHO}(2){3-BrC(6)H(4)C(NO)O}](2)](1b). The cytotoxicity of all compounds was tested by MTT and SRB assays against three human tumor cell lines HL-60, BGC-823 and KB. 1b and 4a have been shown to be more potent antitumor agents than other compounds and cisplatin. Annexin V FITC-PI assay was consistent with the MTT results. Cell cycle assay results indicated that KB cells displayed an arrest in the G(0)/G(1) phase and a decrease of S phase of the cell cycle at the low concentrations of 1b, 4a. PMID- 22226548 TI - Decreased peripheral expression of neuregulin 1 in high-risk individuals who later converted to psychosis. PMID- 22226549 TI - Endocannabinoids limit excessive mast cell maturation and activation in human skin. AB - BACKGROUND: Mast cells (MCs) crucially contribute to many inflammatory diseases. However, the physiological controls preventing excessive activities of MCs in human skin are incompletely understood. OBJECTIVE: Since endocannabinoids are important neuroendocrine MC modifiers, we investigated how stimulation/inhibition of cannabinoid 1 (CB1) receptors affect the biology of human skin MCs in situ. METHODS: This was investigated in the MC-rich connective tissue sheath of organ cultured human scalp hair follicles by quantitative (immuno)histomorphometry, ultrastructural, and quantitative PCR techniques with the use of CB1 agonists or antagonists, CB1 knockdown, or CB1 knockout mice. RESULTS: Kit+ MCs within the connective tissue sheath of human hair follicles express functional CB1 receptors, whose pharmacological blockade or gene silencing significantly stimulated both the degranulation and the maturation of MCs from resident progenitor cells in situ (ie, enhanced the number of tryptase+, FcepsilonRIalpha, or chymase+ connective tissue sheath-MCs). This was, at least in part, stem cell factor-dependent. CB1 agonists counteracted the MC-activating effects of classical MC secretagogues. Similar phenomena were observed in CB1 knockout mice, attesting to the in vivo relevance of this novel MC-inhibitory mechanism. CONCLUSION: By using human hair follicle organ culture as an unconventional, but clinically relevant model system for studying the biology of MCs in situ, we show that normal skin MCs are tightly controlled by the endocannabinoid system. This limits excessive activation and maturation of MCs from resident progenitors via "tonic" CB1 stimulation by locally synthesized endocannabinoids. The excessive numbers and activation of MCs in allergic and other chronic inflammatory skin diseases may partially arise from resident intracutaneous MC progenitors, for example, because of insufficient CB1 stimulation. Therefore, CB1 stimulation is a promising strategy for the future management of allergy and MC-dependent skin diseases. PMID- 22226550 TI - 2-Aminoethoxydiphenyl borate (2-APB) reduces alkaline phosphatase release, CD63 expression, F-actin polymerization and chemotaxis without affecting the phagocytosis activity in bovine neutrophils. AB - 2-Aminoethoxydiphenyl borate (2-APB) interferes with the Ca(2+) influx and reduces the ROS production, gelatinase secretion and CD11b expression in bovine neutrophils. Moreover, it has been suggested that inhibition of the Ca(2+) channel involved in the store operated Ca(2+) entry (SOCE) is a potential target for the development of new anti-inflammatory drugs in cattle, however it is unknown whether 2-APB affects neutrophil functions associated with the innate immune response. This study describes the effect of 2-APB, a putative SOCE inhibitor, on alkaline phosphatase activity a marker of secretory vesicles, CD63 a marker for azurophil granules, F-actin polymerization and in vitro chemotaxis in bovine neutrophils stimulated with platelet-activating factor (PAF). Also, we evaluated the effect of 2-APB in the phagocytic activity against Escherichia coli and Staphylococcus aureus bioparticles. We observed that doses of 2-APB >=10 MUM significantly reduced alkaline phosphatase activity and in vitro chemotaxis, whereas concentrations of 2-APB >=50 MUM reduced CD63 expression and F-actin polymerization. Finally, we observed that 2-APB did not affect the phagocytic activity in neutrophils incubated with E. coli and S. aureus bioparticles. We concluded that inhibition of Ca(2+) influx could be a useful strategy to reduce inflammatory process in cattle. PMID- 22226551 TI - Interferon status and white blood cells during infection with African swine fever virus in vivo. AB - African swine fever virus (ASFV) is the causative agent of African swine fever that is the significant disease of domestic pigs, with high rates of mortality. ASFV is double-stranded DNA virus whose genes encode some proteins that are implicated in the suppression of host immune response. In this study, we have modeled in vivo infection of ASFV for determination of interferon (IFN) status in infected pigs. We measured the level of IFN-alpha, -beta and -gamma by enzyme linked immunosorbent assay and showed that the level of IFN-alpha sharply decreased during infection. Unlike IFN-alpha, the level of IFN-beta and -gamma increased from the 2nd and 4th days post-infection, respectively. Also, we analyzed the population dynamics of peripheral white blood cells of infected pigs due to their important role in host immune system. We showed that the atypical lymphocytes appeared after short time of infection and this result is in accordance with our previous study done in vitro. At the last day of infection about 50% of the total white blood cells were destroyed, and the remaining cells were represented mainly by small-sized lymphocytes, reactive lymphocytes and lymphoblasts. PMID- 22226552 TI - A novel click lysine zwitterionic stationary phase for hydrophilic interaction liquid chromatography. AB - A novel type of zwitterionic HILIC stationary phase was prepared by covalently bonding the l-azido lysine on silica gel via click chemistry. The key intermediate azido lysine was synthesized by transformation the amino group in l Boc-lysine to corresponding azido group and subsequent removal of the N-protected group (Boc). Finally, the azido lysine was covalently bonded to silica beads by click chemistry to get click lysine. Its structure was confirmed by FT-IR and elemental analysis. The new stationary phase showed good HILIC characteristics, when it was applied to separate polar and hydrophilic compounds, such as organic acids, cephalosporins and carbapenems. Compared with the commercial stationary phases, such as Atlantics HILIC and ZIC-HILIC, click lysine displayed better or similar chromatographic behaviors. PMID- 22226553 TI - Determination of glucocorticoids in sewage and river waters by ultra-high performance liquid chromatography-tandem mass spectrometry. AB - In this paper we present a method based on ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) combined with a solid-phase extraction to determine nine glucocorticoids in river waters and sewage. In addition, we attempt the chromatographic separation of two glucocorticoid epimers (betamethasone and dexamethasone) which until now had not been determined simultaneously in environmental matrices. For SPE, we have tested three commercial polymeric polar/non-polar balanced sorbents. The recoveries were close to or above 90% in rivers and sewage influents and effluents. The repeatability expressed as relative standard deviation (%RSD, n=3, 10 ng/L) was less than 8% in all cases. The method obtains LODs for glucocorticoids at low ng/L levels in aqueous environmental matrices (0.5-20 ng/L depending on the matrix and the analyte). The method was applied to determine these compounds in three Catalan rivers (Ebre, Ter and LLobregat) and two sewage treatment plants in the Tarragona area. Cortisone, cortisol, prednisone and prednisolone were frequently determined in influent sewage samples between 21 and 285 ng/L. Moreover, the two epimers were successfully determined below LOQs in some influent sewage samples. PMID- 22226554 TI - Porous ceramic/agarose composite adsorbents for fast protein liquid chromatography. AB - Porous ceramic/agarose composite adsorbents were designed and prepared with silica ceramic beads and 4% agarose gel, and then functionalized with a special ligand carboxymethyl. A novel method was introduced to fabricating of the porous silica ceramic beads. The morphology of SEM shows a spherical shape and a porous structure of the ceramic beads. Nitrogen adsorption-desorption analysis gives an average pore size of 287.5 A, a BET surface area of 29.33 m2/g and a porosity of 41.8%, respectively. Additionally, X-ray diffraction pattern indicates that the amorphous silica has been transformed into two crystal phases of quartz and cristobalite, leading to a porous and rigid skeleton and ensuring the application of the composite beads at high flow velocities. Lysozyme of hen egg-white with the activity of 12,700 U/mg was purified by the composite ion-exchanger in one step and the recovery and purification factor reaches 95.2% and 7.9, respectively. PMID- 22226555 TI - Preparation of a polar monolithic stir bar based on methacrylic acid and divinylbenzene for the sorptive extraction of polar pharmaceuticals from complex water samples. AB - A monolithic, hydrophilic stir bar coating based upon a copolymer of methacrylic acid and divinylbenzene [poly(MAA-co-DVB)] was synthesised and evaluated as a new polymeric phase for the stir bar sorptive extraction (SBSE) of polar compounds from complex environmental water samples. The experimental conditions for the extraction and liquid desorption in SBSE were optimised. Liquid chromatography triple quadrupole mass spectrometry (LC-MS/MS) was used for the determination of a group of polar pharmaceuticals in environmental water matrices. The extraction performance of the poly(MAA-co-DVB) stir bar was compared to the extraction performance of a commercially available polydimethylsiloxane stir bar; it was found that the former gave rise to significantly higher extraction efficiency of polar analytes (% recovery values near to 100% for most of the studied analytes) than the commercial product. The developed method was applied to determine the studied analytes at low ng L-1 in different complex environmental water samples. PMID- 22226556 TI - Characterization of a microscale thermal-electrical field-flow fractionation system. AB - A microscale thermal-electrical field-flow fractionation (ThElFFF) channel is reported for the first time and preliminary characterization results show high retention at certain operating conditions including relatively high flow rates when compared to standard microscale electrical or thermal field-flow fractionation instruments. A new design is presented that simplifies manufacturing and assembly of the prototype and that can provide both an electrical field and a high temperature gradient (~106 degrees C/m). Monodisperse particle retention is carried out with polystyrene nanoparticle samples to characterize the device. Retention ratios as low as 0.045 are observed with the ThElFFF instrument. Size selectivity of 1.77 was achieved for ThElFFF. The comparison with theory shows a marked deviation from the existing theory. Separation of a mixture of polystyrene particles is demonstrated for the first time using a ThElFFF system by separating 130 nm carboxylated polystyrene and 209 nm polystyrene particles. PMID- 22226557 TI - Extraction of explosives from soil followed by gas chromatography-mass spectrometry analysis with negative chemical ionization. AB - A new, simple and accurate method for extraction of explosives from soil was developed and validated. The method includes one hour gentle extraction of compounds from soil in acetonitrile:dichloromethane 50:50 at 30 degrees C. Further analysis was made with GC-MS using cool on-column injection and negative chemical ionization. The method increased the recovery of the more volatile products, generated higher accuracy and was extensively time-saving compared to the conventional EPA (US Environmental Protection Agency) 8330 method. Applications are demonstrated on commercial reference materials. PMID- 22226559 TI - Magnetic bead-based hydrophilic interaction liquid chromatography for glycopeptide enrichments. AB - Purification of glycopeptides prior to the analysis by mass spectrometry (MS) is demanded due to ion suppression effect during ionization caused by the co presence of non-glycosylated peptides. Among various purification methods, hydrophilic interaction liquid chromatography (HILIC) has become a popular method in recent years. In this work, we reported a novel magnetic bead-based zwitterionic HILIC (ZIC-HILIC) material which was fabricated by coating a zwitterionic polymer synthesized by spontaneous acid-catalyzed polymerization of 4-vinyl-pyridinium ethanesulfonate monomer on iron oxide magnetic nanoparticles. The resulting magnetic ZIC-HILIC nanoparticles were shown to provide high specificity and high recovery yield (95-100%) for the enrichment of glycopeptides from a standard glycoprotein, fetuin, using a simple magnetic bar. In addition, we proposed a two-step HILIC enrichment strategy using magnetic ZIC-HILIC nanoparticles for a large scale analysis of glycoproteins in complex biological samples. Using this approach, we identified 85 N-glycosylation sites in 53 glycoproteins from urine samples. Two novel glycosylation sites on N513 of uromodulin and N470 of lysosomal alpha-glucosidase which have not yet been reported were identified by two-step HILIC approach. Furthermore, all these identified sites were confirmed by studies conducted using PNGase F deglycosylation and 18O enzymatic labeling. PMID- 22226558 TI - Comparison of two officinal Chinese pharmacopoeia species of Ganoderma based on chemical research with multiple technologies and chemometrics analysis. AB - AIM OF THE STUDY: To investigate the chemical differences between Ganoderma lucidum (G. lucidum, Chizhi) and Ganoderma sinense (G. sinense, Zizhi). MATERIALS AND METHODS: Thirty two batches of commercial Ganoderma samples were collected, including 20 batches of G. lucidum and 12 batches of G. sinense cultivated in different geographical regions. Chemical substances in aqueous extract and alcoholic extract, mainly polysaccharides and triterpenes respectively, were investigated. Determination of polysaccharides was carried out with a high performance liquid chromatography with an variable wavelength detector. Meanwhile, analysis of triterpenes were performed on an ultraviolet spectrophotometer, an ultra performance liquid chromatography and a rapid resolution liquid chromatograph combined with an electrospray ionization mass spectrometer. Chromatograms and spectra for all batches and reference standards of main components were obtained and used for direct comparison. Further discussion was made on the basis of the result of principal component analysis (PCA). RESULTS: Significant difference of triterpenes was shown between G. lucidum and G. sinense. In 20 batches of G. lucidum, 12 main components, including eight ganoderic acids and four ganoderenic acids were identified and ten of them were quantitatively determined, with the total content from 0.249% to 0.690%. However, none of those triterpenes was found in either batch of G. sinense. As for constituents of polysaccharides, seven monosaccharides were identified and four main components among them were quantitatively determined. Difference of polysaccharides was not directly observed, but latent information was revealed by PCA and the discrimination became feasible. CONCLUSIONS: G. lucidum and G. sinense were chemically different, which might result in pharmacological distinction. Preparations of traditional Chinese medicine (TCM) from Ganoderma should make accurate specification on the origin of species. PMID- 22226560 TI - Analytical tools for the analysis of carotenoids in diverse materials. AB - High-performance liquid chromatography (HPLC) has become the method of choice for carotenoid analysis. Although a number of normal-phase columns have been reported, reverse-phase columns are the most widely used stationary phases for the analysis of these molecules. C18 and C30 stationary phases have provided good resolution for the separation of geometrical isomers and carotenoids with similar polarity. More recently ultra high-performance liquid chromatography (UHPLC) has been used. UHPLC has a number of distinct advantages over conventional HPLC. These include: faster analyses (due to shorter retention times), narrower peaks (giving increased signal-to-noise ratio) and higher sensitivity. High strength silica (HSS) T3 and C18 and ethylene bridged hybrid (BEH) C18 stationary phases, with sub-2 MUm particles have been used successfully for UHPLC analysis and separation of carotenoids. A number of spectroscopic and mass spectrometric techniques have also been used for carotenoid qualitative and quantitative analysis. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI/TOF-MS), atmospheric-pressure solids-analysis probe (ASAP) and Raman spectroscopy are used to profile rapidly and qualitative carotenoids present in different crude extracts. Such detection methods can be used directly for the analysis of samples without the need for sample preparation or chromatographic separation. Consequently, they allow for a fast screen for the detection of multiple analytes. Quantitative carotenoid analysis can be carried out using absorbance or mass detectors. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is efficient for carotenoid identification through the use of transitions for the detection of analytes through precursor and daughter ions. This approach is suitable for the identification of carotenoids with the same molecular mass but different fragmentation patterns. Here we review critically the latest improvements for carotenoid resolution and detection and we discuss a number of analytical techniques for qualitative and quantitative analysis of carotenoids. PMID- 22226561 TI - Applicability of hybrid linear ion trap-high resolution mass spectrometry and quadrupole-linear ion trap-mass spectrometry for mycotoxin analysis in baby food. AB - Recent developments in mass spectrometers have created a paradoxical situation; different mass spectrometers are available, each of them with their specific strengths and drawbacks. Hybrid instruments try to unify several advantages in one instrument. In this study two of wide-used hybrid instruments were compared: hybrid quadrupole-linear ion trap-mass spectrometry (QTRAP(r)) and the hybrid linear ion trap-high resolution mass spectrometry (LTQ-Orbitrap(r)). Both instruments were applied to detect the presence of 18 selected mycotoxins in baby food. Analytical parameters were validated according to 2002/657/CE. Limits of quantification (LOQs) obtained by QTRAP(r) instrument ranged from 0.45 to 45 MUg kg-1 while lower limits of quantification (LLOQs) values were obtained by LTQ Orbitrap(r): 7-70 MUg kg-1. The correlation coefficients (r) in both cases were upper than 0.989. These values highlighted that both instruments were complementary for the analysis of mycotoxin in baby food; while QTRAP(r) reached best sensitivity and selectivity, LTQ-Orbitrap(r) allowed the identification of non-target and unknowns compounds. PMID- 22226562 TI - Changing practice paradigms: negotiating your future. AB - There are many recent and ongoing changes in the practice of medicine from a business standpoint as well as in overall practice management. Economic and lifestyle desires have pushed many physicians to a decision point of whether or not to join a large multispecialty group or to sell their practice and become an employee of a hospital system. There are advantages and disadvantages to both options; however, deciding on the most appropriate path for each individual can be a daunting task. At our recent breakfast session at the vascular annual meeting in Chicago, Illinois, in June 2011, we brought to light these topics to try and help enlighten physicians on which option may be right for them. There is no single answer/option that will fit every practice, but discussion for various practice management designs are outlined and critiqued. This article cannot fully discuss each view in the allotted space, but it is designed to encourage thought and discussion among the vascular surgical community as a whole. PMID- 22226563 TI - Endovascular creation of aortic dissection in a swine model with technical considerations. AB - OBJECTIVE: Creating an experimental model of a type B aortic dissection with a minimally invasive endovascular procedure in swine to help future evaluation of therapies for aortic dissection. METHODS: Aortic dissection was created in 14 swine using endovascular procedures only. Under fluoroscopy, a modified 10F outer catheter with a 14 G stiffening inner metallic cannula was forced via the femoral artery into the aortic vessel wall to create an initial dissection. A .035-inch guidewire and a 4F straight catheter were advanced into the dissected space, and the dissection was extended in a retrograde direction using a technique including loop formation of the guidewire, which was placed carefully against the transmural penetration and extended as far as possible in the descending thoracic aorta up to the point where loop formation of the guidewire reached smoothly. An 8F introducer sheath was advanced with a Brockenbrough needle into the dissected space, and a proximal fenestration was created by puncturing the intima. If required, balloon dilatation was performed to enlarge the proximal and distal tears. Aortography and contrast-enhanced cone beam computed tomography (CBCT) were performed in addition to a detailed histologic evaluation of the dissected portion. RESULTS: Aortic dissection was successfully created in 11 of the 14 swine (78.6%). Among the 11 dissections, nine were located in the thoracoabdominal aorta and two in the abdominal aorta. The initial aortic diameter at the middle portion of the created dissection ranged from 7.4 to 16.8 mm (mean +/- standard deviation, 10.9 +/- 2.9), while after dissection, it ranged from 7.8 to 19.3 mm (12.9 +/- 3.8 mm). The dissected length ranged from 4.4 to 17.7 cm (10.7 +/- 4.6 cm). Aortography and CBCT revealed seven dissections (63.6%) with a smooth and patent false lumen. Histologic evaluation revealed that the outer one-third of the media was separated from the inner two-thirds. In the remaining four dissections (36.4%), imaging procedures revealed the formation of a rough and patent false lumen beside the true lumen, and histologic evaluation revealed greater separation of the outer media. Five animals were chronic dissection models. Three (60%) of these survived for more than 14 days without any symptoms. Moreover, completely patent true and false lumens without thrombus formation were observed in these three animals. The aortic diameter at the dissected portion tended to be dilated compared with the initial diameter. CONCLUSIONS: This new technique of creating an experimental aortic dissection model in swine is promising and should contribute to the development of future therapies for aortic dissection. PMID- 22226564 TI - Regional citrate versus heparin anticoagulation for continuous renal replacement therapy: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Anticoagulation of the extracorporeal circuit is required in continuous renal replacement therapy (CRRT). Heparin is the classic choice for anticoagulation, although it may increase the risk of bleeding. Regional citrate anticoagulation reduces the risk of bleeding, but may cause hypocalcemia and metabolic disturbances. STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). SETTING & POPULATION: Patients admitted to the intensive care unit with acute kidney injury that required CRRT. SELECTION CRITERIA FOR STUDIES: RCTs regardless of publication status or language. INTERVENTION: Regional citrate versus heparin anticoagulation in CRRT. OUTCOMES: The primary outcomes were circuit survival time, the occurrence of major bleeding defined as a site of gross bleeding with a decrease in blood pressure or requiring transfusion of 2 or more units of red blood cells, metabolic alkalosis, hypocalcemia, and thrombocytopenia. The secondary outcome was cost. RESULTS: 6 RCTs with 488 patients were identified. Citrate anticoagulation was associated with a significant decrease in bleeding (RR, 0.34; 95% CI, 0.17-0.65). Circuit survival time, the incidence of metabolic alkalosis, and thrombocytopenia showed no significant difference between groups. Hypocalcemia was more common in patients receiving citrate, although no clinical adverse event was reported in the included studies. LIMITATIONS: Significant heterogeneity in the primary outcome. CONCLUSION: The efficacy of citrate and heparin anticoagulation for CRRT was similar. However, citrate anticoagulation decreased the risk of bleeding with no significant increase in the incidence of metabolic alkalosis. We recommend citrate as an anticoagulation agent in patients who require CRRT but are at high risk of bleeding. PMID- 22226565 TI - Incidence and consequences of acute kidney injury in kidney transplant recipients. AB - BACKGROUND: In the nontransplant setting, acute kidney injury (AKI) may lead to chronic kidney disease (CKD) and end-stage renal disease, but the epidemiology of AKI in transplant recipients has not been characterized. The purpose of this study was to determine the incidence and consequences of AKI in kidney transplant recipients outside the peritransplant period and unrelated to acute rejection. STUDY DESIGN: Retrospective longitudinal cohort study. SETTING & PARTICIPANTS: 27,232 adult Medicare-insured transplant recipients with transplant survival of 6 months or longer in the US Renal Data System in 1995-2000. PREDICTORS: International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) hospital discharge diagnostic codes were used to identify AKI during the first 3 posttransplant years. OUTCOMES: Transplant loss from any cause, mortality (death with a functioning transplant), and death-censored transplant loss. MEASUREMENTS: Estimated glomerular filtration rate calculated by the MDRD (Modification of Diet in Renal Disease) Study equation 6 months posttransplant. RESULTS: 3,066 (11.3%) patients had 4,181 hospitalizations with AKI, of which 14.8% required dialysis therapy. The incidence of AKI more than doubled during the study, and AKI was more frequent in patients with lower levels of transplant function. AKI was associated independently with increased risk of transplant loss from any cause (HR, 2.74; 95% CI, 2.56-2.92), death with a functioning transplant (HR, 2.36; 95% CI, 2.14-2.60), and death-censored transplant loss (HR, 3.17; 95% CI, 2.91-3.46). However, AKI-associated risks paradoxically were higher in patients with earlier CKD stage. LIMITATIONS: Because of the limited sensitivity of ICD-9-CM codes for non-dialysis-requiring AKI events, the overall incidence of AKI likely is underestimated in this study. CONCLUSIONS: We conclude that AKI is increasingly common and associated with transplant failure and death. Later CKD stage increases the risk of AKI, but AKI-associated risks of transplant failure were greater in those with higher levels of kidney function (earlier CKD stage). PMID- 22226566 TI - Small bowel MRI imaging in the DGH - are you doing it yet? AB - The aim of this article is to illustrate the spectrum of disease visualized at small bowel magnetic resonance imaging (MRI) in the district general hospital (DGH) setting. The advantages and disadvantages of small bowel MRI, technique, and service implementation are discussed. PMID- 22226567 TI - Respiratory disease in common variable immunodeficiency and other primary immunodeficiency disorders. AB - Respiratory disease is a significant cause of morbidity and mortality amongst patients with primary immunodeficiency disorders. Computed tomography (CT) plays an important role in the multidisciplinary approach to these conditions, in detecting, characterizing, and quantifying the extent of lung damage and in directing treatment. The aim of this review is to classify the primary immunodeficiency disorders and describe the thoracic complications and the associated CT findings whilst discussing the role of radiology in diagnosis and surveillance. PMID- 22226568 TI - Sentinel node identification using microbubbles and contrast-enhanced ultrasonography. AB - Sentinel lymph node (SLN) biopsy has become the recommended method for surgical staging of the axilla in patients with breast cancer. Grey-scale axillary ultrasonography (US) combined with US-guided biopsy is a widely used preoperative staging procedure but has limited sensitivity. US contrast agent "microbubbles", when injected intradermally, have been shown to have the potential to enter the breast lymphatics, travel rapidly to the axilla, and visualize the putative SLNs. This review illustrates the SLN identification technique using intradermal injection of microbubbles and contrast-enhanced US. The injection method, lymphatic visualization techniques, grey-scale and contrast-enhanced US images of the putative SLNs are reviewed and exemplified. PMID- 22226569 TI - Life-expectancy of patients enrolled in phase 1 clinical trials: a systematic review of published prognostic models. AB - Life-expectancy superior to 3 months is a key-eligibility criterion for contemporary oncology phase 1 trials. Nevertheless, there is no reliable and consensual guidance for estimating this criterion. We have conducted a systematic review of published studies investigating the risk factor for 90-day mortality and the inherent generated scores. Nine studies have been published on this topic. Only two of these prognostic models have been validated on an independent dataset. Most of the models are based on a very subjective and investigator dependent parameter: the performance status. The predictive performance of these prognostic models is poorly evaluated. PMID- 22226570 TI - Mechanisms and dynamics in the thiol/disulfide redox regulatory network: transmitters, sensors and targets. AB - Plant cells sense, weigh and integrate various endogenous and exogenous cues in order to optimize acclimation and resource allocation. The thiol/disulfide redox network appears to be in the core of this versatile integration process. In plant cells its complexity exceeds by far that of other organisms. Recent research has elucidated the multiplicity of the diversified input elements, transmitters (thioredoxin, glutaredoxins), targets and sensors (peroxiredoxins and other peroxidases), controlled processes and final acceptors (reactive oxygen species). An additional level of thiol/disulfide regulation is achieved by introducing dynamics in time and subcompartment and complex association. PMID- 22226571 TI - Mucinous adenocarcinomas: poor prognosis in metastatic colorectal cancer. AB - PURPOSE: Mucinous histology of metastatic colorectal cancer (CRC) has been associated with poor prognosis, however this has never been assessed in large well-defined study populations treated with the current used systemic agents. We investigated the prognostic value of mucinous histology in two large phase III studies in metastatic CRC. PATIENTS AND METHODS: The study population included 1010 metastatic CRC patients who were treated with chemotherapy and targeted therapies in two phase III studies. Patients were classified according to the histology of the primary tumour in mucinous adenocarcinomas (MC) and non-mucinous adenocarcinomas (AC). RESULTS: Patients with MC (n=99) were older, had more often a normal serum lactate dehydrogenase (LDH), extrahepatic localisation of metastases, larger primary tumour diameter and a higher T classification compared to patients with AC (n=911). A deficient mismatch repair system and BRAF mutations were observed in 17% and 22% of patients with MC, compared to 3% and 7% in patients with AC, respectively. Clinical outcome was investigated in both studies separately, showing a worse overall survival (OS), progression free survival and overall response rate in patients with MC compared to patients with AC. Patients with MC received less cycles of treatment compared to AC, but did not suffer from a higher incidence of grade 3/4 toxicity. In multivariate analysis, mucinous histology was as an independent negative prognostic factor for OS, resulting in a combined hazard ratio of 1.78 (95%confidence interval (CI) 1.35-2.35). CONCLUSIONS: Patients with metastatic mucinous CRC have distinct clinicopathological features and poor response to chemotherapy and targeted agents. The strong negative prognostic value of MC warrants the use of this pathological feature as a stratification factor for clinical trials in metastatic CRC. PMID- 22226572 TI - Short-term efficacy and safety of zonisamide as adjunctive treatment for refractory partial seizures: a multicenter open-label single-arm trial in Korean patients. AB - OBJECTIVE: To evaluate the efficacy and safety of adjunctive zonisamide (ZNS) therapy in Korean adults with uncontrolled partial epilepsy. METHODS: Study patients had an average of at least one seizure per 4-week (averaged over a 12 week historical baseline) despite the use of one to three antiepileptic drugs. The starting dose of ZNS was 100mg/day, and was increased to 200mg/day after 2weeks. During the 12-week maintenance period, the dose of ZNS was adjusted to 200-400mg/day based on the physicians' discretion. The global evaluation scale (GES) and quality of life (QOLIE-31) were also evaluated. RESULTS: A total of 121 patients were enrolled, of which 88 patients completed the study. The median percent reduction in weekly seizure frequency over the treatment period was 59.0%. The >=50% and >=75% responder rates were 57.3% and 38.5%, respectively. Seizure freedom over the treatment period was observed in 25 patients, but seizure freedom throughout the 16-week treatment period was attained in only 16 patients. On investigator's GES, 84 patients were considered improved, with 33 patients showing marked improvement. In QOLIE-31 scale, seizure worry improved significantly but emotional well-being deteriorated. Treatment-emergent adverse events (AEs) were reported in 80 patients. The most common AEs were dizziness (28.1%), somnolence (24.0%), anorexia (18.2%), headache (14.0%), nausea (13.2%), and weight loss (10.7%). Twenty-two patients discontinued the trial due to drug related AEs. CONCLUSIONS: Our results suggest that adjunctive ZNS therapy for the treatment of refractory partial epilepsy, though efficacious, is associated with significant tolerability problems. PMID- 22226573 TI - Hypoxia regulates cell proliferation and steroidogenesis through protein kinase A signaling in bovine corpus luteum. AB - Hypoxia is an important physiological process which ensures corpus luteum (CL) formation and development, thus playing an important role in steroidogenesis. Recent studies have shown that CL develops in an analogous to tumorigenesis by accumulation of hypoxia-inducible factor-1 alpha subunit (HIF1A) in response to hypoxia. To investigate the relationship among hypoxia, steroidogenesis, and cell proliferation during CL lifespan, histological and steroidogenic analyses of CL were performed at various CL stages in non-pregnant Holstein. Also, the hypoxia mediated steroidogenesis and cell proliferation were studied in vitro with both primary luteal and luteinized granulosa cells. Our results showed that progesterone (P(4)) concentration increased with the upregulation of steroidogenic protein including steroidogenic acute regulatory protein (STAR) and CYP11A1 (P450scc) in the middle luteal stage. On the other hand, the cell proliferation- or hypoxia-associated proteins were upregulated in the early stage, including the proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor A (VEGFA), HIF1A, and aryl hydrocarbon receptor nuclear translocator (ARNT). In primary culture, phospho-protein kinase A (p-PKA) was downregulated, as were P(4) secretion and steroidogenic proteins both under oxygen-conditioned hypoxia in luteal cells and cobalt chloride-induced hypoxia in luteinized granulosa cells. However, under the treatment of hypoxia, PCNA, which was downregulated in luteal cells, was upregulated together with HIF1A and VEGFA in luteinized granulosa cells. Taken together, present study suggested that hypoxia downregulated steroidogenesis through PKA signaling and that the hypoxia regulated cell proliferation could be activated during CL formation. PMID- 22226574 TI - Cerebral autoregulation in neonates with a hemodynamically significant patent ductus arteriosus. AB - OBJECTIVE: Very low birth weight (VLBW) preterm infants are at risk for impaired cerebral autoregulation with pressure passive blood flow. Fluctuations in cerebral perfusion may occur in infants with a hemodynamically significant patent ductus arteriosus (hsPDA), especially during ductal closure. Our goal was to compare cerebral autoregulation using near-infrared spectroscopy in VLBW infants treated for an hsPDA. STUDY DESIGN: This prospective observational study enrolled 28 VLBW infants with an hsPDA diagnosed by echocardiography and 12 control VLBW infants without an hsPDA. Near-infrared spectroscopy cerebral monitoring was applied during conservative treatment, indomethacin treatment, or surgical ligation. A cerebral pressure passivity index (PPI) was calculated, and PPI differences were compared using a mixed-effects regression model. Cranial ultrasound and magnetic resonance imaging data were also assessed. RESULTS: Infants with surgically ligated hsPDAs were more likely to have had a greater PPI within 2 hours following ligation than were those treated with conservative management (P=.04) or indomethacin (P=.0007). These differences resolved by 6 hours after treatment. CONCLUSIONS: Cerebral autoregulation was better preserved after indomethacin treatment of an hsPDA compared with surgical ligation. Infants requiring surgical hsPDA ligation may be at increased risk for cerebral pressure passivity in the 6 hours following surgery. PMID- 22226575 TI - Crossed-fused testicular ectopia: a case for the use of laparoscopy to evaluate nonpalpable testicles. PMID- 22226576 TI - Diagnostic accuracy of a specific cytokine pattern in hemophagocytic lymphohistiocytosis in children. AB - OBJECTIVE: The study goal was to determine the diagnostic accuracy of a specific cytokine pattern including interferon-gamma (IFN-gamma), interleukin (IL)-10, and IL-6 for hemophagocytic lymphohistiocytosis (HLH) in febrile children. STUDY DESIGN: In this prospective study, 756 patients with fever admitted to a hematology-oncology unit were enrolled. The causes of fever were documented and the serum cytokines, including IFN-gamma, tumor necrosis factor-alpha (TNF alpha), IL-10, IL-6, IL-4, and IL-2, were determined using cytometric bead array techniques. RESULTS: Of 1474 episodes of fever that were analyzed, 71 episodes of HLH manifested a specific cytokine pattern of highly increased levels of IFN gamma (median level: 1088.5 pg/mL) and IL-10 (623.5 pg/mL) but a moderately increased level of IL-6 (51.1 pg/mL). IL-6 was predominantly increased to varied extents in patients in the sepsis group (244.6 pg/mL) and the nonsepsis infection group (34.7 pg/mL). The diagnostic accuracy of IFN-gamma and IL-10 for HLH was 99.5% and 92.8%, respectively. By applying the cutoff point of 100 pg/mL, IFN gamma had a sensitivity of 94.4% and a specificity of 97.2% for HLH. When using the criteria of IFN-gamma >75 pg/mL and IL-10 >60 pg/mL, the specificity reached 98.9% and the sensitivity was 93.0%. CONCLUSIONS: The specific cytokine pattern of markedly elevated levels of IFN-gamma and IL-10 with only modestly elevated IL 6 levels has high diagnostic accuracy for HLH and may be a useful approach to differentiate HLH from infection. PMID- 22226577 TI - Additional information regarding "Dravet syndrome: inroads into understanding epileptic encephalopathies". PMID- 22226578 TI - Effect of sodium ascorbate dose on the shelf life stability of reduced nitrite liver pates. AB - The effect of sodium ascorbate (SA; 500, 750, 1000 mg/kg) and sodium nitrite (SN; 40, 80, 120 mg/kg) doses on the shelf-life stability of liver pates was investigated in a full factorial design. Clear dose-dependent responses of the added SN or SA were found for the concentrations of nitrite, ascorbic acid and dehydroascorbic acid in the raw batters and in the cooked pates before and after 48 h of chilled display. Decreasing the SN dose to 80 mg/kg had no negative impact on the colour stability (a* value) and lipid oxidation (TBARS), and no additional antioxidant effect of SA was noticed. Lowering SN to 40 mg/kg resulted in proper colour formation, but the colour stability was inferior and lipid oxidation increased. Yet, increasing the amount of SA, at this low SN dose, resulted in lower TBARS values. Decreasing the SN dose to 80 or 40 mg/kg had no distinct effect on protein oxidation, which was however only measured by carbonyl content. PMID- 22226580 TI - Open versus laparoscopic nephroureterectomy: is there really a debate? PMID- 22226579 TI - Effect of sodium citrate plus sodium diacetate or buffered vinegar on quality attributes of enhanced beef top sirloins. AB - As new pathogen intervention products come to market, it is important to ensure that they maintain or improve meat quality. Shelf-life and palatability traits were measured for top sirloins enhanced to 110% with solutions containing 0.5% sodium chloride and 0.4% sodium tripolyphosphate (CNT); CNT with a 1% solution of 80% sodium citrate plus 20% sodium diacetate (SC+D); or CNT with 2% buffered vinegar (VIN) in the final product. Enhancement solution did not influence color over 7days of retail display, except VIN was subjectively more red than CNT and SC+D on d 7 and SC+D had less discoloration than CNT on d 7 (P<0.05). VIN was rated lower (P<0.05) than CNT for trained sensory tenderness and there was no difference in shear force between treatments. SC+D and VIN show promise for use in beef enhancement solutions, however, further sensory studies are warranted. PMID- 22226581 TI - Personalized treatment of prostate cancer based on inherited variations of steroid pathway-related genes. PMID- 22226582 TI - Robotic prostatectomy: the rise of the machines or judgment day. PMID- 22226583 TI - Death certificates are valid for the determination of cause of death in patients with upper and lower tract urothelial carcinoma. PMID- 22226584 TI - Does the imprecise definition of overactive bladder serve commercial rather than patient interests? PMID- 22226586 TI - Delivery of membrane impermeable cargo into CHO cells by peptide nanoparticles targeted by a protein corona. AB - Nanocarriers can fulfill essential functions in the stabilization and delivery of drugs: they prevent solubility issues and degradation, reduce side effects and modify the pharmacokinetic profile. However, particle based pharmaceuticals are complex and thus challenging to scale up. As formulation routines account for a large fraction of production costs, reducing complexity in the process of assembly, loading and functionalization of nanoparticles is desirable. Unlike existing approaches with similar goals, our protocol is designed to minimize usage of material and time. Prerequisite to this elegant one-step-procedure is the controlled phase-separation of a hydrophobic peptide to nanoparticles, inducing concurrent cargo-entrapment and association of a protein corona. We demonstrate the process by assembling Flutax-2 containing peptide nanoparticles functionalized with transferrin. Cellular uptake of the particles and cargo release depend on specific particle-cell interactions via transferrin receptor. These data indicate corona-mediated delivery of membrane impermeable cargo in vitro by a particulate delivery system entirely composed of amino acids. PMID- 22226587 TI - Influences of supra-physiological temperatures on microstructure and mechanical properties of skin tissue. AB - Thermal therapies under supra-physiological temperatures are increasingly used to treat skin diseases (e.g., superficial melanoma, removal of port-wine stains pigmented and cutaneous lesions). The efficacy of these therapies depends on the thermal and mechanical loadings that skin experiences during the treatment process. Therefore, it is of great significance to better understand the role of thermally induced changes in skin mechanical behavior and microstructure. In this study, rabbit belly skin was thermally damaged by immersing skin samples into saline solutions with controlled temperatures. We investigated the effect of thermal damage on skin mechanical behavior. We quantified the changes in skin microstructure (i.e., fiber, fibril) using histological staining and transmission electron microscopy (TEM). The results indicate that (i) the elastic modulus of skin, obtained by the uniaxial tensile test, decreased with increasing heating temperature; (ii) the skin tensile behavior was correlated with its microstructure changes induced by thermal denaturation of collagen fibers under supra-physiological temperatures; (iii) skin thermal damage predicted using the Arrhenius burn integration quantitatively agrees well with the evolution of the microstructure (i.e., percentage of the collagen area in Hematoxylin and Eosin (H&E) staining results). This study provides a better understanding of the coupled bio-thermo-mechanical behavior of skin tissue that could help to improve clinical thermal therapies. PMID- 22226588 TI - Multiclass classification of subjects with sleep apnoea-hypopnoea syndrome through snoring analysis. AB - The gold standard for diagnosing sleep apnoea-hypopnoea syndrome (SAHS) is polysomnography (PSG), an expensive, labour-intensive and time-consuming procedure. Accordingly, it would be very useful to have a screening method to allow early assessment of the severity of a subject, prior to his/her referral for PSG. Several differences have been reported between simple snorers and SAHS patients in the acoustic characteristics of snoring and its variability. In this paper, snores are fully characterised in the time domain, by their sound intensity and pitch, and in the frequency domain, by their formant frequencies and several shape and energy ratio measurements. We show that accurate multiclass classification of snoring subjects, with three levels of SAHS, can be achieved on the basis of acoustic analysis of snoring alone, without any requiring information on the duration or the number of apnoeas. Several classification methods are examined. The best of the approaches assessed is a Bayes model using a kernel density estimation method, although good results can also be obtained by a suitable combination of two binary logistic regression models. Multiclass snore based classification allows early stratification of subjects according to their severity. This could be the basis of a single channel, snore-based screening procedure for SAHS. PMID- 22226589 TI - An innovative approach of QRS segmentation based on first-derivative, Hilbert and Wavelet Transforms. AB - The QRS detection and segmentation processes constitute the first stages of a greater process, e.g., electrocardiogram (ECG) feature extraction. Their accuracy is a prerequisite to a satisfactory performance of the P and T wave segmentation, and also to the reliability of the heart rate variability analysis. This work presents an innovative approach of QRS detection and segmentation and the detailed results of the proposed algorithm based on First-Derivative, Hilbert and Wavelet Transforms, adaptive threshold and an approach of surface indicator. The method combines the adaptive threshold, Hilbert and Wavelet Transforms techniques, avoiding the whole ECG signal preprocessing. After each QRS detection, the computation of an indicator related to the area covered by the QRS complex envelope provides the detection of the QRS onset and offset. The QRS detection proposed technique is evaluated based on the well-known MIT-BIH Arrhythmia and QT databases, obtaining the average sensitivity of 99.15% and the positive predictability of 99.18% for the first database, and 99.75% and 99.65%, respectively, for the second one. The QRS segmentation approach is evaluated on the annotated QT database with the average segmentation errors of 2.85+/-9.90ms and 2.83+/-12.26ms for QRS onset and offset, respectively. Those results demonstrate the accuracy of the developed algorithm for a wide variety of QRS morphology and the adaptation of the algorithm parameters to the existing QRS morphological variations within a single record. PMID- 22226590 TI - Trends in esophageal cancer mortality in China during 1987-2009: age, period and birth cohort analyzes. AB - BACKGROUND: Esophageal cancer is one of the most commonly diagnosed malignant tumors in China. The aim of this study was to provide the representative and comprehensive informations about the long-term mortality trends of this disease in China between 1987 and 2009, using joinpoint regression and generalized additive models (GAMs). METHODS: Age-standardized mortality rates (ASMR), overall and truncated (35-64 years), were calculated using the direct calculation method, and joinpoint regression was performed to obtain the estimated annual percentage changes (EAPC). GAMs were fitted to study the effects of age, period and birth cohort on mortality trends. RESULTS: ASMR exhibited an overall remarked decline for rural females (EAPC=-2.3 95%CI: -3.3, -1.2), urban males (EAPC=-1.8 95%CI: 2.6, -1.0) and urban females (EAPC=-3.7 95%CI: -4.9, -2.4), but a small drop observed was not statistically significant for rural males (EAPC=-0.9 95%CI: 2.0, 0.3). The declines in ASMR were more noticeable for urban residents in recent years. Among all the residents, age effect showed an progressively increasing trend, whereas cohort effect declined steadily after the year corresponding to the maximum risk value. Period effect seemed to remain substantially unchanged throughout the years. CONCLUSIONS: Although variations in mortality rates were observed according to sex and area, the overall decreasing trends in esophageal cancer mortality were found in most Chinese people, aside from rural males. The findings could correspond to the changes in age- and cohort related factors in the population. Further study is required to understand these potential factors. PMID- 22226591 TI - Life cycle energy and greenhouse gas profile of a process for the production of ammonium sulfate from nitrogen-fixing photosynthetic cyanobacteria. AB - In this paper, an alternative means for nitrogen fixation that may consume less energy and release less greenhouse gases than the Haber-Bosch process is explored. A life-cycle assessment was conducted on a process to: culture the cyanobacterium, Anabaena sp. ATCC 33047, in open ponds; harvest the biomass and exopolysaccharides and convert these to biogas; strip and convert the ammonia from the biogas residue to ammonium sulfate; dry the ammonium sulfate solution to ammonium sulfate crystals and transport the finished product. The results suggest that substantial reductions in non-renewable energy use and greenhouse gas emissions may be realized. The study opens the possibility that Haber-Bosch ammonia may be replaced with ammonia from a biomass process which simultaneously generates renewable energy. The process is intrinsically safer than the Haber Bosch process. However, there are trade-offs in terms of land use and possibly, water. PMID- 22226592 TI - Particle heterogeneity of corn distillers dried grains with solubles (DDGS). AB - In this study the physical, morphological and chemical characteristics of distillers dried grains with solubles (DDGS) produced by mixing three levels of condensed distillers soluble (CDS) (0%, 3.69% and 7.39% volumetric basis, v.b.) with wet distillers grains and drying were characterized. Decreasing the CDS level from 7.39% to 0% v.b. resulted in a reduction of 13.9% in geometric mean particle size and 8.8% in bulk density while the compressibility of the material increased by 3%. As the CDS level increased, pore volume, particle porosity and effective bulk porosity decreased. Crude fat, crude protein, crude fiber and ash content showed distinct patterns for all three samples studied and suggest that US sieve no. 16 (1190 MUm) may be an inflection point for the chemical characteristics of DDGS granules within a bulk. The observed heterogeneity could cause sampling errors and particle segregation, and as a consequence nutrient and bulk density variability. PMID- 22226593 TI - Effects of harvest date, irrigation level, cultivar type and fruit water content on olive mill wastewater generated by a laboratory scale 'Abencor' milling system. AB - Olive mill wastewaters (OMW) were obtained at laboratory scale by milling olives from four cultivars grown at different irrigation levels and harvested at different times. Samples were compared based on wastewater quantity, pH, suspended matter, salinity, organic load, total phenols, NPK, and phytotoxicity. Principal component analysis discriminated between harvest times, regardless of olive cultivar, indicating substantial influence of fruit ripeness on OMW characteristics. OMW properties were affected both by the composition and the extraction efficiency of fruit water. As the fruit water content increased, the concentrations of solutes in the fruit water decreased, but the original fruit water composed a larger portion of the total wastewater volume. These contradicting effects resulted in lack of correlation between fruit water content and OMW properties. The significant effects shown for fruit ripeness, irrigation and cultivar on OMW characteristics indicate that olive horticultural conditions should be considered in future OMW management. PMID- 22226594 TI - Caffeine prevents acute mortality after TBI in rats without increased morbidity. AB - Severe traumatic brain injury (TBI) is associated with a high incidence of acute mortality followed by chronic alteration of homeostatic network activity that includes the emergence of posttraumatic seizures. We hypothesized that acute and chronic outcome after severe TBI critically depends on disrupted bioenergetic network homeostasis, which is governed by the availability of the brain's endogenous neuroprotectant adenosine. We used a rat lateral fluid percussion injury (FPI) model of severe TBI with an acute mortality rate of 46.7%. A subset of rats was treated with 25mg/kg caffeine intraperitoneally within 1 min of the injury. We assessed neuromotor function at 24h and 4 weeks, and video-EEG activity and histology at 4 weeks following injury. We first demonstrate that acute mortality is related to prolonged apnea and that a single acute injection of the adenosine receptor antagonist caffeine can completely prevent TBI-induced mortality when given immediately following the TBI. Second, we demonstrate that neuromotor function is not affected by caffeine treatment at either 24h or 4 weeks following injury. Third, we demonstrate development of epileptiform EEG bursts as early as 4 weeks post-injury that are significantly reduced in duration in the rats that received caffeine. Our data demonstrate that acute treatment with caffeine can prevent lethal apnea following fluid percussion injury, with no negative influence on motor function or histological outcome. Further, we show epileptiform bursting is reduced after caffeine treatment, suggesting a potential role in the modulation of epilepsy development after severe injury. PMID- 22226596 TI - Spinal neuronal dysfunction after stroke. AB - Central nervous system lesions, such as stroke or spinal cord injury (SCI), are followed by both cortical and spinal neuronal reorganization. In a severe chronic SCI a spinal neuronal dysfunction develops which is reflected in an exhaustion of leg muscle electromyographic (EMG) activity during assisted locomotion and a change in the dominance from an early to a late polysynaptic spinal reflex (SR) component. The aim of this study was to investigate the course of spinal neuronal function after a severe stroke, i.e., a unilateral deprivation of supraspinal input. In 30 hemiparetic stroke subjects locomotor and SR behavior were assessed. SR responses in the tibialis anterior muscle were evoked by non-noxious tibial nerve stimulation on both, the affected and the unaffected leg. In nine stroke subjects EMG activity of the leg muscles was recorded during assisted locomotion. In a similar way to SCI subjects, in severely affected chronic (>12 months post incidence) stroke subjects a late SR component was prominent in the affected leg, while an early one dominated in the unaffected leg. The late SR component correlated with muscle paresis (rho=0.714) and walking ability (rho=0.493). In contrast to SCI subjects, no exhaustion of the EMG activity was observed in the affected leg muscles during prolonged assisted locomotion. It is concluded that spinal neuronal circuits undergo functional changes also after a stroke which have common as well as divergent features compared to SCI subjects. As a consequence, different rehabilitative strategies might be required. PMID- 22226595 TI - Ferric iron chelation lowers brain iron levels after intracerebral hemorrhage in rats but does not improve outcome. AB - Iron-mediated free radical damage contributes to secondary damage after intracerebral hemorrhage (ICH). Iron is released from heme after hemoglobin breakdown and accumulates in the parenchyma over days and then persists in the brain for months (e.g., hemosiderin). This non-heme iron has been linked to cerebral edema and cell death. Deferoxamine, a ferric iron chelator, has been shown to mitigate iron-mediated damage, but results vary with less protection in the collagenase model of ICH. This study used rapid-scanning X-ray fluorescence (RS-XRF), a synchrotron-based imaging technique, to spatially map total iron and other elements (zinc, calcium and sulfur) at three survival times after collagenase-induced ICH in rats. Total iron was compared to levels of non-heme iron determined by a Ferrozine-based spectrophotometry assay in separate animals. Finally, using RS-XRF we measured iron levels in ICH rats treated with deferoxamine versus saline. The non-heme iron assay showed elevations in injured striatum at 3 days and 4 weeks post-ICH, but not at 1 day. RS-XRF also detected significantly increased iron levels at comparable times, especially notable in the peri-hematoma zone. Changes in other elements were observed in some animals, but these were inconsistent among animals. Deferoxamine diminished total parenchymal iron levels but did not attenuate neurological deficits or lesion volume at 7 days. In summary, ICH significantly increased non-heme and total iron levels. We evaluated the latter and found it to be significantly lowered by deferoxamine, but its failure to attenuate injury or functional impairment in this model raises concern about successful translation to patients. PMID- 22226597 TI - Circadian dentate gyrus excitability in a rat model of temporal lobe epilepsy. AB - In human mesial temporal lobe epilepsy (mTLE), seizure occurrence peaks in the late afternoon and early evening. This temporal binding of seizures has been replicated in animal models of mTLE following electrically-induced status epilepticus (SE). We hypothesized that in chronic epilepsy, alterations of circadian excitatory and inhibitory functions of the dentate gyrus (DG), which is believed to regulate the generation of limbic seizures, pathophysiologically contribute to the temporal binding of ictogenesis. We performed electrophysiological single and paired pulse measurements hourly over 24h in the DG of epileptic rats (n=8) 8 weeks after electrically induced SE. Results were compared to individual data obtained before induction of SE and to those of control animals (n=3). Pre and post SE data were analyzed in two distinct phases of the day, i.e. a high-seizure phase between 2p.m. and 10p.m. and a low-seizure phase between 10p.m. and 2p.m. In chronic epileptic animals, latency of evoked potentials was significantly reduced in the high-seizure phase (p=0.027) but not in the low-seizure phase. Compared to baseline values, paired pulse inhibition was significantly increased during the low-seizure phase (interpulse interval (IPI) 25ms, p=0.003; IPI 30ms; p<0.001) but not in the high-seizure phase. Similarly, when compared to controls, inhibition at IPI 20ms was diminished only in the high-seizure phase (p=0.027). Thus, in chronic epileptic animals, DG excitability is increased in the afternoon and early evening possibly contributing to the time of day-dependency of spontaneous seizures in this model system of mTLE. Alterations of circadian DG excitability in epileptic animals may be influenced by changes in hypothalamus-regulated superordinate functions such as excretion of endocrine hormones but further studies are needed. PMID- 22226598 TI - Sleep a therapeutic target for stroke? PMID- 22226599 TI - Structural and functional evaluation of cortical motor areas in Amyotrophic Lateral Sclerosis. AB - The structural and functional data gathered with Magnetic Resonance Imaging (MRI) techniques about the brain cortical motor damage in Amyotrophic Lateral Sclerosis (ALS) are controversial. In fact some structural MRI studies showed foci of gray matter (GM) atrophy in the precentral gyrus, even in the early stage, while others did not. Most functional MRI (fMRI) studies in ALS reported hyperactivation of extra-primary motor cortices, while contradictory results were obtained on the activation of the primary motor cortex. We aimed to investigate the cortical motor circuitries in ALS patients by a combined structural and functional approach. Twenty patients with definite ALS and 16 healthy subjects underwent a structural examination with acquisition of a 3D T1-weighted sequence and fMRI examination during a maximal force handgrip task executed with the right hand, the left-hand and with both hands simultaneously. The T1-weighted images were analyzed with Voxel-Based Morphometry (VBM) that showed several clusters of reduced cortical GM in ALS patients compared to controls including the pre and postcentral gyri, the superior, middle and inferior frontal gyri, the supplementary motor area, the superior and inferior parietal cortices and the temporal lobe, bilaterally but more extensive on the right side. In ALS patients a significant hypoactivation of the primary sensory motor cortex and frontal dorsal premotor areas as compared to controls was observed. The hypoactivated areas matched with foci of cortical atrophy demonstrated by VBM. The fMRI analysis also showed an enhanced activation in the ventral premotor frontal areas and in the parietal cortex pertaining to the fronto-parietal motor circuit which paralleled with disease progression rate and matched with cortical regions of atrophy. The hyperactivation of the fronto-parietal circuit was asymmetric and prevalent in the left hemisphere. VBM and fMRI identified structural and functional markers of an extended cortical damage within the motor circuit of ALS patients. The functional changes in non-primary motor cortices pertaining to fronto-parietal circuit suggest an over-recruitment of a pre-existing physiological sensory-motor network. However, the concomitant fronto-parietal cortical atrophy arises the possibility that such a hyper-activation reflects cortical hyper-excitability due to loss of inhibitory inter-neurons. PMID- 22226600 TI - Immune responses of microglia in the spinal cord: contribution to pain states. AB - The role of microglia and their contribution to the development and maintenance of pain states has emerged as an attractive field of study. Sensitization of central nociceptors and interneurons is thought to be responsible for the symptoms of chronic neuropathic pain states. Microglia interact with these neurons at the site of injury or disease as well as remotely. Microglia can be activated by phagocytosis or through the activation of a number of constitutively expressed cell surface molecules. Once activated, microglia participate in both innate and adaptive immune responses and remain active indefinitely. Activated microglia contribute to pain states through the production of pro-inflammatory cytokines, chemokines and extracellular proteases. Activated microglia also exhibit a modulated cell surface receptor and ion channel profile. The activation of several intracellular pathways in microglia has also been implicated in pain states. Attenuation of microglia activity is being presented as a viable therapeutic approach with regard to not only the reduction of pain symptoms but also in preventing the development of chronic pain states. PMID- 22226601 TI - High pressure-induced retinal ischaemia reperfusion causes upregulation of gap junction protein connexin43 prior to retinal ganglion cell loss. AB - We aimed to characterise the spatial and temporal expression of connexin43 (Cx43) following retinal ischaemia-reperfusion injury and to evaluate its relationship to retinal glial response and subsequent retinal ganglion cell loss. Unilateral retinal ischaemia-reperfusion injury was induced by elevating intraocular pressure to 120mmHg for 60 min and then normalized in Wistar rats. Retinas (n=110) were evaluated at 4, 8, and 24h, and 7, 14, and 21 days in 4 groups: ischaemic, contralateral, sham operated, and uninjured eyes. Immunohistochemistry was used to analyse the spatial and cell-specific expression of Cx43 protein, glial fibrillary acidic protein (astrocytes), glutamine synthetase (Muller cells), Isolectin B4 (vascular endothelium), DAPI (nuclear marker), and BRN3a (retinal ganglion cells). Retinal whole mounts were used to count retinal ganglion cells. Our results show that Cx43 immunoreactivity of the ischaemic eye is significantly increased in the ganglion cell layer and nerve fibre layer, colocalizing with activated retinal astrocytes and Muller cells at 8h. In the inner retinal layers Cx43 was also upregulated and colocalized with retinal vascular endothelium at 4, 8 and 24h post ischaemia. Notably, in the contralateral eye, Cx43 immunoreactivity was also significantly increased in the ganglion cell layer and nerve fibre layer at 8 and 24h, and at 4h in the inner layers. Sham operated controls did not show any change in Cx43 immunoreactivity. Subsequently a significant retinal ganglion cell loss was observed in the ischaemic eye at day 21 with a trend towards retinal ganglion cell loss in the contralateral eye. In conclusion, upregulation of Cx43 occurs in both the ischaemic and contralateral retinas although far more significantly in injured retinas. Cx43 colocalizes primarily with activated retinal astrocytes and Muller cells as well as vascular endothelium, suggesting that gap junction communication and/or hemichannel activity may be a mediator of inflammation, vascular permeability, and subsequently neuronal death. PMID- 22226603 TI - Health inequalities by class and race in the US: what can we learn from the patterns? PMID- 22226602 TI - Auditory brainstem implant outcomes and MAP parameters: report of experiences in adults and children. AB - The auditory brainstem implant (ABI) was first developed to help neurofibromatosis type 2 patients. Recently, its use has been recently extended to adults with non-tumor etiologies and children with profound hearing loss who were not candidates for a cochlear implant (CI). Although the results has been extensively reported, the stimulation parameters involved behind the outcomes have received less attention. OBJECTIVE: The aim of this study is to describe the audiologic outcomes and the MAP parameters in ABI adults and children at our center. METHODS: Retrospective chart review. Five adults and four children were implanted with the ABI24M from September 2005 to June 2009. In the adult patients, four had Neurofibromatosis type 2, and one had postmeningitic deafness with complete ossification of both cochleae. Three of the children had cochlear malformation or dysplasia, and one had complete ossified cochlea due to meningitis. Map parameters as well as the intraoperative electrical auditory brainstem responses were collected. Evaluation was performed with at least six months of device use and included free-field hearing thresholds, speech perception tests in the adult patients and for the children, the Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS) and (ESP) were used to evaluate the development of auditory skills, besides the MUSS to evaluate. RESULTS: The number of active electrodes that did not cause any non-auditory sensation varied from three to nineteen. All of them were programmed with SPEAK strategy, and the pulse widths varied from 100 to 300 MUs. Free-field thresholds with warble tones varied from very soft auditory sensation of 70 dBHL at 250 Hz to a pure tone average of 45 dBHL. Speech perception varied from none to 60% open-set recognition of sentences in silence in the adult population and from no auditory sensation at all to a slight improvement in the IT-MAIS/MAIS scores. CONCLUSION: We observed that ABI may be a good option for offering some hearing attention to both adults and children. In children, the results might not be enough to ensure oral language development. Programming the speech processor in children demands higher care to the audiologist. PMID- 22226604 TI - Health systems, health and wealth: the argument for investment applies now more than ever. PMID- 22226605 TI - Will the recession be bad for our health? It depends. PMID- 22226606 TI - How can our health systems be re-engineered to meet the future challenges? The Swedish experience. PMID- 22226608 TI - The predominant drug-specific T-cell population may switch from cytotoxic T cells to regulatory T cells during the course of anticonvulsant-induced hypersensitivity. AB - BACKGROUND: Delayed hypersensitivity is responsible for severe cutaneous adverse drug reactions (cADRs), especially in Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis, and drug-induced hypersensitivity syndrome (DIHS) (also known as drug rash with eosinophilia and systemic symptoms [DRESS] syndrome). The drug-induced lymphocyte stimulation test (DLST), or lymphocyte transformation test (LTT), is used to identify the culprit drug in severe cADR cases. OBJECTIVE: The aim of this study was to examine the immune reactions in cADR patients through the identification of the drug-specific proliferating cells by flow cytometric DLST (FCM-DLST). METHODS: The peripheral blood mononuclear cells of 16 anticonvulsant-induced cADR patients were investigated by conventional DLST and a FCM-DLST protocol in which CFSE dilution and BrdU incorporation were combined. FCM-DLST allowed for the identification of the drug-specific proliferating cells in six cases. Three of these cases were DIHS cases, whereas there was one case of SJS, one case of maculopapular rash (MP), and one case of erythema multiforme (EM) among the six cases. RESULTS: In FCM-DLST, drug-specific proliferating T cells were detected as CFSE(low) BrdU(high) cells. These cells corresponded to the cells incorporating (3)H-thymidine in conventional DLST. Although CD4(+) T cell proliferation dominated the observed proliferation in most of the cases (in the recovery stage of the three DIHS cases, the MP case, and the EM case), drug specific CD8(+) cytotoxic T lymphocytes (CTLs) were detected, especially in the acute stages of the SJS case and one of the DIHS cases. There was a dramatic switch in the predominant drug-specific proliferating T-cell population in the course of one of the cases of DIHS in which CD8(+) CTLs were predominant initially, whereas CD4(+) T cells were predominant later. Moreover, drug-specific CD4(+) CD25(+) Foxp3(+) regulatory T cells (Tregs) proliferated during the recovery stage in one DIHS case. CONCLUSIONS: FCM-DLST revealed that the cell proliferation detected by conventional DLST is a heterogeneous proliferation of both CD8(+) CTLs and CD4(+) T cells that likely includes Tregs. However, the number of cADR cases in this study was limited, which limits the conclusions that can be drawn from it. PMID- 22226609 TI - Comparison of arthroplasty trial publications after registration in ClinicalTrials.gov. AB - In 2005, the International Committee of Medical Journal Editors established a mandatory trial registration before study enrollment for publication in member journals. Our primary objective was to evaluate the publication rates of arthroplasty trials registered with ClinicalTrials.gov (CTG). We further aimed to examine the consistency of registration summaries with that of final publications. We searched CTG for all trials related to joint arthroplasty and conducted a thorough search for publications resulting from registered closed trials. Of 101 closed and completed trials, we found 23 publications, for an overall publication rate of 22.8%. Registration of arthroplasty trials in CTG does not consistently result in publication or disclosure of results. In addition, changes are frequently made to the final presentation of the data that are not reflected in the trial registry. PMID- 22226607 TI - You've come a long way: c-di-GMP signaling. AB - Cyclic dimeric guanosine monophosphate (c-di-GMP) is a common, bacterial second messenger that regulates diverse cellular processes in bacteria. Opposing activities of diguanylate cyclases (DGCs) and phosphodiesterases (PDEs) control c di-GMP homeostasis in the cell. Many microbes have a large number of genes encoding DGCs and PDEs that are predicted to be part of c-di-GMP signaling networks. Other building blocks of these networks are c-di-GMP receptors which sense the cellular levels of the dinucleotide. C-di-GMP receptors form a more diverse family, including various transcription factors, PilZ domains, degenerate DGCs or PDEs, and riboswitches. Recent studies revealing the molecular basis of c di-GMP signaling mechanisms enhanced our understanding of how this molecule controls downstream biological processes and how c-di-GMP signaling specificity is achieved. PMID- 22226610 TI - Mental health and outcomes in primary total joint arthroplasty. AB - A consecutive series of 640 total joint arthroplasty patients was interviewed before surgery and at a minimum of 2 years following surgery. Statistical analyses were conducted to examine the effect of psychological distress and other patient characteristics on outcomes (Western Ontario and McMaster Universities Osteoarthritis Index, Short Form 36, and Quality of Well-Being index). Before and after surgery, distressed subjects had significantly lower scores than nondistressed subjects for most dependent measures (P range, .05 <= .001). All mean outcomes improved by follow-up in both groups (P <= .001) except mental health scores of nondistressed subjects. Stepwise regression analysis found that low baseline mental health score, non-Hispanic ethnicity, and fewer years since procedure were the strongest predictors of worse Western Ontario and McMaster Universities Osteoarthritis Index scores at follow-up. Although the magnitude of improvement is similar to nondistressed subjects, distressed patients do not achieve comparable functional and psychosocial outcomes. PMID- 22226611 TI - Validation of patient-reported coagulation complications after total knee surgery. PMID- 22226612 TI - Abductor dysfunction and related sciatic nerve palsy, a new complication of metal on-metal arthroplasty. AB - The optimal bearing for use in young patients with hip arthritis remains elusive. Current options include metal-on-cross-linked polyethylene, ceramic-on-cross linked polyethylene, ceramic on ceramic, and metal on metal. Each of these bearing couples has advantages and disadvantages. Metal-on-metal designs allow the use of large heads that decrease impingement and improve stability. This fact has made this bearing an attractive option for surgeons and patients alike. This case report will illustrate a severe adverse reaction to metal debris with necrosis of soft tissues and subsequent damage to the sciatic nerve. PMID- 22226613 TI - Repeat 2-stage exchange for infected total hip arthroplasty: a viable option? AB - We investigated whether performing a repeat 2-stage exchange eradicates infection in patients who previously underwent 2-stage treatment for an infected total hip arthroplasty. We identified 15 patients who had failed a 2-stage total hip arthroplasty and underwent a planned repeat 2-stage between 2000 and 2009. Of the 15 patients, 8 were treated with a complete 2-stage procedure, whereas the remaining 7 patients were treated only with a first-stage resection of the infected implant. Of the 8 patients who underwent complete 2-stage exchange, 1 died because of in-hospital complications, and 1 had a recurrent infection. Repeat infection is highly associated with resistant organisms, obesity, and poor patient health. Of the 7 patients who underwent resection without reimplantation, 3 had a recurrent infection. Our data suggest that if infection can be adequately controlled after repeat resection of the joint prosthesis, reimplantation is a reasonable option. PMID- 22226614 TI - Periacetabular cortical and cancellous bone mineral density loss after press-fit cup fixation: a prospective 7-year follow-up. AB - The impact of total hip arthroplasty on strain adaptive bone remodeling has been extensively analyzed by dual-energy x-ray absorptiometry. In this study, we present a prospective computed tomography-assisted study of periacetabular cortical and cancellous bone mineral density (in milligrams of calcium hydroxyapatite [CaHA] per milliliter, or mgCaHA/mL) changes 10 days and 1, 3, and 7 years after press-fit cup implantation for 38 hips in vivo. Cancellous bone mineral density decreased by O -63% ventral and O -85% dorsal to the cup; cortical bone mineral density, by O -22% ventral and O -18% dorsal to the cup. The presented periacetabular strain adaptive bone mineral density data are the most extensive of the current literature. Even the measured extensive cancellous bone mineral density loss was thus far of no clinical relevance because all cups showed radiographic signs of stable ingrowth. PMID- 22226615 TI - Cognitive models of risky choice: parameter stability and predictive accuracy of prospect theory. AB - In the behavioral sciences, a popular approach to describe and predict behavior is cognitive modeling with adjustable parameters (i.e., which can be fitted to data). Modeling with adjustable parameters allows, among other things, measuring differences between people. At the same time, parameter estimation also bears the risk of overfitting. Are individual differences as measured by model parameters stable enough to improve the ability to predict behavior as compared to modeling without adjustable parameters? We examined this issue in cumulative prospect theory (CPT), arguably the most widely used framework to model decisions under risk. Specifically, we examined (a) the temporal stability of CPT's parameters; and (b) how well different implementations of CPT, varying in the number of adjustable parameters, predict individual choice relative to models with no adjustable parameters (such as CPT with fixed parameters, expected value theory, and various heuristics). We presented participants with risky choice problems and fitted CPT to each individual's choices in two separate sessions (which were 1 week apart). All parameters were correlated across time, in particular when using a simple implementation of CPT. CPT allowing for individual variability in parameter values predicted individual choice better than CPT with fixed parameters, expected value theory, and the heuristics. CPT's parameters thus seem to pick up stable individual differences that need to be considered when predicting risky choice. PMID- 22226616 TI - Adsorption and protection of plasmid DNA on mesoporous silica nanoparticles modified with various amounts of organosilane. AB - Ordered MCM-41-type mesoporous silica nanoparticles (MSNs) with pore size of 2.6 nm were synthesized and were further modified with various amounts of 3 aminopropyltriethoxysilane (APTES), respectively, by a direct co-condensation method. These amine functionalized mesoporous silica nanoparticles (Am-MSNs) were employed to complex with plasmid DNA (pDNA) to study their adsorption and protection capacities. The results demonstrate the MSNs functionalized with aminopropyl groups present advanced adsorption capacities for pDNA immobilization. And Am-MSNs with high APTES amount lead to high amount of pDNA adsorption. Further investigation of pDNA protection shows that Am-MSNs with moderate APTES amount could completely protect pDNA from enzymatic degradation, while those with smaller and/or higher amount of APTES could partially provide protection of pDNA. PMID- 22226617 TI - Large scale fabrication of highly monodispersed rattle-type TiO2@void@SiO2 spheres via synthesis-cum-organization process. AB - Architected nanostructures with interior space have attracted enormous attention due to both their esthetic beauty and their potential applications. It is a current dream to develop a template-free, one-pot and low-temperature synthetic routes for hetero-architecture in liquid media. In this manuscript, we develop a kind of template-free, low-temperature, and one-pot total synthetic strategy for synthesis of inorganic multi-component hetero-architecture. This synthetic strategy analogous to standard organic reactions used in total synthesis is an important breakthrough in inorganic chemical synthesis. We can achieve 1 kilogram (kg) yield of the TiO(2)@void@SiO(2) core-shell sphere one time by using this synthetic strategy, which may lead to practical applications of the sample. By embodying the new reaction and concept into future investigation, a more mature research field in synthetic architecture of nanomaterials can be anticipated. PMID- 22226618 TI - Bayesian spectral deconvolution with the exchange Monte Carlo method. AB - An analytical method to deconvolute spectral data into a number of simple bands is extremely important in the analysis of the chemical properties of matter. However, there are two fundamental problems with such deconvolution methods. One is how to determine the number of bands without resorting to heuristics. The other is difficulty in avoiding the parameter solution trapped into local minima due to the hierarchy and the nonlinearity of the system. In this study, we propose a novel method of spectral deconvolution based on Bayesian estimation with the exchange Monte Carlo method, which is an application of the integral approximation of stochastic complexity and the exchange Monte Carlo method. We also experimentally show its effectiveness on synthetic data and on reflectance spectral data of olivine, one of the most common minerals of terrestrial planets. PMID- 22226619 TI - Selenocompounds in juvenile white sturgeon: evaluating blood, tissue, and urine selenium concentrations after a single oral dose. AB - Selenium (Se) is an essential micronutrient for all vertebrates, however, at environmental relevant levels, it is a potent toxin. In the San Francisco Bay Delta, white sturgeon, an ancient Chondrostean fish of high ecological and economic value, is at risk to Se exposure. The present study is the first to examine the uptake, distribution, and excretion of various selenocompounds in white sturgeon. A combined technique of stomach intubation, dorsal aorta cannulation, and urinary catheterization was utilized, in this study, to characterize the short-term effects of Se in the forms of sodium-selenate (Selenate), sodium-selenite (Selenite), selenocystine (SeCys), l-selenomethionine (SeMet), Se-methylseleno-l-cysteine (MSeCys), and selenoyeast (SeYeast). An ecologically relevant dose of Se (~500 MUg/kg body weight) was intubated into groups of 5 juvenile white sturgeon. Blood and urine samples were repeatedly collected over the 48 h post intubation period and fish were sacrificed for Se tissue concentration and distribution at 48 h. The tissue concentration and distribution, blood concentrations, and urinary elimination of Se significantly differ (p <= 0.05) among forms. In general, organic selenocompounds maintain higher blood concentrations, with SeMeCys maintaining the highest area under the curve (66.3 +/- 8.7 and 9.3 +/- 1.0 MUg h/ml) and maximum Se concentration in blood (2.3 +/- 0.2 and 0.4 +/- 0.2 MUg/ml) in both the protein and non-protein bound fractions, respectively. Selenate, however, did not result in significant increase of Se concentration, compared with the control, in the protein-bound blood fraction. Regardless of source, Se is preferentially distributed into metabolically active tissues, with the SeMet treated fish achieving the highest concentration in most tissues. In contrast, Selenite has very similar blood concentrations and tissue distribution profile to SeCys and SeYeast. From blood and tissue Se concentrations, Selenate is not stored in blood, but taken up rapidly by the liver and white muscle. Urinary elimination of Se is form dependent and peaks between 3 and 12 h post intubation. A basic understanding of the overall Se absorption, distribution, and elimination is provided through monitoring tissue Se concentrations, however, conclusions regarding to the dynamics and the specific processes of Se metabolism can only be inferred, in the absence of kinetic information. PMID- 22226620 TI - Microbial analysis of anodic biofilm in a microbial fuel cell using slaughterhouse wastewater. AB - The ability of dual-chambered microbial fuel cell, fed with slaughterhouse wastewater with an anaerobic mixed-sludge as initial source of bacteria, to generate power is investigated. MFC voltage generation across a fixed 100 Omega load indicates power generation capability, with power production correlated to changes in anolyte VFA content. A maximum MFC power density of 578 mW/m(2) is obtained for an MFC developed under 100 Omega load, compared to a maximum power density of 277 mW/m(2) for an MFC developed under higher resistance (1 MOmega) control conditions. Voltammetry of the biofilm developed under 100 Omega load displays a current-voltage signal indicative of bioelectrocatalytic oxidation of feed at a potential of -0.35 V vs. Ag/AgCl, compared to negligible signals for biofilms developed under control conditions. Denaturing gradient gel electrophoresis of PCR amplified 16S rRNA gene fragments reveals that the anodic bacterial communities in reactors operated under 100 Omega load result in communities of lower diversity than for the control condition, with Geovibrio ferrireducens dominant in the anodic biofilm community. These results indicate that in MFC reactors, functionally stable electroactive bacteria are enriched under 100 Omega load compared to high resistance control conditions, and were able to sustain higher power in MFCs. PMID- 22226621 TI - GEF-H1/RhoA signalling pathway mediates lipopolysaccharide-induced intercellular adhesion molecular-1 expression in endothelial cells via activation of p38 and NF kappaB. AB - The purpose of study is to investigate the effects of GEF-H1/RhoA pathway in regulating intercellular adhesion molecule-1 (ICAM-1) expression in lipopolysaccharide (LPS)-activated endothelial cells. Exposure of human umbilical vein endothelial cells (HUVECs) to LPS induced GEF-H1 and ICAM-1 expression in dose- and time-dependent up-regulating manners. Pretreatment with Clostridium difficile toxin B-10463 (TcdB-10463), an inhibitor of Rho activity, reduced LPS related phosphorylation of p65 at Ser 536 in a dose-dependent manner. Inhibition of TLR4 expression significantly blocked LPS-induced RhoA activity, NF-kappaB transactivation, GEF-H1 and ICAM-1 expression. Coimmunoprecipitation assay indicated that LPS-activated TLR4 and GEF-H1 formed a signalling complex, suggesting that LPS, acting through TLR4, stimulates GEF-H1 expression and RhoA activity, and thereby induces NF-kappaB transactivation and ICAM-1 gene expression. However, GEF-H1/RhoA regulates LPS-induced NF-kappaB transactivation and ICAM-1 expression in a MyD88-independent pathway because inhibition of MyD88 expression could not block LPS-induced RhoA activity. Furthermore, pretreatment with Y-27632, an inhibitor of ROCK, significantly reduced LPS-induced p38, ERK1/2 and p65 phosphorylation, indicating that ROCK acts as an upstream effector of p38 and ERK1/2 to promote LPS-induced NF-kappaB transactivation and ICAM-1 expression. What is more, the p38 inhibitor (SB203580) but not ERK1/2 inhibitor (PD98059) blocked LPS-induce NF-kappaB transactivation and ICAM-1 expression, which demonstrates that RhoA mediates LPS-induced NF-kappaB transactivation and ICAM-1 expression dominantly through p38 but not ERK1/2 activation. In summary, our data suggest that LPS-induced ICAM-1 synthesis in HUVECs is regulated by GEF H1/RhoA-dependent signaling pathway via activation of p38 and NF-kappaB. PMID- 22226622 TI - Odor-enriched environment rescues long-term social memory, but does not improve olfaction in social isolated adult mice. AB - Prolonged permanence of animals under social isolation (SI) arouses a variety of psychological symptoms like aggression, stress, anxiety and depression. However, short-term SI is commonly used to evaluate social memory. Interestingly, the social memory cannot be accessed with delays higher than 30min in SI mice. Our hypothesis is that SI with intermediate duration, like one week (1w), impairs the long-term storage of new social information (S-LTM), without affecting anxiety or other types of memories, because the SI compromises the olfactory function of the animal. Our results demonstrated that SI impaired S-LTM, without affecting other kinds of memory or anxiety. In addition, the SI increased the latency in the buried-food finding task, but did not affect the habituation or the discrimination of odors. Next, we postulated that if continuous input to the olfactory system is fundamental for the maintenance of the olfactory function and social memory persistence, isolated mice under odor-enriched environment (OEE) should behave like group-housed (GH) animals. In fact, the OEE prevented the S LTM deficit imposed by the SI. However, OEE did not restore the SI mice olfaction to the GH mice level. Our results suggest that SI modulates olfaction and social memory persistence, probably, by independent mechanisms. We also showed for the first time that OEE rescued S-LTM in SI mice through a mechanism not necessarily involved with olfaction. PMID- 22226623 TI - Activation of dopamine D1 receptors in the medial septum improves scopolamine induced amnesia in the dorsal hippocampus. AB - In the present study, we investigated the influence of intra-medial septum (intra MS) injections of dopamine D1 receptor agents on amnesia induced by intra-CA1 injections of a muscarinic acetylcholine receptor antagonist, scopolamine. This study used a step-through inhibitory (passive) avoidance task to assess memory in adult male Wistar rats. The results showed that in the animals that received post training intra-MS injections of saline, intra-CA1 administrations of scopolamine (0.75, 1, and 2 MUg/rat) decreased inhibitory avoidance (IA) memory consolidation as evidenced by a decrease in step-through latency on the test day, which was suggestive of drug-induced amnesia. Post-training intra-MS injections of a dopamine D1 receptor agonist, SKF38393 at doses of 0.1, 0.15, and 0.3 MUg/rat had no effect, but at dose of 0.5 MUg/rat impaired IA memory consolidation. Interestingly, intra-MS injections of SKF38393 (0.15, 0.3 and 0.5 MUg/rat) significantly prevented amnesia induced by intra-CA1 injections of scopolamine (1 MUg/rat). Intra-MS injections of a dopamine D1 receptor antagonist, SCH23390 (0.5 and 0.75 MUg/rat) by itself impaired IA memory consolidation, and also at dose of 0.75 MUg/rat increased amnesia induced by intra-CA1 administrations of an ineffective dose of scopolamine (0.5 MUg/rat). Post-training intra-MS injections of ineffective doses of SCH23390 (0.1, 0.3 and 0.5 MUg/rat) prevented an effective dose of SKF38393 response to the impaired effect of scopolamine. These results suggest that dopamine D1 receptors in the MS via projection neurons to the hippocampus affect impairment of memory consolidation induced by intra-CA injections of scopolamine. PMID- 22226625 TI - The elderly patient with surgically resected non-small cell lung cancer--a distinct situation? AB - The worldwide population shift towards older ages will inevitably lead to more elderly patients being diagnosed with cancer. Lung cancer is the number one cause for cancer mortality and surgical resection is the treatment of choice whenever possible. This study investigates whether elderly patients with non-small cell lung cancer (NSCLC) are characterized by distinct clinical and pathologic features and different clinical course after resection. Special emphasis is placed on disease recurrence, which is an important, but rarely described parameter for biological tumor behavior. Sex, stage, histology, differentiation grade, smoking status, performance status, hemoglobin, C-reactive protein, lactate dehydrogenase, Ki-67 index, recurrent disease and overall survival were analyzed in 383 surgically resected NSCLC patients. Calculations were performed comparing patients <70 to >=70 years. A postoperative follow-up period of 15 years enabled detailed correlations. Rate of disease recurrence and disease-free survival did not differ between any age groups and was not influenced by clinico pathologic parameters. Elderly patients with a Ki-67 index of >3% were associated with significantly decreased overall survival time when compared to younger patients (36.3 and 47.3 months respectively, p=0.029). The biological behavior of NSCLC as reflected by characteristics of disease recurrence is similar for surgically resected patients among different age groups and does not warrant specific recommendations for the elderly surgical patient. The Ki-67 index offers prognostic information for overall survival in the elderly. PMID- 22226624 TI - Cellular adaptation contributes to calorie restriction-induced preservation of skeletal muscle in aged rhesus monkeys. AB - We have previously shown that a 30% reduced calorie intake diet delayed the onset of muscle mass loss in adult monkeys between ~16 and ~22 years of age and prevented multiple cellular phenotypes of aging. In the present study we show the impact of long term (~17 years) calorie restriction (CR) on muscle aging in very old monkeys (27-33 yrs) compared to age-matched Control monkeys fed ad libitum, and describe these data in the context of the whole longitudinal study. Muscle mass was preserved in very old calorie restricted (CR) monkeys compared to age matched Controls. Immunohistochemical analysis revealed an age-associated increase in the proportion of Type I fibers in the VL from Control animals that was prevented with CR. The cross sectional area (CSA) of Type II fibers was reduced in old CR animals compared to earlier time points (16-22 years of age); however, the total loss in CSA was only 15% in CR animals compared to 36% in old Controls at ~27 years of age. Atrophy was not detected in Type I fibers from either group. Notably, Type I fiber CSA was ~1.6 fold greater in VL from CR animals compared to Control animals at ~27 years of age. The frequency of VL muscle fibers with defects in mitochondrial electron transport system enzymes (ETS(ab)), the absence of cytochrome c oxidase and hyper-reactive succinate dehydrogenase, were identical between Control and CR. We describe changes in ETS(ab) fiber CSA and determined that CR fibers respond differently to the challenge of mitochondrial deficiency. Fiber counts of intact rectus femoris muscles revealed that muscle fiber density was preserved in old CR animals. We suggest that muscle fibers from CR animals are better poised to endure and adapt to changes in muscle mass than those of Control animals. PMID- 22226626 TI - A meta-analysis of paclitaxel-based chemotherapies administered once every week compared with once every 3 weeks first-line treatment of advanced non-small-cell lung cancer. AB - OBJECTIVE: The published data on the curative effects of comparing the once weekly paclitaxel-based chemotherapies (W-paclitaxel) with the standard every 3 weeks paclitaxel-based chemotherapies (S-paclitaxel) in the first-line treatment of advanced non-small-cell lung cancer (NSCLC) were still controversial. To derive a more precise estimation of the two regimens, a meta-analysis was performed. METHODS: Medical databases and conference proceedings were searched for randomized controlled trials which compared W-paclitaxel with S-paclitaxel in patients with first-line treatment of advanced NSCLC. The following keywords were used: "paclitaxel", "weekly schedule" and "non-small cell lung cancer". Reference lists of original articles and review articles were also examined. The published languages and years were not limited. Endpoints were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and adverse events. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates were two-sided. RESULTS: Five eligible trials involved 940 patients were identified. They were all published as full-text articles. The intention to treatment (ITT) analysis demonstrated that the ORR of W-paclitaxel regimens patients was 30.89% (143/463), whereas the ORR of S-paclitaxel regimens patients was 27.09% (123/454). The overall pooled relative ratio (RR) for ORR was 1.24 (95% confidence intervals (CI)=0.93-1.66; P=0.14) when W-paclitaxel regimens patients were compared with S-paclitaxel regimens patients. Although the patients with W-paclitaxel regimens had an similar OS and PFS in comparison with S paclitaxel regimens (median OS was 9.8 versus 10.7 months; hazard ratio (HR)=1.00; 95%CI=0.86-1.17; P=0.99; median PFS was 5.2 versus 4.7 months; HR=0.90; 95%CI=0.79-1.03; P=0.13, respectively), the W-paclitaxel regimens led to significantly less frequent adverse events of hematological toxicities and nonhematological toxicities. CONCLUSION: These results suggest that the W paclitaxel is not superior than S-paclitaxel regimens. The paclitaxel-based chemotherapies given by every 3 weeks are still standard regimens. For patients, especially for the elder or the people with poor conditions who cannot tolerate the standard regimen, the weekly schedule can be considered. PMID- 22226627 TI - Erlotinib or best supportive care for third-line treatment of advanced non-small cell lung cancer: a real-world cost-effectiveness analysis. AB - Erlotinib has been approved as a third-line treatment for advanced non-small-cell lung cancer (NSCLC) in British Columbia (BC). A cost-effectiveness analysis was conducted to compare costs and effectiveness in patients who received third-line erlotinib to those in a historical patient cohort that would have been eligible had erlotinib been available. METHODS: In a population of patients who have been treated with drugs for advanced NSCLC, overall survival (OS), progression-to death survival (PTD) and probability of survival one year after end of second line (1YS) were determined using a Kaplan-Meier survival analysis. Costs were collected retrospectively from the perspective of the BC health care system. RESULTS: Incremental mean OS was 90 days (0.25 LYG), and incremental mean cost was $11,102 (CDN 2009), resulting in a mean ICER of $36,838/LYG. Univariate sensitivity analysis yielded ICERs ranging from $21,300 to $51,700/LYG. CONCLUSION: Our analysis suggests that erlotinib may be an effective and cost effective third-line treatment for advanced NSCLC compared to best supportive care. PMID- 22226628 TI - History of tuberculosis as an independent prognostic factor for lung cancer survival. AB - INTRODUCTION: It is well known that pulmonary tuberculosis is associated with an increased risk of lung cancer. We investigated whether a history of pulmonary tuberculosis is an independent risk factor for lung cancer survival in Caucasian patients. METHODS: The data of the prospective population-based cohort of The Rotterdam Study were used. During a mean follow-up time of 18 years, there were 214 incident cases of pathology-proven lung cancer in a source population of 7983 study participants. History of tuberculosis was assessed at baseline by interviewers using standardized questionnaires. Associations of lung cancer survival with the occurrence of pulmonary tuberculosis were assessed using Cox's proportional hazard regression analysis adjusted for age, gender, pack-years, educational level and tumor stage. RESULTS: A history of tuberculosis was reported in 13 of the 214 subjects with lung cancer. The survival of patients with lung cancer was significantly shorter in subjects with a history of pulmonary tuberculosis (HR=2.36, CI95%: 1.1-4.9), than in subjects without a history of pulmonary tuberculosis with a mean difference of 311 days. CONCLUSION: The presence of a history of pulmonary tuberculosis may be an important prognostic factor in the survival of lung cancer. PMID- 22226630 TI - Menopause and work--the experience of middle-aged female teaching staff in an Egyptian governmental faculty of medicine. AB - OBJECTIVES: There is a global trend of increasing numbers of older women in the workforce. However, limited information is available regarding the relationship between the menopause transition and work, especially in developing countries. The objectives of this study were to investigate the relationship between experience of the menopause transition and work and to examine the factors affecting how women cope, including the extent to which women disclosed their menopausal status. METHODS: Using a cross-sectional single group design, 131 middle-aged female medical teaching staff working in Zagazig Faculty of Medicine completed questionnaires and semi-structured interviews. RESULTS: Participants, particularly those who were postmenopausal, reported high average scores on depressed mood, memory/concentration, sleep problems, vasomotor symptoms, and sexual behavior subscales of the Women's Health Questionnaire (WHQ). Women reported that poor working environment and work policies and conditions, functioning as sources of work stress, aggravated their menopausal symptoms. Disclosure of their menopausal status was uncommon; limited time and socio cultural barriers were the most commonly reported reasons for non-disclosure. CONCLUSION: It could be concluded that the menopause transition is an important occupational health issue especially for women in developing countries. Implementing health promotion programs, improving working environment and work policies, and raising awareness of menopause are recommended to help women to cope with the menopause transition and to maintain well-being and productivity at work. PMID- 22226629 TI - Daily physical activity and menopausal hot flashes: applying a novel within person approach to demonstrate individual differences. AB - BACKGROUND: Physical activity (PA) may be a useful tool in the management of menopausal hot flashes (HFs) but findings are generally inconsistent. There are few well-designed and sufficiently powered RCTs. Applying a longitudinal within person approach offers an alternative way to examine the PA-HFs relationship which enables complete accommodation of inter-individual differences. OBJECTIVES: Aprospective daily diary study which applied experience sampling methods and time series modeling techniques investigated, at the within-person level, the relationship between objectively measured daily PA of varying intensities and self-reported menopausal HFs. METHODS: Twenty-four symptomatic middle-aged women (M age=50.4; SD=4.9) completed fitness, body composition and hormonal status screening, and reported on daily HFs using an electronic PDA device across one menstrual cycle or for 30 days (if postmenopausal). Daily PA and PA intensity was measured using accelerometry and subjects completed a battery of psychological measures. RESULTS: Within person analysis identified significant relations between PA and HFs in 50% of subjects, although the specific PA indicators that predicted HFs varied, both in terms of direction and magnitude. Perceived control over HFs was the variable that most consistently differentiated between women for whom more PA was associated with fewer HFs as compared to those for whom more PA was associated with more HFs, but other individual difference characteristics such as affect, depressive symptoms, and anxiety were identified. CONCLUSIONS: There is great individual variation in the way daily PA impacts self-reported HFs. Affective outcomes and perceived control may help potentially explain this variability. PMID- 22226631 TI - Systemic arterial inflammation, measured with 18FDG-PET, is common amongst subjects with both recent and prior cerebrovascular disease. AB - OBJECTIVE: To compare systemic arterial inflammation in subjects with recent ischaemic stroke or TIA and controls with prior cerebrovascular disease. METHODS: Systemic arterial inflammation was prospectively measured by (18)F fluorodeoxygluose positron emission tomography in 11 cases with recent ischaemic stroke or TIA, and 11 sex matched controls with prior cerebrovascular disease. RESULTS: Hot spots (both carotid and non-carotid) of localised (18)FDG uptake were found in more than half of all patients with either recent (n = 6) or prior (n = 8) cerebrovascular disease. There was no significant difference in the total number of hotspots, or hotspots at specific sites, in cases compared with controls. Mean standard uptake values (SUV) were similar in the carotid arteries and aorta of cases and controls, and showed a trend toward higher values in the femoral arteries of the controls (median 1.8; IQR 1.6-2.2) compared to cases (median 1.5; IQR 1.4-1.7). CONCLUSION: Arterial inflammation was common, and appeared similar, in patients with recent stroke/TIA, and controls with stroke/TIA more than two years previously. PMID- 22226632 TI - Ventriculo-peritoneal shunts can cause liver injury, juxta and intrahepatic pseudocysts: imaging findings and review of literature. PMID- 22226634 TI - [Utilization of Essure(r) micro-insert for hydrosalpynx occlusion in infertile women]. AB - OBJECTIVE: To assess the feasibility and the results on fertility of tubal hysteroscopic proximal occlusion with Essure((r)) micro-insert in women with hydrosalpinges. PATIENTS AND METHODS: Thirteen infertile women with hydrosalpinges, who underwent hysteroscopic tubal exclusion by Essure((r)) prior to IVF procedure. RESULTS: The placement of micro-insert was feasible and easy in every patient, with no intra-operative complication. Only one postoperative infectious complication (pyosalpinx) occurred. We report a 64 % rate of pregnancy, and a 18 % rate of normally ongoing pregnancies with no Essure((r)) related complication. CONCLUSION: Hydrosalpinges occlusion by Essure((r)) device might be an easy and safe alternative to laparoscopic treatment, with successful results on fertility and without adverse effects on pregnancy outcomes. PMID- 22226633 TI - TAK1 negatively regulates NF-kappaB and p38 MAP kinase activation in Gr-1+CD11b+ neutrophils. AB - Stringent control of NF-kappaB and mitogen-activated protein kinase (MAPK) signaling is critical during innate immune responses. TGF-beta activated kinase-1 (TAK1) is essential for NF-kappaB activation in T and B cells but has precisely the opposite activity in myeloid cells. Specific deletion of TAK1 (Map3k7(DeltaM/DeltaM)) led to development of splenomegaly and lymphomegaly associated with neutrophilia. Compared with wild-type cells, TAK1-deficient neutrophils enhanced the phosphorylation of the kinases IKK, p38, and JNK and the production of interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor-alpha (TNF-alpha), and reactive oxygen species (ROS) after lipopolysaccharide (LPS) stimulation. Map3k7(DeltaM/DeltaM) mice were significantly more susceptible to LPS-induced septic shock and produced higher amounts of IL-1beta, IL-6, and TNF alpha in plasma than do wild-type mice. Specific ablation of p38 rescued the phenotype and functional properties of Map3k7(DeltaM/DeltaM) mice. Our findings identify a previously unrecognized role of TAK1 as a negative regulator of p38 and IKK activation in a cell type-specific manner. PMID- 22226635 TI - Structural and biochemical insight into glycogenin inactivation by the glycogenosis-causing T82M mutation. AB - The X-ray structure of rabbit glycogenin containing the T82M (T83M according to previous authors amino acid numbering) mutation causing glycogenosis showed the loss of Thr82 hydrogen bond to Asp162, the residue involved in the activation step of the glucose transfer reaction mechanism. Autoglucosylation, maltoside transglucosylation and UDP-glucose hydrolyzing activities were abolished even though affinity and interactions with UDP-glucose and positioning of Tyr194 acceptor were conserved. Substitution of Thr82 for serine but not for valine restored the maximum extent of autoglucosylation as well as transglucosylation and UDP-glucose hydrolysis rate. Results provided evidence sustaining the essential role of the lost single hydrogen bond for UDP-glucose activation leading to glycogenin-bound glycogen primer synthesis. PMID- 22226636 TI - Scaling up synthetic biology: Do not forget the chassis. AB - Using comparative genomics and functional analysis, this work summarises how the cell's genome is organised, with emphasis on the importance of the cell's chassis. Some discrete but important engineering constraints are reviewed, beginning with the need for scaffolds, as well as the question posed by the difficult task of putting a very long random thread (DNA) into a limited volume. Subsequently, to illustrate overlooked essential functions, we show the importance of safety valves, as well as the need to cope with leftovers. The third section discusses how transplantation experiments point out a remarkable feature of the cell factory: the program replicates (makes identical copies of itself), whereas the cell reproduces (makes similar copies of itself), placing in the limelight the role of informational maintenance. A final section identifies the need to put together a globally linear behaviour of the cell with intrisically non-linear genetic constructs. The discussion ends with the central question of evolvability of artificial constructs and to suggest that combining in vivo Synthetic Biology with biochemical reactors might be an efficient way forward. PMID- 22226637 TI - The interaction of social risk factors and HPA axis dysregulation in predicting emotional symptoms of five- and six-year-old children. AB - OBJECTIVE: We examined the links of social relational (family environment and peer victimization) and neuroendocrinological (HPA axis dysregulation) risk factors to children's emotional symptoms. We placed special emphasis on the joint effects of these risk factors with respect to the emergence and course of the emotional symptoms. METHODS: One hundred and sixty-six children were interviewed (Berkeley Puppet Interview) at age 5 and 6. Teachers and parents completed the Strengths and Difficulties Questionnaire. Parents completed the Family Environment Scales. Peer victimization was assessed by teacher and child reports. Children's saliva cortisol was measured before and after a highly structured story completion task which targeted their cognitive emotional representations of family conflicts. RESULTS: In the cross-sectional analyses, negative family environment, peer victimization, and cortisol increase during the story completion task independently contributed to the variance of emotional symptoms. There was a significant interaction effect between family environment and cortisol increase: those six-year-olds who had experienced an unfavorable family environment only showed high levels of emotional symptoms if they exhibited a cortisol increase during the story completion task. In the longitudinal analysis, peer victimization at age 5 predicted an increase of emotional symptoms at age 6, but only for those children who exhibited a blunted cortisol response a year earlier. CONCLUSIONS: Negative family environment and peer victimization proved to be independently associated with emotional symptoms. HPA axis reactivity differentially moderated these associations. Therapeutic strategies should take the interaction between negative relational experiences and biological susceptibility to stress into account. PMID- 22226638 TI - Effectiveness of amendments on the spread and phytotoxicity of contaminants in metal-arsenic polluted soil. AB - A metal-arsenic polluted soil from sulphide-mine waste was treated, in all possible combinations, with two different amounts of marble sludge (98% CaCO3), compost (41% organic carbon), and Byferrox (70% Fe). Lixiviate and pore water from each treated and untreated soil were analysed, and lettuce-seed bioassays were performed. None of the treatments decreased the electrical conductivity of lixiviates or the concentrations of all pollutants found in both solutions. Marble sludge and compost increased the pH values and decreased the zinc, cadmium, copper, and lead concentrations in both solutions while increasing the arsenic concentrations in the lixiviates. Byferrox did not alter the physicochemical parameters or the concentrations of zinc, cadmium, copper, or lead in either solution but significantly decreased the arsenic concentrations in pore water. Compared with the Byferrox treatment, the mixture of marble sludge and Byferrox decreased redox potential values, increasing the arsenic concentrations in both solutions and the electrical conductivity of the pore water. All lixiviates were highly phytotoxic and seeds did not germinate. Pore water phytotoxicity was related to electrical conductivity values and heavy-metal concentrations. The combination of marble sludge and compost was most effective at diminishing toxicity in lettuce. The soils treated with Byferrox, alone or mixed with marble sludge or compost, were the most phytotoxic. PMID- 22226639 TI - Do patients with rapid eye movement sleep behavior disorder have a disease specific personality? AB - OBJECTIVES: Rapid eye movement sleep behavior disorder (RBD) occurs idiopathically (iRBD), frequently representing a prodromal phase of Parkinson's disease (PD). Previous reports have described that patients with PD have premorbid personality profiles such as industriousness, inflexibility, cautiousness, and lack of novelty seeking. As well, psychological stress often aggravates RBD symptoms. These phenomena encouraged us to investigate personality profiles in iRBD patients. METHODS: In this study, 53 patients with iRBD and 49 age and sex-matched healthy controls (HC) were enrolled. We used the revised version of the NEO Personality Inventory (NEO-PIR) to measure the personality of these subjects, and the 5 domains and the 30 facets of the NEO-PIR were compared between the two groups. Within the iRBD group, we investigated the association between RBD variables, e.g. the proportion of REM sleep without atonia (RWA/REM), length of RBD morbidity, frequency of vocalization or abnormal behavior, and the variables of NEO-PIR. RESULTS: In the patients, olfactory function was significantly lower than that of healthy controls, but the inventory differences were not significant. The inventory showed no association with any RBD variable, or the existence of aggravation of these symptoms triggered by psychological stress, or olfactory dysfunction. CONCLUSION: These results suggest that RBD patients do not have a personality profile that might predict PD development. The personality profile itself cannot explain the psychological-stress-dependent aggravation of RBD symptoms. PMID- 22226640 TI - Philasterides dicentrarchi, a histophagous ciliate causing scuticociliatosis in olive flounder, Philasterides dicentrarchi--histopathology investigations. AB - Philasterides dicentrarchi is a histophagous scuticociliate infecting Korean olive flounder farms in Jeju Island, South Korea, where it causes significant economic losses. However, the route of entry of these parasites in olive flounder is currently unknown. In the present study, we attempted experimental infection with different doses (concentrations) of P. dicentrarchi by intraperitoneal (IP) injection; maximum cumulative mortality of 95% was recorded on the administration of 2.1*10(8) ciliates/ml. In small size group (3 cm length, 24+/-2 gwt) the ciliates were found in connective tissues of muscle, fins, and nervous tissue while in large size group (5 cm length, 47+/-3 gwt), the ciliates were predominantly occurred with associated symptoms of liquefaction in the central nervous system. The major clinico-pathological manifestations were loss of scales, appearance of bleached spots that coalesced to form brownish patches, hemorrhagic, and severe dermal necrotic lesion. In addition there was degeneration of muscle fibers, necrosis of the hepatic parenchyma, and severe edema of the intestinal walls, extensive fouling, necrotic degeneration and hyperplasia in the gill bronchial epithelium. In this study, many ciliates were found in the blood vessel, brain, dorsal fins, muscle, kidney, and vertebra of infected flounder. The histopathological investigations are of significant importance in view of possible routes of entry into the host and doses of ciliates that trigger fast infection for potential utility of drugs as a strategy for the control of P. dicentrarchi in farmed olive flounder. PMID- 22226642 TI - Altered placental methyl donor transport in the dexamethasone programmed rat. AB - There is increasing evidence for a role for epigenetic modifications in early life 'programming' effects. Altered placental methyl donor transport may impact on the establishment of epigenetic marks in the fetus. This study investigated the effects of prenatal glucocorticoid overexposure on placental methyl donor transport. Glucocorticoids increased folate but decreased choline transport and reduced fetal plasma methionine levels. There was no change in global DNA methylation in fetal liver. These data suggest prenatal glucocorticoid overexposure causes complex alterations in the placental transport of key methyl donors which may have important implications for maternal diet and nutrient supplementation in pregnancy. PMID- 22226641 TI - Testing of viscous anti-HIV microbicides using Lactobacillus. AB - The development of topical microbicides for intravaginal use to prevent HIV infection requires that the drugs and formulated products be nontoxic to the endogenous vaginal Lactobacillus. In 30min exposure tests we found dapivirine, tenofovir and UC781 (reverse transcriptase inhibitor anti-HIV drugs) as pure drugs or formulated as film or gel products were not deleterious to Lactobacillus species; however, PSC-RANTES (a synthetic CCR5 antagonist) killed 2 strains of Lactobacillus jensenii. To demonstrate the toxicity of formulated products a new assay was developed for use with viscous and non-viscous samples that we have termed the Lactobacillus toxicity test. We found that the vortex mixing of vaginal Lactobacillus species can lead to reductions in bacterial viability. Lactobacillus can survive briefly, about 2s, but viability declines with increased vortex mixing. The addition of heat inactivated serum or bovine serum albumin, but not glycerol, prevented the decrease in bacterial viability. Bacillus atrophaeus spores also demonstrated loss of viability upon extended mixing. We observed that many of the excipients used in film formulation and the films themselves also afford protection from the killing during vortex mixing. This method is of relevance for toxicity for cidal activities of viscous products. PMID- 22226644 TI - Provoked arrangement symptoms in obsessive-compulsive disorder using a virtual environment: A preliminary report. AB - The current study aims to explore the effectiveness of virtual environment (VE) in producing anxiety variations to arrangement in order to treat obsessive compulsive disorder. Twenty-four participants completed and performed the virtual arrangement tasks three times with three-day intervals. The results showed that the levels of participants' anxiety decreased significantly from the first to the last day, but the levels of decrement were different depending on the type of tasks: the time limit task was most effective among the three tasks in evoking arrangement anxiety. Also, only the Symmetry, Ordering, and Arrangement Questionnaire (SOAQ) revealed significant positive correlations with anxieties. These VE profiles can serve as an adjunct for better diagnosis and treatment for people with arranging compulsion symptoms. PMID- 22226645 TI - A novel method for prediction of protein interaction sites based on integrated RBF neural networks. AB - Protein interactions are very important for control life activities. If we want to study the principle of protein interactions, we have to find the seats of a protein which are involved in the interactions called interaction sites firstly. In this paper, a novel method based on an integrated RBF neural networks is proposed for prediction of protein interaction sites. At first, a number of features were extracted, i.e., sequence profiles, entropy, relative entropy, conservation weight, accessible surface area and sequence variability. Then 6 sliding windows about these features were made, and they contained 1, 3, 5, 7, 9 and 11 amino acid residues respectively. These sliding windows were put into the input layers of six radial basis functional neural networks that were optimized by Particle Swarm Optimization. Thus, six group results were obtained. Finally, these six group results were integrated by decision fusion (DF) and Genetic Algorithm based Selective Ensemble (GASEN). The experimental results show that the proposed method performs better than the other related methods such as neural networks and support vector machine. PMID- 22226646 TI - The multi-reference contrast method: facilitating set enrichment analysis. AB - Set enrichment analysis (SEA) is used to identify enriched biological categories/terms within high-throughput differential expression experiments. This is done by evaluating the proportion of differentially expressed genes against a background reference (BR). However, the choice of the "appropriate" BR is a perplexing problem and results will depend on it. Here, a visualization procedure that integrates results from several BRs and a stability analysis of enriched terms is presented as a tool to aid SEA. The multi-reference contrast method (MRCM) combines results from multiple BRs in a unique picture. The application of the proposed method was illustrated in one proteomic and three microarray experiments. The MRCM facilitates the exploration task involved in ontology analysis on proteomic/genomic experiments, where consensus terms were found to validate main experimental hypothesis. The use of more than one reference may provide new biological insights. The tool automatically highlights non-consensus terms assisting SEA. PMID- 22226647 TI - Potential of the gastric motility drug lorglumide in prostate cancer imaging. AB - The use of tissue-specific receptor ligands is a promising approach for cancer diagnostics and therapy. Lorglumide, a highly effective competitive ligand for the cholecystokinine-A receptor (CCKRA) was conjugated to a fluorescent dye and a magnetic resonance imaging (MRI) contrast agent to obtain a bifunctional marker for tissue with high CCKRA expression. An intermediate conjugate containing only lorglumide and a fluorescent dye was also produced. By performing CCKRA mRNA expression analysis on carcinoma cell lines we found that CCKRA is highly expressed in PC3 prostate carcinoma cells compared to U373 glioma and U2OS osteosarcoma cells. Uptake, specificity and detection sensitivity of both lorglumide conjugates was evaluated by confocal laser scanning microscopy, fluorescence activated cell sorting (FACS) and magnetic resonance relaxometry. While the conjugate containing only lorglumide and rhodamine isothiocyanate as fluorescent dye showed clearly higher uptake than the bifunctional conjugate in FACS analysis, both conjugates clearly showed preferential staining of the PC3 prostate carcinoma cells. Magnetic resonance relaxometry experiments with the bifunctional conjugate containing the MRI contrast agent gadolinium-1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid confirmed the higher PC3-affinity of the lorglumide ligand. Confocal laser scanning microscopy images of PC3/U2OS mixed cell cultures incubated with the bifunctional conjugate also clearly showed PC3 preference and cytoplasmic dot-like staining concurring with uptake by receptor binding and subsequent receptor internalization. Considering these results, CCKRA ligands like lorglumide could play a role in the future design of prostate-cancer-specific markers. PMID- 22226648 TI - Efficacy of intrathecal administration of liposomal amphotericin B combined with voriconazole in a murine model of cryptococcal meningitis. AB - Meningitis is one of the most fatal manifestations of cryptococcosis, even with specific treatment. Combination of a prompt diagnosis and appropriate therapy are critical to reduce the fungal load and the inflammatory response effects of the proliferation of yeast into the central nervous system (CNS). Mice with experimental acute meningitis caused by Cryptococcus neoformans were treated with liposomal amphotericin B (L-AmB) administered intrathecally (i.t.c.) at 0.006 mg/kg weekly or intravenously (i.v.) at 10 mg/kg daily or with voriconazole (VCZ) administered orally at 30 mg/kg per dose twice daily or with combinations of both drugs, i.e. L-AmB i.t.c.+VCZ or L-AmB i.v.+VCZ at the same doses as used in the monotherapies. All treatments significantly increased the survival of animals in comparison with the control group, with VCZ being less effective in comparison with all other treatments (P <= 0.012). All treatments, with the exception of VCZ (P=0.533), reduced fungal burdens in the brain in comparison with controls. The combination of L-AmB i.t.c.+VCZ showed a synergistic effect in the reduction of fungal load that was significantly superior to any tested therapy (P <= 0.039). Histologically, untreated animals showed a marked inflammatory response with massive fungal cells in the meninges, whilst treated animals showed a variable number of fungal cells in the CNS, with the exception of animals receiving L-AmB i.t.c.+VCZ in which neither yeasts nor inflammation were observed. PMID- 22226649 TI - Update on the prevention and control of community-acquired meticillin-resistant Staphylococcus aureus (CA-MRSA). AB - The rapid dissemination of community-acquired meticillin-resistant Staphylococcus aureus (CA-MRSA) since the early 2000s and the appearance of new successful lineages is a matter of concern. The burden of these infections varies widely between different groups of individuals and in different regions of the world. Estimating the total burden of disease is therefore problematic. Skin and soft tissue infections, often in otherwise healthy young individuals, are the most common clinical manifestation of these infections. The antibiotic susceptibilities of these strains also vary, although they are often more susceptible to 'traditional' antibiotics than related hospital-acquired strains. Preventing the dissemination of these organisms throughout the general population requires a multifaceted approach, including screening and decolonisation, general hygiene and cleaning measures, antibiotic stewardship programmes and, in the future, vaccination. The current evidence on the prevention and control of CA MRSA is appraised and summarised in this review. PMID- 22226650 TI - Emergence of Escherichia coli sequence type 410 (ST410) with KPC-2 beta lactamase. AB - Fifteen carbapenem-non-susceptible Escherichia coli isolates obtained during the period May 2010 to April 2011 in a hospital and a long-term care facility (LTCF) in Larissa (Central Greece) were investigated. Minimum inhibitory concentrations (MICs) to various antimicrobial agents were determined by Etest. Carriage of bla genes, including bla(KPC-2) and bla(CTX-M), was documented by polymerase chain reaction (PCR) and sequencing. Production of beta-lactamases was confirmed by isoelectric focusing. Transfer of resistance was carried out by conjugation. Plasmid incompatibility groups were determined by PCR-based replicon typing and replicon sequence typing. Isolates were genotyped by multilocus sequence typing. Ten E. coli isolates with KPC-2 were derived from seven patients in the University Hospital of Larissa. Six patients had previously been treated for prolonged time periods in a LTCF located in the same city. The remaining isolate was from a patient previously treated in an Athens hospital. Screening of faecal samples from 20 randomly selected LTCF patients yielded eight enterobacteria with KPC-2, of which five were E. coli, showing the wide spread of KPC-2-producers in this institution and confirming that it was the focus of the outbreak. Fourteen of the isolates were classified as sequence type 410 (ST410); the remaining isolate belonged to a novel ST (ST2281). All 15 isolates carried a KPC-2-encoding plasmid of the Inc group FIIK. Additional plasmids encoding enzymes of the CTX-M 1 family were identified in 11 isolates. The bla(KPC-2)-carrying plasmid IncFIIK, widespread amongst Klebsiella pneumoniae in Greece, has probably been acquired by E. coli ST410 known to be associated with CTX-M production. Diffusion of bla(KPC 2) in common pathogens such as E. coli is of concern. PMID- 22226651 TI - How to optimise antimicrobial prescriptions in the Intensive Care Unit: principles of individualised dosing using pharmacokinetics and pharmacodynamics. AB - Optimising antimicrobial dosing for critically ill patients is highly challenging and when it is not achieved can lead to worse patient outcomes. To this end, use of dosing regimens recommended in package inserts from drug manufacturers is frequently insufficient to guide dosing in these patients appropriately. Whilst the effect of critical illness pathophysiology on the pharmacokinetic (PK) behaviour of antimicrobials can be profound, the variability of these changes between patients is still being quantified. The PK effects of hypoproteinaemia, organ dysfunction and the presence of augmented renal clearance may lead to plasma antimicrobial concentrations that are difficult to predict at the bedside, which may result in excess toxicity or suboptimal bacterial killing. This paper outlines the factors that affect pharmacokinetics in critically ill patients and how knowledge of these factors can increase the likelihood of achieving optimal antimicrobial plasma concentrations. In selected settings, we advocate individualised dosing of renally cleared antimicrobials using physiological data such as measured creatinine clearance and published non-renal clearance data. Where such data do not exist, therapeutic drug monitoring may be a useful alternative and has been associated with significant clinical benefits, although it is not currently widely available. PMID- 22226652 TI - Purified 1'acetoxychavicol acetate (1'ACA) from galangal spice affects membrane fatty acid composition and triggers a cell envelope stress response in Staphylococcus aureus. PMID- 22226653 TI - Efficacy of miltefosine treatment in Leishmania amazonensis-infected BALB/c mice. AB - Leishmaniasis is one of the most serious worldwide diseases caused by protozoan parasites of the Leishmania genus, affecting millions of people around the world. All currently available treatments present severe toxic side effects, require long-term compliance, cause serious side effects and are uncomfortable for patients. Leishmania amazonensis, a species endemic to Brazil, causes severe localised or diffuse skin lesions in humans. Owing to the unsatisfactory nature of the currently available chemotherapies, new approaches have been assessed for improved therapeutic intervention strategies against leishmaniasis. Miltefosine is an alkylphospholipid analogue that exhibits potent activity against the different clinical manifestations of leishmaniasis. Thus, the aim of this study was to investigate the long-term efficacy of miltefosine in BALB/c mice infected with L. amazonensis owing to the lack of a profound study demonstrating its dose dependent and long-term effects. It was observed that animals treated with 20-50 mg/kg/day of miltefosine exhibited a significant dose-dependent reduction in lesion size; furthermore, in mice receiving higher doses, lesions disappeared after the end of treatment. To confirm a possible parasitological cure, mice up to 250 days after the end of treatment were analysed. No lesions or presence of parasite DNA were found in mice treated with 30, 40 and 50 mg/kg/day of miltefosine. In summary, these results show that miltefosine may be used to treat cutaneous leishmaniasis caused by L. amazonensis, alone or as combination therapy. PMID- 22226654 TI - Synthesis and antiviral activities of novel gossypol derivatives. AB - In this study, a series of novel gossypol derivatives were synthesized and screened in vitro for their anti-HIV-1 and anti-H(5)N(1) activities, respectively. Replacing the aldehyde groups of gossypol with some amino acids not only reduced the cytotoxicity but also enhanced the activities against HIV-1 and H(5)N(1). Compounds 13-17 showed more potent activities against HIV-1 and H(5)N(1) than the other gossypol derivatives. Meanwhile, these compounds also exhibited more potent activities against H(5)N(1) than 1-adamantylamine. The absence of the COONa group in gossypol derivatives resulted in a loss of anti-HIV 1 activity, suggesting that this group might play an important role in mediating the antiviral activity. Time-of-addition assays indicated that compounds 13-17 had the similar mechanism of anti-HIV-1 action with T20. Molecular modeling analysis demonstrated that compounds 13-17 could fit inside the gp41 hydrophobic pocket through hydrogen bonding network, hydrophobic contacts and strong electrostatic interactions. PMID- 22226655 TI - Aminopurine based JNK inhibitors for the prevention of ischemia reperfusion injury. AB - In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury. PMID- 22226656 TI - Discovery of 7-arylsulfonyl-1,2,3,4, 4a,9a-hexahydro-benzo[4,5]furo[2,3 c]pyridines: identification of a potent and selective 5-HT6 receptor antagonist showing activity in rat social recognition test. AB - Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists. Despite good activity against 5-HT(6) receptor, 3a exhibited poor liver microsome stability in mouse, rat and dog. It was demonstrated that the saturation of the double bond of the tetrahydropyridine ring of 3a enhanced metabolic stability. However the resulting compound, 4a (7-phenylsulfonyl 1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) exhibited ~30 fold loss in potency along with introduction of two chiral centers. In our optimization process for this series, we found that substituents at the 2 or 3 positions on the distal aryl group are important for enhancing activity against 5 HT(6). Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT(6) antagonists with improved PK profiles in rat. A potent, selective 5-HT(6)R antagonist (15k) was identified from this study which showed good oral bioavailability (F=39%) in rat with brain penetration (B/P=2.76) and in vivo activity in a rat social recognition test. PMID- 22226657 TI - Evaluation of vitamin D3 A-ring analogues as Hedgehog pathway inhibitors. AB - A structure-activity relationship study focusing on the A-ring of vitamin D3 (VD3) was undertaken to elucidate its role in inhibiting the Hedgehog pathway and in mediating anti-cancer effects. Analogues resulting from simple functional group substitution at 3' position of VD3 were evaluated in a variety of biological assays to determine their ability to selectively inhibit Hh signaling. Moderately active Hh inhibitors that have insignificant binding affinity for VDR were identified; however, these compounds also activate the traditional VDR pathway, presumably due to metabolites produced in the cultured cells. Thus, further structural modifications to the VD3 scaffold are required to yield potent, selective Hh inhibitors. PMID- 22226658 TI - Activation of colonic mucosal 5-HT(4) receptors accelerates propulsive motility and inhibits visceral hypersensitivity. AB - BACKGROUND & AIMS: 5-hydroxytryptamine receptor (5-HT(4)R) agonists promote gastrointestinal motility and attenuate visceral pain, but concerns about adverse reactions have restricted their availability. We tested the hypotheses that 5 HT(4) receptors are expressed in the colonic epithelium and that 5-HT(4)R agonists can act intraluminally to increase motility and reduce visceral hypersensitivity. METHODS: Mucosal expression of the 5-HT(4)R was evaluated by reverse-transcriptase polymerase chain reaction and immunohistochemical analysis of tissues from 5-HT(4)R(BAC)-enhanced green fluorescent protein mice. Amperometry, histology, and short-circuit current measurements were used to study 5-HT, mucus, and Cl(-) secretion, respectively. Propulsive motility was measured in guinea pig distal colon, and visceromotor responses were recorded in a rat model of colonic hypersensitivity. 5-HT(4)R compounds included cisapride, tegaserod, naronapride, SB204070, and GR113808. RESULTS: Mucosal 5-HT(4) receptors were present in the small and large intestines. In the distal colon, 5 HT(4) receptors were expressed by most epithelial cells, including enterochromaffin and goblet cells. Stimulation of 5-HT(4)Rs evoked mucosal 5-HT release, goblet cell degranulation, and Cl(-) secretion. Luminal administration of 5-HT(4)R agonists accelerated propulsive motility; a 5-HT(4)R antagonist blocked this effect. Bath application of 5-HT(4)R agonists did not affect motility. Oral or intracolonic administration of 5-HT(4)R agonists attenuated visceral hypersensitivity. Intracolonic administration was more potent than oral administration, and was inhibited by a 5-HT(4)R antagonist. CONCLUSIONS: Mucosal 5-HT(4) receptor activation can mediate the prokinetic and antinociceptive actions of 5-HT(4)R agonists. Colon-targeted, intraluminal delivery of 5-HT(4)R agonists might be used to promote motility and alleviate visceral pain, while restricting systemic bioavailability and resulting adverse side effects. PMID- 22226659 TI - Enteropathy-associated T-cell lymphoma complicating an autoimmune enteropathy. AB - Enteropathy-associated T-cell lymphoma (EATL) is a rare non-Hodgkin lymphoma frequently associated with celiac disease. We report a case of EATL complicating adult autoimmune enteropathy (AIE). Analysis of phenotype, rearrangements in T cell receptor genes, and chromosome alterations by high-resolution comparative genomic hybridization identified features distinct from those described for types I and II EATL. Furthermore, EATL arose from a single T-cell clone that had been present for several years in AIE-associated, oligoclonal, intestinal T-cell infiltrate. Emerging T-cell clones should be monitored in patients with AIE who receive long-term immunosuppressive therapy. PMID- 22226660 TI - Phenotypic spectrum of fetal Smith-Lemli-Opitz syndrome. AB - The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital malformation syndrome caused by dehydrocholesterol reductase deficiency. The diagnosis is confirmed by high 7- and secondarily 8 dehydrocholesterol levels in plasma and tissues and/or by detection of biallelic mutations in the DHCR7 gene. The phenotypic spectrum of SLOS is broad, ranging from a mild phenotype combining subtle physical anomalies with behavioral and learning problems, to a perinatally lethal multiple malformations syndrome. The fetal phenotype of SLOS has been poorly described in the literature. We report a series of 10 fetuses with molecularly proven SLOS. Even in young fetuses, the facial dysmorphism appears characteristic. Genital abnormalities are rare in 46,XX subjects. Gonadal differentiation appears histologically normal and in agreement with the chromosomal sex, contrary to what has been previously stated. We observed some previously unreported anomalies: ulnar hypoplasia, vertebral segmentation anomalies, congenital pulmonary adenomatoid malformation, fused lungs, gastroschisis, holomyelia and hypothalamic hamartoma. This latter malformation proves that SLOS phenotypically overlaps with Pallister-Hall syndrome which remains clinically a major differential diagnosis of SLOS. PMID- 22226661 TI - Mitochondrial fumarate reductase as a target of chemotherapy: from parasites to cancer cells. AB - Recent research on respiratory chain of the parasitic helminth, Ascaris suum has shown that the mitochondrial NADH-fumarate reductase system (fumarate respiration), which is composed of complex I (NADH-rhodoquinone reductase), rhodoquinone and complex II (rhodoquinol-fumarate reductase) plays an important role in the anaerobic energy metabolism of adult parasites inhabiting hosts. The enzymes in these parasite-specific pathways are potential target for chemotherapy. We isolated a novel compound, nafuredin, from Aspergillus niger, which inhibits NADH-fumarate reductase in helminth mitochondria at nM order. It competes for the quinone-binding site in complex I and shows high selective toxicity to the helminth enzyme. Moreover, nafuredin exerts anthelmintic activity against Haemonchus contortus in in vivo trials with sheep indicating that mitochondrial complex I is a promising target for chemotherapy. In addition to complex I, complex II is a good target because its catalytic direction is reverse of succinate-ubiquionone reductase in the host complex II. Furthermore, we found atpenin and flutolanil strongly and specifically inhibit mitochondrial complex II. Interestingly, fumarate respiration was found not only in the parasites but also in some types of human cancer cells. Analysis of the mitochondria from the cancer cells identified an anthelminthic as a specific inhibitor of the fumarate respiration. Role of isoforms of human complex II in the hypoxic condition of cancer cells and fetal tissues is a challenge. This article is part of a Special Issue entitled Biochemistry of Mitochondria, Life and Intervention 2010. PMID- 22226662 TI - Diets rich in fruits and vegetables suppress blood biomarkers of metabolic stress in overweight women. AB - OBJECTIVE: This study was performed to evaluate the effects of high vegetable fruit (high-VF) and low vegetable-fruit (low-VF) diet on surrogate biomarkers of adiposity-related metabolic disturbances. METHODS: Overweight women (n=22, 19-29 years) participated in the study between July and August, 2007 in Seoul, Korea. The intervention consisted of either high-VF diet (12 servings of VF/day) or low VF diet (2 servings of VF/day). Plasma concentration of carotenoids and biomarkers of inflammation and oxidative stress were determined before and after each intervention period. RESULTS: Study results indicated that body fat content is positively correlated with plasma interleukin (IL)-6, C-reactive protein (CRP), and leptin concentrations at baseline. Oxidative DNA damage and lipopolysaccharide (LPS)-activated production of IL-1beta and IL-6 in peripheral blood mononuclear cells (PBMCs) were decreased with high-VF diet while low-VF diet increased those markers. Changes in the concentration of plasma total carotenoid and beta-carotene were inversely correlated with change in plasma IL 1beta concentration. Differences in IL-beta production in LPS-activated PBMCs were inversely correlated with changes in plasma concentration of lutein zeaxanthin. Also, changes in plasma total carotenoid and lycopene concentration were inversely correlated with the changes in IL-6 production in LPS-activated PBMCs. CONCLUSION: Daily intake of vegetables and fruits can modify adiposity related metabolic disturbances. PMID- 22226664 TI - Chronic hypoxia induces androgen-independent and invasive behavior in LNCaP human prostate cancer cells. AB - PURPOSE: Tumor hypoxia is a common feature of any cancer, including prostate cancer (CaP), and associated with tumor cell aggressiveness. Although some reports are available on acute hypoxia-response in CaP cells aggressiveness, little is known about chronic hypoxia-response. We investigated the effects of chronic hypoxia on human CaP cells. MATERIALS AND METHODS: The human androgen dependent CaP cell line LNCaP was cultured under normoxia (21% O2), acute hypoxia (1% O2), or chronic hypoxia (1% O2 for over 6 months). The cell growth, cell cycle and cell behavior of these cells were analyzed by cell count, flow cytometric analysis and in vitro cell migration and invasion assay, respectively. The expression of matrix metalloproteinases and intracellular signaling pathways were tested by real time reverse transcriptase-polymerase chain reaction and Western blotting. RESULTS: Chronic hypoxia-conditioned LNCaP cells grew in an androgen-independent manner with acceleration of G1 to S phase cell cycle progression. Chronic hypoxia, but not acute hypoxia, accelerated cell migration and invasion. The expressions of matrix metalloproteinase-7, -9, -14, and -15 were significantly up-regulated in LNCaP cells under chronic hypoxia, but not under acute hypoxia. In addition, PI3K/Akt, JAK/STAT, and HIF-1 pathways were activated in chronic hypoxia-conditioned LNCaP cells. CONCLUSIONS: These results suggested that chronic hypoxia plays an important role in enhancement of malignant potential during androgen-independent CaP progression. PMID- 22226665 TI - A novel role of Id-1 in regulation of epithelial-to-mesenchymal transition in bladder cancer. AB - BACKGROUND AND OBJECTIVE: Inhibitor of differentiation or DNA binding -1 (Id-1) has been shown to be increased in several types of advanced cancer, and to be associated with aggressive and metastatic abilities of cancer cells. Recently, more and more evidence indicates that epithelial-to-mesenchymal transition (EMT) is an important mechanism taking place during tumor invasion and metastasis, but the molecular pathways underlying EMT have not been clearly established. This study was to investigate the expression of Id-1 in bladder cancer and its association with EMT. MATERIALS AND METHODS: A total of 169 tissues, consisting of 147 primary bladder cancers and 22 adjacent normal tissues were included in this study. Id-1, E-cadherin, and beta-catenin were examined immunohistochemically in paraffin sections. The pBabe-Id-1 expression retroviral vector and retroviral vectors containing an Id-1-specific small interfering RNA oligonucleotides (si-Id-1) were transfected into 2 bladder cancer cell lines respectively. Then, we used Western blotting and immunofluorescent staining to detect the cellular expression of epithelial markers and mesenchymal markers. The invasion and migration ability of bladder cancer cells were identified by type I collagen invasion assay and wound closure assay. RESULTS: We demonstrated that increased Id-1 expression was associated with advanced tumor stage and grade. In addition, the increased Id-1 expression in bladder tumors was also correlated with decreased membranous E-cadherin and beta-catenin expression. In vitro, studies showed that inactivation of the Id-1 gene conferred morphologic transition of bladder cancer cells from a fibroblastic to epithelial appearance, and overexpression of Id-1 could lead to acquisition of a fibroblastic spindle cell phenotype accompanied by loss of cell-to-cell contacts. By Western blotting and immunofluorescent staining, we showed that the expression level of Id-1 was correlated with the expression of mesenchymal markers but was inversely correlated with the expression of epithelial markers. Moreover, results of collagen invasion and wound closure assays showed ectopic Id-1 expression led to increased ability of invasion and migration. CONCLUSIONS: Our results suggest that Id-1 may play roles in tumor progression and EMT activation in bladder cancer. PMID- 22226666 TI - Vaccinia viruses isolated from cutaneous disease in horses are highly virulent for rabbits. AB - Two genotypically distinct Vaccinia viruses (VACV), named P1V and P2V, were isolated from an outbreak of cutaneous disease in horses in Southern Brazil. We herein investigated the susceptibility of rabbits, a proposed animal model, to P1V and P2V infection. Groups of weanling rabbits were inoculated intranasally (IN) with P1V or P2V at low (10(2.5) TCID50), medium (10(4.5)TCID50), or high titer (10(6.5)TCID50). Rabbits inoculated with medium and high titers shed virus in nasal secretions and developed serous to hemorrhagic nasal discharge and severe respiratory distress, followed by progressive apathy and high lethality. Clinical signs appeared around days 3-6 post-inoculation (pi) and lasted up to the day of death or euthanasia (around days 5-10). Virus shedding and clinical signs were less frequent in rabbits inoculated with low virus titers. Viremia was detected in all groups, with different frequencies. Viral DNA was detected in the feces of a few animals inoculated with P1V and P2V, low titer, and with P2V at high titer. Gross necropsy findings and histological examination showed diffuse interstitial fibrousing pneumonia with necrosuppurative bronchopneumonia and intestinal liquid content. Neutralizing antibodies were detected in all inoculated animals surviving beyond day 9 pi. These results show that rabbits are highly susceptible to VACV isolated from horses, and develop severe respiratory and systemic disease upon IN inoculation. Thus, rabbits may be used to study selected aspects of VACV infection and disease. PMID- 22226667 TI - H-ficolin (ficolin-3) concentrations and FCN3 gene polymorphism in neonates. AB - Serum H-ficolin (ficolin-3) concentrations (n=613) and FCN3 genotypes (n=529) from a large group of neonates are presented. Both pre-term deliveries and low birthweight (independently of gestational age) were significantly associated with low H-ficolin concentrations but not with heterozygosity for the FCN3 1637delC frameshift mutation. The presence of the variant allele, however, apparently influenced the protein level. No association of FCN3 gene heterozygosity or relative functional H-ficolin insufficiency (determined as serum level <=8.6 MUg/ml) with perinatal infections was found. One premature newborn, with confirmed infection caused by Streptococcus agalactiae, was H-ficolin-deficient (FCN3 variant homozygote, no detectable protein). We present what is only the fourth case report of total H-ficolin deficiency in the world literature. This neonate was however previously found to be mannan-binding lectin (MBL) as well as MBL-associated serine protease-2 (MASP-2) deficient and also had low serum L ficolin. PMID- 22226668 TI - Dynamic appearance of antigenic epitopes effective for viral neutralization during membrane fusion initiated by interactions between HIV-1 envelope proteins and CD4/CXCR4. AB - HIV-1 entry into cells is mediated by interactions between the envelope (Env) gp120 and gp41 proteins with CD4 and chemokine receptors via an intermediate called the viral fusion complex (vFC). Here, mAbs were used to find the dynamic changes in expression of antigenic epitopes during vFC formation. A CD4-specific mAb (R275) and anti-vFC mAbs, designated F12-1, F13-6 and F18-4 that recognize the epitopes only appeared by the co-culture of env-transfected 293FT and CD4 transfected 293 cells, were developed by immunizing ganp-gene transgenic mice with an vFC-like structure formed by the same co-culture. The epitopes recognized by the mAbs appeared at different time points during vFC formation: F18-4 appeared first, followed by F13-6, and finally F12-1. The anti-vFC mAbs had little effect on vFC formation or virus neutralization; however, interestingly F12-1 and F18-4 increased exposure of the OKT4-epitope on the domain 3 in the extracellular region of CD4. R275, which recognizes the epitope closely associated with the OKT4-determinant on the domain 3, showed the marked inhibition of vFC formation and viral neutralization activity. The Ab binding to the epitopes appeared during viral membrane fusion might reinforce the appearance of the target epitopes for effective neutralization activity. PMID- 22226669 TI - An anti-IgE monoclonal antibody that binds to IgE on CD23 but not on high affinity IgE.Fc receptors. AB - A new monoclonal antibody (mAb), specific for human IgE, the central mediator of immediate-type hypersensitivity reactions, has been shown to possess a unique set of binding specificities. The mAb, 8D6, binds to a conformational epitope on the CH3 domain of human e immunoglobulin and can compete with omalizumab for binding to IgE. Like omalizumab, it does not bind to IgE bound by the high-affinity IgE.Fc receptor (FcERI) on basophils and mast cells. It also does not cause activation and degranulation of IgE-pulsed, human FcERI-expressing rat basophilic leukemic cells (RBL SX-38). The mAb can inhibit IgE binding to recombinant alpha chain of human FcERI in ELISA and to human FcERI-expressing RBL SX38 cells in fluorescence flow cytometric analysis. However, unlike omalizumab, 8D6 can bind to IgE already bound by the low-affinity IgE.Fc receptors (FcERII, or CD23), as revealed in ELISA with recombinant CD23 and in flow cytometric analysis with human B cells. Since earlier investigators have shown that anti-CD23 mAbs can inhibit the synthesis of IgE in lymphocyte culture in vitro and can down-regulate IgE production in treated patients, 8D6 may offer pharmacological mechanisms in addition to those mediated by omalizumab, for controlling IgE in patients with allergic diseases. PMID- 22226670 TI - WITHDRAWN: MyD88 is required for the recruitment of eosinophils and neutrophils but dispensable for host protective immune responses during Fasciola hepatica infection. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22226671 TI - Stage II vestibular schwannoma: predictive factors for postoperative hearing loss and facial palsy. AB - OBJECTIVES: To assess predictive factors for deafness and facial palsy after vestibular schwannoma surgery on a translabyrinthine or retrolabyrinthine approach, and to compare sequela results to those for gamma knife radiosurgery. PATIENTS AND METHODS: A retrospective study included 70 patients operated on for stage II vestibular schwannoma (Koos classification). Postoperative hearing was assessed on pure-tone average and speech discrimination score, and facial palsy on the House and Brackmann classification, preoperatively and at 1 year postoperatively. Various predictive factors were assessed for both. Statistical analysis used the Fischer exact test, with a significance threshold of P<0.05. RESULTS: Hearing was conserved in 18.9% of patients operated on with a retrolabyrinthine approach, with 8.1% conserving useful hearing. Facial function was conserved in 91.4%. Predictive factors for hearing conservation did not achieve statistical significance, but showed trends for: preoperative pure-tone average threshold<=30dB and speech discrimination score>= 70%, age less than 55 years, tinnitus, nearly normal auditory brainstem response (ABR) latency, and homogeneous tumor on MRI. Predictive factors for conserved facial function likewise did not achieve statistical significance, but showed trends for: age less than 55 years, deafness of progressive onset, absence of cardiovascular risk factors, nearly normal ABR latency and tumor size<13.5mm on MRI. CONCLUSION: Facial nerve risk is largely the same with surgery or gamma knife radiosurgery. Concerning hearing, gamma knife radiosurgery seems to provide better hearing conservation, but only over the short term. PMID- 22226672 TI - Intraoperative laryngeal nerve monitoring during thyroidectomy and parathyroidectomy: A prospective study. AB - OBJECTIVES: The aim of this study was to stimulate the recurrent laryngeal nerve during thyroidectomy or parathyroidectomy and to record the muscle responses in an attempt to predict postoperative vocal fold mobility. PATIENTS AND METHODS: Intraoperative recurrent laryngeal nerve monitoring during general anaesthesia was performed by using an electrode-bearing endotracheal tube (nerve integrity monitor EMG endotracheal tube [Medtronic Xomed, Jacksonville, Flo, USA]). Two hundred and fifteen recurrent laryngeal nerves from 141 patients undergoing total thyroidectomy (n=74), hemithyroidectomy (n=63), or parathyroidectomy (n=4) were prospectively monitored. In each case, the muscle potential was recorded after stimulation of the recurrent laryngeal nerve by a monopolar probe. RESULTS: The nerve stimulation threshold before and after dissection that induced a muscle response of at least 100 MUV ranged from 0.1 to 0.85 mA (mean 0.4 mA). The supramaximal stimulation intensity was defined as 1 mA. The amplitude of muscle response varied considerably from one patient to another, but the similarity of the muscle response at supramaximal intensity between pre- and postdissection and between postdissection at the proximal and distal exposed portions of the nerve was correlated with normal postoperative vocal fold function. Inversely, alteration of the muscle response indicated a considerable risk of recurrent laryngeal nerve palsy, but was not predictive of whether or not this lesion would be permanent. CONCLUSIONS: Recurrent laryngeal nerve monitoring with a system using surface electrodes is a simple, non-invasive technique that is just as sensitive as monitoring by intramuscular electrodes. Monitoring is helpful for initial nerve identification and is useful to determine nerve function during and after surgery, and to adapt the surgical strategy accordingly. PMID- 22226673 TI - Canal wall up tympanoplasty for middle ear cholesteatoma in adults: modeling cartilage. AB - OBJECTIVES: The authors report their experience with a variant cartilage tympanoplasty technique in a canal wall up (CWU) procedure for middle ear cholesteatoma, comparing reliability with other techniques. Functional results are analyzed according to ossicular chain status. MATERIALS AND METHODS: A retrospective study was performed in adults operated on with CWU tympanoplasty for middle ear cholesteatoma. The surgical technique of "modeling" cartilage is described. RESULTS: One hundred and nine patients were included (113 procedures). There were four recurrences (3.5%). Mean follow-up was 48 months (range, 24-96 months). In case of normal ossicular chain, postoperative pure-tone average air bone gap was always less than 20dB, and less than 20dB following myringostapedopexy in 60% of cases with incus destruction. CONCLUSION: Modeling cartilage is a reliable reconstruction technique to prevent recurrent cholesteatoma, and contributes to the quality of functional results in ossiculoplasty. PMID- 22226674 TI - Does NSQIP enrollment improve colectomy outcomes? PMID- 22226675 TI - Affective picture modulation: valence, arousal, attention allocation and motivational significance. AB - The present study analyses the modulatory effects of affective pictures in the early posterior negativity (EPN), the late positive potential (LPP) and the human startle response on both the peripheral (eye blink EMG) and central neurophysiological levels (Probe P3), during passive affective pictures viewing. The affective pictures categories were balanced in terms of valence (pleasant; unpleasant) and arousal (high; low). The data shows that EPN may be sensitive to specific stimulus characteristics (affective relevant pictures versus neutral pictures) associated with early stages of attentional processing. In later stages, the heightened attentional resource allocation as well as the motivated significance of the affective stimuli was found to elicit enhanced amplitudes of slow wave processes thought to be related to enhanced encoding, namely LPP,. Although pleasant low arousing pictures were effective in engaging the resources involved in the slow wave processes, the highly arousing affective stimuli (pleasant and unpleasant) were found to produce the largest enhancement of the LPP, suggesting that high arousing stimuli may are associated with increased motivational significance. Additionally the response to high arousing stimuli may be suggestive of increased motivational attention, given the heightened attentional allocation, as expressed in the P3 probe, especially for the pleasant pictures. The hedonic valence may then serve as a mediator of the attentional inhibition to the affective priming, potentiating or inhibiting a shift towards defensive activation, as measured by the startle reflex. PMID- 22226676 TI - An experimental and theoretical study of L-Tryptophan in an aqueous solution, combining two-layered ONIOM and SCRF calculations. AB - ONIOM and SCRF calculations were performed to study the most stable theoretical structure of L-tryptophan in an aqueous solution phase and to observe the changes occurring in the structural and vibrational properties of L-tryptophan in the aqueous media. L-Tryptophan was characterized by infrared and Raman spectroscopies in the solid state and as an aqueous solution. Optimized geometries and relative stabilities for the L-tryptophan zwitterion were calculated while taking into account solvent effects using the self-consistent reaction field (SCRF) theory. The obtained results in the aqueous solution were compared with those calculated for the zwitterion in the gas phase by means of two-layered ONIOM calculations. For the complete assignments of the IR and Raman spectra of L-tryptophan in the aqueous solution phase, density functional theory (DFT) calculations were combined with Pulay's scaled quantum mechanical force field (SQMFF) methodology in order to fit the theoretical wavenumber values to the experimental values. Additionally, the roles of specific and bulk contributions from solvent effects on the properties of l-tryptophan were analyzed. Furthermore, bands corresponding to the normal modes of vibration were localized and assigned, and they served as the bases for the calculations of the corresponding force constants. Significant effects on the geometrical and vibrational frequencies were found for the studied zwitterion. PMID- 22226677 TI - The use of a cis-dioxomolybdenum(VI) dinuclear complex with quadradentate 1,4 benzenediylbis(benzyldithiocarbamate)(2-) as model compound for the active site of oxo transfer molybdoenzymes: reactivity, kinetics, and catalysis. AB - Dinuclear cis-dioxomolybdenum(VI) complex [{MoO(2)(Bz(2)Benzenediyldtc)}(2)] coordinated by a quadradentate dithiocarbamate (Bz(2)Benzenediyldtc(2-)=1,4 benzenediylbis(benzyldithiocarbamate)(2-)) has been prepared and characterized by elemental analysis, (13)C NMR, IR and UV-vis spectroscopy. The kinetics of the oxygen atom transfer between [{MoO(2)(Bz(2)Benzenediyldtc)}(2)] and PPh(3) was studied spectrophotometrically in CH(2)Cl(2) medium at 520 nm and four different temperatures, 288, 293, 298 and 303 K, respectively. The reaction follows second order kinetics with the rate constant k=0.163(2)M(-1)S(-1) and its increasingly strong absorption at 520 nm clearly indicate the formation of a MU-oxo molybdenum(V) species as a product. Despite the steric restrictions imposed by the ligand structure to prevent the formation of Mo(V) species, experimental evidence confirms its interference during the process. The product can then be formulated as [MoO(2)(Bz(2)Benzenediyldtc)(2)Mo(2)O(3)(Bz(2)Benzenediyldtc)(2)MoO(2)] which has one MU-oxomolybdenum(V) moiety. An Eyring plot allows the activation parameters DeltaH(?)=64.2(1) kJ mol(-1) and DeltaS(?)=-45.1(6) J K(-1) mol(-1) to be determined from the temperature dependence of the rate constant, suggesting an associative transition state for the oxo transfer reaction. Catalytic oxygen atom transfer reaction from DMSO to PPh(3) was also followed by monitoring the chemical shift changes in (31)P NMR spectroscopy. The substrate oxidation process follows a well-defined catalytic cycle capable of 100% conversion for the reaction of PPh(3) and DMSO without intervention of Mo(V) formation during about 36 h. PMID- 22226678 TI - C-terminal residues of oryza sativa GUN4 are required for the activation of the ChlH subunit of magnesium chelatase in chlorophyll synthesis. AB - Oryza sativa GUN4 together with the magnesium chelatase subunits ChlI, ChlD, and ChlH have been heterologously expressed and purified to reconstitute magnesium chelatase activity in vitro. Maximum magnesium chelatase activity requires pre activation of OsChlH with OsGUN4, Mg(2+) and protoporphyrin-IX. OsGUN4 and OsChlH preincubated without protoporphyrin-IX yields magnesium chelatase activity similar to assays without OsGUN4, suggesting formation of a dead-end complex. Either 9 or 10 C-terminal amino acids of OsGUN4 are slowly hydrolyzed to yield a truncated OsGUN4. These truncated OsGUN4 still bind protoporphyrin-IX and Mg protoporphyrin-IX but are unable to activate OsChlH. This suggests the mechanism of GUN4 activation of magnesium chelatase is different in eukaryotes compared to cyanobacteria as the orthologous cyanobacterial GUN4 proteins lack this C terminal extension. PMID- 22226679 TI - Human lactoferrin suppresses TNF-alpha-induced intercellular adhesion molecule-1 expression via competition with NF-kappaB in endothelial cells. AB - Lactoferrin (Lf) is known to have anti-inflammatory activity, but the mechanisms of action by Lf remain to be elucidated. Here, we demonstrated that TNF-alpha induced expression of intercellular adhesion molecule-1 (ICAM-1) was down regulated by Lf in a DNA-binding dependent manner at transcriptional level in endothelial cells. Our results showed that Lf bound to a DNA region in the ICAM-1 promoter in vitro as well as in chromatin context. Lf inhibited binding of NF kappaB to a proximal NF-kappaB site in ICAM-1 promoter. This type of repression represents an additional mechanism for the action of Lf in regulation of gene expression. PMID- 22226680 TI - The effect of pituitary adenylate cyclase-activating polypeptide on elevated plus maze behavior and hypothermia induced by morphine withdrawal. AB - The aim of the present investigation was to study the effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on morphine withdrawal-induced behavioral changes and hypothermia in male CFLP mice. Elevated plus maze (EPM) and jump tests were used to assess naloxone-precipitated morphine withdrawal induced behavior responses. Different doses of subcutaneous (s.c.) naloxone, (0.1 and 0.2 mg/kg, respectively) were used to precipitate the emotional and psychical aspects of withdrawal on EPM and 1 mg/kg (s.c.) was used to induce the somatic withdrawal signs such as jumping, and the changes in body temperature. In our EPM studies, naloxone proved to be anxiolytic in mice treated with morphine. Chronic intracerebroventricular (i.c.v.) administration of PACAP alone had no significant effect on withdrawal-induced anxiolysis and total activity at doses of 500 ng and 1 MUg. At dose of 500 ng, however, PACAP significantly counteracted the reduced motor activity in the EPM test in mice treated with morphine and diminished the hypothermia and shortened jump latency induced by naloxone in mice treated with morphine. These findings indicate that anxiolytic-like behavior may be mediated via a PACAP-involved pathway and PACAP may play an important role in chronic morphine withdrawal-induced hypothermia as well. PMID- 22226681 TI - Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers - I: formulation, lyoavailability and in vitro antimalarial activity assessment. AB - We recently reported a one-step transesterification of cyclodextrins (CDs) by vinyl-acyl fatty esters catalyzed by thermolysin. By using the solvent displacement method and depending on the experimental conditions, the CD derivatives grafted with decanoic alkyl chains (CD-C(10)) yielded either nanosphere or nanoreservoir-type systems with a size ranging from 70 to 220 nm. Both types of nanostructures were able to associate artemisinin (ART), a well known antimalarial lipophilic drug. The formulation parameters were optimized to reach stable and high ART dosage corresponding to drug levels of 0.3 and 1.6 mg mL(-1) in the colloidal suspension, for the spherical and reservoir-type nanosystems, respectively. PEG surface-decorated nanoparticles were also prepared by co-nanoprecipitation of PEG fatty acid esters and CD-C(10) molecules. The integration of the PEGylated amphiphiles within the CD-C(10) nanostructures did not influence the ART lyoavailability. Both types of ART-loaded nanosystems showed a sustained in vitro release profile over 96 (nanoreservoirs) and 240 h (nanospheres). Finally, the in vitro antimalarial activity was evaluated using the lactate dehydrogenase assay. ART-containing colloidal suspensions inhibited the growth of cultured Plasmodium falciparum, both multi-resistant K1 and susceptible 3D7 strains with IC(50) values (2.8 and 7.0 ng mL(-1)) close to those of reference ART solution. These colloidal nanosystems based on CD derivatives and containing ART may provide a promising alternative formulation for injectable use of ART. PMID- 22226682 TI - Role of expression site switching in the development of resistance to human Trypanosome Lytic Factor-1 in Trypanosoma brucei brucei. AB - Human high-density lipoproteins (HDLs) play an important role in human innate immunity to infection by African trypanosomes with a minor subclass, Trypanosome Lytic Factor-1 (TLF-1), displaying highly selective cytotoxicity to the veterinary pathogen Trypanosoma brucei brucei but not against the human sleeping sickness pathogens Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense. T. b. rhodesiense has evolved the serum resistance associated protein (SRA) that binds and confers resistance to TLF-1 while T. b. gambiense lacks the gene for SRA indicating that these parasites have diverse mechanisms of resistance to TLF-1. Recently, we have shown that T. b. gambiense (group 1) resistance to TLF-1 correlated with the loss of the haptoglobin/hemoglobin receptor (HpHbR) expression, the protein responsible for high affinity binding and uptake of TLF-1. In the course of these studies we also examined TLF-1 resistant T. b. brucei cell lines, generated by long-term in vitro selection. We found that changes in TLF-1 susceptibility in T. b. brucei correlated with changes in variant surface glycoprotein (VSG) expression in addition to reduced TLF-1 binding and uptake. To determine whether the expressed VSG or expression site associated genes (ESAGs) contribute to TLF-1 resistance we prepared a TLF-1 resistant T. b. brucei with a selectable marker in a silent bloodstream expression site (BES). Drug treatment allowed rapid selection of trypanosomes that activated the tagged BES. These studies show that TLF-1 resistance in T. b. brucei is largely independent of the expressed VSG or ESAGs further supporting the central role of HpHbR expression in TLF-1 susceptibility in these cells. PMID- 22226683 TI - Intra-fraction motion during extreme hypofractionated radiotherapy of the prostate using pre- and post-treatment imaging. AB - AIMS: To determine intra-fraction displacement of the prostate during extreme hypofractionated radiotherapy using pre- and post-treatment orthogonal images with three implanted gold seed fiducial markers. MATERIALS AND METHODS: In total, 265 image pairs were obtained from 53 patients who underwent extreme hypofractionated radiotherapy to a dose of 35 Gy in five fractions on standard linear accelerators. Position verification was obtained with orthogonal X-rays before and after treatment and were used to determine intra-fraction prostate displacement. RESULTS: The mean intra-fraction prostate displacements were -0.03 +/- 0.61 mm (one standard deviation), 0.21 +/- 1.50 mm and -0.86 +/- 1.73 mm in the left-right, superior-inferior and anterior-posterior directions, respectively. The mean intra-fraction displacement during the first two fractions was moderately correlated with the displacement in the remaining three fractions, with correlation coefficients of 0.63 (95% confidence interval 0.43-0.77) and 0.47 (95% confidence interval 0.22-0.65) in the superior-inferior and anterior posterior directions, respectively. There was no significant correlation in the left-right direction with a coefficient of -0.04 (95% confidence interval -0.31 0.23). CONCLUSIONS: The mean intra-fraction prostate displacement during a course of extreme hypofractionated radiotherapy is small. A strategy using the first two fractions to predict future displacements >5 mm warrants further validation. PMID- 22226684 TI - Human papillomavirus as a favorable prognostic biomarker in squamous cell carcinomas of the vagina. AB - OBJECTIVE: Recent evidence has confirmed two independent pathways in the development of vaginal squamous cell carcinoma (VaSCC): one related to and the other independent of human papillomavirus (HPV). The aim of our study was to evaluate whether HPV status has prognostic significance in this neoplasm. METHODS: All confirmed primary VaSCCs diagnosed and treated from 1995 to 2009 in two institutions were retrospectively evaluated (n=57). HPV infection was detected by PCR using SPF-10 primers and typed with the INNO-LIPA HPV assay and p16(INK4a) expression by immunohistochemistry. Disease-free and overall survival (DFS and OS) were analyzed by Kaplan-Meier analysis with the log-rank test and a multivariate Cox proportional hazard's model. RESULTS: HR-HPV DNA was detected in 70.2% patients. HPV16 was the most prevalent genotype (67.5% of cases). p16(INK4a) was positive in 97.5% HPV-positive and 17.6% HPV-negative tumors (p<.001). FIGO stage was associated with DFS (p=.042) and OS (p=.008). HPV positive tumors showed better DFS (p=.042) and OS (p=.035) than HPV-negative tumors. Multivariate analysis confirmed better DFS and OS of HPV-positive patients independent of age and stage. This reduced risk of progression and mortality in HPV-positive patients was limited to women with FIGO stages I and II tumors (HR=0.26; 95% CI 0.10-0.69; p=0.006). CONCLUSIONS: HPV-positive early stage (FIGO I and II) VaSCCs have a better prognosis than early HPV-negative tumors. HPV detection and/or p16(INK4a) immunostaining can be easily implemented in routine pathology and should be considered as valuable prognostic biomarkers in the study of patients with VaSCC. PMID- 22226685 TI - 182nd ENMC International Workshop: RYR1-related myopathies, 15-17th April 2011, Naarden, The Netherlands. PMID- 22226686 TI - The COMPASs Study: Community Preferences for Prostate cAncer Screening. Protocol for a quantitative preference study. AB - Background Prostate cancer screening using prostate-specific antigen (PSA) testing remains controversial. Trade-offs between the potential benefits and downsides of screening must be weighed by men deciding whether to participate in prostate cancer screening; little is known about benefit:harm trade-offs men are willing to accept. Methods/Design The Community Preferences for Prostate Cancer Screening (COMPASs) Study examines Australian men's preferences for prostate cancer screening using PSA testing. The aims are to (1) determine which factors influence men's decision to participate in prostate cancer screening or not and (2) determine the extent of trade-offs between benefits and harms that men are willing to accept in making these decisions. Quantitative methods will be used to assess men's preferences for PSA screening. Using data on the quantitative outcomes of PSA testing from the published literature, a discrete choice study will be designed to quantitatively assess men's preferences. A web-based survey will be conducted in approximately 1000 community respondents aged 40-69 years, stratified by family history of prostate cancer, to assess men's preferences for PSA testing. A mixed logit model will be used; model results will be expressed as parameter estimates (beta) and the odds of choosing screening over no screening. Trade-offs between attributes will also be calculated. Ethics and Dissemination The COMPASs study has been approved by the University of Sydney, Human Research Ethics committee (Protocol number 13186). The results will be published in internal reports, in peer-reviewed scientific journals as well as via conference presentations. PMID- 22226687 TI - Can medical thermal images predict acupuncture adverse events? A case history. AB - Malaise and fainting are unpleasant acupuncture adverse effects. This paper shows how the use of thermography might identify subjects before the systematic responses become clinically significant. PMID- 22226688 TI - Changes in intracortical microporosities induced by pharmaceutical treatment of osteoporosis as detected by high resolution micro-CT. AB - Bone's microporosities play important biologic and mechanical roles. Here, we quantified 3D changes in cortical osteocyte-lacunae and other small porosities induced by estrogen withdrawal and two different osteoporosis treatments. Unlike 2D measurements, these data collected via synchrotron radiation-based MUCT describe the size and 3D spatial distribution of a large number of porous structures. Six-month old female Sprague-Dawley rats were separated into four groups of age-matched controls, untreated OVX, OVX treated with PTH, and OVX treated with Alendronate (ALN). Intracortical microporosity of the medial quadrant of the femoral diaphysis was quantified at endosteal, intracortical, and periosteal regions of the samples, allowing the quantification of osteocyte lacunae that were formed primarily before versus after the start of treatment. Across the overall thickness of the medial cortex, lacunar volume fraction (Lc.V/TV) was significantly lower in ALN treated rats compared to PTH. In the endosteal region, average osteocyte lacunar volume () of untreated OVX rats was significantly lower than in age-matched controls, indicating a decrease in osteocyte lacunar size in bone formed on the endosteal surface after estrogen withdrawal. The effect of treatment (OVX, ALN, PTH) on the number of lacunae per tissue volume (Lc.N/TV) was dependent on the specific location within the cortex (endosteal, intracortical, periosteal). In both the endosteal and intracortical regions, Lc.N/TV was significantly lower in ALN than in untreated OVX, suggesting a site-specific effect in osteocyte lacuna density with ALN treatment. There also were a significantly greater number of small pores (5-100 MUm(3) in volume) in the endosteal region for PTH compared to ALN. The mechanical impact of this altered microporosity structure is unknown, but might serve to enhance, rather than deteriorate bone strength with PTH treatment, as smaller osteocyte lacunae may be better able to absorb shear forces than larger lacunae. Together, these data demonstrate that current treatments of osteoporosis can alter the number, size, and distribution of microporosities in cortical rat lamellar bone. PMID- 22226689 TI - Characterization of mesenchymal progenitor cells isolated from human bone marrow by negative selection. AB - Studies on the pathogenesis of osteoporosis and other metabolic bone diseases would be greatly facilitated by the development of approaches to assess changes in gene expression in osteoblast/osteoprogenitor populations in vivo without the potentially confounding effects of in vitro culture and expansion of the cells. While positive selection to identify a progenitor population in human marrow can be used to select for cells capable of osteoblast differentiation, each of the markers that have been used to identify marrow mesenchymal populations (alkaline phosphatase [AP], Stro-1, CD29, CD49a, CD73, CD90, CD105, CD166, CD44, CD146 and CD271) may be expressed on distinct subsets of marrow mesenchymal cells. Thus, positive selection with one or more of these markers could exclude a possibly relevant cell population that may undergo important changes in various clinical conditions. In the present report, we describe the isolation and characterization of human osteoprogenitor cells obtained by depletion of bone marrow cells of all hematopoietic lineage/hematopoietic stem cells and endothelial/endothelial precursor cells (lin-/CD34/CD31-). The yield of lin-/CD34/CD31- cells from ~10 mL of bone marrow (~80 million mononuclear cells) was ~80,000 cells (0.1% of mononuclear cells). While not selected on the basis of expression for the mesenchymal marker, Stro-1, 68% of these cells were Stro-1+. Using linear whole transcriptome amplification followed by quantitative polymerase chain reaction (QPCR) analysis, we also demonstrated that, compared to lin- cells (which are already depleted of hematopoietic cells), lin-/CD34/31- cells expressed markedly lower mRNA levels for the endothelial/hematopoietic markers, CD34, CD31, CD45, and CD133. Lin-/CD34/31- cells were also enriched for the expression of mesenchymal/osteoblastic markers, with a further increase in runx2, osterix, and AP mRNA expression following in vitro culture under osteogenic conditions. Importantly, lin-/CD34/31- cells contained virtually all of the mineralizing cells in human marrow: while these cells displayed robust calcium deposition in vitro, lin-/CD34/31+ cells demonstrated little or no mineralization when cultured under identical osteogenic conditions. Lin-/CD34/31- cells thus represent a human bone marrow population highly enriched for mesenchymal/osteoblast progenitor cells that can be analyzed without in vitro culture in various metabolic bone disorders, including osteoporosis and aging. PMID- 22226690 TI - Warfarin use in nursing home residents: results from the 2004 national nursing home survey. AB - BACKGROUND: Practice guidelines recommend anticoagulation therapy with warfarin for stroke prevention in patients with atrial fibrillation (AF). Despite this, warfarin is underused in older adults. OBJECTIVE: The purpose of this study was to determine the prevalence of AF in nursing home (NH) residents and the use of warfarin or other antiplatelet medications in NH residents with AF who have indications for and no contraindications against warfarin use. The secondary objective was to determine the factors associated with warfarin use in NH residents with AF. METHODS: Cross-sectional analysis of prescription and resident data files from the 2004 National Nursing Home Survey was performed. Residents with a diagnosis of AF were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, and prescriptions of warfarin and antiplatelet medications were identified using Long Term Care Drug Database System (LTCDDS) codes. Resident characteristics, stroke risk factors, and potential bleeding risk factors significant at P < 0.10 in chi(2) analyses were entered in the final multiple logistic regression model to determine the factors associated with warfarin use. RESULTS: From 13,507 NH residents, 1904 (14%) had a diagnosis of AF and 1767 (13%) had a diagnosis of AF with indications for and no contraindications against warfarin use. Of these 1767 residents, 537 (30%) were prescribed warfarin, and of the remaining 1230 residents who were not prescribed warfarin, 283 (23%) received either aspirin or clopidogrel. Thus, of 1767 residents with AF, with indications for and no contraindications to warfarin use, 947 (54%) residents did not receive any antithrombotic therapy in the form of warfarin, aspirin, clopidogrel, or a combination of these medications. Factors that were significantly associated with increased odds of receiving warfarin were congestive heart failure, previous stroke or transient ischemic attack, deep vein thrombosis or peripheral embolus, valvular heart disease, and total number of medications >= 6. Factors that were significantly associated with reduced odds of receiving warfarin were nonwhite race, history of gastrointestinal bleeding, and use of antiplatelets (ie, clopidogrel). CONCLUSIONS: AF is common in NH residents, and more than half of the residents with AF who had indications for and no contraindications against warfarin use were not prescribed either warfarin or antiplatelets, such as aspirin or clopidogrel, suggesting that antithrombotic therapy may be underused in NH residents with AF. PMID- 22226691 TI - Absence of occult HCV infection in HIV-positive patients. PMID- 22226692 TI - Chronic Q fever: review of the literature and a proposal of new diagnostic criteria. AB - A review was performed to determine clinical aspects and diagnostic tools for chronic Q fever. We present a Dutch guideline based on literature and clinical experience with chronic Q fever patients in The Netherlands so far. In this guideline diagnosis is categorized as proven, possible or probable chronic infection based on serology, PCR, clinical symptoms, risk factors and diagnostic imaging. PMID- 22226693 TI - The use of PCT, CRP, IL-6 and SAA in critically ill patients for an early distinction between candidemia and Gram positive/negative bacteremia. PMID- 22226694 TI - In vivo GABA release and kinetics of transgene loss in a GABAergic cell line after long-term transplantation into the rat brain. AB - Ex vivo gene therapy uses modified cells to deliver substances into the brain. Cell line M213-2O CL-4 expresses human glutamate decarboxylase (hGAD(67)) by means of an Epstein-Barr virus-based plasmid. This cell line releases GABA in response to depolarizing stimuli in vitro, and after brain transplantation it modulates seizures in animal models. It is unclear if the functional effects observed can be attributed to GABA release by the grafted cells and if GABA release, in turn, is related to the kinetics of transgene permanence or loss under long-term transplantation conditions. To address these issues, two experiments were performed. The first one evaluated GABA levels in the vicinity of an intranigral transplant by microdialysis followed by high performance liquid chromatography (HPLC) quantification. GABA levels and GAD activity were higher in rats with 8-week-old transplants than in control animals, but this effect was lost in rats with 12-week-old transplants. The second experiment evaluated the number of copies of the plasmid containing the hGAD(67) (GAD1) transgene by real time PCR after transplantation into the hippocampus at the same times. A time dependent loss of the plasmid in the transplants was observed. The mechanism of plasmid loss was explored in vitro by analyzing the effects of DNA methylation and the absence of selection pressure. The results suggest that the loss of plasmid copies from transplants under long-term conditions may be related to methylation of plasmid regions involved in its nuclear retention. Taking these data together, we propose that the reported long-term functional effects of transplants of cell line M213-2O CL-4 may not be attributed exclusively to increased GABA release in the area of the graft, but that a paracrine-like action of GABA may lead to the remodeling of neural circuits in the host. PMID- 22226695 TI - Morphometric variability of nicotinamide adenine dinucleotide phosphate diaphorase neurons in the primary sensory areas of the rat. AB - Even though there is great regional variation in the distribution of inhibitory neurons in the mammalian isocortex, relatively little is known about their morphological differences across areal borders. To obtain a better understanding of particularities of inhibitory circuits in cortical areas that correspond to different sensory modalities, we investigated the morphometric differences of a subset of inhibitory neurons reactive to the enzyme nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) within the primary auditory (A1), somatosensory (S1), and visual (V1) areas of the rat. One hundred and twenty NADPH-d-reactive neurons from cortical layer IV (40 cells in each cortical area) were reconstructed using the Neurolucida system. We collected morphometric data on cell body area, dendritic field area, number of dendrites per branching order, total dendritic length, dendritic complexity (Sholl analysis), and fractal dimension. To characterize different cell groups based on morphology, we performed a cluster analysis based on the previously mentioned parameters and searched for correlations among these variables. Morphometric analysis of NADPH-d neurons allowed us to distinguish three groups of cells, corresponding to the three analyzed areas. S1 neurons have a higher morphological complexity than those found in both A1 and V1. The difference among these groups, based on cluster analysis, was mainly related to the size and complexity of dendritic branching. A principal component analysis (PCA) applied to the data showed that area of dendritic field and fractal dimension are the parameters mostly responsible for dataset variance among the three areas. Our results suggest that the nitrergic cortical circuitry of primary sensory areas of the rat is differentially specialized, probably reflecting peculiarities of both habit and behavior of the species. PMID- 22226696 TI - Histone deacetylase 9 as a negative regulator for choline acetyltransferase gene in NG108-15 neuronal cells. AB - The biological function of histone deacetylases (HDACs), namely, repression of gene expression by removing an acetyl group from a histone N-terminal tail, plays an important role in numerous biological processes such as cell cycle, differentiation, and apoptosis in the development of individual tissues, including the brain. We previously showed the possible role of HDAC activity in the regulation of gene expression of choline acetyltransferase (ChAT), a specific marker for cholinergic neurons and their function, in NG108-15 neuronal cells as an in vitro model of cholinergic neurons. The objectives of the present study were to specify key HDACs and investigate the essential role of HDACs in ChAT gene regulation in NG108-15 cells. The experiments using different types of HDAC inhibitors indicated that class IIa HDACs substantially participate in the regulation of ChAT gene expression. In addition, HDAC9, a class IIa enzyme, was dramatically decreased at the protein levels, and dissociated from the promoter region of ChAT gene during neuronal differentiation. Furthermore, knockdown of HDAC9 by siRNA increased ChAT gene expression in undifferentiated cells. These findings demonstrate that HDAC9 is responsible for repressing ChAT gene expression in NG108-15 neuronal cells, and thus plays an important role in cholinergic differentiation. PMID- 22226697 TI - Commentary to accompany 'Removing the need for cross matched blood in elective EVAR'. PMID- 22226698 TI - Why the United States Center for Medicare and Medicaid Services (CMS) should not extend reimbursement indications for carotid artery angioplasty/stenting. PMID- 22226699 TI - The wonders of a newly available post-analysis CT software in the hands of vascular surgeons. AB - INTRODUCTION: Endovascular treatment of abdominal aortic aneurysms has become a widespread and accepted practice in most Vascular Surgery centres. The optimal method to identify and characterise complications still awaits assessment. CASE REPORT: An 83-year-old woman was admitted to our Institution for volumetric expansion of the aneurysm sac due to a suspected type II endoleak. Post-analysis, using OsiriX, revealed the presence of a hole at the distal portion of the main body in the docking zone near the flow divider. CONCLUSION: OsiriX is an image processing software and an attractive alternative to dedicated workstations and allows rendering and analysis of numerous medical imaging modalities. PMID- 22226700 TI - Femoral artery dissection in vascular type Ehlers-Danlos syndrome; leave well alone? AB - Vascular Ehlers-Danlos Syndrome (EDS) is a rare autosomal dominant condition resulting from a defect in type III procollagen synthesis. This causes the development of severe vascular pathologies, including arterial rupture and pseudoaneurysm formation. We present a case of a young boy previously diagnosed with vascular EDS due to a Gly975Val substitution in the collagen alpha1(III) chain presenting with a common femoral artery dissection secondary to minimal trauma. This was managed conservatively with serial duplex scans and gentle mobilization. At follow up the patient had returned to normal activities, with MRA and duplex scans showing complete resolution of the dissection. PMID- 22226701 TI - Whole genomic analysis reveals the porcine origin of human G9P[19] rotavirus strains Mc323 and Mc345. AB - The group A rotavirus (RVA) P[19] is a rare P-genotype of the RVA VP4 gene, reported so far in humans and pigs. Whole genomic analyses of P[19] strains are essential to study their origin and evolutionary patterns. To date, all the 11 genes of only two P[19] strains, RVA/Human-wt/IND/RMC321/1990/G9P[19] and RVA/Human-wt/IND/mani-97/2006/G9P[19], have been analyzed, providing evidence for their porcine origin. In the present study, the whole genomes of the first reported human P[19] strains, RVA/Human-tc/THA/Mc323/1989/G9P[19] and RVA/Human tc/THA/Mc345/1989/G9P[19], were analyzed. Strains Mc323 and Mc345 exhibited a G9 P[19]-I5-R1-C1-M1-A8-N1-T1-E1-H1 genotype constellation. With the exception of the NSP5 gene, both the strains were closely related to each other. Most of the genes of Mc323 (VP2-4, VP6-7, NSP1-4 genes) and Mc345 (VP2-4, VP6-7 and NSP1-5 genes) appeared to be of porcine origin, whilst the exact origin of VP1 and NSP5 genes of Mc323 and VP1 gene of Mc345 could not be ascertained. Therefore, strains Mc323 and Mc345 were found to have a porcine RVA genetic backbone, and are likely of porcine origin. Taken together, our observations corroborated the hypothesis that P[19] strains might be derived from porcine RVAs, providing important insights into the origin of P[19] strains, and on interspecies transmission of RVAs. PMID- 22226702 TI - Molecular genotyping of Toxoplasma gondii from Central and South America revealed high diversity within and between populations. AB - Recent population studies revealed that a few major clonal lineages of Toxoplasma gondii dominate in different geographical regions. The Type II and III lineages are widespread in all continents and dominate in Europe, Africa and North America. In addition, the type 12 lineage is the most common type in wildlife in North America, the Africa 1 and 3 are among the major types in Africa, and ToxoDB PCR-RFLP #9 is the major type in China. Overall the T. gondii strains are more diverse in South America than any other regions. Here, we analyzed 164 T. gondii isolates from three countries in Central America (Guatemala, Nicaragua, Costa Rica), from one country in Caribbean (Grenada) and five countries from South America (Venezuela, Colombia, Peru, Chile, and Argentina). The multilocous polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) based genotyping of 11 polymorphic markers (SAG1, SAG2, alt.SAG2, SAG3, BTUB, GRA6, L358, PK1, C22-8, C29-2 and Apico) were applied to 148 free-range chicken (Gallus domesticus) isolates and 16 isolates from domestic cats (Felis catus) in Colombia; 42 genotypes were identified. Linkage disequilibrium analysis indicated more frequent genetic recombination in populations of Nicaragua and Colombia, and to a lesser degree in populations of Costa Rica and Argentina. Bayesian structural analysis identified at least three genetic clusters, and phylogenetic network analysis identified four major groups. The ToxoDB PCR-RFLP #7, Type III and II were major lineages identified from Central and South America, with high frequencies of the closely related ToxoDB PCR-RFLP #7 and Type III lineages. Taken together, this study revealed high diversity within and between T. gondii populations in Central and South America, and the dominance of Type III and its closely related ToxoDB PCR-RFLP #7 lineages. PMID- 22226703 TI - West Nile virus population genetics and evolution. AB - West Nile virus (WNV) (Flaviviridae: Flavivirus) is transmitted from mosquitoes to birds, but can cause fatal encephalitis in infected humans. Since its introduction into North America in New York in 1999, it has spread throughout the western hemisphere. Multiple outbreaks have also occurred in Europe over the last 20 years. This review highlights recent efforts to understand how host pressures impact viral population genetics, genotypic and phenotypic changes which have occurred in the WNV genome as it adapts to this novel environment, and molecular epidemiology of WNV worldwide. Future research directions are also discussed. PMID- 22226705 TI - Comparative evolutionary epidemiology of dengue virus serotypes. AB - Evolutionary studies on dengue virus have frequently focused on intra-serotype diversity or on specific epidemics. In this study, we compiled a comprehensive data set of the envelope gene of dengue virus serotypes and conducted an extensive comparative study of evolutionary molecular epidemiology. We found that substitution rates are homogeneous among dengue serotypes, although their population dynamics have differed over the past few years as inferred by Bayesian coalescent methods. On a global scale, DENV-2 is the serotype with the highest effective population size. The genealogies also showed geographical structure within the serotypes. Finally, we also explored the causes of dengue virus serotype diversification by investigating the plausibility that it was driven by adaptive changes. Our results suggest that the envelope gene is under significant purifying selection and the hypothesis that dengue virus serotype diversification was the result of stochastic events cannot be ruled out. PMID- 22226704 TI - The revised Trypanosoma cruzi subspecific nomenclature: rationale, epidemiological relevance and research applications. AB - The protozoan Trypanosoma cruzi, its mammalian reservoirs, and vectors have existed in nature for millions of years. The human infection, named Chagas disease, is a major public health problem for Latin America. T. cruzi is genetically highly diverse and the understanding of the population structure of this parasite is critical because of the links to transmission cycles and disease. At present, T. cruzi is partitioned into six discrete typing units (DTUs), TcI-TcVI. Here we focus on the current status of taxonomy-related areas such as population structure, phylogeographical and eco-epidemiological features, and the correlation of DTU with natural and experimental infection. We also summarize methods for DTU genotyping, available for widespread use in endemic areas. For the immediate future multilocus sequence typing is likely to be the gold standard for population studies. We conclude that greater advances in our knowledge on pathogenic and epidemiological features of these parasites are expected in the coming decade through the comparative analysis of the genomes from isolates of various DTUs. PMID- 22226707 TI - Prevalence of psychiatric disorders among young injection drug users. AB - BACKGROUND: Studies of individuals in treatment for substance use have found high rates of psychiatric disorders, however little is known about the mental health of drug users not in treatment. This study aimed to assess the prevalence of lifetime and recent substance use and psychiatric disorders among young injection drug users (IDU) outside of a treatment setting. METHODS: Participants were recruited through outreach and respondent-driven sampling. Trained interviewers administered the Psychiatric Research Instrument for Substance and Mental Disorders. Interviews were conducted at two field stations operated by Community Outreach Intervention Projects in Chicago. Participants were 570 young adults (18 25 years) who injected drugs in the previous 30 days. Heroin was the primary drug used in this sample. Past 12-month and lifetime substance use disorders and primary and substance-induced mental disorders were based on DSM-IV diagnostic criteria. RESULTS: Nearly all participants met the criteria for heroin dependence. Multiple substance use disorders were common; cannabis was the most common substance involved after heroin, followed by alcohol and cocaine. Major depression, alcohol dependence, antisocial personality disorder, and borderline personality disorder were highly prevalent. Other psychiatric disorders were observed at levels consistent with other young adult samples. CONCLUSIONS: Young IDU experience major depression, alcohol dependence, anti-social personality disorder, and borderline personality disorder at high rates, and multiple substance use disorders are common. Anxiety disorders in this population appear to be similar in prevalence to young adults in general. PMID- 22226708 TI - Detection, annotation and visualization of alternative splicing from RNA-Seq data with SplicingViewer. AB - Alternative splicing is a crucial mechanism by which diverse gene products can be generated from a limited number of genes, and is thought to be involved in complex orchestration of eukaryotic gene expression. Next-generation sequencing technologies, with reduced time and cost, provide unprecedented opportunities for deep interrogation of alternative splicing at the genome-wide scale. In this study, an integrated software SplicingViewer has been developed for unambiguous detection, annotation and visualization of splice junctions and alternative splicing events from RNA-Seq data. Specifically, it allows easy identification and characterization of splice junctions, and holds a versatile computational pipeline for in-depth annotation and classification of alternative splicing with different patterns. Moreover, it provides a user-friendly environment in which an alternative splicing landscape can be displayed in a straightforward and flexible manner. In conclusion, SplicingViewer can be widely used for studying alternative splicing easily and efficiently. SplicingViewer can be freely accessed at http://bioinformatics.zj.cn/splicingviewer. PMID- 22226706 TI - Examining the role of mu opioid receptor endocytosis in the beneficial and side effects of prolonged opioid use: from a symposium on new concepts in mu-opioid pharmacology. AB - Opioid drugs remain the gold standard for the treatment of severe pain, both acute/post-surgical and chronic. However, the utility of opioid drugs for the treatment of chronic pain is compromised by the development of analgesic tolerance which, in turn, leads to dose-escalation and increased likelihood of dangerous side effects, including dependence. Consequently, there remains resistance among clinicians and the general population to using opiates for pain management because of risk of "addiction." These fears are not unwarranted. More than 2.5 million people begin abusing opioid painkillers each year, and prescription opioid abuse is now the second most common type of illegal drug use after marijuana. Some abusers become dependent due to recreational use of prescription painkillers. However, many abusers are among the 40 million people suffering from chronic pain, and developed dependence while using the drugs for legitimate purposes. Both of these trends highlight the need to develop opioid therapeutics with a reduced liability to cause tolerance, dependence and addiction. Identifying the ideal properties of opioid drugs that would retain analgesia but reduce these side-effects has been a goal of my laboratory for more than a decade. During this time, we have proposed the novel hypothesis that opioid drugs that promote desensitization, endocytosis and recycling of the mu opioid-receptor (MOR) will retain analgesic efficacy, but will have a reduced liability to cause tolerance, dependence and addiction. We have generated substantial data, both pharmacological and genetic to suggest that our hypothesis is a valid one. These data are summarized in this review. PMID- 22226709 TI - Overexpression of dehydrin tas14 gene improves the osmotic stress imposed by drought and salinity in tomato. AB - One strategy to increase the level of drought and salinity tolerance is the transfer of genes codifying different types of proteins functionally related to macromolecules protection, such as group 2 of late embryogenesis abundant (LEA) proteins or dehydrins. The TAS14 dehydrin was isolated and characterized in tomato and its expression was induced by osmotic stress (NaCl and mannitol) and abscisic acid (ABA) [Godoy et al., Plant Mol Biol 1994;26:1921-1934], yet its function in drought and salinity tolerance of tomato remains elusive. In this study, transgenic tomato plants overexpressing tas14 gene under the control of the 35SCaMV promoter were generated to assess the function of tas14 gene in drought and salinity tolerance. The plants overexpressing tas14 gene achieved improved long-term drought and salinity tolerance without affecting plant growth under non-stress conditions. A mechanism of osmotic stress tolerance via osmotic potential reduction and solutes accumulation, such as sugars and K(+) is operating in tas14 overexpressing plants in drought conditions. A similar mechanism of osmotic stress tolerance was observed under salinity. Moreover, the overexpression of tas14 gene increased Na(+) accumulation only in adult leaves, whereas in young leaves, the accumulated solutes were K(+) and sugars, suggesting that plants overexpressing tas14 gene are able to distribute the Na(+) accumulation between young and adult leaves over a prolonged period in stressful conditions. Measurement of ABA showed that the action mechanism of tas14 gene is associated with an earlier and greater accumulation of ABA in leaves during short term periods. A good feature for the application of this gene in improving drought and salt stress tolerance is the fact that its constitutive expression does not affect plant growth under non-stress conditions, and tolerance induced by overexpression of tas14 gene was observed at the different stress degrees applied to the long term. PMID- 22226710 TI - Fludarabine and a histone deacetylase inhibitor - strange bedfellows. PMID- 22226711 TI - N-terminally truncated WT1 variant (sWT1) is expressed at very low levels in acute myeloid leukemia and advanced phases of chronic myeloid leukemia. PMID- 22226712 TI - A novel recurrent translocation t(7;17)(q22;p13) and a late-appearing t(2;3)(p13;q26.2) with dysmegakaryopoiesis in acute myeloid leukemia. PMID- 22226713 TI - Hierarchical architectures TiO2: pollen-inducted synthesis, remarkable crystalline-phase stability, tunable size, and reused photo-catalysis. AB - TiO(2) with hierarchical architectures, tunable crystalline phase and thermal stability is successfully fabricated on a large scale through a facile hydrolysis process of TiCl(4) combining with inducing of pollen. The structure of the as prepared TiO(2) is characterized by X-ray diffraction, Raman spectroscopy, infrared spectra, and scanning electron microscopy. The experimental results indicate that different phases (anatase, rutile or mixed crystallite) of TiO(2) can be synthesized by controlling the experimental conditions. The pure phase of rutile or anatase can be obtained at 100 degrees C, while the pure phase of anatase can be retained after being annealed at 900 degrees C. The hierarchical structures TiO(2) are constitute through self-assembly of nanoparticles or nanorods TiO(2), which exhibit high and reused photo-catalytic properties for degradation of methylene blue. PMID- 22226714 TI - Adsorptive removal of alpha-endosulfan from water by hydrophobic zeolites. An isothermal study. AB - This paper deals with the removal of alpha-endosulfan from water over HY and steamed HBEA zeolites. Experiments were performed to understand the adsorption mechanisms of alpha-endosulfan on zeolites and to determine the most efficient adsorbent for the purification of water contaminated by this pesticide. The experiments exhibit that alpha-endosulfan was adsorbed in the micropores. In the case of HY zeolites an adsorption of alpha-endosulfan molecules on BrOnsted sites was pointed out, due to a preferential water adsorption in mesopores. Moreover a physisorption of alpha-endosulfan occurred in micropores. For steamed HBEA zeolites physisorption in micropores was pointed out as the adsorption mode. For both types of zeolites a decrease of the adsorption capacities was noticed when the acidity of zeolites increased. There was also a linear relation between the adsorption capacities of alpha-endosulfan and the hydrophobicity (HI) of the samples and by determining the values of HI for a type of zeolite it was possible to deduce the uptake of alpha-endosulfan. The HY(40) sample was the most efficient for the removal of alpha-endosulfan from water because of preferential adsorption of water molecules in mesopores and lower acidity. For this sample the adsorption capacity for alpha-endosulfan was about 833.33 mg/g where for the most effective HBEA sample (St700(3)) the adsorption capacity was about 793.65 mg/g. PMID- 22226715 TI - Photocatalytic activity of titanium dioxide nanoparticle coatings applied on autoclaved aerated concrete: effect of weathering on coating physical characteristics and gaseous toluene removal. AB - Autoclaved aerated concrete has been coated by TiO(2) nanoparticles through a dip coating (DC) and a novel vacuum saturation (VS) method to investigate the weathering resistance and gaseous toluene removal potential of both coating types. The effect of intensive weathering - corresponding to a period of about 25 years - on the coating characteristics was studied in terms of TiO(2) content, coating thickness and color changes. Toluene removal was investigated in a lab scale flow-through photoreactor at 24 degrees C and 52% relative humidity, and results obtained immediately after application of the coatings and after two weathering stages were compared. Weathering of the DC and VS coated samples resulted into a decrease of the coating layer thickness of more than 98%, confirmed by a decline in TiO(2) content by more than 99% and 93%, respectively. Surprisingly, toluene removal efficiencies before and after weathering kept constant at about 95% for both coating types, corresponding to an elimination rate of 60-70 mg/(m(2)h) at an initial toluene concentration of 15 ppm(v) and a gas residence time of 3 min. Increasing the toluene load by applying higher toluene inlet concentrations (up to 35 ppm(v)) and lower gas residence times (1 min) did decrease the toluene removal efficiency to 32-41%, but elimination rates increased up to 214 mg/(m(2)h), being a factor of 1.6-4.5 times higher than reported in recent work. PMID- 22226716 TI - Adsorption and photocatalytic oxidation of formaldehyde on a clay-TiO2 composite. AB - We investigated the adsorption capacity and photocatalytic removal efficiency of formaldehyde using a hectorite-TiO(2) composite in a bench flow reactor. The same experimental conditions were applied to pure TiO(2) (Degussa P25) as a reference. The catalysts were irradiated with either a UVA lamp (365 nm) or with one of two UVC lamps of 254 nm and 254+185 nm, respectively. Formaldehyde was introduced upstream at concentrations of 100-500 ppb, with relative humidity (RH) in the range 0-66% and residence times between 50 and 500 ms. Under dry air and without illumination, saturation of catalyst surfaces was achieved after ~ 200 min for P25 and ~ 1000 min for hectorite-TiO(2). The formaldehyde uptake capacity by hectorite-TiO(2) was 4.1 times higher than that of P25, almost twice the BET surface area ratio. In the presence of humidity, the difference in uptake efficiency between both materials disappeared, and saturation was achieved faster (after ~ 200 min at 10% RH and ~ 60 min at 65% RH). Under irradiation with each of the three UV sources, removal efficiencies were proportional to the Ti content and increased with contact time. The removal efficiency decreased at high RH. A more complete elimination of formaldehyde was observed with the 254+185 nm UV source. PMID- 22226717 TI - Biodegradation of explosives mixture in soil under different water-content conditions. AB - Soil redox potential plays a key role in the rates and pathways of explosives degradation, and is highly influenced by water content and microbial activity. Soil redox potential can vary significantly both temporally and spatially in micro-sites. In this study, when soil water content increased, the redox potential decreased, and there was significant enhancement in the biodegradation of a mixture of three explosives. Whereas TNT degradation occurred under both aerobic and anaerobic conditions, RDX and HMX degradation occurred only when water content conditions resulted in a prolonged period of negative redox potential. Moreover, under unsaturated conditions, which are more representative of real environmental conditions, the low redox potential, even when measured for temporary periods, was sufficient to facilitate anaerobic degradation. Our results clearly indicate a negative influence of TNT on the biodegradation of RDX and HMX, but this effect was less pronounced than that found in previous slurry batch experiments: this can be explained by a masking effect of the soil in the canisters. Fully or partially saturated soils can promote the existence of micro niches that differ considerably in their explosives concentration, microbial community and redox conditions. PMID- 22226718 TI - Bracken-associated human and animal health hazards: chemical, biological and pathological evidence. AB - Bracken (Pteridium aquilinum) is a widely distributed carcinogenic fern, to whose toxins human populations are exposed through multiple routes. Animals are also affected by bracken toxins, leading to serious production losses yearly. Accordingly, several governmental reports regarding the safeguard of public health against bracken carcinogens have been recently issued. This review describes the main bioactive compounds identified in bracken and their biological effects at the molecular, cellular, pathological and populational levels, with particular emphasis on ptaquiloside, the main bracken carcinogen. Recent biopathological studies shedding further light on the genotoxicity immunotoxicity and carcinogenicity of ptaquiloside are discussed. Key steps on the long effort to understand bracken toxicology are also reviewed, along with the latest findings on new bracken toxins and human exposures routes. The presence of ptaquiloside and related terpene glycosides in milk, meat and water are of particular concern from the viewpoints of both human and animal health. PMID- 22226719 TI - Retention of heavy metals and poly-aromatic hydrocarbons from road water in a constructed wetland and the effect of de-icing. AB - A full-scale remediation facility including a detention basin and a wetland was tested for retention of heavy metals and Poly-Aromatic Hydrocarbons (PAHs) from water drained from a motorway in The Netherlands. The facility consisted of a detention basin, a vertical-flow reed bed and a final groundwater infiltration bed. Water samples were taken of road water, detention basin influent and wetland effluent. By using automated sampling, we were able to obtain reliable concentration averages per 4-week period during 18 months. The system retained the PAHs very well, with retention efficiencies of 90-95%. While environmental standards for these substances were surpassed in the road water, this was never the case after passage through the system. For the metals the situation was more complicated. All metals studied (Cu, Zn, Pb, Cd and Ni) had concentrations frequently surpassing environmental standards in the road water. After passage through the system, most metal concentrations were lower than the standards, except for Cu and Zn. There was a dramatic effect of de-icing salts on the concentrations of Cu, Zn, Cd and Ni, in the effluent leaving the system. For Cu, the concentrations even became higher than they had ever been in the road water. It is advised to let the road water bypass the facility during de-icing periods. PMID- 22226720 TI - Role of uniform pore structure and high positive charges in the arsenate adsorption performance of Al13-modified montmorillonite. AB - Four modified montmorillonite adsorbents with varied Al(13) contents (i.e., Na Mont, AC-Mont, PAC(20)-Mont, and Al(13)-Mont) were synthesized and characterized by N(2) adsorption/desorption, X-ray diffraction, and Fourier-transform infrared analyses. The arsenate adsorption performance of the four adsorbents were also investigated to determine the role of intercalated Al(13), especially its high purity, high positive charge (+7), and special Keggin structure. With increased Al(13) content, the physicochemical properties (e.g., surface area, structural uniformity, basal spacing, and pore volume) and adsorption performance of the modified montmorillonites were significantly but disproportionately improved. The adsorption data well fitted the Freundlich and Redlich-Peterson isotherm model, whereas the kinetic data better correlated with the pseudo-second-order kinetic model. The arsenate sorption mechanism of the montmorillonites changed from physical to chemisorption after intercalation with Al(13). Increasing charges of the intercalated ions enhanced the arsenate adsorption kinetics, but had minimal effect on the structural changes of the montmorillonites. The uniform pore structure formed by intercalation with high-purity Al(13) greatly enhanced the pore diffusion and adsorption rate of arsenate, resulting in the high adsorption performance of Al(13)-Mont. PMID- 22226721 TI - Efficient MgO-based mesoporous CO2 trapper and its performance at high temperature. AB - A novel MgO-based porous adsorbent has been synthesized in a facile co precipitation method for the first time, in order to provide a candidate for trapping CO(2) in flue gas at high temperature. The resulting composite exhibits a mesoporous structure with a wide pore size distribution, due to the even dispersion and distribution of microcrystalline MgO in the framework of alumina to form a concrete-like structure. These sorbents can capture CO(2) at high temperature (150-400 degrees C), possessing high reactivity and stability in cyclic adsorption-desorption processes, providing competitive candidates to control CO(2) emission. PMID- 22226722 TI - Investigation on the conditions mitigating membrane fouling caused by TiO2 deposition in a membrane photocatalytic reactor (MPR) used for dye wastewater treatment. AB - In this study, the effects of MPR's operating conditions such as permeate flux, solution pH, and membrane hydrophobicity on separation characteristics and membrane fouling caused by TiO(2) deposition were investigated. The extent of fouling was measured in terms of TMP and tank turbidity variation. The results showed that, at mildly acidic conditions (pH ~ 5), the turbidity within the tank decreased and the extent of turbidity drop increased with increasing flux for all the membranes. On the other hand, at pH >= 7, the turbidity remained constant at all flux and for all membranes tested. The fouling variation at different pH was closely linked with the surface charge (zeta potential) and hydrophilicity of both membrane and particles. It was observed that the charge differences between the particles and membranes accelerate the intensity of fouling and binding of TiO(2) particles on the membrane surface under different pH conditions. The presence of a very thin layer of TiO(2) can alter the hydrophilicity of the membranes and can slightly decrease the TMP (filtration resistance) of the fouled membranes. Besides, the resistance offered by the dense TiO(2) cake layer would dominate this hydrophilic effect of TiO(2) particles, and it may not alter the filtration resistance of the fouled membranes. PMID- 22226723 TI - Identification and chemical characterization of particulate matter from wave soldering processes at a printed circuit board manufacturing company. AB - In this case study, the elemental composition and mass size distribution of indoor aerosol particles were determined in a working environment where soldering of printed circuit boards (PCB) took place. Single particle analysis using ion and electron microscopy was carried out to obtain more detailed and reliable data about the origin of these particles. As a result, outdoor and indoor aerosol sources such as wave soldering, fluxing processes, workers' activity, mineral dust, biomass burning, fertilizing and other anthropogenic sources could be separated. With the help of scanning electron microscopy, characteristic particle types were identified. On the basis of the mass size distribution data, a stochastic lung deposition model was used to calculate the total and regional deposition efficiencies of the different types of particles within the human respiratory system. The information presented in this study aims to give insights into the detailed characteristics and the health impact of aerosol particles in a working environment where different kinds of soldering activity take place. PMID- 22226724 TI - Compartmentation of GABA metabolism raises intriguing questions. AB - This synopsis covers the compartmentation of gamma-aminobutyrate (GABA) metabolism, highlighting recent progress with Arabidopsis (Arabidopsis thaliana) and raising questions about mitochondrial GABA and succinic semialdehyde (SSA) transport, the fate of succinic semialdehyde once it exits mitochondria, and biochemical interactions between GABA metabolism and related processes such as photorespiration. PMID- 22226725 TI - Production and NMR analysis of the human ibuprofen metabolite 3-hydroxyibuprofen. AB - The anti-inflammatory drug ibuprofen (Ibu) is metabolized in the human liver to a number of metabolites including 1-hydroxyibuprofen (1-OH-Ibu), 2-OH-Ibu, and 3-OH Ibu, respectively. The only human CYP known to produce relevant amounts of 3-OH Ibu is CYP2C9 and as genetic polymorphisms of CYP2C9 influence the metabolization of numerous drugs, the availability of reference standards for CYP2C9-specific metabolites is of considerable interest. The aim of this study was to develop a biological production process for 3-OH-Ibu and to affirm its NMR characteristics. The recombinant fission yeast strain CAD68 coexpressing human CYP2C9 and CPR was used for the whole-cell biotransformation of Ibu to 3-OH-Ibu in 1L batch-scale for 75h. The average space-time yield for the bioproduction of 3-OH-Ibu (125+/ 34MUmol/Ld) considerably exceeded that of 2-OH-Ibu (44+/-10MUmol/Ld). Accordingly, average biotransformation activities normalized to dry biomass weight were 5.0+/-0.8MUmol/gd (3-OH-Ibu) and 1.9+/-0.7MUmol/gd (2-OH-Ibu). The metabolite was prepurified on preparative TLC-plates, isolated by HPLC fractionation, and characterized by LC-MS and NMR. As expected, differential fragmentation patterns of 2-OH-Ibu and 3-OH-Ibu were detected in ESI-LC-MS analysis. 44mg of 3-OH-Ibu was efficiently purified from four 1L batch cultures and its structure was clearly confirmed by one- and two-dimensional NMR. PMID- 22226726 TI - 'Life-style' control networks in Escherichia coli: signaling by the second messenger c-di-GMP. AB - Most bacteria can exist in either a planktonic-motile single-cell state or an adhesive multicellular state known as a biofilm. Biofilms cause medical problems and technical damage since they are resistant against antibiotics, disinfectants or the attacks of the immune system. In recent years it has become clear that most bacteria use cyclic diguanylate (c-di-GMP) as a biofilm-promoting second messenger molecule. C-di-GMP is produced by GGDEF-domain-containing diguanylate cyclases and is degraded by phosphodiesterases featuring EAL or HD-GYP domains. Many bacterial species possess multiple proteins with GGDEF and EAL domains, which actually belong to the most abundant protein families in genomic data bases. Via an unprecedented variety of effector components, which include c-di GMP-binding proteins as well as RNAs, c-di-GMP controls a wide range of targets that down-regulate motility, stimulate adhesin and biofilm matrix formation or even control virulence gene expression. Moreover, local c-di-GMP signaling in macromolecular complexes seems to allow the independent and parallel control of different output reactions. In this review, we use Escherichia coli as a paradigm for c-di-GMP signaling. Despite the huge diversity of components and molecular processes involved in biofilm formation throughout the bacterial kingdom, c-di GMP signaling represents a unifying principle, which suggests that the enzymes that make and break c-di-GMP may be promising targets for anti-biofilm drugs. PMID- 22226727 TI - Dual-source computed tomography angiography for diagnosis and assessment of coronary artery disease: systematic review and meta-analysis. AB - BACKGROUND: Development of an accurate test for noninvasive assessment of coronary arteries has been highly desirable. OBJECTIVES: We performed a systematic review of diagnostic accuracy of the dual-source computed tomography (DSCT) in the diagnosis of coronary artery disease (CAD). METHODS: Eight medical databases were searched for articles published from January 2005 through March 2011. Studies compared DSCT coronary angiography (DSCT-CA) and invasive coronary angiography, as the reference standard, in consecutive patients with suspected or known CAD, and relevant data were extracted by 2 independent reviewers. Summary diagnostic accuracies were calculated, and the effect of covariates on the diagnostic performance was evaluated by meta-regression. RESULTS: Twenty-five studies were included. In per-patient analysis (n = 2303), pooled sensitivity was 99% [95% confidence interval (CI), 97%-99%] with specificity of 89% (95% CI, 84% 92%). The summary positive (+LR) and negative (-LR) likelihood ratios were 8.6 (95% CI, 6.4-11.6) and 0.02 (95% CI, 0.01-0.03), respectively. In per-segment analysis (n = 32,615), pooled sensitivity was 94% (95% CI, 92%-96%) with specificity of 97% (95% CI, 96%--98%). Summary +LR and -LR were 30.2 (95% CI, 22.1-43.5) and 0.06 (95% CI, 0.04-0.08), respectively. CONCLUSIONS: DSCT-CA seems to be robust to elevate heart rates while maintaining a high level of diagnostic performance. PMID- 22226728 TI - Implementation of computerized provider order entry in a neonatal intensive care unit: Impact on admission workflow. AB - OBJECTIVE: The study objective was to determine if computerized provider order entry (CPOE) systems impaired or enhanced workflow in the neonatal intensive care unit (NICU) by comparing the timing of administration of the first dose of antibiotics before and after CPOE system implementation. METHODS: We conducted a pre-post intervention comparative study of the length of time between admission and administration of initial antibiotics in neonates before and after a CPOE system was implemented. Clinical information and timing of antibiotic administration were collected on all inborn infants, who were admitted to the NICU in the first 4h of life and treated with antibiotics, for one year prior to the implementation of computerized order entry and for one year after the implementation. RESULTS: Infants admitted to the NICU were similar in both periods (mean birth weight 2183 g vs. 2091 g, gestational age 33.3 weeks vs. 33.0 weeks). There was no significant difference in mean length of time from admission to antibiotic administration in the pre-CPOE group (131 min [CI 124-139]) compared to the post-CPOE group (125 min [CI 116-133]) (p=0.07). The mean time to pharmacy verification for a subset of patients was significantly shorter for patients in the post-CPOE group (61 +/- 58 min) compared to the pre-CPOE group (88 +/- 76 min) (p=<0.001). CONCLUSIONS: While the introduction of a CPOE system in the NICU did not significantly improve antibiotic administration times, the timeliness of an important aspect of the medication process, time to pharmacy verification, was improved. These findings imply other factors are impeding workflow. Further studies are needed to evaluate how CPOE systems combined with patient care activities affect workflow and overall patient care. PMID- 22226729 TI - Group cognitive behavioural interventions for low back pain in primary care: extended follow-up of the Back Skills Training Trial (ISRCTN54717854). AB - Group cognitive behavioural intervention (CBI) is effective in reducing low back pain and disability over a 12-month period, in comparison to best practice advice in primary care. The aim was to study the effects of this CBI beyond 12 months. We undertook an extended follow-up of our original randomised, controlled trial of a group CBI and best practice advice in primary care, in comparison to best practice advice alone. Participants were mailed a questionnaire including measures of disability, pain, health services resource use, and health-related quality of life. The time of extended follow-up ranged between 20 and 50 months (mean 34 months). Fifty-six percent (395 of 701) of the original cohort provided extended follow-up. Those who responded were older and had less disability and pain at baseline than did the original trial cohort. After 12 months, the improvements in pain and disability observed with CBI were sustained. For disability measures, the treatment difference in favour of CBI persisted (mean difference 1.3 Roland and Morris Disability Questionnaire points, 95% confidence interval 0.27 to 2.26; 5.5 Modified von Korff Scale disability points, 95% confidence interval 0.27 to 10.64). There was no between-group difference in Modified von Korff Scale pain outcomes. The results suggest that the effects of a group CBI are maintained up to an average of 34 months. Although pain improves in response to best practice advice, longer-term recovery of disability remains substantially less. PMID- 22226730 TI - Cloning, phylogenetic analysis and expression of somatolactin and its receptor in Cichlasoma dimerus: their role in long-term background color acclimation. AB - Somatolactin (SL) and SL receptor (SLR) belong to the growth hormone and cytokine type I receptor superfamilies, respectively. However, further research is required to define the duplications and functions of SL and its receptors in basal vertebrates including environmental background color adaptation in fish. In the present study, we cloned and sequenced SL and its putative receptor (SLR), classified and compared the sequences phylogenetically, and determined SL and SLR mRNA expression levels during long-term background color exposure in Cichlasoma dimerus, a freshwater South American cichlid. Our results show that C. dimerus SL and SLR share high sequence similarity with homologous from other perciform fish. Phylogenetic analysis indicates that C. dimerus SL belongs to the SLalpha clade sub-group. C. dimerus SLR is clearly a member of the GHR1 receptor subgroup, which includes the experimentally validated SLR from salmonids. Higher transcript levels of SLalpha in the pituitary and SLR in the epidermis and dermis cells of fish scales were observed in fish following long-term black background color exposure compared to those exposed to a white background. A higher number of melanophores was also observed in fish exposed for 10days to a black background compared to those exposed to a white background. These changes were concomitant to differences in SL or SLR transcript levels found in fish exposed to these two different background colors. Our results suggest, for the first time, that SLR is expressed in fish scales, and that there is an increase in SL in the pituitary and the putative SLR in likely target cells, i.e., melanophores, in long-term black background exposure in C. dimerus. PMID- 22226731 TI - Developmental expression, differential hormonal regulation and evolution of thyroid and glucocorticoid receptor variants in a marine acanthomorph teleost (Sciaenops ocellatus). AB - Interactions between the thyroid hormone (TH) and corticosteroid (CS) hormone axes are suggested to regulate developmental processes in vertebrates with a larval phase. To investigate this hypothesis, we isolated three nuclear receptors from a larval acanthomorph teleost, the red drum (Sciaenops ocellatus), and established their orthologies as thraa, thrb-L and gra-L using phylogenomic and functional analyses. Functional characterization of the TH receptors in COS-1 cells revealed that Thraa and Thrb-L exhibit dose-dependent transactivation of a luciferase reporter in response to T3, while SoThraa is constitutively active at a low level in the absence of ligand. To test whether interactions between the TH and CS systems occur during development, we initially quantified the in vivo receptor transcript expression levels, and then examined their response to treatment with triiodothyronine (T3) or cortisol. We find that sothraa and sothrb L are autoregulated in response to exogenous T3 only during early larval development. T3 did not affect sogra-L expression levels, nor did cortisol alter levels of sothraa or sothrb-L at any stage. While differential expression of the receptors in response to non-canonical ligand hormone was not observed under the conditions in this study, the correlation between sothraa and sogra-L transcript abundance during development suggests a coordinated function of the TH and CS systems. By comparing the findings in the present study to earlier investigations, we suggest that the up-regulation of thraa may be a specific feature of metamorphosis in acanthomorph teleosts. PMID- 22226732 TI - Expression of collagen VI alpha5 and alpha6 chains in human muscle and in Duchenne muscular dystrophy-related muscle fibrosis. AB - Collagen VI is a major extracellular matrix (ECM) protein with a critical role in maintaining skeletal muscle functional integrity. Mutations in COL6A1, COL6A2 and COL6A3 genes cause Ullrich Congenital Muscular Dystrophy (UCMD), Bethlem Myopathy, and Myosclerosis. Moreover, Col6a1(-/-) mice and collagen VI deficient zebrafish display a myopathic phenotype. Recently, two additional collagen VI chains were identified in humans, the alpha5 and alpha6 chains, however their distribution patterns and functions in human skeletal muscle have not been thoroughly investigated yet. By means of immunofluorescence analysis, the alpha6 chain was detected in the endomysium and perimysium, while the alpha5 chain labeling was restricted to the myotendinous junctions. In normal muscle cultures, the alpha6 chain was present in traces in the ECM, while the alpha5 chain was not detected. In the absence of ascorbic acid, the alpha6 chain was mainly accumulated into the cytoplasm of a sub-set of desmin negative cells, likely of interstitial origin, which can be considered myofibroblasts as they expressed alpha-smooth muscle actin. TGF-beta1 treatment, a pro-fibrotic factor which induces trans-differentiation of fibroblasts into myofibroblasts, increased the alpha6 chain deposition in the extracellular matrix after addition of ascorbic acid. In order to define the involvement of the alpha6 chain in muscle fibrosis we studied biopsies of patients affected by Duchenne Muscular Dystrophy (DMD). We found that the alpha6 chain was dramatically up-regulated in fibrotic areas where, in contrast, the alpha5 chain was undetectable. Our results show a restricted and differential distribution of the novel alpha6 and alpha5 chains in skeletal muscle when compared to the widely distributed, homologous alpha3 chain, suggesting that these new chains may play specific roles in specialized ECM structures. While the alpha5 chain may have a specialized function in tissue areas subjected to tensile stress, the alpha6 chain appears implicated in ECM remodeling during muscle fibrosis. PMID- 22226734 TI - The effect of hyperoxia following cardiac arrest - A systematic review and meta analysis of animal trials. AB - AIM: There are conflicting findings from observational studies regarding the nature of the association between hyperoxia and risk of mortality in patients admitted to intensive care following cardiac arrest. This systematic review and meta-analysis evaluates animal data investigating the effect of administration of high concentrations of oxygen following cardiac arrest on neurological outcome and the clinical applicability of this data. METHODS: A systematic search of Medline and Embase identified controlled animal studies modelling cardiac arrest with subsequent cardiopulmonary resuscitation that compared ventilation with 100% oxygen to lower concentrations following return of spontaneous circulation. Eligible studies were included in a meta-analysis in which the inverse variance weighted differences were calculated for the standardised mean difference of the primary outcome measure, the neurological deficit score. RESULTS: Ten studies met the criteria for inclusion in the systematic review. In a meta-analysis of six studies, with 95 animals, treatment with 100% oxygen resulted in a significantly worse neurological deficit score than oxygen administered at lower concentrations, with a standardised mean difference of -0.64 (95% CI -1.06 to 0.22). In four of five studies, histological evidence of increased neuronal damage was present in animals that received 100% oxygen therapy. CONCLUSIONS: The administration of 100% oxygen therapy is associated with worse neurological outcome than lower oxygen concentrations in animal models of cardiac arrest. However, due to limitations in study design and poor generalisability of the animal models to the situation of post cardiac arrest resuscitation in humans, the clinical applicability of this data is uncertain. PMID- 22226735 TI - Altitudinal variation of demographic life-history traits does not mimic latitudinal variation in natterjack toads (Bufo calamita). AB - In anuran amphibians, age- and size-related life-history traits vary along latitudinal and altiudinal gradients. In the present study, we tested the hypothesis that altitudinal and latitudinal effects cause similar responses by assessing demographic life-history traits in nine Bufo calamita populations inhabiting elevations from sea level to 2270 m. Skeletochronologically determined age at maturity and longevity increased at elevations exceeding 2000 m, but female potential reproductive lifespan (PRLS) did not increase with altitude, as it did with latitude. Integrating the available evidence, it was found that lifetime fecundity of natterjacks decreased at the upper altitudinal range because PRLS was about the same as in lowland populations but females were smaller. In contrast, small size of northern females was compensated for by increased PRLS which minimised latitudinal variation of lifetime fecundity. Thus, this study provides evidence that altitudinal effects on life-history traits do not mimic latitudinal effects. Life-history trait variation along the altitudinal gradient seems to respond directly to the shortening of the annual activity period. As there is no evidence for increasing mortality in highland populations, reduced lifetime fecundity may be the ultimate reason for the natterjacks' inability to colonise elevations exceeding 2500 m. PMID- 22226733 TI - Seasonal, locational and size variations in mercury and selenium levels in striped bass (Morone saxatilis) from New Jersey. AB - We examined total mercury and selenium levels in muscle of striped bass (Morone saxatilis) collected from 2005 to 2008 from coastal New Jersey. Of primary interest was whether there were differences in mercury and selenium levels as a function of size and location, and whether the legal size limits increased the exposure of bass consumers to mercury. We obtained samples mainly from recreational anglers, but also by seine and trawl. For the entire sample (n=178 individual fish), the mean (+/-standard error) for total mercury was 0.39+/-0.02 MUg/g (=0.39 ppm, wet weight basis) with a maximum of 1.3 MUg/g (=1.3 ppm wet weight). Mean selenium level was 0.30+/-0.01 MUg/g (w/w) with a maximum of 0.9 MUg/g). Angler-caught fish (n=122) were constrained by legal size limits to exceed 61 cm (24 in.) and averaged 72.6+/-1.3 cm long; total mercury averaged 0.48+/-0.021 MUg/g and selenium averaged 0.29+/-0.01 MUg/g. For comparable sizes, angler-caught fish had significantly higher mercury levels (0.3 vs 0.21 MUg/g) than trawled fish. In both the total and angler-only samples, mercury was strongly correlated with length (Kendall tau=0.37; p<0.0001) and weight (0.38; p<0.0001), but was not correlated with condition or with selenium. In the whole sample and all subsamples, total length yielded the highest r(2) (up to 0.42) of any variable for both mercury and selenium concentrations. Trawled fish from Long Branch in August and Sandy Hook in October were the same size (68.9 vs 70.1cm) and had the same mercury concentrations (0.22 vs 0.21 ppm), but different selenium levels (0.11 vs 0.28 ppm). The seined fish (all from Delaware Bay) had the same mercury concentration as the trawled fish from the Atlantic coast despite being smaller. Angler-caught fish from the North (Sandy Hook) were larger but had significantly lower mercury than fish from the South (mainly Cape May). Selenium levels were high in small fish, low in medium-sized fish, and increased again in larger fish, but overall selenium was correlated with length (tau=0.14; p=0.006) and weight (tau=0.27; p<0.0001). Length-squared contributed significantly to selenium models, reflecting the non-linear relationship. Inter year differences were explained partly by differences in sizes. The selenium:mercury molar ratio was below 1:1 in 20% of the fish and 25% of the angler-caught fish. Frequent consumption of large striped bass can result in exposure above the EPA's reference dose, a problem particularly for fetal development. PMID- 22226736 TI - Modifiable family factors among treatment-seeking families of children with high body mass index: report of a pilot study. AB - PURPOSE: The purpose of this pilot study was to explore parenting style and other potential family and social indicators of an obesogenic or weight-promoting family environment. Modifiable factors were sought on which to base a nursing behavioral intervention that could be combined with diet and exercise to reduce youth weight. METHODS: Twenty-eight parents and their 9- to 18-year-old children who were seeking care for overweight responded to in-home surveys to characterize parenting style (warmth/responsiveness and control). We also examined the extent to which parent modeling of health behavior, child feeding practices, parent knowledge of nutrition, and family social characteristics differed by the control aspect of parenting style. RESULTS: Nearly all youth and parents reported substantial parental love (responsiveness), suggesting little variability in the warmth aspect of parenting style. In contrast, considerable variability was found in the control (moderate versus high) aspect of parenting style. Large effect sizes indicated that mothers with moderate control perceived their lifetime weight to be higher, had more concern about their youth's weight (p = .03), had better knowledge of nutrition, and had a lower body mass index (p = .02) than did mothers with high (firm or restrictive) control. Moderate effect sizes indicated that mothers with moderate control demonstrated better modeling behavior, higher perception of youth weight, practiced less pressure to eat, and had youth with lower body mass index and percent body fat than did mothers with high (firm or restrictive) control. Families who volunteered for the study kept their data gathering appointments, but we recommend a recruitment period of more than 4 months and the inclusion of several referral sites. DISCUSSION: Further study of how parent control is related to youth overweight and how appropriate control can be achieved among families with teens who are overweight is recommended. PMID- 22226737 TI - Novice to expert: the evolution of an advanced practice evaluation tool. AB - Professional performance evaluation provides an opportunity to measure the practice of health providers within healthcare settings. Standardized evaluation can be challenging as a result of diverse practice arenas, multiple evaluators and standards of care. Using Benner's novice to expert model, a Performance Excellence and Accountability tool (PEAC Tool((c))) has been designed to measure advanced practice providers performance based upon facets of professional practice. This article discusses development, practical implementation and evaluation of a PEAC Tool((c)). PMID- 22226738 TI - Regulation of monocyte chemoattractant protein-1 through angiotensin II type 1 receptor in prostate cancer. AB - Monocyte chemoattractant protein-1 (MCP-1/CCL2) is reported to contribute to tumor progression and is regulated by the renin-angiotensin system in hypertensive disease. In this study, we investigated the clinical outcome of MCP 1 expression in patients with prostate cancer (CaP) and the regulation of MCP-1 through angiotensin II (AngII) type 1 receptor (AT1R) in CaP. Specimens were obtained from 138 CaP patients and analyzed by immunostaining for both MCP-1 and macrophages. We investigated the regulation of MCP-1 expression through AT1R both in vivo and in vitro using three human prostate cancer cell lines: LNCaP, C4-2, and C4-2AT6. Specimens with a high Gleason score (>=7) and a high pathological classification (<=pT3), and those with castration-resistant prostate cancer showed significantly higher MCP-1 expression and higher macrophage infiltration than low malignant potential CaP. High MCP-1 expression in CaP correlated significantly with high prostate-specific antigen (PSA) recurrence rates. AngII induced significantly higher MCP-1 levels in C4-2AT6 than in LNCaP, whereas AT1R blockade (ARB) inhibited MCP-1 production via the inhibition of the PI3K/Akt pathway in C4-2AT6. ARB also significantly suppressed MCP-1 expression in C4-2AT6 tumors. Our study is the first to demonstrate that both high MCP-1 expression and high macrophage infiltration in CaP specimens correlate with a high PSA recurrence rate and that ARB inhibits MCP-1 expression through the PI3K/Akt pathway and blocks macrophage infiltration in castration-resistant prostate cancer. PMID- 22226739 TI - CXCR6 and CCR5 localize T lymphocyte subsets in nasopharyngeal carcinoma. AB - The substantial T lymphocyte infiltrate found in cases of nasopharyngeal carcinoma (NPC) has been implicated in the promotion of both tumor growth and immune escape. Conversely, because malignant NPC cells harbor the Epstein-Barr virus, this tumor is a candidate for virus-specific T cell-based therapies. Preventing the accumulation of tumor-promoting T cells or enhancing the recruitment of tumor-specific cytotoxic T cells offers therapeutic potential. However, the mechanisms involved in T cell recruitment to this tumor are poorly understood. Comparing memory T cell subsets that have naturally infiltrated NPC tissue with their counterparts from matched blood revealed enrichment of CD8(+), CD4(+), and regulatory T cells expressing the chemokine receptor CXCR6 in tumor tissue. CD8(+) and (nonregulatory) CD4(+) T cells also were more frequently CCR5(+) in tumor than in blood. Ex vivo studies demonstrated that both receptors were functional. CXCL16 and CCL4, unique chemokine ligands for CXCR6 and CCR5, respectively, were expressed by the malignant cells in tumor tissue from the majority of NPC cases, as was another CCR5 ligand, CCL5. The strongest expression of CXCL16 was found on tumor-infiltrating cells. CCL4 was detected on the tumor vasculature in a majority of cases. These findings suggest that CXCR6 and CCR5 play important roles in T cell recruitment and/or retention in NPC and have implications for the pathogenesis and treatment of this tumor. PMID- 22226740 TI - Clinical and biological significance of KISS1 expression in prostate cancer. AB - For men in the United States, prostate cancer (PCa) is the most frequent malignancy and the second leading cause of cancer mortality. The metastatic spread of PCa is responsible for most deaths related to PCa. Although KISS1 functions as a metastasis suppressor in various cancers, its expression levels and functions in PCa development and progression remain undetermined. The goals of this study were to correlate the expression levels of KISS1 in PCas with clinicopathologic characteristics and to assess the biological relevance of KISS1 to the viability and motility of PCa cells. Strong KISS1 staining was detected in benign prostate tissues, but the staining was weaker in primary and metastatic PCas (both P < 0.001, t-test). Furthermore, the low expression levels of KISS1 in PCas correlated with clinical stage (P < 0.01) and with KISS1R expression (P < 0.001). Overexpression of full-length KISS1 in low KISS1-expressing PC-3M cells, but not KFMDeltaSS, which lacks the secretion signal sequence, induced re sensitization of cells to anoikis, although it had no effect on either cell proliferation or apoptosis. Overexpression of KISS1 also suppressed steps in the metastatic cascade, including motility and invasiveness. Moreover, cells overexpressing KISS1 were found to enhance chemosensitivity to paclitaxel. Collectively, our data suggest that KISS1 functions as a metastasis suppressor in PCas and may serve as a useful biomarker as well as a therapeutic target for aggressive PCas. PMID- 22226742 TI - Cortical surface mapping using topology correction, partial flattening and 3D shape context-based non-rigid registration for use in quantifying atrophy in Alzheimer's disease. AB - Magnetic resonance (MR) provides a non-invasive way to investigate changes in the brain resulting from aging or neurodegenerative disorders such as Alzheimer's disease (AD). Performing accurate analysis for population studies is challenging because of the interindividual anatomical variability. A large set of tools is found to perform studies of brain anatomy and population analysis (FreeSurfer, SPM, FSL). In this paper we present a newly developed surface-based processing pipeline (MILXCTE) that allows accurate vertex-wise statistical comparisons of brain modifications, such as cortical thickness (CTE). The brain is first segmented into the three main tissues: white matter, gray matter and cerebrospinal fluid, after CTE is computed, a topology corrected mesh is generated. Partial inflation and non-rigid registration of cortical surfaces to a common space using shape context are then performed. Each of the steps was firstly validated using MR images from the OASIS database. We then applied the pipeline to a sample of individuals randomly selected from the AIBL study on AD and compared with FreeSurfer. For a population of 50 individuals we found correlation of cortical thickness in all the regions of the brain (average r=0.62 left and r=0.64 right hemispheres). We finally computed changes in atrophy in 32 AD patients and 81 healthy elderly individuals. Significant differences were found in regions known to be affected in AD. We demonstrated the validity of the method for use in clinical studies which provides an alternative to well established techniques to compare different imaging biomarkers for the study of neurodegenerative diseases. PMID- 22226741 TI - Estimation of the time course of neurotransmitter release at central synapses from the first latency of postsynaptic currents. AB - Measurement of the release time course (RTC) and of the quantal content is important for quantifying synaptic precision and understanding the molecular basis of the release process at central synapses. In theory, the RTC can be determined directly from the histogram of first latencies of quantal events only if a maximum of one vesicle is released per trial, but at most synapses multiple vesicles are released. Traditionally, first latency histograms have been corrected for multiple releases using a simple correction, derived by Barrett and Stevens (BS; 1972b) for quantifying release at the neuromuscular junction. This correction has also been used to quantify release at central synapses. We show, by combining an analytical approach and numerical simulations of stochastic quantal release, that the BS correction gives a biased estimate for RTC and quantal content. The bias increases with release probability, and is therefore particularly problematic for central synapses. We show that this is due to assuming infinite availability of releasable vesicles and we derive a formula for estimating the RTC from first latencies without this assumption. The resulting 'binomial correction' requires knowledge of the maximum number of quanta that can be released following an action potential (N), which can be estimated with variance-mean analysis. We show with simulations that estimating RTC and quantal content from first latencies using the binomial correction is robust in the presence of noise and when release probability is non-uniform. We also provide an alternative method for estimating RTC from the first latencies when N cannot be determined. PMID- 22226743 TI - Cisterna magna cannulated repeated CSF sampling rat model--effects of a gamma secretase inhibitor on Abeta levels. AB - Cerebrospinal fluid (CSF) provides a window into central nervous system (CNS) physiology and pathophysiology in human neurodegenerative conditions such as Alzheimer's disease. Changes in CSF bioanalytes also provide a direct readout of target engagement in the CNS following pharmacological interventions in clinical trials. Given the importance of tracking CNS bioanalytes in drug discovery, we have developed a novel cisterna magna cannulated rat model for repeated CSF sampling and used it to assess an amyloid beta (Abeta) lowering agent. The surgically implanted cisterna magna cannula was patent over a period of 1-2 weeks and enabled repeated sampling of CSF (volume of ~30-50MUL/sample) from each rat. CSF Abeta40 levels showed good intra-animal variability across time points and inter-animal variability within a time point. Peripheral treatment with a gamma secretase inhibitor (GSI) led to a rapid and robust decline in CSF Abeta40 levels that returned to baseline over 24-96h after dosing. Terminal brain, CSF and plasma Abeta levels measured at 24h after dosing demonstrated robust Abeta lowering and showed excellent correlation across these compartments. These results are the first pharmacological validation of the repeated CSF sampling rat model for Abeta lowering agents. This model can have broad applicability in pharmacological evaluation for diverse CNS targets. PMID- 22226744 TI - Dogs' gaze following is tuned to human communicative signals. AB - Recent evidence suggests that preverbal infants' gaze following can be triggered only if an actor's head turn is preceded by the expression of communicative intent [1]. Such connectedness between ostensive and referential signals may be uniquely human, enabling infants to effectively respond to referential communication directed to them. In the light of increasing evidence of dogs' social communicative skills [2], an intriguing question is whether dogs' responsiveness to human directional gestures [3] is associated with the situational context in an infant-like manner. Borrowing a method used in infant studies [1], dogs watched video presentations of a human actor turning toward one of two objects, and their eye-gaze patterns were recorded with an eye tracker. Results show a higher tendency of gaze following in dogs when the human's head turning was preceded by the expression of communicative intent (direct gaze, addressing). This is the first evidence to show that (1) eye-tracking techniques can be used for studying dogs' social skills and (2) the exploitation of human gaze cues depends on the communicatively relevant pattern of ostensive and referential signals in dogs. Our findings give further support to the existence of a functionally infant-analog social competence in this species. PMID- 22226745 TI - A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. AB - Mitochondrial respiration relies on electron transport, an essential yet dangerous process in that it leads to the generation of reactive oxygen species (ROS). ROS can be neutralized within the mitochondria through enzymatic activity, yet the mechanism for steady-state removal of oxidized mitochondrial protein complexes and lipids is not well understood. We have previously characterized vesicular profiles budding from the mitochondria that carry selected cargo. At least one population of these mitochondria-derived vesicles (MDVs) targets the peroxisomes; however, the fate of the majority of MDVs was unclear. Here, we demonstrate that MDVs carry selected cargo to the lysosomes. Using a combination of confocal and electron microscopy, we observe MDVs in steady state and demonstrate that they are stimulated as an early response to oxidative stress, the extent of which is determined by the respiratory status of the mitochondria. Delivery to the lysosomes does not require mitochondrial depolarization and is independent of ATG5 and LC3, suggesting that vesicle delivery complements mitophagy. Consistent with this, ultrastructural analysis of MDV formation revealed Tom20-positive structures within the vesicles of multivesicular bodies. These data characterize a novel vesicle transport route between the mitochondria and lysosomes, providing insights into the basic mechanisms of mitochondrial quality control. PMID- 22226746 TI - An ARF6/Rab35 GTPase cascade for endocytic recycling and successful cytokinesis. AB - Cytokinesis bridge instability leads to binucleated cells that can promote tumorigenesis in vivo. Membrane trafficking is crucial for animal cell cytokinesis, and several endocytic pathways regulated by distinct GTPases (Rab11, Rab21, Rab35, ARF6, RalA/B) contribute to the postfurrowing steps of cytokinesis. However, little is known about how these pathways are coordinated for successful cytokinesis. The Rab35 GTPase controls a fast endocytic recycling pathway and must be activated for SEPTIN cytoskeleton localization at the intercellular bridge, and thus for completion of cytokinesis. Here, we report that the ARF6 GTPase negatively regulates Rab35 activation and hence the Rab35 pathway. Human cells expressing a constitutively activated, GTP-bound ARF6 mutant display identical endocytic recycling and cytokinesis defects as those observed upon overexpression of the inactivated, GDP-bound Rab35 mutant. As a molecular mechanism, we identified the Rab35 GAP EPI64B as an effector of ARF6 in negatively regulating Rab35 activation. Unexpectedly, this regulation takes place at clathrin-coated pits, and activated ARF6 reduces Rab35 loading into the endocytic pathway. Thus, an effector of an ARF protein is a GAP for a downstream Rab protein, and we propose that this hierarchical ARF/Rab GTPase cascade controls the proper activation of a common endocytic pathway essential for cytokinesis. PMID- 22226747 TI - The effect of sexual selection on offspring fitness depends on the nature of genetic variation. AB - Whether the changes brought about by sexual selection are, on the whole, congruent or incongruent with the changes favored by natural selection is a fundamentally important question in evolutionary biology. Although a number of theoretical models have assumed that sexual selection reinforces natural selection [1, 2], others assume these forces are in opposition [3-5]. Empirical results have been mixed (see reviews in [1, 6-8]) and the reasons for the differences among studies are unclear. Variable outcomes are expected if populations differ in their evolutionary histories and therefore harbor different amounts and types of segregating genetic variation. Here, we constructed populations of Drosophila melanogaster that differed in this regard to directly test this hypothesis. In well-adapted populations, sexually successful males sired unfit daughters, indicating sexual and natural selection are in conflict. However, in populations containing an influx of maladaptive alleles, attractive males sired offspring of high fitness, suggesting that sexual selection reinforces natural selection. Taken together, these results emphasize the importance of evolutionary history on the outcome of sexual selection. Consequently, studies based on laboratory populations, cultured for prolonged periods under homogeneous conditions, may provide a skewed perspective on the relationship between sexual and natural selection. PMID- 22226748 TI - The RhoGAP domain of CYK-4 has an essential role in RhoA activation. AB - Cytokinesis in animal cells is mediated by a cortical actomyosin-based contractile ring. The GTPase RhoA is a critical regulator of this process as it activates both nonmuscle myosin and a nucleator of actin filaments [1]. The site at which active RhoA and its effectors accumulate is controlled by the microtubule-based spindle during anaphase [2]. ECT-2, the guanine nucleotide exchange factor (GEF) that activates RhoA during cytokinesis, is regulated by phosphorylation and subcellular localization [3-5]. ECT2 localization depends on interactions with CYK-4/MgcRacGAP, a Rho GTPase-activating protein (GAP) domain containing protein [5, 6]. Here we show that, contrary to expectations, the Rho GTPase-activating protein (GAP) domain of CYK-4 promotes activation of RhoA during cytokinesis. Furthermore, we show that the primary phenotype caused by mutations in the GAP domain of CYK-4 is not caused by ectopic activation of CED 10/Rac1 and ARX-2/Arp2. However, inhibition of CED-10/Rac1 and ARX-2/Arp2 facilitates ingression of weak cleavage furrows. These results demonstrate that a GAP domain can contribute to activation of a small GTPase. Furthermore, cleavage furrow ingression is sensitive to the balance of contractile forces and cortical tension. PMID- 22226749 TI - Anillin acts as a bifunctional linker coordinating midbody ring biogenesis during cytokinesis. AB - Animal cell cytokinesis proceeds via constriction of an actomyosin-based contractile ring (CR) [1, 2]. Upon reaching a diameter of ~1 MUm [3], a midbody ring (MR) forms to stabilize the intercellular bridge until abscission [4-6]. How MR formation is coupled to CR closure and how plasma membrane anchoring is maintained at this key transition is unknown. Time-lapse microscopy of Drosophila S2 cells depleted of the scaffold protein Anillin [7-9] revealed that Anillin is required for complete closure of the CR and formation of the MR. Truncation analysis revealed that Anillin N termini connected with the actomyosin CR and supported formation of stable MR-like structures, but these could not maintain anchoring of the plasma membrane. Conversely, Anillin C termini failed to connect with the CR or MR but recruited the septin Peanut to ectopic structures at the equatorial cortex. Peanut depletion mimicked truncation of the Anillin C terminus, resulting in MR-like structures that failed to anchor the membrane. These data demonstrate that Anillin coordinates the transition from CR to MR and that it does so by linking two distinct cortical cytoskeletal elements. One apparently acts as the core structural template for MR assembly, while the other ensures stable anchoring of the plasma membrane beyond the CR stage. PMID- 22226750 TI - IFN-gamma producing T cells contribute to the increase of myeloid derived suppressor cells in tumor-bearing mice after cyclophosphamide treatment. AB - It has been reported that treatment with cyclophosphamide (CTX) as a chemotherapeutic drug in cancer patients or tumor-bearing mice can result in an increase in the proportion of myeloid derived suppressor cells (MDSCs) in blood and lymphoid organs. Here we sought to clarify the possible mechanism of this unwanted increase in proportion of MDSCs in tumor-bearing mice after CTX treatment. We found that both CD4(+) T cells and CD8(+) T cells underwent an expansion and activation before the increase of MDSCs in the early period of CTX treatment in 4T1 breast tumor-bearing mice. The proportion of MDSCs in nude mice lacking T cells after CTX therapy was comparable to that in nude mice without CTX treatment. T cell transfer to 4T1-bearing nude mice enhanced the proportion of MDSCs in tumor-bearing mice after CTX therapy. The co-culture of MDSCs and T cells in vitro also showed that CD4(+) T cells and CD8(+) T cells could facilitate the expansion and survival of MDSCs, and this effect was mediated by IFN-gamma released by T cells. These results gave an explanation of the unwanted consequence resulted from CTX treatment in tumor-bearing mice. It also provided some insights into the strategies for eliminating the bad side of CTX treatment and to make it more effective in cancer therapy. PMID- 22226751 TI - Innate defense regulator peptide synergizes with CpG ODN for enhanced innate intestinal immune responses in neonate piglets. AB - The in vivo immunoadjuvant effects of the combination of CpG oligodeoxynucleotide (CpG ODN) and innate defense-regulator peptides (IDRs) have been studied in mice. However, little is known about the efficacy of these molecules in stimulating the innate intestinal immune system in neonatal piglets. In this study, we observed that intranasal (IN) administration of CpG-IDR (peptide HH2 (VQLRIRVAVIRA)) complex significantly increased intestinal mRNA expression of Th1 cytokines, CC chemokines and CXC chemokines when compared to HH2 and CpG ODN alone. Also an obvious cellular infiltration was observed in the intestine of CpG-HH2-treated neonatal piglets, which was associated with increased protection against Enterotoxigenic Escherichia coli (ETEC). Moreover, we showed that pro inflammatory cytokine TNF-alpha was inhibited when CpG ODN combined with HH2. This was the first report that deciphered the role played by CpG-HH2 complex in the intestine of neonatal piglets. This work clearly demonstrated that efficiency of the IN route inducing intestinal responses in neonatal piglets might be taken into consideration for further vaccine development against neonatal intestinal diseases. PMID- 22226752 TI - A molecular method to assess Phytophthora diversity in environmental samples. AB - Current molecular detection methods for the genus Phytophthora are specific to a few key species rather than the whole genus and this is a recognized weakness of protocols for ecological studies and international plant health legislation. In the present study a molecular approach was developed to detect Phytophthora species in soil and water samples using novel sets of genus-specific primers designed against the internal transcribed spacer (ITS) regions. Two different rDNA primer sets were tested: one assay amplified a long product including the ITS1, 5.8S and ITS2 regions (LP) and the other a shorter product including the ITS1 only (SP). Both assays specifically amplified products from Phytophthora species without cross-reaction with the related Pythium s. lato, however the SP assay proved the more sensitive and reliable. The method was validated using woodland soil and stream water from Invergowrie, Scotland. On-site use of a knapsack sprayer and in-line water filters proved more rapid and effective than centrifugation at sampling Phytophthora propagules. A total of 15 different Phytophthora phylotypes were identified which clustered within the reported ITS clades 1, 2, 3, 6, 7 and 8. The range and type of the sequences detected varied from sample to sample and up to three and five different Phytophthora phylotypes were detected within a single sample of soil or water, respectively. The most frequently detected sequences were related to members of ITS-clade 6 (i.e. P. gonapodyides-like). The new method proved very effective at discriminating multiple species in a given sample and can also detect as yet unknown species. The reported primers and methods will prove valuable for ecological studies, biosecurity and commercial plant, soil or water (e.g. irrigation water) testing as well as the wider metagenomic sampling of this fascinating component of microbial pathogen diversity. PMID- 22226753 TI - Evaluation of novel agars for the enumeration of Campylobacter spp. in poultry retail samples. AB - The purpose of this study was to examine the performance of novel agars for the identification and enumeration of Campylobacter species. The analytical sensitivity and specificity of Campylobacter Selective agar (CASA), Brilliance CampyCount agar (BCCA) and CampyFoodIDagar (CFA) for 84 Campylobacter spp. isolates and 50 non-Campylobacter spp. isolates from 37 distinct genera were of 100% sensitivity, with a 98% specificity for BCCA and CFA, and a 100% specificity for CASA. The application of these selective agars for Campylobacter spp. enumeration in comparison to the conventional agars, modified charcoal cefoperazonedeoxycholate agar (mCCDA) and Campy-Cefex (CCA) was examined using Campylobacter jejuni and Campylobacter coli inoculated samples. From C. jejuni inoculated samples, recovery on BCCA was significantly greater than other media (p<0.05). Recovery on CASA was not significantly different from mCCDA and CCA (p>0.05). With C. coli inoculated samples, recovery was significantly greater on BCCA and CASA than with other media (p<0.05). The recovery of both C. jejuni and C. coli from inoculated samples with CFA was significantly less than with other media (P<0.05). CASA was able to effectively inhibit and differentiate Campylobacter spp. from background microflora while false positive organisms occurred with BCCA and CFA. An examination of 483 randomly selected suspect Campylobacter colonies from naturally contaminated samples demonstrated a colony confirmation rate for CCA, CFA, BCCA, mCCDA, and CASA, of 84%, 87%, 88%, 90%, and 100%, respectively. The media evaluated present an alternative to conventional selective agars for the identification and enumeration of thermotolerant Campylobacter spp. from samples of poultry origin through the farm to fork continuum. PMID- 22226754 TI - Therapy of hyperhomocysteinemia in hemodialysis patients: effects of folates and N-acetylcysteine. AB - OBJECTIVE: Uremia represents a state where hyperhomocysteinemia is resistant to folate therapy, thus undermining intervention trials' efficacy. N-acetylcysteine (NAC), an antioxidant, in addition to folates (5-methyltetrahydrofolate, MTHF), was tested in a population of hemodialysis patients. DESIGN: The study is an open, parallel, intervention study. SETTING: Ambulatory chronic hemodialysis patients. SUBJECTS: Clinically stable chronic hemodialysis patients, on hemodialysis since more than 3 months, undergoing a folate washout. Control group on standard therapy (n = 50). INTERVENTION: One group was treated with intravenous MTHF (MTHF group, n = 48). A second group was represented by patients treated with MTHF, and, during the course of 10 hemodialysis sessions, NAC was administered intravenous (MTHF + NAC group, n = 47). MAIN OUTCOME MEASURE: Plasma homocysteine measured before and after dialysis at the first and the last treatment. RESULTS: At the end of the study, there was a significant decrease in predialysis plasma homocysteine levels in the MTHF group and MTHF + NAC group, compared with the control group, but no significant difference between the MTHF group and MTHF + NAC group. A significant decrease in postdialysis plasma homocysteine levels in MTHF + NAC group (10.27 +/- 0.94 MUmol/L, 95% confidence interval: 8.37-12.17) compared with the MTHF group (16.23 +/- 0.83, 95% confidence interval: 14.55-17.90) was present. In the MTHF + NAC group, 64% of patients reached a postdialysis homocysteine level <12 MUmol/L, compared with 19% in the MTHF group and 16% in the control group. CONCLUSIONS: NAC therapy induces a significant additional decrease in homocysteine removal during dialysis. The advantage is limited to the time of administration. PMID- 22226755 TI - Development and validation of an expedited 10 g protein counter (EP-10) for dietary protein intake quantification. AB - OBJECTIVE: Precise protein quantification is essential in clinical dietetics, particularly in the management of renal, burn, and malnourished patients. The expedited 10 g protein counter (EP-10) was developed to expedite the estimation of dietary protein for nutritional assessment and recommendation. The main objective of this study was to compare the validity and efficacy of the EP-10 with the American Dietetic Association's "Exchange List for Meal Planning" (ADA-7 g) in quantifying dietary protein intake, against computerized nutrient analysis (CNA). DESIGN: Protein intake of 197 food records kept by healthy adult subjects in Singapore was determined thrice using 3 different methods: (1) EP-10, (2) ADA 7 g, and (3) CNA using SERVE program (Version 4.0). Assessments using the EP-10 and ADA-7 g were performed by 2 assessors in a blind crossover manner while a third assessor performed the CNA. All assessors were blind to each other's results. Time taken to assess a subsample (n = 165) using the EP-10 and ADA-7 g was also recorded. RESULTS: Mean difference in protein intake quantification when compared with the CNA was statistically nonsignificant for the EP-10 (1.4 +/- 16.3 g, P = .239) and statistically significant for the ADA-7 g (-2.2 +/- 15.6 g, P = .046). Both the EP-10 and ADA-7 g had clinically acceptable agreement with the CNA, as determined via Bland-Altman plots, although it was found that EP-10 had a tendency to overestimate with protein intakes above 150 g. The EP-10 required significantly less time for protein intake quantification than the ADA-7 g (mean time of 65 +/- 36 seconds vs. 111 +/- 40 seconds, P < .001). CONCLUSION: The EP-10 and ADA-7 g are valid clinical tools for protein intake quantification in an Asian context, with EP-10 being more time efficient. However, a dietician's discretion is needed when the EP-10 is used on protein intakes above 150 g. PMID- 22226756 TI - Effects of nitric oxide on mitochondrial permeability transition pore and thiol mediated responses in cardiac myocytes. AB - Nitric oxide (NO) alters the opening of mitochondrial permeability transition pore (mPTP). However, the signaling pathways of NO on mPTP remain elusive. We aimed to clarify the contribution of thiol-mediated responses to the effects of NO on mPTP in permeabilized myocytes. We found that (1) a high concentration of spermine NONOate (an NO donor; 500 MUM) opened mPTP and depolarized DeltaPsi(m). (2) A low concentration of NONOate (5 MUM) prevented atractyloside (an mPTP opener)-induced mPTP opening. (3) Mn(III) tetrakis (4-benzoic acid) porphyrin (Mn TBAP, ONOO(-) scavenger) attenuated the effect of high-concentration NONOate on mPTP opening, but did not inhibited the preventive effects of low-concentration NONOate. (4) When the interaction of NO with thiol was inhibited by N ethylmaleimide, the opening (by high-concentration NONOate) and preventive effects (by low-concentration NONOate) of NONOate on mPTP were blocked. (5) Dithiothreitol (an inhibitor of disulfide bonds formation) prevented high concentration NONOate-induced mPTP opening. (6) Ascorbic acid (an inhibitor of S nitrosylation) prevented the preventive effects of low-concentration NONOate on mPTP. We conclude that opening of mPTP by high-concentration NO is related to disulfide bonds formation and oxidizing effects of ONOO(-). In contrast, the inhibitory effect of physiological concentrations of NO on mPTP is related to S nitrosylation. PMID- 22226757 TI - Anti-diuretic factors in insects: the role of CAPA peptides. AB - Insects have adapted to live in a wide variety of habitats and utilize an array of feeding strategies that present challenges to their ability to maintain osmotic balance. Regardless of the feeding strategy, water and ion levels within the haemolymph (insect blood) are maintained within a narrow range. This homeostasis involves the action of a variety of tissues, but is often chiefly regulated by the excretory system. Until recently, most research on the hormonal control of the excretory tissues has focused on factors known to have diuretic activities. In this mini-review, the current state of knowledge on anti-diuretic factors in insects will be discussed with a particular emphasis on the CAPA peptides in the blood-feeding Chagas' disease vector, Rhodnius prolixus. PMID- 22226758 TI - The comparative endocrinology of feeding in fish: insights and challenges. AB - Studying the endocrine regulation of food intake in fish can be challenging due to the diversity in appetite-regulating hormones and the diversity within the fish group itself. Studies show that although the structure of the hormones is relatively conserved among vertebrates, their functions might vary between fish and mammals as well as among fish species. In addition, feeding behavior and the action of appetite regulators can be largely modulated by the feeding and reproductive status of the fish as well as the environment in which they evolve. This review gives a brief perspective of the endocrine regulation of feeding in fish, some of the methods used, and challenges encountered when using a comparative approach. PMID- 22226759 TI - The impacts of invaders: basal and acute stress glucocorticoid profiles and immune function in native lizards threatened by invasive ants. AB - As anthropogenic stressors increase exponentially in the coming decades, native vertebrates will likely face increasing threats from these novel challenges. The success or failure of the primary physiological mediator of these stressors--the HPA axis--will likely involve numerous and chaotic outcomes. Among the most challenging of these new threats are invasive species. These have the capacity to simultaneously challenge the HPA axis and the immune system as they are often associated with, or the cause of, emerging infectious diseases, and energetic tradeoffs with the HPA response can have immunosuppressive effects. To determine the effects of invasive species on the vertebrate GC response to a novel stressor, and on immunity, we examined the effects of invasive fire ants on native lizards, comparing lizards from sites with long histories with fire ants to those outside the invasion zone. We demonstrated higher baseline and acute stress (captive restraint) CORT levels in lizards from within fire ant invaded areas; females are more strongly affected than males, suggesting context-specific effects of invasion. We found no effect of fire ant invasion on the immune parameters we measured (complement bacterial lysis and antibody hemagglutination) with the exception of ectoparasite infestation. Mites were far less prevalent on lizards within fire ant invaded sites, suggesting fire ants may actually benefit lizards in this regard. This study suggests that invasive species may impose physiological stress on native vertebrates, but that the consequences of this stress may be complicated and unpredictable. PMID- 22226760 TI - Expression of nerve growth factor and its receptors TrkA and p75 in the uterus of wild female ground squirrel (Citellus dauricus Brandt). AB - In this study, we investigated the presence of nerve growth factor (NGF) and its receptors tyrosine kinase A (TrkA) and p75 in the uterus of the wild ground squirrels during the estrous period, early pregnancy and non-breeding period. In the estrous period and early pregnancy, NGF and TrkA were immunolocalized in stromal cells, luminal epithelial cells, glandular cells and smooth muscle cells whereas in the non-breeding period, both of them were detected only in luminal epithelial cells and glandular cells, but not in stromal cells or smooth muscle cells. Stronger immunostaining of NGF and TrkA was observed in luminal epithelial cells and glandular cells in the estrous period and early pregnancy as compared to the non-breeding period. p75 was immunolocalized only in luminal epithelial and glandular cells during the estrous period, early pregnancy and non-breeding period. The intensity of the immunohistochemical signals for p75 did not vary significantly in the estrous period, early pregnancy and non-breeding period. The mean mRNA levels of NGF and TrkA and p75 were significantly higher in the estrous period and early pregnancy as compared to the non-breeding period. Besides, plasma estradiol-17beta and progesterone concentrations were higher in the estrous period and early pregnancy than in the non-breeding period, suggesting that the expression patterns of NGF and TrkA are correlated with changes in plasma estradiol-17beta and progesterone concentrations. These results indicate that NGF and its receptor TrkA may be involved in the regulation of seasonal changes in the uterine functions of wild female ground squirrels. PMID- 22226761 TI - Dose confirmation and non-interference evaluations of the oral efficacy of a combination of milbemycin oxime and spinosad against the dose limiting parasites, adult cat flea (Ctenocephalides felis) and hookworm (Ancylostoma caninum), in dogs. AB - Two separate controlled and blinded studies were conducted to confirm the dose and non-interference of spinosad and milbemycin oxime (MO) administered orally in combination or alone to dogs for the treatment and control of experimentally induced flea infestations (Ctenocephalides felis) and adult hookworm infections (Ancylostoma caninum). For each study, dogs were allocated randomly based on pre treatment adult flea and hookworm egg counts to one of four treatment groups of 10 animals each. In each study, spinosad and MO in combination, using the lower half (30-45 mg/kg spinosad; 0.5-0.75 mg/kg MO) of the US commercial dose band (30 60 mg/kg spinosad; 0.5-1.0mg/kg MO) of each active ingredient, or individually alone using the full dose range, were given orally to dogs on Day 0 using a tablet formulation. A placebo control was treated similarly. In one study, on Days -1, 5, 12, 19, 28 and 35 each dog was infested with approximately 100 unfed adult C. felis obtained from the investigator's established flea colony. All dogs were infested via the same method. Forty-eight hour post-infestation flea comb counts were conducted on Days 1, 7, 14, 21, 30 and 37 and were used to determine the knockdown and residual flea activity. In the second study, on Day -27 each of 48 dogs were experimentally inoculated with 100 third-stage infective larvae of the hookworm, A. caninum. Dogs were treated on Day 0 and necropsied on Day 7 or Day 8. All nematodes in the intestinal tract were collected on Day 7 or Day 8, identified and counted by species and stage. Post-treatment, the geometric mean live flea counts were significantly different (p-value<0.0001) between the spinosad/MO combination and the spinosad only treatment groups as compared to the vehicle control group. The flea counts in the MO only group and the control group were not statistically different. The spinosad and MO combination group and the spinosad only treatment group demonstrated significantly different knockdown (100%) and post-treatment residual flea efficacy at Day 30 was 100% for both groups as compared to the vehicle control. The presence of MO in combination with spinosad did not interfere with the flea efficacy of spinosad as compared to the spinosad only group. MO alone did not demonstrate any flea efficacy. Post treatment, the geometric mean A. caninum worm counts were significantly different (p-value<0.0001) between the spinosad and MO combination group as compared to the vehicle control group. The worm counts in the MO only group and the combination group were not statistically different. The spinosad and MO combination group (99.8% reduction) and the MO only treatment group (99.5% reduction) both demonstrated significantly different hookworm efficacy as compared to the vehicle control group. The presence of spinosad in combination with MO did not interfere with the hookworm efficacy of MO as compared to the MO only group. Spinosad alone did not demonstrate any hookworm efficacy. In summary, flavored spinosad and MO combination tablets administered orally to dogs at the lower end (30-45 mg/kg spinosad; 0.5-0.75 mg/kg MO) of the US commercial tablet unit dose range (30-60 mg/kg spinosad; 0.5-1.0mg/kg MO) were both safe and highly efficacious delivering 100% knockdown and 30 days of residual adult flea control on experimentally infested dogs as well as >99% adult hookworm efficacy evaluated under laboratory conditions. Interference between either drugs was not demonstrated for both of these dose limiting parasites. PMID- 22226762 TI - Grazing sericea lespedeza for control of gastrointestinal nematodes in lambs. AB - Alternatives to chemical dewormers are needed to counter anthelmintic resistance and improve worm control in organic management systems. The objective was to examine the effectiveness of grazing sericea lespedeza (SL) compared with grass pastures for control of gastrointestinal nematodes (GIN) in lambs. In Experiment 1, Katahdin lambs grazed bermudagrass (BG; n=14), tall fescue (TF; n=7), or SL (n=19) pastures during early summer months. In Experiment 2, lambs grazed TF (n=15) or SL (n=13) pastures during late summer. Stocking rate of pastures was based on forage availability; additional lambs grazed pastures in Experiment 2, but were not sampled. Lambs were dewormed with 0.5 g COWP if FAMACHA((c)) score was >3. In Experiment 1, FEC were reduced within 35 days in SL compared with BG lambs (forage by time, P=0.03). The PCV was more resilient to changes over time in SL compared with other groups of lambs (forage by time, P=0.001). In Experiment 2, FEC were lower (P=0.02) and PCV tended to be higher (P=0.09) in lambs grazing SL compared with TF forage. Incidence of deworming was similar among forage groups in both experiments. Grazing SL reduced FEC in lambs in early and late summer, despite reluctance by lambs to graze. Grazing forage and selective deworming using COWP was effective in lambs. PMID- 22226763 TI - High within-host genetic variation of the nematode Spirocerca lupi in a high density urban dog population. AB - The nematode worm Spirocerca lupi has a cosmopolitan distribution and can cause the death of its final canid host, typically dogs. While its life cycle, which involves a coprophagous beetle intermediate host, a number of non-obligatory vertebrate paratenic hosts and a canid final host, is well understood, surprisingly little is known about its transmission dynamics and population genetic structure. Here we sequenced cox1 to quantify genetic variation and the factors that limit gene flow in a 300 km(2) area in South Africa. Three quarters of the genetic variation, was explained by differences between worms from the same host, whereas a quarter of the variation was explained by differences between worms from different hosts. With the help of a newly derived model we conclude that while the offspring from different infrapopulations mixes fairly frequently in new hosts, the level of admixture is not enough to homogenize the parasite populations among dogs. Small infrapopulation sizes along with clumped transmission may also result in members of infrapopulations being closely related. PMID- 22226764 TI - [Retinal metastasis of cavum tumor]. PMID- 22226765 TI - [Open-globe injuries and intraocular foreign bodies involving the posterior segment]. AB - Open globe injuries involving the posterior segment remain a major cause of visual loss in young adults. They occur more frequently in male than in female populations. The majority is due to domestic accidents, since work-related injuries have been decreasing due to proper education and use of safety equipment. However, leisure-related open globe injuries are on the increase. Prompt recognition and treatment of open globe injuries are essential. At presentation, it is necessary to collect etiological data such as cause, nature, time and place of injury. Anti-tetanus immunization must be confirmed. The presenting visual acuity and clinical examination data must be recorded. The lesion type is classified in accordance with the Birmingham Eye Trauma Terminology. Ocular ultrasound or computed tomography is performed for patients suspected of having an intra- or periocular foreign body. Functional prognosis is negatively influenced by a posterior or large rupture, the presence of an intraocular foreign body, the presence of retinal lacerations or retinal detachment, or the occurrence of posttraumatic infectious endophthalmitis. Recent advances in microsurgical techniques such as pars plana vitrectomy and new visualization techniques may improve the anatomical and functional prognosis for these patients. However, postoperative proliferative vitreoretinopathy remains a major concern: it is responsible for a significant rate of secondary retinal detachment with negative consequences for visual prognosis. PMID- 22226766 TI - [Post-operative residual astigmatism after cataract surgery: Current surgical methods of treatment]. AB - Residual astigmatism after cataract surgery can be corrected by three different techniques: classic limbal relaxing incisions, easy to perform but with limited precision; laser refractive surgery (PRK or Lasik), additionally allowing for correction of spherical equivalent; and more recently the use of a piggyback toric intraocular lens in the ciliary sulcus. PMID- 22226767 TI - Identification of metabolites of Si-Ni-San, a traditional Chinese medicine formula, in rat plasma and urine using liquid chromatography/diode array detection/triple-quadrupole spectrometry. AB - Si-Ni-San (SNS) is a widely used traditional Chinese medicine formula (TCMF) in treating various diseases. However, the in vivo integrated metabolism of its multiple components remains unknown. In this paper, a liquid chromatography coupled with diode array detection and triple-quadrupole spectrometry (LC-DAD MS/MS) method was developed for detection and identification of SNS metabolites in rat plasma and urine at a normal clinical dosage. Accurate structural elucidation was performed using MS/MS, UV data and n-octanol/water partition coefficient. Based on the proposed strategy, 36 absorbed compounds and 29 metabolites in plasma and 33 metabolites in urine were detected by a highly sensitive MRM method. Our results indicated that phase II reactions (e.g., methylation, glucuronidation and sulfation) were the main metabolic pathways of gallic acid and flavanones, while phase I reactions (e.g., hydroxylation) were the major metabolic reaction for triterpenoid saponins. The metabolite profile analysis of SNS provided a comprehensive understanding of the in vivo metabolic fates of constituents in SNS. Moreover, the results in this work demonstrated the present strategy based on the combination of chromatographic, spectrophotometric, mass-spectrometric, and software prediction to detect and identify metabolites was effective and reliable. And such a strategy may also be extended to investigate the metabolism of other TCMF. PMID- 22226768 TI - Isolation and structural elucidation of indole alkaloids from Geissospermum vellosii by mass spectrometry. AB - Alkaloids from the stem bark of Geissospermum vellosii possess a variety of therapeutic properties including antimalarial activities, activity as a sexual stimulant and inhibition of the proliferation of HIV and herpes viruses. Methods currently used to isolate the active components from G. vellosii are time consuming, labor intensive, and result in low recovery. In addition, there is a lack of sensitive and accurate analytical methods for the structural characterization and identification of alkaloid components in minor quantities. A combination of high performance counter-current chromatography and ESI tandem mass spectrometry (MS(n)) was established to isolate alkaloids from the stem bark of G. vellosii, and study their electrospray ionization mass spectrometry fragmentation behavior. Five indole alkaloids were successfully isolated and identified by nuclear magnetic resonance and mass spectrometry. The multi-stage tandem mass spectrometric data were used to study their fragmentation pattern and set a model for detailed structure characterization of related indole alkaloids. The presence of the even mass fragment ion suggestive of an odd number of nitrogen at m/z 144 corresponding to C(10)H(9)N was characteristic to indole alkaloids. The results of the experiments demonstrated that the combination of high performance counter current chromatography and ESI-MS(n) is a sensitive, selective and effective approach for rapid isolation and characterization of alkaloids from G. vellosii. PMID- 22226769 TI - Trends in ultrasensitive proteomics. AB - Here we review recent developments and trends in sample preparation, pre fractionation, chromatography and mass spectrometry contributing towards the ultra-sensitive global analysis of proteins. Highly sensitive MS-based proteomics is not only beneficiary for the proteome analysis of single cells, an aim which is getting into reach, but also clearly relevant for the analysis of (a) subcellular organelles, (b) specific low-abundant cell-types such as adult stem cells, and (c) smaller but more homogeneous cell populations sorted or dissected from (diseased) tissue. PMID- 22226770 TI - Pomegranate enriched diet enhances the hematology, innate immune response, and disease resistance in olive flounder against Philasterides dicentrarchi. AB - Olive flounder, Paralichythys olivaceus fed with pomegranate enriched diet and challenged with or without Philasterides dicentrarchi had a significantly higher white blood cell (WBC) count on weeks 2 and 4 than the infected group fed with non enriched diet (standard diet). Similarly the red blood cell (RBC) counts did not significantly change in control and treated fish on weeks 1 and 2. It was significantly increased in treated fish on week 2 when compared to the control. In both the groups the hemoglobin (Hb) and hematocrit (Ht) levels significantly increased on weeks 2 and 4. The mean corpuscular volume (MCV) did not significantly change at any time in both groups whereas mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) increased significantly on week 4 in the treated group. The leukocytes such as lymphocytes (Lym), monocytes (Mon), neutrophils (Neu), and biochemical parameters such as total protein (TP), glucose (GLU), and calcium (CAL) levels significantly increased in treated groups on week 2 or 4 as compared to the control. The scuticocidal activity and respiratory burst activity were significantly enhanced in treated groups with or without parasite on weeks 2-4. However, the serum lysozyme activity was significantly enhanced from weeks 1 to 4. The protective response in terms of cumulative mortality was low in groups fed with enriched diet against parasite when compared to control. Therefore, we suggest that pomegranate enriched diet following challenge with P. dicentrarchi restores the altered hematological and biochemical parameters, and improves the innate immune system in olive flounder against P. dicentrarchi. PMID- 22226771 TI - Drug targeting systems for inflammatory disease: one for all, all for one. AB - In various systemic disorders, structural changes in the microenvironment of diseased tissues enable both passive and active targeting of therapeutic agents to these tissues. This has led to a number of targeting approaches that enhance the accumulation of drugs in the target tissues, making drug targeting an attractive strategy for the treatment of various diseases. Remarkably, the strategic principles that form the basis of drug targeting are often employed for tumor targeting, while chronic inflammatory diseases appear to draw much less attention. To provide the reader with a general overview of the current status of drug targeting to inflammatory diseases, the passive and active targeting strategies that have been used for the treatment of rheumatoid arthritis (RA) and multiple sclerosis (MS) are discussed. The last part of this review addresses the dualism of platform technology-oriented ("one for all") and disease-oriented drug targeting research ("all for one"), both of which are key elements of effective drug targeting research. PMID- 22226772 TI - Effects of interferon-gamma liposomes targeted to platelet-derived growth factor receptor-beta on hepatic fibrosis in rats. AB - No drugs have been approved clinically for the therapy of hepatic fibrosis. Though interferon-gamma (IFN-gamma) is a highly effective anti-fibrotic agent in vitro and in some animal models in vivo, its anti-fibrotic potential in clinical trials has been disappointing, due to unwanted off-target effects and a short half-life period which results in poor efficacy. The aims of this study are to develop a new targeted drug delivery system to selectively deliver IFN-gamma to hepatic stellate cells (HSCs) and to investigate whether it will improve the anti fibrotic effect of IFN-gamma and reduce its side effects in fibrotic livers. Sterically stable liposomes (SSLs) were modified by cyclic peptides (pPB) with a specific affinity for platelet-derived growth factor receptor-beta (PDGFR-beta), and then IFN-gamma was encapsulated in the targeted liposomes (pPB-SSL-IFN gamma). In vitro, pPB-SSL was found to be taken up and internalized by cultured activated HSCs. The binding of FITC-labeled pPB-SSL to activated HSCs was in a time-dependent and concentration-dependent manner, which could be inhibited by excess unlabelled pPB-SSL, PDGF-BB, suramin or monensin. The inhibitory effect of pPB-SSL-IFN-gamma on the proliferation of activated HSCs was respectively 7.24 fold and 2.95-fold higher than that of free IFN-gamma and IFN-gamma encapsulated in untargeted SSLs. In healthy rats, the tissue distribution, living-body tracing image analyses and pharmacokinetics study showed that pPB-SSL-IFN-gamma accumulated mainly in the livers and had a longer half-life than free IFN-gamma (3.98+/-0.52h vs. 0.21+/-0.03h). Furthermore, in rats with hepatic fibrosis induced by thioacetamide injection, FITC-labeled pPB-SSL was found to predominantly localize in activated HSCs by immunofluorescent double staining for FITC and albumin or alpha-smooth muscle actin (alpha-SMA). The enhanced anti fibrotic effect of pPB-SSL-IFN-gamma treatnment was indicated by significant decreases in the histologic Ishak stage, collagen I-staining positive areas, and alpha-SMA expression levels in fibrotic livers. In addition, pPB-SSL-IFN-gamma treatment improved the leukopenia caused by low- and high-dosage free IFN-gamma treatments. In conclusion, IFN-gamma encapsulated in pPB-SSL had an extended circulation half-life and was selectively delivered to activated HSCs, which enhanced the anti-fibrotic effect of IFN-gamma and reduced its side-effects in rats with hepatic fibrosis. Thus, pPB-SSL-IFN-gamma may be an effective agent for the therapy of hepatic fibrosis. PMID- 22226773 TI - NIR-light triggered delivery of macromolecules into the cytosol. AB - Light-responsive microcapsules constructed by layer-by-layer self-assembly are used as microcarriers to deliver different macromolecules inside cells. The microcapsules carry the macromolecules as cargo in their cavity, while their walls are modified with agglomerated gold nanoparticles. Microcapsules are incorporated by living cells and are then located in lysosomal compartments. Controlled release of the encapsulated material from the interior of the capsule to the cytosol is possible upon NIR-light irradiation. This is based on local heating of the gold nanoparticles upon NIR light and disruption of the capsule wall, what results on release of encapsulated materials. We illustrate several key advances in controlled release induced by light. First, we demonstrate that capsules can be opened individually, which allows for sequentially releasing cargo from different capsules within one single cell. Second, by using a pH indicator as cargo the claim of release from the acidic lysosomal compartments to the neutral cytosol is experimentally evident which until now has been only speculated. Third, green fluorescent protein (GFP) is released to the cytosol while retaining its functionality. This demonstrates that proteins can be released without destruction by the local heating. Fourth, GFP is also administered in biodegradable capsules, which leads to a different release mechanism compared to externally triggering for light-responsive microcapsules. PMID- 22226774 TI - Mucociliary clearance of micro- and nanoparticles is independent of size, shape and charge--an ex vivo and in silico approach. AB - The fate of inhaled particles after deposition onto the pulmonary mucosa is far from being solved, in particular with respect to mucociliary clearance and mucus penetration. Due to the fact that these phenomena govern pulmonary residence time and thus bioavailability, they are highly relevant for any kind of controlled release formulation delivered via that route. This study applies ex vivo and in silico approaches to investigate the dependency of muciliary clearance of micro-, submicrometer and nanoparticles on size, shape, charge and surface chemistry of such particles. In addition, measurement of mucociliary clearance of different particles also provided information about their penetration into mucus. Surprisingly, no significant differences in mucociliary clearance could be found for any type of particle under investigation. As revealed by computational modeling, particle penetration into the mucus gel layer was negligible at least within the time frame allowed by horizontal mucus transport. These data suggest that the observed lack of difference in mucociliary clearance is caused by the lack of immediate penetration of deposited aerosol particles through the mucus blanket. PMID- 22226775 TI - Paromomycin and neomycin B derived cationic lipids: synthesis and transfection studies. AB - Cationic lipid-based nonviral gene delivery is an attractive approach for therapeutic gene transfer. Basically, gene transfection can be achieved by using synthetic vectors that compact DNA, forming cationic lipoplexes which can interact with the cell plasma membrane by electrostatic interactions. Among the basic components of any cationic lipid, the type of cationic headgroup has been shown to have a major role in transfection efficiency. We have previously reported the DNA transfection potential of vectors characterized by a kanamycin A headgroup. The encouraging transfection results obtained with these compounds prompted us to evaluate the potential of cationic lipids bearing headgroups based on other aminoglycosides. Thus, we herein report the synthesis and gene transfection properties of novel cationic lipids consisting of cholesteryl or dioleyl moieties linked, via various spacers, to paromomycin or neomycin B headgroups. Our results confirm that these new aminoglycoside-based cationic lipids are efficient for gene transfection both in vitro and into the mouse airways in vivo. We also investigated physico-chemical properties of the DNA complexes formed by this particular type of synthetic vectors in order to better understand their structure-activity relationships. PMID- 22226776 TI - PEGylated cationic liposomes robustly augment vaccine-induced immune responses: Role of lymphatic trafficking and biodistribution. AB - Lymph nodes (LNs) are peripheral lymphoid organs essential for vaccine-induced immune responses. Although cationic liposomes have been documented as a novel adjuvant and vaccine delivery system, whether enhancing LN targeting would improve the efficiency of cationic liposome-formulated vaccines has not been elucidated yet. In the present study we investigated the effect of PEGylation on LN targeting and the immunogenicity of cationic liposome-formulated vaccines. DOTAP cationic liposomes were incorporated with 1 or 5mol% of DSPE-PEG2000 and labeled with near infrared fluorescent dyes. The lymphatic trafficking and biodistribution of different liposomes after subcutaneous (s.c.) injection were recorded using an in-vivo imaging system. The results showed that incorporation of 1mol% DSPE-PEG2000 not only accelerated the drainage of DOTAP liposomes into draining LNs, but also prolonged their LN retention and enhanced liposome uptake by resident antigen-presenting cells. On the other hand, although incorporating 5mol% of DSPE-PEG2000 into DOTAP liposomes enhanced their LN retention and uptake to a lesser extent, it prolonged blood circulation of DOTAP liposomes and increased their splenic accumulation. In addition, PEGylated DOTAP liposomes augmented primary and secondary anti-OVA antibody responses more potently than nonPEGylated DOTAP liposomes did. Hence, incorporating a small amount of DSPE PEG2000 into DOTAP liposomes not only increased the passive LN targeting of DOTAP formulated vaccines but also modulated their biodistribution in vivo, which consequently improved the efficiency of cationic liposome-formulated vaccines. PMID- 22226777 TI - Glucocorticoids in nano-liposomes administered intravenously and subcutaneously to adjuvant arthritis rats are superior to the free drugs in suppressing arthritis and inflammatory cytokines. AB - We have previously shown that intravenous (i.v.) treatment with sterically stabilized nano-liposomes (NSSL) actively remote-loaded with the glucocorticoid (GC) methylprednisolone hemisuccinate (NSSL-MPS) or betamethasone hemisuccinate (NSSL-BMS) significantly decreased severity of adjuvant arthritis in Lewis rats (a model of human rheumatoid arthritis) throughout all disease stages. Here, we compared i.v. or subcutaneous (s.c.) weekly treatment with each of the two NSSL GC to weekly or daily treatment with the free drugs or with the TNF-alpha antagonists Infliximab and Etanercept. Therapeutic efficacy and effects on the profile of pro-inflammatory (IL-6, TNF-alpha, and INF-gamma) and anti inflammatory (IL-10 and TGF-beta) cytokines in rat sera and splenocyte tissue culture supernatants were compared to those of the liposomal and free drugs. Both s.c. and i.v. NSSL-GC suppressed arthritis significantly, compared to higher doses of the free drugs or to TNF-alpha antagonists. NSSL-GC also suppressed the secretion of pro-inflammatory cytokines, but did not change the levels of TGF- beta. The highly efficacious anti-inflammatory therapeutic feature of these nano drugs makes them candidates for treatment of human rheumatoid arthritis. PMID- 22226778 TI - Drug delivery system for poorly water-soluble compounds using lipocalin-type prostaglandin D synthase. AB - Lipocalin-type prostaglandin D synthase (L-PGDS) is a member of the lipocalin superfamily and a secretory lipid-transporter protein, which binds a wide variety of hydrophobic small molecules. Here we show the feasibility of a novel drug delivery system (DDS), utilizing L-PGDS, for poorly water-soluble compounds such as diazepam (DZP), a major benzodiazepine anxiolytic drug, and 6-nitro-7 sulfamoylbenzo[f]quinoxaline-2,3-dione (NBQX), an alpha-amino-3-hydroxy-5-methyl 4-isoxazolepropionic acid (AMPA) receptor antagonist and anticonvulsant. Calorimetric experiments revealed for both compounds that each L-PGDS held three molecules with high binding affinities. By mass spectrometry, the 1:3 complex of L-PGDS and NBQX was observed. L-PGDS of 500MUM increased the solubility of DZP and NBQX 7- and 2-fold, respectively, compared to PBS alone. To validate the potential of L-PGDS as a drug delivery vehicle in vivo, we have proved the prospective effects of these compounds via two separate delivery strategies. First, the oral administration of a DZP/L-PGDS complex in mice revealed an increased duration of pentobarbital-induced loss of righting reflex. Second, the intravenous treatment of ischemic gerbils with NBQX/L-PGDS complex showed a protective effect on delayed neuronal cell death at the hippocampal CA1 region. We propose that our novel DDS could facilitate pharmaceutical development and clinical usage of various water-insoluble compounds. PMID- 22226779 TI - Monitoring the transport of polymeric micelles across MDCK cell monolayer and exploring related mechanisms. AB - Although some formulations based on nanotechnology are already available, the transport of nanoscale particles including polymeric micelles (PMs) across epithelial cell monolayer was barely studied. To prove the transport of PMs across the epithelial barrier and explain the mechanisms related, a typical PM system containing a fluorescent probe Coumarin 6 (C6) was prepared and the Madin Darby canine kidney (MDCK) cell line was used as an epithelial cell model. Four different approaches were applied to monitor the transport of PMs prepared, including the real-time and in situ imaging by a novel approach developed by our group. And the solid evidence of PMs' transport was obtained. The mechanism related was explored by different techniques. With the absence of caveolae mediated endocytosis and macropinocytosis, the clathrin mediated pathway might play a great role here, and a fraction of PMs bypassed the degradative lysosome pathway, probably due to the clathrin and caveolae independent mechanisms. Interestingly, some inhibitor was found to inhibit transcytosis of PMs significantly but not their endocytosis, suggesting different mechanisms involved in endocytosis and exocytosis. The Forster resonance energy transfer (FRET) phenomenon still existed after FRET PMs were internalized by cells. Anyhow, a multiple process with active transcellular pathway was indicated. PMID- 22226780 TI - Site-directed decapsulation of bolaamphiphilic vesicles with enzymatic cleavable surface groups. AB - Stable nano-sized vesicles with a monolayer encapsulating membrane were prepared from novel bolaamphiphiles with choline ester head groups. The head groups were covalently bound to the alkyl chain of the bolaamphiphiles either via the nitrogen atom of the choline moiety, or via the choline ester's methyl group. Both types of bolaamphiphiles competed with acetylthiocholine for binding to acetylcholine esterase (AChE), yet, only the choline ester head groups bound to the alkyl chain via the nitrogen atom of the choline moiety were hydrolyzed by the enzyme. Likewise, only vesicles composed of bolaamphiphiles with head groups that were hydrolyzed by AChE released their encapsulated material upon exposure to the enzyme. Injection of carboxyfluorescein (CF)-loaded vesicles with cleavable choline ester head groups into mice resulted in the accumulation of CF in tissues that express high AChE activity, including the brain. By comparison, when vesicles with choline ester head groups that are not hydrolyzed by AChE were injected into mice, there was no accumulation of CF in tissues that highly express the enzyme. These results imply that bolaamphiphilic vesicles with surface groups that are substrates to enzymes which are highly expressed in target organs may potentially be used as a drug delivery system with controlled site-directed drug release. PMID- 22226781 TI - Age-changes in gene expression in primary mixed glia cultures from young vs. old rat cerebral cortex are modified by interactions with neurons. AB - Astrocytic GFAP expression increases during normal aging in many brain regions and in primary astrocyte cultures derived from aging rodent brains. As shown below, we unexpectedly found that the age-related increase of GFAP expression was suppressed in mixed glia (astrocytes+microglia). However, the age-related increase of GFAP was observed when E18 neurons were co-cultured with mixed glia. Thus, the presence of microglia can suppress the age-related increase of GFAP, in primary cultures of astrocytes. To more broadly characterize how aging and co culture with neurons alters glial gene expression, we profiled gene expression in mixed glia from young (3 mo) and old (24 mo) male rat cerebral cortex by Affymetrix microarray (Rat230 2.0). The majority of age changes were independent of the presence of neurons. Overall, the expression of twofold more genes increased with age than decreased with age. The minority of age changes that were either suppressed or revealed by the presence of neurons may be useful to analyze glial-neuron interaction during aging. Some in vitro changes are shared with those of aging rat hippocampus in studies from the Landfield group (Rowe et al., 2007; Kadish et al., 2009). PMID- 22226782 TI - Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. AB - More information is needed about genetic factors that initiate development of pancreatic intraepithelial neoplasms-the most common precursors of pancreatic ductal adenocarcinoma. We show that more than 99% of the earliest-stage, lowest grade, pancreatic intraepithelial neoplasm-1 lesions contain mutations in KRAS, p16/CDKN2A, GNAS, or BRAF. These findings could improve our understanding of the development and progression of these premalignant lesions. PMID- 22226783 TI - Pediatric patients with dyspepsia have chronic symptoms, anxiety, and lower quality of life as adolescents and adults. AB - BACKGROUND & AIMS: Little is known about long-term health outcomes of children with dyspeptic symptoms. We studied the natural history of pediatric patients with dyspeptic symptoms, with and without histologic reflux, compared with healthy controls. METHODS: We performed a prospective study of consecutive new patients, ages 8-16 years, who underwent evaluation for dyspepsia, including upper endoscopy. Patients were assigned to groups with histologic evidence of reflux esophagitis (n = 50), or normal histology results (n = 53). Healthy children were followed up as controls (n = 143). Patients and controls were evaluated 5-15 years later. They provided self-reports on severity of dyspeptic symptoms, use of acid suppression, quality of life, anxiety, and depression. RESULTS: When the study began, the groups with histologic evidence of esophagitis and normal histologies did not differ in severity of dyspeptic symptoms, functional disability, or depression. After a mean 7.6-year follow-up period, each group had significantly lower quality-of-life scores and more severe dyspeptic symptoms and functional disability than controls, but did not differ significantly from each other; both groups were significantly more likely than controls to meet criteria for an anxiety disorder. At time of follow-up evaluation, use of acid-suppression medication was significantly greater in the group with histologic evidence for esophagitis, compared with patients who had normal histology findings when the study began. CONCLUSIONS: Among pediatric patients with dyspepsia evaluated by endoscopy and biopsy, those with histologic evidence for esophagitis or normal histology findings are at increased risk for chronic dyspeptic symptoms, anxiety disorder, and reduced quality of life in adolescence and young adulthood. PMID- 22226784 TI - Hyperemesis, gestational hypertensive disorders, pregnancy losses and risk of autoimmune diseases in a Danish population-based cohort. AB - The risk of some female predominant autoimmune diseases (ADs) has previously been shown to be higher in women who experience hyperemesis, gestational hypertensive disorders and idiopathic pregnancy losses. This study assessed the association between such pregnancy-related experiences and the subsequent risk of female predominant and other ADs. Our study cohort comprised 1.6 million Danish women born since 1955 for whom we had information about hyperemesis, gestational hypertensive disorders and pregnancy losses and subsequent hospital contacts for 31 ADs between 1982 and 2008. Ratios of first hospitalization rates (RRs) with 95% confidence intervals (CIs) were calculated using Poisson regression, adjusting for age, birth cohort, calendar period, marital status and childbirths. During 27.0 million person-years of follow-up 51,732 women were hospitalized with one or more ADs. Overall, compared with women without the specific pregnancy experiences, the risk of any AD was significantly increased for women with hyperemesis (RR = 1.41; 95% CI 1.30-1.51), gestational hypertensive disorders (1.21; 1.16-1.26), spontaneous abortions (1.10; 1.07-1.14), missed abortions (1.09; 1.04-1.13), stillbirths (1.25; 1.12-1.40), ectopic pregnancies (1.08; 1.02 1.14) and induced abortions (1.07; 1.04-1.09). Associations with female predominant ADs (i.e., ADs with a female:male ratio >2:1) were strongest in the first five years after the studied pregnancy experiences, but overall there was little difference between the RRs for groups of female predominant ADs and other ADs. Strong and potentially biological associations were observed for a number of specific ADs; including systemic lupus erythematosus, Graves' disease, type 1 diabetes mellitus and pernicious anemia, and for some specific ADs associations persisted even more than five years after the abnormal pregnancy experience. Abnormal pregnancies are associated with increased risk of certain ADs, possibly because of underlying immunologic or hormonal factors that predispose to both adverse pregnancy experiences and AD development. PMID- 22226786 TI - Crossing the scientific line: sins of omission and commission. PMID- 22226785 TI - MicroRNAs and depression. AB - With an estimated life-time prevalence of 15 to 17% and an incapacitating illness in 50% of cases, depressive spectrum disorders represent a heavy public health burden. Despite considerable efforts to underpin the molecular and cellular changes associated with depressive states, a global understanding of the pathophysiology of major depressive disorders (MDD) is still lacking. It is now acknowledged that deficits in synaptic plasticity, such as those resulting from chronic stress, can set the stage for the onset of depression. As a corollary, antidepressants balance neurotransmitter systems and help restore neuronal activity. In recent years, microRNAs have emerged as key protagonists in numerous physiopathological conditions including CNS function and disease. This review summarizes the current evidence for an involvement of microRNAs in the pathophysiology of depression and their contribution to the action of antidepressants. PMID- 22226787 TI - Spatial distribution and temporal trends of persistent organochlorine pollutants in sediments from Lake Maryut, Alexandria, Egypt. AB - Organochlorine compounds (OCs) in surface and core sediments collected from Lake Maryut, Egypt, were examined to elucidate their distribution, ecological risk and historical trend. To our knowledge, this is the first study on residue levels of OCs in sediments from Lake Maryut. Concentrations of PCBs and DDTs were higher than other OCs, ranging from 3.06 to 388 and from 0.07 to 106 ng/g dry wt., respectively. The highest concentrations of OCs were found at stations near the discharge point of sewage and close to industrial areas. The distribution of DDT and its metabolites suggest no recent inputs into the lake environment. Contamination levels of sedimentary PCBs and DDTs, can be categorized moderate to high compared to other urbanized regions worldwide. Temporal trends in OCs levels were influenced by input pathways at two sites. Evaluation of ecotoxicological risks suggests that adverse biological effects are expected mainly in the main basin area. PMID- 22226788 TI - Twenty years of Belgian North Sea aerial surveillance: a quantitative analysis of results confirms effectiveness of international oil pollution legislation. AB - Over the years many policy measures have been taken to prevent illegal oil discharges from ships, like the MARPOL 73/78 Convention (1983) and the Bonn Agreement (1969/1983). However, the number of discharges remained high, leading to chronic oiling of seabirds and sensitive coastlines, therefore further measures were taken. The aim of this study is to quantify the effectiveness of two key legislative regulations: the IMO-designation of the North Sea as MARPOL Special Area which took effect in 1999, and the adoption of the EU Directive on Port Reception Facilities in 2000. Under study is the heavily navigated Belgian Surveillance Area, monitored since 1991, characterised by shallow waters with ecologically important sandbanks. The aerial surveillance data from 1991 to 2010 show a stepwise decrease in ship-source oil pollution. Three time periods can be distinguished with two turning points coinciding with the actual implementation of these key legislative measures, confirming their effectiveness. PMID- 22226789 TI - Successive analysis of antigen trapping and enzymatic digestion on membrane immobilized avidin. AB - Avidin from egg white was migrated toward a cathode of nondenaturing electrophoresis and then immobilized on a polyvinylidene difluoride membrane. Adrenocorticotropic hormone (ACTH) was specifically captured after the biotinylated anti-ACTH antibody was bound to the membrane-immobilized avidin, and the captured ACTH was digested by the biotinylated trypsin on the membrane after extraction. The digested polypeptides from the ACTH were analyzed by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). These results indicate that target substances can be specifically trapped and digested on membrane-immobilized avidin. PMID- 22226790 TI - Elucidating protein inter- and intramolecular interacting domains using chemical cross-linking and matrix-assisted laser desorption ionization-time of flight/time of flight mass spectrometry. AB - Among many methods used to investigate protein/protein interactions, chemical cross-linking combined with mass spectrometry remains a vital experimental approach. Mapping peptides modified by cross-linker provides clues about proteins' interacting domains. One complication is that such modification may result from intra- but not intermolecular interactions. Therefore, for overall data interpretation, a combination of results from various platforms is necessary. It is postulated that the secretory isoform of gelsolin regulates several biological processes through interactions with proteins such as actin, fibronectin, vitamin D-binding protein, and unidentified receptors on the surface of eukaryotes; it also has been shown to self-assemble eventually leading to the formation of homo-multimers. As such, it is an excellent model for this study. We used four cross-linkers with arm length ranging from 7.7 to 21.7A and MALDI TOF/TOF mass spectrometry as the analytical platform. Results of this study show that MALDI-based mass spectrometry generates high quality data to show lysine residues modified by cross-linkers and combined with existing data based on crystallography (Protein Data Bank, PDB) can be used to discriminate between inter- and intramolecular linking. PMID- 22226791 TI - Effect of dielectric spacer thickness on signal intensity of surface plasmon field-enhanced fluorescence spectroscopy. AB - Surface plasmon field-enhanced fluorescence spectroscopy (SPFS) combines enhanced field platform and fluorescence detection. Its advantages are the strong intensity of the electromagnetic field and the high signal/noise (S/N) ratio due to the localized evanescent field at the water/metal interface. However, the energy transfer from the fluorophore to the metal surface diminishes the fluorescence intensity, and this reduces the sensitivity. In this study, we tested whether polystyrene (PSt) could act as a dielectric layer to suppress the energy transfer from the fluorophore to the metal surface. We hypothesized that this would improve the sensitivity of SPFS-based immunoassays. We used alpha fetoprotein (AFP) as a model tumor biomarker in the sandwich-type immunoassay. We determined the relationship between fluorescent signal intensity and PSt layer thickness and compared this to theoretical predictions. We found that the fluorescence signal increased by optimally controlling the thickness of the PSt layer. Our results indicated that the SPFS-based immunoassay is a promising clinical diagnostic tool for quantitatively determining the concentrations of low level biomarkers in blood samples. PMID- 22226792 TI - A rapid and quantitative method for the evaluation of V gene usage, specificities and the clonal size of B cell repertoires. AB - The quantitative simultaneous description of both variable region gene usage and antigen specificity of immunoglobulin repertoires is a major goal in immunology. Current quantitative assays are labor intensive and depend on extensive gene expression cloning prior to screening for antigen specificity. Here we describe an alternative method based on high efficiency single B cell cultures coupled with RT-PCR that can be used for rapid characterization of immunoglobulin gene segment usage, clonal size and antigen specificity. This simplified approach should facilitate the study of antibody repertoires expressed by defined B cell subpopulations, the analysis of immune responses to self and nonself-antigens, the development and screening of synthetic antibodies and the accelerated study and screening of neutralizing antibodies to pathogenic threats. PMID- 22226793 TI - Characterization of a monoclonal antibody against the 3D polymerase of enterovirus 71 and its use for the detection of human enterovirus A infection. AB - Over the last decade, frequent epidemic outbreaks of hand, foot and mouth disease have been observed in the Asia-Pacific region. Hand, foot and mouth disease is caused by different viruses from the enterovirus family, mainly coxsackievirus A16 and enterovirus 71 (EV71) from the human enterovirus A family. Severe disease and neurological complications are associated more often with EV71 infection, and can lead occasionally to fatal brain stem encephalitis in young children. The rapid progression and high mortality of severe hand, foot and mouth disease makes the direct detection of antigens early in infection essential. The best method for virus detection is the use of specific monoclonal antibodies. The generation and characterization of a monoclonal antibody specific for the 3D polymerase of human enterovirus A and the development of a virus detection dot blot assay are described. A recombinant 3CD protein from EV71 C4 strain was used as an immunogen to generate monoclonal antibodies (MAbs). Screening of hybridoma cells led to the isolation of monoclonal antibody 4B12 of the immunoglobulin IgG1 isotype. MAb 4B12 recognizes the linear epitope DFEQALFS close to the active site of the 3D polymerase, corresponding to amino acid positions 53-60 of 3D and 1784-1791 of enterovirus 71 polyprotein. The presence of 3D polymerase and its precursor 3CD proteinase in purified virus particles was confirmed. MAb 4B12 was used successfully to detect all enterovirus 71 subgenotypes in a denaturing dot blot assay with a sensitivity of 10 pg of 3D protein and 10(4) tissue culture infective dose of virus particles. PMID- 22226794 TI - Electromyography and muscle ultrasound in ALS diagnosis, complementary or competitive? PMID- 22226795 TI - Sleep cyclic alternating pattern analysis in infants with apparent life threatening events: a daytime polysomnographic study. AB - OBJECTIVE: Non-REM sleep is characterized by a physiologic oscillating pattern that exhibits different levels of arousal, coded as cyclic alternating pattern. The aim of this study was to analyze the development of cyclic alternating pattern parameters in a group of infants with apparent life-threatening events. METHODS: A total of 26 infants with apparent life-threatening events (14 females, mean age 3.4 months, 2.37 S.D., age range 0.5-9 months) were studied while they slept in the morning between feedings, by means of a 3-h video electroencephalographic-polygraphic recording. Sleep was visually scored using standard criteria. The control group was composed of 36 healthy infants (16 females, mean age 3.2 months, 2.17 S.D., age range 0.5-9 months). RESULTS: Children with apparent life-threatening events showed an increased frequency of periodic breathing, gastroesofageal reflux and of other risk conditions. They presented also an increased obstructive apnoea/hypopnea index. A full NREM sleep development was found in a significantly smaller percentage of patients, and they showed a significant reduction of the percentage of REM sleep, of cyclic alternating pattern A1 subtypes, an increased percentage of A2 and A3 subtypes and increased index of A2, A3 subtypes and arousal, compared to normal controls. Cyclic alternating pattern rate showed a significant positive correlation with age, only in controls. CONCLUSIONS: Our results show a higher level of arousal and an increased non-REM sleep discontinuity in babies with apparent life threatening events, compared to controls. SIGNIFICANCE: The enhanced mechanism of arousal might counteract life-threatening events and represent an important neurophysiologic distinction from future victims of sudden infant death syndrome who also experience similar events. PMID- 22226797 TI - Small animal meningiomas: the information explosion tackles a challenging disease head on. PMID- 22226798 TI - Cardiovascular fitness is associated with altered cortical glucose metabolism during working memory in E4 carriers. AB - BACKGROUND: The possibility that E4 may modulate the effects of fitness in the brain remains controversial. The present exploratory FDG-PET study aimed to better understand the relationship among E4, fitness, and cerebral metabolism in 18 healthy aged women (nine carriers, nine noncarriers) during working memory. METHODS: Participants were evaluated using maximal level of oxygen consumption, California Verbal Learning Test, and FDG-PET, which were collected at rest and during completion of the Sternberg working memory task. RESULTS: Resting FDG-PET did not differ between carriers and noncarriers. Significant effects of fitness on FDG-PET during working memory were noted in the E4 carriers only. High fit E4 carriers had greater glucose uptake in the temporal lobe than the low fit E4 carriers, but low fit E4 carriers had greater glucose uptake in the frontal and parietal lobes. CONCLUSIONS: We demonstrate that fitness differentially affects cerebral metabolism in E4 carriers only, consistent with previous findings that the effects of fitness may be more pronounced in populations genetically at risk for cognitive decline. PMID- 22226799 TI - Using a didactic model to improve patient observation skills in neonatal intensive care nurse trainees - a pilot study. AB - OBJECTIVES: To implement a didactic model for students specialising in intensive care nursing (n=12) and nurses working in neonatal intensive care units (NICU) (n=17). To evaluate nurse self-assessments following observation of children with congenital heart disease (CHD), before and after participation in the programme, as well as the usefulness of the programme. METHODOLOGY/DESIGN: A pilot study with a pre- and post-test design, using self-administered questionnaires. RESULTS: The didactic model increased the number of clinical observations and assessments of physiological factors made by both students and NICU nurses during evaluation of children with suspected CHD. The majority of nurses reported that both participation in the programme and the didactic model were useful and they demonstrated high-level knowledge, according to Bloom's taxonomy for cognitive learning. In particular, subjects found that the literature provided and structured bedside guidance in the clinical setting assisted learning. CONCLUSION: Intensive care students and NICU nurses performed clinical observations and physical factor assessments more frequently after completing the programme, compared with baseline. We speculate that this didactic model may also be useful in other clinical settings. PMID- 22226800 TI - Lexical versus conceptual anticipation during sentence processing: frontal positivity and N400 ERP components. AB - Although the sensitivity of the N400 to semantic processing is well established, late positive ERP components are also elicited during sentence comprehension. We suggest that there are multiple such components differing in scalp topography, and that a larger frontal positivity often follows the larger N400 elicited by congruent but unexpected sentence endings as compared to predictable endings. We evaluated the lexical versus conceptual specificity of this post-N400-positivity. High- and low-constraint sentences were completed by the words most preferred by a normative group (best completions), by words that were nearly synonymous to those best completions, and by other congruent words that were semantically dissimilar to the best completions. The N400 was sensitive to both the predictability (cloze probability) of the words and their semantic similarity to the best completion, consistent with a sensitivity to conceptual expectations that could be fulfilled by alternate words. In contrast, an anterior positivity was elicited by all final words that were not highly predictable, independent of whether they were semantically similar or dissimilar to the most preferred word, indicating a sensitivity to specific lexical expectations. PMID- 22226801 TI - Agency, gait and self-consciousness. AB - Agency is an important aspect of bodily self-consciousness, allowing us to separate own movements from those induced by the environment and to distinguish own movements from those of other agents. Unsurprisingly, theoretical frameworks for agency such as central monitoring are closely tied to computational models of sensorimotor control. Until recently agency research has largely focussed on goal directed movements of the upper limbs. In particular, the influence of performance-related sensory cues and the relevance of prediction signals for agency judgements have been studied through a variety of spatio-temporal mismatches between movement and the sensory consequences of movement. However, agents often perform a different type of movement; highly automated movements that involve the entire body such as walking, cycling, and swimming with potentially different agency mechanisms. Here, we review recent work about agency for full-body movements such as gait, highlighting the effects of performance related visual and auditory cues on gait agency. Gait movements differ from upper limb actions. Gait is cyclic, more rarely immediately goal-directed, and is generally considered one of the most automatic and unconscious actions. We discuss such movement differences with respect to the functional mechanisms of full-body agency and body-part agency by linking these gait agency paradigms to computational models of motor control. This is followed by a selective review of gait control, locomotion, and models of motor control relying on prediction signals and underlining their relevance for full-body agency. PMID- 22226802 TI - Cerebrovascular hemodynamics in Alzheimer's disease and vascular dementia: a meta analysis of transcranial Doppler studies. AB - BACKGROUND AND PURPOSE: Alteration in cerebrovascular hemodynamics has reported in both ageing and dementia. However, it is still unclear whether this alteration follows similar pattern in ageing and in different dementia pathologies. The aim of this meta-analysis was to investigate changes in cerebral blood flow velocity and pulsatility index in two most common forms of dementia; Alzheimer's disease and vascular dementia, using transcranial Doppler studies. METHODS: A literature search was conducted in Pubmed, EMBASE and Web of Science. After initial screening of 304 articles and removing duplicates, a total of 53 articles, published between 1980 and 2010, were reviewed. Finally 12 articles were included in the meta-analysis. For each study, effect sizes (ES) indicating the standardized mean differences of the hemodynamic measures between two groups were calculated. Using random effect models, pooled estimates of ES were measured. RESULTS: Patients with Alzheimer's disease (ES=-1.09, 95% CI -1.77 to -0.44, p=0.004) and vascular dementia (ES=-1.62, 95% CI -2.26 to -0.98, p<0.001) had significantly lower cerebral blood flow velocity compared with healthy aged matched controls. In addition, pulsatility index was significantly higher in both Alzheimer's disease (ES=0.5, 95% CI 0.28-0.72, p<0.001) and vascular dementia patients (ES=2.34, 95% CI 1.39-3.29, p<0.001). Patients with Alzheimer's disease had lower pulsatility index (ES=-1.22, 95% CI -1.98 to -0.46, p=0.002) compared to subjects with vascular type of dementia. CONCLUSIONS: Patients with Alzheimer's disease and vascular dementia have a pronounced disturbance in their cerebrovascular hemodynamics. The severity of disturbances in cerebral hemodynamics is significantly lower in Alzheimer's disease compared to vascular dementia. PMID- 22226803 TI - A new preservation solution for lung transplantation: evaluation in a porcine transplantation model. AB - BACKGROUND: Lung preservation injury is still a major problem in lung transplantation. The aim of the current study was to evaluate the effects of a new preservation solution (Custodiol-N) for lung preservation. METHODS: Using an in vivo pig model, 7 lungs each were preserved for 24 hours after perfusion with: low-potassium dextran (LPD) solution as control (Group I); base solution of Custodiol-N without iron chelators (Group II); Custodiol-N (Group III); or Custodiol-N supplemented with dextran 40 (Group IV). Four animals received a sham operation. After left lung transplantation and contralateral lung exclusion, hemodynamics and blood gases were monitored for 6 hours; tissue samples were taken at the end of the experiments. RESULTS: All animals survived the transplantation procedure. Base solution- and Custodiol-N-preserved lungs (Groups II and III) showed graft function similar to that of LPD-preserved lungs (Group I), showing a trend toward improved values. Custodiol-N with dextran (Group IV) led to a significant reduction of mean pulmonary arterial pressure (20 +/- 2 vs 28 +/- 3 mm Hg, p < 0.01) and pulmonary vascular resistance (410 +/- 51 vs 588 +/ 83 dyne/s/cm(5), p < 0.01), and oxygenation ratio was significantly higher (536 +/- 52 vs 313 +/- 107 mm Hg at 6 hours, p < 0.01) and PCO(2) values were significantly lower (51 +/- 9 vs 77 +/- 5 mm Hg at 6 hours, p < 0.01) at 6 hours compared with LPD (Group I). Custodiol-N (Groups II to IV) showed a trend toward a lower wet/dry ratio and reduced oxidative stress; in the presence of dextran (Group IV), the difference was again statistically significant, when compared with LPD (Group I). CONCLUSIONS: Custodiol-N solution is a new alternative preservation solution for lung transplantation that offers significantly superior protection compared with LPD when dextran 40 is added. PMID- 22226804 TI - Prevalence, predictors, and survival in pulmonary hypertension related to end stage chronic obstructive pulmonary disease. AB - BACKGROUND: The prevalence, prognostic importance, and factors that predict the presence and degree of pulmonary hypertension (PH) diagnosed with right heart catheterization (RHC) in patients with end-stage chronic obstructive pulmonary disease (COPD) remain unclear. METHODS: This retrospective study included 409 patients (61% women) with COPD/emphysema or alpha-1-antitrypsin deficiency who underwent lung transplant evaluation during 1991 to 2010. We analyzed the occurrence and degree of PH and compared demographics, oxygenation, lung function, hemodynamics, functional capacity, and survival in patients with and without PH. Prediction of PH was assessed using univariate and multivariate regression analysis. RESULTS: The mean age at evaluation was 54 +/- 7 years. All patients were in New York Heart Association functional class III-IV, with forced expiratory volume in 1 second of 23% +/- 7% and total lung capacity of 126% +/- 21% of predicted. PH was present in 146 (36%). The analysis excluded 53 (13%) with pulmonary venous hypertension (PVH). The distribution of the mean pulmonary artery pressure (mPAP) in patients with or without PH showed a unimodal normally distributed population, with a mean of 23.8 +/- 6.0 mm Hg. Predictors of PH were partial pressures of oxygen and carbon dioxide. The 5-year survival rate was 37% in COPD patients with PH vs 63% in patients without PH (p = 0.016). Survival after lung transplantation did not differ (p = 0.37). CONCLUSIONS: RHC verified PH in 36% of COPD patients. Hypoxemia and hypercapnia were associated with mPAP. PH is associated with worse survival in COPD, but PH does not influence the prognosis after lung transplantation. PMID- 22226805 TI - Interference of some aqueous two-phase system phase-forming components in protein determination by the Bradford method. AB - The interference of some specific aqueous two-phase system (ATPS) phase-forming components in bovine serum albumin (BSA) determination by the Bradford method was investigated. For this purpose, calibration curves were obtained for BSA in the presence of different concentrations of salts and polymers. A total of 19 salts [Na2SO4, (NH4)2SO4, MgSO4, LiSO4, Na2HPO4, sodium phosphate buffer (pH 7.0), NaH2PO4, K2HPO4, potassium phosphate buffer (pH 7.0), KH2PO4, C6H8O7, Na3C6H5O7, KCHO2, NaCHO2, NaCO3, NaHCO3, C2H4O2, sodium acetate buffer (pH 4.5), and NaC2H3O2] and 7 polymers [PEG 4000, PEG 8000, PEG 20000, UCON 3900, Ficoll 70000, PES 100000, and PVP 40000] were tested, and each calibration curve was compared with the one obtained for BSA in water. Some concentrations of salts and polymers had considerable effect in the BSA calibration curve. Carbonate salts were responsible for the highest salt interference, whereas citric and acetic acids did not produce interference even in the maximum concentration level tested (5 wt%). Among the polymers, UCON gave the highest interference, whereas Ficoll did not produce interference when used in concentrations up to 10 wt%. It was concluded that a convenient dilution of the samples prior to the protein quantification is needed to ensure no significant interference from ATPS phase forming constituents. PMID- 22226808 TI - Prevalence of infection by different genotypes of human papillomavirus in women with cervical pathology. AB - OBJECTIVE: To document the prevalence of different human papillomavirus (HPV) genotypes in our population, and the relationships between different genotypes with age and type of cervical pathology. MATERIAL AND METHODS: Prospective, cross sectional descriptive study. A total of 1007 patients were recruited among those seen at the cervical pathology clinic of Sant Joan de Deu University Hospital in Barcelona (Spain) between January 2003 and March 2011. The statistical analysis was done with SPSS v.19 software. Differences between groups were considered statistically significant at p<0.05. RESULTS: Most patients (73.2%) had HPV infection, and among these women the genotype was considered high-risk in 86.4%. The most frequent genotype was HPV 16, found in 31% of the patients. Other genotypes identified, in decreasing order of frequency (all <10%), were HPV 51, HPV 53, HPV 31, HPV 66, HPV 58, HPV 33 and HPV 18. Mean age of the patients with HPV infection was 32.3 years, versus 39.8 years in women without HPV infection (p<0.05). The prevalence of HPV infection was significantly higher among women with grades 2 or 3 cervical intraepithelial neoplasia (CIN 2/3) (86%) or carcinoma (87%) than in women with grade 1 cervical intraepithelial neoplasia (CIN 1) (64%), HPV-associated changes (50%) or atypical cells (40%). CONCLUSIONS: In the population we studied, the proportion of women with infection by different genotypes of HPV 16 and HPV 18 was high. This finding confirms the need for further studies to compare the efficacy and protection of current vaccines against intraepithelial lesions and cervical cancer. PMID- 22226806 TI - Recovery of cortical effective connectivity and recovery of consciousness in vegetative patients. AB - Patients surviving severe brain injury may regain consciousness without recovering their ability to understand, move and communicate. Recently, electrophysiological and neuroimaging approaches, employing simple sensory stimulations or verbal commands, have proven useful in detecting higher order processing and, in some cases, in establishing some degree of communication in brain-injured subjects with severe impairment of motor function. To complement these approaches, it would be useful to develop methods to detect recovery of consciousness in ways that do not depend on the integrity of sensory pathways or on the subject's ability to comprehend or carry out instructions. As suggested by theoretical and experimental work, a key requirement for consciousness is that multiple, specialized cortical areas can engage in rapid causal interactions (effective connectivity). Here, we employ transcranial magnetic stimulation together with high-density electroencephalography to evaluate effective connectivity at the bedside of severely brain injured, non-communicating subjects. In patients in a vegetative state, who were open-eyed, behaviourally awake but unresponsive, transcranial magnetic stimulation triggered a simple, local response indicating a breakdown of effective connectivity, similar to the one previously observed in unconscious sleeping or anaesthetized subjects. In contrast, in minimally conscious patients, who showed fluctuating signs of non reflexive behaviour, transcranial magnetic stimulation invariably triggered complex activations that sequentially involved distant cortical areas ipsi- and contralateral to the site of stimulation, similar to activations we recorded in locked-in, conscious patients. Longitudinal measurements performed in patients who gradually recovered consciousness revealed that this clear-cut change in effective connectivity could occur at an early stage, before reliable communication was established with the subject and before the spontaneous electroencephalogram showed significant modifications. Measurements of effective connectivity by means of transcranial magnetic stimulation combined with electroencephalography can be performed at the bedside while by-passing subcortical afferent and efferent pathways, and without requiring active participation of subjects or language comprehension; hence, they offer an effective way to detect and track recovery of consciousness in brain-injured patients who are unable to exchange information with the external environment. PMID- 22226809 TI - No evidence for intra-segment recombination of 2009 H1N1 influenza virus in swine. AB - Hao (2011) reported that the PB2 genes of three swine influenza A viruses were likely generated through homologous recombination between two closely related parental strains. However, we show that Hao's observation is an artifact of incorrect taxon sampling arising through the lack of an appropriate evolutionary context. Through rigorous phylogenetic analyses we explain the evolutionary origins of these stains and confirm the lack of any statistical support for intra segmental recombination. PMID- 22226810 TI - Genetic polymorphism of MMP family and coronary disease susceptibility: a meta analysis. AB - The issue that genetic polymorphism of matrix metalloproteinase (MMP) family is in association with coronary disease is controversial. So we did a meta-analysis to clarify it clearly. We made a literature search of PubMed, the Web of Science, and Cochrane Collaboration's database to identify eligible reports. The methodological quality of each included studies was assessed. We calculated the pooled ORs with their 95%CI for each genetic polymorphism in STATA 11 software. Separate analysis was performed to address the consistency of results across the subgroup with different continents. A total of 39 studies were included, with a sample of 42269 individuals. This meta-analysis provided evidence that genetic polymorphism of MMP1-1607 1G/2G, MMP3-Gly45lys, MMP3-376 G/C, MMP3-1171 5A/6A, MMP9-1562 C/T and MMP9-R279Q have a small to medium effect on incidence of coronary disease. There was no evidence that MMP1-519 A/G, MMP1-340 T/C and MMP2 1306 C/T polymorphism could increase risk of coronary disease. Results from subgroup analysis supported a relation between MMP3-1711 5A allele, MMP9-1562 C allele and coronary disease especially in Asian population. The results provide moderate association between the six common genetic polymorphism of matrix metalloproteinase family and coronary disease. However, the challenge for researcher is identifying separate effect on different races. PMID- 22226811 TI - Molecular regulation of catechins biosynthesis in tea [Camellia sinensis (L.) O. Kuntze]. AB - Catechins are bioprospecting molecules present in tea and any effort towards metabolic engineering of this important moiety would require knowledge on gene regulation. These are synthesized through the activities of phenylpropanoid and flavonoid pathways. Expression regulation of various genes of these pathways namely phenylalanine ammonia-lyase (CsPAL), cinnamate 4-hydroxylase (CsC4H), p coumarate:CoA ligase (Cs4CL), flavanone 3-hydroxylase (CsF3H), dihydroflavonol 4 reductase (CsDFR) and anthocyanidin reductase (CsANR) was accomplished previously. In depth analyses of the remaining genes namely, chalcone synthase (CsCHS), chalcone isomerase (CsCHI), flavonoid 3'5'-hydroxylase (CsF3'5'H) and anthocyanidin synthase (CsANS) were lacking. The objective of the work was to clone and analyze these genes so as to generate a comprehensive knowledge on the critical genes of catechins biosynthesis pathway. Gene expression analysis was carried out in response to leaf age and external cues (drought stress, abscisic acid, gibberellic acid treatments and wounding). A holistic analysis suggested that CsCHI, CsF3H, CsDFR, CsANS and CsANR were amongst the critical regulatory genes in regulating catechins content. PMID- 22226812 TI - The soybean aldehyde dehydrogenase (ALDH) protein superfamily. AB - Aldehyde dehydrogenases (ALDHs) are members of NAD(P)(+)-dependent protein superfamily that catalyze the oxidation of a wide range of endogenous and exogenous highly reactive aliphatic and aromatic aldehyde molecules to their corresponding non toxic carboxylic acids. Research evidence has shown that ALDHs represent a promising class of genes to improve growth development, seed storage and environmental stress adaptation in higher plants. The recently completed genome sequences of several plant species have resulted in the identification of a large number of ALDH genes, most of which still need to be functionally characterized. In this paper, we identify members of the ALDH gene superfamily in soybean genome, and provide a unified nomenclature for the entire soybean ALDH gene families. The soybean genome contains 18 unique ALDH sequences encoding members of five ALDH families involved in a wide range of metabolic and molecular detoxification pathways. In addition, we describe the biochemical requirements and cellular metabolic pathways of selected members of ALDHs in soybean responses to environmental stress conditions. PMID- 22226813 TI - Melanoma in situ in a private practice setting 2005 through 2009: location, lesion size, lack of concern. AB - BACKGROUND: Studies have shown that the incidence of melanoma in situ (MIS) is increasing significantly. OBJECTIVE: This study analyzes selected clinical and demographic characteristics of MIS cases observed in private dermatology practices in the United States. METHODS: This study collected 257 MIS cases from 4 private dermatology practices in the United States from January 2005 through December 2009, recording age, gender, anatomic location, lesion size, patient reported change in lesion, and concern about lesion. Case totals for invasive melanoma during the same period were recorded. RESULTS: The data collected showed a higher incidence of MIS in sun-exposed areas of older patients, especially men. The median age of patients at the time of MIS detection was 69 years. The most common site for MIS was the head-neck region. The number of MIS cases collected exceeded the number of invasive malignant melanoma cases during the study period, with an observed ratio of 1.35:1. LIMITATIONS: For 136 patients, data were collected retrospectively for lesion size, location, gender, and age. For these patients, patient-reported change in lesion and concern about lesion were not collected. Patients often did not consent to a full body examination, therefore, it is possible that MIS lesions may have been missed in double-clothed areas. CONCLUSION: Careful attention to pigmented lesions, even lesions less than 4 mm, on sun-exposed areas, including scalp, trunk, and feet, will facilitate earlier diagnosis of MIS. As only 30.4% of male patients and 50% of female patients had concern about these lesions, it still falls to the dermatologist to discover MIS. PMID- 22226814 TI - Orodental manifestations of facial port-wine stains. AB - BACKGROUND: Patients with facial port-wine stains (PWS) often demonstrate oral manifestations of their disorder; however, the spectrum and prevalence of such findings among a cohort of patients with PWS has not been established. As a result, dermatologists and oral health specialists may be uncertain how to counsel their patients with PWS regarding oral hypervascularity, bony oral changes, and oral hygiene. OBJECTIVES: We sought to identify physical findings and complications involving the teeth, oral cavity, and perioral structures in individuals with facial PWS. METHODS: This was a cross-sectional study of 30 patients with facial PWS. Descriptive data were collected through anonymous paired surveys completed by patients and their dentists, and analyzed (Fisher exact test) for trends based on physical findings and stage of the PWS. RESULTS: The most common orodental manifestations according to patients were enlargement of the lip (53.3%), stained gums (46.7%), abnormal bite (30%), and spontaneous bleeding of the gums (26.7%). Staining of the gingiva correlated significantly with gingival hyperplasia (P = .006), maxillary hyperplasia (P = .014), and widened interdental spaces (P = .002), and in all cases gingival staining predated these findings. Lip hyperplasia was reported more frequently by patients than by their dentists (50% vs 18.2%, P = .008). Orodental manifestations were more common among patients with darker and thicker PWS. Hemorrhage after dental procedures was rare (4.5%). LIMITATIONS: Modest sample size and difficulty recruiting control subjects are limitations. CONCLUSIONS: Facial PWS commonly affect the orodental structures, and intraoral staining may predict future complications. PMID- 22226815 TI - Treatment of ruptured intra-cranial internal carotid artery dissection using a flow-diverter stent. AB - In the presence of associated subarachnoid hemorrhage, the treatment of arterial dissection can be classified as either deconstructive (involving occlusion or sacrifice of the parent vessel) or reconstructive (preserving blood-flow through the parent vessel). In both treatment strategies, the main goal is to prevent any further risk of rebleeding. However, reconstructive treatment is reserved only for those patients in whom occlusion of the parent vessel is not feasible due to an insufficient collateral supply. This report is of a case of intra-cranial carotid artery dissection treated by a reconstructive endovascular approach, with deployment of a flow-diverter stent, for the management of an associated subarachnoid hemorrhage. This is, to the authors' knowledge, the first report of the use of a flow-diverter device as the main treatment of a ruptured supraclinoid carotid artery dissection. PMID- 22226816 TI - The transforming growth factor-beta/bone morphogenetic protein signalling pathway in adipogenesis. AB - Rising obesity epidemic makes the better understanding of transcription factor networks regulating adipogenesis very challenging. Adipogenesis begins with the commitment of pluripotent mesenchymal stem cells to the adipocyte lineage, followed by terminal differentiation of preadipocytes to mature adipocytes. Among the molecules that influence the decision of progenitor cells to become adipocytes are members of transforming growth factor-beta superfamily and particularly bone morphogenetic proteins. Transforming growth factor-beta and bone morphogenetic proteins exert their biological functions mainly through their downstream molecules, the Smads. Here, we review the role(s) of transforming growth factor-beta/bone morphogenetic protein signalling pathway in adipocyte differentiation. Unravelling the precise mechanism of each molecule/pathway is necessary for developing suitable inhibitors or mimetic agents in order to treat obesity and improve insulin resistance. Current research efforts aim at discovering drugs that reduce fat mass or change the phenotype of adipose tissue into a more thermogenic one. PMID- 22226817 TI - A portrait of Transforming Growth Factor beta superfamily signalling: Background matters. AB - Ligands of the Transforming Growth Factor beta superfamily like Transforming Growth Factor beta and Bone Morphogenetic Proteins govern developmental processes and regulate adult homeostasis by controlling cellular proliferation, survival, differentiation and migration. Aberrant signalling activity is associated with human disorders such as cancer, cardiovascular, musculoskeletal, or fibrotic disease. Upon binding to specific sets of cognate cell surface receptors, family members induce highly similar pathways which include canonical SMAD dependent signalling as well as pathways without direct involvement of SMAD proteins, which activate signalling molecules like mitogen-activated protein kinases or small GTPases. The diverse ligand functionalities are achieved through regulation and modulation of the pathways at all levels, resulting in a highly quantitative and context sensitive signal integration reflecting the cellular state and background. Strategies to target Transforming Growth Factor beta or Bone Morphogenetic Protein pathways have been developed on the basis of our current understanding and have proven a highly beneficial potential. PMID- 22226818 TI - Freezing mammalian cells for production of biopharmaceuticals. AB - Cryopreservation techniques utilize very low temperatures to preserve the structure and function of living cells. Various strategies have been developed for freezing mammalian cells of biological and medical significance. This paper highlights the importance and application of cryopreservation for recombinant mammalian cells used in the biopharmaceutical industry to produce high-value protein therapeutics. It is a primer that aims to give insight into the basic principles of cell freezing for the benefit of biopharmaceutical researchers with limited or no prior experience in cryobiology. For the more familiar researchers, key cell banking parameters such as the cell density and hold conditions have been reviewed to possibly help optimize their specific cell freezing protocols. It is important to understand the mechanisms underlying the freezing of complex and sensitive cellular entities as we implement best practices around the techniques and strategies used for cryopreservation. PMID- 22226819 TI - Complete genome sequence and characterization of a broad-host range T4-like bacteriophage phiAS5 infecting Aeromonas salmonicida subsp. salmonicida. AB - In this study, we report one lytic Myoviridae bacteriophage (phage) infecting Aeromonas salmonicida subsp. salmonicida. The phage (named as phiAS5) was isolated from environmental river waters in Korea, and showed broad infectivity to other bacterial species in the family Aeromonadaceae as well as antibiotic resistant A. salmonicida subsp. salmonicida strains. The biological properties and complete genome of phiAS5 were simultaneously investigated. The complete genome of phiAS5 composed of linear double-stranded DNA of 225,268 bp with G+C content of 43.0%, and encoded 343 putative ORFs, 69 putative promoters, 33 transcriptional terminator regions and 24 tRNA-encoding genes. A high degree of similarity to other T4-like Aeromonas phage was found in most ORFs of phiAS5. Therefore, the genome of phiAS5 was further compared with T4 phage and the closest relative, Aeromonas phage Aeh1, and the result demonstrated that it could be classified as a new member of the T4-like group. The bacteriolytic activity of phiAS5 against A. salmonicida subsp. salmonicida was evaluated at different doses of multiplicity of infection using one each of virulent strain that possesses the ascV gene and multi-drug resistant strain, and the results proved to be efficient for the reduction of bacterial growth. Based on these results, phiAS5 may have the potential for reducing the impacts of virulent or antibiotic-resistant A. salmonicida subsp. salmonicida in aquaculture and may also advance our understanding of the biodiversity of T4-like Aeromonas phages. PMID- 22226821 TI - Cold tolerance of the Australian spur-throated locust, Austracris guttulosa. AB - The cold tolerance of overwintering adult Spur-throated locusts, Austracris guttulosa, was examined using measures of supercooling point relative to gender, environmental acclimation and feeding state as well as mortality for a range of sub-zero temperature exposure treatments. Freezing was lethal and supercooling points ranged from -6 to -12.8 degrees C, but were statistically independent of fresh mass, body water content, acclimation, and/or gut content in fed and starved individuals. A significant interaction effect of gender and feeding status showed that the larger bodied females had decreased supercooling capacity with increased food material in the digestive tract. Post-freezing dissections revealed differences in the amount of freshly consumed and retained food material in the digestive tract between fed and starved individuals of each gender, which could explain this effect based on inoculation of ice crystallisation by food particles. Above supercooling temperatures, neither gender nor the rate of cooling had a significant effect on mortality. When cooled from 25 degrees C at 0.1 or 0.5 degrees Cmin(-1) to a range of experimental minimum temperatures held for 3h, survival was ~74% to -7 degrees C, but declined sharply to ~37% when cooled to -8 degrees C or lower. Although the laboratory experiments reported here suggest that A. guttulosa is not freeze tolerant and unable to rapidly cold harden, exposure to typical cold and frosty nights that very rarely reach below 8 degrees C as a night minimum in the field would be unlikely to cause mortality in the vast majority of overwintering aggregations. PMID- 22226820 TI - Infectious agents associated with respiratory diseases in 125 farrow-to-finish pig herds: a cross-sectional study. AB - A study was carried out in 125 farrow-to-finish pig herds to assess the relationships between pathogens involved in respiratory disorders and to relate these findings to clinical signs of respiratory diseases and pneumonia and pleuritis at slaughter. Clinical examination and sampling were carried out on four different batches in each herd (pigs aged 4, 10, 16 and 22 weeks). Mycoplasma hyopneumoniae, Actinobacillus pleuropneumoniae, swine influenza viruses (SIV), porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) were detected by serological or PCR tests. Pneumonia-like gross lesions and pleuritis were scored at the slaughterhouse. The results indicate that the percentage of pigs PCR-positive for PCV2 at 4, 10 and 16 weeks old was associated with the percentage of pigs PCR-positive for M. hyopneumoniae at these ages. On the other hand, the percentage of pigs with antibodies against PRRSV at 10, 16 and 22 weeks was positively correlated with the percentage of pigs seropositive for M. hyopneumoniae at 22 weeks, with the percentage of pigs with antibodies against SIV H1N1 and SIV H1N2 and the percentage of pigs sero-positive for A. pleuropneumoniae serotype 2. The findings also indicate that, within the five studied pathogens, M. hyopneumoniae, PRRSV and SIV H1N1 are the major pathogens involved in pneumonia-like gross lesions even though PCV2 may play a role. A. pleuropneumoniae serotype 2, in association with PRRSV, is significantly associated with extensive pleuritis. Respiratory diseases could be significantly reduced by implementing measures including appropriate management practices to control these pathogens. PMID- 22226822 TI - Functional analysis of a fatty acid binding protein produced by Aphidius ervi teratocytes. AB - Aphidius ervi (Hymenoptera, Braconidae) is an endophagous parasitoid of various aphid species, including Acyrthosiphon pisum (Homoptera, Aphididae), the model host used in the present study. Parasitized hosts show a marked increase of their nutritional suitability for the developing parasitoid larvae. This alteration of the biochemical and metabolic profile is due to a castration process mediated by the combined action of the venom, injected at the oviposition, and of the teratocytes, cells deriving from the dissociation of the embryonic membrane. Teratocytes produce and release in the host haemocoel two parasitism-specific proteins, which are of crucial importance for the development of their sister larvae. One of the proteins is a fatty acid binding protein (Ae-FABP), which shows a high affinity for C14-C18 saturated fatty acids (FAs) and for oleic and arachidonic acids. To better define the possible nutritional role of this protein, we have studied its immunolocalization profile in vivo and the impact on FA uptake by the epidermal and midgut epithelia of A. ervi larvae. During the exponential growth of A. ervi larvae, Ae-FABP is distributed around discrete lipid particles, which are abundantly present in the haemocoel of parasitized host aphids and in the midgut lumen of parasitoid larvae. Moreover, a strong immunodetection signal is evident on the surface of the two larval epithelia involved in nutrient absorption: the parasitoid midgut epithelium and the external epidermal layer. These two epithelia can effectively absorb radiolabelled myristic acid, but the FA transport rates are not affected by the presence in the medium of Ae-FABP. The protein appears to act essentially as a vector in the host haemolymph, transferring FAs from the digestion sites of host lipids to the growing parasitoid larvae. These data indicate that the proteins produced by A. ervi teratocytes may play complementary roles in the nutritional exploitation of the host. PMID- 22226823 TI - Saliva of Lygus lineolaris digests double stranded ribonucleic acids. AB - The prospects for development of highly specific pesticides based on double stranded ribonucleic acid have been a recent focus of scientific research. Creative applications have been proposed and demonstrated. However, not all insects are sensitive to double stranded RNA (dsRNA) gene knockdown effects; applications in the order Lepidoptera, for example, have met with varied success. Gene knockdown has been demonstrated in several species in the order Hemiptera. In our laboratory, knockdown experiments relied on microinjection of dsRNA into the hemocoel of the tarnished plant bug, Lygus lineolaris. Subsequent experiments delivering dsRNA to insects by feeding were repeatedly unsuccessful in demonstrating knockdown, and a hypothesis was formulated that the dsRNA was digested and degraded by the insect prior to contact with the insect cells. Exposure of dsRNA to insect saliva, insect salivary glands, and insect hemolymph was compared with commercial RNAase III. The saliva of L. lineolaris was found to rapidly digest double stranded RNA. RNAase inhibitor did not affect the activity but heat treatment slowed enzymatic activity. PMID- 22226825 TI - Complete response after sequential sunitinib-sorafenib treatment in a patient with renal cell carcinoma: a case report. PMID- 22226826 TI - [Idiopathic short stature]. PMID- 22226824 TI - Molecular and functional characterization of the ceramide synthase from Trypanosoma cruzi. AB - In this study, we characterized ceramide synthase (CerS) of the protozoan parasite Trypanosoma cruzi at the molecular and functional levels. TcCerS activity was detected initially in a cell-free system using the microsomal fraction of epimastigote forms of T. cruzi, [(3)H]dihydrosphingosine or [(3)H]sphingosine, and fatty acids or acyl-CoA derivatives as acceptor or donor substrates, respectively. TcCerS utilizes both sphingoid long-chain bases, and its activity is exclusively dependent on acyl-CoAs, with palmitoyl-CoA being preferred. In addition, Fumonisin B(1), a broad and well-known acyl-CoA-dependent CerS inhibitor, blocked the parasite's CerS activity. However, unlike observations in fungi, the CerS inhibitors Australifungin and Fumonisin B(1) did not affect the proliferation of epimastigotes in culture, even after exposure to high concentrations or after extended periods of treatment. A search of the parasite genome with the conserved Lag1 motif from Lag1p, the yeast acyl-CoA dependent CerS, identified a T. cruzi candidate gene (TcCERS1) that putatively encodes the parasite's CerS activity. The TcCERS1 gene was able to functionally complement the lethality of a lag1Delta lac1Delta double deletion yeast mutant in which the acyl-CoA-dependent CerS is not detectable. The complemented strain was capable of synthesizing normal inositol-containing sphingolipids and is 10 times more sensitive to Fumonisin B(1) than the parental strain. PMID- 22226827 TI - [Assessment of parental satisfaction in a neonatal unit]. AB - INTRODUCTION: Parental satisfaction in a neonatal unit needs to be checked as a quality element in health care. OBJECTIVES: 1/To measure how the severity of the newborn condition influences parental satisfaction. 2/To compare the results before and after moving to a new building. METHODS: Parental satisfaction in 87 of the newborns admitted to our neonatal unit over a 10 month period was documented using a questionnaire survey. The newborns were divided into 2 categories, depending on the severity of their condition. Parental satisfaction as regards human and environmental issues was checked as to whether it was affected by the severity of the illness. The impact of the move to a new building on satisfaction was also analysed. Statistical descriptive studies and multivariate models were used. RESULTS: A polarised tendency was seen between human and environmental aspects. The following issues were statistically significant: visiting hours for parents, and criticisms about furniture, light and physical space. Parents of seriously ill children appreciated the visiting hours but judged the environment negatively. Pain perception in procedures was higher in serious illnesses, and 66% of parents would rather be present during those procedures. When comparing both hospitals, the only significant value regarding the new centre, was the lower perception of information given by the staff. Breastfeeding improved significantly. General satisfaction was high. CONCLUSIONS: Parents of seriously ill newborns are mainly concerned about access hours and comfort. Parent visiting hours and lack of noise and light are significant parameters predicting satisfaction in children with long stays. Perception of access to information got worse in the new hospital, probably due to lack of staff adaptation. PMID- 22226828 TI - Metabolic syndrome and mitochondrial dysfunction: insights from preclinical studies with a mitochondrially targeted antioxidant. PMID- 22226829 TI - The antioxidant and anti-inflammatory activities of tocopherols are independent of Nrf2 in mice. AB - The present study investigated the antioxidant and anti-inflammatory actions of tocopherols in mice and determined whether the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is involved in these activities. A mixture of tocopherols (gamma TmT) that is rich in gamma-tocopherol was used. Nrf2 knockout (Nrf2 -/-) and wild type mice were maintained on 0.03, 0.1, or 0.3% gamma-TmT-enriched diet starting 2 weeks before the administration of dextran sulfate sodium (DSS) in drinking water (for 1 week, to induce colonic inflammation), until the termination of the experiment at 3 days after the DSS treatment. Dietary gamma-TmT dose dependently lowered the levels of 8-oxo-deoxyguanosine, nitrotyrosine, inflammation index, and leukocyte infiltration in colon tissues, as well as 8-isoprostane and prostaglandin E2 in the serum, in both Nrf2 (-/-) and wild-type mice. No significant difference on the inhibitory actions of gamma-TmT between the Nrf2 ( /-) and the wild-type mice was observed. The gamma-TmT treatment significantly increased the serum levels of gamma- and delta-tocopherols. Interestingly, the serum levels of tocopherol metabolites, specifically the gamma- and delta-forms of carboxymethylbutyl hydroxychroman and carboxyethyl hydroxychroman, in Nrf2 (-/ ) mice were significantly higher than those in wild-type mice. These findings suggest that the antioxidant and anti-inflammatory activities of gamma-TmT in the colon are mostly due to the direct action of tocopherols in trapping reactive oxygen and nitrogen species, independent of the antioxidant enzymes and anti inflammatory proteins that are regulated by Nrf2; however, Nrf2 knockout appears to affect the serum levels of tocopherol metabolites. PMID- 22226830 TI - Apaf-1 deficiency confers resistance to ultraviolet-induced apoptosis in mouse embryonic fibroblasts by disrupting reactive oxygen species amplification production and mitochondrial pathway. AB - Apoptosis requires tightly regulated cell death pathways. The signaling pathways that trigger a cell to undergo apoptosis after UV radiation are cell type specific and are currently being defined. Here, we have used pharmacological and genetic tools to demonstrate the decisive part of the mitochondrial pathway in UVC-induced apoptosis in mouse embryo fibroblasts (MEFs). UVC-induced apoptosis proceeded independent of the activation of death receptor components. In contrast, soon after UV radiation, MAPK activation and generation of reactive oxygen species (ROS) increased, followed by a decline in mitochondrial membrane potential (MMP) and cytochrome c release, as well as activation of caspase-9 and 3 and the upregulation of p47-phox. Deficiency of apaf-1, a critical member of the apoptosome, dramatically abolished all the UV-induced signal deterioration and cell death. In parallel, UVC-induced apoptosis was largely attenuated by either DN-caspase-9 or Bcl-X(L) overexpression. Pretreatment of cells with N acetylcysteine or catalase but not Tempol decreased UVC-induced MAPK activation and apoptosis. Inhibition of JNK and caspase attenuated p47-phox upregulation. Altogether, we have for the first time demonstrated the critical role of Apaf-1 in the regulation of MAPK, ROS, and MMP in UVC-radiated MEFs and propose that the amplification feedback loop among mitochondrial signal molecules culminates in the demise of the cell. PMID- 22226831 TI - Exploring real-time in vivo redox biology of developing and aging Caenorhabditis elegans. AB - Reactive oxygen species (ROS) are no longer considered merely toxic by-products of the oxidative metabolism. Tightly controlled concentrations of ROS and fluctuations in redox potential may be important mediators of signaling processes. Understanding the role of ROS and redox status in physiology, stress response, development, and aging requires their nondisruptive, spatiotemporal, real-time quantification in a living organism. We established Caenorhabditis elegans strains bearing the genetically encoded fluorescent biosensors HyPer and Grx1-roGFP2 for the detection of hydrogen peroxide (H(2)O(2)) and the glutathione redox potential, respectively. Although, given its transparency and genetic tractability, C. elegans is perfectly suitable as a model organism for such approaches, they have never been tried before in this nematode. We found that H(2)O(2) treatment clearly induces a dose-dependent, reversible response of both biosensors in the living worms. The ratio of oxidized to reduced glutathione decreases during postembryonic development. H(2)O(2) levels increase with age and this effect is delayed when life span is extended by dietary restriction. In young adults, we detected several regions with distinct redox properties that may be linked to their biological function. Our findings demonstrate that genetically encoded biosensors can reveal previously unknown details of in vivo redox biology in multicellular organisms. PMID- 22226833 TI - Predictive parameters for a diagnostic bone marrow biopsy specimen in the work-up of fever of unknown origin. AB - OBJECTIVE: To determine the role of bone marrow biopsy (BMBX), performed in association with comprehensive blood and imaging tests, in the evaluation of patients with fever of unknown origin (FUO). PATIENTS AND METHODS: We reviewed the medical records of 475 hospitalized patients who underwent BMBX in our medical center from January 1, 2005, to April 30, 2010. We identified 75 patients who fulfilled the accepted classic Petersdorf criteria for FUO. All patients underwent in-hospital investigation for fever, including chest and abdominal computed tomography. RESULTS: In 20 patients (26.7%), BMBX established the final diagnosis. Sixteen patients had hematologic disorders, including 8 patients with non-Hodgkin lymphoma, 2 with acute leukemia, 1 with multiple myeloma, 1 with myelodysplastic syndrome, and 4 with myeloproliferative disorders. The remaining patients with diagnostic BMBX specimens had solid tumors (2 patients), granulomatous disease (1 patient), and hemophagocytic syndrome (1 patient). Multivariate analysis revealed the following as the significant positive predictive parameters for a diagnostic BMBX specimen: male sex (odds ratio [OR], 7.35; 95% confidence interval [CI], 1.19-45.45), clinical lymphadenopathy (OR, 21.98; 95% CI, 1.97-245.66), anemia (OR, 2.21; 95% CI, 1.28-3.80), and increased lactate dehydrogenase levels (OR, 1.003; 95% CI, 1.001-1.006). CONCLUSION: Bone marrow biopsy is still a useful ancillary procedure for establishing the diagnosis of FUO, particularly if used in the appropriate clinical setting. Clinical and laboratory parameters associated with hematologic disease are predictive of a diagnostic BMBX specimen in patients with FUO. PMID- 22226832 TI - Histone deacetylase inhibition activates transcription factor Nrf2 and protects against cerebral ischemic damage. AB - Interest in histone deacetylase (HDAC)-based therapeutics as a potential treatment for stroke has grown dramatically. The neuroprotection of HDAC inhibition may involve multiple mechanisms, including modulation of transcription factor acetylation independent of histones. The transcription factor Nrf2 has been shown to be protective in stroke as a key regulator of antioxidant responsive genes. Here, we hypothesized that HDAC inhibition might provide neuroprotection against mouse cerebral ischemia by activating the Nrf2 pathway. We determined that the classic HDAC inhibitor trichostatin A increased neuronal cell viability after oxygen-glucose deprivation (from an OD value of 0.10+/-0.01 to 0.25+/-0.08) and reduced infarct volume in wild-type mice with stroke (from 49.1+/-3.8 to 21.3+/-4.6%). In vitro studies showed that HDAC inhibition reduced Nrf2 suppressor Keap1 expression, induced Keap1/Nrf2 dissociation, Nrf2 nuclear translocation, and Nrf2 binding to antioxidant response elements in heme oxygenase 1 (HO1), and caused HO1 transcription. Furthermore, we demonstrated that HDAC inhibition upregulated proteins downstream of Nrf2, including HO1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase catalytic subunit in neuron cultures and brain tissue. Finally, unlike wild-type mice, Nrf2 deficient mice were not protected by pharmacologic inhibition of HDAC after cerebral ischemia. Our studies suggest that activation of Nrf2 might be an important mechanism by which HDAC inhibition provides neuroprotection. PMID- 22226834 TI - Glutathione biosynthesis in bacteria by bifunctional GshF is driven by a modular structure featuring a novel hybrid ATP-grasp fold. AB - Glutathione is an intracellular redox-active tripeptide thiol with a central role in cellular physiology across all kingdoms of life. Glutathione biosynthesis has been traditionally viewed as a conserved process relying on the sequential activity of two separate ligases, but recently, an enzyme (GshF) that unifies both necessary reactions in one platform has been identified and characterized in a number of pathogenic and free-living bacteria. Here, we report crystal structures of two prototypic GshF enzymes from Streptococcus agalactiae and Pasteurella multocida in an effort to shed light onto the structural determinants underlying their bifunctionality and to provide a structural framework for the plethora of biochemical and mutagenesis studies available for these enzymes. Our structures reveal how a canonical bacterial GshA module that catalyzes the condensation of L-glutamate and L-cysteine to gamma-glutamylcysteine is linked to a novel ATP-grasp-like module responsible for the ensuing formation of glutathione from gamma-glutamylcysteine and glycine. Notably, we identify an unprecedented subdomain in the ATP-grasp module of GshF at the interface of the GshF dimer, which is poised to mediate intersubunit communication and allosteric regulation of enzymatic activity. Comparison of the two GshF structures and mapping of structure-function relationships reveal that the bifunctional GshF structural platform operates as a dynamic dimeric assembly. PMID- 22226835 TI - N-terminal segments modulate the alpha-helical propensities of the intrinsically disordered basic regions of bZIP proteins. AB - Basic region leucine zippers (bZIPs) are modular transcription factors that play key roles in eukaryotic gene regulation. The basic regions of bZIPs (bZIP-bRs) are necessary and sufficient for DNA binding and specificity. Bioinformatic predictions and spectroscopic studies suggest that unbound monomeric bZIP-bRs are uniformly disordered as isolated domains. Here, we test this assumption through a comparative characterization of conformational ensembles for 15 different bZIP bRs using a combination of atomistic simulations and circular dichroism measurements. We find that bZIP-bRs have quantifiable preferences for alpha helical conformations in their unbound monomeric forms. This helicity varies from one bZIP-bR to another despite a significant sequence similarity of the DNA binding motifs (DBMs). Our analysis reveals that intramolecular interactions between DBMs and eight-residue segments directly N-terminal to DBMs are the primary modulators of bZIP-bR helicities. We test the accuracy of this inference by designing chimeras of bZIP-bRs to have either increased or decreased overall helicities. Our results yield quantitative insights regarding the relationship between sequence and the degree of intrinsic disorder within bZIP-bRs, and might have general implications for other intrinsically disordered proteins. Understanding how natural sequence variations lead to modulation of disorder is likely to be important for understanding the evolution of specificity in molecular recognition through intrinsically disordered regions (IDRs). PMID- 22226836 TI - Conformational properties of the unfolded state of Im7 in nondenaturing conditions. AB - The unfolded ensemble in aqueous solution represents the starting point of protein folding. Characterisation of this species is often difficult since the native state is usually predominantly populated at equilibrium. Previous work has shown that the four-helix protein, Im7 (immunity protein 7), folds via an on pathway intermediate. While the transition states and folding intermediate have been characterised in atomistic detail, knowledge of the unfolded ensemble under the same ambient conditions remained sparse. Here, we introduce destabilising amino acid substitutions into the sequence of Im7, such that the unfolded state becomes predominantly populated at equilibrium in the absence of denaturant. Using far- and near-UV CD, fluorescence, urea titration and heteronuclear NMR experiments, we show that three amino acid substitutions (L18A-L19A-L37A) are sufficient to prevent Im7 folding, such that the unfolded state is predominantly populated at equilibrium. Using measurement of chemical shifts, (15)N transverse relaxation rates and sedimentation coefficients, we show that the unfolded species of L18A-L19A-L37A deviates significantly from random-coil behaviour. Specifically, we demonstrate that this unfolded species is compact (R(h)=25 A) relative to the urea-denatured state (R(h)>=30 A) and contains local clusters of hydrophobic residues in regions that correspond to the four helices in the native state. Despite these interactions, there is no evidence for long-range stabilising tertiary interactions or persistent helical structure. The results reveal an unfolded ensemble that is conformationally restricted in regions of the polypeptide chain that ultimately form helices I, II and IV in the native state. PMID- 22226837 TI - Alternative relay and converter domains tune native muscle myosin isoform function in Drosophila. AB - Myosin isoforms help define muscle-specific contractile and structural properties. Alternative splicing of myosin heavy chain gene transcripts in Drosophila melanogaster yields muscle-specific isoforms and highlights alternative domains that fine-tune myosin function. To gain insight into how native myosin is tuned, we expressed three embryonic myosin isoforms in indirect flight muscles lacking endogenous myosin. These isoforms differ in their relay and/or converter domains. We analyzed isoform-specific ATPase activities, in vitro actin motility and myofibril structure/stability. We find that dorsal acute body wall muscle myosin (EMB-9c11d) shows a significant increase in MgATPase V(max) and actin sliding velocity, as well as abnormal myofibril assembly compared to cardioblast myosin (EMB-11d). These properties differ as a result of alternative exon-9-encoded relay domains that are hypothesized to communicate signals among the ATP-binding pocket, actin-binding site and the converter domain. Further, EMB-11d shows significantly reduced levels of basal Ca- and MgATPase as well as MgATPase V(max) compared to embryonic body wall muscle isoform (EMB) (expressed in a multitude of body wall muscles). EMB-11d also induces increased actin sliding velocity and stabilizes myofibril structure compared to EMB. These differences arise from exon-11-encoded alternative converter domains that are proposed to reposition the lever arm during the power and recovery strokes. We conclude that relay and converter domains of native myosin isoforms fine-tune ATPase activity, actin motility and muscle ultrastructure. This verifies and extends previous studies with chimeric molecules and indicates that interactions of the relay and converter during the contractile cycle are key to myosin-isoform-specific kinetic and mechanical functions. PMID- 22226838 TI - The carboxy-terminal third of dystrophin enhances actin binding activity. AB - Dystrophin is an actin binding protein that is thought to stabilize the cardiac and skeletal muscle cell membranes during contraction. Here, we investigated the contributions of each dystrophin domain to actin binding function. Cosedimentation assays and pyrene-actin fluorescence experiments confirmed that a fragment spanning two-thirds of the dystrophin molecule [from N-terminal actin binding domain (ABD) 1 through ABD2] bound actin filaments with high affinity and protected filaments from forced depolymerization, but was less effective in both assays than full-length dystrophin. While a construct encoding the C-terminal third of dystrophin displayed no specific actin binding activity or competition with full-length dystrophin, our data show that it confers an unexpected regulation of actin binding by the N-terminal two-thirds of dystrophin when present in cis. Time-resolved phosphorescence anisotropy experiments demonstrated that the presence of the C-terminal third of dystrophin in cis also influences actin interaction by restricting actin rotational amplitude. We propose that the C-terminal region of dystrophin allosterically stabilizes an optimal actin binding conformation of dystrophin. PMID- 22226839 TI - Crystal structure and regulation mechanisms of the CyaB adenylyl cyclase from the human pathogen Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is an opportunistic bacterial pathogen and a major cause of healthcare-associated infections. While the organism's intrinsic and acquired resistance to most antibiotics hinders treatment of P. aeruginosa infections, the regulatory networks controlling its virulence provide novel targets for drug development. CyaB, a key regulator of P. aeruginosa virulence, belongs to the Class III adenylyl cyclase (AC) family of enzymes that synthesize the second messenger cyclic adenosine 3',5'-monophosphate. These enzymes consist of a conserved catalytic domain fused to one or more regulatory domains. We describe here the biochemical and structural characterization of CyaB and its inhibition by small molecules. We show that CyaB belongs to the Class IIIb subfamily, and like other subfamily members, its activity is stimulated by inorganic carbon. CyaB is also regulated by its N-terminal MASE2 (membrane-associated sensor 2) domain, which acts as a membrane anchor. Using a genetic screen, we identified activating mutations in CyaB. By solving the crystal structure of the CyaB catalytic domain, we rationalized the effects of these mutations and propose that CyaB employs regulatory mechanisms similar to other Class III ACs. The CyaB structure further indicates subtle differences compared to other Class III ACs in both the active site and the inhibitor binding pocket. Consistent with these differences, we observed a unique inhibition profile, including identification of a CyaB selective compound. Overall, our results reveal mechanistic details of the physiological and pharmacological regulation of CyaB and provide the basis for its exploitation as a therapeutic drug target. PMID- 22226840 TI - Clinical course of myelin oligodendrocyte glycoprotein 35-55 induced experimental autoimmune encephalomyelitis is aggravated by glia maturation factor. AB - The role of glia maturation factor (GMF) in myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide-induced experimental autoimmune encephalomyelitis (EAE) was investigated using GMF-deficient (GMF-KO) mice. We demonstrate that GMF-KO mice were resistant to the MOG 35-55 peptide-induced EAE as compared to wild type (Wt) mice (two in eight versus 10 in 10). Next, we examined the effect of administration of recombinant human GMF (rGMF) on MOG 35-55 peptide-induced EAE in mice. Daily administration of rGMF, staring days 1-14, resulted in significant exacerbation of clinical symptoms. Following rGMF injections, both GMF-KO (six in eight) and Wt mice (eight in eight) developed severe EAE (maximal clinical score of 3.5-4.0) with high frequency. The histological examination revealed severe infiltration of inflammatory cells in the spinal cord of MOG-immunized Wt mice while the resistance to EAE in GMF-KO mice was characterized by the absence of inflammatory cells. Administration of rGMF in Wt mice and GMF-KO mice resulted in a significant increase in infiltrating cells in the spinal cord following MOG immunizations. We also evaluated cytokines and chemokines production as parameters of severity of inflammation in the spinal cord of Wt versus GMF-KO mice with and without GMF-reconstitution following MOG-immunizations. Cytokines (TNF-alpha, IFN-gamma, IL-1beta, IL-6) and chemokines (CCL2, CCL3, CXCL10, GM CSF) production were significantly greater in Wt mice than in GMF-KO mice following MOG-immunization. Furthermore, the reconstitution experiment with rGMF showed that the administration of rGMF in both, Wt mice and GMF-KO mice produced significant increase in the GMF-mediated cytokine/chemokine production. PMID- 22226841 TI - CDP-choline treatment induces brain plasticity markers expression in experimental animal stroke. AB - We investigated the effect of CDP-choline on brain plasticity markers expression in the acute phase of cerebral infarct in an experimental animal model. Male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (pMCAO) and treated or not with CDP-choline (500 mg/kg) daily for 14 days starting 30 min after pMCAO. Functional status was evaluated with Roger's test; lesion volume with magnetic resonance imaging (MRI) and hematoxylin and eosin staining (H&E); cell death with TUNEL; cellular proliferation with BrdU immunohistochemistry; vascular endothelial growth factor (VEGF), synaptophysin, glial fibrillary acidic protein (GFAP) and low-density lipoprotein receptor related protein (LRP) by immunofluorescence and Western-blot techniques. CDP choline significantly improved functional recovery and decreased lesion volume on MRI, TUNEL-positive cell number and LRP levels at 14 days. In addition, CDP choline significantly increased BrdU, VEGF and synaptophysin values and decreased GFAP levels in the peri-infarct zone compared with the infarct group. In conclusion, our data indicate that CDP-choline improved functional recovery after permanent middle cerebral artery occlusion in association with reductions in lesion volume, cell death and LRP expression. In fact, CDP-choline increased cell proliferation, vasculogenesis and synaptophysin levels and reduced GFAP levels in the peri-infarct area of the ischemic stroke. PMID- 22226842 TI - Tau protein is involved in morphological plasticity in hippocampal neurons in response to BDNF. AB - Tau protein, a microtubule-associated protein involved in a number of neurological disorders such as Alzheimer's disease (AD), may undergo modifications under both physiological and pathological conditions. However, the signaling pathways that couple tau protein to neuronal physiology such as synaptic plasticity have not yet been elucidated. Here we report that tau protein is involved in morphological plasticity in response to brain derived neurotrophic factor (BDNF). Stimulation of the cultured rat hippocampal neurons with BDNF resulted in increased tau protein expression, as detected by Western blotting. Furthermore, tau protein accumulated in the distal region of the neurite when treated with taxol or taxol plus BDNF. The increased tau protein also protected neurons against nocodazole-induced dendrite loss. Moreover, BDNF promoted spine growth as well as tau protein over-expression. Knockdown of tau protein using specific short-hairpin RNA (shRNA) significantly decreased the spine density. And BDNF could not increase the spine density of tau-knockdown neurons. These results highlight a possible role for tau protein in the dynamic rearrangement of cytoskeletal fibers vital for BDNF-induced synaptic plasticity. PMID- 22226844 TI - Copper export from cultured astrocytes. AB - Copper is an essential trace metal that is required as a catalytic co-factor or a structural component of several important enzymes. However, since excess of copper can also harm cells due to its potential to catalyse the generation of toxic reactive oxygen species, transport of copper and the cellular copper content are tightly regulated. Astrocytes are known to efficiently take up copper ions, but it was not known whether these cells are also able to export copper. Treatment of astrocyte-rich primary cultures for 24 h with copper chloride caused a concentration-dependent increase in the specific cellular copper content. During further 24 h incubation in the absence of copper chloride, the copper loaded astrocytes remained viable and released up to 45% of the accumulated copper. The rate of copper export was proportional to the amount of cellular copper, was almost completely prevented by lowering the incubation temperature to 4 degrees C and was partly prevented by the endocytosis inhibitor amiloride. Copper export is most likely mediated by the copper ATPase ATP7A, since this transporter is expressed in astrocyte cultures and its cellular location is strongly affected by the absence or the presence of extracellular copper. The potential of cultured astrocytes to export copper suggests that astrocytes provide neighbouring cells in brain with this essential trace element. PMID- 22226843 TI - Inhibition of Rho kinase by hydroxyfasudil attenuates brain edema after subarachnoid hemorrhage in rats. AB - The blood-brain barrier (BBB) disruption and brain edema are important pathophysiologies of early brain injury after subarachnoid hemorrhage (SAH). This study is to evaluate whether Rho kinase (Rock) enhances BBB permeability via disruption of tight junction proteins during early brain injury. Adult male rats were assigned to five groups; Sham-operated, SAH treated with saline, a Rock inhibitor hydroxyfasudil (HF) (10 mg/kg) treatment at 0.5 h after SAH, HF treatment at 0.5 and 6 h (10 mg/kg, each) after SAH, and another Rock inhibitor Y27632 (10 mg/kg) treatment at 0.5 h after SAH. The perforation model of SAH was performed and neurological score and brain water content were evaluated 24 and 72 h after surgery. Evans blue extravasation, Rock activity assay, and western blotting analyses were evaluated 24 h after surgery. Treatment of HF significantly improved neurological scores 24 h after SAH. Single treatment with HF and Y27632, and two treatments with HF reduced brain water content in the ipsilateral hemisphere. HF reduced Evans blue extravasation in the ipsilateral hemisphere after SAH. Rock activity increased 24 h after SAH, and HF reversed the activity. SAH significantly decreased the levels of tight junction proteins, occludin and zonula occludens-1 (ZO-1), and HF preserved the levels of occluding and ZO-1 in ipsilateral hemisphere. In conclusion, HF attenuated BBB permeability after SAH, possibly by protection of tight junction proteins. PMID- 22226845 TI - Limb salvage for spreading midfoot osteomyelitis following diabetic foot surgery. AB - Osteomyelitis is a challenging problem when it appears in the feet of patients with diabetes. Although the most frequent port of entry for bacteria is an ulcer, surgical wounds also permit entry of bacteria into the foot. This surgical complication may become limb-threatening, and treatment is a challenge. Here we present two cases of patients with neuropathic feet and palpable distal pulses, who were previously treated with surgery, and who presented with spreading bone infection in the midfoot. Pictures and radiological studies are shown. In both cases, bone infection caused severe destruction of the architecture of the midfoot, and the limbs of both patients were threatened. Midfoot osteomyelitis is associated with a higher rate of major amputations than osteomyelitis of the forefoot. Furthermore, meticillin-resistant Staphylococcus aureus was isolated in one of the cases. Our successful limb salvage approach was based on three steps: 1) removing the infected bone; 2) culture-guided antibiotic treatment; and 3) stabilizing the infected foot by means of total contact casting with openings resulting in a stable foot. To the best of our knowledge, there are no reports of the use of a total contact cast to stabilize an unstable and infected foot. Eight years (Case 1) and four years (Case 2) after complete healing, there were no recurrences of infection. PMID- 22226846 TI - Structure and function of OprD protein in Pseudomonas aeruginosa: from antibiotic resistance to novel therapies. AB - Pseudomonas aeruginosa (P. aeruginosa) is a common pathogen isolated from patients with nosocomial infections. Due to its intrinsic and acquired antimicrobial resistance, limited classes of antibiotics can be used for the treatment of infection with P. aeruginosa. Of these, the carbapenems are very important; however, the occurrence of carbapenem-resistant strains is gradually increasing over time. Deficiency of the outer membrane protein OprD confers P. aeruginosa a basal level of resistance to carbapenems, especially to imipenem. Functional studies have revealed that loops 2 and 3 in the OprD protein contain the entrance and/or binding sites for imipenem. Therefore, any mutation in loop 2 and/or loop 3 that causes conformational changes could result in carbapenem resistance. OprD is also a common channel for some amino acids and peptides, and competition with carbapenems through the channel may also occur. Furthermore, OprD is a highly regulated protein at transcriptional and post-transcriptional levels by some metals, small bioactive molecules, amino acids, and efflux pump regulators. Because of its hypermutability and highly regulated properties, OprD is thought to be the most prevalent mechanism for carbapenem resistance in P. aeruginosa. Developing new strategies to combat infection with carbapenem resistant P. aeruginosa lacking OprD is an ongoing challenge. PMID- 22226847 TI - Control of pH responsive peptide self-association during endocytosis is required for effective gene transfer. AB - Cationic amphipathic histidine rich peptides demonstrate differential nucleic acid binding capabilities at neutral and acidic pH and adopt conformations at acidic pH that enable interaction with endosomal membranes, their subsequent disordering and facilitate entry of cargo to the cell cytosol. To better understand the relative contributions of each stage in the process and consequently the structural requirements of pH responsive peptides for optimal nucleic acid transfer, we used biophysical methods to dissect the series of events that occur during endosomal acidification. Far-UV circular dichroism was used to characterise the solution conformation of a series of peptides, containing either four or six histidine residues, designed to respond at differing pH while a novel application of near-UV circular dichroism was used to determine the binding affinities of the peptides for both DNA and siRNA. The peptide induced disordering of neutral and anionic membranes was investigated using (2)H solid-state NMR. While each of these parameters models key stages in the nucleic acid delivery process and all were affected by increasing the histidine content of the peptide, the effect of a more acidic pH response on peptide self-association was most notable and identified as the most important barrier to further enhancing nucleic acid delivery. Further, the results indicate that Coulombic interactions between the histidine residues modulate protonation and subsequent conformational transitions required for peptide mediated gene transfer activity and are an important factor to consider in future peptide design. PMID- 22226848 TI - Transmembrane and extramembrane contributions to membrane protein thermal stability: studies with the NaChBac sodium channel. AB - The thermal stabilities of the extramembranous and transmembranous regions of the bacterial voltage-gated sodium channel NaChBac have been characterised using thermal-melt synchrotron radiation circular dichroism (SRCD) spectroscopy. A series of constructs, ranging from the full-length protein containing both the C terminal cytoplasmic and the transmembranous domains, to proteins with decreasing amounts of the cytoplasmic domain, were examined in order to separately define the roles of these two types of domains in the stability and processes of unfolding of a membrane protein. The sensitivity of the SRCD measurements over a wide range of wavelengths and temperatures has meant that subtle but reproducible conformational changes could be detected with accuracy. The residues in the C terminal extramembranous domain were highly susceptible to thermal denaturation, but for the most part the transmembrane residues were not thermally-labile and retained their helical character even at very elevated temperatures. The process of thermal unfolding involved an initial irreversible unfolding of the highly labile distal extramembranous C-terminal helical region, which was accompanied by a reversible unfolding of a small number of helical residues in the transmembrane domain. This was then followed by the irreversible unfolding of a limited number of additional transmembrane helical residues at greatly elevated temperatures. Hence this study has been able to determine the different contributions and roles of the transmembrane and extramembrane residues in the processes of thermal denaturation of this multipass integral membrane protein. PMID- 22226849 TI - Reconstitution of integral membrane proteins into isotropic bicelles with improved sample stability and expanded lipid composition profile. AB - Reconstitution of integral membrane proteins into membrane mimetic environments suitable for biophysical and structural studies has long been a challenge. Isotropic bicelles promise the best of both worlds-keeping a membrane protein surrounded by a small patch of bilayer-forming lipids while remaining small enough to tumble isotropically and yield good solution NMR spectra. However, traditional methods for the reconstitution of membrane proteins into isotropic bicelles expose the proteins to potentially destabilizing environments. Reconstituting the protein into liposomes and then adding short-chain lipid to this mixture produces bicelle samples while minimizing protein exposure to unfavorable environments. The result is higher yield of protein reconstituted into bicelles and improved long-term stability, homogeneity, and sample-to-sample reproducibility. This suggests better preservation of protein structure during the reconstitution procedure and leads to decreased cost per sample, production of fewer samples, and reduction of the NMR time needed to collect a high quality spectrum. Furthermore, this approach enabled reconstitution of protein into isotropic bicelles with a wider range of lipid compositions. These results are demonstrated with the small multidrug resistance transporter EmrE, a protein known to be highly sensitive to its environment. PMID- 22226850 TI - Usability of QTc dispersion for the prediction of orthostatic intolerance syndromes. AB - BACKGROUND: Syncope is defined as transient loss of consciousness and muscle tone, usually of short duration. Noncardiac causes of syncope are classified as orthostatic intolerance syndromes (OIS). QT and QTc (corrected QT) dispersions are the measurements of myocardial instability and show predisposition to arrhythmias. In this study; clinical findings, QT and QTc dispersions of the patients who were diagnosed as OIS were evaluated retrospectively. Also, the aim of the study is to clarify the association of clinical characteristics of unexplained syncope with the outcome of the QT and QTc dispersions in children. METHODS: We designed a retrospective study including 152 children and adolescents who had repeated unexplained syncope or presyncope between June 2002 and August 2010. Head-up Tilt table test (HUTT) were performed for all patients. Control group consisted of 67 healthy children. The QT and QTc dispersions were measured from the 12 ECG leads. RESULTS: Eighty-four (55.2%) patients had positive and 68 (44.8%) had negative response to HUTT. QT and QTc dispersions were significantly higher in HUTT-positive group than in negative (p < 0.01, p < 0.001 respectively). Also, QTc dispersion was significantly higher in both vasovagal syncope and postural orthostatic tachycardia syndrome groups than in HUTT negative group (p < 0.001, p < 0.05 respectively). Specifity and sensitivity of QTc dispersion for predicting positive HUTT are 76.5% and 59.5% respectively. The positive predictive value of the test calculated as 75.8%. CONCLUSIONS: These results revealed that we can use QTc dispersion measurement as a noninvasive electrocardiographic test to evaluate OIS for predicting positive result before performing HUTT. PMID- 22226851 TI - The relationship between the increased frequency of serum antineuronal antibodies and the severity of autism in children. AB - BACKGROUND: Autism may involve an autoimmune pathogenesis. Immunotherapy may have a role in autistic children who have brain auto-antibodies. AIM: This study aimed to investigate the frequency of serum antineuronal auto-antibodies, as indicators of the presence of autoimmunity to brain, in a group of autistic children. We are the first to measure the relationship between these antibodies and the degree of the severity of autism. METHODS: Serum antineuronal antibodies were measured, by indirect immunofluorescence technique, in 80 autistic children, aged between 6 and 12 years, in comparison to 80 healthy-matched children. The severity of autism was assessed by using the Childhood Autism Rating Scale. RESULTS: Autistic children had significantly higher percent positivity of serum antineuronal antibodies (62.5%) than healthy controls (5%), P<0.001. The frequency of the positivity of serum antineuronal antibodies was significantly higher in children with severe autism (87.5%) than children with mild to moderate autism (25%), P<0.001. Similarly, the frequency of the positivity of these antibodies was significantly higher in female children with autism (90%) than male autistic children (53.3%), P=0.001. CONCLUSIONS: Serum antineuronal antibodies were found in a subgroup of autistic children and they were significantly correlated to the severity of autism. Thus, autism may be, in part, one of the pediatric autoimmune neuropsychiatric disorders. Further wide-scale studies are warranted to shed light on the etiopathogenic role of antineuronal antibodies in autism. The role of immunotherapy in autistic patients, who are seropositive for antineuronal antibodies, should also be studied. PMID- 22226852 TI - Routine chest and abdominal high-pitch CT: an alternative low dose protocol with preserved image quality. AB - OBJECTIVE: To investigate the radiation dose and image quality of the high-pitch dual source computer tomography (DSCT) for routine chest and abdominal scans. METHODS: 130 consecutive patients (62 female, 68 male, median age 55 years) were included. All patients underwent 128-slice high-pitch DSCT (chest n=99; abdomen n=84) at a pitch of 3.2. Two observers independently rated image quality using a 4-point score (1: excellent to 4: non-diagnostic). Image noise was measured and operational radiation dose quantities were recorded. An additional group of 132 patients (chest, n=80; abdomen n=52) scanned with standard-pitch CT matched for age, gender, and body mass index (BMI) served as control group. RESULTS: Interobserver agreement for image quality rating was good (k=0.74). Subjective image quality of high-pitch CT was diagnostic in all patients (median score chest; 2, median score abdomen: 2). Image noise of high-pitch CT was comparable to standard-pitch for the chest (p=0.32) but increased in the abdomen (p<0.0001). For high-pitch CT radiation dose was 4.4+/-0.9 mSv (chest) and 6.5+/-1.2 mSv (abdomen). These values were significantly lower compared to standard-pitch CT (chest: 5.5+/-1.2 mSv; abdomen: 11.3+/-3.8 mSv). CONCLUSION: Based on the technical background high-pitch dual source CT may serve as an alternative scan mode for low radiation dose routine chest and abdominal CT. PMID- 22226854 TI - Thoraco-abdominal high-pitch dual-source CT angiography: experimental evaluation of injection protocols with an anatomical human vascular phantom. AB - OBJECTIVE: To experimentally evaluate three different contrast injection protocols at thoraco-abdominal high-pitch dual-source computed tomography angiography (CTA), with regard to level and homogeneity of vascular enhancement at different cardiac outputs. MATERIALS AND METHODS: A uniphasic, a biphasic as well as an individually tailored contrast protocol were tested using a human vascular phantom. Each protocol was scanned at 5 different cardiac outputs (3 5L/min, steps of 0.5L/min) using an extracorporeal cardiac pump. Vascular enhancement of the thoraco-abdominal aorta was measured every 5 cm. Overall mean enhancement of each protocol and mean enhancement for each cardiac output within each protocol were calculated. Enhancement homogeneity along the z-axis was evaluated for each cardiac output and protocol. RESULTS: Overall mean enhancement was significantly higher in the uniphasic than in the other two protocols (all p<.05), whereas the difference between the biphasic and tailored protocol was not significant (p=.76). Mean enhancement among each of the 5 cardiac outputs within each protocol was significantly different (all p<.05). Only within the tailored protocol mean enhancement differed not significantly at cardiac outputs of 3.5L/min vs. 5L/min (484 +/- 25 HU vs. 476 +/- 19 HU, p=.14) and 4 vs. 5L/min (443 +/- 49 HU vs. 476 +/- 19 HU, p=.05). Both, uniphasic and tailored protocol yielded homogenous enhancement at all cardiac outputs, whereas the biphasic protocol failed to achieve homogenous enhancement. CONCLUSION: This phantom study suggests that diagnostic and homogenous enhancement at thoraco-abdominal high pitch dual-source CTA is feasible with either a uniphasic or an individually tailored contrast protocol. PMID- 22226855 TI - The influence of passband limitation on the waveform of extracellular action potential. AB - The duration of the extracellular action potential (EAP) in single neuronal recording has often been used as a clue to infer biochemical, physiological or functional substrate of the recorded neurons, e.g. neurochemical type. However, when recording a neuronal activity, the high-pass filter is routinely used to achieve higher signal-to-noise ratio. Signal processing theory predicts that passband limitation stretches the waveform of discrete brief impulse. To examine whether the duration of filtered EAP could be the reliable measure, we investigated the influence of high-pass filter both by simulation and unfiltered unit recording data from monkey dorsal raphe. Consistent with the findings in recent theoretical study, the unfiltered EAPs displayed the sharp wave without following bumps. The duration of unfiltered EAP was not correlated with that of filtered EAP. Thus the duration of original EAP cannot be estimated from filtered EAP. It is needed to reexamine the EAP duration measured for classifying the neurons whose activities were recorded under the passband limitation in the related studies. PMID- 22226853 TI - Cranial ultrasonography and transfontanellar Doppler in premature neonates (24-32 weeks of gestation): dynamic evolution and association with a severe adverse neurological outcome at hospital discharge in the Aquitaine cohort, 2003-2005. AB - OBJECTIVE: To correlate the short-term neurological outcome of early cerebral abnormalities using cranial ultrasonography (US) in premature newborns at their hospital discharge. METHODS: Each newborn born <33 weeks of gestational age (GA) included in a prospective cohort benefited of 3 US: two early in the first week of life (D3 and D8) and one later (Months 1-2) standardized US pulsed Doppler. A US abnormality was >=one morphologic abnormality (moderate: intra-ventricular hemorrhage (IVH) grades 1-2; severe: IVH 3-4, periventricular leukomalacia, persistent flares). Correlates of having a severe adverse neurological outcome were analyzed using a stepwise backward logistic regression adjusted model with gestational age, early cerebral abnormality at Days 3-8, velocity and with variables with correlation probabilities with p<0.25 in the univariate analysis among occurring co-morbidity events previously defined. Two adjusted logistic regression analyses were conducted including or not velocity data because of missing information. RESULTS: Among 452 premature included, 11.3% did not have an early US, 74.8% had a normal early US, 13.9% >=one early morphological US abnormality (10.0% moderate, 3.9% severe). At hospital discharge, 40% were still alive with a normal late US, 33% alive with >=one late morphological US abnormality (10% moderate, 23% severe), and 10% died. Adjusted correlates of a late US severe abnormality or a neurological related death at hospital discharge were: early US abnormality (aOR: 8.7, 95% CI: 2.3-33.6), GA<29 weeks (aOR: 2.8 95% CI: 1.4-5.4). CONCLUSION: This study shows that early US morphological abnormalities increase significantly when the GA decreases and is highly predictive of the occurrence of a further late US severe abnormality or neurological related death at hospital discharge. PMID- 22226856 TI - Anti-asthmatic agents alleviate pulmonary edema by upregulating AQP1 and AQP5 expression in the lungs of mice with OVA-induced asthma. AB - Ovalbumin (OVA)-induced asthma in mouse lungs causes changes in the mRNA and protein levels of aquaporins (AQPs). AQP expression was examined in the presence of various anti-asthmatic agents, including dexamethasone, ambroxol, and terbutaline. The influence of these agents on OVA-induced airway inflammation was also evaluated. The mRNA expression levels of AQP1, 4, and 5 were significantly reduced and that of AQP3 was significantly increased 24h after the last OVA exposure. The protein levels of AQP1, 3, and 5 mirrored the mRNA expression profiles, but AQP4 did not exhibit any changes. Only the mRNA and protein expression levels of AQP1 and AQP5 were significantly increased by these three anti-asthmatic agents. Dexamethasone and ambroxol improved the eosinophil infiltration, mucus secretion, and pulmonary edema caused by OVA, but terbutaline only alleviated pulmonary edema. These results indicate that AQP1 and AQP5 are closely related to pulmonary edema but not to eosinophil infiltration or mucus secretion during asthma. Anti-asthmatic agents could alleviate pulmonary edema through upregulating the expression of AQP1 and AQP5 in mouse lungs that have OVA induced asthma. PMID- 22226857 TI - Acidic sphingomyelinase induced by electrophiles promotes proinflammatory cytokine production in human bladder carcinoma ECV-304 cells. AB - Electrophiles in environmental pollutants or cigarette smoke are high risk factors for various diseases caused by cell injuries such as apoptosis and inflammation. Here we show that electrophilic compounds such as diethyl malate (DEM), methyl mercury and cigarette smoke extracts significantly enhanced the expression of acidic sphingomyelinase (ASMase). ASMase activity and the amount of ceramide of DEM-treated cells were approximately 6 times and 4 times higher than these of non-treated cells, respectively. Moreover, we found that DEM pretreatment enhanced the production of IL-6 induced by TNF-alpha. Knockdown of ASMase attenuated the enhancement of TNF-alpha-dependent IL-6 production. On the other hand, enhancement of TNF-alpha-induced IL-6 production was observed in ASMase-overexpressing cells without DEM. Fractionation of the lipid raft revealed that the TNF receptor 1 (TNFR1) was migrated into the lipid raft in DEM-treated cells or ASMase-overexpressing cells. The TNF-alpha-induced IL-6 expression required the clustering of TNFR1 since IL-6 expression were decreased by the destruction of the lipid raft with filipin. These results demonstrated a new role for ASMase in the acceleration of the production of TNF-induced IL-6 as a pro inflammatory cytokine and indicated that electrophiles could potentiate inflammation response by up-regulating of ASMase expression following formation of lipid rafts. PMID- 22226858 TI - Adult vaccination in 11 Central European countries - calendars are not just for children. AB - As Europe's population ages, disease morbidity and treatment costs in the adult population are likely to rise substantially, making this a pertinent time to review and revise preventive strategies such as vaccination. Vaccine uptake remains a problem for adults and there is a lack of coordinated programmes for vaccination of adults. Countries in Western Europe have begun to identify the need to increase adult vaccination, but the situation in Central European countries remains poorly identified and inadequately described. This paper summarises the evidence to support the development of an adult vaccination calendar in the Central European Vaccination Awareness Group (CEVAG) member countries (Bulgaria, Croatia, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Romania, Slovakia, Slovenia and Turkey). CEVAG recommends the introduction of an adult vaccination calendar, which should include vaccination against diseases that represent a large burden in adults in terms of mortality and morbidity. This calendar could be modified to meet the priorities of individual countries. PMID- 22226859 TI - Medicaid reimbursement and the uptake of adolescent vaccines. AB - BACKGROUND: In light of low adolescent vaccination rates, state-level policies that could improve vaccine coverage should be evaluated. Approximately 1/3 of adolescents are eligible, primarily through Medicaid enrollment, to receive vaccines from state-administered Vaccines for Children (VFC) programs. We investigated whether Medicaid reimbursement, the scope of implementation of VFC programs (i.e. limited or universal purchase), and/or presence of school-based vaccine mandates were associated with adolescent vaccination levels. METHODS: We performed a cross-sectional analysis of state-level associations between these policies and 2009 National Immunization Survey-TEEN vaccination rates for tetanus containing, meningococcal conjugate (MCV4), and among females only, human papillomavirus (HPV) vaccines. RESULTS: Medicaid reimbursement was not associated with vaccine coverage rates after adjusting for presence of vaccine-related school mandates, type of VFC program, proportion of adolescents attending preventive care visits, and state-specific distribution of insurance coverage. Participation in a more expansive VFC program (universal or universal-select) was significantly associated with HPV vaccine coverage, but not tetanus-containing vaccine or MCV4, among states that had mandates for any vaccines. CONCLUSIONS: Our results suggest that, contrary to what has been shown for childhood vaccines, raising Medicaid reimbursement rates may not improve adolescent vaccine utilization. Instead, other policy changes may be more effective, such as expansion of VFC programs into universal purchase programs, further implementation of school-based vaccine mandates and efforts to raise preventive care visits among adolescents. PMID- 22226860 TI - Confounding and bias in studies of DMSS vaccination data. PMID- 22226861 TI - Public health impact of including two lineages of influenza B in a quadrivalent seasonal influenza vaccine. AB - The annual trivalent influenza vaccine (TIV) includes viruses representing three influenza strains - one A/H1N1, one A/H3N2, and one B, although two antigenically distinct lineages of influenza B (Victoria and Yamagata) co-circulate annually in the United States. Predicting which lineage of influenza B will predominate during a season is challenging, and cross-protection by immunization against the other lineage is expected to be low. One proposed alternative is to produce a quadrivalent influenza vaccine (QIV) including an influenza B virus from each of the two circulating lineages. We estimated the additional public health benefit of QIV compared with TIV by calculating the expected impact on influenza-related health outcomes (illness, hospitalization, and death) over ten influenza seasons (1999/2000-2008/2009). We included data on the annual incidence of influenza associated outcomes, virologic circulation, vaccine coverage, and vaccine effectiveness. We also considered annual vaccine production capacity, since available resources would have produced four vaccine viruses instead of three, potentially resulting in fewer doses of QIV. Use of QIV could have reduced annual cases (range: 2200-970,000), hospitalizations (range: 14-8200), and deaths (range: 1-485) in the US. During earlier seasons, adjusting production capacity for a fourth virus in QIV could have resulted in reduced overall influenza vaccine availability and net increases in influenza-associated outcomes. However, in recent seasons, the expected supply of QIV is likely to exceed the doses of vaccine actually administered. The potential net impact of QIV on influenza associated outcomes is expected to vary between seasons, depending on annual variability in the incidence of influenza caused by the two influenza B lineages, vaccine coverage, and effectiveness. The additional protection provided by including a second lineage of influenza B could result in a modest reduction in influenza-associated outcomes. PMID- 22226862 TI - Intrinsic adjuvanting of a novel single-cycle flavivirus vaccine in the absence of type I interferon receptor signaling. AB - Type I interferons (IFNs) are critical for controlling pathogenic virus infections and can enhance immune responses. Hence their impact on the effectiveness of live-attenuated vaccines involves a balance between limiting viral antigen expression and enhancing the development of adaptive immune responses. We examined the influence of type I IFNs on these parameters following immunization with RepliVAX WN, a single-cycle flavivirus vaccine (SCFV) against West Nile virus (WNV) disease. RepliVAX WN-immunized mice produced IFN-alpha and displayed increased IFN-stimulated gene transcription in draining lymph nodes (LN). SCFV gene expression was over 100 fold-higher on days 1-3 post-infection in type I IFN receptor knockout mice (IFNAR(-/-)) compared to wild-type (wt) mice indicating a profound IFN-mediated suppression of SCFV gene expression in the wt animals. IFNAR(-/-) mice produced nearly equivalent levels of WNV-specific serum IgG and WNV-specific CD4(+) T cell responses compared to wt mice. However, significantly higher numbers of WNV-specific CD8(+) T cells were produced by IFNAR(-/-) mice and a significantly greater percentage of these T cells from IFNAR(-/-) mice produced only IFN-gamma following antigen-specific re stimulation. This altered cytokine expression was not associated with increased antigen load suggesting the loss of type I IFN receptor signaling was responsible for the altered quality of the CD8(+) effector T cell response. Together, these results indicate that although type I IFN is not essential for the intrinsic adjuvanting of RepliVAX WN, it plays a role in shaping the cytokine secretion profiles of CD8(+) effector T cells elicited by this SCFV. PMID- 22226863 TI - The effect of passages during Japanese BCG vaccine production on genetic stability and protective efficacy. AB - Many genetic differences have been found among currently available BCG vaccines. To avoid continued accumulation of phenotypic or genotypic changes in the strains, WHO and most national regulatory authorities request that the vaccine should not be prepared by more than 12 passages from the master seed lot. However, it has recently been reported that genetic changes occur even during the passage for vaccine production. In this study, the genetic stability of Japanese BCG vaccine production using currently available PCR methods and protective efficacy using a guinea-pig model during the passages were examined. The results showed that there were no significant differences between the seed lot, the product manufactured by normal procedures, and the 20th passage product. These results indicate that the maximum number of passages as currently required by WHO for BCG vaccine production is adequate for the Japanese vaccine, and that new genetic tools may help to examine the quality control of the BCG vaccine. PMID- 22226864 TI - Identification of Id1-DBL2X of VAR2CSA as a key domain inducing highly inhibitory and cross-reactive antibodies. AB - PURPOSE OF THE RESEARCH: VAR2CSA is considered as the main target of protective immunity against pregnancy-associated malaria. VAR2CSA high molecular weight complicates scaling up production of VAR2CSA recombinant protein for large-scale vaccination programmes. We previously demonstrated that antibodies induced by NTS DBL1X-Id1-DBL2X efficiently block parasite binding to CSA in a similar manner to antibodies induced by the full-length extracellular part of VAR2CSA. In order to identifying the shortest fragment of VAR2CSA carrying major protective epitopes able to elicit inhibitory antibodies, we performed a refined antigenic mapping of NTS-DBL1X-Id1-DBL2X through a DNA vaccination technique. PRINCIPAL RESULTS: Five single or double domains constructs encoding NTS-DBL1X, NTS-DBL1X-Id1, Id1, Id1 DBL2X and DBL2X were made and used to immunize mice. The NTS-DBL1X, NTS-DBL1X Id1, and Id1-DBL2X fragments all raised high titer immune response, as measured by ELISA. The DBL2X fragment raised a weaker antibody titer, and the Id1 construct failed to elicit antibody. Sera from mice immunized with NTS-DBL1X or DBL2X constructs failed to block infected erythrocytes binding to CSA, whereas sera from mice immunized with NTS-DBL1X-Id1 showed partial inhibitory activity, and the Id1-DBL2X fragment elicited antisera that totally abrogated infected erythrocytes adhesion to CSA. IgG purified from Id1-DBL2X antisera showed a similar inhibitory profile than Id1-DBL2X antisera. Anti-FCR3 anti-Id1-DBL2X antibodies also efficiently block the adhesion of erythrocytes infected by the HB3 parasite line to CSA. Id1-DBL2X antisera recognized the surface of field isolates from pregnant women, and inhibited CSA-binding of all 8 isolates tested, although to a variable level. MAJOR CONCLUSIONS: We raised high-titer antibodies against several parts of the protein, and identified Id1-DBL2X as the minimal VAR2CSA fragment inducing antibodies with CSA-binding inhibitory efficiency in the same range as the full-length extracellular part of VAR2CSA. PMID- 22226865 TI - Withdrawal of life-sustaining treatment for newborn infants from a Hindu perspective. PMID- 22226866 TI - Role of the PPAR-alpha agonist fenofibrate in severe pediatric burn. AB - Fenofibrate is a peroxisome proliferator activated receptor alpha agonist that contains both pro and anti-inflammatory properties, and has been used in the treatment of dyslipidemia and diabetes for decades. Its receptors are expressed in the liver, skeletal muscle, cardiac, enteric, and renal cells, which allow it to provide systemic regulation of lipoprotein metabolism, fatty acid oxidation, and fatty acid transport. Hyperglycemia is a common complication found in the burn population because hepatic glucose production and catecholamine-mediated hepatic glycogenolysis are augmented. Insulin resistance occurs often in these patients and is associated with poor outcomes. In the pediatric burn population, fenofibrate has been found to ameliorate or decrease the number of hypoglycemic episodes when compared to management with insulin alone. Its mechanism of action is thought to involve an improvement in insulin signaling in skeletal muscle, as well as improvements in mitochondrial function, glucose oxidation, and insulin sensitivity. The long term use of fenofibrate in severely burned patients may improve hyperglycemia and insulin resistance, as well as improve wound healing, and reduce apoptosis, and oxidative stress. PMID- 22226867 TI - Paediatric injuries associated with the use of disposable barbecues: are we finding ourselves in hot sand? AB - AIM: To document, describe and raise awareness of a preventable injury associated with the use of disposable barbecues. METHODS: We conducted a retrospective study of incidents involving barbecue burns. Cases were identified through the burn injury database of a tertiary paediatric burns referral centre and case notes reviewed. Experiments were performed to evaluate the dissipation of heat from sand. RESULTS: Over a 3-month period, 9 children were identified out of a series of 296. The median age was 5 years and burns were sustained through contact with hot sand where disposable barbecues had been used. 87% (n=13) of the burns were partial thickness and most affected critical areas such as the hands and feet. The majority (93%) responded well to debridement and simple dressings and all patients made a complete recovery. Experiments show that, even after a prolonged period of time, sand can retain sufficient heat to cause a contact burn. DISCUSSION AND CONCLUSION: We have noted an increased incidence of burns with this mechanism of injury. The burns are usually superficial, they tend to occur predominantly in children and involve critical areas. We suggest that areas where disposable barbecues have stood should be cooled and children kept away from the area for at least 5min. The results of the study have been forwarded to the Prevention Committee of the British Burn Association with the aim of raising awareness of this mechanism of burn. PMID- 22226868 TI - Efficient expression of recombinant soluble human FcgammaRI in mammalian cells and its characterization. AB - The extracellular domain of human FcgammaRI which interacts with a human IgG was expressed as recombinant soluble human FcgammaRI (rshFcgammaRI) by Chinese hamster ovary (CHO) cell. Stable CHO cell clones with efficient expression of rshFcgammaRI were established based on a dihydrofolate reductase (DHFR)/methotrexate (MTX) gene-amplification system. The CHO clones efficiently produced rshFcgammaRI under high-density continuous culture in a bioreactor. After 53 days of culture, the number of cells had reached approximately 4 * 106 cells/mL in the bioreactor and the average production of rshFcgammaRI had reached 7.4 mg L-medium-1 day-1. Secreted rshFcgammaRI was purified to a homogeneous state using cation exchange and affinity chromatographies. The binding affinities of rshFcgammaRI to human IgG subclasses were determined using surface plasmon resonance analysis. The binding affinities of rshFcgammaRI to human IgG1/kappa and IgG3/kappa were high (1.59 * 10-10 and 2.81 * 10-10 M, respectively), whereas that of rshFcgammaRI to human IgG4/kappa was lower binding affinity (1.41 * 10-8 M). Binding to IgG2/kappa was not detectable. Examination of circular dichroism spectra indicated that rshFcgammaRI was rich in beta-structures and loop or turn structures, but there were few alpha-helices. These results may be valuable for further studies of the structure and function of human FcgammaRI. PMID- 22226869 TI - Methyl-beta-cyclodextrin is a useful compound for extraction and purification of prenylated enzymes from the retinal disc membrane. AB - cGMP phosphodiesterase 6 (PDE6) and rhodopsin kinase (GRK1) are quantitatively minor prenylated proteins involved in vertebrate phototransduction. Here, we report that methyl-beta-cyclodextrin (MCD), a torus-shaped oligosaccharide with a hydrophobic pore, can be used as a selective extractant for such prenylated proteins from frog retinal disc membranes, and that MCD makes it possible to purify frog PDE6 holoenzyme with very simple procedure. The EC50s of MCD for the extraction of GRK1 and PDE6 from the cytoplasmic surface of the disc membrane were 0.17 and 5.1 mM, respectively. By successive extraction of the membrane by 1 mM and then 20 mM MCD, we obtained crude GRK1 and PDE6, respectively. From the 20mM extract, we were able to purify the PDE6 holoenzyme using one-step anion exchange column chromatography. From 1mM MCD extract, GRK1 was further purified by an affinity column. Following the removal of MCD by ultrafiltration, we were able to confirm integrity of these enzymes by reconstituting phototransduction system in vitro. We have therefore demonstrated that MCD is a useful compound for selective extraction and purification of prenylated peripheral membrane proteins from the cytoplasmic surface of biological membranes. PMID- 22226872 TI - Compliance with nutrition support guidelines in acutely burned patients. AB - BACKGROUND: Adequate and timely provision of nutritional support is a crucial component of care of the critically ill burn patient. The goal of this study was to assess a single center's consistency with Society of Critical Care Medicine/American Society for Parenteral and Enteral Nutrition (SCCM/ASPEN) guidelines for nutritional support in critically ill patients. METHODS: Acutely burned patients >45kg in weight admitted to a regional burn center during a two year period and who required 5 or more days of full enteral nutritional support were eligible for inclusion in this retrospective review. Specific outcomes evaluated include time from admission to feeding tube placement and enteral feeding initiation and percent of nutritional goal received within the first week of hospital stay. Descriptive statistics were used for all analyses. IRB approval was obtained. RESULTS: Thirty-seven patients were included in this retrospective review. Median age of patients was 44.9 years (IQR: 24.2-55.1), and median burn injury size was 30% (IQR: 19-47). Median time to feeding tube placement was 31.1h post admission (IQR: 23.6-50.2h), while median time to initiation of EN was 47.9h post admission (IQR: 32.4-59.9h). The median time required for patients to reach 60% of caloric goal was 3 days post-admission (IQR: 3-4.5). CONCLUSION: The median time for initiation of enteral nutrition was within the SCCM/ASPEN guidelines for initial nutrition in the critically ill patient. This project identified a 16h time lag between placement of enteral access and initiation of enteral nutrition. Development of a protocol for feeding tube placement and enteral nutrition management may optimize early nutritional support in the acutely injured burn patient. PMID- 22226870 TI - Cloning, expression and characterization of the recombinant Yersinia pseudotuberculosis L-asparaginase. AB - We have cloned ansB (YPTB1411) gene from Yersinia pseudotuberculosis Q66CJ2 and constructed stable inducible expression system that overproduce L-asparaginase from Y. pseudotuberculosis (YpA) in Escherichiacoli BL21 (DE3) cells. For purification of YpA we used Q-Sepharose and DEAE-Toyopearl column chromatography. We examined kinetics of the enzyme reaction, catalytic activity as a function of pH, temperature and ionic strength, thermostability and other enzyme properties. Biochemical properties of YpA are similar with those of E. coli type II L asparaginase. K(m) for L-asparagine is 17 +/- 0.9 MUM and pI 5.4 +/- 0.3. Enzyme demonstrates maximum activity at pH 8.0 and 60 degrees C. YpA L-glutaminase activity is relatively low and more than 15 times less than specific activity towards L-asn. We evaluated also the antiproliferative effect of YpA in vitro and in vivo with E. colil-asparaginase (EcA) as the reference substance at similar conditions. PMID- 22226873 TI - Development of intravenous lipid emulsion of tanshinone IIA and evaluation of its anti-hepatoma activity in vitro. AB - The purpose of this study was to develop a lipid emulsion of tanshinone IIA (Tan IIA-LE) for intravenous administration and to investigate its feasibility for future clinical practice. The formulation was optimized using central composite design-response surface methodology (CCD-RSM), and the homogenization process was investigated systematically. The Tan IIA-LE was evaluated in terms of stability, safety and in vitro anti-hepatoma activity. The formulation of Tan IIA-LE is composed of 0.05% (w/v) Tan IIA, 20% (w/v) soybean oil-MCT mixture (1:1, w/w), 1.2% (w/v) soybean lecithin, 0.3% (w/v) F68 and 2.2% (w/v) glycerol, a high pressure homogenization at 100 MPa for 3 cycles was selected as the optimal homogenization process. The Tan IIA-LE was light-sensitive but stable for at least 12 months at room temperature in dark. The safety study demonstrated that the Tan IIA-LE did not cause venous irritation or obvious acute toxicity. Furthermore, the Tan IIA-LE displayed significant anti-tumor activity against human hepatoma cell lines in vitro. Overall, the Tan IIA-LE developed in this study was suggested to be a suitable and safe dosage form of Tan IIA for intravenous administration and has potential in liver cancer therapy in future. PMID- 22226874 TI - Dextran-protamine-solid lipid nanoparticles as a non-viral vector for gene therapy: in vitro characterization and in vivo transfection after intravenous administration to mice. AB - The aim of present work is to evaluate the transfection capacity of a new multicomponent system based on dextran (Dex), protamine (Prot), and solid lipid nanoparticles (SLN) after intravenous administration to mice. The vectors containing the pCMS-EGFP plasmid were characterized in terms of particle size and surface charge. In vitro transfection capacity and cell viability were studied in four cell lines, and compared with the transfection capacity of SLN without dextran and protamine. Transfection capacity was related to the endocytosis mechanism: caveolae or clathrin. The Dex-Prot-DNA-SLN vector showed a higher transfection capacity in those cells with a high ratio of activity of clathrin/caveolae-mediated endocytosis. However, the complex prepared without dextran and protamine (DNA-SLN) was more effective in those cells with a high ratio of activity of caveolae/clathrin-mediated endocytosis. The interaction with erythrocytes and the potential hemolytic effect were also checked. The Dex-Prot DNA-SLN vector showed no agglutination of erythrocytes, probably due to the presence of dextran. After intravenous administration to BALB/c mice, the vector was able to induce the expression of the green fluorescent protein in liver, spleen and lungs, and the protein expression was maintained for at least 7 days. Although additional studies are necessary, this work reveals the promising potential of this new gene delivery system for the treatment of genetic and non genetic diseases through gene therapy. PMID- 22226875 TI - Pluronic@Fe3O4 nanoparticles with robust incorporation of doxorubicin by thermo responsiveness. AB - Doxorubicin was physically incorporated in magnetic nanoparticles by thermo responsive manners. Magnetic nanoparticles were prepared by oxidizing ferric ions in ammonium solution. Thiolated Pluronic was synthesized by sequential modification of terminal hydroxyl groups of Pluronic to amine groups and thiol groups. Magnetic nanoparticles composed of iron oxide were surface-modified with thiolated Pluronic at different molar ratios of iron to thiol groups. Pluronic decoration on the magnetic nanoparticles was characterized by elemental analysis and transmission electron microscopy. Elemental analysis results on carbon atoms in the magnetic nanoparticles showed that the degree of Pluronic decoration was proportional to the feed ratio of thiolated Pluronic to iron oxide. Doxorubicin was incorporated to the magnetic nanoparticles thermo-responsive manners; a mixture of hydrophobized doxorubicin and the magnetic nanoparticles was incubated at 4 degrees C and the temperature was subsequently increased to 37 degrees C for thermally induced structural changes of the decorated Pluronic moieties. Doxorubicin-incorporated magnetic nanoparticles showed dramatic modulations of size distributions according to temperature changes, which was dependent on the degree of Pluronic decoration. Loading efficiency of doxorubicin was significantly affected by the number of decorated Pluronic on the magnetic nanoparticles; the higher Pluronic moieties the nanoparticles had, the higher loading efficiency they showed. Release profiles of doxorubicin from the nanoparticles showed that doxorubicin was liberated from the nanoparticles in response to reducing conditions of the release medium. Anti-cancer activities of the doxorubicin-incorporated nanoparticles were determined by a MTT-based cytotoxicity assay against A549 cell lines. Compared to native doxorubicin, the doxorubicin incorporated magnetites showed attenuated cytotoxicities due to slow release of doxorubicin from the carriers. Thus, thermally induced incorporation of anti-cancer drugs can be a novel method for multifunctional magnetic nanoparticles with imaging and anti-cancer treatments. PMID- 22226876 TI - A comparison between spray drying and spray freeze drying for dry powder inhaler formulation of drug-loaded lipid-polymer hybrid nanoparticles. AB - Lipid-polymer hybrid nanoparticles - polymeric nanoparticles enveloped by lipid layers - have emerged as a potent therapeutic nano-carrier alternative to liposomes and polymeric nanoparticles. Herein we perform comparative studies of employing spray drying (SD) and spray freeze drying (SFD) to produce inhalable dry-powder form of drug-loaded lipid-polymer hybrid nanoparticles. Poly(lactic-co glycolic acid), lecithin, and levofloxacin are employed as the polymer, lipid, and drug models, respectively. The hybrid nanoparticles are transformed into micro-scale nanoparticle aggregates (or nano-aggregates) via SD and SFD, where the effects of (1) different excipients (i.e. mannitol, polyvinyl alcohol (PVA), and leucine), and (2) nanoparticle to excipient ratio on nano-aggregate characteristics (e.g. size, flowability, aqueous reconstitution, aerosolization efficiency) are examined. In both methods, PVA is found more effective than mannitol for aqueous reconstitution, whereas hydrophobic leucineis needed to achieve effective aerosolization as it reduces nano-aggregate agglomeration. Using PVA, both methods are equally capable of producing nano-aggregates having size, density, flowability, yield and reconstitutibility in the range ideal for inhaled delivery. Nevertheless, nano-aggregates produced by SFD are superior to SD in terms of their aerosolization efficiency manifested in the higher emitted dose and fine particle fraction with lower mass median aerodynamic diameter. PMID- 22226877 TI - Preparation and evaluation of palmitic acid-conjugated exendin-4 with delayed absorption and prolonged circulation for longer hypoglycemia. AB - Albumin-binding achieved by fatty-acylation to drugs is considered to be an effective means of prolonging the circulation lifetimes of short-lived peptides. Here, exendin-4 was modified with palmitic acid, and the particle size and albumin-binding of palmitic acid-conjugated exendin-4 (Pal-Ex4) purified was investigated and visualized. Additionally, its pharmacokinetics and pharmacodynamics were evaluated in diabetic rodents. Pal-Ex4 had a greater molecular size (~125nm) and its albumin-binding was 5.6-fold that of Ex4. Molecular imaging showed that the subcutaneous absorption of Pal-Ex4 was delayed until 24h post-injection, whereas Ex4 was rapidly absorbed and distributed systemically. Pharmacokinetic and pharmacodynamic results confirmed these observations, for example, times to reach peak concentration and to achieve a blood glucose level nadir were greatly delayed versus Ex4, and the circulating half-life of Pal-Ex4 was much greater than that of Ex4. Consequently, the hypoglycemic degree of Pal-Ex4 (500 nmol/kg) was 4.2 fold greater than Ex4. Our results show that the extended hypoglycemic efficacy of Pal-Ex4 was due to (i) a delayed absorption due to micelle formation and (ii) an increased in vivo circulating half-life due to albumin-binding. We believe that this prototype of exendin-4 has considerable pharmaceutical potential as a systemic type 2 anti diabetic treatment. PMID- 22226878 TI - Preparation and pharmacokinetic evaluation of curcumin solid dispersion using Solutol(r) HS15 as a carrier. AB - Solubility of curcumin at physiological pH was significantly increased by forming solid dispersion (SD) with Solutol(r) HS15. Since curcumin undergoes hydrolytic degradation, chemical stability study was conducted in pH 1.2, 6.8 and 7.4 buffer media. Solutol(r) HS15 exhibited superior stabilizing effect to Cremophor(r) RH40 and Kollidon(r) 30. The physical state of the dispersed curcumin in the polymer matrix was characterized by differential scanning calorimetry and X-ray diffraction studies. SD preparation transformed curcumin into amorphous form and facilitated micellar incorporation, thereby preventing hydrolysis in aqueous medium. In vitro drug release in pH 6.8 buffer revealed that SD (1:10) improved the dissolution of curcumin with approximately 90% release of the drug within 1h. Pharmacokinetic study of the solid dispersion formulation in rat showed that bioavailability of the drug was significantly improved as compared to pure curcumin. SD containing 1:10 ratio of drug and Solutol(r) HS15 resulted in approximately 5 fold higher AUC(0-12h). SD formulation was physically stable over the study period of 3 months. PMID- 22226879 TI - Paclitaxel loaded nano-aggregates based on pH sensitive polyaspartamide amphiphilic graft copolymers. AB - Polyaspartamide (PASPAM) derivatives grafted with 1-(3-aminopropyl)imidazole (API), O-(2-aminoethyl)-O'-methylpolyethylene glycol (MPEG), and octadecylamine (C18) groups were synthesized and their pH-sensitive structure and Paclitaxel (PTX) load/release properties were investigated. C18/MPEG/API-g-PASPAMs systems synthesized showed a strong pH-dependent phase transition behavior near pH 6.7. Large amount of PTX up to 60-75%, depending on polymer composition, was possibly loaded into the C18/MPEG/API-g-PASPAMs nano-aggregates using a solvent-free protocol. Its pH dependent release pattern was affected correspondingly by the phase transition behavior associated with the composition of graft substituents. The pure C18/MPEG/API-g-PASPAMs systems did not show cell toxicity but the PTX loaded copolymer systems showed a similar cell toxicity to a Taxol-type PTX. From the in vivo animal study, PTX-loaded nano-aggregates showed the much improved inhibition effect on tumor growth compared to the conventional PTX formulation. PMID- 22226880 TI - The effect of a P123 template in mesopores of mesocellular foam on the controlled release of venlafaxine. AB - A series of mesocellular foams (MCFs)-based mesoporous silica nanospheres (DH-MCF P123-n, (n=12, 2, 0.5)) were synthesized as controlled-release deliveries for a typical antidepressant drug, venlafaxine. The foams were 3-(2,3 dihydroxypropoxyl)propyl-grafted and the P123 template partially preserved. We studied the release profiles of venlafaxine-loaded DH-MCF-P123-n in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF), respectively, as well as their corresponding venlafaxine loading capacities. Appropriate amounts of P123 template preserved in mesopores showed an efficient synergetic effect on increasing venlafaxine loading capacity and controlled-release property. Up to 90.87% (mass fraction) of venlafaxine could be loaded into DH-MCF-P123-2. For this carrier, 36% of venlafaxine was released after 1h of incubation in SGF and 53% of venlafaxine was released after 12h in SIF. The mechanisms of the loading and releasing processes were tentatively described based on the release behaviors. PMID- 22226881 TI - Reversal of P-glycoprotein-mediated multidrug resistance by a synthetic alpha aminoxy peptidomimetic. AB - The lack of selectivity and adequate potency of currently known P-glycoprotein (P gp) inhibitors obscured their further development for clinical use to circumvent P-gp-mediated multidrug resistance (MDR), which necessitates the investigation of novel ones with higher potency and better specificity. The present study investigated the reversal effect of a new synthetic alpha-aminoxy lysine peptidomimetic (Lys-P) on P-gp-mediated MDR. Effects of Lys-P on cytotoxicity of P-gp substrate doxorubicin (Dox) and intracellular accumulation of another P-gp substrate rhodamine 123 were examined in HEK293 cells. Its interaction mechanism and effect on P-gp expression were further investigated using ATPase assay and Western blot in Caco-2 cells, respectively. Lys-P restored the cytotoxicity of Dox toward the resistant MDR1-transfected HEK293 and MCF-7 TX400 cells without affecting their corresponding parental cells. It also significantly increased intracellular accumulation (21-fold) of rhodamine 123 in HEK293 MDR1 cells. Further mechanistic studies demonstrated that in the Caco-2 cell monolayer model, Lys-P abolished the P-gp-mediated efflux of Dox due to uncompetitive inhibition of P-gp ATPase without altering P-gp expression. Our findings demonstrated that Lys-P can be used as a promising lead compound for further development into selective and efficient MDR reversing agents for combination use with P-gp substrate drugs in cancer chemotherapy. PMID- 22226882 TI - Cardiac lipoprotein lipase activity in the hypertrophied heart may be regulated by fatty acid flux. AB - Cardiac hypertrophy is characterised by an imbalance between lipid uptake and fatty acid beta-oxidation leading to an accumulation of lipids, particularly triacylglycerol (TAG). It is unclear whether uptake mechanisms such as lipoprotein lipase (LPL) can be attenuated to diminish this uptake. Rats were cold acclimated to induce cardiac hypertrophy and increase cardiac LPL. Lipid uptake and metabolism were altered by feeding a 'Western-style' high fat diet (WSD) or feeding oxfenicine (2g/L) in the drinking water. Diastolic stiffness (increased volume change/unit pressure change) was induced in hypertrophied hearts for rats fed WSD (P<0.05) or WSD+oxfenicine (P<0.01), although absolute performance of cardiac muscle, estimated from stress-strain calculations was unchanged. Cold acclimation increased cardiac endothelial LPL (P<0.05) but this was diminished following oxfenicine. Following WSD LPL was further decreased below WSD-fed control hearts (P<0.05) with no further decrease by oxfenicine supplementation. A negative correlation was noted between plasma TAG and endothelial LPL (correlation coefficient=-0.654; P<0.001) but not cardiac TAG concentration. Transcript levels of angiopoietin-like protein-4 (ANGPTL4) were increased 6-fold by WSD (P<0.05) and increased 15-fold following WSD+oxfenicine (P<0.001). For CA-hearts fed WSD or WSD+oxfenicine ANGPTL4 mRNA levels were preserved at chow-fed levels. VLDLR protein levels were increased 10-fold (P<0.01) by CA. ANGPTL4 protein levels were increased 2-fold (P<0.05) by WSD, but restored following oxfenicine. For CA-hearts WSD increased ANGPTL4 protein levels 3-fold (P<0.01) with WSD+oxfenicine increasing ANGPTL4 protein 4-fold (P<0.01). These data suggest that endothelial LPL levels in the heart are altered to maintain FA flux and may exploit ANGPTL4. PMID- 22226883 TI - Integration of non-vesicular and vesicular transport processes at the Golgi complex by the PKD-CERT network. AB - Non-vesicular transport of ceramide from endoplasmic reticulum to Golgi membranes is essential for cellular lipid homeostasis. Protein kinase D (PKD) is a serine threonine kinase that controls vesicle fission at Golgi membranes. Here we highlight the intimate connections between non-vesicular and vesicular transport at the level of the Golgi complex, and suggest that PKD and its substrate CERT, the ceramide transfer protein, play central roles in coordinating these processes by fine-tuning the local membrane lipid composition to maintain Golgi secretory function. This article is part of a Special Issue entitled Lipids and Vesicular Transport. PMID- 22226884 TI - Multi-year follow-up of fine-needle aspiration biopsy in choroidal melanoma. AB - PURPOSE: To report the local and systemic follow-up of patients undergoing transscleral intraoperative fine-needle aspiration biopsy (FNAB) at the time of iodine-125 plaque brachytherapy for the treatment of choroidal melanoma. DESIGN: Retrospective, single-center, consecutive case cohort study. PARTICIPANTS: A total of 170 consecutive patients with choroidal melanoma. METHODS: All patients with choroidal melanoma treated with iodine-125 brachytherapy and intraoperative FNAB from January 2005 to January 2010 with at least 1 year of clinical follow-up were included. MAIN OUTCOME MEASURES: Outcomes examined were endophthalmitis, orbital dissemination, local treatment failure, rhegmatogenous retinal detachment, monosomy 3 status, and choroidal melanoma metastasis. RESULTS: A total of 170 consecutive patients with clinical diagnosis of choroidal melanoma, intraoperative FNAB, and post-brachytherapy follow-up of 1 to 6 years (mean, 2.7 +/- 1.3 years) were included. For tumors with height of <3.0 mm, 3.0 to 5.0 mm, and >5.0 mm, sufficient biopsy material for fluorescence in situ hybridization (FISH) was obtained in 53%, 68%, and 91%, respectively. During the follow-up period, there was no case of postoperative endophthalmitis, orbital dissemination, or local treatment failure. Three patients developed rhegmatogenous retinal detachment. Fourteen patients developed clinical evidence of metastasis. Of the 14 patients, 8 had monosomy 3 of the primary tumor, 2 had disomy 3, 1 had trisomy 3, and 3 had insufficient material for FISH. The cumulative 5-year Kaplan-Meier metastatic rate was 13%. CONCLUSIONS: Transscleral FNAB at the time of iodine-125 plaque brachytherapy was not associated with endophthalmitis, orbital dissemination, or local treatment failure in this series, and post-brachytherapy retinal detachment occurred in 3 eyes. The cumulative Kaplan-Meier 5-year metastatic rate was not statistically different from the rate of 13% reported by the Collaborative Ocular Melanoma Study for tumors of the same size treated by brachytherapy without biopsy. Rhegmatogenous retinal detachment may occur in young patients secondary to posterior vitreous detachment induced by tumor response to radiation, unrelated to FNAB. PMID- 22226885 TI - Eyes or subjects: are ophthalmic randomized controlled trials properly designed and analyzed? AB - OBJECTIVE: In ophthalmic randomized controlled trials (RCTs), each subject may have 2 potential data points (i.e., eyes) contributing to the clinical trial. Hence, various study designs may arise requiring different statistical tools. This study aimed to assess the appropriateness of study design, statistical tools used, and reporting of results in ophthalmic RCTs. DESIGN: A systematic review of 69 ophthalmic RCTs. METHODS: The study design, sample size calculation, statistical analysis, and reporting methodology of all RCTs published in 4 major general clinical ophthalmology journals in 2009 were assessed. MAIN OUTCOME MEASURES: The study design of each article under review is evaluated. RESULTS: The most common study design was a one-eye design (48%). Within this group, only half described the method of selecting the study eye, among which 5 chose the study eye by random selection. In the remaining trials, there were paired-eye design (13%), subject design (19%), and two-eye design (19%). Among the 13 two eye design studies, 4 allocated both eyes of the subject to the same group, 4 allocated the eyes to different groups, and 4 did not restrict the allocation. None of these studies adjusted for the clustering effect in sample size calculation. Only 5 studies used statistical methods adjusting for nonindependence. CONCLUSIONS: There is currently substantial heterogeneity in the quality among published ophthalmic RCTs in terms of proper use of study design, sample size calculation, randomization method, and statistical tools. Future ophthalmic researchers are suggested to consult a statistician and to follow some guidelines such as the CONSORT statement when performing an RCT to improve further the quality of clinical trial. PMID- 22226886 TI - Comparison of limbus-based and fornix-based trabeculectomy: success, bleb-related complications, and bleb morphology. AB - PURPOSE: To compare the success and complications of trabeculectomy performed with limbus-based and fornix-based conjunctival approaches. DESIGN: Retrospective case series with some prospective data collection. PARTICIPANTS: Consecutive patients undergoing trabeculectomy by 2 surgeons between May 2000 and October 2008. INTERVENTION: We performed limbus-based operations during the first 4 years and fornix-based operations during the last 4 years. We collected data by chart review and by examination at the most recent visit. For each follow-up visit, we defined success as undergoing no further glaucoma procedure and achieving one of our intraocular pressure (IOP) criteria. We used Kaplan-Meier survival analysis, Cox proportional hazards models, and generalized estimating equation (GEE) analysis. During 2009, 439 trabeculectomy sites of 347 patients were quantitatively assessed by the Indiana bleb grading system. MAIN OUTCOME MEASURES: (1) Success rate of trabeculectomy, as determined by the achievement of each of our different IOP goals, with or without IOP-lowering medications; and (2) incidence of surgical complications. RESULTS: During the 4 years after surgery, the success rates of limbus-based and fornix-based trabeculectomy were not statistically different for any of our IOP criteria. Blebs after limbus-based surgery were more likely to be graded as higher and to be avascular (GEE model, both P < 0.0001). Four percent of eyes experienced late-onset bleb leaks within 4 years after both limbus- and fornix-based operations; however, limbus-based cases developed bleb leaks significantly later than did fornix-based cases (2.1 vs. 1.0 years; P=0.002, GEE model). Late bleb-associated infection during the first 4 years after surgery occurred more often in limbus-based operations, although statistical significance was borderline (P=0.054, Cox model). Symptomatic hypotony during all available follow-up was more common with fornix-based operations (P=0.01, GEE model). Eyes undergoing the fornix-based operation had a greater risk of cataract surgery in the 4-year period after surgery (P=0.02, Cox model), and fornix-based cases requiring cataract surgery had the operation earlier than limbus-based cases (P=0.002, GEE model). CONCLUSIONS: Success rates are similar between limbus-based and fornix-based trabeculectomy. Limbus-based procedures produce higher, more avascular blebs, with a greater risk of infection. Fornix-based procedures have more symptomatic hypotony and more and earlier cataract development. PMID- 22226887 TI - Oxidative stress and antioxidant therapy in cystic fibrosis. AB - Cystic fibrosis is a lethal autosomal recessive condition caused by a defect of the transmembrane conductance regulator gene that has a key role in cell homeostasis. A dysfunctional cystic fibrosis transmembrane conductance regulator impairs the efflux of cell anions such as chloride and bicarbonate, and also that of other solutes such as reduced glutathione. This defect produces an increased viscosity of secretions together with other metabolic defects of epithelia that ultimately promote the obstruction and fibrosis of organs. Recurrent pulmonary infections and respiratory dysfunction are main clinical consequences of these pathogenetic events, followed by pancreatic and liver insufficiency, diabetes, protein-energy malnutrition, etc. This complex comorbidity is associated with the extensive injury of different biomolecular targets by reactive oxygen species, which is the biochemical hallmark of oxidative stress. These biological lesions are particularly pronounced in the lung, in which the extent of oxidative markers parallels that of inflammatory markers between chronic events and acute exacerbations along the progression of the disease. Herein, an abnormal flux of reactive oxygen species is present by the sustained activation of neutrophils and other cystic fibrosis-derived defects in the homeostatic processes of pulmonary epithelia and lining fluids. A sub-optimal antioxidant protection is believed to represent a main contributor to oxidative stress and to the poor control of immuno-inflammatory pathways in these patients. Observed defects include an impaired reduced glutathione metabolism and lowered intake and absorption of fat soluble antioxidants (vitamin E, carotenoids, coenzyme Q-10, some polyunsaturated fatty acids, etc.) and oligoelements (such as Se, Cu and Zn) that are involved in reactive oxygen species detoxification by means of enzymatic defenses. Oral supplements and aerosolized formulations of thiols have been used in the antioxidant therapy of this inherited disease with the main aim of reducing the extent of oxidative lesions and the rate of lung deterioration. Despite positive effects on laboratory end points, poor evidence was obtained on the side of clinical outcome so far. These aspects examined in this critical review of the literature clearly suggest that further and more rigorous trials are needed together with new generations of pharmacological tools to a more effective antioxidant and anti-inflammatory therapy of cystic fibrosis patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. PMID- 22226888 TI - Cardiac mechanoreceptor function implicated during premature ventricular contraction. AB - In a premature ventricular contraction (PVC), a systolic blood pressure peak is missing during the affected cardiac cycle, leading to a prolonged reduction in blood pressure which is then followed by a large burst of sympathetic outflow. In a normal ventricular contraction, it is generally believed that peak carotid and aortic distensions associated with systolic pressure is the neural feedback that terminates sympathetic outflow through a baroreflex mechanism. Yet, the characteristically large sympathetic burst following a PVC is terminated without a systolic pressure and evidently without this mechanism. To address this anomaly, we examined the possible role of cardiac receptors in providing an alternative mechanism for the termination of sympathetic outflow in a PVC. For this purpose, recordings of electrocardiogram (ECG), arterial blood pressure (ABP), and muscle sympathetic neural activity (MSNA) were made in a human subject during repeated PVC episodes. The time intervals, or "latencies", from key events within the PVC to the peak of the associated MSNA burst were calculated and compared with the latency in a normal ventricular contraction which is associated with central baroreceptor function. It was found that the only event in a PVC that corresponds with a physiologically plausible latency is that which marks the end of ventricular filling. We conclude with the hypothesis that in the unique circumstances of a PVC, where the systolic pressure peak required to trigger arterial baroreceptors to terminate sympathetic outflow is absent, mechanoreceptors in the heart appear to "step in" to perform this sympathoinhibitory function. PMID- 22226889 TI - Why haematomas cause flap failure: an evidence-based paradigm. AB - BACKGROUND: Haematomas compromise flaps in the absence of a pressure effect and pedicle thrombosis. While animal models confirmed the toxic effect of whole blood on adjacently sited random pattern flaps, our understanding of this phenomenon remains incomplete. Our aim was to identify mechanisms by which a subjacent haematoma leads to flap compromise to inform clinical practice. METHODS: A literature review was conducted of all peer-reviewed publications relating haematoma to tissue compromise including free transferred tissue, vascularised flap models and brain injury. Clinical correlation was made with free vascularised flaps and rhytidectomy skin flaps. RESULTS: Haematomas compromise around 2-4% of free tissue transfers and local flaps. We propose that several mechanisms are responsible. Cytokines, generated by platelet degradation, recruit neutrophils, releasing both reactive oxygen species and proteolytic enzymes. Reactive oxygen species (ROS), including superoxide (O(2)(-)) and hydroxyl (OH-) are also produced by ATP degradation, promoted by NAD+ sequestration. Additionally, the complement cascade is triggered by thrombin. Ferrous ions, freed by complement-mediated lysis of erythrocytes and degradation of haemoglobin also promote generation of ROS. Reactive oxygen species, complement and activated neutrophils cause endothelial cell disruption, leading to activation of pro thrombotic mechanisms and small vessel occlusion, with consequent tissue ischaemia, which in turn generates further ROS. CONCLUSION: Haematomas cause tissue injury by a complex sequence of inter-related biochemical and cellular processes merging on a common pathway of local tissue ischaemia which the overlying tissue is unable to regulate. Emergent evacuation of haematoma must be considered irrespective of envelope tension. PMID- 22226890 TI - The lobular transposition flap: a useful adjunct to reconstruct helical defects. AB - We detail our adjunct to Antia and Buch's chondrocutaneous advancement flap for helical reconstruction. It is simple, reliable and negates the need for transfer of the defect to the lobule and/or V-Y advancement of the helical crus. PMID- 22226891 TI - Comments on the re-assessment study by Sharp et al. of Erschbamer et al. PMID- 22226892 TI - Fiscal analysis of establishment of a double-balloon enteroscopy program and reimbursement. AB - BACKGROUND & AIMS: As double-balloon enteroscopy (DBE) programs continue to be established, further research is needed to assess their financial impact. We evaluated actual financial outcomes and compared them with estimated return on investment (ROI) projections for DBE. METHODS: We retrospectively compared the predicted and actual financial results for outpatients referred for DBE at an academic tertiary referral center. RESULTS: The ROI analysis was based on a 5 year time frame. The analysis projected a net present value of $64,623 and an internal rate of return of 24.6%. The projected first-year volume was 52 outpatient cases; however, the actual experience was 20 outpatient cases. The predicted percent margin for these outpatient cases was 16.6%; the actual margin was 24.4%. After 37 months, 52 outpatient cases were completed, and the actual percent margin was 4.6%. Payer type had a significant influence on the financial outcomes when projected activity and actual activity were compared. CONCLUSIONS: Institutions interested in establishing a DBE program should be aware of the financial implications of program establishment, which can be evaluated in a return on investment analysis. Payer mix significantly influences DBE reimbursement and collection rates. PMID- 22226893 TI - Nonlinear relationship between body mass index and esophageal acid exposure in the extraesophageal manifestations of reflux. AB - BACKGROUND & AIMS: Obesity is believed to be an important etiologic factor in gastroesophageal reflux disease. However, it is not clear how obesity might affect esophageal acid exposure in patients with extraesophageal manifestations of reflux. METHODS: We conducted a cross-sectional study of 223 patients with extraesophageal symptoms suspected of being related to reflux. Participants underwent endoscopy and 48-hour wireless pH testing. The percentage of time at a pH of less than 4 (total, upright, and supine) was measured for each patient, and data were compared with corresponding body mass index (BMI), as continuous and categoric variables (normal, 18.5 to <25; overweight, 25 to <30; and obese, >30). Multivariable linear regression was used to identify variables associated with percentage of total time at a pH less than 4. The primary predictor of interest was BMI; age, sex, esophagitis, and hiatal hernia status were considered potential confounders or precision variables. RESULTS: Esophageal acid exposure was associated significantly (P < .001) with BMI. The percentage of time at a pH less than 4 and total symptomatic reflux events increased significantly (P = .005) with increasing BMI. The relationship between percentage of time at a pH less than 4 and BMI was nonlinear and S-shaped. With BMI ranges, the percentage of time at a pH less than 4 increased by 0.23% (normal BMI), 0.75% (overweight), and 0.07% (obese) for every 1-kg/m(2) increase in BMI (P < .001). CONCLUSIONS: Increases in esophageal acid exposure are greatest among overweight patients and plateau in obese patients. The findings have implications for benefit of weight loss in patients with suspected extraesophageal manifestations of gastroesophageal reflux disease. PMID- 22226894 TI - Selective double quantum resolved correlation experiment for the complete separation of entire proton NMR spectra of enantiomers. AB - The present study reports a two dimensional NMR experiment which separates single quantum spectra of enantiomers from that of a racemic mixture. This is a blend of selective double quantum refocusing, for resolving couplings and chemical shift interactions along two dimensions followed by correlation of the selectively excited protons to the entire coupled spin network. The concept is solely based on the presence of distinct intra methyl dipolar couplings of different enantiomers when dissolved in chiral orienting media. The analysis of single enantiomer spectrum obtained from respective F(2) cross sections yield all the spectral information. PMID- 22226895 TI - The charge excitation in the Raman process as correlated from a classical theory for Raman optical activity: the case study of (+)-(R)-methyloxirane. AB - We developed a classical algorithm to calculate the spectral signs in the Raman optical activity (ROA) spectrum. In this algorithm, the charge re-distributions among the bonds, which are associated to the bond polarizabilities, are included. For (+)-(R)-methyloxirane, we found that if these bond polarizabilities are attributed to the atoms and are properly scaled in order to be combined with the Mulliken charges on the atoms in the ground state, then the experimental ROA spectral signs can be well reproduced. Furthermore, in this process, we are able to determine that around 20% of the electrons in the molecule are excited in the Raman process. PMID- 22226896 TI - A spectroscopic investigations of anticancer drugs binding to bovine serum albumin. AB - The binding of anticancer drugs (i) Uracil (U), (ii) 5-Fluorouracil (5FU) and (iii) 5-Chlorouracil (5ClU), to bovine serum albumin (BSA) at two levels of temperature was studied by the fluorescence of quenching method. UV/Vis, time resolved fluorescence, Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance ((1)H NMR) and scanning electron microscope (SEM) analyses were also made. Binding constants (K(a)) and binding sites (n) at various levels of temperature were calculated. The obtained binding sites were found to be equal to one for all the three quenchers (U, 5FU and 5ClU) at two different temperature levels. Thermodynamic parameters DeltaH, DeltaG and DeltaS have been calculated and were presented in tables. Change in FTIR absorption intensity shows strong binding of anticancer drugs to BSA. Changes in chemical shifts of NMR and fluorescence lifetimes of the drugs indicate the presence of interaction and binding of BSA to anticancer drugs. (1)H NMR spectra and SEM photographs also conform this binding. PMID- 22226897 TI - FTIR, FT-Raman, FT-NMR, UV-visible and quantum chemical investigations of 2-amino 4-methylbenzothiazole. AB - The FT-IR (4000-400 cm(-1)) and FT-Raman (4000-100 cm(-1)) spectral measurements and complete assignments of the observed spectra of 2-amino-4-methylbenzothiazole (2A4MBT) have been proposed. Ab initio and DFT calculations have been performed and the structural parameters of the compound were determined from the optimised geometry with 6-31G(d,p), 6-311++G(d,p) and cc-pVDZ basis sets and giving energies, harmonic vibrational frequencies, depolarisation ratios, IR intensities and Raman activities. (1)H and (13)C NMR spectra were recorded and (1)H and (13)C nuclear magnetic resonance chemical shifts of the molecule were calculated using the gauge independent atomic orbital (GIAO) method. UV-visible spectrum of the compound was also recorded and the electronic properties, such as HOMO, LUMO and band gap energies were measured by time-dependent DFT (TD-DFT) approach. The geometric parameters, energies, harmonic vibrational frequencies, IR intensities, Raman activities chemical shifts and absorption wavelengths were compared with the available experimental data of the molecule. The influences of methyl and amino groups on the skeletal modes and on the proton chemical shifts have been investigated. PMID- 22226898 TI - Cationic pyridinium porphyrins appending different peripheral substituents: spectroscopic studies on their interactions with bovine serum albumin. AB - The interaction of cationic pyridinium porphyrins appending methylpyridyl, hydroxyphenyl, propionoxyphenyl or carboxyphenyl group at meso-20-position of porphyrin core with bovine serum albumin (BSA), was studied by the combination of absorption spectroscopy, surface-enhanced Raman spectroscopy (SERS), circular dichroism (CD) spectroscopy, fluorescence spectroscopy and synchronous spectroscopy. The spectral monitoring results indicate that the studied compounds could bind with the BSA molecule and the calculated binding constants show that the tetracationic porphyrin has higher binding affinity than those tricationic ones. The interactions between porphyrins and BSA employ an electrostatic binding mechanism and there was only one binding site which located on the surface of the protein molecule. PMID- 22226899 TI - Spectrophotometric studies of reactions between pseudo-ephedrine with different inorganic and organic reagents and its micro-determination in pure and in pharmaceutical preparations. AB - Two simple, sensitive, cheep and reliable spectrophotometric methods are suggested for micro-determination of pseudoephedrine in its pure form and in pharmaceutical preparation (Sinofree Tablets). The first one depends on the drug reaction with inorganic sensitive reagent like molybdate anion in aqueous media via formation of ion-pair mechanism. The second one depends on the drug reaction with pi-acceptor reagent like DDQ in non-aqueous media via formation of charge transfer complex. These reactions were studied under various conditions and the optimum parameters were selected. Under proper conditions the suggested procedures were successfully applied for micro-determination of pseudoephedrine in pure and in Sinofree Tablets without interference from excepients. The values of SD, RSD, recovery %, LOD, LOQ and Sandell sensitivity refer to the high accuracy and precession of the applied procedures. The results obtained were compared with the data obtained by an official method, referring to confidence and agreement with DDQ procedure results; but it referred to the more accuracy of the molybdate data. Therefore, the suggested procedures are now successfully being applied in routine analysis of this drug in its pharmaceutical formulation (Sinofree) in Saudi Arabian Pharmaceutical Company (SPIMACO) in Boridah El Qaseem, Saudi Arabia instead of imported kits had been previously used. PMID- 22226901 TI - Predictive information processing is a fundamental learning mechanism present in early development: evidence from infants. AB - Evidence is presented that predictive coding is fundamental to brain function and present in early infancy. Indeed, mismatch responses to unexpected auditory stimuli are among the earliest robust cortical event-related potential responses, and have been measured in young infants in response to many types of deviation, including in pitch, timing, and melodic pattern. Furthermore, mismatch responses change quickly with specific experience, suggesting that predictive coding reflects a powerful, early-developing learning mechanism. PMID- 22226902 TI - Hierarchical structure of the cognitive processes in schizophrenia: the fundamental role of processing speed. AB - OBJECTIVE: Decreased processing speed (PS) is a key feature of schizophrenia with respect to cognition, functional outcome and clinical symptoms. Our objective was to test whether PS slowing mediates other neuropsychological deficits among patients with chronic schizophrenia. METHOD: One hundred patients with schizophrenia and 53 healthy adults completed a series of neuropsychological measures that assess six cognitive domains. In addition to PS these included attention, verbal memory, visual memory, working memory, and executive functioning. Confirmatory factor analysis (CFA) was used to evaluate the fit of the 6-factor model. The cognitive performances of both groups were compared before and after controlling for the effect of PS, but also after controlling for the effect of each cognitive factor at a time. Finally, the PS-related variance was removed and the effect of the other cognitive factors was tested again. RESULTS: CFA supported the hypothesized 6-factor cognitive structure. As expected, the patients and controls differed on all cognitive measures. However, after controlling for the effects of PS, group differences on the other five cognitive factors decreased substantially. Controlling for other factors produced smaller attenuation of group differences, and these effects were also partially accounted for by decreased PS. CONCLUSIONS: PS deficits account for most of the differences in cognition between patients with schizophrenia and healthy controls. PS slowing appears to be a core feature of schizophrenia, one that underlies impairments of working memory, executive functioning, and other abilities. PMID- 22226900 TI - K-complexes are not preferentially evoked to combat sounds in combat-exposed Vietnam veterans with and without post-traumatic stress disorder. AB - The primary objective was to compare the evoked K-complex response to salient versus non-salient auditory stimuli in combat-exposed Vietnam veterans with and without post-traumatic stress disorder (PTSD). Three categories of auditory stimuli (standard 1000Hz tones, trauma-related combat sounds, and affectively neutral environmental sounds) were presented during stage 2 sleep utilizing an oddball paradigm with probabilities of occurrence of 60%, 20% and 20% respectively. Twenty-four combat-exposed Vietnam veterans, 14 with PTSD and 10 without PTSD were studied in a sleep laboratory at the National Center for PTSD in Menlo Park, CA. While significantly fewer K-complexes overall were elicited in patients, there were no differences in the proportion of K-complexes elicited by tones and combat stimuli within either group. Patients produced significantly more K-complexes to neutral stimuli than to tone or combat stimuli. Examination of the N550 component of the evoked K-complex revealed significantly longer latencies in the patient group. Across the entire sample, N550 latencies were longer for combat stimuli relative to tone neutral stimuli. There were no group or stimulus category differences for N550 amplitude. The results suggest that salient information, as defined by trauma-related combat sounds, did not preferentially elicit K-complexes in either the PTSD group or the control group, suggesting that K-complexes function to protect sleep more than to endogenously process meaningful stimuli. PMID- 22226903 TI - Abnormal connectivity between attentional, language and auditory networks in schizophrenia. AB - Brain circuits involved in language processing have been suggested to be compromised in patients with schizophrenia. This does not only include regions subserving language production and perception, but also auditory processing and attention. We investigated resting state network connectivity of auditory, language and attention networks of patients with schizophrenia and hypothesized that patients would show reduced connectivity. Patients with schizophrenia (n = 45) and healthy controls (n = 30) underwent a resting state fMRI scan. Independent components analysis was used to identify networks of the auditory cortex, left inferior frontal language regions and the anterior cingulate region, associated with attention. The time courses of the components where correlated with each other, the correlations were transformed by a Fisher's Z transformation, and compared between groups. In patients with schizophrenia, we observed decreased connectivity between the auditory and language networks. Conversely, patients showed increased connectivity between the attention and language network compared to controls. There was no relationship with severity of symptoms such as auditory hallucinations. The decreased connectivity between auditory and language processing areas observed in schizophrenia patients is consistent with earlier research and may underlie language processing difficulties. Altered anterior cingulate connectivity in patients may be a correlate of habitual suppression of unintended speech, or of excessive attention to internally generated speech. This altered connectivity pattern appears to be present independent of symptom severity, and may be suggestive of a trait, rather than a state characteristic. PMID- 22226904 TI - HPA axis function and symptoms in adolescents at clinical high risk for schizophrenia. AB - BACKGROUND: Stress sensitivity and HPA axis activity may be relevant to the development and expression of psychotic disorders. Cortisol secretion has been associated with positive symptoms both in patients with psychotic disorders and in young people at clinical risk for psychosis. Herein, we aimed to replicate these findings, to determine which positive symptoms may be associated with cortisol levels, and to explore any associations with affective symptoms and impaired stress tolerance. METHODS: Thirty-one clinical high risk patients were evaluated in cross-section for associations between salivary cortisol levels upon clinic entry at 11 am, demographic variables, and clinical symptoms. RESULTS: Salivary cortisol levels were unrelated to medication exposure or demographics, except for higher levels in the ten females studied. Salivary cortisol bore no relationship to overall positive symptom severity but was associated with anxiety, as well as with suspiciousness and impaired stress tolerance, which were themselves highly intercorrelated. CONCLUSIONS: Cortisol secretion in the context of a putative novel social situation (i.e. clinic entry) may be a biological correlate of suspiciousness, impaired stress tolerance and affective symptoms in individuals vulnerable to developing psychosis. These associations are consistent with findings from experience sampling studies in individuals at risk for psychosis as well as basic studies of animal models of schizophrenia. PMID- 22226905 TI - OxLDL causes both epigenetic modification and signaling regulation on the microRNA-29b gene: novel mechanisms for cardiovascular diseases. AB - MicroRNA-29b has been reported to epigenetically regulate proatherogenic genes in response to oxLDL. Since transcription factors and epigenetic regulations are important mechanisms to regulate gene expression, we investigated whether these mechanisms are involved in oxLDL-induced microRNA-29b upregulation. First, we confirmed that microRNA-29b expression was increased in the aorta of mice fed with a high-fat diet, which was consistent with our previous in vitro findings. Next, we found that oxLDL only activated the microRNA-29b-1/microRNA-29a cluster gene on chromosome 7 but not the other distinct microRNA-29b gene located on chromosome 1. Using the promoter reporter assay and chromatin immunoprecipitation, activator protein-1 (AP-1) was shown to bind to the microRNA 29b-1 promoter. We further identified the signaling pathway of LOX 1/Ca(2+)/ROS/ERK/c-Fos was involved in oxLDL-mediated microRNA-29b overexpression after treating with the MAPTAM (Ca(2+) chelator), NAC (ROS scavenger), U0126 (ERK inhibitor) and c-Fos (one of the AP-1 proteins) shRNA, respectively. To investigate epigenetic regulations, we found that microRNA-29b promoter contained no CpG islands for DNA methylation. Therefore we investigated whether histone modifications influence microRNA-29b promoter activity. We showed that down regulation of HDAC1 and the modifications on histone 3 lysine 4 (H3K4) and H3K9 significantly affected microRNA-29b expression. Furthermore, knockdown of c-Fos expression attenuated the effect of oxLDL-induced histone modifications on the microRNA-29b gene expression. Taken together, our data suggest that both transcription factor activation and histone modifications are important regulatory mechanisms of oxLDL-induced atherogenic process. This article is part of a Special Issue entitled OxLDL causes both epigenetic modification and signaling regulation on the microRNA-29b gene: Novel mechanisms for cardiovascular diseases. PMID- 22226906 TI - Nebivolol regulates eNOS and iNOS expressions and alleviates oxidative stress in cerebral ischemia/reperfusion injury in rats. AB - AIMS: Oxidative stress-induced cell damage is reported to contribute to the pathogenesis of cerebral ischemia/reperfusion injury. This study investigated the neuroprotective effect of nebivolol against cerebral ischemia/reperfusion insult in rats. MAIN METHODS: The model adopted was that of surgically-induced forebrain ischemia, performed by means of bilateral common carotid artery occlusion for 1h, followed by reperfusion for 24 h. The effects of 5 and 10 mg/kg nebivolol, treated for 7 days prior to ischemia/reperfusion insult, were investigated by estimating endothelial and inducible nitric oxide synthases (eNOS and iNOS) protein expressions and assessing oxidative stress-related biochemical parameters in the rat forebrain. Also, infarct volume measurement and histopathological study of the forebrain were examined. KEY FINDINGS: Administration of nebivolol increased eNOS expression with simultaneous decrease in iNOS expression in a dose dependent manner. Moreover, nebivolol inhibited ischemia/reperfusion-induced depletion of reduced glutathione level and decreased the elevated total nitric oxide end production and malondialdehyde levels, superoxide dismutase and lactate dehydrogenase activities. A notable finding is that catalase activity was not changed in response to either ischemia/reperfusion insult or nebivolol treatment. However, the results confirmed that nebivolol significantly reduced infarct volume and alleviated ischemia/reperfusion-induced histopathological changes. SIGNIFICANCE: The present study demonstrates the neuroprotective effect of nebivolol against cerebral ischemia/reperfusion insult. Neuroprotection observed with nebivolol may possibly be explained by regulating eNOS and iNOS expressions and by inhibition of oxidative stress-induced injury. Thus, nebivolol may be considered as a potential candidate for treatment in patients who are prone to stroke. PMID- 22226907 TI - T cell responses to DosR and Rpf proteins in actively and latently infected individuals from Colombia. AB - Mycobacterium tuberculosis DosR regulon-encoded proteins elicit strong immune T cell responses in individuals with latent tuberculosis (LTBI). Also, resuscitation (Rpf) proteins can induce such responses. However, variations in the immunogenicity of the DosR and Rpf proteins have been observed in European and African populations, and no data are published from other geographic areas. In Colombian LTBI and patients with recently diagnosed PTB, we therefore studied the immune response to DosR, Rpf, stress, and nominal antigens from Mtb, in 7-day stimulated cultures. Three DosR (Rv1737c, Rv2029c, Rv2628c) and 2 Rpf (Rv0867 and Rv2389c) antigens were recognized most prominently on the basis of the net IFNgamma production (DosR) or the percentage of responding individuals (Rpf). Results show that the selected DosR antigens induced a higher proportion of CD4-T cells producing IFNgamma from LTBI, compared to pulmonary TB patients (PTB), while there were no differences in the proportion of CD8-T cells. An increased frequency of CD4, but not CD8 T-cells with a CD45RO(+)CD27(+) phenotype was observed in LTBI in response to Rv2029c, Rv0867c, and Rv2389c, compared to PTB. The levels of cytokines and chemokines in the supernatants of stimulated cells, showed that the DosR and Rpf antigens induced higher levels of IFNgamma in cultures from LTBI compared to PTB, although the induced pattern of cytokines and chemokines was also antigen dependent. In summary, our results are consistent with the significant immunogenicity of Mtb DosR and Rpf antigens in LTBI individuals, and confirm and extend previously reported data from other TB affected human populations. PMID- 22226908 TI - Rapid imaging of mycoplasma in solution using Atmospheric Scanning Electron Microscopy (ASEM). AB - Mycoplasma is a genus of bacterial pathogen that causes disease in vertebrates. In humans, the species Mycoplasma pneumoniae causes 15% or more of community acquired pneumonia. Because this bacterium is tiny, corresponding in size to a large virus, diagnosis using optical microscopy is not easy. In current methods, chest X-rays are usually the first action, followed by serology, PCR amplification, and/or culture, but all of these are particularly difficult at an early stage of the disease. Using Mycoplasma mobile as a model species, we directly observed mycoplasma in buffer with the newly developed Atmospheric Scanning Electron Microscope (ASEM). This microscope features an open sample dish with a pressure-resistant thin film window in its base, through which the SEM beam scans samples in solution, from below. Because of its 2-3MUm-deep scanning capability, it can observe the whole internal structure of mycoplasma cells stained with metal solutions. Characteristic protein localizations were visualized using immuno-labeling. Cells were observed at low concentrations, because suspended cells concentrate in the observable zone by attaching to sialic acid on the silicon nitride (SiN) film surface within minutes. These results suggest the applicability of the ASEM for the study of mycoplasmas as well as for early-stage mycoplasma infection diagnosis. PMID- 22226909 TI - Functional characterization of the pleckstrin homology domain of a cellulose synthase from the oomycete Saprolegnia monoica. AB - Some oomycetes, for instance Saprolegnia parasitica, are severe fish pathogens that cause important economic losses worldwide. Cellulose biosynthesis is a vital process for this class of microorganisms, but the corresponding molecular mechanisms are poorly understood. Of all cellulose synthesizing enzymes known, only some oomycete cellulose synthases contain a pleckstrin homology (PH) domain. Some human PH domains bind specifically to phosphoinositides, but most PH domains bind phospholipids in a non-specific manner. In addition, some PH domains interact with various proteins. Here we have investigated the function of the PH domain of cellulose synthase 2 from the oomycete Saprolegnia monoica (SmCesA2), a species closely related to S. parasitica. The SmCesA2 PH domain is similar to the C-terminal PH domain of the human protein TAPP1. It binds in vitro to phosphoinositides, F-actin and microtubules, and co-localizes with F-actin in vivo. Our results suggest a role of the SmCesA2 PH domain in the regulation, trafficking and/or targeting of the cell wall synthesizing enzyme. PMID- 22226910 TI - Infection control 'undercover': a patient experience. PMID- 22226911 TI - Influence of oxygen limitation, absence of the cytochrome bc(1) complex and low pH on global gene expression in Gluconobacter oxydans 621H using DNA microarray technology. AB - The genome-wide transcriptional responses of the strictly aerobic alpha proteobacterium Gluconobacter oxydans 621H to oxygen limitation, to the absence of the cytochrome bc(1) complex, and to low pH were studied using DNA microarray analyses. Oxygen limitation caused expression changes of 486 genes, representing 20% of the chromosomal genes. Genes with an increased mRNA level included those for terminal oxidases, the cytochrome bc(1) complex, transhydrogenase, two alcohol dehydrogenases, heme biosynthesis, PTS proteins, proteins involved in cyclic diGMP synthesis and degradation, two sigma factors, flagella and chemotaxis proteins, several stress proteins, and a putative exporter protein. The downregulated genes comprised those for respiratory dehydrogenases, enzymes of central metabolism, PQQ biosynthesis, outer membrane receptors, Sec proteins, and proteins involved in transcription and translation. A DeltaqrcABC mutant of G. oxydans showed a growth defect during cultivation on mannitol at pH 4 under oxygen saturation. Comparison of the transcriptomes of this mutant versus the wild type under these conditions revealed 51 differentially expressed genes. Interestingly, almost all of the 45 genes with increased expression in the DeltaqrcABC mutant at pH 4 were also upregulated in the wild type grown at pH 6 under oxygen limitation. These results support an active role of the cytochrome bc(1) complex in G. oxydans respiration. The transcriptome comparison of G. oxydans wild type at pH 4 versus pH 6 in mannitol medium under oxygen-saturated conditions uncovered only 72 differentially expressed genes. The 35 upregulated genes included those for cytochrome bd oxidase, major polyol dehydrogenase, iron storage and oxidative stress proteins. Among the 37 downregulated genes were some encoding enzymes dealing with carbon dioxide, such as biotin carboxylase, biotin carboxyl carrier protein, and carboanhydrase. These results give first insights into global transcriptional responses of G. oxydans. PMID- 22226912 TI - A rapid generation of adenovirus vector with a genetic modification in hexon protein. AB - The generation of hexon-modified adenovirus vector has proven difficult. In this paper, we developed a novel method for rapid generation of hexon-modified adenoviral vector via one step ligation in vitro followed by quick white/blue color screening. The new system has the following features. First, eGFP expression driven by the CMV promoter in E1 region functions as a reporter to evaluate the tropism of hexon-modified adenovirus in vitro. Second, it has two unique restriction enzyme sites with sticky ends located in the hexon HVR5 region. Third, a lacZ expression cassette under the control of plac promoter is placed between the two restriction enzyme sites, which allows recombinants to be selected using blue/white screening. To prove the principle of the method, genetically modified adenoviruses were successfully produced by insertion of NGR, RGD or Tat PTD peptide into hexon HVR5. Furthermore, the transduction efficiency of the Tat PTD modified virus was shown to be a significant enhancement in A172 and CHO-K1 cells. In conclusion, the novel system makes the production of truly retargeted vectors more promising, which would be of substantial benefit for cancer gene therapy. PMID- 22226913 TI - Medical student research electives: stimulating a new generation of clinician scientists. PMID- 22226914 TI - Validated high performance thin layer chromatographic method for simultaneous quantification of major iridoids in Vitex trifolia and their antioxidant studies. AB - Negundoside (1), agnuside (2) and 6'-p-hydroxy benzoyl mussaenosidic acid (3) are known bioactive metabolites in Vitex trifolia. In the present study a simple precise and reproducible method was developed for simultaneous quantitation of NS (1), AS (2) and HMA (3) and the antioxidant capacity of above markers has also been determined. Marker compounds have been resolved using silica gel 60 F(254) plates, petroleum ether (60-80)/toluene/acetone/water (10:10:80:2 v/v/v/v) as the mobile phases. The method does not employ any derivatisation procedure and can be used as a quality control tool for routine analysis of drugs V. trifolia and V. negundo together with their commercial extracts. NS (1), AS (2) and HMA (3) showed significant activity in DPPH and NO radical scavenging assays. PMID- 22226915 TI - A WWOX-binding molecule, transmembrane protein 207, is related to the invasiveness of gastric signet-ring cell carcinoma. AB - Using the PCR-based subtractive messenger RNA hybridization assay described in this paper, we isolated a hitherto uncharacterized gene, transmembrane protein 207 (TMEM207), which was selectively expressed in collagen gel-invading cultured signet-ring cell carcinoma KATO-III cells. TMEM207 has a C-terminal proline-rich PPxY motif, which binds to the WW domain-containing oxidoreductase, WWOX. Enforced expression of TMEM207 significantly increased Matrigel invasion activity of KATO-III cells in vitro without affecting cell growth. In contrast, expression of TMEM207 with mutations in the PPxY motif did not significantly increase Matrigel invasion activity of KATO-III cells. Immunohistochemical staining showed that TMEM207 was strongly expressed in 7 of 30 gastric signet-ring cell carcinoma tissue specimens. Notably, TMEM207 expression was associated with the depth of cancer invasion and the presence of lymph node metastasis. The results of co immunoprecipitation followed by western immunoblotting showed that TMEM207 is bound to WWOX in a PPxY motif-dependent manner. Small interfering RNA-mediated downregulation of WWOX also significantly increased Matrigel invasion activity of KATO-III cells. Notably, exogenous expression of TMEM207 impaired the WWOX mediated repression of Matrigel invasion activity of another cultured signet-ring cell carcinoma cell line, NUGC-4 cells. Recent studies have highlighted the fact that WWOX acts as a tumor suppressor factor in various malignant tumors, including gastric cancer. On the basis of these findings and the results of the present study, we think that overexpression of TMEM207 may facilitate invasive activity and metastasis of gastric signet-ring cell carcinoma, which possibly occur through binding to WWOX and attenuation of its function. PMID- 22226916 TI - Ku80 functions as a tumor suppressor in hepatocellular carcinoma by inducing S phase arrest through a p53-dependent pathway. AB - Ku80 is a component of the protein complex called DNA-dependent protein kinase, which is involved in DNA double-strand break repair and multiple other functions. Previous studies revealed that Ku80 haplo-insufficient and poly (adenosine diphosphate-ribose) polymerase-null transgenic mice developed hepatocellular carcinoma (HCC) at a high frequency. The role of Ku80 has never been investigated in human HCC. Ku80 expressions in HCC and adjacent liver tissue were investigated by using immunohistochemical staining and western blot. Ku80 was transfected into a Ku80-deficient HCC cell line SMMC7721 cells, and the growth features of the Ku80-expressing cells and vector-transfected cells were studied both in vitro and in vivo. Cell cycle analysis and RNA interference were employed to investigate the mechanisms underlying the growth regulation associated with Ku80 expression. Ku80 was found frequently downregulated in HCC compared with adjacent liver tissue. Ku80 downregulation was significantly correlated with elevated hepatitis B virus-DNA load and severity of liver cirrhosis. Overexpression of Ku80 in SMMC7721 cells significantly suppressed cell proliferation in vitro and in vivo. Ku80 overexpression caused S-phase cell cycle arrest and was associated with upregulation of p53 and p21(CIP1/WAF1), and the inhibition of p53 or p21(CIP1/WAF1) expression by RNA interference overcame the growth suppression and S-phase arrest in the Ku80-expressing cells. A novel mechanism was revealed that Ku80 functions as a tumor suppressor in HCC by inducing S-phase arrest through a p53-dependent pathway. PMID- 22226918 TI - Brown adipose tissue mitochondria oxidizing fatty acids generate high levels of reactive oxygen species irrespective of the uncoupling protein-1 activity state. AB - Mitochondria from brown adipose tissue (BATM) have a high enzymatic capacity for fatty acid oxidation and therefore are an ideal model to examine the sites of reactive oxygen species (ROS) generation during fatty acid oxidation. ROS generation by BATM (isolated from 3-week-old rats) was measured during acylcarnitine oxidation as release of H(2)O(2) into the medium and as inactivation of the matrix enzyme aconitase. The following results were obtained: (1) BATM release large amounts of H(2)O(2) in the coupled as well as in the uncoupled states, several times more than skeletal muscle mitochondria. (2) H(2)O(2) release is especially large with acylcarnitines of medium-chain fatty acids (e.g. octanoylcarnitine). (3) Reverse electron transport does not contribute in a significant extent to the overall ROS generation. (4) Despite the large release of H(2)O(2), the ROS-sensitive matrix enzyme aconitase is not inactivated during acylcarnitine oxidation. (5) In contrast to acylcarnitines, oxidation of alpha-glycerophosphate by BATM is characterized by large H(2)O(2) release and a pronounced aconitase inactivation. We hypothesize that acylcarnitine-supported ROS generation in BATM may be mainly associated with acyl CoA dehydrogenase and electron transferring flavoprotein-ubiquinone reductase rather than with complexes of the respiratory chain. PMID- 22226917 TI - Structural changes that occur upon photolysis of the Fe(II)(a3)-CO complex in the cytochrome ba(3)-oxidase of Thermus thermophilus: a combined X-ray crystallographic and infrared spectral study demonstrates CO binding to Cu(B). AB - The purpose of the work was to provide a crystallographic demonstration of the venerable idea that CO photolyzed from ferrous heme-a(3) moves to the nearby cuprous ion in the cytochrome c oxidases. Crystal structures of CO-bound cytochrome ba(3)-oxidase from Thermus thermophilus, determined at ~2.8-3.2A resolution, reveal a Fe-C distance of ~2.0A, a Cu-O distance of 2.4A and a Fe-C-O angle of ~126 degrees . Upon photodissociation at 100K, X-ray structures indicate loss of Fe(a3)-CO and appearance of Cu(B)-CO having a Cu-C distance of ~1.9A and an O-Fe distance of ~2.3A. Absolute FTIR spectra recorded from single crystals of reduced ba(3)-CO that had not been exposed to X-ray radiation, showed several peaks around 1975cm(-1); after photolysis at 100K, the absolute FTIR spectra also showed a significant peak at 2050cm(-1). Analysis of the 'light' minus 'dark' difference spectra showed four very sharp CO stretching bands at 1970cm(-1), 1977cm(-1), 1981cm(-1), and 1985cm(-1), previously assigned to the Fe(a3)-CO complex, and a significantly broader CO stretching band centered at ~2050cm(-1), previously assigned to the CO stretching frequency of Cu(B) bound CO. As expected for light propagating along the tetragonal axis of the P4(3)2(1)2 space group, the single crystal spectra exhibit negligible dichroism. Absolute FTIR spectrometry of a CO-laden ba(3) crystal, exposed to an amount of X-ray radiation required to obtain structural data sets before FTIR characterization, showed a significant signal due to photogenerated CO(2) at 2337cm(-1) and one from traces of CO at 2133cm(-1); while bands associated with CO bound to either Fe(a3) or to Cu(B) in "light" minus "dark" FTIR difference spectra shifted and broadened in response to X-ray exposure. In spite of considerable radiation damage to the crystals, both X-ray analysis at 2.8 and 3.2A and FTIR spectra support the long held position that photolysis of Fe(a3)-CO in cytochrome c oxidases leads to significant trapping of the CO on the Cu(B) atom; Fe(a3) and Cu(B) ligation, at the resolutions reported here, are otherwise unaltered. PMID- 22226919 TI - Subchronic toxicity study of the total flavonoids from Rosa laevigata Michx fruit in rats. AB - The total flavonoids (TFs) from Rosa laevigata Michx fruit showed hepatoprotective and antioxidant activities. However, the safety of this natural product has not been investigated. In the present paper, a 90-day subchronic toxicity study was conducted, and the tested TFs was orally administered to rats at the doses of 500, 1000 and 2000mg/kg/day. The toxicity of the TFs was evaluated on base of ophthalmic examination, body weight, feed/water consumption, urinalysis, hematology, clinical biochemistry and pathology. No toxic signs of the TFs at the doses of 500 and 1000mg/kg/day were observed. However, decreased PLT was found in the 2000mg/kg/day groups and increased intercellular space of myocardial cells was observed in the male 2000mg/kg/day group compared with control. A significant increase in the relative cardiac weight was observed in the male 1000 and 2000mg/kg/day groups. And the significant decrease in the absolute and relative weight of adrenals in the female 1000 and 2000mg/kg groups was happened. The TFs could cause mild side effects at the dose of 1000mg/kg/day in males and females. Thus, the dose of 500mg/kg/day for male and female were selected as the no-observed-adverse-effect level (NOAEL). The present study provides useful data for subsequent researches and new drug exploration of the TFs from R. laevigata Michx fruit. PMID- 22226920 TI - Characterisation of major component leaching and buffering capacity of RDF incineration and gasification bottom ash in relation to reuse or disposal scenarios. AB - Thermal treatment of refuse derived fuel (RDF) in waste-to-energy (WtE) plants is considered a promising solution to reduce waste volumes for disposal, while improving material and energy recovery from waste. Incineration is commonly applied for the energetic valorisation of RDF, although RDF gasification has also gained acceptance in recent years. In this study we focused on the environmental properties of bottom ash (BA) from an RDF incineration (RDF-I, operating temperature 850-1000 degrees C) and a RDF gasification plant (RDF-G, operating temperature 1200-1400 degrees C), by evaluating the total composition, mineralogy, buffering capacity, leaching behaviour (both at the material's own pH and as a function of pH) of both types of slag. In addition, buffering capacity results and pH-dependence leaching concentrations of major components obtained for both types of BA were analysed by geochemical modelling. Experimental results showed that the total content of major components for the two types of BA was fairly similar and possibly related to the characteristics of the RDF feedstock. However, significant differences in the contents of trace metals and salts were observed for the two BA samples as a result of the different operating conditions (i.e. temperature) adopted by the two RDF thermal treatment plants. Mineralogy analysis showed in fact that the RDF-I slag consisted of an assemblage of several crystalline phases while the RDF-G slag was mainly made up by amorphous glassy phases. The leached concentrations of major components (e.g. Ca, Si) at the natural pH of each type of slag did not reflect their total contents as a result of the partial solubility of the minerals in which these components were chemically bound. In addition, comparison of total contents with leached concentrations of minor elements (e.g. Pb, Cu) showed no obvious relationship for the two types of BA. According to the compliance leaching test results, the RDF-G BA would meet the limits of the Italian legislation for reuse and the European acceptance criteria for inert waste landfilling. RDF-I BA instead would meet the European acceptance criteria for non hazardous waste landfilling. A new geochemical modelling approach was followed in order to predict the leaching behaviour of major components and the pH buffering capacity of the two types of slags on the basis of independent mineralogical information obtained by XRD analysis and the bulk composition of the slag. It was found that the combined use of data regarding the mineralogical characterization and the buffering capacity of the slag material can provide an independent estimate of both the identity and the amount of minerals that contribute to the leaching process. This new modelling approach suggests that only a limited amount of the mineral phases that control the pH, buffering capacity and major component leaching from the solid samples is available for leaching, at least on the time scale of the applied standard leaching tests. As such, the presented approach can contribute to gain insights for the identification of the types and amounts of minerals that control the leaching properties and pH buffering capacity of solid residues such as RDF incineration and gasification bottom ash. PMID- 22226921 TI - Simple scale-up of recombinant antibody production using an UCOE containing vector. AB - Recombinant proteins, in particular antibodies, have become fundamental in biomedical research where they are used in numerous therapeutic and diagnostic applications. For this reason there is an increasing demand for quick and economical production systems for recombinant proteins in mammalian cells. PMID- 22226922 TI - Molecular characterisation of high-level gentamicin-resistant enterococci from bloodstream infections in Denmark: first description of clonal spread of aph(2'') Ib. PMID- 22226923 TI - Mechanism of resistance of a highly carbapenem-resistant Klebsiella oxytoca isolate and comparison of susceptibility to five carbapenems. PMID- 22226924 TI - Production of UCP1 a membrane protein from the inner mitochondrial membrane using the cell free expression system in the presence of a fluorinated surfactant. AB - Structural studies of membrane protein are still challenging due to several severe bottlenecks, the first being the overproduction of well-folded proteins. Several expression systems are often explored in parallel to fulfil this task, or alternately prokaryotic analogues are considered. Although, mitochondrial carriers play key roles in several metabolic pathways, only the structure of the ADP/ATP carrier purified from bovine heart mitochondria was determined so far. More generally, characterisations at the molecular level are restricted to ADP/ATP carrier or the uncoupling protein UCP1, another member of the mitochondrial carrier family, which is abundant in brown adipose tissues. Indeed, mitochondrial carriers have no prokaryotic homologues and very few efficient expression systems were described so far for these proteins. We succeeded in producing UCP1 using a cell free expression system based on E. coli extracts, in quantities that are compatible with structural approaches. The protein was synthesised in the presence of a fluorinated surfactant, which maintains the protein in a soluble form. Further biochemical and biophysical analysis such as size exclusion chromatography, circular dichroism and thermal stability, of the purified protein showed that the protein is non-aggregated, monodisperse and well folded. PMID- 22226925 TI - Key factors influencing the implementation success of a home telecare application. AB - RATIONALE: The introduction of home telecare in healthcare organizations has shown mixed results in practice. The aim of this study is to arrive at a set of key factors that can be used in further implementation of video communication. We argue that key factors are mainly found in the organizational climate for home telecare implementation, the characteristics of the implementation strategy and the available technology. METHODS: Interviews were conducted in three care organizations with 27 respondents of different levels within and outside the organization. Implementation determinants, based on earlier research, were used as a categorization framework for the interviews. RESULTS: We found that most prominent factors influencing implementation outcomes relate to the stability of the technical and the external environment and the alignment of organization, goals and implementation strategy. CONCLUSION: Because of the experimental nature of implementing video communication, attention to telecare influencers has been inconsistent and disorganized but it is becoming increasingly important. According to the respondents, a champion-led roll-out is imperative for implementation in order to advance to the next stage in home telecare and to organize services for substitution of care. PMID- 22226926 TI - Characterizing "information transfer" by using a Joint Cognitive Systems model to improve continuity of care in the aged. AB - PURPOSE: This study explores multidisciplinary and cross-sector health professional experiences with the information needs for safe patient transfers across the care continuum using a Joint Cognitive Systems (JCS) model. Qualitative experiences of three JCS components and their attributes and are presented. METHODS: A qualitative content analysis using Joint Cognitive Systems constructs were extracted from sixteen multidisciplinary and cross-sector health professional interviews. Participants were asked to describe their information needs and experiences with the patient transfer process. RESULTS: Information transfer associated with three JCS constructs (alignment of goals, enhanced control, and co-agency dynamics) was examined. The breakdown in the information transfer process might be due to the relative strengths of each sector's core expertise. Alignment must cross settings and disciplines and consist of the: (1) transfer of goal relevant and integrated information; (2) accommodation to the control attributes of increased clinical complexity, lack of systematic work processes and feedback or feed forward information; and (3) improvement in the co agency dynamics of interdependency, trust, inter-related actions and expertise. CONCLUSIONS: Economic pressures and care complexities of the aged require improved effectiveness and efficiencies in the information transfer process. This study aims to understand the information transfer needs from hospitals to skilled nursing care laying a foundation towards a medical informatics solution. An informatics solution must accommodate the differing contextual environments and subsequent information needs and paradigms of the Joint Cognitive System of care across the continuum. PMID- 22226927 TI - Prospective pilot study of a tablet computer in an Emergency Department. AB - BACKGROUND: The recent availability of low-cost tablet computers can facilitate bedside information retrieval by clinicians. OBJECTIVE: To evaluate the effect of physician tablet use in the Emergency Department. DESIGN: Prospective cohort study comparing physician workstation usage with and without a tablet. SETTING: 55,000 visits/year Level 1 Emergency Department at a tertiary academic teaching hospital. PARTICIPANTS: 13 emergency physicians (7 Attendings, 4 EM3s, and 2 EM1s) worked a total of 168 scheduled shifts (130 without and 38 with tablets) during the study period. INTERVENTION: Physician use of a tablet computer while delivering direct patient care in the Emergency Department. MAIN OUTCOME MEASURES: The primary outcome measure was the time spent using the Emergency Department Information System (EDIS) at a computer workstation per shift. The secondary outcome measure was the number of EDIS logins at a computer workstation per shift. RESULTS: Clinician use of a tablet was associated with a 38min (17-59) decrease in time spent per shift using the EDIS at a computer workstation (p<0.001) after adjusting for clinical role, location, and shift length. The number of logins was also associated with a 5-login (2.2-7.9) decrease per shift (p<0.001) after adjusting for other covariates. CONCLUSION: Clinical use of a tablet computer was associated with a reduction in the number of times physicians logged into a computer workstation and a reduction in the amount of time they spent there using the EDIS. The presumed benefit is that decreasing time at a computer workstation increases physician availability at the bedside. However, this association will require further investigation. PMID- 22226928 TI - Contrasting benefits from contralateral implants and hearing aids in cochlear implant users. AB - In recent years a substantial number of studies have reported results from cochlear implant users who increasingly are being fitted with a contralateral hearing aid or second implant. Often outcomes are discussed in relation to the benefits available to listeners with normal hearing in both ears. The objective of this paper is to consider the available cues that are degraded in different ways when a cochlear implant is combined with a contralateral hearing aid or second implant, and to review the literature in that context. It is found that the data largely confirm the expectations that arise from those considerations, and that outcomes differ substantially for the two types of listeners, with a greater emphasis on better ear selection and comparison of information at the two ears for bilateral implant users, and conversely, on the complementary use of information from the two ears in bimodal listeners. PMID- 22226929 TI - Firategrast for relapsing remitting multiple sclerosis: a phase 2, randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Monoclonal antibody therapy against alpha4beta-integrin is efficacious in patients with multiple sclerosis (MS) with some safety concerns. We assessed the safety and efficacy of firategrast, a small oral anti-alpha4beta integrin molecule, in patients with relapsing remitting MS. METHODS: We did a multicentre, phase 2, randomised, double-blind, placebo-controlled, dose-ranging study in participants with clinically definite relapsing-remitting MS. A 24-week treatment period was followed by 12 weeks of core follow-up and 40 weeks of extended follow-up. Participants were randomly assigned, via computer-generated block randomisation in a 1:2:2:2 ratio, to receive one of four treatments twice a day: firategrast 150 mg, firategrast 600 mg, or firategrast 900 mg (women) or 1200 mg (men), or placebo. Brain scans were obtained at 4-week intervals to the end of core follow-up. The primary outcome was cumulative number of new gadolinium-enhancing brain lesions during the treatment phase and was analysed using a generalised linear model with an underlying negative binomial distribution, adjusted for sex, baseline number of new gadolinium-enhancing lesions, and country. This study is registered with ClinicalTrials.gov, NCT00395317. FINDINGS: Of 343 individuals enrolled, 49 received firategrast 150 mg, 95 received firategrast 600 mg, 100 received firategrast 900 mg or 1200 mg, and 99 received placebo. A 49% reduction (95% CI 21.2-67.6; p=0.0026) in the cumulative number of new gadolinium-enhancing lesions was seen for the 900 mg or 1200 mg firategrast group (n=92, mean number of lesions 2.69 [SE 1.18]) versus the placebo group (90, 5.31 [1.18]). In the 600 mg group (86, 4.12 [SE 1.19]), a non-significant 22% reduction (95% CI -21.3 to 49.7; p=0.2657) occurred in mean number of new gadolinium-enhanced lesions relative to placebo; for the 150 mg group (47, 9.51 [SE 1.24]), a 79% increase (95% CI 4.1-308.1; p=0.0353) occurred relative to placebo. Firategrast was generally well tolerated at all doses. The frequency of all adverse events was similar across all treatment groups except for an increased rate of urinary tract infections in the high-dose firategrast group. No cases of progressive multifocal leukoencephalopathy or evidence of reactivation of JC virus were identified. INTERPRETATION: This study showed efficacy on imaging endpoints for firategrast at the highest dose tested, and suggests that further investigation of oral short-acting alpha4beta integrin blockade therapies is warranted. FUNDING: GlaxoSmithKline. PMID- 22226930 TI - Firategrast: natalizumab in a pill? PMID- 22226931 TI - Pyrroloquinoline quinone modulates the kinetic parameters of the mammalian selenoprotein thioredoxin reductase 1 and is an inhibitor of glutathione reductase. AB - Pyrroloquinoline quinone (PQQ) is a redox active cofactor for bacterial quinoproteins. Dietary PQQ also has prominent physiological effects in mammals although no mammalian quinoprotein has yet been conclusively identified. Here we found that PQQ has substantial effects on the redox active mammalian selenoprotein thioredoxin reductase 1 (TrxR1). PQQ efficiently inhibited the activity of TrxR1 with its main native substrate thioredoxin and acted as a low efficiency substrate in a Sec-dependent TrxR1-catalyzed reduction. Interestingly, PQQ also stimulated redox cycling of TrxR1 with another quinone substrate, juglone, as much as 13-fold (k(cat)/K(m) increased from 105 min(-1) MUM(-1) to 1331 min(-1) MUM(-1) for juglone in the presence of 50 MUM PQQ, mainly through a lowered apparent K(m) for juglone). Glutathione reductase was also inhibited by PQQ but in contrast to the effects of PQQ on TrxR1, its quinone reduction was not further stimulated. These results reveal that glutathione reductase and the mammalian selenoprotein TrxR1 are direct PQQ protein targets, although not being genuine quinoproteins. These findings may help explain several of the effects of PQQ seen in mammals. PMID- 22226932 TI - Role of autophagy in chemoresistance: regulation of the ATM-mediated DNA-damage signaling pathway through activation of DNA-PKcs and PARP-1. AB - Capsaicin treatment was previously reported to reduce the sensitivity of breast cancer cells, but not normal MCF10A cells, to apoptosis. The present study shows that autophagy is involved in cellular resistance to genotoxic stress, through DNA repair. Capsaicin treatment of MCF-7 cells induced S-phase arrest and autophagy through the AMPKalpha-mTOR signaling pathway and the accumulation of p53 in the nucleus and cytosol, including a change in mitochondrial membrane potential. Capsaicin treatment also activated delta-H2AX, ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and poly(ADP-ribose) polymerase (PARP)-1. Genetic or pharmacological disruption of autophagy attenuated capsaicin-induced phospho-ATM and phospho-DNA-PKcs and enhanced apoptotic cell death. ATM inhibitors, including Ku55933 and caffeine, and the genetic or pharmacological inhibition of p53 prevented capsaicin-induced DNA-PKcs phosphorylation and stimulated PARP-1 cleavage, but had no effect on microtubule-associated protein light chain 3 (LC3)-II levels. Ly294002, a DNA PKcs inhibitor, boosted the capsaicin-induced cleavage of PARP-1. In M059K cells, but not M059J cells, capsaicin induced ATM and DNA-PKcs phosphorylation, p53 accumulation, and the stimulation of LC3II production, all of which were attenuated by knockdown of the autophagy-related gene atg5. Ku55933 attenuated capsaicin-induced phospho-DNA-PKcs, but not LC3II, in M059K cells. In human breast tumors, but not in normal tissues, AMPKalpha, ATM, DNA-PKcs, and PARP-1 were activated and LC3II was induced. The induction of autophagy by genotoxic stress likely contributes to the sustained survival of breast cancer cells through DNA repair regulated by ATM-mediated activation of DNA-PKcs and PARP-1. PMID- 22226933 TI - Implementations of the HL7 Context-Aware Knowledge Retrieval ("Infobutton") Standard: challenges, strengths, limitations, and uptake. AB - To support clinical decision-making, computerized information retrieval tools known as "infobuttons" deliver contextually-relevant knowledge resources into clinical information systems. The Health Level Seven International (HL7) Context Aware Knowledge Retrieval (Infobutton) Standard specifies a standard mechanism to enable infobuttons on a large scale. OBJECTIVE: To examine the experience of organizations in the course of implementing the HL7 Infobutton Standard. METHOD: Cross-sectional online survey and in-depth phone interviews. RESULTS: A total of 17 organizations participated in the study. Analysis of the in-depth interviews revealed 20 recurrent themes. Implementers underscored the benefits, simplicity, and flexibility of the HL7 Infobutton Standard. Yet, participants voiced the need for easier access to standard specifications and improved guidance to beginners. Implementers predicted that the Infobutton Standard will be widely or at least fairly well adopted in the next 5 years, but uptake will depend largely on adoption among electronic health record (EHR) vendors. To accelerate EHR adoption of the Infobutton Standard, implementers recommended HL7-compliant infobutton capabilities to be included in the United States Meaningful Use Certification Criteria for EHR systems. LIMITATIONS: Opinions and predictions should be interpreted with caution, since all the participant organizations have successfully implemented the standard and over half of the organizations were actively engaged in the development of the standard. CONCLUSION: Overall, implementers reported a very positive experience with the HL7 Infobutton Standard. Despite indications of increasing uptake, measures should be taken to stimulate adoption of the Infobutton Standard among EHR vendors. Widespread adoption of the Infobutton Standard has the potential to bring contextually relevant clinical decision support content into the healthcare provider workflow. PMID- 22226934 TI - TTC-based screening assay for omega-transaminases: a rapid method to detect reduction of 2-hydroxy ketones. AB - A rapid TTC-based screening assay for omega-transaminases was developed to determine the conversion of substrates with a 2-hydroxy ketone motif. Oxidation of the compounds in the presence of 2,3,5-triphenyltetrazolium chloride (TTC) results in a reduction of the colourless TTC to a red-coloured 1,3,5 triphenylformazan. The enzymatic reductive amination of a wide range of various aliphatic, aliphatic-aromatic and aromatic-aromatic 2-hydroxy ketones can be determined by the decrease of the red colouration due to substrate consumption. The conversion can be quantified spectrophotometrically at 510 nm based on reactions, e.g. with crude cell extracts in 96-well plates. Since the assay is independent of the choice of diverse amine donors a panel of omega-transaminases was screened to detect conversion of 2-hydroxy ketones with three different amine donors: l-alanine, (S)-alpha-methylbenzylamine and benzylamine. The results could be validated using HPLC and GC analyses, showing a deviation of only 5-10%. Using this approach enzymes were identified demonstrating high conversions of acetoin and phenylacetylcarbinol to the corresponding amines. Among these enzymes three novel wild-type omega-transaminases have been identified. PMID- 22226935 TI - Induction of ovarian follicular wave emergence and ovulation in progestin-based timed artificial insemination protocols for Bos indicus cattle. AB - The present study aimed to evaluate the efficacy of different inducers of new follicular wave emergence (FWE) and ovulation in fixed-time artificial insemination (FTAI) synchronization protocols using norgestomet ear implants (NORG) in Bos indicus cattle. In Experiment 1, the synchronization of FWE was evaluated when two different estradiol esters in different doses [2mg estradiol benzoate (EB), 2.5mg EV or 5mg estradiol valerate (EV)] were administered with NORG implant insertion in B. indicus cattle (estrous cyclic heifers and cows with suckling calves; n=10 per treatment). After estradiol treatment, ovarian ultrasonic exams were performed once daily to detect the interval between treatment and FWE. There were significant treatment-by-animal category interaction (P=0.05) on the interval from the estradiol treatment to FWE. An earlier (P<0.0001) and less variable (P=0.02) interval from estradiol treatment to FWE was observed in heifers treated with EB (2.5+/-0.2; mean+/-SE) than in those treated with 2.5mg EV (4.2+/-0.3) or 5mg EV (6.1+/-0.6). Cows treated with 5mg EV (4.0+/-0.5) had longer (P=0.05) interval than cows receiving EB (2.5+/ 0.2), however, there was an intermediate interval in those cows treated with 2.5mg EV (3.1+/-0.4). In Experiment 2, the number of uses of the NORG implant (new; n=305 or previously used once; n=314) and three different ovulation induction hormones [0.5mg estradiol cypionate (EC) at implant removal (n=205), 1mg EB given 24h after implant removal (n=219), or 100MUg gonadorelin (GnRH) given at FTAI (n=195)] were evaluated in Nelore heifers (2*3 factorial design). Similar pregnancy per AI (P/AI; 30 days after FTAI; P>0.05) were achieved using each of the three ovulation induction hormones (EB=40.6%; EC=48.3%, or GnRH=48.7%) and with a new (47.2%) or once-used NORG implant (44.3%). In Experiment 3, the effect of different ovulation induction hormones for FTAI [1mg EC at NORG implant removal (n=228), 10MUg buserelin acetate at FTAI (GnRH; n=212) or both treatments (EC+GnRH; n=215)] on P/AI was evaluated in suckled beef cows treated with a once-used NORG implant and EB to synchronize the FWE. Similar P/AI (P=0.71) were obtained using GnRH (50.9%), EC (51.8%) or both treatments (54.9%) as ovulation induction hormones. Therefore, both doses of EV (2.5 or 5.0mg) with NORG implant delayed and increased the variation of the day of new FWE compared with EB in B. indicus cattle. These effects were more pronounced in B. indicus heifers than cows. Synchronization protocols for FTAI with either a new or once used NORG implant with EB at insertion to induce a new FWE and either the use of EB, EC or GnRH as ovulation induction hormones may be successful in B. indicus heifers. Also, when a once-used NORG implant was used, either the administration of EC, GnRH or both as ovulation inducers resulted in similar P/AI in suckled B. indicus cows, showing no additive effect of the combination of both ovulation induction hormones. PMID- 22226936 TI - Stromal-epithelial interactions modulate the effect of ovarian steroids on goat uterine epithelial cell interleukin-18 release. AB - A primary role of epithelial-stromal interactions in mediating steroid hormone action in the uterus has been established. The present study was undertaken to determine the mode of ovarian steroid action in regulating IL-18 release by goat endometrial epithelial cells (EECs) in the presence and absence of endometrial stromal cells (ESCs). Primary and telomerase-immortalized goat EECs grown alone or cocultured with ESCs were treated with two ovarian steroids, 17beta-estradiol (E(2)) and progesterone (P(4)). The IL-18 mRNA and protein expression in EECs were studied by reverse transcript (RT) PCR, ELISA, and Western blot assay. The E(2) and/or P(4) treatment of EECs led to a significant increase in both IL-18 mRNA and protein expression either in the primary or in the immortalized EECs compared with that in EECs without the steroid treatment. However, in the presence of ESCs, IL-18 expression by EECs treated with steroids was significantly decreased compared with cells untreated with E(2) and/or P(4). In addition, significantly high abundance of IL-18 mRNA and protein expression by primary and telomerase-immortalized goat EECs was observed in the presence of ESCs compared with those cells without ESCs. These findings suggest that steroids are important for the control of IL-18 expression in goat EECs. Underlying ESCs are needed to mediate the inhibitory effects of steroids on the IL-18 secretory activity of goat EECs in vitro. The IL-18 abundance expressed by goat EECs in vitro are enhanced by underlying ESCs without the treatment of E(2) and/or P(4). PMID- 22226937 TI - Cell phones change the way we walk. AB - Cell phone use among pedestrians leads to increased cognitive distraction, reduced situation awareness and increases in unsafe behavior. Performing a dual task, such as talking or texting with a cell phone while walking, may interfere with working memory and result in walking errors. At baseline, thirty-three participants visually located a target 8m ahead; then vision was occluded and they were instructed to walk to the remembered target. One week later participants were assigned to either walk, walk while talking on a cell phone, or walk while texting on a cell phone toward the target with vision occluded. Duration and final location of the heel were noted. Linear distance traveled, lateral angular deviation from the start line, and gait velocity were derived. Changes from baseline to testing were analyzed with paired t-tests. Participants engaged in cell phone use presented with significant reductions in gait velocity (texting: 33% reduction, p=0.01; talking: 16% reduction, p=0.02). Moreover, participants who were texting while walking demonstrated a 61% increase in lateral deviation (p=0.04) and 13% increase in linear distance traveled (p=0.03). These results suggest that the dual-task of walking while using a cell phone impacts executive function and working memory and influences gait to such a degree that it may compromise safety. Importantly, comparison of the two cell phone conditions demonstrates texting creates a significantly greater interference effect on walking than talking on a cell phone. PMID- 22226938 TI - Crosstalk between central pathways of nitric oxide and carbon monoxide in the hypertensive action of cyclosporine. AB - Although the intermediary role of central neurons in the hypertensive and sympathoexcitatory actions of cyclosporine (CSA) has been recognized in previous studies including our own, the underlying mechanism remains obscure. In this study, we tested the hypothesis that central pathways of nitric oxide (NO) and carbon monoxide (CO) modulate the blood pressure (BP) response elicited by CSA in conscious rats. Hemodynamic effects of CSA were evaluated in absence and presence of maneuvers that inhibit or facilitate biosynthesizing enzymes of NO (NOS) or CO (heme oxygenase, HO). CSA (20mg/kg i.v.) produced abrupt increases in BP that peaked in 5min and maintained for at least 45min. The hypertensive effect of CSA disappeared in rats pretreated intracisternally (i.c.) with N(omega)-nitro-l arginine methyl ester (L-NAME, nonselective NOS inhibitor), N(5)-(1-iminoethyl)-l ornithine (L-NIO, selective eNOS inhibitor), N(omega)-propyl-l-arginine (NPLA, selective nNOS inhibitor), or 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one (ODQ, guanylate cyclase inhibitor), suggesting the importance of central eNOS/nNOS/GC cascade in CSA-induced hypertension. L-NAME also abolished the hypotension caused by the sympatholytic drug moxonidine, indicating a tonic sympathoinhibitory action for NO. The inhibition of HO activity by zinc protoporphyrin IX (ZnPP) abrogated the hypertensive action of CSA. The abolition by L-NAME or ZnPP of CSA hypertension was compromised upon simultaneous i.c. exposure to hemin (HO substrate) and l-arginine (NOS substrate), respectively. Together, the interruption of the mutually facilitated NOS/NO and HO/CO pathways and coupled GC/cGMP in central neuronal pools accounts, at least partly, for the hypertensive and perhaps sympathoexcitatory actions of CSA. PMID- 22226939 TI - Impact of bortezomib on bone health in myeloma: a review of current evidence. AB - Bone disease is a key feature in multiple myeloma (MM) and can have a substantial impact on patient morbidity and quality-of-life. The pathogenesis of lytic bone disease in MM is complex and associated with increased osteoclast activity and impaired osteoblast function. Lytic lesions rarely heal in MM; however, the proteasome inhibitor bortezomib has been linked to increased bone formation and osteoblastic activity. Various clinical studies have reported a positive effect of bortezomib on bone health, including fewer bone disease-related MM progression events, increases in bone volume, and improvements in osteolytic lesions. Alkaline phosphatase (total and bone isoenzyme), a marker of bone formation, is increased during bortezomib treatment; the degree of increase may be associated with treatment response. Bortezomib is associated with a reduction in Dickkopf-1, an inhibitor of osteoblast function. Increases of other bone-formation markers and decreases of bone-resorption markers, have also been observed. These clinical effects are supported by preclinical data suggesting bortezomib is associated with an increase in bone formation and osteoblast numbers/activity, arising from direct effects of bortezomib and proteasome inhibition. As reviewed here, a growing body of evidence indicates that bortezomib exerts a positive effect on bone metabolism in MM and has a bone anabolic effect. PMID- 22226940 TI - Adjuvant immunotherapy for non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is the biggest cancer killer in the United States and worldwide. In 2011, there are estimated to be 221,130 new cases of lung cancer in the United States. Over a million people will die of lung cancer worldwide this year alone. When possible, surgery to remove the tumor is the best treatment strategy for patients with NSCLC. However, even with adjuvant (postoperative) chemotherapy and radiation, more than 40% of patients will develop recurrences locally or systemically and ultimately succumb to their disease. Thus, there is an urgent need for developing superior approaches to treat patients who undergo surgery for NSCLC to eliminate residual disease that is likely responsible for these recurrences. Our group and others have been interested in using immunotherapy to augment the efficacy of current treatment strategies. Immunotherapy is very effective against minimal disease burden and small deposits of tumor cells that are accessible by the circulating immune cells. Therefore, this strategy may be ideally suited as an adjunct to surgery to seek and destroy microscopic tumor deposits that remain after surgery. This review describes the mechanistic underpinnings of immunotherapy and how it is currently being used to target residual disease and prevent postoperative recurrences after pulmonary resection in NSCLC. PMID- 22226941 TI - Innate immunity alone is not sufficient for chronic rejection but predisposes healed allografts to T cell-mediated pathology. AB - BACKGROUND: Acute allograft rejection is dependent on adaptive immunity, but it is unclear whether the same is true for chronic rejection. Here we asked whether innate immunity alone is sufficient for causing chronic rejection of mouse cardiac allografts. METHODS: We transplanted primarily vascularized cardiac grafts to recombinase activating gene-knockout (RAG(-/-)) mice that lack T and B cells but have an intact innate immune system. Recipients were left unmanipulated, received adjuvants that stimulate innate immunity, or were reconstituted with B-1 lymphocytes to generate natural IgM antibodies. In a second model, we transplanted cardiac allografts to mice that lack secondary lymphoid tissues (splenectomized aly/aly recipients) and studied the effect of NK cell inactivation on T cell-mediated chronic rejection. RESULTS: Acute cardiac allograft rejection was not observed in any of the recipients. Histological analysis of allografts harvested 50 to 90 days after transplantation to RAG(-/-) mice failed to identify chronic vascular or parenchymal changes beyond those observed in control syngeneic grafts. Chronic rejection of cardiac allografts parked in splenectomized aly/aly mice was observed only after the transfer of exogenously activated T cells. NK inactivation throughout the experiment, or during the parking period alone, reduced the severity of T cell-dependent chronic rejection. CONCLUSIONS: The innate immune system alone is not sufficient for causing chronic rejection. NK cells predispose healed allografts to T cell dependent chronic rejection and may contribute to chronic allograft pathology. PMID- 22226942 TI - Evolutionary walk between (beta/alpha)(8) barrels: catalytic migration from triosephosphate isomerase to thiamin phosphate synthase. AB - The functionally versatile (beta/alpha)(8) barrel scaffold was used to migrate triosephosphate isomerase (TPI) to thiamin phosphate synthase (TPS) activity, two enzymes that share the same fold but catalyze unrelated reactions through different mechanisms. The high sensitivity of the selection methodology was determinant to succeed in finding proteins with the desired activity. A combination of rational design and random mutagenesis was used to achieve the desired catalytic migration. One of the parallel directed evolution strategies followed resulted in TPI derivatives able to complement the thiamin phosphate auxotrophy phenotype of an Escherichia coli strain deleted of thiE, the gene that codes for TPS. Successive rounds of directed evolution resulted in better complementing TPI variants. Biochemical characterization of some of the evolved TPI clones demonstrated that the K(m) for the TPS substrates was similar to that of the native TPS; however and in agreement with the very slow complementation phenotype, the k(cat) was 4 orders of magnitude lower, indicating that substrate binding played a major role on selection. Interestingly, the crystal structure of the most proficient variant showed a slightly modified TPI active site occupied by a thiamin-phosphate-like molecule. Substitution of key residues in this region reduced TPS activity, strongly suggesting that this is also the catalytic site for the evolved TPS activity. The presence of the TPS reaction product at the active site explains the fast inactivation of the enzyme observed. In conclusion, by combining rational design, random mutagenesis and a very sensitive selection, it is possible to achieve enzymatic activity migration. PMID- 22226943 TI - Effect of Cordyceps sinensis and taurine either alone or in combination on streptozotocin induced diabetes. AB - The present study aimed to investigate the antidiabetic effects of Cordyceps sinensis, taurine and their combination in comparison with glibenclamide both in vivo and in vitro using streptozotocin rat model. The diabetic rats were orally given glibenclamide, C. sinensis, taurine or Cordyceps and taurine combination for 21 days. Their effects were studied both in vivo and in vitro. Oral administration of Cordyceps, taurine and their combination decreased serum glucose, fructosamine, total cholesterol, triglycerides levels, insulin resistance index and pancreatic malondialdehyde content. Cordyceps significantly increased serum insulin, HDL-cholesterol, total antioxidant capacity levels, beta cell function percent, and pancreatic reduced glutathione (GSH) content. However, taurine was unable to elevate pancreatic GSH level to a significant level. These natural products and their combinations were more effective than glibenclamide in reducing insulin resistance index and they had stronger antioxidant properties. Cordyceps and taurine significantly enhanced glucose uptake by diaphragms of normal and diabetic rats in absence and presence of insulin. In conclusion, Cordyceps and taurine either alone or in combination have less potent hypoglycemic effects than glibenclamide; however, they have more ability to reduce insulin resistance and stronger antioxidant properties. PMID- 22226944 TI - Dynamics of nonpersistent aphid-borne viruses in lettuce crops covered with UV absorbing nets. AB - Aphid-transmitted viruses frequently cause severe epidemics in lettuce grown under Mediterranean climates. Spatio-temporal dynamics of aphid-transmitted viruses and its vector were studied on lettuce (Lactuca sativa L.) grown under tunnels covered by two types of nets: a commercial UV-absorbing net (Bionet) and a Standard net. A group of plants infected by Cucumber mosaic virus (CMV, family Bromoviridae, genus Cucumovirus) and Lettuce mosaic virus (LMV, family Potyviridae, genus Potyvirus) was transplanted in each plot. The same virus infected source plants were artificially infested by the aphid Macrosiphum euphorbiae (Thomas). Secondary spread of insects was weekly monitored and plants were sampled for the detection of viruses every two weeks. In 2008, the infection rate of both CMV and LMV were lower under the Bionet than under the Standard cover, probably due to the lower population density and lower dispersal rate achieved by M. euphorbiae. However, during spring of 2009, significant differences in the rate of infection between the two covers were only found for LMV six weeks after transplant. The spatial distribution of the viruses analysed by SADIE methodology was "at random", and it was not associated to the spatial pattern of the vector. The results obtained are discussed analyzing the wide range of interactions that occurred among UV-radiation, host plant, viruses, insect vector and environmental conditions. Our results show that UV-absorbing nets can be recommended as a component of an integrated disease management program to reduce secondary spread of lettuce viruses, although not as a control measure on its own. PMID- 22226945 TI - 3CD, but not 3C, cleaves the VP1/2A site efficiently during Aichi virus polyprotein processing through interaction with 2A. AB - Picornavirus genomes are translated into a single large polyprotein, which is processed by virus-encoded proteases into individual functional proteins. 3C of all picornaviruses is a protease, and the leader (L) and 2A proteins of some picornaviruses are also involved in polyprotein processing. Aichi virus (AiV), which is associated with acute gastroenteritis in humans, is a member of the genus Kobuvirus of the family Picornaviridae. The AiV L and 2A proteins have already been shown to exhibit no protease activity. In this study, we investigated AiV polyprotein processing by 3C and 3CD using a cell-free translation system. 3C and 3CD were capable of processing the polyprotein in trans; 3C, however, cleaved the VP1/2A site inefficiently, while 3CD cleaved this site almost completely. Mammalian two-hybrid and coimmunoprecipitation assays showed an interaction between 2A and 3CD. Using a 3CD mutant and various 2A mutants of substrate proteins, we showed a clear correlation between the 2A-3CD interaction and the VP1/2A cleavage by 3CD. Thus, this study suggests that tight interaction of 3CD with the 2A region of a precursor protein is required for efficient cleavage at the VP1/2A site. PMID- 22226946 TI - The Ubiquitin ligase Ubr11 is essential for oligopeptide utilization in the fission yeast Schizosaccharomyces pombe. AB - Uptake of extracellular oligopeptides in yeast is mediated mainly by specific transporters of the peptide transporter (PTR) and oligopeptide transporter (OPT) families. Here, we investigated the role of potential peptide transporters in the yeast Schizosaccharomyces pombe. Utilization of naturally occurring dipeptides required only Ptr2/SPBC13A2.04c and none of the other 3 OPT proteins (Isp4, Pgt1, and Opt3), whereas only Isp4 was indispensable for tetrapeptide utilization. Both Ptr2 and Isp4 localized to the cell surface, but under rich nutrient conditions Isp4 localized in the Golgi apparatus through the function of the ubiquitin ligase Pub1. Furthermore, the ubiquitin ligase Ubr11 played a significant role in oligopeptide utilization. The mRNA levels of both the ptr2 and isp4 genes were significantly reduced in ubr11Delta cells, and the dipeptide utilization defect in the ubr11Delta mutant was rescued by the forced expression of Ptr2. Consistent with its role in transcriptional regulation of peptide transporter genes, the Ubr11 protein was accumulated in the nucleus. Unlike the situation in Saccharomyces cerevisiae, the oligopeptide utilization defect in the S. pombe ubr11Delta mutant was not rescued by inactivation of the Tup11/12 transcriptional corepressors, suggesting that the requirement for the Ubr ubiquitin ligase in the upregulation of peptide transporter mRNA levels is conserved in both yeasts; however, the actual mechanism underlying the control appears to be different. We also found that the peptidomimetic proteasome inhibitor MG132 was still operative in a strain lacking all known PTR and OPT peptide transporters. Therefore, irrespective of its peptide-like structure, MG132 is carried into cells independently of the representative peptide transporters. PMID- 22226948 TI - Abundance, dynamics, and biogeographic distribution of seven polycyclic aromatic hydrocarbon dioxygenase gene variants in coastal sediments of Patagonia. AB - Novel polycyclic aromatic hydrocarbon dioxygenase gene variants were present in abundances similar to or higher than those of phnA1 from Cycloclasticus spp. at a chronically polluted subantarctic coastal marine environment in Patagonia. These novel gene variants were detected over a 6-year time span and were also present in sediments from temperate Patagonian sites. PMID- 22226947 TI - Characterization of Halomonas sp. strain H11 alpha-glucosidase activated by monovalent cations and its application for efficient synthesis of alpha-D glucosylglycerol. AB - An alpha-glucosidase (HaG) with the following unique properties was isolated from Halomonas sp. strain H11: (i) high transglucosylation activity, (ii) activation by monovalent cations, and (iii) very narrow substrate specificity. The molecular mass of the purified HaG was estimated to be 58 kDa by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). HaG showed high hydrolytic activities toward maltose, sucrose, and p-nitrophenyl alpha-D-glucoside (pNPG) but to almost no other disaccharides or malto-oligosaccharides higher than trisaccharides. HaG showed optimum activity to maltose at 30 degrees C and pH 6.5. Monovalent cations such as K(+), Rb(+), Cs(+), and NH(4)(+) increased the enzymatic activity to 2- to 9-fold of the original activity. These ions shifted the activity-pH profile to the alkaline side. The optimum temperature rose to 40 degrees C in the presence of 10 mM NH(4)(+), although temperature stability was not affected. The apparent K(m) and k(cat) values for maltose and pNPG were significantly improved by monovalent cations. Surprisingly, k(cat)/K(m) for pNPG increased 372- to 969-fold in their presence. HaG used some alcohols as acceptor substrates in transglucosylation and was useful for efficient synthesis of alpha d-glucosylglycerol. The efficiency of the production level was superior to that of the previously reported enzyme Aspergillus niger alpha-glucosidase in terms of small amounts of by-products. Sequence analysis of HaG revealed that it was classified in glycoside hydrolase family 13. Its amino acid sequence showed high identities, 60%, 58%, 57%, and 56%, to Xanthomonas campestris WU-9701 alpha glucosidase, Xanthomonas campestris pv. raphani 756C oligo-1,6-glucosidase, Pseudomonas stutzeri DSM 4166 oligo-1,6-glucosidase, and Agrobacterium tumefaciens F2 alpha-glucosidase, respectively. PMID- 22226949 TI - Distribution of intact and core membrane lipids of archaeal glycerol dialkyl glycerol tetraethers among size-fractionated particulate organic matter in hood canal, puget sound. AB - There is great interest in the membrane lipids of archaea (glycerol dialkyl glycerol tetraethers [GDGTs]) as tracers of archaeal biomass because of their utility as paleoproxies and because of the biogeochemical importance of archaea. While core GDGTs (formed by hydrolysis of polar head groups of intact GDGTs after cell death) are appropriate for paleostudies, they have also been used to trace archaeal populations. Also, despite the small size (0.2 by 0.7 MUm) of cultivated marine archaea, 0.7-MUm glass-fiber filters (GFFs) are typically used to collect GDGTs from natural waters. We quantified both core and intact GDGTs in free living (0.2- to 0.7-MUm), suspended (0.7- to 60-MUm), and aggregate (>60-MUm) particle size fractions in Puget Sound (Washington State). On average, the free living fraction contained 36% of total GDGTs, 90% of which were intact. The intermediate-size fraction contained 62% of GDGTs, and 29% of these were intact. The aggregate fraction contained 2% of the total GDGT pool, and 29% of these were intact. Our results demonstrate that intact GDGTs are largely in the free-living fraction. Because only intact GDGTs are present in living cells, protocols that target this size fraction and analyze the intact GDGT pool are necessary to track living populations in marine waters. Core GDGT enrichment in larger-size fractions indicates that archaeal biomass may quickly become attached or entrained in particles once the archaea are dead or dying. While the concentrations of the two pools were generally not correlated, the similar sizes of the core and intact GDGT pools suggest that core GDGTs are removed from the water column on timescales similar to those of cell replication, on timescales of days to weeks. PMID- 22226950 TI - Comparison of gull feces-specific assays targeting the 16S rRNA genes of Catellicoccus marimammalium and Streptococcus spp. AB - Two novel gull-specific quantitative PCR (qPCR) assays were developed using 16S rRNA gene sequences from gull fecal clone libraries: a SYBR green assay targeting Streptococcus spp. (gull3) and a hydrolysis TaqMan assay targeting Catellicoccus marimammalium (gull4). The objectives of this study were to compare the host specificity of a previous C. marimammalium qPCR assay (gull2) with that of the new markers and to examine the presence of the three gull markers in environmental water samples from different geographic locations. Most of the gull fecal samples tested (n = 255) generated positive signals with the gull2 and gull4 assays (i.e., >86%), whereas only 28% were positive with gull3. Low prevalence and abundance of tested gull markers (0.6 to 15%) were observed in fecal samples from six nonavian species (n = 180 fecal samples), whereas the assays cross-reacted to some extent (13 to 31%) with other (nongull) avian fecal samples. The gull3 assay was positive against fecal samples from 11 of 15 avian species, including gull. Of the presumed gull-impacted water samples (n = 349), 86%, 59%, and 91% were positive with the gull2, the gull3, and the gull4 assays, respectively. Approximately 5% of 239 non-gull-impacted water samples were positive with the gull2 and the gull4 assays, whereas 21% were positive witg the gull3 assay. While the relatively high occurrence of gull2 and gull4 markers in waters impacted by gull feces suggests that these assays could be used in environmental monitoring studies, the data also suggest that multiple avian specific assays will be needed to accurately assess the contribution of different avian sources in recreational waters. PMID- 22226952 TI - Characterization of two bacterial hydroxynitrile lyases with high similarity to cupin superfamily proteins. AB - Hydroxynitrile lyases (HNLs) catalyze the cleavage of cyanohydrins. In the reverse reaction, they catalyze the formation of carbon-carbon bonds by enantioselective condensation of hydrocyanic acid with carbonyls. In this study, we describe two proteins from endophytic bacteria that display activity in the cleavage and the synthesis reaction of (R)-mandelonitrile with up to 74% conversion of benzaldehyde (enantiopreference ee 89%). Both showed high similarity to proteins of the cupin superfamily which so far were not known to exhibit HNL activity. PMID- 22226951 TI - High-resolution two-locus clonal typing of extraintestinal pathogenic Escherichia coli. AB - Multilocus sequence typing (MLST) is usually based on the sequencing of 5 to 8 housekeeping loci in the bacterial chromosome and has provided detailed descriptions of the population structure of bacterial species important to human health. However, even strains with identical MLST profiles (known as sequence types or STs) may possess distinct genotypes, which enable different eco- or pathotypic lifestyles. Here we describe a two-locus, sequence-based typing scheme for Escherichia coli that utilizes a 489-nucleotide (nt) internal fragment of fimH (encoding the type 1 fimbrial adhesin) and the 469-nt internal fumC fragment used in standard MLST. Based on sequence typing of 191 model commensal and pathogenic isolates plus 853 freshly isolated clinical E. coli strains, this 2 locus approach-which we call CH (fumC/fimH) typing-consistently yielded more haplotypes than standard 7-locus MLST, splitting large STs into multiple clonal subgroups and often distinguishing different within-ST eco- and pathotypes. Furthermore, specific CH profiles corresponded to specific STs, or ST complexes, with 95% accuracy, allowing excellent prediction of MLST-based profiles. Thus, 2 locus CH typing provides a genotyping tool for molecular epidemiology analysis that is more economical than standard 7-locus MLST but has superior clonal discrimination power and, at the same time, corresponds closely to MLST-based clonal groupings. PMID- 22226954 TI - Aerosol susceptibility of influenza virus to UV-C light. AB - The person-to-person transmission of influenza virus, especially in the event of a pandemic caused by a highly virulent strain of influenza, such as H5N1 avian influenza, is of great concern due to widespread mortality and morbidity. The consequences of seasonal influenza are also substantial. Because airborne transmission appears to play a role in the spread of influenza, public health interventions should focus on preventing or interrupting this process. Air disinfection via upper-room 254-nm germicidal UV (UV-C) light in public buildings may be able to reduce influenza transmission via the airborne route. We characterized the susceptibility of influenza A virus (H1N1, PR-8) aerosols to UV C light using a benchtop chamber equipped with a UVC exposure window. We evaluated virus susceptibility to UV-C doses ranging from 4 to 12 J/m(2) at three relative humidity levels (25, 50, and 75%). Our data show that the Z values (susceptibility factors) were higher (more susceptible) to UV-C than what has been reported previously. Furthermore, dose-response plots showed that influenza virus susceptibility increases with decreasing relative humidity. This work provides an essential scientific basis for designing and utilizing effective upper-room UV-C light installations for the prevention of the airborne transmission of influenza by characterizing its susceptibility to UV-C. PMID- 22226953 TI - Rhodococcus sp. strain CR-53 LipR, the first member of a new bacterial lipase family (family X) displaying an unusual Y-type oxyanion hole, similar to the Candida antarctica lipase clan. AB - Bacterial lipases constitute the most important group of biocatalysts for synthetic organic chemistry. Accordingly, there is substantial interest in developing new valuable lipases. Considering the lack of information concerning the lipases of the genus Rhodococcus and taking into account the interest raised by the enzymes produced by actinomycetes, a search for putative lipase-encoding genes from Rhodococcus sp. strain CR-53 was performed. We isolated, cloned, purified, and characterized LipR, the first lipase described from the genus Rhodococcus. LipR is a mesophilic enzyme showing preference for medium-chain length acyl groups without showing interfacial activation. It displays good long term stability and high tolerance for the presence of ions and chemical agents in the reaction mixture. Amino acid sequence analysis of LipR revealed that it displays four unique amino acid sequence motifs that clearly separate it from any other previously described family of bacterial lipases. Using bioinformatics tools, LipR could be related only to several uncharacterized putative lipases from different bacterial origins, all of which display the four blocks of consensus amino acid sequence motifs that contribute to define a new family of bacterial lipases, namely, family X. Therefore, LipR is the first characterized member of the new bacterial lipase family X. Further confirmation of this new family of lipases was performed after cloning Burkholderia cenocepacia putative lipase, bearing the same conserved motifs and clustering in family X. Interestingly, all lipases grouping in the new bacterial lipase family X display a Y-type oxyanion hole, a motif conserved in the Candida antarctica lipase clan but never found among bacterial lipases. This observation contributes to confirm that LipR and its homologs belong to a new family of bacterial lipases. PMID- 22226955 TI - Counting Legionella cells within single amoeba host cells. AB - Here we present the first attempt to quantify Legionella pneumophila cell numbers within individual amoeba hosts that may be released into engineered water systems. The maximum numbers of culturable L. pneumophila cells grown within Acanthamoeba polyphaga and Naegleria fowleri were 1,348 (mean, 329) and 385 (mean, 44) CFU trophozoite(-1), respectively. PMID- 22226957 TI - Super-resolution fluorescence imaging of chromosomal DNA. AB - Super-resolution microscopy is a powerful tool for understanding cellular function. However one of the most important biomolecules - DNA - remains somewhat inaccessible because it cannot be effectively and appropriately labeled. Here, we demonstrate that robust and detailed super-resolution images of DNA can be produced by combining 5-ethynyl-2'-deoxyuridine (EdU) labeling using the 'click chemistry' approach and direct stochastic optical reconstruction microscopy (dSTORM). This method can resolve fine chromatin structure, and - when used in conjunction with pulse labeling - can reveal the paths taken by individual fibers through the nucleus. This technique should provide a useful tool for the study of nuclear structure and function. PMID- 22226956 TI - New betaproteobacterial Rhizobium strains able to efficiently nodulate Parapiptadenia rigida (Benth.) Brenan. AB - Among the leguminous trees native to Uruguay, Parapiptadenia rigida (Angico), a Mimosoideae legume, is one of the most promising species for agroforestry. Like many other legumes, it is able to establish symbiotic associations with rhizobia and belongs to the group known as nitrogen-fixing trees, which are major components of agroforestry systems. Information about rhizobial symbionts for this genus is scarce, and thus, the aim of this work was to identify and characterize rhizobia associated with P. rigida. A collection of Angico nodulating isolates was obtained, and 47 isolates were selected for genetic studies. According to enterobacterial repetitive intergenic consensus PCR patterns and restriction fragment length polymorphism analysis of their nifH and 16S rRNA genes, the isolates could be grouped into seven genotypes, including the genera Burkholderia, Cupriavidus, and Rhizobium, among which the Burkholderia genotypes were the predominant group. Phylogenetic studies of nifH, nodA, and nodC sequences from the Burkholderia and the Cupriavidus isolates indicated a close relationship of these genes with those from betaproteobacterial rhizobia (beta-rhizobia) rather than from alphaproteobacterial rhizobia (alpha-rhizobia). In addition, nodulation assays with representative isolates showed that while the Cupriavidus isolates were able to effectively nodulate Mimosa pudica, the Burkholderia isolates produced white and ineffective nodules on this host. PMID- 22226959 TI - Metabolically versatile large-genome prokaryotes. AB - Although versatile microorganisms are critical in industrial applications where the ability to cope with change and carry out complex tasks is needed, very little is in fact known about the evolutionary and ecological meanings of versatility in prokaryotes. Testing the hypothesis that a large genome size is a prerequisite for versatility in prokaryotes, we found that putatively versatile prokaryotes are phylogenetically and ecologically diverse and indeed include many well known and commercially relevant versatile microorganisms. Despite individual differences in metabolic abilities, a common trait of large-genome prokaryotes appears that they have gained their large genomes as an evolutionary response to nutrient-scarce and/or variable environments. This insight seriously questions the ability of traditional microbiology methods to isolate versatile prokaryotes and casts doubt on the ecological relevance of knowledge based on the study of specialists. PMID- 22226958 TI - Molecular motors for DNA translocation in prokaryotes. AB - DNA transport is an essential life process. From chromosome separation during cell division or sporulation, to DNA virus ejection or encapsidation, to horizontal gene transfer, it is ubiquitous in all living organisms. Directed DNA translocation is often energetically unfavorable and requires an active process that uses energy, namely the action of molecular motors. In this review we present recent advances in the understanding of three molecular motors involved in DNA transport in prokaryotes, paying special attention to recent studies using single-molecule techniques. We first discuss DNA transport during cell division, then packaging of DNA in phage capsids, and then DNA import during bacterial transformation. PMID- 22226960 TI - EGCG debilitates the persistence of EBV latency by reducing the DNA binding potency of nuclear antigen 1. AB - Because the expression of EBNA1 is prevalent in all EBV-associated tumors, it has become one of the most attractive drug targets for the discovery of anti-EBV compounds. In a cell-based reporter system, EBNA1 consistently upregulated the transcription of an oriP-Luc mini-EBV episome by 6- to 8-fold. The treatment of cells with 50 MUM EGCG effectively blocked the binding of EBNA1 to oriP-DNA both in vivo and in vitro, which led to the abrogation of EBNA1-dependent episome maintenance and transcriptional enhancement. Importantly, the anti-EBNA1 effects caused by EGCG ultimately impaired the persistence of EBV latent infection. Our data suggest that the inhibition of EBNA1 activity by EGCG could be a promising starting point for the development of new protocols for anti-EBV therapy. PMID- 22226961 TI - RNA polymerase II phosphorylation at serine 2 and histone H3 tri-methylation at lysine 36 are key steps for thyroid hormone receptor beta gene activation by thyroid hormone in Rana catesbeiana tadpole liver. AB - Thyroid hormone (TH) is essential for amphibian metamorphosis, during which the expression of many genes is controlled directly or indirectly through TH receptors (TRs). Thyroid hormone binding to TRs induces coregulator switching on regulatory regions of TH-inducible genes: corepressors complexed with unliganded TRs are replaced by coactivators complexed with liganded TR resulting in transcriptionally active states. The coregulator switching is linked to histone acetylation. In our study, we have investigated the acetylation and methylation states of histones H3 and H4 using chromatin immunoprecipitation (ChIP) assays on the 5' coding region of the TRbeta gene, a primary TH-response gene, in the liver from Rana catesbeiana tadpoles either treated with or not treated with 3,3',5 triiodothyronine (T3). 3,3',5-Triiodothyronine treatment for 3 days increased the amount of TRbeta transcript by 19-fold. This increase was associated with increases in the acetylation of histone H4 and lysine 9 in histone H3 (H3-K9), and tri-methylation of lysine 36 in histone H3 (H3-K36). In addition, the amounts of RNA polymerase II (PolII) and serine 2 phosphorylation in PolII (PolII-S2) increased. These results suggest that T3 treatment enhances the elongation activity of PolII on the TRbeta gene in the liver by increasing histone H3-K36 tri-methylation through PolII-S2 phosphorylation. PMID- 22226962 TI - Characterization of germline antibody libraries from human umbilical cord blood and selection of monoclonal antibodies to viral envelope glycoproteins: Implications for mechanisms of immune evasion and design of vaccine immunogens. AB - We have previously observed that all known HIV-1 broadly neutralizing antibodies (bnAbs) are highly divergent from germline antibodies in contrast to bnAbs against Hendra virus, Nipah virus and SARS coronavirus (SARS CoV). We have hypothesized that because the germline antibodies are so different from the mature HIV-1-specific bnAbs they may not bind the epitopes of the mature antibodies and provided the first evidence to support this hypothesis by using individual putative germline-like predecessor antibodies. To further validate the hypothesis and understand initial immune responses to different viruses, two phage-displayed human cord blood-derived IgM libraries were constructed which contained mostly germline antibodies or antibodies with very low level of somatic hypermutations. They were panned against different HIV-1 envelope glycoproteins (Envs), SARS CoV protein receptor-binding domain (RBD), and soluble Hendra virus G protein (sG). Despite a high sequence and combinatorial diversity observed in the cord blood-derived IgM antibody repertoire, no enrichment for binders of Envs was observed in contrast to considerable specific enrichments produced with panning against RBD and sG; one of the selected monoclonal antibodies (against the RBD) was of high (nM) affinity with only few somatic mutations. These results further support and expand our initial hypothesis for fundamental differences in immune responses leading to elicitation of bnAbs against HIV-1 compared to SARS CoV and Hendra virus. HIV-1 uses a strategy to minimize or eliminate strong binding of germline antibodies to its Env; in contrast, SARS CoV and Hendra virus, and perhaps other viruses causing acute infections, can bind germline antibody or minimally somatically mutated antibodies with relatively high affinity which could be one of the reasons for the success of sG and RBD as vaccine immunogens. PMID- 22226963 TI - The impact of extracellular syntaxin4 on HaCaT keratinocyte behavior. AB - Syntaxin4 belongs to t-SNARE protein family and functions as a vesicular fusion mediator in the plasma membrane in a wide variety of cell types. This protein resembles another family member, epimorphin, a subpopulation of which has been shown to be secreted extracellularly in order to exert signaling functions. Here, we demonstrate the secretion of syntaxin4 via a non-classical pathway and its extracellular functions by using the functionally normal keratinocyte HaCaT. Extracellularly presented syntaxin4 appeared to elicit many cell responses similar to epimorphin with an important exception: it clearly facilitated keratinocyte cornification. The circularized peptide ST4n1 was synthesized from the putative functional core of syntaxin4 (a.a. 103-108), which is equivalent to the previously generated antagonist of epimorphin, and neutralized this contradictory effect. Intriguingly, an epimorphin mutant (EP4M) in which the functional core was replaced by that of syntaxin4 behaved like epimorphin, which was again antagonized by ST4n1. Electrophoresis-based analyses demonstrated the distinct structure of syntaxin4 compared to epimorphin or EP4M. These results revealed, for the first time, the extracellular role of syntaxin4 and shed light on the division of the extracellular effects exerted by epimorphin and syntaxin4 on keratinocyte cornification. PMID- 22226964 TI - Klebsiella pneumoniae induces an inflammatory response in human retinal-pigmented epithelial cells. AB - PURPOSE: The retinal pigment epithelium (RPE) is a barrier to Klebsiella pneumoniae infection in endogenous endophthalmitis. Nevertheless, the inflammatory response of RPE cells upon interaction with this pathogen has not been studied. Here we tested the hypothesis that K. pneumoniae induces an inflammatory response in human retinal epithelial cells. METHODS: In this study we set out to investigate the effects of whole K. pneumoniae and of its lipopolysaccharide on RPE cells in vitro using bacterial invasion and cytotoxicity assays, fluorescent microscopy and ELISA. For that, we utilized K. pneumoniae strain ATCC 43816 and the continuous human retinal-pigmented epithelial cell line ARPE-19. RESULTS: Stimulation of ARPE-19 with live K. pneumoniae for 24h induced a 31.5-fold (p=0.0132) increase in IL-6 and 6.5-fold (p=0.0004) increase in MCP-1 levels compared to the non-infected control cells. Purified K. pneumoniae LPS (1MUgml(-1)) also induced cytokine levels, MCP-1 (1.7 fold upregulation; p=0.0006) and IL-6 (1.3-fold upregulation, p=0.065). The tested K. pneumoniae strain ATCC 43816 did not have a significant effect on the viability of ARPE-19 cells (11% decrease, p=0.096) and showed a low ability to invade the cells. CONCLUSIONS: Both whole live K. pneumoniae and K. pneumoniae LPS exert a strong pro-inflammatory effect on retinal pigmented epithelial cells, consistent with clinical manifestations of disease. Bacterial pro-inflammatory effects are not likely related to host cell invasion. This is the first investigation of the interactions of a major endogenous endophthalmitis pathogen, K. pneumoniae with human retinal pigmented epithelial cells. PMID- 22226965 TI - O-GlcNAc modification of PPARgamma reduces its transcriptional activity. AB - The peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily, is a key regulator of adipogenesis and is important for the homeostasis of the adipose tissue. The beta-O-linked N-acetylglucosamine (O-GlcNAc) modification, a posttranslational modification on various nuclear and cytoplasmic proteins, is involved in the regulation of protein function. Here, we report that PPARgamma is modified by O-GlcNAc in 3T3-L1 adipocytes. Mass spectrometric analysis and mutant studies revealed that the threonine 54 of the N terminal AF-1 domain of PPARgamma is the major O-GlcNAc site. Transcriptional activity of wild type PPARgamma was decreased 30% by treatment with the specific O-GlcNAcase (OGA) inhibitor, but the T54A mutant of PPARgamma did not respond to inhibitor treatment. In 3T3-L1 cells, an increase in O-GlcNAc modification by OGA inhibitor reduced PPARgamma transcriptional activity and terminal adipocyte differentiation. Our results suggest that the O-GlcNAc state of PPARgamma influences its transcriptional activity and is involved in adipocyte differentiation. PMID- 22226966 TI - The AAA-ATPase NVL2 is a telomerase component essential for holoenzyme assembly. AB - Continued cell proliferation requires telomerase to maintain functional telomeres that are essential for chromosome integrity. Although the core enzyme includes a telomerase reverse transcriptase (TERT) and a telomerase RNA component (TERC), a number of auxiliary proteins have been identified to regulate telomerase assembly, localization, and enzymatic activity. Here we describe the characterization of the AAA-ATPase NVL2 as a novel hTERT-interacting protein. NVL2 interacts and co-localizes with hTERT in the nucleolus. NLV2 is also found in association with catalytically competent telomerase in cell lysates through an interaction with hTERT. Depletion of endogenous NVL2 by small interfering RNA led to a decrease in hTERT without affecting the steady-state levels of hTERT mRNA, thereby reducing telomerase activity, suggesting that NVL2 is an essential component of the telomerase holoenzyme. We also found that ATP-binding activity of NVL2 is required for hTERT binding as well as telomerase assembly. Our findings suggest that NVL2, in addition to its role in ribosome biosynthesis, is essential for telomerase biogenesis and provides an alternative approach for inhibiting telomerase activity in cancer. PMID- 22226967 TI - Liver kinase B1 expression (LKB1) is repressed by estrogen receptor alpha (ERalpha) in MCF-7 human breast cancer cells. AB - BACKGROUND: Liver kinase 1 (LKB1) is emerging as a multifunctional protein, acting as a key metabolic enzyme, regulator of cell polarity, and transcription factor. Altered LKB1 expression has been linked with various cancers and may be a potential prognostic marker. While the functional role of LKB1 continues to undergo intensive investigation, the molecular mechanisms that regulate its expression remain to be defined more clearly. Recent reports have established a possible link between estrogen receptor alpha (ERalpha) signaling and LKB1 in MCF 7 human breast cancer cells. The current study aimed to investigate whether LKB1 is transcriptionally regulated by ERalpha in MCF-7 cells. METHODS: siRNA transfections were used to transiently knock down LKB1 and ERalpha. LKB1 and ERalpha mRNA and protein levels were evaluated by real-time PCR and Western blotting, respectively. An approximately 3 kilobase pair human LKB1 promoter construct and various truncations were generated, transfected into MCF-7 cells, and luciferase reporter assays were performed. Cells were also treated with various doses of 17-beta-estradiol (E2) to evaluate the effect on LKB1 and ERalpha mRNA levels. RESULTS: LKB1 mRNA and protein levels were significantly lower in ERalpha-positive MCF-7 compared to ERalpha-negative MDA-MB-231 breast cancer cells, suggesting that ERalpha may act as a repressor. siRNA-mediated knock-down of ERalpha in MCF-7 cells significantly increased LKB1 promoter activity and expression at the mRNA and protein levels, and computational analysis revealed the presence of several putative estrogen response element (ERE) DNA binding sites in the LKB1 promoter region. In addition, treatment with E2 led to an increase in LKB1 expression, concomitant with decreased expression of ERalpha in MCF-7 cells. The E2-mediated increase was abrogated by pretreatment with actinomycin D, supporting that the observed changes in LKB1 levels were transcriptionally regulated. CONCLUSIONS: ERalpha repressively modulates the expression of LKB1 at the transcriptional level. Targeting the expression of LKB1 by modulating ERalpha signaling may provide a potential approach to further evaluate its function in ERalpha-positive breast cancers. PMID- 22226968 TI - Ankyrin and band 3 differentially affect expression of membrane glycoproteins but are not required for erythroblast enucleation. AB - During late stages of mammalian erythropoiesis the nucleus undergoes chromatin condensation, migration to the plasma membrane, and extrusion from the cytoplasm surrounded by a segment of plasma membrane. Since nuclear condensation occurs in all vertebrates, mammalian erythroid membrane and cytoskeleton proteins were implicated as playing important roles in mediating the movement and extrusion of the nucleus. Here we use erythroid ankyrin deficient and band 3 knockout mouse models to show that band 3, but not ankyrin, plays an important role in regulating the level of erythroid cell membrane proteins, as evidenced by decreased cell surface expression of glycophorin A in band 3 knockout mice. However, neither band 3 nor ankyrin are required for enucleation. These results demonstrate that mammalian erythroblast enucleation does not depend on the membrane integrity generated by the ankyrin-band 3 complex. PMID- 22226969 TI - Epitope mapping of neutralizing monoclonal antibody in avian influenza A H5N1 virus hemagglutinin. AB - The global spread of highly pathogenic avian influenza A H5N1 viruses raises concerns about more widespread infection in the human population. Pre-pandemic vaccine for H5N1 clade 1 influenza viruses has been produced from the A/Viet Nam/1194/2004 strain (VN1194), but recent prevalent avian H5N1 viruses have been categorized into the clade 2 strains, which are antigenically distinct from the pre-pandemic vaccine. To understand the antigenicity of H5N1 hemagglutinin (HA), we produced a neutralizing monoclonal antibody (mAb12-1G6) using the pre-pandemic vaccine. Analysis with chimeric and point mutant HAs revealed that mAb12-1G6 bound to the loop (amino acid positions 140-145) corresponding to an antigenic site A in the H3 HA. mAb12-1G6 failed to bind to the mutant VN1194 HA when only 3 residues were substituted with the corresponding residues of the clade 2.1.3.2 A/Indonesia/5/05 strain (amino acid substitutions at positions Q142L, K144S, and S145P), suggesting that these amino acids are critical for binding of mAb12-1G6. Escape mutants of VN1194 selected with mAb12-1G6 carried a S145P mutation. Interestingly, mAb12-1G6 cross-neutralized clade 1 and clade 2.2.1 but not clade 2.1.3.2 or clade 2.3.4 of the H5N1 virus. We discuss the cross-reactivity, based on the amino acid sequence of the epitope. PMID- 22226970 TI - Software for precise tracking of cell proliferation. AB - We have developed a multi-target cell tracking program TADOR, which we applied to a series of fluorescence images. TADOR is based on an active contour model that is modified in order to be free of the problem of locally optimal solutions, and thus is resistant to signal fluctuation and morphological changes. Due to adoption of backward tracing and addition of user-interactive correction functions, TADOR is used in an off-line and semi-automated mode, but enables precise tracking of cell division. By applying TADOR to the analysis of cultured cells whose nuclei had been fluorescently labeled, we tracked cell division and cell-cycle progression on coverslips over an extended period of time. PMID- 22226971 TI - Coordinated regulation of IL-4 and IL-13 expression in human T cells: 3C analysis for DNA looping. AB - Asthma is a chronic allergic disorder characterised by chronic inflammation. The balance of type I and type II (CD4+) T helper cells is of critical importance. In asthma there is an overexpression of T(H)2 cytokines, such as IL-4, IL-5 and IL 13. The genes encoding these cytokines are located together the same chromosomal region, 5q31.1 in humans. Here we confirm a central role for the transcription factors NFAT and GATA3 in the regulation of human IL-4 and IL-13. Chromatin Conformation Capture (3C) demonstrated the formation of specific ligation products containing spliced IL-4 and IL-13 DNA sequences in human T(H)2 polarised HuT-78 cells. This suggests that co-ordinate expression of T(H)2 cytokines, under the control of GATA3 and NFAT1 is due to the formation of a chromatin hub by DNA looping. PMID- 22226972 TI - Epidemiology of the metabolic syndrome in Hungary. AB - OBJECTIVES: Hungary has high cardiovascular mortality. Recent studies have revealed a high prevalence of several cardiovascular risk factors, including obesity, diabetes and hypertension. The objective of this study was to assess the prevalence of the metabolic syndrome in Hungary. STUDY DESIGN: Cross-sectional study. METHODS: Within the framework of the Hungarian General Practitioners' Morbidity Sentinel Stations Programme, a random sample of 2006 individuals aged 20-69 years was selected in 2006. Physical examinations, blood sampling and data collection were performed by general practitioners. Information on environmental factors was gathered using a questionnaire. The population prevalence was estimated based on the sample frequencies. RESULTS: The overall response rate was 91%. The age-adjusted prevalence of the metabolic syndrome using the 2009 Harmonized definition was 38% [95% confidence interval (CI) 35-42%] in males and 30% (95% CI 28-33%) in females aged 20-69 years. There were no significant regional differences in the frequency figures. CONCLUSIONS: The high prevalence of the metabolic syndrome is a serious public health problem in Hungary, and remains a major determinant of the high burden of cardiovascular disease. PMID- 22226973 TI - Osteoclasts derived from patients with neurofibromatosis 1 (NF1) display insensitivity to bisphosphonates in vitro. AB - A total of 20 patients with neurofibromatosis 1 (NF1) were screened for NF1 related osteoporosis, and blood samples were collected for isolation of peripheral blood osteoclast progenitors. Patients with NF1 had higher levels of serum bone turnover markers (CTX and PINP) compared to controls. In addition, persons with high bone resorption in vitro on average had high levels of serum CTX. Of the 20 patients with NF1, 15 had low bone mineral density (osteopenia/osteoporosis), but these 15 patients did not have marked risk factors for low bone mineral density. Thus, we recommend screening for osteoporosis to all adult patients with NF1. Our aim was also to characterize the effects of bisphosphonates on NF1 osteoclasts in vitro. NF1 osteoclasts and osteoclasts from healthy controls in vitro were treated with zoledronic acid, alendronate and clodronate. These bisphosphonates caused a marked reduction in the number of normal control osteoclasts in vitro, while only a slight change was observed in the number of NF1 osteoclasts. Ras-inhibitor FTS counteracted this NF1-related insensitivity to zoledronic acid, suggesting that Ras may play a role in this phenomenon. PMID- 22226974 TI - Cardioprotective effects of saponins from Panax japonicus on acute myocardial ischemia against oxidative stress-triggered damage and cardiac cell death in rats. AB - AIM: To study the cardioprotective effects of saponins from Panax japonicus (SPJ) on acute myocardial ischemia injury rats induced by ligating of the left anterior descending branch (LAD), on the basis of this investigation, the possible mechanism of SPJ was elucidated. MATERIALS AND METHODS: SPJ was identified by high performance liquid chromatography-evaporative light scattering detection. Male Sprague-Dawley rats (200-220g) were randomly divided into four groups: sham operated, LAD, LAD+l-SPJ (SPJ, 50mg/kg/day, orally) and LAD+h-SPJ (SPJ, 100mg/kg/day, orally). Before operation, the foregoing groups were pretreated with homologous drug once a day for 7 days, respectively. After twelve hours in LAD, the cardioprotective effects of SPJ were evaluated by infarct size, biochemical values, hemodynamic, and histopathological observations and the antioxidative and antiapoptotic relative gene expressions. RESULTS: SPJ significantly improved heart function and decreased infarct size; remarkably decreased levels of serum lactate dehydrogenase, creatine kinase, xanthine oxide and malondialdehyde content, increased contents of serum total antioxidant capacity, superoxide dismutase (SOD), glutathione peroxidase, catalase; quantitative real-time PCR results showed that SPJ might markedly reverse the down-regulated mRNA expressions of the SOD1, SOD2 and SOD3, ameliorate the increased Bax and caspase-3 mRNA expressions and decreased Bcl-2 mRNA expression and ratios of Bcl-2 to Bax. Histopathological observations provided supportive evidence for biochemical analyses, and with the dose of SPJ increasing, the aforesaid improvement became more and more strong. CONCLUSIONS: The studies demonstrated that in ischemic myocardium, oxidative stress caused the overgeneration and accumulation of reactive oxygen species (ROS), which was central of cardiac ischemic injury. SPJ exerted beneficially cardioprotective effects on myocardial ischemia injury rats, mainly scavenging oxidative stress triggered overgeneration and accumulation of ROS, alleviating myocardial ischemia injury and cardiac cell death. PMID- 22226975 TI - In vivo and in vitro inhibitory effects of a traditional Chinese formulation on LPS-stimulated leukocyte-endothelial cell adhesion and VCAM-1 gene expression. AB - AIM OF THE STUDY: A traditional Chinese formulation Huang-Lian-Jie-Du-Tang (HLJDT) exerts anti-inflammatory effects. The present study aimed to investigate the effect of HLJDT on the LPS-stimulated leukocyte-endothelial cell adhesion and VCAM-1 gene expression both in vivo and in vitro. MATERIALS AND METHODS: HLJDT was extracted from rhizoma coptidis, radix scutellariae, cortex phellodendri and fructus gardeniae in a weight rario of 1:1:1:1. In vivo leukocyte-endothelial cell adhesion was observed in rat lung after LPS stimulation (5mg/kg, i.p.) with or without HLJDT (350 or 700mg/kg, i.g.) pretreatment. The protein expression of vascular cell adhesion molecule 1 (VCAM-1) was analyzed by immunohistochemical method. In vitro leukocyte-endothelial cell adhesion was performed by examining the adhesion of THP-1cells to LPS-stimulated human vascular endothelial cells with or without HLJDT pretreatment. The VCAM-1 expression at the RNA and protein levels was investigated by RT-PCR and western blot analysis, respectively. The activation of NF-kappaB was examined by the nuclear translocation of NF-kappaB by immunocytochemical method. RESULTS: In vivo, HLJDT dose-dependently reduced the number of leukocytes adhered to endothelium and VCAM-1 protein expression in lung venules of LPS-challenged rats. In vitro, HLJDT dose-dependently decreased the number of THP-1cells adhered to LPS-stimulated endothelial cells and the expression of VCAM-1 both at the RNA and protein levels. The LPS-induced nuclear translocation of NF-kappa B in endothelial cells was also dose-dependently inhibited by HLJDT. CONCLUSIONS: The present study demonstrated an additional mechanism underlying the anti-inflmmatory effect of HLJDT by inhibiting the leukocyte-endothelial cell adhesion and VCAM-1 gene expression. The inhibition of NF-kappa B activation by HLJDT might suggest a profound anti-inflammatory consequences. PMID- 22226976 TI - New strategies for drug discovery in tropical forests based on ethnobotanical and chemical ecological studies. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hypotheses from ethnobotany and chemical ecology can increase our ability to predict the pharmaceutical potential of tropical flora. In order to illustrate how bioprospecting studies can benefit from the incorporation of these hypotheses, especially in tropical dry forests, we discuss evidence from ethnobotanical studies that examine hypotheses about the ecology of plant defense against herbivory. MATERIALS AND METHODS: We focus on two hypotheses regarding defense patterns in plants-the plant apparency hypothesis and the resource availability hypothesis-and analyze how these can help us understand the use of medicinal plants by traditional communities. RESULTS: The evidence suggests that medicinal plants in the dry forest are a rich source of drugs in which phenolic compounds, especially tannins, are directly responsible for the therapeutic activity. Phenolic compounds and their potential therapeutic activity are likely good candidates for bioprospecting efforts. CONCLUSION: We believe that following strategies to link ethnobotanical and chemical ecological approaches will increase the efficiency of bioprospecting studies in tropical forests. PMID- 22226978 TI - Glucose uptake mediated by glucose transporter 1 is essential for early tooth morphogenesis and size determination of murine molars. AB - Glucose is an essential source of energy for body metabolism and is transported into cells by glucose transporters (GLUTs). Well-characterized class I GLUT is subdivided into GLUTs1-4, which are selectively expressed depending on tissue glucose requirements. However, there is no available data on the role of GLUTs during tooth development. This study aims to clarify the functional significance of class I GLUT during murine tooth development using immunohistochemistry and an in vitro organ culture experiment with an inhibitor of GLUTs1/2, phloretin, and Glut1 and Glut2 short interfering RNA (siRNA). An intense GLUT1-immunoreaction was localized in the enamel organ of bud-stage molar tooth germs, where the active cell proliferation occurred. By the bell stage, the expression of GLUT1 in the dental epithelium was dramatically decreased in intensity, and subsequently began to appear in the stratum intermedium at the late bell stage. On the other hand, GLUT2-immunoreactivity was weakly observed in the whole tooth germs throughout all stages. The inhibition of GLUTs1/2 by phloretin in the bud-stage tooth germs induced the disturbance of primary enamel knot formation, resulting in the developmental arrest of the explants and the squamous metaplasia of dental epithelial cells. Furthermore, the inhibition of GLUTs1/2 in cap-to-bell-stage tooth germs reduced tooth size in a dose dependent manner. These findings suggest that the expression of GLUT1 and GLUT2 in the dental epithelial and mesenchymal cells seems to be precisely and spatiotemporally controlled, and the glucose uptake mediated by GLUT1 plays a crucial role in the early tooth morphogenesis and tooth size determination. PMID- 22226977 TI - Tbx20 regulation of cardiac cell proliferation and lineage specialization during embryonic and fetal development in vivo. AB - TBX20 gain-of-function mutations in humans are associated with congenital heart malformations and myocardial defects. However the effects of increased Tbx20 function during cardiac chamber development and maturation have not been reported previously. CAG-CAT-Tbx20 transgenic mice were generated for Cre-dependent induction of Tbx20 in myocardial lineages in the developing heart. betaMHCCre mediated overexpression of Tbx20 in fetal ventricular cardiomyocytes results in increased thickness of compact myocardium, induction of cardiomyocyte proliferation, and increased expression of Bmp10 and pSmad1/5/8 at embryonic day (E) 14.5. betaMHCCre-mediated Tbx20 overexpression also leads to increased expression of cardiac conduction system (CCS) genes Tbx5, Cx40, and Cx43 throughout the ventricular myocardium. In contrast, Nkx2.5Cre mediated overexpression of Tbx20 in the embryonic heart results in reduced cardiomyocyte proliferation, increased expression of a cell cycle inhibitor, p21(CIP1), and decreased expression of Tbx2, Tbx5, and N-myc1 at E9.5, concomitant with decreased phospho-ERK1/2 expression. Together, these analyses demonstrate that Tbx20 differentially regulates cell proliferation and cardiac lineage specification in embryonic versus fetal cardiomyocytes. Induction of pSmad1/5/8 at E14.5 and inhibition of dpERK expression at E9.5 are consistent with selective Tbx20 regulation of these pathways in association with stage-specific effects on cardiomyocyte proliferation. Together, these in vivo data support distinct functions for Tbx20 in regulation of cardiomyocyte lineage maturation and cell proliferation at embryonic and fetal stages of heart development. PMID- 22226979 TI - The formation of an angiogenic astrocyte template is regulated by the neuroretina in a HIF-1-dependent manner. AB - The vascular and nervous systems display a high degree of cross-talk and depend on each other functionally. In the vascularization of the central nervous system, astrocytes have been thought to sense tissue oxygen levels in hypoxia-inducible factors (HIFs)-dependent manner and control the vascular growth into the hypoxic area by secreting VEGF. However, recent genetic evidences demonstrate that not only astrocyte HIFs but also astrocyte VEGF expression is dispensable for developmental angiogenesis of the retina. This study demonstrates that hypoxia inducible factor 1 alpha subunit (HIF-1alpha), a key transcription factor involved in cellular responses to hypoxia, is most abundantly expressed in the neuroretina, especially retinal progenitor cells (RPCs). A neuroretina-specific knockout of HIF-1alpha (alphaCre(+)Hif1alpha(flox/flox)) showed impaired vascular development characterized by decreased tip cell filopodia and reduced vessel branching. The astrocyte network was hypoplastic in alphaCre(+)Hif1alpha(flox/flox) mice. Mechanistically, platelet-derived growth factor A (PDGF-A), a mitogen for astrocytes, was downregulated in the neuroretina of alphaCre(+)Hif1alpha(flox/flox) mice. Supplementing PDGF-A restored reduced astrocytic and vascular density in alphaCre(+)Hif1alpha(flox/flox) mice. Our data demonstrates that the neuroretina but not astrocytes acts as a primary oxygen sensor which ultimately controls the retinal vascular development by regulating an angiogenic astrocyte template. PMID- 22226980 TI - Evaluation of the RIDAQuick norovirus immunochromatographic test kit. AB - BACKGROUND: Norovirus infections occur frequently and are widespread throughout the US population causing greater than half of all foodborne gastroenteritis cases. A rapid norovirus assay would be a useful clinical tool for identification of this common virus in gastroenteritis patient samples, thereby identifying outbreaks and facilitating rapid implementation of control measures. OBJECTIVES: To determine the suitability of the RIDAQuick norovirus kit as a clinical tool by determining the specificity and sensitivity of the assay, and its cross reactivity with other enteric viruses. STUDY DESIGN: Archived stool specimens containing norovirus genogroup I or II or other viruses were tested using the RIDAQuick norovirus assay and results compared to those obtained with real-time RT-PCR. RESULTS: We tested 62 samples: 19 norovirus genogroup I, 25 genogroup II samples, and 18 norovirus negative samples. Compared to PCR results, RIDAQuick assay sensitivity was 61.4%, and specificity was 100%. The low sensitivity was mainly due to poor results with genogroup I specimens; only 11 of 19 were detected. Additionally, samples of four other common enteric viruses all tested negative with the RIDAQuick assay. CONCLUSIONS: The RIDAQuick kit effectively detects norovirus genogroup II strains, but not genogroup I strains. We found no cross-reactivity with several common enteric viruses. As most norovirus cases are currently genogroup II strains, positive results with RIDAQuick can be used for rapid detection of norovirus in a large percentage of cases, thus also aiding in identification of outbreaks. However, final confirmation and negative results require further testing with more sensitive methods. PMID- 22226981 TI - Synthesis, anticancer activity and pharmacokinetic analysis of 1-[(substituted 2 alkoxyquinoxalin-3-yl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives. AB - Based on the anticancer activity of novel quinoxalinyl-piperazine compounds, 1 [(5 or 6-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives published in Bioorg. Med. Chem.2010, 18, 7966, we further explored the synthesis of 7 or 8-substituted quinoxalinyl piperazine derivatives. From in vitro studies of the newly synthesized compounds using human cancer cell lines, we identified some of the 8-substituted compounds, for example 6p, 6q and 6r, which inhibited the proliferation of various human cancer cells at nanomolar concentrations. Compound 6r, in particular, showed the lowest IC(50) values, ranging from 6.1 to 17nM, in inhibition of the growth of cancer cells, which is better than compound 6k (compound 25 in the reference cited above). In order to select and develop a leading compound among the quinoxaline compounds with substitutions on positions 5, 6, 7 or 8, the compounds comparable to compound 6k in in vitro cancer cell growth inhibition were chosen and their pharmacokinetic properties were evaluated in rats. In these studies, compound 6k showed the highest oral bioavailability of 83.4%, and compounds 6j and 6q followed, with 77.8% and 57.6%, respectively. From the results of in vitro growth inhibitory activities and the pharmacokinetic study, compound 6k is suggested for further development as an orally deliverable anticancer drug. PMID- 22226982 TI - Creating a unique environment for selecting reactive enzymes with DNA: 'Sticky' binding of oligocation-grafted polymers to DNA. AB - To provide colloidally stable polyplexes formed between pDNA and cationic polymers, cationic polymers have been modified with hydrophilic polymers to form a hydrophilic shell. Block copolymers of cationic and hydrophilic polymers and cationic polymers grafted with hydrophilic polymers are representative designs of such polymers. Here, we report a new design of cationic polymers and oligocationic peptide-grafted polymers. We synthesized 15 kinds of graft copolymers by varying the number of cationic charges of the peptides and their grafting density. We found that graft copolymers with less cationic peptides and less grafting density formed colloidally stable polyplexes. Interestingly, the less cationic graft copolymers bind to excess amounts of pDNA. We also found that the graft copolymers showed selectivity toward reactive enzymes affording the reaction of pDNA with nucleases, while suppressing both the replication of DNA by DNA polymerase and gene expression. The suppression of the replication and expression is considered to result from the high capacity of the graft copolymers for binding with pDNA. The polynucleotides produced by DNA polymerase or RNA polymerase would be captured by the graft copolymers to impede these enzymatic reactions. PMID- 22226984 TI - Conservation of endemic and threatened wildlife: molecular forensic DNA against poaching of the Cypriot mouflon (Ovis orientalis ophion, Bovidae). AB - Molecular DNA techniques in combination with appropriate reference population database and statistical methods are fundamental tools to forensic wildlife investigations. This is even more relevant when taxa with uncertain systematics are involved, as is the case of the genus Ovis (Bovidae), whose evolution has been influenced by multiple events of domestication. The Cypriot mouflon, Ovis orientalis ophion, a protected subspecies endemic to Cyprus, is threatened by poaching. This study deals with a case of alleged poaching that occurred in Cyprus (September, 2010). A car did not stop at a checkpoint and when finally blocked by the police, several bloodstained exhibits (n=12) were recovered. Three recently deceased mouflons were found by game wardens at the roadside. The Cyprus Veterinary Services established that these animals had been killed by gunshot. As part of the investigation, DNA testing was performed to establish if there was a link between the dead mouflons and the bloodstained exhibits. The mitochondrial Cytochrome-b gene (Cyt-b) and 12 loci of microsatellite DNA were used as markers. The Cyt-b sequences were obtained from 11 exhibits. They were the same as each other and the same as the single haplotype obtained from the three dead mouflons and all the investigated wild Cypriot mouflons (20 individuals). A database of wild mouflons (47 individuals) from which the unknown samples may have originated was generated. The probability of identity (P(ID)) of the microsatellite panel, computed by genotyping all 47 wild mouflons (10 selected loci, P(ID)=10(-5)), allowed us to assign nine exhibits to two out of the three carcasses (seven with very strong support: Likelihood Ratio, LR>3000 and Random Match Probability, RMP, <10(-3)). This study represents the first genetic reference for the Cypriot mouflon and the first published material of forensic wildlife investigations in Cyprus. PMID- 22226985 TI - Clustering of DNA words and biological function: a proof of principle. AB - Relevant words in literary texts (key words) are known to be clustered, while common words are randomly distributed. Given the clustered distribution of many functional genome elements, we hypothesize that the biological text per excellence, the DNA sequence, might behave in the same way: k-length words (k mers) with a clear function may be spatially clustered along the one-dimensional chromosome sequence, while less-important, non-functional words may be randomly distributed. To explore this linguistic analogy, we calculate a clustering coefficient for each k-mer (k=2-9bp) in human and mouse chromosome sequences, then checking if clustered words are enriched in the functional part of the genome. First, we found a positive general trend relating clustering level and word enrichment within exons and Transcription Factor Binding Sites (TFBSs), while a much weaker relation exists for repeats, and no relation at all exists for introns. Second, we found that 38.45% of the 200 top-clustered 8-mers, but only 7.70% of the non-clustered words, are represented in known motif databases. Third, enrichment/depletion experiments show that highly clustered words are significantly enriched in exons and TFBSs, while they are depleted in introns and repetitive DNA. Considering exons and TFBSs together, 1417 (or 72.26%) in human and 1385 (or 72.97%) in mouse of the top-clustered 8-mers showed a statistically significant association to either exons or TFBSs, thus strongly supporting the link between word clustering and biological function. Lastly, we identified a subset of clustered, diagnostic words that are enriched in exons but depleted in introns, and therefore might help to discriminate between these two gene regions. The clustering of DNA words thus appears as a novel principle to detect functionality in genome sequences. As evolutionary conservation is not a prerequisite, the proof of principle described here may open new ways to detect species-specific functional DNA sequences and the improvement of gene and promoter predictions, thus contributing to the quest for function in the genome. PMID- 22226983 TI - Identification and validation of protein targets of bioactive small molecules. AB - Identification and validation of protein targets of bioactive small molecules is an important problem in chemical biology and drug discovery. Currently, no single method is satisfactory for this task. Here, we provide an overview of common methods for target identification and validation that historically were most successful. We have classified for the first time the existing methods into two distinct and complementary types, the 'top-down' and 'bottom-up' approaches. In a typical top-down approach, the cellular phenotype is used as a starting point and the molecular target is approached through systematic narrowing down of possibilities by taking advantage of the detailed existing knowledge of cellular pathways and processes. In contrast, the bottom-up approach entails the direct detection and identification of the molecular targets using affinity-based or genetic methods. A special emphasis is placed on target validation, including correlation analysis and genetic methods, as this area is often ignored despite its importance. PMID- 22226986 TI - Identification and functional analysis of the small membrane-associated protein pUL11 of avian infectious laryngotracheitis virus. AB - pUL11 is a highly conserved, small, acylated, membrane-associated tegument protein of herpesviruses. It is involved in final envelopment of nascent virions in the cytoplasm, although the precise mechanism is still unknown. By screening of mouse monoclonal antibodies (mAb) raised against purified particles of infectious laryngotracheitis virus (ILTV) of chickens (Veits et al., 2003a), we identified two mAb recognizing the 15 kDa UL11 protein (pUL11) of this avian alphaherpesvirus. These mAb permitted detection and precise localization of pUL11 in mature ILT virions, as well as in the cytoplasm of infected chicken cells by Western blot analyses, indirect immunofluorescence tests, and immunoelectron microscopy. For investigation of gene function UL11-deleted ILTV recombinants were generated. Like its homologues in several other alphaherpesviruses, ILTV pUL11 was shown to be nonessential for productive virus replication. However, compared to wild-type and UL11 rescued ILTV the deletion mutants exhibited significantly reduced virus yields and moderately impaired spread in cell culture. In the absence of pUL11, electron microscopy of infected cells revealed accumulations of tegument proteins with nucleocapsids, and marked distortions of Golgi membranes in the cytoplasm, which obviously inhibited the formation of mature, enveloped virus particles. Taken together, our results demonstrate that pUL11 is relevant for secondary envelopment of ILTV, and confirm functional conservation of this protein in herpesviruses. The now available unique pUL11 specific mAb will help to further analyze this function, which is presumably mediated by physical interactions with other viral gene products, in cultured cells and in the natural animal host of ILTV. PMID- 22226987 TI - Anti-inflammatory properties of culinary herbs and spices that ameliorate the effects of metabolic syndrome. AB - Obesity and metabolic syndrome are increasing global health problems. In addition to the malnutrition of a sedentary lifestyle, high calorie intake leads to obesity with many negative health consequences. Macrophages infiltrate adipose tissue and induce chronic inflammation by secreting pro-inflammatory cytokines, including COX-2 and iNOS, among other mediators of inflammation. Free fatty acids mediate adipose tissue signalling through toll-like receptor 4 and the expression of these pro-inflammatory mediators via NF-kappaB or JNK. PPAR gamma activators can inhibit the activation of NF-kappaB, down-regulating the expression of pro inflammatory cytokines. Here we provide an overview of how different culinary herbs and spices exert anti-inflammatory activities and the extent to which they activate PPAR alpha and PPAR gamma, inhibit the activation of NF-kappaB, and enhance expression of anti-inflammatory cytokines. Spices can play essential roles as anti-inflammatory agents in our diet, acting as pan PPAR activators and improving insulin sensitivity, counteracting dyslipidaemia and weight gain. The effects of chronic inflammation caused by obesity are counteracted and, consequently, the progression of diseases associated with chronic inflammation slowed. PMID- 22226988 TI - Age, weight and obesity. AB - The western world is facing the consequences of higher standards of medical care and improved living conditions. While people are living longer the prevalence of overweight and obesity is escalating which increases the risk of developing non communicable diseases. However it must be noted that there is a U shaped relationship between weight and mortality with both under and overweight increasing risk. This review examines possible contributory factors for overweight and obesity in older people: life style, depression, changes in body composition, endocrine alterations, sympathetic tone, oxidative stress and concomitant disease. PMID- 22226989 TI - Role of gonadal hormones in anxiety and fear memory formation and inhibition in male mice. AB - Recent research investigating Pavlovian fear conditioning and fear extinction has elucidated the neurocircuitry involved in acquisition and inhibition of fear responses. Modulatory factors that may underlie individual differences in fear acquisition and inhibition, however, are not well understood. Testosterone is known to affect anxiety-like behavior and cognitive processing. In this study, we hypothesized that castration would increase anxiety and reduce memory for contextual fear conditioning in an age-dependent manner. In addition, castration would reduce the rate of extinction to context, as high levels of testosterone correlate with reduced PTSD-like symptoms. We compared behaviors in male mice that were castrated at one of two different time points, either before puberty (at 4 weeks) or after puberty (at 10 weeks) to sham-operated control mice. The behaviors investigated included: anxiety, cued and contextual fear conditioning, and extinction of the fear memory. An interaction of hormone status and age and a significant effect of age were measured in the elevated plus maze, a measure of anxiety. Castration caused a significant reduction of contextual fear memory, but no effect on cued fear memory. There was no significant effect of castration on extinction. Interestingly, a significant effect of age of the mouse at the time of testing was observed on extinction. These results suggest that endogenous androgens during puberty are important for anxiety and fear memory formation. In addition, these results define a late post-adolescent developmental time point for changes in anxiety and fear extinction. PMID- 22226990 TI - Feeding status and basking requirements of freshwater turtles in an invasion context. AB - Thermoregulatory behavior and feeding status are strongly related in ectotherms. A trade-off between maintenance of energy balance and digestion efficiency has been recently proposed to affect thermoregulation in these animals. On the other hand, competition for basking sites has been described between Iberian turtles and the introduced red-eared slider (Trachemys scripta elegans). T. scripta negatively interferes with basking behavior of native turtles and benefits from a greater capacity to retain body heat, which may likely result in thermoregulatory advantages for the introduced sliders. Consequently, complex effects and alterations in metabolic rates of native turtles might derive from a deficient basking behavior. We compared the basking requirements of the endangered native Spanish terrapin (Mauremys leprosa) and those of the introduced red-eared slider, analyzing the upper set point temperature (USP) (defined as the body temperature at which basking ceased) of both native and introduced turtles, under feeding and fasting conditions. We found higher values of USP in the native species, and a reduction of this temperature associated with food deprivation in the two turtle species. This adjustment of thermoregulatory behavior to the nutritional status found in freshwater turtles suggests that ectotherms benefit from metabolic depression as an adaptive mechanism to preserve energy during periods of fasting. However, a reduction in metabolic rates induced by competition with sliders might lead M. leprosa to a prolonged deficiency of their physiological functions, thus incurring increased predation risk and health costs, and ultimately favoring the recession of this native species in Mediterranean habitats. PMID- 22226991 TI - Context-dependent responses to novelty in Rainbow trout (Oncorhynchus mykiss), selected for high and low post-stress cortisol responsiveness. AB - Previous studies in a rainbow trout model, selectively bred for high (HR) and low (LR) post stress plasma cortisol levels, have yielded data that are indicative of contrasting stress coping styles. Fish from the HR line have been suggested to display a more diverse behavioral repertoire in challenging situations than the LR counterpart. The present study addressed whether such variation in behavioral flexibility traits was evident in different experimental settings using these selection lines. The fish were subjected to three sets of challenges (novel object test, resident-intruder test and confinement stressor test), all which were repeated a week later. Introducing a novel object evoked a divergent behavioral response in association with feeding: fish from the LR line displayed consistently suppressed feed intake while the HR fish remained unaffected. This observation was found to be repeatable along with attack latency and movement activity from the resident-intruder and confinement stressor tests. These results indicate that the behavioral responses in this animal model are context-dependent and shed new light on the expression of behavioral flexibility. PMID- 22226992 TI - The effect of a covert manipulation of ambient temperature on heat storage and voluntary exercise intensity. AB - The modulation of sub-maximal voluntary exercise intensity during heat stress has been suggested as a behavioral response to maintain homeostasis; however, the relationship between thermophysiological cues and the associated response remains unclear. Awareness of an environmental manipulation may influence anticipatory planning before the start of exercise, making it difficult to isolate the dynamic integration of thermophysiological afferents during exercise itself. The purpose of the present study was to examine the direct real-time relationship between thermophysiological afferents and the behavioral response of voluntary exercise intensity. Participants were tasked with cycling at a constant rating of perceived exertion while ambient temperature (T(a)) was covertly changed from 20 degrees C to 35 degrees C and then back to 20 degrees C at 20-minute intervals. Overall, power output (PO) and heat storage, quantified using repeated measures ANOVA, changed significantly over 20-minute intervals (135 +/- 39 W, 133 +/- 46 W, 120 +/- 45 W; 52.35 +/- 36.15 W.m(-2), 66.34 +/- 22.02 W.m(-2), -66.53 +/- 56.01 W.m(-2)). The synchronicity of PO fluctuations with changes in thermophysiological status was quantified using Auto-Regressive Integrated Moving Average (ARIMA) time series analysis. Fluctuations in PO were not synchronized in real time with changes in T(a); heat storage; rectal, skin, or mean body temperature; or sweat rate (stationary-r(2) <= 0.10 and Ljung-Box statistic > 0.05 for all variables). We conclude that, while the thermal environment affects physiological responses and voluntary power output while cycling at a constant perceived effort, the behavioral response of voluntary exercise intensity did not depend on a direct response to real-time integration of thermal afferent inputs. PMID- 22226993 TI - Introduction for the allostatic load special issue. PMID- 22226995 TI - Polyps in continent catheterizable bladder channels. AB - OBJECTIVE: We describe our experience with polyps encountered in bladder continent catheterizable channels. MATERIAL AND METHODS: An IRB-approved retrospective study was conducted on all patients at Children's Hospital of Wisconsin with continent catheterizable channels managed by a single physician over a 16-year time period. RESULTS: Fifty-five patients were identified with bladder channels. During a median follow-up of 7 years (range 3-16 years), 20% (11/55) of bladder channels developed polyps. The time to diagnosis of a polyp in bladder channels from initial surgery ranged from 3 months to 8 years (median of 29 months). Fifty-five percent (6/11) of patients who developed bladder polyps were symptomatic. All patients' symptoms resolved after treatment by endoscopic resection. Forty-five percent (5/11) of polyps recurred after resection. The time of recurrence ranged from 4 months to 7 years (median of 19 months). Polyps were universally benign inflammatory granulomatous tissue. CONCLUSION: This is the first series reporting the incidence of polyps in bladder catheterizable channels. Patients with continent catheterizable bladder channels can develop symptomatic polyps in their channels, of unknown long-term significance and risk. PMID- 22226994 TI - Sequence learning and the role of the hippocampus in rodent navigation. AB - The hippocampus has long been associated with navigation and spatial representations, but it has been difficult to link directly the neurophysiological correlates of hippocampal place cells with navigational planning and action. In recent years, large-scale population recordings of place cells have revealed that spatial sequences are stored and activated in ways that may support navigational strategies. Plasticity mechanisms allow the hippocampus to store learned sequences of locations that may allow predictions of future locations based on past experience. These sequences can also be activated during navigational behavior in ways that may allow the animal to learn trajectories toward goals. Task-dependent alterations in place cell firing patterns may reflect the operation of the hippocampus in associating locations with navigationally relevant decision variables. PMID- 22226996 TI - Evaluation of coagulation and fibrinolytic parameters in adult onset GH deficiency and the effects of GH replacement therapy: a placebo controlled study. AB - OBJECTIVE: Increased cardiovascular mortality/morbidity observed in patients with hypopituitarism is ascribed to growth hormone deficiency (GHD) because of its unfavorable cardiovascular risk profile. Abnormalities in the coagulation system may also contribute to increased cardiovascular morbidity/mortality. To get a better insight into the role of hemostasis in GHD we assessed several hemostatic markers at baseline and after 6 months of GH replacement therapy (GHRT). DESIGN PATIENTS: Nineteen patients with adult onset GHD were enrolled (twelve patients into the treatment and seven patients into the placebo group) into the study. Platelet count, collagen/epinephrine closure time, collagen/ADP closure time, fibrinogen, prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin III (AT III), protein C activity, protein S activity, lupus anticoagulant, antiphospholipid antibody immunoglobulin M, and antiphospholipid antibody immunoglobulin G were measured at baseline and 6 months after treatment. RESULTS: The investigated parameters in the groups were similar at baseline except for low protein S (PS) activity. Protein S deficiency was observed in three of the patients in the GH treatment group at baseline, however the PS activity values normalized following GHRT. AT III and protein C activities decreased when compared to baseline values in the treatment group but not in the placebo group. CONCLUSIONS: We observed protein S deficiency more frequent than seen in the general population and normalization of protein S activity and decreases, in other natural anticoagulants following GHRT. Further studies are required to understand the impact of these changes in cardiovascular morbidity and mortality in this patient population. PMID- 22226997 TI - The influence of approximal restoration extension on the development of secondary caries. AB - OBJECTIVES: To evaluate whether occlusoproximal restorations with cervical margins apical to the cemento-enamel junction (CEJ) are more prone to failure than restorations with margins coronal to the CEJ, in particular failure due to secondary caries. METHODS: A method was developed for scoring cervical margin extension on bitewings, and validated in vitro. Records from patients with at least one occlusoproximal restoration replaced due to secondary caries were selected from an existing database. Cervical margins of approximal restoration sites were scored on bitewings in relation to the CEJ (supra vs. sub CEJ). For all restorations dates of placement, replacement and reason for failure were recorded. Survival times were calculated and Cox-regression analysis was applied to assess influence of selected variables on survival of restorations: extension of cervical margins, number of restored surfaces, restoration material and age of the patient. RESULTS: Records of 84 patients with 1912 restoration sites were examined, 655 failed; 399 supra CEJ and 256 sub CEJ. 257 restorations failed because of secondary caries. Restorations ending below the CEJ showed significantly increased risk for failure (HR=1.28, p=0.020), however, no relation with secondary caries was found (p=0.130). Amalgam restorations showed decreased risk for secondary caries (HR=0.51, p<0.001). CONCLUSION: Occlusoproximal restorations with cervical margins apical to the CEJ do not fail more often due to secondary caries. However, those restorations did show larger risk of failure overall compared to restorations with margins coronal to the CEJ. Resin composite restorations showed increased risk for secondary caries compared to amalgam restorations. CLINICAL SIGNIFICANCE: Within the limitations of this study, no association was found clinically between extension of restoration margins below the CEJ and the occurrence of secondary caries. PMID- 22226998 TI - The BK(Ca) channels deficiency as a possible reason for radiation-induced vascular hypercontractility. AB - It is likely that large-conductance Ca2+-activated K+ (BK(Ca)) channels channelopathy tightly involved in vascular malfunctions and arterial hypertension development. In the present study, we compared the results of siRNAs-induced alpha-BK(Ca) gene silencing and vascular abnormalities produced by whole-body ionized irradiation in rats. The experimental design comprised RT-PCR and patch clamp technique, thoracic aorta smooth muscle (SM) contractile recordings and arterial blood pressure (BP) measurements on the 30th day after whole body irradiation (6Gy) and following siRNAs KCNMA1 gene silencing in vivo. The expression profile of BK(Ca) mRNA transcripts in SM was significantly decreased in siRNAs-treated rats in a manner similar to irradiated SM. In contrast, the mRNA levels of K(v) and K(ATP) were significantly increased while L-type calcium channels mRNA transcripts demonstrated tendency to increment. The SMCs obtained from irradiated animals and after KCNMA1 gene silencing showed a significant decrease in total K+ current density amplitude. Paxilline (500 nM)-sensitive components of outward current were significantly decreased in both irradiated and gene silencing SMCs. KCNMA1 gene silencing increased SM sensitivity to norepinephrine while Ach-induced relaxation had decreased. The silencing of KCNMA1 had no significant effect on BP while radiation produced sustained arterial hypertension. Therefore, radiation alters the form and function of the BK(Ca) channel and this type of channelopathy may contribute to related vascular abnormalities. Nevertheless, it is unlikely that BK(Ca) can operate as a crucial factor for radiation-induced arterial hypertension. PMID- 22226999 TI - Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons. AB - Amyotrophic lateral sclerosis (ALS) is the most common adult-onset fatal motor neuron disease. In spinal motor neurons of patients with sporadic ALS, normal RNA editing of GluA2, a subunit of the L-alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor, is inefficient. Adenosine deaminase acting on RNA 2 (ADAR2) specifically mediates RNA editing at the glutamine/arginine (Q/R) site of GluA2 and motor neurons expressing Q/R site unedited GluA2 undergo slow death in conditional ADAR2 knockout mice. Therefore, investigation into whether inefficient ADAR2-mediated GluA2 Q/R site-editing occurs universally in motor neurons of patients with ALS would provide insight into the pathogenesis of ALS. We analyzed the extents of GluA2 Q/R site-editing in an individual laser-captured motor neuron of 29 ALS patients compared with those of normal and disease control subjects. In addition, we analyzed the enzymatic activity of three members of the ADAR family (ADAR1, ADAR2 and ADAR3) in ALS motor neurons expressing unedited GluA2 mRNA and those expressing only edited GluA2 mRNA. Q/R site-unedited GluA2 mRNA was expressed in a significant proportion of motor neurons from all of the ALS cases examined. Conversely, motor neurons of the normal and disease control subjects expressed only edited GluA2 mRNA. ADAR2, but not ADAR1 or ADAR3, was significantly downregulated in all the motor neurons of ALS patients, more extensively in those expressing Q/R site unedited GluA2 mRNA than those expressing only Q/R site-edited GluA2 mRNA. These results indicate that ADAR2 downregulation is a profound pathological change relevant to death of motor neurons in ALS. PMID- 22227000 TI - Induced pluripotent stem cell lines from Huntington's disease mice undergo neuronal differentiation while showing alterations in the lysosomal pathway. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an excessive expansion of a CAG trinucleotide repeat in the gene encoding the protein huntingtin, resulting in an elongated stretch of glutamines near the N-terminus of the protein. Here we report the derivation of a collection of 11 induced pluripotent stem (iPS) cell lines generated through somatic reprogramming of fibroblasts obtained from the R6/2 transgenic HD mouse line. We show that CAG expansion has no effect on reprogramming efficiency, cell proliferation rate, brain-derived neurotrophic factor level, or neurogenic potential. However, genes involved in the cholesterol biosynthesis pathway, which is altered in HD, are also affected in HD-iPS cell lines. Furthermore, we found a lysosomal gene upregulation and an increase in lysosome number in HD-iPS cell lines. These observations suggest that iPS cells from HD mice replicate some but not all of the molecular phenotypes typically observed in the disease; additionally, they do not manifest increased cell death propensity either under self-renewal or differentiated conditions. More studies will be necessary to transform a revolutionary technology into a powerful platform for drug screening approaches. PMID- 22227001 TI - Loss of circadian clock accelerates aging in neurodegeneration-prone mutants. AB - Circadian clocks generate rhythms in molecular, cellular, physiological, and behavioral processes. Recent studies suggest that disruption of the clock mechanism accelerates organismal senescence and age-related pathologies in mammals. Impaired circadian rhythms are observed in many neurological diseases; however, it is not clear whether loss of rhythms is the cause or result of neurodegeneration, or both. To address this important question, we examined the effects of circadian disruption in Drosophila melanogaster mutants that display clock-unrelated neurodegenerative phenotypes. We combined a null mutation in the clock gene period (per(01)) that abolishes circadian rhythms, with a hypomorphic mutation in the carbonyl reductase gene sniffer (sni(1)), which displays oxidative stress induced neurodegeneration. We report that disruption of circadian rhythms in sni(1) mutants significantly reduces their lifespan compared to single mutants. Shortened lifespan in double mutants was coupled with accelerated neuronal degeneration evidenced by vacuolization in the adult brain. In addition, per(01)sni(1) flies showed drastically impaired vertical mobility and increased accumulation of carbonylated proteins compared to age-matched single mutant flies. Loss of per function does not affect sni mRNA expression, suggesting that these genes act via independent pathways producing additive effects. Finally, we show that per(01) mutation accelerates the onset of brain pathologies when combined with neurodegeneration-prone mutation in another gene, swiss cheese (sws(1)), which does not operate through the oxidative stress pathway. Taken together, our data suggest that the period gene may be causally involved in neuroprotective pathways in aging Drosophila. PMID- 22227002 TI - Amelioration of social isolation-triggered onset of early Alzheimer's disease related cognitive deficit by N-acetylcysteine in a transgenic mouse model. AB - Epidemiological study reveals that socially isolated persons have increased risk of developing Alzheimer's disease (AD). Whether this risk arises from an oxidative stress is unclear. Here we show that N-acetylcysteine (NAC), an anti oxidant, is capable of preventing social isolation-induced accelerated impairment of contextual fear memory and rundown of hippocampal LTP in 3-month old APP/PS1 mice. Increased hippocampal levels of gamma-secretase activity, Abeta-40 and Abeta-42 seen in the isolated APP/PS1 mice were reduced by chronic treatment of NAC. In addition, social isolation-induced increase in calpain activity and p25/p35 ratio concomitant with decrease in membrane-associated p35 and p35/Cdk5 activity was normalized by NAC. NAC pretreatment also reversed isolation-induced decrease in GluR1 Ser831 phosphorylation, surface expression of AMPARs and p35 GluR1-CaMKII interactions. These results suggest that NAC decreases gamma secretase activity resulting in the attenuation of Abeta production, calpain activity and conversion of p35 to p25 which stabilized p35-GluR1-CaMKII interactions and restored GluR1 and GluR2 surface expression. Our results indicate that NAC is effective in mouse models of AD and has translation potential for the human disorder. PMID- 22227003 TI - Molecular cloning and expression of two beta-defensin and two mucin genes in common carp (Cyprinus carpio L.) and their up-regulation after beta-glucan feeding. AB - In this study, we described the partial structure, mRNA tissue distribution and regulation of two carp mucin and two beta-defensin genes. This is the first description of these genes in fish. The genes might provide relevant tools to monitor feed-related improvements of fish health under aquaculture conditions. Carp mucin 2 and mucin 5B genes show a high similarity to their mammalian and avian counterparts. The carp beta-defensin 1 and beta-defensin 2 genes cluster together well with their piscine family members. The influence of a beta-glucan immunomodulant on the expression of these genes in mucosal tissues could be confirmed for the first time. Muc5B expression was significantly increased in the skin. For Muc2 no significant up- or down-regulation could be observed. Significantly higher expression levels of beta-defensin 2 in gills and both beta defensin genes in skin were found. Thus, the mucosal system can be influenced by the addition of beta-glucans to the food. PMID- 22227004 TI - Effects of NV gene knock-out recombinant viral hemorrhagic septicemia virus (VHSV) on Mx gene expression in Epithelioma papulosum cyprini (EPC) cells and olive flounder (Paralichthys olivaceus). AB - To determine whether the NV gene of viral hemorrhagic septicemia virus (VHSV) is related to the type I interferon response of hosts, expression of Mx gene in Epithelioma papulosum cyprini (EPC) cells and in olive flounder (Paralichthys olivaceus) in response to infection with either wild-type VHSV or recombinant VHSVs (rVHSV-DeltaNV-EGFP and rVHSV-wild) was investigated. A reporter vector was constructed for measuring Mx gene expression using olive flounder Mx promoter, in which the reporter Metridia luciferase was designed to be excreted to culture medium to facilitate measurement. The highest increase of luciferase activity was detected from supernatant of cells infected with rVHSV-DeltaNV-EGFP. In contrast cells infected with wild-type VHSV showed a slight increase of the luciferase activity. Interestingly, cells infected with rVHSV-wild that has artificially changed nucleotides just before and after the NV gene ORF, also showed highly increased luciferase activity, but the increased amplitude was lower than that by rVHSV-DeltaNV-EGFP. These results strongly suggest that the NV protein of VHSV plays an important role in suppressing interferon response in host cells, which provides a condition for the viruses to efficiently proliferate in host cells. In an in vivo experiment, the Mx gene expression in olive flounder challenged with the rVHSV-DeltaNV-EGFP was clearly higher than fish challenged with rVHSV-wild or wild-type VHSV, suggesting that lacking of the NV gene in the genome of rVHSV DeltaNV-EGFP brought to strong interferon response that subsequently inhibit viral replication in fish. PMID- 22227005 TI - Age-dependent disruption in hippocampal theta oscillation in amyloid-beta overproducing transgenic mice. AB - Transgenic mice are used to model increased brain amyloid-beta (Abeta) and amyloid plaque formation reflecting Alzheimer's disease pathology. In our study hippocampal network oscillations, population spikes, and long-term potentiation (LTP) were recorded in APPswe/PS1dE9 (APP/PS1) and presenilin1 (PS1) transgenic and wild type mice at 2, 4, and 8 months of age under urethane anesthesia. Hippocampal theta oscillations elicited by brainstem stimulation were similar in wild type and PS1 mice at all age groups. In contrast, APP/PS1 mice showed an age dependent decrease in hippocampal activity, characterized by a significant decline in elicited theta power and frequency at 4 and 8 months. Magnitudes of population spikes and long-term potentiation in the dentate gyrus were similar across groups at both 4 and 8 months. In APP/PS1 mice, soluble and insoluble Abeta, and hippocampal and cortical plaque load increased with age, and the disruption in hippocampal theta oscillation showed a significant correlation with plaque load. Our study shows that, using in vivo electrophysiological methods, early Abeta-related functional deficits can be robustly detected in the brainstem hippocampus multisynaptic network. PMID- 22227006 TI - Musical experience offsets age-related delays in neural timing. AB - Aging disrupts neural timing, reducing the nervous system's ability to precisely encode sound. Given that the neural representation of temporal features is strengthened with musical training in young adults, can musical training offset the negative impact of aging on neural processing? By comparing auditory brainstem timing in younger and older musicians and nonmusicians to a consonant vowel speech sound /da/. we document a musician's resilience to age-related delays in neural timing. PMID- 22227007 TI - Receptor for advanced glycation endproducts (RAGE) deficiency protects against MPTP toxicity. AB - Parkinson's disease (PD) is a common neurodegenerative disorder of unknown pathogenesis characterized by the loss of nigrostriatal dopaminergic neurons. Oxidative stress, microglial activation and inflammatory responses seem to contribute to the pathogenesis. The receptor for advanced glycation endproducts (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules. The formation of advanced glycation end products (AGEs), the first ligand of RAGE identified, requires a complex series of reactions including nonenzymatic glycation and free radical reactions involving superoxide-radicals and hydrogen peroxide. Binding of RAGE ligands results in activation of nuclear factor-kappaB (NF-kappaB). We show that RAGE ablation protected nigral dopaminergic neurons against cell death induced by the neurotoxin MPTP that mimics most features of PD. In RAGE-deficient mice the translocation of the NF kappaB subunit p65 to the nucleus, in dopaminergic neurons and glial cells was inhibited suggesting that RAGE involves the activation of NF-kappaB. The mRNA level of S100, one of the ligands of RAGE, was increased after MPTP treatment. The dopaminergic neurons treated with MPP(+) and S100 protein showed increased levels of apoptotic cell death, which was attenuated in RAGE-deficient mice. Our results suggest that activation of RAGE contributes to MPTP/MPP(+)-induced death of dopaminergic neurons that may be mediated by NF-kappaB activation. PMID- 22227008 TI - The flavonoid eupatorin inactivates the mitotic checkpoint leading to polyploidy and apoptosis. AB - The spindle assembly checkpoint (SAC) is a conserved mechanism that ensures the fidelity of chromosome distribution in mitosis by preventing anaphase onset until the correct bipolar microtubule-kinetochore attachments are formed. Errors in SAC function may contribute to tumorigenesis by inducing numerical chromosome anomalies (aneuploidy). On the other hand, total disruption of SAC can lead to massive genomic imbalance followed by cell death, a phenomena that has therapeutic potency. We performed a cell-based high-throughput screen with a compound library of 2000 bioactives for novel SAC inhibitors and discovered a plant-derived phenolic compound eupatorin (3',5-dihydroxy-4',6,7 trimethoxyflavone) as an anti-mitotic flavonoid. The premature override of the microtubule drug-imposed mitotic arrest by eupatorin is dependent on microtubule kinetochore attachments but not interkinetochore tension. Aurora B kinase activity, which is essential for maintenance of normal SAC signaling, is diminished by eupatorin in cells and in vitro providing a mechanistic explanation for the observed forced mitotic exit. Eupatorin likely has additional targets since eupatorin treatment of pre-mitotic cells causes spindle anomalies triggering a transient M phase delay followed by impaired cytokinesis and polyploidy. Finally, eupatorin potently induces apoptosis in multiple cancer cell lines and suppresses cancer cell proliferation in organotypic 3D cell culture model. PMID- 22227009 TI - Characterization of mechanical behavior of an epithelial monolayer in response to epidermal growth factor stimulation. AB - Cell signaling often causes changes in cellular mechanical properties. Knowledge of such changes can ultimately lead to insight into the complex network of cell signaling. In the current study, we employed a combination of atomic force microscopy (AFM) and quartz crystal microbalance with dissipation monitoring (QCM D) to characterize the mechanical behavior of A431 cells in response to epidermal growth factor receptor (EGFR) signaling. From AFM, which probes the upper portion of an individual cell in a monolayer of cells, we observed increases in energy dissipation, Young's modulus, and hysteresivity. Increases in hysteresivity imply a shift toward a more fluid-like mechanical ordering state in the bodies of the cells. From QCM-D, which probes the basal area of the monolayer of cells collectively, we observed decreases in energy dissipation factor. This result suggests a shift toward a more solid-like state in the basal areas of the cells. The comparative analysis of these results indicates a regionally specific mechanical behavior of the cell in response to EGFR signaling and suggests a correlation between the time-dependent mechanical responses and the dynamic process of EGFR signaling. This study also demonstrates that a combination of AFM and QCM-D is able to provide a more complete and refined mechanical profile of the cells during cell signaling. PMID- 22227010 TI - The Sunn pest, Eurygaster integriceps Puton (Hemiptera: Scutelleridae) digestive tract: histology, ultrastructure and its physiological significance. AB - The Sunn pest, Eurygaster integriceps Put. (Hemiptera: Scutelleridae), is a key pest of wheat in the Middle East and some other areas which causes severe qualitative and quantitative damage. The objective of the current work is to describe the morphology of the midgut of E. integriceps adult. Microscopic studies revealed that foregut consists of oral cavity, pharynx and oesophagus likely other phytophagous Hemiptera. In the Midgut, four anatomical regions could be identified: the first ventriculus (V1), the second ventriculus (V2), the third ventriculs (V3), and the fourth ventriculus (V4). The microvilli and perimicrovillar membrane (PMM) were found in V1-V3 regions with columnar cells characterized by presence of mitochondria, rough endoplasmic reticulum and basal infoldings in the basal portion. However, V2 and V3 showed less developed basal plasma membrane infoldings. Three cell types: columnar, endocrine and regenerative cells were found in V1-V3. The V4 region showed different histological features from the other three midgut regions by showing a vacuolated epithelium with crypts storing symbiotic bacteria. The hindgut had a short ileum followed by a well-developed rectum with an epithelial cell layer and a thin cuticular intima. The current results suggest V1-V3 midgut regions play a role in enzyme and absorption, whereas V4 seems to have no function in digestion. PMID- 22227011 TI - GFP immunogold staining, from light to electron microscopy, in mammalian cells. AB - GFP has emerged as an important reporter for monitoring gene expression, protein localization, cell transformation and cell lineage. The development of GFP as a marker in many different biological systems has emphasized the need to image GFP at high resolution. GFP immunogold labeling with colloidal gold particles becomes essential for electron microscopy (EM) ultrastructural detection. Because of the small size, colloidal gold particles require silver enhancement, a procedure to increase the size of the particle as well as gold toning to stabilize the silver layer. GFP preembedding immunogold staining enables high quality cellular ultrastructural EM analysis mainly for two reasons, on one hand it allows adequate fixation for EM analysis maintaining GFP antigenicity, on the other hand it also enables the epoxy resins inclusion after immunogold staining. Both of them help to preserve better the ultrastructure. However GFP immunogold staining presents some drawbacks, such as the progressive decrease in immunogold labeling with tissue depth. Special attention must be taken when using GFP-tagged protein, since the fusion could interfere with their localization and function. In this review we provide a detailed protocol of the GFP immunogold staining, their main applications for EM and possible troubles. PMID- 22227012 TI - Development and preliminary application of an indirect ELISA for detecting antibodies against Avian Influenza Virus. AB - Fragment of 759 bp DNA spanning the Matrix 1 (M1) gene of Avian Influenza Virus (AIV) was inserted into an expression vector pET28c to construct a recombinant plasmid pET28c-M1. The pET28c-M1 plasmid was transformed into the Escherichia coli BL21 (DE3) competent cell to produce a recombinant strain E. coli 21 (DE3). After being induced by Isopropyl-b-D-galactopyranoside (IPTG), E. coli 21 (DE3) expressed a 28-kDa fusion protein at a high level. This protein can bind anti-AIV (H5N1) positive serum by Western-blot analysis. After being denatured, renatured, and purified by Ni(2+)-column, the fusion protein was used as an antigen to develop Matrix 1 Enzyme-Linked Immunosorbent Assay (M1-ELISA) for detecting antibodies against AIV from chicken serum. We found that this indirect M1-ELISA was sensitive for differentiating antisera against AIV and antisera against other six kinds of avian viruses apart from AIV and this method is more sensitive than Hemagglutination Inhibition (HI) test. When compared with HI test and ELISA (IDEXX) in evaluating 581 serum samples from field vaccinated chickens, this assay showed 93.3% agreement ratio with the HI test, as well as 96.0% agreement ratio with ELISA (IDEXX). In a preliminary application, the assay successfully detected 19 AIVs from 51 nonvaccinated chicken lungs. It concludes that an indirect ELISA was successfully developed for detecting AIV. The assay is specific and sensitive. The application will greatly contribute to the long-term prevention and control of avian influenza in China. PMID- 22227013 TI - Acquired resistance to drugs targeting receptor tyrosine kinases. AB - Development of resistance to chemotherapeutic drugs represents a significant hindrance to the effective treatment of cancer patients. The molecular mechanisms responsible have been investigated for over half a century and have revealed the lack of a single cause. Rather, a multitude of mechanisms have been delineated ranging from induction and expression of membrane transporters that pump drugs out of cells (multidrug resistance (MDR) phenotype), changes in the glutathione system and altered metabolism to name a few. Treatment of cancer patients/cancer cells with chemotherapeutic agents and/or molecularly targeted drugs is accompanied by acquisition of resistance to the treatment administered. Chemotherapeutic agent resistance was initially assumed to be due to induction of mutations leading to a resistant phenotype. This has also been true for molecularly targeted drugs. Considerable experience has been gained from the study of agents targeting the Bcr-Abl tyrosine kinase including imatinib, dasatinib and sunitinib. It is clear that mutations alone are not responsible for the many resistance mechanisms in play. Rather, additional mechanisms are involved, ranging from epigenetic changes, alternative splicing and the induction of alternative/compensatory signaling pathways. In this review, resistance to receptor tyrosine kinase inhibitors (RTKIs), RTK-directed antibodies and antibodies that inactivate ligands for RTKs are discussed. New approaches and concepts aimed at avoiding the generation of drug resistance will be examined. The recent observation that many RTKs, including the IGF-1R, are dependence receptors that induce apoptosis in a ligand-independent manner will be discussed and the implications this signaling paradigm has on therapeutic strategies will be considered. PMID- 22227016 TI - Functional polymeric nanoparticles for dexamethasone loading and release. AB - Poly(phenylacetylene) (PPA) and poly(phenylacetylene-co-acrylic acid) (P(PA-co AA)), nanoparticles bioconjugated with dexamethasone (DXM) during the synthesis, named PPA@DXM and P(PA-co-AA)@DXM, were prepared by a modified surfactant free emulsion method. The loading was studied as a function of different functionality grades of the copolymer and different amounts of drug, obtaining up to 90% of drug loading for P(PA-co-AA)@DXM with 8/1 PA/AA monomer ratio. The SEM images and DLS measurements showed spheres with average diameters in the range 190-500 nm, depending on the content of acrylic acid monomer units in the copolymer and of DXM loading. zeta-potential and surface charge density of DXM loaded nanoparticles were also investigated and confirm the charge density modulation in the range 0.62-2.68sigma (MUC/m(2)). The results highlight the enhanced capability of our copolymer of hosting DXM, with the advantage of a control of size, surface functionality, charge and release. Moreover we demonstrate for the first time the ability of P(PA-co-AA) DXM loaded nanoparticles to be used in the apoptosis inhibition of human tumor cells (HeLa). On the basis of the results obtained by comparing the effects elicited in HeLa cells by free DXM versus DXM loaded nanoparticles we confirmed the biological efficacy of our preparation. PMID- 22227015 TI - Mutant BRAF induces DNA strand breaks, activates DNA damage response pathway, and up-regulates glucose transporter-1 in nontransformed epithelial cells. AB - Although the oncogenic functions of activating BRAF mutations have been clearly demonstrated in human cancer, their roles in nontransformed epithelial cells remain largely unclear. Investigating the cellular response to the expression of mutant BRAF in nontransformed epithelial cells is fundamental to the understanding of the roles of BRAF in cancer pathogenesis. In this study, we used two nontransformed cyst108 and RK3E epithelial cell lines as models in which to compare the phenotypes of cells expressing BRAF(WT) and BRAF(V600E). We found that transfection of the BRAF(V600E), but not the BRAF(WT), expression vector suppressed cellular proliferation and induced apoptosis in both cell types. BRAF(V600E) generated reactive oxygen species, induced DNA double-strand breaks, and caused subsequent DNA damage response as evidenced by an increased number of pCHK2 and gammaH2AX nuclear foci as well as the up-regulation of pCHK2, p53, and p21. Because BRAF and KRAS (alias Ki-ras) mutations have been correlated with GLUT1 up-regulation, which encodes glucose transporter-1, we demonstrated here that expression of BRAF(V600E), but not BRAF(WT), was sufficient to up-regulate GLUT1. Taken together, our findings provide new insights into mutant BRAF-induced oncogenic stress that is manifested by DNA damage and growth arrest by activating the pCHK2-p53-p21 pathway in nontransformed cells, while it also confers tumor promoting phenotypes such as the up-regulation of GLUT1 that contributes to enhanced glucose metabolism that characterizes tumor cells. PMID- 22227017 TI - 5-amino-2-mercapto-1,3,4-thidiazole modified single-use sensors for electrochemical DNA analysis. AB - In this study, single-use graphite electrodes modified with 5-amino-2-mercapto 1,3,4-thidiazole (AMT) were fabricated for electrochemical monitoring of DNA. The surfaces of AMT modified pencil graphite electrodes (PGEs) were characterized by scanning electron microscopy (SEM). Electrochemical behaviors of these electrodes were investigated using differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). The effects of pretreatment of PGE and immobilization time and concentration of AMT were studied to facilitate an effective immobilization on PGE surface. The efficiency of immobilization is verified by measuring the oxidation signals of either AMT itself or adenine base of DNA, immobilized onto AMT modified electrodes. PMID- 22227018 TI - Structural changes of soy proteins at the oil-water interface studied by fluorescence spectroscopy. AB - Fluorescence spectroscopy was used to acquire information on the structural changes of proteins at the oil/water interface in emulsions prepared by using soy protein isolate, glycinin, and beta-conglycinin rich fractions. Spectral changes occurring from differences in the exposure of tryptophan residues to the solvent were evaluated with respect to spectra of native, urea-denatured, and heat treated proteins. The fluorescence emission maxima of the emulsions showed a red shift with respect to those of native proteins, indicating that the tryptophan residues moved toward a more hydrophilic environment after adsorption at the interface. The heat-induced irreversible transitions were investigated using microcalorimetry. Fluorescence spectroscopy studies indicated that while the protein in solution underwent irreversible structural changes with heating at 75 and 95 degrees C for 15 min, the interface-adsorbed proteins showed very little temperature-induced rearrangements. The smallest structural changes were observed in soy protein isolate, probably because of the higher extent of protein-protein interactions in this material, as compared to the beta-conglycinin and to the glycinin fractions. This work brings new evidence of structural changes of soy proteins upon adsorption at the oil water interface, and provides some insights on the possible protein exchange events that may occur between adsorbed and unadsorbed proteins in the presence of oil droplets. PMID- 22227014 TI - Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53. AB - Chemotherapy is the bedrock for the clinical management of cancer, and the tumor suppressor p53 has a central role in this therapeutic modality. This protein facilitates favorable antitumor drug response through a variety of key cellular functions, including cell cycle arrest, senescence, and apoptosis. These functions essentially cease once p53 becomes mutated, as occurs in ~50% of cancers, and some p53 mutants even exhibit gain-of-function effects, which lead to greater drug resistance. However, it is becoming increasingly evident that resistance is also seen in cancers harboring wild-type p53. In this review, we discuss how wild-type p53 is inactivated to render cells resistant to antitumor drugs. This may occur through various mechanisms, including an increase in proteasomal degradation, defects in post-translational modification, and downstream defects in p53 target genes. We also consider evidence that the resistance seen in wild-type p53 cancers can be substantially greater than that seen in mutant p53 cancers, and this poses a far greater challenge for efforts to design strategies that increase drug response in resistant cancers already primed with wild-type p53. Because the mechanisms contributing to this wild-type p53 "gain-of-resistance" phenotype are largely unknown, a concerted research effort is needed to identify the underlying basis for the occurrence of this phenotype and, in parallel, to explore the possibility that the phenotype may be a product of wild-type p53 gain-of-function effects. Such studies are essential to lay the foundation for a rational therapeutic approach in the treatment of resistant wild type p53 cancers. PMID- 22227019 TI - The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide. AB - The FDA-approved glucagon-like-peptide-1 receptor (GLP-1R) agonists exendin-4 and liraglutide reduce food intake and body weight. Nausea is the most common adverse side effect reported with these GLP-1R agonists. Whether food intake suppression by exendin-4 and liraglutide occurs independently of nausea is unknown. Further, the neurophysiological mechanisms mediating the nausea associated with peripheral GLP-1R agonist use are poorly understood. Using two established rodent models of nausea [conditioned taste avoidance (CTA) and pica (ingestion of nonnutritive substances)], results show that all peripheral doses of exendin-4 that suppress food intake also produce CTA, whereas one dose of liraglutide suppresses intake without producing CTA. Chronic (12 days) daily peripheral administration of exendin-4 produces a progressive increase in pica coupled with stable, sustained food intake and body weight suppression, whereas the pica response and food intake reduction by daily liraglutide are more transient. Results demonstrate that the nausea response accompanying peripheral exendin-4 occurs via a vagal independent pathway involving GLP-1R activation in the brain as the exendin-4 induced pica response is attenuated with CNS co-administration of the GLP-1R antagonist exendin-(9-39), but not by vagotomy. Direct administration of exendin 4 to the medial subnucleus of the nucleus tractus solitarius (mNTS), but not to the central nucleus of the amygdala, reduced food intake and produced a pica response, establishing the mNTS as a potential GLP-1R-expressing site mediating nausea responses associated with GLP-1R agonists. PMID- 22227020 TI - Hypothalamic expression of urocortin 3 and the type 2 corticotropin-releasing factor receptor is regulated according to feeding state in lean but not obese Zucker rats. AB - Urocortin 3 (Ucn3) is an anorexigenic neuropeptide with high affinity for the type 2 corticotropin-releasing factor receptor (CRF2-R). How the expression of hypothalamic Ucn3 is regulated by fasting and refeeding in genetically obese (fa/fa) Zucker rats is not known. Obese Zucker rats develop early hyperphagia associated with low expression of CRF2-R in the ventromedial hypothalamic nucleus (VMH) in this phenotype. Although lean (Fa/?) Zucker rats have strong basal expression of CRF2-R in the VMH, and normally consume less food compared to their obese littermates, at the beginning of refeeding, the lean rats ingested almost the same amount of food as the obese animals. The present study was designed to investigate the dynamics of the expression of CRF2-R and Ucn3 in the brain of lean and obese Zucker rats fed ad libitum, food-deprived for 48 h, or refed for 1 and 24 h. The levels of expression of Ucn3 mRNA were analyzed in the rostral perifornical hypothalamus (rPFH) and dorsal medial amygdala (MeD), and CRF2-R mRNA in the VMH and lateral septum (LS) using in situ hybridization. The results showed that in the ad libitum-fed state, both phenotypes had comparable levels of expression of rPFH Ucn3, but the obese rats had lower levels of expression of VMH CRF2-R. Food deprivation decreased hypothalamic expression of Ucn3 and CRF2-R in lean but not obese rats. One hour of refeeding triggered expression of rPFH Ucn3 but not VMH CRF2-R in lean rats, and at 24 h of refeeding the levels of hypothalamic expression of Ucn3 and CRF2-R returned to those seen in the ad libitum-fed state in both phenotypes. In the LS, the levels of expression of CRF2 R were not affected by feeding and phenotype. In the MeD, the Ucn3 transcript increased by food deprivation in obese but not lean rats. Therefore, the increase of Ucn3 expression in the MeD in obese food-deprived rats may reflect stronger behavioral effects of food deprivation in this phenotype. The hypothalamic expression of Ucn3 and CRF2)-R was modulated by the feeding states in lean but not obese rats. The low levels of VMH CRF2-R may limit anorexigenic Ucn3 effects in the obese phenotype. The low VMH CRF2-R levels at the beginning of refeeding in lean rats may allow them to ingest a considerable amount of food regardless of the rapidly increased expression of rPFH Ucn3 by refeeding in this phenotype. This article is part of a Special Issue entitled 'Central Control of Food Intake'. PMID- 22227021 TI - GenRev: exploring functional relevance of genes in molecular networks. AB - We introduce GenRev, a network-based software package developed to explore the functional relevance of genes generated as an intermediate result from numerous high-throughput technologies. GenRev searches for optimal intermediate nodes (genes) for the connection of input nodes via several algorithms, including the Klein-Ravi algorithm, the limited kWalks algorithm and a heuristic local search algorithm. Gene ranking and graph clustering analyses are integrated into the package. GenRev has the following features. (1) It provides users with great flexibility to define their own networks. (2) Users are allowed to define each gene's importance in a subnetwork search by setting its score. (3) It is standalone and platform independent. (4) It provides an optimization in subnetwork search, which dramatically reduces the running time. GenRev is particularly designed for general use so that users have the flexibility to choose a reference network and define the score of genes. GenRev is freely available at http://bioinfo.mc.vanderbilt.edu/GenRev.html. PMID- 22227023 TI - Tumor-targeted Nanobullets: Anti-EGFR nanobody-liposomes loaded with anti-IGF-1R kinase inhibitor for cancer treatment. AB - The epidermal growth factor receptor (EGFR) is a validated target for anti-cancer therapy and several EGFR inhibitors are used in the clinic. Over the years, an increasing number of studies have reported on the crosstalk between EGFR and other receptors that can contribute to accelerated cancer development or even acquisition of resistance to anti-EGFR therapies. Combined targeting of EGFR and insulin-like growth factor 1 receptor (IGF-1R) is a rational strategy to potentiate anti-cancer treatment and possibly retard resistance development. In the present study, we have pursued this by encapsulating the kinase inhibitor AG538 in anti-EGFR nanobody-liposomes. The thus developed dual-active nanobody liposomes associated with EGFR-(over)expressing cells in an EGFR-specific manner and blocked both EGFR and IGF-1R activation, due to the presence of the EGFR blocking nanobody EGa1 and the anti-IGF-1R kinase inhibitor AG538 respectively. AG538-loaded nanobody-liposomes induced a strong inhibition of tumor cell proliferation even upon short-term exposure followed by a drug-free wash-out period. Therefore, AG538-loaded nanobody-liposomes are a promising anti-cancer formulation due to efficient intracellular delivery of AG538 in combination with antagonistic and downregulating properties of the EGa1 nanobody-liposomes. PMID- 22227022 TI - Gene transcripts associated with BMI in the motor cortex and caudate nucleus of calorie restricted rhesus monkeys. AB - Obesity affects over 500 million people worldwide, and has far reaching negative health effects. Given that high body mass index (BMI) and insulin resistance are associated with alterations in many regions of brain and that physical activity can decrease obesity, we hypothesized that in Rhesus monkeys (Macaca mulatta) fed a high fat diet and who subsequently received reduced calories BMI would be associated with a unique gene expression signature in motor regions of the brain implicated in neurodegenerative disorders. In the motor cortex with increased BMI we saw the upregulation of genes involved in apoptosis, altered gene expression in metabolic pathways, and the downregulation of pERK1/2 (MAPK1), a protein involved in cellular survival. In the caudate nucleus with increased BMI we saw the upregulation of known obesity related genes (the insulin receptor (INSR) and the glucagon-like peptide-2 receptor (GLP2R)), apoptosis related genes, and altered expression of genes involved in various metabolic processes. These studies suggest that the effects of high BMI on the brain transcriptome persist regardless of two months of calorie restriction. We hypothesize that active lifestyles with low BMIs together create a brain homeostasis more conducive to brain resiliency and neuronal survival. PMID- 22227024 TI - Multiple drug delivery hydrogel system for spinal cord injury repair strategies. AB - The multifactorial pathological progress of spinal cord injury (SCI) is probably the main reason behind the absence of efficient therapeutic approaches. Hence, very recent highlights suggest the use of new multidrug delivery systems capable of local controlled release of therapeutic agents. In this work, a biocompatible hydrogel-based system was developed as multiple drug delivery tool, specifically designed for SCI repair strategies. Multiple release profiles were achieved by loading gel with a combination of low and high steric hindrance molecules. In vitro, in vivo and ex vivo release studies showed an independent combination of fast diffusion-controlled kinetics for smaller molecules together with slow diffusion-controlled kinetics for bigger ones. A preserved functionality of loaded substances was always achieved, confirming the absence of any chemical stable interactions between gel matrix and loaded molecules. Moreover, the relevant effect of the cerebrospinal fluid flux dynamics on the drug diffusion in the spinal cord tissue was here revealed for the first time: an oriented delivery of the released molecules in the spinal cord tract caudally to the gel site is demonstrated, thus suggesting a more efficient gel positioning rostrally to the lesion. PMID- 22227025 TI - Cyclosporin pro-dispersion liposphere formulation. AB - OBJECTIVE: Preparation and characterization of an oral pro-dispersion liposphere formulation for cyclosporin, a water insoluble drug with limited bioavailability. METHODS: Pro-dispersion formulation consisted of a solid fat, dispersing agents and amphiphilic solvents as the major components besides cyclosporin A (CsA) were prepared in the present work. For preparation of this formulation, phospholipid was dissolved in pharmaceutically acceptable water soluble organic solvent, thereafter CsA along with other components was added and formulation optimization was carried out. After formulation preparation, particle size determination and in vitro release study was carried out. Additionally, ultracentrifugation, TEM, Cryo-TEM and DSC techniques were used for in vitro characterization of formulation. The prepared system was also compared with marketed Neoral(r) microemulsion formulation. RESULTS: Liposphere formulations were prepared and optimized as according to procedure. Though, determination of in vitro characteristics of such formulations is complex and difficult, yet selected and performed tests confirmed formation and existence of solid liposphere particles upon dispersion of formulation in water. It was also observed that particle size is influenced by the type of solid fat used and amphiphilic solvent present in the formulation. Prepared pro-dispersion was found to be stable for 2 years under normal storage conditions. CONCLUSION: Prepared pro-dispersion liposphere formulation is a homogeneous solution of a lipophilic drug such as cyclosporin in a mixture of surfactants, lipids and ethyl lactate proved to spontaneously form dispersion when added to aqueous media. This formulation concept has a potential clinical use for improved bioavailability of water insoluble drugs. PMID- 22227026 TI - [Anemia and prognosis in acute coronary syndromes]. PMID- 22227027 TI - Change in employment status of 5-year cancer survivors. AB - AIMS: To follow the employment status of 5-year cancer survivors for 5 years after diagnosis with their first lifetime invasive cancer and to identify socio demographic, work-related and cancer-related predictors of employment status after 5 years. METHODS: This prospective registry study concerned all 3278 people in Norway (18-61 years old) diagnosed with their first lifetime invasive cancer in 1999 and alive in 2004 and a cancer-free control group (n = 6368) matched by sex, age, educational level and employment status in 1998. RESULTS: The employment rate among male cancer survivors declined steadily every year, from 94% the year before diagnosis (1998) to 77% 5 years after diagnosis (2004). This change did not differ significantly from that of male controls. The employment rate of female survivors also declined steadily, from 87% (1998) to 69% (2004). This decline was greater than that among female controls, and in 2004 survivors had a significantly lower employment rate. For both men and women, the significant pre-diagnosis predictors of being employed in 2004 concerned higher socio-economic position. For both sexes, lung cancer survivors had the highest decline in employment rate, and male skin cancer survivors had a lower decline in employment rate than controls. Socio-demographic and work-related factors explained more of the variance in employment status than did cancer diagnosis. CONCLUSION: The employment rate among 5-year cancer survivors did not change significantly except for female survivors. Low socio-economic position is a risk factor for decline in employment rate and should be focused on to prevent cancer related inequity. PMID- 22227028 TI - Design of novel tyrosine-nitrogen mustard hybrid molecules active against uterine, ovarian and breast cancer cell lines. AB - L-para-Tyrosine was linked to ortho-hydroxyaniline, meta-hydroxyaniline and para hydroxyaniline giving three distinct tyrosinamide molecules. The new extended amino acid derivatives were constructed to imitate, in part, the estradiol (E(2), the natural female sex hormone) nucleus. The resulting tyrosinamides were then linked to chlorambucil either directly, or via a 5 and 10 carbon atoms spacer chain. This was done in an attempt to target cancerous cells expressing the estrogen receptor alpha (ERalpha) and to obtain a more specific chemotherapeutic agent. The tyrosinamide-chlorambucil molecules were designed and synthesized in good yields, according to two different approaches. The novel compounds were evaluated for their anticancer efficacy in hormone-dependent and hormone independent (ER+; MCF-7 and ER-; MDA-MB-231) breast cancer cell lines. Interestingly, the meta-hydroxyphenyl-tyrosinamide-chlorambucil derivatives were more active than the ortho- and para- analogs. The molecules bearing a 5 carbon atoms spacer were selected for additional biological study using a panel of female cancerous cells; breast (ZR-75-1, MDA-MB-436, MDA-MB-468), ovarian (OVCAR 3, A2780) and uterine (Ishikawa, HEC-1A). It was discovered that for breast cancer cells, the new compounds were up to 4.2 times more active than chlorambucil itself. PMID- 22227029 TI - School refusal by patients with gender identity disorder. AB - OBJECTIVE: The accumulating evidence suggests that school refusal behavior is associated with severe negative outcomes. However, previous research has not addressed school refusal by patients with gender identity disorder (GID). In this study, we tried to clarify the prevalence of school refusal among GID patients and the relationship of school refusal to demographic characteristics. METHODS: A total of 579 consecutive Japanese GID patients at the outpatient GID Clinic of Okayama University Hospital between April 1997 and October 2005 were evaluated. RESULTS: The prevalence of school refusal was 29.2% of the total sample. School refusal was more frequent among GID patients with divorced parents than those with intact families. Multiple logistic regression analysis showed that younger age at consultation and divorce of parents were significantly associated with school refusal among the male-to-female GID patients. CONCLUSION: The rate of school refusal among GID patients is high, and school refusal is closely related with a low level of education and current unemployment. We should pay more attention to GID patients of school age to prevent their school refusal, which results in low educational achievement. PMID- 22227030 TI - Postpartum catatonia treated with electroconvulsive therapy: a case report. AB - Catatonia is a rare syndrome that occurs in mood and psychotic disorders, and general medical conditions. Postpartum depression affects 10%-15% of women within 6 months after delivery. Postpartum psychosis affects 0.1%-0.5% of women within weeks after delivery, though it can occur within hours; it carries risk for suicide and infanticide. There is limited evidence available to guide treatment. We review a case of postpartum psychosis that presented with catatonia and was resistant to medications, but responded to electroconvulsive therapy. PMID- 22227031 TI - Validation of the Risk Model for Delirium in hip fracture patients. AB - OBJECTIVE: The Risk Model for Delirium (RD) score is a 10-item questionnaire that allocates hip fracture patients after admission to hospital to be either at high or at low risk for delirium. This allows targeted preventive actions. Clinical reliability, validity and feasibility of the RD score are discussed. METHODS: Demographic data, RD score and delirium incidence of all consecutive admissions for hip fractures in patients 65 years and older were collected. In 102 patients, the RD score was repeated. Interobserver reliability and validity were determined. The correlation between delirium and items both included and not included in the RD score was calculated. RESULTS: A total of 378 patients were included; 102 (27%) were diagnosed with a delirium. The intraclass correlation coefficient of the RD score was 0.77 [confidence interval (CI) 0.68-0.84]. Sensitivity was 80.4% (71.4-87.6), and specificity was 56.2% (50.1-62.1). Area under the receiver operating characteristic curve was 0.73 (CI 0.68-0.77). A multivariable logistic regression analysis showed that besides the RD score, a trochanteric fracture and male gender were independent risk factors for delirium. CONCLUSIONS: The RD score is a reliable, feasible and valid instrument for predicting delirium in hip fracture patients. PMID- 22227032 TI - Cobalamin deficiency presenting as obsessive compulsive disorder: case report. AB - Cobalamin deficiency commonly presents with a wide range of neuropsychiatric manifestations ranging from myelopathy, neuropathy, optic neuritis and dementia to mood disorders, chronic fatigue and psychosis even without classical hematological abnormalities like anemia and macrocytosis. However, obsessive compulsive disorder (OCD) in relation to vitamin B12 deficiency has not been described so far. We report a case of middle-aged man presenting with OCD, low serum cobalamin and a positive family history of vitamin B12 deficiency who responded well to methylcobalamin replacement. PMID- 22227033 TI - It's time for an epilepsy Twitter revolution. PMID- 22227034 TI - Magnetoencephalography's higher sensitivity to epileptic spikes may elucidate the profile of electroencephalographically negative epileptic seizures. AB - Video electroencephalography (EEG) plays an important role in judging whether a clinical spell is an epileptic seizure or paroxysmal event, but its interpretation is not always straightforward. If clinical events without EEG correlates are strongly suggestive of seizures, we usually regard these spells as epileptic seizures. However, the electric/magnetic physiological profile of EEG negative epileptic seizures remains unknown. We describe a 19-year-old man known to have epileptic seizures, in which both magnetoencephalography (MEG)-unique and EEG/MEG spikes were seen. Both types of spikes originated from the same source, but the EEG/MEG spikes were of significantly higher magnitude than the MEG-unique spikes. Therefore, some epileptic seizures, even though generated identically to the MEG-positive seizures, could be EEG-negative because of their smaller magnitude. PMID- 22227035 TI - The validity and reliability of a Direct Observation of Procedural Skills assessment tool: assessing colonoscopic skills of senior endoscopists. AB - BACKGROUND: Practitioners increasingly need to be able to evidence the quality of their care and their clinical competence for purposes of recredentialing and relicensing. Although this may be accomplished by audit and performance data, detailed and robust assessments of competence may be valuable in certain circumstances. OBJECTIVE: To develop and evaluate a detailed assessment of performance of colonoscopy. DESIGN: Evaluation of a Direct Observation of Procedural Skills (DOPS) method developed by an expert group of colonoscopists and clinical educationalists. SETTING: English National Health Service National Bowel Cancer Screening Programme (BCSP). SUBJECTS AND METHODS: Aspirant colonoscopists wishing to participate in the BCSP were assessed by using the DOPS. Reliability was estimated by using generalizability theory (G), and the candidates' and assessors' perspectives on validity were evaluated by questionnaire. INTERVENTIONS: Grading of performance by 2 assessors over 2 consecutive real cases. MAIN OUTCOME MEASUREMENTS: DOPS grades, global expert evaluation, performance data, evaluation questionnaire scores. RESULTS: The assessment had high relative reliability: G = 0.81. The DOPS grades correlated highly with a global expert assessment. The candidates and assessors believed that the DOPS was a valid assessment of competence. LIMITATIONS: Not guaranteed to assess therapeutic skills; evaluation questionnaire influenced by result of assessment. CONCLUSIONS: This is the first evaluation of a DOPS assessment on independent practitioners. It performs well, with good levels of reliability and validity, and is sufficient to be used in a high-stakes assessment. Similar approaches should be considered for assessment of competence in other areas of clinical practice for relicensing or recredentialing. PMID- 22227037 TI - UV-induced ablation of the epidermal basal layer including p53-mutant clones resets UV carcinogenesis showing squamous cell carcinomas to originate from interfollicular epidermis. AB - Chronic ultraviolet (UV) exposure induces clones of cells overexpressing mutant p53 in the interfollicular (IF) epidermis and subsequently squamous cell carcinomas (SCCs) with similar p53 mutations. Mutated p53 may give cells growth advantage over neighbouring cells by impaired apoptosis. We tested this by UV overexposure of skin laden with p53-mutant clones and assessed the impact on subsequent tumour development. P53-mutant clones were induced in two groups of hairless SKH1 mice by daily exposures (500 J/m(2) UV from TL12 lamps) for 28 days. On day 29, one group was overexposed (to 10 kJ/m(2) UV), whereas the control group received the regular daily dose. After 1 week of recovery, the daily exposures were resumed in both groups to induce SCCs. UV overexposure forced the entire IF basal layer into caspase-3-driven apoptosis while leaving overlying layers with sunburn cells intact. No apparent regions were spared from apoptosis. Pulse-chase BrdU labelling showed the IF epidermis to be repopulated from the hair follicles (remaining p63 positive). One week after overexposure, the p53-mutant clones had virtually disappeared (0.6, 95% confidence interval 0.5 0.8 per mouse versus 102, 59-179, without overexposure). Tumour development was significantly delayed after UV overexposure (P < 0.0001) by an average of 27 days (standard error of the mean 3); a period matching that of daily exposures preceding the overexposure. Thus, we found that UV-induced ablation of the IF epidermal basal layer eliminates p53-mutant clones and resets UV carcinogenesis. Furthermore, and in contrast with earlier reports, our data show that UV-induced p53-mutant clones and SCCs originate from the IF epidermis. PMID- 22227036 TI - p15(INK4b) plays a crucial role in murine lymphoid development and tumorigenesis. AB - To investigate if the cooperation between the Rgr oncogene and the inactivation of INK4b (a CDK inhibitor), as described previously in a sarcoma model, would be operational in a lymphoid system in vivo, we generated a transgenic/knockout murine model. Transgenic mice expressing the Rgr oncogene under a CD4 promoter were crossed into a p15(INK4b)-deficient background. Unexpectedly, mice with a complete ablation of both p15(INK4b) alleles had a lower tumor incidence and higher survival rate when compared with CD4-Rgr progeny with homozygous or heterozygous expression of p15(INK4b). Also, a similar survival pattern was observed in a parallel model in which transgenic mice expressing a constitutively activated N-Ras mutant were crossed into a p15(INK4b)-deficient background. To analyze this paradoxical event, we investigated the hypothesis that the absence of both p15(INK4b) alleles in the presence of the Rgr oncogene could be deleterious for proper thymocyte development. When analyzed, thymocyte development was blocked at the double negative (DN) 3 and DN4 stages in mice missing one or both alleles of p15(INK4b), respectively. We found reduction in overall apoptotic levels in the thymocytes of mice expressing Rgr, compared with their wild-type mice, supporting thymocyte escape from programmed cell death and subsequently facilitating the onset of thymic lymphomas but less for those missing both p15 alleles. These findings provide evidence of the complex interplay between oncogenes and tumor suppressor genes in tumor development and indicate that in the lymphoid tissue the inactivation of both p15 alleles is unlikely to be the first event in tumor development. PMID- 22227038 TI - ZEB2 upregulates integrin alpha5 expression through cooperation with Sp1 to induce invasion during epithelial-mesenchymal transition of human cancer cells. AB - Epithelial-mesenchymal transition (EMT) is a process implicated in tumor invasion, metastasis, embryonic development and wound healing. ZEB2 is a transcription factor involved in EMT that represses E-cadherin transcription. Although E-cadherin downregulation is a major event during EMT and tumor progression, E-cadherin reduction is probably not sufficient for full invasiveness. The mechanisms by which E-cadherin transcriptional repressors induce mesenchymal genes during EMT remain largely unknown. Here, we investigated the role of ZEB2 in the induction of integrin alpha5 during cancer EMT and its underlying mechanism. In human cancer cells, ZEB2 was found to directly upregulate integrin alpha5 transcription in a manner that is independent of the regulation of E-cadherin expression. Conversely, depletion of ZEB2 by small interfering RNA suppressed integrin alpha5 expression, leading to reduced invasion. Suppression of integrin alpha5 inhibited cancer cell invasion, suggesting an important role for integrin alpha5 in cancer progression. Furthermore, ZEB2 was found to activate the integrin alpha5 and vimentin promoters by interacting with and activating the transcription factor Sp1, suggesting that cooperation between ZEB2 and Sp1 represents a novel mechanism of mesenchymal gene activation during EMT. These findings increase our understanding of the pathways beyond E-cadherin reduction that regulate mesenchymal gene expression during EMT and cancer progression. PMID- 22227040 TI - Role of protein kinase C in phospholemman mediated regulation of alpha2beta1 isozyme of Na+/K+-ATPase in caveolae of pulmonary artery smooth muscle cells. AB - We have recently reported that alpha(2)beta(1) and alpha(1)beta(1) isozymes of Na(+)/K(+)-ATPase (NKA) are localized in the caveolae whereas only the alpha(1)beta(1) isozyme of NKA is localized in the non-caveolae fraction of pulmonary artery smooth muscle cell membrane. It is well known that different isoforms of NKA are regulated differentially by PKA and PKC, but the mechanism is not known in the caveolae of pulmonary artery smooth muscle cells. Herein, we examined whether this regulation occurs through phospholemman (PLM) in the caveolae. Our results suggest that PKC mediated phosphorylation of PLM occurs only when it is associated with the alpha(2) isoform of NKA, whereas phosphorylation of PLM by PKA occurs when it is associated with the alpha(1) isoform of NKA. To investigate the mechanism of regulation of alpha(2) isoform of NKA by PKC-mediated phosphorylation of PLM, we have purified PLM from the caveolae and reconstituted into the liposomes. Our result revealed that (i) in the reconstituted liposomes phosphorylated PLM (PKC mediated) stimulate NKA activity, which appears to be due to an increase in the turnover number of the enzyme; (ii) phosphorylated PLM did not change the affinity of the pump for Na(+); and (iii) even after phosphorylation by PKC, PLM still remains associated with the alpha(2) isoform of NKA. PMID- 22227041 TI - Follow-up frequency and compliance in women with probably benign findings on breast magnetic resonance imaging. AB - RATIONALE AND OBJECTIVES: Six-month short-interval follow-up is recommended for probably benign findings on breast magnetic resonance imaging (MRI). We wanted to examine patient adherence to follow-up recommendation for Breast Imaging Reporting and Data System (BI-RADS) category 3 lesions at a tertiary care medical center. MATERIALS AND METHODS: We performed a retrospective review of frequency and adherence rates to follow-up recommendation for women with an initial BI-RADS 3 breast MRI between 2005 and 2007. RESULTS: A total of 132 women with BI-RADS 3 breast MRI recommendations were included. Ninety-six of 132 (72.7%) women adhered to the first follow-up recommendation or elected to have tissue diagnosis; 78/132 (59.1%) had follow-up MRI and 18/132 (13.6%) had tissue diagnosis. Thirty-six of 132 (27.3%) women did not return for follow-up. Nine of nine (100%) of BRCA carriers returned for follow-up or had tissue diagnosis, compared to 87/123 (70.7%) of non-BRCA carriers. A total of 35/41 (85.4%) of patients with a prior history of breast cancer returned for follow-up or had tissue diagnosis, compared to 61/91 (67%) of patients without a history of breast cancer. Only 5/15 (33%) of patients undergoing MRI for symptom alone adhered to follow-up recommendations. CONCLUSION: Adherence to BI-RADS category 3 follow-up recommendation is often low. Women with a history of breast cancer or who were BRCA carriers were significantly more likely to adhere to follow-up recommendation than women without a history of breast cancer or women undergoing MRI for symptoms alone. Strategies to improve adherence should be developed. PMID- 22227039 TI - Epidemiology of glial and non-glial brain tumours in Europe. AB - To the central nervous system (CNS) belong a heterogeneous group of glial and non glial rare cancers. The aim of the present study was to estimate the burden (incidence, prevalence, survival and proportion of cured) for the principal CNS cancers in Europe (EU27) and in European regions using population-based data from cancer registries participating in the RARECARE project. We analysed 44,947 rare CNS cancers diagnosed from 1995 to 2002 (with follow up at 31st December 2003): 86.0% astrocytic (24% low grade, 63% high grade and 13% glioma NOS), 6.4% oligodendroglial (74% low grade), 3.6% ependymal (85% low grade), 4.1% Embryonal tumours and 0.1% choroid plexus carcinoma. Incidence rates vary widely across European regions especially for astrocytic tumours ranging from 3/100,000 in Eastern Europe to 5/100,000 in United Kingdom and Ireland. Overall, about 27,700 new rare CNS cancers were estimated every year in EU27, for an annual incidence rate of 4.8 per 100,000 for astrocytic, 0.4 for oligodendroglial, 0.2 for ependymal and embryonal tumours and less than 0.1 for choroid plexus carcinoma. More than 154,000 persons with rare CNS were estimated alive (prevalent cases) in the EU at the beginning of 2008. Five-year relative survival was 14.5% for astrocytic tumours (42.6% for low grade, 4.9% for high grade and 17.5% for glioma NOS), 54.5% for oligodendroglial (64.9% high grade and 29.6% low grade), 74.2% for ependymal (80.4% low grade and 36.6% high grade), 62.8% for choroid plexus carcinomas and 56.8% for embryonal tumours. Survival rates for astrocytic tumours were relatively higher in Northern and Central Europe than in Eastern Europe and in UK and Ireland. The different availability of diagnostic imaging techniques and/or radiation therapy equipment across Europe may contribute to explain the reported survival differences. The estimated proportion of cured patients was 7.9% for the 'glial' group to which belong astrocytic tumours. Overall results are strongly influenced by astrocytic tumours that are the most common type. This is the first study to delineate the rare CNS cancer burden in Europe by age, sex and European region. PMID- 22227042 TI - Proteomic analysis reflects different histologic subtypes of epithelial ovarian cancer. AB - Ovarian carcinoma is a significant cause of cancer mortality in women worldwide. As a heterogeneous disease, distinct clinical and molecular characteristics exist among different histologic subtypes. With the developments in proteomics, surfaced-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) is sensitive enough to detect minute quantity of proteins from serum or microdissected cryostat sections. Herein we hypothesized that differentially expressed protein profiles exist in ovarian carcinomas with distinct histologic subtypes. Compared with endometrioid carcinoma, two peaks were significantly higher in serous carcinoma with the m/z of 3622 Da and 4778 Da, reinforcing the need to treat different histologic subtypes of ovarian cancer as different disease entities. Better understanding of these potential diagnostic and therapeutic biomarkers followed with proof-of-target effect will finally contribute to rational combinations of novel therapy and improve individual ovarian cancer patient outcome. PMID- 22227043 TI - Design, synthesis and biological evaluation of pyrazole derivatives as potential multi-kinase inhibitors in hepatocellular carcinoma. AB - We described the optimization, by molecular modelling, of small pyrazole derivatives, as kinase inhibitors, obtained through a 1,3-dipolar cycloaddition between nitrile imines and functionalized acetylenes. The two compounds, selected as potential agents active against hepatocellular carcinoma (HCC) were then evaluated in vitro for their biological activity on HCC-derived cell lines. The compounds show a promising inhibitory growth efficacy (IC(50) 50-100 MUM) in SNU449 cell line, as well as block of cell cycle progression and induction of apoptosis, and can be considered as lead compounds for further SAR developments. PMID- 22227044 TI - Prevalence of obesity and overweight in children: a study in government primary schools in Rabat, Morocco. AB - BACKGROUND AND AIMS: We undertook this study to assess the prevalence of obesity and overweight in children enrolled in government primary schools in the city of Rabat, Morocco. METHODS: Twenty three schools were randomly selected. A cross sectional study was conducted between April 2010 and June 2010. The survey was conducted on the basis of two questionnaires for both parents and children. The references used are those of the WHO (2007). RESULTS: Our study involved a sample of 1570 children with an average age of 9.7 +/- 0.95 years. The prevalence of overweight and obesity was 8.7%. Overweight affected 5.1% and obesity affected 3.6%. The majority of our population consisted of children of low socioeconomic status where 59% of fathers are laborers and 85% of mothers are unemployed. CONCLUSION: Overweight and obesity do not spare the most underprivileged social strata of our country. Therefore, prevention strategies and programs to raise awareness of risks and threats involved must be a public health priority. PMID- 22227045 TI - Influenza vaccine and healthcare workers. AB - We undertook this study to review attitudes, beliefs and practices of healthcare workers (HCW) toward pandemic influenza A vaccine (H1N1) 2009 reported in the literature. Relevant papers published from 2009-2011 reporting attitudes, beliefs and practices of HCW towards pandemic influenza vaccine were identified. Variables such as age, gender, profession, work place area, and previous vaccination uptake were analyzed. In this study, 30 articles regarding attitudes and beliefs toward pandemic influenza vaccination, vaccine uptake and intention to accept vaccine were analyzed. Most studies were cross-sectional in design. Vaccination intention and uptake varies among different countries, 13.5-89.0% and 7.5-63.0%, respectively. Most common reasons for rejection were fear of adverse events, doubt regarding efficacy, not feeling as belonging to a high-risk group and believing that influenza is not a serious illness. Physicians show more favorable attitudes compared to nurses. The main predictor of vaccine uptake was having received previous influenza vaccination. Pandemic influenza uptake was low in most countries. The main reason among HCW for rejection was concern regarding side effects. It is necessary to establish educational programs to provided reliable information and raise awareness of HCW about vaccine use so that they can act as vaccine promoters among the general population. PMID- 22227046 TI - Human immunodeficiency virus is the major determinant of steatosis and hepatitis C virus of insulin resistance in virus-associated fatty liver disease. AB - BACKGROUND AND AIMS: To promote our understanding of the relative contribution of metabolic and viral factors, the independent predictors of fatty liver and insulin resistance (IR) were assessed by comparing patients with nonalcoholic fatty liver disease (NAFLD) to individuals with virus-associated fatty liver disease (VAFLD): human immunodeficiency virus (HIV)-VAFLD, hepatitis C virus (HCV)-VAFLD and HIV-HCV-VAFLD. METHODS: One hundred eighty eight consecutive patients with viral infections (103 HIV, 85 patients with HCV genotype 1 infection: 45 mono-infected and 40 HIV/HCV co-infected) with or without steatosis and 126 NAFLD patients were analyzed. Steatosis was diagnosed by ultrasonography. To assess the odds ratio (OR) of steatosis and IR, HCV and NAFLD, respectively, were used as the reference values. IR was evaluated through homeostasis model (HOMA) and the metabolic syndrome (MetS) using standard criteria. RESULTS: The prevalence of VAFLD was 47%. Multivariate logistic regression analysis was carried out using HCV as the reference. VAFLD was predicted by HIV, HIV/HCV, female gender, waist circumference (WC) and HOMA (OR = 3.99, 3.76, 2.80, 1.08 and 1.18). According to multiple linear regression using NAFLD as the reference, IR was predicted by HCV, HIV and HIV/HCV, WC, triglycerides (coefficient beta = 2.25, 0.99, 1.86, 0.08, 0.05, respectively). In linear models, for any given number of components of MetS, HCV and HCV/HIV-associated fatty liver disease had greater HOMA compared to NAFLD (p <0.001). CONCLUSIONS: Whereas HIV confers a higher risk of steatosis, VAFLD is associated with higher IR than NAFLD and such an effect is specifically linked to HCV rather than to HIV infection. PMID- 22227047 TI - Magnetic resonance imaging of resting OEF and CMRO2 using a generalized calibration model for hypercapnia and hyperoxia. AB - We present a method allowing determination of resting cerebral oxygen metabolism (CMRO2) from MRI and end-tidal O2 measurements acquired during a pair of respiratory manipulations producing different combinations of hypercapnia and hyperoxia. The approach is based on a recently introduced generalization of calibrated MRI signal models that is valid for arbitrary combinations of blood flow and oxygenation change. Application of this model to MRI and respiratory data during a predominantly hyperoxic gas manipulation yields a specific functional relationship between the resting BOLD signal M and the resting oxygen extraction fraction OEF0. Repeating the procedure using a second, primarily hypercapnic, manipulation provides a different functional form of M vs. OEF0. These two equations can be readily solved for the two unknowns M and OEF0. The procedure also yields the resting arterial O2 content, which when multiplied by resting cerebral blood flow provides the total oxygen delivery in absolute physical units. The resultant map of oxygen delivery can be multiplied by the map of OEF0 to obtain a map of the resting cerebral metabolic rate of oxygen consumption (CMRO2) in absolute physical units. Application of this procedure in a group of seven human subjects provided average values of 0.35 +/- 0.04 and 6.0 +/- 0.7% for OEF0 and M, respectively in gray-matter (M valid for 30 ms echo-time at 3T). Multiplying OEF0 estimates by the individual values of resting gray matter CBF (mean 52 +/- 5 ml/100 g/min) and the measured arterial O2 content gave a group average resting CMRO2 value of 145 +/- 30 MUmol/100 g/min. The method also allowed the generation of maps depicting resting OEF, BOLD signal, and CMRO2. PMID- 22227049 TI - Differential effects of surface area, gyrification and cortical thickness on voxel based morphometric deficits in schizophrenia. AB - Voxel Based Morphometry (VBM) and Surface Based Morphometry (SBM) are the two most commonly used methods to study the structure of gray matter in various disease states such as schizophrenia. Though overlapping changes have been observed in same datasets using the two procedures, the proportional contribution of the anatomical properties of the cortical mantle such as thickness, surface area and gyrification to the group differences in gray matter volume (GMV) observed using VBM is unknown. In the present study, we investigate the relationship between the GMV and the anatomical properties of the cortical mantle in regions showing significant VBM changes in schizophrenia using a sample of 57 patients and 41 healthy controls. To this end, we obtained significant clusters showing VBM changes in schizophrenia and studied the contribution of the three anatomical properties derived from SBM to the observed group differences in the GMV using a multiple mediation analysis. Our results suggest that while SBM measures make distinct but regionally variable contribution to the VBM differences, a large proportion of the group difference observed using VBM is not explained by the individual surface anatomical properties. While VBM may be more sensitive in identifying the regions with gray matter abnormalities, studies investigating the pathophysiology of illnesses such as schizophrenia are better informed when both SBM and VBM analyses are performed concurrently. PMID- 22227048 TI - Resting oscillations and cross-frequency coupling in the human posteromedial cortex. AB - Using rare intracranial recordings from the posterior interhemispheric region of the human brain, we explored the oscillatory properties of the posteromedial cortex (PMC) during rest. The PMC is a core structure of the default mode network, which is known for its higher activity during the resting state. We found that resting PMC spectral power peaked in the theta band range (4-7 Hz) and was clearly distinguishable from adjacent cortical sites in the occipital lobe displaying peaks in the alpha band range (8-12 Hz). Additionally, the phase of PMC theta oscillations modulated the amplitude of ongoing high gamma (70-180 Hz) activity during the resting state. The magnitude of this cross-frequency modulation was shown to fluctuate at time scales comparable to those observed in functional neuroimaging studies of intrinsic functional connectivity networks (~0.1 Hz). The difference of canonical oscillations in the PMC compared to its adjacent cortical sites conforms to functional specialization across anatomical boundaries. Such differences may reflect separate oscillatory preferences between networks that are functionally connected. PMID- 22227050 TI - Task-driven ICA feature generation for accurate and interpretable prediction using fMRI. AB - Functional Magnetic Resonance Imaging (fMRI) shows significant potential as a tool for predicting clinically important information such as future disease progression or drug effect from brain activity. Multivariate techniques have been developed that combine fMRI signals from across the brain to produce more robust predictive capabilities than can be obtained from single regions. However, the high dimensionality of fMRI data makes overfitting a significant problem. Reliable methods are needed for transforming fMRI data to a set of signals reflecting the underlying spatially extended patterns of neural dynamics. This paper demonstrates a task-specific Independent Component Analysis (ICA) procedure which identifies signals associated with coherent functional brain networks, and shows that these signals can be used for accurate and interpretable prediction. The task-specific ICA parcellations outperformed other feature generation methods in two separate datasets including parcellations based on resting-state data and anatomy. The pattern of response of the task-specific ICA parcellations to particular feature selection strategies indicates that they identify important functional networks associated with the discriminative task. We show ICA parcellations to be robust and informative with respect to non-neural artefacts affecting the fMRI series. Together, these results suggest that task-specific ICA parcellation is a powerful technique for producing predictive and informative signals from fMRI time series. The results presented in this paper also contribute evidence for the general functional validity of the parcellations produced by ICA approaches. PMID- 22227051 TI - The NOS1 variant rs6490121 is associated with variation in prefrontal function and grey matter density in healthy individuals. AB - A common polymorphism within the nitric oxide sythanse-1 (NOS1) gene (rs6490121), initially identified as risk variant for schizophrenia, has been associated with variation in working memory and IQ. Here we investigated how this variation might be mediated at the level of brain structure and function. In healthy individuals (N=157), voxel based morphometry was used to compare grey matter (GM) volume between homozygous and heterozygous carriers of the 'G' allele (i.e. the allele associated with impaired cognition and schizophrenia risk) and homozygous carriers of the non-risk 'A' allele. Functional brain imaging data were also acquired from 48 participants during performance of a spatial working memory (SWM) task, and analysed to determine any effect of NOS1 risk status. An a priori region-of-interest analysis identified a significant reduction in ventromedial prefrontal GM volume in 'G' allele carriers. Risk carriers also exhibited altered patterns of activation in the prefrontal cortex, caudate, and superior parietal lobe, which were characteristic of abnormal increases in activation in frontoparietal working memory networks and a failure to disengage regions of the default mode network. These functional changes suggest a NOS1-mediated processing inefficiency, which may contribute to cognitive dysfunction in schizophrenia. While the mechanisms by which NOS1 may influence brain structure and/or function have not yet been well delineated, these data provide further evidence for a role of NOS1 in risk for schizophrenia via an impact upon cognitive function. PMID- 22227052 TI - Left hemisphere plasticity and aphasia recovery. AB - A recent study by our group revealed a strong relationship between functional brain changes in the left hemisphere and anomia treatment outcome in chronic stroke patients (N=26) with aphasia (Fridriksson, 2010). The current research represents a continuation of this work in which we have refined our methods and added data from four more patients (for a total sample size of 30) to assess where in the left hemisphere treatment-related brain changes occur. Unlike Fridriksson (2010) which only focused on changes in correct naming as a marker of treatment outcome, the current study examined the relationship between changes in left hemisphere activity and changes in correct naming, semantic paraphasias, and phonemic paraphasias following treatment. We also expanded on the work by Fridriksson by examining whether neurophysiological measures taken at baseline (defined henceforth as the time-point before the start of anomia treatment) predict treatment outcome. Our analyses revealed that changes in activation in perilesional areas predicted treatment-related increases in correct naming in individuals with chronic aphasia. This relationship was most easily observed in the left frontal lobe. A decrease in the number of semantic and phonemic paraphasias was predicted by an activation change in the temporal lobe involving cortical areas that were shown to be active during picture naming in 14 normal subjects. In contrast, a far less certain relationship was found between baseline neurophysiological measures and anomia treatment outcome. Our findings suggest that improved naming associated with behavioral anomia treatment in aphasia is associated with modulation of the left frontal lobe whereas a reduction in naming errors is mediated by left posterior regions that classically are thought to be involved in language processing. PMID- 22227053 TI - The effect of handedness on the shape of the central sulcus. AB - Sinistrals differ from dextrals in the size of certain cortical folds. For instance, handedness has an impact on central sulcus surface area: the sulcus is larger in the dominant left hemisphere of dextrals and vice versa for sinistrals. However, the impact of handedness on the shape of the central sulcus is largely unexplored. In this paper, we propose first an original strategy based on manifold learning to quantify the shape of the central sulcus. Using this approach we show that the "hand knob", a major landmark of the hand motor representation, is sited more dorsally in the left hemisphere in dextrals than in sinistrals. Sinistrals forced to write with their non-preferred right hand display a pattern of central sulcus size asymmetry which is typical of dextrals, yet forced dextrality does not shift the handedness-specific location of the "hand knob". Hence, cortical morphology in adults holds an accumulated record of both innate biases and early developmental experience. Characterizing normal variation of cortical morphology provides a means of systematically correlating behavior with cortical development. PMID- 22227054 TI - Monitoring blood flow alterations in the Tg2576 mouse model of Alzheimer's disease by in vivo magnetic resonance angiography at 17.6 T. AB - Many neurodegenerative diseases including Alzheimer's disease are linked to abnormalities in the vascular system. In AD, the deposition of amyloid beta (Abeta) peptide in the cerebral vessel walls, known as cerebral amyloid angiopathy (CAA) is frequently observed, leading to blood flow abnormalities. Visualization of the changes in vascular structure is important for early diagnosis and treatment. Blood vessels can be imaged non-invasively by magnetic resonance angiography (MRA). In this study we optimized high resolution MRA at 17.6 T to longitudinally monitor morphological changes in cerebral arteries in a Tg2576 mouse model, a widely used model of AD. Our results at 17.6 T show that MRA significantly benefits from the ultra-high magnetic field strength especially to visualize smaller vessels. Visual and quantitative analysis of MRA results revealed severe blood flow defects in large and medium sized arteries in Tg2576 mice. In particular blood flow defects were observed in the middle cerebral artery (MCA) and in the anterior communicating artery (AComA) in Tg2576 mice. Histological data show that Abeta levels in the vessel wall may be responsible for impaired cerebral blood flow, thereby contributing to the early progression of AD. To our knowledge this is the first ultra-high field MRA study monitoring blood flow alterations longitudinally in living Tg2576 mice, consequently providing a powerful tool to test new therapeutic intervention related to CAA in a mouse model of AD. PMID- 22227055 TI - Development and validation of a fully automated online human dried blood spot analysis of bosentan and its metabolites using the Sample Card And Prep DBS System. AB - This paper describes the development and validation of a liquid chromatography (LC)-electrospray ionization tandem mass spectrometry assay for the fully automated simultaneous determination of bosentan, a dual endothelin receptor antagonist used in the treatment of pulmonary arterial hypertension, and its three primary metabolites hydroxy bosentan (Ro 48-5033), desmethyl bosentan (Ro 47-8634), and hydroxy desmethyl bosentan (Ro 64-1056) in human dried blood spots (DBS) by use of the Sample Card And Prep (SCAP) DBS System. The system enabled the online extraction of compounds from filter paper cards without the need for punching and sample pretreatment. This was realized by automatic introduction of DBS sample cards into the LC flow via a pneumatically controlled clamp module. Using a three-column setup comprised of two pre columns for successive online DBS sample cleanup and a SynergiTM POLAR-RP C(18) analytical column for chromatographic separation under gradient conditions with a mobile phase A consisting of 1% acetic acid and a mobile phase B consisting of 1% acetic acid in methanol/2-propanol (80/20, v/v). MS/MS detection was performed in the positive multiple reaction monitoring mode using a Sciex API 4000 triple quadrupole LC MS/MS system equipped with a TurboIonSprayTM source. The total run time was 9.0min. The individual phases of online human DBS analysis were synchronized by automated valve switching. The analytical method was shown to be sensitive and selective with inter-day accuracy and precision of 91.6-108.0% and 3.4-14.6%, respectively, and it exhibited good linearity (r(2)>=0.9951 for all analytes) over the concentration range of 2ng/mL (5ng/mL for Ro 47-8634)-1500ng/mL. The analytes were stable in human DBS over 3.5 months at ambient temperature and accurate and precise results were obtained when using a blood spot volume between 20 and 30MUL. Furthermore, no apparent (-8.9 to 12.6%) impact of hematocrit values ranging from 0.35 to 0.65 was observed on the quantification of the analytes. The system allowed very good recoveries of all analytes, between 83.0% and 92.3% for bosentan, between 94.4% and 100% for Ro 48-5033, between 98.0% and 100% for Ro 47-8634, and between 94.3% and 100% for Ro 64-1056. The validation demonstrated that the SCAP DBS System provides a robust automated platform for DBS analysis. PMID- 22227056 TI - Quantification of protein posttranslational modifications using stable isotope and mass spectrometry. II. Performance. AB - In this report, we examine the performance of a mass spectrometry (MS)-based method for quantification of protein posttranslational modifications (PTMs) using stable isotope labeled internal standards. Uniform labeling of proteins and highly similar behavior of the labeled vs nonlabeled analyte pairs during chromatographic separation and electrospray ionization (ESI) provide the means to directly quantify a wide range of PTMs. In the companion report (Jiang et al., Anal. Biochem., 421 (2012) 506-516.), we provided principles and example applications of the method. Here we show satisfactory accuracy and precision for quantifying protein modifications by using the SILIS method when the analyses were performed on different types of mass spectrometers, such as ion-trap, time of-flight (TOF), and quadrupole instruments. Additionally, the stable isotope labeled internal standard (SILIS) method demonstrated an extended linear range of quantification expressed in accurate quantification up to at least a 4 log concentration range on three different types of mass spectrometers. We also demonstrate that lengthy chromatographic separation is no longer required to obtain quality results, offering an opportunity to significantly shorten the method run time. The results indicate the potential of this methodology for rapid and large-scale assessment of multiple quality attributes of a therapeutic protein in a single analysis. PMID- 22227058 TI - Transmembrane protein 166 regulates autophagic and apoptotic activities following focal cerebral ischemic injury in rats. AB - Transmembrane protein 166 (TMEM166) is a lysosomal/endoplasmic reticulum associated protein found in various species where it acts as a regulator of programmed cell death, mediating both autophagy and apoptosis. In the present study, we investigated the role of TMEM166 following MCAO injury in rats to determine whether the structural damages following injury were orchestrated in part by TMEM166. One hundred and fifty six male Sprague-Dawley rats were randomly divided into 4 groups: Sham, MCAO, MCAO+control siRNA, MCAO+TMEM166 siRNA. Outcomes were measured including mortality rate, brain edema, BBB disruption, and neurobehavioral testing. Western blotting techniques measured the expression of key pro-autophagic and apoptotic proteins such as TMEM166, Beclin-1, cleaved casepase-3 and Bcl-2/Bax. The study found that TMEM166 siRNA treatment significantly reduced the mortality rate, cerebral edema, neurobehavioral deficits, and BBB disruption as measured by Evan's blue assay following MCAO injury. Immunohistochemical staining and western blotting analysis demonstrated an increased expressions of TMEM166, Beclin-1, LC3, cleaved casepase-3 and Bcl 2/Bax in the infarcted areas. This study suggests that TMEM166 induces autophagy and apoptosis may in fact play a significant role in cell death following MCAO injury and its mediation may be through the crosstalk of Bcl-2. By blocking the activity of TMEM166 using siRNA, we were able to prevent the cell loss that occured following cerebral ischemia injury. This translated into a preservation of functional integrity and an improvement in mortality. PMID- 22227057 TI - The NMDA-NR1 receptor subunit and the mu-opioid receptor are expressed in somatodendritic compartments of central nucleus of the amygdala neurons projecting to the bed nucleus of the stria terminalis. AB - The pathway between the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) is emerging as a critical mediator of stress related affective processes. Evidence also indicates that exposure to drugs of abuse, like opioids, is associated with NMDA-type glutamate receptor-dependent plasticity in the CeA and BNST. However, there is little evidence that NMDA receptors are expressed in CeA neurons projecting to the BNST, or are required for opioid-induced BNST neural activation. Immunoelectron microscopy, tract tracing, and conditional gene deletion technology were used to investigate the synaptic organization of the NMDA receptor and the mu-opioid receptor (MUOR) in the CeA-BNST pathway. By dual labeling electron microscopy, numerous CeA-BNST projection neurons expressed the NMDA-NR1 receptor subunit (NR1) or MUOR. By triple labeling, it was also found that NR1 and MUOR were co-expressed in some CeA-BNST projection neurons. Despite being colocalized in somato-dendritic compartments of CeA neurons, NR1 and MUOR were rarely expressed in their axonal terminations in the BNST. Deleting the NR1 gene in CeA neurons resulted in a reduction of morphine-induced Fos protein labeling in the ventral BNST. In summary, NR1 and MUOR are coexpressed in somatodendritic sites of CeA neurons, including those projecting to the BNST. In addition, expression of the NR1 gene in CeA neurons is required for morphine-induced BNST neural activation. Thus, postsynaptic NMDA receptors and MUORs are positioned for the co-modulation of CeA projection neurons to the BNST, which may provide a synaptic substrate for stress induced emotional processes critically involved in opioid addictive behaviors. PMID- 22227060 TI - Nutritional restriction of omega-3 fatty acids alters topographical fine tuning and leads to a delay in the critical period in the rodent visual system. AB - The development and maturation of sensory systems depends on the correct pattern of connections which occurs during a critical period when axonal elimination and synaptic plasticity are involved in the formation of topographical maps. Among the mechanisms involved in synaptic stabilization, essential fatty acids (EFAs), available only through diet, appear as precursors of signaling molecules involved in modulation of gene expression and neurotransmitter release. Omega-3 fatty acids, such as docosahexaenoic acid (DHA), are considered EFAs and are accumulated in the brain during fetal period and neonatal development. In this study, we demonstrated the effect of omega-3/DHA nutritional restriction in the long-term stabilization of connections in the visual system. Female rats were fed 5 weeks before mating with either a control (soy oil) or a restricted (coconut oil) diet. Litters were fed until postnatal day 13 (PND13), PND28 or PND42 with the same diets when they received an intraocular injection of HRP. Another group received a single retinal lesion at the temporal periphery at PND21. Omega-3 restriction induced an increase in the optical density in the superficial layers of the SC, as a result of axonal sprouting outside the main terminal zones. This effect was observed throughout the SGS, including the ventral and intermediate sub-layers at PND13 and also at PND28 and PND42. The quantification of optical densities strongly suggests a delay in axonal elimination in the omega3(-) groups. The supplementation with fish oil (DHA) was able to completely reverse the abnormal expansion of the retinocollicular projection. The same pattern of expanded terminal fields was also observed in the ipsilateral retinogeniculate pathway. The critical period window was studied in lesion experiments in either control or omega-3/DHA restricted groups. DHA restriction induced an increased sprouting of intact, ipsilateral axons at the deafferented region of the superior colliculus compared to the control group, revealing an abnormal extension of the critical period. Finally, in omega-3 restricted group we observed in the collicular visual layers normal levels of GAP-43 with decreased levels of its phosphorylated form, p-GAP-43, consistent with a reduction in synaptic stabilization. The data indicate, therefore, that chronic dietary restriction of omega-3 results in a reduction in DHA levels which delays axonal elimination and critical period closure, interfering with the maintenance of terminal fields in the visual system. PMID- 22227059 TI - Conditioning lesions before or after spinal cord injury recruit broad genetic mechanisms that sustain axonal regeneration: superiority to camp-mediated effects. AB - Previous studies indicate that peripheral nerve conditioning lesions significantly enhance central axonal regeneration via modulation of cAMP-mediated mechanisms. To gain insight into the nature and temporal dependence of neural mechanisms underlying conditioning lesion effects on central axonal regeneration, we compared the efficacy of peripheral sciatic nerve crush lesions to cAMP elevations (in lumbar dorsal root ganglia) on central sensory axonal regeneration when administered either before or after cervical spinal cord lesions. We found significantly greater effects of conditioning lesions compared to cAMP elevations on central axonal regeneration when combined with cellular grafts at the lesion site and viral neurotrophin delivery; further, these effects persisted whether conditioning lesions were applied prior to or shortly after spinal cord injury. Indeed, conditioning lesions recruited extensively greater sets of genetic mechanisms of possible relevance to axonal regeneration compared to cAMP administration, and sustained these changes for significantly greater time periods through the post-lesion period. We conclude that cAMP-mediated mechanisms account for only a portion of the potency of conditioning lesions on central axonal regeneration, and that recruitment of broader genetic mechanisms can extend the effect and duration of cellular events that support axonal growth. PMID- 22227061 TI - Stress and corticosteroid modulation of seizures and synaptic inhibition in the hippocampus. AB - The role of stress hormones in the initiation of epileptic seizures has been studied extensively in the past decade, with conflicting observations, from suppression to exacerbation of spontaneous seizures. We have now studied the effects of an acute stress on reactivity of juvenile rats to kainic acid (KA), which produces epileptic seizures. With a short (30s) stress-KA delay, stress exacerbated epilepsy via activation of mineralocorticosterone receptors (MR). With a long (60 min) stress-KA delay, seizures were suppressed through activation of a glucocorticosterone receptor (GR). In a parallel study with CA1 pyramidal neurons in acute hippocampal slices, activation of MRs reduced the frequency of mIPSCs, whereas activation of GRs produced a slow onset, 2.5 fold increase in amplitudes of mIPSCs. GR effects were not mediated by protein synthesis, but did require activation of some protein kinases. These experiments suggest that stress can either facilitate or suppress seizures, in a time and receptor dependent manner. PMID- 22227062 TI - Phrenic motoneuron expression of serotonergic and glutamatergic receptors following upper cervical spinal cord injury. AB - Following cervical spinal cord injury at C(2) (SH hemisection model) there is progressive recovery of phrenic activity. Neuroplasticity in the postsynaptic expression of neurotransmitter receptors may contribute to functional recovery. Phrenic motoneurons express multiple serotonergic (5-HTR) and glutamatergic (GluR) receptors, but the timing and possible role of these different neurotransmitter receptor subtypes in the neuroplasticity following SH are not clear. The current study was designed to test the hypothesis that there is an increased expression of serotonergic and glutamatergic neurotransmitter receptors within phrenic motoneurons after SH. In adult male rats, phrenic motoneurons were labeled retrogradely by intrapleural injection of Alexa 488-conjugated cholera toxin B. In thin (10MUm) frozen sections of the spinal cord, fluorescently labeled phrenic motoneurons were visualized for laser capture microdissection (LCM). Using quantitative real-time RT-PCR in LCM samples, the time course of changes in 5-HTR and GluR mRNA expression was determined in phrenic motoneurons up to 21 days post-SH. Expression of 5-HTR subtypes 1b, 2a and 2c and GluR subtypes AMPA, NMDA, mGluR1 and mGluR5 was evident in phrenic motoneurons from control and SH rats. Phrenic motoneuron expression of 5-HTR2a increased ~8-fold (relative to control) at 14 days post-SH, whereas NMDA expression increased ~16 fold by 21-days post-SH. There were no other significant changes in receptor expression at any time post-SH. This is the first study to systematically document changes in motoneuron expression of multiple neurotransmitter receptors involved in regulation of motoneuron excitability. By providing information on the neuroplasticity of receptors expressed in a motoneuron pool that is inactivated by a higher-level spinal cord injury, appropriate pharmacological targets can be identified to alter motoneuron excitability. PMID- 22227063 TI - Pattern-specific changes and discordant prognostic values of individual leg muscle motor evoked potentials during spinal surgery. AB - OBJECTIVE: The aim of the study is to evaluate the efficacy of muscle motor evoked potentials (mMEPs) in individual leg muscles for spinal surgery monitoring. METHODS: Data were obtained from 209 patients who underwent spine surgery with intra-operative mMEP monitoring in the tibialis anterior (TA) and abductor hallucis (AH) muscles. The mMEP generation, pattern-specific mMEP loss and recovery, and the accuracy of individual mMEP changes in predicting postoperative motor deficit were assessed. RESULTS: Generation rate of mMEPs was higher in the AH than in the TA (p<0.001). The mMEP in the TA was more sensitive in detecting mMEP loss than in the AH (p<0.001); however, mMEP in the AH was more sensitive in detecting mMEP recovery (p<0.001). The mMEPs in the TA had high sensitivity in predicting sustained postoperative motor deficits. By contrast, mMEPs in the AH showed a high positive predictive value. CONCLUSIONS: Although mMEPs were generated at a high rate in the AH, mMEP in the TA can play an important complementary role in intra-operative mMEP monitoring, because mMEP in the TA can be more sensitive to potential neural damage. SIGNIFICANCE: Using a combination of muscles with individual sensitivities and clinical significances will improve intra-operative mMEP monitoring strategies. PMID- 22227064 TI - Additional analysis of dendrochemical data of Fallon, Nevada. AB - Previously reported dendrochemical data showed temporal variability in concentration of tungsten (W) and cobalt (Co) in tree rings of Fallon, Nevada, US. Criticism of this work questioned the use of the Mann-Whitney test for determining change in element concentrations. Here, we demonstrate that Mann Whitney is appropriate for comparing background element concentrations to possibly elevated concentrations in environmental media. Given that Mann-Whitney tests for differences in shapes of distributions, inter-tree variability (e.g., "coefficient of median variation") was calculated for each measured element across trees within subsites and time periods. For W and Co, the metals of highest interest in Fallon, inter-tree variability was always higher within versus outside of Fallon. For calibration purposes, this entire analysis was repeated at a different town, Sweet Home, Oregon, which has a known tungsten powder facility, and inter-tree variability of W in tree rings confirmed the establishment date of that facility. Mann-Whitney testing of simulated data also confirmed its appropriateness for analysis of data affected by point-source contamination. This research adds important new dimensions to dendrochemistry of point-source contamination by adding analysis of inter-tree variability to analysis of central tendency. Fallon remains distinctive by a temporal increase in W beginning by the mid 1990s and by elevated Co since at least the early 1990s, as well as by high inter-tree variability for W and Co relative to comparison towns. PMID- 22227065 TI - The role of harvesting in age-structured populations: disentangling dynamic and age truncation effects. AB - Understanding the processes generating fluctuations of natural populations lies at the very heart of academic ecology. It is also very important for applications such as fisheries management and pest control. We are interested in the effect of harvesting on population fluctuations and for that purpose we develop and analyze an age-structured model where recruitment is a stochastic process and the adult segment of the population is harvested. When a constant annual harvest is taken the coefficient of variation of the adult population increases for most parameter values due to the age truncation effect, i.e. an increased variability in a juvenescent population due to the removal of older individuals. However, if a constant proportion of the adults is harvested the age truncation effect is sometimes counteracted by a stabilizing dynamic effect of harvesting. Depending on parameter values mirroring different life histories, proportional harvest can either increase or decrease the relative fluctuations of an exploited population. When there is a demographic Allee effect the ratio of juveniles to adults may actually decrease with harvesting. We conclude that, depending on life history and harvest strategy, harvesting can either reinforce or dampen population fluctuations due to the relative importance of stabilizing dynamic effects and the age truncation effect. The strength of the latter is highly dependent on the fished population's endogenous, age-structured dynamics. More specifically, we predict that populations with strong and positively autocorrelated dynamics will show stronger age truncation effect, a testable prediction that offers a simple rule-of-thumb assessment of a population's vulnerability to exploitation. PMID- 22227066 TI - Combined effects of exercise and soy isoflavone diet on paraoxonase, nitric oxide and aortic apoptosis in ovariectomized rats. AB - Menopause is associated with an increased risk of cardiovascular disease (CVD). Exercise and soy isoflavone diets have been suggested to reduce the risk of CVD in postmenopausal women. We investigated the effects of exercise, or combined exercise and soy isoflavone diet, on plasma lipid profiles, paraoxonase (PON), nitric oxide (NO) and apoptosis in the aorta of ovariectomized (OVX) rats. Thirty two female Sprague-Dawley rats were divided into four groups: OVX with general diet (OVX-GD), OVX with isoflavone diet (OVX-ISO), OVX-GD with exercise training (OVX-ET) and OVX-ISO with exercise training (OVX-ISO+ET). The experimental rats undertook treadmill training (30 min/day, 4 days/week) and/or were supplied a soy isoflavone diet (added to the experimental diet at 2.39 mg/g protein) for 12 weeks. Body weight and levels of total cholesterol (TC), triglyceride (TG), LDL cholesterol (LDL-C) increased in the OVX rats and HDL-C decreased. These effects were reduced by exercise and/or soy isoflavone supplementation. PON and NO activities were higher in the OVX-ISO+ET group than in the OVX-GD group. In addition, this group had lower caspase-9 and -3 and higher Bcl-2 expression, and there was less aortic apoptotic cell death. These results suggest that a combination of exercise and a soy isoflavone diet has beneficial effects in terms of protecting against cardiovascular risk factors by controlling lipid profiles and the related enzyme, PON, as well as NO activity and apoptosis of the aorta in OVX rats. PMID- 22227067 TI - Explaining dietary intake in adolescent girls from disadvantaged secondary schools. A test of Social Cognitive Theory. AB - Much of the research on the determinants of dietary behavior has been guided by Bandura's Social Cognitive Theory (SCT), yet few studies have tested the utility of its proposed structural paths. The aim of this paper was to test the capacity of SCT to explain dietary behaviors in a sample of 357 adolescent girls (13.2+/ 0.5 years) from 12 secondary schools located in low-income communities in New South Wales, Australia. Participants completed validated SCT scales assessing nutrition-related self-efficacy, intention, behavioral strategies, family support, situation, outcome expectations, and outcome expectancies. Participants completed a validated food frequency questionnaire, from which, the percentage of total kilojoules from core-foods, non-core foods and saturated fat were calculated. The theoretical models were tested using structural equation modeling in AMOS. The models explained 48-51% and 13-19% of the variance in intention and dietary behavior, respectively. The models provided an adequate fit to the data, and self-efficacy was positively associated with healthy eating and inversely associated with unhealthy eating. However, the pathway from intention to behavior was not statistically significant in any of the models. While this study has demonstrated the utility of SCT constructs to explain behavior in adolescents girls, the proposed structural pathways were not supported. Further study of the role that implementation intentions play in explaining adolescent girls' dietary behaviors is required. PMID- 22227068 TI - Linkage study of embryopathy-polygenic inheritance of diabetes-induced skeletal malformations in the rat. AB - We developed an inbred rat model of diabetic embryopathy, in which the offspring displays skeletal malformations (agnathia or micrognathia) when the mother is diabetic, and no malformations when she is not diabetic. Our aim was to find genes controlling the embryonic maldevelopment in a diabetic environment. We contrasted the fetal outcome in inbred Sprague-Dawley L rats (20% skeletal malformations in diabetic pregnancy) with that of inbred Wistar Furth rats (denotedW, no skeletal malformations in diabetic pregnancy). We used offspring from the backcross F(1)*L to probe for the genetic basis for malformation of the mandible in diabetic pregnancy. A set of 186 fetuses (93 affected, 93 unaffected) was subjected to a whole genome scan with 160 micro satellites. Analysis of genotype distribution indicated 7 loci on chromosome 4, 10 (3 loci), 14, 18, and 19 in the teratogenic process (and 14 other loci on 12 chromosomes with less strong association to the malformations), several of which contained genes implicated in other experimental studies of diabetic embryopathy. These candidate genes will be scrutinized in further experimentation. We conclude that the genetic involvement in rodent diabetic embryopathy is polygenic and predisposing for congenital malformations. PMID- 22227069 TI - Sinus mucocele: natural history and long-term recurrence rate. AB - OBJECTIVE: To define the natural history, clinical signs, treatment and the modalities of medium- and long-term follow-up of patients operated for sinus mucocele. PATIENTS AND METHOD: Retrospective study of all patients operated for sinus mucocele between January 1993 and December 2009 (n=68). Demographic data, symptoms, medical imaging findings, surgical treatment and results were recorded. RESULTS: The mean age of patients in this series was 53 years (range: 27-82 years, sex ratio: 3/2). The most common site was fronto-ethmoidal. Fifty-one patients (75%) had a history of sinus surgery, essentially for nasal polyposis. Only 15% of mucoceles occurred spontaneously. Presenting symptoms, in decreasing order of frequency, were facial pain or headache (38%), ocular or orbital complications (28%), while 20% of patients were asymptomatic. Surgery was performed by endonasal endoscopic sinus surgery (n=57, 84%) or via a combined, transfacial and endonasal approach, associated with navigation after January 2003. The mean follow-up was 7 years (range: 4 months-16 years). During this follow-up period, 23.5% of patients developed recurrence or a second mucocele after a mean interval of 4 years. CONCLUSION: This study demonstrates the high recurrence rate of mucocele, particularly in multi-operated patients with chronic sinusitis. Long-term, regular, clinical and radiological follow-up is necessary to detect asymptomatic lesions prior to the onset of complications. PMID- 22227070 TI - Histopathological alterations of juvenile green (Acipenser medirostris) and white sturgeon (Acipenser transmontanus) exposed to graded levels of dietary methylmercury. AB - Triplicate groups of juvenile green and white sturgeon (average weight of 30 +/- 2 g) were exposed to one of four concentrations of dietary methylmercury (MeHg; 0, 25, 50, and 100 mg MeHg/kg diet) for 8 weeks to determine and compare the sensitivity of the two sturgeon species from a histopathological perspective. After 4- and 8-week exposure, histological changes were examined in the kidney, liver, gill, skeletal muscle, and heart muscle of both species using light microscopy. Marked abnormalities were observed in the kidney and liver of both sturgeon species after each exposure period; the abnormalities showed progressive histological alterations in severity with increasing doses and duration of exposure. Renal lesions included tubular epithelium degeneration and necrosis, renal corpuscular disintegration, and interstitial tissue degeneration. The changes observed in the livers of both sturgeon species were glycogen depletion and vacuolar degeneration. In the gill and skeletal and heart muscle of green and white sturgeon fed MeHg-added diets, mild histological changes were observed but did not show pronounced difference between the two species. Although the lowest observed effect concentration in both species was the 25 mg MeHg/kg diet, the histological changes in the kidney and liver were more pronounced at all treatments groups of green sturgeon than those of white sturgeon. The current results on structural changes of kidney and liver (i.e., more severe glycogen depletion and tubular epithelium degeneration in green sturgeon) confirmed our previous results, in that green sturgeon exhibited a higher mortality, lower growth rate, and lower protein, lipid, and energy contents in their whole body than white sturgeon under the same MeHg exposures. PMID- 22227071 TI - Lower plasma NAMPT/visfatin levels are associated with impaired hepatic mitochondrial function in non-diabetic obese women: a potential link between obesity and non-alcoholic fatty liver disease. PMID- 22227072 TI - Lysosomal lipase deficiency: molecular characterization of eleven patients with Wolman or cholesteryl ester storage disease. AB - Wolman Disease (WD) and cholesteryl ester storage disease (CESD) represent two distinct phenotypes of the same recessive disorder caused by the complete or partial deficiency of lysosomal acidic lipase (LAL), respectively. LAL, encoded by the LIPA gene, hydrolyzes cholesteryl esters derived from cell internalization of plasma lipoproteins. WD is a rapidly progressive and lethal disease characterized by intestinal malabsorption, hepatic and adrenal failure. CESD is characterized by hepatic fibrosis, hyperlipidemia and accelerated atherosclerosis. Aim of the study was the identification of LIPA mutations in three WD and eight CESD patients. The WD patients, all deceased before the first year of age, were homozygous for two novel mutations (c.299+1G>A and c.419G>A) or a mutation (c.796G>T) previously reported as compound heterozygosity in a CESD patient. The two mutations (c.419G>A and c.796G>T) resulting in truncated proteins (p.W140* and p.G266*) and the splicing mutation (c.229+1G>A) were associated with undetectable levels of LIPA mRNA in fibroblasts. All eight CESD patients carried the common mutation c.894G>A known to result not only in a major non-functional transcript with the skipping of exon 8 (p.S275_Q298del), but also in a minor normally spliced transcript producing 5-10% residual LAL activity. The c.894G>A mutation was found in homozygosity in four patients and, as compound heterozygosity, in association with a known (p.H295Y and p.G342R) or a novel (p.W140*) mutation in four other CESD patients. Segregation analysis performed in all patients harboring c.895G>A showed its occurrence on the same haplotype suggesting a common founder ancestor. The other WD and CESD mutations were associated with different haplotypes. PMID- 22227073 TI - Progressive mesenteric lymphadenopathy with protein-losing enteropathy; a devastating complication in Gaucher disease. AB - Mesenteric lymphadenopathy has been rarely reported in pediatric patients with Gaucher disease, developing despite the enzyme replacement therapy. The clinical implication of this condition is undetermined, with no consensus on treatment strategies. However, this condition can reflect the progression of Gaucher disease. Moreover, it can be accompanied by the serious complication, protein losing enteropathy. Our experience underlines the importance of careful monitoring and early intervention for mesenteric lymphadenopathy, especially in pediatric patients with neuronopathic Gaucher disease. PMID- 22227074 TI - Prognosis of an abnormal one-leg balance in community-dwelling patients with Alzheimer's disease: a 2-year prospective study in 686 patients of the REAL.FR study. AB - OBJECTIVES: The aim of this study was to explore the predictive value of an abnormal one-leg balance (OLB) test for functional decline, nursing home admission, and mortality in community-dwelling patients affected with Alzheimer's disease (AD). DESIGN: A 2-year prospective, observational cohort study. SETTING: Nineteen memory centers across France. PARTICIPANTS: A total of 686 community dwelling patients with AD. MEASUREMENTS: Mini-mental state examination, Activity of Daily Living scale, and balance (ability to stand unassisted for 5 seconds on 1 leg) were reported every 6 months. Functional decline was defined as a loss of 0.5 or more points at a 5-point Activity of Daily Living score (bathing, dressing, toileting, continence, and feeding). Nursing home admission and mortality were recorded. Neuropsychiatric symptoms, medication, and caregiver's burden were assessed every 6 months. Time-to-event analyses were used. RESULTS: At baseline, 632 patients with AD had a balance measurement (mean age = 77.8 years, SD = 6.9; 72.2% were women) and 15.2% had an abnormal OLB test: these patients were older, had lower mini-mental state examination and Activity of Daily Living scores, and more neuropsychiatric symptoms, osteoarthritis, comorbidities and medications (all P < .05). After adjustment for age and sex, the risk of functional decline (hazard ratio [HR]: 1.69; 95% confidence interval [CI], 1.26-2.26), nursing home admission (HR: 2.51; 95% CI, 1.69-3.73), and death (HR: 2.42; 95% CI, 1.43-4.11) was higher in patients with an abnormal OLB. After adjustment for other potential confounders, the presence of an abnormal OLB was significantly associated only with nursing home admission (HR: 1.73, 95% CI, 1.09 2.75). CONCLUSION: In the present study, an abnormal OLB predicts nursing home admission in patients with AD. Although statistically significant when solely adjusted for age and sex, an abnormal OLB test failed to predict functional decline and mortality when adjusted for multiple confounders. PMID- 22227075 TI - Comparative protection of two different commercial vaccines against Yersinia ruckeri serotype O1 and biotype 2 in rainbow trout (Oncorhynchus mykiss). AB - Differentially extended specific protection by two commercial vaccines against Yersinia ruckeri serotype O1 biotype 2 was studied following 30s immersion exposure. Rainbow trout were challenged intra-peritoneally (i.p.) with Y. ruckeri serotype O1, biotype 2 (~10(6) to 10(7)CFU/fish) at 4, 6 and 8 months after vaccination with vaccines containing either biotype 1 (AquaVac((r)) ERM) or both biotypes 1 and 2 (AquaVac((r)) RELERATM). The specific pattern of vaccine mediated protection was evaluated by relative percentage survival (RPS) analysis at 4 and 6 months post-vaccination and by obtaining gross pathological observations at 4 and 8 months respectively. We determined specific significant and superior protection in terms of increased survivability in AquaVac((r)) RELERATM vaccinated fish and observed correspondingly fewer pathological changes. The challenge trials indicated a longer protection for at least 6 months without any booster vaccination. A specific and adaptive response induced by AquaVac((r)) RELERATM vaccine against Y. ruckeri biotype 2 was clearly indicated. In addition, some degree of cross protection rendered by AquaVac((r)) ERM containing biotype 1 during infection with Y. ruckeri biotype 2 was also noted. PMID- 22227076 TI - Development of tertiary lymphoid structures in the kidneys of pigs with chronic leptospiral nephritis. AB - Tertiary lymphoid organs (TLOs) are structures that are morphologically and functionally similar to secondary lymphoid organs. TLOs usually arise in a background of chronic inflammation. Several histological patterns of interstitial nephritis have been documented in porcine leptospirosis. Among them the lympho follicular pattern is characterized by infiltrates of mononuclear cells organized in lymphoid follicle-like structures. Immunohistological analysis of 5 cases of porcine lympho-follicular nephritis associated with Leptospira Pomona infection demonstrated the presence of inflammatory cell populations, including B cells, T cells, macrophages and follicular dendritic cells (FDCs), which were compartmentalized as in TLOs. Immunohistochemistry for Leptospira Pomona revealed an intimate association between leptospiral antigen and FDCs. Overexpression of MHCII in different populations of both professional and non-professional antigen presenting cells was also demonstrated. FDCs play role during TLOs induction for their ability to retain non-self antigens in the form of immune complexes, thus causing persistent T cell activation, generation of a complex cytokine network and stimulation of humoral immunity. Sustained bacterial antigen presentation in the context of chronic leptospiral nephritis, may also lead to autoimmune mechanisms involved in the generation of TLOs. Whether lymphoid neogenesis and TLOs play a protective role in porcine leptospiral nephritis is still unclear. PMID- 22227077 TI - Reliability of the validated clinical diagnosis of pneumonia on validated outcomes after intracranial hemorrhage. AB - PURPOSE: Reducing the incidence of hospital-acquired pneumonia (PNU) is important but depends on accurate assessment. We sought to determine the interrater reliability of diagnosis of PNU and its impact on resource utilization and functional outcomes in a high-risk population. MATERIALS AND METHODS: Patients admitted in 2007 with intracranial hemorrhage were prospectively identified. Pneumonia was prospectively diagnosed by Centers for Disease Control criteria by a neurointensivist and infection control. An independent retrospective determination was made by a fellow, an infectious disease attending physician, and a pulmonologist after review of the electronic medical records and radiographs. Interrater reliability was analyzed with kappa statistics. One and 3 month outcomes were measured with the modified Rankin scale. RESULTS: Of 103 patients, the incidence of PNU ranged from 5% to 25%. Interrater reliability was poor (median kappa = 0.30 [0.19-0.42]; P < .001). Any ascertainment of PNU was associated with longer intensive care unit length of stay, more fever and ventilator dependence, and worse functional outcomes. CONCLUSIONS: Pneumonia had poor interrater reliability despite highly trained reviewers and validated criteria. Although the clinical assessment of PNU is difficult, it was associated with greater resource use and worse outcomes. Diagnosis of clinical PNU may be suboptimal for measuring quality of intensive care. PMID- 22227078 TI - Predictors of prolonged vasopressin infusion for the treatment of septic shock. AB - PURPOSE: Prolonged catecholamine use has been linked with poor clinical outcomes, including higher mortality. The objective was to identify characteristics that may be predictive of prolonged arginine vasopressin (AVP) use for 7 days or more in patients with septic shock. MATERIALS AND METHODS: This was a retrospective nested cohort analysis of adult patients receiving AVP as initial hemodynamic support for septic shock, either alone or in combination with norepinephrine, between 2008 and 2010. RESULTS: Univariate factors predictive of patients requiring extended AVP support were peripheral vascular disease (PVD) (48% vs 18%, P = .001), congestive heart failure (30% vs 12%, P = .024), and acute kidney injury (AKI) (83% vs 49%, P = .003). Patients requiring extended AVP support more frequently experienced a new intensive care unit (ICU) arrhythmia, typically atrial fibrillation (39% vs 7%, P < .001), and had higher 28-day mortality (74% vs 20%, P < .001). Multivariate analysis revealed that the strongest independent predictors of prolonged AVP dependence were new ICU arrhythmia (odds ratio [OR], 5.3; 95% confidence interval [CI], 1.6-17.8), PVD (OR, 4.3; 95% CI, 1.4-13.1), and AKI (OR, 3.9; 95% CI, 1.1-14.5). CONCLUSIONS: Patients with preexisting PVD and AKI and those experiencing a new ICU arrhythmia on AVP may be more likely to remain on AVP for 7 or more days. PMID- 22227079 TI - Blood glucose amplitude variability as predictor for mortality in surgical and medical intensive care unit patients: a multicenter cohort study. AB - PURPOSE: The aim of this study was to test the hypothesis that blood glucose amplitude variability (BGAV) is associated with mortality in critically ill patients. METHOD: A prospectively collected multicenter data set including all glucose measurements during intensive care unit (ICU) treatment and outcome was analyzed. We used logistic regression to assess the association between hospital mortality and standard deviation (SD), mean amplitude of glycemic excursions (MAGE), mean absolute glucose change per hour (MAG), and glycemic lability index (GLI). The analysis was adjusted for ICU, Acute Physiology And Chronic Health Evaluation IV-expected mortality, the presence of severe hypoglycemia, mean glucose, mean glucose measurement interval, and interaction between the latter 2. RESULTS: There were 855,032 glucose measurements included of 20,375 patients admitted to 37 Dutch ICUs in 2008 and 2009. Median Acute Physiology And Chronic Health Evaluation IV-predicted mortality was 14%, and median glucose was 7.3 mmol/L. In all patients combined, adjusted hospital mortality was associated with SD and MAGE, but not with MAG and GLI. In surgical patients, adjusted hospital mortality was associated with SD, MAGE, and MAG, but not GLI. In medical patients, adjusted mortality was associated with SD but not with other BGAV measures. CONCLUSION: Not all BGAV measures were associated with mortality. Blood glucose amplitude variability as quantified by SD was consistently independently associated with hospital mortality. PMID- 22227080 TI - Cerebral vasoreactivity to acetazolamide is not impaired in patients with severe sepsis. AB - INTRODUCTION: The pathophysiology of sepsis-associated encephalopathy (SAE) is not entirely clear, but one of the possible underlying mechanisms is the alteration of the cerebral microvascular function. The aim of the present work was to test whether cerebral vasomotor reactivity is impaired in patients with severe sepsis. METHODS: Patients fulfilling the criteria of clinical sepsis and showing at least 2 organ dysfunctions were included (n = 16). Nonseptic healthy persons without previous diseases affecting cerebral vasoreactivity served as controls (n = 16). Transcranial Doppler blood flow velocities were measured at rest and at 5, 10, 15, and 20 minutes after intravenous administration of 15 mg/kg acetazolamide. The time course of the acetazolamide effect on cerebral blood flow velocity (cerebrovascular reactivity [CVR]) and the maximal vasodilatory effect of acetazolemide (cerebrovascular reserve capacity [CRC]) were compared among the groups. RESULTS: Absolute blood flow velocities after administration of the vasodilator drug did not differ between control and septic patients. Assessment of the time course of the vasomotor reaction showed that patients with sepsis reacted in a similar fashion to the vasodilatory stimulus than control persons. When assessing the maximal vasodilatory ability of the cerebral arterioles to acetazolamide during vasomotor testing, we found that there was no difference in vasodilatory ability between septic and healthy subjects (CRC controls, 54.8% +/- 11.1%; CRC sepsis-associated encephalopathy, 61.1% +/- 34.4%; P = .49). CONCLUSIONS: We conclude that cerebrovascular reactivity is not impaired in patients with severe sepsis. It is conceivable that cerebral vasoreactivity may be differently involved at different severity stages of the septic process. PMID- 22227081 TI - Survival and functional outcomes after cardiopulmonary resuscitation in the intensive care unit. AB - PURPOSE: Comparatively less is known about the outcomes of cardiopulmonary resuscitation (CPR) in patients in the intensive care unit (ICU) compared with those not in an ICU. In this study, we evaluated survival rates, functional status, and predictors of good outcomes after in-ICU CPR. METHODS: We used the Project IMPACT (Cerner Corporation, Kansas City, Mo) database to conduct a retrospective cohort study of adults who underwent in-ICU CPR in the United States from 2001 to 2008. We characterized survival rates and functional outcomes and identified predictors of better prognosis using multivariate logistic regression analyses. RESULTS: Of 362074 ICU admissions, 6518 (1.8%) received in ICU CPR with 15.7% (n = 1025) surviving to hospital discharge. Survival decreased with age, more comorbidities, and for certain admitting diagnoses, such as sepsis. Patients who survived incurred significant functional morbidity. Of survivors, only 33.6% were discharged home, and only 20.1% were functionally independent on hospital discharge. A total of 63.4% had a decrease in functional status compared with admission. Only 3.3% of all patients (21.7% of survivors) were both functionally independent and discharged home ("optimal" functional outcome). Among survivors, the risk-adjusted odds of having an optimal functional outcome decreased with age (P <= .022) and with failure of 3 or more organs during ICU stay (P = .006). CONCLUSIONS: Only 1 of 6 adults receiving in-ICU CPR survives to hospital discharge, and less than 5% are discharged home with independent function. Among survivors, most show large decreases in functional status compared with hospital admission. PMID- 22227082 TI - Disagreement between ion selective electrode direct and indirect sodium measurements: estimation of the problem in a tertiary referral hospital. AB - PURPOSE: We estimated the proportion of indirect ion selective electrode (ISE) plasma sodium analyses in intensive care unit (ICU) and hospital wide, exhibiting important disagreement with direct ISE results in relation to abnormal plasma protein concentrations. MATERIALS AND METHODS: Direct and indirect ISE plasma sodium measurements were performed on 346 clinical specimens selected to reflect low, normal, or high total protein concentrations. Important intermethod disagreement was defined as |4| mmol/L or higher. Results were extrapolated to a 3-month laboratory series of 48,033 indirect ISE assays, including 2877 samples from intensive care. RESULTS: Intermethod sodium disagreement at |4| mmol/L or higher was predicted for 25% of ICU samples. Almost all (97%) occurred in hypoproteinemic samples where indirect tended to exceed direct ISE estimates. Hospital wide, such disagreement was projected to occur in 8% of samples, of which the majority (70%) were also hypoproteinemic. CONCLUSIONS: Important disagreement between indirect and direct ISE sodium measurements may exist in up to 1 in 4 ICU specimens and 1 in 12 hospital-wide samples. The main problem is indirect ISE overestimation associated with hypoproteinemia, potentially leading to misclassifications of pseudohypernatremia and pseudonormonatremia. We recommend that hospital laboratories consider standardization using direct ISE sodium measurement. PMID- 22227083 TI - Early bacterial genome detection in body fluids from patients with severe sepsis: a pilot study. AB - PURPOSE: The purpose of this study is to evaluate the feasibility and interest of real-time polymerase chain reaction (RT-PCR) testing for bacterial genomes in body fluids other than blood in patients with acute severe sepsis. METHODS: Twenty-six consecutive patients admitted for severe sepsis or septic shock were prospectively studied. Body fluids were sampled as clinically indicated and tested using standard microbiological methods and modified RT-PCR methods (universal PCR and specific PCRs). Results of standard microbiological tests were compared with those of PCR tests. RESULTS: Direct RT-PCR testing was successfully performed on all nonblood body fluids. Of 29 body fluids collected, 23 were positive for at least 1 microorganism with conventional tests. Of 18 microbiological tests positive for a single microorganism, 15 fully agreed with RT-PCR assays, and the remaining 3 samples were infected with bacteria not screened by PCR testing. Among the 5 polymicrobial results obtained with conventional tests, RT-PCR agreed in 4 patients. The RT-PCR tests allowed additional clinically relevant bacterial identification in 3 of 6 samples with negative microbiological culture. CONCLUSIONS: Our results indicate that direct PCR testing may improve the detection of bacteria in body fluids other than blood in patients with acute severe sepsis. PMID- 22227084 TI - Implementation challenges in the intensive care unit: the why, who, and how of daily interruption of sedation. AB - PURPOSE: Despite strong medical evidence and policy initiatives supporting the use of daily interruption of sedation in mechanically ventilated patients, compliance remains suboptimal. We sought to identify new barriers to daily interruption of sedation. MATERIALS AND METHODS: We conducted 5 focus groups of intensive care unit physicians, nurses, and respiratory therapists during a 2 month period to identify attitudes, barriers, and motivations to perform a daily interruption of sedation. Each focus group was audiotaped, and the transcripts were analyzed using qualitative methods to identify recurrent themes. RESULTS: There was wide consensus on the importance of daily interruptions of sedation; however, practitioners usually performed sedation interruption for 1 of 5 distinct reasons: minimizing the dose of sedation, performing a neurologic examination, facilitating ventilator weaning, reducing intensive care unit length of stay, and assessing patient pain. Participants rarely espoused more than 1 main reason, and there was no shared understanding of why one might do a daily interruption of sedation. This lack of shared understanding led to different patients being selected and diverse approaches to carrying out the DIS. CONCLUSIONS: Despite apparent consensus, lack of shared understanding of the rationale for an intervention may lead to divergent practice patterns and failure to implement standardized, evidence-based practice. PMID- 22227085 TI - Factors associated with acute lung injury in combat casualties receiving massive blood transfusions: a retrospective analysis. AB - PURPOSE: We sought to determine if use of warm fresh whole blood (WFWB), rather than blood component therapy, alters rates of acute lung injury (ALI) in patients with trauma. MATERIALS AND METHODS: We retrospectively analyzed rates of ALI in patients undergoing massive blood transfusions while at a combat support hospital. Patients with ALI were compared with those not developing ALI with respect to demographics, trauma type, severity of illness, crystalloid volume given, and exposure to WFWB. Logistic regression was used to identify variables associated with ALI. RESULTS: The cohort included 591 subjects (mean age, 28 +/- 8.1 years; male, 96.7%). Acute lung injury occurred in 11.2%, and 34.4% received WFWB. After adjusting for the type of trauma, severity of illness, and volume of crystalloid administered, WFWB remained independently associated with ALI (adjusted odds ratio [AOR], 1.06; 95% confidence interval [CI], 1.00-1.13). Nearly two thirds of persons with ALI never received WFWB; factors associated with the use of WFWB were also examined. Severity of illness (AOR, 1.18; 95% CI, 1.02-1.35), crystalloid volume (AOR, 1.12; 95% CI, 1.06-1.18), recombinant factor VIIa use (AOR, 1.94; 95% CI, 1.06-3.57), and US citizenship (AOR, 3.06; 95% CI, 1.74-5.37) correlated with WFWB use. CONCLUSIONS: Warm fresh whole blood may be associated with an increased risk of ALI, but this is confounded by increased injury and crystalloid use in patients receiving WFWB. PMID- 22227086 TI - A weaning protocol administered by critical care nurses for the weaning of patients from mechanical ventilation. AB - PURPOSE: The primary objective of this clinical trial of patients on mechanical ventilation was to determine if a weaning protocol implemented solely by nurses could reduce the weaning time relative to usual care (UC). MATERIALS AND METHODS: This study is a prospective, randomized, controlled trial conducted from January 2007 to January 2009 that compared protocol-based weaning (PBW) with UC. A total of 122 patients who received invasive ventilation in the medical ICU of the Asan Medical Center were examined. Nurses operated the mechanical ventilators according to a predesigned ventilator-weaning protocol for the PBW group (n = 61), and intensive care unit (ICU) physicians managed weaning in the UC group (n = 61). RESULTS: There were no significant differences in the 2 groups at baseline. The number of patients who successfully discontinued mechanical ventilation was similar in the 2 groups (PBW, 46 patients, 75.4%; UC, 47 patients, 77.0%; P = .832). The weaning time was 47 hours (interquartile range, 24-168 hours) in the UC group and 25 hours (interquartile range, 5.75-134 hours) in the PBW group (P = .010). CONCLUSIONS: The weaning protocol administered by the nurses was safe and reduced the weaning time from mechanical ventilation in patients who were recovering from respiratory failure. PMID- 22227087 TI - Respiratory syncytial virus morbidity, premorbid factors, seasonality, and implications for prophylaxis. AB - OBJECTIVES: We investigated factors associated with morbidity and pediatric intensive care unit (PICU) admission in children with respiratory syncytial virus (RSV) infection and explored seasonality and implication of prophylaxis. METHODS: A retrospective study between 2006 and 2008 of every child with a laboratory confirmed RSV infection was included. RESULTS: Six hundred seventy RSV admissions were identified. Ten (1.5%) required PICU admissions. Children admitted to PICU were younger than non-PICU admissions (median [interquartile range] age, 0.3 [0.11-0.48] vs 1.18 [0.46-2.49] years; P = .001). Odds associated with PICU admissions included history of chronic lung disease (odds ratio [95% confidence interval], 18.08 [2.29-114.95]; P = .010), history of acyanotic heart disease (7.61 [1.04-42.59], P = .043), and neurodevelopmental conditions (mental retardation, cerebral palsy, or neuromuscular disease; 8.41 [1.63-38.57], P = .012). Odds of bacterial coinfections was 13.50 (1.77-81.29), P = .017. There appeared no significant PICU predilection in terms of sex, history of prematurity, cyanotic heart disease, seizure disorders, chromosomal disorders, or malignancy. Admissions associated with proven RSV infections accounted for 2.4% of PICU annual admissions. The duration of PICU stay was generally brief (median, 3 days). However, median length of hospital stay was significantly longer in the PICU category (8.5 vs 3 days, P < .001). There was no death in the study period. Only 5 (0.75%) of 665 patients were readmitted to the pediatric infectious disease isolation ward in consecutive years, and none required PICU support. Twenty (3%) of admissions involved neonates younger than 30 days. There was no definite seasonality, but incidence was lowest between October and January. CONCLUSIONS: Most infants have mild disease and do not require PICU support. Young infants with history of chronic lung disease, congenital heart disease, and neurodevelopmental conditions appear to be at significantly increased risk for PICU support. There is no winter seasonality for RSV disease in Hong Kong. Therefore, any prophylaxis for at-risk population should provide adequate coverage for the warmer months in subtropical regions. PMID- 22227088 TI - Model for End-Stage Liver Disease score for predicting outcome in critically ill medical patients with liver cirrhosis. AB - PURPOSE: We hypothesized that the Model for End-Stage Liver Disease (MELD) score at admission to the intensive care unit (ICU) can predict in-hospital mortality for patients with liver cirrhosis. We also tested the MELD-natremia (Na) score and compared the predictive value of the 2 models. MATERIALS AND METHODS: This is a retrospective cohort study. A total of 441 consecutive patients with liver cirrhosis admitted to the ICU were included. The MELD and MELD-Na scores and other variables were obtained upon patients' admission to the ICU. RESULTS: The area under the receiver operating characteristic curve to predict in-hospital mortality was 0.77 (95% confidence interval, 0.73-0.82) for the MELD score and 0.77 (95% confidence interval, 0.73-0.81) for the MELD-Na score. CONCLUSION: The MELD scoring system provides useful prognostic information for critically ill patients with liver cirrhosis admitted to an ICU. The MELD and MELD-Na scores had similar predictive value. PMID- 22227089 TI - Fever in non-neurological critically ill patients: a systematic review of observational studies. AB - PURPOSE: There is no recommendation on how increased body temperature should be treated in non-neurological critically ill patients. To understand the epidemiology of fever and its association with mortality, we conducted a systematic review of the literature to search for data related to the association between fever and mortality. MATERIALS AND METHODS: We searched MEDLINE and PUBMED related articles and reference lists from January 1978 to July 2011 to select observational studies for assessment of the association of fever with mortality in non-neurological critically ill patients. RESULTS: We reviewed 1464 articles and found 9 relevant articles. We found that (1) there is no uniform definition of fever, (2) fever (37.5 degrees C to >39.0 degrees C) was not significantly associated with mortality (odds ratio, 1.22; P = .52), and (3) high fever (39.3 degrees C to 39.5 degrees C) was significantly associated with mortality (odds ratio, 2.95; P = .03). We also found that there has been no multicenter prospective observational study including important confounding factors, such as the use of antipyretic treatments, steroids, and extracorporeal circuits. CONCLUSIONS: The limited evidence available suggests that the recommended definition of fever (38.3 degrees C) might be too low to predict increased mortality. Because fever is common in the intensive care unit, there is an urgent need for more studies in this field. PMID- 22227090 TI - Failure to reduce C-reactive protein levels more than 25% in the last 24 hours before intensive care unit discharge predicts higher in-hospital mortality: a cohort study. AB - PURPOSE: To discharge a patient from the intensive care unit (ICU) is a complex decision-making process because in-hospital mortality after critical illness may be as high as up to 27%. Static C-reactive protein (CRP) values have been previously evaluated as a predictor of post-ICU mortality with conflicting results. Therefore, we evaluated the CRP ratio in the last 24 hours before ICU discharge as a predictor of in-hospital outcomes. METHODS: A retrospective cohort study was performed in 409 patients from a 6-bed ICU of a university hospital. Data were prospectively collected during a 4-year period. Only patients discharged alive from the ICU with at least 72 hours of ICU length of stay were evaluated. RESULTS: In-hospital mortality was 18.3% (75/409). Patients with reduction less than 25% in CRP concentrations at 24 hours as compared with 48 hours before ICU discharge had a worse prognosis, with increased mortality (23% vs 11%, P = .002) and post-ICU length of stay (26 [7-43] vs 11 [5-27] days, P = .036). Moreover, among hospital survivors (n = 334), patients with CRP reduction less than 25% were discharged later (hazard ratio, 0.750; 95% confidence interval, 0.602-0.935; P = .011). CONCLUSIONS: In this large cohort of critically ill patients, failure to reduce CRP values more than 25% in the last 24 hours of ICU stay is a strong predictor of worse in-hospital outcomes. PMID- 22227092 TI - Genetic variability of interleukin4 gene in Taiwanese children with biliary atresia. AB - Biliary atresia (BA) is a neonatal cholangiopathy of unknown etiology that leads to biliary cirrhosis and is the most common cause of liver transplantation in children. A still undetermined hepatobiliary viral infection may elicit an uncontrollable autoimmune response against the biliary epithelial cells in genetically predisposed children and culminates in atresia of the biliary trees. Interleukin 4 (IL4) is crucial for the differentiation of naive T helper cells into the T helper 2 effector cells that promote humoral immunity. This study aims to investigate whether polymorphisms of the IL4 gene are associated with susceptibility to BA. Genomic DNA was extracted from whole blood samples of 53 Taiwanese children with BA and 904 ethnically-matched healthy controls. The IL4 590 C/T, -33 C/T, and 8375 A/G polymorphisms were genotyped using the Pre Developed TaqMan Allelic Discrimination Assay in a real-time polymerase chain reaction system. No significant difference between children with BA and healthy controls were found when comparing genotype, allele, carrier, and haplotype frequencies of these IL4 gene variants. These results suggest that the tested polymorphisms of IL4 gene are unlikely to contribute significantly to BA susceptibility in Taiwanese children. PMID- 22227093 TI - Signaling pathways involved in the regulation of TNFalpha-induced toll-like receptor 2 expression in human gingival fibroblasts. AB - Periodontitis is a chronic inflammatory disease characterized by a host inflammatory response against bacteria that leads to destruction of the supporting structures of the teeth. Bacterial components of pathogens in the periodontal pocket are recognized by toll-like receptors (TLRs) that trigger an inflammatory response. In this study, we investigated the effects of the pro inflammatory cytokine tumor necrosis factor alpha (TNFalpha) on TLR2 expression in human gingival fibroblasts. In addition, we examined the signaling pathways involved in the regulation of TNFalpha-induced TLR2 expression. Our results showed that TNFalpha increased TLR2 mRNA and protein expression. Microarray analysis and the inhibition of specific signaling pathways demonstrated that c Jun N-terminal kinases (JNK) and nuclear factor kappa B (NF-kappaB) were involved in the regulation of TNFalpha-induced TLR2 expression in gingival fibroblasts. Furthermore, the prostaglandin E(2) (PGE(2)) regulatory enzyme cytosolic phospholipase A(2) (cPLA(2)) and the anti-inflammatory prostaglandin 15-deoxy Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), were found to regulate TLR2 mRNA expression stimulated by TNFalpha. Our findings suggest that these pathways and mediators, through the regulation of TLR2 expression in gingival fibroblasts, may be involved in the pathogenesis of periodontitis. The study provides new insights into the molecular mechanisms underlying the regulation of TLR2, implicated in the chronic inflammatory disease periodontitis. PMID- 22227094 TI - Cerebellar lesions alter performance monitoring on the antisaccade task--an event related potentials study. AB - Error processing is associated with distinct event-related potential components (ERPs), i.e. the error-related negativity (ERN) which occurs within approximately 150 ms and is typically more pronounced than the correct-response negativity (CRN), and the error positivity (Pe) emerging from about 200 to 400 ms after an erroneous response. The short latency of the ERN suggests that the internal error monitoring system acts on rapidly available central information such as an efference copy signal rather than slower peripheral feedback. The cerebellum has been linked to an internal forward-model which enables online performance monitoring by predicting the sensory consequences of actions, most probably by making use of efference copies. In the present study it was hypothesized that the cerebellum is involved in the fast evaluation of saccadic response accuracy as reflected by the ERN. Error processing on an antisaccade task was investigated in eight patients with focal vascular lesions to the cerebellum and 22 control subjects using ERPs. While error rates were comparable between groups, saccadic reaction times (SRTs) were enhanced in the patients, and the error-correct difference waveforms showed reduced amplitudes for patients relative to controls in the ERN time window. Notably, this effect was mainly driven by an increased CRN in the patients. In the later Pe time window, the difference signal yielded higher amplitudes in patients compared to controls mainly because of smaller Pe amplitudes on correct trials in patients. The altered ERN/CRN pattern suggests that the cerebellum is critically involved in fast classification of saccadic accuracy. Largely intact performance accuracy together with increased SRTs and the altered Pe pattern may indicate a compensatory mechanism presumably related to slower, more conscious aspects of error processing in the patients. PMID- 22227095 TI - [Hereditary angioedema: a therapeutic revolution]. AB - Hereditary angioedema is a rare disease, often diagnosed with delay because of a heterogeneous clinical presentation. Before diagnosis, patients frequently present subcutaneous edema or abdominal pains during many years. Laryngeal edema can be life-threatening. Hereditary angioedema may impair the quality of life of the patients and their social and professional life. It is important that the physicians recognize and treat the disease as soon as possible after the first attacks. Since the past five years, new drugs developed for hereditary angioedema have changed dramatically the outcome of this disorder. The objective of this review is to detail the new therapeutic guidelines. PMID- 22227096 TI - X-ray mosaic nanotomography of large microorganisms. AB - Full-field X-ray microscopy is a valuable tool for 3D observation of biological systems. In the soft X-ray domain organelles can be visualized in individual cells while hard X-ray microscopes excel in imaging of larger complex biological tissue. The field of view of these instruments is typically 10(3) times the spatial resolution. We exploit the assets of the hard X-ray sub-micrometer imaging and extend the standard approach by widening the effective field of view to match the size of the sample. We show that global tomography of biological systems exceeding several times the field of view is feasible also at the nanoscale with moderate radiation dose. We address the performance issues and limitations of the TOMCAT full-field microscope and more generally for Zernike phase contrast imaging. Two biologically relevant systems were investigated. The first being the largest known bacteria (Thiomargarita namibiensis), the second is a small myriapod species (Pauropoda sp.). Both examples illustrate the capacity of the unique, structured condenser based broad-band full-field microscope to access the 3D structural details of biological systems at the nanoscale while avoiding complicated sample preparation, or even keeping the sample environment close to the natural state. PMID- 22227097 TI - Features of the retinal environment which affect the activities and product profile of cholesterol-metabolizing cytochromes P450 CYP27A1 and CYP11A1. AB - The retina is the sensory organ in the back of the eye which absorbs and converts light to electrochemical impulses transferred to the brain. Herein, we studied how retinal environment affects enzyme-mediated cholesterol removal. We focused on two mitochondrial cytochrome P450 enzymes, CYPs 27A1 and 11A1, which catalyze the first steps in metabolism of cholesterol in the retina and other tissues. Phospholipids (PL) from mitochondria of bovine neural retina, retinal pigment epithelium, liver and adrenal cortex were isolated and compared for the effect on kinetic properties of purified recombinant CYPs in the reconstituted system in vitro. The four studied tissues were also evaluated for the mitochondrial PL and cholesterol content and levels of CYPs 27A1, 11A1 and their redox partners. The data obtained were used for modeling the retinal environment in the in vitro enzyme assays in which we detected the P450 metabolites, 22R-hydroxycholesterol and 5-cholestenoic acid, unexpectedly found by us in the retina in our previous studies. The effect of the by-product of the visual cycle pyridinium bis-retinoid A2E on kinetics of CYP27A1-mediated cholesterol metabolism was also investigated. The results provide insight into the retina's regulation of the enzyme-mediated cholesterol removal. PMID- 22227098 TI - Binding to retinoblastoma pocket domain does not alter the inter-domain flexibility of the J domain of SV40 large T antigen. AB - Simian Virus 40 uses the large T antigen (Tag) to bind and inactivate retinoblastoma tumor suppressor proteins (Rb), which can result in cellular transformation. Tag is a modular protein with four domains connected by flexible linkers. The N-terminal J domain of Tag is necessary for Rb inactivation. Binding of Rb is mediated by an LXCXE consensus motif immediately C-terminal to the J domain. Nuclear magnetic resonance (NMR) and small angle X-ray scattering (SAXS) were used to study the structural dynamics and interaction of Rb with the LXCXE motif, the J domain and a construct (N(260)) extending from the J domain through the origin binding domain (OBD). NMR and SAXS data revealed substantial flexibility between the domains in N(260). Binding of pRb to a construct containing the LXCXE motif and the J domain revealed weak interactions between pRb and the J domain. Analysis of the complex of pRb and N(260) indicated that the OBD is not involved and retains its dynamic independence from the remainder of Tag. These results support a 'chaperone' model in which the J domain of Tag changes its orientation as it acts upon different protein complexes. PMID- 22227099 TI - Structural aspects of human leukocyte antigen class I epitopes detected by human monoclonal antibodies. AB - This study addresses the concept that human leukocyte antigen (HLA) class I specific alloantibodies are specific for epitopes that correspond to HLAMatchmaker-defined eplets. Eplets are essential parts of so-called structural epitopes that make contact with the 6 complementarity determining regions of an antibody. From published molecular models of crystallized protein antigen antibody complexes, we have calculated that contact residues on structural HLA epitopes should reside within a 15-A radius of a mismatched eplet. This study addresses the structural basis of high-frequency HLA class I epitopes reacting with human monoclonal antibodies (mAbs) derived from women sensitized during pregnancy. All mAbs were tested in Luminex assays with single HLA allele panels. The HLAMatchmaker algorithm was used to determine their specificity in context with eplet sharing between the immunizing allele and antibody-reactive alleles. To assess the autoreactive B cell origin of these antibodies, we have applied the recently developed nonself-self paradigm of epitope immunogenicity to analyze residue differences between the immunizer and the alleles of the antibody producer. A total of 9 mAbs were specific for epitopes associated with the 41T, 80NRG, 163LW, 69AA, or 80ERILR eplets. In each case, the immunizing allele had within 15 A of the mismatched eplet, no residue differences with 1 of the alleles of the antibody producer. This observation is consistent with the concept that these mAbs originated from B cells with self HLA immunoglobulin receptors. Eplet carrying alleles exhibited different levels of reactivity, which, when compared with the immunizing allele, ranged from high to intermediate to very low. In many cases, lower reactivities were associated with differences from self to nonself residues in surface locations within 15 A of the specific eplet. Apparently, such locations may serve as critical contact sites for the antibody. In other cases, other residue differences did not appear to affect binding with the antibody, suggesting that these locations do not play a major role in antibody binding. For these mAbs we did not obtain convincing evidence that residue differences in hidden positions below the molecular surface had significant effects on antibody binding. These findings have increased our understanding of the structural basis of the immunogenicity and antigenicity of HLA class I epitopes and provide a basis for interpreting HLA antibody reactivity patterns in Luminex assays with single alleles. PMID- 22227100 TI - Effects of Laminaria japonica on the physico-chemical and sensory characteristics of reduced-fat pork patties. AB - Reduced-fat pork patties produced with the addition of Laminaria japonica powder were evaluated for the chemical composition, cooking characteristics and sensory properties. Reduced-fat pork patties containing L. japonica powder had significantly higher moisture, ash, carbohydrate content, yellowness, and springiness than the control sample (P<0.05). Protein and fat contents, energy value, lightness, redness, cooking loss, reduction in diameter, reduction in thickness, hardness, gumminess, and chewiness of the regular-fat (20%) control samples were significantly higher than reduced-fat pork patties containing L. japonica (P<0.05). The sensory evaluations indicated that the greatest overall acceptability in reduced-fat pork patties was attained at a L. japonica concentration of 1 or 3%. Pork patties with fat contents reduced from 20% to 10% and supplemented with 1 or 3% L. japonica had improved quality characteristics that were similar to the control patties containing a fat content of 20%. PMID- 22227101 TI - Ephrin-B2 and ephrin-B3 as functional henipavirus receptors. AB - Members of the ephrin cell-surface protein family interact with the Eph receptors, the largest family of receptor tyrosine kinases, mediating bi directional signaling during tumorogenesis and various developmental events. Surprisingly, ephrin-B2 and -B3 were recently identified as entry receptors for henipaviruses, emerging zoonotic paramyxoviruses responsible for repeated outbreaks in humans and animals in Australia, Southeast Asia, India and Bangladesh. Nipah virus (NiV) and Hendra virus (HeV) are the only two identified members in the henipavirus genus. While the initial human infection cases came from contact with infected pigs (NiV) or horses (HeV), in the more recent outbreaks of NiV both food-borne and human-to-human transmission were reported. These characteristics, together with high mortality and morbidity rates and lack of effective anti-viral therapies, make the henipaviruses a potential biological agent threat. Viral entry is an important target for the development of anti viral drugs. The entry of henipavirus is initiated by the attachment of the viral G envelope glycoprotein to the host cell receptors ephrin-B2 and/or -B3, followed by activation of the F fusion protein, which triggers fusion between the viral envelop and the host membrane. We review recent progress in the study of henipavirus entry, particularly the identification of ephrins as their entry receptors, and the structural characterization of the ephrin/Henipa-G interactions. PMID- 22227102 TI - Monoterpenic aldehydes as potential anti-Leishmania agents: activity of Cymbopogon citratus and citral on L. infantum, L. tropica and L. major. AB - In order to contribute for the search of new drugs for leishmaniasis, we study the susceptibility of Leishmania infantum, Leishmania tropica and Leishmania major to Cymbopogon citratus essential oil and major compounds, mrycene and citral. C. citratus and citral were the most active inhibiting L. infantum, L. tropica and L. major growth at IC(50) concentrations ranging from 25 to 52 MUg/ml and from 34 to 42 MUg/ml, respectively. L. infantum promastigotes exposed to essential oil and citral underwent considerable ultrastructural alterations, namely mitochondrial and kinetoplast swelling, autophagosomal structures, disruption of nuclear membrane and nuclear chromatin condensation. C. citratus essential oil and citral promoted the leishmanicidal effect by triggering a programmed cell death. In fact, the leishmanicidal activity was mediated via apoptosis as evidenced by externalization of phosphatidylserine, loss of mitochondrial membrane potential, and cell-cycle arrest at the G(0)/G(1) phase. Taken together, ours findings lead us to propose that citral was responsible for anti-Leishmania activity of the C. citratus and both may represent a valuable source for therapeutic control of leishmaniasis. PMID- 22227103 TI - Information routing in the basal ganglia: highways to abnormal connectivity in autism?: Comment on "Disrupted cortical connectivity theory as an explanatory model for autism spectrum disorders" by Kana et al. PMID- 22227104 TI - Low concentrations of bisphenol a suppress thyroid hormone receptor transcription through a nongenomic mechanism. AB - Bisphenol (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Various rodent and in vitro studies have shown that thyroid hormone (TH) function can be impaired by BPA. However, it is still unknown if low concentrations of BPA can suppress the thyroid hormone receptor (TR) transcription. The present study aims to investigate the possible suppressing effects of low concentrations of BPA on TR transcription and the involved mechanism(s) in CV-1 cells derived from cercopithecus aethiops monkey kidneys. Using gene reporter assays, BPA at concentrations as low as 10(-9)M suppresses TR or steroid receptor coactivator 1(SRC-1)-enhanced TR transcription, but not reducing TR/SRC-1 interaction in mammalian two-hybrid and glutathione S-transferase pull-down studies. It has been further shown that both nuclear receptor co-repressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) are recruited to the TR-beta1 by BPA in the presence of physiologic concentrations of T3 or T4. However, the overexpression of beta3 integrin or c-Src significantly reduces BPA induced recruitment of N-CoR/SMRT to TR or suppression of TR transcription. Furthermore, BPA inhibits the T3/T4-mediated interassociation of the beta3 integrin/c-Src/MAPK/TR-beta1 pathways by the co-immunoprecipitation. These results indicate that low concentrations of BPA suppress the TR transcription by disrupting physiologic concentrations of T3/T4-mediated beta3 integrin/c Src/MAPK/TR-beta1 pathways, followed by recruiting N-CoR/SMRT to TR-beta1, providing a novel insight regarding the TH disruption effects of low concentration BPA. PMID- 22227105 TI - Influence of sub-lethal antioxidant doses, water potential and temperature on growth, sclerotia, aflatoxins and aflD (=nor-1) expression by Aspergillus flavus RCP08108. AB - Effects of interacting conditions of sub-lethal levels of antioxidants, water potential (Psi) and temperature were evaluated on growth, sclerotial characteristics, aflatoxin B(1) (AFB(1)) production and aflD (=nor-1) gene expression by Aspergillus flavus strain RCP08108. These studies were carried out on peanut meal extract agar osmotically modified to -2.8,-7.1, -9.9 and -16.0 MPa and incubated at 28 and 20 degrees C. The food grade antioxidants added were butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) at (1+1 mM-M1) and (5+5 mM-M2). To relate the aflD expression after toxigenic A. flavus grew under interacting stress conditions, real-time PCR was used. Antioxidant mixtures caused a higher and significant (p<0.001) reduction in growth rate. The major impact on size and volume sclerotia was produced by Psi; followed by antioxidant mixtures. High AFB(1) levels were observed in response to the M1 applied at -7.1 MPa. Induction of the aflD gene was observed in response to the M1 treatment at 2.8, -7.1 and -9.9 MPa; but significant decreases of AFB(1) production and aflD transcripts were observed; when the fungus grew in the presence of the M2 treatment. These results showed that it is necessary to apply food-grade antioxidants into the peanut storage system at levels higher than 5 mM. This is an important tool to avoid sub-lethal antioxidant doses that can lead to fungal growth, increase resistance structures, and stimulate aflD gene expression and AFB(1) accumulation in this substrate. PMID- 22227106 TI - Expert opinion of the risk factors for morbidity and mortality in blunt chest wall trauma: results of a national postal questionnaire survey of Emergency Departments in the United Kingdom. AB - OBJECTIVE: Blunt chest wall trauma is a common injury treated in the Emergency Departments and has a high reported morbidity and mortality. No national guidelines exist for the management of this patient group unless the patient has severe immediate life-threatening injuries. The aim of this study was to investigate current management of blunt chest wall trauma patients in the UK and to gather expert opinion of the risk factors for morbidity and mortality. METHODOLOGY: A sample of 100 physicians working in Emergency Departments in the UK were purposively selected and sent a postal questionnaire to complete. Non responder analysis was undertaken in order to assess bias. The completed questionnaires were analysed with descriptive statistics. RESULTS: A response rate of 90% was achieved. The different type of hospital providing emergency care was well represented in the results. The general surgical team was the most frequently used ward-based team when the patient required admission to hospital (51%). Inconsistencies exist regarding the use of guidelines for the management of the blunt chest wall patient. The risk factors for morbidity and mortality suggested by the sample concurred with current literature including patient age, pre-existing conditions and number of ribs fractured and areas for further research were highlighted. CONCLUSION: Variation exists in the management of blunt chest wall trauma patients in the UK. This study provides the expert opinion of a sample of 90 physicians working in Emergency Departments in the UK regarding the risk factors for morbidity and mortality in blunt chest wall trauma patients. PMID- 22227108 TI - Characterization of the PEG layer of sterically stabilized liposomes: a SAXS study. AB - Synchrotron small-angle X-ray scattering analysis of the bilayer structure of a pharmacologically relevant sterically stabilized liposome system is presented. Describing the electron density profile of the bilayer with the superposition of Gaussian functions, the contribution of the poly(ethylene glycol) (PEG) layers to the total electron density was identified. The changes in the thickness of the PEG layer as well as the distribution of the PEG chains among the outer and inner leaflets of the bilayers were followed by changing the molar ratio of the PEG lipid and the molar weight of the PEG molecule. PMID- 22227107 TI - Combined posteroanterior fusion versus transforaminal lumbar interbody fusion (TLIF) in thoracolumbar burst fractures. AB - BACKGROUND: The optimal treatment strategy for burst fractures of the thoracolumbar junction is discussed controversially in the literature. Whilst 360 degrees fusion has shown to result in better radiological outcome, recent studies have failed to show its superiority concerning clinical outcome. The morbidity associated with the additional anterior approach may account for these findings. The aim of this prospective observational study was therefore to compare two different techniques for 360 degrees fusion in thoracolumbar burst fractures using either thoracoscopy or a transforaminal approach (transforaminal lumbar interbody fusion (TLIF)) to support the anterior column. METHODS: Posterior reduction and short-segmental fixation using angular stable pedicle screw systems were performed in all patients as a first step. Monocortical strut grafts were used for the anterior support in the TLIF group, whilst tricortical grafts or titanium vertebral body replacing implants of adjustable height were used in the combined posteroanterior group. At final follow-up, the radiological outcome was assessed by performing X-rays in a standing position. The clinical outcome was measured using five validated outcome scores. The morbidity associated with the approaches and the donor site was assessed as well. RESULTS: There were 21 patients in the TLIF group and 14 patients in the posteroanterior group included. The postoperative loss of correction was higher in the TLIF group (4.9 degrees +/-8.3 degrees versus 3.4 degrees +/-6.4 degrees , p>0.05). There were no significant differences regarding the outcome scores between the two groups. There were no differences in terms of return to employment, leisure activities and back function either. More patients suffered from donor-site morbidity in the TLIF group, whilst the morbidity associated with the surgical approach was higher in the posteroanterior group. CONCLUSION: The smaller donor site morbidity in the posteroanterior group is counterbalanced by an additional morbidity associated with the anterior approach resulting in similar clinical outcome. Mastering both techniques will allow the spine surgeon to be more flexible in specific situations, for example, in patients with neurological deficits or severe concomitant thoracic trauma. PMID- 22227109 TI - Phosphatidylglucoside: its structure, thermal behavior, and domain formation in plasma membranes. AB - Phosphatidylglucoside (PtdGlc) is a unique glyco-glycerophospholipid that is found in both bacterial and mammalian cells. The discovery of PtdGlc in mammalian cells is relatively recent (Nagatsuka et al., 2001. FEBS Lett. 497, 141-147). Chemical structural analysis of the PtdGlc found in mammalian organs and cultured cells showed that PtdGlc is composed exclusively of a single pair of saturated fatty acid chains; the sn-1 chain is stearic acid (C18:0) and the sn-2 chain is arachidic acid (C20:0). PtdGlc forms distinct domains, which are different from cholesterol-based sphingolipid domains, on the outer leaflet of the plasma membrane. In this review, we summarize recent studies of PtdGlc. Special attention is paid to the thermal behavior of PtdGlc in a pure system and in mixtures with other lipid components that may relate to the formation of PtdGlc domains in biomembranes. Finally, we discuss proposed biological functions of PtdGlc based on recent experimental results. PMID- 22227110 TI - Real-time imaging of lipid domains and distinct coexisting membrane protein clusters. AB - A detailed understanding of biomembrane architecture is still a challenging task. Many in vitro studies have shown lipid domains but much less information is known about the lateral organization of membrane proteins because their hydrophobic nature limits the use of many experimental methods. We examined lipid domain formation in biomimetic Escherichia coli membranes composed of phosphatidylethanolamine and phosphatidylglycerol in the absence and presence of 1% and 5% (mol/mol) membrane multidrug resistance protein, EmrE. Monolayer isotherms demonstrated protein insertion into the lipid monolayer. Subsequently, Brewster angle microscopy was applied to image domains in lipid matrices and lipid-protein mixtures. The images showed a concentration dependent impact of the protein on lipid domain size and shape and more interestingly distinct coexisting protein clusters. Whereas lipid domains varied in size (14-47MUm), protein clusters exhibited a narrow size distribution (2.6-4.8MUm) suggesting a non random process of cluster formation. A 3-D display clearly indicates that these proteins clusters protrude from the membrane plane. These data demonstrate distinct co-existing lipid domains and membrane protein clusters as the monofilm is being compressed and illustrate the significant mutual impact of lipid-protein interactions on lateral membrane architecture. PMID- 22227111 TI - The effectiveness of long-term psychoanalytic psychotherapy--a meta-analysis of randomized controlled trials. AB - The effectiveness of psychoanalysis and long-term psychoanalytic psychotherapy (LTPP) is debated. We evaluated the effectiveness of LTPP, compared to other treatments or no treatment, in patients with clearly defined metal disorders. We selected randomised or quasi-randomised controlled trials on LTPP. Two authors independently identified trials for inclusion. Eleven trials were eligible. The risk difference for recovery (primary outcome) at the longest available follow-up was 0.00 (95% CI: -0.17 to 0.17; p=0.96; I-squared: 58%). The combined Hedges' g, at the longest follow-up for each study, were: for target problems: -0.05 (95% CI -0.55 to 0.46; p=0.86; I-squared=88%); general psychiatric symptoms: 0.69 (95% CI -0.19 to 1.57; p=0.13; I-squared=96%); personality pathology: 0.17 (95% CI: -0.25 to 0.59; p=0.42; I-squared=41%); social functioning: 0.20 (95% CI -0.10 to 0.50; p=0.19; I-squared=53%); overall effectiveness: 0.33 (95% CI -0.31 to 0.96; p=0.32; I-squared=94%); and quality of life: -0.37 (95% CI: -0.78 to 0.04; p=0.08; I-squared=55%). A subgroup analysis of the domain target problem showed that LTPP did significantly better when compared to control treatments without a specialized psychotherapy component, but not when compared to various specialized psychotherapy control treatments. An exploratory meta-regression indicated that there might be a relation between the difference in treatment intensity between the intervention and control group (session ratio) and effect size. We came to conclude that the recovery rate of various mental disorders was equal after LTPP or various control treatments, including treatment as usual. The effect sizes of the individual trials varied substantially in direction and magnitude. In contrast to previous reviews, we found the evidence for the effectiveness of LTPP to be limited and at best conflicting. PMID- 22227112 TI - Pressor doses of vasopressin result in only transient elevations in plasma peptide levels. AB - We recently reported that neuronostatin, a novel neuropeptide, biphasically increased mean arterial pressure, first through the activation of the sympathetic nervous system followed by the release of vasopressin. In those experiments, we found that centrally administered neuronostatin increased plasma vasopressin levels only 2-3 times greater than levels observed in saline-treated controls, and that the increase in mean arterial pressure (approximately 15 mm Hg) could be blocked by pretreatment with a V1-vasopressin antagonist. Here we report the relationship between two to three fold elevations in plasma vasopressin levels and concomitant changes in mean arterial pressure in conscious, unrestrained male rats. We injected increasing doses of vasopressin (5, 20, and 100 ng/kg, intra arterially) and measured both changes in plasma vasopressin levels and the elevation in mean arterial pressure achieved. At 5-min post injection, plasma levels of vasopressin and mean arterial pressures were similar to those observed following central neuronostatin administration in our earlier study. Thus we conclude that small increases in circulating vasopressin levels can result in significant elevations in mean arterial pressure at least in the conscious rat. PMID- 22227113 TI - Dual probe DNA capture for sensitive real-time PCR detection of Cryptosporidium and Giardia. AB - Nucleic acid amplification for the enteropathogens Cryptosporidium and Giardia is complicated by low target template concentrations and PCR inhibitors. In this work we designed dual capture oligonucleotides for both Cryptosporidium and Giardia 18S rRNA targets which when utilized during DNA extraction from stool improved the limit of detection of our multiplex PCR assay by 1-2 logs, to as little as 10 cysts. When applied to clinical specimens, the method improved the real-time PCR C(T) by an average of 10.7 +/- 9.7 cycles. This work provides a highly sensitive protocol for Cryptosporidium and Giardia when limit of detection is of utmost importance. PMID- 22227114 TI - An assessment of genetic variability in the mitochondrial cytochrome c oxidase subunit 1 gene of Cercopithifilaria sp. (Spirurida, Onchocercidae) from dog and Rhipicephalus sanguineus populations. AB - This study investigates sequence variation in mitochondrial cytochrome c oxidase subunit 1 gene within Cercopithifilaria sp. recorded recently in Italy. Fourteen sequence types (haplotypes) were characterized for 163 (7.7%) amplicons from 2111 Genomic DNA samples prepared from skin samples from dogs and from Rhipicephalus sanguineus (ticks) from different geographical areas of the Mediterranean basin (i.e., Italy, Spain and Greece). The most prevalent sequence types represented haplotypes I (70.5%) and X (16.0%), followed by haplotype VIII (4.9%) and other 11 haplotypes (8.6%). Three haplotypes (II, V and VI) were found exclusively in ticks. The overall intraspecific nucleotide variation among pcox1 haplotypes ranged from 0.4 to 3.5% (mean = 1.6%), whereas a mean interspecific difference of 9.5% was detected as compared with other onchocercids. Phylogenetic analysis of the nucleotide sequence data showed a clustering of Cercopithifilaria sp. with the other Cercopithifilaria species (with strong statistical support) to the exclusion of other onchocercids. The number of haplotypes identified here might be explained by complex ecology and transmission patterns as well as the high mutation rate of mitochondrial DNA and/or inbreeding associated with hosts and their vectors. PMID- 22227117 TI - Muscle pain differentially modulates short interval intracortical inhibition and intracortical facilitation in primary motor cortex. AB - Excitability of the motor cortex can be suppressed during muscle pain. Yet the mechanisms are largely unknown. Short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were examined as possible candidate mechanisms to underpin this change. SICI and ICF were investigated in 11 healthy individuals before, during and after infusion of hypertonic saline into right first dorsal interosseous (FDI). Using paired-pulse transcranial magnetic stimulation (TMS), interstimulus intervals of 2, 3, and 13 ms were investigated. Pain intensity and quality were recorded using a 10-cm visual analogue scale and the McGill Pain Questionnaire. Resting motor threshold and motor-evoked potentials (MEPs) to single TMS stimuli were recorded before and after pain. Electromyographic recordings were made from right FDI and abductor digiti minimi. Participants reported an average pain intensity of 5.8 (1.6) cm. MEP amplitudes decreased in both muscles. Compared with the pre-pain condition, SICI was increased following pain, but not during. ICF was decreased both during and after pain when compared with the pre-pain condition. These findings suggest that muscle pain differentially modulates SICI and ICF. Although the functional relevance is unknown, we hypothesize decreased facilitation and increased inhibition may contribute to the restriction of movement of a painful body part. PERSPECTIVE: This article provides evidence for decreased intracortical facilitation and increased short interval intracortical inhibition in response to muscle pain. This finding is relevant to clinicians as a mechanism which may underlie restricted movement in acute and chronic pain. PMID- 22227115 TI - Structure and mechanism of the CMR complex for CRISPR-mediated antiviral immunity. AB - The prokaryotic clusters of regularly interspaced palindromic repeats (CRISPR) system utilizes genomically encoded CRISPR RNA (crRNA), derived from invading viruses and incorporated into ribonucleoprotein complexes with CRISPR-associated (CAS) proteins, to target and degrade viral DNA or RNA on subsequent infection. RNA is targeted by the CMR complex. In Sulfolobus solfataricus, this complex is composed of seven CAS protein subunits (Cmr1-7) and carries a diverse "payload" of targeting crRNA. The crystal structure of Cmr7 and low-resolution structure of the complex are presented. S. solfataricus CMR cleaves RNA targets in an endonucleolytic reaction at UA dinucleotides. This activity is dependent on the 8 nt repeat-derived 5' sequence in the crRNA, but not on the presence of a protospacer-associated motif (PAM) in the target. Both target and guide RNAs can be cleaved, although a single molecule of guide RNA can support the degradation of multiple targets. PMID- 22227118 TI - Investigation of the antiviral properties of copper iodide nanoparticles against feline calicivirus. AB - This study demonstrated the antiviral properties of copper iodide (CuI) nanoparticles against the non-enveloped virus feline calicivirus (FCV) as a surrogate for human norovirus. The effect of CuI nanoparticles on FCV infectivity to Crandell-Rees feline kidney (CRFK) cells was elucidated. The infectivity of FCV to CRFK cells was greatly reduced by 7 orders of magnitude at 1000MUgml(-1) CuI nanoparticles. At the conditions, electron spin resonance (ESR) analysis proved hydroxyl radical production in CuI nanoparticle suspension. Furthermore, amino acid oxidation in the viral capsid protein of FCV was determined by nanoflow liquid chromatography-mass spectrometric (nano LC-MS) analysis. The use of CuI nanoparticles showed extremely high antiviral activity against FCV. The high antiviral property of CuI nanoparticles was attributed to Cu(+), followed by ROS generation and subsequent capsid protein oxidation. CuI nanoparticles could be proposed as useful sources of a continuous supply of Cu(+) ions for efficient virus inactivation. Furthermore, this study brings new insights into toxic actions of copper iodide nanoparticles against viruses. PMID- 22227116 TI - Essential features and rational design of CRISPR RNAs that function with the Cas RAMP module complex to cleave RNAs. AB - Small RNAs target invaders for silencing in the CRISPR-Cas pathways that protect bacteria and archaea from viruses and plasmids. The CRISPR RNAs (crRNAs) contain sequence elements acquired from invaders that guide CRISPR-associated (Cas) proteins back to the complementary invading DNA or RNA. Here, we have analyzed essential features of the crRNAs associated with the Cas RAMP module (Cmr) effector complex, which cleaves targeted RNAs. We show that Cmr crRNAs contain an 8 nucleotide 5' sequence tag (also found on crRNAs associated with other CRISPR Cas pathways) that is critical for crRNA function and can be used to engineer crRNAs that direct cleavage of novel targets. We also present data that indicate that the Cmr complex cleaves an endogenous complementary RNA in Pyrococcus furiosus, providing direct in vivo evidence of RNA targeting by the CRISPR-Cas system. Our findings indicate that the CRISPR RNA-Cmr protein pathway may be exploited to cleave RNAs of interest. PMID- 22227119 TI - Multi-locus genotyping of bottom fermenting yeasts by single nucleotide polymorphisms indicative of brewing characteristics. AB - Yeast plays a capital role in brewing fermentation and has a direct impact on flavor and aroma. For the evaluation of competent brewing strains during quality control or development of novel strains it is standard practice to perform fermentation tests, which are costly and time-consuming. Here, we have categorized DNA markers which enable to distinguish and to screen brewing strains more efficiently than ever before. Sequence analysis at 289 loci in the genomes of six bottom fermenting Saccharomyces pastorianus strains revealed that 30 loci contained single nucleotide polymorphisms (SNPs). By determining the nucleotide sequences at the SNP-loci in 26 other S. pastorianus strains and 20 strains of the top fermenting yeast Saccharomyces cerevisiae, almost all these strains could be discriminated solely on the basis of the SNPs. By comparing the fermentative phenotypes of these strains we found that some DNA markers showed a strong association with brewing characteristics, such as the production of ethyl acetate and hydrogen sulphide (H2S). Therefore, the DNA markers we identified will facilitate quality control and the efficient development of brewing yeast strains. PMID- 22227120 TI - Growth control of genetically modified cells using an antibody/c-Kit chimera. AB - Gene therapy has been regarded as an innovative potential treatment against serious congenital diseases. However, applications of gene therapy remain limited, partly because its clinical success depends on therapeutic gene transduced cells acquiring a proliferative advantage. To address this problem, we have developed the antigen-mediated genetically modified cell amplification (AMEGA) system, which uses chimeric receptors to enable the selective proliferation of gene-transduced cells. In this report, we describe mimicry of c Kit signaling and its application to the AMEGA system. We created an antibody/c Kit chimera in which the extracellular domain of c-Kit is replaced with an anti fluorescein single-chain Fv antibody fragment and the extracellular D2 domain of the erythropoietin receptor. A genetically modified mouse pro-B cell line carrying this chimera showed selective expansion in the presence of fluorescein conjugated BSA (BSA-FL) as a growth inducer. By further engineering the transmembrane domain of the chimera to reduce interchain interaction we attained stricter ligand-dependency. Since c-Kit is an important molecule in the expansion of hematopoietic stem cells (HSCs), this antibody/c-Kit chimera could be a promising tool for gene therapy targeting HSCs. PMID- 22227122 TI - Possible multifactorial etiology of isolated microtia/anotia--a population-based study. AB - OBJECTIVE: To test the possible multifactorial-threshold model in the origin of isolated microtia/anotia (IMA). METHOD: The observed number of IMA in the first degree relatives of cases affected was compared with the expected number of affected first degree relatives based on the multifactorial-threshold model in the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. RESULTS: Of 354 cases with IMA, 14 (4.0%) had the affected first degree relatives with IMA. There was a low and similar rate of familial occurrence of IMA in parents and siblings of cases. The observed numbers of affected first degree relatives of cases with IMA and their expected numbers did not show significant difference (p=0.47). Some other findings (e.g. male excess and the interaction of triggering environmental factors with polygenic predisposition) confirmed this hypothesis. CONCLUSIONS: The familial pattern of cases with IMA does not reject the hypothesis that the multifactorial threshold model, i.e. gene-environmental interaction, may be the explanation for the origin of this congenital abnormality group, although the number of familial cases was quite small in the study. PMID- 22227121 TI - Evaluation of cochlear function using transient evoked otoacoustic emission in children with Familial Mediterranean Fever. AB - OBJECTIVE: The aim of this study was to investigate cochlear functions in children with Familial Mediterranean Fever (FMF). METHODS: Fifty-six FMF patients (112 ears) and 30 healthy control subjects (60 ears) were included in the study. Transient evoked otoacoustic emission (TEOAE) was investigated. Numerical measurements of TEOAE, except the correlation percentage (%), included response amplitude (dB) and signal/noise (SN) ratio. RESULTS: There was no statistically significant difference in age and sex in the two groups. Mean TEOAE correlation percentage, signal/noise ratio, TEOAE amplitudes in 1, 1.5, 2, 3 and 4 Hz frequency values were not different between the two groups (p>0.05). CONCLUSIONS: In this study using the TEOAE test, we found that FMF did not cause outer cell hair damage in children. In the literature, there is no study on outer cell hair damage in children or adults with FMF, so this is the first investigational study. PMID- 22227123 TI - Vaccinia virus-induced smallpox postvaccinal encephalitis in case of blood-brain barrier damage. AB - Smallpox vaccination is the only currently effective mean to combat the threat of variola virus used as a bioterrorism agent, although it is responsible for a rare but serious complication, the postvaccinal encephalitis (PVE). Development of safer vaccines therefore is a high priority as the PVE physiopathology is not well understood to date. If vaccinia virus (VACV) is responsible for PVE by central nervous system (CNS) dissemination, trans-migration of the VACV across the blood-brain barrier (BBB) would be supposed to be essential. Given the complexity of the pathogenesis of vaccinia neurovirulence, an in vitro BBB model was used to explore the mechanism of VACV to induce BBB permeability. Two VACV strains were studied, the neurovirulent Western Reserve strain (VACV-WR) and the vaccine reference Lister strain (VACV-List). A mouse model was also developed to study the ability of these two viral strains to propagate in the brain from the blood compartment, their neurovirulence and their neuropathogenesis. In vitro, the loss of permeability resulted from the tight-junctions disruption was induced by virus replication. The ability of VACV to release infectious particles at the abluminal side suggests the capacity of both VACV strains to migrate across the BBB from the blood to the CNS. In vivo, the virus replication in mice CNS was strain-dependent. The VACV-WR laboratory strain proved to be neuroinvasive and neurovirulent, whereas the VACV-List strain is safe in physiological conditions. Mice PVE was observed only with VACV-WR in the co-infection model, when BBB opening was obtained by lipopolysaccharide (LPS) treatment. This study suggests that VACV is able to cross the BBB but encephalitis occurs only in the presence of a co-infection by bacteria. So, a model of co-infection, mimicked by LPS treatment, could have important implication towards the assessment of neurovirulence of new vaccines. PMID- 22227124 TI - Wave intensity analysis of para-aortic counterpulsation. AB - Wave intensity analysis (WIA) was used to delineate and maximize the efficacy of a newly developed para-aortic blood pump (PABP). The intra-aortic balloon pump (IABP) was employed as the comparison benchmark. Acute porcine experiments using eight pigs, randomly divided into IABP (n = 4) and PABP (n = 4) groups, were conducted to compare the characteristics of intra- and para-aortic counterpulsation. We measured pressure and velocity with probes installed in the left anterior descending coronary artery and aorta, during and without PABP assistance. Wave intensity for aortic and left coronary waves were derived from pressure and flow measurements with synchronization correction applied. To achieve maximized support efficacy, deflation timings ranging from 25 ms ahead of to 35 ms after the R-wave were tested. Similar to those associated with IABP counterpulsation, the PABP-generated backward-traveling waves predominantly drove aortic and coronary blood flows. However, in contrast with IABP counterpulsation, the nonocclusive nature of the PABP allowed systolic unloading to be delayed into early systole, which resulted in near elimination of coronary blood steal without diminution of systolic left ventricular ejection wave intensities. WIA can elucidate subtleties among different counterpulsatile support means with high sensitivity. Total accelerating wave intensity (TAWI), which was defined as the sum of the time integration of accelerated parts of the positive and negative wave intensities, was used to quantify counterpulsation efficacy. In general, the larger the TAWI gain, the better the counter-pulsatile support efficacy. However, when PABP deflation timings were delayed to after the R-wave, the TAWI was found to be inversely correlated with coronary perfusion. In this delayed deflation timing setting, greater wave cancellation occurred, which led to decreased TAWI but increased coronary perfusion attributed to blood regurgitation reduction. PMID- 22227125 TI - Cannabinoid receptor CB2 protects against balloon-induced neointima formation. AB - Cannabinoid receptor CB(2) activation inhibits inflammatory proliferation and migration of vascular smooth muscle cells in vitro. The potential in vivo relevance of these findings is unclear. We performed carotid balloon distension injury in hypercholesterolemic apolipoprotein E knockout (ApoE(-/-)) mice receiving daily intraperitoneal injection of the CB(2) agonist JWH133 (5 mg/kg) or vehicle, with the first injection given 30 min before injury. Alternatively, we subjected CB(2)(-/-) and wild-type (WT) mice to balloon injury. We determined CB(2) mRNA and protein expression in dilated arteries of ApoE(-/-) mice. Neointima formation was assessed histologically. We used bone marrow-derived murine CB(2)(-/-) and WT macrophages to study adhesion to plastic, fibronectin, or collagen, and migration was assayed by modified Boyden chamber. Aortic smooth muscle cells were isolated to determine in vitro proliferation rates. We found increased vascular CB(2) expression in ApoE(-/-) mice in response to balloon injury. Seven to twenty-one days after dilatation, injured vessels of JWH133 treated mice had less intimal nuclei numbers as well as intimal and medial areas, associated with less staining for proliferating cells, smooth muscle cells, and macrophages. Complete endothelial repair was observed after 14 days in both JWH133- and vehicle-treated mice. CB(2) deficiency resulted in increased intima formation compared with WT, whereas JWH133 did not affect intimal formation in CB(2)(-/-) mice. Apoptosis rates assessed by in situ terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining 1 h postballooning were significantly higher in the CB(2) knockouts. In vitro, bone marrow-derived CB(2)( /-) macrophages showed enhanced adherence and migration compared with WT cells and elevated mRNA levels of adhesion molecules, chemokine receptors CCR1 and 5, and chemokine CCL2. Proliferation rates were significantly increased in CB(2)(-/ ) smooth muscle cells compared with WT. In conclusion, pharmacological activation or genetic deletion of CB(2) receptors modulate neointima formation via protective effects in macrophages and smooth muscle cells. PMID- 22227127 TI - Intermedin elicits a negative inotropic effect in rat papillary muscles mediated by endothelial-derived nitric oxide. AB - Intermedin (IMD) is a novel vasoactive peptide from the calcitonin gene-related peptide (CGRP) implicated in cardiac regulation, yet the contractile effects of IMD remain controversial, since previous studies in vivo and isolated cardiomyocytes documented contradictory results. We hypothesized cardiac endothelial cells involvement in IMD modulation of cardiac function as an explanation for these opposing observations. With this in mind, we investigated the direct action of increasing concentrations of IMD (10(-8) to 10(-6)M) on myocardial performance parameters in rat left ventricular (LV) papillary muscles with and without endocardial endothelium (EE) and in presence of receptor antagonists and intracellular pathways inhibitors. In LV papillary muscles with intact EE, IMD induced a concentration-dependent negative inotropic action (%decrease relative to baseline, at IMD concentration of 10(-6)M, active tension of 14 +/- 4%, and maximum velocity of tension rise of 10 +/- 4%). These effects were blunted by EE removal, AM receptor antagonist (AM(22-52)), and CGRP receptor antagonist (CGRP(8-37)). Additionally, nitric oxide (NO) synthase inhibition with N(G)-nitro-l-arginine (l-NAME) in muscles with and without EE and guanylyl cyclase inhibition with {1H-[1,2,4]oxadiazole-[4,4-a]-quinoxalin-1-one} not only blunted the negative inotropic action of IMD but also unmasked IMD-positive inotropic effect dependent on CGRP receptor PKA activation. Western blot quantification of phosphorylated cardiac troponin I (P-cTnI) in IMD-treated papillary muscles revealed a significant increase in P-cTnI when compared with untreated muscles, while in l-NAME-pretreated papillary muscles IMD failed to increase P-cTnI. Finally, we found that stimulation of both EE and microvascular endothelial cells with IMD significantly increased NO production by 40 +/- 3 and 38 +/- 3%, respectively, suggesting the role of cardiac endothelial cells in NO production upon IMD stimulation. Our findings establish IMD negative inotropic effect in isolated myocardium due to NO/cGMP pathway activation with concomitant thin myofilament desensitization by increase in cTnI phosphorylation and provide a coherent explanation for the previously reported contradictory results. PMID- 22227128 TI - G protein-mediated stretch reception. AB - Mechanosensation and -transduction are important for physiological processes like the senses of touch, hearing, and balance. The mechanisms underlying the translation of mechanical stimuli into biochemical information by activating various signaling pathways play a fundamental role in physiology and pathophysiology but are only poorly understood. Recently, G protein-coupled receptors (GPCRs), which are essential for the conversion of light, olfactory and gustatory stimuli, as well as of primary messengers like hormones and neurotransmitters into cellular signals and which play distinct roles in inflammation, cell growth, and differentiation, have emerged as potential mechanosensors. The first candidate for a mechanosensitive GPCR was the angiotensin-II type-1 (AT(1)) receptor. Agonist-independent mechanical receptor activation of AT(1) receptors induces an active receptor conformation that appears to differ from agonist-induced receptor conformations and entails the activation of G proteins. Mechanically induced AT(1) receptor activation plays an important role for myogenic vasoconstriction and for the initiation of cardiac hypertrophy. A growing body of evidence suggests that other GPCRs are involved in mechanosensation as well. These findings highlight physiologically relevant, ligand-independent functions of GPCRs and add yet another facet to the polymodal activation spectrum of this ubiquitous protein family. PMID- 22227126 TI - The renin-angiotensin system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome. AB - The renin-angiotensin system (RAS) is an important therapeutic target in the treatment of hypertension. Obesity has emerged as a primary contributor to essential hypertension in the United States and clusters with other metabolic disorders (hyperglycemia, hypertension, high triglycerides, low HDL cholesterol) defined within the metabolic syndrome. In addition to hypertension, RAS blockade may also serve as an effective treatment strategy to control impaired glucose and insulin tolerance and dyslipidemias in patients with the metabolic syndrome. Hyperglycemia, insulin resistance, and/or specific cholesterol metabolites have been demonstrated to activate components required for the synthesis [angiotensinogen, renin, angiotensin-converting enzyme (ACE)], degradation (ACE2), or responsiveness (angiotensin II type 1 receptors, Mas receptors) to angiotensin peptides in cell types (e.g., pancreatic islet cells, adipocytes, macrophages) that mediate specific disorders of the metabolic syndrome. An activated local RAS in these cell types may contribute to dysregulated function by promoting oxidative stress, apoptosis, and inflammation. This review will discuss data demonstrating the regulation of components of the RAS by cholesterol and its metabolites, glucose, and/or insulin in cell types implicated in disorders of the metabolic syndrome. In addition, we discuss data supporting a role for an activated local RAS in dyslipidemias and glucose intolerance/insulin resistance and the development of hypertension in the metabolic syndrome. Identification of an activated RAS as a common thread contributing to several disorders of the metabolic syndrome makes the use of angiotensin receptor blockers and ACE inhibitors an intriguing and novel option for multisymptom treatment. PMID- 22227129 TI - Identification of residues involved in water versus glycerol selectivity in aquaporins by differential residue pair co-evolution. AB - Aquaporins (AQPs) are members of the Major Intrinsic Protein (MIP) family that can transport water or glycerol, as well as other compounds. The rationale for substrate selectivity at the structural level is still incompletely understood. The information present in multiple sequence alignments (MSAs) can help identify both structural and functional features, especially the complex networks of interactions responsible for water or glycerol selectivity. Herein, we have used the method of Statistical Coupling Analysis (SCA) to identify co-evolving pairs of residues in two separate groups of sequences predicted to correspond to water or glycerol transporters. Differentially co-evolved pairs between the two groups were tested by their efficacy in correctly classifying a training set of MSAs, and binary classifiers were built with these pairs. Up to 50% of the residues found in hundreds of binary classifiers corresponded to only ten positions in the MSA of aquaporins. Most of these residues are close to the lining of the aquaporin pore and have been identified previously as important for selectivity. Therefore, this method can shed light on the residues that are important for substrate selectivity of aquaporins and other proteins. SCA requires a very large sequence dataset with relatively low homology amongst its members, and these requirements are met by aquaporins. PMID- 22227130 TI - Oxygen metabolism, oxygen extraction and positron emission tomography: Historical perspective and impact on basic and clinical neuroscience. AB - Oxygen utilization is central to the human brain's high metabolic rate. Measurement of this fundamental process, in both disease and health, has been a focus of research attention over the last 35 years. This review plots the course of the use of oxygen-15 to study regional cerebral oxygen extraction and metabolism using Positron Emission Tomography (PET) in disease and in health. The scientific discoveries and resulting conceptual changes to both basic and clinical neuroscience, as well as the new methodological approaches brought about by this area of research, are also summarized. We conclude with a brief overview of the current status of oxygen-15 PET in neuroscience, along with our visions for future developments and applications. PMID- 22227131 TI - Cortico-subthalamic white matter tract strength predicts interindividual efficacy in stopping a motor response. AB - The subthalamic nucleus (STN) is a small but vitally important structure in the basal ganglia. Because of its small volume, and its localization in the basal ganglia, the STN can best be visualized using ultra-high resolution 7 Tesla (T) magnetic resonance imaging (MRI). In the present study, first we individually segmented 7 T MRI STN masks to generate atlas probability maps. Secondly, the individually segmented STN masks and the probability maps were used to derive cortico-subthalamic white matter tract strength. Tract strength measures were then taken to test two functional STN hypotheses which account for the efficiency in stopping a motor response: the right inferior fronto-subthalamic (rIFC-STN) hypothesis and the posterior medial frontal cortex-subthalamic (pMFC-STN) hypothesis. Results of two independent experiments show that increased white matter tract strength between the pMFC and STN results in better stopping behaviour. PMID- 22227133 TI - Imaging first impressions: distinct neural processing of verbal and nonverbal social information. AB - First impressions profoundly influence our attitudes and behavior toward others. However, little is known about whether and to what degree the cognitive processes that underlie impression formation depend on the domain of the available information about the target person. To investigate the neural bases of the influence of verbal as compared to nonverbal information on interpersonal judgments, we identified brain regions where the BOLD signal parametrically increased with increasing strength of evaluation based on either short text vignettes or mimic and gestural behavior. While for verbal stimuli the increasing strength of subjective evaluation was correlated with increased neural activation of precuneus and posterior cingulate cortex (PC/PCC), a similar effect was observed for nonverbal stimuli in the amygdala. These findings support the assumption that qualitatively different cognitive operations underlie person evaluation depending upon the stimulus domain: while the processing of nonverbal person information may be more strongly associated with affective processing as indexed by recruitment of the amygdala, verbal person information engaged the PC/PCC that has been related to social inferential processing. PMID- 22227132 TI - Imaging attention networks. AB - The study of attention has largely been about how to select among the various sensory events but also involves the selection among conflicting actions. Prior to the late 1980s, locating bottlenecks between sensory input and response dominated these studies, a different view was that attentional limits involved the importance of maintaining behavioral coherence rather than resulting from a bottleneck. In both cases ideas of resource limits taken over from economics were important. Early evidence relating to the anatomy of attention came from neurological investigations of lesioned patients, but the major impetus for the anatomical approach came from neuroimaging studies that provided evidence of brain networks related to orienting to sensory events and control of response tendencies. The presence of a functional anatomy has supported studies of the development of attention networks and the role of neuromodulators and genetic polymorphisms in their construction. Together these developments have enhanced our understanding of attention and paved the way for significant applications to education, pathology and prevention of mental illness. PMID- 22227134 TI - Neural correlates of performance variability during motor sequence acquisition. AB - During the initial training of a motor sequence, performance becomes progressively faster but also increasingly reproducible and consistent. However, performance temporarily becomes more variable at mid-training, reflecting a change in the motor representation and the eventual selection of the optimal performance mode (Adi-Japha et al., 2008). At the cerebral level, whereas performance speed is known to be related to the activity in cerebello-cortical and striato-cortical networks, the neural correlates of performance variability remain unknown. We characterized the latter using functional magnetic resonance imaging (fMRI) during the initial training to the Finger Tapping Task (FTT), during which participants produced a 5-element finger sequence on a keyboard with their left non-dominant hand. Our results show that responses in the precuneus decrease whereas responses in the caudate nucleus increase as performance becomes more consistent. In addition, a variable performance is associated with enhanced interaction between the hippocampus and fronto-parietal areas and between the striatum and frontal areas. Our results suggest that these dynamic large-scale interactions represent a cornerstone in the implementation of consistent motor behavior in humans. PMID- 22227135 TI - The motor system and its disorders. AB - The motor system has been intensively studied using the emerging neuroimaging technologies over the last twenty years. These include early applications of positron emission tomography of brain perfusion, metabolic rate and receptor function, as well as functional magnetic resonance imaging, tractography from diffusion weighted imaging, and transcranial magnetic stimulation. Motor system research has the advantage of the existence of extensive electrophysiological and anatomical information from comparative studies which enables cross-validation of new methods. We review the impact of neuroimaging on the understanding of diverse motor functions, including motor learning, decision making, inhibition and the mirror neuron system. In addition, we show how imaging of the motor system has supported a powerful platform for bidirectional translational neuroscience. In one direction, it has provided the opportunity to study safely the processes of neuroplasticity, neural networks and neuropharmacology in stroke and movement disorders and offers a sensitive tool to assess novel therapeutics. In the reverse direction, imaging of clinical populations has promoted innovations in cognitive theory, experimental design and analysis. We highlight recent developments in the analysis of structural and functional connectivity in the motor system; the advantages of integration of multiple methodologies; and new approaches to experimental design using formal models of cognitive-motor processes. PMID- 22227136 TI - Towards the utilization of EEG as a brain imaging tool. AB - Recent advances in signal analysis have engendered EEG with the status of a true brain mapping and brain imaging method capable of providing spatio-temporal information regarding brain (dys)function. Because of the increasing interest in the temporal dynamics of brain networks, and because of the straightforward compatibility of the EEG with other brain imaging techniques, EEG is increasingly used in the neuroimaging community. However, the full capability of EEG is highly underestimated. Many combined EEG-fMRI studies use the EEG only as a spike counter or an oscilloscope. Many cognitive and clinical EEG studies use the EEG still in its traditional way and analyze grapho-elements at certain electrodes and latencies. We here show that this way of using the EEG is not only dangerous because it leads to misinterpretations, but it is also largely ignoring the spatial aspects of the signals. In fact, EEG primarily measures the electric potential field at the scalp surface in the same way as MEG measures the magnetic field. By properly sampling and correctly analyzing this electric field, EEG can provide reliable information about the neuronal activity in the brain and the temporal dynamics of this activity in the millisecond range. This review explains some of these analysis methods and illustrates their potential in clinical and experimental applications. PMID- 22227137 TI - The neurochemical profile quantified by in vivo 1H NMR spectroscopy. AB - Proton NMR spectroscopy is emerging from translational and preclinical neuroscience research as an important tool for evidence based diagnosis and therapy monitoring. It provides biomarkers that offer fingerprints of neurological disorders even in cases where a lesion is not yet observed in MR images. The collection of molecules used as cerebral biomarkers that are detectable by (1)H NMR spectroscopy define the so-called "neurochemical profile". The non-invasive quality of this technique makes it suitable not only for diagnostic purposes but also for therapy monitoring paralleling an eventual neuroprotection. The application of (1)H NMR spectroscopy in basic and translational neuroscience research is discussed here. PMID- 22227138 TI - Quantification of serotonin transporter availability with [11C]MADAM--a comparison between the ECAT HRRT and HR systems. AB - The High Resolution Research Tomograph (HRRT) is the PET system providing the highest resolution for imaging of the human brain. In this study, the improved quantitative performance of the HRRT was evaluated in comparison with a previously developed lower resolution PET system, the ECAT HR. The radioligand [(11)C]MADAM was chosen for the purpose since it provides a signal for serotonin transporter (5-HTT) binding in cortical and sub-cortical brain regions of different sizes and expressing different 5-HTT densities. A secondary objective was to assess the effect of partial volume effect (PVE) correction on the cross comparability between the two systems. METHOD: Six male control subjects (ages 20 35 yr) were examined twice using the HRRT and the HR system, respectively. Regions of interest (ROIs) included cortical regions (frontal cortex, temporal cortex, insula, anterior cingulate cortex, and hippocampus), sub-cortical regions (caudate, putamen, thalamus, dorsal brainstem and ventral midbrain) and cerebellum. The ROIs were manually delineated on T1-weighted MRI-images and subsequently applied to both HRRT and HR images. Regional binding potential (BP(ND)) values were calculated with the simplified reference tissue model (SRTM) using cerebellum as the reference region. The percent difference in BP(ND) between the systems was calculated for each ROI. In addition, both HRRT and HR data were corrected for PVE using established MRI-based methods described by Meltzer and Muller-Gartner. The effect of PVE correction (PVEc) on the agreement between the systems was assessed via percent difference calculation and linear regression analysis. RESULTS: Quantification with SRTM showed that regional BP(ND) values for [(11)C]MADAM were on average 23% higher for the HRRT than those obtained by the HR system. More specifically, BP(ND) measured with HRRT was 31.1+/-48.1% higher in neocortical/limbic regions and 14.6+/-20.9% higher in sub cortical regions. The effect of PVEc varied between regions. After correction according to Muller-Gartner, the agreement between systems was best in the neocortical/limbic regions (3.7+/-22.5%). With the exception of the caudate, in which the agreement was improved by approximately 17% using the Meltzer method, the effect of PVEc in sub-cortical regions was less pronounced. Linear regression analysis showed improved correlation between the two systems after PVEc, particularly in the neocortical/limbic regions. CONCLUSION: As expected, BP(ND) values measured with the HRRT were higher than those measured with the HR due to higher resolution and recovery. The difference in BP(ND) between the two systems was approximately 30% in the neocortical/limbic regions. PVEc improved the agreement between the systems in particular for the neocortical/limbic regions. In these regions, the best agreement was found after applying Muller-Gartner's PVEc. The demonstrated agreement provides an opportunity for combining data between the two systems in clinical studies aimed at evaluating receptor/transporter availability in cortical brain regions. PMID- 22227140 TI - Acupuncture--deep pain with an autonomic dimension? AB - Stimulation of acupuncture point Pc6, located above the median nerve, has been shown to be effective in treating nausea and vomiting. It has also frequently been reported to cause a heart rate reduction. The mechanism behind this autonomic reaction has not been clarified, so far. We combined brainstem sensitive functional magnetic resonance imaging with heart rate recording and time-resolved rating of the needling sensation to measure neuronal correlates of sensations and autonomic reactions during acupuncture. On the cortical level, needling sensation activated typical pain-related areas, of which the ventromedial and dorsolateral prefrontal cortex and perigenual anterior cingulate cortex were further involved in mediating the heart rate response. In the brainstem, needling sensation activated nuclei of the descending pain control system, in which a network of hypothalamus, periaqueductal gray, rostral ventromedial medulla, and ventrolateral medulla was identified as the source of the heart rate changes. Our findings indicate that acupuncture may be a special pain stimulus, whose autonomic concomitants could explain its non-analgesic effects and in some cases even have a therapeutic potential. PMID- 22227139 TI - Limbic responses to reward cues correlate with antisocial trait density in heavy drinkers. AB - Antisocial traits are common among alcoholics- particularly in certain subtypes. Although people with antisocial tendencies show atypical brain activation in some emotion and reward paradigms, how the brain reward systems of heavy drinkers (HD) are influenced by antisocial traits remains unclear. We used subjects' preferred alcohol drink odors (AO), appetitive (ApCO) and non-appetitive (NApO) control odors in functional magnetic resonance imaging (fMRI) to determine if reward system responses varied as a function of antisocial trait density (ASD). In this retrospective analysis, we examined 30 HD who had participated in imaging twice: once while exposed to clamped intravenous alcohol infusion targeted to 50mg%, and once during placebo saline infusion. Under placebo, there were positive correlations between ASD and blood oxygenation level dependent (BOLD) activation in the [AO>ApCO] contrast in the left dorsal putamen, while negative correlations were present in medial orbitofrontal cortex (OFC) and the bilateral amygdala. A similar pattern was observed in the correlation with the [AO>NApO] contrast. This inverse relationship between ASD and activation in OFC and amygdala was specific to AO. However, negative correlations between ASD and the [ApCO>NApO] contrast were also present in the insula, putamen, and medial frontal cortex. These data suggest that frontal and limbic reward circuits of those with significant ASD are less responsive to reward cues in general, and particularly to alcohol cues in medial OFC and amygdala. These findings are broadly consistent with the reward deficiency syndrome hypothesis, although positive correlation in the striatum suggests regional variability. PMID- 22227141 TI - Neural mechanisms underlying the conditioned diminution of the unconditioned fear response. AB - Recognizing cues that predict an aversive event allows one to react more effectively under threatening conditions, and minimizes the reaction to the threat itself. This is demonstrated during Pavlovian fear conditioning when the unconditioned response (UCR) to a predictable unconditioned stimulus (UCS) is diminished compared to the UCR to an unpredictable UCS. The present study investigated the functional magnetic resonance imaging (fMRI) signal response associated with Pavlovian conditioned UCR diminution to better understand the relationship between individual differences in behavior and the neural mechanisms of the threat-related emotional response. Healthy volunteers participated in a fear conditioning study in which trait anxiety, skin conductance response (SCR), UCS expectancy, and the fMRI signal were assessed. During acquisition trials, a tone (CS+) was paired with a white noise UCS and a second tone (CS-) was presented without the UCS. Test trials consisted of the CS+ paired with the UCS, CS- paired with the UCS, and presentations of the UCS alone to assess conditioned UCR diminution. UCR diminution was observed within the dorsolateral PFC, dorsomedial PFC, cingulate cortex, inferior parietal lobule (IPL), anterior insula, and amygdala. The threat-related activity within the dorsolateral PFC, dorsomedial PFC, posterior cingulate cortex, and IPL varied with individual differences in trait anxiety. In addition, anticipatory (i.e. CS elicited) activity within the PFC showed an inverse relationship with threat-related (i.e. UCS elicited) activity within the PFC, IPL, and amygdala. Further, the emotional response (indexed via SCR) elicited by the threat was closely linked to amygdala activity. These findings are consistent with the view that the amygdala and PFC support learning-related processes that influence the emotional response evoked by a threat. PMID- 22227142 TI - Ultrasound-assisted compatible in situ hydrolysis of sugarcane bagasse in cellulase-aqueous-N-methylmorpholine-N-oxide system for improved saccharification. AB - To fully exploit the benefits of N-methylmorpholine-N-oxide (NMMO) in lignocelluloses bioconversion, a compatible system was established for efficient in situ saccharification of cellulose in NMMO-aqueous media in which the NMMO is able to activate and solubilize the cellulose, and the cellulases possess high stability and activity. Cellulase retained its original activity after being pre incubated in 15% and 20% (w/v) NMMO solutions. After optimization of reaction parameters, high saccharification rate (96.5%) was obtained in aqueous-NMMO media by ultrasound assisted treatment of cellulose. The viscosity and FTIR analysis revealed that NMMO-treated cellulose under ultrasonic condition was porous and amorphous, which led to improved saccharification. The addition of trifle lignin in lower concentration improved the saccharification efficiency of sugarcane bagasse, while higher concentration interferes with hydrolysis. In conclusion, these findings provided great implications to develop a continuous process NMMO cellulases system for transformation of native biomass. PMID- 22227143 TI - Solid state bioconversion of wheat straw into digestible and nutritive ruminant feed by Ganoderma sp. rckk02. AB - Solid state fermentation (SSF) of wheat straw with Ganoderma sp. rckk02 was carried out for 15 days for improving its digestibility and nutrients. Fungal growth caused a significant (P<0.05) decrease in acid detergent fiber (ADF), neutral detergent fiber (NDF), hemicellulose, lignin and cellulose content till 15th day. In vitro gas production (IVGP) test revealed that 10th day fermented feed possessed higher metabolizable energy (ME: 4.87 MJ/kg), in vitro organic matter digestibility (OMD: 334 g/kg) and short chain fatty acids (SCFAs: 1.82 mmol/g Dry Matter). The fermented feed was also evaluated in vivo in goats fed with either untreated wheat straw (T1) or fungal treated straw (T2). Dry matter intake (DMI), digestible crude protein (DCP), total digestible nutrients (TDN) and nitrogen (N) intake were found significantly (P<0.05) increased in T2 group. The study shows that fermentation of wheat straw with Ganoderma sp. rckk02 holds potential in improving its nutritive value. PMID- 22227144 TI - Effect of inoculum to substrate ratio on the hydrolysis and acidification of food waste in leach bed reactor. AB - The aim of present study was to determine an appropriate ISR (inoculum to substrate ratio) to enhance the hydrolysis rate and reduce the solid retention time of food waste in hydrolytic-acidogenesis leach bed reactor (LBR). LBR 1-4 were inoculated with 0%, 5%, 20% and 80% (w/w basis) of anaerobically digested sludge, respectively, using artificial food waste as substrate. Experiments were conducted in batch mode at mesophilic condition (35 degrees C) for 17 days. Higher ISR resulted in 4.3-fold increase in protein hydrolysis; whereas, only a modest increase in the decomposition of carbohydrate. Two kinetic models for carbohydrate and protein degradation were proposed and evaluated. The differences among four ISRs in volatile solids removal efficiencies were marginal, i.e. 52.4%, 62.8%, 63.2% and 71.7% for LBR 1-4, respectively; indicating that higher ISR was insignificant in enhancing the overall hydrolysis rate in LBR. Therefore, a lower ISR of 20% was recommended in the hydrolytic-acidogenic process. PMID- 22227145 TI - Shift of pathways during initiation of thermophilic methanogenesis at different initial pH. AB - To investigate the metabolic pathways during the initiation of methanogenesis from acid crisis, the influence of initial pH (5.0-6.5) on thermophilic methanogenic conversion of 100mmol/L acetate was monitored based on the isotopic signature and selective-inhibition method combined with analysis of the microbial structure. The results showed, lower pH extended the lag phase for methanogenesis which was inhibited at pH5.0 throughout the incubation. At initial pH6.0-6.5, methanogenesis was primarily initiated via acetoclastic methanogenesis (AM), with the fraction of the hydrogenotrophic pathway (f(mc)) accounting for 21-22% of total methane formation. Conversely, at initial pH5.5, the dominant pathway shifted to syntrophic acetate oxidation coupled with hydrogenotrophic methanogenesis (SAO-HM), with f(mc) rising to 51% and the abundance of syntrophic acetate-oxidizing bacteria increasing remarkably. Methanogenesis could initiate independently via SAO-HM pathway when AM pathway was inhibited. Acetate-oxidizing syntrophs could function as the initiation center of methanogenesis from low-pH crisis. PMID- 22227146 TI - Vaccination coverage in Haiti: results from the 2009 national survey. AB - INTRODUCTION: Since 1977, vaccinations to protect against tuberculosis, diphtheria, tetanus, pertussis, polio, and measles (and rubella since 2009) have been offered to children in Haiti through the routine immunization program. From April to July 2009, a national vaccination coverage survey was conducted to assess the success of the routine immunization program at reaching children in Haiti. METHODS: A multi-stage cluster survey was conducted using a modified WHO method for household sampling. A standardized questionnaire was administered to collect vaccination histories, demographic information, and reasons for under vaccination of children aged 12-23 months. A child who received the eight recommended routine vaccinations was considered fully vaccinated. The routine vaccination schedule was used to define valid doses and estimate the percentage of children vaccinated on time. RESULTS: Among 1345 children surveyed, 40.4% (95% CI: 36.6-44.2) of the 840 children with vaccination cards had received all eight recommended vaccinations. Coverage was highest for the Bacille Calmette-Guerin vaccine (87.3%), the first doses of the diphtheria-tetanus-pertussis vaccine (92.0%), and oral poliovirus vaccine (93.4%) and lowest for measles vaccine (46.9%). Timely vaccination rates were lower. Assuming similar coverage for the 505 children without cards, coverage with the complete vaccination series among all surveyed children 31.9%. Reasons for under-vaccination included not having enough time to reach the vaccination location (24.8%), having a child who was ill (13.8%), and not knowing when, or forgetting, to go for vaccination (12.8%). CONCLUSIONS AND RECOMMENDATIONS: Coverage for early-infant vaccines was high; however, most children did not complete the full vaccination series, and many children received vaccinations later than recommended. Efforts to improve the immunization program should include increasing the frequency of outreach services, training for vaccination staff to minimize missed opportunities, and better communicating the timing of vaccinations to encourage caregivers to bring their children for vaccinations at the recommended age. Efforts to promote the benefits of vaccination and card retention are also needed. PMID- 22227147 TI - Antibody levels against B. pertussis in neonates measured in dried blood spots. AB - AIM: We designed this study to investigate if immunoglobuline G-Pertussis toxin (IgG-PT) against Bordetella pertussis in umbilical cord blood can reliably be determined in dried blood spots on filter paper (Guthrie) cards. PATIENTS AND METHODS: We prospectively included 129 mothers and their newborns born in a general hospital in the Netherlands. The relation between IgG-PT against B. pertussis from the umbilical cord measured in dried blood spots (Guthrie card) and in serum samples was studied by means of a Bland-Altman graph, using regression analysis to evaluate the level of agreement of both measurement methods. RESULTS: IgG-PT in Guthrie cards show a high coefficient of correlation with IgG-PT in serum samples from the umbilical cord when calibrated against blood spot calibrators (p<0.05). CONCLUSION: Maternal IgG-PT against B. pertussis measured in cord blood applied to Guthrie cards and calibrated against blood spot calibrators show good agreement with measurement of IgG-PT in cord serum. This offers new perspectives for future studies concerning B. pertussis antibodies. PMID- 22227148 TI - Identification process in mass graves from the Spanish Civil War II. AB - The identification process of a mass grave from the Spanish Civil War (1936-1939) is presented. The presumed location of the grave, as well as the presumed number and identities of the persons buried in the grave were obtained exclusively from witnesses' and relatives' testimonies. In agreement with the testimonies, the grave was located at the indicated location and five skeletons were exhumed. Also in agreement with the testimonies, the osteological and DNA study led investigators to propose the identification of two kin groups, a father and his son and a pair of brothers. But the genetic study did not support the identification of a fifth man presumed to have been buried in the grave. The differences and similarities between this case and another case reported earlier are discussed. PMID- 22227149 TI - Fundamental studies of bloodstain formation and characteristics. AB - A detailed understanding of blood droplet impact dynamics and stain formation is an essential prerequisite to the interpretation of both individual bloodstains and spatter patterns. The current literature on theoretical models for the spreading and splashing of liquid drops on surfaces relevant to the forensic context of bloodstain formation has been reviewed. These models have been evaluated for a paper substrate using experimental data obtained as function of droplet size, impact velocity and angle. It is shown that for perpendicular impact there are fairly simple mathematical models for the spreading diameter and the number of scallops or spines formed around the stain though these have quite limited ranges of validity in their basic form. In particular, predictions for the diameter are best for small droplets impacting at high velocity and the number of spines saturates for higher impact velocities. In the case of spreading, a modification to the energy conservation model is found to provide excellent agreement with experimental stain diameters across a wide range of impact velocities. For non-perpendicular impact, the width of stains is found to depend principally on the normal component of impact velocity and may be predicted by an appropriate modification to the expression for the perpendicular case. Limitations in the calculation of impact angle from the stain aspect ratio are identified and a theoretical basis for the prediction of spines around an elliptical stain is proposed. Some key issues for future research are identified which include a systematic, quantitative study of the effect of surface properties on bloodstain formation. PMID- 22227150 TI - Comparison of quantitative PCR and culture-based methods for evaluating dispersal of Bacillus thuringiensis endospores at a bioterrorism hoax crime scene. AB - Since the anthrax mail attacks of 2001, law enforcement agencies have processed thousands of suspicious mail incidents globally, many of which are hoax bioterrorism threats. Bio-insecticide preparations containing Bacillus thuringiensis (Bt) spores have been involved in several such threats in Australia, leading to the requirement for rapid and sensitive detection techniques for this organism, a close relative of Bacillus anthracis. Here we describe the development of a quantitative PCR (qPCR) method for the detection of Bt crystal toxin gene cry1, and evaluation of the method's effectiveness during a hoax bioterrorism event in 2009. When combined with moist wipe sampling, the cry1 qPCR was a rapid, reliable, and sensitive diagnostic tool for detecting and quantifying Bt contamination, and mapping endospore dispersal within a mail sorting facility. Results from the cry1 qPCR were validated by viable counts of the same samples on Bacillus-selective agar (PEMBA), which revealed a similar pattern of contamination. Extensive and persistent contamination of the facility was detected, both within the affected mailroom, and extending into office areas up to 30m distant from the source event, emphasising the need for improved containment procedures for suspicious mail items, both during and post-event. The cry1 qPCR enables detection of both viable and non-viable Bt spores and cells, which is important for historical crime scenes or scenes subjected to decontamination. This work provides a new rapid method to add to the forensics toolbox for crime scenes suspected to be contaminated with biological agents. PMID- 22227151 TI - Quantitative determination of sibutramine in adulterated herbal slimming formulations by TLC-image analysis method. AB - A simple thin layer chromatographic (TLC)-image analysis method was developed for rapid determination and quantitation of sibutramine hydrochloride (SH) adulterated in herbal slimming products. Chromatographic separation of SH was achieved on a silica gel 60 F(254) TLC plate, using toluene-n-hexane-diethylamine (9:1:0.3, v/v/v) as the mobile phase and Dragendorff reagent as spot detection. Image analysis of the scanned TLC plate was performed to quantify the amount of SH. The polynomial regression data for the calibration plots showed good linear relationship in the concentration range of 1-6 MUg/spot. The limits of detection and quantitation were 190 and 634 ng/spot, respectively. The method gave satisfactory specificity, precision, accuracy, robustness and was applied for determination of SH in herbal formulations. The contents of SH in adulterated samples determined by the TLC-image analysis and TLC-densitometry were also compared. PMID- 22227152 TI - Evaluation of the catalytic decomposition of H2O2 through use of organo-metallic complexes--a potential link to the luminol presumptive blood test. AB - Forensic scientists use several presumptive tests to detect latent blood stains at crime scenes; one of the most recognizable being the luminol reagent. Luminol, under basic conditions, reacts with an oxidizing species which, with the help of a transition metal catalyst facilitates a luminescent response. The typical oxidizing species used in the luminol reaction is hydrogen peroxide (H(2)O(2)). While the luminol reaction has been studied since its inception, the mechanistic pathway is still an area of great debate. Previous work suggests that the luminol reaction with latent blood stains possesses a correlation to the Fenton Decomposition reaction mechanism, which decomposes H(2)O(2) into the strongly oxidizing hydroxyl radical (*OH) species. This work seeks to understand the luminol reaction on a mechanistic level and to determine if a synergy exists between the chemiluminescence observed in the reaction and the production of the hydroxyl radical via Fenton-like processes. Results indicate that organo-metallic complexes produce hydroxyl radicals at different rates and different concentrations. These findings appear to be related to structural differences in the organo-metallic complex, which conform to the 18 electron rule or are one electron rich/deficient. Furthermore, the production of *OH is controlled by the chemical environment which governs complex stability at high pH conditions, reflective of the luminol process. Model hemoglobin systems reveal a strong correlation between the rate of *OH production via the Fenton-like pathway and maximum chemiluminescent intensity. PMID- 22227153 TI - Nitric oxide synthase in post-ischaemic remodelling: new pathways and mechanisms. AB - The three isoforms of nitric oxide synthase (NOS), spatially confined in specific intracellular compartments in cardiac cells, have distinct roles in the regulation of contractility in pathophysiological situations. Recently, evidence has emerged that implicates NOS in modulating myocardial remodelling during cardiac stress, including after ischaemic insults. As long as they remain in a coupled state the NOS mostly attenuate hypertrophic remodelling through both cGMP dependent and independent mechanisms. We review the evidence provided from the phenotype of genetic mouse models as well as from in vitro cell experiments dissecting the signalling effectors involved in the NOS-mediated regulation that justify new therapeutic interventions on the NOS-cGMP axis to attenuate the development of heart failure. PMID- 22227154 TI - MicroRNA-214 inhibits angiogenesis by targeting Quaking and reducing angiogenic growth factor release. AB - AIMS: Angiogenesis is a critical component of many pathological conditions in adult tissues and is essential for embryonic development. MicroRNAs are indispensable for normal vascular development, but their exact role in regulating angiogenesis remains unresolved. Previously, we have observed that miR-214 is differentially expressed in compensatory arteriogenesis. Here, we investigated the potential role of miR-214 in the process of angiogenesis. METHODS AND RESULTS: miR-214 is expressed in all major vascular cell types, and modulation of miR-214 levels in endothelial cells significantly affected tubular sprouting. In vivo silencing of miR-214 enhanced the formation of a perfused vascular network in implanted Matrigel plugs and retinal developmental angiogenesis in mice. miR 214 directly targets Quaking, a protein critical for vascular development. Quaking knockdown reduced pro-angiogenic growth factor expression and inhibited endothelial cell sprouting similar to miR-214 overexpression. In accordance, silencing of miR-214 increased the secretion of pro-angiogenic growth factors, including vascular endothelial growth factor, and enhanced the pro-angiogenic action of the endothelial cell-derived conditioned medium, whereas miR-214 overexpression had the opposite effect. CONCLUSION: Here, we report a novel role for miR-214 in regulating angiogenesis and identify Quaking as a direct target of miR-214. The anti-angiogenic effect of miR-214 is mediated through the down regulation of Quaking and pro-angiogenic growth factor expression. This study presents miR-214 as a potential important target for pro- or anti-angiogenic therapies. PMID- 22227156 TI - Morphological study of accessory gland of Bothrops jararaca and its secretory cycle. AB - The venom gland apparatus of Bothrops jararaca is composed of four distinct parts: main venom gland, primary duct, accessory gland and secondary duct. Despite the numerous studies concerning morphology and venom production and secretion in the main venom gland, there are few studies about the accessory gland and its secretion. We characterized the accessory gland of B. jararaca snake and determined the secretion cycle by morphological analysis using light and transmission electron microscopy. Our data showed that the accessory gland of B. jararaca has a simple secretory epithelium with at least six types of cells in the anterior region: two types of secretory cells, mitochondria-rich cells without secretory vesicles, horizontal cells, dark cells and basal cells, and in the posterior region a simple epithelium with two types of cells: seromucous cells and horizontal cells. Furthermore, the mucous secretory cells of the accessory gland show a delayed and massive exocytosis that occurs four days after the extraction of venom. Morphological analysis at different steps after venom extraction showed that the accessory gland has a long cycle of production and secretion, which is not synchronous with the main venom gland secretory cycle. PMID- 22227155 TI - Heterogeneous atrial wall thickness and stretch promote scroll waves anchoring during atrial fibrillation. AB - AIMS: Atrial dilatation and myocardial stretch are strongly associated with atrial fibrillation (AF). However, the mechanisms by which the three-dimensional (3D) atrial architecture and heterogeneous stretch contribute to AF perpetuation are incompletely understood. We compared AF dynamics during stretch-related AF (pressure: 12 cmH(2)O) in normal sheep hearts (n = 5) and in persistent AF (PtAF, n = 8)-remodelled hearts subjected to prolonged atrial tachypacing. We hypothesized that, in the presence of stretch, meandering 3D atrial scroll waves (ASWs) anchor in regions of large spatial gradients in wall thickness. METHODS AND RESULTS: We implemented a high-resolution optical mapping set-up that enabled simultaneous epicardial- and endoscopy-guided endocardial recordings of the intact atria in Langendorff-perfused normal and PtAF (AF duration: 21.3 +/- 11.9 days) hearts. The numbers and lifespan of long-lasting ASWs (>3 rotations) were greater in PtAF than normal (lifespan 0.9 +/- 0.5 vs. 0.4 +/- 0.2 s/(3 s of AF), P< 0.05). Than normal hearts, focal breakthroughs interacted with ASWs at the posterior left atrium and left atrial appendage to maintain AF. In PtAF hearts, ASW filaments seemed to span the atrial wall from endocardium to epicardium. Numerical simulations using 3D atrial geometries (Courtemanche-Ramirez-Nattel human atrial model) predicted that, similar to experiments, filaments of meandering ASWs stabilized at locations with large gradients in myocardial thickness. Moreover, simulations predicted that ionic remodelling and heterogeneous distribution of stretch-activated channel conductances contributed to filament stabilization. CONCLUSION: The heterogeneous atrial wall thickness and atrial stretch, together with ionic and anatomic remodelling caused by AF, are the main factors allowing ASW and AF maintenance. PMID- 22227157 TI - Effects of tetanus toxin on spontaneous and evoked transmitter release at inhibitory and excitatory synapses in the rat SDCN neurons. AB - We observed the effects of tetanus toxin (TeNT) on spontaneous miniature and evoked postsynaptic currents at inhibitory (glycinergic) and excitatory (glutamatergic) synapses in SDCN of rat spinal cord, by use of 'synaptic bouton' preparations, under voltage clamp condition. TeNT (>10 pM) dose-dependently decreased the frequency without affecting amplitude of glycinergic spontaneous miniature IPSCs. However, TeNT (100 pM) had no effect on frequency or amplitude of glutamatergic spontaneous EPSCs. Focal paired electrical stimulation of 'synaptic boutons' elicited two consecutive glycinergic eIPSCs or glutamatergic eEPSCs with large amplitude and low failure rate (Rf). TeNT (100 pM) reduced the amplitude and increased the failure rate of the first glycinergic eIPSCs and greatly enhanced the ratio of the second to first (P2/P1) eIPSCs. Application of 4-AP restored glycinergic eIPSCs suppressed by TeNT (100 pM). However, TeNT (100 pM) had no effect on the amplitude, Rf or P2/P1 ratio of glutamatergic eEPSCs. These results show that TeNT pre-synaptically affects spontaneous and evoked, and inhibitory and excitatory neurotransmitter release differentially, thereby suggesting that molecular events underlying spontaneous and evoked, inhibitory and excitatory neurotransmitter release may be different in CNS, and that the release machinery becomes less sensitive to Ca2+ in TeNT poisoned 'synaptic boutons'. PMID- 22227158 TI - Feature-based attention spreads preferentially in an object-specific manner. AB - We studied the spreading of feature-based attention from attended to ignored motion fields (linear, circular, and combinations). When observers attended one of two superimposed motion fields on one side of the visual midline, sub threshold priming by an ignored motion field was altered significantly on the opposite side of the midline. This attentional spreading was observed only when attended and ignored motion fields conformed to a complex global flow, not when they shared the same linear motion. These findings corroborate an earlier study (Festman & Braun, 2010), which obtained similar results with a complementary methodology. We conclude that feature-based attention is more complex than hitherto appreciated in that it spreads preferentially in an object-specific manner. PMID- 22227159 TI - Mixed training at high and low accuracy levels leads to perceptual learning without feedback. AB - In this study, we investigated whether mixing easy and difficult trials can lead to learning in the difficult conditions. We hypothesized that while feedback is necessary for significant learning in training regimes consisting solely of low training accuracy trials, training mixtures with sufficient proportions of high accuracy training trials would lead to significant learning without feedback. Thirty-six subjects were divided into one experimental group in which trials with high training accuracy were mixed with those with low training accuracy and no feedback, and five control groups in which high and low accuracy training were mixed in the presence of feedback; high and high training accuracy were mixed or low and low training accuracy were mixed with and without feedback trials. Contrast threshold improved significantly in the low accuracy condition in the presence of high training accuracy trials (the high-low mixture group) in the absence of feedback, although no significant learning was found in the low accuracy condition in the group with the low-low mixture without feedback. Moreover, the magnitude of improvement in low accuracy trials without feedback in the high-low training mixture is comparable to that in the high accuracy training without feedback condition and those obtained in the presence of trial-by-trial external feedback. The results are both qualitatively and quantitatively consistent with the predictions of the Augmented Hebbian Re-Weighting model. We conclude that mixed training at high and low accuracy levels can lead to perceptual learning at low training accuracy levels without feedback. PMID- 22227160 TI - The veA gene of the pine needle pathogen Dothistroma septosporum regulates sporulation and secondary metabolism. AB - Fungi possess genetic systems to regulate the expression of genes involved in complex processes such as development and secondary metabolite biosynthesis. The product of the velvet gene veA, first identified and characterized in Aspergillus nidulans, is a key player in the regulation of both of these processes. Since its discovery and characterization in many Aspergillus species, VeA has been found to have similar functions in other fungi, including the Dothideomycete Mycosphaerella graminicola. Another Dothideomycete, Dothistroma septosporum, is a pine needle pathogen that produces dothistromin, a polyketide toxin very closely related to aflatoxin (AF) and sterigmatocystin (ST) synthesized by Aspergillus spp. Dothistromin is unusual in that, unlike most other secondary metabolites, it is produced mainly during the early exponential growth phase in culture. It was therefore of interest to determine whether the regulation of dothistromin production in D. septosporum differs from the regulation of AF/ST in Aspergillus spp. To begin to address this question, a veA ortholog was identified and its function analyzed in D. septosporum. Inactivation of the veA gene resulted in reduced dothistromin production and a corresponding decrease in expression of dothistromin biosynthetic genes. Expression of other putative secondary metabolite genes in D. septosporum such as polyketide synthases and non-ribosomal peptide synthases showed a range of different responses to loss of Ds-veA. Asexual sporulation was also significantly reduced in the mutants, accompanied by a reduction in the expression of a putative stuA regulatory gene. The mutants were, however, able to infect Pinus radiata seedlings and complete their life cycle under laboratory conditions. Overall this work suggests that D. septosporum has a veA ortholog that is involved in the control of both developmental and secondary metabolite biosynthetic pathways. PMID- 22227161 TI - Paralyzed by beauty. PMID- 22227162 TI - Intractable neuropathic pain due to ulnar nerve entrapment treated with cannabis and ketamine 10%. PMID- 22227163 TI - Changes in fibrinopeptide A peptides in the sera of rats chronically exposed to low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitously distributed endocrine disruptors. To investigate peptide changes in the sera of rats chronically exposed to TCDD and to explore the association of these changes with liver morphology, TCDD was administrated to male rats at doses of 140, 350, and 875 ng/kg/week for 29 weeks. Serum was collected and proteomic analysis was performed using automated Bruker Daltonics ClinProt with matrix-assisted laser desorption/ionization time-of-flight mass spectrometer. One peptide at 1740.89 was found to be significantly decreased and further identified with nano LC-MS/MS system. The MS BLAST homology search engine reported the peptide to be a partial sequence of fibrinopeptide A. Liver fatty degeneration and necrosis were assessed by hematoxylin and eosin staining. Liver fatty degeneration and necrosis were both found to be significantly increased after TCDD exposure. Levels of fibrinopeptide A were significantly correlated with liver fatty degeneration and necrosis. PMID- 22227164 TI - Pharmacokinetics and tissue residues of hydrochloric acid albendazole sulfoxide and its metabolites in crucian carp (Carassius auratus) after oral administration. AB - The pharmacokinetics and residues elimination of hydrochloric acid albendazole sulfoxide (ABZSO) and its metabolites were studied in healthy crucian carp (Carassius auratus, 250 +/- 30 g) kept at water temperatures of 10 degrees C and 25 degrees C. The concentrations of ABZSO and its metabolites concentration in plasma and tissues were determined using high-performance liquid chromatography (HPLC) using an ultraviolet detector. The results revealed that the plasma concentration of ABZSO in plasma was significantly higher than that of albendazole sulfone (ABZSO(2)), whereas albendazole-2-aminosulfone (ABZ SO(2)NH(2)) was not detected. The plasma concentrations of ABZSO and its main metabolite ABZSO(2) concentration-time data were fitted using a single compartment model at 10 degrees C and 25 degrees C. The absorption half-life (t1/2ka) of ABZSO was 3.86 h at 10 degrees C and 1.29 h at 25 degrees C, whereas the elimination half-life (t1/2ke) was 16.34 h at 10 degrees C and 6.72 h at 25 degrees C; the maximum plasma concentration (C(max)) and the time-point of maximum plasma concentration (T(p)) were calculated as 3.20 MUg mL(-1) and 10.58 h at 10 degrees C, 4.39 MUg mL(-1) and 3.80 h at 25 degrees C. The distribution volume (V(d)/F) of ABZSO was estimated to be 1.99 L kg(-1) at 10 degrees C and 1.53 L kg(-1) at 25 degrees C; the total body clearance (CL(b)) of ABZSO were computed as 0.08 and 0.19 L/(h kg) at 10 and 25 degrees C, respectively; the areas under the concentration-time curve (AUC) was 118.22 MUg mL(-1)h at 10 degrees C and 63.12 MUg mL(-1)h at 25 degrees C. The [Formula: see text] of ABZSO(2) was found to be 6.39 degrees C at 10 degrees C and 3.73 h at 25 degrees C, whereas the [Formula: see text] was 12.86 h at 10 degrees C and 6.56 h at 25 degrees C; the C(max) and T(p) of ABZSO(2) was calculated as 0.78 MUg mL(-1) and 12.82 h at 10 degrees C, 1.03 MUg mL(-1) and 7.04 h at 25 degrees C, respectively; the V(d)/F of ABZSO(2) were estimated to be 6.43 L kg( 1) at 10 degrees C and 4.61 Lkg(-1) at 25 degrees C; the CL(b) of ABZSO(2) were computed as 0.34 and 0.49 L/(h kg) at 10 degrees C and 25 degrees C, respectively; the AUC of ABZSO(2) were 28.86 MUg mL(-1)h at 10 degrees C and 20.52 MUg mL(-1)h at 25 degrees C. It was demonstrated that ABZSO(2) was the main metabolite of ABZSO. The concentrations of ABZSO and its main metabolite (ABZSO(2)) were detected in muscle, skin, liver and kidney, whereas ABZ SO(2)NH(2) was only detected in liver and kidney. The ABZSO and it metabolite (ABZSO(2)) could still be detected at 4 d time-point after administration at both temperatures in all tissues. The results revealed that the depletion of ABZSO and its metabolite (ABZSO(2)) in crucian carp was slower with a long half-life time, especially at lower water temperature. PMID- 22227165 TI - Urinary metabonomics study on biochemical changes in an experimental model of chronic renal failure by adenine based on UPLC Q-TOF/MS. AB - BACKGROUND: Chronic renal failure (CRF) is a serious clinical symptom, occurring as the end result of all kinds of chronic kidney disease and its pathophysiological mechanism is not yet well understood. We investigated the metabolic profiling of urine samples from CRF model rats to find potential disease biomarkers and research pathology of CRF. METHODS: An animal model of CRF was produced by adenine. Metabolic profiling of the urine was performed by using ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC Q-TOF/MS). Acquired data were subjected to principal component analysis (PCA) for differentiating the CRF and the normal control groups. Potential biomarkers were screened by using S-plot and were identified by the accurate mass, isotopic pattern and MS(E) fragments information obtained from UPLC Q-TOF/MS analysis. RESULTS: 12 metabolites in urine were identified as potential biomarkers. Adenine-induced CRF rats were characterized by the increase of phytosphingosine, adrenosterone, tryptophan, 2,8-dihydroxyadenine, creatinine, and dihydrosphingosine together with the decrease of N-acetylleucine, 3-O methyldopa, ethyl-N2-acetyl-L-argininate, dopamine, phenylalanine and kynurenic acid in urine. The altered metabolites demonstrated perturbations of amino acids metabolism, phospholipids metabolism and creatinine metabolism in CRF rats. CONCLUSION: This work shows that metabonomics method is a valuable tool in CRF mechanism study and assists in clinical diagnosis of CRF. PMID- 22227166 TI - The association of the UGT1A8, SLCO1B3 and ABCC2/ABCG2 genetic polymorphisms with the pharmacokinetics of mycophenolic acid and its phenolic glucuronide metabolite in Chinese individuals. AB - BACKGROUND: This study aimed to evaluate the effect of UGT1A8*2, SLCO1B3 T334G, ABCC2 C-24T and ABCG2 C421A polymorphisms on the pharmacokinetics (PKs) of mycophenolic acid (MPA) and its phenolic glucuronide (MPAG) in healthy Chinese volunteers and in stable renal transplant patients. METHODS: The data were extracted from comparative bioavailability studies conducted in 42 healthy individuals and 37 renal transplant patients. A complete PK profile was obtained over 48 h for healthy volunteers and over 12h for the transplant patients. The MPA/MPAG plasma concentrations were measured by HPLC. The genotypes were determined using either the Taqman probe technique or direct sequencing. A multivariate analysis was used to assess the effect of the genotypes (UGT1A8*2, SLCO1B3 T334G, ABCC2 C-24T and ABCG2 C421A) and other covariates (age, weight, height, calculated creatinine clearance, serum albumin, haemoglobin and drug comedication) on the AUC(4-12) and AUC(0-12) for MPA and MPAG in the healthy volunteers and patients. RESULTS: In the healthy volunteers, the dose-adjusted geometric means (GM) of the MPA AUC(4-12) in individuals with the SLCO1B3 334T allele were 30.4% lower than those values in the 334G homozygote carriers (P<0.05); in the transplant patients, the steroid dose was associated with a negative effect on the AUC of MPAG (P<0.03) and weight was associated with a negative effect on the AUC for MPA in the healthy volunteers and patients (P<0.03). No other significant effect of genotype or of the other studied variables on AUC(4-12) or AUC(0-12) of MPA/MPAG was found in the healthy volunteers or patients. CONCLUSIONS: The PKs of MPA is affected by the SLCO1B3 polymorphism in healthy Chinese individuals. The absence of an effect of SLCO1B3 polymorphisms in transplant patients may be due to the co-administration of cyclosporine (CsA). Concomitant steroid dose and weight are two important covariates of the AUC of MPA and MPAG, which should be taken into account in clinical use. Further confirmatory in vivo studies are needed. PMID- 22227167 TI - Expression of protease-activated receptor (PAR)-2, but not other PARs, is regulated by inflammatory cytokines in rat astrocytes. AB - Protease-activated receptors (PARs) are widely expressed in the central nervous system (CNS) and are believed to play an important role in normal brain functioning as well as in development of various inflammatory and neurodegenerative disorders. Pathological conditions cause altered expression of PARs in brain cells and therefore altered responsiveness to PAR activation. The exact mechanisms of regulation of PAR expression are not well studied. Here, we evaluated in rat astrocytes the influence of LPS, pro-inflammatory cytokines TNFalpha and IL-1beta and continuous PAR activation by PAR agonists on the expression levels of PARs. These stimuli are important in inflammatory and neurological disorders, where their levels are increased. We report that LPS as well as cytokines TNFalpha and IL-1beta affected only the PAR-2 level, but their effects were opposite. LPS and TNFalpha increased the functional expression of PAR-2, whereas IL-1beta down-regulated the functional response of PAR-2. Agonists of PAR-1 specifically increased mRNA level of PAR-2, but not protein level. Transcript levels of other PARs were not changed after PAR-1 activation. Stimulation of the cells with PAR-2 or PAR-4 agonists did not alter PAR levels. We found that up-regulation of PAR-2 is dependent on PKC activity, mostly via its Ca2+-sensitive isoforms. Two transcription factors, NFkappaB and AP-1, are involved in up-regulation of PAR-2. These findings provide new information about the regulation of expression of PAR subtypes in brain cells. This is of importance for targeting PARs, especially PAR-2, for the treatment of CNS disorders. PMID- 22227168 TI - Safety-promoting behaviors of community-dwelling abused Chinese women after an advocacy intervention: a randomized controlled trial. AB - OBJECTIVE: To examine the effect of an advocacy intervention on the use of safety promoting behaviors in community-dwelling abused Chinese women as compared to a control condition of usual care. DESIGN: This efficacy trial used a randomized controlled, parallel group design. PARTICIPANTS AND METHODS: A total of 200 Chinese women in a community setting who screened positive for intimate partner violence using the Chinese version of the Abuse Assessment Screen were randomized to receive either an advocacy intervention (intervention group, n=100) or usual community care (control group, n=100). The outcome measured was the change in the self-reported safety-promoting behaviors as measured by the Safety-promoting Behavior Checklist over three time-points (baseline, 3-month follow-up and 9 month follow-up). Participants and assessors were blinded to the study hypothesis. Assessors were further blinded to the group membership of the participants. RESULTS: The Safety-promoting Behavior Checklist scores in the intervention group increased from the baseline on average by 5.65 (95% confidence interval [CI], 4.92-6.39) at 3-month and 6.65 (95% CI, 5.90-7.39) at 9-month follow-ups, while the scores in the control group also increased by 1.71 (95% CI, 1.06-2.37) at 3-month and 1.79 (95% CI, 1.15-2.43) at 9-month follow-ups. After adjusting for baseline differences, the between-group differences in scores were significant at 3-month and 9-month follow-ups (p=0.04). The intervention group increased the scores by 3.61 (95% CI, 2.61-4.61, p<0.001) more than the control group at 3-month and by 4.53 (95% CI, 3.53-5.53, p<0.001) at 9-month follow-ups. CONCLUSION: An advocacy intervention is efficacious in increasing the use of safety-promoting behaviors as compared to usual community care in community dwelling abused Chinese women. PMID- 22227170 TI - Healthcare disparities in Asians and Pacific Islanders with hepatocellular cancer. AB - BACKGROUND: Hawaii has the highest incidence of hepatocellular cancer (HCC) in the United States and the largest proportion of Asians and Pacific Islanders. HCC studies generally combine these groups into 1 ethnicity, and we sought to examine differences between Asian and Pacific Islander subpopulations. METHODS: Demographic, clinical, and treatment data for 617 patients with HCC (420 Asians, 114 whites, and 83 Pacific Islanders) were reviewed. Main outcome measures included HCC screening and liver transplantation. RESULTS: Asian and Pacific Islander subgroups had significantly more immigrants, and age was different between groups. Compared with whites, Pacific Islanders and Filipinos had less HCC screening and liver transplantation procedures, fewer met Milan criteria, and a smaller proportion of those with Milan criteria actually underwent transplantation. CONCLUSIONS: There were significant differences in risk factors, clinical presentation, treatment, and access to care among Asian, Pacific Islander, and white patients with HCC. Future HCC studies may benefit from differentiating subgroups within Asian and Pacific Islander populations to better focus these efforts. PMID- 22227169 TI - Error-related negativity in individuals with obsessive-compulsive symptoms: toward an understanding of hoarding behaviors. AB - The error-related negativity (ERN), an event-related potential component elicited by error responses in cognitive tasks, has been shown to be abnormal in most, but not all, studies of obsessive-compulsive disorder or obsessive-compulsive symptoms (OCD/S); these inconsistencies may be due to task selection, symptom subtype, or both. We used meta-analysis to further characterize the ERN in OCD/S, and pooled data across studies to examine the ERN in OCD/S with hoarding. We found an enhanced ERN in OCD/S relative to controls, as well as heterogeneity across tasks. When stratified, OCD/S showed a significantly enhanced ERN only in response conflict tasks. However, OCD/S+hoarding showed a marginally larger ERN than OCD/S-hoarding, but only for probabilistic learning tasks. These results suggest that abnormal ERN in OCD/S is task-dependent, and that OCD/S+hoarding show different ERN activity from OCD/S-hoarding perhaps suggesting different pathophysiological mechanisms of error monitoring. PMID- 22227171 TI - Expression of vascular endothelial growth factor-C in gastric carcinoma and the effect of its antisense gene transfection on the proliferation of human gastric cancer cell line SGC-7901. AB - PURPOSE: The aim of this study was to investigate the relationship between the expression of vascular endothelial growth factor-C (VEGF-C) in gastric carcinoma and tumor lymphangiogenesis and to determine the effect of antisense-VEGF-C gene transfection on proliferation. METHODS: Adjacent cancer tissues were collected from 72 gastric carcinoma cases and compared with 10 nongastric carcinoma tissues to detect the expression of VEGF-C and its messenger RNA (mRNA) and calculate the density of neonatal lymphatic microvessels. The in vitro-cultured gastric cancer cell line SGC-7901 was transfected with recombinant plasmid pCI-neo-anti VEGF-C. The expression in the transfected cells and the proliferation were determined. RESULTS: The positive rate of VEGF-C mRNA in the lymph node metastasis tissues was 85.7% compared with negative controls (20%, P < .05). The density of lymphatic vessels in the metastasis group was 6.65 +/- 1.57 compared with the negative group (3.75 +/- 1.47, P < .05). Protein and mRNA of VEGF-C were reduced in transfected cells. Proliferation was inhibited as well. CONCLUSIONS: VEGF-C can increase the invasiveness of gastric cancer and promote lymphangiogenesis in adjacent tissues. Transfection with antisense VEGF-C can reduce the expression of VEGF-C and inhibit the proliferation. VEGF-C can inhibit the tumor growth and reduce its metastasis and recurrence. PMID- 22227172 TI - [Intrasellar schwannoma: a rare case of pituitary incidentaloma]. PMID- 22227173 TI - Evaluation of relative importance of ultrasound reactor parameters for the removal of estrogen hormones in water. AB - The growing interest in sonochemistry as a tool for environmental remediation leads to the need for process optimization. Sonochemistry is a complex process, which depends on physical parameters and also on the process conditions. Physical parameters are interrelated and therefore a systematic approach has to be taken to optimize the process. The effect of physical parameters on the destruction of seven estrogen hormones (17alpha-estradiol, 17beta-estradiol, estriol, 17alpha ethinylestradiol, 17alpha-dihydroequilin, estrone and equilin) is reported in this study. Artificial neural networks (ANN) was used as a tool to identify the correlations between these process parameters. ANN enabled the establishment of relationship between sonication parameters such as power density, power intensity, ultrasound amplitude, as well as the reactor design parameters. The major significance was attributed to the area-specific power density and the volume-specific power intensity. The results of this work provide a sound basis to design pilot and full-scale ultrasound treatment systems. Process optimization lead to a 5-fold decrease in energy consumption as compared to the commercially available reactors, thereby making the process attractive for field applications. PMID- 22227174 TI - Prevention of salt-induced renal injury by activation of NAD(P)H:quinone oxidoreductase 1, associated with NADPH oxidase. AB - NADPH oxidase (NOX) is a predominant source of reactive oxygen species (ROS), and the activity of NOX, which uses NADPH as a common rate-limiting substrate, is upregulated by prolonged dietary salt intake. beta-Lapachone (betaL), a well known substrate of NAD(P)H:quinone oxidoreductase 1 (NQO1), decreases the cellular NAD(P)H/NAD(P)(+) ratio via activation of NQO1. In this study, we evaluated whether NQO1 activation by betaL modulates salt-induced renal injury associated with NOX-derived ROS regulation in an animal model. Dahl salt sensitive (DS) rats fed a high-salt (HS) diet were used to investigate the renoprotective effect of NQO1 activation. betaL treatment significantly lowered the cellular NAD(P)H:NAD(P)(+) ratio and dramatically reduced NOX activity in the kidneys of HS diet-fed DS rats. In accordance with this, total ROS production and expression of oxidative adducts also decreased in the betaL-treated group. Furthermore, HS diet-induced proteinuria and glomerular damage were markedly suppressed, and inflammation, fibrosis, and apoptotic cell death were significantly diminished by betaL treatment. This study is the first to demonstrate that activation of NQO1 has a renoprotective effect that is mediated by NOX activity via modulation of the cellular NAD(P)H:NAD(P)(+) ratio. These results provide strong evidence that NQO1 might be a new therapeutic target for the prevention of salt-induced renal injury. PMID- 22227175 TI - Metastatic gastrointestinal stromal tumor to the thoracic and lumbar spine: first reported case and surgical treatment. AB - BACKGROUND CONTEXT: Metastatic epidural spinal cord compression from gastrointestinal stromal tumors (GISTs) is a rarely reported phenomenon. PURPOSE: To describe the surgical management of metastatic GIST to two noncontiguous regions of the spinal column. STUDY DESIGN: Case report. METHODS: Review of the medical chart, radiographic studies, and relevant literature. RESULTS: The patient underwent direct surgical decompression and stabilization of the cervicothoracic junction and the lumbar region during treatment of two distinct sites of metastatic pathology. CONCLUSIONS: Treatment of epidural compression from metastatic GIST with direct decompression and stabilization is safe and feasible. PMID- 22227177 TI - Predictors of short-term work-related disability among active duty US Navy personnel: a cohort study in patients with acute and subacute low back pain. AB - BACKGROUND CONTEXT: Musculoskeletal disorders of the spine in the US military account for the single largest proportion of the absence of sickness causes leading to early termination. We explored if selected psychological and physical factors were associated with poor outcome after episodes of low back pain (LBP). PURPOSE: To identify clinical, demographic, and psychological factors predictive of work duty status after a complaint of LBP. STUDY DESIGN: A prospective clinical cohort of US Navy personnel treated for LBP. PATIENT SAMPLE: Eligible cases were active duty US Navy or Marine Corps personnel presenting to an emergency clinic or primary care clinic with a complaint of LBP, where the index episode of LBP was no more than 12 weeks duration before enrollment. OUTCOME MEASURES: The subject's work status (full duty, light duty, sick in quarters [SIQ], limited duty, or medically released to full duty) was abstracted from the subject's electronic medical record at approximately 4 weeks and then again 12 weeks after study enrollment. Work status in this study population is assigned by a Navy health-care provider at the time of a clinical visit and based on the health-care provider's determination of medical fitness for duty. This study collapsed work status into two groups, "full duty" (consisting of "full duty" and "medically released to full duty") and "not at full duty" (consisting of "light duty," "SIQ," and "limited duty"). METHODS: Volunteers completed a baseline questionnaire consisting of recommended well-validated measures, including attitudes and beliefs about LBP and work (Fear-Avoidance Beliefs Questionnaire [FABQ] and the Tampa Scale of Kinesiophobia), distress (the Pain Catastrophizing Scale), clinical depression (The Center for Epidemiologic Studies Depression scale), a numeric pain intensity scale, self-perceived disability (Oswestry Disability Index), and general health status (12-Item Short Form Health Survey). Navy health-care providers conducted a back pain-specific medical evaluation. Associations are expressed as multivariate-adjusted prevalence ratios (PRs) estimated using Poisson regression. RESULTS: Two hundred fifty-three participants were enrolled. Work status outcome was collected for 239 participants. Predictors of "not at full duty" at 4 weeks after enrollment included having back pain for 4 weeks or less before study enrollment (PR, 2.69; 95% CI, 1.21-5.97) and increased FABQ Work subscale score (PR, 1.05; 95% CI, 1.01-1.08). The sole predictor of work status at 12 weeks after enrollment was increased FABQ Physical Activity (FABQ Physical) subscale score (PR=1.14; 95% CI, 1.00-1.30). CONCLUSIONS: The findings that fear-avoidance beliefs were predictive of subsequent work status among active duty service personnel in this study population (after adjusting for clinical, demographic, and psychological covariates) suggest the clinical utility of addressing these factors during treatment of back pain episodes in the military. These findings reflect the important role that psychological factors may play in the return to work process in an active duty military population. PMID- 22227178 TI - Expert judgement of poisonings and human biomonitoring--the BfR three-level and matrix model. AB - German physicians are obligated (Para 16e Chemicals Law) to submit essential data on poisonings to the Centre for Documentation and Assessment of Poisonings at the Federal Institute for Risk Assessment (Bundesinstituts fur Risikobewertung, BfR). In addition, German poison centres are subjected to compulsory reporting of their findings of general importance gained in the context of their activities. The BfR assessment of poisonings has important significance for human case data collection, risk identification, and German toxicological monitoring. Using more than 60,000 reports on cases of poisoning, the BfR developed a structured expert judgement trial for poisonings. This judgement is based on a three-level model, accompanied by two different matrix procedures for an enhanced and more exact assessment of the exposures and the causality between health impairment and exposure. Particularly for low-dose exposures, human biomonitoring data is extremely valuable for the assessment process. Especially in chronic low-dose level exposures, the scientific assessment of related health impairments is often not possible without existing human biomonitoring data. For the future improvement of public health related to poisonings, ingestions by children, workplace chemical exposures, and incidents, we have to establish a nation-wide programme for monitoring human exposures which keeps pace with the progressive production of new chemicals. This must be done in close co-operation with physicians, poison centres, government safety organisations, and environmental health specialists and must be based on proven expert judgement tools and available human biomonitoring data. PMID- 22227176 TI - Impact of coexistent lumbar spine disorders on clinical outcomes and physician charges associated with total hip arthroplasty. AB - BACKGROUND CONTEXT: Despite the common prevalence of lumbar spine and degenerative hip disorders, there are few descriptions of patients with coexisting hip disorders and lumbar spine disorders (LSDs). The independent economic burden of each disorder is substantial, but the financial burden when the disorders are coexisting is unknown. PURPOSE: To determine the prevalence of coexisting hip disorders and LSDs in a large cohort of patients with hip osteoarthritis (OA) treated with total hip arthroplasty (THA) as well as the impact on pain and functional THA outcomes and physician charges. STUDY DESIGN: This is a retrospective study performed at a tertiary university. PATIENT SAMPLE: Three thousand two hundred six patients underwent total hip replacement from 1996 to 2008. OUTCOME MEASURES: Self-report measures: visual analog scale. Functional measures: modified Harris Hip Score (mHHS) and University of California Los Angeles (UCLA) hip questionnaire. Economic impact measures: physician medical charges. METHODS: International Classification of Diseases, Version 9, billing codes related to LSDs were cross-referenced with the 3,206 patients who had undergone a THA to determine which patients were also evaluated by a spine specialist. Demographic, hip clinical outcomes, and physician charges for patients with THA alone (THA alone) were compared with patients treated with THA and diagnosed with an LSD (THA+LSD). RESULTS: Of 3,206 patients who underwent THA, 566 (18%) were also evaluated by a spine specialist. Of those with an LSD, 334 (59%) were women with an older average age (64.5 +/- 13.3 years) compared with patients treated with THA alone (51%, 58.5 +/- 15.5 years, p = .0001). Patients in the THA alone group as compared with the THA+LSD group had greater improvement in the mHHS (p=.0001), UCLA score (p=.0001), and pain (p=.0001). Patients in the THA+LSD group incurred on average $2,668 more in charges per episode of care as compared with patients in the THA alone group (p<.001). Patients in the THA+LSD group had more days per episode of care (p=.001). CONCLUSIONS: Patients undergoing THA alone had greater improvement in function and pain relief with fewer medical charges as compared with patients undergoing a THA and treatment for an LSD. The prevalence of coexisting hip disorders and spine disorders is likely higher than currently documented. Further study is needed to improve therapeutic recommendations and determine the potential for reduction in medical expenses associated with concurrent treatment of hip OA and LSDs. PMID- 22227179 TI - In vitro cytotoxicity and morphological assessment of smoke from polymer combustion in human lung derived cells (A549). AB - The application of polymer and composites in building and modern transport interiors raises concerns of potential health hazards during combustion. Cytotoxicity and morphological assessment of smoke from polymer combustion in human lung derived cells (A549) has been investigated. A laboratory scale vertical tube furnace was used for the generation of combustion products. A range of materials used in the building and transport industry including high density polyethylene (HDPE), polypropylene (PP), polycarbonate (PC), and polyvinyl chloride (PVC), fiberglass reinforced polymers (FRPs), and melamine faced plywood (MFP) were studied. The exposure of combustion toxicants to human lung cells (A549) at the air/liquid interface was acquired using a Harvard Navicyte Chamber. Cytotoxic effects on human cells were assessed based on cell viability using a selected in vitro cytotoxicity assays, including NRU (neutral red uptake) and ATP (adenosine triphosphate). Morphological assessment on the effects of combustion products in human lung cells from selected materials including PVC, FRP and MFP was assessed using scanning electron microscopy (SEM). The volatile organic compounds from thermal decomposition products were identified using ATD-GCMS (Automatic Thermal Desorption Gas Chromatography Mass Spectrometry). NOAEC (No Observable Adverse Effect Concentration), IC(10) (10% inhibitory concentration), IC(50) (50% inhibitory concentration), and TLC (Total Lethal Concentration) values (mg/l) were generated. The following toxicity ranking was observed from the most toxic material to the least toxic using the NRU assay: PVC>PP>HDPE>PC >FRP-10>MFP>FRP-16; and the ATP assay: PVC>HDPE>PP>FRP-10>FRP-16>MFP>PC. The method described here could potentially be an alternative to current fire toxicity standards. PMID- 22227180 TI - Radioactivity from Fukushima Dai-ichi in air over Europe; part 1: spatio-temporal analysis. AB - Radionuclides emitted from the Fukushima I nuclear power plant have been detected in air all over Europe. Concentrations remained far below levels which could have caused radiological concern: probably the committed thyroid dose due to inhalation remained below about 1 MUSv (for 10 y children), within the investigated region. They provided, however, a spatio-temporal signal which could be used to develop and test tools to provide additional information on the large scale situation (Europe-wide, in this case) during a nuclear emergency. In this part we discuss the spatial distribution of the contaminated air masses over Europe. Using (131)I as an example, we present a method to construct maps of the time-cumulated (131)I concentration in air and of the peak concentrations. Procedures to deal with the statistical limitations of a data set stemming from different monitoring schemes are discussed. As over all results, the mean (over the investigated region) cumulated concentration of particular (131)I is estimated about 9 mBq d/m(3), with observed maximum of about 23 mBq d/m(3). The probability that much higher concentrations occurred at unsampled locations, than have been observed anywhere, is assessed low, e.g. about 2.5% for the cumulated (131)I(part.) concentration to exceed 30 mBq d/m(3). Our method can be used in nuclear emergencies for providing spatial analyses if radionuclide concentrations of health concern are detected by atmospheric monitoring stations. We suggest considering such methods of data harmonization if synoptic assessment based on heterogeneous datasets is attempted. PMID- 22227181 TI - Underreporting of energy intake in maintenance hemodialysis patients: a cross sectional study. AB - OBJECTIVE: To analyze the reported energy intake (EI(rep)) in hemodialysis (HD) patients by total energy expenditure (TEE) measured by a dedicated device. DESIGN: Cross-sectional study. SETTING: RenalCor and RenalVida Clinics (Rio de Janeiro, Brazil). PATIENTS AND OTHERS PARTICIPANTS: Forty-eight HD patients (51.4 +/- 12.2 years, 62% men, body mass index [BMI], 23.8 +/- 4.5 kg/m(2)) were studied. MAIN OUTCOME MEASURE: EI(rep) was evaluated using a 3-day food record. TEE was measured over a 2-day period by SWA (SenseWear Pro2 Armband, BodyMedia Inc., Pittsburgh, PA). Subjects were identified as underreporters (URs), acceptable reporters (ARs), or overreporters (ORs) from their EI(rep)/TEE ratio. ARs were defined as having the EI(rep)/TEE ratio in the range of 0.76 to 1.24, URs as EI(rep)/TEE <0.76, ORs as EI(rep)/TEE >1.24 according to Goldberg index. RESULTS: The mean TEE and EI(rep) were 34.7 +/- 9.4 kcal/kg/day and 22.8 +/- 10.6 kcal/kg/day, respectively, and 37.5% of patients presented overweight or obesity. Thirty-one patients (65%) were identified as URs, and the mean of Goldberg index was 0.54 +/- 0.12 (0.23 to 0.75), versus 0.95 +/- 0.12 (0.79 to 1.2) for ARs. There were no ORs among the patients studied. There were negative correlations between Goldberg index and BMI (r = -0.35, P < .01) and % body fat (r = -0.4, P < .01) and between EI(rep) and BMI (r = -0.58, P < .001). CONCLUSION: These results confirm a high prevalence of underreporting of EI in HD patients, particularly in patients with high BMI. PMID- 22227182 TI - Vitamin C affects the expression of hepcidin and erythropoietin receptor in HepG2 cells. AB - BACKGROUNDS: Hepcidin modulates the de novo absorption of iron from the duodenum and the recycling of iron released from the reticuloendothelial system. In patients with chronic renal failure, administration of higher doses of erythropoietin (EPO) or vitamin C (Vit C) can correct the functional iron deficiency. While EPO-regulated hepcidin expression within hepatocytes has been recently identified, the relation between vitamin C with hepcidin expression is still uncertain. METHODS: Hepcidin-producing HepG2 cells (a human liver carcinoma cell line) were cultured with 50- to 100-MUg/mL vitamin C or 0.25- to 1.0-U/mL EPO for 6 hours. Reverse transcription polymerase chain reaction was performed for quantitative measurements of hepcidin, EPO, and EPO receptor (EPOR) expression. RESULTS: EPO and vitamin C inhibited hepcidin expression within HepG2 cells; the EPO effect was dose dependent. EPO downregulated EPOR and vitamin C and upregulated EPOR. However, vitamin C had little effect on the expression of EPO. CONCLUSIONS: EPO is capable of downregulating EPOR when it acts early. Vitamin C directly inhibits hepcidin expression within HepG2 cells. Moreover, by enhancing EPOR production, vitamin C may correct the downregulating EPOR from EPO, which has additional effect with EPO in treating anemia. PMID- 22227183 TI - Association of 1,25-dihydroxyvitamin D levels with physical performance and thigh muscle cross-sectional area in chronic kidney disease stage 3 and 4. AB - BACKGROUND: Declines in 1,25-dihydroxyvitamin D (1,25(OH)2D) levels and physical functioning follow the course of chronic kidney disease (CKD). Although the molecular actions of vitamin D in skeletal muscle are well known, and muscle weakness and atrophy are observed in vitamin D-deficient states, there is little information regarding vitamin D and muscle function and size in CKD. OBJECTIVE: To examine associations of vitamin D with physical performance (PF) and muscle size. DESIGN: Cross-sectional. SETTING: CKD clinic. SUBJECTS: Twenty-six patients (61 +/- 13 years, 92% men) with CKD stage 3 or 4. MAIN OUTCOME MEASURES: Gait speed, 6-minute walk, sit-to-stand time, 1-legged balance, and thigh muscle cross sectional area (MCSA), measured by magnetic resonance imaging (MRI). RESULTS: Overall, 73% were 25-hydroxyvitamin D (25(OH)D) deficient (n = 10) or insufficient (n = 9) (Kidney Disease Outcomes Quality Initiative guidelines). 25(OH)D level was associated with normal gait speed only (r = 0.41, P = .04). Normal and fast gait speed, the distance walked in 6 minutes, and sit-to-stand time were best explained by 1,25(OH)2D and body mass index (P < .05 for all) and 1-legged stand by 1,25(OH)2D (r = 0.40, P < .05) only. There were no associations of age, estimated glomerular filtration rate (eGFR), intact parathyroid hormone (iPTH), or albumin with any PF measures. MCSA was associated with eGFR (r = 0.54, P < .01) only. Variance in MCSA was best explained by a model containing 1,25(OH)2D, plasma Ca2+, and daily physical activity (by accelerometry) (P < .05 for all). Once these variables were in the model, there was no contribution of eGFR. CONCLUSION: These results suggest that 1,25(OH)2D is a determinant of PF and muscle size in patients with stage 3 and 4 CKD. PMID- 22227184 TI - Intake of antioxidants and their status in chronic kidney disease patients. AB - OBJECTIVE: To evaluate the intake and status of antioxidants in chronic kidney disease (CKD) patients. DESIGN: Randomized control trial. SETTING: Hospital outpatient department. SUBJECTS: One hundred eighty-five subjects (145 predialysis CKD patients and 40 apparently healthy controls) were enrolled for this study. The patients were divided into moderate and severe renal failure groups based on their creatinine and glomerular filtration rates. INTERVENTION: All patients completed a food frequency questionnaire, 24-hour dietary recall form, and anthropometric measurements and underwent biochemical and antioxidant lab tests. MAIN OUTCOME MEASURES: Dietary intake, anthropometry, biochemical measures of blood and antioxidant enzymes as well as oxidative stress. RESULTS: Overall, the diet was significantly lower in antioxidant-rich food intake in all the CKD patients as compared with controls. The oxidative stress measured in blood was found to be in consonance with the intake from diet. CONCLUSION: Micronutrients play a major role in the antioxidant status of the patients and must be monitored, as deficiency of these might elevate the oxidative stress of the body, especially in the chronic diseases. PMID- 22227185 TI - Effect of hypoxia-inducible factor 1-alpha on hypoxia/reoxygenation-induced apoptosis in primary neonatal rat cardiomyocytes. AB - We studied the role of hypoxia-inducible factor 1-alpha (HIF-1alpha) in hypoxia/reoxygenation (H/R)-induced apoptosis in primary neonatal rat cardiomyocytes and its possible molecular mechanisms. Isolated neonatal and adult rat cardiac myocytes were cultured for 48h and were submitted to 5h of hypoxia followed by 2, 6, or 12h of reoxygenation. Small interfering RNA was used to target the HIF-1alpha gene. Cardiac myocyte apoptosis induced by H/R was assessed by Annexin V-FITC apoptosis assay. HIF-1alpha, Bnip3 and caspase-3 levels were determined by real-time reverse transcription polymerase chain reaction and western blot for mRNA and protein, respectively. H/R resulted in severe injury in cultured rat cardiomyocytes and it upregulated HIF-1alpha and proapoptotic Bnip3 mRNA and protein expression. HIF-1alpha activity inhibited by siRNA significantly decreased (P<0.01) the rate of apoptotic cardiomyocytes induced by 5h of hypoxia followed by 6h of reoxygenation compared with cardiomyocytes without siRNA treatment. Additionally, the expression of Bnip3 and caspase-3 was also markedly reduced. We conclude that HIF-1alpha is a key regulator of apoptosis of cardiomyocytes induced by H/R. H/R enhances primary neonatal rat cardiomyocyte apoptosis through the activation of HIF-1alpha and the mechanism might involve Bnip3 and caspase-3. HIF-1alpha may be a possible therapeutic target to limit myocardial injury after myocardial infarction. PMID- 22227186 TI - Isolated mouse islets respond to glucose with an initial peak of glucagon release followed by pulses of insulin and somatostatin in antisynchrony with glucagon. AB - Recent studies of isolated human islets have shown that glucose induces hormone release with repetitive pulses of insulin and somatostatin in antisynchrony with those of glucagon. Since the mouse is the most important animal model we studied the temporal relation between hormones released from mouse islets. Batches of 5 10 islets were perifused and the hormones measured with radioimmunoassay in 30s fractions. At 3mM glucose, hormone secretion was stable with no detectable pulses of glucagon, insulin or somatostatin. Increase of glucose to 20mM resulted in an early secretory phase with a glucagon peak followed by peaks of insulin and somatostatin. Subsequent hormone secretion was pulsatile with a periodicity of 5min. Cross-correlation analyses showed that the glucagon pulses were antisynchronous to those of insulin and somatostatin. In contrast to the marked stimulation of insulin and somatostatin secretion, the pulsatility resulted in inhibition of overall glucagon release. The cytoarchitecture of mouse islets differs from that of human islets, which may affect the interactions between the hormone-producing cells. Although indicating that paracrine regulation is important for the characteristic patterns of pulsatile hormone secretion, the mouse data mimic those of human islets with more than 20-fold variations of the insulin/glucagon ratio. The data indicate that the mouse serves as an appropriate animal model for studying the temporal relation between the islet hormones controlling glucose production in the liver. PMID- 22227187 TI - Binding of neuronal alpha-synuclein to beta-III tubulin and accumulation in a model of multiple system atrophy. AB - Multiple system atrophy (MSA) is a neurodegenerative disease caused by alpha synuclein (alpha-syn) accumulation in oligodendrocytes and neurons. We generated a transgenic (Tg) mouse model in which human alpha-syn was overexpressed in oligodendrocytes. Our previous studies have revealed that oligodendrocytic alpha syn inclusions induced neuronal alpha-syn accumulation, thereby resulting in progressive neuronal degeneration in mice. We also demonstrated that an insoluble complex of alpha-syn and beta-III tubulin in microtubules progressively accumulated in neurons, thereby leading to neuronal degeneration. In the present study, we demonstrated that neuronal accumulation of the insoluble complex was derived from binding of alpha-syn to beta-III tubulin and not from alpha-syn self aggregation. Thus, interaction between alpha-syn and beta-III tubulin plays an important role in neuronal alpha-syn accumulation in an MSA mouse model. PMID- 22227188 TI - Saccharomyces cerevisiae Tel2 plays roles in TORC signaling and telomere maintenance that can be mutationally separated. AB - The evolutionary conserved Tel2 protein appears to function as a co-chaperone required for the activity of phosphatidylinositol 3-kinase-like protein kinases (PIKKs). Since Saccharomyces cerevisiae Tel2 is essential for viability and only a single point mutant (Tel2-1) had been characterized so far, the possible range of phenotypes associated with Tel2 mutations was unknown. We used random in vitro mutagenesis and plasmid shuffling to create additional point mutants. No significant sensitivity towards DNA damaging agents or hydroxyurea was evident, indicating that Tel2 is not required for Mec1 function. However, as frequent novel phenotypes, we detected slow growth or enhanced lethality in response to rapamycin that could be correlated with lower level and activity of Tor1 or of both Tor1 and Tor2, respectively. The newly isolated mutant with the most severe phenotype, Tel2-13, is comprised of 8 amino acid changes. Two mutated residues of Tel2-13 near the N-terminus and close to Tel2-1 are sufficient for shortened telomeres whereas multiple mutations within the C-terminal two thirds of the protein are required for enhanced rapamycin lethality. Our findings demonstrate separation of function explainable by differential binding of Tel2 to its PIKK substrates Tel1 or Tor1/Tor2 and thus a critical contribution of Tel2 to the interface that links various PIKKs to this chaperone complex. PMID- 22227189 TI - The matrix metalloproteinase-7 regulates the extracellular shedding of syndecan-2 from colon cancer cells. AB - The cell surface heparan sulfate proteoglycan syndecan-2 regulates the activation of matrix metalloproteinase-7 (MMP-7) as a docking receptor. Here, we demonstrate the role of MMP-7 on syndecan-2 shedding in colon cancer cells. Western blot analysis showed that shed syndecan-2 was found in the culture media from various colon cancer cells. Overexpression of MMP-7 enhanced syndecan-2 shedding, whereas the opposite was true when MMP-7 levels were knocked-down using small inhibitory RNAs. Consistently, HT29 cells treated with MMP-7, but neither MMP-2 nor MMP-9, showed increased shed syndecan-2 in a time- and concentration-dependent manner. Furthermore, MALDI-TOF MS analysis and N-terminal amino acid sequencing revealed that MMP-7 cleaved both recombinant syndecan-2 and an endogenously glycosylated syndecan-2 ectodomain in the N-terminus at Leu(149) residue in vitro. Taken together, the data suggest that MMP-7 directly mediates shedding of syndecan-2 from colon cancer cells. PMID- 22227190 TI - Using a ubiquitin ligase as an unfolded protein sensor. AB - A significant fraction of all proteins are misfolded and must be degraded. The ubiquitin-proteasome pathway provides an essential protein quality control function necessary for normal cellular homeostasis. Substrate specificity is mediated by proteins called ubiquitin ligases. In the endoplasmic reticulum (ER) a specialized pathway, the endoplasmic reticulum associated degradation (ERAD) pathway provides means to eliminate misfolded proteins from the ER. One marker used by the ER to identify misfolded glycoproteins is the presence of a high mannose (Man5-8GlcNAc2) glycan. Recently, FBXO2 was shown to bind high mannose glycans and participate in ERAD. Using glycan arrays, immobilized glycoprotein pulldowns, and glycan competition assays we demonstrate that FBXO2 preferentially binds unfolded glycoproteins. Using recombinant, bacterially expressed GST-FBXO2 as an unfolded protein sensor we demonstrate it can be used to monitor increases in misfolded glycoproteins after physiological or pharmaceutical stressors. PMID- 22227191 TI - The structural basis of the response regulator DrRRA from Deinococcus radiodurans. AB - DrRRA, a vital and recently discovered gene product of Deinococcus radiodurans, is a member of the OmpR/PhoB family of response regulators that couple with the cognate histidine kinase (HK) to form a typical two component system (TCS). It is known that the DrRRA is responsible for the transcriptional levels of numerous genes mostly relating to the stress response and DNA repair. In this paper, the crystal structures of the effector domain and full-length protein of DrRRA with resolutions of 1.6 and 2.3A, respectively, are determined. These crystal structures depicted that DrRRA has the structural features of the OmpR/PhoB subfamily and were also confirmed by SAXS investigation of the protein in solution. Our data suggest that the receiver domain blocks the binding of DNA to the DNA recognition helix of effector domain; while the interdomain interface would be unwrapped, via the phosphorylation of receiver domain and/or the inducement of DNA, in order to provide DNA binding. PMID- 22227192 TI - Acetylation of sphingosine kinase 1 regulates cell growth and cell-cycle progression. AB - Sphingosine kinase 1 (SPK1) is a key enzyme in the sphingolipid metabolic pathway. It forms an essential checkpoint to regulate the relative levels of bioactive sphingolipid metabolites, ceramide, sphingosine, and sphingosine 1 phosphate (S1P). Here, we present evidence that SPK1 is acetylated by the intrinsic acetyltransferase activity of p300/cAMP-response element-binding protein (CREB)-binding protein (CBP) at a conserved acetylation motif (the GK motif). This post-translational modification may be an important regulator of SPK1 protein, as acetylation by p300 or CBP increased its stability. Mutation of two lysine (K) residues in its GK motif to either arginine (R) or glutamine (Q) blocked SPK1 ubiquitination and prevented its degradation by the proteasome. The processes of acetylation and ubiquitination may compete for the same lysine residues and, therefore, form a switch for SPK1 protein regulation. Intriguingly, human embryonic kidney (HEK) 293 cells stably expressed the mutated form of SPK1, in which the K residue was mutated to Q (Q-SPK1), and this mutated form mimicked acetylated SPK1. These cells were larger in size and had a slower growth rate compared to cells that expressed wild-type SPK1 (W-SPK1) or the K/R-mutated SPK1 (R-SPK1). These data suggest that SPK1 acetylation plays a key role in cell growth, cell size, and cell-cycle control. PMID- 22227193 TI - Casuarinin suppresses TARC/CCL17 and MDC/CCL22 production via blockade of NF kappaB and STAT1 activation in HaCaT cells. AB - Casuarinin is a naturally occurring tannin that is isolated from the leaves of Hippophae rhamnoides. It has been shown to have anti-oxidant, anti-cancer, anti viral, and anti-inflammatory activities. The aim of this study was to investigate the possible mechanism by which casuarinin inhibits TNF-alpha/IFN-gamma-induced Th2 chemokines expression in the human keratinocytes cell line HaCaT. We found that casuarinin suppressed TNF-alpha/IFN-gamma-induced expression of TARC and MDC mRNA and protein in HaCaT cells. Casuarinin significantly inhibited TNF-alpha/IFN gamma-induced activation of NF-kappaB, STAT1, and p38 MAPK. Furthermore, we observed that p38 MAPK contributes to inhibition of TNF-alpha/IFN-gamma-induced TARC and MDC production by blocking NF-kappaB and STAT1 activation in HaCaT cells. Taken together, these results suggest that casuarinin may exert anti inflammatory responses by suppressing TNF-alpha/IFN-gamma-induced expression of TARC and MDC via blockage of p38 MAPK activation and subsequent activation of NF kappaB and STAT1. We propose that it could therefore be used as a therapeutic agent against inflammatory skin diseases. PMID- 22227194 TI - The late endosome/lysosome-anchored p18-mTORC1 pathway controls terminal maturation of lysosomes. AB - The late endosome/lysosome membrane adaptor p18 (or LAMTOR1) serves as an anchor for the mammalian target of rapamycin complex 1 (mTORC1) and is required for its activation on lysosomes. The loss of p18 causes severe defects in cell growth as well as endosome dynamics, including membrane protein transport and lysosome biogenesis. However, the mechanisms underlying these effects on lysosome biogenesis remain unknown. Here, we show that the p18-mTORC1 pathway is crucial for terminal maturation of lysosomes. The loss of p18 causes aberrant intracellular distribution and abnormal sizes of late endosomes/lysosomes and an accumulation of late endosome specific components, including Rab7, RagC, and LAMP1; this suggests that intact late endosomes accumulate in the absence of p18. These defects are phenocopied by inhibiting mTORC1 activity with rapamycin. Loss of p18 also suppresses the integration of late endosomes and lysosomes, resulting in the defective degradation of tracer proteins. These results suggest that the p18-mTORC1 pathway plays crucial roles in the late stages of lysosomal maturation, potentially in late endosome-lysosome fusion, which is required for processing of various macromolecules. PMID- 22227195 TI - Enhanced response of T lymphocytes from Pgap3 knockout mouse: Insight into roles of fatty acid remodeling of GPI anchored proteins. AB - Glycosylphosphatidylinositol (GPI) is a complex glycolipid that serves as a membrane anchor for many cell-surface proteins, such as Thy-1 and CD48. GPI anchored proteins (GPI-APs) play important roles in many biological processes, such as signal transduction and cell-cell interaction, through their association with lipid rafts. Fatty acid remodeling of GPI-APs in the Golgi apparatus is required for their efficient association with lipid rafts, i.e., the unsaturated fatty acid at the sn-2 position of the PI moiety is exchanged for the saturated fatty acid by PGAP2 and PGAP3. To investigate the immunological role of the fatty acid remodeling of GPI-APs, we generated a Pgap3 knockout mouse. In this mouse, GPI-APs are expressed on the cell surface without fatty acid remodeling, and fail to associate with lipid rafts. Male Pgap3 knockout mice were born alive at a ratio lower than expected from Mendel's law, whereas the number of female mice followed Mendel's law. All mice exhibited growth retardation and abnormal reflexes such as limb grasping. We focused T cell function in these mice and found that T cell development in the absence of Pgap3 was normal. However, the response of T cells was enhanced in Pgap3 knockout mice in both in vitro and in vivo studies, including alloreactive response, antigen-specific immune response, and experimental autoimmune encephalomyelitis. Cross-linking of Thy-1 in wild type cells inhibited the signal transduced by the T cell receptor (TCR), whereas cross-linking of Thy-1 in Pgap3 knockout cells enhanced the TCR signal. These results suggest that GPI-APs localized in lipid rafts may modulate signaling through the TCR. PMID- 22227196 TI - miR-30 inhibits TGF-beta1-induced epithelial-to-mesenchymal transition in hepatocyte by targeting Snail1. AB - Epithelial-to-mesenchymal transition (EMT) has been implicated in embryonic development and various pathological events. Snail1 is a well-known E-cadherin transcriptional repressor that is significantly upregulated during the TGF-beta1 induced EMT in hepatocyte. However, the functional involvement of microRNA during the EMT process in hepatocyte remains to be determined. Here, we revealed that while the expression of Snail1 increased during the TGF-beta1-induced EMT in AML12 murine hepatocytes, the expression of miR-30 family members exhibited significant downregulation. Computational microRNA target predictions detected a conserved sequence matching to the seed region of miR-30 in the 3'UTR of Snail1 mRNA. Our results demonstrated that miR-30 could negatively regulate the expression of Snail1 by direct targeting the predicted binding site. More importantly, transfection of miR-30b mimics significantly inhibited the TGF-beta1 induced EMT in AML12 cells as assessed through cell morphology changes and the expression profiles of Snail1, E-cadherin and other fibroblast markers. Finally, we demonstrated that TGF-beta1-induced hepatocyte migration was greatly suppressed in cells transfected with miR-30b mimics. Our results provide a new insight into the role of miR-30 in regulating EMT, which could be of importance in understanding the related physiologic and pathologic processes. PMID- 22227197 TI - The effect of salt on oligocation-induced chromatin condensation. AB - Condensation of model chromatin in the form of fully saturated 12-mer nucleosome arrays, induced by addition of cationic ligands (epsilon-oligolysines with charge varied from +4 to +11), was studied in a range of KCl concentrations (10-500mM) using light scattering and precipitation assay titrations. The dependence of EC(50) (ligand concentration at the midpoint of the array condensation) on C(KCl) displays two regimes, a salt-independent at low C(KCl) and a salt-dependent at higher salt concentrations. In the salt-dependent regime EC(50) rises sharply with increase of C(KCl). Increase of ligand charge shifts the transition from the salt-independent to salt-dependent regime to higher salt. In the nucleosome array system, due to the partial neutralization of the DNA charge by histones, a lower oligocation concentration is needed to provoke condensation in the salt independent regime compared to the related case of DNA condensation by the same cation. In the physiological range of salt concentrations (C(KCl)=50-300mM), K(+) ions assist array condensation by shifting EC(50) of the epsilon-oligolysines to lower values. At higher C(KCl), K(+) competes with the cationic ligands, which leads to increase of EC(50). Values of salt-dependent dissociation constant for the epsilon-oligolysine-nucleosome array interaction were obtained, by fitting to a general equation developed earlier for DNA, describing the dependence of EC(50) on dissociation constant, salt and polyelectrolyte concentrations. PMID- 22227198 TI - Human thermoregulation and the cardiovascular system. AB - A key but little understood function of the cardiovascular system is to exchange heat between the internal body tissues, organs and the skin to maintain internal temperature within a narrow range in a variety of conditions that produce vast changes in external (exogenous) and/or internal (endogenous) thermal loads. Heat transfer via the flowing blood (i.e. vascular convective heat transfer) is the most important heat-exchange pathway inside the body. This pathway is particularly important when metabolic heat production increases many-fold during exercise. During exercise typical of many recreational and Olympic events, heat is transferred from the heat-producing contracting muscles to the skin surrounding the exercising limbs and to the normally less mobile body trunk and head via the circulating blood. Strikingly, a significant amount of heat produced by the contracting muscles is liberated from the skin of the exercising limbs. The local and central mechanisms regulating tissue temperature in the exercising limbs, body trunk and head are essential to avoid the deleterious consequences on human performance of either hyperthermia or hypothermia. This brief review focuses on recent literature addressing the following topics: (i) the dynamics of heat production in contracting skeletal muscle; (ii) the influence of exercise and environmental heat and cold stress on limb and systemic haemodynamics; and (iii) the impact of changes in muscle blood flow on heat exchange in human limbs. The paper highlights the need to investigate the responses and mechanisms of vascular convective heat exchange in exercising limbs to advance our understanding of local tissue temperature regulation during exercise and environmental stress. PMID- 22227199 TI - Local sweating on the forehead, but not forearm, is influenced by aerobic fitness independently of heat balance requirements during exercise. AB - The present study investigated the influence of maximal oxygen uptake (V(O2 max)) on local steady-state sudomotor responses to exercise, independently of evaporative requirements for heat balance (E(req)). Eleven fit (F; (V(O2 max))61.9 +/- 6.0 ml kg(-1) min(-1)) and 10 unfit men (UF; (V(O2 max)) 40.4 +/- 3.8 ml kg(-1) min(-1)) cycled for 60 min at an air temperature of 24.5 +/- 0.8 degrees C and ambient humidity of 0.9 +/- 0.3 kPa at a set metabolic heat production per unit surface area, producing the same E(req) in all participants (BAL trial) and, in a second trial, at 60% of (V(O2 max)). During the BAL trial, absolute power (F 107 +/- 2 and UF 102 +/- 2 W; P = 0.126), E(req) (F 175 +/- 5 and UF 176 +/- 9 W m(-2); P = 0.855), steady-state whole-body sweat rate (F 0.44 +/- 0.02 and UF 0.47 +/- 0.02 mg cm(-2) min(-1); P = 0.385) and local sweat rate on the arm (F 0.29 +/- 0.03 and UF 0.35 +/- 0.03 mg cm(-2) min(-1); P = 0.129) were not different between groups; however, local sweat rate on the forehead in UF (1.67 +/- 0.20 mg cm(-2) min(-1)) was almost double (P = 0.002) that of F (0.87 +/- 0.11 mg cm(-2) min(-1)). Heart rate, ratings of perceived exertion and relative exercise intensity were also significantly greater in UF (P < 0.05). There was a trend towards an elevated minute ventilation in UF (P = 0.052), while end-tidal P(CO2) was significantly lower in UF (P = 0.028). At 60% (V(O2 max)), absolute power (F 174 +/- 6 and UF 110 +/- 5 W; P < 0.001), E(req) (F 291 +/- 14 and UF 190 +/- 17 W m(-2); P < 0.001), steady-state whole-body sweat rate (F 0.84 +/- 0.05 and UF 0.53 +/- 0.03 mg cm(-2) min(-1); P < 0.001) and local sweat rate on the arm (F 0.75 +/- 0.04 and UF 0.35 +/- 0.03 mg cm(-2) min(-1); P < 0.001) and on the forehead (F 2.92 +/- 0.42 and UF 1.68 +/- 0.23 mg cm(-2) min(-1); P = 0.022) were all significantly greater in F compared with UF. Heart rate and ratings of perceived exertion were similar at all time points (P > 0.05). Significantly greater minute ventilation (P < 0.001) and end-tidal P (CO2) responses (P = 0.017) were found in F. In conclusion, aerobic fitness alters local sweating on the forehead, but not the forearm, independently of evaporative requirements for heat balance, and may be the result of differential control of sweating in these skin areas associated with the relative intensity of exercise. PMID- 22227200 TI - Na+ transport across rumen epithelium of hay-fed sheep is acutely stimulated by the peptide IGF-1 in vitro. AB - An energy-rich diet leads to enhanced ruminal Na(+) absorption, which is associated with elevated plasma insulin-like growth factor 1 (IGF-1) levels and an increased number of IGF-1 receptors in rumen papillae. This study examined the in vitro effect of IGF-1 on Na(+) transport across the rumen epithelium of hay fed sheep, in which the IGF-1 concentration in plasma is lower than in concentrate-fed animals. At concentrations ranging from 20 to 100 MUg l(-1), serosal LR3-IGF-1, a recombinant analogue of IGF-1, rapidly (within 30 min) stimulated the mucosal-to-serosal Na(+) flux (J(ms)Na) and consequently the net Na(+) flux (J(net)Na). Compared with controls, J(net)Na increased by about 60% (P < 0.05) following the serosal application of LR3-IGF-1 (20 MUg l(-1)). The IGF-1 induced increment of J(ms)Na and J(net)Na was inhibited by mucosal amiloride (1 mmol l(-1)). Neither IGF-1 nor amiloride altered tissue conductance or the short circuit current of the isolated rumen epithelium. These data support the assumption that the stimulating effect of serosally applied IGF-1 on Na(+) transport across the rumen epithelium is mediated by Na(+)-H(+) exchange (NHE). A further study was performed with cultured rumen epithelial cells and a fluorescent probe (BCECF) to estimate the rate of pH(i) recovery after acid loading. The pH(i) of isolated rumen epithelial cells was 6.43 +/- 0.15 after butyrate loading and recovered by 0.26 +/- 0.02 pH units (15 min)(-1). Application of LR3-IGF-1 (20 MUg l(-1)) significantly increased the rate of pH(i) recovery to 0.33 +/- 0.02 pH units (15 min)(-1). Amiloride administration reduced the recovery rate in both control and IGF-1-stimulated cells. These results show, for the first time, that an acute effect of IGF-1 on Na(+) absorption across rumen epithelium results from increased NHE activity. Insulin-like growth factor 1 is thus important for the fast functional adaptation of ruminal Na(+) transport via NHE. PMID- 22227201 TI - Perspective on the role of P2X-purinoceptor activation in human vas deferens contractility. AB - The contractile actions of alpha,beta-methylene ATP (alpha,beta-meATP) and ATP and the effects of K(+) channel blockers in longitudinal and circular muscles of human vas deferens were investigated with a view to clarifying the functional importance of P2X(1)-purinoceptor activation and K(+) channels in modulating contractility of the tissues. The results provide an experiment-based perspective for resolving differing reports on purinergic activation of the tissues and uncertain roles of large-conductance Ca(2+)-activated K(+) (BK(Ca)) and voltage gated delayed rectifier K(+) (K(V)) channels. alpha,beta-Methylene ATP (3-100 MUm) evoked suramin-sensitive contractions of longitudinal muscle but rarely of circular muscle. ATP (0.1-3 mm) less reliably activated only longitudinal muscle contractions. These were enhanced by ARL 67156 (100 MUm), but a different ectonucleotidase inhibitor, POM 1, was ineffective. Both muscle types were unresponsive to ADP-betaS (100 MUm), a P2Y-purinoceptor agonist. Longitudinal muscle contractions in response to alpha,beta-meATP were enhanced by FPL 64176 (1 MUm), an L-type Ca(2+) agonist, TEA (1 mm), a non-specific K(+) channel blocker, 4-aminopyridine (0.3 mm), a selective blocker of K(V) channels, and iberiotoxin (0.1 MUm), a selective blocker of BK(Ca) channels. Quiescent circular muscles responded to alpha,beta-meATP reliably in the presence of FPL 64176 or iberiotoxin. Apamin (0.1 MUm), a selective blocker of small conductance Ca(2+) activated K(+) (SK(Ca)) channels had no effect in both muscle types. Y-27632 (1 10 MUm) reduced longitudinal muscle contractions in response to alpha,beta-meATP, suggesting involvement of Rho-kinase-dependent contractile mechanisms. The results indicate that P2X(1)-purinoceptor stimulation elicits excitatory effects that: (a) lead to longitudinal muscle contraction and secondary activation of 4 aminopyridine-sensitive (K(V)) and iberiotoxin-sensitive (BK(Ca)) K(+) channels; and (b) are subcontractile in circular muscle due to ancillary activation of BK(Ca) channels. The novel finding of differential action by P2X(1)-purinoceptor agonists in the muscle types has functional implication in terms of the purinergic contribution to overall contractile function of human vas deferens. The modulatory effects of K(V) and BK(Ca) channels following P2X(1)-purinoceptor activation may be pivotal in providing the crucial physiological mechanism that ensures temporal co-ordination of longitudinal and circular muscle contractility. PMID- 22227202 TI - Temperature-dependent release of ATP from human erythrocytes: mechanism for the control of local tissue perfusion. AB - Human limb muscle and skin blood flow increases significantly with elevations in temperature, possibly through physiological processes that involve temperature sensitive regulatory mechanisms. Here we tested the hypothesis that the release of the vasodilator ATP from human erythrocytes is sensitive to physiological increases in temperature both in vitro and in vivo, and examined potential channel/transporters involved. To investigate the source of ATP release, whole blood, red blood cells (RBCs), plasma and serum were heated in vitro to 33, 36, 39 and 42 degrees C. In vitro heating augmented plasma or 'bathing solution' ATP in whole blood and RBC samples, but not in either isolated plasma or serum samples. Heat-induced ATP release was blocked by niflumic acid and glibenclamide, but was not affected by inhibitors of nucleoside transport or anion exchange. Heating blood to 42 degrees C enhanced (P < 0.05) membrane protein abundance of cystic fibrosis transmembrane conductance regulator (CFTR) in RBCs. In a parallel in vivo study in humans exposed to whole-body heating at rest and during exercise, increases in muscle temperature from 35 to 40 degrees C correlated strongly with elevations in arterial plasma ATP (r(2) = 0.91; P = 0.0001), but not with femoral venous plasma ATP (r(2) = 0.61; P = 0.14). In vitro, however, the increase in ATP release from RBCs was similar in arterial and venous samples heated to 39 degrees C. Our findings demonstrate that erythrocyte ATP release is sensitive to physiological increases in temperature, possibly via activation of CFTR-like channels, and suggest that temperature-dependent release of ATP from erythrocytes might be an important mechanism regulating human limb muscle and skin perfusion in conditions that alter blood and tissue temperature. PMID- 22227203 TI - Pulmonary intravascular macrophages and lung health: what are we missing? AB - Pulmonary intravascular macrophages (PIMs) are constitutively found in species such as cattle, horse, pig, sheep, goat, cats, and whales and can be induced in species such as rats, which normally lack them. It is believed that human lung lacks PIMs, but there are previous suggestions of their induction in patients suffering from liver dysfunction. Recent data show induction of PIMs in bile-duct ligated rats and humans suffering from hepato-pulmonary syndrome. Because constitutive and induced PIMs are pro-inflammatory in response to endotoxins and bacteria, there is a need to study their biology in inflammatory lung diseases such as sepsis, asthma, chronic obstructive pulmonary diseases, or hepato pulmonary syndrome. We provide a review of PIM biology to make an argument for increased emphasis and better focus on the study of human PIMs to better understand their potential role in the pathophysiology and mechanisms of pulmonary diseases. PMID- 22227205 TI - Effect of alveolar epithelial cell plasticity on the regulation of GM-CSF expression. AB - Local pulmonary expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) is critically important for defense of the pulmonary alveolar space. It is required for surfactant homeostasis and pulmonary innate immune responses and is protective against lung injury and aberrant repair. Alveolar epithelial cells (AEC) are a major source of GM-CSF; however, the control of homeostatic expression of GM-CSF is incompletely characterized. Increasing evidence suggests considerable plasticity of expression of AEC phenotypic characteristics. We tested the hypothesis that this plasticity extends to regulation of expression of GM-CSF using 1) MLE-12 cells (a commonly used murine cell line expressing some features of normal type II AEC, 2) primary murine AEC incubated under standard conditions [resulting in rapid spreading and loss of surfactant protein C (SP-C) expression with induction of the putative type I cell marker (T1alpha)], or 3) primary murine AEC on a hyaluronic acid/collagen matrix in defined medium, resulting in preservation of SP-C expression. AEC in standard cultures constitutively express abundant GM-CSF, with further induction in response to IL 1beta but little response to TNF-alpha. In contrast, primary cells cultured to preserve SP-C expression and MLE-12 cells both express little GM-CSF constitutively, with significant induction in response to TNF-alpha and limited response to IL-1beta. We conclude that constitutive and cytokine-induced expression of GM-CSF by AEC varies in concert with other cellular phenotypic characteristics. These changes may have important implications both for the maintenance of normal pulmonary homeostasis and for the process of repair following lung injury. PMID- 22227204 TI - Direct and indirect roles for beta-catenin in facultative basal progenitor cell differentiation. AB - The conducting airway epithelium is maintained and repaired by endogenous progenitor cells. Dysregulated progenitor cell proliferation and differentiation is thought to contribute to epithelial dysplasia in chronic lung disease. Thus modification of progenitor cell function is an attractive therapeutic goal and one that would be facilitated by knowledge of the molecular pathways that regulate their behavior. We modeled the human tracheobronchial epithelium using primary mouse tracheal epithelial cell cultures that were differentiated by exposure to the air-liquid-interface (ALI). A basal cell subset, termed facultative basal cell progenitors (FBP), initiate these cultures and are the progenitor for tracheal-specific secretory cells, the Clara-like cell, and ciliated cells. To test the hypothesis that beta-catenin is necessary for FBP function, ALI cultures were generated from mice homozygous for the Ctnb(flox(E2 6)) allele. In this model, exons 2-6 of the beta-catenin gene are flanked by LoxP sites, allowing conditional knockout of beta-catenin. The beta-catenin locus was modified through transduction with Adenovirus-5-encoding Cre recombinase. This approach generated a mosaic epithelium, comprised of beta-catenin wild-type and beta-catenin knockout cells. Dual immunostaining and quantitative histomorphometric analyses demonstrated that beta-catenin played a direct role in FBP-to-ciliated cell differentiation and that it regulated cell-cell interactions that were necessary for FBP-to-Clara-like cell differentiation. beta-catenin was also necessary for FBP proliferation and long-term FBP viability. We conclude that beta-catenin is a critical determinant of FBP function and suggest that dysregulation of the beta-catenin signaling pathway may contribute to disease pathology. PMID- 22227206 TI - BMP type II receptor deficiency confers resistance to growth inhibition by TGF beta in pulmonary artery smooth muscle cells: role of proinflammatory cytokines. AB - Mutations in the bone morphogenetic protein (BMP) type II receptor (BMPR-II) underlie most cases of heritable pulmonary arterial hypertension (HPAH) and a significant proportion of sporadic cases. Pulmonary artery smooth muscle cells (PASMCs) from patients with pulmonary arterial hypertension (PAH) not only exhibit attenuated growth suppression by BMPs, but an abnormal mitogenic response to transforming growth factor (TGF)-beta1. We sought to define the mechanism underlying this loss of the antiproliferative effects of TGF-beta1 in BMPR-II deficient PASMCs. The effect of TGF-beta1 on PASMC proliferation was characterized in three different models of BMPR-II dysfunction: 1) HPAH PASMCs, 2) Bmpr2(+/-) mouse PASMCs, and 3) control human PASMCs transfected with BMPR-II small interfering RNA. BMPR-II reduction consistently conferred insensitivity to growth inhibition by TGF-beta1. This was not associated with altered canonical TGF-beta1/Smad signaling but was associated with a secreted factor. Microarray analysis revealed that the transcriptional responses to TGF-beta1 differed between control and HPAH PASMCs, particularly regarding genes associated with interleukins and inflammation. HPAH PASMCs exhibited enhanced IL-6 and IL-8 induction by TGF-beta1, an effect reversed by NF-kappaB inhibition. Moreover, neutralizing antibodies to IL-6 or IL-8 restored the antiproliferative effect of TGF-beta1 in HPAH PASMCs. This study establishes that BMPR-II deficiency leads to failed growth suppression by TGF-beta1 in PASMCs. This effect is Smad-independent but is associated with inappropriately altered NF-kappaB signaling and enhanced induction of IL-6 and IL-8 expression. Our study provides a rationale to test anti-interleukin therapies as an intervention to neutralize this inappropriate response and restore the antiproliferative response to TGF-beta1. PMID- 22227208 TI - Ginsenoside Rd attenuates the inflammatory response via modulating p38 and JNK signaling pathways in rats with TNBS-induced relapsing colitis. AB - In this study, we investigated the effects and the protective mechanism of ginsenoside Rd (GRd) which has been identified as one of the effective compounds from ginseng on relapsing colitis model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats. After inducing relapsing colitis in experimental rats on two occasions by intracolonic injection of TNBS, GRd (10, 20 and 40 mg/kg) was administered to experimental colitis rats for 7 days. The inflammatory degree was assessed by macroscopic score, histology and myeloperoxidase (MPO) activity. The levels of proinflammatory cytokines, such as TNF-alpha, IL-1beta, and IL-6 were determined by ELISA. Mitogen-activated protein kinase (MAPK) phosphorylation was analyzed by western blotting method. The results showed that GRd markedly attenuates the inflammatory response to TNBS-induced relapsing colitis, as evidenced by improved signs, increased body weight, decreased colonic weight/length ratio, reduced colonic macroscopic and microscopic damage scores, inhibited the activity of MPO, lowered proinflammatory cytokine levels and suppressed phosphorylation of p38 and JNK. The possible mechanism of protection on experimental colitis after GRd administration was that it could reduce the accumulation of leukocytes and down-regulate multiple proinflammatory cytokines through modulation of JNK and p38 activation. PMID- 22227207 TI - miR-21 regulates chronic hypoxia-induced pulmonary vascular remodeling. AB - Chronic hypoxia causes pulmonary vascular remodeling leading to pulmonary hypertension (PH) and right ventricle (RV) hypertrophy. Aberrant expression of microRNA (miRNA) is closely associated with a number of pathophysiologic processes. However, the role of miRNAs in chronic hypoxia-induced pulmonary vascular remodeling and PH has not been well characterized. In this study, we found increased expression of miR-21 in distal small arteries in the lungs of hypoxia-exposed mice. Putative miR-21 targets, including bone morphogenetic protein receptor (BMPR2), WWP1, SATB1, and YOD1, were downregulated in the lungs of hypoxia-exposed mice and in human pulmonary artery smooth muscle cells (PASMCs) overexpressing miR-21. We found that sequestration of miR-21, either before or after hypoxia exposure, diminished chronic hypoxia-induced PH and attenuated hypoxia-induced pulmonary vascular remodeling, likely through relieving the suppressed expression of miR-21 targets in the lungs of hypoxia exposed mice. Overexpression of miR-21 enhanced, whereas downregulation of miR-21 diminished, the proliferation of human PASMCs in vitro and the expression of cell proliferation associated proteins, such as proliferating cell nuclear antigen, cyclin D1, and Bcl-xL. Our data suggest that miR-21 plays an important role in the pathogenesis of chronic hypoxia-induced pulmonary vascular remodeling and also suggest that miR-21 is a potential target for novel therapeutics to treat chronic hypoxia associated pulmonary diseases. PMID- 22227209 TI - In end stage osteoarthritis, cartilage tissue pentosidine levels are inversely related to parameters of cartilage damage. AB - OBJECTIVES: Age is the most prominent predisposition for development of osteoarthritis (OA). Age-related changes of articular cartilage are likely to play a role. Advanced glycation endproducts (AGEs) accumulate in cartilage matrix with increasing age and adversely affect the biomechanical properties of the cartilage matrix and influence chondrocyte activity. In clinical studies AGEing of cartilage and its relation to actual cartilage damage can only be measured by surrogate markers (e.g., serum, skin or urine AGE levels and imaging or biochemical markers of cartilage damage). In this study actual cartilage AGE levels were directly related to actual cartilage damage by use of cartilage obtained at joint replacement surgery. METHODS: Cartilage and urine samples were obtained from 69 patients undergoing total knee replacement. Samples were analyzed for pentosidine as marker of AGE. Cartilage damage was evaluated macroscopically, histologically, and biochemically. RESULTS: Cartilage and urine pentosidine both increased with increasing age. The higher the macroscopic, histological, and biochemical cartilage damage the lower the cartilage pentosidine levels were. In multiple regression analysis age is not found to be a confounder. CONCLUSION: There is an inverse relation between cartilage AGEs and actual cartilage damage in end-stage OA. This is likely due to ongoing (ineffective) increased turnover of cartilage matrix proteins even in end stage disease. PMID- 22227210 TI - Anion inhibition studies of an alpha-carbonic anhydrase from the living fossil Astrosclera willeyana. AB - An alpha-carbonic anhydrase (CA, EC 4.2.1.1) isolated from the living fossil sponge Astrosclera willeyana, Astrosclerin, was investigated for its inhibition profile with simple inorganic anions, complex anions and other small molecules known to interact with these zinc enzymes. Astrosclerin is a catalytically highly efficient enzyme, and is inhibited in the low micromolar range by sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid, and in the submillimolar range by a variety of anions including fluoride, chloride, cyanate, thiocyanate, cyanide, hydrogen sulfide, bisulfate, stannate, perosmate, divanadate, perrhenate, perruthenate, selenocyanide, trithiocarbonate, diethyldithiocarbamate and iminodisulfonate. Less efficient Astrosclerin inhibitors were sulfate, bromide, iodide, azide, bicarbonate, carbonate, tetraborate and perchlorate (K(I)s of 5.11-30.6mM) whereas tetrafluoroborate was not at all inhibitory. Because Astrosclerin is involved in calcification processes in vivo, its anion inhibition profile may be important for future studies designed to shed light on the physiologic functions of alpha-CAs in marine organisms. PMID- 22227211 TI - Intrinsic curvature in duplex DNA inhibits Human Topoisomerase I. AB - Human Topoisomerase I (hTopo I) have been known as a potential target for cancer therapy. A series of duplex DNA with different intrinsic curvatures have been designed as inhibitors to hTopo I. The activities of hTopo I on relaxing supercoiled plasmid pUC 19 are apparently diminished in the presence of the curved DNA. More potent inhibitions and smaller IC(50) are achieved by duplex DNA with higher curvatures. EMSA indicates that hTopo I can recognize the curved DNA through binding interactions. Our studies demonstrate that the activity of hTopo I can be modulated by the intrinsic curvature of linear DNA and provide a new avenue to design curved DNA as hTopo I inhibitors with high therapeutic efficiency and low toxicity. PMID- 22227212 TI - Pyrazoloquinolines as PDE10A inhibitors: discovery of a tool compound. AB - A series of pyrazoloquinolines, possessing (hetero)arylhydroxymethyl substituents at the quinoline C-4 position were evaluated as PDE10A inhibitors. Among these, methylpyrimidyl analogue 15 was identified as having good rodent and monkey exposure, and a MED of 10 mg/kg in an in vivo model. PMID- 22227213 TI - Identification of novel SAR properties of the Jak2 small molecule inhibitor G6: significance of the para-hydroxyl orientation. AB - In this study, we analyzed the structure-activity relationship properties of the small molecule Jak2 inhibitor G6. We synthesized a set of derivatives containing the native para-hydroxyl structure or an alternative meta-hydroxyl structure and examined their Jak2 inhibitory properties. We found that the para-hydroxyl derivative known as NB15 had excellent Jak2 inhibitory properties in silico, in vitro, and ex vivo when compared with meta-hydroxyl derivatives. These results indicate that NB15 is a potent derivative of the Jak2 inhibitor G6, and that maintaining the para-hydroxyl orientation of G6 is critical for its Jak2 inhibitory potential. PMID- 22227214 TI - Discovery of novel selective inhibitors for EGFR-T790M/L858R. AB - Through a receptor-based and ligand-based combined virtual screening protocol, 21 novel compounds covering 15 scaffolds were identified as novel inhibitors for EGFR-T790M/L858R, among which, 12 of them were identified as selective inhibitors for EGFR-T790M/L858R to wild-type EGFR, and 5 of them exhibited 'dual-effective' to wild-type and mutant EGFR. Meanwhile, their antiproliferative effects toward EGFR high-expressing human lung cancer cell (A549), epidermoid carcinoma cell (A431), and the mutant EGFR-dependent cell (NCI-H1975) were also evaluated. PMID- 22227215 TI - Alterations in oxidative stress biomarkers associated with mild hyperlipidemia and smoking. AB - Oxidative stress may increase the risk of atherosclerosis. The association of mild forms of hyperlipidemia, particularly primary hypertriglyceridemia, with oxidative stress has not been fully investigated. The aim of this study was to assess the alterations in oxidative stress biomarkers associated with three major types of mild untreated hyperlipidemia (hypercholesterolemia, hypertriglyceridemia and combined hyperlipidemia) in nonsmoker and smoker individuals. Five biomarkers were measured in 139 adult healthy men (83 nonsmokers and 56 smokers, ages 18-75), which included normolipidemic and hyperlipidemic subjects. Triglyceride levels were associated with a significant main effect on ferric reducing antioxidant power (FRAP) and 8-iso-prostaglandin F2alpha (iPF2alpha) levels in plasma (p<0.05 and p<0.005, respectively). Smokers with hypercholesterolemia, hypertriglyceridemia and combined hyperlipidemia had alterations in 1, 3 and 2 oxidative stress biomarkers compared to nonsmoker normolipidemics. Smokers (including normolipidemics and hyperlipidemics) had higher plasma FRAP (120.8 vs. 102.0 MUM quercetin/l, p<0.05) and erythrocyte catalase activity (5125 vs. 4093 U/g Hb, p<0.01), while they had lower erythrocyte glutathione peroxidase activity (20.3 vs. 23.0 U/g Hb, p<0.05) compared to nonsmokers. These findings show that mild forms of hyperlipidemia, particularly in smokers, are associated with alterations in some oxidative stress biomarkers. PMID- 22227217 TI - Development and validation of a gas chromatography-mass spectrometry method for determination of deoxynivalenol and its metabolites in human urine. AB - The determination of deoxynivalenol (DON) and its metabolites such as deepoxy deoxynivalenol (DOM-1) in human urine is complicated due its low levels (ng/mL) and the complexity of the matrix. A gas chromatography-mass spectrometry method was optimized and validated for the confirmation analysis of DON and its metabolites in urine samples using 13C isotopic-labeled DON as internal standard. In the sample preparation the type and amount of beta-glucuronidase for enzymatic hydrolysis was investigated as well as the cleanup procedure, being compared the immunoaffinity column with solid-phase extraction (SPE). As far as we know, SPE C18 cleanup procedure was applied for the first time in the analysis of DON and its metabolites in human urine. Using this analytical methodology the detection and quantification limits achieved ranged from 0.06 to 0.30 ng/mL and from 0.2 to 1.0 ng/mL, respectively. Recoveries were higher than 73% for fortification levels between 25 and 100 ng/mL and repeatability were lower than 13%. The natural occurrence of DON and its metabolites in human urine samples from the north zone of Portugal was studied. Free DON was detected in 15% of the samples whereas total (free+conjugated) DON was detected in 69% of the samples. Deepoxy deoxynivalenol, 3-acetyldeoxynivalenol and 15-acetyldeoxynivalenol were not detected in any of the samples analyzed. PMID- 22227216 TI - Lonicera japonica THUNB. protects 6-hydroxydopamine-induced neurotoxicity by inhibiting activation of MAPKs, PI3K/Akt, and NF-kappaB in SH-SY5Y cells. AB - In this study, we investigated the neuroprotective effects of Lonicera japonica THUNB. extract (LJ) on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH SY5Y cells. We found that LJ significantly increased cell viability decrease, lactate dehydrogenase release (LDH), morphological changes, nuclear condensation, fragmentation, and reactive oxygen species (ROS) production induced by 6-OHDA in SH-SY5Y cells. The cytoprotection afforded by pretreatment with LJ was associated with increases of the glutathione (GSH) level, superoxide dismutase (SOD) activity, and catalase (CAT) activity in 6-OHDA-induced SH-SY5Y cells. In addition, LJ strikingly inhibited 6-OHDA-induced mitochondrial dysfunctions including reduction of mitochondria membrane potential (MMP) and activation of cleaved poly-ADP-ribose polymerase (PARP), cleaved caspase-3, cleaved caspase-9, increased Bax, as well as decreased Bcl-2 and Bcl-xL. Additionally, LJ dramatically attenuated 6-OHDA-induced phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), extracellular signal regulated kinase 1/2 (ERK 1/2), and phosphoinositide 3-kinase (PI3K)/Akt. Meanwhile, LJ counteracted nuclear factor-kappaB (NF-kappaB) activation by blocking its translocation to the nucleus. These findings suggest that LJ has a potent anti-parkinsonism; this effect was mediated, at least in part, by inhibition of neurotoxicity, apoptotic cascade events, and oxidative stress via activation of MAPKs, PI3K/Akt, and NF-kappaB. PMID- 22227218 TI - Evaluation of IgE reactivity of active and thermally inactivated actinidin, a biomarker of kiwifruit allergy. AB - Actinidin, an abundant cysteine protease from kiwifruit, is a specific biomarker of isolated allergy to kiwifruit. This study evaluates the IgE-binding properties of biologically active and thermally inactivated actinidin. Employing two different activity assays (caseinolytic assay and zymogram with gelatin) we showed that actinidin obtained from kiwifruit extract under native conditions represents a mixture of inactive and active enzyme. The structural integrity of actinidin was confirmed by SDS-PAGE, Edman degradation, mass fingerprint and Western blot with polyclonal antibodies. Although it was capable of inducing positive skin prick test reactions, we failed to detect IgE reactivity of active actinidin in Western blot with patient sera. Thermally inactivated actinidin exhibited IgE reactivity both in vivo and in vitro, indicating that heat processed kiwifruit products may induce clinical reactivity. These findings imply that apart from the allergenic epitopes on its surface, actinidin also contains hidden epitopes inside the protein which become accessible to IgE upon thermal treatment. PMID- 22227219 TI - Development of a homologous enzyme-linked immunosorbent assay for European sea bass FSH. Reproductive cycle plasma levels in both sexes and in yearling precocious and non-precocious males. AB - Since the late 1980s, gonadotropins have been isolated and characterized in several fish species, but specific immunoassays for the follicle-stimulating hormone (FSH) have only been developed for a few. The present study reports the development and use of a specific and homologous competitive ELISA for measuring FSH in European sea bass (Dicentrarchus labrax) using a recombinant FSH and its specific antiserum. Recombinant European sea bass FSHbeta and FSH heterodimer were produced in the methylotrophic yeast Pichia pastoris and a baculovirus expression system, respectively. Specific polyclonal antibodies, generated by rabbit immunization against recombinant FSHbeta, were used at a final dilution of 1:8000. Recombinant FSH heterodimer was used to generate a standard curve and for coating of microplates (166 MUg/ml). The sensitivity of the assay was 0.5 ng/ml [B(0)-2SD], and the intra- and inter-assay coefficients of variation were 2.12% (n=10) and 5.44% (n=16) (B(i)/B(0) ~45%), respectively. A high degree of parallelism was observed between the standard curve and serially diluted plasma and pituitary samples of European sea bass. The ELISA developed was used to study the plasma FSH profiles of mature males and females during the reproductive cycle, and those of immature juvenile males under different light regimes. The analysis showed that FSH increased significantly during the intermediate stages of spermatogenesis and during vitellogenesis. Analyses in immature juvenile males showed that the continuous light photoperiod significantly reduced plasma FSH levels, and consequently, testicular growth and precocious puberty. In conclusion, the immunoassay developed has proven to be sensitive, specific and accurate for measuring European sea bass FSH, and it represents a valuable tool for future studies on the reproductive endocrinology of this species. PMID- 22227220 TI - Role of potassium channels in the antidepressant-like effect of folic acid in the forced swimming test in mice. AB - Potassium (K(+)) channels have been implicated in depressive disorders and in the mechanism of action of antidepressants. Considering that several studies have indicated that folic acid plays an important role in the pathophysiology of depression, the present study investigated the involvement of potassium channels in the antidepressant-like effect of this vitamin. For this aim, the effect of the combined administration of different types of K(+) channel blockers and folic acid in the forced swimming test (FST) was investigated. Treatment of mice by intracerebroventricular (i.c.v.) route with subactive doses of glibenclamide (an ATP-sensitive K(+) channels blocker, 0.5pg/site), charybdotoxin (a large- and intermediate-conductance calcium-activated K(+) channel blocker, 25pg/site) or apamin (a small-conductance calcium-activated K(+) channel blocker, 10pg/site), augmented the effect of folic acid (10mg/kg, p.o., subeffective dose) in the FST. Additionally, the administration of folic acid and the K(+) channel blockers, alone or in combination, did not affect locomotion in the open-field test. Moreover, the reduction in the immobility time in the FST elicited by folic acid administered at a higher dose (50mg/kg, p.o.) was prevented by the pretreatment of mice with the K(+) channel opener cromakalim (10MUg/site, i.c.v.), without affecting locomotor activity. The results of this study indicate that the antidepressant-like effect of folic acid in the FST may be at least partly due to its modulatory effects on neuronal excitability, via inhibition of K(+) channels. PMID- 22227221 TI - Analgesic, anticonvulsant and antioxidant activities of 3-[4-(3-trifluoromethyl phenyl)-piperazin-1-yl]-dihydrofuran-2-one dihydrochloride in mice. AB - Recently we have shown that 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl] dihydrofuran-2-one dihydrochloride (LPP1) is an antinociceptive and local anesthetic agent in rodents. Below an extended study of the pharmacological activity of LPP1 is described. In vitro LPP1 has no affinity for GABA(A), opioidergic MU and serotonergic 5-HT(1A) receptors. The total antioxidant capacity of LPP1 (1-10mM) measured as ABTS radical cation-scavenging activity showed that LPP1 has dose-dependent antioxidant properties in vitro. Low plasma concentration of this compound detected by means of HPLC method 30min after its intraperitoneal administration suggests a rapid conversion to metabolite(s) which may be responsible for its analgesic and anticonvulsant activities in vivo. In vivo the compound's influence on the electroconvulsive threshold and its activity in the maximal electroshock seizure test (MES) were evaluated. The results demonstrated that LPP1 had an anticonvulsant activity in the MES model (ED(50)=112mg/kg) and at a dose of 50mg/kg was able to elevate the electroconvulsive threshold for 8mA as compared to the vehicle-treated mice. The analgesic activity of LPP1 was investigated in the acetic acid-induced writhing test in two groups of mice: animals with sensory C-fibers ablated, and mice with C-fibers unimpaired. It proved the potent activity of this compound in both groups (approximately 85% as compared to the vehicle-treated mice). The adverse effects of LPP1 were evaluated as acute toxicity (LD(50)=747.8mg/kg) and motor coordination impairments in the rotarod and chimney tests. The results from these tests show that LPP1 at doses higher than 100mg/kg is likely to impair the motor performance of experimental animals. Concluding, LPP1 is an analgesic and anticonvulsant compound which has antioxidant properties in vitro. Further studies are necessary to assess whether the antioxidant activity and the receptor profiling demonstrated in vitro can be confirmed for its metabolite(s) that are formed in vivo. PMID- 22227222 TI - Hormone and metabolite changes associated with extended breeding fasts in male northern elephant seals (Mirounga angustirostris). AB - We measured metabolic hormones and several key metabolites in breeding adult male northern elephant seals to examine the regulation of fuel metabolism during extended natural fasts of over 3 months associated with high levels of energy expenditure. Males were sampled twice, early and late in the fast, losing an average of 23% of body mass and 47% of adipose stores between measurements. Males exhibited metabolic homeostasis over the breeding fast with no changes in glucose, non-esterified fatty acids, or blood urea nitrogen. Ketoacids increased over the fast but were very low when compared to other fasting species. Changes within individuals in total triiodothyronine (tT(3)) were positively related to daily energy expenditure (DEE) and protein catabolism. Differences in levels of thyroid hormones relative to that observed in weaned pups and females suggest a greater deiodination of T(4) to support the high DEE of breeding males. Relative levels of leptin and ghrelin were consistent with the suppression of appetite but a significant reduction in growth hormone across the fast was contrary to expectation in fasting mammals. The lack of the increase in cortisol during fasting found in conspecific weaned pups and lactating females may contribute to the ability of breeding males to spare protein despite high levels of energy expenditure. Together these findings reveal significant differences with conspecifics under varying nutrient demands, suggesting metabolic adaptation to extended high energy fasts. PMID- 22227224 TI - Predicting changes in lifestyle and clinical outcomes in preventing diabetes: the Greater Green Triangle Diabetes Prevention Project. AB - OBJECTIVES: To analyse how psychosocial determinants of lifestyle changes targeted in the Greater Green Triangle Diabetes Prevention Project conducted in Southeast Australia in 2004-2006 predict changes in dietary behaviour and clinical risk factors. METHODS: A longitudinal pre-test and post-test study design was used. The group program was completed by 237 people at high risk of type 2 diabetes. Associations between changes in the variables were examined by structural equation modelling using a path model in which changes in psychological determinants for lifestyle predicted changes in dietary behaviours (fat and fibre intake), which subsequently predicted changes in waist circumference and other clinical outcomes. Standardised regression weights are presented, with beta=+/-0.1 and beta=+/-0.3 representing small and medium associations, respectively. RESULTS: Improvements in coping self-efficacy and planning predicted improvements in fat (beta=-0.15, p<0.05 and beta=-0.32, p<0.001, respectively) and fibre intake (beta=0.15, p<0.05 and beta=0.23, p<0.001, respectively) which in turn predicted improvements in waist circumference (beta=0.18, p<0.01 and beta=-0.16, p<0.05, respectively). Improvements in waist circumference predicted improvements in diastolic blood pressure (beta=0.13, p<0.05), HDL (beta=-0.16, p<0.05), triglycerides (beta=0.17, p<0.01), and fasting glucose (beta=0.15, p<0.05). CONCLUSIONS: Psychological changes predicted behaviour changes, resulting in 12-month biophysical changes. The findings support the theoretical basis of the interventions. PMID- 22227223 TI - Financial incentives for smoking cessation among pregnant and newly postpartum women. AB - OBJECTIVE: Smoking during pregnancy is the leading preventable cause of poor pregnancy outcomes in the U.S., causing serious immediate and longer-term adverse effects for mothers and offspring. In this report we provide a narrative review of research on the use of financial incentives to promote abstinence from cigarette smoking during pregnancy, an intervention wherein women earn vouchers exchangeable for retail items contingent on biochemically-verified abstinence from recent smoking. METHODS: Published reports based on controlled trials are reviewed. All of the reviewed research was conducted by one of two research groups who have investigated this treatment approach. RESULTS: Results from six controlled trials with economically disadvantaged pregnant smokers support the efficacy of financial incentives for increasing smoking abstinence rates antepartum and early postpartum. Results from three trials provide evidence that the intervention improves sonographically estimated fetal growth, mean birth weight, percent of low-birth-weight deliveries, and breastfeeding duration. CONCLUSIONS: The systematic use of financial incentives has promise as an efficacious intervention for promoting smoking cessation among economically disadvantaged pregnant and recently postpartum women and improving birth outcomes. Additional trials in larger and more diverse samples are warranted to further evaluate the merits of this treatment approach. PMID- 22227225 TI - The association between rainfall and seropositivity to Leptospira in outdoor reared pigs. AB - Outdoor reared pigs were used as indicators for investigating the effect of weather conditions in the seroprevalence of Leptospira. Over the period February to March 2008, sera from 386 sows on 11 farms in southern Sweden were tested for antibodies to the following Leptospira serovars: L. interrogans serovar (sv) Bratislava, L. kirschneri sv Grippotyphosa, L. interrogans sv Icterohaemorrhagiae, L. interrogans sv Pomona, L. borgpetersenii sv Tarassovi and one domestic strain (mouse 2A) related to L. borgpetersenii sv Sejroe and L. borgpetersenii sv Istrica. The highest seroprevalence was to this strain (8.0%) followed by sv Bratislava (3.9%). Six of the 11 farms had sows which were seropositive to at least one of the Leptospira serovars. Data on rainfall and temperature were retrieved for the respective farms. For each millimetre of extra rainfall, there was an increase in the odds ratio (OR) for seropositivity to sv Bratislava of 4.3 (95% CI 1.9-10), and to strain mouse 2A of 2.5 (95% CI 1.0 6.4). There was no association between seropositivity and temperature. This study indicates that different climate conditions within the northern temperate climate zone may be of importance for the presence of Leptospira-seropositivity in mammals. PMID- 22227226 TI - Comparison of injectable robenacoxib versus meloxicam for peri-operative use in cats: results of a randomised clinical trial. AB - The objective of this study was to evaluate the efficacy and tolerability of robenacoxib, a selective cyclooxygenase-2 inhibitor, for the treatment of post operative pain and inflammation in cats. The study was a prospective, multi centre, randomised, blinded, non-inferiority design clinical study to compare robenacoxib to meloxicam. Ninety-six cats undergoing surgery at eight centres in Japan were allocated randomly to receive a single s.c. injection of robenacoxib (2 mg/kg, n=67) or meloxicam (0.3 mg/kg, n=29) shortly before induction of anaesthesia. Most cats underwent soft tissue surgery (n=87), mainly ovariectomy (n=68). Post-operative pain and inflammation were assessed at 3, 8 and 22 h after recovery from anaesthesia using numerical rating scales. For the primary efficacy endpoint (total clinician score), robenacoxib had significantly better efficacy than meloxicam, the relative efficacy ratio being 1.47 (95% confidence interval 1.19-1.78, P=0.0003). For the secondary efficacy endpoints, robenacoxib was superior to meloxicam when assessed on the basis of posture, behaviour, pain on palpation and overall pain control, while meloxicam was superior with respect to wound heat. No cat in either group required rescue analgesia therapy. In tolerability assessments, pain during injection and pain and inflammation at the injection site 22 h after recovery from anaesthesia were rated significantly less with robenacoxib compared to meloxicam. Both treatments were well tolerated on the basis of clinical observations and blood tests, with no significant differences between groups. In conclusion, single pre-operative administration of robenacoxib was well tolerated and had superior efficacy to meloxicam in reducing post-operative pain in cats. PMID- 22227227 TI - The role of mobile small RNA species during root growth and development. AB - In animals and plants, small RNAs have been identified as important regulatory factors controlling cell fate. A bidirectional cell-to-cell communication involving the mobile transcription factor SHR and microRNA165/166 species specifies the radial position of two types of xylem vessels in Arabidopsis roots. The microRNAs provide short-range non-cell-autonomous developmental signals that are transported through the plasmodesmata (PD) via the symplastic pathway. 21-24 nucleotide-long small RNA species have been shown to move from the shoot to the root. In this review, we highlight the presence of small RNA species as an emerging class of important mobile signals associated with the growth and development of the root. PMID- 22227228 TI - Structure, function and dynamics of nuclear subcompartments. AB - The nucleus contains a plethora of different dynamic structures involved in the regulation and catalysis of nucleic acid metabolism and function. Over the past decades countless factors, molecular structures, interactions and posttranslational modifications have been described in this context. On the one side of the size scale X-ray crystallography delivers static snapshots of biomolecules at atomic resolution and on the other side light microscopy allows insights into complex structures of living cells and tissues in real time but poor resolution. Recent advances in light and electron microscopy are starting to close the temporal and spatial resolution gap from the atomic up to the cellular level. Old challenges and new insights are illustrated with examples of DNA replication and nuclear protein dynamics. PMID- 22227230 TI - Early detection and visualization of human adenovirus serotype 5-viral vectors carrying foot-and-mouth disease virus or luciferase transgenes in cell lines and bovine tissues. AB - Recombinant replication-defective human adenovirus type 5 (Ad5) vaccines containing capsid-coding regions from foot-and-mouth disease virus (FMDV) have been demonstrated to induce effective immune responses and provide homologous protective immunity against FMDV in cattle. However, basic mechanisms of Ad5-FMDV vaccine function including virus tropism, transgene expression, and antigen presentation, remain incompletely understood. The current study characterized the dynamics of Ad5 viral vector (Ad5-FMDV-A24 and Ad5-luciferase) infection in cell lines and early post-inoculation vector-host interactions in cattle. Adenovirus dissemination was described utilizing novel rPCR, rRT-PCR, luminometry, and immunomicroscopy techniques. In vitro infection of human and bovine cells with both Ad5 vectors resulted in dose-dependent detection of vector DNA, mature mRNA transcripts, and transgene-encoded proteins. Subsequent to intramuscular inoculation of cattle, Ad5 and transgene products were detected at the injection sites of all animals at all time-points examined (6, 24, and 48 hpi). Microscopically, injection sites were characterized by marked infiltrates of interstitium consisting of predominantly large mononuclear cells. Immunomicroscopy indicated these cells infrequently contained adenovirus and/or transgenic proteins and were phenotypically consistent with antigen-presenting cells (macrophages and dendritic cells). Vector DNA and mature mRNA transcripts were first detected at the draining and local lymph nodes as early as 6 hpi and systemically at 24 hpi. These results provide novel insights for understanding Ad5-mediated immunity against FMDV using novel techniques that will contribute to ongoing efforts for the improvement of future Ad-FMDV vaccine platforms. PMID- 22227229 TI - Safety and immunogenicity of a modified process hepatitis B vaccine in healthy neonates. AB - BACKGROUND: A manufacturing process using a modified adjuvant was developed to optimize the consistency and immunogenicity for recombinant hepatitis B vaccine (control: RECOMBIVAX-HBTM). This modified process hepatitis B vaccine (mpHBV), which was previously shown to have an acceptable safety and immunogenicity profile in young adults, has now been studied in newborn infants. METHODS: Healthy 1-10-day-old neonates (N=566) received 3 intramuscular doses (5MUg hepatitis B surface antigen [HBsAg] per dose) of either mpHBV or control at Day 1, and Months 1 and 6. Serum antibody to HBsAg (anti-HBs) was assayed at Month 7 (1 month Postdose 3). Anti-HBs geometric mean titers (GMTs) and seroprotection rates (SPRs) (% of subjects with an anti-HBs titer >=10mIU/mL) were compared at Month 7. After each dose, injection-site adverse experiences (AEs) and axillary temperatures were recorded for 5 days; systemic AEs were recorded for Days 1-14. RESULTS: Month 7 SPR was 97.9% for the mpHBV group and 98.9% for the control. The GMT was 843.7mIU/mL for the mpHBV group and 670.1mIU/mL for the control. The GMT ratio (mpHBV/control) was 1.26 (95% confidence interval [CI]: 0.94, 1.69), meeting the prespecified non-inferiority criteria. The percentages of subjects reporting any AE, injection-site AEs, or systemic AEs were similar across the 2 vaccination groups. There were no serious AEs. CONCLUSIONS: The safety profile of mpHBV was comparable to that of the control vaccine. The geometric mean antibody titer for mpHBV was higher than control vaccine in this infant population, but the difference did not meet the predefined statistical criterion for superiority. PMID- 22227231 TI - Different patterns of metabolic cryo-damage in domestic cat (Felis catus) and cheetah (Acinonyx jubatus) spermatozoa. AB - Felid spermatozoa are sensitive to cryopreservation-induced damage, but functional losses can be mitigated by post-thaw swim-up or density gradient processing methods that selectively recover motile or structurally-normal spermatozoa, respectively. Despite the importance of sperm energy production to achieving fertilization, there is little knowledge about the influence of cryopreservation or post-thaw processing on felid sperm metabolism. We conducted a comparative study of domestic cat and cheetah sperm metabolism after cryopreservation and post-thaw processing. We hypothesized that freezing/thawing impairs sperm metabolism and that swim-up, but not density gradient centrifugation, recovers metabolically-normal spermatozoa. Ejaculates were cryopreserved, thawed, and processed by swim-up, Accudenz gradient centrifugation, or conventional washing (representing the 'control'). Sperm glucose and pyruvate uptake, lactate production, motility, and acrosomal integrity were assessed. Mitochondrial membrane potential (MMP) was measured in cat spermatozoa. In both species, lactate production, motility, and acrosomal integrity were reduced in post-thaw, washed samples compared to freshly-collected ejaculates. Glucose uptake was minimal pre- and post-cryopreservation, whereas pyruvate uptake was similar between treatments due to high coefficients of variation. In the cat, swim-up, but not Accudenz processing, recovered spermatozoa with increased lactate production, pyruvate uptake, and motility compared to controls. Although confounded by differences in non-specific fluorescence among processing methods, MMP values within treatments were positively correlated to sperm motility and acrosomal integrity. Cheetah spermatozoa isolated by either selection method exhibited improved motility and/or acrosomal integrity, but remained metabolically compromised. Collectively, findings revealed a metabolically-robust subpopulation of cryopreserved cat, but not cheetah, spermatozoa, recovered by selecting for motility rather than morphology. PMID- 22227232 TI - [Failed forceps extraction: risk factors and maternal and neonatal morbidity]. AB - OBJECTIVES: To evaluate risk factors associated with failed forceps delivery and to compare the maternal and neonatal morbidity. PATIENTS AND METHODS: In this retrospective case-control study, all failed forceps delivery cases were analyzed from January 2005 to June 2008 and were compared to a successful forceps delivery cohort. RESULTS: The rate of failed forceps extraction was 4.4% (40/918). Specific risk factors were extraction above a foetal station of S+2 (OR=43.03; IC 95%: 3.8-475.41), occipito-posterior position (OR=34.64; IC 95%: 4.08-293.5), and biparietal diameter higher than 95mm (OR=10.74; IC 95%: 1.4-82.41). Maternal and neonatal morbidity was few in both groups. CONCLUSIONS: Diagnosis of presentation level and variety of presentation are necessary before instrumental extraction. A "trial of forceps" should be performed with caution in a setting where a caesarean delivery could follow. Vacuum extraction could be interesting in case of occipito-posterior position. PMID- 22227233 TI - [Pheochromocytoma: rare lethal challenging diagnosis that may be encountered by gynecologists and obstetricians]. AB - Pheochromocytomas are rare but potentially lethal tumors responsible for malignant hypertension. They may be encountered by gynecologists and obstetricians. The diagnosis is difficult because it can be mistaken for diseases more frequent like preeclampsia or other pelvic tumors. We report two cases highlighting clinical clues such as labile hypertension, headache, sweating, palpitations and failure to respond to conventional treatment should prompt physicians to screen patients for pheochromocytoma by measuring the 24-hour urinary catecholamines. The surgery must be performed after using an appropriate preoperative treatment, in order not to trigger lethal outcome. During pregnancy, C-section is recommended. PMID- 22227234 TI - [Which biological test to confirm rupture of membranes?]. AB - Rupture of membranes (ROM) occurs frequently and requires specific management depending on gestational age in order to avoid maternal and fetal complications. In 80% of cases, ROM is associated with large amniotic fluid (AF) leakage making diagnosis easy. The aim of the current review is to precise which biological test is useful for the physician facing ambiguous clinical picture. Vaginal pH assessment demonstrates alkalinisation (6.5-7.5) when AF is present (sensitivity 73-91%, specificity 72-83%). Drying test, fern test or fetal cells staining have been supplanted by detection of AF proteins. Diamine oxidase activity required specific radioanalytical assay leading to restrictive use and progressive abandon. Immunoassay tests detecting Insulin-like Growth Factor-Binding Protein-1 (IGFBP-1) or Placental Alpha 1-Microglobulin (PAMG-1) are currently considered as the most useful tools for ROM diagnosis. Literature fails to provide sufficient evidence that one of these two approaches should be favoured. Distinction between IGFBP-1 and PAMG-1 remains controversial as they seem to correspond to the same molecule. PMID- 22227235 TI - Regulation of human thyroid follicular cell function by inhibition of vascular endothelial growth factor receptor signalling. AB - The potential autocrine role of human thyroid vascular endothelial growth factors (VEGFs) was examined using the VEGF receptor (VEGFR) inhibitor, ZM306416HCl. ZM306416HCl reduced VEGFR2 phosphorylation and inhibited endogenous, steady-state levels of p42/44 MAPK phosphorylation. It potently inhibited the secretion of plasminogen activators (PA) and increased (125)I uptake. Cell survival was compromised but rescued with insulin and TSH. Although the EGF receptor remained responsive to challenge by EGF in p42/44 MAPK assays, stimulatory effects of EGF on PA production were prevented by ZM306416HCl and those of protein kinase C stimulator, TPA reduced. In assays of (125)I uptake, ZM306416HCl prevented the inhibitory effects of EGF but not those of TPA. We conclude that autocrine VEGF may modulate thyroid function and that VEGFR inhibition increases iodide uptake and decreases PA production through regulation of p42/44 MAPK phosphorylation. VEGFR inhibition may have effects on thyroid function which may contribute to "off target" effects in clinical trials. PMID- 22227236 TI - Reprint of: bullying victimisation, self harm and associated factors in Irish adolescent boys. AB - School bullying victimisation is associated with poor mental health and self harm. However, little is known about the lifestyle factors and negative life events associated with victimisation, or the factors associated with self harm among boys who experience bullying. The objectives of the study were to examine the prevalence of bullying in Irish adolescent boys, the association between bullying and a broad range of risk factors among boys, and factors associated with self harm among bullied boys and their non-bullied peers. Analyses were based on the data of the Irish centre of the Child and Adolescent Self Harm in Europe (CASE) study (boys n = 1870). Information was obtained on demographic factors, school bullying, deliberate self harm and psychological and lifestyle factors including negative life events. In total 363 boys (19.4%) reported having been a victim of school bullying at some point in their lives. The odds ratio of lifetime self harm was four times higher for boys who had been bullied than those without this experience. The factors that remained in the multivariate logistic regression model for lifetime history of bullying victimisation among boys were serious physical abuse and self esteem. Factors associated with self harm among bullied boys included psychological factors, problems with schoolwork, worries about sexual orientation and physical abuse, while family support was protective against self harm. Our findings highlight the mental health problems associated with victimisation, underlining the importance of anti-bullying policies in schools. Factors associated with self harm among boys who have been bullied should be taken into account in the identification of boys at risk of self harm. PMID- 22227237 TI - Being differently the same: the mediation of identity tensions in the sharing of illness experiences. AB - The sharing of experiences between patients has become increasingly privileged as a source of knowledge and support in contemporary healthcare. Despite this, relatively little is known about the processes whereby people's experiences become, or fail to become, valued as sources of health-related knowledge in different contexts. Through a secondary analysis of 87 interviews conducted between 2006 and 2008 in the UK with people affected by motor neurone disease (46 interviews) and Parkinson's disease (41 interviews), we explore the identity work involved in turning other people's experiences into 'experiential knowledge' that can be shared between patients. Of particular interest is how the turning of others' experiences into knowledge is presupposed by negotiating a particular type of identity tension - what, drawing on the work of Paul Ricoeur (2003) on metaphor, we refer to as 'being differently the same'. We examine the way in which people living with motor neurone disease and Parkinson's disease spoke of managing this tension as part of the process of accessing and valuing other patients' experiences, both epistemologically and emotionally. Instead of treating others' experiences as a pre-given source of knowledge, we emphasise how experience comes to be embodied and articulated through different media - bodies, speech, text, and images. Moreover, we suggest that paying closer attention to these media provides opportunities for enhancing our understanding of how people with different chronic and/or terminal illnesses use or do not use different forms of peer support - and in particular online ones - as a source of health related experiential knowledge. Some of the implications of this are discussed in the specific context of people diagnosed with incurable neurodegenerative conditions characterised by visible physical deterioration and associated emotional distress. PMID- 22227238 TI - Gender, health behavior, and intimate relationships: lesbian, gay, and straight contexts. AB - Many studies focus on health behavior within the context of intimate ties. However, this literature is limited by reliance on gender socialization theory and a focus on straight (i.e., heterosexual) marriage. We extend this work with an analysis of relationship dynamics around health behavior in 20 long-term straight marriages as well as 15 gay and 15 lesbian long-term cohabiting partnerships in the United States (N = 100 individual in-depth interviews). We develop the concept of "health behavior work" to align activities done to promote health behavior with theories on unpaid work in the home. Respondents in all couple types describe specialized health behavior work, wherein one partner works to shape the other partner's health behavior. In straight couples, women perform the bulk of specialized health behavior work. Most gay and lesbian respondents but few straight respondents--also describe cooperative health behavior work, wherein partners mutually influence one another's health behaviors. Findings suggest that the gendered relational context of an intimate partnership shapes the dynamics of and explanations for health behavior work. PMID- 22227239 TI - Fate of sulfonamide antibiotics in contact with activated sludge--sorption and biodegradation. AB - The sorption and biodegradation of three sulfonamide antibiotics, namely sulfamethoxazole (SMX), sulfadimethoxine (SDM), and sulfamonomethoxine (SMM), in an activated sludge system were investigated. Experiments were carried out by contacting 100 MUg/L of each sulfonamide compound individually with 2.56 g/L of MLSS at 25+/-0.5 degrees C, pH 7.0, and dissolved oxygen of 3.0+/-0.1 mg/L in a batch reactor over different periods of 2 d and 14 d. All sulfonamides were removed completely over 11-13 d. Sorptive equilibrium was established well within the first few hours, followed by a lag period of 1-3 days before biodegradation was to deplete the antibiotic compounds linearly in the ensuing 10 days. Apparent zeroth-order rate constants were obtained by regression analysis of measured aqueous concentration vs. time profiles to a kinetic model accounting for sorption and biodegradation; they were 8.1, 7.9, and 7.7 MUg/L/d for SDM, SMX, and SMM, respectively, at activated sludge concentration of 2.56 g/L. The measured kinetics implied that with typical hydraulic retention time (e.g. 6 h) provided by WWTP the removal of sulfonamide compounds from the wastewater during the activated sludge process would approximate 2 MUg/L. PMID- 22227240 TI - Biochemical and pathological toxic effects induced by the cyanotoxin Cylindrospermopsin on the human cell line Caco-2. AB - Cylindrospermopsin (CYN), a cyanotoxin produced by several freshwater cyanobacteria, causes human intoxications and animal mortalities. The present study focuses on the cytotoxic effects of CYN on Caco-2 cells at 24 and 48 h. The basal cytotoxicity endpoints studied were total protein content (TP), neutral red uptake (NR) and reduction of the tetrazolium salt (MTS). The effect of non cytotoxic concentrations of CYN on the generation of intracellular reactive oxygen species (ROS), gamma-glutamylcysteine synthetase (GCS) activity and glutathione (GSH) content was also studied and the morphological alterations in the Caco-2 cells subsequent to CYN exposure were recorded. The most sensitive endpoint - the reduction of MTS - showed that the viability of Caco-2 cells after exposure to the highest concentration assayed (40 MUg/mL CYN) was reduced by about 90%. Intracellular ROS production increased only when exposed to a concentration of 1.25 MUg/mL CYN, while GSH content and GCS activity increased when exposed to 2.5 MUg/mL CYN. The main insights provided by the present study are the ultrastructural alterations, which reveal lipid degeneration, mitochondrial damage and nucleolar segregation with altered nuclei. Therefore, it has been demonstrated that CYN can induce toxic effects in Caco-2 cells in a time concentration dependent manner. Moreover, unlike the cytotoxic and biochemical alterations, which were only evident at higher concentrations, morphological damage at the ultrastructural level was noticeable even at the lowest concentration used. PMID- 22227241 TI - Effect of pumping on the spatio-temporal distribution of microbial communities in a water well field. AB - A water well field adjacent to the North Saskatchewan River (City of North Battleford, Saskatchewan, Canada) with a history of rapid deterioration of both well water quality and yield was selected to study the spatial and temporal distribution of subsurface microbial communities and their response to water pumping. A range of conventional cultural, microscopic and molecular techniques, including confocal laser scanning microscopy (CLSM), Biolog, qPCR and Denaturing Gradient Gel Electrophoresis (DGGE), was used during this study. Redox data and water and sediment chemistry showed that the aquifer was anoxic and harbored substantial amounts of Fe and Mn. CLSM analyses of incubated coupons indicated extensive biofilm growth in the zone immediately surrounding the well and was coincident with reduced water well yield. PCR screening and qPCR analyses showed that the potential for iron- and sulfate-reducing activity increased with proximity to the well. Bacterial communities inhabiting the zone closest to the well showed the greatest changes and differences in metabolic activities and composition as revealed by PCA (Principal Components Analysis) of the Biolog and DGGE data. The sequence analysis of all the samples revealed that Sulfuricurvum spp., Methylobacter spp., Geobacter spp. and Rhodobacter spp. were most commonly detected in this aquifer. Overall the findings demonstrated that the microbial numbers, metabolic activities and the community composition changed in response to water pumping but effects did not extend beyond 1-2m zone from the well. PMID- 22227242 TI - Water hammer reduces fouling during natural water ultrafiltration. AB - Today's ultrafiltration processes use permeate flow reversal to remove fouling deposits on the feed side of ultrafiltration membranes. We report an as effective method: the opening and rapid closing of a valve on the permeate side of an ultrafiltration module. The sudden valve closure generates pressure fluctuations due to fluid inertia and is commonly known as "water hammer". Surface water was filtrated in hollow fiber ultrafiltration membranes with a small (5%) crossflow. Filtration experiments above sustainable flux levels (>125 l (m2h)(-1)) show that a periodic closure of a valve on the permeate side improves filtration performance as a consequence of reduced fouling. It was shown that this effect depends on flux and actuation frequency of the valve. The time period that the valve was closed proved to have no effect on filtration performance. The pressure fluctuations generated by the sudden stop in fluid motion due to the valve closure are responsible for the effect of fouling reduction. High frequency recording of the dynamic pressure evolution shows water hammer related pressure fluctuations to occur in the order of 0.1 bar. The pressure fluctuations were higher at higher fluxes (higher velocities) which is in agreement with the theory. They were also more effective at higher fluxes with respect to fouling mitigation. PMID- 22227243 TI - Mechanisms of N2O production in biological wastewater treatment under nitrifying and denitrifying conditions. AB - Nitrous oxide (N2O) is an important greenhouse gas and a major sink for stratospheric ozone. In biological wastewater treatment, microbial processes such as autotrophic nitrification and heterotrophic denitrification have been identified as major sources; however, the underlying pathways remain unclear. In this study, the mechanisms of N2O production were investigated in a laboratory batch-scale system with activated sludge for treating municipal wastewater. This relatively complex mixed population system is well representative for full-scale activated sludge treatment under nitrifying and denitrifying conditions. Under aerobic conditions, the addition of nitrite resulted in strongly nitrite dependent N2O production, mainly by nitrifier denitrification of ammonia oxidizing bacteria (AOB). Furthermore, N2O is produced via hydroxylamine oxidation, as has been shown by the addition of hydroxylamine. In both sets of experiments, N2O production was highest at the beginning of the experiment, then decreased continuously and ceased when the substrate (nitrite, hydroxylamine) had been completely consumed. In ammonia oxidation experiments, N2O peaked at the beginning of the experiment when the nitrite concentration was lowest. This indicates that N2O production via hydroxylamine oxidation is favored at high ammonia and low nitrite concentrations, and in combination with a high metabolic activity of ammonia-oxidizing bacteria (at 2 to 3 mgO2/l); the contribution of nitrifier denitrification by AOB increased at higher nitrite and lower ammonia concentrations towards the end of the experiment. Under anoxic conditions, nitrate reducing experiments confirmed that N2O emission is low under optimal growth conditions for heterotrophic denitrifiers (e.g. no oxygen input and no limitation of readily biodegradable organic carbon). However, N2O and nitric oxide (NO) production rates increased significantly in the presence of nitrite or low dissolved oxygen concentrations. PMID- 22227244 TI - Evaluation of migration forces of a retrievable filter: experimental setup and finite element study. AB - The aim of this paper is to provide a computational study of migration forces of a retrievable filter (Gunther Tulip inferior vena cava filter). Using an experimental setup and finite element simulation, the migration forces and stress at the end of the anchored hooks in the struts were estimated. After that, the estimation value of migration stress (tau(rup)) was used to analyze the effect of different mechanical factors (strut thickness, vena cava diameter) in the migration of the IVC filter. Our results show that the migration stress is tau(rup)=4.37 N/mm(2). Using this value we obtain that the filter with higher strut diameter (phi(strut)=0.45 mm) shows the maximal migration forces in every cava diameter. On the other hand, the value of the migration force decreases when the cava diameter increases. In addition, the finite element simulations also show that there are contact between the struts of the filter and the vein in regions close to the anchors. PMID- 22227245 TI - Design and evaluation of a novel microphone-based mechanomyography sensor with cylindrical and conical acoustic chambers. AB - Mechanomyography has recently been proposed as a control modality for alternative access technologies for individuals with disabilities. However, MMG recordings are highly susceptible to contamination from limb movements. Pressure-based transducers are touted to be the most robust to external movement although there is some debate about their optimal chamber geometry, in terms of low frequency gain and spectral flatness. To investigate the question of preferred geometry, transducers with cylindrical and conical chambers of varying dimensions were designed, manufactured and tested. Using a computer-controlled electrodynamic shaker, the frequency response of each chamber geometry was empirically derived. Of the cylindrical chambers, the highest gain and the flattest frequency response was exhibited by a chamber 10 mm in diameter and 5-7 mm in height. However, conical chambers offered an average rise in gain of 6.79 +/- 1.06 dB/Hz over that achievable with cylindrical geometries. The highest gain and flattest response was achieved with a transducer consisting of a low-frequency MEMS microphone, a 4 MUm aluminized mylar membrane and a rigid conical chamber 7 mm in diameter and 5mm in height. This design is recommended for MMG applications where limb movement is prevalent. PMID- 22227247 TI - SnoN oncoprotein enhances estrogen receptor-alpha transcriptional activity. AB - Estrogen receptor-alpha (ERalpha) and transforming growth factor-beta (TGF-beta) signaling pathways are essential regulators during mammary gland development and tumorigenesis. Ski-related novel gene (SnoN) is an oncoprotein and a negative feedback inhibitor of TGF-beta signaling. We have previously reported that low expression of SnoN in ERalpha positive breast carcinomas is associated with favorable prognosis (Zhang et al. Cancer Res. (2003) 63, 5005-5010). Here we have studied the mechanism of a possible cross-talk between ERalpha and SnoN. We find that SnoN interacts with the estrogen-activated form of ERalpha in the nucleus. SnoN contains two highly conserved nuclear receptor binding LxxLL-like motifs and we show that mutations in these motifs reduce the interaction of SnoN with ERalpha. Over-expression of SnoN enhanced the transcriptional activity of ERalpha in estrogen response element (ERE)-reporter assays, augmented the expression of several ERalpha target genes and increased the proliferation of MCF7 breast carcinoma cells in an estrogen-dependent manner. Chromatin immunoprecipitation demonstrated that SnoN interacts with ERalpha at the TTF1 (pS2) gene promoter. Conversely, silencing of SnoN reduced both ERE-reporter activity and the expression of ERalpha target genes in MCF7 and T-47D breast cancer cells. Histone deacetylase inhibition increased the level of SnoN and SnoN-dependent enhancement of ERalpha-dependent transcription and SnoN supported the recruitment of p300 histone acetylase to ERalpha. This study reveals a novel mechanism that interconnects ERalpha and TGF-beta signaling pathways by SnoN. Accordingly, the results indicate that high SnoN level promotes ERalpha signaling and possibly breast cancer progression. PMID- 22227248 TI - Differential PKC-dependent and -independent PKD activation by G protein alpha subunits of the Gq family: selective stimulation of PKD Ser748 autophosphorylation by Galphaq. AB - Protein kinase D (PKD) is activated within cells by stimulation of multiple G protein coupled receptors (GPCR). Earlier studies demonstrated a role for PKC to mediate rapid activation loop phosphorylation-dependent PKD activation. Subsequently, a novel PKC-independent pathway in response to Galphaq-coupled GPCR stimulation was identified. Here, we examined further the specificity and PKC dependence of PKD activation using COS-7 cells cotransfected with different Gq family Galpha and stimulated with aluminum fluoride (AlF4-). PKD activation was measured by kinase assays, and Western blot analysis of activation loop sites Ser744, a prominent and rapid PKC transphosphorylation site, and Ser748, a site autophosphorylated in the absence of PKC signaling. Treatment with AlF4- potently induced PKD activation and Ser744 and Ser748 phosphorylation, in the presence of cotransfected Galphaq, Galpha11, Galpha14 or Galpha15. These treatments achieved PKD activation loop phosphorylation similar to the maximal levels obtained by stimulation with the phorbol ester, PDBu. Preincubation with the PKC inhibitor GF1 potently blocked Galpha11-, Galpha14-, and Galpha15-mediated enhancement of Ser748 phosphorylation induced by AlF4-, and largely abolished Ser744 phosphorylation. In contrast, Ser748 phosphorylation was almost completely intact, and Ser744 phosphorylation was significantly activated in cells cotransfected with Galphaq. Importantly, the differential Ser748 phosphorylation was also promoted by treatment of Swiss 3T3 cells with Pasteurella multocida toxin, a selective activator of Galphaq but not Galpha11. Taken together, our results suggest that Galphaq, but not the closely related Galpha11, promotes PKD activation in response to GPCR ligands in a unique manner leading to PKD autophosphorylation at Ser748. PMID- 22227249 TI - Spermine, a molecular switch regulating EGFR, integrin beta3, Src, and FAK scaffolding. AB - Intracellular polyamine levels are highly regulated by the activity of ornithine decarboxylase (ODC), which catalyzes the first rate-limiting reaction in polyamine biosynthesis, producing putrescine, which is subsequently converted to spermidine and spermine. We have shown that polyamines regulate proliferation, migration, and apoptosis in intestinal epithelial cells. Polyamines regulate key signaling events at the level of the EGFR and Src. However, the precise mechanism of action of polyamines is unknown. In the present study, we demonstrate that ODC localizes in lamellipodia and in adhesion plaques during cell spreading. Spermine regulates EGF-induced migration by modulating the interaction of the EGFR with Src. The EGFR interacted with integrin beta3, Src, and focal adhesion kinase (FAK). Active Src (pY418-Src) localized with FAK during spreading and migration. Spermine prevented EGF-induced binding of the EGFR with integrin beta3, Src, and FAK. Activation of Src and FAK was necessary for EGF-induced migration in HEK293 cells. EGFR-mediated Src activation in live HEK293 cells using a FRET based Src reporter showed that polyamine depletion significantly increased Src kinase activity. In vitro binding studies showed that spermine directly binds Src, and preferentially interacts with the SH2 domain of Src. The physical interaction between Src and the EGFR was severely attenuated by spermine. Therefore, spermine acts as a molecular switch in regulating EGFR-Src coupling both physically and functionally. Upon activation of the EGFR, integrin beta3, FAK and Src are recruited to EGFR leading to the trans-activation of both the EGFR and Src and to the Src-mediated phosphorylation of FAK. The activation of FAK induced Rho GTPases and subsequently migration. This is the first study to define mechanistically how polyamines modulate Src function at the molecular level. PMID- 22227250 TI - Congenital quadricuspid aortic valve: a rare valvular pathology leading to aortic valve insufficiency. PMID- 22227251 TI - Clinical features of adult patients with Eisenmenger's syndrome in Japan and Korea. AB - BACKGROUND: There are few articles on mortality and morbidity of adult patients with Eisenmenger's syndrome (ES) in the current era when disease targeting therapy (DTT) has been available. METHODS AND RESULTS: 198 patients (a median age 35 years, 64% female) with ES who visited the 16 participating institutes in Japan and Korea from 1998 to 2009 were enrolled. Clinical data during adulthood were collected from each institutional chart and analyzed centrally. During a median follow-up of 8 years, 30 patients died including 14 sudden deaths. 89 patients took oral medication of DTT and clinical improvement was observed in 54 of them. However, survival rate in patients taking DTT was not different from those without (87% vs 84%, p=0.55). When the clinical data in between first and last clinic visits were compared in 85 patients, the patients with NYHA >/=III increased from 24% to 48% (p<0.001), SpO2 decreased from 89% to 85% (p=0.008) and hematocrit increased from 51.4% to 52.9% (p=0.04). Non-survivors had poorer NYHA function class, lower body weight (BW), lower body mass index (BMI), and higher serum level of Cr at the first visits than survivors. CONCLUSIONS: Long term survival and clinical status of adult patients with ES remains unsatisfactory even in the current era of DTT. Poor NYHA functional class, low BW, low BMI and high serum level of Cr were related to mortality. DTT therapy improved clinical status in many patients with Eisenmenger's syndrome, but no significant impact on survival could be shown. PMID- 22227252 TI - Blood leukocytes in heart failure with preserved ejection fraction: impact on prognosis. PMID- 22227253 TI - Apical noncompaction in metabolic myopathy may be missed on echocardiography but visible on cardiac MRI or misinterpreted as apical hypokinesia. PMID- 22227254 TI - Posterior fascicular block obscuring the right bundle branch block pattern. PMID- 22227255 TI - Effects of untreated obstructive sleep apnea on left and right ventricular myocardial function. PMID- 22227256 TI - Myocardial perfusion-fibrosis pattern in systemic sclerosis assessed by cardiac magnetic resonance. PMID- 22227257 TI - Nitric oxide: is it the cause of muscle soreness? AB - Skeletal muscle hosts all of the isoforms of nitric oxide synthase (NOS). It is well documented that nitric oxide (NO) regulates force generation and satellite cell activation, and therefore, damage repair of skeletal muscle. NO can also activate nociceptors of C-fibers, thereby causing the sensation of pain. Although delayed-onset of muscle soreness (DOMS) is associated with decreased maximal force generation, pain sensation and sarcomere damage, there is a paucity of research linking NO and DOMS. The present mini-review attempts to elucidate the possible relationship between NO and DOMS, based upon current literature. PMID- 22227258 TI - CT in children--dose protection and general considerations when planning a CT in a child. AB - Today CT represents about 10% of all ionizing radiation based imaging modalities, but delivers more than 50% of the total collective dose for diagnostic imaging. Compared to adults the radiation sensitivity of children is considerable higher than in adults. Additionally children differ from adults--factors like body size, mass, density, proportions as well as metabolism have to be mentioned. Children grow and mature--all this components have to be mapped in examination protocols by Pediatric Radiology. The total dose of a CT examination depends on the settings of several factors such as the scout view, the scan length, exposure settings including automated exposure control, type of scanning (single slice, helical, volume mode), slice thickness, pitch values as well as on image reconstruction parameters. If intravenous contrast media injection is needed bolus tracking or timing represents another source of radiation. The aim of the paper is to present and discuss all aspects of defining a pediatric age and query adapted CT protocol particularly concerning all dose relevant factors in pediatric CT and their adjustment in children. Moreover hints are given concerning optimization of intravenous contrast media injection as well as special (low dose) imaging protocols. PMID- 22227259 TI - Detection of metastatic bone lesions in breast cancer patients: fused (18)F Fluoride-PET/MDCT has higher accuracy than MDCT. Preliminary experience. AB - PURPOSE: So far, no studies comparing (18)F-Fluoride-PET/CT and MDCT for the detection of bone metastases are available. We compared the accuracy of (18)F Fluoride-PET/CT (MDCT: 3.75 mm thickness-image-reconstruction), whole-body Multi Detector-CT (MDCT: 1.25 mm thickness-image-reconstruction) and (18)F-Fluoride PET/MDCT (MDCT: 1.25 mm thickness-image-reconstruction) in identifying bone metastases in breast cancer patients. METHODS: We studied 39 breast cancer patients for bone metastases. Imaging was performed on an integrated PET/MDCT system; CT images were reconstructed at 3.75 mm and 1.25 mm thickness. Two nuclear medicine physicians and one radiologist interpreted blindly (18)F Fluoride-PET/CT, (18)F-Fluoride-PET/MDCT and MDCT. MDCT at 12 months served as the standard of reference. RESULTS: Overall, 662 bone lesions were detected in our analysis. Of these, 542 were malignant and 120 were benign according to the standard of reference. (18)F-Fluoride-PET/CT detected 491 bone metastases, 114 (23%) of which displayed no clear morphological changes on MDCT, whereas MDCT detected 416 bone metastases, 39 (9.3%) of which showed no (18)F-Fluoride-PET uptake. Overall sensitivity and specificity were: 91% and 91%, respectively, for (18)F-Fluoride-PET/CT, and 77% and 93% for MDCT. The integrated assessment of (18)F-Fluoride-PET/MDCT yielded sensitivity and specificity values of 98% and 93%, respectively. CONCLUSIONS: (18)F-Fluoride-PET/MDCT has higher diagnostic accuracy than (18)F-Fluoride-PET/CT and MDCT for the evaluation of bone metastases in breast cancer. PMID- 22227260 TI - Complications of percutaneous stereotactic vacuum assisted breast biopsy system utilizing radio frequency. AB - OBJECTIVE: The Breast Lesion Excision System (BLES) is a novel, automatic breast biopsy device that utilizes radiofrequency to excise suspicious non-palpable mammographic lesions. The purpose of the present prospective study is to report and evaluate the complications of this new technique. MATERIALS AND METHODS: In a two year period, we used the BLES device in 132 consecutive patients (134 procedures) with non-palpable mammographic lesions. The inclusion criteria consisted of suspicious microcalcifications, solid lesions and asymmetric density. In order to retrieve an intact biopsy specimen, we used the 12mm, 15mm or 20mm tissue basket under local anesthesia, depending on the size of the lesion. Complications were recorded and classified as immediate if occurring during or shortly after the procedure, or late, if occurring in the post procedure days. RESULTS: The procedure was considered successful in all cases, with mammographic confirmation of appropriate excision of the targeted lesion. Although, in a single case the basket initially failed to deploy. Immediate complications were encountered in 11 patients, with minor hemorrhage being the most common (n=6). 17 patients suffered late complications, in seven of whom delayed wound healing was observed. Overall, 27 patients suffered Grade 1 complications (20.14%), one patient experienced a Grade 2 complication while no patients encountered Grade 3-5 complications. CONCLUSIONS: According to our experience, the BLES device is an efficient and safe breast biopsy method, with low complication rates, which are minor in their majority. It appears to be a very promising alternative to other, minimally invasive, breast biopsy techniques. PMID- 22227261 TI - Experience with volumetric (320 rows) pediatric CT. AB - The introduction of helical computer tomography (CT) and further progress to multi-slice CT enabled new applications. Most recent developments like the 320 row detector facilitate volume CT, which avoids the over-beaming effect of helical scanning. The 320-row multi-slice detector CT (MDCT) is based on a 16cm detector; a special acquisition mode allows reconstructing 640 slices from these 16cm. The shortest tube rotation time is in cardiac mode 0.35s, otherwise 0.4s and 0.5s used. At 0.5s the machine already reaches the maximum numbers of sub second projections. Scan modes can be volume, helical and single slice mode. For image acquisition all dose savings technologies like variable tube position for scano-view, active collimation, automated exposure control, bolus and ECG tracking are available. Additionally special acquisition and post-processing techniques like head and body perfusion CT are ready for use on the console. For image reconstruction properties like filtered back projection as well as the latest development of iterative algorithms, an appropriate number of kernels and multi-planar reconstruction in all directions from the volume data at every increment are available. Volume CT allows sub second scanning of 16cm z-coverage which, however, makes administration of intravenous contrast medium to "hit or miss" event. The aim of this paper is to present the application of volume CT to body scanning in children. Representative examples of neck, cardiac and skeletal investigations are given. PMID- 22227262 TI - Multi-organ perfusion CT in the abdomen using a 320-detector row CT scanner: preliminary results of perfusion changes in the liver, spleen, and pancreas of cirrhotic patients. AB - PURPOSE: To utilize 320-detector row CT in perfusion CT of multiple abdominal organs and to compare the tissue perfusion between patients with and without liver cirrhosis. MATERIALS AND METHODS: This study included 21 patients with cirrhosis and 20 without cirrhosis. The 320-detector row CT scanner enabled multi organ perfusion CT without requiring the scanner table to be moved. Perfusion was calculated using the maximum slope model for the aorta, the portal vein, the right and left lobes of the liver, the head and body of the pancreas, the spleen, and the corpus and antrum of the stomach. Perfusion in each organ of patients with and without cirrhosis was compared. RESULTS: Portal venous perfusion of the right and left lobes of the liver in patients with cirrhosis (117 and 100 mL min( 1)100mL(-1), respectively) was significantly less than that in patients without cirrhosis (213 and 174 mL min(-1)100mL(-1), respectively; p=0.0081 and 0.0294, respectively). Arterial perfusion of the spleen (111 mL min(-1)100mL(-1)) and the body of the pancreas (112 mL min(-1)100mL(-1)) in patients with cirrhosis was also significantly decreased compared with that in patients without cirrhosis (spleen, 162 mL min(-1)100mL(-1), p=0.0020; body of pancreas, 133 mL min( 1)100mL(-1), p=0.0405). CONCLUSION: The results of the perfusion CT suggest that arterial perfusion of the spleen and the body of the pancreas, as well as portal perfusion of the liver, in cirrhotic patients was decreased compared with that in non-cirrhotic patients. PMID- 22227263 TI - Enchondroma vs. chondrosarcoma: a simple, easy-to-use, new magnetic resonance sign. AB - INTRODUCTION: There is no clear radiologic or pathologic agreement on the differences between enchondroma and conventional chondrosarcoma, which has huge therapeutic consequences. Microscopically, an enchondroma is composed of "islands of intramedullary hyaline cartilage surrounded by marrow fat", and a chondrosarcoma a "diffuse cartilaginous replacement (invasion) of the marrow which leads to complete 'trapping' of host lamellar bone trabeculae." The marrow around islands of cartilage should be detectable on magnetic resonance imaging (MR). Enchondroma may be the precursor of chondrosarcoma; benign cartilaginous islands are often seen microscopically at the periphery of chondrosarcoma. We attempted to detect these islands at the periphery of chondrosarcomas on MR and correlate them microscopically. MATERIALS AND METHODS: We examined our database for all patients with a chondrosarcoma of the long and flat bones between 1990 and 2007. Only those with a preoperative MR who underwent an en bloc resection were included, yielding 32 patients. We looked for low-signal islands surrounded by high (fat) signal on T1-weighted images, and high-signal islands surrounded by low signal on T2-weighted fat saturated images at the periphery of the main tumour mass. Microscopic correlation was performed in all cases. RESULTS: On microscopy, there were 23 conventional chondrosarcomas, nine dedifferentiated. Peripheral islands surrounded by fat were detected on MR in 19 cases, corresponding to benign cartilage in 18 cases and to the benign scar of a needle biopsy tract in one. There were no peripheral islands detected radiographically or microscopically in 13 cases. CONCLUSION: Cartilaginous islands microscopically detected at the periphery of some chondrosarcomas are easily and reliably diagnosed on MR. PMID- 22227264 TI - Diagnostic performance of MRI and EUS in the differentiation of benign from malignant pancreatic cyst and cyst communication with the main duct. AB - PURPOSE: To assess the diagnostic ability of MRI and EUS for differentiating benign from malignant pancreatic cyst focusing on cyst communication with pancreatic duct. MATERIALS AND METHODS: During 44 months, we performed MRI on 65 pancreatic cysts. Among them, 36 patients had confirmed cyst communication with duct by ERCP or surgery and 39 patients underwent EUS. Fifty-one had proven by surgery or aspiration. Among them, 36 had confirmed malignant cysts. Two radiologists independently graded cyst communication with duct and the likelihood of malignancy. When the readers' interpretations differed, third opinion was obtained. They also measured the size of cyst and main duct. The diagnostic performance was analyzed using the ROC curve. The Mann-Whitney U test and kappa statistics were used to determine interobserver agreement. RESULTS: The Az of MRI and EUS for determining diagnostic performance regarding the cyst communication with duct, were 0.931 and 0.930, without statistically difference (p=0.6). Interobserver agreement was excellent (kappa=0.81) on MRI and substantial (kappa=0.69) on EUS. The Az of MRI and EUS for assessing diagnostic performance to differentiate malignant from benign cyst, was 0.902 and 0.923, without statistically difference (p=0.587). Interobserver agreement was excellent (kappa=0.81) on MRI and moderate (kappa=0.47) on EUS. The mean cyst size (3.98 cm+2.74: 3.17 cm+1.26, p=0.327) and the duct size (5.20 mm+3.22: 4.39 mm+4.12, p=0.227) showed no statistically difference between malignant and benign cysts. CONCLUSION: MRI and EUS can accurately assess pancreatic cyst communication with duct and are very useful for obtaining a differential diagnosis of malignant cyst versus benign pancreatic cyst. PMID- 22227266 TI - Effect of hydration on the structure of non aqueous ethyl cellulose/propylene glycol dicaprylate gels. AB - Changes in the structural properties of ethyl cellulose/propylene glycol dicaprylate systems (EC/PGD), intended for topical drug delivery, upon addition of water were investigated. Although designed to be a non-aqueous vehicle for moisture sensitive drugs, these systems are expected to experience an aqueous environment during production, storage and application on the skin. Hence, the interaction of water molecules with the non aqueous gel system and their distribution within the gel network is of interest and critical to its application. Experimental techniques of this study were small-deformation dynamic oscillation in shear, modulated differential scanning calorimetry (MDSC), (2)H NMR spectroscopy, ATR-infrared spectroscopy, wide-angle X-ray diffraction patterns and light microscopy. Rheological profiles of the gels containing moisture from 0.1 to 40.0% (w/w) deviated considerably from that of the non aqueous system at levels of water above 10.0% in preparations. Gradual replacement of the EC/PGD dipole interactions with stronger hydrogen bonding between ethyl cellulose chains, as the level of hydration increased, contributed to these observations. Formation of clusters of ethyl cellulose, observed under a light microscope, was thus ensued. X-ray diffraction patterns showed that the rearrangement of the polymer chains led to the loss of liquid crystal structures found in the anhydrous gel. MDSC and (2)H NMR were used to further shed light on the thermodynamic state of added water molecules in the gels. Plots of enthalpy obtained calorimetrically and a good correlation between MDSC and (2)H NMR data indicate that gels with less than two percent hydration contain water in a non freezable bound state, whereas freezable moieties are obtained at levels of hydration above five percent in composite (EC/PGD/water) gels. PMID- 22227265 TI - Role of the adenosine(2A) receptor-epoxyeicosatrienoic acid pathway in the development of salt-sensitive hypertension. AB - Activation of rat adenosine(2A) receptors (A(2A) R) dilates preglomerular microvessels, an effect mediated by epoxyeicosatrienoic acids (EETs). High salt (HS) intake increases epoxygenase activity and adenosine levels. A greater vasodilator response to a stable adenosine analog, 2-chloroadenosine (2-CA), was seen in kidneys obtained from HS-fed rats which was mediated by increased EET release. Because this pathway is antipressor, we examined the role of the A(2A) R EET pathway in a genetic model of salt-sensitive hypertension, the Dahl salt sensitive (SS) rats. Dahl salt resistant (SR) rats fed a HS diet demonstrated a greater renal vasodilator response to 2-CA. In contrast, Dahl SS rats did not exhibit a difference in the vasodilator response to 2-CA whether fed normal salt (NS) or HS diet. In Dahl SR but not Dahl SS rats, HS intake significantly increased purine flux, augmented the protein expression of A(2A) R and cytochrome P450 2C23 and 2C11 epoxygenases, and elevated the renal efflux of EETs. Thus the Dahl SR rat is able to respond to HS intake by recruiting EET formation, whereas the Dahl SS rat appears to have exhausted its ability to increase EET synthesis above the levels observed on NS intake. In vivo inhibition of the A(2A) R-EET pathway in Dahl SR rats fed a HS diet results in reduced renal EETs levels, diminished natriuretic capacity and hypertension, thus supporting a role for the A(2A) R-EET pathway in the adaptive natriuretic response to modulate blood pressure during salt loading. An inability of Dahl SS rats to upregulate the A(2A) R-EET pathway in response to salt loading may contribute to the development of salt-sensitive hypertension. PMID- 22227267 TI - Coffee polyphenol caffeic acid but not chlorogenic acid increases 5'AMP-activated protein kinase and insulin-independent glucose transport in rat skeletal muscle. AB - Chlorogenic acid is an ester of caffeic and quinic acids, and is one of the most widely consumed polyphenols because it is abundant in foods, especially coffee. We explored whether chlorogenic acid and its metabolite, caffeic acid, act directly on skeletal muscle to stimulate 5'-adenosine monophosphate-activated protein kinase (AMPK). Incubation of rat epitrochlearis muscles with Krebs buffer containing caffeic acid (>=0.1 mM, >=30 min) but not chlorogenic acid increased the phosphorylation of AMPKalpha Thr(172), an essential step for kinase activation, and acetyl CoA carboxylase Ser(79), a downstream target of AMPK, in a dose- and time-dependent manner. Analysis of isoform-specific AMPK activity revealed that AMPKalpha2 activity increased significantly, whereas AMPKalpha1 activity did not change. This enzyme activation was associated with a reduction in phosphocreatine content and an increased rate of 3-O-methyl-d-glucose transport activity in the absence of insulin. These results suggest that caffeic acid but not chlorogenic acid acutely stimulates skeletal muscle AMPK activity and insulin-independent glucose transport with a reduction of the intracellular energy status. PMID- 22227268 TI - Licochalcone E activates Nrf2/antioxidant response element signaling pathway in both neuronal and microglial cells: therapeutic relevance to neurodegenerative disease. AB - Oxidative stress and neuroinflammation are hallmarks of neurodegenerative diseases, which do not play independently but work synergistically through complex interactions exacerbating neurodegeneration. Therefore, the mechanism that is directly implicated in controlling oxidative stress and inflammatory response could be an attractive strategy to prevent the onset and/or delay the progression of neurodegenerative diseases. The transcription factor nuclear factor-E2-related factor-2 (Nrf2) is the guardian of redox homeostasis by regulating a battery of antioxidant and phase II detoxification genes, which are relevant to defense mechanism against oxidative stress and inflammatory responses. In this study, we show that a recently identified Glycyrrhiza-inflata derived chalcone, licochalcone E (Lico-E), attenuates lipopolysaccharide-induced inflammatory responses in microglial BV2 cells and protects dopaminergic SH-SY5Y cells from 6-hydroxydopamine cytotoxicity. Lico-E activates Nrf2-antioxidant response element (ARE) system and up-regulates downstream NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1). Anti-inflammatory and cytoprotective effects of Lico-E are attenuated in siRNA-mediated Nrf2-silencing cells as well as in the presence with specific inhibitor of HO-1 or NQO1, respectively. Lico-E also has neuroprotective effect against 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine-induced nigrostriatal dopaminergic neurodegeneration in mice, with up-regulation of HO-1 and NQO1 in the substantia nigra of the brain. This study demonstrates that Lico-E is a potential activator of the Nrf2/ARE-dependent pathway and is therapeutically relevant not only to oxidative stress-related neurodegeneration but also inflammatory responses of microglial cells both in vitro and in vivo. PMID- 22227269 TI - In vitro study of the effects of fluoride-releasing dental materials on remineralization in an enamel erosion model. AB - OBJECTIVES: This study was conducted to compare the remineralization effects of five regimens on the loss of fluorescence intensity, surface microhardness, roughness and microstructure of bovine enamel after remineralization. We hope that these results can provide some basis for the clinical application of these materials. METHODS: One hundred bovine incisors were prepared and divided into the following five groups, which were treated with distinct dental materials: (1) ClinproTM XT varnish (CV), (2) F-varnish (FV), (3) Tooth Mousse (TM), (4) Fuji III LC((r)) light-cured glass ionomer pit and fissure sealant (FJ) and (5) Base Cement((r)) glass polyalkenoate cement (BC). Subsequently, they were detected using four different methods: quantitative light-induced fluorescence, microhardness, surface 3D topography and scanning electron microscopy (SEM). RESULTS: The loss of fluorescence intensity of CV, BC and FJ groups showed significant decreases after remineralization (p<0.05). The microhardness values of the BC group were significantly higher than those of the other groups (p<0.05) after 6 weeks of remineralization. The CV group's surface roughness was significantly lower than those of the other groups after 6 weeks of remineralization (p<0.05). Regarding microstructure values, the FV group showed many round particles deposited in the bovine enamel after remineralization. However, the other four groups mainly showed needle-like crystals. CONCLUSIONS: Glass ionomer cement (GIC)-based dental materials can promote more remineralization of the artificial enamel lesions than can NaF-based dental materials. Resin-modified GIC materials (e.g., CV and FJ) have the potential for more controlled and sustained release of remineralized agents. The effect of TM requires further study. PMID- 22227270 TI - Dream experience and a revisionist account of delusions of misidentification. AB - Standard accounts of delusion explain them as responses to experience. Cognitive models of feature binding in the face recognition systems explain how experiences of mismatch between feelings of "familiarity" and faces can arise. Similar mismatches arise in phenomena such as deja and jamais vu in which places and scenes are mismatched to feelings of familiarity. These cognitive models also explain similarities between the phenomenology of these delusions and some dream states which involve mismatch between faces, feelings of familiarity and identities. Given these similarities it makes sense to retain that aspect of the standard account in the face of revisionist arguments that feature binding anomalies which lead to delusions of misidentification are not consciously experienced. PMID- 22227271 TI - Laterality briefed: laterality modulates performance in a numerosity-congruity task. AB - It is widely agreed that irrelevant numerical values are automatically activated. However, automatic and intentional activations may give rise to different numerical representations. We examined processing of symbolic and non-symbolic (i.e., numerosity) representations asking whether they differ in automatic and intentional processing. Participants were presented with two-dimensional displays containing repetitions of a digit and were asked to report, in different blocks, whether the digit or numerosity was smaller or larger than 5. Incongruent trials differed either in laterality between the relevant and irrelevant dimensions (i.e., the location of both dimensions in reference to the midpoint 5) or in numerical distance between dimensions. Congruency affected performance regardless of symbolic or non-symbolic presentation. For incongruent trials, laterality (not distance) affected performance, again regardless of presentation. This implies that automaticity does not mean similar processing of relevant and irrelevant dimensions. Specifically, the relevant dimension is processed elaborately whereas the irrelevant dimension is processed crudely. PMID- 22227272 TI - Lamotrigine is a substrate for OCT1 in brain endothelial cells. AB - The mechanisms that underpin the passage of lamotrigine at the blood-brain barrier to its site of action in the brain is poorly understood. Lamotrigine has been postulated to be delivered to its site of action in the brain favourably despite its physicochemical properties. The aim of this study was to investigate the transport of lamotrigine in an in-vitro model of the BBB. In this study, lamotrigine was found to have a distribution coefficient of 0 at pH 7.4 indicating that it was not highly lipophilic. Human brain endothelial cells (hCMEC/D3) were used to probe the interaction of lamotrigine with drug transporters. The uptake of lamotrigine into hCMEC/D3 cells was found to be an active process (K(m) = 62 +/- 14 MUM; V(max) = 385 +/- 30 pmol/min/million cells). Furthermore, use of a panel of transporter inhibitors indicated that this active uptake was mediated by organic cation transporter 1 (OCT1). OCT1 mRNA and protein were shown to be expressed in hCMEC/D3 cells. KCL22 cells overexpressing OCT1 were then used to validate these findings. Lamotrigine was confirmed to be a substrate and inhibitor in OCT1-transfected KCL22 cells. A putative pharmacokinetic drug-drug interaction (DDI) between quetiapine and lamotrigine was recently reported in patients and we show here that quetiapine is a potent inhibitor of the OCT1-mediated transport of lamotrigine. This is the first time that a specific influx transporter has been shown to transport lamotrigine. The clinical implications of these findings with respect to the efficacy of lamotrigine and its potential for DDI require further investigation. PMID- 22227273 TI - Curcumin as anti-endometriotic agent: implication of MMP-3 and intrinsic apoptotic pathway. AB - The disease of reproductive women, endometriosis represents implantation of functional endometrial glands outside uterine cavity. This invasive disorder is associated with dysregulation of matrix metalloproteases (MMP)s and extracellular matrix (ECM) remodeling. In this study, we investigated the role of MMP-3 on apoptosis during endometriosis. We also checked whether curcumin has potency to regress endometriosis by modulating MMP-3 and apoptotic pathway. Mouse model of endometriosis was designed by intraperitoneal inoculation of endometrial tissues to syngeneic female BALB/c. At 15th day, stable endometriotic developments were observed with increased MMP-3 expression. TUNEL positive cells were also found with endometriotic progression, which might resulted from destruction of local immune cells. We speculate that increased MMP-3 activity might be involved in the Fas mediated apoptosis. Curcumin treatment regressed endometriosis by inhibiting NFkappaB translocation and MMP-3 expression. It also accelerated apoptosis in endometriomas predominantly via cytochrome-c mediated mitochondrial pathway. Involvement of mitochondria in apoptosis was further confirmed by atomic force microscopy (AFM). These results were also supported by our therapeutic study, where curcumin induced apoptosis both by p53 dependent and independent manner, while celecoxib followed only p53 independent pathway. Altogether, our study establishes the novel role of curcumin as a potent anti-endometriotic compound. PMID- 22227274 TI - Dog bites man or man bites dog? The enigma of the amino acid conjugations. AB - The proposition posed is that the value of amino acid conjugation to the organism is not, as in the traditional view, to use amino acids for the detoxication of aromatic acids. Rather, the converse is more likely, to use aromatic acids that originate from the diet and gut microbiota to assist in the regulation of body stores of amino acids, such as glycine, glutamate, and, in certain invertebrates, arginine, that are key neurotransmitters in the central nervous system (CNS). As such, the amino acid conjugations are not so much detoxication reactions, rather they are homeostatic and neuroregulatory processes. Experimental data have been culled in support of this hypothesis from a broad range of scientific and clinical literature. Such data include the low detoxication value of amino acid conjugations and the Janus nature of certain amino acids that are both neurotransmitters and apparent conjugating agents. Amino acid scavenging mechanisms in blood deplete brain amino acids. Amino acids glutamate and glycine when trafficked from brain are metabolized to conjugates of aromatic acids in hepatic mitochondria and then irreversibly excreted into urine. This process is used clinically to deplete excess nitrogen in cases of urea cycle enzymopathies through excretion of glycine or glutamine as their aromatic acid conjugates. Untoward effects of high-dose phenylacetic acid surround CNS toxicity. There appears to be a relationship between extent of glycine scavenging by benzoic acid and psychomotor function. Glycine and glutamine scavenging by conjugation with aromatic acids may have important psychosomatic consequences that link diet to health, wellbeing, and disease. PMID- 22227275 TI - Correspondence regarding "Long term treatment with ACE inhibitor enalapril decreases body weight gain and increases life span in rats". PMID- 22227276 TI - WITHDRAWN: Histone epigenetic alterations in systemic lupus erythematosus could be reversed by specific modifying agents. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22227277 TI - Partial tandem duplication of mtDNA-tRNA(Phe) impairs mtDNA translation in late onset mitochondrial myopathy. AB - An 80-year-old woman (PI) has been suffering of late onset progressive weakness and wasting of lower-limb muscles, accompanied by high creatine kinase levels in blood. A muscle biopsy, performed at 63 years, showed myopathic features with partial deficiency of cytochrome c oxidase. A second biopsy taken 7 years later confirmed the presence of a mitochondrial myopathy but also of vacuolar degeneration and other morphological features resembling inclusion body myopathy. Her 46-year-old daughter (PII) and 50-year-old son (PIII) are clinically normal, but the creatine kinase levels were moderately elevated and the EMG was consistently myopathic in both. Analysis of mitochondrial DNA sequence revealed in all three patients a novel, homoplasmic 15 bp tandem duplication adjacent to the 5' end of mitochondrial tRNA(Phe) gene, encompassing the first 11 nucleotides of this gene and the four terminal nucleotides of the adjacent D-loop region. Both mutant fibroblasts and cybrids showed low oxygen consumption rate, reduced mitochondrial protein synthesis, and decreased mitochondrial tRNA(Phe) amount. These findings are consistent with an unconventional pathogenic mechanism causing the tandem duplication to interfere with the maturation of the mitochondrial tRNA(Phe) transcript. PMID- 22227278 TI - Oxytocin modulates cooperation within and competition between groups: an integrative review and research agenda. AB - The author reviews evidence that hypothalamic release (or infusion) of the neuropeptide oxytocin modulates the regulation of cooperation and conflict among humans because of three reasons. First, oxytocin enables social categorization of others into in-group versus out-group. Second, oxytocin dampens amygdala activity and enables the development of trust. Third, and finally, oxytocin up-regulates neural circuitries (e.g., inferior frontal gyrus, ventromedial prefrontal cortex, caudate nucleus) involved in empathy and other-concern. Consistent with an evolutionary perspective on the functionality of cooperation, it is concluded that oxytocin-motivated cooperation is mostly parochial-it motivates (i) in-group favoritism, (ii) cooperation towards in-group but not out-group members, and (iii) defense-motivated non-cooperation towards threatening outsiders. Thus, in addition to its well-known role in reproduction and pair-bond formation, oxytocin's primary functions include in-group "tend-and-defend." This review concludes with avenues for new research on oxytocin's functions in within-group cooperation and between-group competition. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID- 22227279 TI - CD38 and its role in oxytocin secretion and social behavior. AB - Here, we review the functional roles of cyclic ADP-ribose and CD38, a transmembrane protein with ADP-ribosyl cyclase activity, in mouse social behavior via the regulation of oxytocin (OXT) release, an essential component of social cognition. Herein we describe data detailing the molecular mechanism of CD38 dependent OXT secretion in CD38 knockout mice. We also review studies that used OXT, OXT receptor (OXTR), or CD38 knockout mice. Additionally, we compare the behavioral impairments that occur in these knockout mice in relation to the OXT system and CD38. This review also examines autism spectrum disorder (ASD), which is characterized by social and communication impairments, in relation to defects in the OXT system. Two single nucleotide polymorphisms (SNPs) in the human CD38 gene are possible risk factors for ASD via inhibition of OXT function. Further analysis of CD38 in relation to the OXT system may provide a better understanding of the neuroendocrinological roles of OXT and CD38 in the hypothalamus and of the pathophysiology of ASD. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID- 22227280 TI - The role of food culture and marketing activity in health disparities. AB - Marketing activities have attracted increased attention from scholars interested in racial disparities in obesity prevalence, as well as the prevalence of other preventable conditions. Although reducing the marketing of nutritionally poor foods to racial/ethnic communities would represent a significant step forward in eliminating racial disparities in health, we focus instead on a critical-related question. What is the relationship between marketing activities, food culture, and health disparities? This commentary posits that food culture shapes the demand for food and the meaning attached to particular foods, preparation styles, and eating practices, while marketing activities shape the overall environment in which food choices are made. We build on prior research that explores the socio cultural context in which marketing efforts are perceived and interpreted. We discuss each element of the marketing mix to highlight the complex relationship between food culture, marketing activities, and health disparities. PMID- 22227281 TI - A novel extract from bovine colostrum whey supports anti-bacterial and anti-viral innate immune functions in vitro and in vivo: I. Enhanced immune activity in vitro translates to improved microbial clearance in animal infection models. AB - OBJECTIVE: To evaluate effects on the innate immune system after exposure to, a consumable low-molecular weight fraction (CLMWF) of immunoglobulin-depleted bovine colostrum whey. METHODOLOGY: Cell-based immune assays were performed in vitro, and host resistance towards bacterial and viral infection was evaluated in two mouse studies. RESULTS: In vitro data showed a multimodal effect, as CLMWF treatment resulted in a rapid increase in phagocytosis. CLMWF increased chemotaxis of polymorphonuclear cells towards the bacterial peptide f-MLP. CLMWF treatment of natural killer cells increased expression of the CD69 activation marker. Mononuclear phagocytes showed decreased numbers of CD14(bright) and increased number of CD14(dim) cells. The remaining CD14(bright) cells showed reduced expression of CD80 and CD86, whereas CD14(dim) cells showed increased expression of CD80 and CD86, suggesting dendritic cell maturation. Mouse models were applied to evaluate the immune-modulating capacity of CLMWF when consumed acutely during bacterial (Streptococcus) and viral (Influenza) infections in vivo. Reduced bacterial and viral loads were observed in lungs within 24h. Viral load was also reduced when CLMWF was introduced intranasally. CONCLUSION: The data suggest that the support of antimicrobial immune defense mechanisms and maturation of antigen-presenting cells in vitro translates to protection in vivo when product is introduced across mucosal membranes. PMID- 22227282 TI - Radiation risks: critical analysis and commentary. AB - OBJECTIVES: 1) To review and summarize what is known about the health risks of radiation. 2) To compare risks from medical imaging to background radiation and to exposure from nuclear accidents. METHODS: Literature review and summative critical analysis. RESULTS: Over the past several years, physicians and patients have become increasingly aware of the potential risks of radiation exposure from medical imaging. The Fukushima disaster further heightened public awareness of hazards associated with radiation and radioactivity. In the case of medical imaging, small but real risks of cancer and other radiation-induced disease must be balanced against potential benefits of improved diagnostic accuracy. The ethical principle of autonomy tells us that patients should be informed of potential benefits and harms of radiation imaging, and should participate in shared decision making. In the case of nuclear power, benefits and especially harms are exceptionally difficult to estimate accurately. Nevertheless, we know that hazards from today's nuclear power plants will persist for many years, affecting future generations not benefiting from electrical power generated today. CONCLUSIONS: A deeper and more widespread understanding of potential benefits and harms of personal and societal choices relating to radiation exposure may lead to improved medical and societal decision-making. PMID- 22227283 TI - Isoflavones as a smart curer for non-alcoholic fatty liver disease and pathological adiposity via ChREBP and Wnt signaling. AB - OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) and pathological adiposity has emerged as an important modern disease. Along with this, the requirement for alternative and natural medicine for preventing NAFLD and adiposity has been increasing rapidly and considerably. In this report, we will review the biological effect and mechanisms of soy isoflavones on NAFLD and pathologic adiposity mainly through the novel pathways, de novo lipogenic carbohydrate responsive element binding protein (ChREBP) and anti-adipogenic Wnt signaling. METHODS: This paper reviews in vitro and in vivo isoflavone studies published in 2002 to 2011 in North America and East Asia. RESULTS: Collectively, the data support a beneficial relation of isoflavones and NAFLD and/or adiposity. Isoflavones suppress ChREBP signaling via protein kinase A (PKA) and/or 5'-AMP activated protein kinase (AMPK)-dependent phosphorylation, which prevents ChREBP from binding to the promoter regions of lipogenic enzyme. Furthermore, isoflavones directly stimulate Wnt signaling via estrogen receptors-dependent pathway, which inactivates glycogen synthase kinase-3 beta (GSK-3beta), transactivate T-cell factor/lymphoid-enhancer factor (TCF/LEF), the effector of Wnt signaling, degrade adipogenic peroxisome proliferator-activated receptor gamma (PPARgamma), augment p300/CBP, the transcriptional co-activators of TCF/LEF. CONCLUSIONS: Natural compound isoflavones may be useful alternative medicines in preventing NAFLD and pathological adiposity and this action may be partially associated with ChREBP and Wnt signaling. PMID- 22227284 TI - Cross-sectional associations between occupational and leisure-time sitting, physical activity and obesity in working adults. AB - AIM: To examine associations between occupational and leisure-time sitting, physical activity and obesity in working adults. METHODS: We analyzed data from workers from the 2007-08 Australian National Health Survey (n=10,785). Participants reported their activity at work (mostly sitting, standing, walking, or heavy labor), transport-related walking, leisure-time sitting and physical activity. Body mass index was objectively measured. Adjusted Cox proportional hazard regression models examined associations between occupational activity category, leisure-time sitting, physical activity and obesity risk. RESULTS: Substantial proportions of men (42%) and women (47%) mostly sit at work. Workers with sitting jobs were significantly more likely to be sufficiently active during leisure-time than workers with mostly standing, walking or heavy labor jobs (RR=0.88, 0.80, 0.86 respectively). Workers with mostly sitting jobs had significantly higher overweight/obesity risk than workers with mostly standing jobs (RR=0.88, 95% CI: 0.82-0.95) independent of physical activity and leisure time sitting. Workers with leisure-time sitting of less than four hours per day had significantly lower obesity risk than workers with four or more hours per day of leisure-time sitting (RR=0.77, 95%CI: 0.69-0.87) independent of physical activity and occupational activity. CONCLUSIONS: Sitting time and physical activity are independently associated with obesity. Leisure-time sitting may have a stronger association with obesity risk than occupational sitting. PMID- 22227285 TI - Cultural consonance: linking culture, the individual and health. PMID- 22227286 TI - n-3 fatty acids prevent impairment of neurogenesis and synaptic plasticity in B cell activating factor (BAFF) transgenic mice. AB - OBJECTIVE: Autoimmune-prone B-cell activating factor transgenic mice, a mouse model of systemic lupus erythematosus and Sjogren's syndrome exhibit neuroinflammation, anxiety-like phenotype, deficit in adult hippocampal neurogenesis and impaired neurogenesis-dependent and neurogenesis-independent dentate gyrus long-term potentiation. Given that n-3 polyunsaturated fatty acids regulate hippocampal plasticity and inflammatory responses, we investigated whether n-3 polyunsaturated fatty acids-enriched diet might prevent age-dependent hippocampal changes in B-cell activating factor transgenic mice. METHODS: B-cell activating factor transgenic mice were fed for 12 weeks with either n-3 polyunsaturated fatty acids-enriched or control diet and we tested the effect of this dietary supplementation on hippocampal inflammation, progenitor cell proliferation and neurogenesis-dependent and neurogenesis-independent long-term potentiation. RESULTS: Dietary supplementation with n-3 polyunsaturated fatty acids significantly decreased hippocampal microglial activation and increased the density of bromodeoxyuridine and doublecortin-positive newly-formed cells in the subventricular zone of hippocampus. Furthermore, B-cell activating factor transgenic mice fed with n-3 polyunsaturated fatty acids-enriched diet displayed normal long-term potentiation at the medial perforant pathway/dentate gyrus connections. CONCLUSIONS: The results indicate that n-3 fatty acids prevent neuroinflammation and deficits of hippocampal plasticity in B-cell activating factor transgenic mice and suggest that increased n-3 fatty acids intake might represent a potential therapeutic option to prevent neuropsychiatric symptoms associated with autoimmune diseases. PMID- 22227287 TI - More accurate 1J(CH) coupling measurement in the presence of 3J(HH) strong coupling in natural abundance. AB - J couplings are essential for measuring RDCs (residual dipolar couplings), now routinely used to deduce molecular structure and dynamics of glycans and proteins. Accurate measurement of (1)J(CH) is critical for RDCs to reflect the true structure and dynamics in the molecule of interest. We report noticeable discrepancies between (1)J(CH) values measured with HSQC type pulse sequences in the (1)H dimension from those measured in the (13)C dimension for 17 sugars and show that these discrepancies arise from strong scalar coupling. In order to determine how to minimize errors in measuring (1)J(CH), we analyze the strong coupling effects in detail using the product operator-formalism and spectral simulations based on the solution of the Liouville equation (not considering relaxation effects) in the presence of strong coupling. We report that the apparent (1)J(CH) measured with 2D HSQC-based sequences in either dimension can be in error by up to 4 Hz and that the values measured in the (1)H dimension can disagree with those in the (13)C dimension by up to 7 Hz. We demonstrate that spectral simulations can reproduce the errors induced by strong coupling and that these can be used to extract true (1)J(CH) values. We find that the (1)J(CH) values measured using a modified Z-filtered coupled HSQC are still affected by strong coupling. We conclude that spectral simulation yields accurate (1)J(CH) with errors as low as 1% in the presence of strong coupling. PMID- 22227288 TI - 3D localized 2D ultrafast J-resolved magnetic resonance spectroscopy: in vitro study on a 7 T imaging system. AB - 2D Magnetic Resonance Spectroscopy (MRS) is a well known tool for the analysis of complicated and overlapped MR spectra and was therefore originally used for structural analysis. It also presents a potential for biomedical applications as shown by an increasing number of works related to localized in vivo experiments. However, 2D MRS suffers from long acquisition times due to the necessary collection of numerous increments in the indirect dimension (t(1)). This paper presents the first 3D localized 2D ultrafast J-resolved MRS sequence, developed on a small animal imaging system, allowing the acquisition of a 3D localized 2D J resolved MRS spectrum in a single scan. Sequence parameters were optimized regarding Signal-to-Noise ratio and spectral resolution. Sensitivity and spatial localization properties were characterized and discussed. An automatic post processing method allowing the reduction of artifacts inherent to ultrafast excitation is also presented. This sequence offers an efficient signal localization and shows a great potential for in vivo dynamic spectroscopy. PMID- 22227289 TI - Determination of size and sign of hetero-nuclear coupling constants from 2D 19F 13C correlation spectra. AB - Fluorinated organic compounds have become increasingly important within the polymer and the pharmaceutical industry as well as for clinical applications. For the structural elucidation of such compounds, NMR experiments with fluorine detection are of great value due to the favorable NMR properties of the fluorine nucleus. For the investigation of three fluorinated compounds, triple resonance 2D HSQC and HMBC experiments were adopted to fluorine detection with carbon and/or proton decoupling to yield F-C, F-C{H}, F-C{C(acq)} and F-C{H,C(acq)} variants. Analysis of E.COSY type cross-peak patterns in the F-C correlation spectra led, apart from the chemical shift assignments, to determination of size and signs of the J(CH), J(CF), and J(HF) coupling constants. In addition, the fully coupled F-C HMQC spectrum of steroid 1 was interpreted in terms of E.COSY type patterns. This example shows how coupling constants due to different nuclei can be determined together with their relative signs from a single spectrum. The analysis of cross-peak patterns, as presented here, not only provides relatively straightforward routes to the determination of size and sign of hetero-nuclear J couplings in fluorinated compounds, it also provides new and easy ways for the determination of residual dipolar couplings and thus for structure elucidation. The examples and results presented in this study may contribute to a better interpretation and understanding of various F-C correlation experiments and thereby stimulate their utilization. PMID- 22227290 TI - Association between TNF-alpha promoter -308A/G polymorphism and tardive dyskinesian Chinese Han patients with schizophrenia. AB - OBJECTIVE: Previous studies have indicated that the immune may be involved in the pathogenesis of tardive dyskinesia (TD). Some genetic polymorphisms in the human leukocyte antigen (HLA) I and II regions have been associated with TD, and the tumor necrosis factor-alpha (TNF-alpha) gene is located in the HLA III region. TNF-alpha levels in the striatum significantly increased in haloperidol-induced TD in rats. The TNF-alpha gene -308A/G single nucleotide polymorphism (SNP) has been shown to directly influence TNF-alpha expression. The genetic association between the TNF-alpha gene -308A/G SNP and TD is unclear. The present study investigated whether this variation is associated with clinical phenotypes and TD in schizophrenia in a genetically homogeneous northern Chinese Han population. METHODS: We genotyped the TNF-alpha gene -308A/G SNP in patients with schizophrenia with TD (n=350) and without TD (n=410). The Abnormal Involuntary Movement Scale (AIMS) and Positive and Negative Syndrome Scale (PANSS) were used to assess the severity of TD and psychopathology of schizophrenia, respectively. RESULTS: The allele and genotype frequencies did not significantly differ between patients with schizophrenia with and without TD (p>0.05). No significant difference was found in the total AIMS score between the genotypes (p>0.05). However, the PANSS negative symptom subscore was associated with risk for TD (p=0.004), and a significant difference was found in total AIMS score between the genotypes in TD patients (p=0.013). CONCLUSION: The TNF-alpha gene -308A/G polymorphism does not appear to play a major role in the susceptibility to TD in patients with schizophrenia in a northern Chinese Han population. However this polymorphism may play a role in the TD severity. PMID- 22227291 TI - Differential effects of methylphenidate and atomoxetine on attentional processes in children with ADHD: an event-related potential study using the Attention Network Test. AB - Methylphenidate (MPH) and atomoxetine (ATX) are effective medications in the treatment of attention deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate differential effects of MPH and ATX on attentional functions at the performance and the neuronal level in children with ADHD. Using the Attention Network Test (ANT), differential effects of both medications on the noradrenergic alerting network and the dopaminergic executive attention network were considered. Nineteen children with ADHD performed the ANT three times while event-related potentials (ERPs) were recorded. The baseline testing was conducted without medication. In two medication blocks of 8 weeks each, medication was individually titrated for each child (cross-over design, balanced order). At the end of the medication blocks the testing was repeated. While both medications comparably reduced ADHD symptomatology, MPH had some advantages over ATX with regard to performance measures on the ANT and the underlying neuronal mechanisms. Compared with ATX, MPH led to a larger reduction in reaction time variability, which was accompanied by an MPH-related increase in the contingent negative variation (CNV) compared to the baseline testing. Contrary to our expectations, specific alerting network effects were not observed with ATX. Due to the chosen study design, it remains unresolved to what extent e.g. shortened reaction times and smaller conflict scores that were observed with both medications reflect practice or medication effects. The differential pattern of MPH vs. ATX effects on attentional functions in children with ADHD may be explained by the dopaminergic effects of MPH within the cortico-striato-thalamo-cortical circuit. PMID- 22227292 TI - Characterization of human DNA polymerase kappa promoter in response to benzo[a]pyrene diol epoxide. AB - DNA polymerase kappa (Pol kappa), a member of Y-family DNA polymerases, can synthesize DNA with moderate fidelity on undamaged DNAs and replicate accurately in vitro thymine glycol, 8-oxo-G and aromatic adducts such as benzo[a]pyrene diol epoxide (BPDE). However, few studies have been done on the transcriptional regulation of Pol kappa. In this study, we predicted and cloned the promoter region of the human POLK gene. Through the analysis of deletion constructs of the POLK promoter, we demonstrated that the region -336/-141 contained repressing elements and the region -141/+226 contained positive regulatory elements for transcription of human Pol kappa. Furthermore, quantitative RT-PCR showed that human POLK mRNA expression was dysregulated in FL cells treated by BPDE. The transcriptional activities of the POLK promoter regions -336/+437 and +20/+437 were significantly reduced by BPDE treatment, indicating that transcription factors in this two regions, such as HSF1, may regulate the transcription of human POLK gene in response to BPDE. PMID- 22227293 TI - Adiponectin-AdipoR1/2-APPL1 signaling axis suppresses human foam cell formation: differential ability of AdipoR1 and AdipoR2 to regulate inflammatory cytokine responses. AB - OBJECTIVE: Adiponectin is an adipokine that exerts anti-inflammatory and anti atherogenic effects during macrophage transformation into foam cells. To further understand the signaling pathways of adiponectin involved in macrophage foam cell transformation, we investigated the roles of two adiponectin receptors (AdipoR1 and AdipoR2) and their downstream adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1 (APPL1) in mediating adiponectin action on foam cell transformation. METHODS AND RESULTS: Transfections were performed to overexpress or knockdown AdipoR1 or AdipoR2 genes in human THP-1 monocytes. Lentiviral-shRNAs were also used to knockdown APPL1 gene in these cells. Foam cell transformation was induced via exposure to oxidized low-density lipoprotein (oxLDL). Our results showed that both AdipoR1 and AdipoR2 were critical for transducing the adiponectin signal that suppresses lipid accumulation and inhibits transformation from macrophage to foam cell. However, AdipoR1 and AdipoR2 were found to have differential effects in diminishing proinflammatory responses. While AdipoR1 was required by adiponectin to suppress tumor necrosis factor alpha (TNFalpha) and monocyte chemotactic protein 1 (MCP-1) gene expression, AdipoR2 served as the dominant receptor for adiponectin suppression of scavenger receptor A type 1 (SR-AI) and upregulation of interleukin-1 receptor antagonist (IL-1Ra). Knockdown of APPL1 significantly abrogated the ability of adiponectin to inhibit lipid accumulation, SR-AI and nuclear factor-kappaB (NF kappaB) gene expression, and Akt phosphorylation in macrophage foam cells. CONCLUSIONS: In current studies, we have demonstrated that adiponectin's abilty to suppress macrophage lipid accumulation and foam cell formation is mediated through AdipoR1 and AdipoR2 and the APPL1 docking protein. However, AdipoR1 and AdipoR2 exhibited a differential ability to regulate inflammatory cytokines and SR-A1. These novel data support the idea that the adiponectin-AdipoR1/2-APPL1 axis may serve as a potential therapeutic target for preventing macrophage foam cell formation and atherosclerosis. PMID- 22227294 TI - Fifty years of structural glycoproteins. AB - During decades preceding and following the last war, a favourite subject of biochemists was to study glycoproteins. One class of these substances, found in connective tissues were characterised as polysaccharides, most of them found to be linked to proteins, designated later as glycosaminoglycans and proteoglycans. Another family of glycoconjugates represented epithelial mucins as found in the gastro-intestinal and respiratory tracts and conduits. A third family of glycoconjugates is represented by circulating glycoproteins isolated from the blood plasma, mostly studied by medical biochemists in relation to pathological conditions comprising those increasing during the inflammatory reaction: acute phase glycoproteins. Their study suggested that they might be derived from connective tissues. Although inflammatory glycoproteins derive mostly from the liver, the possibility of connective tissue origin of glycoproteins remained open. Using cornea, an avascular tissue, we could show that connective tissues also synthesize glycoproteins. We proposed to designate them "structural glycoproteins" (SGP-s) to distinguish them from circulating, blood-born glycoproteins coming from the liver. They play locally "structural" roles in connective tissues where they are synthesized. Soon after fibronectin was identified and shown to mediate cell-matrix interactions. A large family of glycoproteins were then isolated from a variety of sources, cells, tissues others than liver, confirming our original hypothesis. The first experiments on these glycoproteins were published from 1961/1962 giving the opportunity to recapitulate this biochemical adventure 50 years later, together with the celebration of the foundation of the first connective tissue society in Europe, as described in the first article in this issue. PMID- 22227295 TI - Stem cell dynamics in sebaceous gland morphogenesis in mouse skin. AB - The hair follicle (HF) and the sebaceous gland (SG) constitute the two integral parts of the pilosebaceous unit and significantly contribute to the barrier function of mammalian skin. Considerable progress has been made in our understanding how HF formation is regulated. However, the development of the SG is poorly understood, both at the molecular and cellular level. Here, we investigate the process of SG morphogenesis and the dynamics of its cellular organisation in more detail. The spatial and temporal organisation of distinct stem and progenitor compartments was analysed during morphogenesis of the pilosebaceous unit in mouse tail epidermis. Our experiments reveal a dynamic expression pattern for diverse HF stem cell marker molecules including Sox9 and Lrig1. Surprisingly, Sox9 and Lrig1 are initially coexpressed by epidermal progenitor cells and are confined to different regions within the pilosebaceous unit when the specification of the sebocyte cell lineage takes place. We demonstrate that SG development at the distal part of the HF is driven by asymmetric cell fate decision of Lrig1 positive stem cells, whereas MTS24/Plet1 positive precursor cells seem not to play a role in this process. Importantly, our data clearly show that distinct stem and progenitor compartments are established at different time points of development. By studying the process of SG morphogenesis more precisely, we discovered that the two prominent SGs attached to one tail HF originate from one small cluster of sebocyte cells. Finally, we show regional specificity for HF patterning and spatio-temporal control of the underlying molecular signals initiating the development of the pilosebaceous unit. PMID- 22227296 TI - Chorein-sensitive polymerization of cortical actin and suicidal cell death in chorea-acanthocytosis. AB - Chorea-acanthocytosis is an inevitably lethal genetic disease characterized by a progressive hyperkinetic movement disorder and cognitive and behavioral abnormalities as well as acanthocytosis. The disease is caused by loss-of function mutations of the gene encoding vacuolar protein sorting-associated protein 13A (VPS13A) or chorein, a protein with unknown function expressed in various cell types. How chorein deficiency leads to the pathophysiology of chorea acanthocytosis remains enigmatic. Here we show decreased phosphoinositide-3 kinase (PI3K)-p85-subunit phosphorylation, ras-related C3 botulinum toxin substrate 1 (Rac1) activity, and p21 protein-activated kinase 1 (PAK1) phosphorylation as well as depolymerized cortical actin in erythrocytes from patients with chorea-acanthocytosis and in K562-erythrocytic cells following chorein silencing. Pharmacological inhibition of PI3K, Rac1, or PAK1 similarly triggered actin depolymerization. Moreover, in K562 cells, both chorein silencing and PAK1 inhibition with IPA-3 decreased phosphorylation of Bad, a Bcl2 associated protein, promoting apoptosis by forming mitochondrial pores, followed by mitochondrial depolarization, DNA fragmentation, and phosphatidylserine exposure at the cell surface, all hallmarks of apoptosis. Our observations reveal chorein as a novel powerful regulator of cytoskeletal architecture and cell survival, thus explaining erythrocyte misshape and possibly neurodegeneration in chorea-acanthocytosis. PMID- 22227297 TI - Artesunate activates Nrf2 pathway-driven anti-inflammatory potential through ERK signaling in microglial BV2 cells. AB - Chronic inflammatory response in the brain is a characteristic etiopathology of various neurodegenerative diseases; consequently increasing the intrinsic anti inflammatory potency could be an especially desirable strategy to prevent inflammation-related neuronal injuries. Transcription factor NF-E2-related factor 2 (Nrf2)-mediated control of redox homeostasis may participate in the modulation of microglial responses by regulating expression of important antioxidant and phase II detoxification genes. In our present work, we show that artesunate, a semi-synthetic derivative of anti-malarial agent artemisinin, attenuates LPS induced inflammatory responses in microglial BV2 cells. Artesunate activates Nrf2 ARE system, and leads to an increase in the level of downstream heme oxygenase-1. Artesunate also activates PI3K/Akt, ERK, and JNK MAPKs signaling, but artesunate induced activation of Nrf2 signaling and up-regulation of heme oxygenase-1 are ERK pathway-dependent. Collectively, this study demonstrates that artesunate is a potential activator of the Nrf2/ARE-dependent pathway and is therapeutically relevant to inflammatory responses of microglial cells. PMID- 22227298 TI - The atypical cannabinoid O-1602 increases hind paw sensitisation in the chronic constriction injury model of neuropathic pain. AB - O-1602 is an atypical cannabinoid that acts as an agonist at GPR55, a g protein coupled receptor that previous studies have indicated may have a pronociceptive role in neuropathic pain. We administered O-1602 to both naive rats and rats that had undergone chronic constriction injury surgery. O-1602 did not cause any changes in hind paw responses to Von Frey hair testing in naive rats. However, O 1602 reversed the desensitising effects of ETOH, which was used as an active and opposing vehicle. Our results are consistent with the hypothesis that GPR55 has a pronociceptive role in neuropathic pain. PMID- 22227299 TI - Heparanase overexpression reduces carrageenan-induced mechanical and cold hypersensitivity in mice. AB - Heparanase controls the structure and functions of extracellular matrix (ECM) by degrading heparan sulfate proteoglycans. Heparanase is involved in inflammatory process through modulating the functions of inflammatory cytokines. The present study aimed to find out whether overexpression of heparanase in mice affects carrageenan-induced localized inflammation and inflammatory hyperalgesia. Without challenge, the heparanase overexpression did not significantly affect the mice in response to mechanical, cold and heat stimulation. Unilateral subcutaneous administration of carrageenan produced hypersensitivity to mechanical and cold in both wildtype and the heparanase overexpression (Hpa-tg) mice 24h after treatment. In comparison to wildtype animals, the Hpa-tg mice showed significantly reduced mechanical and cold hypersensitivity. This may, at least partially, due to the reduced mast cell infiltration at the site of inflammation in Hpa-tg mice. These data support a role for heparanase that reduces localized inflammation and inflammatory hyperalgesia in mice. PMID- 22227300 TI - A life-long learning vector quantization approach for interactive learning of multiple categories. AB - We present a new method capable of learning multiple categories in an interactive and life-long learning fashion to approach the "stability-plasticity dilemma". The problem of incremental learning of multiple categories is still largely unsolved. This is especially true for the domain of cognitive robotics, requiring real-time and interactive learning. To achieve the life-long learning ability for a cognitive system, we propose a new learning vector quantization approach combined with a category-specific feature selection method to allow several metrical "views" on the representation space of each individual vector quantization node. These category-specific features are incrementally collected during the learning process, so that a balance between the correction of wrong representations and the stability of acquired knowledge is achieved. We demonstrate our approach for a difficult visual categorization task, where the learning is applied for several complex-shaped objects rotated in depth. PMID- 22227301 TI - An impact assessment methodology for urban surface runoff quality following best practice treatment. AB - The paper develops an easy to apply desk-based semi-quantitative approach for the assessment of residual receiving water quality risks associated with urban surface runoff following its conveyance through best practice sustainable drainage systems (SUDS). The innovative procedure utilises an integrated geographical information system (GIS)-based pollution index approach based on surface area impermeability, runoff concentrations/loadings and individual SUDS treatment performance potential to evaluate the level of risk mitigation achievable by SUDS drainage infrastructure. The residual impact is assessed through comparison of the determined pollution index with regulatory receiving water quality standards and objectives. The methodology provides an original theoretically based procedure which complements the current acute risk assessment approaches being widely applied within pluvial flood risk management. PMID- 22227302 TI - Assessing dietary exposure to cadmium in a metal recycling community in Vietnam: age and gender aspects. AB - This study estimates the dietary exposure to cadmium (Cd), and associated potential health risks, for individuals living and working in a metal recycling community (n=132) in Vietnam in comparison to an agricultural (reference) community (n=130). Individual-level exposure to Cd was estimated through analysis of staple foodstuffs combined with information from a food frequency questionnaire. Individual-level exposure estimates were compared with published 'safe' doses to derive a Hazard Quotient (HQ) for each member of the study population. Looking at the populations as a whole, there were no significant differences in the diets of the two villages. However, significantly more rice was consumed by working age adults (18-60 years) in the recycling village compared to the reference village (p<0.001). Rice was the main staple food with individuals consuming 461+/-162g/d, followed by water spinach (103+/-51kg/d). Concentrations of Cd in the studied foodstuffs were elevated in the metal recycling village. Values of HQ exceeded unity for 87% of adult participants of the metal recycling community (39% had a HQ>3), while 20% of adult participants from the reference village had an HQ>1. We found an elevated health risk from dietary exposure to Cd in the metal recycling village compared to the reference community. WHO standard of 0.4mg Cd/kg rice may not be protective where people consume large amounts of rice/have relatively low body weight. PMID- 22227303 TI - CMAQ predictions of tropospheric ozone in the U.S. southwest: influence of lateral boundary and synoptic conditions. AB - Phoenix, Arizona, has been an ozone nonattainment area for the past several years and it remains so. Mitigation strategies call for improved modeling methodologies as well as understanding of ozone formation and destruction mechanisms during seasons of high ozone events. To this end, the efficacy of lateral boundary conditions (LBCs) based on satellite measurements (adjusted-LBCs) was investigated, vis-a-vis the default-LBCs, for improving the predictions of Models 3/CMAQ photochemical air quality modeling system. The model evaluations were conducted using hourly ground-level ozone and NO(2) concentrations as well as tropospheric NO(2) columns and ozone concentrations in the middle to upper troposphere, with the 'design' periods being June and July of 2006. Both included high ozone episodes, but the June (pre-monsoon) period was characterized by local thermal circulation whereas the July (monsoon) period by synoptic influence. Overall, improved simulations were noted for adjusted-LBC runs for ozone concentrations both at the ground-level and in the middle to upper troposphere, based on EPA-recommended model performance metrics. The probability of detection (POD) of ozone exceedances (>75ppb, 8-h averages) for the entire domain increased from 20.8% for the default-LBC run to 33.7% for the adjusted-LBC run. A process analysis of modeling results revealed that ozone within PBL during bulk of the pre-monsoon season is contributed by local photochemistry and vertical advection, while the contributions of horizontal and vertical advections are comparable in the monsoon season. The process analysis with adjusted-LBC runs confirms the contributions of vertical advection to episodic high ozone days, and hence elucidates the importance of improving predictability of upper levels with improved LBCs. PMID- 22227304 TI - Use of stakeholder analysis to inform risk communication and extension strategies for improved biosecurity amongst small-scale pig producers. AB - Extension and communication needs amongst small-scale pig producers, described as pig producers with less than 100 sows, have been previously identified. These producers, who are believed to pose a biosecurity risk to commercial livestock industries, are characterized by a lack of formal networks, mistrust of authorities, poor disease reporting behaviour and motivational diversity, and reliance on other producers, veterinarians and family for pig health and production advice. This paper applies stakeholder identification and analysis tools to determine stakeholders' influence and interest on pig producers' practices. Findings can inform a risk communication process and the development of an extension framework to increase producers' engagement with industry and their compliance with biosecurity standards and legislation in Australia. The process included identification of stakeholders, their issues of concerns regarding small-scale pig producers and biosecurity and their influence and interest in each of these issues. This exercise identified the capacity of different stakeholders to influence the outcomes for each issue and assessed their success or failure to do so. The disconnection identified between the level of interest and influence suggests that government and industry need to work with the small-scale pig producers and with those who have the capacity to influence them. Successful biosecurity risk management will depend on shared responsibility and building trust amongst stakeholders. Flow-on effects may include legitimating the importance of reporting and compliance systems and the co-management of risk. Compliance of small-scale pig producers with biosecurity industry standards and legislation will reduce the risks of entry and spread of exotic diseases in Australia. PMID- 22227305 TI - Aloe emodin inhibits colon cancer cell migration/angiogenesis by downregulating MMP-2/9, RhoB and VEGF via reduced DNA binding activity of NF-kappaB. AB - Aloe emodin (AE), a natural anthraquinone, is reported to have antiproliferative activity in various cancer cell lines. In this study we analyzed molecular mechanisms involved in the antimigratory and antiangiogenic activity of this hydroxy anthraquinone in colon cancer cell, WiDr. Our results show that a relatively non toxic concentration of AE suppressed the phorbol-12-myristyl-13 acetate (PMA) induced migration and invasion of tumor cells. On analysis for the molecules involved in the migration/invasion, we found AE downregulated mRNA expression and promoter/gelatinolytic activity of Matrix Metalloproteinase (MMP) 2/9, as well as the RhoB expression at gene and protein level. It was also a strong inhibitor of Vascular Endothelial Growth Factor (VEGF) expression, promoter activity and endothelial cell migration/invasion and in vitro angiogenesis. AE suppressed the nuclear translocation and DNA binding of NF kappaB, which is an important transcription factor for controlling MMP-2/9 and VEGF gene expression. Taken together these data indicate that AE target multiple molecules responsible for cellular invasion, migration and angiogenesis. Inhibitory effect on angiogenic and metastatic regulatory processes make AE a sensible candidate as a specific blocker of tumor associated events. PMID- 22227306 TI - Synthesis and characterization of magnetic beta-cyclodextrin-chitosan nanoparticles as nano-adsorbents for removal of methyl blue. AB - A novel nano-adsorbent, beta-cyclodextrin-chitosan (CDC) modified Fe(3)O(4) nanoparticles (CDCM) is fabricated for removal of methyl blue (MB) from aqueous solution by grafting CDC onto the magnetite surface. The characteristics results of FTIR, SEM and XRD show that CDC is grafted onto Fe(3)O(4) nanoparticles. The grafted CDC on the Fe(3)O(4) nanoparticles contributes to an enhancement of the adsorption capacity because of the strong abilities of CDCM, which includes the multiple hydroxyl, carboxyl groups, amino groups and the formation of an inclusion complex due to the beta-CD molecules through host-guest interactions, to adsorb MB. The adsorption of MB onto CDCM is found to be dependent on pH and temperature. Adsorption equilibrium is achieved in 50 min and the adsorption kinetics of MB is found to follow a pseudo-second-order kinetic model. Equilibrium data for MB adsorption are fitted well by Langmuir isotherm model. The maximum adsorption capacity for MB is estimated to be 2.78 g/g at 30 degrees C. The CDCM was stable and easily recovered. Moreover the adsorption capacity was about 90% of the initial saturation adsorption capacity after being used four times. PMID- 22227307 TI - Production of alkali tolerant cellulase free xylanase in high levels by Bacillus pumilus SV-205. AB - The fermentation conditions were optimized for hyper production of xylanase from Bacillus pumilus SV-205. The bacterium secretes high levels (7382.7+/-1200 IU/mL) of cellulase-free xylanase using wheat bran led to 21.63 fold increase in activity. A combination of yeast extract and peptone stimulated highest xylanase production (2448.0 IU/mL) as compared to other combinations. The most important characteristic of the enzyme is its high pH stability (100%) over a broad pH range of 6-11 for 24h. Thermostability studies revealed that enzyme retained 65% activity after an incubation of 2h at 60 degrees C. The level of production is remarkable as compared to earlier reports. PMID- 22227308 TI - Mycobacterium avium complex infection-related immune reconstitution inflammatory syndrome of the central nervous system in an HIV-infected patient: case report and review. AB - Disseminated Mycobacterium avium complex (MAC) infection involves the central nervous system (CNS) less frequently than tuberculosis, and MAC-related immune reconstitution inflammatory syndrome (IRIS) of the CNS in AIDS patients is even more rarely described. We report a case of MAC-related IRIS of the CNS in an HIV infected patient who presented with meningoencephalitis and myelitis 2 months after discontinuation of antiMAC therapy, when he had achieved prolonged suppression of HIV replication and restoration of CD4 counts to >100 cells/MUL for 1 year. Cases of MAC-related IRIS of the CNS reported in the literature are reviewed. PMID- 22227309 TI - Daam2 is required for dorsal patterning via modulation of canonical Wnt signaling in the developing spinal cord. AB - The Daam family of proteins consists of Daam1 and Daam2. Although Daam1 participates in noncanonical Wnt signaling during gastrulation, Daam2 function remains completely uncharacterized. Here we describe the role of Daam2 in canonical Wnt signal transduction during spinal cord development. Loss-of function studies revealed that Daam2 is required for dorsal progenitor identities and canonical Wnt signaling. These phenotypes are rescued by beta-catenin, demonstrating that Daam2 functions in dorsal patterning through the canonical Wnt pathway. Complementary gain-of-function studies demonstrate that Daam2 amplifies Wnt signaling by potentiating ligand activation. Biochemical examination found that Daam2 association with Dvl3 is required for Wnt activity and dorsal patterning. Moreover, Daam2 stabilizes Dvl3/Axin2 binding, resulting in enhanced intracellular assembly of Dvl3/Axin2 complexes. These studies demonstrate that Daam2 modulates the formation of Wnt receptor complexes, revealing new insight into the functional diversity of Daam proteins and how canonical Wnt signaling contributes to pattern formation in the developing spinal cord. PMID- 22227310 TI - Exit from proliferation during leaf development in Arabidopsis thaliana: a not-so gradual process. AB - Early leaf growth is sustained by cell proliferation and subsequent cell expansion that initiates at the leaf tip and proceeds in a basipetal direction. Using detailed kinematic and gene expression studies to map these stages during early development of the third leaf of Arabidopsis thaliana, we showed that the cell-cycle arrest front did not progress gradually down the leaf, but rather was established and abolished abruptly. Interestingly, leaf greening and stomatal patterning followed a similar basipetal pattern, but proliferative pavement cell and formative meristemoid divisions were uncoordinated in respect to onset and persistence. Genes differentially expressed during the transition from cell proliferation to expansion were enriched in genes involved in cell cycle, photosynthesis, and chloroplast retrograde signaling. Proliferating primordia treated with norflurazon, a chemical inhibitor of retrograde signaling, showed inhibited onset of cell expansion. Hence, differentiation of the photosynthetic machinery is important for regulating the exit from proliferation. PMID- 22227311 TI - Flavobacterium oncorhynchi sp. nov., a new species isolated from rainbow trout (Oncorhynchus mykiss). AB - Eighteen isolates of a Gram-negative, catalase and oxidase-positive, rod-shaped bacterium, recovered from diseased rainbow trout (Oncorhynchus mykiss), were characterized, using a polyphasic taxonomic approach. Studies based on comparative 16S rRNA gene sequence analysis showed that that the eighteen new isolates shared 99.2-100% sequence similarities. Phylogenetic analysis revealed that isolates from trout belonged to the genus Flavobacterium, showing the highest sequence similarities to F. chungangense (98.6%), F. frigidimaris (98.1%), F. hercynium (97.9%) and F. aquidurense (97.8%). DNA-DNA reassociation values between the trout isolates (exemplified by strain 631-08(T)) and five type strains of the most closely related Flavobacterium species exhibited less than 27% similarity. The G+C content of the genomic DNA was 33.0 mol%. The major respiratory quinone was observed to be menaquinone 6 (MK-6) and iso-C(15:0), C(15:0) and C(16:1) omega7c the predominant fatty acids. The polar lipid profile of strain 631-08(T) consisted of phosphatidylethanolamine, unknown aminolipids AL1 and AL3, lipids L1, L2, L3 and L4 and phospholipid PL1. The novel isolates were differentiated from related Flavobacterium species by physiological and biochemical tests. On the basis of the evidence from this polyphasic study, it is proposed that the isolates from rainbow trout be classified as a new species of the genus Flavobacterium, Flavobacterium oncorhynchi sp. nov. The type strain is 631-08(T) (= CECT 7678(T) = CCUG 59446(T)). PMID- 22227312 TI - Feeding-suppressive mechanism of sulfated cholecystokinin (26-33) in chicks. AB - The anorexigenic effect of cholecystokinin (CCK) is well documented in mammals, but documentation in neonatal chicks is limited. Thus, the present study investigated the mechanism underlying the anorexigenic effect of CCK in neonatal chicks. Intraperitoneal (IP) injection of sulfated CCK(26-33) (CCK8S) significantly decreased food intake in chicks at 60 and 300 nmol/kg. Non-sulfated CCK(26-33) (CCK8) also significantly decreased food intake, but its anorexigenic effect was observed only at the highest dose (300 nmol/kg) and short-lived. However, CCK(30-33) (CCK4) had no effect on food intake. Also, the intracerebroventricular (ICV) injection of CCK8S (0.2 and 1 nmol) significantly decreased food intake in chicks. Similar to IP administration, the anorexigenic effect of CCK8 was weak and CCK4 did not affect food intake. IP and ICV injections of CCK8S caused conditioned aversion and increased plasma corticosterone concentrations, suggesting that their anorexigenic effects might be related to stress and/or malaise. This might be true in ICV-injected CCK8S because co-injection of astressin, a corticotropin-releasing hormone receptor antagonist, tended to attenuate the effect of CCK8S. The present study revealed that N-terminal amino acids and the sulfation of Tyr are important for the anorexigenic effect of CCK8S after IP and ICV administered in chicks. Additionally, the effect of central CCK8S might be related to stress and/or malaise. PMID- 22227313 TI - Malnutrition may affect common sole (Solea solea L.) growth, pigmentation and stress response: molecular, biochemical and histological implications. AB - In the last decades there have been several evidences that traditionally used live preys like rotifers and Artemia salina have nutritional deficiencies that result in a general decrease of fish health, causing anomalies in the development, in growth and in pigmentation. In this study a partial of total replacement of traditional live preys with preserved copepods that represent the natural food of the larvae was evaluated during Solea solea culture. In this study a positive effect of co-feeding preserved copepods in sole larviculture was observed since larvae fed this diet growth and survived better, showed a better tolerance to captive conditions and had a better response to the final thermal/density stress-test with respect to larvae fed a traditional diet. Morphometric data were fully supported by molecular and biochemical ones. Moreover, liver histological investigations, revealed that the inclusion of preserved copepods in the larval diet was able to improve lipid assimilation. In conclusion, preserved copepods may be considered a suitable food for sole when used as a supplement to the traditional diet based on rotifers and Artemia nauplii. PMID- 22227314 TI - Environmental and nutritional regulation of expression and function of two peptide transporter (PepT1) isoforms in a euryhaline teleost. AB - Expression and function of the oligopeptide transporter PepT1 in response to changes in environmental salinity have received little study despite the important role that dipeptides play in piscine nutrition. We cloned and sequenced two novel full-length cDNAs that encode Fundulus heteroclitus PepT1-type oligopeptide transporters, and examined their expression and functional properties in freshwater- and seawater-acclimated fish and in response to fasting and re-feeding. Phylogenetic analysis of vertebrate SLC15A1 sequences confirms the presence of two PepT1 isoforms, named SLC15A1a and SLC15A1b, in fish. Similar to other vertebrate SLC15A1s, these isoforms have 12 transmembrane domains, and amino acids essential for PepT1 function are conserved. Expression analysis revealed novel environment-specific expression of the SLC15A1 isoforms in F. heteroclitus, with only SLC15A1b expressed in seawater-acclimated fish, and both isoforms expressed in freshwater-acclimated fish. Fasting and re-feeding induced changes in the expression of SLC15A1a and SLC15A1b mRNA. Short-term fasting resulted in up-regulation of PepT1 mRNA levels, while prolonged fasting resulted in down-regulation. The resumption of feeding resulted in up-regulation of PepT1 above pre-fasted levels. Experiments using the in vitro gut sac technique suggest that the PepT1 isoforms differ in functional characteristics. An increased luminal pH resulted in decreased intestinal dipeptide transport in freshwater acclimated fish but suggested an increased dipeptide transport in seawater acclimated fish. Overall, this is the first evidence of multiple isoforms of PepT1 in fish whose expression is environmentally dependent and results in functional differences in intestinal dipeptide transport. PMID- 22227315 TI - A new approach to quantify trabecular resorption adjacent to cemented knee arthroplasty. AB - A new micro-computed tomography (MUCT) image processing approach to estimate the loss of cement-bone interlock was developed using the concept that PMMA cement flows and cures around trabeculae during the total knee arthroplasty procedure. The initial mold shape of PMMA cement was used to estimate the amount of interdigitated bone at the time of implantation and following in vivo service using enbloc human postmortem retrievals. Laboratory prepared specimens, where there would be no biological bone resorption, were used as controls to validate the approach and estimate errors. The image processing technique consisted of identifying bone and cement from the MUCT scan set, dilation of the cement to identify the cement cavity space, and Boolean operations to identify the different components of the interdigitated cement-bone regions. For laboratory prepared specimens, there were small errors in the estimated resorbed bone volume fraction (reBVfr=0.11 +/- 0.09) and loss in contact area fraction (CAfr=0.06 +/- 0.15). These values would be zero if there were no error in the method. For the postmortem specimens, the resorbed volume fraction (reBVfr=0.85 +/- 0.16) was large, meaning that only 15% of the cement mold shape was still filled with bone. The loss of contact area fraction (CAfr=0.84 +/- 0.17) was similarly large. This new approach provides a convenient method to visualize and quantify trabecular bone loss from interdigitated regions from postmortem retrievals. The technique also illustrates for the first time that there are dramatic changes in how bone is fixed to cement following in vivo service. PMID- 22227316 TI - Effect of low pass filtering on joint moments from inverse dynamics: implications for injury prevention. AB - Analyses of joint moments are important in the study of human motion, and are crucial for our understanding of e.g. how and why ACL injuries occur. Such analyses may be affected by artifacts due to inconsistencies in the equations of motion when force and movement data are filtered with different cut-off frequencies. The purpose of this study was to quantify the effect of these artifacts, and compare joint moments calculated with the same or different cut off frequency for the filtering of force and movement data. 123 elite handball players performed sidestep cutting while the movement was recorded by eight 240 Hz cameras and the ground reaction forces were recorded by a 960 Hz force plate. Knee and hip joint moments were calculated through inverse dynamics, with four different combinations of cut-off frequencies for signal filtering: movement 10 Hz, force 10 Hz, (10-10); movement 15 Hz, force 15 Hz; movement 10 Hz, force 50 Hz (10-50); movement 15 Hz, force 50 Hz. The results revealed significant differences, especially between conditions with different filtering of force and movement. Mean (SD) peak knee abduction moment for the 10-10 and 10-50 condition were 1.27 (0.53) and 1.64 (0.68) Nm/kg, respectively. Ranking of players based on knee abduction moments were affected by filtering condition. Out of 20 players with peak knee abduction moment higher than mean+1S D with the 10-50 condition, only 11 were still above mean+1 SD when the 10-10 condition was applied. Hip moments were very sensitive to filtering cut-off. Mean (SD) peak hip flexion moment was 3.64 (0.75) and 5.92 (1.80) under the 10-10 and 10-50 conditions, respectively. Based on these findings, force and movement data should be processed with the same filter. Conclusions from previous inverse dynamics studies, where this was not the case, should be treated with caution. PMID- 22227318 TI - Evidence for Gardnerella vaginalis uptake and internalization by squamous vaginal epithelial cells: implications for the pathogenesis of bacterial vaginosis. AB - Bacterial vaginosis (BV), a common condition seen in premenopausal women, is associated with preterm labor, pelvic inflammatory disease, and delivery of low birth weight infants. Gardnerella vaginalis is the predominant bacterial species associated with BV, although its exact role in the pathology of BV is unknown. Using immunofluorescence, confocal and transmission electron microscopy, we found that VK2 vaginal epithelial cells take up G. vaginalis after exposure to the bacteria. Confocal microscopy also indicated the presence of internalized G. vaginalis within vaginal epithelial cells obtained from a subject with BV. Using VK2 cells and (35)S labeled bacteria in an invasion assay, we found that a 1 h uptake of G. vaginalis was 21.8-fold higher than heat-killed G. vaginalis, 84 fold compared to Lactobacillus acidophilus and 6.6-fold compared to Lactobacillus crispatus. Internalization was inhibited by pre-exposure of cells to cytochalasin D. In addition, the cytoskeletal protein vimentin was upregulated in VK2 cells exposed to G. vaginalis, but there was no change in actin cytoskeletal polymerization/rearrangements or vimentin subcellular relocalization post exposure. Cytoskeletal protein modifications could represent a potential mechanism for G. vaginalis mediated internalization by vaginal epithelial cells. Finally, understanding vaginal bacteria/host interactions will allow us to better understand the underlying mechanisms of BV pathogenesis. PMID- 22227317 TI - How mesenchymal stem cells interact with tissue immune responses. AB - Mesenchymal stem cells (MSCs), also called multipotent mesenchymal stromal cells, exist in almost all tissues and are a key cell source for tissue repair and regeneration. Under pathological conditions, such as tissue injury, these cells are mobilized towards the site of damage. Tissue damage is usually accompanied by proinflammatory factors, produced by both innate and adaptive immune responses, to which MSCs are known to respond. Indeed, recent studies have shown that there are bidirectional interactions between MSCs and inflammatory cells, which determine the outcome of MSC-mediated tissue repair processes. Although many details of these interactions remain to be elucidated, we provide here a synthesis of the current status of this newly emerging and rapidly advancing field. PMID- 22227319 TI - Norepinephrine depletion of antimicrobial peptides from the skin glands of Xenopus laevis. AB - The dermal granular glands of the South African clawed frog, Xenopus laevis, contain antimicrobial peptides (AMPs) that are secreted following local nerve stimulation. These natural antibiotics are active against bacteria and fungi including Batrachochytrium dendrobatidis, a fungal pathogen that causes the skin disease chytridiomycosis. Granular gland secretion can be stimulated in the laboratory by norepinephrine injection. We found that two injections of 80nmol/g norepinephrine were necessary to fully deplete the AMP stores. One injection resulted in the secretion of most of the stored peptides. A second injection, 2 days later, released a small amount of additional AMPs that are not compositionally different from those released by the first injection. A third injection, 4 days after the first, did not result in further AMP release. Mass spectrometry and histology confirmed that glands are depleted after two injections. Periodic acid-Schiff staining indicated that mucus gland secretion was also induced by norepinephrine. PMID- 22227321 TI - Effects of single-sided inferior turbinectomy on nasal function and airflow characteristics. AB - Knowledge of airflow characteristics in the nasal cavity is essential to understanding the physiologic and pathologic aspects of nasal breathing. Airflows inside post-surgery models were investigated both experimentally and numerically to simulate the inferior turbinectomy. The left cavities of all three models are normal and right cavity is modified by (1) excision of the head of the inferior turbinate, (2) resection of the lower fifth of the inferior turbinate, and (3) resection of almost the entire inferior turbinate. Thin-slice CT (computed tomography) data (0.6mm deep) and meticulous refinement of the model surface by over a decade-long collaboration between engineers and an experienced ENT doctor resulted in the creation of sophisticated nasal cavity models. After numerical experiments and validation by comparison with the PIV results, the CFD code using the Reynolds stress turbulent model and variable temperature boundary condition on the mucosal wall was chosen as the proper numerical framework. Both global quantities (pressure drop, flow rate ratio, total wall heat transfer) and local changes (velocity, temperature, humidity, pressure gradient, and wall shear stress) were numerically investigated. The turbinectomy obviously altered the main stream direction. The flow rate in the upper airway near the olfactory slit decreased in models (1) and (3). This may weaken the olfactory function of the nose. Fluid and thermal properties that are believed to be related with physiology and prognosis are dependent on turbinate resection volume, position, and manner. Widening of the inferior airway does not always result in decreased flow resistance or wall heat transfer. The gains and losses of inferior turbinectomy were considered by analysis of the post-surgery model results. Nasal resistance was increased in model (1) due to sudden airway expansion. Nasal resistance increased and the wall heat transfer decreased in model (3) due to sudden airway expansion and excessive reduction of the mucosal wall surface area. Local shear stress and pressure gradient levels were increased in models (1) and (3). PMID- 22227320 TI - Rapid intravenous infusion of 20 mL/kg saline alters the distribution of perfusion in healthy supine humans. AB - Rapid intravenous saline infusion, a model meant to replicate the initial changes leading to pulmonary interstitial edema, increases pulmonary arterial pressure in humans. We hypothesized that this would alter lung perfusion distribution. Six healthy subjects (29 +/- 6 years) underwent magnetic resonance imaging to quantify perfusion using arterial spin labeling. Regional proton density was measured using a fast-gradient echo sequence, allowing blood delivered to the slice to be normalized for density and quantified in mL/min/g. Contributions from flow in large conduit vessels were minimized using a flow cutoff value (blood delivered > 35% maximum in mL/min/cm(3)) in order to obtain an estimate of blood delivered to the capillary bed (perfusion). Images were acquired supine at baseline, after infusion of 20 mL/kg saline, and after a short upright recovery period for a single sagittal slice in the right lung during breath-holds at functional residual capacity. Thoracic fluid content measured by impedance cardiography was elevated post-infusion by up to 13% (p<0.0001). Forced expiratory volume in 1s was reduced by 5.1% post-20 mL/kg (p=0.007). Infusion increased perfusion in nondependent lung by up to 16% (6.4 +/- 1.6 mL/min/g baseline, 7.3 +/- 1.8 post, 7.4 +/- 1.7 recovery, p=0.03). Including conduit vessels, blood delivered in dependent lung was unchanged post-infusion; however, was increased at recovery (9.4 +/- 2.7 mL/min/g baseline, 9.7 +/- 2.0 post, 11.3 +/- 2.2 recovery, p=0.01). After accounting for changes in conduit vessels, there were no significant changes in perfusion in dependent lung following infusion (7.8 +/- 1.9 mL/min/g baseline, 7.9 +/- 2.0 post, 8.5 +/- 2.1 recovery, p=0.36). There were no significant changes in lung density. These data suggest that saline infusion increased perfusion to nondependent lung, consistent with an increase in intravascular pressures. Dependent lung may have been "protected" from increases in perfusion following infusion due to gravitational compression of the pulmonary vasculature. PMID- 22227322 TI - Anti-alpha-galactosidase A antibody response to agalsidase beta treatment: data from the Fabry Registry. AB - Agalsidase beta, a form of recombinant human alpha-galactosidase A (alphaGAL), is approved for use as enzyme replacement therapy (ERT) for Fabry disease. An immunogenic response against a therapeutic protein could potentially impact its efficacy or safety. The development of anti-alphaGAL IgG antibodies was evaluated in 571 men and 251 women from the Fabry Registry who were treated with agalsidase beta. Most men developed antibodies (416 of 571, 73%), whereas most women did not (31 of 251, 12%). Women were also significantly more likely to tolerize than men; whereas 18 of 31 women tolerized (58%, 95%CI: 52%-64%), only 47 of 416 men tolerized during the observation period (11%, 95% CI: 8%-15%). Patients who eventually tolerized had lower median peak anti-alphaGAL IgG antibody titers than patients who remained seropositive at their most recent assessment (400 versus 3200 in men, 200 versus 400 in women, respectively). Patients with nonsense mutations in the GLA gene were more likely to develop anti-alphaGAL IgG antibodies than patients with missense mutations. Approximately 26% of men (151 of 571) reported infusion-associated reactions (IARs), compared to 11% of women (27 of 251). Men who developed anti-alphaGAL IgG antibodies were more likely to experience IARs compared to those who remained seronegative. Nine percent of seronegative men and women (34 of 375) reported IARs. The majority of IARs occurred during the first 6 to 12 months of agalsidase beta treatment and decreased over time, in both seroconverted and seronegative patients. PMID- 22227323 TI - A novel fluorometric enzyme analysis method for Hunter syndrome using dried blood spots. AB - Mucopolysaccharidosis type II (MPS II) or Hunter syndrome is a lysosomal storage disease caused by deficiency of iduronate-2-sulfatase (IDS). A convenient single step fluorometric microplate enzyme assay has been developed and validated for clinical diagnosis of MPS II using dried blood spots (DBS). The assay compared well with a recently reported digital microfluidic method, from which it was adapted. Results show that this DBS assay is robust and reproducible using both technologies. PMID- 22227324 TI - A novel splicing mutation causes analbuminemia in a Portuguese boy. AB - Analbuminemia is a rare autosomal recessive disorder manifested by the absence or severe reduction of circulating serum albumin in homozygous or compound heterozygous subjects. It is an allelic heterogeneous defect, caused by a variety of mutations within the albumin gene. The analbuminemic condition was suspected in a Portuguese boy who presented with low albumin level (about 3.8 g/L) and a significant hypercholesterolemia, but with no clinical findings. The albumin gene was screened by single strand conformational polymorphism and heteroduplex analysis and submitted to direct DNA sequencing. The proband was found to be homozygous for a previously unreported G>A change at position c.1289+1, the first base of intron 10, which inactivates the strongly conserved GT dinucleotide at the 5' splice site consensus sequence of the intron. The effect of this mutation was evaluated by examining the cDNA obtained by RT-PCR from the albumin mRNA extracted from proband's leukocytes. The splicing defect results in the skipping of the preceding exon. The subsequent reading frame-shift in exon 11 produces a premature stop codon located 33 codons downstream the 5' end of the exon. This extensive cDNA alteration is responsible for the analbuminemic trait. Both parents were found to be heterozygous for the same mutation. DNA and cDNA sequence analysis established the diagnosis of congenital analbuminemia in the proband. The effects of the so far identified splice-site mutations in the albumin gene are discussed. PMID- 22227325 TI - Is E326K glucocerebrosidase a polymorphic or pathological variant? PMID- 22227326 TI - From genomics to metagenomics. AB - Next-generation sequencing has changed metagenomics. However, sequencing DNA is no longer the bottleneck, rather, the bottleneck is computational analysis and also interpretation. Computational cost is the obvious issue, as is tool limitations, considering most of the tools we routinely use have been built for clonal genomics or are being adapted to microbial communities. The current trend in metagenomics analysis is toward reducing computational costs through improved algorithms and through analysis strategies. Data sharing and interoperability between tools are critical, since computation for metagenomic datasets is very high. PMID- 22227327 TI - Carbonic anhydrase XIV in the normal and hypertrophic myocardium. AB - Two AE3 transcripts, full-length (AE3fl) and cardiac (AE3c) are expressed in the heart. AE3 catalyzes electroneutral Cl(-)/HCO(3)(-) exchange across cardiomyocyte sarcolemma. AE proteins associate with carbonic anhydrases (CA), including CAII and CAIV, forming a HCO(3)(-) transport metabolon (BTM), increasing HCO(3)(-) fluxes and regulating cardiomyocytes pH. CAXIV, which is also expressed in the heart's sarcolemma, is a transmembrane enzyme with an extracellular catalytic domain. Herein, AE3/CAXIV physical association was examined by coimmunoprecipitation using rodent heart lysates. CAXIV immunoprecipitated with anti-AE3 antibody and both AE3fl and AE3c were reciprocally immunoprecipitated using anti-CAXIV antibody, indicating AE3fl-AE3c/CAXIV interaction in the myocardium. Coimmunoprecipitation experiments on heart lysates from a mouse with targeted disruption of the ae3 gene, failed to pull down AE3 with the CAXIV antibody. Confocal images demonstrated colocalization of CAXIV and AE3 in mouse ventricular myocytes. Functional association of AE3fl and CAXIV was examined in isolated hypertrophic rat cardiomyocytes, using fluorescence measurements of BCECF to monitor cytosolic pH. Hypertrophic cardiomyocytes of spontaneously hypertensive rats (SHR) presented elevated myocardial AE-mediated Cl(-)/HCO(3)(-) exchange activity (J(HCO3-) mM.min(-1)) compared to normal (Wistar) rats (7.5+/ 1.3, n=4 versus 2.9+/-0.1, n=6, respectively). AE3fl, AE3c, CAII, CAIV, and CAIX protein expressions were similar in SHR and Wistar rat hearts. However, immunoblots revealed a twofold increase of CAXIV protein expression in the SHR myocardium compared to normal hearts (n=11). Furthermore, the CA-inhibitor, benzolamide, neutralized the stimulatory effect of extracellular CA on AE3 transport activity (3.7+/-1.5, n=3), normalizing AE3-dependent HCO(3)(-) fluxes in SHR. CAXIV/AE3 interaction constitutes an extracellular component of a BTM which potentiates AE3-mediated HCO(3)(-) transport in the heart. Increased CAXIV expression and consequent AE3/CAXIV complex formation would render AE3 hyperactive in the SHR heart. PMID- 22227328 TI - Homocysteine induces cardiomyocyte dysfunction and apoptosis through p38 MAPK mediated increase in oxidant stress. AB - Elevated plasma homocysteine (Hcy) is a risk factor for cardiovascular disease. While Hcy has been shown to promote endothelial dysfunction by decreasing the bioavailability of nitric oxide and increasing oxidative stress in the vasculature, the effects of Hcy on cardiomyocytes remain less understood. In this study we explored the effects of hyperhomocysteinemia (HHcy) on myocardial function ex vivo and examined the direct effects of Hcy on cardiomyocyte function and survival in vitro. Studies with isolated hearts from wild type and HHcy mice (heterozygous cystathionine-beta synthase deficient mice) demonstrated that HHcy mouse hearts had more severely impaired cardiac relaxation and contractile function and increased cell death following ischemia reperfusion (I/R). In isolated cultured adult rat ventricular myocytes, exposure to Hcy for 24 h impaired cardiomyocyte contractility in a concentration-dependent manner, and promoted apoptosis as revealed by terminal dUTP nick-end labeling and cleaved caspase-3 immunoblotting. These effects were associated with activation of p38 MAPK, decreased expression of thioredoxin (TRX) protein, and increased production of reactive oxygen species (ROS). Inhibition of p38 MAPK by the selective inhibitor SB203580 (5 MUM) prevented all of these Hcy-induced changes. Furthermore, adenovirus-mediated overexpression of TRX in cardiomyocytes significantly attenuated Hcy-induced ROS generation, apoptosis, and impairment of myocyte contractility. Thus, Hcy may increase the risk for CVD not only by causing endothelial dysfunction, but also by directly exerting detrimental effects on cardiomyocytes. PMID- 22227330 TI - Neferine, an alkaloid ingredient in lotus seed embryo, inhibits proliferation of human osteosarcoma cells by promoting p38 MAPK-mediated p21 stabilization. AB - Identification of natural products that have antitumor activity is invaluable to the chemoprevention and therapy of cancer. The embryos of lotus (Nelumbo nucifera) seeds are consumed in beverage in some parts of the world for their presumed health-benefiting effects. In this report we studied the effects of neferine, a major alkaloid component in lotus embryos, on human osteosarcoma cells and the underlying mechanisms. We found that neferine possessed a potent growth-inhibitory effect on human osteosarcoma cells, but not on non-neoplastic human osteoblast cells. The inhibitory effect of neferine on human osteosarcoma cells was largely attributed to cell cycle arrest at G1. The induction of G1 arrest was p21(WAF1/CIP1)-dependent, but was independent of p53 or RB (retinoblastoma-associated protein). The up-regulation of p21 by neferine was due to an increase in the half-life of p21 protein. We examined four kinases that are known to affect the stabilization of p21, and found that p38 MAPK and JNK were activated by neferine. However, only SB203580 (an inhibitor of p38), but not SP600125 (the inhibitor of JNK), can attenuate the up-regulation of p21 in response to neferine. Furthermore, the p21-stabilizing effect of neferine was abolished when p38 was silenced by RNA interference. Finally, we showed that neferine treatment led to an increased phosphorylation of p21 at Ser130 that was dependent on p38. Our results for the first time showed a direct antitumor effect of neferine, suggesting that consumption of neferine may have cancer-preventive and cancer-therapeutic benefit. PMID- 22227329 TI - In vitro and in vivo anti-inflammatory activities of columbin through the inhibition of cycloxygenase-2 and nitric oxide but not the suppression of NF kappaB translocation. AB - Columbin, a diterpenoid furanolactone, was isolated purely for the first time from the plant species Tinspora bakis. The anti-inflammatory effects of columbin were studied in vitro, in silico and in vivo. The effect of columbin on nitric oxide was examined on lipopolysaccharide-interferon-gamma (LPS/IFN) induced RAW264.7 macrophages. In vitro and in silico cyclooxygenase-1 and cyclooxygenase 2 inhibitory activities of columbin using biochemical kit and molecular docking, respectively, were investigated. Mechanism of columbin in suppressing NF-kappaB translocation was tested using Cellomics(r)NF-kappaB activation assay and ArrayScan Reader in LPS-stimulated RAW264.7 cells. Moreover, effects of columbin in vivo that were done on carrageenan-induced mice paw-oedema were tested. Lastly, the in vitro and in vivo toxicities of columbin were examined on human liver cells and mice, respectively. Treatment with columbin or N(omega)-nitro-l arginine methyl ester (l-NAME) inhibited LPS/IFN-gamma-induced NO production without affecting the viability of RAW264.7. Pre-treatment of stimulated cells with columbin did not inhibit the translocation of NF-kappaB to the nucleus in LPS-stimulated cells. COX-1 and COX-2 inhibitory activities of columbin were 63.7+/-6.4% and 18.8+/-1.5% inhibition at 100MUM, respectively. Molecular docking study further helped in supporting the observed COX-2 selectivity. Whereby, the interaction of columbin with Tyr385 and Arg120 signifies its higher activity in COX-2, as Tyr385 was reported to be involved in the abstraction of hydrogen from C-13 of arachidonate, and Arg120 is critical for high affinity arachidonate binding. Additionally, columbin inhibited oedema formation in mice paw. Lastly, the compound was observed to be safe in vitro and in vivo. This study presents columbin as a potential anti-inflammatory drug. PMID- 22227331 TI - The effect of serotonin 5HT1B receptor ligands on amphetamine self-administration in rats. AB - A number of data indicate that serotonin (5-HT) 5-HT(1B) receptor ligands affect the behavioral effects of psychostimulants. In the present study we examined effects of the selective 5-HT(1B) receptor antagonist N-[3-[3 (dimethylamino)ethoxy]-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3 yl)-[1,1'-biphenyl]-4-carboxamide hydrochloride (SB 216641) and the agonist 5 propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine hydrochloride (CP 94253) on amphetamine self-administration in rats. SB 216641 administered in doses of 2.5-7.5 mg/kg did not affect the self-administration of amphetamine injected in unit doses of 0.06 or 0.12 mg/kg/infusion. On the other hand, CP 94253 administered in doses of 2.5 or 5 mg/kg attenuated amphetamine self-administration, yet the effect of 2.5 mg/kg of the agonist was fairly weak and significant only in case of a higher unit dose of the psychostimulant. The inhibitory effect of CP 94253 administered in a dose of 5mg/kg on the self administration of amphetamine injected in a unit dose of 0.06 mg/kg/infusion was significantly reduced by SB 216641 administrated in a dose of 7.5 mg/kg. These results indicate that tonic activation of 5-HT(1B) receptors is not involved in the self-administration of amphetamine, while pharmacological stimulation of these receptors attenuates this behavioral phenomenon. PMID- 22227332 TI - Autophagy inhibited Ehrlich ascitic tumor cells apoptosis induced by the nitrostyrene derivative compounds: relationship with cytosolic calcium mobilization. AB - Apoptosis induction is often associated with increased autophagy, indicating interplay between these two important cellular events in cell death and survival. In this study, the programmed cell death and autophagy induced by two nitrostyrene derivative compounds (NTS1 and NTS2) was studied using the tumorigenic Ehrlich ascitic tumor (EAT) cells. EAT cells were highly sensitive to NTS1 and NTS2 cytotoxicity in a dose-dependent manner. NTS1 and NTS2 IC(50) was less than 15.0MUM post 12h incubation. Apoptosis was primarily induced by both compounds, as demonstrated by an increase in Annexin-V positive cells, concurrently with cytochrome c release from mitochondria to cytosol and caspase-3 activation. Although cytosolic Ca(2+) mobilization is involved in autophagy as well as apoptosis in response to cellular stress in many cancer cell types, from the two nitrostyrene derivative compounds studied, mainly NTS1 mobilized this ion and disparate autophagy in EAT cells. These results suggest that EAT induced cell death by NTS1 and NTS2 involved a Ca(2+)-dependent and a Ca(2+)-independent pathways, respectively. In accordance with these results, the treatment of EAT cells with 3 methyladenine (3-MA), an autophagy inhibitor; significantly increased the number of apoptotic cells after NTS1 treatment, suggesting that pharmacological modulation of autophagy augments the NTS1 efficacy. Thus, we denote the importance of studies involving autophagy and apoptosis during pre clinical studies of new drugs with anticancer properties. PMID- 22227333 TI - Flavangenol (pine bark extract) and its major component procyanidin B1 enhance fatty acid oxidation in fat-loaded models. AB - Flavangenol, one of several pine bark extract products, is expected to prevent metabolic diseases with its potent antioxidant effect, its anti-obesity effect and its improvement of insulin sensitivity. In this study, targeting the liver as one of the organs that plays an important role in energy metabolism, Flavangenol was investigated for its effect on non-alcoholic fatty liver disease (NAFLD), its action mechanism and its active ingredients, using in vivo and in vitro experiment systems. Flavangenol suppressed intrahepatic fat accumulation in Western diet-loaded Tsumura Suzuki Obese Diabetes (TSOD) mice, which develop various metabolic diseases. In addition, Flavangenol significantly increased the mRNA expression levels of fatty acid oxidative enzymes (peroxisomal proliferator activated receptor alpha, acyl-CoA oxidase, carnitine palmitoyltransferase). In order to investigate the direct effect of Flavangenol on the liver, an in vitro fatty liver model prepared by adding a free fatty acid to human liver cancer cells (HepG2 cells) was used. In this model, Flavangenol significantly suppressed intracellular fat accumulation. Procyanidin B1, one of the major components of Flavangenol, also suppressed fat accumulation and induced mRNA expression of the fatty acid oxidative enzymes. As mentioned above, Flavangenol showed a significant suppressive effect in the NAFLD model, and it was suggested that the molecular mechanism is induction of fatty acid oxidation, with the effect mainly attributed to procyanidin B1. PMID- 22227334 TI - IGF-I receptor signaling pathway is involved in the neuroprotective effect of genistein in the neuroblastoma SK-N-SH cells. AB - Genistein, an isoflavone naturally found in soy products, displays estrogenic properties. Our previous study clearly demonstrated that genistein can activate the insulin-like growth factor-I receptor (IGF-IR) signaling pathway in human breast cancer MCF-7 cells. The present study aims to test the hypothesis that the IGF-I receptor signaling pathway is involved in the neuroprotective effects of genistein in neuroblastoma SK-N-SH cells. Our results revealed that pretreatment with genistein resulted in an enhancement in the survival of human neuroblastoma SK-N-SH cells against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. 6-OHDA arrested the cells at G(0)G(1) phase and prevented S phase entry. Genistein pretreatment could reverse the cytostatic effect of 6-OHDA on cell cycle. The decreased mitochondrial membrane potential induced by 6-OHDA could be also reversed by genistein pretreatment. These effects could be completely blocked by co-treatment with JB-1, which is the specific antagonist of the IGF-I receptor. Furthermore, genistein pretreatment restored the 6-OHDA-induced up-regulation of Bax and down-regulation of Bcl-2 mRNA and protein expression. Genistein treatment alone could significantly increase the phosphorylation level of MEK and induce ERE luciferase activity. Co-treatment with IGF-I could enhance the effect of genistein on cell proliferation and MEK phosphorylation. This study provides the first evidence that genistein has neuroprotective effects against 6-OHDA-induced neurotoxicity in SK-N-SH cells and activation of the IGF-I receptor signaling pathway might be involved in actions of genistein. PMID- 22227336 TI - Amelioration of glucose homeostasis by glycyrrhizic acid through gluconeogenesis rate-limiting enzymes. AB - The activities of phosphoenolpyruvate carboxykinase (PEPCK) are influenced by active glucocorticoids which are activated by 11-beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) while hexose-6-phosphate dehydrogenase (H6PDH) influences the activities of 11-betaHSD1 in a cofactor manner. Dysregulation of PEPCK and H6PDH has been associated with the pathogenesis of metabolic syndrome. Sixteen male Sprague Dawley rats, fed ad libitum, were assigned to two groups, control and treated, with the treated group being given GA at 100mg/kg for one week. Blood and subcutaneous and visceral adipose tissue, abdominal and quadriceps femoris muscle, liver and kidney were examined. GA treatment led to an overall significant decrease in blood glucose while HOMA-IR. PEPCK activities decreased in the liver but increased in the visceral adipose tissue. H6PDH activities also decreased significantly in the liver while 11beta-HSD1 activities decreased significantly in all studied tissues except for subcutaneous adipose tissue. Adipocytes in the subcutaneous and visceral depots showed a reduction in size. Though increased glycogen storage was seen in the liver, no changes were observed in the kidneys and muscles. Results from this study may imply that GA could counteract the development of type 2 diabetes mellitus by improving insulin sensitivity and probably by reduction of H6PDH, 11beta-HSD1 and a selective decrease in PEPCK activities. PMID- 22227337 TI - Sigma-1 receptors do not regulate calcium influx through voltage-dependent calcium channels in mouse brain synaptosomes. AB - Several lines of evidence suggest that sigma(1) receptors regulate intracellular calcium concentration [Ca(2+)](i). However, no previous studies have demonstrated a consistent role for these receptors in the modulation of extracellular calcium entry through plasmalemmal voltage-dependent calcium channels (VDCCs). To search for evidence of such a role we compared [Ca(2+)](i) under basal conditions and after depolarization with KCl in fura-2-loaded synaptosomes from wild-type and sigma(1) receptor knockout (sigma(1)R-KO) mice. We also tested the effects of the selective sigma(1) receptor agonists PRE-084 and (+)-pentazocine and antagonists BD-1047 and NE-100 on the increase in [Ca(2+)](i) induced by depolarization with 60mM KCl. Mibefradil, a nonselective blocker of VDCCs, was used as a positive control. Basal [Ca(2+)](i) and the increase in [Ca(2+)](i) caused by KCl-induced depolarization were similar in brain synaptosomes from both wild-type and sigma(1)R-KO mice. Mibefradil (1-30 MUM) and all sigma(1) receptor ligands studied (3-100 MUM) inhibited the KCl-induced increase in [Ca(2+)](i) in a concentration-dependent way. The order of maximum inhibition for the ligands compared here was NE-100>BD-1047=PRE 084>(+)-pentazocine. There were no appreciable differences in their effects between wild-type and sigma(1)R-KO mice. These findings indicate that sigma(1) receptors are not involved in calcium influx through VDCCs or in the inhibitory effects of these sigma(1) ligands on Ca(2+) channels. PMID- 22227335 TI - The role of reactive oxygen species in the modulation of the contraction induced by angiotensin II in carotid artery from diabetic rat. AB - The modulation played by reactive oxygen species on the angiotensin II-induced contraction in type I-diabetic rat carotid was investigated. Concentration response curves for angiotensin II were obtained in endothelium-intact or endothelium-denuded carotid from control or streptozotocin-induced diabetic rats, pre-treated with tiron (superoxide scavenger), PEG-catalase (hydrogen peroxide scavenger), dimethylthiourea (hydroxyl scavenger), apocynin [NAD(P)H oxidase inhibitor], SC560 (cyclooxygenase-1 inhibitor), SC236 (cyclooxygenase-2 inhibitor) or Y-27632 (Rho-kinase inhibitor). Reactive oxygen species were measured by flow cytometry in dihydroethidium (DHE)-loaded endothelial cells. Cyclooxygenase and AT(1)-receptor expression was assessed by immunohistochemistry. Diabetes increased the angiotensin II-induced contraction but reduced the agonist potency in rat carotid. Endothelium removal, tiron or apocynin restored the angiotensin II-induced contraction in diabetic rat carotid to control levels. PEG-catalase, DMTU or SC560 reduced the angiotensin II-induced contraction in diabetic rat carotid at the same extent. SC236 restored the angiotensin II potency in diabetic rat carotid. Y-27632 reduced the angiotensin II-induced contraction in endothelium-intact or -denuded diabetic rat carotid. Diabetes increased the DHE-fluorescence of carotid endothelial cells. Apocynin reduced the DHE-fluorescence of endothelial cells from diabetic rat carotid to control levels. Diabetes increased the muscular cyclooxygenase-2 expression but reduced the muscular AT(1)-receptor expression in rat carotid. In summary, hydroxyl radical, hydrogen peroxide and superoxide anion-derived from endothelial NAD(P)H oxidase mediate the hyperreactivity to angiotensin II in type I-diabetic rat carotid, involving the participation of cyclooxygenase-1 and Rho-kinase. Moreover, increased muscular cyclooxygenase-2 expression in type I-diabetic rat carotid seems to be related to the local reduced AT(1)-receptor expression and the reduced angiotensin II potency. PMID- 22227338 TI - Effects of brown alga, Ecklonia cava on glucose and lipid metabolism in C57BL/KsJ db/db mice, a model of type 2 diabetes mellitus. AB - Recently, there has been a growing interest in alternative therapies of marine algae for diabetes. Therefore, the anti-diabetic effects of brown alga, Ecklonia cava was investigated in type 2 diabetic animal. Male C57BL/KsJ-db/db (db/db) mice were divided into control, dieckol rich extract of E. cava (AG-dieckol), or rosiglitazone (RG) groups. The blood glucose, blood glycosylated hemoglobin levels, and plasma insulin levels were significantly lower in the AG-dieckol and RG groups than in the control db/db mice group, while glucose tolerance was significantly improved in the AG-dieckol group. AG-dieckol markedly lowered plasma and hepatic lipids concentration compared to the control db/db mice group. The antioxidant enzyme activities were significantly higher in the AG-dieckol group than in the control db/db mice group, yet its TBARS level was markedly lower compared to the RG group. With regard to hepatic glucose regulating enzyme activities, glucokinase activity was enhanced in the AG-dieckol group mice, while glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities in the AG dieckol group mice were significantly lowered than those in the control db/db mice group. These results suggest that AG-dieckol exert an anti-diabetic effect in type 2 diabetic mice by improving the glucose and lipid metabolism and antioxidant enzymes. PMID- 22227339 TI - RFX2 is broadly required for ciliogenesis during vertebrate development. AB - In Caenorhabditis elegans, the RFX (Daf19) transcription factor is a major regulator of ciliogenesis, controlling the expression of the many essential genes required for making cilia. In vertebrates, however, seven RFX genes have been identified. Bioinformatic analysis suggests that Rfx2 is among the closest homologues of Daf19. We therefore hypothesize that Rfx2 broadly controls ciliogenesis during vertebrate development. Indeed, here we show that Rfx2 in Xenopus is expressed preferentially in ciliated tissues, including neural tube, gastrocoel roof plate, epidermal multi-ciliated cells, otic vesicles, and kidneys. Knockdown of Rfx2 results in cilia-defective embryonic phenotypes and fewer or truncated cilia are observed in Rfx2 morphants. These results indicate that Rfx2 is broadly required for ciliogenesis in vertebrates. Furthermore, we show that Rfx2 is essential for expression of several ciliogenic genes, including TTC25, which we show here is required for ciliogenesis, HH signaling, and left right patterning. PMID- 22227340 TI - Roles of ADAM13-regulated Wnt activity in early Xenopus eye development. AB - Pericellular proteolysis by ADAM family metalloproteinases has been widely implicated in cell signaling and development. We recently found that Xenopus ADAM13, an ADAM metalloproteinase, is required for activation of canonical Wnt signaling during cranial neural crest (CNC) induction by regulating a novel crosstalk between Wnt and ephrin B (EfnB) signaling pathways (Wei et al., 2010b). In the present study we show that the metalloproteinase activity of ADAM13 also plays important roles in eye development in Xenopus tropicalis. Knockdown of ADAM13 results in reduced expression of eye field markers pax6 and rx1, as well as that of the pan-neural marker sox2. Activation of canonical Wnt signaling or inhibition of forward EfnB signaling rescues the eye defects caused by loss of ADAM13, suggesting that ADAM13 functions through regulation of the EfnB-Wnt pathway interaction. Downstream of Wnt, the head inducer Cerberus was identified as an effector that mediates ADAM13 function in early eye field formation. Furthermore, ectopic expression of the Wnt target gene snail2 restores cerberus expression and rescues the eye defects caused by ADAM13 knockdown. Together these data suggest an important role of ADAM13-regulated Wnt activity in eye development in Xenopus. PMID- 22227341 TI - Core lab analysis of baseline echocardiographic studies in the STICH trial and recommendation for use of echocardiography in future clinical trials. AB - BACKGROUND: The Surgical Treatment for Ischemic Heart Failure (STICH) randomized trial was designed to identify an optimal management strategy for patients with ischemic cardiomyopathy. Baseline echocardiographic examinations were required for all patients. The primary aim of this report is to describe the baseline STICH Echocardiography Core Laboratory data. The secondary aim is to provide recommendations regarding how echocardiography should be used in clinical practice and research on the basis of the experience gained from echocardiography in STICH. METHODS: Between September 2002 and January 2006, 2,136 patients with ejection fractions (EFs) <= 35% and coronary artery disease amenable to coronary artery bypass grafting were enrolled. Echocardiography was acquired by 122 clinical enrolling sites, and measurements were performed by the Echocardiography Core Laboratory after a certification process for all clinical sites. RESULTS: Echocardiography was available for analysis in 2,006 patients (93.9%); 1,734 (86.4%) were men, and the mean age was 60.9 +/- 9.5 years. The mean left ventricular end-systolic volume index, measureable in 72.8%, was 84.0 +/- 30.9 mL/m(2), and the mean EF was 28.9 +/- 8.3%, with 18.5% of patients having EFs > 35%. Single-plane measurements of left ventricular and left atrial volumes were similar to their volumes by biplane measurement (r = 0.97 and r = 0.92, respectively). Mitral regurgitation severity by visual assessment was associated with a wide range of effective regurgitant orifice area, while effective regurgitant orifice area >= 0.2 cm(2) indicated at least moderate mitral regurgitation by visual assessment. Deceleration time of mitral inflow velocity had a weak correlation with EF (r = 0.25) but was inversely related to estimated pulmonary artery systolic pressure (r = -0.49). CONCLUSIONS: In STICH patients with ischemic cardiomyopathy, Echocardiography Core Laboratory analysis of baseline echocardiographic findings demonstrated a wide spectrum of left ventricular shape, function, and hemodynamics, as well as the feasibility and limitations of obtaining essential echocardiographic measurements. It is critical that the use of echocardiographic parameters in clinical practice and research balance the strengths and weaknesses of the technique. PMID- 22227342 TI - Therapeutic antibodies: market considerations, disease targets and bioprocessing. AB - Antibodies are well established in mainstream clinical practice and present an exciting area for collaborative research and development in industry and academia alike. In this review, we will provide an overview of the current market and an outlook to 2015, focussing on whole antibody molecules while acknowledging the next generation scaffolds containing variable fragments. The market will be discussed in the context of disease targets, particularly in the areas of oncology and immune disorders which generate the greatest revenue by a wide margin. Emerging targets include central nervous system disorders which will also stimulate new delivery strategies. It is becoming increasingly apparent that a better understanding of bioprocessing is required in order to optimize the steps involved in the preparation of a protein prior to formulation. The latter is outside the scope of this review and nor is it our intention to discuss protein delivery and pharmacokinetics. The challenges that lie ahead include the discovery of new disease targets and the development of robust bioprocessing operations. PMID- 22227343 TI - Prestin binding peptides as ligands for targeted polymersome mediated drug delivery to outer hair cells in the inner ear. AB - Targeted delivery of treatment agents to the inner ear using nanoparticles is an advanced therapeutic approach to cure or alleviate hearing loss. Designed to target the outer hair cells of the cochlea, two 12-mer peptides (A(665) and A(666)) with affinity to prestin were identified following 3 rounds of sequential phage display. Two-round display with immobilized prestin protein was used to enrich the library for full-length prestin. The last round was performed using Cos-7 cells transiently transfected with a cCFP-prestin plasmid to display phages expressing peptides restrictive to the extracellular loops of prestin. The binding properties of A(665) and A(666) shown by flow cytometry demonstrated selectivity to prestin-expressing Chinese hamster ovary cells. PEG6K-b-PCL19K polymersomes covalently labelled with these peptides demonstrated effective targeting to outer hair cells in a rat cochlear explant study. PMID- 22227344 TI - Clotrimazole nanoemulsion for malaria chemotherapy. Part I: preformulation studies, formulation design and physicochemical evaluation. AB - Clotrimazole was formulated in nanoemulsion based system with the aim of improving its solubility and dissolution, which can further used for its preclinical evaluation. Clotrimazole nanoemulsion was prepared using spontaneous nanoemulsification method. Preformulation studies were preformed to evaluate drug excipient compatibility, solution state pH stability and pH solubility profile. Solubility of clotrimazole in oils, surfactants and cosurfactants was determined to identify nanoemulsion components. Surfactants and cosurfactants were screened for their ability to emulsify selected oily phases. Phase diagrams were constructed to identify area of nanoemulsification. Influence of clotrimazole and pH of dilution medium on phase behavior were assessed. Drug-excipient chemical compatibility study facilitated to anticipate acid catalyzed degradation of clotrimazole. The pH of nanoemulsion was adjusted to 7.5, which could stabilize clotrimazole. Nanoemulsion composed of Capryol 90, Solutol HS 15 and Gelucire 44/14 enhanced solubility of clotrimazole up to 25mg/ml. The optimized clotrimazole nanoemulsion could withstand the extensive dilution and did not show any phase separation or drug precipitation. The nanoemulsion exhibited mean globule size <25 nm, which was not affected by pH of dilution medium. Dissolution profile of clotrimazole nanoemulsion in various media showed 100% drug release within 15 min irrespective of pH of medium. PMID- 22227345 TI - Validation of a new scale to assess olfactory dysfunction in patients with Parkinson's disease. AB - BAKCKGROUND: Olfactory dysfunction is present in up to 90% of Parkinson's disease (PD) patients. It is usually evaluated by means of objective standardized tests; however no self-administered scales have been developed for olfactory dysfunction bedside assessment. We present validation of a new scale to assess this symptom in PD patients. METHODS: Seventy-five PD patients and 25 control subjects were evaluated using a Hyposmia Rating Scale developed in-house, combined with the extended Sniffin' Sticks test. RESULTS: Total score of the 6-item Hyposmia Rating Scale showed significant correlation with threshold, discrimination, identification and total Sniffin' Sticks test scores (r = 0.53; r = 0.60; r = 0.57; r = 0.65 respectively, p < 0.001 for all values). Area under the curve of the receiver operating curve for the ability of Hyposmia Rating Scale to discriminate patients with Sniffin' Sticks test total scores below or above the cut-off point was 80 +/- 6% (p < 0.001). Considering Sniffin' Sticks test as the gold standard method for olfactory dysfunction detection, an affirmative response to a single screening question about smelling ability problems showed 35% sensitivity (95%CI = 23-47%) and 100% specificity. The best cut-off point for Hyposmia Rating Scale was 22.5 with a sensitivity of 70% (60-81%) and a specificity of 85% (65-100%). CONCLUSION: The Hyposmia Rating Scale here presented may offer a simple, cost-effective, time-saving and reliable approach to evaluate olfactory dysfunction in PD patients. PMID- 22227346 TI - Regulatory mechanisms of thymus and T cell development. AB - The thymus is a central hematopoietic organ which produces mature T lymphocytes with diverse antigen specificity. During development, the thymus primordium is derived from the third pharyngeal endodermal pouch, and then differentiates into cortical and medullary thymic epithelial cells (TECs). TECs represent the primary functional cell type that forms the unique thymic epithelial microenvironment which is essential for intrathymic T-cell development, including positive selection, negative selection and emigration out of the thymus. Our understanding of thymopoiesis has been greatly advanced by using several important animal models. This review will describe progress on the molecular mechanisms involved in thymus and T cell development with particular focus on the signaling and transcription factors involved in this process in mouse and zebrafish. PMID- 22227347 TI - [Study of anxiety levels in neonatal unit staff]. AB - INTRODUCTION: The professionals who routinely work in neonatal units become under stress due to the working conditions and the nature of the tasks carried out. As a consequence of this, they may have high levels of anxiety. Anxiety is defined as an emotional response or response patterns that include cognitive, physiological and behavioural aspects. METHODS: A prospective cross-sectional study was conducted on all neonatologist, nurses and care assistants who were given two self-administered questionnaires under baseline conditions, to assess Sate Anxiety and Trait Anxiety. (IDDA-EA; STAI, State-Trait Anxiety Inventory). RESULTS: The response rate was 88.5%, and 36% scored between 30 and 70 percentiles on State Anxiety, with 11.8% above the 70 percentile and 51% below the 30 percentile. There were no significant differences in relation to occupation or age. There were also no significant differences between State and Trait Anxiety. Regarding gender, it has obtained A statistically significant difference of 8 points higher was obtained for women. CONCLUSIONS: For the majority professionals everyday situations in which are involved do not significantly raise the burden of anxiety, as half of them have levels below the average. They perceive themselves as competent and able to cope with their tasks. They have a high degree of interest and attention in the activities performed. PMID- 22227348 TI - [Respiratory variations in aortic blood flow and response to fluids]. PMID- 22227349 TI - [Insulin resistance in overweight cystic fibrosis paediatric patients]. AB - AIM: To determine the prevalence of overweight in paediatric patients with cystic fibrosis (CF) and to analyse its role as diabetogenic insulin resistance factor and risk of hypertriglyceridaemia. PATIENTS AND METHODS: A total of 109 CF patients (47% males) between 5 and 18 years were divided into 3 groups according to body mass index (BMI): underweight, normal and overweight. Total cholesterol, triglycerides, C- reactive protein (CRP), glycosylated haemoglobin, HOMA-IR and QUICKI index were determined. Insulinogenic index, ISI composite and areas under the curve (AUC) for glucose and insulin were obtained by oral glucose tolerance test (OGTT). RESULTS: Six patients (5.5%) were overweight. All groups had similar distribution by age, sex and CFTR mutation, although the proportion of pancreatic sufficient (3/6, 50%) was higher in overweight patients (P=.003). The prevalence of glycaemic disorders was similar between groups. Baseline insulin, HOMA-IR, and insulin during the OGTT (peak and AUC) were higher in overweight patients. All patients had a delayed insulin response in OGTT. CONCLUSIONS: Overweight CF patients do not have a higher incidence of glycaemic disorders, but their hyperinsulinism and insulin resistance may be additional diabetogenic risk factors. PMID- 22227350 TI - A simple way to acquire T(1)-weighted MR images of rat liver with respiratory triggering. AB - To acquire high-resolution T(1)-weighted images of the liver in rats, for which breath-holding cannot be ensured, respiratory triggering is essential. At the respiratory rate of 30-60 times/min in rats, however, T(1)-weighted images cannot be obtained with simple triggering. As a simple solution to this, we applied multiple repeated acquisitions with one trigger signal. With this technique, sufficient T(1) contrast could be easily achieved in rat liver enhanced by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid infusion. PMID- 22227351 TI - Temperature mapping in bread dough using SE and GE two-point MRI methods: experimental and theoretical estimation of uncertainty. AB - Two-dimensional (2D)-SE, 2D-GE and tri-dimensional (3D)-GE two-point T(1) weighted MRI methods were evaluated in this study in order to maximize the accuracy of temperature mapping of bread dough during thermal processing. Uncertainties were propagated throughout each protocol of measurement, and comparisons demonstrated that all the methods with comparable acquisition times minimized the temperature uncertainty to similar extent. The experimental uncertainties obtained with low-field MRI were also compared to the theoretical estimations. Some discrepancies were reported between experimental and theoretical values of uncertainties of temperature; however, experimental and theoretical trends with varying parameters agreed to a large extent for both SE and GE methods. The 2D-SE method was chosen for further applications on prefermented dough because of its lower sensitivity to susceptibility differences in porous media. It was applied for temperature mapping in prefermented dough during chilling prior to freezing and compared locally to optical fiber measurements. PMID- 22227352 TI - Partial least squares for discrimination in fMRI data. AB - Multivariate methods for discrimination were used in the comparison of brain activation patterns between groups of cognitively normal women who are at either high or low Alzheimer's disease risk based on family history and apolipoprotein E4 status. Linear discriminant analysis (LDA) was preceded by dimension reduction using principal component analysis (PCA), partial least squares (PLS) or a new oriented partial least squares (OrPLS) method. The aim was to identify a spatial pattern of functionally connected brain regions that was differentially expressed by the risk groups and yielded optimal classification accuracy. Multivariate dimension reduction is required prior to LDA when the data contain more feature variables than there are observations on individual subjects. Whereas PCA has been commonly used to identify covariance patterns in neuroimaging data, this approach only identifies gross variability and is not capable of distinguishing among-groups from within-groups variability. PLS and OrPLS provide a more focused dimension reduction by incorporating information on class structure and therefore lead to more parsimonious models for discrimination. Performance was evaluated in terms of the cross-validated misclassification rates. The results support the potential of using functional magnetic resonance imaging as an imaging biomarker or diagnostic tool to discriminate individuals with disease or high risk. PMID- 22227353 TI - Hepatic parenchymal enhancement at Gd-EOB-DTPA-enhanced MR imaging: correlation with morphological grading of severity in cirrhosis and chronic hepatitis. AB - The aim was to clarify whether enhancement effects of the liver parenchyma in the hepatobiliary phase (HP) of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MR imaging were correlated with the morphological grading of the severity in cirrhosis. A total of 62 patients with chronic hepatitis or cirrhosis underwent Gd-EOB-DTPA-enhanced MR imaging. Relative enhancement (RE) of liver parenchyma was calculated from signal intensity (SI) measurements obtained at precontrast images (SIpre) and 20-min postcontrast HP images (SIpost) as: (SIpost-SIpre)/SIpre. Morphological MR grades of severity in cirrhosis were divided into four groups. Then, RE of liver parenchyma and morphologic MR grading were correlated. Regarding the morphologic severity of cirrhosis, the numbers of patients with MR grade 1, 2, 3 and 4 were 14 (23%), 7 (11%), 28 (45%) and 13 (21%), respectively. The mean REs of liver parenchyma in each group of MR morphologic grade 1, 2, 3 and 4 were 0.71+/-0.21, 0.62+/-0.16, 0.70+/-0.22 and 0.77+/-0.18, respectively. There was no significant correlation between the MR grading of morphologic severity and the RE of liver parenchyma at 20-min HP. Hepatic parenchymal enhancement in the HP of Gd-EOB-DTPA enhanced MR imaging did not necessarily decrease according to the severity of morphologic changes in cirrhosis. This fact may suggest that the hepatic uptake of Gd-EOB-DTPA depends on the preserved hepatocytes function rather than the severity of morphologic changes in cirrhosis. PMID- 22227354 TI - Anaesthetists' perceptions of facilitative weaning strategies from mechanical ventilator in the intensive care unit (ICU): a qualitative interview study. AB - AIM: This study aimed to examine anaesthetists' perceptions of facilitative weaning from the mechanical ventilator in the intensive care unit (ICU). METHODS: Explorative qualitative interviews in a phenomenographic reference frame with a purposive sample of 14 eligible anaesthetists from four different ICUs with at least one year of clinical experience of ICU and of ventilator weaning. FINDINGS: Four categories of anaesthetists' perceptions of facilitative decision-making strategies for ventilator weaning were identified. These were the instrumental, the interacting, the process-oriented and the structural strategies" for ventilator weaning. The findings refer to a supportive multidisciplinary holistic ICU quality of care. Choice of strategy for ventilator weaning was flexible and individually tailored to the patients'. CONCLUSIONS: Choice of strategy was flexible and individually adjustable. Introduction of evidence-based guidelines from ventilator weaning is necessary in the ICU. The guidelines should also cover the responsibilities of various professional groups. Regular evaluations of methods and strategies used in practice need to be implemented. This may facilitate decision-making strategies for ventilator weaning in practice at the ICU. Greater attention needs to focus on family members' experiences. The strategies should be an integral part of continuous staff training. PMID- 22227355 TI - Integrating a multidisciplinary mobility programme into intensive care practice (IMMPTP): a multicentre collaborative. AB - BACKGROUND: ICU immobility can contribute to physical deconditioning, increased ICU and hospital length of stay and complications post discharge. Despite evidence of the beneficial outcomes of early mobility, many ICUs and providers lack necessary processes and resources to effectively integrate early mobility into their daily practice. OBJECTIVE: To create a progressive mobility initiative that will help ICU teams to address key cultural, process and resource opportunities in order to integrate early mobility into daily care practices. METHODS: An initiative to integrate the latest evidence on mobility practice into current ICU culture in 13 ICUs in eight hospitals within the US was launched. A user-friendly, physiologically grounded evidence-based mobility continuum was designed and implemented. Appropriate education and targeted messaging was used to engage stakeholders. To support and sustain the implementation process, mechanisms including coaching calls and various change interventions were offered to modify staffs' practice behaviour. Qualitative data was collected at two time points to assess cultural and process issues around mobility and provided feedback to the stakeholders to support change. Quantitative date on ventilator days and timing of physical therapy consultation was measured. RESULTS: Qualitative reports of the mobility programme participants suggest that the methods used in the collaborative approach improved both the culture and team focus on the process of mobility. There were no significant differences demonstrated in any of the mobility intervention group measurement however, a reduction in ventilator days (3.0days pre vs. 2.1 days post) approached significance (p=0.06). CONCLUSION: This multi-centre, ICU collaborative has shown that improvements in team culture, communication and resources can improve adoption of early mobility in ICU patients. PMID- 22227356 TI - Impact of visual learning on facial expressions of physical distress: a study on voluntary and evoked expressions of pain in congenitally blind and sighted individuals. AB - The ability to facially communicate physical distress (e.g. pain) can be essential to ensure help, support and clinical treatment for the individual experiencing physical distress. So far, it is not known to which degree this ability represents innate and biologically prepared programs or whether it requires visual learning. Here, we address this question by studying evoked and voluntary facial expressions of pain in congenitally blind (N=21) and sighted (N=42) individuals. The repertoire of evoked facial expressions was comparable in congenitally blind and sighted individuals; however, blind individuals were less capable of facially encoding different intensities of experimental pain. Moreover, blind individuals were less capable of voluntarily modulating their pain expression. We conclude that the repertoire of facial muscles being activated during pain is biologically prepared. However, visual learning is a prerequisite in order to encode different intensities of physical distress as well as for up- and down-regulation of one's facial expression. PMID- 22227357 TI - Impact of the probe solutes set on orthogonality evaluation in reverse phase chromatographic systems. AB - Two-dimensional liquid chromatography (2DLC) is a very attractive technique for the characterization of complex samples due to its separation power obtained via the coupling of two separation modes exhibiting different mechanisms, i.e. orthogonality. In reverse phase, orthogonality is mainly governed by three factors: the pH of the mobile phase, the structure of the stationary phase and the nature of the organic modifier. In the present paper, we studied the impact of the nature of the probe solutes on orthogonality evaluation. A set of 63 compounds with various physicochemical properties was used to evaluate 32 reverse phase chromatographic systems (2 pH * 8 stationary phases * 2 organic modifiers). Principle component analysis revealed that the solutes could be split into three subsets according to their charge in the experimental conditions. The factors affecting orthogonality and the magnitude of their effect were shown to depend on the charge of the compounds. For positively charged (basic) compounds, the pH was the most important factor, followed by the nature of the stationary phase. For negatively charged (acidic) compounds, the nature of the stationary phase had the highest impact. For neutral compounds, only the nature of the stationary phase and, to a smaller extent, the organic modifier had an influence. The present study also showed that a reduced set of only 9 test compounds instead of whole set of the 63 could enable an appropriate orthogonality evaluation. PMID- 22227358 TI - Sensitive determination of bromate in ozonated and chlorinated water, and sea water by gas chromatography-mass spectrometry after derivatization. AB - A sensitive gas chromatographic method has been established for the determination of bromate in ozonated and chlorinated water, and in sea water. With acidic conditions, bromate reacts with chloride to form bromine, which reacts with 2,6 dialkylphenol to form 4-bromo-2,6-dialkylphenol. The organic derivative was extracted with ethyl acetate after quenching remaining oxidants with ascorbic acid, and then measured by gas chromatography-mass spectrometry (GC-MS). The lowest detection limit and limit of quantification of bromate in drinking water were 0.02 and 0.07 MUg/L, respectively, and the calibration curve showed good linearity with r2=0.998. The 32 common ions did not interfere even when present in 100-fold excess over the bromated ion. The accuracy was in a range of 102-106% and the precision of the assay was less than 6% in chlorinated and ozonated tap water, ozonated mineral water, and sea water. The method was sensitive, reproducible and simple enough to permit reliable analysis of bromate to the ng/L level in water. PMID- 22227359 TI - Overlapping elution-extrusion counter-current chromatography: a novel method for efficient purification of natural cytotoxic andrographolides from Andrographis paniculata. AB - Counter-current chromatography (CCC) is extremely useful for the separation, purification, and isolation of natural products. Recently, Berthod et al. established an elution-extrusion CCC method in metabolic analysis by combining regular chromatographic elution with stationary-phase extrusion, which extends the hydrophobicity window of a counter-current separation. In this study, a novel overlapping elution-extrusion CCC method was developed and applied to the preparation of natural cytotoxic andrographolides from the aerial parts of Andrographis paniculata, a well-known Traditional Chinese Medicine (TCM) with potent anti-inflammatory effect and anti-cancer activity. Its theory was first developed, and then a series of CCC experiments were performed to investigate the efficiency of the method in the separation of the ethanol extracts from A. paniculata. Results show that overlapping elution-extrusion CCC is an efficient method to prepare a cytotoxic natural diterpenoid combination of 14-deoxy andrographolide and 14-deoxy-11,12-didehydroandrographolide with the molar ratio of 1:2 as well as andrographolide using an optimized solvent system composed of hexane-ethyl acetate-ethanol-water (5:5:4:6, v/v) with an on-demand solvent preparation mode. All components obtained showed potent cytotoxic activity against human hepatocellular liver carcinoma cells HepG2 and doxorubicin resistant R-HepG2 cells. Molecular structures have been identified by electrospray ionization mass spectrometry (ESI-MS), electrospray ionization time of-flight mass spectrometry (ESI-TOF-MS), one- and two-dimensional nuclear magnetic resonance (1D- and 2D-NMR). The method appears to be very useful for the high-throughput purification of natural products. PMID- 22227360 TI - Determination of alkylphenols and bisphenol A in seawater samples by dispersive liquid-liquid microextraction and liquid chromatography tandem mass spectrometry for compliance with environmental quality standards (Directive 2008/105/EC). AB - A fast, simple, sensitive and green analytical chemistry method for the simultaneous determination of alkylphenols (4-tert-octylphenol, 4-octylphenol, 4 n-nonylphenol, nonylphenol) and bisphenol A in seawater was developed and validated. The procedure was based on a dispersive liquid-liquid microextraction (DLLME) of a small volume of seawater sample (30 mL) using only 100 MUL of 1 octanol, combined with liquid chromatography-electrospray ionization tandem mass spectrometry in negative mode (LC-ESI-MS/MS). The matrix effect was studied and compensated using deuterated labelled standards as surrogate standards for the quantitation of target compounds. The analytical features of the proposed method were satisfactory: repeatability and intermediate precision were <10% and recoveries were around 84-104% for all compounds. Uncertainty assessment of measurement was estimated on the basis of an in-house validation according to EURACHEM/CITAC guide. Quantitation limits of the method (MQL) ranged between 0.005 and 0.03 MUg L-1, therefore the levels established in the Directive 2008/105/EC were achieved. The applicability of the proposed method was demonstrated analyzing seawater samples from different sites of A Coruna (Northwest of Spain). The analyses showed the presence of all compounds at levels between 0.035 (bisphenol A) and 0.14 MUg L-1 (nonylphenol). PMID- 22227361 TI - Estimation of the uncertainty associated with the results based on the validation of chromatographic analysis procedures: application to the determination of chlorides by high performance liquid chromatography and of fatty acids by high resolution gas chromatography. AB - This article presents a model to calculate the uncertainty associated with an analytical result based on the validation of the analysis procedure. This calculation model is proposed as an alternative to commonly used bottom-up and top-down methods. This proposal is very advantageous as the validation of the procedures and the estimation of the uncertainty of the measurement are part of the technical requirements needed in order to obtain the ISO 17025:2005 accreditation. This model has been applied to the determination of chloride by liquid chromatography in lixiviates and in the determination of palmitic acid and stearic acid by gas chromatography in magnesium stearate samples. PMID- 22227362 TI - Predicting the chromatographic retention of polymers: application of the polymer model to poly(styrene/ethylacrylate)copolymers. AB - The retention behavior of a range of statistical poly(styrene/ethylacrylate) copolymers is investigated, in order to determine the possibility to predict retention volumes of these copolymers based on a suitable chromatographic retention model. It was found that the composition of elution in gradient chromatography of the copolymers is closely related to the eluent composition at which, in isocratic chromatography, the transition from elution in adsorption to exclusion mode occurs. For homopolymers this transition takes place at a critical eluent composition at which the molar mass dependence of elution volume vanishes. Thus, similar critical eluent compositions can be defined for statistical copolymers. The existence of a critical eluent composition is further supported by the narrower peak width, indicating that the broad molar mass distribution of the samples does not contribute to the retention volume. It is shown that the existing retention model for homopolymers allows for correct quantitative predictions of retention volumes based on only three appropriate initial experiments. The selection of these initial experiments involves a gradient run and two isocratic experiments, one at the composition of elution calculated from first gradient run and second at a slightly higher eluent strength. PMID- 22227363 TI - Multi-walled carbon nanotubes as alternative reversed-dispersive solid phase extraction materials in pesticide multi-residue analysis with QuEChERS method. AB - A multi-residue method based on modified QuEChERS sample preparation with multi walled carbon nanotubes (MWCNTs) as reversed-dispersive solid phase extraction (r DSPE) material and gas chromatography-mass spectrometry determination by selected ion monitoring (GC/MS-SIM) mode was validated on 30 representative pesticides residues in vegetables and fruits. The acetonitrile-based QuEChERS (quick, easy, cheap, effective, rugged and safe) sample preparation technique was used to obtain the extracts, and the further cleanup was carried out by applying r-DSPE. It was found that the amount of MWCNTs influenced the cleanup performance and the recoveries. The optimal amount of 10mg MWCNTs was suitable for cleaning up all selected matrices, as a suitable alternative r-DSPE material to primary secondary amine (PSA). This method was validated on cabbage, spinach, grape and orange spiked at concentration levels of 0.02 and 0.2 mg/kg. The recoveries of 30 pesticides were in the range of 71-110%, with relative standard deviations (RSDs, n=5) lower than 15%. Matrix effects were observed by comparing the slope of matrix-matched standard calibration with that of solvent. Good linearity was achieved at the concentration levels of 0.02-0.5 mg/L. The limits of quantification (LOQs) and the limits of detection (LODs) for 30 pesticides ranged from 0.003 to 0.05 mg/kg and 0.001 to 0.02 mg/kg at the signal-to-noise ratio (S/N) of 10 and 3, respectively. The method was successfully applied to analysis real samples in Beijing. In conclusion, the modified QuEChERS method with MWCNTs cleanup step showed reliable method validation performances and good cleanup effects in this study. PMID- 22227364 TI - Correlation between DNA defect and sperm-head morphology. AB - The utility of sperm DNA testing remains controversial. However, it may be helpful in couples with unexplained failures of multiple assisted reproductive techniques and/or recurrent abortions. This study analysed 10,400 spermatozoa of 26 patients for sperm-head morphology with high-magnification microscopy, DNA fragmentation and sperm chromatin decondensation. A significant negative correlation was demonstrated between sperm-parameters and abnormal sperm-head morphology as assessed by high magnification (score 0 according to this study's classification): concentration (r=-0.41; P=0.03), motility (r=-0.42; P=0.03), morphology (r=-0.63; P=0.0008). No correlation was found with DNA fragmentation. However, the sperm chromatin-decondensation rate of score-0 spermatozoa was twice as high as the controls (19.5% versus 10.1%; P<0.0001). This observation suggests that score-0 spermatozoa should not be selected for intracytoplasmic sperm injection. PMID- 22227365 TI - The pathophysiology of heart failure. AB - Heart failure is a clinical syndrome that results when the heart is unable to provide sufficient blood flow to meet metabolic requirements or accommodate systemic venous return. This common condition affects over 5 million people in the United States at a cost of $10-38 billion per year. Heart failure results from injury to the myocardium from a variety of causes including ischemic heart disease, hypertension, and diabetes. Less common etiologies include cardiomyopathies, valvular disease, myocarditis, infections, systemic toxins, and cardiotoxic drugs. As the heart fails, patients develop symptoms which include dyspnea from pulmonary congestion, and peripheral edema and ascites from impaired venous return. Constitutional symptoms such as nausea, lack of appetite, and fatigue are also common. There are several compensatory mechanisms that occur as the failing heart attempts to maintain adequate function. These include increasing cardiac output via the Frank-Starling mechanism, increasing ventricular volume and wall thickness through ventricular remodeling, and maintaining tissue perfusion with augmented mean arterial pressure through activation of neurohormonal systems. Although initially beneficial in the early stages of heart failure, all of these compensatory mechanisms eventually lead to a vicious cycle of worsening heart failure. Treatment strategies have been developed based upon the understanding of these compensatory mechanisms. Medical therapy includes diuresis, suppression of the overactive neurohormonal systems, and augmentation of contractility. Surgical options include ventricular resynchronization therapy, surgical ventricular remodeling, ventricular assist device implantation, and heart transplantation. Despite significant understanding of the underlying pathophysiological mechanisms in heart failure, this disease causes significant morbidity and carries a 50% 5-year mortality. PMID- 22227366 TI - Fibroblast growth factor-2 promotes in vitro heart valve interstitial cell repair through the Akt1 pathway. AB - BACKGROUND: Fibroblast growth factor-2 promotes in vitro heart valve interstitial cell repair. Fibroblast growth factor-2 acts through betaglycan which is known to bind both transforming growth factor-beta and fibroblast growth factor-2 at different locations on the molecule. When fibroblast growth factor-2 binds to betaglycan, transforming growth factor-beta binding to betaglycan is reduced, allowing for more transforming growth factor-beta to be available to activate pSmad2/3 which then promotes repair. This study investigates another pathway through which fibroblast growth factor-2 regulates valve interstitial cell repair. METHODS: We used an in vitro model of cell culture disruption. Confluent valve interstitial cell monolayers were disrupted, creating an experimental wound in the confluent monolayer, and incubated in treatments of exogenous fibroblast growth factor-2, anti-fibroblast growth factor receptor antibody, active Akt1, and Akt inhibitor. Valve interstitial cell monolayers were immunohistochemically stained and quantified for nuclear pSmad2/3 at the wound edge. The extent of closure was measured up to 96 h after disruption. RESULTS: Anti-fibroblast growth factor receptor antibody significantly increased both nuclear pSmad2/3 staining at the wound edge and wound closure compared to nontreated control. This increase was less than that seen when valve interstitial cells were treated with fibroblast growth factor-2 and combined treatments of fibroblast growth factor-2 and anti-fibroblast growth factor receptor antibody did not further increase nuclear pSmad2/3 staining compared to fibroblast growth factor-2 alone. This suggested that the regulation of wound closure by fibroblast growth factor-2 also involved pathways other than transforming growth factor-beta/Smad signaling. Treatment with Akt1 significantly increased wound closure, while Akt inhibitor reduced closure as compared to nontreated valve interstitial cells. Fibroblast growth factor-2 and fibroblast growth factor-2 neutralizing antibody up-regulated and down-regulated phosphorylated Akt1 expression in valve interstitial cells, respectively. CONCLUSION: Fibroblast growth factor-2 promotes valve interstitial cell repair in two ways: the fibroblast growth factor-2/fibroblast growth factor 2 receptor interaction through the activation of Akt1 independent of the transforming growth factor-beta/Smad2/3 signaling pathway and the previously described transforming growth factor-beta/Smad signaling. PMID- 22227367 TI - Tissue localization of nanoparticles is altered due to hypoxia resulting in poor efficacy of curcumin nanoparticles in pulmonary hypertension. AB - The present study is an attempt to leverage therapeutic benefits of curcumin in pulmonary hypertension by encapsulating it in biodegradable poly(lactide-co glycolic) acid nanoparticles. Pulmonary hypertension is induced in experimental animals by subjecting them to chronic hypoxic conditions. The ability of curcumin encapsulated nanoparticles to manage pulmonary hypertension is measured by right ventricular hypertrophy, haematocrit, vascular remodelling and target tissue levels of curcumin. Further, single oral dose tissue distribution of the nanoparticulate curcumin was also assessed under normoxic and hypoxic conditions. Orally administered nanoparticulate curcumin failed to offer any protection against hypoxia induced pulmonary hypertension as indicated by insignificant changes in right ventricular hypertrophy and vascular remodelling that are similar to untreated groups. A significant difference in the target tissue levels was observed between normoxic vs. hypoxic rats. The study suggests that hypoxia has a major role in the particle localization in lungs probably due to the altered blood flow, increased barrier properties of the lung vasculature and decreased endocytosis. The target tissue levels of curcumin under hypoxia are much lower to that achieved in normoxic rats probably due to difference in particle dynamics, resulting in the failure of treatment. PMID- 22227369 TI - A non-covalent interaction between small ubiquitin-like modifier-1 and Zac1 regulates Zac1 cellular functions. AB - Zac1, a zinc-finger protein that regulates apoptosis and cell cycle arrest 1, such as p53, can induce cell-cycle arrest and apoptosis. The transactivation and coactivation functions of Zac1 may occur at non-promyelocytic leukemia nuclear body (PML-NB) sites in the presence of other PML-NB components, including ubiquitin-conjugating 9 (Ubc9). It is unclear whether post-translational modification of Zac1 by the small ubiquitin-like modifier SUMO plays a role in the coactivation functions of Zac1 for the regulation of the p21 gene. Mutagenesis experiments revealed that the two SUMO-binding lysine residues of Zac1, K237 and K424, repress the transactivation activity of Zac1. Studies using a SUMO-1 C-terminal di-glycine motif mutant that is deficient in the ability to form covalent bonds with lysines, SUMO-1 (GA), and a dominant-negative Ubc9 construct (C93S) indicated that SUMO-1 might regulate Zac1 transactivation and coactivation via a non-covalent interaction. Unlike the wild-type Zac1, which induced apoptosis, the Zac1 (K237/424R) double mutant had the ability to induce autophagy. The functional role of p21 remains to be investigated. SUMO-1 selectively suppressed the induction of the p21 gene and protein by wild-type Zac1 but not by the Zac1 (K237/424R) double mutant. Moreover, wild-type Ubc9 but not Ubc9 (C93S) further potentiated the suppression of SUMO-1 in all Zac1-induced p21 promoter activities. Our data reveal that p21 may be an important factor for the prevention of Zac1-induced apoptosis without affecting autophagosome formation. This work indicates that Zac1 functions are regulated, at least in part, via non-covalent interactions with SUMO-1 for the induction of p21, which is important for the modulation of apoptosis. PMID- 22227368 TI - Controlled systemic delivery by polymeric implants enhances tissue and plasma curcumin levels compared with oral administration. AB - Curcumin possesses potent anti-inflammatory and anti-proliferative activities but with poor biopharmaceutical attributes. To overcome these limitations, curcumin implants were developed and tissue (plasma, brain and liver) curcumin concentrations were measured in female ACI rats for 3 months. Biological efficacy of tissue levels achieved was analyzed by modulation of hepatic cytochromes. Curcumin implants exhibited diffusion-mediated biphasic release pattern with ~2 fold higher in vivo release as compared to in vitro. Plasma curcumin concentration from implants was ~3.3 ng/ml on day 1, which dropped to ~0.2 ng/ml after 3 months, whereas only 0.2-0.3 ng/ml concentration was observed from 4-12 days with diet and was undetected subsequently. Almost 10-fold higher curcumin levels were observed in brain on day 1 from implants compared with diet (30.1 +/- 7.3 vs 2.7 +/- 0.8 ng/g) and were still significant even after 90 days (7.7 +/- 3.8 vs 2.2 +/- 0.8 ng/g). Although curcumin levels were similar in liver from both the routes (~25-30 ng/g from day 1-4 and ~10-15 ng/g at 90 days), implants were more efficacious in altering hepatic CYP1A1 levels and CYP3A4 activity at ~28-fold lower doses at 90 days. Curcumin implants provided much higher plasma and tissue concentrations and are a viable alternative for delivery of curcumin to various organs like brain. PMID- 22227370 TI - Characterization of a myostatin gene (MSTN1) from spotted halibut (Verasper variegatus) and association between its promoter polymorphism and individual growth performance. AB - Myostatin (MSTN) is a member of the transforming growth factor-beta superfamily which could play an important role in negatively regulating skeletal muscle growth and development in mammal and non-mammal species. In the present study, a MSTN1 gene (designated as VvMSTN1) was cloned and characterized in one flatfish species, spotted halibut (Verasper variegatus). In the 3078 bp genomic sequence, three exons, two introns and a promoter sequence were identified. Sequence analysis of the promoter region revealed that it contained several cis-regulatory elements such as CAAT-box, TATA-box and E-boxes. The deduced protein sequence included a signal peptide, a TGF-beta propeptide in the N-terminal region and the TGF-beta active peptide in the C-terminal region. Phylogenetic analysis suggested that VvMSTN1 is an orthologue of teleost MSTN1 proteins which arose along with MSTN2 during a duplication event at the base of teleost evolution. Quantitative real-time PCR analysis revealed that VvMSTN1 mRNA was ubiquitously expressed in all nine tested tissues, with the most transcriptionally abundant in skeletal muscle. A primary assessment of sequence variability revealed five single nucleotide polymorphisms (SNPs) existed in the promoter region, among which three (G-653T, T-355C and G-253A) were genotyped with an advanced melting temperature (T(m))-shift method and tested for their association with growth traits (body length, body depth and total mass). Results indicated that genotype CC of locus T 355C had significantly higher growth traits than genotype TC and TT (P<0.05) in female spotted halibut. These results suggest that V. variegatus MSTN could be selected as a candidate gene for the future molecular breeding of stains with enhanced individual growth performance. PMID- 22227371 TI - Vanadium accumulation in ascidian coelomic cells is associated with enhanced pentose phosphate pathway capacity but not overall aerobic or anaerobic metabolism. AB - Some suborders of ascidians (sea squirts) accumulate remarkable levels of the heavy metal vanadium while others accumulate negligible amounts. The function of this vanadium is unclear, but enhanced pentose phosphate pathway (PPP) has been implicated in its reduction and accumulation. We compared aspects of intermediary metabolism in coelomic cells from ascidian species that have a wide range of vanadium accumulation including non-accumulators. All species appear to have similar aerobic poise with no apparent link to vanadium accumulation. Similarly, all species examined have a limited anaerobic poise that does not seem to relate to vanadium levels. Based on the activities of phosphoglucose isomerase and glucose-6 phosphate dehydrogenase we demonstrate that, relative to the capacity for entry into glycolysis, vanadium-accumulating species have enhanced capacity to metabolize glucose-6 phosphate via the PPP compared to non-accumulators. This finding provides the first comparative support for enhanced PPP capacity linked to vanadium accumulation in tunicates. PMID- 22227372 TI - Hepatic and extrahepatic distribution of ornithine urea cycle enzymes in holocephalan elephant fish (Callorhinchus milii). AB - Cartilaginous fish comprise two subclasses, the Holocephali (chimaeras) and Elasmobranchii (sharks, skates and rays). Little is known about osmoregulatory mechanisms in holocephalan fishes except that they conduct urea-based osmoregulation, as in elasmobranchs. In the present study, we examined the ornithine urea cycle (OUC) enzymes that play a role in urea biosynthesis in the holocephalan elephant fish, Callorhinchus milii (cm). We obtained a single mRNA encoding carbamoyl phosphate synthetase III (cmCPSIII) and ornithine transcarbamylase (cmOTC), and two mRNAs encoding glutamine synthetases (cmGSs) and two arginases (cmARGs), respectively. The two cmGSs were structurally and functionally separated into two types: brain/liver/kidney-type cmGS1 and muscle type cmGS2. Furthermore, two alternatively spliced transcripts with different sizes were found for cmgs1 gene. The longer transcript has a putative mitochondrial targeting signal (MTS) and was predominantly expressed in the liver and kidney. MTS was not found in the short form of cmGS1 and cmGS2. A high mRNA expression and enzyme activities were found in the liver and muscle. Furthermore, in various tissues examined, mRNA levels of all the enzymes except cmCPSIII were significantly increased after hatching. The data show that the liver is the important organ for urea biosynthesis in elephant fish, but, extrahepatic tissues such as the kidney and muscle may also contribute to the urea production. In addition to the role of the extrahepatic tissues and nitrogen metabolism, the molecular and functional characteristics of multiple isoforms of GSs and ARGs are discussed. PMID- 22227374 TI - Regulation of chromosomal replication in Caulobacter crescentus. AB - The alpha-proteobacterium Caulobacter crescentus is characterized by its asymmetric cell division, which gives rise to a replicating stalked cell and a non-replicating swarmer cell. Thus, the initiation of chromosomal replication is tightly regulated, temporally and spatially, to ensure that it is coordinated with cell differentiation and cell cycle progression. Waves of DnaA and CtrA activities control when and where the initiation of DNA replication will take place in C. crescentus cells. The conserved DnaA protein initiates chromosomal replication by directly binding to sites within the chromosomal origin (Cori), ensuring that DNA replication starts once and only once per cell cycle. The CtrA response regulator represses the initiation of DNA replication in swarmer cells and in the swarmer compartment of pre-divisional cells, probably by competing with DnaA for binding to Cori. CtrA and DnaA are controlled by multiple redundant regulatory pathways that include DNA methylation-dependent transcriptional regulation, temporally regulated proteolysis and the targeting of regulators to specific locations within the cell. Besides being critical regulators of chromosomal replication, CtrA and DnaA are also master transcriptional regulators that control the expression of many genes, thus connecting DNA replication with other events of the C. crescentus cell cycle. PMID- 22227373 TI - Study of nanoscale structures in hydrated biomaterials using small-angle neutron scattering. AB - Distribution of water in three classes of biomedically relevant and degradable polymers was investigated using small-angle neutron scattering. In semicrystalline polymers, such as poly(lactic acid) and poly(glycolic acid), water was found to diffuse preferentially into the non-crystalline regions. In amorphous polymers, such as poly(d,l-lactic acid) and poly(lactic-co-glycolic acid), the scattering after 7 days of incubation was attributed to water in microvoids that form following the hydrolytic degradation of the polymer. In amorphous copolymers containing hydrophobic segments (desaminotyrosyl-tyrosine ethyl ester) and hydrophilic blocks (poly(ethylene glycol) (PEG)), a sequence of distinct regimes of hydration were observed: homogeneous distribution (~10A length scales) at <13 wt.% PEG (~1 water per EG), clusters of hydrated domains (~50A radius) separated at 24 wt.% PEG (1-2 water per EG), uniformly distributed hydrated domains at 41 wt.% PEG (~4 water per EG) and phase inversion at >50 wt.% PEG (>6 water per EG). Increasing the PEG content increased the number of these domains with only a small decrease in distance between the domains. These discrete domains appeared to coalesce to form submicron droplets at ~60 degrees C, above the melting temperature of crystalline PEG. The significance of such observations on the evolution of micrometer-size channels that form during hydrolytic erosion is discussed. PMID- 22227375 TI - The acute and sub-chronic exposures of goldfish to naphthenic acids induce different host defense responses. AB - Naphthenic acids (NAs) are believed to be the major toxic component in oil sands process-affected water (OSPW) produced by the oil sands mining industry in Northern Alberta, Canada. We recently reported that oral exposure to NAs alters mammalian immune responses, but the effect of OSPW or NAs on the immune mechanisms of aquatic organisms has not been fully elucidated. We analyzed the effects of acute and sub-chronic NAs exposures on goldfish immune responses by measuring the expression of three pro-inflammatory cytokine genes, antimicrobial functions of macrophages, and host defense after challenge with a protozoan pathogen (Trypanosoma carassii). One week after NAs exposure, fish exhibited increased expression of pro-inflammatory cytokines (IFNgamma, IL-1beta1, TNF alpha2) in the gills, kidney and spleen. Primary macrophages from fish exposed to NAs for one week, exhibited increased production of nitric oxide and reactive oxygen intermediates. Goldfish exposed for one week to 20 mg/L NAs were more resistant to infection by T. carassii. In contrast, sub-chronic exposure of goldfish (12 weeks) to NAs resulted in decreased expression of pro-inflammatory cytokines in the gills, kidney and spleen. The sub-chronic exposure to NAs reduced the ability of goldfish to control the T. carassii infection, exemplified by a drastic increase in fish mortality and increased blood parasite loads. This is the first report analyzing the effects of OSPW contaminants on the immune system of aquatic vertebrates. We believe that the bioassays depicted in this work will be valuable tools for analyzing the efficacy of OSPW remediation techniques and assessment of diverse environmental pollutants. PMID- 22227376 TI - Radiation-induced damage in different segments of the rat intestine after external beam irradiation of the liver. AB - INTRODUCTION: The out-of-field effects on the intestine, caused by radiation treatment of a parenchymatous organ, have not previously been studied. METHODS: A single dose of 25Gy was administered percutaneously to the liver of male Wistar rats after a planning CT-scan. Sham-irradiated animals served as controls. At 1, 6, 24, 96h, 1.5 and 3months the duodenum, jejunum, ileum and distal colon were removed, washed and deep-frozen or prepared for paraffin staining. RESULTS: All animals survived the treatment. Epithelial cell damage occurred in all small intestinal segments. However, prolonged denudation of the villi together with destruction of the crypt lining was only observed in the ileum, resulting in deficient regeneration. In the colon, changes were minor. Radiation mucositis with granulocyte (MP0+) infiltration was seen from 1 to 24h in the duodenum and jejunum, when ED1+ macrophages, CD3+ T-lymphocytes, and CD34+ hematopoietic precursor cells were recruited, accompanied by an increase in the chemokines MCP 1, MIP-1alpha, MIP3alpha and Il-8. In the ileum, early granulocyte infiltration was delayed but continuous. Recruitment of macrophages and lymphocytes was deficient and induction of chemokines as of the adhesion molecules PECAM-1, ICAM 1 was lacking. CONCLUSION: Post-irradiation damage to the ileum was delayed and followed by an altered repair process with structural changes of the villi. The observed changes might result from a higher sensitivity to oxidative stress mechanisms with subsequent damage of the regenerative capacity of the crypt villus axis, accompanied by a sustained "inflammatory response" and vascular damage with a lack of regeneratory cell recruitment. PMID- 22227377 TI - Genes encoding hevein-like defense peptides in wheat: distribution, evolution, and role in stress response. AB - Hevein-like plant defense peptides WAMP-1a/b with a unique 10-Cys motif are found in the wheat Triticum kiharae seeds. Three different wamp genomic and cDNA sequences were derived from T. kiharae; no introns were spotted in the protein coding regions of the genes. The deduced Wamp precursor proteins consist of a signal peptide, mature peptide (WAMP) and C-terminal prosequence. Origin of WAMPs from class I/IV chitinases via deletion of the catalytic domain is proposed based on homology between their genes. Genome screening of several cereals and goatgrasses from the genera Triticum and Aegilops was performed. No wamp homologues were identified in Triticum monococcum (A(b)A(b)) or Triticum urartu (A(u)A(u)), diploid species with an A genome. To the contrary, highly homologous wamp genes were discovered in hexaploid Triticum aestivum (A(u)A(u)BBDD) and T. kiharae (A(b)A(b)GGDD), and the putative genome donors Triticum timopheevii (A(b)A(b)GG), Aegilops speltoides (BB), and Aegilops tauschii (DD), providing strong evidence for the ancient origin of these genes and their association with the B, D and G genomes. The role of T. kiharae WAMPs in biotic stress is suggested by their antifungal activity and increased accumulation of wamp transcripts in response to phytopathogen challenge. Differential reaction to fungi was demonstrated: Fusarium oxysporum enhanced expression of wamp genes, whereas Aspergillus niger induced transcription reprogramming and alternative polyadenylation. WAMPs participate in plant response also to abiotic stress. Although no changes were noted at elevated or decreased temperatures, high salt concentrations enhanced wamp expression, the first indication of hevein-type peptide participation in salinity stress. PMID- 22227378 TI - Testing the faux-UTR model for NMD: analysis of Upf1p and Pab1p competition for binding to eRF3/Sup35p. AB - Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that accelerates the degradation of mRNAs containing premature translation termination codons. This quality control pathway depends on the NMD-specific factors, Upf1p, Upf2p/Nmd2p, and Upf3p, as well as the two release factors, eRF1 and eRF3 (respectively designated Sup45p and Sup35p in yeast). NMD activation is also enabled by the absence of the poly(A)-binding protein, Pab1p, downstream of a termination event. Since Sup35p interacts with both Upf1p and Pab1p we considered the possibility that differential binding of the latter factors to Sup35p may be a critical determinant of NMD sensitivity for an mRNA. Here we describe three approaches to assess this hypothesis. First, we tethered fragments or mutant forms of Sup35p downstream of a premature termination codon in a mini-pgk1 nonsense-containing mRNA and showed that the inhibition of NMD by tethered Sup35p does not depend on the domain necessary for the recruitment of Pab1p. Second, we examined the Sup35p interaction properties of Upf1p and Pab1p in vitro and showed that these two proteins bind differentially to Sup35p. Finally, we examined competitive binding between the three proteins and observed that Upf1p inhibits Pab1p binding to Sup35p whereas the interaction between Upf1p and Sup35p is relatively unaffected by Pab1p. These data indicate that the binding of Upf1p and Pab1p to Sup35p may be more complex than anticipated and that NMD activation could involve more than just simple competition between these factors. We conclude that activation of NMD at a premature termination codon is not solely based on the absence of Pab1p and suggest that a specific recruitment step must commit Upf1p to the process and Upf1p-associated mRNAs to NMD. PMID- 22227379 TI - Treatment with dipyridamole improves cardiac function and prevent injury in a rat model of hemorrhage. AB - Hemorrhagic shock is a leading cause of death despite the improvement in emergency services. One reason is that the resuscitation policies are designed to reestablish tissue perfusion, but not to prevent the inflammatory response to shock that cause myocardial dysfunction and injury. Dipyridamole is a platelet inhibitor that promotes anti-inflammatory effects. The present study investigated the therapeutic value of treatment with dipyridamole before resuscitation from hemorrhagic shock on myocardial injury and protection. Male Sprague-Dawley rats were assigned to 3 experimental groups (n=6 per group): 1) hemorrhage, 2) hemorrhage treated with dipyridamole, and 3) sham hemorrhage. Rats were hemorrhaged over 60min to reach a mean arterial blood pressure of 40mmHg. After 60min hemorrhagic shock, rats were treated or not by injection of 1mL of (20MUg/L) dipyridamole intra-arterially. Resuscitation was made in vivo by reinfusion of the shed blood to restore norm tension for 30min. Arterial blood samples were collected for measurements of TNF-alpha. Left ventricular generated pressure and +dP/dtmax was significantly higher in dipyridamole treated rats compared to the untreated group. Myocardial biopsy samples were taken for light and electron microscopy. Dipyridamole decreased the number of inflammatory cells and mitochondrial swollen. Dipyridamole also decreased the plasma levels of TNF alpha. Our results demonstrate that treatment with dipyridamole before in vivo resuscitation of hemorrhagic shock protect the myocardium against post resuscitation myocardial dysfunction by decreasing the inflammatory response to shock. PMID- 22227380 TI - An association between neutrophils and immunoglobulin free light chains in the pathogenesis of chronic obstructive pulmonary disease. AB - RATIONALE: Neutrophils are key players in chronic obstructive pulmonary disease (COPD), and increased numbers of neutrophils are present in sputum and lung tissue of patients with COPD. Interestingly, immunoglobulin free light chains (IgLC) are able to prolong the life of neutrophils; therefore, IgLC may contribute to the chronic state of inflammation. OBJECTIVES: In this study, the relation between IgLC and COPD has been investigated. METHODS: We investigated the presence of IgLC in different murine lung emphysema models. IgLC levels in serum from mice and patients with COPD were examined by Western blot analysis and ELISA, respectively. IgLC levels in lung tissue were determined by immunohistochemistry. Fluorescence-activated cell sorter and immunofluorescent analysis were used to detect binding between IgLC and human neutrophils. Interleukin-8 (CXCL8) release by neutrophils after IgLC incubation was measured by ELISA. The effect of F991, an IgLC antagonist, was examined on the neutrophil influx in murine lungs after 5 days of smoke exposure. MEASUREMENTS AND MAIN RESULTS: Increased levels of IgLC in serum of cigarette smoke-exposed and cigarette smoke extract-treated mice compared with control mice were observed. Patients with COPD showed increased serum IgLC and expression of IgLC in lung tissue compared with healthy volunteers. Interestingly, IgLC bound to neutrophils and activated neutrophils to release CXCL8. F991 inhibited the IgLC binding to neutrophils and reduced the smoke-induced neutrophil influx in murine lungs after smoke exposure. CONCLUSIONS: This study describes for the first time an association between neutrophils and IgLC in the pathophysiology of COPD, which could open new avenues to targeted treatment of this chronic disease. PMID- 22227381 TI - The role of ventilation-induced surfactant dysfunction and atelectasis in causing acute respiratory distress syndrome. AB - This Pulmonary Perspective describes a new pathophysiologic scenario by which the acute respiratory distress syndrome (ARDS) might develop, summarizes the literature on which this new scenario is based, and discusses the resulting implications with respect to patient management. Rather than ARDS occurring as a result of the inflammatory response associated with predisposing risk factors, the proposed scenario theorizes that the initiating problem is atelectasis that develops as a result of a surfactant abnormality that is caused by spontaneous or mechanical ventilation, together with our current approaches to patient positioning and sedation. The proposed pathophysiology implies that ventilation induced lung injury occurs before, and causes, ARDS (rather than developing after the fact and only serving to magnify the existing injury) and that some instances of ARDS are iatrogenic. If the proposed scenario is correct, it also implies that at least some instances of ARDS might be prevented by implementing a number of simple, safe modifications in patient care. PMID- 22227383 TI - Emergency department crowding is associated with 28-day mortality in community acquired pneumonia patients. AB - OBJECT: Although emergency department (ED) crowding has been shown to be associated with delayed antibiotics treatment in community-acquired pneumonia (CAP) patients, association between ED crowding with mortality has not been investigated. We hypothesized emergency department crowding is associated with 28 day mortality in CAP patients. METHODS: A retrospective observational study using prospective database was performed on CAP patients who visited a single, urban, tertiary care hospital ED between April 1, 2008 and September 30, 2009. Main outcomes were 28-day mortality and timeliness of antibiotic therapy (within 2, 4, 6, and 8 h of arrival). ED crowding was measured by Emergency Department Occupancy (EDO) rate. A multivariate logistic regression was performed to determine the association of 28-day mortality with EDO rate after adjusting for factors such as time-to-first-antibiotic-dose (TFAD), pneumonia severity index and laboratory markers. RESULTS: 477 cases were enrolled during the study period. 28-day mortality rate was 4.8%. EDO rate ranged from 37.2% to 162.8%, and median was 97.7% (IQR: 80.2%-116.3%). When categorized into tertiles by EDO rate, high crowding condition (EDO rate >109.3%) was significantly associated with a higher 28-day mortality (adjusted OR = 9.48, 95% CI 1.53-58.90). However, TFAD was not associated with 28-day mortality. ED crowding was not associated with delay of TFAD at various time intervals (2, 4, 6, and 8 h). CONCLUSIONS: ED crowding measured by EDO rate was associated with higher 28-day mortality in CAP patients after adjusting TFAD, pneumonia severity index (PSI), and laboratory markers, although there was no association between ED crowding and TFAD. PMID- 22227382 TI - Platelet activation, P-selectin, and eosinophil beta1-integrin activation in asthma. AB - RATIONALE: Eosinophil beta1-integrin activation correlates inversely with FEV1 and directly with eosinophil-bound P-selectin in subjects with nonsevere allergic asthma. OBJECTIVES: Determine the relationships between beta1-integrin activation and pulmonary function or eosinophil-bound P-selectin in subjects with asthma of varying severity and discern the source of eosinophil-bound P-selectin. METHODS: Blood was assayed by flow cytometry for P-selectin and activated beta1-integrin on eosinophils and platelets. Plasma was analyzed with ELISA for soluble P selectin, platelet factor 4, and thrombospondin-1. MEASUREMENTS AND MAIN RESULTS: Activated beta1-integrin correlated with eosinophil-bound P-selectin among all subjects with asthma even though activated beta1-integrin was higher in subjects with nonsevere asthma than severe asthma. Activated beta1-integrin correlated inversely with FEV1 corrected for FVC only in younger subjects with nonsevere asthma. Paradoxically, platelet surface P-selectin, a platelet activation marker, was low in subjects with severe asthma, whereas plasma platelet factor 4, a second platelet activation marker, was high. Correlations indicated that P selectin-positive platelets complexed to eosinophils are the major source of the eosinophil-bound P-selectin associated with beta1-integrin activation. After whole-lung antigen challenge of subjects with nonsevere asthma, a model of asthma exacerbation known to cause platelet activation, circulating eosinophils bearing P-selectin and activated beta1-integrin disappeared. CONCLUSIONS: The relationship between eosinophil beta1-integrin activation and pulmonary function was replicated only for younger subjects with nonsevere asthma. However, we infer that platelet activation and binding of activated platelets to eosinophils followed by P-selectin-mediated eosinophil beta1-integrin activation occur in both nonsevere and severe asthma with rapid movement of platelet-eosinophil complexes into the lung in more severe disease. PMID- 22227384 TI - Breakthrough invasive mould infections in patients treated with caspofungin. AB - OBJECTIVES: To describe and estimate the rate of breakthrough invasive mould diseases (IMD) in patients receiving caspofungin. METHODS: Retrospective, non interventional study conducted in three University Hospitals. RESULTS: Nineteen breakthrough infections have been identified including 13 aspergillosis, 2 mucormycosis, a fusariosis, a Hormographiella aspergillata infection and 2 possible IMD. Cases were equally distributed between the centres. Fourteen patients had a haematologic malignancy, four were transplant recipients (allogeneic haematopoietic stem cells in three, liver in one) and one had hepatic cirrhosis. Caspofungin has been prescribed as prophylaxis (n = 3), empirical therapy (n = 9) or directed therapy for candidemia (n = 5) or aspergillosis (n = 2). Aspergillus galactomannan was positive in serum or in bronchoalveolar lavage fluid in 10 of the 13 aspergillosis. Median duration of caspofungin treatment before breakthrough IMD was 15 days. Nine patients died within twelve weeks. Rate of breakthrough IMD in onco-haematology patients has been estimated to 7.3% for all mould infections and to 4.2% when restricted to documented aspergillosis. CONCLUSIONS: Our data call for Aspergillus galactomannan monitoring and close clinical and radiological examination in case of persistence or recurrence of infection signs in high-risk patients receiving caspofungin. PMID- 22227385 TI - Modeling and visualization techniques for virtual stenting of aneurysms and stenoses. AB - In this work, we present modeling and visualization techniques for virtual stenting of aneurysms and stenoses. In particular, contributions to support the computer-aided treatment of artery diseases - artery enlargement (aneurysm) and artery contraction (stenosis) - are made. If an intervention takes place, there are two different treatment alternatives for this kind of artery diseases: open surgery and minimally invasive (endovascular) treatment. Computer-assisted optimization of endovascular treatments is the main focus of our work. In addition to stent simulation techniques, we also present a computer-aided simulation of endoluminal catheters to support the therapy-planning phase. The stent simulation is based on a three-dimensional Active Contour Method and is applicable to both non-bifurcated (I-stents) and bifurcated stents (Y-stents). All methods are introduced in detail and are evaluated with phantom datasets as well as with real patient data from the clinical routine. Additionally, the clinical prototype that is based upon these methods is described. PMID- 22227386 TI - DNA sequence context conceals alpha-anomeric lesions. AB - DNA sequence context has long been known to modulate detection and repair of DNA damage. Recent studies using experimental and computational approaches have sought to provide a basis for this observation. We have previously shown that an alpha-anomeric adenosine (alphaA) flanked by cytosines (5'CalphaAC-3') resulted in a kinked DNA duplex with an enlarged minor groove. Comparison of different flanking sequences revealed that a DNA duplex containing a 5'CalphaAG-3' motif exhibits unique substrate properties. However, this substrate was not distinguished by unusual thermodynamic properties. To understand the structural basis of the altered recognition, we have determined the solution structure of a DNA duplex with a 5'CalphaAG-3' core, using an extensive set of restraints including dipolar couplings and backbone torsion angles. The NMR structure exhibits an excellent agreement with the data (total R(X) <5.3%). The alphaA base is intrahelical, in a reverse Watson-Crick orientation, and forms a weak base pair with a thymine of the opposite strand. In comparison to the DNA duplex with a 5'CalphaAC-3' core, we observe a significant reduction of the local perturbation (backbone, stacking, tilt, roll, and twist), resulting in a straighter DNA with narrower minor groove. Overall, these features result in a less perturbed DNA helix and obscure the presence of the lesion compared to the 5'CalphaAC-3' sequence. The improved stacking of the 5'CalphaAG-3' core also affects the energetics of the DNA deformation that is required to form a catalytically competent complex. These traits provide a rationale for the modulation of the recognition by endonuclease IV. PMID- 22227387 TI - Thermodynamic measurements of bilayer insertion of a single transmembrane helix chaperoned by fluorinated surfactants. AB - Accurate determination of the free energy of transfer of a helical segment from an aqueous into a transmembrane (TM) conformation is essential for understanding and predicting the folding and stability of membrane proteins. Until recently, direct thermodynamically sound measurements of free energy of insertion of hydrophobic TM peptides were impossible due to peptide aggregation outside the lipid bilayer. Here, we overcome this problem by using fluorinated surfactants that are capable of preventing aggregation but, unlike detergents, do not themselves interact with the bilayer. We have applied the fluorescence correlation spectroscopy methodology to study surfactant-chaperoned insertion into preformed POPC (palmitoyloleoylphosphatidylcholine) vesicles of the two well studied dye-labeled TM peptides of different lengths: WALP23 and WALP27. Extrapolation of the apparent free-energy values measured in the presence of surfactants to a zero surfactant concentration yielded free-energy values of 9.0+/-0.1 and -10.0+/-0.1 kcal/mol for insertion of WALP23 and WALP27, respectively. Circular dichroism measurements confirmed helical structure of peptides in lipid bilayer, in the presence of surfactants, and in aqueous mixtures of organic solvents. From a combination of thermodynamic and conformational measurements, we conclude that the partitioning of a four-residue L-A-L-A segment in the context of a continuous helical conformation from an aqueous environment into the hydrocarbon core of the membrane has a favorable free energy of 1 kcal/mol. Our measurements, combined with the predictions of two independent experimental hydrophobicity scales, indicate that the per-residue cost of transfer of the helical backbone from water to the hydrocarbon core of the lipid bilayer is unfavorable and is equal to +2.13+/-0.17 kcal/mol. PMID- 22227388 TI - Engineering and structural characterization of a linear polyubiquitin-specific antibody. AB - Polyubiquitination is an essential posttranslational modification that plays critical roles in cellular signaling. PolyUb (polyubiquitin) chains are formed by linking the carboxyl-terminus of one Ub (ubiquitin) subunit to either a lysine residue or the amino-terminus of an adjacent Ub. Linkage through the amino terminus results in linear polyubiquitination that has recently been demonstrated to be a key step in nuclear factor kappaB activation; however, tools to study linear chains have been lacking. We therefore engineered a linear-linkage specific antibody that is functional in Western blot, immunoprecipitation, and immunofluorescence applications. A crystal structure of the linear-linkage specific antibody Fab fragment in complex with linear diubiquitin provides molecular insight into the nature of linear chain specificity. We use the antibody to demonstrate that linear polyUb is up-regulated upon tumor necrosis factor alpha stimulation of cells, consistent with a critical role in nuclear factor kappaB signaling. This antibody provides an essential tool for further investigation of the function of linear chains. PMID- 22227390 TI - Fibrillization propensity for short designed hexapeptides predicted by computer simulation. AB - Assembly of normally soluble proteins into ordered aggregates, known as amyloid fibrils, is a cause or associated symptom of numerous human disorders, including Alzheimer's and the prion diseases. Here, we test the ability of discontinuous molecular dynamics (DMD) simulations based on PRIME20, a new intermediate resolution protein force field, to predict which designed hexapeptide sequences will form fibrils, which will not, and how this depends on temperature and concentration. Simulations were performed on 48-peptide systems containing STVIIE, STVIFE, STVIVE, STAIIE, STVIAE, STVIGE, and STVIEE starting from random coil configurations. By the end of the simulations, STVIIE and STVIFE (which form fibrils in vitro) form fibrils over a range of temperatures, STVIEE (which does not form fibrils in vitro) does not form fibrils, and STVIVE, STAIIE, STVIAE, and STVIGE (which do not form fibrils in vitro) form fibrils at lower temperatures but stop forming fibrils at higher temperatures. At the highest temperatures simulated, the results on the fibrillization propensity of the seven short de novo designed peptides all agree with the experiments of Lopez de la Paz and Serrano. Our results suggest that the fibrillization temperature (temperature above which fibrils cease to form) is a measure of fibril stability and that by rank ordering the fibrillization temperatures of various sequences, PRIME20/DMD simulations could be used to ascertain their relative fibrillization propensities. A phase diagram showing regions in the temperature-concentration plane where fibrils are formed in our simulations is presented. PMID- 22227391 TI - Conformational dynamics of a membrane transport protein probed by H/D exchange and covalent labeling: the glycerol facilitator. AB - Glycerol facilitator (GF) is a tetrameric membrane protein responsible for the selective permeation of glycerol and water. Each of the four GF subunits forms a transmembrane channel. Every subunit consists of six helices that completely span the lipid bilayer, as well as two half-helices (TM7 and TM3). X-ray crystallography has revealed that the selectivity of GF is due to its unique amphipathic channel interior. To explore the structural dynamics of GF, we employ hydrogen/deuterium exchange (HDX) and oxidative labeling with mass spectrometry (MS). HDX-MS reveals that transmembrane helices are generally more protected than extramembrane segments, consistent with data previously obtained for other membrane proteins. Interestingly, TM7 does not follow this trend. Instead, this half-helix undergoes rapid deuteration, indicative of a highly dynamic local structure. The oxidative labeling behavior of most GF residues is consistent with the static crystal structure. However, the side chains of C134 and M237 undergo labeling although they should be inaccessible according to the X-ray structure. In agreement with our HDX-MS data, this observation attests to the fact that TM7 is only marginally stable. We propose that the highly mobile nature of TM7 aids in the efficient diffusion of guest molecules through the channel ("molecular lubrication"). In the absence of such dynamics, host-guest molecular recognition would favor semipermanent binding of molecules inside the channel, thereby impeding transport. The current work highlights the complementary nature of HDX, covalent labeling, and X-ray crystallography for the characterization of membrane proteins. PMID- 22227389 TI - Human tRNA(Lys3)(UUU) is pre-structured by natural modifications for cognate and wobble codon binding through keto-enol tautomerism. AB - Human tRNA(Lys3)(UUU) (htRNA(Lys3)(UUU)) decodes the lysine codons AAA and AAG during translation and also plays a crucial role as the primer for HIV-1 (human immunodeficiency virus type 1) reverse transcription. The posttranscriptional modifications 5-methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U(34)), 2 methylthio-N(6)-threonylcarbamoyladenosine (ms(2)t(6)A(37)), and pseudouridine (Psi(39)) in the tRNA's anticodon domain are critical for ribosomal binding and HIV-1 reverse transcription. To understand the importance of modified nucleoside contributions, we determined the structure and function of this tRNA's anticodon stem and loop (ASL) domain with these modifications at positions 34, 37, and 39, respectively (hASL(Lys3)(UUU)-mcm(5)s(2)U(34);ms(2)t(6)A(37);Psi(39)). Ribosome binding assays in vitro revealed that the hASL(Lys3)(UUU) mcm(5)s(2)U(34);ms(2)t(6)A(37);Psi(39) bound AAA and AAG codons, whereas binding of the unmodified ASL(Lys3)(UUU) was barely detectable. The UV hyperchromicity, the circular dichroism, and the structural analyses indicated that Psi(39) enhanced the thermodynamic stability of the ASL through base stacking while ms(2)t(6)A(37) restrained the anticodon to adopt an open loop conformation that is required for ribosomal binding. The NMR-restrained molecular-dynamics-derived solution structure revealed that the modifications provided an open, ordered loop for codon binding. The crystal structures of the hASL(Lys3)(UUU) mcm(5)s(2)U(34);ms(2)t(6)A(37);Psi(39) bound to the 30S ribosomal subunit with each codon in the A site showed that the modified nucleotides mcm(5)s(2)U(34) and ms(2)t(6)A(37) participate in the stability of the anticodon-codon interaction. Importantly, the mcm(5)s(2)U(34).G(3) wobble base pair is in the Watson-Crick geometry, requiring unusual hydrogen bonding to G in which mcm(5)s(2)U(34) must shift from the keto to the enol form. The results unambiguously demonstrate that modifications pre-structure the anticodon as a key prerequisite for efficient and accurate recognition of cognate and wobble codons. PMID- 22227392 TI - Estimating the size of the active translocation pore of an autotransporter. AB - Autotransporters (ATs) are large virulence factors secreted by Gram-negative bacteria. The passenger domain, carrying the virulence functions, is transported across the bacterial outer membrane in a step that is facilitated by a C-terminal beta-domain. This domain folds into a beta-barrel with a central aqueous pore of ~1 nm inner diameter according to crystal structures. However, these static dimensions are not compatible with the observed secretion of passengers that may contain natural short-spaced disulfide bonds or artificially fused folded elements. Here, we have systematically analyzed the dimensions of the active AT passenger translocator by inserting peptides of different length and structural complexity in the passenger of the AT hemoglobin protease. The peptides were introduced in a short loop protruding from the main structure and flanked by two single cysteines. Our results show that the attained secondary structure may be more critical for secretion than the length of peptide inserted. Furthermore, the data suggest that, during passenger translocation, at least four extended polypeptides or an extended polypeptide and an alpha-helix are accommodated in the translocator, indicating that the diameter of the active translocation pore is up to 1.7 nm. If the beta-domain functions as the translocator, it must be forced into an expanded conformation during passenger translocation. PMID- 22227393 TI - The C-terminal tail of human neuronal calcium sensor 1 regulates the conformational stability of the Ca2+- activated state. AB - Neuronal calcium sensor 1 (NCS-1) and orthologs are expressed in all organisms from yeast to humans. In the latter, NCS-1 plays an important role in neurotransmitter release and interacts with a plethora of binding partners mostly through a large solvent-exposed hydrophobic crevice. The structural basis behind the multispecific binding profile is not understood. To begin to address this, we applied NMR spectroscopy to determine the solution structure of calcium-bound human NCS-1. The structure in solution demonstrates interdomain flexibility and, in the absence of a binding partner, the C-terminal tail residues occupy the hydrophobic crevice as a ligand mimic. A variant with a C-terminal tail deletion shows lack of a defined structure but maintained cooperative unfolding and dramatically reduced global stability. The results suggest that the C-terminal tail is important for regulating the conformational stability of the Ca(2+) activated state. Furthermore, a single amino acid mutation that was recently diagnosed in a patient with autistic spectrum disorder was seen to affect the C terminal tail and binding crevice in NCS-1. PMID- 22227394 TI - An analog of BIX-01294 selectively inhibits a family of histone H3 lysine 9 Jumonji demethylases. AB - BIX-01294 and its analogs were originally identified and subsequently designed as potent inhibitors against histone H3 lysine 9 (H3K9) methyltransferases G9a and G9a-like protein. Here, we show that BIX-01294 and its analog E67 can also inhibit H3K9 Jumonji demethylase KIAA1718 with half-maximal inhibitory concentrations in low micromolar range. Crystallographic analysis of KIAA1718 Jumonji domain in complex with E67 indicated that the benzylated six-membered piperidine ring was disordered and exposed to solvent. Removing the moiety (generating compound E67-2) has no effect on the potency against KIAA1718 but, unexpectedly, lost inhibition against G9a-like protein by a factor of 1500. Furthermore, E67 and E67-2 have no effect on the activity against histone H3 lysine 4 (H3K4) demethylase JARID1C. Thus, our study provides a new avenue for designing and improving the potency and selectivity of inhibitors against H3K9 Jumonji demethylases over H3K9 methyltransferases and H3K4 demethylases. PMID- 22227395 TI - The componential model of reading: predicting first grade reading performance of culturally diverse students from ecological, psychological, and cognitive factors assessed at kindergarten entry. AB - This study, framed by the component model of reading (CMR), examined the relative importance of kindergarten-entry predictors of first grade reading performance. Specifically, elements within the ecological domain included dialect, maternal education, amount of preschool, and home literacy; elements within the psychological domain included teacher-reported academic competence, social skills, and behavior; and elements within the cognitive domain included initial vocabulary, phonological, and morpho-syntactic skills, and alphabetic and word recognition skills. Data were obtained for 224 culturally diverse kindergarteners (58% Black, 34% White, and 8% Hispanic or other; 58% received free or reduced price lunch) from a larger study conducted in seven predominantly high poverty schools (n = 20 classrooms) in a midsized city school district in northern Florida. Results from a hierarchical multiple regression (with variables in the ecological domain entered first, followed by the psychological and cognitive domains) revealed a model that explained roughly 56% of the variance in first grade reading achievement, using fall-of-kindergarten predictors. Letter-word reading and morpho-syntactic skill were the strongest significant predictors. The findings largely support the CMR model as a means to understand individual differences in reading acquisition and, in turn, to support data-based instructional decisions for a wider range of children. PMID- 22227396 TI - Proteome changes in tomato fruits prior to visible symptoms of chilling injury are linked to defensive mechanisms, uncoupling of photosynthetic processes and protein degradation machinery. AB - A comparative proteomic analysis between tomato fruits stored at chilling and non chilling temperatures was carried out just before the appearance of visible symptoms of chilling injury. At this stage of the stress period it was possible to discriminate between proteins involved in symptoms and proteins implicated in response. To investigate the changes in the tomato fruit proteome under this specific stressful condition, two-dimensional differential in-gel electrophoresis coupled with spot identification by mass spectrometry was applied. This proteomic approach allowed the identification of differentially expressed proteins which are involved in two main biological functions: (i) defensive mechanisms represented by small heat shock and late embryogenesis proteins; and (ii) reaction to the uncoupling of photosynthetic processes and the protein degradation machinery. One of the first changes observed in chilled fruits is the down-regulation of ATP synthase, 26S proteasome subunit RPN11 and aspartic proteinase, whereas the first responses in order to deal with the stress are mainly multifunctional proteins involved not only in metabolism but also in stress regulation such as glyceraldehyde phosphate dehydrogenase, 2-oxoglutarate dehydrogenase and invertase. In addition, our data seem to indicate a possible candidate to be used as a protein marker for further studies on cold stress: aldose-1-epimerase, which seems to have an important role in low temperature tolerance. PMID- 22227397 TI - Paraneoplastic encephalitis associated with myasthenia gravis and malignant thymoma. AB - We present a patient with type B2 thymoma (World Health Organization Thymoma Classification) with the complications of anti-muscle acetylcholine receptor antibody-positive myasthenia gravis and anti-voltage-gated potassium channel antibodies associated with paraneoplastic encephalitis. A timing difference between the onset of these neurological disorders and a dissociation of clinical symptoms was observed during the disease. This report alerts clinicians that long term follow-up is needed where patients have a residual thymoma and attention should be paid to other concomitant autoimmune disorders. PMID- 22227398 TI - Special issue on the production of recombinant proteins. PMID- 22227399 TI - Synthetic biology: new strategies for directing design. AB - The advancement of synthetic biology is thanks, in large part, to continuing improvements in DNA synthesis. The expansion of synthetic biology into the realm of metabolic engineering has shifted the focus from simply making novel synthetic biological parts to answering the question of how we employ these biological parts to construct genomes that ultimately give rise to useful phenotypes. Much like protein engineering, the answer to this will be arrived at following the combination of rational design and evolutionary approaches. This review will highlight some of the new DNA synthesis-enabled search methods and discuss the application of such methods to the creation of synthetic gene networks and genomes. PMID- 22227400 TI - How many spots with missing values can be tolerated in quantitative two dimensional gel electrophoresis when applying univariate statistics? AB - Quantitative proteomic comparisons require a sufficient number of samples to reach an acceptable level of significance. But 2D gel electrophoresis commonly results in incomplete data sets due to spots with missing values reducing thereby the number of parallel measurements for individual proteins. Here we investigated how many missing values per spot can be tolerated. The number of spots in common between all gels was found to decrease with the number of parallel gels in a non linear fashion. Increasing numbers of missing values were associated with a moderate increase in the quantitative variation of spot volumes. Based on the missing value pattern in 20 gels we performed an analysis of the multiple testing power for the hypothetical scenario of a comparative 2DE study with six or twelve parallel gels. The calculation considered the statistical power of the individual spot as well as the number of spots included in the analysis. The power increased with inclusion of spots with higher number of missing values and showed an optimum at a specific minimum number of spot replicates. The results suggest that proteins with missing values can be included in a univariate analysis as long as a sufficient number of parallel gels are made. PMID- 22227401 TI - Mass spectrometry for nutritional peptidomics: How to analyze food bioactives and their health effects. AB - We describe nutritional peptidomics for discovery and validation of bioactive food peptide and their health effects. Understanding nature and bioactivity of nutritional peptides means comprehending an important level of environmental regulation of the human genome, because diet is the environmental factor with the most profound life-long influence on health. We approach the theme from three angles, namely the analysis, the discovery and the biology perspective. Food peptides derive from parent food proteins via in vitro hydrolysis (processing) or in vivo digestion by various unspecific and specific proteases, as opposed to the tryptic peptides typically generated in biomarker proteomics. A food bioactive peptide may be rare or unique in terms of sequence and modification, and many food genomes are less well annotated than e.g. the human genome. Bioactive peptides can be discovered either empirically or by prediction: we explain both the classical hydrolysis strategy and the bioinformatics-driven reversed genome engineering. In order to exert bioactivity, food peptides must be either ingested and then reach the intestine in their intact form or be liberated in situ from their parent proteins to act locally, that is in the gut, or even systemically, i.e. through the blood stream. This article is part of a Special Section entitled: Understanding genome regulation and genetic diversity by mass spectrometry. PMID- 22227402 TI - Comparison of cryoprecipitate with fibrinogen concentrate for acquired hypofibrinogenaemia. AB - BACKGROUND: The benefits of fibrinogen concentrate in hypofibrinogenaemia have been established in congenital and has been used in acquired disorders. Most European countries have already changed their practice, using fibrinogen concentrate. METHODS: We compared the use of fibrinogen concentrate in acquired hypofibrinogenaemia to cryoprecipitate, which continues to be the standard of care in the UK. We undertook a retrospective analysis of fibrinogen increment in patients treated for acquired hypofibrinogenaemia. RESULTS: Sixty four transfusion episodes receiving cryoprecipitate and 36 episodes receiving fibrinogen concentrate were compared. The median increment following 10 donor pools (two bags) of cryoprecipitate was 0.26 g/l, compared to 0.44 g/l following 2g of fibrinogen concentrate. CONCLUSION: With its superior safety profile from infectious diseases, this provides further evidence to support the use of fibrinogen concentrate. PMID- 22227403 TI - A graphical systems model and tissue-specific functional gene sets to aid transcriptomic analysis of chemical impacts on the female teleost reproductive axis. AB - Oligonucleotide microarrays and other 'omics' approaches are powerful tools for unsupervised analysis of chemical impacts on biological systems. However, the lack of well annotated biological pathways for many aquatic organisms, including fish, and the limited power of microarray-based analyses to detect low level differential expression of individual genes can hinder the ability to infer and understand chemical effects based on transcriptomic data. Here we report on the supervised assembly of a series of tissue-specific functional gene sets intended to aid transcriptomic analysis of chemical impacts on the female teleost reproductive axis. Gene sets were defined based on an updated graphical systems model of the teleost brain-pituitary-gonadal-hepatic axis. Features depicted in the model were organized into gene sets and mapped to specific probes on three zebrafish (Danio rerio) and two fathead minnow (Pimephales promelas) microarray platforms. Coverage of target genes on the microarrays ranged from 48% for the fathead minnow arrays to 88% for the most current zebrafish platform. Additionally, extended fathead minnow gene sets, incorporating first degree neighbors identified from a Spearman correlation network derived from a large compendium of fathead minnow microarray data, were constructed. Overall, only 14% of the 78 genes queried were connected in the network. Among those, over half had less than five neighbors, while two genes, cyclin b1 and zona pellucida glycoprotein 3, had over 100 first degree neighbors, and were neighbors to one another. Gene set enrichment analyses were conducted using microarray data from a zebrafish hypoxia experiment and fathead minnow time-course experiments conducted with three different endocrine-active chemicals. Results of these analyses demonstrate the utility of the approach for supporting biological inference from ecotoxicogenomic data and comparisons across multiple toxicogenomic experiments. The graphical model, gene mapping, and gene sets described are now available to the scientific community as tools to support ecotoxicogenomic research. PMID- 22227404 TI - Cyclophosphamide and etoposide canine studies demonstrate the cross-species potential of the flow cytometric peripheral blood micronucleated reticulocyte endpoint. AB - Erythrocyte-based micronucleus tests have traditionally been performed with bone marrow specimens, since, in most preclinical animal models, the spleen can efficiently remove aberrant erythrocytes from the circulation. Even so, evidence is mounting that by examining tens of thousands of young (CD71-positive) circulating reticulocytes for the presence of micronuclei via flow cytometry, a sensitive assay of cytogenetic damage is realized. The work described herein was designed to test this hypothesis further, using an important preclinical toxicology model, the beagle dog. In these experiments, purebred male beagles were treated for five consecutive days with cyclophosphamide (0, 6.25, 12.5 or 25mg/m(2)/day) or for two consecutive days with etoposide (0, 1.56, 6.25 or 12.5mg/m(2)/day). Before treatment, and on each day of administration, blood specimens were collected and processed for flow cytometric scoring of micronucleated reticulocyte (MN-RET) frequency. Twenty-four hours after the final administration, blood MN-RET frequencies were determined via flow cytometry, and frequencies of micronucleated bone marrow polychromatic erythrocytes (MN-PCE) were determined using acridine orange and May-Grunwald Giemsa staining. In the case of cyclophosphamide, elevated blood MN-RET frequencies were observed 2 days after treatment began, and the maximal frequency was achieved 1 day later. Similarly, etoposide-induced blood MN-RET were not evident 1 day after administration began, but a robust effect was apparent 2 days after treatments were initiated. Twenty-four hours after the final administrations, dose-related micronucleus responses were evident for both agents and in both blood and bone marrow compartments. Good overall agreement between MN-RET and MN-PCE frequencies was evidenced by high Spearman's correlation coefficients-0.89 for blood flow cytometry versus bone marrow acridine orange staining and 0.83 for blood flow cytometry versus bone marrow May-Grunwald Giemsa staining. Taken together, these results provide further support for the cross-species utility of flow cytometry based blood MN-RET measurements. PMID- 22227405 TI - Prevalidation study of the Syrian hamster embryo (SHE) cell transformation assay at pH 7.0 for assessment of carcinogenic potential of chemicals. AB - The European Centre for the Validation of Alternative Methods (ECVAM) has organised an interlaboratory prevalidation study on the Syrian hamster embryo (SHE) cell transformation assay (CTA) at pH 7.0 for the detection of rodent carcinogens. The SHE CTA at pH 7.0 has been evaluated for its within-laboratory reproducibility, transferability and between-laboratory reproducibility. Four laboratories using the same basic protocol with minor modifications participated in this study and tested a series of six coded-chemicals: four rodent carcinogens (benzo(a)pyrene, 3-methylcholanthrene, 2,4-diaminotoluene and o-toluidine HCl) and two non-carcinogens (anthracene and phthalic anhydride). All the laboratories found the expected results with coded chemicals except for phthalic anhydride which resulted in a different call in only one laboratory. Based on the outcome of this study, it can be concluded that a standardised protocol is available that should be the basis for future use. This protocol and the assay system itself are transferable between laboratories and the SHE CTA at pH 7.0 is reproducible within- and between-laboratories. PMID- 22227406 TI - TOR signaling is involved in PTTH-stimulated ecdysteroidogenesis by prothoracic glands in the silkworm, Bombyx mori. AB - The prothoracicotropic hormone (PTTH) is a stimulator of ecdysteroidogenesis in prothoracic gland of larval insects. Our recent studies showed that phosphoinositide 3-kinase (PI3K)/Akt signaling was involved in PTTH-stimulated ecdysteroidogenesis by Bombyx mori prothoracic glands. In the present study, downstream signaling of PI3K/Akt was further investigated. Results showed that PTTH rapidly enhanced the phosphorylation of translational repressor 4E-binding protein (4E-BP) and p70 ribosomal protein S6 kinase (S6K), two known downstream signaling targets of the target of rapamycin complex 1 (TORC1). PTTH stimulated 4E-BP phosphorylation in time- and dose-dependent manners. Injection of PTTH into day-6 last instar larvae greatly increased 4E-BP phosphorylation, verifying the in vitro effect. PTTH-stimulated 4E-BP phosphorylation was blocked by both LY294002 and wortmannin, indicating the involvement of PI3K. Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitors (PD 98059 and U0126), did not inhibit PTTH-stimulated 4E-BP phosphorylation, implying that ERK signaling is not related to PTTH-stimulated 4E BP phosphorylation. The phosphorylation of S6K was also stimulated by PTTH both in vitro and in vivo. PI3K signaling appears to be involved in PTTH-stimulated phosphorylation of S6K. Rapamycin, a specific inhibitor of mammalian TOR signaling attenuated PTTH-stimulated phosphorylation of 4E-BP and S6K of the glands, and greatly inhibited PTTH-stimulated ecdysteroidogenesis. Examination of gene expression levels of 4E-BP and S6K showed that PTTH inhibited mRNA levels of both 4E-BP and S6K, indicating that PTTH may exert its action at both the transcriptional and phosphorylation levels. These results suggest that PTTH/PI3K/TOR/4E-BP (S6K) signaling is involved in PTTH-stimulated ecdysteroidogenesis by prothoracic glands in B. mori. PMID- 22227407 TI - Improvement of psoriasis during exenatide treatment in a patient with diabetes. AB - CONTEXT AND AIM: Psoriasis is an immune-mediated skin disorder frequently associated with obesity and type 2 diabetes (T2D). This report is of a clinically significant improvement in psoriasis lesions in a patient with T2D during treatment with a GLP-1 receptor agonist (exenatide). OBSERVATION: A 61-year-old male patient (BMI: 25.5 kg/m(2)) with T2D treated with metformin and sulphonylureas had also complained, since 1980, of extensive psoriasis that required multiple steroid-based treatments [Psoriasis Area and Sensitivity Index (PASI) score: 11]. In September 2008, his diabetes treatment was intensified with exenatide (Byetta((r))) to improve poor glycaemic control. The patient, as expected, lost weight and reduced HbA(1c) levels from 65 mmol/mol to 56 mmol/mol. However, after just 1 month of treatment with exenatide, the patient also reported a dramatic improvement in psoriatic plaques that was confirmed at the 1 year follow-up (PASI: estimated at 3-4). Withdrawal of exenatide was associated with weight gain, deterioration of glycaemic control and deterioration of psoriasis (PASI:>10). After reinstating exenatide treatment, the patient again reported a prompt improvement in psoriasis (PASI: 3.1). CONCLUSION: There was a major and rapid improvement in psoriasis in our patient with T2D following treatment with exenatide. A possible mechanism might be through direct modulation of the immune system by GLP-1 receptor agonists. PMID- 22227408 TI - Hyaluronic acid influence on platelet-induced airway smooth muscle cell proliferation. AB - Hyaluronic acid (HA) is one of the main components of the extracellular matrix (ECM) and is expressed throughout the body including the lung and mostly in areas surrounding proliferating and migrating cells. Furthermore, platelets have been implicated as important players in the airway remodelling process, e.g. due to their ability to induce airway smooth muscle cell (ASMC) proliferation. The aim of the present study was to investigate the role of HA, the HA-binding surface receptor CD44 and focal adhesion kinase (FAK) in platelet-induced ASMC proliferation. Proliferation of ASMC was measured using the MTS-assay, and we found that the CD44 blocking antibody and the HA synthase inhibitor 4 Methylumbelliferone (4-MU) significantly inhibited platelet-induced ASMC proliferation. The interaction between ASMC and platelets was studied by fluorescent staining of F-actin. In addition, the ability of ASMC to synthesise HA was investigated by fluorescent staining using biotinylated HA-binding protein and a streptavidin conjugate. We observed that ASMC produced HA and that a CD44 blocking antibody and 4-MU significantly inhibited platelet binding to the area surrounding the ASMC. Furthermore, the FAK-inhibitor PF 573228 inhibited platelet induced ASMC proliferation. Co-culture of ASMC and platelets also resulted in increased phosphorylation of FAK as detected by Western blot analysis. In addition, 4-MU significantly inhibited the increased FAK-phosphorylation. In conclusion, our findings demonstrate that ECM has the ability to influence platelet-induced ASMC proliferation. Specifically, we propose that HA produced by ASMC is recognised by platelet CD44. The platelet/HA interaction is followed by FAK activation and increased proliferation of co-cultured ASMC. We also suggest that the mitogenic effect of platelets represents a potential important and novel mechanism that may contribute to airway remodelling. PMID- 22227410 TI - Comment to: "Spontaneous transformation of adult mesenchymal stem cells from cynomolgus macaques in vitro" by Z. Ren et al. Exp. Cell Res. 317 (2011) 2950 2957: spontaneous transformation of mesenchymal stem cells in culture: facts or fiction? AB - There is at present a controversy in the literature whether MSCs are susceptible to spontaneous in vitro transformation or not. Several groups have reported spontaneous transformation of MSCs from various species. However, some of these reports were not true transformations and later proven to be due to cross contaminating cancer cells. To date there is no solid evidence that MSCs can undergo spontaneous transformation in culture. Only two groups used DNA fingerprinting to authenticate their transformed cells, and both groups later showed cross-contamination of cancer cells in their cultures. In this commentary, we address the paper "Spontaneous transformation of adult mesenchymal stem cells from cynomolgus macaques in vitro" by Z. Ren et al. Exp. Cell Res. 317 (2011) 2950-2957. In this article the authors characterize the transformed mesenchymal cells (TMCs) and claim to have verified their origin. We question the authentication of the TMCs made by the authors and we also believe it is in the interest of the scientific community, that a highly controversial finding, such as spontaneous transformation of MSCs, should be properly verified by stringent methods, preferably DNA fingerprinting, in order to validate if an actual transformation event has occurred. PMID- 22227409 TI - Abrogation of Gli3 expression suppresses the growth of colon cancer cells via activation of p53. AB - p53, the major human tumor suppressor, appears to be related to sonic hedgehog (Shh)-Gli-mediated tumorigenesis. However, the role of p53 in tumor progression by the Shh-Gli signaling pathway is poorly understood. Herein we investigated the critical regulation of Gli3-p53 in tumorigenesis of colon cancer cells and the molecular mechanisms underlying these effects. RT-PCR analysis indicated that the mRNA level of Shh and Gli3 in colon tumor tissues was significantly higher than corresponding normal tissues (P<0.001). The inhibition of Gli3 by treatment with Gli3 siRNA resulted in a clear decrease in cell proliferation and enhanced the level of expression of p53 proteins compared to treatment with control siRNA. The half-life of p53 was dramatically increased by treatment with Gli3 siRNA. In addition, treatment with MG132 blocked MDM2-mediated p53 ubiquitination and degradation, and led to accumulation of p53 in Gli3 siRNA-overexpressing cells. Importantly, ectopic expression of p53 siRNA reduced the ability of Gli3 siRNA to suppress proliferation of those cells compared with the cells treated with Gli3 siRNA alone. Moreover, Gli3 siRNA sensitized colon cancer cells to treatment with anti-cancer agents (5-FU and bevacizumab). Taken together, our studies demonstrate that loss of Gli3 signaling leads to disruption of the MDM2-p53 interaction and strongly potentiate p53-dependent cell growth inhibition in colon cancer cells, indicating a basis for the rational use of Gli3 antagonists as a novel treatment option for colon cancer. PMID- 22227411 TI - Flagellin/TLR5 responses induce mucus hypersecretion by activating EGFR via an epithelial cell signaling cascades. AB - Mucus hypersecretion is an important manifestation in patients with chronic inflammatory airway diseases. Excessive production of mucin leads to airway mucus obstruction and contributes to morbidity and mortality in these diseases. The molecular mechanisms underlying mucin overproduction, however, still remain largely unknown. Here, we report that the bacterium Pseudomonas aeruginosa (P. aeruginosa), an important human respiratory pathogen, induced MUC5AC mucin expression via an epithelial cell signaling cascade in human airway epithelial cells. The flagellin purified from P. aeruginosa up-regulated MUC5AC expression by activating its receptor Toll-like receptor 5 (TLR5) in 16HBE cells. This effect was inhibited by NADPH oxidase inhibitor (DPI), small interfering RNA of dual oxidase 2 (Duox2) and reactive oxygen species (ROS) scavengers (nPG and DMSO). Flagellin induced TGF-alpha release, and stimulated phosphorylated epidermal growth factor receptor (EGFR) and MUC5AC overproduction. These effects were prevented by EGFR and TGF-alpha neutralizing antibodies, metalloprotease inhibitors (GM6001 and TNF-alpha protease inhibitor-1) and specific knockdown of TNF-alpha-converting enzyme (TACE) with TACE siRNA. These findings may bring new insights into the molecular pathogenesis of P. aeruginosa infections and lead to novel therapeutic intervention for mucin overproduction in patients with P. aeruginosa infections. PMID- 22227413 TI - The use of rodent skilled reaching as a translational model for investigating brain damage and disease. AB - Neurological diseases, including Parkinson's disease, Huntington's disease, and brain damage caused by stroke, cause severe motor impairments. Deficits in hand use are one of the most debilitating motor symptoms and include impairments in body posture, forelimb movements, and finger shaping for manipulating objects. Hand movements can be formally studied using reaching tasks, including the skilled reaching task, or reach-to-eat task. For skilled reaching, a subject reaches for a small food item, grasps it with the fingers, and places it in the mouth for eating. The human movement and its associated deficits can be modeled by experimental lesions to the same systems in rodents which in turn provide an avenue for investigating treatments of human impairments. Skilled reaching movements are scored using three methods: (1) end point measures of attempts and success, (2) biometric measures, and (3) movement element rating scales derived from formal descriptions of movement. The striking similarities between human and rodent reaching movements allow the analysis of the reach-to-eat movement to serve as a powerful tool to generalize preclinical research to clinical conditions. PMID- 22227414 TI - Localization of Dirac-like excitations in graphene in the presence of smooth inhomogeneous magnetic fields. AB - The present paper discusses magnetic confinement of the Dirac excitations in graphene in the presence of inhomogeneous magnetic fields. In the first case a magnetic field directed along the z axis whose magnitude is proportional to 1/r is chosen. In the next case we choose a more realistic magnetic field which does not blow up at the origin and gradually fades away from the origin. The magnetic fields chosen do not have any finite/infinite discontinuity for finite values of the radial coordinate. The novelty of the two magnetic fields is related to the equations which are used to find the excited spectra of the excitations. It turns out that the bound state solutions of the two-dimensional hydrogen atom problem are related to the spectra of graphene excitations in the presence of the 1/r (inverse-radial) magnetic field. For the other magnetic field profile one can use the knowledge of the bound state spectrum of a two-dimensional cutoff Coulomb potential to dictate the excitation spectra of graphene. The spectrum of the graphene excitations in the presence of the inverse-radial magnetic field can be exactly solved while the other case cannot be. In the later case we give the localized solutions of the zero-energy states in graphene. PMID- 22227412 TI - Genetic diversity of the human pathogen Vibrio vulnificus: a new phylogroup. AB - The biotype 3 group of the human pathogen Vibrio vulnificus emerged in Israel probably as a result of genome hybridization of two bacterial populations. We performed a genomic and phylogenetic study of V. vulnificus strains isolated from the environmental niche from which this group emerged - fish aquaculture in Israel. The genetic relationships and evolutionary aspects of 188 environmental and clinical isolates of the bacterium were studied by genomic typing. Genetic relations were determined based on variation at 12 variable number tandem repeat (VNTR, also termed SSR) loci. Analysis revealed a new cluster, in addition to the main groups of biotype 1& 2 and biotype 3. Similar grouping results were obtained with three different statistical approaches. Isolates forming this new cluster presented unclear biochemical profile nevertheless were not identified as biotype 1 or biotype 3. Further examination of representative strains by multilocus sequence typing (MLST) of 10 housekeeping genes and 5 conserved hypothetical genes supported the identification of this as yet undiscovered phylogroup (phenotypically diverse), termed clade A herein. This new clonal subgroup includes environmental as well as clinical isolates. The results highlight the fish aquaculture environment, and possibly man-made ecological niches as a whole, as a source for the emergence of new pathogenic strains. PMID- 22227415 TI - Increased prevalence of torque teno viruses in porcine respiratory disease complex affected pigs. AB - The role of swine torque teno sus viruses (TTSuVs) as co-factors in disease syndromes involving porcine circovirus strain 2 (PCV2) and porcine reproductive and respiratory disease syndrome virus (PRRSV) has been a debatable subject. In this study, the prevalence of TTSuVs in Iowa, the leading pork producing state in the U.S., was estimated by a duplex PCR. The PCR is capable of simultaneously detecting both teno sus viruses 1 and 2 (TTSuV1 and 2). Based on an analysis of 300 random samples representing six major geographical regions of the state, the overall prevalence rates for TTSuV1 and 2 were 47.34% and 24.67% respectively while the combined prevalence rate was 52.33%. The epidemiological association of TTSuV1 and 2 with the common etiological agents of the porcine respiratory disease complex (PRDC) namely porcine PRRSV, PCV2, Mycoplasma hyopneumoniae and swine influenza virus (SIV) was estimated in lung tissue derived from 45 pigs showing clinical signs of PRDC. Notably, 86.67% of the PRDC-suspect samples were positive for TTSuV1 in comparison to the baseline population prevalence rate of 47.34%. However, the prevalence of TTSuV2 (26.67%) was not significantly different. TTSuV1 was detected in 80.00%, 81.81%, 75.00% and 77.78% of the PRRSV, SIV, M. hyopneumoniae and PCV2 positive PRDC-suspect samples respectively. Our results indicate that TTSuV1 is strongly associated with clinical PRDC and support the hypothesis that TTSuVs might function as co-factors in PRDC. Further studies to define their possible role in the pathogenesis of swine respiratory diseases are warranted. PMID- 22227416 TI - Systematic mutation analysis of two-component signal transduction systems reveals EsrA-EsrB and PhoP-PhoQ as the major virulence regulators in Edwardsiella tarda. AB - Edwardsiella tarda is a Gram-negative broad-host-range pathogen that causes hemorrhagic septicemia in many commercially important fish species. Its ability to adapt to and thrive in diverse environments outside and inside of its hosts prompts us to investigate the roles of the previously identified 33 putative two component signal transduction systems (TCSs) in E. tarda. In this work, we successfully constructed deletion mutations in each of the response regulator genes, suggesting that none of the TCSs are essential for cell viability in E. tarda. The mutants were further examined for roles in biofilm formation, antibiotic resistance, stress response, expression and secretion of proteins involved in either the type III secretion system (T3SS) or type VI secretion system (T6SS), as well as virulence. Through these assays, we identified four regulators of biofilm development, two regulators of antibiotic resistance, and four regulators involved in stress responses. We found that two regulators, EsrB and PhoP, are essential for the pathogenicity of E. tarda and further demonstrated that these two regulators have codependent and independent contributions to E. tarda virulence. Mutation of EsrB resulted in the complete loss of both the T3SS and T6SS proteins, while PhoP partially regulated the expression of T3SS and T6SS genes through EsrB, and was essential for resistance to antimicrobial peptides. This work suggested that these two response regulators are involved in the regulation of the complex virulence network of this bacterium and merit as candidate genes for live attenuated vaccine construction. PMID- 22227417 TI - Airway epithelial cells from asthmatic children differentially express proremodeling factors. AB - BACKGROUND: The airway epithelium can express factors that drive subepithelial airway remodeling. TGF-beta2, vascular epithelial growth factor (VEGF), a disintegrin and metalloprotease 33 (ADAM33), and periostin are hypothesized to be involved in subepithelial remodeling and are overexpressed in adult asthmatic airways. Epidemiologic data suggest that lung function deficits in asthmatic patients are acquired in childhood. OBJECTIVES: We sought to determine whether airway epithelial cells (AECs) from asthmatic children differentially express TGF beta2, VEGF, ADAM33, or periostin compared with cells from atopic nonasthmatic and healthy children intrinsically or in response to IL-4/IL-13 stimulation. METHODS: Bronchial and nasal epithelial cells were obtained from brushings from well-characterized asthmatic (n = 16), atopic nonasthmatic (n = 9), and healthy (n = 15) children after achievement of anesthesia for elective procedures. After differentiation at an air-liquid interface (ALI) for 3 weeks, conditioned media were sampled and RNA was extracted from unstimulated and IL-4/IL-13-stimulated cultures. TGF-beta2 and VEGF levels were measured with ELISA. ADAM33 and periostin expression was assessed by using real-time PCR. RESULTS: TGF-beta2 and VEGF production was significantly greater in bronchial and nasal ALI cultures from asthmatic children than in cultures from atopic nonasthmatic and healthy children. TGF-beta2 levels increased significantly in asthmatic cultures after IL 4/IL-13 stimulation. Within-subject correlation between nasal and bronchial ALI production of TGF-beta2 (r = 0.64, P = .001) and VEGF (r = 0.73, P < .001) was good. Periostin expression was 3.7-fold higher in bronchial cells (P < .001) and 3.9-fold higher in nasal cells (P < .004) from asthmatic children than in cells from atopic nonasthmatic or healthy children. ADAM33 was not differentially expressed by AECs from asthmatic patients compared with that from cells from atopic nonasthmatic or healthy children. CONCLUSION: AECs from asthmatic children differentially express TGF-beta2, VEGF, and periostin compared with cells from atopic nonasthmatic and healthy children. Nasal epithelial cells might be a suitable surrogate for bronchial cells that could facilitate investigation of the airway epithelium in future longitudinal pediatric studies. PMID- 22227419 TI - Regional anesthesia considerations for awake endotracheal intubation and prevention and management of dental injuries. PMID- 22227418 TI - The airway epithelium nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome is activated by urban particulate matter. AB - BACKGROUND: The airway epithelium is the first line of defense against inhaled insults and therefore must be capable of coordinating appropriate inflammatory and immune responses. OBJECTIVE: We sought to test the hypothesis that the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome, an intracellular danger-sensing complex, plays a critical role in airway epithelium-mediated immune responses to urban particulate matter (PM) exposure. METHODS: In this study we (1) identified NLRP3 and caspase-1 expression in human airway epithelium bronchus and primary cells, (2) characterized NLRP3 inflammasome-mediated IL-1beta production from human airway epithelium in response to PM, and (3) performed in vivo PM exposure experiments with wild-type and Nlrp3(-/-) mice. RESULTS: Our results demonstrate that human airway epithelium contains a functional NLRP3 inflammasome that responds to PM exposure with caspase-1 cleavage and production of IL-1beta. Exposure of Nlrp3(-/-) and wild-type mice to PM in vivo demonstrates NLRP3-dependent production of IL-1beta in the lung, airway neutrophilia, and increases in CD11c(+hi)/MHC class II(+hi) cell numbers in intrathoracic lymph nodes. CONCLUSION: Our study is the first to characterize airway epithelial NLRP3 inflammasome-mediated immune responses to PM exposure, which might have implications in patients with asthma and other lung diseases. PMID- 22227420 TI - Focused local anesthesia and analgesia for head and neck surgery. AB - Facility in the use of head and neck regional blocks will provide excellent perioperative analgesia and patient satisfaction. The scope of ambulatory surgical care for head and neck surgery will undoubtedly increase as expertize in these blocks expand in the face of strict criteria for patient selection. Supplemental sedation will be more precise with the intended result of less hangover and nausea and vomiting. PMID- 22227421 TI - Regional anesthesia procedures for shoulder and upper arm surgery upper extremity update--2005 to present. AB - This review of the literature since 2005 assesses developments of RA techniques commonly used for shoulder surgery, and their effectiveness for postoperative analgesia. Advantages of regional techniques include site-specific anesthesia and decreased postoperative opioid use. For shoulder surgeries, the ISB provides effective analgesia with minimal complications, whereas the impacts of IA single injections remain unclear. When combined with GA, ISB can be used in lower volumes and reducing the complications for shoulder and proximal upper extremity. USG ISB and SCB are both effective and safe for shoulder surgery with a low incidence of complications, especially PONS.53 When compared with intravenous patient-controlled opioid analgesia, a perineural LA infusion using a disposable pump with patient-controlled LA bolus function has led to better pain relief and functional recovery while decreasing the need for rescue analgesics and the number of adverse events after ambulatory orthopedic surgery. The most remarkable advance in RA in the past 5 years is the increased usage of USG. Although there are no large-scale prospective studies to show the safety, efficacy, and success and complication rates for USG blocks, USG RA theoretically could have less risk for neurologic symptoms, except for those induced by LA (less likely perineurally, much more likely intraneurally). The next "quantum leap" lies in reducing LA concentrations and augmenting anesthetic-analgesic effects with perineural additives (including clonidine, buprenorphine, and likely low-dose dexamethasone). Since 2005, perineural catheters have been an analgesic option that offers improved pain relief among other benefits, and are now being used at home. It is clear that patients benefit greatly from a single injection and continuous nerve block for postoperative pain management,but the financial and logistical aspects need to be resolved, not to mention the phrenic hemiparesis coin toss. Whether combined perineural analgesic adjuvants prolong low concentration LA nerve blocks sufficiently to render brachial plexus catheters as unnecessary would certainly represent another quantum leap. PMID- 22227422 TI - Outpatient regional anesthesia for upper extremity surgery update (2005 to present) distal to shoulder. AB - Multiple different approaches to the brachial plexus are available for the regional anesthesiologist to provide successful anesthesia and analgesia for ambulatory surgery of the upper extremity. Although supraclavicular and infraclavicular blocks are faster to perform than axillary blocks, the operator needs to keep in mind that blocks performed around the clavicle carry the risk for specific side effects and complications, no matter whether ultrasound or nerve stimulation is the chosen modality for neurolocation. Owing to the ambulatory nature of the planned surgical intervention, even significant side effects may not become clinically symptomatic until the patient is discharged from the facility. For example, due to pneumothorax risks, axillary or mid humeral blocks remain the most logical approaches for ambulatory surgical procedures at and below the elbow, while reserving infra-clavicularor supraclavicular approaches for surgery from the proximal humerus to above the elbow. Smaller interventions such as carpal tunnel release or trigger finger release can be performed under elbow, wrist, or digital blocks. The regional anesthesiologist should strive to develop a tailored plan for each individual case to provide the most effective and safest nerve block technique for their patients. PMID- 22227423 TI - Paravertebral blocks. AB - PVB remains an underused block. It is easy to perform reliable and effective blocks for a wide variety of applications both for acute or chronic pain. As evidence continues to be published showing the advantages of PVB versus traditional methods of pain control, it is hoped that PVB will become part of the standard repertoire of blocks used in teaching hospitals and in private practice. PMID- 22227424 TI - Trunk blocks 101: transversus abdominis plane, ilioinguinal-iliohypogastric, and rectus sheath blocks. PMID- 22227425 TI - Intrathecal chloroprocaine--not yet "safe" by US FDA parameters. PMID- 22227426 TI - Management of bladder volumes when using neuraxial anesthesia. AB - The major principles of management of bladder function during outpatient neuraxial blockade include choice of short-acting local anesthetics, avoidance of adding epinephrine, and reasonable fluid administration (750 to 1000 mL) to avoid overdistention of the bladder. Data suggest that low-risk patients are at no greater risk of retention than after general anesthesia, and may be discharged home with similar instructions regarding return if unable to void. High-risk patients may require closer monitoring with a BUS, and catheter drainage if volumes exceed 600 mL. PMID- 22227427 TI - Toward outpatient arthroplasty: accelerating discharge with ambulatory continuous peripheral nerve blocks. PMID- 22227428 TI - Forecast for perineural analgesia procedures for ambulatory surgery of the knee, foot, and ankle: applying patient-centered paradigm shifts. AB - Although much of the current clinical research is directed toward practitioner centered refinement of RA techniques and technology, it is important to consider pharmacologic advances in perineural analgesia as the next major patient-centered advancement of our specialty. With all due respect to excellent bench science work with novel drugs and toxins that may not gain approval of the Food and Drug Administration for many years, it is useful to know that four Food and Drug Administration-approved drugs are commercially available for potentially ground breaking off-label use, pending ongoing research. The extent to which estimated clinical concentrations of clonidine, buprenorphine, and dexamethasone, seem to not influence A-fiber conduction holds significant progress for lower extremity perineural analgesia when weight bearing may be desired, if not at least reducing the risk of falls after these surgeries using typical local anesthetic nerve blocks. Research is also needed to determine the extent to which these four drugs may reduce the needed local anesthetic concentration to achieve a surgical nerve block (on bolus injection). Ongoing research in this direction seems to represent the next major advancement in the subspecialty, being distinguished from refinement research involving strictly techniques and technology. PMID- 22227430 TI - Preface--Updates in head-to-toe applications of regional anesthesia for ambulatory surgery. PMID- 22227431 TI - MNK1 expression increases during cellular senescence and modulates the subcellular localization of hnRNP A1. AB - Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is an RNA-binding protein that modulates splice site usage, polyadenylation, and cleavage efficiency. This protein has also been implicated in mRNA stability and transport from the nucleus. We have previously demonstrated that hnRNP A1 had diminished protein levels and showed cytoplasmic accumulation in senescent human diploid fibroblasts. Furthermore, we have shown that inhibition of p38 MAPK, a key regulator of cellular senescence, elevated hnRNP A1 protein levels and inhibited hnRNP A1 cytoplasmic localization. In this study, we have explored the possible involvement of MNK1, one of the downstream effector of p38 MAPK, in the regulation of hnRNP A1. We have demonstrated that pharmacological inhibition of MNK1 by CGP 57380 decreased the phosphorylation levels of hnRNP A1 in young and senescent fibroblast cells and blocked the cytoplasmic accumulation of hnRNP A1 in senescent cells. In addition, MNK1 formed a complex with hnRNP A1 in vivo. The expression levels of MNK1, phospho-MNK1, and phospho-eIF4E proteins were found to be elevated in senescent cells. These data suggest that MNK1 regulates the phosphorylation and the subcellular distribution of hnRNP A1 and that MNK1 may play a role in the induction of senescence. PMID- 22227432 TI - On the biomechanics and mechanobiology of growing skin. AB - Skin displays an impressive functional plasticity, which allows it to adapt gradually to environmental changes. Tissue expansion takes advantage of this adaptation, and induces a controlled in situ skin growth for defect correction in plastic and reconstructive surgery. Stretches beyond the skin's physiological limit invoke several mechanotransduction pathways, which increase mitotic activity and collagen synthesis, ultimately resulting in a net gain in skin surface area. However, the interplay between mechanics and biology during tissue expansion remains unquantified. Here, we present a continuum model for skin growth that summarizes the underlying mechanotransduction pathways collectively in a single phenomenological variable, the strain-driven area growth. We illustrate the governing equations for growing biological membranes, and demonstrate their computational solution within a nonlinear finite element setting. In displacement-controlled equi-biaxial extension tests, the model accurately predicts the experimentally observed histological, mechanical, and structural features of growing skin, both qualitatively and quantitatively. Acute and chronic elastic uniaxial stretches are 25% and 10%, compared to 36% and 10% reported in the literature. Acute and chronic thickness changes are -28% and 12%, compared to -22% and -7% reported in the literature. Chronic fractional weight gain is 3.3, compared to 2.7 for wet weight and 3.3 for dry weight reported in the literature. In two clinical cases of skin expansion in pediatric forehead reconstruction, the model captures the clinically observed mechanical and structural responses, both acutely and chronically. Our results demonstrate that the field theories of continuum mechanics can reliably predict the mechanical manipulation of thin biological membranes by controlling their mechanotransduction pathways through mechanical overstretch. We anticipate that the proposed skin growth model can be generalized to arbitrary biological membranes, and that it can serve as a valuable tool to virtually manipulate living tissues, simply by means of changes in the mechanical environment. PMID- 22227433 TI - Magnetocrystalline anisotropy of magnetite. AB - The spin reorientation temperature T(SR) of stoichiometric Fe(3)O(4), as well as of magnetite with a small number of vacancies and magnetite containing a low concentration of Ti, Zn, Al and Ga was measured on single-crystal samples using the ac susceptibility. In the same experiment the temperature T(V) of the Verwey transition was also found. The results show that a correlation between T(SR) and T(V) exists. The electronic structure of the compounds studied was determined using the density-functional-based GGA + U method. For stoichiometric magnetite the first and second cubic anisotropy constants were calculated, while for magnetite with defects the distribution of electron density using the 'atoms in molecules' approach was determined. Based on a combination of experimental results with the electronic structure calculations an explanation of the temperature dependence of the magnetocrystalline anisotropy of magnetite is suggested. PMID- 22227434 TI - Mechanical stretch induced calcium efflux from bone matrix stimulates osteoblasts. AB - The mechanisms by which bone cells sense critically loaded regions of bone are still a matter of ongoing debate. Animal models to investigate response to microdamage involve post mortem immunohistological analysis and do not allow real time monitoring of cellular response during the emergence of the damage in bone. Most in vitro mechanical stimulation studies are conducted on non-bone substrates, neglecting the damage-related alterations in the pericellular niche and their potential effects on bone cells. The current study reports spontaneous efflux of calcium ions (Ca(2+)) (1.924+/-0.742 pmol cm(-2)s(-1)) from regions of devitalized bone matrix undergoing post-yield strains, induced by a stress concentrator. When these samples are seeded with MC3T3-E1 osteoblasts, the strain induced Ca(2+) efflux from bone elicits cell response at the stress concentration site as manifested by activation of intracellular calcium signaling (increase in fluorescence by 52%+/-27%). This activity is associated with extracellular calcium because the intracellular calcium signaling in response to mechanical loading subsides when experiments are repeated using demineralized bone substrates (increase in fluorescence by 6%+/-10%). These results imply a novel perspective where bone matrix acts as an intermediary mechanochemical transducer by converting mechanical strain into a chemical signal (pericellular calcium) to which cells respond. Such a mechanism may be responsible for triggering repair at locations of bone matrix undergoing critical deformation levels. PMID- 22227435 TI - Determinants of vitamin D status in a general population of Danish adults. AB - BACKGROUND AND AIMS: Danish legislation regarding food fortification has been very restrictive and vitamin D deficiency is thought to be common in Denmark due to inadequate dietary intakes and the fact that in Denmark (latitude 56 degrees N) vitamin D is only synthesized in the skin after exposure to solar radiation during summertime (April-September). The purpose of this study was to evaluate the vitamin D status of a general adult population in Denmark and, in addition, associations between vitamin D status and distinct lifestyle factors were studied. METHODS: A random sample of 6784 persons from a general population aged 30-60 years participated in a health examination in 1999-2001. Serum samples from all participants were stored and levels of 25-hydroxyvitamin D (25(OH)D) were measured by HPLC in 2009. The method was compared to another HPLC method. Information on dietary intake of vitamin D and other lifestyle factors were obtained by questionnaires. A total of 6146 persons defined as ethnic Danes and with successful measurements of 25(OH)D were included in the analyses. RESULTS: The overall prevalence of vitamin D deficiency (25(OH)D<25 nmol/l) and insufficiency (25(OH)D<50 nmol/l) were 13.8% and 52.2%, respectively. A marked seasonal fluctuation was seen in serum levels of 25(OH)D - median values of 25(OH)D were lowest in February and highest in August. In multiple logistic regression models (n=5506), low vitamin D status was significantly associated with obesity (BMI>=30), daily smoking and a sedentary lifestyle. However, measurements of 25(OH)D were not associated with the estimated dietary intake of vitamin D. Comparison of two HPLC methods demonstrated considerable differences in accuracy. DISCUSSION AND CONCLUSIONS: Our results suggest that poor vitamin D status is common among adults in a Northern European country without food fortification with vitamin D. Methodological issues are, however, of great importance when using cut-off values to define poor vitamin D status. In addition, we demonstrated that low serum levels of 25(OH)D were associated with several lifestyle factors. PMID- 22227437 TI - Investigations on training, recall and reversal learning of a Y-maze by dwarf goats (Capra hircus): the impact of lateralisation. AB - We investigated maze learning in dwarf goats (Capra hircus) and the impact of lateralisation on learning. Lateralisation refers to the collection of phenomena in which external stimuli are perceived and processed differentially on the two sides of the brain and/or certain behaviours are preferentially performed by one side of the body. We trained 29 dwarf goats in a Y-maze, directing them to the opposite alley from that chosen in a free pre-run. In total, 13 goats were trained to the left alley (L-goats) and 16 goats to the right alley (R-goats). Recall of the trained alley was tested three months later. We then analysed reversal learning across 10 reversals. During training, the direction of the alley had an impact on learning. The number of runs required to reach the learning criterion was significantly lower in the L- than the R-goats. The goats recalled the trained alley three months later, with no difference between the L- and the R-goats. During the reversal learning, the reversal only tended to impact learning performance, whereas the directions of the new and the initially trained alley did not. Goats did not adopt a general rule with which to master the maze (e.g., win-stay/lose-shift) across the 10 reversals. Our results indicate a right hemisphere bias in the processing of visuospatial cues in the maze during initial training; however, no such impact was detected during reversal learning. PMID- 22227438 TI - Induction of cytochrome P4501A by highly purified hexachlorobenzene in primary cultures of ring-necked pheasant and Japanese quail embryo hepatocytes. AB - Primary cultures of ring-necked pheasant (Phasianus colchicus) and Japanese quail (Coturnix japonica) embryo hepatocytes were used to compare the potencies of highly purified hexachlorobenzne (HCB-P), reagent-grade HCB (RG-HCB) and 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) as inducers of ethoxyresorufin O-deethylase (EROD) activity, cytochrome P4501A (CYP1A4) messenger ribonucleic acid (mRNA) and CYP1A5 mRNA. HCB-P, RG-HCB and TCDD all induced EROD activity and up-regulated CYP1A4 and CYP1A5 mRNA. Induction was not caused by contamination of HCB with polychlorinated dibenzo-p-dioxins, dibenzofurans or biphenyls. Based upon a comparison of the EC(50) and EC(threshold) values for EROD and CYP1A4/5 concentration-response curves, the potency of HCB relative to TCDD was 0.001 in ring-necked pheasant and 0.01 in Japanese quail embryo hepatocytes. Differences in species sensitivity to HCB were found to be mainly dictated by differences in species sensitivity to TCDD rather than differences in the absolute potency of HCB. Consequently, ring-necked pheasant and Japanese quail embryo hepatocytes were found to be equally sensitive to HCB exposure. Species sensitivity comparisons were also made with chicken (Gallus gallus domesticus) and revealed that chicken embryo hepatocytes were less responsive to EROD induction (lower maximal response) by HCB compared to the embryo hepatocytes of pheasant and quail. PMID- 22227436 TI - Bone marrow-derived heparan sulfate potentiates the osteogenic activity of bone morphogenetic protein-2 (BMP-2). AB - Lowering the efficacious dose of bone morphogenetic protein-2 (BMP-2) for the repair of critical-sized bone defects is highly desirable, as supra-physiological amounts of BMP-2 have an increased risk of side effects and a greater economic burden for the healthcare system. To address this need, we explored the use of heparan sulfate (HS), a structural analog of heparin, to enhance BMP-2 activity. We demonstrate that HS isolated from a bone marrow stromal cell line (HS-5) and heparin each enhances BMP-2-induced osteogenesis in C2C12 myoblasts through increased ALP activity and osteocalcin mRNA expression. Commercially available HS variants from porcine kidney and bovine lung do not generate effects as great as HS5. Heparin and HS5 influence BMP-2 activity by (i) prolonging BMP-2 half-life, (ii) reducing interactions between BMP-2 with its antagonist noggin, and (iii) modulating BMP2 distribution on the cell surface. Importantly, long-term supplementation of HS5 but not heparin greatly enhances BMP-2-induced bone formation in vitro and in vivo. These results show that bone marrow-derived HS effectively supports bone formation, and suggest its applicability in bone repair by selectively facilitating the delivery and bioavailability of BMP-2. PMID- 22227439 TI - Endosulfan and flutamide, alone and in combination, target ovarian growth in juvenile catfish, Clarias batrachus. AB - Juvenile Catfish(es), Clarias batrachus of 50 days post hatch (dph) were exposed to endosulfan (2.5 parts per billion [ppb]) and flutamide (33 ppb), alone and in combination for 50 days to access their impact on ovarian development. The doses used in this study were nominal considering pervious reports. Sampling was done at 100 dph to perform histology and measurement of various transcripts, estradiol 17beta and aromatase activity. In general, treatments enhanced expression of ovary-specific transcription factors, steroidogenic enzymes steroidogenic acute regulatory protein and aromatases while transcripts of tryptophan hydroxylase2 (tph2) and catfish gonadotropin-releasing hormone declined in the brain of all treated groups with maximum reduction in the endosulfan group. Significant reduction of tph2 immunoreactivity in the forebrain/telencephalon-preoptic area endorsed our results. Increased number of pre-vitellogenic and less immature oocytes in the treated groups indicated hastened ovarian growth. Elevated ovarian aromatase activity and plasma estradiol-17beta levels were noticed in the treated groups with maximum being in the endosulfan group. These data together demonstrate that the exposure of endosulfan causes synchronous precocious ovarian development better than flutamide, alone or in combination. Our results suggest that both endosulfan and flutamide alter ovarian growth by triggering precocious development in catfish. PMID- 22227440 TI - The effect of hypoxia on intermediary metabolism and oxidative status in gilthead sea bream (Sparus aurata) fed on diets supplemented with methionine and white tea. AB - The present study evaluates the influence of previous nutritional status, fish fed on diets supplemented with tea and methionine, on acute hypoxia tolerance and subsequent recovery of Sparus aurata juveniles. Four isonitrogenous (45% of protein) and isolipidic (18% lipid) diets were formulated to contain 0.3% methionine, 2.9% white tea dry leaves or 2.9% of white tea dry leaves+0.3% methionine. An unsupplemented diet was used as control. Hepatic key enzymes of intermediary metabolism and antioxidant status, superoxide dismutase isoenzyme profile, glutathione (total, reduced and oxidized) and oxidative damage markers were determined under normoxia, hypoxia challenge and during normoxia recovery. Dietary white tea inclusion decreased plasma glucose levels under normoxia and seemed to induce an increase in anaerobic pathways as showed by enhanced liver lactate dehydrogenase activity. Hypoxia challenge reversed some of the responses induced by diet tea supplementation. Hypoxia decreased plasma glucose levels, increased glucose 6-P-dehydrogeanse activity, decreased superoxide dismutase activity (especially Mn-SOD and CuZn-SOD isoforms) and increased glutathione peroxidase activity in all dietary treatments. Catalase activity during hypoxia varied with dietary treatments and glutathione reductase was not modified. Antioxidant defenses were insufficient to avoid an oxidative stress condition under hypoxia, independently of dietary treatment. In general, pre-challenge values were recovered for almost all parameters within 6 h recovery time. PMID- 22227441 TI - Correlating 3T MRI and histopathology in patients undergoing epilepsy surgery. AB - PURPOSE: To investigate whether specific semi-quantitative 3T MRI parameters are associated with particular histological features in temporal lobe specimens in epilepsy surgery patients whose conventional MRI scan appeared normal. These MRI techniques have the potential to visualise subtle structural abnormalities currently undetected on conventional MRI; but correlation between pre-operative in vivo MRI and histopathology is needed to understand the basis of these MRI abnormalities. Predicting subtle histopathology with semi-quantitative MRI techniques could contribute to pre-surgical evaluation of epilepsy patients. MATERIALS AND METHODS: MRI techniques: normalised FLAIR signal intensity (nFSI), grey matter probability and diffusion tensor imaging (DTI) were correlated with quantitative histopathological measures: NeuN (neuronal nuclear antigen); GFAP (glial fibrillary acidic protein) and MBP (myelin basic protein) field fractions and stereological neuronal densities obtained in grey and white matter regions in twenty-four patients who underwent anterior temporal lobe resections. RESULTS: There were no significant correlations between the histopathological measurements and MRI values in grey or white matter in macroscopically normal appearing tissue. CONCLUSION: Findings suggest that in macroscopically normal appearing tissue, the studied semiquantitative MRI measurements are not significantly related to the measures of gliosis, neuronal loss/gain and myelin used in the current study. Studies of macroscopically abnormal tissue as well as improvements to the MRI techniques may increase the sensitivity of future correlative studies to improve our understanding of the histopathological basis of MRI signal characteristics. PMID- 22227442 TI - Estimation of the spatiotemporal structure of event-related desynchronization and synchronization in magnetoencephalography. AB - We present a comprehensive methodology for identifying cerebral areas involved in event-related changes of electromagnetic activity of the human brain, and also for tracing the temporal evolution of this activity. Information from pre- and peristimulus time intervals--in terms of event-related synchronization (ERS) and desynchronization (ERD) of the magnetoencephalographic (MEG) signal--was directly incorporated in the relevant test statistics. For the individual steps of the analysis, we used particular estimations of the time-frequency distribution of the energy along with particular error control methods, that is, short-time Fourier transform and false-discovery rate at the sensor level and multitapers and familywise error rate at the source level. This procedure was applied to two types of group-level tests, a within-condition test and a between-conditions test. The performance of the proposed methodology is assessed by (1) analyzing the event-related brain activity from two experimental conditions of an auditory MEG experiment--passive listening to a sequence of frequency-modulated sweeps and their active categorization with respect to the direction of frequency modulation, and (2) comparing the findings with those obtained with a widely used cluster-based analysis. PMID- 22227443 TI - Expert-like performance of an autonomous spike tracking algorithm in isolating and maintaining single units in the macaque cortex. AB - Isolating action potentials of a single neuron (unit) is essential for intra cortical neurophysiological recordings. Yet, during extracellular recordings in semi-chronic awake preparations, the relationship between neuronal soma and the recording electrode is typically not stationary. Neuronal waveforms often change in shape, and in the absence of counter-measures, merge with the background noise. To avoid this, experimenters can repeatedly re-adjust electrode positions to maintain the shapes of isolated spikes. In recordings with a larger number of electrodes, this process becomes extremely difficult. We report the performance of an automated algorithm that tracks neurons to obtain well isolated spiking, and autonomously adjusts electrode position to maintain good isolation. We tested the performance of this algorithm in isolating units with multiple individually adjustable micro-electrodes in a cortical surface area of macaque monkeys. We compared the performance in terms of signal quality and signal stability against passive placement of microelectrodes and against the performance of three human experts. The results show that our SpikeTrack2 algorithm achieves significantly better signal quality compared to passive placement. It is as least as good as humans in initially finding and isolating units, and better as the average and at least as good as the most proficient of three human experimenters in maintaining signal quality and signal stability. The autonomous tracking performance, the scalability of the system to large numbers of individual channels, and the possibility to objectify single unit recording criteria makes SpikeTrack2 a highly valuable tool for all multi-channel recording systems with individually adjustable electrodes. PMID- 22227444 TI - Comparison of transcranial magnetic stimulation measures obtained at rest and under active conditions and their reliability. AB - Transcranial magnetic stimulation (TMS) studies investigating motor cortex reorganization in clinical populations use a variety of measurements, with some performed at rest and others with the muscle slightly contracted. Surprisingly there are still a limited number of studies focusing on relationship between TMS measures obtained at rest and during active muscle contraction in healthy individuals. The purpose of this study was to: (1) compare resting and active TMS measures and assess their association; (2) determine their respective short- and long-term reliability. Motor threshold (MT), motor evoked potentials (MEP) amplitude, map area, normalized map volume, map center of gravity (CoG) and short interval intracortical inhibition (SICI) of the first dorsal interosseous (FDI) muscle were assessed in 12 healthy subjects. Subjects were tested three times (with a short (four days) and a long (>1 month) inter-session interval). No significant difference was found between resting and active measures, except for MT. Active MT was on average at 82% of resting MT. Good short- and long-term reliability were found for MT and CoG (in resting and active conditions), for the SICI and MEP amplitude at rest and for the normalized map volume under active condition. In conclusion, maps of FDI muscle obtained at rest and during active contraction are very similar to each other in healthy individuals when differences in MT are taken into account. Most TMS measures present good reliability when obtained under the appropriate condition, with comparable short term and long-term reliability. PMID- 22227445 TI - Plasma/platelets/red blood cell ratio in the management of the bleeding traumatized patient: does it matter? AB - PURPOSE OF REVIEW: The scope of this review is to describe what is known about blood product ratios and their effects on acute trauma coagulopathy. Assessing how ratios matter to trauma patients is important to improve massive transfusion strategies. RECENT FINDINGS: A growing body of evidence supports that high ratios of fresh frozen plasma and platelets to red blood cells improve survival of the massively bleeding traumatized patient. Acting quickly is also critical. Reducing transfusion delay can be achieved through massive transfusion protocol implementations, which incorporate local agreements with blood banks and 'trauma packs' in organized trauma systems. Thawed plasma and freeze-dried plasma allow immediate delivery of plasma. SUMMARY: Fresh frozen plasma/platelet/red blood cell ratios matter to define the content of packs immediately available within the golden hour to the right, accurately screened trauma patients. Research is needed in developing novel transfusion approaches for massively bleeding patients. PMID- 22227446 TI - Spontaneous breathing activity in acute lung injury and acute respiratory distress syndrome. AB - PURPOSE OF REVIEW: We aimed at providing the most recent and relevant evidence regarding spontaneous breathing activity during mechanical ventilation in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Both clinical and experimental data are depicted. RECENT FINDINGS: The use of unsupported spontaneous breathing has been associated with the most beneficial effects reported to date, but recent data favors also pressure-supported breathing activity in experimental ALI. In patients with ALI/ARDS, unsupported spontaneous breathing in combination with mandatory cycles has been shown to improve lung function, reduce the need for sedation and cardiocirculatory drug therapy, and speed weaning, with no effect on mortality. On the other hand, strong clinical evidence shows that the use of neuromuscular blocking agents in the first 48 h of mechanical ventilation with the volume assist-control ventilation mode reduces morbidity and mortality in severe ARDS compared to placebo. SUMMARY: In our opinion, spontaneous breathing activity should be avoided in the first 48 h of mechanical ventilation in patients with severe ARDS (PaO2/FIO2 <120 mmHg), but it may be useful in less severe ARDS and ALI. Clearly, further clinical and experimental investigations on the use of different ventilation modes of supported/unsupported spontaneous breathing in ALI/ARDS are needed. PMID- 22227447 TI - Mechanical ventilation in acute lung injury/acute respiratory distress syndrome: more protection, better outcome. PMID- 22227448 TI - Withdrawal of life sustaining treatment for newborn infants from a Jewish perspective. AB - Jewish law covers all aspects of the Orthodox Jew's life, including questions of life and death. Talmudic texts already discussed the status of the newborn infant and this serves as a guide in modern times when faced with complex questions of withdrawing life from such infants when it is deemed that they will not survive. This paper reviews the essence of Jewish law and provides some directives in answering such questions. PMID- 22227449 TI - Parents perceptions of withdrawal of life support treatment to newborn infants. AB - The decision to withdraw life support challenges health care professionals and parents. Parents need to fulfil their role as parents, part of which involves difficult decision making. They desire to fully understand the care of their infant in order to help in this process. Parents work to a different time frame than health care professionals and therefore require detailed information and support to make decisions. Available approaches to care need to address ethical decisions regarding treatment, pain and suffering, quality of life and decisions to move from active to palliative care. Communication requires an investment of time, repeated discussions and a compassionate approach by health care professionals to educate parents in order for them to make an informed decision. Follow-on care to help parents come to terms with the decisions they have made is a requirement of good practice. PMID- 22227450 TI - Early apoptosis of rod photoreceptors in Rpe65(-/-) mice is associated with the upregulated expression of lysosomal-mediated autophagic genes. AB - RPE65-related Leber's congenital amaurosis (LCA) is a rod-cone dystrophy whose clinical outcome is mainly attributed to the loss of rod photoreceptors followed by cone degeneration. Pathogenesis in Rpe65(-/-) mice is characterized by a slow and progressive degeneration of rods dependent on the constitutive activation of unliganded opsin. We previously reported that this opsin-mediated apoptosis of rods was dependent on Bcl-2-apoptotic pathway and Bax-induced pro-death activity. In this study, we report early initial apoptosis in the newly differentiated retina of Rpe65(-/-) mice. Apoptotic photoreceptors were identified as rods and resulted from pathological phototransduction signaling. This wave of early apoptosis triggered Bcl-2-related pathway and Bax apoptotic activity, while activation of the caspases was not induced. Following cellular stress, multiple signaling pathways are initiated which either commit cells to death or trigger pro-survival responses including autophagy. We report that Bcl-2-related early rod apoptosis was associated with the upregulation of autophagy markers including chaperone-mediated autophagy (CMA) substrate receptor LAMP-2 and lysosomal hydrolases Cathepsin S and Lysozyme. This suggests that lysosomal-mediated autophagy may be triggered in response to early rod apoptosis in Rpe65-LCA disease. These results highlight that Rpe65-related primary stress induces early signaling events, which trigger Bax-induced-apoptotic pathway and autophagy mediated cellular response. These events may determine retinal cell fate, progression and severity of the disease. PMID- 22227451 TI - Use of viral vectors to create animal models for Parkinson's disease. AB - Parkinson's disease is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. While sporadic in the majority of cases, PD-linked dominant mutations in the alpha-synuclein and LRRK-2 genes, and recessive mutations in the parkin, DJ-1 and PINK-1 genes have been identified in PD families in recent years. In this review we describe viral animal models for PD, i.e. models that are based on PD-associated mutations, and have been generated by viral delivery of the respective disease genes to the substantia nigra of rodents and non-human primates. To date, viral PD models comprise alpha-synuclein and LRRK-2-based overexpression models, as well as models that mimic parkin loss of function by overexpression of the parkin substrates Pael-R, CDCrel-1, p38/JTV or synphilin-1. These viral models provide valuable insights into Parkinson disease mechanisms, help to identify therapeutic targets and may contribute to the development of therapeutic approaches. PMID- 22227452 TI - The beneficial effects of regular exercise on cognition in REM sleep deprivation: behavioral, electrophysiological and molecular evidence. AB - Inadequate sleep is prevalent in modern societies and is known to profoundly impair cognitive function. We examined the impact of 4 weeks of regular treadmill exercise on sleep deprivation induced spatial learning and memory, synaptic plasticity and related signaling molecules in area CA1 of the rat hippocampus. Rats were exercised on a treadmill and subsequently sleep-deprived for 24h using the modified multiple platform technique. Testing of learning and short-term memory performance in the radial arm water maze showed that although sedentary sleep deprived rats were severely impaired, exercised sleep deprived rats' performance was normal. Extracellular recording from area CA1 of anesthetized rats revealed that early phase LTP (E-LTP) was markedly impaired in the sedentary sleep deprived animals, but was normal in the exercised sleep deprived group. Additionally, immunoblot analysis of CA1 area before (basal) and after expression of E-LTP indicated that the significant down-regulation of the brain derived neurotrophic factor (BDNF) and phosphorylated calcium-calmodulin dependent protein kinase II (P-CaMKII) levels in sleep deprived animals was prevented by the regular exercise regimen. The results suggest that the regular exercise protocol prevents the sleep deprivation induced impairments in short-term memory and E-LTP by preventing deleterious changes in the basal and post-stimulation levels of P-CaMKII and BDNF associated with sleep deprivation. PMID- 22227453 TI - Lithium reverses increased rates of cerebral protein synthesis in a mouse model of fragile X syndrome. AB - Individuals with fragile X syndrome (FXS), an inherited form of cognitive disability, have a wide range of symptoms including hyperactivity, autistic behavior, seizures and learning deficits. FXS is caused by silencing of FMR1 and the consequent absence of fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that associates with polyribosomes and negatively regulates translation. In a previous study of a mouse model of FXS (Fmr1 knockout (KO)) we demonstrated that in vivo rates of cerebral protein synthesis (rCPS) were elevated in selective brain regions suggesting that the absence of FMRP in FXS may result in dysregulation of cerebral protein synthesis. Lithium, a drug used clinically to treat bipolar disorder, has been used to improve mood dysregulation in individuals with FXS. We reported previously that in the Fmr1 KO mouse chronic dietary lithium treatment reversed or ameliorated both behavioral and morphological abnormalities. Herein we report that chronic dietary lithium treatment reversed the increased rCPS in Fmr1 KO mice with little effect on wild type mice. We also report our results of analyses of key signaling molecules involved in regulation of mRNA translation. Our analyses indicate that neither effects on the PI3K/Akt nor the MAPK/ERK 1/2 pathway fully account for the effects of lithium treatment on rCPS. Collectively our findings and those from other laboratories on the efficacy of lithium treatment in animal models support further studies in patients with FXS. PMID- 22227454 TI - DA neurons derived from hES cells that express HLA-G1 are capable of immunosuppression. AB - Human embryonic stem (hES) cells have the capacity for self-renewal and exhibit multipotentiality. hES cells have promise for serving as an unlimited source of ideal seed cells for cell transplantation. However, the rejection that occurs between the transplant recipient and the transplanted cell poses a major challenge for therapeutic transplantation. This study was designed to devise methods to enhance immune tolerance in cell therapy. We established an hES cell line that could stably express human leukocyte antigen-G1 (HLA-G1). The established HLA-G1-H1 hES cells still retained all the characteristics of normal human embryonic stem cells. By using the SDIA method, we induced dopaminergic (DA) neurons by coculturing HLA-G1-H1 hES cells with the mouse stromal cell line PA6. Tyrosine hydroxylase (TH)+neurons were detected on the 10th day of differentiation, and 70% of the HLA-G1-H1 hES cells were TH+mature DA neurons because the differentiation time was only 3 weeks. Cells that had been differentiating for different periods of time still expressed HLA-G1, and these differentiated DA neurons released dopamine and other catecholamines in response to K+ depolarization as measured by HPLC. After careful study, we found that HLA G1-H1 hES cells are capable of inhibiting the proliferation of mixed T lymphocytes. DA neurons derived from HLA-G1-H1 hES attenuated the release of proinflammatory cytokines IL-1beta and IFN-gamma from lipopolysaccharide (LPS) stimulated BV2 microglia. The efficiency of inhibition was significant and dose dependent. This method might be used to treat Parkinson's patients via cell transplantation. PMID- 22227456 TI - Application of albumin prior to delayed thrombolysis reduces brain edema and blood brain barrier permeability in an embolic stroke model. AB - To explore whether human albumin (Alb) administration prior to thrombolysis with recombinant tissue plasminogen activator (rt-PA) can eliminate brain damage induced by this treatment given after the effective and safe window of 3h after stroke onset. Rats were subjected to embolic stroke by unilateral embolic middle cerebral artery occlusion (MCAO). Three or six hours after the onset of stroke, rats were administered intravenously with saline (control), rt-PA (thrombolysis) or rt-PA+Alb (additional Alb 3h after MCAO, combination). Cerebral blood flow, infarct volume, space-occupying effect and blood brain barrier (BBB) leakage of gadopentetate dimeglumine (Gd-DTPA) were assessed dynamically by magnetic resonance imaging (MRI) at 24h, 7 and 14days after treatment. BBB leakage of both fluoro-isothiocyanate dextran (FITC-dextran) and erythrocytes was also evaluated 14days after treatment. The space-occupying effect in the combination group at 7days after treatment declined significantly compared with that at 24h after treatment (P<0.05), but additional Alb treatment failed to reduce the infarct volumes or improve cerebral blood volume. Furthermore, BBB leakage of both small (Gd-DTPA) and large (FITC-dextran and erythrocytes) molecules decreased significantly in the combination compared to the saline or thrombolysis groups (P<0.05). Alb administration prior to thrombolysis (3h after stroke) can reduce delayed rt-PA treatment-induced brain edema and BBB permeability. PMID- 22227455 TI - Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats. AB - BACKGROUND: In rats, prepulse inhibition (PPI) of acoustic startle is disrupted by systemic administration of dopaminergic agonists, such as the dopamine D3 receptor (D3R)-preferential agonist pramipexole (PPX). PPX has D3R-active (S) and -inactive (R) stereoisomers. Here, we tested the neuroanatomical and stereochemical selectivity of PPX effects on PPI. METHODS: (S)-PRA or (R)-PRA (0, 0.47, 1.42, 4.73 MUmol/kg) was injected sc 15 min prior to PPI testing in adult male Sprague Dawley rats. In separate rats, (S)-PPX (0, 3, 10 MUg/0.5MUl/side, ic) was infused into the nucleus accumbens (NAc), caudodorsal striatum (CS), or olfactory tubercle/Islands of Calleja (ICj) 15 min prior to PPI testing. D3R expression in these brain regions was assessed using quantitative rt-PCR. The PPI disruptive effects of systemic (S)-PPX were also tested after pretreatment with the D3R-selective antagonist, U99194 (10mg/kg). RESULTS: Systemic administration of PPX stereoisomers demonstrated a dose-dependent effect of (S)-PPX on PPI, while (R)-PPX had no effect on PPI. PPX decreased PPI when infused into the NAc and ICj, but not the CS. Quantitative rt-PCR revealed D3R expression in ICj>NAc>CS. The PPI-disruptive effects of PPX were prevented by U99194. CONCLUSION: The PPI-reducing effects of PPX are stereospecific for the D3R-active (S)-isomer, neuroanatomically preferential for the D3R-rich ventral vs. D3R poor caudodorsal striatum, and prevented by pharmacologic D3R blockade. These findings are consistent with the conclusion that PPX disrupts PPI via stimulation of mesolimbic D3Rs. PMID- 22227457 TI - Cortical correlates of self-generation in verbal paired associate learning. AB - Behavioral studies have shown that verbal information is better retained when it is self-generated rather than read (learned passively). We used fMRI and a paired associates task to examine brain networks underlying self-generated memory encoding. Subjects were 49 healthy English speakers ages 19-62 (30 female). In the fMRI task, related word pairs were presented in a "read" condition, where subjects viewed both words and read the second word aloud, or a "generate" condition, where the second word was presented with only the first letter and the subject was required to generate the word. Thirty word pairs were presented in each condition. After the fMRI scan, words that were read or generated were presented, each with two foils, in a forced-choice recognition task. On the recognition post-test, words from the "generate" condition were more correctly recognized than from the "read" condition (80.0% for generated words versus 72.0% for read words; t(48)=5.17, p<0.001). FMRI revealed increased activation for generate>read in inferior/middle frontal gyri bilaterally (L>R), anterior cingulate, and caudate nucleus and the temporo-parietal-occipital junction bilaterally. For the "read" condition, better subsequent memory performance across individual subjects was positively correlated with activation in the cuneus bilaterally. In the "generate" condition, better subsequent memory performance was positively correlated with activation in the left superior temporal gyrus. These results suggest that self-generation improves memory performance, that enhanced cortical activation accompanies self-generated encoding, and that recruitment of a specific brain network underlies self generated encoding. The findings may have implications for the development of procedures to enhance memory performance. PMID- 22227459 TI - Native nephrectomy in pediatric transplantation--less is more! AB - OBJECTIVE: Indications for pre-transplantation native nephrectomy (PTNN) include chronic renal parenchymal infection, proteinuria, intractable hypertension, polycystic kidneys and malignancy. Our aim was to establish the frequency and reasons for PTNN in children undergoing renal transplant at our center. MATERIALS AND METHODS: Children listed for renal transplant between 1998 and 2010 who underwent PTNN were analyzed. Etiology of established renal failure, indication for nephrectomy, stage of chronic kidney disease, laterality, complications, and timing of subsequent transplant were determined. Outcome of children, and that of preserved native kidneys following transplant, was reviewed. RESULTS: 21/203 children listed for transplant (10.3%) underwent PTNN (32 nephrectomies). Indications were drug-resistant proteinuria (6 children), recurrent upper tract urosepsis (6), refractory hypertension (4), malignancy/malignant predisposition (4), concomitant procedure during ureterocystoplasty (1). Median age at nephrectomy was 3.3 years; 86% had impaired renal function at time of (first) nephrectomy. Median time until transplantation following bilateral nephrectomy was 1.7 years. 19/21 children have been transplanted; 17 reached stable graft function. Only 2 children who did not undergo PTNN required nephrectomy post transplant. CONCLUSION: When malignancies were excluded, PTNN was performed in a minority (8.4%) of children, mainly for proteinuria. This adds great advantage by reducing morbidity. Resulting graft function seems favorable. PMID- 22227458 TI - Expression and function of myelin-associated proteins and their common receptor NgR on oligodendrocyte progenitor cells. AB - Nogo-A, oligodendrocyte myelin glycoprotein (OMgp) and myelin-associated glycoprotein (MAG) are known as myelin-associated proteins that inhibit axon growth by binding a common receptor, the Nogo66 receptor (NgR). In the CNS, Nogo A, OMgp and MAG are predominantly expressed by oligodendrocytes. As our previous study revealed that oligodendrocyte progenitor cells (OPCs) did not inhibit neurite outgrowth, it is not clear whether these myelin-associated proteins are expressed in OPCs, and what functions they perform if they are expressed in OPCs. In the present study, with OPCs induced from neural precursor cells (NPCs) derived from rat embryonic spinal cord, and oligodendrocytes differentiated from OPCs, we have observed the expression patterns of Nogo-A, OMgp, MAG and NgR in NPCs, OPCs and oligodendrocytes by immunostaining and western blot assay. We found that Nogo-A could be detected in all tested cells; OMgp could be detected in OPCs and oligodendrocytes, but not in NPCs; MAG was only detected in oligodendrocytes; while NgR could be detected in NPCs and OPCs, but not in oligodendrocytes. These results indicated that the expression pattern of MAG and NgR in OPCs was totally different from that of oligodendrocytes, which might be one of the factors that led to the discrepancy between the two cells in promoting neurite outgrowth. By respectively blocking Nogo-A, OMgp and NgR expressed on OPCs with their corresponding antibodies, we further investigated their roles in the proliferation and differentiation of OPCs, as well as the possible signal pathways involved in. Our results showed that when OPCs were cultured under proliferation condition, blocking Nogo-A, OMgp or NgR did not affect the proliferation of OPCs, but could all significantly prolong their processes. And this effect on OPC processes might involve the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. When OPCs were cultured under differentiation condition (containing tri-iodothyronine, T3), blocking Nogo-A, OMgp or NgR could all inhibit the differentiation of OPCs, and this effect might involve the extracellular signal-regulated kinases1/2 (Erk1/2) signaling pathway. These results suggested that under proliferation environment, the functions of Nogo-A, OMgp and NgR expressed in OPCs might be to control the length of processes, thus maintaining the morphology of OPCs. While in differentiation environment, the functions of Nogo-A, OMgp and NgR expressed in OPCs turned to promote the differentiation of OPCs, thus facilitating the maturation of oligodendrocytes. And NgR, as the common receptor for Nogo-A and OMgp, might be the main molecule that mediated these functions in OPCs. PMID- 22227460 TI - 20-HETE in neovascularization. AB - Cytochrome P450 4A/F (CYP4A/F) converts arachidonic acid (AA) to 20-HETE by omega hydroxylation. The contribution of 20-HETE to the regulation of myogenic response, blood pressure, and mitogenic actions has been well summarized. This review focuses on the emerging role of 20-HETE in physiological and pathological vascularization. 20-HETE has been shown to regulate vascular smooth muscle cells (VSMC) and endothelial cells (EC) by affecting their proliferation, migration, survival, and tube formation. Furthermore, the proliferation, migration, secretion of proangiogenic molecules (such as HIF-1alpha, VEGF, SDF-1alpha), and tube formation of endothelial progenitor cells (EPC) are stimulated by 20-HETE. These effects are mediated through c-Src- and EGFR-mediated downstream signaling pathways, including MAPK and PI3K/Akt pathways, eNOS uncoupling, and NOX/ROS system activation. Therefore, the CYP4A/F-20-HETE system may be a therapeutic target for the treatment of abnormal angiogenic diseases. PMID- 22227461 TI - Cinnamic aldehydes affect hydrolytic enzyme secretion and morphogenesis in oral Candida isolates. AB - Effect of cinnamaldehyde (CD), 4-hydroxy-3-methoxy cinnamaldehyde (HMCD) and 3,5 dimethoxy-4-hydroxy cinnamaldehyde (HDMCD) on growth and virulence factors of standard (Candida albicans 90028) and 26 oral isolates of C. albicans has been investigated. Growth was significantly inhibited by all three compounds in both solid and liquid medium, no systematic difference was observed between various isolates. MIC90 ranged from 125 to 450 MUg/ml for CD, 100-250 MUg/ml for HMCD and 62.5-125 MUg/ml for HDMCD. All oral isolates were found to be proteinase and phospholipase secretors, both proteinase and phospholipase secretion was significantly inhibited by all the three tested molecules. No systematic difference in secretion or its inhibition was observed between standard and oral isolates as also between various isolates. Average drop in proteinase and phospholipase secretion caused by 1/2 MIC of CD was 33% and 28%, HMCD; 46% and 44%, HDMCD; 59% and 54%. The standard strain and all the 26 oral isolates displayed morphogenesis under triggering experimental conditions; no difference was seen between standard and various isolates. In the absence of test compounds hyphae development at 300 min was 83% for standard strain whereas average hyphae development for oral isolates was 85%. Average hyphal transition was suppressed by all tested compounds. At 1/2 MIC concentration at 300 min average hyphal transition of standard and oral isolates was CD; 49% and 57%, HMCD; 45% and 38%, HDMCD; 5% and 5%. Average haemolytic activity of the three tested compounds varied from 10 to 15% at their highest MIC compared to 20% shown by fluconazole at typical MIC of 30 MUg/ml. PMID- 22227462 TI - Chemical modulators working at pharmacological interface of target proteins. AB - For last few decades, the active site cleft and substrate-binding site of enzymes as well as ligand-binding site of the receptors have served as the main pharmacological space for drug discovery. However, rapid accumulation of proteome and protein network analysis data has opened a new therapeutic space that is the interface between the interacting proteins. Due to the complexity of the interaction modes and the numbers of the participating components, it is still challenging to identify the chemicals that can accurately control the protein protein interactions at desire. Nonetheless, the number of chemical drugs and candidates working at the interface of the interacting proteins are rapidly increasing. This review addresses the current case studies and state-of-the-arts in the development of small chemical modulators controlling the interactions of the proteins that have pathological implications in various human diseases such as cancer, immune disorders, neurodegenerative and infectious diseases. PMID- 22227463 TI - 2-(4-Methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure-activity relationships in the B and C-regions. AB - On the basis of the previous lead N-4-t-butylbenzyl 2-(3-fluoro-4 methylsulfonylaminophenyl) propanamide (3) as a potent TRPV1 antagonist, structure-activity relationships for the B (propanamide part) and C-region (4-t butylbenzyl part) have been investigated for rTRPV1 in CHO cells. The B-region was modified with dimethyl, cyclopropyl and reverse amides and then the C-region was replaced with 4-substituted phenyl, aryl alkyl and diaryl alkyl derivatives. Among them, compound 50 showed high binding affinity with K(i)=21.5nM, which was twofold more potent than 3 and compound 54 exhibited potent antagonism with K(i(ant))=8.0nM comparable to 3. PMID- 22227464 TI - Predictors of travel-related hepatitis A and B among native adult Danes: a nationwide case-control study. AB - OBJECTIVES: To assess journey length and other predictors of travel-related acute hepatitis A (HAV) and B (HBV) virus infection among native Danes and determine the sensitivity and specificity of current pre-travel vaccination guidelines. METHODS: A nationwide case-control study was perfomed involving 60 Danes with HAV and 14 with HBV who acquired hepatitis in non-western countries from 2000 to 2010. Non-immune travellers from a nationwide survey (1188 HAV and 1709 HBV) served as controls. RESULTS: The odds ratios (ORs) for HAV and HBV increased with increasing journey length (p<0.0001). However, 90% of HAV and 62% of HBV cases travelled for less than 4 weeks, and the daily infection rate did not increase with journey length; rather, for HAV it decreased. Increasing age (p<0.0001) and journeys to Africa (OR 6.1 (3.2-11)) raised the risk of acute HAV. Travelling alone or with friends as compared to travelling with a partner/family (OR: 15 (3.2-134)) strongly predicted HBV risk. Danish vaccination guidelines had HAV/HBV sensitivities of 86%/31%, and specificities of 27%/95%, respectively. Incidence rates were 12.8 (HAV) and 10.2 (HBV) per 100,000 non-immune travel months, and acute disease severity affected HAV and HBV cases equally. CONCLUSIONS: These results may support revision of current pre-travel vaccination guidelines. PMID- 22227465 TI - Hcv coinfection, an important risk factor for hepatotoxicity in pregnant women starting antiretroviral therapy. AB - OBJECTIVES: This retrospective cohort study evaluated the risk of hepatotoxicity in HIV-1 positive pregnant and non-pregnant women starting combined ART. METHODS: Data were used from the ATHENA observational cohort. The study population consisted of HIV-1 infected, therapy naive, pregnant and non-pregnant women, followed between January 1997 and February 2008. Demographic, treatment and pregnancy related data were collected. Risk of hepatotoxicity was determined using univariate and multivariate logistic regression. Analyses were adjusted for age, region of origin, baseline HIV-RNA levels and CD4 cell counts, cART regimen and hepatitis B and C coinfection. ALT and AST values of more than 5 times ULN were considered as hepatotoxicity. RESULTS: Four-hundred and twenty-five pregnant and 1121 non-pregnant women were included. Independent risk factors of hepatotoxicity in all women were the presence of detectable HCV RNA (OR 5.48, 95% CI 2.25-13.38, p<0.001) and NVP use (OR 2.63, 95% CI 1.54-4.55, p<0.001). Stratified for pregnancy, the adjusted risk of hepatotoxicity was significantly associated with HCV coinfection only during pregnancy (OR 23.53, 95% CI 4.69 118.01, p<0.001). NVP use is related to hepatotoxicity in pregnant (OR 5.26, 95% CI 1.61-16.67, p<0.005) as well as in non-pregnant women (OR 2.13, 95% CI 1.11 4.00, p=0.02). CONCLUSION: HCV coinfection and NVP use are associated with a higher risk of cART induced hepatotoxicity in pregnant women. PMID- 22227466 TI - Risk of secondary cases of Clostridium difficile infection among household contacts of index cases. AB - OBJECTIVES: We aimed to estimate the risk of secondary cases of Clostridium difficile infection (CDI) among household contacts of index cases. METHODS: We reviewed all 2222 patients with confirmed CDI in a region of Quebec, Canada, during 1998-2009. Our laboratory serves a well-defined population for which it is the sole centre providing CDI testing, enabling us to calculate accurate population annual incidence rates of CDI. Cases with the same phone number were verified individually to determine whether they were indeed related. We considered as related two cases occurring in the same household within one year of each other. RESULTS: We estimated that 1061 spouses and 501 children (<25 years-old) lived in the same household as the index cases, of which respectively 5 and 3 developed CDI. Among spouses and children, the attack rate was 4.71/1000 and 5.99/1000 respectively, and the relative risk was 7.61 (95%CI: 5.77-9.78) and 90.6 (95%CI: 33.89-487.64) for the three months after the diagnosis in the index case. CONCLUSIONS: Although the relative risk of CDI among household contacts is somewhat increased for a few months, the absolute risk is too low to justify interventions, apart from avoiding unnecessary courses of antimicrobials. PMID- 22227467 TI - T-cell changes after a short-term exposure to maraviroc in HIV-infected patients are related to antiviral activity. AB - OBJECTIVES: Analyze the short-term immunological effect directly attributable to MRV without interference of other drugs. METHODS: MRV group included experienced HIV-infected patients undergoing an 8-day MRV monotherapy. A comparison population included naive HIV-infected patients starting combined antiretroviral therapy (cART group). Absolute CD4(+) and CD8(+) T-cells and T-lymphocyte subsets were determined at day 0 and 8. RESULTS: Fifty-nine patients who underwent MRV monotherapy and 28 naive patients were analyzed. Forty-one patients in the MRV group experienced a significant viral load decrease (MRV positive subgroup). Virological response and CD4(+) T-cell change were comparable in the MRV positive and cART groups. CD8(+) T-cell increase in the MRV positive subgroup showed a trend toward superiority when compared with the cART group. T-lymphocyte subset changes showed a similar profile in the MRV positive and cART groups with a differential effect in the TemRA cells related to MRV. No immunological effect (absolute lymphocyte counts or subsets) was observed in patients without virological response to MRV. CONCLUSIONS: MRV produced CD4(+) and CD8(+) T-cell gains related to antiviral activity and comparable or even superior in terms of CD8(+) T-cells to naive patients starting cART. No immunological effect occurred in subjects without virological response to MRV. PMID- 22227468 TI - [Involved-node radiotherapy combined with deep-inspiration breath-hold technique in patients with Hodgkin lymphoma]. AB - PURPOSE: To assess the clinical outcome of the involved-node radiotherapy (INRT) concept with the use of deep-inspiration breath-hold (DIBH) technique in patients with localized supra-diaphragmatic Hodgkin lymphoma. PATIENTS AND METHODS: All were patients with stage I-II Hodgkin lymphoma and they were treated with chemotherapy prior to irradiation. Radiation treatments were delivered using the involved-node radiotherapy concept according to the European Organization for Research and Treatment of Cancer Guidelines and a spirometer dedicated to DIBH radiotherapy was used for every patient. RESULTS: Twenty-seven patients with Hodgkin lymphoma (26 patients with primary Hodgkin lymphoma, one with refractory disease), treated from November 2004 to October 2010, were retrospectively analysed. The median age was 27 years (range 16 to 54). Seventeen (63%) patients had stage I-IIA and 10 (37%) had stage I-IIB disease. All patients received two to six cycles of adriamycin, bleomycin, vinblastine and dacarbazine. The median radiation dose to patients was 30,6 Gy (range: 19,8-40). Protection of various organs at risk was satisfactory. Median follow-up, 3-year progression-free and 3 year overall survival were 38 months (range: 7-70), 96% (95%CI: 79-99%) and 95% (95%CI: 75-99%), respectively. Recurrence occurred in one patient (mediastinal in field relapse). There was one grade 3 acute toxicity (transient pneumonitis). CONCLUSIONS: Our results suggest that patients with localized Hodgkin lymphoma can be safely and efficiently treated using deep-inspiration breath technique and the involved-node radiotherapy concept. Longer follow-up is needed to assess late toxicity, especially for the heart and the coronary arteries. PMID- 22227469 TI - The truth-telling motor cortex: response competition in M1 discloses deceptive behaviour. AB - Neural circuits associated with response conflict are active during deception. Here we use transcranial magnetic stimulation to examine for the first time whether competing responses in primary motor cortex can be used to detect lies. Participants used their little finger or thumb to respond either truthfully or deceitfully regarding facial familiarity. Motor-evoked-potentials (MEPs) from muscles associated with both digits tracked the development of each motor plan. When preparing to deceive, the MEP of the non-responding digit (i.e. the plan corresponding to the truth) exceeds the MEP of the responding digit (i.e. the lie), whereas a mirror-reversed pattern occurs when telling the truth. This give away response conflict interacts with the time of stimulation during a speeded reaction period. Lies can even activate digit-specific cortical representations when only verbal responses are made. Our findings support neurobiological models which blend cognitive decision-making with motor programming, and suggest a novel index for discriminating between honest and intentionally false facial recognition. PMID- 22227470 TI - Phosphodiesterase inhibitors control A172 human glioblastoma cell death through cAMP-mediated activation of protein kinase A and Epac1/Rap1 pathways. AB - AIMS: We investigated whether cAMP-mediated protein kinase A(PKA) and Epac1/Rap1 pathways differentially affect brain tumor cell death using 4-(3-cyclopentyloxy-4 methoxyphenyl)-2-pyrrolidone(rolipram), specific phosphodiesterase type IV(PDE IV) inhibitor. MAIN METHODS: A172 and U87MG human glioblastoma cells were used. Percentage of cell survival was determined by MTT assay. PKA and Epac1/Rap1 activation was determined by western blotting and pull-down assay, respectively. Cell cycle and hypodiploid cell formation were assessed by flow cytometry analysis. KEY FINDINGS: Non-specific PDE inhibitors, isobutylmethylxanthine(IBMX) and theophylline reduce survival percentage of A172 and U87MG cells. The expression of PDE4A and PDE4B was detected in A172 and U87MG cells. Rolipram treated A172 or U87MG cell survival was lower in the presence of forskolin, adenylate cyclase activator, than that in its absence. Co-treatment with rolipram and forskolin also enhanced CREB phosphorylation on serine 133 that was inhibited by H-89, PKA inhibitor and cAMP-responsive guanine nucleotide exchange factor 1(Epac1), a Rap GDP exchange factor-mediated Rap1 activity in A172 cells. When A172 cells were treated with cell-permeable dibutyryl-cAMP(dbcAMP), PKA activator or 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate(CPT), Epac1 activator, basal level of cell death was increased and cell cycle was arrested at the phase of G2/M. Rolipram-induced A172 cell death was also increased by the co-treatment with dbcAMP or CPT, but it was inhibited by the pre treatment with H-89. SIGNIFICANCE: These findings demonstrate that PKA and Epac1/Rap1 pathways could cooperatively play a role in rolipram-induced brain tumor cell death. It suggests that rolipram might regulate glioblastoma cell density through dual pathways of PKA- and Epac1/Rap1-mediated cell death and cell cycle arrest. PMID- 22227471 TI - The effects of ethanol upon hydric balance and arterial pressure in rats: folic acid as a possible hypotensor. AB - AIMS: Chronic alcohol intake is related to hypertension. There are, however, few studies concerning the effect of ethanol upon hydric balance in relation to arterial pressure. Folic acid intake has beneficial effects upon the cardiovascular system decreasing hyperhomocysteinemia, however, more studies imply that it is related with other mechanisms. Therefore, we have studied the effects of chronic alcohol intake (30% v/v) upon hydric-saline balance and hypertension and have found that dietary supplementation with folic acid (8 mg/kg) improves the above parameters. MAIN METHODS: Our study used four experimental groups of rats: control, alcohol, alcohol with folic acid and control with folic acid. In all cases we measured the clearance of Na(+), K(+) and aldosterone; osmolarity in urine, liquid and solid ingestion; homocysteine levels in serum; cardiac frequency and arterial blood pressure. KEY FINDINGS: The alcohol intake increases serum aldosterone and homocysteine, which is reflected in an increase in arterial blood pressure. In addition, we have found that alcohol intake reduces both liquid and solid ingestion (causing a malnourishment status), the clearance of creatinine, aldosterone, Na(+) and K(+), and the ratio ClNa(+)/ClCr; it also increases urine osmolarity. Folic acid supplementation increases the clearance of Na(+) and the ratio ClNa(+)/ClCr. SIGNIFICANCE: Folic acid intake improves the hypertension provoked by alcohol by increasing the aldosterone clearance, drastically reducing the serum levels of this hormone and thus its hypertensor effect. PMID- 22227472 TI - 17-beta estradiol in the acetylcholinesterase activity and lipid peroxidation in the brain and blood of ovariectomized adult and middle-aged rats. AB - AIMS: To investigate the 17-beta estradiol in the acetylcholinesterase activity and lipid peroxidation in the brain and blood of ovariectomized rats of different ages. MAIN METHODS: Animals were randomly assigned into three experimental groups of each age (n=6). Control groups consisted of adult (sham-A) and middle-aged (sham-MA) female rats, ovariectomized adult (OVX-A) and middle-aged (OVX-MA) rats without estrogen therapy reposition, and ovariectomized adult (OVX+E2-A) and middle-aged (OVX+E2-MA) rats treated with 17-beta estradiol for 30days. After this period, AChE activity and lipid peroxidation were measured in the brain and blood. KEY FINDINGS: The AChE activity increased (p<0.05) in striatum (ST) in OVX A, OVX+E2-A and OVX-MA, and hippocampus (HP) in OVX-MA. The enzyme activity decreased (p<0.05) in ST of OVX+E2-MA, and cerebral cortex (CC) in OVX+E2-A, OVX MA and OVX+E2-MA. Blood AChE activity increased (p<0.05) in OVX+E2-A and decreased (p<0.05) in OVX-MA. Lymphocyte AChE activity increased (p<0.05) in OVX A and OVX+E2-A and decreased (p<0.05) in OVX-MA. Lipid peroxidation increased (p<0.05) in ST of OVX-A, CC of OVX-A and OVX-MA, HP of OVX-A, and cerebellum (CE) of OVX-A, OVX-MA, and OVX+E2-MA. Lipid peroxidation decreased (p<0.05) in ST, CC and CE of OVX+E2-A, and ST and HP of OVX+E2-MA. Similar values of lipid peroxidation to control groups were found in ST and HP of OVX-MA, HP of OVX+E2-A and CC of OVX+E2-MA. SIGNIFICANCE: 17-beta estradiol is able to modulate the AChE activity and non-neuronal cholinergic response as well as to reduce lipid peroxidation. Its response is dependent on the age and brain structure analyzed. PMID- 22227474 TI - Propofol decreases the axonal excitability in rat primary sensory afferents. AB - AIMS: The aim of this present study was to investigate the changes of peripheral sensory nerve excitability produced by propofol. MAIN METHODS: In a recently described in vitro model of rodent saphenous nerve we used the technique of threshold tracking (QTRAC(r)) to measure changes of axonal nerve excitability of Abeta-fibres caused by propofol. Concentrations of 10 MUMol, 100 MUMol and 1000 MUMol were tested. Latency, peak response, strength-duration time constant (tauSD) and recovery cycle of the sensory neuronal action potential (SNAP) were recorded. KEY FINDINGS: Our results have shown that propofol decreases nerve excitability of rat primary sensory afferents in vitro. Latency increased with increasing concentrations (0MUMol: 0.96 +/- 0.07ms; 1000MUMol 1.10 +/- 0.06ms, P<0.01). Also, propofol prolonged the relative refractory period (0MUMol: 1.79 +/ 1.13ms; 100 MUMol: 2.53 +/- 1.38ms, P<0.01), and reduced superexcitability (0 MUMol: -14.0+/-4.0%; 100MUMol: -9.5 +/- 5.5%) and subexcitability (0MUMol: 7.5 +/ 1.2%; 1000MUMol: 3.6 +/- 1.2) significantly during the recovery cycle (P<0.01). SIGNIFICANCE: Our results have shown that propofol decreases nerve excitability of primary sensory afferents. The technique of threshold tracking revealed that axonal voltage-gated ion channels are significantly affected by propofol and therefore might be at least partially responsible for earlier described analgesic effects. PMID- 22227473 TI - Cell-cell junction remodeling in the heart: possible role in cardiac conduction system function and arrhythmias? AB - Anchoring cell-cell junctions (desmosomes, fascia adherens) play crucial roles in maintaining mechanical integrity of cardiac muscle cells and tissue. Genetic mutations and/or loss of critical components in these macromolecular structures are increasingly being associated with arrhythmogenic cardiomyopathies; however, their specific roles have been primarily attributed to effects within the working (ventricular) cardiac muscle. Growing evidence also points to a key role for anchoring cell-cell junction components in cardiac muscle cells of the cardiac conduction system. This is not only evidenced by the molecular and ultra structural presence of anchoring cell junctions in specific compartments/structures of the cardiac conduction system (sinoatrial node, atrioventricular node, His-Purkinje system), but also because conduction system related arrhythmias can be found in humans and mouse models of cardiomyopathies harboring defects and/or mutations in key anchoring cell-cell junction proteins. These studies emphasize the clinical need to understand the molecular and cellular role(s) for anchoring cell-cell junctions in cardiac conduction system function and arrhythmias. This review will focus on (i) experimental findings that underline an important role for anchoring cell-cell junctions in the cardiac conduction system, (ii) insights regarding involvement of these structures in age related cardiac remodeling of the conduction system, (iii) summarizing available genetic mouse models that can target cardiac conduction system structures and (iv) implications of these findings on future therapies for arrhythmogenic heart diseases. PMID- 22227475 TI - Fructose-1,6-bisphosphate attenuates induction of nitric oxide synthase in microglia stimulated with lipopolysaccharide. AB - AIMS: Fructose-1,6-bisphosphate (FBP) is a glycolytic intermediate with neuroprotective action in various brain injury models. However, the mechanism underlying the neuroprotection of FBP has not been fully defined. In this study, we investigated whether FBP inhibits endotoxin-induced nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in microglial cells and explored the possible mechanisms of the effects of FBP. MAIN METHODS: Murine microglial cell line BV2 and primary cultured murine microglial cells were used. NO production and iNOS expression were determined by Griess reaction, RT PCR and Western blot. Luciferase assay using iNOS promoter-luciferase (iNOS-Luc) construct was adopted for measuring transcriptional activity. KEY FINDINGS: FBP dose-dependently suppressed lipopolysaccharide (LPS)-induced NO production, along with reducing the expression of iNOS at both the protein and mRNA level in primary cultured murine microglia and BV2 cells. FBP significantly inhibited iNOS promoter activity but stabilized iNOS mRNA. Among transcription factors known to be related to iNOS expression, activator protein (AP-1) activation was significantly blocked by FBP. FBP suppressed LPS-induced phosphorylation of three MAPK subtypes-p38 MAPK, JNK and ERK. FBP inhibited LPS-induced production of reactive oxygen species (ROS) and decreased intracellular GSSG/GSH ratio. SIGNIFICANCE: Our findings suggest that FBP attenuates the LPS-induced iNOS expression through inhibition of JNK and p38 MAPK, which might be related to ROS downregulation. PMID- 22227476 TI - The effect of hyperbaric oxygen on neuroregeneration following acute thoracic spinal cord injury. AB - AIMS: Although hyperbaric oxygen (HBO) treatment following spinal cord injury (SCI) have been studied in terms of neurological function and tissue histology, there is a limited number studies on spinal cord tissue enzyme levels. MAIN METHODS: The effect of HBO treatment in SCI was investigated by measuring superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), nitric oxide synthase (NOS) and nitric oxide (NO) activity in the injured tissue. SCI was induced by applying an aneurysm clip extradurally at the level of T9-T11 vertebrae. Preoperative HBO (preopHBO) treatment was applied for 5days and postoperative HBO (postopHBO) for 7days. KEY FINDINGS: In the preopHBO group, a significant decrease was observed in NOS and NO compared to the SCI group. There was a decrease in SOD, NOS and NO in the postopHBO group when compared to the SCI group. In the pre-postHBO group SOD, GPx, NOS and NO decreased significantly. There was a decrease in SOD in postopHBO compared to preopHBO. In the prepostopHBO, SOD decreased significantly compared to that in the preopHBO group. The prepostopHBO presented a significant decrease in GPx compared to postopHBO (p<0.05 for all parameters). No significant difference was observed for catalase for all groups. Significant improvement was found in BBB scores for both postopHBO and prepostHBO groups when compared to the SCI group (p<0.05). SIGNIFICANCE: HBO treatment was found to be beneficial following SCI in terms of biochemical parameters and functional recovery in the postoperative period. PMID- 22227477 TI - Imaging meningiomas with (99m)Tc-tetrofosmin SPECT. PMID- 22227478 TI - Sublabial approach for symptomatic basilar impression. PMID- 22227479 TI - Breschet and Batson. PMID- 22227480 TI - Intraoperative ICG angiography. PMID- 22227483 TI - Higher complications and no improvement in mortality in the ACGME resident duty hour restriction era: an analysis of more than 107,000 neurosurgical trauma patients in the Nationwide Inpatient Sample database. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education resident duty-hour restrictions were implemented in July 2003 based on the supposition that resident fatigue contributes to medical errors. OBJECTIVE: To examine the effect of duty-hour restrictions on outcome in neurotrauma patients. METHODS: The Nationwide Inpatient Sample database was analyzed for a time period with no restrictions (years 1999-2002) compared with a period with restrictions (years 2005-2008) for (1) mortality and (2) complications. We analyzed both teaching and nonteaching hospitals to account for potential differences attributed to non resident-related factors. RESULTS: There were 107,006 teaching hospital and 115,604 nonteaching hospital admissions for neurotrauma. Multivariate logistic regression demonstrated significantly more complications in the time period with restrictions in teaching hospitals. In nonteaching hospitals, there was no difference in complications. In both teaching and nonteaching hospitals, there was no difference in mortality between the 2 time periods. For teaching and nonteaching hospitals, there was no difference in hospital length of stay, but hospital charges were significantly higher in the period with restrictions. The occurrence of a complication was significantly associated with longer hospital length of stay and higher hospital charges in both time periods in both teaching and nonteaching hospitals. CONCLUSION: The implementation of the Accreditation Council for Graduate Medical Education resident duty-hour restrictions was associated with increased complications and no change in mortality for neurotrauma patients in teaching hospitals. In nonteaching hospitals, there was no change in complications and mortality. The occurrence of a complication was associated with longer length of stay and higher hospital charges in both time periods in both teaching and nonteaching hospitals. PMID- 22227484 TI - Spinal nerve origins of the muscular branches of the radial nerve: an electrophysiological study. AB - BACKGROUND: In injuries of the lower brachial plexus, finger flexion can be restored by nerve or tendon transfer. However, there is no technique that can guarantee good recovery of finger and thumb extension. OBJECTIVE: To determine the spinal nerve origins of the muscular branches of the radial nerve and identify potential intraplexus donor nerves for neurotization of the posterior interosseous nerve in patients with lower brachial plexus injuries. METHODS: An intraoperative electrophysiological study was carried out during 16 contralateral C7 nerve transfers. The compound muscle action potential of each muscle innervated by the radial nerve was recorded while the C5-T1 nerves were individually stimulated. RESULTS: The triceps brachii muscle primarily received root contributions from C7. The C5 and C6 nerve roots displayed greater amplitudes for the brachioradialis and supinator muscles compared with those of the C7, C8, and T1 nerve roots (P < .05). The extensor carpi radialis branch was innervated by C5, C6, and C7, and no significant differences were detected between them (P > .05). The amplitudes obtained for the extensor digitorum communis branch were the largest from C7 and C8, without a significant difference between them (P > .05), whereas the amplitudes of the extensor carpi ulnaris and extensor pollicis longus were largest from the C8 root (P < .05). CONCLUSION: The supinator muscle branch is likely the best donor nerve for the repair of lower brachial plexus injuries affecting muscles that are innervated by the posterior interosseous nerve. PMID- 22227485 TI - Influence of sex hormones and genetic predisposition in Sjogren's syndrome: a new clue to the immunopathogenesis of dry eye disease. AB - Sjogren's syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration, destruction of lacrimal and salivary glands and the presence of serum autoantibodies. Most women that suffer from SS are post menopausal however, not all post-menopausal women develop SS, suggesting that other factors, in addition to the decrease in ovarian hormones, are necessary for the development of SS. The purposes of this study were to investigate a) the time course of lymphocytic infiltration and apoptosis in the lacrimal gland after ovariectomy, b) if a predisposed genetic background for SS aggravates the effects of decreasing levels of sex hormones in the lacrimal glands and c) if physiological doses of estrogen or androgen prevent the effects observed after ovariectomy. Six weeks old mice that are genetically predisposed to SS (NOD.B10.H2(b)) and control (C57BL/10) mice were either sham operated, ovariectomized (OVX), OVX + 17beta estradiol (E(2)) or OVX + Dihydrotestosterone (DHT). Lacrimal glands were collected at 3, 7, 21 or 30 days after surgery and processed for immunohistochemistry to measure CD4(+), CD8(+) T cells, B220(+) B cells, nuclear DNA degradation and cleaved caspase-3 activity. Quantification of the staining was done by light microscopy and Image Pro Plus software. The results of our study show that lymphocytic infiltration preceded lacrimal gland apoptosis after ovariectomy. Moreover, removal of ovarian sex hormones accelerated these effects in the genetically predisposed animal and these effects were more severe and persistent compared to control animals. In addition, sex hormone replacement at physiological levels prevented these symptoms. The mechanisms by which decreased levels of sex hormones caused lymphocytic infiltration and apoptosis and the interaction of lack of sex hormones with the genetic elements remain to be elucidated. PMID- 22227486 TI - Structural properties and 4f -> 5d absorptions in Ce-doped LuAlO3: a first principles study. AB - The structural properties and the 4f -> 5d absorptions of Ce-doped LuAlO(3) have been studied using the density functional theory-based generalized gradient approximation PBE + U (PBE: Perdew, Burke and Ernzerhof) and wavefunction-based embedded cluster calculations, respectively. The PBE or PBE + U calculations reveal that the substitution of Ce for Lu induces a strongly anisotropic distortion of the local atomic structure around the dopant site, which is largely insensitive to the value of U for the Ce 4f states. The calculated electronic structures depend explicitly on the value of U, and a value of U ~ 6 eV is determined by comparison with experimental x-ray photoelectron data for CeAlO(3). On the basis of the PBE-optimized structure, CASSCF/CASPT2 (complete-active-space self-consistent-field/second-order perturbation theory) embedded cluster calculations for the Ce(3+) 4f -> 5d transitions yield energy and intensity patterns in fairly good agreement with those estimated from the experimental absorption spectrum. A Mulliken spin population analysis for the 5d(1) states shows that the origins of the states are significantly different from being caused by the cubic crystal field, confirming an earlier conclusion as regards the origin of the 5d(1) states based on semiempirical molecular orbital calculations. The importance of spin-orbit effects on the energies and wavefunctions of the Ce 5d(1) states is highlighted. PMID- 22227487 TI - Polymorphisms in inflammasome' genes and susceptibility to HIV-1 infection. AB - The involvement of inflammasome genes in the susceptibility to HIV-1 infection was investigated. Twelve single nucleotide polymorphisms within NLRP1, NLRP3, NLRC4, CARD8, CASP1, and IL1B genes were analyzed in 150 HIV-1-infected Brazilian subjects and 158 healthy controls. The 2 polymorphisms rs10754558 in NLRP3 and rs1143634 in IL1B were significantly associated to the HIV-1 infection. These findings supported the previously hypothesized involvement of NALP3-inflammasome in HIV-1 pathogenesis, underlining once more the key role of inflammation and innate immunity in the susceptibility to HIV-1 infection. PMID- 22227488 TI - Identifying at-risk populations in Kenya and South Africa: HIV incidence in cohorts of men who report sex with men, sex workers, and youth. AB - OBJECTIVE: To identify and describe populations at risk for HIV in 3 clinical research centers in Kenya and South Africa. DESIGN: Prospective cohort study. METHODS: Volunteers reporting recent sexual activity, multiple partners, transactional sex, sex with an HIV-positive partner, or, if male, sex with men (MSM; in Kenya only) were enrolled. Sexually active minors were enrolled in South Africa only. Risk behavior, HIV testing, and clinical data were obtained at follow-up visits. RESULTS: From 2005 to 2008, 3023 volunteers were screened, 2113 enrolled, and 1834 contributed data on HIV incidence. MSM had the highest HIV incidence rate of 6.8 cases per 100 person-years [95% confidence interval (CI): 4.9 to 9.2] followed by women in Kilifi and Cape Town (2.7 cases per 100 person years, 95% CI: 1.7 to 4.2). No seroconversions were observed in Nairobi women or men in Nairobi or Cape Town who were not MSM. In 327 MSM, predictors of HIV acquisition included report of genital ulcer (Hazard Ratio: 4.5, 95% CI: 1.7 to 11.6), not completing secondary school education (HR: 3.4, 95% CI: 1.6 to 7.2) and reporting receptive anal intercourse (HR: 8.2, 95% CI: 2.7 to 25.0). Paying for sex was inversely associated with HIV infection (HR: 0.2, 95% CI: 0.04 to 0.8). 279 (13.0%) volunteers did not return after the first visit; subsequent attrition rates ranged from 10.4 to 21.8 volunteers per 100 person-years across clinical research centers. CONCLUSIONS: Finding, enrolling, and retaining risk populations for HIV prevention trials is challenging in Africa. African MSM are not frequently engaged for research, have high HIV incidence, need urgent risk reduction counseling, and may represent a suitable population for future HIV prevention trials. PMID- 22227490 TI - Incidence, patterns, and predictors of repeat pregnancies among HIV-infected women in the United Kingdom and Ireland, 1990-2009. AB - OBJECTIVE: To explore the pattern of repeat pregnancies among diagnosed HIV infected women in the United Kingdom and Ireland, estimate the rate of these sequential pregnancies, and investigate the demographic and clinical characteristics of women experiencing them. DESIGN: Diagnosed HIV-infected pregnant women are reported through an active confidential reporting scheme to the National Study of HIV in Pregnancy and Childhood. METHODS: Pregnancies occurring during 1990-2009 were included. Multivariable analyses were conducted fitting Cox proportional hazards models. RESULTS: There were 14,096 pregnancies in 10,568 women; 2737 (25.9%) had 2 or more pregnancies reported. The rate of repeat pregnancies was 6.7 (95% confidence interval: 6.5 to 7.0) per 100 woman years. The proportion of pregnancies in women who already had at least 1 pregnancy reported increased from 20.3% (32 of 158) in 1997 to 38.6% (565 of 1465) in 2009 (P < 0.001). In multivariable analysis, the probability of repeat pregnancy significantly declined with increasing age at first pregnancy. Parity was also inversely associated with repeat pregnancy. Compared with women born in the United Kingdom or Ireland, those from Europe, Eastern Africa, and Southern Africa were less likely to have a repeat pregnancy, whereas women from Middle Africa and Western Africa were more likely to. Maternal health at first pregnancy was not associated with repeat pregnancy. CONCLUSIONS: The number of diagnosed HIV-infected women in the United Kingdom and Ireland experiencing repeat pregnancies is increasing. Variations in the probability of repeat pregnancies, according to demographic and clinical characteristics, are an important consideration when planning reproductive health services and HIV care for people living with HIV. PMID- 22227491 TI - Violence toward women, men's sexual risk factors, and HIV infection among women: findings from a national household survey in Rwanda. AB - OBJECTIVES: We used the third Rwanda demographic and health survey data to examine the relationship between violence toward women, men sexual risk factors, and HIV prevalence among women. METHODS: The Rwanda demographic and health survey was conducted in 10,272 households in 2005. Analyses were restricted to 2715 women and 2461 men who were legally married or cohabiting. We used logistic regression to analyze associations between HIV and violence toward women. Couple specific analyses were carried out for assessing the relationship between men sexual risk factors and intimate partner violence (IPV) reported by their wives. RESULTS: Respectively, 29.2%, 22.2%, and 12.4% of women reported having experienced physical, psychological, and sexual IPV, whereas 52.1% reported control practices by their partners. There was a positive link between IPV reported by women and attitudes justifying wife beating endorsed by their husband. After controlling for sociodemographic variables and women sexual risk factors, the odds of HIV prevalence was 3.23 (confidence interval: 1.30 to 8.03) among women with a score from 3 to 4 on the psychological IPV scale compared with those with a score from 0 to 2. Women who reported having experienced interparental violence (father who beat mother) were more likely to test HIV positive as follows: adjusted odds ratio: 1.95; 95% confidence interval: 1.11 to 3.43. There was also a statistically significant relationship between men risky sexual factors and experience of IPV and HIV prevalence among women. CONCLUSIONS: Violence toward women is associated with HIV in Rwanda. Intervention to reduce gender-based violence should be integrated into HIV/AIDS policy. PMID- 22227492 TI - Molecular cloning and characterization of the sheep alpha-TTP gene and its expression in response to different vitamin E status. AB - The alpha-tocopherol transfer protein (alpha-TTP) is a ~32 kDa protein that exhibits a marked ligand specificity and selectively recognizes of alpha tocopherol, which is the most active form of vitamin E. The alpha-TTP gene has been cloned and its physiological functions have been studied in numbers of species, however, the understanding of sheep alpha-TTP is still in his infancy. In this study, the full-length cDNA of sheep alpha-TTP gene was cloned from sheep liver by using of rapid amplification of complementary DNA ends (RACE). As a result, the sheep alpha-TTP gene was 1098 bp in nucleotide which contained 23 bp 5'-untranslated region (UTR), 226 bp 3'-UTR and 849 bp open reading frame (ORF) that encoded a basic protein of 282 amino acids. Further bioinformatic analysis indicated that the sheep alpha-TTP gene had a high homologous of both nucleotide and amino acid sequences compared with that of other species and had a Sec14p like lipid-binding domain which called the CRAL-TRIO domain. Moreover, the expression of sheep alpha-TTP mRNA and protein in response to different vitamin E supplemented levels were observed according to quantitative real-time PCR (qRT PCR) and Western blotting analysis. The results showed that dietary vitamin E levels did not affect alpha-TTP mRNA expression significantly while the low vitamin E supplemented level groups of sheep had significantly higher alpha-TTP protein compared to high-vitamin E groups. PMID- 22227493 TI - Arbuscular mycorrhizal protein mRNA over-expression in bread wheat seedlings by Trichoderma harzianum Raifi (KRL-AG2) elicitation. AB - Association between arbuscular mycorrhizal fungi (AMF) and majority of terrestrial plant species provides many benefits to plants that range from stress alleviation and bioremediation in soils polluted with heavy metals to plant growth promotion and yield quantity. Some non-arbuscular mycorrhizal fungi such as, Trichoderma harzianum, are known to enhance the AMF symbiosis with vascular plants. However, information about their role in AMF symbiosis is still limited. Shoots of (Avocet S) wheat seedlings were sprayed with the fungal culture filtrate and gene expression patterns were analyzed in the treated tissues. An increase in the level of mRNA of arbuscular mycorrhizal protein comparing with control was found. The over-expression of this protein in wheat tissues might contribute in initiation of AMF colonization in wheat tissues. The result of this study can spark future researches to elucidate possible role of this protein in the symbiotic interaction mechanisms between soil AMF and various plant roots. PMID- 22227495 TI - Identification of a novel isoform of DHRS4 protein with a nuclear localization signal. AB - The DHRS4 gene encodes an NADP(H)-dependent retinol dehydrogenase/reductase (NRDR) and plays an important role in regulating the synthesis of retinoic acid. In the present study, we identified a novel splice RNA variant, designated NRDRA2, of the human DHRS4 gene by RT-PCR, 3' RACE, and 5' RACE. NRDRA2 mRNA lacked exons 4 and 6, and had a shift in the reading frame when compared to DHRS4 mRNA, resulting in loss of the peroxisomal targeting signal of NRDR and gain of a nuclear localization signal in the predicted NRDRA2 protein. Endogenous NRDRA2 protein was identified in the human cervical carcinoma cell line HeLa by immunoprecipitation and mass spectrometric assay. A green fluorescent protein reporter assay showed that NRDRA2 protein mainly localized to the nuclei, confirming the sequence at its C-terminus as a legitimate nuclear localization signal sequence. This study identifies the alternative transcript variant NRDRA2 encoding a subcellular nuclear localized NRDRA2 protein. PMID- 22227494 TI - The Bxb1 gp47 recombination directionality factor is required not only for prophage excision, but also for phage DNA replication. AB - Mycobacteriophage Bxb1 encodes a serine-integrase that catalyzes both integrative and excisive site-specific recombination. However, excision requires a second phage-encoded protein, gp47, which serves as a recombination directionality factor (RDF). The viability of a Bxb1 mutant containing an S153A substitution in gp47 that eliminates the RDF activity of Bxb1 gp47 shows that excision is not required for Bxb1 lytic growth. However, the inability to construct a Delta47 deletion mutant of Bxb1 suggests that gp47 provides a second function that is required for lytic growth, although the possibility of an essential cis-acting site cannot be excluded. Characterization of a mutant prophage of mycobacteriophage L5 in which gene 54 - a homologue of Bxb1 gene 47 - is deleted shows that it also is defective in induced lytic growth, and exhibits a strong defect in DNA replication. Bxb1 gp47 and its relatives are also unusual in containing conserved motifs associated with a phosphoesterase function, although we have not been able to show robust phosphoesterase activity of the proteins, and amino acid substitutions with the conserved motifs do not interfere with RDF activity. We therefore propose that Bxb1 gp47 and its relatives provide an important function in phage DNA replication that has been co-opted by the integration machinery of the serine-integrases to control the directionality of recombination. PMID- 22227496 TI - "Delayed death" phenomenon: a synergistic action of cyclophosphamide and exogenous DNA. AB - Morbidity and mortality in mice were observed upon administration of exogenous DNA following their pre-treatment with a cytostatic agent cyclophosphamide. Upon intraperitoneal injections, the fragments of exogenous DNA reached bone marrow cells. These cells were also found to internalize up to 1800 kb of exogenous DNA ex vivo. The 18-24 h time frame represents a final stage in the repair of DNA double-strand breaks, so when exogenous DNA was administered within this critical period of time, pathological changes were observed in many target organs. Namely, bone marrow cells underwent a sustained increase in apoptosis. Copy number of B1 and B2 DNA repeats in bone marrow cells remained unchanged, whereas in the control group of animals their levels were significantly decreased. Finally, the bone marrow cells of moribund animals completely lacked lymphoid progenitors, yet the CD34+ hematopoietic stem cell counts were normal. Histopathology analysis suggested that mice died due to accidental involution of lymphoid organs combined with a systemic inflammatory process induced by massive administration of exogenous DNA and depletion of lymphoid lineage. PMID- 22227497 TI - Regulation of gene transcription by the oncoprotein MYC. AB - The proteins of the MYC/MAX/MAD network are central regulators of many key processes associated with basic cell physiology. These include the regulation of protein biosynthesis, energy metabolism, proliferation, and apoptosis. Molecularly the MYC/MAX/MAD network achieves these broad activities by controlling the expression of many target genes, which are primarily responsible for the diverse physiological consequences elicited by the network. The MYC proteins of the network possess oncogenic activity and their functional deregulation is associated with the majority of human tumors. Over the last years we have witnessed the accumulation of a considerable number of molecular observations that suggest many different biochemical means and tools by which MYC controls gene expression. We will summarize the more recent findings and discuss how these different building blocks might come together to explain how MYC regulates gene transcription. We note that despite the many molecular details known, we do not have an integrated view of how MYC uses the different tools, neither in a spatial nor in a temporal order. PMID- 22227498 TI - Can post resuscitation electrocardiogram be a 'stand alone' criterion for patient selection for emergency angiography after recovery from out of hospital cardiac arrest? PMID- 22227499 TI - Early findings on brain computed tomography and the prognosis of post-cardiac arrest syndrome: application of the score for stroke patients. AB - AIM: To examine whether early findings of the brain computed tomography (CT) evaluated by the modified Alberta stroke programme early CT (m-ASPECT) score is useful for determining the prognosis of post-cardiac arrest syndrome (PCAS) patients or not. MATERIALS: From 2003 through 2010, 149 consecutive PCAS patients: (1) with various aetiologies but neither from haemorrhagic stroke nor trauma, (2) who were 15 years old or older and (3) whose brain CT was available were admitted to our intensive care unit. Early findings on all of their CT images were rated with the m-ASPECT scoring system by three raters, and an inter rater comparison was conducted. Next, the images within 24 h from arrest were collected from 133 patients (89 males, age 60.2+/-17.6 years), and a relation of the scores with outcome at day 30 of the patients was analysed. RESULTS: According to the inter-rater comparison based on a linear regression analysis, agreement between the raters was good (correlation coefficient 0.76-0.88). A receiver operating curve analysis revealed that the m-ASPECT scores within 24 h were a good predictor of poor outcome (dead or vegetative state) with an area under the curve of 0.905. An m-ASPECT score <=13 was 100% predictive of a poor outcome, with a negative predictive value of 0.57. The m-ASPECT score was the best predictor of poor outcome (odds ratio 45.62) among various factors including cause or duration of arrest. CONCLUSION: The m-APSECT score evaluated within 24 h from arrest was found to be the most predictive factor for outcome at day 30. PMID- 22227500 TI - Comparison of the T-piece resuscitator with other neonatal manual ventilation devices: a qualitative review. AB - AIM: To review the literature surrounding various aspects of T-piece resuscitator use, with particular emphasis on the evidence comparing the device to other manual ventilation devices in neonatal resuscitation. DATA SOURCES: The Medline, EMBASE, Cochrane databases were searched in April 2011. Ongoing trials were identified using www.clinicaltrials.gov and www.controlled-trials.com. Additional studies from reference lists of eligible articles were considered. All studies including T-piece resuscitator use were eligible for inclusion. RESULTS: Thirty studies were included. There were two randomised controlled trials in newborn infants comparing the devices, one of which addressed short and intermediate term morbidity and mortality outcomes and found no difference between the T-piece resuscitator and self inflating bag. From manikin studies, advantages to the T piece resuscitator include the delivery of inflating pressures closer to predetermined target pressures with least variation, the ability to provide prolonged inflation breaths and more consistent tidal volumes. Disadvantages include a technically more difficult setup, more time required to adjust pressures during resuscitation, a larger mask leak and less ability to detect changes in compliance. CONCLUSIONS: There is a need for appropriately designed randomised controlled trials in neonates to highlight the efficacy of one device over another. Until these are performed, healthcare providers should be appropriately trained in the use of the device available in their departments, and be aware of its own limitations. PMID- 22227502 TI - Ulnar subluxation of the median nerve following carpal tunnel release: a case report. AB - Complications of carpal tunnel release, while infrequent, include incomplete release resulting in persistent symptoms or recurrence due to postoperative scarring, as well as iatrogenic damage to nerves and vessels. We present the case of a patient who underwent carpal tunnel release with resolution of symptoms in the immediate postoperative period. At one and a half years post release he started to experience numbness and tingling in a median nerve distribution triggered by repetitive ulnar to radial deviation of the wrist, with no symptoms at rest. Dynamic ultrasound showed a subluxation of the median nerve from one side of the palmaris longus tendon to the other. The patient's symptoms were triggered as the median nerve squeezed in between the palmaris longus and flexor digitorum superficialis tendons. PMID- 22227503 TI - An in vivo mouse model of human skin replacement for wound healing and cell therapy studies. PMID- 22227504 TI - Long-term follow-up of syndromic craniosynostosis after Le Fort III halo distraction: a cephalometric and CT evaluation. AB - BACKGROUND: Midface distraction osteogenesis (DO) in craniofacial synostosis (CFS) patients has been described by several authors. However, very few cephalometric and computed tomography (CT) long-term follow-up studies are available. METHOD: A total of 40 consecutive patients affected by CFS subjected to Le Fort III and rigid external distraction (RED) were examined. All patients had pre-DO cephalometric records, immediately post-DO and 6-12 months post-DO. Twenty-seven patients had mid-term records (3 years post-DO) and 20 patients had long-term records (5-10 years post-DO). Fourteen patients had CT data within 1 year of DO, while 10 patients had long-term CT data (range 5-9 years). RESULTS: Excellent post-surgical stability was recorded. Short- and long-term CT data demonstrated excellent ossification at the osteotomy sites post-DO. In the growing patients, surface resorption in the zygomatic-temporal and in the subspinal area (p < 0.05) was observed in the long-term follow-up, as well as a mild increment of the corrected exorbitism (p < 0.05), as only appositional and no sutural growth occurs post Le Fort III, whereby orbital volume does not increase after surgery. CONCLUSION: Significant advancement of the midface can be achieved and maintained through Le Fort III and RED. In the long term, in growing patients, in general a class III malocclusion does not re-occur, but physiological remodelling processes at the maxillary-zygomatic level, not coupled with sutural growth, tend to mildly re-express the original midfacial phenotype and the exorbitism. PMID- 22227505 TI - Chronic ethanol exposure during adolescence alters the behavioral responsiveness to ethanol in adult mice. AB - Alcohol exposure during early adolescence is believed to durably alter the behavioral properties of ethanol, increasing the likelihood of later alcohol related disorders. The aim of the present experiments was to characterize changes in the behavioral effects of ethanol in adult female Swiss mice after a chronic ethanol exposure during adolescence, extending from postnatal day 28 to postnatal day 42. After a chronic ethanol exposure during adolescence (daily injections of 0, 2.5 or 4 g/kg ethanol for 14 consecutive days), adult mice were tested at postnatal day 63. The locomotor stimulant effects of ethanol, together with ethanol sensitization were tested in experiment 1. In experiment 2, the sedative effects of ethanol were assessed with the loss of righting reflex procedure. Finally, in experiment 3, the anxiolytic effects of ethanol were tested with the light/dark box test. Adult mice chronically exposed to ethanol during adolescence showed a lower basal locomotor activity, but higher locomotor stimulant effects of ethanol than non-exposed mice. Additionally, these adult mice developed higher rates of ethanol sensitization after chronic re-exposure to ethanol in adulthood. Adult mice exposed to ethanol during adolescence also had a stronger tolerance to the sedative effects of high ethanol doses, although they showed no evidence of changes in the anxiolytic effects of ethanol. These results are in agreement with the thesis that chronic alcohol consumption during adolescence, especially in high amounts, increases the risk of later alcohol-related disorders. PMID- 22227506 TI - Effects of MK-801 on recognition and neurodegeneration in an MPTP-induced Parkinson's rat model. AB - Several years after the diagnosis of Parkinson's disease (PD), 20-30% of PD patients develop dementia, known as Parkinson's disease dementia (PDD), the features of which include impairment of short-term memory and recognition function. Hyperactivation of the glutamatergic system is implicated in the neurodegeneration seen in PD. The aim of this study was to determine the effects of MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, on short-term memory and object recognition in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat animal model. MPTP was injected stereotaxically into the substantia nigra pars compacta (SNc) of male Wistar rats, then, starting 1 day later (day 1), the rats were injected daily with MK-801 (0.2 mg/kg/day, i.p.) and rats underwent a bar test on days 1-7, a T-maze test on days 8-10, and object recognition test on days 12-14. On day 1, the animals showed motor dysfunction, which recovered to control levels on day 7. MPTP-lesioned rats showed impairment of working memory in the T-maze test and of recognition in the object recognition test, both of which were prevented by MK-801 treatment. Furthermore, MPTP lesion induced dopaminergic degeneration in the nigrostriatal system, microglial activation in the SNc, and cell loss in the hippocampal CA1 area were all improved by MK-801 treatment. These results suggest that NMDA receptors are involved in PD-related neuronal and behavioral dysfunction. PMID- 22227507 TI - Trial-to-trial variability differentiates motor imagery during observation between low versus high responders: a functional near-infrared spectroscopy study. AB - Trial-to-trial variability is a well-known issue in brain signals measured using functional near-infrared spectroscopy (fNIRS). We aimed to investigate whether trial-to-trial variability does provide information about individual performance. Seventeen subjects observed a virtual reality grasping task in first-person view while either imagining (motor imagery during observation, MIO) or imitating (motor execution, ME) the movements. Each condition was performed with the display in one of two positions, a conventional vertical position and a mirrored horizontal position which placed the virtual arm in the correct position relative to the viewpoint. Averaged oxy-hemoglobin concentration Delta[O(2)Hb] showed that the responses could be differentiated into two distinct groups: low responders (LR) and high responders (HR). Within groups, two main sources of trial-to-trial variability were identified: (a) the Delta[O(2)Hb] amplitude, with largest amplitudes in ME conditions (group HR) and smallest amplitudes in MIO conditions (group LR), and (b) the sign of Delta[O(2)Hb], with positive responses occurring most frequently during ME (group HR) and negative responses most frequently during MIO (group LR). Furthermore, the trial-to-trial dynamics differed between groups and could be described in group LR as inverted polynomial U-shaped curve in the mirror conditions (ME-mirror, MIO-mirror). Last, trial-to-trial variability was significantly dependent on task modality, i.e. ME (group HR) versus MIO (group LR), and/or the mirrored display positions (group LR). Our results show a relationship of trial-to-trial variability to individual MI performance, which may be of significance for neurorehabilitation applications. Although the sources of trial-to-trial variability remain unknown, we suggest that they may contribute to future neurofeedback applications. PMID- 22227509 TI - White matter impairment in the basal ganglia-thalamocortical circuit of drug naive childhood absence epilepsy. AB - PURPOSE: It is unknown whether white matter abnormalities exist in childhood absence epilepsy (CAE), a syndrome of idiopathic epilepsy (IGE). Diffusion tensor imaging (DTI) can noninvasively quantify white matter integrity. This study used DTI to investigate abnormal changes in white matter of untreated CAE patients. METHODS: Subjects included nine patients with untreated CAE and nine age-and sex matched healthy controls. Diffusion tensor imaging parameters were voxel based and statistically compared between patients and controls. The correlations between DTI parameters in regions of interest (ROIs) and age of seizure onset or duration of epilepsy were analyzed. RESULTS: Untreated CAE patients had a significantly higher fractional anisotropy (FA) value in the bilateral thalamus, anterior corpus callosum and upper brainstem, while also displaying a lower FA value in prefrontal white matter, anterior cingulate, and bilateral posterior limbs of the internal capsule compared to control subjects. An increase in mean diffusivity (MD) value was observed in parietal lobe white matter, prefrontal white matter, and posterior cerebellar hemispheres, in addition to subcortical structures including bilateral putamen and posterior limb of internal capsule. MD significant correlations between ROI diffusion parameters and the duration of the disease or the age of onset. CONCLUSIONS: The results showed white matter integrity impairment in the basal ganglia-thalamocortical circuit of drug-naive CAE patients. These abnormalities in white matter may be related to increased cortical excitability and cause cognitive, linguistic, and behavioral/emotional deficits both during and between seizures. PMID- 22227508 TI - Measures of anxiety, sensorimotor function, and memory in male and female mGluR4 /- mice. AB - Metabotropic glutamate receptors (mGluRs) are coupled to second messenger pathways via G proteins and modulate synaptic transmission. Of the eight different types of mGluRs (mGluR1-mGluR8), mGluR4, mGluR6, mGluR7, and mGluR8 are members of group III. Group III receptors are generally located presynaptically, where they regulate neurotransmitter release. Because of their role in modulating neurotransmission, mGluRs are attractive targets for therapies aimed at treating anxiety disorders. Previously we showed that the mGluR4-selective allosteric agonist VU 0155041 reduces anxiety-like behavior in wild-type male mice. Here, we explore the role of mGluR4 in adult (6-month old) and middle-aged (12-month old) male and female mice lacking this receptor. Compared to age- and sex-matched wild type mice, middle-aged mGluR4(-/-) male mice showed increased measures of anxiety in the open field and elevated zero maze and impaired sensorimotor function on the rotarod. These changes were not seen in adult 6-month-old male mice. In contrast to the male mice, mGluR4(-/-) female mice showed reduced measures of anxiety in the open field and elevated zero maze and enhanced rotarod performance. During the hidden platform training sessions of the water maze, mGluR4(-/-) mice swam farther away from the platform than wild-type mice at 6, but not at 12, months of age. mGluR4(-/-) mice also showed enhanced amygdala dependent cued fear conditioning. No genotype differences were seen in hippocampus-dependent contextual fear conditioning. These data indicate that effects of mGluR4 on sensorimotor function and measures of anxiety, but not cued fear conditioning, are critically modulated by sex and age. PMID- 22227510 TI - Rupture of the whole calcified Achilles' tendon. PMID- 22227511 TI - A fatal case of kaposi sarcoma due to immune reconstitution inflammatory syndrome. AB - The prevalence of AIDS-related Kaposi sarcoma (KS) has markedly declined in the era of highly active antiretroviral therapy (HAART) although it remains one of the most common AIDS-defining malignancies. Although immune reconstitution inflammatory syndrome (IRIS)-related KS (IRIS-KS) represents only a fraction of the IRIS cases, it can be a life-threatening situation. This report describes a fatal case of IRIS-KS. A 32-year-old man with HIV/AIDS was initiated on HAART and experienced rapid immunological and virological response to therapy. He subsequently experienced progressively severe dyspnea and papulonodular skin lesions and was admitted to the hospital with hypoxic respiratory failure. Bronchoscopy revealed numerous friable endobronchial lesions. Histopathology of a skin lesion was consistent with KS. The relatively rapid progression of disease in the setting of improvement in immune function after initiating HAART suggested IRIS-KS. This report reviews previously published cases of IRIS-KS and describes risk factors, immunopathogenesis and treatment options. PMID- 22227512 TI - Fistula formation between the right and left main bronchus caused by endobronchial tuberculosis. AB - The prevalence of endobronchial tuberculosis (EBTB) in patients with active tuberculosis is about 10% to 40%. The most common complication of EBTB is bronchial stenosis. Fistula formation by pulmonary tuberculosis is a very rare complication and is most commonly bronchopleural. The authors present a 53-year old woman presented with chronic cough and abnormality in chest computed tomography scan. According to chest computed tomography scan finding, bronchoscopic study was done and bronchial lavage was obtained. Bronchial lavage was positive for acid fast bacilli. Bronchoscopy showed fistula formation between the right and left main bronchus, a rare manifestation of EBTB. The patient was treated with antituberculosis therapy, and her symptoms improved and radiological findings showed regression of pulmonary lesions. PMID- 22227513 TI - Epoprostenol-induced hypersplenism in portopulmonary hypertension. AB - Portopulmonary hypertension (POPH) is a not infrequent but serious complication of liver cirrhosis. Continuous intravenous epoprostenol infusion is a treatment option for this condition. Progressive splenomegaly with pancytopenia (hypersplenism) is associated with epoprostenol use in POPH. After recognizing a case of epoprostenol-induced hypersplenism that resolved upon stopping the drug, the authors retrospectively reviewed all patients treated with epoprostenol at the center for both POPH and pulmonary hypertension due to other causes. Five of 11 patients with POPH developed hypersplenism secondary to epoprostenol. In 1 patient, and possibly in a second, the hypersplenism resolved upon discontinuation of epoprostenol. None of 9 patients with pulmonary hypertension due to other causes developed splenomegaly. This report confirms hypersplenism as a complication of epoprostenol therapy for POPH. Furthermore, the authors demonstrate for the first time that hypersplenism may be reversed by stopping the medication and propose a mechanism for this phenomenon. PMID- 22227514 TI - Unicentric Castleman's disease presenting with growth retardation and iron deficiency anemia. AB - A 16-year-old boy presented with growth retardation and iron deficiency anemia. The disease was identified incidentally in the pararenal retroperitoneum after computed tomography and magnetic resonance imaging scans. A retroperitoneal lesion was removed in its entirety and was histologically confirmed to be a symptom of Castleman's disease of the unicentric plasma cell type. The unicentric plasma cell type appears so rarely in the retroperitoneum that a similar case has been reported only once. The patient was discharged on day 9 after surgery without significant complications and grew 18 cm within a year. PMID- 22227515 TI - Radiological signs in achalasia. PMID- 22227516 TI - Iron deficiency anemia related to hereditary hemorrhagic telangiectasia: response to treatment with bevacizumab. AB - Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant condition associated with arteriovenous malformations (AVMs) or telangiectasias of the pulmonary, gastrointestinal or hepatic circulations. The authors present a case of a 52-year-old woman with a known diagnosis of HHT who presented for evaluation of anemia. She had an extensive history of iron sucrose infusions, frequent blood transfusions and hospitalizations for anemia related to gastrointestinal bleeding and epistaxis. The patient was treated with bevacizumab at a dose of 5 mg/kg infusion every 2 weeks for 4 cycles. In the next 4 months, her hemoglobin improved to 13.7 g/dL and she did not require iron or packed red blood cell transfusions for the next 8 months. Abnormal angiogenesis primarily due to mutations in the transforming growth factor beta receptor endoglin and the activin receptor-like kinases is a central contributor to the formation of AVMs in HHT. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor and therefore may be a useful treatment against AVM formation in patients with HHT. The authors do caution that therapy has to be individualized as there are no randomized trials regarding its usage in patients with HHT. PMID- 22227517 TI - Tumoral calcinosis of shoulders. PMID- 22227518 TI - A useful method for the detection of ethylenediaminetetraacetic acid- and cold agglutinin-dependent pseudothrombocytopenia. AB - INTRODUCTION: Pseudothrombocytopenia (PTCP), caused by platelet (PLT) aggregation, is usually associated with ethylenediaminetetraacetic acid (EDTA) dependent antibodies and cold aggluti-nins against PLT antigens. The aim of this study was to identify the PTCP and discover the most practical method to distinguish it from real thrombocytopenia. METHODS: This study included 85 patients without hemorrhagic abnormalities and suspected PTCP. Blood samples containing EDTA, citrate and EDTA-kanamycin (KN) were analyzed at room temperature and 37 degrees C. RESULTS: PTCP was detected in 24 of 85 patients. In 23 of 24 patients, EDTA-dependent pseudothrombocytopenia (EDTA-PTCP) was detected; 5 of whom had also the cold agglutinin-dependent PTCP. In only 1 of 24 patients, the cold agglu-tinin-dependent PTCP was found. In this study, no significant difference was observed in leukocyte counts comparing EDTA and citrate blood samples in cases with EDTA-PTCP. CONCLUSION: In clinical laboratories, a significant portion of the cases with low PLT counts was attributable to EDTA-PTCP and, therefore, did not require treatment. Even if these cases can be detected by bringing the blood samples containing EDTA to 37 degrees C or by adding KN to blood samples containing EDTA, the use of blood samples containing citrate taken for erythrocyte sedimentation rate analysis is a more practical priority method. PMID- 22227519 TI - Ablation of Rassf2 induces bone defects and subsequent haematopoietic anomalies in mice. AB - RASSF2 belongs to the Ras-association domain family (RASSF) of proteins, which may be involved in the Hippo signalling pathway. However, the role of RASSF2 in vivo is unknown. Here, we show that Rassf2 knockout mice manifest a multisystemic phenotype including haematopoietic anomalies and defects in bone remodelling. Bone marrow (BM) transplantation showed that Rassf2(-/-) BM cells had a normal haematopoietic reconstitution activity, indicating no intrinsic haematopoietic defects. Notably, in vitro differentiation studies revealed that ablation of Rassf2 suppressed osteoblastogenesis but promoted osteoclastogenesis. Co-culture experiments showed that an intrinsic defect in osteoblast differentiation from Rassf2(-/-) osteoblast precursors likely leads to both haematopoiesis and osteoclast defects in Rassf2(-/-) mice. Moreover, Rassf2 deficiency resulted in hyperactivation of nuclear factor (NF)-kappaB during both osteoclast and osteoblast differentiation. RASSF2 associated with IkappaB kinase (IKK) alpha and beta forms, and suppressed IKK activity. Introduction of either RASSF2 or a dominant-negative form of IKK into Rassf2(-/-) osteoclast or osteoblast precursors inhibited NF-kappaB hyperactivation and normalized osteoclast and osteoblast differentiation. These observations indicate that RASSF2 regulates osteoblast and osteoclast differentiation by inhibiting NF-kappaB signalling. PMID- 22227520 TI - The architecture of functional modules in the Hsp90 co-chaperone Sti1/Hop. AB - Sti1/Hop is a modular protein required for the transfer of client proteins from the Hsp70 to the Hsp90 chaperone system in eukaryotes. It binds Hsp70 and Hsp90 simultaneously via TPR (tetratricopeptide repeat) domains. Sti1/Hop contains three TPR domains (TPR1, TPR2A and TPR2B) and two domains of unknown structure (DP1 and DP2). We show that TPR2A is the high affinity Hsp90-binding site and TPR1 and TPR2B bind Hsp70 with moderate affinity. The DP domains exhibit highly homologous alpha-helical folds as determined by NMR. These, and especially DP2, are important for client activation in vivo. The core module of Sti1 for Hsp90 inhibition is the TPR2A-TPR2B segment. In the crystal structure, the two TPR domains are connected via a rigid linker orienting their peptide-binding sites in opposite directions and allowing the simultaneous binding of TPR2A to the Hsp90 C terminal domain and of TPR2B to Hsp70. Both domains also interact with the Hsp90 middle domain. The accessory TPR1-DP1 module may serve as an Hsp70-client delivery system for the TPR2A-TPR2B-DP2 segment, which is required for client activation in vivo. PMID- 22227522 TI - Thymic function after allogeneic stem cell transplantation is dependent on graft source and predictive of long term survival. AB - T-cell deficiency after allogeneic stem cell transplantation (ASCT) is common and has major impact on clinical outcome. In this retrospective study 210 patients were analyzed with regards to levels of T-cell receptor excision circles (TRECs) during the first 24 months after transplantation. We could for the first time show a significant correlation between the use of bone marrow grafts and higher TREC levels >6 months post-ASCT (p<0.001). Treatment with anti-thymocyte globulin was correlated with lower TREC levels <=6 months post-ASCT (p<0.001). Patients with TREC levels above median at 3 months had a superior overall survival, 80% vs. 56% (p=0.002), and lower transplantation-related mortality, 7% vs. 21% (p=0.01). We conclude that graft source and conditioning regimen may have a significant effect on T-cell reconstitution after ASCT and can thus affect outcome. These results strongly support the use of TREC measurement as part of the standard repertoire of immunological monitoring after ASCT. PMID- 22227521 TI - Genetic evidence of a redox-dependent systemic wound response via Hayan protease phenoloxidase system in Drosophila. AB - Systemic wound response (SWR) through intertissue communication in response to local wounds is an essential biological phenomenon that occurs in all multicellular organisms from plants to animals. However, our understanding of SWR has been greatly hampered by the complexity of wound signalling communication operating within the context of an entire organism. Here, we show genetic evidence of a redox-dependent SWR from the wound site to remote tissues by identifying critical genetic determinants of SWR. Local wounds in the integument rapidly induce activation of a novel circulating haemolymph serine protease, Hayan, which in turn converts pro-phenoloxidase (PPO) to phenoloxidase (PO), an active form of melanin-forming enzyme. The Haemolymph Hayan-PO cascade is required for redox-dependent activation of the c-Jun N-terminal kinase (JNK) dependent cytoprotective program in neuronal tissues, thereby achieving organism level of homeostasis to resist local physical trauma. These results imply that the PO-activating enzyme cascade, which is a prominent defense system in humoral innate immunity, also mediates redox-dependent SWR, providing a novel link between wound response and the nervous system. PMID- 22227523 TI - Expression of a single-copy hsp-16.2 reporter predicts life span. AB - The level of green fluorescent protein expression from an hsp-16.2-based transcriptional reporter predicts life span and thermotolerance in Caenorhabditis elegans. The initial report used a high-copy number reporter integrated into chromosome IV. There was concern that the life-span prediction power of this reporter was not attributable solely to hsp-16.2 output. Specifically, prediction power could stem from disruption of some critical piece of chromatin on chromosome IV by the gpIs1 insertion, a linked mutation from the process used to create the reporter, or from an artifact of transgene regulation (multicopy transgenes are subject to regulation by C elegans chromatin surveillance machinery). Here we determine if the ability to predict life span and thermotolerance is specific to the gpIs1 insertion or a general property of hsp 16.2-based reporters. New single-copy hsp-16.2-based reporters predict life span and thermotolerance. We conclude that prediction power of hsp-16.2-based transcriptional reporters is not an artifact of any specific transgene configuration or chromatin surveillance mechanism. PMID- 22227524 TI - Occurrence of hypotension in older participants. Which 24-hour ABPM parameter better correlate with? AB - OBJECTIVES: The aim of the present study was to investigate the prevalence of hypotension in older participants and to identify which 24-hour ambulatory blood pressure monitoring parameter better correlated with the occurrence of hypotension. METHODS: We studied 588 elderly participants (mean age 78.7 +/- 7.1 years; 70% women) who underwent a 24-hour ambulatory blood pressure (BP) monitoring, without moderate-to-severe cognitive impairment, myocardial infarction, or stroke within the previous 6 months; renal (serum creatinine > 2.5 mg/dL), respiratory, or liver insufficiency; and atrial fibrillation. RESULTS: In older participants, the occurrence of systolic hypotension is very common (~55% presenting at least one episode of systolic blood pressure (SBP) < 100 mmHg and about 20% presenting >=10% of the SBP registrations < 100 mmHg). More than 30% of participants with 24-hour SBP, daytime, and nighttime above the reference threshold had hypotension. Hypotension did not correlated with BP variability indices (standard deviation of BPs). None of the parameters commonly present in 24-hour ambulatory BP monitoring clinical reports is able to accurately identify those older participants with episode of hypotension. CONCLUSION: Episodes of SBP hypotension are extremely common in older participants and do not appear to relate to BP variability indices. Indeed, no parameter of 24-hour ambulatory BP monitoring was capable to accurately identify the occurrence of hypotension. We expect that ongoing studies will contribute to identification of specific factors predicting hypotensive episodes in the older participants. PMID- 22227525 TI - Treatment for relapsed acute myeloid leukemia: what is new? AB - PURPOSE OF REVIEW: Despite enormous progress in the understanding of leukemia pathophysiology and novel transplantation protocols, the prognosis following acute myeloid leukemia (AML) relapse is still uniformly poor. In the current review, advances in risk stratification, protocols involving novel agents and allogeneic stem cell transplantation (ASCT) will be discussed in light of the vision of personalized therapy. RECENT FINDINGS: The role of ASCT in relapsed/refractory AML is well established and has been recently confirmed as mandatory for cure. Retrospective observations of different large cohorts categorized patients with early relapse, poor cytogenetics or fms-like tyrosine kinase receptor-3 internal tandem duplication mutation as the most challenging population. Multiple novel agents have been studied with various promising results; however, these agents can only serve as a bridge to transplantation. If ASCT is not an option, therapy should focus on prolongation of patient's life at its best possible quality. Accumulated molecular data open new horizons for personalizing therapy and assigning each patient to the drug or protocol from which the patient will benefit most. SUMMARY: Relapsed/refractory AML is a heterogeneous disease and no uniform protocol will provide cure to all patients. Molecular tests may contribute to future personalizing therapy resulting in improved outcome. Meanwhile, novel and more effective induction and postremission protocols are warranted to lower the relapse rate. PMID- 22227526 TI - Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission: have the indications changed? AB - PURPOSE OF REVIEW: Many improvements in chemotherapy and supportive care, as well as greater understanding of immunology and procuring graft sources, have led to more acute myeloid leukemia patients proceeding to hematopoietic cell transplantation, now the most common indication for this procedure. RECENT FINDINGS: As treatment-related mortality rates have been reduced, more practitioners and patients are amenable to use of this modality if the risk : benefit ratio appears justified. Clinical factors initially were used to identify patients at highest risk for relapse using conventional approaches, a strategy supplanted by one based on the genetic alterations of the leukemia cells. More recently, molecular factors are used to identify such candidates; the issue of which first remission acute myeloid leukemia patients receive hematopoietic cell transplantation is referred to as risk stratification. SUMMARY: With significant improvements in donor : recipient matching and a more varied graft source, greater numbers of patients can proceed to alternative donor hematopoietic cell transplantation. Advancing age appears to be less of a barrier and outcomes are reasonable in patients with good performance status and few comorbidities. The most interesting aspect of the moving target of which patients to take to hematopoietic cell transplantation is to define those with favorable-risk disease and avoid the procedure, while using the armamentarium at hand to identify those at higher and highest risk for relapse as the group most likely to benefit. The field, however, still awaits the data that demonstrate improved outcome in these poor-risk patients using the hematopoietic cell transplantation approach. PMID- 22227527 TI - Transplantation for myelodysplastic syndrome in the era of hypomethylating agents. AB - PURPOSE OF REVIEW: This review summarizes the available data on the role of hypomethylating agents in the setting of hematopoietic cell transplantation (HCT) for myelodysplastic syndrome (MDS). RECENT FINDINGS: Although hypomethylating agents have been established as standard of therapy for MDS in the nontransplant setting, the role of these agents in patients who are candidates for HCT or are undergoing HCT is less well defined. Hypomethylation therapy has been investigated in both the pre-HCT and post-HCT setting. Patients who are transplant candidates and are given pre-HCT hypomethylating therapy should proceed with HCT when 'best response' is achieved; HCT when hypomethylation has failed is associated with inferior outcome. Only limited data have been presented on the use of hypomethylating agents after HCT. Although this approach may prove to be useful in reducing post-HCT relapse, such therapy should only be given in the setting of clinical trials. SUMMARY: Treatment planning for patients with MDS who are HCT candidates should comprise the entire treatment arc including pre-HCT debulking, possibly with hypomethylating agents, conditioning regimen, and potential post-HCT treatment, be it prophylactic, pre-emptive or therapeutic. PMID- 22227529 TI - Current treatment strategies in chronic myeloid leukemia. AB - PURPOSE OF REVIEW: Imatinib was registered several years ago for the treatment of chronic-phase chronic myeloid leukemia. Because of the occurrence of resistance with imatinib, new drugs have been developed recently, two of which, nilotinib and dasatinib, are being registered for frontline therapy. However physicians may be confused as to how to treat and manage their newly diagnosed patients. The value of new scoring systems and well known surrogate markers such as cytogenetic and molecular responses as well as recent data from phase II or III trials are presented and discussed. RECENT FINDINGS: The analysis of trials comparing 400 mg of imatinib to higher doses suggests that 400 mg still seems to be the appropriate initial dose. However, doses of 800 mg could be proposed for high risk patients or for those with slower response. Sokal and Euro scoring systems are useful and should be calculated before initiating the treatment. The achievement of early complete cytogenetic response is still a valid surrogate marker, although close molecular monitoring is also mandatory. Second-generation tyrosine kinase inhibitors have proved their efficacy by reducing the rate of progression to advanced phases. SUMMARY: Long-term follow-up of ongoing trials investigating tyrosine kinase inhibitors, alone or in combination with interferon, will assess their efficacy on overall survival. PMID- 22227528 TI - New generation small-molecule inhibitors in myeloproliferative neoplasms. AB - PURPOSE OF REVIEW: Myeloproliferative neoplasms (MPNs) are diseases that carry the JAK2 (V617F) mutation in about 70% of the patients. The purpose of this review is to describe the recent advances in the therapy of MPNs with JAK2 inhibitors. RECENT FINDINGS: Many drugs are now under investigations targeting different pathways critical for MPN development, such as the JAK-STAT (JAK2 inhibitors: INCB018424 or ruxolitinib, TG101348 or SAR302503, CYT387, SB1518, CEP701 and LY2784544) and the PI3K/AKT/mTOR (everolimus) pathways, or act through remodeling of chromatin with a key role in epigenetics (givinostat, panobinostat and vorinostat). The most relevant effects were spleen size reduction and relief of constitutional symptoms. SUMMARY: Patients who might benefit from JAK2 inhibitors in clinical practice are mostly those with splenomegaly or with constitutional symptoms. We should alert patients with lower hemoglobin levels that these therapies might, although temporarily, favor the need for red blood cell transfusions. PMID- 22227530 TI - Resveratrol plus ethanol counteract the ethanol-induced impairment of energy metabolism: 31P NMR study of ATP and sn-glycerol-3-phosphate on isolated and perfused rat liver. AB - The effects of trans-resveratrol (RSV) combined with ethanol (EtOH) were evaluated by (31)P NMR on total ATP and sn-glycerol-3-phosphate (sn-G3P) contents measured in real time in isolated and perfused whole liver of the rat. Mitochondrial ATP turnover was assessed by using specific inhibitors of glycolytic and mitochondrial ATP supply (iodacetate and KCN, respectively). In RSV alone, the slight decrease in ATP content (-14+/-5% of the initial content), sn-G3P content and ATP turnover were similar to those in the Krebs-Henseleit buffer control. Compared to control, EtOH alone (14 or 70 mmol/L) induced a decrease in ATP content (-24.95+/-2.95% of initial content, p<0.05) and an increase in sn-G3P (+158+/-22%), whereas ATP turnover tended to be increased. RSV (20 MUmol/L) combined with EtOH, (i) maintained ATP content near 100%, (ii) induced a 1.6-fold increase in mitochondrial ATP turnover (p=0.049 and p=0.004 vs EtOH 14 and 70 mmol/L alone, respectively) and (iii) led to an increase in sn-G3P (+49+/-9% and +81+/-6% for 14 and 70 mmol/L EtOH, respectively). These improvements were obtained only when glycolysis was efficient at the time of addition of EtOH+RSV. Glycolysis inhibition by iodacetate (IAA) evidenced an almost 21% contribution of this pathway to ATP content. RSV alone or RSV+EtOH prevented the ATP decrease induced by IAA addition (p<0.05 vs control). This is the first demonstration of the combined effects of RSV and EtOH on liver energy metabolism. RSV increased (i) the flux of substrates through ATP producing pathways (glycolysis and phosphorylative oxidation) probably via the activation of AMPkinase, and (ii) maintained the glycolysis deviation to sn-G3P linked to NADH+H+ re-oxidation occurring during EtOH detoxication, thus reducing the energy cost due to the latter. PMID- 22227531 TI - Vertical self-assembly of modified multiwalled carbon nanotubes on gold surfaces induced by chitosan and Tween. AB - Multiwalled carbon nanotubes modified with 2-aminoethanethiol (MWNT-AET) were vertically self-assembled on gold electrodes with the assistance of chitosan and Tween. According to AFM and cyclic voltammetric determinations the best results were achieved using chitosan. PMID- 22227532 TI - Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. AB - In an effort to uncover systematic learnings that can be applied to improve compound survival, an analysis was performed on data from Phase II decisions for 44 programs at Pfizer. It was found that not only were the majority of failures caused by lack of efficacy but also that, in a large number of cases (43%), it was not possible to conclude whether the mechanism had been tested adequately. A key finding was that an integrated understanding of the fundamental pharmacokinetic/pharmacodynamic principles of exposure at the site of action, target binding and expression of functional pharmacological activity (termed together as the 'three Pillars of survival') all determine the likelihood of candidate survival in Phase II trials and improve the chance of progression to Phase III. PMID- 22227533 TI - Synthesis of alpha-indanones via intramolecular direct arylation with cyclopropanol-derived homoenolates. AB - A palladium-catalysed, tandem cyclopropanol rearrangement and direct arylation approach for the synthesis of 1-indanones is reported. The reaction is generally high yielding, uses oxygen as the terminal oxidant and tolerates a range of functional groups on the aryl ring. PMID- 22227534 TI - Accurate quantification of tetanus neurotoxin-induced focal spasticity in mice using complex running wheels. AB - Tetanus neurotoxin (TeNT) enhances activity of motoneurons by blocking spinal inhibitory interneurons. Based on this pathomechanism, we propose that low-dosage intramuscular injections of TeNT could serve as a specific treatment for central paretic muscles. However in vivo TeNT research is restricted because of the fear of triggering widespread muscle spasms. In addition, no reliable test to measure the in vivo toxicity of low-dosage TeNT is available. We introduce a novel wheel running-based paradigm with mice to quantify functional effects and thus the toxicity of low-dosage TeNT in vivo. We accustomed three groups of wildtype mice (n=14) to using a complex running wheel with irregularly spaced crossbars. Each group received an injection with a different low-dosage of TeNT (0.15 ng, 0.1 ng or 0.05 ng TeNT) into both tibialis anterior muscles. The maximum running velocity and accumulative running time of the groups were recorded during the following weeks. Three days after TeNT injections, the mice exhibited an increase in muscle tone of the injected tibialis anterior muscles but no generalized symptoms. However, we found that normal running in the complex wheel set-up was disturbed such that the maximum running velocity and running time of the mice decreased with the size of the dose. This effect peaked on the fifth and sixth nights after injection and returned to baseline level again within the next two weeks. With this novel in vivo automated paradigm we can accurately and objectively quantify the duration and degree of TeNT-induced focal increase in muscle tone. PMID- 22227535 TI - Complex-number representation of informed basis functions in general linear modeling of Functional Magnetic Resonance Imaging. AB - Functional Magnetic Resonance Imaging (fMRI), measuring Blood Oxygen Level Dependent (BOLD), is a widely used tool to reveal spatiotemporal pattern of neural activity in human brain. Standard analysis of fMRI data relies on a general linear model and the model is constructed by convolving the task stimuli with a hypothesized hemodynamic response function (HRF). To capture possible phase shifts in the observed BOLD response, the informed basis functions including canonical HRF and its temporal derivative, have been proposed to extend the hypothesized hemodynamic response in order to obtain a good fitting model. Different t contrasts are constructed from the estimated model parameters for detecting the neural activity between different task conditions. However, the estimated model parameters corresponding to the orthogonal basis functions have different physical meanings. It remains unclear how to combine the neural features detected by the two basis functions and construct t contrasts for further analyses. In this paper, we have proposed a novel method for representing multiple basis functions in complex domain to model the task-driven fMRI data. Using this method, we can treat each pair of model parameters, corresponding respectively to canonical HRF and its temporal derivative, as one complex number for each task condition. Using the specific rule we have defined, we can conveniently perform arithmetical operations on the estimated model parameters and generate different t contrasts. We validate this method using the fMRI data acquired from twenty-two healthy participants who underwent an auditory stimulation task. PMID- 22227536 TI - In vitro malignant transformation of human bronchial epithelial cells induced by benzo(a)pyrene. AB - In this study, the human bronchial epithelial cells (16HBE) were treated five times with 10MUM benzo(a)pyrene (BaP), followed by 20 passages culture, and the in vitro BaP-induced malignant transformation of 16HBE cells was established. Five colonies in soft agarose were then amplified and donated as T-16HBE-C1~5 cells, respectively. T-16HBE-C1~5 cells can form tumors subcutaneously in nude mice. Histopathological changes in the tumors indicated nests growth, high nuclear-cytoplasmic ratios, coarse and clumped chromatin, numerous and distinctly atypical mitoses, cell necrosis and surrounding normal adipose, muscle and connective tissue immersed. In addition, lung metastasis was observed in nude mice in T-16HBE-C1, 3 and 4 groups. In vitro cell migration assay results indicated that T-16HBE-C2~5 cells showed much lower migration capabilities than 16HBE cells. Western blotting analysis showed that the expressions of p53 and p Akt (Ser473) in T-16HBE-C1~5 cells were significant higher than those in 16HBE cells. Our results demonstrated that BaP could induce the malignant transformation of 16HBE cells, and p53 and p-Akt (Ser473) might play crucial roles in BaP-induced carcinogenesis. The five monoclonal cell lines (T-16HBE C1~5) with different migration capabilities could be used as research models for further understanding the mechanisms of BaP-induced carcinogenesis and cell migration. PMID- 22227537 TI - Determination of 239Pu/240Pu isotopic ratio by high-resolution alpha-particle spectrometry using the ADAM program. AB - A novel analysis program to unfold alpha-particle energy spectra was introduced, demonstrated and validated using radiochemically processed test sources, which contained different amounts of (239)Pu and (240)Pu. A high-resolution alpha spectrometer was used for data acquisition. The software known as ADAM unfolds the spectra using nuclide-specific decay data as a constraint. The peaks can have different shapes and the software can also cope with the coincidences between alpha particles and electrons/photons. In the present paper, the (239)Pu/(240)Pu activity ratios from alpha spectrometry agreed, within the stated uncertainties, with the reference values. Number of counts in the (239,240)Pu peak group must be larger than 100 to obtain reliable values when using semiconductor detector of energy resolution FWHM=10.6 keV. PMID- 22227538 TI - Measurement of natural radioactivity in building materials of Namakkal, Tamil Nadu, India using gamma-ray spectrometry. AB - The natural level of radioactivity in building materials is one of the major causes of external exposure to gamma-rays. The primordial radionuclides in building materials are one of the sources of radiation hazard in dwellings made of these materials. By the determination of the radioactivity level in building materials, the indoor radiological hazard to human health can be assessed. This is an important precautionary measure whenever the dose rate is found to be above the recommended limits. The aim of this work was to measure the specific activity concentration of (226)Ra, (232)Th and (40)K in commonly used building materials from Namakkal, Tamil Nadu, India, using gamma-ray spectrometer. The radiation hazard due to the total natural radioactivity in the studied building materials was estimated by different approaches. The concentrations of the natural radionuclides and the radium equivalent activity in studied samples were compared with the corresponding results of different countries. From the analysis, it is found that these materials may be safely used as construction materials and do not pose significant radiation hazards. PMID- 22227539 TI - Supine craniospinal irradiation in children: patient position modification, dose uniformity and early adverse effects. AB - BACKGROUND: Different craniospinal irradiation techniques are complex. The homogeneity of the dose to the target and the normal tissues at risk affect both the control rate and the level of adverse effects. PATIENTS AND METHODS: Thirty one patients were treated with CSI in the supine position. Custom-made Styrofoam was tailored for each patient to straighten the convexity and concavity of the spinal axis allowing better dose distribution uniformity during CSI technique. In the first 6 patients, CT simulation were performed twice: one time with the patient lying directly on the vacuum mattress without the foam (the conventional way) and the second while lying on the foam. Dose distribution was calculated using a 3D conformal planning. The gap between the fields was determined using isodose alignment method. All treatment portals were verified during the first 3 treatment sessions and once weekly thereafter using either cone-beam or portal image device. Weekly feathering (shifting of the junction between the 2 adjacent radiation fields) was routinely performed. RESULTS: The 95% dose distribution had better coverage with the foam (p=0.042) while the hot volume of 110% and 105% dosage were significantly lesser than conventional technique (both p=0.028). The organs at risk received nearly similar radiation doses in the 2 positions. The CSI led to minimal immediate adverse effects that were reversible. Weight loss was experienced by 55% of patients. CONCLUSION: This modified technique of CSI is simple, ensuring better dose distribution to CSI target without increasing the dose to the surrounding organs at risk. It is tolerable and safe to apply. PMID- 22227540 TI - Colorectal carcinoma at Al-Gamhouria Teaching Hospital, Aden, Yemen. AB - OBJECTIVE: Colorectal cancer is the first common cause of cancer in men and the fourth cause after breast, NHL and ovary in women in Aden. This study aims to retrospectively analyze the pattern of patients with colorectal cancer seen in Oncology Unit, at Al-Gamhouria Teaching Hospital from January to December 2008. MATERIAL AND METHODS: All cases of colorectal cancer presented at oncology unit, Al-Gamhouria Teaching Hospital in Aden Yemen between January and December 2008 were reviewed and the data was analyzed to determine age, gender, residency, clinical presentation, histological types and staging of disease and treatment. RESULTS: A total of 50 cases were included in the study, 34 (68%) male and 16 (34%) were female. (M:F 2.1:1). The mean age at presentation was 48.8 years for females and 56.4 for males. Abdominal pain (70%) and bleeding per rectum (50%) were the main presenting complaints. The most common sites are rectum (34%), caecum and ascending colon (30%) and sigmoid in 18% of cases. 82% of tumors of colorectal region were adenocarcinomas, the majority of which (66%) were well to moderately differentiated adenocarcinoma. Stages at presentation were: stage I (12%), stage II (18%), stage III (52%) and stage IV (18%). CONCLUSION: There is an increased incidence of colorectal carcinoma. Bad outcome directly related to late detection of cancer and >70 % of cases in stages III and IV. There is need to increase awareness through public education about this malignancy and its management. Any adult with complaints of vague abdominal pain, blood or mucus in the stool or features of haemorrhoids which may herald the onset of colorectal cancer should be adequately investigated with digital rectal examination (DRE) and proctosigmoidoscopy and barium enema where appropriate. PMID- 22227541 TI - Treatment of Stage I Seminoma testis with extended field adjuvant radiation. AB - With an aim to analyze and document the outcome of Stage I Seminoma patients we undertook a retrospective analysis of patients treated between January 1990 and December 1998. The treatment charts of patients treated between January 1990 and December 1998 were reviewed. Patient and tumor characteristics, treatment details, relapse rates, late toxicities, or occurrence of second primary was noted. Royal Marsden Staging System was utilized because of its simplicity and wide-use in the above period. Out of 137 patients, 41 (30%) patients did not receive any further treatment, 96 (70%) patients received prophylactic radiotherapy to para-aortic and pelvic nodes. The observation group patients had a median follow-up 20 months, 9 patients had nodal relapse with 7 in retroperitoneal nodes and 2 patients in inguinal nodes. Of these, 7 patients received BEP chemotherapy and 2 patients Chemoradiation. Four patients had complete remission while remaining 5 patients had partial response. The histopathologies of all the 5 patients with partial response were reviewed to reconfirm the diagnosis. Patients of prophylactic radiotherapy group had a follow up of 33 months, 6 patients relapsed, RP nodal disease in 5 patients and distant metastasis in 1 patient. All these patients received BEP chemotherapy. One had complete response and remaining 5 patients had partial response. The group of patients under observation had a significantly higher relapse rate and lower disease free compared to the adjuvant radiotherapy group (73.5% vs. 91% at five years, p value 0.004). Disease specific survivals for the two groups were however similar (89% vs. 93%) at five years, p value 0.18). We conclude that Stage I Seminoma patients treated with prophylactic radiation to paraaortic and pelvic region had better outcome. PMID- 22227542 TI - Comparison of homogeneity indices for quantitative evaluation of dose homogeneity for IMRT treatments of head and neck cancers. AB - The purpose of this study was to evaluate different homogeneity indices for IMRT of head and neck cancers and to suggest the best representative homogeneity index for quantitative measure of dose homogeneity. In this study 3 different homogeneity indices were evaluated for 22 head and neck cancer patients receiving dynamic IMRT treatments on Clinac-DHX linear accelerator with 6 MV photon beam. IMRT planning was carried out with Helios software on Eclipse treatment planning system. H index, HI index and S index proposed by Yoon (2007) were calculated for these patients. The H-index, HI index and S index values varied between 1.024 to 1.112, 4.03 to 16.9 and 0.94 to 3.43 respectively. H index values for patient 5 and 10 are identical (H index-1.06) though different in DVH distributions but the S index values for these patients are different (1.36 and 2.01). Similarly the HI index for the patient 11 and 16 are identical in spite of different DVH distributions but S index values are different for patient 11 and 16. Since the S index represents the whole DVH curve unlike the conventional indices which depends on dose at a point, it is the better method to quantify the dose homogeneity. These results indicate that H and HI indices do not provide the accurate dose homogeneity information, but the S indices uniquely provide quantitative information about the dose homogeneity. PMID- 22227543 TI - GIST in Saudi Arabia: multicentric histopathological genetic study of 75 surgically excised cases. AB - The availability of CD117 (Ckit) immunohistochemical testing in most hospital laboratories has facilitated the diagnosis of GIST in cKit positive cases. The aim of this study was to describe the histopathological variations of GIST in Saudi Arabia. The study involved analysis of paraffin blocks of 75 surgically excised GIST and GIST-like stromal tumors obtained from four major referral hospitals in Saudi Arabia (Riyadh Military Hospital, King Abdulaziz Medical City, King Faisal Specialist Hospital & Research Center and Aramco's hospital) between 1998 and 2009. Patient sex and age were noted in addition to the following tumor variables: size, site, histological grade and type, immunohistochemical profile and genetic analysis of the cKit mutation. The stomach was the commonest site for tumors and spindle cell type was the most frequently seen variant. Further sub classification of the histopathological type was made in order to recognize the morphological pattern of the tumor. The most common tumor grades seen were of low risk and high-risk groups. There was one case of familial GISTparaganglioma syndrome and the youngest subject was an 8-year-old girl with high-risk spindle cell gastric GIST. Genetic study in 34 cases revealed exon 11 mutations in all of the cKit genes. PMID- 22227544 TI - Immuno-histochemical evaluation of Cathepsin D in malignant salivary gland carcinomas. AB - OBJECTIVE: Cathepsin D is a lysosomal acid protease secreted in increased levels in several malignancies. However, its role in salivary gland tumors has not been studied extensively. The present study aims to assess the expression of Cathepsin D in malignant salivary gland tumors and to compare its expression in these tumors. STUDY DESIGN: A total of 30 cases of malignant salivary gland carcinomas which included 16 cases of adenoid cystic carcinoma (ACC), 9 cases of mucoepidermoid carcinoma (MEC), and 5 cases of polymorphous low grade adenocarcinoma (PLGA) were evaluated immunohistochemically using anti-Cathepsin D antibody. RESULT: All the cases showed positivity (100%) for Cathepsin D with intense expression noted in ACC and MEC as compared to PLGA. Comparison of these tumors revealed statistical significant difference in expression between ACC and PLGA. CONCLUSION: Intense expression of Cathepsin D in high grade carcinomas may be a marker for invasive potential and aggressive behavior. PMID- 22227545 TI - Epidemiology of breast cancer patients at a tertiary care center in the Eastern Province of Saudi Arabia. AB - BACKGROUND: Breast cancer is the most common cancer in Saudi Arabia. However, detailed published epidemiologic data are scarce. In this study, breast cancer patients at a tertiary care hospital were characterized and compared with data from the United States. METHODS: Medical records were retrospectively reviewed of female patients with confirmed diagnosis of invasive breast cancer who consulted with Saad Specialist Hospital between 2004 and 2011. Descriptive statistics were calculated and compared with published data. RESULTS: Two-hundred and sixty-two female patients with cytologically or histologically confirmed diagnosis of invasive breast cancer were identified and analyzed. Compared to published American data derived from the SEER database, patients were diagnosed at a markedly younger age (<50 years: 57.5% versus 12.5%) and more advanced disease (localized disease: 28.6% versus 61.2%). The difference of the age at diagnosis could not be fully explained by the different age structures of the Saudi Arabian and American population in our analysis. Although the overall mastectomy rate was higher (58.2% versus 38.5%), no relevant difference in the mastectomy rates was found if analyzed by stage. CONCLUSION: Our data suggest that breast cancer in this part of Saudi Arabia is diagnosed at a much higher stage compared to the United States. More effort in awareness campaigns, easier access to screening and treatment are needed to improve the prognosis and to reduce the currently relatively high mastectomy rate. PMID- 22227546 TI - Expression of oestrogen progestrone and androgen receptors in salivary gland tumours. A review of literature. AB - Hormone therapy is highly recommended on patients with breast cancer who show positive nuclear staining of the cancer cells. It is not known however whether salivary gland tumours can respond to hormone therapy. Twenty eight studies undertaken between 1980 to 2009 involving different types of salivary gland cancers were evaluated and taken into consideration the type of used antibody and the criteria to assess the intensity staining. This review has shown that estrogen progesterone and androgen receptors were detected in few cases of salivary gland tumours. Different types of used antibodies were identified, and the criteria of assessment of the staining intensity were different as well. The outcome of this review indicated that the growth of those tumours was not dependent on hormone function. It is recommended that sensitive and specific biochemical methods can be used to determine if estrogen and progesterone receptors can be detected in salivary gland cancers. It is necessary to use one criterion such as positive or negative nuclear staining to determine the existence of estrogen and progesterone receptors and to avoid any bias. The discrepancy in the results reflects a clear need for consensus on a protocol for scoring of immunohistochemical staining. PMID- 22227547 TI - Replaced common hepatic artery from superior mesenteric artery during pancreaticoduodenectomy. AB - The hepatic arterial anatomy is highly variable. A 67 year female with pancreatic mass and replaced common hepatic artery originating from the superior mesenteric artery underwent pancreaticoduodenectomy (PD). The anomalous vessel was discovered on preoperative CT scan and MRI. The vessel was dissected and preserved as it passed dorsal to the pancreas. Preservation of the blood supply to the liver and biliary tree is important after PD to prevent biliary fistula and hepatic ischaemia. PMID- 22227548 TI - Lipoadenoma of the parathyroid gland - a rare cause of hyperparathyroidism. AB - Lipoadenoma of parathyroid gland is an unusual morphologic variant of parathyroid adenoma in which the glandular elements are associated with abundant mature adipose tissue. The lesion has also been reported as parathyroid lipohyperplasia, parathyroid hamartoma, and parathyroid adenoma with myxoid stroma. Most cases are functioning and are associated with hyperparathyroidism. Lipoadenoma of parathyroid gland are difficult to diagnose as a cause of hyperparathyroidism because of rarity of these lesions and overlap with normal parathyroid tissue on microscopic evaluation. Only few cases have been documented in the literature so far. The lesion may be overlooked by both surgeon and pathologists alike, if they are not aware of this specific clinicopathologic entity. PMID- 22227549 TI - Multiple ancient schwannoma of the accessory nerve: a case report. AB - We are reporting a case of multiple ancient schwannoma of the accessory nerve in a 57 year old male. Accessory schwannomas are rare with only 19 cases reported in literature so far. Ancient schwannoma is even rarer in the head and neck region with no other cases associated with the accessory nerve being reported in literature so far. PMID- 22227550 TI - Renal Cell Carcinoma metastasizing to larynx: a case report. AB - Renal Cell Carcinoma (RCC) is a malignant tumor occurring in 5th-6th decade of life with an increasing incidence reported in the US but stable in Europe. The metastasis of RCC to head and neck region is infrequent and very rarely seen in larynx. Very few cases of RCC metastasizing to larynx are reported in literature. We report a case of RCC in a middle aged male with metastasis to larynx, 7 years after initial diagnosis and nephrectomy. These unusual tumor metastases have unique pathobiology and route of metastasis, and there can be a long interval from initial diagnosis of primary tumor. The diagnosis of metastatic RCC in unusual locations is often not easy. Treatment options include metastasectomy, radiotherapy and systemic chemotherapy but with a poor outcome. A differential diagnosis should always be considered in metastatic head and neck tumors. The need for prompt accurate diagnosis, risk stratification at initial primary diagnosis, surveillance, and long term regular follow up is emphasized. PMID- 22227551 TI - Fine needle aspiration diagnosis of ipsilateral synchronous neoplasm - mucoepidermoid carcinoma with warthin tumor in parotid gland. AB - Warthin tumor (WT) owing to its heterogeneous appearance, biological behavior and multicentricity poses a diagnostic challenge to cytologists worldwide. We report a rare double pathology of mucoepidermoid carcinoma (MEC) with WT which was diagnosed by fine needle aspiration (FNA). Cytological smears revealed sheets of epithelial cells and small clusters of squamous cells in a background of mucoid material along with a few small groups and scattered oncocytic cells and inflammatory cells (mainly lymphocytes). In view of the cytological findings various differentials such as oncocytic lesions, benign lesions of the parotid with extensive lymphoid reaction, necrotizing sialometaplasia, WT with extensive squamous/mucoid metaplasia, metastatic squamous cell carcinoma (SCC) with or without cystic change, oncocytic variant of MEC and a possibility of a synchronous MEC with WT were considered. By means of extensive review of the smears and clinic-pathological meets as discussed below, 2 differential diagnoses were given- MEC with WT versus an oncocytic variant of MEC with "?" lymphoid (tumor response) reaction. Subsequent histopathological examination confirmed the diagnosis of MEC with WT. Recent discovery of t(11; 19) translocation generating a novel fusion gene CRTC1/MAML2 which has been demonstrated in both MEC and WT has helped in providing the missing link in confirming the genetic relatedness and proof of development of a subset of WT with concomitant MEC. The case discusses the FNA findings of a rare collision tumor (MEC with WT), its possible differentials and highlights the importance of noting the background material in a case of double pathology on FNA. PMID- 22227552 TI - Simultaneous ultrasound and microwave new reactor: detailed description and energetic considerations. AB - A new reactor in which microwaves (MW), delivered by a coaxial dipole antenna, and ultrasound (US), delivered by a metallic horn, can be simultaneously used in a liquid to perform different types of processes, widely referenced in literature, is presented in detail. Calibrations of thermal energy delivered to two liquids having very different dipolar moments (i.e. water and cyclohexane) using MW and US, both separately and simultaneously, are performed by employing the traditional calorimetric method. The main results are: (i) MW and US used simultaneously increase the thermal energy delivered to the two liquids with respect to their separate use, but differently using water or cyclohexane, and (ii) the total power absorbed by polar or non polar liquids is very different, both using MW and US. PMID- 22227553 TI - Mechanistic considerations for the degradation of methyl tert-butyl ether (MTBE) by sonolysis: effect of argon vs. oxygen saturated solutions. AB - The ultrasonic degradation mechanism of methyl tert-butyl ether (MTBE) in aqueous solution is complex because of the competition between hydroxyl radical attack, pyrolysis, and hydrolysis reactions. A detailed investigation of degradation pathways using sonolysis has been performed using reaction byproducts identification. The observed bi-product distributions are rationalized in terms of hydroxyl radical (()OH) mediated processes and pyrolysis. The role of oxygen mediated and pyrolytic pathways were assessed using O(2) and Ar saturated solutions. Chemical destruction by sonolysis is often rationalized using hydroxyl radical chemistry. Pyrolysis is unique to this advanced oxidation process, and is important in the case of MTBE because it transfers into the cavitating bubbles. While alpha-hydrogen abstraction by ()OH and low temperature pyrolysis was important, it was also shown that beta-hydrogen abstraction leads, in some cases, to the same reaction byproducts, which emphasized the importance of alpha hydrogen abstraction. High temperature pyrolysis resulted in minor degradation reactions based on the formation of reaction by-products. PMID- 22227554 TI - Sonodegradation and photodegradation of methyl orange by InVO4/TiO2 nanojunction composites under ultrasonic and visible light irradiation. AB - The InVO(4)/TiO(2) nanojunction composites with different weight ratio of 1:10, 1:25, 1:50 and 1:100 were successfully constructed using an ion impregnate method, followed by calcining temperature 400 degrees C for 2h in Ar. The sono- and photo-catalytic activities of the InVO(4)/TiO(2) nanojunction composites were evaluated through the degradation of methyl orange (MO) in aqueous solution under ultrasonic and visible light irradiation, respectively. The experimental results determined that the (1:50) InVO(4)/TiO(2) nanojunction composite has exhibited the highest sonocatalytic activity. It can be ascribed to vectorial charge transfer at the co-excited InVO(4)/TiO(2) interface under ultrasonic irradiation, results in the complete separation of electrons and holes. Interestingly, the (1:25) InVO(4)/TiO(2) nanojunction composite displayed superior photocatalytic activity for MO degradation under visible light, indicating that InVO(4) as a narrow band gap sensitizer can expand photocatalytic activity of TiO(2) to visible region, and the charge transfer can be formed from high energy level of InVO(4) conduction band to the low energy level of TiO(2) conduction band in a present of excited InVO(4) alone under visible light irradiation. The sono- and photo-catalytic activities of the InVO(4)/TiO(2) nanojunction composites were found to be dependent significantly on different InVO(4) contents, which can be explained by the influence of charge transfer on the basis of the work functions of different catalysis mechanism. PMID- 22227555 TI - Ultrasound influence upon calcium carbonate precipitation on bacterial cellulose membranes. AB - The effect of ultrasonic irradiation (40 kHz) on the calcium carbonate deposition on bacterial cellulose membranes was investigated using calcium chloride (CaCl(2)) and sodium carbonate (Na(2)CO(3)) as starting reactants. The composite materials containing bacterial cellulose-calcium carbonate were characterized by means of scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and color measurements. The polymorphs of calcium carbonate that were deposited on bacterial cellulose membranes in the presence or in the absence of ultrasonic irradiation were calcite and vaterite. The morphology of the obtained crystals was influenced by the concentration of starting solutions and by the presence of ultrasonic irradiation. In the presence of ultrasonic irradiation the obtained crystals were bigger and in a larger variety of shapes than in the absence of ultrasounds: from cubes of calcite to spherical and flower-like vaterite particles. Bacterial cellulose could be a good matrix for obtaining different types of calcium carbonate crystals. PMID- 22227556 TI - Synergistic effects of C-Cr codoping in TiO2 and enhanced sonocatalytic activity under ultrasonic irradiation. AB - C and Cr co-doped TiO(2) (C-Cr-TiO(2)) sonocatalyst were synthesized by doping TiO(2) with glucose and CrCl(3) in a sol-gel method. The samples were characterized by X-ray diffraction, transmission electron microscopy, ultraviolet visible (UV-vis) diffuse reflectance spectroscopy, and X-ray photoelectron emission spectroscopy (XPS). C and Cr were detected by XPS analysis. The influence of dopants on the properties and sonocatalytic activity of TiO(2) was studied. The sonodegradation products of methylene blue were analyzed by UV-vis absorption spectroscopy. The presence of C-Cr-TiO(2) catalysts substantially enhanced the sonocatalytic degradation of MB in aqueous suspensions. The possible sonocatalytic mechanisms were also discussed. PMID- 22227557 TI - Bisphenol-A acts as a potent estrogen via non-classical estrogen triggered pathways. AB - Bisphenol-A (BPA) is an estrogenic monomer commonly used in the manufacture of numerous consumer products such as food and beverage containers. Widespread human exposure to significant doses of this compound has been reported. Traditionally, BPA has been considered a weak estrogen, based on its lower binding affinity to the nuclear estrogen receptors (ERs) compared to 17-beta estradiol (E2) as well as its low transcriptional activity after ERs activation. However, in vivo animal studies have demonstrated that it can interfere with endocrine signaling pathways at low doses during fetal, neonatal or perinatal periods as well as in adulthood. In addition, mounting evidence suggests a variety of pathways through which BPA can elicit cellular responses at very low concentrations with the same or even higher efficiency than E2. Thus, the purpose of the present review is to analyze with substantiated scientific evidence the strong estrogenic activity of BPA when it acts through alternative mechanisms of action at least in certain cell types. PMID- 22227558 TI - Effects of risperidone and haloperidol on superoxide dismutase and nitric oxide in schizophrenia. AB - Oxidative stress may be involved in the pathophysiology of schizophrenia. No double-blind study has compared the effects of typical and atypical antipsychotics on both antioxidant enzyme activity and nitric oxide (NO) levels in schizophrenic patients. Seventy-eight inpatients with chronic schizophrenia were randomly assigned to 12 weeks of treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol using a double-blind design. Clinical efficacy was determined using the Positive and Negative Syndrome Scale. Blood superoxide dismutase (SOD) and plasma NO levels were measured in patients and 30 normal controls. Our results showed that following a 2-week washout period, levels of SOD and NO were significantly increased in patients with schizophrenia compared to normal controls. Both risperidone and haloperidol equivalently reduced the elevated blood SOD levels in schizophrenia, but neither medication reduced the elevated plasma NO levels in schizophrenia. Low blood SOD levels at baseline predicted greater symptom improvement during treatment, and greater change in SOD was correlated with greater symptom improvement. These results suggest that both typical and atypical antipsychotic drugs may at least partially normalize abnormal free radical metabolism in schizophrenia, and some free radical parameters at baseline may predict antipsychotic responses of schizophrenic patients. PMID- 22227559 TI - Intrabullous ventilation in pulmonary emphysema: assessment with dynamic xenon 133 gas SPECT. AB - PURPOSE: Intrabullous ventilation in patients with pulmonary emphysema (PE) was cross-sectionally evaluated using dynamic xenon-133 gas single photon emission computed tomography (SPECT). METHODS: Fifty-two patients with PE with a total of 109 bullae of more than 4 cm in maximum diameter underwent xenon-133 gas SPECT. The real xenon-133 gas half-clearance time (T1/2) at each bulla was compared with that at the surrounding lung in the same lobe. The emphysema subtype of the surrounding lung was classified into centrilobular, panlobular, and paraseptal on computed tomography (CT). RESULTS: All bullae except for one in all patients showed xenon-133 gas wash-in. Of the 108 bullae with wash-in, 95 (87.9%) bullae in 46 (88%) patients showed marked xenon-133 gas retention with a T1/2 beyond 110 s (mean: 184 s +/- 91). The surrounding lungs of these bullae also showed marked retention with a T1/2 of greater than 100 s (mean: 174 s +/- 82), and the majority (N=92, 96.8%) were centrilobular or panlobular on CT. The remaining 13 (12.0%) bullae in six (11%) patients showed minimal retention with a T1/2 of less than 80 s (mean: 62 s +/- 11), regardless of no significant difference in size compared with the bullae with marked retention. All the surrounding lungs of these bullae except for one also showed minimal retention with a T1/2 of less than 70 s (mean: 60 s +/- 18), which was significantly less compared with that of the bullae with marked retention (P<0.0001), and the majority (N=11, 84.6%) were paraseptal with or without an interstitially fibrotic change and predominantly located at the lower lung lobe on CT. The T1/2 of the 108 bullae with xenon-133 gas wash-in was significantly correlated with that of the surrounding lungs (r=0.884, P<0.0001). CONCLUSION: Intrabullous ventilation in patients with PE appears to depend on the ventilation status of the surrounding lung, and bullae with the surrounding lungs of paraseptal-type emphysema tend to show minimal air trapping. Xenon-133 gas SPECT is useful for assessment of the interaction between intrabullous and surrounding lung's ventilation, which is difficult on CT. PMID- 22227560 TI - FDG PET/CT interobserver agreement in head and neck cancer: FDG and CT measurements of the primary tumor site. AB - BACKGROUND: Interobserver agreement in measuring positron emission tomography (PET)/computed tomography (CT) parameters is critical for head and neck cancer management. The purpose of this study is to assess the interobserver agreement when measuring the standardized uptake value (SUV) parameters and the diameter of primary head and neck tumors between readers with varied experience in PET/CT. METHODS: PET/CT images of 47 patients (59.8 +/- 10.6 years, range 26-86 years) with head and neck cancer who had a baseline PET/CT at our institution (January 2007-May 2009) were retrieved and independently reviewed by four readers with varying experience reading PET/CT. Novice reader 1 was a preinternship medical student; novice reader 2 was a fourth-year radiology resident; expert reader 1 was a board-certified radiologist with a nuclear radiology fellowship and a junior faculty; and expert reader 2 was a dual radiology and nuclear medicine board-certified radiologist and a senior faculty. Intraclass correlation coefficients (ICCs) were estimated separately across novice and expert readers, between novice 1 and expert 1, and between novice 2 and expert 1 readers. RESULTS: The ICCs (95% confidence interval) for primary tumor diameter, primary tumor SUVmax, and primary tumor SUVmax normalized to liver SUVmean within novices were 0.36 (0.09-0.59) (slight agreement), 0.60 (0.38-0.80) (fair agreement), and 0.91 (0.84-0.94) (almost perfect agreement), respectively. ICCs within experts were 0.84 (0.73-0.90) (almost perfect agreement), 0.91 (0.84-0.94) (almost perfect agreement), and 0.91 (0.84-0.95) (almost perfect agreement), respectively. The ICCs between novice 1 and experts are lower than those between novice 2 and experts for all parameters, and this disparity is greater for anatomic diameter than for fluorodeoxyglucose metabolic parameters. CONCLUSION: Fluorodeoxyglucose metabolic parameters have higher interobserver agreement than anatomic diameter measurement and are more robust in the setting of varied reading experiences. PMID- 22227561 TI - Regulation of a disintegrin and metalloprotease-33 expression by transforming growth factor-beta. AB - The asthma susceptibility gene, a disintegrin and metalloprotease-33 (ADAM33), is selectively expressed in mesenchymal cells, and the activity of soluble ADAM33 has been linked to angiogenesis and airway remodeling. Transforming growth factor (TGF)-beta is a profibrogenic growth factor, the expression of which is increased in asthma, and recent studies show that it enhances shedding of soluble ADAM33. In this study, we hypothesized that TGF-beta also affects ADAM33 expression in bronchial fibroblasts in asthma. Primary fibroblasts were grown from bronchial biopsies from donors with and those without asthma, and treated with TGF-beta(2) to induce myofibroblast differentiation. ADAM33 expression was assessed using quantitative RT-PCR and Western blotting. To examine the mechanisms whereby TGF beta(2) affected ADAM33 expression, quantitative methylation-sensitive PCR, chromatin immunoprecipitation, and nuclear accessibility assays were conducted on the ADAM33 promoter. We found that TGF-beta(2) caused a time- and concentration dependent reduction in ADAM33 mRNA expression in normal and asthmatic fibroblasts, affecting levels of splice variants similarly. TGF-beta(2) also induced ADAM33 protein turnover and appearance of a cell-associated C-terminal fragment. TGF-beta(2) down-regulated ADAM33 mRNA expression by causing chromatin condensation around the ADAM33 promoter with deacetylation of histone H3, demethylation of H3 on lysine-4, and hypermethylation of H3 on lysine-9. However, the methylation status of the ADAM33 promoter did not change. Together, these data suggest that TGF-beta(2) suppresses expression of ADAM33 mRNA in normal or asthmatic fibroblasts. This occurs by altering chromatin structure, rather than by gene silencing through DNA methylation as in epithelial cells. This may provide a mechanism for fine regulation of levels of ADAM33 expression in fibroblasts, and may self-limit TGF-beta(2)-induced ectodomain shedding of ADAM33. PMID- 22227563 TI - Role of endoplasmic reticulum stress in age-related susceptibility to lung fibrosis. AB - The incidence of idiopathic pulmonary fibrosis (IPF) increases with age. The mechanisms that underlie the age-dependent risk for IPF are unknown. Based on studies that suggest an association of IPF and gammaherpesvirus infection, we infected young (2-3 mo) and old (>=18 mo) C57BL/6 mice with the murine gammaherpesvirus 68. Acute murine gammaherpesvirus 68 infection in aging mice resulted in severe pneumonitis and fibrosis compared with young animals. Progressive clinical deterioration and lung fibrosis in the late chronic phase of infection was observed exclusively in old mice with diminution of tidal volume. Infected aging mice showed higher expression of transforming growth factor-beta during the acute phase of infection. In addition, aging, infected mice showed elevation of proinflammatory cytokines and the fibrocyte recruitment chemokine, CXCL12, in bronchoalveolar lavage. Analyses of lytic virus infection and virus reactivation indicate that old mice were able to control chronic infection and elicit antivirus immune responses. However, old, infected mice showed a significant increase in apoptotic responses determined by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling assay, levels of caspase-3, and expression of the proapoptotitc molecule, Bcl-2 interacting mediator. Apoptosis of type II lung epithelial cells in aging lungs was accompanied by up regulation of endoplasmic reticulum stress marker, binding immunoglobulin protein, and splicing of X-box-binding protein 1. These results indicate that the aging lung is more susceptible to injury and fibrosis associated with endoplasmic reticulum stress, apoptosis of type II lung epithelial cells, and activation of profibrotic pathways. PMID- 22227562 TI - Increased hyperoxia-induced lung injury in nitric oxide synthase 2 null mice is mediated via angiopoietin 2. AB - Supplemental oxygen is frequently prescribed. However, prolonged exposure to high concentrations of oxygen causes hyperoxic acute lung injury (HALI), which manifests as acute respiratory distress syndrome in adults and leads to bronchopulmonary dysplasia in newborns (NBs). Nitric oxide (NO), NO synthases (NOSs), and angiopoietin (Ang) 2 have been implicated in the pathogenesis of HALI. However, the mechanisms of the contributions of NOS/NO and the relationship(s) between NOS/NO and Ang2 have not been addressed. In addition, the relevance of these moieties in adults and NBs has not been evaluated. To address these issues, we compared the responses in hyperoxia of wild-type (NOS [+/+]) and NOS null (-/-) young adult and NB mice. When compared with NOS2(+/+) adult controls, NOS2(-/-) animals manifest exaggerated alveolar-capillary protein leak and premature death. These responses were associated with enhanced levels of structural cell death, enhanced expression of proapoptotic regulatory proteins, and Ang2. Importantly, silencing RNA knockdown of Ang2 decreased the levels of cell death and the expression of proapoptotic mediators. These effects were at least partially NOS2 specific, and were development dependent, because survival was similar in adult NOS3(+/+) and NOS3(-/-) mice and NB NOS2(+/+) and NOS2(-/-) mice, respectively. These studies demonstrate that NOS2 plays an important protective role in HALI in adult animals. They also demonstrate that this response is mediated, at least in part, by the ability of NOS2 to inhibit hyperoxia-induced Ang2 production and thereby decrease Ang2-induced tissue injury. PMID- 22227564 TI - Human embryonic stem cell model of ethanol-mediated early developmental toxicity. AB - BACKGROUND: Fetal alcohol syndrome is an important clinical problem. Human embryonic stem cells (hESC) have not been widely used to study developmental alcohol toxicity. Here we document the phenotype of hESC exposed to clinically relevant, low dose ethanol (20mM). METHODS: All cultures were maintained in 3% O2 to reflect normal physiologic conditions. Undifferentiated hESC were expanded with basic fibroblast growth factor (bFGF), with or without ethanol, then differentiated without ethanol. Proliferation and apoptosis in response to ethanol were assayed, and PCR used to examine expression of GABA receptor subunits. Whole cell patch clamping was used to examine GABA(A) receptor function in undifferentiated hESC. Immunocytochemistry and western blotting were used to follow differentiation of early neurons, astrocytes, and oligodendrocytes, PRINCIPAL FINDINGS: Exposure to 20mM ethanol resulted in larger colonies of undifferentiated hESC despite an increase in apoptosis, because proliferation of the undifferentiated cells (and neuroblasts) was significantly increased. Differentiation of hESC (following a week of ethanol exposure) resulted in decreased expression of GFAP (by western) compared to unexposed cells, suggesting that astrocyte differentiation was reduced, while markers of oligodendrocyte and neuron differentiation were unchanged. At the message level, undifferentiated hESC express all GABA(A) receptor subunits, but functional receptors were not found by whole cell patch clamping. CONCLUSION: Our results in hESC suggest a complex mix of ethanol-induced phenotypic changes when ethanol exposure occurs very early in development. Not only increased apoptosis, but inappropriate proliferation and loss of trophic astrocytes could result from low-dose ethanol exposure very early in development. More generally, these studies support a role for hESC in developing hypotheses and focusing questions to complement animal studies of developmental toxicities. PMID- 22227565 TI - Cutting edge: Regulatory T cells selectively attenuate, not terminate, T cell signaling by disrupting NF-kappaB nuclear accumulation in CD4 T cells. AB - A key consequence of regulatory T cell (Treg) suppression of CD4 T cells is the inhibition of IL-2 production, yet how Tregs attenuate IL-2 has not been defined. Current models predict a termination of TCR signaling, by disrupting T-APC contacts, or TCR signal modification, through mechanisms such as cAMP. To directly define Treg effects on TCR signaling in CD4 T cell targets, we visualized changes in nuclear accumulation of transcription factors at time points when IL-2 was actively suppressed. Nuclear accumulation of NFAT was highly dependent on sustained TCR signaling in the targets. However, in the presence of Tregs, NFAT and AP-1 signals were sustained in the target cells. In contrast, NF kappaB p65 was selectively attenuated. Thus, Tregs do not generally terminate TCR signals. Rather, Tregs selectively modulate TCR signals within hours of contact with CD4 targets, independent of APCs, resulting in the specific loss of NF kappaB p65 signals. PMID- 22227566 TI - Human T lymphotropic virus type 1 increases T lymphocyte migration by recruiting the cytoskeleton organizer CRMP2. AB - Recruitment of virus-infected T lymphocytes into the CNS is an essential step in the development of virus-associated neuroinflammatory diseases, notably myelopathy induced by retrovirus human T leukemia virus-1 (HTLV-1). We have recently shown the key role of collapsin response mediator protein 2 (CRMP2), a phosphoprotein involved in cytoskeleton rearrangement, in the control of human lymphocyte migration and in brain targeting in animal models of virus-induced neuroinflammation. Using lymphocytes cloned from infected patients and chronically infected T cells, we found that HTLV-1 affects CRMP2 activity, resulting in an increased migratory potential. Elevated CRMP2 expression accompanies a higher phosphorylation level of CRMP2 and its more pronounced adhesion to tubulin and actin. CRMP2 forms, a full length and a shorter, cleaved one, are also affected. Tax transfection and extinction strategies show the involvement of this viral protein in enhanced full-length and active CRMP2, resulting in prominent migratory rate. A role for other viral proteins in CRMP2 phosphorylation is suspected. Full-length CRMP2 confers a migratory advantage possibly by preempting the negative effect of short CRMP2 we observe on T lymphocyte migration. In addition, HTLV-1-induced migration seems, in part, supported by the ability of infected cell to increase the proteosomal degradation of short CRMP2. Finally, gene expression in CD69(+) cells selected from patients suggests that HTLV-1 has the capacity to influence the CRMP2/PI3K/Akt axis thus to positively control cytoskeleton organization and lymphocyte migration. Our data provide an additional clue to understanding the infiltration of HTLV-1 infected lymphocytes into various tissues and suggest that the regulation of CRMP2 activity by virus infection is a novel aspect of neuroinflammation. PMID- 22227569 TI - ICOS-dependent homeostasis and function of Foxp3+ regulatory T cells in islets of nonobese diabetic mice. AB - A progressive waning in Foxp3(+) regulatory T cell (Treg) functions is thought to provoke autoimmunity in the NOD model of type 1 diabetes (T1D). A deficiency in IL-2 is one of the main triggers for the defective function of Tregs in islets. Notably, abrogation of the ICOS pathway in NOD neonates or BDC2.5-NOD (BDC2.5) mice exacerbates T1D, suggesting an important role for this costimulatory pathway in tolerance to islet Ags. Thus, we hypothesize that ICOS selectively promotes Foxp3(+) Treg functions in BDC2.5 mice. We show that ICOS expression discriminates effector Foxp3(-) T cells from Foxp3(+) Tregs and specifically designates a dominant subset of intra-islet Tregs, endowed with an increased potential to expand, secrete IL-10, and mediate suppressive activity in vitro and in vivo. Consistently, Ab-mediated blockade or genetic deficiency of ICOS selectively abrogates Treg-mediated functions and T1D protection and exacerbates disease in BDC2.5 mice. Moreover, T1D progression in BDC2.5 mice is associated with a decline in ICOS expression in and expansion and suppression by intra-islet Foxp3(+) Tregs. We further show that the ICOS(+) Tregs, in contrast to their ICOS(-) counterparts, are more sensitive to IL-2, a critical signal for their survival and functional stability. Lastly, the temporal loss in ICOS(+) Tregs is readily corrected by IL-2 therapy or protective Il2 gene variation. Overall, ICOS is critical for the homeostasis and functional stability of Foxp3(+) Tregs in prediabetic islets and maintenance of T1D protection. PMID- 22227568 TI - TLR2 signaling depletes IRAK1 and inhibits induction of type I IFN by TLR7/9. AB - Pathogens may signal through multiple TLRs with synergistic or antagonistic effects on the induction of cytokines, including type I IFN (IFN-I). IFN-I is typically induced by TLR9, but not TLR2. Moreover, we previously reported that TLR2 signaling by Mycobacterium tuberculosis or other TLR2 agonists inhibited TLR9 induction of IFN-I and IFN-I-dependent MHC-I Ag cross processing. The current studies revealed that lipopeptide-induced TLR2 signaling inhibited induction of first-wave IFN-alpha and IFN-beta mRNA by TLR9, whereas induction of second-wave IFN-I mRNA was not inhibited. TLR2 also inhibited induction of IFN-I by TLR7, another MyD88-dependent IFN-I-inducing receptor, but did not inhibit IFN I induction by TLR3 or TLR4 (both Toll/IL-1R domain-containing adapter-inducing IFN-beta dependent, MyD88 independent). The inhibitory effect of TLR2 was not dependent on new protein synthesis or intercellular signaling. IL-1R-associated kinase 1 (IRAK1) was depleted rapidly (within 10 min) by TLR2 agonist, but not until later (e.g., 2 h) by TLR9 agonist. Because IRAK1 is required for TLR7/9 induced IFN-I production, we propose that TLR2 signaling induces rapid depletion of IRAK1, which impairs IFN-I induction by TLR7/9. This novel mechanism, whereby TLR2 inhibits IFN-I induction by TLR7/9, may shape immune responses to microbes that express ligands for both TLR2 and TLR7/TLR9, or responses to bacteria/virus coinfection. PMID- 22227567 TI - Matrix metalloproteinase-dependent microsomal prostaglandin E synthase-1 expression in macrophages: role of TNF-alpha and the EP4 prostanoid receptor. AB - Matrix metalloproteinase (MMP)-9 contributes to the pathogenesis of chronic inflammatory diseases and cancer. Thus, identifying targetable components of signaling pathways that regulate MMP-9 expression may have broad therapeutic implications. Our previous studies revealed a nexus between metalloproteinases and prostanoids whereby MMP-1 and MMP-3, commonly found in inflammatory and neoplastic foci, stimulate macrophage MMP-9 expression via the release of TNF alpha and subsequent induction of cyclooxygenase-2 and PGE(2) engagement of EP4 receptor. In the current study, we determined whether MMP-induced cyclooxygenase 2 expression was coupled to the expression of prostaglandin E synthase family members. We found that MMP-1- and MMP-3-dependent release of TNF-alpha induced rapid and transient expression of early growth response protein 1 in macrophages followed by sustained elevation in microsomal prostaglandin synthase 1 (mPGES-1) expression. Metalloproteinase-induced PGE(2) levels and MMP-9 expression were markedly attenuated in macrophages in which mPGES-1 was silenced, thereby identifying mPGES-1 as a therapeutic target in the regulation of MMP-9 expression. Finally, the induction of mPGES-1 was regulated, in part, through a positive feedback loop dependent on PGE(2) binding to EP4. Thus, in addition to inhibiting macrophage MMP-9 expression, EP4 antagonists emerge as potential therapy to reduce mPGES-1 expression and PGE(2) levels in inflammatory and neoplastic settings. PMID- 22227571 TI - 2-deoxy D-glucose prevents cell surface expression of NKG2D ligands through inhibition of N-linked glycosylation. AB - NKG2D ligand surface expression is important for immune recognition of stressed and neotransformed cells. In this study, we show that surface expression of MICA/B and other NKG2D ligands is dependent on N-linked glycosylation. The inhibitor of glycolysis and N-linked glycosylation, 2-deoxy-D-glucose (2DG), potently inhibited surface expression of MICA/B after histone deacetylase inhibitor treatment; the inhibition occurred posttranscriptionally without affecting MICA promoter activity. Transient overexpression of MICA surface expression was also inhibited by 2DG. 2DG blocks N-linked glycosylation of MICA/B by a reversible mechanism that can be alleviated by addition of d-mannose; this does not, however, affect the inhibition of glycolysis. Addition of d-mannose restored MICA/B surface expression after 2DG treatment. In addition, specific pharmacological or small interfering RNA-mediated targeting of glycolytic enzymes did not affect MICA/B surface expression, strongly suggesting that N-linked glycosylation, and not glycolysis, is essential for MICA/B surface expression. Corroborating this, tunicamycin, a selective inhibitor of N-linked glycosylation, abolished MICA/B surface expression without compromising activation of MICA promoter activity. NK cell-mediated killing assay and staining with a recombinant NKG2D-Fc fusion protein showed that all functional NKG2D ligands induced by histone deacetylase inhibitor treatment were abolished by 2DG treatment and fully reconstituted by further addition of d-mannose. Our data suggest that posttranslational N-linked glycosylation is strictly required for NKG2D ligand surface expression. Cancer and infection often result in aberrant glycosylation, which could likely be involved in modulation of NKG2D ligand expression. Our data further imply that chemotherapeutic use of 2DG may restrict NKG2D ligand surface expression and inhibit secretion of immunoinhibitory soluble NKG2D ligands. PMID- 22227572 TI - X-ray absorption spectroscopy studies of spin-orbit coupling in 5d transition metal oxides. AB - In order to examine the effects of strong valence band spin-orbit coupling (SOC) in 5d transition metal oxides (TMOs), we have investigated the L(2) and L(3) edge white-line intensities of the x-ray absorption spectra of several 5d TMOs. The white-line intensities at both edges are found to decrease monotonously with increasing 5d electron occupancy, while their ratio showed anomalous behavior for late 5d TMOs (IrO(2), PtO(2), and Au(2)O(3)), deviating significantly from the theoretical value of 2 expected for the case of weak SOC. This observation serves as a clear experimental indication of strong SOC effects in 5d TMOs. We also discussed how the 5d TMOs can have charge transfer effects different from their counterpart 5d elemental metals by making comparative studies. Our works demonstrate the importance of j quantum states due to strong SOC in the 5d system. PMID- 22227570 TI - Serine protease inhibitor 6 is required to protect dendritic cells from the kiss of death. AB - How dendritic cells (DC) present Ag to cytotoxic T cells (CTL) without themselves being killed through contact-mediated cytotoxicity (so-called kiss of death) has proved to be controversial. Using mice deficient in serine protease inhibitor 6 (Spi6), we show that Spi6 protects DC from the kiss of death by inhibiting granzyme B (GrB) delivered by CTL. Infection of Spi6 knockout mice with lymphocytic choriomeningitis virus revealed impaired survival of CD8alpha DC. The impaired survival of Spi6 knockout CD8alpha DC resulted in impaired priming and expansion of both primary and memory lymphocytic choriomeningitis virus-specific CTL, which could be corrected by GrB deficiency. The rescue in the clonal burst obtained by GrB elimination demonstrated that GrB was the physiological target through which Spi6 protected DC from CTL. We conclude that the negative regulation of DC priming of CD8 T lymphocyte immunity by CTL killing is mitigated by the physiological inhibition of GrB by Spi6. PMID- 22227573 TI - Hair as a biomarker of polybrominated diethyl ethers' exposure in infants, children and adults. AB - Over the last 20 years hair has moved from being a highly questionable biological matrix to mainstream and acceptable biomarker in forensic sciences where it is primarily used to determine past and present exposure to illicit drugs. In contrast, the use of hair to assess exposure to pesticides and persistent environmental pollutants is still not common. The applicability of this matrix to assess an individual's body burden of chemicals such as polybrominated diethyl ethers (PBDEs) can provide critical insight into current, but also to past exposure levels, which is not possible with more conventional matrices such as blood and urine. Furthermore, as PBDEs cross the placenta and since the hair the fetus is born with begins to grow during the third trimester, this matrix can be used to assess in utero exposure. These features of hair may therefore be used to determine the potential roles of chemicals such as PBDEs in mediating physiological or anatomical abnormalities in infants, children or adults. PMID- 22227574 TI - Smac: Its role in apoptosis induction and use in lung cancer diagnosis and treatment. AB - Apoptosis is a conserved and regulated cell suicide process, the malfunction of which is closely linked with carcinogenesis. Caspases control the induction of apoptosis through an enzymatic cascade that can be activated by both the mitochondrial and death receptor pathways. Smac is a mitochondrial protein that interacts with Inhibitor of Apoptosis Proteins (IAPs) and, upon apoptotic stimuli, is released into the cytoplasm to inhibit the capase-binding activity of IAPs. Smac plays key roles in both the diagnosis and treatment of cancer, especially lung cancer. Our review will focus on the roles of Smac in lung carcinogenesis and cancer progression and its relevance in lung cancer treatment. PMID- 22227575 TI - Self-organized Au nanoarrays on vertical graphenes: an advanced three-dimensional sensing platform. AB - A three-dimensional surface enhanced Raman scattering (SERS)/plasmonic sensing platform based on plasma-enabled, catalyst-free, few-layer vertical graphenes decorated with self-organized Au nanoparticle arrays is demonstrated. This platform is viable for multiple species detection and overcomes several limitations of two-dimensional sensors. PMID- 22227576 TI - The effect of a computer-based intervention on adult children of alcoholics. AB - OBJECTIVES: People who grow up with a family member who has a substance use disorder (SUD) are at risk for serious problems, and yet support for family members focuses mainly on the individual with the SUD. Technology may offer a way to make support widely available to family members of those with SUDs. This small randomized trial examined an online system of resources called CHESS (Comprehensive Health Enhancement Support System) for adult children of alcoholics (ACOAs), a population at greater risk for SUDs, depression, and other difficulties than adults whose parents were not alcoholics. METHODS: The study randomized 23 self-identified ACOAs to 3 interventions for 8 weeks. The goal was to increase participants' treatment compliance and psychological health. The interventions were therapy only, CHESS only, and CHESS plus therapy. We used 2 measures: compliance with treatment, gauged by attendance in group therapy for the 2 groups assigned to therapy, and aspects of psychological health or distress, measured by a survey with items from 7 scales. RESULTS: The CHESS-plus therapy group had an attendance rate in group therapy of 81.5% compared to 42.8% for the therapy-only group. The CHESS-only intervention had the largest effect size on 5 of the 7 measures of psychological health or distress. In 4 of the 5 cases, the effect size was large; in 1 case, it was moderate. CONCLUSIONS: The findings of this pilot study are based on a small sample, but they suggest the need for more research and the potentially important role of technology in behavioral health treatment. PMID- 22227577 TI - What does self-identified drug of choice tell us about individuals under community corrections supervision? AB - OBJECTIVES: The term "drug of choice" (DOC) refers to substance abusers' preferred drug and this information often adds to the clinical picture of the patient because substance users often meet diagnostic criteria for dependence on multiple drugs. Characteristics such as age, race, marital status, and psychiatric illnesses have been shown to differentiate among individuals with different DOC preferences. However, no studies have examined DOC in the context of criminal behavior and other drug dependencies. METHODS: The participants (N = 15,475) of a community corrections program, Treatment Alternatives for Safer Communities (TASC), were classified by DOC for the 4 main drugs of abuse (alcohol, marijuana, cocaine, and opioids) and each drug class was compared with the other 3 DOC using binary logistic regression. RESULTS: Alcohol as DOC was associated with being older, white, male, having private health insurance, being medicated for a mental health disorder, and having a criminal history of person offenses. Cocaine as DOC was associated with being older, black, female, attempting suicide, having less than a high school education, living in a shelter or with relatives, being unemployed, being uninsured, being physically and sexually abused, and committing property and court offenses but not person or substance offenses. Marijuana as DOC was associated with being younger, black, male, never being married, and committing substance but not property or court offenses. Opioids as DOC were associated with being white, female, being married, higher education, being unemployed, and being medicated for a mental health disorder. CONCLUSIONS: Overall, there were substantial differences between the 4 DOC groups, and the results are commensurate with expectations based on the abuse and dependency literature. PMID- 22227578 TI - Internet addiction as an important predictor in early detection of adolescent drug use experience-implications for research and practice. AB - We present results from a cross-sectional study of the entire adolescent student population aged 14 to 18 years of the island of Kos, on the correlates between personality, illicit chemical substance use, and Internet abuse. Results demonstrate that adolescents who have used illicit substances and are abusing the Internet as well appear to share some common personality characteristics, namely those that are classified under the label of "psychoticism" in the Eysenck's personality model. An increase in the severity of pathological Internet use has been linked to increased chances of having used an illicit substance. Taking into account any common personality attributes, Internet addiction can still be useful as a predictor variable for substance use experiences. Future research should attempt to verify any biological common factors between chemical substances use and Internet abuse. Targeting the adolescent population that engages in increased Internet use may be of benefit for drug abuse prevention programs. PMID- 22227579 TI - Evidence for activation of mutated p53 by apigenin in human pancreatic cancer. AB - Pancreatic cancer is an exceedingly lethal disease with a five-year survival that ranks among the lowest of gastrointestinal malignancies. Part of its lethality is attributable to a generally poor response to existing chemotherapeutic regimens. New therapeutic approaches are urgently needed. We aimed to elucidate the anti neoplastic mechanisms of apigenin-an abundant, naturally-occurring plant flavonoid-with a particular focus on p53 function. Pancreatic cancer cells (BxPC 3, MiaPaCa-2) experienced dose and time-dependent growth inhibition and increased apoptosis with apigenin treatment. p53 post-translational modification, nuclear translocation, DNA binding, and upregulation of p21 and PUMA were all enhanced by apigenin treatment despite mutated p53 in both cell lines. Transcription dependent p53 activity was reversed by pifithrin-alpha, a specific DNA binding inhibitor of p53, but not growth inhibition or apoptosis suggesting transcription independent p53 activity. This was supported by immunoprecipitation assays which demonstrated disassociation of p53/BclXL and PUMA/BclXL and formation of complexes with Bak followed by cytochrome c release. Treated animals grew smaller tumors with increased cellular apoptosis than those fed control diet. These results suggest that despite deactivating mutation, p53 retains some of its function which is augmented following treatment with apigenin. Cell cycle arrest and apoptosis induction may be mediated by transcription-independent p53 function via interactions with BclXL and PUMA. Further study of flavonoids as chemotherapeutics is warranted. PMID- 22227580 TI - Phosphatidylinositol 3-kinase and protein kinase D1 specifically cooperate to negatively regulate the insulin-like growth factor signaling pathway. AB - Insulin receptor substrate-1 (IRS-1) is a key protein in the insulin-like growth factor (IGF) signaling whose tyrosine phosphorylation by the type 1 IGF receptor is necessary for the recruitment and activation of the downstream effectors. Through the analysis of cross-talks occurring between different tyrosine kinase receptor-dependent signaling pathways, we investigated how two growth factors [epidermal growth factor (EGF) and fibroblast growth factor (FGF)] could modulate the IGF-I-induced IRS-1 tyrosine phosphorylation and its downstream signaling. EGF and FGF inhibited IGF-I-stimulated tyrosine phosphorylation of IRS-1 and the subsequent IGF-I-induced phosphatidylinositol 3-kinase (PI 3-kinase) activity. These EGF- and FGF-inhibitory effects were dependent on both PI 3-kinase and protein kinase D1 (PKD1) signaling pathways but independent on the extracellular signal-regulated kinase (ERK) pathway. PKD1, which was activated independently of the PI 3-kinase pathway, associated with IRS-1 in response to EGF or FGF. Unlike PI 3-kinase, PKD1 did not mediate the EGF- or FGF-induced-IRS-1 serine 307 phosphorylation which was described to inhibit IRS-1. Interestingly, specific inhibition of either PI 3-kinase or PKD1 totally impaired EGF- or FGF-induced inhibition of IGF-I-stimulated IRS-1 tyrosine phosphorylation. This indicated that serine 307 phosphorylation of IRS-1 is not sufficient per se to inhibit the IGF signaling pathway and demonstrated for the first time that the negative regulation of IRS-1 requires the coordinated action of PI 3-kinase and PKD1. This further suggests that PKD1 may be an attractive target for innovative strategies that target the IGF signaling pathway. PMID- 22227581 TI - Histone deacetylase inhibitors upregulate MMP11 gene expression through Sp1/Smad complexes in human colon adenocarcinoma cells. AB - MMP-11 (stromelysin-3) is a matrix metalloproteinase associated with tumor progression and poor prognosis. Its expression was initially described exclusively in stromal cells surrounding tumors, but more recently it has also been detected in macrophages and hepatocarcinoma cells. Here we show MMP-11 expression in human epithelial colon adenocarcinoma cell lines (Caco-2, HT-29 and BCS-TC2). Treatment of BCS-TC2 cells with butyrate and trichostatin A (TSA) (histone deacetylase inhibitors) increases MMP11 promoter activity and protein expression. Using electrophoretic mobility shift assay (EMSA) and supershift assays, we demonstrate for the first time that Sp1 is able to bind to the GC boxes within the MMP11 proximal promoter region; this binding has been confirmed by chromatin immunoprecipitation. Sp1 is involved in MMP11 basal expression and it is essential for the upregulation of transcription by histone deacetylase inhibitors as deduced from mutant constructs lacking the Sp1 sites and by inhibition of its binding to the promoter with mithramycin. This regulation requires the formation of Sp1/Smad2 heterocomplexes, which is stimulated by an increase in the acetylation status of Smad after butyrate or TSA treatments. We have also found that ERK1/2-mitogen-activated protein kinase (MAPK), but not p38 MAPK or JNK, is involved in the upregulation of MMP11 by HDAC inhibitors. PMID- 22227583 TI - Comprehension and retention of study-information: further studies needed. PMID- 22227582 TI - Involvement of ERK-RSK cascade in phenylephrine-induced phosphorylation of GATA4. AB - GATA4 has been characterized as a crucial regulator of cardiac development and hypertrophy. Multiple signaling pathways involving MAPK contribute to GATA4 activation via direct phosphorylation. MSK and RSK are two kinase families mediating signal transduction downstream of the MAPK cascade. In this study, we investigated the effects of MSK and RSK on GATA4 activation. Overexpression of RSK2 greatly increased phosphorylation of GATA4 at Ser261. This phosphorylation enhanced its transcriptional and DNA binding activity. RSK-dependent phosphorylation of GATA4 also led to enhanced interaction with NKX2.5 and p300. Sequential phosphorylation of the ERK-RSK-GATA4 cascade and nuclear accumulation of RSK in cardiomyocytes were observed after phenylephrine treatment. Inhibition of RSK using the small molecule SL0101 abrogated GATA4 phosphorylation at Ser261, ultimately leading to a repression of fetal cardiac genes. Adenovirus-mediated overexpression of MSK1 had no direct effect on GATA4 phosphorylation but increased GATA4 expression. Together with GATA4 phosphorylation at Ser105 by ERK1/2, our findings show dual phosphorylation of GATA4 by the ERK-RSK cascade and suggest that MSK and RSK have distinct effects in PE-induced cardiac hypertrophic response. PMID- 22227584 TI - Preventing HIV transmission through antiretroviral treatment-mediated virologic suppression: aspects of an emerging scientific agenda. AB - PURPOSE OF REVIEW: This review describes important aspects of the research agenda that have emerged as a result of the recent findings of the HIV transmission study in sero-discordant couples conducted by the National Institute of Allergy and Infectious Disease (NIAID)-supported HIV Prevention Trials Network (HPTN) and referred to as HPTN 052. RECENT FINDINGS: The HPTN 052 study provided strong evidence that antiretroviral treatment (ART), given to HIV-infected partners with the purpose of achieving and maintaining full virologic suppression, could prevent linked HIV transmission in sero-discordant couples. These findings have implications in all future combination prevention strategies. SUMMARY: The HPTN 052 study demonstrated that sustained virus suppression, below detectable levels, can prevent HIV transmission in sero-discordant couples. As a result of this study, we have now identified ART as a key component for all combination prevention strategies. Additionally, this study demonstrates that HIV testing is the single door of entry for individualized HIV treatment and prevention. The challenge now is to create a robust, seamless linkage and retention system so that the vision of HIV treatment as prevention can be realized. Such a system will maximize both the treatment and the prevention benefits of ART. The research agenda outlined here describes the need to extend this finding to areas of implementation science, such as the development of simpler, easier to use point of-care assays for virus load, and improved, better tolerated, more durable combinations and formulations of antiretroviral drugs. PMID- 22227586 TI - Reaping the prevention benefits of highly active antiretroviral treatment: policy implications of HIV Prevention Trials Network 052. AB - PURPOSE OF REVIEW: This review explores the policy implications of findings from the HIV Prevention Trials Network (HPTN 052) treatment as prevention (TasP) study. RECENT FINDINGS: To date, the potential of antiretrovirals to prevent sexual transmission of HIV by infected persons has been grounded in observational cohort, ecological, mathematical modeling, and meta-analytic studies. HPTN 052 represents the first randomized controlled trial to test the secondary prevention benefit of HIV transmission using antiretroviral treatment in largely asymptomatic persons with high CD4 cell counts. SUMMARY: The US National HIV/AIDS Strategy has among its key goals the reduction of incident HIV infections, improved access to quality care and associated outcomes, and the reduction in HIV associated health disparities and inequities. HPTN 052 demonstrates that providing TasP, in combination with other effective prevention strategies offers the promise of achieving these life-saving goals. But HPTN 052 also highlights the need for cautious optimism and underscores the importance of addressing current gaps in the HIV prevention, treatment, and care continuum in order for 'TasP' strategies to achieve their full potential. Among these are necessary improvements in the capacity to expand HIV testing, facilitate effective linkage and retention in care, and improve treatment initiation, maintenance, and virus suppression. PMID- 22227585 TI - HIV treatment as prevention and HPTN 052. AB - PURPOSE OF REVIEW: This review summarizes the development and implementation of a large clinical trial, HIV Prevention Trials Network (HPTN) 052, whose initial results were recently presented and published. RECENT FINDINGS: A randomized, clinical trial demonstrated that antiretroviral therapy reduces the sexual transmission of HIV in HIV-serodiscordant couples by more than 96%. The logistical challenges in preparing for and conducting such a trial were considerable. SUMMARY: HPTN 052 required many years of preparation, considerable collaboration between National Institute of Health and six pharmaceutical companies, and careful ongoing consideration of a large number of ethical issues. HPTN 052 revealed the magnitude of benefit when using antiretroviral therapy to prevent the transmission of HIV, and served as proof of a concept. The results have proven central to the development of new global HIV-prevention efforts. PMID- 22227587 TI - HIV treatment as prevention among injection drug users. AB - PURPOSE OF REVIEW: The use of highly active antiretroviral therapy (HAART) as a strategy to prevent the transmission of HIV infection is of substantial international interest. Injection drug users (IDUs) are an important population with respect to HIV treatment as prevention because they are often less likely to access HAART in comparison with other risk groups. RECENT FINDINGS: A recent multicentre randomized clinical trial demonstrated a 96% reduction in HIV transmission among heterosexual serodiscordant couples prescribed early HAART. Consistent with these results, independent observational studies from Baltimore and Vancouver have demonstrated that population level rates of HAART use among IDUs are associated with reduced rates of HIV incidence. In addition, impact assessments of HAART delivery to IDUs have generally demonstrated no negative effects of HAART use on rates of unsafe sex or syringe sharing. SUMMARY: HAART prevents HIV transmission because it dramatically decreases HIV-1 RNA levels in biological fluids. This is relevant to vertical and sexual HIV transmission and also to blood-borne HIV transmission, as it is often the case among IDUs. Efforts to expand HAART to IDUs should be redoubled in an effort to realize both the individual and public health benefits of HAART. PMID- 22227588 TI - Treatment-for-prevention: clinical considerations. AB - PURPOSE OF REVIEW: This article will discuss some of the potential clinical implications of the widespread use of antiretroviral treatment-as-prevention in patients with high CD4 cell counts, including the balance of clinical benefit vs. toxicity, adherence, drug resistance, and risk compensation. RECENT FINDINGS: Recent studies have definitively demonstrated that antiretroviral treatment (ART) markedly reduces heterosexual transmission of HIV-1 to HIV-uninfected partners among patients with CD4 counts less than 550 cells/MUl. At the same time, an increasing body of evidence suggests that uncontrolled HIV replication may be associated with immune activation and inflammation, both of which increase the risk of non-HIV-related diseases; and that initiation of ART at even higher CD4 counts might improve patient outcomes. ART regimens continue to become better tolerated, safer, and easier to take, and rates of adherence and virologic suppression also appear to be improving. Nevertheless, acceptability of and adherence to 'treatment for prevention' are unknown, and the spread of drug resistance in the setting of suboptimal adherence among less-motivated patients are substantive concerns with treatment-for-prevention. SUMMARY: Earlier ART may confer clinical benefits, and ART regimens are becoming safer and better tolerated. However, high-quality data are urgently needed with regards to the acceptability of, adherence to, and clinical outcomes with treatment-for prevention among patients with high CD4 counts, as well as risk compensation and the emergence and spread of drug resistance that may occur with implementation of this HIV prevention strategy. PMID- 22227589 TI - Peripheral blood CD34+ cell enumeration as a predictor of apheresis yield: an analysis of more than 1,000 collections. AB - The role of the peripheral blood (PB) CD34(+) cell count in predicting the CD34(+) cell yield in hematopoietic progenitor cell apheresis collections is well established. However, sometimes unexpectedly poor CD34(+) cell yields are obtained. To determine the effect, if any, of a range of factors on the ability of the PB CD34(+) count to predict collection CD34(+) cell count, we performed a retrospective analysis on consecutive hematopoietic progenitor cell apheresis collections between 2004 and 2008. Factors investigated included mobilization regimen, PB white blood cell count, body weight, and disease. After exclusion of collections involving apheresis complications, a total of 1,225 PB CD34(+) cell results with corresponding collection CD34(+) cell results from 458 patients were analyzed. Although differences in the median PB CD34(+) cell counts and collection CD34(+) cell counts were seen between mobilized collections with chemotherapy plus granulocyte colony-stimulating factor and those with granulocyte colony-stimulating factor alone, the predictive capability of the PB CD34(+) cell count for the collection CD34(+) cell yield remained similar. Although poorer collection efficiencies were observed in the myelodysplastic syndrome/myeloproliferative disorder diagnostic subgroup, our findings confirm that PB CD34(+) cell analysis remains a powerful and irreplaceable tool for predicting hematopoietic progenitor cell apheresis CD34(+) cell yield. PMID- 22227590 TI - IL-2-targeted therapy ameliorates the severity of graft-versus-host disease: ex vivo selective depletion of host-reactive T cells and in vivo therapy. AB - T cell depletion prevents graft-versus-host disease (GVHD) but also removes T cell-mediated support of hematopoietic cell engraftment. A chimeric molecule composed of IL-2 and caspase-3 (IL2-cas) has been evaluated as a therapeutic modality for GVHD and selective ex vivo depletion of host-reactive T cells. IL2 cas does not affect hematopoietic cell engraftment and significantly reduces the clinical and histological severity of GVHD. Early administration of IL2-cas reduced the lethal outcome of haploidentical transplants, and survivor mice displayed markedly elevated levels of X-linked forkhead/winged helix (FoxP3(+); 50%) and CD25(+)FoxP3(+) T cells (35%) in the lymph nodes. The chimeric molecule induces in vitro apoptosis in both CD4(+)CD25(-) and CD4(+)CD25(+) subsets of lymphocytes from alloimmunized mice, and stimulates proliferation of cells with highest levels of CD25 expression. Adoptive transfer of IL2-cas-pretreated viable splenocytes into sublethally irradiated haploidentical recipients resulted in 60% survival after a lethal challenge with lipopolysaccharide, which is associated with elevated fractions of CD25(high)FoxP3(+) T cells in the lymph nodes of survivors. These data demonstrate that ex vivo purging of host-presensitized lymphocytes is effectively achieved with IL2-cas, and that IL-2-targeted apoptotic therapy reduces GVHD severity in vivo. Both approaches promote survival in lethal models of haploidentical GVHD. The mechanism of protection includes direct killing of GVHD effectors, prevention of transition to effector/memory T cells, and induction of regulatory T cell proliferation, which becomes the dominant subset under conditions of homeostatic expansion. PMID- 22227591 TI - In vitro evaluation of graft-versus-graft alloreactivity as a tool to identify the predominant cord blood unit before double cord blood transplantation. AB - The transplantation of two cord blood (CB) units obtained from unrelated donors (double CBT) is an effective strategy for adult patients with hematologic malignancies. Sustained hematopoiesis after double CBT is usually derived from a single donor, and only a few transplantation recipients displaying a stable mixed donor-donor chimerism have been reported. We investigated the mechanisms underlying single-donor predominance in double CBT by studying in vitro the role of the graft-versus-graft cell-mediated immune effect in two-way mixed-lymphocyte culture, along with the contribution of differential hematopoietic progenitor (HP) potency in HP mixed cultures. Results for the two-way mixed-lymphocyte culture showed that despite the weak and variable alloantigen-specific cytotoxic potential displayed by CB mononuclear cells, an immune-mediated dominance for one of the two CB units was detected in the majority of experiments. Alloantigen induced cytotoxic activity was directed toward both CB-HP and phytohemagglutinin (PHA)-activated T lymphoblastoid cells. The CB unit with the higher fold expansion of CD34(+) cells in single-expansion culture was prevalent in the HP mixed-expansion culture, as shown by DNA chimerism evaluation. Based on these data, we hypothesize that the dominant CB unit is able to develop prevalent cytotoxic activity toward activated lymphocytes of the other CB unit, thereby preventing them from exerting alloantigen-specific cytotoxic potential against both activated lymphocytes and HPs of the dominant unit. In accordance with this hypothesis, we propose the evaluation of alloantigen-induced cytotoxic activity generated in two-way mixed-lymphocyte culture and directed toward PHA-activated T lymphoblastoid cells as a tool to identify the potentially predominant CB unit before double CBT. PMID- 22227592 TI - Do recurrent seizure-related head injuries affect seizures in people with epilepsy? AB - Seizure-related head injuries (SRHIs) are among the most commonly encountered injuries in people with epilepsy (PWE). Whether head injury has an effect on preexisting epilepsy is not known. The purpose of this study was to systematically assess for any possible effects of SRHIs on seizure frequency and seizure semiology over a 2-year period. We identified 204 patients who have been followed at the Baylor Comprehensive Epilepsy Center from 2008 to 2010. SRHI occurred in 18.1% of the cohort. Most injuries (91%) were classified as mild. Though seizure frequency varied following head injury, overall seizure frequency was not significantly impacted by presence or absence of SRHI over the 2-year study period. Changes in seizure semiology were not observed in those with SRHIs. Although mild SRHI is common among PWE, it does not appear to have an effect on seizure characteristics over a relatively short period. PMID- 22227593 TI - Evidence-based review on epilepsy and driving. AB - OBJECTIVE: The aim of this study was to synopsize the evidence on predictors of crashes and driving status in people with epilepsy (PWE). METHODS: Evidence-based review of the published English literature was the method used. We searched various databases and extracted data from 16 (of 77) primary studies. On the basis of American Academy of Neurology criteria, we assigned each study a class of evidence (I-IV, where I indicates the highest level of evidence) and made recommendations (Level A: predictive or not; Level B: probably predictive or not; Level C: possibly predictive or not; Level U: no recommendations). RESULTS: For PWE, the following characteristics are considered useful: For identifying crash risk, epilepsy (level B) and short seizure-free intervals (>=3 months) (Level C) are not predictive of motor vehicle crash (MVC). For self/proxy-reported crash risk, epilepsy surgery (Level B), seizure-free intervals (6-12 months) (Level B), few prior non-seizure-related crashes (Level B), and regular antiepileptic drug adjustments (Level B) are protective against crashes; seizures contribute to MVCs (Level C); mandatory reporting does not contribute to reduced crashes (Level C). No recommendations for reliable auras, age, and gender (Level U), as data are inadequate to make determinations. For self-reported driving or licensure status, employment and epilepsy surgery are predictive of driving (Level C); there are no recommendations for antiepileptic drug use, self-reported driving, gender, age, receiving employment benefits, or having reduced seizure frequency (Level U). CONCLUSION: Limitations, that is, heterogeneity among studies, examining the English literature from 1994 to 2010, must be considered. Yet, this is the first evidence-based review to synopsize the current PWE and driving literature and to provide recommendation(s) to clinicians and policy makers. Class I studies, matched for age and gender, yielding Level A recommendations are urgently needed to define the risks, benefits, and causal factors underlying driving performance issues in PWE. PMID- 22227594 TI - Cognitive proficiency in pediatric epilepsy. AB - Cognitive proficiency (CP) is a sensitive gauge of neurological status, but it is not typically viewed in relation to focal cerebral function. We examined CP and its relationship to general intellectual ability and seizure focus in 90 patients with pediatric epilepsy. CP was significantly lower than general ability (GA) in the overall sample. In particular, it was more deficient than GA in patients with right- than left-lateralized epilepsy onset, and in patients with frontal- than temporal-onset epilepsy. The discrepancy between CP and GA varied with participants' overall intelligence, being more pronounced (i.e., GA-CP difference larger) in individuals of lower overall ability. Deficits in CP are a defining characteristic of pediatric epilepsy and serve as an important marker of neurocognitive status, especially when seizures originate from a primary epileptogenic focus within the right hemisphere or the frontal lobe. PMID- 22227595 TI - Anticonvulsant action of Calotropis procera latex proteins. AB - Calotropis procera (Ait.) R.Br. is a laticiferous plant belonging to the Apocynaceae family. C. procera latex proteins were evaluated with respect to anticonvulsant and sedative activity in mouse models of pentylenetetrazol (PTZ)-, pilocarpine-, and strychnine-induced convulsions or turning behavior and pentobarbital-induced sleep. In the strychnine- and pilocarpine-induced seizure models, C. procera latex proteins caused no significant alterations in latencies to convulsions and death, as compared with controls. In the PTZ-induced seizure model, administration of C. procera latex proteins in high doses (50 or 100mg/kg) and diazepam caused significant increases in latencies to convulsions and death. C. procera latex proteins (50 or 100mg/kg) and 2mg/kg diazepam caused a decrease in sleep latency and an increase in sleep time compared with the control group and groups treated with 5 or 10mg/kg. Our results suggest that C. procera latex proteins have a central nervous system-depressant activity as reflected in their potentiation of pentobarbital-induced sleeping time and their anticonvulsant action in the PTZ-induced seizure model. PMID- 22227596 TI - Using anticoagulants to steer clear of clots. PMID- 22227597 TI - Early warning systems: the next level of rapid response. PMID- 22227598 TI - Expression and purification of E. coli BirA biotin ligase for in vitro biotinylation. AB - The extremely tight binding between biotin and avidin or streptavidin makes labeling proteins with biotin a useful tool for many applications. BirA is the Escherichia coli biotin ligase that site-specifically biotinylates a lysine side chain within a 15-amino acid acceptor peptide (also known as Avi-tag). As a complementary approach to in vivo biotinylation of Avi-tag-bearing proteins, we developed a protocol for producing recombinant BirA ligase for in vitro biotinylation. The target protein was expressed as both thioredoxin and MBP fusions, and was released from the corresponding fusion by TEV protease. The liberated ligase was separated from its carrier using HisTrap HP column. We obtained 24.7 and 27.6 mg BirA ligase per liter of culture from thioredoxin and MBP fusion constructs, respectively. The recombinant enzyme was shown to be highly active in catalyzing in vitro biotinylation. The described protocol provides an effective means for making BirA ligase that can be used for biotinylation of different Avi-tag-bearing substrates. PMID- 22227599 TI - Tuning the effects of Landau level mixing on anisotropic transport in quantum Hall systems. AB - Electron-electron interactions in half-filled high Landau levels in two dimensional electron gases in a strong perpendicular magnetic field can lead to states with anisotropic longitudinal resistance. This longitudinal resistance is generally believed to arise from broken rotational invariance, which is indicated by charge density wave order in Hartree-Fock calculations. We use the Hartree Fock approximation to study the influence of externally tuned Landau level mixing on the formation of interaction-induced states that break rotational invariance in two-dimensional electron and hole systems. We focus on the situation when there are two non-interacting states in the vicinity of the Fermi level and construct a Landau theory to study coupled charge density wave order that can occur as interactions are tuned and the filling or mixing are varied. We consider numerically a specific example where mixing is tuned externally through Rashba spin-orbit coupling. We calculate the phase diagram and find the possibility of ordering involving coupled striped or triangular charge density waves in the two levels. Our results may be relevant to recent transport experiments on quantum Hall nematics in which Landau level mixing plays an important role. PMID- 22227600 TI - Role of beta-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-alpha2-glycoprotien (ZAG). AB - OBJECTIVES: The goal of the current study is to determine whether the beta adrenoreceptor (beta-AR) plays a role in the anti-obesity and anti-diabetic effects of zinc-alpha2-glycoprotein (ZAG). MATERIAL AND METHODS: This has been investigated in CHO-K1 cells transfected with the human beta1-, beta2-, beta3-AR and in ob/ob mice. Cyclic AMP assays were carried out along with binding studies. Ob/ob mice were treated with ZAG and glucose transportation and insulin were examined in the presence or absence of propranolol. RESULTS: ZAG bound to the beta3-AR with higher affinity (Kd 46+/-1nM) than the beta2-AR (Kd 71+/-3nM) while there was no binding to the beta1-AR, and this correlated with the increases in cyclic AMP in CHO-K1 cells transfected with the various beta-AR and treated with ZAG. Treatment of ob/ob mice with ZAG increased protein expression of beta3-AR in gastrocnemius muscle, and in white and brown adipose tissues, but had no effect on expression of beta1- and beta2-AR. A reduction of body weight was seen and urinary glucose excretion, increase in body temperature, reduction in maximal plasma glucose and insulin levels in the oral glucose tolerance test, and stimulation of glucose transport into skeletal muscle and adipose tissue, were completely attenuated by the non-specific beta-AR antagonist propranolol. CONCLUSION: The results suggest that the effects of ZAG on body weight and insulin sensitivity in ob/ob mice are manifested through a beta-3AR, or possibly a beta2-AR. PMID- 22227601 TI - Transition-metal-free highly chemo- and regioselective arylation of unactivated arenes with aryl halides over recyclable heterogeneous catalysts. AB - A novel heterogeneous catalysis system using metal-organic frameworks as catalyst demonstrated excellent chemo- and regioselectivity for the direct arylation of unactivated arenes with aryl iodides/bromides without the assistance of any transition metals. PMID- 22227602 TI - Microwave-assisted synthesis of small molecules targeting the infectious diseases tuberculosis, HIV/AIDS, malaria and hepatitis C. AB - The unique properties of microwave in situ heating offer unparalleled opportunities for medicinal chemists to speed up lead optimisation processes in early drug discovery. The technology is ideal for small-scale discovery chemistry because it allows full reaction control, short reaction times, high safety and rapid feedback. To illustrate these advantages, we herein describe applications and approaches in the synthesis of small molecules to combat four of the most prevalent infectious diseases; tuberculosis, HIV/AIDS, malaria and hepatitis C, using dedicated microwave instrumentation. PMID- 22227603 TI - Loading hydrophilic drug in solid lipid media as nanoparticles: statistical modeling of entrapment efficiency and particle size. AB - Solid lipid nanoparticle (SLN) is a very well tolerated carrier systems for dermal application due to the employment physiological and/or biodegradable lipids. The effects of five factors, two categorical and three quantitative factors, were studied on the mean diameter and entrapment efficiency of the produced SLNs using response surface method (RSM), D-optimal design. Two methods of microemulsion and solvent diffusion and two types of lipid, cetyl palmitate and stearic acid, were examined comparatively. The quantitative variables were studied in three levels; amount of original Paromomycin (60, 90 and 120 mg), fraction of surfactant (0.5, 0.75 and 1 w/v %) and drug to lipid ratio (2, 4 and 6). Mean particle size and entrapment efficiency of the loaded Paromomycin were modeled statistically and the optimal condition was determined to approach to the maximum entrapment efficiency. The drug release profile of the optimal formulated material was examined in aqueous media and 64% of the Paromomycin loaded in SLNs was gradually released during 24h, which reveals efficient prolonged release of the drug. PMID- 22227604 TI - Antacid co-encapsulated polyester nanoparticles for peroral delivery of insulin: development, pharmacokinetics, biodistribution and pharmacodynamics. AB - The in vitro/in vivo characterization of antacid-insulin co-encapsulated poly(lactide-co-glycolide) (PLGA) nanoparticles is presented here. The optimized nanoparticle composition has 1% surfactant (didodecyl dimethylammonium bromide) and 2% antacid (magnesium hydroxide or zinc carbonate) in the size range ~136 143nm with ~81-85% entrapment of insulin at a 4% (w/w) initial load to that of polymer. Molecular characterization using circular dichroism, fluorescence and Fourier transform infrared spectroscopy showed that the structural integrity of insulin was maintained during formulation. Furthermore, the encapsulated insulin was well protected under in vitro simulated gastric and intestinal fluids. Nanoparticle insulin results in six fold increase in oral bioavailability to that of plain insulin in healthy rats. In diabetic rats, a 120 IU/kg oral dose of insulin nanoparticles achieved an equivalent blood glucose lowering effect to a 20 IU/kg subcutaneous (sc) dose of insulin solution, the nadir in blood glucose concentration occurring 24h and 1h post-administration, respectively. Both sc insulin and oral nanoparticle insulin partially attenuated hyperglycemia-induced inflammation caused by tumor necrosis factor alpha, but not by interleukin-6 or C reactive protein; on the other hand, subcutaneous insulin was found to be more effective on lipid profile measured in the form of high density lipoprotein, cholesterol and triglyceride. Successful oral insulin could be beneficial in type II complications. PMID- 22227605 TI - Effects of protein binding on the biodistribution of PEGylated PLGA nanoparticles post oral administration. AB - The surface of nanoparticles is often functionalised with polymeric surfactants, in order to increase systemic circulation time. This has been investigated mainly for intravenously administered nanoparticles. This study aims to elucidate the effect of surface coating with various concentrations of polymeric surfactants (PEG and Pluronics F127) on the in vitro protein binding as well as the tissue biodistribution, post oral administration, of PLGA nanoparticles. The in vitro protein binding varied depending on the polymeric surfactant used. However, in vivo, 1% PEG and 1% Pluronics F127 coated particles presented similar biodistribution profiles in various tissues over seven days. Furthermore, the percentage of PEG and Pluronics coated particles detected in plasma was higher than that of uncoated PLGA particles, indicating that systemic circulation time can also be increased with oral formulations. The difference in the in vitro protein binding as a result of the different poloxamers used versus similar in vivo profiles of these particles indicates that in vitro observations for nanoparticles cannot represent or be correlated to the in vivo behaviour of the nanoparticles. Our results therefore suggest that more studies have to be conducted for oral formulations to give a better understanding of the kinetics of the particles. PMID- 22227606 TI - Clinical evaluation of hip joint rotation range of motion in adults. AB - INTRODUCTION: Data on hip joint rotation range of motion (ROM) are rare; the methods of measurement vary and reproducibility has not been evaluated, in particular in relation to the subject's position (prone or supine, seated). HYPOTHESIS: Hip joint rotation ROM is symmetrical, and ROM is not modified by the patient's position when data is obtained. PATIENTS AND METHODS: This series included 120 adults between 20 and 60 years old (71 women, 49 men), who had no hip, spine or lower extremity disorders. External (ER) and internal (IR) rotation ROM was obtained using a photographic method by two observers. Measurements were obtained with the patient in three positions: the dorsal decubitus (supine) (P1), and ventral decubitus (prone) (P2) with the hip in extension and seated with the hip in flexion (P3). RESULTS: Hip rotation ROM was P1: 68.1 degrees (ER=38.5 degrees ; IR=29.6 degrees ); P2: 77.1 degrees (ER=41.8 degrees ; IR=35.2 degrees ); P3: 78.5 degrees (ER=78.5 degrees ; IR=37.9 degrees ) with no significant difference among the three positions. Interobserver reproducibility was satisfactory (concordance correlation coefficient (ccc) 0.7) and was comparable in the three positions with a ccc of 0.7072 (P1), 0.7426 (P2) and 0.7332 (P3), respectively. Hip rotation ROM balance was ER predominant in 47.5%, neutral in 39.5% and IR predominant in 13%. Hip rotation ROM balance was symmetric in both hips in 73 subjects (61%). Hip rotation ROM was reduced with age (P<0.0001), and was 4.7 degrees less in men (P=0.0078), and in overweight subjects (P<0.0006). DISCUSSION: Our values are probably lower than those in the literature because of the difference in study population. In our series, age, BMI and gender seemed to be determining factors. Hip rotation ROM balance is usually ER predominant or neutral. Hip rotation ROM can be measured in the three positions with no significant difference, with satisfactory interobserver reproducibility for each. TYPE OF STUDY: Diagnostic prospective study: level III. PMID- 22227607 TI - Effects of part-based similarity on visual search: the Frankenbear experiment. AB - Do the target-distractor and distractor-distractor similarity relationships known to exist for simple stimuli extend to real-world objects, and are these effects expressed in search guidance or target verification? Parts of photorealistic distractors were replaced with target parts to create four levels of target distractor similarity under heterogenous and homogenous conditions. We found that increasing target-distractor similarity and decreasing distractor-distractor similarity impaired search guidance and target verification, but that target distractor similarity and heterogeneity/homogeneity interacted only in measures of guidance; distractor homogeneity lessens effects of target-distractor similarity by causing gaze to fixate the target sooner, not by speeding target detection following its fixation. PMID- 22227608 TI - A simple nonparametric method for classifying eye fixations. AB - There is no standard method for classifying eye fixations. Thresholds for speed, acceleration, duration, and stability of point of gaze have each been employed to demarcate data, but they have no commonly accepted values. Here, some general distributional properties of eye movements were used to construct a simple method for classifying fixations, without parametric assumptions or expert judgment. The method was primarily speed-based, but the required optimum speed threshold was derived automatically from individual data for each observer and stimulus with the aid of Tibshirani, Walther, and Hastie's 'gap statistic'. An optimum duration threshold, also derived automatically from individual data, was used to eliminate the effects of instrumental noise. The method was tested on data recorded from a video eye-tracker sampling at 250 frames a second while experimental observers viewed static natural scenes in over 30,000 one-second trials. The resulting classifications were compared with those by three independent expert visual classifiers, with 88-94% agreement, and also against two existing parametric methods. Robustness to instrumental noise and sampling rate were verified in separate simulations. The method was applied to the recorded data to illustrate the variation of mean fixation duration and saccade amplitude across observers and scenes. PMID- 22227609 TI - The role of 5-HT1A receptors in phencyclidine (PCP)-induced novel object recognition (NOR) deficit in rats. AB - RATIONALE: Atypical antipsychotic drugs (APDs), many of which are direct or indirect serotonin (5-HT)(1A) agonists, and tandospirone, a 5-HT(1A) partial agonist, have been reported to improve cognition in schizophrenia. OBJECTIVES AND METHODS: We tested the effect of 5-HT(1A) agonism, alone, and in combination with other psychotropic agents, including the atypical APD, lurasidone, in reversing the deficit in novel object recognition (NOR) induced by subchronic treatment with the non-competitive NMDA receptor antagonist, phencyclidine (PCP) (2 mg/kg, b.i.d., for 7 days). RESULTS: Subchronic treatment with PCP induced a persistent NOR deficit. Lurasidone (0.1 mg/kg), a potent 5-HT(1A) partial agonist, 5-HT(2A) antagonist, and weaker D(2) antagonist, tandospirone (0.6 mg/kg), and the selective post-synaptic 5-HT(1A) agonist, F15599 (0.16 mg/kg), ameliorated the subchronic PCP-induced-NOR deficit. The 5-HT(1A) antagonist, WAY100635 (0.6 mg/kg), blocked the ameliorating effects of tandospirone and lurasidone. The combination of sub-effective doses of tandospirone (0.2 mg/kg) and lurasidone (0.03 mg/kg) also reversed the PCP-induced NOR-deficit. Buspirone, a less potent partial 5-HT(1A) agonist than tandospirone, was less effective. Co-administration of tandospirone (0.2 mg/kg) and pimavanserin (3 mg/kg), a relatively selective 5 HT(2A) receptor inverse agonist, did not reverse the effect of sub-chronic PCP on NOR. The D(2) antagonist, haloperidol, blocked the ameliorating effect of tandospirone on the PCP-induced deficit in NOR. CONCLUSIONS: These results indicate that 5-HT(1A) agonism is adequate to ameliorate the PCP-induced impairment in NOR and suggest further study of utilizing the combination of a 5 HT(1A) agonist and an atypical APD to ameliorate some types of cognitive impairment in schizophrenia. PMID- 22227611 TI - Sex differences in stimulus expectancy and pharmacologic effects of a moderate dose of alcohol on smoking lapse risk in a laboratory analogue study. AB - RATIONALE: Alcohol use is often implicated in initial lapses to smoking during quit smoking attempts. Mechanisms explaining this association are unknown but could include (a) learned associations between drinking and smoking or (b) direct pharmacologic effects of alcohol. OBJECTIVES: In a 2 (told alcohol vs. told placebo) * 2 (0.4 g/kg vs. 0.0 g/kg ethanol) between-subjects balanced placebo design, we examined instruction and beverage condition effects on smokers' ability to resist initiating smoking and whether these effects differed by sex. METHODS: Participants were 96 heavy alcohol drinkers, smoking 10-30 cigarettes per day. After 15 h of smoking abstinence, participants consumed either an alcoholic or a nonalcoholic beverage and 35 min later completed a smoking lapse task. RESULTS: Overall, neither instructions nor beverage contents influenced behavior on the smoking lapse task. However, the instruction condition had different effects in men and women. Women, but not men, were more likely to smoke and reported expecting greater satisfaction from smoking when they were told alcohol compared to told placebo. The effects of instruction condition on smoking behavior were not mediated by self-reported expected satisfaction from smoking. CONCLUSIONS: Women may be more likely to choose to smoke after drinking moderate amounts of alcohol because of their expectations rather than the pharmacological effects of the alcohol. PMID- 22227612 TI - Amphetamine challenge decreases yohimbine binding to alpha2 adrenoceptors in Landrace pig brain. AB - RATIONALE: The noradrenaline (NA) system is implicated in neurodegenerative and psychiatric disorders; however, our understanding is impaired by the lack of well validated radioligands to assess NA function and release. Yohimbine, an alpha2 adrenoceptor antagonist, has recently been developed as a carbon-11 [11C]-labeled radioligand for positron emission tomography (PET) imaging studies. OBJECTIVES: Here we explore the hypothesis that yohimbine can be used as an in vivo tracer of NA receptor binding and release during amphetamine challenges in Landrace pigs. METHODS: Pigs underwent baseline PET scans with [11C]yohimbine and were then challenged with 10 mg/kg d-amphetamine 20 min prior to a second [11C]yohimbine scan. Using the Logan analysis model, volumes of distribution were calculated from fits of the kinetic data 25-90 min post-yohimbine injection. RESULTS: Amphetamine decreased [11C]yohimbine volume of distribution in the brain regions under investigation, including the thalamus, caudate nucleus, and cortical regions. CONCLUSION: These data suggest that the binding of [11C]yohimbine to alpha2 adrenoceptors may be displaceable by increases in synaptic concentrations of the endogenous ligand, NA, and possibly dopamine, suggesting the possibility that [11C]yohimbine may be used as a surrogate marker of NA release in vivo. PMID- 22227614 TI - Guidelines or 10 commandments. PMID- 22227613 TI - Is it possible to model the risk of malignancy of focal abnormalities found at prostate multiparametric MRI? AB - OBJECTIVE: To evaluate whether focal abnormalities (FAs) depicted by prostate MRI could be characterised using simple semiological features. METHODS: 134 patients who underwent T2-weighted, diffusion-weighted and dynamic contrast-enhanced MRI at 1.5 T before prostate biopsy were prospectively included. FAs visible at MRI were characterised by their shape, the degree of signal abnormality (0 = normal to 3 = markedly abnormal) on individual MR sequences, and a subjective score (SS(1) = probably benign to SS(3) = probably malignant). FAs were then biopsied under US guidance. RESULTS: 56/233 FAs were positive at biopsy. The subjective score significantly predicted biopsy results (P < 0.01). As compared to SS(1) FAs, the odds ratios (OR) of malignancy of SS(2) and SS(3) FAs were 9.9 (1.8 55.9) and 163.8 (11.5-2331). Unlike FAs' shape, a simple combination of MR signal abnormalities (into "low-risk", "intermediate" and "high-risk" groups) significantly predicted biopsy results (P < 0.008). As compared to "low risk" FAs, the OR of malignancy of "intermediate" and "high-risk" FAs were 4.5 (1.1 18.4) and 52.7 (6.8-407) in the overall population and 5.4 (1.1-27.2) and 118.2 (6.1-2301) in PZ. CONCLUSIONS: A simple combination of signal abnormalities of individual MR sequences can significantly stratify the risk of malignancy of FAs, holding promise of a more standardised interpretation of MRI by readers with varying experience. KEY POINTS: * Using multiparameter(mp)-MRI, experienced uroradiologists can stratify the malignancy risk of prostatic lesions * The shape of prostatic focal abnormalities in the peripheral zone does not help predicting malignancy. * A simple combination of findings at mp-MRI can help less experienced radiologists. PMID- 22227615 TI - Reverse transcription loop-mediated isothermal amplification of RNA for sensitive and rapid detection of southern rice black-streaked dwarf virus. AB - Southern rice black-streaked dwarf virus (SRBSDV) causes one of the most serious viral diseases of rice in Southeast Asia. A reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay was developed for detection of SRBSDV using total RNA extracted from rice tissues and the insect pest, white-backed planthopper. The assay was based on a set of four primers matching a total of six sequences in the S9 region of SRBSDV genome. Presence of the virus could be detected in RT-LAMP reactions containing 1.2*10(-6)MUg of a total RNA extract, which was ten times more sensitive than a classical RT-PCR assay. The SRBSDV could be distinguished from the closely related rice black-streaked dwarf virus (RBSDV) by this method, indicating a high degree of specificity. This simple and sensitive RT-LAMP assay shows potential for detection of SRBSDV in field samples of hosts or vectors at a relatively low cost. PMID- 22227616 TI - Development of a reporter bovine viral diarrhea virus and initial evaluation of its application for high throughput antiviral drug screening. AB - Bovine viral diarrhea virus (BVDV) causes lethal mucosal disease of cattle and leads to severe economic loss of cattle production and reproduction worldwide. Over the past decades, vaccination was not very successful in providing prevention of BVDV infection. This reality demands that anti-BVDV drugs should be used as an alternative treatment strategy. In this study, a BAC cDNA of noncytopathic BVDV strain SD-1 is constructed to contain an enhanced green fluorescence protein (eGFP) gene between viral NS3 and NS4A coding sequences. The recombinant reporter virus is generated subsequently by transfection of MDBK cells with the transcripts produced in vitro. The rescued reporter virus is stable in MDBK cells and the eGFP protein is expressed and processed properly. Of most importance, the reporter virus shows a growth property similar to the SD-1 parent and the fluorescent signal intensity increases in parallel to the reporter virus RNA and protein replication. In addition, two known anti-BVDV drug G418 (viral assembly/release inhibitor) and ribavirin (viral RNA replication inhibitor) are identified as hits in a high-throughput format, suggesting that this system is capable of identifying BVDV inhibitors that target different steps in viral life cycle. The cell-based system developed provides a useful and versatile tool which should facilitate the identification of BVDV inhibitors on a large scale. PMID- 22227617 TI - Recombinant envelope protein (rgp90) ELISA for equine infectious anemia virus provides comparable results to the agar gel immunodiffusion. AB - Equine infectious anemia (EIA) is an important viral infection affecting horses worldwide. The course of infection is accompanied generally by three characteristic stages: acute, chronic and inapparent. There is no effective EIA vaccine or treatment, and the control of the disease is based currently on identification of EIAV inapparent carriers by laboratory tests. Recombinant envelope protein (rgp90) was expressed in Escherichia coli and evaluated via enzyme-linked immunosorbent assay (ELISA). There was an excellent agreement (95.42%) between the ELISA results using rgp90 and agar gel immunodiffusion test results. AGID is considered the "gold-standard" serologic test for equine infectious anemia (EIA). After 1160 serum samples were tested, the relative sensitivity and specificity of the ELISA were 96.1% and 96.4%, respectively. Moreover, analysis diagnostic accuracy of the ELISA was performed. The ELISA proved robust. Furthermore, good reproducibility was observed for the negative controls and, positive controls for all plates tested. PMID- 22227618 TI - MRI assessment of amplitude of low-frequency fluctuation in rat brains with acute cerebral ischemic stroke. AB - To investigate fluctuations in the amplitude of low-frequency blood oxygenation level-dependent (BOLD) fMRI during acute brain ischemia, and to evaluate the use of amplitude of low-frequency fluctuations (ALFFs) in resting state fMRI for assessing super-acute focal cerebral ischemic stroke. A super-acute stroke model with middle cerebral artery occlusion (MCAO) in the rat was employed. Spontaneous fluctuations were recorded using a series of gradient echo-planar imaging (EPI) images before and 30 min, 60 min, 2 h, 6 h, 12 h, and 24 h after MCAO. After preprocessing, serial fMRI data were obtained by fast Fourier transformation to calculate the ALFFs. Statistical parametric mapping software was used for the statistical analysis of ALFFs. T2-weighted images and diffusion weighted images (DWI) were also performed to detect the ischemic lesion. The signal intensities of abnormal ALFFs increased and migrated from the core of the ischemic lesion areas to the edge of lesion following MCAO. The dynamic changes in the ALFF maps demonstrated that the sizes of the ALFF regions exceeded beyond the borderline of the DWI lesions during the super-acute ischemic stroke stage. There was a significant difference in the ALFFs maps between the ischemic stroke group and the control group (P<0.005; cluster size>10 voxels), which mainly occurred in the periphery of the ischemic region in the cortex. These data suggest that ALFF maps provide hemodynamic BOLD information on neural activity, and have potential for predicting survival and prognosis of acute ischemic brain tissues. PMID- 22227619 TI - Hippocampal long term potentiation in rats under different regimens of vitamin D: an in vivo study. AB - Evidence indicates that vitamin D involves in development of brain as well as its function. This study assesses occurrence of long term potentiation (LTP), as an experimental form of synaptic plasticity, in adult rats under the normal regimen (CON), and the regimens without vitamin D (CON-D) or with a supplement of 1,25(OH)2D3 (CON+D). Stimulating the Schaffer collaterals pre- and post-tetanus excitatory postsynaptic potentials (EPSPs) were recorded in the CA1 area of hippocampus in anesthetized animals. Amplitude change of the EPSPs was considered for comparisons. Our results indicated that the basic EPSPs were similar in the three groups. Tetanization elicited a considerable LTP in both the CON and CON+D rats but a moderate potentiation in the CON-D group. We concluded that optimal level of vitamin D is required for induction of LTP. PMID- 22227620 TI - Post-treatment with rapamycin does not prevent epileptogenesis in the amygdala stimulation model of temporal lobe epilepsy. AB - Approximately 30% of all epilepsy cases are acquired. At present there is no effective strategy to stop epilepsy development after the precipitating insult. Recent data from experimental models pointed to the mTOR pathway, which can be potently inhibited by rapamycin. However, data on the antiepileptic and antiepileptogenic properties of rapamycin are conflicting. Therefore, we tested whether rapamycin post-treatment influences epileptogenesis in the amygdala stimulation model of temporal lobe epilepsy in rats. Animals were treated with rapamycin (6mg/kg) or vehicle daily for 2 wks, beginning 24h after stimulation. Sham-operated animals were treated with rapamycin or vehicle but were not stimulated. Animals were video-EEG monitored to detect spontaneous seizures. Animals were sacrificed 4 wks later and brains were collected for Timm staining. There were no significant differences in the number of stimulated rats developing epilepsy; latency to first spontaneous seizure; number of seizures, or seizure frequency in epileptic animals. The area occupied by mossy fibers was significantly increased in stimulated vs. sham-operated animals but was not different in animals treated with rapamycin vs. vehicle. Collectively, our data suggest that the antiepileptic or antiepileptogenic action of rapamycin is not a universal phenomenon and might be limited to certain experimental models or experimental conditions. PMID- 22227621 TI - Patient-derived olfactory mucosa cells but not lung or skin fibroblasts mediate axonal regeneration of retinal ganglion neurons. AB - Although human olfactory mucosa derived cells (OMC) have been used in animal models and clinical trials with CNS repair purposes, the exact identity of these cells in culture with respect to their tissue of origin is not fully understood and their neuroregenerative capacity in vitro has not yet been demonstrated. In this study we have compared human OMC with human ensheathing glia from olfactory bulb (OB) and human fibroblasts from skin and lung. Our results indicate that these different cultured cell types exhibit considerable overlap of antigenic markers such that it is presently not possible to distinguish them immunocytochemically. However, in rat retinal ganglion neuron coculture assays the axonal regenerative activity of OMC and OB ensheathing glia was dramatically higher than that exhibited by all fibroblast samples, confirming neuroregenerative activity as a unique property shared by cultured cells derived from the human olfactory system. PMID- 22227622 TI - A highly sensitive fluorogenic chemodosimeter for rapid visual detection of phosgene. AB - A highly sensitive chemodosimeter was identified from a panel of rhodamine derivatives for rapid and visual detection of phosgene with a detection limit of 50 nM triphosgene. Visual detection of gaseous phosgene with chemodosimeter absorbed paper strips was demonstrated. PMID- 22227623 TI - Genetic associations of fatigue and other symptom domains of the acute sickness response to infection. AB - The acute sickness response to infection is a conserved set of changes in physiology and behaviour, featuring fever, fatigue, musculo-skeletal pain, disturbed mood, and cognitive difficulties. The manifestations differ somewhat between individuals, including those infected with pathogens which do not have genetic variability--suggesting host determinants. Principal components analysis (PCA) was applied to acute phase, self-report symptom data from subjects in the Dubbo Infection Outcomes Study (n=296) to empirically derive indices of fatigue, pain, neurocognitive difficulties, and mood disturbance, as well as overall illness severity. Associations were sought with functional single nucleotide polymorphisms (SNPs) in the cytokine genes, interleukin (IL)-6, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and IL-10. The summed individual symptom indices correlated with overall severity and also with functional status. The relative contribution of individual symptom domains to the overall illness was stable over time within subjects, but varied between subjects with the same infection. The T allele of the IFN-gamma +874 T/A SNP was associated with increased fatigue (p=0.0003; OR: 3.3). The C allele of the IL-10 -592 C/A SNP exerted a protective effect on neurocognitive difficulties (p=0.017; OR: 0.52); while the A allele for the IL-10 -592 SNP was associated with increased mood disturbance (p=0.044; OR: 1.83), as was the G allele of the IL-6 -174 G/C SNP (p=0.051; OR: 1.83). The acute sickness response has discrete symptom domains including fatigue, which have unique genetic associations. These data provide novel insights into the pathophysiology of fatigue states. PMID- 22227624 TI - Condom use before marriage and its correlates: evidence from India. AB - CONTEXT: Little evidence is available from India concerning young people's use of condoms in premarital relationships. METHODS: Data from a subnationally representative study of Indian youth conducted in 2006-2008 were used to assess condom use in premarital relationships. Analyses used survey data from 2,408 married or unmarried youth aged 15-24 who had had premarital sex, and qualitative data from 271 such youth who completed in-depth interviews. Logistic regression was used to identify characteristics associated with four measures of condom use (ever-use, consistent use, use at first sex and use at last sex). RESULTS: Only 7% of young women and 27% of young men who had had premarital sex had ever used condoms. Among both sexes, discomfort with approaching a provider or pharmacist for condoms was inversely correlated with most measures of condom use (odds ratios, 0.5), while having peers who had had premarital sex was generally positively correlated (1.6-2.9). Females who had had premarital sex only with nonromantic partners were less likely than those with only romantic partners to have used a condom at last sex (0.2), while males were generally more likely to use condoms with nonromantic than romantic partners (1.5-1.6). Among men, education level, age at sexual initiation and neighborhood economic status were positively associated with use. CONCLUSION: Programs that encourage condom use are needed. Service delivery structures should be modified to enable youth to obtain condoms easily and privately. PMID- 22227625 TI - Do men and women report their sexual partnerships differently? Evidence from Kisumu, Kenya. AB - CONTEXT: It is generally believed that men and women misreport their sexual behaviors, which undermines the ability of researchers, program designers and health care providers to assess whether these behaviors compromise individuals' sexual and reproductive health. METHODS: Data on 1,299 recent sexual partnerships were collected in a 2007 survey of 1,275 men and women aged 18-24 and living in Kisumu, Kenya. Chi-square and t tests were used to examine how sample selection bias and selective partnership reporting may result in gender differences in reported sexual behaviors. Correlation coefficients and kappa statistics were calculated in further analysis of a sample of 280 matched marital and nonmarital couples to assess agreement on reported behaviors. RESULTS: Even after adjustment for sample selection bias, men reported twice as many partnerships as women (0.5 vs. 0.2), as well as more casual partnerships. However, when selective reporting was controlled for, aggregate gender differences in sexual behaviors almost entirely disappeared. In the matched-couples sample, men and women exhibited moderate to substantial levels of agreement for most relationship characteristics and behaviors, including type of relationship, frequency of sex and condom use. Finally, men and women tended to agree about whether men had other nonmarital partners, but disagreed about women's nonmarital partners. CONCLUSIONS: Both sample selection bias and selective partnership reporting can influence the level of agreement between men's and women's reports of sexual behaviors. Although men report more casual partners than do women, accounts of sexual behavior within reported relationships are generally reliable. PMID- 22227626 TI - Clients' perceptions of the quality of care in Mexico city's public-sector legal abortion program. AB - CONTEXT: In 2007, first-trimester abortion was legalized in Mexico City. Limited research has been conducted to understand clients' perceptions of the abortion services available in public-sector facilities. METHODS: Perceptions of quality of care were measured among 402 women aged 18 or older who had obtained abortions at any of three public-sector sites in Mexico City in 2009. Six domains of quality of care (client-staff interaction, information provision, technical competence, postabortion contraceptive services, accessibility and the facility environment) were assessed, and ordinal logistic regression analysis was conducted to identify the domains that were important in women's overall evaluation of care. RESULTS: Clients gave overall services a high rating, with a mean of 8.8 out of 10. In multivariate analysis, overall ratings were higher among women who said the doctor made them feel comfortable (odds ratio, 3.3), the receptionist was respectful (1.7), the staff was very careful to protect their privacy (2.5), they had received sufficient information on self-care at home following the abortion and on postabortion emotions (1.9 and 2.0, respectively) and they felt confident in the doctor's technical skill (2.5). Rating site hours as very convenient (2.4), waiting time as acceptable (2.8) and the facility as very clean (1.9) were all associated with higher overall scores. Compared with women who had given birth, those who had not rated the services lower overall (0.6). CONCLUSION: Efforts to improve patient experiences with abortion services should focus on client-staff interaction, information provision, service accessibility, technical competence and the facility environment. The most highly significant factor appears to be whether a doctor makes a woman feel comfortable during her visit. PMID- 22227627 TI - What happens to contraceptive use after injectables are introduced? An analysis of 13 countries. AB - CONTEXT: Although the introduction of a new method is generally hailed as a boon to contraceptive prevalence, uptake of new methods can reduce the use of existing methods. It is important to examine changing patterns of contraceptive use and method mix after the introduction of new methods. METHODS: Demographic and Health Survey data from 13 countries were used to analyze changes in method use and method mix after the introduction of the injectable in the early 1990s. Subgroup analyses were conducted among married women who reported wanting more children, but not in the next two years (spacers), and those who reported wanting no more children (limiters). RESULTS: Modern method use and injectable use rose for each study country. Increases in modern method use exceeded those in injectable use in all but three countries. Injectable use rose among spacers, as well as among limiters of all ages, particularly those younger than 35. In general, the increase in injectable use was partially offset by declines in use of other methods, especially long-acting or permanent methods. CONCLUSION: Family planning programs could face higher costs and women could experience more unintended pregnancies if limiters use injectables for long periods, rather than changing to longer acting and permanent methods, which provide greater contraceptive efficacy at lower cost, when they are sure they want no more children. PMID- 22227628 TI - Can family planning programs reduce high desired family size in Sub-Saharan Africa? AB - During the past half century, fertility declines have been pervasive in Asia and Latin America. Between the early 1950s and the early 2000s, the total fertility rate (TFR)-the average number of live births a woman would have during her lifetime, assuming constant fertility rates-dropped from 5.7 to 2.4 births per woman in Asia and from 5.9 to 2.3 births per woman in Latin America.1 Only a handful of countries in these regions still have fertility rates higher than four births per woman. In Sub-Saharan Africa, however, fertility remains high in the large majority of countries. Although some declines have occurred, the average total fertility rate in 2005-2010 exceeded 5.1 births per woman-more than double the levels observed in Asia and Latin America. PMID- 22227629 TI - Spatial awareness in Natural Orifice Transluminal Endoscopic Surgery (NOTES) navigation. AB - OBJECTIVE: To characterise navigational patterns in the abdominal cavity associated with different spatial awareness status of the operator during navigation of Natural Orifice Transluminal Endoscopic Surgery (NOTES). It is hypothesised that poor spatial awareness will manifest as erratic navigational patterns and poor performance. SUBJECTS AND METHODS: Ten endoscopic novices navigated a defined course in a NOTES phantom (NOSsE) simulating the path of peritoneoscopic examination. Subjects performed the task three times without and once with an additional laparoscopic camera. Electromagnetic tracking was used to trace the tip of the endoscope during the navigation. Metrics of performance included the number of correctly visualised course targets, between targets localisation time and path length, and total completion time. Spatial awareness was explored by means of topological modelling of the navigation trace. Spatial navigation maps were generated from the tip trace footprint, differentiated using the Earth Movers Distance (EMD) and captured in a two dimensional chart where proximity in the projected space reflects similarity of navigation behaviour. Groups were identified displaying idiosyncratic target to target transitions in endoscopic navigation behaviour. RESULTS: No significant differences were found between four sessions in terms of the path length. Time was statistically improved when using supplemental visualisation (p<0.05). Four awareness groups were identified based on the subjects exhibited navigation footprint over the frontal plane, namely: (1) consistent navigation and performance; (2) inconsistent navigation and performance; (3) improvements in navigation and performance despite undifferentiated behavioural signatures; and (4) inconsistent navigation with improvements in performance. CONCLUSIONS: Tracking the tip of the endoscope permits reconstruction of the navigation path during extraluminal navigation. The spatial location of the tip of the endoscope during navigation was used to unveil the operator's spatial awareness. Navigation routes in this study have been projected onto a 2D scene, related to performance and classified according to exhibited spatial awareness. Our assessment of this relationship suggests that poor spatial awareness is accompanied by erratic manoeuvres, often leading to poor performances, and vice versa. Tracking the location of the tip of the endoscope is an important issue in NOTES, and similarly understanding the spatial awareness of the operator is crucial in terms of the safety in NOTES. This work may have significant implications for training and assessment of new NOTES or minimally invasive surgeons. It may also lead to the new designs of endoscopes for NOTES. PMID- 22227630 TI - Hygiene behaviour and health attitudes in African countries. AB - PURPOSE OF REVIEW: In African countries, the biggest killers of young children are respiratory infections and diarrhoeal disease, and both are preventable via hand washing. Regular tooth brushing, at least twice a day, is one of the most effective methods for the control and prevention of dental caries and periodontal diseases. Both these oral diseases are infectious diseases (caused by bacteria) and thus can be controlled by proper oral hygiene. This review aims to provide updated research related to hygiene behaviours in African countries in three areas: children, community and healthcare setting. RECENT FINDINGS: Suboptimal hygiene knowledge and behaviour (hand washing, hand washing with soap and oral hygiene) were found among African children, contributing to diarrhoeal diseases, helminth infections, dental caries, periodontal diseases and other communicable diseases. Several promising intervention studies have been done to increase hygiene behaviours among children and adolescents and may need to be scaled up. Community studies found faecal contamination on hands to be common and to be associated with various ill-health conditions. Several innovative interventions to improve hand hygiene behaviours in the community setting show promising results. Healthcare-associated infections due to lack of hand hygiene are common in Africa and interventions need to be developed and implemented. SUMMARY: Hand and oral hygiene are suboptimal in both community and healthcare settings. Several promising hygiene intervention strategies have been found effective and may be scaled up in African countries. PMID- 22227631 TI - Cognitive bias modification procedures in the management of mental disorders. AB - PURPOSE OF REVIEW: To review recent research on the therapeutic impact of cognitive bias modification (CBM) procedures, designed to train direct change in the patterns of attentional and interpretive bias known to characterize particular forms of psychopathology. RECENT FINDINGS: CBM designed to change attentional selectivity has proven capable of modifying attentional biases associated with emotional dysfunction, pain disorders, eating disorders and addictions. CBM designed to change interpretive selectivity has proven capable of modifying the tendency to resolve ambiguity in a negative manner that is characteristic of emotional dysfunction. Recent research confirms that both forms of CBM can alter the severity of symptoms associated with psychopathology. Extended delivery of such CBM approaches now has been shown to yield therapeutic benefits for a range of anxiety disorders, and in the case of CBM-A has augmented the efficacy of treatment for alcohol dependence. SUMMARY: CBM approaches have passed the proof-of-concept stage, and recent small-scale trials attest to their likely clinical value. There is a pressing need for large-scale randomized controlled trials, to compare the efficacy of CBM with that of alternative approaches, and to identify how CBM can most effectively be integrated into multimodal treatment programs. PMID- 22227632 TI - New developments in the understanding and management of persistent pain. AB - PURPOSE OF REVIEW: It is proposed that central rather than peripheral factors may be important in pain chronicity. We review recent empirical findings on these processes and discuss implications for treatment and prevention. RECENT FINDINGS: The literature on neuroimaging of pain and on learning processes shows that learning-induced functional and structural brain changes involving sensorimotor, as well as limbic and frontal, areas are important in the transition from acute to chronic pain. These alterations share many similarities with brain changes in emotional disorders and the specificity for pain needs to be determined. Further important contributors to chronic pain may be disturbed processing of the body image, impaired multisensory integration and faulty feedback from interoceptive processes. These findings have led to new treatment approaches that focus on the extinction of aversive memories, restoration of the body image and normal brain function and include approaches such as brain stimulation, mirror training, virtual reality applications or behavioral extinction training. SUMMARY: We propose that chronic pain is characterized by learning-related and memory-related plastic changes of the central nervous system with concomitant maladaptive changes in body perception. These alterations require new treatments that focus on the alteration of central pain memories and maladaptive body perception. PMID- 22227633 TI - Drug abuse continues to inflict its harm "skin deep". PMID- 22227634 TI - Iatrogenic burns from garlic. PMID- 22227635 TI - "J-wave syndromes" bring the ATP-sensitive potassium channel back in the spotlight. PMID- 22227636 TI - Expecting the unpredictable. PMID- 22227637 TI - Gene expression analysis of ABC efflux transporters, CYP1A and GSTalpha in Nile tilapia after exposure to benzo(a)pyrene. AB - The aim of this study was to evaluate the response of ABC transporters, CYP1A and class alpha (alpha) GST genes, upon water and dietary exposures to benzo(a)pyrene (BaP) in Oreochromis niloticus. Partial mRNA sequences of ABC transporters (ABCB1b, ABCB11, ABCC1, ABCC2 and ABCG2) were identified, and their tissue distribution patterns evaluated in liver, gill and intestine, showing similarities with other fish and mammals. After 14 days of water exposure to BaP, ABC transporters mRNA expression was up-regulated, namely ABCC2 in gill (up to 16 fold) and ABCG2 in liver (up to 2-fold) and proximal intestine (up to 7-fold). CYP1A mRNA expression was up-regulated in water exposed animals, with maximum fold inductions of 5, 35 and 155, respectively in liver, gill and proximal intestine. After dietary exposure, intestinal CYP1A mRNA showed a 13-fold increase in exposed animals. No significant changes were seen in ABCB1b, ABCC1 and GSTalpha mRNA expression after both routes of exposure to BaP. In conclusion, this study has shown that transcriptional expression of some ABC transporters and CYP1A respond to the presence of BaP, indicating a possible involvement and cooperation in the detoxification process in Nile tilapia. PMID- 22227638 TI - Higher-dose oxytocin and hemorrhage after vaginal delivery: a randomized controlled trial. AB - OBJECTIVE: Higher-dose oxytocin is more effective than lower-dose regimens to prevent postpartum hemorrhage after cesarean delivery. We compared two higher dose regimens (80 units and 40 units) to our routine regimen (10 units) among women who delivered vaginally. METHODS: In a double-masked randomized trial, oxytocin (80 units, 40 units, or 10 units) was administered in 500 mL over 1 hour after placental delivery. The primary outcome was a composite of any treatment of uterine atony or hemorrhage. Prespecified secondary outcomes included outcomes in the primary composite and a decline of 6% or more in hematocrit. A sample size of 600 per group (N=1,800) was planned to compare each of the 80-unit and 40-unit groups to the 10-unit group. At planned interim review (n=1,201), enrollment in the 40-unit group was stopped for futility and enrollment continued in the other groups. RESULTS: Of 2,869 women, 1,798 were randomized as follows: 658 to 80 units; 481 to 40 units; and 659 to 10 units. Most characteristics were similar across groups. The risk of the primary outcome in the 80-unit group (6%; relative risk [RR] 0.93, 95% confidence interval [CI] 0.62-1.40) or the 40-unit group (6%; RR 0.94, 95% CI 0.61-1.47) was not different compared with the 10-unit group (7%). Treatment with additional oxytocin after the first hour was less frequent with 80 units compared with 10 units (RR 0.41, 95% CI 0.19-0.88), as was a 6% or more decline in hematocrit (RR 0.83, 95% CI 0.69-0.99); both outcomes declined with increasing oxytocin dose. Outcomes were similar between the 40-unit and 10 unit groups. CONCLUSION: Compared with 10 units, 80 units or 40 units of prophylactic oxytocin did not reduce overall postpartum hemorrhage treatment when administered in 500 mL over 1 hour for vaginal delivery. Eighty units decreased the need for additional oxytocin and the risk of a decline in hematocrit of 6% or more. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00790062. LEVEL OF EVIDENCE: I. PMID- 22227639 TI - Pelvic floor disorders after vaginal birth: effect of episiotomy, perineal laceration, and operative birth. AB - OBJECTIVE: To investigate whether episiotomy, perineal laceration, and operative delivery are associated with pelvic floor disorders after vaginal childbirth. METHODS: This is a planned analysis of data for a cohort study of pelvic floor disorders. Participants who had experienced at least one vaginal birth were recruited 5-10 years after delivery of their first child. Obstetric exposures were classified by review of hospital records. At enrollment, pelvic floor outcomes, including stress incontinence, overactive bladder, anal incontinence, and prolapse symptoms were assessed with a validated questionnaire. Pelvic organ support was assessed using the Pelvic Organ Prolapse Quantification system. Logistic regression analysis was used to estimate the relative odds of each pelvic floor disorder by obstetric history, adjusting for relevant confounders. RESULTS: Of 449 participants, 71 (16%) had stress incontinence, 45 (10%) had overactive bladder, 56 (12%) had anal incontinence, 19 (4%) had prolapse symptoms, and 64 (14%) had prolapse to or beyond the hymen on examination. Forceps delivery increased the odds of each pelvic floor disorder considered, especially overactive bladder (odds ratio [OR] 2.92, 95% confidence interval [CI] 1.44-5.93), and prolapse (OR 1.95, 95% CI 1.03-3.70). Episiotomy was not associated with any of these pelvic floor disorders. In contrast, women with a history of more than one spontaneous perineal laceration were significantly more likely to have prolapse to or beyond the hymen (OR 2.34, 95% CI 1.13-4.86). Our multivariable results suggest that one additional woman would have development of prolapse for every eight women who experienced at least one forceps birth (compared with delivering all her children by spontaneous vaginal birth). CONCLUSION: Forceps deliveries and perineal lacerations, but not episiotomies, were associated with pelvic floor disorders 5-10 years after a first delivery. LEVEL OF EVIDENCE: II. PMID- 22227640 TI - A vector space model approach to identify genetically related diseases. AB - OBJECTIVE: The relationship between diseases and their causative genes can be complex, especially in the case of polygenic diseases. Further exacerbating the challenges in their study is that many genes may be causally related to multiple diseases. This study explored the relationship between diseases through the adaptation of an approach pioneered in the context of information retrieval: vector space models. MATERIALS AND METHODS: A vector space model approach was developed that bridges gene disease knowledge inferred across three knowledge bases: Online Mendelian Inheritance in Man, GenBank, and Medline. The approach was then used to identify potentially related diseases for two target diseases: Alzheimer disease and Prader-Willi Syndrome. RESULTS: In the case of both Alzheimer Disease and Prader-Willi Syndrome, a set of plausible diseases were identified that may warrant further exploration. DISCUSSION: This study furthers seminal work by Swanson, et al. that demonstrated the potential for mining literature for putative correlations. Using a vector space modeling approach, information from both biomedical literature and genomic resources (like GenBank) can be combined towards identification of putative correlations of interest. To this end, the relevance of the predicted diseases of interest in this study using the vector space modeling approach were validated based on supporting literature. CONCLUSION: The results of this study suggest that a vector space model approach may be a useful means to identify potential relationships between complex diseases, and thereby enable the coordination of gene-based findings across multiple complex diseases. PMID- 22227641 TI - From structural architecture to cellular organization: celebrating the scientific contributions of Ueli Aebi on the occasion of his retirement. PMID- 22227643 TI - Lack of association of VEGF gene 3'- UTR polymorphisms (C702T, C936T and G1612A) and the risk of developing advanced retinopathy of prematurity (ROP). PMID- 22227642 TI - Can we measure mesopic pupil size with the cobalt blue light slit-lamp biomicroscopy method? AB - BACKGROUND: The aim of this work is to assess a previously described slit-lamp biomicroscopy-based method (SLBM) for measuring pupil diameter and compare it to Colvard infrared pupillometry (CIP). METHODS: Two examiners performed three repeated measurements with each instrument in 40 healthy eyes. We determined the agreement of SLBM and CIP, intraobserver and interobserver repeatabilities, and interobserver concordance (kappa) and SLBM ability for detecting pupil sizes over 6.0 mm. RESULTS: The mean (+/-standard deviation [SD]) pupil diameter was 5.81 +/ 0.70 mm with SLBM and 6.26 +/- 0.68 mm with CIP (p = 0.01) averaging both examiner's results. Mean differences between the SLBM and CIP were -0.60 mm and 0.30 mm for each examiner using the average of the three readings (p = 0.02), and they were very similar using the first reading. Intraobserver reproducibility: the width of the 95% LoA ranged from 1.79 to 2.30 mm. The ICCs were 0.97 and 0.92 for SLBM, and 0.96 and 0.90 for CIP. Interobserver reproducibility: the width of the LoA ranged from 1.82 to 2.09 mm. Kappa statistics were 0.39 and 0.49 for the first and mean SLBM readings, respectively, and 0.45 for both the first and mean CIP readings. Sensitivity and specificity of SLBM for detection of pupils larger than 6 mm ranged from 55.56% to 73.68% and from 76.19% to 95.45%, respectively. The best trade-off between sensitivity and specificity ranged from 5.4 mm to 6.2 mm. CONCLUSIONS: Although the SLBM is quite repeatable, it underestimates mesopic pupil size and shows a too wide range of agreement with CIP. SLBM shows low sensitivity in detecting pupils larger than 6 mm, which may be misleading when planning anterior segment surgery. Previous grading-consensus training strategies may increase interrater reproducibility, and compensation for the systematic underestimation could improve accuracy of the SLBM. PMID- 22227644 TI - Fighting science with politics. PMID- 22227645 TI - Biotech entrepreneurs swoon over proposed fundraising changes. PMID- 22227647 TI - EU court gets tough on patent extensions for combo products. PMID- 22227646 TI - More trials are cut short, but not the debate over their trajectory. PMID- 22227648 TI - Drugmaker reaps what it sows with first plant-made biologic. PMID- 22227649 TI - Are drugmakers fishing for a market with prescription omega-3s? PMID- 22227650 TI - Next-generation proteasome blockers promise safer cancer therapy. PMID- 22227652 TI - HHS ruling on Plan B introduces new risk for drugmakers. PMID- 22227653 TI - New NIH genetics center focuses its lens on exome, despite doubts. PMID- 22227654 TI - Straight talk with... Ronald DePinho. Interview by Rebecca Hersher. PMID- 22227657 TI - One way to help science: become Republican. PMID- 22227656 TI - An act of tolerance. PMID- 22227659 TI - Host defense against malaria favors Salmonella. PMID- 22227660 TI - PDGF-B exploits stromal EPO. PMID- 22227661 TI - Finding a sirtuin truth in Huntington's disease. PMID- 22227662 TI - Telomerase at the center of collapsing glomerulopathy. PMID- 22227663 TI - The value of HPV vaccination. PMID- 22227664 TI - Tumor strengths and frailties: Cancer SUMmOns Otto's metabolism. PMID- 22227665 TI - Tumor strengths and frailties: Aspiring to prevent colon cancer. PMID- 22227670 TI - Unraveling the autoimmune translational research process layer by layer. PMID- 22227671 TI - Dysregulation of immune homeostasis in autoimmune diseases. PMID- 22227672 TI - The problems and promises of research into human immunology and autoimmune disease. PMID- 22227673 TI - Re-establishing immunological self-tolerance in autoimmune disease. PMID- 22227675 TI - Autoimmunity's next top models. PMID- 22227674 TI - Optimization of current and future therapy for autoimmune diseases. PMID- 22227676 TI - Endogenous ethanol and acetaldehyde in the mechanisms regulating vital activities during hibernation. PMID- 22227677 TI - Generation of output information in the vertical semicircular canals. PMID- 22227679 TI - Recovery of electrogenesis in skeletal muscles after cell therapy of myodystrophy in MDX mice. PMID- 22227678 TI - Impaired spatial and working memory in ageing mice with targeted inactivation of alpha-synuclein gene. PMID- 22227680 TI - A novel natriuretic factor in hypervolemia. PMID- 22227681 TI - The effect of low-density lipoproteins on mesenchymal stromal cells of adipose tissue. PMID- 22227682 TI - The tapeworm Diphyllobothrium dendriticum (Cestoda) produces prostaglandin E2, a regulator of host immunity. PMID- 22227683 TI - Digestion of cellulose fibers in the digestive tract of wild ruminants. PMID- 22227684 TI - Seasonal changes in the mannitol and proline contents of the brown alga Fucus vesiculosus L. on the Murman coast of the Barents Sea. PMID- 22227685 TI - Influence of nanostructure organization of soil gels on the water stability of soil structure. PMID- 22227686 TI - A star cell complex as the heart of colonial Kamptozoa. PMID- 22227687 TI - Differences in the fatty acid compositions of blood-sucking mosquito larvae and imagoes and the water-to-land export of essential acids. PMID- 22227688 TI - Modification of water ecosystems during and after the reduction of anthropogenic pollution. PMID- 22227689 TI - Sexual dimorphism of the juvenile hormone gonadotropic function in Drosophila. PMID- 22227690 TI - Nuclear-cytoplasm conflict in crosses of pea subspecies is controlled by alleles of a nuclear gene on linkage group III. PMID- 22227691 TI - Stages of speciation in Drosophila sibling species, the groups virilis Palaearctic. PMID- 22227692 TI - Influence of exopolysaccharides of the ring rot pathogen on the kinetic parameters of adenylate cyclases in potato plants. PMID- 22227693 TI - Diversity of microsatellite loci in the Panax vietnamensis Ha et Grushv. (Araliaceae) population. PMID- 22227694 TI - Effect of the observed climate changes and extreme weather phenomena on the emission component of the carbon cycle in different ecosystems of the southern taiga zone. PMID- 22227695 TI - Trimetazidine blocks store-operated Ca(2+) channels in HL-60 and THP-1 cell lines and inhibits the secretion of tumor necrosis factor. PMID- 22227696 TI - Dynamics of the calcium ion level in rat hepatocytes primary cultures and its age related changes. PMID- 22227697 TI - Tricyclo[3.2.2.0(2,4)]non-8-en-6,7-dicarbonic acid derivatives efficiently inhibits the replication of different orthopoxvirus species. PMID- 22227698 TI - Severe acute hypophosphatemia during renal replacement therapy adversely affects outcome of critically ill patients with acute kidney injury. AB - PURPOSE: Hypophosphatemia during renal replacement therapy (RRT) is common in critically ill patients with acute kidney injury (AKI). The clinical consequences of RRT-induced phosphate depletion are not well defined in this patient population, and there is no evidence that intravenous sodium phosphate supplementation (PS) prevents the clinical sequelae of acute hypophosphatemia. The purpose of this retrospective analysis of the Acute Renal Support Registry of the University of Munich was to examine the association between severe hypophosphatemia and severity of and recovery from AKI. METHODS: 289 ICU patients with AKI on intermittent hemodialysis (IHD) were included in the study. One hundred and forty-nine patients received PS during IHD. Outcomes were short-term (at discharge) and long-term (at 1 year) recovery of renal function and mortality. RESULTS: The two patient groups did not differ in demographics, clinical features, renal characteristics, and frequency of hypophosphatemia at initiation of IHD. Without PS, the frequency of hypophosphatemia increased from 20 to 35%. Severe hypophosphatemia was found in 50% of these patients. By comparison, PS was not associated with an increased frequency of hypophosphatemia. Compared with patients with acute phosphate depletion, patients receiving PS developed less oliguria during IHD, had shorter duration of AKI, higher incidence of complete renal recovery at discharge, and a lower risk of de novo chronic kidney disease. Hypophosphatemia was associated with higher all cause in-hospital mortality and higher risk of long-term mortality. CONCLUSIONS: This multicenter study indicates for the first time that hypophosphatemia during IHD adversely affects short- and long-term outcome of critically-ill patients with AKI. The clinical consequences of the acute hypophosphatemic syndrome may be prevented by PS. PMID- 22227699 TI - Formation and partial melting of two types of spin-cluster glass behavior in vanadate spinel. AB - We report the doping effect on the various properties of spinels Co(1 x)Zn(x)V(2)O(4) (0 <= x <= 0.2). For the parent compounds, the rise in magnetization, the valley in thermal conductance, the transition from the ferromagnetic arrangement to non-collinear alignment indicated by the specific heat for the V sublattice, especially the frequency dependence of AC susceptibility around T(1) = 59 K, verify the occurrence of the transition at T(1) besides the ferrimagnetic transition at T(C). The ferrimagnetic transition at T(C) induces the spin-cluster glass behavior and the transition at T(1) yields the new spin-cluster glass (NSCG) behavior. As the Zn(2+)-doped content increases, the above phenomena are gradually weakening to vanishing, but the glassy behavior at T(C) still exists for all samples. Through the fourth-order perturbation theory, we discuss the reasons for the gradual vanishing of the transition at T(1). PMID- 22227700 TI - PEG coated biocompatible cadmium chalcogenide quantum dots for targeted imaging of cancer cells. AB - Cancer stands as a leading cause of mortality worldwide and diagnostics of cancer still faces drawbacks. Optical imaging of cancer would allow early diagnosis, evaluation of disease progression and therapy efficiency. To that aim, we have developed highly biocompatible PEG functionalized cadmium chalcogenide based three differently luminescent quantum dots (QDs) (CdS, CdSe and CdTe). Folate targeting scheme was utilized for targeting cancer cell line, MCF-7. We demonstrate the biocompatibility, specificity and efficiency of our nanotool in detection of cancer cells sparing normal cell lines with retained fluorescence of functionalized QDs as parental counterpart. This is the first time report of utilizing three differently fluorescent QDs and we have detailed about the internalization of these materials and time dependent saturation of targeting schemes. We present here the success of utilizing our biocompatible imaging tool for early diagnosis of cancer. PMID- 22227702 TI - Syntheses and pH sensing applications of imine-coupled phenol and polyphenol species derived from 2-amino-4-nitrophenol. AB - Developing of new generation optical polymeric pH sensors has increasing importance due to their stable structures. Available polymeric sensors for different pH ranges are already needed. In the present study new kinds of monomeric and polymeric absorption pH sensors (HBANP and PHBANP) derived from 2 amino-4-nitrophenol were prepared. The novel sensors were investigated in various pH values using spectrophotometric, spectrofluorometric, and electrochemical techniques. The sensors showed sigmoidal correlations vs. pH range in optical measurements. These correlations were improved as mathematical formula to obtain the solution pH. HBANP and PHBANP differed from each other by response fields. HBANP had a sharp absorption increase between the pH of 6.5->7.5 while PHBANP spectrophotometrically responded at lower pHs. HBANP was colorless in acidic pHs, yellow-colored in neutral media and red-colored in alkaline pHs. With its colorimetric responses in various pHs HBANP can be used to develop color-tunable pH sensors. Electrochemical oxidation peak potentials and currents also particularly changed in various pHs. PMID- 22227701 TI - A fluorescence turn-on sensor for Hg2+ with a simple receptor available in sulphide-rich environments. AB - Detection of Hg(2+) in complex natural environmental conditions is extremely challenging, and no entirely successful methods currently exist. Here we report an easy-to-prepare fluorescent sensor B3 with 2-aminophenol as Hg(2+) receptor, which exhibits selective fluorescence enhancement toward Hg(2+) over other metal ions. Especially, the fluorescence enhancement was unaffected by anions and cations existing in environment and organism. Moreover, B3 can detect Hg(2+) in sulphide-rich environments without cysteine, S(2-) or EDTA altering the fluorescence intensity. Consequently, B3 is capable of distinguishing between safe and toxic levels of Hg(2+) in more complicated natural water systems with detection limit <=2 ppb. PMID- 22227703 TI - Dye doped Eosin yellowish silica nanoparticles as novel fluorophore for a peroxyoxalate chemiluminescence system. AB - In this work, we report the preparation and characterization of novel dye doped fluorophore Eosin yellowish silica nanoparticles (ESNPs). We synthesized ESNPs by the Stober method via encapsulation of Eosin Yellowish in silica particles by the condensation of tetraethyl orthosilicate under alkaline condition at room temperature. The resulted ESNPs were characterized by transmission electron microscopy, atomic force microscopy; UV-Visible, fluorescence and Fourier transform infrared spectroscopy. The sizes of the nanoparticles have been found to be 300.0 (+/-1.0), 400.0 (+/-1.1) and 500.0 (+/-5.2) nm depending the reaction conditions under which they were synthesized. Furthermore, because of intense light emission, the ESNPs were used as fluorophore in a peroxyoxalate chemiluminescence system. The effect of solvent and concentrations of necessary reagents, bis(2,4,6-trichlorophenyl)oxalate, sodium salicylate, hydrogen peroxide and the effects of size of the ESNP and temperature on the luminescence efficiency of the system were examined. The activation kinetic parameters of the system were also evaluated from the temperature investigation. PMID- 22227704 TI - Freezing effect on chirality amplification of L-asparagine by crystallization of the racemate in preferential condition. AB - The role of freezing in stereoselection by crystallization of a saturated DL asparagine solution in preferential condition of L-asparagine, has been investigated. To this end, the L-asparagine excess obtained by crystallization and then kept of different lengths of time at n20 degree C in frozen aqueous solution was analyzed. The samples of the yielded materials were derivatised according to Marfey's method. These derivatives were traced and evaluated by RP HPLC analysis. The relatively best effects appeared after a one day treatment, where the freezing induced asymmetry amplifications and it increased the L enantiomer excess from 10 mol percent to 34.9, 35.0 and 35.5 mol percent, respectively. Here we provide the first example of the influence of freezing on chirality amplification by preferential crystallization. Also some speculations are made about the implications of our findings in the prebiotic events of L amino acids. PMID- 22227705 TI - Palm cryobanking. AB - We describe the development of an efficient cryopreservation protocol for proembryogenic masses (PEMs) of date palm variety 'Barhee'. Proembryos were induced by inoculating small pieces of juvenile leaves on MS medium supplemented with 0.3 mg per liter 2,4-D. Application of these in vitro conditions led to true to-type plants as observed after plant fructification. When compared to the standard vitrification protocol, the ultra-rapid droplet-vitrification technique proved to be superior. Sucrose preculture considerably increased post cryopreservation recovery. The highest regeneration after cryogenic exposure reached 63.3 percent when PEMs were treated with PVS2 for 30 min at 0 degree C and 56.7 percent when PVS2 treatment lasted for 15 min at 25 degree C. The first signs of regrowth of cryopreserved PEMs were observed after 2 to 3 weeks. Cryopreservation did not affect the morphogenetic capacities of the plant material. Moreover, highly proliferating suspension cultures could be established from the cryopreserved material. The overall production of somatic embryos from 500 mg cryopreserved PEMs reached 1030 +/- 50 units after 1 month. The morphological study of date palms regenerated from cryopreserved material confirmed the stability of clonal material following cryopreservation. PMID- 22227706 TI - Cryopreservation of shoot tips and cotyledons of the north american ginseng (Panax quinquefolius l.). AB - North American ginseng (NAG) (Panax quinqueolius L.) is a medicinal plant in high demand due to its health benefits. Cryopreservation is a good alternative for long-term conservation of NAG germplasm. Pretreatments of shoot tips (0.8-1 mm) and cotyledons (1-2 mm) on sucrose and abscisic acid (ABA) enriched medium were tested to determine the effects on regrowth following cryopreservation in liquid nitrogen. The maximum regrowth (60 percent) following PVS2 vitrification occurred with shoot tips after three weeks of cold acclimation and pretreatment on sucrose (0.3 M) or a combination of ABA (0.1 M) and sucrose in the third week. Cotyledon recovery was best with the combination pretreatment. Shoot tips showed normal development and cotyledons produced embryogenic callus after the cryopreservation process. This is the first report on cryopreservation of shoot tips and cotyledons of Panax species. This cryopreservation protocol provides a safe long term storage method for important NAG selections and makes it possible to use cryopreservation for improving the security of NAG germplasm. PMID- 22227707 TI - Seminal freezing in pure breed andalusian horse: difference in individual stallions and correlation between pre and post-freezing sperm parameters. AB - The aim of this study was the optimization of the sperm freezing protocols for the Pure Breed Andalusian Horse (AH) stallions. The study was performed in 84 ejaculates from 14 stallions (6 ejaculates per stallion). We examined the effect of individual stallion, centrifugal force and centrifugation extender on post thaw sperm quality. Neither centrifugal force nor centrifugal extender had any significant effect on post-centrifugation or post-thawing sperm quality. Stallion was the principal source of variation in our experiments, showing individual significant differences (p < 0.05) in all parameters. Individual differences were more extreme prior to freezing than after freezing-thawing. There are significant positive correlations (p < 0.05 and p < 0.01) between all post-centrifugation and post-thawing parameters. PMID- 22227708 TI - Geneticallly enginereed trehalose accumulation improves cryopreservation tolerance of chrysanthemum (Dendranthema grandiflorum kitam.) shoot-tips. AB - Shoot-tips isolated from two transgenic lines of chrysanthemum (Dendranthema grandiflorum Kitam.) var. Indianapolis in vitro plantlets with induced capacity to biosynthesize trehalose, and from a non-transformed line, were subjected to cryopreservation using a vitrification procedure. After dissection, apices were precultured on semi-solid MS medium with 0.3 M sucrose for 4 days, loaded in a 0.4 M sucrose + 2 M glycerol solution for 20-30 min and exposed to PVS2 or PVS3 vitrification solutions for 0, 20, 40 or 60 min at room temperature prior to rapid immersion in liquid nitrogen. The highest shoot regeneration after cryopreservation was obtained with exposure to either PVS solution for 40 min. Plant regeneration from cryopreserved shoot-tips ranged between 48 percent and 67 percent for transgenic lines and between 33 percent and 36 percent for non transgenic lines. No polymorphic loci were detected in plantlets regenerated from cryopreserved and non-cryopreserved shoot-tips with RAPD techniques using eight primers that amplified 101 monomorphic loci. PMID- 22227709 TI - Improved cryopreservation of chrysanthemum (Chrysanthemum morifolium) using droplet-vitrification. AB - A droplet-vitrification protocol has been established for cryopreserving Chrysanthemum morifolium cv. Peak using axillary shoot tips and apical shoots of in vitro plants. In the optimized procedure, explants were submitted to a step wise preculture in liquid sucrose-enriched medium (0.3, 0.5 and 0.7 M for 31,17 and 7 h, respectively). Precultured explants were treated for 40 min with C4 loading solution comprising (w/v) 17.5 percent glycerol + 17.5 percent sucrose, then dehydrated with PVS3 vitrification solution (w/v, 50 percent glycerol + 50 percent sucrose) for 60 min (axillary shoot tips) or 90 min (apical shoots). Explants were cryopreserved by direct immersion in liquid nitrogen in minute drops of PVS3 attached to aluminum foil strips. The optimal age of donor plants was 4-5.5 weeks for apical shoots and 7 weeks for axillary shoot tips, producing post-cryopreservation regeneration percentages of 81.9 percent and 84.9 percernt, respectively. Plants regenerated from cryopreserved samples showed no phenotypical abnormalities and similar profiles of relative DNA content were recorded for control and cryopreserved plants. Our results suggest that the modified droplet-vitrification protocol described in this paper is highly effective and may prove user-friendlier than the cryopreservation protocols already published for chrysanthemum. PMID- 22227710 TI - Long-term conservation through cryopreservation of immature seed of Mantisia spathulata and Mantisia wengeri; two endangered plants of north-east India. AB - A successful protocol for long-term conservation of two endangered plants viz. Mantisia spathulata and M. wengeri has been devised through cryopreservation of immature seeds. Immature seeds of both the species were precultured in 0.6 M Sucrose and 2 M Glycerol for 3 h at 24 +/- 2 degree C. Precultured seeds were then desiccated under the airflow of 27 +/- 3 m min -1 velocity inside laminar air flow cabinet for different time periods. The seeds were then cryostored in liquid nitrogen for an hour. A maximum of 40 percent and 36.6 percent seed germination was recorded after cryostorage at moisture contents of 26.0 percent and 16.2 percent for M. spathulata and M. wengeri respectively. To protect these rare plants against loss due to disease, insect damage, or natural disaster a back up collection has been established using the protocol and applied to a large number of immature seeds that were obtained from the ex situ plants growing in the experimental garden of the North-eastern Hill University, Shillong. PMID- 22227711 TI - Effect of preculture, pvs2 and vitamin C on survival of recalcitrant Nephelium ramboutan-ake shoot tips after cryopreservation by vitrification. AB - This paper reports the cryopreservation of Nephelium ramboutan-ake shoot tips derived from in vitro shoot multiplication and in vitro seed germination using vitrification. Preculture with either 0.5 M sucrose for 2 days or a combination of 0.3 M sucrose and 0.5 M glycerol for 3 days enhanced dehydration tolerance and resulted in the highest survival of shoot tips; however, none of the shoot tips withstood liquid nitrogen (LN) exposure. The use of a lower temperature (0 degree C) during exposure to plant vitrification solution (PVS2) led to higher survival of shoot tips, compared to exposure at 25 degree C. The survival percentage of shoot tips exposed to PVS2 for up to 20 min at 0 degrees C was 83.3 percent. It was only 53.3 percent when shoot tips were exposed to PVS2 at 25 degree C for 5 min. The importance of vitamin C for reducing oxidative stress in shoots tips was demonstrated. The addition of 0.28 mM vitamin C during critical steps of the vitrification process resulted in a high survival (96.7 percent) without LN exposure, compared to 73.3 percent for shoot tips not treated with vitamin C. Moreover, 3.3 percent shoot tips withstood LN exposure when vitamin C was added during the loading step. This result suggests that cryopreservation is possible for this tropical, recalcitrant seeded tree species. PMID- 22227712 TI - Freeze-thawing single human embryonic stem cells induce e-cadherin and actin filament network disruption via g13 signaling. AB - Poor adhesion of single human embryonic stem (hES) cells after freeze-thawing causes death. To investigate mechanisms responsible for this, Rho-dependent protein kinase (ROCK) inhibitor Y-27632-treated and untreated single hES cells were analyzed for E-cadherin and F-actin distribution by immunostaining and phalloidin staining respectively and for G13 signaling pathway components by DNA microarray and quantitative polymerase chain reaction (PCR). Y-27632-treated cells clustered rapidly and maintained E-cadherin and F-actin distribution without losing Oct-3/4. Immediately after thawing, E-cadherin in untreated hES cells dotted along the membrane and then displayed eccentric cytoplasmic localization. Bleb formation and early Oct-3/4 loss occurred after F-actin network condensation in the cytoplasm. Microarray analyses and quantitative PCR indicated upregulation of two actin reorganization-associated components of the G13 signaling pathway, Arhgdib and Cdc42, in untreated cells. Considering these findings and that cell death was partly interrupted by Y-27632, E-cadherin and actin cytoskeleton network disruption through the G13 signaling pathway may cause hES cell death after freeze-thawing. PMID- 22227713 TI - Impact of cryoprotectants and cryopreservation on metabolic activity and cytoskeleton proteins of zebrafish (Danio rerio) ovarian fragments. AB - Cryopreservation of reproductive cells and tissues of aquatic species offers many benefits to the field of conservation, aquaculture and biomedicine. Although cryopreservation of fish sperm has been successfully achieved, cryopreservation of embryos and oocytes remains unsuccessful. Several studies have been undertaken on cryopreservation of isolated fish ovarian follicles at different stages, although the protocols used lead to a compromised viability. The present study investigates the effect of cryoprotectants and cryopreservation on the viability of ovarian tissues of zebrafish (Danio rerio). The effect of permeating cryoprotectants (CPAs) methanol, dimethyl sulfoxide (DMSO), and ethylene glycol (EG) on ovarian tissues were investigated in a series of toxicity tests. Controlled slow cooling of ovarian tissues using 1M and 4M methanol was also carried out. Ovarian tissue viability was assessed by trypan blue (TB) and fluorescence diacetate (FDA)-propidium iodide (PI) tests. In addition, the effect of methanol exposure and cryopreservation on ovarian follicle ATP level, mitochondria, actin and tubulin distribution were also investigated. Results showed that cryoprotectant toxicity to ovarian fragments increased in the order of methanol, DMSO and EG. The results from controlled slow cooling showed that 1M methanol was more effective than 4M methanol although subsequent cryopreservation induced decreases in ATP levels. Immunocytochemistry and actin staining results showed impacts of cryopreservation on mitochondria and cytoskeleton proteins distribution. PMID- 22227714 TI - Optimal indications for second-line chemotherapy in advanced gastric cancer. AB - As it remains uncertain whether patients with advanced gastric cancer who progress after first-line chemotherapy should receive second-line chemotherapy, we attempted to identify the optimal indications for second-line chemotherapy. In this retrospective study, 101 patients were included in univariate and multivariate analyses to identify clinicopathological variables independently associated with longer survival postprogression (SPP), defined as the time from recognition of disease progression on first-line chemotherapy to death from any cause or last follow-up. The median SPP was 340 days. On multivariate analysis, performance status 2 [hazard ratio (HR), 14.234; 95% confidence interval (CI), 2.766-73.258], serum albumin level less than 3.5 g/dl (HR, 2.088; 95% CI, 1.047 4.060) at initiation of second-line chemotherapy, and time to progression less than 170 days on first-line chemotherapy (HR, 2.497; 95% CI, 1.227-5.083) were identified as independent prognostic factors associated with shorter SPP. The median SPP was 496, 375, and 232 days in patients with 0, 1, and 2 of these 3 negative prognostic factors, respectively (P=0.0002). The present study suggests that second-line chemotherapy would not be beneficial in patients with two or more of the following three negative prognostic factors: performance status 2, serum albumin less than 3.5 g/dl at initiation of second-line chemotherapy and time to progression less than 170 days on first-line chemotherapy. PMID- 22227715 TI - Second generation specific-enzyme-activated rotaxane propeptides. AB - A [2]rotaxane, in which the peptidic axle is protected from degradation by the macrocyclic sheath and terminated with a novel glycosidase-cleavable stopper, is rendered water-soluble by derivatisation with tetra(ethylene glycol) (TetEG) or glucosylated tetra(ethylene glycol) (Glc-TetEG) chains using the CuAAC 'click' reaction. The Glc-TetEG-derivatised rotaxane propeptide is >50 000 times more soluble in aqueous media than the parent rotaxane. Activation of the water soluble rotaxane propeptide with a beta-galactosidase efficiently releases the parent peptide. PMID- 22227716 TI - Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) with preserved refractory period: report of three cases. AB - BACKGROUND: Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform attacks with cranial autonomic features (SUNA) are rare primary headache syndromes characterized by spontaneous or triggered attacks of unilateral, brief, multiple, orbitofrontal pain associated with ipsilateral autonomic features. SUNCT is considered as a subset of SUNA. In SUNA, there may be cranial autonomic symptoms other than conjunctival injection and lacrimation, or either of two is present. SUNCT/SUNA can be triggered immediately after or at the decrescendo phase of the ongoing attack without any intervening refractory period. Refractory period is usually present in trigeminal neuralgia. Absent refractory period is thought to reliably differentiate SUNCT/SUNA from trigeminal neuralgia and has been proposed for inclusion into the International Classification of Headache Disorders (ICHD) diagnostic criteria for SUNCT. CASE REPORTS: We report three patients of SUNCT syndrome with preserved intervening refractory period of variable duration observed at different times. DISCUSSION: Trigeminal neuralgias with autonomic features, SUNA and SUNCT share a common pathophysiological mechanism and actually represent a continuum. It is well known that patient with trigeminal neuralgia may transform into SUNCT/SUNA. Similarly, being a continuum, the presence or the absence of refractory period and its duration may change in a patient with SUNCT/SUNA at different time points. CONCLUSION: The presence of refractory period should not exclude the diagnosis of SUNCT in a patient with other clinical features suggestive of SUNCT. PMID- 22227717 TI - Common atlas format and 3D brain atlas reconstructor: infrastructure for constructing 3D brain atlases. AB - One of the challenges of modern neuroscience is integrating voluminous data of diferent modalities derived from a variety of specimens. This task requires a common spatial framework that can be provided by brain atlases. The first atlases were limited to two-dimentional presentation of structural data. Recently, attempts at creating 3D atlases have been made to offer navigation within non standard anatomical planes and improve capability of localization of different types of data within the brain volume. The 3D atlases available so far have been created using frameworks which make it difficult for other researchers to replicate the results. To facilitate reproducible research and data sharing in the field we propose an SVG-based Common Atlas Format (CAF) to store 2D atlas delineations or other compatible data and 3D Brain Atlas Reconstructor (3dBAR), software dedicated to automated reconstruction of three-dimensional brain structures from 2D atlas data. The basic functionality is provided by (1) a set of parsers which translate various atlases from a number of formats into the CAF, and (2) a module generating 3D models from CAF datasets. The whole reconstruction process is reproducible and can easily be configured, tracked and reviewed, which facilitates fixing errors. Manual corrections can be made when automatic reconstruction is not sufficient. The software was designed to simplify interoperability with other neuroinformatics tools by using open file formats. The content can easily be exchanged at any stage of data processing. The framework allows for the addition of new public or proprietary content. PMID- 22227719 TI - Distinctive morphological features of antibody-mediated and T-cell-mediated acute rejection in pancreas allograft biopsies. AB - PURPOSE OF REVIEW: Two main histopathological types of acute rejection are recognized in solid organ transplantation: T-cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR). In pancreas allografts the contrasting morphological features of these entities have only recently been described. RECENT FINDINGS: Acute TCMR is characterized by active septal infiltrates composed predominantly of T cells and often involving veins (venulitis) and ducts (ductitis). Inflammation of the arterial endothelium (intimal arteritis or endarteritis) may be present. Focal or diffuse acinar inflammation (acinitis) is also typical of TCMR. Acute AMR in contrast, is characterized by predominantly macrophagic (+/- neutrophilic) inflammation, concentrated in, and around the interacinar microvasculature (interacinar inflammation, capillaritis) and typically shows focal or diffuse C4d staining of the interacinar capillaries. Architectural preservation is common in milder forms of AMR, whereas severe or untreated forms lead to extensive vascular injury and secondary parenchymal hemorrhagic necrosis. These morphological features strongly correlate with the presence of circulating donor-specific antibody (DSA)+. SUMMARY: Stereotypical TCMR and AMR, as well as mixed forms of rejection can be confidently diagnosed in pancreas allograft biopsies with the combination of three elements: systematic analysis of the histological features; evaluation of C4d staining; and determination of the DSA status. PMID- 22227718 TI - Characterization of hepatic cellular uptake of alpha1-acid glycoprotein (AGP), part 2: involvement of hemoglobin beta-chain on plasma membranes in the uptake of human AGP by liver parenchymal cells. AB - Human alpha(1) -acid glycoprotein (AGP), a lipocalin family member, serves as a carrier for basic drugs and endogenous hormones. It is mainly distributed in the liver and also has anti-inflammatory effects. We previously discovered a protein in liver parenchymal cells that interacts with AGP and it was identified as hemoglobin beta-chain (HBB). The purpose of this study was to clarify the role of HBB in the hepatic cellular uptake of AGP. Ligand blotting experiments showed that the interaction of (125) I-AGP with hemoglobin was saturable and was significantly suppressed in the presence of excess unlabeled AGP. In addition, the cellular uptake of fluorescein isothiocianate-AGP by HepG2 cells was saturable and temperature dependent. This uptake was inhibited by fillipin and methyl-beta-cyclodextrin, but not chlorpromazine, suggesting that AGP is taken up via caveolae/lipid rafts endocytic pathway. Immunostaining showed that HBB and caveolin-1, exclusively expressed in caveolae, were partially colocalized on the plasma membranes of HepG2 cells. HBB knockdown with siRNA decreased the uptake of AGP by HepG2 cells by 40%, and exogenous hemoglobin inhibited the uptake by 40% 50%. These findings indicate that HBB is located on the liver plasma membrane and that it contributes to the intracellular uptake of AGP. PMID- 22227720 TI - Immunomodulative cell therapy after solid organ transplantation: which cell type when? PMID- 22227721 TI - Pancreas transplantation: in for the long run. PMID- 22227722 TI - Tolerogenic dendritic cells: applications for solid organ transplantation. AB - PURPOSE OF REVIEW: We discuss the use of tolerogenic dendritic cells (TolDCs) as a therapeutic tool in solid organ transplantation, with particular emphasis on recent experimental and preclinical data supporting the clinical translation of TolDC therapy. RECENT FINDINGS: TolDC have been successfully used in rodents to promote long-term allograft survival. Although most studies have focused on donor dendritic cells or donor antigen-pulsed dendritic cells, our group investigated a strategy based on the administration of autologous dendritic cells (not pulsed with donor antigens). We discuss the therapeutic efficacy, mechanisms, and potential risks and advantages of each strategy. We also highlight recent findings on the generation of clinical grade human TolDC from blood monocytes. Finally, we discuss preliminary experience with dendritic cells in humans and critical issues regarding the implementation of TolDC therapy to clinical organ transplantation. SUMMARY: TolDC hold therapeutic promise for the treatment of transplanted patients. Cell therapy with unpulsed, autologous dendritic cells appears as a well tolerated, clinically relevant approach that might help in improving long-term allograft survival and limit the harmful effects of immunosuppressive treatments. PMID- 22227723 TI - The toxic effect of Amiodarone on valve formation in the developing heart of zebrafish embryos. AB - BACKGROUND: Amiodarone is a class D drug given to treat arrhythmia, including pregnant women, but its effects on the developing heart have not been studied. Although some studies have suggested that this drug is safe for fetuses, they have been conducted on mothers with fetuses at or beyond six months of gestational age. RESULTS: The occurrence of valve defect was positively proportional to Amiodarone concentrations over 9 MUM, but not lower than 6 MUM. Ectopic overexpression of versican was observed at the atrioventricular canal of the Amiodarone-treated embryos at 15 MUM (EC(50)). VE-cadherin (cdh5), normally downregulated at the endocardial cushion, was also ectopically overexpressed in the Amiodarone-treated embryos. Knockdown of either versican or cdh5 in the Amiodarone-treated embryos could rescue the valve defect caused by Amiodarone. CONCLUSIONS: By inducing versican ectopical overexpression, leading, in turn, to cdh5 ectopical overexpression, Amiodarone treatment causes failure of cardiac valve formation in zebrafish embryos. PMID- 22227724 TI - Percutaneous endoscopic gastrostomy as a method of nutrition support in children with chronic kidney disease. AB - Chronic kidney disease (CKD) exerts a significant impact on children's growth and development. In infants and children with CKD, feeding-related problems are not infrequent, leading to protein-energy malnutrition and resulting in retarded physical development. Because spontaneous energy intake is usually inadequate in children with CKD, special dietary counseling with supportive procedures are often required. Placement of a percutaneous endoscopic gastrostomy (PEG) tube is one practical way to allow home tube feeding. Such nutrition support is valuable in children with CKD, and although it is not free from complications and technical problems, it seems to be helpful in providing required nutrition intake. In this report, the authors describe their own experience with PEG implantation and use in 3 children with CKD. PMID- 22227725 TI - Effects of fish oil on inflammatory modulation in surgical intensive care unit patients. AB - BACKGROUND: The benefit of omega-3 fatty acids in fat emulsion remains controversial. This study evaluated the effect of omega-3 fatty acids on immune and inflammatory modulation in surgical intensive care unit (SICU) patients. METHODS: Thirty-eight patients admitted to the SICU after major surgery were enrolled in this prospective controlled study and randomized to receive parenteral nutrition (PN) with equal volume and calories from glucose, nitrogen, and fat but different lipid components for 7 postoperative days. Group A (n = 12) received a mixture of soybean and medium-chain triglyceride oils; group B (n = 18) received a fat emulsion with part of the lipid replaced by fish oil. Blood tests, including lipid profile, routine biochemistry, inflammatory cytokines, and lymphocyte subpopulations, were evaluated preoperatively and on postoperative days 4 and 7. RESULTS: Both lipid regimens were well tolerated. There was a trend toward reduced serum inflammatory cytokines in group B vs group A with significant differences regarding interleukin (IL)-1, IL-8, and interferon (IFN) gamma on postoperative day 4 (P < .05) and IL-1, IL-8, IFN-gamma, IL-6, and tumor necrosis factor-alpha on postoperative day 7 (P < .05). There was a reduction in postoperative liver dysfunction (A vs B: 50% vs 33.3%) and infection rate (A vs B: 41.7% vs 27.8%) in group B, although this was not statistically significant. There was no mortality in either group. CONCLUSION: This study suggests that supplementation of parenteral omega-3 fatty acids in PN is safe and may improve immune and hyperinflammatory response for SICU patients after major surgery. PMID- 22227726 TI - Prevalence of vitamin D insufficiency among breast cancer survivors. AB - BACKGROUND: Recent research has linked inadequate vitamin D levels with risk of breast cancer, but there are less data regarding the actual concentrations of vitamin D in women who have survived breast cancer. The objective of this study was to determine if vitamin D insufficiency is a prevalent problem for female breast cancer survivors who have completed treatment for breast cancer. METHODS: Ninety-nine breast cancer survivors and a control population of 54 women with no history of breast cancer participated in this study. Serum 25-hydroxy vitamin D concentrations were measured throughout 2007. Dietary and supplemental intake of vitamin D was assessed by a food frequency questionnaire. Zip code of residence was used to evaluate potential for skin production of vitamin D. RESULTS: Vitamin D insufficiency (<32 ng/mL) was observed in 76 of 99 (77%) of breast cancer survivors and 51 of 54 (94%) of controls. Women taking vitamin D supplements >1000 IU/d were less likely to exhibit vitamin D insufficiency, but supplementation did not guarantee sufficiency. CONCLUSION: Vitamin D insufficiency appears to be prevalent among both controls and breast cancer survivors. Vitamin D status should be routinely evaluated for all women as part of regular preventive care if supplemental vitamin D intake is <1000 IU daily. PMID- 22227727 TI - Selection of top 10 quality indicators for nutrition therapy. AB - BACKGROUND: The identification of useful quality indicators for nutrition therapy (QINTs) is of great interest and a challenge. This study attempted to identify the 10 QINTs that best suit the practice of quality control in nutrition therapy (NT) by evaluating the opinion of experts in NT with the use of psychometric techniques and statistical tools. METHODS: Thirty-six QINTs available for clinical application in Brazil were assessed in 2 distinct phases. In phase 1, 26 nutrition experts ranked QINTs by scoring 4 attributes (utility, simplicity, objectivity, low cost) to assess each QINT on a 5-point Likert scale. The top 10 QINTs were identified from the 10 best scores obtained, and the reliability of expert opinion for each indicator was assessed by Cronbach's alpha. In phase 2, experts provided feedback regarding the selected top 10 QINTs by answering 2 closed questions. RESULTS: The top 10 QINTs, in descending order, are the frequency of nutrition screening of hospitalized patients, diarrhea, involuntary withdrawal of enteral feeding tubes, feeding tube obstruction, fasting longer than 24 hours, glycemic dysfunction, estimated energy expenditure and protein needs, central venous catheter infection, compliance of NT indication, and frequency of application of subjective global assessment. Opinions were consistent among the interviewed experts. During feedback, 96% of experts were satisfied with the top 10 QINTs, and 100% had considered them in accordance with their previous opinion. CONCLUSION: The top 10 QINTs were identified according to their usefulness in clinical practice by obtaining adequate agreement and representativeness of opinion of nutrition experts. PMID- 22227728 TI - Case report of acute thiamine deficiency occurring as a complication of vitamin free parenteral nutrition. AB - Parenteral nutrition (PN) is a relatively recent life-saving development in medicine but brings with it a range of new potential complications. Much of our knowledge about the signs and symptoms of individual micronutrient deficiencies comes from observations of patients receiving PN, and an example of this is the pivotal paper by Velez and colleagues published in Journal of Parenteral and Enteral Nutrition in 1985. This case report was the first published study to identify acute thiamine deficiency with cardiopathy and metabolic acidosis occurring in adult patients receiving vitamin-free PN. Although the importance of thiamine has been recognized since the late 19th century, it is still unclear exactly what dose is required for full repletion of a deficient patient, and further research would be useful to elucidate this question. PMID- 22227730 TI - Assessing constipation: the devil is in the details. PMID- 22227731 TI - Recent safety concerns with proton pump inhibitors. AB - There have been recent concerns about the safety of proton pump inhibitors (PPIs). We focus here on 3 specific concerns-the possible interaction between PPIs and clopidogrel, the postulated link between PPI use and fractures, and the possibility that long-term PPI use might lead to hypomagnesemia. There is evidence for an in vitro interaction between clopidogrel and at least some PPIs. The Food and Drug Administration (FDA) has warned against the use of certain PPIs by patients on clopidogrel. However, a randomized controlled trial that compared clopidogrel alone with the combination of clopidogrel and omeprazole found no increase in adverse cardiovascular outcomes and a reduction in the rate of adverse gastrointestinal outcomes attributable to omeprazole. PPI use may be a weak risk factor for certain fractures, but the quality of evidence is relatively poor and there is a strong possibility of confounding. The mechanism whereby PPI use might increase fracture risk is unknown. Currently, no additional measures concerning calcium supplementation or bone mineral density monitoring are recommended for patients on a PPI. The FDA has suggested monitoring serum magnesium levels in patients on PPI therapy. The mechanism and frequency of PPI induced hypomagnesemia are unclear. PPI treatment should not be withheld from patients who genuinely require it, but the PPI should be taken in the lowest effective dose and only for as long as clinically indicated. The same is, of course, true for all medicines. The benefits of PPI therapy greatly outweigh the risks. PMID- 22227732 TI - Compromise of patient safety in research report. PMID- 22227729 TI - Treatment of neuroterrorism. AB - Bioterrorism is defined as the intentional use of biological, chemical, nuclear, or radiological agents to cause disease, death, or environmental damage. Early recognition of a bioterrorist attack is of utmost importance to minimize casualties and initiate appropriate therapy. The range of agents that could potentially be used as weapons is wide, however, only a few of these agents have all the characteristics making them ideal for that purpose. Many of the chemical and biological weapons can cause neurological symptoms and damage the nervous system in varying degrees. Therefore, preparedness among neurologists is important. The main challenge is to be cognizant of the clinical syndromes and to be able to differentiate diseases caused by bioterrorism from naturally occurring disorders. This review provides an overview of the biological and chemical warfare agents, with a focus on neurological manifestation and an approach to treatment from a perspective of neurological critical care. PMID- 22227735 TI - Living in a well-serviced urban area is associated with maintenance of frequent walking among seniors in the VoisiNuAge study. AB - OBJECTIVE: This paper examined whether or not closer proximity to local services and amenities was associated with maintenance of more frequent walking over time among urban-dwelling seniors over and above individual-level characteristics. METHOD: A sample of 521 adults who were part of the VoisiNuAge study and who resided in a large North American urban area reported on the frequency of walking outside the home over a 3-year period and on their health, sociodemographic characteristics, social support and resources, and perceptions of different features of their residential environment. Information about the distance between their home and 16 services and amenities was obtained from a geographic information system. Seniors were then classified into quartiles of proximity (Q1, Q2, Q3, Q4). RESULTS: Unadjusted and adjusted ordinal growth curve models showed that closer proximity to services and amenities was associated with greater likelihood of frequent walking at all times throughout the 3-year period. DISCUSSION: Findings are consistent with the notion that environments may act as buoys for the maintenance of important health behaviors. Future experimental and quasi-experimental research is required to explore whether or not the environment can play a causal role in influencing patterns of walking over time. PMID- 22227736 TI - Positivity and well-being among community-residing elders and nursing home residents: what is the optimal affect balance? AB - OBJECTIVES: To explore whether a ratio of positive to negative affect, from the work of Fredricksen and Losada, could predict high levels of well-being in elderly samples and especially in nursing home residents despite multiple chronic health conditions, consonant with Ryff and Singer's notion of "flourishing under fire." METHOD: We used two samples: a probability sample of community-residing elders and a sample from nursing homes. We calculated ratios of positive to negative affect in each sample and measured well-being with social interaction, mental health, life satisfaction, and general well-being. RESULTS: The positivity ratio of 2.9 differentiated high levels of well-being in both the samples, as in previous research on younger samples. DISCUSSION: Although we expected the positivity ratio to perform less well among nursing home residents, we found that it differentiated residents with high well-being just as well as in the community sample. The ability to regulate positive affect to maintain a relative ratio of positive over negative affect appears to be an important aspect of successful adjustment in late life. Further research is needed on objective indicators of quality of life and on whether intra-individual shifts in affect balance are coupled with shifts in indicators of positive mental health. PMID- 22227737 TI - Structural and ultrastructural changes of full-cycle cultured Pacific bluefin tuna (Thunnus orientalis) muscle slices during chilled storage. AB - BACKGROUND: This study examined the structural and ultrastructural changes of dorsal and ventral muscle tissues of full-cycle cultured Pacific bluefin tuna (PBT), Thunnus orientalis Temminck & Schlegel 1844, cut into slices simulating sashimi and placed in chilled storage for varying periods. Structural and ultrastructural changes were determined in order to understand the physical texture by breaking strength measurement. RESULTS: Progressive deterioration of myofibril structure was observed during chilled storage (4 degrees C) of PBT muscle slices over 5 days post mortem. Muscle degradation included detachment between myofibres, detachment of the plasmalemma, disruption of mitochondria, loss of Z-line density and alignment, cementation of myofibrils, loss of the hexagonal arrangement of thick versus thin myofilaments and migration of subsarcolemmal nuclei to intermyofibrillar spaces. CONCLUSION: Loss of myofibre myofibre adhesion, detachment of the plasmalemma and disruption of other components did not lower the breaking strength of PBT muscle. This provides evidence that the muscle breaking strength of PBT is not only associated with the detachment of myofibres or detachment of the plasmalemma. Other factors that produce cement-like substances, such as cementation of the myofibrillar components and degradation of the sarcoplasmic reticulum, may also increase breaking strength. PMID- 22227738 TI - Enzymatic biofuel cells utilizing a biomimetic cofactor. AB - The performance of immobilized enzyme systems is often limited by cofactor diffusion and regeneration. Here, we demonstrate an engineered enzyme capable of utilizing the minimal cofactor nicotinamide mononucleotide (NMN(+)) to address these limitations. Significant gains in performance are observed with NMN(+) in immobilized systems, despite a decreased turnover rate with the minimal cofactor. PMID- 22227739 TI - IL-12 concentrations in the aqueous humor and serum of diabetic retinopathy patients. AB - BACKGROUND: Previous studies suggest that inflammation plays an important part in the pathogenesis of diabetes. Cytokines may have a role in both positive and negative control of immunological reactions. Among many cytokines, interleukin 12 (IL-12) is known to be a strong pro-inflammatory cytokine. METHODS: A total of 76 participants were enrolled in this study and classified into four groups: 23 diabetic patients with non-treated retinopathy, 17 diabetic patients with treated retinopathy, 12 diabetic patients without retinopathy, and 24 healthy control patients. Serum and aqueous humor samples were taken for the analysis of IL-12 concentration. RESULTS: The aqueous humor IL-12 concentration was significantly elevated in the patients with non-treated diabetic retinopathy (chi(2)(3, n = 76) = 27.137; p < 0.001). No significant differences in IL-12 serum concentrations between the groups were found (F = 0.405, p = 0.750). Correlation analysis of IL 12 concentrations in the serum and aqueous humor showed a linear association between the two variables only in non-diabetic patients (p = 0.003). CONCLUSIONS: This is the first study to show a significantly higher concentration of pro inflammatory cytokine IL-12 in the aqueous humor of non-treated diabetic retinopathy patients in comparison with diabetic patients treated for retinopathy, without retinopathy, or with healthy individuals. Because the serum levels of IL-12 did not differ considerably between the studied groups, it is plausible that this is due to its local production and secretion. PMID- 22227740 TI - Does pre-exposure inhibit fear context conditioning? A Virtual Reality Study. AB - Several studies in animals and humans have indicated that familiarity toward cues reduces cue-conditioning effects. The influence of familiarity of a context on context conditioning has been confirmed in animal studies only. Thus, this study examined contextual fear conditioning in humans depending on pre-exposure to the to-be-conditioned context. To accomplish this, a virtual reality paradigm presented via a head mounted display was realized. During conditioning, participants were exposed to one of two office rooms (contexts), of which one became associated with aversive electric stimuli (UCS). 1 day before conditioning, participants were randomly exposed to either the later to-be conditioned context (n = 20) or to an unrelated virtual environment (n = 20). Startle reflex, skin conductance response, heart rate, and ratings of valence, arousal, and anxiety were measured to assess context conditioning. Successful context conditioning was demonstrated for both ratings and physiological indicators. Pre-exposure did not prevent successful context conditioning. We conclude that in humans, contextual fear conditioning is not easily modified by pre-exposure to the context. PMID- 22227741 TI - Preparation of graphene-encapsulated magnetic microspheres for protein/peptide enrichment and MALDI-TOF MS analysis. AB - The Fe(3)O(4)@SiO(2)@graphene microspheres were prepared and demonstrated to be highly efficient enrichment materials for proteins and peptides in MALDI-TOF MS analysis. PMID- 22227742 TI - Fully automated production of 11C-doxepin for PET imaging histamine H1 receptor. AB - OBJECTIVES: (11)C-Doxepin is an established positron emission tomography (PET) probe for imaging the histamine H1 receptor, which is associated with various neurological disorders and allergic diseases. A fully automated current Good Manufacturing Practices (cGMP)-compliant radiosynthesis is therefore desirable in order to facilitate clinical PET studies. We report here a fully automated production method for (11)C-doxepin using a multipurpose PET module for clinical use. METHODS: (11)C-Doxepin was radiosynthesized by N-[(11)C]methylation of nordoxepin using [(11)C]methyl iodide in DMF solvent, and then purified by HPLC, and finally reformulated with solid phase extraction (SPE) using a cGMP-compliant automated multipurpose PET module developed in house. The final product was analyzed and subjected to quality control according to current US Pharmacopeia requirements. RESULTS: The radiochemical yield (decay corrected) of (11)C-doxepin for clinical use was 47.0 +/- 5.2% (n = 12) based on [(11)C]methyl iodide, moreover the radiochemical purity of (11)C-doxepin was more than 97.5% with 1,200 +/- 500 Ci/mmol specific activity(end of production). The total production time of (11)C-doxepin was 37 min from end of bombardment (EOB) with the final product passing all tests under cGMP requirements for clinical use. CONCLUSIONS: A simplified and reliable fully automated production of (11) C-doxepin for clinical use was developed, allowing the synthesis of the tracer with high yield using a cGMP-compliant module and procedure. The success of this approach could make the PET tracer (11) C-doxepin more accessible for clinical studies. PMID- 22227743 TI - Fast and high yield post-synthetic modification of metal-organic frameworks by vapor diffusion. AB - Vapor-phase post-synthetic modification (VP-PSM) is herein described. VP-PSM is a tool that overcomes limitations of standard PSM methods by giving a higher yield in short reaction times and will give more flexibility in designing metal-organic frameworks with functionalization for chemical and physical applications. PMID- 22227744 TI - Application of mass spectrometric techniques for the trace analysis of short lived iodine-containing volatiles emitted by seaweed. AB - Knowledge of the composition and emission rates of iodine-containing volatiles from major widespread seaweed species is important for modeling the impact of halogens on gas-phase atmospheric chemistry, new particle formation, and climate. In this work, we present the application of mass spectrometric techniques for the quantification of short-lived iodine-containing volatiles emitted by eight different seaweeds from the intertidal zone of Helgoland, Germany. A previously developed online time-of-flight aerosol mass spectrometric method was used to determine I(2) emission rates and investigate temporally resolved emission profiles. Simultaneously, iodocarbons were preconcentrated on solid adsorbent tubes and quantified offline using thermodesorption-gas chromatography-mass spectrometry. The total iodine content of the seaweeds was determined using microwave-assisted tetramethylammonium hydroxide extraction followed by inductively coupled-plasma mass spectrometry analysis. The highest total iodine content was found in the Laminariales, followed by the brown algae Ascophyllum nodosum, Fucus vesiculosus, Fucus serratus, and both red algae Chondrus crispus and Delesseria sanguinea. Laminariales were found to be the strongest I(2) emitters. Time series of the iodine release of Laminaria digitata and Laminaria hyperborea showed a strong initial I(2) emission when first exposed to air followed by an exponential decline of the release rate. For both species, I(2) emission bursts were observed. For Laminaria saccharina und F. serratus, a more continuous I(2) release profile was detected, however, F. serratus released much less I(2). A. nodosum and F. vesiculosus showed a completely different emission behavior. The I(2) emission rates of these species were slowly increasing with time during the first 1 to 2 h until a more or less stable I(2) emission rate was reached. The lowest I(2) emission rates were detected for the red algae C. crispus and D. sanguinea. Total iodocarbon emission rates showed almost the same general trend, however, the total iodocarbon emission rates were about one to two orders of magnitude lower than those of molecular iodine, demonstrating that I(2) is the major iodine containing volatile released by the investigated seaweed species. In addition, a clear dependency of iodocarbon emission from the ozone level (0-150 ppb O(3)) was found for L. digitata. PMID- 22227745 TI - Automated analysis of perfluorinated compounds in human hair and urine samples by turbulent flow chromatography coupled to tandem mass spectrometry. AB - Perfluorinated compounds (PFCs) are ubiquitous contaminants of humans and animals worldwide. PFCs are bioaccumulated because of their affinity for proteins. It has been shown they could have a variety of toxicological effects and cause damage to human health, emphasizing the need for sensitive and robust analytical methods to assess their bioaccumulation in humans. In this paper we report the development and validation of an analytical method for analysis of PFCs in the non-invasive human matrices hair and urine. The method is based on rapid and simple sample pre treatment followed by online turbulent flow liquid chromatography and tandem mass spectrometry (TFC-LC-MS-MS) for analysis of 21 PFCs. The method was validated for both matrices. Percentage recovery was between 60 and 105 for most compounds in both matrices. Limits of quantification ranged from 0.1 to 9 ng mL(-1) in urine and from 0.04 to 13.4 in hair. The good performance of the method was proved by investigating the presence of selected PFCs in 24 hair and 30 urine samples from different donors living in Barcelona (NE Spain). The results were indicative of bioaccumulation of these compounds in both types of sample. PFOS and PFOA were most frequently detected in hair and PFBA in urine. PMID- 22227746 TI - Electrochemical oxidation and protein adduct formation of aniline: a liquid chromatography/mass spectrometry study. AB - Historically, skin sensitization tests are typically based on in vivo animal tests. However, for substances used in cosmetic products, these tests have to be replaced according to the European Commission regulation no. 1223/2009. Modification of skin proteins by electrophilic chemicals is a key process associated with the induction of skin sensitization. The present study investigates the capabilities of a purely instrumental setup to determine the potential of commonly used non-electrophilic chemicals to cause skin sensitization by the generation of electrophilic species from the parent compound. In this work, the electrophiles were generated by the electrochemical oxidation of aniline, a basic industrial chemical which may also be released from azo dyes in cosmetics. The compound is a known sensitizer and was oxidized in an electrochemical thin-layer cell which was coupled online to electrospray ionization-mass spectrometry. The electrochemical oxidation was performed on a boron-doped diamond working electrode, which is able to generate hydroxyl radicals in aqueous solutions at high potentials. Without any pretreatment, the oxidation products were identified by electrospray ionization/time-of-flight mass spectrometry (ESI-ToF-MS) using their exact masses. A mass voltammogram was generated by plotting the obtained mass spectra against the applied potential. Oligomerization states with up to six monomeric units in different redox states of aniline were observed using this setup. This approach was extended to generate adducts between the oxidation products of aniline and the tripeptide glutathione. Two adducts were identified with this trapping experiment. Protein modification was carried out subsequently: Aniline was oxidized at a constant potential and was allowed to react with beta-lactoglobulin A (beta-LGA) or human serum albumin (HSA), respectively. The generated adducts were analyzed by liquid chromatography coupled to ESI-ToF-MS. For both beta-LGA and HSA, aniline adducts were successfully generated and identified. PMID- 22227747 TI - Analysis of paint cross-sections: a combined multivariate approach for the interpretation of MUATR-FTIR hyperspectral data arrays. AB - The present research is aimed at introducing a suitable approach for the exploitation of the hyperspectral data obtained by MUATR-FTIR analyses of paint cross-sections. The application of principal component analysis for chemical mapping is well-established, even if a very limited number of applications to MUFTIR data have been reported so far in the field of analytical chemistry for cultural heritage. Moreover, in many cases, chemometric tools are under-utilized and the outcomes under-interpreted. As a consequence, results and conclusions may be considerably compromised. In an attempt to overcome such drawbacks, the present work is proposing a comprehensive and efficient procedure based on an interactive brushing approach, which combines the structural information of the score scatter plots and the spatial information of the principal component (PC) score maps. In particular, the study demonstrates not only how the multivariate approach may provide more information than the univariate one, but also how the integration of different chemometric tools may allow a more comprehensive interpretation of the results with respect to the studies up to now reported in the literature. The examination of the average spectral profile of each score cluster, jointly with the loading analysis, is functional to characterize each area investigated on the basis of its spectral features. A multivariate comparison with spectra of standard compounds, projected in the PC score space, helps in supporting the chemical identification. The approach was validated on two real case studies. PMID- 22227748 TI - Nylon membrane as a fluorimetric probe for the herbicide bentazone. AB - The fluorimetric signal produced by bentazone retained in selected solid surfaces was investigated. Among the different tested supports, only a microporous nylon membrane produced the desired signal. The quantitative study was carried out by second-order calibration using parallel factor analysis, allowing the determination in a highly interfering medium. A detection limit of 0.4 ng mL(-1), a prediction relative error of 8%, and a sample frequency of ten samples per hour were obtained in spiked natural waters using green analytical chemistry principles. PMID- 22227749 TI - Legal challenges for substance abuse treatment during disasters. AB - Certain groups with preexisting mental and behavioral health conditions, such as substance use disorders, may be especially vulnerable during and shortly after disasters. Researchers have found that substance abuse treatment programs and the individuals they serve experienced major disruptions after the September 11, 2001, attacks on the World Trade Center and the Pentagon and after Hurricane Katrina. This column considers legal challenges that may arise when a rapid influx of licensed providers is needed for substance abuse treatment during disasters and reviews specific legal issues that disasters may raise for opioid treatment programs. Opportunities to mitigate legal challenges and facilitate substance abuse treatment during disasters are discussed. PMID- 22227750 TI - Strengthening the evidence base to support PSAs. PMID- 22227752 TI - Datapoints: psychotropic drug use among elderly patients in home care in the United States. PMID- 22227753 TI - Best practices: recovery centers for people with a mental illness: an emerging best practice? AB - The authors report a process evaluation that used rigorous qualitative methods consistent with best practice to assess the development and impact of a nascent recovery center in the New York City area. The center successfully delivered services that focused on helping increasing numbers of consumers achieve educational and functional improvements. Consumers perceived the center as providing a strong sense of community while also serving as a "stepping stone" to wider opportunities. Because they offer a feasible and popular means to help individuals with mental illness acquire skills, recovery centers may be an emerging best practice. Further research is necessary to test their efficacy. PMID- 22227754 TI - An analysis of the slowdown in growth of spending for psychiatric drugs, 1986 2008. AB - OBJECTIVE: This study analyzed recent trends in spending on psychiatric prescription drugs and underlying factors that served as drivers of these changes. METHODS: Data were collected from the MarketScan Commercial Claims and Encounters Database (1997-2008), Substance Abuse and Mental Health Services Administration spending estimates (1986-2005), and the Medical Expenditure Panel Survey (1997-2007). The trends in medication spending derived from the data were decomposed into three categories: percentage of enrollees who used psychiatric medications, days supplied per user, and cost per day supplied. RESULTS: The average annual rate of growth in expenditures per enrollee slowed from 18.5% in 1997-2001 to 6.3% in 2001-2008. A decline in the growth rate of cost per day supplied, from 8% to 2%, accounted for 49% of the overall decline in spending growth, and a decline in the growth of the percentage of enrollees who used medication, from 7% to 2%, contributed 41% to the overall decline. There was a smaller change in days supplied per user, from 3% to 2%, that contributed 10% to the overall decline. The increased entry of generic medications, which constituted 70% of all psychiatric prescriptions by 2008, particularly generic antidepressants, was a key contributor to the slower growth in costs. CONCLUSIONS: Past high growth in psychiatric drug spending arising from growth in utilization of branded medications has declined significantly, which may have implications for access and new product investment. PMID- 22227756 TI - Incarceration among adults who are in the public mental health system: rates, risk factors, and short-term outcomes. AB - OBJECTIVE: Incarceration of people with mental illness has become a major social, clinical, and economic concern, with an estimated 2.1 million incarcerations in 2007. Prior studies have primarily focused on mental illness rates among incarcerated persons. This study examined rates of and risk factors for incarceration and reincarceration, as well as short-term outcomes after incarceration, among patients in a large public mental health system. METHODS: The data set included 39,463 patient records combined with 4,544 matching incarceration records from the county jail system during fiscal year 2005-2006. Risk factors for incarceration and reincarceration were analyzed with logistic regression. Time after release from the index incarceration until receiving services was examined with survival analysis. RESULTS: During the year, 11.5% of patients (N=4,544) were incarcerated. Risk factors for incarceration included prior incarcerations; co-occurring substance-related diagnoses; homelessness; schizophrenia, bipolar, or other psychotic disorder diagnoses; male gender; no Medicaid insurance; and being African American. Patients older than 45, Medicaid beneficiaries, and those from Latino, Asian, and other non-Euro-American racial ethnic groups were less likely to be incarcerated. Risk factors for reincarceration included co-occurring substance-related diagnoses; prior incarceration; diagnosed schizophrenia or bipolar disorder; homelessness; and incarceration for three or fewer days. Patients whose first service after release from incarceration was outpatient or case management were less likely to receive subsequent emergency services or to be reincarcerated within 90 days. CONCLUSIONS: Modifiable factors affecting incarceration risk include homelessness, substance abuse, lack of medical insurance, and timely receipt of outpatient or case management services after release from incarceration. PMID- 22227755 TI - Perceptions of the state policy environment and adoption of medications in the treatment of substance use disorders. AB - OBJECTIVE: Despite growing interest in the use of evidence-based treatment practices for treating substance use disorders, adoption of medications by treatment programs remains modest. Drawing on resource dependence and institutional theory, this study examined the relationships between adoption of medications by treatment programs and their perceptions about the state policy environment. METHODS: Data were collected through mailed surveys and telephone interviews with 250 administrators of publicly funded substance abuse treatment programs in the United States between 2009 and 2010. Multiple imputation and multivariate logistic regression were used to estimate the associations between perceptions of the state policy environment and the odds of adopting at least one medication for the treatment of substance use disorders. RESULTS: A total of 91 (37%) programs reported having prescribed any medication for treatment of a substance use disorder. Programs were significantly more likely to have adopted at least one medication if they perceived greater support for medications by the Single State Agency. The odds of adoption were significantly greater if the program was aware that at least one medication was included on their state's Medicaid formulary and that state-contract funding permitted the purchase of medications. CONCLUSIONS: States may play significant roles in promoting the adoption of medications, but adequate dissemination of information about state policies and priorities may be vital to further adoption. Future research should continue to study the relationships between the adoption of medications for treating substance use disorders and the evolving policy environment. PMID- 22227757 TI - Prevalence of involvement in the criminal justice system during severe mania and associated symptomatology. AB - OBJECTIVE: This study sought to determine the prevalence of criminal justice involvement during episodes of mania and to identify whether specific manic symptoms contribute to this risk. METHODS: Data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions, a nationally representative sample of noninstitutionalized U.S. adults (N=43,093), were analyzed to determine the rate of legal involvement (being arrested, held at the police station, or jailed) of individuals with bipolar I disorder during the most severe lifetime manic episode. RESULTS: Among the 1,044 respondents (2.5%) who met criteria for having experienced a manic episode, 13.0% reported legal involvement during the most severe manic episode. Unadjusted analyses found legal involvement more likely among those with episode-specific symptoms of increased self-esteem or grandiosity, increased libido, excessive engagement in pleasurable activities with a high risk of painful consequences, having six or more criterion B manic symptoms, and having both social and occupational impairment. The risk was lower among those with hypertalkativeness or pressured speech. When analyses adjusted for other manic symptoms and static variables, males, those with a first episode at age 23 or younger, and persons with mania-associated social indiscretions, excessive spending or reckless driving, and both social and occupational impairment were at greater risk. CONCLUSIONS: A large percentage of persons experience legal involvement during a manic episode, and it is associated with specific symptoms of mania. Efforts to reduce such involvement among persons during manic episodes may be enhanced by focusing attention and resources on this high-risk group. PMID- 22227758 TI - Events preceding changes in conflict and containment rates on acute psychiatric wards. AB - OBJECTIVE: The main objective of this study was to learn more about what increases or decreases the likelihood of patient conflict (such as verbal abuse, violence, and rule breaking) and containment (such as seclusion, manual restraint, and enforced medication) events in acute inpatient psychiatric wards. METHODS: Line graphs that mapped the total conflict and containment scores over two years on 16 acute inpatient psychiatric wards in the United Kingdom (London) were matched with chronological events that were documented in 120 qualitative semistructured interviews with ward managers and consultant psychiatrists during the same two-year period. Conflict and containment scores were derived from the validated Patient-Staff Conflict Checklist-Shift Report, which was completed by nurses at the end of each shift to log the frequency of conflict behaviors of patients and the staff containment measures. RESULTS: A total of 463 score transitions (upturns and downturns) were identified in the graphs. A total of 323 events were matched to these transitions. A thematic analysis of these events produced 40 themes, which were organized into four categories: patient centered, staff centered, practice or ward centered, or other themes. Thirteen themes were significantly associated with conflict and containment score transitions, 11 of which were staff centered. For example, negative staff morale and staffing change resulting in a negative impact significantly increased the likelihood that conflict and containment would occur, whereas report of positive staff practice significantly decreased the likelihood of such events occurring. CONCLUSIONS: The results support the theory that ward staff play a crucial role in influencing the likelihood that conflict or containment events will occur in inpatient psychiatric settings. PMID- 22227759 TI - Assessing recovery of people with serious mental illness: development of a new scale. AB - OBJECTIVES: The authors describe the development of the Maryland Assessment of Recovery in People with Serious Mental Illness, or MARS, a 25-item self-report instrument that measures recovery of people with serious mental illness, and report a study of its psychometric properties. METHODS: Doctoral-level scientists with expertise in serious mental illness drafted a set of survey items about the recovery process. Items reflected recovery domains outlined by the Substance Abuse and Mental Health Services Administration. After consultation with a panel of experts on recovery that included consumers and clinical scientists and with a small group of consumers, the instrument was narrowed to 67 items and administered to 166 individuals recruited from outpatient mental health clinics in two states. Item response theory and classical item analysis were used to select best-fitting items, reduce item redundancy, and improve the psychometric properties of the scale. Principal components analysis and confirmatory factor analysis were conducted to further examine dimensions of recovery measured by the scale. RESULTS: The MARS is quite practical for use with individuals with serious mental illness. It demonstrated excellent internal consistency (Cronbach's alpha=.95) and test-retest reliability (r=.898) and good face and content validity. CONCLUSIONS: The data provide initial support for use of the MARS to measure recovery of people with serious mental illness. PMID- 22227760 TI - Effects of a peer-run course on recovery from serious mental illness: a randomized controlled trial. AB - OBJECTIVE: Research on the effectiveness of peer-run services on the recovery of people with major psychiatric problems has been limited and poorly controlled. This study evaluated the effects of a 12-week peer-run course on recovery, "Recovery Is Up to You." METHODS: Recruitment of people with major psychiatric problems took place in the Netherlands between 2006 and 2008, and the effects of the peer-run intervention were evaluated in a randomized controlled trial. A total of 333 people were randomly assigned to the experimental (N=168) or control (N=165) condition. Self-report instruments used were the Herth Hope Index, the Manchester Short Assessment of Quality of Life, the Mental Health Confidence Scale, the Dutch Empowerment Scale, and the Loneliness Scale. Assessments took place at baseline, after three months (at the end of the course), and after six months. Data were analyzed by using linear mixed modeling. RESULTS: The intervention had a significant and positive effect on empowerment, hope, and self efficacy beliefs but not on quality of life and loneliness. The effects of the intervention persisted three months after participants completed the course. CONCLUSIONS: The results suggest that the peer-run course contributed to improvement in important domains of recovery. Peer-run services, such as "Recovery Is Up to You," add value to recovery-oriented mental health care because they offer participants an opportunity to make an active start on their recovery. PMID- 22227761 TI - Partners in recovery: social support and accountability in a consumer-run mental health center. AB - OBJECTIVE: Consumer-run mental health programs that include advocacy, peer counseling, and mentoring are somewhat commonplace in community mental health services, yet fully peer-operated mental health centers remain novel in the public mental health landscape. This ethnographic study of a consumer-run mental health center had two major aims: to learn what is distinctive about consumer-run services-for example, how they might strengthen personal capacity for social integration-and to explore how the development of these capacities might promote recovery. METHODS: Data collection for this modified ethnographic study consisted of ten months of participant observation, coupled with semistructured interviews (N=25), a focus group (N=22), and dramatic skits (N=17), to identify and define the distinctive features of the program, both structurally and from the point of view of participants. Inquiry was framed theoretically by the capabilities approach. RESULTS: Participants in this consumer-run mental health program experienced themselves as accountable for and to their peers in what amounts to a shared project of recovery. CONCLUSIONS: As part of a capacity-building approach in consumer-run services, programs should aim to not only provide social support for participants but also foster a culture in which service users are accountable for their peers. Such reciprocity may help to strengthen socialization skills, which could better prepare consumers for participation in the community at large. PMID- 22227762 TI - Low use of mental health services among older Americans with mood and anxiety disorders. AB - OBJECTIVE: It is unclear why late-life mood and anxiety disorders are highly undertreated, despite being common among older adults. Thus this study examined prevalence of and key factors associated with nonuse of mental health services among older community-dwelling adults with these disorders. METHODS: The sample included 348 participants aged 55 years or older who met 12-month criteria for DSM-IV mood and anxiety disorders and responded to the National Comorbidity Survey Replication (NCS-R), a population-based probability sample. Analyses included frequency measures and logistic regression with weights and complex design-corrected statistical tests. Key factors associated with not using mental health services were determined in a final multivariable model based on a systematic approach that accounted for a comprehensive list of potential predictors. RESULTS: Approximately 70% of older adults with mood and anxiety disorders did not use services. Those who were from racial-ethnic minority groups, were not comfortable with discussing personal problems, were married or cohabitating, and had middle- versus high-income status had increased odds of not using mental health services. In addition, respondents with mild versus serious disorders, no chronic pain complaints, and low versus high perceived cognitive impairment had greater odds of nonuse. CONCLUSIONS: Results indicate that improvements are needed in the following areas to combat the very high number of mood and anxiety disorders that go untreated in older Americans: awareness of need, comfort in discussing personal problems with a health care professional, and screening and other prevention efforts. PMID- 22227763 TI - Clinician reactions to patients with eating disorders: a review of the literature. AB - OBJECTIVE: The delivery of psychiatric services may be affected by clinicians' negative reactions to treatment-resistant or stigmatized patient groups. Some research has found that clinicians across professional disciplines react negatively to patients with eating disorders, but empirical data related to this topic have not been systematically reviewed. The authors sought to review all published empirical studies of clinician reactions to patients with eating disorders in order to characterize negative reactions to these patients and identify patient or clinical factors associated with negative reactions. METHODS: The authors conducted a comprehensive online search for all published studies of clinician reactions in regard to patients with eating disorders. The reference lists of articles found in the literature search were examined to identify additional studies. RESULTS: Twenty studies, published between 1984 and 2010, were found. Clinician negative reactions in regard to patients with eating disorders typically reflected frustration, hopelessness, lack of competence, and worry. Inexperienced clinicians appeared to hold more negative attitudes toward patients with eating disorders than toward other patient groups, but experienced psychotherapists did not experience strong negative reactions to patients with eating disorders. Medical practitioners consistently reported strong feelings of lack of competence in treating eating disorders. Negative reactions to patients with eating disorders were associated with patients' lack of improvement and personality pathology and with clinicians' stigmatizing beliefs, inexperience, and gender. CONCLUSIONS: Research about the impact of negative clinician attitudes toward patients with eating disorders on psychiatric service delivery, including multivariate analyses using larger samples, comparison groups, validated instruments, and experimental methods, is much needed. PMID- 22227764 TI - Where is the evidence supporting public service announcements to eliminate mental illness stigma? AB - Advocates and social marketers have used substantial resources to develop public service announcements (PSAs) as a lead strategy in public education and awareness campaigns meant to eliminate stigma associated with mental illness. Evaluations of PSAs are needed to determine whether this is a good investment. The author notes that very few studies have been reported in the peer-reviewed medical and psychological research literature addressing this question. Reports of government contractors suggest that PSAs have some effect as measured by population penetration, but such data provide no meaningful evidence about the impact of PSAs, such as real-world change in prejudicial attitudes and discriminatory behaviors. The author considers reasons for the limited impact of PSAs and proposes that social marketing campaigns could enhance their impact by targeting local groups. PMID- 22227765 TI - Trends in use of second-generation antipsychotics for treatment of bipolar disorder in the United States, 1998-2009. AB - OBJECTIVE: The authors examined trends in the use of second-generation antipsychotics for treatment of bipolar disorder before and after the U.S. Food and Drug Administration's approval in 2000 of olanzapine for use in treating acute manic episodes of bipolar disorder. METHODS: The IMS Health National Disease and Therapeutic Index was used to derive monthly patient treatment visits between January 1998 and December 2009 by individuals 18 and older with a diagnosis of bipolar disorder who were treated with one or more pharmacotherapies. RESULTS: The percentage of treatment visits in which a second generation antipsychotic was prescribed increased from 18% in 1998 to 49% in 2009. Use of mood stabilizers and first-generation antipsychotics declined substantially. In the 12 months after approval of olanzapine for bipolar disorder, its use increased by 92%, and use of other second-generation antipsychotics increased by 42%. CONCLUSIONS: Second-generation antipsychotics are increasingly used for bipolar disorder, and their effectiveness compared with therapeutic alternatives merits further research. PMID- 22227766 TI - Predictors of relapse in the year after hospital discharge among patients with schizophrenia. AB - OBJECTIVE: Relapse and its predictors were examined among patients with schizophrenia in the year after hospital discharge. METHODS: The sample included 200 patients with schizophrenia participating in a German multicenter study. Relapse was defined as a worsening of psychopathological symptoms or rehospitalization in the year after hospital discharge. Predictors examined were variables related to course of illness and to response and remission at discharge. RESULTS: Fifty-two percent of participants had a relapse. Patients whose symptoms were not in remission at discharge were more likely to have a relapse, as were those who had more severe symptoms and more side effects at discharge. Those who experienced a relapse were less likely to be taking a second generation antipsychotic at discharge, less likely to have a positive attitude toward treatment adherence, and less likely to be employed. CONCLUSIONS: The high rate of relapse among patients with schizophrenia highlights the need to improve current treatment strategies. PMID- 22227767 TI - Usefulness of symptom feedback to providers in an integrated primary care--mental health care clinic. AB - OBJECTIVE: Measurement-based care has been endorsed but not embraced in mental health settings. There is currently little guidance regarding the best methods to implement measurement-based care. METHODS: A survey of mental health providers was conducted before (N=15) and after (N=17) the implementation of a patient self report symptom measurement system. RESULTS: At baseline, respondents rarely used the patient self-assessment information (mean+/-SD=1.8+/-1.8); they reported the patient data to be marginally useful (4.1+/-1.9), and only slightly recommended the use of patient assessments (4.3+/-2.0). Possible scores ranged from 1 to 7, with higher scores indicating more positivity. At follow-up, respondents almost always used the information in the assessments (6.3+/-1.7), found the patient report data very useful (6.4+/-.8), and highly recommended continued use of patient surveys in the integrated clinic (6.6+/-.5). CONCLUSIONS: Providers' lack of enthusiasm about integration of routine data collection and reporting of patient symptoms may be overcome by simply exposing providers to this process. PMID- 22227768 TI - Using telemedicine to coordinate inpatient and outpatient psychiatric care. PMID- 22227769 TI - Risk and recovery group for offenders with mental disorders. PMID- 22227770 TI - OECD report highlights impact of mental illness on the workforce, recommends policy changes. PMID- 22227772 TI - Random perturbations of arterial blood pressure for the assessment of dynamic cerebral autoregulation. AB - The assessment of cerebral autoregulation (CA) relies mostly on methods that modulate arterial blood pressure (ABP). Despite advances, the gold standard of assessment remains elusive and clinical practicality is limited. We investigate a novel approach of assessing CA, consisting of the intermittent application of thigh cuffs using square wave sequences. Our aim was to increase ABP variability whilst minimizing volunteer discomfort, thus improving assessment acceptability. Two random square wave sequences and two maximum pressure settings (80 and 150 mmHg) were used, corresponding to four manoeuvres that were conducted in random order after a baseline recording. The intermittent application of thigh cuffs resulted in an amplitude dependent increase in ABP (p = 0.001) and cerebral blood flow velocity (CBFV) variability (p = 0.026) compared to baseline. No statistically significant differences in mean heart rate or heart rate variability were observed (p = 0.108 and p = 0.350, respectively), suggesting that no significant sympathetic response was elicited. No significant differences in the CBFV step response were observed, suggesting no distortion of autoregulatory parameters resulted from the use of thigh cuffs. We conclude that pseudorandom binary sequences are an effective and safe alternative for increasing ABP variability. This new approach shows great promise as a tool for the robust assessment of CA. PMID- 22227773 TI - Mapping cancer disease using geographical information system (GIS) in Gezira State-Sudan. AB - In Sudan, the prevalence of cancer cases increased and cancer ranked as the major cause of death. Therefore, forming a cancer control program and putting strategic action plans into practice became an important matter for the health industry. The correlation of variations in different societies and environmental factors should be examined spatially with reliable data. The aim of this study is to produce base maps for implementation of cancer control program and cancer density maps through the utilization of GIS in health work. In this study, a database was built with the use of GIS to examine the distribution of cancer cases and maps relating to cancer events in allocation units were created. Cancer cases data registered from 1999 to 2008, by the Institute of Nuclear Medicine and Molecular Biology and Treatment of Tumors--University of Gezira in El Gezira State, was used as case in this study. Using ArcGIS, the distribution of cancer cases were presented on cancer maps including allocation units and incidence values, which were calculated for each villages and locality region. According to the world standards, cancer rates were determined and examined by the spatial analysis power of GIS. The research concluded that cancer cases were increased, in some localities over the past 10 years (1999-2008). This can be related to many reasons including the existence of the Gezira Scheme were farmers used fertilizers and pesticides, as well as increasing health awareness among the citizens through the establishment of use in the state. PMID- 22227774 TI - Perceived barriers to adopting an Asian-language quitline service: a survey of state funding agencies. AB - This study examined the perceived barriers to adopting an Asian-language quitline service among agencies that fund current state quitline services across the U.S. A self-administered survey on organizational readiness was sent to the funding agencies of 47 states plus Washington D.C. that currently fund state quitlines in English and Spanish, but not in Asian languages (response rate = 58%). The 2010 Census and the 2009 North American Quitline Consortium Survey were used to obtain the proportion of Asians among the state population and state quitline funding level, respectively. The most frequently cited reasons for not adopting an Asian quitline are: the Asian population in the state would be too small (71.4%), costs of service would be too high (57.1%), and the belief that using third-party translation for counseling is sufficient (39.3%). However, neither the actual proportion of Asians among the state population (range = 0.7% to 7.3%), nor the quitline funding level (range = $0.17 to $20.8 per capita) predicts the reported reasons. The results indicate that quitline funding agencies need more education on the necessity and the feasibility of an Asian-language quitline. Three states are currently participating in a multi-state Asian-language quitline in which each state promotes the service to its residents and one state (CA) provides the services for all the states. This centralized multi-state Asian-language quitline operation, which helps reduce practical barriers in adoption and disparity in access to service, could be extended. PMID- 22227775 TI - Preventing excessive weight gain among publicly insured pregnant women. AB - The purpose of this study is to develop an intervention to help women meet weight gain goals during pregnancy. From 2007 to 2008, pregnant women were recruited at a clinic in Chicago. Intervention participants received an educational pamphlet at their first prenatal visit. At follow up visits, provider counseling was encouraged via a weight gain trend graph and targeted feedback checklist. The primary outcome was the total weight gained over the course of prenatal care. We analyzed 57 intervention group participants and 109 controls. Demographic composition was similar between the groups except for parity. Patients in the intervention group and routine care group gained similar weight (24.5 + 13.5 lb vs. 25.3 + 14.0 lb, P = 0.71). After controlling for baseline weight, the intervention was associated with 4.6 pounds lower follow-up weight (P = 0.029). After controlling for baseline BMI and other covariates, participants who received the intervention were only 34% as likely to gain weight exceeding IOM guidelines (P = 0.009). This pilot prenatal care obesity prevention project was associated with lower weight gain in pregnancy. The feedback checklist, weight gain graph, and educational pamphlet on weight gain proved to be favorable components of this project and merit further examination in a larger intervention trial. PMID- 22227776 TI - Spectral characteristics of the PhNR in the full-field flash electroretinogram of normals and glaucoma patients. AB - Flash electroretinogram responses were measured in normal subjects to different chromatic combinations of flashes and backgrounds. The amplitudes of the flash response components were measured at different flash strengths and could be described by a generalized Naka-Rushton function. The measurements were repeated at different background luminances to study adaptation effects. It was found that when flash strength and background luminance were expressed in photometric terms (cd s/m2 and cd/m2, respectively), then the responses were very similar for all chromatic combinations with the exception of the condition in which blue (peak wavelength 458 nm) was flashed upon an orange (peak wavelength 591 nm) background. We propose that in this condition, a second (possibly S-cone or rod driven) mechanism intrudes. The negative response after the b-wave (here called "photopic negative response" or PhNR for all conditions) is thought to reflect ganglion cell activity and was also largest at this condition. Responses were measured to the 458 nm flash on 591 nm background and the reversed combination in a population of 39 normal subjects and 49 glaucoma patients. It was found that the PhNR amplitude was affected by glaucoma in all conditions. Other component parameters, reflecting responses and adaptation dynamics, were not altered. The best stimulus condition among the conditions used to separate the PhNR amplitude of normals and patients was a 1 cd s/m2 458 nm flash on a 10 cd/m2 591 nm background. PMID- 22227777 TI - Stopping sports injuries in kids: an overview of the last year in publications. AB - PURPOSE OF REVIEW: Sports participation is common among children and adolescents throughout the United States; along with that participation comes risk of injury, sometimes serious. Over 4 million sports or recreational injuries are sustained by school-age children per year in the USA. This injury prevalence has led to significant interest in prevention strategies. In this review, we examine the last year of publications related to sports injury prevention in the pediatric population. RECENT FINDINGS: Pediatric and adolescent athletes differ from adults in significant ways that often render them more susceptible to injury. Concussion is a particular problem, as are injuries to the thrower's elbow and injury to the female athlete's knee. Recognition, proper rest, and attention to mechanics may assist in decreasing the incidence and severity of these issues. SUMMARY: Further inquiry into the nature, prevalence, causes, and, in particular, sequelae of pediatric sports injuries is required. In the interim, attention to proper technique, core and neuromuscular conditioning, and helmet use are important preventive measures; avoidance of overtraining and providing adequate rest for recovery are essential for pediatric and adolescent athletes. PMID- 22227779 TI - The hygiene hypothesis revisited: does exposure to infectious agents protect us from allergy? AB - PURPOSE OF REVIEW: The increase in incidence and prevalence of allergic disease remains a mystery and cannot be explained solely by genetic factors. The hygiene hypothesis provides the strongest epidemiological explanation for the rise in allergic disease. This review evaluates the recent epidemiological and mechanistic research in the role of infectious agents in the pathogenesis of or protection from allergic disease. RECENT FINDINGS: Recent literature has extended the epidemiological findings of the protective effect of being born and reared in a farm environment and associates an increased diversity of organisms in house dust samples with protection from allergic disease. Furthermore, human and animal studies provide increasing evidence for the role of both the innate and adaptive immune systems, including regulatory cells, as mediators of this protective effect. SUMMARY: There is evidence that exposure to some infectious organisms can protect from atopy, whereas other infections appear to promote allergic diseases. The timing of exposure to infection and the properties of the infectious agent, in addition to the genetic susceptibility of the host, play an important role in the future development of allergic disease. PMID- 22227778 TI - Recent insights into inherited bone marrow failure syndromes. AB - PURPOSE OF REVIEW: Inherited bone marrow failure syndromes (IBMFS) are a diverse set of genetic disorders characterized by the inability of the bone marrow to produce sufficient circulating blood cells. The purpose of this review is to highlight novel findings in recent years and their impact on the understanding of IBMFS. RECENT FINDINGS: Mutations in over 80 different genes have been associated with the development of bone marrow failure (BMF). The products of the genes mutated in IBMFS frequently participate in housekeeping pathways, which are important for cell growth and division rather than being specific for hematopoiesis. The common theme of these pathways, when disturbed, is the activation of p53, leading to cell cycle arrest, senescence, and cell death. With continued improvement in therapy for IBMFS, late complications, such as development of malignancies, are seen more frequently. This highlights the importance of understanding the affected pathways and their roles in cancer development. SUMMARY: The recent advancement of our understanding of IBMFS has come largely through the identification of the genetic lesions responsible for disease and the investigations of their pathways. Applied in clinical practice, these findings make it possible to unambiguously identify mutation carriers even before the development of BMF and exclude or confirm a suspected clinical diagnosis for many of the more common IBMFS. The further characterization of the pathways leading to IBMFS is likely to reveal novel targets for screening tests, prognostic biomarkers, and improved and specific therapeutics. PMID- 22227780 TI - Clinical and research issues in neonatal anemia and thrombocytopenia. AB - PURPOSE OF REVIEW: Anemia and thrombocytopenia are the most common hematological problems in neonates. Red blood cell (RBC) and platelet transfusions are the mainstays of therapy, but data to guide neonatal transfusion practices have been sparse. Recombinant hematopoietic growth factors represent another therapeutic alternative, but their use in this population requires a solid understanding of the developmental differences between fetal and adult hematopoiesis. RECENT FINDINGS: Recently, follow-up studies from children randomized as neonates to either liberal or restrictive RBC transfusion approaches were published. Results of these studies have so far been contradictory and have generated more questions than answers. New developmental stage-specific problems associated with RBC transfusions were also uncovered, such as the transfusion-associated necrotizing enterocolitis. Finally, two thrombopoietin (Tpo) mimetics were approved by the FDA for the treatment of adults with chronic immune thrombocytopenia, thus offering a novel potential therapeutic alternative for thrombocytopenic neonates. SUMMARY: In this review, we will discuss the currently available data regarding neonatal RBC and platelet transfusion thresholds, as well as the potential limitations, and concerns associated with the use of erythropoietin and Tpo mimetics in this patient population. Finally, we will point out specific areas wherein additional research is critically needed. PMID- 22227781 TI - Update on topical glucocorticoid use in children. AB - PURPOSE OF REVIEW: This monograph reviews recent studies, examining topical glucocorticoid use in children. Emphasis is placed on mechanism of action, relative potency, cutaneous absorption, adverse affects, steroid phobia, and treatment compliance. RECENT FINDINGS: Recent literature has shown that over 80% of patients prescribed topical glucocorticoids are fearful of side effects and fail to use them appropriately. This lack of compliance leads to decreased therapeutic benefits. Despite this 'steroid phobia', multiple studies indicate that proper use of glucocorticoids in children is well tolerated and effective. Recent studies have failed to show clinically significant hypothalamic-pituitary adrenal suppression and cutaneous atrophy in children. High-potency steroids have been shown to cause growth restriction when used during pregnancy. Steroid allergy occurs with a prevalence of 2.7% and should be considered in children who fail to respond as expected to topical glucocorticoids. SUMMARY: Topical glucocorticoids continue to be well tolerated, effective and cost-effective in the treatment of inflammatory cutaneous conditions in children. PMID- 22227782 TI - Evaluation and management of urinary tract infections in the neonate. AB - PURPOSE OF REVIEW: The prevalence of urinary tract infections (UTIs) among full term neonates has been reported to be up to 1.1%, increasing up to 7% among those with fever. UTI in neonates may be the first indicator of underlying abnormalities of kidneys and the urinary tract. RECENT FINDINGS: Early recognition and therapy of UTI and detection of risk factors offer chances for applying strategies to avoid renal damage and recurrences. However, established diagnostic strategies and prophylactic concepts today are under debate. Currently, the main focus has been on renal changes as indicators for underlying risk factors like vesicoureteral reflux, attaching much importance to dimercaptosuccinyl acid scans. Serum and urine markers will probably allow more restrictive diagnostic imaging. Prenatal and postnatal ultrasound screenings provide additional opportunities for prophylactic measures. SUMMARY: Main objectives in the management of neonatal UTIs are the prevention of acute infection-related complications and renal damage. Neonates and very young infants with suspicious pyelonephritis should obligatorily be treated with a combination of parenterally administered antibiotics. As far as possible, diagnostic imaging should be risk-oriented and restricted to noninvasive, nonstressful procedures. The strategies of antibacterial prophylaxis for the prevention of recurrent UTIs are changing. In infants at risk, its benefits have not yet been proven by evident data. PMID- 22227783 TI - Update on acute kidney injury in the neonate. AB - PURPOSE OF REVIEW: Acute kidney injury (AKI) is associated with increased risk of morbidity and mortality in critically ill children and adults. Neonates remain an understudied group, although previous evidence suggests that this association holds true for them as well. RECENT FINDINGS: Attention to the issue of neonatal AKI is increasing. New studies in very low-birthweight infants, infants with congenital heart disease who undergo cardiopulmonary bypass, those who receive extracorporeal membrane oxygenation and infants with perinatal depression continue to demonstrate that AKI is common in neonates and associated with increased risk of morbidity and mortality. Additional advances in the field of neonatal AKI include adaptation of modern, categorical AKI definitions, as well as further evaluation of novel urinary biomarkers (e.g., neutrophil gelatinase associated lipocalin) in this patient group. SUMMARY: AKI is an independent risk factor for poor outcomes in critically ill neonates. Our ability to improve outcomes for these patients depends on heightened awareness of this issue both at the bedside as well as in research, commitment to using standardized AKI definitions in order to pool and compare data more effectively and improvement in our diagnostic methods with better AKI biomarkers so that we can identify AKI and intervene much earlier in the disease course. PMID- 22227784 TI - Interventions for adolescent alcohol use. AB - PURPOSE OF REVIEW: Adolescent alcohol use is a considerable public health problem, contributing to the leading causes of adolescent morbidity and mortality. Additionally, adolescent alcohol use is a major risk factor for adult alcohol use disorders. Successful prevention of and interventions for adolescent alcohol use may thus have significant public health impact. This article reviews the current literature on adolescent alcohol prevention and intervention strategies. RECENT FINDINGS: Systematic reviews and meta-analyses find that a variety of adolescent alcohol interventions are effective at reducing adolescents' alcohol use, as well as harmful behaviors associated with alcohol use. Long-term treatment is not necessarily superior, as brief interventions have been found to have a large effect size. Additionally, universal interventions (i.e., those that target all families within a group) may be more successful than selective interventions (i.e., those that target only certain families within a group). Intervention effects tend to wane 6-12 months after the cessation of treatment. The results of prevention interventions are more mixed. Many different intervention modalities have been shown to be effective, particularly family based interventions, as have both universal and targeted interventions. SUMMARY: A wide range of interventions are effective at reducing the harm of adolescent alcohol use. It is unclear which intervention(s) is/are optimal or most efficacious. Additionally, further research is needed on how to maintain long term intervention effects. It is less clear which prevention strategies are most efficacious. Family-based interventions appear to be most promising. PMID- 22227785 TI - HIV and club drugs in emerging adulthood. AB - PURPOSE OF REVIEW: To evaluate the incidence of club drug use in pediatric patients, especially those aged 13-25, and how it relates to the spread of HIV. RECENT FINDINGS: Transmission of HIV among younger patients has become largely associated with risky sexual behaviors, as the rate of transmission from vertical infection and intravenous drug use has decreased. Use of club drugs in emerging adult populations contributes to the HIV epidemic through a combination of decreased inhibitions as well as physiological effects that increase high-risk sexual practices. Robust data exists linking the use of club drugs by the men who have sex with men population with spread of HIV, but this data in other at-risk populations (e.g. African Americans) is not as robust. Additional research is needed to identify the rates of transmission among adolescents and emerging adults, as well as knowledge, attitudes, beliefs, and practices that affect HIV transmission in this population. SUMMARY: Use of club drugs by adolescents and emerging adults contributes to the current rate of HIV transmission among this age group. PMID- 22227786 TI - Neonatal abstinence syndrome. AB - PURPOSE OF REVIEW: This review will discuss the complex nature of maternal and other factors that can affect the infant's display of neonatal abstinence syndrome (NAS), clinical presentation and treatment of NAS, and the impact of recent findings on future directions for research. RECENT FINDINGS: NAS has traditionally been described as a constellation of signs/symptoms displayed by the neonate upon withdrawal of gestational opioid exposure; however, recent research has advanced our understanding of this disorder. Other psychoactive substances, such as increasingly prescribed serotonin reuptake inhibitors, may produce an independent or synergistic discontinuation syndrome. The wide variability in NAS presentation has generated interest in the interplay of prenatal and postnatal environmental and genetic factors that may moderate or mediate its expression. Finally, recent advances in the treatment of opioid dependent pregnant women have suggested buprenorphine as an alternative treatment to methadone during pregnancy, largely due to reduced NAS severity in exposed neonates. SUMMARY: Physicians should be aware of the complexity of the maternal, fetal, and infant factors that combine to create the infant's display of NAS, and incorporate these aspects into comprehensive assessment and care of the dyad. Further research regarding the pathophysiology and treatment of NAS is warranted. PMID- 22227787 TI - Antenatal magnesium sulfate and neuroprotection. AB - PURPOSE OF REVIEW: Antenatal magnesium sulfate may reduce the excessive rates of cerebral palsy in survivors of very preterm birth. RECENT FINDINGS: There are five randomized controlled trials of magnesium sulfate therapy given to the mother prior to very preterm birth which have reported neurological outcomes for the child, in four of which the primary aim of the trial was neuroprotection for the fetus. From meta-analysis of these randomized trials, the rate of cerebral palsy was reduced by magnesium sulfate [relative risk (RR) = 0.69; 95% confidence interval (CI) = 0.54-0.87; five trials; 6145 infants). Magnesium sulfate also lowered the rate of substantial motor dysfunction in early childhood (RR = 0.61; 95% CI = 0.44-0.85; four trials; 5980 infants). In addition, where the main aim of the trial was neuroprotection of the fetus, the rates of the combined outcomes of death or cerebral palsy (RR = 0.86; 95% CI = 0.74-0.98; four trials; 4446 infants) and death or substantial motor dysfunction (RR = 0.85; 95% CI = 0.73 0.98; three trials; 4387 infants) were significantly lower with magnesium. SUMMARY: On the basis of these findings several countries have now released clinical practice guidelines recommending antenatal magnesium sulfate prior to very preterm birth. PMID- 22227788 TI - Epidermal growth factor and necrotizing enterocolitis. AB - PURPOSE OF REVIEW: This review will summarize the clinical and experimental studies evaluating the role of epidermal growth factor (EGF) in prophylaxis and treatment of necrotizing enterocolitis (NEC). RECENT FINDINGS: Clinical studies have suggested the importance of EGF in protection of the intestine against NEC, as well as its safety for infants suffering from NEC. The recent experimental studies identified the molecular mechanisms EGF uses for intestinal protection, which involves regulation of intestinal epithelial homeostasis and barrier function. Further studies are necessary to identify the optimal dose, timing, and route of administration of EGF to NEC patients. No clinical studies are currently underway. SUMMARY: NEC is a devastating problem for preterm neonates, but the exact disease pathogenesis remains unclear. Growing clinical evidence supports the use of EGF as a predictive marker of NEC and its use for prevention and treatment of NEC. In addition, experimental data indicate potential mechanisms of EGF prevention against NEC. These include reduction of inflammation, improvement of barrier function, and regulation of epithelial apoptosis and autophagy. PMID- 22227789 TI - Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. PMID- 22227790 TI - Practice advisory for perioperative visual loss associated with spine surgery: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Visual Loss. PMID- 22227791 TI - Complex suicide with black powder muzzle loading derringer. AB - Planned complex suicide is defined as the combination of more than one method of suicide, previously planned by the victim, to prevent failure of the first method. Herein, we present a case of planned complex suicide, committed by a black powder muzzle loading handgun and hanging. A 39-year-old man was found dead in the bathroom of his flat, hanging by the neck with a huge atypical gunshot entrance in the right temporal region of his head with extensive backspatter. The skin defects, as well as soft tissues in the subcutaneous pocket undermining, were heavily burnt. Along the wound canal were multiple bone fragments, and at the end of the path at the left temple was an embedded lead ogival projectile with a cross shaped artificial incision at its tip. The hanging was incomplete. There were no fractures of the hyoid bone and laryngeal cartilages. Cervical muscles and vessels were intact. Simon's sign was negative. Signs of asphyxia were not present. This is the first reported case of complex suicide with a black powder derringer and manipulated projectile. PMID- 22227792 TI - The role of toxicology interpretations in prevention of sudden death. AB - Inappropriate combinations of pharmaceutical drugs are often detected in deaths reported to a coroner. However, the involvement of drug combinations in the cause of death can be overlooked in cases when significant natural disease or external injury is also present. This study examined pathology reports and coroner's findings between January 2002 and December 2008. Cases that included exposure to a selection of serotonergic drugs were examined to determine the role of different death investigators in drug-associated deaths in Victoria, Australia. Of the 326 cases identified, the involvement of drugs in the death was discussed to some degree in 66% of cases. Recommendations by the coroner pertaining to death prevention were made in 12 cases (4%). In 16 cases (5%) the drugs were not mentioned in the findings, including at least 11 cases of probable major adverse drug interactions. Death investigations serve an important public health and safety role, however, the potential involvement of drugs in many cases is not always recognized. PMID- 22227793 TI - Mortality among young injection drug users in San Francisco: a 10-year follow-up of the UFO study. AB - This study examined associations between mortality and demographic and risk characteristics among young injection drug users in San Francisco, California, and compared the mortality rate with that of the population. A total of 644 young (<30 years) injection drug users completed a baseline interview and were enrolled in a prospective cohort study, known as the UFO ("U Find Out") Study, from November 1997 to December 2007. Using the National Death Index, the authors identified 38 deaths over 4,167 person-years of follow-up, yielding a mortality rate of 9.1 (95% confidence interval: 6.6, 12.5) per 1,000 person-years. This mortality rate was 10 times that of the general population. The leading causes of death were overdose (57.9%), self-inflicted injury (13.2%), trauma/accidents (10.5%), and injection drug user-related medical conditions (13.1%). Mortality incidence was significantly higher among those who reported injecting heroin most days in the past month (adjusted hazard ratio = 5.8, 95% confidence interval: 1.4, 24.3). The leading cause of death in this group was overdose, and primary use of heroin was the only significant risk factor for death observed in the study. These findings highlight the continued need for public health interventions that address the risk of overdose in this population in order to reduce premature deaths. PMID- 22227794 TI - CT-guided adrenal biopsy: comparison of ipsilateral decubitus versus prone patient positioning for biopsy approach. AB - OBJECTIVES: To compare ipsilateral decubitus and prone patient positioning for performing computed tomography guided adrenal biopsy using the requirements for out-of-plane approach (OOP) and the needle insertion time (NIT) as a surrogate for procedure complexity. METHODS: The study included 106 adrenal biopsies performed in 104 patients with lesions measuring <= 4 cm that were divided into two groups: Ipsilateral decubitus (Group I) and prone (Group II) positions. The frequency of use of an OOP biopsy path and the NIT were recorded as well as diagnostic yield, adverse events and transgression of organs to approach the target lesion. RESULTS: Groups I and II comprised 54 and 50 patients, respectively. The use of the OOP approach was significantly less frequent (P < 0.01) in Group I (n = 4) compared to Group II (n = 38). NIT was statistically shorter (P < 0.01) in Group I (9 min and 43 s) compared to Group II (19 min and 7 s). There were fewer organs traversed in Group I versus Group II. Diagnostic yield and post-biopsy complications were equal in both groups. CONCLUSION: Ipsilateral adrenal biopsy approach is a less complex, equally reliable and safe compared to the prone approach based on the less frequent use of the OOP approach and the shorter NIT. KEY POINTS: * Ipsilateral adrenal biopsy decubitus positioning provides a direct, non-transpulmonary path for sampling * Ipsilateral decubitus positioning reduces the need for potentially dangerous out-of-plane approaches (OOP) * Ipsilateral decubitus and prone positioning are equally reliable and safe techniques. PMID- 22227795 TI - Footprint-based estimates of arch structure are confounded by body composition in adults. AB - Previous research employing indirect measures of arch structure, such as those derived from footprints, have indicated that obesity results in a "flatter" foot type. In the absence of radiographic measures, however, definitive conclusions regarding the osseous alignment of the foot cannot be made. We determined the effect of body mass index (BMI) on radiographic and footprint-based measures of arch structure. The research was a cross-sectional study in which radiographic and footprint-based measures of foot structure were made in 30 subjects (10 males, 20 female) in addition to standard anthropometric measures of height, weight, and BMI. Multiple (univariate) regression analysis demonstrated that both BMI (beta = 0.39, t(26) = 2.12, p = 0.04) and radiographic arch alignment (beta = 0.51, t(26) = 3.32, p < 0.01) were significant predictors of footprint-based measures of arch height after controlling for all variables in the model (R(2) = 0.59, F(3,26) = 12.3, p < 0.01). In contrast, radiographic arch alignment was not significantly associated with BMI (beta = -0.03, t(26) = -0.13, p = 0.89) when Arch Index and age were held constant (R(2) = 0.52, F(3,26) = 9.3, p < 0.01). Adult obesity does not influence osseous alignment of the medial longitudinal arch, but selectively distorts footprint-based measures of arch structure. Footprint-based measures of arch structure should be interpreted with caution when comparing groups of varying body composition. PMID- 22227796 TI - 3D computational parametric analysis of eccentric atheroma plaque: influence of axial and circumferential residual stresses. AB - Plaque rupture plays a role in the majority of acute coronary syndromes. Rupture has usually been associated with stress concentrations, which are mainly affected by the plaque geometry and the tissue properties. The aim of this study is to evaluate the influence of morphology on the risk of plaque rupture, including the main geometrical factors, and to assess the role of circumferential and axial residual stresses by means of a parametric 3D finite element model. For this purpose, a 3D parametric finite element model of the coronary artery with eccentric atheroma plaque was developed. Healthy (adventitia and media in areas without atheroma plaque) and diseased (fibrotic and lipidic) tissues were considered in the model. The geometrical parameters used to define and design the idealized coronary plaque anatomy were the lipid core length, the stenosis ratio, the fibrous cap thickness, and the lipid core ratio. Finally, residual stresses in longitudinal and circumferential directions were incorporated into the model to analyse the influence of the important mechanical factors in the vulnerability of the plaque. Viewing the results, we conclude that residual stresses should be considered in the modelling of this kind of problems since they cause a significant alteration of the vulnerable plaque region limits. The obtained results show that the fibrous cap thickness and the lipid core length, in combination with the lipid core width, appear to be the key morphological parameters that play a determinant role in the maximal principal stress (MPS). However, the stenosis ratio is found to not play a significant role in vulnerability related to the MPS. Plaque rupture should therefore be observed as a consequence, not only of the cap thickness, but as a combination of the stenosis ratio, the fibrous cap thickness and the lipid core dimensions. PMID- 22227797 TI - Sudden onset of refusal to eat on waking after a nightmare in a 6-year-old girl. AB - CASE: Bridgette is a 6-year-old girl, who presented with sudden onset of refusal to eat or drink. The only precipitating event was a nightmare the previous night. She described a dream in which her mother and maternal aunt, dressed as witches, and father and maternal uncle, appearing as bats, wanted to kill her by making her eat and drink from a cauldron. Bridgette stated, "I can't eat anymore, I'm afraid of dying." Bridgette's eating pattern and behavior were described as previously normal. Motor, social, and language milestones were also normal. Her parents reported that she occasionally refused nonpreferred foods, and they believed that her food intake had decreased at age 4 years. She was a full-term infant without perinatal problems and breast fed until 8 months. Her medical history was significant for strabismus surgery, before 6 months. Her mental health history revealed mildly depressed mood and irritability related to teasing at school after her strabismus surgery. Her parents described her as "always looking for attention." Her teachers reported that she had normal intelligence and described her behavior as shy, slightly withdrawn, and distrustful. Social history revealed an only child of married parents without marital or work-related problems. Bridgette went to her maternal grandmother's home after school and during school holidays.Her parents pleaded with her to eat, but she refused. She was evaluated at urgent care where her physical examination was described as normal. Her body mass index was above the 97th percentile (3 SD above the mean). The parents were described as fearful and despairing. Laboratory tests included a complete blood count with differential, an electroencephalogram, and a computed tomography scan, all of which were normal. Intravenous fluids were administered on the day of presentation and the following day. She continued to refuse to eat or drink, and after 2 days, she was hospitalized for nasogastric tube feeding. PMID- 22227798 TI - Using hydrogen/deuterium exchange mass spectrometry to study conformational changes in granulocyte colony stimulating factor upon PEGylation. AB - PEGylation is the covalent attachment of polyethylene glycol to proteins, and it can be used to alter immunogenicity, circulating half life and other properties of therapeutic proteins. To determine the impact of PEGylation on protein conformation, we applied hydrogen/deuterium exchange mass spectrometry (HDX MS) to analyze granulocyte colony stimulating factor (G-CSF) upon PEGylation as a model system. The combined use of HDX automation technology and data analysis software allowed reproducible and robust measurements of the deuterium incorporation levels for peptic peptides of both PEGylated and non-PEGylated G CSF. The results indicated that significant differences in deuterium incorporation were induced by PEGylation of G-CSF, although the overall changes observed were quite small. PEGylation did not result in gross conformational rearrangement of G-CSF. The data complexity often encountered in HDX MS measurements was greatly reduced through a data processing and presentation format designed to facilitate the comparison process. This study demonstrates the practical utility of HDX MS for comparability studies, process monitoring, and protein therapeutic characterization in the biopharmaceutical industry. PMID- 22227799 TI - Various metal nanoparticles produced by accelerated electron beam irradiation of room-temperature ionic liquid. AB - Various metal nanoparticles including base metal were produced by a brief accelerated electron beam irradiation of 1-alkyl-3-methylimidazolium bis((trifluoromethyl)sulfonyl)amide room-temperature ionic liquid without a stabilizing agent, which is usually employed so as to prevent aggregation. PMID- 22227800 TI - Complete genome sequence of a potyvirus infecting yam beans (Pachyrhizus spp.) in Peru. AB - In 2010, yam beans in a field trial in Peru showed viral disease symptoms. Graft transmission and positive ELISA results using potyvirus-specific antibodies suggested that the symptoms could be the result of a potyviral infection. Small interfering RNA (siRNA) were extracted from one of the samples and sent for high throughput sequencing. The full genome of a new potyvirus could be assembled from the resulting siRNA sequences, and it was sufficiently different from other sequences to be considered a member of a new species, which we have designated Yam bean mosaic virus (YBMV). Sequence similarity suggests that YBMV has also been detected in yam beans in Indonesia. PMID- 22227801 TI - Complex morphology and functional dynamics of vital murine intestinal mucosa revealed by autofluorescence 2-photon microscopy. AB - The mucosa of the gastrointestinal tract is a dynamic tissue composed of numerous cell types with complex cellular functions. Study of the vital intestinal mucosa has been hampered by lack of suitable model systems. We here present a novel animal model that enables highly resolved three-dimensional imaging of the vital murine intestine in anaesthetized mice. Using intravital autofluorescence 2 photon (A2P) microscopy we studied the choreographed interactions of enterocytes, goblet cells, enteroendocrine cells and brush cells with other cellular constituents of the small intestinal mucosa over several hours at a subcellular resolution and in three dimensions. Vigorously moving lymphoid cells and their interaction with constituent parts of the lamina propria were examined and quantitatively analyzed. Nuclear and lectin staining permitted simultaneous characterization of autofluorescence and admitted dyes and yielded additional spectral information that is crucial to the interpretation of the complex intestinal mucosa. This novel intravital approach provides detailed insights into the physiology of the small intestine and especially opens a new window for investigating cellular dynamics under nearly physiological conditions. PMID- 22227803 TI - Community Health and the Built Environment: examining place in a Canadian chronic disease prevention project. AB - The Community Health and the Built Environment (CHBE) project investigated the role of place in interventions for chronic disease prevention in order to identify contextual factors that may foster or inhibit intervention success. This paper presents a project model comprising objective-outsider and subjective insider perspectives in a multi-method, community-based participatory research approach with an emphasis on knowledge exchange. The collaborative process generated valuable lessons concerning effective conduct of community-based research. The CHBE project model contributes a mechanism for investigating how place influences health behaviours and the outcomes of health promotion interventions. PMID- 22227802 TI - Insulin-like growth factor 1 enhances the proliferation and osteogenic differentiation of human periodontal ligament stem cells via ERK and JNK MAPK pathways. AB - Insulin-like growth factor 1 (IGF-1) is a potent mitogenic protein which can enhance the osteogenic differentiation of periodontal ligament (PDL) fibroblasts. However, it remains unclear whether IGF-1 can stimulate the osteogenic differentiation and osteogenesis of human periodontal ligament stem cells (PDLSCs). In this study, STRO-1(+) PDLSCs were isolated from human PDL tissues, treated with IGF-1, and their osteogenic capacity was investigated in vitro and in vivo. Dimethyl-thiazol-diphenyl tetrazolium bromide assay and flow cytometry results demonstrated that 10-200 ng/mL IGF-1 can stimulate the proliferation ability of PDLSCs and 100 ng/mL is the optimal concentration. Exogenous IGF-1 can modify the ultrastructure, enhance the alkaline phosphatase activity, the mineralization ability of PDLSCs, and increase the expression of osteogenic markers (runt-related transcription factor 2, osterix, and osteocalcin) at mRNA and protein levels. In vivo transplantation illustrated that IGF-1 treated implants generated more mineralized tissues, and presented stronger expression of RUNX2, OSX, and OCN than control group. Moreover, the expression of phosphor-ERK and phosphor-JNK in these stem cells was upregulated by IGF-1, indicating that MAPK signaling pathway was activated during the osteogenic differentiation of PDLSCs mediated by IGF-1. Together, the results showed that IGF-1 can promote the osteogenic differentiation and osteogenesis of STRO-1(+) PDLSCs via ERK and JNK MAPK pathway, suggesting that IGF-1 is a potent agent for stem cell-based periodontal tissue regeneration. PMID- 22227804 TI - Cuprous oxide nanoparticles dispersed on reduced graphene oxide as an efficient electrocatalyst for oxygen reduction reaction. AB - Cuprous oxide (Cu(2)O) nanoparticles dispersed on reduced graphene oxide (RGO) were prepared by reducing copper acetate supported on graphite oxide using diethylene glycol as both solvent and reducing agent. The Cu(2)O/RGO composite exhibits excellent catalytic activity and remarkable tolerance to methanol and CO in the oxygen reduction reaction. PMID- 22227805 TI - Construction and repair of highly ordered 2D covalent networks by chemical equilibrium regulation. AB - The construction of well-ordered 2D covalent networks via the dehydration of di borate aromatic molecules was successfully realized through introducing a small amount of water into a closed reaction system to regulate the chemical equilibrium. PMID- 22227806 TI - Remediation of 4-nonylphenol in aqueous solution by using free radicals generated by the oxidative reactions. AB - INTRODUCTION: This study relates to use of zerovalent iron to generate hydroxyl free radicals and undergo subsequent oxidation to destroy 4-nonylphenol (NP) by mild process in aqueous solution and activation of oxygen gas (O2) at room temperature. This technology is based on a novel oxidative mechanism mediated by zerovalent iron rather than commonly used reduction mechanism. MATERIALS AND METHODS: A laboratory scale device consisting of a 250 ml pyrex serum vials fixed to a Vortex agitator was used. Different amounts of zerovalent iron powder (ZVI; 1, 10, and 30 g/l) at pH 4 and room temperature with bubbling of oxygen gas were investigated. RESULTS AND CONCLUSION: Experiments showed an observed degradation rate k (obs) directly proportional to the amount of iron. 4-Nonylphenol degradation reactions demonstrated first-order kinetics with a half-life of about 10.5 +/- 0.5 and 3.5 +/- 0.2 min when experiments were conducted at [ZVI] = 1 and 30 g/l respectively. Three analytical techniques were employed to monitor 4 nonylphenol degradation and mineralization: (1) spectrofluorimetry; (2) high performance liquid chromatography; (3) total organic carbon meter (TOC meter). Results showed a complete disappearance of 4-nonylphenol after 20 min of contact with ZVI. The intermediate by-products of the reaction were not identified but the disappearance of NP was monitored by the three above-mentioned techniques. PMID- 22227807 TI - Kinetic analysis of constructed systems for the recovery of contaminated areas by acid mine drainage. AB - INTRODUCTION: Flowing of the acid mine drainage may contaminate the adjacent water bodies causing substantial changes in the aquatic ecosystem. This aspect is the most relevant problem in the southern of Santa Catarina once the contaminated areas are inserted in the watershed of the Ararangua, Urussanga, and Tubarao rivers, increasing the need for recovery studies. These areas are between Criciuma, Icara, Urussanga, Sideropolis, Lauro Muller, Orleans, and Alfredo Wagner towns where a conservation unit exist called the Environmental Preservation Area of Baleia Franca. Aiming to compare the kinetics of the ash derived from burning coal and to neutralize acid mine drainage, different neutralizer, limestone, fly, and bottom ash, was mounted on a pilot scale experiment. DISCUSSION: The transport parameters showed the same order of infiltration and dispersion: fly ash < bottom ash < limestone. The order of measured alkalinity was: limestone < fly ash < bottom ash, with pH values of 9.34, 12.07, and 12.25, respectively. The limestone kinetics of acidic drainage neutralization was first order with reaction rate constant k = 0.0963 min(-1), bottom ash was 3/4 with k = 0.0723 mol(1/4) L(-1/4) min(-1), and the fly ash had higher order kinetics, 4/3, with reaction rate constant k = 27.122 L(1/3) mol( 1/3) min(-1). However, by mathematical modeling, it was found that due to a combination of transport and kinetics, only limestone treatment reached a pH above 6 within 5 years, corresponding to the ideal as planned. PMID- 22227808 TI - Changes in character of organics in the receiving environment of effluent from a sulphite pulp mill. AB - PURPOSE: The characteristics of organics in sulphite pulp mill effluent and in the receiving environment of effluent discharge were investigated to assess the basis for the persistence or attenuation of colour. METHODS: Characterization of organics was conducted through determination of SUVA, specific colour, and molecular weight distribution of organics using high performance size exclusion chromatography and by solid-state (13) C cross polarization (CP) NMR. The characteristics of organics from mill wastewater before and after secondary aerobic treatment, followed by lime treatment and from the receiving environment, an enclosed brackish lake were compared. Changes in the character of organics in lake water over a period of 14 years were studied in the context of changes in mill processing and climate impacts. RESULTS: High colour in mill effluent and in receiving waters correlated with high SUVA and specific colour levels, high molecular weight range and aromatic content. Conversely, lake waters with low colour had UV absorbing compounds of much lower molecular weight range and low relative abundance of aromatic compounds. Attenuation of colour and changes in the character of organics in the receiving environment coincided with increased concentrations of metal cations. CONCLUSIONS: These increased concentrations appear to be due to the effects of climate change, lake management and their presence in mill effluent, with subsequent discharge to the lake. Attenuation of colour was found to be predominantly through removal of high molecular weight aromatic compounds where the removal processes could be through adsorption and co precipitation with divalent metals, as well as through dilution processes. PMID- 22227809 TI - Short-term effects of diesel fuel on rhizosphere microbial community structure of native plants in Yangtze estuarine wetland. AB - PURPOSE: In this work, short-term effects of diesel fuel on Huangpu-Yangtze estuarine wetland soil microbial community structure were studied under simulated conditions through phospholipid fatty acids (PLFAs) analysis. Four native plant species, bulrush (Scirpus tripueter), galingale (Cyperus rotundus), wildrice (Zizania latifolia), and reed (Phragmites australis) were tested in the experiments. METHOD: In the pot experiment, 20 g rhizosphere soils were mixed with 20 g diesel-blended soils. The concentration of total petroleum hydrocarbon was 16,000 mg/kg. All pots were incubated for 14 days in dark at 28 degrees C and watered with 12 mL sterile distilled water to keep a liquid level. Microbial activity of the samples was assessed by hydrolysis of fluorescein diacetate. Measurements of soil PLFAs and analysis on gas chromatography were performed. RESULTS: The microbial activity in the samples of reed was highest after the exposure. In all samples, the common PLFA was straight-chain saturated fatty acid (SFA) and monounsaturated fatty acid (MUFA). After the exposure the relative abundance of MUFA and polyunsaturated fatty acid decreased by 20%, and the relative abundance of straight-chain SFA increased by 20%. The results of diversity and PCA indicated that the effect of diesel pollutant on the microbial community was far stronger than the root effect and the reed roots enhanced the tolerance of soil microorganisms to diesel significantly. CONCLUSIONS: All results showed that the soil microbial community structure differed significantly with the exposure to diesel. In reed rhizosphere, the soil microorganisms exhibited a strong resistance to diesel fuel. It confirmed that the root of reed improved the biodegradation ability of soil microorganisms for diesel pollutants and they could be reasonably matched to cure and restore the ecological environment of oil-contaminated wetlands. PMID- 22227810 TI - Patient-specific simulations and measurements of the magneto-hemodynamic effect in human primary vessels. AB - This paper investigates the main characteristics of the magneto-hemodynamic (MHD) response for application as a biomarker of vascular blood flow. The induced surface potential changes of a volunteer exposed to a 3 T static B0 field of a magnetic resonance imaging (MRI) magnet were measured over time at multiple locations by an electrocardiogram device and compared to simulation results. The flow simulations were based on boundary conditions derived from MRI flow measurements restricted to the aorta and vena cava. A dedicated and validated low frequency electromagnetic solver was applied to determine the induced temporal surface potential change from the obtained 4D flow distribution using a detailed whole-body model of the volunteer. The simulated MHD signal agreed with major characteristics of the measured signal (temporal location of main peak, magnitude, variation across chest and along torso) except in the vicinity of the heart. The MHD signal is mostly influenced by the aorta; however, more vessels and better boundary conditions are needed to analyze the finer details of the response. The results show that the MHD signal is strongly position dependent with highly variable but reproducibly measurable distinguished characteristics. Additional investigations are necessary before determining whether the MHD effect is a reliable reference for location-specific information on blood flow. PMID- 22227811 TI - An overview on education of analytical chemistry in Japan. PMID- 22227813 TI - A resonance light-scattering off-on system for studies of the selective interaction between adriamycin and DNA. AB - On the basis of the resonance light scattering (RLS) of Ag nanoparticles (AgNPs), an RLS off-on system was developed for studies of the selective interaction between adriamycin (ADM) and DNA. In this strategy, addition of ADM could induce a proportional decrease in the RLS intensity of AgNPs; this could be used to detect trace amounts of ADM with a detection limit of 12.75 ng mL(-1) in the range 0.021-10.0 MUg mL(-1). Subsequently, by investigating the ability of different DNA sequences to restore the RLS intensity of the analytical systems, we found that ADM was selective to dsDNA and had an obvious preference for sequences that were rich in guanine and cytosine bases. In order to validate the results of the RLS assay, fluorescence quenching was used, and binding constants and binding numbers of each system were calculated. Compared with other methods, this RLS off-on strategy was more sensitive, fast, and reliable. It has also supplied a novel method for studying the sequence selectivity of DNA-targeted anticancer drugs and is a novel application of the RLS technique in analytical chemistry. PMID- 22227812 TI - On-line electrochemistry-bioaffinity screening with parallel HR-LC-MS for the generation and characterization of modified p38alpha kinase inhibitors. AB - In this study, an integrated approach is developed for the formation, identification and biological characterization of electrochemical conversion products of p38alpha mitogen-activated protein kinase inhibitors. This work demonstrates the hyphenation of an electrochemical reaction cell with a continuous-flow bioaffinity assay and parallel LC-HR-MS. Competition of the formed products with a tracer (SKF-86002) that shows fluorescence enhancement in the orthosteric binding site of the p38alpha kinase is the readout for bioaffinity. Parallel HR-MS(n) experiments provided information on the identity of binders and non-binders. Finally, the data produced with this on-line system were compared to electrochemical conversion products generated off-line. The electrochemical conversion of 1-{6-chloro-5-[(2R,5S)-4-(4-fluorobenzyl)-2,5 dimethylpiperazine-1-carbonyl]-3aH-indol-3-yl}-2-morpholinoethane-1,2-dione resulted in eight products, three of which showed bioaffinity in the continuous flow p38alpha bioaffinity assay used. Electrochemical conversion of BIRB796 resulted, amongst others, in the formation of the reactive quinoneimine structure and its corresponding hydroquinone. Both products were detected in the p38alpha bioaffinity assay, which indicates binding to the p38alpha kinase. PMID- 22227816 TI - Health insurance coverage is the single most prominent socioeconomic factor associated with cardiovascular drug delivery in the French population. AB - OBJECTIVE: Although the French population benefits from universal health coverage, prescribed drugs are in most cases only partially reimbursed by the national insurance plan (65% of the cost), raising the possibility of reduced drug access for patients with low socioeconomic status. METHODS: To explore this question, the delivery of cardiovascular drugs in relation to socioeconomic position was analysed in a cross-sectional survey of a nationally representative sample of patients with cardiovascular condition (n = 4646). RESULTS: Among eight socioeconomic indicators and after adjustment for healthcare needs, only health coverage is independently associated with cardiovascular drug delivery, which is reduced by half [odds ratio (95% confidence interval): 0.54 (0.39-0.74), P = 0.0001] in patients partially covered by universal health insurance compared with those fully covered by supplemental insurance. This reduced delivery in patients with partial health coverage seems to apply to all cardiovascular drug classes as it is observed for both antihypertensive and hypolipemic drugs when these classes are tested separately. Although physician access is also reduced in patients with partial health coverage [0.54 (0.40-0.75), P = 0.0002], this does not explain the decreased delivery of cardiovascular drugs that is still observed [0.59 (0.43 0.82), P = 0.001] after further adjustment for the number of physician visits during the survey. CONCLUSION: These results suggest that health insurance coverage has a prominent role among socioeconomic factors in determining the delivery of prescribed medications as essential as cardiovascular drugs in the French population. They emphasize that full health coverage should remain a priority for public health policies in this country. PMID- 22227815 TI - Ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid inhibits hepatocellular carcinoma in vitro and in vivo via stabilizing IkBalpha. AB - Ent-11-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F) isolated from Pteris Semipinnata L is known to inhibit certain tumor cells in vitro. The information on the in vivo effect of 5F is limited and its effect on hepatocellular carcinoma (HCC) is unknown. In this study, the anti-tumor effect of 5F was investigated in a diethylnitrosamine (DEN)-induced mouse HCC model. In addition to therapeutic effect, the potential side effect was monitored. A panel of cultured HCC cells was used to confirm the in vivo data and explore the responsible molecular pathway. The result showed that 5F significantly inhibited the DEN-induced HCC tumors by reducing the number of tumor foci and the volume of tumors. Furthermore, 5F induced the death of cultured HCC cells in dose- and time dependent manners. The cell death was confirmed to be apoptotic by in vivo and in vitro TUNEL assays. 5F inhibited NF-kB by stabilizing its inhibitor IkBalpha, reducing the nuclear p65 and inhibiting NF-kB activity. Subsequently it affected the NF-kB downstream molecules with a decrease in anti-apoptotic Bcl-2 and increase in pro-apoptotic Bax and Bak. During the whole period of the experiment, mice receiving 5F appeared to be healthy, though they suffered from a mild degree of hair loss. 5F did not damage liver and renal functions. In conclusion, 5F is effective against HCC with minimal side effects. It induces apoptosis in HCC cells via inhibiting NF-kB, leading to the decrease of Bcl-2 but the increase of Bax and Bak. PMID- 22227817 TI - Hypertension and kidney disease: is renalase a new player or an innocent bystander? AB - Most patients on dialysis are hypertensive and their blood pressure (BP) control is often poor. Renalase is preferentially expressed in proximal tubules, but it is also present in glomeruli and distant tubules, as well as in cardiomyocytes, liver, and skeletal muscle. It had been proposed that renalase had a flavin adenine dinucleotide (FAD)-binding domain and that FAD was an essential cofactor for its stability and monoamine oxidase activity. It was reported that renalase, secreted by the kidney and circulating in the blood, degraded catecholamines and might play a role in the regulation of sympathetic tone and BP. It has been also proposed that renalase-coding gene is a novel susceptibility gene for essential hypertension and its variations may influence BP. In addition, polymorphisms of the renalase gene in hemodialysed patients were associated with hypertension. However, several unresolved and controversial issues still remain such as how to measure renalase and its physiological activity. Furthermore, there are few data on possible activators and/or inhibitors of renalase. We are at the very beginning of solving the problem of whether renalase is a causative factor of hypertension in kidney disease or just an innocent bystander. Therefore, more research is needed to establish whether renalase can become a useful therapeutic target. PMID- 22227818 TI - High normal thyroid-stimulating hormone is associated with arterial stiffness in healthy postmenopausal women. AB - OBJECTIVE: Apart from the effects of a dysfunctional thyroid gland on the cardiovascular system, thyroid function within the reference range may have an impact on the vasculature. The present study aimed to evaluate the association between thyroid function and markers of arterial structure and function in euthyroid postmenopausal women. METHODS: The present cross-sectional study recruited 106 healthy postmenopausal women with a mean age of 55.0 years and thyroid-stimulating hormone (TSH) levels within the laboratory reference range (0.4-4.5 MUIU/ml). Anthropometric and biochemical measures as well as blood pressure were determined in each individual. Vascular structure and function were assessed by intima-media thickness, pulse wave velocity (PWV), augmentation index and flow-mediated dilation, respectively. We evaluated the associations between arterial markers and serum TSH, free triiodothyronine, free thyroxin, as well as serum thyroid peroxidase and thyroglobulin autoantibodies. RESULTS: Mean levels of PWV increased linearly across increasing TSH quartiles (P value = 0.014). Individuals with serum TSH greater than 2.5 MUIU/ml had significantly higher values of PWV when compared with individuals with TSH levels below 2.5 MUIU/ml (9.68 +/- 1.97 vs. 8.54 +/- 1.83 m/s; P = 0.030). In multivariate analysis, age, insulin resistance and TSH above 2.5 MUIU/ml were the only significant predictors of PWV (TSH, beta-coefficient = 0.222; P = 0.014). No associations were found between the remaining markers and levels of thyroid hormones, whereas thyroid antibodies were not associated with any of the arterial markers. CONCLUSION: Women with TSH levels in the upper reference range have increased arterial stiffness compared to women with lower TSH. The upper limit of normal TSH in postmenopausal women may need re-evaluation with respect to the effects on the vasculature. PMID- 22227819 TI - Evaluation of risk for incident hypertension using glomerular filtration rate in the normotensive general population. AB - OBJECTIVES: The present study tested the hypothesis that glomerular filtration rate can predict the onset of hypertension in individuals with normal blood pressure in the general population. METHODS: Normotensive individuals (n = 7684) who visited our hospital for a routine physical examination were enrolled in the study (4907 men; mean age 52.1 +/- 11.1 years) and were followed up with the endpoint being the development of hypertension. The relationship between estimated glomerular filtration rate at baseline and the incidence of hypertension was evaluated. RESULTS: During the follow-up period (median 4.0 years; actual follow-up 30 624 person-years), hypertension developed in 2031 participants (66.3 per 1000 person-years). After adjustment for possible risk factors, the hazard ratio of incident hypertension (first tertile as reference) in the second and third tertiles was 1.03 (95% confidence interval 0.92-1.16) and 1.40 (95% confidence interval 1.26-1.57), respectively. Multivariate Cox proportional hazard regression analysis, in which estimated glomerular filtration rate was taken as a continuous variable and adjustments were made for known risk factors, also indicated that baseline estimated glomerular filtration rate independently predicted the onset of hypertension (P < 0.0001). Furthermore, multiple regression analysis revealed that a longitudinal increase in SBP was significantly associated with baseline estimated glomerular filtration rate after adjustment for known risk factors (P < 0.01). CONCLUSION: Estimated glomerular filtration rate in normotensive individuals is a good predictor of the onset of hypertension in the general population. PMID- 22227820 TI - 'Volume-expanded' hypertension: the effect of fluid overload and the role of the sympathetic nervous system in salt-dependent hypertension. AB - It is widely believed that salt-dependent hypertension is induced and maintained by expansion of intravascular fluid volume resulting from excessive retention of sodium. The purpose of this brief article is to present a series of arguments in support of the thesis that volume overload per se does not raise the arterial blood pressure. Several investigators in the 1960s and 1970s reported that excessive retention of salt - regardless of cause - leads to sympathetic activation mediated by the effects of the Na ion on alpha(2)-adrenergic receptors located mostly in the brainstem. In recent years, the cloning and characterization of alpha(2)-adrenergic receptors subtypes permitted differentiation of their hemodynamic effects via use of salt loading of nephrectomized animals submitted to genetic engineering or gene treatment. These studies indicate that sodium alters the balance between the sympathoinhibitory alpha(2A)-adrenergic receptors and the sympathoexcitatory alpha(2B)-adrenergic receptors, leading to a hyperadrenergic hypertensive state unrelated to volume overload. PMID- 22227821 TI - Comprehensive MRI analysis of early cardiac and vascular remodeling in middle aged patients with abdominal obesity. AB - OBJECTIVES: To determine, using a comprehensive MRI investigation, prevalence and vascular correlates of early left-ventricular concentric remodeling in middle aged patients with abdominal obesity. Left-ventricular and vascular remodeling are commonly associated with hypertension, but little is known for abdominal obesity patients, a population with definite increase in cardiovascular risk and high rates of further developments of hypertension and of the metabolic syndrome. METHODS: Seventy middle-aged abdominal obesity patients (56 +/- 5 years, 49% women, 69% with body mass index > 30 kg/m), who had no additional cardiovascular risk factor except for untreated stage 1 hypertension (16%), and 40 controls underwent MRI for detecting concentric remodeling (increase in left-ventricular mass/end-diastolic volume ratio) and identifying potential determinants, including arterial compliance indexes [aortic pulse wave velocity and total arterial compliance (TAC)] and total peripheral vascular resistances (TPVRs). RESULTS: Twenty abdominal obesity patients (29%) had concentric remodeling (concentric remodeling+), whereas 50 did not (concentric remodeling-). Concentric remodeling+ patients were mostly men (85%), they frequently had stage 1 hypertension (45%) and few had left-ventricular hypertrophy (20%). When adjusted for sex, there was a step-by-step decline in TAC between controls (mean +/- SEM: 2.10 +/- 0.06 ml/mmHg), concentric remodeling- (1.82 +/- 0.06 ml/mmHg) and concentric remodeling+ (1.42 +/- 0.09 ml/mmHg, P < 0.005 for inter-group comparisons) and TPVRs were lower than controls for concentric remodeling- (14.7 +/- 0.5 vs. 16.8 +/- 0.5 ml/mmHg, P = 0.005) but not for concentric remodeling+ (17.5 +/- 0.7 mmHg/min per l). CONCLUSIONS: Concentric remodeling is frequently documented by MRI in the middle-aged men with abdominal obesity and in association with a decrease in TAC no longer counter-balanced by a decrease in TPVR, suggesting a remodeling from proximal to peripheral vasculature. PMID- 22227822 TI - Which clinical risk factors determine a pathological urodynamic evaluation in patients with multiple sclerosis? an analysis of 100 prospective cases. AB - BACKGROUND: Urinary tract symptoms are an underestimated problem in multiple sclerosis (MS). OBJECTIVE: Hundred urodynamics of MS patients have been evaluated prospectively. DESIGN, SETTING AND PARTICIPANTS: In an inpatient rehabilitation, all persons with MS who also suffered from urinary tract symptoms received a voiding diary, post-void sonography and an urodynamic examination according to International Continence-Society-Standard. RESULTS AND LIMITATIONS: Between 10/2009 and 3/2011, 100 patients (79 women; 21 men; mean EDSS, 4.52 +/- 2.26) were examined who had primary progressive MS (9*), relapsing-remitting MS (41*), secondary progressive MS (43*) and CIS (1*). The mean duration of MS was 10.26 +/ 10.09 years and mean duration of LUTS, 6.9 +/- 7.75 years. Urodynamic testing showed normal findings in 22 patients, detrusor overactivity in 7, increased bladder sensation without detrusor overactivity in 21, detrusor-sphincter dyssynergia in 26, detrusor hypocontractility in 12, detrusor acontractility in 4 and unclear diagnosis in 8 patients. Statistically significant risk factors for pathological urodynamic findings were as follows: wheelchair dependency, use of more than one incontinence pad per day and a MS type other than relapsing remitting. CONCLUSIONS: The urodynamic investigation at hand showed urinary tract dysfunction in 78 of 100 MS patients with lower urinary tract symptoms (LUTS). The long latency between the occurrence of MS and/or the beginning of LUTS and the first neuro-urological evaluation indicates a deficit in treatment. Beyond national guidelines, all MS patients should at regular intervals be questioned about LUTS and receive urodynamic assessment especially according to the presented risk profile. PMID- 22227823 TI - Outcomes of mild therapeutic hypothermia after in-hospital cardiac arrest. AB - BACKGROUND: Although the benefits of mild therapeutic hypothermia (MTH) in selected patients after out-of-hospital cardiac arrest have been consistently demonstrated, no controlled trial of MTH in selected patients after in-hospital cardiac arrest (IHCA) has been published. We sought to assess the benefit of MTH after IHCA in patients meeting our institutions IHCA MTH inclusion criteria. METHODS: A retrospective, historical control study was performed. During the 3 year period before and after the 2006 MTH protocol implementation at our institution, we identified a total of 118 patients admitted to our Medical Intensive Care Unit after resuscitation from an IHCA. Two blinded investigators identified all patients meeting our institutions MTH protocol inclusion criteria and the patients in each time period were compared. The primary outcome was discharge with good neurological function. RESULTS: 33 IHCA patients met MTH protocol inclusion criteria; 16 patients were admitted prior to MTH protocol implementation and thus were not treated with MTH post arrest while 17 patients were admitted after implementation and were all treated with MTH post arrest. 91% of patients had an arrest rhythm of asystole or pulseless electrical activity. Good neurological function at discharge was found in 24% of MTH patients and 31% of controls (P = .62). CONCLUSIONS: No difference in neurological outcome at discharge was detected in predominantly non-shockable IHCA patients treated with MTH. This finding, if confirmed with further study, may define a population of patients for whom this costly and resource intensive therapy should be withheld. PMID- 22227824 TI - Quantification of cardiac autonomic nervous activities in ambulatory dogs by eliminating cardiac electric activities using cubic smoothing spline. AB - With the development of an implantable radio transmitter system, direct measurement of cardiac autonomic nervous activities (CANAs) became possible for ambulatory animals for a couple of months. However, measured CANAs include not only CANA but also cardiac electric activity (CEA) that can affect the quantification of CANAs. In this study, we propose a novel CEA removal method using moving standard deviation and cubic smoothing spline. This method consisted of two steps of detecting CEA segments and eliminating CEAs in detected segments. Using implanted devices, we recorded stellate ganglion nerve activity (SGNA), vagal nerve activity (VNA) and superior left ganglionated plexi nerve activity (SLGPNA) directly from four ambulatory dogs. The CEA-removal performance of the proposed method was evaluated and compared with commonly used high-pass filtration (HPF) for various heart rates and CANA amplitudes. Results tested with simulated CEA and simulated true CANA revealed stable and excellent performance of the suggested method compared to the HPF method. The averaged relative error percentages of the proposed method were less than 0.67%, 0.65% and 1.76% for SGNA, VNA and SLGPNA, respectively. PMID- 22227825 TI - Sex-hormone receptors pattern on regulatory T-cells: clinical implications for multiple sclerosis. AB - Cellular mechanisms underlying sexual dimorphism in the immune response remain largely unknown. Concerning the interactions among the nervous, endocrine and immune systems, we reported that during gestation, a period during which multiple sclerosis (MS) clearly ameliorates, there is a physiological expansion of regulatory T-lymphocytes (T(Reg)). Given that alterations in T(Reg) proportions and suppressive function are involved in MS pathophysiology, we investigated the in vitro effect of sex hormones on T(Reg). Here, we show that both E2 and progesterone (P2) enhance T(Reg) function in vitro, although only E2 further induces a T(Reg) phenotype in activated responder T-cells (CD4(+)CD25(-)) (P < 0.01). E2 receptor beta (ERbeta) percentages and mean fluorescence intensity (MFI) on T(Reg) were lower in MS patients than in controls (P < 0.05), in parallel with lower E2 plasma levels (P < 0.05). Importantly, percentages and MFI of ERbeta were higher in T(Reg) than in T-responder cells (P < 0.0001) both in MS patients and controls. We show a unique differential pattern of higher ER and PR levels in T(Reg), which may be relevant for the in vivo responsiveness of these cells to sex hormones and hence to MS physiopathology. PMID- 22227826 TI - Simulation of the oxidative metabolism of diclofenac by electrochemistry/(liquid chromatography/)mass spectrometry. AB - Diclofenac is a frequently prescribed drug for rheumatic diseases and muscle pain. In rare cases, it may be associated with a severe hepatotoxicity. In literature, it is discussed whether this toxicity is related to the oxidative phase I metabolism, resulting in electrophilic quinone imines, which can subsequently react with nucleophiles present in the liver in form of glutathione or proteins. In this work, electrochemistry coupled to mass spectrometry is used as a tool for the simulation of the oxidative pathway of diclofenac. Using this purely instrumental approach, diclofenac was oxidized in a thin layer cell equipped with a boron doped diamond working electrode. Sum formulae of generated oxidation products were calculated based on accurate mass measurements with deviations below 2 ppm. Quinone imines from diclofenac were detected using this approach. It could be shown for the first time that these quinone imines do not react with glutathione exclusively but also with larger molecules such as the model protein beta-lactoglobulin A. A tryptic digest of the generated drug protein adduct confirms that the protein is modified at the only free thiol containing peptide. This simple and purely instrumental set-up offers the possibility of generating reactive metabolites of diclofenac and to assess their reactivity rapidly and easily. PMID- 22227827 TI - Defence response of Sitka spruce before and after inoculation with Heterobasidion annosum: 1H NMR fingerprinting of bark and sapwood metabolites. AB - Metabolite fingerprinting of Sitka spruce (Picea sitchensis) bark and sapwood was carried out by (1)H nuclear magnetic resonance after wounding and artificial inoculation with the white rot fungus Heterobasidion annosum sensu stricto. The aim was to determine whether metabolites would differ in clones showing differing levels of susceptibility to H. annosum, in the fungal as compared with the control treatment (wounding, no fungus) and the reference (healthy sample collected at 0 days), at two different locations on the host, and at different sampling times (3 and 43 days after treatment). The results suggested that different metabolic processes occur in bark and sapwood after wounding and fungal inoculation, compared with healthy samples collected before treatment: In bark, greater peaks were elicited in the aromatic region whereas, in sapwood, lower amounts of all metabolites were observed in inoculated samples, compared with healthy samples. Multivariate statistical analysis carried out with analysis of variance-principal component analysis showed highly significant effects of reference, location, and time (PC1), and significant effects of clone and fungus. Differences between clones were apparent in sapwood but not in bark and were due to peaks in the aliphatic and carbohydrate regions. Over time, in bark, there was a decrease in carbohydrate peaks, followed by an increase in aliphatic and aromatic peaks. Sapwood, by contrast, showed a decrease in all peaks, followed by an increase in carbohydrate and aliphatic peaks. Changes in carbohydrate levels were observed within the lesion compared with the more distal location in both bark and sapwood. PMID- 22227829 TI - Polymer matrix dependence of conformational dynamics within a pi-stacked perylenediimide dimer and trimer revealed by single molecule fluorescence spectroscopy. AB - The conformation of embedded molecule in a polymer matrix is sensitive to the local nano-environment that the molecule experiences. Particularly, single molecule spectroscopic methods have been utilized to visualize each molecular conformation in local sites of the polymer matrix by monitoring rotational diffusion and fluctuating fluorescence of the molecule. Here, we have performed single molecule spectroscopic experiments on a pi-stacked perylenediimide (PDI) dimer and trimer, in which enhanced pi-pi interaction in pi-stacked PDIs makes the fluorescence lifetime longer, embedded in two different polymers, namely poly(methyl methacrylate) (PMMA) and poly(butyl methacrylate) (PBMA), to reveal the conformational change depending on the polymer matrix. The fluorescence lifetimes of pi-stacked PDIs are influenced by polymer surroundings because their molecular conformations are dependent on their interactions with the local environment in the polymer matrix. Furthermore, from an in-depth analysis of autocorrelation functions of fluorescence intensity trajectories, we could assign that the first autocorrelation value (lag 1) is larger as the intensity trace becomes more fluctuating. Thus, we expect that pi-stacked PDIs, a model system for the formation of PDI excimer-like states, can be utilized to probe the surrounding nano-environment by monitoring the conformational change in real time. PMID- 22227828 TI - Synergistic activity of the Hsp90 inhibitor ganetespib with taxanes in non-small cell lung cancer models. AB - Systemic chemotherapy using two-drug platinum-based regimens for the treatment of advanced stage non-small cell lung cancer (NSCLC) has largely reached a plateau of effectiveness. Accordingly, efforts to improve survival and quality of life outcomes have more recently focused on the use of molecularly targeted agents, either alone or in combination with standard of care therapies such as taxanes. The molecular chaperone heat shock protein 90 (Hsp90) represents an attractive candidate for therapeutic intervention, as its inhibition results in the simultaneous blockade of multiple oncogenic signaling cascades. Ganetespib is a non-ansamycin inhibitor of Hsp90 currently under clinical evaluation in a number of human malignancies, including NSCLC. Here we show that ganetespib potentiates the cytotoxic activity of the taxanes paclitaxel and docetaxel in NSCLC models. The combination of ganetespib with paclitaxel, docetaxel or another microtubule targeted agent vincristine resulted in synergistic antiproliferative effects in the H1975 cell line in vitro. These benefits translated to improved efficacy in H1975 xenografts in vivo, with significantly enhanced tumor growth inhibition observed in combination with paclitaxel and tumor regressions seen with docetaxel. Notably, concurrent exposure to ganetespib and docetaxel improved antitumor activity in 5 of 6 NSCLC xenograft models examined. Our data suggest that the improved therapeutic indices are likely to be mechanistically multifactorial, including loss of pro-survival signaling and direct cell cycle effects resulting from Hsp90 modulation by ganetespib. Taken together, these findings provide preclinical evidence for the use of this combination to treat patients with advanced NSCLC. PMID- 22227831 TI - Modeling and optimization of reductive degradation of chloramphenicol in aqueous solution by zero-valent bimetallic nanoparticles. AB - PURPOSE: The present study aims to investigate the individual and combined effects of temperature, pH, zero-valent bimetallic nanoparticles (ZVBMNPs) dose, and chloramphenicol (CP) concentration on the reductive degradation of CP using ZVBMNPs in aqueous medium. METHOD: Iron-silver ZVBMNPs were synthesized. Batch experimental data were generated using a four-factor statistical experimental design. CP reduction by ZVBMNPs was optimized using the response surface modeling (RSM) and artificial neural network-genetic algorithm (ANN-GA) approaches. The RSM and ANN methodologies were also compared for their predictive and generalization abilities using the same training and validation data set. Reductive by-products of CP were identified using liquid chromatography-mass spectrometry technique. RESULTS: The optimized process variables (RSM and ANN-GA approaches) yielded CP reduction capacity of 57.37 and 57.10 mg g(-1), respectively, as compared to the experimental value of 54.0 mg g(-1) with un optimized variables. The ANN-GA and RSM methodologies yielded comparable results and helped to achieve a higher reduction (>6%) of CP by the ZVBMNPs as compared to the experimental value. The root mean squared error, relative standard error of prediction and correlation coefficient between the measured and model predicted values of response variable were 1.34, 3.79, and 0.964 for RSM and 0.03, 0.07, and 0.999 for ANN models for the training and 1.39, 3.47, and 0.996 for RSM and 1.25, 3.11, and 0.990 for ANN models for the validation set. CONCLUSION: Predictive and generalization abilities of both the RSM and ANN models were comparable. The synthesized ZVBMNPs may be used for an efficient reductive removal of CP from the water. PMID- 22227832 TI - Occurrence of psychoactive compounds and their metabolites in groundwater downgradient of a decommissioned sewage farm in Berlin (Germany). AB - PURPOSE: Psychoactive compounds-meprobamate, pyrithyldione, primidone, and its metabolites, phenobarbital, and phenylethylmalonamide-were detected in groundwater within the catchment area of a drinking water treatment plant located downgradient of a former sewage farm in Berlin, Germany. The aim of this study was to investigate the distribution of the psychoactive compounds in anoxic groundwater and to assess the risk of drinking water contamination. Groundwater age was determined to achieve a better understanding of present hydrogeological conditions. METHODS: A large number of observation and production wells were sampled. Samples were analyzed using solid-phase extraction and ultrahigh performance liquid chromatography-tandem mass spectrometry. Groundwater age was estimated using the helium-tritium ((3)He-(3)H) dating method. RESULTS: Concentrations of psychoactive compounds up to 1 MUg/L were encountered in the contamination plume. Generally, concentrations of phenobarbital and meprobamate were the highest. Elevated concentrations of the analytes were also detected in raw water from abstraction wells located approximately 2.5 km downgradient of the former sewage farm. Concentrations in the final drinking water were below the limit of quantification owing to dilution. The age of shallow groundwater samples ranged from years to a decade, whereas groundwater was up to four decades old at 40 m below ground. Concentrations of the compounds increased with groundwater age. CONCLUSIONS: Elevated concentrations of psychoactive drugs indicate a strong persistence of these compounds in the environment under anoxic aquifer conditions. Results suggest that the heritage of sewage irrigation will affect raw water quality in the area for decades. Therefore, further monitoring of raw and final drinking water is recommended to ensure that contaminant concentrations remain below the health-based precautionary value. PMID- 22227833 TI - The effect of mindfulness on extinction and behavioral resurgence. AB - In the present experiments, we investigated the effects of mindfulness on behavioral extinction and resurgence. Participants received instrumental training; either they received FI training (Experiment 1), or they were trained to emit high rates and low rates of response via exposure to a multiple VR yoked VI schedule prior to exposure to a multiple FI FI schedule in order to alter their rates of responding learned during Experiment 2. Participants were then exposed to either a focused- (mindfulness) or an unfocused-attention induction task. All participants were finally exposed to an extinction schedule in order to determine whether a mindfulness induction task presented immediately prior to extinction training affected extinction (Experiment 1) and behavioral resurgence (Experiment 2). During the extinction phase, the rates of responding were higher in the control group than in the mindfulness group, indicating that the mindfulness group was more sensitive to the contingencies and, thus, their prior performance extinguished more readily (Experiment 1). Moreover, rates of response in the extinction components less precisely reflected previous training in the mindfulness group, suggesting less resurgence of past behaviors after the mindfulness induction (Experiment 2). PMID- 22227835 TI - Optimisation of microwave-assisted extraction for functional properties of Vitis coignetiae extract by response surface methodology. AB - BACKGROUND: Consumer preference for selection of natural substances, with their safe and beneficial effects on the human body as well as various physiological efficacies, is increasing. In this study, response surface methodology (RSM) was used to monitor the extraction characteristics of Vitis coignetiae (wild grape) and thereby optimise the functional properties of the resulting extract. RESULTS: A maximum total polyphenol content (TPC) of 415.74 mg per 100 g was obtained at a microwave power (MWP) of 102.36 W, an ethanol concentration (ETC) of 42.62% (by volume) and an extraction time (EXT) of 12.35 min. Electron-donating ability (EDA) reached a maximum of 69.20% at 125.65 W MWP, 41.81% ETC and 13.65 min EXT. The maximum nitrite-scavenging ability (NSA) obtained was 87.50% at 119.13 W MWP, 37.41% ETC and 13.20 min EXT. Superoxide dismutase (SOD) showed a maximum pseudo activity (SDA) of 56.74% at 69.54 W MWP, 94.88% ETC and 10.32 min EXT. The effect of ETC was most prominent among the studied factors. CONCLUSION: Based on the superimposition of four-dimensional response surfaces with respect to TPC, EDA, NSA and SDA, the optimum ranges of extraction conditions were 70-150 W MWP, 30 50% ETC and 8-18 min EXT. PMID- 22227836 TI - Application of X-ray photoelectron spectroscopic analysis to protein adsorption on materials relevant to biomanufacturing. AB - X-ray photoelectron spectroscopy (XPS) has been used to analyze the adsorption of a therapeutic monoclonal antibody (mAb), rituximab, and polyclonal human IgG (hIgG) on materials relevant to biomanufacturing of protein drug products. Details of the methods used to obtain qualitative confirmation of protein adsorption, using both the nitrogen (N 1s) signal originating from mAb proteins and an iodine heteroatom label, are presented. Both rituximab and hIgG were found to adsorb to a glass vial surface, vial rubber cap liner, syringe plunger tip, cell culture flask, serological pipette, and microcentrifuge tube. There was no evidence of protein adsorption on samples of polyvinylchloride (PVC) tubing or the barrel of a syringe. Differences in XPS heteroatom peak intensities, based on whether the heteroatom label was added to the protein prior to surface adsorption or after, suggest that adsorbed rituximab on a glass vial surface is in a structural conformation that allows extensive heteroatom labeling. Using a simple uniform overlayer model, the coverage of rituximab on a glass vial surface was determined by XPS to be 3.6 mg/m(2) , a value consistent with that expected for a theoretical monolayer. PMID- 22227834 TI - The role of calcium in chloroplasts--an intriguing and unresolved puzzle. AB - More than 70 years of studies have indicated that chloroplasts contain a significant amount of calcium, are a potential storage compartment for this ion, and might themselves be prone to calcium regulation. Many of these studies have been performed on the photosynthetic light reaction as well as CO(2) fixation via the Calvin-Benson-Bassham cycle, and they showed that calcium is required in several steps of these processes. Further studies have indicated that calcium is involved in other chloroplast functions that are not directly related to photosynthesis and that there is a calcium-dependent regulation similar to cytoplasmic calcium signal transduction. Nevertheless, the precise role that calcium has as a functional and regulatory component of chloroplast processes remains enigmatic. Calcium concentrations in different chloroplast subcompartments have been measured, but the extent and direction of intra plastidal calcium fluxes or calcium transport into and from the cytosol are not yet very well understood. In this review we want to give an overview over the current knowledge on the relationship between chloroplasts and calcium and discuss questions that need to be addressed in future research. PMID- 22227837 TI - Role of vulvar care guidelines in the initial management of vulvar complaints. AB - OBJECTIVE: This study aimed to determine the effectiveness of vulvar care guidelines as the initial treatment of vulvar complaints. MATERIALS AND METHODS: A chart review was conducted at the Saint Louis University Vulvar and Vaginal Disease Center. Women with vulvar symptoms in the absence of specific identifiable causes were evaluated and given guidelines for vulvar care. An 11 point Likert scale was used to rate symptoms at the initial and follow-up visits. Compliance level was determined. RESULTS: A decrease in mean scores was shown for dyspareunia (7.5 +/- 2.0 to 4.6 +/- 3.1, p < .001), burning after intercourse (6.8 +/- 2.7 to 3.4 +/- 2.4, p = .10), vulvar burning (5.7 +/- 2.6 to 2.1 +/- 1.9, p < .001), vulvar itching (4.9 +/- 2.8 to 2.5 +/- 2.6, p < .001), and vulvar pain (5.8 +/- 2.8 to 2.2 +/- 3.0, p < .01). The mean dyspareunia difference scores were significant between the low- and high-compliance groups. CONCLUSIONS: Vulvar care guidelines are successful for the management of vulvar complaints. PMID- 22227838 TI - A case of parametrial lymph node involvement in stage IA2 squamous cell carcinoma of the cervix treated with radical hysterectomy and a review of the literature: a case report. AB - Cervical cancer classified as stage IA2 and IB1 according to the International Federation of Gynecology and Obstetrics has historically been treated with radical hysterectomy and bilateral lymph node dissection, but recent recommendations suggest more conservative treatment modalities. We report a woman with stage IA2 cervical cancer at low risk for parametrial spread including no lymphovascular space invasion, clear conization margins, and tumor size less than 2 cm, who underwent radical hysterectomy and was found to have a single positive metastatic parametrial lymph node. This case report is an important reminder that parametrial involvement occurs in low-risk early-stage cervical cancers. PMID- 22227839 TI - An unusual case of hematometra in a postmenopausal woman associated with Manchester repair. AB - BACKGROUND: Hematometra is a rare condition caused by obstruction of the lower female genital tract resulting in an accumulation of menstrual fluid in the uterine cavity. Although most commonly a result of congenital abnormalities, in older women, the obstruction is usually acquired and occurs at the level of the cervix.The Manchester repair procedure, done for uterocervical prolapse as an alternative to vaginal hysterectomy, carries a risk of cervical scarring resulting in stenosis and hematometra. CASE REPORT: A 61-year-old woman presenting with acute pelvic pain on a background of chronic pelvic pain and urinary retention was found to have a pelvic mass. She underwent magnetic resonance imaging, and her case was discussed in the gynecologic oncology multidisciplinary meeting. She underwent a midline laparotomy and was found to have hematometra. This was a result of the post-Manchester repair amenorrhea being considered as menopause, leading to a gradually accumulating hematometra. CONCLUSIONS: Very few Manchester repairs are being carried out these days. Although advocated as a safe alternative to vaginal hysterectomy, clinicians doing this procedure should be aware of long-term complications like cervical stenosis. PMID- 22227840 TI - A simplified classification for describing colposcopic vaginal patterns. AB - OBJECTIVE: This study aimed to highlight that colposcopic vaginal patterns are not specific, unlike cervical colposcopic patterns, and to provide a simpler classification of vaginal colposcopic patterns. MATERIALS AND METHODS: A total of 223 patients who underwent colposcopy with Schiller test were assessed (hierarchical log-linear model) retrospectively. RESULTS: The greatest predictability for histologically confirmed warts and cancers is represented by colposcopic patterns of wart and cancer. Lugol-negative area is strongly predictive of koilocytosis, even if it is found in other vaginal lesions. Thickened epithelium seems to better predict a severe vaginal lesion, whereas thin white epithelium better suggests a mild vaginal lesion. Colposcopic patterns were simplified as follows: Lugol-negative area, white epithelia (thin white epithelium and white thickened epithelium), vascular lesions (regular and irregular mosaicisms and punctations), wart, and cancer. Thus, koilocytosis is predicted by the Lugol-negative area, whereas white epithelia patterns and vascular patterns are not specific, suggesting overall vaginal intraepithelial neoplasias. Wart and cancer patterns are pathognomonic for histologically confirmed warts and cancers. CONCLUSIONS: Vaginal colposcopy poorly predicts the severity of vaginal lesions. By including each type of white epithelium within a new category called "white epithelia patterns" and each type of vascular pattern within a new category called "vascular patterns," it is possible to simplify vaginal colposcopy without compromising its accuracy. PMID- 22227842 TI - Comparison of knowledge and attitudes toward human papillomavirus, HPV vaccine, pap tests, and cervical cancer between US and Peruvian women. AB - OBJECTIVES: The purpose of this study was to determine and compare the knowledge and attitudes toward human papillomavirus (HPV), HPV vaccine, Pap tests, and cervical cancer among US and Peruvian women. MATERIALS AND METHODS: A convenience sample of 275 US women in Augusta, GA, and 702 Peruvian women living in or near Cusco, Peru, completed 22- or 21-item questionnaires, respectively. These questionnaires determined their knowledge about HPV, the HPV vaccine, Pap tests, and cervical cancer. Simple logistic regression was used to determine the relationship between location and language on the correct responses. Odds ratios (ORs) and 95% confidence intervals were calculated. RESULTS: US Spanish- (OR = 0.02), Quechua- (OR = 0.05), and Peru Spanish-speaking women (OR = 0.03) were significantly less likely to know that HPV causes cervical cancer compared with US non-Spanish-speaking women. US Spanish- (OR = 10.61, OR = 5.74), Quechua- (OR = 11.08, OR = 9.89), and Peru Spanish-speaking women (OR = 17.25, 14.43) were significantly more likely to be embarrassed and afraid, respectively, to get a Pap test compared with US non-Spanish-speaking women. US Spanish- (OR = 0.11), Quechua- (OR = 0.14), and Peru Spanish-speaking women (OR = 0.11) women were significantly less likely to know the HPV vaccine is safe and effective compared with US non-Spanish-speaking women. CONCLUSIONS: Education must be implemented to address serious misconceptions and worrisome attitudes toward Pap tests and the HPV vaccine to decrease the rate of cervical cancer in Peru and US Spanish speaking women. PMID- 22227841 TI - Correlating knowledge of cervical cancer prevention and human papillomavirus with compliance after colposcopy referral. AB - OBJECTIVE: This study aimed to assess the impact of knowledge of cervical cancer biology and prevention as well as noncognitive measures on compliance with colposcopy referral in a high-risk population. METHODS: Participants in a US cohort of women with human immunodeficiency virus (HIV) infection and at-risk comparison women completed behavior questionnaires and instruments measuring knowledge of cervical cancer prevention, depressive symptoms, trust in physicians, and perceived stress. Examinations including Pap tests also were conducted. Associations with compliance with resulting indicated colposcopy were assessed in multivariable models. RESULTS: Of 326 women with indicated colposcopy, 222 (68%) were compliant with colposcopy referral and 104 (32%) were noncompliant. In multivariable analysis, better colposcopy compliance was associated with less education (odds ratio [OR] for compliance = 2.24, 95% confidence interval = 1.12-4.51 vs more than high school), previous abnormal Pap result (OR per previous abnormal Pap result = 1.08, 95% CI = 1.01-1.15), study site (OR for site with best vs worst compliance = 16.1, 95% CI = 2.91-88.6), and higher stress (OR for perceived stress scale 10 score >16 vs lower 3.25, 95% CI = 1.45-7.26). CONCLUSIONS: Noncognitive factors and how sites manage abnormal Pap testing affect colposcopy compliance. Educational interventions alone are unlikely to improve colposcopy compliance in similar high-risk populations. PMID- 22227843 TI - Primary breast cancer of the vulva: a case report. AB - The occurrence of primary breast cancer of the vulva is extremely rare (24 cases described in the English-language literature). We report a case of a primary breast carcinoma of the vulva. An 82-year-old woman presented with a nodule of the left labia minor, which was excised. The histologic examination revealed the presence of adenocarcinoma of mammary origin, positive for common breast markers and for estrogen and progesterone receptors. The study for orthotopic breast carcinoma was negative, as well as the study for metastatic disease. The diagnosis of primary breast carcinoma was established. Our patient was then submitted to pelvic and inguinal radiotherapy as well as an aromatase inhibitor (letrozole), and she remained completely asymptomatic. Because of the rarity of this condition, guidelines for therapy are unavailable. The management suggested in the literature is that of primary orthotopic breast neoplasm of a similar stage. PMID- 22227844 TI - A cost-effectiveness analysis of anal cancer screening in HIV-positive women. AB - OBJECTIVE: Anal cancer rates have increased in HIV+ patients. The prevalence of anal intraepithelial neoplasias (AINs) and progression to anal cancer in HIV+ men who have sex with men has been well described, and screening is cost-effective. Our objective was to determine whether anal cancer screening in HIV+ women is cost-effective. MATERIALS AND METHODS: A Markov model analysis of 100 HIV+ women was constructed. All women had a CD4 count less than 200 and were assumed to be on antiretrovirals. Rates of AIN were based on previous studies. Progression rates were extrapolated from previous data on HIV+ men who have sex with men. The 5-year model included 3 screening approaches: none, annual, and biennial. Anoscopy and biopsy were performed after an abnormal cytologic result. Low-grade AIN was followed with repeat cytology, and high-grade AIN was treated surgically. Anal cancer was treated surgically followed by chemotherapy and radiation. Sensitivity analyses (SAs) were performed to account for variable rates of AIN progression, anal cancer mortality, and anal cancer and HIV quality-adjusted life years. RESULTS: The incremental cost-effectiveness ratio of biennial anal cancer screening compared to no screening was $34,763. Cost-effectiveness was maintained across all assumptions in SA except for decreased progression rate of high-grade AIN to anal cancer. CONCLUSIONS: Biennial anal cancer screening in HIV+ women with CD4 counts less than 200 is cost-effective. Annual screening was not cost effective, likely because of the slow progression of AIN to anal cancer. Further data on rates of AIN progression in HIV+ women based on CD4 count are needed to determine whether screening is cost-effective in women with higher CD4 counts. PMID- 22227845 TI - Giant neurofibroma of labia major. AB - A 21-year-old woman presented with a large, slowly growing, pedunculated mass from her right labia major interfering with her physical activity. Surgical excision was performed, and pathologic evaluation confirmed the diagnosis of neurofibroma. PMID- 22227846 TI - Jones fracture fixation: a biomechanical comparison of partially threaded screws versus tapered variable pitch screws. AB - BACKGROUND: Stabilization of fifth metatarsal Jones fractures with intramedullary screw fixation is the most common method for surgical fixation when operative treatment is indicated. Conventional partially threaded screws of various diameters are routinely used for Jones fracture fixation. Recently, the use of tapered variable pitch screws has become popular, but information regarding their performance in Jones fracture fixation is limited. No previous studies have compared conventional and tapered variable pitch screws in Jones fracture fixation under physiologic cyclic loading conditions. PURPOSE: To determine whether biomechanical differences exist between appropriately sized conventional partially threaded screws and tapered variable pitch screws under physiologic cyclic loading conditions with regard to Jones fracture fixation. STUDY DESIGN: Controlled laboratory study. METHODS: Simulated Jones fractures were created in 23 matched pairs of fresh-frozen fifth metatarsals. One bone from each pair was stabilized with a conventional partially threaded screw and the contralateral bone with a tapered variable pitch screw. Initial compression, as well as fracture site compression, angulation, and bending stiffness, was compared between groups throughout 1000 physiologic cyclic loads. RESULTS: Conventional partially threaded screws obtained significantly greater initial compression compared with tapered variable pitch screws. Significantly greater compression was maintained throughout cyclic loading with conventional screw fixation compared with tapered variable pitch screws. Fracture site angulation was significantly greater using tapered variable pitch screws from the tenth load cycle through completion of cyclic loading. Despite a trend toward increased fracture site bending stiffness when using conventional screws, no difference in fixation stiffness was demonstrable between the 2 screw types. CONCLUSION: In this cadaveric Jones fracture fixation model, conventional partially threaded screws provided improved fracture site compression and decreased fracture site angulation but offered no advantage in improving fracture site stiffness compared with tapered variable pitch screws. These results provide empirical evidence to guide implant selection decision making for operative fixation of Jones fractures. CLINICAL RELEVANCE: While the use of tapered variable pitch screws is a potential alternative for fixation of fifth metatarsal Jones fractures, conventional partially threaded screws may provide better biomechanical stability, the effect of which on fracture healing is unknown. PMID- 22227849 TI - Comparison of methods for removing electromagnetic noise from electromyographic signals. AB - The purpose of this investigation was to compare three different methods of removing noise from monopolar electromyographic (EMG) signals: (a) electrical shielding with a Faraday cage, (b) denoising with a digital notch-filter and (c) applying a bipolar differentiation with another monopolar EMG signal. Ten men and ten women (mean age = 24.0 years) performed isometric muscle actions of the leg extensors at 10-100% of their maximal voluntary contraction on two separate occasions. One trial was performed inside a Faraday tent (a flexible Faraday cage made from conductive material), and the other was performed outside the Faraday tent. The EMG signals collected outside the Faraday tent were analyzed three separate ways: as a raw signal, as a bipolar signal, and as a signal digitally notch filtered to remove 60 Hz noise and its harmonics. The signal-to-noise ratios were greatest after notch-filtering (range: 3.0-33.8), and lowest for the bipolar arrangement (1.6-10.2). Linear slope coefficients for the EMG amplitude versus force relationship were also used to compare the methods of noise removal. The results showed that a bipolar arrangement had a significantly lower linear slope coefficient when compared to the three other conditions (raw, notch and tent). These results suggested that an appropriately filtered monopolar EMG signal can be useful in situations that require a large pick-up area. Furthermore, although it is helpful, a Faraday tent (or cage) is not required to achieve an appropriate signal-to-noise ratio, as long as the correct filters are applied. PMID- 22227850 TI - Use of bilateral information to determine the walking direction during orientation to a pheromone source in the silkmoth Bombyx mori. AB - Odor source localization is an important animal behavior. Male moths locate mates by tracking sex pheromone emitted by conspecific females. During this type of behavior, males exhibit a combination of upwind surge and zigzagging flight. Similarly, the male walking moth Bombyx mori responds to transient pheromone exposure with a surge in movement, followed by sustained zigzagging walking. The initial surge direction is known to be influenced by the pheromone input pattern. Here, we identified the sensory input patterns that determine the initial walking direction of males. We first quantified the stimulus by measuring electroantennogram values, which were used as a reference for subsequent tests. We used a brief stimulus pulse to examine the relationship between sensory stimulus patterns and the turning direction of initial surge. We found that the difference in input timing and intensity between left and right antennae affected the walking direction, indicating that B. mori integrate bilateral pheromone information during orientation behavior. When we tested pheromone stimulation for longer periods, turning behavior was suppressed, which was induced by stimulus cessation. This study contributes toward understanding efficient strategies for odor-source localization that is utilized by walking insects. PMID- 22227851 TI - Effect of volume of milk consumed on the attenuation of exercise-induced muscle damage. AB - Exercise-induced muscle damage (EIMD) leads to decrements in muscle performance, increases in intramuscular proteins and delayed-onset of muscle soreness (DOMS). Previous research demonstrated that one litre of milk-based protein-carbohydrate (CHO) consumed immediately following muscle damaging exercise can limit changes in markers of EIMD possibly due to attenuating protein degradation and/or increasing protein synthesis. If the attenuation of EIMD is derived from changes in protein metabolism then it can be hypothesised that consuming a smaller volume of CHO and protein will elicit similar effects. Three independent matched groups of 8 males consumed 500 mL of milk, 1,000 mL of milk or a placebo immediately following muscle damaging exercise. Passive and active DOMS, isokinetic muscle performance, creatine kinase (CK), myoglobin and interleukin-6 were assessed immediately before and 24, 48 and 72 h after EIMD. After 72 h 1,000 mL of milk had a likely benefit for limiting decrements in peak torque compared to the placebo. After 48 h, 1,000 mL of milk had a very likely benefit of limiting increases in CK in comparison to the placebo. There were no differences between consuming 500 or 1,000 mL of milk for changes in peak torque and CK. In conclusion, decrements in isokinetic muscle performance and increases in CK can be limited with the consumption of 500 mL of milk. PMID- 22227852 TI - Effects of eccentric exercise on systemic concentrations of pro- and anti inflammatory cytokines and prostaglandin (E2): comparison between young and postmenopausal women. AB - The present study aimed to analyze the magnitude of muscle damage and inflammatory responses induced by eccentric exercise in young (YW) and postmenopausal women (PMW). Seventeen healthy women (nine YW, 23.89 +/- 2.03 years; and eight PMW, 51.13 +/- 5.08 years) performed five sets of six maximal eccentric actions of the elbow flexors. Changes in isometric strength, range of motion, muscle soreness, and upper-arm circumference were evaluated pre, post, 24, 48, and 72 h following eccentric exercise. Changes in creatine kinase activity, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha), and prostaglandin E(2) (PGE(2)) were measured pre, 24, 48, and 72 h following eccentric exercise. For intra and inter-group analysis, a two-way repeated measures ANOVA was applied followed by a Tukey's post hoc test. Pearson's correlation was used to analyze the correlations between variables. It was observed no differences between groups for the markers of muscle damage, although significant modifications (p < 0.05) occurred within groups throughout time for all variables. Post menopausal women showed significantly higher values for TNF-alpha (p < 0.05). Also, IL-6 presented superior pre value for PMW. For YW, IL-6 and IL-10 values increased 72 h post-eccentric exercise compared to pre. Further, IL-10 was higher for YW than PMW 72 h post-eccentric exercise. Significant correlations (p < 0.05) were found between age and soreness, and between age and PGE(2). In conclusion, YW do not have attenuated muscle damage compared to PMW who do not make use of hormonal replacement therapy. In addition, YW have a greater anti-inflammatory response after eccentric exercise compared to PMW. PMID- 22227853 TI - Determination of the lactate threshold by means of salivary biomarkers: chromogranin A as novel marker of exercise intensity. AB - This study examined intra-individual variations in salivary lactate (sLac), alpha amylase (sAA) and chromogranin A (sCgA) with reference to the accumulation of blood lactate (bLac) during incremental maximal exercise in swimmers. Samples of blood and saliva were collected simultaneously from 12 male professional athletes during an incremental test that consisted of eight series of 100 m in front crawl with increasing velocity (0.03 m s(-1) each) and 70-s intervals. The concentration of blood and salivary lactate was determined by an electro enzymatic assay, whereas sAA and CgA were analysed by Western blotting. Inflection points in the concentration of bLAc, sLac, sAA and CgA were found in all subjects. The accumulation of lactate in saliva followed the same pattern observed in blood with a high correlation between the two (r = 0.91). Similar results were observed between the dynamics of sAA (r = 0.81) and sCgA (r = 0.82) in relation to bLac. These findings support the usefulness of saliva for the determination of the lactate threshold and provide the first demonstration of sCgA as a novel marker of exercise intensity in well-trained men. PMID- 22227854 TI - A study of PKM2, PFK-1, and ANT1 expressions in cervical biopsy tissues in China. AB - This present study explored the association of Pyruvate Kinase isozyme M2 (PKM2), Phosphofructokinase 1 (PFK-1) and Adenine nucleotide translocator 1 (ANT1) with cervical carcinoma. A case-control method was designed by the collected 95 cervical biopsy samples, which were divided into 30 controls and 60 cases. Cases were subdivided into mild cervical carcinoma (MCC-25), intermediate cervical carcinoma (ICC-20), and severe cervical carcinoma (SCC-20) by method of cervical pathology. The expression of PKM2, PFK-1, and ANT1 was examined by methods of immunohistochemistry and western blotting (WB). The results showed that the positive proportions of PKM2 and PFK-1 in case group were higher than that of control, and the increased positive proportions of PKM2 and PFK-1 were also revealed with the order of Control, MCC, ICC, SCC (P<0.05). Further, the results of WB confirmed the enhanced expressions of PKM2 and PFK-1 in case group and the increasing trend of PKM2 and PFK-1 expressions in Control, MCC, ICC, and SCC groups. In addition, the WB result of ANT1 showed a lower level of expression in SCC group, while the positive proportion of ANT1 was not significant between cases group and control. In conclusion, PKM2 and PFK-1 genes are associated closely with cervical carcinoma. The enhanced expressions of PKM2 and PFK-1 indicate one developing signal of cervical carcinoma. PMID- 22227855 TI - From the editor's desk. PMID- 22227857 TI - Gas-phase lanthanide chloride clusters: relationships among ESI abundances and DFT structures and energetics. AB - Anionic lanthanide chloride clusters, Ln(n)Cl(3n+1)(-), were produced by electrospray ionization (ESI) of LnCl(3) in isopropanol, where Ln = La-Lu (except Pm); the clusters were characterized using a quadrupole ion trap mass spectrometer. High-abundance "magic number" clusters were apparent at n = 4 for the early Ln (La-Sm), and at n = 5 for the late Ln (Dy-Lu). Density functional theory computations of La(n)Cl(3n+1)(-) and Lu(n)Cl(3n+1)(-) clusters (n = 1-6) indicate that the clusters with n = 4-6 are rings with a central chlorine atom. Computed structures show six-coordinate Ln in distorted octahedral sites in "magic number" La(4)Cl(13)(-) and Lu(5)Cl(16)(-), which have particularly large dissociation energies. For lanthanum, larger anionic chloride clusters with multiple charges of down to -5 were observed; their fragmentation by collision induced dissociation in the ion trap revealed La(4)Cl(13)(-) as a common product. Gas-phase hydrolysis to Ln(n)Cl(3n+1-y)(OH)(y)(-) (y = 1, 2) was prevalent for the late lanthanides, but only for small clusters, n = 2 or 3; larger clusters were evidently resistant to gas-phase hydrolysis. ESI of selected LnBr(3) and LnI(3) resulted in Ln(n)X(3n+1)(-) clusters (X = Br, I)--in contrast to Ln(n)Cl(3n+1)(-) clusters, the only observed (minor) high-abundance clusters were La(4)Br(13)(-) and Ce(4)Br(13)(-). PMID- 22227856 TI - Functional synchronization in repetitive bimanual prehension movements. AB - To examine the mechanisms of functional bimanual synchronization in goal-directed movements, we studied the movement kinematics of motorically unimpaired subjects while they performed repetitive prehension movements (either unimanually or bimanually) to small food items. Compared to unimanual conditions, bimanual movement execution yielded a significantly prolonged mouth contact phase. We hypothesized that this threefold prolongation led to a proper functional synchronization of the movement onsets of both hands at the beginning of each new movement cycle. That these temporal adjustments occurred in the movement phase with maximal haptic input points to the importance of sensory feedback for bimanual coordination. These results are discussed with respect to the important role of sensory feedback in the timing of coordinated bimanual movements. Furthermore, we propose that time-based coordinating schemas, which are implemented by the cerebellum and the posterior parietal cortex using sensory feedback, underlie functional inter-limb coordination. PMID- 22227858 TI - Regioselective synthesis of isocoumarins by ruthenium-catalyzed aerobic oxidative cyclization of aromatic acids with alkynes. AB - The highly regioselective aerobic oxidative cyclization of aromatic, heteroaromatic and alkenyl acids with alkynes in the presence of catalytic amounts of [{RuCl(2)(p-cymene)}(2)], AgSbF(6) and Cu(OAc)(2).H(2)O providing isocoumarin derivatives was investigated. PMID- 22227859 TI - Assessment of toxicity and potential risk of the anticoagulant rodenticide diphacinone using Eastern screech-owls (Megascops asio). AB - In the United States, new regulatory restrictions have been placed on the use of some second-generation anticoagulant rodenticides. This action may be offset by expanded use of first-generation compounds (e.g., diphacinone; DPN). Single-day acute oral exposure of adult Eastern screech-owls (Megascops asio) to DPN evoked overt signs of intoxication, coagulopathy, histopathological lesions (e.g., hemorrhage, hepatocellular vacuolation), and/or lethality at doses as low as 130 mg/kg body weight, although there was no dose-response relation. However, this single-day exposure protocol does not mimic the multiple-day field exposures required to cause mortality in rodent pest species and non-target birds and mammals. In 7-day feeding trials, similar toxic effects were observed in owls fed diets containing 2.15, 9.55 or 22.6 ppm DPN, but at a small fraction (<5%) of the acute oral dose. In the dietary trial, the average lowest-observed-adverse-effect level for prolonged clotting time was 1.68 mg DPN/kg owl/week (0.24 mg/kg owl/day; 0.049 mg/owl/day) and the lowest lethal dose was 5.75 mg DPN/kg owl/week (0.82 mg/kg owl/day). In this feeding trial, DPN concentration in liver ranged from 0.473 to 2.21 MUg/g wet weight, and was directly related to the daily and cumulative dose consumed by each owl. A probabilistic risk assessment indicated that daily exposure to as little as 3-5 g of liver from DPN-poisoned rodents for 7 days could result in prolonged clotting time in the endangered Hawaiian short eared owl (Asio flammeus sandwichensis) and Hawaiian hawk (Buteo solitarius), and daily exposure to greater quantities (9-13 g of liver) could result in low-level mortality. These findings can assist natural resource managers in weighing the costs and benefits of anticoagulant rodenticide use in pest control and eradication programs. PMID- 22227860 TI - Halophilic properties of metal binding protein characterized by high histidine content from Chromohalobacter salexigens DSM3043. AB - Periplasmic metal binding protein characterized by high histidine content was cloned from moderate halophile, Chromohalobacter salexigens. The protein, termed histidine-rich metal binding protein (HP), was expressed in and purified from E. coli as a native form. HP bound to Ni- and Cu-loaded chelate columns with high affinity, and Co- and Zn-columns with moderate affinity. Although the secondary structure was not grossly altered by the addition of 0.2-2.0 M NaCl, the thermal transition pattern was considerably shifted to higher temperature with increasing salt concentration: melting temperature was raised by ~20 degrees C at 2.0 M NaCl over the melting temperature at 0.2 M NaCl. HP showed reversible refolding from thermal melting in 0.2-1.15 M NaCl, while it formed irreversible aggregates upon thermal melting at 2 M NaCl. Addition of 0.01-0.1 mM NiSO4 stabilized HP against thermal melting with high reversibility, while addition above 0.5 mM resulted in irreversible melting due to aggregation. PMID- 22227862 TI - Semantic priming of familiar songs. AB - We explored the functional organization of semantic memory for music by comparing priming across familiar songs both within modalities (Experiment 1, tune to tune; Experiment 3, category label to lyrics) and across modalities (Experiment 2, category label to tune; Experiment 4, tune to lyrics). Participants judged whether or not the target tune or lyrics were real (akin to lexical decision tasks). We found significant priming, analogous to linguistic associative-priming effects, in reaction times for related primes as compared to unrelated primes, but primarily for within-modality comparisons. Reaction times to tunes (e.g., "Silent Night") were faster following related tunes ("Deck the Hall") than following unrelated tunes ("God Bless America"). However, a category label (e.g., Christmas) did not prime tunes from within that category. Lyrics were primed by a related category label, but not by a related tune. These results support the conceptual organization of music in semantic memory, but with potentially weaker associations across modalities. PMID- 22227863 TI - Land reclamation and short-term cultivation change soil microbial communities and bacterial metabolic profiles. AB - BACKGROUND: Soil microbes play an important role in many critical ecosystem processes, but little is known about the effects of land reclamation and short term cultivation on microbial communities in red soil. In this study, soil microbial communities under five land use patterns-artificial pine forest (Fp), tussock and shrub (TS), shrubbery (Sh), sugarcane (Su) and maize and cassava rotation (Ma)-were characterised by DNA fingerprinting and metabolic profiling to reveal how land reclamation and cultivation affect the underlying diversity and function of soil microbial communities in southwestern China. RESULTS: Eight years of reclamation and cultivation significantly affected population size, composition and structure, bacterial metabolic profiles and diversity values (Shannon-Wiener index) of soil microbial communities. Soil organic carbon and pH were the most important factors shaping the underlying microbial communities; however, with significant correlations between soil carbon/nitrogen ratio and bacterial taxonomic and metabolic diversities, soil total nitrogen was a potentially important factor for soil microbial composition and function, as well as soil moisture, cation exchange capacity and physical structure to a lesser extent. In addition, the lowest pH, lower nutrient availability and the most compact soil in pine forest resulted in the lowest microbial taxonomic and metabolic diversities among the five land use patterns studied. CONCLUSION: Soil organic carbon, nitrogen and pH appeared to be the most important factors influencing microbial biomass, composition and function in red soil of southwestern China. The study suggests that measures to lessen the impact of changes in this edaphic environment should be taken to avoid an imbalance of microbial function and improve ecological sustainability in southwestern China. PMID- 22227864 TI - Development of a combination microbicide gel formulation containing IQP-0528 and tenofovir for the prevention of HIV infection. AB - In light of the increasing worldwide AIDS pandemic, there is a continuing need to develop new prevention strategies to inhibit the transmission of HIV-1. In the absence of a successful vaccine, topical microbicides represent the best strategies to reduce the epidemic. Following the success of HIV therapeutic cocktail strategies, combinations of microbicides including nucleotide reverse transcriptase inhibitors (NtRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) may offer significant protection from infection over single agents. We have developed a combination microbicide gel formulation for the delivery of IQP-0528, a novel NNRTI, and tenofovir (TFV), a NtRTI. Gel formulations were evaluated based on quantitative viscoelastic and physiochemical evaluations defined by a target product profile (TPP). For the majority of the evaluations, the gel formulations behaved similarly; all showed shear thinning behavior, were stable, nontoxic, and active against HIV-1 infection. Gel formulation F2759 displayed increased drug release of 289 +/- 100 ug/(cm(2) h(1/2) ) and a tissue permeability of 60 times the half maximal effective concentration (EC(50) ) of TFV and 800 times the EC(50) of IQP-0528. In addition, F2759 showed osmolality within TPP and the highest performance in gel spreading. We have identified a gel formulation to deliver a combination microbicide of IQP 0528 and TFV that has significant potential to prevent infection of HIV-1. PMID- 22227861 TI - Homeobox gene expression profile indicates HOXA5 as a candidate prognostic marker in oral squamous cell carcinoma. AB - The search for molecular markers to improve diagnosis, individualize treatment and predict behavior of tumors has been the focus of several studies. This study aimed to analyze homeobox gene expression profile in oral squamous cell carcinoma (OSCC) as well as to investigate whether some of these genes are relevant molecular markers of prognosis and/or tumor aggressiveness. Homeobox gene expression levels were assessed by microarrays and qRT-PCR in OSCC tissues and adjacent non-cancerous matched tissues (margin), as well as in OSCC cell lines. Analysis of microarray data revealed the expression of 147 homeobox genes, including one set of six at least 2-fold up-regulated, and another set of 34 at least 2-fold down-regulated homeobox genes in OSCC. After qRT-PCR assays, the three most up-regulated homeobox genes (HOXA5, HOXD10 and HOXD11) revealed higher and statistically significant expression levels in OSCC samples when compared to margins. Patients presenting lower expression of HOXA5 had poorer prognosis compared to those with higher expression (P=0.03). Additionally, the status of HOXA5, HOXD10 and HOXD11 expression levels in OSCC cell lines also showed a significant up-regulation when compared to normal oral keratinocytes. Results confirm the presence of three significantly upregulated (>4-fold) homeobox genes (HOXA5, HOXD10 and HOXD11) in OSCC that may play a significant role in the pathogenesis of these tumors. Moreover, since lower levels of HOXA5 predict poor prognosis, this gene may be a novel candidate for development of therapeutic strategies in OSCC. PMID- 22227865 TI - Metabolism and neurotoxicity of homocysteine thiolactone in mice: protective role of bleomycin hydrolase. AB - Genetic or nutritional disorders in homocysteine (Hcy) metabolism elevate Hcy thiolactone and cause heart and brain diseases. Hcy-thiolactone has been implicated in these diseases because it has the ability to modify protein lysine residues and generate toxic N-Hcy-proteins with auto-immunogenic, pro-thrombotic, and amyloidogenic properties. Bleomycin hydrolase (Blmh) has the ability to hydrolyze L-Hcy-thiolactone (but not D-Hcy-thiolactone) to Hcy in vitro, but whether this reflects a physiological function has been unknown. Here, we show that Blmh (-/-) mice excreted in urine 1.8-fold more Hcy-thiolactone than wild type Blmh (+/+) animals (P = 0.02). Hcy-thiolactone was elevated 2.3-fold in brains (P = 0.004) and 2.0-fold in kidneys (P = 0.047) of Blmh (-/-) mice relative to Blmh (+/+) animals. Plasma N-Hcy-protein was elevated in Blmh (-/-) mice fed a normal (2.3-fold, P < 0.001) or hyperhomocysteinemic diet (1.5-fold, P < 0.001), compared with Blmh (+/+) animals. More intraperitoneally injected L-Hcy thiolactone was recovered in plasma in Blmh (-/-) mice than in wild-type Blmh (+/+) animals (83.1 vs. 39.3 MUM, P < 0.0001). In Blmh (+/+) mice injected intraperitoneally with D-Hcy-thiolactone, D,L-Hcy-thiolactone, or L-Hcy thiolactone, 88, 47, or 6.3%, respectively, of the injected dose was recovered in plasma. The incidence of seizures induced by L-Hcy-thiolactone injections (3,700 nmol/g body weight) was higher in Blmh (-/-) than in Blmh (+/+) mice (93.8 vs. 29.5%, P < 0.001). Using the Blmh null mice, we provide the first direct evidence that a specific Hcy metabolite, Hcy-thiolactone, rather than Hcy itself, is neurotoxic in vivo. Taken together, our findings indicate that Blmh protects mice against L-Hcy-thiolactone toxicity by metabolizing it to Hcy and suggest a mechanism by which Blmh might protect against neurodegeneration associated with hyperhomocysteinemia and Alzheimer's disease. PMID- 22227867 TI - Mechanism of photocatalytic activities in Cr-doped SrTiO3 under visible-light irradiation: an insight from hybrid density-functional calculations. AB - We used hybrid density-functional calculations to clarify the effect of substituting chromium for titanium (Cr(Ti)) on photocatalytic activities of Cr doped SrTiO(3). A singly negative Cr(Ti)-, which is relevant to a lower oxidation state of Cr, is advantageous for the visible light absorption without forming electron trapping centers, while other charge states are inactive for the photocatalytic reaction. Stabilizing the desirable charge state (Cr(Ti)-) is feasible by shifting the Fermi level towards the conduction band. Our theory sheds light on the photocatalytic properties of metal-doped semiconductors. PMID- 22227866 TI - Cis-trans peptide variations in structurally similar proteins. AB - The presence of energetically less favourable cis peptides in protein structures has been observed to be strongly associated with its structural integrity and function. Inter-conversion between the cis and trans conformations also has an important role in the folding process. In this study, we analyse the extent of conservation of cis peptides among similar folds. We look at both the amino acid preferences and local structural changes associated with such variations. Nearly 34% of the Xaa-Proline cis bonds are not conserved in structural relatives; Proline also has a high tendency to get replaced by another amino acid in the trans conformer. At both positions bounding the peptide bond, Glycine has a higher tendency to lose the cis conformation. The cis conformation of more than 30% of beta turns of type VIb and IV are not found to be conserved in similar structures. A different view using Protein Block-based description of backbone conformation, suggests that many of the local conformational changes are highly different from the general local structural variations observed among structurally similar proteins. Changes between cis and trans conformations are found to be associated with the evolution of new functions facilitated by local structural changes. This is most frequent in enzymes where new catalytic activity emerges with local changes in the active site. Cis-trans changes are also seen to facilitate inter-domain and inter-protein interactions. As in the case of folding, cis-trans conversions have been used as an important driving factor in evolution. PMID- 22227868 TI - Titanium and iron in lung of a soldier with nonspecific interstitial pneumonitis and bronchiolitis after returning from Iraq. PMID- 22227869 TI - Sarcoidosis and World Trade Center disaster. PMID- 22227871 TI - The use of alcohol-based hand sanitizers by pregnant health care workers. PMID- 22227873 TI - The economic consequences of rheumatoid arthritis: analysis of Medical Expenditure Panel Survey 2004, 2005, and 2006 data. AB - OBJECTIVE: Determine the prevalence and costs of rheumatoid arthritis (RA) during three consecutive years: 2004, 2005, and 2006. METHODS: Medical Expenditure Panel Survey was used for persons with RA. Regressions estimate health care costs and income loss. Absenteeism and age-adjusted workforce participation compared means and rates. RESULTS: The prevalence of RA was 0.40% in 2004, 0.44% in 2005, and 0.43% in 2006. Health care cost associated with RA was $4422, $2902, and $1882 (all P < 0.01) in 2004, 2005, and 2006, respectively. Rheumatoid arthritis sufferers were employed, 36.8%, 39.5%, and 44% compared with 70.5%, 69.8%, and 71%. Individuals with RA also missed more days of work, 4.86 in 2004 (P = 0.04), 1.70 in 2005 (P = 0.22), and 2.99 in 2006 (P = 0.04). Rheumatoid arthritis reduced income by $2404 (P = 0.03), $2207 (P < 0.001), and $1212 (P = 0.002). CONCLUSIONS: Costs of RA are considerable. PMID- 22227872 TI - A case-crossover study of risk factors for occupational eye injuries. AB - OBJECTIVE: To study transient risk factors for occupational eye injuries. METHODS: A case-crossover study was conducted among patients treated for occupational eye injuries in the emergency department at an eye hospital in Alabama. A questionnaire was administered to collect information regarding risk factors at the time of and prior to eye treatment. Incidence rate ratios were used to measure the relationship between each risk factor and injury occurrence. RESULTS: Protective eyewear reduced the risk of occupational eye injury, while increased risk was observed for the following: being distracted, use of tools, tool malfunction, performing an unfamiliar task, being rushed, working overtime, and feeling fatigued. CONCLUSIONS: Although use of protective eyewear can significantly reduce the risk of an eye injury, other factors are important contributors. Identification of potentially modifiable transient risk factors can be used to prevent occupational eye injuries. PMID- 22227874 TI - Association between cumulative fiber exposure and respiratory outcomes among Libby vermiculite workers. AB - OBJECTIVE: To examine the association between cumulative fiber exposure and health outcomes in workers (n = 336) with Libby amphibole exposure. METHODS: Exposure-response relationships were explored by the use of logistic regression, with cumulative fiber exposure modeled in categories and as a continuous variable. RESULTS: The use of spline functions with lifetime cumulative fiber exposure as a continuous variable showed that the odds of localized pleural thickening were significantly elevated at less than 1 f/cc-y. Odds of parenchymal abnormalities, restrictive spirometry, and chronic bronchitis were also significantly elevated at 108, 166, and 24 f/cc-y, respectively. CONCLUSIONS: The odds of several pulmonary health outcomes are correlated with cumulative exposure to Libby amphibole. That relatively low-lifetime cumulative exposures are associated with localized pleural thickening has implications for the non-cancer risk assessment for Libby amphibole. PMID- 22227875 TI - Are international standards for ethics the same for all occupational health professionals? PMID- 22227878 TI - Meniscal calcification, pathogenesis and implications. AB - PURPOSE OF REVIEW: The purpose of this review is to discuss recent advances in the understanding of the nature of meniscal calcification and its relationships with meniscal degeneration and cartilage lesions in osteoarthritis. RECENT FINDINGS: Calcium crystals are universally present in hyaline articular cartilage, as well as the meniscus of the knee of end-stage osteoarthritis patients. Osteoarthritis meniscal cells display a distinct gene-expression profile different from normal meniscal cells, have elevated expression of ankylosis progressive analog (ANKH) and ectonucleotide pyrophosphatase/phosphodiesterase1 (ENPP1) and produce more calcium minerals than normal meniscal cells in vitro. Meniscal calcification is positively associated with meniscal degeneration, which is an early event in the development of osteoarthritis and correlates with cartilage lesions and clinical osteoarthritis scores. Phosphocitrate is a potent calcification inhibitor of osteoarthritis meniscal cell-mediated calcium deposition. Its effect on preventing meniscal degeneration and the molecular mechanisms underlying its disease-modifying activity in osteoarthritis remains elusive. SUMMARY: Recent findings support a pathogenic role of meniscal calcification in osteoarthritis. Meniscal calcification, similar to meniscal degeneration, is a predisposing factor for cartilage lesions. Meniscal calcification is a new target for the development of therapeutic disease-modifying drugs for osteoarthritis. PMID- 22227879 TI - Disability due to gouty arthritis. AB - PURPOSE OF REVIEW: Disability, or activity limitation, is a common problem in patients with gout. This study explores recent studies examining the nature and extent of disability in gout and addresses the merits and limitations of current self-reported measures of disability. RECENT FINDINGS: Gout has a significant impact on patients' ability to perform normal self-care activities, recreational and social activities, and work. Comparative studies indicate that gout patients' physical functioning is strongly reduced and comparable to those with other severe rheumatic conditions. Moreover, gout has been shown to result in substantial work absence and reduced productivity. However, few studies have thoroughly examined the concept of disability in gout. Additionally, assessment of disability due to gout still seems particularly challenging and it is unclear whether current measurement instruments are sufficiently valid and accurate. SUMMARY: Gout-related disability is an underestimated and understudied problem. More qualitative and quantitative studies are needed that examine the concept of disability in gout and its impact on patients' lives, both during and between disease flares. Moreover, future studies should try to identify gout-specific disability issues and examine the relevance and comprehensiveness of existing measures to further improve the assessment of disability in gout. PMID- 22227880 TI - Systemic lupus and malignancies. AB - PURPOSE OF REVIEW: Individuals with systemic lupus erythematosus (SLE) have an increased susceptibility to certain types of cancer. Given concerns focused on this issue, we present a review of this important topic. RECENT FINDINGS: In non Hodgkin lymphoma (NHL), a several-fold increased risk is seen in SLE versus the general population. It has long been suspected that immunosuppressive drugs play a role in this risk, but there may be other important driving factors as well. Lupus disease activity may itself heighten the risk of lymphoma in diseases like SLE. Lung cancer risk also is increased in SLE; smoking appears to drive this risk. Additionally, cervical dysplasia risk is increased in SLE, particularly with immunosuppressive drug exposure. An altered clearance of cancer-related viral agents in SLE (due to the disease and/or immunosuppression) may contribute to this risk and may also drive the risk for other cancers (such as vulvovaginal and hepatic carcinomas) in SLE. On the positive side, one new and significant finding is that SLE patients seem to have a decreased risk of certain nonhematologic cancers (breast, ovarian, endometrial, and prostate). SUMMARY: Though much has been learnt so far regarding the risk in SLE, much yet remains unknown. PMID- 22227881 TI - Molecular response of the patellar tendon to fatigue loading explained in the context of the initial induced damage and number of fatigue loading cycles. AB - Accumulation of sub-rupture fatigue damage has been implicated in the development of tendinopathy. We previously developed an in vivo model of damage accumulation using the rat patellar tendon. Our model allows us to control the input loading parameters to induce fatigue damage in the tendon. Despite this precise control, the resulting induced damage could vary among animals because of differences in size or strength among their patellar tendons. In this study, we used number of applied cycles and initial (day-0) parameters that are indicative of induced damage to assess the molecular response 7 days after fatigue loading. We hypothesized that day-0 hysteresis, elongation, and stiffness of the loading and unloading load-displacement curves would be predictive of the 7-day molecular response. Results showed correlations between the 7-day molecular response and both day-0 elongation and unloading stiffness. Additionally, loading resulted in upregulation of several extracellular matrix genes that suggest adaptation; however, several of these genes (Col-I, -XII, MMP 2, and TIMP 3) shut down after a high level of damage was induced. We showed that evaluating the 7-day molecular profile in light of day-0 elongation provides important insight that is lost from comparing number of fatigue loading cycles only. Our data showed that loading generally results in an adaptive response. However, the tendon's ability to effectively respond deteriorates as greater damage is induced. PMID- 22227882 TI - A class III semaphorin (Sema3e) inhibits mouse osteoblast migration and decreases osteoclast formation in vitro. AB - Originally identified as axonal guidance cues, semaphorins are expressed throughout many different tissues and regulate numerous non-neuronal processes. We demonstrate that most class III semaphorins are expressed in mouse osteoblasts and are differentially regulated by cell growth and differentiation: Sema3d expression is increased and Sema3e expression decreased during proliferation in culture, while expression of Sema3a is unaffected by cell density but increases in cultures of mineralizing osteoblasts. Expression of Sema3a, -3e, and -3d is also differentially regulated by osteogenic stimuli; inhibition of GSK3beta decreased expression of Sema3a and -3e, while 1,25-(OH)(2)D(3) increased expression of Sema3e. Parathyroid hormone had no effect on expression of Sema3a, 3b, or -3d. Osteoblasts, macrophages, and osteoclasts express the Sema3e receptor PlexinD1, suggesting an autocrine and paracrine role for Sema3e. No effects of recombinant Sema3e on osteoblast proliferation, differentiation, or mineralization were observed; but Sema3e did inhibit the migration of osteoblasts in a wound-healing assay. The formation of multinucleated, tartrate-resistant acid phosphatase-positive osteoclasts was decreased by 81% in cultures of mouse bone marrow macrophages incubated with 200 ng/mL Sema3e. Correspondingly, decreased expression of osteoclast markers (Itgb3, Acp5, Cd51, Nfatc1, CalcR, and Ctsk) was observed by qPCR in macrophage cultures differentiated in the presence of Sema3e. Our results demonstrate that class III semaphorins are expressed by osteoblasts and differentially regulated by differentiation, mineralization, and osteogenic stimuli. Sema3e is a novel inhibitor of osteoclast formation in vitro and may play a role in maintaining local bone homeostasis, potentially acting as a coupling factor between osteoclasts and osteoblasts. PMID- 22227884 TI - Optimizing the order of operations for movement scrubbing: Comment on Power et al. AB - A recent study by Power and colleagues shows that BOLD artifacts induced by head movement can substantially alter patterns of resting-state functional connectivity and proposes a novel procedure for reducing these artifacts by deleting (or "scrubbing") movement-contaminated volumes. The authors acknowledge that this work is descriptive and not prescriptive, and note that future studies may refine the proposed scrubbing method. Nevertheless, it is worth pointing out that this method can be improved substantially by a single transposition in the order of operations. Temporal filtering is known to introduce ringing artifacts that emanate from sharp transitions in signal intensity. The method proposed in the target article applies temporal filtering before deleting contaminated volumes-in effect, spreading movement-related artifacts backwards and forwards in time, but deleting only the originally contaminated data. Using simulated data, we show that deleting and replacing contaminated volumes before temporal filtering removes a greater proportion of artifactual signal while retaining a greater proportion of the original data. PMID- 22227883 TI - A comprehensive reliability assessment of quantitative diffusion tensor tractography. AB - Diffusion tensor tractography is increasingly used to examine structural connectivity in the brain in various conditions, but its test-retest reliability is understudied. The main purposes of this study were to evaluate 1) the reliability of quantitative measurements of diffusion tensor tractography and 2) the effect on reliability of the number of gradient sampling directions and scan repetition. Images were acquired from ten healthy participants. Ten fiber regions of nine major fiber tracts were reconstructed and quantified using six fiber variables. Intra- and inter-session reliabilities were estimated using intraclass correlation coefficient (ICC) and coefficient of variation (CV), and were compared to pinpoint major error sources. Additional pairwise comparisons were made between the reliability of images with 30 directions and NEX 2 (DTI30-2), 30 directions and NEX 1 (DTI30-1), and 15 directions and NEX 2 (DTI15-2) to determine whether increasing gradient directions and scan repetition improved reliability. Of the 60 tractography measurements, 43 showed intersession CV <= 10%, ICC >= .70, or both for DTI30-2, 40 measurements for DTI30-1, and 37 for DTI15-2. Most of the reliable measurements were associated with the tracts corpus callosum, cingulum, cerebral peduncular fibers, uncinate fasciculus, and arcuate fasciculus. These reliable measurements included factional anisotropy (FA) and mean diffusivity of all 10 fiber regions. Intersession reliability was significantly worse than intra-session reliability for FA, mean length, and tract volume measurements from DTI15-2, indicating that the combination of MRI signal variation and physiological noise/change over time was the major error source for this sequence. Increasing the number of gradient directions from 15 to 30 while controlling the scan time, significantly affected values for all six variables and reduced intersession variability for mean length and tract volume measurements. Additionally, while increasing scan repetition from 1 to 2 had no significant effect on the reliability for DTI with 30 directions, this significantly reduced the upward bias in FA values from all 10 fiber regions and fiber count, mean length, and tract volume measurements from 5 to 7 fiber regions. In conclusion, diffusion tensor tractography provided many measurements with high test-retest reliability across different fiber variables and various fiber tracts even for images with 15 directions (NEX 2). Increasing the number of gradient directions from 15 to 30 with equivalent scan time reduced variability whereas increasing repetition from 1 to 2 for 30-direction DTI improved the accuracy of tractography measurements. PMID- 22227885 TI - Quantitative measurement of changes in calcium channel activity in vivo utilizing dynamic manganese-enhanced MRI (dMEMRI). AB - The ability of manganese ions (Mn(2+)) to enter cells through calcium ion (Ca(2+)) channels has been used for depolarization dependent brain functional imaging with manganese-enhanced MRI (MEMRI). The purpose of this study was to quantify changes to Mn(2+) uptake in rat brain using a dynamic manganese-enhanced MRI (dMEMRI) scanning protocol with the Patlak and Logan graphical analysis methods. The graphical analysis was based on a three-compartment model describing the tissue and plasma concentration of Mn. Mn(2+) uptake was characterized by the total distribution volume of manganese (Mn) inside tissue (V(T)) and the unidirectional influx constant of Mn(2+) from plasma to tissue (K(i)). The measurements were performed on the anterior (APit) and posterior (PPit) parts of the pituitary gland, a region with an incomplete blood brain barrier. Modulation of Ca(2+) channel activity was performed by administration of the stimulant glutamate and the inhibitor verapamil. It was found that the APit and PPit showed different Mn(2+) uptake characteristics. While the influx of Mn(2+) into the PPit was reversible, Mn(2+) was found to be irreversibly trapped in the APit during the course of the experiment. In the PPit, an increase of Mn(2+) uptake led to an increase in V(T) (from 2.8+/-0.3 ml/cm(3) to 4.6+/-1.2 ml/cm(3)) while a decrease of Mn(2+) uptake corresponded to a decrease in V(T) (from 2.8+/-0.3 ml/cm(3) to 1.4+/-0.3 ml/cm(3)). In the APit, an increase of Mn(2+) uptake led to an increase in K(i) (from 0.034+/-0.009 min(-1) to 0.049+/-0.012 min(-1)) while a decrease of Mn(2+) uptake corresponded to a decrease in K(i) (from 0.034+/-0.009 min(-1) to 0.019+/-0.003 min(-1)). This work demonstrates that graphical analysis applied to dMEMRI data can quantitatively measure changes to Mn(2+) uptake following modulation of neural activity. PMID- 22227886 TI - Support vector machine classification and characterization of age-related reorganization of functional brain networks. AB - Most of what is known about the reorganization of functional brain networks that accompanies normal aging is based on neuroimaging studies in which participants perform specific tasks. In these studies, reorganization is defined by the differences in task activation between young and old adults. However, task activation differences could be the result of differences in task performance, strategy, or motivation, and not necessarily reflect reorganization. Resting state fMRI provides a method of investigating functional brain networks without such confounds. Here, a support vector machine (SVM) classifier was used in an attempt to differentiate older adults from younger adults based on their resting state functional connectivity. In addition, the information used by the SVM was investigated to see what functional connections best differentiated younger adult brains from older adult brains. Three separate resting-state scans from 26 younger adults (18-35 yrs) and 26 older adults (55-85) were obtained from the International Consortium for Brain Mapping (ICBM) dataset made publically available in the 1000 Functional Connectomes project www.nitrc.org/projects/fcon_1000. 100 seed-regions from four functional networks with 5mm(3) radius were defined based on a recent study using machine learning classifiers on adolescent brains. Time-series for every seed-region were averaged and three matrices of z-transformed correlation coefficients were created for each subject corresponding to each individual's three resting-state scans. SVM was then applied using leave-one-out cross-validation. The SVM classifier was 84% accurate in classifying older and younger adult brains. The majority of the connections used by the classifier to distinguish subjects by age came from seed regions belonging to the sensorimotor and cingulo-opercular networks. These results suggest that age-related decreases in positive correlations within the cingulo-opercular and default networks, and decreases in negative correlations between the default and sensorimotor networks, are the distinguishing characteristics of age-related reorganization. PMID- 22227887 TI - Multivariate pattern analysis reveals common neural patterns across individuals during touch observation. AB - In a recent study we found that multivariate pattern analysis (MVPA) of functional magnetic resonance imaging (fMRI) data could predict which of several touch-implying video clips a subject saw, only using voxels from primary somatosensory cortex. Here, we re-analyzed the same dataset using cross individual MVPA to locate patterns of information that were common across participants' brains. In this procedure a classifier learned to distinguish the neural patterns evoked by each stimulus based on the data from a sub-group of the subjects and was then tested on data from an individual that was not part of that sub-group. We found prediction performance to be significantly above chance both when using voxels from the whole brain and when only using voxels from the postcentral gyrus. SVM voxel weight maps established based on the whole-brain analysis as well as a separate searchlight analysis suggested foci of especially high information content in medial and lateral occipital cortex and around the intraparietal sulcus. Classification across individuals appeared to rely on similar brain areas as classification within individuals. These data show that observing touch leads to stimulus-specific patterns of activity in sensorimotor networks and that these patterns are similar across individuals. More generally, the results suggest that cross-individual MVPA can succeed even when applied to restricted regions of interest. PMID- 22227888 TI - Coma and consciousness: paradigms (re)framed by neuroimaging. AB - The past 15 years have provided an unprecedented collection of discoveries that bear upon our scientific understanding of recovery of consciousness in the human brain following severe brain damage. Highlighted among these discoveries are unique demonstrations that patients with little or no behavioral evidence of conscious awareness may retain critical cognitive capacities and the first scientific demonstrations that some patients, with severely injured brains and very longstanding conditions of limited behavioral responsiveness, may nonetheless harbor latent capacities for significant recovery. Included among such capacities are particularly human functions of language and higher-level cognition that either spontaneously or through direct interventions may reemerge even at long time intervals or remain unrecognized. Collectively, these observations have reframed scientific inquiry and further led to important new insights into mechanisms underlying consciousness in the human brain. These studies support a model of consciousness as the emergent property of the collective behavior of widespread frontoparietal network connectivity modulated by specific forebrain circuit mechanisms. We here review these advances in measurement and the scientific and broader implications of this rapidly progressing field of research. PMID- 22227889 TI - Quantitative analysis of lateral root development: pitfalls and how to avoid them. AB - The advent of the postgenomics era has led to increased interest in exploring the role of gene networks and signaling pathways in controlling plant development. The last two decades have seen a particular increase in the number of studies focusing on the development of the Arabidopsis thaliana root system. However, the investigation of such a seemingly simple system as an Arabidopsis root can lead to problems in quantification and errors in interpretation if knowledge of root organization is lacking. In this article, we identify a number of these problems and give examples of potentially erroneous and correct determinations of lateral root parameters. Our aim is to bring this important issue to the attention of the plant science community and to suggest ways in which the problems inherent in quantifying the process of lateral root development can be avoided. PMID- 22227890 TI - Analyzing lateral root development: how to move forward. AB - Roots are important to plants for a wide variety of processes, including nutrient and water uptake, anchoring and mechanical support, storage functions, and as the major interface between the plant and various biotic and abiotic factors in the soil environment. Therefore, understanding the development and architecture of roots holds potential for the manipulation of root traits to improve the productivity and sustainability of agricultural systems and to better understand and manage natural ecosystems. While lateral root development is a traceable process along the primary root and different stages can be found along this longitudinal axis of time and development, root system architecture is complex and difficult to quantify. Here, we comment on assays to describe lateral root phenotypes and propose ways to move forward regarding the description of root system architecture, also considering crops and the environment. PMID- 22227891 TI - Pericentromeric effects shape the patterns of divergence, retention, and expression of duplicated genes in the paleopolyploid soybean. AB - The evolutionary forces that govern the divergence and retention of duplicated genes in polyploids are poorly understood. In this study, we first investigated the rates of nonsynonymous substitution (Ka) and the rates of synonymous substitution (Ks) for a nearly complete set of genes in the paleopolyploid soybean (Glycine max) by comparing the orthologs between soybean and its progenitor species Glycine soja and then compared the patterns of gene divergence and expression between pericentromeric regions and chromosomal arms in different gene categories. Our results reveal strong associations between duplication status and Ka and gene expression levels and overall low Ks and low levels of gene expression in pericentromeric regions. It is theorized that deleterious mutations can easily accumulate in recombination-suppressed regions, because of Hill-Robertson effects. Intriguingly, the genes in pericentromeric regions-the cold spots for meiotic recombination in soybean-showed significantly lower Ka and higher levels of expression than their homoeologs in chromosomal arms. This asymmetric evolution of two members of individual whole genome duplication (WGD) derived gene pairs, echoing the biased accumulation of singletons in pericentromeric regions, suggests that distinct genomic features between the two distinct chromatin types are important determinants shaping the patterns of divergence and retention of WGD-derived genes. PMID- 22227892 TI - A nitrate transporter for both roots and shoots. PMID- 22227895 TI - Translational medicine in China I: perspectives from Chinese physicians and scientists. PMID- 22227893 TI - The Arabidopsis nitrate transporter NRT2.4 plays a double role in roots and shoots of nitrogen-starved plants. AB - Plants have evolved a variety of mechanisms to adapt to N starvation. NITRATE TRANSPORTER2.4 (NRT2.4) is one of seven NRT2 family genes in Arabidopsis thaliana, and NRT2.4 expression is induced under N starvation. Green fluorescent protein and beta-glucuronidase reporter analyses revealed that NRT2.4 is a plasma membrane transporter expressed in the epidermis of lateral roots and in or close to the shoot phloem. The spatiotemporal expression pattern of NRT2.4 in roots is complementary with that of the major high-affinity nitrate transporter NTR2.1. Functional analysis in Xenopus laevis oocytes and in planta showed that NRT2.4 is a nitrate transporter functioning in the high-affinity range. In N-starved nrt2.4 mutants, nitrate uptake under low external supply and nitrate content in shoot phloem exudates was decreased. In the absence of NRT2.1 and NRT2.2, loss of function of NRT2.4 (triple mutants) has an impact on biomass production under low nitrate supply. Together, our results demonstrate that NRT2.4 is a nitrate transporter that has a role in both roots and shoots under N starvation. PMID- 22227894 TI - Analysis of the MMP-dependent and independent functions of tissue inhibitor of metalloproteinase-2 on the invasiveness of breast cancer cells. AB - Matrix metalloproteinases (MMPs) are secreted endopeptidases that play an essential role in remodeling the extracellular matrix (ECM). MMPs are primarily active during development, when the majority of ECM remodeling events occurs. In adults, elevated MMP activity has been observed in many pathological conditions such as cancer and osteoarthritis. The proteolytic activity of MMPs is controlled by their natural inhibitors - the tissue inhibitor of metalloproteinases (TIMPs). In addition to blocking MMP-mediated proteolysis, TIMPs have a number of MMP independent functions including binding to cell surface proteins thereby stimulating signaling cascades. TIMP-2, the most studied member of the family, can both inhibit and activate MMPs directly, as well as inhibit MMP activity indirectly by upregulating expression of RECK, a membrane anchored MMP regulator. While TIMP-2 has been shown to play important roles in breast cancer, we describe how the MMP-independent effects of TIMP-2 can modulate the invasiveness of MCF-7, T47D and MDA-MB-231 breast cancer cells. Using an ALA + TIMP-2 mutant which is devoid of MMP inhibition, but still capable of initiating specific cell signaling cascades, we show that TIMP-2 can differentially affect MMP activity and cellular invasiveness in both an MMP dependent and independent manner. More specifically, MMP activity and invasiveness is increased with the addition of exogenous TIMP-2 in poorly invasive cell lines whereas it is decreased in highly invasive cells lines (MDA-MB-231). Conversely, the addition of ALA + TIMP-2 resulted in decreased invasiveness regardless of cell line. PMID- 22227896 TI - Translational medicine should translate medical science and technology into health care for everyone in China. PMID- 22227897 TI - Translational medicine: what is in a name from the perspective of Chinese clinicians? PMID- 22227898 TI - Targeted and personalized therapy for cancer: theory and practice in China. PMID- 22227899 TI - Translational research: lessons from past research, growing up nowadays, and development goal in future. PMID- 22227900 TI - Progress, challenges and new concepts in microRNAs. PMID- 22227901 TI - Atrial remodeling in atrial fibrillation and association between microRNA network and atrial fibrillation. AB - Atrial fibrillation (AF) remains one of the leading causes of morbidity and mortality in the world which are related to palpitations, fainting, congestive heart failure or stroke. The mechanism for atrial fibrillation has been identified as electrical remodeling, structure remodeling and intracellular calcium handling remodeling. microRNAs (miRNAs) have recently emerged as one of the important factors in regulating gene expression. So far, thousands of miRNA genes have been found in diverse animals with the function of regulating cell death, cell proliferation, haematopoiesis and even participate in the processing of cardiovascular disease. In this review, we summarize the mechanism of AF and the association of microRNAs network with AF. We provide a potential perspective of miRNAs as the therapeutic target for AF. PMID- 22227902 TI - MicroRNAs in neural cell development and brain diseases. AB - MicroRNAs play important roles in post-transcriptional regulation of gene expression by inhibiting protein translation and/or promoting mRNA degradation. Importantly, biogenesis of microRNAs displays specific temporal and spatial profiles in distinct cell and tissue types and hence affects a broad spectrum of biological functions in normal cell growth and tumor development. Recent discoveries have revealed sophisticated mechanisms that control microRNA production and homeostasis in response to developmental and extracellular signals. Moreover, a link between dysregulation of microRNAs and human brain disorders has become increasingly evident. In this review, we focus on recent advances in understanding the regulation of microRNA biogenesis and function in neuronal and glial development in the mammalian brain, and dysregulation of the microRNA pathway in neurodevelopmental and neurodegenerative diseases. PMID- 22227903 TI - Cardinal roles of miRNA in cardiac development and disease. AB - MicroRNAs (miRNAs) are small noncoding RNAs that are emerging as pivotal modulators in virtually all aspects of cardiac biology, from cardiac development to cardiomyocyte survival and hypertrophy. The miRNA profiling, following gain- and loss-of-function studies using in vitro and in vivo models, has identified wide-ranging functions for miRNAs in the heart, providing new perspectives on their contributions to cardiac pathogenesis, and revealing potential therapeutic targets and diagnostic biomarkers. This review summarizes current progress in regulation of miRNAs in heart development and disease. PMID- 22227904 TI - Overview of available methods for diverse RNA-Seq data analyses. AB - RNA-Seq technology is becoming widely used in various transcriptomics studies; however, analyzing and interpreting the RNA-Seq data face serious challenges. With the development of high-throughput sequencing technologies, the sequencing cost is dropping dramatically with the sequencing output increasing sharply. However, the sequencing reads are still short in length and contain various sequencing errors. Moreover, the intricate transcriptome is always more complicated than we expect. These challenges proffer the urgent need of efficient bioinformatics algorithms to effectively handle the large amount of transcriptome sequencing data and carry out diverse related studies. This review summarizes a number of frequently-used applications of transcriptome sequencing and their related analyzing strategies, including short read mapping, exon-exon splice junction detection, gene or isoform expression quantification, differential expression analysis and transcriptome reconstruction. PMID- 22227905 TI - De novo transcriptome assembly of RNA-Seq reads with different strategies. AB - De novo transcriptome assembly is an important approach in RNA-Seq data analysis and it can help us to reconstruct the transcriptome and investigate gene expression profiles without reference genome sequences. We carried out transcriptome assemblies with two RNA-Seq datasets generated from human brain and cell line, respectively. We then determined an efficient way to yield an optimal overall assembly using three different strategies. We first assembled brain and cell line transcriptome using a single k-mer length. Next we tested a range of values of k-mer length and coverage cutoff in assembling. Lastly, we combined the assembled contigs from a range of k values to generate a final assembly. By comparing these assembly results, we found that using only one k-mer value for assembly is not enough to generate good assembly results, but combining the contigs from different k-mer values could yield longer contigs and greatly improve the overall assembly. PMID- 22227906 TI - Genotypic variation in phosphorus acquisition from sparingly soluble P sources is related to root morphology and root exudates in Brassica napus. AB - Genotypic variations in the adaptive response to low-phosphorus (P) stress and P uptake efficiency have been widely reported in many crops. We conducted a pot experiment to evaluate the P-acquisition ability of two rapeseed (Brassica napus) genotypes supplied with two sparingly soluble sources of P, Al-P and Fe-P. Then, the root morphology, proton concentrations, and carboxylate content were investigated in a solution experiment to examine the genotypic difference in P acquisition efficiency. Both genotypes produced greater biomass and accumulated more P when supplied with Al-P than when supplied with Fe-P. The P-efficient genotype 102 showed a significantly greater ability to deplete sparingly soluble P from the rhizosphere soil because of its greater biomass and higher P uptake compared with those of the P-inefficient genotype 105. In the solution experiment, the P-efficient genotype under low-P conditions developed dominant root morphological traits, and it showed more intensive rhizosphere acidification because of greater H(+) efflux, higher H(+)-ATPase activity, and greater exudation of carboxylates than the P-inefficient genotype. Thus, a combination of morphological and physiological mechanisms contributed to the genotypic variation in the utilization of different sparingly soluble P sources in B. napus. PMID- 22227907 TI - Transient silencing mediated by in vitro synthesized double-stranded RNA indicates that PsCdc14 is required for sporangial development in a soybean root rot pathogen. AB - In many eukaryotic organisms, Cdc14 phosphatase regulates multiple biological events during anaphase and is essential for mitosis. It has been shown that Cdc14 is required for sporulation in the potato blight pathogen Phytophthora infestans; however, the role that the Cdc14 homolog (PsCdc14) plays in the soil-borne soybean root rot pathogen P. sojae remains ambiguous. PsCdc14 is highly expressed in sporulation, zoospore, and cyst life stages, but not in vegetative mycelia and infection stages, suggesting that it contributes to asexual reproduction and thus the spread of the disease. Double-stranded RNA (dsRNA) mediates gene silencing, a post-transcriptional and highly conserved process in eukaryotes, involving specific gene silencing through degradation of target mRNA. We combined in vitro dsRNA synthesis and a polyethylene glycol-mediated transformation system to construct a dsRNA-mediated transient gene silencing system; and then performed a functional analysis of PsCdc14 in P. sojae. PsCdc14 mRNA was dramatically reduced in transformants after protoplasts were exposed in in vitro synthesized PsCdc14 dsRNA, resulting in low sporangial production and abnormal development in P. sojae silencing lines. Furthermore, dsRNA-mediated transient gene silencing could enable elucidation of P. sojae rapid gene function, facilitating our understanding of the development and pathogenicity mechanisms of this oomycete fungus. PMID- 22227908 TI - A highlight of recent advances in immunology. PMID- 22227909 TI - Some research advances of immune mechanism during infection in China. PMID- 22227910 TI - A brief review on current progress in neuroscience in China. PMID- 22227911 TI - Effect of astigmatism on apparent accommodation in pseudophakic eyes. AB - PURPOSE: To investigate the factors affecting apparent accommodation in pseudophakic eyes from a clinical viewpoint and the effects of corneal and refractive astigmatism on this accommodation from an optical viewpoint. METHODS: We retrospectively examined 62 eyes of 33 patients who had undergone phacoemulsification with monofocal intraocular lens implantation. We quantitatively assessed the amplitude of apparent accommodation using an accommodometer 3 months after surgery. Multiple regression analysis was used to assess the factors affecting apparent accommodation. We also estimated the accommodation in eyes with corneal astigmatism by optical simulation. RESULTS: The mean amplitude of apparent accommodation was 1.58 = 0.65 D. Explanatory variables relevant to this accommodation were in order of influence, pupil diameter (partial regression coefficient B = 0.293, p = 0.008), and corneal multifocality (B = 0.101, p = 0.03). Other explanatory variables such as age, gender, axial length, corneal astigmatism, and refractive astigmatism showed no significant relationship with this accommodation. The estimated apparent accommodations for a 3.0 mm pupil by optical simulation were 1.25, 1.25, 1.25, 0.75, and 0 D, in eyes with corneal astigmatism of 0, 0.5, 1.0, 1.5, and 2.0 D, respectively. Similar results were obtained for a 4.0 mm pupil. CONCLUSIONS: Eyes with smaller pupil diameter and eyes with greater corneal multifocality are more predisposed to have greater apparent accommodation. However, from clinical and optical viewpoints, corneal or refractive astigmatism does not significantly contribute to apparent accommodation after cataract surgery, suggesting that it may be of less significance that the astigmatism is consciously retained in consideration of this accommodation in astigmatic eyes. PMID- 22227912 TI - Multicenter case-control study of the role of lens materials and care products on the development of corneal infiltrates. AB - PURPOSE: To evaluate the association of symptomatic soft contact lens (SCL) related corneal infiltrative events (CIEs) with SCL material, lens care products (LCPs), and other risk factors. METHODS: Cases with symptomatic CIEs were identified in a retrospective, multicenter case-control study at five academic eye care centers. Each case was matched to three controls each who had received eye care near the time of the case's last full examination at that center but were not matched for demographic or other factors. Infiltrate status was established by an expert panel who were masked to sponsor, SCL, and LCP brand. Stratified analyses were conducted removing all daily disposable (DD) and all extended wear (EW) cases. RESULTS: Clinical records from 166 patients with symptomatic CIEs and known EW status were included. Cases used >50 SCL brands and >10 LCP brands. Increased risk in univariate analysis for LCP was not significant after adjustment for other factors. In the multivariate analysis of all cases, use of reusable SCLs (4.03*; 95% C.I. 1.12 to 14.67) and EW (3.98*; 2.32 to 6.84) increased risk and patient age (per year older) was protective (0.96*; 0.94 to 0.98). Among daily wear cases (n = 102 cases), use of reusable SCLs (12.46*; 1.54 to 100.62) and silicone hydrogel (SiHy) (1.99*; 1.06 to 3.75) and age (0.95*: 0.92 to 0.97) were associated. Without DD cases (n = 162), EW (4.42*; 2.53 to 7.70), SiHy use (1.84*; 1.03 to 3.29), and patient age (0.96* 0.94 to 0.98) were significant factors. No specific SCL or LCP brands were associated with increased risk. CONCLUSIONS: In this community-based trial, younger patients were at increased risk of infiltrative events. DD lenses were protective relative to reusable lenses. Overnight use increased risk in all analyses and silicone hydrogels increased risk in daily wearers, regardless of LCP brand. Improvements in lens storage case hygiene and environment may be a mechanism for reducing risk of CIEs related to SCL use. PMID- 22227913 TI - Interpretation of health and vision utilities in low vision patients. AB - PURPOSE: The purpose of the study is to evaluate the relationship between time trade off (TTO) and standard gamble (SG) estimates of health and vision utilities in a low vision patient sample. METHODS: Telephone surveys were conducted on 74 low vision patients. All study participants were administered utility questionnaires that used the TTO and SG methods as they relate to health and vision. RESULTS: There is high between-person variability in the relationship of TTO- to SG-estimated utilities for both vision and health. However, when transformed to logits, differences between TTO and SG utilities for health are equal to differences between TTO and SG utilities for vision. These differences are symmetrically distributed around the origin. The data were consistent with a model that includes both health or vision state and personal response criteria. The model explains between-person variability in the relationship of TTO to SG utilities as idiosyncratic differences within people between response criteria for making TTO and SG judgments. CONCLUSIONS: The large between-person variability in the relation of utilities estimated from TTO to those estimated from SG can be explained by large between- and within-person variability in personal TTO and SG response criteria. However, within each person, the response criteria used to judge health state are the same as the response criteria used to judge vision state. This observation leads to the conclusion that health and vision states are in the same units when estimated from utilities. A meta analysis of published studies that compared TTO with SG utilities for different health states confirms the conclusion of the model that average utilities across people are criterion-free estimates of average health-related states on a common logit scale. PMID- 22227914 TI - Corneal and crystalline lens dimensions before and after myopia onset. AB - PURPOSE: To describe corneal and crystalline lens dimensions before, during, and after myopia onset compared with age-matched emmetropic values. METHODS: Subjects were 732 children aged 6 to 14 years who became myopic and 596 emmetropic children participating between 1989 and 2007 in the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error Study. Refractive error was measured using cycloplegic autorefraction, corneal power using a hand-held autokeratometer, crystalline lens parameters using video-based phakometry, and vitreous chamber depth (VCD) using A-scan ultrasonography. Corneal and crystalline lens parameters in children who became myopic were compared with age , gender-, and ethnicity-matched model estimates of emmetrope values annually from 5 years before through 5 years after the onset of myopia. The comparison was made without and then with statistical adjustment of emmetrope component values to compensate for the effects of longer VCDs in children who became myopic. RESULTS: Before myopia onset, the crystalline lens thinned, flattened, and lost power at similar rates for emmetropes and children who became myopic. The crystalline lens stopped thinning, flattening, and losing power within +/-1 year of onset in children who became myopic compared with emmetropes statistically adjusted to match the longer VCDs of children who became myopic. In contrast, the cornea was only slightly steeper in children who became myopic compared with emmetropes (<0.25 D) and underwent little change across visits. CONCLUSIONS: Myopia onset is characterized by an abrupt loss of compensatory changes in the crystalline lens that continue in emmetropes throughout childhood axial elongation. The mechanism responsible for this decoupling remains speculative but might include restricted equatorial growth from internal mechanical factors. PMID- 22227915 TI - Effect of simulated astigmatic refractive error on reading performance in the young. AB - PURPOSE: Few studies have specifically investigated the functional effects of uncorrected astigmatism on measures of reading fluency. This information is important to provide evidence for the development of clinical guidelines for the correction of astigmatism. METHODS: Participants included 30 visually normal, young adults (mean age, 21.7 +/- 3.4 years). Distance and near visual acuity and reading fluency were assessed with optimal spectacle correction (baseline) and for two levels of astigmatism, 1.00 diopter cylinder (DC) and 2.00 DC, at two axes (90 and 180 degrees ) to induce both against-the-rule (ATR) and with-the rule (WTR) astigmatism. Reading and eye movement fluency were assessed using standardized clinical measures including the test of Discrete Reading Rate (DRR), the Developmental Eye Movement test (DEM), and by recording eye movement patterns with the Visagraph (III) during reading for comprehension. RESULTS: Both distance and near acuity were significantly decreased compared with baseline for all the astigmatic lens conditions (p < 0.001). Reading speed with the DRR for N16 print size was significantly reduced for the 2.00 DC ATR condition (a reduction of 10%), whereas for smaller text sizes, reading speed was reduced by up to 24% for the 1.00 DC ATR and 2.00 DC condition in both axis directions (p < 0.05). For the DEM, subtest completion speeds were significantly impaired, with the 2.00 DC condition affecting both vertical and horizontal times and the 1.00 DC ATR condition affecting only horizontal times (p < 0.05). Visagraph reading eye movements were not significantly affected by the induced astigmatism. CONCLUSIONS: Induced astigmatism impaired performance on selected tests of reading fluency, with ATR astigmatism having significantly greater effects on performance than did WTR, even for relatively small amounts of astigmatic blur of 1.00 DC. These findings have implications for the minimal prescribing criteria for astigmatic refractive errors. PMID- 22227916 TI - The effects of an unexpected spider stimulus on skin conductance responses and eye movements: an inattentional blindness study. AB - Are spiders evolutionarily relevant threat cues that capture attention automatically and preattentively-also in non-fearful persons? Previous studies concerning this question did not examine responses to unexpected spider stimuli, although this is an ecologically valid situation. Therefore, we conducted an inattentional blindness (IB) experiment. While unselected participants (N = 120) were focusing their attention on a visual discrimination task, suddenly a spider or a flower image appeared. The rates of reported detection were not enhanced for spider images, and fear of spiders had no moderating influence on IB rates. However, spider pictures in general elicited greater skin conductance responses than flower pictures, and this difference was also observed for pictures that were not reported afterward. Moreover, eye movement data revealed that the spider stimulus was initially fixated more often than the flower stimulus. In sum, our findings imply that enhanced reactions to unexpected spider images are independent of fear level and include early engagement processes. Awareness of a spider picture does not seem to be a prerequisite for elevated arousal. PMID- 22227917 TI - Influence of atorvastatin on the pharmacodynamic and pharmacokinetic activity of repaglinide in rats and rabbits. AB - Dyslipidemia is common in patients with type 2 diabetes. Statins are used as the first choice in treatment of diabetic dyslipidemia. Atorvastatin represents a first-line treatment option, alongside other hydroxyl methylglutaryl coenzyme A reductase inhibitors. Repaglinide is a short-acting, oral, insulin secretagogue that is used in the treatment of type 2 diabetes mellitus. Both the category of drugs undergo extensive metabolism with cytochrome enzyme system. This may lead to drug-drug interaction problems with altered repaglinide activity which is cautious. Repaglinide/atorvastatin/atorvastatin + repaglinide were administered orally to normal, diabetic rats, and to normal rabbits. Blood samples were collected at different time intervals and were analyzed for blood glucose by GOD POD method using commercial glucose kits and repaglinide estimation in plasma by HPLC method. Diabetes was induced by alloxan 100 mg/kg body weight administered by I.P route. In the presence of atorvastatin, repaglinide activity was increased and maintained for longer period in diabetic rats compared with repaglinide matching control. The present study concludes co-administration of atorvastatin was found to improve repaglinide responses significantly in diabetic rats and improved glucose metabolism of atorvastatin played an important role and increased repaglinide levels by competitive CYP 3A4 enzyme inhibition by atorvastatin could be added advantage for anti hyperglycemic activity. PMID- 22227918 TI - iTRAQ-coupled 2D LC-MS/MS analysis on differentially expressed proteins in denervated tibialis anterior muscle of Rattus norvegicus. AB - To understand the molecular aspects of denervation-induced atrophy of skeletal muscles, isobaric tags for relative and absolute quantitation (iTRAQ) coupled with two-dimensional liquid chromatography-tandem mass spectrometry were performed to detect a total of 260 proteins that were differentially expressed in the rat tibialis anterior muscle at different times (1, 4, and 8 weeks) after rat sciatic nerve transection. Western blot, gene ontology, and Kyoto Encyclopedia of Genes and Genomes analyses were further conducted for protein validation, functional annotation, and pathway identification, respectively. Among 260 dysregulated proteins, metabolic enzymes represented the largest class of proteins differentially expressed; a down-regulation of beta-enolase might be associated with a decreased expression of fast-twitch myosin-4; the 14-3-3 proteins displayed an up-regulation, which might facilitate the inhibition of mTOR signaling; an up-regulation of alpha-crystallin B chain might be related to the later onset and the slower progress of atrophy; an up-regulation of phosphatidylethanolamine-binding protein-1 perhaps progressively abrogated the cell survival and antiapoptotic properties during muscle atrophy. These results might contribute to the understanding of molecular mechanisms regulating denervation-induced muscle atrophy. PMID- 22227919 TI - Nuclear-mitochondrial cross-talk in global myocardial ischemia. A time-course analysis. AB - Myocardial ischemia results in early and progressive damage to mitochondrial structure and function, but the molecular events leading to these changes have not been clearly established. We hypothesized that mitochondrial dysfunction and a coordinated expression of nuclear and mitochondrial genes occur in a time dependent manner by relating the time courses of changes in parameters of mitochondrial bioenergetics after ischemia-reperfusion. Using a Langendorff rat heart model, mitochondrial bioenergetics and protein levels were assessed at different times of ischemia and ischemia/reperfusion. Mitochondrial and nuclear gene expression (super array analysis) and mitochondrial DNA levels were evaluated after late ischemia. Ischemia induced progressive and marked decreases in complex I, III, and V activities. Reperfusion (15, 30, and 60 min) after 45 min of ischemia had little further effect on enzyme activities or respiration. Super array analysis after 45 min ischemia revealed increased levels of the proteins with more pronounced increases in the corresponding mRNAs. Expression of mitochondrial and nuclear genes involved in oxidative phosphorylation increased after 45 min of ischemia but not after reperfusion. Myocardial ischemia induces mitochondrial dysfunction and differential but coordinated expression of nuclear and mitochondrial genes in a time-dependent manner. Our observations are pertinent to the search for molecular stimuli that generate mitochondrial defects and alter mitochondrial and nuclear transcriptional responses that may impact ischemic preconditioning and cardioprotection. PMID- 22227921 TI - Risk of subsequent primary thyroid cancer after another malignancy: latency trends in a population-based study. AB - PURPOSE: To evaluate the risk of a subsequent primary thyroid cancer (SPTC) in patients with common invasive cancers, with attention to latency trends and histology associations. METHODS: Patients with one of 10 common invasive cancers were followed from 1975 to 2008 in 9 registries participating in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. Standardized incidence ratios (SIRs) for SPTC were determined by the multiple primary-SIR program in SEER*Stat. RESULTS: A total of 2502 SPTCs were observed. Greatly elevated SIRs for SPTC were noted for 9 of 10 evaluated cancers in the 12 months after initial diagnosis. The SIRs remained elevated 12-59 months after diagnosis for all cancers except leukemia, uterine, and bladder cancers. Increased risks persisted 60-119 months beyond diagnosis for renal (SIR 2.56) and breast cancer (SIR 1.16); and 120+ months for renal cancer (SIR 2.46). Increased SPTC risk after renal and female breast cancers was mostly seen in nonirradiated patients. The principal histology association was between papillary thyroid cancer and renal cell carcinomas. CONCLUSIONS: Many common cancers are associated with increased risk of SPTC beyond 12 months of initial diagnosis. Although this can be explained partly by continued surveillance bias, radiation effects, and known rare familial associations for some tumors, these factors alone are unlikely to explain the persistent, significant two-way association with renal and breast cancers. Additional research is needed to further define the biological and environmental mechanisms underlying these associations. PMID- 22227922 TI - Accuracy of predicting axillary lymph node positivity by physical examination, mammography, ultrasonography, and magnetic resonance imaging. AB - BACKGROUND: Axillary lymph node status continues to be among the most important prognostic variables regarding breast cancer survival. We were interested in our ability to accurately predict axillary nodal involvement by using physical examination and standard breast imaging studies in combination. METHODS: A retrospective review was performed of 244 consecutive patients diagnosed with invasive breast carcinoma between May 2008 and December 2010 who underwent physical examination of the axilla, digital mammography, axillary ultrasonography, and contrast-enhanced breast magnetic resonance imaging and who had subsequent histopathologic evaluation of one or more axillary lymph nodes. RESULTS: A total of 62 (25%) of 244 women were found to have positive axillary lymph nodes on final histopathologic examination, 42% of whom were able to be identified preoperatively. The sensitivity for predicting axillary metastasis if any one or more examination modalities were suspicious was 56.5%. The specificity for predicting axillary metastasis if any three or more modalities were suspicious was 100%. Of the patients who had all four modalities negative, 14% were ultimately found to have histologically positive nodes at the time of surgery. CONCLUSIONS: Physical examination and multimodal imaging in combination are useful for preoperative axillary staging and treatment planning. However, they remain inadequate definitive predictors of axillary lymph node involvement. PMID- 22227923 TI - Regulation of somatic growth and gene expression of the GH-IGF system and PRP PACAP by dietary lipid level in early juveniles of a teleost fish, the pejerrey (Odontesthes bonariensis). AB - Growth and mRNA levels of the pituitary adenylate cyclase-activating polypeptide (PACAP) and its related peptide (PRP), and the system controlled by the growth hormone (GH) and insulin-like growth factors (IGFs) were analyzed in pejerrey fry fed with graded levels of dietary lipids: 10% (L10), 13% (L13) and 21% (L21). First, the full sequence of pejerrey PRP-PACAP was obtained by RT-PCR, using primers based on conserved fragments of teleosts PACAP sequences. The growth of the fish at 83 days after hatching (dah) and the GH mRNA levels were not significantly affected by the dietary treatment. Conversely, PRP-PACAP expression significantly decreased with increasing dietary lipids (L10 > L21). While GH receptor (GHR)-I and IGF-I transcripts did not differ among groups, GHR-II transcripts decreased in group L21. IGF-II expression apparently followed the same trend. These results in combination with the lower expression of the anorexigenic PRP-PACAP in fish fed diet L21 and the correlation analysis evidencing a particularly fine tuning of the GH-IGF system in group L13, suggest that this diet may cover the energy demands for growing pejerrey from 27 dah onwards. Our results show for first time in fish a differential response of PRP PACAP transcripts to dietary manipulations, and confirm the sensitivity of the pejerrey GH-IGF system to changes in diet composition despite the lack of (or in advance to) a clear response of somatic growth. PMID- 22227924 TI - Benefits of thermal acclimation in a tropical aquatic ectotherm, the Arafura filesnake, Acrochordus arafurae. AB - The presumption that organisms benefit from thermal acclimation has been widely debated in the literature. The ability to thermally acclimate to offset temperature effects on physiological function is prevalent in ectotherms that are unable to thermoregulate year-round to maintain performance. In this study we examined the physiological and behavioural consequences of long-term exposure to different water temperatures in the aquatic snake Acrochordus arafurae. We hypothesised that long dives would benefit this species by reducing the likelihood of avian predation. To achieve longer dives at high temperatures, we predicted that thermal acclimation of A. arafurae would reduce metabolic rate and increase use of aquatic respiration. Acrochordus arafurae were held at 24 or 32 degrees C for 3 months before dive duration and physiological factors were assessed (at both 24 and 32 degrees C). Although filesnakes demonstrated thermal acclimation of metabolic rate, use of aquatic respiration was thermally independent and did not acclimate. Mean dive duration did not differ between the acclimation groups at either temperature; however, warm-acclimated animals increased maximum and modal dive duration, demonstrating a longer dive duration capacity. Our study established that A. arafurae is capable of thermal acclimation and this confers a benefit to the diving abilities of this snake. PMID- 22227926 TI - Inexorable spread: inexorable death? The fate of neo-XY chromosomes of grasshoppers. PMID- 22227927 TI - Domain combination of the vertebrate-like TLR gene family: implications for their origin and evolution. AB - Domain shuffling, which is an important mechanism in the evolution of multi domain proteins, has shaped the evolutionary development of the immune system in animals. Toll and Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate and adaptive immune systems. Draft genome sequences provide the opportunity to compare the Toll/TLR gene repertoire among representative metazoans. In this study, we investigated the combination of Toll/interleukin-1 receptor (TIR) and leucine-rich repeat (LRR) domains of metazoan Toll/TLRs. Before Toll with both domains occurred in Cnidaria (sea anemone, Nematostella vectensis), through domain combinations, TIR-only and LRR only proteins had already appeared in sponges (Amphimedon queenslandica). Although vertebrate-like TIR (V-TIR) domain already appeared in Cnidaria, the vertebrate-like TLR (V-TLR) with both domains appeared much later. The first combination between V-TIR domain and vertebrate-like LRR (V-LRR) domain for V-TLR may have occurred after the divergence of Cnidaria and bilateria. Then, another combination for V-TLR, a recombination of both domains, possibly occurred before or during the evolution of primitive vertebrates. Taken together, two rounds of domain combinations may thus have co-shaped the vertebrate TLRs. PMID- 22227928 TI - Wheat kernel dimensions: how do they contribute to kernel weight at an individual QTL level? AB - Kernel dimensions (KD) contribute greatly to thousand-kernel weight (TKW) in wheat. In the present study, quantitative trait loci (QTL) for TKW, kernel length (KL), kernel width (KW) and kernel diameter ratio (KDR) were detected by both conditional and unconditional QTL mapping methods. Two related F(8:9) recombinant inbred line (RIL) populations, comprising 485 and 229 lines, respectively, were used in this study, and the trait phenotypes were evaluated in four environments. Unconditional QTL mapping analysis detected 77 additive QTL for four traits in two populations. Of these, 24 QTL were verified in at least three trials, and five of them were major QTL, thus being of great value for marker assisted selection in breeding programmes. Conditional QTL mapping analysis, compared with unconditional QTL mapping analysis, resulted in reduction in the number of QTL for TKW due to the elimination of TKW variations caused by its conditional traits; based on which we first dissected genetic control system involved in the synthetic process between TKW and KD at an individual QTL level. Results indicated that, at the QTL level, KW had the strongest influence on TKW, followed by KL, and KDR had the lowest level contribution to TKW. In addition, the present study proved that it is not all-inclusive to determine genetic relationships of a pairwise QTL for two related/causal traits based on whether they were co-located. Thus, conditional QTL mapping method should be used to evaluate possible genetic relationships of two related/causal traits. PMID- 22227929 TI - Mating with large males decreases the immune defence of females in Drosophila melanogaster. AB - Mating has been widely reported to be a costly event for females. Studies indicate that female cost of mating in terms of fecundity and survivorship can be affected by their mates, leading to antagonistic coevolution between the sexes. However, as of now, there is no evidence that the female cost of mating in terms of immune defence is affected by their mates. We assess the effect of different sized males on antibacterial immune defence and reproductive fitness of their mates. We used a large outbred population of Drososphila melanogaster as the host and Serratia marcescens as the pathogen. We generated three different male phenotypes: small, medium and large, by manipulating larval densities. Compared to females mating with small males, those mating with large males had higher bacterial loads and lower fecundity. There was no significant effect of male phenotype on the fraction of females mated or copulation duration (an indicator of ejaculate investment). Thus, our study is the first clear demonstration that male phenotype can affect the cost of mating to females in terms of their antibacterial immune defence. Mating with large males imposes an additional cost of mating to females in terms of reduced immune defence. The observed results are very likely due to qualitative/quantitative differences in the ejaculates of the three different types of males. If the phenotypic variation that we observed in males in our study is mirrored by genetic variation, then, it can potentially lead to antagonistic coevolution of the sexes over immune defence. PMID- 22227930 TI - Eight paths of ERK1/2 signalling pathway regulating hepatocyte proliferation in rat liver regeneration. AB - Although it is known that hormones, growth factors and integrin promote hepatocyte proliferation in liver regeneration (LR) through ERK1/2 signalling pathway, reports about regulating processes of its intracellular paths in hepatocytes of LR are limited. This study aims at exploring which paths of ERK1/2 signalling pathway participate in the regulation of rat LR, especially in hepatocyte proliferation, and how they do so. In all, 14 paths and 165 genes are known to be involved in ERK1/2 signalling pathway. Of them, 161 genes are included in Rat Genome 230 2.0 Array. This array was used to detect expression changes of genes related to ERK1/2 signalling pathway in isolated hepatocytes of rat LR, showing that 60 genes were related to hepatocytes of LR. In addition, bioinformatics and systems biology methods were used to analyse the roles of 14 above paths in regenerating hepatocytes. We found that three paths, RTK->SHC >GRB2/SOS->RAS->RAF, IntegrinBeta->FAK->RAC->PAK->RAF and GBetagamma >PI3KBetagamma->RAC->PAK->RAF, promoted the G1 phase progression of hepatocytes by activating ERK1/2. A further four paths, Gq->PLCBeta->PKC->SRC/PYK2->GRB2/SOS >RAS->RAF, RTK->PLCgamma->PKC->SRC/PYK2->GRB2/SOS->RAS->RAF, IntegrinBeta >FAK/SRC->GRB2/SOS->RAS->RAF and IntegrinBeta->FAK->RAC->PAK->RAF, advanced the cell progression of S phase and G(2)/M checkpoint by activating ERK1/2, and so did PP1/2->Mek1/2 by decreasing the negative influence on ERK1/2. At the late phase of LR, Galphas->AC->EPAC->Rap1->Raf blocked hepatocyte proliferation by decreasing the activity of ERK1/2 and so did PP1/2->Mek1/2. In summary, 60 genes and 8 paths of ERK1/2 signalling pathway regulated hepatocyte proliferation in rat LR. PMID- 22227931 TI - Male-limited evolution suggests no extant intralocus sexual conflict over the sexually dimorphic cuticular hydrocarbons of Drosophila melanogaster. AB - Sexually dimorphic traits are likely to have evolved through sexually antagonistic selection. However, recent empirical data suggest that intralocus sexual conflict often persists, even when traits have diverged between males and females. This implies that evolved dimorphism is often incomplete in resolving intralocus conflict, providing a mechanism for the maintenance of genetic variance in fitness-related traits. We used experimental evolution in Drosophila melanogaster to directly test for ongoing conflict over a suite of sexually dimorphic cuticular hydrocarbons (CHCs) that are likely targets of sex-specific selection. Using a set of experimental populations in which the transmission of genetic material had been restricted to males for 82 generations, we show that CHCs did not evolve, providing experimental evidence for the absence of current intralocus sexual conflict over these traits. The absence of ongoing conflict could indicate that CHCs have never been the target of sexually antagonistic selection, although this would require the existing dimorphism to have evolved via completely sexlinked mutations or as a result of former, but now absent, pleiotropic effects of the underlying loci on another trait under sexually antagonistic selection. An alternative interpretation, and which we believe to be more likely, is that the extensive CHC sexual dimorphism is the result of past intralocus sexual conflict that has been fully resolved, implying that these traits have evolved genetic independence between the sexes and that genetic variation in them is therefore maintained by alternative mechanisms. This latter interpretation is consistent with the known roles of CHCs in sexual communication in this species and with previous studies suggesting the genetic independence of CHCs between males and females. Nevertheless, direct estimates of sexually antagonistic selection will be important to fully resolve these alternatives. PMID- 22227932 TI - The effect of genotyping errors on the robustness of composite linkage disequilibrium measures. AB - We conclude that composite linkage disequilibrium (LD) measures be adopted in population-based LD mapping or association mapping studies since it is unaffected by Hardy-Weinberg disequilibrium. Although some properties of composite LD measures have been recently studied, the effects of genotyping errors on composite LD measures have not been examined. In this report, we derived deterministic formulas to evaluate the impact of genotyping errors on the composite LD measures Delta'AB and rAB, and compared the robustness of Delta'AB and rAB in the presence of genotyping errors. The results showed that Delta'AB and rAB depend on the allele frequencies and the assumed error model, and show varying degrees of robustness in the presence of errors. In general, whether there is HWD or not, rAB is more robust than Delta'AB except some special cases and the difference of robustness between Delta'AB and rAB becomes less severe as the difference between the frequencies of two SNP alleles A and B becomes smaller. PMID- 22227933 TI - Timing of gene expression from different genetic systems in shaping leucine and isoleucine contents of rapeseed (Brassica napus L.) meal. AB - Experiments were conducted on rapeseed (Brassica napus L.) using a diallel design with nine parents: Youcai 601, Double 20-4, Huashuang 3, Gaoyou 605, Zhongyou 821, Eyouchangjia, Zhong R-888, Tower and Zheshuang 72. The seed developmental process was divided into five stages, namely initial (days 1-15 after flowering), early (days 16-22 after flowering), middle (days 23-29), late (days 30-36), and maturing (days 37-43) developmental stages. The variation of dynamic genetic effects for leucine and isoleucine contents of rapeseed meal was analysed at five developmental stages, across different environments using the genetic models with time-dependent measures. The results from unconditional and conditional analyses indicated that the expression of diploid embryo, cytoplasmic and diploid maternal plant genes were important for leucine and isoleucine contents at different developmental stages of rapeseed, particularly at the initial and early developmental stages. Among different genetic systems, nutrition quality traits were mainly controlled by the accumulative or net maternal main effects and their GE interaction effects, except at maturity when the net diploid embryo effects were larger. The expression of genes was affected by the environmental conditions on 15, 22, 29 or 36 days after flowering, but was more stable at mature stage. For the isoleucine content the narrow-sense heritabilities on 15, 22, 29, 36, and 43 days after flowering were 43.0, 65.7, 60.1, 65.5 and 78.2%, respectively, while for the leucine content the corresponding narrow-sense heritabilities were relatively smaller. The interaction heritabilities were more important than the general heritabilities at the first three developmental times. The improvement for isoleucine content could be achieved by selection based on the higher narrow sense heritabilities. Various genetic systems exhibited genetic correlations among the developmental times or leucine and isoleucine contents. A simultaneous improvement of leucine and isoleucine contents seems possible because of the significant positive genetic correlation components from different genetic systems at different developmental times. PMID- 22227934 TI - Differential expression of PARP1 mRNA in leucocytes of patients with Down's syndrome. PMID- 22227935 TI - Molecular and clinical characterization of a small duplication Xp in a human female with psychiatric disorders. PMID- 22227936 TI - Major genes with additive effects for seed size in kabuli chickpea (Cicer arietinum L.). PMID- 22227938 TI - Inheritance of deficient tocopherol accumulation in sunflower seeds. PMID- 22227937 TI - A novel POLH gene mutation in a xeroderma pigmentosum-V Tunisian patient: phenotype-genotype correlation. PMID- 22227939 TI - Determination of gene action for some biometrical traits in Lens culinaris Medik. under mid-hill conditions of northwestern Himalayas. PMID- 22227940 TI - Positive association between NTNG1 and schizophrenia in Chinese Han population. PMID- 22227941 TI - Evaluation of suitable reference genes for gene expression studies in Lycoris longituba. PMID- 22227942 TI - Molecular subgrouping of Wolbachia and bacteriophage WO infection among some Indian Drosophila species. PMID- 22227945 TI - Lytic peptides with improved stability and selectivity designed for cancer treatment. AB - Lytic peptides are a group of membrane-acting peptides, which have excellent activity to drug-resistant cells. In this study, the stability and tumor selectivity of newly designed pH-activated lytic peptides were studied. We found that despite varied secondary structures, pH-induced structure changes could not be directly linked to the activity and pH sensitivity of peptides. On the contrary, formation of aggregates had great impacts on peptide binding and insertion into the lipid bilayer of cell membrane. It was found that the pH controlled peptide aggregation and dissolution was responsible for the pH dependent membrane lysis activity of peptides. One peptide (PTP-7c) formed stable amyloid fibrils, which did not completely dissolve under acidic conditions. As a result, PTP-7c had the lowest membrane lysis and cell killing activities among tested lytic peptides. As solid tumors have consistently low extracellular pHs, peptides with acid-activation features showed improved selectivity to cancer cells. In addition, self-assembled lytic peptides were found to become more stable and showed dramatically increased half lives (up to 11 h) in human plasma. These new lytic peptides with good stability and acid-activated cell lysis activity will have wide biomedical applications especially for the treatment of cancers in which drug resistance has developed. PMID- 22227946 TI - Emotional distraction unbalances visual processing. AB - Brain mechanisms used to control nonemotional aspects of cognition may be distinct from those regulating responses to emotional stimuli, with activity of the latter being detrimental to the former. Previous studies have shown that suppression of irrelevant emotional stimuli produces a largely right-lateralized pattern of frontal brain activation, thus predicting that emotional stimuli may invoke temporary, lateralized costs to performance on nonemotional cognitive tasks. To test this, we briefly (85 ms) presented a central, irrelevant, expressive (angry, happy, sad, or fearful) or neutral face 100 ms prior to a letter search task. The presentation of emotional versus neutral faces slowed subsequent search for targets appearing in the left, but not the right, hemifield, supporting the notion of a right-lateralized, emotional response mechanism that competes for control with nonemotional cognitive processes. Presentation of neutral, scrambled, or inverted neutral faces produced no such laterality effects on visual search response times. PMID- 22227947 TI - Nothing concentrates the mind: thoughts of death improve recall. AB - It seems likely that awareness of one's mortality is in some respects advantageous (e.g., because it helps individuals forestall death), but little research has explored the psychological mechanisms that might confer such an advantage. Recent research has shown that processing stimuli in terms of survival relevance enhances memory relative to a host of deep-processing conditions, so it is plausible that human memory has been selected to operate more efficiently when death thoughts (e.g., survival concerns) are activated. If so, then the mortality salience as a general psychological state should be sufficient to increase recall; the present experiments show this to be the case. The enhancing effect of mortality salience on recall occurred for both incidental and intentional learning tasks, relative to a variety of comparison conditions, and did not appear to be mediated by affect or arousal. Follow-up analyses revealed the effect to be mediated by the complexity of participants' elaborations about mortality. Potential theoretical implications are discussed. PMID- 22227948 TI - The effect of rice straw incorporation into paddy soil on carbon sequestration and emissions in the double cropping rice system. AB - BACKGROUND: Soil organic carbon (SOC) sequestration, methane emission, and the net carbon sink represented by rice straw incorporated into soil (RIS) were studied using long-term experimentation with rice straw incorporated into soil (LRIS) and short-term experimentation with different patterns of rice straw incorporated into soil (SPRIS). RESULTS: Soil organic carbon could be improved by RIS combined with soil ploughing. The increased rate of SOC deposition per cultivated layer was 0.10 t C ha(-1) for 2.625 t ha(-1) straw incorporated each season in LRIS and 0.36 t C ha(-1) for 4.5 t straw ha(-1) season(-1) incorporated in SPRIS; the apparent SOC conversion by rice straw (stubble) was reduced as the amount of incorporated straw increased. However, RIS methane emission from paddy fields also significantly exacerbated the CH(4) emission flux observed during the early and late rice growing seasons, which was increased by 75.0% (P < 0.01) and 251.5% (P < 0.01), respectively, compared with combined application of nitrogen, phosphorus and potassium fertiliser (NPK). The apparent methane conversion of straw was almost uniform with a similar rice yield and soil cultivating mode. Among the patterns of RIS, methane emission was significantly reduced under straw covering untilled land, and this property led to the lowest apparent methane conversion. CONCLUSION: RIS with ploughing and tilling resulted in negative carbon sequestration because of increased methane emissions. A combined NPK application with only rice stubble incorporation may be sustainable for a higher rice yield, but this approach has a reduced rate of negative carbon sequestration in the paddy field. Straw covering with no tillage was the best measure to realise high yield and low carbon emission for RIS. PMID- 22227949 TI - Biophysical Neural Spiking, Bursting, and Excitability Dynamics in Reconfigurable Analog VLSI. AB - We study a range of neural dynamics under variations in biophysical parameters underlying extended Morris-Lecar and Hodgkin-Huxley models in three gating variables. The extended models are implemented in NeuroDyn, a four neuron, twelve synapse continuous-time analog VLSI programmable neural emulation platform with generalized channel kinetics and biophysical membrane dynamics. The dynamics exhibit a wide range of time scales extending beyond 100 ms neglected in typical silicon models of tonic spiking neurons. Circuit simulations and measurements show transition from tonic spiking to tonic bursting dynamics through variation of a single conductance parameter governing calcium recovery. We similarly demonstrate transition from graded to all-or-none neural excitability in the onset of spiking dynamics through the variation of channel kinetic parameters governing the speed of potassium activation. Other combinations of variations in conductance and channel kinetic parameters give rise to phasic spiking and spike frequency adaptation dynamics. The NeuroDyn chip consumes 1.29 mW and occupies 3 mm * 3 mm in 0.5 MUm CMOS, supporting emerging developments in neuromorphic silicon-neuron interfaces. PMID- 22227950 TI - Cellular accumulation and DNA interaction studies of cytotoxic trans-platinum anticancer compounds. AB - Forty years after the discovery of the anticancer effects of cisplatin, scientists are still pursuing the development of platinum complexes with improved properties regarding side effects and resistance, which are two main problems in cisplatin treatment. Among these compounds, trans-configured platinum complexes with oxime ligands emerged as a new class with features distinct from those of established anticancer agents, including different DNA binding behavior, increased cellular accumulation, and a different pattern of protein interaction. We report herein on the reactivity with biomolecules of three novel pairs of cis- and trans-configured acetone oxime platinum(II) complexes and one pair of 3 pentanone oxime platinum(II) complexes. Cellular accumulation experiments and in vitro DNA platination studies were performed and platinum contents were determined by inductively coupled plasma mass spectrometry. The trans-configured complexes were accumulated in SW480 cells in up to 100 times higher amounts than cisplatin and up to 50 times higher amounts than their cis-configured counterparts; r (b) values (number of platinum atoms per nucleotide) were more than tenfold increased in cells treated with trans complexes compared with cells treated with cisplatin. The interaction of the complexes with DNA was studied in cell-free experiments with plasmid DNA (pUC19), in capillary zone electrophoresis with the DNA model 2-deoxyguanosine 5'-monophosphate, and in in vitro experiments showing the degree of DNA damage in the comet assay. Whereas incubation with cis compounds did not induce degradation of DNA, the trans complexes led to pronounced strand cleavage. PMID- 22227951 TI - Visible light-responsive micelles formed from dialkoxyanthracene-containing block copolymers. AB - A class of dialkoxyanthracene-containing diblock copolymers is synthesized which possesses visible light-responsivity. These copolymers can self-assemble into a micellar structure in water. Green visible light (540 nm) is able to scissor these anthracene species and cleave the diblock copolymer into two fragments, inducing disassembly of the self-assembled micelles. PMID- 22227952 TI - Structural, odd-even chain alternation and thermal investigation of a homologous series of anhydrous silver(I) n-alkanoates. AB - Molecular and lattice structures of a homologous series (n(c) = 8-20, inclusive) of silver (I) n-alkanoates are determined from X-ray Powder Diffraction, Solid State spin decoupled (13)C-NMR and variable temperature Fourier Transform Infrared Spectroscopies. The compounds crystallize in a monoclinic crystal system with hydrocarbon chains in the fully extended all-trans conformation. Moreover, the chains are tilted ca. 75 degrees with respect to the metal basal plane and are arranged as methyl(tail)-to-methyl(tail) bilayers within a lamellar. The methyl chain ends, from different layers in the bilayer, do not overlap but are in such close proximity to cause methyl-methyl interactions. In a molecule, two carboxylate groups bind in a syn-syn type bridging bidentate mode to two silver atoms to form an eight-membered structure. Intramolecular silver-silver and intermolecular Ag-O-Ag interactions stabilize the head group and promote the formation of layer type polymeric sheets. Though the compounds are nearly isostructural, odd-even chain alternation is observed in density, anti-symmetric stretching vibrations of methyl and unusually, carboxylate (head) groups, as a result of packing differences of hydrocarbon chains within the crystal lattice. These arise from the relative vertical distances between polymeric sheets, which are not in the same plane. Thus, for odd chain length compounds, where those distances are less than for even chains, more ordered packing and hence higher densities are observed for these adducts. Also, the numbers and natures of the thermotropic phase transitions are chain length dependent and irreversible. PMID- 22227954 TI - Describing the epidemiology of rheumatic diseases: methodological aspects. AB - PURPOSE: Producing descriptive epidemiology data is essential to understand the burden of rheumatic diseases (prevalence) and their dynamic in the population (incidence). IMPORTANT CONSIDERATIONS: No matter how simple such indicators may look, the correct collection of data and the appropriate interpretation of the results face several challenges: distinguishing indicators, facing the costs of obtaining data, using appropriate definition, identifying optimal sources of data, choosing among many survey methods, dealing with estimates precision, and standardizing results. SUMMARY: This study describes the underlying methodological difficulties to be overcome so as to make descriptive indicators reliable and interpretable. PMID- 22227953 TI - Blood lipid levels, lipid-lowering medications, and the incidence of atrial fibrillation: the atherosclerosis risk in communities study. AB - BACKGROUND: Several cardiovascular risk factors have been associated with the risk of atrial fibrillation (AF). Limited and inconsistent evidence exists on the association of blood lipid levels and lipid-lowering medication use with AF risk. METHODS AND RESULTS: We analyzed 13 969 participants (25% African American, 45% men) free of AF at baseline from the Atherosclerosis Risk in Communities study. Fasting high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), triglycerides, and total cholesterol were measured at baseline (1987-1989) and each of 3 follow-up visits. The incidence of AF was ascertained through 2007. The association of the use of statins and other lipid lowering medications with AF was estimated in 13 044 Atherosclerosis Risk in Communities participants attending visit 2 (1990-1992), adjusting for covariates from the previous visit. During a median follow-up of 18.7 years, there were 1433 incident AF cases. Multivariable hazard ratios (HRs) and 95% CIs of AF associated with a 1-SD increase in lipid levels were as follows: HDLc, 0.97 (0.91-1.04); LDLc, 0.90 (0.85-0.96); total cholesterol, 0.89 (0.84-0.95); and triglycerides, 1.00 (0.96-1.04). Participants taking lipid-lowering medications had an adjusted HR (95% CI) of AF of 0.96 (0.82-1.13) compared with those not taking medications, whereas those taking statins had an adjusted HR of 0.91 (0.66-1.25) compared with those taking other lipid-lowering medications. CONCLUSIONS: Higher levels of LDLc and total cholesterol were associated with a lower incidence of AF. However, HDLc and triglycerides were not independently associated with AF incidence. No association was found between the use of lipid-lowering medications and incident AF. PMID- 22227955 TI - Soft tissue and subcutaneous calcification in connective tissue diseases. AB - PURPOSE OF REVIEW: Calcinosis is a recognized manifestation of many connective tissue diseases, especially juvenile dermatomyositis (JDM) and systemic sclerosis; however, little is known about the pathogenesis and the treatment of this condition. The purpose of this review is to discuss the most recently published data about calcinosis in connective-tissue diseases with emphasis on the pathogenesis and its treatment. RECENT FINDINGS: Calcinosis is more common in patients with sustained disease-activity and longer disease duration. JDM patients with anti-p140 antibodies and tumour necrosis factor (TNF) alpha-308AA allele are at an increased risk. Low levels of the calcium-regulating proteins, fetuin-A and osteopontin, have been found in the serum of patients with JDM. Macrophages and cytokines interleukin (IL) 6, IL-1beta and TNFalpha isolated from the calcific tissues in JDM have also been implicated in the pathologic process. Raised tissue expression of advanced glycation end products and their receptor has been noted in patients with systemic sclerosis and systemic lupus erythematosus with calcinosis. SUMMARY: Many agents have been used for treatment of calcinosis but none has been accepted as a standard therapy. Case studies have shown that aggressive treatment of the underling inflammatory condition with intravenous immunoglobulin, anti TNF agents, thalidomide and haematopoietic stem cell transplantation has also led to improvement of the calcinosis. Aggressive management of the underlying inflammatory condition should help in treating as well as decreasing the incidence of calcinosis. Some case studies have focused on agents such as warfarin, bisphosphonates, diltiazem and others, which are primarily aimed at treating the process of calcinosis with varying success. PMID- 22227956 TI - Application of thrombelastography in liver injury induced by endotoxin in rat. AB - Liver injury developing in patients with sepsis may lead to an increased risk of mortality. Thrombelastography (TEG) is generally applied to evaluate hemostatic disturbance in patients undergoing liver transplantation or cardiopulmonary bypass. The aim of this study was to investigate the development of liver injury and coagulopathy in a lipopolysaccharide (LPS)-induced animal model and to assess the relationship between TEG variables and liver injury. Male Wistar rats received LPS (30 mg/kg over a 4-h intravenous infusion) to induce experimental liver injury or isotonic saline as a control. Variables of hemodynamics and liver biochemistry were measured during the subsequent 6 h after the start of infusion. TEG variables (R-time, K-time, alpha-angle and maximal amplitude), thrombin antithrombin complex and plasminogen activator inhibitor-1 were also measured. After LPS infusion, liver injury [examined by biochemical variables (e.g. alanine aminotransferase, ALT) and histological studies] was developed and inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) were raised. At the initial period of LPS infusion, R-time was shortened and alpha-angle was increased. Thereafter, alpha-angle and maximal amplitude were decreased progressively, demonstrating that endotoxin induced coagulation disturbances. Furthermore, there were strong positive correlation between K-time and natural log (Ln)(ALT) (r = 0.823, P = 0.001); also, there were strong negative correlations between alpha-angle and Ln(ALT) (r = -0.762, P = 0.002) as well as maximal amplitude and Ln(ALT) (r = -0.732, P = 0.004) at 6 h after LPS infusion. These results demonstrated that TEG could be a potential tool to evaluate the development of liver injury in endotoxemia. PMID- 22227957 TI - Analytical performance of the new ACL AcuStar HemosIL D-Dimer. AB - Several lines of clinical evidence as well as guidelines and recommendations suggest that the overall diagnostic performance of D-dimer testing outstrips that of any other biomarker in the diagnostic approach of patients with venous thromboembolism or disseminated intravascular coagulation. Along with specific technical characteristics, the analytical performance of each D-dimer immunoassay should, however, be assessed before implementation in clinical practice. The aim of this study was to evaluate the analytical performance of HemosIL AcuStar D Dimer immunoassay, a novel chemiluminescent immunoassay specifically designed for the instrument Instrumentation Laboratory ACL AcuStar. The within and between-run imprecision (n = 20) was comprised between 3.6 and 5.8%. The linearity was excellent up to 16 200 ng/ml (r = 1.00; P < 0.001), and optimal between 224 and 69 900 ng/ml (r = 0.992; P < 0.001). A significant agreement of values was observed between HemosIL AcuStar D-Dimer and HemosIL D-Dimer HS for ACL TOP (r = 0.884; P < 0.001), as well as with Vidas D-Dimer (r = 0.791; P < 0.001). Results of HemosIL AcuStar D-Dimer displayed a modest negative bias as compared with those of Vidas D-dimer (mean bias -22%; 95% Confidence Interval, -122% to 49%). The analytical accuracy assessed against Vidas D-dimer also yielded an area under the curve of 0.998 (P < 0.001). As regards, the preliminary definition of cutoff value, optimal sensitivity (100%) and specificity (96%) were found at a diagnostic threshold of 466 ng/ml. The results of this investigation attest that the novel HemosIL AcuStar D-Dimer is characterized by remarkable accuracy and precision, optimal linearity and excellent agreement with the reference immunoassay. As such, its technical and analytical performance would make it a suitable method for the rapid and accurate quantification of D-dimer in clinical laboratories. PMID- 22227958 TI - Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. AB - The objective of the present study was to assess the suitability of an accurate, sensitive, standardized, chronometric blood coagulation test to determine the anticoagulation activity of dabigatran and to quantify concentrations of dabigatran in plasma. Dabigatran was spiked at increasing concentrations in pooled citrated normal human plasma to measure diluted thrombin time with the HEMOCLOT THROMBIN INHIBITOR assay. Calibration curve linearity, inter-assay and intra-assay precision, and assay accuracy were investigated. Dabigatran stability in plasma and the feasibility of lyophilized dabigatran standards for assay calibration were assessed. Data are presented as back-calculated plasma concentrations of dabigatran using regression analysis. Dabigatran's calibration curve for thrombin clotting time was linear over the concentration range 0-4000 nmol/l (0-1886 ng/ml). The R was 0.99. Total assay imprecision for dabigatran was 4.7-12.0% coefficient of variation, with 1.2-3.1% for intra-run imprecision, 4.0-10.0% for inter-run precision and 0.3-8.3% for between-day imprecision. Assay accuracy was determined at three dabigatran concentrations; deviation from sample target concentrations ranged from -20.7% (100 nmol/l; 47.15 ng/ml) to 5.6% (1500 nmol/l; 707.3 ng/ml). Assay robustness was determined by analysing identical dabigatran samples in two independent laboratories. The mean bias of dabigatran coagulation times between laboratories was 6.6%. The HEMOCLOT Thrombin Inhibitors assay is suitable for determining the anticoagulant activity and calculating plasma concentrations of dabigatran using simple and widely available chronometric coagulation devices. The use of this rapid, established, standardized and calibrated assay should provide accurate and consistent results when assessing the anticoagulant activity of dabigatran. PMID- 22227959 TI - Profile of thrombin generation in children with acute lymphoblastic leukemia treated by Berlin-Frankfurt-Munster (BFM) protocols. AB - Treatment with L-asparaginase is associated with coagulation disturbances with deep venous thrombosis being the most common clinical consequence. Use of the calibrated automated thrombogram allows precise estimation of thrombin generated in vitro. We show the first data on thrombin generation, measured by calibrated automated thrombography (CAT), in children with acute lymphoblastic leukemia treated with L-asparaginase. Thrombin generation was measured by means of CAT in 23 children treated for acute lymphoblastic leukemia. Samples were obtained at predefined time points during the induction and reinduction phase of acute lymphoblastic leukemia-intercontinental Berlin-Frankfurt-Munster (BFM) 2000 or Associazione Italiana Ematologica Oncologia Pedaitrica Interim BFM 2000 protocols. Antihrombin and fibrinogen were measured on the same sample. Twenty eight sets of thrombin generation measurements were collected from 23 patients. We observed no significant effect of antithrombin deficiency and/or hypofibrinogenemia on thrombin generation. Endogenous thrombin generation and peak thrombin were significantly higher during induction than in the reinduction phase (P < 0.001). Four patients with severe infection experienced an increase in thrombin generation, reaching maximum in a median of 7.5 days after the onset of infection. Two of those patients developed deep venous thrombosis at the time of peaked endogenous thrombin generation. Thrombin generation in children with acute lymphoblastic leukemia treated according to BFM protocols is significantly higher during the induction phase compared with reinduction and is not substantially affected by hypofibrinogenemia and/or antithrombin deficiency. Severe infection during the induction phase enhances thrombin generation with subsequent risk of thrombosis. PMID- 22227960 TI - The effects of denervation, reinnervation, and muscle imbalance on functional muscle length and elbow flexion contracture following neonatal brachial plexus injury. AB - The pathophysiology of paradoxical elbow flexion contractures following neonatal brachial plexus injury (NBPI) is incompletely understood. The current study tests the hypothesis that this contracture occurs by denervation-induced impairment of elbow flexor muscle growth. Unilateral forelimb paralysis was created in mice in four neonatal (5-day-old) BPI groups (C5-6 excision, C5-6 neurotomy, C5-6 neurotomy/repair, and C5-T1 global excision), one non-neonatal BPI group (28-day old C5-6 excision), and two neonatal muscle imbalance groups (triceps tenotomy +/ C5-6 excision). Four weeks post-operatively, motor function, elbow range of motion, and biceps/brachialis functional lengths were assessed. Musculocutaneous nerve (MCN) denervation and reinnervation were assessed immunohistochemically. Elbow flexion motor recovery and elbow flexion contractures varied inversely among the neonatal BPI groups. Contracture severity correlated with biceps/brachialis shortening and MCN denervation (relative axon loss), with no contractures occurring in mice with MCN reinnervation (presence of growth cones). No contractures or biceps/brachialis shortening occurred following non-neonatal BPI, regardless of denervation or reinnervation. Neonatal triceps tenotomy did not cause contractures or biceps/brachialis shortening, nor did it worsen those following neonatal C5-6 excision. Denervation-induced functional shortening of elbow flexor muscles leads to variable elbow flexion contractures depending on the degree, permanence, and timing of denervation, independent of muscle imbalance. PMID- 22227961 TI - Lack of toxicity after paracetamol overdose in a extremely preterm neonate. PMID- 22227962 TI - Nitric oxide decreases the enzymatic activity of insulin degrading enzyme in APP/PS1 mice. AB - Nitric oxide has been implicated in the regulation of enzyme activity, particularly the activity of metalloproteinases. Since the inducible form of the nitric oxide synthase (NOS2), is upregulated in Alzheimer's disease, we investigated the activity of two amyloid beta degrading enzymes, IDE and neprilysin. In vitro we demonstrated that the activity of IDE was inhibited by *NO donor Sin-1, whereas activity of neprilysin remained unaffected. In vivo the activity of insulin-degrading enzyme was lowered in APP/PS1 mice, but not in APP/PS1/NOS2(-/-) mice. These data suggest that NOS2 upregulation impairs amyloid beta degradation through negative regulation of IDE activity and thus loss of NOS2 activity will positively influence amyloid beta clearance. PMID- 22227963 TI - Unusual timing of CD127 expression by mouse uterine natural killer cells. AB - Decidualization, a progesterone-dependent process that alters endometrial stromal cells at implantation sites in humans and rodents, is accompanied by a highly regulated, NK cell-dominated leukocyte influx into decidual basalis (DB). Whether uNK cells differentiate from uterine progenitor cells is unknown, as are the mechanisms restricting leukocytes to DB. We asked if cells expressing the early NK lineage marker CD127 (IL-7Ralpha) occurred in mouse decidua. CD127 was absent from gd6.5 decidual lymphoid cells but became expressed by a mature uNK cell subset in gd10.5 DB. DB and transient myometrial structures (MLAp) that ring maternal blood vessels supplying placentae expressed IL-7 and TSLP, the CD127 ligands, but with differing temporal and spatial patterns. UNK cells expressed TSLPR, and study of gd10.5 implantation sites from mice deleted for IL-7, CD127, or TSLPR suggested that IL-7 and its receptor have physiological roles in limiting expansion of immature uNK cells within MLAp, while the TSLP signaling pathway is used in DB to sustain IFN-gamma production from a subset of mature uNK cells. Regionalized, dynamic expression of the additional lymphoid organ stromal markers gp38/podoplanin and ER-TR7, but not CD157, were seen by immunohistochemistry in implantation sites, and DB and MLAp contained transcripts for Aire, a tolerance-promoting factor. These observations suggest that CD127(+) NK lineage progenitors are not present in the early postimplantation period of mouse uterus and that decidualized endometrial stroma has key immunoregulatory properties. PMID- 22227965 TI - Hypercholesterolemic LDL receptor-deficient mice mount a neutrophilic response to tuberculosis despite the timely expression of protective immunity. AB - The prevalence of hypercholesterolemia is rising in industrialized and developing countries. We reported previously that host defense against Mtb was impaired by hypercholesterolemia in ApoE(-/-) mice, raising the possibility that people with HC could be more vulnerable to TB. The present study examined whether TB immunity was similarly impaired in a different hypercholesterolemic model, LDL-R(-/-) mice, which developed comparable elevation of total serum cholesterol as ApoE(-/ )mice when fed HC or LC diets. Like ApoE(-/-) mice, LDL-R(-/-) mice had an exaggerated lung inflammatory response to Mtb with increased tissue necrosis. Inflammation, foamy macrophage formation, and tissue necrosis in LDL-R(-/-) mice increased with the degree of hypercholesterolemia. Unlike ApoE(-/-) mice, LDL-R( /-) mice fed a HC diet mounted a timely and protective adaptive immune response that restricted mycobacterial replication comparably with WT mice. Thus, ApoE(-/ ) and LDL-R(-/-) mice share a cholesterol-dependent hyperinflammatory TB phenotype but do not share the impairment of adaptive immunity found in ApoE(-/-) mice. The impact of hypercholesterolemia on TB immunity is more complex than appreciated by total cholesterol alone, possibly reflecting the different functional effect of specific lipoprotein particles. PMID- 22227966 TI - Tissue stroma as a regulator of leukocyte recruitment in inflammation. AB - The stromal milieu (cellular and matrix components) helps establish tissue "address-codes" that direct leukocyte behavior in inflamed tissue. Coordinated interactions among the stroma, leukocytes, and ECs dictate which leukocytes are recruited, whether they are retained within the inflamed site, and how long they survive. Herein, we discuss how the stromal milieu influences the leukocyte recruitment cascade. Moreover, we explore how corruption of the stromal phenotype in chronic inflammatory diseases contributes to undesired, continuous recruitment of leukocytes. Emerging complex, multicellular, multilayered (co-)culture models are now addressing the molecular circuitry involved in regulating stromal organization during inflammation. Understanding context-specific changes in pro- or anti-inflammatory agents derived from the stroma, such as IL-6 (and its cofactors), is important for the generation of therapeutic strategies that restore the balance between recruitment and clearance of the inflammatory infiltrate in chronic disease. PMID- 22227967 TI - Founders of bioethics: concepts in tension, dialogue, and development. PMID- 22227968 TI - Kawasaki disease and sensorineural hearing loss: an (un)expected complication. AB - Kawasaki disease (KD) is an acute, self-limiting, idiopathic form of vasculitis. The preventive effect of early therapy on coronary artery aneurysms, the hallmark of the disease, is well established. The spectrum of complication includes not only cardiac involvement but also central nervous system lesions. We report a 4 year-old boy with a clinical presentation suggestive of KD treated with intravenous immunoglobulin and acetylsalicylic acid. Clinical manifestations regressed within 24 hours and cardiac anomalies were not seen. Two weeks later, the parents noticed a sudden absence of response to sound stimuli. Investigations confirmed bilateral severe sensorineural hearing loss for which oral steroid therapy was given. This resulted in an improvement only on the right side, with severe hearing loss persisting on the left. CONCLUSION: Sensorineural hearing loss is an uncommonly reported complication of KD. Pediatricians should be aware of this potential complication to allow for early intervention. PMID- 22227964 TI - Monocyte maturation, HIV susceptibility, and transmigration across the blood brain barrier are critical in HIV neuropathogenesis. AB - HIV continues to be a global health crisis with more than 34 million people infected worldwide (UNAIDS: Report on the Global AIDS Epidemic 2010, Geneva, World Health Organization). HIV enters the CNS within 2 weeks of infection and establishes a spectrum of HAND in a large percentage of infected individuals. These neurologic deficits greatly impact the quality of life of those infected with HIV. The establishment of HAND is largely attributed to monocyte transmigration, particularly that of a mature CD14(+)CD16(+) monocyte population, which is more susceptible to HIV infection, across the BBB into the CNS parenchyma in response to chemotactic signals. To enter the CNS, junctional proteins on the monocytes must participate in homo- and heterotypic interactions with those present on BMVECs of the BBB as they transmigrate across the barrier. This transmigration is responsible for bringing virus into the brain and establishing chronic neuroinflammation. While there is baseline trafficking of monocytes into the CNS, the increased chemotactic signals present during HIV infection of the brain promote exuberant monocyte transmigration into the CNS. This review will discuss the mechanisms of monocyte differentiation/maturation, HIV infectivity, and transmigration into the CNS parenchyma that contribute to the establishment of cognitive impairment in HIV-infected individuals. It will focus on markers of monocyte subpopulations, how differentiation/maturation alters HIV infectivity, and the mechanisms that promote their increased transmigration across the BBB into the CNS. PMID- 22227969 TI - Arabidopsis ETR1 and ERS1 differentially repress the ethylene response in combination with other ethylene receptor genes. AB - The ethylene response is negatively regulated by a family of five ethylene receptor genes in Arabidopsis (Arabidopsis thaliana). The five members of the ethylene receptor family can physically interact and form complexes, which implies that cooperativity for signaling may exist among the receptors. The ethylene receptor gene mutations etr1-1((C65Y))(for ethylene response1-1), ers1 1((I62P)) (for ethylene response sensor1-1), and ers1(C65Y) are dominant, and each confers ethylene insensitivity. In this study, the repression of the ethylene response by these dominant mutant receptor genes was examined in receptor-defective mutants to investigate the functional significance of receptor cooperativity in ethylene signaling. We showed that etr1-1((C65Y)), but not ers1 1((I62P)), substantially repressed various ethylene responses independent of other receptor genes. In contrast, wild-type receptor genes differentially supported the repression of ethylene responses by ers1-1((I62P)); ETR1 and ETHYLENE INSENSITIVE4 (EIN4) supported ers1-1((I62P)) functions to a greater extent than did ERS2, ETR2, and ERS1. The lack of both ETR1 and EIN4 almost abolished the repression of ethylene responses by ers1(C65Y), which implied that ETR1 and EIN4 have synergistic effects on ers1(C65Y) functions. Our data indicated that a dominant ethylene-insensitive receptor differentially repressed ethylene responses when coupled with a wild-type ethylene receptor, which supported the hypothesis that the formation of a variety of receptor complexes may facilitate differential receptor signal output, by which ethylene responses can be repressed to different extents. We hypothesize that plants can respond to a broad ethylene concentration range and exhibit tissue-specific ethylene responsiveness with differential cooperation of the multiple ethylene receptors. PMID- 22227970 TI - Induction of DNA damage by deguelin is mediated through reducing DNA repair genes in human non-small cell lung cancer NCI-H460 cells. AB - It has been shown that deguelin, one of the compounds of rotenoids from flavonoid family, induced cytotoxic effects through induction of cell cycle arrest and apoptosis in many types of human cancer cell lines, but deguelin-affected DNA damage and repair gene expression (mRNA) are not clarified yet. We investigated the effects of deguelin on DNA damage and associated gene expression in human lung cancer NCI-H460 cells in vitro. DNA damage was assayed by using the comet assay and DNA gel electrophoresis and the results indicated that NCI-H460 cells treated with 0, 50, 250 and 500 nM deguelin led to a longer DNA migration smear based on the single cell electrophoresis and DNA fragmentation occurred based on the examination of DNA gel electrophoresis. DNA damage and repair gene expression (mRNA) were evaluated by using real-time PCR assay and the results indicated that 50 and 250 nM deguelin for a 24-h exposure in NCI-H460 cells, decreased the gene levels of breast cancer 1, early onset (BRCA1), DNA-dependent serine/threonine protein kinase (DNA-PK), O6-methylguanine-DNA methyltransferase (MGMT), p53, ataxia telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) mRNA expressions. Collectively, the present study showed that deguelin caused DNA damage and inhibited DNA damage and repair gene expressions, which might be due to deguelin-inhibited cell growth in vitro. PMID- 22227972 TI - Bayesian image analysis of dexamethasone and shear stress-induced glucocorticoid receptor intracellular movement. AB - Endothelial cells are continuously exposed to hemodynamic shear stress, which has been shown to induce an array of physiological responses at the cellular and molecular levels. Uniform high shear stress is protective against vascular diseases such as atherosclerosis which preferentially occur at regions of disturbed flow and low shear. The glucocorticoid receptor (GR), a member of the steroid nuclear receptors with anti-inflammatory functions, has been shown to be activated by shear stress. Using a unique expectation-maximization (EM) algorithm based on Bayesian statistics, we have developed an image analysis algorithm to quantitatively assess GR nuclear translocation based on time-lapse images of green fluorescence protein-tagged GR (GFP-GR) under continuous exposure to a shear stress of 10 or 25 dynes/cm(2) as well as to Dexamethasone, a GR agonist. Average fluorescence brightness is generated for nucleus and cytoplasm. Real-time imaging of sheared cells revealed a steady and significant nuclear GFP-GR increase of approximately 20% within 2 h, compared to a rapid 60% increase in Dexamethasone-treated cells within 30 min. Furthermore, we found that that GFP-GR nuclear translocation under shear is not dependent on an intact cytoskeleton. Our image analysis algorithm provides a novel quantitative method to further study shear-sensitive mechanotransduction pathways in endothelial cells. PMID- 22227974 TI - Optical and opto-acoustic interventional imaging. AB - Many clinical interventional procedures, such as surgery or endoscopy, are today still guided by human vision and perception. Human vision however is not sensitive or accurate in detecting a large range of disease biomarkers, for example cellular or molecular processes characteristic of disease. For this reason advanced optical and opto-acoustic (photo-acoustic) methods are considered for enabling a more versatile, sensitive and accurate detection of disease biomarkers and complement human vision in clinical decision making during interventions. Herein, we outline developments in emerging fluorescence and opto acoustic sensing and imaging techniques that can lead to practical implementations toward improving interventional vision. PMID- 22227973 TI - Applying simulated in vivo motions to measure human knee and ACL kinetics. AB - Patients frequently experience anterior cruciate ligament (ACL) injuries but current ACL reconstruction strategies do not restore the native biomechanics of the knee, which can contribute to the early onset of osteoarthritis in the long term. To design more effective treatments, investigators must first understand normal in vivo knee function for multiple activities of daily living (ADLs). While the 3D kinematics of the human knee have been measured for various ADLs, the 3D kinetics cannot be directly measured in vivo. Alternatively, the 3D kinetics of the knee and its structures can be measured in an animal model by simulating and applying subject-specific in vivo joint motions to a joint using robotics. However, a suitable biomechanical surrogate should first be established. This study was designed to apply a simulated human in vivo motion to human knees to measure the kinetics of the human knee and ACL. In pursuit of establishing a viable biomechanical surrogate, a simulated in vivo ovine motion was also applied to human knees to compare the loads produced by the human and ovine motions. The motions from the two species produced similar kinetics in the human knee and ACL. The only significant difference was the intact knee compression force produced by the two input motions. PMID- 22227975 TI - Neonatal tetanus: a continuing challenge. AB - The authors retrospectively analyzed the case records of all the newborns admitted with the diagnosis of neonatal tetanus (NT) over a period of 36 mo. A total of 27 cases of neonatal tetanus were admitted over a period of 36 mo. Out of these 27 neonates, 17 died and thus the overall mortality was 63%. The mean age of onset of symptoms in those who survived was 8.1 +/- 2.02 d whereas in those who died was 5.7 +/- 1.39 d, which was statistically significant (p = 0.001). The babies with age of onset <7 d were almost 5 times more likely to die than those manifesting at 7 d or later. Thus, NT is still contributing to neonatal deaths especially in the backward areas of the country and onset of symptoms within a wk of birth is a very high risk factor for mortality. PMID- 22227976 TI - Role of GERD in children with otitis media with effusion. AB - OBJECTIVES: To establish whether Gastroesophageal reflux disease (GERD) plays a significant role in the etiopathogenesis of otitis media with effusion (OME) patients and to find if there is any association between GERD symptoms and OME. Also, to detect presence of pepsinogen in the middle ear aspirate and to demonstrate pepsinogen band by electrophoresis. METHODS: This is a prospective study conducted in a tertiary care hospital. Middle ear effusion samples were collected from 32 children undergoing surgery for OME.The samples were measured for pepsinogen level as well as total protein content. Samples were subjected to electrophoresis study by SDS PAGE (Sodium Dodecyl Sulphate Polyacrylamide Gel Electrophoresis). RESULTS: A total of 21 patients out of 32 were found to have higher pepsinogen level in their middle ear effusion samples than the cut off value of 90 mg/ml.The lack of symptoms associated with GERD among the children in this study corroborates with other similar studies in the world literature. It was also statistically shown that the association between GERD score and pepsinogen level was insignificant (P = 0.512). CONCLUSIONS: OME appears to be multifactorial disease.GERD may be one of the contributing factors in the etiopathogenisis of OME. PMID- 22227977 TI - Evaluation of healthcare-associated infection surveillance in Pennsylvania hospitals. AB - OBJECTIVE: In Pennsylvania, reporting of healthcare-associated infections (HAIs) was mandated in 2007, and hospitals were encouraged to implement qualified electronic surveillance (QES) systems to assist HAI detection. This study evaluated the usefulness of these systems in reducing HAIs. DESIGN: Online survey and retrospective cohort study. Eligible facilities had a QES or manual system in place for the entire study period and sufficient data in selected hospital units. METHODS: Surveys were sent to infection preventionists (IPs) in all Pennsylvania hospitals to gather qualitative information about their systems. National Healthcare Safety Network data from Pennsylvania hospitals for July 2008 through June 2010 were used to compare catheter-associated urinary tract infection (CAUTI) rates in facilities with and without a QES system. PARTICIPANTS: IPs from 174 facilities responded to the survey. Data from 119 of 234 hospitals were analyzed. RESULTS: IPs in facilities with a QES system reported spending as much time on data management and education as IPs in hospitals with manual surveillance. Significant interaction was observed in CAUTI rates over time between groups of facilities with and without a QES system after controlling for device-utilization ratio, location within hospital, and licensed bed size (P < .01). QES hospitals showed a significant decline in CAUTI rates (P < .01) manual surveillance facilities showed no change in rates (P > .05). CONCLUSIONS: Over the 2-year period, a significant decline in CAUTI rates was observed in facilities with a QES system. This suggests that electronic systems may aid in reducing HAI rates. Additional data are needed to see whether these improvements and trends persist. PMID- 22227978 TI - Use of electronic surveillance to drive improvement in hospital infection rates. PMID- 22227980 TI - The art of oversimplification: the challenge of measuring hospital-acquired MRSA. PMID- 22227979 TI - Inclusion of 30-day postdischarge detection triples the incidence of hospital onset methicillin-resistant Staphylococcus aureus. AB - BACKGROUND: Hospitalized patients are at increased risk for acquisition of methicillin-resistant Staphylococcus aureus (MRSA). As hospital length of stay shortens, hospital-acquired MRSA events may be more likely to be detected after discharge. OBJECTIVE: We assessed the impact of attributing MRSA cases discovered within 30 days after discharge to the most recent hospitalization and identified patient characteristics associated with MRSA detection after discharge. DESIGN: Retrospective cohort study. SETTING: Twenty-seven acute care hospitals in Orange County, California. PARTICIPANTS: Adult acute care admissions (2002-2007). METHODS: Using a countywide hospital data set containing diagnostic codes with present-on-admission (POA) indicators, we identified the first admission with a MRSA code for each patient. This incident MRSA admission was defined as predischarge-detected (pre-DD) hospital-onset MRSA (HO-MRSA) when MRSA was not POA. If MRSA was POA and a prior admission occurred within 30 days, this prior admission was assigned postdischarge-detected (post-DD) HO-MRSA. We evaluated the impact of including post-DD HO-MRSA in the calculation of hospital HO-MRSA incidence using signed-rank tests and reviewed changes in hospital rankings. We conducted multivariate comparisons of patient characteristics of pre-DD versus post-DD HO-MRSA patients. RESULTS: Among 1,217,253 at-risk hospitalizations, the inclusion of post-DD HO-MRSA tripled the median hospital HO-MRSA incidence, from 12.2 to 35.7 cases per 10,000 at-risk admissions (P < .0001). Hospital ranking changed substantially when including post-DD HO-MRSA. Patients with shorter stays were more likely to have post-DD MRSA. CONCLUSIONS: On the basis of administrative claims data, the inclusion of post-DD HO-MRSA significantly increased the estimated HO-MRSA incidence and altered hospital rankings. This finding underscores the limitations of single-facility data when deriving HO-MRSA incidence and rank. PMID- 22227981 TI - Performance, revision, and extension of the National Nosocomial Infections Surveillance system's risk index in Brazilian hospitals. AB - OBJECTIVE: To assess the benefit of using procedure-specific alternative cutoff points for National Nosocomial Infections Surveillance (NNIS) risk index variables and of extending surgical site infection (SSI) risk prediction models with a postdischarge surveillance indicator. DESIGN: Open, retrospective, validation cohort study. SETTING: Five private, nonuniversity Brazilian hospitals. PATIENTS: Consecutive inpatients operated on between January 1993 and May 2006 (other operations of the genitourinary system [n = 20,723], integumentary system [n = 12,408], or musculoskeletal system [n = 15,714] and abdominal hysterectomy [n = 11,847]). METHODS: For each procedure category, development and validation samples were defined nonrandomly. In the development samples, alternative SSI prognostic scores were constructed using logistic regression: (i) alternative NNIS scores used NNIS risk index covariates and cutoff points but locally derived SSI risk strata and rates, (ii) revised scores used procedure-specific alternative cutoff points, and (iii) extended scores expanded revised scores with a postdischarge surveillance indicator. Performances were compared in the validation samples using calibration, discrimination, and overall performance measures. RESULTS: The NNIS risk index showed low discrimination, inadequate calibration, and predictions with high variability. The most consistent advantage of alternative NNIS scores was regarding calibration (prevalence and dispersion components). Revised scores performed slightly better than the NNIS risk index for most procedures and measures, mainly in calibration. Extended scores clearly performed better than the NNIS risk index, irrespective of the measure or operative procedure. CONCLUSIONS: Locally derived SSI risk strata and rates improved the NNIS risk index's calibration. Alternative cutoff points further improved the specification of the intrinsic SSI risk component. Controlling for incomplete postdischarge SSI surveillance provided consistently more accurate SSI risk adjustment. PMID- 22227982 TI - Evaluation of organizational culture among different levels of healthcare staff participating in the Institute for Healthcare Improvement's 100,000 Lives Campaign. AB - BACKGROUND: Little is known about how hospital organizational and cultural factors associated with implementation of quality initiatives such as the Institute for Healthcare Improvement's (IHI) 100,000 Lives Campaign differ among levels of healthcare staff. DESIGN: Evaluation of a mixed qualitative and quantitative methodology ("trilogic evaluation model"). SETTING: Six hospitals that joined the campaign before June 2006. PARTICIPANTS: Three strata of staff (executive leadership, midlevel, and frontline) at each hospital. RESULTS. Surveys were completed in 2008 by 135 hospital personnel (midlevel, 43.7%; frontline, 38.5%; executive, 17.8%) who also participated in 20 focus groups. Overall, 93% of participants were aware of the IHI campaign in their hospital and perceived that 58% (standard deviation, 22.7%) of improvements in quality at their hospital were a direct result of the campaign. There were significant differences between staff levels on the organizational culture (OC) items, with executive-level staff having higher scores than midlevel and frontline staff. All 20 focus groups perceived that the campaign interventions were sustainable and that data feedback, buy-in, hardwiring (into daily activities), and leadership support were essential to sustainability. CONCLUSIONS: The trilogic model demonstrated that the 3 levels of staff had markedly different perceptions regarding the IHI campaign and OC. A framework in which frontline, midlevel, and leadership staff are simultaneously assessed may be a useful tool for future evaluations of OC and quality initiatives such as the IHI campaign. PMID- 22227983 TI - Infection prevention promotion program based on the PRECEDE model: improving hand hygiene behaviors among healthcare personnel. AB - BACKGROUND: Healthcare-associated infections (HAIs) result in significant morbidity and mortality. Hand hygiene remains a cornerstone intervention for preventing HAIs. Unfortunately, adherence to hand hygiene guidelines among healthcare personnel is poor. OBJECTIVE: To assess short- and long-term effects of an infection prevention promotion program on healthcare personnel hand hygiene behaviors. DESIGN: Time series design. SETTING: Our study was conducted at a tertiary care academic center. PARTICIPANTS: Hospital healthcare personnel. METHODS: We developed a multimodal program that included a multimedia communications campaign, education, leadership engagement, environment modification, team performance measurement, and feedback. Healthcare personnel hand hygiene practices were measured via direct observations over a 3-year period by "undercover" observers. RESULTS: Overall hand hygiene compliance increased by 2-fold after full program implementation (P < .001), and this increase was sustained over a 20-month follow-up period (P < .001). The odds for compliance with hand hygiene increased by 3.8-fold in the 6 months after full program implementation (95% confidence interval, 3.53-4.23; P < .001), and this increase was sustained. There was even a modest increase at 20 months of follow up. Hand hygiene compliance increased among all disciplines and hospital units. Hand hygiene compliance increased from 35% in the first 6 months after program initiation to 77% in the last 6 months of the study period among nursing providers (P < .001), from 38% to 62% among medical providers (P < .001), and from 27% to 75% among environmental services staff (P < .001). CONCLUSIONS: Implementation of the infection prevention promotion program was associated with a significant and sustained increase in hand hygiene practices among healthcare personnel of various disciplines. PMID- 22227984 TI - Cost-effectiveness of preoperative nasal mupirocin treatment in preventing surgical site infection in patients undergoing total hip and knee arthroplasty: a cost-effectiveness analysis. AB - OBJECTIVE: To perform a cost-effectiveness analysis to evaluate preoperative use of mupirocin in patients with total joint arthroplasty (TJA). DESIGN: Simple decision tree model. SETTING: Outpatient TJA clinical setting. PARTICIPANTS: Hypothetical cohort of patients with TJA. INTERVENTIONS: A simple decision tree model compared 3 strategies in a hypothetical cohort of patients with TJA: (1) obtaining preoperative screening cultures for all patients, followed by administration of mupirocin to patients with cultures positive for Staphylococcus aureus; (2) providing empirical preoperative treatment with mupirocin for all patients without screening; and (3) providing no preoperative treatment or screening. We assessed the costs and benefits over a 1-year period. Data inputs were obtained from a literature review and from our institution's internal data. Utilities were measured in quality-adjusted life-years, and costs were measured in 2005 US dollars. MAIN OUTCOME MEASURE: Incremental cost-effectiveness ratio. RESULTS: The treat-all and screen-and-treat strategies both had lower costs and greater benefits, compared with the no-treatment strategy. Sensitivity analysis revealed that this result is stable even if the cost of mupirocin was over $100 and the cost of SSI ranged between $26,000 and $250,000. Treating all patients remains the best strategy when the prevalence of S. aureus carriers and surgical site infection is varied across plausible values as well as when the prevalence of mupirocin-resistant strains is high. CONCLUSIONS: Empirical treatment with mupirocin ointment or use of a screen-and-treat strategy before TJA is performed is a simple, safe, and cost-effective intervention that can reduce the risk of SSI. S. aureus decolonization with nasal mupirocin for patients undergoing TJA should be considered. LEVEL OF EVIDENCE: Level II, economic and decision analysis. PMID- 22227985 TI - Prior vancomycin use is a risk factor for reduced vancomycin susceptibility in methicillin-susceptible but not methicillin-resistant Staphylococcus aureus bacteremia. AB - OBJECTIVE: Staphylococcus aureus is a cause of community- and healthcare-acquired infections and is associated with substantial morbidity, mortality, and costs. Vancomycin minimum inhibitory concentrations (MICs) among S. aureus have increased, and reduced vancomycin susceptibility (RVS) may be associated with treatment failure. We aimed to identify clinical risk factors for RVS in S. aureus bacteremia. DESIGN: Case-control. SETTING: Academic tertiary care medical center and affiliated urban community hospital. PATIENTS: Cases were patients with RVS S. aureus isolates (defined as vancomycin E-test MIC >1.0 MUg/mL). Controls were patients with non-RVS S. aureus isolates. RESULTS: Of 392 subjects, 134 (34.2%) had RVS. Fifty-eight of 202 patients (28.7%) with methicillin susceptible S. aureus (MSSA) isolates had RVS, and 76 of 190 patients (40.0%) with methicillin-resistant S. aureus (MRSA) isolates had RVS (P = .02). In unadjusted analyses, prior vancomycin use was associated with RVS (odds ratio [OR], 2.08; 95% confidence interval [CI], 1.00-4.32; P = .046). In stratified analyses, there was significant effect modification by methicillin susceptibility on the association between vancomycin use and RVS (P =.04). In multivariable analyses, after hospital of admission and prior levofloxacin use were controlled for, the association between vancomycin use and RVS was significant for patients with MSSA infection (adjusted OR, 4.02; 95% CI, 1.11-14.50) but not MRSA infection (adjusted OR, 0.87; 95% CI, 0.36-2.13). CONCLUSIONS: A substantial proportion of patients with S. aureus bacteremia had RVS. The association between prior vancomycin use and RVS was significant for patients with MSSA infection but not MRSA infection, suggesting a complex relationship between the clinical and molecular epidemiology of RVS in S. aureus. PMID- 22227986 TI - An outbreak of heterogeneous glycopeptide-intermediate Staphylococcus aureus related to a device source in an intensive care unit. AB - OBJECTIVE: The emergence of Staphylococcus aureus with reduced susceptibility to glycopeptides (glycopeptide-intermediate S. aureus [GISA] and heterogeneous GISA [h-GISA]) leads to intensive care unit (ICU) outbreaks that frequently result in ward closure. We investigated the role of hospital hygiene in the transmission and eradication of an h-GISA outbreak. DESIGN: The study is a description of an original environmental investigation around a series of 12 cases. SETTING AND PATIENTS: The outbreak occurred in a 20-bed polyvalent/trauma ICU in a 2,800-bed tertiary care university hospital in France. INTERVENTIONS: Specimens were obtained for surveillance and diagnostic cultures from all patients in the unit. Surface sampling was also performed. Geographic cohorting, contact isolation, emphasis on adherence to infection control practices, and environmental cleaning were implemented. RESULTS: Twelve patients with h-GISA infection (n = 5) or colonization (n = 7) were identified. The mean interval between admission and h GISA detection was 23.6 days (range, 10-89 days), with a median of 16.5 days. Environmental investigation identified an unexpected reservoir, namely, SpO(2) sensors. The outbreak was controlled by a combination of measures, including eradication of this reservoir, avoiding total ward closure. CONCLUSIONS: Targeted surface sampling helps to secure the environment through active investigation of various reservoirs while maintaining normal activity on the ward. In our study, this method led to the detection of an unsuspected reservoir, the eradication of which helped control the h-GISA epidemic. Further applications of this original investigative procedure should allow confirmation of its relevance and efficiency. PMID- 22227987 TI - High proportion of false-positive Clostridium difficile enzyme immunoassays for toxin A and B in pediatric patients. AB - OBJECTIVES: To determine the frequency of false-positive Clostridium difficile toxin enzyme immunoassay (EIA) results in hospitalized children and to examine potential reasons for this false positivity. DESIGN: Nested case-control. SETTING: Two tertiary care pediatric hospitals. METHODS: As part of a natural history study, prospectively collected EIA-positive stools were cultured for toxigenic C. difficile, and characteristics of children with false-positive and true-positive EIA results were compared. EIA-positive/culture-negative samples were recultured after dilution and enrichment steps, were evaluated for presence of the tcdB gene by polymerase chain reaction (PCR), and were further cultured for Clostridium sordellii, a cause of false-positive EIA toxin assays. RESULTS: Of 112 EIA-positive stools cultured, 72 grew toxigenic C. difficile and 40 did not, indicating a positive predictive value of 64% in this population. The estimated prevalence of C. difficile infection (CDI) in the study sites among children tested for this pathogen was 5%-7%. Children with false-positive EIA results were significantly younger than those with true-positive tests but did not differ in other characteristics. No false-positive specimens yielded C. difficile when cultured after enrichment or serial dilution, 1 specimen was positive for tcdB by PCR, and none grew C. sordellii. CONCLUSIONS: Approximately one-third of EIA tests used to evaluate pediatric inpatients for CDI were falsely positive. This finding was likely due to the low prevalence of CDI in pediatric hospitals, which diminishes the test's positive predictive value. These data raise concerns about the use of EIA assays to diagnosis CDI in children. PMID- 22227988 TI - Investigation and control of an outbreak of Achromobacter xylosoxidans bacteremia. AB - OBJECTIVE: To define the extent of an outbreak of Achromobacter xylosoxidans bacteremia, determine the source of the outbreak, and implement control measures. DESIGN: An outbreak investigation, including environmental and infection control assessment, and evaluation of hypotheses using the binomial distribution and case control studies. SETTING: A 50-bed medical surgical unit in a hospital in Illinois during the period January 1-July 15, 2006. INTERVENTIONS: Discontinuation of use of opioid delivery via patient-controlled analgesia (PCA) until the source of the outbreak was identified and implementation of new protocols to ensure more rigorous observation of PCA pump cartridge manipulations. RESULTS: Calculations based on the binomial distribution indicated the probability that all 9 patients with A. xylosoxidans bacteremia were PCA pump users by chance alone was <.001. A subsequent case control study identified PCA pump use for administration of morphine as a risk factor for A. xylosoxidans bacteremia (odds ratio, undefined; P < .001). Having a PCA pump cartridge with morphine started by nurse C was significantly associated with becoming a case patient (odds ratio, 46; 95% confidence interval, 4.0-525.0; P < .001). CONCLUSIONS: We hypothesize that actions related to diversion of morphine by nurse C were the likely cause of the outbreak. An aggressive pain control program involving the use of opioid medication warrants an equally aggressive policy to prevent diversion of medication by staff. PMID- 22227990 TI - Ultraviolet powder versus ultraviolet gel for assessing environmental cleaning. AB - We compared cleaning rates associated with use of a white ultraviolet (UV) powder versus a transparent UV gel among units with various degrees of previous experience with UV powder. The study outcome was the presence of discordant cleaning (removal of powder without the removal of gel, or vice versa). We found higher frequency of discordance in high-experience units (31%) than in no experience units (8%) (P < .001). In 92% of discordant findings, the powder was removed but not the gel (P < .001). These findings suggest preferential cleaning of visible UV targets among units with high levels of previous experience with powder. PMID- 22227989 TI - An outbreak of Legionnaires disease associated with a decorative water wall fountain in a hospital. AB - OBJECTIVE: To detect an outbreak-related source of Legionella, control the outbreak, and prevent additional Legionella infections from occurring. DESIGN AND SETTING: Epidemiologic investigation of an acute outbreak of hospital-associated Legionnaires disease among outpatients and visitors to a Wisconsin hospital. PATIENTS: Patients with laboratory-confirmed Legionnaires disease who resided in southeastern Wisconsin and had illness onsets during February and March 2010. METHODS: Patients with Legionnaires disease were interviewed using a hypothesis generating questionnaire. On-site investigation included sampling of water and other potential environmental sources for Legionella testing. Case-finding measures included extensive notification of individuals potentially exposed at the hospital and alerts to area healthcare and laboratory personnel. RESULTS: Laboratory-confirmed Legionnaires disease was diagnosed in 8 patients, all of whom were present at the same hospital during the 10 days prior to their illness onsets. Six patients had known exposure to a water wall-type decorative fountain near the main hospital entrance. Although the decorative fountain underwent routine cleaning and maintenance, high counts of Legionella pneumophila serogroup 1 were isolated from cultures of a foam material found above the fountain trough. CONCLUSION: This outbreak of Legionnaires disease was associated with exposure to a decorative fountain located in a hospital public area. Routine cleaning and maintenance of fountains does not eliminate the risk of bacterial contamination. Our findings highlight the need to evaluate the safety of water fountains installed in any area of a healthcare facility. PMID- 22227991 TI - Pandemic influenza A(H1N1)2009 in hospital healthcare workers in New Zealand. AB - We evaluated A/H1N1 influenza in healthcare workers (HCWs) and in a flu room during the 2009 pandemic. The flu room aided HCW care and management by facilitating rapid diagnosis and treatment. Absence of fever was common, and symptoms were nonspecific. A higher rate of H1N1 occurred in HCWs deployed in acute services. PMID- 22227992 TI - Evaluation of the antimicrobial properties of copper surfaces in an outpatient infectious disease practice. PMID- 22227993 TI - Beyond 30 days: does limiting the duration of surgical site infection follow-up limit detection? PMID- 22227994 TI - Latent tuberculosis infection in nurses exposed to tuberculous patients cared for in rooms without negative pressure after the 2011 great east Japan earthquake. PMID- 22227995 TI - The role of intention-to-treat analyses in randomized trials. PMID- 22227998 TI - A decrease in the percentage of circulating mDC precursors in patients with coronary heart disease: a relation to the severity and extent of coronary artery lesions? AB - Inflammation plays a pivotal role in coronary heart disease. Dendritic cells (DCs) are principal players in inflammation and atherosclerosis. Although the percentage of circulating DC precursors in coronary heart disease have been investigated, circulating myeloid DC (mDC) and plasmacytoid DC (pDC) precursors have not been extensively studied, particularly in relation to the severity of coronary artery lesions in patients with coronary heart disease. In this study, we recruited controls (n = 29), patients with stable angina pectoris (SAP, n = 30), patients with unstable angina pectoris (UAP, n = 56), and patients with acute myocardial infarction (AMI, n = 50). The severity and extent of coronary artery lesions was evaluated by Gensini score, following coronary angiograms. The percentage of circulating mDC and pDC precursors was determined by fluorescence activated cell sorting (FACS). Plasma levels of MCP-1 and MMP-9, which correlate with atherosclerosis and DC migration, were also measured. The percentage of circulating mDC precursors was reduced in patients with AMI and UAP compared with control and SAP patients, respectively (p < 0.01 for AMI vs. SAP and Control, p < 0.05 for UAP vs. SAP and Control). The percentage of circulating pDC precursors was not significant changed. The levels of plasma MMP-9 and MCP-1 and Genisi score were all increased in patients with AMI and UAP, compared to control and SAP patients, respectively (p < 0.01 for AMI vs. SAP and control, p < 0.05 for UAP vs. SAP and control). Overall, the percentage of circulating mDC precursors was negatively correlated with MCP-1 (p < 0.001), MMP-9 (p < 0.001) and Genisi scores (p < 0.001). Genisi scores were positively correlated with the levels of MCP-1 (p < 0.001) and MMP-9 (p < 0.001). Our study suggested that the percentage of circulating mDC precursors is negatively correlated with the severity and extent of coronary artery lesions in patients with coronary heart disease. PMID- 22228000 TI - Impact of early and high amino acid supplementation on ELBW infants at 2 years. AB - OBJECTIVE: The aim of the present study was to examine the effects of early and high intravenous (IV) amino acid (AA) supplementation on growth, health, and neurodevelopment of extremely-low-birth-weight (ELBW) infants throughout their first 2 years of life. METHODS: Infants were prospectively randomized in a double masked fashion and treated for 7 days with either IV AA starting at 0.5 g . kg ( 1) . day(-1) and increased by 0.5 g . kg(-1) every day to 3 g . kg(-1). day(-) or starting at 2 g . kg (-1) . day(-1) of IV AA and advanced by 1 g . kg(-1) every day to 4 g . kg (-1) . day(-1). Plasma AA concentrations were determined by reverse-phase high-performance liquid chromatography. Survivors were longitudinally assessed with Bayley II Scales of Infant Development and physical, social, and global health. RESULTS: Forty-three of 51 survivors were studied. Mental Developmental Index (MDI) and Psychomotor Developmental Index were similar between groups; however, the early and high AA group had a lower MDI at 18 months. This difference disappeared at 2 years of age. The early and high AA group z score means for weight, length, and head circumferences were significantly lower than the standard AA group at most visits. Cumulative and single plasma AA concentrations correlated negatively with MDI and postnatal growth. CONCLUSIONS: ELBW infants who received early and high IV AA during the first week of life were associated with poor overall growth at 2 years. PMID- 22227999 TI - Natural history of Helicobacter pylori infection in Mexican schoolchildren: incidence and spontaneous clearance. AB - OBJECTIVES: The aim of the present study was to estimate the incidence and spontaneous clearance rate of Helicobacter pylori infection and the effect of some variables on these outcomes in schoolchildren. METHODS: From May 2005 to December 2010, 718 schoolchildren enrolled in 3 public boarding schools in Mexico City participated in the follow-up. At the beginning of the study and every 6 months thereafter, breath samples were taken to detect H pylori infection; blood samples and anthropometric measurements were taken to evaluate nutritional status. Data on sociodemographic characteristics were collected. RESULTS: The prevalence of H pylori infection was 38%. The incidence rate was 6.36%/year. Schoolchildren with anemia or iron deficiency at the beginning of the study (who received iron supplements) showed a higher infection acquisition rate than those with normal iron nutritional status, hazard ratio (HR) 12.52 (95% confidence interval [CI] 4.01%-39.12%), P < 0.001 and HR 2.05 (95% CI 1.09%-3.87%), P = 0.027, respectively. The spontaneous clearance rate of the infection was 4.74%/year. The spontaneous clearance rate was higher in children who had iron deficiency (who received iron supplements), HR 5.02 (95% CI 1.33%-18.99%), P = 0.017, compared with those with normal nutritional iron status. It was lower in schoolchildren with >= 2 siblings compared with schoolchildren with 1 or no siblings, HR 0.23 (95% CI 0.08%-0.63%), P = 0.004. CONCLUSIONS: H pylori infection status is dynamic in schoolchildren. Variables related to health status and infection transmission, such as iron status and number of siblings, are important for the incidence and spontaneous clearance of H pylori infection. PMID- 22228001 TI - Terminal ileitis caused by Yersinia pseudotuberculosis mimicking Crohn disease in childhood. PMID- 22228002 TI - Helicobacter pylori detection by polymerase chain reaction in pediatric gastritis. PMID- 22228004 TI - Clinical presentation, response to therapy, and outcome of gastroparesis in children. AB - OBJECTIVES: The aims of the present study was to define the clinical features, response to therapy, and outcome of pediatric gastroparesis. METHODS: Retrospective review of 230 children with gastroparesis. Demographics, gastric emptying times, symptoms, response to medications, and outcome were determined for each of 3 groups (infants, children, and adolescents). RESULTS: Mean age was 9 years, with boys predominating among infants and girls among adolescents. Postviral gastroparesis occurred in 18% and mitochondrial dysfunction (MD) in 8%. Symptoms varied with age, with children experiencing more vomiting and adolescents reporting more nausea and abdominal pain. The addition of promotility drugs was an effective therapy. Overall rates of symptom resolution were 22% at 6 months, 53% at 18 months, and 61% at 36 months, with median time to resolution of 14 months. Factors associated with symptom resolution included younger age, male sex, postviral gastroparesis, shorter duration of symptoms, response to addition of promotility therapy, and absence of MD. In multivariate analysis, longer duration of symptoms and MD both predicted lower rates of resolution, whereas younger age and response to addition of promotility therapy predicted a higher rate. CONCLUSIONS: Pediatric gastroparesis is a complex condition with variable symptomatology and outcome depending on multiple parameters. Understanding the clinical features and response to therapy will improve our diagnosis and treatment of this disorder. PMID- 22228003 TI - Protective antibody responses to influenza A/H1N1/09 vaccination in children with celiac disease. AB - Patients with celiac disease have an increased risk for severe influenza infection and they show less of a response to certain vaccine types. During the influenza A/H1N1/09 pandemic, we prospectively investigated pandemic vaccine responses in 14 pediatric patients with celiac disease and age-/sex-matched controls. All of the children with celiac disease reached protective antibody titers (>=40) and showed a geometric mean titer comparable with the control group (530 vs 573). PMID- 22228005 TI - What have studies of genomic disorders taught us about our genome? AB - The elucidation of genomic disorders began with molecular technologies that enabled detection of genomic changes which were (a) smaller than those resolved by traditional cytogenetics (less than 5 Mb) and (b) larger than what could be determined by conventional gel electrophoresis. Methods such as pulsed field gel electrophoresis (PFGE) and fluorescent in situ hybridization (FISH) could resolve such changes but were limited to locus-specific studies. The study of genomic disorders has rapidly advanced with the development of array-based techniques. These enabled examination of the entire human genome at a higher level of resolution, thus allowing elucidation of the basis of many new disorders, mechanisms that result in genomic changes that can result in copy number variation (CNV), and most importantly, a deeper understanding of the characteristics, features, and plasticity of our genome. In this chapter, we focus on the structural and architectural features of the genome, which can potentially result in genomic instability, delineate how mechanisms, such as NAHR, NHEJ, and FoSTeS/MMBIR lead to disease-causing rearrangements, and briefly describe the relationship between the leading methods presently used in studying genomic disorders. We end with a discussion on our new understanding about our genome including: the contribution of new mutation CNV to disease, the abundance of mosaicism, the extent of subtelomeric rearrangements, the frequency of de novo rearrangements associated with sporadic birth defects, the occurrence of balanced and unbalanced translocations, the increasing discovery of insertional translocations, the exploration of complex rearrangements and exonic CNVs. In the postgenomic era, our understanding of the genome has advanced very rapidly as the level of technical resolution has become higher. This leads to a greater understanding of the effects of rearrangements present both in healthy subjects and individuals with clinically relevant phenotypes. PMID- 22228006 TI - Microdeletion and microduplication syndromes. AB - During the past decade, widespread use of microarray-based technologies, including oligonucleotide array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) genotyping arrays have dramatically changed our perspective on genome-wide structural variation. Submicroscopic genomic rearrangements or copy-number variation (CNV) have proven to be an important factor responsible for primate evolution, phenotypic differences between individuals and populations, and susceptibility to many diseases. The number of diseases caused by chromosomal microdeletions and microduplications, also referred to as genomic disorders, has been increasing at a rapid pace. Microdeletions and microduplications are found in patients with a wide variety of phenotypes, including Mendelian diseases as well as common complex traits, such as developmental delay/intellectual disability, autism, schizophrenia, obesity, and epilepsy. This chapter provides an overview of common microdeletion and microduplication syndromes and their clinical phenotypes, and discusses the genomic structures and molecular mechanisms of formation. In addition, an explanation for how these genomic rearrangements convey abnormal phenotypes is provided. PMID- 22228007 TI - Structural genomic variation in intellectual disability. AB - The genetic causes of mental retardation are highly heterogeneous and for a large proportion unknown. Mutations as well as large chromosomal abnormalities are known to contribute to mental retardation, and recently more subtle structural genomic variations have been shown to contribute significantly to this common and complex disorder. Genomic microarrays with increasing resolution levels have revealed the presence of rare de novo CNVs in approximately 15% of all mentally retarded patients. Microarray-based CNV screening is rapidly replacing conventional karyotyping in the diagnostic workflow, resulting in an increased diagnostic yield as well as biological insight into this disorder. In this chapter, an overview is given of the detection and interpretation of copy number variations in mental retardation, with a focus on diagnostic applications. In addition, a detailed protocol is provided for the diagnostic interpretation of copy-number variations in mental retardation. PMID- 22228008 TI - Copy number variation and psychiatric disease risk. AB - Psychiatric disorders are multifactorial in nature with complex genetic architecture. A number of recent studies, building upon earlier findings of copy number variants (CNVs) at the 22q11.2 locus, suggest that rare CNVs represent an important component of genetic heterogeneity in the etiology of complex psychiatric diseases, such as schizophrenia. De novo CNVs are found with higher frequency among sporadic cases, whereas inherited CNVs are enriched among familial cases. Despite substantial progress, a number of challenges remain, such as pinpointing causative relationships between specific gene(s) affected by CNVs and disease phenotypes as well as distinguishing abnormal structural mutations from neutral polymorphisms and establishing a clear association between individual pathogenic CNV and disease phenotypes. PMID- 22228009 TI - Detection and characterization of copy number variation in autism spectrum disorder. AB - There now exist multiple lines of evidence pointing to a significant genetic component underlying the aetiology of autism spectrum disorders (ASDs). The advent of methodologies for scanning the human genome at high resolution, coupled with the recognition of copy number variation (CNV) as a prevalent source of genomic variation, has led to new strategies in the identification of clinically relevant loci. Balanced genomic changes, such as translocations and inversions, also contribute to ASD, but current studies have shown that screening with microarrays has up to fivefold increase in diagnostic yield. Recent work by our group and others has shown unbalanced genomic alterations that are likely pathogenic in upwards of 10% of cases, highlighting an important role for CNVs in the genetic aetiology of ASD. A trend in our empirical data has shifted focus for discovery of candidate loci towards individually rare but highly penetrant CNVs instead of looking for common variants of low penetrance. This strategy has proven largely successful in identifying ASD-susceptibility candidate loci, including gains and losses at 16p11.2, SHANK2, NRXN1, and PTCHD1. Another emerging and intriguing trend is the identification of the same genes implicated by rare CNVs across neurodevelopmental disorders, including schizophrenia, attention deficit hyperactivity disorder, and intellectual disability. These observations indicate that similar pathways may be involved in phenotypically distinct outcomes. Although interrogation of the genome at high resolution has led to these novel discoveries, it has also made cataloguing, characterization, and clinical interpretation of the increasing amount of CNV data difficult. Herein, we describe the history of genomic structural variation in ASD and how CNV discovery has been used to pinpoint novel ASD-susceptibility loci. We also discuss the overlap of CNVs across neurodevelopmental disorders and comment on the current challenges of understanding the relationship between CNVs and associated phenotypes in a clinical context. PMID- 22228010 TI - Structural variation in subtelomeres. AB - Subtelomeres are an incredibly dynamic part of the human genome located at the ends of chromosomes just proximal to telomere repeats. Although subtelomeric variation contributes to normal polymorphism in the human genome and is a by product of rapid evolution in these regions, rearrangements in subtelomeres can also cause intellectual disabilities and birth defects, making robust methods of detecting copy number variation in chromosome ends a must for cytogenetics labs. In recent years, methods for detecting structural variation in subtelomeres have moved from fluorescence in situ hybridization (FISH) to array technology; however, FISH is still necessary to determine the chromosomal structure of subtelomeric gains and losses identified by arrays. PMID- 22228011 TI - Array-based approaches in prenatal diagnosis. AB - The diagnostic benefits of array comparative genomic hybridisation (CGH) have been demonstrated, with this technique now being applied as the first-line test for patients with intellectual disabilities and/or multiple congenital anomalies in numerous laboratories. There are no technical barriers preventing the introduction of array CGH to prenatal diagnosis. The question is rather how this is best implemented, and for whom. The challenges lie in the interpretation of copy number variations, particularly those which exhibit reduced penetrance or variable expression, and how to deal with incidental findings, which are not related to the observed foetal anomalies, or unclassified variants which are currently of uncertain clinical significance. Recently, applications of array technologies to the field of pre-implantation genetic diagnosis have also been demonstrated. It is important to address the ethical questions raised concerning the genome-wide analysis of prenatal samples to ensure the maximum benefit for patients. We provide an overview of the recent developments on the use of array CGH in the prenatal setting, and address the challenges posed. PMID- 22228012 TI - Structural variation and its effect on expression. AB - Structural variation, whether it is caused by copy number variants or present in a balanced form, such as reciprocal translocations and inversions, can have a profound and dramatic effect on the expression of genes mapping within and close to the rearrangement, as well as affecting others genome wide. These effects can be caused by altering the copy number of one or more genes or regulatory elements (dosage effect) or from physical disruption of links between regulatory elements and their associated gene or genes, resulting in perturbation of expression. Similarly, large-scale structural variants can result in genome-wide expression changes by altering the positions that chromosomes occupy within the nucleus, potentially disrupting not only local cis interactions, but also trans interactions that occur throughout the genome. Structural variation is, therefore, a significant factor in the study of gene expression and is discussed here in more detail. PMID- 22228013 TI - The challenges of studying complex and dynamic regions of the human genome. AB - Recent work has emphasised that the human genome is not simple and static, but complex and dynamic. This review focuses on the regions that are particularly hard to dissect and analyse, yet hold clues to how the genome changes during evolution and disease. I begin by summarising recent key advances in the understanding of the variable structure of our genome, and then I discuss a medley of methods that may allow us to analyse this structure in fine detail. In the final part, I describe potential future developments in this field, and make an argument that, just as we routinely genotype single-nucleotide polymorphisms now and will routinely re-sequence genomes in the near future, we should be aiming to physically re-map the individual human genome for each individual we study. PMID- 22228014 TI - Population genetic nature of copy number variation. AB - Copy number variation has recently received considerable attention, and copy number variants (CNVs) have been shown to be both common in mammalian genomes and important for understanding genetic and phenotypic variation. As empirical knowledge and detection methods are quickly advancing, evolutionary theories about CNVs are rapidly updated and often revised. Here, we review recent progress on understanding CNVs, and we discuss some key issues for future research. In essence, we discuss four major forces in population genetics, recombination, mutation, selection, and demography, in relation to CNVs. PMID- 22228015 TI - Detection and interpretation of genomic structural variation in mammals. AB - Structural variation (SV) encompasses diverse types of genomic variants including deletions, duplications, inversions, transpositions, translocations, and complex rearrangements, and is now recognized to be an abundant class of genetic variation in mammals. Different individuals, or strains, of a given species can differ by thousands of variants. However, despite a large number of studies over the past decade and impressive progress on many fronts, there remain significant gaps in our knowledge, particularly in species other than human. Arguably the most relevant among these are genetically tractable models such as mouse, rat, and dog. The emergence of efficient and affordable DNA sequencing technologies presents an opportunity to make rapid progress toward understanding the nature, origin, and function of SV in these, and other, domesticated species. Here, we summarize the current state of knowledge of SV in mammals, with a focus on the similarities and differences between domesticated species and human. We then present methods to identify SV breakpoints from next-generation sequence (NGS) data by paired-end mapping, split-read mapping, and local assembly, and discuss challenges that arise when interpreting these data in lineages with complex breeding histories and incomplete reference genomes. We further describe technical modifications that allow for identification of variants involving repetitive DNA elements such as transposons and segmental duplications. Finally, we explore a few of the key biological insights that can be gained by applying NGS methods to model organisms. PMID- 22228016 TI - Structural genetic variation in the context of somatic mosaicism. AB - Somatic mosaicism is the result of postzygotic de novo mutation occurring in a portion of the cells making up an organism. Structural genetic variation is a very heterogeneous group of changes, in terms of numerous types of aberrations that are included in this category, involvement of many mechanisms behind the generation of structural variants, and because structural variation can encompass genomic regions highly variable in size. Structural variation rapidly evolved as the dominating type of changes behind human genetic diversity, and the importance of this variation in biology and medicine is continuously increasing. In this review, we combine the evidence of structural variation in the context of somatic cells. We discuss the normal and disease-related somatic structural variation. We review the recent advances in the field of monozygotic twins and other models that have been studied for somatic mutations, including other vertebrates. We also discuss chromosomal mosaicism in a few prime examples of disease genes that contributed to understanding of the importance of somatic heterogeneity. We further highlight challenges and opportunities related to this field, including methodological and practical aspects of detection of somatic mosaicism. The literature devoted to interindividual variation versus papers reporting on somatic variation suggests that the latter is understudied and underestimated. It is important to increase our awareness about somatic mosaicism, in particular, related to structural variation. We believe that further research of somatic mosaicism will prove beneficial for better understanding of common sporadic disorders. PMID- 22228017 TI - Online resources for genomic structural variation. AB - Genomic structural variation (SV) can be thought of on a continuum from a single base pair insertion/deletion (INDEL) to large megabase-scale rearrangements involving insertions, deletions, duplications, inversions, or translocations of whole chromosomes or chromosome arms. These variants can occur in coding or noncoding DNA, they can be inherited or arise sporadically in the germline or somatic cells. Many of these events are segregating in the population and can be considered common alleles while others are new alleles and thus rare events. All species studied to date harbor structural variants and these may be benign, contributing to phenotypes such as sensory perception and immunity, or pathogenic resulting in genomic disorders including DiGeorge/velocardiofacial, Smith Margenis, Williams-Beuren, and Prader-Willi syndromes. As structural variants are identified, validated, and their significance, origin, and prevalence are elucidated, it is of critical importance that these data be collected and collated in a way that can be easily accessed and analyzed. This chapter describes current structural variation online resources (see Fig. 1 and Table 1), highlights the challenges in capturing, storing, and displaying SV data, and discusses how dbVar and DGVa, the genomic structural variation databases developed at NCBI and EBI, respectively, were designed to address these issues. PMID- 22228018 TI - Algorithm implementation for CNV discovery using Affymetrix and Illumina SNP array data. AB - SNP array data can be analysed for the purpose of calling SNP alleles but also for determining the absolute copy number of a certain genomic segment. Here, the method for detecting copy number (CN) change using intensity data from SNP arrays is focused on. Methods incorporating data from the two main genotyping platforms, Affymetrix and Illumina, are described and possible options and problems that may be faced are examined. We discuss the importance of the quality control when using this analysis method and present some guidelines for implementation, both prior and post to algorithm use. A discussion of algorithms available for CN detection is included as well as ideas for further analysis protocols. PMID- 22228019 TI - Targeted screening and validation of copy number variations. AB - The accessibility of genome-wide screening technologies considerably facilitated the identification and characterization of copy number variations (CNVs). The increasing amount of available data describing these variants, clearly demonstrates their abundance in the human genome. This observation shows that not only SNPs, but also CNVs and other structural variants strongly contribute to genetic variation. Even though not all structural variants have an obvious phenotypic effect, there is evidence that CNVs influence gene dosage and hence can have profound effects on human disease susceptibility, disease manifestation, and disease severity. Therefore, CNV screening and analysis methodologies, specifically focusing on disease-related CNVs are actively progressing. This chapter specifically describes different techniques currently available for the targeted screening and validation of CNVs. We not only provide an overview of all these CNV analysis methods, but also address their strong and weak points. Methods covered include fluorescence in situ hybridization (FISH), quantitative real-time PCR (qPCR), paralogue ratio test (PRT), molecular copy-number counting (MCC), and multiplex PCR-based approaches, such as multiplex amplifiable probe hybridization (MAPH), multiplex ligation-dependent probe amplification (MLPA), multiplex PCR-based real-time invader assay (mPCR-RETINA), quantitative multiplex PCR of short fluorescent fragments (QMPSF), and multiplex amplicon quantification (MAQ). We end with some general remarks and conclusions, furthermore briefly addressing the future perspectives. PMID- 22228020 TI - High-resolution copy number profiling by array CGH using DNA isolated from formalin-fixed, paraffin-embedded tissues. AB - We describe protocols to acquire high-quality DNA from formalin-fixed, paraffin embedded (FFPE) tissues for the use in array comparative genome hybridization (CGH). Formalin fixation combined with paraffin embedding is routine procedure for solid malignancies in the diagnostic practice of the pathologist. As a consequence, large archives of FFPE tissues are available in pathology institutes across the globe. This archival material is for many research questions an invaluable resource, with long-term clinical follow-up and survival data available. FFPE is, thus, highly attractive for large genomics studies, including experiments requiring samples for test/learning and validation. Most larger array CGH studies have, therefore, made use of FFPE material and show that CNAs have tumor- and tissue-specific traits (Chin et al. Cancer Cell 10: 529-541, 2006; Fridlyand et al. BMC Cancer 6: 96, 2006; Weiss et al. Oncogene 22: 1872-1879, 2003; Jong et al. Oncogene 26: 1499-1506, 2007). The protocols described are tailored to array CGH of FFPE solid malignancies: from sectioning FFPE blocks to specific cynosures for pathological revisions of sections, DNA isolation, quality testing, and amplification. The protocols are technical in character and elaborate up to the labeling of isolated DNA while further processes and interpretation and data analysis are beyond the scope. PMID- 22228021 TI - Characterizing and interpreting genetic variation from personal genome sequencing. AB - Since the completion of the human genome project, there has been enormous progress in the development of novel technologies for DNA sequencing. The advent of next-generation sequencing technologies now makes it possible to sequence an entire human genome in one or a few experiments. As a consequence, several individual human genomes have now been fully sequenced, using different experimental strategies. Although the protocols differ between the various sequencing technologies, the challenges of analyzing the data, calling variation, and interpreting the results are similar for all platforms. Here, we give an overview of the human genome sequencing projects completed to date. The strategies for aligning sequence reads and extracting information about different types of genetic variation from the sequence data are discussed. Identification of structural variation, such as copy number variation and insertion-deletion variants, can be complex, and there are a plethora of algorithms and analysis tools available. We also give an overview of the challenge of interpreting the whole-genome sequence data both from a technical and clinical perspective. PMID- 22228023 TI - Relation between insertion torque and bone-implant contact percentage: an artificial bone study. AB - OBJECTIVES: The purpose of this study was to determine the correlation between the peak insertion torque value (ITV) of a dental implant and the bone-implant contact percentage (BIC%). MATERIAL AND METHODS: Dental implants were inserted into specimens comprising a 2-mm-thick artificial cortical shell representing cortical bone and artificial foam bone representing cancellous bone with four densities (groups 1 to 4--0.32, 0.20, 0.16, and 0.12 g/cm(3)). Each specimen with an inserted implant was subjected to micro-computed tomography (micro-CT) scanning, from which the 3D BIC% values were calculated. Pearson's correlation coefficients (r) between the ITV and BIC% were calculated. RESULTS: The ITVs in groups 1 to 4 were 56.2 +/- 4.6 (mean+/-standard deviation), 45.6 +/- 0.9, 43.3 +/- 4.3, and 38.5 +/- 3.4 N cm, respectively, and the corresponding BIC% values were 41.5 +/- 0.5%, 39.0 +/- 1.0%, 30.8 +/- 1.1%, and 26.2 +/- 1.6%. Pearson's correlation coefficient between the ITV and BIC% was r = 0.797 (P < 0.0001). CONCLUSION: The initial implant stability, quantified as the ITV, was strongly positively correlated with the 3D BIC% obtained from micro-CT images. CLINICAL RELEVANCE: The ITV of a dental implant can be used to predict the initial BIC%; this information may provide the clinician with important information on the optimal loading time. PMID- 22228022 TI - Massively parallel sequencing approaches for characterization of structural variation. AB - The emergence of next-generation sequencing (NGS) technologies offers an incredible opportunity to comprehensively study DNA sequence variation in human genomes. Commercially available platforms from Roche (454), Illumina (Genome Analyzer and Hiseq 2000), and Applied Biosystems (SOLiD) have the capability to completely sequence individual genomes to high levels of coverage. NGS data is particularly advantageous for the study of structural variation (SV) because it offers the sensitivity to detect variants of various sizes and types, as well as the precision to characterize their breakpoints at base pair resolution. In this chapter, we present methods and software algorithms that have been developed to detect SVs and copy number changes using massively parallel sequencing data. We describe visualization and de novo assembly strategies for characterizing SV breakpoints and removing false positives. PMID- 22228025 TI - Increased TGF-beta1-mediated suppression of growth and motility in castrate resistant prostate cancer cells is consistent with Smad2/3 signaling. AB - BACKGROUND: Elevated TGF-beta levels are associated with prostate cancer progression. Although TGF-beta is a tumor suppressor for normal epithelial and early-stage cancer cells, it may act paradoxically as a tumor promoter in more advanced cancers, although its effects are largely cell and context dependent. This study analyzed prostate cancer responses to TGF-beta signaling in an isogenic model of androgen-sensitive and castration-resistant prostate cancer cells. METHODS: Phosphorylation and nuclear translocation of Smad2 and Smad3 were analyzed using immunoblotting. Proliferation and cell cycle responses to TGF beta1 (5 ng/ml) were assessed using growth assays and flow cytometry for DNA content, as well as Western blot and immunoprecipitation of cell cycle proteins. RESULTS: Both androgen-sensitive (LNCaP) and castration-resistant (C4-2 and C4 2B) prostate cancer cell lines demonstrated TGF-beta1-induced phosphorylation and nuclear translocation of Smad2/3 that was robust in metastatic lines. Smad phosphorylation was completely abrogated with inhibition of ALK-5 kinase activity using the kinase inhibitor, SB-431542. Increased sensitivity to TGF-beta1 mediated growth inhibition was observed in C4-2 and C4-2B cells, as compared to LNCaP cells. This was paralleled with downregulation of Cyclin D and increased association of p15(Ink4b) or p27(Kip) with CDK's. Additionally, TGF-beta1 inhibited motility and invasion of metastatic cell lines. CONCLUSIONS: TGF-beta mediated suppression of growth and motility is enhanced in metastatic, castration resistant prostate cancer cells. Enhanced TGF-beta1-induced Smad2 and -3 signaling in prostate cancer cells may correlate with tumor suppressive activity. Therefore, the direct effects of TGF-beta1 on prostate cancer cells post castration may be anti-tumorigenic and growth-suppressive. PMID- 22228024 TI - The association between complete absence of post-treatment periapical lesion and quality of root canal filling. AB - AIM: The technical quality of a root canal treatment is clinically judged by the apical extension and homogeneity of the filling material imaged by periapical radiographs (PA). The aim of this experiment was to evaluate the association between the technical quality of the root canal filling and treatment outcome. MATERIALS AND METHODS: In 234 teeth (268 roots) that underwent root-canal treatment, the quality of the root canal filling as well as the outcome of the treatment were assessed with both PA and cone-beam computed tomography (CBCT) 2 years after treatment. Satisfactory root filling on PA was defined as 0-2 mm within the radiographic apex without voids; on CBCT scans, the apical end of the canal replaced the radiographic apex. The outcome predictors were analyzed using multivariate logistic regression. RESULTS: At recall, periapical radiolucent areas were absent in 198 (74%) roots on PA and 164 (61%) roots on CBCT scans. The presence of preoperative periapical radiolucency and the quality of root filling and coronal restoration were identified by both PA and CBCT as outcome predictors (p < 0.01). Complete absence of post-treatment periapical radiolucency was observed in CBCT scans in 81% and 49% of satisfactory and unsatisfactory root fillings, respectively, as compared to 87% and 61% revealed by PA. CONCLUSION: Satisfactory root fillings were associated with a favorable outcome, confirmed by both PA and CBCT. CLINICAL RELEVANCE: The outcome of root canal treatment is improved once the filling is 0-2 mm from the apex, and no voids could be detected. Technical skills and performance of root canal filling procedures should be emphasized, and suitable methods should be developed in order to achieve more compacted filling materials without voids and at the correct length. PMID- 22228026 TI - Enhancement of felodipine dissolution rate through its incorporation into Eudragit(r) E-PHB polymeric microparticles: in vitro characterization and investigation of absorption in rats. AB - In this study, felodipine was incorporated into microparticles prepared with Eudragit(r) E and it blended with poly(3-hydroxybutyrate) (PHB) using the emulsion-solvent evaporation technique, with the aim of improving the dissolution rate of the drug. The formulation prepared with Eudragit(r) E showed irregular and fragmented microparticles, with a loading efficiency (LE) of 82.6%. When the microparticles were prepared with a blend of Eudragit(r) E and PHB, they had a spherical form with a LE of 103.9%. X-ray diffraction and differential thermal analysis indicated a reduction in the crystallinity of felodipine after its incorporation into the microparticles, which caused a significant increase in the felodipine dissolution rate. An investigation into the absorption in rats was carried out using high-performance liquid chromatography analysis of the blood collected 20 and 60 min after the animals were administered felodipine [30 mg/Kg, orally (p.o.)] or felodipine microparticles (30 mg/Kg, p.o.). Animals that were given felodipine showed mean plasmatic levels of 0.0125 (+/-0.00156) and 0.0240 (+/-0.0069) MUg mL(-1) after 20 and 60 min, respectively, whereas animals that received microparticles containing felodipine showed respective mean plasmatic levels of 0.0651 (+/-0.0120) and 0.0369 (+/-0.0145) MUg mL(-1) . Our data suggest that the incorporation into microparticles significantly enhanced the release of felodipine, improving its absorption in rats. PMID- 22228027 TI - The influence of local factors on the prediction of fumonisin contamination in maize. AB - BACKGROUND: Contamination by mycotoxins is a major concern to the maize industry in north-east Italy where maize grain is often spoiled by Fusarium spp. In this work, fumonisins, deoxynivalenol and zearalenone were determined and an artificial neural network (ANN) model suitable for predicting mycotoxin contamination of maize at harvest time was developed. RESULTS: The occurrence of deoxynivalenol and zearalenone was very limited, while fumonisins concentration ranged from 163 and to 3663 ug kg(-1) in 2007, and from 333 to 11473 ug kg(-1) in 2008. Statistical data analysis of factors affecting fumonisins concentration revealed that irrigation, chemical treatment against the European corn borer and harvest date significantly affected the level of contamination (P < 0.05), although the relevance of the factors was different in 2007 and 2008. The neural network approach showed a significant correlation between ascertained values and predictions based on agronomic data. CONCLUSION: This is the first time that an artificial neural network has been used to predict fumonisin accumulation in maize: the prediction has been shown to have the potential for the development of a new approach for the rapid cataloging of grain lots. PMID- 22228029 TI - Clinical outcomes, quality of life, advantages and disadvantages of metal stent placement in the upper gastrointestinal tract. AB - PURPOSE OF REVIEW: This review will discuss the immediate- and long-term success, complications and overall benefits of self-expandable metal stents (SEMSs) in malignant or benign obstruction of the oesophagus, stomach and duodenum. Over recent years, indications such as benign disease have expanded, as has SEMS diversity with self-expandable plastic stents (SEPSs) or fully covered and biodegradable stents, for example. RECENT FINDINGS: SEMSs have been increasingly used in malignant upper gastrointestinal obstruction with many reports confirming efficacy, despite a significant complication rate. Fully covered stents are increasingly used for a variety of benign oesophageal disease, but their place in gastric outlet obstruction is still unclear. Covered and uncovered stents have different functional characteristics and stent type must be selected on an individual basis. Biodegradable stents show promise and the outcome of experience in larger patient cohorts is eagerly awaited. SUMMARY: This area is an evolving field, in which the clinician requires up-to-date knowledge of therapeutic options to make individualized treatment choices in difficult clinical circumstances. Technical and clinical success for oesophageal or gastroduodenal SEMSs are then above 90%. Minor complications are common, but serious complications seldom occur. Biodegradable stents may be useful, especially when stenting is needed for a short period of time. PMID- 22228028 TI - Novel drugs to ameliorate gastrointestinal normal tissue radiation toxicity in clinical practice: what is emerging from the laboratory? AB - PURPOSE OF REVIEW: To give an overview of promising novel agents under development for the prevention and reduction of gastrointestinal radiation injury. RECENT FINDINGS: Currently, several novel agents are being tested as drugs to prevent or reduce gastrointestinal radiation injury. These drugs may not only prevent injury, but also mitigate toxicity, that is, reduce injury after radiation exposure has occurred. Promising novel agents include the somatostatin analogue SOM230, growth factors, agents acting on the toll-like receptor 5 pathway, endothelial protectants, and the vitamin E analogue gamma-tocotrienol. SUMMARY: Gastrointestinal radiation injury is the most important dose-limiting factor during radiotherapy of the abdomen or pelvis. It may severely affect the quality of life both during radiotherapy treatment and in cancer survivors. To date, there are no agents that can prevent or reduce intestinal radiation injury. Hence, there is an urgent need for the development of novel drugs to ameliorate intestinal toxicity during and after radiotherapy. This review summarizes the several agents that have been shown to reduce intestinal radiation injury in animals. Further research is needed to investigate their safety and efficacy in patients receiving radiotherapy for abdominal or pelvic tumours. PMID- 22228030 TI - Gastrointestinal symptoms in cancer patients with advanced disease: new methodologies, insights, and a proposed approach. AB - PURPOSE OF REVIEW: This review summarizes recent developments in the management of gastrointestinal symptoms experienced by cancer patients and provides a framework for education, assessment and monitoring, and treatment. RECENT FINDINGS: Although many viable treatment options exist, gastrointestinal symptoms - particularly nausea and vomiting, constipation, and diarrhea - continue to challenge both patients and clinicians. Current clinical guidelines now recommend that patients treated with moderate emetic risk chemotherapy regimens be preferentially treated with the 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, palonosetron, in combination with dexamethasone. A large randomized trial has also recently validated that single-dose fosaprepitant is equivalent to the standard 3-day, aprepitant regimen. New medications, such as skin patch delivery of granisetron for nausea or methylnaltrexone for constipation, show promise in both the management of symptoms and as preventive agents. The integration of complementary and alternative therapies, such as relaxation techniques, ginger, and electroacupuncture may also assist with symptom relief. Accurate assessment is essential, but often problematic, especially as the patient's experience of gastrointestinal distress is often disproportionate with objective measures. New methodologies that harness technology to collect patient reported outcomes may improve the accuracy of assessment, provide a better picture of the patient's experience of gastrointestinal symptoms, and deliver a means to simultaneously monitor symptoms, educate patients, and collect longitudinal data. SUMMARY: Palliative management of gastrointestinal symptoms in advanced cancer patients requires a multipronged approach that entails effective assessment, judicious use of latest evidence-based approaches, and monitoring that incorporates both clinical measures and patient-reported outcomes. When combined with refinements in the overall clinical approach to symptom management, standardized instruments that streamline data collection and enable data warehousing will support better symptom management. PMID- 22228031 TI - Opioid genetics in the context of opioid switching. AB - PURPOSE OF REVIEW: On a population level, there is no difference in terms of efficacy or side-effects between any of the strong opioids. On an individual level, however, there is marked variation in response to opioids. This review presents some of the recent advances in opioid pharmacogenetic studies. RECENT FINDINGS: A growing number of genes have been studied in a number of different patient populations. Most data have come from candidate-gene studies. There have been two genome-wide association studies in pain and opioid response. The clinical and genetic complexity of response to opioids has limited the clinical applicability of the genetic results. Currently, interindividual variation in opioid response is managed clinically through a process known as opioid switching. The evidence supporting the efficacy of opioid switching is poor, mainly because randomized controlled trials in this area are lacking. SUMMARY: Adequately powered studies to allow identification of genetic variants with small effect size and exploration of gene-gene interaction are needed. Integration of genetic analysis in clinical studies with carefully defined outcome measures will increase the likelihood of identifying clinical and genetic factors which can be used to predict opioid response. PMID- 22228032 TI - Entangled coordination polymers with mixed N- and O-donor organic linkers: a case of module-matching priority. AB - A series of four coordination polymers showing entangled architectures based on cobalt and mixed N-donor/O-donor ligands, namely [Co(4,4'-BPIPA)(TP)].2DMF (1), [Co(4,4'-BPIPA)(2,6-NDC)(DMF)].DMF (2), [Co(4,4'-BPIPA)(2,6-NDC)].2DMF (3) and [Co(4,4'-BPIPA)(4,4'-BPDC)].2DMF (4) (4,4'-BPIPA = N,N'-bis-4-pyridinyl isophthalamide, TP = terephthalic acid, 2,6-NDC = 2,6-naphthalenedicarboxylic acid, 4,4'-BPDC = 4,4'-biphenyldicarboxylic acid), have been synthesized under solvothermal conditions. Complex 1, containing 4,4'-BPIPA and relatively short dicarboxylate ligands (TP), exhibits two-dimensional (2D) two-fold interpenetration of double wavy 4(4)-sql nets. Complex 2 displays interesting 2D >3D parallel polycatenation of undulated 2D 4(4)-sql layers built by 4,4'-BPIPA and moderate dicarboxylate ligands (2,6-NDC). Complexes 3 and 4, although constructed of dicarboxylate ligands with different lengths (moderate 2,6-NDC and long 4,4'-BPDC), possess similar 3-fold interpenetration of identical self catenated single nets with 6(5).8-mok topologies. It has been found that the length of the dicarboxylate ligands plays a key role of module-matching in the self-assemblies of complexes 1-4. Moreover, the effect of the conformations of 4,4'-BPIPA, which can be controlled by tuning reaction temperatures, is also discussed. PMID- 22228033 TI - Self-assembly and selective exchange of oligoanions on the surface of monolayer protected Au nanoparticles in water. AB - Self-assembled monolayers on Au nanoparticles terminating with TACN.Zn(II) head groups are attractive scaffolds for the formation of multivalent supramolecular structures at submicromolar concentrations in water. PMID- 22228034 TI - The tumor suppressor role of Src homology phosphotyrosine phosphatase 2 in hepatocellular carcinoma. AB - PURPOSE: The human gene PTPN11, which encodes the non-receptor protein tyrosine phosphatase of Src homology phosphotyrosine phosphatase 2 (Shp2), has been previously well interpreted as a proto-oncogene in a variety of malignancies. However, the tumor suppressor role of Shp2 has also been reported. The present study was conducted to investigate the role of Shp2 expression and its associated clinical manifestations in hepatocellular carcinoma (HCC). METHODS: A tissue microarray of 333 pairs of HCC and self-matched adjacent non-tumor tissues was constructed, and the expression of Shp2 was determined by immunohistochemistry. The results were also conformed by Western blotting and quantitative PCR of 31 self-paired fresh HCC specimens. The associations of Shp2 expression with 25 clinicopathologic features were analyzed. Overall survival analysis and multivariate analysis were performed. RESULTS: Significantly decreased Shp2 expression in tumor tissues (T) compared with adjacent non-tumor tissues (NT) could be detected, and the positive rate was 66.1 and 96.7%, respectively. We combined the T and NT Shp2 immunoreactivity by a variable of the decrease in Shp2 expression (DeltaShp2) and divided cases into 2 groups: T < NT and T >= NT. Survival analysis showed both low Shp2 expression and T < NT group were significantly associated with short overall survival. Multivariate analysis showed DeltaShp2 was an independent prognostic marker (P = 0.033; HR: 0.527; 95% CI: 0.293-0.950). CONCLUSION: Shp2 is a tumor suppressor, and the decrease in Shp2 expression was a new prognostic marker in HCC. The oncogenic role of Shp2 was tissue specific, and the therapeutic target of human gene PTPN11 should be reconsidered. PMID- 22228035 TI - 3D-QSAR and molecular docking analysis of biphenyl amide derivatives as p38alpha mitogen-activated protein kinase inhibitors. AB - The p38alpha mitogen-activated protein (MAP) kinase plays a vital role in treating many inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, Crohn's disease and psoriasis. Herein, we have performed 3D-QSAR and molecular docking analysis on a novel series of biphenyl amides to design potent p38 MAP kinase inhibitors. This study correlates the p38 MAP kinase inhibitory activities of 80 biphenyl amide derivatives to several stereochemical parameters representing steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields. The resulting model from CoMFA and CoMSIA exhibited excellent [Formula: see text] values of 0.979 and 0.942, and [Formula: see text] values of 0.766 and 0.748, respectively. CoMFA predicted [Formula: see text] of 0.987 and CoMSIA predicted [Formula: see text] of 0.761 showed that the predicted values were in good agreement with experimental values. Glide (5.5) program gave the path for binding mode exploration between the inhibitors and p38alpha MAP kinase. We have accordingly designed novel p38alpha MAP kinase inhibitors by utilizing LeapFrog and predicted with excellent activity in the developed models. PMID- 22228037 TI - Acute heat stress impairs performance parameters and induces mild intestinal enteritis in broiler chickens: role of acute hypothalamic-pituitary-adrenal axis activation. AB - Studies on the environmental consequences of stress are relevant for economic and animal welfare reasons. We recently reported that long-term heat stressors (31 +/ 1 degrees C and 36 +/- 1 degrees C for 10 h/d) applied to broiler chickens (Gallus gallus domesticus) from d 35 to 42 of life increased serum corticosterone concentrations, decreased performance variables and the macrophage oxidative burst, and produced mild, multifocal acute enteritis. Being cognizant of the relevance of acute heat stress on tropical and subtropical poultry production, we designed the current experiment to analyze, from a neuroimmune perspective, the effects of an acute heat stress (31 +/- 1 degrees C for 10 h on d 35 of life) on serum corticosterone, performance variables, intestinal histology, and peritoneal macrophage activity in chickens. We demonstrated that the acute heat stress increased serum corticosterone concentrations and mortality and decreased food intake, BW gain, and feed conversion (P < 0.05). We did not find changes in the relative weights of the spleen, thymus, and bursa of Fabricius (P > 0.05). Increases in the basal and the Staphylococcus aureus-induced macrophage oxidative bursts and a decrease in the percentage of macrophages performing phagocytosis were also observed. Finally, mild, multifocal acute enteritis, characterized by the increased presence of lymphocytes and plasmocytes within the lamina propria of the jejunum, was also observed. We found that the stress-induced hypothalamic pituitary-adrenal axis activation was responsible for the negative effects observed on chicken performance and immune function as well as for the changes in the intestinal mucosa. The data presented here corroborate with those presented in other studies in the field of neuroimmunomodulation and open new avenues for the improvement of broiler chicken welfare and production performance. PMID- 22228038 TI - Contributions to an animal trait ontology. AB - Improved understanding of the biology of traits of livestock species necessitates the use and combination of information that is stored in a variety of different sources such as databases and literature. The ability to effectively combine information from different sources, however, depends on a high level of standardization within and between various resources, at least with respect to the used terminology. Ontologies represent a set of concepts that facilitate standardization of terminology within specific domains of interest. The biological mechanisms underlying quantitative traits of farm animal species related to reproduction and host pathogen interactions are complex and not well understood. This knowledge could be improved through the availability of domain specific ontologies that provide enhanced possibilities for data annotation, data retrieval, data integration, data exchange, data analysis, and ontology-based searches. Here we describe a framework for domain-specific ontologies and the development of 2 first-generation ontologies: Reproductive Trait and Phenotype Ontology (REPO) and Host Pathogen Interactions Ontology . In these first generation ontologies, we focused on "female fertility in cattle" and "interactions between pigs and Salmonella". Through this, we contribute to the global initiative toward the development of an Animal Trait Ontology for livestock species. To demonstrate its usefulness, we show how REPO can be used to select candidate genes for fertility. PMID- 22228039 TI - Interactions of phytate and myo-inositol phosphate esters (IP1-5) including IP5 isomers with dietary protein and iron and inhibition of pepsin. AB - Phytic acid (IP(6)) and myo-inositol phosphate esters (IP(1-5)), including IP(5) isomers prepared chemically and enzymatically with bacterial and fungal phytases, were examined for their effects on protein aggregation of soy protein and beta casein, interaction with Fe(3+), and pepsin activity. The results indicated that the aggregating capabilities of IP esters (IP(1-6)) on the 2 proteins decreased dramatically from IP(6) to IP(5) and became negligible with IP(1-4). Among the IP(5) isomers tested, InsP(5)(1,2,3,4,5) produced by 6-phytase was slightly less powerful in aggregating protein than InsP(5)(1,2,4,5,6) produced by 3-phytase (P = 0.001). For protein hydrolysis, IP esters of IP(3-4) still showed inhibition of pepsin though to a lesser extent than IP(5-6). The in vitro data with IP(1-5) generated with microbial 3- and 6-phytases indicate that, for complete alleviation of pepsin inhibition, IP(6) needs to be broken down to IP(1-2.) In contrast to the aggregation with protein, the reactivity of IP(1-6) toward Fe(3+) decreased proportionally from IP(6) to IP(3.) Based on the radical decrease in turbidity of IP(6) -protein complex observed, as a result of IP(6) dephosphorylation to IP(5), a novel qualitative and semi-quantitative phytase plate assay was established using IP(6)-protein complex incorporated into an agarose petri-dish as substrate. Phytase activity was shown as the development of clear halos on the agarose plate with time. This simple phytase plate assay method can be used at animal farms, control laboratories, and even for the screening of engineered phytase variants. The current study, thus, stresses the importance of the efficient hydrolysis of IP(6) at lower pH range to alleviate the negative effect of phytic acid and its degradation products on protein and Fe(3+) digestion. PMID- 22228040 TI - Oscillometric sphygmomanometers: a critical appraisal of current technology. AB - AIM: Blood pressure (BP), a key vital sign, monitors general health. Oscillometric devices are increasingly used for measurement, although their accuracy continues to be critically debated. A functional block diagram is used to review the components that affect accuracy. METHODS: A block diagram is presented covering the components from cuff to algorithm. The oscillometric waveform is described, considering factors that can alter its shape. Methods used to assess accuracy, including the potential use of simulators, are described. RESULTS AND DISCUSSION: The block diagram focuses attention on cuff, amplifier, signal processing and algorithm. The importance of correct cuff size is emphasized. Accuracy can be affected by the extraction of the oscillometric pulses and the interpolation to compensate for higher deflation rates. Modern electronic amplifiers are assumed to be stable and do not drift, an assumption largely untested. Crucial to accuracy is the algorithm, but there is no standard algorithm and limited theoretical basis, leading to significant measurement errors in groups of patients, even by approved devices. The causes are not well understood, but differences in oscillometric waveform shape between patient groups have been observed and may explain auscultatory-oscillometric differences. The ability of theoretical models to explain the effects of arterial stiffness on BP measurements is discussed. Validation remains statistical though steps have been taken to improve it. CONCLUSION: The indirect nature of BP measurement poses particularly problems for ensuring accuracy. Critical assessment has done much to improve standards, but a solid theoretical understanding of the technique has not been formulated and further work is required. PMID- 22228041 TI - Impaired inflammatory responses to multiple toll-like receptor ligands in alveolar macrophages of streptozotocin-induced diabetic mice. AB - OBJECTIVE: To investigate the effect of hyperglycemic state on the activation of alveolar macrophages (AMs) mediated via Toll-like receptors (TLRs) typically associated with bacterial infection. METHODS: AMs obtained from normoglycemic control mice and streptozotocin-induced diabetic mice were stimulated ex vivo with the following: a TLR2 ligand, peptidoglycan (PGN); a TLR4 ligand, lipopolysaccharide (LPS); or a TLR5 ligand, flagellin (FLG). Cytokine production and mRNA expression were measured by ELISA and real-time PCR, respectively. TLR expression was assessed by real-time PCR and flow cytometry. RESULTS: AMs from diabetic mice produced significantly less TNF-alpha after PGN or FLG stimulation, and less IL-6 after FLG stimulation, compared with AMs from control mice. The decrease in the production of these cytokines was associated with reduced mRNA expression of the corresponding cytokines. In contrast, production of TNF-alpha and IL-6 after LPS stimulation did not differ between groups. Furthermore, there was no substantial difference in the expression of TLR2, TLR4, and TLR5 in AMs between the groups. The increased JNK phosphorylation induced by PGN or FLG stimulation was downregulated in AMs from diabetic mice. CONCLUSIONS: Hyperglycemic state impairs the reactivity of AMs to multiple TLR ligands. This effect might result from hyperglycemia-induced alteration of intracellular signaling and is unlikely due to the modulation of TLR expression. PMID- 22228043 TI - Does the use of doxazosin influence the success of SWL in the treatment of upper ureteral stones? A multicenter, prospective and randomized study. AB - The objective of the study is to investigate the effect of doxazosin, administered to the subjects who underwent SWL due to upper ureteral stones, on therapeutic outcomes. The study enrolled the patients with a radio-opaque stone >=5 mm in upper ureter. Patients were randomized into two groups: the first group underwent SWL following the diagnosis and they were recommended to receive oral hydration. The second group underwent SWL after initiating alpha blocker (doxazosin controlled-release tablet 4 mg/day) and drug therapy was continued until that the patient has been stone free. Parameters of SWL procedure, Steinstrasse, pain score at admission, time to stone passage, the complications developed, the additional procedures that were administered and number of hospital visits done due to pain during the treatment were recorded. A total of 79 patients were enrolled to the study. The subjects evaluated included 35 patients, who received an alpha blocker and 44 patients who did not receive an alpha blocker. For both groups, the level of energy applied per SWL session, the diameter of the stone, the number of hospital visits done due to pain, pain score and the need for analgesia were found to be similar (p > 0.05). The group of doxazosin was more advantageous in terms of stone-free rate, the need for additional procedures and Steinstrasse (p < 0.05). In conclusion, the addition of doxazosin to SWL therapy administered for upper ureteral stones reduces Steinstrasse, and thereby, the need for additional procedures and increases post treatment stone-free rate. A positive effect of doxazosin on the time to stone passage was not shown. PMID- 22228044 TI - Evaluation of MBECTM-HTP biofilm model for studies of implant associated infections. AB - The bacteria in implant-related infections can evade host defenses by forming biofilms. The more we understand biofilm behavior, the better we can fight against then clinically. In vitro models for biofilms allow tests simulating in vivo conditions. In this study we evaluated the Minimum Biofilm Eradication Concentration-High Throughput Plates (MBECTM-HTP) as biofilm in vitro model for studies of implant associated infections. Staphylococcus aureus and Staphylococcus epidermidis biofilms were grown on MBECTM-HTP. To ensure the biofilm formation, antibiotic susceptibility tests and scanning electron microscopy (SEM) was carried out. Susceptibility tests were carried out using gentamicin, vancomycin, rifampicin, fosfomycin, clindamycin, and linezolid. Colony forming units counting were carried out. Minimal inhibitory concentration (MIC) and biofilm inhibitory concentration (BIC) were estimated. The CFU counting showed potency of rifampicin and daptomycin against S. epidermidis biofilms and rifampicin against S. aureus biofilms. SEM images showed proteic material in contact with cells. The differences between BIC and MIC demonstrated the biofilm formation as well as the SEM images. Rifampicin and daptomycin are good choices against biofilm related infections. Moreover, after suggested modifications, the model used in this study is eligible to further studies of implant associated infections. PMID- 22228045 TI - Hyperlipidemic versus normal-lipid acute necrotic pancreatitis: proteomic analysis using an animal model. AB - OBJECTIVES: Hyperlipidemia is associated with a variety of pancreatic diseases. However, the underlying pathophysiology and molecular mechanisms between hyperlipidemia and acute pancreatitis remain undefined. Gel electrophoresis and mass spectrometry can be used in proteomic analysis to elucidate these mechanisms. METHODS: A comparative proteomic analysis was conducted to identify proteins that were altered in pancreases of hyperlipidemic acute necrotic pancreatitis rats compared with those of normal-lipid acute necrotic pancreatitis rats. A comparative proteomic approach using a hyperlipidemic rat model was used. RESULTS: Thirty-nine differentially expressed proteins were significantly changed in pancreatic samples from hyperlipidemic acute necrotic pancreatitis rats. Differentially expressed proteins in hyperlipidemic pancreatitis include pancreatic proteolytic enzymes, such as lipase, amylase, carboxypolypeptidase, and alpha-1-antiproteinase; endoplasmic reticulum stress-related proteins; and calcium influx-related proteins including protein disulfide isomerase, calreticulin, annexin A, glucose-regulated protein 78, heat shock protein 60, and peroxiredoxin. Other proteins associated with DNA replication and damage repair, apoptosis, cell metabolism, circulatory dysfunction, and signal transduction were identified in hyperlipidemic pancreatitis. CONCLUSIONS: Hyperlipidemia intensifies acute necrotic pancreatitis through various ways. These enzymes may be putative biomarkers of hyperlipidemic acute necrotic pancreatitis. PMID- 22228046 TI - Acute pancreatic pseudocyst: incidence, risk factors, and clinical outcomes. AB - OBJECTIVES: The aim of this study was to analyze the incidence, risk factors, and clinical outcomes of pancreatic pseudocyst after acute or acute-on-chronic pancreatitis. METHODS: We retrospectively reviewed the medical records of 350 patients with acute pancreatitis and 55 patients with acute-on-chronic pancreatitis. RESULTS: Pancreatic pseudocyst developed in 14.6% of acute pancreatitis and in 41.8% of acute-on-chronic pancreatitis (P = 0.00). In the acute-on-chronic pancreatitis group, interval from symptom onset to hospital visit was longer, and the incidence of recurrent pancreatitis and alcoholic etiology was higher than that of the acute pancreatitis group (P < 0.01). There was no significant difference in the spontaneous resolution rate between both groups. Of the total 68 conservatively treated patients with pseudocyst, the pseudocyst decreased in size or disappeared in 77.9% and showed no change in 1.5%. The risk factors of pseudocyst were the presence of underlying chronic pancreatitis, the interval from symptom onset to visiting the hospital, and an alcoholic etiology. The factor-predicted spontaneous resolution was a single lesion. CONCLUSIONS: Pseudocyst developed more frequently in patients with acute on-chronic pancreatitis, and most pseudocysts improved spontaneously irrespective of underlying chronic pancreatitis. A longer period of a "wait-and-see" policy for more than 6 weeks is suggested for asymptomatic pseudocyst, especially for a single lesion. PMID- 22228048 TI - Assessment of Chronic Pancreatitis: Use of Whole Pancreas Perfusion With 256 Slice Computed Tomography. AB - OBJECTIVE: We aimed to compare perfusion computed tomography (CTP) characteristics of the normal pancreas with those of chronic pancreatitis (CP) and to examine the possibility of evaluating pancreatic exocrine function with CTP. METHODS: Thirty-two patients (control group, n = 18; CP group, n = 14) who completed the whole pancreas CT perfusion examination with 256-slice CT were studied. Four parameters, including perfusion (PF), peak enhancement intensity (PEI), time-to-peak (TTP), and blood volume (BV), were measured and compared between the control and CP groups, and between patients with and without exocrine pancreatic insufficiency (EPI) in the CP group. Pancreatic exocrine function was determined via serum trypsinogen. RESULTS: There was no significant difference between the distribution of PF, PEI, and BV in different pancreas regions, namely, the head, body, and tail (P > 0.05). PF, PEI, and BV of the CP group were significantly decreased, and TTP was significantly increased compared with the control group (P < 0.05). A significant decrease of PF, PEI, and BV and increase of TTP were observed in patients with EPI than in patients without EPI (P < 0.05). CONCLUSIONS: Perfusion CT is an appropriate imaging technique to diagnose CP and may be useful as a screening test to rule out early EPI. PMID- 22228047 TI - Surgical management of insulinomas in multiple endocrine neoplasia type 1. AB - OBJECTIVE: This study aimed to evaluate the accuracy of preoperative and intraoperative diagnostic tools and the surgical strategy to obtain cure in multiple endocrine neoplasia type 1 (MEN-1) patients affected with insulinoma. METHODS: Eight MEN-1 patients (1992-2009) were operated on for hypoglycemic crisis. Preoperative tumor localization was carried out. Ultrasound and modification of the insulin/glucose (I/G) ratio were applied intraoperatively. Pancreatic lesions larger than 0.5 cm were removed by resection of the most affected pancreatic region and by enucleation of nodules in least affected regions. RESULTS: Two pancreatoduodenectomies and 6 distal pancreatectomies were performed; enucleation of nodules was necessary in 6 patients. There was no postoperative mortality. At the histopathologic analysis, a mean of 6 macrotumors and of 15.5 microlesions were found. Intraoperative ultrasound proved a sensitivity of 87.5% for detecting pancreatic insulinoma. Decrease in the I/G ratio after resection predicted postoperative outcome in all patients. At a mean follow-up of 81.5 months, all patients were normoglycemic with no evidence of disease recurrence. CONCLUSIONS: Multiple endocrine neoplasia type 1 insulinomas should be considered surgically curable. Pancreatic resection seems preferable to a less radical surgical approach in ensuring higher cure rates. Intraoperative ultrasound and I/G ratio are of value in the assessment of surgical decision and in the evaluation of the surgical cure. PMID- 22228049 TI - Clinicopathologic assessment of pancreatic ductal carcinoma located at the head of the pancreas, in relation to embryonic development. AB - OBJECTIVES: Pancreaticoduodenectomy is performed for pancreatic head cancer that originated from the dorsal or ventral primordium. Although the extent of lymph node (LN) dissection is the same irrespective of the origin, the lymphatic continuities may differ between the 2 primordia. METHODS: Between March 2003 and September 2010, 152 patients underwent pancreaticoduodenectomy for pancreatic cancer. One hundred six patients were assigned into 2 groups according to tumor location on preoperative computed tomography, and their clinical and pathological features were retrospectively analyzed in view of the embryonic development of the pancreas. RESULTS: Sixty of 106 patients were classified with tumors that were derived from the dorsal pancreas (D group) and 46 from the ventral pancreas (V group). The frequency of LN involvement around the middle colic artery (LN 15) in the D group was higher than in the V group (P = 0.008). The rate of additional resection of the pancreas tended to be higher in the D group (P = 0.067). CONCLUSIONS: The present study showed the detailed pattern of spread of pancreatic ductal carcinoma to the LNs and provided important information for determining the optimal surgical strategy. PMID- 22228050 TI - Diagnostic Strategy for Differentiating Autoimmune Pancreatitis From Pancreatic Cancer: Is an Endoscopic Retrograde Pancreatography Essential? AB - OBJECTIVES: The purpose of this study was to determine whether the choice for performance of endoscopic retrograde pancreatography (ERP) could be tailored to findings on computed tomography (CT) in patients with suspected autoimmune pancreatitis (AIP). METHODS: Eighty-four AIP patients and 73 pathology-proven pancreatic cancer patients from a prospectively maintained database were retrospectively included. Computed tomography and ERP images were reviewed in consensus by 2 blinded radiologists. The diagnostic performance of CT alone and combined use of CT and ERP (CT-ERP) were compared. RESULTS: The area under the receiver operating characteristic curve of CT-ERP was significantly greater than that of CT alone (0.97 vs 0.87, P < 0.001). When patients with AIP were divided into 2 subgroups according to CT features (typical vs atypical), 24 (69%) of 35 AIP patients with atypical CT findings were correctly diagnosed with AIP at CT ERP and received benefits from additional ERP. Endoscopic retrograde pancreatography had little added benefit in patients with typical CT findings for AIP (n = 49), because no alternative diagnoses were established after ERP. CONCLUSIONS: In patients with suspected AIP, the decision to perform ERP could be tailored to findings on CT. PMID- 22228051 TI - Effects of mitogen-activated protein kinase signaling pathway inhibition on the development of cerulein-induced acute pancreatitis in mice. AB - OBJECTIVES: Extracellular signal-regulated kinase (ERK) influences a number of pathways in all cells. The ERK cascade has long been known to be central to the activation of cellular processes such as proliferation, differentiation, and oncogenic transformation. The mitogen-activated protein (MAP) serine/threonine family of protein kinases, of which ERK is a member, is evolutionarily conserved and is activated by a mechanism that includes protein kinase cascades. The aim of this study was to investigate the effects of PD98059 [2-(2-amino-3-methoxyphenyl) 4H-1-benzopyran-4-one], a highly selective inhibitor of MAP/ERK kinase 1 (MEK1) activation, on the development of acute pancreatitis. METHODS: Pancreatitis was induced by intraperitoneal injection of cerulein (hourly * 5, 50 MUg/kg) and PD98059 (10 mg/kg, 10% dimethylsulfoxide, intraperitoneally) was administrated 1 and 3 hours after cerulein administration. RESULTS: Cerulein injection resulted in acute necrotizing pancreatitis. On the contrary, pancreatitis histological features, amylase, lipase, pancreas edema, and immunohistochemical staining for leukocyte adhesion molecules, transforming growth factor beta, and apoptosis related proteins were found reduced in PD98059-treated mice. CONCLUSIONS: We propose that this study could help to clarify the role of MAPK in the regulation of the inflammatory process as acute pancreatitis. PMID- 22228052 TI - Clinicopathologic study of intrapancreatic cancer spread in carcinoma of the body and tail of the pancreas. AB - OBJECTIVE: The aims of this study were to clarify the type of intrapancreatic spread of cancer of the pancreatic body and tail and to assess whether a 2-cm transection margin is adequate to ensure negative margins. METHODS: We selected 66 patients who underwent distal pancreatectomy for cancer of the pancreatic body and tail. We investigated intrapancreatic cancer spread in these patients histopathologically and analyzed the relationship between 2-cm-margin positivity and other clinicopathological characteristics. RESULTS: Two-centimeter-margin positivity was observed in 17 cases. In these, tumors had a tendency to spread toward the pancreatic head along the main pancreatic duct. As a result of statistical analysis, we considered venous invasion (odds ratio [OR], 15.48; 95% confidence interval [CI], 1.61-148.94; P = 0.0177), 2-cm-margin fibrosis (OR, 173.88; 95% CI, 8.96-3375.03; P = 0.0007), and 2-cm-margin hardness (OR, 5.97; 95% CI, 1.07-33.46; P = 0.0420) as being independently related to 2-cm-margin positivity. CONCLUSIONS: The results suggest that 2 cm is not a safe length to ensure a negative margin. In the future, preoperative and intraoperative evaluation of the degree of fibrosis of pancreatic parenchyma could lead to cancer-free pancreatic cut-end margins. PMID- 22228053 TI - Endoscopic ultrasonography of the pancreas as an indirect method to predict pancreatic exocrine insufficiency in patients with chronic pancreatitis. AB - OBJECTIVES: Functional evaluation of the pancreas is hindered by invasiveness and/or methodological difficulties. Endoscopic ultrasonography (EUS) provides with highly accurate images of pancreatic ducts and parenchyma. The aim of the study was to analyze the probability of pancreatic exocrine insufficiency (PEI) according to EUS criteria in patients with a diagnosis of chronic pancreatitis. METHODS: A total of 128 consecutive patients (mean age, 52 years; 104 men) with chronic pancreatitis were prospectively included. Pancreatic exocrine insufficiency was diagnosed by the carbon 13-mixed triglyceride breath test. Endoscopic ultrasonography was performed and EUS criteria of chronic pancreatitis evaluated by 2 different experienced endosonographers who were blinded to the results of the pancreatic function test. RESULTS: Forty-eight patients (37.5%) had PEI. The percentage of patients with PEI increased linearly with the number of EUS criteria. The presence of intraductal calcifications, hyperechogenic foci with shadowing, and dilation of the main pancreatic duct were significantly and independently associated to PEI. The probability of PEI in the presence of calculi in the main pancreatic duct is 80% and increases to 82.8% if, in addition, the main duct is dilated. CONCLUSIONS: Endoscopic ultrasonography findings allow predicting the probability of PEI in patients with chronic pancreatitis and thus the need for pancreatic enzyme replacement therapy. PMID- 22228055 TI - Beyond informed consent. PMID- 22228054 TI - Systemic-to-pulmonary collateral flow, as measured by cardiac magnetic resonance imaging, is associated with acute post-Fontan clinical outcomes. AB - BACKGROUND: Systemic-pulmonary collateral (SPC) flow occurs commonly in single ventricle patients after superior cavo-pulmonary connection, with unclear clinical significance. We sought to evaluate the association between SPC flow and acute post-Fontan clinical outcomes using a novel method of quantifying SPC flow by cardiac magnetic resonance (CMR) imaging. METHODS AND RESULTS: All patients who had SPC flow quantified by CMR imaging before Fontan were retrospectively reviewed to assess for acute clinical outcomes after Fontan completion. Forty four subjects were included who had Fontan completion between May 2008 and September 2010. SPC flow prior to Fontan measured 1.5+/-0.9 L/min/m(2), accounting for 31+/-11% of total aortic flow and 44+/-15% of total pulmonary venous flow. There was a significant linear association between natural log transformed duration of hospitalization and SPC flow as a proportion of total aortic (rho=0.31, P=0.04) and total pulmonary venous flow (rho=0.29, P=0.05). After adjustment for Fontan type and presence of a fenestration, absolute SPC flow was significantly associated with hospital duration >=7 days (odds ratio [OR]=9.2, P=0.02) and chest tube duration >=10 days (OR=22.7, P=0.009). Similar associations exist for SPC flow as a percentage of total aortic (OR=1.09, P=0.048 for hospitalization >=7 days; OR=1.24, P=0.007 for chest tube duration >=10 days) and total pulmonary venous flow (OR=1.07, P=0.048 for hospitalization >=7 days; OR=1.18, P=0.006 for chest tube duration >=10 days). CONCLUSIONS: Increasing SPC flow before Fontan, as measured by CMR imaging, is associated with increased duration of hospitalization and chest tube following Fontan completion. PMID- 22228056 TI - Research participants' perspectives on genotype-driven research recruitment. AB - Genotype-driven recruitment is a potentially powerful approach for studying human genetic variation but presents ethical challenges. We conducted in-depth interviews with research participants in six studies where such recruitment occurred. Nearly all responded favorably to the acceptability of recontact for research recruitment, and genotype-driven recruitment was viewed as a positive sign of scientific advancement. Reactions to questions about the disclosure of individual genetic research results varied. Common themes included explaining the purpose of recontact, informing decisions about further participation, reciprocity, "information is valuable," and the possibility of benefit, as well as concerns about undue distress and misunderstanding. Our findings suggest contact about additional research may be least concerning if it involves a known element (e.g., trusted researchers). Also, for genotype-driven recruitment, it may be appropriate to set a lower bar for disclosure of individual results than the clinical utility threshold recommended more generally. PMID- 22228057 TI - Epilepsy patient-participants and genetic research results as "answers". AB - Better understanding of how research participants with a known condition ascribe meaning to individual genetic results is important to help researchers and institutional review boards evaluate the potential benefits and harms of disclosing results in the context of genotype-driven research recruitment. Based on 29 in-depth interviews with epilepsy patients participating in a genetic study, we found that this population of research subjects anticipated that genetic research results would provide answers to a range of questions about the research process and their condition. Their multi-layered interpretations underscore the need for clear communication about the nature and limitations of results if individual or aggregate genetic results are returned in the process of recruitment for additional research. PMID- 22228058 TI - The meaning of genetic research results: reflections from individuals with and without a known genetic disorder. AB - In the debate about whether to return individual genetic results to research participants, consideration of the nature of results has taken precedence over contextual factors associated with different study designs and populations. We conducted in-depth interviews with 24 individuals who participated in a genotype driven study of cystic fibrosis: 9 of the individuals had cystic fibrosis, 15 had participated as healthy volunteers, and all had gene variants of interest to the researchers. These interviews revealed that the two groups had different ideas about the meaningfulness of genetic results. Our findings point to the importance of understanding research context, such as participants' relationship with the researcher and whether they have the disease condition under study, when considering whether to return individual results. PMID- 22228059 TI - Parent perspectives on pediatric genetic research and implications for genotype driven research recruitment. AB - As genetic research is increasingly conducted in children, it is important to understand how parents make decisions about enrolling their children and what they think about receiving their children's genetic research results. We conducted semi-structured phone interviews with 23 parents of children enrolled in genetic studies of autism or diabetes. Qualitative thematic analysis focused on two important components of genetic research and genotype-driven recruitment: participation in genetic research and return of results. Our findings suggest that parents' preferences and perspectives may be specific to their child's disease and the needs of the family as a whole. Assessing the expectations of target research populations will be beneficial for developing best practices for pediatric genetic research, return of results, and genotype-driven recruitment. PMID- 22228061 TI - "My parents decide if I can. I decide if I want to." Children's views on participation in medical research. AB - The participation of children in medical research raises many ethical issues, in particular regarding assent. However, little is known about children's own views on participation. This study presents results from interviews with children 10-12 years old with and without experience in a large-scale longitudinal screening study. We identified five themes: (1) knowledge about research, (2) a sense of altruism, (3) shared decision-making and right to dissent, (4) notions of integrity, privacy, and access, and (5) understanding of disease risk and personal responsibilities. We conclude that the children feel positive towards medical research, and want to take an active part in decisions and have their integrity respected. However, the study also indicates that children who had participated in longitudinal screening had a limited understanding, suggesting the vital importance of providing information appropriate to their age and maturity. This information should be provided out of respect for the children as persons, but also to promote their willingness to continue participating in longitudinal studies. PMID- 22228060 TI - Informed consent and genomic incidental findings: IRB chair perspectives. AB - It is unclear how genomic incidental finding (GIF) prospects should be addressed in informed consent processes. An exploratory study on this topic was conducted with 34 purposively sampled Chairs of institutional review boards (IRBs) at centers conducting genome-wide association studies. Most Chairs (96%) reported no knowledge of local IRB requirements regarding GIFs and informed consent. Chairs suggested consent processes should address the prospect of, and study disclosure policy on, GIFs; GIF management and follow-up; potential clinical significance of GIFs; potential risks of GIF disclosure; an opportunity for participants to opt out of GIF disclosure; and duration of the researcher's duty to disclose GIFs. Chairs were concerned about participant disclosure preferences changing over time; inherent limitations in determining the scope and accuracy of claims about GIFs; and making consent processes longer and more complex. IRB Chair and other stakeholder perspectives can help advance informed consent efforts to accommodate GIF prospects. PMID- 22228062 TI - Information that should be given to HIV cohort participants during ongoing research: the viewpoints of patient representatives and research professionals. AB - While investigators have a duty to provide research participants with summary findings at the end of a study, providing general information during the course of research is rarely considered. However, this raises an important ethical issue in the context of long-term studies such as cohorts or biobanks. We investigated this issue in the context of two ANRS cohorts of HIV-infected patients, AQUITAINE and COPILOTE. Face-to-face interviews were conducted with HIV patient representatives and research professionals concerning the delivery of information in the course of the research. Respondents stated that participants wish to be informed of research results (both aggregate and individual) but also expect general information about the cohort itself, research progression, and what their participation may provide. It was concluded that information provided during the course of the research may help participants to distinguish between care and research. The essential role of clinicians-investigators in providing information was emphasized. PMID- 22228063 TI - What women who use drugs have to say about ethical research: findings of an exploratory qualitative study. AB - Drug users are generally seen as a vulnerable population requiring special protection in research; however, to date there has been little empirical research into the ethics of research with illicit drug users. Moreover, the available research has tended to treat "drug users" as a homogeneous category, and has failed to consider potential gender differences in users' experiences. Drawing on focus groups with twenty-seven female drug users in Vancouver, Canada, this study examines women's experiences of research and what they see as ethical and respectful engagement. Many study participants talked about feeling dehumanized as a result of prior research participation. Women were critical of the assumption that drug users lack the capacity to take part in research, and affirmed the appropriateness of financial incentives. A variety of motivations for research participation were identified, including a desire for financial gain and altruistic concerns such as a desire to help others. These findings suggest that women drug users' views on ethical research differ from prevailing assumptions among institutional review boards about how research with such populations should proceed. PMID- 22228064 TI - A multicenter study of the awareness and attitudes of Egyptian faculty towards research ethics: a pilot study. AB - The awareness and attitudes of faculty towards research ethics committees (RECs) and research ethics practices are largely unknown. Accordingly, we conducted a cross-sectional survey study involving various faculties (Medicine, Nursing, Pharmacy, and Dentistry) from four universities in Egypt. A large majority (> 85%) held positive attitudes towards RECs, but almost a third thought that RECs would delay research. More than half had not received prior training in research or medical ethics, but more than 90% thought that this subject matter should be taught to postgraduates. A large majority recognized the need for informed consent and confidentiality protections in research, but some held attitudes regarding certain research ethics practices that were questionable. We conclude that a curriculum in research ethics should be developed for university faculty and that further qualitative studies should explore the basis of several of the attitudes regarding practices in research ethics. PMID- 22228068 TI - Difference in risk behaviors and STD prevalence between street-based and establishment-based FSWs in Guangdong Province, China. AB - The major mode of HIV/AIDS transmission in China is now heterosexual activities, but risk for HIV and sexually transmitted diseases (STDs) may differ among different strata of female sex workers (FSWs). Respondent-driven sampling was used to recruit 320 FSWs in Guangdong Province, China. The respondents were interviewed using a structured questionnaire, and tested for HIV, syphilis, gonorrhea, and Chlamydia. The street-based FSWs had lower education levels, a higher proportion supporting their families, charged less for their services, and had engaged in commercial sex for a longer period of time than establishment based FSWs. The proportion consistently using condoms with clients and with regular non-paying partners was also lower. The prevalence of syphilis, gonorrhea, and Chlamydia was higher among street-based sex workers. Being a street-based sex worker, having regular non-paying sex partners, and having non regular non-paying partners were independent risk factors for inconsistent condom. Street-based FSWs had more risk behaviors than establishment-based FSWs, and should therefore be specifically targeted for HIV as well as STD intervention programs. PMID- 22228069 TI - The role of self-efficacy and motivation to explain the effect of motivational interviewing time on changes in risky sexual behavior among people living with HIV: a mediation analysis. AB - Little is known about the amount of Motivational Interviewing (MI) needed to reduce risky sexual behavior among People Living with HIV/AIDS (PLWHA) or the roles self-efficacy and motivation to practice safer sex play. Among 183 PLWHA who received safer sex MI and were surveyed every 4 months over a 12 month period, we used hierarchical negative binomial regression models to examine the association between amount of counseling time and sexual risk behavior. We performed mediation analysis to evaluate whether changes in self-efficacy and motivation explained this association. This study found that as MI time and number of provided sessions increased, participants' sexual risk behavior decreased. The effect of MI time and number of sessions on sexual behavior was mediated by self-efficacy but not by motivation to practice safer sex. PMID- 22228070 TI - Epithelial salivary gland tumors in two distant geographical locations, Finland (Helsinki and Oulu) and Israel (Tel Aviv): a 10-year retrospective comparative study of 2,218 cases. AB - Salivary gland tumors (SGTs) of epithelial origin are relatively rare, and worldwide reports show considerable variations in their epidemiology. The aim of this study was to examine, for the first time, the records of SGTs from two very distant geographical locations, Finland (two medical centers) and Israel (one medical center) between 1999 and 2008, based exclusively on the 2005 WHO classification of head and neck tumors, and to compare those data to the other available (single-center) studies that used the same classification. A total of 2,218 benign and malignant tumors diagnosed in the three centers were analyzed. Differences in classification of the tumors were found between the two geographical locations as well as between the two centers from Finland. There was a higher ratio of benign-to-malignant SGTs in the Finnish centers (5.4:1 and 7:1) compared to the Israeli center (2:1), a higher frequency of tumors of minor salivary glands in the Israeli center (34%) than in the Finnish centers (4 and 11%), and a higher frequency of malignant SGTs in the minor salivary glands in Israel (64.5%) than in Finland (10.9 and 27%). The diversity of these multicenter data are compatible with reports from different parts of the world. We conclude that conducting epidemiologic surveys based on the latest WHO classification provides clinicopathologic correlations on SGTs that seem to be characteristic even in small geographical regions. PMID- 22228071 TI - Cytoplasmic ezrin and moesin correlate with poor survival in head and neck squamous cell carcinoma. AB - Members of the 4.1 superfamily of proteins, including ezrin, moesin, merlin, and willin regulate many normal physiologic processes such as cellular shape, motility, and proliferation. In addition, they contribute both to tumor development and tumor progression. We reported previously that strong cytoplasmic ezrin expression was independently associated with poorer patient survival. One hundred and thirty-one histologically confirmed primary head and neck squamous cell carcinomas were examined prospectively for cancer progression and survival at a large health care center in the Bronx, NY, USA. Immunohistochemical analysis of ezrin, moesin, merlin, and willin expression in tissue microarray samples of primary head and neck squamous cell carcinoma revealed a significant association of increased cytoplasmic ezrin with poor cancer survival. Global RNA analyses suggest that cancers with high cytoplasmic ezrin have a more invasive phenotype. This study supports our previous findings associating cytoplasmic ezrin with more aggressive behavior and poorer outcome and indicates the need for a multi institutional study to validate the use of cytoplasmic ezrin as a biomarker for treatment planning in head and neck squamous cell carcinoma. PMID- 22228072 TI - Community severance and health: what do we actually know? AB - Community severance occurs where road traffic (speed or volume) inhibits access to goods, services, or people. Appleyard and Lintell's seminal study of residents of three urban streets in San Francisco found an inverse relationship between traffic and social contacts. The extent of social networks predicts unhealthy behaviors, poor health, and mortality; high rather than low social integration is associated with reduced mortality, with an effect size of similar magnitude to stopping smoking. Although community severance diminishes social contacts, the implications of community severance for morbidity and mortality have not been empirically established. Based on a systematic literature search, we discuss what is actually known about community severance. There is empirical evidence that traffic speed and volume reduces physical activity, social contacts, children's play, and access to goods and services. However, no studies have investigated mental or physical health outcomes in relation to community severance. While not designed specifically to do so, recent developments in road design may also ameliorate community severance. PMID- 22228073 TI - Near-miss events are really missed! Reflections on incident reporting in a department of pediatric surgery. AB - PURPOSE: The aim of this study was to evaluate the frequency of surgical and organizational events that occurred in the whole Department of Paediatric Surgery at Gaslini Children's Hospital through an incident-reporting system in order to identify the vulnerabilities of this system and improve it. MATERIALS AND METHODS: This is a 6-month prospective observational study (1st January-1st July 2010) of all events (including surgical and organizational events, and near misses) that occurred in our department of surgery (pediatric surgery, orthopedics and neurosurgery units). RESULTS: Over a 6-month study period, 3,635 children were admitted: 1,904 out of 3,635 (52.4%) children underwent a surgical procedure. A total number of 111 adverse events and 4 near misses were recorded in 100 patients. A total of 108 (97.3%) adverse events occurred following a surgical procedure. Of 111 adverse events, 34 (30.6%) required re-intervention. Eighteen of 100 patients (18%) required a re-admission, and 18 of 111 adverse events (16.2%) were classified as organizational. Infection represented the most common event. CONCLUSIONS: An electronic physician-reported event tracking system should be incorporated into all surgery departments to report more accurately adverse events and near misses. In this system, all definitions must be standardized and near misses should be considered as important as the other events, being a rich source of learning. PMID- 22228074 TI - Metabolic adjustments of Dentex dentex to prolonged starvation and refeeding. AB - The particular metabolic strategies of the common dentex (Dentex dentex) to face a period of prolonged starvation and subsequent refeeding were assessed. Plasma metabolites, endogenous reserves, and the activity of key enzymes of intermediary metabolism in liver, white muscle, and heart were evaluated. Plasma glucose, total lipid, triglycerides, total-, HDL- and LDL-cholesterol, and protein levels, liver, and white muscle glycogen, and perivisceral, and muscle fat were significantly reduced by starvation, whereas liver lipid content was surprisingly increased. Those enzymes involved in phosphorylation and oxidation of glucose and lipid synthesis, as well as alanine aminotransferase activity, were significantly depressed in liver of starved fish. The increase in beta-hydroxyacyl-CoA dehydrogenase (HOAD) indicated an enhanced fatty acid oxidation during starvation. Part of the acetyl-CoA generated by beta-oxidation was oxidized in the hepatic Krebs cycle, as reflected the increased citrate synthase (CS) activity. The oxaloacetate required for the reaction catalized by CS activity would be supplied by aspartate aminotransferase (ASAT) activity whose activity was also enhanced. Glutamate dehydrogenase also increased to deaminate the glutamate produced by transaminases, especially by the increased ASAT activity. Liver gluconeogenesis of starved fish was maintained at the same rate that in controls, with glycerol playing an important role as glucogenic substrate. The increased hepatic beta-hydroxybutyrate dehydrogenase (beta-OHBDH) activity indicates that part of the acetyl-CoA arriving from beta-oxidation was being diverted for ketone bodies production with dentex liver playing an important role in providing ketone bodies as fuels for other tissues under such circumstances. Most enzyme activities in white muscle of starved dentex were significantly depressed. In heart, starvation induced an important inhibition of those enzymes involved in glucose and protein metabolism, whereas CS, HOAD, and beta-OHBDH activities were maintained at control levels. Although several biomarkers assayed returned to control values after refeeding, many others did not, which indicate that after 3 weeks of refeeding, pre-starved dentex is still experiencing a transient period of metabolic adjustments directed toward the restoration of body mass. PMID- 22228075 TI - Effects of microcystin-containing cyanobacterial extract on hematological and biochemical parameters of common carp (Cyprinus carpio L.). AB - The aim of the study was to assess the effects of a cyanobacterial extract containing microcystins (MCs) on selected hematological and biochemical parameters in common carp (Cyprinus carpio L.), as well as to determine the accumulation of toxins in fish tissues. The fish were immersed for 5 days in water containing toxins at a final concentration of 12 MUg/L of microcystin LR equivalent. Microcystin LR residues were detected in fish liver, reaching 207, 238 and 260 ng/g f.w. of the tissues taken 24 h, 72 h and 5 days after the end of intoxication, respectively. The most substantial changes were found in fish plasma, including increases in creatine kinase, lactate dehydrogenase, ammonia, glucose, aspartate aminotransferase and alanine aminotransferase levels. A decline of about 50% in lysozyme activity was observed by the end of the experimental period. Moreover, a marked increase in ceruloplasmin activity was detected 24 h after the end of intoxication with a subsequent decrease in its activity after 72 h and 5 days. This study concludes that not only consumption of food containing toxins but also MCs dissolved in water may pose a threat to fish health. Additionally, detected changes in lysozyme and ceruloplasmin activity may have distinct effects in fish resistance against pathogens or oxidative stress, which should be taken into account in the future studies. PMID- 22228076 TI - Distinct gut microbiota in southeastern African and northern European infants. AB - BACKGROUND AND OBJECTIVE: The intestinal microbiota composition in infants reflects the early environment. Our objective was to compare the gut microbiota in 6-month-old infants living in rural Malawi with children of the same age living in urban Finland, both being breast-fed and having an age-appropriate diet typical for each area. METHODS: Malawian 6-month-old infants (n=44) were compared with Finnish infants (n=31) of the same age. In both cohorts, infant stool samples were available for microbiota characterization by flow cytometry fluorescent in situ hybridization and quantitative polymerase chain reaction methods. RESULTS: Bifidobacteria were dominant at 6 months of age in all of the infants, although in greater proportions in Malawian (70.8%) than in Finnish infants (46.8%; P<0.001). Additional distinctions in bacterial group composition comprised Bacteroides-Prevotella (17.2% vs 4.7%; P<0.001) and Clostridium histolyticum (4.4% vs 2.8%; P=0.01), respectively. The species Bifidobacterium adolescentis, Clostridium perfringens, and Staphylococcus aureus were absent in Malawian but detected in Finnish infants. CONCLUSIONS: The gut microbiota of 6 month-old infants in a low-income country differs significantly from that in a high-income country. This may have an effect on both the energy harvest from the diet typifying malnutrition and diarrheal diseases in low-income countries and Western lifestyle diseases in high-income countries. PMID- 22228077 TI - Feasibility and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) in children. AB - OBJECTIVES: Transjugular intrahepatic portosystemic shunt (TIPS) is a valuable tool in managing complications of severe portal hypertension (PH) in adults. In children, TIPS is regarded as a temporary and technically demanding procedure. We report the first paediatric series of TIPS and review its feasibility and efficacy in children. METHODS: Children with severe PH that is unresponsive to nonselective beta-blockers and endoscopic treatment were considered candidates for TIPS placement with an expanded polytetrafluoroethylene-covered Viatorr stent graft. Indications were cirrhotic PH, noncirrhotic PH, and portal vein thrombosis, in both native and transplanted livers. RESULTS: Thirteen children were selected for TIPS between 2005 and 2010. The indications were bleeding in 8 (61.5%) and ascites in 5 (38.5%). TIPS was successfully placed in 11 children, median age 9.8 years (range 2.2-18) and median weight 30 kg (11.5-96). Two patients had a portal cavernoma and 3 had received split liver transplantation. Following TIPS, the portosystemic gradient decreased to 10 mmHg (5-15 mmHg) (P < 0.00001); PH complications resolved in 10 of 11 patients (91%); no patient developed clinical encephalopathy; and 3 patients required a TIPS revision. All of the shunts were patent at last follow-up (20.4 months, range 0.2-67) in 7 or liver transplantation (6 months, 1.5-33) in 4. CONCLUSIONS: Our results suggest that TIPS is feasible and effective in children with ascites or gastrointestinal bleeding unresponsive to medical and endoscopic treatment. TIPS should become part of the armamentarium that is used to manage PH complications in children, both in native livers and in transplanted grafts, as a bridge to transplantation and for long-term management. PMID- 22228078 TI - When should we perform TIPS in children? PMID- 22228079 TI - Appendicoumbilical fistula: cause of an umbilical mass with drainage. PMID- 22228080 TI - Metabolic symbiosis in cancer: refocusing the Warburg lens. AB - Using relatively primitive tools in the 1920s, Otto Warburg demonstrated that tumor cells show an increased dependence on glycolysis to meet their energy needs, regardless of whether they were well-oxygenated or not. High rates of glucose uptake, fueling glycolysis, are now used clinically to identify cancer cells. However, the Warburg effect does not account for the metabolic diversity that has been observed amongst cancer cells nor the influences that might direct such diversity. Modern tools have shown that the oncogenes, variable hypoxia levels, and the utilization of different carbon sources affect tumor evolution. These influences may produce metabolic symbiosis, in which lactate from a hypoxic, glycolytic tumor cell population fuels ATP production in the oxygenated region of a tumor. Lactate, once considered a waste product of glycolysis, is an important metabolite for oxidative phosphorylation in many tissues. While much is known about how muscle and the brain use lactate in oxidative phosphorylation, the contribution of lactate in tumor bioenergetics is less defined. A refocused perspective of cancer metabolism that recognizes metabolic diversity within a tumor offers novel therapeutic targets by which cancer cells may be starved from their fuel sources, and thereby become more sensitive to traditional cancer treatments. PMID- 22228081 TI - Activation of Nod1 and Nod2 induces innate immune responses of prostate epithelial cells. AB - BACKGROUND: Nod1 and Nod2 are cytosolic receptors which are responsible for sensing bacterial peptidoglycan derivatives. In this study, we determined whether Nod1 and Nod2 are involved in the innate immune responses of prostate epithelial cells. METHODS: The expression of Nod1 and Nod2 was examined by RT-PCR and immunohistochemistry. ELISA was performed to determine the production of cytokines/chemokines. Activation of NF-kappaB and MAPK was examined using western blot analysis. RESULTS: The Nod1 gene was distinctly expressed in all tested cells including DU145, PC3, and TRAMP-C2 cells, whereas Nod2 expression was weak. Both Nod1 and Nod2 proteins were expressed in normal mouse prostate epithelia with difference of expression levels. Tri-DAP (Nod1 agonist), but not MDP (Nod2), increased the production of IL-8 (or KC) and IL-6 in prostate epithelial cells. Tri-DAP and MDP could upregulate the gene expression of COX-2 and activate NF kappaB and MAPK. In addition, Tri-DAP and MDP synergized with TLR agonists to induce the production of IL-8/KC or IL-6 in PC3 and TRAMP-C2 cells. We finally showed that Nod1 and Nod2 were also expressed in a wide range of prostate lesions including prostate intraepithelial neoplasm (PIN), phyllodes-like tumor, and adenocarcinoma in TRAMP (transgenic adenocarcinoma of the mouse prostate) mice, even though the expression level of Nod1 and Nod2 was different. CONCLUSION: These results indicate that Nod1 and Nod2 may play important roles in the innate immune response of prostate epithelial cells and the development and progression of prostate cancer. PMID- 22228082 TI - Experimental and theoretical study of dilute polyacrylamide solutions: effect of salt concentration. AB - The structure and intrinsic viscosity of the partially hydrolyzed polyacrylamide (HAPM) and polyacrylamide (PAM) in aqueous solution were investigated by comparative studies of molecular dynamics simulation over a wide range of the NaCl concentration. The radius of gyration (R(g)), the hydrodynamic radius (R(h)) and the ratio of the radius gyration and the hydrodynamic radius (rho) were calculated for the PAM or HPAM in solutions with different NaCl concentrations at 298 K. The conformational changes of the polymer chain in different aqueous solution were discussed according to the molecular shapes. It was found that the change of the R(h) or the R(g) can reflect the change in the [eta]. And the changes in the structure of the polymer chain with different NaCl concentrations were discussed via the rho which can predict [eta] changes. The results showed that behavior of the polymer solution calculated from the simulation agreed with the experimental measurements. Furthermore, the radial distribution functions for the HPAM solutions were investigated, which verified the micro-mechanism for the change of the structure. The results of this research showed that the computational method used in this work has practical applicability. PMID- 22228083 TI - FPGA-Based Pulse Pileup Correction. AB - Modern Field Programmable Gate Arrays (FPGAs) are capable of performing complex discrete signal processing algorithms with clock rates above 100MHz. This combined with FPGA's low expense, ease of use, and selected dedicated hardware make them an ideal technology for a data acquisition system for a positron emission tomography (PET) scanner. The University of Washington is producing a high-resolution, small-animal PET scanner that utilizes FPGAs as the core of the front-end electronics. For this next generation scanner, functions that are typically performed in dedicated circuits, or offline, are being migrated to the FPGA. This will not only simplify the electronics, but the features of modern FPGAs can be utilizes to add significant signal processing power to produce higher resolution images. In this paper we report on an all-digital pulse pileup correction algorithm that is being developed for the FPGA. The pileup mitigation algorithm will allow the scanner to run at higher count rates without incurring large data losses due to the overlapping of scintillation signals. This correction technique utilizes a reference pulse to extract timing and energy information for most pileup events. Using pulses were acquired from a Zecotech Photonics MAPDN with an LFS-3 scintillator, we show that good timing and energy information can be achieved in the presence of pileup. PMID- 22228084 TI - Surfactant-free preparation of supported cubic platinum nanoparticles. AB - A novel method has been developed for preparing supported cubic platinum nanoparticles. Carbon monoxide and hydrogen are used to reduce platinum precursors present at a solid-gas interface and to control the shape of the growing Pt nanoparticles. By avoiding the use of any organic agents in the synthesis, cubic Pt particles free of hydrocarbons are formed, thereby avoiding possible contamination of the catalyst surface. The approach used is simple and readily scalable. PMID- 22228085 TI - Endoscopic sonography in the diagnosis and treatment of a gastric wall abscess: a case report and review of the literature. AB - We report a case of a gastric wall abscess in a 50-year-old man who presented with epigastralgia and fever. Gastroscopy revealed a subepithelial lesion on the posterior wall of the gastric body into the antrum. A follow-up abdominal CT scan showed cystic lesions around the stomach. Endoscopic sonography helped to diagnose a gastric wall abscess. The gastric wall abscess was treated endoscopically with a needle knife incision for internal drainage. The patient was treated with antibiotics for 1 week and was discharged without complication. A follow-up endoscopy with endoscopic sonography 1 month later revealed complete resolution of the lesion. PMID- 22228086 TI - Comparison of genomic DNA extraction techniques from whole blood samples: a time, cost and quality evaluation study. AB - Genomic DNA obtained from patient whole blood samples is a key element for genomic research. Advantages and disadvantages, in terms of time-efficiency, cost effectiveness and laboratory requirements, of procedures available to isolate nucleic acids need to be considered before choosing any particular method. These characteristics have not been fully evaluated for some laboratory techniques, such as the salting out method for DNA extraction, which has been excluded from comparison in different studies published to date. We compared three different protocols (a traditional salting out method, a modified salting out method and a commercially available kit method) to determine the most cost-effective and time efficient method to extract DNA. We extracted genomic DNA from whole blood samples obtained from breast cancer patient volunteers and compared the results of the product obtained in terms of quantity (concentration of DNA extracted and DNA obtained per ml of blood used) and quality (260/280 ratio and polymerase chain reaction product amplification) of the obtained yield. On average, all three methods showed no statistically significant differences between the final result, but when we accounted for time and cost derived for each method, they showed very significant differences. The modified salting out method resulted in a seven- and twofold reduction in cost compared to the commercial kit and traditional salting out method, respectively and reduced time from 3 days to 1 hour compared to the traditional salting out method. This highlights a modified salting out method as a suitable choice to be used in laboratories and research centres, particularly when dealing with a large number of samples. PMID- 22228087 TI - The effect of sevoflurane postconditioning on cardioprotection against ischemia reperfusion injury in rabbits. AB - Sevoflurane postconditioning is a potential clinical measure to protect myocardial. This experiment was designed to investigate the efficacy of sevoflurane postconditioning against ischemia-reperfusion injury. A total of 132 Japanese White Rabbits were enrolled into this study. They were underwent 15-, 30 , or 60-min left anterior descending coronary (LAD) artery occlusion, respectively. At the end of LAD artery occlusion, they randomly received a 5-min inhalation of air (control group), 1% sevoflurane (1% sev group), 2% sevoflurane (2% sev group), 4% sevoflurane (4% sev group) or an IV bolus injection of 5 mg/kg of NIM811 [a specific inhibitor of mitochondrial permeability transition pores (mPTP)]. Infarct size was determined after 2 h of reperfusion (triphenyltetrazolium chloride straining, percentage of risk area). The infarct sizes were significantly (P < 0.05) reduced after 15 min ischemia (5.5 +/- 3.3%, 5.8 +/- 3.6% vs. 20.3 +/- 6.9% for 2% sev, 4% sev vs. control, respectively) and 30 min ischemia (23.5 +/- 5.0%, 20.7 +/- 5.9% vs. 50.9 +/- 10.2%, for 2% sev, 4% sev vs. control, respectively; P < 0.05). However, it had no effect on infarct size after 60 min ischemia (64.1 +/- 5.9%, 62.3 +/- 7.6% vs. 72.7 +/- 9.2% for 2% sev, 4% sev vs. control, respectively, P > 0.05).The efficacy of sevoflurane postconditioning gradually weakened with increasing ischemia duration and disappears after 60 min ischemia in rabbits in vivo. PMID- 22228089 TI - Pediatric donor lungs for adult transplant recipients: feasibility and outcomes. AB - BACKGROUND: There is a limited experience using pediatric organs for adult lung transplantation (LTx), with size matching the major concern. We reviewed our experience transplanting pediatric donor lungs into adult recipients with endpoints of post-LTx complications and overall patient survival. METHODS: From 2/1990 to 12/2007, 609 adults underwent primary LTx at our institution. Thirty eight (6.2%) patients underwent LTx with organs from pediatric donors (<=16 years). Of these, median donor age was 13 years (range: 7 to 16) and median recipient age 55 (range: 24 to 66). Endpoints analyzed included size matching accuracy, airway and pleural complications, time to extubation, intensive care unit (ICU) and hospital lengths of stay, as well as survival. RESULTS: Gross undersizing of the donor lung was present in 2/38 (5.3%) and of the donor bronchus in 11/38 (29%). Five patients (13%) experienced a major postoperative airway complication. Thoracentesis prior to discharge was necessary in 4/38 (11%) patients and chest tube reinsertion in 10/38 (26%) for pleural effusion. Median time to extubation was 2 days. ICU and hospital lengths of stay were 6 and 16 days, respectively. Kaplan-Meier survival at 30 days, 1 year, 3 years, and 5 years post-transplant was 89%, 74%, 63%, and 55%. CONCLUSIONS: Despite sizing concerns, transplantation of pediatric lungs into adult recipients is feasible. Size mismatch may predispose to higher rates of airway and pleural complications. Hospital course and overall survival appear comparable to adult-to-adult LTx, and concerns over size matching should not preclude pediatric organ use for adult candidates. PMID- 22228088 TI - Dual effects of sodium butyrate on hepatocellular carcinoma cells. AB - Sodium butyrate (NaBu), a histone deacetylase inhibitor, has been shown to inhibit cell growth, induce cell differentiation and apoptosis in multiple cell lines. In present study, we revealed the dual effects of NaBu in regulating hepatocellular carcinoma (HCC) cells. In two different HCC cell lines, SK-Hep1 and SMMC-7721, low concentrations of NaBu induced a significant increase in cell growth ratio and S-phase cell percentage, accompanied by a reduced p21 Cip1 expression at both mRNA and protein levels, while dissimilarly, high concentrations of NaBu inhibited cell growth and induced G1 arrest through up regulation of p21 Cip1 and p27 Kip1 protein expression. The reduction of p45 Skp2 expression further indicated that the ubiquitin-mediated protein degradation might play a role in NaBu-induced up-regulation of p21 Cip1 and p27 Kip1. Moreover, the high concentration of NaBu was also able to trigger HCC cell apoptosis. Taken together, these results demonstrate the distinct effects of NaBu at different dosages. This finding may contribute to develop more effective tumor therapeutic protocols of NaBu in HCC. PMID- 22228090 TI - Management of lung metastases from colorectal cancer: video-assisted thoracoscopic surgery versus thoracotomy--a case-matched study. AB - OBJECTIVES: The benefits of video-assisted thoracoscopic surgery (VATS) for performing pulmonary metastasectomy are considered controversial. This case matched study aimed to compare long-term outcomes after surgical resection of pulmonary metastases from colorectal cancer using different approaches (VATS vs. thoracotomy). METHODS: Between 1997 and 2008, 143 patients with colorectal cancer who had received their first pulmonary metastasectomy were selected. Fifty-three patients underwent a surgical procedure that utilized a thoracotomy approach (Group 1), and 90 patients underwent a surgical procedure that used a VATS-based approach (Group 2). After being matched for tumor number, diameter (measured by computed tomography), and surgical procedure (wedge resection or lobectomy), 35 pairs of patients were finally enrolled. Study endpoints included tumor recurrence and survival. RESULTS: There was no hospital mortality in both groups. Within the mean follow-up period of 50 months, 47.1% patients developed a recurrence (52% at the pulmonary level and 48% at systemic level), and 52.9% of the patients were alive at the time of analysis. There was no difference between Groups 1 and 2 in terms of overall recurrences (54 vs. 40%, p = 0.23), all pulmonary recurrences (25.7 vs. 22.9%, p = 0.78), and same side lung recurrences (14.3 vs. 20%, p = 0.75). The 5-year overall survival (OS) after lung resection was 43 and 51% in Groups 1 and 2, respectively (p = 0.21). CONCLUSIONS: Our case matched study showed that survival outcome of pulmonary metastasectomy using VATS is not inferior to that of open thoracotomy in selected cases. PMID- 22228092 TI - Dual functional rhodamine-immobilized silica toward sensing and extracting mercury ions in natural water samples. AB - A reversible solid optical sensor (SGIR) for Hg(2+) based on silica gel was designed and synthesized. The binding and adsorption abilities of SGIR for metal cations were investigated with fluorophotometry and cold vapor atomic absorption spectrometry, respectively. The SGIR exhibits high selectivity for sensing Hg(2+) over other metal cations in aqueous media because the Hg(2+) ion selectively induces a ring opening of the rhodamine fluorophores, and the SGIR was also found to adsorb 72% of Hg(2+) ion. The determination of Hg(2+) in both tap and lake water samples displays satisfactory results, and the SGIR can also be easily recovered by treatment of a solution of TBA(+)OH(-). PMID- 22228091 TI - Risk factors for distal Contegra stenosis: results of a prospective European multicentre study. AB - Objectives The EUCon study was designed to identify risk factors for distal anastomotic stenosis after bovine jugular vein (Contegra) implantation in children. Methods Between March 2006 and August 2008, 104 devices were implanted in nine European centers. Preoperative, intraoperative, and follow-up data (at discharge, 6, 12, 24 months) including standardized echocardiography were prospectively registered, source data verified and collected in a central database. Main endpoint was distal stenosis (either postvalvular gradient of >=50 mm Hg or need for intervention for distal stenosis). Eight potential risk factors (age <2 years, diagnosis, running suture, use of glue, flapless anastomosis, oversizing less than + 2 z, anticoagulation, implantation site) were investigated. Cox regression, decision tree analyses, and "Clustering by Response" were applied. Results Patient age ranged from 0 to18 years, mean 6.0 +/ 6.1, median 3.2 years. Implantation reasons: 88% congenital malformations, 12% Ross operations. Follow-up was 88.3% complete. Durability (freedom from death, reoperation, degeneration, endocarditis, and explantation) compared well to corresponding homograft literature. Sixteen patients reached study endpoints. Age <2 years was the only invariably significant risk factor (p = 0.044); "Clustering By Response" found young anticoagulated patients with oversized conduits to be at a higher risk than the others (p = 0.018, OR = 3.2). Conclusion Patient age is the main risk factor for development of distal anastomosis stenosis after Contegra implantation. The influence of the other investigated factors is too small to be proven in 104 patients after 2 years, or other risk factors must be taken into consideration to explain outcome differences among recipients under 2 years. PMID- 22228093 TI - Evaluation of photodynamic activity of C60/2-hydroxypropyl-beta-cyclodextrin nanoparticles. AB - The objective of this study is to evaluate the ability of C(60)/2-hydroxypropyl beta-cyclodextrin (HP-beta-CyD) naonparticles to generate reactive oxygen species (ROS) and to induce cell toxicity by the photoirradiation. C(60) nanoparticles were prepared by cogrinding with HP-beta-CyD for 3 h at 4 degrees C under reduced pressure. The photodynamic activity of C(60)/HP-beta-CyD nanoparticles was evaluated by spectroscopic methods, including the electron spin resonance spin trapping method, and by the cell viability test using Hela cells. C(60)/HP-beta CyD nanoparticles efficiently generated not only superoxide anion radical (O(2)(. )) and hydroxyl radical (.OH), but also singlet oxygen ((1)O(2)) through photoirradiation. The ROS generation was enhanced by decreasing the mean particle diameter of C(60) nanoparticles, and the particle size smaller than 90 nm showed a high generation of .OH and (1)O(2). In addition, HP-beta-CyD enhanced the generation of (1)O(2), compared with polyvinylpyrrolidone (an effective solubillizer for C(60)), due to partial disposition of C(60) in the hydrophobic CyD cavity. Furthermore, C(60) /HP-beta-CyD nanoparticles showed cell toxicity after the light irradiation, but no toxicity was observed without the light irradiation. Therefore, HP-beta-CyD is useful for the preparation of stable C(60) nanoparticles with high ROS generation ability, and C(60)/HP-beta-CyD nanoparticles are a promising photosensitizer for photodynamic therapy. PMID- 22228094 TI - The Lowe syndrome protein OCRL1 is involved in primary cilia assembly. AB - Lowe syndrome (LS) is a devastating, X-linked genetic disease characterized by the presence of congenital cataracts, profound learning disabilities and renal dysfunction. Unfortunately, children affected with LS often die early of health complications including renal failure. Although this syndrome was first described in the early 1950s and the affected gene, OCRL1, was identified more than 17 years ago, the mechanism by which Ocrl1 defects lead to LS's symptoms remains unknown. Here we show that LS display characteristics of a ciliopathy. Specifically, we found that patients' cells have defects in the assembly of primary cilia and this phenotype was reproduced in cell lines by knock-down of Ocrl1. Importantly, this defect could be rescued by re-introduction of WT Ocrl1 in both patient and Ocrl1 knock-down cells. In addition, a zebrafish animal model of LS exhibited cilia defects and multiple morphological and anatomical abnormalities typically seen in ciliopathies. Mechanistically, we show that Ocrl1 is involved in protein trafficking to the primary cilia in an Rab8-and IPIP27/Ses dependent manner. Taking into consideration the relevance of the signaling pathways hosted by the primary cilium, our results suggest hitherto unrecognized mechanisms by which Ocrl1 deficiency may contribute to the phenotypic characteristics of LS. This conceptual change in our understanding of the disease etiology may provide an alternative avenue for the development of therapies. PMID- 22228095 TI - Mutations in mouse Ift144 model the craniofacial, limb and rib defects in skeletal ciliopathies. AB - Mutations in components of the intraflagellar transport (IFT) machinery required for assembly and function of the primary cilium cause a subset of human ciliopathies characterized primarily by skeletal dysplasia. Recently, mutations in the IFT-A gene IFT144 have been described in patients with Sensenbrenner and Jeune syndromes, which are associated with short ribs and limbs, polydactyly and craniofacial defects. Here, we describe an N-ethyl-N-nitrosourea-derived mouse mutant with a hypomorphic missense mutation in the Ift144 gene. The mutant twinkle-toes (Ift144(twt)) phenocopies a number of the skeletal and craniofacial anomalies seen in patients with human skeletal ciliopathies. Like other IFT-A mouse mutants, Ift144 mutant embryos display a generalized ligand-independent expansion of hedgehog (Hh) signalling, in spite of defective ciliogenesis and an attenuation of the ability of mutant cells to respond to upstream stimulation of the pathway. This enhanced Hh signalling is consistent with cleft palate and polydactyly phenotypes in the Ift144(twt) mutant, although extensive rib branching, fusion and truncation phenotypes correlate with defects in early somite patterning and may reflect contributions from multiple signalling pathways. Analysis of embryos harbouring a second allele of Ift144 which represents a functional null, revealed a dose-dependent effect on limb outgrowth consistent with the short-limb phenotypes characteristic of these ciliopathies. This allelic series of mouse mutants provides a unique opportunity to uncover the underlying mechanistic basis of this intriguing subset of ciliopathies. PMID- 22228096 TI - LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. AB - The leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of autosomal-dominant Parkinson disease (PD). Mitochondrial dysfunction represents a critical event in the pathogenesis of PD. We demonstrated that wild-type (WT) LRRK2 expression caused mitochondrial fragmentation along with increased mitochondrial dynamin-like protein (DLP1, also known as DRP1), a fission protein, which was further exacerbated by expression of PD-associated mutants (R1441C or G2019S) in both SH-SY5Y and differentiated primary cortical neurons. We also found that LRRK2 interacted with DLP1, and LRRK2-DLP1 interaction was enhanced by PD-associated mutations that probably results in increased mitochondrial DLP1 levels. Co-expression of dominant-negative DLP1 K38A or WT Mfn2 blocked LRRK2 induced mitochondrial fragmentation, mitochondrial dysfunction and neuronal toxicity. Importantly, mitochondrial fragmentation and dysfunction were not observed in cells expressing either GTP-binding deficient mutant LRRK2 K1347A or kinase-dead mutant D1994A which has minimal interaction with DLP1 and did not increase the mitochondrial DLP1 level. We concluded that LRRK2 regulates mitochondrial dynamics by increasing mitochondrial DLP1 through its direct interaction with DLP1, and LRRK2 kinase activity plays a critical role in this process. PMID- 22228097 TI - Balancing neural crest cell intrinsic processes with those of the microenvironment in Tcof1 haploinsufficient mice enables complete enteric nervous system formation. AB - The enteric nervous system (ENS) comprises a complex neuronal network that regulates peristalsis of the gut wall and secretions into the lumen. The ENS is formed from a multipotent progenitor cell population called the neural crest, which is derived from the neuroepithelium. Neural crest cells (NCCs) migrate over incredible distances to colonize the entire length of the gut and during their migration they must survive, proliferate and ultimately differentiate. The absence of an ENS from variable lengths of the colon results in Hirschsprung's disease (HSCR) or colonic aganglionosis. Mutations in about 12 different genes have been identified in HSCR patients but the complex pattern of inheritance and variable penetrance suggests that additional genes or modifiers must be involved in the etiology and pathogenesis of this disease. We discovered that Tcof1 haploinsufficiency in mice models many of the early features of HSCR. Neuroepithelial apoptosis diminished the size of the neural stem cell pool resulting in reduced NCC numbers and their delayed migration along the gut from E10.5 to E14.5. Surprisingly however, we observe continued and complete colonization of the entire colon throughout E14.5-E18.5, a period in which the gut is considered to be non- or less-permissive to NCC. Thus, we reveal for the first time that reduced NCC progenitor numbers and delayed migration do not unequivocally equate with a predisposition for the pathogenesis of HSCR. In fact, these deficiencies can be overcome by balancing NCC intrinsic processes of proliferation and differentiation with extrinsic influences of the gut microenvironment. PMID- 22228098 TI - Admixture mapping identifies a locus on 6q25 associated with breast cancer risk in US Latinas. AB - Among US Latinas and Mexican women, those with higher European ancestry have increased risk of breast cancer. We combined an admixture mapping and genome-wide association mapping approach to search for genomic regions that may explain this observation. Latina women with breast cancer (n= 1497) and Latina controls (n= 1272) were genotyped using Affymetrix and Illumina arrays. We inferred locus specific genetic ancestry and compared the ancestry between cases and controls. We also performed single nucleotide polymorphism (SNP) association analyses in regions of interest. Correction for multiple-hypothesis testing was conducted using permutations (P(corrected)). We identified one region where genetic ancestry was significantly associated with breast cancer risk: 6q25 [odds ratio (OR) per Indigenous American chromosome 0.75, 95% confidence interval (CI): 0.65 0.85, P= 1.1 * 10(-5), P(corrected)= 0.02]. A second region on 11p15 showed a trend towards association (OR per Indigenous American chromosome 0.77, 95% CI: 0.68-0.87, P= 4.3 * 10(-5), P(corrected)= 0.08). In both regions, breast cancer risk decreased with higher Indigenous American ancestry in concordance with observations made on global ancestry. The peak of the 6q25 signal includes the estrogen receptor 1 (ESR1) gene and 5' region, a locus previously implicated in breast cancer. Genome-wide association analysis found that a multi-SNP model explained the admixture signal in both regions. Our results confirm that the association between genetic ancestry and breast cancer risk in US Latinas is partly due to genetic differences between populations of European and Indigenous Americans origin. Fine-mapping within the 6q25 and possibly the 11p15 loci will lead to the discovery of the biologically functional variant/s behind this association. PMID- 22228099 TI - BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes. AB - There are numerous genes for which loss-of-function mutations do not produce apparent phenotypes even though statistically significant quantitative changes to biological pathways are observed. To evaluate the biological meaning of small effects is challenging. Bardet-Biedl syndrome (BBS) is a heterogeneous autosomal recessive disorder characterized by obesity, retinopathy, polydactyly, renal malformations, learning disabilities and hypogenitalism, as well as secondary phenotypes including diabetes and hypertension. BBS knockout mice recapitulate most human phenotypes including obesity, retinal degeneration and male infertility. However, BBS knockout mice do not develop polydacyly. Here we showed that the loss of BBS genes in mice result in accumulation of Smoothened and Patched 1 in cilia and have a decreased Shh response. Knockout of Bbs7 combined with a hypomorphic Ift88 allele (orpk as a model for Shh dysfuction) results in embryonic lethality with e12.5 embryos having exencephaly, pericardial edema, cleft palate and abnormal limb development, phenotypes not observed in Bbs7(-/-) mice. Our results indicate that BBS genes modulate Shh pathway activity and interact genetically with the intraflagellar transport (IFT) pathway to play a role in mammalian development. This study illustrates an effective approach to appreciate the biological significance of a small effect. PMID- 22228100 TI - Regulation of retinal progenitor expansion by Frizzled receptors: implications for microphthalmia and retinal coloboma. AB - Nineteen Wnt ligands and 10 Frizzled (Fz) receptors mediate multiple distinct cellular events during neuronal development. However, their precise roles in cell type specification and organogenesis are poorly delineated because of overlapping functions and expression profiles. Here, we have explored the role of two closely related Frizzled receptors, Fz5 and Fz8, in mouse retinal development. We previously showed that Fz5(-/-) mice exhibit mild coloboma and microphthalmia at ~50% penetrance. Fz8 expression overlaps with Fz5 in the neural retina and optic fissure/disc. Mice lacking Fz8 show minimal eye and retinal defects. The embryos lacking both Fz5 and Fz8 die early in development, but a majority of triallelic Fz5(-/-);Fz8(+/-) mutants survive until birth. The triallelic mutant develops severe retinal coloboma and microphthalmia with full penetrance. At the cellular level, impaired neurogenesis is indicated by increased early-born retinal neurons that result from accelerated cell cycle exit of progenitors. Deficiency of apical retinal neuroepithelium is indicated by altered localization of apical junction markers, such as atypical protein kinase C, RhoA and beta-catenin. Hes1 expression, which is critical for retinal progenitor expansion, is down-regulated in the triallelic mutant mouse. Furthermore, blocking Frizzled receptors in cultured retinal explants led to basally shifted divisions of retinal progenitors. Together, our studies suggest a dose-dependent regulation of signaling by Fz5 and Fz8 in optic fissure/disc formation and progenitor expansion. PMID- 22228102 TI - Anti-arthritic activity of agnuside mediated through the down-regulation of inflammatory mediators and cytokines. AB - OBJECTIVE AND DESIGN: The purpose of this study was to elucidate the probable mechanism for the anti-arthritic activity of agnuside (AGN), a compound isolated from the leaf extract of Vitex negundo. METHODOLOGY: The anti-inflammatory activity of AGN within a dose range of 1.56-12.50 mg/kg in normal and adrenalectomized rats was evaluated against different inflammagens. An array of pro-inflammatory mediators (PGE(2) and LTB(4)) and T-cell-mediated cytokines (IL 2, TNF-alpha, IFN-gamma, IL-4, IL-10, IL-17) was assayed using flow cytometry, in arthritic paw tissue homogenate and splenocytes of treated animals. RESULTS: Significant anti-arthritic activity was observed in the polyarthritis test in rats and this was associated with significant suppression of inflammatory mediators and T-cell-mediated cytokines (Th1/Th2). The anti-inflammatory activity in adrenalectomized rats confirmed that the effect of AGN is not mediated by the pituitary-adrenal axis. AGN also showed inhibition of vascular permeability and leukocyte migration in vivo. CONCLUSION: The study suggests the possible development of AGN as a therapeutic agent in the treatment of arthritis by the modulation of the host immune response. PMID- 22228103 TI - Effect of serum amyloid A1 treatment on global gene expression in THP-1-derived macrophages. AB - OBJECTIVE: To investigate the effect of serum amyloid A1 (SAA1) on global gene expression in macrophages derived from THP-1 monocytes. MATERIALS AND METHODS: Global genetic expression in THP-1-derived macrophages was determined using Illumina HT-12 microarray chips and the results were validated by real-time PCR. Cytokine levels in cellular supernatant were quantified by ELISA. RESULTS: In total, 55 genes were upregulated with fold difference greater than two when THP-1 derived macrophages were incubated with SAA1 for 8 h. SAA1 is a strong cytokine inducer with significant upregulation of chemokines CCL1, CCL3, and CCL4 and this was confirmed by both real-time PCR and ELISA quantification. SAA1 also promotes the upregulation of genes involved in phagocytosis, anti-apoptosis, and tissue remodeling. CONCLUSIONS: SAA1 appears to play an important role during the immune response and in chronic inflammatory diseases through the stimulation of genes involved in cytokine production, phagocytosis, and anti-apoptosis. PMID- 22228104 TI - An international multicenter randomized controlled trial of G17DT in patients with pancreatic cancer. AB - OBJECTIVES: This study aimed to investigate G17DT, an immunogen producing neutralizing antibodies against the tumor growth factors amidated and glycine extended forms of gastrin-17, in the treatment of pancreatic cancer. METHODS: A randomized, double-blind, placebo-controlled, group-sequential multicenter trial of G17DT in patients with advanced pancreatic cancer unsuitable for or unwilling to take chemotherapy. Inclusion criteria were a Karnofsky performance score of 60 or higher and a life expectancy of more than 2 months. Patients received G17DT or placebo emulsion at weeks 0, 1, 3, 24, and 52. The primary end point was survival, and secondary end points were tolerability, Karnofsky performance. RESULTS: A total of 154 patients were recruited: 79 G17DT and 75 placebo. A final analysis of the intention-to-treat population, using a proportional hazards model, stratifying by disease stage and adjusting for interim analysis, gave a hazard ratio for mortality of 0.75 (95% confidence interval, 0.51-1.10, P = 0.138; G17DT/placebo). A conventional analysis without adjustment for disease stage or interim analysis, censoring for chemotherapy and excluding protocol violators, gave median survival periods of 151 (G17DT) and 82 days (placebo) (log rank test, P = 0.03).Patients developing anti-G17DT responses (73.8%) survived longer than nonresponders or those on placebo (median survival, 176 vs 63 vs 83; log-rank test, P = 0.003). G17DT was well tolerated. PMID- 22228101 TI - Mapping of the UGT1A locus identifies an uncommon coding variant that affects mRNA expression and protects from bladder cancer. AB - A recent genome-wide association study of bladder cancer identified the UGT1A gene cluster on chromosome 2q37.1 as a novel susceptibility locus. The UGT1A cluster encodes a family of UDP-glucuronosyltransferases (UGTs), which facilitate cellular detoxification and removal of aromatic amines. Bioactivated forms of aromatic amines found in tobacco smoke and industrial chemicals are the main risk factors for bladder cancer. The association within the UGT1A locus was detected by a single nucleotide polymorphism (SNP) rs11892031. Now, we performed detailed resequencing, imputation and genotyping in this region. We clarified the original genetic association detected by rs11892031 and identified an uncommon SNP rs17863783 that explained and strengthened the association in this region (allele frequency 0.014 in 4035 cases and 0.025 in 5284 controls, OR = 0.55, 95%CI = 0.44 0.69, P = 3.3 * 10(-7)). Rs17863783 is a synonymous coding variant Val209Val within the functional UGT1A6.1 splicing form, strongly expressed in the liver, kidney and bladder. We found the protective T allele of rs17863783 to be associated with increased mRNA expression of UGT1A6.1 in in-vitro exontrap assays and in human liver tissue samples. We suggest that rs17863783 may protect from bladder cancer by increasing the removal of carcinogens from bladder epithelium by the UGT1A6.1 protein. Our study shows an example of genetic and functional role of an uncommon protective genetic variant in a complex human disease, such as bladder cancer. PMID- 22228105 TI - Abnormal duodenal [HCO3-] following secretin stimulation develops sooner than endocrine insufficiency in minimal change chronic pancreatitis. AB - OBJECTIVES: Direct pancreatic function tests (PFTs) are often used to diagnose chronic pancreatitis (CP). We aimed to determine the temporal relationship between an abnormal PFT result, cross-sectional imaging, and clinical symptoms. METHODS: All patients referred for endoscopic ultrasound (EUS) and PFT for suspected CP at our medical center from 2008 to 2010 were included. Each subject underwent EUS and PFT on the same day using secretin stimulation. RESULTS: Seventeen patients had duodenal HCO3 values of less than 80 mEq/L and were labeled as abnormal; the 25 other patients had at least 1 duodenal HCO3 values of 80 mEq/L or greater. Patients with abnormal PFTs had more parenchymal (2.0 vs 0.92, P = 0.012), ductal (1.18 vs 0.6, P = 0.036), and total features (3.18 vs 1.52, P = 0.009) than those with normal PFTs on EUS examination. There was no difference in regard to the frequency of abnormal CT scans (25% vs 15%, P = 0.139), diarrhea (67% vs 60%, P = 0.463), fat-soluble vitamin deficiency (33% vs 26%, P = 0.315), or diabetes (10% vs 4%, P = 0.066). CONCLUSIONS: Patients with equivocal imaging and abnormally low duodenal HCO3 have more EUS features of CP than do patients with normal duodenal HCO3 values, suggesting that low duodenal HCO3 values are among the first measurable abnormalities in CP. PMID- 22228106 TI - Risk reduction strategy for radiation exposure during percutaneous nephrolithotomy. AB - PURPOSE OF REVIEW: To discuss the risk of radiation exposure to patients with nephrolithiasis. To review the risk factors for increased radiation exposure to patients during percutaneous nephrolithotomy (PNL) from fluoroscopy. To review the techniques to reduce patient radiation doses during PNL. RECENT FINDINGS: Patients with nephrolithiasis are at risk for significant radiation exposure from diagnostic imaging. Fluoroscopy used during surgical treatment of nephrolithiasis also contributes to patient radiation exposure. On average, PNL with fluoroscopy exposes patients to more radiation than a noncontrast computed tomography of the abdomen and pelvis. Risk factors for increased radiation during PNL include obesity, larger stone size and increased access tracts. Following the principles of As Low As Reasonably Achievable, use of air instead of contrast for retrograde pyelogram and use of ultrasound all reduce radiation exposure during PNL. SUMMARY: It is important to be aware of the amount of radiation patients with nephrolithiasis receive. These patients are at risk for multiple imaging studies and multiple procedures during their lifetime. Whenever possible, the techniques outlined in this review should be implemented to reduce the amount of radiation to which patients are exposed during PNL. PMID- 22228107 TI - 'Microperc' micro percutaneous nephrolithotomy: evidence to practice. AB - PURPOSE OF REVIEW: Miniaturization of instruments in percutaneous nephrolithotomy (PCNL) has spawned an interest in so-called 'microperc' in which the procedure is carried out through 16-gauge needle. RECENT FINDINGS: The greatest limitation of extracorporeal shock wave lithotripsy is its unpredictable results. The main limitation of retrograde intrarenal surgery is high sustainable cost and poor durability. The main limitation of PCNL is its invasiveness and associated morbidity. The interest in reducing the tract size was to potentially reduce the invasiveness of the procedure, and, therefore, attending complications. In a historical study, postrenal biopsy bleeding was found to be significant only after the tract of the needle was less than 16 gauge. Microperc extended the concept of 'All-seeing needle' to perform PCNL through a 4.85-Fr (16 gauge) tract. The working hypothesis of the 'All-seeing needle' is that if the initial tract is perfect, then the tract-related morbidity could be reduced. The optical needle helps to avoid any traversing viscera and confirms the visual cues of a correct papilla. The other advantage of microperc is that it is a novel single step renal access procedure, resulting in a shorter insertion to lithotripsy time. This may provide a new standard of obtaining renal access. SUMMARY: Only a few published studies have documented efficacy and safety. Till further prospective and multicentric articles are published, it is still an experimental procedure requiring further research. PMID- 22228109 TI - Urolithiasis: newer trends and practice. PMID- 22228108 TI - Rendering stone fragments paramagnetic with iron-oxide microparticles to improve the efficiency of endoscopic stone fragment retrieval. AB - PURPOSE OF REVIEW: Flexible ureteroscopes have allowed us to treat renal stones endoscopically through natural orifices. Unfortunately, there continues to be the problem of remnant stone fragments that continue to pose a health problem to patients with the risk of recurrent symptoms, obstruction and infection. RECENT FINDINGS: This article describes the research around a novel method of stone fragment extraction using microparticles and magnets. We explore the studies related to the efficiency of stone extraction and preliminary safety data. SUMMARY: This novel technique has the potential to improve the efficiency of stone fragment retrieval during retrograde intrarenal stone surgery, potentially improving stone-free rates of the surgery. Further research needs to be carried out before it is ready for human use. PMID- 22228110 TI - Influence of weight distribution asymmetry on the biomechanics of a barbell back squat. AB - The purpose of this study was to investigate the influence of weight distribution (WtD) asymmetry on the biomechanics of a barbell back squat. This study included 2 groups of trained individuals who were separated based on a WtD test (n = 14 in each group). They performed the barbell back squats with 2 resistance levels (60 and 75% of 1 repetition maximum) to measure vertical ground reaction force (GRF), tilting, and rotational angular bar displacements. A symmetry index (SI) score of the vertical GRF and the 2 bar displacements were examined to identify the group difference. Results showed that the unequal WtD group displayed a higher vertical GRF SI score (p < 0.05) and greater degrees of the tilting (p < 0.05) and rotational (p < 0.05) angular bar displacements. The 2 resistances did not influence the magnitude of the dependent variables, and no interactions were found. The unequal WtD captured at the WtD test carried over to the SI score during the back squat test. The unequal WtD was also a partial factor of displaying greater bar displacements. The lack of postural control to distribute body weight evenly should be treated properly to gain levelness before participating in high volume of resistance training, and coaches should be conscious of moving in a symmetrical fashion with minimal bar displacements in tilting and rotational manner. PMID- 22228111 TI - Effect of core strength on the measure of power in the extremities. AB - The purpose of this study was to (a) develop a functional field test to assess the role of the core musculature and its impact on sport performance in an athletic population and (b) develop a functional field test to determine how well the core can transfer forces from the lower to the upper extremities. Twenty-five DI collegiate football players performed medicine ball throws (forward, reverse, right, and left) in static and dynamic positions. The results of the medicine ball throws were compared with several athletic performance measurements: 1 repetition maximum (1RM) squat, squat kg/bw, 1RM bench press, bench kg/bw, countermovement vertical jump (CMJ), 40-yd dash (40 yd), and proagility (PrA). Push press power (PWR) was used to measure the transfer of forces through the body. Several correlations were found in both the static and dynamic medicine ball throws when compared with the performance measures. Static reverse correlated with CMJ (r = 0.44), 40 yd (r = 0.5), and PrA (r = 0.46). Static left correlated with bench kg/bw (0.42), CMJ (0.44), 40 yd (0.62), and PrA (0.59). Static right also correlated with bench kg/bw (0.41), 40 yd (0.44), and PrA (0.65). Dynamic forward (DyFw) correlated with the 1RM squat (r = 0.45) and 1RM bench (0.41). Dynamic left and Dynamic right correlated with CMJ, r = 0.48 and r = 0.40, respectively. Push press power correlated with bench kg/bw (0.50), CMJ (0.48), and PrA (0.48). A stepwise regression for PWR prediction identified 1RM squat as the best predictor. The results indicate that core strength does have a significant effect on an athlete's ability to create and transfer forces to the extremities. Currently, plank exercises are considered an adequate method of training the core for athletes to improve core strength and stability. This is a problem because it puts the athletes in a nonfunctional static position that is very rarely replicated in the demands of sport-related activities. The core is the center of most kinetic chains in the body and should be trained accordingly. PMID- 22228112 TI - Effect of interrepetition rest on power output in the power clean. AB - The effect of interrepetition rest (IRR) periods on power output during performance of multiple sets of power cleans is unknown. It is possible that IRR periods may attenuate the decrease in power output commonly observed within multiple sets. This may be of benefit for maximizing improvements in power with training. This investigation involved 10 college-aged men with proficiency in weightlifting. The subjects performed 3 sets of 6 repetitions of power cleans at 80% of their 1 repetition maximum with 0 (P0), 20 (P20), or 40 seconds (P40) of IRR. Each protocol (P0, P20, P40) was performed in a randomized order on different days each separated by at least 72 hours. The subjects performed the power cleans while standing on a force plate with 2 linear position transducers attached to the bar. Peak power, force, and velocity were obtained for each repetition and set. Peak power significantly decreased by 15.7% during P0 in comparison with a decrease of 5.5% (R1: 4,303 +/- 567 W, R6: 4,055 +/- 582 W) during P20 and a decrease of 3.3% (R1: 4,549 +/- 659 W, R6: 4,363 +/- 476 W) during P40. Peak force significantly decreased by 7.3% (R1: 2,861 +/- 247 N, R6: 2,657 +/- 225 N) during P0 in comparison with a decrease of 2.7% (R1: 2,811 +/- 327 N, R6: 2,730 +/- 285 N) during P20 and an increase of 0.4% (R1: 2,861 +/- 323 N, R6: 2,862 +/- 280 N) during P40. Peak velocity significantly decreased by 10.2% (R1: 1.97 +/- 0.15 m.s(-1), R6: 1.79 +/- 0.11 m.s(-1)) during P0 in comparison with a decrease of 3.8% (R1: 1.89 +/- 0.13 m.s(-1), R6: 1.82 +/- 0.12 m.s(-1)) during P20 and a decrease of 1.7% (R1: 1.93 +/- 0.17 m.s(-1), R6: 1.89 +/- 0.14 m.s(-1)) during P40. The results demonstrate that IRR periods allow for the maintenance of power in the power clean during a multiple set exercise protocol and that this may have implications for improved training adaptations. PMID- 22228113 TI - Common variants of the resistance mechanism in the Smith machine: analysis of mechanical loading characteristics and application to strength-oriented and hypertrophy-oriented training. AB - The Smith machine is a pervasive weight-training apparatus, used extensively by a wide population of weight trainers, from novices to high-level athletes. The advantages of using a Smith machine over free-weight resistance are disputed, with conflicting findings reported in the literature. In this study, we are interested in practical differences between 3 types of loading mechanisms found in modern Smith machines. In addition to the basic design comprising a constrained weighted barbell, alterations with a counterweight and a viscous resistance component are examined. The approach taken is that of employing a recently proposed representation of force characteristics that may be exhibited by a trainee and a predictive model of thus effected adaptation. A computer simulation is used to predict the effects of the 3 linear Smith machine designs in the framework of different exercise protocols. Our results demonstrate that each resistance component, vertically constrained load, counterweight, and viscous, can be matched with a particular training context, in which it should be preferred. Thus, a number of practical guidelines for weight-training practitioners are recommended. In summary, (a) at low intensities (55-75% of 1 repetition maximum [1RM]) used in strength-endurance training, a viscous resistance containing the Smith machine was found to offer advantages over both a constrained load only and counterweighted designs; (b) at medium intensities (75 85% of 1RM) typically employed in hypertrophy-specific training, the counterweighted Smith machine design was found to offer the best choice in terms of high-force development and total external work performed; finally, (c) at high training intensity (90-100% of 1RM), the optimal prescription was found to be more dependent on the specific athlete's weaknesses, highlighting the need for continual monitoring of the athlete's force production capabilities. To ensure that appropriate adjustments are made to the athlete's training regimen, the practitioner should consider the full set of findings of this article and the accompanying discussion. PMID- 22228114 TI - Anaerobic threshold assessment through the ventilatory method during roller-ski skating testing: right or wrong? AB - This study aimed at questioning the validity of the ventilatory method to determine the anaerobic threshold (respiratory compensation point [RCP]) during an incremental roller-ski skating test to exhaustion. Nine elite crosscountry skiers were evaluated. The skiers carried out an incremental roller-ski test on a treadmill with the V2 skating technique. Ventilatory parameters were continuously collected breath by breath, thanks to a portable gas exchange measurement system. Poling signal was obtained using instrumented ski poles. For each stage, ventilatory and poling signals were synchronized and averaged. The poor coefficient of interobserver reliability for the time at RCP confirmed the great difficulty felt by the 3 blinded reviewers for the RCP determination. Moreover, the reviewer agreed with the impossibility of determining RCP in 4 of the 9 skiers. There was no significant difference between breathing frequency (Bf) and poling frequency (Pf) during the last 8 stages. However, it seems that the differences observed during the first stages arose from the use of either a strictly 1:1 or a 1:2 Bf to Pf ratio when the exercise intensity was still moderate. So, even if there were significant differences between the frequencies, the Bf was strictly subordinate to the Pf during the entire test. In the same way, the normalized tidal volume and peak poling forces curves were superposable. These findings showed that when the upper body is mainly involved in the propulsion, the determinants of the ventilation are strictly dependent on the poling pattern during an incremental test to exhaustion. Thus, during roller-ski skating, the determination of RCP must be used cautiously because too much depending on mechanical factors. PMID- 22228115 TI - Clinical significance of lymph vessel density in T3 colorectal carcinoma. AB - PURPOSE: The purpose of the present study is to characterise the lymphatic vessel density (LVD) in the T3 colorectal carcinoma and to correlate it with N status, grading and presence of tumour budding. METHODS: A total of 56 cases of T3 colorectal carcinoma were retrieved from the pathology's archive of Klinikum Augsburg. All slides were stained immunohistochemically with D2-40 (lymphatic endothelium) and with pancytokeratin to assess the tumour budding. Tumour budding and lymph vessel density were investigated independently by BM and CC. The highest density of lymphatic vessels was counted both in tumour centre (ILVD) and at the periphery of the tumour (PLVD) within an area of 0.24 mm(2). RESULTS: Due to the strong intra-observer (BM and CC) difference in ILVD and PLVD, all cases were re-evaluated establishing a consensus that has been used for the further analyses. There was a significant difference between PLVD and ILVD (12 +/- 4 versus 6 +/- 3; P < 0.001). Moreover, we found a non-significant trend towards high PLVD in the cases with nodal metastasis versus the negative one, 13 +/- 5/hpf versus 11 +/- 4 (P = 0.072). There was no association between tumour budding and ILVD and PLVD (P = 0.249 and 0.38). CONCLUSION: Colorectal carcinoma induces lymphangiogenesis. A higher PLVD could increase the capability of cancer cell to invade the lymphatic system. However, the obvious difficulties in immunohistochemical evaluation and the rather small differences between nodal positive and negative cases in T3 colorectal cancer seem to limit the clinical value of LVD evaluation. PMID- 22228116 TI - Update of complications and functional outcome of the ileo-pouch anal anastomosis: overview of evidence and meta-analysis of 96 observational studies. AB - OBJECTIVE: The objective of this study is to provide a comprehensive update of the outcome of the ileo-pouch anal anastomosis (IPAA). DATA SOURCES: An extensive search in PubMed, EMBASE, and The Cochrane Library was conducted. STUDY SELECTION AND DATA EXTRACTION: All studies published after 2000 reporting on complications or functional outcome after a primary open IPAA procedure for UC or FAP were selected. Study characteristics, functional outcome, and complications were extracted. DATA SYNTHESIS: A review with similar methodology conducted 10 years earlier was used to evaluate developments in outcome over time. Pooled estimates were compared using a random-effects logistic meta-analyzing technique. Analyses focusing on the effect of time of study conductance, centralization, and variation in surgical techniques were performed. RESULTS: Fifty-three studies including 14,966 patients were included. Pooled rates of pouch failure and pelvic sepsis were 4.3% (95% CI, 3.5-6.3) and 7.5% (95% CI 6.1-9.1), respectively. Compared to studies published before 2000, a reduction of 2.5% was observed in the pouch failure rate (p = 0.0038). Analysis on the effect of the time of study conductance confirmed a decline in pouch failure. Functional outcome remained stable over time, with a 24-h defecation frequency of 5.9 (95% CI, 5.0-6.9). Technical surgery aspects did not have an important effect on outcome. CONCLUSION: This review provides up to date outcome estimates of the IPAA procedure that can be useful as reference values for practice and research. It is also shows a reduction in pouch failure over time. PMID- 22228117 TI - Disposition of human recombinant lubricin in naive rats and in a rat model of post-traumatic arthritis after intra-articular or intravenous administration. AB - We have recently demonstrated that intra-articular (IA) administration of human recombinant lubricin, LUB:1, significantly inhibited cartilage degeneration and pain in the rat meniscal tear model of post-traumatic arthritis. In this report, we show that after a single IA injection to naive rats and rats that underwent unilateral meniscal tear, [(125)I]LUB:1 had a tri-phasic disposition profile, with the alpha, beta, and gamma half-life estimates of 4.5 h, 1.5 days, and 2.1 weeks, respectively. We hypothesize that the terminal phase kinetics was related to [(125)I]LUB:1 binding to its ligands. [(125)I]LUB:1 was detected on articular cartilage surfaces as long as 28 days after single IA injection. Micro autoradiography analysis suggested that [(125)I]LUB:1 tended to localize to damaged joint surfaces in rats with meniscal tear. After a single intravenous (IV) dose to rats, [(125)I]LUB:1 was eliminated rapidly from the systemic circulation, with a mean total body clearance of 154 mL/h/kg and a mean elimination half-life (t (1/2)) of 6.7 h. Overall, LUB:1 has met a desired disposition profile of a potential therapeutic intended for an IA administration: target tissue (knee) retention and fast elimination from the systemic circulation after a single IA or IV dose. PMID- 22228118 TI - Parathyroidectomy improves bone geometry and microarchitecture in female patients with primary hyperparathyroidism: a one-year prospective controlled study using high-resolution peripheral quantitative computed tomography. AB - Following parathyroidectomy (PTX), bone mineral density (BMD) increases in patients with primary hyperparathyroidism (PHPT), yet information is scarce concerning changes in bone structure and strength following normalization of parathyroid hormone levels postsurgery. In this 1-year prospective controlled study, high-resolution peripheral quantitative computed tomography (HR-pQCT) was used to evaluate changes in bone geometry, volumetric BMD (vBMD), microarchitecture, and estimated strength in female patients with PHPT before and 1 year after PTX, compared to healthy controls. Twenty-seven women successfully treated with PTX (median age 62 years; range, 44-75 years) and 31 controls (median age 63 years; range, 40-76 years) recruited by random sampling from the general population were studied using HR-pQCT of the distal radius and tibia as well as with dual-energy X-ray absorptiometry (DXA) of the forearm, spine, and hip. The two groups were comparable with respect to age, height, weight, and menopausal status. In both radius and tibia, cortical (Ct.) vBMD and Ct. thickness increased or were maintained in patients and decreased in controls (p < 0.01). Radius cancellous bone architecture was improved in patients through increased trabecular number and decreased trabecular spacing compared with changes in controls (p < 0.05). No significant cancellous bone changes were observed in tibia. Estimated bone failure load by finite element modeling increased in patients in radius but declined in controls (p < 0.001). Similar, albeit borderline significant changes in estimated failure load were found in tibia (p = 0.06). This study showed that females with PHPT had improvements in cortical bone geometry and increases in cortical and trabecular vBMD in both radius and tibia along with improvements in cancellous bone architecture and estimated strength in radius 1 year after PTX, reversing or attenuating age related changes observed in controls. PMID- 22228119 TI - A high concentration of genistein down-regulates activin A, Smad3 and other TGF beta pathway genes in human uterine leiomyoma cells. AB - Previously, we found that high doses of genistein show an inhibitory effect on uterine leiomyoma (UtLM) cell proliferation. In this study, using microarray analysis and Ingenuity Pathways AnalysisTM, we identified genes (up- or down regulated, >= 1.5 fold, P <= 0.001), functions and signaling pathways that were altered following treatment with an inhibitory concentration of genistein (50 MUg/ml) in UtLM cells. Downregulation of TGF-beta signaling pathway genes, activin A, activin B, Smad3, TGF-beta2 and genes related to cell cycle regulation, with the exception of the upregulation of the CDK inhibitor P15, were identified and validated by real- time RT-PCR studies. Western blot analysis further demonstrated decreased protein expression of activin A and Smad3 in genistein-treated UtLM cells. Moreover, we found that activin A stimulated the growth of UtLM cells, and the inhibitory effect of genistein was partially abrogated in the presence of activin A. Overexpression of activin A and Smad3 were found in tissue samples of leiomyoma compared to matched myometrium, supporting the contribution of activin A and Smad3 in promoting the growth of UtLM cells. Taken together, these results suggest that downregulation of activin A and Smad3, both members of the TGF-beta pathway, may offer a mechanistic explanation for the inhibitory effect of a high-dose of genistein on UtLM cells, and might be potential therapeutic targets for treatment of clinical cases of uterine leiomyomas. PMID- 22228120 TI - Frequency and determinants of disagreement and error in gleason scores: a population-based study of prostate cancer. AB - BACKGROUND: To examine factors that affect accuracy and reliability of prostate cancer grade we compared Gleason scores documented in pathology reports and those assigned by urologic pathologists in a population-based study. METHODS: A stratified random sample of 318 prostate cancer cases was selected to ensure representation of whites and African-Americans and to include facilities of various types. The slides borrowed from reporting facilities were scanned and the resulting digital images were re-reviewed by two urologic pathologists. If the two urologic pathologists disagreed, a third urologic pathologist was asked to help arrive at a final "gold standard" result. The agreements between reviewers and between the pathology reports and the "gold standard" were examined by calculating kappa statistics. The determinants of discordance in Gleason scores were evaluated using multivariate models with results expressed as odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The kappa values (95% CI) reflecting agreement between the pathology reports and the "gold standard," were 0.61 (95% CI: 0.54, 0.68) for biopsies, and 0.37 (0.23, 0.51) for prostatectomies. Sixty three percent of discordant biopsies and 72% of discordant prostatectomies showed only minimal differences. Using freestanding laboratories as reference, the likelihood of discordance between pathology reports and expert assigned biopsy Gleason scores was particularly elevated for small community hospitals (OR = 2.98; 95% CI: 1.73, 5.14). CONCLUSIONS: The level of agreement between pathology reports and expert review depends on the type of diagnosing facility, but may also depend on the level of expertise and specialization of individual pathologists. PMID- 22228121 TI - Anomalous thermal transition and crystallization of ionic liquids confined in graphene multilayers. AB - Anomalous thermal transition and crystallization behaviors of three room temperature ionic liquids (RTILs) in graphene multilayers (GMLs), in a different manner to bulk RTILs, occurred due to the molecular orientation of the confined system triggered by the complex pi-pi stacking and hydrogen bonding interactions. PMID- 22228122 TI - Ependymoma with cartilaginous metaplasia might have more aggressive behavior: a case report and literature review. AB - Ependymoma with cartilaginous metaplasia with or without bone formation is exceedingly rare. Only eight cases have been reported in the literature. We report a case of ependymoma with cartilaginous and osseous metaplasia in a 5-year old boy. Microscopically, the tumor was composed of neoplastic ependymal tissue and mature cartilage and bone. Immunohistochemically, glial fibrillary acidic protein and epithelial membrane antigen were positive for ependymoma cells but negative for cartilage and bone. Recurrence occurred after 15-month follow-up. The patient deteriorated rapidly and died after 1 month. Reviewing 8 reported cases and our latest case, we found that 3 cases of ependymoma with cartilaginous metaplasia were treated with radiotherapy. Six cases had recurrence from 6 months to 8 years and 2 cases died on the day of operation. These findings suggest that ependymoma with cartilaginous metaplasia might have more aggressive clinical behavior. PMID- 22228123 TI - Does weight loss predict accuracy of setup in head and neck cancer patients treated with Intensity-Modulated Radiation Therapy? AB - PURPOSE: This prospective study reports the impact of weight loss on setup of head and neck (H&N) cancer patients treated by Intensity-Modulated Radiation Therapy (IMRT). MATERIALS AND METHODS: Setup errors of H&N cancer patients treated by IMRT from January to June 2010 were prospectively analysed and statistically related to weight loss. A mixed linear model was used for statistical evaluations. Setup margins of our institute were also calculated. RESULTS: Twenty-two patients and 128 pairs of Electronic Portal Images (EPI) were analysed. Setup errors varied between -0.6 and +0.6, -0.7 and +0.8 and -0.2 and +0.8 in the anterior-posterior, superior-inferior and right-left direction, respectively. Median and mean weight loss were 2.1 and 3.1 kg (range 0-12 kg), respectively; median and mean percent of weight loss were 2.95% and 4.64% (range 0.3-19.7%), respectively. No statistical relation was seen between weight loss and the setup errors. CONCLUSIONS: Weight loss is not a good clinical parameters for predicting an increase of setup errors. Other clinical and/or anthropometrical features should be prospectively evaluated in order to assess the need for re-planning. PMID- 22228124 TI - Endovascular radiofrequency renal denervation in treating refractory arterial hypertension: a preliminary experience. AB - PURPOSE: This study was done to investigate the efficacy and safety of percutaneous renal denervation with the Symplicity catheter for reducing blood pressure in patients with essential hypertension resistant to medical therapy (systolic blood pressure >160 mmHg despite the use of three or more antihypertensive drugs, including a diuretic). MATERIALS AND METHODS: In September 2010, five patients affected by essential hypertension resistant to medical therapy were treated. All patients were studied by computed tomography angiography (CTA) of the renal arteries before the procedure and underwent follow up at 30 and 60 days with colour Doppler ultrasound (CDUS) with evaluation of resistive index, glomerular filtration rate (GFR), 24-h blood pressure and serum catecholamine concentration. Student's t test was used to assess the effectiveness of the procedure in lowering blood pressure. RESULTS: In treated patients, mean blood pressure at baseline was 171/100 mmHg [standard deviation (SD) +/- 8/10]; mean GFR was 91.6 ml/min/1.73 m(2) (SD +/- 15). Blood pressure after the procedure was reduced by -18/-5 and -13/-10 mmHg at 30 and 60 days, respectively, with a mean medication reduction of 3.6. No complications occurred during the intra- or periprocedural period or during short-term follow-up. CONCLUSIONS: The Symplicity system proved to be efficacious and without serious adverse events in reducing blood pressure and antihypertensive medication use in patients affected by essential hypertension resistant to medical therapy. Although encouraging, our data are preliminary and need to be validated by larger prospective randomised studies. PMID- 22228125 TI - Prevalence study of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: preliminary data. AB - PURPOSE: This study aimed to evaluate the prevalence of chronic cerebrospinal venous insufficiency (CCSVI) in patients with multiple sclerosis (MS). MATERIAL AND METHODS: From November 2009 to February 2010, 74 participants (40 MS patients and 34 healthy controls) were enrolled in a randomised singleblind prospective study. All participants underwent ultrasonography (US) to detect signs of CCSVI. RESULTS: CCSVI was detected in 55% of patients in the MS group and 35% in the control group; the difference was not statistically significant (p=0.089). CONCLUSIONS: In our experience, a slight difference exists in the prevalence of CCSVI between MS and healthy controls, but it is not as yet clear which parameters may be most significant. This preliminary study failed to show a statistically significant difference in the prevalence of CCSVI among patients affected by MS. It did, however, reveal a tendency that requires a larger number of patients to achieve statistically significant results. PMID- 22228126 TI - Three-dimensional anal endosonography in depicting anal-canal anatomy. AB - PURPOSE: This report describes the advantages of 3D anal endosonography in depicting the normal anatomy of the anal canal in relation to sex and age. MATERIALS AND METHODS: A retrospective study was performed of 85 patients, 33 men and 52 women, previously examined with 3D anal ultrasound (US) for clinically suspected anorectal disease but found to be negative. The examinations were performed with a Bruel and Kjaer US system with a 2050 transducer, scanning from the anorectal junction to the subcutaneous portion of the external anal sphincter (EAS). The 3D reconstructions provided an estimation of sphincter length in the anterior and posterior planes, and axial 2D images enabled calculation of the thickness of the internal anal sphincter (IAS) and EAS in the anterior, posterior and lateral transverse planes. RESULTS: Distribution of the sphincter complex is asymmetric in both sexes: the EAS and IAS are significantly shorter in females, especially in the anterior longitudinal plane (p=0.005 and p<0.001, respectively). EAS and IAS thickness increases with age, especially the lateral IAS (R(2)=0.37, p<0.001) and the posterior EAS (R(2)=0.29, p=0.01). CONCLUSIONS: A good knowledge of anal-canal anatomy is essential to detect sphincter abnormalities when assessing pelvic floor dysfunction. PMID- 22228127 TI - CT diagnosis of the nature of bowel obstruction: morphological evaluation of the transition point. AB - PURPOSE: This study evaluated transition-point morphology for defining the nature of bowel obstructions. MATERIALS AND METHODS: Computed tomography (CT) examinations of 95 patients affected by severe bowel obstruction (23 neoplastic, 72 nonneoplastic) were retrospectively reviewed. RESULTS: The transition point was identified in 89 patients (94%); morphology in relation to the proximal loop was concave in 64 cases (68%), linear in five (5%) and convex in 20 (21%). Concave transition-point morphology was indicative of a nonneoplastic condition, with sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy values of 89%, 100%, 100%, 74% and 92%, respectively. A linear shape had almost identical incidence among neoplastic (60%) and nonneoplastic (40%) conditions. A convex appearance correlated with neoplastic disease with sensitivity, specificity, PPV, NPV and diagnostic accuracy values of 87%, 100%, 100%, 96% and 97%, respectively. CONCLUSIONS: In the case of bowel obstruction, transitionpoint detection indicates the obstruction site, whereas its morphological evaluation can contribute to defining the nature of the obstruction. A concave morphology indicates a nonneoplastic condition with a high probability; a convex morphology correlates with neoplastic disease, whereas linearity is not significant. PMID- 22228129 TI - Imaging in congenital deformities of the spinal cord. AB - Vertebromedullary malformations are a heterogeneous group of anomalies of mesenchymal and neuroectodermal tissue differentiation or closure in the midline of the back. On the basis of an embryological analysis, the authors describe the more common malformations, placing them at different times of onset and describing the pathological features and radiological findings based on the use of the most appropriate imaging techniques. The most common malformations have been divided into dysraphic and nondysraphic types and malformations affecting the vertebral bodies. The most complex malformations are detected during the antenatal period by ultrasound or foetal magnetic resonance imaging (MRI). Conversely, during the postnatal period, when the patient's clinical conditions do not warrant emergency surgical treatment, the disorder can be better defined with a detailed MRI scan of the brain and spinal cord. In less complex dysraphisms, although MRI is the imaging modality of choice, it may be useful to integrate the study with plain radiography (X-ray) and multidetector computed tomography (MDCT) for a better assessment of the skeletal components. In these disorders, the use of imaging is aimed at both identifying malformative defects and postoperative follow-up of more complex forms. PMID- 22228128 TI - Unusual complications of endovascular repair of the thoracic aorta: MDCT findings. AB - With the development of minimally invasive surgical techniques, endovascular stent-graft placement has become an accepted and widely used alternative to the traditional surgical repair of aortic disease and is gaining acceptance as the treatment of choice. Many studies show that endovascular stent-graft therapy is safe and effective, although complications related to this treatment are also recognised. Although the incidence of major complication is low, neurological sequelae remain the major concern of endovascular repair. With growing experience, however, the spectrum of mid- and long-term complications has broadened to include potentially disastrous events, other than paraplegia or stroke, that require diligent surveillance. Three-dimensional data sets acquired quickly by multidetector computed tomography (MDCT) allow multiplanar reformations and 3D viewing, as well as quantitative assessment of vessel lumens, walls and surroundings. Although a large portion of radiologists will not be involved in the actual endograft deployment, many will be involved in the interpretation of postprocedural surveillance studies. Accordingly, the goal of this report is to summarise our experience with the presentation, diagnostic approach, management and outcomes of these unusual, but potentially catastrophic, postendovascular aortic repair complications to highlight their significance and increase familiarity with them among the imaging community. Increasing awareness of these complications may facilitate rapid diagnosis and/or triage and treatment. PMID- 22228130 TI - Slice-thickness evaluation in CT and MRI: an alternative computerised procedure. AB - PURPOSE: The efficient use of computed tomography (CT) and magnetic resonance imaging (MRI) equipment necessitates establishing adequate quality-control (QC) procedures. In particular, the accuracy of slice thickness (ST) requires scan exploration of phantoms containing test objects (plane, cone or spiral). To simplify such procedures, a novel phantom and a computerised LabView-based procedure have been devised, enabling determination of full width at half maximum (FWHM) in real time. MATERIALS AND METHODS: The phantom consists of a polymethyl methacrylate (PMMA) box, diagonally crossed by a PMMA septum dividing the box into two sections. The phantom images were acquired and processed using the LabView-based procedure. RESULTS: The LabView (LV) results were compared with those obtained by processing the same phantom images with commercial software, and the Fisher exact test (F test) was conducted on the resulting data sets to validate the proposed methodology. CONCLUSIONS: In all cases, there was no statistically significant variation between the two different procedures and the LV procedure, which can therefore be proposed as a valuable alternative to other commonly used procedures and be reliably used on any CT and MRI scanner. PMID- 22228131 TI - Endovascular treatment of visceral artery aneurysms and pseudoaneurysms: our experience. AB - PURPOSE: The aim of this study was to analyse our 8 years of experience with endovascular treatment of visceral aneurysms and pseudoaneurysms. MATERIALS AND METHODS: From January 2002 to September 2009, we used an endovascular approach to treat 30 patients (22 men, eight women) affected by aneurysm (n=18) or pseudoaneurysm (n=13) of the splenic (n=11), hepatic (n=6), renal (n=5), pancreaticoduodenal (n=3), left gastric (n=2), gastroduodenal (n=1), rectal (n=1) or middle colic (n=1) arteries and the coeliac axis (n=1). Of these, 26/31 were treated with metal coils, 3/31 with Cardiatis multilayer stent, 1/31 with a coated stent and 1/31 with coils and Amplatzer plug. Procedures were performed electively in 10/30 cases and during haemorrhage in 20/30 cases. Follow-up was performed clinically (cessation of bleeding) and at 1, 6 and 12 months by colour Doppler ultrasound (CDUS) and computed tomography (CT) angiography. RESULTS: In 31/31 aneurysms and pseudoaneurysms we obtained immediate exclusion. In four patients with aneurysm and in four with pseudoaneurysm, parenchymal ischaemia occurred; one was treated with surgical splenectomy. One patient with pseudoaneurysm of the coeliac axis died 10 days later because of new bleeding. During follow-up, all aneurysms and pseudoaneurysms remained excluded. CONCLUSIONS: Percutaneous treatment is effective and safe, with a small number of complications, especially when compared with traditional surgery. PMID- 22228132 TI - Interobserver agreement in breast radiological density attribution according to BI-RADS quantitative classification. AB - PURPOSE: The authors sought to assess interobserver agreement in classifying mammography density according to quantitative Breast Imaging Reporting and Data System (BI-RADS) criteria. MATERIALS AND METHODS: Six expert mammography readers were tested on a set of 100 mammograms. Interobserver agreement was determined according to the kappa statistic, adjusting for chance agreement, on a four category (D1 vs. D2 vs. D3 vs. D4) or two-category (D1-2 vs. D3-4) basis. Agreement with a panel of 12 readers who had been tested on the same set in a previous study was also assessed. RESULTS: The six readers showed good agreement when compared in pairs [agreement on a four-category basis was substantial (kappa=0.60-0.80) for 13 pairs and almost perfect (kappa>0.80) for two pairs); agreement on a two-category basis was substantial for 12 pairs and almost perfect for three pairs) or compared with the panel (on a four-category basis, agreement was substantial for five of six readers and almost perfect for one; on a two category basis, agreement was substantial for all readers). CONCLUSIONS: In agreement with previous studies, visual classification of mammography density according to BI-RADS quantitative criteria was highly reproducible among readers; nevertheless, attribution to the "dense breast" (BI-RADS D3-4) category, which might be adopted as a determinant of different screening protocols (such as adjunct ultrasonography or yearly interval) varied among readers (range 6-15%). Controlled studies should be performed comparing visual with computer-density category attribution, the latter possibly being a better alternative due to its absolute reproducibility. PMID- 22228133 TI - Radiation doses to the population of the Emilia-Romagna region from medical exposures. AB - PURPOSE: The aim of this study was to supplement the analysis of data related to conventional radiography (CR), computed tomography (CT) and nuclear medicine (NM) with those related to interventional radiology (IR), and illustrate the contribution of all these radiological procedures to radiation exposure of the Emilia-Romagna population in Italy. MATERIALS AND METHODS: We gathered information about the number and mean doses of 30 interventional procedures performed in 17 hospitals of the Emilia-Romagna region. Seven hospitals were selected, and requests were made for numerical values of the dose-area product (DAP) in various IR procedures measured in the field. From these values, we calculated the 2006 annual collective effective dose (S), per-procedure dose and total dose, as well as the average per-capita dose to the Emilia-Romagna population. RESULTS: The 20 procedures amongst CR, CT, NM and IR that in 2006 contributed the most to Emilia-Romagna population radiation dose are described in detail: CR, CT, NM and IR contribute to approximately 10%, 66%, 9% and 15% of the total dose, and to 70%, 21%, 3% and 6% of procedure frequency, respectively. The S and average per-capita doses were 5,237 person-Sv and 1.2 mSv, respectively. CONCLUSIONS: IR procedures deliver high doses to the patient. Therefore, the same attention should be paid to radiation protection as with other high-dose examinations. As IR operators are often not radiologists, special attention should be paid to education in radiation protection of the professionals involved. PMID- 22228134 TI - MDCT findings of aortic branch artery pseudoaneurysms associated with type B intramural haematoma. AB - PURPOSE: The purpose of this study was to evaluate prevalence, morphological characteristics and evolution of aortic branch artery pseudoaneurysms associated with type B aortic intramural haematoma (IMH) using multidetector computed tomography (MDCT). MATERIALS AND METHODS: We enrolled 14 patients (nine men; mean age 64.6+/-9.6; range 42-75 years) with a diagnosis in the acute phase of type B IMH without evidence of intimal tear. All patients underwent clinical and MDCT follow-up. RESULTS: Twenty-two pseudoaneurysms in six patients (6/14, 43%) were observed at MDCT. In the majority of patients (5/6, 83%) the pseudoaneurysms were multiple and involved the branches of the descending thoracic aorta (14/22, 64%), mainly the intercostal arteries (11/22, 50%). At a mean follow-up of 10.6+/-8.7 months, 21 pseudoaneurysms showed resolution, reduction or dimensional stability (95%), whereas only one increased in size (5%). CONCLUSIONS: Aortic branch artery pseudoaneurysms associated with IMH may be considered a benign disease, as the majority of cases resolved or did not change in size, with haematoma resorption. However, because a dynamic change in pseudoaneurysms in the acute and subacute phases was frequently observed, close clinical and imaging follow-up is mandatory. PMID- 22228135 TI - Evolution of the Design of a Second Generation FireWire Based Data Acquisition System. AB - Our laboratory has previously reported on the basic design concepts of an updated FireWire based data acquisition system for depth-of-interaction detector systems designed at the University of Washington. The new version of our data acquisition system leverages the capabilities of modern field programmable gate arrays (FPGA) and puts almost all functions into the FPGA, including the FireWire elements, the embedded processor, and pulse timing and integration. The design is centered around an acquisition node board (ANB) that includes 64 serial ADC channels, one high speed parallel ADC, FireWire 1394b support, the FPGA, a serial command bus and signal lines to support a rough coincidence window implementation to reject singles events from being sent on the FireWire bus. Adapter boards convert detector signals into differential paired signals to connect to the ANB. In this paper we discuss many of the design details, including steps taken to minimize the number of layers in the printed circuit board and to avoid skewing of parallel signals and unwanted bandwidth limitations. PMID- 22228136 TI - Genetic structure of traditional varieties of bitter manioc in three soils in Central Amazonia. AB - Manioc is the most important food crop that originated in Amazonia. Many studies have increased our understanding of its evolutionary dynamics under cultivation. However, most of them focused on manioc cultivation in environments with low soil fertility, generally Oxisols. Recent ethnobotanical observations showed that bitter manioc also performs well in high fertility soils, such as Amazonian dark earths (ADE) and the floodplain. We used 10 microsatellite loci to investigate the genetic diversity and structure of bitter manioc varieties grown in different soil types in communities of smallholder farmers along the middle Madeira River in Central Amazonia. The genetic diversity of some sweet varieties and seedlings was also evaluated. Adult individuals showed higher levels of genetic diversity and smaller inbreeding coefficients (A ( R ) = 5.52, H ( O ) = 0.576, f = 0.086) than seedlings (A ( R ) = 4.39, H ( O ) = 0.421, f = 0.242). Bitter manioc varieties from the floodplain showed higher levels of genetic diversity (A ( R ) = 5.19, H ( O ) = 0.606) than those from ADE (A ( R ) = 4.45, H ( O ) = 0.538) and from Oxisols (A ( R ) = 4.15, H ( O ) = 0.559). The varieties grown in the floodplain were strongly differentiated from the varieties grown in Oxisols (F ( ST ) = 0.093) and ADE (F ( ST ) = 0.108), suggesting important genetic structuring among varieties grown in the floodplain and upland soils (ADE and Oxisols). This is the first time that genetic divergence of bitter manioc varieties in cultivation in different Amazonian soils in a small geographic area is reported. PMID- 22228138 TI - The impact of pesticides on the pathogen Batrachochytrium dendrobatidis independent of potential hosts. AB - Amphibians around the world are experiencing the greatest organismal decline in recent history. Xenobiotics, such as pesticides, and pathogenic biotic perturbations, including the fungus Batrachochytrium dendrobatidis (Bd), have played major roles in amphibian decreases. We conducted laboratory culture studies to determine the effects of three pesticides {carbaryl, glyphosate, and thiophanate-methyl [TM; Topsin-M(R) (Cerexagri-Nisso LLC)]} on Bd zoospore production and zoosporangia growth. We applied Bd to pesticides mixed in an agar culture to simulate pathogen introduction to a system with pre-existing pesticides (Bd addition). Alternatively, pesticides were applied to pre established Bd to simulate pesticide introduction after Bd establishment (pesticide addition). We then measured Bd zoosporangia and zoospore production. All pesticides significantly inhibited zoospore production; however, glyphosate and TM were more effective at doing so than carbaryl. In addition, only carbaryl and glyphosate inhibited zoosporangia production. Our data suggest that carbaryl and glyphosate are equally effective at inhibiting both zoosporangia and zoospore production; however, TM is selectively toxic to zoospores but not zoosporangia. One possible explanation for this observation could be that TM is toxic to zoospores but not the protective zoosporangia. In the case of pesticides applied to established Bd cultures, all pesticides caused significant mortality in both zoosporangia and zoospores, and no differences were found among pesticides. We conclude that examining pesticide and pathogen interactions independent of hosts provides mechanistic understanding of such interactions before and after host infection or contamination. PMID- 22228137 TI - Expression of tumor suppressor gene ING4 in ovarian carcinoma is correlated with microvessel density. AB - PURPOSE: Angiogenesis, estimated by microvessel density (MVD), has been shown to predict poor progression-free survival in women with advanced epithelial ovarian cancer. Inhibitor of growth (ING) family proteins inhibit angiogenesis in a number of cancers. We evaluated the role of ING4 in regulation of angiogenesis in patients with epithelial ovarian cancer. METHODS: Semi-quantitative RT-PCR was used to determine ING4 mRNA levels in 40 ovarian cancer patients and 40 normal controls. Also, we used immunohistochemistry to evaluate (1) ING4 protein expression levels and (2) the level of MVD by staining CD34, a microvessel marker, in these patients. Through statistical analysis, the possible correlation between the ING4 expression and angiogenesis was explored. RESULTS: ING4 mRNA and protein were significantly downregulated in all ovarian cancer patients compared to normal controls (P < 0.001). Endometrioid carcinoma tissue had significantly lower ING4 levels compared to serous or mucinous ovarian cancer. ING4 expression correlated negatively with stage and histological grade of ovarian cancers. MVD correlated negatively with ING4 protein and mRNA levels (rho = -0.865; P < 0.001 and rho = -0.724; P < 0.001, respectively). CONCLUSIONS: Loss of ING4 may promote microvessel formation and plays a role in facilitating the development of ovarian cancer. Although the specific mechanisms are not yet understood, our data suggest that ING4 may be a promising target for the treatment for ovarian cancer. PMID- 22228139 TI - Theoretical design of the biradical character in 1,3-diphosphacyclobutanediyl and homologous structures. AB - The electronic nature of 1,3-diphosphacyclobutane-2,4-diyl is explored with wavefunction based and density functional methods. According to MCSCF calculations the singlet state of the title compound is a biradicaloid with closed shell character, the number of unpaired electrons, assigned upon the analysis of the natural orbitals, is close to one. The participation of closed shell contributions in the overall wavefunction arises from a strong mixing of canonical structures, which emphasizes (a) the phosphorane type of bonding as well as (b) pi-delocalization within the ring system. The bonding situation changes when sigma-attracting substituents, e.g. amino groups, are attached to the phosphorus atoms. They inhibit possible cyclic pi-delocalization and enhance the biradical character within the ring system. PMID- 22228140 TI - Oleispira lenta sp. nov., a novel marine bacterium isolated from Yellow sea coastal seawater in Qingdao, China. AB - The taxonomic position of strain DFH11(T), which was isolated from coastal seawater off Qingdao, People's Republic of China in 2007, was determined. Strain DFH11(T) comprised Gram-negative, motile, strictly aerobic spirilli that did not produce catalase. Comparative 16S rRNA gene sequence analysis revealed that strain DFH11(T) shared ~97.2, 93.3, 91.8, 91.7 and 91.5% sequence similarities with Oleispira antarctica, Spongiispira norvegica, Bermanella marisrubri, Oceaniserpentilla haliotis and Reinekea aestuarii, respectively. DNA-DNA hybridization experiments indicated that the strain was distinct from its closest phylogenetic neighbour, O. antarctica. The strain grew optimally in 2-3% (w/v) NaCl, at pH 5.0-10.0 (optimally at pH 7.0) and between 0 and 30 degrees C (optimum growth temperature 28 degrees C). The strain exhibited a restricted substrate profile, with a preference for aliphatic hydrocarbons, that is consistent with its closest phylogenetic neighbour O. antarctica. Growth of the isolate at different temperatures affected the cellular fatty acid profile. 28 degrees C cultured cells contained C(16:1)omega7c and/or iso-C(15:0) 2-OH (50.4%) and C(16:0) (19.2%) as the major fatty acids. However, the major fatty acids of the cells cultured at 4 degrees C were C(16:1)omega7c and/or C(16:1)omega6c (40.2%), C(16:0) (17.2%) and C(17:1)omega8c (10.1%). The G+C content of the genomic DNA was 42.7 mol%. Phylogeny based on 16S rRNA gene sequences together with data from DNA-DNA hybridization, phenotypic and chemotaxonomic characterization revealed that DFH11(T) should be classified as a novel species of the genus Oleispira, for which the name Oleispira lenta sp. nov. is proposed, with the type strain DFH11(T) (=NCIMB 14529(T) = LMG 24829(T)). PMID- 22228141 TI - The p73 G4C14-to-A4T14 polymorphism is associated with risk of lung cancer in the Han nationality of North China. AB - p73, a structural and functional homolog of p53, plays an important role in tumor carcinogenesis. Previous studies have suggested that the association between the p73 G4C14-to-A4T14 polymorphism and the risk of lung cancer, but the results have not been entirely consistent. We examined whether the p73 G4C14-to-A4T14 polymorphism was related to the risk of developing lung cancer in a Chinese population. The p73 G4C14-to-A4T14 polymorphism was genotyped in 293 lung cancer patients and 380 cancer-free controls of Han nationality in North China using PCR RFLP. Multivariate logistic regression analysis was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). We observed that compared with the GC/GC genotype, the genotypes containing AT allele (GC/AT + AT/AT genotypes) were associated with significantly increased susceptibility to lung cancer (OR, 1.48; 95% CI, 1.08-2.02; P = 0.014). In addition, compared with the GC/GC genotype, the GC/AT genotype was also significantly associated with increased susceptibility to lung cancer (OR, 1.46; 95% CI, 1.06-2.02; P = 0.046). Our findings suggest that the p73 G4C14-to-A4T14 polymorphism contributes to the risk of developing lung cancer in Chinese population. PMID- 22228142 TI - Chronic effects of pyridoxine in the gerbil hippocampal CA1 region after transient forebrain ischemia. AB - In a previous study, we reported that the administration of pyridoxine (vitamin B(6)) to mice for 3 weeks significantly increased cell proliferation and neuroblast differentiation in the dentate gyrus without any neuronal damage. In the present study, we investigated the restorative potentials of pyridoxine on ischemic damage in the hippocampal CA1 region of Mongolian gerbils. Gerbils were subjected to 5 min of transient ischemia, and surgical operation success was assessed by ophthalmoscope during occlusion of common carotid arteries and spontaneous motor activity at 1 day after ischemia/reperfusion. Pyridoxine (350 mg/kg) or its vehicle (physiological saline) was intraperineally administered to ischemic gerbils twice a day starting 4 days after ischemia/reperfusion for 30 or 60 days. The repeated administration of pyridoxine for 30 and 60 days significantly increased doublecortin-immunoreactive neuroblasts in the dentate gyrus and increased NeuN-immunoreactive mature neurons and betaIII-tubulin immunoreactive dendrites in the hippocampal CA1 region. Furthermore, brain derived neurotrophic factor (BDNF) protein levels were significantly increased in pyridoxine-treated groups compared to those in the vehicle-treated groups. These results suggest that chronic administration of pyridoxine enhances neuroblast differentiation in the dentate gyrus and induces new mature neurons in the hippocampal CA1 region by up-regulating BDNF expression in hippocampal homogenates. PMID- 22228143 TI - Modulation of the translocation of peptides through nanopores by the application of an AC electric field. AB - The interaction of two peptides with the alpha-hemolysin pore was studied in the presence of a MHz AC field. For an alpha-helical peptide the proportion of bumping events increased with increasing AC field whereas for a linear peptide with no dipole moment only small changes in the event profiles were observed. PMID- 22228144 TI - A comparative field study on dust measurements by different sampling methods with emphasis on estimating factors for recalculation from chinese 'total dust' measurements to respirable dust concentrations. AB - In China, dust samplers were originally designed to collect 'total dust' for a short term during production, which is different from the widely adopted sampling strategy for dust. With the aim to provide the conversion factor from Chinese total dust to US and German respirable dust and to look at the influences on conversion factors from environment, production, and instruments, a comparative field study on the dust concentration measurements by different sampling methods was carried out in the same Chinese industries as in the 1989-1990 study and in some other factories. A supplemental experiment was also conducted in a wind tunnel. Dust concentration was measured with a parallel sampling strategy by using the following samplers: 10-mm nylon cyclone for US respirable dust (AR), FSP-Berufsgenossenschaftliches Institut fur Arbeitssicherheit (BIA) cyclone for German respirable dust (GR), and samplers for Chinese total dust (CT). Totally, 1434 samples were collected (269 AR, 198 GR, and 967 CT), from which 429 matched sample pairs (249 pairs of AR/CT, 180 GR/CT) were available to calculate conversion ratios. Industry- and job-based conversion factors are presented in this study. The conversion factor of AR/CT was 0.38 for tungsten mines, 0.19 for copper/iron mines, 0.65 for tin mines, and 0.20 for pottery industry, while the factor of GR/CT was 0.69 for tungsten, 0.37 for copper/iron, and 0.52 for pottery. In the job category, AR/CT factors varied from 0.16 to 0.96 and GR/CT from 0.12 to 0.72. For the industries studied in 1988-1989, the AR/CT and GR/CT factors were 0.29 and 0.45, respectively. Both factors were definitely influenced by production, CT dust concentration, sample gain, and variation of dust concentration. Moreover, the respirable dust concentration by FSP-BIA was significantly higher than that by 10-mm cyclones, 63.27-73.10% more as showed also by the wind tunnel experiment. Meanwhile, the GR/CT ratio was significantly larger than the AR/CT in every industry or job with only few exceptions. The GR/CT estimates should be considered as independent ones. Following these results, there is a need to use 'ideal samplers' (consistent with the internationally accepted respirable fraction) in practice and to assess the existent samplers in order to homogenize the exposure data situation. PMID- 22228145 TI - Gender's impact on outcome in coronary surgery with minimized extracorporeal circulation. AB - BACKGROUND: The role of female gender in cardiac surgery is still controversial. We examined the impact of gender on mortality after coronary artery bypass grafting (CABG) with minimized extracorporeal circulation (MECC). METHODS: Between January 2004 and May 2009, 1,662 patients (439 females, 1,223 males) underwent CABG with MECC at the University Medical Center Regensburg. Perioperative data were retrospectively analyzed; primary end point was in hospital mortality. RESULTS: At operation, women were older, had a higher prevalence of diabetes and impaired renal function, and underwent more often non elective surgery. Unadjusted mortality was significantly lower for men and than for women (2.3 vs. 5.7%; p = 0.001). Risk-adjusted mortality rates were derived by stepwise logistic regression. The final model reduced the gender-related mortality gap from 147 to 32%. Goodness of fit and discriminatory performance (AUC = 0.83) were good. Female gender, however, could not be identified as an independent risk factor for adverse outcome (OR 1.6; 95% CI 0.8-3.4). Risk adjusted mortality was calculated as 4.9% in females and 2.6% in males. Low body surface area (<1.66 m(2)) was associated with excess mortality in females. CONCLUSIONS: Gender-related disparity in outcome still remains present after surgery with minimized extracorporeal circulation. However, female gender per se is not an independent risk factor for in-hospital mortality, but close attention should be paid on modifiable risk factors. PMID- 22228146 TI - Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. AB - BACKGROUND: The prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was undertaken to determine whether there is a reduction in prostate cancer mortality from screening using serum prostate specific antigen (PSA) testing and digital rectal examination (DRE). Mortality after 7-10 years of follow-up has been reported previously. We report extended follow-up to 13 years after the trial. METHODS: A total of 76 685 men, aged 55-74 years, were enrolled at 10 screening centers between November 1993 and July 2001 and randomly assigned to the intervention (organized screening of annual PSA testing for 6 years and annual DRE for 4 years; 38 340 men) and control (usual care, which sometimes included opportunistic screening; 38 345 men) arms. Screening was completed in October 2006. All incident prostate cancers and deaths from prostate cancer through 13 years of follow-up or through December 31, 2009, were ascertained. Relative risks (RRs) were estimated as the ratio of observed rates in the intervention and control arms, and 95% confidence intervals (CIs) were calculated assuming a Poisson distribution for the number of events. Poisson regression modeling was used to examine the interactions with respect to prostate cancer mortality between trial arm and age, comorbidity status, and pretrial PSA testing. All statistical tests were two-sided. RESULTS: Approximately 92% of the study participants were followed to 10 years and 57% to 13 years. At 13 years, 4250 participants had been diagnosed with prostate cancer in the intervention arm compared with 3815 in the control arm. Cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10 000 person years, respectively, resulting in a relative increase of 12% in the intervention arm (RR = 1.12, 95% CI = 1.07 to 1.17). After 13 years of follow-up, the cumulative mortality rates from prostate cancer in the intervention and control arms were 3.7 and 3.4 deaths per 10 000 person-years, respectively, resulting in a non-statistically significant difference between the two arms (RR = 1.09, 95% CI = 0.87 to 1.36). No statistically significant interactions with respect to prostate cancer mortality were observed between trial arm and age (P(interaction) = .81), pretrial PSA testing (P(interaction) = .52), and comorbidity (P(interaction) = .68). CONCLUSIONS: After 13 years of follow-up, there was no evidence of a mortality benefit for organized annual screening in the PLCO trial compared with opportunistic screening, which forms part of usual care, and there was no apparent interaction with age, baseline comorbidity, or pretrial PSA testing. PMID- 22228149 TI - Physiologically based pharmacokinetic (PBPK) modelling tools: how to fit with our needs? AB - In 2005, a survey compared a number of commercial PBPK software available at the time, mainly focusing on 'ready to use' modelling tools. Since then, these tools and software have been further developed and improved to allow modellers to perform WB-PBPK modelling including ADME processes at a high level of sophistication. This review presents a comparison of the features, values and limitations of both the 'ready to use' software and of the traditional user customizable software that are frequently used for the building and use of PBPK models, as well as the challenges associated with the various modelling approaches regarding their current and future use. PBPK models continue to be used more and more frequently during the drug development process since they represent a quantitative, physiologically realistic platform with which to simulate and predict the impact of various potential scenarios on the pharmacokinetics and pharmacodynamics of drugs. The 'ready to use' PBPK software has been a major factor in the increasing use of PBPK modelling in the pharmaceutical industry, opening up the PBPK approach to a broader range of users. The challenge is now to educate and to train scientists and modellers to ensure their appropriate understanding of the assumptions and the limitations linked both to the physiological framework of the 'virtual body' and to the scaling methodology from in vitro to in vivo (IVIVE). PMID- 22228148 TI - Percutaneous fluoroscopically guided n-butyl cyanoacrylate (NBCA) injection for iatrogenic femoral arterial pseudoaneurysm under temporary balloon occlusion of arterial blood flow. AB - PURPOSE: To evaluate the safety and efficacy of n-butyl cyanoacrylate (NBCA) injection under fluoroscopy for iatrogenic femoral artery pseudoaneurysms under temporary balloon occlusion. MATERIALS AND METHODS: This treatment was approved by the Ethics Committee of our institute, and informed consent was obtained from the patients. Three male patients aged 82, 77, and 51 years developed femoral arterial pseudoaneurysms after catheterization. The pseudoaneurysms (diameter: 30, 12, and 15 mm; neck diameter: 1.8, 5.2, and 1.4 mm) were treated with percutaneous NBCA injection under fluoroscopy after failed ultrasound (US)-guided compression. First, a 4-Fr balloon catheter was inserted into the responsible femoral artery via the contralateral approach. An 18-gauge needle was placed in the pseudoaneurysm under US guidance, and a test injection of contrast medium was performed under fluoroscopic guidance to evaluate the extent of the pseudoaneurysm. NBCA-lipiodol (Lp) (ratio, 1:3) was then injected under balloon inflation. The balloon catheter was deflated and withdrawn after treatment. RESULTS: The total volume of the injected NBCA-Lp was 0.4-1.5 ml. In each case, angiography immediately after NBCA-Lp injection showed eradication of the pseudoaneurysm, and color Doppler US revealed no blood flow signal. No complications were observed. Color Doppler US showed no recurrence in the three patients at their last follow-ups at 6, 12, and 12 months. CONCLUSION: Percutaneous NBCA injection under fluoroscopy with the support of balloon inflation was safe, feasible, and useful for eradicating iatrogenic femoral artery pseudoaneurysms in three cases following failed US compression. PMID- 22228147 TI - InterSCOPE study: Associations between esophageal squamous cell carcinoma and human papillomavirus serological markers. AB - BACKGROUND: The role of human papillomavirus (HPV) in the causation of esophageal squamous cell carcinoma is unclear. We examined the associations between esophageal squamous cell carcinoma and 28 centrally measured HPV serological markers in serum from six existing case-control studies conducted in regions with differing background risks of esophageal cancer. METHODS: We used centralized multiplex serology to test serum samples from 1561 case subjects and 2502 control subjects from six case-control studies for antibodies to the major HPV capsid protein (L1) and/or the early proteins E6 and/or E7 of eight high-risk, two low risk, and four cutaneous HPV types. Study-specific odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using conditional logistic regression with adjustment for smoking, alcohol consumption, and other potential confounders. Pooled odds ratios and 95% confidence intervals were calculated using either a linear mixed-effects approach or a joint fixed-effects approach. All statistical tests were two-sided. RESULTS: We found statistically significant associations between esophageal squamous cell carcinoma and antibodies to E6 for HPV16 (OR = 1.89, 95% CI = 1.09 to 3.29, P = .023) and HPV6 (OR = 2.53, 95% CI = 1.51 to 4.25, P < .001) but not for other tested HPV types. There were no statistically significant associations between esophageal squamous cell carcinoma and antibodies to E7 for any of the tested HPV types. Simultaneous seropositivity for HPV16 E6 and E7 was rare (four case subjects, two control subjects; OR = 5.57, 95% CI = 0.90 to 34.35; P = .064). We also found statistically significant associations between esophageal squamous cell carcinoma and capsid antibodies for the high-risk mucosal type HPV33 L1 (OR = 1.30, 95% CI = 1.00 to 1.69; P = .047) and the low-risk mucosal types HPV6 (OR = 1.22, 95% CI = 1.05 to 1.42; P = .010) and HPV11 (OR = 1.30, 95% CI = 1.09 to 1.56, P = .0036). CONCLUSIONS: We found limited serological evidence of an association between esophageal squamous cell carcinoma and HPV in the populations studied. Although HPV does not appear to be an important risk factor for esophageal squamous cell carcinoma, we cannot exclude the possibility that certain HPV types may be involved in a small subset of cancers. PMID- 22228150 TI - Impact of curcumin supersaturation in antibacterial photodynamic therapy--effect of cyclodextrin type and amount: studies on curcumin and curcuminoides XLV. AB - Curcumin has been investigated as a potential photosensitizer (PS) in antimicrobial photodynamic therapy (aPDT). The phototoxic effect of curcumin is dependent on proper formulations of the compound because of the lipophilic nature of the molecule and the extremely low water solubility at physiological conditions. In the present study, the combination of curcumin with either a methylated beta-cyclodextrin (CD) or polyethylene glycol-based beta-CD or gamma CD polymers was investigated in aPDT using Escherichia coli (E. coli) and Enterococcus faecalis as model bacteria. Solutions with various supersaturation ratios of curcumin were prepared with the selected CD or CD polymers. The concept of supersaturation was then investigated as a mean to enhance the phototoxic effect of curcumin, especially toward the gram-negative bacteria E. coli. A high supersaturation ratio corresponded with high phototoxicity of E. coli. Depending on the curcumin preparation, the bacterial survival ranged from 0.01% to no significant effect after irradiation with blue light (29 J/cm(2) ). Temporal stabilization of the supersaturated state is necessary in order to retain high and predictable photoreactivity of the PS. Further studies will be needed in order to formulate curcumin preparations with acceptable hydrolytic and photolytic stability and a temporal stabilization of a supersaturated state. PMID- 22228151 TI - Surgical genomics: using new technology to answer age-old questions. PMID- 22228152 TI - Mutations in IRGM are associated with more frequent need for surgery in patients with ileocolonic Crohn's disease. AB - BACKGROUND: There are no clear criteria for judging the severity of disease in patients with Crohn's disease. Yet classification of patients into low- and high risk severity groups would benefit both medical and surgical management. At the time of this study, approximately 80 single-nucleotide polymorphisms within 55 genes had been associated with IBD. OBJECTIVE: The aim of this study was to identify genetic determinants (single-nucleotide polymorphisms) that could be markers of Crohn's disease severity by the use of frequency of ileocolic surgery as a surrogate for disease severity. DESIGN: Sixty-six patients (30 male) with ileocolonic Crohn's disease who previously underwent ileocolectomy were retrospectively studied. The severity of Crohn's disease was quantified by dividing the total number of ileocolectomy procedures by the time between IBD diagnosis and the patient's last clinic visit, the rationale being that more severe disease would be associated with a more frequent need for surgery. Genotyping for the 83 single-nucleotide polymorphisms associated with IBD was done on a customized Illumina Veracode genotyping platform. Three genetic models (general, additive, and dominant) were used to statistically quantify the genetic association of the studied single-nucleotide polymorphisms to the frequency of surgery after adjusting for covariates (age, smoking, family history, disease location, and disease behavior). RESULTS: For the entire group the average number of ileocolectomies per patient was 1.7 (range, 1-5) with an average duration of disease of 14.7 years. Single-nucleotide polymorphism rs4958847 in the IRGM gene (immunity-related GTPase family, M) was the most significant single-nucleotide polymorphism in all 3 models tested (p = 0.007) as being associated with ileocolectomy, and it remained significant even after a Benjamini-Hochberg false discovery correction for multiple observations. Patients carrying the "at-risk" allele for this single-nucleotide polymorphism (n = 20) had an average of 1 surgery every 6.87 +/- 1.33 years in comparison with patients carrying the wild type genotype (n = 46) who averaged 1 surgery in 11.43 +/- 1.21 years (p = 0.007, Mann-Whitney U test). CONCLUSIONS: : Single-nucleotide polymorphism rs4958847 in the IRGM gene correlated very significantly with frequency of surgery in patients with ileocolonic Crohn's disease. IRGM is a mediator of innate immune responses and is involved in autophagy. The presence of this IRGM SNP may be a marker for disease severity and/or early recurrence after ileocolectomy and may assist in surgical and medical decision making. PMID- 22228153 TI - Rate of residual disease after complete endoscopic resection of malignant colonic polyp. AB - BACKGROUND: Following polypectomy, colectomy is performed selectively to ensure complete clearance of neoplasia. OBJECTIVE: This study aimed to determine the risk factors associated with residual disease at colectomy following malignant polypectomy. DESIGN: This is a retrospective study. SETTING: This investigation took place at a tertiary teaching cancer center. PATIENTS: Consecutive patients undergoing polypectomy followed by colectomy from 1990 to 2007 were identified from a prospective database. MAIN OUTCOME MEASURES: Factors associated with residual disease at colectomy were associated with clinicopathologic features. RESULTS: Colectomy following polypectomy was performed in 143 patients: 127 with clear invasion of polyp submucosa (invasive disease), and 16 suspicious for submucosal invasion. Residual disease after colectomy was diagnosed in 27 (19%) of 143 patients. Disease was present in the colonic wall in 19 patients (13%): invasive in 16 (11%), and noninvasive in 3 (2.1%). Of the 16 patients with residual invasive disease at colectomy, 15 had clearly invasive disease at polypectomy and 1 was suspicious for invasive disease at polypectomy. Lymph node metastasis was noted in 10 (7.0%) patients. When analyzing patients with clearly invasive disease at polypectomy by margin status, residual invasive disease in the colon wall was noted in 8 of 50 (16%) with <1 mm (positive) polypectomy margin, 7 of 33 (21%) with indeterminate polypectomy margin, and 0 of 44 with >=1 mm (negative) polypectomy margin (p = 0.009). Nodal metastasis was associated with the presence of lymphovascular invasion (p = 0.01). LIMITATIONS: This study is limited by its retrospective nature and selection bias. CONCLUSIONS: Following malignant polypectomy, colectomy should be considered in medically fit patients if the polypectomy margin is positive (<=1 mm) or unknown, or if lymphovascular invasion is present. PMID- 22228154 TI - BRAF mutations in colorectal cancer are associated with distinct clinical characteristics and worse prognosis. AB - BACKGROUND: Colorectal cancer is a heterogeneous disease with multiple underlying genetic mutations causing different clinical phenotypes. Mutation in the BRAF oncogene is a key step in malignant transformation within the methylator pathway to colorectal cancer. However, there is a paucity of information about BRAF mutant colorectal tumors. OBJECTIVE: This study defines the clinical characteristics and oncologic outcome associated with colorectal cancer BRAF mutations. DESIGN: Colorectal adenocarcinomas from a single-institution frozen tumor biobank were studied. Genomic DNA was isolated and analyzed for mutations in the BRAF oncogene by polymerase chain reaction amplification followed by direct sequencing. A sample was classified as mutant if any of the tested loci were mutated. Patient and tumor characteristics were recorded including patient age, sex, tumor location, tumor differentiation, and microsatellite instability. MAIN OUTCOME MEASURES: Statistical associations with BRAF mutant tumors were determined by the Fisher exact probability test, chi test, or Wilcoxon analysis. Kaplan-Meier estimates and multivariate Cox regression analysis were performed for overall survival. RESULTS: Four hundred seventy-five colorectal adenocarcinomas were included in the study population; 56 samples harbored a BRAF mutation (12%). There were significant differences between BRAF wild-type and mutant tumors in age (66 vs 75 years, p = 0.004), female sex (44% vs 71%, p < 0.001), proximal tumor location (44% vs 95%, p < 0.001), and frequency of microsatellite instability (16% vs 76%, p < 0.001). There was no difference in cancer stage between BRAF mutant and wild-type populations. Survival data were analyzed for 322 patients with stage I to III disease, and patients with a BRAF mutation had decreased overall survival than those without a mutation (p = 0.018). With the use of Cox regression analysis, BRAF mutation conferred a worse overall survival (HR 1.79, CI 1.05-3.05, p = 0.03) independent of microsatellite instability status. CONCLUSIONS: BRAF mutations in colorectal cancers are associated with distinct clinical characteristics and worse prognosis. PMID- 22228155 TI - Single-port laparoscopic right hemicolectomy: the first 100 resections. AB - BACKGROUND: Single-port laparoscopy remains a novel technique in the field of colorectal surgery. Several small series have examined its safety for colon resection. OBJECTIVE: Our aim was to analyze our entire experience and short-term outcomes with single-port laparoscopic right hemicolectomy since its introduction at our institution. We assert that this approach is feasible and safe for the wide array of patients and indications encountered by a colorectal surgeon. DESIGN: This is a retrospective analysis of prospectively gathered data for all patients who underwent single-port laparoscopic right hemicolectomy with the use of standard laparoscopic instrumentation, for malignant or benign disease, between July 2009 and November 2010 in a high-volume, academic, colorectal surgery practice. MAIN OUTCOME MEASURES: Demographic, clinical, operative, and pathologic factors were reviewed and analyzed. All conversions to conventional laparoscopic or open operations were considered in this analysis. RESULTS: One hundred patients underwent single-port laparoscopic right hemicolectomy during the study period. Mean age was 63 years, and 61% of the patients were men. Forty three percent had undergone previous abdominal surgery, and the median body mass index was 26 (range, 18-46). Median ASA classification was 3 (range, 1-4). Five percent of the operations were performed urgently, and 56% were performed for carcinoma, of which half were T3 or T4 tumor stage. Median operative duration was 105 (range, 64-270) minutes. Mean and median blood loss was 106 and 50 mL. Two percent required conversion to multiport laparoscopy, and 4% converted to the open approach. Median postoperative stay was 4 (range, 2-48) days. Median lymph node number was 18 (range, 11-42). There was one mortality in this series. Morbidity, including wound infection, was 13%. CONCLUSIONS: This represents the largest experience with single-port laparoscopic right hemicolectomy to date. This technique was used with acceptable morbidity and mortality and without compromise of conventional oncologic parameters by colorectal surgeons experienced in minimally invasive technique. These findings support the use of a single-port approach for patients requiring right hemicolectomy. PMID- 22228156 TI - Single-incision laparoscopic surgery for ileocolic resection in Crohn's disease. AB - BACKGROUND: Single-incision laparoscopic surgery is a development in the field of minimally invasive surgery that is being increasingly used for colorectal procedures. OBJECTIVE: We report on the short-term results of single-port laparoscopic ileocolic resection in patients with ileocecal Crohn's disease. DESIGN: This investigation is a retrospective matched-pair control study. Data were obtained from a prospectively maintained single-institution inflammatory bowel disease database. SETTINGS: This study was conducted at a tertiary care university hospital. PATIENTS: Twenty consecutive patients receiving elective single-port ileocolic resection between April 2010 and May 2011 were included (6 male, 14 female; age, 31.6 +/- 10.8 years; BMI, 21.5 +/- 2.6 kg/m). Their data were compared with the data of 20 individually matched patients who had undergone standard 3-trocar laparoscopic-assisted ileocolic resection between 2007 and 2010 (6 male, 14 female; age, 31.7 +/- 10.7 years; BMI, 21.2 +/- 2.5 kg/m). All patients had medically refractory stenosis of the terminal ileum in histologically confirmed Crohn's disease. INTERVENTIONS: Single-port laparoscopic assisted or standard laparoscopic-assisted ileocolic resection was performed. MAIN OUTCOME MEASURES: The primary outcomes measured were the surgical details and early outcome. RESULTS: : The mean length of the paraumbilical single-port incision was 3.8 cm (range, 2.5-5.0 cm). Conversion rates were similar in both groups (1/20 vs 2/20, p = 0.55). Additional strictureplasties or short-segment small-bowel resections were performed in both groups. The overall complication rate was 20% (4/20) in both groups. There were no observed differences in postoperative pain scores and hospital stay duration. LIMITATIONS: The limitations of this study were as follows: this study was a comparison of 2 different time points with possible selection bias, there was no prestudy power calculation, and the study might be underpowered. CONCLUSIONS: Single-port ileocolic resection is a safe procedure for the surgical treatment of stenotizing Crohn's disease of the terminal ileum. Avoidance of additional trocars was the only identified benefit. PMID- 22228157 TI - Long-term quality of life and sexual and urinary function after abdominoperineal resection for distal rectal cancer. AB - BACKGROUND: Permanent colostomy, pelvic dissection, and radiotherapy after abdominoperineal resection can put quality of life and sexual and urinary function at risk; however, there are limited data using validated instruments on patients undergoing abdominoperineal resection regarding these outcome measures. OBJECTIVE: We evaluated the quality of life and the sexual and urinary function of patients undergoing abdominoperineal resection for rectal cancer and compared the outcomes of patients who received and did not receive pre- or postoperative pelvic radiotherapy. METHODS: European Organization for Research and Treatment of Cancer Quality of Life Questionnaires C30 and CR38, International Consultation on Incontinence Questionnaire, American Urological Association Symptom Index, Brief Sexual Function Inventory for men, and sexual function module of the Cancer Rehabilitation Evaluation System for women were mailed to 219 patients who underwent abdominoperineal resection between 1994 and 2004. RESULTS: One-hundred forty-three patients responded (response rate, 65%), of whom 55 (38%) were treated with surgery alone and 88 (62%) received pelvic radiotherapy. Generic and disease-specific quality of life and sexual and urinary function were similar between patients not receiving and receiving pelvic radiotherapy. However, a proportion of patients experienced adverse quality of life after surgery, and this was associated with a younger age, male sex, and sexual inactivity. In sexually active men, sexual function after abdominoperineal resection was diminished compared with population-based controls. LIMITATIONS: This study was limited by the lack of baseline data and cross-sectional nature of survey. CONCLUSIONS: Quality of life and sexual function can be impaired after abdominoperineal resection, although the impact of pelvic radiotherapy appears to be limited. Indication and timing of radiotherapy should be based on oncological indications, but quality of life and functional outcomes should be considered when counseling patients. PMID- 22228158 TI - T-pouch: results of the first 10 years with a nonintussuscepting continent ileostomy. AB - BACKGROUND: Continent ileostomy is an alternative for patients who are either not candidates for an ileo-anal pullthrough or in whom an ileo-anal pullthrough failed. We previously described a new type of continent ileostomy (T-pouch) with a nonintussuscepting valve. OBJECTIVE: This study performed an outcomes analysis of the first 10 years with 40 patients. DESIGN: A prospective database of patients with a T-pouch from 2000 to 2010 was retrospectively analyzed. MAIN OUTCOME MEASURES: The primary outcomes measured were demographics and surgical recovery information and the functional data obtained via questionnaire: incontinence, difficulty of pouch intubation, restrictions (work, social, diet, and sexual), quality of health and life, and level of satisfaction with surgery, which were rated on a scale of 0 to 10. RESULTS: Twenty-three women and 17 men (mean age, 51.2) received a T-pouch. Median follow-up was 6.2 years (range, 0.8 11 years). Five patients (12.5%) experience a leak; 3 leaks were managed conservatively and/or with drain placement. Pouch intubations were done 4 times per day in a mean of 6.8 minutes; the insertion difficulty was rated as 2.5 of 10. Ninety-two percent achieved good continence. All quality-of-life and dysfunction/restriction scores showed significant improvement. Major abdominal surgeries for pouch-related reasons were needed in 30%; minor service operations of the skin-level stoma were needed in 25% of the patients. Of the patients, 87.5% would do the surgery again; 90% would recommend it to others with the same diagnosis. LIMITATIONS: This study was limited by the cohort size and the lack of long-term data. CONCLUSION: Ten years with 40 patients confirmed that creation of a T-pouch is complex but could be performed with an acceptable rate of complications. It dramatically improved functional outcomes; most notably, it improved fecal control and decreased social, sexual, and work restrictions. PMID- 22228159 TI - Is it possible to improve the outcome of transanal advancement flap repair for high transsphincteric fistulas by additional ligation of the intersphincteric fistula tract? AB - BACKGROUND: Transanal advancement flap repair is successful in 2 of every 3 patients with a cryptoglandular fistula passing through the middle or upper third of the external anal sphincter. It has been suggested that ongoing disease in the remaining fistula tract contributes to failure. Ligation of the intersphincteric fistula tract might be a useful tool to eradicate this ongoing disease. OBJECTIVE: The aim of the present study was to evaluate the effect of an additional ligation of the fistula tract on the outcome of transanal advancement flap repair. DESIGN: This investigation was designed as a prospective clinical study. SETTINGS: The study took place in a university hospital. PATIENTS: A consecutive series of 41 patients with a high transsphincteric fistula of cryptoglandular origin were included. INTERVENTION: Ligation of the intersphincteric fistula tract was performed in addition to flap repair. MAIN OUTCOME MEASURES: Early and late complications were recorded. Continence scores were determined with the use of the Fecal Incontinence Severity Index. RESULTS: Median duration of follow-up was 15 months. Primary healing was observed in 21 patients (51%). Of the 20 patients with a failure, the original transsphincteric fistula persisted in 12 patients. In 8 patients, the transsphincteric fistula was converted into an intersphincteric fistula. These patients underwent subsequent fistulectomy, which was successful in all of them. The overall healing rate was 71%. LIMITATIONS: This was a preliminary observational study with no control group. CONCLUSIONS: : The ligation of the intersphincteric fistula tract procedure is prone to infection and does not enhance the outcome of flap repair. PMID- 22228160 TI - Defunctioning loop ileostomy for pelvic anastomoses: predictors of morbidity and nonclosure. AB - OBJECTIVE: The aim of this study was to determine the morbidity of a defunctioning loop ileostomy and the subsequent closure rate, and to identify the predictors of complications and nonclosure of stoma. DESIGN: This study is a retrospective review of a single-institution experience. PATIENTS: All patients who underwent a planned temporary defunctioning loop ileostomy performed synchronously with a pelvic anastomosis during a 6-year period were included. MAIN OUTCOME MEASURES: The primary outcome measures were the ileostomy complication rate for the entire spectrum of care, readmission and reoperation rates to treat ileostomy complications, and subsequent closure rate. Patient and treatment factors were evaluated for their independent effect on complications and closure rate with the use of multivariable logistic regression. RESULTS: One hundred twenty-three patients were identified (median age, 51 years). Of these patients, 64.2% developed >=1 minor or major ileostomy complications (13.8% during index hospitalization, 52.8% as outpatient, and 23.4% after closure). Readmitted for dehydration following ileostomy formation were 11.4% of patients. The ileostomy was closed in 76.4% of patients with 8.6% requiring a midline laparotomy. The overall ileostomy-related reoperation rate was 10.4% (2.4% during index hospitalization, 1.6% at readmission, and 6.4% following ileostomy closure). Obesity (BMI >=30 kg/m) was associated with a higher overall ileostomy complication rate (OR 8.56, 95% CI 1.64-44.74) and outpatient complication rate (OR 7.69, 95% CI 2.48-23.81). Age >65 years (OR 53.34, 95% CI 4.21-676.14) and hypertension (OR 8.36, 95% CI 1.09-64.43) increased the risks of high ileostomy output and dehydration. Obesity (OR 4.61, 95% CI 1.14-18.54) and smoking (4.47, 95% CI 1.43-13.98) decreased the likelihood of ileostomy closure. LIMITATION: This study was limited by its retrospective nature. CONCLUSIONS: The morbidity of a defunctioning loop ileostomy remains significant. Obesity is an independent predictor of ileostomy complications. Older age and hypertension increase the risks of high-output stoma and dehydration. Almost one quarter of patients never have the ileostomy closed. Obesity and smoking are associated with less likelihood of a subsequent ileostomy closure. PMID- 22228161 TI - Dehydration is the most common indication for readmission after diverting ileostomy creation. AB - BACKGROUND: Early readmission after discharge from the hospital is an undesirable outcome. Ileostomies are commonly used to prevent symptomatic anastomotic complications in colorectal resections. OBJECTIVE: The aim of this study was to identify factors predictive of readmission after colectomy/proctectomy and diverting loop ileostomy. DESIGN: This study is a retrospective review. PATIENTS: Patients were included who underwent colon and rectal resections with ileostomy at our institution. Sex, age, type of disease, comorbidities, elective vs urgent procedure, type of ileostomy, operative method, steroid use, ASA score, and the use of diuretics were evaluated as potential factors for readmission. MAIN OUTCOME MEASURES: The primary outcomes measured were the need for readmission and the presence of dehydration (ostomy output >=1500 mL over 24 hours and a blood urea nitrogen/creatinine level >=20, or physical findings of dehydration). RESULTS: Six hundred three loop ileostomies were created mostly in white (95.3%), male (55.6%) patients undergoing colon or rectal resections. IBD was the most common indication at 50.9%, with rectal cancer at 16.1%, and other at 31.0%. The 60-day readmission rate was 16.9% (n = 102) with the most common cause dehydration (n = 44, 43.1%). Regression analysis demonstrated that the laparoscopic approach (p = 0.02), lack of epidural anesthesia (p = 0.004), preoperative use of steroids (p = 0.04), and postoperative use of diuretics (p = 0.0001) were highly predictive for readmission. Furthermore, regression analysis for readmission for dehydration identified the use of postoperative diuretics as the sole risk factor (p = 0.0001). LIMITATIONS: This study is limited by the retrospective analysis of data, and it does not capture patients that were treated at home or in clinic. CONCLUSION: Readmission after colon or rectal resection with diverting loop ileostomy was high at 16.9%. Dehydration was the major cause for readmission. Patients receiving diuretics are at increased risk for readmission for dehydration. High-risk patients should be treated more cautiously as inpatients and closely monitored in the outpatient setting to help reduce dehydration and readmission. PMID- 22228162 TI - Clinicopathologic and molecular characteristics of synchronous colorectal cancers: heterogeneity of clinical outcome depending on microsatellite instability status of individual tumors. AB - BACKGROUND: The contribution of chromosomal instability, microsatellite instability, and epigenetic instability to the development of synchronous colorectal carcinomas is controversial. OBJECTIVE: This study aimed to investigate the relative roles of microsatellite instability and epigenetic instability in the development of synchronous colorectal cancers. DESIGN: This was a retrospective study of medical records with histologic, immunohistochemical, and molecular examination of stored tissue samples. SETTING: The study took place at Seoul National University Hospital, Korea. PATIENTS: A total of 46 patients with synchronous colorectal cancers and 105 patients with solitary colorectal cancers were included. MAIN OUTCOME MEASURES: Clinicopathologic and molecular characteristics including microsatellite instability, mismatch repair gene expression, CpG island methylator phenotype, and mutation of KRAS and BRAF were analyzed. RESULTS: Patients with synchronous tumors were more likely to be men than those with solitary tumors and had a tendency toward colocalization of individual tumors in the left or right colon. MSI-deficient cancers were more frequent in synchronous than in solitary cancers. The frequencies of CpG island methylator phenotype-high and KRAS and BRAF mutations were not different between synchronous and solitary cancers. No differences between synchronous cancers and solitary cancers were observed in overall survival or progression-free survival. Within the synchronous cancer group, patients with individual tumors discordant for microsatellite instability status had the worst clinical outcome, whereas those with individual tumors concordant for microsatellite instability-deficient status had the best clinical outcome. LIMITATIONS: The study was limited by its retrospective nature. Molecular analysis was performed only on cancerous lesions. CONCLUSIONS: Our findings suggest that microsatellite instability plays a more important role than does epigenetic instability in the development of synchronous colorectal cancers, and that information regarding concordant or discordant microsatellite instability status between individual tumors might help to predict clinical outcome of synchronous colorectal cancers. PMID- 22228163 TI - Risk factors for rectal stump cancer in inflammatory bowel disease. AB - BACKGROUND: Patients with long-standing colitis carry an increased risk of colorectal cancer and are therefore enrolled in colonoscopic surveillance programs. It is presently not known if endoscopic surveillance of patients with colitis with a closed rectal stump after a subtotal colectomy is justified. Neither is it clear which of these patients might be at increased risk for rectal stump cancer. OBJECTIVE: The aim of this study is to identify the risk factors for rectal stump cancer. DESIGN: This investigation is a retrospective descriptive case-control study. SETTINGS: This study was conducted at tertiary referral centers in the Netherlands. PATIENTS: Colorectal cancer cases associated with inflammatory bowel disease diagnosed between 1990 and 2006 were selected in a nationwide pathology archive. Patients with rectal stump cancer were selected from this group. The pathology archive was also used to identify inflammatory bowel disease controls matched for referral center with a closed rectal stump after subtotal colectomy, but without neoplasia. Follow-up started at the date of subtotal colectomy with the formation of a rectal stump. Demographic and disease characteristics were collected at baseline. MAIN OUTCOME MEASUREMENTS: Hazard ratios with 95% confidence intervals were calculated for factors associated with the development of rectal stump cancer with the use of univariate Cox regression analysis. End points were rectal stump cancer, end of follow-up, or death. RESULTS: A total of 12 patients with rectal stump cancer and 18 matching controls without neoplasia were identified. Univariate analysis showed an association between rectal stump cancer and primary sclerosing cholangitis, and disease duration until subtotal colectomy. LIMITATIONS: This study is limited by its retrospective design, and, despite being the largest series to date, it still has a limited number of cases. CONCLUSIONS: Risk factors for rectal stump cancer in a closed rectal stump after subtotal colectomy were primary sclerosing cholangitis and disease duration until subtotal colectomy. PMID- 22228164 TI - Pathological evaluation of mesocolic resection quality and ex vivo methylene blue injection: what is the impact on lymph node harvest after colon resection for cancer? AB - BACKGROUND: Although the National Quality Forum has endorsed the harvest of >=12 lymph nodes as a standard quality indicator for colon cancer surgery, this minimum quantity is not reached in many centers. OBJECTIVE: The aim of this study was to assess the impact of the implementation of a mesocolon evaluation pathological protocol and ex vivo arterial methylene blue injection on the number of nodes harvested after colon cancer resection. DESIGN: A prospective series was compared with a historical group. SETTINGS: This study was conducted by a specialized colorectal multidisciplinary team at a tertiary teaching hospital. PATIENTS: From June 2009 to December 2009, all the specimens after colon resection for cancer were analyzed with the use of a "mesocolon quality pathological evaluation" protocol. Moreover, a consecutive series of specimens was analyzed after arterial ex vivo injection of methylene blue. We compared the study groups with our previous series (2005-2009). INTERVENTIONS: The "mesocolon quality pathological evaluation" protocol was used with or without arterial methylene blue ex vivo injection. MAIN OUTCOME MEASURE: The primary outcome measure was the number of lymph nodes harvested. RESULTS: The mean number (SD) of lymph nodes collected was 20.6 (10.5), 37.1 (12.8), and 47.6 (12.9) (p < 0.0001) in the control, protocol, and methylene blue groups. In the control group, the minimum number of 12 and 18 lymph nodes collected was not reached in 92 (15.9%) and 258 (44.6%) patients. In contrast, all patients in the protocol and methylene blue groups had more than 18 lymph nodes collected. The multivariate analysis confirmed the application of the "mesocolon quality pathological evaluation" protocol and the methylene blue ex vivo injection, along with the type of resection and the length of the specimen, to be independent factors determining the number of nodes collected. LIMITATIONS: The patients are not randomly selected and are compared with a retrospective series. CONCLUSION: The implementation of a "mesocolon quality pathological evaluation" protocol along with the arterial ex vivo injection of methylene blue can significantly increase the number of nodes isolated after colonic resection, reaching a 100% rate of specimens with more than 12 nodes. PMID- 22228165 TI - Perioperative use of statins in elective colectomy. AB - BACKGROUND: Statins have many beneficial effects and may attenuate the proinflammatory and metabolic stress response to surgery and consequently reduce postoperative morbidity. OBJECTIVE: This study investigated whether perioperative use of statins improved short-term outcomes after elective colectomy. DESIGN: This study is a retrospective review of prospectively collected data. SETTINGS AND PATIENTS: This study was conducted in consecutive patients undergoing elective colonic resection within an enhanced recovery program at a tertiary hospital (Manukau Surgery Centre, Middlemore Hospital, Auckland, New Zealand) from January 2005 to December 2010. MAIN OUTCOME MEASURES: Complications, hospital stay, and readmissions were recorded for 30 days postoperatively. Postoperative functional recovery was measured by the use of the validated Surgical Recovery Score. Serum proinflammatory cytokines were measured on postoperative day 1. RESULTS: There were 269 patients; 86 patients were on a statin perioperatively, whereas 183 patients had no statin. Members of the statin group were older (median age, 72 vs 69 years; p = 0.021), included more men (53% vs 40%; p = 0.049), and included a higher number of patients with an ASA score of 3 (55% vs 22%; p < 0.001). Patients on statin therapy had a significantly lower number of anastomotic leaks (1% vs 7%; p = 0.031). However, there was no significant difference in total complications or median hospital stay. The 2 groups had comparable functional recovery, and there was no significant difference in serum cytokine levels. LIMITATIONS: This retrospective study did not analyze type, duration, or dose of statins given perioperatively. CONCLUSION: Patients on perioperative statins had greater baseline perioperative risks compared with nonusers, but they achieved equivalent outcomes overall. Statin use was associated with reduced anastomotic leaks. Thus, perioperative statin use may reduce morbidity after elective colectomy, and this finding warrants further investigation. PMID- 22228166 TI - Viscoelastic assessment of anal canal function using acoustic reflectometry: a clinically useful technique. AB - BACKGROUND: Anal acoustic reflectometry is a new reproducible technique that allows a viscoelastic assessment of anal canal function. Five new variables reflecting anal canal function are measured: the opening and closing pressure, opening and closing elastance, and hysteresis. OBJECTIVE: The aim of this study was to assess whether the parameters measured in anal acoustic reflectometry are clinically valid between continent and fecally incontinent subjects. DESIGN: This was an age- and sex-matched study of continent and incontinent women. SETTING: The study was conducted at a university teaching hospital. PATIENTS: One hundred women (50 with fecal incontinence and 50 with normal bowel control) were included in the study. Subjects were age matched to within 5 years. MAIN OUTCOME MEASURES: Parameters measured with anal acoustic reflectometry and manometry were compared between incontinent and continent groups using a paired t test. Diagnostic accuracy was assessed by the use of receiver operator characteristic curves. RESULTS: Four of the 5 anal acoustic reflectometry parameters at rest were significantly different between continent and incontinent women (eg, opening pressure in fecally incontinent subjects was 31.6 vs 51.5 cm H2O in continent subjects, p = 0.0001). Both anal acoustic reflectometry parameters of squeeze opening pressure and squeeze opening elastance were significantly reduced in the incontinent women compared with continent women (50 vs 99.1 cm H2O, p = 0.0001 and 1.48 vs 1.83 cm H2O/mm, p = 0.012). In terms of diagnostic accuracy, opening pressure at rest measured by reflectometry was significantly superior in discriminating between continent and incontinent women in comparison with resting pressure measured with manometry (p = 0.009). CONCLUSIONS: Anal acoustic reflectometry is a new, clinically valid technique in the assessment of continent and incontinent subjects. This technique, which assesses the response of the anal canal to distension and relaxation, provides a detailed viscoelastic assessment of anal canal function. This technique may not only aid the investigation of fecally incontinent subjects, but it may also improve our understanding of anal canal physiology during both the process of defecation and maintenance of continence. PMID- 22228167 TI - Transparent cap-assisted colonoscopy versus standard adult colonoscopy: a systematic review and meta-analysis. AB - BACKGROUND: Cap-assisted colonoscopy uses a transparent plastic hood attached to the tip of the colonoscope to flatten the semilunar folds and improve mucosal exposure. Several studies have examined the effect of cap-assisted colonoscopy on polyp detection, but the data are inconsistent. OBJECTIVE: This study aimed to evaluate whether cap-assisted colonoscopy improves the yield of colorectal neoplasia detected compared with standard colonoscopy. DATA SOURCES: A systematic search of the PubMed, MEDLINE, Embase, and Cochrane databases identified 12 studies that met the inclusion criteria for data extraction. STUDY SELECTION: Publications that compared cap-assisted colonoscopy vs standard colonoscopy in adults in a prospective randomized controlled study were selected for review. MAIN OUTCOME MEASURES: The primary outcomes used for meta-analysis were cecal intubation rate, cecal intubation time, and polyp detection rate. The analysis was performed using a fixed-effect model. Outcomes were calculated as odds ratios or standardized mean differences with 95% confidence intervals. The average polyp miss rate determined by tandem colonoscopy was also calculated. RESULTS: The outcomes of 6185 patients were studied. Cap-assisted colonoscopy detected significantly more patients with polyps (OR 1.13; p = 0.030) and had a lower average polyp miss rate (12.2% vs 28.6%) than standard colonoscopy. Cap-assisted colonoscopy had a significantly higher cecal intubation rate than standard colonoscopy (OR 1.36; p = 0.020), whereas the time to cecal intubation (standard mean difference, 0.04 min; p = 0.280) was similar for the 2 colonoscope types. CONCLUSIONS: Cap-assisted colonoscopy is associated with improved detection of colorectal neoplasia and higher cecal intubation rates than standard adult colonoscopy. PMID- 22228168 TI - CT scans in diagnosing diverticulitis in the emergency department: is the radiation exposure warranted? PMID- 22228172 TI - Preparation and ESR study of Sc3C2@C80 bis-addition fulleropyrrolidines. AB - The bis-adducts of Sc(3)C(2)@C(80) fulleropyrrolidines were prepared and isolated. ESR study showed that these bis-addition fulleropyrrolidines have varied paramagnetism resulting from diverse reaction sites for the second pyrrolidine addend. PMID- 22228169 TI - Reverse-hybrid robotic mesorectal excision for rectal cancer. AB - PURPOSE: The robotic system offers potential technical advantages over laparoscopy for total mesorectal excision with radical lymphadenectomy for rectal cancer. However, the requirement for fixed docking limits its utility when the working volume is large or patient repositioning is required. The purpose of this study was to evaluate short-term outcomes associated with a novel setup to perform total mesorectal excision and radical lymphadenectomy for rectal cancer by the use of a "reverse" hybrid robotic-laparoscopic approach. METHODS: This is a prospective consecutive cohort observational study of patients who underwent robotic rectal cancer resection from January 2009 to March 2011. During the study period, a technique of reverse-hybrid robotic-laparoscopic rectal resection with radical lymphadenectomy was developed. This technique involves reversal of the operative sequence with lymphovascular and rectal dissection to precede proximal colonic mobilization. This technique evolved from a conventional-hybrid resection with laparoscopic vascular control, colonic mobilization, and robotic pelvic dissection. Perioperative and short-term oncologic outcomes were analyzed. RESULTS: Thirty patients underwent reverse-hybrid resection. Median tumor location was 5 cm (interquartile range 3-9) from the anal verge. Median BMI was 27.6 (interquartile range 25.0-32.1 kg/m). Twenty (66.7%) received neoadjuvant chemoradiation. There were no conversions. Median blood loss was 100 mL (interquartile range 75-200). Total operation time was a median 369 (interquartile range 306-410) minutes. Median docking time was 6 (interquartile range 5-8) minutes, and console time was 98 (interquartile range 88-140) minutes. Resection was R0 in all patients; no patients had an incomplete mesorectal resection. Six patients (20%) underwent extended lymph node dissection or en bloc resection. CONCLUSIONS: Reverse-hybrid robotic surgery for rectal cancer maximizes the therapeutic applicability of the robotic and conventional laparoscopic techniques for optimized application in minimally invasive rectal surgery. PMID- 22228173 TI - Association of drop vertical jump displacement with select performance variables. AB - Drop vertical jumps (DVJs) stimulate enhanced countermovement loading as would occur with a run-up before jumping. A variety of performance variables have been associated with DVJ performance including ground contact time (GCT), reactive strength index (RSI), eccentric utilization ratio (EUR), and elasticity index (EI). This study examined the stability reliability and precision of these variables and their associations with DVJ displacement in trained men and women. The EUR and EI measures were redundant, so only EUR findings were reported. Except for EUR, data for all variables were both reliable and precise (intraclass correlation coefficient >= 0.70, coefficient of variation [CV%] <= 15.0) although EUR data were precise (CV% <= 15.0). Correlations with DVJ displacement were low for GCT, moderate for RSI, and negligible for EUR. Therefore, GCT and EUR likely represent unique performance characteristics not related to DVJ displacement. Furthermore, the variability in DVJ performance accounted for by RSI may primarily reflect the inclusion of displacement as the numerator in the quotient for calculating it. PMID- 22228174 TI - Upper Quarter Y Balance Test: reliability and performance comparison between genders in active adults. AB - The inclusion of movement tests before performance training and sport participation is gaining popularity as part of musculoskeletal screening for injury. The identification of an athlete's asymmetries and poor performance in the preseason allows coaches and sports medicine clinicians the opportunity to proactively address these deficits to reduce the potential for injury. Currently, there are no tests reported in the literature that simultaneously require shoulder and core stability while taking the subjects through a large range of motion at the end range of their stability. Thus, the purpose of this article was to describe the Upper Quarter Y Balance Test and report the gender differences in the performance of the test. Upper extremity reach distances were measured in 95 active adults using a standardized upper extremity balance-and-reach protocol. Intraclass correlation coefficients were used to assess reliability, and gender differences were analyzed using an independent samples t-test, whereas bilateral differences were analyzed using a dependent samples t-test for the normalized composite reach scores. Intraclass correlation coefficient (3.1) for test-retest reliability ranged from 0.80 to 0.99. Intraclass correlation coefficient (3.1) for interrater reliability was 1.00. Average composite scores (right/left) reported as a percentage of limb length were 81.7/82.3% for men and 80.7/80.7% for women. The results of the study suggest that the Upper Quarter Y Balance Test is a reliable test for measuring upper extremity reach distance while in a closed chain position. It was further determined that there was no significant difference in performance between genders or between sides on the test when normalized to limb length. Coaches and sports medicine professionals may consider incorporating the Upper Quarter Y Balance Test as part of their preprogram testing to identify movement limitations and asymmetries in athletes and thereby may reduce injury. PMID- 22228175 TI - Quantitative RT-PCR analysis of PSA and prostate-specific membrane antigen mRNA to detect circulating tumor cells improves recurrence-free survival nomogram prediction after radical prostatectomy. AB - BACKGROUND: Circulating tumor cell (CTC) analysis is a potential new biomarker in prostate cancer. We hypothesize that quantitative detection of CTCs in patients pre- and post-radical prostatectomy (RP) using quantitative TaqMan(r) fluorogenic RT-PCR will improve the accuracy of the Kattan nomogram to predict the probability of recurrence-free survival (RFS) post-RP. METHODS: Ninty-two patients who underwent RP between 2004 and 2009 had venous blood samples taken pre- (Day - 1) and post-operatively (Day + 7). We performed quantitative Taqman(r) RT-PCR to detect circulating prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) mRNA. We calculated both the logarithmic ratio of Day + 7/Day - 1 for PSA (PSAr) and PSMA (PSMAr) expression (log(Day+7/Day-1) ) and the Kattan nomogram predicted probability of disease recurrence for each patient. We then analyzed how the AUC-ROC analysis for the Kattan nomogram prediction alone (K) compared to the addition of the PSAr and PSMAr in predicting 5-year RFS. RESULTS: The mean age (years), PSA (ng/ml), and follow-up (mo) was 65.1, 9.13, and 72, respectively. The AUCs for K, PSAr + K, and PSMAr + K were 0.752 (95%CI 0.620-0.860), 0.830 (95%CI 0.740-0.911), and 0.837 (95%CI 0.613-0.923), respectively (P = 0.03). The Kattan 5-year PSA RFS was 75%. The actual 5-year PSA RFS survival rate was 77%. CONCLUSIONS: Data from modern quantitative RT-PCR to detect circulating prostate-derived PSA and PSM mRNA pre- and post-RP improves the accuracy of the Kattan nomogram to predict biochemical recurrence. PMID- 22228176 TI - The discovery of placenta growth factor and its biological activity. AB - Angiogenesis is a complex biological phenomenon crucial for a correct embryonic development and for post-natal growth. In adult life, it is a tightly regulated process confined to the uterus and ovary during the different phases of the menstrual cycle and to the heart and skeletal muscles after prolonged and sustained physical exercise. Conversly, angiogenesis is one of the major pathological changes associated with several complex diseases like cancer, atherosclerosis, arthritis, diabetic retinopathy and age-related macular degeneration. Among the several molecular players involved in angiogenesis, some members of VEGF family, VEGF-A, VEGF-B and placenta growth factor (PlGF), and the related receptors VEGF receptor 1 (VEGFR-1, also known as Flt-1) and VEGF receptor 2 (VEGFR-2, also known as Flk-1 in mice and KDR in human) have a decisive role. In this review, we describe the discovery and molecular characteristics of PlGF, and discuss the biological role of this growth factor in physiological and pathological conditions. PMID- 22228177 TI - Anti-inflammatory mechanisms and therapeutic opportunities in myocardial infarct healing. AB - The wound healing response after myocardial infarction (MI) involves a cascade of molecular and cellular events that lead to a replacement of the necrotic area with a collagen-rich scar. Clearance of necrotic debris by neutrophils, monocytes, and macrophages is a critical component of infarct healing; however, tight control and timely repression of this inflammatory response is important to prevent excessive tissue degradation leading to infarct expansion and heart failure. Genetic ablation or blockade of anti-inflammatory pathways tends to be detrimental after MI, whereas genetic ablation of pro-inflammatory pathways tends to be beneficial. Accordingly, therapies enhancing endogenous anti-inflammatory pathways or blocking endogenous pro-inflammatory pathways have been found to improve wound healing and to reduce the risk of heart failure in rodent models of acute MI. Besides their scavenger function, inflammatory cells promote healing by stimulating angiogenesis and granulation tissue formation via paracrine factors. Moreover, signaling mediators that are active in inflammatory cells may be active also in non-inflammatory cell types involved in infarct healing. Some anti inflammatory interventions are therefore deleterious. However, interventions that carefully adjust the balance between the essential and detrimental facets of inflammation may provide new therapeutic opportunities for patients with large MIs who continue to be at risk of developing heart failure, despite modern reperfusion and anti-remodeling strategies. PMID- 22228178 TI - Gastrin inhibits a novel, pathological colon cancer signaling pathway involving EGR1, AE2, and P-ERK. AB - Human anion exchanger 2 (AE2) is a plasma membrane protein that regulates intracellular pH and cell volume. AE2 contributes to transepithelial transport of chloride and bicarbonate in normal colon and other epithelial tissues. We now report that AE2 overexpression in colon cancer cells is correlated with expression of the nuclear proliferation marker, Ki67. Survival analysis of 24 patients with colon cancer in early stage or 33 patients with tubular adenocarcinoma demonstrated that expression of AE2 is correlated with poor prognosis. Cellular and molecular experiments indicated that AE2 expression promoted proliferation of colon cancer cells. In addition, we found that transcription factor EGR1 underlies AE2 upregulation and the AE2 sequester p16INK4a (P16) in the cytoplasm of colon cancer cells. Cytoplasmic P16 enhanced ERK phosphorylation and promoted proliferation of colon cancer cells. Gastrin inhibited proliferation of colon cancer cells by suppressing expression of EGR1 and AE2 and by blocking ERK phosphorylation. Taken together, our data describe a novel EGR1/AE2/P16/P-ERK signaling pathway in colon carcinogenesis, with implications for pathologic prognosis and for novel therapeutic approaches. PMID- 22228179 TI - Identification and characterization of a noncoding RNA at the mouse Pcna locus. AB - AK007836 encodes a noncoding RNA (ncRNA) consisting of 2 exons. Since AK007836 is located just upstream of Pcna and transcribed in the opposite direction to that of Pcna, we analyzed its expression pattern. Both ncRNA and Pcna expressions were detected in in vitro and in vivo cells, showing a positive correlation. A 177 bp region separating the first exons of Pcna and AK007836 has a bidirectional promoter activity. When the expression of ncRNA was reduced by siRNA, Pcna expression was also reduced in normal cells, but not in cancer cells. These results suggest that the ncRNA is divergently transcribed from the bidirectional promoter, positively regulating the neighboring protein-coding Pcna gene transcription, and this regulatory function is somehow disrupted in cancer cells. PMID- 22228180 TI - Activation of rice Yellow Stripe1-Like 16 (OsYSL16) enhances iron efficiency. AB - Graminaceous plants release ferric-chelating phytosiderophores that bind to iron. These ferric-phytosiderophore complexes are transported across the plasma membrane by a protein produced from Yellow Stripe 1 (YS1). Here, we report the characterization of OsYSL16, one of the YS1-like genes in rice. Real-time analysis revealed that this gene was constitutively expressed irrespective of metal status. Promoter fusions of OsYSL16 to beta-glucuronidase (GUS) showed that OsYSL16 was highly expressed in the vascular tissues of the root, leaf, and spikelet, and in leaf mesophyll cells. The OsYSL16-green fluorescence protein (GFP) fusion protein was localized to the plasma membrane. From a pool of rice T DNA insertional lines, we identified two independent activation-tagging mutants in OsYSL16. On an Fe-deficient medium, those mutants retained relatively high chlorophyll concentrations compared with the wild-type (WT) controls, indicating that they are more tolerant to a lack of iron. The Fe concentration in shoots was also higher in the OsYSL16 activation lines than in the WT. During germination, the rate of Fe-utilization from the seeds was higher in the OsYSL16 activation lines than in the WT seeds. Our results suggest that the function of OsYSL16 in Fe-homeostasis is to enable distribution of iron within a plant. PMID- 22228181 TI - Expression profiling after induction of demethylation in MCF-7 breast cancer cells identifies involvement of TNF-alpha mediated cancer pathways. AB - Epigenetic methylation change is a major process that occurs during cancer development. Even though many tumor-related genes have been identified based on their relationship between methylation and expression, few studies have been conducted to investigate the relevant biological pathways involved in these changes. To identify essential pathways likely to be affected by methylation in breast cancer, we examined a pool of genes in which expression was upregulated after induction of demethylation by 5-Aza-2'-deoxycytidine (Aza) in the MCF-7 breast cancer cell line. Genome-wide demethylation was confirmed by monitoring the demethylation of a previously known gene, SULT1A1. Overall, 210 and 213 genes were found to be upregulated and downregulated (fold change >= 2), respectively, in common in cells treated with 5 and 10 MUM of Aza. Network analysis of these 423 genes with altered expression patterns identified the involvement of a cancer related network of genes that were heavily regulated by TNF-alpha in breast tumorigenesis. Our results suggest that epigenetic dysregulation of cellular processes relevant to TNF-alpha-dependent apoptosis may be intimately involved in tumorigenesis in MCF-7 cells. PMID- 22228182 TI - Interspecies signaling through QscR, a quorum receptor of Pseudomonas aeruginosa. AB - The QS machinery of Pseudomonas aeruginosa, an opportunistic human pathogen, consists of three acyl-homoserine lactone (acyl-HSL) signaling systems, LasR-I, RhlR-I, and QscR. QscR, known as an orphan receptor and a repressor of other QS systems, operates its own regulon using N-3-oxododecanoyl HSL (3OC12), which is synthesized by LasI, as its signal. In this study, we addressed the role of QscR in interspecies communication. We found that QscR auto-activates its own transcription in the presence of 3OC12. In a single population of P. aeruginosa, where 3OC12 is the sole signal available for QscR, the QscR regulon is activated by 3OC12 produced by the LasI-R system. However, the broad signal specificity of QscR allowed it to respond to a non-P. aeruginosa signal, such as N-decanoyl HSL (C10) and N-3-hydroxydecanoyl HSL (3OHC10), which preferentially activated QscR to LasR. The signal extracts from Pseudomonas fluorescens and Burkholeria vietnamiensis also preferentially activated QscR. These non-P. aeruginosa signals activated QscR more strongly than 3OC12, the authentic P. aeruginosa signal. Since a variety of acyl-HSLs are produced in the multi-species habitat of nature, our study provides a clue for the particular situation that allows QscR to secede from the conventional QS cascade in mixed microbial community. PMID- 22228183 TI - Dissection of the dimerization modes in the DJ-1 superfamily. AB - The DJ-1 superfamily (DJ-1/ThiJ/PfpI superfamily) is distributed across all three kingdoms of life. These proteins are involved in a highly diverse range of cellular functions, including chaperone and protease activity. DJ-1 proteins usually form dimers or hexamers in vivo and show at least four different binding orientations via distinct interface patches. Abnormal oligomerization of human DJ 1 is related to neurodegenerative disorders including Parkinson's disease, suggesting important functional roles of quaternary structures. However, the quaternary structures of the DJ-1 superfamily have not been extensively studied. Here, we focus on the diverse oligomerization modes among the DJ-1 superfamily proteins and investigate the functional roles of quaternary structures both computationally and experimentally. The oligomerization modes are classified into 4 types (DJ-1, YhbO, Hsp, and YDR types) depending on the distinct interface patches (I-IV) upon dimerization. A unique, rotated interface via patch I is reported, which may potentially be related to higher order oligomerization. In general, the groups based on sequence similarity are consistent with the quaternary structural classes, but their biochemical functions cannot be directly inferred using sequence information alone. The observed phyletic pattern suggests the dynamic nature of quaternary structures in the course of evolution. The amino acid residues at the interfaces tend to show lower mutation rates than those of non-interfacial surfaces. PMID- 22228184 TI - In vivo imaging of differences in early donor cell proliferation in graft-versus host disease hosts with different pre-conditioning doses. AB - Graft-versus-host disease (GVHD) results from immunemediated attacks on recipient tissues by donor-originated cells through the recognition of incompatible antigens expressed on host cells. The pre-conditioning irradiation dose is a risk factor influencing GVHD severity. In this study, using newly generated luciferase transgenic mice on a B6 background (B6.Luc(Tg)) as bone marrow and splenocyte donors, we explored the effects of irradiation doses on donor cell dynamics in major histocompatibility complex (MHC)-matched allogeneic GVHD hosts via bioluminescence imaging (BLI). Results from BLI of GVHD hosts showed higher emission intensities of luminescence signals from hosts irradiated with 900 cGy as compared with those irradiated with 400 cGy. In particular, BLI signals from target organs, such as the spleen, liver, and lung, and several different lymph nodes fluctuated with similar time kinetics soon after transplantation, reflecting the synchronous proliferation of donor cells in the different organs in hosts irradiated with 900 cGy. The kinetic curves of the BLI signals were not synchronized between the target organs and the secondary organs in hosts irradiated with 400 cGy. These results demonstrate that pre-conditioning doses influence the kinetics and degree of proliferation in the target organs soon after transplantation. The results from this study are the first describing donor cell dynamics in MHC-matched allogeneic GVHD hosts and the influence of irradiation doses on proliferation dynamics, and will provide spatiotemporal information to help understand GVHD pathophysiology. PMID- 22228185 TI - Activation of Rice nicotianamine synthase 2 (OsNAS2) enhances iron availability for biofortification. AB - Because micronutrients in human diets ultimately come from plant sources, malnutrition of essential minerals is a significant public health concern. By increasing the expression of nicotianamine synthase (NAS), we fortified the level of bioavailable iron in rice seeds. Activation of iron deficiency-inducible OsNAS2 resulted in a rise in Fe content (3.0-fold) in mature seeds. Its ectopic expression also increased that content. Enhanced expression led to higher tolerance of Fe deficiency and better growth under elevated pH. Mice fed with OsNAS2-D1 seeds recovered more rapidly from anemia, indicating that bioavailable Fe contents were improved by this increase in OsNAS2 expression. PMID- 22228186 TI - Giant chloroplast development in ethylene response1-1 is caused by a second mutation in ACCUMULATION AND REPLICATION OF CHLOROPLAST3 in Arabidopsis. AB - The higher plants of today array a large number of small chloroplasts in their photosynthetic cells. This array of small chloroplasts results from organelle division via prokaryotic binary fission in a eukaryotic plant cell environment. Functional abnormalities of the tightly coordinated biochemical event of chloroplast division lead to abnormal chloroplast development in plants. Here, we described an abnormal chloroplast phenotype in an ethylene insensitive ethylene response1-1 (etr1-1) of Arabidopsis thaliana. Extensive transgenic and genetic analyses revealed that this organelle abnormality was not linked to etr1-1 or ethylene signaling, but linked to a second mutation in ACCUMULATION AND REPLICATION3 (ARC3), which was further verified by genetic complementation analysis. Despite the normal expression of other plastid division-related genes, the loss of ARC3 caused the enlargement of chloroplasts as well as the diminution of a photosynthetic protein Rubisco in etr1-1. Our study has suggested that the increased size of the abnormal chloroplasts may not be able to fully compensate for the loss of a greater array of small chloroplasts in higher plants. PMID- 22228188 TI - Indeed, what has changed! PMID- 22228187 TI - Association of GSTM1, GSTT1, GSTP1 and CYP2E1 single nucleotide polymorphisms with colorectal cancer in Iran. AB - Colorectal cancer is a major cause of morbidity and mortality both globally and in Iran. The aim of this study was to determine the association between genetic polymorphisms of glutathione S-transferases P1, M1 and T1 (GSTP1, M1, T1) and susceptibility to colorectal cancer (CRC). Genotyping of GSTP1, GSTM1 and GSTT1 was performed by the use of pyrosequencing. One hundred cases and healthy controls were enrolled into this study. Mean GSTT1 polymorphism type was significantly (P < 0.01) higher in cases as compared to controls (P < 0.0001: OR, 2.43: 95% CI, 1.47-4). On the other hand there is no significant association between GSTM1, GSTP1 and colorectal cancer. GSTs measurement may be useful as a colorectal marker in colorectal cancer and biopsies obtained at colonoscopy can be used to measure tumor markers. PMID- 22228189 TI - Influence of bone affinity on the skeletal distribution of fluorescently labeled bisphosphonates in vivo. AB - Bisphosphonates are widely used antiresorptive drugs that bind to calcium. It has become evident that these drugs have differing affinities for bone mineral; however, it is unclear whether such differences affect their distribution on mineral surfaces. In this study, fluorescent conjugates of risedronate, and its lower-affinity analogues deoxy-risedronate and 3-PEHPC, were used to compare the localization of compounds with differing mineral affinities in vivo. Binding to dentine in vitro confirmed differences in mineral binding between compounds, which was influenced predominantly by the characteristics of the parent compound but also by the choice of fluorescent tag. In growing rats, all compounds preferentially bound to forming endocortical as opposed to resorbing periosteal surfaces in cortical bone, 1 day after administration. At resorbing surfaces, lower-affinity compounds showed preferential binding to resorption lacunae, whereas the highest-affinity compound showed more uniform labeling. At forming surfaces, penetration into the mineralizing osteoid was found to inversely correlate with mineral affinity. These differences in distribution at resorbing and forming surfaces were not observed at quiescent surfaces. Lower-affinity compounds also showed a relatively higher degree of labeling of osteocyte lacunar walls and labeled lacunae deeper within cortical bone, indicating increased penetration of the osteocyte canalicular network. Similar differences in mineralizing surface and osteocyte network penetration between high- and low affinity compounds were evident 7 days after administration, with fluorescent conjugates at forming surfaces buried under a new layer of bone. Fluorescent compounds were incorporated into these areas of newly formed bone, indicating that "recycling" had occurred, albeit at very low levels. Taken together, these findings indicate that the bone mineral affinity of bisphosphonates is likely to influence their distribution within the skeleton. PMID- 22228193 TI - Latent Variable Model for Learning in Pairwise Markov Networks. AB - Pairwise Markov Networks (PMN) are an important class of Markov networks which, due to their simplicity, are widely used in many applications such as image analysis, bioinformatics, sensor networks, etc. However, learning of Markov networks from data is a challenging task; there are many possible structures one must consider and each of these structures comes with its own parameters making it easy to overfit the model with limited data. To deal with the problem, recent learning methods build upon the L1 regularization to express the bias towards sparse network structures. In this paper, we propose a new and more flexible framework that let us bias the structure, that can, for example, encode the preference to networks with certain local substructures which as a whole exhibit some special global structure. We experiment with and show the benefit of our framework on two types of problems: learning of modular networks and learning of traffic networks models. PMID- 22228192 TI - Balancing risk prevention and health promotion: towards a harmonizing approach in care for older people in the community. AB - Many older people in western countries express a desire to live independently and stay in control of their lives for as long as possible in spite of the afflictions that may accompany old age. Consequently, older people require care at home and additional support. In some care situations, tension and ambiguity may arise between professionals and clients whose views on risk prevention or health promotion may differ. Following Antonovsky's salutogenic framework, different perspectives between professionals and clients on the pathways that lead to health promotion might lead to mechanisms that explain the origin of these tensions and how they may ultimately lead to reduced responsiveness of older clients to engage in care. This is illustrated with a case study of an older woman living in the community, Mrs Jansen, and her health and social care professionals. The study shows that despite good intentions, engagement, clear division of tasks and tailored care, the responsiveness to receive care can indeed not always be taken for granted. We conclude that to harmonize differences in perspectives between professionals and older people, attention should be given to the way older people endow meaning to the demanding circumstances they encounter (comprehensibility), their perceived feelings of control (manageability), as well as their motivation to comprehend and manage events (meaningfulness). Therefore, it is important that both clients and professionals have an open mind and attempt to understand each others' perspective, and have a dialogue with each other, taking the life narrative of clients into account. PMID- 22228194 TI - The unprecedented preparation of dinuclear zinc(II) complexes from 4-halido-2-[(3 cyclohexylaminopropylimino)methyl]phenol. AB - Three new centrosymmetric trinuclear nickel(II) and manganese(II) complexes, Ni[Ni(CH(3)COO)(CPA)](2) (1), Ni[Ni(CH(3)COO)(BPA)](2) (2), Mn[Mn(CH(3)COO)(BPA)](2) (3), where H(2)CPA = N,N'-bis(5-chlorosalicylidene)-1,3 propanediamine, H(2)BPA = N,N'-bis(5-bromosalicylidene)-1,3-propanediamine, and two new centrosymmetric dinuclear zinc(II) complexes, [Zn(2)(CMP)(2)] (4) and [Zn(2)(BMP)(2)] (5), where H(2)CMP = 4-chloro-2-{[3-(5-chloro-2 hydroxybenzyl)aminopropylimino]methyl}phenol, and H(2)BMP = 4-bromo-2-{[3-(5 bromo-2-hydroxybenzyl)aminopropylimino]methyl}phenol, have been prepared from the Schiff bases derived from 5-halido-substituted salicylaldehydes with N hexylpropane-1,3-diamine under solvothermal conditions. The complexes have been characterised by elemental analysis, IR spectroscopy and single-crystal X-ray diffraction studies. The complexes 1, 2, and 3 crystallise in the monoclinic space group P2(1)/c with cell dimensions a = 9.347(1), b = 11.507(2), c = 18.539(2) A, beta = 93.774(2) degrees , Z = 2 (for 1), a = 9.111(4), b = 12.089(6), c = 18.724(8) A, beta = 92.117(7) degrees , Z = 2 (for 2), and a = 11.328(2), b = 22.468(5), c = 8.270(2) A, beta = 93.74(3) degrees , Z = 2 (for 3), while complexes 4 and 5 crystallise in the triclinic space group P1, with cell dimensions a = 7.483(1), b = 9.990(2), c = 12.155(2) A, alpha = 75.27(3), beta = 85.00(3), gamma = 73.82(3) degrees , Z = 1 (for 4), and a = 7.008(1), b = 10.081(2), c = 13.095(3) A, alpha = 100.62(3), beta = 95.51(3), gamma = 104.03(3) degrees , Z = 1 (for 5). It is interesting that the mono-Schiff bases 4-chloro-2 [(3-cyclohexylaminopropylimino)methyl]phenol (HCCP) and 4-bromo-2-[(3 cyclohexylaminopropylimino)methyl]phenol (HBCP) used to prepare the nickel(II) and manganese(II) complexes were transferred to bis-Schiff bases H(2)CPA and H(2)BPA in the complexes 1, 2, and 3, while the mono-Schiff bases HCCP and HBCP used to prepare the zinc(II) complexes were transferred to novel ligands H(2)CMP and H(2)BMP, bearing the unexpected, newly formed carbon-nitrogen single bond. PMID- 22228196 TI - Gender balance, representativeness, and statistical power in sexuality research using undergraduate student samples. PMID- 22228195 TI - Diversification of hAT transposase paralogues in the sugarcane genome. AB - Transposons are abundant components of eukaryotic genomes, and play important role in genome evolution. The knowledge about these elements should contribute to the understanding of their impact on the host genomes. The hAT transposon superfamily is one of the best characterized superfamilies in diverse organisms, nevertheless, a detailed study of these elements was never carried in sugarcane. To address this question we analyzed 32 cDNAs similar to that of hAT superfamily of transposons previously identified in the sugarcane transcriptome. Our results revealed that these hAT-like transposases cluster in one highly homogeneous and other more heterogeneous lineage. We present evidences that support the hypothesis that the highly homogeneous group is a domesticated transposase while the remainder of the lineages are composed of transposon units. The first is common to grasses, clusters significantly with domesticated transposases from Arabidopsis, rice and sorghum and is expressed in different tissues of two sugarcane cultivars analyzed. In contrast, the more heterogeneous group represents at least two transposon lineages. We recovered five genomic versions of one lineage, characterizing a novel transposon family with conserved DDE motif, named SChAT. These results indicate the presence of at least three distinct lineages of hAT-like transposase paralogues in sugarcane genome, including a novel transposon family described in Saccharum and a domesticated transposase. Taken together, these findings permit to follow the diversification of some hAT transposase paralogues in sugarcane, aggregating knowledge about the co-evolution of transposons and their host genomes. PMID- 22228197 TI - Estrogen receptors alpha (rs2234693 and rs9340799), and beta (rs4986938 and rs1256049) genes polymorphism in prostate cancer: evidence for association with risk and histopathological tumor characteristics in Iranian men. AB - We evaluated the effect of estrogen receptor (ER)-alpha and ER-beta genes polymorphisms on development of prostate cancer (PCa) and its correlation with serum reproductive hormones and with clinicopathological characteristics in a sample of Iranian men. One hundred sixty-two men with PCa (mean age 63.7 +/- 3.4 years) and 324 age-matched healthy controls (mean age 63.1 +/- 3.2 years) were recruited in this study. Genotypes for ER-alpha and ER-beta genes polymorphisms were identified by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Serum levels of reproductive hormones were also measured. Of PCa patients, 38.3%, and 61.7% had localized and advanced tumor, and 45.7%, and 54.3%, had low grade and high-grade cancer, respectively. There was a significant difference in genotype frequency distribution of ER-alpha gene polymorphism (P = 0.002), and ER-beta gene polymorphism (P = 0.003) between cancer patients and controls. The ER-alpha Pvull C allele carriers (TC or CC) had a significantly increased risk of PCa compared with the TT homozygotes [odds ratio (OR) 3.12; 95% confidence interval (CI) 1.87-5.84, and OR = 4.73, 95% CI:2.44-7.33, respectively]. It was also found that the ER-alpha XbaI AG (OR = 4.36; 95% CI:2.47-6.68; P = 0.001) and ER-beta AluI AG (OR = 2.66, 95% CI:1.61 4.16; P = 0.004) genotypes were significantly associated with increased risk of PCa. The ER-beta RsaI genotype was not associated with PCa. Baseline serum free E2 levels tended to be lower in men with PCa (0.35 +/- 0.04 pg/ml) compared to healthy men (0.48 +/- 0.05 pg/ml). Genotypes which confer susceptibility for developing PCa, accompanied with lowest serum levels of free E2. In the Iranian population, genetic polymorphisms of the ER-alpha and ER-beta genes may be involved in the etiology of PCa. PMID- 22228198 TI - Effects of varying dietary iodine supplementation levels as iodide or iodate on thyroid status as well as mRNA expression and enzyme activity of antioxidative enzymes in tissues of grower/finisher pigs. AB - PURPOSE: The objective of this study was to investigate the influence of high dietary iodine supply and different iodine sources on thyroid status and oxidative stress in target tissues of the thyroid hormones in fattening pigs. METHODS: Eighty castrates (body weight: 33.3 +/- 0.4 kg) were randomly allotted into five different treatments: The control diet contained 150 MUg I/kg as KI, the other feeding groups were supplemented with 4,000 MUg I/kg (as KI and KIO(3)) and 10,000 MUg I/kg (as KI and KIO(3)), respectively. The mRNA expression levels of sodium/iodide symporter (NIS) and key antioxidant enzymes (Cu/Zn SOD, CAT, GPx) were analyzed in thyroid gland, liver, kidney, muscle, and adipose tissue sampled during slaughter. Furthermore, antioxidant enzyme activities and the effect on lipid peroxidation (MDA) were determined in liver and muscle. RESULTS: In thyroid gland, a significant downregulation of NIS and Cu/Zn SOD mRNA expression was observed in high-iodine groups. In liver, a source effect on the mRNA expression of Cu/Zn SOD between KI and KIO(3) at 4,000 MUg I/kg was shown. In contrast, not SOD but GPx activity was affected by iodine source with strongest downregulation in high KIO(3) group. In muscle, GPx activity was affected by both iodine source and dose, showing stronger downregulation in KI groups. In kidney and adipose tissue, oxidative stress parameters showed no or only unsystematic changes. However, variation in iodine supply had no effect on MDA concentrations. CONCLUSIONS: NIS expression was significantly decreased with increased iodine supplementation, which is to ensure the thyroid gland function. However, the alleviating effect of iodine supplementation observed in antioxidant enzyme mRNA expression and activity did not reflect on the lipid peroxide level. PMID- 22228199 TI - Health behaviors and occupational stress of Brazilian civil servants living in an urban center. AB - BACKGROUND: Occupational stress and unhealthy lifestyles are common characteristics of urban workers. The association between health behaviors and job stress of urban Brazilian civil servants was studied. METHODS: A cross sectional study included 893 workers. Health markers, the dependent variables, were: Fruit/vegetable (FV) and alcohol (A) intake, physical activity (PA), including at work (PAW), smoking (S), BMI >= 25 Kg/m(2). Occupational stress, assessed by Job Stress Scale-Brazilian version, classified employees into: High strain, Low-strain, Active, and Passive. Prevalence rates and multivariate Poisson models were adopted. RESULTS: On average, employees (mean age = 40.2 years; 69.1% female) reported healthy lifestyle factors: FV (56%); PA (59.7%); S (13.3%); however, 49.4% were overweight. Compared to low-strain, high-strain workers reported higher PAW; passive workers lesser PA and higher PAW. After adjusting for socio-demographics and work characteristics, the occupational stress dimensions were no longer associated to health behaviors. CONCLUSIONS: Our results do not support the hypothesis of an effect for occupational stress on urban employees' health behaviors. PMID- 22228200 TI - Protective effects of mGluR5 positive modulators against traumatic neuronal injury through PKC-dependent activation of MEK/ERK pathway. AB - Several previous studies utilizing selective pharmacological antagonists have demonstrated that type 5 metabotropic glutamate receptors (mGluR5) are potential therapeutic targets for the treatment of numerous disorders of the central nervous system, but the role of mGluR5 activation in traumatic brain injury (TBI) is not fully understood. Here in an in vitro TBI model, the mGluR5 agonist (RS)-2 chloro-5- hydroxyphenylglycine (CHPG) and the positive allosteric modulators 3 cyano-N-(1,3- diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) were used to investigate the neuroprotective potency of mGluR5 activation. Data showed that CHPG and CDPPB suppressed the increase of LDH release and caspase-3 activation induced by traumatic neuronal injury in a dose-dependent manner, and the salutary effects were also present when these compounds were added 1 h after injury. Western blot was used to examine the activation of three members of mitogen activated protein kinases: extracellular signal-regulated kinase (ERK), c-Jun N terminal kinase (JNK), and p38 kinase (p38). CHPG and CDPPB enhanced the activation of ERK after traumatic neuronal injury, and PD98059 and U0126, two selective MEK/ERK inhibitors, partly revised the protective effects. Furthermore, we also investigated the role of protein kinase C (PKC) in CHPG and CDPPB-induced neuroprotection. With the pretreatment of chelerythrine chloride, a PKC inhibitor, the surpressing effects of CHPG and CDPPB on traumatic injury-evoked LDH release and caspase-3 activation were blocked. All of these findings extended the protective role of mGluR5 activation in an in vitro model of TBI and suggested that these protective effects might be mediated by the PKC-dependent activation of MEK/ERK pathway. These results may have important implications for the development of mGluR5 modulators to treat TBI. PMID- 22228202 TI - Laparoscopic ventral rectopexy for internal rectal prolapse using biological mesh: postoperative and short-term functional results. AB - BACKGROUND: Laparoscopic ventral mesh rectopexy is a novel procedure to correct internal and external rectal prolapse. Several authors have shown that this approach is safe and improves obstructive defaecation symptoms and faecal incontinence, without inducing new-onset constipation, possible after posterior rectopexy. Over the last decade, as for other procedures, biological meshes are used to correct pelvic floor disorders. Literature data are scant. In this study, we present our experience with this procedure using biological mesh. PATIENTS AND METHODS: Prospectively collected data on laparoscopic ventral mesh rectopexy for internal rectal prolapse were analysed. All patients underwent preoperative evaluation with defaecating proctography and/or pelvic dynamic MRI, full colonoscopy, anal physiology studies and endo-anal ultrasound. End-points were to evaluate surgical complications and functional results of this technique such as changes in bowel function (Wexner Constipation Score and Faecal Incontinence Severity Index) at 3 and 6 months. Analysis was performed using Mann-Whitney U test for unpaired data and Wilcoxon signed rank test for paired data (two-sided p test). RESULTS: Thirty-four consecutive patients underwent laparoscopic ventral mesh rectopexy (median age 59, range 25-78 years, mean follow-up was 12 months). Twenty-eight patients (82%) had a constipation score >= 5, while 14 (41%) a FISI score >= 10. Nine patients (26%) had mixed obstructed defaecation and faecal incontinence. One patient required conversion to open (3%). Median length of stay was 2 days. Overall complication rate was 23.5%. Preoperative constipation (median Wexner score 15) and faecal incontinence (median FISI score 12) improved significantly at 3 months (Wexner 5, FISI 5, both p < 0.001). Two patients experienced prolapse persistence or recurrence. No patients had function worsening or complained of sexual dysfunction. CONCLUSIONS: Laparoscopic ventral mesh rectopexy using biological mesh for internal rectal prolapse is safe and effective in ameliorating symptoms of obstructed defaecation and faecal incontinence. PMID- 22228203 TI - A genome-wide association study of inflammatory biomarker changes in response to fenofibrate treatment in the Genetics of Lipid Lowering Drug and Diet Network. AB - OBJECTIVE: Despite the evidence in support of the anti-inflammatory and triglyceride-lowering effects of fenofibrate, little is known about genetic determinants of the observed heterogeneity in treatment response. This study provides the first genome-wide examination of fenofibrate effects on systemic inflammation. METHODS: Biomarkers of inflammation were measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n=1092) before and after a 3-week daily treatment with 160 mg of fenofibrate. Two inflammatory patterns [high-sensitivity C-reactive protein-interleukin-6 and monocyte chemoattractant protein-1-tumor necrosis factor (MCP1-TNF-alpha)] were derived using principal component analysis. Associations between single nucleotide polymorphisms on the Affymetrix 6.0 chip and phenotypes were assessed using mixed linear models, adjusted for age, sex, study center, and ancestry as fixed effects and pedigree as a random effect. RESULTS: Before fenofibrate treatment, the strongest evidence for association was observed for polymorphisms near or within the IL2RA gene with the high-sensitivity C-reactive protein-interleukin-6 (IL6) pattern (rs7911500, P=5*10 and rs12722605, P=5*10). Associations of the MCP1-TNF alpha pattern with loci in several biologically plausible genes [CYP4F8 (rs3764563), APBB1IP (rs1775246), COL13A1 (rs2683572), and COMMD10 (rs1396485)] approached genome-wide significance (P=3*10, 5*10, 6*10, and 7*10, respectively) before fenofibrate treatment. After fenofibrate treatment, the rs12722605 locus in IL2RA was also associated with the MCP1-TNF-alpha pattern (P=3*10). The analyses of individual biomarker response to fenofibrate did not yield genome wide significant results, but the rs6517147 locus near the immunologically relevant IFNAR2 gene was suggestively associated with IL6 (P=7*10). CONCLUSION: We have identified several novel biologically relevant loci associated with systemic inflammation before and after fenofibrate treatment. PMID- 22228204 TI - The influence of CYP2C19*2 and *17 on on-treatment platelet reactivity and bleeding events in patients undergoing elective coronary stenting. AB - OBJECTIVES: To investigate the impact of genotypes on the basis of the loss-of function variant CYP2C19*2 and the gain-of-function variant CYP2C19*17 on on treatment platelet reactivity and on the occurrence of Thrombolysis in Myocardial Infarction (TIMI) major bleedings in 820 clopidogrel-treated patients who underwent elective coronary stenting. METHODS: On-treatment platelet reactivity was quantified using ADP-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay. Postdischarge TIMI major bleedings within 1 year after enrollment were recorded. RESULTS: In total, 25 major bleedings (3.0% of the study population) were observed. Patients with the CYP2C19*1/*17 and *17/*17 diplotypes exhibited a lower magnitude of platelet reactivity as compared with patients with the CYP2C19*1/*1 diplotype (for the light transmittance aggregometry-adjusted mean difference: -5.8%, 95% confidence interval: -9.6 to 2.1, P=0.002). Patients with the *1/*17 and *17/*17 genotype had a 2.7-fold increased risk in the occurrence of major bleedings [adjusted hazard ratio: 2.7, 95% confidence interval: 1.1-7.0, P=0.039]. The diplotypes *2/*17, *1/*2, and *2/*2 exhibited higher on-treatment platelet reactivity as compared with the wild type (P<0.0001). However, this was not translated into an altered risk on major bleedings as compared with the wild type [hazard ratio: 1.3 (0.45-4.0), P=0.60]. Results have not been adjusted for multiple testing. CONCLUSION: Patients with the CYP2C19*1/*17 and *17/*17 diplotype have a lower magnitude of on-treatment platelet reactivity and are at a 2.7-fold increased risk of postdischarge TIMI major bleeding events after coronary stenting than patients with the *1/*1 genotype. The diplotypes *2/*17, *1/*2, and *2/*2 are associated with increased on-treatment platelet reactivity; however, this is not translated into a lower risk of bleeding events. PMID- 22228201 TI - Drug resistance in glioblastoma: a mini review. AB - Glioblastoma multiforme (GBM) is recognized as the most common and lethal form of central nervous system cancer. Currently used surgical techniques, chemotherapeutic agents, and radiotherapy strategies have done very little in extending the life expectancies of patients diagnosed with GBM. The difficulty in treating this malignant disease lies both in its inherent complexity and numerous mechanisms of drug resistance. In this review, we summarize several of the primary mechanisms of drug resistance. We reviewed available published literature in the English language regarding drug resistance in glioblastoma. The reasons for drug resistance in glioblastoma include drug efflux, hypoxic areas of tumor cells, cancer stem cells, DNA damage repair, and miRNAs. Many potential therapies target these mechanisms, including a series of investigated alternative and plant derived agents. Future research and clinical trials in glioblastoma patients should pursue combination of therapies to help combat drug resistance. The emerging new data on the potential of plant-derived therapeutics should also be closely considered and further investigated. PMID- 22228205 TI - Glucuronidation of trans-3'-hydroxycotinine by UGT2B17 and UGT2B10. AB - OBJECTIVES: Trans-3'-Hydroxycotinine (3HC) and its glucuronide are major nicotine metabolites excreted in the urine of smokers and other tobacco users. Although several members of the UDP-glucuronosyltransferase (UGT) family of enzymes were previously shown to be active in catalyzing the formation of 3HC and its glucuronide, a comprehensive screening of all known human UGT1A and 2B enzymes for glucuronidation activity against 3HC was not previously performed. METHODS: In the present study, human liver microsomes (HLM), eight UGT1A and six UGT2B enzymes were screened for activity against 3HC. RESULTS: UGT2B17 exhibited the highest O-glucuronidation activity, exhibiting a four-fold lower (P<0.005) KM (8.3 mmol/l) compared with that observed for UGTs 1A9 (35 mmol/l) or 2B7 (31 mmol/l) and a KM smaller compared with that observed for human liver microsomes (HLM; 26 mmol/l). The KM for 3HC-O-Gluc formation was 3.1-fold lower (P<0.0005) in HLM from male participants exhibiting the wild-type genotype UGT2B17 (*1/*1) compared with that in HLM from participants homozygous for the UGT2B17 deletion genotype [UGT2B17 (*2/*2)]. Both UGTs 2B10 and 1A4 exhibited 3HC-N-Gluc formation activity, with UGT2B10 exhibiting a four-fold lower (P<0.05) KM (13 mmol/l) compared with that observed for UGT1A4 (57 mmol/l) and, which was similar to the KM observed in HLM (14 mmol/l). There was 91 (P<0.0001) and 39% (P<0.001) decreases in the 3HC-N-Gluc formation activities in HLM from participants with the UGT2B10 (*2/*2) and UGT2B10 (*1/*2) genotypes, respectively, compared with that of HLM from participants with the wild-type UGT2B10 (*1/*1) genotype. CONCLUSION: These results suggest that UGT2B17 and UGT2B10 play key roles in the glucuronidation of 3HC in the human liver and that functional polymorphisms in UGT2B17 and UGT2B10 are associated with significantly reduced glucuronidation activities against 3HC. PMID- 22228206 TI - Copper nanoparticles modified silicon nanowires with enhanced cross-coupling catalytic ability. AB - Copper nanoparticles modified silicon nanowires show enhanced catalytic activity for the coupling reaction of benzene halides (iodobenzene, bromobenzene, and chlorobenzene) and aniline. PMID- 22228207 TI - Intravitreal kinetics of hesperidin, hesperetin, and hesperidin G: effect of dose and physicochemical properties. AB - Hesperidin, a flavanone glycoside, and its aglycone hesperetin are potential candidates for the treatment of diabetic retinopathy and macular edema. The objective of this study was to delineate vitreal pharmacokinetics of hesperidin and hesperetin and the hydrophilic derivative glucosyl hesperidin (hesperidin G) following intravitreal administration in anaesthetized rabbits. Concentration changes in vitreous humor were monitored using microdialysis sampling procedure. All three molecules were administered intravitreally at three dose levels (50 uL injection volume containing 1.5, 4.5, and 15 ug of the drug, resulting in a final vitreal concentration of 1, 3, and 10 ug/mL). Vitreal microdialysis samples were collected every 20 min over a period of 10 h. All three molecules exhibited linear pharmacokinetics within the dose range tested because area under the curve and maximum concentration (C(max) ) increased linearly with increasing dose and a significant difference in the elimination parameters such as clearance or half life was not observed. The vitreal elimination half-life of these three compounds was observed to correlate with the molecular weight and lipophilicity of the molecules. The findings from this study provide practical information that will be useful in the future design of ocular drug delivery strategies for bioflavonoids. PMID- 22228208 TI - Molecular chirality induction to an achiral pi-conjugated polymer by circularly polarized light. AB - A preferred-handed helical conformation was induced to poly(9,9-dioctylfluoren 2,7-diyl) (PDOF) in a thin film form upon irradiation with single-handed circularly polarized light (CPL) where the induction was reversible. PMID- 22228210 TI - Variations of the iliolumbar and ascending lumbar veins. AB - STUDY DESIGN: A cadaveric retrospective study. OBJECTIVE: To verify the variation of tributaries draining into the iliac system at the lumbosacral junction. SUMMARY OF BACKGROUND DATA: Special attention to vascular anatomy at the great venous bifurcation during anterior lumbar surgery is needed as more tributaries may increase the rate of operative bleeding. Although important, there have been very few detailed anatomic studies about variations of the ascending and iliolumbar veins. The latter tributary forms a horizontal system draining blood into the iliac vein. METHODS: A total of 116 formaldehyde-preserved specimens (61 male and 55 female) were studied. All specimens were dissected and simply classified into patterns and subpatterns according to the similar or different tributaries and their entry points. RESULTS: There were 2 patterns of tributaries: symmetric and asymmetric. More variants were found in the asymmetric group. Each pattern comprising 58 specimens was further classified into 3 subpatterns according to their main tributary trunks. One to 3 tributaries may enter into any trunk of the iliac vein. The most common trunk was the common iliac vein seen in 75.9% of specimens. Draining into the external and internal veins was found in 21.6% and 2.6% of specimens, respectively. One common drainage of the ascending and iliolumbar veins on 1 or both sides was found in 0.9% and > 50% of specimens, respectively (right, 51.7%; left, 56%), whereas 2 or more tributaries were seen in < 50% of specimens (right, 47.4%; left, 43.1%). There was no significant statistical difference among sexes and body sides. CONCLUSIONS: Draining into the iliac system has a high frequency of variations through a number of tributaries and their entry points. The iliolumbar vein will mainly drain into the common iliac vein with frequently 2 or 3 tributaries, whereas drainage into the external iliac or the internal vein is less often observed. PMID- 22228211 TI - The effect of angular mismatch between vertebral endplate and vertebral body replacement endplate on implant subsidence. AB - STUDY DESIGN: Comparative biomechanical study. OBJECTIVE: To determine whether an angular mismatch between the vertebral body replacement (VBR) endplate and the simulated foam vertebral endplate leads to accelerated subsidence in a cyclic compression model of the VBR-vertebra interface. SUMMARY OF BACKGROUND DATA: One of the main complications of the VBR surgery is postoperative subsidence and collapse of the VBR implant into the adjacent vertebral bodies. Although numerous factors affecting intervertebral cage subsidence have been cited, few studies have proposed factors responsible for VBR cage subsidence. METHODS: Hardwood blocks at 0-30-degree angles and polyurethane foam blocs have been used as base for this experimental setting. One end of the Synex (Synthes) expandable cage was attached to a material testing machine. The endplate of the implant was placed at a similar spot on the block in such a manner that there was an exact match between the Synex endplate and the foam block at 0 degrees, subsequent angled blocks would tilt the foam endplates by the 10-, 20-, and 30-degree increments as needed. Cyclic axial loads were applied in 9 load-unload cycles. RESULTS: Five samples were tested at each mismatch angle (0, 10, 20, and 30 degrees), for a total of 20 trials. Implant subsidence significantly increased for each 10-degree increase in mismatch angle. This effect, however, did not follow a uniform trend at all angles. The curve appeared exponential at 0 degree of angular mismatch, became linear at 10-20 degrees of mismatch, and then demonstrated some ability to resist load at 30 degrees, leading to a plateau at the higher loads. CONCLUSIONS: Increasing mismatch angles are an important factor in leading to increased cage subsidence into polyurethane blocks. Consequently, the incidence of subsidence in the clinical setting could be reduced by paying careful attention to ensuring that both the prosthetic and bony endplates are well apposed at the end of surgery. PMID- 22228209 TI - Molecular and functional properties of three different peroxiredoxin isotypes in Chinese cabbage. AB - Peroxiredoxins (Prxs), which are classified into three isotypes in plants, play important roles in protection systems as peroxidases or molecular chaperones. The three Prx isotypes of Chinese cabbage, namely C1C-Prx, C2C-Prx, and C-PrxII, have recently been identified and characterized. The present study compares their molecular properties and biochemical functions to gain insights into their concerted roles in plants. The three Prx isotype genes were differentially expressed in tissue- and developmental stage-specific manners. The transcript level of the C1C-Prx gene was abundant at the seed stage, but rapidly decreased after imbibitions. In contrast, the C2C-Prx transcript was not detected in the seeds, but its expression level increased at germination and was maintained thereafter. The C-PrxII transcript level was mild at the seed stage, rapidly increased for 10 days after imbibitions, and gradually disappeared thereafter. In the localization analysis using GFP-fusion proteins, the three isotypes showed different cellular distributions. C1C-Prx was localized in the cytosol and nucleus, whereas C2C-Prx and C-Prx were found mainly in the chloroplast and cytosol, respectively. In vitro thiol-dependent antioxidant assays revealed that the relative peroxidase activities of the isotypes were CPrxII > C2C-Prx > C1C Prx. C1C-Prx and C2C-Prx, but not C-PrxII, prevented aggregation of malate dehydrogenase as a molecular chaperone. Taken together, these results suggest that the three isotypes of Prx play specific roles in the cells in timely and spatially different manners, but they also cooperate with each other to protect the plant. PMID- 22228212 TI - Three solutions to a single problem: alternative casting frames for treating infantile idiopathic scoliosis. AB - STUDY DESIGN: This is a technique article discussing 3 alternative frames for casting children with infantile scoliosis. OBJECTIVE: To provide surgeons with alternatives to expensive specialized casting tables to allow local treatment of these children utilizing readily available materials present at most institutions. SUMMARY OF BACKGROUND: Casting for infantile scoliosis has become more popular as reports have shown promising results with this technique without the morbidity and complications associated with more invasive procedures. However, without a specialized casting table, treating these patients has been limited to a few centers throughout the country often causing patients to travel large distances to receive care. METHODS: Three different alternatives to commercially available casting frames are presented. Requirements, setup, and techniques are discussed. RESULTS: Each surgeon has had success with each of these frames. These provide adequate support and traction while allowing enough access to the trunk to apply a well-molded cast. CONCLUSIONS: Cotrel/Metha casting for infantile scoliosis can be accomplished without a specialized table using commonly available equipment. PMID- 22228213 TI - SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis. AB - Suppressor of Cytokine Signaling-2 (SOCS2) is a negative regulator of growth hormone (GH) signaling and bone growth via inhibition of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. This has been classically demonstrated by the overgrowth phenotype of SOCS2(-/-) mice, which has normal systemic insulin-like growth factor 1 (IGF-1) levels. The local effects of GH on bone growth are equivocal, and therefore this study aimed to understand better the SOCS2 signaling mechanisms mediating the local actions of GH on epiphyseal chondrocytes and bone growth. SOCS2, in contrast to SOCS1 and SOCS3 expression, was increased in cultured chondrocytes after GH challenge. Gain and loss-of-function studies indicated that GH-stimulated chondrocyte STATs-1, 3, and -5 phosphorylation was increased in SOCS2(-/-) chondrocytes but not in cells overexpressing SOCS2. This increased chondrocyte STAT signaling in the absence of SOCS2 is likely to explain the observed GH stimulation of longitudinal growth of cultured SOCS2(-/-) embryonic metatarsals and the proliferation of chondrocytes within. Consistent with this metatarsal data, bone growth rates, growth plate widths, and chondrocyte proliferation were all increased in SOCS2(-/ ) 6-week-old mice as was the number of phosphorylated STAT-5-positive hypertrophic chondrocytes. The SOCS2(-/-) mouse represents a valid model for studying the local effects of GH on bone growth. PMID- 22228214 TI - Application of IVIVE and PBPK modeling in prospective prediction of clinical pharmacokinetics: strategy and approach during the drug discovery phase with four case studies. AB - Prospective simulations of human pharmacokinetic (PK) parameters and plasma concentration-time curves using in vitro in vivo extrapolation (IVIVE) and physiologically based pharmacokinetic (PBPK) models are becoming a vital part of the drug discovery and development process. This paper presents a strategy to deliver prospective simulations in support of clinical candidate nomination. A three stage approach of input parameter evaluation, model selection and multiple scenario simulation is utilized to predict the key components influencing human PK; absorption, distribution and clearance. The Simcyp(r) simulator is used to illustrate the approach and four compounds are presented as case studies. In general, the prospective predictions captured the observed clinical data well. Predicted C(max) was within 2-fold of observed data for all compounds and AUC was within 2-fold for all compounds following a single dose and three out of four compounds following multiple doses. Similarly, t(max) was within 2-fold of observed data for all compounds. However, C(last) was less accurately captured with two of the four compounds predicting C(last) within 2-fold of observed data following a single dose. The trend in results was towards overestimation of AUC and C(last) , this was particularly apparent for compound 2 for which clearance was likely underestimated via IVIVE. The prospective approach to simulating human PK using IVIVE and PBPK modeling outlined here attempts to utilize all available in silico, in vitro and in vivo preclinical data in order to determine the most appropriate assumptions to use in prospective predictions of absorption, distribution and clearance to aid clinical candidate nomination. PMID- 22228216 TI - The role of clinical decision support tools to reduce blood pressure variability in critically ill patients receiving vasopressor support. AB - Current monitoring systems for patients receiving vasopressor support generally rely on bedside monitors with audible alarms that are activated when blood pressure declines below pre-established thresholds, which can result in fluctuations that may increase risk of myocardial ischemia. This pilot study evaluated the effects of three bedside monitors on mean arterial blood pressure and percentage of time at mean arterial pressure among critically ill patients. The monitors were the standard display with audible alarm or one of two types of clinical decision support systems including Intellivue Horizon Trends (Philips Healthcare, Andover, MA) and Horizon Trends and ST Map (Philips Healthcare). Patients in the two groups monitored with Horizon Trends had significantly higher mean arterial pressure (72.8 +/- 7.0 mm Hg) compared with those monitored with the standard monitor (68.1 +/- 6.8 mm Hg; P= .004). Patients monitored with Horizon Trends also spent a significantly higher percentage of time within their target mean arterial pressure range compared with those in the standard monitor group (P = .031). These findings suggest that further study is needed to assess the impact of clinical decision support tools on management of blood pressure variability in critically ill patients receiving vasopressor therapy. PMID- 22228215 TI - LINE-1 hypomethylation in familial and sporadic cancer. AB - Increased and decreased methylation at specific sequences (hypermethylation and hypomethylation, respectively) is characteristic of tumor DNA compared to normal DNA and promotes carcinogenesis in multiple ways including genomic instability. Long interspersed element (LINE), an abundant class of retrotransposons, provides a surrogate marker for global hypomethylation. We developed methylation-specific multiplex ligation-dependent probe amplification assays to study LINE-1 methylation in cases of colorectal, gastric, and endometrial cancer (N = 276), stratified by patient category [sporadic; Lynch syndrome (LS); familial colorectal cancer type X (FCCX)] and microsatellite instability status. Within each patient group, LINE-1 showed lower methylation in tumor DNA relative to paired normal DNA and hypomethylation was statistically significant in most cases. Interestingly, normal colorectal mucosa samples from different patient groups displayed differences in LINE-1 methylation that mirrored differences between the respective tumor tissues, with a decreasing trend for LINE-1 methylation from patients with sporadic colorectal cancer to LS to FCCX. Despite the fact that the degree of LINE-1 methylation is generally tissue specific, normal colorectal mucosa, gastric mucosa, and endometrium from LS patients showed similar levels of LINE-1 methylation. Our results suggest that the degree of LINE 1 methylation may constitute a "field defect" that may predispose normal tissues for cancer development. PMID- 22228217 TI - Effect of screen-based computer simulation on knowledge and skill in nursing students' learning of preoperative and postoperative care management: a randomized controlled study. AB - Screen-based computer simulations are considered a method of skill teaching in health education. This study examined the effect of screen-based computer simulation on knowledge, skill, and the clinical decision-making process in teaching preoperative and postoperative care management to second-year students in an undergraduate school of nursing. It is a randomized controlled study. The study sample was composed of 82 students. They received education in screen-based computer simulation (n = 41) and skill laboratories (n = 41). Three instruments were used: a preoperative and postoperative care management cognitive level assessment test, skill control lists of preoperative and postoperative care management, and the Clinical Decision Making in Nursing Scale. There was not a significant difference between the students' posteducation knowledge levels (P = .421), practical deep breathing and coughing exercise education skills (P = .867), or clinical decision-making scale total and subscale scores (P = .065). However, a significant difference was found between the admission of the patient in the surgical clinic after surgery skill scores of the students (P = .04). Education provided in the screen-based computer simulation laboratory was equivalent to that provided in the skill laboratory. PMID- 22228219 TI - Shift work and the incidence of injury among police officers. AB - BACKGROUND: Police officers may be injury prone due to fatigue, erratic work hours, and insufficient sleep. This study explored injury incidence among police officers across shifts. METHODS: Day-to-day shift data from computerized payroll records (1994-2010) were available from a mid-sized urban police department (n = 430). Sleep duration, shift activity level, returning to work after days off, and injury incidence over time were also examined. RESULTS: Age-adjusted incidence rate ratio (IRR) for injury on the midnight shift was 72% larger than the day shift (IRR = 1.72; 95% CI = 1.26-2.36) and 66% larger than the afternoon shift (IRR = 1.66; 95% CI = 1.23-2.25). Injury incidence for the first day back on the midnight shift was 69% larger than day shift (IRR = 1.69; 95% CI = 1.23-2.32) and 54% larger than the afternoon shift (IRR = 1.54; 95% CI = 1.36-1.76). High activity level combined with midnight shift work put officers at increased injury risk (IRR = 2.31; P = 0.0003). Probability of remaining free of injury was significantly higher for day shift than midnight shift (P < 0.0001). CONCLUSIONS: Higher injury risk was associated with night shift work in police officers. Night shift combined with high work activity was strongly associated with injury risk. There was a significantly higher probability of not being injured on day compared to midnight or afternoon shifts. PMID- 22228218 TI - The vulnerability of nitrergic neurons to transient spinal cord ischemia: a quantitative immunohistochemical and histochemical study. AB - Spinal cord ischemia belongs to serious and relatively frequent diseases of CNS. The aim of the present study was to find out the vulnerability of nitrergic neurons to 15 min transient spinal cord ischemia followed by 1 and 2 weeks of reperfusion. We studied neuronal nitric oxide synthase (nNOS) and nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) in structural elements of lumbosacral spinal cord along its rostrocaudal axis. In addition, a neurological deficit of experimental animals was evaluated. Spinal cord ischemia, performed on the rabbit, was induced by abdominal aorta occlusion using Fogarty catheter introduced into the right femoral artery for a period of 15 min. After surgical intervention the animals survived for 7 and 14 days. nNOS-immunoreactivity (nNOS IR) was measured by immunohistochemical and NADPHd-positivity by histochemical method, and both immunohistochemical and histochemical stainings were quantified by densitometric analyses. Neurological deficit was evaluated according Zivin's criteria. The number of nNOS-IR and/or NADPH-d positive neurons and the density of neuropil were markedly increased in superficial dorsal horn (laminae I-III) after 15 min ischemia and 7 days of reperfusion. However, ischemia followed by longer time of survival (14 days) returned the number of nNOS-IR and NADPH-d positive neurons to control. In the pericentral region (lamina X) containing interneurons and crossing fibers of spinal tracts, than in lamina VII and in dorsomedial part of the ventral horn (lamina VIII) we recorded a decreased number of nNOS-IR and NADPH-d positive neurons after both ischemia/reperfusion periods. In the medial portion of lamina VII and dorsomedial part of the ventral horn (lamina VIII) we observed many necrotic loci. This area was the most sensitive to ischemia/reperfusion injury. Fifteen minute ischemia caused a marked deterioration of neurological function of hind limbs, often developing into paraplegia. A quantitative immunohistochemical and histochemical study have shown a strong vulnerability of nitrergic neurons in intermediate zone to transient spinal cord ischemia. PMID- 22228220 TI - The molecular basis for the inhibition of human cytochrome P450 1A2 by oroxylin and wogonin. AB - In our previous kinetics studies the natural products oroxylin and wogonin were shown to have strong biological affinity for, and inhibitory effects against, human cytochrome P450 1A2, with IC(50) values of 579 and 248 nM, respectively; this might lead to the occurrence of drug-drug interactions when co-administered clinically. However, their inhibitory mechanisms against 1A2 remain elusive. In this study, molecular docking and molecular dynamics simulations were performed to better understand the molecular basis of their inhibitory mechanisms towards 1A2. Structural analysis revealed that oroxylin has a different binding pattern from wogonin and another very strongly binding inhibitor alpha-naphthoflavone (ANF, IC(50) = 49 nM). The O(7) atom of oroxylin forms hydrogen bonds with the OD1/OD2 atoms of Asp313, which is not observed in the 1A2-wogonin complex. Because of energetically unfavorable repulsions with the methoxy group at the 6 position of the oroxylin ring, significant conformational changes were observed for the sidechain of Thr118 in the MD simulated model. As a result, the larger and much more open binding-site architecture of the 1A2-oroxylin complex may account for its weaker inhibitory effect relative to the 1A2-ANF complex. Energy analysis indicated that oroxylin has a less negative predicted binding free energy of -19.8 kcal/mol than wogonin (-21.1 kcal/mol), which is consistent with our experimental assays. Additionally, our energy results suggest that van der Waals/hydrophobic and hydrogen-bonding interactions are important in the inhibitory mechanisms of oroxylin whereas the former is the underlying force responsible for strong inhibition by ANF and wogonin. PMID- 22228221 TI - BIOCLAIMS standard diet (BIOsd): a reference diet for nutritional physiology. AB - Experimental replication is fundamental for practicing science. To reduce variability, it is essential to control sources of variation as much as possible. Diet is an important factor that can influence many processes and functional outcomes in studies performed with rodent models. This is especially true for, but not limited to, nutritional studies. To compare functional effects of different nutrients, it is important to use standardized, semi-purified diets. Here, we propose and describe a standard reference diet, the BIOCLAIMS standard diet. The diet is AIN-93 based, but further defined with dietary and experimental requirements taken into account that allow for experiments with bioactive food components and natural (non-expensive) labeling. This diet will be implemented by two European research consortia, Mitofood and BIOCLAIMS, to ensure inter laboratory comparability. PMID- 22228223 TI - Young researchers to tackle future Grand Challenges. PMID- 22228222 TI - Enhanced expression of lipogenic genes may contribute to hyperglycemia and alterations in plasma lipids in response to dietary iron deficiency. AB - Iron deficiency (ID) remains a public health concern affecting ~25% of the world's population. Metabolic consequences of ID include elevated plasma glucose concentrations consistent with increased reliance on glucose as a metabolic substrate, though the mechanisms controlling these responses remain unclear. To further characterize the metabolic response to ID, weanling male Sprague-Dawley rats were fed either a control (C; 40 mg Fe/kg diet) or iron-deficient (ID; 3 mg Fe/kg diet) diet or were pair-fed (PF) the C diet to the level of intake of the ID group for 21 days. In addition to reductions in hemoglobin, hematocrit, and plasma iron, the ID group also exhibited higher percent body fat and plasma triglycerides compared to the PF group. Steady-state levels of both plasma glucose and insulin increased 40 and 45%, respectively, in the ID group compared to the PF group. Plasma cortisol levels were decreased 67% in the ID group compared to the PF diet group. The systematic evaluation of the expression of genes involved in insulin signaling, glucose metabolism, and fatty acid metabolism in the liver and skeletal muscle revealed significant alterations in the expression of 48 and 52 genes in these tissues, respectively. A significant concurrent increase in lipogenic gene expression and decrease in gene expression related to beta-oxidation in both the liver and skeletal muscle, in combination with differential tissue expression of genes involved in glucose metabolism, provides novel insight into the adaptive metabolic response in rodent models of severe iron deficiency anemia. PMID- 22228224 TI - EZH2 genetic variants affect risk of gastric cancer in the Chinese Han population. AB - Enhancer of zeste 2 (EZH2) gene encodes a histone methyltransferase that constitutes the catalytic component of the polycomb repressive complex-2 (PRC2) to initiate epigenetic silencing of genes. It is reported that the expression level of EZH2 in gastric cancer tissue was highly correlated with tumor progression, however, whether EZH2 genetic variants were associated with the risk of gastric cancer remains yet unknown. In this study, we conducted a genotyping analysis for EZH2 in 311 cases of gastric cancer and 425 controls from the Chinese Han population. We found five single nucleotide polymorphisms (SNP; rs12670401, rs6464926, rs2072407, rs734005, and rs734004) of EZH2 gene were significantly associated with the risk of gastric cancer. Of which, the rs12670401 with the minor allele C and rs6464926 with the minor allele T revealed strong associations with increased gastric cancer risk [P = 0.009, adjusted odds ratio (aOR) = 1.327, 95% CI = 1.075-1.683 and P = 0.012, aOR = 1.310, 95% CI = 1.059-1.619]. The other three SNPs, rs2072407, rs734005, and rs734004 contributed to significantly reduced risk of gastric cancer (P = 0.033, aOR = 0.787, 95% CI = 0.633-0.981, P = 0.045, aOR = 0.799, 95% CI = 0.642-0.995 and P = 0.048, aOR = 0.803, 95% CI = 0.645-0.999), respectively. We further found that rs12670401 and rs6464926 were in a strong LD while rs2072407, rs734005, and rs734004 were in another. Haplotype analysis of the five SNPs showed that haplotype CCTCT reduced the risk of gastric cancer (P = 0.031 and aOR = 0.784), while haplotype GTCTC significantly elevated the risk of gastric cancer (P = 0.011 and aOR = 1.310). We concluded that EZH2 variants were significantly associated with gastric cancer risk. Our results for the first time provided new insight into susceptibility factors of EZH2 gene variants in carcinogenesis of gastric cancer of the Chinese Han population. PMID- 22228225 TI - Quantitative full-colour transmitted light microscopy and dyes for concentration mapping and measurement of diffusion coefficients in microfluidic architectures. AB - A simple and versatile methodology has been developed for the simultaneous measurement of multiple concentration profiles of colourants in transparent microfluidic systems, using a conventional transmitted light microscope, a digital colour (RGB) camera and numerical image processing combined with multicomponent analysis. Rigorous application of the Beer-Lambert law would require monochromatic probe conditions, but in spite of the broad spectral bandwidths of the three colour channels of the camera, a linear relation between the measured optical density and dye concentration is established under certain conditions. An optimised collection of dye solutions for the quantitative optical microscopic characterisation of microfluidic devices is proposed. Using the methodology for optical concentration measurement we then implement and validate a simplified and robust method for the microfluidic measurement of diffusion coefficients using an H-filter architecture. It consists of measuring the ratio of the concentrations of the two output channels of the H-filter. It enables facile determination of the diffusion coefficient, even for non-fluorescent molecules and nanoparticles, and is compatible with non-optical detection of the analyte. PMID- 22228226 TI - Expression of enzymes and transcription factors involved in n-3 long chain PUFA biosynthesis in limousin bull tissues. AB - The current low consumption of n-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) led scientists to wonder about the possible enrichment of human food, including meats such as beef, with n-3 LCPUFA. However, their biosynthesis from dietary n-3 PUFA seems limited in mammalian tissues implying that a better understanding of the molecular mechanisms responsible for this down regulation is needed. This study aimed at identifying and comparing the limiting steps of n-3 LCPUFA synthesis in liver, intermuscular adipose tissue (IM-AT) and semitendinosus muscle (ST) from six Limousin bulls. Tissue FA composition was analysed by GLC and mRNA abundance of enzymes and transcription factors involved in n-3 LCPUFA synthesis was assessed by RT-qPCR. In liver, mRNA encoding proteins involved in n-3 LCPUFA synthesis were present in agreement with the significant high content of n-3 LCPUFA (8.4 mol% of total FA, 257 mg/100 g of fresh tissue) in this organ. In IM-AT, these mRNA were all present, but at a tenfold lower intensity than in liver in agreement with the low contents of n-3 LCPUFA in this tissue. In ST muscle, these mRNA were all present except elongase 5 mRNA which was only present as trace, the corresponding protein being undetectable, probably inducing a break of n-3 LCPUFA synthesis from 18:4n-3. In conclusion, Limousin bull ST muscle seemed unable to synthesize n-3 LCPUFA. However, the presence of 20:5n-3 (EPA) and 22:5n-3 (DPAn-3) in muscle raised the question of the origin of these n-3 LCPUFA. PMID- 22228227 TI - A low-protein, high-carbohydrate diet increases fatty acid uptake and reduces norepinephrine-induced lipolysis in rat retroperitoneal white adipose tissue. AB - A low-protein, high-carbohydrate (LPHC) diet for 15 days increased the lipid content in the carcass and adipose tissues of rats. The aim of this work was to investigate the mechanisms of this lipid increase in the retroperitoneal white adipose tissue (RWAT) of these animals. The LPHC diet induced an approximately two- and tenfold increase in serum corticosterone and TNF-alpha, respectively. The rate of de novo fatty acid (FA) synthesis in vivo was reduced (50%) in LPHC rats, and the lipoprotein lipase activity increased (100%). In addition, glycerokinase activity increased (60%), and the phosphoenolpyruvate carboxykinase content decreased (27%). Basal [U-14C]-glucose incorporation into glycerol triacylglycerol did not differ between the groups; however, in the presence of insulin, [U-14C]-glucose incorporation increased by 124% in adipocytes from only control rats. The reductions in IRS1 and AKT content as well as AKT phosphorylation in the RWAT from LPHC rats and the absence of an insulin response suggest that these adipocytes have reduced insulin sensitivity. The increase in NE turnover by 45% and the lack of a lipolytic response to NE in adipocytes from LPHC rats imply catecholamine resistance. The data reveal that the increase in fat storage in the RWAT of LPHC rats results from an increase in FA uptake from circulating lipoproteins and glycerol phosphorylation, which is accompanied by an impaired lipolysis that is activated by NE. PMID- 22228228 TI - Iodized BODIPY as a long wavelength light sensitizer for the near-infrared emission of ytterbium(III) ion. AB - Novel 8-HOQ-BODIPY-3I was developed as an efficient sensitizer for the near infrared emission of ytterbium(III) ion at 980 nm under long wavelength excitation. PMID- 22228230 TI - X-ray microtomography analysis of intragranular drug migration during fluidized bed and oven tray drying. AB - During the drying process of a wet granulate, water-soluble compounds can migrate to the outer layers of the granule with the evaporating solvent. This migration can affect structural and mechanical characteristics of the granules as the solute accumulates on the granule's outer crust. The objective of this study was to compare the effect of the fluidized bed and oven tray at different drying temperatures on the characteristics of intragranular migration. The extent of migration and the migration effect on granule structure and granule strength were investigated using light microscopy and computerized X-ray microtomography, in both qualitative and quantitative terms. In addition, a mechanical tester was used to assess granule strength and granule failure type. Multivariate analysis of variance with a follow-up discriminant analysis was conducted to investigate the effect of the drying method and the drying temperature on the granule structure. There were significant differences in the intragranular distribution of water-soluble compound as well as in the granule structures and mechanical properties between the drying methods, where drying temperature had only a marginal effect. PMID- 22228229 TI - Genome-wide investigation and expression analysis suggest diverse roles of auxin responsive GH3 genes during development and response to different stimuli in tomato (Solanum lycopersicum). AB - In plants, auxin-mediated responses are regulated by diverse proteins. One such class of proteins, i.e. GH3, is involved in the conjugation of IAA to amino acids and provides a negative feedback loop to control auxin homoeostasis. In order to have a better understanding of the mechanism of the auxin action, 15 genes encoding GH3 members were identified using existing EST databases of tomato. Their orthologs were identified from tobacco, potato, N. benthemiana, pepper, and petunia. Phylogenetic analysis of AtGH3, SlGH3, and their Solanaceae orthologs provided insights into various orthologous relationships among these proteins. These genes were found to be responsive to a variety of signals including, phytohormones and environmental stresses. Analysis of AuxRE elements in their promoters showed variability in the sequence as well as number of this element. Up-regulation of only 11 SlGH3 genes, in response to exogenous auxin, suggested possible relationship between the diversity in the sequence and number of AuxRE element with the auxin inducibility. Expression analysis of SlGH3 genes in different vegetative and reproductive tissues/stages suggested limited or no role for most of the SlGH3 genes at the initiation of fruit ripening. However, up regulation of SlGH3-1 and -2 at the onset of fruit ripening indicates that these genes could have a role in fruit ripening. The present study characterizes GH3 gene family of tomato and its evolutionary relationship with members of this family from other Solanaceae species and Arabidopsis. It could help in the identification of GH3 genes and revelation of their function during vegetative/reproductive development stages from other Solanaceae members. PMID- 22228232 TI - Pneumococcal bacteremia in a vaccinated pediatric sickle cell disease population. AB - The incidence of pneumococcal disease in sickle cell disease declined significantly with penicillin prophylaxis as well as with the pneumococcal polysaccharide and heptavalent conjugate vaccines. In this report, we describe our experience with pneumococcal bacteremia in pediatric patients with sickle cell disease in the post-heptavalent pneumococcal conjugate vaccine era. Despite established prophylactic strategies, pneumococcal bacteremia continues to occur in patients with sickle cell disease. PMID- 22228233 TI - Chronic granulomatous disease masquerading as Behcet disease: a case report and review of the literature. AB - We describe a patient who presented at 9 years of age with oral ulcers and cutaneous lesions, meeting diagnostic criteria for Behcet disease. At 11 years of age, she developed infectious complications and was proven to have chronic granulomatous disease, with characterization of the specific genetic mutation. We review available literature regarding overlap of these symptom complexes leading to delay in securing this important diagnosis. This is the second reported case of chronic granulomatous disease mimicking Behcet disease, and the first report to include identification of the specific genetic mutation of the nicotinamide adenine dinucleotide phosphate oxidase complex. PMID- 22228231 TI - Safety, reactogenicity and immunogenicity of the human rotavirus vaccine in preterm European Infants: a randomized phase IIIb study. AB - BACKGROUND: Rotavirus disease is more severe in preterm infants than in full-term infants. This study assessed the safety, reactogenicity and immunogenicity of a human rotavirus vaccine, RIX4414, in European preterm infants. METHODS: A total of 1009 preterm infants were randomized (2:1, vaccine:placebo) and stratified into 2 groups: 20% of early (27-30 weeks, group 1) and 80% of late (31-36 weeks, group 2) gestational age preterm infants in each group. Two doses of RIX4414/placebo were administered to these preterm infants according to the recommended chronologic age for full-term infants with an interval of 30-83 days between doses. Serious adverse events were recorded throughout the study period. Solicited and unsolicited adverse events were recorded for 15 and 31 days post each dose. Antirotavirus IgA concentrations (enzyme-linked immunosorbent assay cutoff = 20 U/mL) and geometric mean concentration were determined pre-dose 1 and 30-83 days post-dose 2 in a subset of 300 infants. This study is registered with ClinicalTrials.gov, number NCT00420745 (eTrack106481). RESULTS: Serious adverse events were reported at a similar frequency in both groups (P = 0.266). Fifty seven infants reported at least 1 serious adverse event (5.1% [3.5-7.0] in the RIX4414 group and 6.8% [4.3-10.0] in the placebo group). During the 15-day postvaccination follow-up period, diarrhea, vomiting and fever occurred at a similar frequency in both groups; fever could have been due to concomitant vaccines. Five cases (RIX4414 = 3, Placebo = 2) of rotavirus gastroenteritis were reported. The onset of rotavirus gastroenteritis in the RIX4414 group was 1-5 days after vaccination (vaccine strain identified in all cases) and in the placebo group it was 3-4 days after receiving placebo (wild-type rotavirus identified from both cases). Antirotavirus IgA seroconversion rates at 30-83 days post-dose 2 were 85.7% (79.0-90.9) in the RIX4414 group and 16.0% (8.8-25.9) in the placebo group. Geometric mean concentrations were 202.2 U/mL (153.1-267.1) in the RIX4414 group and <20 U/mL in the placebo group. Seroconversion rate in groups 1 and 2 in RIX4414 recipients were 75.9% (95% confidence interval [CI]: 56.5-89.7%) and 88.1% (95% CI: 80.9-93.4%), respectively; the geometric mean concentrations in the respective groups were 110.2 U/mL (95% CI: 56.1-216.5) and 234.8 U/mL (95% CI: 173.4-318.0; exploratory analysis). CONCLUSIONS: Two doses of RIX4414 were immunogenic and well-tolerated in European preterm infants. PMID- 22228234 TI - Characteristics and outcomes of pandemic 2009/H1N1 versus seasonal influenza in children with cancer. AB - BACKGROUND: Novel 2009/H1N1 influenza has significant impact on immunocompromised children with cancer; however, it is uncertain how it compares with seasonal influenza (SFlu) in this vulnerable population. We compared clinical characteristics and outcomes for these 2 infections in children with cancer and identified risk factors for progression to lower respiratory infection (LRI) and/or death. METHODS: Influenza infections confirmed by positive viral culture and/or fluorescence antigen test between January 1998 and February 2010 were identified from microbiology databases at a comprehensive cancer center. Characteristics and outcomes were compared for the 2 groups. Kaplan-Meier survival curves and Cox proportional hazards model were generated to identify risk factors for LRI and/or death. RESULTS: When compared with SFlu, 2009/H1N1 cases had significantly lower acute physiology and chronic health evaluation II score (median: 9 versus 14), fewer comorbidities (15% versus 46%), fewer hematopoietic stem-cell transplantation (5% versus 16%), more solid tumors (45% versus 16%), higher LRI at presentation (20% versus 4%), higher rates of antiviral therapy (90% versus 48%) and higher mortality (10% versus 0%). Male gender (hazard ratio [HR]: 8.4, 95% confidence interval [CI]: 1.08-65.2, P = 0.042), acute physiology and chronic health evaluation II score > 15 (HR: 3.29, 95% CI: 1.04-10.39, P = 0.027) and a 24-hour delay in initiation of antiviral treatment (HR: 1.12, 95% CI: 1.02-1.23, P = 0.015) were the most significant predictors of progression to LRI and mortality, regardless of virus strain. CONCLUSIONS: Significant differences between 2009/H1N1 and SFlu with respect to clinical presentation, management and associated outcomes were identified. Early diagnosis and prompt initiation of antiviral therapy may prevent serious complications of influenza in children with cancer. PMID- 22228235 TI - Efficacy and immunogenicity of live-attenuated human rotavirus vaccine in breast fed and formula-fed European infants. AB - BACKGROUND: Rotavirus is the main cause of severe gastroenteritis and diarrhea in infants and young children less than 5 years of age. Potential impact of breast feeding on the efficacy and immunogenicity of human rotavirus G1P[8] vaccine was examined in this exploratory analysis. METHODS: Healthy infants (N = 3994) aged 6 14 weeks who received 2 doses of human rotavirus vaccine/placebo according to a 0 1 or 0-2 month schedule were followed for rotavirus gastroenteritis during 2 epidemic seasons. Rotavirus IgA seroconversion rate (anti-IgA antibody concentration >= 20 mIU/mL) and geometric mean concentrations were measured prevaccination and 1-2 months post-dose 2. Vaccine efficacy against any and severe rotavirus gastroenteritis was analyzed according to the infants being breast-fed or exclusively formula-fed at the time of vaccination. RESULTS: Antirotavirus IgA seroconversion rate was 85.5% (95% confidence interval [CI]: 82.4-88.3) in breast-fed and 89.2% (95% CI: 84.2-93) in exclusively formula-fed infants; geometric mean concentrations in the respective groups were 185.8 U/mL (95% CI: 161.4-213.9) and 231.5 U/mL (95% CI: 185.9-288.2). Vaccine efficacy was equally high in breast-fed and exclusively formula-fed children in the first season but fell in breast-fed infants in the second rotavirus season. During the combined 2-year efficacy follow-up period, vaccine efficacy against any rotavirus gastroenteritis was 76.2% (95% CI: 68.7-82.1) and 89.8% (95% CI: 77.6-95.9) and against severe rotavirus gastroenteritis 88.4% (95% CI: 81.6-93) and 98.1% (95% CI: 88.2-100) in the breast-fed and exclusively formula-fed infants, respectively. CONCLUSIONS: The difference in immunogenicity of human rotavirus vaccine in breast-fed and exclusively formula-fed infants was small. Vaccine efficacy was equally high in breast-fed and exclusively formula-fed children in the first season. Breast-feeding seemed to reduce slightly the efficacy in the second season. PMID- 22228236 TI - Influence of antibiotic susceptibility patterns on empiric antibiotic prescribing for children hospitalized with community-acquired pneumonia. AB - OBJECTIVE: The aim of this study was to determine the influence of pneumococcal penicillin-nonsusceptibility patterns on individual antibiotic prescription among 33 children's hospitals using a multilevel, random- intercept, logistic regression analysis. METHODS: It was a multilevel cross-sectional study. The participants were children, 1-18 years of age, with community-acquired pneumonia (CAP) who were discharged in 2006. Hospital antibiotic susceptibility data were collected from surveys, and patient data were obtained from an administrative database. The primary exposure was the proportion of penicillin-nonsusceptible pneumococcal isolates reported in 2005 by each hospital. A secondary exposure included using the proportion of penicillin-resistant pneumococcal isolates to determine whether a threshold of susceptibility existed. Receipt of broad spectrum empiric antibiotic therapy in 2006 (ie, antibiotics other than penicillins or aminopenicillins) was the main outcome measure. RESULTS: Four thousand eight hundred eighty-eight children diagnosed with CAP were eligible. The proportion of penicillin-nonsusceptible isolates ranged from 9% to 70% across hospitals whereas the proportion of penicillin-resistant isolates ranged from 0% to 60%. Broad-spectrum antibiotics were prescribed to 93% of patients; 45% of patients received cephalosporin class antibiotics alone. There was no significant association between the proportion of pencillin-nonsusceptible pneumococcal isolates at individual hospitals and narrow-spectrum prescribing. However, every 10% increase in penicillin-resistant pneumococcal isolates was associated with a 39% increase in broad-spectrum antibiotic prescribing (adjusted odds ratio: 1.39; 95% confidence interval: 1.08-1.69). CONCLUSIONS: There was substantial variability in empiric antibiotic prescribing for CAP among children's hospitals in the United States. High-levels (ie, resistant) but not modest-levels (ie, intermediate susceptibility) of penicillin resistance were associated with broad spectrum antibiotic prescribing. PMID- 22228237 TI - The practical value of biologics registries in Africa and Middle East: challenges and opportunities. AB - Biologics, including tumor necrosis factor (TNF) inhibitors, are increasingly used for the treatment of inflammatory conditions such as rheumatoid arthritis (RA), psoriatic arthritis, and ankylosing spondylitis. The efficacy of these drugs has been demonstrated in randomized controlled trials (RCTs). However, these studies are conducted in controlled environments, and the results may not necessarily reflect clinical outcomes in daily clinical practice. In Europe and other western countries, numerous biologics registries that enroll and monitor patients receiving biologics have been established. These registries follow patients irrespective of whether they continue with the initial biologic drug. Thus, real-life efficacy data from these registries can be used to assess the long-term safety of biologics through longitudinal studies. In Africa and Middle East (AFME), such registries currently exist only in Morocco and South Africa. In light of the increasing availability of biologics and scarcity of long-term safety data of these agents in the AFME population, there is a need to establish biologics registries in other countries across the region. This review discusses the value of biologics registries versus RCTs as well as safety and efficacy data from observational studies presented as lessons from well-established biologics registries. In addition, the rationale for establishing such registries in the AFME region is also presented. PMID- 22228238 TI - Preoperative and intraoperative prediction of risk of cardiac dysfunction following open heart surgery. AB - CONTEXT: Cardiac dysfunction following open heart surgery is a major determinant of subsequent morbidity and mortality. OBJECTIVES: To develop a specific risk prediction model for postoperative cardiac dysfunction based on preoperative variables, to investigate whether prediction could be improved by inclusion of selected intraoperative variables and to compare our model with five previously published risk scores. DESIGN: Single-centre prospectively collected data. SETTING: Tertiary care centre, Middle Norway. PATIENTS: Four thousand nine hundred and eighty-nine patients (all eligible) undergoing open cardiac surgery from 2000 to 2007. MAIN OUTCOME MEASURES: Logistic regression models for postoperative cardiac dysfunction: predictive accuracy/calibration, discrimination as shown by area under the receiver operating characteristics curve, internal validity as indicated by bootstrapping, comparison of goodness-of fit with predictions based on alternative risk scores. RESULTS: The preoperative model included chronic cardiac insufficiency, previous myocardial infarction, previous cardiac operation, pulmonary hypertension, renal dysfunction, low haemoglobin concentration, urgent operation and operation type other than isolated coronary artery bypass surgery. The area under the curve was 0.838 [95% confidence interval (CI) 0.812-0.864]. Risk prediction was accurate apart from a slight overestimation in the 2% of highest risk patients. Inclusion of a few intraoperative variables (inotropic or vasoconstrictor drugs, plasma or red cell transfusion) improved the model slightly, increasing the area under the curve to 0.875 (95% CI 0.854-0.896) or 0.890 (95% CI 0.863-0.902) for two equivalent models. On the basis of estimated shrinkage factors of 0.94, 0.97 and 0.98, respectively, the models should behave with 6% or less error in future datasets. Our preoperative model was significantly better than the previously published risk scores (P < 0.0002 for comparison of area under the curves). CONCLUSION: The preoperative model including variables obtained easily in routine clinical work performed well and was improved only slightly by inclusion of intraoperative variables. Performance was better than those of the five previously published risk scores. PMID- 22228239 TI - Effects of four different positive airway pressures on right internal jugular vein catheterisation. AB - CONTEXT: The right internal jugular vein (RIJV) is often used for central venous catheterisation in patients undergoing major surgery. The efficacy of this route correlates with the diameter of the vein which can be influenced by airway pressure. OBJECTIVE: To investigate four positive airway pressures (PAPs) in mechanically ventilated patients and to determine the most suitable of these for RIJV catheterisation. DESIGN: Prospective, randomised, controlled study. SETTING: Two Chinese medical centres. PATIENTS: Two hundred and forty patients scheduled for gastrointestinal tract surgery under general anaesthesia (male-to-female ratio, 135 : 105; American Society of Anesthesiologists' physical status class, I III; age range, 19-81 years); patients were excluded from the study if they had a history of haematological disease, external neck injury, RIJV catheterisation, severe cardiovascular disease, RIJV thrombosis, injection-site infection, pneumothorax and pulmonary bulla. INTERVENTIONS: They were randomised into four groups of 60, each to undergo RIJV catheterisation at a PAP of 0 (1 cmH2O = 0.098 kPa, group A); 15 (group B); 20 (group C); and 25 cmH2O (group D). MAIN OUTCOME MEASURES: Primary outcomes were central venous pressure (CVP) and RIJV cross sectional area which were measured before and during PAP; the number of catheterisations completed in 30 s; the number of first pass punctures; heart rate and mean arterial pressure which were monitored continuously; and the incidence of complications which included local haematoma, pneumothorax and internal carotid artery (ICA) puncture. RESULTS: Two patients were excluded following ICA puncture, leaving 238 for analysis. In groups C and D, the CVP and the cross-sectional area of RIJV were significantly larger; the number completing catheterisation within 30 s and the number of first pass punctures increased significantly and was comparable between these two groups. Compared with groups A and B, the incidences of hypotension and bradycardia were significantly increased in groups C and D. The incidence of local haematoma was significantly increased in group D compared with other groups. RIJV catheterisation was completed successfully in all but two patients in group A. CONCLUSION: A PAP of 20 cmH2O seems most suitable for successful RIJV catheterisation in mechanically ventilated patients. It is associated with an increase in cross-sectional RIJV area and CVP, which facilitate cannulation, and results in fewer puncture-related complications. However, meticulous haemodynamic monitoring is needed to avoid hypotension and bradycardia. PMID- 22228240 TI - Bilateral bispectral index differences in asymptomatic internal carotid stenosis. PMID- 22228241 TI - Electrolyte-stimulated biphasic dissolution profile and stability enhancement for tablets containing drug-polyelectrolyte complexes. AB - PURPOSE: Recently introduced drug-polyelectrolyte complexes prepared by hot-melt extrusion should be processed to solid dosage forms with tailor-made release properties. Their potential of stability enhancement should be investigated. METHODS: Milled hot-melt extruded naproxen-EUDRAGIT(r) E PO polyelectrolyte complexes were subsequently processed to double-layer tablets with varying complex loadings on a rotary-die press. Physicochemical interactions were studied under ICH guideline conditions and using the Gordon-Taylor equation. Sorption and desorption were determined to investigate the influence of moisture and temperature on the complex and related to stability tests under accelerated conditions. RESULTS: Naproxen release from the drug-polyelectrolyte complex is triggered by electrolyte concentration. Depending on the complex loading, phosphate buffer pH 6.8 stimulated a biphasic dissolution profile of the produced double-layer tablets: immediate release from the first layer with 65% loading and prolonged release from the second layer within 24 h (98.5% loading). XRPD patterns proved pseudopolymorphism for tablets containing the pure drug under common storage conditions whereas the drug-complex was stable in the amorphous state. CONCLUSIONS: Drug-polyelectrolyte complexes enable tailor-made dissolution profiles of solid dosage forms by electrolyte stimulation and increase stability under common storage conditions. PMID- 22228242 TI - QTL linkage analysis of connected populations using ancestral marker and pedigree information. AB - The common assumption in quantitative trait locus (QTL) linkage mapping studies that parents of multiple connected populations are unrelated is unrealistic for many plant breeding programs. We remove this assumption and propose a Bayesian approach that clusters the alleles of the parents of the current mapping populations from locus-specific identity by descent (IBD) matrices that capture ancestral marker and pedigree information. Moreover, we demonstrate how the parental IBD data can be incorporated into a QTL linkage analysis framework by using two approaches: a Threshold IBD model (TIBD) and a Latent Ancestral Allele Model (LAAM). The TIBD and LAAM models are empirically tested via numerical simulation based on the structure of a commercial maize breeding program. The simulations included a pilot dataset with closely linked QTL on a single linkage group and 100 replicated datasets with five linkage groups harboring four unlinked QTL. The simulation results show that including parental IBD data (similarly for TIBD and LAAM) significantly improves the power and particularly accuracy of QTL mapping, e.g., position, effect size and individuals' genotype probability without significantly increasing computational demand. PMID- 22228244 TI - Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p. AB - Two studies recently identified a GGGGCC hexanucleotide repeat expansion in a non coding region of the chromosome 9 open-reading frame 72 gene (C9ORF72) as the cause of chromosome 9p-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In a cohort of 231 probands with ALS, we identified the C9ORF72 mutation in 17 familial (27.4%) and six sporadic (3.6%) cases. Patients with the mutation presented with typical motor features of ALS, although subjects with the C9ORF72 mutation had more frequent bulbar onset, compared to those without this mutation. Dementia was significantly more common in ALS patients and families with the C9ORF72 mutation and was usually early onset FTD. There was striking clinical heterogeneity among the members of individual families with the mutation. The associated neuropathology was a combination of ALS with TDP-ir inclusions and FTLD-TDP. In addition to TDP-43 immunoreactive pathology, a consistent and specific feature of cases with the C9ORF72 mutation was the presence of ubiquitin-positive, TDP-43-negative inclusions in a variety of neuroanatomical regions, such as the cerebellar cortex. These findings support the C9ORF72 mutation as an important newly recognized cause of ALS, provide a more detailed characterization of the associated clinical and pathological features and further demonstrate the clinical and molecular overlap between ALS and FTD. PMID- 22228243 TI - Retention of agronomically important variation in germplasm core collections: implications for allele mining. AB - The primary targets of allele mining efforts are loci of agronomic importance. Agronomic loci typically exhibit patterns of allelic diversity that are consistent with a history of natural or artificial selection. Natural or artificial selection causes the distribution of genetic diversity at such loci to deviate substantially from the pattern found at neutral loci. The germplasm utilized for allele mining should contain maximum allelic variation at loci of interest, in the smallest possible number of samples. We show that the popular core collection assembly procedure "M" (marker allele richness), which leverages variation at neutral loci, performs worse than random assembly for retaining variation at a locus of agronomic importance in sugar beet (Beta vulgaris L. subsp. vulgaris) that is under selection. We present a corrected procedure ("M+") that outperforms M. An extensive coalescent simulation was performed to demonstrate more generally the retention of neutral versus selected allelic variation in core subsets assembled with M+. A negative correlation in level of allelic diversity between neutral and selected loci was observed in 42% of simulated data sets. When core collection assembly is guided by neutral marker loci, as is the current common practice, enhanced allelic variation at agronomically important loci should not necessarily be expected. PMID- 22228245 TI - Proteomics analysis of in vitro protein methylation during Src-induced transformation. AB - Src, a nonreceptor tyrosine kinase, was the first oncogene identified from an oncogenic virus. Mechanistic studies of Src-induced transformations aid in understanding the pathologic processes underlying tumorigenesis and may provide new strategies for cancer therapy. Although several pathways and protein modifications are reportedly involved in Src-induced transformation, the detailed mechanisms of their regulation remain unclear. Protein methylation is an important PTM that is widely involved in cellular physiology. In this study, we determined if protein methylation was involved in Src activation and which methylated proteins were associated with this activity. Using in vitro methylation and 2-DE analysis of viral Src (v-Src)-transformed rat kidney epithelial cells (RK3E), several known and novel methylated proteins were identified based on their changes in methylation signal intensity upon transformation. Among these, elongation factor 2 (EF-2), heterogeneous nuclear ribonucleoprotein K (hnRNP K), and beta-tubulin protein expressions remained unchanged, indicating that their altered methylation levels were due to Src activation. In addition, the altered expression of beta-actin, vimentin, and protein phosphatase 2, catalytic subunit (PPP2C) as well as protein phosphatase 2, catalytic subunit methylation were also confirmed in RK3E cells transformed with a human oncogenic Src mutant (Src531), supporting their association with Src induced transformation in human cancer. Together, we showed putative involvement of protein methylation in Src activation and our identification of methylated proteins provides important targets for extensively studying Src-induced transformations. PMID- 22228246 TI - Health care use and expenditures associated with access to the medical home for children and youth. AB - BACKGROUND: The pediatric medical home is an approach to the delivery of family centered health care. Policy-makers and payers are interested in potential changes to health care utilization and expenditures under this model. OBJECTIVE: To test associations between having a medical home and health service use and expenditures among US children and youth. RESEARCH DESIGN: Observational cross sectional study. SUBJECTS: A total of 26,221 children aged 0 to 17 years surveyed in the 2005 to 2007 Medical Expenditure Panel Surveys. MEASURES: Parent report of a child's access to a medical home was developed from multiple survey items in the Medical Expenditure Panel Surveys. Negative binomial regression examined the association between the medical home and parent-reported counts of annual outpatient, inpatient, emergency department, and dental visits. Two-part models examined associations between the medical home and parent-reported annual total, outpatient, inpatient, emergency department, and other health care expenditures. Models accounted for potential self-selection into a medical home using propensity scores. RESULTS: Children with a medical home had a greater incidence of preventive visits [incidence rate ratio (IRR)=1.11; (95% confidence intervals (CI), 1.03-1.20)] and dental visits [IRR=1.09 (95% CI, 1.02-1.17)] and a lower incidence of emergency department visits [IRR=0.87 (95% CI, 0.79-0.97)] compared with children without a medical home. Children with a medical home also had greater odds of incurring total, outpatient, prescription medication, and dental expenditures, OR's ranging from 1.09 to 1.38. Despite greater odds of incurring certain expenditures, expenditures were no different for children with and without a medical home. CONCLUSIONS: The medical home is associated with several domains of health service use, yet there is no evidence for its association with health care expenditures for children and youth. PMID- 22228247 TI - Effect of ambiguous hemochromatosis gene test results on physician utilization. AB - BACKGROUND: Genetic test results may be available to greater numbers of people through genetic screening projects and other means. The effects of widespread genetic testing and notification of genetic test results, particularly added costs through increased physician utilization, have not been clearly established. METHODS: A primary care-based cohort of 20,306 participants (Hemochromatosis and Iron Overload Study, Ontario site) were tested for the C282Y and H63D mutations of the HFE gene and for abnormal serum ferritin (SF) and transferrin saturation levels. The primary outcome variable was the total number of physician claims per patient after genetic test notification by mail. Multiple Poisson regression was used to adjust for age, sex, baseline SF, diagnoses of arthritis, diabetes, heart failure and impotence, self-rated health, and the number of claims during the 12 months before notification of results. The reference group had no HFE mutations (wild type) and normal transferrin saturation/SF values. RESULTS: Participants with an ambiguous hemochromatosis gene test and normal iron levels had statistically significantly higher average physician utilization of 3.0%. Participants with HFE mutations (excluding C282Y homozygotes) and elevated iron values showed a 6% increase in physician utilization. CONCLUSIONS: The health effects, if any, of increased utilization in heterozygotes or those with mild ferritin elevations are unknown but are unlikely to be large at the population level. Ambiguous genetic test results are associated with increased physician service use and should be considered when assessing the complete societal costs of widespread genetic testing. PMID- 22228249 TI - Prevalence and costs of co-occurring traumatic brain injury with and without psychiatric disturbance and pain among Afghanistan and Iraq War Veteran V.A. users. AB - BACKGROUND: Traumatic brain injury (TBI) is the "signature injury" in the Afghanistan and Iraq wars [Operation Enduring Freedom in Afghanistan (OEF)/Operation Iraqi Freedom (OIF)]. Patients with combat-related TBI also have high rates of psychiatric disturbances and pain. OBJECTIVES: To determine the prevalence of TBI alone and TBI with other conditions and the average cost of medical care for veterans with these diagnoses. METHODS: Observational study using national inpatient, outpatient, and pharmacy data from Veterans Health Administration (VHA) datasets. Costs are estimated from utilization related to care within the VHA system. Participants were all OEF/OIF VHA users in 2009. RESULTS: Among 327,388 OEF/OIF veterans using VHA services in 2009, 6.7% were diagnosed with TBI. Among those with TBI diagnoses, 89% were diagnosed with a psychiatric diagnosis [the most frequent being posttraumatic stress disorder (PTSD) at 73%], and 70% had a diagnosis of head, back, or neck pain. The rate of comorbid PTSD and pain among those with and without TBI was 54% and 11%, respectively. The median annual cost per patient was nearly 4-times higher for TBI-diagnosed veterans as compared with those without TBI ($5831 vs. $1547). Within the TBI group, cost increased as diagnostic complexity increased, such that those with TBI, pain, and PTSD demonstrated the highest median cost per patient ($7974). CONCLUSIONS: The vast majority of VHA patients diagnosed with TBI also have a diagnosed mental disorder and more than half have both PTSD and pain. Patients with these comorbidities incur substantial medical costs and represent a target population for future research aimed at improving health care efficiency. PMID- 22228248 TI - Mental comorbidity and quality of diabetes care under Medicaid: a 50-state analysis. AB - BACKGROUND: Patients with comorbid medical and mental conditions are at risk for poor quality of care. With the anticipated expansion of Medicaid under health reform, it is particularly important to develop national estimates of the magnitude and correlates of quality deficits related to mental comorbidity among Medicaid enrollees. METHODS: For all 657,628 fee-for-service Medicaid enrollees with diabetes during 2003 to 2004, the study compared Healthcare Effectiveness Data and Information Set (HEDIS) diabetes performance measures (hemoglobin A1C, eye examinations, low density lipoproteins screening, and treatment for nephropathy) and admissions for ambulatory care-sensitive conditions (ACSCs) between persons with and without mental comorbidity. Nested hierarchical models included individual, county, and state-level measures. RESULTS: A total of 17.8% of the diabetic sample had a comorbid mental condition. In adjusted models, presence of a mental condition was associated with a 0.83 (0.82-0.85) odds of obtaining 2 or more HEDIS indicators, and a 1.32 (1.29-1.34) increase in odds of one or more ACSC hospitalization. Among those with diabetes and mental comorbidities, living in a county with a shortage of primary care physicians was associated with reduced performance on HEDIS measures; living in a state with higher Medicaid reimbursement fees and department of mental health expenses per client were associated both with higher quality on HEDIS measures and lower (better) rates of ACSC hospitalizations. CONCLUSIONS: Among persons with diabetes treated in the Medicaid system, mental comorbidity is an important risk factor for both underuse and overuse of medical care. Modifiable county and state-level factors may mitigate these quality deficits. PMID- 22228250 TI - Calciotropic hormones and the risk of hip and nonspine fractures in older adults: the Health ABC Study. AB - The effects of vitamin D and parathyroid hormone (PTH) levels on incident fracture remain uncertain. To test the hypothesis that increasing serum 25 hydroxyvitamin D [25(OH)D] and decreasing PTH levels are associated with decreased risk of hip and any nonspine fracture, we conducted a prospective cohort study among 2614 community-dwelling white and black participants, aged >=70 years, from the Health, Aging and Body Composition (Health ABC) Study. Serum and plasma samples were drawn at year 2, which formed the baseline for this analysis. Serum 25(OH)D and intact PTH (1-84) were measured using radioimmunoassay with DiaSorin reagents and EDTA plasma with a two-site immunoradiometric assay kit, respectively. Incident fractures (hip and any nonspine) were assessed after year 2, every 6 months, by self-report and validated by radiology reports. The median (interquartile range) follow-up times for hip and any nonspine fractures were 6.4 (6.1-6.5) and 6.4 (5.5-6.5) years, respectively. Cox proportional hazards regression was used to estimate the hazard ratios (HR) with 95% confidence intervals (CI) for fracture. There were 84 hip and 247 nonspine fractures that occurred over the follow-up period. The multivariable adjusted HRs (95% CIs) of hip fracture for participants in the lowest (<=17.78 ng/mL), second (17.79 to 24.36 ng/mL), and third quartiles (24.37 to 31.94 ng/mL) of 25(OH)D were 1.92 (0.97 to 3.83), 0.75 (0.32 to 1.72) and 1.86 (1.00 to 3.45), respectively, compared with participants in the highest 25(OH)D quartile (>31.94 ng/mL) (p trend = 0.217). Additional adjustment for IL-6 (p = 0.107), PTH (p = 0.124), and hip areal bone mineral density (p = 0.137) attenuated HRs of hip fracture in the lowest quartile by 16.3%, 17.4%, and 26.1%, respectively. There was no evidence of an association between 25(OH)D and any nonspine fractures, or between PTH and hip or any nonspine fractures. We found limited evidence to support an association between calciotropic hormones and hip and nonspine fractures in older men and women. PMID- 22228251 TI - Factors determining nurse acceptance of hospital information systems. AB - This study proposed an evaluation model, derived from the Technology Acceptance Model and Information System Success Model, to explore factors influencing the acceptance of hospital information systems by nurses. Although many healthcare institutions have applied hospital information systems, relatively few studies have investigated the perceptions of nurses regarding the usefulness, ease of use, or acceptance of these systems. This study recruited the nursing staff of a regional hospital in Taiwan. A total of 297 questionnaires were sent, and 277 were returned, for a response rate of 93.3%. The results indicated that system quality, information quality, and service quality were positively correlated with the perceived ease of use (R=0.69) and perceived usefulness (R=0.72). Information quality has the greatest influence on perceived usefulness (gamma3=0.57, P<.001) and ease of use (gamma4=0.61, P<.001). Perceived usefulness and ease of use have a significant influence on system acceptance (R=0.75). Perceived usefulness (beta1=0.61, P<.001) has a significant influence on system acceptance. These findings indicated that nursing care requires high-quality healthcare information to support the daily activities of nursing professionals. The results of this study also provide a valuable reference for hospital administrators in developing hospital information systems. PMID- 22228252 TI - The NEXUS criteria: do they stand the test of time? AB - The National Emergency X-ray Utilisation Study (NEXUS) criteria and the Canadian cervical spine rules are validated clinical decision-making tools used to facilitate selective cervical spine (C-spine) radiography. The NEXUS criteria are frequently used, as the Canadian cervical spine rules have been noted to be difficult to learn, remember and implement. We present a series of significant C spine injury in three elderly patients who would not have warranted C-spine imaging using the NEXUS criteria. Each patient was mobile and fully orientated after the injury. There was no midline tenderness, neurological deficit, distracting injury or alcohol/drug involvement. Plain film imaging was initially performed as each patient had a reduced range of movement. Significant odontoid peg injury was confirmed on subsequent computed tomography/MRI imaging for all patients. Despite previous validation studies of the NEXUS criteria in the elderly population, we would urge caution in using the NEXUS criteria alone in determining radiography of the C-spine in the elderly. PMID- 22228253 TI - Screening for diabetes. AB - The prevalence of type 2 diabetes is rapidly increasing. A strong rationale exists for identifying asymptomatic individuals who are at high risk or are likely to have diabetes. Screening programs may provide a conduit through which diabetes intervention may be targeted towards those who might benefit most. Diabetes screening could lessen disease burden in two ways. Firstly, by identifying people with undiagnosed diabetes, the burden of diabetes complications could be lessened through appropriate management of the condition. Secondly, by indentifying people at high risk of developing diabetes, and entering these people into diabetes prevention programs, the number of people with diabetes could be reduced. Screening for diabetes should ideally involve a non-invasive risk assessment followed by blood testing for those found to be at high risk. It should be noted that conclusive randomised controlled trial data to support the long-term health and economic impact of screening programs is lacking. The answers surrounding who and how we should screen for diabetes and the associated long term benefits will continue to evolve as the evidence base builds. As the use of screening for diabetes builds in popularity, it is essential that health care systems are sufficiently equipped to effectively manage the newly identified high risk and prevalent cases of type 2 diabetes. PMID- 22228254 TI - Screening for familial hypercholesterolaemia. AB - Familial hypercholesterolaemia (FH) is an autosomal dominant disorder characterised by increased plasma concentrations of low density lipoprotein (LDL) cholesterol leading to atherosclerosis and premature coronary heart disease (CHD) and death. The clinical diagnosis of FH is based on a personal and family history, physical examination findings and LDL-cholesterol concentrations. FH is primarily caused by mutations in the LDL-receptor gene (LDLR), and less frequently by mutations in genes for APOB and the more recently identified PCSK9. Lifestyle modification and pharmacotherapy can delay or prevent the onset of CHD in FH. It is estimated that only 20% of cases have been diagnosed in Australia and that the majority are inadequately treated. Screening options for FH include population screening (of children or adults), targeted screening of patients with premature CHD and their relatives, or opportunistic screening such as flagging laboratory lipid reports. Cascade screening, a form of targeted screening, is an ethically acceptable, cost-effective strategy for the identification of FH. However, for screening to be successful, medical practitioners need to be aware of the signs and diagnosis of FH and the benefits of early treatment. PMID- 22228255 TI - Pharmacogenetic screening for drug therapy: from single gene markers to decision making in the next generation sequencing era. AB - Pharmacogenetics has substantially added to our understanding of the variability of drug response. A number of single gene markers have been established and are ready to use in clinical practice. Here we review the validity and utility of markers in a number of genes (CYP2D6, CYP2C19, CYP2C9, VKORC1, TPMT, UGT1A1, OATP1B1, KRAS and HLA locus) for therapy decisions. As drug response is a complex trait in the majority of cases, most of the identified functional variants will only explain a limited part of the variability of drug response. In this sense, a phenotype is the product of many low-penetrance variations. Technical progress has not only improved the cost-effectiveness of screening for single gene markers, but offers the possibility of generating vast amounts of genome-wide single nucleotide polymorphism (SNP) or sequence data for each patient. The latest challenge is to incorporate these amounts of data into pharmacogenetic decision support. We discuss here the challenges associated with choosing the correct therapy for patients who present to their physicians with personal genome data. PMID- 22228256 TI - Acceptance and opinions of Intanza/IDflu intradermal influenza vaccine in the Czech Republic and Turkey. AB - INTRODUCTION: Intanza((r))/IDflu((r)) (Sanofi Pasteur SA, Lyon, France), a split virion, trivalent influenza vaccine delivered by intradermal injection with a microinjection system, became available in adults 18-59 years of age (9 MUg) and >=60 years of age (15 MUg) as of the 2010/2011 northern hemisphere influenza season. METHODS: This study assessed the acceptability of intradermal vaccination with Intanza/IDflu in routine clinical practice in adult vaccinees and their vaccine prescribers. Vaccine prescribers and adults who had elected to be vaccinated with Intanza/IDflu during the 2010/2011 northern hemisphere influenza season were recruited to complete surveys about their opinions of influenza vaccination and their acceptance of the intradermal vaccination. Czech subjects 18-59 years of age were vaccinated with the 9 MUg formulation and those >=60 years of age with the 15 MUg formulation of Intanza/IDflu. All Turkish subjects were vaccinated with the 9 MUg formulation, as Intanza/IDflu 15 MUg was not available in Turkey at the time the survey was conducted. RESULTS: One thousand and twelve vaccinees and 28 vaccine prescribers in the Czech Republic, and 249 vaccinees and 15 vaccine prescribers in Turkey completed questionnaires. Overall, 96.1% of vaccinees were satisfied or very satisfied with Intanza/IDflu. The main reason for satisfaction was that the injection was considered minimally painful. Most (93.9%) vaccinees reported that they would prefer to receive the same vaccination next year. Furthermore, 95.3% of vaccine prescribers were satisfied or very satisfied with the intradermal vaccine, and 82.6% preferred intradermal over intramuscular vaccination. CONCLUSIONS: Intradermal vaccination for seasonal influenza using Intanza/IDflu is well accepted by adult vaccinees and vaccine prescribers. By providing an additional, well-accepted method, Intanza/IDflu might help increase seasonal influenza vaccination rates in adults. PMID- 22228257 TI - Studies on purification of allicin by molecular distillation. AB - BACKGROUND: With recent improvements in living standards, people have been giving more consideration to the healthcare effects of foods. In this respect, allicin, which is the most important organosulfur compound in garlic and plays a key role in physiological function, has been receiving much attention. RESULTS: Allicin obtained from garlic by supercritical CO(2) extraction was purified by molecular distillation (MD). The effects of operating conditions such as absolute pressure (AP), distillation temperature (DT) and feed flow rate (FFR) on allicin purity and yield were studied. The optimal AP, DT and FFR levels in first-stage MD were found to be 200 Pa, 50 degrees C and 15 mL min(-1) respectively. After three stages of MD the contents of allicin, diallyl disulfide (DADS) and diallyl trisulfide (DATS) were 68.04, 9.19 and 5.91% (w/w) respectively. CONCLUSION: This study has provided a safe and effective method for the purification of allicin. PMID- 22228258 TI - Efficient biocatalyst for large-scale synthesis of cephalosporins, obtained by combining immobilization and site-directed mutagenesis of penicillin acylase. AB - We describe the rational design of a new efficient biocatalyst and the development of a sustainable green process for the synthesis of cephalosporins bearing a NH2 group on the acyl side chain. The new biocatalyst was developed starting from the WT penicillin acylase (PA) from Escherichia coli by combining enzyme mutagenesis, in position alpha146 and beta24 (betaF24A/alphaF146Y), and immobilization on an appropriate modified industrial support, glyoxyl Eupergit C250L. The obtained derivative was used in the kinetically controlled synthesis of cephalexin, cefprozil and cefaclor and compared to the WT-PA and an already described mutant, PA-betaF24A, with improved properties. The new biocatalyst posses a very high ratio between the rates of the synthesis and two undesired hydrolyses (acylating ester and the amidic product). In particular, a very low amidase activity was observed with PA-betaF24A/alphaF146Y and, consequently, the hydrolysis of the produced antibiotic was avoided during the process. Taking advantage of this property, higher conversions in the synthesis of cephalexin (99% versus 76%), cefaclor (99% versus 65%) and cefprozil (99% versus 60%) were obtained compared to the WT enzyme. Furthermore, the new mutant also show a higher synthetic activity compared to PA-betaF24A immobilized on the same support, allowing the maximum yields to be achieved in very short reaction times. The production of cephalexin with the immobilized betaF24A/alphaF146Y acylase has been developed on a pre-industrial scale (30 l). After 20 cycles, the average yield was 93%. The biocatalyst showed good stability properties and no significant decrease in performance. PMID- 22228259 TI - Silica gel-encapsulated AtzA biocatalyst for atrazine biodegradation. AB - Encapsulation of recombinant Escherichia coli cells expressing a biocatalyst has the potential to produce stable, long-lasting enzyme activity that can be used for numerous applications. The current study describes the use of this technology with recombinant E. coli cells expressing the atrazine-dechlorinating enzyme AtzA in a silica/polymer porous gel. This novel recombinant enzyme-based method utilizes both adsorption and degradation to remove atrazine from water. A combination of silica nanoparticles (Ludox TM40), alkoxides, and an organic polymer was used to synthesize a porous gel. Gel curing temperatures of 23 or 45 degrees C were used either to maintain cell viability or to render the cells non viable, respectively. The enzymatic activity of the encapsulated viable and non viable cells was high and extremely stable over the time period analyzed. At room temperature, the encapsulated non-viable cells maintained a specific activity between (0.44 +/- 0.06) MUmol/g/min and (0.66 +/- 0.12) MUmol/g/min for up to 4 months, comparing well with free, viable cell-specific activities (0.61 +/- 0.04 MUmol/g/min). Gels cured at 45 degrees C had excellent structural rigidity and contained few viable cells, making these gels potentially compatible with water treatment facility applications. When encapsulated, non-viable cells were assayed at 4 degrees C, the activity increased threefold over free cells, potentially due to differences in lipid membranes as shown by FTIR spectroscopy and electron microscopy. PMID- 22228260 TI - Perstraction of intracellular pigments by submerged cultivation of Monascus in nonionic surfactant micelle aqueous solution. AB - "Milking processing" describes the cultivation of microalgae in a water-organic solvent two-phase system that consists of simultaneous fermentation and secretion of intracellular product. It is usually limited by the conflict between the biocompatibility of the organic solvent to the microorganisms and the ability of the organic solvent to secret intracellular product into its extracellular broth. In the present work, submerged cultivation of Monascus in the nonionic surfactant Triton X-100 micelle aqueous solution for pigment production is exploited, in which the fungus Monascus remains actively growing. Permeabilization of intracellular pigments across the cell membrane and extraction of the pigments to the nonionic surfactant micelles of its fermentation broth occur simultaneously. "Milking" the intracellular pigments in the submerged cultivation of Monascus is a perstraction process. The perstractive fermentation of intracellular pigments has the advantage of submerged cultivation by secretion of the intracellular pigments to its extracellular broth and the benefit of extractive microbial fermentation by solubilizing the pigments into nonionic surfactant micelles. It is shown as the marked increase of the extracellular pigment concentration by the submerged cultivation of Monascus in the nonionic surfactant Triton X-100 micelle solution. PMID- 22228261 TI - Common genetic variants in TERT contribute to risk of cervical cancer in a Chinese population. AB - Single-nucleotide polymorphisms (SNPs) of TERT rs2736098, rs2736100, and CLPTM1L rs402710 at 5p15.33 are significantly associated with risk of a spectrum of cancers. However, cervical cancer has been rarely evaluated. In this study, we genotyped the three SNPs in a case-control study with 1,033 cervical cancer cases and 1,053 cancer-free controls in a Chinese population. Logistic regression analyses showed that the two TERT SNPs both significantly associated with cervical cancer risk in the recessive model (rs2736098, AA vs. AG/GG: adjusted OR = 1.35, 95% CI = 1.06-1.72; rs2736100, CC vs. AC/AA: adjusted OR = 1.38, 95% CI = 1.11-1.73). However, no association was found between CLPTM1L rs402710 and cervical cancer. These results suggest that genetic variants in 5p15.33, especially in TERT, may be markers for susceptibility to cervical cancer. PMID- 22228262 TI - Response of photosynthetic carbon gain to ecosystem retrogression of vascular plants and mosses in the boreal forest. AB - In the long-term absence of rejuvenating disturbances, forest succession frequently proceeds from a maximal biomass phase to a retrogressive phase characterized by reduced nutrient availability [notably nitrogen (N) and phosphorus (P)] and net primary productivity. Few studies have considered how retrogression induces changes in ecophysiological responses associated with photosynthetic carbon (C) gain, and only for trees. We tested the hypothesis that retrogression would negatively impact photosynthetic C gain of four contrasting species, and that this impact would be greater for vascular plants (i.e., trees and shrubs) than for non-vascular plants (i.e., mosses). We used a 5,000-year-old chronosequence of forested islands in Sweden, where retrogression occurs in the long-term absence of lightning-ignited wildfires. Despite fundamental differences in plant form and ecological niche among species, vascular plants and mosses showed similar ecophysiological responses to retrogression. The most common effects of retrogression were reductions in photosynthesis and respiration per unit foliar N, increases in foliar N, delta(13)C and delta(15)N, and decreases in specific leaf areas. In contrast, photosynthesis per unit mass or area generally did not change along the chronosequence, but did vary many-fold between vascular plants and mosses. The consistent increases in foliar N without corresponding increases in mass- or area-based photosynthesis suggest that other factor(s), such as P co-limitation, light conditions or water availability, may co-regulate C gain in retrogressive boreal forests. Against our predictions, traits of mosses associated with C and N were generally highly responsive to retrogression, which has implications for how mosses influence ecosystem processes in boreal forests. PMID- 22228263 TI - GSTM1 and GSTP1 gene variants and the effect of air pollutants on lung function measures in South African children. AB - BACKGROUND: Several genes are associated with an increased susceptibility to asthma, which may be exacerbated by ambient air pollution. These genes include GSTM1 (glutathione-S-transferase M1 gene) and GSTP1 (glutathione-S-transferase P1 gene), which may modulate the response to epithelial oxidative changes caused by air pollutant exposure. This study evaluated fluctuations in the forced expiratory volume in one second (FEV(1)) in relation to lagged daily averages of ambient air pollutants (SO(2), NO(2), NO, and PM(10)) while considering genotype as an effect modifier. METHODS: A longitudinal cohort of 129 schoolchildren of African descent from Durban, South Africa was assessed. GSTM1 (null vs. present genotype) and GSTP1 (Ile105Val; AA -> AG/GG) genotypes were determined using standard techniques. SO(2), NO(2), NO, and PM(10) were measured continuously over a year using validated methods. The outcome was intraday variability in FEV(1) . Data were collected daily over a 3-week period in each of four seasons (2004 2005). RESULTS: Among the children tested, 27% had the GSTM1 null genotype and 81% carried the GSTP1 G allele. Approximately 26 out 104 children (25%) showed evidence of bronchial hyperreactivity, 13% reported having symptoms in keeping with persistent asthma, and a further 25% reported symptoms of mild intermittent asthma. PM(10) and SO(2) levels were moderately high relative to international guidelines. Neither GSTM1 nor GSTP1 genotypes alone were significantly associated with FEV(1) intraday variability. In models not including genotype, FEV(1) variability was statistically significantly associated only with NO(2) for 5-day lags (% change in intraday variability in FEV1 per interquartile range = 1.59, CI 0.58, 2.61). The GSTP1 genotype modified the effect of 3 days prior 24-hr average PM(10) and increased FEV(1) variability. A similar pattern was observed for lagged 3 day SO(2) exposure (P interaction < 0.05). Adverse effects of these pollutants were limited to individuals carrying the G allele for this polymorphism. CONCLUSION: Among this indigenous South African children cohort, the GSTP1 genotype modified the effects of ambient exposures to PM(10) and SO(2) and lung function. A plausible mechanism for these observed effects is decreased capacity to mount an effective response to oxidative stress associated with the GSTP1 AG + GG genotype. PMID- 22228264 TI - Microfabricated passive vapor preconcentrator/injector designed for microscale gas chromatography. AB - The design, fabrication, and preliminary testing of a micromachined-Si passive vapor preconcentrator/injector (MUPPI) are described. Intended for incorporation in a gas chromatographic microsystem (MUGC) for analyzing organic vapor mixtures, the MUPPI captures vapors from the air at a known rate by means of passive diffusion (i.e., without pumping) and then desorbs the vapor sample thermally by means of an integrated heater and injects it downstream (with pumping). The MUPPI chip comprises a 1.8 MUL deep reactive-ion-etched (DRIE) Si cavity with a resistively heated membrane floor and a DRIE-Si cap containing >1500 parallel diffusion channels, each 54 * 54 * 200 MUm. The cavity is packed with 750 MUg of a commercial graphitized carbon adsorbent. Fluidic and heat-transfer modeling was used to guide the design process to ensure power-efficient sample transfer during thermal desorption. Experiments performed with toluene at concentrations of ~1 ppm gave a constant sampling rate of 9.1 mL min(-1) for up to 30 min, which is within 2% of theoretical predictions and corresponds to a linear dynamic mass uptake range of ~1 MUg. The cavity membrane could be heated to 250 degrees C in 0.23 s with 1 W of applied power and, with 50 mL min(-1) of suction flow provided by a downstream pump, yielded >95% desorption/injection efficiency of toluene samples over an 8-fold range of captured mass. PMID- 22228265 TI - Fixation of tibial plateau fractures with synthetic bone graft versus natural bone graft: a comparison study. AB - PURPOSE: The goal of this study was to determine differences in fracture stability and functional outcome between synthetic bone graft and natural bone graft with internal fixation of tibia plateau metaphyseal defects. METHODS: Hydroxyapatite calcium carbonate synthetic bone graft was utilised in 14 patients (six males and eight females). Allograft/autograft were utilised in the remaining 10 patients (six males and four females). All the 24 patients had clinical, radiological and subjective functional score assessments. RESULTS: There was no significant statistical difference between the groups for post-operative articular reduction, long-term subsidence, and WOMAC scores. The degree of subsidence was not related to age or fracture severity. Maintenance of knee flexion was found to be better in the allograft/autograft group (p = 0.048) when compared between the groups. Multivariate analysis compared graft type, fracture severity, post-operative reduction, subsidence rate, range of movement and WOMAC score. The only finding was a statistical significant association with the graft type related to the 6-month range of movement figures. CONCLUSIONS: Use of autologous or allogenic bone graft allows better recovery of long-term flexion, possibly due to reduced inflammatory response compared with synthetic bone composites. However, all other parameters, such as maintenance of joint reduction and subjective outcome measures were comparable with the use of hydroxyapatite calcium carbonate bone graft. This study shows that synthetic bone graft may be a suitable alternative in fixation of unstable tibia plateau fractures, avoiding risk of disease transmission with allograft and donor site morbidity associated with autograft. PMID- 22228266 TI - Incidence of early symptomatic port-site hernia: a case series from a department where laparoscopy is the preferred surgical approach. AB - INTRODUCTION: Potential benefits of laparoscopic surgery include decreased post operative pain, improved cosmesis and a shorter hospital stay. However as the volume and complexity of laparoscopic procedures increase, there appears to be a simultaneous increase in complications relating to laparoscopic access. Development of a port-site hernia is one such complication. AIMS: The aim of this study was to evaluate our experience relating to the incidence, presentation and interventions for early, symptomatic port-site hernias following laparoscopic surgery in a unit where minimal access surgery is the preferred approach. MATERIALS AND METHODS: A retrospective review of the medical records of all patients who underwent laparoscopic procedures performed by the colorectal service over a 3-year period was conducted. Patients who developed port-site hernias were identified. Additional information on patient demographics, patient co-morbidities, the length and nature of the laparoscopic procedure, the presenting symptoms, the timing of these symptoms as well as the relative investigations and interventions were recorded. All trocars used in this series were bladed. RESULTS: A total of 647 patients underwent laparoscopic procedures over a 3-year period. Eight (1.23%) hernias were identified as occurring at the trocar entry site. All were symptomatic and all required surgical intervention. CONCLUSIONS: Development of a port-site hernia in the early post-operative period can be associated with significant morbidity. This complication should be considered in patients presenting with post-operative bowel obstruction. With meticulous closure of port sites 10 mm and bigger, the incidence of hernia may be reduced. PMID- 22228267 TI - Copper-catalyzed domino intramolecular cyclization: a facile and efficient approach to polycyclic indole derivatives. AB - A mild and efficient Cu(2)O-catalyzed domino intramolecular C-N coupling/C-Y (Y = O, S, N) bond formation was successfully achieved. Thus oxazino[3,2-a]indole, thiazino[3,2-a]indole and indolo[2,1-b]quinazoline derivatives were facilely assembled from readily accessible gem-dibromovinyl systems. The protocol is general and practical, affording a variety of the indole-incorporated products in good to excellent yields even under air atmosphere. PMID- 22228268 TI - Clinically definite ALS presenting weeks after mild electric injury: causality or coincidence? AB - Motor neuron syndromes including typical ALS develop very rarely after electrotrauma, with possible causality discussed but not confirmed. We report on a 44-year-old male who developed clinically definite ALS by the revised El Escorial criteria with onset weeks after mild electric injury. He presented with asymmetric upper limb amyotrophy and weakness beginning around the entry point of the current. Over 1 year he developed generalized wasting, weakness and fasciculations, including the bulbar and thoracic muscles, with prominent spasticity and pyramidal tract signs. Electrodiagnostic studies confirmed widespread denervation, very unstable neurogenic motor units in the bulbar, cervical, thoracic and lumbosacral segments with normal motor velocities and normal sensory parameters. This is a well-documented case of fast-progressive ALS that seems related to electric injury. PMID- 22228269 TI - Exercise and amyotrophic lateral sclerosis. AB - Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease in which much burden is geared towards end-of-life care. Particularly in the earlier stages of ALS, many people have found both physiological and psychological boosts from various types of physical exercise for disused muscles. Proper exercise is important for preventing atrophy of muscles from disuse-a key for remaining mobile for as long as possible-and as long as it is possible to exercise comfortably and safely, for preserving cardiovascular fitness. However, the typical neuromuscular patient features a great physical inactivity and disuse weakness, and for that reason many controversial authors have contested exercise in these patients during years, especially in ALS which is rapidly progressive. There is an urgent need for dissecting in detail the real risks or benefits of exercise in controlled clinical trials to demystify this ancient paradigm. Yet, recent research studies document significant benefits in terms of survival and quality of life in ALS, poor cooperation, small sample size, uncontrolled and short-duration trials, remain the main handicaps. Sedentary barriers such as early fatigue and inherent muscle misuse should be overcome, for instance with body-weight supporting systems or non-invasive ventilation, and exercise should be faced as a potential non-monotonous way for contributing to better health related quality of life. PMID- 22228272 TI - Primary cutaneous adenoid cystic carcinoma of the upper lid: a case report and literature review. AB - To report on the diagnostic challenge of an adenoid cystic carcinoma arising from the eyelid. A 77-year-old male was referred to our center with a clinical diagnosis of upper eyelid chalazion for a lesion that had appeared 2 years before. A loss of cilia was observed over the cutaneous area of induration, but there was no reddening or ulceration. Incisional biopsy was performed and the specimen was submitted in formalin for histopathological examination. On light microscopy, the lesion was composed of basaloid epithelial and myoepithelial cells that were arranged in strands or nests and associated with cystic spaces that contained a deeply eosinophilic secretory substance and an Alcian blue positive material, characteristic of adenoid cystic carcinoma. After histological diagnosis, tumor re-excision was performed to ensure adequacy of resection margins, as well as a sentinel lymph node procedure, resulting in complete excision of the malignant tumor. No recurrence was observed during the first 18 months after surgery. Adenoid cystic carcinoma is a rare and aggressive epithelial malignancy, which tends to grow slowly and should be considered in the differential diagnosis of eyelid tumors simulating chalazion. PMID- 22228273 TI - Distribution and accumulation of metals in the surface sediments of Coleroon river estuary, East coast of India. AB - This study deals with the geochemical nature of distribution of metals (iron, manganese, lead and zinc) in bulk sediments and its association with sand, silt, clay and organic carbon. Ten numbers of surface sediment samples were collected during summer season of 2009 from Coleroon estuary. The sediments are mostly sandy silt in nature. The organic carbon distribution indicates that they are brought in the surroundings of coastal areas. Correlation analysis clearly indicates that fine particles and organic carbon control the distribution of metals. The most evident the significant correlations where zinc vs manganese (r = 0.641), manganese versus iron (r = 0.618), lead versus manganese (r = 0.574). The correlation between organic carbon versus manganese (r = 0.768), organic carbon versus sand (r = 0.872), organic carbon versus silt (r = 0.902), organic carbon versus clay (r = 0.793). The degree of correlation between metals and other major constituents is often used to indicate the origin of the metals. Strong positive correlation coefficient of all the above said metals and organic carbon are mainly associated with the fine grained sediments. PMID- 22228274 TI - Potential toxicity of polycyclic aromatic hydrocarbons and organochlorine pesticides in sediments from the Ebro River basin in Spain. AB - This study was carried out to estimate the potential toxicity of 8 Polycyclic Aromatic Hydrocarbons (PAHs) and 5 organochlorine pesticides (OCPs) in sediments in the Ebro River Basin (20 sampling points) according to different methodologies. Detection limit (DL) concentrations were used for compounds reported below the DL (worst-case scenario). The majority of PAH concentrations were found to be below their method detection limit. DL concentrations for OCPs were above the threshold values set by one guideline. In such cases, no toxicity assessment was carried out. It should be noted that no sediment is expected to cause adverse effects on the benthic species living in these sediments according to the methodologies applied. PMID- 22228275 TI - Modeling of droplet traffic in interconnected microfluidic ladder devices. AB - The problem of controlling the droplet motion in multiphase flows on the microscale has gained increasing attention because the droplet-based microfluidic devices provide great potentials for chemical and biological applications. It is critical to understand the relevant physics on droplet hydrodynamics and thus control the generation, motion, splitting, and coalescence of droplets in complex microfluidic networks. Numerical simulations using the volume of fluid algorithm are conducted to investigate the time-dependent dynamics of droplets in gas liquid multiphase devices. An analytical model based on the electronic-hydraulic analogy is developed to describe the hydrodynamic behavior of the droplets in interconnected microfluidic ladder devices. It is found that the pressure drop caused by the droplets plays a critical role in the droplet synchronization. A fitted formula for pressure drops in the presence of surfactant is achieved by using numerical simulations. Both the numerical and the theoretical results agree well with the corresponding experimental results. PMID- 22228276 TI - The value of cyclooxygenase-2 expression in differentiating between early melanomas and histopathologically difficult types of benign human skin lesions. AB - Early cutaneous melanomas may present a substantial diagnostic challenge. We have already reported that expression of cyclooxygenase-2 (COX-2) may be useful for differentiating between cutaneous melanomas and naevi. The purpose of this study was to examine the value of COX-2 in a challenging task of differential diagnosis of early melanomas and melanocytic naevi considered by histopathologists as morphologically difficult to unequivocally diagnose as benign lesions. The material for the study comprised formalin-fixed paraffin-embedded samples of 46 naevi (including 27 cases of dysplastic, Spitz and Reed naevi) and 30 early human cutaneous melanomas. The expression of COX-2 was detected immunohistochemically. Melanomas expressed COX-2 significantly more strongly compared with naevi. The test, on the basis of determination of the percentage fractions of COX-2-positive cells, allows for differentiation of early skin melanomas and naevi with high sensitivity and specificity. Receiver operating characteristic analysis of the test results yielded areas under receiver operating characteristics curves (AUC)=0.946+/-0.030 for central regions and AUC=0.941+/-0.031 for the peripheries of the lesions. The performance of the test in differentiating between melanomas and the naevi group comprising dysplastic, Spitz and Reed naevi was also good, with AUC=0.933+/-0.034 and 0.923+/-0.037 for the central and the border regions of the lesions, respectively. Using a more complex diagnostic algorithm also accounting for the staining intensity did not result in an improvement in the resolving power of the assay. A diagnostic algorithm using differences in the percentage fractions of cells expressing COX-2 may serve as a useful tool in aiding the differential diagnosis of 'histopathologically difficult' benign melanocytic skin lesions and early melanomas. PMID- 22228277 TI - Increased stromal cell-derived factor-1 concentration levels in aqueous from patients with uveal melanoma. PMID- 22228278 TI - Extracorporeal shock wave therapy in early osteonecrosis of the femoral head: prospective clinical study with long-term follow-up. AB - INTRODUCTION: Extracorporeal shock wave therapy (ESWT) may exert beneficial effects in avascular necrosis of femoral head (AVNFH). PATIENTS: The current study evaluated the effectiveness of ESWT in reducing pain and in slowing down the progression of bone damage in 36 patients with unilateral AVNFH of stage Association Research Circulation Osseous (ARCO) I, II and III. At the beginning of the study, 10 hips were classified as stage I, 11 as stage II and 15 as stage III. Each treatment cycle included four sessions, with 2,400 impulses each administered at 0.50 mJ/mm(2), at 48-72 h intervals. Follow-up examinations were scheduled at 3, 6, 12 and then 24 months. METHOD: Clinical assessments included assessment of pain scores, Harris Hip Scores and Roles and Maudsley score. Plain radiographs and magnetic resonances of the hip were used to evaluate the size of the lesion, the extent of collapse of subchondral bone, and degenerative changes of the hip joint. RESULTS: Patients from ARCO stage I group and stage II group achieved significantly better results than patients from ARCO stage III group at all follow-up time points (p < 0.005). During the follow-up period, 10 of the 15 stage III ARCO patients received an arthroplasty. ARCO stages I and II lesions were unchanged on radiographs and on magnetic resonance images. CONCLUSION: ESWT in ARCO stages I and II may help to prevent progression of the area of avascular necrosis and manage pain. PMID- 22228279 TI - Diagnosis of discogenic low back pain in patients with probable symptoms but negative discography. AB - OBJECTIVE: The purpose of the current study was to determine, whenever the patients complained of probable symptoms of discogenic low back pain and had obvious disc pathological changes on magnetic resonance imaging (MRI) but showed negative in discography, whether we could absolutely exclude the diagnosis of discogenic pain or not. METHODS: The patients we selected in our study had only one segmental disc pathology on MRI for the purpose of minimizing the interference and all patients complained of probable discogenic pain symptoms. Some special lumbar diseases were excluded by physical examination and CT or MRI scan. Finally, 45 isolated patients with negative discography were enrolled in our study from January 2006 to June 2008. Twenty-three patients were randomly distributed in experimental group, who underwent provocative discography plus intradiscal injection of dexamethasone (5 mg in each patient), while the other 22 patients in the control group received intradiscal injection of saline as a placebo. Visual analog scale (VAS) and Oswestry Disability Index (ODI) were used to evaluate the changes of pain and function after discography. RESULTS: The mean age of the 16 male and 29 female patients was 44.9 years, whose main clinical manifestations included axial back pain (100%), pain in the region of Groin (33.3%), pain in the anterior or posterior region of thigh (42.2%), buttock pain (24.4%) and lower extremity pain (11.1%), and among them L3-L4 pathological disc was found in three patient, L4-L5 pathological disc in 28 patients and L5-S1 pathological disc in 14 patients. Discography and CT scans of the 45 patients revealed that there were grade 5 in 38 discs and grade 4 in seven discs by means of Modified Dallas classification. After about 6-month follow-up, the results showed that VAS scores and ODI scores were greatly improved during the first 3 month follow-up in the experimental group compared with pre-discography and between groups (p < 0.05), but no statistically significant difference after 24 week follow-up (p > 0.05). The probable symptoms of discogenic low back pain were significantly improved in the experimental group in the short term. CONCLUSION: The study indicated that negative discography in patients with probable symptoms of discogenic low back pain cannot absolutely exclude the diagnosis of discogenic pain. Patients of this kind may suffer from other diseases, but we cannot ignore the existence of discogenic pain. PMID- 22228280 TI - Trochanteric osteotomy in primary and revision total hip arthroplasty: risk factors for non-union. AB - BACKGROUND: Trochanteric osteotomies (TO) facilitate exposure and "true hip reconstruction" in complex primary and revision total hip arthroplasty (THA). However, non-union represents a clinically relevant complication. The purpose of the present study was to identify risk factors for trochanteric non-union. METHODS: All cases of THA approached by TO during the past 10 years were analyzed with respect to potential risk factors for non-union. RESULTS: In 298 cases complete data were available for analysis. Trochanteric union occurred in 80.5%, fibrous union in 5.4% and non-union 14.1%. Risk factor analysis revealed a four times higher risk for non-union in anterior trochanteric slide osteotomies compared to extended trochanteric osteotomies and a three times higher risk in cemented versus non-cemented stems. Multiple logistic regression analysis revealed patient's age and use of cement to be independent risk factors for non union. CONCLUSIONS: Femoral cementation and increasing age negatively influence the union of trochanteric osteotomies. PMID- 22228281 TI - Low-cost and ready-to-go remote-facilitated simulation-based learning. AB - INTRODUCTION: Remote-facilitated simulation-based learning was developed for team training with low-cost, preexisting, and easy-access resources to disseminate training with limited number of the faculty. This study was performed to examine the technical feasibility and to describe its characteristics compared with an on site simulation system. METHOD: We performed 2 pilot remote-facilitated sessions, followed by 3 additional sessions where 16 participants and 2 facilitators assessed the system using posttraining surveys containing items using 5-point Likert scale. All sessions consisted of briefing, simulation scenarios, and debriefing. RESULTS: Eighty-seven percent of the participants rated the remote system at least as effective as the on-site system. All the participants rated the sound quality of the system at least as good as the on-site one and indicated that they could understand what the facilitator said at least as well as the on site one. Fourteen of 16 participants would like to receive simulation training through remote facilitation. Facilitators reported that the operability of the remote system was the same as the on-site simulation system. CONCLUSIONS: Remote facilitated simulation-based learning is technically feasible with low-cost, preexisting, and easy-access resources. Learners rated this system as equally effective as the on-site system and facilitators indicated that the operability was adequate. PMID- 22228282 TI - Emergency department patient flow simulations using spreadsheets. AB - INTRODUCTION: Patient flow computer simulations allow Emergency Department stakeholders to assess operational interventions, develop utilization and performance measures, and produce estimates for budgeting or planning purposes. Key challenges of traditional discrete-event computer simulation software are their inherent complexity for modeling, coding, or analyzing output and their significant costs and training. We propose a simulation platform that runs in spreadsheets. Because of their low cost, popularity and powerful functionality and performance, spreadsheets also allow for the development and management of simulations that efficiently output results that are just as reliable as those from traditional software. METHODS: A spreadsheet simulation is developed by modeling one row as one simulated minute (more than 20,000 rows for a 2-week period). Uncertainty in arrivals, patient type, routing, and treatment times is modeled using the "rand()" function to simulate the state of the Emergency Department at a given point in time. The patient is tracked with embedded "if()" functions and summary statistics are obtained through range functions. We use an equivalence test to determine whether the resulting average length-of-stay figures are the same as those of a traditional simulation platform. RESULTS: We find little significant difference in average length-of-stay figures between both models. CONCLUSIONS: Spreadsheet simulations are as effective as traditional simulations but easier to use, understand, and implement. Spreadsheet software is widely available, at a fraction of the cost of discrete-event simulation software. Coding spreadsheet simulations may be more challenging as it requires a different and more novel expertise than traditional computer programming. However, spreadsheets can be organized to reference existing datasets, thus minimizing the burden of copying and likelihood of transcription errors and information leakage. Output analysis can also be customized with user-specific performance statistics and charts. PMID- 22228283 TI - Misassembled bellows housing leading to failure of mechanical ventilation during general anesthesia. PMID- 22228284 TI - Decay in blood loss estimation skills after web-based didactic training. AB - INTRODUCTION: Accuracy in blood loss estimation has been shown to improve immediately after didactic training. The objective of this study was to evaluate retention of blood loss estimation skills 9 months after a didactic web-based training. METHODS: Forty-four participants were recruited from a cohort that had undergone web-based training and testing in blood loss estimation. The web-based posttraining test, consisting of pictures of simulated blood loss, was repeated 9 months after the initial training and testing. The primary outcome was the difference in accuracy of estimated blood loss (percent error) at 9 months compared with immediately posttraining. RESULTS: At the 9-month follow-up, the median error in estimation worsened to -34.6%. Although better than the pretraining error of -47.8% (P = 0.003), the 9-month error was significantly less accurate than the immediate posttraining error of -13.5% (P = 0.01). CONCLUSION: Decay in blood loss estimation skills occurs by 9 months after didactic training. PMID- 22228285 TI - Can a virtual patient trainer teach student nurses how to save lives--teaching nursing students about pediatric respiratory diseases. AB - INTRODUCTION: Virtual environments offer a variety of benefits and may be a powerful medium with which to provide nursing education. The objective of this study was to compare the achievement of learning outcomes of undergraduate nursing students when a virtual patient trainer or a traditional lecture was used to teach pediatric respiratory content. METHODS: This was a randomized, controlled, posttest design. A virtual pediatric hospital unit was populated with four virtual pediatric patients having different respiratory diseases that were designed to meet the same learning objectives as a traditional lecture. The study began in Spring 2010 with 93 Senior I, baccalaureate nursing students. Students were randomized to receive either a traditional lecture or an experience with a virtual patient trainer. Students' knowledge acquisition was evaluated using multiple-choice questions, and knowledge application was measured as timeliness of care in two simulated clinical scenarios using high-fidelity mannequins and standardized patients. RESULTS: Ninety-three students participated in the study, of which 46 were in the experimental group that received content using the virtual patient trainer. After the intervention, students in the experimental group had significantly higher knowledge acquisition (P = 0.004) and better knowledge application (P = 0.001) for each of the two scenarios than students in the control group. CONCLUSIONS: The purpose of this project was to compare a virtual patient trainer to a traditional lecture for the achievement of learning outcomes for pediatric respiratory content. Although the virtual patient trainer experience produced statistically better outcomes, the differences may not be clinically significant. The results suggest that a virtual patient trainer may be an effective substitute for the achievement of learning outcomes that are typically met using a traditional lecture format. Further research is needed to understand how best to integrate a virtual patient trainer into undergraduate nursing education. PMID- 22228286 TI - Iatrogenic tracheal rupture: bovine pericardial patch repair without flap reinforcement. AB - We describe a case of an extensive post-intubation membranous tracheal rupture in a 67-year old patient after emergency intubation. This was managed surgically by bovine pericardial patch repair. Other cases of autologous and bovine patch repair of tracheal lacerations exist in the literature, and we believe this is the first report of successful bovine patch repair without accessory autologous tissue reinforcement. This technique may be used in surgically managed cases of membranous tracheal rupture where primary repair is unsuitable, thereby reducing procedural complexity. PMID- 22228287 TI - Minimally invasive thoracoscopic hybrid treatment of lone atrial fibrillation: early results of monopolar versus bipolar radiofrequency source. AB - We compare results of a hybrid monopolar vs. a hybrid bipolar thoracoscopic approach employing radiofrequency (RF) sources for the surgical treatment of lone atrial fibrillation (LAF). From January 2008 to June 2010, 19 patients (35.1%) underwent RF monopolar/monolateral RF ablation, whereas 35 (64.9%) had RF bipolar/bilateral thoracoscopic ablation. One-year time-related prevalence of postoperative AF was 13.3 (11.0-17.4) and 5.2% (4.2-6.7), in monopolar and bipolar groups, respectively (P < 0.001). It was 21.1 (17.6-24.9) vs. 8.2% (5.1 11.6) in long standing persistent (P < 0.001), 13.2 (10.6-17.8) vs. 3.8% (1.4 6.9) in persistent (P < 0.001) and 5.6 (2.8-8.3) vs. 3.2% (1.0-6.5) in paroxysmal AF (P = 0.64). At 12 months, estimated prevalence of anti-arrhythmic drugs was 26 (22.4-30.1) and 18.0% (15.5-21.7, P = 0.04), whereas prevalence of warfarin use was 48.2 (44.2-52.2) and 29.0% (26.2-33.1, P < 0.001) in the monopolar and bipolar groups, respectively. Left atrial (LA) reverse remodelling occurred in 47.3% of monopolar patients (n = 9) and in 77.1% of bipolar patients (P = 0.03). The hybrid bilateral approach with a bipolar device for the treatment of LAF showed a good 1-year success rate independently of the AF type and seems to be the better choice for longstanding persistent and persistent LAF. PMID- 22228288 TI - Is a fully heparin-bonded cardiopulmonary bypass circuit superior to a standard cardiopulmonary bypass circuit? AB - A best-evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'Is a fully heparin bonded cardiopulmonary bypass circuit superior to a standard cardiopulmonary bypass circuit?' Altogether more than 792 papers were found using the reported search, of which 13 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated (Table 1). The studies analysed show that perfusion with heparin-coated and heparin-polymer coated bypass does not increase the risk of adverse effects but reduces blood loss, re-operation rates, ventilation time, length of intensive care unit (ICU) and hospital stay and is also associated with improved biocompatibility, as evidenced by platelet preservation, reduced leucocyte and complement activation, and proinflammatory cytokine production. The various coated circuits have comparable biocompatibility as evaluated by a range of inflammatory markers and clinical outcomes. Three studies documented a significant decrease in post operative blood loss (P = 0.001-0.54) and a meta-analysis found that perfusion with a heparin-bonded circuit resulted in a reduction in blood transfusion requirements (20%), ventilation time (P < 0.01), length of time in the ICU (P < 0.01) and also hospital stay (P = 0.02). Two studies found reduced levels of polymorphonuclear elastase (P < 0.018-0.001) and two trials concluded that the use of heparin-coated circuits in combination with low-dose systemic heparin (activated clotting time >250) resulted in the greatest clinical benefit and improvement in inflammation. One study documented significant platelet preservation with the use of third-generation heparin-polymer-bonded circuits (P <= 0.05). We conclude that despite heparin-bonded and newer third-generation heparin-polymer-bonded cardiopulmonary bypass circuits having a greater cost per person, their improved clinical outcomes and biocompatibility in patients undergoing cardiac surgery make them a preferable option to standard non-heparin bonded circuits. PMID- 22228289 TI - A 15-cm aneurysm of the right coronary artery presenting as a pericardial cyst. AB - We report an unusual case of a giant right coronary artery aneurysm, measuring 15 cm in diameter, in a 76-year old woman. The aneurysm was initially identified when the patient was investigated for signs of congestive cardiac failure with a computed tomography scan of her thorax; at this stage, the lesion was misdiagnosed as a large pericardial cyst. The aneurysm was successfully excised at surgery and her heavily diseased right coronary artery was secured with a saphenous vein graft. PMID- 22228291 TI - Identifying risk factors for hamstring and groin injuries in sport: a daunting task. PMID- 22228292 TI - Does generalized joint hypermobility predict joint injury in sport? A review. PMID- 22228293 TI - New paradigms for managing preoperative anemia. PMID- 22228294 TI - Cannulation of a persistent left superior vena cava or a pericardiophrenic vein? PMID- 22228295 TI - Low-Temperature, solution-processed and alkali metal doped ZnO for high performance thin-film transistors. PMID- 22228296 TI - Equisetum arvense (Field Horsetail)-induced liver injury. PMID- 22228298 TI - Enhanced propionic acid production from Jerusalem artichoke hydrolysate by immobilized Propionibacterium acidipropionici in a fibrous-bed bioreactor. AB - Propionic acid is an important chemical that is widely used in the food and chemical industries. To enhance propionic acid production, a fibrous-bed bioreactor (FBB) was constructed and Jerusalem artichoke hydrolysate was used as a low-cost renewable feedstock for immobilized fermentation. Comparison of the kinetics of immobilized-cell fermentation using the FBB with those of fed-batch free-cell fermentation showed that immobilized-cell fermentation gave a much higher propionic acid concentration (68.5 vs. 40.6 g/L), propionic acid yield (0.434 vs. 0.379 g/g) and propionic acid productivity (1.55 vs. 0.190 g/L/h) at pH 6.5. Furthermore, repeated batch fermentation, carried out to evaluate the stability of the FBB system, showed that long-term operation with a high average propionic acid yield of 0.483 g/g, high productivity of 3.69 g/L/h and propionic acid concentration of 26.2 g/L were achieved in all eight repeated batches during fermentation for more than 200 h. It is thus concluded that the FBB culture system can be utilized to realize the economical production of propionic acid from Jerusalem artichoke hydrolysate during long-term operation. PMID- 22228299 TI - Effect of mixing time, freeze-drying and baking on phenolics, anthocyanins and antioxidant capacity of raspberry juice during processing of muffins. AB - BACKGROUND: Consumption of baked products constitutes an important part of a daily breakfast considering that people are continually grabbing meals on the go. Among baked products, muffins rank third in breakfast products and attract a broad range of consumers. Incorporation of red raspberry juice into muffins can add value to the product while preserving health benefits to the consumer. The purpose of this study was to evaluate the effect of mixing time, freeze-drying and baking on the phenolic and anthocyanin contents and antioxidant capacity of raspberry juice during the preparation of muffins. RESULTS: Freeze-drying of raspberry batters reduced their phenolic content and antioxidant capacity regardless of mixing time. Non-freeze-dried raspberry batter mixed for 5 min had the highest phenolic content (0.88 mg gallic acid equivalent g(-1) dry matter (DM)). Non-freeze-dried raspberry muffins had the highest antioxidant capacity (0.041 umol Trolox equivalent g(-1) DM). Freeze-dried raspberry batters mixed for 5 and 10 min had the highest anthocyanin content (0.065 mg cyanidin-3-glucoside g(-1) DM). Baking reduced the anthocyanin content of both non-freeze-dried and freeze-dried raspberry muffins. CONCLUSION: Despite the reduction in valuable compounds, muffin is a vehicle for the delivery of these compounds. PMID- 22228300 TI - Growth of Acinetobacter gerneri P7 on polyurethane and the purification and characterization of a polyurethanase enzyme. AB - A soil microorganism, designated as P7, was characterized and investigated for its ability to degrade polyurethane (PU). This bacterial isolate was identified as Acinetobacter gerneri on the basis of 16 s rRNA sequencing and biochemical phenotype analysis. The ability of this organism to degrade polyurethane was characterized by the measurement of growth, SEM observation, measurement of electrophoretic mobility and the purification and characterization of a polyurethane degrading enzyme. The purified protein has a molecular weight of approximately 66 kDa as determined by SDS-PAGE. Substrate specificity was examined using p-nitrophenyl substrates with varying carbon lengths. The highest substrate specificity was observed using p-nitrophenyl-propanate with an activity of 37.58 +/- 0.21 U mg(-1). Additionally, the enzyme is inhibited by phenylmethylsulfonylfluoride and by ethylenediamine-tetra acetic acid. When grown on Impranil DLN(TM) YES medium, a lag phase was noted for the first 3 h which was followed by logarithmic growth for 5 h. For the linear portion of growth between 5 and 9 h, a MU value of 0.413 doublings h(-1) was calculated. After 9 h of incubation the cell number dramatically decreased resulting in a chalky precipitate. Measurements of electrophoretic mobility indicated the formation of a complex between the PU and A. gerneri P7 cells. A hybrid zeta potential had been generated between the cells and polyurethane. Further evidence for a complex was provided by SEM observation where cells appeared to cluster along the surface of polyurethane particles and along edges of polyurethane films. Occasionally, the cells established an anchor-like structure that connected the cells to polyurethane particles. PMID- 22228301 TI - Extensive chromosomal variation in a recently formed natural allopolyploid species, Tragopogon miscellus (Asteraceae). AB - Polyploidy, or whole genome duplication, has played a major role in the evolution of many eukaryotic lineages. Although the prevalence of polyploidy in plants is well documented, the molecular and cytological consequences are understood largely from newly formed polyploids (neopolyploids) that have been grown experimentally. Classical cytological and molecular cytogenetic studies both have shown that experimental neoallopolyploids often have meiotic irregularities, producing chromosomally variable gametes and progeny; however, little is known about the extent or duration of chromosomal variation in natural neoallopolyploid populations. We report the results of a molecular cytogenetic study on natural populations of a neoallopolyploid, Tragopogon miscellus, which formed multiple times in the past 80 y. Using genomic and fluorescence in situ hybridization, we uncovered massive and repeated patterns of chromosomal variation in all populations. No population was fixed for a particular karyotype; 76% of the individuals showed intergenomic translocations, and 69% were aneuploid for one or more chromosomes. Importantly, 85% of plants exhibiting aneuploidy still had the expected chromosome number, mostly through reciprocal monosomy-trisomy of homeologous chromosomes (1:3 copies) or nullisomy-tetrasomy (0:4 copies). The extensive chromosomal variation still present after ca. 40 generations in this biennial species suggests that substantial and prolonged chromosomal instability might be common in natural populations after whole genome duplication. A protracted period of genome instability in neoallopolyploids may increase opportunities for alterations to genome structure, losses of coding and noncoding DNA, and changes in gene expression. PMID- 22228302 TI - Drosophila RNA polymerase III repressor Maf1 controls body size and developmental timing by modulating tRNAiMet synthesis and systemic insulin signaling. AB - The target-of-rapamycin pathway couples nutrient availability with tissue and organismal growth in metazoans. The key effectors underlying this growth are, however, unclear. Here we show that Maf1, a repressor of RNA polymerase III dependent tRNA transcription, is an important mediator of nutrient-dependent growth in Drosophila. We find nutrients promote tRNA synthesis during larval development by inhibiting Maf1. Genetic inhibition of Maf1 accelerates development and increases body size. These phenotypes are due to a non-cell autonomous effect of Maf1 inhibition in the fat body, the main larval endocrine organ. Inhibiting Maf1 in the fat body increases growth by promoting the expression of brain-derived insulin-like peptides and consequently enhanced systemic insulin signaling. Remarkably, the effects of Maf1 inhibition are reproduced in flies carrying one extra copy of the initiator methionine tRNA, tRNA(i)(Met). These findings suggest the stimulation of tRNA(i)(Met) synthesis via inhibition of dMaf1 is limiting for nutrition-dependent growth during development. PMID- 22228304 TI - Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism. AB - Glutamine is an essential nutrient for cancer cell proliferation, especially in the context of citric acid cycle anaplerosis. In this manuscript we present results that collectively demonstrate that, of the three major mammalian glutaminases identified to date, the lesser studied splice variant of the gene gls, known as Glutaminase C (GAC), is important for tumor metabolism. We show that, although levels of both the kidney-type isoforms are elevated in tumor vs. normal tissues, GAC is distinctly mitochondrial. GAC is also most responsive to the activator inorganic phosphate, the content of which is supposedly higher in mitochondria subject to hypoxia. Analysis of X-ray crystal structures of GAC in different bound states suggests a mechanism that introduces the tetramerization induced lifting of a "gating loop" as essential for the phosphate-dependent activation process. Surprisingly, phosphate binds inside the catalytic pocket rather than at the oligomerization interface. Phosphate also mediates substrate entry by competing with glutamate. A greater tendency to oligomerize differentiates GAC from its alternatively spliced isoform and the cycling of phosphate in and out of the active site distinguishes it from the liver-type isozyme, which is known to be less dependent on this ion. PMID- 22228303 TI - p63-microRNA feedback in keratinocyte senescence. AB - We investigated the expression of microRNAs (miRNAs) associated with replicative senescence in human primary keratinocytes. A cohort of miRNAs up-regulated in senescence was identified by genome-wide miRNA profiling, and their change in expression was validated in proliferative versus senescent cells. Among these, miRNA (miR)-138, -181a, -181b, and -130b expression increased with serial passages. miR-138, -181a, and -181b, but not miR-130b, overexpression in proliferating cells was sufficient per se to induce senescence, as evaluated by inhibition of BrdU incorporation and quantification of senescence-activated beta galactosidase staining. We identified Sirt1 as a direct target of miR-138, -181a, and -181b, whereas DeltaNp63 expression was inhibited by miR-130b. We also found that DeltaNp63alpha inhibits miR-138, -181a, -181b, and -130b expression by binding directly to p63-responsive elements located in close proximity to the genomic loci of these miRNAs in primary keratinocytes. These findings suggest that changes in miRNA expression, by modulating the levels of regulatory proteins such as p63 and Sirt1, strongly contribute to induction of senescence in primary human keratinocytes, thus linking these two proteins. Our data also indicate that suppression of miR-138, -181a, -181b, and -130b expression is part of a growth promoting strategy of DeltaNp63alpha in epidermal proliferating cells. PMID- 22228305 TI - Full-length myosin Va exhibits altered gating during processive movement on actin. AB - Myosin Va (myoV) is a processive molecular motor that transports intracellular cargo along actin tracks with each head taking multiple 72-nm hand-over-hand steps. This stepping behavior was observed with a constitutively active, truncated myoV, in which the autoinhibitory interactions between the globular tail and motor domains (i.e., heads) that regulate the full-length molecule no longer exist. Without cargo at near physiologic ionic strength (100 mM KCl), full length myoV adopts a folded (approximately 15 S), enzymatically-inhibited state that unfolds to an extended (approximately 11 S), active conformation at higher salt (250 mM). Under conditions favoring the folded, inhibited state, we show that Quantum-dot-labeled myoV exhibits two types of interaction with actin in the presence of MgATP. Most motors bind to actin and remain stationary, but surprisingly, approximately 20% are processive. The moving motors transition between a strictly gated and hand-over-hand stepping pattern typical of a constitutively active motor, and a new mode with a highly variable stepping pattern suggestive of altered gating. Each head of this partially inhibited motor takes longer-lived, short forward (35 nm) and backward (28 nm) steps, presumably due to globular tail-head interactions that modify the gating of the individual heads. This unique mechanical state may be an intermediate in the pathway between the inhibited and active states of the motor. PMID- 22228306 TI - Collective and single cell behavior in epithelial contact inhibition. AB - Control of cell proliferation is a fundamental aspect of tissue physiology central to morphogenesis, wound healing, and cancer. Although many of the molecular genetic factors are now known, the system level regulation of growth is still poorly understood. A simple form of inhibition of cell proliferation is encountered in vitro in normally differentiating epithelial cell cultures and is known as "contact inhibition." The study presented here provides a quantitative characterization of contact inhibition dynamics on tissue-wide and single cell levels. Using long-term tracking of cultured Madin-Darby canine kidney cells we demonstrate that inhibition of cell division in a confluent monolayer follows inhibition of cell motility and sets in when mechanical constraint on local expansion causes divisions to reduce cell area. We quantify cell motility and cell cycle statistics in the low density confluent regime and their change across the transition to epithelial morphology which occurs with increasing cell density. We then study the dynamics of cell area distribution arising through reductive division, determine the average mitotic rate as a function of cell size, and demonstrate that complete arrest of mitosis occurs when cell area falls below a critical value. We also present a simple computational model of growth mechanics which captures all aspects of the observed behavior. Our measurements and analysis show that contact inhibition is a consequence of mechanical interaction and constraint rather than interfacial contact alone, and define quantitative phenotypes that can guide future studies of molecular mechanisms underlying contact inhibition. PMID- 22228307 TI - Uncovering the hidden geometry behind metabolic networks. AB - Metabolism is a fascinating cell machinery underlying life and disease and genome scale reconstructions provide us with a captivating view of its complexity. However, deciphering the relationship between metabolic structure and function remains a major challenge. In particular, turning observed structural regularities into organizing principles underlying systemic functions is a crucial task that can be significantly addressed after endowing complex network representations of metabolism with the notion of geometric distance. Here, we design a cartographic map of metabolic networks by embedding them into a simple geometry that provides a natural explanation for their observed network topology and that codifies node proximity as a measure of hidden structural similarities. We assume a simple and general connectivity law that gives more probability of interaction to metabolite/reaction pairs which are closer in the hidden space. Remarkably, we find an astonishing congruency between the architecture of E. coli and human cell metabolisms and the underlying geometry. In addition, the formalism unveils a backbone-like structure of connected biochemical pathways on the basis of a quantitative cross-talk. Pathways thus acquire a new perspective which challenges their classical view as self-contained functional units. PMID- 22228308 TI - Safety of plasma-derived protein C for treating disseminated intravascular coagulation in adult patients with active cancer. AB - Cancer-related disseminated intravascular coagulation (DIC) is a life-threatening condition for which no effective treatment is currently available. Protein C (PC), a modulator of coagulation as well as the inflammatory system, has been successfully tested (in its activated recombinant form [a-rPC]) in sepsis-related coagulopathy, but with an increased risk for major bleeding. Plasma-derived PC (pd-PC) is more suitable than a-rPC in patients at high risk from bleeding due to its self-limiting process. We carried out a single-arm study evaluating the role of pd-PC in adult cancer patients with overt DIC. Over a period of 3 years, we treated 19 patients with overt DIC and a PC plasma concentration <50%; all received PC concentrate (Ceprotin((r)), Baxter) for 72 hr in adjusted doses to restore normal PC values (70-120%). Blood coagulation, haematological tests, and the DIC score were recorded after 12, 24, 48 hr, 7 and 10 days, while clinical outcomes (bleeding, thrombosis and mortality) were recorded up to 28 days. Within 48 hr of starting pd-PC therapy, laboratory tests as well as the DIC score improved in all patients. At 28-days follow-up, no bleeding or thrombosis was observed. This is the first study to investigate the use of pd- PC for treatment of cancer-related overt DIC. PMID- 22228309 TI - Electroanalytical sensing of chromium(III) and (VI) utilising gold screen printed macro electrodes. AB - We report the fabrication of gold screen printed macro electrodes which are electrochemically characterised and contrasted to polycrystalline gold macroelectrodes with their potential analytical application towards the sensing of chromium(III) and (VI) critically explored. It is found that while these gold screen printed macro electrodes have electrode kinetics typically one order of magnitude lower than polycrystalline gold macroelectrodes as is measured via a standard redox probe, in terms of analytical sensing, these gold screen printed macro electrodes mimic polycrystalline gold in terms of their analytical performance towards the sensing of chromium(III) and (VI), whilst boasting additional advantages over the macro electrode due to their disposable one-shot nature and the ease of mass production. An additional advantage of these gold screen printed macro electrodes compared to polycrystalline gold is the alleviation of the requirement to potential cycle the latter to form the required gold oxide which aids in the simplification of the analytical protocol. We demonstrate that gold screen printed macro electrodes allow the low micro-molar sensing of chromium(VI) in aqueous solutions over the range 10 to 1600 MUM with a limit of detection (3sigma) of 4.4 MUM. The feasibility of the analytical protocol is also tested through chromium(VI) detection in environmental samples. PMID- 22228310 TI - Measurement of oxidative stress and endothelial dysfunction in patients with hypopituitarism and severe deficiency adult growth hormone deficiency. AB - Patients with adult GH deficiency (AGHD) have a high cardiovascular risk and probably an alteration of the oxidative balance, although evidence is lacking. To evaluate the presence of endothelial dysfunction and oxidative stress in patients with AGHD. Biochemical parameters of oxidative stress and endothelial dysfunction were compared in 25 patients with previously untreated AGHD and 25 healthy controls matched by age and sex. Multivariate analysis was performed to identify independent predictors of oxidative stress. Vascular function of subcutaneous resistance arteries was also analyzed by means of wire myography in 7 patients with untreated AGHD and in 7 healthy controls with similar characteristics. The values of C-reactive protein, interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha), were higher in the AGHD group (4.6 vs. 0.2 MUg/L, P = 0.02; 5.6 vs. 1.2 pg/mL, P = 0.001; 6.7 vs. 2.1 pg/mL, P = 0.04; respectively). The levels of type-1 vascular cell adhesion molecule, total anti-oxidant state, oxidized LDL (LDL-ox) were also greater in AGHD patients (678 vs. 423 ng/mL, P = 0.004; 1235.6 vs. 1002.3 MUmol/L, P = 0.01; 172.2.5 vs. 42.3 ng/mL, P = 0.02; respectively). Nitric oxide (NO), reduced glutathione (GSH) and reduced/oxidized glutathione ratio (GSH/GSSG) values were lower than controls (18.7 vs. 31.6 mmol/mg protein, P = 0.01; 372.2 vs. 756.2 MUmol/L, P = 0.03; 17.2 vs. 38.4, P = 0.04; respectively). Multiple regression analysis showed that AGHD was an independent predictor of increased LDL-ox (P = 0.002) and decreased GSH (P = 0.000). Furthermore, the degree of vascular relaxation to repeated exposure of acetylcholine was lower in AGHD (P = 0.025). Patients with AGHD have an increased degree of oxidative stress and endothelial dysfunction that could already be present in early stages of the disease. Studies with a greater number of patients are needed in order to confirm our findings. PMID- 22228311 TI - A homogeneous assay for protein analysis in droplets by fluorescence polarization. AB - We present a novel homogeneous ("mix-incubate-read") droplet microfluidic assay for specific protein detection in picoliter volumes by fluorescence polarization (FP), for the first time demonstrating the use of FP in a droplet microfluidic assay. Using an FP-based assay we detect streptavidin concentrations as low as 500 nM and demonstrate that an FP assay allows us to distinguish droplets containing 5 MUM rabbit IgG from droplets without IgG with an accuracy of 95%, levels relevant for hybridoma screening. This adds to the repertoire of droplet assay techniques a direct protein detection method which can be performed entirely inside droplets without the need for labeling of the analyte molecules. PMID- 22228312 TI - Engineering Corynebacterium glutamicum for the production of pyruvate. AB - A Corynebacterium glutamicum strain with inactivated pyruvate dehydrogenase complex and a deletion of the gene encoding the pyruvate:quinone oxidoreductase produces about 19 mM L: -valine, 28 mM L: -alanine and about 55 mM pyruvate from 150 mM glucose. Based on this double mutant C. glutamicum ?aceE ?pqo, we engineered C. glutamicum for efficient production of pyruvate from glucose by additional deletion of the ldhA gene encoding NAD(+)-dependent L: -lactate dehydrogenase (LdhA) and introduction of a attenuated variant of the acetohydroxyacid synthase (?C-T IlvN). The latter modification abolished overflow metabolism towards L: -valine and shifted the product spectrum to pyruvate production. In shake flasks, the resulting strain C. glutamicum ?aceE ?pqo ?ldhA ?C-T ilvN produced about 190 mM pyruvate with a Y (P/S) of 1.36 mol per mol of glucose; however, it still secreted significant amounts of L: -alanine. Additional deletion of genes encoding the transaminases AlaT and AvtA reduced L: alanine formation by about 50%. In fed-batch fermentations at high cell densities with adjusted oxygen supply during growth and production (0-5% dissolved oxygen), the newly constructed strain C. glutamicum ?aceE ?pqo ?ldhA ?C-T ilvN ?alaT ?avtA produced more than 500 mM pyruvate with a maximum yield of 0.97 mol per mole of glucose and a productivity of 0.92 mmol g ((CDW)) (-1) h(-1) (i.e., 0.08 g g((CDW)) (-1) h(-1)) in the production phase. PMID- 22228313 TI - Psychopathic traits and physiological responses to aversive stimuli in children aged 9-11 years. AB - Atypical eletrodermal and cardiovascular response patterns in psychopathic individuals are thought to be biological indicators of fearless and disinhibition. This study investigated the relationship between psychopathic traits and these autonomic response patterns using a countdown task in 843 children (aged 9-10 years). Heart rate (HR) and non-specific skin conductance responses (NS-SCRs) were recorded while participants anticipated and reacted to 105 dB signaled or un-signaled white-noise bursts. Using multilevel regression models, both larger HR acceleration and fewer NS-SCR were found to be significantly associated with psychopathic traits during anticipation of signaled white-noise bursts. However, two divergent patterns appeared for HR and SCR: (1) larger HR acceleration was specific to the callousness-disinhibition factor of psychopathic traits while reduced NS-SCR was only associated with the manipulative-deceitfulness factor; (2) the negative association between the manipulative-deceitfulness factor and NS-SCR was only found in boys but not in girls. These findings replicated what has been found in psychopathic adults, suggesting that autonomic deficits present in children at risk may predispose them to later psychopathy. The divergent findings across psychopathic facets and sexes raised the possibility of different etiologies underlying psychopathy, which may in turn suggest multiple treatment strategies for boys and girls. PMID- 22228315 TI - Detections of the neonicotinoid insecticide imidacloprid in surface waters of three agricultural regions of California, USA, 2010-2011. AB - Seventy-five surface water samples were collected from three agricultural regions of California and analyzed for the neonicotinoid insecticide imidacloprid. Samples were collected during California's relatively dry-weather irrigation seasons in 2010 and 2011. Imidacloprid was detected in 67 samples (89%); concentrations exceeded the United States Environmental Protection Agency's chronic invertebrate Aquatic Life Benchmark of 1.05 MUg/L in 14 samples (19%). Concentrations were also frequently greater than similar toxicity guidelines developed for use in Europe and Canada. The results indicate that imidacloprid commonly moves offsite and contaminates surface waters at concentrations that could harm aquatic organisms following use under irrigated agriculture conditions in California. PMID- 22228314 TI - Current status of food-borne trematode infections. AB - Food-borne trematodiases constitute an important group of the most neglected tropical diseases, not only in terms of research funding, but also in the public media. The Trematoda class contains a great number of species that infect humans and are recognized as the causative agents of disease. The biological cycle, geographical distribution, and epidemiology of most of these trematode species have been well characterized. Traditionally, these infections were limited, for the most part, in populations living in low-income countries, particularly in Southeast Asia, and were associated with poverty. However, the geographical limits and the population at risk are currently expanding and changing in relation to factors such as growing international markets, improved transportation systems, and demographic changes. The diagnosis of these diseases is based on parasitological techniques and only a limited number of drugs are currently available for treatment, most of which are unspecific. Therefore, in depth studies are urgently needed in order to clarify the current epidemiology of these helminth infections and to identify new and specific targets for both effective diagnosis and treatment. In this review, we describe the biology, medical and epidemiological features, and current treatment and diagnostic tools of the main groups of flukes and the corresponding diseases. PMID- 22228316 TI - Is antipsychotic treatment linked to low bone mineral density and osteoporosis? A review of the evidence and the clinical implications. AB - OBJECTIVE: Osteoporosis is increasingly common worldwide and there is a growing concern that the long-term use of antipsychotic medications increases the risk of this disorder. In this review, we consider whether antipsychotics may contribute to the development of osteoporosis through reductions in bone mineral density, discuss the possible mechanisms involved and consider the clinical implications of such a relationship. METHODS: We searched the literature for studies in this area published between 1966 and 2010 using the Medline and PubMed databases, supplemented by hand searches of retrieved reports. RESULTS: The available data indicate that statistically significant reductions in bone mineral density are frequently seen in patients prescribed with antipsychotic medications and suggest that there is a higher incidence of clinically significant reductions compared with the normal population. CONCLUSIONS: Clinicians should be aware for the potential negative effects of antipsychotic medications on bone mineral density, particularly in patients with additional risk factors for osteoporosis. Recommendations regarding routine monitoring of bone mineral density for patients prescribed antipsychotic medications cannot be made on the basis of existing evidence, and more research is required. PMID- 22228317 TI - Stopping breastfeeding to prevent vertical transmission of HTLV-1 in resource poor settings: beneficial or harmful? PMID- 22228318 TI - Liver transplantation--economics in the less developed world. PMID- 22228319 TI - White spotting variant mouse as an experimental model for ovarian aging and menopausal biology. AB - OBJECTIVE: Menopause is a unique phenomenon in modern women, as most mammalian species possess a reproductive period comparable with their life span. Menopause is caused by the depletion of germ cell-containing ovarian follicles and in laboratory studies is usually modeled in animals in which the ovarian function is removed through ovariectomy or chemical poisoning of the germ cells. Our objective was to explore and characterize the white spotting variant (Wv) mice that have reduced ovarian germ cell abundance, a result of a point mutation in the c-kit gene that decreases kinase activity, as a genetic model for use in menopause studies. METHODS: Physiological and morphological features associated with menopause were determined in female Wv/Wv mice compared with age-matched wildtype controls. Immunohistochemistry was used to evaluate the presence and number of follicles in paraffin-embedded ovaries. Bone density and body composition were evaluated using the PIXImus x-ray densitometer, and lipids, calcium, and hormone levels were determined in serum using antigen-specific enzyme immunoassays. Heart and body weight were measured, and cardiac function was evaluated using transthoracic echocardiography. RESULTS: The ovaries of the Wv/Wv females have a greatly reduced number of normal germ cells at birth compared with wildtype mice. The remaining follicles are depleted by around 2 months, and the ovaries develop benign epithelial lesions that resemble morphological changes that occur during ovarian aging, whereas a normal mouse ovary has numerous follicles at all stages of development and retains some follicles even in advanced age. Wv mice have elevated plasma gonadotropins and reduced estrogen and progesterone levels, a significant reduction in bone mass density, and elevated serum cholesterol and lipoprotein levels. Moreover, the Wv female mice have enlarged hearts and reduced cardiac function. CONCLUSIONS: The reduction of c-kit activity in Wv mice leads to a substantially diminished follicular endowment in newborn mice and premature depletion of follicles in young mice, although mutant females have a normal life span after cessation of ovarian function. The Wv female mice exhibit consistent physiological changes that resemble common features of postmenopausal women. These alterations include follicle depletion, morphological aging of the ovary, altered serum levels of cholesterol, gonadotropins and steroid hormones, decreased bone density, and reduced cardiac function. These changes were not observed in male mice, either age-matched male Wv/Wv or wildtype mice, and are improbably caused by global loss of c-kit function. The Wv mouse may be a genetic, intact-ovary model that mimics closely the phenotypes of human menopause to be used for further studies to understand the mechanisms of menopausal biology. PMID- 22228321 TI - Laboratory and ambulatory evaluation of vasomotor symptom monitors from the Menopause Strategies Finding Lasting Answers for Symptoms and Health network. AB - OBJECTIVE: The aim of this study was to evaluate monitors for assessing vasomotor symptoms (VMS) in laboratory and ambulatory settings before use in the Menopause Strategies Finding Lasting Answers for Symptoms and Health network clinical trials testing VMS therapies. METHODS: This was a three-phase study. Phase 1 included laboratory testing of the Freedman and prototype Bahr Monitor, phase 2 included laboratory testing of the commercial Bahr Monitor and Biolog, and phase 3 included ambulatory testing of the commercial Bahr Monitor and Biolog. All phases enrolled midlife women with VMS, midlife women without VMS, and young women without VMS. The participants self-reported VMS by pressing event marker buttons. Questionnaires assessed demographics (all phases) and monitor acceptability (phases 2 and 3). RESULTS: Phase I testing was stopped because of sensitivity of the Freedman device to ambient humidity changes and lack of analytic software for the prototype Bahr Monitor. In phases 2 and 3, agreement between event-marked and commercial Bahr Monitor or Biolog-recorded VMS was higher in the laboratory than in the ambulatory setting; however, agreement between monitors was poor in two of three laboratory groups (midlife no VMS and young no VMS) and in all ambulatory groups. During ambulatory monitoring, the mean number of Bahr Monitor VMS was 16.33 in midlife women with VMS, 9.61 in midlife women without VMS, and 14.63 in young women without VMS (software version, March 2011). The Bahr Monitor was more acceptable than the larger Biolog, but feedback reflected annoyance at having to wear a device that itched and was visible under clothing. CONCLUSIONS: The Bahr Monitor and Biolog seem suitable for use in controlled laboratory conditions during short periods of time. However, the current versions of these monitors may not be suitable for ambulatory clinical trials at this time. PMID- 22228322 TI - An empirically validated responder definition for the reduction of moderate to severe hot flushes in postmenopausal women. AB - OBJECTIVE: The aim of this study was to derive an empirically validated definition of treatment responders for the reduction of moderate to severe hot flushes in postmenopausal women. METHODS: This study used prospective blinded data analysis from a placebo-controlled study to investigate the efficacy of a treatment of moderate to severe hot flushes in postmenopausal women. Seven hundred ten postmenopausal women with at least 50 moderate to severe hot flushes per week participated in the study. The participants recorded the number of moderate to severe hot flushes each day in a diary. They also assessed their satisfaction with treatment on a Clinical Global Impression-improvement rating scale. Changes in the weekly number of moderate to severe hot flushes were compared with participants' self-assessments to derive an empirically validated minimal clinically important difference. This anchor-based value was compared with the conventional half-SD rule for minimal clinically important difference in participant-reported outcomes. RESULTS: Anchor- and distribution-based minimal clinically important differences between "no change/worse" and "minimally improved" were an absolute reduction of 19.1 and 18.6 in the weekly number of moderate to severe hot flushes, respectively. In addition, the threshold between "minimally improved" compared with "much improved or better" was determined, based on the anchor method, as an absolute reduction of 40.3 in the weekly number of moderate to severe hot flushes. CONCLUSIONS: A responder was defined as having at least an improvement of 19.1 hot flushes per week at week 4 and an improvement of 40.3 hot flushes per week at week 12. PMID- 22228320 TI - Exogenous estrogen protects mice from the consequences of obesity and alcohol. AB - OBJECTIVE: Breast cancer is the second leading cause of cancer death among American women. Risk factors for breast cancer include obesity, alcohol consumption, and estrogen therapy. In the present studies, we determine the simultaneous effects of these three risk factors on wingless int (Wnt)-1 mammary tumor growth. METHODS: Ovariectomized female mice were fed diets to induce different body weights (calorie restricted, low fat, high fat), provided water or 20% alcohol, implanted with placebo or estrogen pellets and injected with Wnt-1 mouse mammary cancer cells. RESULTS: Our results show that obesity promoted the growth of Wnt-1 tumors and induced fatty liver. Tumors tended to be larger in alcohol-consuming mice and alcohol exacerbated fatty liver in obese mice. Estrogen treatment promoted weight loss in obese mice, which was associated with the suppression of tumor growth and fatty liver. CONCLUSIONS: In summary, we show that estrogen protects against obesity, which is associated with the inhibition of fatty liver and tumor growth. PMID- 22228323 TI - Women, work, and menopause. PMID- 22228324 TI - Organocatalytic asymmetric synthesis of 3-difluoroalkyl 3-hydroxyoxindoles. AB - We report the first example of highly enantioselective organocatalytic synthesis of 3-difluoroalkyl substituted 3-hydroxyoxindoles. The total synthesis of the difluoro analogue of convolutamydine E was achieved by this method. PMID- 22228325 TI - Tracheal traction exercise reduces the occurrence of postoperative dysphagia after anterior cervical spine surgery. AB - STUDY DESIGN: We designed a novel anterior cervical spine surgery preoperative treatment comprising mechanical trachea/esophagus traction and compared the postoperative outcome regarding dysphagia with nontreated patients. OBJECTIVE: We investigated whether the newly developed preoperative tracheal/esophageal traction exercise (TTE) treatment has an effect on postoperative dysphagia after anterior cervical spine surgery. SUMMARY OF BACKGROUND DATA: Dysphagia is a postoperative complication that occurs after anterior cervical spine surgery, and known treatments are perioperative application of methylprednisolone, monitoring of endotracheal tube cuff pressure, and the use of low-profile plates. METHODS.: We compared the neck disability index, visual analogue scale scores for arm and neck pain, and Bazaz dysphagia scores, a dysphagia index, of 2 randomized groups, 1 week, 3 weeks, 6 weeks, 3 months, and 6 months after cervical spine surgery. One group received TTE treatment for 3 consecutive days before surgery, whereas the control group did not. RESULTS.: In the first week after operation, the Bazaz dysphagia scores for patients with second- to fourth-level fusions in the TTE group were significantly better than that in the control group (P = 0.000 for second- and third-level fusions and P = 0.013 for fourth-level fusion). Also at 3 weeks after surgery, the second- to fourth-level fusion patients in the TTE group had better Bazaz scores than those in the control group (P = 0.000 for second- and third-level fusions and P = 0.004 for fourth-level fusion). There was no significant difference of neck disability index and visual analogue scale scores between the 2 groups. CONCLUSION: Dysphagia could be reduced in patients with multiple-level fusion after anterior cervical spine surgery by preoperative TTE treatment. PMID- 22228326 TI - Adjacent-level range of motion and intradiscal pressure after posterior cervical decompression and fixation: an in vitro human cadaveric model. AB - STUDY DESIGN: This in vitro human cadaveric study measured adjacent-level kinematics after posterior cervical decompression and fixation. OBJECTIVE: Quantify adjacent-level changes in range of motion (ROM) and intradiscal pressure after posterior cervical decompression and fixation. SUMMARY OF BACKGROUND DATA: Optimal length of instrumentation after posterior decompression is unclear. Longer posterior cervical fixation constructs may increase the risk of adjacent segment degeneration. METHODS: Eight cervicothoracic spines were evaluated intact, with C3-C6 laminectomy, C3-C6 laminectomy + C3-C6 fixation, C3-C6 laminectomy + C3-C7 fixation, C3-C7 laminectomy, C3-C7 laminectomy + C3-C7 fixation, C3-C7 laminectomy + C2-C7 fixation, C3-C7 laminectomy + C3-T2 fixation, and C3-C7 laminectomy + C2-T2 fixation. Testing included intact moments (+/- 2.0 N.m) in flexion/extension, axial rotation, and lateral bending, with quantification of ROM at C2-C3, C6-C7, and C7-T1 normalized to the intact spine. Intradiscal pressures were also measured at each level. RESULTS: For the C3-C6 laminectomy group, there were no differences in adjacent-level flexion/extension ROM or intradiscal pressure based on construct length, except at C6-C7, where ROM was significantly decreased when fixation was extended to C7 (P < 0.05). After C3 C7 laminectomy and reconstruction, the greatest increase in C2-C3 flexion/extension ROM and intradiscal pressure occurred in the C3-T2 fixation subgroup (ROM: 348% [P < 0.05]; intradiscal pressure: 319 +/- 243 psi [pounds per square inch] vs. 65 +/- 41 psi intact [P < 0.05]). At C7-T1, the greatest increase in flexion/extension ROM and intradiscal pressure occurred after C2-C7 fixation (ROM: 531% [P < 0.05]; intradiscal pressure: 152 +/- 83 psi vs. 21 +/- 14 psi intact [P < 0.05]). CONCLUSION: For C3-C6 laminectomy, instrumentation to C7 significantly decreased flexion/extension ROM and intradiscal pressure at C6 C7 without significantly increasing either measure at C2-C3 or C7-T1 relative to C3-C6 fixation. In the setting of a C3-C7 laminectomy, when instrumenting to either C2 or T2, consideration should be given to including both levels within these constructs. PMID- 22228327 TI - SF-6D values stratified by specific diagnostic indication. AB - STUDY DESIGN: Longitudinal cohort. OBJECTIVE: To present Oswestry Disability Index scores and SF-6D utility values among patients with different diagnostic etiologies who underwent fusion surgery. SUMMARY OF BACKGROUND DATA: Several studies have increased our understanding of health-related quality-of-life measures in patients with low back pain. With rising health care costs, cost utility analysis is increasingly used by decision makers. Thus, clinicians and researchers need to understand the psychometrics and clinical importance of health state utility values in patients with spine disorders. METHODS: A total of 1104 patients who had decompression and lumbar fusion with complete data to compute the SF-6D score at baseline and 2-year follow-up were identified. Primary surgical cases were classified as disc pathology (n = 200), spondylolisthesis (n = 288), instability (n = 43), stenosis (n = 134), or scoliosis (n = 44). Revision cases were classified as nonunion (n = 94), adjacent-level degeneration (n = 98), or postdiscectomy revision (n = 203). Baseline SF-6D and change in SF-6D scores at 2 years were compared among the groups as well as primary versus revision cases. RESULTS: There were 674 women and 430 men. The mean age at surgery was 56.65 +/- 12.7 years. There were 220 (19.9%) smokers. The worst mean baseline SF 6D score was in patients with nonunion (0.492), followed by disc pathology (0.493), adjacent-level degeneration (0.494), postdiscectomy revision (0.499), stenosis (0.504), instability (0.512), spondylolisthesis (0.520), and scoliosis (0.530). There was a statistically significant difference in baseline SF-6D score among the different groups (P = 0.002). The mean change in SF-6D score was greatest in patients with stenosis (0.088), followed by spondylolisthesis (0.085), scoliosis (0.076), disc pathology (0.076), instability (0.073), postdiscectomy revision (0.070), adjacent-level degeneration (0.066), and nonunion (0.050). There was no statistically significant difference in change in SF-6D score among the different groups (P = 0.096). However, revision cases had statistically significantly smaller gains in SF-6D score (0.064) than primary cases (0.082, P = 0.012). CONCLUSION: Patients with lumbar degenerative disorders have health state values similar to patients with chronic renal disease, Crohn's disease, or coronary artery disease. Health state values of patients with different indications for surgery differ at baseline and after surgery. Revision cases have worse baseline SF-6D scores and less improvement in scores at 2 years after surgery than primary cases. Further studies are needed to gain a greater understanding of health state utility values in patients with lumbar degenerative disorders. PMID- 22228328 TI - Expression of ezrin, MMP-9, and COX-2 in 50 chordoma specimens: a clinical and immunohistochemical analysis. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To investigate the immunohistochemical expression profile of ezrin, matrix metalloproteinase-9 (MMP 9), and cyclooxygenase-2 (COX)-2 in chordomas. SUMMARY OF BACKGROUND DATA: Ezrin, MMP-9, and COX-2 are expressed in different solid tumors, including chordomas. This study investigates the immunohistochemical expression of the aforementioned biomarkers and the clinical outcome in regard to immunohistochemistry, tumor volume, and localization. METHODS: Fifty brachyury-verified chordoma specimens of 34 primary and 16 recurrent tumors of 44 patients were tested for ezrin, MMP-9, and COX-2 as possible therapeutical targets by immunohistochemistry. The clinical evaluation concentrated on tumor location, volume, and age-related data. RESULTS: Ezrin expression was detected in 33 of 34 primary chordomas and in 16 of 16 recurrent cases. The primary chordomas located in the sacrum and the spine demonstrated a significantly higher percentage of positively stained tumor cells (P = 0.034) than the skull-based chordomas. An expression of MMP-9 and COX-2 was observed in 33 of 34 primary chordomas and in 16 of 16 recurrences, and in 13 of 34 primary chordomas and in 11 of 16 recurrences, respectively. Patients' survival was significantly influenced by age (P = 0.01), tumor location (P = 0.029), and tumor volume (P = 0.002). A significant positive correlation between tumor volume and the anatomic distance of the chordoma from the skull was calculated (P = 0.00002). CONCLUSION: En bloc resection with tumor-free margins is seldom feasible, particularly in the sacrum. Intralesional excisions mostly end in early local recurrence; therefore, the demand for further treatment options is frequently posed. The marked trend of the investigated biomarkers of this study may build a starting point for further investigations as molecular targets for future adjuvant therapies in chordomas. Future multicenter studies on larger patients' series are necessary to elucidate these preliminary data and to test new treatment options for patients with chordomas. PMID- 22228329 TI - Multivariate analysis of factors associated with kyphosis maintenance in adolescent idiopathic scoliosis. AB - STUDY DESIGN: Multicenter retrospective cohort study of 269 patients. OBJECTIVE: The purpose of this study is to evaluate the surgical and radiographical factors in adolescent idiopathic scoliosis (AIS) surgery that significantly affect kyphosis maintenance. SUMMARY OF BACKGROUND DATA: Decreased kyphosis in the thoracic spine is a component of the 3-dimensional deformity in AIS. Suboptimal sagittal alignment after spinal fusion has been identified as a possible cause of lumbar and cervical spinal degeneration and junctional malalignment. Segmental spinal instrumentation continues to evolve, and although excellent coronal plane correction is readily achieved, sagittal plane thoracic hypokyphosis may be seen postoperatively. METHODS: A retrospective analysis of prospectively collected data from a multicenter AIS database was performed to evaluate factors associated with kyphosis maintenance. A total of 526 patients were enrolled in the database and had a mean thoracic kyphosis (T5-T12) of 22 degrees . In total, 269 patients were identified who had kyphosis of less than 22 degrees and thus comprised the group to be included in this analysis. A complete radiographical series was obtained for each patient preoperatively, immediately postoperatively, and at 2 years postoperatively. All operative data, including the number of levels fused and implant type and density, were also recorded. Multivariate and regression analysis were performed. RESULTS: Eight variables were found to be significantly correlated with kyphosis maintenance at 2 years postoperatively. Anterior approach (r = 0.37, P < 0.001), increased thoracic coronal curve (r = 0.20, P = 0.001), and a greater percentage of hooks in the construct (r = 0.18, P = 0.034) were associated with increased kyphosis at follow-up. A greater number of levels fused (r = -0.33, P < 0.001), preoperative kyphosis (r = -0.39, P < 0.001), percentage of screws in the construct (r = -0.18, P = 0.03), using standard stainless steel rods (r = -0.47, P = 0.011), and percent decrease in thoracic curve (r = -0.23, P < 0.001) all were correlated with hypokyphosis at follow-up. CONCLUSION: Our multivariate analysis demonstrates that in patients with AIS who have thoracic hypokyphosis as part of their deformity, certain factors must be taken into account in the preoperative planning to prevent hypokyphosis after surgical correction. PMID- 22228331 TI - Investigating the role of grain boundaries in CZTS and CZTSSe thin film solar cells with scanning probe microscopy. PMID- 22228332 TI - Glucose transporter 1 expression, tumor proliferation, and iodine/glucose uptake in thyroid cancer with emphasis on poorly differentiated thyroid carcinoma. AB - PURPOSE: Glucose transporters 1 (GLUT1) facilitates glucose uptake in cancer. An inverse relationship between I-131 and F-18 fluorodeoxyglucose (FDG) uptake in PET/CT ("flip-flop phenomenon") was described for thyroid cancers (TCs) during dedifferentiation. We investigated the relationship among GLUT1 expression, proliferation, iodine concentration, and glucose uptake in different TC types, with emphasis on "poorly differentiated thyroid carcinoma" (PDTC). METHODS: For immunohistochemistry, 95 thyroid tumors (follicular adenoma, papillary TC, follicular TC, PDTC, and anaplastic TC [ATC]) were investigated for GLUT1 expression and proliferation (Ki-67 index). For PET/CT study, 47 F-18 FDG PET/CT of patients with TC (22 PDTC), 39 corresponding I-124 PET/CT, and glucose and iodine uptake were evaluated. PTC and FTC were summarized under differentiated TC (DTC). RESULTS: Immunohistochemistry: 65% of TC expressed GLUT1. The number of GLUT1-positive TC and GLUT1 expression increased with escalating dedifferentiation/aggressiveness of TC types (P < 0.001). A correlation between proliferation and GLUT1 expression was noted (P < 0.001). PET/CT study: F-18 FDG uptake was measured in 81% of cases. Occurrence of F-18 FDG-avid cases as well as median F-18 FDG maximum standardized uptake values were lowest in DTC, intermediate in PDTC, and highest in ATC. Accordingly, numbers of iodine-avid cases and median I-124 maximum standardized uptake value featured an inverse pattern. CONCLUSIONS: Dedifferentiation in TC is accompanied by GLUT1 upregulation and increased proliferation. PDTC was found to be intermediate between DTC and ATC in terms of GLUT1 expression and F-18 FDG or I-124 uptake, suggesting that the flip-flop phenomenon occurs at a dedifferentiation stage in between. Furthermore, the results suggest that F-18 FDG PET/CT is an important imaging modality for ATC and PDTC. PMID- 22228333 TI - Combination of preoperative cerebral blood flow and 123I-iomazenil SPECT imaging predicts postoperative cognitive improvement in patients undergoing uncomplicated endarterectomy for unilateral carotid stenosis. AB - PURPOSE: The purpose of the present study was to determine whether preoperative cerebral blood flow (CBF) or cortical central benzodiazepine receptor binding potential as measured by brain perfusion or (123)I-iomazenil (IMZ) single-photon emission computed tomography (SPECT) imaging, respectively, can predict cognitive improvement after uncomplicated carotid endarterectomy (CEA). METHODS: Neuropsychological testing was performed preoperatively and after 1 month postoperatively in 140 patients who underwent CEA for unilateral internal carotid artery (ICA) stenosis (>= 70%). Brain perfusion SPECT using N-isopropyl-p [(123)I]-iodoamphetamine and IMZ SPECT was also performed before surgery. SPECT data were analyzed using a 3-dimensional stereotaxic region-of-interest template. RESULTS: Fourteen patients (10%) showed improved cognitive function postoperatively. Logistic regression analysis demonstrated that, among the variables tested, low relative CBF in the cerebral hemisphere ipsilateral to surgery was significantly associated with postoperative cognitive improvement (95% confidence interval: 0.623-0.868; P = 0.0003). The combination of reduced relative CBF and moderately reduced relative uptake of IMZ identified development of postoperative cognitive improvement with 100.0% sensitivity, 84.9% specificity, a positive predictive value of 42.4%, and a negative predictive value of 100%. Further, in a subgroup of patients with reduced relative CBF and moderately reduced relative uptake of IMZ, the difference between these 2 values was significantly greater in patients with postoperative cognitive improvement than in those without (P < 0.0001). CONCLUSIONS: The combination of preoperative CBF and cortical central benzodiazepine receptor binding potential as determined by SPECT can predict cognitive improvement after CEA. PMID- 22228334 TI - Hepatic uptake of Tc-99m DPD on bone scintigraphy: the influence of the interval with gadolinium-containing contrast of MRI. AB - PURPOSE: There are various etiologies, which can result in nonosseous, nonurologic uptake in bone scintigraphy. This study aimed to evaluate the influence of the interval between gadolinium (Gd)-containing contrast of MRI and Tc-99m DPD (Tc-99m 3,3-diphosphono-1,2-propanedicarboxylic acid) on bone scintigraphy. MATERIALS AND METHODS: We retrospectively analyzed 1028 patients with bone scintigraphy performed between January 2010 and February 2011. All these 1028 patients had MRI contrast administration prior to bone scintigraphy. Fifty patients (8 women, 42 men) showed hepatic uptake on bone scintigraphy. The patients were subdivided into 2 groups (group A: MRI performed on the same day with bone scintigraphy, group B: MRI performed 1 or 2 days before bone scintigraphy). RESULTS: Among 1028 subjects, hepatic uptake in patients with MRI and bone scintigraphy on the same day was shown in 39 of the 585 bone scintigraphies (6.67%), while hepatic uptake with interval of 1 and 2 days was visualized in 8 of the 186 (4.30%) and 3 of the 87 (3.45%) subjects. No patients with interval more than 2 days showed hepatic uptake of bone scintigraphy. CONCLUSION: The interval between MRI with Gd-contrast and bone scintigraphy has an influence on hepatic uptake. Gd-containing contrast injection before bone scintigraphy within 2 days might affect the nonosseous uptake of Tc-99m DPD. At least 2 days of interval between MRI and bone scintigraphy might be needed to avoid hepatic uptake of bone scintigraphy. PMID- 22228335 TI - Visualization of distal spinal cord on F-18 FDG PET/CT. AB - AIM: The purpose of this study was to evaluate frequency, intensity, and associations of distal spinal cord F-18 FDG uptake visible on PET/CT. Normal cervical, but not distal cord uptake, has been reported previously. METHODS: This is a retrospective review of consecutive oncologic whole body PET/CTs from 14 June, 2006 to 9 August, 2006 in 108 patients (49 male, 59 female; mean age, 61.9 years; range, 26-91 years) on Siemens Biograph 6 at 60 minutes post IV F-18 FDG (median dose 577.2 MBq). Distal spinal cord visual intensity was graded on a 3 point scale. Age, gender, race, weight, diabetes, glucose level, F-18 FDG dose, scan delay, and standard uptake value (SUV) of distal cord, vertebra, blood pool, and liver were recorded. The electronic medical record was reviewed more than 2 years later for history of radiation therapy (RT) or evidence of distal spinal cord malignancy, which might cause uptake. RESULTS: There was visible distal spinal cord uptake in 55% of patients, mild in 39% and moderate in 16%, seen as a narrow band of activity up to 2 segments in length at T11-L1. None showed history of regional RT or spinal cord malignancy on medical record review. Statistically significant associations were found between distal cord visual intensity and younger age, lower blood glucose, female gender, and white race (P < 0.05, chi(2) test). In multiple predictor fitted regression, age and glucose were statistically significant (P < 0.05); gender and race were not. Higher visual intensity was associated with higher distal cord SUV (highest maximal SUV, 3.7) and higher SUV ratios to vertebra, blood pool, and liver, but with much overlap. There was no significant association with other variables. CONCLUSION: Mild to moderate distal spinal cord F-18 FDG uptake on PET/CT is a common normal variant, more common in younger age and in patients with lower glucose levels. It likely represents metabolic activity of lumbosacral plexus nerve cell bodies. PMID- 22228336 TI - Radioguided surgery in neuroendocrine tumors using Ga-68-labeled somatostatin analogs: a pilot study. AB - BACKGROUND: Previous studies of the intraoperative use of a hand-held gamma probe to localize metastases and primary tumors have shown improved assessment of tumor spread and changes in surgical management based on additional information gained by radioguided surgery (RGS). PURPOSE: The aim was to test the feasibility and advantages of doing RGS using a gallium-68 labeled with somatostatin receptor analogs in the intraoperative detection of neuroendocrine tumors. METHODS: Ga-68 somatostatin receptor PET/CT imaging was performed preoperatively in 9 patients with gastroenteropancreatic neuroendocrine tumors. Statistical analyses were performed to find out the correlation between the pathologic size of the tumor lesions and the maximum standardized uptake value on PET/CT as well as the target/nontarget ratio (T/NT) of gamma probe counts. Thereafter, the impact of the planned operation procedure and the lesion-based sensitivity of tumor detection (surgical palpation vs. PET/CT vs. gamma probe) had been observed. RESULTS: Overall, 72 locations in 9 patients were examined intraoperatively using gamma probes. The gamma probe detected 94% of the whole histologically quantified lesions, whereas the PET/CT allocated 69% and surgical palpation, 50%. RGS resulted in change in the operative procedure in 56%. There was a significant correlation between the maximum standardized uptake value and tumor size (0.74; P < 0.005). CONCLUSION: Hand-held gamma probe surgery using gallium-68-labeled somatostatin analogs is a feasible and an attractive option for real-time detection of small metastases and primaries of neuroendocrine tumors. PMID- 22228337 TI - Evaluation of surgical completeness in endoscopic thyroidectomy compared with open thyroidectomy with regard to remnant ablation. AB - PURPOSE: To assure the surgical completeness of the bilateral axillo-breast approach (BABA) endoscopic thyroidectomy (ET), we compared ET and open thyroidectomy (OT) by means of the radioactive iodine (RAI) uptake of remnant thyroid. MATERIALS AND METHODS: From January 2003 to May 2007, 46 patients who had received RAI ablation after total thyroidectomy because of papillary thyroid microcarcinoma were enrolled. Of total, 25 patients underwent ET and the other 21 underwent OT. The RAI activity of remnant thyroid was measured by the neck-to skull uptake ratio on the first postoperative RAI ablation scan. Stimulated thyroglobulin levels, the total number of RAI ablation sessions, and doses of RAI for completion of ablation were also compared. RESULTS: There were no significant differences in regards of the RAI uptake ratio, the stimulated thyroglobulin level, the total number of RAI ablation sessions, and doses of RAI for completion of ablation, between ET and OT groups. CONCLUSION: The completeness of the surgical removal by BABA ET was comparable with that of OT. The BABA ET might give a safe option for patients with low-risk thyroid cancer. PMID- 22228338 TI - Comparison between endoscopic macroscopic classification and F-18 FDG PET findings in gastric mucosa-associated lymphoid tissue lymphoma patients. AB - PURPOSE: The aim of this study was to compare endoscopic macroscopic classification with fluorine-18 fluorodeoxyglucose (F-18 FDG) uptake in gastric mucosa-associated lymphoid tissue (MALT) lymphoma and to investigate the usefulness of F-18 FDG positron emission tomography (PET) for diagnosing gastric MALT lymphoma. MATERIALS AND METHODS: Sixteen patients with gastric MALT lymphoma who underwent F-18 FDG PET and gastrointestinal imaging modalities were included in this study. Sixteen healthy asymptomatic participants undergoing both F-18 FDG PET and endoscopy for cancer screening were in the control group. We investigated the difference of F-18 FDG uptake between the gastric MALT lymphoma and the control group and compared the uptake pattern in gastric MALT lymphoma with our macroscopic classification. RESULTS: The endoscopic findings of 16 gastric MALT lymphoma patients were classified macroscopically as chronic gastritis-like tumors (n = 6), depressed tumors (n = 5), and protruding tumors (n = 5). Abnormal gastric F-18 FDG uptake was observed in 63% of tumors in the gastric MALT lymphoma group and 50% of cases in the control group. The median maximum standardized uptake values for gastric MALT lymphoma patients and control group were 4.0 and 2.6, respectively, the difference of which was statistically significant (P = 0.003). F-18 FDG uptake results were positive for all protruding tumors but only 50% for chronic gastritis-like tumors and 40% for depressed-type tumors. CONCLUSIONS: F-18 FDG PET may be a useful method for evaluating protrusion-type gastric MALT lymphoma. When strong focal or diffuse F-18 FDG uptake is detected in the stomach, endoscopic biopsy should be performed, even if the endoscopic finding is chronic gastritis. PMID- 22228339 TI - Comparison of F-18 FDG and C-11 methionine PET/CT for the evaluation of recurrent primary brain tumors. AB - PURPOSE OF STUDY: With the availability of multiple positron emission tomography (PET) tracers for neurooncology, there is a need to define the appropriate tracer in a given clinical setting, and it is in this regard that we undertook this study to directly compare F-18 flurodeoxyglucose (FDG) PET and C-11 methionine (MET) PET for the evaluation of recurrence in primary brain tumors. PATIENTS AND METHODS: Thirty-seven patients with a history of treated primary brain tumors referred for evaluation of recurrent disease were initially included in the study. Two patients had to be excluded because of insufficient follow-up. There were 23 males and 12 females, mean age: 33.7 +/- 16.4 years; range: 5 to 65 years. All patients underwent the MET and FDG study on the same day. Visual image interpretation was performed independently by 2 PET physicians for each tracer using the plain PET and fused PET/CT images; the FDG images were evaluated first. Images were analyzed semiquantitatively using tumor to normal contralateral cortex ratios (T/N). Each patient was followed up for a minimum of 18 months. Imaging results were compared with histopathology on tumor excision or biopsy in 14 patients and with clinical follow-up and MRI/MRS at the end of 18 months in 21 patients. RESULTS: The final diagnosis was tumor recurrence in 24 patients and no recurrence/stable disease in 11 patients. On FDG, findings in 15/35 (42%) were suggestive of recurrent tumors. On MET, findings in 24/34 (70.5%) cases were suggestive of recurrent tumors. Spatially separated secondary lesions including intraventricular deposits were clearly delineated in 5 cases, 3 were glioblastoma multiforme (GBM) and 2 were anaplastic astrocytomas. One of the secondary lesions was missed on FDG PET. Using a cutoff for T/N ratio on FDG of >0.75 to differentiate recurrence from no recurrence, sensitivity of FDG was 81.2% (confidence interval [CI] = 54.4%-96%), whereas specificity was 88.9% (CI = 51.8% 99.7%). Area under the curve was 0.819 (CI = 0.615-0.943), P = 0.0003. Using a cutoff for T/N ratio of >1.9 to differentiate recurrence from no recurrence, sensitivity of MET was 94.7% (CI = 74.0%-99.9%), whereas specificity was 88.89% (CI = 51.8%-99.7%). Area under the curve was 0.942 (CI = 0.785-0.995), P < 0.0001. Interobserver agreement, kappa coefficient, for MET was 0.93, suggesting good interobserver agreement, whereas for FDG, it was fair (0.23). CONCLUSIONS: MET should be the radiotracer of choice in the evaluation of recurrence of primary brain tumors because the sensitivity for detection and delineation of the possible recurrent tumor, as well as secondary deposits, is higher with MET. MET PET is an easier technique to interpret, irrespective of the glioma grade, with less interobserver variability and straightforward localization of tumorous accumulation. PMID- 22228340 TI - Planning and conducting meetings effectively, part III: keeping meetings on track. AB - The attendees at a meeting have different ways in which they get information and make decisions, different personal needs, and different ways in which they participate in groups. Some have counterproductive behaviors in committee meetings, such as attacking others, talking too long but not saying much, talking too little, deliberately trying to undermine the process, bringing up unrelated issues, engaging in private conversations with others, or silencing others. The chairperson must meet all of these challenges to have a productive meeting. This article gives some tips on how to run meetings well. PMID- 22228341 TI - Tumor perfusion using first-pass F-18 FDG PET images. AB - Many reports in the literature have focused on FDG PET imaging at conventional (60 minutes after injection) or delayed (several hours after injection) intervals, which exploits increased glycolysis in tumors for diagnosis. However, in rapidly growing tumors, accelerated glycolysis is, among other factors, mediated by hypoxia and poor perfusion. Interestingly, first-pass (0-2 minutes after injection) FDG PET images were shown to provide an index of perfusion. Here, we illustrate that tracer uptake by various (parts of) tumors is discrepant between first-pass and conventional PET images, probably reflecting the direct control of glucose transporter overexpression by hypoxia, resulting from poor perfusion (Warburg's hypothesis). PMID- 22228342 TI - Radiation-induced myositis mimicking chest wall tumor invasion in two patients with lung cancer: a PET/CT study. AB - Two patients with lung cancer who had undergone stereotactic body radiation therapy (SBRT) exhibited increased F-18 FDG uptake in the chest wall after 6 months and 18 months, respectively, after SBRT. The prescribed dose of 50 Gy to the planning target volume was delivered on 4 consecutive days in each patient. It is important for nuclear medicine physicians to be familiar with F-18 FDG PET/CT findings ascribed to radiation-induced myositis in lung cancer patients treated with SBRT so that an appropriate differential diagnosis can be established. PMID- 22228343 TI - Heterotrophic ossification in a patient suspected of having osteomyelitis: additional value of SPECT/CT. AB - A 46-year-old man, with a history of bilateral amputations, presented with a long standing chronic nonhealing wound at the left below-knee amputation, which was sustained after a crush injury. The patient was referred for a bone scan to exclude osteomyelitis of the left stump. The bone scan showed increased uptake in the left below-knee amputation stump, raising the possibility of an infection. However, SPECT/CT of this area confirmed the uptake to correspond to the heterotrophic ossification of the left below-knee stump and no evidence of osteomyelitis. PMID- 22228344 TI - Bone scan in enthesopathy involving tendo Achilles. AB - Inflammatory enthesitis is a hallmark of spondyloarthropathies (SSA) and may antedate other clinical manifestations. The involvement of Achilles tendon and plantar aponeurosis is common, with strong tendency toward fibrosis and calcification. We are describing imaging characteristics in a patient with positive HLA B-27 antigen with bilateral calcific achilles tendonitis who had pain in heels for 3 years. PMID- 22228345 TI - Bilateral and multifocal Warthin's tumors of parotid glands: PET/CT imaging. AB - Unilateral hypermetabolic lesion of parotid gland demonstrated on PET/CT imaging may originate from a large spectrum of benign or malignant processes, such as adenoma, Warthin's tumor, oncocytic neoplasm, lymphoma, and primary or secondary malignancy of the gland. Bilateral and multifocal parotid gland disease is less common but possible because of the known characteristics of Warthin's tumors. The authors present such a case that was incidentally documented during PET/CT evaluation of solitary pulmonary nodule. PMID- 22228346 TI - False-positive I-131 uptake by an ovarian serous cystadenofibroma. AB - We present the case of a 53-year-old woman after thyroidectomy with metastatic multifocal papillary carcinoma and encapsulated focal Hurthle cell carcinoma. Postoperatively, an I-131 whole-body scan revealed uptake in the low midline anterior neck. She was treated with 151.5 mCi of I-131. The 1-year follow-up I 131 whole-body scan revealed a new pelvic mass with I-131 uptake. Pelvic CT showed bilateral complex ovarian masses. She underwent surgical excision, revealing a right ovarian endometriotic cyst and a left ovarian cystadenofibroma, without thyroid tissue involvement. I-131 uptake in a cystadenofibroma is extremely rare and has been reported only once to our knowledge. PMID- 22228347 TI - Usefulness of F-18 FDG PET/CT in the follow-up of POEMS syndrome after autologous peripheral blood stem cell transplantation. AB - We report a case of a patient with relapse of POEMS syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) that occurred 6 years after an autologous peripheral blood stem cell transplantation. F-18 FDG PET/CT showed several hypermetabolic as well as nonhypermetabolic bone lesions. Based on these findings, the patient was referred for radiotherapy to the hypermetabolic bone lesions. After autologous peripheral blood stem cell transplantation, F-18 FDG PET/CT may play a pivotal role in detecting new bone lesions in patients with POEMS syndrome, which may be treated by a focalized radiotherapy and/or systemic therapy. PMID- 22228348 TI - Imaging findings in a rare case of extra-articular chondrocalcinosis. AB - We report the imaging findings in extra-articular chondrocalcinosis in a 53-year old man with swelling and pain in right scapular area for 1 year. Plain radiography showed a right scapular area calcific mass. The clinical suspicion was of a soft tissue sarcoma. As a part of diagnostic workup, a bone scan and a PET/CT scan were done. Bone scan revealed intense MDP uptake in the right scapular area. FDG PET/CT revealed intense FDG uptake in the mass. The biopsy revealed chondrocalcinosis. This is an addition to our long list of causes of extraosseous uptake of MDP. PMID- 22228349 TI - Evolution of a ureteric stone from the renal pelvis to the ureter on skeletal scintigraphy with CT correlation. AB - Because bone-seeking radiopharmaceuticals are excreted into the urine by the kidneys, normal kidneys and bladder are well visualized on skeletal scintigrams leading to incidental detection of urinary tract abnormalities in up to 15% of bone scans. Although the findings pertaining to the urinary tract on skeletal scintigraphy are seldom suggestive of a definitive diagnosis, they are highly specific for renal disease, with fewer than 2% false-positive studies reported. In the presented case, we demonstrate the evolution of a ureteric stone from the renal pelvis into the ureter on sequential skeletal scintigraphy with CT correlation. PMID- 22228350 TI - The appearance of osseous PEComa on F-18 FDG PET/CT. AB - A 29-year-old male presented with a 6-month history of left hip pain. Radiography and CT demonstrated a 6-cm lytic lesion of the left acetabulum. F-18 FDG PET for staging of the biopsy-proven malignant PEComa demonstrated intense hypermetabolism corresponding to the lytic left acetabulum. The patient underwent left hemipelvectomy with reconstructive surgery. On a follow-up F-18 FDG PET scan 3 months after initial surgery, a left lung pleural-based 9-mm nodule with hypermetabolism (SUVmax 4.1) was discovered and pathologically proven to be metastases from the primary osseous PEComa. PMID- 22228351 TI - Incidental finding of Tc-99m MDP bone scintigraphy in a case of X-linked spondyloepiphyseal dysplasia tarda. AB - A 26-year-old male presented with a history of backache and multijoint pain over the preceding 15 years. Bone scintigraphy demonstrated a short spine in addition to abnormally increased activity in multiple joints. The patient was eventually diagnosed to have X-linked spondyloepiphyseal dysplasia tarda. PMID- 22228352 TI - F-18 FDG PET/CT detects muscle involvement in Erdheim-Chester disease. AB - A case of Erdheim-Chester disorder, a rare non-Langerhans' cell histiocytosis, was referred for restaging by F-18 FDG PET/CT more than 10 years after initial diagnosis. The patient presented diabetes insipidus, hypergondotropic hypogonadism, and osteosclerotic lesions. Previous bone scintigraphy documented pathognomonic long bones' involvement. Chronic steroid and hormone replacement therapy was administered, and the patient was asymptomatic. F-18 FDG PET/CT was useful for disease restaging at cardiac and soft tissues level. PMID- 22228353 TI - Incidental detection of gastrointestinal stromal tumor by Tc-99m MDP bone scan. AB - This case demonstrates extraosseous 99m-technetium methylene diphosphonate (Tc 99m MDP) accumulation from a gastrointestinal stromal tumor. A 75-year-old woman underwent a temporal bone CT for conductive hearing loss that showed sclerosis in the right occipital condyle. Follow-up Tc-99m MDP bone scan for osseous metastases instead showed a mass-like extraosseous accumulation of Tc-99m MDP in the anterior left upper quadrant. Differential diagnoses included gastric cancer, lymphoma, metastatic melanoma, systemic hypercalcemia, or heterotopic mesenteric ossification. Contrast CT showed a well-circumscribed mass arising from the stomach, and subsequent pathology confirmed gastrointestinal stromal tumor. These tumors rarely can contain osteoclast-like giant cells and should be considered for extraosseous Tc-99m MDP accumulation. PMID- 22228354 TI - Usefulness of F-18 FDG PET/CT as one-stop-shop imaging modality for diagnosis of occult primary and estimation of disease burden in patients with intraocular masses. AB - Metastases are the most common intraocular malignancy. Determination of the primary site and entire burden of disease as a part of initial staging is important in choosing the most appropriate management strategy. F-18 FDG PET/CT can demonstrate primary neoplasms and the whole-body total burden of disease. We present 2 cases of intraocular metastases from lung carcinoma where F-18 FDG PET/CT was useful as one-stop-shop imaging modality in detection of the primary and in assessment of total disease burden. PMID- 22228355 TI - F-18 FDG PET/CT imaging of follicular dendritic cell sarcoma of the mediastinum. AB - A 52-year-old female smoker presenting with unexplained weight loss underwent CT and FDG PET/CT imaging, which demonstrated an extremely hypermetabolic mediastinal mass with calcification, necrosis, and features of local invasiveness. Mediastinoscopy and biopsy were followed by successful surgical resection of an encapsulated mass showing the typical histologic features of follicular dendritic cell sarcoma (FDCS). FDCS of the mediastinum is a rare neoplasm arising from accessory cells of the immune system. Integrated FDG PET/CT of mediastinal FDCS highlights the importance of histologic assessment of mediastinal tumors that may seem unresectable on initial imaging. PMID- 22228356 TI - F-18 FDG and C-11 methionine PET/CT in intracranial dural metastases. AB - A 58-year-old woman with breast carcinoma, after mastectomy, radiotherapy, and chemotherapy, underwent a whole-body F-18 FDG PET/CT for restaging, which revealed multiple skeletal metastasis. Hypometabolism was noted in the right frontal lobe. The patient subsequently underwent a C-11 methionine brain scan, which demonstrated multiple dural-based metastatic foci confirmed on contrast enhanced MR. FDG PET has limitations in brain tumor detection. Amino acid tracers are particularly attractive for imaging of brain tumors because of relatively high tumor to brain activity ratios. PMID- 22228357 TI - Multiple intraabdominal purulent collections demonstrated on FDG PET/CT in staging of non-Hodgkin lymphoma. AB - A 56-year-old man, recently diagnosed with non-Hodgkin lymphoma, was referred for a FDG PET/CT scan to stage disease. Unexpected large fluid collections with FDG avid peripheries and central photopenia were demonstrated in the abdomen and pelvis on the FDG PET/CT study. The collections were urgently drained with subsequent resolution. After antibiotic treatment, repeat FDG PET/CT study confirmed rapidly progressive lymphoma necessitating urgent chemotherapy. PMID- 22228358 TI - Papillary thyroid microcarcinoma and ectopic papillary thyroid carcinoma in mediastinum: a case report. AB - Papillary thyroid microcarcinoma is defined as a papillary thyroid cancer measuring <10 mm in its largest diameter. We present the scan images of a 36-year old white woman, with the diagnosis of an incidental papillary thyroid microcarcinoma of 2 mm developed from lymphatic thyroiditis, associated with an invasive papillary thyroid carcinoma with lymph node metastases occurring in an ectopic thyroid gland in the mediastinum. This case underlines the need to evaluate individually and carefully every patient with papillary thyroid microcarcinoma, to accurately plan a therapeutic strategy. PMID- 22228359 TI - Current readings in nuclear medicine. PMID- 22228360 TI - Is there an optimal scan time for 6-[F-18]fluoro-L-DOPA PET in pheochromocytomas and paragangliomas? AB - PURPOSE: To define the appropriate scan time for fluorine-18-labeled dihydroxyphenylalanine (F-18 DOPA) PET in oncological imaging of pheochromocytomas and paragangliomas. MATERIALS AND METHODS: F-18 DOPA PET examinations were performed in 9 patients with 7 pheochromocytomas and 4 head and neck paragangliomas using a dedicated PET scanner. The acquisition started with a dynamic single-bed scan in the tumor region over the first 60 minutes after tracer injection followed by a late time whole-body scan at approximately 130 minutes. Standard uptake values (SUVs) were calculated in tumors, surrounding background, and adjacent normal tissues of relevance. Furthermore, kinetic analysis was performed using a 2-compartment model with rate constants for uptake (K1'), release (k2'), metabolism (k3'), and reverse reaction (k4') for region of interest and pixel-wise analysis. RESULTS: All tumors show a marked increased F 18 DOPA uptake, which was visually detectable and distinguishable from the surrounding tissue. The SUV is significantly lower in neck paraganglioma compared with abdominal pheochromocytomas. Mean time-activity curves of F-18 DOPA in tumors show a rapid uptake of the tracer. Already 2 minutes after the injection, the activity in the tumor is beyond that of the blood pool. The average maximum value (SUVmean = 8.2) has already been reached after 20 minutes. Afterward, a very slight decrease of the tumor SUV starts, which still amounts to 80% of the maximum value after 132 minutes. Due to the continuous decrease of activity in the background tissue, the tumor-to-background ratio of SUVs shows a constant increase within the entire period of examination. The mean values of apparent kinetic constants obtained by region of interest analysis averaged over all tumors are as follows: K1' = 2.89 +/- 2.56 min(-1), k2' = 2.59 +/- 2.81 min(-1), k3' = 0.301 +/- 0.395 min(-1), and k4' = 0.044 +/- 0.043 min(-1). CONCLUSIONS: Pheochromocytoma and paraganglioma take up F-18 DOPA very quickly. At best, the acquisition for static clinical PET imaging of paraganglioma with F-18 DOPA can start at 20 minutes postinjection for maximum uptake in tumors. Separation of tumor, background, and adjacent normal tissues is feasible due to their differences in SUV values and kinetics. The kinetic analysis demonstrates an F-18 DOPA accumulation within the tumor due to considerable differences between the rate constants of uptake and metabolism. Second, in contradiction to healthy brain, paraganglionic tumors show a reversible F-18 DOPA metabolism. PMID- 22228361 TI - Diagnosis of primary aldosteronism in chronic kidney disease by I-131 NP-59 SPECT/CT imaging. AB - Primary aldosteronism (PA) may be missed in patients with chronic kidney disease (CKD), because CKD may disturb the renin-angiotensin-aldosterone system. Adrenal vein sampling has increased risks in patients with CKD. We report the case of a 58-year-old man with CKD and suspected PA. Left adrenal aldosteronism was diagnosed by NP-59 SPECT/CT. Left adrenalectomy demonstrated adrenocortical nodular hyperplasia. Plasma aldosterone normalized and blood pressure stabilized after surgery. NP-59 SPECT/CT may be a helpful diagnostic tool for detecting and lateralizing PA in CKD patients. PMID- 22228362 TI - Assessment of rhabdoid brain tumor by F-18 FDG PET, C-11 methionine PET and MRI. AB - A 28-year-old man with headache, nausea, and decreased vision had a left parieto occipital tumor demonstrated by MRI. Postradical resection and histology showed a solid mass containing rhabdoid cells, 10% positive for Ki-67. After completing chemotherapy and radiotherapy treatment, follow-up MRI revealed possible tumoral recurrence. Cerebral F-18 FDG PET revealed no pathologic uptake, and C-11 methionine PET showed a pathologic low uptake. These findings suggested recurrence of a mild-grade aggressiveness tumor, which was confirmed by a second neurosurgical resection. PMID- 22228363 TI - Incidental finding of meningioma on C11-PIB PET. AB - As a healthy volunteer for amyloid imaging study, a 83-year-old woman with no history of neurologic or psychiatric illness underwent carbon 11-labeled Pittsburgh compound-B (PIB) PET, which showed focal increased PIB binding in the right anterior temporal region. This focal PIB uptake turned out to be a mass lesion on MRI, which was consistent with a benign meningioma. This is the first case report on the incidentally found intracranial meningioma by PIB PET scan, highlighting the excellent sensitivity of PIB radiotracer in detecting brain amyloid deposition. PMID- 22228364 TI - Accidental finding on bone scan: isolated upper sternal cleft in an adult. AB - Cleft sternum is an extremely rare anomaly of development. It results from failure of fusion of midline structures that contribute to the formation of the sternum. The defect may affect the upper sternum, the lower sternum, or the whole sternum. Most cases are diagnosed in childhood when it is associated with serious midline defects. We present a case of an isolated upper sternal cleft in a 55 year-old adult, found accidentally on bone scan. To our knowledge, no bone scan image of cleft sternum could be found in the literature. PMID- 22228365 TI - Unexploited Acacia cyanophylla seeds: potential food sources of omega6 fatty acids and antioxidants? AB - BACKGROUND: In order to investigate new sources of dietary phytochemicals, recent studies have focused on underexploited seeds. In this study the total lipid contents, fatty acid profiles and levels of soluble proteins, minerals and antioxidants in seeds from 12 Acacia cyanophylla ecotypes commonly grown in Tunisia were determined. RESULTS: Total lipids averaged 101.7 g kg(-1) on a dry weight basis. Linoleic (61.11-65.45% of total fatty acid content), oleic (19.67 22.85%) and palmitic (9.18-9.98%) acids were the principal fatty acids. Smaller proportions of stearic (1.49-1.82%), vaccenic (1.13-2.05%) and palmitoleic (0.34 0.58%) acids were also quantified. Proteins (by Kjeldahl assay) averaged 107.2 g kg(-1) on a dry weight basis. Total phenolics averaged 1.91 g gallic acid equivalent kg(-1) dry weight (DW) and total flavonoids averaged 0.40 g rutin equivalent kg(-1) DW. The free radical-scavenging activity determined by 2,2 diphenyl-1-picrylhydrazyl assay averaged 0.59 mmol L(-1) Trolox equivalent antioxidant capacity (TEAC), while that determined by 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) assay averaged 0.28 mmol L(-1) TEAC. CONCLUSION: The findings of this study confirm the presence of omega6 fatty acids at high levels in A. cyanophylla seeds. These metabolites could be used as such and/or extracted for the formulation of supplements and/or ingredients to provide a ratio close to the ideal for the omega3/omega6 balance. PMID- 22228367 TI - Production of lipase from Pseudomonas gessardii using blood tissue lipid and thereof for the hydrolysis of blood cholesterol and triglycerides and lysis of red blood cells. AB - The study demonstrates the production of lipase (LIP) from Pseudomonas gessardii using blood tissue lipid as the substrate for the hydrolysis of blood cholesterol and triglycerides. The lipase was purified with the specific activity of 828 U/mg protein and the molecular weight of 56 kDa. The maximum lipase activity was observed at the pH 7.0 and the temperature 37 degrees C. The amino acid composition of purified lipase was determined by HPLC. The mesoporous activated carbon (MAC) was used for the immobilization of lipase for the repeated use of the enzyme catalyst. The K (m) value of immobilized lipase (MAC-LIP) and the free lipase (LIP) was 0.182 and 1.96 mM, respectively. The V (max) value of MAC-LIP and LIP was 1.33 and 1.26 mM/min, respectively. The MAC and MAC-LIP were characterized by scanning electron microscopy (SEM). The hydrolysis study showed 78 and 100% hydrolysis of triglycerides and cholesterol, respectively, for LIP and 84 and 100% hydrolysis of triglycerides and cholesterol, respectively, for MAC-LIP at the reaction time of 1 h. The effect of lipase on cell wall lysis was carried out on the RBCs of blood plasma. Interestingly, 99.9% lysis of RBCs was observed within 2 h. SEM images and phase contrast microscopy confirmed the lysis of RBCs. This work provides a potential biocatalyst for the hydrolysis of blood cholesterol and triglycerides. PMID- 22228368 TI - Predictive validity of the Glasgow Blatchford Bleeding Score in an unselected emergency department population in continental Europe. AB - BACKGROUND AND AIM: Glasgow Blatchford Bleeding Score stratifies patients presenting with acute upper gastrointestinal haemorrhage at the emergency department according to the likelihood of the need for treatment. The objective of this study was to validate the Glasgow Blatchford Bleeding Score for use in an emergency department in the Netherlands. Furthermore, we assessed its clinical usefulness for safe discharge of low-risk acute upper gastrointestinal haemorrhage patients and compared its test validity to that of other scoring systems. METHODS: This multicentre historic cohort study was conducted in two hospitals in the Netherlands. All 478 patients presenting with a suspicion of acute upper gastrointestinal haemorrhage at our emergency departments during a 1 year period were included. For each patient we calculated Glasgow Blatchford Bleeding Score and other commonly used scores. Test validity was assessed using the receiver operated characteristics curve analysis; calibration plots were used to assess the probability of the need for treatment of different levels of the scores. RESULTS: Glasgow Blatchford Bleeding Score had a good discriminative ability in predicting the need for treatment, receiver operated characteristics curve analysis showed an area under the curve of 0.879. Counting a score of 2 or less as low risk (negative), 104 patients (21.7%) were classified as low-risk, with a negative predictive value of 98.1%. These results were superior to those of the other scoring systems. CONCLUSION: Patients presenting at an emergency department in continental Europe with acute upper gastrointestinal haemorrhage and a Glasgow Blatchford Bleeding Score of 2 or less can be safely discharged. The Glasgow Blatchford Bleeding Score performed better than the other commonly used scoring systems. PMID- 22228369 TI - A case report of cecal plasmablastic lymphoma in a HIV-negative patient. AB - Plasmablastic lymphoma (PBL) is a unique type of diffuse proliferation of large neoplastic lymphoid cells most of which resemble B immunoblasts, but all tumor cells show the immunophenotype of plasma cells. It has a strong predilection for jaw and oral cavity in HIV-positive patients. Incidences of extraoral location of this tumor is increasingly being recognized especially in HIV-negative patients for example, stomach, jejunum, omentum, anorectum, lungs, testes, soft tissues, lymph nodes, bone marrow, skin, and central nervous system. We present a case of PBL found in cecum in an HIV-negative patient. It was accompanied by lung and lymph node involvement and presented as abdominal mass. This is only the second reported case of PBL originating in cecum. PMID- 22228366 TI - Advances in Aspergillus secondary metabolite research in the post-genomic era. AB - This review studies the impact of whole genome sequencing on Aspergillus secondary metabolite research. There has been a proliferation of many new, intriguing discoveries since sequencing data became widely available. What is more, the genomes disclosed the surprising finding that there are many more secondary metabolite biosynthetic pathways than laboratory research had suggested. Activating these pathways has been met with some success, but many more dormant genes remain to be awakened. PMID- 22228370 TI - Is the SPINK1 variant p.N34S overrepresented in patients with acute pancreatitis? AB - OBJECTIVES: Serine Protease Inhibitor Kazal type 1 (SPINK1) protects against premature intracellular activation of trypsinogen and development of acute pancreatitis. Our aim was to determine the prevalence of SPINK1 mutations (a) in unselected patients with first-time acute pancreatitis and (b) in the Danish background population (c) in a meta-analysis to combine the results with findings in similar investigations worldwide and (d) to evaluate whether patients with SPINK1 mutations had a more severe clinical course. METHODS: A total of 75 consecutive patients admitted to a surgical department with first-time acute pancreatitis were prospectively included. In addition, 188 healthy controls were tested for the SPINK1 variants: p.N34S, p.P55S, p.R65Q, p.R67C, and IVS3+2 T>C, in order to calculate the prevalence of SPINK1 mutations in the Danish background population. A meta-analysis was conducted on previous studies on acute pancreatitis and SPINK1 mutations. RESULTS: Two patients (2.7%) and two controls (1.1%) were heterozygous for the p.N34S variant. The meta-analysis confirmed that the p.N34S variant is overrepresented in patients with acute pancreatitis compared with the background population (OR=3.16, P<0.001). But this analysis did not clarify whether this was only true for patients with first-time acute pancreatitis or recurrent pancreatitis as the present studies do not provide this information, and those who do not have enough patients to reach levels of statistic significance, even if data are pooled. CONCLUSION: The SPINK1 variant p.N34S is overrepresented in patients with acute pancreatitis, but more studies distinguishing between first-time and recurrent acute pancreatitis have to be done to determine whether this is only true for patients with recurrent acute pancreatitis. PMID- 22228371 TI - Fulminant liver failure in Wilson's disease with histologic features of postinfantile giant cell hepatitis; cytomegalovirus as the trigger for both? AB - Giant cell hepatitis is a well-known histological feature of several neonatal and infantile liver diseases. In contrast, postinfantile giant cell hepatitis is rarely identified in adult liver biopsies. It has been associated with varying etiologies, mainly viral infections, drug toxicity, and autoimmunity. Here, we report an 18-year-old, previously healthy man with acute liver failure, who showed giant cell hepatitis in a liver biopsy. There was no evidence of viral hepatitis A-E, autoimmunity, and no drug history. Diagnostic work-up revealed Wilson's disease as the underlying disease. As syncytial giant cell formation is thought to be a uniform reaction pattern not related to any specific etiology, copper toxicity in Wilson's disease might cause giant cell formation. In contrast, our patient recalled a recent cytomegalovirus infection, which was confirmed serologically. Therefore, the giant cell formation might also be a fingerprint of an intercurrent cytomegalovirus infection as the common trigger for both giant cell hepatitis and decompensation of Wilson's disease. PMID- 22228372 TI - The role of microRNAs in liver cancer. AB - Hepatocellular carcinoma and cholangiocarcinoma constitute the majority of primary malignant tumors located in the liver, with hepatocellular carcinoma accounting for approximately 80% of these tumors and cholangiocarcinoma representing the remaining 20%. Both are aggressive malignancies, heterogeneous in terms of biological activities and clinical behavior, with dismal outcomes and an increasing incidence worldwide. Radical surgical resection remains the gold standard to date, as adjuvant therapeutic modalities have failed to show a consistent and adequate curative response. However, radical surgical resection is not feasible in most of the patients with such tumors, as tumor size or functional status of the parenchyma does not permit extended hepatic resection. In addition, patients who undergo curative resection often have a high rate of relapse. Multimodal therapeutic approaches, such as the combination of invasive methods (surgical resection, radiofrequency ablation, and two-step or three-step procedures with intermittent portal vein embolization) with interferon-alpha, systemic chemotherapy, or transarterial catheter embolization, may prolong survival in some patients, but have, however, failed to demonstrate satisfactory results. Therefore, an obvious need emerges for the discovery of new biomarkers to understand the events leading to hepatocarcinogenesis, to relate different phenotypes with differences in clinical behavior and prognosis, and, if possible, to predict response rates to adjuvant therapeutic modalities or, furthermore, to establish novel mechanism-based treatments for hepatic tumors. PMID- 22228374 TI - Costs of gastroenteritis in the Netherlands, with special attention for severe cases. AB - In 1999, the costs of gastroenteritis in the Netherlands were estimated using data on hospitalizations from national registries, together with data on etiology and self-reported data on health care resource use in a community-based study. Now, more information on hospitalizations is available and these data were used to update the total costs of gastroenteritis in the Netherlands. The costs of severe gastroenteritis in the Netherlands were estimated in more depth using a hospital-based study, with patient questionnaires including a follow-up period of 6 months. The overall costs of gastroenteritis were calculated taking direct medical costs, direct non-medical costs, and indirect non-medical costs into account. The costs for severe gastroenteritis in 2009 were estimated at 2,203 per hospitalized child and 6,834 per hospitalized adult. The overall costs of gastroenteritis in 2009 were estimated at 611-695 million, which is 133-151 per gastroenteritis case or 37-42 per inhabitant. The total health care costs for gastroenteritis were about 50% higher in 2009 compared to 1999, which is mostly due to the rise in health care costs. The costs per gastroenteritis episode in adults are higher compared to children, mainly due to differences in the reasons for hospitalization and course of disease, and productivity losses. PMID- 22228373 TI - Polymorphism in the protease-activated receptor-4 gene region associates with platelet activation and perioperative myocardial injury. AB - Protease-activated receptors (PAR)-1 and -4 are the principal receptors for thrombin-mediated platelet activation. Functional genetic variation has been described in the human PAR1 gene, but not in the PAR4 gene (F2RL3). We sought to identify variants in and around F2RL3 and to determine their association with perioperative myocardial injury (PMI) after coronary artery bypass graft surgery. We further explored possible mechanisms for F2RL3 single nucleotide polymorphism (SNP) associations with PMI including altered receptor expression and platelet activation. Twenty-three SNPs in the F2RL3 gene region were genotyped in two phases in 934 Caucasian subjects. Platelets from 43 subjects (23 major allele, 20 risk allele) homozygous for rs773857 (SNP with the strongest association with PMI) underwent flow cytometry to assess PAR4 receptor number and response to activation by a specific PAR4 activating peptide (AYPGKF) measured by von Willebrand factor (vWf) binding and P-selectin release and PAC-1 binding. We identified a novel association of SNP rs773857 with PMI (OR = 2.4, P = 0.004). rs773857 risk allele homozygotes have significantly increased platelet counts and platelets showed a significant increase in P-selectin release after activation (P = 0.004). We conclude that rs773857 risk allele homozygotes are associated with risk for increased platelet count and hyperactivity. PMID- 22228375 TI - Revision following patello-femoral arthoplasty. AB - PURPOSE: To describe the population of patients undergoing patello-femoral arthroplasty (PFA) revision and the reasons for which these implants are being revised. To compare this information with the observed failure patterns described in other national registries and with those seen for total knee replacement (TKR). METHODS: Using data accessed from the National Joint Registry for England and Wales, we identified 4634 primary PFA implanted between 1 April 2003 and 30 June 2010. As of 1 July 2010, 195 PFAs had been revised. The epidemiology of PFA revision is described with specific emphasis upon the reasons for revision. RESULTS: The median age at revision was 61 years (145 F:50 M). Revision occurred at a median of 2.0 years following primary surgery. Sixty of the 98 centres (61%) performing PFA revisions undertook only one such procedure. The 195 revisions were undertaken by 140 different consultants. Unexplained pain was the reason for revision in 46% of cases where a reason was stated. Progression of tibio-femoral arthritis was seen in only 14% of cases. Undiagnosed pain remained the most common reason for revision irrespective of patient age and time to revision, and was twice as common for PFA revision when compared to a matched group of failed TKR (43% vs. 19%, P < 0.001). CONCLUSIONS: Unexplained pain is the principal indication for early revision of the failing PFA. The high proportion of revisions performed for unexplained pain raises questions about the adequacy of surgical selection for patients undergoing PFA. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 22228376 TI - A biomechanical comparison of the primary stability of two minimally invasive techniques for repair of ruptured Achilles tendon. AB - PURPOSE: To compare the primary stability of two minimally invasive procedures of Achilles tendon (AT) repair, namely a modified percutaneous repair of ruptured AT and the Achillon suture configuration. METHODS: Eighteen (nine matched pairs) frozen ovine ATs were tenotomized 5 cm from the calcaneal insertion. In each pair, one tendon was randomly allocated to one of the two techniques: a modified percutaneous repair group and the Achillon device suture configuration. Specimens were tested performing an unidirectional tensile load to failure using a servo hydraulic testing device (MTS Systems, Eden Prairie, MN, USA), controlled by an electropulse e3000 INSTRON machine (Instron Ltd, Buckinghamshire, UK). The tendons were then loaded to failure at a rate of 10 mm/s. RESULTS: Two of the nine pairs of specimens were discarded because one specimen for each of the pair pulled out of the pneumatic clamp during mechanical testing. The remaining seven matched pairs were successfully tested. There were no differences in mean strength, mean maximum load, mean failure elongation, tension, stiffness and mode of failure between the two groups. CONCLUSION: The Achillon-like configuration and the modified percutaneous repair of ruptured AT provided similar biomechanical performance. PMID- 22228377 TI - New mechanism of the posterior elbow dislocation. AB - PURPOSE: To suggest a new model on the most common kind of posterior elbow dislocation using MRI findings on acute elbow injuries. METHODS: Fifteen patients with simple elbow dislocation (Group A) and 19 patients sustaining pure ligament injuries (Group B) were enrolled in this study. Using MRI scans, bony contusion at radial head and posterior capitellum (lateral bone contusion) and medial aspect of the ulnohumeral joint (medial bone contusion) were investigated with the injury patterns of the collateral ligament and overlying muscles. In Group A, the injury patterns of the ulnar and lateral ulnar collateral ligaments were classified into distraction or stripping type; in Group B, into rupture or strain. Based on these findings, we speculated the injury mechanism of the elbow dislocation. RESULTS: In Group A, posterolateral (PL) dislocation was found in 12 cases of distractive ulnar collateral ligament type and stripping lateral ulnar collateral ligament type, where lateral bone contusion was found in 11 cases. Posteromedial (PM) dislocation was observed in only two cases of distraction type of the LUCL, where medial bone contusion was seen in two cases. In PL dislocation of the elbow joint, we always found more severe damage of soft tissue at the medial side of the elbow joint compared to the lateral side. Lateral bone contusion was speculated to be caused by bony abutment under pathologic forearm external rotation (PFER) and medial bone contusion, by bony abutment under varus stress. In Group B, the ulnar collateral ligament was more commonly injured than the lateral ulnar collateral ligament, and lateral bone contusion accompanied most cases. CONCLUSION: PL dislocation is thought to start from the medial side in contrary to PM dislocation beginning at the lateral side. If the disengagement of the coronoid process is not completed due to the insufficient valgus/varus distraction, a coronoid fracture will develop at the same time as the elbow dislocation during PFER. PMID- 22228378 TI - Infections associated with spinal implants. AB - Spinal infections represent a difficult challenge to treating clinicians. Infections in the presence of implants are even more so. In this review the literature appears to reflect a change of practice in which the aim is to retain implants if possible. The newer spinal procedures such as disc replacements pose different problems largely due to the more difficult access. The situation in the spine is more difficult than in general orthopaedics when dealing with infection due to the requirement for stability and to protect neurological function. The main thrust of management, therefore, is early diagnosis and a high index of suspicion followed by adequate if not radical management in a multidisciplinary setting. In the event prevention is better than cure and therefore consideration of the various mechanisms to avoid infection must be taken. There are some 'novel' considerations for the avoidance of infection alongside the tried and tested techniques. There are also new procedures for wound closure and the elimination of dead space. PMID- 22228379 TI - Relationship of endothelial function and atherosclerosis to treatment response in late-life depression. AB - OBJECTIVE: Treatment response in late-life depression has been linked to cerebrovascular disease notably via the vascular depression hypothesis. This study investigated the relationship between endothelial function and atherosclerosis and treatment response to antidepressant monotherapy. METHODS: Twenty five patients with late-life depression were compared with 21 non depressed control subjects in a case control study. Nine of the depressed subjects were responders to antidepressant monotherapy and 16 were not. Vascular measures included assessment of carotid intima media thickness (IMT) representing atherosclerosis and biopsied small artery dilatation to acetylcholine to assess endothelial function in a subset of subjects. RESULTS: There were no group differences in vascular risks or sociodemographic variables. There was a significant group difference (responders versus non-responders versus controls) on both IMT and endothelial function (p < 0.01 and p < 0.05, respectively) with a significant difference between controls and non-responders (p < 0.001) on IMT and between controls and responders (p < 0.05) and control versus non-responders (p < 0.05) on endothelial function but no significant difference between responders and non-responders. On both IMT and endothelial function, there was a gradient across groups, with control subjects having best vascular structure or function, non-responders worse and responders in-between. CONCLUSIONS: The results are consistent with a hypothesis that poorer antidepressant response in later life depressive disorder may be linked to an underlying vascular dysfunction and pathology. The study is small, and the results require replication but if confirmed, trials with vasoprotective medication aimed at improving vascular function in order to alter the prognosis of late-life depression would be a rational development. PMID- 22228380 TI - Chiral separation of Huperzine A using CE - method validation and application in pharmaceutical formulations. AB - The aim of this work is the development, validation and application of an MEKC method for the chiral separation of Huperzine A. Huperzine A is an important compound that is used to treat Alzheimer's disease. However, only the (-)-form of this compound is biologically active and behaves as a potential acetylcholinesterase inhibitor. Therefore, the separation of the (-)-form from the (+)-form is of greatest importance. Optimal conditions, regarding resolution and analysis time, were established by altering several experimental parameters, such as temperature, field strength, pH, type and concentration of BGE and chiral selector. A major problem that had to be solved in this study was the low intensity and efficiency of the peaks. More parameters were examined, such as the addition of modifiers, to optimize further the separation, and particularly the efficiency. Baseline enantioseparation was achieved by using a BGE of 50 mM acetate (pH 5.0), supplemented with 0.2% w/v poly(sodium N-undecanoyl-ll-alanyl valinate) and 10% v/v tert-butanol. Finally, the optimum conditions were applied to a pharmaceutical formulation, to demonstrate the ability of the method to control the purity of the (-)-Huperzine A in pharmaceutical formulations. PMID- 22228381 TI - Cardiovascular effects of black tea and nicotine alone or in combination against experimental induced heart injury. AB - The present study was designed to elucidate the outcome of subchronic co administration of black tea and nicotine on cardiovascular performance and whether these substances could modulate the isoproterenol-induced cardiac injury. Animal groups were control, black tea, nicotine and black tea plus nicotine. Test groups received nicotine (2 mg/kg s.c.) and black tea brewed (p.o.) each alone and in combination for 4 weeks. On the 28th day, myocardial damage was induced by isoproterenol (50 mg/kg i.p.), and blood samples were taken. On day 29, after hemodynamic parameters recording, hearts were removed for histopathological evaluation. Tea or nicotine consumption had no significant effects on hemodynamic indices of animals without heart damage. When the cardiac injury was induced, tea consumption maintained the maximum dp/dt, and nicotine significantly decreased the pressure-rate product. Moreover, severity of heart lesions was lower in the presence of nicotine or black tea. Concomitant use of these materials did not show extra effects on mentioned parameters more than the effect of each of them alone. The results suggest that subchronic administration of black tea or nicotine for a period of 4 weeks may have a mild cardioprotective effect, while concomitant use of these materials cannot intensify this beneficial effect. PMID- 22228382 TI - Prospective investigation of pituitary functions in patients with acute infectious meningitis: is acute meningitis induced pituitary dysfunction associated with autoimmunity? AB - Previous case reports and retrospective studies suggest that pituitary dysfunction may occur after acute bacterial or viral meningitis. In this prospective study we assessed the pituitary functions, lipid profile and anthropometric measures in adults with acute bacterial or viral meningitis. Moreover, in order to investigate whether autoimmune mechanisms could play a role in the pathogenesis of acute meningitis-induced hypopituitarism we also investigated the anti-pituitary antibodies (APA) and anti-hypothalamus antibodies (AHA) prospectively. Sixteen patients (10 males, 6 females; mean +/- SD age 40.9 +/- 15.9) with acute infectious meningitis were included and the patients were evaluated in the acute phase, and at 6 and 12 months after the acute meningitis. In the acute phase 18.7% of the patients had GH deficiency, 12.5% had ACTH and FSH/LH deficiencies. At 12 months after acute meningitis 6 of 14 patients (42.8%) had GH deficiency, 1 of 14 patients (7.1%) had ACTH and FSH/LH deficiencies. Two of 14 patients (14.3%) had combined hormone deficiencies and four patients (28.6%) had isolated hormone deficiencies at 12 months. Four of 9 (44.4%) hormone deficiencies at 6 months were recovered at 12 months, and 3 of 8 (37.5%) hormone deficiencies at 12 months were new-onset hormone deficiencies. At 12 months there were significant negative correlations between IGF-I level vs. LDL-C, and IGF-I level vs. total cholesterol. The frequency of AHA and APA positivity was substantially high, ranging from 35 to 50% of the patients throughout the 12 months period. However there were no significant correlations between AHA or APA positivity and hypopituitarism. The risk of hypopituitarism, GH deficiency in particular, is substantially high in the acute phase, after 6 and 12 months of the acute infectious meningitis. Moreover we found that 6th month after meningitis is too early to make a decision for pituitary dysfunction and these patients should be screened for at least 12 months. In addition, the occurrence of AHA and APA positivity due to acute infectious meningitis was demonstrated for the first time. Further longer-term prospective investigations need to be carried out on a larger cohort of patients to understand the role of autoimmunity in the pathogenesis of late hypopituitarism after acute infectious meningitis. PMID- 22228384 TI - Copper complexes of a novel non-innocent quadridentate ligand. AB - Quadridentate ligand H(2)L binds Cu(I) to form salt [Cu(I)(H(2)L)]BF(4) which undergoes aerial oxidation in solution with isolation of the diamagnetic salt [Cu(II)L(-)]BF(4) where pi-radical anion L(-) is the (1e(-), 2H(+)) oxidation product of H(2)L. PMID- 22228383 TI - Does dynamical synchronization among neurons facilitate learning and enhance task performance? AB - Synchronization among groups of neurons is an interesting yet mysterious mechanism in the brain. We propose and demonstrate that the adjustable timing of neural activities can produce profound effect on learning and task implementation. On one hand, learning of more complex patterns becomes possible because of the enhanced capability of classification. On the other hand, implementation of a complex task is aided through active maintenance and control of multiple rules and items. This sheds light on the development of new intelligent system, as well as the cause of impaired learning and task performance in patients. PMID- 22228385 TI - A case with vesicouterine fistula: mini review. AB - AIM: The objective is to present a case with vesicouterine fistula after cesarean section. CASE: A 27-year-old female patient, G2P2, was admitted to hospital with the complaint of severe crampy pelvic pain and dysuria during micturition without any incontinence. She had two cesarean sections, last was 14 months before admission. Her urinalysis revealed microscopic hematuria. Diagnosis of uterovesical fistula suspected by transvaginal ultrasonography and diagnosed by hysterography. Vesicouterine fistula operated by transperitoneal approach without any complication. CONCLUSION: Increasing cesarean section rates concomitantly carries increasing maternal and neonatal adverse outcomes including operative complications as genitourinary fistulae. PMID- 22228386 TI - A case of yolk sac tumor of the vagina in an infant. AB - We report a case of a vaginal yolk sac tumor in a 5-month-old female infant who presented with short history of bleeding per vagina. Magnetic resonance imaging showed a mass occupying most of the vagina that had lobulated outlines and heterogeneous echo texture. The serum alpha-fetoprotein was elevated, and a biopsy revealed a vaginal yolk sac tumor. The patient was given six cycles of chemotherapy and continues to be disease-free on follow up. To preserve sexual and reproductive function, we encourage consideration of chemotherapy as a sole modality to treat this rare tumor. PMID- 22228387 TI - Reducing staff isolation and developing evidence-informed practice in the aged care environment through an action research approach to falls prevention. AB - This study aimed to examine whether an action research approach was effective in reducing the isolation of staff in 2 residential aged care facilities, within the context of an evidence-informed falls prevention program. A Falls Action Research Group comprising 12 nursing/nonnursing staff across 2 residential aged care facilities was established and engaged in critical dialogue and action over 12 months to improve their fall prevention activities. Through the group members' engagement, a research community was established that diminished staff isolation by engaging members in a sustained process of collaboration around falls prevention, which worked to disrupt occupational silos and challenge traditional staff hierarchies. PMID- 22228388 TI - Race and microaggression in nursing knowledge development. AB - Race is a social environmental element in many nursing knowledge contexts. We explore how race and racism have been conceptualized in nursing research and theory, situating these issues in the debate between Critical Race Theory and postracialism. Contemporarily, racism is more subtle than overt. Subtle racism takes the form of microaggressions in everyday discourse and practices by whites toward African Americans. This occurs with little to no awareness on the part of whites. Using this concept, practice and education are explored. We hold that microaggressions contribute to stress for the target person, which may partly account for racial health disparities. PMID- 22228389 TI - Super-compressibility of ultralow-density nanoporous silica. PMID- 22228390 TI - Efficacy of normal saline versus heparinized saline solution for locking catheters of totally implantable long-term central vascular access devices in adult cancer patients. AB - BACKGROUND: Heparin solution is routinely used to maintain the patency of infusion devices. Literature supports the alternative use of normal saline solution for flushing and locking intravenous infusion devices especially for pediatric patients. There is uncertainty regarding safety and efficacy of this policy for intermittent locking of implanted ports. OBJECTIVE: This study evaluates efficacy and safety of normal saline solution for intermittent locking procedures of implanted ports. METHODS: This is a retrospective observational cohort study of 610 implanted ports receiving 2 different locking solutions conducted at the National Institute for Cancer Research, IST Genova, Italy, from January 2007 to August 2009. Group A (n = 297) received heparinized solution (10 mL/500 U heparin), whereas group B (n = 313), 10 mL normal saline. Primary endpoint was irreversible port occlusion. Minimum follow-up was 12 months. The role of age, type of tumor, disease stage, access site, access body side, catheter tip position, and concomitant use of parenteral nutrition and chemotherapy was evaluated in secondary aim. RESULTS: : Results fail to show statistically significant differences in implanted ports survival free from failure for occlusive events between the use of heparinized solution and that of normal saline for the maintenance of port patency, both in univariate (P = .9) and in multivariate analyses (P = .7). CONCLUSION: Normal saline solution seems to be as effective as heparinized solution for keeping patent implanted ports in adult cancer patients. IMPLICATIONS FOR PRACTICE: Switching from heparinized solution to normal saline for catheter intermittent lock of ports seems a safe procedure. PMID- 22228391 TI - Common biological pathways underlying the psychoneurological symptom cluster in cancer patients. AB - BACKGROUND: A symptom cluster is a group of symptoms that occur together and are interrelated. The clinical implication of symptom cluster research is to use the clustering patterns of symptoms to understand the mechanisms for these symptoms and develop management strategies targeted at multiple symptoms. OBJECTIVE: The purposes of this review were to summarize the evidence for a psychoneurological symptom cluster in cancer patients, to provide information regarding the underlying biological mechanisms for each of the psychoneurological symptoms within the cluster, and to propose possible common biological pathways that may underlie this cluster. METHODS: A systematic review of the literature was conducted. RESULTS: Empirical evidence exists to support a cluster of psychoneurological symptoms (ie, depressive symptoms, cognitive disturbance, fatigue, sleep disturbance, pain). At a molecular level, common biological pathways (ie, proinflammatory cytokines, hypothalamic-pituitary-adrenal axis, and monoamine neurotransmission system) may underlie the development of symptoms within this cluster. Activation of proinflammatory cytokines is proposed as a first stage of mechanistic pathway. However, other biological factors, such as lowered estrogen or hemoglobin levels, may influence psychoneurological cluster. CONCLUSION: Additional studies are needed to confirm the roles of cytokines as well as other biological factors in the development of the psychoneurological cluster and to determine the biomarkers to identify the subgroups of cancer patients who are at greatest risk for this cluster. IMPLICATIONS FOR PRACTICE: This information can be used by researchers and clinicians to guide the selection of symptom management strategies that are ideally targeted to the biological mechanisms that underlie this symptom cluster. PMID- 22228392 TI - The effect of a pain management program on patients with cancer pain. AB - BACKGROUND: Pain is 1 of the most common symptoms that a cancer patient would experience. A significant barrier to positive pain management is patients' misconceptions regarding analgesics and inadequate use of nonpharmacological strategies as pain relief. OBJECTIVE: The purpose of this study was to investigate the effectiveness of a pain management program (PMP) on pain intensity, use of PRN drugs and nonpharmacological strategies as pain relief, and barriers to managing pain in cancer patients. METHODS: The study was conducted in the palliative care and hospice ward of a public hospital in Hong Kong. Patients were randomized to either an experimental group (receiving the PMP) or a control group (routine care). There were 38 hospitalized patients, with 20 (13 males and 7 females) in the experimental group and 18 (11 males and 7 females) in the control group; mean age was 61.95 years (experimental group) to 63.94 years (control group). RESULTS: Upon the completion of PMP, pain scores were significantly reduced in both groups, yet patients in the experimental group showed a significant increase in the use of PRN analgesics and nonpharmacological strategies to relieve pain (P < .05) and significantly reduce barriers to managing their cancer pain (P < .05) compared with the control group. CONCLUSION: Cancer patients should be empowered with pain management education to gain knowledge and correct misconceptions in managing their cancer pain. IMPLICATIONS FOR PRACTICE: Integration of the PMP into routine clinical work may help to improve the standard of care for cancer patients. It is recommended to provide pain management education to all cancer patients. PMID- 22228393 TI - Who will drop out and who will drop in: exercise adherence in a randomized clinical trial among patients receiving active cancer treatment. AB - BACKGROUND: Adherence has significantly affected the efficacy of a randomized clinical trial (RCT) to test exercise interventions. OBJECTIVE: The aims of this study were to analyze exercise-related adherence patterns among patients receiving active cancer treatment and to identify factors related to exercise adherence and contamination in both the intervention and control groups. METHODS: This is a secondary analysis of data from an RCT of a home-based walking intervention for patients receiving active cancer treatment. Hierarchical Poisson regression analysis was used to identify factors related to exercise adherence and exercise contamination in the exercise intervention and control groups. RESULTS: A total of 126 patients finished the study. Exercise adherence rate in the intervention group was 32.35%, whereas exercise contamination rate in the control group was 12.07%. Independent predictors of adherence for the exercise group were baseline physical fitness, pretreatment fatigue level, treatment related mood disturbance, and marital status (P < .01); exercise history significantly predicted exercise contamination (P < .00) in the control group. CONCLUSION: Adherence remains an issue in an exercise RCT among patients on active cancer treatment. Adherence is related to symptom, physical function, and exercise history. IMPLICATIONS FOR PRACTICE: Exercise researchers should consider stratifying samples based on pretreatment variables found to be significantly associated with outcome variables in this study to reduce confounding effects. Oncology clinicians can use the study findings to appropriately tailor strategies to encourage exercise adherence among patients receiving active cancer treatment so that these patients can receive the known benefits of exercise. PMID- 22228395 TI - Cancer cachexia care: the contribution of qualitative research to evidence-based practice. AB - BACKGROUND: Despite its prevalence and prognostic impact, primary cachexia is not well understood. Its potential to cause considerable psychological stress indicates the need for qualitative research to help understand the perspectives of those affected. OBJECTIVE: The aims of this study were to describe the perspectives of patients with primary cachexia, of their relatives, and of the healthcare professionals involved in their care and to demonstrate how this evidence can be applied in practice at 4 different levels of application ranging from empathy to coaching. METHODS: A review of the qualitative literature and empirical qualitative investigation was used to understand the experiences of patients and relatives and the perspectives of professionals. RESULTS: The main worries expressed by patients and relatives concerned appetite loss, changing appearance, prognosis, and social interaction. We also describe their coping responses and their views of professionals' responses. The main concerns of professionals related to poor communication, lack of clinical guidance, and lack of professional education. CONCLUSIONS: Understanding patients', families', and professionals' perspectives, and mapping that understanding onto what we know about the trajectory and prognosis of the condition, provides the evidence base for good practice. Qualitative research has a central role to play in providing the knowledge base for the nursing care of patients with cachexia. IMPLICATIONS FOR PRACTICE: The evidence provided can improve nurses' insight and assist them in assessment of status, the provision of guidance, and coaching. There is a need for the development of a holistic, information-based integrated care pathway for those with cancer cachexia and their families. PMID- 22228394 TI - Health-related quality of life of african american breast cancer survivors compared with healthy African American women. AB - BACKGROUND: The diagnosis and treatment of breast cancer can result in an array of late cancer-specific side effects and changes in general well-being. Research has focused on white samples, limiting our understanding of the unique health related quality of life outcomes of African American breast cancer survivors (BCSs). Even when African American BCSs have been targeted, research is limited by small samples and failure to include comparisons of peers without a history of breast cancer. OBJECTIVE: The purpose of this study was to compare health-related quality of life of African American female BCSs with that of African American women with no history of breast cancer (control group). METHODS: A total of 140 women (62 BCSs and 78 controls), 18 years or older and 2 to 10 years postdiagnosis, were recruited from a breast cancer clinic and cancer support groups. Participants provided informed consent and completed a 1-time survey based on the proximal-distal health-related quality of life model of Brenner et al (1995). RESULTS: After adjusting for age, education, income, and body mass index, results show that African American BCSs experienced more fatigue (P = .001), worse hot flashes (P < .001), and worse sleep quality (P < .001) but more social support from their partner (P = .028) and more positive change (P = .001) compared with African American female controls. CONCLUSIONS: Our results suggest that African American female BCSs may experience unique health-related outcomes that transcend age, education, socioeconomic status, and body mass index. IMPLICATIONS FOR PRACTICE: Findings suggest the importance of understanding the survivorship experience for particular racial and ethnic subgroups to proactively assess difficulties and plan interventions. PMID- 22228396 TI - A descriptive study of the psychosocial well-being and quality of life of childhood cancer survivors in Hong Kong. AB - BACKGROUND: Research indicates that increased survival rates are accompanied by an increase in associated psychosocial problems. Whereas much of the attention has focused on the physiological care of childhood cancer survivors, the consequences of cancer and its treatments on psychosocial well-being and quality of life remain relatively underexplored. OBJECTIVE: The aim of this study was to describe the psychosocial well-being and quality of life of Hong Kong Chinese childhood cancer survivors. METHODS: A cross-sectional study was used. A total of 137 childhood cancer survivors (9- to 16-year olds) who underwent medical follow up in the outpatient clinic were invited to participate in the study. RESULTS: A significant number of childhood cancer survivors had low self-esteem and experienced high levels of depression. The study also indicated that greater symptoms of depression in childhood cancer survivors were associated with higher state anxiety, lower self-esteem, and poor quality of life. CONCLUSIONS: Cancer and its treatments can have adverse effects on the psychosocial well-being and quality of life of survivors. IMPLICATIONS FOR PRACTICE: It is essential for nurses to develop and evaluate interventions with the aim of promoting psychosocial well-being and quality of life for childhood cancer survivors. Knowing the self-esteem and coping behavior of survivors can help design appropriate and effective psychosocial interventions to promote their psychosocial well-being. PMID- 22228397 TI - Zinc deficiency in field-grown pecan trees: changes in leaf nutrient concentrations and structure. AB - BACKGROUND: Zinc (Zn) deficiency is a typical nutritional disorder in pecan trees [Carya illinoinensis (Wangenh.) C. Koch] grown under field conditions in calcareous soils in North America, including northern Mexico and south-western United States. The aim of this study was to assess the morphological and nutritional changes in pecan leaves affected by Zn deficiency as well as the Zn distribution within leaves. RESULTS: Zinc deficiency led to decreases in leaf chlorophyll concentrations, leaf area and trunk cross-sectional area. Zinc deficiency increased significantly the leaf concentrations of K and Ca, and decreased the leaf concentrations of Zn, Fe, Mn and Cu. All nutrient values found in Zn-deficient leaves were within the sufficiency ranges, with the only exception of Zn, which was approximately 44, 11 and 9 ug g(-1) dry weight in Zn sufficient, moderately and markedly Zn-deficient leaves, respectively. Zinc deficiency led to decreases in leaf thickness, mainly due to a reduction in the thickness of the palisade parenchyma, as well as to increases in stomatal density and size. The localisation of Zn was determined using the fluorophore Zinpyr-1 and ratio-imaging technique. Zinc was mainly localised in the palisade mesophyll area in Zn-sufficient leaves, whereas no signal could be obtained in Zn-deficient leaves. CONCLUSION: The effects of Zn deficiency on the leaf characteristics of pecan trees include not only decreases in leaf chlorophyll and Zn concentrations, but also a reduction in the thickness of the palisade parenchyma, an increase in stomatal density and pore size and the practical disappearance of Zn leaf pools. These characteristics must be taken into account to design strategies to correct Zn deficiency in pecan tree in the field. PMID- 22228399 TI - Reversible, opto-mechanically induced spin-switching in a nanoribbon-spiropyran hybrid material. AB - It has recently been shown that electronic transport in zigzag graphene nanoribbons becomes spin-polarized upon application of an electric field across the nanoribbon width. However, the electric fields required to experimentally induce this magnetic state are typically large and difficult to apply in practice. Here, using both first-principles density functional theory (DFT) and time-dependent DFT, we show that a new spiropyran-based, mechanochromic polymer noncovalently deposited on a nanoribbon can collectively function as a dual opto mechanical switch for modulating its own spin-polarization. These calculations demonstrate that upon mechanical stress or photoabsorption, the spiropyran chromophore isomerizes from a closed-configuration ground-state to a zwitterionic excited-state, resulting in a large change in dipole moment that alters the electrostatic environment of the nanoribbon. We show that the electronic spin distribution in the nanoribbon-spiropyran hybrid material can be reversibly modulated via noninvasive optical and mechanical stimuli without the need for large external electric fields. Our results suggest that the reversible spintronic properties inherent to the nanoribbon-spiropyran material allow the possibility of using this hybrid structure as a resettable, molecular-logic quantum sensor where opto-mechanical stimuli are used as inputs and the spin polarized current induced in the nanoribbon substrate is the measured output. PMID- 22228398 TI - Inhibition of cathepsin K for treatment of osteoporosis. AB - Cathepsin K is the protease that is primarily responsible for the degradation of bone matrix by osteoclasts. Inhibitors of cathepsin K are in development for treatment of osteoporosis. Currently available antiresorptive drugs interfere with osteoclast function. They inhibit both bone resorption and formation, due to the coupling between these processes. Cathepsin K inhibitors, conversely, target the resorption process itself and may not interfere with osteoclast stimulation of bone formation. In fact, when cathepsin K is absent or inhibited in mice, rabbits, or monkeys, bone formation is maintained or increased. In humans, inhibition of cathepsin K is associated with sustained reductions in bone resorption markers but with smaller and transient reductions in bone formation markers. The usefulness of cathepsin K inhibitors in osteoporosis is now being examined in phase 2 and phase 3 clinical trials of postmenopausal osteoporotic women. PMID- 22228400 TI - How to manage thyroid nodules with two consecutive non-diagnostic results on ultrasonography-guided fine-needle aspiration. AB - BACKGROUND: The aim of this study was to investigate the factors for considering surgery on thyroid nodules that had non-diagnostic results on two consecutive cytology examinations. METHODS: A total of 104 thyroid nodules with two consecutive non-diagnostic cytology examinations in 104 patients were investigated. Nodules with one or more suspicious ultrasonography (US) features of marked hypoechogenicity, a not well defined margin, microcalcifications, or a taller-than-wide shape were assessed as sonographically suspicious. Those without any suspicious features were assessed as sonographically benign. The clinicopathologic characteristics of patients and US features of the nodules were compared according to malignancy and benignity. The odds ratio for predicting malignancy was calculated. RESULTS: Altogether, 12 nodules were malignant, and 92 were benign. Age, sex, nodule size, and solidness were not associated with malignancy (P = 0.73, 0.92, 0.48, and 0.73, respectively). The malignancy rate of sonographically suspicious nodules was 25.7%, higher than the 4.3% of sonographically benign nodules (P = 0.002). The odds ratio of sonographically suspicious nodules for predicting malignancy was 16.01 (95% confidence interval 2.36-108.54, P = 0.005). CONCLUSIONS: Based on sonographic features, surgery can be performed selectively on nodules with two consecutive non-diagnostic cytology results. PMID- 22228401 TI - Pierson syndrome in an adolescent girl with nephrotic range proteinuria but a normal GFR. AB - BACKGROUND: Pierson syndrome, caused by mutations in the LAMB2 gene, was originally described as a combination of microcoria and congenital nephrotic syndrome, rapidly progressing to end-stage renal failure. CASE DIAGNOSIS/TREATMENT: We report a minor variant of Pierson syndrome in a teenage girl with severe myopia since early infancy and proteinuria first detected at age 6. At the age of 11 she was found to carry a unique homozygous non-truncating LAMB2 mutation in exon 2: c.T240G (p.S80R). Renal biopsy revealed mild diffuse mesangial sclerosis and residual expression of laminin beta2. Today at age 14, on treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, she continues to have nephrotic range proteinuria, but a normal glomerular filtration rate. CONCLUSIONS: LAMB2 mutations should be considered in all patients with glomerular proteinuria and abnormal ocular phenotype, irrespective of age and disease severity. PMID- 22228402 TI - Zosuquidar and an albumin-binding prodrug of zosuquidar reverse multidrug resistance in breast cancer cells of doxorubicin and an albumin-binding prodrug of doxorubicin. AB - The P-glycoprotein (P-gp) is a 170-kDa protein that acts as an energy dependent, transmembrane efflux pump and is encoded by the MDR1 gene. It has been shown to be responsible for multidrug resistance (MDR) in a defined subpopulation of breast cancer patients and thus represents a molecular target for circumventing MDR in this tumor indication. MDR modulators have been developed and demonstrated high selectivity for P-gp with inhibitory activities in the low nanomolar range. Although some objective responses were achieved in clinical trials, combination therapy with these MDR modulators, such as Ca2+ antagonists caused unacceptable toxicity. Targeting P-gp inhibitors to the tumor site is a mean to increase their therapeutic index, and in this context binding of tailor-made prodrugs to circulating albumin is an established technology to reduce the toxicity and enhance the efficacy of anticancer drugs. In this study, we consequently developed an acid-sensitive albumin-binding prodrug of the P-gp inhibitor zosuquidar (LY335979) in a two-step synthesis using a maleimide hydrazone linker system established in our laboratory that first introduces acetylbenzoic acid at the HO-group of zosuquidar followed by derivatization with 6-maleimidocaproyl hydrazide to form the acid-sensitive hydrazone bond. The maleimide group enables the prodrug to bind rapidly and selectively to the cysteine-34 position of endogenous albumin after intravenous administration. HPLC analysis demonstrated rapid albumin binding of the zosuquidar prodrug as well as the quantitative release of the acetylbenzoic ester derivative of zosuquidar at pH 5.0. Subsequently, its ability to circumvent MDR was tested in two doxorubicin resistant breast carcinoma cell lines (MCF-7/ADR and MT-3/ADR). The MDR status of these cell lines can be reversed by zosuquidar which was confirmed in a rhodamine 123 assay using fluorescence microscopy and FACS analysis. Furthermore, zosuquidar as well its acid-sensitive albumin conjugate re-sensitized cells to doxorubicin as well as to an albumin-binding prodrug of doxorubicin, i.e., the 6 maleimidocaproyl hydrazone derivative of doxorubicin, achieving IC50 values in the same order of magnitude as the parental cell lines. Thus, a novel formulation of zosuquidar has been developed that could have the potential to improve the toxicity issues and tumor targeting properties of the original compound. PMID- 22228403 TI - Characteristics of translocation (16;16)(p13;q22) acute myeloid leukemia. AB - A subgroup of patients with core binding factor acute myeloid leukemias (AML) is characterized by the presence of the fusion gene CBFb-Myh11. At the cytogenetic level, most of these patients are identified by the presence of an inversion of chromosome 16 [inv(16)(p13q22)] and rarely by a translocation t(16;16)(p13;q22). The aim of this study is to describe the natural history of patients with t(16;16) [N = 6] treated at MD Anderson Cancer Center and compared them with a cohort of patients with inv(16)(p13q22) [n = 61]. In patients with t(16;16) the complete remission rate (CR) was 100% when treated with a combination of fludarabine and high-dose cytarabine. Median overall survival (OS) had not been achieved. There was no difference in response or OS or progression free survival between both groups. Presence of additional chromosomal abnormalities and molecular aberrations had no effect on prognosis. In conclusion, and consistent with previous reports, the natural history of patients with t(16:16)(p13;q22) is similar to that of classic patients with inv16 AML and therefore should be treated similarly. PMID- 22228404 TI - Vagal versus recurrent laryngeal nerve monitoring in thyroid surgery. PMID- 22228405 TI - NHC-catalyzed thioesterification of aldehydes by external redox activation. AB - The NHC-catalyzed thioesterification of aromatic or aliphatic aldehydes with a range of thiols was developed in the presence of a stoichiometric amount of an organic oxidant. Among the oxidants examined, phenazine was shown to give the best results in terms of chemical yield and compatibility with thiols. PMID- 22228406 TI - Biomarkers in catfish Sciades herzbergii (Teleostei: Ariidae) from polluted and non-polluted areas (Sao Marcos' Bay, Northeastern Brazil). AB - Biomarkers based on specific enzyme activities and histological alterations are useful tools for evaluating toxicological effects of xenobiotics in wild fish. In this work, an experimental system of biomarkers with enzyme glutathione S transferase (GST) and branchial lesions in catfish (Sciades herzbergii) was mathematically modeled. The fish were collected along known pollution gradients (S1) and from areas regarded relatively free of anthropogenic input (S2) in Sao Marcos' Bay, Brazil. GST was measured spectrophotometrically, and branchial lesions were examined by light microscope. The databases from this analysis were compiled, and non-linear models were used to analyze the dependence of the enzyme activity on the areas of sampling and on selected biological parameters of the fish. Fish weight, length, and somatic indices (gonadosomatic index) were significant in the model of GST activity only in A2. Brachial lesions were significant in the model of GST activity only in A1. The obtained model indicates that when the GST ceases to act, serious branchial lesions are observed in the fish of the contaminated regions. PMID- 22228407 TI - Ecotype dependent expression and alternative splicing of epithiospecifier protein (ESP) in Arabidopsis thaliana. AB - Epithiospecifier protein (ESP) is responsible for diverting glucosinolate hydrolysis from the generation of isothiocyanates to that of epithionitriles or nitriles, and thereby negatively affects the ability of the plant to defend itself against certain insects. Despite this important role of ESP, little is known about its expression in plant tissues and the regulation thereof. We therefore investigated ESP expression by qPCR and Western blot in different organs during the growth cycle of the two Arabidopsis thaliana ecotypes Col-0 and Mt-0. Besides the fact that ESP transcript and protein levels were revealed to be much higher in Mt-0 than in Col-0 in all cases, our qPCR results also indicated that ESP expression is regulated differently in the two A. thaliana ecotypes. No ESP protein was detected by Western blot in any organ or developmental stage for Col-0. During the assays an alternative splice variant of ESP was identified in Col-0, but not Mt-0, leading to a mis-spliced transcript which could explain the low expression levels of ESP in the former ecotype. Analysis of genomic sequences containing the ESP splice sites, of ESP protein level and ESP activity from seven A. thaliana ecotypes showed a positive correlation between the presence of a non canonical 5' splice site for ESP and the absence of detectable ESP protein levels and ESP activity. When analysing the expression of both transcript variants in Col-0 after treatment with methyl jasmonate, a condition known to "induce ESP", it was indeed the alternative splice variant that was preferentially induced. PMID- 22228408 TI - A chloroplast-derived C4V3 polypeptide from the human immunodeficiency virus (HIV) is orally immunogenic in mice. AB - Although the human immunodeficiency virus (HIV) causes one of the most important infectious diseases worldwide, attempts to develop an effective vaccine remain elusive. Designing recombinant proteins capable of eliciting significant and protective mammalian immune responses remain a priority. Moreover, large-scale production of proteins of interest at affordable cost remains a challenge for modern biotechnology. In this study, a synthetic gene encoding a C4V3 recombinant protein, known to induce systemic and mucosal immune responses in mammalian systems, has been introduced into tobacco chloroplasts to yield high levels of expression. Integration of the transgene into the tobacco plastome has been verified by Southern blot hybridization. The recombinant C4V3 protein is also detected in tobacco chloroplasts by confocal microscopy. Reactivity of the heterologous protein with both an anti-C4V3 rabbit serum as well as sera from HIV positive patients have been assayed using Western blots. When administered by the oral route in a four-weekly dose immunization scheme, the plant-derived C4V3 has elicited both systemic and mucosal antibody responses in BALB/c mice, as well as CD4+ T cell proliferation responses. These findings support the viability of using plant chloroplasts as biofactories for HIV candidate vaccines, and could serve as important vehicles for the development of a plant-based candidate vaccine against HIV. PMID- 22228409 TI - Regulation of AtSUS2 and AtSUS3 by glucose and the transcription factor LEC2 in different tissues and at different stages of Arabidopsis seed development. AB - Sucrose synthase (SUS) is a key enzyme of carbon metabolism in heterotrophic tissues of plants. The Arabidopsis genome contains six SUS genes. Two members of this family, namely AtSUS2 (At5g49190) and AtSUS3 (At4g02280) are strongly and differentially expressed in Arabidopsis seed. Expression analysis was carried out using SUS:promoter-GUS fusion lines in a wild-type genetic background or in a mutant carrying a lesion in the transcription factor LEAFY COTYLEDON 2 (LEC2; At1g28300). The accumulation patterns of mRNA, protein, and SUS activity were altered in the lec2 mutant during seed development 9-18 days after flowering. This indicates that LEC2 acts epistatically on the expression of AtSUS2 and AtSUS3. It appears that LEC2 is required for cotyledon-specific expression of both SUS genes but it is not responsible for expression in the radicle tip during embryo development. The AtSUS2 promoter was induced in planta by feeding of glucose but less so by sucrose and trehalose. Non-phosphorylable glucose analogs such as 3-O-methyl-glucose and 2-deoxyglucose also caused an induction, suggesting that sugar signaling proceeds by a hexokinase-independent pathway, possibly involving hexose sensing. Analysis of transgenic lines carrying of truncated versions of the AtSUS2:promoter fused to Beta-glucuronidase activity revealed an internal 421 bp region that was responsible for expression in seeds. Bioinformatic sequence analysis revealed regulatory cis-elements putatively responsible for the spatio-temporal pattern of AtSUS2 expression such as the SEF3 (aaccca) and W-box (ttgact) motifs. These findings are discussed in relation to the roles played by AtSUS2, AtSUS3 and LEC2 in the biosynthesis of seed storage products in Arabidopsis. PMID- 22228411 TI - Efficacy of pulmonary vein isolation with a novel hot balloon ablation catheter. AB - BACKGROUND: Due to the variable anatomy of the human pulmonary vein (PV), PV isolation for atrial fibrillation ablation is challenging. A novel hot balloon ablation catheter has been developed to improve ablation outcomes. The efficacy, histopathologic lesion characteristics, and thermodynamics of this technology were examined. METHODS: Swine underwent left atrial (n = 24) and superior vena cava (SVC, n = 7) catheterization with a compliant balloon catheter filled with saline and contrast. After PV mapping and angiography, ablation was performed with radiofrequency energy heating of the balloon contents. Central balloon temperatures were varied from 60 degrees C to 90 degrees C, and durations of energy delivery were varied from 60 to 300 s. Endocardial and epicardial temperatures were recorded contiguous to the balloon during SVC ablations. Pathology was examined. RESULTS: With a mean of 1.4 +/- 0.9 ablations per PV at 70 degrees C, 93% were electrically isolated. Necropsy exam revealed extraostial lesions without charring. PVs ablated at temperatures >=80 degrees C and durations >=180 s were associated with a high rate of successful isolation with a single ablation. Higher-temperature lesions displayed greater histopathologic uniformity, but more marked fibrin deposition. Chronic lesions revealed granulation tissue and fibrosis. No thromboembolic events were observed and histopathology of the phrenic nerve and esophagus was normal in all specimens. CONCLUSIONS: The hot balloon ablation catheter appears to be a safe and effective tool for PV isolation. Higher temperatures and longer ablation durations are associated with a higher single ablation success rate. PMID- 22228410 TI - Predictive value of left atrial volume measured by non-invasive cardiac imaging in the treatment of paroxysmal atrial fibrillation. AB - PURPOSE: We investigate the role of left atrial volume (LAV) as a predictor of outcome following pulmonary vein isolation (PVI) in patients with exclusive paroxysmal atrial fibrillation (AF). METHODS: PVI was performed in 213 patients (80 females, aged 60 +/- 10 years) with paroxysmal AF using either the pulmonary vein ablation catheter (PVAC, n = 78) or conventional single-tip ablation (n = 135). LAV was assessed by multi-detector computed tomography (n = 39) or cardiac magnetic resonance imaging (n = 174) prior to ablation. LA diameter (LAD) and LA area were determined by echocardiography. Patients were followed up for 12 months clinically and with 72-h Holter ECG. RESULTS: The mean LAV was 85 +/- 28 ml (range, 22-189 ml). Mean LAD and mean LA area were 43 +/- 6 mm and 23 +/- 6 cm2. After a follow-up period of 18 +/- 5 months, 202 patients were analyzed. AF recurrence was documented in 50 (23%) patients. Univariate analysis showed age (59 +/- 11 vs. 65 +/- 6 years, p = 0.049), LA area (23 +/- 5 vs. 27 +/- 6 cm2, p = 0.03), and LAV (80 +/- 27 vs. 96 +/- 28 ml, p = 0.04) to be significantly associated with the outcome. Multivariate analysis revealed that none of these parameters were statistically significant (hazards ratio LAV, 0.52-1.12, p = 0.058; LA area, 0.63-1.14, p = 0.069; and age, 0.90-1.09, p = 0.41). In the case of AF recurrence, patients with LAV >95 ml showed a significantly higher probability for the occurrence of persistent AF (24% vs. 8%, p = 0.02). CONCLUSIONS: The assessment of LA size should not be incorporated as a main factor with regard to predicted ablation success in patients with paroxysmal AF being considered for PVI, as PVI may be successful even with considerable LA enlargement. Ablation should be performed promptly in patients with LAV <= 95 ml to prevent further LA dilatation, as patients with LAV >95 ml have an increased probability to develop persistent AF in the case of ablation failure. PMID- 22228412 TI - Determining an appropriate cutting score for indication of impairment on the Montreal Cognitive Assessment. AB - OBJECTIVE/METHODS: The Montreal Cognitive Assessment (MoCA) is a brief yet comprehensive cognitive instrument used to assess level of impairment in neurological populations. The purpose of the present study was to assess the ability of the MoCA to detect cognitive impairment in a veteran patient population referred for neuropsychological testing and to determine optimal cutoff scores on the MoCA when compared with widely used neuropsychological measures. RESULTS: Using receiver operator characteristic (ROC) analyses, the findings indicate that the optimal cutoff score to detect impairment (i.e., <= 20) in the present sample was notably lower than that suggested by others. CONCLUSIONS: Use of the previously suggested cut score of <26 may overpathologize neurologically intact individuals. Further research utilizing ROC curve analysis should be conducted to establish appropriate cutoff scores for various populations which may differ from the present sample. PMID- 22228413 TI - Pulsed dye laser treatment with different onset times for new surgical scars: a single-blind randomized controlled trial. PMID- 22228414 TI - Human complement factor 3 polymorphism determination by capillary electrophoresis of serum. AB - Variability of complement factor 3 (C3) mobility in serum protein electrophoresis was investigated. We found that the migration time of C3 can be reproducibly determined (beween-run CV=0.76%) using clinical capillary electrophoresis (CE) equipment (the CapillarysTM 2 system, Sebia). Moreover, we found a significant difference (p<0.001) in migration times of the major C3 phenotypes FF (fast fast), FS (fast-slow) and SS (slow-slow). Glycosylation did not significantly affect test results. This is the first report on the migration time of C3 phenotypes on a clinical CE instrument. The presented method allows faster data than agarose-electrophoresis or genotyping. Moreover, reference ranges for serum C3 concentration depend on C3 phenotype, which allows a better tailored clinical interpretation of C3 concentrations. PMID- 22228415 TI - A randomized trial with steroids and antithymocyte globulins comparing cyclosporine/azathioprine versus tacrolimus/mycophenolate mofetil (CATM2) in renal transplantation. AB - BACKGROUND: The best immunosuppressive regimen in benefit-risk ratio in renal transplantation is debated. Nowadays, tacrolimus (Tac) and mycophenolate mofetil (MMF) are considered more efficient than cyclosporine A (CsA) and MMF, but recent studies have challenged this assumption. METHODS: We conducted a monocentric, prospective, open-labeled, randomized, and controlled trial comparing CsA/azathioprine (Aza) versus Tac/MMF in 289 kidney transplant recipients treated with antithymocyte globulins and prednisone. Primary outcome was the number of patients with clinically suspected acute rejection at 1 year. Secondary outcomes were the number of patients with biopsy-proven acute rejection (BPAR), estimated glomerular filtration rate (eGFR), patient and graft survivals, and adverse events at 1 and 3 years. RESULTS: During the first year, 21 patients had clinically suspected acute rejection with CsA/Aza (14.4%) vs. 11 (7.7%) with Tac/MMF (P=0.07). BPAR, including borderline, was more frequent in the CsA/Aza group (14.4%) than in the Tac/MMF group (5.6%; P=0.013). At 1 year, patient and graft survivals were not different, and eGFR was 48+/-1 in the CsA/Aza group and 53+/-1 mL/min/1.73 m in the Tac/MMF group (P=0.007). There was no significant difference in diabetes after transplantation (16.8% and 18.8%, respectively). CONCLUSIONS: With antithymocyte globulins and steroids, clinically suspected acute rejections did not differ between CsA/Aza and Tac/MMF arms. Analysis of secondary endpoints showed a lower rate of BPAR, including border line, and a higher eGFR in the Tac/MMF group. CsA/Aza allowed a low acute rejection rate, but Tac/MMF seemed as a better regimen regarding severe secondary outcomes. PMID- 22228416 TI - Allosensitization rate of male patients awaiting first kidney grafts after leuko depleted blood transfusion. AB - BACKGROUND: Blood transfusions are generally avoided for potential renal transplant recipients due to risk of human leukocyte antigen (HLA) allosensitization. Despite the near universal use of erythropoiesis-stimulating agents, there are still occasions when patients require blood transfusions for reasons such as resistance to erythropoiesis-stimulating agents or cardiovascular instability. The risk of allosensitization in renal patients is believed to be lower with leuko-depleted blood. We sought to quantify the risk of blood transfusion per se in male renal patients on the transplant waiting list for their first kidney graft, using sensitive solid phase antibody detection. METHOD: Cross-sectional survey looking at the prevalence of HLA antibody detected using single antigen Luminex beads in male patients awaiting first renal transplantation. RESULTS: One hundred sixteen male patients awaiting their first kidney transplant were identified on our waiting list. Seven of the 42 patients (16.7%) who received at least one unit of leuko-depleted blood developed HLA antibody (HLAab). Of the remaining 74 patients without a history of transfusion, 3 (4.1%) were found to have HLAab. All the antibodies identified were directed against class I antigens. A history of blood transfusion gave a relative risk of 4.1 of developing HLAab (P=0.02). CONCLUSION: Male patients awaiting their first organ transplant had a fourfold increased risk of developing HLA antibody if they had been previously transfused when compared with those who did not have a history of a transfusion. Transfusion even in the postleukodepletion era continues to pose a significant risk of sensitization. PMID- 22228419 TI - Early association of low-grade albuminuria and allograft dysfunction predicts renal transplant outcomes. AB - BACKGROUND: Data on the combined associations of albuminuria and estimated glomerular filtration rate (eGFR) with renal transplant outcomes are limited. Our objective was to explore how renal transplant outcomes could be predicted by a combined variable of early low-grade albuminuria and allograft dysfunction. METHODS: We studied a cohort of adult deceased-donor kidney transplant recipients who were subdivided into four groups according to median albuminuria (100 mg/day, interquartile range, 0-470 mg/day) and median eGFR (60 mL/min/1.73 m(2); interquartile range, 30-73 mL/min/1.73 m(2)) at third month posttransplantation as follows: group I (albuminuria <100 and eGFR >60, n=238); group II (albuminuria >=100 and eGFR >60, n=151); group III (albuminuria <100 and eGFR <=60; n=167); and group IV (albuminuria >=100 and eGFR <=60, n=228). RESULTS: Death-censored graft survival was significantly lower in group IV compared with the rest (P<0.0001). Multivariate Cox regression analysis using fixed and time-dependent covariates showed that the combination of low-grade albuminuria and lower eGFR was associated with graft failure (hazard ratio, 2.2, 95% confidence interval, 1.3-3.7; P=0.003). Likewise, but to a lesser extent, the risk of mortality was increased for group IV (hazard ratio, 1.7, 95% confidence interval, 1.01-2.8; P=0.042). CONCLUSIONS: Early association of low-grade albuminuria and allograft dysfunction represents an important risk factor of graft failure and mortality. This additive effect should be considered to identify individuals at risk for adverse kidney transplantation outcomes. PMID- 22228417 TI - Perceived discrimination predicts longer time to be accepted for kidney transplant. AB - BACKGROUND: Although end-stage kidney disease in African Americans (AAs) is four times greater than in whites, AAs are less than one half as likely to undergo kidney transplantation (KT). This racial disparity has been found even after controlling for clinical factors such as comorbid conditions, dialysis vintage and type, and availability of potential living donors. Therefore, studying nonmedical factors is critical to understanding disparities in KT. METHODS: We conducted a longitudinal cohort study with 127 AA and white patients with end stage kidney disease undergoing evaluation for KT (December 2006 to July 2007) to determine whether, after controlling for medical factors, differences in time to acceptance for transplant is explained by patients' cultural factors (e.g., perceived racism and discrimination, medical mistrust, religious objections to living donor KT), psychosocial characteristics (e.g., social support, anxiety, depression), or transplant knowledge. Participants completed two telephone interviews (shortly after initiation of transplant evaluation and after being accepted or found ineligible for transplant). RESULTS: Results indicated that AA patients reported higher levels of the cultural factors than did whites. We found no differences in comorbidity or availability of potential living donors. AAs took significantly longer to get accepted for transplant than did whites (hazard ratio=1.49, P=0.005). After adjustment for demographic, psychosocial, and cultural factors, the association of race with longer time for listing was no longer significant. CONCLUSIONS: We suggest that interventions to address racial disparities in KT incorporate key nonmedical risk factors in patients. PMID- 22228420 TI - Update: adjuncts to mechanical ventilation. AB - PURPOSE OF REVIEW: To describe the most recent advances and clinical applications of adjunctive techniques in mechanical ventilation, focusing on their overall impact on mortality and their potential indications in critically ill patients. RECENT FINDINGS: The modern variants of extracorporeal membrane oxygenation are not only rescue alternatives but also therapeutic options for patients with severe but potentially reversible acute respiratory distress syndrome. Prone positioning returns as a desirable therapeutic option for patients with severe acute respiratory distress syndrome. Recent reports suggest that permissive hypercapnia, therapeutic paralysis, sedation, and controlled hypothermia could potentially improve important clinical outcomes. Although more clinical trials are clearly needed to support the use of inhaled prostacyclins in severe respiratory failure, encouraging results have been described in recent publications. SUMMARY: Giving the complexity and dynamism of acute lung injury, timing, severity, and pathophysiologic pertinence are mandatory components of decision-making when considering the application of adjunctive measures to support mechanical ventilation. PMID- 22228418 TI - Innate and adaptive immune responses are tolerized in chimeras prepared with nonmyeloablative conditioning. AB - BACKGROUND: Mixed chimerism is an effective approach for tolerance induction in transplantation. Strategies to achieve mixed chimerism with relatively low toxicity have significantly expanded the clinical use of chimerism. METHODS: Allogeneic bone marrow transplants were performed between B6 (H2(b)) and BALB/c (H2(d)) mice. Recipient B6 mice were nonmyeloablatively conditioned with anti alphabeta-T-cell receptor, anti-CD154, or rapamycin alone or in different combinations. A total of 15 * 10(6) BALB/c bone marrow cells were transplanted after varying doses of cGy of total body irradiation. RESULTS: Pretreatment of recipients with anti-CD154 and rapamycin with or without T-cell lymphodepletion reduced the total body irradiation requirement to 100 cGy for establishing stable mixed chimerism. The mixed chimeras accepted donor islet allografts long term. Lymphocytes from mixed chimeras did not respond to host or donor antigens, yet were reactive to major histocompatibility complex-disparate third-party alloantigens, demonstrating functional donor-specific T-cell tolerance. No antibodies against donor and host were detected in mixed chimeras, suggesting humoral tolerance. Mixed chimeras showed no cytotoxicity to donor cells, but a similar rapid killing rate for major histocompatibility complex disparate third party B10.BR cells compared with T-cell-deficient and wild-type controls in in vivo cytotoxicity assays, suggesting donor-specific tolerance in the innate immune cells was achieved in mixed chimeras. CONCLUSIONS: Mixed chimeras prepared with low-intensity nonmyeloablative conditioning exhibit systemic tolerance in innate immunity and tolerance in adaptive T- and B-cell immune responses. PMID- 22228421 TI - Protective ventilation for lung transplantation. AB - PURPOSE OF REVIEW: Lung transplantation has been one of the great medical advances as the last option for the treatment of end-stage pulmonary disease. Optimal pulmonary care of potential donors and recipients can definitely increase the number of successful lung retrievals and reduce the incidence of complications. RECENT FINDINGS: The use of a lung-protective ventilatory strategy, associated with recruitment maneuvers, has a profound clinical impact, doubling the number of lungs available for transplant. Postoperatively, it is important to use a lung-protective ventilation strategy, whereas for patients with life-threatening reperfusion injury, extracorporeal membrane oxygenation can ensure a survival rate between 50 and 80%. Pumpless extracorporeal carbon dioxide removal system allows the maintenance of normal gas exchange and can be maintained in the perioperative period. SUMMARY: Perioperative ventilatory care of the transplanted patient still represents a challenge for the ICU clinician. The lung-protective strategy and the early application of carbon dioxide removal systems can increase the number of lung donor eligibility. Further studies are needed to increase the viability of other organs and to develop new strategies that reduce the risk of ischemia-reperfusion injury, which still represents the most common complication in the postoperative period. PMID- 22228422 TI - The effects of rooibos (Aspalathus linearis), green tea (Camellia sinensis) and commercial rooibos and green tea supplements on epididymal sperm in oxidative stress-induced rats. AB - Reactive oxygen species (ROS) are involved in many physiological functions of mammalian sperm. Numerous endogenous antioxidants belonging to both enzymatic and non-enzymatic groups can remove excess ROS and prevent oxidative stress (OS). This study compares the modulation of OS by rooibos, Chinese green tea and commercial rooibos and green tea supplements in rat sperm. Male Wistar rats (n = 60) were supplemented with fermented rooibos, 'green' rooibos, Chinese green tea, rooibos supplement, green tea supplement or water for 10 weeks while OS was induced during the last 2 weeks. Sperm count and motility were significantly higher for rats consuming fermented rooibos and 'green' rooibos when compared with the other groups. Catalase activity was significantly higher in the sperm of rats consuming fermented rooibos, 'green' rooibos and both the rooibos and green tea supplements. Superoxide dismutase concentration in the sperm of rats supplemented with fermented rooibos, 'green' rooibos and green tea was higher. Sperm glutathione levels of rats consuming the fermented and 'green' rooibos were also significantly higher. Rooibos fermented and 'green' rooibos showed a tendency to lower the levels of ROS and lipid peroxidation when compared with the control group. In conclusion, both rooibos extracts could offer a measure of protection against induced oxidative damage by increasing the antioxidant defence mechanisms and thereby improving the sperm quality and function. PMID- 22228423 TI - Inability of some Aeromonas hydrophila strains to act as recipients of plasmid pRAS1 in conjugal transfer experiments. AB - Plasmids belonging to the IncU incompatibility group are mobile genetic elements isolated frequently from Aeromonas spp. These plasmids share structural and functional characteristics and often carry Class-1 integrons bearing antibiotic resistance genes. In this work the ability of two IncU plasmids, pAr-32 and pRAS1 to establish in different A. hydrophila strains after conjugal transfer was studied. In vitro transfer frequencies on solid surface ranged from 10(-1) to 10( 6) for pAr-32 and from 10(-3) to 10(-5) for pRAS1. While carrying out these experiments we detected four strains unable to acquire plasmid pRAS1, indicating that the genetic background of recipients affects the establishment of the plasmid. We explored the possible reasons why these strains failed to yield transconjugants after mating experiments using A. salmonicida 718 as a donor. Factors included donor cell recognition, incompatibility, surface exclusion and restriction of incoming DNA. We found that none of these factors could explain the refractivity of non-receptive A. hydrophila strains to yield transconjugants. Although we do not know the reasons of this refractivity, we may speculate that these isolates lack a product necessary to replicate or stabilize plasmid pRAS1. Alternatively, these strains could contain a product that impedes plasmid establishment. PMID- 22228424 TI - Regarding "reasons for diagnostic delay in gynecological malignancies". PMID- 22228425 TI - Significance of perioperative infection in survival of patients with ovarian cancer. AB - OBJECTIVES: Perioperative infectious diseases comprise some of the most common causes of surgical mortality in women with ovarian cancer. This study was aimed to evaluate the significance of perioperative infections in survival of patients with ovarian cancer. METHODS: Patients who underwent primary cytoreductive surgery were included in the analysis (n = 276). The enumeration and speciation of pathogens, antimicrobial agents used, and sensitivity assay results were culled from medical records and correlated to clinicopathologic demographics and survival outcomes. Perioperative infection was determined as a positive microbiology result obtained within a 6-week postoperative period. RESULTS: The incidence of perioperative infection was 15.9% (common sites: urinary tract, 57.3%, and surgical wound, 21.4%). Commonly isolated pathogens were Enterococcus species (22.4%) and Escherichia coli (19.4%) in urinary tract infection, and Bacteroides fragilis, E. coli, and Klebsiella pneumoniae (all, 16%) in surgical wound infection. Imipenem represents one of the least resistant antimicrobial agents commonly seen in urinary tract and surgical wound infections in our institution. Perioperative infection was associated with diabetes, serous histology, lymph node metastasis, bowel resection, decreased bicarbonate, and elevated serum urea nitrogen in multivariate analysis. Perioperative infections were associated with increased surgical mortality, delay in chemotherapy treatment, decreased chemotherapy response, shorter progression-free survival (median time, 8.4 vs 17.6 months; P < 0.001), and decreased overall survival (29.0 vs 51.8 months; P = 0.011). Multivariate analysis showed that perioperative infections other than urinary tract infection remained a significant risk factor for decreased survival (progression-free survival, P = 0.02; and overall survival, P = 0.019). CONCLUSION: Perioperative infectious disease comprises an independent risk factor for survival of patients with ovarian cancer. PMID- 22228426 TI - Age-specific seroprevalence of human papillomavirus 16, 18, 31, and 58 in women of a rural town of Colombia. AB - OBJECTIVE: The study's objective was to estimate human papillomavirus (HPV) genotype-specific seroprevalence to determine population HPV exposure and inform vaccine policy. METHODS: This study is a cross-sectional prevalence survey of 878 women of Pueblorrico, a rural town of Colombia. A standardized questionnaire was used to obtain information on demographic characteristics, sexual and reproductive history, and smoking habits. Seropositivity to HPV-16, -18, -31, and -58 was determined by virus-like particles in an enzyme-linked immunosorbent assay. RESULTS: Overall seropositivity to any HPV genotype was 27.9%. The combined seroprevalence of women 15 to 19 and 20 to 24 years old was 35.4% (95% confidence interval [CI], 25.9-46.2) and 36.0% (95% CI, 27.7-45.3), respectively. Seroprevalence for HPV-16 was 17% (95% CI, 14.6-19.6); for HPV-18, 9.8% (95% CI, 8.0-11.9); for HPV-31, 11.4% (95% CI, 9.5-13.7); and for HPV 58, 12.5% (95% CI, 10.5-14.9). Higher HPV seropositivity was associated with the lifetime number of occasional sexual partners (odds ratio, 3.05; 95% CI, 1.26-7.37) and having more than 2 regular sexual partners (odds ratio, 3.00; 95% CI, 1.21-7.45) in women younger than 44 and older than 45 years old, respectively. Use of oral contraceptives and tobacco/cigarettes was significantly associated with reduced HPV seropositivity in women older than 45 but not in women younger than 44 years old. CONCLUSIONS: Human papillomavirus seropositivity is associated with measures of sexual behavior, particularly a greater lifetime number of sexual partners. Hormonal and tobacco/cigarette use may be factors influencing the HPV seropositivity in women older than 45 years old. PMID- 22228427 TI - Prognostic impact of the history of breast cancer and of hormone therapy in uterine carcinosarcoma. AB - OBJECTIVE: Recent studies reveal an association between hormone therapy for breast cancer (BC), such as tamoxifen (TAM) and toremifene (TOR), and uterine carcinosarcoma (UCS). The aim of this study was to investigate the characteristics and prognosis of patients with UCS after BC and hormone therapy. METHODS: Between January 1997 and December 2007, we treated 51 patients with UCS. The medical records of these patients were reviewed, and factors that influenced their survival were retrospectively analyzed using univariate and multivariate analyses. RESULTS: Ten (19.6%) of the 51 patients had a history of BC; 6 (11.8%) had received hormone therapy with TAM or TOR. The characteristics of the patients with UCS were similar regardless of whether they had a history of BC or hormone therapy. On univariate analysis, age greater than 56 years, elevated serum lactate dehydrogenase levels, residual tumors, FIGO (International Federation of Gynecology and Obstetrics) stage higher than stage IIIa, and non-endometrioid carcinomatous components were identified as prognostic factors. On multivariate analysis, in addition to residual tumors, FIGO stage higher than stage IIIa, and non-endometrioid carcinomatous components, a history of BC (relative risk, 0.14), a history of TAM use (relative risk, 15.9), and a history of TOR use (relative risk, 16.9) were also identified as independently significant prognostic factors. CONCLUSIONS: Our data suggest that a history of BC and hormone therapy for BC is a risk factor for developing UCS without obvious impacts on the characteristics of UCS. Both of these factors had statistically significant impacts on the prognosis of patients with UCS. Further studies are necessary to clarify and validate these associations. PMID- 22228428 TI - Purified vitexin compound 1 suppresses tumor growth and induces cell apoptosis in a mouse model of human choriocarcinoma. AB - OBJECTIVE: In our previous study, we had isolated a series of lignan compounds, termed vitexins, from the seed of Chinese herb Vitex negundo and found broad antitumor activities of these compounds in many cancer xenograft models and cell lines. This study was aimed to determine the antitumor effect of purified vitexin compound 1 (VB1) on choriocarcinoma in vitro and in vivo. MATERIALS AND METHODS: The severe combined immunodeficiency mouse model of choriocarcinoma was established to investigate the in vivo effect of VB1. Its effect on proliferation and apoptosis in JEG-3 cell line was evaluated by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay, colony formation assay and flow cytometry, respectively. The expression of caspase-3, Bcl-2, and some molecules involved in the mammalian target of rapamycin (mTOR) signaling was detected by Western blot. RESULTS: Vitexin compound 1 significantly inhibited the growth of choriocarcinoma in severe combined immunodeficient mice and reduced the serum beta-human chorionic gonadotropin level. Vitexin compound 1 inhibited cell proliferation, induced apoptosis, and inhibited the mTOR signaling in JEG-3 cell line. CONCLUSION: Vitexin compound 1 could inhibit choriocarcinoma via inducing cell apoptosis and suppressing the mTOR pathway. PMID- 22228429 TI - [Mortality and morbidity of tetanus in the infectious diseases department, Point G teaching hospital, in Bamako, Mali (2004-2009)]. AB - Our study objectives were to determine annual cases of the tetanus and to describe its clinical, evolutionary and prognostic aspects. It was a transverse study from data records and medical records of patients aged 15 years and above hospitalized for tetanus in the service of infectious diseases of the Point G CHU from January 1, 2004 to December 31, 2009. The tetanus was diagnosed based on clinical (trismus, dysphagia, seizures and point consecutive to an injury) and epidemiological arguments (absence of a correct tetanus immunization, entry way). We collected a total of 119 cases of tetanus out of 1,839 hospitalizations making a prevalence of 6.5%. The hospitalization period was 5 days (73%) for most of the patients. Unskilled laborer and farmers were the most frequent with respectively 30.2 and 21.8% of cases. Tetanus occurred in the course of a traumatic road accident (16%) and from other traumatic causes (48.7%). The clinical form was a generalized type for 94.4% of the cases. A wound was the entry way for 64.7% of the patients. The entry way was located on the lower members 49.6% of the time. The co-morbidity was recorded with infection by Plasmodium falciparum (15 cases, 12.6%) and HIV (1 case). Hospital lethality was 46.2%. The death was statistically linked to clinical severity according to the Dakar score (P = 0.0005) and the Mollaret stage (P = 0.0001). A need for strengthening communication for behaviour change for the gaining of a correct and sustained immunization exists. A strategy based on the capacity building for a rapid tetanus diagnosis and a combined co-morbidities care may reduce the lethality in the context of our limited technical environment. PMID- 22228430 TI - One step multifunctional micropatterning of surfaces using asymmetric glow discharge plasma polymerization. AB - Micropatterning of surfaces with varying chemical, physical and topographical properties usually requires a number of fabrication steps. Herein, we describe a micropatterning technique based on plasma enhanced chemical vapour deposition (PECVD) that deposits both protein resistant and protein repellent surface chemistries in a single step. The resulting multifunctional, selective surface chemistries are capable of spatially controlled protein adhesion, geometric confinement of cells and the site specific confinement of enzyme mediated peptide self-assembly. PMID- 22228431 TI - Molecular and clinical characterization of an in frame deletion of uncertain clinical significance in the BRCA2 gene. AB - In this study, we analyzed a "variant of uncertain significance" (VUS) located in exon 23 of the BRCA2 gene exhibited by six members of five distinct families with hereditary breast cancer (BC). The variant was identified by DNA sequencing, and cDNA analysis revealed its co-expression with wild-type mRNA. We analyzed co occurrence with other pathological mutations in BRCA1/2, performed a case-control study, looked for evolutionary data and used in-silico analyses to predict its potential clinical significance. Sequencing revealed an in frame deletion of 126 nucleotides in exon 23, leading to a deletion of 42 amino acids (c.9203_9328del126, p.Pro2992_Thr3033del). All of the VUS-carriers suffered from either BC or ovarian/pancreatic cancer. No other definite pathologic mutation of BRCA genes was found in the five families. The identified deletion could not be observed in a control cohort of 2,652 healthy individuals, but in 5 out of 916 (0.5%) tested BC families without a bona fide pathogenic BRCA1/2 mutation (P = 0.0011). According to these results, the in frame deletion c.9203_9328del126 is a rare mutation strongly associated with familial BC. In summary, our investigations indicate that this BRCA2 deletion is pathogenic. PMID- 22228432 TI - Methylation of O6-methylguanine-DNA methyltransferase (MGMT) promoter gene in triple-negative breast cancer patients. AB - Triple-negative breast cancers are characterized by the triple-negative (ER/PgR/Her2 negative) phenotype, are frequently associated with BRCA gene mutation, and are not candidate to currently available endocrine and HER2 targeted treatments. MGMT is involved in direct DNA repair exerted by cleavage of mutagenic alkyl adducts within DNA, and its epigenetic silencing confers susceptibility to DNA-damaging alkylating agents in glioblastomas and melanomas. MGMT methylation status has not been extensively investigated in breast cancer patients. The goal of our study was to evaluate the MGMT methylation status in TNBC patients, for most of which BRCA1 and BRCA2 mutational status was known. We evaluated MGMT methylation status by methylation-specific PCR (MSP) in formalin fixed and paraffin-embedded tumor specimens from 92 TNBC patients. By using the GelDoc system (Biorad) software, the cases were further classified as follows: 0 (absence of methylated signal), 1 (prevalence of unmethylated signal, U/M ratio>1), 2 (prevalence of methylated signal, U/M ratio<1), and 3 (absence of unmethylated signal). MSP products were obtained in 89 (96.7%) of the cases. Overall, 15 (16.9%) cases were classified as 0, 33 (37.1%) cases as 1, 39 (43.8%) cases as 2, and 2 (2.2%) cases as 3. The 48 cases classified as 0 and 1 were considered as MGMT unmethylated, and the 41 cases classified as 2 and 3 as MGMT methylated. The prevalence of MGMT methylation in patients with BRCA1 mutated, wild-type, and unknown was 30.2% (13/43), 63.6% (14/22), and 58.3% (14/24), respectively. MGMT methylation was unrelated to the main clinical pathological characteristics, with the exception of a weak association with advanced age. In conclusion, our data suggest that in TNBC with wild-type BRCA1, the direct DNA repair system may be frequently (63.6%) silenced by MGMT methylation. The evaluation of the MGMT status could offer a new adjunct in predicting tumor response to alkylating drugs in TNBC patients. PMID- 22228433 TI - Anthocyanin-rich red cabbage (Brassica oleracea L.) extract attenuates cardiac and hepatic oxidative stress in rats fed an atherogenic diet. AB - BACKGROUND: Oxidative stress induced by reactive oxygen species plays an important role in the aetiology of several diseases including atherosclerosis and coronary heart disease. Anthocyanin-rich extracts have been shown to possess a variety of therapeutic roles, including antioxidant, cardioprotective and hepatoprotective properties. The present inventory was undertaken to evaluate the protective role of anthocyanin-rich red cabbage extract (ARCE) on an atherogenic (ATH) diet-induced hypercholesterolaemia and related cardiac and, hepatic oxidative stress in rats. RESULTS: ARCE (100 mg kg(-1) body weight) treatment of rats fed the ATH diet significantly prevented elevation in serum and tissue lipids, circulating levels of cardiac and hepatic damage markers, and resulted in excretion of lipids through faeces. Also, the ARCE extract significantly attenuated alterations in the cardiac and hepatic antioxidants and lipid peroxidation, and histopathological changes in cardiac and hepatic tissue. CONCLUSION: Thus, the present study provides the first scientific evidence for a protective role of ARCE against ATH diet-induced hypercholesterolaemia and cardiac and hepatic oxidative stress. PMID- 22228434 TI - Plasmon-enhanced sub-wavelength laser ablation: plasmonic nanojets. AB - In response to the incident light's electric field, the electron density oscillates in the plasmonic hotspots producing an electric current. Associated Ohmic losses raise the temperature of the material within the plasmonic hotspot above the melting point. A nanojet and nanosphere ejection can then be observed precisely from the plasmonic hotspots. PMID- 22228435 TI - Zinc balance is critical for NFI-C mediated regulation of odontoblast differentiation. AB - Zinc is trace element essential for diverse metabolic and cellular signaling pathways for the growth, development, and maintenance. Zinc deficiency is involved in bone malformations and oral disease. Mice deficient in zinc transporter Zip13 show connective tissue and skeletal disorders, abnormal incisor teeth, and reduced root dentin formation in the molar teeth and share a morphologically similar phenotype to nuclear factor I-C (NFI-C)-deficient mice. However, the precise function of zinc in NFI-C signaling-mediated odontoblast differentiation and dentin formation remains unclear. Here, we show that zinc stimulated the expression of metal transcription factor-1, but decreased NFI-C expression in odontoblastic MDPC-23 cells. Zinc also enhanced the phosphorylation of Smad2/3 (p-Smad2/3) and increased the binding efficiency of NFI-C and p Smad2/3 in the cytoplasm. In contrast, zinc deficiency resulted in the accumulation of NFI-C into nucleus. Consequently, NFI-C had the biologic properties of a transcription factor, including DNA binding affinity for metallothionein-1 and the dentin sialophosphoprotein (DSPP) promoter, and transcriptional activation of the DSPP gene. Furthermore, zinc deficiency condition promoted DSPP expression in odontoblasts and dentin mineralization, while zinc sufficiency condition decreased DSPP expression and slightly delayed dentin mineralization. These data suggest that zinc equilibrium is required for odontoblast differentiation and dentin formation during dentinogenesis through the nuclear accumulation and modulation of NFI-C. PMID- 22228436 TI - Urine interleukin-18 and cystatin-C as biomarkers of acute kidney injury in critically ill neonates. AB - BACKGROUND: Urinary interleukin-18 and cystatin-C are suggested to be biomarkers for predicting acute kidney injury (AKI). The aims of this study are to examine whether the urinary concentrations of interleukin-18 and cystatin-C vary with gestational age and other factors in non-AKI control neonates, and to determine whether urinary interleukin-18 and cystatin-C can predict AKI development in non septic critically ill neonates, independently of potential confounders. METHODS: We enrolled 62 non-septic critically ill neonates. Urine was collected every 48 72 h during the first 10 days of life. RESULTS: Urinary concentration of cystatin C, but not interleukin-18, decreased with increasing gestational age and body weight, but not with increasing postnatal age in non-AKI control neonates. Both urinary interleukin-18 and cystatin-C were associated with AKI, even after controlling for gestational and postnatal age, birth weight, gender, Apgar score and the score for neonatal acute physiology in non-septic critically ill neonates. Urinary interleukin-18 and cystatin-C had odds ratios of 2.27 and 2.07, and achieved the area under-the-receiver-operating-characteristic curve of 0.72 and 0.92, respectively, for predicting AKI. CONCLUSIONS: The urinary concentration of cystatin-C, but not interleukin-18, may decrease with increasing renal maturity. Both urinary interleukin-18 and cystatin-C are independently predictive of AKI in non-septic critically ill neonates. PMID- 22228437 TI - Evidence that NPHS2-R229Q predisposes to proteinuria and renal failure in familial hematuria. AB - BACKGROUND: Familial hematuria (FH) is associated with at least two pathological entities: thin basement membrane nephropathy (TBMN), caused by heterozygous COL4A3/COL4A4 mutations, and C3 nephropathy caused by CFHR5 mutations. It is now known that TBMN patients develop proteinuria and changes of focal segmental glomerulosclerosis when biopsied. End-stage kidney disease (ESKD) is observed in 20% of carriers, at ages 50-70. A similar progression is observed in CFHR5 nephropathy. Recent evidence suggests that NPHS2-R229Q, a podocin polymorphism, may contribute to proteinuria in TBMN and to micro-albuminuria in the general population. CASE-DIAGNOSIS/TREATMENT: NPHS2-R229Q was screened in a Cypriot FH cohort. 102 TBMN patients with three known COL4 mutations and 45 CFHR5 male patients with a single mutation were categorized as "Mild" or "Severe", based on the presence of microhematuria only, or proteinuria and chronic kidney disease. Nine R229Q carriers were found in the "Severe" category and none in the "Mild" (p=0.010 for genotypic association; p=0.043 for allelic association, adjusted for patients' relatedness), thus supporting the possible contribution of 229Q allele in disease progress. CONCLUSIONS: Our results offer more evidence that in patients with FH, NPHS2-R229Q predisposes to proteinuria and ESKD. R229Q may be a good prognostic marker for young hematuric patients. PMID- 22228438 TI - Stereoselective synthesis and applications of nitrogen substituted donor-acceptor cyclopropanes (N-DACs) in the divergent synthesis of azacycles. AB - A new, highly stereoselective intramolecular cyclopropanation of vinylogous carbamates with carbenes in the presence of Cu(acac)(2) as the catalyst has been developed for the construction of cyclopropapyrrolidinones. The 'syn' isomer of N DAC can be converted to the 'anti' isomer by simple silica gel treatment. Regioselective cleavage of each of the cyclopropane bonds of these two acceptor substituted N-DACs led to a diverse array of azacycles. PMID- 22228439 TI - Palatal implants in the treatment of obstructive sleep apnea: a randomised, placebo-controlled single-centre trial. AB - Palatal implants have been used to treat snoring and mild to moderate obstructive sleep apnea (OSA). Two previous controlled trials have published conflicting results regarding the effects of palatal implants on objective outcome measures, although they both could demonstrate superiority over placebo. The aim of the present study was to assess the effects of palatal implants in patients with mild to moderate sleep apnea in a randomised, placebo-controlled trial. Twenty-two patients with mild to moderate OSA (AHI 18 +/- 5, BMI 28 +/- 3, age 51 +/- 13 years) due to palatal obstruction were enrolled in this randomised, double-blind, placebo-controlled trial. Respiratory parameters and sleep efficiency (evaluated by polysomnography), snoring (evaluated by the bed partner), and daytime sleepiness (evaluated by ESS) were assessed before and 90 days after surgery. One patient in each group did not show up for follow-up. The AHI, HI and LSAT showed statistically significant improvement in the treatment group (p < 0.05). Snoring as rated by bed partners also showed statistically significant improvement within the treatment group (p = 0.025). There was no statistical difference when comparing the means of the treatment group with the placebo group. There were no peri- or post-operative complications and no extrusions during the follow-up period. The study supports the idea that palatal implants lead to a reduction in respiratory events in patients with mild to moderate OSA, although a statistically significant superiority of palatal implants over placebo could not be demonstrated in this trial. PMID- 22228440 TI - The photosynthetic apparatus and photoinduced electron transfer in the aerobic phototrophic bacteria Roseicyclus mahoneyensis and Porphyrobacter meromictius. AB - Photosynthetic electron transfer has been examined in whole cells, isolated membranes and in partially purified reaction centers (RCs) of Roseicyclus mahoneyensis, strain ML6 and Porphyrobacter meromictius, strain ML31, two species of obligate aerobic anoxygenic phototrophic bacteria. Photochemical activity in strain ML31 was observed aerobically, but the photosynthetic apparatus was not functional under anaerobic conditions. In strain ML6 low levels of photochemistry were measured anaerobically, possibly due to incomplete reduction of the primary electron acceptor (Q(A)) prior to light excitation, however, electron transfer occurred optimally under low oxygen conditions. Photoinduced electron transfer involves a soluble cytochrome c in both strains, and an additional reaction center (RC)-bound cytochrome c in ML6. The redox properties of the primary electron donor (P) and Q(A) of ML31 are similar to those previously determined for other aerobic phototrophs, with midpoint redox potentials of +463 mV and -25 mV, respectively. Strain ML6 showed a very narrow range of ambient redox potentials appropriate for photosynthesis, with midpoint redox potentials of +415 mV for P and +94 mV for Q(A). Cytoplasm soluble and photosynthetic complex bound cytochromes were characterized in terms of apparent molecular mass. Fluorescence excitation spectra revealed that abundant carotenoids not intimately associated with the RC are not involved in photosynthetic energy conservation. PMID- 22228441 TI - Isolation, characterization and differentiation potential of cardiac progenitor cells in adult pigs. PMID- 22228442 TI - Transcriptome analysis of pellicle formation of Shewanella oneidensis. AB - Although the pellicle is one of the major growth modes of microorganisms, the metabolic features of pellicle cells and the determinative factors for pellicle formation are largely unknown. In recent years, biofilm development of Shewanella oneidensis, an important model organism for bioremediation studies, has been extensively studied. In this paper, a transcriptional profiling of pellicle cells relative to planktonic cells indicated that cells in pellicles were more metabolically active than the planktonic cells. Most notably, up-transcription of general secretion system proteins and iron/heme uptake and transport proteins was observed in pellicle cells. Unexpectedly, neither the hmuT nor hugA heme transport mutant exhibited a significant defect in pellicle formation. Expectedly, three type I secretion system mutants were severely deficient in pellicle formation, suggesting an essential role of these proteins. PMID- 22228443 TI - Electron transport and oxidative stress in Zymomonas mobilis respiratory mutants. AB - The ethanol-producing bacterium Zymomonas mobilis is of great interest from a bioenergetic perspective because, although it has a very high respiratory capacity, the respiratory system does not appear to be primarily required for energy conservation. To investigate the regulation of respiratory genes and function of electron transport branches in Z. mobilis, several mutants of the common wild-type strain Zm6 (ATCC 29191) were constructed and analyzed. Mutant strains with a chloramphenicol-resistance determinant inserted in the genes encoding the cytochrome b subunit of the bc (1) complex (Zm6-cytB), subunit II of the cytochrome bd terminal oxidase (Zm6-cydB), and in the catalase gene (Zm6-kat) were constructed. The cytB and cydB mutants had low respiration capacity when cultivated anaerobically. Zm6-cydB lacked the cytochrome d absorbance at 630 nm, while Zm6-cytB had very low spectral signals of all cytochromes and low catalase activity. However, under aerobic growth conditions, the respiration capacity of the mutant cells was comparable to that of the parent strain. The catalase mutation did not affect aerobic growth, but rendered cells sensitive to hydrogen peroxide. Cytochrome c peroxidase activity could not be detected. An upregulation of several thiol-dependent oxidative stress-protective systems was observed in an aerobically growing ndh mutant deficient in type II NADH dehydrogenase (Zm6-ndh). It is concluded that the electron transport chain in Z. mobilis contains at least two electron pathways to oxygen and that one of its functions might be to prevent endogenous oxidative stress. PMID- 22228444 TI - Controllable selective exfoliation of high-quality graphene nanosheets and nanodots by ionic liquid assisted grinding. AB - Bulk quantities of graphene nanosheets and nanodots have been selectively fabricated by mechanical grinding exfoliation of natural graphite in a small quantity of ionic liquids. The resulting graphene sheets and dots are solvent free with low levels of naturally absorbed oxygen, inherited from the starting graphite. The sheets are only two to five layers thick. The graphene nanodots have diameters in the range of 9-29 nm and heights in the range of 1-16 nm, which can be controlled by changing the processing time. PMID- 22228445 TI - Asparagine and glutamine differ in their propensities to form specific side chain backbone hydrogen bonded motifs in proteins. AB - Short range side chain-backbone hydrogen bonded motifs involving Asn and Gln residues have been identified from a data set of 1370 protein crystal structures (resolution <= 1.5 A). Hydrogen bonds involving residues i - 5 to i + 5 have been considered. Out of 12,901 Asn residues, 3403 residues (26.4%) participate in such interactions, while out of 10,934 Gln residues, 1780 Gln residues (16.3%) are involved in these motifs. Hydrogen bonded ring sizes (C(n), where n is the number of atoms involved), directionality and internal torsion angles are used to classify motifs. The occurrence of the various motifs in the contexts of protein structure is illustrated. Distinct differences are established between the nature of motifs formed by Asn and Gln residues. For Asn, the most highly populated motifs are the C(10)(CO(delta)(i) ...NH(i + 2)), C(13)(CO(delta)(i) ...NH(i + 3)) and C(17)(N(delta)H(i) ...CO(i - 4)) structures. In contrast, Gln predominantly forms C(16)(CO(epsilon)(i) ...NH(i - 3)), C(12)(N(epsilon)H(i) ...CO(i - 2)), C(15)(N(epsilon)H(i) ...CO(i - 3)) and C(18)(N(epsilon)H(i) ...CO(i - 4)) motifs, with only the C(18) motif being analogous to the Asn C(17) structure. Specific conformational types are established for the Asn containing motifs, which mimic backbone beta-turns and alpha-turns. Histidine residues are shown to serve as a mimic for Asn residues in side chain-backbone hydrogen bonded ring motifs. Illustrative examples from protein structures are considered. PMID- 22228446 TI - Development and validation of a prediction index for hand-foot skin reaction in cancer patients receiving sorafenib. AB - BACKGROUND: This study describes a repeated measures prediction index to identify patients at high risk of >=grade 2 hand-foot skin reaction (HFSR) before each week of sorafenib therapy. METHODS: Data from 451 patients who received a sorafenib (400 mg bid) as part of a clinical trial were reviewed (Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: 125-134). Generalized estimating equations were used to develop the final risk model. A risk-scoring algorithm (range 0-58) was then derived from the final model coefficients. External validation was then carried out on a new sample of 1145 patients who received sorafenib under an expanded access program. RESULTS: Pretreatment white blood cell count, female gender, good performance status, presence of lung and liver metastases and number of affected organs were predictors for >=grade 2 HFSR. A nonlinear association between HFSR risk and treatment duration was also identified where risk was maximized at week 5 followed by a gradual decline. Before each week of therapy, patients with risk scores>40 would be considered at high risk for developing >=grade 2 HFSR. CONCLUSIONS: The application and planned continued refinement of this prediction tool will be an important source of patient-specific risk information for the development of moderate to severe HFSR. PMID- 22228447 TI - Prognostic significance of L1CAM in ovarian cancer and its role in constitutive NF-kappaB activation. AB - BACKGROUND: Overexpression of L1-cell adhesion molecule (L1CAM) has been observed for various carcinomas and correlates with poor prognosis and late-stage disease. In vitro, L1CAM enhances proliferation, cell migration, adhesion and chemoresistance. We tested L1CAM and interleukin-1 beta (IL-1beta) expression in tumor samples and ascitic fluid from ovarian carcinoma patients to examine its role as a prognostic marker. PATIENTS AND METHODS: We investigated tumor samples and ascitic fluid from 232 serous ovarian carcinoma patients for L1CAM by enzyme linked immunosorbent assay. L1CAM expression was correlated with pathoclinical parameters and patients' outcome. IL-1beta levels were measured in tumor cell lysates. Ovarian cancer cell lines were analyzed for the contribution of L1CAM to IL-1beta production and nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-kappaB) activation. RESULTS: We observed that L1CAM-expressing tumors show a highly invasive phenotype associated with restricted tumor resectability at primary debulking surgery and increased lymphogenic spread. Soluble L1CAM proved to be a marker for poor progression-free survival and chemoresistance. In ovarian carcinoma cell lines, the specific knock-down of L1CAM reduces IL-1beta expression and NF-kappaB activity. CONCLUSIONS: L1CAM expression contributes to the invasive and metastatic phenotype of serous ovarian carcinoma. L1CAM expression and shedding in the tumor microenvironment could contribute to enhanced invasion and tumor progression through increased IL-1beta production and NF-kappaB activation. PMID- 22228448 TI - Effect of autoimmune diseases on mortality and survival in subsequent digestive tract cancers. AB - BACKGROUND: Patients with some autoimmune diseases (AIDs) are at increased risk of cancer, possibly a result of an underlying dysregulation of the immune system, medication, treatment or, probably, surveillance bias. Data on cancer mortality and survival in patients previously diagnosed with AIDs would provide novel information on these comorbidities and their clinical implications. PATIENTS AND METHODS: Standardized mortality ratios (SMRs) and hazard ratios (HRs) were calculated for subsequent deaths from seven digestive tract cancers between 1964 and 2008 in patients hospitalized for any of 33 AIDs. RESULTS: There were 33 increased SMRs for specific cancers after a defined AID; similarly, 21 HRs were increased. Both the SMR and HR were increased after 10 autoimmune disorders, including pernicious anemia, systemic lupus erythematosus and psoriasis. Increased SMRs and unchanged HRs were noted for 23 cancers. Myasthenia gravis was associated with SMRs for five cancers but no increases in HRs. For nine cancers, including esophageal cancer after ulcerative colitis and rheumatoid arthritis, the SMR was unchanged but the HR increased. CONCLUSIONS: The increases in SMRs provide evidence that cancer risks were truly increased and largely unaffected by surveillance bias. The prognostic survival data should contribute to clinical evaluation and therapeutic planning. PMID- 22228449 TI - Multicenter phase II study of sunitinib in patients with non-clear cell renal cell carcinoma. AB - BACKGROUND: Retrospective and molecular biologic data suggest that sunitinib may be effective in patients with non-clear cell renal cell carcinoma (nccRCC). PATIENTS AND METHODS: Eligibility criteria included advanced nccRCC except for collecting duct carcinoma and sarcomatoid carcinoma without identifiable renal cell carcinoma subtypes. Patients were treated with 50 mg/day oral sunitinib for 4 weeks, followed by 2 weeks of rest. The primary end point was overall response rate (RR). RESULTS: Thirty-one eligible patients were enrolled. Twenty-four patients (77%) had prior nephrectomy. By Memorial Sloan-Kettering Cancer Center criteria, 8 patients (26%) had poor risk and 14 (45%) had intermediate risk. Twenty-two patients had papillary renal cell carcinoma (RCC), and three had chromophobe RCC. Eleven patients had partial response with a RR of 36% (95% confidence interval (CI) 19% to 52%) and an additional 17 patients (55%) had stable disease. Median duration of response was 12.7 months (95% CI 6.3-19.1 months), and median progression-free survival was 6.4 months (95% CI 4.2-8.6 months). At a median follow-up duration of 18.7 months (95% CI 13.7-23.7 months), 13 patients (42%) had died, resulting in an estimated median survival of 25.6 months (95% CI 8.4-42.9 months). Toxicity profiles were commensurate with prior reports. CONCLUSIONS: Sunitinib has promising activity in patients with nccRCC (NCT01219751). PMID- 22228450 TI - Early ultrasonographic finding of septic thrombophlebitis is the main indicator of central venous catheter removal to reduce infection-related mortality in neutropenic patients with bloodstream infection. AB - BACKGROUND: Septic thrombophlebitis increases patient morbidity and mortality following metastatic infections, pulmonary emboli, and/or septic shock. Central venous catheter (CVC) removal for occult septic thrombophlebitis challenges current strategy in neutropenic patients. PATIENTS AND METHODS: We prospectively evaluated infection-related mortality in 100 acute leukemia patients, with CVC related bloodstream infection (CRBSI) after chemotherapy, who systematically underwent ultrasonography to identify the need for catheter removal. Their infection-related mortality was compared with that of a historical cohort of 100 acute leukemia patients, with CRBSI after chemotherapy, managed with a clinically driven strategy. Appropriate antimicrobial therapy was administered in all patients analyzed. RESULTS: In the prospective series, 30/100 patients required catheter removal for ultrasonography-detected septic thrombophlebitis after 1 median day from BSI onset; 70/100 patients without septic thrombophlebitis retained their CVC. In the historical cohort, 60/100 patients removed the catheter (persistent fever, 40 patients; persistent BSI, 10 patients; or clinically manifest septic thrombophlebitis, 10 patients) after 8 median days from BSI onset; 40/100 patients retained the CVC because they had not clinical findings of complicated infection. At 30 days median follow-up, one patient died for infection in the ultrasonography-assisted group versus 17 patients in the historical cohort (P<0.01). With the ultrasonography-driven strategy, early septic thrombophlebitis detection and prompt CVC removal decrease infection related mortality, whereas clinically driven strategy leads to inappropriate number, reasons, and timeliness of CVC removal. CONCLUSION: Ultrasonography is an easy imaging diagnostic tool enabling effective and safe management of patients with acute leukemia and CRBSI. PMID- 22228451 TI - Fertility and gonadal function in female survivors after treatment of early unfavorable Hodgkin lymphoma (HL) within the German Hodgkin Study Group HD14 trial. AB - BACKGROUND: In the HD14 trial, 2*BEACOPPescalated+2*ABVD (2+2) has improved the primary outcome. Compared with 4*ABVD, this benefit might be compromised by more infertility in women. Therefore, we analyzed gonadal function and fertility. PATIENTS AND METHODS: Women<=45 years in ongoing remission at least 1 year after therapy were included. Hormone parameters, menopausal symptoms, measures to preserve fertility, menstrual cycle, pregnancies, and offspring were evaluated. RESULTS: Three hundred and thirty one of 579 women addressed participated (57.2%) and 263 per-protocol treated patients qualified (A=ABVD: 137, B=2+2: 126, mean time after therapy 42 and 43 months, respectively). Regular menstrual cycle after treatment (A: 87%, B: 83%) and time to recovery (<=12 months) were not different. Follicle-stimulating hormone and anti-Muellerian hormone were significantly better in arm A. However, pregnancies after therapy favored arm B (A: 15%, B: 26%, P=0.043) and motherhood rates were equivalent to the German normal population. Multivariate analysis revealed prophylactic use of gonadotropin releasing hormone (GnRH) analogues as highly significant prognostic factor for preservation of fertility (odds ratio=12.87, P=0.001). Severe menopausal symptoms were frequent in women>=30 years (A: 21%, B: 25%). CONCLUSIONS: Hormonal levels after 2+2 indicate a reduced ovarian reserve. However, 2+2 in combination with GnRH analogues does not compromise fertility within the evaluated observation time. PMID- 22228452 TI - Body mass index and incidence of localized and advanced prostate cancer--a dose response meta-analysis of prospective studies. AB - BACKGROUND: The relationship between obesity and risk of prostate cancer (PCa) is unclear; however, etiologic heterogeneity by subtype of PCa (localized, advanced) related to obesity was suggested. Therefore, we conducted a dose-response meta analysis of prospective studies to assess the association between body mass index (BMI) and risk of localized and advanced PCa. MATERIALS AND METHODS: Relevant prospective studies were identified by a search of Medline and Embase databases to 03 October 2011. Twelve studies on localized PCa (1,033,009 men, 19,130 cases) and 13 on advanced PCa (1,080,790 men, 7067 cases) were identified. We carried out a dose-response meta-analysis using random-effects model. RESULTS: For localized PCa, we observed an inverse linear relationship with BMI [Ptrend<0.001, relative risk (RR): 0.94 (95% confidence interval, 95% CI, 0.91-0.97) for every 5 kg/m2 increase]; there was no evidence of heterogeneity (Pheterogeneity=0.27). For advanced PCa, we observed a linear direct relationship with BMI (Ptrend=0.001, RR: 1.09 (95% CI 1.02-1.16) for every 5 kg/m2 increase); there was weak evidence of heterogeneity (Pheterogeneity=0.08). Omitting one study that contributed substantially to the heterogeneity yielded a pooled RR of 1.07 (95% CI 1.01-1.13) for every 5 kg/m2 increase (Pheterogeneity=0.26). CONCLUSIONS: The quantitative summary of the accumulated evidence indicates that obesity may have a dual effect on PCa-a decreased risk for localized PCa and an increased risk for advanced PCa. PMID- 22228453 TI - Identification of a novel recurrent gain on 20q13 in chronic lymphocytic leukemia by array CGH and gene expression profiling. AB - BACKGROUND: The presence of genetic changes is a hallmark of chronic lymphocytic leukemia (CLL). The most common cytogenetic abnormalities with independent prognostic significance in CLL are 13q14, ATM and TP53 deletions and trisomy 12. However, CLL displays a great genetic and biological heterogeneity. The aim of this study was to analyze the genomic imbalances in CLL cytogenetic subsets from both genomic and gene expression perspectives to identify new recurrent alterations. PATIENTS AND METHODS: The genomic imbalances and expression levels of 67 patients were analyzed. The novel recurrent abnormalities detected with bacterial artificial chromosome array were confirmed by FISH and oligonucleotide microarrays. In all cases, gene expression profiling was assessed. RESULTS: Copy number alterations were identified in 75% of cases. Overall, the results confirmed FISH studies for the regions frequently involved in CLL and also defined a new recurrent gain on chromosome 20q13.12, in 19% (13/67) of the CLL patients. Oligonucleotide expression correlated with the regions of loss or gain of genomic material, suggesting that the changes in gene expression are related to alterations in copy number. CONCLUSION: Our study demonstrates the presence of a recurrent gain in 20q13.12 associated with overexpression of the genes located in this region, in CLL cytogenetic subgroups. PMID- 22228454 TI - Dose-response relationships for the antifeedant effects of Humulus lupulus extracts against larvae and adults of the Colorado potato beetle. AB - BACKGROUND: Dose-response relationships for antifeedant effects of H. lupulus extracts against larvae and adults of the Colorado potato beetle (CPB) were determined in laboratory conditions. The larval and adult beetles were fed on potato leaflets treated with H. lupulus extract ranging from 0.4 to 40 mg mL(-1) in a no-choice situation. Their feeding behavior was recorded, and larval growth and antifeedant indexes were calculated. RESULTS: H. lupulus treatments significantly affected larval growth rate, and at higher concentrations the larval weights were significantly reduced over the course of the assay. Adults of CPB were more sensitive to the extracts than the larvae, and, even at lower doses, adult beetles were arrested for longer periods than larvae. CONCLUSION: These results indicate that H. lupulus extracts may have potential for control of CPB, particularly in organic farms where conventional insecticides are not available. PMID- 22228455 TI - Assessment of enveloping distribution sampling to calculate relative free enthalpies of binding for eight netropsin-DNA duplex complexes in aqueous solution. AB - The performance of enveloping distribution sampling (EDS) simulations to estimate free enthalpy differences associated with seven alchemical transformations of A-T into G-C base pairs at the netropsin binding site in the minor groove of a 13 base pair DNA duplex in aqueous solution is evaluated. It is demonstrated that sufficient sampling can be achieved with a two-state EDS Hamiltonian even for large perturbations such as the simultaneous transformation of up to three A-T into three G-C base pairs. The two parameters required to define the EDS reference state Hamiltonian are obtained automatically using a modified version of a scheme presented in earlier work. The sensitivity of the configurational sampling to a variation of these parameters is investigated in detail. Although for relatively small perturbations, that is, one base pair, the free enthalpy estimate depends only weakly on the EDS parameters, the sensitivity is stronger for the largest perturbation. Yet, EDS offers various convenient measures to evaluate the degree of sampling and thus the reliability of the free enthalpy estimate and appears to be an efficient alternative to the conventional thermodynamic integration methodology to obtain free energy differences for molecular systems. PMID- 22228456 TI - Musculoskeletal: what's different in children? Playing with a friend: hooks fingers in friends t-shirt: left pinky is sore and swollen. PMID- 22228457 TI - Aconitum C20-diterpenoid alkaloid derivatives regulate the growth and differentiation of cord blood derived human hematopoietic stem/progenitor cells. AB - The pharmacological activity of Aconitum alkaloids depends on their fundamental structure. While C19-norditerpenoid alkaloids present significant toxicity to the central nervous system, C20-diterpenoid alkaloids have reduced toxicities. However, there is little information regarding the precise pharmacological properties of C20-diterpenoid alkaloids. C20-diterpenoid alkaloid derivatives have explicit structure-activity relationships targeting various tumor cells, which depend on the C11-substrate. However, the present study showed that C6 derivatives additively or synergistically sustained proliferation of CD34+ hematopoietic stem/progenitor cells derived from the placental/umbilical cord blood. It revealed that identical structures belonging to C20-diterpenoid alkaloids surprisingly have opposing proliferative effects depending on the derivatization sites (C6 versus C11). PMID- 22228458 TI - Preload evaluation of different screws in external hexagon joint. AB - PURPOSE: This study compared the maintenance of tightening torque in different retention screw types of implant-supported crowns. MATERIALS AND METHODS: Twelve metallic crowns in UCLA abutments cast with cobalt-chromium alloy were attached to external hexagon osseointegrated implants with different retention screws: group A: titanium alloy retention screw; group B: gold alloy retention screw with gold coating; group C: titanium alloy retention screw with diamond-like carbon film coating; and group D: titanium alloy retention screw with aluminum titanium nitride coating. Three detorque measurements were obtained after torque insertion in each replica. Data were evaluated by analysis of variance (ANOVA), Tukey's test (P < 0.05), and t test (P < 0.05). RESULTS: Detorque value reduced in all groups (P < 0.05). Group A retained the highest percentage of torque in comparison with the other groups (P < 0.05). Groups B and D retained the lowest percentage of torque without statistically significant difference between them (P > 0.05). CONCLUSIONS: All screw types exhibited reduction in the detorque value. The titanium screw maintained the highest percentage of torque whereas the gold coated screw and the titanium screw with aluminum titanium nitride coating retained the lowest percentage. PMID- 22228459 TI - Fatigue reliability of 3 single-unit implant-abutment designs. AB - OBJECTIVES: Because the mechanical behavior of the implant-abutment system is critical for the longevity of implant-supported reconstructions, this study evaluated the fatigue reliability of different implant-abutment systems used as single-unit crowns and their failure modes. METHODS AND MATERIALS: Sixty-three Ti 6Al-4V implants were divided in 3 groups: Replace Select (RS); IC-IMP Osseotite; and Unitite were restored with their respective abutments. Anatomically correct central incisor metal crowns were cemented and subjected to separate single load to failure tests and step-stress accelerated life testing (n = 18). A master Weibull curve and reliability for a mission of 50,000 cycles at 200 N were calculated. Polarized-light and scanning electron microscopes were used for failure analyses. RESULTS: The load at failure mean values during step-stress accelerated life testing were 348.14 N for RS, 324.07 N for Osseotite, and 321.29 N for the Unitite systems. No differences in reliability levels were detected between systems, and only the RS system mechanical failures were shown to be accelerated by damage accumulation. Failure modes differed between systems. CONCLUSIONS: The 3 evaluated systems did not present significantly different reliability; however, failure modes were different. PMID- 22228460 TI - Natural teeth used as provisionals in immediate implant loading in the maxilla: a case report. AB - PURPOSE: The purpose of this article is to describe a clinical case in which the patient's natural teeth were extracted and used as provisionals immediately after the implants had been placed. PATIENT PRESENTATION: A 52-year-old woman was treated with implants at the 2 maxillary central incisors using osseotite-tapered certain implants (Biomet 3I Inc., Palm Beach Gardens, FL), length: 15 mm, diameter: 4.1 mm; and the extracted teeth were used as provisionals. RESULTS: After 4 months of using the temporary teeth, the treatment was concluded with the placement of 2 metal-free crowns on the implants and light polymerized resin on teeth 7 and 10. CONCLUSIONS: This work showed the possibility of using the patient's extracted teeth as provisional teeth during the period of osseointegration, preserving aesthetics and favoring gingival tissue healing with a correct emergence profile and maintenance of the gingival papillae. PMID- 22228461 TI - Buccal bone plate in the immediately placed and restored maxillary single implant: a 7-year retrospective study using computed tomography. AB - AIM: The aim of this retrospective study is to assess the long-term buccal bone plate changes in cases of single implants in the maxillary aesthetic area placed and restored immediately after extraction. MATERIAL AND METHODS: A private practice's database was reviewed to find patients who had a standard computed tomography (CT) scan taken no more than 24 hours after insertion of a single, immediately restored, postextractive implant in the anterior maxilla. After a minimum period of 7 years, a cone beam computed tomography (CBCT) was performed. Buccal bone plate measurements were performed on CT and CBCT Dicom images and in vivo records. RESULTS: Two thousand nine hundred eighty patient records were scanned. Sixteen of them met the primary inclusion criteria. Three CTs were excluded because of poor imaging. Thirteen patients were then eligible to be recalled and 12 of them agreed to a follow-up. One implant failed due to severe periimplantitis. The resulting 11 patients were scanned by CBCT. Vertical mean resorption of 0.5 mm at buccal aspect and an average of 0.9-mm thick buccal bone plate was revealed. In 2 patients (18.18%), the bone peak resorbed under the level of the implant shoulder. CONCLUSION: The buccal bone plate of single implants placed and restored immediately after tooth extraction in the maxillary aesthetic areas was subjected to a moderate vertical and horizontal reabsorption 7 years after surgery. If a careful selection of the patient and strict clinical protocol are observed, the immediate placement of a single implant in a fresh extraction socket and its immediate restoration do not compromise the preservation of the buccal bone plate. PMID- 22228462 TI - Dental implant failure associated with bacterial infection and long-term bisphosphonate usage: a case report. AB - Although the risk of developing osteonecrosis of the jaw for oral implants in patients using oral bisphosphonates (BPs) is low, the devastating complications still require caution. We document a case of severe periimplant infection that developed after the patient had used oral BPs for 3 years. Exposed bone and osteonecrosis persisted for more than 2 months after 1 infected implant was explanted by a dentist unaware that the patient was taking BPs. After oral BPs had been stopped, another involved implant was explanted, sequestra were removed, a primary closure was sutured, and the antibiotic was changed; then the wound was finally under control. The explanted implant with attached bone was processed for undecalcified ground sections, and specimens from the bony lesion were sent to pathology for examination. Osteonecrosis, severe inflammatory osteolysis, and heavy bacterial colonization were found. Patients at risk must be alerted about the potential risks of implant failure and developing BP-related osteonecrosis of the jaw. PMID- 22228463 TI - Augmentation of the anterior maxilla with intraoral onlay grafts for implant placement. AB - The use of autogenous cortical cancellous block grafts to augment the premaxilla is a safe and effective technique to provide adequate bone height and width when reconstructing patients with atrophic premaxilla ridge when endosteal implants are planned. Intraoral bone graft harvests have the advantages of proximity of the donor site to the graft site, convenient surgical access, minimal operative time, and ease of performance in an office setting. The major limitation of these donor sites is the smaller quantity of graft obtainable compared with iliac crest bone harvest sites. PMID- 22228464 TI - Brief report: ultraviolet radiation exposure, considering acculturation among Hispanics (project URECAH). AB - Very few studies have examined acculturation of Hispanics as it relates to skin cancer prevention attitudes and behaviors. This pilot study used the Abbreviated Acculturation Rating Scale for Mexican Americans-II to classify 14-25-year-old Hispanics as traditional, bicultural, or acculturated. More acculturated individuals reported significantly higher perceived benefits of ultraviolet radiation exposure and lower worry about skin damage than traditional individuals. Bicultural individuals reported using sunscreen significantly more often than acculturated individuals. These preliminary data suggest that more acculturated Hispanic young adults may demonstrate riskier skin cancer-related attitudes and behaviors than others. PMID- 22228465 TI - Association between chronic periodontitis and rheumatoid arthritis: a hospital based case-control study. AB - Rheumatoid arthritis (RA) and chronic periodontitis are the most common chronic inflammatory diseases with remarkable pathological and clinical similarities. A lot of similarities exist between RA and periodontitis at cellular and molecular levels. The relationship between these two chronic inflammatory diseases is still unclear. This case-control study was undertaken to determine the possible association between chronic inflammatory diseases like RA and periodontitis. The case group consisted of 100 patients attending the Rheumatology clinic who have rheumatoid arthritis (RA group). Age- and gender-matched 112 patients without RA attending the Outpatient wing of Department of General Medicine formed the control group (NRA group). The number of missing teeth, gingival index (GI), oral hygiene index-simplified (OHI-S), probing pocket depth (PPD) and clinical attachment levels (CAL) were evaluated in both the groups. Rheumatoid disease activity was assessed by DAS-28 score system. Systemic markers of inflammation like erythrocytic sedimentation rate (ESR) and serum levels of C-reactive protein (CRP) were assessed. There was a statistically significant difference in GI, OHI S, PPD, CAL, ESR and CRP levels between cases (RA group) and controls (NRA group) (P < 0.05). Among subjects with RA, there was no association between the rheumatoid disease activity and the severity of periodontal disease. The occurrence and severity of periodontitis was found to be higher in RA subjects as compared to subjects without RA, suggesting a positive relation between these two chronic inflammatory diseases. PMID- 22228466 TI - Age-related differences in the clinical characteristics of systemic lupus erythematosus in children. AB - The objective of this study was to determine how the clinical presentation of systemic lupus erythematosus in pediatric varied with the age of onset of the disease. We reviewed the charts of a total of 88 Chinese pediatric patients (pSLE) diagnosed and admitted first time to our hospitals between 2005 and 2008. Patients were divided into 3 groups, depending on the age at diagnosis: preschool (1-6 years), school age (7-11 years), and adolescent groups (12-18 years). Among the three groups, we compared the sex ratio, disease duration at diagnosis, symptoms at the onset of the disease, clinical manifestations, laboratory examinations, SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) 2000, and SLICC/ACR SDI (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for Systemic Lupus Erythematosus). Most pediatric patients were in the adolescent group (47.7%), while the disease duration at diagnosis was shortest in preschool-age patients (0.65 +/- 0.5 months). The most common symptoms at the onset of pSLE were fever, rash, arthritis, and seizures. Hematologic system and neuropsychiatric system were damaged commonly. The preschool-age patients had the shortest disease duration at diagnosis, the highest incidence of neuropsychiatric system involvement, and the poorest prognosis of all the age groups, especially the boys. Patients in adolescence had the peak incidence of pediatric SLE and high disease activity, begins to acquire some of the adult characteristics. School-age is a transition stage between other stages. PMID- 22228467 TI - Perylene imides for organic photovoltaics: yesterday, today, and tomorrow. AB - Perylene imides have been an object of research for 100 years and their derivatives are key n-type semiconductors in the field of organic electronics. While perylene diimides have been applied in many electronic and photonic devices, their use can be traced back to the first efficient organic solar cell. By functionalizing different positions of the in total 12 positions (four peri, four bay, and four ortho-positions) on the perylene core, perylene imides with significantly different optical, electronic and morphological properties may be prepared. Perylene imides and their derivatives have been used in several types of organic photovoltaics, including flat-, and bulk-heterojunction devices as well as dye-sensitized solar cells. Additionally perylene imides-based copolymers or oligomers play an important role in single junction devices. In this review, the relationship between the photovoltaic performance and the structure of perylene imides is discussed. PMID- 22228469 TI - Sexual fusion of protoplasts in a marine green alga, Bryopsis plumosa. AB - We isolated protoplasts from male and female gametophytes of a strictly dioecious strain of the coenocytic marine green alga Bryopsis plumosa. The protoplasts successfully developed into macrothalli. These in turn produced swimming cells, which appeared similar to biflagellated gametes even when the mixed protoplasts were comprised of protoplasm from male and female gametophytes. We found that swimming cell sizes depended on the male/female protoplasm ratio; macrothalli successfully produced swimming cells with male/female protoplasm ratios of 10:0; 9:1; 7:3; 5:5; 1:9; and 0:10. In male/female protoplasm ratios ranging from equal to strongly female biased (5:5; 3:7; 1:9), swimming cells exhibited normal behaviors of gametes and resultant zygotes, displaying positive and negative phototaxis, respectively. Negatively phototactic swimming cells were quadriflagellated and had two nuclei, apparently as a result of fusion, but never developed into microthalli. Thus, these swimming cells might lack functionality essential for normal gametes. Our findings suggested that natural monoecy observed in this genus did not originate from hybridization of protoplasm between the sexes. PMID- 22228470 TI - Activation of PKR/eIF2alpha signaling cascade is associated with dihydrotestosterone-induced cell cycle arrest and apoptosis in human liver cells. AB - Androgen receptor (AR) signaling plays an important role in the development and progression of several liver diseases, including hepatocellular carcinoma (HCC) and non-alcoholic fatty liver disease (NAFLD). Dihydrotestosterone (DHT) is the active metabolite of the major circulating androgen, testosterone. In this study, we investigated the effect of DHT on human liver cells. We found that DHT not only induces cell cycle arrest but also initiates apoptosis in androgen-sensitive liver cells, such as SMMC-7721 and L02. Importantly, DHT/AR induces the activation of RNA-dependent protein kinase (PKR)/eukaryotic initiation factor-2 alpha (eIF2alpha) cascades in androgen-sensitive liver cells. PKR/eIF2alpha activation-induced growth arrest and DNA damage-inducible gene 153 (GADD153) and heat shock protein 27 (Hsp27) expression contribute to cell cycle arrest in response to DHT. It is notable that DHT administration results in androgen sensitive liver cells apoptosis, at least in part, through PKR/eIF2alpha/GADD153 cascades. These results suggest that the androgen/AR pathway plays a pivotal role in liver cell growth and apoptosis regulating, whose deregulation might be involved in the pathogenesis of liver diseases. PMID- 22228473 TI - Bis(N-methylindolyl)methane-based chemical probes for Hg2+ and Cu2+ and molecular IMPLICATION gate operating in fluorescence mode. AB - Bis(N-methylindolyl)methane derivatives behave as chemosensors for Hg(2+) and Cu(2+) ions relying on the absorption as well as emission changes. Rarely reported IMPLICATION logic gate operating in the fluorescence mode has been developed with respect to the emission band of one of the derivatives as output, with Hg(2+) and I(-) as inputs. PMID- 22228472 TI - Potential of Bacillus cereus strain RS87 for partial replacement of chemical fertilisers in the production of Thai rice cultivars. AB - BACKGROUND: There is increasing interest in the development of technologies which can reduce the requirement for chemical fertilisers in rice production. The objective of this study was to investigate the efficacy of Bacillus cereus strain RS87 for the partial replacement of chemical fertiliser in rice production. A greenhouse experiment was designed using different fertiliser regimes, with and without strain RS87. Six Thai rice cultivars were tested separately. RESULTS: Maximum rice growth and yield were obtained in rice receiving the full recommended fertiliser rate in combination with the strain RS87. Interestingly, all rice cultivars which were treated with strain RS87 and 50% recommended fertiliser rate provided equivalent plant growth and yield to that receiving the full recommended fertiliser rate only. A paired comparison between rice treated with 50% of the recommended fertiliser rate with the bacterial inoculant and the full fertiliser rate alone was further examined in small experimental rice paddy fields. Growth and yield of all rice cultivars which received the 50% fertiliser rate supplemented with strain RS87 gave a similar yield to that receiving the full fertiliser rate alone. CONCLUSION: Bacterial strain RS87 showed the potential to replace 50% of the recommended fertiliser rate for yield production. Integration of plant growth-promoting rhizobacterial inoculants with reduced application rates of chemical fertiliser appears promising for future agriculture. PMID- 22228471 TI - Chinese multi-center study of lung scintigraphy and CT pulmonary angiography for the diagnosis of pulmonary embolism. AB - To evaluate diagnostic value of the PISA-PED and PIOPED II criteria for lung scintigraphy and compare it with CT pulmonary angiography (CTPA) for the detection of pulmonary embolism (PE). Five hundred and forty-four consecutive patients with suspected PE were enrolled. All patients underwent lung ventilation/perfusion (V/P) scan, chest radiography, and CTPA. Two readers used the PIOPED II criteria, and 2 used the PISA-PED criteria for the interpretation of lung scintigraphy. CTPA scans were interpreted by two experienced radiologists. Lung scintigraphy and CTPA were categorized as PE present, absent or non-diagnostic. PE was present in 321 of 544 patients. Using PIOPED II criteria, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 85.1, 82.5, 88.1, and 78.4% respectively for V/P scan. Using PISA-PED criteria, sensitivity, specificity, PPV, and NPV were 86.0, 81.2, 86.8, and 80.1% respectively, and none was non-diagnostic. Sensitivity, specificity, PPV, and NPV were 81.7, 93.4, 94.9, and 77.3%, respectively for CTPA. PISA-PED interpretation has similar diagnostic accuracy to PIOPED II interpretation, does not have non-diagnostic scan, with lower cost and radiation, thus should be considered as a choice for patients with suspected PE. PMID- 22228474 TI - Enhanced photochemical activity of alpha-Fe2O3 films supported on SrTiO3 substrates under visible light illumination. AB - The visible light photochemical reactivity of a 50 nm thick alpha-Fe(2)O(3)(0001) (hematite) film on a SrTiO(3)(111) substrate is compared to the reactivities of bulk hematite and the same film supported by alpha-Al(2)O(3)(0001). The hematite film supported by SrTiO(3)(111) is far more reactive then the other two cases. PMID- 22228475 TI - AutoMatch: target-binding protein design and enzyme design by automatic pinpointing potential active sites in available protein scaffolds. AB - Proteins perform their functions mainly via active sites, whereas other parts of the proteins comprise the scaffolds, which support the active sites. One strategy for protein functional design is transplanting active sites, such as catalytic sites for enzyme or binding hot spots for protein-protein interactions, onto a new scaffold. AutoMatch is a new program designed for efficiently elucidating suitable scaffolds and potential sites on the scaffolds. Backrub motions are used to treat backbone flexibility during the design process. A step-by-step checking strategy and cluster-representation examination strategy were developed to solve the large combinatorial problem for the matching of active-site conformations. In addition, a grid-based binding energy scoring method was used to filter the solutions. An enzyme design benchmark and a protein-protein interaction design benchmark were built to test the algorithm. AutoMatch could identify the hot spots in the nonbinding protein and rank them within the top five results for 8 of 10 target-binding protein design cases. In addition, among the 15 enzymes tested, AutoMatch can identify the catalytic active sites in the apoprotein and rank them within the top five results for 13 cases. AutoMatch was also tested for screening scaffold library in designing binding proteins targeting influenza hemagglutinin, HIV gp120, and epidermal growth factor receptor kinase, respectively. AutoMatch, and the two test sets, ActApo and ActFree, are available for noncommercial applications at http://mdl.ipc.pku.edu.cn/cgi-bin/down.cgi. PMID- 22228476 TI - Lack of association of Toll-like receptor 9 polymorphisms with susceptibility to systemic lupus erythematosus in an Asian population: a meta-analysis. AB - The association of Toll-like receptor 9 (TLR9) gene polymorphisms with systemic lupus erythematosus (SLE) risk remains controversial and ambiguous. To more precisely estimate the relationship between TLR9 gene polymorphisms and the susceptibility to SLE, a meta-analysis was performed. A total of seven independent studies were involved in this analysis. Meta-analysis was performed for three TLR9 gene polymorphisms (rs187084, rs352139, and rs352140). We have compared allele or genotype frequencies of the polymorphisms in SLE patients and controls. When available studies were pooled into the meta-analysis, there was no evidence showing a significant association between rs187084 and SLE risk in an Asian population (for C vs. T: OR = 0.81, P = 0.117; for CC vs. TT: OR = 0.71, P = 0.158; for CT vs. TT: OR = 0.86, P = 0.085; for CC + CT vs. TT: OR = 0.78, P = 0.093; for CC vs. CT + TT: OR = 0.81, P = 0.285). Similar results were found between rs352139 and SLE. No significant association was detected in any genetic model in the Asian population either (for G vs. A: OR = 1.11, P = 0.095; for GG vs. AA: OR = 1.32, P = 0.238; for GA vs. AA: OR = 1.17, P = 0.084; for GG + GA vs. AA: OR = 1.17, P = 0.073; for GG vs. GA + AA: OR = 1.17, P = 0.404). We found no association between TLR9 gene rs352140 polymorphism and SLE in the Asian population (for A vs. G: OR = 1.02, P = 0.728). In conclusion, there is still not enough evidence to indicate an association between TLR9 gene rs187084, rs352139, and rs352140 polymorphisms and the development of SLE in the Asian population. PMID- 22228477 TI - Oligonucleotide-mediated gene editing is underestimated in cells expressing mutated green fluorescent protein and is positively associated with target protein expression. AB - BACKGROUND: Single-stranded DNA oligonucleotides (ssODNs) can introduce small, specific sequence alterations into genomes. Potential applications include creating disease-associated mutations in cell lines or animals, functional studies of single nucleotide polymorphisms and, ultimately, clinical therapy by correcting genetic point mutations. Here, we report feasibility studies into realizing this potential by targeting a reporter gene, mutated enhanced green fluorescent protein (mEGFP). METHODS: Three mammalian cell lines, CHO, HEK293T and HepG2, expressing multiple copies of mEGFP were transfected with a 27-mer ssODN capable of restoring fluorescence. Successful cell correction was quantified by flow cytometry. RESULTS: Gene editing in each isogenic cell line, as measured by percentage of green cells, correlated tightly with target protein levels, and thus gene expression. In the total population, 2.5% of CHO-mEGFP cells were successfully edited, although, remarkably, in the highest decile producing mEGFP protein, over 20% of the cells had restored green fluorescence. Gene-edited clones initially selected for green fluorescence lost EGFP expression during cell passaging, which partly reflected G2-phase cycle arrest and perhaps eventual cell death. The major cause, however, was epigenetic down-regulation; incubation with sodium butyrate or 5-aza-2'-deoxycytidine reactivated fluorescent EGFP expression and hence established that the repaired genotype was stable. CONCLUSIONS: Our data establish that ssODN-mediated gene editing is underestimated in cultured mammalian cells expressing nonfluorescent mutated EGFP, because of variable expression of this mEGFP target gene in the cell population. This conclusion was endorsed by studies in HEK293T-mEGFP and HepG2 mEGFP cells. We infer that oligonucleotide-directed editing of endogenous genes is feasible, particularly for those that are transcriptionally active. PMID- 22228478 TI - Tuning ratios, densities, and supramolecular spacing in bifunctional DNA-modified gold nanoparticles. AB - Methods for combining multiple functions into well-defined nanomaterials are still lacking, despite their need in nanomedicine and within the broader field of nanotechnology. Here several strategies for controlling the amount and the ratio of combinations of labeled DNA on 13-nm gold nanoparticles using self-assembly of thiolated DNA and/or DNA-directed assembly are explored. It is found that the self-assembly of mixtures of fluorescently labeled DNA can lead to a higher amount of labeled DNA per particle; however, the ratio of fluorophores on the nanoparticles differs greatly from that in the self-assembly solution. In contrast, when fluorescently labeled DNA are hybridized to DNA-modified gold nanoparticles, the fluorophore ratio on the nanoparticles is much closer to their ratio in solution. The use of bifunctional DNA-doublers in self-assembly and DNA directed assembly is also explored to increase the complexity of these materials and control their composition. Finally, tuning the distance between the labels from 2.9 to 5.4 nm was achieved using different hybridized DNA clamp complexes. Fluorescent results suggest that assembling these clamps on nanoparticle surfaces may be possible, although the resulting label spacing could not be quantified. PMID- 22228479 TI - Thrombin-activatable fibrinolysis inhibitor is activated in vivo in a baboon model of Escherichia coli induced sepsis. AB - Activated thrombin-activatable fibrinolysis inhibitor (TAFIa or CPU) is a carboxypeptidase that is able to attenuate fibrinolysis. Although its role in fibrinolysis and inflammation has been studied extensively in vitro, its levels and subsequent effect in vivo has not been studied to the same extent. Using our recently developed assay that is specific for TAFIa, we were able to quantify its levels in plasma samples obtained from an Escherichia coli (E. coli) challenged baboon sepsis model. TAFIa levels accumulated appeared to be E. coli dose dependent, where the lethal dose of 10(10) CFU/kg generated a peak TAFIa level of 24 nM by 2 h, which represents almost 32% of total plasma level of its precursor, thrombin-activatable fibrinolysis inhibitor (TAFI or proCPU). Furthermore, our data suggest that there is continual TAFI activation under lethal level of E. coli as the apparent half-life of TAFIa is increased from 8 min to 2.2 h. Two sublethal doses of 10(8) and 10(6) CFU/kg generated peak TAFIa levels of 1.1 and 0.4 nM, respectively, both by 6 h. Taken together, our data show that TAFIa is generated at systemic levels, in a dose-dependent manner, that can substantially affect both fibrinolysis and inflammatory response in the E. coli challenged baboon sepsis model. PMID- 22228480 TI - Efficient sequential assignments in proteins with reduced dimensionality 3D HN(CA)NH. AB - We present reduced dimensionality (RD) 3D HN(CA)NH for efficient sequential assignment in proteins. The experiment correlates the (15)N and (1)H chemical shift of a residue ('i') with those of its immediate N-terminal (i - 1) and C terminal (i + 1) neighbors and provides four-dimensional chemical shift correlations rapidly with high resolution. An assignment strategy is presented which combines the correlations observed in this experiment with amino acid type information obtained from 3D CBCA(CO)NH. By classifying the 20 amino acid types into seven distinct categories based on (13)C(beta) chemical shifts, it is observed that a stretch of five sequentially connected residues is sufficient to map uniquely on to the polypeptide for sequence specific resonance assignments. This method is exemplified by application to three different systems: maltose binding protein (42 kDa), intrinsically disordered domain of insulin-like growth factor binding protein-2 and Ubiquitin. Fast data acquisition is demonstrated using longitudinal (1)H relaxation optimization. Overall, 3D HN(CA)NH is a powerful tool for high throughput resonance assignment, in particular for unfolded or intrinsically disordered polypeptides. PMID- 22228481 TI - Evaluation of the combination of 1,3-dichloropropene and dazomet as an efficient alternative to methyl bromide for cucumber production in China. AB - BACKGROUND: The combination of 1,3-dichloropropene (1,3-D) and dazomet (DZ) offers a potential alternative to methyl bromide (MB) for soil disinfection. MB is scheduled to be withdrawn from routine use by 2015 in developing countries. Combination treatments of 1,3-D + DZ were evaluated in a laboratory study and in two commercial cucumber fields. RESULTS: Laboratory studies found that nearly all of the tested combinations of 1,3-D and DZ displayed positive synergistic activity on root-knot nematodes (Meloidogyne spp.), two major soilborne fungi (Fusarium spp. and Phytophthora spp.) and the seeds of two major weed species (Digitaria sanguinalis and Abutilon theophrasti). Field trials revealed that the combination of 1,3-D and DZ (at 10 + 25 g m(-2) ) successfully suppressed Meloidogyne spp. root galling, sharply reduced Fusarium spp. and Phytophthora spp. and maintained high cucumber yields. The combination treatment of 1,3-D + DZ was more effective than 1,3-D or DZ alone and provided results similar to methyl bromide with respect to pest control, plant mortality, plant height, yield and income. All of the treatments were significantly better than the non-treated control. CONCLUSION: The results indicate that the tested combination of 1,3-D and DZ offers an efficient alternative to methyl bromide for cucumber production. PMID- 22228482 TI - Scutellarin inhibits cytochrome P450 isoenzyme 1A2 (CYP1A2) in rats. AB - Scutellarin is the most important flavone glycoside in the herbal drug Erigeron breviscapus (Vant.) Hand.-Mazz. It is used frequently in the clinic to treat ischemic vascular diseases in China. However, the direct relationship between scutellarin and cytochrome P450 (CYP450) is unclear. The present study investigated the in vitro and in vivo effects of scutellarin on cytochrome P450 1A2 (CYP 1A2) metabolism. According to in vitro experiments, scutellarin (10-250 uM) decreased the formation of 4-acetamidophenol in a concentration-dependent manner, with an IC50 value of 108.20 +/- 0.657 uM. Furthermore, scutellarin exhibited a weak mixed-type inhibition against the activity of CYP1A2 in rat liver microsomes, with a K(i) value of 95.2 uM. Whereas in whole animal studies, scutellarin treatment for 7 days (at 5, 15, 30 mg/kg, i.p.) decreased the clearance (CL), and increased the T(1/2) (at 15, 30 mg/kg, i.p.), it did not affect the V(d) of phenacetin. Scutellarin treatment (at 5, 15, 30 mg/kg, i.p.) increased the AUC(0-infinity) by 14.3%, 67.3% and 159.2%, respectively. Scutellarin at 30 mg/kg also weakly inhibited CYP1A2 activity, in accordance with our in vitro study. Thus, the results indicate that CYP1A2 is inhibited directly, but weakly, by scutellarin in vivo, and provide useful information on the safe and effective use of scutellarin in clinical practice. PMID- 22228483 TI - On the application of light therapy in German-speaking countries. AB - Many studies have investigated seasonal affective disorder (SAD; fall-winter depression) and its treatment with light therapy (LT). However, to the best of our knowledge, no other study has investigated the usage of LT in Europe since 1994. Thus, we performed a survey in hospitals with adult psychiatric departments in German-speaking countries by questionnaire. First, a questionnaire was constructed, considering also recent developments in LT. This questionnaire was sent to all hospitals with adult psychiatric departments listed in the "Deutsches Krankenhaus Adressbuch," which contains hospitals from all German-speaking countries (Germany, Switzerland, and Austria). Non-responders were asked to answer the questionnaire by mail and by phone. We achieved a completion rate of 58%. Data show almost no relevant, non-artificial differences between countries as well as between type of hospital. LT is more frequently used in university and state hospitals than in other types of treatment facilities. Compared to 1994, the major findings are (1) a substantial increase in the use of LT from 13.0 to 69.8% with no differences between Germany, Austria, and Switzerland, (2) this increase is mostly due to treatment for various forms of depression and further possible applications are less often considered, (3) there is a shift in the usage of LT from monotherapy to combination of pharmacotherapy with LT as an adjunctive treatment, and (4) a north-south comparison showed no substantial differences. Considerably higher rates of usage of LT have been found compared to the last survey in German-speaking countries taking place in 1994. Usage almost tripled; however, possible indications for LT other than SAD and non-seasonal depression are not applied to full extent. Further efforts on the propagation of LT should therefore be undertaken, with the same rigorous studies as for pharmacotherapy. PMID- 22228484 TI - Association of ferritin autoantibodies with giant cell arteritis/polymyalgia rheumatica. AB - OBJECTIVES: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are relatively common inflammatory disorders. Establishing the diagnosis however may be difficult, since so far no specific biomarkers of the disorders are available. METHODS: As a screening procedure, the authors used protein arrays for the detection of new autoantigens in GCA and PMR. The results of the protein array were confirmed by different ELISAs detecting IgG antibodies against the human ferritin heavy chain, N-terminal 27 amino acids of the human ferritin heavy chain or the homologous peptide of Staphylococcus epidermidis. Sera of patients with only GCA (n=64), only PMR (n=47) and both PMR and GCA (n=31) were used. RESULTS: In the ELISA using the human ferritin peptide, the sensitivity of IgG antibodies against ferritin was 92% in 36 GCA and/or PMR patients before initiation of treatment, 22/32 (69%) in patients with disease flares and 64/117 (55%) in the total cohort including treated and inactive patients. In controls, the false positive rate was 11/38 (29%) in systemic lupus erythematosus, 1/36 (3%) in rheumatoid arthritis, 0/31 (0%) in late onset rheumatoid arthritis, 3/46 (6.5%) in B-non-Hodgkin's lymphoma and 1/100 (1%) in blood donors. In the ELISA using the ferritin peptide of S epidermidis, 89% of 27 patients with untreated GCA and PMR were positive. CONCLUSION: Antibodies against the ferritin peptide were present in up to 92% of untreated, active GCA and PMR patients. They can be useful as a diagnostic marker of PMR and GCA. PMID- 22228485 TI - Can you see what they are saying? Breast cancer images and text in Canadian women's and fashion magazines. AB - Media are an important source of breast cancer information for women. Visual images influence recall and comprehension of information. Research on breast cancer in the media has infrequently focused on images. Using directed content analysis, we compared content, tone, and themes in images (n = 91) and articles (n = 31) in Canadian women's and fashion (n = 6) magazines (2005-2010). About half of the articles (51.6%) had both positive and negative tone; in contrast, 87.7% of women in the images had positive facial expressions. Women in the images were Caucasian (80.9%), young (81.3%), attractive (99.2%), had a healthy body type (93.8%), and appeared to have intact breasts (100%). Images of screening/treatment (5.5%) and visual impact of disease/treatment on the body (4.4%) were rare. The most common theme in the articles was medical issues (35.5%); in the images, it was beauty or fashion (15.4%). The potential impact of these divergent messages for breast cancer education is discussed. PMID- 22228486 TI - Lennard-Jones parameters for small diameter carbon nanotubes and water for molecular mechanics simulations from van der Waals density functional calculations. AB - Lennard-Jones (LJ) parameters are derived for classical nonpolarizable force fields for carbon nanotubes (CNTs) and for CNT-water interaction from van der Waals (vdW) enhanced density functional calculations. The new LJ parameters for carbon-carbon interactions are of the same order as those previously used in the literature but differ significantly for CNT-water interactions. This may partially originate from the fact that in addition to pure vdW interactions the polarization and other quantum mechanics effects are embedded into the LJ potential. PMID- 22228487 TI - Effect of salinity on nitrogenase activity and composition of the active diazotrophic community in intertidal microbial mats. AB - Microbial mats are often found in intertidal areas experiencing a large range of salinities. This study investigated the effect of changing salinities on nitrogenase activity and on the composition of the active diazotrophic community (nifH transcript libraries) of three types of microbial mats situated along a littoral gradient. All three mat types exhibited highest nitrogenase activity at salinities close to ambient seawater or lower. The response to lower or higher salinity was strongest in mats higher up in the littoral zone. Changes in nitrogenase activity as the result of exposure to different salinities were accompanied by changes in the active diazotrophic community. The two stations higher up in the littoral zone showed nifH expression by Cyanobacteria (Oscillatoriales and Chroococcales) and Proteobacteria (Gammaproteobacteria and Deltaproteobacteria). At these stations, a decrease in the relative contribution of Cyanobacteria to the nifH transcript libraries was observed at increasing salinity coinciding with a decrease in nitrogenase activity. The station at the low water mark showed low cyanobacterial contribution to nifH transcript libraries at all salinities but an increase in deltaproteobacterial nifH transcripts under hypersaline conditions. In conclusion, increased salinities caused decreased nitrogenase activity and were accompanied by a lower proportion of cyanobacterial nifH transcripts. PMID- 22228488 TI - PTU-induced ANCA-positive vasculitis: an innocent or a life-threatening adverse effect? AB - Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides are rare, but they can be triggered by chemicals, infections and drugs; among them, antithyroid drugs are common. Autoimmune disorders, such as vasculitis, are unusual, but serious complications of antithyroid therapy. Both propylthiouracil (PTU) and methimazole may induce ANCA-associated vasculitis. PTU-induced vasculitides may have different organ involvement patterns. Herein, we report four cases with ANCA-associated vasculitis with different clinical manifestations. PMID- 22228489 TI - Salicylideneamino-2-thiophenol enhances osteogenic differentiation through the activation of MAPK pathways in multipotent bone marrow stem cell. AB - Osteoporosis is a reduction in skeletal mass due to an imbalance between bone formation and bone resorption. Therefore, the identification of specific stimulators of bone formation is of therapeutic significance in the treatment of osteoporosis. Salicylideneamino-2-thiophenol (Sal-2) consists of two benzene rings, has been reported to possess antioxidant activity, and is an effective remedy for fever and rheumatic diseases. However, until now the effects of osteoblastic bone formation by Sal-2 were unknown. In this study, we investigated the effects of Sal-2 on osteogenic differentiation of multipotent bone marrow stromal stem cells by alizarin red S staining for osteogenic differentiation, RT PCR and western blot for alkaline phosphatase (ALP) activity and signaling pathways, FACS analysis and immunofluorescence staining for CD44 and CD51 expression, calcium assays, and immunofluorescence staining for signaling pathways. We found that Sal-2 enhanced the osteogenic differentiation of multipotent bone marrow stromal stem cells. Sal-2 treatment induced the expression and activity of ALP, and enhanced the levels of CD44 and CD51 expression as well as Ca2+ content, in multipotent bone marrow stromal stem cells. Moreover, we found that Sal-2-induced osteogenic differentiation and expression of osteogenesis-related molecules involve the activation of the MAPK and nuclear factor-kappaB pathways. Our findings provide insight into both the mechanism and effects of Sal-2 on osteogenic differentiation and demonstrate that Sal-2 may be a beneficial adjuvant in stimulating bone formation in osteoporotic diseases. PMID- 22228490 TI - Metal uptake by microalgae: underlying mechanisms and practical applications. AB - Metal contamination of a few aquatic, atmospheric, and soil ecosystems has increased ever since the industrial revolution, owing to discharge of such elements via the effluents of some industrial facilities. Their presence to excessive levels in the environment will eventually lead to serious health problems in higher animals owing to accumulation throughout the food web. Current physicochemical methods available for recovery of metal pollutants (e.g., chemical precipitation, oxidation/reduction, or physical ion exchange) are either expensive or inefficient when they are present at very low concentrations. Consequently, removal of toxic metals by microorganisms has emerged as a potentially more economical alternative. Microalgae (in terms of both living and nonliving biomass) are an example of microorganisms suitable to recover metals and able to attain noteworthy percent removals. Their relatively high metal binding capacities arise from the intrinsic composition of their cell walls, which contain negatively charged functional groups. Consequently, microalgal cells are particularly efficient in uptake of those contaminants when at low levels. Self-defense mechanisms developed by microalgal cells to survive in metal containing media and environmental factors that affect their removal (e.g., pH, temperature, and biomass concentration) are reviewed here in a comprehensive way and further discussed in attempts to rationalize this form of remediation vis-a vis with conventional nonbiological alternatives. PMID- 22228493 TI - Synthesis of nanoamorphous germanium and its transformation to nanocrystalline germanium. AB - A simple reaction between a mild reducing agent such as a trialkoxysilane and Ge(IV) species such as germanium tetraalkoxides in a room-temperature water/alcohol solution produces silica-coated ultrasmall (2-3 nm) amorphous germanium nanoparticles (na-Ge/SiO2). The initial reaction involves the straightforward hydrolysis and condensation of the precursors, Ge(OCH2 CH3)4 and (CH3CH2O)3 SiH, where the reaction rate depends on the water concentration in the reaction medium. These processes can be further accelerated by adding acid to the reaction medium or carrying out the reaction at higher temperatures. At low water contents (up to 50% water/ethanol) and low acid concentrations, the reaction proceeds as a clear solution, and no precipitation is observed. The initially colorless clear solution progressively changes to pale yellow, yellow, orange, red, and finally dark red as the na-Ge particles grow. Evaporation of the solvent yields a reddish-brown powder/monolith consisting of na-Ge, embedded in an encapsulating amorphous silica matrix, na-Ge/SiO2. The formation of na-Ge proceeds extremely slowly and follows a first-order dependence on both water concentration and diameter of the na-Ge particles under the reaction conditions used. Annealing of the na-Ge/SiO2 powder under an inert atmosphere at 600 degrees C produces ultrasmall germanium nanocrystals (nc-Ge) embedded in amorphous silica (nc-Ge/SiO2). Freestanding, colloidally stable nc-Ge is obtained by chemical etching of the encapsulating silica matrix. PMID- 22228495 TI - Particle-like and fluid-like settling of a stratified suspension. AB - The gravitational settling of inhomogeneously suspended particles in a fluid has been investigated. Of particular interest is whether collective or individual motion of particles is dominant during their settlings, i.e., whether the particles settle as a continuous suspension or they settle individually relative to the surrounding fluid. We observed the settling of a stratified suspension which has the lower and upper concentration interfaces in a quasi-two-dimensional vessel. In some cases, the suspension behaves perfectly as a continuous fluid and the motion of the constituent particle is subject to bulk flow caused by the interfacial instability. In other cases, the particle behaves individually relative to the surrounding fluid. The existence of a concentration interface plays a significant role in these extreme behaviors of suspension. The transition from the collective to individual behaviors can be predicted quantitatively by a parameter which expresses the border resolution of the concentration interface. PMID- 22228494 TI - Prevalence, molecular fingerprinting and drug resistance profile of enterovirulent Escherichia coli isolates from free-ranging yaks of Tawang district, Arunachal Pradesh, India. AB - Of 273 samples (rectal swab) collected from free-ranging yaks of Tawang district, Arunachal Pradesh, 42 Shiga toxin-producing Escherichia coli (STEC), six enteropathogenic E. coli (EPEC) and 27 enterotoxigenic E. coli (ETEC) strains were isolated. All the STEC and EPEC strains were further investigated for respective stx variants (for STEC only) and additional putative virulence factors. The 27 ETEC strains were also screened for characteristic enterotoxin gene(s) and colonization factors. Occurrence of ETEC was significantly (p < 0.05) higher in the diarrheic yaks and yaks of less than 1 year of age. Majority of enterovirulent E. coli isolates were resistant to amikacin, azithromycin, chloramphenicol, colistin, doxycycline, furazolidone, nalidixic acid, nitrofurantoin, streptomycin and tetracycline. Dendrogram, constructed with molecular fingerprinting profiles obtained from RAPD (Randomly Amplified Polymorphic DNA) and ERIC (Enterobacterial Repetitive Intergenic Consensus) PCR, placed the isolates in different clusters irrespective of their serotypes, virulence gene and drug resistance pattern. Collectively, the study indicates that yaks, being a potential reservoir of multidrug resistant STEC and EPEC, may represent significant risk to public health in this region. Higher recovery of ETEC isolates from yaks with diarrhea points out that ETEC may be a major determinant for repeated occurrence of diarrhea in yaks. PMID- 22228496 TI - Serum sphingolipids and inflammatory mediators in adolescents at risk for metabolic syndrome. AB - The purpose of this study was to determine low-grade inflammation associated with obesity that is mediated partially by TNF-alpha, an adipocytokine which stimulates sphingomyelinase activity in adipocytes. Circulating ceramide (Cer) and sphingosine 1-phosphate (S1P) are elevated in genetically obese (ob/ob) mice. We aimed to determine whether serum sphingolipid concentrations correlate with measures of obesity, insulin resistance, and lipid profiles in overweight versus lean adolescents. This cross-sectional study recruited 30 healthy overweight (body mass index, BMI >= 85%) and 15 lean (BMI 10-84%) adolescents. Anthropometric measurements and fasting blood samples were collected at one clinic visit. Serum glucose, insulin, and fasting lipid profiles were measured. Serum adipocytokine concentrations were measured by ELISA or colorimetric assay and sphingolipids were measured by HPLC-mass spectrometry. Between group differences in serum sphingolipid concentrations were assessed. Correlations between sphingolipid concentrations and (i) body mass index, (ii) calculated homeostasis model assessment of insulin resistance (HOMA-IR), (iii) adipocytokines, and (iv) lipoproteins were determined. The results showed that significant differences in HOMA-IR (4.5 +/- 3.2 vs. 1.2 +/- 0.7), free fatty acids (0.8 +/- 0.3 mmol/l vs. 0.4 +/- 0.3 mmol/l), and adiponectin (6.4 +/- 3.8 vs. 12.6 +/- 9.9 MUg/ml) were seen between groups (overweight vs. lean). There were significant correlations between Cer and TNF-alpha (r = 0.429), S1P and TNF alpha (r = 0.288), Cer and adiponectin (r = 0.321), Cer:S1P and adiponectin (r = 0.324), Cer and HOMA-IR (r = 0.307), and Cer:S1P and LDL cholesterol (r = 0.453); these associations persisted after adjustment for BMI Z-score, sex, and Tanner stage. We concluded that elevated sphingolipid concentrations correlate with TNF alpha, adiponectin, lipoprotein profiles, and HOMA-IR. Ceramide is associated with atherogenic lipid profiles and the development of insulin resistance in obese adolescents, similar to adults. PMID- 22228498 TI - Toxicity of 6-hydroxydopamine: live cell imaging of cytoplasmic redox flux. AB - Oxidative stress contributes to several debilitating neurodegenerative diseases. To facilitate direct monitoring of the cytoplasmic oxidation state in neuronal cells, we have developed roTurbo by including several mutations: F223R, A206K, and six of the mutations for superfolder green fluorescent protein. Thus we have generated an improved redox sensor that is much brighter in cells and oxidizes more readily than roGFP2. Cytoplasmic expression of the sensor demonstrated the temporal pattern of 6-hydroxydopamine (6-OHDA) induced oxidative stress in a neuroblastoma cell line (SH-SY5Y). Two distinct oxidation responses were identified in SH-SY5Y cells but a single response observed in cells lacking monoamine transporters (HEK293). While both cell lines exhibited a rapid transient oxidation in response to 6-OHDA, a second oxidative response coincident with cell death was observed only in SH-SY5Y cells, indicating an intracellular metabolism of 6-OHDA, and or its metabolites are involved. In contrast, exogenously applied hydrogen peroxide induced a cellular oxidative response similar to the first oxidation peak, and cell loss was minimal. Glucose deprivation enhanced the oxidative stress induced by 6-OHDA, confirming the pivotal role played by glucose in maintaining a reduced cytoplasmic environment. While these studies support previous findings that catecholamine auto-oxidation products cause oxidative stress, our findings also support studies indicating 6 OHDA induces lethal oxidative stress responses unrelated to production of hydrogen peroxide. Finally, temporal imaging revealed the sporadic nature of the toxicity induced by 6-OHDA in neuroblastoma cells. PMID- 22228499 TI - Dezocine: a novel drug to prevent fentanyl-induced cough during general anesthesia induction? PMID- 22228500 TI - Forehead pressure sore following a prolonged operation and the role of the Mayfield head frame in re-operation. PMID- 22228497 TI - Clinical outcomes in the management of congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia (CAH) is a group of disorders affecting adrenal steroid synthesis. The most common form, 21-hydroxylase deficiency, leads to decreased production of cortisol and aldosterone with increased androgen secretion. In classic CAH glucocorticoid treatment can be life-saving, and provides symptom control, but must be given in an unphysiological manner with the risk of negative long-term outcomes. A late diagnosis or a severe phenotype or genotype has also a negative impact. These factors can result in impaired quality of life (QoL), increased cardiometabolic risk, short stature, osteoporosis and fractures, benign tumors, decreased fertility, and vocal problems. The prognosis has improved during the last decades, thanks to better clinical management and nowadays the most affected patients seem to have a good QoL. Very few patients above the age of 60 years have, however, been studied. Classifying patients according to genotype may give additional useful clinical information. The introduction of neonatal CAH screening may enhance long-term results. Monitoring of different risk factors and negative consequences should be done regularly in an attempt to improve clinical outcomes further. PMID- 22228501 TI - Preventive effects of hesperidin, glucosyl hesperidin and naringin on hypertension and cerebral thrombosis in stroke-prone spontaneously hypertensive rats. AB - The effects of hesperidin, glucosyl hesperidin (G-hesperidin), a water-soluble derivative of hesperidin, and naringin on blood pressure and cerebral thrombosis were investigated using stroke-prone spontaneously hypertensive rats (SHRSP). Hesperidin, G-hesperidin and naringin were mixed with diet and fed to the animals for 4 weeks. No effect was evident on body weight, but the supplements significantly suppressed the age related increase in blood pressure. Thrombotic tendency, as assessed using a He-Ne laser technique in the cerebral blood vessels, was significantly decreased in the treated animals compared with the control animals. Measurements of 8-hydroxy-2'-deoxyguanosine (8-OHdG) demonstrated that the supplements had strong antioxidant activity. Furthermore, these supplements significantly increased the production of nitric oxide (NO) metabolites in urine measured with Griess reagent. Vasodilation induced by acetylcholine-mediated NO production in the endothelium was assessed using thoracic aortic ring preparations and indicated that endothelial function was significantly improved by the administration of these supplements. These findings suggest that the strong antioxidant properties of hesperidin, G-hesperidin and naringin could modulate the inactivation of NO and protect endothelial function from reactive oxygen species (ROS). In this manner, the flavonoids could contribute beneficial effects on the mechanisms of hypertension and thrombosis by increasing the bioavailability of NO. PMID- 22228502 TI - Optimisation of hydrolysis of purple sea urchin (Strongylocentrotus nudus) gonad by response surface methodology and evaluation of in vitro antioxidant activity of the hydrolysate. AB - BACKGROUND: Hydrolysates prepared from sea urchin (Strongylocentrotus nudus) gonad by enzymatic treatment showed strong 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity and reducing power. RESULTS: Hydrolysis of S. nudus gonad by the commercial protease papain was optimised for maximum degree of hydrolysis (DH) and trichloroacetic acid-soluble peptide index (TCA-SPI) using response surface methodology. Results showed that the optimal conditions were the following: temperature of 48.83 degrees C, pH of 6.92, enzyme-to-substrate ratio of 3143 U g(-1), and substrate concentration of 83.5 g L(-1). Under these conditions, a DH of 27.96 +/- 0.54% and a TCA-SPI of 57.32 +/- 0.63% were obtained. The hydrolysate prepared in the optimal conditions was fractionated by an ultra-filtration system and the resultant fraction below 10 kDa was found to effectively scavenge hydroxyl radical (EC(50) = 13.29 +/- 0.33 mg mL(-1)) and hydrogen peroxide (EC(50) = 16.40 +/- 0.37 mg mL(-1)), inhibit lipid peroxidation (EC(50) = 11.05 +/- 0.62 mg mL(-1)), chelate Fe(2+) (EC(50) = 7.26 +/- 0.44 mg mL(-1)), and protect mice macrophages against death induced by tert-butyl hydroperoxide. CONCLUSION: Hydrolysates prepared from S. nudus gonad have the potential to be applied as natural antioxidant agents. PMID- 22228503 TI - Interaction of proteinase inhibitors with Cry1Ac toxicity and the presence of 15 chymotrypsin cDNAs in the midgut of the tobacco budworm, Heliothis virescens (F.) (Lepidoptera: Noctuidae). AB - BACKGROUND: The potential development of resistance to Bacillus thuringiensis (Bt) cotton and surging of non-targeted insects is a major risk in the durability of Bt plant technology. Midgut proteinases are involved in Bt activation and degradation. Proteinase inhibitors may be used to control a wide range of insects and delay Bt resistance development. Proactive action to examine proteinase inhibitors for synergistic interaction with Bt toxin and cloning of proteinase cDNAs for RNAi is necessary to make transgenic cotton more versatile and durable. RESULTS: A sublethal dose (15 ppb) of Cry1Ac, 0.5% benzamidine and 0.02% phenylmethylsulfonyl fluoride significantly suppressed midgut azocaseinase, tryptic and chymotryptic activities, and resulted in reductions in larval and pupal length and mass of Heliothis virescens. The combination of proteinase inhibitor and Bt suppressed 20-37% more larval body mass and 26-80% more enzymatic activities than the inhibitor only or Bt only. To facilitate knockdown resistance-related proteinase genes, 15 midgut chymotrypsin cDNAs were sequenced. Most predicted chymotrypsins contained the conserved N-termini IVGG, three catalytic center residues (His, Asp and Ser), substrate specificity determinant (Ser or Gly) and cysteines for disulfide bridges. These putative chymotrypsins were separated into three distinct groups, indicating the diverse proteinases evolved in this polyphagous insect. CONCLUSION: H. virescens has evolved diverse midgut proteinase genes. Proteinase inhibitors have potential insecticidal activity, and the interaction of Bt with proteinase inhibitors is desirable for enhancing Bt toxicity and delaying resistance development. Intensive sequencing of chymotrypsin cDNAs will facilitate future functional examinations of individual roles in Bt toxicity and resistance development and facilitate targeted control using RNAi and/or proteinase inhibitors. PMID- 22228504 TI - Staged-probability strategy of processing shotgun proteomic data to discover more functionally important proteins. AB - Biologically important proteins related to membrane receptors, signal transduction, regulation, transcription, and translation are usually low in abundance and identified with low probability in mass spectroscopy (MS)-based analyses. Most valuable proteomics information on them were hitherto discarded due to the application of excessively strict data filtering for accurate identification. In this study, we present a staged-probability strategy for assessing proteomic data for potential functionally important protein clues. MS based protein identifications from the second (L2) and third (L3) layers of the cascade affinity fractionation using the Trans-Proteomic Pipeline software were classified into three probability stages as 1.00-0.95, 0.95-0.50, and 0.50-0.20 according to their distinctive identification correctness rates (i.e. 100%-95%, 95%-50%, and 50%-20%, respectively). We found large data volumes and more functionally important proteins located at the previously unacceptable lower probability stages of 0.95-0.50 and 0.50-0.20 with acceptable correctness rate. More importantly, low probability proteins in L2 were verified to exist in L3. Together with some MS spectrogram examples, comparisons of protein identifications of L2 and L3 demonstrated that the staged-probability strategy could more adequately present both quantity and quality of proteomic information, especially for researches involving biomarker discovery and novel therapeutic target screening. PMID- 22228506 TI - Antitumor effect of chondroitin sulfate-coated ternary granulocyte macrophage colony-stimulating factor plasmid complex for ovarian cancer. AB - BACKGROUND: Although replication-competent viruses have been developed for treating cancers, their cytotoxic effects are insufficient as a result of infection inhibited by the generation of neutralizing antibodies, and systemic administration is difficult as a result of the life-threatening serious side effects of virus-induced cytokine surge. To overcome these critical problems, we devised a plasmid/polycation/polyanion complex and assessed the potential of ternary plasmid complexes coated with chondroitin sulfate in gene therapy for ovarian cancer. The antitumor effects of chondroitin sulfate-coated complex as an anionic component were compared with those of hyaluronic acid on ovarian cancer. METHODS: Plasmid harboring the gene of murine granulocyte macrophage-colony stimulating factor (mGM-CSF) was complexed with polyethyleneimine (PEI) and hyaluronic acid or chondroitin sulfate. Murine ovarian cancer cells were injected into (C57BL/6 * C3H/He) F(1) mice to prepare a subcutaneous or intraperitoneal tumor model. RESULTS: DNA/PEI was charged positively and DNA/PEI/chondroitin sulfate or DNA/PEI/hyaluronic acid was charged negatively. Plasmid-green fluorescent protein (GFP)/PEI coated with 10-kilodalton (kDa) chondroitin sulfate increased transfection efficiency compared to coating with chondroitin sulfate of higher-molecular-weight or hyaluronic acid. The transfection efficiency of GFP/PEI/10-kDa chondroitin sulfate in ovarian cancer cells was six-fold higher than that in normal cells. Intraperitoneal injection of mGM-CSF/PEI coated with 10-kDa chondroitin sulfate prolonged survival compared to that coated with hyaluronic acid. Intratumoral injection of mGM-CSF/PEI coated with 10-kDa chondroitin sulfate achieved mouse survival rates of 100%, although that with hyaluronic acid did not. CONCLUSIONS: These findings suggest that GM-CSF/PEI coated with 10-kDa chondroitin sulfate has the potential for use in gene therapy of ovarian cancer. PMID- 22228505 TI - Altered nuclear cofactor switching in retinoic-resistant variants of the PML RARalpha oncoprotein of acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) results from a reciprocal translocation that fuses the gene for the PML tumor suppressor to that encoding the retinoic acid receptor alpha (RARalpha). The resulting PML-RARalpha oncogene product interferes with multiple regulatory pathways associated with myeloid differentiation, including normal PML and RARalpha functions. The standard treatment for APL includes anthracycline-based chemotherapeutic agents plus the RARalpha agonist all-trans retinoic acid (ATRA). Relapse, which is often accompanied by ATRA resistance, occurs in an appreciable frequency of treated patients. One potential mechanism suggested by model experiments featuring the selection of ATRA resistant APL cell lines involves ATRA-resistant versions of the PML-RARalpha oncogene, where the relevant mutations localize to the RARalpha ligand-binding domain (LBD). Such mutations may act by compromising agonist binding, but other mechanisms are possible. Here, we studied the molecular consequence of ATRA resistance by use of circular dichroism, protease resistance, and fluorescence anisotropy assays employing peptides derived from the NCOR nuclear corepressor and the ACTR nuclear coactivator. The consequences of the mutations on global structure and cofactor interaction functions were assessed quantitatively, providing insights into the basis of agonist resistance. Attenuated cofactor switching and increased protease resistance represent features of the LBDs of ATRA-resistant PML-RARalpha, and these properties may be recapitulated in the full-length oncoproteins. PMID- 22228507 TI - Activation of target signal transducers utilizing chimeric receptors with signaling-molecule binding motifs. AB - Cellular fates such as proliferation, differentiation, and death are controlled by a variety of cytokine receptors, which are crucial in initiating downstream signaling cascades. To initiate signaling, the cytokine receptor cytoplasmic domain recruits specific signaling molecules with a range of tyrosine-containing motifs. Thus, we postulate that it is possible to regulate signal transduction artificially by locating the tyrosine motif of interest into the intracellular domain of specific receptors. Construction of such artificial receptors was based on an anti-fluorescein ScFv/c-Mpl chimera (S-Mpl). We selected several known tyrosine motifs from native cytokine receptors that strongly bind to their target molecule, and located them downstream of the Janus kinase (JAK) binding domain of S-Mpl, which would be necessary for phosphorylation of the receptor. Next, we used retroviral transduction to express chimeric receptors in a murine IL-3 dependent pro-B cell line, Ba/F3, which was stimulated with BSA-fluorescein. The results indicated that each chimeric receptor preferentially activated the corresponding signaling molecule. We also examined whether the position of the tyrosine motif in the receptor could influence the activation levels of the signal transducer, and found that the chimeric receptors could activate the corresponding signaling molecule even when the tyrosine motif was distant from the JAK binding domain. PMID- 22228508 TI - Changes in exhaled nitric oxide levels after bronchial allergen challenge. AB - BACKGROUND: Fractional exhaled nitric oxide (FeNO) is a marker of inflammation of the airways accompanying changes in the clinical condition of asthma. Allergen exposure has been associated with a delayed elevation of FeNO. The aim of this study was to assess airway inflammation with FeNO measurements during bronchial allergen challenge (BAC), and to determine the diagnostic performance of FeNO changes. METHODS: Thirty-four patients with asthma and sensitization to inhalant allergens were studied. BAC with common or high-molecular-weight occupational aeroallergens was performed. FeNO was measured before and 24 h after BAC. Receiver operating characteristics curve was built to assess the sensitivity and specificity of increase in FeNO levels associated with BAC outcome. RESULTS: In 21 patients (61.76%) a positive asthmatic reaction (responders) was observed. A significant increase in postchallenge FeNO was observed in this group of patients compared to the group of nonresponders. A median increase (FeNO postchallenge FeNO prechallenge) of 14.0 ppb was observed in the group of responders, whereas a -1.0 ppb change was attained in the nonresponder group (P < 0.001). The cutoff point providing maximal sensitivity and specificity for %DeltaFeNO after BAC was 12%. This change in FeNO levels has a sensitivity of 0.81 and a specificity of 0.92 for predicting a positive outcome in the BAC. CONCLUSION: FeNO measurements can be used as a surrogate of airway inflammation accompanying the asthmatic reaction induced by BAC. FeNO measurements may be a useful and reliable tool in the monitoring and interpreting specific bronchial challenge test with allergens. PMID- 22228509 TI - Dispersive interactions in water bilayers at metallic surfaces: a comparison of the PBE and RPBE functional including semiempirical dispersion corrections. AB - The accuracy and reliability of the density functional theory (DFT)-D approach to account for dispersion effects in first-principles studies of water-metal interfaces has been addressed by studying several water-metal systems. In addition to performing periodic DFT calculations for semi-infinite substrates using the popular PBE and RPBE functionals, the water dimer and water-metal atom systems have also been treated by coupled-cluster calculations. We show that indeed semiempirical dispersion correction schemes can be used to yield thermodynamically stable water bilayers at surfaces. However, the actual density functional needs to be chosen carefully. Whereas the dispersion-corrected RPBE functional yields a good description of both the water-water and the water-metal interaction, the dispersion-corrected PBE functional overestimates the energies of both systems. In contrast thereto, the adsorption distances predicted by the PBE functional is hardly changed due to the additional dispersion interaction, explaining the good performance of previous DFT-PBE studies of water-metal systems. PMID- 22228511 TI - Multiscale modeling of macromolecular biosystems. AB - In this article, we review the recent progress in multiresolution modeling of structure and dynamics of protein, RNA and their complexes. Many approaches using both physics-based and knowledge-based potentials have been developed at multiple granularities to model both protein and RNA. Coarse graining can be achieved not only in the length, but also in the time domain using discrete time and discrete state kinetic network models. Models with different resolutions can be combined either in a sequential or parallel fashion. Similarly, the modeling of assemblies is also often achieved using multiple granularities. The progress shows that a multiresolution approach has considerable potential to continue extending the length and time scales of macromolecular modeling. PMID- 22228510 TI - Self-focus and social evaluative threat increase salivary cortisol responses to acute stress in men. AB - This experiment tested the hypothesis that self-focused attention might increase cortisol release. Social self-preservation theory suggests that social evaluation and associated feelings of shame are associated with cortisol reactivity, whereas one implication of objective self-awareness theory is that self-critical awareness and associated feelings of anxiety might be associated with increases in cortisol. 120 participants completed a public speech task either in front of an evaluative panel (social threat), in a non-evaluative setting while watching themselves in real-time on a television (self-focus), or in the mere presence of a non-evaluative person (control). Cortisol increased comparably among men in the social threat and self-focus conditions, but not among men in the control condition. There were no effects for women. Shame was correlated with increased cortisol in the social threat condition, whereas anxiety was correlated with increased cortisol in the self-focus condition. One broad implication of this work is that negative evaluation may increase cortisol regardless of whether this source comes from oneself or others. PMID- 22228512 TI - Absorption enhancement of oligothiophene dyes through the use of a cyanopyridone acceptor group in solution-processed organic solar cells. AB - Improvements in the performance of small molecule-based organic solar cells have been reported through the use of a cyanopyridone acceptor group. This acceptor fragment enhances the absorbance of an oligothiophene-based dye and enables the addition of a solubilising alkyl chain that facilitates simple device fabrication from solution. PMID- 22228514 TI - A brave and startling truth: Parse's humanbecoming school of thought in the context of the contemporary nursing discipline. PMID- 22228515 TI - Presence: the eye of the needle. AB - This column explores the meanings of presence from philosophical, theological, psychological, and nursing perspectives. The eye of the needle is used as a metaphor to emphasize the capacities required for living presence. The humanbecoming concept of true presence is emphasized and examples are given of living true presence in nursing. PMID- 22228516 TI - Stories and programs of research: revelations about humanbecoming. AB - In this column, humanbecoming theory will be considered from a concrete perspective using stories about Katie written by Dr. Kristine Florczak. It will also be discussed as it relates to more scholarly endeavors in the form of programs of research conducted by Dr. Steven Baumann and Dr. Thomas Doucet. PMID- 22228517 TI - A humanbecoming program of research. AB - The author of this column describes the evolution of program of research underpinned by the humanbecoming school of thought. PMID- 22228518 TI - A humanbecoming program of research: having faith. AB - The author of this column describes the evolution of program of research underpinned by the humanbecoming school of thought. PMID- 22228519 TI - Acting faithfully in community. AB - The phenomenon of acting faithfully in the nurse-person relationship is an important ethical topic of interest to the discipline of nursing. It may also be conceptually defined and illuminated in nurse-community relationships. This column begins an articulation of what it potentially means to have straight thinking about nurses' obligations with persons in community. The language of nurse science from the humanbecoming school of thought will be used to explore the phenomenon. PMID- 22228520 TI - Celebrating now in teaching-learning. AB - Nursing education often focuses attention on the interminable amount of information required of students to learn. This learning must be accomplished in a short time frame and at a rapid pace. With attention focused here, students and faculty may not recognize the importance of taking time to celebrate the now. In this column, the author recognizes Rosemarie Rizzo Parse as a prominent nurse theorist and offers a variety of ways to celebrate now moments through re visiting Parse's teaching-learning model. The activities suggested require minimal time while encouraging reflection on self and respect for all. PMID- 22228521 TI - Seeing the forest through the trees. AB - The purpose of this column is to stimulate discussion among nurses regarding the importance of nursing theory-guided practice. The use of metaphor may shed light on defining nursing by its own terms. The time has come for nursing to recognize its worth as an autonomous discipline and own its contributions. PMID- 22228522 TI - Connections between nursing science and public health. PMID- 22228523 TI - Nursing science and public health: contributions to the discipline of nursing. AB - This column highlights the unique relationship of nursing science and public health in the broader context of the discipline of nursing and healthcare. An integrated framework is used to illustrate that nursing knowledge is the product of interaction and interdependence of four domains -the discipline and science of nursing, the philosophy of nursing, the nursing profession, and nursing practice. In the context of the integrated framework, knowledge specific to public health nursing is shown to inform the discipline of nursing and other health disciplines. Ongoing challenges related to clarifying and describing unique contributions to nursing and public health are explored. In addition, under utilization of theoretical and conceptual nursing knowledge from public health nursing for the advancement nursing science in education, practice, and research is addressed. PMID- 22228524 TI - New humanbecoming conceptualizations and the humanbecoming community model: expansions with sciencing and living the art. AB - The purposes of this article are to: introduce a new humanbecoming ontological conceptualization, the becoming visible-invisible becoming of the emerging now; describe the epistemological shift from universal lived experience to universal living experience; and further explicate the humanbecoming community model. The community change concepts (moving-initiating, anchoring-shifting, and pondering shaping) are clarified with explanations in light of the findings of a nine country translinguistic Parse research method study on hope and insights from living the art of humanbecoming. PMID- 22228525 TI - The lived experience of feeling disappointed: a parse research method study. AB - The purpose of this study was to enhance understanding of the lived experience of feeling disappointed. The research question was: What is the structure of the lived experience of feeling disappointed? Parse's phenomenological-used to answer the research question. Participants included 7 women and 2 men ranging in age from 46 to 80 years of age. The major finding of this study is: feeling disappointed is disheartening discontent with diminishing aspirations, as diverse affiliations surface in prevailing with struggle. New knowledge emerging from the study is presented along with recommendations for future research and implications for nursing practice. PMID- 22228526 TI - Feeling strong: a parse research method study. AB - In this article the author reports findings from a Parse research study on the experience of feeling strong with 10 participants living in community. The central finding of the study is the structure: Feeling strong is propelling resolutely amid adversity, as jubilant fulfilling assuredness surfaces with discerning spirited envisioning with treasured alliances. The findings are discussed in relation to the humanbecoming school of thought and extant literature. PMID- 22228527 TI - Feeling unsure: a lived experience of humanbecoming. AB - The aim of this study was to explore the phenomenon of feeling unsure as viewed from the humanbecoming school of thought. The Parse research method was used to guide this study and answer the question: What is the structure of the lived experience of feeling unsure? The central finding of the study is: Feeling unsure is wavering irresolutely with discerning ponderings arising in venturing with trepidation, while revering alliances. The findings are discussed in relation to the humanbecoming school of thought and related literature. PMID- 22228528 TI - The lived experience of doing the right thing: a parse method study. AB - The purposes of this research were to discover the structure of the experience of doing the right thing and to contribute to nursing knowledge. The Parse research method was used in this study to answer the research question: What is the structure of the lived experience of doing the right thing? Participants were 10 individuals living in the community. The central finding of this study was the following structure: The lived experience of doing the right thing is steadfast uprightness amid adversity, as honorableness with significant affiliations emerges with contentment. New knowledge extended the theory of humanbecoming and enhanced understanding of the experience of doing the right thing. PMID- 22228529 TI - Living on the edge: frontier voices. AB - Living on the edge is a universal lived experience. The humanbecoming school of thought is the theoretical underpinning described here to expand understanding of this phenomenon and contribute to nursing knowledge. A synthetic definition derived with concept inventing was created. The experience of living on the edge is risking venturing with sureness-unsureness surfacing with cherished engaging. At the theoretical level living on the edge is powering the originating of valuing connecting-separating. PMID- 22228530 TI - Educating international students. PMID- 22228531 TI - Using Parse's humanbecoming theory in Japan. AB - In this paper the authors discuss the use of Parse's humanbecoming theory in Japan. Elements of the theory are used in the nursing approach to an 88 year-old Japanese man who had complications following surgery. Process recordings of the dialogues between the patient, the patient's wife, and the nurse were made and considered in light of the three methodologies of Parse's theory; illuminating meaning, synchronizing rhythms, and mobilizing transcendence. The theory is seen as useful in Japan. PMID- 22228532 TI - Acknowledging the not-yet in health policy processes. PMID- 22228533 TI - Humanbecoming: transcending the now to explore the possibles in health policy. AB - Nurses have been identified as key players in moving quality of care forward. Nursing knowledge guides nurses as they provide that care. The author in this column explores Parse's theory of humanbecoming and nursing's engagement in health policy. Current focus on the person as primary decision maker in healthcare is congruent with the theory's key concept of quality of life as defined by the person or community. The author provides several examples of how humanbecoming has been used to guide policy activities and decisions and offers suggestions for the future. PMID- 22228534 TI - Thoughts about nursing science and nursing sciencing on the event of the 25th anniversary of Nursing Science Quarterly. AB - This paper presents an essay about nursing science and asks readers to consider terminology that will encompass all types of nursing discipline-specific knowledge. The essay was written to acknowledge the 25th anniversary of the founding of Nursing Science Quarterly. PMID- 22228536 TI - Effect of heavy oil exposure on antibacterial activity and expression of immune related genes in Japanese flounder Paralichthys olivaceus. AB - Heavy oil (HO) pollution is one of the most important environmental issues globally. However, little is known about the immunotoxicity of HO in fish. We therefore investigated the effects of HO exposure on immunocompetence and expression of immune-related genes in Japanese flounder, Paralichthys olivaceus. To test immunocompetency, serum collected from the fish was mixed with Edwardsiella tarda, plated, and the resultant numbers of bacterial colonies were counted. Plates with serum from HO-exposed fish (5 d postexposure [dpe]) had significantly higher numbers of colonies than those of the untreated control group, suggesting that HO exposure suppresses immunocompetency. Downregulation of the immunoglobulin light chain (IgM) gene in HO-exposed fish at 5 dpe was detected by real-time polymerase chain reaction. These results suggest that IgM mediated immunity is suppressed by HO exposure. We measured polycyclic aromatic hydrocarbon (PAH) concentrations in the liver of the fish. Low molecular weight PAHs were found to be taken up at high concentrations in fish liver; therefore, they are likely the cause of immune suppression in the fish. PMID- 22228538 TI - Seminumerical calculation of the Hartree-Fock exchange matrix: application to two component procedures and efficient evaluation of local hybrid density functionals. AB - A two-component extension of the seminumerical procedure for the calculation of the Hartree-Fock (HF) exchange matrix recently presented by Neese et al. (Chem Phys 2009, 356, 98) was implemented into the program system TURBOMOLE. It is demonstrated that this allows for efficient self-consistent treatment of spin orbit coupling at HF and hybrid density functional theory level. One-component HF calculations were performed to study the accuracy of integration grids and the exploitation of the molecular point group symmetry. The efficiency was tested, and for one-component calculations compared to the implementation realized by Neese. It was further demonstrated that local hybrid density functionals can be evaluated with this technique. The "prototype" of this class of functionals, Lh BLYP, was applied to an organic molecule with more than 150 atoms. PMID- 22228537 TI - Micrometer-scale oxygen delivery rearranges cells and prevents necrosis in tumor tissue in vitro. AB - Oxygen availability plays a critical role in cancer progression and is correlated with poor prognosis. Despite this connection, the independent effects of oxygen gradients on tumor tissues have not been measured. To address this, we developed an oxygen delivery device that uses microelectrodes to generate oxygen directly underneath three-dimensional tumor cylindroids composed of colon carcinoma cells. The extent of cell death was measured using fluorescence staining. Supplying oxygen for 60 h eliminated the necrotic region typically found in the center of cylindroids despite the continued presence of other nutrient gradients. A mathematical model of cylindroid growth showed that the rate of cell death was more sensitive to oxygen than the growth rate. After oxygenation, a ring of dead cells was observed at the outside edge of cylindroids, and dead cells were observed moving outward from cylindroid centers. This movement suggests that dead cells were pushed by viable cells migrating in response to oxygen gradients, a mechanism that may connect transient oxygen gradients to metastasis formation. These measurements show that oxygen gradients are a primary factor governing cell viability and rearrange cells in tumors. PMID- 22228539 TI - Sweet blue lupin (Lupinus angustifolius L.) seed as a substitute for concentrate mix supplement in the diets of yearling washera rams fed on natural pasture hay as basal diet in Ethiopia. AB - In the mixed crop-livestock farming system of Ethiopia where crop residues are the major feed resources and concentrate supplement feeds are not common, home grown legume protein sources can help to minimise the feed problem. A 69-day feeding experiment on sheep was conducted to evaluate the potential of sweet blue lupin (Lupinus angustifolius L.) cultivar Sanabor seed as a substitute for commercial concentrate supplement. Thirty yearling male intact Washera sheep with initial body weight of 21 +/- 1.38 kg (mean +/- SD) were used. The design was a randomised complete block design with six replications. The five experimental supplement feeds were 453 g concentrate (T1), 342 g concentrate + 74 g lupin seed (T2), 228 g concentrate + 147 g lupin seed (T3), 116 g concentrate + 219 g lupin seed (T4) and 290 g lupin seed (T5) in dry matter basis to supplement around 100 g crude protein per day per animal. There were significant differences (P < 0.05) in total dry matter, crude protein, ash and organic matter intakes among treatments. The average daily body weight gain for T1, T2, T3, T4 and T5 was 91, 79, 79, 87 and 74 g/day, respectively, and this difference was not significant (P > 0.05). It was concluded that blue lupin seed has a potential to substitute the commercial concentrate supplement feed in Ethiopia. PMID- 22228540 TI - Fatty acid profiles, antioxidant compounds and antiradical properties of Pinus halepensis Mill. cones and seeds. AB - BACKGROUND: Pinus halepensis (Aleppo pine) is a widespread tree that can be found in both natural and urban environments. A discrimination study based on the antioxidant compounds, antioxidant capacity and fatty acid (FA) profile of P. halepensis cones (PHC) and seeds (PHS) was performed. RESULTS: The total amount of phenols was about 72-fold higher in PHC extract than in PHS extract (P < 0.001). Anthocyanin and carotenoid contents were 10- and 12-fold higher respectively in PHC extract. PHC and PHS extracts at a concentration of 1 mg mL( 1) differed significantly in free radical-scavenging activity on 2,2-diphenyl-1 picrylhydrazyl radical (DPPH(*)) (86.65 vs 16.97%). PHC had higher antioxidant ability on 2,2'-azino-bis(3-ethylbenzothialozine-6-sulfonic acid) radical cation (ABTS(*+)) than PHS (EC(50) 0.368 vs 2.345 mg mL(-1)). The FA profile of PHC oil revealed its richness in saturated FAs (41.5%) and high levels of trans FA isomers, with a predominance of trans,trans-linoleic acid (4.74%). However, polyunsaturated FAs in PHS oil represented more than 64% of total FAs. CONCLUSION: PHC showed important antioxidant activities as well as high levels of bioactive compounds. Thus PHC is a potential source of natural antioxidants that may afford several health benefits. However, the lipid extract of PHS seems to have more nutritional value as a polyunsaturated oil than that of PHC, which is high in saturated and trans FAs. PMID- 22228541 TI - Model averaging in the analysis of leukemia mortality among Japanese A-bomb survivors. AB - Epidemiological studies often include numerous covariates, with a variety of possible approaches to control for confounding of the association of primary interest, as well as a variety of possible models for the exposure-response association of interest. Walsh and Kaiser (Radiat Environ Biophys 50:21-35, 2011) advocate a weighted averaging of the models, where the weights are a function of overall model goodness of fit and degrees of freedom. They apply this method to analyses of radiation-leukemia mortality associations among Japanese A-bomb survivors. We caution against such an approach, noting that the proposed model averaging approach prioritizes the inclusion of covariates that are strong predictors of the outcome, but which may be irrelevant as confounders of the association of interest, and penalizes adjustment for covariates that are confounders of the association of interest, but may contribute little to overall model goodness of fit. We offer a simple illustration of how this approach can lead to biased results. The proposed model averaging approach may also be suboptimal as way to handle competing model forms for an exposure-response association of interest, given adjustment for the same set of confounders; alternative approaches, such as hierarchical regression, may provide a more useful way to stabilize risk estimates in this setting. PMID- 22228542 TI - Induction and repair of DNA double-strand breaks assessed by gamma-H2AX foci after irradiation with pulsed or continuous proton beams. AB - In particle tumor therapy including beam scanning at accelerators, the dose per voxel is delivered within about 100 ms. In contrast, the new technology of laser plasma acceleration will produce ultimately shorter particle packages that deliver the dose within a nanosecond. Here, possible differences for relative biological effectiveness in creating DNA double-strand breaks in pulsed or continuous irradiation mode are studied. HeLa cells were irradiated with 1 or 5 Gy of 20-MeV protons at the Munich tandem accelerator, either at continuous mode (100 ms), or applying a single pulse of 1-ns duration. Cells were fixed 1 h after 1-Gy irradiation and 24 h after 5-Gy irradiation, respectively. A dose-effect curve based on five doses of X-rays was taken as reference. The total number of phosphorylated histone H2AX (gamma-H2AX) foci per cell was determined using a custom-made software macro for gamma-H2AX foci counting. For 1 h after 1-Gy 20 MeV proton exposures, values for the relative biological effectiveness (RBE) of 0.97 +/- 0.19 for pulsed and 1.13 +/- 0.21 for continuous irradiations were obtained in the first experiment 1.13 +/- 0.09 and 1.16 +/- 0.09 in the second experiment. After 5 Gy and 24 h, RBE values of 0.99 +/- 0.29 and 0.91 +/- 0.23 were calculated, respectively. Based on the gamma-H2AX foci numbers obtained, no significant differences in RBE between pulsed and continuous proton irradiation in HeLa cells were detected. These results are well in line with our data on micronucleus induction in HeLa cells. PMID- 22228543 TI - Potential for clinical radionuclide-based imaging and therapy of common cancers expressing EGFR-family receptors. AB - High expression of epidermal growth factor receptor (EGFR)-family receptors, especially EGFR, HER2, and HER3, makes them interesting for targeted radionuclide based imaging and therapy of disseminated cancer. The expression in some commonly occurring cancers such as breast, prostate, colorectal, and urinary bladder cancers is summarized. Possible strategies for radionuclide-based imaging and therapy are briefly discussed, especially in relation to the receptor expression in metastases. PMID- 22228544 TI - Microarray analysis of global gene regulation in the Cry1Ab-resistant and Cry1Ab susceptible strains of Diatraea saccharalis. AB - BACKGROUND: Extensive adoption of transgenic Bt corn in recent years for stalk borer control has increased risk of resistance evolution in the target pest populations. A Bt-resistant strain of the sugarcane borer, Diatraea saccharalis, was approximately 100-fold more tolerant to Cry1Ab toxin than the susceptible counterpart. To gain a better understanding of the molecular mechanisms of Bt resistance, the Cry1Ab-susceptible (Cry1Ab-SS) and Cry1Ab-resistant (Cry1Ab-RR) strains of D. saccharalis were subjected to a microarray analysis. RESULTS: Results showed that the expression levels of many genes were significantly different between the Cry1Ab-RR and Cry1Ab-SS strains. Microarray analysis of 7145 cDNAs revealed 384 differentially expressed genes. A total of 273 genes were significantly upregulated 2-51.6-fold, and 111 genes were significantly downregulated 2-22.6-fold in the Cry1Ab-RR strain. The upregulation of three potential resistance-related genes, coding for a glutathione S-transferase (GST), a chymotrypsin-like protease (CHY) and a lipase (LP), was confirmed using real time PCR, indicating a reproducibility of the microarray data. Ontology analysis revealed that more than twice the number of metabolic-related genes were upregulated compared with downregulated genes with the same biological function. Up to 35.2% of the upregulated genes in the resistant strain were associated with catalytic activity, while only 9.5% of the downregulated genes were related to the same catalytic molecular function. CONCLUSION: The large portion of metabolic or catalytic-related genes with significant upregulations indicated a potential large increase in metabolic or catalytic activities in the Cry1Ab-RR strain. This cDNA microarray gene expression data could be used to characterize and identify new genes that may be associated with Bt resistance in D. saccharalis. PMID- 22228545 TI - The genus Broussonetia: a review of its phytochemistry and pharmacology. AB - Plants belonging to the genus Broussonetia (Moraceae), which grow naturally in Asian and Pacific countries, have long been used in traditional Chinese medicine to treat various conditions, particularly tinea, dysentery, hernia and oedema. Various parts of plants of this genus such as the fruits, bark, leaves, flowers and roots are used medicinally. According to Flora of China, the inner bark fibre is used in making paper, and the wood is used for furniture. Several active compounds including coumarins, polyphenols, alkaloids, flavonoids, glycosides, lignans and diterpenes have been isolated from the plants of this genus in the past few years, and some members of these constituents have been demonstrated to exert antioxidant, antiinflammatory, antiplatelet, antityrosinase, antimicrobial and antinociceptive effects. Antidiabetic and antitumoural properties seem possible, but need further support. Due to the lack of clinical trials, there are few published reports on target-organ toxicity or side effects. Currently, some East Asian nations such as China, South Korea and Japan have shown increased interest in these plants. This article reviews the phytochemical and potential beneficial therapeutic effects of plants of this genus reported since 2000. PMID- 22228546 TI - Molecular insight into substrate recognition by human cytosolic sialidase NEU2. AB - Sialidases or neuramidases are glycoside hydrolases removing terminal sialic acid residues from sialo-glycoproteins and sialo-glycolipids. Viral neuraminidases (NAs) have been extensively characterized and represent an excellent target for antiviral therapy through the synthesis of a series of competitive inhibitors that block the release of newly formed viral particles from infected cells. The human cytosolic sialidase NEU2 is the only mammalian enzyme structurally characterized and represents a valuable model to study the specificity of novel NA inhibitory drugs. Moreover, the availability of NEU2 3D structure represents a pivotal step toward the characterization of the molecular basis of natural substrates recognition by the enzyme. In this perspective, we have carried out a study of molecular docking of NEU2 active site using natural substrates of increasing complexity. Moreover, selective mutations of the residues putatively involved into substrate(s) interaction/recognition have been performed, and the resulting mutant enzymes have been preliminary tested for their catalytic activity and substrate specificity. We found that Q270 is involved in the binding of the disaccharide alpha(2,3) sialyl-galactose, whereas K45 and Q112 bind the distal glucose of the trisaccharide alpha(2,3) sialyl-lactose, corresponding to the oligosaccharide moiety of GM3 ganglioside. In addition, E218, beside D46, is proved to be a key catalytic residue, being, together with Y334, the second member of the nucleophile pair required for the catalysis. Overall, our results point out the existence of a dynamic network of interactions that are possibly involved in the recognition of the glycans bearing sialic acid. PMID- 22228547 TI - CD40-targeted adenoviral cancer vaccines: the long and winding road to the clinic. AB - The ability of dendritic cells (DCs) to orchestrate innate and adaptive immune responses has been exploited to develop potent anti-cancer immunotherapies. Recent clinical trials exploring the efficacy of ex vivo modified autologous DC based vaccines have reported some promising results. However, in vitro generation of autologous DCs for clinical administration, their loading with tumor associated antigens (TAAs) and their activation, is laborious and expensive, and, as a result of inter-individual variability in the personalized vaccines, remains poorly standardized. An attractive alternative approach is to load resident DCs in vivo by targeted delivery of TAAs, using viral vectors and activating them simultaneously. To this end, we have constructed genetically-modified adenoviral (Ad) vectors and bispecific adaptor molecules to retarget Ad vectors encoding TAAs to the CD40 receptor on DCs. Pre-clinical human and murine studies conducted so far have clearly demonstrated the suitability of a 'two-component' (i.e. Ad and adaptor molecule) configuration for targeted modification of DCs in vivo for cancer immunotherapy. This review summarizes recent progress in the development of CD40-targeted Ad-based cancer vaccines and highlights pre-clinical issues in the clinical translation of this approach. PMID- 22228548 TI - Neuronal architectures with axo-dendritic polarity above silicon nanowires. AB - An approach is developped to gain control over the polarity of neuronal networks at the cellular level by physically constraining cell development by the use of micropatterns. It is demonstrated that the position and path of individual axons, the cell extension that propagates the neuron output signal, can be chosen with a success rate higher than 85%. This allows the design of small living computational blocks above silicon nanowires. PMID- 22228549 TI - Linking oppositional behaviour trajectories to the development of depressive symptoms in childhood. AB - Oppositional defiant disorder in childhood is a predictor of later mood disorders. This study assessed whether groups of children can be identified by their course of co-occurring oppositional and depressive symptoms in childhood using group based trajectory modeling. Participants were a cohort of 932 4 or 5 year old offspring of women participating in the National Longitudinal Study of Youth whose symptom trajectories were modeled across ages 4-13 years. Three co occurring trajectory groups were found: oppositional symptoms only (23%), oppositional symptoms preceding increasing depressive symptoms over time (16%) and absence of any symptoms (61%). Of all children who developed depressive symptoms, all had moderate or high levels of pre-existing oppositional symptoms. Oppositional symptoms typically precede, or co-occur with depressive symptoms in childhood. PMID- 22228551 TI - Antiobesity effects of a sulfur compound thiacremonone mediated via down regulation of serum triglyceride and glucose levels and lipid accumulation in the liver of db/db mice. AB - Garlic is widely used as a spice. Garlic extracts exert anticancer and antiinflammatory effects, but its antiobesity efficacy studies have produced conflicting results. The antiobesity effects of thiacremonone, a sulfur compound isolated from garlic, was evaluated in obese db/db mice. Thiacremonone was orally administrated to mice for 3 weeks. The thiacremonone-treated db/db mice showed a loss of body weight and decrease in blood triglyceride and glucose levels compared with the control mice. Histological analysis further revealed that thiacremonone significantly decreased lipid accumulation in the fatty livers of treated db/db mice. It was observed that GLUT-4 expression and glucose uptake were up-regulated by thiacremonone in 3T3-L1 adipocytes. Thiacremonone treatment also suppressed expression levels of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), which are involved in lipid metabolism, in the liver of db/db mice. In addition, thiacremonone enhanced peroxisome proliferator-activated receptor gamma (PPARgamma) expression in the fatty liver. Taken together, these results suggest that thiacremonone may play a vital role in improving the management of obesity and related metabolic syndromes via inhibition of lipid accumulation. PMID- 22228550 TI - The role of innate cells is coupled to a Th1-polarized immune response in pediatric nonalcoholic steatohepatitis. AB - BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory liver disease influenced by risk factors for the metabolic syndrome. In adult patients, NASH is associated with an altered phenotype and functionality of peripheral immune cells, the recruitment of leukocytes and intrahepatic activation, and an exacerbated production of reactive oxygen species (ROS) and cytokines. It remains unclear if the previously described differences between pediatric and adult nonalcoholic fatty liver diseases also reflect differences in their pathogenesis. AIMS: We aimed to investigate the phenotype and functionality of circulating immune cells and the potential contribution of liver infiltrating leukocytes to the immunological imbalance in pediatric NASH. RESULTS: By a real-time PCR-based analysis of cytokines and immunohistochemical staining of liver biopsies, we demonstrated that the hepatic microenvironment is dominated by interferon-gamma (IFN-gamma) but not interleukin-4 and is infiltrated by a higher number of CD8(+) cells in pediatric NASH. The number of infiltrating neutrophils positively correlated with ROS generation by peripheral polymorphonuclear cells. By a flow cytometric analysis of peripheral blood lymphocytes, a distinctive increase in CD8(+) CD45RO and CD8(+) CD45RA subpopulations and an increased production of IFN gamma by CD4(+) and CD8(+) cells were shown. The production of ROS following PMA stimulation was augmented in circulating neutrophils but not in monocytes. CONCLUSION: In sum, the distinctive phenotype and functionality of infiltrating and circulating cells suggest that the role of innate cells is coupled to a Th1 polarized immune response in pediatric NASH. PMID- 22228552 TI - The occurrence and severity of musculoskeletal disorders in Swedish military personnel during peacekeeping operations in Afghanistan. AB - BACKGROUND: Not much is known about musculoskeletal disorders (MSD) in peacekeeping missions and to what extent such conditions are disabling. The objective of this study was to assess the occurrence and severity of MSD in Swedish military personnel on 6 months duty in Afghanistan. METHODS: When returning from Afghanistan 440 individuals received a questionnaire including questions about pain conditions during their mission abroad. A manikin was used to mark the area(s) in pain and which body area had bothered them the most. A modified version of chronic pain questionnaire was used to assess pain and disability. RESULTS: The response rate was 78% (n = 344). Any MSD during the 6 months was reported by 70% (95% CI 65-75). The three most bothersome areas were lumbar spine [17% (95% CI 13-20)], shoulders [17% (95% CI 13-21)] and lower extremities [14% (95% CI 11-18)]. 57% (95% CI 49-65) had grade I pain (low pain/low disability), 36% (95% CI 28-45) had grade II pain (high pain/low disability) and 5% (95% CI 3-10) had grade III pain (any pain/high disability). Of all MSD, more than half were new episodes since arrival and gradual onset was common. CONCLUSION: Musculoskeletal pain was common during peacekeeping mission and gradual onset was dominating. Most often, it did not affect the daily activities. Nevertheless, it may be of important to consider broadening the medical disciplines onsite to provide preventive measures and treatment at an early stage, and thereby reducing the risk of chronicity. PMID- 22228553 TI - Evaluation of a new battery of toxicity tests for boreal forest soils: assessment of the impact of hydrocarbons and salts. AB - The ability to assess the toxic potential of soil contamination within boreal regions is currently limited to test species representative of arable lands. This study evaluated the use of six boreal plant species (Pinus banksiana, Picea glauca, Picea mariana, Populus tremuloides, Calamagrostis Canadensis, and Solidago canadensis) and four invertebrate species (Dendrodrilus rubidus, Folsomia nivalis, Proisotoma minuta, and Oppia nitens) and compared their performance to a suite of standard agronomic soil test species using site soils impacted by petroleum hydrocarbon (PHC) and salt contamination. To maintain horizon-specific differences, individual soil horizons were collected from impacted sites and relayered within the test vessels. Use of the boreal species was directly applicable to the assessment of the contaminated forest soils and, in the case of the hydrocarbon-impacted soil, demonstrated greater overall sensitivity (25th percentile of estimated species sensitivity distribution [ESSD25] = 5.6% contamination: 10,600 mg/kg fraction 3 [F3; equivalent hydrocarbon range of >C16 to C34] Of/Oh horizon, and 270 mg/kg F3 Ahg horizon) relative to the standard test species (ESSD25 = 23% contamination: 44,000 mg/kg F3 Of/Oh horizon, and 1,100 mg/kg F3 Ahg horizon). For salinity, there was no difference between boreal and standard species with a combined ESSD25 = 2.3%, equating to 0.24 and 0.25 dS/m for the Ah and Ck horizons. The unequal distribution of soil invertebrates within the layered test vessels can confound test results and the interpretation of the toxic potential of a site. The use of test species relevant to boreal eco-zones strengthens the applicability of the data in support of realistic ecological risk assessments applicable to the boreal regions. PMID- 22228554 TI - Sport Concussion Assessment Tool-2: baseline values for high school athletes. AB - BACKGROUND: Concussion head injuries are common in high school athletes. The Sport Concussion Assessment Tool-2 (SCAT2) has been recommended and widely adopted as a standardised method of evaluating an injured athlete with a suspected concussion. Sideline return to play decisions can hinge on the results of a SCAT2 score. However, most athletes will not have had baseline testing performed for comparison if injury occurs. Therefore, establishing of age-, sex- and sport-matched normative data for the high school athlete population is critical. PURPOSE: To determine baseline scores in all SCAT2 domains among high school athletes with no prior history of a concussion and to examine subgroup differences for girls and boys, age and sport to establish normative ranges. MATERIALS AND METHODS: The SCAT2 was administered to 214 high school athletes (155 males and 59 females) who participated in football, women's soccer, men's basketball, gymnastics, baseball, softball and track with no prior history of concussion. There were 111 athletes in the 13-15-year-old cohort and 103 in the 16-19-year-old group with a mean age of 15.7 years of age. In all SCAT2 domains the mean and SD of the results were determined. The domains were analysed using age, sex and sport as covariates. Component parts of the cognitive (concentration) domain (digit sequencing and months of year in reverse order) were also analysed by age, sex and sport. The percentage of high school athletes able to perform each digit-sequencing test was calculated as was the percentage of participants who could recite the months of the year in reverse order. RESULTS: The average SCAT2 score for these high school athletes was 89 of a possible 100 with a SD of 6 units. Athletes reported two or three symptoms at baseline with older students reporting more symptoms than younger ones. The average balance score was 25.82 (of 30), and all athletes were able to complete the double-leg stance. Females scored significantly higher on the balance, immediate memory and concentration scores. Concentration scores in non-concussed high school athletes were low. Only 67% of high school athletes could recite the months of the year backward and only 41% could correctly sequence 5 digits backward. Only 55% of high school football players could correctly recite the months of the year backward and 32% could sequence 5 digits. CONCLUSIONS: Non concussed high school athletes scored near the total possible in most domains of the SCAT2 with the exception of concentration testing and balance testing. All athletes were able to complete the double-leg stance at baseline; however, there was significant variability of tandem and single-leg stance. Baseline testing is important when considering balance tests. Concentration testing in high school athletes is unreliable because of high baseline error and is likely to result in a high rate of false positives and false negatives. Return to play decisions should not rely on concentration testing without a baseline test for comparison. PMID- 22228555 TI - Lack of tumor uptake of 131-I labeled rituximab in a patient with a CD20 positive lymphoma lesion. AB - Radioimmunotherapy has emerged as a treatment modality for patients with CD20 positive B-cell non-Hodgkin's lymphoma (NHL). Prior to administration of a therapeutic dose, confirmation of uptake of the radiolabeled compound in tumor locations and calculation of an appropriate dose can be performed using a diagnostic dose and subsequent imaging. We report the case of a 69-year-old male with a relapsed mantle cell lymphoma scheduled for radioimmunotherapy, where diagnostic imaging with 131-I labeled rituximab revealed unexpected new insights with implications for treatment. Persistence of the mantle cell lymphoma in a lymph node in the left arm was demonstrated by an 18-F fluorodeoxyglucose scan. However, a scan after a diagnostic dose of 131-I labeled rituximab did not show any uptake of the tracer, even though subsequent cytological analysis unequivocally confirmed a CD20 positive B-cell population in the lesion. The administration of a therapeutic dose of 131-I labeled rituximab was therefore cancelled. We here discuss the mechanisms that may explain lack of targeting in a proven CD20-positive lymphoma and provide recommendations for further studies. PMID- 22228556 TI - Interactive quantum chemistry: a divide-and-conquer ASED-MO method. AB - We present interactive quantum chemistry simulation at the atom superposition and electron delocalization molecular orbital (ASED-MO) level of theory. Our method is based on the divide-and-conquer (D&C) approach, which we show is accurate and efficient for this non-self-consistent semiempirical theory. The method has a linear complexity in the number of atoms, scales well with the number of cores, and has a small prefactor. The time cost is completely controllable, as all steps are performed with direct algorithms, i.e., no iterative schemes are used. We discuss the errors induced by the D&C approach, first empirically on a few examples, and then via a theoretical study of two toy models that can be analytically solved for any number of atoms. Thanks to the precision and speed of the D&C approach, we are able to demonstrate interactive quantum chemistry simulations for systems up to a few hundred atoms on a current multicore desktop computer. When drawing and editing molecular systems, interactive simulations provide immediate, intuitive feedback on chemical structures. As the number of cores on personal computers increases, and larger and larger systems can be dealt with, we believe such interactive simulations-even at lower levels of theory should thus prove most useful to effectively understand, design and prototype molecules, devices and materials. PMID- 22228557 TI - In vitro mutagenesis and identification of mutants via ISSR in lily (Lilium longiflorum). AB - An efficient in vitro mutagenesis protocol for Lilium longiflorum Thunb. cv. White fox has been established. The effect of 6-BA and NAA on adventitious bud formation from the bulblet-scale thin cell layers was tested. Results showed that the optimal medium for adventitious bud induction is MS basal medium supplemented with 2.0 mg/l 6-BA and 0.1 mg/l NAA. The differentiation frequency and the average number of adventitious buds reached 95.55% and 3.00, respectively. Various doses (0.0, 0.5, 1.0, 1.5, 2.0, and 2.5 Gy) of gamma rays were applied to investigate the effect of radiation on adventitious bud formation from bulblet scale thin cell layers. The forming capacity of the adventitious buds significantly decreased with the increase of radiation dose. The results suggested that the optimal irradiation dose is 1.0 Gy. Dose of 1.0 Gy treatment resulted in 55.33% survival of irradiated bulblet-scale thin cell layers and 39.27% mutagenesis rate. The genetic variations among the morphological mutants were evaluated by DNA fingerprinting using ISSR molecular marker. The genetic variation frequency reached 36.06% using seven ISSR primers. Out of the 50 mutant lines transferred to the greenhouse, 9 were observed to have significantly different morphological characters than those of the controls. PMID- 22228558 TI - Corticomedullary mixed tumor of the adrenal gland-a clinical and pathological chameleon: case report and review of literature. AB - Adrenal tumors mostly present with specific and unique clinical features, regarding their endocrine metabolism. A 53-year-old man came to our Department for a left adrenal mass discovered incidentally. Biochemical and imaging findings were suspicious for a pheochromocytoma. The patient underwent a laparoscopic left adrenalectomy. A well-circumscribed 5.5-cm mass was removed. It was composed of adrenal cells intimately admixed with pheochromocytes. Immunohistochemical studies were positive both for cortical cells (inibin-alpha, synaptophysine and melan-A) and medullary cells (S-100 and chromogranine A). Final pathology was of corticomedullary mixed tumor (CMT). CMT is a rare tumor with 14 cases previously reported in literature, with wide variable biochemical behavior, such as his radiological and pathological features. Prevalence and actual malignant potential are yet unknown to our knowledge. PMID- 22228559 TI - Purification of diamine oxidase and its properties in germinated fava bean (Vicia faba L.). AB - BACKGROUND: gamma-Aminobutyric acid (GABA) is a non-protein amino acid with bioactive functions for human health. Diamine oxidase (DAO, EC 1.4.3.6) is one of the key enzymes for GABA formation. In the present study, this enzyme was purified from 5 day germinated fava bean and its properties were investigated in vitro. RESULTS: The molecular mass of the enzyme estimated by Sephadex G-100 gel filtration was 121 kDa. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) displayed a single band at a molecular mass of 52 kDa. The enzyme had optimal activity at 40 degrees C and retained its activity after being incubated at 30 degrees C for 30 min. It showed higher activity at pH 6.5 than at other pH values. The enzyme was significantly inhibited by Mg(2+), Cu(2+), Fe(3+), aminoguanidine, ethylene glycol tetraacetic acid (EGTA), ethylene diamine tetraacetic acid disodium salt (EDTA-Na(2)), L-cysteine and beta-mercaptoethanol. The K(m) value of DAO was 0.23 mmol L(-1) for putrescine and 0.96 mmol L(-1) for spermidine. However, the enzyme did not degrade spermine. CONCLUSION: DAO from germinated fava bean was purified. The optimal reaction temperature and pH of the enzyme were mild. The enzyme had higher affinity to putrescine than to spermidine and spermine. PMID- 22228560 TI - Pharmacokinetic comparison of a generic coenzyme Q10 solubilizate and a formulation with soybean phytosterols. AB - Coenzyme Q10 (CoQ10) is essential for all cells, and deficiency has been implicated in cardiovascular disease. Plant phytosterols inhibit cholesterol absorption, and may thereby also reduce cardiovascular risk. This study compared the relative bioavailability of CoQ10 solubilized in low-dose soybean phytosterols (SterolQ10) with a generic CoQ10 solubilizate. In a randomized, cross-over design, 36 healthy males received a single 100 mg dose of CoQ10, as SterolQ10 or generic CoQ10, with a two-week washout between treatments. Plasma CoQ10 was analysed at baseline, and at 2, 4, 6, 8 and 10 h after supplement ingestion. Subjects were then administered either 100 mg/day of generic CoQ10 or SterolQ10 for 4 weeks. Fasting plasma CoQ10 levels were measured at baseline and following supplementation. The two preparations were bioequivalent in regard to the area under the curve (AUC(0-10h) ) and maximum increase in concentration (C(max) ), with geometric mean ratios of 0.89 (CI 0.81-0.98) and 0.88 (CI 0.80 0.96), respectively. Four-weeks of CoQ10 resulted in a comparable twofold increase in CoQ10 levels for both formulations (p < 0.001), which was similar between preparations (p = 0.74). The combined CoQ10 and phytosterol formulation, SterolQ10, showed bioequivalence to the generic CoQ10 following a single CoQ10 dose, and demonstrated comparable bioavailability following multiple dose administration. PMID- 22228561 TI - The effect of a piperonyl butoxide/tau-fluvalinate mixture on pollen beetle (Meligethes aeneus) and honey bees (Apis mellifera). AB - BACKGROUND: Previous work has characterised pyrethroid resistance in pollen beetle (Meligethes aeneus F.) as principally an oxidative mechanism. Piperonyl butoxide (PBO) can synergise this resistance in the field, but its effects on the honey bee are thought to be unacceptable. RESULTS: A field trial in Poland was conducted to show that a mixture of PBO and tau-fluvalinate at the registered rate gave increased and longer-lasting control of resistant pollen beetle. Four days after spraying with tau-fluvalinate, only 20% of pollen beetles were controlled, compared with 70% if the tau-fluvalinate/PBO mixture was used. No detriment to honey bee health was observed using the same mixture. CONCLUSIONS: PBO, if used in conjunction with a pyrethroid of relatively low bee toxicity, can successfully overcome pyrethroid resistance in pollen beetle without incurring an increased loss of honey bees, even if they are present at the time of spraying. PMID- 22228562 TI - The effects of rigid motions on elastic network model force constants. AB - Elastic network models provide an efficient way to quickly calculate protein global dynamics from experimentally determined structures. The model's single parameter, its force constant, determines the physical extent of equilibrium fluctuations. The values of force constants can be calculated by fitting to experimental data, but the results depend on the type of experimental data used. Here, we investigate the differences between calculated values of force constants and data from NMR and X-ray structures. We find that X-ray B factors carry the signature of rigid-body motions, to the extent that B factors can be almost entirely accounted for by rigid motions alone. When fitting to more refined anisotropic temperature factors, the contributions of rigid motions are significantly reduced, indicating that the large contribution of rigid motions to B factors is a result of over-fitting. No correlation is found between force constants fit to NMR data and those fit to X-ray data, possibly due to the inability of NMR data to accurately capture protein dynamics. PMID- 22228564 TI - Nanoengineered metal surface capsules: construction of a metal-protection system. PMID- 22228563 TI - EphrinA1-EphA2 interaction-mediated apoptosis and FMS-like tyrosine kinase 3 receptor ligand-induced immunotherapy inhibit tumor growth in a breast cancer mouse model. AB - BACKGROUND: The receptor tyrosine kinase EphA2 is overexpressed in several types of cancers and is currently being pursued as a target for breast cancer therapeutics. The EphA2 ligand EphrinA1 induces EphA2 phosphorylation and intracellular internalization and degradation, thus inhibiting tumor progression. The hematopoietic growth factor, FMS-like tyrosine kinase 3 receptor ligand (Flt3L), promotes expansion and mobilization of functional dendritic cells. METHODS: We tested the EphrinA1-EphA2 interaction in MDA-MB-231 breast cancer cells focusing on the receptor-ligand-mediated apoptosis of breast cancer cells. To determine whether EphrinA1-EphA2 interaction-associated apoptosis and Flt3L mediated immunotherapy would have an additive effect in inhibiting tumor growth, we used an immunocompetent mouse model of breast cancer to evaluate intratumoral (i.t.) inoculation strategies with human adenovirus (HAd) vectors expressing either EphrinA1 (HAd-EphrinA1-Fc), Flt3L (HAd-Flt3L) or a combination of EphrinA1 Fc + Flt3L (HAd-EphrinA1-Fc + HAd-Flt3L). RESULTS: In vitro analysis demonstrated that an EphrinA1-EphA2 interaction led to apoptosis-related changes in breast cancer cells. In vivo, three i.t. inoculations of HAd-EphrinA1-Fc showed potent inhibition of tumor growth. Furthermore, increased inhibition in tumor growth was observed with the combination of HAd-EphrinA1-Fc and HAd-Flt3L accompanied by the generation of an anti-tumor adaptive immune response. CONCLUSIONS: The results obtained in the present study, indicating the induction of apoptosis and inhibition of mammary tumor growth, show the potential therapeutic benefits of HAd-EphrinA1-Fc. In combination with HAd-Flt3L, this represents a promising strategy for effectively inducing mammary tumor regression by HAd vector-based therapy. PMID- 22228565 TI - Predicting US- and state-level cancer counts for the current calendar year: Part I: evaluation of temporal projection methods for mortality. AB - BACKGROUND: A study was undertaken to evaluate the temporal projection methods that are applied by the American Cancer Society to predict 4-year-ahead projections. METHODS: Cancer mortality data recorded in each year from 1969 through 2007 for the United States overall and for each state from the National Center for Health Statistics was obtained. Based on the mortality data through 2000, 2001, 2002, and 2003, Projections were made 4 years ahead to estimate the expected number of cancer deaths in 2004, 2005, 2006, 2007, respectively, in the United States and in each state, using 5 projection methods. These predictive estimates were compared to the observed number of deaths that occurred for all cancers combined and 47 cancer sites at the national level, and 21 cancer sites at the state level. RESULTS: Among the models that were compared, the joinpoint regression model with modified Bayesian information criterion selection produced estimates that are closest to the actual number of deaths. Overall, results show the 4-year-ahead projection has larger error than 3-year-ahead projection of death counts when the same method is used. However, 4-year-ahead projection from the new method performed better than the 3-year-ahead projection from the current state-space method. CONCLUSIONS: The Joinpoint method with modified Bayesian information criterion model has the smallest error of all the models considered for 4-year-ahead projection of cancer deaths to the current year for the United States overall and for each state. This method will be used by the American Cancer Society to project the number of cancer deaths starting in 2012. PMID- 22228566 TI - Activity of childhood lupus nephritis is linked to altered T cell and cytokine homeostasis. AB - PURPOSE: Standard therapy for lupus nephritis is based on non-specific immunosuppression. We aimed to identify specific alterations in T cell and cytokine homeostasis and possible associations with disease activity in children with lupus nephritis (LN). METHODS: The phenotype of circulating T cells from children with LN and healthy controls (HC) was analyzed by flow cytometry. Intracellular expression of IL-17 and INF-gamma was assessed after stimulation with anti-CD3 and anti-CD28. Serum concentrations of IP10, CCL2, TGF-beta, IL-17, and IL-23 were measured by ELISA. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index 2000 update (SLEDAI-2K). RESULTS: Children with active LN displayed increased frequencies of effector memory CD4(+)CD45RO(+)CCR7(-) and terminal differentiated CD4(+)CD45RA(+)CCR7(-) T cells and reduced naive CD4(+)CD45RA(+)CCR7(+) T cells compared to those with inactive LN or HC. Circulating CD4(+)CXCR3(+) and CD4(+)CCR2(+) T cells correlated inversely with the renal SLEDAI-2K, whereas IP10 and CCL2 showed a positive correlation. Reduced CD4(+)Foxp3(+) T cells and serum TFG-beta levels in active LN were associated with high serum IL-17 and IL-23 levels and correlated inversely with the renal SLEDAI-2K (r = -0.5855, p = 0.0013 and r = -0.6246, p = 0.0005, respectively), whereas IL-17 and IL-23 correlated positively (r = 0.5516, p = 0.0029 and r = 0.6116, p = 0.0007, respectively). Expansion of Th17 and Th1/Th17 cells in children with LN was significantly greater than in HC (p = 0.0304 and p = 0.0067, respectively). CONCLUSION: Children with active LN display high levels of pro-inflammatory cytokines associated with an increase in effector T cells and reduction of regulatory T cells. Therapeutic regulation of the aberrant cytokine profile might specifically interrupt pathogenic mechanisms. PMID- 22228567 TI - Clinical and genetic characteristics of XIAP deficiency in Japan. AB - Deficiency of X-linked inhibitor of apoptosis (XIAP) caused by XIAP/BIRC4 gene mutations is an inherited immune defect recognized as X-linked lymphoproliferative syndrome type 2. This disease is mainly observed in patients with hemophagocytic lymphohistiocytosis (HLH) often associated with Epstein-Barr virus infection. We described nine Japanese patients from six unrelated families with XIAP deficiency and studied XIAP protein expression, XIAP gene analysis, invariant natural killer T (iNKT) cell counts, and the cytotoxic activity of CD8(+) alloantigen-specific cytotoxic T lymphocytes. Of the nine patients, eight patients presented with symptoms in infancy or early childhood. Five patients presented with recurrent HLH, one of whom had severe HLH and died after cord blood transplantation. One patient presented with colitis, as did another patient's maternal uncle, who died of colitis at 4 years of age prior to diagnosis with XIAP deficiency. Interestingly, a 17-year-old patient was asymptomatic, while his younger brother suffered from recurrent HLH and EBV infection. Seven out of eight patients showed decreased XIAP protein expression. iNKT cells from patients with XIAP deficiency were significantly decreased as compared with age-matched healthy controls. These results in our Japanese cohort are compatible with previous studies, confirming the clinical characteristics of XIAP deficiency. PMID- 22228568 TI - Immune-mediated diseases and immunodeficiencies associated with thymic epithelial neoplasms. AB - INTRODUCTION: This retrospective study aimed to characterize the clinical hematological and immunological features of patients with thymic epithelial neoplasms. METHODS: From a cohort of 512 patients with thymic epithelial neoplasms, 79 patients diagnosed with autoimmune/immunodeficiency conditions or signs and/or symptoms suggesting an autoimmune or immunodeficiency state were evaluated by standard immunological and hematological testing. RESULTS: Elevated percentages of CD2+, CD3+, and CD8+ lymphocytes were observed in 44 (57.1%), 33 (41.8%), and 32 (40.5%) patients. Low CD4+ and CD19+ percentages were observed in 25 (31.6%) and 36 (46.2%), respectively; CD4+:CD8+ ratios were inverted in 18 (22.8%). IgG, IgA, and IgM levels were low in 12 (15.8%), 9 (11.7%) and 15 (19.7%) patients, respectively. Patients with immunodeficiency condition(s) were more likely to have high CD8+ percentages (p = 0.040), low CD19+ percentages (p = 0.025), and/or inverted CD4+/CD8+ ratios (p = 0.034). Patients with autoimmune condition(s) were more likely to have a high/normal CD4+ percentage (p = 0.038). High CD2+ percentages were associated with lower mean IgG and IgA levels (p = 0.030 and p = 0.017, respectively). High CD3+ and CD8+ percentages were associated with lower mean IgA levels (p = 0.046 and p = 0.013, respectively). Low CD19+ percentages were associated with lower mean IgG and IgA levels (p = 0.004 and p < 0.001, respectively). CONCLUSION: Signs/symptoms and history of autoimmune and immunodeficiency conditions among patients with thymic epithelial neoplasms are associated with high frequencies of abnormalities in immunoglobulin levels and lymphocyte immunophenotypes, suggesting a role for their assessment. PMID- 22228569 TI - Subcutaneous immunoglobulin replacement therapy with Hizentra(r) is safe and effective in two infants. AB - Hizentra(r) is a 20% liquid IgG product approved for subcutaneous administration in adults and children greater than 2 years of age. We report two infants less than 2 years in which administration of Hizentra(r) was safe and effective. PMID- 22228570 TI - Cytokine production is altered in monocytes from children with hemolytic uremic syndrome. AB - PURPOSE: The interaction of Shiga toxin (Stx) and/or lipopolysaccharide (LPS) with monocytes (Mo) may be central to the pathogenesis of hemolytic uremic syndrome (HUS), providing the cytokines necessary to sensitize endothelial cells to Stx action. We have previously demonstrated phenotypical alterations in Mo from HUS patients, including increased number of CD16+ Mo. Our aim was to investigate cytokine production in Mo from HUS patients. METHODS: We evaluated TNF-alpha and IL-10 intracellular contents and secretion in the different Mo subsets in mild (HUS 1) and moderate/severe (HUS 2 + 3) patients. As controls, we studied healthy (HC) and infected children (IC). We also studied Mo responsive capacity towards LPS, measuring the modulation of Mo surface molecules and cytokine production. RESULTS: In basal conditions, the intracellular measurement of TNF-alpha and IL-10 revealed that the highest number of cytokine-producing Mo was found in HUS 2 + 3 and IC, whereas LPS caused a similar increase in TNF-alpha and IL-10-producing Mo for all groups. However, when evaluating the release of TNF-alpha and IL-10, we found a diminished secretion capacity in the entire HUS group and IC compared to HC in basal and LPS conditions. Similarly, a lower Mo response to LPS in HUS 2 + 3 and IC groups was observed when surface markers were studied. CONCLUSION: These results indicate that Mo from severe cases of HUS, similar to IC but different to mild HUS cases, present functional changes in Mo subpopulations and abnormal responses to LPS. PMID- 22228571 TI - A novel mouse CD133 binding-peptide screened by phage display inhibits cancer cell motility in vitro. AB - Increased expression of CD133 (Prominin-1), an important cancer stem cell associated marker, has been observed in the cancer stem cells of a variety of human and mouse cancers. However, no natural ligand of CD133 has yet been identified and little is known about its function. In the present study, LS-7 (amino acid sequence: LQNAPRS), a specific binding peptide targeting mouse CD133, was screened and identified for the first time by phage-displayed peptide library technology. The in vitro and in vivo affinity and specificity of LS-7 were determined, and MTT, adhesion, and migration assays were performed to evaluate the effects of LS-7 on the biological behaviors of cancer cells. To determine which signaling pathways are affected by LS-7, HMGB1, S-100A4, CXCR7, uPAR, AMFR, STAT3, and c-Met gene and protein expression were evaluated by RT-PCR and Western blot. Flow cytometry and immunofluorescence assays showed specific, high-affinity binding of the peptide to mCD133 in vitro. Confocal microscopy confirmed the co localization of LS-7 positive cells and CD133-positive cells. Migration and wound healing assays showed that LS-7 significantly inhibited the migration of colon and breast cancer cells in a concentration-dependent manner. In vivo experiments also confirmed the high specificity and affinity of LS-7 to mCD133. RT-PCR and Western blot showed that the expressions of only c-Met and STAT3 decreased obviously in colon and breast cancer cells exposed to LS-7. These findings may provide a novel tool for anti-motility and anti-metastasis strategies in cancer research and cancer stem cell therapy. PMID- 22228572 TI - Enhancement of metastatic ability by ectopic expression of ST6GalNAcI on a gastric cancer cell line in a mouse model. AB - ST6GalNAcI is a sialyltransferase responsible for the synthesis of sialyl Tn (sTn) antigen which is expressed in a variety of adenocarcinomas including gastric cancer especially in advanced cases, but the roles of ST6GalNAcI and sTn in cancer progression are largely unknown. We generated sTn-expressing human gastric cancer cells by ectopic expression of ST6GalNAcI to evaluate metastatic ability of these cells and prognostic effect of ST6GalNAcI and sTn in a mouse model, and identified sTn carrier proteins to gain insight into the function of ST6GalNAcI and sTn in gastric cancer progression. A green fluorescent protein tagged human gastric cancer cell line was transfected with ST6GalNAcI to produce sTn-expressing cells, which were transplanted into nude mice. STn-positive gastric cancer cells showed higher intraperitoneal metastatic ability in comparison with sTn-negative control, resulting in shortened survival time of the mice, which was mitigated by anti-sTn antibody administration. Then, sTn-carrying proteins were immunoprecipitated from culture supernatants and lysates of these cells, and identified MUC1 and CD44 as major sTn carriers. It was confirmed that MUC1 carries sTn also in human advanced gastric cancer tissues. Identification of sTn carrier proteins will help understand mechanisms of metastatic phenotype acquisition of gastric cancer cells by ST6GalNAcI and sTn. PMID- 22228573 TI - Ten-year survey reveals differences in GP management of neck and back pain. AB - PURPOSE: Clinical guidelines provide similar recommendations for the management of new neck pain and low back pain (LBP) but it is unclear if general practitioner's (GP) care is similar. While GP's management of LBP is well documented, little is known about GP's management of neck pain. We aimed to describe GP's management of new neck pain and compare this to GP's management of new LBP in Australia between April 2000 and March 2010. METHODS: All GP-patient encounters for a new (i.e. first visit to any medical practitioner) neck pain or LBP problem were compared in terms of treatment delivered, referral patterns and requests for laboratory and imaging investigations. RESULTS: General practitioners in Australia have managed new neck pain and LBP problems at a rate of 3.1 and 5.8 per 1,000 GP-patient encounters, respectively. GP's primarily utilised medications, in particular non-steroidal anti-inflammatory drugs, to manage new neck and LBP problems and referred approximately 25% of all patients for imaging. Patients with new neck pain are more frequently managed using physical treatments and were referred more often to allied health professionals and specialists. In comparison, patients with new LBP were managed more frequently with medication, advice, provision of a sickness certificate and ordering of pathology tests. CONCLUSIONS: This is the first time GP management of a new episode of neck pain has been documented using a nationally representative sample and it is also the first time that the management of back and neck pain has been compared. Despite guidelines endorsing a similar approach for the management of new neck pain and LBP, in actual clinical practice Australian GPs manage these two conditions differently. PMID- 22228574 TI - C2 lamina reconstruction using locking miniplate for the intradural tumor of the craniocervical junction (two case reports). AB - OBJECTIVE: To describe a technique for C2 lamina reconstruction using locking miniplates for the extirpation of spinal tumors in the craniocervical junction. Many spinal surgery cases in which lamina reconstructions have been performed using non-locking miniplates have been reported. However, there is only one report of the use of locking miniplates for lamina reconstruction in spinal tumor cases. METHODS: We performed C2 lamina reconstructions using locking miniplates in a patient with a spinal tumor and another with a cystic lesion. The clinical and radiologic features of both cases are reported, and the surgical technique is described. RESULTS: A 62-year-old female and a 30-year-old male were diagnosed with meningioma and a neurenteric cyst, respectively, in the craniocervical junction. Extirpation of these lesions was performed in combination with C2 lamina reconstruction and reattachment of the paraspinous muscle to the C2 spinous process. A follow-up examination at 1 year postoperatively demonstrated no significant change in the sagittal alignment of the cervical spine and a good postoperative course in both cases. Bony fusion was detected in both cases, and no implant failure occurred in either case. CONCLUSIONS: This procedure results in rigid fixation of the reimplanted C2 lamina and helps to restore the paraspinous muscles. For these reasons, it appears to be a useful surgical procedure for spinal tumors requiring C2 laminectomy and does not cause postoperative kyphosis of the cervical spine. PMID- 22228575 TI - Selenium, arsenic, and mercury in fish inhabiting a fly ash exposure gradient: interspecific bioaccumulation patterns and elemental associations. AB - Releases from coal ash impoundments can be a significant source of trace elements to the aquatic environment. In the present study, whole-body concentrations of As, Hg, and Se in various fish species inhabiting streams receiving a gradient of fly ash exposure are reported. High-exposure sites had elevated water concentrations of As, Mo, Se, and SO(4) . Fish were collected during two seasons in 2007. Mercury concentrations in all fish samples were low (range = 1.2-99 ng/g wet wt); highest As concentrations occurred in fish from high-exposure sites. Whole-body Se concentrations were low at reference sites but increased as the magnitude of fly exposure increased. For all sites combined, a significant (r(2) = 0.60) correlation was observed between the geometric mean of each species' whole-body Se concentration and log-transformed water Se concentration. A significant inverse relationship was apparent with log-transformed whole-body Hg and Se concentrations (r(2) = 0.56 for all species and sites combined), suggesting that high tissue Se levels antagonistically regulated Hg bioaccumulation. Sunfish (Lepomis sp.) from high- and medium-exposure sites had significantly higher Se body residues, but significantly lower Hg, relative to fish from low-exposure and reference sites. Ninety percent of fish from high exposure sites had a surplus of Se, whereas all fish from reference sites had Se/Hg molar ratios <1.0. These ratios increased as water Se increased. Where fish have moderate to high exposure to fly ash-influenced water, Se tissue levels can be expected to be elevated (as well as As, in some cases), but tissue Hg concentrations will likely be low. PMID- 22228577 TI - Content of selenium, total and inorganic arsenic and bioaccessibility of arsenic in children diets of Mexico. AB - BACKGROUND: The aim of this study was to evaluate the intake of selenium, total and inorganic arsenic and the bioaccessibility of arsenic in diets of Mexican schoolchildren using an in vitro method. RESULTS: Total and inorganic arsenic concentrations in the diets ranged from 0.05 to 1.15 mg kg(-1) dry weight (DW) and from 0.023 to 0.088 mg kg(-1) DW respectively, while selenium levels were between 0.08 and 0.20 mg kg(-1) DW. Daily intake of total and inorganic arsenic ranged from 0.15 to 10.49 ug day(-1) kg(-1) body weight (BW) and from 0.06 to 1.11 ug day(-1) kg(-1) BW respectively, while that of selenium varied from 0.29 to 2.63 ug day(-1) kg(-1) BW. Bioaccessibility of total and inorganic arsenic ranged from 4 to 97% (mean 44 +/- 21.5%) and from 33 to 97% (mean 71 +/- 22.5%) respectively. CONCLUSION: Inorganic arsenic levels in the diets were low. Therefore there appears to be a low risk of adverse effects resulting from excess inorganic arsenic intake from these diets. PMID- 22228576 TI - In utero and early-life exposure of rats to a Wi-Fi signal: screening of immune markers in sera and gestational outcome. AB - An experimental approach was used to assess immunological biomarkers in the sera of young rats exposed in utero and postnatal to non-ionizing radiofrequency fields. Pregnant rats were exposed free-running, 2 h/day and 5 days/week to a 2.45 GHz Wi-Fi signal in a reverberation chamber at whole-body specific absorption rates (SAR) of 0, 0.08, 0.4, and 4 W/kg (with 10, 10, 12, and 9 rats, respectively), while cage control rats were kept in the animal facility (11 rats). Dams were exposed from days 6 to 21 of gestation and then three newborns per litter were further exposed from birth to day 35 postnatal. On day 35 after birth, all pups were sacrificed and sera collected. The screening of sera for antibodies directed against 15 different antigens related to damage and/or pathological markers was conducted using enzyme-linked immunosorbent assay (ELISA). No change in humoral response of young pups was observed, regardless of the types of biomarker and SAR levels. This study also provided some data on gestational outcome following in utero exposure to Wi-Fi signals. Mass evaluation of dams and pups and the number of pups per litter was monitored, and the genital tracts of young rats were observed for abnormalities by measuring anogenital distance. Under these experimental conditions, our observations suggest a lack of adverse effects of Wi-Fi exposure on delivery and general condition of the animals. PMID- 22228578 TI - Mutations in the sodium channel associated with pyrethroid resistance in the greenhouse whitefly, Trialeurodes vaporariorum. AB - BACKGROUND: Trialeurodes vaporariorum Westwood is an important pest of protected crops in temperate regions of the world. Resistance to pyrethroid insecticides is long established in this species, but the molecular basis of the mechanism(s) responsible has not previously been disclosed. RESULTS: Mortality rates of three European strains of T. vaporariorum to the pyrethroid bifenthrin were calculated, and each possessed significant resistance (up to 662-fold) when compared with a susceptible reference strain. Direct sequencing revealed three amino acid substitutions in the para-type voltage-gated sodium channel (the pyrethroid and DDT target site) of bifenthrin-resistant T. vaporariorum at positions previously implicated with pyrethroid or DDT resistance (M918L, L925I and T929I) in other related species. CONCLUSION: This study indicates that resistance to bifenthrin in T. vaporariorum is associated with target-site insensitivity, and that the specific mutations in the sodium channel causing resistance may differ between localities. PMID- 22228579 TI - Characterization of temporary metabolic changes following Cantonese herbal tea intervention. AB - Cantonese herbal tea (CHT) has been consumed in South China to alleviate feelings of discomfort due to the heat and humidity in the body according to the theory of traditional Chinese medicine (TCM). To understand the in vivo mechanism of CHT, a 1H-NMR-based metabonomic approach was used to investigate the global biological characterization of rat serum following the intake of CHT and to understand the mechanisms of action of CHT. Serum samples from rats with consecutive CHT intake after 10, 20 and 30 days and corresponding control rats were analysed by high resolution 1H-NMR spectroscopy. Principal component analysis (PCA) and orthogonal projection on latent structures discriminant analysis (OPLS-DA) were utilized for 1H-NMR spectra analysis and temporal metabolic changes identification. For the 10 day CHT intake group, no significant metabolic response was detected, whereas the 20-day group showed elevation of glucogeneogenesis and a shift in energy metabolism from carbohydrate metabolism to lipid metabolism. In addition, a notable decrease in pyruvate content with a consistent increase in lactate content, and significant decrease in both lipoprotein and glucose contents was observed for the 30-day group, indicating potential metabolic dysfunction. The metabonomics technique combining metabolic profiles with multivariate analysis enhanced our current understanding of the host's metabolic response to CHT intake. PMID- 22228581 TI - An overview of asthma and airway hyper-responsiveness in Olympic athletes. AB - Data from the past five Olympic Games obtained from athletes seeking to inhale beta2 adrenoceptor agonists (IBA) have identified those athletes with documented asthma and airway hyper-responsiveness (AHR). With a prevalence of about 8%, asthma/AHR is the commonest chronic medical condition experienced by Olympic athletes. In Summer and Winter athletes, there is a marked preponderance of asthma/AHR in endurance-trained athletes. The relatively late onset of asthma/AHR in many older athletes is suggestive that years of endurance training may be a contributory cause. Inspiring polluted or cold air is considered a significant aetiological factor in some but not all sports. During the last five Olympic Games, there has been improved management of athletes with asthma/AHR with a much higher proportion of athletes combining inhaled corticosteroids (ICS) with IBA and few using long-acting IBA as monotherapy. Athletes with asthma/AHR have consistently outperformed their peers, which research suggests is not due to their treatment enhancing sports performance. Research is necessary to determine how many athletes will continue to experience asthma/AHR in the years after they cease intensive endurance training. PMID- 22228580 TI - Artifact versus reality--how astrocytes contribute to synaptic events. AB - The neuronal doctrine, developed a century ago regards neuronal networks as the sole substrate of higher brain function. Recent advances in glial physiology have promoted an alternative hypothesis, which places information processing in the brain into integrated neuronal-glial networks utilizing both binary (neuronal action potentials) and analogue (diffusional propagation of second messengers/metabolites through gap junctions or transmitters through the interstitial space) signal encoding. It has been proposed that the feed-forward and feed-back communication between these two types of neural cells, which underlies information transfer and processing, is accomplished by the release of neurotransmitters from neuronal terminals as well as from astroglial processes. Understanding of this subject, however, remains incomplete and important questions and controversies require resolution. Here we propose that the primary function of perisynaptic glial processes is to create an "astroglial cradle" that shields the synapse from a multitude of extrasynaptic signaling events and provides for multifaceted support and long-term plasticity of synaptic contacts through variety of mechanisms, which may not necessarily involve the release of "glio" transmitters. PMID- 22228582 TI - Intrathymic injection of lentiviral vector curtails the immune response in the periphery of normal mice. AB - BACKGROUND: Gene transfer in the thymus, based on HIV-derived lentiviral vectors, is a promising avenue for modulation of T cell selection and autoimmunity. However, the impact of intrathymic (IT) injections on an antigen-specific immune response elicited in the periphery of normal mice has not been investigated yet. METHODS: Highly concentrated stocks of lentiviral vectors expressing the soluble form of hemaglutinin of the influenza virus (LvHA) were injected in the thymus of normal BALB/c mice. The CD4 and CD8-mediated immune responses to HA after peripheral immunization were measured by various parameters. RESULTS: We first show that a lentiviral vector expressing the luciferase was detected for at least 2 months after IT-injections. We then show that the LvHA vector could elicit a functional CD4- and CD8-T cell-mediated immune responses in the peripheral lymphoid organs of BALB/c mice. IT-injection of the LvHA vector significantly curbed this response: lower numbers of transferred HA-specific CD4(+) T cells were found in LvHA-injected compared to control animals. Furthermore, lower frequencies of HA-specific CD8(+) T cells, interferon gamma-producing cells and cytotoxic cells were detected from 3 weeks to 3 months in LvHA-injected mice compared to controls. However, these reduced CD8-mediated responses were not increased after depletion of CD25(+) cells in vitro or in vivo. CONCLUSIONS: The results obtained in the present study show that injection of the LvHA lentiviral vector significantly curtailed the immune response to the same antigen in the periphery. Increased selection of HA-specific regulatory T cells and negative selection of HA-specific CD8(+) T cell precursors may explain the results. Our work establish the feasibility of IT-injections of lentiviral vectors to manipulate T cell tolerance in the thymus of normal mice, for basic and pre clinical research. PMID- 22228583 TI - Predicting US- and state-level cancer counts for the current calendar year: Part II: evaluation of spatiotemporal projection methods for incidence. AB - BACKGROUND: The current study was undertaken to evaluate the spatiotemporal projection models applied by the American Cancer Society to predict the number of new cancer cases. METHODS: Adaptations of a model that has been used since 2007 were evaluated. Modeling is conducted in 3 steps. In step I, ecologic predictors of spatiotemporal variation are used to estimate age-specific incidence counts for every county in the country, providing an estimate even in those areas that are missing data for specific years. Step II adjusts the step I estimates for reporting delays. In step III, the delay-adjusted predictions are projected 4 years ahead to the current calendar year. Adaptations of the original model include updating covariates and evaluating alternative projection methods. Residual analysis and evaluation of 5 temporal projection methods were conducted. RESULTS: The differences between the spatiotemporal model-estimated case counts and the observed case counts for 2007 were < 1%. After delays in reporting of cases were considered, the difference was 2.5% for women and 3.3% for men. Residual analysis indicated no significant pattern that suggested the need for additional covariates. The vector autoregressive model was identified as the best temporal projection method. CONCLUSIONS: The current spatiotemporal prediction model is adequate to provide reasonable estimates of case counts. To project the estimated case counts ahead 4 years, the vector autoregressive model is recommended to be the best temporal projection method for producing estimates closest to the observed case counts. PMID- 22228584 TI - Combining stir-bar sorptive extraction and large volume injection-gas chromatography-mass spectrometry for the determination of benzotriazole UV stabilizers in wastewater matrices. AB - Stir-bar sorptive extraction and liquid desorption followed by large volume injection-gas chromatography coupled to mass spectrometry under selected ion monitoring mode acquisition (SBSE-LD/LVI-GC-MS(SIM)) was applied for the determination of six benzotriazole UV stabilizers (Tinuvin P, Allyl-bzt, Tinuvin 320, Tinuvin 326, Tinuvin 327 and Tinuvin 328) in wastewater matrices. Parameters affecting the performance of extraction and desorption steps were thoroughly evaluated using uni- and multivariate optimization strategies, based on the use of experimental factorial designs. Assays performed with stir bars, coated with 24 MUL of polydimethylsiloxane, on 25 mL of ultra-pure water samples spiked at the 0.5 ng/mL level, yielded recoveries ranging from 47.9+/-1.4% (Tinuvin P) to 103.1+/-3.6% (Tinuvin 326), under optimized experimental conditions. When applied to complex matrices (e.g. wastewater), the methodology showed also excellent linear dynamic ranges (0.02-10.00 ng/mL) for the six benzotriazole UV stabilizers studied with correlation coefficients higher than 0.9970, limits of quantification in between 0.004 and 0.015 ng/mL, suitable repeatability (RSD<12.7%) and reproducibility (RSD<4.5%). The application of the proposed methodology to urban sewage waters from Spain and Portugal wastewater plants revealed the presence of low contents of some benzotriazole UV stabilizers. PMID- 22228585 TI - Mineralization pattern of vertebral bone material following fragility fracture of the spine. AB - Little is known whether trabecular bone matrix mineralization is altered at the site of osteoporotic vertebral fractures. Bone mineralization density distribution (BMDD) was assessed in trabecular bone of acute, single-level compression fractures of the spine at various stages of fracture repair using quantitative backscattered electron imaging (qBEI). The grading of the repair stage was performed by histological methods. From 20 patients, who underwent either kyphoplasty (n=18) or vertebroplasty (n=2), a vertebral bone biopsy was taken prior to cement augmentation. Six patients took bisphosphonates (BP) prior to fracture. Three study groups were formed: N1=early-, N2=late-healing and B=BP treatment at late healing stage. In general, all groups had an altered BMDD when compared to historical normative reference data. Mean matrix mineralization (CaMean) was significantly (p<0.001) lower in all groups (N1: -5%, N2: -16%, and B2: -16%). In N2, CaMean was -13.1% (p<0.001) lower than N1. At this stage, deposition of new bone matrix and/or formation of woven bone are seen, which also explains the more heterogeneous matrix mineralization (CaWidth). Moreover, BP treatment (B2) led to a significant reduction in CaWidth (-28.5%, p<0.001), when compared to N2. Bone tissue from vertebrae with acute compression fractures reveals a large variation in matrix mineralization depending on the stage of repair. Bisphosphonate treatment does affect the mineralization pattern of tissue repair. The low mineralization values found in early stage of repair suggest that altered bone material properties may play a role in the occurrence of fragility fractures of the spine. PMID- 22228586 TI - Lipid-soluble extracts from Salvia miltiorrhiza inhibit production of LPS-induced inflammatory mediators via NF-kappaB modulation in RAW 264.7 cells and perform antiinflammatory effects in vivo. AB - Salvia miltiorrhiza, a traditional Chinese herbal medicine, is used to treat various inflammatory diseases. In the present study, the antiinflammatory effects of S. miltiorrhiza lipid-soluble extracts (SMLE) were demonstrated in vitro and in vivo, along with its underlying mechanism of action. SMLE significantly inhibited the production of NO, TNF-alpha, IL-1beta and IL-6 in lipopolysaccharides (LPS)-stimulated RAW 264.7 cells. SMLE also inhibited the LPS induced degradation of IkappaB-alpha in the cytoplasm and the translocation of p65 to the nucleus in RAW 264.7 cells. In addition, SMLE inhibited the production of intracellular reactive oxygen species (ROS) and the surface expression of CD14 induced by LPS. In animal models, intraperitoneal administration of SMLE increased the survival rate of endotoxemia and sepsis in mice. The topical administration of SMLE significantly inhibited ear edema induced by PMA. It was found that SMLE inhibits the LPS-induced gene and protein expression of iNOS, TNF alpha, IL-1beta and IL-6 in macrophages by blocking NF-kappaB activation, and these effects are mediated, at least in part, through the inhibition of intracellular ROS generation and the surface expression of CD14. The results suggest a possible therapeutic application of SMLE in inflammatory diseases and provide scientific evidence in support of the traditional Chinese medical practice of treatment with S. miltiorrhiza. PMID- 22228587 TI - Circulating microRNAs as biomarkers: a new frontier in diagnostics. PMID- 22228588 TI - Determination of tocopherol and tocotrienol content of Greek barley varieties under conventional and organic cultivation techniques using validated reverse phase high-performance liquid chromatography method. AB - BACKGROUND: Tocotrienols and tocopherols (tocols) are important phytochemical compounds with antioxidant activity and potential benefits for human health. Among cereals, barley is a good source of tocols. In the present study the effect of two cultivation methods, organic and conventional, on the tocol content in 12 Greek barley varieties was investigated. A validated reverse phase high performance liquid chromatography method (RP-HPLC) with fluorescence detection (excitation at 292 nm, emission at 335 nm) was applied along with direct solvent extraction with acetonitrile at a 1:30 (w/v) sample/solvent ratio for tocol quantification. RESULTS: The results showed statistically significant differences (P < 0.05) between the two cultivation methods (except for delta-tocopherol) as well as among varieties. In the case of organic cultivation the four homologues of tocotrienol (alpha-, beta + gamma- and delta-) increased, by 3.05-37.14% for alpha-tocotrienol, 15.51-41.09% for (beta + gamma)-tocotrienol and 30.45-196.61% for delta-tocotrienol, while those of tocopherol (alpha- and beta + gamma- but not delta-) decreased, by 5.90-36.34% for alpha-tocopherol and 2.84-46.49% for (beta + gamma)-tocopherol. A simple correlation analysis between tocols revealed a good correlation between (beta + gamma)-tocotrienol and delta-tocotrienol. Although there was a significant decrease in the important alpha-tocopherol in the varieties studied under organic cultivation, there was an overall increase in tocotrienol content. CONCLUSION: The cultivation method (organic or conventional) had an important effect on tocotrienol and tocopherol concentrations in barley. An overall increase in total tocol content and a clear increment in the tocotrienol/tocopherol ratio were observed. PMID- 22228590 TI - Droplet size control with methanol-repellent surface in a sampling device for continuous annular electrochromatography. AB - The eluent droplet size defines the number of sampling compartments in a continuously operated annular electrochromatograph and therefore influences separation efficiency. In this work, an assembly of two capillaries, a feeding capillary on the top and a receiving capillary placed under it, has been investigated to control droplet size. The receiving capillary prevents the liquid droplet formation beyond a critical size, which reduces the volume of sampling compartment as compared with the case of the electrolyte flow driven solely by gravity. With a receiving capillary, the electrolyte droplet size was reduced from 1.5 to 0.46 mm. Further decrease of droplet size was not possible due to a so-called droplet jump upwards effect which has been observed on a hydrophilic glass surface with water. A typical electrolyte used in CAEC has high methanol content. In an attempt to improve the methanol-repellent properties of the glass surface, two approaches have been implemented: (i) self-assembled chemisorbed monolayers of an alkylsiloxane and (ii) fabrication of a nano-pin film. The methanol-repellent surface of the feeding capillary suppressed the droplet jump upwards effect. The surface remained methanol repellent in different solutions with lower polarity than that of water. PMID- 22228591 TI - CCL19 (ELC) improves TH1-polarized immune responses and protective immunity in a murine Her2/neu DNA vaccination model. AB - BACKGROUND: DNA vaccination is an attractive approach for tumor vaccination because plasmid DNA (pDNA) can be used as a 'general vaccine' across major histocompatibility complex barriers. Coexpression of immunomodulatory molecules can help to amplify the immunogenicity of DNA vaccines. CCL19 (ELC) is a CC chemokine with immunoregulatory properties, binding to the chemokine receptor CCR7 that is expressed on dendritic cells (DCs) and T cells. In vivo, CCL19 is a key regulator for the interactions between DCs and T cells in regional lymph nodes. METHODS: pDNA encoding Her2/neu and CCL19 was used as an intramuscular vaccine. Vaccination was performed in BALB/c mice, which were subsequently challenged with syngeneic Her2/neu(+) tumor cells. Groups of mice were immunized with pDNA(Her2/neu) plus pDNA(CCL19), pDNA(Her2/neu) plus pDNA(CCL19) plus pDNA(GM-CSF), pDNA(Her2/neu) plus pDNA(GM-CSF), pDNA(Her2/neu), pDNA(CCL19), pDNA(GM-CSF) or mock vector. Tumor protection by the vaccine and immune responses were monitored. RESULTS: Coadministration of pDNA(Her2/neu) and pDNA(CCL19) led to substantial improvement of tumor protection by the vaccine and induced a TH1 polarized, Her2/neu-specific immune response. Forty-seven days after the tumor challenge, 58% of the mice coinjected with pDNA(Her2/neu) and pDNA(CCL19) remained tumor-free compared to 22% after vaccination with pDNA(Her2/neu) alone. Additional administration of pDNA(GM-CSF) led to further improvement of tumor protection and an amplification of Her2/neu-specific immune responses. CONCLUSIONS: CCL19 is able to induce a TH-1 polarization of the anti-Her2/neu immune response, which can be further amplified by granulocyte macrophage-colony stimulating factor (GM-CSF). Clinical use of a pDNA(Her2/neu-CCL19 +/- GM-CSF) vaccine might be promising in Her2/neu + breast cancer in the clinical situation of minimal residual disease. PMID- 22228589 TI - APOE genotype alters glial activation and loss of synaptic markers in mice. AB - The epsilon4 allele of the Apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and affects clinical outcomes of chronic and acute brain damages. The mechanisms by which apoE affect diverse diseases and disorders may involve modulation of the glial response to various types of brain damage. We examined glial activation in a mouse model where each of the human APOE alleles are expressed under the endogenous mouse APOE promoter, as well as in APOE knock-out mice. APOE4 mice displayed increased glial activation in response to intracerebroventricular lipopolysaccharide (LPS) compared to APOE2 and APOE3 mice by several measures. There were higher levels of microglia/macrophage, astrocytes, and invading T-cells after LPS injection in APOE4 mice. APOE4 mice also displayed greater and more prolonged increases of cytokines (IL-1beta, IL-6, TNF-alpha) than APOE2 and APOE3 mice. We found that APOE4 mice had greater synaptic protein loss after LPS injection, as measured by three markers: PSD-95, drebin, and synaptophysin. In all assays, APOE knock-out mice responded similar to APOE4 mice, suggesting that the apoE4 protein may lack anti-inflammatory characteristics of apoE2 and apoE3. Together, these findings demonstrate that APOE4 predisposes to inflammation, which could contribute to its association with Alzheimer's disease and other disorders. PMID- 22228592 TI - Chronic cyanidin-3-glucoside administration improves short-term spatial recognition memory but not passive avoidance learning and memory in streptozotocin-diabetic rats. AB - This research study was conducted to evaluate the efficacy of chronic cyanidin-3 glucoside (C3G) on alleviation of learning and memory deficits in diabetic rats as a result of the observed antidiabetic and antioxidant activity of C3G. Male Wistar rats were divided into control, diabetic, C3G-treated-control and diabetic groups. The C3G was administered i.p. at a dose of 10 mg/kg on alternate days for eight weeks. For evaluation of learning and memory, initial latency (IL) and step-through latency (STL) were determined at the end of study using passive avoidance test. Meanwhile, spatial recognition memory was assessed as alternation in the Y-maze task. Oxidative stress markers in brain tissue were also measured. It was found that the alternation score of the diabetic rats was lower than that of control (p < 0.01) and C3G-treated diabetic rats showed a higher alternation score as compared to diabetic group (p < 0.05). Diabetic rats also developed a significant impairment in retention and recall in passive avoidance test (p < 0.01) and C3G treatment of diabetic rats did not produce any significant improvement. Meanwhile, increased level of malondialdehyde (MDA) in diabetic rats was significantly reduced following C3G treatment (p < 0.05). Taken together, chronic C3G could improve short-term spatial recognition memory disturbance in the Y-maze test but not retention and recall capability in passive avoidance test in STZ-diabetic rats. PMID- 22228593 TI - Mesenchymal stem cell transplantation to promote bone healing. AB - An overall decline in the availability of osteogenic precursor cells and growth factors in the bone marrow microenvironment have been associated with impaired bone formation and osteopenia in humans. The objective of the current study was to determine if transplantation of mesenchymal stromal cells (MSC) from a healthy, young donor mouse into an osteopenic recipient mouse could enhance osseointegration of a femoral implant. MSC harvested from normal young adult mice differentiated into bone forming osteoblasts when cultured on implant grade titanium surfaces ex vivo and promoted bone formation around titanium-coated rods implanted in the femoral canal of osteopenic recipient mice. Micro computed tomographic imaging and histological analyses showed more, better quality, bone in the femur that received the MSC transplant compared with the contra-lateral control femur that received carrier alone. These results provide pre-clinical evidence that MSC transplantation promotes peri-implant bone regeneration and suggest the approach could be used in a clinical setting to enhance bone regeneration and healing in patients with poor quality bone. PMID- 22228594 TI - Isolation and quantitation of ecologically important phloroglucinols and other compounds from Eucalyptus jensenii. AB - INTRODUCTION: Eucalyptus jensenii has not been explored for its phytoconstituents except for its essential oil although a formylated phloroglucinol compound jensenone has been the focus of several ecological studies. OBJECTIVE: i) To optimise the extraction conditions for preparative scale isolation of jensenone and other secondary metabolites from leaves. (ii) To develop an RP-HPLC method for simultaneous determination of phloroglucinols and other compounds in Eucalyptus leaves. METHODOLOGY: Jensenone and other compounds were isolated from acetone extract using VLC over TLC grade silica. HPLC quantitation of isolated compounds was undertaken on a C18-column using acetonitrile-water (2% formic acid) gradient elution. RESULTS: Extraction conditions for isolation of jensenone were optimised and more than 99% pure jensenone was obtained in a yield of 2.1% from the dried leaves. Ten phloroglucinol compounds, including a new nuclear methylated phloroglucinol named 4-O-demethyl miniatone, and two triterpenoids were also isolated. A RP-HPLC method was developed for simultaneous quantitation of phloroglucinols and other compounds in different extracts of E. jensenii leaves. A total of 19 compounds reported from different species of Eucalyptus was separated by this method. CONCLUSION: The method described for isolation of jensenone is a simple, rapid and low-cost procedure amenable to the preparative scale. A new monomeric phloroglucinol compound was isolated and characterised from the acetone extract of E. jensenii leaves. The HPLC method developed can be applied successfully to different eucalypt matrices for precise and accurate determination of 19 secondary metabolites belonging to different chemical classes. PMID- 22228595 TI - CHM/REP1 cDNA delivery by lentiviral vectors provides functional expression of the transgene in the retinal pigment epithelium of choroideremia mice. AB - BACKGROUND: Choroideremia (CHM) is a progressive X-linked degeneration of three ocular layers: photoreceptors, retinal pigment epithelium (RPE) and choroid, caused by the loss of Rab Escort Protein-1 (REP1). As a recessive monogenic disorder, CHM is potentially curable by gene addition therapy. The present study aimed to evaluate the potential use of lentiviral vectors carrying CHM/REP1 cDNA transgene for CHM treatment. METHODS: We generated lentiviral vectors carrying either CHM/REP1 cDNA or EGFP transgene under the control of the elongation factor 1alpha promoter (EF-1alpha) or its shortened version EFS. We transduced human (HT1080) and dog (D17) cells, CHM patient's fibroblasts and mouse primary RPE cells in vitro, as well as wild-type and CHM mouse retinas in vivo by subretinal injections. Transgene expression was confirmed by immunoblotting, fluorescence activated cell sorting, immunofluorescence and confocal microscopy. CHM/REP1 transgene functionality was assessed by an in vitro prenylation assay. RESULTS: Lentiviral vectors with CHM/REP1 and EGFP transgenes efficiently transduced HT1080, D17 and CHM fibroblast cells; CHM/REP1 transgene lead to an increase in prenylation activity. Subretinal injections of lentiviral vectors into mouse retinas resulted in efficient transduction of the RPE (30-35% of total RPE cells transduced after a 1-ul injection), long-term expression for at least 6 months and a decrease in amount of unprenylated Rabs in the CHM RPE. Transduction of neuroretinal cells was restricted to the injection site. CONCLUSIONS: Lentiviral CHM/REP1 cDNA transgene rescues the prenylation defect in CHM mouse RPE and thus could be used to restore REP1 activity in the RPE of CHM patients. PMID- 22228596 TI - Cryptotanshinone from Salviae miltiorrhizae radix inhibits sodium-nitroprusside induced apoptosis in neuro-2a cells. AB - The root of Salvia miltiorrhiza (Salviae miltiorrhizae radix), a herbal medicine has widely been used for the treatment of pain, miscarriage and oedema. In this study, we evaluated the neuroprotective effect of cryptotanshinone (CRT) from Salviae miltiorrhizae radix on sodium-nitroprusside (SNP)-induced apoptosis in neuro-2a (N2a) cells, and further investigated its action mechanism in signalling pathways. The effects of CRT against SNP-induced toxicity, mitochondrial membrane potential (MMP) changes, and oxidants/antioxidant defences and apoptotic signalling pathways were investigated in N2a cells. Cryptotanshinone significantly inhibited SNP-induced cell toxicity and the generation of reactive oxygen and nitrogen species (RONS), and improved MMP in N2a cells. Cryptotanshinone significantly suppressed SNP-induced peroxidation of lipid and protein, and the expression of Gclc mRNA. In the signalling pathway, CRT effectively blocked SNP-induced activation of NF-kappaB and ERK1/2 and JNK MAPK pathways through the elevation of Akt and cyclic AMP response element binding protein. Furthermore, CRT remarkably reduced the increase of mitochondrial Bax/Bcl-2 ratio, the release of cytochrome c from mitochondria to cytosol, and the activations of cytosolic procaspase-3 and nuclear inactive poly ADP (adenosine diphosphate)-ribose polymerase by SNP-induced apoptosis. These results indicate that CRT has neuroprotective effects against SNP-induced apoptosis in neuronal cells via the regulation of mitochondrial apoptotic cascades and antiapoptotic cellular signalling pathways. PMID- 22228597 TI - Active flow management in preparative chromatographic separations: a preliminary investigation into enhanced separation using a curtain flow inlet fitting and segmented flow outlet fitting. AB - Active flow management in the form of curtain flow sample introduction and segmented outlet flow control has been shown to enable sample to elute through a chromatography column under the principles of the "infinite diameter column". Such an elution process avoids the detrimental effects of the heterogeneity of particle-packed chromatographic columns by injecting the sample directly into the radial core region of the column, thus avoiding wall effects. The process described herein illustrates how the principles of the infinite diameter column can be applied using conventional injection devices suitable for long-term analysis that requires robust protocols. Using this approach, sensitivity in separation was 2.5 times greater than conventional chromatography, yielding a product at twice the concentration. Benefits of curtain flow injection are thus relevant to both preparative-scale and analytical-scale separations. PMID- 22228598 TI - Effect of age and gender on cell proliferation and cell surface characterization of synovial fat pad derived mesenchymal stem cells. AB - Cell based therapies are being investigated for biological repair of a variety of disorders. Previous work has shown that mesenchymal stem cells (MSCs) from older patients have reduced proliferation rates. As age is associated with greater musculoskeletal morbidity, e.g., osteoarthritis, an optimal MSC expansion strategy is required for older patients. In this in vitro study we investigate how age and gender affect MSC proliferation rate and cell surface characterization, as well as identify a relationship between seeding density and proliferation that could be applied to therapeutic MSC uses. Synovial fat pad derived MSCs were isolated and expanded from 14 patients undergoing total knee replacements. The cells were seeded at densities between 50 and 10,000 cells/cm(2) and cell proliferation studies, flow cytometry, and cell surface staining were performed. Females were found to have consistently higher cell proliferation and cell surface marker expression. The cell surface marker CD105 had a constant expression irrespective of age. A statistically significant inverse relationship was found between seeding densities and cell proliferation rates. This study has shown that patient characteristics do effect cell proliferation rate and cell surface characterization, but as seeding density has a significant relationship with proliferation rate, it can be altered, possibly along with other cell culturing strategies, to compensate for the effects of patient factors on MSCs. We have also shown that gender affects cell proliferation and cell surface characterization, something most previous studies may have failed to identify as they group male and female patients together. PMID- 22228599 TI - A posteriorly pedicled middle turbinate mucoperiosteal flap resurfacing nasopharynx after endoscopic nasopharyngectomy for recurrent nasopharyngeal carcinoma. PMID- 22228600 TI - Frontal sinus pneumocele associated with respiratory epithelial adenomatoid hamartoma and nasal polyps. PMID- 22228601 TI - The Draf III mucosal grafting technique: a prospective study. AB - OBJECTIVE: The Draf III procedure is an advanced surgical option for frontal sinus disease refractory to endoscopic frontal sinusotomy and is used to expose the anterior limit of resection of the skull base during endoscopic management of anterior skull base tumors. Our objective was to evaluate outcomes of a strategy using mucosal grafts to decrease postoperative closure. STUDY DESIGN: Prospective cohort. SETTING: Tertiary care facility. SUBJECTS AND METHODS: Patients requiring a Draf III procedure were prospectively enrolled in the study. Demographics, reason for the procedure, percentage graft viability, and complications were recorded. The primary outcome measure was anterior-posterior (AP) diameter at 3 months. RESULTS: Mucosal grafting was performed during 29 Draf III procedures from 2008 to 2011. Twenty-seven patients (average age, 58 years) were available for measurement at 3 months (average postoperative follow-up, 15.4 months; range, 3-30 months). Reasons for the procedure included tumor (n = 14), chronic rhinosinusitis (CRS) with frontal ostium stenosis (n = 12), and trauma (n = 1). Average intraoperative AP diameter was 11.7 mm. All patients met the definition of success (<50% reduction in diameter), maintaining a patent combined frontal sinus ostium for the duration of follow-up (average diameter 10.8 mm at 3 months). Nine patients with CRS and frontal ostium stenosis had openings similar to the entire cohort (>1-year follow-up; average, 19.3 months) with significant symptom reduction (SNOT-22 preop 62.3 +/- 20.8 vs 3 months 27.8 +/- 14.8 and 1 year 21.4 +/- 13.6; P < .0001). CONCLUSION: Cicatricial stenosis and osteoneogenesis are common following the Draf III procedure. This study indicates that the use of mucosal grafts may assist with postoperative stenosis and should be considered a routine strategy for preventing closure. PMID- 22228602 TI - Synthesis of main-chain metallo-copolymers containing donor and acceptor bis terpyridyl ligands for photovoltaic applications. AB - Two random (Zn(II)-based P1-P2) and two alternating (Ru(II)-based P3-P4) metallo copolymers containing bis-terpyridyl ligands with various central donor (i.e., fluorene or carbazole) and acceptor (i.e., benzothiadiazole) moieties were synthesized. The effects of electron donor-acceptor interactions with metal (Zn(II) and Ru(II)) ions on their thermal, optical, and electrochemical properties were investigated. Because of the strong ICT transitions between donor and acceptor ligands in both Zn(II)- and Ru(II)-based metallo-coplymers and MLCT transitions in Ru(II)-based metallo-coplymers, the absorption spectra covered a broad range of 260-750 nm with the band gaps of 1.57-1.77 eV. In addition, the introduction of Ru(II)-based metallo-coplymer P4 mixed with PC(60)BM as an active layer of the BHJ solar cell device exhibited the highest PCE value up to 0.90%. PMID- 22228603 TI - The role of physical therapists in smoking cessation: opportunities for improving treatment outcomes. PMID- 22228604 TI - Changes in body weight after total hip arthroplasty: short-term and long-term effects. AB - BACKGROUND: Elevated body weight is associated with hip osteoarthritis (OA) and subsequently with total hip arthroplasty (THA). Patients with hip OA who are overweight often mention their restricted mobility as a factor that thwarts their attempts to be physically active and lose weight. There is some evidence that THA increases physical activity, but none for losing body weight after THA. OBJECTIVE: The purpose of this study was to analyze the short-term (1-year) and long-term (4.5-year) effects of a THA on body weight. DESIGN: This was an observational, multicenter cohort study. METHODS: For the short-term effect, all patients (N=618) were analyzed; for the long-term effect, a random subgroup (n=100) was analyzed. Preoperative and postoperative body weight and height were self-reported. Patients were categorized according to their preoperative body mass index (BMI <25 kg/m(2)=normal weight, 25-30 kg/m(2)=overweight, >30 kg/m(2)=obese). Clinical relevancy was set at a minimum of 5% weight loss compared with baseline. RESULTS: The mean age of the study group was 70 years (SD=8), 74% were women, and mean preoperative body mass was 79 kg (SD=14). One year after THA, a significant decrease in body weight of 1% and 3.4% occurred for the overweight and obese BMI categories, respectively. After 4.5 years, a significant decrease in body weight of 6.4% occurred for the obese BMI category. LIMITATIONS: Height and weight-and thus BMI-were self-reported. CONCLUSION: Patients in the overweight and obese groups showed a decrease, albeit not clinically relevant, in body weight after 1 year. After 4.5 years, a decrease that was relevant clinically was observed in the patients who were obese. It can be concluded that no clinically relevant reduction of weight occurred after THA, except in the long term for patients who were obese. PMID- 22228605 TI - Use of visual and proprioceptive feedback to improve gait speed and spatiotemporal symmetry following chronic stroke: a case series. AB - BACKGROUND AND PURPOSE: Persistent deficits in gait speed and spatiotemporal symmetry are prevalent following stroke and can limit the achievement of community mobility goals. Rehabilitation can improve gait speed, but has shown limited ability to improve spatiotemporal symmetry. The incorporation of combined visual and proprioceptive feedback regarding spatiotemporal symmetry has the potential to be effective at improving gait. CASE DESCRIPTION: A 60-year-old man (18 months poststroke) and a 53-year-old woman (21 months poststroke) each participated in gait training to improve gait speed and spatiotemporal symmetry. Each patient performed 18 sessions (6 weeks) of combined treadmill-based gait training followed by overground practice. To assist with relearning spatiotemporal symmetry, treadmill-based training for both patients was augmented with continuous, real-time visual and proprioceptive feedback from an immersive virtual environment and a dual belt treadmill, respectively. OUTCOMES: Both patients improved gait speed (patient 1: 0.35 m/s improvement; patient 2: 0.26 m/s improvement) and spatiotemporal symmetry. Patient 1, who trained with step length symmetry feedback, improved his step-length symmetry ratio, but not his stance-time symmetry ratio. Patient 2, who trained with stance-time symmetry feedback, improved her stance-time symmetry ratio. She had no step-length asymmetry before training. DISCUSSION: Both patients made improvements in gait speed and spatiotemporal symmetry that exceeded those reported in the literature. Further work is needed to ascertain the role of combined visual and proprioceptive feedback for improving gait speed and spatiotemporal symmetry after chronic stroke. PMID- 22228606 TI - Use of quality indicators in physical therapist practice: an observational study. AB - BACKGROUND: The Patient Protection and Affordable Care Act and the Health Care and Education Reconciliation Act of 2010 contain provisions specific to health care quality that apply to physical therapists. Published evidence examining gaps in the quality of physical therapy services is limited. OBJECTIVE: The primary purpose of this study was to determine the use of quality indicators in physical therapist practice. DESIGN: This was an observational study. METHODS: All members of the Orthopaedic and Private Practice sections of the American Physical Therapy Association were invited to participate by completing an electronic survey. The survey included 22 brief patient descriptions, each followed by questions regarding the use of examinations and interventions based on the 2009 list of Medicare-approved quality measures. Separate multivariate logistic regression models were used to determine the odds ratios related to the performance of each examination and intervention on more than 90% of patients, given perceptions of its importance to care, the burden of performing it, and the level of evidence supporting its use. RESULTS: Participants (n=2,544) reported a relatively low frequency of performing examinations and interventions supporting primary and secondary prevention (3.6%-51.3%) and use of standardized measures (5.5%-35.8%). Perceptions of high importance and low burden were associated with greater odds of performing an examination or intervention. Importance and burden were more influential factors than the perceived availability of evidence to support use of identified techniques. LIMITATIONS: The survey was not assessed for test-retest reliability. A low response rate was a source of potential bias. CONCLUSION: The study findings suggest that physical therapists may not see themselves as providers of primary or secondary prevention services. Patient management strategies associated with these types of services also may be perceived as relatively unimportant or burdensome. PMID- 22228607 TI - Constraint-induced therapy with trunk restraint for improving functional outcomes and trunk-arm control after stroke: a randomized controlled trial. AB - BACKGROUND: Studies have suggested that constraint-induced therapy combined with trunk restraint (CIT-TR) improves arm movement and reduces trunk compensation. Whether participants who receive CIT-TR can translate the benefits to real-life circumstances awaits further investigation. OBJECTIVE: The effects of distributed CIT-TR (dCIT-TR) on motor function, daily function, quality of life (QOL), and arm-trunk control were investigated. DESIGN: The study was a single-blind, randomized controlled trial. SETTING: The study took place at 4 hospitals. PARTICIPANTS: Participants were 57 people who had had a stroke 6 to 55 months earlier. INTERVENTION: Participants received a dose-matched intervention (2 hours per day, 5 days per week, for 3 weeks) of dCIT-TR, distributed constraint-induced therapy (dCIT), or control therapy. MEASUREMENTS: The Action Research Arm Test (ARAT), Motor Activity Log, Frenchay Activities Index (FAI), and Stroke Impact Scale (SIS) were used to evaluate motor function, daily function, and QOL. Data for reaching kinematics were recorded. RESULTS: Participants receiving dCIT-TR and dCIT exhibited higher overall scores on the ARAT, FAI, and hand function domain of the SIS and better quality of movement and larger amount of use (of the affected arm) on the Motor Activity Log than participants in the control group. Participants receiving dCIT-TR further demonstrated greater improvements on the ARAT grip subscale and FAI outdoor activities scale than participants receiving dCIT or participants in the control group. However, participants receiving dCIT showed greater improvements on the strength domain of the SIS after training than participants receiving dCIT-TR or participants in the control group. Limitations Research with a larger sample size is needed. CONCLUSIONS: Participants who received dCIT-TR were able to translate gains in arm-trunk control into functional performance and QOL, specifically in grip function and outdoor activities. A long-term study to examine the recovery course for force output may be needed to evaluate people's perception of less improvement in strength after dCIT-TR. PMID- 22228608 TI - Shoulder position sense during passive matching and active positioning tasks in individuals with anterior shoulder instability. AB - BACKGROUND: Altered neuromuscular control due to compromised joint position sense may contribute to recurrent shoulder instability. OBJECTIVE: The purpose of the present study was to examine whether individuals with anterior shoulder instability exhibit larger shoulder position sense errors than those with healthy shoulders in both passive matching and active positioning. DESIGN: This was a between-groups study with repeated measures. METHODS: Ten people with anterior shoulder instability and 15 people with healthy shoulders participated in the study. Shoulder position sense was examined with 3 different protocols (passive motion to remembered shoulder rotation angles and active shoulder abduction and rotation to verbally specified positions) in positions of both mid-range and end range of motion. RESULTS: Participants with unstable shoulders exhibited significantly larger errors (by 1.8 degrees on average) in perception of shoulder position compared with those with healthy shoulders during passive matching. During active positioning, participants with unstable shoulders were able to voluntarily move the shoulder to verbally specified angles as accurately as those with healthy shoulders in both abduction (0.85 degrees difference) and rotation (0.99 degrees difference) tasks. CONCLUSIONS: Results of this study indicate that people with unstable shoulders can perceive shoulder angles as accurately as people with healthy shoulders in activities with voluntary arm movements. Compared with passive matching, better information from muscle spindles and other sources during voluntary arm movements may compensate for the potential joint position sense deficits after the injury. Therefore, individuals with an unstable shoulder may have adequate neuromuscular control to engage proper protective mechanisms to stabilize the shoulder joint during functional activities. PMID- 22228609 TI - Clinical decision making in exercise prescription for fall prevention. AB - BACKGROUND: Physical therapists often prescribe exercises for fall prevention. Understanding the factors influencing the clinical decision-making processes used by expert physical therapists working in specialist fall and balance clinics may assist other therapists in prescribing exercises for fall prevention with greater efficacy. OBJECTIVES: The objective of this study was to describe the factors influencing the clinical decision-making processes used by expert physical therapists to prescribe exercises for fall prevention. DESIGN: This investigation was a qualitative study from a phenomenological perspective. METHODS: Semistructured telephone interviews were conducted with 24 expert physical therapists recruited primarily from the Victorian Falls Clinic Coalition. Interviews focused on 3 exercise prescription contexts: face-to-face individual therapy, group exercise programs, and home exercise programs. Interviews elicited information about therapist practices and the therapist, patient, and environmental factors influencing the clinical decision-making processes for the selection of exercise setting, type, dosage (intensity, quantity, rest periods, duration, and frequency), and progression. Strategies for promoting adherence and safety were also discussed. Data were analyzed with a framework approach by 3 investigators. RESULTS: Participants described highly individualized exercise prescription approaches tailored to address key findings from physical assessments. Dissonance between prescribing a program that was theoretically correct on the basis of physiological considerations and prescribing one that a client would adhere to was evident. Safety considerations also were highly influential on the exercise type and setting prescribed. Terminology for describing the intensity of balance exercises was vague relative to terminology for describing the intensity of strength exercises. CONCLUSIONS: Physical therapists with expertise in fall prevention adopted an individualized approach to exercise prescription that was based on physical assessment findings rather than "off-the-shelf" exercise programs commonly used in fall prevention research. Training programs for people who prescribe exercises for older adults at risk of falling should encompass these findings. PMID- 22228610 TI - Vibration-induced motor responses of infants with and without myelomeningocele. AB - BACKGROUND: The severity of myelomeningocele (MMC) stems both from a loss of neurons due to neural tube defect and a loss of function in viable neurons due to reduced movement experience during the first year after birth. In young infants with MMC, the challenge is to reinforce excitability and voluntary control of all available neurons. Muscle vibration paired with voluntary movement may increase motoneuron excitability and contribute to improvements in neural organization, responsiveness, and control. OBJECTIVES: This study examined whether infants with or without MMC respond to vibration by altering their step or stance behavior when supported upright on a treadmill. DESIGN: This was a cross-sectional study. METHODS: Twenty-four 2- to 10-month-old infants, 12 with typical development (TD) and 12 with MMC (lumbar and sacral lesions), were tested. Infants were supported upright with their feet in contact with a stationary or moving treadmill during 30-second trials. Rhythmic alternating vibrations were applied to the right and left rectus femoris muscles, the lateral gastrocnemius muscle, or the sole of the foot. Two cameras and behavior coding were used to determine step count, step type, and motor response to vibration onset. RESULTS: Step count decreased and swing duration increased in infants with TD during vibration of the sole of the foot on a moving treadmill (FT-M trials). Across all groups the percentage of single steps increased during vibration of the lateral gastrocnemius muscle on a moving treadmill. Infants with MMC and younger infants with TD responded to onset of vibration with leg straightening during rectus femoris muscle stimulation and by stepping during FT-M trials more often than older infants with TD. CONCLUSIONS: Vibration seems a viable option for increasing motor responsiveness in infants with MMC. Follow-up studies are needed to identify optimal methods of administering vibration to maximize step and stance behavior in infants. PMID- 22228611 TI - Enhanced intracellular delivery and multi-target gene silencing triggered by tripodal RNA structures. AB - BACKGROUND: The development of gene interfering RNA (iRNA) molecules such as small interfering RNAs (siRNAs) and antagomirs provides promising therapeutic modalities for targeting specific mRNAs and microRNAs (miRNAs) involved in disease mechanisms. Therapeutic iRNA strategy against cancer or hypermutable viruses prefers targeting multiple genes simultaneously to achieve synergistic inhibition and to prevent resistance. METHODS: In the present study, we report chemically synthesized, multi-target gene interfering RNA structures based upon branched, tripodal interfering RNAs (termed T-tiRNAs). RESULTS: The T-tiRNAs could simultaneously inhibit up to three different mRNAs or miRNAs by harboring three siRNA or antagomir units. Moreover, when complexed with cationic delivery vehicles, T-tiRNAs showed enhanced gene interfering activity over conventional siRNAs or antagomirs as a result of increased intracellular delivery. CONCLUSIONS: The data obtained in the present study provide an example of synthetic multi-functional RNA structures that enable multiple gene interference in mammalian cells, which could become powerful tools for an efficient combinatorial iRNA strategy. PMID- 22228612 TI - Beneficial effects of swertiamarin on dyslipidaemia in streptozotocin-induced type 2 diabetic rats. AB - Dyslipidaemia is one of the major risk factors for cardiovascular disease in diabetes mellitus. Lipid changes associated with diabetes mellitus are attributed to increases in free fatty acid flux, secondary to insulin resistance. In the present study, we have investigated the beneficial effects of swertiamarin on dyslipidaemic conditions associated with type 2 diabetes in streptozotocin induced type 2 diabetic rats. Swertiamarin (50 mg/kg, i.p.) administered once a day for 6 weeks resulted in significant (p < 0.001) reductions in serum triglycerides, cholesterol and low-density lipoprotein levels in diabetic animals as compared with diabetic control animals. Serum fasting glucose was significantly (p < 0.05) decreased, moreover, the insulin sensitivity index was significantly (p < 0.05) increased in swertiamarin treated animals. Overall the data suggest that swertiamarin has beneficial effects on diabetic associated complications such as dyslipidaemia. PMID- 22228613 TI - Fit-for-purpose in veterinary drug residue analysis: development and validation of an LC-MS/MS method for the screening of thirty illicit drugs in bovine urine. AB - A selective and sensitive method for screening 31 analytes (nine corticosteroids, eight beta-agonists, seven anabolic steroids, six promazines and zeranol) in bovine urine was validated according to 2002/657/EC guidelines. Upon optimization of sample treatment conditions, the extraction was performed by diethylether at pH 9, after deconjugation. Extraction yields (R%) proved higher than 70% for 19 analytes, 5075% quartile (P = 0.009)]. Patients with pmKRAS levels higher than 75% had a disease control rate of 0% compared with 42% in patients with lower pmKRAS (P = 0.048). Cox analysis confirmed the prognostic importance of both cfDNA and pmKRAS. High levels were clear indicators of a poor outcome. CONCLUSIONS: KRAS analysis in plasma is a viable alternative to tissue analysis. Quantitative levels of cfDNA and pmKRAS are strongly correlated and hold promise of clinical application. PMID- 22228632 TI - Notch signaling promotes growth and invasion in uveal melanoma. AB - PURPOSE: To determine whether uveal melanoma, the most common primary intraocular malignancy in adults, requires Notch activity for growth and metastasis. EXPERIMENTAL DESIGN: Expression of Notch pathway members was characterized in primary tumor samples and in cell lines, along with the effects of Notch inhibition or activation on tumor growth and invasion. RESULTS: Notch receptors, ligands, and targets were expressed in all five cell lines examined and in 30 primary uveal melanoma samples. Interestingly, the three lines with high levels of baseline pathway activity (OCM1, OCM3, and OCM8) had their growth reduced by pharmacologic Notch blockade using the gamma-secretase inhibitor (GSI) MRK003. In contrast, two uveal melanoma lines (Mel285 and Mel290) with very low expression of Notch targets were insensitive to the GSI. Constitutively active forms of Notch1 and Notch2 promoted growth of uveal melanoma cultures and were able to rescue the inhibitory effects of GSI. MRK003 treatment also inhibited anchorage independent clonogenic growth and cell invasion and reduced phosphorylation levels of STAT3 and extracellular signal-regulated kinase (Erk)1/2. Suppression of canonical Notch activity using short hairpin RNA targeting Notch2 or CBF1 was also able to reduce tumor growth and invasion. Finally, intraocular xenograft growth was significantly decreased by GSI treatment. CONCLUSION: Our findings suggest that Notch plays an important role in inducing proliferation and invasion in uveal melanoma and that inhibiting this pathway may be effective in preventing tumor growth and metastasis. PMID- 22228633 TI - Phase II trial of temozolomide in patients with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker. AB - PURPOSE: This phase II study was conducted to assess the efficacy of temozolomide in patients with relapsed small cell lung cancer (SCLC). EXPERIMENTAL DESIGN: Patients with disease progression after one or two prior chemotherapy regimens received temozolomide at 75 mg/m(2)/d for 21 days of a 28-day cycle. The primary endpoint was the overall response rate [ORR; complete response (CR) plus partial response (PR)], which was evaluated separately in sensitive and refractory cohorts. In the available tissue, we assessed O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status by PCR and MGMT expression by immunohistochemistry. RESULTS: Sixty-four patients were accrued: 48 patients in the sensitive cohort and 16 in the refractory group. One CR and 10 PRs were noted in sensitive patients [ORR, 23%; 95% confidence interval (CI), 12%-37%]. Two PRs were seen in the refractory cohort (ORR, 13%; 95% CI, 2%-38%). As second- and third-line treatment, the ORR was 22% (95% CI, 9%-40%) and 19% (95% CI, 7% 36%), respectively. Among patients with target brain lesions, 38% had a CR or PR (95% CI, 14%-68%). Grade >=3 thrombocytopenia and neutropenia were observed in nine patients (14%). A greater number of cases with methylated MGMT had a response compared to those with unmethylated MGMT (38% vs. 7%; P = 0.08). CONCLUSION: Temozolomide has activity in relapsed SCLC, particularly for brain metastases. Response to temozolomide may correlate with MGMT methylation in SCLC. PMID- 22228634 TI - Immunochemotherapy with intensive consolidation for primary CNS lymphoma: a pilot study and prognostic assessment by diffusion-weighted MRI. AB - PURPOSE: We evaluated a novel therapy for primary central nervous system lymphoma (PCNSL) with induction immunochemotherapy with high-dose methotrexate, temozolomide, and rituximab (MT-R) followed by intensive consolidation with infusional etoposide and high-dose cytarabine (EA). In addition, we evaluated the prognostic value of the minimum apparent diffusion coefficient (ADC(min)) derived from diffusion-weighted MRI (DW-MRI) in patients treated with this regimen. EXPERIMENTAL DESIGN: Thirty-one patients (median age, 61 years; median Karnofsky performance score, 60) received induction with methotrexate every 14 days for 8 planned cycles. Rituximab was administered the first 6 cycles and temozolomide administered on odd-numbered cycles. Patients with responsive or stable central nervous system (CNS) disease received EA consolidation. Pretreatment DW-MRI was used to calculate the ADC(min) of contrast-enhancing lesions. RESULTS: The complete response rate for MT-R induction was 52%. At a median follow-up of 79 months, the 2-year progression-free and overall survival were 45% and 58%, respectively. For patients receiving EA consolidation, the 2-year progression free and overall survival were 78% and 93%, respectively. EA consolidation was also effective in an additional 3 patients who presented with synchronous CNS and systemic lymphoma. Tumor ADC(min) less than 384 * 10(-6) mm(2)/s was significantly associated with shorter progression-free and overall survival. CONCLUSIONS: MT-R induction was effective and well tolerated. MT-R followed by EA consolidation yielded progression-free and overall survival outcomes comparable to regimens with chemotherapy followed by whole-brain radiotherapy consolidation but without evidence of neurotoxicity. Tumor ADC(min) derived from DW-MRI provided better prognostic information for PCNSL patients treated with the MTR-EA regimen than established clinical risk scores. PMID- 22228635 TI - Detection of TIMP3 promoter hypermethylation in salivary rinse as an independent predictor of local recurrence-free survival in head and neck cancer. AB - PURPOSE: To validate a panel of methylation-based salivary rinse biomarkers (P16, CCNA1, DCC, TIMP3, MGMT, DAPK, and MINT31) previously shown to be independently associated with poor overall survival and local recurrence in a larger, separate cohort of patients with head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN: One hundred ninety-seven patients were included. All pretreatment saliva DNA samples were evaluated for the methylation status of the gene promoters by quantitative methylation-specific PCR. The main outcome measures were overall survival, local recurrence-free survival, and disease-free survival. RESULTS: In univariate analyses, the detection of hypermethylation of CCNA1, MGMT, and MINT31 was significantly associated with poor overall survival; the detection of hypermethylation of TIMP3 was significantly associated with local recurrence-free survival; and the detection of hypermethylation of MINT31 was significantly associated with poor disease-free survival. In multivariate analyses, detection of hypermethylation at any single marker was not predictive of overall survival in patients with HNSCC; detection of hypermethylation of TIMP3 in salivary rinse had an independent, significant association with local recurrence-free survival (HR = 2.51; 95% CI: 1.10-5.68); and none of the studied markers was significantly associated with disease-free survival. CONCLUSION: The detection of promoter hypermethylation of the seven genes in salivary rinse as an independent prognostic indicator of overall survival in patients with HNSCC was not validated. Detection of promoter hypermethylation of TIMP3 in pretreatment salivary rinse is independently associated with local recurrence-free survival in patients with HNSCC and may be a valuable salivary rinse biomarker for HNSCC recurrence. PMID- 22228636 TI - Combination of a novel gene expression signature with a clinical nomogram improves the prediction of survival in high-risk bladder cancer. AB - PURPOSE: We aimed to validate and improve prognostic signatures for high-risk urothelial carcinoma of the bladder. EXPERIMENTAL DESIGN: We evaluated microarray data from 93 patients with bladder cancer managed by radical cystectomy to determine gene expression patterns associated with clinical and prognostic variables. We compared our results with published bladder cancer microarray data sets comprising 578 additional patients and with 49 published gene signatures from multiple cancer types. Hierarchical clustering was utilized to identify subtypes associated with differences in survival. We then investigated whether the addition of survival-associated gene expression information to a validated postcystectomy nomogram utilizing clinical and pathologic variables improves prediction of recurrence. RESULTS: Multiple markers for muscle invasive disease with highly significant expression differences in multiple data sets were identified, such as fibronectin 1 (FN1), NNMT, POSTN, and SMAD6. We identified signatures associated with pathologic stage and the likelihood of developing metastasis and death from bladder cancer, as well as with two distinct clustering subtypes of bladder cancer. Our novel signature correlated with overall survival in multiple independent data sets, significantly improving the prediction concordance of standard staging in all data sets [mean DeltaC-statistic: 0.14; 95% confidence interval (CI), 0.01-0.27; P < 0.001]. Tested in our patient cohort, it significantly enhanced the performance of a postoperative survival nomogram (DeltaC-statistic: 0.08, 95% CI, -0.04-0.20; P < 0.005). CONCLUSIONS: Prognostic information obtained from gene expression data can aid in posttreatment prediction of bladder cancer recurrence. Our findings require further validation in external cohorts and prospectively in a clinical trial setting. PMID- 22228637 TI - Regulation of CD20 in rituximab-resistant cell lines and B-cell non-Hodgkin lymphoma. AB - PURPOSE: The aim of this research was to further investigate the contribution of CD20 antigen expression to rituximab activity and define the mechanisms responsible for CD20 downregulation in rituximab-resistant cell lines (RRCL). EXPERIMENTAL DESIGN: Rituximab-sensitive cell lines, RRCL, and primary neoplastic B cells were evaluated by chromium-51 release assays, ImageStream image analysis, immunohistochemical staining, flow cytometric analysis, CD20 knockdown, promoter activity, chromatin immunoprecipitation (ChIP) analysis of CD20 promoter, and CD20 plasmid transfection experiments to identify mechanisms associated with CD20 regulation in RRCL. RESULTS: RRCL exhibited a gradual loss of CD20 surface expression with repeated exposure to rituximab. We identified a CD20 antigen surface threshold level required for effective rituximab-associated complement mediated cytotoxicity (CMC). However, a direct correlation between CD20 surface expression and rituximab-CMC was observed only in rituximab-sensitive cell lines. CD20 promoter activity was decreased in RRCL. Detailed analysis of various CD20 promoter fragments suggested a lack of positive regulatory factors in RRCL. ChIP analysis showed reduced binding of several key positive regulatory proteins on CD20 promoter in RRCL. Interleukin-4 (IL-4) induced higher CD20 promoter activity and CD20 expression but modestly improved rituximab activity in RRCL and in primary B-cell lymphoma cells. Forced CD20 expression restored cytoplasmic but not surface CD20, suggesting the existence of a defect in CD20 protein transport in RRCL. CONCLUSIONS: We identified several mechanisms that alter CD20 expression in RRCL and showed that, whereas CD20 expression is important for rituximab activity, additional factors likely contribute to rituximab sensitivity in B-cell lymphoma. PMID- 22228639 TI - Epidermal growth factor receptor protein detection in head and neck cancer patients: a many-faceted picture. AB - PURPOSE: Epidermal growth factor receptor (EGFR) overexpression is associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC). Despite intensive biomarker studies, a consensual method for assessing EGFR protein expression is still lacking. Here we set out to compare three EGFR detection methods in tumor specimens from HNSCC patients. EXPERIMENTAL DESIGN: Tumors were prospectively excised from a series of 79 high-risk HNSCC patients enrolled in a GORTEC-sponsored clinical trial. EGFR expression was determined using a ligand binding assay on membranes, Western blotting (WB) on membranes and total homogenates, and immunohistochemistry (IHC) on tissue microarrays. In addition, phosphorylated EGFR (pEGFR) was measured by WB on membranes. RESULTS: Distributions and ranges of tumor EGFR expression were method dependent. Moderate positive correlations (Spearman coefficient r ~ 0.50) were observed between EGFR expression measured by the binding assay and WB or IHC. pEGFR levels positively and significantly correlated with total EGFR expression measured by WB or ligand binding, but not by IHC. The highest correlation (r = 0.85) was observed between EGFR and pEGFR levels, both measured by WB on membranes. Interestingly, the fraction of phosphorylated receptor (pEGFR/EGFR both measured by WB on membranes) significantly declined with increasing tumor EGFR expression, by all assessment methods used. CONCLUSION: This study shows significant correlations between EGFR detection methods. The observed relationships between EGFR and pEGFR indicate that high-throughput pEGFR/EGFR analyses merit further investigations and consideration for routine use in patient samples. PMID- 22228638 TI - Randomized phase II trial of sorafenib with temsirolimus or tipifarnib in untreated metastatic melanoma (S0438). AB - PURPOSE: Signaling pathway stimulation by activating mutations of oncogenes occurs in most melanomas and can provide excellent targets for therapy, but the short-term therapeutic success is limited by intrinsic and acquired resistance. The mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT/mTOR pathways are activated in most cutaneous melanomas. The purpose of this trial was to prospectively evaluate 2 molecularly targeted drug combinations in patients with untreated metastatic melanoma. EXPERIMENTAL DESIGN: This randomized phase II study enrolled patients between May 2008 and November 2009 with nonocular melanoma, no prior systemic chemotherapy, and no history of brain metastasis. Arm A received oral sorafenib 200 mg twice daily plus i.v. temsirolimus 25 mg weekly; and arm B received oral sorafenib 400 mg every morning, 200 mg every night daily plus oral tipifarnib 100 mg twice daily, 3 weeks of every 4. The primary objectives were to evaluate progression-free survival (PFS), objective response rate, and toxicity for the 2 regimens. RESULTS: On arm A (63 evaluable patients), the median PFS was 2.1 months and median overall survival (OS) was 7 months. Three patients achieved partial response (PR). Thirty-nine evaluable patients were accrued to arm B, which closed after first-stage accrual; the median PFS was 1.8 months and OS was 7 months, with 1 patient achieving PR. CONCLUSIONS: The combinations of molecularly targeted agents tested did not show sufficient activity to justify further use. Newer agents and improved patient selection by characterization of the molecular targets in individual tumors show great promise and should be incorporated into future studies, along with appropriate laboratory correlates. PMID- 22228640 TI - Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations. AB - PURPOSE: There is persistent controversy as to whether EGFR and KRAS mutations occur in pulmonary squamous cell carcinoma (SQCC). We hypothesized that the reported variability may reflect difficulties in the pathologic distinction of true SQCC from adenosquamous carcinoma (AD-SQC) and poorly differentiated adenocarcinoma due to incomplete sampling or morphologic overlap. The recent development of a robust immunohistochemical approach for distinguishing squamous versus glandular differentiation provides an opportunity to reassess EGFR/KRAS and other targetable kinase mutation frequencies in a pathologically homogeneous series of SQCC. EXPERIMENTAL DESIGN: Ninety-five resected SQCCs, verified by immunohistochemistry as DeltaNp63(+)/TTF-1(-), were tested for activating mutations in EGFR, KRAS, BRAF, PIK3CA, NRAS, AKT1, ERBB2/HER2, and MAP2K1/MEK1. In addition, all tissue samples from rare patients with the diagnosis of EGFR/KRAS-mutant "SQCC" encountered during 5 years of routine clinical genotyping were reassessed pathologically. RESULTS: The screen of 95 biomarker-verified SQCCs revealed no EGFR/KRAS [0%; 95% confidence interval (CI), 0%-3.8%], four PIK3CA (4%; 95% CI, 1%-10%), and one AKT1 (1%; 95% CI, 0%-5.7%) mutations. Detailed morphologic and immunohistochemical reevaluation of EGFR/KRAS-mutant "SQCC" identified during clinical genotyping (n = 16) resulted in reclassification of 10 (63%) cases as AD-SQC and five (31%) cases as poorly differentiated adenocarcinoma morphologically mimicking SQCC (i.e., adenocarcinoma with "squamoid" morphology). One (6%) case had no follow-up. CONCLUSIONS: Our findings suggest that EGFR/KRAS mutations do not occur in pure pulmonary SQCC, and occasional detection of these mutations in samples diagnosed as "SQCC" is due to challenges with the diagnosis of AD-SQC and adenocarcinoma, which can be largely resolved by comprehensive pathologic assessment incorporating immunohistochemical biomarkers. PMID- 22228641 TI - Changes in keratin expression during metastatic progression of breast cancer: impact on the detection of circulating tumor cells. AB - PURPOSE: Circulating tumor cells (CTC) might function as early markers for breast cancer metastasis or monitoring therapy efficacy. Enrichment and identification of CTCs are based on epithelial markers that might be modulated during epithelial mesenchymal transition. Little is known about the expression of keratins in CTCs and whether all CTCs can be detected with antibodies directed against a limited panel of keratins. EXPERIMENTAL DESIGN: Protein expression of keratin 2, 4-10, 13 16, 18, and 19 were assessed by a cocktail of antibodies (C11, AE1, AE3, and K7) and keratin antibodies C11 and A45-B/B3 alone in 11 breast cancer cell lines and 50 primary breast carcinomas and their lymph node metastases. Furthermore, CTCs were assessed in blood of 70 metastatic breast cancer patients. RESULTS: Claudin low cell lines did not show expression of normal breast epithelial keratins but were positive for K14 and K16, detected by the cocktail only. Primary breast carcinomas showed changes in keratin expression during metastatic progression to the lymph nodes. In 35 of 70 patients CTCs were identified, of which 83%, 40%, and 57% were identified by the cocktail, C11 and A45-B/B3, respectively. Identification of CTCs by the cocktail was associated with shorter survival (P < 0.01). In silico analyses revealed association between KRT16 expression and shorter relapse-free survival in metastatic breast cancer. CONCLUSION: Breast cancer cells show a complex pattern of keratin expression with potential biologic relevance. Individual keratin antibodies recognizing only a limited set of keratins inherit the risk to miss biologically relevant CTCs in cancer patients, and antibody cocktails including these keratins are therefore recommended. PMID- 22228643 TI - Change we can believe in: using perceptions of changeability to promote system change motives over system-justification motives in information search. AB - People are motivated to defend and rationalize the status quo, a phenomenon known as system justification. We propose the existence of a second, countervailing system-level motivation: system-change motivation, which is concerned with bettering the status quo over time. The opportunity to receive diagnostic information about the status quo pits the two system-level motives against each other. Whereas system justification promotes a preference for positive information about the status quo, system-change motivation promotes a preference for negative information about the status quo. In three experiments, we found that people preferred negative over positive feedback about the status quo when it was presented as being changeable. Our findings are the first to suggest the operation of a system-change motive. PMID- 22228642 TI - Does cannabis onset trigger cocaine onset? A case-crossover approach. AB - Psychiatric researchers tend to select the discordant co-twin design when they seek to hold constant genetic influence while estimating exposure-associated disease risk. The epidemiologic case-crossover research design developed for the past two decades represents a viable alternative, not often seen in psychiatric studies. Here, we turn to the epidemiologic case-crossover approach to examine the idea that cannabis onset is a proximal trigger for cocaine use, with the power of "subject-as-own-control" research used to hold constant antecedent characteristics of the individual drug user, including genetic influence and other traits experienced up to the time of the observed hazard and control intervals. Data are from newly incident cocaine users identified in the 2002-2006 US National Surveys on Drug Use and Health. Among these cocaine users, 48 had both cannabis onset and cocaine onset in the same month-long hazard interval; the expected value is 30 users, based on the control interval we had pre-specified for case-crossover estimation (estimated relative risk, RR = 1.6; exact mid-p = 0.042). Within the framework of a subject-as-own-control design, the evidence is consistent with the hypothesis that cannabis onset is a proximal trigger for cocaine use, with genetic influences (and many environmental conditions and processes) held constant. Limitations are noted and implications are discussed. PMID- 22228647 TI - Formaldehyde encapsulated in lithium-decorated metal-organic frameworks: a density functional theory study. AB - The stability of monomeric formaldehyde encapsulated in the lithium-decorated metal-organic framework Li-MOF-5 was investigated by means of density functional calculations with the M06-L functional and the 6-31G(d,p) basis set. To assess the efficiency of Li-MOF-5 for formaldehyde preservation, we consider the reaction kinetics and the thermodynamic equilibrium between formaldehyde and its trimerized product, 1,3,5-trioxane. We propose that trimerization of encapsulated formaldehyde takes place in a single reaction step with an activation energy of 34.5 kcal mol(-1). This is 17.2 kcal mol(-1) higher than the corresponding activation energy in the bare system. In addition, the reaction energy of the system studied herein is endothermic by 6.1 kcal mol(-1) and the Gibbs free energy (DeltaG) of the reaction becomes positive (11.0 kcal mol(-1)). Consequently, the predicted reverse rate for the trimerization reaction in the Li MOF-5 is significantly faster than the forward rate. The calculations show that the oligomerization of formaldehyde in Li-MOF-5 is a reversible reaction, suggesting that such a zeolite might be a good candidate material for preserving formaldehyde in its monomeric form. PMID- 22228644 TI - Carrot eaters or moving heads: inductive inference is better supported by salient features than by category labels. AB - How do words affect generalization, and how do these effects change during development? One theory posits that even early in development, linguistic labels function as category markers and thus are different from the features of the stimuli they represent. Another theory holds that early in development, labels are akin to other features, but that they may become category markers in the course of development. We addressed this issue in two experiments with 4- to 5 year-olds and adults. In both experiments, participants performed a categorization task (in which they predicted a category label) and an induction task (in which they predicted a missing feature). In the latter task, the category label was pitted against a highly salient feature, such that reliance on the label and reliance on the salient feature would result in different patterns of responses. Results indicated that children relied on the salient feature when performing induction, whereas many adults relied on the category label. These results suggest that early in development, labels are no more than features, but that they may become category markers in the course of development. PMID- 22228648 TI - Comparative efficiency of energy transfer from CdSe-ZnS quantum dots or nanorods to organic dye molecules. AB - Fluorescence resonance energy transfer (FRET) in conjugates of CdSe-ZnS semiconductor nanocrystals of different shapes (FRET donors) and an Alexa Fluor organic dye (FRET acceptors) is examined. The dye molecules are chemically conjugated with quantum dots (QDs) or nanorods (NRs) in dimethyl sulfoxide colloidal solutions, and FRET efficiency in the purified conjugates is measured. The FRET from NR to a single dye molecule is less efficient than that of the QD dye conjugates and this effect is explained in terms of distance-limited energy transfer rate in the case of a point-like acceptor and extended donor dipoles. However, the larger surface area of NRs allows for many more dye acceptors to be bound, and the total FRET efficiency in NR-dye conjugates approaches those of QD dye conjugates. PMID- 22228650 TI - Electrospun fiber template for replica molding of microtopographical neural growth guidance. AB - A method for replica molding electrospun (ES) fibers on the surface of polydimethylsiloxane (PDMS) is developed for culturing and guiding of cells, instead of ES fibers. With this method, microgrooves and microstructures composed of microgrooves can be obtained. PDMS is integrated into the microfluidic chip as a substrate to successfully pattern and guide neurites on the PDMS surface with microgrooves. PMID- 22228651 TI - Analysis of isoflavones in soybeans employing direct analysis in real-time ionization-high-resolution mass spectrometry. AB - A direct analysis in real-time (DART) ion source coupled to a high-resolution orbitrap mass spectrometer was used for the quantitative analysis of isoflavones isolated from soybeans. For the isolation of genistein, daidzein, glycitein, and their respective acetyl, malonyl, and glucoside forms, an extraction employing 80% aqueous MeOH enhanced by sonication was used. As far as the total isoflavones (expressed as aglycones) were to be determined, an acid hydrolysis with 80% aqueous EtOH and refluxing had to be employed, while in the latter case a good agreement of the results with the data generated by the UHPLC-orbitrap MS method was achieved, in the case of the analysis of non-hydrolyzed extracts, some overestimation of the results as compared with those generated by UHPLC-orbitrap MS was observed. A careful investigation of this phenomenon showed that the free aglycones originated from the conjugated forms of isoflavones in the DART ion source, thus contributing significantly to the "free" genistein/daidzein/glycitein signals during the DART analysis. Good recoveries (95-102%) and repeatabilities (RSD: 7-15%) were obtained at the spiking levels of 0.5, 1, and 0.05 g/kg, for daidzein, genistein, and glycitein, respectively. The limits of detection estimated for the respective analytes were 5 mg/kg. PMID- 22228652 TI - Sphingomyelinase selectively reduces M1 muscarinic receptors in rat hippocampal membranes. AB - Although there is evidence that nicotinic acetylcholine (Ach) receptors are influenced by ceramides, we do not currently know whether or not these sphingolipids can also regulate the muscarinic subtypes of Ach receptors. Using the whole-cell patch technique, we demonstrated that the effectiveness of the muscarinic receptor agonist pilocarpine, in enhancing spontaneous inhibitory postsynaptic currents in CA1 pyramidal cells, was completely abolished in hippocampal slices pre-exposed to the ceramide-generating enzyme sphingomyelinase (SMase). Western blot experiments, performed with biotinylated hippocampal membranes, showed that this electrophysiological defect possibly relies on the loss of M1 muscarinic Ach receptors at the cell surface. However, the effect appears to be relatively specific as the cell-surface expression of M4 muscarinic receptors was not found to be impacted by SMase treatment. Interestingly, we observed that G protein-coupled receptor kinases 2 and beta-arrestin1/2 interactions with M1-immunoprecipitated proteins were substantially augmented in SMase-treated slices and that the reduction of cell-surface M1 muscarinic receptor expression generated was completely suppressed by the muscarinic antagonist atropine. Collectively, our data suggest that selective internalization of M1 muscarinic receptors can be accentuated in neurons subjected to high ceramide levels. The potential physiopathological implications of this finding are presented. PMID- 22228653 TI - Alteribacillus bidgolensis gen. nov., sp. nov., a moderately halophilic bacterium from a hypersaline lake, and reclassification of Bacillus persepolensis as Alteribacillus persepolensis comb. nov. AB - A novel Gram-stain-positive, moderately halophilic bacterium, designated strain P4B(T), was isolated from water of the hypersaline Aran-Bidgol lake in Iran and characterized taxonomically by using a polyphasic approach. Cells of strain P4B(T) were non-motile rods producing ellipsoidal endospores at a central position in non-swollen sporangia. Strain P4B(T) was strictly aerobic and catalase- and oxidase-positive. It was able to grow at NaCl concentrations of 0.5 12.5% (w/v), with optimum growth occurring at 5-7.5% (w/v) NaCl. The optimum temperature and pH for growth were 35 degrees C and pH 7.0. On the basis of 16S rRNA gene sequence analysis, strain P4B(T) was shown to belong to the phylum Firmicutes and shared highest similarity with Bacillus persepolensis HS136(T) (97.1%) and Bacillus salarius BH169(T) (95.1%). However, it shared only 91.3% 16S rRNA gene sequence similarity with Bacillus subtilis subsp. subtilis DSM 10(T), indicating that strain P4B(T) might not be a member of the genus Bacillus. The DNA G+C content of this new isolate was 38.9 mol%. DNA-DNA hybridization experiments revealed a low level of relatedness between strain P4B(T) and B. persepolensis HS136(T) (6%). The major cellular fatty acids of strain P4B(T) were iso-C(15:0) and anteiso-C(15:0), as for B. persepolensis HS136(T) but in contrast to B. salarius DSM 16461(T) and B. subtilis subsp. subtilis DSM 10(T). Its polar lipid pattern consisted of phosphatidylglycerol, an aminoglycolipid and an unknown phospholipid. This polar lipid profile was similar to that obtained for B. persepolensis DSM 21632(T) but different from those of B. salarius DSM 16461(T) and B. subtilis subsp. subtilis DSM 10(T). The isoprenoid quinones were MK-7 (88%) and MK-8 (2%). The peptidoglycan contained meso-diaminopimelic acid as the diagnostic diamino acid. All these features indicate placement of strain P4B(T) within the Firmicutes, closely related to B. persepolensis but with features clearly distinct from those of the genus Bacillus and other related genera. On the basis of these data, strain P4B(T) is considered to represent a novel species of a new genus, for which the name Alteribacillus bidgolensis gen. nov., sp. nov. is proposed. The type strain of Alteribacillus bidgolensis is P4B(T) (=CCM 7963(T)=CECT 7998(T)=DSM 25260(T)=IBRC-M 10614(T)=KCTC 13821(T)). It is also suggested to transfer B. persepolensis to this new genus, as Alteribacillus persepolensis comb. nov. The type strain of Alteribacillus persepolensis is HS136(T) (=CCM 7595(T)=DSM 21632(T)=JCM 15720(T)=LMG 25222(T)). PMID- 22228654 TI - Lachnoanaerobaculum gen. nov., a new genus in the Lachnospiraceae: characterization of Lachnoanaerobaculum umeaense gen. nov., sp. nov., isolated from the human small intestine, and Lachnoanaerobaculum orale sp. nov., isolated from saliva, and reclassification of Eubacterium saburreum (Prevot 1966) Holdeman and Moore 1970 as Lachnoanaerobaculum saburreum comb. nov. AB - Two novel obligately anaerobic, Gram-stain-positive, saccharolytic and non proteolytic spore-forming bacilli (strains CD3:22(T) and N1(T)) are described. Strain CD3:22(T) was isolated from a biopsy of the small intestine of a child with coeliac disease, and strain N1(T) from the saliva of a healthy young man. The cells of both strains were observed to be filamentous, approximately 5 to >20 um long, some of them curving and with swellings. The novel organisms produced H(2)S, NH(3), butyric acid and acetic acid as major metabolic end products. Phylogenetic analyses, based on comparative 16S rRNA gene sequencing, revealed close relationships (98% sequence similarity) between the two isolates, as well as the type strain of Eubacterium saburreum and four other Lachnospiraceae bacterium-/E. saburreum-like organisms. This group of bacteria were clearly different from any of the 19 known genera in the family Lachnospiraceae. While Eubacterium species are reported to be non-spore-forming, reanalysis of E. saburreum CCUG 28089(T) confirmed that the bacterium is indeed able to form spores. Based on 16S rRNA gene sequencing, phenotypic and biochemical properties, strains CD3:22(T) and N1(T) represent novel species of a new and distinct genus, named Lachnoanaerobaculum gen. nov., in the family Lachnospiraceae [within the order Clostridiales, class Clostridia, phylum Firmicutes]. Strain CD3:22(T) (=CCUG 58757(T) =DSM 23576(T)) is the type strain of the type species, Lachnoanaerobaculum umeaense gen. nov., sp. nov., of the proposed new genus. Strain N1(T) (=CCUG 60305(T)=DSM 24553(T)) is the type strain of Lachnoanaerobaculum orale sp. nov. Moreover, Eubacterium saburreum is reclassified as Lachnoanaerobaculum saburreum comb. nov. (type strain CCUG 28089(T) =ATCC 33271(T) =CIP 105341(T) =DSM 3986(T) =JCM 11021(T) =VPI 11763(T)). PMID- 22228655 TI - Nocardioides lianchengensis sp. nov., an actinomycete isolated from soil. AB - A novel Gram-stain-positive, aerobic, rod-shaped bacterium, designated strain D94 1(T), was isolated from soil collected in Liancheng county, Fujian province, PR China. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain D94-1(T) was a member of the genus Nocardioides and was most closely related to Nocardioides salarius DSM 18239(T) (98.54% 16S rRNA gene sequence similarity), Nocardioides marinisabuli DSM 18965(T) (98.30%), Nocardioides basaltis KCTC 19365(T) (98.10%) and Nocardioides dokdonensis KCTC 19309(T) (97.76%). Phenotypic characteristics and DNA-DNA relatedness data served to distinguish strain D94-1(T) from N. salarius, N. marinisabuli, N. basaltis and N. dokdonensis. The chemotaxonomic properties of strain D94-1(T) were consistent with those of the genus Nocardioides: the cell-wall peptidoglycan type was based on ll-diaminopimelic acid, the predominant menaquinone was MK-8(H(4)) and the major fatty acids were iso-C(16:0) (29.15%) and anteiso-C(17:0) (21.0%). The DNA G+C content was 71.8 mol%. On the basis of the evidence presented in this study, strain D94-1(T) represents a novel species of the genus Nocardioides, for which the name Nocardioides lianchengensis sp. nov. is proposed. The type strain is D94 1(T) (=DSM 24663(T)=CGMCC 4.6858(T)). PMID- 22228656 TI - Rhodanobacter caeni sp. nov., isolated from sludge from a sewage disposal plant. AB - Two Gram-reaction-negative, motile bacteria, designated strains MJ01(T) and MJ14, were isolated from sludge collected from the Daejeon sewage disposal plant in South Korea. The taxonomic positions of both strains were determined using a polyphasic approach. In phylogenetic analyses based on 16S rRNA gene sequences, strains MJ01(T) and MJ14 appeared indistinguishable and to be most closely related to members of the genus Rhodanobacter in the family Xanthomonadaceae of the Gammaproteobacteria (96.4-98.8% sequence similarity). Strain MJ01(T) exhibited a relatively high level of DNA-DNA relatedness with strain MJ14 (89.3 %) but relatively low DNA-DNA relatedness values with established species in the genus Rhodanobacter (<60 %). The genomic DNA G+C contents of strains MJ01(T) and MJ14 were 65.3 and 64.8 mol%, respectively. The major respiratory quinone of both novel strains was the ubiquinone Q-8. The major fatty acids of both strains were iso-C(15 : 0), iso-C(16 : 0), iso-C(17:0) and iso-C(17 : 1)omega9c, and the polar lipid profiles of the two strains contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and minor amounts of unidentified aminophospholipids and phospholipids. Based on the phenotypic, genotypic and phylogenetic evidence, strains MJ01(T) and MJ14 represent a single novel species in the genus Rhodanobacter, for which the name Rhodanobacter caeni sp. nov. is proposed. The type strain is MJ01(T) ( = KCTC 22449(T) = JCM 16242(T)), with MJ14 ( = KCTC 22460 = JCM 16243) as a reference strain. PMID- 22228657 TI - Ruegeria conchae sp. nov., isolated from the ark clam Scapharca broughtonii. AB - A slightly halophilic, Gram-negative, strictly aerobic, non-motile rod, designated TW15(T), was isolated from an ark clam in South Korea. Growth occurred at 10-37 degrees C, with 1-5% (w/v) NaCl and at pH 7.0-10.0. Optimal growth occurred at 25-30 degrees C, with 2% (w/v) NaCl and at pH 8.0. Strain TW15(T) exhibited both oxidase and catalase activities. The major fatty acids of strain TW15(T) were summed feature 8 (consisting of C(18:1)omega7c and/or C(18:1)omega6c) and 11-methyl C(18:1)omega7c. The predominant isoprenoid quinone was ubiquinone-10 (Q-10). The polar lipids of strain TW15(T) comprised phosphatidylcholine, phosphatidylglycerol, diphosphatidylglycerol, an unidentified phospholipid, an unidentified aminolipid and five unidentified lipids. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain TW15(T) was most closely related to Ruegeria lacuscaerulensis DSM 11314(T) (98.0% 16S rRNA gene sequence similarity). DNA-DNA relatedness with closely related strains was <52 +/- 3%. The DNA G+C content was 55.7 mol%. On the basis of phenotypic, genotypic and phylogenetic data, strain TW15(T) represents a novel species of the genus Ruegeria, for which the name Ruegeria conchae sp. nov. is proposed. The type strain is TW15(T) ( = KACC 15115(T) = JCM 17315(T)). PMID- 22228658 TI - Mucilaginibacter litoreus sp. nov., isolated from marine sand. AB - A Gram-staining-negative, non-spore-forming, facultatively anaerobic, non flagellated, non-gliding, rod-shaped bacterium, designated strain BR-18(T), was isolated from marine sand collected on the western coast of South Korea. The taxonomic position of the novel strain was determined using a polyphasic approach. Strain BR-18(T) grew optimally at 25 degrees C, at pH 6.5-7.0 and in the absence of NaCl. In phylogenetic analyses based on 16S rRNA gene sequences, the novel strain fell within a clade comprising members of the genus Mucilaginibacter and appeared most closely related to Mucilaginibacter lutimaris BR-3(T) (96.6 % sequence similarity) and Mucilaginibacter rigui WPCB133(T) (95.9 %). The novel strain showed lower levels of 16S rRNA gene sequence similarity with the type strains of other members of the genus Mucilaginibacter (93.4-95.5 %) and those of other species included in the phylogenetic analyses (<91.6 %). Strain BR-18(T) contained MK-7 as its predominant menaquinone, summed feature 3 (C(16 : 1)omega7c and/or iso-C(15 : 0) 2-OH) and iso-C(15 : 0) as its major fatty acids, phosphatidylethanolamine and an unidentified aminophospholipid as its major polar lipids, and sphingolipids. The genomic DNA G+C content of the novel strain was 42.4 mol%. Based on the phylogenetic and phenotypic data, strain BR 18(T) represents a novel species of the genus Mucilaginibacter, for which the name Mucilaginibacter litoreus sp. nov. is proposed. The type strain is BR-18(T) ( = KCTC 23697(T) = CCUG 61484(T)). PMID- 22228659 TI - Rhodoplanes piscinae sp. nov. isolated from pond water. AB - Two strains (JA266(T) and JA333) of Gram-negative, rod-shaped, phototrophic, purple non-sulfur bacteria were isolated from a freshwater fish pond and an industrial effluent. Both strains were capable of phototrophic and chemotrophic growth. Bacteriochlorophyll a and carotenoids of the spirilloxanthin series were present as photosynthetic pigments. The major fatty acid for both strains was C(18 : 1)omega7c (>65 %), with minor amounts of 11-methyl C(18 : 1)omega7c, C(16 : 0), C(16 : 1)omega7c and C(18 : 0) also present. Both strains have the lamellar type of intracellular photosynthetic membranes. Ubiquinone-10 (Q(10)) and rhodoquinone-10 (RQ(10)) were present as primary quinone components. Diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and phosphatidylcholine were the major polar lipids, while minor amounts of amino lipids (AL1, AL2) and an unidentified lipid (L1) were common to both strains. The DNA G+C contents of strains JA266(T) and JA333 were 71.3 and 69.9 mol%, respectively. Phylogenetic analysis on the basis of 16S rRNA gene sequences showed that both strains clustered with members of the genus Rhodoplanes in the class Alphaproteobacteria. Strains JA266(T) and JA333 had gene sequence similarity of 98.7 and 98.9 % with Rhodoplanes serenus TUT3530(T), 96.4 and 96.5 % with Rhodoplanes elegans AS130(T), respectively, and less than 96 % with other members of the genus Rhodoplanes. 16S rRNA gene sequence similarity between the two strains was 99.3 % and they exhibited high (84.7 %) relatedness based on DNA DNA hybridization. Furthermore, both strains had less than 65 % DNA-DNA relatedness with the type strain R. serenus TUT3530(T). On the basis of phenotypic and genotypic data, it is proposed that strain JA266(T) be classified as a novel species of the genus Rhodoplanes, with the species name Rhodoplanes piscinae sp. nov. The type strain of the proposed novel species is JA266(T) ( = JCM 14934(T) = KCTC 5627(T)), while strain JA333 ( = NBRC 107574 = KCTC 5962) is an additional strain. PMID- 22228660 TI - Reclassification and emended description of Caulobacter leidyi as Sphingomonas leidyi comb. nov., and emendation of the genus Sphingomonas. AB - 'Caulobacter leidyi' DSM 4733(T) has been shown to be affiliated with the family Sphingomonadaceae instead of the Caulobacteraceae, and due to its poor characterization has been omitted from the current edition of Bergey's Manual of Systematic Bacteriology and removed to limbo. We isolated a novel sphingoglycolipid-containing dimorphic prosthecate bacterium, designated strain 247, from a pre-alpine freshwater lake. Strain 247 and 'Caulobacter leidyi' DSM 4733(T) were characterized in detail. The rod-shaped cells were Gram-stain negative, aerobic, catalase- and oxidase-positive, and formed a stalk or polar flagellum. Both strains grew optimally at 28-30 degrees C, and pH 6.0-8.0. The major fatty acids were C(18 : 1)omega7c, C(16 : 0) and 11-methyl C(18 : 1)omega7c. C(14 : 0) 2-OH represents the major 2-hydroxy fatty acid. Q-10 was the major respiratory quinone and the major polar lipids were diphosphatidylglycerol, phosphatidyldimethylethanolamine, phosphatidylglycerol, phosphatidylmonomethylethanolamine, phosphatidylethanolamine, phosphatidylcholine, three glycolipids, two phosphoaminolipids and two unidentified sphingoglycolipids. The major polyamine was sym-homospermidine. The G+C content of genomic DNA of strains 247 and DSM 4733(T) was 67.6 mol% and 67.0 mol%, respectively. According to 16S rRNA gene sequence analysis and DNA-DNA hybridization, strains DSM 4733(T) and 247 were phylogenetically closely related (99.6 % 16S rRNA gene sequence similarity, 82.9 % DNA-DNA hybridization value) and affiliated to the genus Sphingomonas. The closest recognized species was Sphingomonas aquatilis DSM 15581(T) (98.1 % sequence similarity). In addition, the presence of cystine arylamidase, absence of beta-galactosidase, and the inability to utilize l-arabinose, galactose and sucrose distinguished strains DSM 4733(T) and 247 from most other members of the family Sphingomonadaceae. So far, the dimorphic life cycle that involves a prosthecate and a flagellated stage is unique for strains DSM 4733(T) and 247 among all members of the family Sphingomonadaceae. Therefore, Caulobacter leidyi is reclassified as Sphingomonas leidyi, with the type strain DSM 4733(T) ( = ATCC 15260(T) = CIP 106443(T) = VKM B-1368(T)) and strain 247 (DSM 25078 = LMG 26658) as an additional strain of this species. PMID- 22228661 TI - Actibacterium mucosum gen. nov., sp. nov., a marine alphaproteobacterium from Mediterranean seawater. AB - Strain R46(T), a marine alphaproteobacterium, was isolated from Mediterranean seawater at Malvarrosa beach, Valencia, Spain. It is an aerobic chemo organotrophic, mesophilic and slightly halophilic organism, with complex ionic requirements. Phylogenetic analyses based on the 16S rRNA and gyrB gene sequences showed that strain R46(T) formed a separate branch within the family Rhodobacteraceae, bearing similarities below 94.7 and 80.3%, respectively, to any other recognized species. It contained Q10 as the predominant isoprenoid quinone and C(18:1)omega7c/C(18:1)omega6c as the major cellular fatty acid. Phosphatidylglycerol was the only identified polar lipid, although other lipids were also detected. The DNA G+C content of the genomic DNA was 61.3 mol%. On the basis of extensive phenotypic and phylogenetic comparative analysis, it is concluded that the strain represents a novel genus and species, for which the name Actibacterium mucosum gen. nov., sp. nov. is proposed. The type strain of the type species is Actibacterium mucosum R46(T) ( = CECT 7668(T) = KCTC 23349(T)). PMID- 22228662 TI - Deinococcus humi sp. nov., isolated from soil. AB - A Gram-staining-positive, strictly aerobic, spherical, non-motile, red-pigmented bacterium, designated strain MK03(T), was isolated from a soil sample collected in South Korea. The taxonomic position of the novel strain was investigated using a polyphasic approach. In phylogenetic analyses based on 16S rRNA gene sequences, strain MK03(T) was placed in a clade formed by members of the genus Deinococcus in the family Deinococcaceae and appeared to be most closely related to Deinococcus aerolatus 5516T-9(T) (97.4% sequence similarity), Deinococcus marmoris AA-63(T) (97.2%), Deinococcus radiopugnans ATCC 19172(T) (97.2%) and Deinococcus saxicola AA-1444(T) (96.9%). The genomic DNA G+C content of the novel strain was 64.5 mol%. The chemotaxonomic characteristics of strain MK03(T) were typical of members of the genus Deinococcus: MK-8 was identified as the predominant respiratory quinine, the major fatty acids were C(16:1)omega7c, C(15:1)omega6c, C(16:0) and C(15:0, )ornithine was found to be the diamino acid in the cell-wall peptidoglycan and the novel strain showed resistance to gamma radiation, with a D(10) value (i.e. the dose required to reduce the bacterial population by 10-fold) in excess of 9 kGy. In hybridization experiments, only low DNA-DNA relatedness values (11.6-34.5%) were recorded between the novel strain and its closest relatives in the genus Deinococcus. Based on the phylogenetic, chemotaxonomic, phenotypic and DNA-DNA relatedness data, strain MK03(T) represents a novel species of the genus Deinococcus, for which the name Deinococcus humi sp. nov. is proposed. The type strain is MK03(T) ( = KCTC 13619(T) = JCM 17915(T)). PMID- 22228663 TI - Mesorhizobium muleiense sp. nov., nodulating with Cicer arietinum L. AB - Three chickpea rhizobial strains (CCBAU 83963(T), CCBAU 83939 and CCBAU 83908), which were identified previously as representing a distinctive genospecies, were further studied here and compared taxonomically with related species in the genus Mesorhizobium. Results from SDS-PAGE of whole-cell soluble proteins revealed differences from closely related recognized species of the genus Mesorhizobium. Levels of DNA-DNA relatedness were 15.28-50.97% between strain CCBAU 83963(T) and the type strains of recognized Mesorhizobium species (except for Mesorhizobium thiogangeticum). Strain CCBAU 83963(T) contained fatty acids characteristic of members of the genus Mesorhizobium, but it possessed high concentrations of C(19:0) cyclo omega8c and iso-C(17:0). Strain CCBAU 83963(T) had phosphatidylcholine, phosphatidylethanolamine and phosphatidylglycerol as major polar lipids, and an ornithine-containing lipid, phosphatidyl-N dimethylethanolamine and cardiolipin as minor components. Nodulation tests demonstrated the distinct symbiotic character of strain CCBAU 83963(T); only Cicer arietinum, its host plant, could be invaded to form effective nitrogen fixing nodules. The narrow spectrum of utilization of sole carbon sources, lower resistance to antibiotics, and NaCl, pH and temperature growth ranges differentiated these novel rhizobia from recognized species of the genus Mesorhizobium. Based on the data presented, the three novel rhizobial strains are considered to represent a novel species of the genus Mesorhizobium, for which the name Mesorhizobium muleiense sp. nov. is proposed. The type strain is CCBAU 83963(T) (=HAMBI 3264(T)=CGMCC 1.11022(T)). PMID- 22228664 TI - Candida adriatica sp. nov. and Candida molendinolei sp. nov., two yeast species isolated from olive oil and its by-products. AB - Thirteen strains isolated from virgin olive oil or its by-products in several Mediterranean countries were found to be phenotypically and genetically divergent from currently recognized yeast species. Sequence analysis of the large subunit (LSU) rDNA D1/D2 domain and internal transcribed spacer regions/5.8S rDNA revealed that the strains represented two novel species described as Candida adriatica sp. nov. (type strain ZIM 2334(T) = CBS 12504(T) = NCAIM Y.02001(T)) and Candida molendinolei sp. nov. (type strain DBVPG 5508(T) = CBS 12508(T) = NCAIM Y.02000(T)). Phylogenetic analysis based on concatenated sequences of the small subunit rRNA gene, the D1/D2 region of the LSU rDNA and the translation elongation factor-1alpha gene suggested that C. adriatica sp. nov. and C. molendinolei sp. nov. should be placed within the Lindnera and Nakazawaea clades, respectively. PMID- 22228665 TI - Alpinimonas psychrophila gen. nov., sp. nov., an actinobacterium of the family Microbacteriaceae isolated from alpine glacier cryoconite. AB - A Gram-type positive, Gram-reaction variable, non-motile, psychrophilic actinobacterium, designated Cr8-25(T), was isolated from alpine glacier cryoconite and was able to grow well over a temperature range of 1-15 degrees C. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain Cr8 25(T) belonged to the family Microbacteriaceae and showed highest 16S rRNA gene sequence similarity with Klugiella xanthotipulae 44C3(T) (97.0%). However, strain Cr8-25(T) could be differentiated from the type strain of K. xanthotipulae on the level of genomospecies by a DNA-DNA relatedness value of only 37.2%. Strain Cr8 25(T) contained a cell-wall peptidoglycan that was cross-linked according to the B-type, which is based on 2,4-diaminobutyric acid. The cell wall contained the sugars galactose, fucose and rhamnose. The predominant cellular fatty acids of strain Cr8-25(T) were C(15:0) anteiso (64.6%) and iso-C(16:0) (22.5%) and the major menaquinones were MK-11 and MK-10. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and unknown glycolipids. The G+C content of the genomic DNA was 58.8 mol%. On the basis of the phenotypic characteristics, phylogenetic and chemotaxonomic analyses and DNA-DNA relatedness data, strain Cr8-25(T) represents a novel species of a new genus in the family Microbacteriaceae, for which the name Alpinimonas psychrophila gen. nov., sp. nov. is proposed. The type strain is Cr8-25(T) (=DSM 23737(T)=LMG 26215(T)). PMID- 22228666 TI - Arthrobacter cupressi sp. nov., an actinomycete isolated from the rhizosphere soil of Cupressus sempervirens. AB - An actinobacterial strain, designated D48(T), was isolated from the rhizosphere soil of a cypress tree collected from Mianyang in Sichuan province, China. The strain was Gram-stain-positive, catalase-positive, oxidase-negative and non motile, with lysine as the peptidoglycan diagnostic diamino acid and acetyl as the peptidoglycan acyl type. The predominant menaquinone was MK-9(H(2)); small amounts of MK-7(H(2)), MK-10(H(2)) and MK-6 were also present. The major fatty acids were anteiso-C(15:0), anteiso-C(17:0) and iso-C(16:0). The isolate underwent a rod-coccus morphological cycle, had a high DNA G+C content, was aerobic and grew between 12 and 37 degrees C (optimum, 28 degrees C). On the basis of the phenotypic and chemotaxonomic analyses, 16S rRNA gene sequence comparisons and DNA-DNA hybridization data, the isolate represents a novel species of the genus Arthrobacter, for which the name Arthrobacter cupressi sp. nov. is proposed. The type strain is D48(T) (=DSM 24664(T)=CGMCC 1.10783(T)). PMID- 22228668 TI - Phytohabitans flavus sp. nov., Phytohabitans rumicis sp. nov. and Phytohabitans houttuyneae sp. nov., isolated from plant roots, and emended description of the genus Phytohabitans. AB - An actinomycete strain, designated K09-0627(T), was isolated from the roots of an orchid collected in Okinawa Prefecture, Japan. Two actinomycete strains K11 0047(T) and K11-0057(T) were isolated from the roots of Rumex acetosa and Houttuynia cordata collected in Kanagawa Prefecture, Japan. 16S rRNA gene sequence analyses indicated that the isolates belonged to the genus Phytohabitans, and that they were closely related to each other and to Phytohabitans suffuscus K07-0523(T). The DNA-DNA relatedness values between the three isolates and Phytohabitans suffuscus were below 70%. On the basis of phylogenetic analysis, DNA-DNA relatedness values and phenotypic characteristics, the strains should be classified as novel species in the genus Phytohabitans, for which the names Phytohabitans flavus sp. nov. (type strain, K09-0627(T)=JCM 17387(T)=NBRC 107702(T)=DSM 45551(T)), Phytohabitans rumicis sp. nov. (type strain, K11-0047(T)=JCM 17829(T)=NBRC 108638(T)=BCC 48146(T)) and Phytohabitans houttuyneae sp. nov. (type strain, K11-0057(T)=JCM 17830(T)=NBRC 108639(T)=BCC 48147(T)) are proposed. PMID- 22228667 TI - Enteractinococcus coprophilus gen. nov., sp. nov., of the family Micrococcaceae, isolated from Panthera tigris amoyensis faeces, and transfer of Yaniella fodinae Dhanjal et al. 2011 to the genus Enteractinococcus as Enteractinococcus fodinae comb. nov. AB - A novel actinobacterium, designated strain YIM 100590(T), was isolated from Panthera tigris amoyensis faeces collected from Yunnan Wild Animal Park in Yunnan province, south-west China. Phylogenetic analysis based on 16S rRNA gene sequence data showed that strain YIM 100590(T) is a member of the family Micrococcaceae. Cells were coccoid to oval (0.7-1.5 um in diameter) occurring singly or in clusters. Growth was observed at 10-37 degrees C (optimum 28 degrees C) and at pH 7.0-11.0 (optimum pH 8.0). The major fatty acids were iso-C(15:0) (32.22%), anteiso-C(15:0) (31.64%) and iso-C(16:0) (17.38%). The peptidoglycan was of A4alpha type (L-Lys-Gly-L-Glu). The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannosides, dimannosyl diacylglycerol, an unknown glycolipid and two unknown phospholipids. The quinone system comprised menaquinones MK-7 (91.9%) and MK-8 (8.3%). The DNA G+C content of strain YIM 100590(T) was 56.2 mol%. Chemotaxonomic data indicated that the strain belongs to the family Micrococcaceae. On the basis of morphological and chemotaxonomic data and phylogenetic analysis, strain YIM 100590(T) is considered to represent a novel species of a new genus within the family Micrococcaceae, for which the name Enteractinococcus coprophilus gen. nov., sp. nov. is proposed. The type strain of Enteractinococcus coprophilus is YIM 100590(T) (=DSM 24083(T)=JCM 17352(T)). Yaniella fodinae DSM 22966(T) was transferred to the new genus as Enteractinococcus fodinae comb. nov. (type strain G5(T)=DSM 22966(T)=JCM 17931(T)=MTCC 9846(T)). PMID- 22228669 TI - Gordonia caeni sp. nov., isolated from sludge of a sewage disposal plant. AB - A Gram-stain-positive, strictly aerobic, short-rod-shaped, non-motile strain (designated MJ32(T)) was isolated from a sludge sample of the Daejeon sewage disposal plant in South Korea. A polyphasic approach was applied to study the taxonomic position of strain MJ32(T). Strain MJ32(T) showed highest 16S rRNA gene sequence similarity to Gordonia hirsuta DSM 44140(T) (98.1%) and Gordonia hydrophobica DSM 44015(T) (97.0%); levels of sequence similarity to the type strains of other recognized Gordonia species were less than 97.0%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain MJ32(T) belonged to the clade formed by members of the genus Gordonia in the family Gordoniaceae. The G+C content of the genomic DNA of strain MJ32(T) was 69.2 mol%. Chemotaxonomically, strain MJ32(T) showed features typical of the genus Gordonia. The predominant respiratory quinone was MK-9(H(2)), the mycolic acids present had C(56)-C(60) carbon atoms, and the major fatty acids were C(16:0) (34.6%), tuberculostearic acid (21.8%), C(16:1)omega7c (19.5%) and C(18:1)omega9c (12.7%). The peptidoglycan type was based on meso-2,6-diaminopimelic acid as the diagnostic diamino acid with glycolated sugars. On the basis of phylogenetic inference, fatty acid profile and other phenotypic properties, strain MJ32(T) is considered to represent a novel species of the genus Gordonia, for which the name Gordonia caeni sp. nov. is proposed. The type strain is MJ32(T) (=KCTC 19771(T)=JCM 16923(T)). PMID- 22228670 TI - Algiphilus aromaticivorans gen. nov., sp. nov., an aromatic hydrocarbon-degrading bacterium isolated from a culture of the marine dinoflagellate Lingulodinium polyedrum, and proposal of Algiphilaceae fam. nov. AB - A strictly aerobic, halotolerant, Gram-stain-negative, rod-shaped bacterium, designated strain DG1253(T), was isolated from a laboratory culture of the marine dinoflagellate Lingulodinium polyedrum (CCAP 1121/2). The strain was able to degrade two- and three-ring polycyclic aromatic hydrocarbons. It exhibited a narrow nutritional spectrum, preferring to utilize aliphatic and aromatic hydrocarbon compounds and small organic acids. Cells produced surface blebs and contained a single polar flagellum. The predominant isoprenoid quinone of strain DG1253(T) was Q-8. The fatty acid profile was dominated by C(18:1)omega7c. The mean DNA G+C content of strain DG1253(T) was 63.6 +/- 0.25 mol%. 16S rRNA gene sequence analysis placed this organism within the order Xanthomonadales of the class Gammaproteobacteria. Its closest relatives included representatives of the Hydrocarboniphaga-Nevskia-Sinobacter clade (<= 89.9% 16S rRNA gene sequence similarity) in the family Sinobacteraceae. On the basis of distinct phenotypic and genotypic characteristics, strain DG1253(T) is considered to represent a novel species of a new genus in the class Gammaproteobacteria, for which the name Algiphilus aromaticivorans gen. nov., sp. nov. is proposed. The type strain of the type species, Algiphilus aromaticivorans, is DG1253(T) (=ATCC BAA-2243(T)=DSM 24793(T)). In addition, a new family, Algiphilaceae fam. nov., is proposed to accommodate the genus Algiphilus. PMID- 22228671 TI - Kinematic design considerations for minimally invasive surgical robots: an overview. AB - BACKGROUND: Kinematic design is a predominant phase in the design of robotic manipulators for minimally invasive surgery (MIS). However, an extensive overview of the kinematic design issues for MIS robots is not yet available to both mechanisms and robotics communities. METHODS: Hundreds of archival reports and articles on robotic systems for MIS are reviewed and studied. In particular, the kinematic design considerations and mechanism development described in the literature for existing robots are focused on. RESULTS: The general kinematic design goals, design requirements, and design preferences for MIS robots are defined. An MIS-specialized mechanism, namely the remote center-of-motion (RCM) mechanism, is revisited and studied. Accordingly, based on the RCM mechanism types, a classification for MIS robots is provided. A comparison between eight different RCM types is given. Finally, several open challenges for the kinematic design of MIS robotic manipulators are discussed. CONCLUSIONS: This work provides a detailed survey of the kinematic design of MIS robots, addresses the research opportunity in MIS robots for kinematicians, and clarifies the kinematic point of view to MIS robots as a reference for the medical community. PMID- 22228672 TI - Standing arrays of gold nanorods end-tethered with polymer ligands. AB - Nanomaterials with vectoral electromagnetic properties have potential applications in solar cells, plasmonic cavity resonators, light polarizers, and biosensing. Here a new, simple, solution-based method for producing nanomaterials comprising vertically aligned standing arrays of gold nanorods (NRs) end functionalized with polymer ligands is reported. The method utilizes the side-by side assembly of the NRs into large 2D superlattices, followed by the precipitation of the lattices on a solid substrate. The critical design rules for the self-assembly of superlattices are demonstrated, and they show the generality of the method by forming standing arrays from the NRs end-tethered with poly(N vinylcarbazole) or with polystyrene molecules. PMID- 22228673 TI - Prescriptive contraceptive use among isotretinoin users in the Netherlands in comparison with non-users: a drug utilisation study. AB - PURPOSE: To assess the compliance with the isotretinoin Pregnancy Prevention Programme (PPP) by evaluating the use of prescribed contraceptives among isotretinoin users. The PPP contains a requirement for the use of contraceptive methods for women of childbearing potential. METHODS: A drug utilisation study was performed using data from a drug prescription database (containing Dutch community pharmacy data) covering a population of 500 000 patients. Contraceptive use in female isotretinoin users and in a reference group of female non isotretinoin users (aged 15-49 years) was compared using data from 1999 until 2006 in 2-year periods. Descriptive statistics were used. RESULTS: Of the female isotretinoin users (n = 651), 52%-54% filled prescriptions on contraceptives in strict accordance to the PPP, used before, during, and after discontinuation of isotretinoin, compared with 39%-46% in the reference group. A more liberal approach of a minimum of one prescription for a contraceptive method showed 61% 64% use of contraceptives among isotretinoin users. Similar patterns were seen when data were broken down in age groups. Furthermore, a higher proportion of female patients using isotretinoin prescribed by general practitioners used prescribed contraceptives compared with those receiving isotretinoin by specialists. CONCLUSION: Compliance with the contraceptive use according to a PPP for a teratogenic drug such as isotretinoin is 52%-64%, which is lower than anticipated. Reasons for the low compliance will need to be clarified before further measures can be taken. PMID- 22228674 TI - An opportunity not to be missed--how do we improve postpartum screening rates for women with gestational diabetes? AB - The ability to detect postpartum dysglycaemia, intervene and prevent type 2 diabetes in this high-risk population may be the most compelling reason to diagnose gestational diabetes. However, most studies show that less than 50% of women receive any glucose screening in the postpartum period and are thus denied this opportunity. Although many have advocated for simpler testing, the 75-g oral glucose tolerance test remains the gold standard as fasting glucose level will miss 30-40% of cases of type 2 diabetes and will not detect isolated impaired glucose tolerance. Haemoglobin A(1c) as a screening test has not been adequately studied. To improve postpartum screening rates, we need to increase awareness of the very high risk of type 2 diabetes, improve communication between providers, reduce fragmentation of care and introduce system factors that facilitate screening adherence. PMID- 22228675 TI - Highly size- and shape-controlled synthesis of silver nanoparticles via a templated Tollens reaction. AB - A mild, facile one-step synthetic strategy for the preparation of size- and shape controlled silver nanoparticles (AgNPs) is presented. The high degree of size- and shape-control of these AgNPs is achieved by the use of triazole sugar ligands scaffolded by a central resorcinol ether core. Both the triazoles and the resorcinol ether core mediate the nucleation, growth, and passivation phases of the preparation of AgNP in the presence of the Tollens reagent as the silver source. Kinetic and (1)H NMR titration data is presented describing the nature of the interactions between the Tollens reagent and these ligands. PMID- 22228676 TI - Clonal outbreak of ST17 multidrug-resistant Enterococcus faecium harbouring an Inc18-like::Tn1546 plasmid in a haemo-oncology ward of a Spanish hospital. AB - OBJECTIVES: To report a clonal outbreak of ST17 vancomycin-resistant Enterococcus faecium (VREfm) carrying Tn1546 (vanA) in a haemo-oncology ward of a tertiary teaching hospital in the south of Spain (January-September 2009). PATIENTS AND METHODS: Twenty-two VREfm strains from 13 patients were characterized by PFGE, multiple-locus variable-number tandem-repeat analysis (MLVA) and multilocus sequence typing (MLST). Genes encoding antibiotic resistance and putative virulence traits and the Tn1546 backbone were investigated by PCR. Plasmid characterization included determination of size (S1-PFGE) and replication modules (PCR, hybridization and sequencing). Patient clinical records were analysed retrospectively. RESULTS: A single ST17 E. faecium clone (MT-7 MLVA type) carrying esp and hyl plus a 30 kb Inc18-like::Tn1546 (IS1216) plasmid was identified. Ampicillin resistance was linked to PBP5 showing mutations at positions 24, 27, 34, 66, 68, 85, 100, 144, 172, 177, 204, 216, 324, 462, 466', 470, 485, 496, 499, 525, 546, 558, 582, 586, 629, 632, 642 and 667. Other resistance genes identified were erm(B), ant(6')-Ia and aph(3')-IIIa. Fluoroquinolone resistance was attributable to ParC (Arg-61 -> Gly and Ser-80 -> Arg) and GyrA (Ser-83 -> Arg) mutations. CONCLUSIONS: A nosocomial outbreak caused by an ST17 (CC17) E. faecium clone harbouring Esp and Hyl and a 30 kb Inc18-like::Tn1546 plasmid among haemo-oncology patients is reported. The failure of early infection control practices indicates an undetected reservoir and the ability of this strain to persist over long periods. The potential spread of epidemic clones and broad host plasmids carrying vancomycin resistance in Spain is of concern since it might contribute towards a higher rate of VREfm infection. PMID- 22228677 TI - Parental trust in health care--a prospective study from the Children's Cancer Hospital in Egypt. AB - OBJECTIVE: Patient-physician communication and patient satisfaction are important elements of cancer care. Trust is considered to be crucial for the patient physician relationship, yet little is to be found in the literature regarding what factors may influence trust. METHODS: We assessed predictors of trust in health-care professionals and in the medical care by administering two questionnaires, one at start of chemotherapy treatment and one at the time of the third chemotherapy cycle, to 304 parents of children with newly diagnosed cancer at the Children's Cancer Hospital in Cairo, Egypt. RESULTS: Parents' trust in the medical care at the time of the child's third chemotherapy cycle was significantly associated with the following at the start of treatment: having received at least moderate information about the disease (relative risk (RR) 13.2; 95% CI 7.8-22.3) and the treatment (RR 17.2; 95% CI 9.5-31.4), having the opportunity to communicate with the child's physicians (RR 21.3; 95% CI 11.7 38.8), being satisfied with the physicians conversation style (RR 30.6; 95% CI 14.4-64.9), having the emotional needs met (RR 22.2; 95% CI 11.8-41.9), and being met with care by the child's physicians (RR 32.0; 95% CI 15.2-67.7). After multivariable model selection, the strongest predictor of trust at the time of the third chemotherapy cycle was to be met with care at the start of treatment. CONCLUSION: Parents being met with care by the child's physicians at the beginning of the child's chemotherapy treatment develop an increased trust in the medical care. PMID- 22228678 TI - Through the looking glass: gestational diabetes as a predictor of maternal and offspring long-term health. AB - Gestational diabetes mellitus (GDM) is gaining in importance as a predictor of future health risks for women and their offspring. In women, it is associated with increased long-term risks of diabetes, metabolic syndrome and increased cardiovascular disorders. For offspring of mothers with GDM, risks of GDM include abnormal glucose tolerance, obesity and metabolic syndrome. This review presents the evidence for GDM as a predictor of long-term health risks for mothers and their offspring. We highlight GDM as an opportune time to screen for and possibly intervene to prevent adverse health outcomes for both women and their offspring. PMID- 22228680 TI - Pulling tethers from pore-spanning bilayers: towards simultaneous determination of local bending modulus and lateral tension of membranes. PMID- 22228679 TI - Enterocyte STAT5 promotes mucosal wound healing via suppression of myosin light chain kinase-mediated loss of barrier function and inflammation. AB - Epithelial myosin light chain kinase (MLCK)-dependent barrier dysfunction contributes to the pathogenesis of inflammatory bowel diseases (IBD). We reported that epithelial GM-CSF-STAT5 signalling is essential for intestinal homeostatic response to gut injury. However, mechanism, redundancy by STAT5 or cell types involved remained foggy. We here generated intestinal epithelial cell (IEC) specific STAT5 knockout mice, these mice exhibited a delayed mucosal wound healing and dysfunctional intestinal barrier characterized by elevated levels of NF-kappaB activation and MLCK, and a reduction of zonula occludens expression in IECs. Deletion of MLCK restored intestinal barrier function in STAT5 knockout mice, and facilitated mucosal wound healing. Consistently, knockdown of stat5 in IEC monolayers led to increased NF-kappaB DNA binding to MLCK promoter, myosin light chain phosphorylation and tight junction (TJ) permeability, which were potentiated by administration of tumour necrosis factor-alpha (TNF-alpha), and prevented by concurrent NF-kappaB knockdown. Collectively, enterocyte STAT5 signalling protects against TJ barrier dysfunction and promotes intestinal mucosal wound healing via an interaction with NF-kappaB to suppress MLCK. Targeting IEC STAT5 signalling may be a novel therapeutic approach for treating intestinal barrier dysfunction in IBD. PMID- 22228681 TI - Promotion and support of physical activity among cancer survivors: a service provider perspective. AB - OBJECTIVE: Cancer survivors are a population group at higher risk of a number of adverse health outcomes. Physical activity during and post-treatment is beneficial, yet participation in physical activity tends to be low amongst cancer survivors. There is still much to be learnt about how service providers can successfully translate research evidence about the benefits of physical activity for cancer survivors into effective and widely available interventions to support physical activity participation. The aim of this qualitative study is to describe some of the current approaches used by the Cancer Society of New Zealand (CSNZ) to supporting physical activity among survivors and the opportunities and challenges associated with this. METHODS: Participants were Supportive Care Managers and representatives of the CSNZ. A generic qualitative approach included semi-structured interviews, transcription, member checking and analysis via thematic coding by two of the research team. RESULTS: Four major themes frame the discussion of the results: (i) existing physical activity programmes and resources for cancer survivors; (ii) gaps and needs in the provision of physical activity programmes for cancer survivors; (iii) barriers, facilitators and preferences in relation to physical activity participation; and (iv) considerations for service providers involved in developing physical activity programmes for cancer survivors. CONCLUSIONS: The implications for future research and for service provision of physical activity programmes for cancer survivors are discussed. Potential strategies to increase physical activity participation among cancer survivors are put forward. PMID- 22228682 TI - Effect of patient age, breast density, and topical anesthetic cream on perceived pain with sentinel lymph node scintigraphy. AB - Although an extremely useful technique for sentinel lymph node (SLN) identification in breast cancer, injections of (99m)Tc-sulfur colloid can be quite painful. The purpose of this study was to determine whether there is a correlation between perceived pain of injection and age, breast density, or timing of topical anesthetic cream administration. METHODS: A retrospective review was conducted of women with breast cancer who received injections for sentinel lymphoscintigraphy from 2008 to 2010. After receiving 4 unilateral, intradermal, periareolar injections, women ranked their pain using a comparative scale (0 = no pain; 10 = unbearable pain). There were 3 categories based on length of time that topical anesthetic cream (2.5% lidocaine and 2.5% prilocaine) was applied before injection (1 h prior, 20 min prior, or no cream). In addition, other demographic information and breast density on mammography were analyzed for correlation with the comparative pain scale. RESULTS: Among the 82 women (mean age, 58 y; range, 32-87 y), a wide spectrum on the comparative pain scale was recorded (mean, 4.0; SD, 2.6), with 35% attesting to significant pain, rated 5 or greater. The demographic information and breast density per the Breast Imaging Reporting and Data System were retrospectively reviewed (density: fatty, 14.6%; scattered fibroglandular, 36.6%; heterogeneous, 39.0%; extremely dense, 9.8%). Using bivariate linear regression, no correlation between the comparative pain scale and age (R(2) = 0.0029, P = 0.63) or breast density (R(2) = 0.00049, P = 0.84) was identified. Most patients had topical anesthetic cream applied 20 min before injection (n = 47, or 57.3%) with 24 (29.3%) having topical anesthetic cream applied 1 h beforehand. Eleven women (13.4%) had no topical anesthetic cream applied because of patient preference or concern about allergy. Again, no correlation was found between comparative pain scale and time of application or use of topical anesthetic cream (Kruskal-Wallis: chi(2)(2) = 1.0, P = 0.61). CONCLUSION: A wide range of pain is experienced with sentinel lymphoscintigraphy injections. In this study, the severity of perceived pain did not correlate with age or breast density. There was no correlation between the use or timing of anesthetic cream and perceived pain from injection. The use of topical anesthetic cream may need to be reexamined, and other means of pain control should be further investigated. PMID- 22228683 TI - Verification of screening level for decontamination implemented after Fukushima nuclear accident. AB - The screening level for decontamination that has been applied for the surface of the human body and contaminated handled objects after the Fukushima nuclear accident was verified by assessing the doses that arise from external irradiation, ingestion, inhalation and skin contamination. The result shows that the annual effective dose that arises from handled objects contaminated with the screening level for decontamination (i.e. 100 000 counts per minute) is <1 mSv y( 1), which can be considered as the intervention exemption level in accordance with the International Commission on Radiological Protection recommendations. Furthermore, the screening level is also found to protect the skin from the incidence of a deterministic effect because the absorbed dose of the skin that arises from direct deposition on the surface of the human body is calculated to be lower than the threshold of the deterministic effect assuming a practical exposure duration. PMID- 22228684 TI - Rapid determination of 226Ra in urine samples. AB - A new radiochemical separation method has been developed for rapid analysis of (226)Ra in urine samples. In this method, radium is separated from urine matrix using cation and anion exchange column chromatography. A (224)Ra tracer is added, together with its parent in the (228)Th standard, for chemical recovery correction. After separation, the sample is precipitated with hydrous titanium oxide and then prepared for counting by creating a thin-layer counting source using BaSO(4) micro-precipitation. The radium isotopes are then counted by alpha spectrometry. Replicate spike and blank samples were analysed for validation of the procedure. The detection limit was determined to be 0.22 Bq l(-1) with 4 h of counting for 20 ml of urine sample. Using this method, the results can be reported within an 8 h turn-around time. This method is suitable for quick dose assessment of (226)Ra exposure following a radiation emergency. PMID- 22228685 TI - Development of a database of organ doses for paediatric and young adult CT scans in the United Kingdom. AB - Despite great potential benefits, there are concerns about the possible harm from medical imaging including the risk of radiation-related cancer. There are particular concerns about computed tomography (CT) scans in children because both radiation dose and sensitivity to radiation for children are typically higher than for adults undergoing equivalent procedures. As direct empirical data on the cancer risks from CT scans are lacking, the authors are conducting a retrospective cohort study of over 240,000 children in the UK who underwent CT scans. The main objective of the study is to quantify the magnitude of the cancer risk in relation to the radiation dose from CT scans. In this paper, the methods used to estimate typical organ-specific doses delivered by CT scans to children are described. An organ dose database from Monte Carlo radiation transport-based computer simulations using a series of computational human phantoms from newborn to adults for both male and female was established. Organ doses vary with patient size and sex, examination types and CT technical settings. Therefore, information on patient age, sex and examination type from electronic radiology information systems and technical settings obtained from two national surveys in the UK were used to estimate radiation dose. Absorbed doses to the brain, thyroid, breast and red bone marrow were calculated for reference male and female individuals with the ages of newborns, 1, 5, 10, 15 and 20 y for a total of 17 different scan types in the pre- and post-2001 time periods. In general, estimated organ doses were slightly higher for females than males which might be attributed to the smaller body size of the females. The younger children received higher doses in pre-2001 period when adult CT settings were typically used for children. Paediatric-specific adjustments were assumed to be used more frequently after 2001, since then radiation doses to children have often been smaller than those to adults. The database here is the first detailed organ-specific paediatric CT scan database for the UK. As well as forming the basis for the UK study, the results and description of the methods will also serve as a key resource for paediatric CT scan studies currently underway in other countries. PMID- 22228686 TI - Retraction: Acharya CR, et al. Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer. JAMA. 2008;299(13):1574 1587. PMID- 22228687 TI - Avoiding the slippery slope: preventing the development of diabetes in women with a history of gestational diabetes. AB - Women with a history of gestational diabetes are at increased risk of developing type 2 diabetes. By identifying this high-risk group who has not yet developed the disease, we have the opportunity to try to prevent this progression to diabetes. In this article, we review the evidence for different strategies used to prevent the onset of diabetes in women with a history of gestational diabetes. These strategies include lifestyle changes, medications and breastfeeding. PMID- 22228689 TI - BTJ - looking back to look ahead. PMID- 22228690 TI - Breaking down the walls to achieve interdisciplinary science and engineering. PMID- 22228694 TI - Biopharmaceutical process development - shortcut to market: an interview with Rolf Werner from Boehringer Ingelheim. PMID- 22228696 TI - Engineered redox-responsive PEG detachment mechanism in PEGylated nano-graphene oxide for intracellular drug delivery. AB - In biomedical applications, polyethylene glycol (PEG) functionalization has been a major approach to modify nanocarriers such as nano-graphene oxide for particular biological requirements. However, incorporation of a PEG shell poses a significant diffusion barrier that adversely affects the release of the loaded drugs. This study addresses this critical issue by employing a redox-responsive PEG detachment mechanism. A PEGylated nano-graphene oxide (NGO-SS-mPEG) with redox-responsive detachable PEG shell is developed that can rapidly release an encapsulated payload at tumor-relevant glutathione (GSH) levels. The PEG shell grafted onto NGO sheets gives the nanocomposite high physiological solubility and stability in circulation. It can selectively detach from NGO upon intracellular GSH stimulation. The surface-engineered structures are shown to accelerate the release of doxorubicin hydrochloride (DXR) from NGO-SS-mPEG 1.55 times faster than in the absence of GSH. Confocal microscopy shows clear evidence of NGO-SS mPEG endocytosis in HeLa cells, mainly accumulated in cytoplasm. Furthermore, upon internalization of DXR-loaded NGO with a disulfide-linked PEG shell into HeLa cells, DXR is effectively released in the presence of an elevated GSH reducing environment, as observed in confocal microscopy and flow cytometric experiments. Importantly, inhibition of cell proliferation is directly correlated with increased intracellular GSH concentrations due to rapid DXR release. PMID- 22228697 TI - Benefits and harms of mammography screening. PMID- 22228698 TI - A man with a blistering eruption and tuberculosis. PMID- 22228699 TI - Expert panel will examine feasibility of setting levels for drug driving. PMID- 22228700 TI - European doctors worry about the care they will receive when they are old. PMID- 22228701 TI - Inverse relationship of serum adiponectin concentration with type 2 diabetes mellitus incidence in middle-aged Japanese workers: six-year follow-up. AB - BACKGROUND: It was suggested that inflammation may mediate or modify biological effects of adiponectin. Few studies examined the association between circulating adiponectin levels and type 2 diabetes (T2DM) while controlling for variables related to inflammation. In addition, East Asians were reported to have lower adiponectin levels but higher diabetes prevalence at a given degree of obesity than Caucasians, raising some possibility that the adiponectin-diabetes association may differ by race. Therefore, we prospectively investigated the associations with a number of covariates including C-reactive protein and smoking status in a cohort of Japanese workers aged 35-66 years. METHODS: Serum adiponectin concentration and other covariates were obtained in 2002 for 3008 civil servants free of T2DM at baseline in urban/suburban Japan. T2DM incidence was defined as the year when annually assessed fasting blood glucose level first exceeded 126 mg/dL or self-reported initiation of medication through 2007. T2DM incidence was examined in relation to the adiponectin quintile. RESULTS: Age- and sex-adjusted homeostasis model assessment insulin resistance was inversely associated with adiponectin quintiles at baseline. During six years of follow-up, 164 individuals developed T2DM. In a fully adjusted model, hazard ratios (95% confidence intervals) of T2DM in Q2 to Q5 compared with that in Q1 were 0.62 (0.41-0.94), 0.44 (0.25-0.77), 0.40 (0.20-0.78) and 0.85 (0.48-1.49), respectively. CONCLUSIONS: Low adiponectin was related to increased incidence of T2DM independent of baseline levels of blood glucose, insulin and C-reactive protein as well as other confounding variables in middle-aged Japanese. Whether high adiponectin is linearly associated with decreased T2DM risk needs further investigation. PMID- 22228702 TI - An evaluation of cellulose saccharification and fermentation with an engineered Saccharomyces cerevisiae capable of cellobiose and xylose utilization. AB - Commercial-scale cellulosic ethanol production has been hindered by high costs associated with cellulose-to-glucose conversion and hexose and pentose co fermentation. Simultaneous saccharification and fermentation (SSF) with a yeast strain capable of xylose and cellobiose co-utilization has been proposed as a possible avenue to reduce these costs. The recently developed DA24-16 strain of Saccharomyces cerevisiae incorporates a xylose assimilation pathway and a cellodextrin transporter (CDT) that permit rapid growth on xylose and cellobiose. In the current work, a mechanistic kinetic model of cellulase-catalyzed hydrolysis of cellulose was combined with a multi-substrate model of microbial growth to investigate the ability of DA24-16 and improved cellobiose-consuming strains to obviate the need for exogenously added beta-glucosidase and to assess the impact of cellobiose utilization on SSF and separate hydrolysis and fermentation (SHF). Results indicate that improved CDT-containing strains capable of growing on cellobiose as rapidly as on glucose produced ethanol nearly as rapidly as non-CDT-containing yeast supplemented with beta-glucosidase. In producing 75 g/L ethanol, SSF with any strain did not result in shorter residence times than SHF with a 12 h saccharification step. Strains with improved cellobiose utilization are therefore unlikely to allow higher titers to be reached more quickly in SSF than in SHF. PMID- 22228703 TI - Predictive gold nanocluster formation controlled by metal-ligand complexes. AB - The formation of ligand-protected gold nanoclusters during size-selective syntheses is seemingly driven by the inherent properties of the protecting ligands, but a general description of the product formation has not been presented. This study uses diphosphine-protected Au clusters as a model system to examine i) control of metal-ligand complex distributions in methanol-chloroform solutions, ii) role of solution perturbations, e.g., oxidation, and iii) nanocluster formation through reduction of characterized complex distributions. By selectively reducing complexes and monitoring cluster formation with electrospray ionization mass spectrometry and UV-vis, data show the distribution of complexes can be controlled through ligand exchange, and the reduction of specific complexes produce characteristic ligated gold clusters based on ligand class. Specifically, 1,n-bis(diphenylphosphino)n-alkane ligands, L(n), where n = 1 through 6, are classified into two distinct sets. The classes represent ligands that either form mainly [AuL(n)(2)](+) (Class I, n = 1-3) or bridged [Au(2)L(n)(2)](2+) (Class II, n = 4-6) complexes after complete ligand exchange with AuClPPh(3). Selectively reducing gold-phosphine ligand complexes allows mapping of product formation, resulting collectively in a predictive tool for ligated gold cluster production by simply monitoring the initial complex distribution prior to reduction. PMID- 22228704 TI - REST regulates oncogenic properties of glioblastoma stem cells. AB - Glioblastoma multiforme (GBM) tumors are the most common malignant primary brain tumors in adults. Although many GBM tumors are believed to be caused by self renewing, glioblastoma-derived stem-like cells (GSCs), the mechanisms that regulate self-renewal and other oncogenic properties of GSCs are only now being unraveled. Here we showed that GSCs derived from GBM patient specimens express varying levels of the transcriptional repressor repressor element 1 silencing transcription factor (REST), suggesting heterogeneity across different GSC lines. Loss- and gain-of-function experiments indicated that REST maintains self-renewal of GSCs. High REST-expressing GSCs (HR-GSCs) produced tumors histopathologically distinct from those generated by low REST-expressing GSCs (LR-GSCs) in orthotopic mouse brain tumor models. Knockdown of REST in HR-GSCs resulted in increased survival in GSC-transplanted mice and produced tumors with higher apoptotic and lower invasive properties. Conversely, forced expression of exogenous REST in LR GSCs produced decreased survival in mice and produced tumors with lower apoptotic and higher invasive properties, similar to HR-GSCs. Thus, based on our results, we propose that a novel function of REST is to maintain self-renewal and other oncogenic properties of GSCs and that REST can play a major role in mediating tumorigenicity in GBM. PMID- 22228705 TI - A custom rat and baboon hypertension gene array to compare experimental models. AB - One challenge in understanding the polygenic disease of hypertension is elucidating the genes involved and defining responses to environmental factors. Many studies focus on animal models of hypertension; however, this does not necessarily extrapolate to humans. Current technology and cost limitations are prohibitive in fully evaluating hypertension within humans. Thus, we have designed a single-array platform that allows direct comparison of genes relevant to hypertension in animal models and non-human primates/human hypertension. The custom array is targeted to 328 genes known to be potentially related to blood pressure control. Studies compared gene expression in the kidney from normotensive rats and baboons. We found 74 genes expressed in both the rat and baboon kidney, 41 genes expressed in the rat kidney that were not detected in the baboon kidney and 34 genes expressed in the baboon kidney that were not detected in the rat kidney. To begin the evaluation of the array in a pathological condition, kidney gene expression was compared between the salt-sensitive deoxycorticosterone acetate (DOCA) rat model of hypertension and sham animals. Gene expression in the renal cortex and medulla from hypertensive DOCA compared with sham rats revealed three genes differentially expressed in the renal cortex: annexin A1 (up-regulated; relative intensity: 1.316 +/- 0.321 versus 2.312 +/- 0.283), glutamate-cysteine ligase (down-regulated; relative intensity: 3.738 +/- 0.174 versus 2.645 +/- 0.364) and glutathione-S transferase (down-regulated; relative intensity: 5.572 +/- 0.246 versus 4.215 +/- 0.411) and 21 genes differentially expressed in the renal medulla. Interestingly, few genes were differentially expressed in the kidney in the DOCA-salt model of hypertension; this may suggest that the complexity of hypertension may be the result of only a few gene-by-environment responsive events. PMID- 22228706 TI - Alteration in myocardial prostaglandin D synthase expression in pressure overload induced left ventricular remodeling in rats. AB - We hypothesized that acute pharmacological blockade of cyclooxygenase-2 (COX-2) using nimesulide (Nime) would prevent maladaptive changes in left ventricular (LV) structure and function secondary to abdominal aortic coarctation-induced pressure overload (PO). In vivo LV chamber dimension and function were assessed by pressure/volume admittance catheter at 14 days' postsurgery in three groups (n >= 6/group): sham-operated (Sham); untreated PO; and selective COX-2 inhibitor nimesulide-treated PO (PO + Nime; 25 mg/kg/d). Treatment was initiated 24 h prior to surgical induction of PO. Relative to Sham, there was a marked increase in LV mass index in the PO groups (2.2 +/- 0.01 mg/g versus 2.9 +/- 0.10 mg/g Sham versus PO, PO+Nime: 2.5 +/- 0.03 mg/g). End diastolic volume, an indicator of chamber size, was significantly decreased in the PO animals compared with Sham (202 +/- 17MUL versus 143 +/- 16 MUL Sham versus PO, PO + Nime: 226 +/- 9 MUL). Collagen levels in PO rats assessed by hydroxyproline analysis were significantly elevated relative to Sham values. Nimesulide treatment attenuated: (1) the increase in LV mass index; (2) the reduction in end diastolic volume; and (3) the PO-induced increase in myocardial collagen. In summary, acute COX-2 inhibition with nimesulide attenuated the maladaptive changes in the LV after PO. Acknowledging the clinical failure of chronic COX-2 inhibitor use, we propose that acute treatment with COX-2 inhibition during the initial stages of cardiac remodeling can be beneficial in maintaining the normal cardiac structure and function during PO. PMID- 22228708 TI - New design concepts for the fabrication of nanometric gap structures: electrochemical oxidation of OTS mono- and bilayer structures. PMID- 22228707 TI - Genotoxic stress and activation of novel DNA repair enzymes in human endothelial cells and in the retinas and kidneys of streptozotocin diabetic rats. AB - BACKGROUND: Mammalian excision repair cross-complementing 1 (ERCC1) and ERCC4 (a.k.a xeroderma pigmentosum complementation group F) are nucleotide excision repair enzymes, which excise the 5' end of damaged DNA. ERCC1 and ERCC4 have an interactive relationship with poly (adenosine diphosphate ribose) polymerase (PARP). We studied the role of ERCC1 and ERCC4 in glucose-induced extracellular matrix protein production in human endothelial cells and in the retinas and kidneys of streptozotocin diabetic rats. METHODS: Human umbilical vein endothelial cells were grown with low (5 mM) and high glucose (25 mM). The cells were subjected to ERCC1 and ERCC4 small interfering RNA transfections, PARP blocker (3-aminobenzamide, ABA) and p300 blocker (curcumin). Retinas and kidneys from 1-month-old streptozotocin diabetic rats with or without treatment with curcumin and ABA were examined. Cells and tissues were studied for oxidative stress markers, fibronectin, ERCC1 and ERCC4, PARP and p300 mRNA. Western blot of nuclear proteins was performed. RESULTS: ERCC1 and ERCC4 messenger RNA and protein levels were higher in high glucose than in low glucose, along with increasing oxidative stress and augmented p300 and fibronectin production. ABA, curcumin, ERCC1 and ERCC4 silencing reduced such upregulations and oxidative stress. Similar changes were seen in the kidneys and retinas of diabetic rats. ABA and curcumin treatment significantly reduced such changes. CONCLUSIONS: These data indicate that glucose-induced ERCC1 and ERCC4 upregulation leads to increased fibronectin production via a p300-dependent pathway in umbilical endothelial cells, as well as in the retina and in the kidneys of streptozotocin diabetic rats. ERCC1 and ERCC4 may play important roles in the development of diabetic retinopathy and nephropathy. PMID- 22228709 TI - A taxometric investigation of developmental dyslexia subtypes. AB - Long-standing issues with the conceptualization, identification and subtyping of developmental dyslexia persist. This study takes an alternative approach to examine the heterogeneity of developmental dyslexia using taxometric classification techniques. These methods were used with a large sample of 671 children ages 6-8 who were diagnosed with severe reading disorders. Latent characteristics of the sample are assessed in regard to posited subtypes with phonological deficits and naming speed deficits, thus extending prior work by addressing whether these deficits embody separate classes of individuals. Findings support separate taxa of dyslexia with and without phonological deficits. Different latent structure for naming speed deficits was found depending on the definitional criterion used to define dyslexia. Non phonologically based forms of dyslexia showed particular difficulty with naming speed and reading fluency. PMID- 22228710 TI - Preventing diabetes in women with gestational diabetes. AB - The immediate consequences of gestational diabetes on pregnancy are well known but the complications decades later for the mother and child are just now emerging. This trio of papers discuss the long-term consequences of gestational diabetes, the importance of screening this high risk group of women for type 2 diabetes, and the evidence for lifestyle, medications and breastfeeding for the prevention of type 2 diabetes in these women. PMID- 22228711 TI - In vivo imaging of the systemic delivery of small interfering RNA. AB - Short interfering RNAs (siRNAs) have emerged as a potent new class of therapeutics, which regulate gene expression through sequence-specific inhibition of mRNA translation. Human trials of siRNAs have highlighted the need for robust delivery and detection techniques that will enable the application of these therapeutics to increasingly complex disease and organ systems. Efforts to monitor the in vivo trafficking and efficacy of siRNAs have routinely involved bioluminescence imaging of naked siRNA molecules. More recently, siRNAs have been incorporated into a variety of molecular imaging probes to promote their detection with clinically relevant imaging modalities. Lipid-, polymer-, and nanoparticle-based siRNA delivery vehicles have proven effective in improving the stability, bioavailability, and target specificity of siRNAs following systemic administration in vivo. Additionally, these methods provide a platform to modify siRNAs with a variety of contrast agents and have enabled nuclear and magnetic resonance imaging of siRNA delivery in preclinical studies. These image-guided delivery approaches represent a crucial step in the transition of siRNA therapeutics to the clinic. PMID- 22228712 TI - Binary assembly of colloidal semiconductor nanorods with spherical metal nanoparticles. PMID- 22228713 TI - Heritable transmission of diabetic metabolic memory in zebrafish correlates with DNA hypomethylation and aberrant gene expression. AB - Metabolic memory (MM) is the phenomenon whereby diabetes complications persist and progress after glycemic recovery is achieved. Here, we present data showing that MM is heritable and that the transmission correlates with hyperglycemia induced DNA hypomethylation and aberrant gene expression. Streptozocin was used to induce hyperglycemia in adult zebrafish, and then, following streptozocin withdrawal, a recovery phase was allowed to reestablish a euglycemic state. Blood glucose and serum insulin returned to physiological levels during the first 2 weeks of the recovery phase as a result of pancreatic beta-cell regeneration. In contrast, caudal fin regeneration and skin wound healing remained impaired to the same extent as in diabetic fish, and this impairment was transmissible to daughter cell tissue. Daughter tissue that was never exposed to hyperglycemia, but was derived from tissue that was, did not accumulate AGEs or exhibit increased levels of oxidative stress. However, CpG island methylation and genome wide microarray expression analyses revealed the persistence of hyperglycemia induced global DNA hypomethylation that correlated with aberrant gene expression for a subset of loci in this daughter tissue. Collectively, the data presented here implicate the epigenetic mechanism of DNA methylation as a potential contributor to the MM phenomenon. PMID- 22228714 TI - CGI-58/ABHD5-derived signaling lipids regulate systemic inflammation and insulin action. AB - Mutations of comparative gene identification 58 (CGI-58) in humans cause Chanarin Dorfman syndrome, a rare autosomal recessive disease in which excess triacylglycerol (TAG) accumulates in multiple tissues. CGI-58 recently has been ascribed two distinct biochemical activities, including coactivation of adipose triglyceride lipase and acylation of lysophosphatidic acid (LPA). It is noteworthy that both the substrate (LPA) and the product (phosphatidic acid) of the LPA acyltransferase reaction are well-known signaling lipids. Therefore, we hypothesized that CGI-58 is involved in generating lipid mediators that regulate TAG metabolism and insulin sensitivity. Here, we show that CGI-58 is required for the generation of signaling lipids in response to inflammatory stimuli and that lipid second messengers generated by CGI-58 play a critical role in maintaining the balance between inflammation and insulin action. Furthermore, we show that CGI-58 is necessary for maximal TH1 cytokine signaling in the liver. This novel role for CGI-58 in cytokine signaling may explain why diminished CGI-58 expression causes severe hepatic lipid accumulation yet paradoxically improves hepatic insulin action. Collectively, these findings establish that CGI-58 provides a novel source of signaling lipids. These findings contribute insight into the basic mechanisms linking TH1 cytokine signaling to nutrient metabolism. PMID- 22228715 TI - Storage rates of circulating free fatty acid into adipose tissue during eating or walking in humans. AB - We measured subcutaneous adipose tissue free fatty acid (FFA) storage rates in postprandial and walking conditions to better understand the contributions of this pathway to body fat distribution. Palmitate tracers were infused intravenously and fat biopsies collected to measure palmitate storage in upper- (UBSQ) and lower-body subcutaneous (LBSQ) fat in 41 (17 men) and 40 (16 men) volunteers under postprandial and under postabsorptive walking conditions, respectively. Postprandial palmitate storage was greater in women than men in UBSQ (0.50+/-0.25 vs. 0.33+/-0.37 MUmol?kg fat(-1)?min(-1); P=0.007) and LBSQ fat (0.37+/-0.25 vs. 0.22+/-0.20 MUmol?kg fat(-1)?min(-1); P=0.005); storage rates were significantly greater in UBSQ than LBSQ fat in both sexes. During walking, UBSQ palmitate storage did not differ between sexes, whereas LBSQ storage was greater in women than men (0.40+/-0.22 vs. 0.25+/-0.15 MUmol?kg fat(-1)?min(-1); P=0.01). In women only, walking palmitate storage was significantly greater in LBSQ than UBSQ fat. Adipocyte CD36 and diacylglycerol acyltransferase (DGAT) correlated with LBSQ palmitate storage in the postprandial and walking condition, respectively. We conclude that UBSQ fat is the preferred postprandial FFA storage depot for both sexes, whereas walking favors storage in LBSQ fat in women. Transmembrane transport (CD36) and esterification into triglycerides (DGAT) may be rate-limiting steps for LBSQ FFA storage during feeding and exercise. PMID- 22228716 TI - Morbidly obese human subjects have increased peripheral blood CD4+ T cells with skewing toward a Treg- and Th2-dominated phenotype. AB - Obesity is associated with local T-cell abnormalities in adipose tissue. Systemic obesity-related abnormalities in the peripheral blood T-cell compartment are not well defined. In this study, we investigated the peripheral blood T-cell compartment of morbidly obese and lean subjects. We determined all major T-cell subpopulations via six-color flow cytometry, including CD8+ and CD4+ T cells, CD4+ T-helper (Th) subpopulations, and natural CD4+CD25+FoxP3+ T-regulatory (Treg) cells. Moreover, molecular analyses to assess thymic output, T-cell proliferation (T-cell receptor excision circle analysis), and T-cell receptor beta (TCRB) repertoire (GeneScan analysis) were performed. In addition, we determined plasma levels of proinflammatory cytokines and cytokines associated with Th subpopulations and T-cell proliferation. Morbidly obese subjects had a selective increase in peripheral blood CD4+ naive, memory, natural CD4+CD25+FoxP3+ Treg, and Th2 T cells, whereas CD8+ T cells were normal. CD4+ and CD8+ T-cell proliferation was increased, whereas the TCRB repertoire was not significantly altered. Plasma levels of cytokines CCL5 and IL-7 were elevated. CD4+ T-cell numbers correlated positively with fasting insulin levels. The peripheral blood T-cell compartment of morbidly obese subjects is characterized by increased homeostatic T-cell proliferation to which cytokines IL-7 and CCL5, among others, might contribute. This is associated with increased CD4+ T cells, with skewing toward a Treg- and Th2-dominated phenotype, suggesting a more anti inflammatory set point. PMID- 22228717 TI - TIMP3 overexpression in macrophages protects from insulin resistance, adipose inflammation, and nonalcoholic fatty liver disease in mice. AB - The tissue inhibitor of metalloproteinase (TIMP)3, a stromal protein that restrains the activity of proteases and receptors, is reduced in inflammatory metabolic disorders such as type 2 diabetes mellitus (T2DM) and atherosclerosis. We overexpressed Timp3 in mouse macrophages (MacT3) to analyze its potential antidiabetic and antiatherosclerotic effects. Transgenic mice with myeloid cells targeting overexpression of TIMP3 were generated and fed a high-fat diet for 20 weeks. Physical and metabolic phenotypes were determined. Inflammatory markers, lipid accumulation, and insulin sensitivity were measured in white adipose tissue (WAT), liver, and skeletal muscle. In a model of insulin resistance, MacT3 mice were more glucose tolerant and insulin sensitive than wild-type mice in both in vitro and in vivo tests. Molecular and biochemical analyses revealed that increased expression of TIMP3 restrained metabolic inflammation and stress related pathways, including Jun NH2-terminal kinase and p38 kinase activation, in WAT and liver. TIMP3 overexpression in macrophages resulted in reduced activation of oxidative stress signals related to lipid peroxidation, protein carbonylation, and nitration in WAT and liver. Our data show that macrophage-specific overexpression of TIMP3 protects from metabolic inflammation and related metabolic disorders such as insulin resistance, glucose intolerance, and nonalcoholic steatohepatitis. PMID- 22228718 TI - Activation of endoplasmic reticulum stress by hyperglycemia is essential for Muller cell-derived inflammatory cytokine production in diabetes. AB - Inflammation plays an important role in diabetes-induced retinal vascular leakage. The purpose of this study is to examine the role of endoplasmic reticulum (ER) stress and the signaling pathway of ER stress-induced activating transcription factor 4 (ATF4) in the regulation of Muller cell-derived inflammatory mediators in diabetic retinopathy. In diabetic animals, elevated ER stress markers, ATF4, and vascular endothelial growth factor (VEGF) expression were partially localized to Muller cells in the retina. In cultured Muller cells, high glucose induced a time-dependent increase of ER stress, ATF4 expression, and inflammatory factor production. Inducing ER stress or overexpressing ATF4 resulted in elevated intracellular adhesion molecule 1 and VEGF proteins in Muller cells. In contrast, alleviation of ER stress or blockade of ATF4 activity attenuated inflammatory gene expression induced by high glucose or hypoxia. Furthermore, we found that ATF4 regulated the c-Jun NH2-terminal kinase pathway resulting in VEGF upregulation. ATF4 was also required for ER stress-induced and hypoxia-inducible factor-1alpha activation. Finally, we showed that administration of chemical chaperone 4-phenylbutyrate or genetic inhibition of ATF4 successfully attenuated retinal VEGF expression and reduced vascular leakage in mice with STZ-induced diabetes. Taken together, our data indicate that ER stress and ATF4 play a critical role in retinal inflammatory signaling and Muller cell-derived inflammatory cytokine production in diabetes. PMID- 22228720 TI - MPs warn government over wasting aid money in fragile states. PMID- 22228719 TI - Common variants of IL6, LEPR, and PBEF1 are associated with obesity in Indian children. AB - The increasing prevalence of obesity in urban Indian children is indicative of an impending crisis of metabolic disorders. Although perturbations in the secretion of adipokines and inflammatory molecules in childhood obesity are well documented, the contribution of common variants of genes encoding them is not well investigated. We assessed the association of 125 common variants from 21 genes, encoding adipocytokines and inflammatory markers in 1,325 urban Indian children (862 normal weight [NW group] and 463 overweight/obese [OW/OB group]) and replicated top loci in 1,843 Indian children (1,399 NW children and 444 OW/OB children). Variants of four genes (PBEF1 [rs3801266] [P = 4.5 * 10(-4)], IL6 [rs2069845] [P = 8.7 * 10(-4)], LEPR [rs1137100] [P = 1.8 * 10(-3)], and IL6R [rs7514452] [P = 2.1 * 10(-3)]) were top signals in the discovery sample. Associations of rs2069845, rs1137100, and rs3801266 were replicated (P = 7.9 * 10(-4), 8.3 * 10(-3), and 0.036, respectively) and corroborated in meta-analysis (P = 2.3 * 10(-6), 3.9 * 10(-5), and 4.3 * 10(-4), respectively) that remained significant after multiple testing corrections. These variants also were associated with quantitative measures of adiposity (weight, BMI, and waist and hip circumferences). Allele dosage analysis of rs2069845, rs1137100, and rs3801266 revealed that children with five to six risk alleles had an approximately four times increased risk of obesity than children with less than two risk alleles (P = 1.2 * 10(-7)). In conclusion, our results demonstrate the association of the common variants of IL6, LEPR, and PBEF1 with obesity in Indian children. PMID- 22228721 TI - Ignoring evidence has led to ineffective drug policies, shows research. PMID- 22228722 TI - Doctors' views will be sought on direction of new IT strategy. PMID- 22228723 TI - Determining the most effective concentration of cypermethrin and the appropriate carrier particle size for fire ant (Hymenoptera: Formicidae) bait. AB - BACKGROUND: The purpose of this study was to determine the most effective particle size of DDGS (distiller's dried grains with solubles) as fire ant bait carrier, as well as the most effective concentration of cypermethrin as a toxicant against the red imported fire ant (RIFA) Solenopsis invicta Buren under laboratory conditions. RESULTS: The DDGS particle size did not affect the fire ant's preference for the bait, but it did affect the mass of DDGS being carried back to the nest. The size of the DDGS particles and the mass of DDGS being carried back to the nest were positively correlated. The most efficient particle size of DDGS was 0.8-2 mm. The concentration of cypermethrin has a specific range for killing fire ants in an efficient manner. Neither a very low nor a very high concentration of cypermethrin was able to kill fire ants efficiently. The most effective concentration of cypermethrin was 0.13% in DDGS when mixed with 15% shrimp shell powders and 11% soybean oil. CONCLUSION: Based on its ability to kill fire ants when mixed with cypermethrin, as well as the advantage of having a larger area coverage when sprayed in the field, DDGS as the carrier and cypermethrin as the toxicant can be considered to be an efficient way to prepare fire ant bait for controlling fire ants in infested areas. PMID- 22228724 TI - Visual hallucinations in the differential diagnosis of parkinsonism. AB - Visual hallucinations (VH) occur commonly in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) but are reported much less frequently in other neurodegenerative causes of parkinsonism, such as progressive supranuclear palsy, multiple system atrophy and corticobasal degeneration syndrome. This clinical sign may be helpful when considering the differential diagnosis of patients with parkinsonism. The observation that VH may be specific to Lewy body pathology probably reflects a greater vulnerability of the visual systems to PD and DLB neurodegeneration compared with other diseases. Topographic differences in pathology are probably the major factor producing VH in Lewy body diseases, rather than neurophysiological changes that are specific to alpha-synuclein protein accumulation. VH correlate with pathology in the limbic system and more specifically the amygdale that is frequently affected in PD and DLB but relatively preserved in other forms of parkinsonism often misdiagnosed as PD. In this review, the published frequencies of VH in these different conditions are compared to put into context the notion of VH as a clinical clue to underlying Lewy body pathology. PMID- 22228725 TI - Autopsy confirmed multiple system atrophy cases: Mayo experience and role of autonomic function tests. AB - BACKGROUND: Multiple system atrophy (MSA) is a sporadic progressive neurodegenerative disorder characterised by autonomic failure, manifested as orthostatic hypotension or urogenital dysfunction, with combinations of parkinsonism that is poorly responsive to levodopa, cerebellar ataxia and corticospinal dysfunction. Published autopsy confirmed cases have provided reasonable neurological characterisation but have lacked adequate autonomic function testing. OBJECTIVES: To retrospectively evaluate if the autonomic characterisation of MSA is accurate in autopsy confirmed MSA and if consensus criteria are validated by autopsy confirmation. METHODS: 29 autopsy confirmed cases of MSA evaluated at the Mayo Clinic who had undergone formalised autonomic testing, including adrenergic, sudomotor and cardiovagal functions and Thermoregulatory Sweat Test (TST), from which the Composite Autonomic Severity Score (CASS) was derived, were included in the study. RESULTS: PATIENT CHARACTERISTICS: 17 men, 12 women; age of onset 57+/-8.1 years; disease duration to death 6.5+/-3.3 years; first symptom autonomic in 18, parkinsonism in seven and cerebellar in two. Clinical phenotype at first visit was MSA-P (predominant parkinsonism) in 18, MSA-C (predominant cerebellar involvement) in eight, pure autonomic failure in two and Parkinson's disease in one. Clinical diagnosis at last visit was MSA for 28 cases. Autonomic failure was severe: CASS was 7.2+/-2.3 (maximum 10). TST% was 65.6+/-33.9% and exceeded 30% in 82% of patients. The most common pattern was global anhidrosis. Norepinephrine was normal supine (203.6+/ 112.7) but orthostatic increment of 33.5+/-23.2% was reduced. Four clinical features (rapid progression, early postural instability, poor levodopa responsiveness and symmetric involvement) were common. CONCLUSION: The pattern of severe and progressive generalised autonomic failure with severe adrenergic and sudomotor failure combined with the clinical phenotype is highly predictive of MSA. PMID- 22228727 TI - Impact commentaries. A prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project, 1981-86. PMID- 22228726 TI - Subcortical white matter hyperintensities within the cholinergic pathways of Parkinson's disease patients according to cognitive status. AB - BACKGROUND: White matter hyperintensities (WMH) in the cholinergic pathways show a stronger correlation with cognitive performance than general WMH in Alzheimer's disease. However, the role of WMH within the cholinergic pathways in cognitive dysfunction has not been investigated in Parkinson's disease (PD). METHOD: The severity of WMH within the cholinergic pathways of PD subgroups with intact cognition (PD-IC, n=44), mild cognitive impairment (PD-MCI, n=87) and dementia (PDD, n=40) were compared using the Cholinergic Pathways Hyperintensities Scale (CHIPS), and the correlation between the CHIPS score and performance on individual tests of cognitive subdomains were analysed. RESULTS: The mean CHIPS score was significantly higher in patients with PDD compared with those with PD IC (p=0.03) or PD-MCI (p=0.015). The CHIPS score in patients with PD was negatively correlated with general cognition assessed using the Mini-Mental State Examination (r=-0.28, p<0.001) and positively with the Unified Parkinson's Disease Rating Scale motor score (r=0.24, p=0.002). The CHIPS score showed a significant correlation with cognitive performance on individual cognitive subdomains and had the highest independent correlations with contrasting programme (beta=-0.33, p<0.001) and forward digit span (beta=-0.17, p=0.04). CONCLUSIONS: This study demonstrated that the burden of WMH within cholinergic pathways was significantly higher in patients with PDD relative to other groups, and that cholinergic WMH was significantly correlated with a decline in frontal executive function and attention. PMID- 22228728 TI - Impact commentaries. Functional abilities after stroke: measurement, natural history and prognosis. PMID- 22228729 TI - Improving the recruitment activity of clinicians in randomised controlled trials: a systematic review. AB - Background Poor recruitment to randomised controlled trials (RCTs) is a widespread problem. Provision of interventions aimed at supporting or incentivising clinicians may improve recruitment to RCTs. Objectives To quantify the effects of strategies aimed at improving the recruitment activity of clinicians in RCTs, complemented with a synthesis of qualitative evidence related to clinicians' attitudes towards recruiting to RCTs. Data sources A systematic review of English and non-English articles identified from: The Cochrane Library, Ovid MEDLINE, Ovid EMBASE, Ovid PsycINFO, Ebsco CINAHL, Index to Theses and Open SIGLE from 2001 to March 2011. Additional reports were identified through citation searches of included articles. Study eligibility criteria Quantitative studies were included if they evaluated interventions aimed at improving the recruitment activity of clinicians or compared recruitment by different groups of clinicians. Information about host trial, study design, participants, interventions, outcomes and host RCT was extracted by one researcher and checked by another. Studies that met the inclusion criteria were assessed for quality using a standardised tool, the Effective Public Health Practice Project tool. Qualitative studies were included if they investigated clinicians' attitudes to recruiting patients to RCTs. All results/findings were extracted, and content analysis was carried out. Overarching themes were abstracted, followed by a metasummary analysis. Studies that met the inclusion criteria were assessed for quality using the Critical Appraisal Skills Programme qualitative checklist. Data extraction Data extraction was carried out by one researcher using predefined data fields, including study quality indicators, and verified by another. Results Eight quantitative studies were included describing four interventions and a comparison of recruiting clinicians. One study was rated as strong, one as moderate and the remaining six as weak when assessed for quality using the Effective Public Health Practice Project tool. Effective interventions included the use of qualitative research to identify and overcome barriers to recruitment, reduction of the clinical workload associated with participation in RCTs and the provision of extra training and protected research time. Eleven qualitative studies were identified, and eight themes were abstracted from the data: understanding of research, communication, perceived patient barriers, patient-clinician relationship, effect on patients, effect on clinical practice, individual benefits for clinicians and methods associated with successful recruitment. Metasummary analysis identified the most frequently reported subthemes to be: difficulty communicating trial methods, poor understanding of research and priority given to patient well-being. Overall, the qualitative studies were found to be of good quality when assessed using the Critical Appraisal Skills Programme checklist. Conclusions There were few high-quality trials that tested interventions to improve clinicians' recruitment activity in RCTs. The most promising intervention was the use of qualitative methods to identify and overcome barriers to clinician recruitment activity. More good quality studies of interventions are needed to add to the evidence base. The metasummary of qualitative findings identified understanding and communicating RCT methods as a key target for future interventions to improve recruitment. Reinforcement of the potential benefits, both for clinicians and for their patients, could also be a successful factor in improving recruitment. A bias was found towards investigating barriers to recruitment, so future work should also encompass a focus on successfully recruiting trials. PMID- 22228730 TI - Characterization and functional analysis of atl, a novel gene encoding autolysin in Streptococcus suis. AB - Streptococcus suis serotype 2 (S. suis 2) is an important swine and human pathogen responsible for septicemia and meningitis. A novel gene, designated atl and encoding a major autolysin of S. suis 2 virulent strain HA9801, was identified and characterized in this study. The Atl protein contains 1,025 amino acids with a predicted molecular mass of 113 kDa and has a conserved N acetylmuramoyl-l-alanine amidase domain. Recombinant Atl was expressed in Escherichia coli, and its bacteriolytic and fibronectin-binding activities were confirmed by zymography and Western affinity blotting. Two bacteriolytic bands were shown in the sodium dodecyl sulfate extracts of HA9801, while both were absent from the atl inactivated mutant. Cell chains of the mutant strain became longer than that of the parental strain. In the autolysis assay, HA9801 decreased to 20% of the initial optical density (OD) value, while the mutant strain had almost no autolytic activity. The biofilm capacity of the atl mutant was reduced ~30% compared to the parental strain. In the zebrafish infection model, the 50% lethal dose of the mutant strain was increased up to 5-fold. Furthermore, the adherence to HEp-2 cells of the atl mutant was 50% less than that of the parental strain. Based on the functional analysis of the recombinant Atl and observed effects of atl inactivation on HA9801, we conclude that Atl is a major autolysin of HA9801. It takes part in cell autolysis, separation of daughter cells, biofilm formation, fibronectin-binding activity, cell adhesion, and pathogenesis of HA9801. PMID- 22228731 TI - Legionella pneumophila LidA affects nucleotide binding and activity of the host GTPase Rab1. AB - Legionella pneumophila, the causative agent of a severe pneumonia known as Legionnaires' disease, intercepts material from host cell membrane transport pathways to create a specialized vacuolar compartment that supports bacterial replication. Delivery of bacterial effector proteins into the host cell requires the Dot/Icm type IV secretion system. Several effectors, including SidM, SidD, and LepB, were shown to target the early secretory pathway by manipulating the activity of the host GTPase Rab1. While the function of these effectors has been well characterized, the role of another Rab1-interacting protein from L. pneumophila, the effector protein LidA, is poorly understood. Here, we show that LidA binding to Rab1 stabilized the Rab1-guanosine nucleotide complex, protecting it from inactivation by GTPase-activating proteins (GAPs) and from nucleotide extraction. The protective effect of LidA on the Rab1-guanine nucleotide complex was concentration dependent, consistent with a 1:1 stoichiometry of the LidA-Rab1 complex. The central coiled-coil region of LidA was sufficient for Rab1 binding and to prevent GAP-mediated inactivation or nucleotide extraction from Rab1. In addition, the central region mediated binding to phosphatidylinositol 3-phosphate and other phosphoinositides. When bound to Rab1, LidA interfered with the covalent modification of Rab1 by phosphocholination or AMPylation, and it also blocked de-AMPylation of Rab1 by SidD and dephosphocholination by Lem3. Based on these findings, we propose a role for LidA in bridging the membrane of the Legionella-containing vacuole (LCV) with that of secretory transport vesicles surrounding the LCV. PMID- 22228732 TI - Physiology of resistant Deinococcus geothermalis bacterium aerobically cultivated in low-manganese medium. AB - This dynamic proteome study describes the physiology of growth and survival of Deinococcus geothermalis, in conditions simulating paper machine waters being aerobic, warm, and low in carbon and manganese. The industrial environment of this species differs from its natural habitats, geothermal springs and deep ocean subsurfaces, by being highly exposed to oxygen. Quantitative proteome analysis using two-dimensional gel electrophoresis and bioinformatic tools showed expression change for 165 proteins, from which 47 were assigned to a function. We propose that D. geothermalis grew and survived in aerobic conditions by channeling central carbon metabolism to pathways where mainly NADPH rather than NADH was retrieved from the carbon source. A major part of the carbon substrate was converted into succinate, which was not a fermentation product but likely served combating reactive oxygen species (ROS). Transition from growth to nongrowth resulted in downregulation of the oxidative phosphorylation observed as reduced expression of V-type ATPase responsible for ATP synthesis in D. geothermalis. The battle against oxidative stress was seen as upregulation of superoxide dismutase (Mn dependent) and catalase, as well as several protein repair enzymes, including FeS cluster assembly proteins of the iron-sulfur cluster assembly protein system, peptidylprolyl isomerase, and chaperones. Addition of soluble Mn reinitiated respiration and proliferation with concomitant acidification, indicating that aerobic metabolism was restricted by access to manganese. We conclude that D. geothermalis prefers to combat ROS using manganese dependent enzymes, but when manganese is not available central carbon metabolism is used to produce ROS neutralizing metabolites at the expense of high utilization of carbon substrate. PMID- 22228733 TI - Three-dimensional structures of pathogenic and saprophytic Leptospira species revealed by cryo-electron tomography. AB - Leptospira interrogans is the primary causative agent of the most widespread zoonotic disease, leptospirosis. An in-depth structural characterization of L. interrogans is needed to understand its biology and pathogenesis. In this study, cryo-electron tomography (cryo-ET) was used to compare pathogenic and saprophytic species and examine the unique morphological features of this group of bacteria. Specifically, our study revealed a structural difference between the cell envelopes of L. interrogans and Leptospira biflexa involving variations in the lipopolysaccharide (LPS) layer. Through cryo-ET and subvolume averaging, we determined the first three-dimensional (3-D) structure of the flagellar motor of leptospira, with novel features in the flagellar C ring, export apparatus, and stator. Together with direct visualization of chemoreceptor arrays, DNA packing, periplasmic filaments, spherical cytoplasmic bodies, and a unique "cap" at the cell end, this report provides structural insights into these fascinating Leptospira species. PMID- 22228734 TI - Roles of long and short replication initiation proteins in the fate of IncP-1 plasmids. AB - Broad-host-range IncP-1 plasmids generally encode two replication initiation proteins, TrfA1 and TrfA2. TrfA2 is produced from an internal translational start site within trfA1. While TrfA1 was previously shown to be essential for replication in Pseudomonas aeruginosa, its role in other bacteria within its broad host range has not been established. To address the role of TrfA1 and TrfA2 in other hosts, efficiency of transformation, plasmid copy number (PCN), and plasmid stability were first compared between a mini-IncP-1beta plasmid and its trfA1 frameshift variant in four phylogenetically distant hosts: Escherichia coli, Pseudomonas putida, Sphingobium japonicum, and Cupriavidus necator. TrfA2 was sufficient for replication in these hosts, but the presence of TrfA1 enhanced transformation efficiency and PCN. However, TrfA1 did not contribute to, and even negatively affected, long-term plasmid persistence. When trfA genes were cloned under a constitutive promoter in the chromosomes of the four hosts, strains expressing either both TrfA1 and TrfA2 or TrfA1 alone, again, generally elicited a higher PCN of an IncP1-beta replicon than strains expressing TrfA2 alone. When a single species of TrfA was produced at different concentrations in E. coli cells, TrfA1 maintained a 3- to 4-fold higher PCN than TrfA2 at the same TrfA concentrations, indicating that replication mediated by TrfA1 is more efficient than that by TrfA2. These results suggest that the broad-host-range properties of IncP-1 plasmids are essentially conferred by TrfA2 and the intact replication origin alone but that TrfA1 is nonetheless important to efficiently establish plasmid replication upon transfer into a broad range of hosts. PMID- 22228735 TI - Regulation of bacteriocin production and cell death by the VicRK signaling system in Streptococcus mutans. AB - The VicRK two-component signaling system modulates biofilm formation, genetic competence, and stress tolerance in Streptococcus mutans. We show here that the VicRK modulates bacteriocin production and cell viability, in part by direct modulation of competence-stimulating peptide (CSP) production in S. mutans. Global transcriptome and real-time transcriptional analysis of the VicK-deficient mutant (SmuvicK) revealed significant modulation of several bacteriocin-related loci, including nlmAB, nlmC, and nlmD (P < 0.001), suggesting a role for the VicRK in producing mutacins IV, V, and VI. Bacteriocin overlay assays revealed an altered ability of the vic mutants to kill related species. Since a well conserved VicR binding site (TGTWAH-N(5)-TGTWAH) was identified within the comC coding region, we confirmed VicR binding to this sequence using DNA footprinting. Overexpression of the vic operon caused growth-phase-dependent repression of comC, comDE, and comX. In the vic mutants, transcription of nlmC/cipB encoding mutacin V, previously linked to CSP-dependent cell lysis, as well as expression of its putative immunity factor encoded by immB, were significantly affected relative to the wild type (P < 0.05). In contrast to previous reports that proposed a hyper-resistant phenotype for the VicK mutant in cell viability, the release of extracellular genomic DNA was significantly enhanced in SmuvicK (P < 0.05), likely as a result of increased autolysis compared with the parent. The drastic influence of VicRK on cell viability was also demonstrated using vic mutant biofilms. Taken together, we have identified a novel regulatory link between the VicRK and ComDE systems to modulate bacteriocin production and cell viability of S. mutans. PMID- 22228736 TI - A new susceptibility locus for estrogen receptor-negative breast cancer. PMID- 22228738 TI - PP13, decidual zones of necrosis, and spiral artery remodeling--preeclampsia revisited? PMID- 22228737 TI - DNA methylation: an epigenetic risk factor in preterm birth. AB - Spontaneous preterm birth (PTB; birth prior to 37 weeks of gestation) is a complex phenotype with multiple risk factors that complicate our understanding of its etiology. A number of recent studies have supported the hypothesis that epigenetic modifications such as DNA methylation induced by pregnancy-related risk factors may influence the risk of PTB or result in changes that predispose a neonate to adult-onset diseases. The critical role of timing of gene expression in the etiology of PTB makes it a highly relevant disorder in which to examine the potential role of epigenetic changes. Because changes in DNA methylation patterns can result in long-term consequences, it is of critical interest to identify the epigenetic patterns associated with adverse pregnancy outcomes. This review examines the potential role of DNA methylation as a risk factor for PTB and discusses several issues and limitations that should be considered when planning DNA methylation studies. PMID- 22228739 TI - Decreased spermatogenesis, fertility, and altered Slc2A expression in Akt1-/- and Akt2-/- testes and sperm. AB - Akt is serine/threonine protein kinase associated with various cellular processes and 3 different isoforms exist. This work describes the reproductive phenotype of Akt1-/- and Akt2-/- in male mice. The seminiferous tubule diameter in Akt1-/- testes was less than wild-type or Akt2-/- testes. The expression of phospho phosphatase and tensin homologue deleted on chromosome 10 (p-PTEN) and phospho glycogen synthase kinase 3beta (GSK-3beta) was elevated in Akt1-/- testes. Alterations in expression and localization to the plasma membrane of several facilitative glucose transporters (Slc2a8, 9a and 9b) were detected in these knockout compared to wild-type mice. Apoptotic sperm were more prevalent in both null mice compared to wild-type mice, whereas sperm concentration and motility were significantly lower in the null sperm. Finally, Akt2-/- sperm had a markedly decreased fertilization rate by in vitro fertilization (IVF) and resulting embryos displayed increased fragmentation and poor growth. These results suggest that altered SLC2A expression and increased PTEN and GSK3beta activity may be responsible for the decreased spermatogenesis, sperm maturation, and fertilization in the Akt1-/- and Akt2-/- male mice. PMID- 22228740 TI - Myometrial tumor necrosis factor-alpha receptors increase with gestation and labor and modulate gene expression through mitogen-activated kinase and nuclear factor-kappaB. AB - Previously, we found that myometrial tumor necrosis factor-alpha (TNF-alpha) messenger RNA (mRNA) expression did not increase with preterm or term labor. To further investigate the role of TNF-alpha in human labor, we studied TNF-alpha receptor (TNFR1A and B) expression, regulation, and associated intracellular signaling pathways in human myometrial samples obtained both before and after the onset of labor and in primary cultures of uterine smooth muscle cells (USMCs). We found that the mRNA expression of both receptors increased with advancing gestation and labor and protein levels of TNFR1B were significantly higher in term laboring myometrial samples than in nonlabor controls. Tumor necrosis factor treatment of USMCs activated all mitogen-activated protein kinase (MAPK) subtypes and nuclear factor kappa-B (NF-kappaB). The TNF-alpha induced increases in the expression of TNFR1B and prostaglandin H synthase type 2 were reduced by inhibitors of NF-kappaB and MAPKs, respectively. The TNF-alpha induced increase in interleukin 8 (IL-8) appeared to be independent of MAPK and NF-kappaB pathway. These data suggest that the uterus may become more sensitive to the action of TNF alpha with advancing gestation and labor and that TNF-alpha acts via MAPK and NF kappaB to promote labor-associated gene expression. PMID- 22228741 TI - Dehydroepiandrosterone (DHEA) inhibition of monocyte binding by vascular endothelium is associated with sialylation of neural cell adhesion molecule. AB - RATIONALE: Adhesion of monocytes to vascular endothelium is necessary for atheroma formation. This adhesion requires binding of endothelial neural cell adhesion molecule (NCAM) to monocyte NCAM. NCAM:NCAM binding is blocked by sialylation of NCAM (polysialylated NCAM; PSA-NCAM). Since estradiol (E2) and dihydrotestosterone (DHT) induced PSA-NCAM and decreased monocyte adhesion, in consideration of possible clinical applications we tested whether their prohormone dehydroepiandrosterone (DHEA) has similar effects. EXPERIMENTAL: (1) DHEA was administered to cultured human coronary artery endothelial cells (HCAECs) from men and women. Monocyte binding was assessed using fluorescence labeled monocytes. (2) HCEACs were incubated with E2, DHT, DHEA alone, or with trilostane, fulvestrant or flutamide. Expression of PSA-NCAM was assessed by immunohistochemistry and Western blotting. RESULTS: Dehydroepiandrosterone inhibited monocyte adhesion to HCAECs by >=50% (P < .01). Fulvestrant or flutamide blockade of DHEA's inhibition of monocyte binding appeared to be gender dependent. The DHEA-induced expression of PSA-NCAM was completely blocked by trilostane. CONCLUSIONS: In these preliminary in vitro studies, DHEA increased PSA-NCAM expression and inhibited monocyte binding in an estrogen- and androgen receptor-dependent manner. Dehydroepiandrosteroneappears to act via its end metabolites, E2 and DHT. Dehydroepiandrosterone could furnish clinical prevention against atherogenesis and arteriosclerosis. PMID- 22228742 TI - Variants in the SIRT1 gene may affect diabetes risk in interaction with prenatal exposure to famine. AB - OBJECTIVE: To investigate whether SIRT1, a nutrient-sensing histone deacetylase, influences fetal programming during malnutrition. RESEARCH DESIGN AND METHODS: In 793 individuals of the Dutch Famine Birth Cohort, we analyzed the interaction between three SIRT1 single nucleotide polymorphisms (SNPs) and prenatal exposure to famine on type 2 diabetes risk. RESULTS: In the total population (exposed and unexposed), SIRT1 variants were not associated with type 2 diabetes. A significant interaction was found between two SIRT1 SNPs and exposure to famine in utero on type 2 diabetes risk (P = 0.03 for rs7895833; P = 0.01 for rs1467568). Minor alleles of these SNPs were associated with a lower prevalence of type 2 diabetes only in individuals who had been exposed to famine prenatally (odds ratio for rs7895833 0.50 [95% CI 0.24-1.03], P = 0.06; for rs1467568 0.48 [0.25-0.91], P = 0.02). CONCLUSIONS: SIRT1 may be an important genetic factor involved in fetal programming during malnutrition, influencing type 2 diabetes risk later in life. PMID- 22228743 TI - Effect of alpha-lipoic acid on platelet reactivity in type 1 diabetic patients. AB - OBJECTIVE: Type 1 diabetes is associated with increased platelet reactivity. We investigated whether alpha-lipoic acid (ALA) has any effect on platelet reactivity in these patients. RESEARCH DESIGN AND METHODS: We randomly assigned 51 type 1 diabetic patients to ALA (600 mg once daily) or placebo for 5 weeks. Platelet reactivity was evaluated by the PFA-100 method and by measuring CD41 and CD62 platelet expression. C-reactive protein (CRP) and 8-iso-prostaglandin F2alpha serum levels also were measured. RESULTS: Baseline variables were similar in the two groups. After treatment, closure time was longer (P = 0.006) and CD62P platelet expression was lower, both before (P = 0.002) and after (P = 0.009) ADP stimulation in the ALA group compared with the placebo group. CRP and 8-iso prostaglandin F2alpha levels showed no differences between the two groups. CONCLUSIONS: Our data show that ALA reduces measures of platelet reactivity ex vivo in type 1 diabetic patients, independently of antioxidant or anti inflammatory effects. PMID- 22228744 TI - When is diabetes distress clinically meaningful?: establishing cut points for the Diabetes Distress Scale. AB - OBJECTIVE: To identify the pattern of relationships between the 17-item Diabetes Distress Scale (DDS17) and diabetes variables to establish scale cut points for high distress among patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Recruited were 506 study 1 and 392 study 2 adults with type 2 diabetes from community medical groups. Multiple regression equations associated the DDS17, a 17-item scale that yields a mean-item score, with HbA(1c), diabetes self efficacy, diet, and physical activity. Associations also were undertaken for the two-item DDS (DDS2) screener. Analyses included control variables, linear, and quadratic (curvilinear) DDS terms. RESULTS: Significant quadratic effects occurred between the DDS17 and each diabetes variable, with increases in distress associated with poorer outcomes: study 1 HbA(1c) (P < 0.02), self-efficacy (P < 0.001), diet (P < 0.001), physical activity (P < 0.04); study 2 HbA(1c) (P < 0.03), self-efficacy (P < 0.004), diet (P < 0.04), physical activity (P = NS). Substantive curvilinear associations with all four variables in both studies began at unexpectedly low levels of DDS17: the slope increased linearly between scores 1 and 2, was more muted between 2 and 3, and reached a maximum between 3 and 4. This suggested three patient subgroups: little or no distress, <2.0; moderate distress, 2.0-2.9; high distress, >=3.0. Parallel findings occurred for the DDS2. CONCLUSIONS: In two samples of type 2 diabetic patients we found a consistent pattern of curvilinear relationships between the DDS and HbA(1c), diabetes self-efficacy, diet, and physical activity. The shape of these relationships suggests cut points for three patient groups: little or no, moderate, and high distress. PMID- 22228745 TI - Potential implications of coronary artery calcium testing for guiding aspirin use among asymptomatic individuals with diabetes. AB - OBJECTIVE: It is unclear whether coronary artery calcium (CAC) is effective for risk stratifying patients with diabetes in whom treatment decisions are uncertain. RESEARCH DESIGN AND METHODS: Of 44,052 asymptomatic individuals referred for CAC testing, we studied 2,384 individuals with diabetes. Subjects were followed for a mean of 5.6 +/- 2.6 years for the end point of all-cause mortality. RESULTS: There were 162 deaths (6.8%) in the population. CAC was a strong predictor of mortality across age-groups (age <50, 50-59, >=60), sex, and risk factor burden (0 vs. >=1 additional risk factor). In individuals without a clear indication for aspirin per current guidelines, CAC stratified risk, identifying patients above and below the 10% risk threshold of presumed aspirin benefit. CONCLUSIONS: CAC can help risk stratify individuals with diabetes and may aid in selection of patients who may benefit from therapies such as low-dose aspirin for primary prevention. PMID- 22228746 TI - Long-term prognostic value of dobutamine stress echocardiography in diabetic patients with limited exercise capability: a 13-year follow-up study. AB - OBJECTIVE: To determine the incremental prognostic value of dobutamine stress echocardiography (DSE) at 13-year follow-up (SD 3.2 years) for predicting mortality and cardiac events in diabetic patients. RESEARCH DESIGN AND METHODS: A total of 396 diabetic patients (mean age 61 +/- 11 years; 252 men [64%]) with limited exercise capacity who underwent DSE for evaluation of ischemia were studied. End points were all causes of mortality, cardiac death, and hard cardiac events (cardiac death and nonfatal myocardial infarction). RESULTS: During a mean follow-up of 13 years, 230 patients (58%) died (121 cardiac deaths), and 30 patients had nonfatal myocardial infarction. Cumulative survival in patients with an abnormal DSE at 5, 10, and 15 years was 68, 49, and 41%, respectively. In patients with a normal DSE, these respective numbers were 74, 57, and 44%. Multivariate analyses showed that DSE provided incremental value over clinical characteristics and stress test parameters for prediction of mortality and cardiac events. Survival analysis showed that DSE provided optimal risk stratification up to 7 years after initial testing; after that period, the risk of adverse outcome increased comparably in both normal and abnormal DSE patients. CONCLUSIONS: DSE provided restricted predictive value of adverse outcome in patients with diabetes who were unable to perform an adequate exercise stress test. DSE provided optimal risk stratification up to 7 years after initial testing. Repeated DSE at that time might add to its prognostic value. PMID- 22228747 TI - Attitudes toward diabetes affect maintenance of drug-free remission in patients with newly diagnosed type 2 diabetes after short-term continuous subcutaneous insulin infusion treatment. AB - OBJECTIVE: Short-term intensive insulin treatment in patients with newly diagnosed type 2 diabetes can improve beta-cell function and insulin sensitivity, which results in long-term remission without need for further antidiabetes medication. Patient attitudes toward their disease were assessed using the Diabetes Care Profile (DCP) tool to evaluate the potential impact on maintaining long-term remission. RESEARCH DESIGN AND METHODS: Newly diagnosed patients with type 2 diabetes were recruited and treated with continuous subcutaneous insulin infusion (CSII) for 2-3 weeks. They were also invited to participate in diabetes self-management intervention during hospitalization and complete a DCP questionnaire on attitudes toward diabetes at baseline and 3, 6, and 12 months after suspension of CSII. RESULTS: Near normoglycemia was achieved by 118 patients after short-term CSII, with 65 remaining in drug-free remission for >1 year. They had significantly better glycemic control and greater restoration of acute insulin response after CSII as well as higher educational attainment compared with patients experiencing relapse. They also achieved higher scores in positive attitude, (belief in) importance of care, care ability, self-care adherence, and less negative attitude. Differences between the two groups became greater over time. Cox proportional hazards model analysis indicated that greater self-care adherence (hazard ratio 0.184, P < 0.001) and homeostasis model assessment of insulin resistance before treatment (0.854, P = 0.053) were independent predictors for long-term remission, whereas elevated 2-h postprandial plasma glucose after CSII (1.156, P = 0.015) was a risk factor for relapse. CONCLUSIONS: Attitudes toward diabetes affect long-term drug-free remission in newly diagnosed patients with type 2 diabetes after short-term CSII. PMID- 22228748 TI - Respective roles of CYP2A5 and CYP2F2 in the bioactivation of 3-methylindole in mouse olfactory mucosa and lung: studies using Cyp2a5-null and Cyp2f2-null mouse models. AB - The aim of this study was to determine whether mouse CYP2A5 and CYP2F2 play critical roles in the bioactivation of 3-methylindole (3MI), a tissue-selective toxicant, in the target tissues, the nasal olfactory mucosa (OM) and lung. Five metabolites of 3MI were identified in NADPH- and GSH-fortified microsomal reactions, including 3-glutathionyl-S-methylindole (GS-A1), 3-methyl-2 glutathionyl-S-indole (GS-A2), 3-hydroxy-3-methyleneindolenine (HMI), indole-3 carbinol (I-3-C), and 3-methyloxindole (MOI). The metabolite profiles and enzyme kinetics of the reactions were compared between OM and lung, and among wild-type, Cyp2a5-null, and Cyp2f2-null mice. In lung reactions, GS-A1, GS-A2, and HMI were detected as major products, and I-3-C and MOI, as minor metabolites. In OM reactions, all five metabolites were detected in ample amounts. The loss of CYP2F2 affected formation of all 3MI metabolites in the lung and formation of HMI, GS-A1, and GS-A2 in the OM. In contrast, loss of CYP2A5 did not affect formation of 3MI metabolites in the lung but caused substantial decreases in I-3 C and MOI formation in the OM. Thus, whereas CYP2F2 plays a critical role in the 3MI metabolism in the lung, both CYP2A5 and CYP2F2 play important roles in 3MI metabolism in the OM. Furthermore, the fate of the reactive metabolites produced by the two enzymes through common dehydrogenation and epoxidation pathways seemed to differ with CYP2A5 supporting direct conversion to stable metabolites and CYP2F2 supporting further formation of reactive iminium ions. These results provide the basis for understanding the respective roles of CYP2A5 and CYP2F2 in 3MI's toxicity in the respiratory tract. PMID- 22228749 TI - Predictions of cytochrome P450-mediated drug-drug interactions using cryopreserved human hepatocytes: comparison of plasma and protein-free media incubation conditions. AB - Cryopreserved human hepatocytes suspended in human plasma (HHSHP) have previously provided accurate CYP3A drug-drug interaction (DDI) predictions from a single IC(50) that captures both reversible and time-dependent inhibition. The goal of this study was to compare the accuracy of DDI predictions by a protein-free human hepatocyte system combined with the fraction unbound in plasma for inhibitor(s) with those obtained with protein-containing incubations. Seventeen CYP3A, CYP2C9, or CYP2D6 inhibitors were incubated with hepatocytes in human plasma or hepatocyte maintenance medium (HMM) for 20 min over a range of concentrations after which midazolam 1'-hydroxylation, diclofenac 4'-hydroxylation or (R) bufuralol 1'-hydroxylation were used to quantify the corresponding cytochrome P450 (P450) catalytic activities. Two methods were used to predict the human exposure ratio of the victim drug in the presence and absence of inhibitor. The HMM K(i, app) values were combined with the free average systemic plasma concentration ("free [I] with HMM K(i, app)") and the plasma K(i, app) values were combined with the total average systemic plasma concentration ("total [I] with plasma K(i, app)"). Of 63 clinical DDI studies, the total [I] with plasma K(i, app) method predicted 89% of cases within 2-fold of the reported interaction whereas the free [I] with HMM K(i, app) method predicted only 59%. There was a general underprediction by the free [I] with HMM K(i, app) method, which is consistent with an underestimation of in vitro inhibition potency in this system. In conclusion, the HHSHP system proved to be a simple, accurate predictor of DDIs for three major P450s and superior to the protein-free approach. PMID- 22228750 TI - Adolescent social cognitive and affective neuroscience: past, present, and future. AB - In this article, we review three areas of research within adolescent social cognitive and affective neuroscience: (i) emotion reactivity and regulation, (ii) mentalizing and (iii) peer relations, including social rejection or acceptance as well as peer influence. The review provides a context for current contributions to the special issue of Social Cognitive and Affective Neuroscience on Adolescence, and highlights three important themes that emerge from the special issue, which are relevant to future research. First, the age of participants studied (and labels for these age groups) is a critical design consideration. We suggest that it might be logical to reduce the reliance on convenience samples of undergraduates to represent adults in psychology and cognitive neuroscience studies, since there is substantial evidence that the brain is still developing within this age range. Second, developmental researchers are broadening their scope of inquiry by testing for non-linear effects, via increased use of longitudinal strategies or much wider age ranges and larger samples. Third, there is increasing appreciation for the interrelatedness of the three areas of focus in this special issue (emotion reactivity and regulation, mentalizing, and peer relations), as well as with other areas of interest in adolescent development. PMID- 22228751 TI - The development of emotion regulation: an fMRI study of cognitive reappraisal in children, adolescents and young adults. AB - The ability to use cognitive reappraisal to regulate emotions is an adaptive skill in adulthood, but little is known about its development. Because reappraisal is thought to be supported by linearly developing prefrontal regions, one prediction is that reappraisal ability develops linearly. However, recent investigations into socio-emotional development suggest that there are non-linear patterns that uniquely affect adolescents. We compared older children (10-13), adolescents (14-17) and young adults (18-22) on a task that distinguishes negative emotional reactivity from reappraisal ability. Behaviorally, we observed no age differences in self-reported emotional reactivity, but linear and quadratic relationships between reappraisal ability and age. Neurally, we observed linear age-related increases in activation in the left ventrolateral prefrontal cortex, previously identified in adult reappraisal. We observed a quadratic pattern of activation with age in regions associated with social cognitive processes like mental state attribution (medial prefrontal cortex, posterior cingulate cortex, anterior temporal cortex). In these regions, we observed relatively lower reactivity-related activation in adolescents, but higher reappraisal-related activation. This suggests that (i) engagement of the cognitive control components of reappraisal increases linearly with age and (ii) adolescents may not normally recruit regions associated with mental state attribution, but (iii) this can be reversed with reappraisal instructions. PMID- 22228752 TI - Facing puberty: associations between pubertal development and neural responses to affective facial displays. AB - Adolescence is marked by profound psychosocial and physiological changes. Although investigations into the interactions between these forces have begun to shed light on the neural correlates of affective processing during the transition to adolescence, relatively little is known about the relationship between pubertal development and emotion perception at the neural level. In the current longitudinal study, 45 neurotypical participants were shown affective facial displays while undergoing fMRI, at ages 10 and 13. Neural responses to emotional expressions at both time points were then correlated with a self-report measure of pubertal development, revealing positive associations with activity in amygdala, thalamus and visual cortical areas at age 10 that increased in magnitude and extent by age 13. At the latter time point, pubertal development was additionally correlated with enhanced responses to faces in temporal pole, ventrolateral prefrontal cortex (PFC) and dorsomedial PFC. Longitudinal comparisons revealed that the relationships between pubertal development and activity in the amygdala, hippocampus and temporal pole were significantly stronger during early adolescence than late childhood. These results suggest that pubertal development per se is linked to neural processing of socioemotional stimuli, particularly with respect to the integration of complex perceptual input and higher order cortical processing of affective content. PMID- 22228753 TI - Expression of NPAS3 in the human cortex and evidence of its posttranscriptional regulation by miR-17 during development, with implications for schizophrenia. AB - NPAS3 is a developmentally important transcription factor that has been associated with psychiatric illness. Our aim is to better define the regulation of NPAS3 mRNA (messenger RNA) levels during normal human prefrontal cortical development and in schizophrenia. Utilizing postmortem tissue from 134 human brains, we assessed: 60 normal brains ranging in age from birth to adulthood, 37 chronic individuals with schizophrenia, and 37 matched controls. mRNA and microRNA (miRNA) expressions were measured by microarray and quantitative real time PCR. Protein expression was measured by Western blotting. During human postnatal cortical development (neonate to adult), we found decreased NPAS3 mRNA yet increased NPAS3 protein expression, suggesting the involvement of posttranscriptional regulation. Through screening, we identified one NPAS targeted miRNA (miR-17) that changed in a pattern consistent with the developmental regulation of NPAS3. Using luciferase reporter assays, we assessed the impact of miR-17 on NPAS3 translation and demonstrated that miR-17 alters NPAS3 biosynthesis by binding to the NPAS3 3'untranslated region (UTR). In schizophrenia prefrontal cortex, we found significant elevations in miR-17 expression. While NPAS3 mRNA was unaltered, reduced NPAS3 protein expression was detected in a subpopulation of people with schizophrenia. The reciprocal expression of NPAS3 mRNA and protein during postnatal development mediated by a schizophrenia-associated change in miR-17 suggests that there is complex control over NPAS3 synthesis in the human prefrontal cortex and that if NPAS3 is dysregulated in schizophrenia, it is not evident by large changes in NPAS3 expression. Further studies into how changes in NPAS3 or its miRNA regulator may influence the development of schizophrenia are warranted. PMID- 22228754 TI - Absence of the Cdk5 activator p35 causes adult-onset neurodegeneration in the central brain of Drosophila. AB - Altered function of Cdk5 kinase is associated with many forms of neurodegenerative disease in humans. We show here that inactivating the Drosophila Cdk5 ortholog, by mutation of its activating subunit, p35, causes adult-onset neurodegeneration in the fly. In the mutants, a vacuolar neuropathology is observed in a specific structure of the central brain, the 'mushroom body', which is the seat of olfactory learning and memory. Analysis of cellular phenotypes in the mutant brains reveals some phenotypes that resemble natural aging in control flies, including an increase in apoptotic and necrotic cell death, axonal fragmentation, and accumulation of autophagosomes packed with crystalline-like depositions. Other phenotypes are unique to the mutants, notably age-dependent swellings of the proximal axon of mushroom body neurons. Many of these phenotypes are also characteristic of mammalian neurodegenerative disease, suggesting a close relationship between the mechanisms of Cdk5-associated neurodegeneration in fly and human. Together, these results identify the cellular processes that are unleashed in the absence of Cdk5 to initiate the neurodegenerative program, and they provide a model that can be used to determine what part each process plays in the progression to ultimate degeneration. PMID- 22228755 TI - Generation of primary tumors with Flp recombinase in FRT-flanked p53 mice. AB - The site-specific recombinases Cre and Flp can mutate genes in a spatially and temporally restricted manner in mice. Conditional recombination of the tumor suppressor gene p53 using the Cre-loxP system has led to the development of multiple genetically engineered mouse models of human cancer. However, the use of Cre recombinase to initiate tumors in mouse models limits the utilization of Cre to genetically modify other genes in tumor stromal cells in these models. To overcome this limitation, we inserted FRT (flippase recognition target) sites flanking exons 2-6 of the endogenous p53 gene in mice to generate a p53(FRT) allele that can be deleted by Flp recombinase. We show that FlpO-mediated deletion of p53 in mouse embryonic fibroblasts impairs the p53-dependent response to genotoxic stress in vitro. In addition, using FSF-Kras(G12D/+); p53(FRT/FRT) mice, we demonstrate that an adenovirus expressing FlpO recombinase can initiate primary lung cancers and sarcomas in mice. p53(FRT) mice will enable dual recombinase technology to study cancer biology because Cre is available to modify genes specifically in stromal cells to investigate their role in tumor development, progression and response to therapy. PMID- 22228757 TI - Negative pressure therapy: a viable option for general surgical management of the open abdomen. AB - BACKGROUND: Management of the open abdomen (OA) is challenging for surgeons and requires experienced medical teamwork. The need for improvements in temporary abdominal closure methods has led to the development of a negative-pressure therapy (NPT; ABThera OA NPT, KCI USA, Inc, San Antonio, TX). METHOD: The authors present a 19-patient case series documenting their use of NPT for OA management in nontraumatic surgery. All received NPT until the fascia was considered ready for closure. RESULTS: Of 19 patients, 17 (89.5%) achieved fascial closure with a Kaplan-Meier (KM) median time to closure of 6 days. Mean hospital and intensive care unit stays were 32.1 and 26.6 days, respectively. During their hospitalization, 5 patients (26.3%) died, with a KM median time to mortality of 53 days. CONCLUSION: These findings demonstrate effective use of NPT for managing the OA in critically ill patients, and this has led the authors to use it in their general surgery practice. PMID- 22228756 TI - Sall1 regulates cortical neurogenesis and laminar fate specification in mice: implications for neural abnormalities in Townes-Brocks syndrome. AB - Progenitor cells in the cerebral cortex undergo dynamic cellular and molecular changes during development. Sall1 is a putative transcription factor that is highly expressed in progenitor cells during development. In humans, the autosomal dominant developmental disorder Townes-Brocks syndrome (TBS) is associated with mutations of the SALL1 gene. TBS is characterized by renal, anal, limb and auditory abnormalities. Although neural deficits have not been recognized as a diagnostic characteristic of the disease, ~10% of patients exhibit neural or behavioral abnormalities. We demonstrate that, in addition to being expressed in peripheral organs, Sall1 is robustly expressed in progenitor cells of the central nervous system in mice. Both classical- and conditional-knockout mouse studies indicate that the cerebral cortex is particularly sensitive to loss of Sall1. In the absence of Sall1, both the surface area and depth of the cerebral cortex were decreased at embryonic day 18.5 (E18.5). These deficiencies are associated with changes in progenitor cell properties during development. In early cortical progenitor cells, Sall1 promotes proliferative over neurogenic division, whereas, at later developmental stages, Sall1 regulates the production and differentiation of intermediate progenitor cells. Furthermore, Sall1 influences the temporal specification of cortical laminae. These findings present novel insights into the function of Sall1 in the developing mouse cortex and provide avenues for future research into potential neural deficits in individuals with TBS. PMID- 22228758 TI - Transumbilical single-incision laparoscopy surgery splenectomy plus pericaudial devascularization in one case with portal hypertension: the first report. AB - OBJECTIVE: Single-incision laparoscopy surgery (SILS) has rapidly developed as both a cosmetic advantage of natural orifice translumenal endoscopic surgery and a standard surgical procedure. In this article, the authors report on the new technique of SILS splenectomy plus pericaudial devascularization with conventional laparoscopic instruments. METHODS: The technique of SILS splenectomy plus pericaudial devascularization in one patient with portal hypertension was introduced. RESULTS: The procedure was feasible with conventional laparoscopic instruments. Operative time was 240 minutes, and blood loss was 350 mL. No intraoperative or postoperative complications, such as secondary hemorrhage or pancreatic leakage, were recorded. The patient was fully recovered, and the single umbilical scar was well healed. CONCLUSION: SILS splenectomy plus pericaudial devascularization is feasible when performed by experienced laparoscopic surgeons. It may have the same cosmetic advantage as natural orifice translumenal endoscopic surgery and may offer the safety of conventional laparoscopic operation. As far as the authors are aware, this is the first report. PMID- 22228759 TI - Different modalities of intercellular membrane exchanges mediate cell-to-cell p glycoprotein transfers in MCF-7 breast cancer cells. AB - Multi-drug resistance (MDR) is a phenomenon by which tumor cells exhibit resistance to a variety of chemically unrelated chemotherapeutic drugs. The classical form of multidrug resistance is connected to overexpression of membrane P-glycoprotein (P-gp), which acts as an energy dependent drug efflux pump. P glycoprotein expression is known to be controlled by genetic and epigenetic mechanisms. Until now processes of P-gp gene up-regulation and resistant cell selection were considered sufficient to explain the emergence of MDR phenotype within a cell population. Recently, however, "non-genetic" acquisitions of MDR by cell-to-cell P-gp transfers have been pointed out. In the present study we show that intercellular transfers of functional P-gp occur by two different but complementary modalities through donor-recipient cells interactions in the absence of drug selection pressure. P-glycoprotein and drug efflux activity transfers were followed over 7 days by confocal microscopy and flow cytometry in drug-sensitive parental MCF-7 breast cancer cells co-cultured with P-gp overexpressing resistant variants. An early process of remote transfer was established based on the release and binding of P-gp-containing microparticles. Microparticle-mediated transfers were detected after only 4 h of incubation. We also identify an alternative mode of transfer by contact, consisting of cell-to cell P-gp trafficking by tunneling nanotubes bridging neighboring cells. Our findings supply new mechanistic evidences for the extragenetic emergence of MDR in cancer cells and indicate that new treatment strategies designed to overcome MDR may include inhibition of both microparticles and Tunneling nanotube-mediated intercellular P-gp transfers. PMID- 22228760 TI - Lipid peroxidation product 4-hydroxy-trans-2-nonenal causes endothelial activation by inducing endoplasmic reticulum stress. AB - Lipid peroxidation products, such as 4-hydroxy-trans-2-nonenal (HNE), cause endothelial activation, and they increase the adhesion of the endothelium to circulating leukocytes. Nevertheless, the mechanisms underlying these effects remain unclear. We observed that in HNE-treated human umbilical vein endothelial cells, some of the protein-HNE adducts colocalize with the endoplasmic reticulum (ER) and that HNE forms covalent adducts with several ER chaperones that assist in protein folding. We also found that at concentrations that did not induce apoptosis or necrosis, HNE activated the unfolded protein response, leading to an increase in XBP-1 splicing, phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2alpha, and the induction of ATF3 and ATF4. This increase in eukaryotic translation initiation factor 2alpha phosphorylation was prevented by transfection with protein kinase-like ER kinase siRNA. Treatment with HNE increased the expression of the ER chaperones, GRP78 and HERP. Exposure to HNE led to a depletion of reduced glutathione and an increase in the production of reactive oxygen species (ROS); however, glutathione depletion and ROS production by tert-butyl-hydroperoxide did not trigger the unfolded protein response. Pretreatment with a chemical chaperone, phenylbutyric acid, or adenoviral transfection with ATF6 attenuated HNE-induced monocyte adhesion and IL-8 induction. Moreover, phenylbutyric acid and taurine-conjugated ursodeoxycholic acid attenuated HNE-induced leukocyte rolling and their firm adhesion to the endothelium in rat cremaster muscle. These data suggest that endothelial activation by HNE is mediated in part by ER stress, induced by mechanisms independent of ROS production or glutathione depletion. The induction of ER stress may be a significant cause of vascular inflammation induced by products of oxidized lipids. PMID- 22228761 TI - Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome. AB - Hyperphosphatasia mental retardation syndrome (HPMR), an autosomal recessive disease characterized by mental retardation and elevated serum alkaline phosphatase (ALP) levels, is caused by mutations in the coding region of the phosphatidylinositol glycan anchor biosynthesis, class V (PIGV) gene, the product of which is a mannosyltransferase essential for glycosylphosphatidylinositol (GPI) biosynthesis. Mutations found in four families caused amino acid substitutions A341E, A341V, Q256K, and H385P, which drastically decreased expression of the PIGV protein. Hyperphosphatasia resulted from secretion of ALP, a GPI-anchored protein normally expressed on the cell surface, into serum due to PIGV deficiency. In contrast, a previously reported PIGM deficiency, in which there is a defect in the transfer of the first mannose, does not result in hyperphosphatasia. To provide insights into the mechanism of ALP secretion in HPMR patients, we took advantage of CHO cell mutants that are defective in various steps of GPI biosynthesis. Secretion of ALP requires GPI transamidase, which in normal cells, cleaves the C-terminal GPI attachment signal peptide and replaces it with GPI. The GPI-anchored protein was secreted substantially into medium from PIGV-, PIGB-, and PIGF-deficient CHO cells, in which incomplete GPI bearing mannose was accumulated. In contrast, ALP was degraded in PIGL-, DPM2-, or PIGX-deficient CHO cells, in which incomplete shorter GPIs that lacked mannose were accumulated. Our results suggest that GPI transamidase recognizes incomplete GPI bearing mannose and cleaves a hydrophobic signal peptide, resulting in secretion of soluble ALP. These results explain the molecular mechanism of hyperphosphatasia in HPMR. PMID- 22228762 TI - Formation of new high density glycogen-microtubule structures is induced by cardiac steroids. AB - Cardiac steroids (CS), an important class of naturally occurring compounds, are synthesized in plants and animals. The only established receptor for CS is the ubiquitous Na(+),K(+)-ATPase, a major plasma membrane transporter. The binding of CS to Na(+),K(+)-ATPase causes the inhibition of Na(+) and K(+) transport and elicits cell-specific activation of several intracellular signaling mechanisms. It is well documented that the interaction of CS with Na(+),K(+)-ATPase is responsible for numerous changes in basic cellular physiological properties, such as electrical plasma membrane potential, cell volume, intracellular [Ca(2+)] and pH, endocytosed membrane traffic, and the transport of other solutes. In the present study we show that CS induces the formation of dark structures adjacent to the nucleus in human NT2 and ACHN cells. These structures, which are not surrounded by membranes, are clusters of glycogen and a distorted microtubule network. Formation of these clusters results from a relocation of glycogen and microtubules in the cells, two processes that are independent of one another. The molecular mechanisms underlying the formation of the clusters are mediated by the Na(+),K(+)-ATPase, ERK1/2 signaling pathway, and an additional unknown factor. Similar glycogen clusters are induced by hypoxia, suggesting that the CS-induced structural change, described in this study, may be part of a new type of cellular stress response. PMID- 22228763 TI - Ethanol suppresses ureagenesis in rat hepatocytes: role of acetaldehyde. AB - We proposed previously that closure of voltage-dependent anion channels (VDAC) in the mitochondrial outer membrane after ethanol exposure leads to suppression of mitochondrial metabolite exchange. Because ureagenesis requires extensive mitochondrial metabolite exchange, we characterized the effect of ethanol and its metabolite, acetaldehyde (AcAld), on total and ureagenic respiration in cultured rat hepatocytes. Ureagenic substrates increased cellular respiration from 15.8 +/ 0.9 nmol O(2)/min/10(6) cells (base line) to 29.4 +/- 1.7 nmol O(2)/min/10(6) cells in about 30 min. Ethanol (0-200 mM) suppressed extra respiration after ureagenic substrates (ureagenic respiration) by up to 51% but not base line respiration. Urea formation also declined proportionately. Inhibition of alcohol dehydrogenase, cytochrome P450 2E1, and catalase with 4-methylpyrazole, trans-1,2 dichloroethylene, and 3-amino-1,2,3-triazole restored ethanol-suppressed ureagenic respiration by 46, 37, and 66%, respectively. By contrast, inhibition of aldehyde dehydrogenase with phenethyl isothiocyanate increased the inhibitory effect of ethanol on ureagenic respiration by an additional 60%. AcAld, an intermediate product of ethanol oxidation, suppressed ureagenic respiration with an apparent IC(50) of 125 MUM. AcAld also inhibited entry of 3-kDa rhodamine conjugated dextran in the mitochondrial intermembrane space of digitonin permeabilized hepatocytes, indicative of VDAC closure. In conclusion, AcAld, derived from ethanol metabolism, suppresses ureagenesis in hepatocytes mediated by closure of VDAC. PMID- 22228764 TI - Reductive activation of type 2 ribosome-inactivating proteins is promoted by transmembrane thioredoxin-related protein. AB - Members of the type 2 ribosome-inactivating proteins (RIPs) family (e.g. ricin, abrin) are potent cytotoxins showing a strong lethal activity toward eukaryotic cells. Type 2 RIPs contain two polypeptide chains (usually named A, for "activity", and B, for "binding") linked by a disulfide bond. The intoxication of the cell is a consequence of a reductive process in which the toxic domain is cleaved from the binding domain by oxidoreductases located in the lumen of the endoplasmic reticulum (ER). The best known example of type 2 RIPs is ricin. Protein disulfide isomerase (PDI) was demonstrated to be involved in the process of ricin reduction; however, when PDI is depleted from cell fraction preparations ricin reduction can still take place, indicating that also other oxidoreductases might be implicated in this process. We have investigated the role of TMX, a transmembrane thioredoxin-related protein member of the PDI family, in the cell intoxication operated by type 2 RIPs ricin and abrin. Overexpressing TMX in A549 cells resulted in a dramatic increase of ricin or abrin cytotoxicity compared with control mock-treated cells. Conversely, no difference in cytotoxicity was observed after treatment of A549 cells or control cells with saporin or Pseudomonas exotoxin A whose intracellular mechanism of activation is not dependent upon reduction (saporin) or only partially dependent upon it (Pseudomonas exotoxin A). Moreover, the silencing of TMX in the prostatic cell line DU145 reduced the sensitivity of the cells to ricin intoxication further confirming a role for this enzyme in intracellular ricin activation. PMID- 22228765 TI - Protein kinase D regulates RhoA activity via rhotekin phosphorylation. AB - The members of the protein kinase D (PKD) family of serine/threonine kinases are major targets for tumor-promoting phorbol esters, G protein-coupled receptors, and activated protein kinase C isoforms (PKCs). The expanding list of cellular processes in which PKDs exert their function via phosphorylation of various substrates include proliferation, apoptosis, migration, angiogenesis, and vesicle trafficking. Therefore, identification of novel PKD substrates is necessary to understand the profound role of this kinase family in signal transduction. Here, we show that rhotekin, an effector of RhoA GTPase, is a novel substrate of PKD. We identified Ser-435 in rhotekin as the potential site targeted by PKD in vivo. Expression of a phosphomimetic S435E rhotekin mutant resulted in an increase of endogenous active RhoA GTPase levels. Phosphorylation of rhotekin by PKD2 modulates the anchoring of the RhoA in the plasma membrane. Consequently, the S435E rhotekin mutant displayed enhanced stress fiber formation when expressed in serum-starved fibroblasts. Our data thus identify a novel role of PKD as a regulator of RhoA activity and actin stress fiber formation through phosphorylation of rhotekin. PMID- 22228766 TI - Translation elongation regulates substrate selection by the signal recognition particle. AB - The signal recognition particle (SRP) is a universally conserved cellular machinery responsible for delivering membrane and secretory proteins to the proper cellular destination. The precise mechanism by which fidelity is achieved by the SRP pathway within the in vivo environment is yet to be understood. Previous studies have focused on the SRP pathway in isolation. Here we describe another important factor that modulates substrate selection by the SRP pathway: the ongoing synthesis of the nascent polypeptide chain by the ribosome. A slower translation elongation rate rescues the targeting defect of substrate proteins bearing mutant, suboptimal signal sequences both in vitro and in vivo. Consistent with a kinetic origin of this effect, similar rescue of protein targeting was also observed with mutant SRP receptors or SRP RNAs that specifically compromise the kinetics of SRP-receptor interaction during protein targeting. These data are consistent with a model in which ongoing protein translation is in constant kinetic competition with the targeting of the nascent proteins by the SRP and provides an important factor to regulate the fidelity of substrate selection by the SRP. PMID- 22228767 TI - CHCM1/CHCHD6, novel mitochondrial protein linked to regulation of mitofilin and mitochondrial cristae morphology. AB - The structural integrity of mitochondrial cristae is crucial for mitochondrial functions; however, the molecular events controlling the structural integrity and biogenesis of mitochondrial cristae remain to be fully elucidated. Here, we report the functional characterization of a novel mitochondrial protein named CHCM1 (coiled coil helix cristae morphology 1)/CHCHD6. CHCM1/CHCHD6 harbors a coiled coil helix-coiled coil helix domain at its C-terminal end and predominantly localizes to mitochondrial inner membrane. CHCM1/CHCHD6 knockdown causes severe defects in mitochondrial cristae morphology. The mitochondrial cristae in CHCM1/CHCHD6-deficient cells become hollow with loss of structural definitions and reduction in electron-dense matrix. CHCM1/CHCHD6 depletion also leads to reductions in cell growth, ATP production, and oxygen consumption. CHCM1/CHCHD6 through its C-terminal end strongly and directly interacts with the mitochondrial inner membrane protein mitofilin, which is known to also control mitochondrial cristae morphology. CHCM1/CHCHD6 also interacts with other mitofilin-associated proteins, including DISC1 and CHCHD3. Knockdown of CHCM1/CHCHD6 reduces mitofilin protein levels; conversely, mitofilin knockdown leads to reduction in CHCM1 levels, suggesting coordinate regulation between these proteins. Our results further indicate that genotoxic anticancer drugs that induce DNA damage down-regulate CHCM1/CHCHD6 expression in multiple human cancer cells, whereas mitochondrial respiratory chain inhibitors do not affect CHCM1/CHCHD6 levels. CHCM1/CHCHD6 knockdown in human cancer cells enhances chemosensitivity to genotoxic anticancer drugs, whereas its overexpression increases resistance. Collectively, our results indicate that CHCM1/CHCHD6 is linked to regulation of mitochondrial cristae morphology, cell growth, ATP production, and oxygen consumption and highlight its potential as a possible target for cancer therapeutics. PMID- 22228768 TI - Osmotic stress resistance imparts acquired anti-apoptotic mechanisms in lymphocytes. AB - Apoptosis is a stochastic, physiological form of cell death that is characterized by unique morphological and biochemical properties. A defining feature of apoptosis in all cells is the apoptotic volume decrease or AVD, which has been considered a passive component of the cell death process. Most cells have inherent volume regulatory increase (RVI) mechanisms to contest an imposed loss in cell size, however T-cells are unique in that they do not have a RVI response. We utilized this property to explore potential regulatory roles of a RVI response in apoptosis. Exposure of immature T-cells to hyperosmotic stress resulted in a rapid, synchronous, and caspase-dependent apoptosis. Multiple rounds of osmotic stress followed by recovery of cells in normal media resulted in the development of a population of cells that were resistant to osmotic stress induced apoptosis. These cells were also resistant to other apoptotic stimuli that activate via the intrinsic cell death pathway, while remaining sensitive to extrinsic apoptotic stimuli. Interestingly, these osmotic stress resistant cells showed no increase in anti-apoptotic proteins, and released cytochrome c from their mitochondria following exposure to intrinsic apoptotic stimuli. The osmotic stress resistant cells developed a RVI response, and inhibition of the RVI restored sensitivity to apoptotic agents. Analysis of apoptotic signaling pathways showed a sustained increase in phospho-AKT, whose inhibition also prevented an RVI response resulting in apoptosis. These results define a critical role of volume regulation mechanisms in apoptotic resistance. PMID- 22228769 TI - Identification of N-acetyltaurine as a novel metabolite of ethanol through metabolomics-guided biochemical analysis. AB - The influence of ethanol on the small molecule metabolome and the role of CYP2E1 in ethanol-induced hepatotoxicity were investigated using liquid chromatography mass spectrometry (LC-MS)-based metabolomics platform and Cyp2e1-null mouse model. Histological and biochemical examinations of ethanol-exposed mice indicated that the Cyp2e1-null mice were more resistant to ethanol-induced hepatic steatosis and transaminase leakage than the wild-type mice, suggesting CYP2E1 contributes to ethanol-induced toxicity. Metabolomic analysis of urinary metabolites revealed time- and dose-dependent changes in the chemical composition of urine. Along with ethyl glucuronide and ethyl sulfate, N-acetyltaurine (NAT) was identified as a urinary metabolite that is highly responsive to ethanol exposure and is correlated with the presence of CYP2E1. Subsequent stable isotope labeling analysis using deuterated ethanol determined that NAT is a novel metabolite of ethanol. Among three possible substrates of NAT biosynthesis (taurine, acetyl-CoA, and acetate), the level of taurine was significantly reduced, whereas the levels of acetyl-CoA and acetate were dramatically increased after ethanol exposure. In vitro incubation assays suggested that acetate is the main precursor of NAT, which was further confirmed by the stable isotope labeling analysis using deuterated acetate. The incubations of tissues and cellular fractions with taurine and acetate indicated that the kidney has the highest NAT synthase activity among the tested organs, whereas the cytosol is the main site of NAT biosynthesis inside the cell. Overall, the combination of biochemical and metabolomic analysis revealed NAT is a novel metabolite of ethanol and a potential biomarker of hyperacetatemia. PMID- 22228770 TI - Transcription factor GATA4 is activated but not required for insulin-like growth factor 1 (IGF1)-induced cardiac hypertrophy. AB - Insulin-like growth factor 1 (IGF1) promotes a physiological type of cardiac hypertrophy and has therapeutic effects in heart disease. Here, we report the relationship of IGF1 to GATA4, an essential transcription factor in cardiac hypertrophy and cell survival. In cultured neonatal rat ventricular myocytes, we compared the responses to IGF1 (10 nmol/liter) and phenylephrine (PE, 20 MUmol/liter), a known GATA4 activator, in concentrations promoting a similar extent of hypertrophy. IGF1 and PE both increased nuclear accumulation of GATA4 and phosphorylation at Ser(105) (PE, 2.4-fold; IGF1, 1.8-fold; both, p < 0.05) and increased GATA4 DNA binding activity as indicated by ELISA and by chromatin IP of selected promoters. Although IGF1 and PE each activated GATA4 to the same degree, GATA4 knockdown by RNA interference only blocked hypertrophy by PE but not by IGF1. PE induction of a panel of GATA4 target genes (Nppa, Nppb, Tnni3, Myl1, and Acta1) was inhibited by GATA4 knockdown. In contrast, IGF1 regulated only Acta1 in a GATA4-dependent fashion. Consistent with the in vitro findings, Gata4 haploinsufficiency in mice did not alter cardiac structure, hyperdynamic function, or antifibrotic effects induced by myocardial overexpression of the IGF1 receptor. Our data indicate that GATA4 is activated by the IGF1 pathway, but although it is required for responses to pathological stimuli, it is not necessary for the effects of IGF1 on cardiac structure and function. PMID- 22228771 TI - Broad antiviral activity and crystal structure of HIV-1 fusion inhibitor sifuvirtide. AB - Sifuvirtide (SFT) is an electrostatically constrained alpha-helical peptide fusion inhibitor showing potent anti-HIV activity, good safety, and pharmacokinetic profiles, and it is currently under phase II clinical trials in China. In this study, we demonstrate its potent and broad anti-HIV activity by using diverse HIV-1 subtypes and variants, including subtypes A, B, and C that dominate the AIDS epidemic worldwide, and subtypes B', CRF07_BC, and CRF01_AE recombinants that are currently circulating in China, and those possessing cross resistance to the first and second generation fusion inhibitors. To elucidate its mechanism of action, we determined the crystal structure of SFT in complex with its target N-terminal heptad repeat region (NHR) peptide (N36), which fully supports our rational inhibitor design and reveals its key motifs and residues responsible for the stability and anti-HIV activity. As anticipated, SFT adopts fully helical conformation stabilized by the multiple engineered salt bridges. The designing of SFT also provide novel inter-helical salt bridges and hydrogen bonds that improve the affinity of SFT to NHR trimer. The extra serine residue and acetyl group stabilize alpha-helicity of the N-terminal portion of SFT, whereas Thr-119 serves to stabilize the hydrophobic NHR pocket. In addition, our structure demonstrates that the residues critical for drug resistance, located at positions 37, 38, 41, and 43 of NHR, are irreplaceable for maintaining the stable fusogenic six-helix bundle structure. Our data present important information for developing SFT for clinical use and for designing novel HIV fusion inhibitors. PMID- 22228773 TI - Comparative efficacy and safety of fenofibrate/pravastatin plus ezetimibe triple therapy and simvastatin/ezetimibe dual therapy in type 2 diabetic patients with mixed hyperlipidaemia and cardiovascular disease. AB - BACKGROUND: This study was designed to compare the efficacy and safety of a fenofibrate/pravastatin 160/40 mg fixed-dose combination plus ezetimibe 10 mg triple therapy and simvastatin 20 mg plus ezetimibe 10 mg dual therapy in patients with type 2 diabetes, mixed hyperlipidaemia and cardiovascular disease. METHOD: After a 6-week run-in period on simvastatin 20 mg, 273 patients with non high-density lipoprotein cholesterol (non-HDL-C) >= 100 mg/dl or low-density lipoprotein cholesterol (LDL-C) >= 70 mg/dl were randomised to receive 12-week treatment with triple therapy or dual therapy, followed by a 12-week safety period during which all patients received the triple therapy. RESULTS: At week 12, similar significant decreases in non-HDL-C were observed with both treatments. The triple therapy has induced a greater decrease in triglycerides (between-treatment difference: -14.6%, p = 0.007) and the dual therapy a greater decrease in LDL-C (between-treatment difference: +5.3%, p = 0.05). Both treatments were generally well tolerated. CONCLUSION: The fenofibrate/pravastatin plus ezetimibe therapy improves the global atherogenic lipid profile in type 2 diabetic patients with mixed hyperlipidaemia. PMID- 22228772 TI - Gender-based divergence of cardiovascular outcomes in asymptomatic patients with type 2 diabetes: results from the DIAD study. AB - Gender differences in cardiovascular outcomes were compared in asymptomatic men and women with type 2 diabetes (T2DM) in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study. Of 1123 participants, 290 men and 271 women were randomised to screening with stress myocardial perfusion imaging (MPI); 311 men and 251 women were randomised to no screening. Follow-up was 4.8+/-0.9 years for the occurrence of cardiac events (CE; cardiac death or non-fatal myocardial infarction). The frequency of abnormal screening was similar in men (24%) and women (19%), (p=0.2), although women trended to have smaller MPI abnormalities. CE rates were lower in women than men (1.7% vs. 3.8%, p=0.04). No CEs occurred in 17 high-risk (UKPDS risk engine) women, whereas 14 (11.2%) occurred in 125 high risk men. Asymptomatic women with T2DM have significantly better cardiac outcomes than their male counterparts and represent a subgroup for which screening for coronary artery disease does not appear warranted. PMID- 22228774 TI - Human histone acetyltransferase 1 protein preferentially acetylates H4 histone molecules in H3.1-H4 over H3.3-H4. AB - In mammalian cells, canonical histone H3 (H3.1) and H3 variant (H3.3) differ by five amino acids and are assembled, along with histone H4, into nucleosomes via distinct nucleosome assembly pathways. H3.1-H4 molecules are assembled by histone chaperone CAF-1 in a replication-coupled process, whereas H3.3-H4 are assembled via HIRA in a replication-independent pathway. Newly synthesized histone H4 is acetylated at lysine 5 and 12 (H4K5,12) by histone acetyltransferase 1 (HAT1). However, it remains unclear whether HAT1 and H4K5,12ac differentially regulate these two nucleosome assembly processes. Here, we show that HAT1 binds and acetylates H4 in H3.1-H4 molecules preferentially over H4 in H3.3-H4. Depletion of Hat1, the catalytic subunit of HAT1 complex, results in reduced H3.1 occupancy at H3.1-enriched genes and reduced association of Importin 4 with H3.1, but not H3.3. Finally, depletion of Hat1 or CAF-1p150 leads to changes in expression of a H3.1-enriched gene. These results indicate that HAT1 differentially impacts nucleosome assembly of H3.1-H4 and H3.3-H4. PMID- 22228776 TI - A cross-cultural three-step process model for assessing motivational interviewing treatment fidelity in Thailand. AB - The provision of culturally relevant yet evidence-based interventions has become crucial to global HIV prevention and treatment efforts. In Thailand, where treatment for HIV has become widely available, medication adherence and risk behaviors remain an issue for Thai youth living with HIV. Previous research on motivational interviewing (MI) has proven effective in promoting medication adherence and HIV risk reduction in the United States. However, to test the efficacy of MI in the Thai context a feasible method for monitoring treatment fidelity must be implemented. This article describes a collaborative three-step process model for implementing the MI Treatment Integrity (MITI) across cultures while identifying linguistic issues that the English-originated MITI was not designed to detect as part of a larger intervention for Thai youth living with HIV. Step 1 describes the training of the Thai MITI coder, Step 2 describes identifying cultural and linguistic issues unique to the Thai context, and Step 3 describes an MITI booster training and incorporation of the MITI feedback into supervision and team discussion. Throughout the process the research team collaborated to implement the MITI while creating additional ways to evaluate in session processes that the MITI is not designed to detect. The feasibility of using the MITI as a measure of treatment fidelity for MI delivered in the Thai linguistic and cultural context is discussed. PMID- 22228777 TI - Malignant glomus tumor of the leg developed in the context of a superficial typical glomus tumor. AB - A 41-year-old man presented with a 2-cm painful subcutaneous nodule in his right leg, which had been present for more than 10 years and was recently enlarging. Histologically, the tumor was composed of sheets and nests of cells with variable cytomorphology, including typical round/ovoid glomus cells with clear cytoplasm and well-defined borders, small cells, and spindle cells. Numerous medium to large vessels were present. Nodules with moderate to high cellularity, nuclear atypia, and frequent mitotic figures (42 per 50 high-power fields) were noted. Immunohistochemistry showed cytoplasmic and membranous expression of smooth muscle actin, vimentin, and membranous expression of type IV collagen. Whereas superficiality, dimensions, and long-term follow-up may suggest classification as a symplastic or uncertain potential glomus tumor (GT), histological features and immunoprofile are indicative of malignant nodules developed in a typical GT. The follow-up has been negative for recurrence/metastases. A search of the literature revealed 17 cases of malignant GTs between 1995 and 2010, all fatal, of which 10 had skin as the primary site. PMID- 22228775 TI - Stressed out and overcommitted! The relationships between time demands and family rules and parents' and their child's weight status. AB - OBJECTIVE: This study aimed to determine the relationship between parent time demands and presence and enforcement of family rules and parent/child dyad weight status. METHOD: In dyads of one child/parent per family (N = 681 dyads) in Twin Cities, Minnesota, 2007-2008, height and weight were measured, and a survey of demographics, time demands, and family rules-related questions was taken. Parent/child dyads were classified into four healthy weight/overweight categories. Multivariate linear associations were analyzed with SAS, testing for interaction by work status and family composition (p < .10). RESULTS: In adjusted models, lack of family rules and difficulty with rule enforcement were statistically lower in dyads in which the parent or child was healthy weight compared with dyads in which the parent and child were both overweight (difference in family rules scores = 0.49, p = .03; difference in rule enforcement scores = 1.09, p <= .01). Of parents who worked full-time, healthy weight dyads reported lower time demands than other dyads (difference in time demands scores = 1.44, p = .01). CONCLUSIONS: Family experiences of time demands and use of family rules are related to the weight status of parents and children within families. PMID- 22228778 TI - Dried blood spot bioanalysis: an evaluation of techniques and opportunities for reduction and refinement in mouse and juvenile rat toxicokinetic studies. AB - Toxicokinetic investigations are an essential component of nonclinical toxicology studies and generally rely on bioanalysis of plasma samples, which requires relatively large volumes of blood and, often, additional numbers of animals. Dried blood spot (DBS) analysis can substantially reduce the volume of blood needed and, therefore, presents a particular opportunity for reducing animal use in studies involving small animals; an approach consistent with industry objectives to reduce animal use and refine methods that are minimally invasive and improve animal welfare. Investigations using mice and juvenile rats indicate that implementation of DBS technology can reduce the number of animals used, and data are as good as those derived from whole blood in terms of AUC, drug concentration-over-time curves, quantitation, accuracy, variability, and precision. These factors, and the improved data quality arising from less reliance on composite data, suggest that DBS analysis should be considered from the early stages of nonclinical development. PMID- 22228779 TI - Psychometric evaluation of the Turkish version of the Zarit Burden Interview in family caregivers of inpatients in medical and surgical clinics. AB - The aim of this study was to adapt the Zarit Burden Interview (ZBI) to family caregivers of inpatients in medical and surgical clinics to assess the validity and reliability of the Turkish version. The study design was descriptive and methodological. A total of 223 family caregivers providing care to patients for at least 1 week in clinics were selected through convenience sampling. Data were collected using the Turkish translation of the ZBI. The psychometric testing of the adapted instrument was carried out to establish internal consistency, interitem correlation, and construct validity. The content validity procedure resulted in a final scale comprising 18 items. Cronbach's alpha was .82. Factor analysis yielded one factor. The Turkish version of the ZBI adapted to the clinics can be used as a one-factor tool. PMID- 22228780 TI - Study abroad as a tool for promoting cultural safety in nursing education. AB - Nurse educators are calling for the transformation of nursing education toward curricula that promote clinical reasoning through reflective practice and understanding of patient experiences in an effort to motivate students to become change agents. Study abroad programs can play an important role in this transformation through educating nurses in the delivery of culturally safe health care in a diverse world. Exposing nursing students to study abroad experiences that are guided by critical approaches such as a postcolonial feminist framework provides nursing students with opportunities to be immersed in the life and culture of people who have a completely different positioning and location while reflecting on the "us" versus "them" phenomenon that is pervasive in modern Western society and generates negative cultural comparisons. Attention to the design and implementation of such programs is important if nursing schools in the Western world are to uphold ethical standards, promote equality in relationships with host communities and avoid inadvertent exploitation and marginalization of vulnerable peoples. We present the development and implementation of a community health study abroad program for American nursing students in Malawi, Africa using a postcolonial feminist framework. PMID- 22228781 TI - Putting the world as classroom: an application of the inequalities imagination model in nursing and health education. AB - This article focuses on the description of an educational initiative, the Interdisciplinary Population Health Project (IPHP) conducted in the academic year of 2006-2007 with a group of nursing and health care students. Inspired by population health, community development, critical pedagogy, and the inequalities imagination model, students participated in diverse educational activities to become immersed in the everyday life of an underserved urban neighborhood. A sample of convenience composed of 158 students was recruited from 4 health disciplines in a Western Canadian university. Data were collected using a modified version of the Parsell and Bligh's Readiness of Health Care Students for Interprofessional Learning Scale. A one group pretest-posttest design was used to assess the outcomes of the IPHP. Paired t tests and one-way analyses of variance were used to compare the responses of students from different academic programs to determine if there were differences across disciplines. Findings suggest that students' readiness to work in interprofessional teams did not significantly change over the course of their participation in the IPHP. However, the inequalities imagination model may be useful to enhance the quality and the effectiveness of fieldwork learning activities as a means of educating culturally and socially conscious nurses and other health care professionals of the future. PMID- 22228782 TI - The influence of eastern philosophy on elder care by Chinese Americans: attitudes toward long-term care. AB - Chinese philosophy has been a major cornerstone of Chinese culture for millennia and has bestowed on the world traditions such as Taoism, Yin and Yang, and filial piety. Although these beliefs have remained steadfast over thousands of years, their ability to survive unchanged in the future is uncertain. As the world forges ahead into the 21st century, several pertinent questions arise: Will age old axioms, primarily those concerning elderly Chinese and their relationship with their children, survive? When ancient, traditional beliefs conflict with newer, Western ideas, which system of thought is likely to be the victor? Moreover, will elderly Chinese Americans and their perceptions concerning long term care facilities cause problems with the traditional familial unit? This article will discuss these issues in detail. PMID- 22228783 TI - Transthyretin Val30Met familial amyloid polyneuropathy: a considerably different clinical picture and natural course in endemic and non-endemic areas. PMID- 22228784 TI - Impact Commentaries. EMG analysis of stereotyped voluntary movements in man. PMID- 22228785 TI - Natural history of transthyretin Val30Met familial amyloid polyneuropathy: analysis of late-onset cases from non-endemic areas. AB - OBJECTIVE: The objective of this study was to elucidate the natural history of late-onset transthyretin Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) in non-endemic areas. METHODS: The authors retrospectively assessed the development of major clinical landmarks and abnormalities of nerve conduction and cardiac examination indices in 50 patients with an age of onset older than 50 years and no relationship to endemic foci. RESULTS: Once the neuropathic process was initiated, sensory and motor symptoms of both the upper and lower extremities appeared within a period of one and a half years. Digestive and orthostatic symptoms also tended to occur in the early phase of the disease, whereas urinary symptoms appeared in the middle of the disease progress. Along with pain in the extremities, these symptoms progressed over time and significantly disturbed the quality of life during the late phase of the disease, resulting in the need for wheelchair use. Although cardiomyopathy became clinically apparent only in the late phase of the disease, it was found to be the major cause of death. The mean duration of the disease onset to death was 7.3 years. Although values at the time of diagnosis were extremely variable, serial measurements of electrophysiological indices, the cardiothoracic ratio and interventricular septum thickness indicated a steady exacerbation in these outcomes among patients within a span of a couple of years. CONCLUSIONS: The ages of onset of each clinical landmark were extremely variable between patients. However, once an initial symptom appeared, the chronological sequence of other clinical landmarks tended to be uniform, occurring within a relatively short time span. PMID- 22228786 TI - The mental health and psychosocial effects of organized violence: a qualitative study in northern Haiti. AB - Historically, organized violence has been a chronic pervasive problem in Haiti. We set out to elicit Haitians' views on its effects to guide the development of interventions. In March 2006 we studied a population in the slum area of Cap Haitien, Haiti's second largest city, and the nearby towns of Milot and Limbe. A convenience sample of adults was asked to free list all current problems affecting victims of organized violence. Two major categories emerged: psychological problems and financial problems. The psychological problems of "feeling startled and loss of self control," "sadness/grief," "continuing to suffer from reliving/reexperiencing past events," "problems in the head/mental problems," "deep suffering in the heart," and "thinking too much" emerged as themes from key-informant interviews. These may correspond to constructs of depression, dysthymia, and anxiety disorders including posttraumatic stress disorder in psychiatric nosology. The development of effective interventions can therefore consider those known to be effective for these problems in other settings. However in selecting interventions, considerations must also include local acceptability, perceived causes of problems, and their social effects. PMID- 22228787 TI - The NIH Undiagnosed Diseases Program: bonding scientists and clinicians. AB - The majority of the biomedical research workforce and funds are focused on studying common diseases and the development of drugs to treat them. However, some of the most remarkable discoveries in physiology and medicine are uncovered by studying rare conditions, because the importance of certain molecular mechanisms is revealed only when their dysfunction results in disease. In 2008, the National Institutes of Health (NIH) launched the NIH Undiagnosed Diseases Program (UDP), which recruits and selects patients who suffer from diseases of unknown etiology, and studies their causes at the clinical, genetic and cellular levels. In this Editorial, we discuss how the UDP has enabled the discovery of several new diseases and disease mechanisms through collaborations between clinical and basic science teams, using the power of both clinical medicine and biological models. Establishing programs with similar infrastructure at other centers around the world could help to benefit patients, their families and the entire medical community, by enhancing research productivity for rare and novel diseases. PMID- 22228788 TI - Breaking down barriers to clinical translation: an interview with Laurie Glimcher. Interview by Sarah Allan. PMID- 22228792 TI - Development of immunotoxicity testing strategies for immunomodulatory drugs. AB - The ICH S8 immunotoxicity testing guideline for human pharmaceuticals was published in 2006 and was intended to provide guidance for assessing the immunotoxicity potential of low-molecular-weight drugs that are not intended to alter the immune system. For drugs intended to modulate the immune system, immunotoxicity testing strategies are generally developed on a case-by-case approach since the targets, intended patient population, and mechanisms of action of the test compound will determine the type of testing needed. Some of the general principles of ICH S8, however, may be applied to immunotoxicity testing strategies for immunomodulatory drugs. A weight-of-evidence approach using factors discussed in ICH S8 in concert with an assessment of the potential value of additional immunotoxicity testing should be considered. For most situations, immunotoxicity studies with immunomodulatory compounds evaluate off-target effects on the immune system and exaggerated pharmacology. The potential use of data from these studies and considerations such as translatability to humans are discussed. PMID- 22228789 TI - Preeclampsia: multiple approaches for a multifactorial disease. AB - Preeclampsia is a pregnancy-specific disorder characterized by hypertension and excess protein excretion in the urine. It is an important cause of maternal and fetal morbidity and mortality worldwide. The disease is almost exclusive to humans and delivery of the pregnancy continues to be the only effective treatment. The disorder is probably multifactorial, although most cases of preeclampsia are characterized by abnormal maternal uterine vascular remodeling by fetally derived placental trophoblast cells. Numerous in vitro and animal models have been used to study aspects of preeclampsia, the most common being models of placental oxygen dysregulation, abnormal trophoblast invasion, inappropriate maternal vascular damage and anomalous maternal-fetal immune interactions. Investigations into the pathophysiology and treatment of preeclampsia continue to move the field forward, albeit at a frustratingly slow pace. There remains a pressing need for novel approaches, new disease models and innovative investigators to effectively tackle this complex and devastating disorder. PMID- 22228793 TI - Novel mechanistic insights into arginine deiminase pharmacology suggest 18F-FDG is not suitable to evaluate clinical response in melanoma. AB - Because of deficiencies in l-arginine biosynthesis, some cancers are susceptible to therapeutic intervention with arginine deiminase (ADI), an enzyme responsible for consuming the dietary supply of l-arginine to deprive the disease of an essential nutrient. ADI is currently being evaluated in several clinical trials, and fully realizing the drug's potential will depend on invoking the appropriate metrics to judge clinical response. Without a clear biologic mandate, PET/CT with (18)F-FDG is currently used to monitor patients treated with ADI. However, it is unclear if it can be expected that (18)F-FDG responses will indicate (or predict) clinical benefit. METHODS: (18)F-FDG responses to ADI therapy were studied in preclinical models of melanoma in vitro and in vivo. The molecular mechanism of response to ADI therapy was also studied, with a particular emphasis on biologic pathways known to regulate (18)F-FDG avidity. RESULTS: Although proliferation of SK-MEL 28 was potently inhibited by ADI treatment in vitro and in vivo, no clear declines in (18)F-FDG uptake were observed. Further investigation showed that ADI treatment induces the posttranslational degradation of phosphatase and tensin homolog and the activation of the PI3K signaling pathway, an event known to enhance glycolysis and (18)F-FDG avidity. A more thorough mechanistic study showed that ADI triggered a complex mechanism of cell death, involving apoptosis via poly (ADP-ribose) polymerase cleavage-independent of caspase 3. CONCLUSION: These findings suggest that some unexpected pharmacologic properties of ADI preclude using (18)F-FDG to evaluate clinical response in melanoma and, more generally, argue for further studies to explore the use of PET tracers that target apoptotic pathway activation or cell death. PMID- 22228790 TI - A model 450 million years in the making: zebrafish and vertebrate immunity. AB - Since its first splash 30 years ago, the use of the zebrafish model has been extended from a tool for genetic dissection of early vertebrate development to the functional interrogation of organogenesis and disease processes such as infection and cancer. In particular, there is recent and growing attention in the scientific community directed at the immune systems of zebrafish. This development is based on the ability to image cell movements and organogenesis in an entire vertebrate organism, complemented by increasing recognition that zebrafish and vertebrate immunity have many aspects in common. Here, we review zebrafish immunity with a particular focus on recent studies that exploit the unique genetic and in vivo imaging advantages available for this organism. These unique advantages are driving forward our study of vertebrate immunity in general, with important consequences for the understanding of mammalian immune function and its role in disease pathogenesis. PMID- 22228794 TI - The use of 18F-FDG PET in the diagnosis of cardiac sarcoidosis: a systematic review and metaanalysis including the Ontario experience. AB - Cardiac sarcoidosis is a potentially fatal complication of sarcoidosis. The 1993 guidelines of the Ministry of Health, Labour, and Welfare (MHLW) of Japan have been used as the diagnostic gold standard and for comparison with imaging modalities. (18)F-FDG PET is not currently included in the guidelines. However, studies have shown promising data using (18)F-FDG PET. We conducted a systematic review of studies that evaluated the accuracy of (18)F-FDG PET for the diagnosis of cardiac sarcoidosis compared with MHLW guidelines. Data from a prospective Ontario provincial registry are also reported and included in the metaanalysis. METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies that satisfied predetermined criteria. Quality evaluation using the Quality Assessment for Diagnostic Accuracy Studies was performed by 2 independent masked observers. Data were extracted and analyzed to measure study-specific and pooled accuracy for (18)F-FDG PET compared with the MHLW as the reference. RESULTS: A total of 519 titles was identified; 7 studies, including the Ontario registry, were selected for inclusion. Metaanalysis of these 7 studies was conducted, with a total of 164 patients, most of whom had been diagnosed with systemic sarcoidosis. The prevalence of cardiac sarcoidosis was 50% in the whole population. Pooled estimates for (18)F-FDG PET yielded 89% sensitivity (95% confidence interval [CI], 79%-96%), 78% specificity (95% CI, 68% 86%), a 4.1 positive likelihood ratio (95% CI, 1.7-10), and a 0.19 negative likelihood ratio (95% CI, 0.1-0.4). The overall diagnostic odds ratio was 25.6 (95% CI, 7.3-89.5), and the area under the summary receiver operator characteristic curve was 93% +/- 3.5. The Ontario study yielded sensitivity and specificity of 79% and 70%, respectively. CONCLUSION: The high diagnostic accuracy determined for (18)F-FDG PET in this metaanalysis suggests potential value for diagnosis of cardiac sarcoidosis compared with the MHLW guidelines. These results may affect patient care by providing supportive evidence for more effective use of (18)F-FDG PET in the diagnosis of cardiac sarcoidosis. Large scale multicenter studies are required to further evaluate this role. PMID- 22228795 TI - Comparison of clinical tools for measurements of regional stress and rest myocardial blood flow assessed with 13N-ammonia PET/CT. AB - Several models for the quantitative analysis of myocardial blood flow (MBF) at stress and rest and myocardial flow reserve (MFR) with (13)N-ammonia myocardial perfusion PET have been implemented for clinical use. We aimed to compare quantitative results obtained from 3 software tools (QPET, syngo MBF, and PMOD), which perform PET MBF quantification with either a 2-compartment model (QPET and syngo MBF) or a 1-compartment model (PMOD). METHODS: We considered 33 adenosine stress and rest (13)N-ammonia studies (22 men and 11 women). Average age was 54.5 +/- 15 y, and average body mass index was 26 +/- 4.2. Eighteen patients had a very low likelihood of disease, with no chest pain, normal relative perfusion results, and normal function. All data were obtained on a PET/CT scanner in list mode with CT attenuation maps. Sixteen dynamic frames were reconstructed (twelve 10-s, two 30-s, one 1-min, and one 6-min frames). Global and regional stress and rest MBF and MFR values were obtained with each tool. Left ventricular contours and input function region were obtained automatically in system QPET and syngo MBF and manually in PMOD. RESULTS: The flow values and MFR values were highly correlated among the 3 packages (R(2) ranging from 0.88 to 0.92 for global values and from 0.78 to 0.94 for regional values. Mean reference MFR values were similar for QPET, syngo MBF, and PMOD (3.39 +/- 1.22, 3.41 +/- 0.76, and 3.66 +/- 1.19, respectively) by 1-way ANOVA (P = 0.74). The lowest MFR in very low likelihood patients in any given vascular territory was 2.25 for QPET, 2.13 for syngo MBF, and 2.23 for PMOD. CONCLUSION: Different implementations of 1- and 2-compartment models demonstrate an excellent correlation in MFR for each vascular territory, with similar mean MFR values. PMID- 22228796 TI - Targeted near-infrared imaging of the erythropoietin receptor in human lung cancer xenografts. AB - The putative presence of the erythropoietin receptor (EpoR) on human cancer cells has given rise to controversial discussion about the use of recombinant human erythropoietin (rhuEpo) for treatment of patients with chemotherapy-induced anemia. In vivo analysis of the EpoR status in tumors could help in elucidating the role of erythropoietin in cancer. Thus, the aim of this study was to develop a targeted EpoR probe for the investigation of EpoR expression in human lung cancer xenografts by fluorescence-mediated tomography. METHODS: Epo-Cy5.5 was generated by coupling Cy5.5 to rhuEpo. In vitro binding assays were performed using the EpoR-positive non-small cell lung cancer (NSCLC) cell lines A549 (lower EpoR expression) and H838 (higher EpoR expression), the EpoR-negative cell line H2030, and EpoR/EGFP-overexpressing HeLa cells. In vivo specificity of Epo-Cy5.5 was confirmed by competition analyses using micro-CT/fluorescence-mediated tomography fusion imaging. Biodistribution was analyzed over 50 h after injection. Binding of Epo-Cy5.5 was validated on tumor cryosections. RESULTS: After intravenous injection, the probe was rapidly cleared from the circulation. An accumulation was observed in liver and kidneys, with a maximum at 7 h after injection followed by a decline, indicating renal excretion. Almost constant accumulation of Epo-Cy5.5 was found in bone marrow and tumors, indicating specific receptor binding. The probe allowed the discrimination between H838 with higher EpoR expression (89.54 +/- 15.91 nM at 25 h) and A549 tumors with lower EpoR expression (60.45 +/- 14.59 nM at 25 h, P < 0.05). Tumor accumulation of Epo Cy5.5 could be significantly reduced by adding unlabeled rhuEpo (P < 0.05 at 4, 7, and 24 h). In vitro validation confirmed specific binding of Epo-Cy5.5 to the tumor cells, and this binding correlated with the EpoR expression level. Binding was also observed on endothelial cells. Vessel density and Epo-Cy5.5 binding on endothelial cells were comparable. CONCLUSION: Epo-Cy5.5 allows the longitudinal analysis of EpoR expression in tumors and thereby can investigate the influence of erythropoietin on EpoR expression, tumor growth, and angiogenesis. PMID- 22228797 TI - Adaptation to sensory-motor reflex perturbations is blind to the source of errors. AB - In the study of visual-motor control, perhaps the most familiar findings involve adaptation to externally imposed movement errors. Theories of visual-motor adaptation based on optimal information processing suppose that the nervous system identifies the sources of errors to effect the most efficient adaptive response. We report two experiments using a novel perturbation based on stimulating a visually induced reflex in the reaching arm. Unlike adaptation to an external force, our method induces a perturbing reflex within the motor system itself, i.e., perturbing forces are self-generated. This novel method allows a test of the theory that error source information is used to generate an optimal adaptive response. If the self-generated source of the visually induced reflex perturbation is identified, the optimal response will be via reflex gain control. If the source is not identified, a compensatory force should be generated to counteract the reflex. Gain control is the optimal response to reflex perturbation, both because energy cost and movement errors are minimized. Energy is conserved because neither reflex-induced nor compensatory forces are generated. Precision is maximized because endpoint variance is proportional to force production. We find evidence against source-identified adaptation in both experiments, suggesting that sensory-motor information processing is not always optimal. PMID- 22228798 TI - Mutualism with plants drives primate diversification. AB - Understanding the origin of diversity is a fundamental problem in biology. Evolutionary diversification has been intensely explored during the last years due to the development of molecular tools and the comparative method. However, most studies are conducted using only information from extant species. This approach probably leads to misleading conclusions, especially because of inaccuracy in the estimation of extinction rates. It is critical to integrate the information generated by extant organisms with the information obtained from the fossil record. Unfortunately, this integrative approach has been seldom performed, and thus, our understanding of the factors fueling diversification is still deficient. Ecological interactions are a main factor shaping evolutionary diversification by influencing speciation and extinction rates. Most attention has focused on the effect of antagonistic interactions on evolutionary diversification. In contrast, the role of mutualistic interactions in shaping diversification has been much less explored. In this study, by combining phylogenetic, neontological, and paleontological information, we show that a facultative mutualistic plant-animal interaction emerging from frugivory and seed dispersal has most likely contributed to the diversification of our own lineage, the primates. We compiled diet and seed dispersal ability in 381 extant and 556 extinct primates. Using well-established molecular phylogenies, we demonstrated that mutualistic extant primates had higher speciation rates, lower extinction rates, and thereby higher diversification rates than nonmutualistic ones. Similarly, mutualistic fossil primates had higher geological durations and smaller per capita rates of extinction than nonmutualistic ones. As a mechanism underlying this pattern, we found that mutualistic extinct and extant primates have significantly larger geographic ranges, which promotes diversification by hampering extinction and increasing geographic speciation. All these outcomes together strongly suggest that the establishment of a facultative mutualism with plants has greatly benefited primate evolution and fueled its taxonomic diversification. PMID- 22228800 TI - Taxon influence index: assessing taxon-induced incongruities in phylogenetic inference. AB - Understanding the evolutionary history of species is at the core of molecular evolution and is done using several inference methods. The critical issue is to quantify the uncertainty of the inference. The posterior probabilities in Bayesian phylogenetic inference and the bootstrap values in frequentist approaches measure the variability of the estimates due to the sampling of sites from genes and the sampling of genes from genomes. However, they do not measure the uncertainty due to taxon sampling. Taxa that experienced molecular homoplasy, recent selection, a spur of evolution, and so forth may disrupt the inference and cause incongruences in the estimated phylogeny. We define a taxon influence index to assess the influence of each taxon on the phylogeny. We found that although most taxa have a weak influence on the phylogeny, a small fraction of influential taxa strongly alter it even in clades only loosely related to them. We conclude that highly influential taxa should be given special attention and sampling them more thoroughly can lead to more dependable phylogenies. PMID- 22228801 TI - Increasing psychotherapy dose from 8 to 16 sessions does not improve social functioning in people with major depressive disorder receiving pharmacotherapy. PMID- 22228799 TI - Multiple continental radiations and correlates of diversification in Lupinus (Leguminosae): testing for key innovation with incomplete taxon sampling. AB - Replicate radiations provide powerful comparative systems to address questions about the interplay between opportunity and innovation in driving episodes of diversification and the factors limiting their subsequent progression. However, such systems have been rarely documented at intercontinental scales. Here, we evaluate the hypothesis of multiple radiations in the genus Lupinus (Leguminosae), which exhibits some of the highest known rates of net diversification in plants. Given that incomplete taxon sampling, background extinction, and lineage-specific variation in diversification rates can confound macroevolutionary inferences regarding the timing and mechanisms of cladogenesis, we used Bayesian relaxed clock phylogenetic analyses as well as MEDUSA and BiSSE birth-death likelihood models of diversification, to evaluate the evolutionary patterns of lineage accumulation in Lupinus. We identified 3 significant shifts to increased rates of net diversification (r) relative to background levels in the genus (r = 0.18-0.48 lineages/myr). The primary shift occurred approximately 4.6 Ma (r = 0.48-1.76) in the montane regions of western North America, followed by a secondary shift approximately 2.7 Ma (r = 0.89-3.33) associated with range expansion and diversification of allopatrically distributed sister clades in the Mexican highlands and Andes. We also recovered evidence for a third independent shift approximately 6.5 Ma at the base of a lower elevation eastern South American grassland and campo rupestre clade (r = 0.36-1.33). Bayesian ancestral state reconstructions and BiSSE likelihood analyses of correlated diversification indicated that increased rates of speciation are strongly associated with the derived evolution of perennial life history and invasion of montane ecosystems. Although we currently lack hard evidence for "replicate adaptive radiations" in the sense of convergent morphological and ecological trajectories among species in different clades, these results are consistent with the hypothesis that iteroparity functioned as an adaptive key innovation, providing a mechanism for range expansion and rapid divergence in upper elevation regions across much of the New World. PMID- 22228802 TI - Comorbid dyslipidaemia and diabetes, but not antipsychotic use, is associated with unexplained sudden death among psychiatric patients. PMID- 22228803 TI - Cochrane review: In adults with chronic kidney disease regular exercise improves physical fitness, walking capacity, heart rate and blood pressure and some nutritional parameters. PMID- 22228804 TI - Pharmacokinetics of melamine and cyanuric acid and their combinations in F344 rats. AB - The intentional adulteration of pet food with melamine and cyanuric acid has been implicated in the kidney failure and death of a large number of cats and dogs in the United States. Although individually these compounds present low toxicity in a range of experimental animals, coexposure can lead to the formation of melamine cyanurate crystals in the nephrons and eventual kidney failure. Given this mode of action, a good understanding of the pharmacokinetic profiles of melamine and cyanuric acid and their combinations is essential to define properly the risk associated with different exposure scenarios. Previous studies have investigated the individual pharmacokinetic profiles of melamine and cyanuric acid. In this work, we report a comparison between the pharmacokinetic profiles of melamine and cyanuric acid administered individually, administered simultaneously as the individual compounds, and administered as a preformed melamine cyanurate complex. Although the oral coadministration of 1 mg/kg body weight of melamine and cyanuric acid did not alter significantly the pharmacokinetic profiles in relation to those determined upon individual oral administration of each compound, the administration of equal amounts of each triazine as the preformed melamine cyanurate complex significantly altered the pharmacokinetics, with reduced bioavailability of both compounds, lower observed maximum serum concentrations, delayed peak concentrations, and prolonged elimination half lives. These results indicate that in order to estimate properly the combined nephrotoxic potential of melamine and cyanuric acid, the experimental design of toxicological experiments and the evaluation of animal or human exposure scenarios should consider the detailed mode of exposure, with particular emphasis on any possible ex vivo formation of melamine cyanurate. PMID- 22228807 TI - RN486, a selective Bruton's tyrosine kinase inhibitor, abrogates immune hypersensitivity responses and arthritis in rodents. AB - Genetic mutation and pharmacological inhibition of Bruton's tyrosine kinase (Btk) both have been shown to prevent the development of collagen-induced arthritis (CIA) in mice, providing a rationale for the development of Btk inhibitors for treating rheumatoid arthritis (RA). In the present study, we characterized a novel Btk inhibitor, 6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5 (4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl} phenyl)-2H-isoquinolin-1-one (RN486), in vitro and in rodent models of immune hypersensitivity and arthritis. We demonstrated that RN486 not only potently and selectively inhibited the Btk enzyme, but also displayed functional activities in human cell-based assays in multiple cell types, blocking Fcepsilon receptor cross linking-induced degranulation in mast cells (IC(50) = 2.9 nM), Fcgamma receptor engagement-mediated tumor necrosis factor alpha production in monocytes (IC(50) = 7.0 nM), and B cell antigen receptor-induced expression of an activation marker, CD69, in B cells in whole blood (IC(50) = 21.0 nM). RN486 displayed similar functional activities in rodent models, effectively preventing type I and type III hypersensitivity responses. More importantly, RN486 produced robust anti inflammatory and bone-protective effects in mouse CIA and rat adjuvant-induced arthritis (AIA) models. In the AIA model, RN486 inhibited both joint and systemic inflammation either alone or in combination with methotrexate, reducing both paw swelling and inflammatory markers in the blood. Together, our findings not only demonstrate that Btk plays an essential and conserved role in regulating immunoreceptor-mediated immune responses in both humans and rodents, but also provide evidence and mechanistic insights to support the development of selective Btk inhibitors as small-molecule disease-modifying drugs for RA and potentially other autoimmune diseases. PMID- 22228805 TI - Inherent and benzo[a]pyrene-induced differential aryl hydrocarbon receptor signaling greatly affects life span, atherosclerosis, cardiac gene expression, and body and heart growth in mice. AB - Little is known of the environmental factors that initiate and promote disease. The aryl hydrocarbon receptor (AHR) is a key regulator of xenobiotic metabolism and plays a major role in gene/environment interactions. The AHR has also been demonstrated to carry out critical functions in development and disease. A qualitative investigation into the contribution by the AHR when stimulated to different levels of activity was undertaken to determine whether AHR-regulated gene/environment interactions are an underlying cause of cardiovascular disease. We used two congenic mouse models differing at the Ahr gene, which encodes AHRs with a 10-fold difference in signaling potencies. Benzo[a]pyrene (BaP), a pervasive environmental toxicant, atherogen, and potent agonist for the AHR, was used as the environmental agent for AHR activation. We tested the hypothesis that activation of the AHR of different signaling potencies by BaP would have differential effects on the physiology and pathology of the mouse cardiovascular system. We found that differential AHR signaling from an exposure to BaP caused lethality in mice with the low-affinity AHR, altered the growth rates of the body and several organs, induced atherosclerosis to a greater extent in mice with the high-affinity AHR, and had a huge impact on gene expression of the aorta. Our studies also demonstrated an endogenous role for AHR signaling in regulating heart size. We report a gene/environment interaction linking differential AHR signaling in the mouse to altered aorta gene expression profiles, changes in body and organ growth rates, and atherosclerosis. PMID- 22228806 TI - Activation of protein kinase C (PKC)alpha or PKCepsilon as an approach to increase morphine tolerance in respiratory depression and lethal overdose. AB - Long-term use of opioids is hindered by respiratory depression and the possibility for fatal overdose in drug abusers. This is attributed to higher levels of tolerance that develops against antinociception than to respiratory depression. Identifying important mechanisms that would increase morphine respiratory depression and overdose tolerance could lead to the safer use of opioids. Because protein kinase C (PKC) activity mediates the development and maintenance of morphine antinociceptive tolerance, we hypothesized that activating PKCalpha or PKCepsilon at the pre-Botzinger complex (preBotC) can increase morphine tolerance in respiration and overdose. Laser microdissection and quantitative reverse transcriptase-polymerase chain reaction were used to compare the relative mRNA abundances of PKCalpha, gamma, and epsilon between ventrolateral periaqueductal gray (vlPAG) and preBotC. To test whether PKCalpha or epsilon could enhance morphine tolerance in respiratory depression and overdose, lentivirus carrying the wild type, constitutively activated mutants, and small interference RNA against PKCalpha or epsilon was stereotaxically injected into the preBotC. Expression of constitutively active PKC (CAPKC) alpha or epsilon, but not wild-type PKC (WTPKC) alpha or epsilon, at the preBotC allowed rats to develop tolerance to morphine respiratory depression. In terms of lethality, expression of WTPKCepsilon, CAPKCalpha, or CAPKCepsilon at preBotC increased morphine tolerance to lethal overdose. CAPKCepsilon-expressing rats developed the highest level of respiratory depression tolerance. Furthermore, when CAPKCepsilon lentivirus was injected into the vlPAG, rats were able to develop significant antinociceptive tolerance at low doses of morphine that normally do not cause tolerance. The approach of increasing morphine respiratory depression and lethality tolerance by increasing PKCalpha or epsilon activity at preBotC could be used to make opioids safer for long-term use. PMID- 22228808 TI - Interferon-gamma activates transglutaminase 2 via a phosphatidylinositol-3-kinase dependent pathway: implications for celiac sprue therapy. AB - The mechanism for activation of extracellular transglutaminase 2 (TG2) in the small intestine remains a fundamental mystery in our understanding of celiac sprue pathogenesis. Using the T84 human enterocytic cell line, we show that interferon-gamma (IFN-gamma), the predominant cytokine secreted by gluten reactive T cells in the celiac intestine, activates extracellular TG2 in a dose dependent manner. IFN-gamma mediated activation of TG2 requires phosphatidylinositol-3-kinase (PI3K) activity, but is uninfluenced by a number of other kinases reported to be active in T84 cells. Pharmacological inhibition of PI3K in the presence of IFN-gamma prevents TG2 activation as well as the previously characterized increase in transepithelial permeability. Our findings therefore establish PI3K as an attractive target for celiac sprue therapy, a possibility that is underscored by the encouraging safety profiles of several PI3K inhibitors undergoing human clinical trials. PMID- 22228810 TI - Trends in excipient safety evaluation. AB - Excipients are used in all drug products and in most food products. New technologies are being tested to increase the amount or rate of absorption of drugs and new and novel excipients may be included among them. New physical approaches such as nanoparticles of drug and excipients or lysosomes may offer better drug delivery especially of hard to absorb or difficult to formulate oral drugs. New excipients may improve or mask the flavor of foods, drugs, and dietary supplements. Recently, impurities in drug products have become subject to greater scrutiny and various international and national guidelines, guidances, and regulations have been proposed and accepted for use; excipient evaluation is included in these efforts. This symposium discussed new developmental concepts, guidelines/guidances and regulations involving impurities in excipients, new drug delivery systems involving excipients, and thoughts for possible improvement to these guidelines to promote faster regulatory acceptance of these substances. PMID- 22228809 TI - Recovery from glycerol-induced acute kidney injury is accelerated by suramin. AB - Acute kidney injury (AKI) is a common and potentially life-threatening complication after ischemia/reperfusion and exposure to nephrotoxic agents. In this study, we examined the efficacy and mechanism(s) of suramin in promoting recovery from glycerol-induced AKI, a model of rhabdomyolysis-induced AKI. After intramuscular glycerol injection (10 ml of 50% glycerol per kilogram) into male Sprague-Dawley rats, serum creatinine maximally increased at 24 to 72 h and then decreased at 120 h. Creatinine clearance (CrCl) decreased 75% at 24 to 72 h and increased at 120 h. Suramin (1 mg/kg i.v.) administered 24 h after glycerol accelerated recovery of renal function as demonstrated by increased CrCl, decreased renal kidney injury molecule-1, and improved histopathology 72 h after glycerol injection. Suramin treatment decreased interleukin-1beta (IL-1beta) mRNA, transforming growth factor-beta(1) (TGF-beta(1)), phospho-p65 of nuclear factor-kappaB (NF-kappaB), and cleaved caspase-3 at 48 h compared with glycerol alone. Suramin treatment also decreased glycerol-induced activation of intracellular adhesion molecule-1 (ICAM-1) and leukocyte infiltration at 72 h. Urinary/renal neutrophil gelatinase-associated lipocalin 2 (NGAL) levels, hemeoxygenase-1 expression, and renal cell proliferation were increased by suramin compared with glycerol alone at 72 h. Mechanistically, suramin decreases early glycerol-induced proinflammatory (IL-1beta and NF-kappaB) and growth inhibitory (TGF-beta(1)) mediators, resulting in the prevention of late downstream inflammatory effects (ICAM-1 and leukocyte infiltration) and increasing compensatory nephrogenic repair. These results support the hypothesis that delayed administration of suramin is effective in abrogating apoptosis, attenuating inflammation, and enhancing nephrogenic repair after glycerol-induced AKI. PMID- 22228811 TI - Dr Peter J. Bugelski (1953-2011). PMID- 22228812 TI - American College of Toxicology: policy statement on the use of animals in toxicology. PMID- 22228813 TI - Giant aortic pseudoaneurysm fistulized into right atrium. PMID- 22228814 TI - Association between low income, depression, self-efficacy and mass-incident related strains: an understanding of mass incidents in China. AB - BACKGROUND: This study investigated the associations between income, depression, self-efficacy and health and the strains associated with mass incidents in a Chinese city. It further investigated whether depression, self-efficacy and health status mediate relationships between income and mass-incident-related strains. SUBJECTS AND METHODS: A representative sample of mass-incident participants from Chong Qing, aged 18 years and over, participated using a questionnaire. Of the 480 surveys returned, 465 (88%) were usable. Structural equation modelling was used to analyse the relationship model to use strains as the main outcome variable, income as a predictor and self-rated general health status, depression and self-efficacy as mediators. RESULTS: High levels of strains were significantly associated with low levels of income, and this association was mediated by a fair to poor level of health status, depression and low levels of self-efficacy. CONCLUSIONS: Income as an indicator of social inequality revealed its significant predictive role in the occurrence of mass incidents through its impact on high levels of strains and its association with depression, fair to poor health and low levels of self-efficacy. Further study will benefit from a follow-up study to determine the causal relationship between income and strains, and a representative population that includes children and the elderly be included in the next phase of the study. PMID- 22228815 TI - High-frequency analysis of the complex linkage between soil CO(2) fluxes, photosynthesis and environmental variables. AB - High-frequency soil CO(2) flux data are valuable for providing new insights into the processes of soil CO(2) production. A record of hourly soil CO(2) fluxes from a semi-arid ponderosa pine stand was spatially and temporally deconstructed in attempts to determine if variation could be explained by logical drivers using (i) CO(2) production depths, (ii) relationships and lags between fluxes and soil temperatures, or (iii) the role of canopy assimilation in soil CO(2) flux variation. Relationships between temperature and soil fluxes were difficult to establish at the hourly scale because diel cycles of soil fluxes varied seasonally, with the peak of flux rates occurring later in the day as soil water content decreased. Using a simple heat transport/gas diffusion model to estimate the time and depth of CO(2) flux production, we determined that the variation in diel soil CO(2) flux patterns could not be explained by changes in diffusion rates or production from deeper soil profiles. We tested for the effect of gross ecosystem productivity (GEP) by minimizing soil flux covariance with temperature and moisture using only data from discrete bins of environmental conditions (+/-1 degrees C soil temperature at multiple depths, precipitation-free periods and stable soil moisture). Gross ecosystem productivity was identified as a possible driver of variability at the hourly scale during the growing season, with multiple lags between ~5, 15 and 23 days. Additionally, the chamber-specific lags between GEP and soil CO(2) fluxes appeared to relate to combined path length for carbon flow (top of tree to chamber center). In this sparse and heterogeneous forested system, the potential link between CO(2) assimilation and soil CO(2) flux may be quite variable both temporally and spatially. For model applications, it is important to note that soil CO(2) fluxes are influenced by many biophysical factors, which may confound or obscure relationships with logical environmental drivers and act at multiple temporal and spatial scales; therefore, caution is needed when attributing soil CO(2) fluxes to covariates like temperature, moisture and GEP. PMID- 22228816 TI - Evaluation of four phloem-specific promoters in vegetative tissues of transgenic citrus plants. AB - 'Mexican' lime (Citrus aurantifolia Swingle) was transformed with constructs that contained chimeric promoter-gus gene fusions of phloem-specific rolC promoter of Agrobacterium rhizogenes, Arabidopsis thaliana sucrose-H(+) symporter (AtSUC2) gene promoter of Arabidopsis thaliana, rice tungro bacilliform virus (RTBV) promoter and sucrose synthase l (RSs1) gene promoter of Oryza sativa (rice). Histochemical beta-glucuronidase (GUS) analysis revealed vascular-specific expression of the GUS protein in citrus. The RTBV promoter was the most efficient promoter in this study while the RSs1 promoter could drive low levels of gus gene expression in citrus. These results were further validated by reverse transcription real-time polymerase chain reaction and northern blotting. Southern blot analysis confirmed stable transgene integration, which ranged from a single insertion to four copies per genome. The use of phloem-specific promoters in citrus will allow targeted transgene expression of antibacterial constructs designed to battle huanglongbing disease (HLB or citrus greening disease), associated with a phloem-limited Gram-negative bacterium. PMID- 22228817 TI - Increased resin flow in mature pine trees growing under elevated CO2 and moderate soil fertility. AB - Warmer climates induced by elevated atmospheric CO(2) (eCO(2)) are expected to increase damaging bark beetle activity in pine forests, yet the effect of eCO(2) on resin production--the tree's primary defense against beetle attack--remains largely unknown. Following growth-differentiation balance theory, if extra carbohydrates produced under eCO(2) are not consumed by respiration or growth, resin production could increase. Here, the effect of eCO(2) on resin production of mature pines is assessed. As predicted, eCO(2) enhanced resin flow by an average of 140% (P=0.03) in canopy dominants growing in low-nitrogen soils, but did not affect resin flow in faster-growing fertilized canopy dominants or in carbohydrate-limited suppressed individuals. Thus, pine trees may become increasingly protected from bark beetle attacks in an eCO(2) climate, except where they are fertilized or are allowed to become overcrowded. PMID- 22228818 TI - Cognitive neuroenhancement: false assumptions in the ethical debate. AB - The present work critically examines two assumptions frequently stated by supporters of cognitive neuroenhancement. The first, explicitly methodological, assumption is the supposition of effective and side effect-free neuroenhancers. However, there is an evidence-based concern that the most promising drugs currently used for cognitive enhancement can be addictive. Furthermore, this work describes why the neuronal correlates of key cognitive concepts, such as learning and memory, are so deeply connected with mechanisms implicated in the development and maintenance of addictive behaviour so that modification of these systems may inevitably run the risk of addiction to the enhancing drugs. Such a potential risk of addiction could only be falsified by in-depth empirical research. The second, implicit, assumption is that research on neuroenhancement does not pose a serious moral problem. However, the potential for addiction, along with arguments related to research ethics and the potential social impact of neuroenhancement, could invalidate this assumption. It is suggested that ethical evaluation needs to consider the empirical data as well as the question of whether and how such empirical knowledge can be obtained. PMID- 22228819 TI - Fibroblast growth factor-2 is an important factor that maintains cellular immaturity and contributes to aggressiveness of osteosarcoma. AB - Osteosarcoma is the most frequent, nonhematopoietic, primary malignant tumor of bone. Histopathologically, osteosarcoma is characterized by complex mixtures of different cell types with bone formation. The role of environmental factors in the formation of such a complicated tissue structure as osteosarcoma remains to be elucidated. Here, a newly established murine osteosarcoma model was used to clarify the roles of environmental factors such as fibroblast growth factor-2 (Fgf2) or leukemia-inhibitory factor (Lif) in the maintenance of osteosarcoma cells in an immature state. These factors were highly expressed in tumor environmental stromal cells, rather than in osteosarcoma cells, and they potently suppressed osteogenic differentiation of osteosarcoma cells in vitro and in vivo. Further investigation revealed that the hyperactivation of extracellular signal regulated kinase (Erk)1/2 induced by these factors affected in the process of osteosarcoma differentiation. In addition, Fgf2 enhanced both proliferation and migratory activity of osteosarcoma cells and modulated the sensitivity of cells to an anticancer drug. The results of the present study suggest that the histology of osteosarcoma tumors which consist of immature tumor cells and pathologic bone formations could be generated dependent on the distribution of such environmental factors. The combined blockade of the signaling pathways of several growth factors, including Fgf2, might be useful in controlling the aggressiveness of osteosarcoma. PMID- 22228820 TI - CD4+ T-lymphocyte count/CD8+ T-lymphocyte count ratio: surrogate for HIV infection in infants? AB - INTRODUCTION: Early diagnosis and treatment is necessary to prevent HIV-infected infants progressing to AIDS. Antibody testing is not confirmatory before the age of 18 months and PCR not widely available in resource-poor settings. We studied the accuracy of CD4(+) T-lymphocyte count, CD4% and CD4/CD8 ratio as surrogate markers of infant HIV infection. METHODS: Two hundred and fifty-eight HIV-exposed Indian infants at a median age of 5 months (range 1-18) had DNA PCR and CD4, CD8 counts performed. RESULTS: Fifty five infants tested positive by HIV-1 DNA PCR whereas 203 were negative. Median CD4 count, CD4% and CD4/CD8 ratio were significantly lower in DNA PCR+ infants. Overall sensitivity and specificity of CD4/CD8 ratio <1.0 in predicting HIV was 91 and 92% with a negative predicted value (NPV) and positive predicted value (PPV) of 97 and 76%, respectively. CONCLUSION: CD4/CD8 ratio <1.0 is a more sensitive surrogate marker of HIV infection in Indian infants than a CD4 count <1500 cells/ul or CD4% <25%. PMID- 22228821 TI - Why prevention of rheumatic heart disease should be a component of primary healthcare. PMID- 22228822 TI - The EGFR T790M mutation in acquired resistance to an irreversible second generation EGFR inhibitor. AB - Molecular target therapies using first-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib or erlotinib, have been shown to be effective for patients with non-small cell lung cancer (NSCLC) who harbor activating mutations in EGFR. However, these patients eventually develop resistance to the reversible TKIs, and this has led to the development of second-generation, irreversible EGFR inhibitors. Currently, the mechanism of acquired resistance to irreversible EGFR inhibitors is not clear. Using an in vitro cell culture system, we modeled the acquired resistance to first-line treatment with second-generation EGFR-TKIs using an EGFR-mutant NSCLC cell line. Here, we report a mechanism of resistance involving T790M secondary mutation as well as a corresponding clinical case. The results of these findings suggest that inhibition of EGFR by currently available second-generation EGFR TKIs may not be sufficient to physiologically prevent the emergence of cells that are still dependent on EGFR signaling. This finding bears important implications on the limitations of currently available second-generation EGFR-TKIs. PMID- 22228823 TI - Studies on genotoxicity and carcinogenicity of antibacterial, antiviral, antimalarial and antifungal drugs. AB - This review provides a compendium of retrievable results of genotoxicity and animal carcinogenicity studies performed of antibacterial, antiviral, antimalarial and antifungal drugs of long-term or intermittent frequent use. Of the 48 drugs considered, 9 (18.75%) do not have retrievable data, whereas the other 39 (81.25%) have at least one genotoxicity or carcinogenicity tests result. Of these 39 drugs, 24 tested positive in at least one genotoxicity assay and 19 in at least one carcinogenicity assay; 14 of them gave a positive response in both at least one genotoxicity assay and at least one carcinogenicity assay. Concerning the predictivity of genetic toxicology findings for the results of long-term carcinogenesis assays, of 23 drugs with both genotoxicity and carcinogenicity data: 2 (8.7%) were neither genotoxic nor carcinogenic, 2 (8.7%) tested positive in at least one genotoxicity assay but were non-carcinogenic, 4 (17.4%) tested negative in genotoxicity assays but were carcinogenic, and 15 (65.2%) gave a positive response in at least one genotoxicity assay and in at least one carcinogenicity assay. Only 18 (37.5%) of the 48 drugs examined had all data required by present guidelines for testing of pharmaceuticals, but a fraction of them (49%) were developed and marketed prior to the present regulatory climate. In the absence of compelling indications, the prescription of the 19 drugs that are animal carcinogens should be avoided. PMID- 22228824 TI - Montreal cognitive assessment in detecting cognitive impairment in Chinese elderly individuals: a population-based study. AB - The Montreal Cognitive Assessment (MoCA) has been proved brief and sensitive to screen for mild cognitive impairment (MCI) and early dementia in some developed countries or areas. However, little MoCA data are available from mainland China. In this study, the MoCA was applied to 8411 Chinese community dwellers aged 65 or older (6283 = cognitively normal [CN], 1687 = MCI, and 441 = dementia). The MoCA norms were established considering significant influential factors. The optimal cutoff points were 13/14 for illiterate individuals, 19/20 for individuals with 1 to 6 years of education, and 24/25 for individuals with 7 or more years of education. With the optimal cutoffs, the sensitivity of the MoCA was 83.8% for all cognitive impairments, 80.5% for MCI and 96.9% for dementia, and the specificity for identifying CN was 82.5%. These indicate that with optimal cutoffs, the MoCA is valid to screen for cognitive impairment in elderly Chinese living in communities. PMID- 22228826 TI - Depressive symptoms in Parkinson disease: degree of association and rate of agreement of clinician-based and self-report measures. AB - Depression in Parkinson disease (PD) is associated with faster disease progression, lower activities of daily living, and more severe cognitive impairment. Even mild symptoms of depression may impact outcomes in patients with PD. Nevertheless, a low rate of agreement has been reported between patient and clinician ratings of depression, suggesting that clinicians may underestimate depression in patients with PD. However, to accurately compare the rates of agreement, comparable estimates are needed so that patient and clinician ratings have similar meaning (eg, mild, moderate, severe, etc). The purpose of this study was to examine this question by investigating the degree of association and rate of agreement of levels of symptom severity among self-report and clinician ratings using established cutoffs that correspond to more comparable estimates of these levels for both patient and clinician. Our findings suggest that patient's self-report of depressive symptoms was significantly correlated with clinician based report irrespective of the stage of disease. Moreover, patients demonstrated a 72% rate of agreement with clinicians in classifying symptoms as asymptomatic, mildly symptomatic, or fully symptomatic, a rate significantly higher than the rate of 35% previously reported. This difference in rate of agreement may be accounted for using varying criteria for severity levels across the studies. Findings suggest that clinician and patient reports show a high rate of agreement across a range of depressive symptoms and that self-report measures may provide a relatively efficient means of detecting depressive symptoms especially if patients are disinclined to initiate their report. PMID- 22228825 TI - Stress-related cognitive dysfunction in dementia caregivers. AB - In a cross-sectional study, 31 dementia caregivers were compared to a group of 25 noncaregiving controls to evaluate whether the stress of being the primary caregiver of a person with dementia produces cognitive dysfunction. Cognitive differences were examined to evaluate the relationships between cognitive function and stress-related physiological and psychological measures to contribute information regarding its potential mechanism. The cognitive assessments were 2 measures of attention-executive function and 1 word list memory task. Physiological and self-rated stress-related measurements included cortisol, perceived stress, depression, self-efficacy, mindfulness, sleep quality, fatigue, and neuroticism. Caregivers performed worse than noncaregivers on the 2 attention tasks but not on the word list memory test. There was no interaction of caregiver status and age on cognitive performance. The caregivers and noncaregivers differed in morning salivary cortisol and most of the self rated stress-related measures with the caregiver values reflecting greater stress. Of note, impaired sleep was the only potential mediator of the caregiver effect on cognitive performance in our small sample. PMID- 22228827 TI - Telephone-based cognitive-behavioral therapy for depression in Parkinson disease. AB - BACKGROUND: Although face-to-face cognitive-behavioral therapy (CBT) was found to be beneficial for the treatment of depression in Parkinson disease (dPD) in a recent randomized-controlled trial, access to care was identified as a critical issue that needs to be addressed in order to improve the management of this nonmotor complication in PD. The purpose of this study was to examine the feasibility and effect of telephone-based CBT for dPD. METHODS: Twenty-one depressed people with PD participated in a National Institutes of Health sponsored uncontrolled pilot trial of telephone-based CBT in an academic medical center from October 2009 to February 2011. The Hamilton Depression Rating Scale was the primary outcome. Treatment was provided to people with PD for 10 weeks, modified for delivery over the phone, and supplemented with 4 separate phone based caregiver educational sessions. Assessments were completed at baseline and 5 (midpoint), 10 (end-of-treatment), and 14 weeks (follow-up) post-enrollment. RESULTS: Twenty (95%) people with PD completed the study treatment. Phone-based CBT was associated with significant improvements in depression, anxiety, negative thoughts, and coping. Mean Hamilton Depression Rating Scale change from baseline to week 10 was 7.91 points (P < .001, Cohen d = 1.21). CONCLUSIONS: Telephone based CBT may be a feasible and helpful approach for treating dPD and warrants further exploration in randomized-controlled trials. Results were comparable to those observed in the few in-person cognitive-behavioral treatment studies for dPD conducted to date. PMID- 22228828 TI - Are vascular risk factors associated with post-stroke depressive symptoms? AB - OBJECTIVE: Vascular risk factors (VRFs) have been associated with stroke and cognitive impairment, however, the role of VRFs in predicting post-stroke depression (PSD) has not been assessed. The objective of the current study was to determine whether VRFs are associated with the risk of PSD in an acute stroke population. METHODS: In this observational study, patients meeting World Health Organization MONICA Project and National Institute of Neurological Disorders and Stroke criteria for stroke were eligible. Patients were assessed for depression, cognition, and stroke severity, and VRF and demographic information were obtained. RESULTS: A total of 102 patients were recruited within 4 months post stroke. Using a score of >=16 on the Center for Epidemiological Studies Depression scale to determine depressive symptoms, 38 patients (age 72.1 +/- 15.6, 44.7% male) screened positive for depressive symptoms and 64 (age 70.1 +/- 13.6, 51.6% male) screened negative. Analysis of VRFs showed that only hypertension (P = .044) independently predicted the presence of depressive symptoms (chi(2) = 4.742, P = .029, Nagelkerke R (2) = .062). CONCLUSIONS: Hypertension was associated with post-stroke depressive symptoms, while there was no relationship between PSD and other VRFs. Hypertension may have a greater impact than other VRFs on mood following stroke and may have a role in prevention and treatment of PSD. PMID- 22228829 TI - Sertraline for the treatment of depression in Alzheimer disease: genetic influences. AB - OBJECTIVE: To assess the potential for genetic influences on sertraline treatment efficacy for depression of Alzheimer disease (dAD). Four functional genetic variants were studied: 2 serotonin receptors (HTR2A-T102C and HTR2C-Cys23Ser), the serotonin transporter (5HTT-LPR), and brain-derived neurotrophic factor (BDNF Val66Met). Treatment response by genotype was measured by (1) the modified Alzheimer's Disease Cooperative Study Clinical Global Impression of Change, (2) the Cornell scale for Depression in Dementia, and (3) remission of depression. METHODS: We utilized data from the Depression in Alzheimer's Disease Study 2 (DIADS-2), a 24-week, randomized, multicenter trial showing no significant treatment effect of sertraline on dAD. Proportional odds logistic regression and mixed effects models were used to examine the above mentioned outcome measures. RESULTS: No significant interactions were seen between any of the genetic polymorphisms and the selected outcomes above at 12 or 24 weeks. DISCUSSION: Treatment outcomes in the DIADS-2 trial were not significantly influenced by genetic variation at the loci that were assessed. Future studies should continue to examine the interaction of depression-related genetic variants with antidepressant treatment in Alzheimer disease patients with depression. PMID- 22228830 TI - Irritability and social isolation in dementia patients with and without depression. AB - This study examined the prevalence of irritability and social isolation in veterans with dementia, with and without depression. Participants were diagnosed with dementia and enrolled in a dementia care-coordination and support-service intervention. Participants were interviewed and underwent assessment with the 10 item Center for Epidemiologic Studies Depression scale, a Patient Strain Measure and the Short Blessed Test. In all, of 294 participants completing interviews, 77 (26.2%) were depressed and 107 (36.4%) endorsed irritability; mean social isolation score was 1.59 +/- 1.96. Irritability was significantly more likely to be present in depressed versus nondepressed participants (P < .0001), but this relationship was moderated by dementia severity. The mean social isolation score was also significantly more elevated in depressed rather than nondepressed patients (2.82 +/- 1.96 vs 1.15 +/- 1.76, respectively). CONCLUSIONS: Depressed persons with dementia are significantly more likely to experience irritability and social isolation than those who are not depressed. PMID- 22228831 TI - XRCC4's interaction with XLF is required for coding (but not signal) end joining. AB - XRCC4 and XLF are structurally related proteins important for DNA Ligase IV function. XRCC4 forms a tight complex with DNA Ligase IV while XLF interacts directly with XRCC4. Both XRCC4 and XLF form homodimers that can polymerize as heterotypic filaments independently of DNA Ligase IV. Emerging structural and in vitro biochemical data suggest that XRCC4 and XLF together generate a filamentous structure that promotes bridging between DNA molecules. Here, we show that ablating XRCC4's affinity for XLF results in DNA repair deficits including a surprising deficit in VDJ coding, but not signal end joining. These data are consistent with a model whereby XRCC4/XLF complexes hold DNA ends together- stringently required for coding end joining, but dispensable for signal end joining. Finally, DNA-PK phosphorylation of XRCC4/XLF complexes disrupt DNA bridging in vitro, suggesting a regulatory role for DNA-PK's phosphorylation of XRCC4/XLF complexes. PMID- 22228832 TI - A highly efficient and effective motif discovery method for ChIP-seq/ChIP-chip data using positional information. AB - Identification of DNA motifs from ChIP-seq/ChIP-chip [chromatin immunoprecipitation (ChIP)] data is a powerful method for understanding the transcriptional regulatory network. However, most established methods are designed for small sample sizes and are inefficient for ChIP data. Here we propose a new k-mer occurrence model to reflect the fact that functional DNA k mers often cluster around ChIP peak summits. With this model, we introduced a new measure to discover functional k-mers. Using simulation, we demonstrated that our method is more robust against noises in ChIP data than available methods. A novel word clustering method is also implemented to group similar k-mers into position weight matrices (PWMs). Our method was applied to a diverse set of ChIP experiments to demonstrate its high sensitivity and specificity. Importantly, our method is much faster than several other methods for large sample sizes. Thus, we have developed an efficient and effective motif discovery method for ChIP experiments. PMID- 22228833 TI - The story of the evolution of a unique tai chi form: origins, philosophy, and research. AB - The purpose of this article is to introduce a unique tai chi form that has been successfully implemented in two large randomized clinical trials. The intervention is composed of a series of tai chi movements chosen for their particular meanings, thus adding a cognitive component to the practice of a moving meditation. Over the last decade, the intervention has continued to evolve as it has been used in different populations. Most recently, medical qigong has been integrated to strengthen its potential impact on a variety of biobehavioral measures associated with cardiometabolic risk in women. Following an appraisal of the authors' process as well as the philosophy, practice, and research of tai chi and qigong, the authors share the story of their intervention to contribute to the evolving research of these safe, well-received, low-cost, and beneficial practices. PMID- 22228835 TI - 35% CO2 sensitivity in social anxiety disorder. AB - The 35% carbon dioxide (CO(2)) challenge is a well-established model of panic. This study aimed to investigate 35% CO(2) sensitivity in patients with social anxiety disorder (SAD) compared with patients with panic disorder (PD) and normal controls. First, a 35% CO(2) challenge was conducted including 16 patients with generalized SAD, 16 with PD and 16 normal subjects. Outcome was assessed by a Visual Analogue Scale for Fear (VAS-F) and the Panic Symptom List (PSL). Second, meta-analyses of fear and panic scores were performed, including data from the present experiment and from previous 35% CO(2) challenge studies in patients with SAD. The present 35% CO(2) challenge found equal increases in VAS-F and PSL in patients with SAD compared with normal controls, whereas the CO(2) response in patients with PD was significantly stronger than in controls. The meta-analyses confirmed the experimental data from this study, and in addition showed an intermediate panic rate in SAD patients, in between that of normal controls and patients with PD. In conclusion, neither our experiment nor the meta-analyses found evidence for a similarly exaggerated 35% CO(2) sensitivity in SAD and PD, suggesting that the pathogenesis of SAD is different from PD, although patients with SAD may be slightly more sensitive than non-anxious controls. PMID- 22228834 TI - Correction of RT-qPCR data for genomic DNA-derived signals with ValidPrime. AB - Genomic DNA (gDNA) contamination is an inherent problem during RNA purification that can lead to non-specific amplification and aberrant results in reverse transcription quantitative PCR (RT-qPCR). Currently, there is no alternative to RT(-) controls to evaluate the impact of the gDNA background on RT-PCR data. We propose a novel method (ValidPrime) that is more accurate than traditional RT(-) controls to test qPCR assays with respect to their sensitivity toward gDNA. ValidPrime measures the gDNA contribution using an optimized gDNA-specific ValidPrime assay (VPA) and gDNA reference sample(s). The VPA, targeting a non transcribed locus, is used to measure the gDNA contents in RT(+) samples and the gDNA reference is used to normalize for GOI-specific differences in gDNA sensitivity. We demonstrate that the RNA-derived component of the signal can be accurately estimated and deduced from the total signal. ValidPrime corrects with high precision for both exogenous (spiked) and endogenous gDNA, contributing ~60% of the total signal, whereas substantially reducing the number of required qPCR control reactions. In conclusion, ValidPrime offers a cost-efficient alternative to RT(-) controls and accurately corrects for signals derived from gDNA in RT qPCR. PMID- 22228836 TI - Light-microscopic characteristics of IgG4-related tubulointerstitial nephritis: distinction from non-IgG4-related tubulointerstitial nephritis. AB - BACKGROUND: IgG4-related disease is a multi-organ disorder characterized by a high level of serum IgG4 and dense infiltration of IgG4-positive cells into affected organs. In routine studies, however, IgG subclasses are not estimated. In the present study, we attempted to clarify the light-microscopic characteristics of IgG4-related tubulointerstitial nephritis (TIN) to facilitate distinction from non-IgG4-related TIN in specimens obtained by renal biopsy using routine staining. METHODS: In specimens from 34 cases of TIN (13 IgG4-related and 21 non-IgG4-related), 9 nephrologists independently reviewed the following histological features of interstitial lesions: (i) cell infiltration extending into the renal capsule, (ii) cell infiltration into the renal medulla, (iii) regional lesion distribution, (iv) lymphoid follicles, (v) granulomatous lesions, (vi) necrotizing angiitis, (vii) eosinophil infiltration, (viii) neutrophil infiltration, (ix) tubulitis, (x) peritubular capillaritis, (xi) storiform fibrosis and (xii) the stage of interstitial fibrosis. The modified nominal group technique was applied to obtain a consensus in the pathological interpretation. RESULTS: Consensus was successfully attained among the diagnosticians for all but one pathological feature (regional lesion distribution). Storiform fibrosis was demonstrated in 12 of 13 (92.3%) cases of IgG4-related TIN but in none of the cases of other types of TIN. Cell infiltration extending into the renal capsule was also observed only in IgG4-related TIN. Conversely, neutrophil infiltration, severe tubulitis, severe peritubular capillaritis, granulomatous lesions and necrotizing angiitis were evident only in non-IgG4-related TIN. CONCLUSIONS: This study revealed some useful and characteristic features for distinguishing IgG4 related from non-IgG4-related TIN on the basis of light-microscopic observation. PMID- 22228837 TI - Extracorporeal membrane oxygenation for 2009 influenza A (H1N1) acute respiratory distress syndrome: single-centre experience with 1-year follow-up. AB - OBJECTIVES: During 2009, pandemic influenza A (H1N1) affected France and several patients developed influenza A (H1N1)-associated acute respiratory distress syndrome. The use of extracorporeal membrane oxygenation (ECMO) could be advocated as therapeutic solution. We present our experience with ECMO utilized in patients with influenza A (H1N1)-associated respiratory failure. METHODS: We conducted a retrospective observational analysis of our experience with veno venous ECMO for 2009 influenza A (H1N1)-associated respiratory failure. We have excluded from our study all not confirmed cases of influenza A (H1N1). Veno venous ECMO was always instituted using a percutaneous cannulation technique. Mechanical circulatory support was maintained until respiratory function recovery. RESULTS: Between October 2009 and February 2010, we performed veno venous ECMO support in 12 patients with influenza A (H1N1)-associated respiratory failure. Mean age was 33 +/- 12 years (14-63 years) and there was a prevalence of female sex. Median time from influenza A (H1N1) onset to mechanical ventilation (MV) initiation was 6 days (1-17 days); median time from MV to veno-venous ECMO support was 3 days (1-20 days). Six patients (50%) suffered ventilator-associated pneumonia during ECMO support. Eight patients (66.6%) suffered significant haemorrhage requiring transfusion of more than 2 packed red cells. In two patients (16.6%), there was a thrombosis of the inferior vena cava and one of them experienced pulmonary embolism. Mean duration of ECMO support was 23 +/- 14 days (3-47 days); mean duration of mechanical ventilatory support was 24 +/- 21 days (6-70 days). ECMO was weaned in 10 patients (83.3%) and all these patients are still alive after a period of follow-up of 13.8 +/- 1.12 months (11.03-14.83 months). Two patients (in-hospital mortality of 16.6%) died under ECMO support for refractory septic shock. CONCLUSIONS: Veno-venous ECMO for 2009 H1N1 associated respiratory failure gives good results with a very low mortality rate. The use of a mobile unit is a safe procedure and may improve survival of patients who might not be otherwise eligible for transfer to our institution. Larger studies are however required in order to optimize and refine the best treatment strategy in this subgroup of patients. PMID- 22228839 TI - Thoracoscopic segmentectomy for T1 classification of non-small cell lung cancer: a single center experience. AB - OBJECTIVES: Segmentectomy is one of the treatment options for small-sized non small cell lung cancer (NSCLC). Although growing results support the feasibility and efficacy, it still remains unclear in segmentectomy. The International Association for the Study of Lung Cancer recommended a revised classification of TNM staging in 2009 (the seventh edition) and multidisciplinary classification of adenocarcinoma. We report here the outcome of totally thoracoscopic segmentectomy and lobectomy for T factor and adenocarcinoma. METHODS: Ninety patients with Stage IA NSCLC underwent thoracoscopic segmentectomy between September 2003 and June 2011. A total of 124 patients were referred as a control group to compare the peri-operative outcome, local recurrence rate and survival. These survivals were analysed using the Kaplan-Meier method with the log-rank test and propensity score analyses. RESULTS: The peri-operative outcome, including operative time, blood loss, duration of chest tube drainage and length of hospital stay, was not significantly different between groups. The number of dissected lymph nodes with segmentectomy was less than that with lobectomy. Morbidity and mortality were not significantly different between groups. Seven patients relapsed in each group and propensity score analysis in disease-free and overall survivals showed no differences between two groups in Stage IA. Subclass analyses revealed that disease-free and overall survivals in T1a and T1b were not significantly different between the two groups. CONCLUSIONS: Our study demonstrated that thoracoscopic segmentectomy was feasible with regard to peri-operative and oncological outcomes for Stage IA NSCLC, especially T1a and carefully selected T1b descriptor. PMID- 22228840 TI - A prospective randomized trial to assess the effectiveness of Coseal to seal air leaks in lung surgery. PMID- 22228841 TI - Mediastinal lymph node dissection in early-stage non-small cell lung cancer: totally thoracoscopic vs thoracotomy. AB - OBJECTIVES: Although major pulmonary resections for early-stage non-small cell lung cancer (NSCLC) are more and more frequently performed through thoracoscopy, the adequacy of lymphadenectomy achieved via this approach is still questioned. The aim of this study was to evaluate the results of lymph node dissection (LND) during totally thoracoscopic (TT) major pulmonary resections. METHODS: Clinical and pathological data of consecutive patients who underwent lobectomy or segmentectomy for clinical-N0 NSCLC between 1 January 2007 and 31 December 2009 were reviewed. The main evaluation criterion was the number of mediastinal lymph nodes (LNs) and mediastinal stations dissected through a TT approach when compared with the classical posterolateral thoracotomy (PLT) approach. RESULTS: A total of 296 major pulmonary resections (278 lobectomies and 18 anatomic segmentectomies) for clinical stages I-II NSCLC were performed, 96 via a TT approach and 200 through PLT. Patients' clinical characteristics were similar in both groups. The overall-i.e mediastinal and lobar-number of dissected mediastinal LNs and of dissected mediastinal stations were similar in both groups (TT: mean +/- SD = 17.7 +/- 8.2; PLT: 18.2 +/- 9.3(P < 0.937) and 3.2 +/- 0.9 vs 3.4 +/- 0.9, respectively). The overall numbers of stations (TT: mean +/- SD 5.1 +/- 1.1; PLT: 4.5 +/- 1.2) and LNs (TT: 22.6 +/- 9.4, PLT: 25.4 +/- 10.8) were slightly but significantly different between the two groups (P < 0.001 and P = 0.033, respectively); there was no difference in terms of post-operative complications, although patients from the TT group had significantly fewer days with the chest tube (mean +/- SD = 4.0 +/- 1.8 vs 5.7 +/- 3.9, P < 0.001) and shorter length of stay (7.0 +/- 2.5 days vs 10.3 +/- 7.4, P < 0.001). CONCLUSIONS: For patients undergoing thoracoscopic lobectomy or segmentectomy for clinical early-stage NSCLC, the quality of mediastinal LND is equivalent to that performed by thoracotomy. PMID- 22228842 TI - Transcatheter pulmonary valve implantation in native pulmonary outflow tract using the Edwards SAPIENTM transcatheter heart valve. AB - Percutaneous pulmonary valve implantation (PPVI) is now an accepted alternative option to conventional surgery for patients with dysfunctional conduits between the right ventricle and pulmonary artery. PPVI will reduce the total number of repeat operations in such patients. However, surgery remains the primary option in postoperative tetralogy of Fallot patients with severe pulmonary regurgitation who underwent transannular patch reconstruction of their right ventricular outflow tract (RVOT). Traditionally, an RVOT patch is considered a relative contraindication to PPVI, however, in selected patients PPVI was successfully performed. We report the case of a 12-year-old patient after neonatal repair of tetralogy of Fallot and pulmonary atresia, who developed advanced liver disease and severe pulmonary regurgitation. In this patient, the risk for surgical valve replacement was considered too high and he was treated with percutaneous implantation of the Edwards SAPIENTM transcatheter heart valve. PMID- 22228843 TI - A survivor of late prosthesis migration and rotation following percutaneous transcatheter aortic valve implantation. AB - Transcatheter aortic valve implantation (TAVI) has emerged as a viable alternative endovascular technique in selected patients with severe aortic stenosis, who are either inoperable or at high risk for surgical aortic valve replacement. We report a case of delayed displacement and rotation of an aortic bioprosthesis, 43 days after successful TAVI via the transfemoral approach, with the patient surviving the subsequent open heart surgery required for device retrieval. PMID- 22228844 TI - Is it time to draw such a conclusion concerning the use of washed donor blood during paediatric cardiopulmonary bypass? PMID- 22228845 TI - Ventricular assist device implantation in patients on percutaneous extracorporeal life support without switching to conventional cardiopulmonary bypass system. AB - OBJECTIVES: Ventricular assist device (VAD) implantation using cardiopulmonary bypass (CPB) is an established procedure. However, the well-described complications of CPB may exacerbate multiple organ failure and increase blood product transfusions especially in end-stage heart failure patients. METHODS: We describe our successful experience in six consecutive patients with profound cardiogenic shock, who were provided on an emergency basis with a percutaneous extracorporeal life support (ECLS) system via the peripheral vessels. After stabilization, a VAD was implanted using ECLS without switching to a conventional CPB system to reduce its side effects. We compared the data with those of 11 patients in whom the VAD was placed with the aid of an additional CPB system. RESULTS: The six patients demonstrated a shorter duration of operating room time compared with the patients requiring CPB for device placement. During and after surgery, blood loss and blood product transfusions were lower in these patients. The need for mechanical ventilation and inotropic support was shorter and the survival rate (100% at 30 days, 83.3% at 3 months and 83.3% at 6 months) was higher when compared with patients who were operated upon with CPB. Two patients were successfully bridged to transplantation. One patient died due to cerebral bleeding after 7 weeks. CONCLUSIONS: Our experience suggests that VAD implantation using percutaneous ECLS without switching to conventional CPB is a safe alternative in the bridge to bridge concept, especially in high-risk patients with cardiogenic shock who would benefit from the avoidance of the adverse sequels associated with conventional CPB. PMID- 22228846 TI - The values of intrapleural pressure before the removal of chest tube in non complicated pulmonary lobectomies. AB - OBJECTIVES: Digitalized chest drainage systems allow for quantification of air leak and measurement of intrapleural pressure. Little is known about the value of intrapleural pressure during the postoperative phase and its role in the recovering process after pulmonary resection. The objective of this investigation was to measure the values of pleural pressure immediately before the removal of chest tube after different types of pulmonary lobectomy. METHODS: Prospective observational analysis on 203 consecutive patients submitted to pulmonary lobectomy during a 12-month period at two centres. Multiple measurements were recorded in the last hour before the removal of chest tube and averaged for the analysis. All patients were seated in bed in a 45 degrees up-right position or in a chair, had a single chest tube and were not connected to suction during the evaluation period. Analysis of variance (ANOVA) was used to assess the differences in pleural pressure between different types of lobectomies. RESULTS: The average maximum, minimum and differential pressures were -6.1, -19.5 and 13.3 cmH(2)O, respectively. The average pressures were similar in all types of lobectomies (ANOVA, P = 0.2) and ranged from -11 to -13 cmH(2)O, with the exception of right upper bilobectomy (-20 cmH(2)O, all P-values vs. other types of lobectomies <0.05). Similar values were also recorded for maximum pressures (range -4.4 to -8.4 cmH(2)O) and minimum pressures (-31.6 cmH(2)O vs. ranged from -15.4 to -20.5 cmH(2)O, all P-values <0.01). The average pleural pressure was not associated with FEV1 (P = 0.9), DLCO (P = 0.2) or FEV1/FVC ratio (P = 0.6), when tested with linear regression. Similarly, the average pleural pressure was similar in patients with and without COPD (-12.1 vs. -13.0 cmH(2)O, P = 0.4). The ANOVA test was used to assess differences in pressures between different lobectomies. CONCLUSIONS: The so-called water seal status may actually correspond to intrapleural pressures ranging from -13 to -20 cmH(2)O. Modern electronic chest drainage devices allow a stable control of the intrapleural pressure. Thus, the values found in this study may be used as target pressures for different types of lobectomies, in order to favour lung recovery after surgery. PMID- 22228847 TI - Are all antegrade cerebral perfusion techniques equal? PMID- 22228848 TI - Clinicopathological characteristics of surgically resected pulmonary pleomorphic carcinoma. AB - OBJECTIVES: Since few large-scale studies of patients with pleomorphic carcinoma have been documented, factors affecting survival after pulmonary resection for pleomorphic carcinoma, as well as its clinicopathological characteristics, are still unknown. For a better understanding of the patients undergoing resection of pulmonary pleomorphic carcinoma, we reviewed our experience with these patients. METHODS: Between 2002 and 2010, 26 patients with pulmonary pleomorphic carcinoma underwent macroscopically complete pulmonary resections. Various perioperative variables were investigated retrospectively to confirm a role for pulmonary resection and to analyse prognostic factors for overall survival and disease-free survival after lung resection. RESULTS: Twenty-four patients (92%) were male. Twenty-one patients (81%) were smokers and all of them smoked more than 30 pack years. In 25 patients (96%), the tumour was located peripherally. Twenty-three of these 25 patients revealed the tumour touching the visceral pleura widely in the preoperative chest computed tomography. In all 26 patients, the tumour was completely resected macroscopically; however, three patients (12%) had microscopically positive surgical margins. Among them, additional irradiation was conducted in two patients and additional surgical resection was performed in one patient. Combined resections were performed in 11 patients (42%), including chest wall resections in 7 patients. Overall survival rate after pulmonary resection was 48% at 5 years. Disease-free survival rate after pulmonary resection was 33% at 5 years. Patients with tumours invading the visceral pleural surface and microscopically positive surgical margin had significantly worse overall survivals (P = 0.048 and 0.037, respectively). However, there were no significant prognostic factors for disease-free survival. CONCLUSIONS: Despite small number of cases, we found that pleural invasion suggested a worse prognosis for resection of pulmonary pleomorphic carcinoma. Surgical strategy might be constructed to achieve not only macroscopically, but also microscopically complete resection for such large tumours with aggressive nature and peripheral preference. PMID- 22228849 TI - Oral beta-glucan reduces infarction size and improves regional contractile function in a porcine ischaemia/reperfusion model. AB - OBJECTIVES: We previously reported a cardioprotective effect of oral beta-glucan in patients who underwent coronary artery bypass grafting. The present study was conducted to determine whether oral beta-glucan could reduce myocardial infarction size and whether these changes would be reflected by better preservation of contractile indices measured by speckle tracking echocardiography (STE). METHODS: Fourteen pigs were randomized to receive oral beta-glucan 50 mg/kg (n = 7) or placebo (control, n = 7) 10 days before they were anaesthetized and subjected to 1 h clamping of the left anterior descending coronary artery followed by reperfusion for 3 h. Longitudinal strain, circumferential strain and radial strain were assessed by STE after 3 h of reperfusion. Infarction size and area at risk were determined by Evans blue and 2,3,5-triphenyltetrazolium chloride staining. RESULTS: Pretreatment with beta-glucan reduced the infarct area/area at risk ratio by 36% (P < 0.05) and the total necrotic area of the left ventricle by 37% (P < 0.05) compared with controls. Viable myocardium at risk was 30% higher in the beta-glucan vs. control group (P < 0.05). Anterior apical strain values for beta-glucan vs. control were -4.7 +/- 9.4 vs. 5.9 +/- 6.1% (P < 0.05) for longitudinal strain, -14.7 +/- 6.6 vs. -7.7 +/- 4.3 (P < 0.05) for circumferential strain, 15.1 +/- 7.7 vs. 7.1 +/- 11.8 (ns) for radial strain. CONCLUSIONS: Oral beta-glucan pretreatment reduces infarction size and improves regional contractile function in a porcine ischaemia/reperfusion model. PMID- 22228850 TI - In vitro comparison of three techniques for ventriculo-aortic junction annuloplasty. AB - OBJECTIVES: In aortic valve repair, reduction and stabilization of the ventriculo aortic junction (VAJ) is generally recommended. In this in vitro study, we compare three techniques of annuloplasty: the subcommissural annuloplasty (SCA), the internal ring (IR) and the external ring (ER) annuloplasty. METHODS: Ten fresh porcine aortic valve preparations were tested in a pulsatile mock loop. Each sample was tested untreated (baseline: B). The annuloplasty techniques were then performed successively in each sample. Each technique was tested, then removed and the following technique performed. SCA was applied at 50% of interleaflet triangle height; the ER and IR were applied with a moderate reduction (15-20%) of the VAJ. Hydrodynamic, video and echographic parameters were collected. Flow rate and arterial pressure were maintained consistently between groups. RESULTS: Effective orifice area decreased significantly with each annuloplasty technique compared with baseline (P < 0.001). Mean transvalvular pressure drop was significantly higher in the ER and IR vs SCA (P = 0.007). Annuloplasty reduced valve opening and closing time in comparison to baseline. Echocardiography confirmed that the VAJ experienced a greater reduction with the ER and IR vs SCA. A narrowing of the lower third of the sinuses of Valsalva was observed after the ER, and subvalvular narrowing was observed after the IR. Valve coaptation increased with all annuloplasty techniques. CONCLUSIONS: The three annuloplasty techniques examined demonstrated differential effects on aortic valve function and root morphology. The ER and IR have greater potential to reduce VAJ diameter in comparison to SCA. The IR induced a subvalvular remodelling of the VAJ, whereas the ER induced a paravalvular remodelling. PMID- 22228851 TI - Extrapericardial cardiac tamponade by a retrosternal haematoma after blunt chest trauma. PMID- 22228852 TI - Valve-sparing replacement of the ascending aorta and aortic arch in a child with Loeys-Dietz syndrome. AB - We describe a successful surgical treatment in a 2.5-year old boy with Loeys Dietz syndrome, in whom we performed aortic arch and ascending aorta replacement with a valve-sparing operation (VSO) of the aortic root because of significant aortic insufficiency and dilation of the aortic root. We believe that VSO is ideal for treating young patients with aortic root aneurysm with normal or minimally diseased aortic cusps to avoid the disadvantages of prosthetic valve replacements. PMID- 22228855 TI - FAWC considers role of education in animal welfare. PMID- 22228853 TI - Herpes simplex virus type 1 thymidine kinase-armed bovine herpesvirus type 4 based vector displays enhanced oncolytic properties in immunocompetent orthotopic syngenic mouse and rat glioma models. AB - Gliomas are devastating tumors of the brain resistant to therapies. Although some therapies can prolong the survival time among the affected persons, gliomas are not curable and new therapeutic approaches need to be investigated. Oncolytic viruses seem to represent an interesting alternative, because anticancer agents and new viral agents have to be explored to identify the one with the best characteristics. Bovine herpesvirus type 4 (BoHV-4) is a gammaherpesvirus with a striking tropism and permissive replication toward cancer cells and rat, mouse, and human glioma cells. However, BoHV-4 does not replicate into the normal brain parenchyma. The BoHV-4 genome was cloned as a bacterial artificial chromosome to easily manipulate this large genome and be used as a viral vector platform. In the present study, a herpes simplex virus type 1 thymidine kinase suicide gene armed BoHV-4 was constructed, characterized, and proven to be highly efficient in killing by apoptosis glioma cells in vitro when co-administered with the pro-drug ganciclovir (GCV). When the armed BoHV-4/GCV therapeutic approach was tested in immunocompetent orthotopic syngenic mouse and rat glioma models in vivo, a significant increase in survival among the treated animals was achieved, and some animals were completely cured. The BoHV-4-based vector represents a promising alternative oncolytic virus for glioma and, perhaps, other types of cancer treatment that merit further investigation. This article represents the result of a mutual interaction between human medical science and veterinary science, a combination of scientific knowledge often neglected. PMID- 22228854 TI - Business mergers and acquisitions and the risk of mental disorders: a population based study. AB - OBJECTIVES: Mergers and acquisitions (M&A) activities are increasing and may negatively affect workers mental health. However, the impact of M&A on the risk of developing a mental disorder, rather than psychiatric symptoms, has not been investigated. The objectives of this study were to estimate and compare the 12 month incidence of depressive and anxiety disorders in workers who had and who had not experienced M&A in the last year. METHODS: Employees aged 25 and 64 years old were randomly selected from the community and were followed for 1 year (n=3280). Questions about their experience in M&A in the past 12 months were asked. WHO's Composite International Diagnostic Interview-Auto 2.1 was used to assess depressive and anxiety disorders. The 12-month prevalence and 1-year incidence of mental disorders were estimated and compared in relation to M&A. RESULTS: Participants who were exposed to M&A had a significant higher 1-year incidence of generalised anxiety disorder (GAD) (6.7%) than the unexposed (2.4%). They were not different in the incidence of major depressive disorder. The exposed participants were 2.8 times more likely to have had a GAD than others and were about 2.4 times more likely to have developed any anxiety disorders over 1 year. CONCLUSIONS: M&A may lead to increased risk of GAD, which may, in return, evolve into major depression. Governments, employers and health professionals should be aware of this and work out plans to reduce the negative health outcomes of M&A. PMID- 22228856 TI - New pet travel rules could save owners 7 pound million, says Defra. PMID- 22228857 TI - Veterinary response to Kenyan drought. PMID- 22228858 TI - Moredun reviews its research. PMID- 22228860 TI - French veterinary profession plans to reduce use of antibiotics. PMID- 22228864 TI - Widening access to the veterinary profession. PMID- 22228865 TI - Vaccination against bluetongue. PMID- 22228866 TI - Cross-sectional imaging: the key to anatomy. PMID- 22228867 TI - Non-healing hoof lesions in dairy cows. PMID- 22228868 TI - Improving the health and welfare of all dogs. PMID- 22228869 TI - Canine distemper outbreak in ferrets in the UK. PMID- 22228870 TI - Exerting political influence. PMID- 22228871 TI - Shooting badgers. PMID- 22228872 TI - Disposal of medicinal products. PMID- 22228878 TI - The burden of hepatic encephalopathy in Latin America. AB - Hepatic encephalopathy (HE) is a neuropsychiatric syndrome characterized by changes in cognitive function, behavior, and personality, as well as by transient neurological symptoms and electroencephalographic changes, which occur in the context of acute or chronic liver failure. Cirrhosis is the main disease associated to HE, and it is known that its incidence is increasing worldwide. As a cause of mortality, cirrhosis is ranked 14 worldwide, but 10 in developed countries. It has been demonstrated that the incidence of liver disease is increasing, in part because of the ascending prevalence of NAFLD, HCV, HCC, as well of alcohol consumption. The real incidence of cirrhosis in Latin America is unknown, although in some Latin American countries that provided national data, cirrhosis death rates were between 5 and 17/100,000 for men and 3 and 5/100,000 for women. Disability, quality of life, and social aspects should be considered when assessing the impact of a disease. In this context, preliminary estimates of the global burden of disease attributable to chronic liver disease seem to be substantial. Hepatic encephalopathy, a main complication of liver failure, occurs in 30-45% of patients as overt encephalopathy, but when subclinical or minimal hepatic encephalopathy (MHE) is considered, estimates of the incidence of encephalopathy vary from 20 to 60%. In USA, the 2009 NIH Report on the Costs of Digestive Diseases stated that liver disease was the second most costly disease in direct and indirect costs (13.1 billion dollars). Although the economic cost of HE has not been assessed, it is obvious that the economic impact of HE on daily activities of living is extremely high, as the costs of diminished work performance and lost wages are substantial. PMID- 22228879 TI - Review of the final report of the 1998 Working Party on definition, nomenclature and diagnosis of hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is a heterogeneous disease that develops as a result of serious liver disease, such as in fulminant hepatitis or cirrhosis, or a portosystemic shunt. It manifests as a spectrum of abnormalities involving cognition, attention, functional ability, personality and intellect. The neuropsychiatric impairment associated with HE can range from mild alteration of cognition and consciousness to coma, depending on the stage of the illness. In 1998, the World Gastroenterology Organization formed a working party to develop guidelines and recommendations for the diagnosis, grading and treatment of HE for research and practice. In this report, we discuss the various tests available for diagnosis and grading and the recommendations of the working party, which provide a framework for further studies on clinical trial methodology. PMID- 22228880 TI - Prevalence of minimal hepatic encephalopathy in cirrhotic patients. AB - Background. Minimal hepatic encephalopathy (MHE) has implications for health related quality of life as well as for survival of cirrhotic patients, but a standardized diagnostic test is not available. Objective. To determine the prevalence of MHE among cirrhotic patients by using the psychometric hepatic encephalopathy score (PHES) system and the critical flicker frequency (CFF) test to diagnose MHE and to identify factors that influence the results of these tests. Material and methods. From April 2007 to March 2008, PHES and CFF tests were performed on patients with cirrhosis but no overt hepatic encephalopathy. Descriptive statistics were used to express the results and the Spearman correlation was used to evaluate CFF and PHES results according to age and education level. Results. We studied 104 patients. The prevalence of MHE was 55.8% (n = 58) based on a positive result for either the PHES or the CFF test, 32.7% (n = 34) based on positive PHES results alone, 34.6% (n = 36) based on positive CFF test results alone and 11.5% (n = 12) based on a positive result for both tests. According to PHES, the incidence of MHE was correlated with education level (r = 0.333, p = 0.001), but not with age. According to CFF, the incidence of MHE was correlated with age (r = -0.93, p = 0.049), but not with education level. Conclusion. The prevalence of MHE was similar to that previously reported. Patient literacy influences MHE diagnosis with PHES but not with CFF. CFF is a simple and feasible method that identifies patients with MHE who may benefit from treatment independently of their education level. PMID- 22228881 TI - Nutritional support in the treatment of chronic hepatic encephalopathy. AB - The prevalence of under nutrition in cirrhotic patients is 61% and it usually progresses as the disease becomes more advanced. The deterioration in the nutritional status and its associated metabolic derangements has raised doubts about the benefits of severe and prolonged protein restriction as a treatment for hepatic encephalopathy. However, the practice of dietary protein restriction for patients with liver cirrhosis is deeply embedded among medical practitioners and dietitians. To date, no solid conclusions may be drawn about the benefit of protein restriction. However, the negative effects of protein restriction are clear, that is, increased protein catabolism, the release of amino acids from the muscle, and possible worsening of hepatic encephalopathy. In conclusion, chronic protein restriction causes progressive and harmful protein depletion and must be avoided. PMID- 22228882 TI - Minimal hepatic encephalopathy. AB - The term minimal hepatic encephalopathy (MHE) refers to the subtle changes in cognitive function, electrophysiological parameters, cerebral neurochemical/neurotransmitter homeostasis, cerebral blood flow, metabolism, and fluid homeostasis that can be observed in patients with cirrhosis who have no clinical evidence of hepatic encephalopathy; the prevalence is as high as 84% in patients with hepatic cirrhosis. Physician does generally not perceive cirrhosis complications, and neuropsychological tests and another especial measurement like evoked potentials and image studies like positron emission tomography can only make diagnosis. Diagnosis of minimal hepatic encephalopathy may have prognostic and therapeutic implications in cirrhotic patients. The present review pretends to explore the clinic, therapeutic, diagnosis and prognostic aspects of this complication. PMID- 22228883 TI - Efficacy of oral L-ornithine L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. AB - Hyperammonemia and associated cerebral edema cause neurological abnormalities in liver disease patients. Although only 15% of ammonia production originates in the colon, management strategies for hepatic encephalopathy (HE) have focused on reducing ammonia generation from the bowel rather than on manipulating systemic mechanisms involved in ammonia metabolism. Administration of L-ornithine L aspartate (LOLA) improves mental status and decreases serum and spinal fluid ammonia levels by stimulating both the urea cycle and glutamine (Gln) synthesis, which are key metabolic pathways in ammonia detoxification. LOLA was shown to be superior to a placebo for management of HE, and the results of several clinical trials suggest that its effectiveness could be higher with the more severe grades of this syndrome. Compared with the standard treatment, LOLA is effective not only in reducing hyperammonemia and the severity of this disease, but also in improving the patient's perceived quality of life. Therefore, LOLA is a promising alternative for the management of HE. PMID- 22228884 TI - Determination of ammonia concentrations in cirrhosis patients-still confusing after all these years? AB - By the end of the nineteenth century, ammonia had been identified as the main factor responsible for hepatic encephalopathy syndrome. Ammonia is one of the principal products of hepatic metabolism and high concentrations are toxic to the body. Under physiological conditions, the main way by which the body restricts the blood concentration of ammonia to a nontoxic level is by converting it to urea in the liver via the Krebs cycle. The synthesis of glutamine represents an alternative pathway for ammonia detoxification in cirrhotic patients. Although high concentrations of ammonia have been strongly associated with brain edema, estimates of the strength of the correlation between serum ammonia levels and the severity of hepatic encephalopathy vary. The accuracy of ammonia assays depends on the site of specimen collection, treatment of the specimen and the analytical method used. New methods involving measurement of the partial pressure of ammonia and new noninvasive techniques involving quantification of ammonium in the breath have been described. The purpose of this review is to identify factors that affect serum ammonia levels, from its origin and metabolism to its analysis and interpretation of results in the laboratory. In conclusion, variations in estimates of serum ammonia level and the severity of hepatic encephalopathy arise because of individual differences in ammonia metabolism and differences in the accuracy of analytical methods. PMID- 22228885 TI - Critical analysis of studies evaluating the efficacy of infusion of L-ornithine L aspartate in clinical hepatic encephalopathy in patients with liver failure. AB - Introduction. Hepatic encephalopathy (HE) refers to a complex neuropsychiatric syndrome that is progressive but potentially reversible and may have a significant impact on quality of life, as it is characterized by alterations in cognitive function, behavior and personality as well as transient neurological symptoms and electroencephalographic abnormalities. Objective. The aim of this study was to evaluate scientific evidence for the effectiveness and safety of LOLA infusions for treatment of clinical hepatic encephalopathy in patients with chronic liver disease. Material and methods. We included all randomized, controlled, double-blind, and humans' studies that were published in indexed journals. Results. Were identified 48 references (17 using PubMed, 12 using Medline and 19 using the Cochrane database). Of these, six were selected as having met the inclusion criteria. A total of 623 patients were randomized in these publications. Conclusion. The available scientific evidence supports the adoption of LOLA infusion as a treatment for clinical encephalopathy in patients with liver failure, because it has been shown to improve neuropsychiatric status and decrease serum levels of ammonia with a low incidence of adverse effects (less than 5%). PMID- 22228886 TI - Albumin dialysis with molecular adsorbent recirculating system (MARS) for the treatment of hepatic encephalopathy in liver failure. AB - Acute, acute-on-chronic and chronic liver diseases are major health issues worldwide, and most cases end with the need for liver transplantation. Up to 90% of the patients die waiting for an organ to be transplanted. Hepatic encephalopathy is a common neuropsychiatric syndrome that usually accompanies liver failure and impacts greatly on the quality of life. The molecular adsorbent recirculating system (MARS) is a recently developed form of artificial liver support that functions on a base of albumin dialysis. It facilitates the dialysis of albumin-bound and water-soluble toxins, allowing the patient to survive and even improving some clinical features of liver failure. The following manuscript reviews the technical features of MARS operation and some of the clinical trials that analyze the efficacy of the system in the therapy of liver diseases. PMID- 22228889 TI - [Editorial comment. The current TNM staging system of renal cell carcinoma: are further improvements needed?]. PMID- 22228888 TI - The current TNM staging system of renal cell carcinoma: are further improvements needed? AB - Objective of the study is to review the current 7th edition of the TNM classification of renal tumors and to perform a critical analysis of the recent evidence in order to identify the limitations of this new staging system. A search of the english literature was performed through the Medline and Pubmed database using the following keywords: renal cell carcinoma, staging system and TNM. Overall, 2600 references were initially scrutinized. Forty papers were selected based on their pertinence with the topic of the review, level of evidence provided and overall contribution to the field. Few changes have been made in the current version of the TNM staging system of renal tumors. pT2 tumors have been divided in 2 subgroups based on tumor size with a cut-off at 10 cm; the invasion of the renal vein was classified as pT3a; finally, the invasion of the ispsilateral adrenal gland was classified as pT4. However, other changes were suggested by the analysis of the recent literature and have not been introduced in this new version. Further improvements of the TNM classification for renal tumors are needed especially with regard to locally advanced tumors and node-positive disease, in order to improve the accuracy of this important prognostic tool in renal oncology. PMID- 22228890 TI - Two-stage urethroplasties and perineal urethrostomy. AB - OBJECTIVES: Complex stenoses of the bulbar urethra and long stenoses of the penile urethra are very difficult to solve. Which surgical techniques must be applied in these cases is not clear. The objectives of this work were to define whether two-stage urethroplasties and definitive perineal urethrostomies are currently valid techniques for these cases and to clarify to what extent patients accept perineal urethrostomy. METHOD: 167 cases of urethral stenosis are reviewed: 73 of them correspond to long penile, both bulbar and penile, multiple or panurethral stenosis. The surgical procedures carried out in these 73 cases, essentially definitive perineal urethrostomy or two-stage surgery with a cutaneous graft implant, are analyzed. The results are evaluated as positive or negative according to the quality of voiding measured by the degree of satisfaction and urethrocystogram. RESULTS: Far from being obsolete, these techniques are shown on the one hand to be ideal nowadays, with good results between 96.1% in penile urethra stenosis and 71.4% in panurethral stenosis, and, on the other to be an opportunity for a definitive perineal derivation chosen voluntarily by 55% of patients who were programmed for a second stage. The most frequently-occurring complications in this type of surgery, like graft necrosis and retraction of the perineal meatus, are confirmed. We recognize the number of cases studied is limited to make representative statistical conclusions, but the work is justified by their infrequency and the need to contribute with our experience. CONCLUSIONS: Two-stage urethral stenosis surgery and definitive perineal urethrostomy are highly acceptable techniques in certain complex cases. In two-stage urethral stenosis the grafts at the level of penile urethra produce better results and are easier to implant than bulbar-penile urethra grafts. Patients accept definitive perineal urethrostomies well. PMID- 22228891 TI - [Editorial comment. Two-stage urethroplasties and perineal urethrostomy]. PMID- 22228887 TI - Recent progress in targeting cancer. AB - In recent years, numerous new targets have been identified and new experimental therapeutics have been developed. Importantly, existing non-cancer drugs found novel use in cancer therapy. And even more importantly, new original therapeutic strategies to increase potency, selectivity and decrease detrimental side effects have been evaluated. Here we review some recent advances in targeting cancer. PMID- 22228892 TI - Evaluation of Fournier's necrosis in a high complexity hospital. AB - OBJECTIVES: To determine clinical characteristics of the population with Fournier's necrosis at Hospital Universitario del Valle (HUV) in Cali during the period 2003-2008. METHODS: We performed a retrospective review of patients with the diagnosis of Fournier's necrosis at HUV during the period 2003-2008. We collected information on age,personal history, duration of illness, hospitalization, surgeries performed, time to surgical treatment, isolated germs, and mortality. Univariate descriptive analysis was performed in STATA v 10.1. RESULTS: 42 patients with mean age 51 years and 12 days mean disease duration. 26% had diabetes mellitus and 21.4% urethral trauma before admission. Average time to surgical debridement was 41.4 hours. 62% required suprapubic cystostomy, 14.3% derivative colostomy, 9.5% and 2.4% orchiectomy and penectomy respectively. The average hospital stay was 23 days and 12% required ICU care. Scrotal cultures were positive in 59.5%: 64% a single germ and 36% polymicrobial. Reported mortality was 17%. CONCLUSION: Fournier's necrosis is a life-threatening clinical entity in patients with multiple comorbidities requiring multiple interventions. Broad-spectrum antimicrobial therapy, aggressive debridement of necrotic tissue and comprehensive management of these patients are the mainstays in the treatment of these severely ill patients. PMID- 22228893 TI - Bladder augmentation using the gastrointestinal tract. Indication, follow up and complications. AB - The purpose of bladder augmentation using the gastrointestinal tract is to create a low-pressure and high-capacity reservoir, permitting suitable continence and voiding, preserving the upper urinary tract. OBJECTIVE: To analyze the indications, complications and results of our series of augmentation enterocystoplasties. METHOD: We retrospectively reviewed patients undergoing augmentation enterocystoplasty in our department between 1997 and 2010, both included. The indications were: Interstitial cystitis, neurogenic bladder and inflammatory bladder retraction. In all cases a cystography, urethrocystoscopy, urodynamic study and studies of each condition. Bladder release is performed by means of medial laparotomy and an extraperitoneal approach with bivalve opening to the urethral orifices. The bladder augmentation is performed with a 15-20 cm segment of detubularized ileum obtained at 20 cm from the ileocecal valve; in cases of kidney failure, a 7-cm gastric body wedge is added. The bladder catheter was removed following cystogram after 15 days. Monitoring was performed by means of ultrasound with postvoid residual, blood analyses, urine culture and voiding diary. We performed a descriptive study of the demographic characteristics, postoperative complications according to the Clavien classification and in the long term. RESULTS: We included 24 patients, 19 women and 5 men with a mean age of 48.5 years and a median of 47 (21-77). Mean follow up was 7.5 years with a median of 8 (1-11). The indications were: 7 interstitial cystitis, 8 bladder retraction and 7 neurogenic bladder. There were no intraoperative complications. The postoperative complications were 3 Clavien I, 2 type II, 2 IIIA and 1 IIIB. In the long term, 3 patients presented urinary incontinence, 2 mild metabolic acidosis, 5 required self-catheterization, 6 bladder stones, 2 febrile urinary tract infections and 1 stricture of the anastomotic mouth. In three cases, an ileogastrocystoplasty was performed without hydroelectrolytic impairment or impairment of kidney function. CONCLUSIONS: In selected patients, augmentation enterocystoplasty constitutes an efficacious therapeutic option in the treatment of lower urinary tract dysfunction with scant morbidity and few complications. PMID- 22228894 TI - Diagnostic performance of malignant prostatic cells detection in blood for early detection of prostate cancer: comparison to prostatic biopsy. AB - OBJECTIVES: Serum prostate specific antigen and digital rectal examination are the tests used as screening tests to detect prostate cancer. However, only approximately 30% of men with suspicion of cancer have it confirmed on prostate biopsy, and not all of these need treatment. Detection of circulating tumor cells in localized prostate cancer has given variable results, but it could be a useful complementary screening tool to detect prostate cancer in men with abnormal screening tests before the evaluation with prostate biopsy. To evaluate the diagnostic yield of the detection of mCPC as a complementary PC screening test in a population fulfilling criteria for a prostate biopsy for suspicion of PC. METHODS: A prospective screening study of consecutive patients aged 45-80 years presenting to the urologist for PC screening. Inclusion criteria were PSA >4.0 ng/ml, PSA velocity >0.35 ng/ml/year and/or DRE suspicious for cancer. Patients fulfilling inclusion criteria had blood taken for mCPC detection and then underwent 12-core transrectal prostate biopsy. Double immune-histochemical staining with anti-PSA and anti-P504S was used to detect mCPC. Both cytologist and pathologist were blinded to the results of the biopsy, mCPC results and clinical details. The diagnostic yield of the presence or absence of mCPC was evaluated; the prostate biopsy was classified as cancer or no -cancer. RESULTS: 228 men participated, with a mean age of 66.8 +/- 8.8 years and a median serum PSA of 5.15 ng/ml. 28.6% of the biopsies were positive for PC, and mCPC were detected in 31.0%of all cases. Sensibility, specificity and negative predictive value were 86.2%, 90.8% and 94.3% respectively. The negative and positive like lihood ratios were 9.36 and 0.15. In men with a PSA <4.0ngml, 13.3% had cancer detected on biopsy, with a sensibility and specificity for mCPC detection of 83.3% and 84.6% and negative predictive value of 97.1%. All the mCPC determinations were interpretable. There were 9 false negative cases, all with small low grade tumors. CONCLUSIONS: The use of mCPC detection could be useful as a complementary prostate cancer screening test, especially for excluding cancer, including patients with a serum PSA <4.0 ng/ml. PMID- 22228895 TI - Analysis of clinical-pathologic variables, staging and prognostic groups, and therapeutic results of 106 germ-cell testicular tumors. AB - OBJECTIVES: Retrospective review of 106 germ-cell testicular tumors treated in our center between 1992 and 2009. METHODS: Description and analysis of several clinical-pathologic and prognostic variables and survival analysis. RESULTS: 68% of our patients were diagnosed in the last 5 years. 54.7% presented seminoma histology. The mean age at diagnosis was 33.47 for the seminoma (S) and 27.63 for non seminoma (NS), p=0,001. The median tumoral size in mm was 45.99mm (globally). 44.3% presented elevation of at least one tumor marker; Alpha-fetoprotein (AFP) or Human chorionic gonadotropin (HCG) .29.3% in the S and 60.4% in NS; p=0.02. The percentage of patients with increased HCG in S was 29.3% and 52.1% in NS; p=0.017 and AFP was elevated in 5.2% of S and 45.8% of NS; P <0.001. Accordingly to the classification of The Royal Marsden Hospital 96.5% of S and 83.2% of NS were diagnosed in stage I-II. Using the classification of the International Germ Cell Cancer Collaborative Group (IGCCG) for patients with advanced disease, 98.2% of S and 83.2% of NS belonged to the good prognostic group. Regarding the risk factors for relapse in stage I S (Rete testis invasion (RTI) and tumoral size (TS)> 4cm) 28% of our patients presented both risk factors. 18% of stage I NS presented vascular (VI) or lymphatic invasion (LI). Following the treatment protocols in consideration with the histology, stage and risk factors, 100% of stage I S with both risk factors and 100% of NS with vascular or lymphatic invasion received adjuvant therapy. Almost all the stage II-IV S and NS received different protocols of chemotherapy. In 2.8% of stage II NS a retroperitoneal lymph node dissection was performed. Residual tumor resection was documented in eight patients with stage II-IV NS. With a median follow-up of 60 months, the event free survival (EFS) was 93.3%. CONCLUSIONS: Our study has similar characteristics compared to other studies. PMID- 22228896 TI - Penile metastasis of rectal carcinoma. Case report and bibliographic review. AB - OBJECTIVE: Contribution of a case of penile metastasis in a patient with metastatic rectal carcinoma. METHODS: A 70-Year-old patient was referred to our consultation after the discovery of "penis indurations" having been diagnosed of rectal carcinoma 18 months before. After physical examination penile biopsies were carried out. RESULTS: The pathological results of the Glans biopsy was "rectal adenocarcinoma metastasis". CONCLUSIONS: Metastases in the penis are rare, and usually occur in the context of advanced oncological disease. PMID- 22228897 TI - Penile metastasis of prostatic adenocarcinoma. Case report. AB - OBJECTIVE: Penile metastases are late manifestations of a primary tumor, and they are a sign of poor prognosis. We report a case of a rare presentation: penile metastases from prostate cancer. METHODS: 77 year-old male presented hematuria and acute urinary retention; on physical examination multiple hard lesions were detected. The patient underwent a Doppler ultrasound, subsequent penile and prostate biopsy, and staging study. Currently he is being treated with complete androgen blockade. RESULTS: A histological study of the penile biopsy showed penile metastasis from prostate adenocarcinoma. The histological study of prostate biopsy confirmed Gleason 8 (4+4) adenocarcinoma. CONCLUSIONS: Despite of the different therapeutic alternatives for treatment of symptomatic penile metastases, it would be with palliative target; due to the median survival of these patients is less than a year. PMID- 22228898 TI - Surgical treatment of corpora cavernosa fracture with complete urethral rupture. AB - OBJECTIVE: To analyze in a short and concise way the diagnosis and treatment of traumatic fracture of both corpora cavernosa and urethra. METHODS: We present our experience with a rare case of traumatic fracture of both corpora cavernosa associated to complete urethral rupture. RESULTS/CONCLUSIONS: The diagnosis of penile fractures can be done with the clinical history and physical examination only. Surgery is the best treatment, the main objective of which is to enable voiding and restore the anatomy of the penis to prevent complications such as erectile dysfunction. PMID- 22228899 TI - Spermatic cord dermoid cyst as paratesticular mass. Case report and bibliographic review. AB - OBJECTIVE: Presentation of a new case of dermoid cyst of the spermatic cord and to perform a review of the literature. METHODS: We describe the case of a 48 year old male who consulted because of reappearance of a mass in the left high scrotal area and inguinal zone. He was operated for left inguinal hernia two years before. RESULTS: Since physical examination and ultrasound were inconclusive, we performed a surgical exploration with complete excision of the mass. Intraoperartive pathologic analysis confirmed the benign nature of the mass so we did not proceed to radical orquiectomy. CONCLUSIONS: Among paratesticular tumors, benign in the majority of cases, dermoid cyst is a rare pathology of the spermatic cord that the clinician always has to take into account before making a decision when we treat the spermatic cord masses. PMID- 22228900 TI - Right renal rupture after motor vehicular accident. PMID- 22228901 TI - Rectourethral fistula after prenatal treatment of posterior urethra valves. PMID- 22228904 TI - Short peptide tools for monitoring caspase and proteasome activities in embryonal and adult rat brain lysates: an approach for the differential identification of proteases. AB - The numerous caspase-like activities present in nervous tissue can be investigated with labelled peptides. However, the cross-reactivities of peptides with both proteasomes and caspases complicate the analysis of protease activity. The pharmacological features of substrates and inhibitors specific for either caspases or proteasome caspase-like proteases in rat brain lysates were similar or identical to the profiles of commercially purified proteasome preparations. Caspase inhibitors bind directly to active proteasome centres, thus competing with selective antagonists of proteasomes. Separation of lysates by molecular weight does not separate active caspases from proteasomes because these enzymes co-localize under native electrophoresis. The addition of ATP or its analogues is associated with the differential modulation of proteasomal activity, which also leads to ambiguity in the data. However, induced caspase activity could be successfully differentiated from proteasome activity in embryonal brain lysates with the non-selective caspase inhibitors Z-VAD-FMK and Q-VD-OPh and the proteasome inhibitor AdaAhx(3)L(3)VS that are not cross-reactive. This strategy is proposed for the simultaneous examination of caspases and proteasomes using proteolysis experiments. The present study reveals that all of the caspase-like activities in the tissue lysates of non-injured adult rat brains were related to proteasomal caspase-like activities. PMID- 22228905 TI - Colorectal cancer staging using TNM 7: is it time to use this new staging system? AB - The authors audited pathological colorectal cancer staging according to tumour node metastasis (TNM) 7 and using TNM 5 as a gold standard. 144 consecutive colorectal cancer resection specimens were staged prospectively using both TNM 5 and TNM 7 criteria during routine reporting by specialist gastrointestinal pathologists within a single institution. The pN stage remained the same under both systems apart from the required subclassification of pN1 and pN2 under TNM 7. The TNM 7 pN1c category was used in only 3% of cases. All cases staged as pT4 underwent reversal of pT4 subclassification using TNM 7 compared with TNM 5. A previous study revealed stage migration from pN1 to pN2 in 32.6% of cases under TNM 7 compared with TNM 5. The difference in frequency of pN stage migration between this study and our audit suggests that the application of TNM 7 to the assessment of discontinuous/satellite tumour foci is subject to significant inter observer variability. PMID- 22228906 TI - Decreased Toll-interacting protein and peroxisome proliferator-activated receptor gamma are associated with increased expression of Toll-like receptors in colon carcinogenesis. AB - BACKGROUND: Animal data suggest that Toll-like receptors (TLR) may play an important role in colon carcinogenesis. Studies in humans to support that hypothesis are scarce. AIM: To evaluate the expression of TLR2, TLR4 and TLR5, and the expression of several other related molecules, in different human colonic lesions. METHODS: Colon biopsy samples from normal mucosa, normal mucosa adjacent to lesion, adenoma or sporadic carcinoma were obtained from 35 consecutive patients undergoing colonoscopy. Quantification of TLR2, TLR4, TLR5, Toll interacting protein (TOLLIP), peroxisome proliferator-activated receptor gamma (PPAR-gamma), nuclear factor kappaB, tumour necrosis factor (TNF) alpha, cyclooxygenase (COX) 1 and 2 mRNA was performed by real-time reverse transcription PCR. TLR2, TLR4 and TLR5 protein expression was quantified by immunohistochemistry. RESULTS: When compared with normal mucosa (1.0 arbitrary unit (AU)), adjacent normal mucosa presented higher expression of COX-2 (1.86+/ 0.3 AU, p=0.01) and TNFalpha (1.44+/-0.18 AU, p=0.04) and lower TOLLIP expression (0.75+/-0.05 AU, p=0.004). Adenomas and carcinomas presented higher expression of COX-2 (1.63+/-0.27 and 1.38+/-0.14 AU, p=0.03 and p=0.05, respectively) and lower expression of TOLLIP (0.44+/-0.04 AU, p<0.001), with diffuse and higher TLR protein expression (p<0.001). Carcinomas also expressed higher TLR2 (2.31+/-0.32 AU, p=0.006) and lower PPAR-gamma (0.56+/-0.12 AU, p=0.003). There was a trend towards decreased TOLLIP (p<0.001) and PPAR-gamma (p=0.05) from normal mucosa to adenoma/carcinoma. CONCLUSIONS: Persistently positive TLR expression and lower expression of TLR inhibitors was associated with higher TLR protein levels throughout the spectrum of lesions of colon carcinogenesis. Increasing activation of these receptors by bacteria may play a crucial role in colon carcinogenesis and tumour progression. PMID- 22228907 TI - The utility of a novel antibody in the pathological diagnosis of pancreatic acinar cell carcinoma. AB - AIMS: Acinar cell carcinomas (ACCs) are rare tumours of the exocrine pancreas accounting for about 1-2% of all pancreatic neoplasms in adults. It is therefore difficult to come across a large number of ACC cases in a single medical institution, and only a few serial studies have been published. Since ACCs present a wide variety of morphological patterns, immunohistochemical analysis is useful. In this study, the authors established a novel monoclonal antibody 2P-1-2 1 by means of a subtractive immunisation method. METHODS: Immunohistochemical staining was performed using 50 primary pancreatic tumors, including 7 ACCs, 7 neuroendocrine tumours (NETs), 5 solid-pseudopapillary neoplasms (SPNs), and 31 ductal carcinomas and organs other than the pancreas. RESULTS: Non-neoplastic acinar cells were stained diffusely, but epithelial cells of the pancreatic duct and the islets of Langerhans were not stained. In pancreatic tumours, all the seven ACCs were diffusely positive for the 2P-1-2-1 antibody. However, no positive staining was found in other pancreatic tumours including NETs, SPNs and ductal adenocarcinomas. The sensitivity and specificity of the 2P-1-2-1 antibody for ACCs were both 100%. In other organs studied, positive staining was observed only in the ectopic pancreas. CONCLUSIONS: It was shown that the 2P-1-2-1 antibody specifically stained the pancreatic acinar cells and tumours of acinar cell origin, such as ACCs. Although it remains unclear at this time to which proteins the monoclonal antibody 2P-1-2-1 is directed, it is suggested to be useful for the pathological diagnosis of ACCs and for the exclusion of other pancreatic tumours. PMID- 22228908 TI - Hardy's "Small" Discovery Remembered. PMID- 22228909 TI - Chronic perchlorate exposure impairs stickleback reproductive behaviour and swimming performance. AB - We describe behavioural changes in two generations of threespine stickleback (Gasterosteus aculeatus) exposed to environmentally relevant concentrations of perchlorate. The first generation (G(0,2002)) was exposed as two-year-old adults to perchlorate in experimental groups ranging in concentration from less than the method detection limit (<1.1 ppb) to 18.6 ppm for up to 22 days during their courtship, spawning, egg guarding, and first five days of fry guarding. No differences were noted in the behaviour or reproductive output of these fish that were exposed as adults. However, perchlorate exposure throughout development caused widespread effects in the second generation (G(1,2003)), which was spawned and raised through sexual maturity in one of four nominal experimental groups (0, 30 and 100 ppm, and a 'variable' treatment that progressively increased from <1.1 ppb to approximately 60 ppm perchlorate). Dose-dependent effects were found during the G(1,2003)'s swimming and behavioural evaluations, including higher mortality rates among treated fish following stressful events. Perchlorate exposed fish had higher failure rates during swimming trials and failed at lower flow rates than control fish. A number of treated fish exhibited seizures. Progressively fewer males completed benchmark metrics, such as nest building, spawning, nursery formation, or fry production, in a dose-dependent manner. Fewer males from higher treatments courted females, and those that did initiated courtship later and had a reduced behavioural repertoire compared to fish from lower treatments. The lowest observed adverse effect level (LOAEL) for swimming performance, reproductive behaviour, survivorship and recruitment was 30 ppm perchlorate (our lowest G(1,2003) treatment), and near complete inhibition of reproductive activity was noted among males raised in 100 ppm perchlorate. A small number of treated G(1,2003) females were isolated in aquaria, and some performed reproductive behaviour typical of males, such as biting, leading and zig-zagging in the presence of gravid females. These findings have profound implications for recruitment in wild fish populations exposed to perchlorate, and suggest that perchlorate may disrupt behaviour in other vertebrates as well. PMID- 22228910 TI - Enhanced enzyme activity through electron transfer between single-walled carbon nanotubes and horseradish peroxidase. AB - Better understanding of electron transfer (ET) taking place at the nano-bio interface can guide design of more effective functional materials used in fuel cells, biosensors, and medical devices. Single-walled carbon nanotube (SWCNT) coupled with biological enzymes serves as a model system for studying the ET mechanism, as demonstrated in the present study. SWCNT enhanced the activity of horseradish peroxidase (HRP) in the solution-based redox reaction by binding to HRP at a site proximate to the enzyme's activity center and participating in the ET process. ET to and from SWCNT was clearly observable using near-infrared spectroscopy. The capability of SWCNT in receiving electrons and the direct attachment of HRP to the surface of SWCNT strongly affected the enzyme activity due to the direct involvement of SWCNT in ET. PMID- 22228911 TI - Cognitive function, numeracy and retirement saving trajectories. AB - This paper examines the extent to which cognitive abilities relate to differences in trajectories for key economic outcomes as individuals move towards and through their retirement. We look at whether differences in baseline numeracy (measured in the English Longitudinal Study of Ageing in 2002) and broader cognitive ability predict the subsequent trajectories of outcomes such as wealth, retirement income and key dimensions of retirement expectations. Those with lower numeracy are shown to have different wealth trajectories both pre- and post retirement than their more numerate counterparts, but the distributions of retirement expectations and net replacement rates are similar across numeracy groups. PMID- 22228912 TI - The Long Reach of Childhood Health and Circumstance: Evidence from the Whitehall II Study. AB - We use data from the Whitehall II Study to examine the joint evolution of health status and economic status over the life course. We study the links between health and socioeconomic status in childhood and health and employment status at older ages. We find early life socioeconomic status is significantly associated with health over the life course, even though selection into Whitehall mutes the effects of childhood. In addition, we find that current position in the civil service is not associated with future self-assessed health, but current self assessed health is significantly associated with promotion in the civil service. PMID- 22228913 TI - X-ray Fluorescence Emission Tomography (XFET) with Novel Imaging Geometries - A Monte Carlo Study. AB - This paper presents a feasibility study for using two new imaging geometries for synchrotron X-ray fluorescence emission tomography (XFET) applications. In the proposed approaches, the object is illuminated with synchrotron X-ray beams of various cross-sectional dimensions. The resultant fluorescence photons are detected by high-resolution imaging-spectrometers coupled to collimation apertures. To verify the performance benefits of the proposed methods over the conventional line-by-line scanning approach, we have used both Monte Carlo simulations and an analytical system performance index to compare several different imaging geometries. This study has demonstrated that the proposed XFET approach could lead to a greatly improved imaging speed, which is critical for making XFET a practical imaging modality for a wide range of applications. PMID- 22228914 TI - FeP(Im)-AB Bonding Energies Evaluated with A Large Number of Density Functionals (P = porphine, Im = imidazole, AB = CO, NO, and O(2)). AB - Sixty-four (64) density functionals, ranging from GGA, meta-GGA, hybrid GGA to hybrid meta-GGA, were tested to evaluate the FeP(Im)-AB bonding energies (E(bond)) in the heme model complexes FeP(Im)(AB) (P = porphine, Im = imidazole, AB = CO, NO, and O(2)). The results indicate that an accurate prediction of E(bond) for the various ligands to heme is difficult with the DFT methods; usually a functional successful for one system does not perform equally well for the other system(s). Relatively satisfactory results for the various FeP(Im)-AB bonding energies are obtained with the meta-GGA funtionals BLAP3 and Bmtau1; they yield E(bond) values of ca.1.1, 1.2, and 0.4 eV for AB = CO, NO, and O(2), respectively, which are in reasonable agreement with experimental data (0.78 - 0.85 eV for CO, 0.99 eV for NO, and 0.44 - 0.53 eV for O(2)). The other functionals show more or less deficiency for one or two of the systems. The performances of the various functionals in describing the spin-state energetics of the five-coordinate FeP(Im) complex were also examined. PMID- 22228915 TI - Measuring Submicron-Sized Fractionated Particulate Matter on Aluminum Impactor Disks. AB - Sub-micron sized airborne particulate matter (PM) is not collected well on regular quartz or glass fiber filter papers. We used a micro-orifice uniform deposit impactor (MOUDI) to fractionate PM into six size fractions and deposit it on specially designed high purity thin aluminum disks. The MOUDI separated PM into fractions 56-100 nm, 100-180 nm, 180-320 nm, 320-560 nm, 560-1000 nm, and 1000-1800 nm. Since the MOUDI has a low flow rate (30 L/min), it takes several days to collect sufficient carbon on 47 mm foil disks. The small carbon mass (20 200 microgram C) and large aluminum substrate (~25 mg Al) present several challenges to production of graphite targets for accelerator mass spectrometry (AMS) analysis. The Al foil consumes large amounts of oxygen as it is heated and tends to melt into quartz combustion tubes, causing gas leaks. We describe sample processing techniques to reliably produce graphitic targets for (14)C-AMS analysis of PM deposited on Al impact foils. PMID- 22228916 TI - SNOWBALL VERSUS RESPONDENT-DRIVEN SAMPLING. PMID- 22228917 TI - THE DEVELOPMENT AND FEASIBILITY OF A BRIEF RISK REDUCTION INTERVENTION FOR NEWLY HIV-DIAGNOSED MEN WHO HAVE SEX WITH MEN. AB - Men who have sex with men (MSM) represent more than half of all new HIV infections in the United States. Utilizing a collaborative, community based approach, a brief risk reduction intervention was developed and pilot tested among newly HIV-diagnosed MSM receiving HIV care in a primary care setting. Sixty five men, within 3 months of diagnosis, were randomly assigned to the experimental condition or control condition and assessed at baseline, 3-month, and 6-month follow-up. Effect sizes were calculated to explore differences between conditions and over time. Results demonstrated the potential effectiveness of the intervention in reducing risk behavior, improving mental health, and increasing use of ancillary services. Process evaluation data demonstrated the acceptability of the intervention to patients, clinic staff, and administration. The results provide evidence that a brief intervention can be successfully integrated into HIV care services for newly diagnosed MSM and should be evaluated for efficacy. PMID- 22228918 TI - Implementation Intentions Increase Parent-Teacher Communication Among Latinos. AB - This research tested an implementation intentions intervention to increase parent teacher communication among Latino parents of young children. Parents (n=57) were randomly assigned to form implementation intentions or simply goal intentions to communicate with their child's teacher. They completed measures of communication and goal intentions immediately prior to the manipulation, and after the manipulation for 6 consecutive weeks. Implementation intentions increased parent teacher communication among parents with higher initial (pre-manipulation) goal intentions, but not among those with lower initial goal intentions. The findings support existing work on the conditions for implementation intentions to work, and address an important aspect of Latino children's educational success. PMID- 22228919 TI - Maturation, Peer Context, and Indigenous Girls' Early-Onset Substance Use. AB - This paper examines a biosocial model of the impact of puberty on Indigenous girls' early-onset substance use by considering the potential mediating role of peer context (i.e. mixed-sex peer groups and substance use prototypes) on the puberty and substance use relationship. Data include responses from 360 girls of a common Indigenous cultural group residing on reservations/reserves in the upper Midwest and Canada. Results of structural equation modeling revealed that the statistically significant relationship between girls' pubertal development and early-onset substance use was mediated by both mixed-sex/romantic peer groups and favorable social definitions of substance use. Implications for substance use prevention work include addressing the multiple and overlapping effects of peer influence from culturally-relevant perspectives. PMID- 22228920 TI - Green Synthesis of Fe and Fe/Pd Bimetallic Nanoparticles in Membranes for Reductive Degradation of Chlorinated Organics. AB - Membranes containing reactive nanoparticles (Fe and Fe/Pd) immobilized in a polymer film (polyacrylic acid, PAA-coated polyvinylidene fluoride, PVDF membrane) are prepared by a new method. In the present work a biodegradable, non toxic -"green" reducing agent, green tea extract was used for nanoparticle (NP) synthesis, instead of the well-known sodium borohydride. Green tea extract contains a number of polyphenols that can act as both chelating/reducing and capping agents for the nanoparticles. Therefore, the particles are protected from oxidation and aggregation, which increases their stability and longevity. The membrane supported NPs were successfully used for the degradation of a common and highly important pollutant, trichloroethylene (TCE). The rate of TCE degradation was found to increase linearly with the amount of Fe immobilized on the membrane, the surface normalized rate constant (k(SA)) being 0.005 L/m(2)h. The addition of a second catalytic metal, Pd, to form bimetallic Fe/Pd increased the k(SA) value to 0.008 L/m(2)h. For comparison purposes, Fe and Fe/Pd nanoparticles were synthesized in membranes using sodium borohydride as a reducing agent. Although the initial k(SA) values for this case (for Fe) are one order of magnitude higher than the tea extract synthesized NPs, the rapid oxidation reduced their reactivity to less than 20 % within 4 cycles. For the green tea extract NPs, the initial reactivity in the membrane domain was preserved even after 3 months of repeated use. The reactivity of TCE was verified with "real" water system. PMID- 22228921 TI - A Hybrid Geometric Phase II/III Clinical Trial Design based on Treatment Failure Time and Toxicity. AB - The problem of comparing several experimental treatments to a standard arises frequently in medical research. Various multi-stage randomized phase II/III designs have been proposed that select one or more promising experimental treatments and compare them to the standard while controlling overall Type I and Type II error rates. This paper addresses phase II/III settings where the joint goals are to increase the average time to treatment failure and control the probability of toxicity while accounting for patient heterogeneity. We are motivated by the desire to construct a feasible design for a trial of four chemotherapy combinations for treating a family of rare pediatric brain tumors. We present a hybrid two-stage design based on two-dimensional treatment effect parameters. A targeted parameter set is constructed from elicited parameter pairs considered to be equally desirable. Bayesian regression models for failure time and the probability of toxicity as functions of treatment and prognostic covariates are used to define two-dimensional covariate-adjusted treatment effect parameter sets. Decisions at each stage of the trial are based on the ratio of posterior probabilities of the alternative and null covariate-adjusted parameter sets. Design parameters are chosen to minimize expected sample size subject to frequentist error constraints. The design is illustrated by application to the brain tumor trial design. PMID- 22228922 TI - Women with Childhood ADHD: Comparisons by Diagnostic Group and Gender. AB - This study compared adult women with childhood ADHD to adult women without childhood ADHD and to adult men with childhood ADHD. The participants, all from a larger longitudinal study, included 30 women and 30 men (approximately age 23 to 24) with childhood ADHD, and 27 women without ADHD. Women with childhood ADHD were matched to comparison women on age, ethnicity, and parental education, and to men with childhood ADHD on age, ethnicity, and IQ. Self- and parent-reports of internalizing, interpersonal, academic, and job impairment, as well as substance use and delinquency indicated group differences on measures of self-esteem, interpersonal and vocational functioning, as well as substance use. Follow-up planned comparison tests revealed that almost all of these differences emerged by diagnostic status, and not by gender. This study adds to research on the negative adult outcomes of ADHD and demonstrates that the outcomes of men and women with childhood ADHD are relatively similar. PMID- 22228923 TI - Flavonoid intakes in the Baltimore Longitudinal Study of Aging. AB - Major sources of flavonoids were identified, and mean intakes over several decades were reported, among 1638 participants (mean age 62.1 +/- 16.0 y), of the Baltimore Longitudinal Study of Aging (BLSA). Dietary data were collected using 7 day diet records during three time periods (1980s, 1990s and 2000-present), and the USDA flavonoid, proanthocyanidin and isoflavone databases were used to estimate dietary flavonoid intakes. Dietary intake data were divided according to decade of visit. Foods were matched with appropriate foods in the USDA databases. Mixed dishes were disaggregated to individual foods and a similar procedure was followed. Total flavonoids and five sub-classes of flavonoids, including flavonols, flavones, flavanones, flavan-3-ols and anthocyanidins, were computed by summing appropriate compounds. The median intakes of flavonoids and the contributions of various foods to intakes were calculated by decade. Age and sex adjusted mean (SE) daily intakes of flavonoids increased from 250 (7.4) in the 1980s to 280 (9.9) mg in the 2000s. Top contributors of flavonoids were tea, apple/pear (and juices), citrus fruits (and juices), peaches, plums, grapes, nectarines (and juices) and chocolate. The data show an increase in the consumption of flavonoids over the three decades, which appears to be related to intake of fruit. PMID- 22228924 TI - Modeling the development of written language. AB - Alternative models of the structure of individual and developmental differences of written composition and handwriting fluency were tested using confirmatory factor analysis of writing samples provided by first- and fourth-grade students. For both groups, a five-factor model provided the best fit to the data. Four of the factors represented aspects of written composition: macro-organization (use of top sentence and number and ordering of ideas), productivity (number and diversity of words used), complexity (mean length of T-unit and syntactic density), and spelling and punctuation. The fifth factor represented handwriting fluency. Handwriting fluency was correlated with written composition factors at both grades. The magnitude of developmental differences between first grade and fourth grade expressed as effect sizes varied for variables representing the five constructs: large effect sizes were found for productivity and handwriting fluency variables; moderate effect sizes were found for complexity and macro organization variables; and minimal effect sizes were found for spelling and punctuation variables. PMID- 22228925 TI - Substrate-Independent Layer-by-Layer Assembly by Using Mussel-Adhesive-Inspired Polymers. PMID- 22228926 TI - On the quality assurance and verification of modern radiation therapy treatment. PMID- 22228927 TI - A simple plan evaluation index based on the dose to critical structures in radiotherapy. AB - The dose to critical structures plays a very important role in treatment plan evaluation and forms a major challenging parameter in radiotherapy treatment planning. In this study, a simple index, Plan Normal tissue complication Index (PNI) has been proposed for treatment plan evaluation based on the dose to surrounding critical structures. To demonstrate the proposed index, four different critical treatment sites that include the prostate, upper abdominal cancer, lung, and head and neck were selected for this study. A software progam (PNIcalc) has been developed to compute the PNI from the exported dose-volume histogram data and from the tissue tolerance data published by Emami et al. and Kehwar et al. The software also shows the parameters that exceed the threshold limits of dose-volume parameters presented in the QUANTEC recommendations (2010). In all the studied cases, PNI gave an overall picture of the dose received by the critical structures and also indicate the fractional volume exceeding the tolerance limit. The proposed index, PNI gives a quick comparison and selection of treatment plans that result in reduced dose to the critical structures. It can be used as an additional tool for routine treatment plan evaluation in external beam radiotherapy. PMID- 22228928 TI - Effect of low-density heterogeneities in telecobalt therapy and validation of dose calculation algorithm of a treatment planning system. AB - Telecobalt machines are still prominently used for the treatment of a variety of cancer cases in developing countries. The human body is a heterogeneous composition of variety of tissues and cavities which vary widely in their physical and radiological properties. The presence of heterogeneities in the path of telecobalt beam presents an altered dose distribution in the region of clinical interests. A computerized treatment planning system (TPS) is generally used for calculating the dose distribution in the patient. Experimental measurements were carried out in a telecobalt beam with the objectives to study the effects of low-density heterogeneities and to verify the ability of the ASHA radiotherapy TPS in predicting the altered dose distribution along the central axis and off-axis of the beam. Locally available kailwood was tested for its lung equivalence and measurements were carried out in a polymethyl methacrylate phantom by introducing lung equivalent and air gap heterogeneities. A comparison of experimentally measured and TPS calculated dose values indicates that the TPS overestimates the dose by 11.6% in lung equivalent (kailwood) heterogeneity along the central axis. Similarly, it was found that the TPS overestimates the dose by 3.9% and 5.9%, respectively, with air heterogeneity of 1.0 and 2.0 cm. While testing the adequacy of TPS in off-axis region, it was found that the TPS calculation does not indicate the widening of the beam profile in the low-density heterogeneity region. This study suggests that the effective path length based algorithm of the ASHA radiotherapy TPS is unable to achieve the recommended 3% accuracy of clinical dose calculation in heterogeneous media. PMID- 22228929 TI - Megavoltage cone beam computed tomography: Commissioning and evaluation of patient dose. AB - The improvement in conformal radiotherapy techniques enables us to achieve steep dose gradients around the target which allows the delivery of higher doses to a tumor volume while maintaining the sparing of surrounding normal tissue. One of the reasons for this improvement was the implementation of intensity-modulated radio therapy (IMRT) by using linear accelerators fitted with multi-leaf collimator (MLC), Tomo therapy and Rapid arc. In this situation, verification of patient set-up and evaluation of internal organ motion just prior to radiation delivery become important. To this end, several volumetric image-guided techniques have been developed for patient localization, such as Siemens OPTIVUE/MVCB and MVision megavoltage cone beam CT (MV-CBCT) system. Quality assurance for MV-CBCT is important to insure that the performance of the Electronic portal image device (EPID) and MV-CBCT is suitable for the required treatment accuracy. In this work, the commissioning and clinical implementation of the OPTIVUE/MVCB system was presented. The geometry and gain calibration procedures for the system were described. The image quality characteristics of the OPTIVUE/MVCB system were measured and assessed qualitatively and quantitatively, including the image noise and uniformity, low-contrast resolution, and spatial resolution. The image reconstruction and registration software were evaluated. Dose at isocenter from CBCT and the EPID were evaluated using ionization chamber and thermo-luminescent dosimeters; then compared with that calculated by the treatment planning system (TPS- XiO 4.4). The results showed that there are no offsets greater than 1 mm in the flat panel alignment in the lateral and longitudinal direction over 18 months of the study. The image quality tests showed that the image noise and uniformity were within the acceptable range, and that a 2 cm large object with 1% electron density contrast can be detected with the OPTIVUE/MVCB system with 5 monitor units (MU) protocol. The registration software was accurate within 2 mm in the anterior-posterior, left-right, and superior-inferior directions. The additional dose to the patient from MV-CBCT study set with 5 MU at the isocenter of the treatment plan was 5 cGy. For Electronic portal image device (EPID) verification using two orthogonal images with 2 MU per image the additional dose to the patient was 3.8 cGy. These measured dose values were matched with that calculated by the TPS-XiO, where the calculated doses were 5.2 cGy and 3.9 cGy for MVCT and EPID respectively. PMID- 22228930 TI - The effects of cutouts on output, mean energy and percentage depth dose of 12 and 14 MeV electrons. AB - Electron field-shaping cerrobend cutouts on the linear accelerator applicator have some effects on the output and percentage depth dose. These effects which arise from the lateral scatter nonequilibrium are particularly evident in higher energies and in cutouts with smaller radius. Dose measurements for circular, square, and triangular cutouts as well as open field was performed in a 10 * 10 cm applicator, using plane parallel type ion chamber with a 100 cm source surface distance. The Percentage Depth Doses curves were drawn and the outputs were measured for each of these cutouts. The output factors, normalized to open 10 * 10 cm field, varied between 0.891 and 0.996 depending on the energy, cutout shape, and cavity area. With the use of cutouts, R(100) shifted toward the surface. The shifts ranged from 9 to 0 mm and from 13 to 0 mm for 12 and 14 MeV, respectively, depending on the shape and cavity area. For R(90), R(80), and R(50) the ranges for observed shifts narrowed down and practically no shifts were observed for R(20). We present these changes in the form of predictive formulas, which would be useful in clinical applications. PMID- 22228931 TI - Dose volume histogram analysis and comparison of different radiobiological models using in-house developed software. AB - The purpose of this study is to compare Lyman-Kutcher-Burman (LKB) model versus Niemierko model for normal tissue complication probability (NTCP) calculation and Niemierko model versus Poisson-based model for tumor control probability (TCP) calculation in the ranking of different treatment plans for a patient undergoing radiotherapy. The standard normal tissue tolerance data were used to test the NTCP models. LKB model can reproduce the same complication probability data of normal tissue response on radiation, whereas Niemierko model cannot reproduce the same complication probability. Both Poisson-based and Niemierko models equally reproduce the same standard TCP data in testing of TCP. In case of clinical data generated from treatment planning system, NTCP calculated using LKB model was found to be different from that calculated using Niemierko model. When the fractionation effect was considered in LKB model, the calculated values of NTCPs were different but comparable with those of Niemierko model. In case of TCP calculation using these models, Poisson-based model calculated marginally higher control probability as compared to Niemierko model. PMID- 22228932 TI - Effect of surface waves on radiotherapy dosimetric measurements in water tanks. AB - The effect of surface waves, generated by moving the scanning arms in water phantoms, on radiation dosimetry is studied. It is shown that in large water tanks, high arm speeds can result in dosimetric errors of up to 5%. The measurements that are started after damping the water waves can result in about a 50% improvement in accuracy of measurements. It is shown that the water surfaces at the start of the measurements have high fluctuations that transform to a steady phase by elapsing time. PMID- 22228933 TI - Evaluation of pencil beam convolution and anisotropic analytical algorithms in stereotactic lung irradiation. AB - The aim of this study was to evaluate differences in dose distributions in stereotactic body radiation therapy treatment plans for lung tumors calculated with pencil beam convolution (PBC) algorithm with modified Batho power law (MBPL) versus heterogeneity corrected anisotropic analytical algorithm (AAA) of the Varian Eclipse treatment planning system. The four-dimensional computed tomography images from 20 patients with lung cancer were used to create treatment plans. Plans used five to seven nonopposing coplanar 6 MV beams. Plans generated with the PBC algorithm and MBPL for tissue heterogeneity corrections were optimized to deliver 60 Gy in three fractions to at least 95% of the planned target volume, and the normal tissue doses for spinal cord, esophagus, heart, and ipsilateral bronchus were restricted to less than 18, 27, 30, and 30 Gy, respectively. Plans were recalculated with AAA, retaining identical beam arrangements, photon beam fluences, and monitor units. The pencil beam plans, designed to deliver 60 Gy, delivered on average 51.6 Gy when re-calculated with the AAA, suggesting a reduction of at least 10% to prescription dose is appropriate when calculating with the AAA. PMID- 22228934 TI - On "ruby" in myocardial perfusion imaging. PMID- 22228935 TI - Circulating CYFRA 21-1 is a Specific Diagnostic and Prognostic Biomarker in Biliary Tract Cancer. AB - BACKGROUND: Biliary tract cancer (BTC) has a poor prognosis, in part related to difficulties in diagnosis. Cytokeratin 19 (CK19) is a constituent of the intermediate filament proteins of epithelial cells. CK19 fragments (CYFRA 21-1) are rarely identified in the blood of healthy individuals. We assessed the utility of CYFRA 21-1 as a diagnostic and prognostic marker of BTC. METHODS: Blood was prospectively collected from patients with benign biliary disease (n = 39), primary sclerosing cholangitis (n = 19), PSC-related cholangiocarcinoma (n = 6) and sporadic BTC (n = 60). CYFRA 21-1 levels were measured in duplicate by ELISA. RESULTS: CYFRA 21-1 (>= 1.5 ng/mL) had a sensitivity of 56% and specificity of 88%, compared with figures of 79% and 78% for CA 19-9 (>= 37U/mL). Using a higher cut-off of 3 ng/mL, CYFRA 21-1 had a sensitivity of 30% and specificity of 97%. Combination of CYFRA 21-1 (>= 1.5 ng/mL) and CA 19-9 (>= 37 U/mL) resulted in sensitivity and specificity of 45% and 96%. In contrast to CA 19-9, CYFRA 21-1 (>= 3.0 ng/mL) alone was a strong predictor of prognosis (median survival 2 months vs 10 months, p = 0.001). CONCLUSION: Elevated circulating CYFRA 21-1 is a specific, but less sensitive diagnostic marker than CA 19-9, predicts a poor outcome and may act as a surrogate marker of circulating tumor cells in BTC. Further prospective studies of its utility in assessing operability and response to chemotherapy are needed. PMID- 22228936 TI - Phytoconstituents as photoprotective novel cosmetic formulations. AB - Phytoconstituents are gaining popularity as ingredients in cosmetic formulations as they can protect the skin against exogenous and endogenous harmful agents and can help remedy many skin conditions. Exposure of skin to sunlight and other atmospheric conditions causes the production of reactive oxygen species, which can react with DNA, proteins, and fatty acids, causing oxidative damage and impairment of antioxidant system. Such injuries damage regulation pathways of skin and lead to photoaging and skin cancer development. The effects of aging include wrinkles, roughness, appearance of fine lines, lack of elasticity, and de or hyperpigmentation marks. Herbal extracts act on these areas and produce healing, softening, rejuvenating, and sunscreen effects. We have selected a few photoprotective phytoconstituents, such as curcumin, resveratrol, tea polyphenols, silymarin, quercetin and ascorbic acid, and have discussed the considerations to be undertaken for the development of herbal cosmetic formulations that could reduce the occurrence of skin cancer and delay the process of photoaging. This article is aimed at providing specific and compiled knowledge for the successful preparation of photoprotective herbal cosmetic formulations. PMID- 22228938 TI - Importance of novel drug delivery systems in herbal medicines. AB - Novel drug delivery system is a novel approach to drug delivery that addresses the limitations of the traditional drug delivery systems. Our country has a vast knowledge base of Ayurveda whose potential is only being realized in the recent years. However, the drug delivery system used for administering the herbal medicine to the patient is traditional and out-of-date, resulting in reduced efficacy of the drug. If the novel drug delivery technology is applied in herbal medicine, it may help in increasing the efficacy and reducing the side effects of various herbal compounds and herbs. This is the basic idea behind incorporating novel method of drug delivery in herbal medicines. Thus it is important to integrate novel drug delivery system and Indian Ayurvedic medicines to combat more serious diseases. For a long time herbal medicines were not considered for development as novel formulations owing to lack of scientific justification and processing difficulties, such as standardization, extraction and identification of individual drug components in complex polyherbal systems. However, modern phytopharmaceutical research can solve the scientific needs (such as determination of pharmacokinetics, mechanism of action, site of action, accurate dose required etc.) of herbal medicines to be incorporated in novel drug delivery system, such as nanoparticles, microemulsions, matrix systems, solid dispersions, liposomes, solid lipid nanoparticles and so on. This article summarizes various drug delivery technologies, which can be used for herbal actives together with some examples. PMID- 22228939 TI - Hawthorn (Crataegus spp.) in the treatment of cardiovascular disease. AB - The medicinal properties of hawthorn (Crataegus spp., a genus comprising approximately 300 species) have been utilized by many cultures for a variety of therapeutic purposes for many centuries. In the Western world cardiovascular disease (CVD) has become one of the single most significant causes of premature death. Echoing this situation, more recent research into the therapeutic benefits of hawthorn preparations has focused primarily upon its cardiovascular effects. This review covers research into the various mechanisms of action proposed for Crataegus preparations, clinical trials involving Crataegus preparations, and the herb's safety profile.Clinical trials reviewed have been inconsistent in terms of criteria used (sample size, preparation, dosage, etc) but have been largely consistent with regard to positive outcomes. An investigation into data available to date regarding hawthorn preparations and herb/drug interactions reveals that theoretical adverse interactions have not been experienced in practice. Further, adverse reactions relating to the use of hawthorn preparations are infrequent and mild, even at higher dosage ranges. A recent retrospective study by Zick et al. has suggested a negative outcome for the long-term use of hawthorn in the prognosis of heart failure. These findings are examined in this paper.Although further research is needed in certain areas, current research to date suggests that hawthorn may potentially represent a safe, effective, nontoxic agent in the treatment of CVD and ischemic heart disease (IHD). PMID- 22228937 TI - Secondary metabolites as DNA topoisomerase inhibitors: A new era towards designing of anticancer drugs. AB - A large number of secondary metabolites like alkaloids, terpenoids, polyphenols and quinones are produced by the plants. These metabolites can be utilized as natural medicines for the reason that they inhibit the activity of DNA topoisomerase which are the clinical targets for anticancer drugs. DNA topoisomerases are the cellular enzymes that change the topological state of DNA through the breaking and rejoining of DNA strands. Synthetic drugs as inhibitors of topoisomerases have been developed and used in the clinical trials but severe side effects are a serious problem for them therefore, there is a need for the development of novel plant-derived natural drugs and their analogs which may serve as appropriate inhibitors with respect to drug designing. The theme for this review is how secondary metabolites or natural products inactivate the action of DNA topoisomerases and open new avenues towards isolation and characterization of compounds for the development of novel drugs with anticancer potential. PMID- 22228940 TI - Mangifera indica (mango). AB - Mangifera indica, commonly used herb in ayurvedic medicine. Although review articles on this plant are already published, but this review article is presented to compile all the updated information on its phytochemical and pharmacological activities, which were performed widely by different methods. Studies indicate mango possesses antidiabetic, anti-oxidant, anti-viral, cardiotonic, hypotensive, anti-inflammatory properties. Various effects like antibacterial, anti fungal, anthelmintic, anti parasitic, anti tumor, anti HIV, antibone resorption, antispasmodic, antipyretic, antidiarrhoeal, antiallergic, immunomodulation, hypolipidemic, anti microbial, hepatoprotective, gastroprotective have also been studied. These studies are very encouraging and indicate this herb should be studied more extensively to confirm these results and reveal other potential therapeutic effects. Clinical trials using mango for a variety of conditions should also be conducted. PMID- 22228941 TI - Phytopharmacologic aspects of Canscora decussata Roem and Schult. AB - Nature is an inexhaustible source of secondary metabolites-different types of alkaloids, terpenoids, phenolics, and other classes of organic compounds. In the process of isolation, purification and determination of the structures of lead, with their biological effectiveness, every type of experimental tool and strategy, known too and developed over the years by various practitioners. The present review is an attempt to compile information on various aspects of Canscora decussata, "Shankhpushpi" of Indian traditional system of medicine. The phytoconstituents, such as phenolic compounds, xanthones, and triterpenoids were isolated from different parts of the plant. The plant possesses immunomodulatory, analgesic, anticonvulsant, antitubercular, antiinflammatory, spermicidal, central nervous system-depressive, and cardiostimulant properties. Clinical trials of marketed formulation showed very encouraging results. PMID- 22228942 TI - Euphorbia hirta: Its chemistry, traditional and medicinal uses, and pharmacological activities. AB - The oldest remedies known to mankind are herbal medicines. India is known worldwide for its Ayurvedic treatment. Euphorbia hirta is often used traditionally for female disorders, respiratory ailments (cough, coryza, bronchitis, and asthma), worm infestations in children, dysentery, jaundice, pimples, gonorrhea, digestive problems, and tumors. It is reported to contain alkanes, triterpenes, phytosterols, tannins, polyphenols, and flavanoids. This review describes the medicinal properties, chemical constituents, and other important aspects of Euphorbia hirta. PMID- 22228943 TI - The chemistry, pharmacologic, and therapeutic applications of Polyalthia longifolia. AB - Medicinal plants are nature's gift to human beings to lead a disease-free, healthy life. They play a vital role in preserving our health. India is one of the most medicoculturally diverse countries in the world, where the medicinal plant sector is part of a time-honored tradition that is respected even today. Medicinal plants are believed to be much safer and proved as elixir in the treatment of various ailments. In our country, more than 2000 medicinal plants are recognized. Polyalthia longifolia cv. pendula (Annonaceae) is native to the drier regions of India and is locally known as "Ashoka" and is commonly cultivated in Pakistan and Sri Lanka. This plant is used as an antipyretic agent in indigenous systems of medicine. Pharmacologic studies on the bark and leaves of this plant show effective antimicrobial activity, cytotoxic function, antiulcer activity, hypoglycemic activity, and hypotensive effect. The present article includes the detailed exploration of pharmacologic properties of P. longifolia in an attempt to provide a direction for further research. PMID- 22228944 TI - Psoralea corylifolia Linn.-"Kushtanashini". AB - Plants have been the basis of many traditional medicines throughout the world for thousands of years and continue to provide new remedies to mankind. Plants have been one of the important sources of medicines since the beginning of human civilization. The recent resurgence of plant remedies resulted from several factors, such as effectiveness of plant medicines and lesser side effects compared with modern medicines. Psoralea corylifolia, commonly known as babchi, is a popular herb, which has since long been used in traditional Ayurvedic and Chinese medicine for its magical effects to cure various skin diseases. This plant is also pharmacologically studied for its chemoprotective, antioxidant, antimicrobial, and antiinflammatory properties. This review attempts to highlight the available literature on P. corylifolia with respect to its ethnobotany, pharmacognostic characteristics, traditional uses, chemical constituents, and summary of its various pharmacologic activities and clinical effects. Other aspects, such as toxicology and precautions are also discussed. This will be helpful to create interest toward babchi and may be useful in developing new formulations with more therapeutic and economical value. PMID- 22228946 TI - Leucas aspera: A review. AB - Leucas aspera commonly known as 'Thumbai' is distributed throughout India from the Himalayas down to Ceylon. The plant is used traditionally as an antipyretic and insecticide. Medicinally, it has been proven to possess various pharmacological activities like antifungal, antioxidant, antimicrobial, antinociceptive and cytotoxic activity. Further, studies reveal the presence of various phytochemical constituents mainly triterpenoids, oleanolic acid, ursolic acid and b-sitosterol, nicotine, sterols, glucoside, diterpenes, phenolic compounds (4-(24-hydroxy-1-oxo-5-n-propyltetracosanyl)-phenol). These studies reveal that L. aspera is a source of medicinally active compounds and have various pharmacological effects; hence, this drug encourage finding its new therapeutic uses. PMID- 22228945 TI - The phytochemical and pharmacological profile of Persea americana Mill. AB - Over the past decades, herbal medicine has become a thing of global significance with medicinal and economic implications. Wide spread use of herbs throughout the globe has raised serious concerns over its quality, safety, and efficacy. Thus, exact scientific assessment has become a precondition for acceptance of herbal health claims. Persea americana Mill. (avocado) is a tree, native to central America, cultivated in tropical and subtropical climates around the world, belonging to the family Lauraceae, is widely used in Ayurveda and evidence-based phototherapy. There are 3 principal races or groups of avocado: Mexican, Guatemalan, and West Indian named for the areas where they were originally cultivated. The plant is used in traditional medicine for the treatment of various ailments, such as monorrhagia, hypertension, stomach ache, bronchitis, diarrhea, and diabetes. Peptone, b-galactoside, glycosylated abscisic acid, alkaloids, cellulose, polygalacto urease, polyuronoids, cytochrome P-450, and volatile oils are reported to be present in this plant. Biotechnologic approaches show that modified MS medium supplemented with 1.0 mg benzyladenine/L, 0-1mg Indole Butyric Acid/L, 0.1 mg Gibberalic Acid 3/L was optimum for adventitious shoot development. In the present review, an effort has been made to study the different aspects of P. americana Mill. PMID- 22228947 TI - Semecarpus anacardium Linn.: A review. AB - Semecarpus anacardium Linn. (Family: Anacardiaceae), commonly known 'Ballataka' or 'Bhilwa', has been used in various traditional system of medicines for various ailments since ancient times. Its nuts contain a variety of biologically active compounds such as biflavonoids, phenolic compounds, bhilawanols, minerals, vitamins and amino acids, which show various medicinal properties. The fruit and nut extract shows various activities like antiatherogenic, antiinflammatory, antioxidant, antimicrobial, anti-reproductive, CNS stimulant, hypoglycemic, anticarcinogenic and hair growth promoter. The article reviews the various activities of the plant. PMID- 22228948 TI - Ocimum sanctum Linn. A reservoir plant for therapeutic applications: An overview. AB - The medicinal plants are widely used by the traditional medicinal practitioners for curing various diseases in their day to day practice. In traditional system of medicine, different parts (leaves, stem, flower, root, seeds and even whole plant) of Ocimum sanctum Linn. have been recommended for the treatment of bronchitis, malaria, diarrhea, dysentery, skin disease, arthritis, eye diseases, insect bites and so on. The O. sanctum L. has also been suggested to possess anti fertility, anticancer, antidiabetic, antifungal, antimicrobial, cardioprotective, analgesic, antispasmodic and adaptogenic actions. Eugenol (1-hydroxy-2-methoxy-4 allylbenzene), the active constituents present in O. sanctum L. have been found to be largely responsible for the therapeutic potentials. The pharmacological studies reported in the present review confirm the therapeutic value of O. sanctum L. The results of the above studies support the use of this plant for human and animal disease therapy and reinforce the importance of the ethno botanical approach as a potential source of bioactive substances. PMID- 22228949 TI - Extracts from the history and medical properties of garlic. AB - At the time when antibiotics and other pharmacy products did not exist, a bulb of garlic itself represented a whole pharmacy industry due to the broad spectrum of effects. Most different suppositions involving this herb are mentioned; some of them were so pointless that they disappeared in time, but some of them have remained until the present days. The garlic was given different names that are still in use such as 'Russian penicillin', 'natural antibiotic', 'vegetable viagra', 'plant talisman', 'rustic's theriac', 'snake grass' etc. Presentation of the development of ideas associated with garlic and the evolution of the notions increased the ability of the pharmacists and physicians to respond to the challenges of their professional services in facilitating human life. PMID- 22228950 TI - Current knowledge and future direction of research on soy isoflavones as a therapeutic agents. AB - Isoflavones, the most abundant phytoestrogens in Soy beans, are structurally similar to 17beta-estradiol. The antioxidant property of the soy isoflavones, namely, genistein and daidzein is well established in different experimental models and also in clinical studies. The compounds have been found effective in the management of diabetes by acting on peroxisome proliferator-activated receptors. It reduces the risk of coronary heart disease by reducing the level of low-density lipoprotein and triglycerides. Soy isoflavones have the potential in the treatment of osteoporosis to act on osteoclasts further to inhibit tyrosine kinase. Among the soy isoflavones, genistein is the potential compound found effective in the treatment of cancer by acting on androgen receptor further to inhibit tyrosine kinases. In this article, various aspects of the diverse biological activities of soy isoflavones and their potential clinical implications with mechanism of action, especially in the treatment and prevention of diabetes, cardiovascular diseases, cancer, osteoporosis, neuroprotection, and also future area of research on soy isoflavones are reviewed and discussed. PMID- 22228951 TI - Free radicals, antioxidants and functional foods: Impact on human health. AB - In recent years, there has been a great deal of attention toward the field of free radical chemistry. Free radicals reactive oxygen species and reactive nitrogen species are generated by our body by various endogenous systems, exposure to different physiochemical conditions or pathological states. A balance between free radicals and antioxidants is necessary for proper physiological function. If free radicals overwhelm the body's ability to regulate them, a condition known as oxidative stress ensues. Free radicals thus adversely alter lipids, proteins, and DNA and trigger a number of human diseases. Hence application of external source of antioxidants can assist in coping this oxidative stress. Synthetic antioxidants such as butylated hydroxytoluene and butylated hydroxyanisole have recently been reported to be dangerous for human health. Thus, the search for effective, nontoxic natural compounds with antioxidative activity has been intensified in recent years. The present review provides a brief overview on oxidative stress mediated cellular damages and role of dietary antioxidants as functional foods in the management of human diseases. PMID- 22228953 TI - A potential of some medicinal plants as an antiulcer agents. AB - Peptic ulcers are a broad term that includes ulcers of digestive tract in the stomach or the duodenum. The formation of peptic ulcers depends on the presence of acid and peptic activity in gastric juice plus a breakdown in mucosal defenses. There are two major factors that can disrupt the mucosal resistance to injury: non-steroidal antiinflammatory drugs (NSAIDs) example, aspirin and Helicobacter pylori infection. Numerous natural products have been evaluated as therapeutics for the treatment of a variety of diseases, including peptic ulcer. There has been considerable pharmacological investigation into the antiulcer activity of some compounds. In this work, we shall review the literature on different medicinal plant and alkaloids with antiulcer activity. This article reviews the antiacid/anti-peptic, gastroprotective and/or antiulcer properties of the most commonly employed herbal medicines and their identified active constituents. The experimental parameters used for antiulcer activity were cold restraint stress-induced ulcer model, Diclofenac-induced ulcer model in rats, (HCl-ethanol)-induced ulcer in mice and water immersion stress-induced ulcer in rats. The ideal aims of treatment of peptic ulcer disease are to relieve pain, heal the ulcer and delay ulcer recurrence. About 70% of patients with peptic ulcer disease are infected by Helicobacter pylori and eradication of this microorganism seems to be curative for this disease. This article reviews drugs derived from medicinal plant more commonly used in the world for peptic ulcer and, if reported, the antiulcer activity. This article will be concerned only with the antiulcer and gastro-protective effects. PMID- 22228952 TI - Medicinal mushrooms: Towards a new horizon. AB - The arising awareness about functional food has created a boom in this new millennium. Mushrooms are widely consumed by the people due to their nutritive and medicinal properties. Belonging to taxonomic category of basidiomycetes or ascomycetes, these mushrooms possess antioxidant and antimicrobial properties. They are also one of the richest source of anticancer and immunomodulating agents. Thus these novel myochemicals from these mushrooms are the wave of future. PMID- 22228954 TI - Erythrina variegata Linn: A review on morphology, phytochemistry, and pharmacological aspects. AB - This review gives an account of the current knowledge on the morphology, phytochemistry, and pharmacological aspects of Erythrina variegata. E. variegata also called Erythrina indica is a thorny deciduous tree growing to 60 feet tall. A wide range of chemical compounds have been isolated, mainly alkaloids, flavonoids, triterpenoids, and lectin. Different parts of the plant have been used in traditional medicine as nervine sedative, collyrium in opthalmia, antiasthmatic, antiepileptic, antiseptic, and as an astringent. The alkaloids extracted from the leaves of E. variegata are reported to have anti-inflammatory and analgesic activity. Isoflavonoids isolated from E. variegata having antibacterial and anthelmintic activity. E. variegata shows several other characteristic pharmacological effects like neuromuscular blocking, smooth muscle relaxant, CNS depressant, and hydrocholeretic, which are consistent with the reported uses of the plant extracts in the indigenous system of medicine. Hence the present article includes the detailed exploration of morphology, phytochemistry, and pharmacological aspects of E. variegata in an attempt to provide a direction for further research. PMID- 22228955 TI - Pistia stratiotes (Jalkumbhi). AB - Pistia stratiotes (Family: Araceae) is commonly used in Ayurvedic medicine. This review article is a compilation of all the updated information on its phytochemical and pharmacological activities, which were performed by different methods. Studies indicate that P. stratiotes possesses diuretic, antidiabetic, antidermatophytic, antifungal, and antimicrobial properties. These results are very encouraging and indicate that this plant should be studied more extensively to confirm the reproducibility of these results and also to reveal other potential therapeutic effects, along with some "leads" with possible isolation of active biomoieties and their mechanism of action. PMID- 22228956 TI - A review on Cressa cretica Linn.: A halophytic plant. AB - Herbal medicine is used by up to 80% of the population in developing countries. Cressa cretica L. is a popular holophytic plant and is used in folklore medicine for ailments including diabetes, ulcers, asthma, anthelmintic, stomachic, tonic and aphrodisiac purposes, enriches the blood, and is useful in constipation, leprosy, and urinary discharges. The plant is traditionally used in Bahrain as expectorant and antibilious agent. Scientific evidence suggests its versatile biological functions such as its antibacterial, antifungal, antitussive, anticancer with some other plants, anti-inflammatory, and improving testicular function in rats. In this article, a comprehensive account of the morphology, phytochemical constituents, ethnobotany, and biological activities are included in view of the recent findings of importance on the plant, C. cretica. PMID- 22228957 TI - Hygrophila spinosa: A comprehensive review. AB - Hygrophila spinosa T Ander, belonging to the family Acanthaceae, is a promising medicinal plant with great economic potential. The medicinal value of H. spinosa has been appreciated in the ancient medical literature. The plant contains terpenoids, alkaloids, flavonoids, and is traditionally known as an aphrodisiac, renal tonic, and for its health-promoting properties. The plant is cultivated throughout India. However, systematic information on the different aspects of this species is not available. In this review, an attempt has been made to present this information. PMID- 22228958 TI - Argyreia speciosa (Linn. f.) sweet: A comprehensive review. AB - Argyreia speciosa (Linn. f.) Sweet is a popular Indian medicinal plant, which has long been used in traditional Ayurvedic Indian medicine for various diseases. This plant is pharmacologically studied for nootropic, aphrodisiac, immunomodulatory, hepatoprotective, antioxidant, antiinflammatory, antihyperglycemic, antidiarrheal, antimicrobial, antiviral, nematicidal, antiulcer, anticonvulsant, analgesic and central nervous depressant activities. A wide range of phytochemical constituents have been isolated from this plant. A comprehensive account of the morphology, phytochemical constituents and pharmacological activities reported are included in view of the many recent findings of importance on this plant. PMID- 22228959 TI - Anethum graveolens: An Indian traditional medicinal herb and spice. AB - Anethum graveolens L. (dill) has been used in ayurvedic medicines since ancient times and it is a popular herb widely used as a spice and also yields essential oil. It is an aromatic and annual herb of apiaceae family. The Ayurvedic uses of dill seeds are carminative, stomachic and diuretic. There are various volatile components of dill seeds and herb; carvone being the predominant odorant of dill seed and alpha-phellandrene, limonene, dill ether, myristicin are the most important odorants of dill herb. Other compounds isolated from seeds are coumarins, flavonoids, phenolic acids and steroids. The main purpose of this review is to understand the significance of Anethum graveolens in ayurvedic medicines and non-medicinal purposes and emphasis can also be given to the enhancement of secondary metabolites of this medicinal plant. PMID- 22228960 TI - The genus Gelsemium: An update. AB - The review includes 103 references on the genus Gelsemium, and comprises ethnopharmacology, morphology, phytoconstituents, pharmacological reports, clinical studies and toxicology of the prominent species of Gelsemium. Alkaloids and iridoids constitute major classes of phytoconstituents of the genus. Most popular species of the genus are the Asian G. elegans and the two North American related species, G. sempervirens and G. rankinii. Gelsemium species are categorized under medicinal as well as poisonous plants. Amongst various species, G. elegans and G. sempervirens possess medicinal value, and have been traditionally used as nervous system relaxant. These plants have been explored exhaustively for their anticancer activity. In the concluding part, the future scope of Gelsemium species has been emphasized with a view to establish their multifarious biological activities and mode of actions. PMID- 22228961 TI - Phytopharmacology of Ficus religiosa. AB - Herbs have always been the principal form of medicine in India. Medicinal plants have curative properties due to the presence of various complex chemical substances of different composition, which are found as secondary plant metabolites in one or more parts of these plants. Ficus religiosa (L.), commonly known as pepal belonging to the family Moraceae, is used traditionally as antiulcer, antibacterial, antidiabetic, in the treatment of gonorrhea and skin diseases. F. religiosa is a Bo tree, which sheltered the Buddha as he divined the "Truths." The present review aims to update information on its phytochemistry and pharmacological activities. PMID- 22228962 TI - Crocus sativus L.: A comprehensive review. AB - Crocus sativus L. belonging to the family Iridaceae (syn - kesar) comprises the dried red stigma and is widely cultivated in Iran and other countries such as India and Greece. Saffron contains more than 150 volatile and aroma-yielding compounds mainly terpenes, terpene alcohol, and their esters. The bitter taste and an iodoform or hay-like fragrance are caused by chemicals picrocrocin and safranal. C. sativus possesses a number of medicinally important activities such as antihypertensive, anticonvulsant, antitussive, antigenototoxic and cytotoxic effects, anxiolytic aphrodisiac, antioxidant, antidepressant, antinociceptive , anti-inflammatory, and relaxant activity. It also improves memory and learning skills, and increases blood flow in retina and choroid. The present review explores the historical background, chemical constituents, pharmacological actions, uses, substitutes and adulterants, and toxicity. It also deals with its evaluation, formulations, and chemical tests in detail. PMID- 22228963 TI - Salvadora persica. AB - Salvadora persica (kharijal) is a large, well-branched, and evergreen shrub or a tree resembling Salvadora oleoides (meethijal) found in the dry and arid regions of India. Chewing sticks have been used for centuries for tooth cleaning, and are recommended by the World Health Organization in areas where their use is customary. Salvadora persica has enormous reported activities. It has potential medicinal and research activities. Salvadora persica is a promising product and is useful to produce antiplaque, analgesic, anticonvulsant, antibacterial, antimycotic, cytotoxic, antifertility, deobstruent, carminative, diuretic, astringent, and also used in biliousness, and rheumatism. This review highlights the pharmacologic effects and therapeutic effects of Salvadora persica. The chemical constituents present in different parts of the plant are also discussed. PMID- 22228964 TI - Chemical constituents of Asparagus. AB - Asparagus species (family Liliaceae) are medicinal plants of temperate Himalayas. They possess a variety of biological properties, such as being antioxidants, immunostimulants, anti-inflammatory, antihepatotoxic, antibacterial, antioxytocic, and reproductive agents. The article briefly reviews the isolated chemical constituents and the biological activities of the plant species. The structural formula of isolated compounds and their distribution in the species studied are also given. PMID- 22228965 TI - Recurrence and rejection in liver transplantation for primary sclerosing cholangitis. AB - Primary sclerosing cholangitis (PSC) is a chronic progressive inflammatory disease affecting the bile ducts, leading to fibrosis and eventually cirrhosis in most patients. Its etiology is unknown and so far no effective medical therapy is available. Liver transplantation (LTX) is the only curative treatment and at present PSC is the main indication for LTX in the Scandinavian countries. Close to half of the PSC patients experience one or more episodes of acute cellular rejection (ACR) following transplantation and approximately 1/5 of the transplanted patients develop recurrent disease in the graft. In addition, some reports indicate that ACR early after LTX for PSC can influence the risk for recurrent disease. For these important post-transplantation entities affecting PSC patients, we have reviewed the current literature on epidemiology, pathogenesis, treatment and the possible influence of rejection on the risk of recurrent disease in the allograft. PMID- 22228967 TI - An update on chemotherapy of colorectal liver metastases. AB - Surgical resection of liver metastases of colorectal cancer greatly improves the clinical outcome of patients with advanced disease. Developments in chemotherapeutic agents and strategies bring hope of a cure to patients with initially unresectable colorectal liver metastases (CLM). Perioperative chemotherapy significantly improves the survival time of patients who receive curative-intent hepatectomy. Even for unresectable CLM, recent studies demonstrated that active preoperative chemotherapy could achieve shrinkage of liver metastasis and thus render some for resection. Furthermore, an increase in tumor resection rate and prolonged survival time among patients with CLM has been observed following the application of monoclonal antibodies in recent years. However, the value of chemotherapy via hepatic arterial infusion is still unclear. More trials should be conducted in patients with CLM in order to improve survival. PMID- 22228966 TI - Multi-modality treatment of colorectal liver metastases. AB - Liver metastases synchronously or metachronously occur in approximately 50% of colorectal cancer patients. Multimodality comprehensive treatment is the best therapeutic strategy for these patients. However, the optimal pattern of multimodality therapy is still controversial, and it raises several significant concerns. Liver resection is the most important treatment for colorectal liver metastases. The definition of resectability has shifted to focus on the completion of R0 resection and normal liver function maintenance. The role of neoadjuvant and adjuvant chemotherapy still needs to be clarified. The management of either progression or complete remission during neoadjuvant chemotherapy is challenging. The optimal sequencing of surgery and chemotherapy in synchronous colorectal liver metastases patients is still unclear. Conversional chemotherapy, portal vein embolization, two-stage resection, and tumor ablation are effective approaches to improve resectability for initially unresectable patients. Several technical issues and concerns related to these methods need to be further explored. For patients with definitely unresectable liver disease, the necessity of resecting the primary tumor is still debatable, and evaluating and predicting the efficacy of targeted therapy deserve further investigation. This review discusses different patterns and important concerns of multidisciplinary treatment of colorectal liver metastases. PMID- 22228969 TI - Influence of proton pump inhibitor treatment on Helicobacter pylori stool antigen test. AB - AIM: To investigate the effects of proton pump inhibitor (PPI) treatment on stool antigen test using the TestMate pylori enzyme immunoassay. METHODS: This study assessed 28 patients [16 men and 12 women; mean age (63.1 +/- 5.9) years; range, 25-84 years] who underwent stool antigen test and urea breath test (UBT) before and after PPI administration. RESULTS: Using the UBT as the standard, the sensitivity, specificity and agreement of the stool antigen test in all 28 patients were 95.2%, 71.4%, and 89.3%, respectively, before PPI administration, and 88.9%, 90.9%, and 89.3%, respectively, after PPI treatment. Mean UBT values were 23.98% +/- 5.33% before and 16.19% +/- 4.75% after PPI treatment and, in 15 patients treated for >= 4 wk, were significantly lower after than before 4 wk of PPI treatment (12.58% +/- 4.49% vs 24.53% +/- 8.53%, P = 0.048). The mean optical density (A(450/630)) ratios on the stool antigen test were 1.16 +/- 0.20 before and 1.17 +/- 0.24 after PPI treatment (P = 0.989), and were 1.02 +/- 0.26 and 0.69 +/- 0.28, respectively, in the group treated for > 4 wk (P = 0.099). CONCLUSION: The stool antigen test was equally sensitive to the UBT, making it a useful and reliable diagnostic method, even during PPI administration. PMID- 22228968 TI - Increased numbers of Foxp3-positive regulatory T cells in gastritis, peptic ulcer and gastric adenocarcinoma. AB - AIM: To determine the number of regulatory T cells (Tregs) in gastric mucosa of patients with gastritis, peptic ulcers and gastric cancer. METHODS: This study was a retrospective analysis of gastric antrum biopsy specimens from healthy controls (n = 22) and patients with gastritis (n = 30), peptic ulcer (n = 83), or gastric cancer (n = 32). Expression of CD4, CD25 and Foxp3 was determined by immunohistochemistry in three consecutive sections per sample. RESULTS: Compared with healthy controls, there was an increased number of CD25(+) and Foxp3(+) cells in patients with gastritis (P = 0.004 and P = 0.008), peptic ulcer (P < 0.001 and P < 0.001), and gastric cancer (P < 0.001 and P < 0.001). The ratio of CD25(+)/CD4(+) or Foxp3(+)/CD4(+) cells was also significantly higher in all disease groups (P < 0.001, respectively). The number of CD4(+), CD25(+), and Foxp3(+) cells, and the ratio of CD25(+)/CD4(+) and Foxp3(+)/CD4(+) cells, were associated with the histological grade of the specimens, including acute inflammation, chronic inflammation, lymphoid follicle number, and Helicobacter pylori infection. The number of CD4(+), CD25(+) and Foxp3(+) cells, and the ratio of CD25(+)/CD4(+) and Foxp3(+)/CD4(+) cells, were negatively associated with intestinal metaplasia among gastritis (P < 0.001, P < 0.001, P < 0.001, P = 0.002 and P = 0.002) and peptic ulcer groups (P = 0.013, P = 0.004, P < 0.001, P = 0.040 and P = 0.003). CONCLUSION: Tregs are positively associated with endoscopic findings of gastroduodenal diseases and histological grade but negatively associated with intestinal metaplasia in gastritis and peptic ulcer groups. PMID- 22228970 TI - Outcome after gastrectomy in gastric cancer patients with type 2 diabetes. AB - AIM: To evaluate the prognosis of type II diabetes mellitus (T2DM) after gastrectomy and related factors in gastric cancer patients. METHODS: 403 gastric cancer patients with T2DM were studied, who underwent gastrectomy between May 2003 and September 2009. A review of medical records and telephone interviews was performed in this cross-sectional study. The factors included in the statistical analysis were as follows: gender, age, type of surgery, preoperative body mass index (BMI), current BMI, BMI reduction ratio, preoperative insulin or oral diabetic medicine requirement, follow-up duration, and current state of diabetes. Assessment of diabetes status after surgery was classified into four categories according to the change in hypoglycemic agents after surgery and present status of T2DM: resolution, improvement, same, and worse. RESULTS: The mean follow-up duration was 33.7 mo (+/- 20.6 mo), preoperative BMI was 24.7 kg/m(2) (+/- 3.0 kg/m(2)), and BMI reduction ratio was 9.8% (+/- 8.6%). After surgery, T2DM was cured in 58 patients (15.1%) and was improved in 117 patients (30.4%). According to the type of surgery, the BMI reduction ratio was significantly higher in the total gastrectomy and Roux-en-Y reconstruction group [14.2% +/- 9.2% vs 9.2% +/- 7.7% (Billroth II group), P < 0.001] and significantly lower in the subtotal gastrectomy and Billroth I reconstruction group [7.6% +/- 8.0%, 9.2% +/- 7.7% (Billroth II group), P < 0.001]. The BMI reduction ratio, follow-up duration after surgery, type of surgery, extent of gastrectomy, and performance of duodenal bypass were significantly correlated to the course of T2DM (P < 0.05). The BMI reduction ratio was the most influential factor on T2DM status. In a subgroup analysis of patients with a BMI reduction ratio of 10% or less (n = 206), T2DM was cured in 15 (7.6%) patients and was improved in 57 (28.8%) patients after surgery, and only the duration of surgery was significantly correlated to T2DM status (P = 0.022). CONCLUSION: The course of T2DM was significantly correlated to the BMI reduction ratio but not to the type of surgery without a significant change in BMI. PMID- 22228972 TI - Risk factors for adverse outcome in low rectal cancer. AB - AIM: To demonstrate the oncologic outcomes of low rectal cancer and to clarify the risk factors for survival, focusing particularly on the type of surgery performed. METHODS: Data from patients with low rectal carcinomas who underwent surgery, either sphincter-preserving surgery (SPS) or abdominoperineal resection (APR), at The First Affiliated Hospital of Sun Yat-sen University in China from August 1994 to December 2005 were retrospectively analyzed. RESULTS: Of 331 patients with low rectal cancer, 159 (48.0%) were treated with SPS. A higher incidence of positive resection margins and a higher 5-year cumulative local recurrence rate (14.7% vs 6.8%, P = 0.041) were observed in patients after APR compared to SPS. The five-year overall survival (OS) was 54.6% after APR and 66.8% after SPS (P = 0.018), and the 5-year disease-free survival (DFS) was 52.9% after APR and 65.5% after SPS (P = 0.013). In multivariate analysis, poor OS and DFS were significantly related to positive resection margins, pT3-4, and pTNM III IV but not to the type of surgery. CONCLUSION: Despite a higher rate of positive resection margins after APR, the type of surgery was not identified as an independent risk factor for survival. PMID- 22228971 TI - Efficacy and safety of treatment of hepatitis C virus infection in renal transplant recipients. AB - AIM: To assess the efficacy and safety of combined pegylated interferon and ribavirin therapy in hepatitis C virus (HCV) infection in renal transplant recipients. METHODS: This is a retrospective chart review of post renal transplant patients who were positive for anti-HCV and HCV-RNA, and who have received treatment with combination of pegylated interferon and ribavirin between October 2003 and December 2008. Only patients with stable graft function and absence of evidence of cirrhosis and who received the therapy for continuous 48 wk were included. Nineteen patients (13 male and 6 female) were identified and included. The patient's complete blood count, liver and kidney profile, and calculated glomerular filtration rate (GFR) were monitored every 6-8 wk while on treatment. HCV-RNA was tested at 12 wk for early virological response, at 48 wk for end of treatment response (ETR), and then retested at 24, and 48 wk after completion of therapy for sustained virological response (SVR). Liver biopsies were obtained before treatment from all patients and graft kidney biopsies were performed as required. RESULTS: Of the entire cohort, 9 patients (47.4%) showed an ETR and 8 had SVR (42.1%). Of the 8 patients with abnormal alanine aminotransferase (ALT) levels at baseline, 78.9% had their ALT normalized (including the virological non responders). ALT was normal in all responders at the end of therapy and at 24 wk post therapy (100%). Only one patient (5.3%) developed an increase in creatinine and decline in GFR from baseline towards the end of treatment. This patient's kidney biopsy revealed borderline rejection. There was no impact on response by HCV-genotype, initial HCV RNA load, age or sex of the patient or duration post transplant before commencement of therapy. All patients tolerated treatment in the same way as non-transplant with no unusual or increased occurrence of side effects. CONCLUSION: The combination of pegylated interferon and ribavirin is effective in suppressing HCV-RNA, with a low risk of graft rejection or failure in HCV infected renal transplant recipients. PMID- 22228973 TI - Germline promoter hypermethylation of tumor suppressor genes in gastric cancer. AB - AIM: To explore germline hypermethylation of the tumor suppressor genes MLH1, CDH1 and P16(INK4a) in suspected cases of hereditary gastric cancer (GC). METHODS: A group of 140 Chinese GC patients in whom the primary cancer had developed before the age of 60 or who had a familial history of cancer were screened for germline hypermethylation of the MLH1, CDH1 and P16(INK4a) tumor suppressor genes. Genomic DNA was extracted from peripheral blood leukocytes and modified by sodium bisulfite. The treated DNA was then subjected to bisulfite DNA sequencing for a specific region of the MLH1 promoter. The methylation status of CDH1 or P16(INK4a) was assayed using methylation-specific PCR. Clonal bisulfite allelic sequencing in positive samples was performed to obtain a comprehensive analysis of the CpG island methylation status of these promoter regions. RESULTS: Methylation of the MLH1 gene promoter was detected in the peripheral blood DNA of only 1/140 (0.7%) of the GC patient group. However, this methylation pattern was mosaic rather than the allelic pattern which has previously been reported for MLH1 in hereditary non-polyposis colorectal cancer (HNPCC) patients. We found that 10% of the MLH1 alleles in the peripheral blood DNA of this patient were methylated, consistent with 20% of cells having one methylated allele. No germline promoter methylation of the CDH1 or P16(INK4a) genes was detected. CONCLUSION: Mosaic germline epimutation of the MLH1 gene is present in suspected hereditary GC patients in China but at a very low level. Germline epimutation of the CDH1 or P16(INK4a) gene is not a frequent event. PMID- 22228974 TI - Growth inhibitory effect of 4-phenyl butyric acid on human gastric cancer cells is associated with cell cycle arrest. AB - AIM: To investigate the growth effects of 4-phenyl butyric acid (PBA) on human gastric carcinoma cells and their mechanisms. METHODS: Moderately-differentiated human gastric carcinoma SGC-7901 and lowly-differentiated MGC-803 cells were treated with 5, 10, 20, 40, and 60 MUmol/L PBA for 1-4 d. Cell proliferation was detected using the MTT colorimetric assay. Cell cycle distributions were examined using flow cytometry. RESULTS: The proliferation of gastric carcinoma cells was inhibited by PBA in a dose- and time-dependent fashion. Flow cytometry showed that SGC-7901 cells treated with low concentrations of PBA were arrested at the G0/G1 phase, whereas cells treated with high concentrations of PBA were arrested at the G2/M phase. Although MGC-803 cells treated with low concentrations of PBA were also arrested at the G0/ G1 phase, cells treated with high concentrations of PBA were arrested at the S phase. CONCLUSION: The growth inhibitory effect of PBA on gastric cancer cells is associated with alteration of the cell cycle. For moderately-differentiated gastric cancer cells, the cell cycle was arrested at the G0 /G1 and G2/M phases. For lowly-differentiated gastric cancer cells, the cell cycle was arrested at the G0/G1 and S phases. PMID- 22228976 TI - Inflammatory pseudotumor of the liver and spleen diagnosed by percutaneous needle biopsy. AB - An inflammatory pseudotumor (IPT) is a relatively rare lesion characterized by chronic infiltration of inflammatory cells and areas of fibrosis. IPTs are difficult to diagnose because of the absence of specific symptoms or of characteristic hematological or radiological findings. In this study, a case of a woman aged over 70 years was reported, who presented with a general malaise lasting more than two months. A computed tomography scan demonstrated a diffusely spread lesion of the liver with a portal vein occlusion and a splenic lesion surrounded by a soft density layer. Since the percutaneous liver biopsy showed findings that suggested an IPT, although the radiological findings did not exclude the possibility of a malignancy, we performed a percutaneous spleen biopsy to enable a more definitive diagnosis. The microscopic findings from the spleen specimen lead us to a diagnosis of IPT involving the liver and spleen. Subsequent steroid pulse therapy was effective, and rapid resolution of the disease was observed. PMID- 22228975 TI - Unsuccessful treatment of four patients with acute graft-vs-host disease after liver transplantation. AB - AIM: To investigate appropriate therapeutic strategies for graft-vs-host disease (GVHD) following liver transplantation. METHODS: Four patients who developed GVHD after liver transplantation in West China Hospital were included in this study. Therapeutic strategies with augmentation or withdrawal of immunosuppressants combined with supportive therapy were investigated in these patients. In addition, a literature review of patients who developed GVHD after liver transplantation was performed. RESULTS: Although a transient response to initial treatment was detected, all four patients died of complications from GVHD: one from sepsis with multiple organ failure, one from gastrointestinal bleeding, and the other two from sepsis with gastrointestinal bleeding. Few consensuses for the treatment of GVHD after liver transplantation have been reached. CONCLUSION: New and effective treatments are required for GVHD after liver transplantation to improve the prognosis of patients with this diagnosis. PMID- 22228977 TI - Laparoscopic resection of gastric gastrointestinal stromal tumors presenting as left adrenal tumors. AB - Gastrointestinal stromal tumors (GISTs) are rare gastrointestinal malignancies. They are rarely seen near the urinary tract. In a literature review, only one case of GIST presenting as a left adrenal tumor was reported. We report two documented cases of gastric GISTs mimicking left adrenal tumors which were successfully treated with pure laparoscopic adrenalectomy and wedge resection of the stomach by excising the tumor from the stomach with serial firing of endoscopic gastrointestinal staplers. The surgical margins were clear, and the patients recovered smoothly. No adjuvant therapy with imatinib was prescribed. During the surveillance for 9 mo and 44 mo respectively, no tumor recurrence and metastasis were documented. Laparoscopic tumor excision, when adhering to the principles of surgical oncology, seems feasible and the prognosis is favorable for such tumors. PMID- 22228978 TI - Ablation of Dental Hard Tissues with a Microsecond Pulsed Carbon Dioxide Laser Operating at 9.3-MUm with an Integrated Scanner. AB - Pulsed carbon dioxide lasers operating at the highly absorbed 9.3 and 9.6-MUm wavelengths with pulse durations in the microsecond range are ideally suited for dental hard tissue modification and removal. The purpose of these studies was to demonstrate that a low cost 9.3-MUm CO(2) laser system utilizing low-energy laser pulses (1-5 mJ /pulse) delivered at a high repetition rate (400-Hz) is feasible for removing dental hard tissues. The laser beam was focused to a small spot size to achieve ablative fluence and an integrated/programmable optical scanner was used to scan the laser beam over the desired area for tissue removal. Pulse durations of 35, 60 and 75-MUs were employed and the enamel and dentin ablation rate and ablation efficiency were measured. Laser irradiated human and bovine samples were assessed for peripheral thermal and mechanical damage using polarized light microscopy. The heat accumulation during rapid scanning ablation with water-cooling at 400-Hz was monitored using micro-thermocouples. The laser was able to ablate both enamel and dentin without excessive peripheral thermal damage or heat accumulation. These preliminary studies suggest that a low-cost RF excited CO(2) laser used in conjunction with an integrated scanner has considerable potential for application to dental hard tissues. PMID- 22228979 TI - Near-IR Multi-modal Imaging of Natural Occlusal Lesions. AB - Reflectance and transillumination imaging show demineralization with high contrast in the near-IR. The objective of this study is to use lesion size and contrast acquired in reflectance and transillumination near-infrared imaging modes to estimate the severity of natural occlusal caries lesions. Previous studies have shown that near-infrared (NIR) light can be used to effectively image artificial carious lesions. However, its efficacy on natural lesions requires further exploration. Fifty extracted teeth with varying amounts of occlusal decay were examined using a NIR imaging system operating at 1310-nm. Image analysis software was used to calculate contrast values between sound and carious tooth structure. After imaging, teeth were histologically sampled at 1-mm intervals in order to determine lesion depth. Lesion contrast in transillumination mode significantly increased with lesion depth (p<0.001), while lesion contrast in reflectance mode did not increase. The lesion area demonstrated a significant increase with lesion severity in both imaging modes. These results suggest that lesion contrast and area can be used to estimate lesion severity in NIR images. PMID- 22228980 TI - Near-IR Polarization Imaging of Sound and Carious Dental Enamel. AB - A thorough understanding of how polarized near-IR light propagates through sound and carious dental hard tissues is important for the development of dental optical imaging systems. New optical imaging tools for the detection and assessment of dental caries (dental decay) such as near-IR imaging and optical coherence tomography can exploit the enhanced contrast provided by polarization sensitivity. In this investigation, an automated system was developed to collect images for the full 16-element Mueller Matrix. The polarized light was controlled by linear polarizers and liquid crystal retarders and the 36 images were acquired as the polarized near-IR light propagates through the enamel of extracted human thin tooth sections. In previous work, we reported that polarized light is rapidly depolarized by demineralized enamel, and sound and demineralized dentin.(1) The rapid depolarization of polarized light by dental caries in the near-IR provides high contrast for caries imaging and detection. In this initial study, major differences in the Mueller matrix elements were observed in both sound and demineralized enamel which supports this approach and warrants further investigation. PMID- 22228981 TI - Imaging Natural Occlusal Caries Lesions with Optical Coherence Tomography. AB - Several studies have demonstrated that polarization-sensitive optical coherence tomography (PS-OCT) can be used to nondestructively measure the severity of demineralization in the important occlusal surfaces. The purpose of this study was to assess the potential of PS-OCT and OCT methods for the measurement of the depth of natural occlusal carious lesions. Teeth were screened for potential occlusal lesions using near infrared imaging (NIR). A PS-OCT system operating at 1310-nm was used to acquire polarization resolved images of the area of interest on the occlusal surface. The teeth were serial sectioned to 200 MUm thickness and examined with polarized light microscopy (PLM) and Transverse Microradiography (TMR) for comparison. The lesion depth measured nondestructively with PS-OCT was compared to the lesion depth measured with PLM and TMR to assess the performance of these methods and determine if polarization sensitivity is required. The lesion depth measured using OCT correlated well with the lesion depths measured with TMR and PLM. Although polarization sensitivity provided better contrast it was not necessary to have polarization sensitivity to identify deep occlusal lesions. PMID- 22228982 TI - Reliability of PEDOT-PSS Strain Gauge on foam structure. AB - Reliability is one important issue in using PEDOT: PSS as a strain gauge for large strain measurements. In our research, PEDOT: PSS strain gauge is fabricated on the polyurethane and porous substrate, which enhances the mechanical property when large strain and cyclic loads are applied to it. Our result shows that with the polyurethane as the substrate adhesion layer, the strain of PEDOT: PSS can go up to 17.7% and stabilize without reference resistance drifting. PMID- 22228983 TI - TLR-mediated innate immune recognition. PMID- 22228984 TI - Sexual Minority Women and Alcohol: Intersections between drinking, relational contexts, stress and coping. AB - Few studies explore sexual minority women's experiences and perceptions of alcohol. Qualitative interviews were conducted with six sexual minority women who reported having sought help for alcohol problems in the past and six who did not. Themes emerged in two broad areas: stressors that contributed to heavy or problem drinking and factors that enhanced coping and reduced both stress and problem use. Alcohol use across groups was framed in terms of social context (e.g., bar patronage), stress management, and addiction. The findings of the study underscore the importance of considering the role of alcohol in managing stress as well coping factors that may inform social service interventions. PMID- 22228985 TI - Treatment of acute pelvic inflammatory disease. AB - Pelvic inflammatory disease (PID), one of the most common infections in nonpregnant women of reproductive age, remains an important public health problem. It is associated with major long-term sequelae, including tubal factor infertility, ectopic pregnancy, and chronic pelvic pain. In addition, treatment of acute PID and its complications incurs substantial health care costs. Prevention of these long-term sequelae is dependent upon development of treatment strategies based on knowledge of the microbiologic etiology of acute PID. It is well accepted that acute PID is a polymicrobic infection. The sexually transmitted organisms, Neisseria gonorrhoeae and Chlamydia trachomatis, are present in many cases, and microorganisms comprising the endogenous vaginal and cervical flora are frequently associated with PID. This includes anaerobic and facultative bacteria, similar to those associated with bacterial vaginosis. Genital tract mycoplasmas, most importantly Mycoplasma genitalium, have recently also been implicated as a cause of acute PID. As a consequence, treatment regimens for acute PID should provide broad spectrum coverage that is effective against these microorganisms. PMID- 22228986 TI - Inadvertent Percutaneous Endoscopic Gastrostomy Tube Placement through the Transverse Colon to the Stomach Causing Intractable Diarrhea: A Case Report. AB - Background. Among patients with chronic disease, percutaneous endoscopic gastrostomy (PEG) tubes are a common mechanism to deliver enteral feedings to patients unable to feed by mouth. While several cases in the literature describe difficulties with and complications of the initial placement of the PEG, few studies have documented the effects of a delayed diagnosis of a misplaced tube. Methods. This case study reviews the hospitalization of an 82 year old male with an inadvertent placement of a PEG tube through the transverse colon. Photos of the placement in the stomach as well as those of the follow up colonoscopy, and a recording of the episodes of diarrhea during the hospitalization were made. Results. The records of this patient reveal complaints of gastrointestinal distress and diarrhea immediately after placement of the tube. Placement in the stomach was verified by endoscopy, with discovery of the tube only after a follow up colonoscopy. The tube remained in place after this discovery, and was removed weeks after the diarrhea was unsuccessfully treated with antibiotics. After tube removal, the patient recovered well and was sent home. PMID- 22228987 TI - Therapeutic implications of mesenchymal stem cells in liver injury. AB - Mesenchymal stem cells (MSCs), represent an attractive tool for the establishment of a successful stem-cell-based therapy of liver diseases. A number of different mechanisms contribute to the therapeutic effects exerted by MSCs, since these cells can differentiate into functional hepatic cells and can also produce a series of growth factors and cytokines able to suppress inflammatory responses, reduce hepatocyte apoptosis, regress liver fibrosis, and enhance hepatocyte functionality. To date, the infusion of MSCs or MSC-conditioned medium has shown encouraging results in the treatment of fulminant hepatic failure and in end stage liver disease in experimental settings. However, some issues under debate hamper the use of MSCs in clinical trials. This paper summarizes the biological relevance of MSCs and the potential benefits and risks that can result from translating the MSC research to the treatment of liver diseases. PMID- 22228988 TI - Tissue expression and actin binding of a novel N-terminal utrophin isoform. AB - Utrophin and dystrophin present two large proteins that link the intracellular actin cytoskeleton to the extracellular matrix via the C-terminal-associated protein complex. Here we describe a novel short N-terminal isoform of utrophin and its protein product in various rat tissues (N-utro, 62 kDa, amino acids 1 539, comprising the actin-binding domain plus the first two spectrin repeats). Using different N-terminal recombinant utrophin fragments, we show that actin binding exhibits pronounced negative cooperativity (affinity constants K(1) = -5 * 10(6) and K(2) =-1 * 10(5 )M(-1)) and is Ca(2+)-insensitive. Expression of the different fragments in COS7 cells and in myotubes indicates that the actin binding domain alone binds exclusively to actin filaments. The recombinant N-utro analogue binds in vitro to actin and in the cells associates to the membranes. The results indicate that N-utro may be responsible for the anchoring of the cortical actin cytoskeleton to the membranes in muscle and other tissues. PMID- 22228989 TI - Quantitative proteomics analysis by isobaric tags for relative and absolute quantitation identified Lumican as a potential marker for acute aortic dissection. AB - Acute aortic dissection (AAD) is a serious vascular disease. Currently the diagnosis relies on clinical and radiological means whereas serum biomarkers are lacking. The purpose of this study was to identify potential serum biomarkers for AAD using isobaric tags for relative and absolute quantitation (iTRAQ) approach. A total of 120 serum samples were collected from three groups: AAD patients (n = 60), patients with acute myocardial infarction (AMI, n = 30), and healthy volunteers (n = 30), whereas the first 10 samples from each group were used for iTRAQ analysis. Using iTRAQ approach, a total of 174 proteins were identified as significantly different between AAD patients and healthy subjects. Among them, forty-six proteins increased more than twofold, full-scale analysis using serum sample for the entire 120 subjects demonstrated that Lumican level was significantly increased relative to control and AMI samples. Further, Lumican level correlated with time from onset to admission in AAD but not AMI samples. Using iTRAQ approach, our study showed that Lumican may be a potential AAD related serum marker that may assist the diagnosis of AAD. PMID- 22228990 TI - Cyclodextrin-erythromycin complexes as a drug delivery device for orthopedic application. AB - BACKGROUND: Erythromycin, a hydrophobic antibiotic used to treat infectious diseases, is now gaining attention because of its anti-inflammatory effects and ability to inhibit osteoclasts formation. The aim of this study was to explore a cyclodextrin-erythromycin (CD-EM) complex for sustained treatment of orthopedic inflammation. METHODS AND RESULTS: Erythromycin was reacted with beta cyclodextrin to form a nonhost-guest CD-EM complex using both kneading and stirring approaches. Physiochemical measurement data indicated that erythromycin and cyclodextrin formed a packing complex driven by intermolecular forces instead of a host-guest structure due to the limited space in the inner cavity of beta cyclodextrin. The CD-EM complex improved the stability of erythromycin in aqueous solution and had a longer duration of bactericidal activity than free erythromycin. Cytotoxicity and cell differentiation were evaluated in both murine MC3T3 preosteoblast cells and RAW 264.7 murine macrophage cells. The CD-EM complex was noncytotoxic and showed significant inhibition of osteoclast formation but had little effect on osteoblast viability and differentiation. CONCLUSION: These attributes are especially important for the delivery of an adequate amount of erythromycin to the site of periprosthetic inflammation and reducing local inflammation in a sustained manner. PMID- 22228991 TI - Gd2O3 nanoparticles in hematopoietic cells for MRI contrast enhancement. AB - As the utility of magnetic resonance imaging (MRI) broadens, the importance of having specific and efficient contrast agents increases and in recent time there has been a huge development in the fields of molecular imaging and intracellular markers. Previous studies have shown that gadolinium oxide (Gd(2)O(3)) nanoparticles generate higher relaxivity than currently available Gd chelates: In addition, the Gd(2)O(3) nanoparticles have promising properties for MRI cell tracking. The aim of the present work was to study cell labeling with Gd(2)O(3) nanoparticles in hematopoietic cells and to improve techniques for monitoring hematopoietic stem cell migration by MRI. Particle uptake was studied in two cell lines: the hematopoietic progenitor cell line Ba/F3 and the monocytic cell line THP-1. Cells were incubated with Gd(2)O(3) nanoparticles and it was investigated whether the transfection agent protamine sulfate increased the particle uptake. Treated cells were examined by electron microscopy and MRI, and analyzed for particle content by inductively coupled plasma sector field mass spectrometry. Results showed that particles were intracellular, however, sparsely in Ba/F3. The relaxation times were shortened with increasing particle concentration. Relaxivities, r(1) and r(2) at 1.5 T and 21 degrees C, for Gd(2)O(3) nanoparticles in different cell samples were 3.6-5.3 s(-1) mM(-1) and 9.6-17.2 s( 1) mM(-1), respectively. Protamine sulfate treatment increased the uptake in both Ba/F3 cells and THP-1 cells. However, the increased uptake did not increase the relaxation rate for THP-1 as for Ba/F3, probably due to aggregation and/or saturation effects. Viability of treated cells was not significantly decreased and thus, it was concluded that the use of Gd(2)O(3) nanoparticles is suitable for this type of cell labeling by means of detecting and monitoring hematopoietic cells. In conclusion, Gd(2)O(3) nanoparticles are a promising material to achieve positive intracellular MRI contrast; however, further particle development needs to be performed. PMID- 22228992 TI - Effective transcutaneous immunization by antigen-loaded flexible liposome in vivo. AB - BACKGROUND: Transcutaneous vaccines have received wide attention due to their easy-to-use, needle-free, noninvasive delivery. However, the novel barrier function of stratum corneum hinders the transport of antigen and adjuvant in transcutaneous immunization. Novel nanoscale delivery systems employing, for example, liposomes and nanoparticles, have been widely investigated to overcome the penetration barrier of stratum corneum for effective transcutaneous immunization. OBJECTIVE: The objective of this study was to prepare two types of flexible liposomes and determine their efficacies for the transcutaneous delivery of antigen and the subsequent immune response induced in vivo. METHODS: Ovalbumin (OVA) liposome-based transcutaneous vaccines were prepared using reverse-phase evaporation and film-dispersion methods. Particle sizes and antigen encapsulating efficiency were then evaluated. After application to bare mouse skin, topical sites were examined for the presence of fluorescence-labeled liposome. The efficacy of the transcutaneously delivered OVA-loaded flexible liposome in activating the immune responses was investigated by detecting serum immunoglobulin G levels. The influence of an adjuvant, imiquimod, in the transcutaneous immunization was also tested. RESULTS: Two flexible liposomes with well-encapsulated OVA were successfully prepared by film-dispersion or reverse phase evaporation methods. The sizes of the prepared flexible liposomes ranged from 200 to 400 nm. In vivo, the fluorescence-labeled liposome was detected in hair-follicle ducts, indicating that the flexible liposome can penetrate the skin barrier through the hair follicles. Upon transcutaneous administration, the OVA encapsulated flexible liposome elicited a strong immune response similar to that of positive control (ie, OVA solution administrated by subcutaneous injection with Al(OH)(3) as an adjuvant). Co-administration of imiquimod with the OVA loaded liposome expressed a significant enhancement on the transcutaneous immune responses. CONCLUSION: Results of this study highlight the nanoscale formulation, flexible liposome, as a promising carrier for the transcutaneous delivery of antigen proteins. Imiquimod was shown to be an effective adjuvant as a transcutaneous immunization enhancer with the potential for transcutaneous vaccine development. PMID- 22228993 TI - Grafting of a novel gold(III) complex on nanoporous MCM-41 and evaluation of its toxicity in Saccharomyces cerevisiae. AB - The goal of this research was to investigate the potential of newly synthesized gold complex trichloro(2,4,6-trimethylpyridine)Au(III) as an anticancer agent. The gold(III) complex was synthesized and grafted on nanoporous silica, MCM-41, to produce AuCl(3)@PF-MCM- 41 (AuCl(3) grafted on pyridine-functionalized MCM 41). The toxicity of trichloro(2,4,6- trimethylpyridine)Au(III) and AuCl(3)@PF MCM-41 in Saccharomyces cerevisiae (as a model system) was studied. The gold(III) complex showed a mid cytotoxic effect on yeast viability. Using the drug delivery system, nanoporous MCM-41, the gold(III) complex became a strong inhibitor for growth of yeast cells at a very low concentration. Furthermore, the animal tests revealed a high uptake of AuCl(3)@PF-MCM-41 in tumor cells. The stability of the compound was confirmed in human serum. PMID- 22228994 TI - Fe3O4/Au magnetic nanoparticle amplification strategies for ultrasensitive electrochemical immunoassay of alfa-fetoprotein. AB - BACKGROUND: The purpose of this study was to devise a novel electrochemical immunosensor for ultrasensitive detection of alfa-fetoprotein based on Fe(3)O(4)/Au nanoparticles as a carrier using a multienzyme amplification strategy. METHODS AND RESULTS: Greatly enhanced sensitivity was achieved using bioconjugates containing horseradish peroxidase (HRP) and a secondary antibody (Ab(2)) linked to Fe(3)O(4)/Au nanoparticles (Fe(3)O(4)/Au-HRP-Ab(2)) at a high HRP/Ab(2) ratio. After a sandwich immunoreaction, the Fe(3)O(4)/Au-HRP-Ab(2) captured on the electrode surface produced an amplified electrocatalytic response by reduction of enzymatically oxidized hydroquinone in the presence of hydrogen peroxide. The high content of HRP in the Fe(3)O(4)/Au-HRP-Ab(2) could greatly amplify the electrochemical signal. Under optimal conditions, the reduction current increased with increasing alfa-fetoprotein concentration in the sample, and exhibited a dynamic range of 0.005-10 ng/mL with a detection limit of 3 pg/mL. CONCLUSION: The amplified immunoassay developed in this work shows good precision, acceptable stability, and reproducibility, and can be used for detection of alfa-fetoprotein in real samples, so provides a potential alternative tool for detection of protein in the laboratory. Furthermore, this immunosensor could be regenerated by simply using an external magnetic field. PMID- 22228995 TI - Solid dispersions in the form of electrospun core-sheath nanofibers. AB - BACKGROUND: The objective of this investigation was to develop a new type of solid dispersion in the form of core-sheath nanofibers using coaxial electrospinning for poorly water-soluble drugs. Different functional ingredients can be placed in various parts of core-sheath nanofibers to improve synergistically the dissolution and permeation properties of encapsulated drugs and to enable drugs to exert their actions. METHODS: Using acyclovir as a model drug, polyvinylpyrrolidone as the hydrophilic filament-forming polymer matrix, sodium dodecyl sulfate as a transmembrane enhancer, and sucralose as a sweetener, core-sheath nanofibers were successfully prepared, with the sheath part consisting of polyvinylpyrrolidone, sodium dodecyl sulfate, and sucralose, and the core part composed of polyvinylpyrrolidone and acyclovir. RESULTS: The core sheath nanofibers had an average diameter of 410 +/- 94 nm with a uniform structure and smooth surface. Differential scanning calorimetry and x-ray diffraction results demonstrated that acyclovir, sodium dodecyl sulfate, and sucralose were well distributed in the polyvinylpyrrolidone matrix in an amorphous state due to favoring of second-order interactions. In vitro dissolution and permeation studies showed that the core-sheath nanofiber solid dispersions could rapidly release acyclovir within one minute, with an over six fold increased permeation rate across the sublingual mucosa compared with that of crude acyclovir particles. CONCLUSION: The study reported here provides an example of the systematic design, preparation, characterization, and application of a novel type of solid dispersion consisting of multiple components and structural characteristics. PMID- 22228997 TI - Effect of dispersants of multi-walled carbon nanotubes on cellular uptake and biological responses. AB - Although there have been many reports about the cytotoxicity of multi-walled carbon nanotubes (MWCNTs), the results are still controversial. To investigate one possible reason, the authors investigated the influence of MWCNT dispersants on cellular uptake and cytotoxicity. Cytotoxicity was examined (measured by alamarBlue((r)) assay), as well as intracellular MWCNT concentration and cytokine secretion (measured by flow cytometry) in human bronchial epithelial cells (BEAS 2B) exposed to a type of highly purified MWCNT vapor grown carbon fiber (VGCF((r)), Showa Denko Kabushiki-gaisha, Tokyo, Japan) in three different dispersants (gelatin, carboxylmethyl cellulose, and 1,2-dipalmitoyl-sn-glycero-3 phosphocholine). The authors also researched the relationship between the intracellular concentration of MWCNTs and cytotoxicity by using two cell lines, BEAS-2B and MESO-1 human malignant pleural mesothelioma cells. The intracellular concentration of VGCF was different for each of the three dispersants, and the levels of cytotoxicity and inflammatory response were correlated with the intracellular concentration of VGCF. A relationship between the intracellular concentration of VGCF and cytotoxic effects was observed in both cell lines. The results indicate that dispersants affect VGCF uptake into cells and that cytotoxicity depends on the intracellular concentration of VGCF, not on the exposed dosage. Thus, toxicity appears to depend on exposure time, even at low VGCF concentrations, because VGCF is biopersistent. PMID- 22228996 TI - Nanomedicine as an emerging approach against intracellular pathogens. AB - Diseases such as tuberculosis, hepatitis, and HIV/AIDS are caused by intracellular pathogens and are a major burden to the global medical community. Conventional treatments for these diseases typically consist of long-term therapy with a combination of drugs, which may lead to side effects and contribute to low patient compliance. The pathogens reside within intracellular compartments of the cell, which provide additional barriers to effective treatment. Therefore, there is a need for improved and more effective therapies for such intracellular diseases. This review will summarize, for the first time, the intracellular compartments in which pathogens can reside and discuss how nanomedicine has the potential to improve intracellular disease therapy by offering properties such as targeting, sustained drug release, and drug delivery to the pathogen's intracellular location. The characteristics of nanomedicine may prove advantageous in developing improved or alternative therapies for intracellular diseases. PMID- 22228998 TI - Synthetic poly(ester amine) and poly(amido amine) nanoparticles for efficient DNA and siRNA delivery to human endothelial cells. AB - Biodegradable poly(ester amine) (PEA)-based and poly(amido amine) (PAA)-based nanoparticles were developed for efficient in vitro siRNA delivery to human umbilical vein endothelial cells (HUVECs). They were screened, characterized, and compared with traditionally studied DNA-containing particles. Several of the polymeric nanoparticles tested were found to be effective for delivering functional siRNA to green fluorescent protein (GFP) + HUVECs, achieving 60%-75% GFP knockdown while maintaining high viability. While PEAs have been used previously to form polyplexes or nanoparticles for DNA delivery, highly effective siRNA delivery in hard-to-transfect human cell types has not been previously reported. PEAs and linear nondendrimeric PAAs were also found to be effective for DNA delivery to HUVECs using GFP-encoding plasmid DNA (up to 50%-60% transfection efficiency). PEAs and PAAs can be separated into groups that form polymeric nanoparticles effective for siRNA delivery, for DNA delivery, or for both. PMID- 22228999 TI - Supramolecular micellar nanoaggregates based on a novel chitosan/vitamin E succinate copolymer for paclitaxel selective delivery. AB - BACKGROUND: Nowadays, many cytotoxic anticancer drugs exhibit low solubility and poor tumor selectivity, which means that the drug formulation is very important. For example, in the case of paclitaxel (PTX), Cremophor EL((r)) (BASF, Ludwigshafen, Germany) needs to be used as a solubilizer in its clinical formulation (Taxol((r)), Bristol-Myers Squibb, New York, NY), although it can cause serious side effects. Nanomicellar systems are promising carriers to resolve the above problems, and the polymer chosen is the key element. METHODS: In this study, a novel amphiphilic chitosan/vitamin E succinate (CS-VES) copolymer was successfully synthesized for self-assembling polymeric micelles. Proton nuclear magnetic resonance spectroscopy and infrared were used to characterize the molecular structure of the copolymer. The PTX-loaded CS-VES polymeric micelles (PTX-micelles) were characterized by dynamic light scattering, transmission electron microscopy, X-ray diffraction, and differential scanning calorimetry. RESULTS: The critical micelle concentration of CS-VES was about 12.6 MUg/mL, with the degree of amino group substitution being 20.4%. PTX-micelles were prepared by a nanoprecipitation/dispersion technique without any surfactant being involved. PTX-micelles exhibited a drug loading as high as 21.37% and an encapsulation efficiency of 81.12%, with a particle size ranging from 326.3 to 380.8 nm and a zeta potential of +20 mV. In vitro release study showed a near zero-order sustained release, with 51.06%, 50.88%, and 44.35% of the PTX in the micelles being released up to 168 hours at three drug loadings of 7.52%, 14.09%, and 21.37%, respectively. The cellular uptake experiments, conducted by confocal laser scanning microscopy, showed an enhanced cellular uptake efficiency of the CS-VES micelles in MCF-7 cells compared with Taxol. The PTX-micelles exhibited a comparable but delayed cytotoxic effect compared with Taxol against MCF-7 cells, due to the sustained-release characteristics of the nanomicelles. More interestingly, blank nanomicelles based on CS-VES copolymer demonstrated significant cytotoxicity against MCF-7 cells. CONCLUSION: The supramolecular micellar aggregates based on CS-VES copolymer is a promising nanocarrier and efficacy enhancer when used as an anticancer drug-delivery system. PMID- 22229000 TI - Encapsulation of plasmid DNA in calcium phosphate nanoparticles: stem cell uptake and gene transfer efficiency. AB - BACKGROUND: The purpose of this study was to develop calcium phosphate nanocomposite particles encapsulating plasmid DNA (CP-pDNA) nanoparticles as a nonviral vector for gene delivery. METHODS: CP-pDNA nanoparticles employing plasmid transforming growth factor beta 1 (TGF-beta1) were prepared and characterized. The transfection efficiency and cell viability of the CP-pDNA nanoparticles were evaluated in mesenchymal stem cells, which were identified by immunofluorescence staining. Cytotoxicity of plasmid TGF-beta1 and calcium phosphate to mesenchymal stem cells were evaluated by MTT assay. RESULTS: The integrity of TGF-beta1 encapsulated in the CP-pDNA nanoparticles was maintained. The well dispersed CP-pDNA nanoparticles exhibited an ultralow particle size (20 50 nm) and significantly lower cytotoxicity than LipofectamineTM 2000. Immunofluorescence staining revealed that the cultured cells in this study were probably mesenchymal stem cells. The cellular uptake and transfection efficiency of the CP-pDNA nanoparticles into the mesenchymal stem cells were higher than that of needle-like calcium phosphate nanoparticles and a standard calcium phosphate transfection kit. Furthermore, live cell imaging and confocal laser microscopy vividly showed the transportation process of the CP-pDNA nanoparticles in mesenchymal stem cells. The results of a cytotoxicity assay found that both plasmid TGF-beta1 and calcium phosphate were not toxic to mesenchymal stem cells. CONCLUSION: CP-pDNA nanoparticles can be developed into an effective alternative as a nonviral gene delivery system that is highly efficient and has low cytotoxicity. PMID- 22229001 TI - Influence of a prophylaxis paste on surface roughness of different composites, porcelain, enamel and dentin surfaces. AB - OBJECTIVE: To investigate the effect of a prophylaxis paste on surface roughness of different composites, enamel, dentin and porcelain surfaces. METHODS: Three different composites (FiltekZ250/Group1, Filtek Supreme XT/Group2, Premise/Group3), enamel/Group4, dentin/Group5 and porcelain/Group6 samples were used in this study. All specimens were prepared flat by SiC discs and polished with a diamond polishing paste. The surface roughness measurements were determined with a profilometer after polishing (initial surface roughness). Prophylaxis paste was applied to the samples for 12 seconds, renewing every 6 seconds. After cleaning the samples, roughness values were measured again. Data were analyzed by Kruskal Wallis and Dunn's multiple comparison test. Wilcoxon test was performed for the comparison of the initial and final surface roughness values (P<.05). The results were evaluated within the P<.05 confidence level. RESULTS: The initial and final surface roughness values (MUm) were determined as follows: Group1: 0.039+/-0.009 and 0.157+/-0.018, Group2: 0.023+/-0.005 and 0.145+/-0.027, Group3: 0.028+/-0.008 and 0.109+/-0.012, Group4: 0.024+/-0.006 and 0.071+/-0.015, Group5: 0.030+/-0.007 and 0.143+/-0.029, Group6: 0.024+/-0.006 and 0.064+/-0.014. Significant difference was determined between the initial and final values for all groups. CONCLUSIONS: Composite and dentin surfaces were more affected by the application of prophylaxis paste than enamel and porcelain surfaces. The prophylaxis paste increased the surface roughness of all groups, but did not reach the bacterial retention roughness rate of 0.2MUm. PMID- 22229002 TI - FEM analysis of a new miniplate: stress distribution on the plate, screws and the bone. AB - OBJECTIVES: Non-homogeneous force distribution along the miniplates and the screws is an unsolved question for skeletal anchorage in orthodontics. To overcome this issue, a miniplate structure was designed featuring spikes placed on the surface facing the cortical bone. The aim of this study was to examine and compare the force distribution of the newly designed plate-screw systems with the conventional one. METHODS: A model of bone surface with 1.5 mm cortical thickness, along with the two newly designed miniplates and a standard miniplate screw were simulated on the three-dimensional model. 200 g experimental force was applied to the tip of the miniplates and the consequential effects on the screws and cortical bone was evaluated using three-dimensional finite element method. RESULTS: As a result of this finite element study, remarkably lower stresses were observed on the screws and the cortical bone around the screws with the newly designed miniplate when compared with the conventional one. CONCLUSION: The newly designed miniplate that has spikes was found effective in reducing the stress on and around the screws and the force was distributed more equivalently. PMID- 22229003 TI - Bonding of adhesives to Er:YAG laser-treated dentin. AB - OBJECTIVE: The shear bond strength of adhesives applied to dentin was investigated after irradiation with an erbium-doped yttrium aluminum garnet (Er:YAG) laser. METHODS: Superficial and deep dentin specimens from human molars were treated either with carbide bur or an Er:YAG laser. Two etch and rinse adhesives (Single Bond and XP Bond) and two self-etch adhesives (Prompt L-Pop and Xeno III) were employed to bond the composite. Shear bond strength (SBS) was determined after storage in water for 24 h using a universal testing machine with a crosshead speed of 0.5 mm/min. Failure patterns and modes were analyzed and evaluated using a stereomicroscope. In addition, samples were processed for Scanning Electron Microscopy SEM evaluation. A linear mixed model was used, and pairwise comparisons were made using the Bonferroni test. RESULTS: Results showed significant differences between the levels of dentin treatment (p=.01) in carbide bur-cut dentin and lased dentin, as well as significant interaction effects due to the depth of dentin and the bonding system used. The etch and rinse adhesives bonded less effectively with lased dentin than with carbide bur-cut dentin, while self-etch adhesives bonded equally well with lased and bur-cut superficial dentin but much less effectively with lased deep dentin than with bur-cut deep dentin. SEM revealed a predominantly adhesive failure mode in laser-ablated fractured specimens, while a mixed failure mode was apparent in the bur-cut fractured specimens. CONCLUSIONS: Cavities prepared by laser seem less receptive to adhesive procedures than conventional bur-cut cavities. PMID- 22229004 TI - Color and opacity of composites protected with surface sealants and submitted to artificial accelerated aging. AB - OBJECTIVES: To evaluate the color similarity, stability and opacity of composites (TPH, Charisma, and Concept, shade A2) protected with surface sealants (Fortify Plus and Biscover) and cyanoacrylate (Super Bonder). METHODS: Forty specimens of each composite were made and separated into 4 groups (n=10) according to the surface protection: GI - without sealant; GII - cyanoacrylate; GIII - Fortify Plus; GIV - Biscover. Color and opacity readings were taken before and after Artificial Acelerated Aging (AAA) and the values obtained for color stability were submitted to statistical analysis by 2-way ANOVA and Bonferroni's test (P<.05). The values acquired for color similarity were submitted to 1-way ANOVA and Tukey's test (P<.05). The specimen sufaces were compared before and after AAA using Scanning Electronic Microscopy (SEM). RESULTS: Studied composites did not present the same values for the coordinates L*, a* and b * before AAA, indicating that there was no color similarity among them. All composites presented color alteration after AAA with clinically unacceptable values. Protected groups presented lower opacity variation after AAA, in comparison with the control goup. SEM evaluation demonstrated that AAA increased the surface irregularities in all of the studied groups. CONCLUSION: Surface sealants were not effective in maintaining composite color, but were able to maintain opacity. PMID- 22229005 TI - Progression of non-cavitated lesions in dentin through a nonsurgical approach: a preliminary 12-month clinical observation. AB - OBJECTIVE: Considering the minimally invasive approach to dentistry, the scientific community has focused on non-invasive treatments for caries lesions. The aim of this study was to evaluate the efficacy of a nonsurgical approach to arrest occlusal non-cavitated dentin lesions through glass ionomer sealing. METHODS: In this controlled clinical trial, 51 teeth with clinically non cavitated occlusal caries radiographically located beneath the enamel-dentine junction (radiolucent area) were selected among patients presenting a moderate to high risk of caries. The teeth were randomly divided into two groups: an experimental group receiving an application of Vidrion-R (SS White) glass ionomer and a control group not submitted to any clinical intervention. Caries progression was monitored by clinical and radiographic examination at 4-monthly intervals over a period of one year. In addition, marginal integrity of the sealant was evaluated in the experimental group. RESULTS: Clinical examination showed no statistical difference between the groups (P=.13). On the other hand, sealed teeth presented lower caries progression when analyzed by radiographic examination (P=.004). CONCLUSION: A glass ionomer sealant over non-cavitated occlusal caries lesions in dentin may not be sufficiently effective in arresting their progression. PMID- 22229006 TI - Development of an intracanal mature Enterococcus faecalis biofilm and its susceptibility to some antimicrobial intracanal medications; an in vitro study. AB - OBJECTIVES: To develop a mature biofilm of Enterococcus faecalis inside the root canal system and to test its susceptibility to some antimicrobial medications in vitro. METHODS: Single rooted premolars were mechanically enlarged, sterilized, and then infected with a clinical isolate of E. faecalis. Biofilm formation and maturation was monitored using SEM. Biofilm bacteria were exposed to Amoxicillin+clavulanate, Ciprofloxacin, Clindamycin, Doxycycline, and calcium hydroxide as intracanal medications for 1 week. Finally bacterial samples were collected, and colony-forming units were enumerated. RESULTS: SEM examination confirmed the formation of a mature biofilm at the end of the incubation period. All the chemotherapeutic agents used were significantly better than Calcium hydroxide in elimination of biofilm bacteria. The antimicrobial effect of Amoxicillin + clavulanate, Ciprofloxacin and Clindamycin was significantly better than Doxycycline (P=.05). However the difference in the antimicrobial effectiveness among them was statistically non-significant (P=.05). CONCLUSIONS: The method used for bacterial biofilm development and maturation is reliable and can be used to assess the anti bacterial potential of endodontic materials. Also, the local application of antibacterial agents can be beneficial in resistant cases of apical periodontitis but only after careful culture and sensitivity testing to choose the appropriate agent for the existing flora. PMID- 22229007 TI - Characteristics of occlusion in primary dentition of preschool children of Udaipur, India. AB - OBJECTIVE: The present study aimed to study the occlusion characteristics of the primary dentition in a group of 3-5 year-old Indian children and the differences with age in the same group. METHODS: The study was a cross-sectional survey based on examination of the primary dentition of 200 preschool children aged 3-5 years who were selected from nursery schools in Udaipur, India, using a stratified random sampling technique. The study group was assessed for the several occlusal parameters, which included primary molar and canine relationship, degree of overjet and overbite, anterior and posterior crossbite, and the presence or absence of physiologic spaces and crowding. RESULTS: Flush terminal plane was more common at 3-4 years of age, mesial step at 4-5 years, and class I canine relationship in both age groups. The prevalence of overjet less than 1 mm and overjet exceeding 1 mm was almost comparable in both groups. Overbite with less than 30% overlap was most frequently observed in both age groups, with 30-60% overlap following closely behind. Physiologic and primate spacing were observed in less than half of the children examined, while a small percentage displayed the presence of either single-segment or two-segment crowding. CONCLUSION: The present study provided insight into the state of dentition, occlusal pattern, spacing, and crowding in the primary dentition of Indian children of Udaipur. PMID- 22229008 TI - Influence of previous acid etching on interface morphology and bond strength of self-etching adhesive to cavosurface enamel. AB - OBJECTIVES: The aim of this study was to evaluate the (1) bond strength of a etch and-rinse and self-etching adhesive systems to cavosurface enamel, (2) influence of the previous acid etching with phosphoric acid 35% to the self-etching adhesive application on bond strength values, and (3) analysis of the cavosurface enamel morphology submitted to different types of conditioning, with the use of a scanning electronic microscope (SEM). METHODS: Twenty four human third molars were sectioned on mesio-distal direction, resulting in two slices. The specimens were ground flat with 600-grit aluminum oxide papers, and were randomly divided into three groups: Group 1 (etch-and-rinse adhesive system (control group)), Group 2 (self-etching adhesive), and Group 3 (self-etching adhesive with previous 35% phosphoric acid-etching for 15 s). Four cylinders (0.75 mm of diameter, 1 mm height) were confectioned prior to the microshear test. Four samples for each group were prepared according the cavosurface enamel treatment and were analyzed in an SEM. RESULTS: Group 3 had the highest values on bond strength to cavosurface enamel compared to the other two groups, which presented statistically similar values. The performance of acid etching before the application of the self-etching adhesive results in an etching pattern that is different than the other groups, favoring the adhesion to the cavosurface enamel. CONCLUSIONS: Acid etching increases the bond strength values of the self-etching adhesive to cavosurface enamel, promoting a conditioning pattern that favors the adhesion to this substrate. PMID- 22229009 TI - Optimal acidulated phosphate fluoride gel etching time for surface treatment of feldspathic porcelain: on shear bond strength to resin composite. AB - OBJECTIVES: This in vitro study evaluated the shear bond strength (SBS) of resin composite to feldspathic porcelain after acidulated phosphate fluoride (APF) gel treatment over different periods of time. METHODS: One hundred and fifty-six feldspathic specimens were divided into 12 groups. Group C received no treatment (control group). Groups APF1 through APF10, ten experimental groups, were treated with 1.23% APF gel. Each group obtained 1 to 10 minutes of etching time in 1 minute increments, respectively. Group HF2 was treated with 9.6% hydrofluoric acid (HF) for 2 minutes. All specimens were then bonded to a resin composite cylinder using Adper Scotchbond Multi-purpose (3M ESPE) after silane (Monobond-S, Ivoclar Vivadent AG) application. Specimens were stored at 37oC for 24 hours before the SBS was performed and were recorded in MPa at fracture. Data were analyzed using one-way ANOVA and Tukey's test (alpha=.05). RESULTS: HF etching yielded the highest SBS (18.0 +/- 1.5 MPa), which was not significantly different from APF gel etching for 6 to 10 minutes (16.0 +/- 2.1 to 17.2 +/- 1.6 MPa) (P>.05). CONCLUSIONS: APF gel etching for 6 minutes might be used as an alternative etchant to HF acid for bonding resin composite to silanized feldspathic porcelain. PMID- 22229010 TI - Effect of different palatal vault shapes on the dimensional stability of glass fiber-reinforced heat-polymerized acrylic resin denture base material. AB - OBJECTIVE: The aim of this study was to determine the effect of different palatal vault shapes on the dimensional stability of a glass fiber reinforced heat polymerized acrylic resin denture base material. METHODS: Three edentulous maxilla with shallow, deep and medium shaped palatal vaults were selected and elastomeric impressions were obtained. A maxillary cast with four reference points (A, B, C, and D) was prepared to serve as control. Point (A) was marked in the anterior midline of the edentulous ridge in the incisive papillary region, points (B) and (C) were marked in the right and left posterior midlines of the edentulous ridge in the second molar regions, and point (D) was marked in the posterior palatal midline near the fovea palatina media (Figure 2). To determine linear dimensional changes, distances between four reference points (A-B, A-C, A D and B-C) were initially measured with a metal gauge accurate within 0.1 mm under a binocular stereo light microscope and data (mm) were recorded. RESULTS: No significant difference of interfacial distance was found in sagittal and frontal sections measured 24 h after polymerization and after 30 days of water storage in any of experimental groups (P>.05). Significant difference of linear dimension were found in all experimental groups (P<.01) between measurements made 24 h after polymerization of specimens and 30 days after water storage. CONCLUSION: Palatal vault shape and fiber impregnation into the acrylic resin bases did not affect the magnitude of interfacial gaps between the bases and the stone cast surfaces. PMID- 22229011 TI - Evaluation of surface roughness and hardness of different glass ionomer cements. AB - OBJECTIVES: The aim of this study was to evaluate surface roughness and hardness of a nanofiller GIC, a resin-modified GIC, three conventional GICs, and a silver reinforced GIC. METHODS: For each material, 11 spcecimens were prepared and then stored in distilled water at 37 degrees C for 24 h. The surface roughness of 5 specimens was measured using a surface profilometer before polishing and after polishing with coarse, medium, fine, superfine aluminum oxide abrasive Sof-Lex discs respectively. The hardness of the upper surfaces of the remaining 6 specimens was measured with a Vickers microhardness measuring instrument. RESULTS: All tested GICs showed lower surface roughness values after the polishing procedure. Surface finish of nanofiller GIC was smoother than the other tested GICs after polishing. This was followed by resin-modified GIC, Fuji II LC; then silver-reinforced GIC, Argion Molar, conventional GICs, Aqua Ionofil Plus, Fuji IX, and Ionofil Molar, respectively. The result of the hardness test indicated that the microhardness value of silver-reinforced GIC was greater than that of the other GICs. When the hardness values of all tested GICs were compared, the differences between materials (except Aqua Ionofil Plus with Ionofil Molar and Ketac N100 with Fuji II LC (P>.05)) were found statistically significant (P<.05). CONCLUSIONS: According to the results of this study, it can be concluded that the differences in the composition of GICs may affect their surface roughness and hardness. PMID- 22229012 TI - Effect of cavity preparation techniques and different preheating procedures on microleakage of class V resin restorations. AB - OBJECTIVES: This study aimed to evaluate the extent of microleakage of a single type of composite resin (Clearfil Majesty Posterior, Kuraray, Osaka, Japan) following different preheating procedures in Class V cavities prepared with a diamond bur or Er:YAG (erbium: yttrium aluminum garnet) laser. METHODS: The study randomly divided 72 permanent molar teeth divided into eight groups (n = 9): G1: Diamond bur-unheated composite resin (room temperature-24 oC); G2: Diamond bur composite preheated to 37 oC; G3: Diamond bur-composite preheated to 54 oC; G4: Diamond bur-composite preheated to 68 oC; G5: Er:YAG laser-unheated composite resin (room temperature-24 oC); G6: Er:YAG laser-composite preheated to 37 oC; G7: Er:YAG laser-composite preheated to 54 oC; and G8: Er:YAG laser-composite preheated to 68 oC. The specimens were subjected to a thermal cycling regimen of 5000 cycles between 5 and 55 oC; then they were immersed in a solution of 0.5% basic fuchsin dye for 24 hours. The dyed specimens were sectioned in the buccolingual direction and dye penetration was scored in a blinded manner using a five-point qualitative scale. Microleakage scores were analyzed with the Kruskall Wallis, Mann-Whitney U, and Wilcoxon tests. RESULTS: There were no statistically significant differences between the microleakages of composite applied to cavities prepared by either the Er:YAG laser or diamond bur (P>.05). Statistical analysis revealed significant differences between the enamel and dentin in all restorations (P<.001). However, there were no significant differences among the preheated groups (P>.05). CONCLUSIONS: For all groups, microleakage values were higher at gingival margins than at occlusal margins. The use of the Er:YAG laser at different preheating procedures did not influence the marginal sealing in Class V composite resin restorations. PMID- 22229013 TI - Severe periodontal destruction in a patient with advanced anemia: A case report. AB - Anemia is a worldwide health problem that manifests in different types. This illness has some causes, which affect body health generally. Studies have shown that some anemia types make humans more sensitive to infections.A 23-year-old woman was referred to our clinic with complaints about tooth mobility. Generalized severe alveolar bone loss was verified by a radiographic examination. After a comprehensive clinical examination and taking her medical history, we decided to schedule a medical consultation with a physician. Medical consultation revealed that the patient suffered from severe anemia. Her periodontal treatment was modified because of her systemic situation. After treatment, the patient was monitored for one year. Her periodontal and systemic statuses were stable during this period.In this case report, severe periodontal destruction was observed in a patient with severe iron and B(12) deficiency anemia. PMID- 22229014 TI - Single tooth replacement using a ceramic resin bonded fixed partial denture: A case report. AB - This article describes the use of an all ceramic resin-bonded fixed partial denture as a conservative solution for the replacement of an incisor. It is a minimally invasive technique that does not discolor the abutment teeth. PMID- 22229015 TI - Conservative reconstruction of the smile by orthodontic, bleaching, and restorative procedures. AB - The following is a clinical case report of a patient whose chief complaint was the presence of generalized spacing in the maxillary anterior segment following orthodontic treatment. After meticulous clinical analyses and discussions of the clinical procedures to be adopted, dental bleaching was performed in both arches with 10% hydrogen peroxide (Opalescence Treswhite Supreme 10% Hydrogen Peroxide - Ultradent Products, Inc., South Jordan, USA) after the conclusion and stabilization of orthodontic treatment. Then, the orthodontic appliance was removed and the diastemas in the maxillary anterior teeth were closed with Amelogen Plus (Ultradent Products, Inc., South Jordan, USA) resin composite. It was observed that the association of orthodontic, bleaching, and restorative procedures was capable of restoring dental shape, function, and esthetics, allowing the patient to smile without hesitation. PMID- 22229016 TI - Apert syndrome: A case report. AB - The purpose of this report is to present Apert syndrome patient by highlighting craniofacial characteristics and orthodontic approach to treatment.The patient, a 16-day-old female and the second child of healthy parents, was admitted to our department with primary complaint of cleft palate. She had a cone-shaped calvarium, midface hypoplasia, syndactyly of the hands and feet, hypertelorism, proptosis and cleft palate. After taking maxillary impression, an acrylic appliance was applied to orientate the growing and enable the feeding.A case with Apert syndrome undergoes the orthodontic treatment for a long time and also a multidisciplinary approach is essential to determine the best collaborative corrective plan for the deficiencies of the patient. PMID- 22229017 TI - Pre-Clinical Assessment of Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease. AB - Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC) vector, use of (177)Lu was investigated. The combination of a 6.7 d half-life, lower energy beta(-)-emissions (500 keV max; 130 keV ave), and an imagable gamma emission make (177)Lu an attractive candidate for radioimmunotherapy (RIT) regimens for treatment of larger tumor burdens not possible with alpha-zparticle radiation. Radiolabeling trastuzumab-CHX-A"-DTPA with (177)Lu was efficient with a specific binding of 60.8 +/- 6.8% with HER2 positive SKOV-3 cells. Direct quantitation of tumor targeting and normal tissue uptake was performed with athymic mice bearing subcutaneous and intraperitoneal LS-174T xenografts; a peak tumor %ID/g of 24.70 +/- 10.29 (96 h) and 31.70 +/- 16.20 (72 h), respectively, was obtained. Normal tissue uptake of the RIC was minimal. Tumor targeting was also demonstrated by gamma-scintigraphy. A therapy study administering escalating doses of (177)Lu-trastuzumab to mice bearing three day LS-174T i.p. xenografts established the effective therapeutic dose of i.p. administered (177)Lu trastuzumab at 375 MUCi with a median survival of 124.5 d while a median survival of 10 d was noted for the control (untreated) group. In conclusion, trastuzumab radiolabeled with (177)Lu has potential for treatment of disseminated, HER2 positive, peritoneal disease. PMID- 22229019 TI - Neutral Organometallic Halogen Bond Acceptors: Halogen Bonding in Complexes of PCPPdX (X = Cl, Br, I) with Iodine (I(2)), 1,4-Diiodotetrafluorobenzene (F4DIBz), and 1,4-Diiodooctafluorobutane (F8DIBu). AB - The behavior of a sterically crowded neutral pincer {2,6-bis[(di-t butylphosphino)methyl]-phenyl}palladium (PCPPd) halides, PCPPdX (X = Cl, Br or I), as XB acceptors with strong halogen bond (XB) donors, iodine (I(2)), 1,4 diiodotetrafluorobenzene (F4DIBz), and 1,4-diiodooctafluorobutane (F8DIBu) were studied in the solid state. The co-crystallization experiments afforded high quality single crystals of XB complexes PCPPdCl-I(2) (1a), PCPPdBr-I(2) (2a), PCPPdI-I(2)(3a), PCPPdCl-F4DIBz (1b), PCPPdBr-F4DIBz (2b), and PCPPdBr-F8DIBu (2c). The 1:1 iodine complexes (1a, 2a, and 3a) all showed a strong halogen bonding interaction, the reduction of the sum of the van der Waals radii of halogen to iodine being 24.6 (1a), 23.9 (2a), and 19.4% (3a) with X...I-I angles of 177, 176, and 179 degrees , respectively. While the pincer palladium chloride 1 and bromide 2 were crystallographically isomorphous and showed similar XB behavior, the palladium iodide complex, 3, exhibited markedly different properties, and unlike 1 and 2 it does not, under similar conditions, result in XB complexes with the weaker XB donors F4DIBz and F8DIBu. The results indicate that PCPPdI is not nucleophilic enough to have XB interactions with other donors than iodine. However, the weaker XB donors F4DIBz and F8DIBu form XB complexes with the chloride 1 and especially with the bromide 2. The prevalence of the halogen bonding with 2 is probably not only electronic in origin, and it seems to offer the best balance between electron poorness and steric availability. The XB interactions with F4DIBz and F8DIBu are much weaker than with iodine, the reduction of the sum of the van der Waals radii of halogen to iodine being 13.5, 12.3, and 14.6% with C-I...X angles between 163 and 179 degrees for 1b, 2b, and 2c, respectively, and results in polymeric (...1...F4DIBz...1...F4DIBz...)(n), (...2...F4DIBz...2...F4DIBz...)(n), and (...2...F8DIBu...2...F8DIBu...)(n) one dimensional zigzag chains in the solid state. PMID- 22229018 TI - Lasting impacts of prenatal cannabis exposure and the role of endogenous cannabinoids in the developing brain. AB - Cannabis is the most commonly used illicit substance among pregnant women. Human epidemiological and animal studies have found that prenatal cannabis exposure influences brain development and can have long-lasting impacts on cognitive functions. Exploration of the therapeutic potential of cannabis-based medicines and synthetic cannabinoid compounds has given us much insight into the physiological roles of endogenous ligands (endocannabinoids) and their receptors. In this article, we examine human longitudinal cohort studies that document the long-term influence of prenatal exposure to cannabis, followed by an overview of the molecular composition of the endocannabinoid system and the temporal and spatial changes in their expression during brain development. How endocannabinoid signaling modulates fundamental developmental processes such as cell proliferation, neurogenesis, migration and axonal pathfinding are also summarized. PMID- 22229020 TI - Mechanisms of Stone Formation. PMID- 22229021 TI - The Soft Underbelly of System Change: The Role of Leadership and Organizational Climate in Turnover during Statewide Behavioral Health Reform. AB - This study examined leadership, organizational climate, staff turnover intentions, and voluntary turnover during a large-scale statewide behavioral health system reform. The initial data collection occurred nine months after initiation of the reform with a follow-up round of data collected 18 months later. A self-administered structured assessment was completed by 190 participants (administrators, support staff, providers) employed by 14 agencies. Key variables included leadership, organizational climate, turnover intentions, turnover, and reform-related financial stress ("low" versus "high") experienced by the agencies. Analyses revealed that positive leadership was related to a stronger empowering climate in both high and low stress agencies. However, the association between more positive leadership and lower demoralizing climate was evident only in high stress agencies. For both types of agencies empowering climate was negatively associated with turnover intentions, and demoralizing climate was associated with stronger turnover intentions. Turnover intentions were positively associated with voluntary turnover. Results suggest that strong leadership is particularly important in times of system and organizational change and may reduce poor climate associated with turnover intentions and turnover. Leadership and organizational context should be addressed to retain staff during these periods of systemic change. PMID- 22229023 TI - The Effect of Massachusetts' Health Reform on Employer-Sponsored Insurance Premiums. AB - In this paper, we use publicly available data from the Medical Expenditure Panel Survey - Insurance Component (MEPS-IC) to investigate the effect of Massachusetts' health reform plan on employer-sponsored insurance premiums. We tabulate premium growth for private-sector employers in Massachusetts and the United States as a whole for 2004 - 2008. We estimate the effect of the plan as the difference in premium growth between Massachusetts and the United States between 2006 and 2008-that is, before versus after the plan-over and above the difference in premium growth for 2004 to 2006. We find that health reform in Massachusetts increased single-coverage employer-sponsored insurance premiums by about 6 percent, or $262. Although our research design has important limitations, it does suggest that policy makers should be concerned about the consequences of health reform for the cost of private insurance. PMID- 22229022 TI - Local Effects of Vaginally Administered Estrogen Therapy: A Review. AB - The results of the Women's Health Initiative (WHI) led to a distinct decline in the routine use of estrogen as preventive therapy for vasomotor symptoms, osteoporosis, and cardiovascular disease in postmenopausal women. Without estrogen replacement, one third of women experience symptoms of atrophic vaginitis including dryness, irritation, itching and or dyspareunia. Local application of estrogen has been shown to relieve these symptoms and improve quality of life for these women. In addition, local estrogen therapy may have a favorable effect on sexuality, urinary tract infections, vaginal surgery, and incontinence. This review examines the effects of vaginally applied estrogen on the vaginal epithelium, urethra and endometrium. An accompanying review examines the systemic effects of vaginally applied estrogen. PMID- 22229024 TI - Excess of non-verbal cases of autism spectrum disorders presenting to orthodox clinical practice in Africa - a trend possibly resulting from late diagnosis and intervention. AB - OBJECTIVES: Characteristics of children with autism spectrum disorders (ASDs) in Africa are not known because of unavailability of large-scale epidemiological studies in this region. This review explored the age at first presentation to orthodox clinical practice of African children with ASDs and their expressive language ability at presentation. METHODS: A literature search of case series and case reports of ASDs from Africa was done through PubMed/MEDLINE, Google Scholar, African Journals Online (AJOL), and archives of the Nigerian Journal of Psychiatry. Six articles included content relating to age of the child at first presentation to orthodox clinical practice and symptoms at presentation related to expressive language ability and therefore fulfilled the inclusion criteria. Suggestions are made to explain the observations emanating from the review. RESULTS: An excess of non-verbal over verbal cases of ASDs have been presenting to orthodox clinical practice and there is a common denominator of late presentation/diagnosis and in turn late intervention, with most cases presenting for the first time well above 8 years of age. Attempts to explain these observations included low levels of knowledge and awareness about ASDs in Africa; problems with help-seeking behaviour; and lack of mental healthcare facilities and trained personnel. CONCLUSIONS: Enhancement of processes directed at ensuring early diagnosis and interventions, especially interventions aimed at improving speech and language development well and sufficiently early, may bring about a shift in the trend of excess non-verbal cases of ASDs over verbal cases presenting to orthodox clinical practice. PMID- 22229025 TI - Prostate cancer in Germany among migrants from the Former Soviet Union. AB - BACKGROUND: In Germany, prostate cancer is the leading cause of cancer and the third leading cause of death from cancer in males. We investigate prostate cancer in Gernmany among migrants from the Former Soviet Union (FSU) and compare them to indigenous German population with regard to prostate cancer incidence, mortality and longitudinal effects. METHODS: Data were obtained from two migrant cohorts residing in the federal states of North Rhine Westphalia (n=34,393) and Saarland (n=18,619). Vital status was ascertained through local population registries. Causes of death were obtained from the federal statistical office or from local health authorities. Cancer incidence of the Saarland cohort was derived from the Saarland Cancer Registry using record linkage. RESULTS: From 1990 to 2005 we observed 3360 deaths of which 28 were due to prostate cancer. In the Saarland cohort 35 men were diagnosed with prostate cancer during the respective period. Migrants had lower prostate cancer incidence (SIR 0.74 (95% CI: 0.52-1.03)) and mortality (SMR 0.57 (95% CI: 0.38-0.83)) compared to the German population. Multivariate analysis showed a strong age effect on incidence meaning young migrants (below age 60) were diagnosed significantly more often with prostate cancer compared to Germans of the same age. However, mortality did not show any effects. DISCUSSION: Lower prostate cancer mortality and incidence among migrants may reflect an ongoing situation in the FSU. Additionally, longitudinal analysis did not reveal convergence of migrant prostate cancer to German rates as expected from lifestyle driven cancer sites. Therefore, our results support the hypothesis of a genetic effect on prostate cancer risk. PMID- 22229026 TI - How to Group Genes according to Expression Profiles? AB - The most commonly applied strategies for identifying genes with a common response profile are based on clustering algorithms. These methods have no explicit rules to define the appropriate number of groups of genes. Usually the number of clusters is decided on heuristic criteria or through the application of different methods proposed to assess the number of clusters in a data set. The purpose of this paper is to compare the performance of seven of these techniques, including traditional ones, and some recently proposed. All of them produce underestimations of the true number of clusters. However, within this limitation, the gDGC algorithm appears to be the best. It is the only one that explicitly states a rule for cutting a dendrogram on the basis of a testing hypothesis framework, allowing the user to calibrate the sensitivity, adjusting the significance level. PMID- 22229027 TI - Fatigue in medical residents leads to reactivation of herpes virus latency. AB - The main objective of this study was to detect fatigue-induced clinical symptoms of immune suppression in medical residents. Samples were collected from the subjects at rest, following the first night (low-stress), and the last night (high-stress) of night float. Computerized reaction tests, Epworth Sleepiness Scale, and Wellness Profile questionnaires were used to quantify fatigue level. DNA of human herpes viruses HSV-1, VZV, EBV, as well as cortisol and melatonin concentrations, were measured in saliva. Residents at the high-stress interval reported being sleepier compared to the rest interval. EBV DNA level increased significantly at both stress intervals, while VZV DNA level increased only at low stress. DNA levels of HSV-1 decreased at low-stress but increased at high-stress. Combined assessment of the viral DNA showed significant effect of stress on herpes virus reactivation at both stress intervals. Cortisol concentrations at both stress intervals were significantly higher than those at rest. PMID- 22229028 TI - Polynomial supertree methods revisited. AB - Supertree methods allow to reconstruct large phylogenetic trees by combining smaller trees with overlapping leaf sets into one, more comprehensive supertree. The most commonly used supertree method, matrix representation with parsimony (MRP), produces accurate supertrees but is rather slow due to the underlying hard optimization problem. In this paper, we present an extensive simulation study comparing the performance of MRP and the polynomial supertree methods MinCut Supertree, Modified MinCut Supertree, Build-with-distances, PhySIC, PhySIC_IST, and super distance matrix. We consider both quality and resolution of the reconstructed supertrees. Our findings illustrate the tradeoff between accuracy and running time in supertree construction, as well as the pros and cons of voting- and veto-based supertree approaches. Based on our results, we make some general suggestions for supertree methods yet to come. PMID- 22229030 TI - Cigarette smoke and cancer. PMID- 22229029 TI - Genetics of isolated hypogonadotropic hypogonadism: role of GnRH receptor and other genes. AB - Hypothalamic gonadotropin releasing hormone (GnRH) is a key player in normal puberty and sexual development and function. Genetic causes of isolated hypogonadotropic hypogonadism (IHH) have been identified during the recent years affecting the synthesis, secretion, or action of GnRH. Developmental defects of GnRH neurons and the olfactory bulb are associated with hyposmia, rarely associated with the clinical phenotypes of synkinesia, cleft palate, ear anomalies, or choanal atresia, and may be due to mutations of KAL1, FGFR1/FGF8, PROKR2/PROK2, or CHD7. Impaired GnRH secretion in normosmic patients with IHH may be caused by deficient hypothalamic GPR54/KISS1, TACR3/TAC3, and leptinR/leptin signalling or mutations within the GNRH1 gene itself. Normosmic IHH is predominantly caused by inactivating mutations in the pituitary GnRH receptor inducing GnRH resistance, while mutations of the beta-subunits of LH or FSH are very rare. Inheritance of GnRH deficiency may be oligogenic, explaining variable phenotypes. Future research should identify additional genes involved in the complex network of normal and disturbed puberty and reproduction. PMID- 22229031 TI - The Effectiveness of Poly-(4-vinyl-N-hexylpyridiniumbromide) as an Antibacterial Implant Coating: An In Vitro Study. AB - The clinical success of osseointegrated dental implants depends on the strong attachment of the surrounding hard and soft tissues. Bacterial adhesion on implant surfaces can cause inflammatory reactions and may influence healing and long-term success of dental implants. Promising implant coatings should minimize bacterial adhesion, but allow epithelial and connective tissue attachment. Therefore, the present study has examined the bioactive effect of poly-(4-vinyl-N hexylpyridiniumbromide) regarding typical oral bacteria as well as cytotoxicitiy to human cells considering different methods of connecting polymers to silicate containing surfaces. The results revealed that the application of putative antibacterial and biocompatible polymer in coating strategies is affected by a variety of parameters. Published findings regarding reduced bacterial adhesion could not be verified using oral pathogens whereas hexylated polymers seem problematic for strong adhesion of soft tissue. Concerning innovative coatings for dental implants basic aspects (surface roughness, thickness, alkylation, combination with other polymers) have to be considered in further investigations. PMID- 22229033 TI - Cochlear implantation after bacterial meningitis in infants younger than 9 months. AB - Objective. To describe the audiological, anesthesiological, and surgical key points of cochlear implantation after bacterial meningitis in very young infants. Material and Methods. Between 2005 and 2010, 4 patients received 7 cochlear implants before the age of 9 months (range 4-8 months) because of profound hearing loss after pneumococcal meningitis. Results. Full electrode insertions were achieved in all operated ears. The audiological and linguistic outcome varied considerably, with categories of auditory performance (CAP) scores between 3 and 6, and speech intelligibility rating (SIR) scores between 0 and 5. The audiological, anesthesiological, and surgical issues that apply in this patient group are discussed. Conclusion. Cochlear implantation in very young postmeningitic infants is challenging due to their young age, sequelae of meningitis, and the risk of cochlear obliteration. A swift diagnostic workup is essential, specific audiological, anesthesiological, and surgical considerations apply, and the outcome is variable even in successful implantations. PMID- 22229032 TI - Nucleocytoplasmic shuttling of cytoskeletal proteins: molecular mechanism and biological significance. AB - Various nuclear functional complexes contain cytoskeletal proteins as regulatory subunits; for example, nuclear actin participates in transcriptional complexes, and actin-related proteins are integral to chromatin remodeling complexes. Nuclear complexes such as these are involved in both basal and adaptive nuclear functions. In addition to nuclear import via classical nuclear transport pathways or passive diffusion, some large cytoskeletal proteins spontaneously migrate into the nucleus in a karyopherin-independent manner. The balance of nucleocytoplasmic distribution of such proteins can be altered by several factors, such as import versus export, or capture and release by complexes. The resulting accumulation or depletion of the nuclear populations thereby enhances or attenuates their nuclear functions. We propose that such molecular dynamics constitute a form of cytoskeleton-modulated regulation of nuclear functions which is mediated by the translocation of cytoskeletal components in and out of the nucleus. PMID- 22229034 TI - Clinical outcomes of gamma knife radiosurgery in the treatment of patients with trigeminal neuralgia. AB - Since its introduction by Leksell, Gamma Knife radiosurgery (GKRS) has become increasingly popular as a management approach for patients diagnosed with trigeminal neuralgia (TN). For this reason, we performed a modern review of the literature analyzing the efficacy of GKRS in the treatment of patients who suffer from TN. For patients with medically refractory forms of the condition, GKRS has proven to be an effective initial and repeat treatment option. Cumulative research suggests that patients treated a single time with GKRS exhibit similar levels of facial pain control when compared to patients treated multiple times with GKRS. However, patients treated on multiple occasions with GKRS are more likely to experience facial numbness and other facial sensory changes when compared to patients treated once with GKRS. Although numerous articles have reported MVD to be superior to GKRS in achieving facial pain relief, the findings of these comparison studies are weakened by the vast differences in patient age and comorbidities between the two studied groups and cannot be considered conclusive. Questions remain regarding optimal GKRS dosing and targeting strategies, which warrants further investigation into this controversial matter. PMID- 22229036 TI - An Unusual Association between Unilateral Intracranial Vessels Occlusion with Iron Deficiency Anaemia and Alpha-Thalassemia Trait: A Case Report. AB - We report a 33-year-old Malay woman presented with acute left dense hemiparesis and an NIHSS score of 11/15. Computed tomography (CT) scan brain showed a massive right middle cerebral artery (MCA) territory infarct. The right internal carotid artery (ICA) and right proximal MCA were shown occluded from digital substraction angiography (DSA). Carotid dissection, carotid canal anomaly, and intercavernous communication were systematically ruled out. She had no risk factors for atherosclerosis. The connective tissue screening and thrombophilic markers were negative. However, she was anaemic on admission and subsequent investigations revealed that she had alpha-thalassemia and iron deficiency anaemia. The right ICA remained occluded from a repeat CT cerebral angiogram after one year, but otherwise she was neurologically stable. This case illustrates an unusual association between intracranial vessel occlusion with iron deficiency anaemia and alpha-thalassemia trait. PMID- 22229035 TI - Use of biologic agents in ocular manifestations of rheumatic disease. AB - Biologic agents have dramatically shifted the treatment paradigm for rheumatic disease. Use of these agents can decrease disease burden, allow the patient to be weaned from corticosteroids, and reduce the likelihood of relapse. Eye disease associated with rheumatic conditions may present with a wide range of signs and symptoms. This coexisting pathology should not be overlooked and should be considered a reason for initiation or continuation of biologic therapy. Additionally, many of the ocular manifestations of rheumatic disease respond preferentially to specific targeting molecules. This paper summarizes the available studies on the use, efficacy, and safety of biologic agents in the treatment of ocular manifestations of rheumatic disease. PMID- 22229037 TI - Primary Squamous Cell Carcinoma of the Breast during Pregnancy: A Case Report. AB - Primary squamous cell carcinoma of the breast (SCCB) is a very rare malignancy of the breast and is generally aggressive. It is even rarer during the gestational period. Only few cases have been reported during pregnancy and lactation (Rokutanda et al., 2000). SCCB seen within the gestational period tends to be very aggressive and has a larger size than other breast carcinomas. Pure SCCB is derived from the epidermis of the breast, nipple, or metaplasia on chronic inflammatory background (Bige et al., 2007), such as complicated breast cyst, dermoid cyst, or abscess. We report a case of SCCB in a 30-year-old primigravida that had an aggressive propensity and fatal outcome. PMID- 22229038 TI - Pulmonary effects of neonatal hydrocortisone treatment in ventilator-dependent preterm infants. AB - Background/Objective. Hydrocortisone, administered to ventilated preterm neonates to facilitate extubation, has no adverse long-term effects, but short-term pulmonary effects have not been described previously. In the present study, we analyzed effects of hydrocortisone on ventilator settings and FiO(2) in ventilator-dependent preterm infants. Patients and Methods. Fifty-five preterm children were included in this retrospective cohort study. Hydrocortisone was administered at a postnatal age of > 7 days to treat chronic lung disease (CLD). Ventilator settings before and after hydrocortisone administration were recorded as well as FiO(2) at 36 weeks' gestational age. Presence of cerebral palsy was assessed at a mean corrected age of 24.1 months. Results. Hydrocortisone administered at a median postnatal age of 14 days significantly reduced FiO(2) from a median of 0.39 to 0.30, mean airway pressure (MAP) from a median of 10.0 cm H(2)O to 7.6 cm H(2)O, and PaCO(2) from a median of 53.5 mmHg to 47 mmHg. Extubation was achieved in all patients. CLD at 36 weeks was present in 11 of the 52 patients (21.1%). None developed cerebral palsy. Conclusions. Hydrocortisone was effective in reducing the FiO(2), MAP, and PaCO(2) and facilitated extubation. Hydrocortisone was not associated with cerebral palsy. PMID- 22229039 TI - Immune modulation in primary vaccinia virus zoonotic human infections. AB - In 2010, the WHO celebrated the 30th anniversary of the smallpox eradication. Ironically, infections caused by viruses related to smallpox are being increasingly reported worldwide, including Monkeypox, Cowpox, and Vaccinia virus (VACV). Little is known about the human immunological responses elicited during acute infections caused by orthopoxviruses. We have followed VACV zoonotic outbreaks taking place in Brazil and analyzed cellular immune responses in patients acutely infected by VACV. Results indicated that these patients show a biased immune modulation when compared to noninfected controls. Amounts of B cells are low and less activated in infected patients. Although present, T CD4(+) cells are also less activated when compared to noninfected individuals, and so are monocytes/macrophages. Similar results were obtained when Balb/C mice were experimentally infected with a VACV sample isolated during the zoonotic outbreaks. Taking together, the data suggest that zoonotic VACVs modulate specific immune cell compartments during an acute infection in humans. PMID- 22229040 TI - Randomised, double blind, placebo-controlled trial of echinacea supplementation in air travellers. AB - Objective. To identify whether a standardised Echinacea formulation is effective in the prevention of respiratory and other symptoms associated with long-haul flights. Methods. 175 adults participated in a randomised, double-blind placebo controlled trial travelling back from Australia to America, Europe, or Africa for a period of 1-5 weeks on commercial flights via economy class. Participants took Echinacea (root extract, standardised to 4.4 mg alkylamides) or placebo tablets. Participants were surveyed before, immediately after travel, and at 4 weeks after travel regarding upper respiratory symptoms and travel-related quality of life. Results. Respiratory symptoms for both groups increased significantly during travel (P < 0.0005). However, the Echinacea group had borderline significantly lower respiratory symptom scores compared to placebo (P = 0.05) during travel. Conclusions. Supplementation with standardised Echinacea tablets, if taken before and during travel, may have preventive effects against the development of respiratory symptoms during travel involving long-haul flights. PMID- 22229041 TI - Influence of expert-dependent variability over the performance of noninvasive fibrosis assessment in patients with chronic hepatitis C by means of texture analysis. AB - Texture analysis is viewed as a method to enhance the diagnosis power of classical B-mode ultrasound image. The present paper aims to evaluate and eliminate the dependence between the human expert and the performance of such a texture analysis system in predicting the cirrhosis in chronic hepatitis C patients. 125 consecutive chronic hepatitis C patients were included in this study. Ultrasound images were acquired from each patient and four human experts established regions of interest. Textural analysis tool was evaluated. The performance of this approach depends highly on the human expert that establishes the regions of interest (P < 0.05). The novel algorithm that automatically establishes regions of interest can be compared with a trained radiologist. In classical form met in the literature, the noninvasive diagnosis through texture analysis has limited utility in clinical practice. The automatic ROI establishment tool is very useful in eliminating the expert-dependent variability. PMID- 22229043 TI - Latest advances in the medical treatment of cancer: a 2011 snapshot. PMID- 22229042 TI - Free energy, value, and attractors. AB - It has been suggested recently that action and perception can be understood as minimising the free energy of sensory samples. This ensures that agents sample the environment to maximise the evidence for their model of the world, such that exchanges with the environment are predictable and adaptive. However, the free energy account does not invoke reward or cost-functions from reinforcement learning and optimal control theory. We therefore ask whether reward is necessary to explain adaptive behaviour. The free energy formulation uses ideas from statistical physics to explain action in terms of minimising sensory surprise. Conversely, reinforcement-learning has its roots in behaviourism and engineering and assumes that agents optimise a policy to maximise future reward. This paper tries to connect the two formulations and concludes that optimal policies correspond to empirical priors on the trajectories of hidden environmental states, which compel agents to seek out the (valuable) states they expect to encounter. PMID- 22229044 TI - Sunitinib in advanced pancreatic neuroendocrine tumors: latest evidence and clinical potential. AB - Based on preclinical data available in the RIP1-Tag2 transgenic mouse model, sunitinib is an inhibitor of angiogenesis in pancreatic neuroendocrine tumors blocking vascular endothelial growth factor receptors and platelet-derived growth factor receptors in endothelial cells and pericytes, respectively. Evidence of objective response in phase I trials justified the initiation of a large phase II/III program using sunitinib in patients with advanced/metastatic well differentiated pancreatic neuroendocrine tumors. In the phase II study, sunitinib showed potent antitumor activity and a safe toxicity profile. In a recent double blind placebo-controlled randomized phase III trial, sunitinib doubled the progression-free survival of patients, induced objective responses, and reduced the risk of death of patients with advanced/metastatic well-differentiated tumors. These data allowed the approval of sunitinib in several countries including Europe and the United States of America. These recent data provide hope for patients with well-differentiated pancreatic neuroendocrine tumors and will change standards of care in this disease. PMID- 22229045 TI - Erlotinib in the treatment of advanced non-small cell lung cancer: an update for clinicians. AB - Inhibition of epidermal growth factor receptor (EGFR) has become an important target in the treatment of advanced non-small cell lung cancer (NSCLC). Erlotinib and gefitinib, two small molecular agents that target the tyrosine kinase domain of the EGFR, were approved in many countries for the treatment of locally advanced or metastatic NSCLC as a second- or third-line regimen. Since then, randomized trials have evaluated the role of these two targeted agents alone or combined with chemotherapy in maintenance and first-line settings. This review summarizes the results of recent clinical trials with these tyrosine kinase inhibitors, with a focus on erlotinib, as first-line treatment towards a form of personalized medicine aimed at improving clinical outcome in advanced NSCLC. PMID- 22229046 TI - Epithelial-mesenchymal transition in pulmonary carcinosarcoma: case report and literature review. AB - Pulmonary carcinosarcoma is a rare and aggressive neoplasm that has both epithelial and mesenchymal components. We report on a 63-year-old woman who was found to have a right upper-lobe pulmonary carcinosarcoma with metastases to the liver and gastric fundus. There are currently no published guidelines on the treatment of pulmonary sarcomatoid carcinomas. However, with our expanding knowledge of cancer metastasis, cases of carcinosarcoma illustrate our current understanding of epithelial-mesenchymal transition in action. Here, we discuss the development and treatment of these biphasic tumors and the possible role of epithelial-mesenchymal transition. PMID- 22229047 TI - Impact of protein binding on the analytical detectability and anticancer activity of thymoquinone. AB - Thymoquinone (TQ), an active component of Nigella sativa L., is known to have anti-cancer and anti-inflammatory effects; however, no studies on its analytical detection in serum and its protein binding have been published. Using high performance liquid chromatography analysis, we show that the average recovery of TQ from serum is 2.5% at 10 MUg/ml of TQ and 72% at 100 MUg/ml. The low recovery of TQ from serum is due to its extensive binding to plasma proteins, as more than 99% of TQ was bound within 30 min of incubation. The binding of TQ to the major plasma proteins, bovine serum albumin (BSA) and alpha -1 acid glycoprotein (AGP), was studied and found to be 94.5 +/- 1.7% for BSA and 99.1 +/- 0.1% for AGP. Mass spectrometric analysis revealed that TQ was bound covalently to BSA, specifically on Cyst-34. Using WST-1 proliferation assay, we showed that BSA plays a protective role against TQ-induced cell death; pre-incubation with BSA prevented TQ from exerting its anti-proliferative effects against DLD-1 and HCT-116 human colon cancer cells. On the other hand, binding of TQ to AGP did not alter its anti-proliferative activity against both cell lines. When TQ was pre-incubated with AGP prior to the addition of BSA, the activity of TQ against DLD-1 was maintained, suggesting that AGP prevented the binding of TQ to BSA. This is the first time the covalent binding and inhibitory effect of BSA on TQ is documented. These data offer new grounds for TQ future pharmacokinetic analysis in vivo. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12154-010-0052-4) contains supplementary material, which is available to authorized users. PMID- 22229048 TI - Delivering a lifestyle and weight loss intervention to individuals in real-world mental health settings: Lessons and opportunities. AB - BACKGROUND: Most weight loss interventions for obesity-related risks exclude people with serious mental health conditions. PURPOSE: To adapt a successful lifestyle/weight loss intervention for this population, deliver it in an HMO and two public mental health clinics, and concurrently measure implementation factors. METHODS: Developmental and implementation-focused formative evaluations guided adaptations and identified barriers/facilitators to successful program deployment. RESULTS: Adaptations included content specific to the population's needs, consciousness-raising among clinicians and patients, additional case management, and greater program flexibility. Barriers included instability in both settings from different sources. Facilitators included familiarity with groups, manual integrity, and appreciation of the program. It was delivered consistently across settings with maximum exposure and fairly good fidelity to the protocol (mean rating=1.7, 2.0=complete fidelity). CONCLUSIONS: This mixed method implementation evaluation demonstrated that lifestyle/weight loss interventions in mental health settings are complex, but feasible, and valued by participants. Main program outcomes will be reported at the trial's conclusion. PMID- 22229049 TI - Factors Influencing Post-Operative Short-Term Outcomes of Vesicovaginal Fistula Repairs in a Community Hospital in Liberia. AB - OBJECTIVES: To assess factors influencing short-term outcomes of vesicovaginal fistula (VVF) repairs in community-dwelling women of Liberia, Africa. METHODS: Forty patients who underwent VVF repairs were analyzed. Primary outcome was continence status at 14 days post repair. Factors influencing continence status were characterized. RESULTS: The mean duration of leakage was 9.6 +/- 8.3 years, (3 months-28 years). Thirteen (33%) had previous repairs, and 6 (15%) had multiple fistula sites. Twenty-eight (70%) were continent at catheter removal. First time repairs had a higher continence rate compared to women with previous repairs, 78% and 54% respectively (p= 0.15). Seven (47%) juxtaurethral repairs were considered failures, while only one (9%) juxtacervical fistulas remained incontinent (p= 0.069). Controlling for duration of leakage, women with previous repairs were significantly less likely to be continent (p = 0.04; adjusted OR = 0.07; 95% CI: 0.005, 0.83). CONCLUSIONS: Patients with previous VVF repairs and juxtaurethral fistulae experience lower success rates; surgery remains an effective treatment for many VVF patients. PMID- 22229050 TI - Early iron deficiency enhances stimulus-response learning of adult rats in the context of competing spatial information. AB - Iron deficiency early in life results in neurocognitive deficits that persist into adulthood despite iron treatment. The hippocampus is particularly vulnerable to iron deficiency during the fetal and neonatal periods as evidenced by poorer hippocampus-mediated spatial recognition learning. However, the extent to which early iron deficiency alters interactions between hippocampus-based and extra hippocampus based learning systems remains undetermined. The present study used an ambiguous maze-learning task to examine the learning process in iron sufficient young adult rats that had recovered from iron deficiency in the fetal and neonatal period. Animals were presented with a stimulus response-learning task in the context of spatial information; a procedure designed to elicit competition between dorsal striatum- and hippocampus-based systems respectively. Formerly iron deficient adult rats showed enhanced stimulus-response learning in the context of competing spatial/distal cue information, a finding suggestive of reduced hippocampal functional influence. The study provides evidence that early iron deficiency alters how different learning systems develop and ultimately interact in adulthood. The potential unbalancing of activity among major memory systems during early life has been postulated by others as a relevant factor underlying the developmental origins of certain psychiatric disorders. PMID- 22229055 TI - Mutual information for the detection of crush. AB - Fatal crush conditions occur in crowds with tragic frequency. Event organizers and architects are often criticised for failing to consider the causes and implications of crush, but the reality is that both the prediction and prevention of such conditions offer a significant technical challenge. Full treatment of physical force within crowd simulations is precise but often computationally expensive; the more common method of human interpretation of results is computationally "cheap" but subjective and time-consuming. This paper describes an alternative method for the analysis of crowd behaviour, which uses information theory to measure crowd disorder. We show how this technique may be easily incorporated into an existing simulation framework, and validate it against an historical event. Our results show that this method offers an effective and efficient route towards automatic detection of the onset of crush. PMID- 22229057 TI - Estimation of individual muscle force using elastography. AB - BACKGROUND: Estimation of an individual muscle force still remains one of the main challenges in biomechanics. In this way, the present study aimed: (1) to determine whether an elastography technique called Supersonic Shear Imaging (SSI) could be used to estimate muscle force, (2) to compare this estimation to that one provided by surface electromyography (EMG), and (3) to determine the effect of the pennation of muscle fibers on the accuracy of the estimation. METHODS AND RESULTS: Eleven subjects participated in two experimental sessions; one was devoted to the shear elastic modulus measurements and the other was devoted to the EMG recordings. Each session consisted in: (1) two smooth linear torque ramps from 0 to 60% and from 0 to 30% of maximal voluntary contraction, for the first dorsal interosseous and the abductor digiti minimi, respectively (referred to as "ramp contraction"); (2) two contractions done with the instruction to freely change the torque (referred to as "random changes contraction"). Multi-channel surface EMG recordings were obtained from a linear array of eight electrodes and the shear elastic modulus was measured using SSI. For ramp contractions, significant linear relationships were reported between EMG activity level and torque (R2 = 0.949+/-0.036), and between shear elastic modulus and torque (R2 = 0.982+/-0.013). SSI provided significant lower RMS(deviation) between measured torque and estimated torque than EMG activity level for both types of contraction (1.4+/-0.7 vs. 2.8+/-1.4% of maximal voluntary contraction for "ramp contractions", p<0.01; 4.5+/-2.3 vs. 7.9+/-5.9% of MVC for "random changes contractions", p<0.05). No significant difference was reported between muscles. CONCLUSION: The shear elastic modulus measured using SSI can provide a more accurate estimation of individual muscle force than surface EMG. In addition, pennation of muscle fibers does not influence the accuracy of the estimation. PMID- 22229058 TI - Effective Classroom Instruction: Implications of Child Characteristics by Reading Instruction Interactions on First Graders' Word Reading Achievement. AB - Too many children fail to learn how to read proficiently with serious consequences for their overall well-being and long term success in school. This may be because providing effective instruction is more complex than many of the current models of reading instruction portray; there are child characteristic by instruction (CXI) interactions. Here we present efficacy results for a randomized control field trial of the Individualizing Student Instruction (ISI) intervention, which relies on dynamic system forecasting intervention models to recommend amounts of reading instruction for each student, taking into account CXI interactions that consider his or her vocabulary and reading skills. The study, conducted in seven schools with 25 teachers and 396 first graders, revealed that students in the ISI intervention classrooms demonstrated significantly greater reading skill gains by spring than did students in control classrooms. Plus, they were more likely to receive differentiated reading instruction based on CXI interaction guided recommended amounts than were students in control classrooms. The precision with which students received the recommended amounts of each type of literacy instruction, the distance from recommendation, also predicted reading outcomes. PMID- 22229056 TI - A genomic reappraisal of symbiotic function in the aphid/Buchnera symbiosis: reduced transporter sets and variable membrane organisations. AB - Buchnera aphidicola is an obligate symbiotic bacterium that sustains the physiology of aphids by complementing their exclusive phloem sap diet. In this study, we reappraised the transport function of different Buchnera strains, from the aphids Acyrthosiphon pisum, Schizaphis graminum, Baizongia pistaciae and Cinara cedri, using the re-annotation of their transmembrane proteins coupled with an exploration of their metabolic networks. Although metabolic analyses revealed high interdependencies between the host and the bacteria, we demonstrate here that transport in Buchnera is assured by low transporter diversity, when compared to free-living bacteria, being mostly based on a few general transporters, some of which probably have lost their substrate specificity. Moreover, in the four strains studied, an astonishing lack of inner-membrane importers was observed. In Buchnera, the transport function has been shaped by the distinct selective constraints occurring in the Aphididae lineages. Buchnera from A. pisum and S. graminum have a three-membraned system and similar sets of transporters corresponding to most compound classes. Transmission electronic microscopic observations and confocal microscopic analysis of intracellular pH fields revealed that Buchnera does not show any of the typical structures and properties observed in integrated organelles. Buchnera from B. pistaciae seem to possess a unique double membrane system and has, accordingly, lost all of its outer-membrane integral proteins. Lastly, Buchnera from C. cedri revealed an extremely poor repertoire of transporters, with almost no ATP-driven active transport left, despite the clear persistence of the ancestral three-membraned system. PMID- 22229059 TI - The Use of Principal Component Analysis in MALDI-TOF MS: a Powerful Tool for Establishing a Mini-optimized Proteomic Profile. AB - BACKGROUND: Recently, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) technology has been applied to the exploration of biomarkers for early cancer diagnosis, but more effort is required to identify a single sensitive and specific biomarker. For early diagnosis, a proteomic profile is the gold standard, but inconvenient for clinical use since the profile peaks are quantitative. It would therefore be helpful to find a minimized profile, comprising fewer peaks than the original using an existing algorithm and compare it with other traditional statistical methods. METHODS: In the present study, principal component analysis (PCA) in the ClinProt-Tools of MALDI-TOF MS was used to establish a mini-optimized proteomic profile from gastric cancer patients and healthy controls, and the result was compared with t-test and Flexanalysis software. RESULTS: Eight peaks were selected as the mini-optimized proteomic profile to help differentiate between gastric cancer patients and healthy controls. The peaks at m/z 4212 were regarded as the most important peak by the PCA algorithm. The peaks at m/z 1866 and 2863 were identified as deriving from complement component C3 and apolipoprotein A1, respectively. CONCLUSIONS: PCA enabled us to identify a mini-optimized profile consisting of significantly differentiating peaks and offered the clue for further research. PMID- 22229060 TI - Testing the transition preparation training program: A randomized controlled trial. AB - The effectiveness of a cognitive-behavioral program, Transition Preparation Training (TPT), in combination with spina bifida (SB) management was compared to adolescents with SB who received only SB management. Design, setting and participants: Prospective controlled trial with an ethnically diverse sample (94%) of 65 adolescents with SB (31 in treatment group [mean age: 16.19]; 34 in control group [mean age: 15.71]) conducted at Childrens Hospital Los Angeles between September 2006 and September 2008. INTERVENTIONS: TPT was a three-module, eight sessions program offered in a 2 day workshop format to facilitate development of health care transition plan. MAIN OUTCOME MEASURES: Subjective well being as measured by the Personal Adjustment and Role Skills Scale (PARS III), Role mastery measured using Community Life Skills Scale (CLSS), and Self Care Practice with the Denyes Self-Care Practice Instrument (DSCPI-90(c)). RESULTS: No significant differences were found between groups of any treatment effect or treatment follow-up interaction. No substantial changes in the scores either between treatments of post treatments were found. PMID- 22229061 TI - Prenatal diagnosis of unilateral pulmonary dysplasia. AB - Pulmonary hypoplasia is a rare congenital disorder; most cases occur in association with other congenital abnormalities, including congenital diaphragmatic hernia, oligohydramnios, and/or skeletal deformities. The authors report a case of unilateral pulmonary hypoplasia diagnosed prenatally and confirmed at autopsy. PMID- 22229062 TI - Vascular network modeling reveals significant differences in vascular morphology in growth-restricted placentas. AB - AIM: To construct and examine models of the vascular networks using the technique of vascular corrosion casting in placentas collected from normal pregnancies and from pregnancies complicated by fetal growth restriction (FGR). METHODS: Twenty placentas were collected from normal term pregnancies (Group NP) and an equal number from pregnancies with idiopathic term FGR (Group FGR) and placental vascular network models constructed by perfusing an acrylic-based solution separately into the umbilical vein and arteries. Placental blood volumes and blood vessel characteristics (number of branches, diameter, and morphology) were then examined and compared. RESULTS: In placentas from Group NP, the veins branched five to seven times with a peripheral artery-to-vein ratio ranging from 1:2 to 1:3. In placentas from Group FGR, the veins branched only four to five times with an artery-to-vein ratio of 1:1 to 2:1 and increased evidence of nodularity and pitting of the vessel walls. The two groups showed significant differences in placental blood volume and in the mean diameters of umbilical veins and arteries. In Group FGR, significant positive correlations could be found between birth weight and placental volume, venous diameters, and select arterial diameters. CONCLUSION: Vascular network models can be constructed from term placentas. Such modeling may provide novel insights and improve our understanding of the placental vascular system in both health and disease. PMID- 22229063 TI - An evidence-based approach to determining route of delivery for twin gestations. AB - Approximately 50% of twin pregnancies deliver preterm, and major complications associated with prematurity include respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, and sepsis. These complications drive the perinatal mortality rate of twins to seven times that of singletons. Although delivery may take place due to iatrogenic or spontaneous etiologies-no matter what the indication-optimizing the route of delivery for twins is an important component of care that must be thoughtfully considered. PMID- 22229064 TI - Laparoscopic surgical staging of early ovarian cancer. AB - Since its advent in the early 1990s, laparoscopic surgical staging for early ovarian cancer has been explored as an option with the potential to offer women equivalent cancer control and survival as provided by laparotomy but with the clear benefits of minimally invasive surgery. A limited but expanding body of literature suggests aggressive surgical staging can be performed with equivalent tissue assessment compared with laparotomy. Given the lack of randomized, controlled trials, the risks and benefits of such a procedure remain ambiguous. This review summarizes the current body of literature regarding the role of laparoscopy in upfront surgical staging of ovarian cancer. This review presents the history, rationale, and established benefits and risks of utilizing this approach in women who present with malignancy that appears confined to the ovary. Although retrospective data confirm the feasibility, safety, and efficacy of laparoscopic staging of early ovarian cancer, more prospective data will be required to confirm equivalent survival in a patient population that has the potential to be cured. PMID- 22229066 TI - Multivitamin Supplementation During Pregnancy: Emphasis on Folic Acid and l Methylfolate. PMID- 22229065 TI - Side docking: an alternative docking method for gynecologic robotic surgery. AB - The authors propose an alternative method of robotic docking for gynecologic surgery. In this side-docking method, the robot is docked at an approximately 45 degrees angle to the lower torso, aligned with the outer border of either the left or right stirrup, depending on the surgeon's preference for left or right side-docking. The remainder of the patient and trocar setup is similar to traditional docking. The authors have had an excellent experience with this method as there does not seem to be an increased risk of robotic arm collision as long as the surgeon respects the basic principle of maintaining at least an 8- to 10-cm distance between each of the instrument ports. The significantly improved access to the vagina and perineum may facilitate robotically assisted gynecologic surgical procedures and reduce assistant fatigue and the potential for injury due to a collision with the robotic arms. PMID- 22229067 TI - Bilateral salpingo-oophorectomy at hysterectomy? PMID- 22229068 TI - Thyroid antibodies associated with miscarriage and preterm birth. PMID- 22229069 TI - Bisphosphonates and femoral fractures. PMID- 22229070 TI - Cancer screening and survival. PMID- 22229071 TI - Intrauterine contraceptive devices following termination of pregnancy. PMID- 22229072 TI - Snippets. PMID- 22229073 TI - A case report - Volatile metabolomic signature of malignant melanoma using matching skin as a control. AB - Melanoma is the most serious form of skin cancer. The quest for melanoma diagnostic biomarkers is paramount since early detection of melanoma and surgical excision represent the only effective treatment of this capricious disease. Our recent study tested the hypothesis that melanoma forms a unique volatile signature that is different than control, healthy tissue. Here, we are reporting a case study, the analysis of the volatile metabolic signature of a malignant melanoma using matched, non-neoplastic skin tissue from the same patient as a control. This is a significant improvement in the methodology, since it is well known that diet, skin type, genetic background, age, sex and environment all contribute to individual variation in the skin volatile signature. In the present study, we have identified 32 volatile compounds; 9 volatile compounds were increased in melanoma when compared to normal skin and 23 volatile compounds were detected only in melanoma and not in normal skin. Out of these 32 compounds, 10 have been reported previously by our group, thus confirming our results and adding additional confidence in our untargeted metabolomics approach for detection of melanoma biomarkers. PMID- 22229074 TI - Tuning the Surface Structure and Optical Properties of CdSe Clusters Using Coordination Chemistry. AB - A series of nonstoichiometric CdSe clusters with lowest energy electronic absorptions between 409 - 420 nm has been prepared from cadmium 1-naphthoate, 2 naphthoate, 4-thiomethyl-1-naphthaote, and 1-naphthalene thiolate complexes and diphenylphosphine selenide (DPPSe). Pair distribution function analysis of X-ray diffraction data, ligand exchange experiments, and NMR molecular weight analyses suggest the nanocrystal core changes minimally among these clusters despite significant changes to their absorption and luminescence spectra. Photoluminescence excitation spectra obtained at 77 K reveal an energy transfer process between the surface-trapped excited state and the naphthalene-containing ligands that leads to ligand phosphorescence. A Dexter energy transfer mechanism is proposed to explain the observation of ligand phosphorescence on excitation of the cluster. These compounds demonstrate that cluster absorption and trap luminescence can be controlled with surface coordination chemistry. PMID- 22229075 TI - Piperidine acetic acid based gamma-secretase modulators directly bind to Presenilin-1. AB - Abeta42 is believed to play a causative role in Alzheimer's disease (AD) pathogenesis. gamma-Secretase modulators (GSMs) are actively being pursued as potential AD therapeutics because they selectively alter the cleavage site of the amyloid precursor protein (APP) to reduce the formation of Abeta42. However, the binding partner of acid based GSMs was unresolved until now. We have developed clickable photoaffinity probes based on piperidine acetic acid GSM-1 and identified PS1 as the target within the gamma-secretase complex. Furthermore, we provide evidence that allosteric interaction of GSMs with PS1 results in a conformational change in the active site of the gamma-secretase complex leading to the observed modulation of gamma-secretase activity. PMID- 22229076 TI - Novel Modeling Approach to Generate a Polymeric Nanofiber Scaffold for Salivary Gland Cells. AB - BACKGROUND: Electrospun nanofibers have been utilized in many biomedical applications as biomimetics of extracellular matrix proteins that promote self organization of cells into 3D tissue constructs. As progress towards an artificial salivary gland tissue construct, we prepared nanofiber scaffolds using PLGA, a biodegradable and biocompatible material. METHOD OF APPROACH: We used electrospinning to prepare nanofiber scaffolds using PLGA with both DMF and HFIP as solvents. Using a design of experiment (DOE) approach, system and process parameters were optimized concurrently and their effects on the diameter of the resulting fibers were computed into a single model. A transfer function was used to reproducibly produce nanofibers of a defined diameter, which was confirmed by SEM. The mouse salivary gland epithelial cell line, SIMS, was seeded on the nanofiber scaffolds, and morphology, cell proliferation, and viability were assayed. RESULTS: Varying two or more parameters simultaneously yielded trends diverging from the linear response predicted by previous studies. Comparison of two solvents revealed that the diameter of PLGA nanofibers generated using HFIP is less sensitive to changes in the system and process parameters than are fibers generated using DMF. Inclusion of NaCl reduced morphological inconsistencies and minimized process variability. The resulting nanofiber scaffolds supported attachment, survival and cell proliferation of a mouse salivary gland epithelial cell line. In comparison with glass and flat PLGA films, the nanofibers promoted self-organization of the salivary gland cells into 3D cell clusters, or aggregates. CONCLUSIONS: These data indicate that nanofiber scaffolds promote salivary gland cell organization, and suggest that a nanofiber scaffold could provide a platform for engineering of an artificial salivary gland tissue construct. This study additionally provides a method for efficient production of nanofiber scaffolds for general application in tissue engineering. PMID- 22229077 TI - Dynamic contrast-enhanced MR imaging findings of bone metastasis in patients with prostate cancer. AB - AIM: To evaluate the dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) findings of bone metastasis in prostate cancer patients. METHODS: Sixteen men with a diagnosis of metastatic prostate cancer to bones were examined with DCE-MRI at 1.5 Tesla. The mean contrast agent concentration vs time curves for bone metastasis and normal bone were calculated and K(trans) and ve values were estimated and compared. RESULTS: An early significant enhancement (wash-out: n = 6, plateau: n = 8 and persistent: n = 2) was detected in all bone metastases (n = 16). Bone metastasis from prostate cancer showed significant enhancement and high K(trans) and ve values compared to normal bone which does not enhance in the elderly population. The mean K(trans) was 0.101/min and 0.0051/min (P < 0.001), the mean ve was 0.141 and 0.0038 (P < 0.001), for bone metastases and normal bone, respectively. CONCLUSION: DCE-MRI and its quantitative perfusion parameters may have a role in improving the detection of skeletal metastasis in prostate cancer patients. PMID- 22229078 TI - Lipoma of the pancreas, a case report and a review of the literature. AB - Lipomas of the pancreas are very rare. There are fewer than 25 reported cases of lipoma originating from the pancreas. We present a case of pancreatic lipoma in a 61-year-old woman with magnetic resonance imaging findings and confirmatory histological findings. We discuss and highlight the radiological features distinguishing a pancreatic lipoma from other fatty lesions of the pancreas and pancreatic liposarcoma and provide a brief review of the literature. PMID- 22229079 TI - Theranostic applications: Non-ionizing cellular and molecular imaging through innovative nanosystems for early diagnosis and therapy. AB - Modern medicine is expanding the possibilities of receiving "personalized" diagnosis and therapies, providing minimal invasiveness, technological solutions based on non-ionizing radiation, early detection of pathologies with the main objectives of being operator independent and with low cost to society. Our research activities aim to strongly contribute to these trends by improving the capabilities of current diagnostic imaging systems, which are of key importance in possibly providing both optimal diagnosis and therapies to patients. In medical diagnostics, cellular imaging aims to develop new methods and technologies for the detection of specific metabolic processes in living organisms, in order to accurately identify and discriminate normal from pathological tissues. In fact, most diseases have a "molecular basis" that detected through these new diagnostic methodologies can provide enormous benefits to medicine. Nowadays, this possibility is mainly related to the use of Positron Emission Tomography, with an exposure to ionizing radiation for patients and operators and with extremely high medical diagnostics costs. The future possible development of non-ionizing cellular imaging based on techniques such as Nuclear Magnetic Resonance or Ultrasound, would represent an important step towards modern and personalized therapies. During the last decade, the field of nanotechnology has made important progress and a wide range of organic and inorganic nanomaterials are now available with an incredible number of further combinations with other compounds for cellular targeting. The availability of these new advanced nanosystems allows new scenarios in diagnostic methodologies which are potentially capable of providing morphological and functional information together with metabolic and cellular indications. PMID- 22229081 TI - Long term effects of high fat or high carbohydrate diets on glucose tolerance in mice with heterozygous carnitine palmitoyltransferase-1a (CPT-1a) deficiency: Diet influences on CPT1a deficient mice. AB - BACKGROUND: Abnormal fatty acid metabolism is an important feature in the mechanisms of insulin resistance and beta-cell dysfunction. Carnitine palmitoyltransferase-1a (CPT-1a, liver isoform) plays a pivotal role in the regulation of mitochondrial fatty acid oxidation. We investigated the role of CPT 1a in the development of impaired glucose tolerance using a mouse model for CPT 1a deficiency when challenged by either a high-carbohydrate (HCD) or a high-fat diet (HFD) for a total duration of up to 46 weeks. METHODS: Insulin sensitivity and glucose tolerance were assessed in heterozygous CPT-1a deficient (CPT-1a+/-) male mice after being fed either a HCD or a HFD for durations of 28 weeks and 46 weeks. Both glucose and insulin tolerance tests were used to investigate beta cell function and insulin sensitivity. Differences in islet insulin content and hepatic steatosis were evaluated by morphological analysis. RESULTS: CPT-1a+/- mice were more insulin sensitive than CPT-1a+/+ mice when fed either HCD or HFD. The increased insulin sensitivity was associated with an increased expression of Cpt-1b (muscle isoform) in liver, as well as increased microvesicular hepatic steatosis compared to CPT-1a+/+ mice. CPT-1a+/- mice were more glucose tolerant than CPT-1a+/+ mice when fed the HCD, but there was no significant difference when fed HFD. Moreover, CPT-1a+/- mice fed HFD or HCD had fewer and smaller pancreatic islets than CPT-1a+/+ mice. CONCLUSIONS: CPT-1a deficiency preserved insulin sensitivity when challenged by long term feeding of either diet. Furthermore, CPT-1a deficient mice had distinct phenotypes dependent on the diet fed demonstrating that both diet and genetics collectively play a role in the development of impaired glucose tolerance. PMID- 22229082 TI - Renal transplantation in hepatitis C positive patients: a single centre experience. AB - Introduction. Hepatitis C virus (HCV) infection is an independent risk factor for renal transplantation (RTx). Immunosuppression minimization can render better quality of life to these patients. Methods. We analyzed 132 HCV-positive RTx patients (group A) transplanted under tolerance induction protocol (TIP) and compared them with 79 controls (group B) transplanted using standard triple drugs. TIP consisted of 1 donor-specific transfusion, peripheral blood stem cell infusion, portal infusion of bone marrow, and target-specific irradiation. Their immunosuppression was cyclosporin, 2 +/- 1 mg/kg BW/day + prednisone, 10 mg/day. Results. TIP had no side effects. Although unequal in size, the groups were well balanced. Group A patient survival at 1, 5, and 10 years was 92.4%, 70.4%, and 63.7%, respectively, versus 75.6%, 71.7%, and 55.7% in later, and graft survival was 92.9%, 81.5%, and 79.1% versus 91.7%, 75.7%, and 67.7%, respectively. Mean serum creatinine (mg/dL) at these time periods in former was 1.38, 1.72, and 1.87, versus 1.3, 1.75, and 2.1 in later. Altered liver functions were noted in 22% patients in former versus 31% in later. Group A had lesser rejection episodes. Conclusion. RTx using TIP in HCV-positive patients is a viable option with acceptable outcome. PMID- 22229080 TI - Development of regional chemotherapies: feasibility, safety and efficacy in clinical use and preclinical studies. AB - Conventional oral and intravenous chemotherapies permeate throughout the body, exposing healthy tissues to similar cytotoxic drug levels as tumors. This leads to significant dose-limiting toxicities that may prevent patients from receiving sufficient treatment to overcome cancers. Therefore, a number of locoregional drug-delivery strategies have been evaluated and implemented in preclinical studies, clinical trials and in practice, in the past decades to minimize systemic toxicities from chemotherapeutic agents and to improve treatment outcomes. Localized treatment is beneficial because many cancers, such as melanoma, peritoneal cancer and breast cancer, advance locally adjacent to the site of the primary tumors prior to their circulatory invasion. In this article, we will review the feasibility, safety and efficacy of multiple localized chemotherapies in clinical use and preclinical development. PMID- 22229083 TI - Psychosocial determinants of health behaviour change in an e-counseling intervention for hypertension. AB - We evaluated the influence of psychological stress and depression on motivation to adhere to recommended guidelines for exercise and diet. This study was conducted within a larger e-counseling trial. Subjects diagnosed with hypertension (n = 387, age = 44-74 years, 59% female) completed assessments at baseline and within 2 weeks after a 4-month intervention period. Outcomes included mean level of readiness to change diet and exercise and symptoms of depression and stress. Per protocol analysis defined e-counseling support as follows: >=8 e-mails = therapeutic dose, 1-7 e-mails = subtherapeutic dose, and 0 e-mails = Controls. Baseline adjusted symptoms of depression and stress were inversely correlated with improvement in exercise (partial R = -.14, P = .01, and partial R = -.17, P = .01, resp.) but not diet or e-counseling. Subjects who received a therapeutic dose of e-counseling demonstrated greater readiness for diet adherence versus Controls (P = .02). Similarly, subjects receiving a therapeutic level of e-counseling demonstrated significantly greater readiness for exercise adherence versus Controls (P = .04). In sum, e-counseling is associated with improved motivation to adhere to exercise and diet among patients with hypertension, independent of symptoms of psychological stress and depression. PMID- 22229084 TI - Hypertension and dementia in the elderly: the leisure world cohort study. AB - Recent studies have highlighted the deleterious role of cardiovascular risk factors, including hypertension, on the incidence of dementia. Although midlife hypertension is associated with later development of dementia, the role of late life hypertension remains unclear. We explored the association of hypertension and its treatment with incident dementia in 13978 older (median = 74 years) adults followed from 1981 to 2010 (median = 13 years) and calculated risk estimates using Cox regression analysis in two age groups (<75 and 75+ years) in men and women separately. Dementia status was determined from in-person evaluations, followup questionnaires, hospital data, and death certificates. In the older women, current users of blood pressure medication at baseline had a 26% increased risk of dementia (95% CI 1.06-1.51). In the younger men, those with untreated hypertension and those with past use of blood pressure medication use had about a 30% nonsignificant increased risk of dementia. High blood pressure and its treatment appear to have different effects in men and women and in the old and older. PMID- 22229085 TI - Ambulatory blood pressure monitoring in the elderly. AB - The incidence of hypertension is high in the elderly and is present in 2/3 of the patients older than 65 years. Prevalence can reach 90% in patients older than 80 years. The presence of isolated systolic hypertension (ISH) is characteristic of this population. However, the prevalence of hypertension by ambulatory blood pressure monitoring (ABPM) is not well known. In this study, we analyzed the special characteristics of hypertension in this population, giving special emphasis on ABPM readings. PMID- 22229086 TI - Compassion fatigue: an application of the concept to informal caregivers of family members with dementia. AB - Introduction. Compassion fatigue is a concept used with increasing frequency in the nursing literature. The objective of this paper is to identify common themes across the literature and to apply these themes, and an existing model of compassion fatigue, to informal caregivers for family members with dementia. Findings. Caregivers for family members with dementia may be at risk for developing compassion fatigue. The model of compassion fatigue provides an informative framework for understanding compassion fatigue in the informal caregiver population. Limitations of the model when applied to this population were identified as traumatic memories and the emotional relationship between parent and child, suggesting areas for future research. Conclusions. Research is needed to better understand the impact of compassion fatigue on informal caregivers through qualitative interviews, to identify informal caregivers at risk for compassion fatigue, and to provide an empirical basis for developing nursing interventions for caregivers experiencing compassion fatigue. PMID- 22229087 TI - Preferences for advance directives in Korea. AB - Background. The goal of advance directives is to help patients retain their dignity and autonomy by making their own decisions regarding end-stage medical treatment. The purpose of this study was to examine preferences of advance directives among general population in Korea. Method. A descriptive cross sectional survey was performed from October 2007 to June 2008 in Seoul, Korea. A total of 336 city-dwelling adults self-administered the questionnaire and returned it via mail. Data analyses were conducted using SPSS 17.0. Results. Subjects reported the need for healthcare providers' detailed explanations and recommendations regarding end-of-life care. When there is no hope of recovery and death is imminent, most subjects did not want to receive cardiopulmonary resuscitation nor an IV or tube feeding. However, most of the subjects wanted pain management care. Conclusions. The present study showed that many Korean people have an interest in advance directives. The results show that the autonomy and dignity of patient have increased in importance. To provide better end-of life care, there is a need to educate patients on the definition and intent of an advance directive. Additional proactive communication between patients and their caregivers should be educated to healthcare providers. PMID- 22229088 TI - Glutaminase immunoreactivity and enzyme activity is increased in the rat dorsal root ganglion following peripheral inflammation. AB - Following inflammation, primary sensory neurons in the dorsal root ganglion (DRG) alter the production of several proteins. Most DRG neurons are glutamatergic, using glutaminase as the enzyme for glutamate production, but little is known about glutaminase following inflammation. In the present study, adjuvant-induced arthritis (AIA) was produced in rats with complete Freund's adjuvant into the hindpaw. At 7 days of AIA, DRG were examined with glutaminase immunohistochemistry, Western blot immunoreactivity, and enzyme activity. Image analysis revealed that glutaminase was elevated most in small-sized neurons (21%) (P < 0.05). Western blot analysis revealed a 19% increase (P < 0.05) in total glutaminase and 21% in mitochondrial glutaminase (P < 0.05). Glutaminase enzyme activity was elevated 29% (P < 0.001) from 2.20 to 2.83 moles/kg/hr. Elevated glutaminase in primary sensory neurons could lead to increased glutamate production in spinal primary afferent terminals contributing to central sensitization or in the peripheral process contributing to peripheral sensitization. PMID- 22229089 TI - Interstitial lung disease in rheumatoid arthritis in the era of biologics. AB - Interstitial lung disease (ILD) represents a severe manifestation in connective tissue diseases (CTD), with an overall incidence of 15%, and it is still a challenge for clinicians evaluation and management. ILD is the most common manifestation of lung involvement in Rheumatoid Arthritis (RA), observed in up to 80% of biopsies, 50% of chest Computed Tomography (CT) and only 5% of chest radiographs. Histopatological patterns of ILD in RA may present with different patterns, such as: usual interstitial pneumonia, non specific interstitial pneumonia, desquamative interstitial pneumonia, organizing pneumonia, and eosinophilic infiltration. The incidence of ILD in RA patients is not only related to the disease itself, many drugs may be in fact associated with the development of pulmonary damage. Some reports suggest a causative role for TNFalpha inhibitors in RA-ILD development/worsening, anyway, no definitive statement can be drawn thus data are incomplete and affected by several variables. A tight control (pulmonary function tests and/or HRCT) is mandatory in patients with preexisting ILD, but it should be also performed in those presenting risk factors for ILD and mild respiratory symptoms. Biologic therapy should be interrupted, and, after excluding triggering infections, corticosteroids should be administered. PMID- 22229090 TI - Adsorption of urinary proteins on the conventionally used urine collection tubes: possible effects on urinary proteome analysis and prevention of the adsorption by polymer coating. AB - One possible factor determining recovery of trace amount of protein biomarker candidates during proteome analyses could be adsorption on urine tubes. This issue, however, has not been well addressed so far. Recently, a new technical device of surface coating by poly(2-methacryloyloxyethyl phosphorylcholine (MPC) co-n-butyl methacrylate (BMA)) (poly(MPC-co-BMA)) has been developed mainly to prevent the adsorption of plasma proteins. We assessed whether conventionally used urine tubes adsorb trace amount of urinary proteins and, if any, whether the surface coating by poly(MPC-co-BMA) can minimize the adsorption. Proteinuric urine samples were kept in poly(MPC-co-BMA)-coated and noncoated urine tubes for 15 min and possibly adsorbed proteins and/or peptides onto urine tubes were analyzed by SDS-PAGE, 2-DE, and the MALDI-TOF MS. It was found that a number of proteins and/or peptides adsorb on the conventionally used urine tubes and that surface coating by poly(MPC-co-BMA) can minimize the adsorption without any significant effects on routine urinalysis test results. Although it remains to be clarified to what extent the protein adsorption can modify the results of urinary proteome analyses, one has to consider this possible adsorption of urinary proteins when searching for trace amounts of protein biomarkers in urine. PMID- 22229091 TI - Lung cancer proteomics: recent advances in biomarker discovery. AB - Lung cancer is the most common cause of cancer death in both men and women in Western countries, with a 5-year survival rate of 15%, which is among the lowest of all cancers. The high mortality from lung cancer is due not only to the late stage diagnosis but also to the lack of effective treatments even for patients diagnosed with stage I lung cancer. Therefore, there is an urgent need to identify new markers for early diagnosis and prognosis that could serve to open novel therapeutic avenues. Proteomics can represent an important tool for the identification of biomarkers and therapeutic targets for lung cancer since DNA based biomarkers did not prove to have adequate sensitivity, specificity, and reproducibility. In this paper we will describe studies focused on the identification of new diagnostic, prognostic, and predictive markers for lung cancer, using proteomics technologies. PMID- 22229092 TI - Priming DNA replication from triple helix oligonucleotides: possible threestranded DNA in DNA polymerases. AB - Triplex associate with a duplex DNA presenting the same polypurine or polypyrimidine-rich sequence in an antiparallel orientation. So far, triplex forming oligonucleotides (TFOs) are known to inhibit transcription, replication, and to induce mutations. A new property of TFO is reviewed here upon analysis of DNA breakpoint yielding DNA rearrangements; the synthesized sequence of the first direct repeat displays a skewed polypurine- rich sequence. This synthesized sequence can bind the second homologous duplex sequence through the formation of a triple helix, which is able to prime further DNA replication. In these case, the d(G)-rich Triple Helix Primers (THP) bind the homologous strand in a parallel manner, possibly via a RecA-like mechanism. This novel property is shared by all tested DNA polymerases: phage, retrovirus, bacteria, and human. These features may account for illegitimate initiation of replication upon single-strand breakage and annealing to a homologous sequence where priming may occur. Our experiments suggest that DNA polymerases can bind three instead of two polynucleotide strands in their catalytic centre. PMID- 22229093 TI - How does the canadian general public rate moderate Alzheimer's disease? AB - Objectives. The objectives of this study were to elicit health utility scores for moderate Alzheimer's disease (AD) using members of the general public. Methods. Five-hundred Canadians were chosen randomly to participate in a telephone interview. The EQ-5D was administered to estimate the health utility score for respondents' current health status (i.e., no AD) and for a hypothetical moderate AD health state. Regression analyses were conducted to explain the perceived utility decrement associated with AD. Results. The mean age of the respondents was 51 years, 60% were female, and 42% knew someone with AD. Respondents' mean EQ 5D scores for their current health status and a hypothetical moderate AD were 0.873 (SD: 0.138) and 0.638 (SD: 0.194), respectively (P < 0.001). Age, gender, and education were significant factors explaining this decrement in utility. Conclusion. Members of the general public may serve as an alternative to patients and caregivers in the elicitation of health-related quality of life in AD. PMID- 22229094 TI - Novel insights into the role of caveolin-2 in cell- and tissue-specific signaling and function. AB - Caveolin-2 is one of the major protein components of cholesterol- and glycosphingolipid-rich flask-shaped invaginations of plasma membrane caveolae. A new body of evidence suggests that caveolin-2 plays an important, and often more direct, role than caveolin-1 in regulating signaling and function in a cell- and tissue type-specific manner. The purpose of this paper is to primarily focus on discussing how these recent discoveries may help better understand the specific contribution of caveolin-2 to lipid raft- and caveolae-regulated cell/tissue specific signaling and functions. PMID- 22229095 TI - Folic acid and birth defects: a case study (Iran). AB - The aim of this study was to evaluate the impact of folic acid use in pregnancy for the reduction of neural tube defects (NTDs) in the northwest region of Iran. We studied 243 women with pregnancies complicated by some forms of birth defect(s). These patients were identified by medical diagnostic tests as having a fetus with some types of congenital anomalies. The prevalence of NTDs among pregnant women who were referred for therapeutic termination of pregnancy was 24.7 percent. Consumption of folic acid prevented NTDs by 79 percent (Odds Ratio = 0.21, CI 95%: 0.12-0.40) and 94 percent (Odds Ratio = 0.06, CI 95%: 0.03-0.15) compared to pregnancies complicated by other anomalies and normal pregnancies, respectively. Hydrops fetalis, hydrocephaly, Down syndrome, and limb anomalies did not have any significant association with the folic acid use. Along with the advice for the consumption of folic acid for pregnant women, they should be offered prenatal screening or diagnostic tests to identify fetal abnormalities for possible termination of pregnancy. PMID- 22229096 TI - Factors implicated in radiation therapy failure and radiosensitization of prostate cancer. AB - Tissue markers may be helpful in enhancing prediction of radiation therapy (RT) failure of prostate cancer (PCa). Among the various biomarkers tested in Phase III randomized trials conducted by the Radiation Therapy Oncology Group, p16, Ki 67, MDM2, COX-2, and PKA yielded the most robust data in predicting RT failure. Other pathways involved in RT failure are also implicated in the development of castration-resistant PCa, including the hypersensitive androgen receptor, EGFR, VEGF-R, and PI3K/Akt. Most of them are detectable in PCa tissue even at the time of initial diagnosis. Emerging evidence suggests that RT failure of PCa results from a multifactorial and heterogeneous disease process. A number of tissue markers are available to identify patients at high risk to fail RT. Some of these markers have the promise to be targeted by drugs currently available to enhance the efficacy of RT and delay disease progression. PMID- 22229097 TI - Prevention and management of bacterial infections in cirrhosis. AB - Patients with cirrhosis of liver are at risk of developing serious bacterial infections due to altered immune defenses. Despite the widespread use of broad spectrum antibiotics, bacterial infection is responsible for up to a quarter of the deaths of patients with liver disease. Cirrhotic patients with gastrointestinal bleed have a considerably higher incidence of bacterial infections particularly spontaneous bacterial peritonitis. High index of suspicion is required to identify infections at an early stage in the absence of classical signs and symptoms. Energetic use of antibacterial treatment and supportive care has decreased the morbidity and mortality over the years; however, use of antibiotics has to be judicious, as their indiscriminate use can lead to antibiotic resistance with potentially disastrous consequences. Preventive strategies are still in evolution and involve use of antibiotic prophylaxis in patients with gastrointestinal bleeding and spontaneous bacterial infections and selective decontamination of the gut and oropharynx. PMID- 22229099 TI - Factors Affecting Intention among Students to Be Vaccinated against A/H1N1 Influenza: A Health Belief Model Approach. AB - The outbreak of A/H1N1 influenza (henceforth, swine flu) in 2009 was characterized mainly by morbidity rates among young people. This study examined the factors affecting the intention to be vaccinated against the swine flu among students in Israel. Questionnaires were distributed in December 2009 among 387 students at higher-education institutions. The research questionnaire included sociodemographic characteristics and Health Belief Model principles. The results show that the factors positively affecting the intention to take the swine flu vaccine were past experience with seasonal flu shot and three HBM categories: higher levels of perceived susceptibility for catching the illness, perceived seriousness of illness, and lower levels of barriers. We conclude that offering the vaccine at workplaces may raise the intention to take the vaccine among young people in Israel. PMID- 22229098 TI - Role of adaptive immunity in alcoholic liver disease. AB - Stimulation of innate immunity is increasingly recognized to play an important role in the pathogenesis of alcoholic liver disease (ALD), while the contribution of adaptive immunity has received less attention. Clinical and experimental data show the involvement of Th-1 and Th-17 T-lymphocytes in alcoholic hepatitis. Nonetheless, the mechanisms by which alcohol triggers adaptive immunity are still incompletely characterized. Patients with advanced ALD have circulating IgG and T lymphocytes recognizing epitopes derived from protein modification by hydroxyethyl free radicals and end products of lipid-peroxidation. High titers of IgG against lipid peroxidation-derived antigens are associated with an increased hepatic production of proinflammatory cytokines/chemokines. Moreover, the same antigens favor the breaking of self-tolerance towards liver constituents. In particular, autoantibodies against cytochrome P4502E1 (CYP2E1) are evident in a subset of ALD patients. Altogether these results suggest that allo- and autoimmune reactions triggered by oxidative stress might contribute to hepatic inflammation during the progression of ALD. PMID- 22229100 TI - Endometrial cancer patients: a cohort previous to changes in tumour behaviour and treatment strategies. AB - Nowadays, the incidence of endometrial cancer is rising, especially of high-grade endometrial tumours. Recently, the FIGO classification of endometrial cancer has changed worldwide. Besides that, treatment strategies are changing. The purpose of this study was to analyse the adherence to the national guidelines of cancer treatment and to analyse patterns of disease relapse and survival. We focused on a group of patients (n = 191) with endometrial cancer, in a time period in which new treatment strategies are not yet completely implemented. Because of multiple upcoming changes in patient characteristics, tumour classification, as well as treatment regimens, a more heterogeneous cohort of patients diagnosed with endometrial cancer will appear. From now on, all those changes will have their effects on the followup of conventional endometrial cancer treatment. In our opinion, it is, therefore, valuable to have the current, more homogenous, cohort clearly described. PMID- 22229102 TI - Effects of the chernobyl disaster on thyroid cancer incidence in Turkey after 22 years. AB - Background. Separate studies involving people who survived atomic bombs have shown that the risk for cancer remains high after 40 years, compared with the risk in the general population. An elevated risk may also remain in regions of Turkey near the Chernobyl disaster. Patients and Methods. A multidisciplinary study conducted in 2008, 22 years after the Chernobyl disaster, examined the thyroid cancer incidence in Rize, a province of Turkey located on the shore of the middle Black Sea. Approximately 100,000 people were screened, and a fine needle aspiration biopsy was performed in 89 patients. Results. Based on postoperative histopathological examinations, thyroid cancer was diagnosed in six of the 100,000 people screened. Conclusion. Given a thyroid cancer frequency of approximately 8 in 100,000 in the Turkish population, according to the Turkish Cancer Research Association, the rate in Rize reflects no increase in the thyroid cancer incidence 22 years after the Chernobyl disaster. PMID- 22229101 TI - Review of breast conservation therapy: then and now. AB - Breast conservation therapy (BCT), which is the marriage of breast conserving surgery and radiation therapy to the breast, has revolutionized the treatment of breast cancer over the last few decades. Surgical direction had seen a heightened interest in the performance of cosmetically superior partial and segmental resections in breast conservation as well as increased demand by patients for breast preservation. The broadening of approaches to delivery of breast irradiation from whole breast to accelerated partial breast has allowed more patients to opt for breast conservation and allowed for what appears to be comparable measurable outcomes in emerging data. As well, the addition of state of-the-art chemotherapeutic and hormonal therapies has allowed improved outcomes of patients from both local regional recurrence and overall survival standpoints. This paper will provide an overview of BCT and review some of the newest developments in optimizing this therapy for patients with breast cancer from a surgical-, medical-, and radiation-oncology standpoint. PMID- 22229103 TI - Oromandibular reconstruction: the history, operative options and strategies, and our experience. AB - Oromandibular reconstruction resulting from resection of benign tumor, malignant cancer, osteomyelitic or osteoradionecrotic mandible remains a challenge for plastic surgeons today. At present, fibula osteocutaneous flap is the perhaps most commonly used technique for oromandibular reconstruction because of its potential for contouring, immediate dental implant placement, and favorable donor site morbidity. In this study, we review the history of oromandibular reconstruction, summarize the characteristics of different osteocutaneous flaps, offer surgical options of different osteocutaneous flaps, and provide reconstructive strategies for different locations of mandibular defects. Furthermore, we give a detailed description of various modifications in oromandibular reconstruction: (1) the myoosseous flap for lateral segmental defect repair may reduce donor site complication; (2) to improve the function of oral commissure in patients with obscure recipient vessels, we modify the fibula osteocutaneous flap with anterolateral thigh flap and combine the tensor fascia lata using one set of recipient vessel for composite oromandibular reconstruction; (3) to decrease the likelihood of neck infection and improve aesthetic result, we add the segmental soleus muscle to the fibula osteocutaneous flap to obliterate and augment submandibular dead space. Lastly, dental rehabilitation considerations associated with mandibular reconstruction have been given to help assist in surgical treatment planning. PMID- 22229104 TI - Congenital diaphragmatic hernia: review of current concept in surgical management. AB - CONGENITAL DIAPHRAGMATIC HERNIAS (CDHS) OCCUR MAINLY IN TWO LOCATIONS: the foramen of Morgagni and the more common type involving the foramen of Bochdalek. Hiatal hernia and paraesophageal hernia have also been described as other forms of CDH. Pulmonary hypertension and pulmonary hypoplasia have been recognized as the two most important factors in the pathophysiology of congenital diaphragmatic hernia. Advances in surgical management include delayed surgical approach that enables preoperative stabilization, introduction of fetal intervention due to improved prenatal diagnosis, the introduction of minimal invasive surgery, in addition to the standard open repair, and the use of improved prosthetic devices for closure. PMID- 22229106 TI - Cell-type-dependent thyroid hormone effects on glioma tumor cell lines. AB - Purpose. The present study investigated the potential effects of long-term T3 treatment on glioma tumor cell lines. Thyroid hormone action on cell growth, differentiation and survival during development may be of therapeutic relevance Methods and Results 1321N1 cell line, an astrocytoma grade II, and U87MG, a glioblastoma grade IV, were exposed for 2 and 4 days in medium deprived of T3 and in medium containing 1 nM T3. T3 promoted re-differentiation in both cell lines. However, T3 increased cell proliferation in 1321N1 (2 days) which declined thereafter (4 days) while in U87MG resulted in suppression of cell proliferation. At the molecular level, a 2.9 fold increase in the expression of TRalpha1 receptor was observed in U87MG versus 1321N1, P < 0.05. TRbeta1 receptor was undetectable. These changes corresponded to a distinct pattern of T3-induced kinase signaling activation; T3 had no effect on ERK activation in both cell lines but significantly increased phospho-Akt levels in 1321N1. Conclusion. In conclusion, T3 can re-differentiate glioma tumor cells, whereas its effect on cell proliferation appears to be dependent on the type of tumor cell line with aggressive tumors being more sensitive to T3. TRalpha1 receptor may, at least in part, be implicated in this response. PMID- 22229105 TI - Th17 response and inflammatory autoimmune diseases. AB - The proinflammatory activity of T helper 17 (Th17) cells can be beneficial to the host during infection. However, uncontrolled or inappropriate Th17 activation has been linked to several autoimmune and autoinflammatory pathologies. Indeed, preclinical and clinical data show that Th17 cells are associated with several autoimmune diseases such as arthritis, multiple sclerosis, psoriasis, and lupus. Furthermore, targeting the interleukin-17 (IL-17) pathway has attenuated disease severity in preclinical models of autoimmune diseases. Interestingly, a recent report brings to light a potential role for Th17 cells in the autoinflammatory disorder adult-onset Still's disease (AOSD). Whether Th17 cells are the cause or are directly involved in AOSD remains to be shown. In this paper, we discuss the biology of Th17 cells, their role in autoimmune disease development, and in AOSD in particular, as well as the growing interest of the pharmaceutical industry in their use as therapeutic targets. PMID- 22229107 TI - Long-Term Outcomes of the Total or Supracervical Hysterectomy (TOSH) Trial. AB - BACKGROUND: Participants in the multi-center, randomized Total or Supracervical Hysterectomy (TOSH) trial showed within-group improvement in pelvic floor symptoms 2 years post-surgery and no differences between supracervical (SCH) versus total hysterectomy (TAH). This study describes longer term outcomes from the largest recruiting site. STUDY DESIGN: Questionnaires addressing pelvic symptoms, sexual function, and health-related quality of life were administered. Linear models and McNemar's test were utilized. RESULTS: Thirty-seven participants (69%) responded (19 TAH, 18 SCH); mean follow up was 9.1+/-0.7 years. No between-group differences emerged in urinary incontinence, voiding dysfunction, pelvic prolapse symptoms and overall health related quality of life (HRQOL). Within-group analysis showed significant improvement in the ability to have and enjoy sex (P = 0.002) and in the SF-36 physical component summary score (P = 0.03) among women randomized to TAH. CONCLUSION: 9 years after surgery, TOSH participants continue to experience improvement and show no major between group differences in lower urinary tract or pelvic floor symptoms conferring no major benefit of SCH over TAH. PMID- 22229108 TI - Design Optimization of Concentric Tube Robots Based on Task and Anatomical Constraints. AB - Concentric tube robots are a novel continuum robot technology that is well suited to minimally invasive surgeries inside small body cavities such as the heart. These robots are constructed of concentrically combined pre-curved elastic tubes to form 3D curves. Each telescopic section of the robot is either of fixed or variable curvature. One advantage of this approach is that the component tube curvatures, lengths and stiffnesses can easily be fabricated to be procedure- and patient-specific. This paper proposes an optimization framework for solving the robot design problem. Given a 3D description of the constraining anatomy, the number of fixed and variable curvature robot sections and a tip workspace description, the algorithm solves for the robot design that possesses the desired workspace, remains inside the anatomical constraints and minimizes the curvature and length of all sections. The approach is illustrated in the context of beating heart closure of atrial septal defects. PMID- 22229109 TI - Metal MEMS Tools for Beating-heart Tissue Approximation. AB - Achieving superior outcomes through the use of robots in medical applications requires an integrated approach to the design of the robot, tooling and the procedure itself. In this paper, this approach is applied to develop a robotic technique for closing abnormal communication between the atria of the heart. The goal is to achieve the efficacy of surgical closure as performed on a stopped, open heart with the reduced risk and trauma of a beating-heart catheter-based procedure. In the proposed approach, a concentric tube robot is used to percutaneously access the right atrium and deploy a tissue approximation device. The device is constructed using a metal MEMS fabrication process and is designed to both fit the manipulation capabilities of the robot as well as to reproduce the beneficial features of surgical closure by suture. Experimental results demonstrate device efficacy through manual in-vivo deployment and bench-top robotic deployment. PMID- 22229110 TI - Detection of Curved Robots using 3D Ultrasound. AB - Three-dimensional ultrasound can be an effective imaging modality for image guided interventions since it enables visualization of both the instruments and the tissue. For robotic applications, its realtime frame rates create the potential for image-based instrument tracking and servoing. These capabilities can enable improved instrument visualization, compensation for tissue motion as well as surgical task automation. Continuum robots, whose shape comprises a smooth curve along their length, are well suited for minimally invasive procedures. Existing techniques for ultrasound tracking, however, are limited to straight, laparoscopic-type instruments and thus are not applicable to continuum robot tracking. Toward the goal of developing tracking algorithms for continuum robots, this paper presents a method for detecting a robot comprised of a single constant curvature in a 3D ultrasound volume. Computational efficiency is achieved by decomposing the six-dimensional circle estimation problem into two sequential three-dimensional estimation problems. Simulation and experiment are used to evaluate the proposed method. PMID- 22229111 TI - State Estimation and Feedforward Tremor Suppression for a Handheld Micromanipulator with a Kalman Filter. AB - Active compensation of physiological tremor for handheld micromanipulators depends on fast control and actuation responses. Because of real-world latencies, real-time compensation is usually not completely effective at eliminating unwanted hand motion. By modeling tremor, more effective cancellation is possible by anticipating future hand motion. We propose a feedforward control strategy that utilizes tremor velocity from a state-estimating Kalman filter. We demonstrate that estimating hand motion in a feedforward controller overcomes real-world latencies in micromanipulator actuation. In hold-still tasks with a fully handheld micromanipulator, the proposed feedforward approach improves tremor rejection by over 50%. PMID- 22229112 TI - Identifying Persons at Highest Risk of Melanoma Using Self-Assessed Risk Factors. AB - OBJECTIVE: To develop a self-assessed melanoma risk score to identify high-risk persons for screening METHODS: We used data from a 1997 melanoma case-control study from Washington State, USA, where 386 cases with invasive cutaneous melanoma and 727 controls were interviewed by telephone. A logistic regression prediction model was developed on 75% of the data and validated in the remaining 25% by calculating the area under the receiver operating characteristic curve (AUC), a measure of predictive accuracy from 0.5-1 (higher scores indicating better prediction). A risk score was calculated for each individual, and sensitivities for various risk cutoffs were calculated. RESULTS: The final model included sex, age, hair color, density of freckles, number of severe sunburns in childhood and adolescence, number of raised moles on the arms, and history of non melanoma skin cancer. The area under the receiver operating characteristic curve(AUC) was 0.70 (95% CI: 0.64, 0.77). The top 15% risk group included 50% of melanomas (sensitivity 50%). CONCLUSIONS: This self-assessed score could be used as part of a comprehensive melanoma screening and public education program to identify high-risk individuals in the general population. This study suggests it may be possible to capture a large proportion of melanomas by screening a small high-risk group. Further study is needed to determine the costs, feasibility, and risks of this approach. PMID- 22229113 TI - Pathogenesis of A Clinical Ocular Strain of Streptococcus pneumoniae and the Interaction of Pneumolysin with Corneal Cells. AB - Streptococcus pneumoniae is an important cause of bacterial keratitis, an infectious disease of the cornea. This study aimed to determine the importance of pneumolysin (PLY), a pneumococcal virulence factor, in keratitis using a clinical keratitis isolate (K1263) and its isogenic mutant deficient in PLY (K1263DeltaPLY) and determine the effect of these strains on primary rabbit corneal epithelial (RCE) cells. Each strain was injected into the corneal stromas of rabbits, clinical examinations were performed, and the recovered bacterial loads were determined. Bacterial extracts were exposed to RCE cells, and morphology and viability were assessed. The mutant strain deficient in PLY, K1263DeltaPLY, caused significantly lower ocular disease scores than the parent strain (K1263), although a higher bacterial load was recovered from corneas infected with the mutant strain. Histological examination showed increased inflammatory cells in the anterior chamber and increased edema in eyes infected with the parent strain. RCE cells exposed to the parent strain had significantly decreased cell viability and showed increased evidence of cellular damage. This study confirms that in a strain that can cause clinical keratitis, PLY is a significant cause of the damage associated with pneumococcal keratitis. It also shows for the first time that the results from an in vitro model using RCE cells correlates with in vivo results thereby establishing a less invasive way to study the mechanisms of pneumococcal keratitis. PMID- 22229114 TI - Common Variants in 6 Lipid-Related Genes Discovered by High-Resolution DNA Melting Analysis and Their Association with Plasma Lipids. AB - BACKGROUND: Total cholesterol was among the earliest identified risk factors for coronary heart disease (CHD). We sought to identify genetic variants in six genes associated with lipid metabolism and estimate their respective contribution to risk for CHD. METHODS: For 6 lipid-associated genes (LCAT, CETP, LIPC, LPL, SCARB1, and ApoF) we scanned exons, 5' and 3' untranslated regions, and donor and acceptor splice sites for variants using Hi-Res Melting(r) curve analysis (HRMCA) with confirmation by cycle sequencing. Healthy subjects were used for SNP discovery (n=64), haplotype determination/tagging SNP discovery (n=339), and lipid association testing (n=786). RESULTS: In 17,840 bases of interrogated sequence, 90 variant SNPs were identified; 19 (21.1%) previously unreported. Thirty-four variants (37.8%) were exonic(16 non-synonymous), 28 (31.1%) in intron exon boundaries, and 28 (31.1%) in the 5' and 3' untranslated regions. Compared to cycle sequencing, HRMCA had sensitivity of 99.4% and specificity of 97.7%. Tagging SNPs (n=38) explained >90% of the variation in the 6 genes and identified linkage disequilibrium (LD) groups. Significant beneficial lipid profiles were observed for CETP LD group 2, LIPC LD groups 1 and 7, and SCARB1 LD groups 1, 3 and 4. Risk profiles worsened for CETP LD group 3, LPL LD group 4. CONCLUSIONS: These findings demonstrate the feasibility, sensitivity, and specificity of HRMCA for SNP discovery. Variants identified in these genes may be used to predict lipid-associated risk and reclassification of clinical CHD risk. PMID- 22229115 TI - Parenthood, Life Course Expectations, and Mental Health. AB - Although past research indicates that early and premarital childbearing negatively affect mental health, little is known about the role of individual expectations in shaping these associations. Using data from the National Longitudinal Survey of Youth 1979, we consider how individual expectations, measured prior to the entry into parenthood, shape mental health outcomes associated with premarital childbearing and birth timing, and consider gender and race/ethnic variations. Results indicate that expecting children before marriage ameliorates the negative mental health consequences of premarital first births and that subsequently deviating from expected birth timing, either early or late, results in increased distress at all birth ages. In both cases, however, the degree and manner in which expectations matter differ by gender and race/ethnicity. Results indicate that expectations for premarital childbearing matter only for African-Americans' mental health and although later than expected births are associated with decreased mental health for all groups, earlier than expected births are only associated with decreased mental health for women, Hispanics, and non-Hispanic whites. PMID- 22229116 TI - Neuropathological alterations in Alzheimer disease. AB - The neuropathological hallmarks of Alzheimer disease (AD) include "positive" lesions such as amyloid plaques and cerebral amyloid angiopathy, neurofibrillary tangles, and glial responses, and "negative" lesions such as neuronal and synaptic loss. Despite their inherently cross-sectional nature, postmortem studies have enabled the staging of the progression of both amyloid and tangle pathologies, and, consequently, the development of diagnostic criteria that are now used worldwide. In addition, clinicopathological correlation studies have been crucial to generate hypotheses about the pathophysiology of the disease, by establishing that there is a continuum between "normal" aging and AD dementia, and that the amyloid plaque build-up occurs primarily before the onset of cognitive deficits, while neurofibrillary tangles, neuron loss, and particularly synaptic loss, parallel the progression of cognitive decline. Importantly, these cross-sectional neuropathological data have been largely validated by longitudinal in vivo studies using modern imaging biomarkers such as amyloid PET and volumetric MRI. PMID- 22229117 TI - Developing therapeutic approaches to tau, selected kinases, and related neuronal protein targets. AB - A hallmark of the Alzheimer disease (AD) brain is the presence of inclusions within neurons that are comprised of fibrils formed from the microtubule stabilizing protein tau. The formation of misfolded multimeric tau species is believed to contribute to the progressive neuron loss and cognitive impairments of AD. Moreover, mutations in tau have been shown to cause a form of frontotemporal lobar degeneration in which tau neuronal inclusions observed in the brain are similar to those seen in AD. Here we review the more compelling strategies that are designed to reduce the contribution of misfolded tau to AD neuropathology, including those directed at correcting a possible loss of tau function resulting from sequestration of cellular tau and to minimizing possible gain-of-function toxicities caused by multimeric tau species. Finally, we discuss the challenges and potential benefits of tau-directed drug discovery programs. PMID- 22229118 TI - Infantile hemangioma-mechanism(s) of drug action on a vascular tumor. AB - Infantile hemangioma (IH), a benign vascular tumor, is the most common tumor of infancy, with an incidence of 5%-10% at the end of the first year. The tumor displays a distinctive life cycle consisting of a proliferating phase, occurring in the first months of life, followed by an involuting phase. Thus, IH represents a unique model of postnatal vasculogenesis, angiogenesis, and vessel regression. Traditionally, corticosteroids were the drug of choice when treatment of IH was indicated. In recent years, beta-blockers, most specifically propranolol, have serendipitously been shown to be an effective pharmacological treatment. This article will focus on the mechanism of action of these two drugs, the old and the new treatments, in slowing the growth and accelerating involution of IH. PMID- 22229119 TI - alphaV integrins in angiogenesis and cancer. AB - During angiogenesis, alphav integrins are overexpressed on the endothelial cell surface to facilitate the growth and survival of newly forming vessels. Accordingly, blocking alphav integrin function by disrupting ligand binding can produce an antiangiogenic effect. Although the integrin ectodomain regulates ligand binding specificity, the short cytoplasmic tail facilitates intracellular signaling pathways through the recruitment and activation of specific kinases and signaling intermediates. This in turn controls endothelial cell adhesion, morphology, migration, invasion, proliferation, and survival. These same integrin mediated signaling pathways are exploited in cancer to promote the invasiveness and survival of tumor cells and to manipulate the host microenvironment to provide ample blood vessel and stromal resources to support tumor growth and metastatic spread. Because expression of alphav integrins on distinct cell types contributes to cancer growth, alphav integrin antagonists have the potential to disrupt multiple aspects of disease progression. PMID- 22229120 TI - Origins of HIV and the AIDS pandemic. AB - Acquired immunodeficiency syndrome (AIDS) of humans is caused by two lentiviruses, human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2). Here, we describe the origins and evolution of these viruses, and the circumstances that led to the AIDS pandemic. Both HIVs are the result of multiple cross-species transmissions of simian immunodeficiency viruses (SIVs) naturally infecting African primates. Most of these transfers resulted in viruses that spread in humans to only a limited extent. However, one transmission event, involving SIVcpz from chimpanzees in southeastern Cameroon, gave rise to HIV-1 group M-the principal cause of the AIDS pandemic. We discuss how host restriction factors have shaped the emergence of new SIV zoonoses by imposing adaptive hurdles to cross-species transmission and/or secondary spread. We also show that AIDS has likely afflicted chimpanzees long before the emergence of HIV. Tracing the genetic changes that occurred as SIVs crossed from monkeys to apes and from apes to humans provides a new framework to examine the requirements of successful host switches and to gauge future zoonotic risk. PMID- 22229121 TI - HIV latency. AB - HIV-1 can establish a state of latent infection at the level of individual T cells. Latently infected cells are rare in vivo and appear to arise when activated CD4(+) T cells, the major targets cells for HIV-1, become infected and survive long enough to revert back to a resting memory state, which is nonpermissive for viral gene expression. Because latent virus resides in memory T cells, it persists indefinitely even in patients on potent antiretroviral therapy. This latent reservoir is recognized as a major barrier to curing HIV-1 infection. The molecular mechanisms of latency are complex and include the absence in resting CD4(+) T cells of nuclear forms of key host transcription factors (e.g., NFkappaB and NFAT), the absence of Tat and associated host factors that promote efficient transcriptional elongation, epigenetic changes inhibiting HIV-1 gene expression, and transcriptional interference. The presence of a latent reservoir for HIV-1 helps explain the presence of very low levels of viremia in patients on antiretroviral therapy. These viruses are released from latently infected cells that have become activated and perhaps from other stable reservoirs but are blocked from additional rounds of replication by the drugs. Several approaches are under exploration for reactivating latent virus with the hope that this will allow elimination of the latent reservoir. PMID- 22229123 TI - Rational design of vaccines to elicit broadly neutralizing antibodies to HIV-1. AB - The development of a highly effective AIDS vaccine will likely depend on success in designing immunogens that elicit broadly neutralizing antibodies to naturally circulating strains of HIV-1. Although the antibodies induced after natural infection with HIV-1 are often directed to strain-specific or nonneutralizing determinants, it is now evident that 10%-25% of HIV-infected individuals generate neutralizing antibody responses of considerable breadth. In the past, only four broadly neutralizing monoclonal antibodies had been defined, but more than a dozen monoclonal antibodies of substantial breadth have more recently been isolated. An understanding of their recognition sites, the structural basis of their interaction with the HIV Env, and their development pathways provides new opportunities to design vaccine candidates that will elicit broadly protective antibodies against this virus. PMID- 22229122 TI - Vaccine design for CD8 T lymphocyte responses. AB - Vaccines are arguably the most powerful medical intervention in the fight against infectious diseases. The enormity of the global human immunodeficiency virus type 1 (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic makes the development of an AIDS vaccine a scientific and humanitarian priority. Research on vaccines that induce T-cell immunity has dominated much of the recent development effort, mostly because of disappointing efforts to induce neutralizing antibodies through vaccination. Whereas T cells are known to limit HIV and other virus infections after infection, their role in protection against initial infection is much less clear. In this article, we will review the rationale behind a T-cell-based vaccine approach, provide an overview of the methods and platforms that are being applied, and discuss the impact of recent vaccine trial results on the future direction of T-cell vaccine research. PMID- 22229124 TI - The history of Parkinson's disease: early clinical descriptions and neurological therapies. AB - Although components of possible Parkinson's disease can be found in very early documents, the first clear medical description was written in 1817 by James Parkinson. In the mid-1800s, Jean-Martin Charcot was particularly influential in refining and expanding this early description and in disseminating information internationally about Parkinson's disease. He separated Parkinson's disease from multiple sclerosis and other disorders characterized by tremor, and he recognized cases that later would likely be classified among the Parkinsonism-plus syndromes. Early treatments of Parkinson's disease were based on empirical observation, and anticholinergic drugs were used as early as the nineteenth century. The discovery of dopaminergic deficits in Parkinson's disease and the synthetic pathway of dopamine led to the first human trials of levodopa. Further historically important anatomical, biochemical, and physiological studies identified additional pharmacological and neurosurgical targets for Parkinson's disease and allow modern clinicians to offer an array of therapies aimed at improving function in this still incurable disease. PMID- 22229126 TI - Target identification using drug affinity responsive target stability (DARTS). AB - Drug Affinity Responsive Target Stability is a general methodology for identifying and studying protein-ligand interactions. The technique is based on the principle that when a small molecule compound binds to a protein, the interaction stabilizes the target protein's structure such that it becomes protease resistant. DARTS is particularly useful for the initial identification of the protein targets of small molecules, but can also be used to validate potential protein-ligand interactions predicted or identified by other means and to estimate the affinity of interactions. The approach is simple and advantageous because it can be performed using crude cell lysates and other complex protein mixtures (without requiring purified proteins), and uses native, unmodified small molecules. The protocols provided in this article describe the general approach for performing DARTS experiments, which can be easily modified and scaled to fit the criteria and purpose of any individual project. PMID- 22229127 TI - Blepharospasm plus Cervical Dystonia with Predominant Anterocollis: A Distinctive Subphenotype of Segmental Craniocervical Dystonia? AB - BACKGROUND: Dystonia of the eyelids often spreads to affect other muscles in the craniocervical region. Certain blepharospasm-plus subphenotypes may be clinically unique. METHODS: Seven subjects with the subphenotype of late-onset blepharospasm with apraxia of eyelid opening and cervical dystonia with predominant anterocollis were identified from a database of over 1800 patients with primary dystonia. RESULTS: Blepharospasm was the first affected site in 6/7 subjects, followed by spread of the disease to the cervical muscles. Although four patients also had other forms of dystonia (laryngeal, lower face), none showed spread outside the craniocervical region. A family history of dystonia was present in 4/7. No mutations were identified in THAP1 or TOR1A. Overall, blepharospasm was difficult to treat, typically requiring both myectomy and substantial doses of botulinum toxin into the pretarsal orbicularis oculi muscles. In one subject, anterocollis markedly improved after deep brain stimulation. DISCUSSION: Delineation and characterization of craniocervical dystonia subphenotypes may serve to guide genetic and therapeutic studies, in addition to clinical interventions. The blepharospasm with apraxia of eyelid opening and anterocollis subphenotype can be therapeutically challenging. PMID- 22229128 TI - Positron Emission Tomography and Near-Infrared Fluorescence Imaging of Vascular Endothelial Growth Factor with Dual-Labeled Bevacizumab. AB - The pivotal role of vascular endothelial growth factor (VEGF) in cancer is underscored by the approval of bevacizumab (Bev, a humanized anti-VEGF monoclonal antibody) for first line treatment of cancer patients. The aim of this study was to develop a dual-labeled Bev for both positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging of VEGF. Bev was conjugated to a NIRF dye (i.e. 800CW) and 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7 triacetic acid (p-SCN-Bn-NOTA) before (64)Cu-labeling. Flow cytometry analysis of U87MG human glioblastoma cells revealed no difference in VEGF binding affinity/specificity between Bev and NOTA-Bev-800CW. (64)Cu-labeling of NOTA-Bev 800CW was achieved with high yield. Serial PET imaging of U87MG tumor-bearing female nude mice revealed that tumor uptake of (64)Cu-NOTA-Bev-800CW was 4.6 +/- 0.7, 16.3 +/- 1.6, 18.1 +/- 1.4 and 20.7 +/- 3.7 %ID/g at 4, 24, 48 and 72 h post injection respectively (n = 4), corroborated by in vivo/ex vivo NIRF imaging and biodistribution studies. Tumor uptake as measured by ex vivo NIRF imaging had a good linear correlation with the %ID/g values obtained from PET (R(2) = 0.93). Blocking experiments and histology both confirmed the VEGF specificity of (64)Cu NOTA-Bev-800CW. The persistent, prominent, and VEGF-specific uptake of (64)Cu NOTA-Bev-800CW in the tumor, observed by both PET and NIRF imaging, warrants further investigation and future clinical translation of such Bev-based imaging agents. PMID- 22229129 TI - Hydrogels to modulate lentivirus delivery in vivo from microporous tissue engineering scaffolds. AB - Numerous strategies to induce tissue regeneration employ scaffolds to create space and present biological cues that promote development. In this report, microporous scaffolds that provide structural support were filled with hydrogels to regulate cell adhesion and migration and were investigated as delivery vehicles for gene therapy vectors in vivo. Porous scaffolds were filled with either lentivirus-entrapped collagen or fibrin hydrogels, both of which support cell adhesion yet have varied rates for degradation and cell infiltration. Empty scaffolds and alginate hydrogels were employed as controls, with the latter not supporting cell infiltration. Hydrogel-filled scaffolds retained the lentivirus more effectively than empty scaffolds, and transgene expression was observed for all scaffold conditions. Empty and fibrin-filled scaffolds had maximal transgene expression in vivo, followed by collagen and alginate, with similar levels. Transduced macrophages and dendritic cells were initially present at the scaffold boundary and adjacent tissue and within the scaffold at later time points for all but the alginate condition. At days 3 and 7, expression was also imaged throughout the spleen and thymus, which may result from cell migration from the implant. These studies demonstrate that hydrogels can modulate gene delivery from scaffolds used in cell transplantation and regenerative medicine. PMID- 22229130 TI - What's new in critical illness and injury science? Managing acute respiratory distress syndrome is still a challenge. PMID- 22229125 TI - A guide to neurotoxic animal models of Parkinson's disease. AB - Parkinson's disease (PD) is a neurological movement disorder primarily resulting from damage to the nigrostriatal dopaminergic pathway. To elucidate the pathogenesis, mechanisms of cell death, and to evaluate therapeutic strategies for PD, numerous animal models have been developed. Understanding the strengths and limitations of these models can significantly impact the choice of model, experimental design, and data interpretation. The primary objectives of this article are twofold: First, to assist new investigators who are contemplating embarking on PD research to navigate through the available animal models. Emphasis will be placed on common neurotoxic murine models in which toxic molecules are used to lesion the nigrostriatal dopaminergic system. And second, to provide an overview of basic technical requirements for assessing the pathology, structure, and function of the nigrostriatal pathway. PMID- 22229131 TI - Hepatoprotective effects of select water-soluble PARP inhibitors in a carbon tetrachloride model. AB - BACKGROUND: Inhibitors of the nuclear enzyme poly (ADP-ribose) polymerase (PARP 1) have been demonstrated to attenuate pathophysiologic conditions associated with oxidative stress, specifically with carbon tetrachloride (CT)-induced hepatotoxicity. SETTINGS AND DESIGN: In this investigation, we evaluated 3 previously untested water-soluble PARP-1 inhibitors, namely, 3-aminobenzamide (ABA), 5-aminoisoquinolinone (AIQ), and N-(6-oxo-5,6-dihydro-phenanthridin-2-yl) N,N-dimethylacetamide HCl (PJ-34) to determine their efficacy in blocking or attenuating CT-induced hepatotoxicity in male imprinting control region (ICR) mice. STATISTICAL ANALYSIS: Indicators of hepatotoxicity were compared with F tests among groups to determine statistically significant effects. Pearson's correlation coefficients were used to evaluate the correlation between PARP inhibition and the attenuation of hepatotoxicity. RESULTS AND CONCLUSIONS: CT treatment resulted in hepatic cytotoxicity, increased serum transaminase (ALT), lipid peroxidation (MDA), intracellular glutathione (GSH) depletion, increased carbonyl content, and substantially increased PARP-1 activity. CT treatment also produced profound observable hemorrhagic necrosis in the hepatic centrilobular region of ICR mice. Pretreatment with PJ-34, ABA, and AIQ before CT treatment significantly decreased PARP-1 activity in hepatocytes after CT treatment by 3.4, 2.0, and 1.9 times, respectively. Corresponding to this reduction in PARP-1 activity, a significant reduction in the ALT levels and MDA and a reduction in the GSH depletion were observed. Also, there were no visible tissue defects in the liver samples from animals pretreated with individual PARP-1 inhibitors before CT administration. These results demonstrate the efficacy of the 3 previously untested water-soluble PARP-1 inhibitors in attenuating CT-induced hepatocellular toxicity and further characterize the role of PARP-1 activation and oxidative stress among the cascade of events in hepatocellular necrosis induced by CT treatment. PMID- 22229133 TI - Resource utilization in the management of traumatic brain injury patients in a critical care unit: An audit from rural setup of a developing country. AB - INTRODUCTION: Traumatic brain injuries (TBI) are steadily increasing and are a major cause of mortality and morbidity, particularly in the young population, leading to the loss of life and productivity in the developing countries. Providing critical care to these patients with TBI is a challenge even in well advanced centers in major cities of India. In the present study, we describe our experience of resource utilization in the management of TBI in a critical care unit (CCU) from a rural setup. MATERIALS AND METHODS: All consecutive patients who were admitted from January 2007 to December 2009 in the CCU for the management of traumatic brain injury were included in the study. The case records of the patients were reviewed retrospectively, and data were collected on age, gender, severity of head injury, associated injuries, total CCU stay, total hospital stay, and outcome. RESULTS: The total duration (days) of hospital stay was 8.96+/-6.16 days and a median of 8 days, and CCU stay was 3.77+/-6.34 days with a median of 2 days. No deaths occurred with mild head injury. A total of 73 (19.16%) deaths occurred in 381 admitted subjects in CCU. The risk of death among both the sexes is not significantly different, that is, odds ratio (OR) 1.032 [95% confidence interval (CI) 0.351-3.03], so also the risk of death among the different age groups is also not significant having OR, 0.978 (95% CI, 0.954 1.00). The severity of head injury (mild, moderate, and severe) and CCU stay parameters had significant difference with risk of death [OR, 3.22 (95% CI, 2.49 4.16) and OR, 2.50 (95% CI, 1.9-3.2)]. CONCLUSIONS: Apparently it seems possible to use the existing health care structures in rural areas to improve trauma care. It becomes particularly relevant in poor resource, developing countries, where health care facilities and access to specialized care units are still far below the acceptable standard, there is a need to compare with the reference group to further support the evidence. PMID- 22229132 TI - Pre-injury polypharmacy as a predictor of outcomes in trauma patients. AB - BACKGROUND: One of the hallmarks of modern medicine is the improving management of chronic health conditions. Long-term control of chronic disease entails increasing utilization of multiple medications and resultant polypharmacy. The goal of this study is to improve our understanding of the impact of polypharmacy on outcomes in trauma patients 45 years and older. MATERIALS AND METHODS: Patients of age >=45 years were identified from a Level I trauma center institutional registry. Detailed review of patient records included the following variables: Home medications, comorbid conditions, injury severity score (ISS), Glasgow coma scale (GCS), morbidity, mortality, hospital length of stay (LOS), intensive care unit (ICU) LOS, functional outcome measures (FOM), and discharge destination. Polypharmacy was defined by the number of medications: 0-4 (minor), 5-9 (major), or >=10 (severe). Age- and ISS-adjusted analysis of variance and multivariate analyses were performed for these groups. Comorbidity-polypharmacy score (CPS) was defined as the number of pre-admission medications plus comorbidities. Statistical significance was set at alpha = 0.05. RESULTS: A total of 323 patients were examined (mean age 62.3 years, 56.1% males, median ISS 9). Study patients were using an average of 4.74 pre-injury medications, with the number of medications per patient increasing from 3.39 for the 45-54 years age group to 5.68 for the 75+ year age group. Age- and ISS-adjusted mortality was similar in the three polypharmacy groups. In multivariate analysis only age and ISS were independently predictive of mortality. Increasing polypharmacy was associated with more comorbidities, lower arrival GCS, more complications, and lower FOM scores for self-feeding and expression-communication. In addition, hospital and ICU LOS were longer for patients with severe polypharmacy. Multivariate analysis shows age, female gender, total number of injuries, number of complications, and CPS are independently associated with discharge to a facility (all, P < 0.02). CONCLUSION: Over 40% of trauma patients 45 years and older were receiving 5 or more medications at the time of their injury. Although these patients do not appear to have higher mortality, they are at increased risk for complications, lower functional outcomes, and longer hospital and intensive care stays. CPS may be useful when quantifying the severity of associated comorbid conditions in the context of traumatic injury and warrants further investigation. PMID- 22229134 TI - A comparison between two different alveolar recruitment maneuvers in patients with acute respiratory distress syndrome. AB - BACKGROUND: Alveolar recruitment is a physiological process that denotes the reopening of previously gasless lung units exposed to positive pressure ventilation. The current study was aimed to compare two recruitment maneuvers, a high continuous positive airway pressure (CPAP), and an extended sigh in patients with ARDS. MATERIALS AND METHODS: Forty patients with acute respiratory distress syndrome were randomly divided into two groups, 20 patients each. Group I received a CPAP of 40 cm H(2)O for 40 seconds and group II received extended sigh (providing a sufficient recruiting pressure * time). In our study, we assessed the effects of both recruitment maneuvers on respiratory mechanics, gas exchange, and hemodynamics. These data were analyzed using two-way analysis of variance (ANOVA) followed by a Student--Newman--Keuls post hoc comparison test. P < 0.05 was considered statistically significant. RESULTS: Both methods improved the compliance, increased arterial oxygenation (PaO(2)), increased the PaO(2)/FiO(2) ratio, and reduced the pulmonary shunt fraction (Q(s)/Q(t)). However, the extended sigh improved both PaO(2) and PaO(2)/FiO(2) ratios more than continuous positive airway pressure. Also the hemodynamic parameters were better maintained during the extended sigh. CONCLUSION: Alveolar recruitment maneuvers are effective in management of mechanically ventilated ARDS patients. We conclude that extended sigh is more effective than continuous positive airway pressure as a recruitment maneuver. PMID- 22229135 TI - Educating the delivery of bad news in medicine: Preceptorship versus simulation. AB - Simulation experiences have begun to replace traditional education models of teaching the skill of bad news delivery in medical education. The tiered apprenticeship model of medical education emphasizes experiential learning. Studies have described a lack of support in bad news delivery and inadequacy of training in this important clinical skill as well as poor familial comprehension and dissatisfaction on the part of physicians in training regarding the resident delivery of bad news. Many residency training programs lacked a formalized training curriculum in the delivery of bad news. Simulation teaching experiences may address these noted clinical deficits in the delivery of bad news to patients and their families. Unique experiences can be role-played with this educational technique to simulate perceived learner deficits. A variety of scenarios can be constructed within the framework of the simulation training method to address specific cultural and religious responses to bad news in the medical setting. Even potentially explosive and violent scenarios can be role-played in order to prepare physicians for these rare and difficult situations. While simulation experiences cannot supplant the model of positive, real-life clinical teaching in the delivery of bad news, simulation of clinical scenarios with scripting, self reflection, and peer-to-peer feedback can be powerful educational tools. Simulation training can help to develop the skills needed to effectively and empathetically deliver bad news to patients and families in medical practice. PMID- 22229136 TI - The death of Ivan Ilych: A blueprint for intervention at the end of life. AB - Medical practice and the field of humanities frequently intersect. It is uncanny how problems presented or described in literature that are several hundred years old still present themselves to us on a regular basis. Often, our answers to these dilemmas are not perfect, but we continue our attempts at providing solutions through an enlightened evolution of our thought and approaches. Leo Tolstoy's novella, The Death of Ivan Ilych, is a classic piece of literature that allows a view of the dying process in an ordinary human being, and presents us with an opportunity to observe, not only the intersection of medicine and humanities, but also that of critical care and palliative medicine. Here Tolstoy, through his keen observation of the human condition at the end of life, allows us an opportunity to view a 19(th) century perspective that has an all too familiar persistence that needs a 21(st) century intervention. PMID- 22229137 TI - End of life in the Burn/Trauma unit: A nursing perspective. AB - The issues related to end of life decisions and mortality in the intensive care unit are common occurrences for the nursing staff. For the Critical Care/Burn nurse, issues such as who should be resuscitated, what are the end points of treatment, and what will be the quality of life for the patient if he/she survives are major factors in end of life decisions. Furthermore, the close relationships that can develop between the nurse and the patient and/or the patient's family make end of life decisions emotionally difficult. Unlike the other members of the multidisciplinary team, the nurses spend more time with the dying patient and his/her family, answering questions, explaining the care and course of the illness, and assisting the patient and family in understanding what the doctors have said. Repeated explanations are needed because the family and patient are under tremendous stress. Nurses experience emotional distress and need to develop resilience to continue to care for and work with patients approaching the end stages of life. The purpose of this paper is to briefly review the literature and use a case scenario to illustrate the challenges the Critical Care/Burn nurse faces when caring for the dying patient. PMID- 22229138 TI - Advance directives in the trauma intensive care unit: Do they really matter? AB - Despite advances in the care of the injured patient, 22% of trauma patients admitted to the intensive care unit will die from their injuries. As a majority of these deaths will occur due to withdrawal of care, intensivists should be proficient in their ability to discuss end-of-life care with patients and families. While the use of advance directives to document patients' wishes has increased, their utility is uncertain. We review the effectiveness and obstacles of advance directives. PMID- 22229141 TI - Cultural and religious aspects of palliative care. AB - For most clinicians and patients, the discussion of palliative care is a difficult topic. It is complicated by both the clinician's and patient's belief systems, which are frequently heavily influenced by cultural and religious upbringing. This article discusses the impact of some of those differences on attitudes toward end of life decisions. Several different religions and cultures have been evaluated for their impact on perceptions of palliative care and the authors will share some examples. PMID- 22229140 TI - Palliative critical care in the intensive care unit: A 2011 perspective. AB - Pain relief and palliative care play an increasingly important role in the overall approach to critically ill and injured patients. Despite significant progress in clinical patient care, our understanding of death and the dying process remains limited. For various reasons, people tend to delay facing questions associated with end-of-life, and the fear of the unknown often creates an environment of avoidance and an atmosphere of taboo. The topic of end-of-life care is multifaceted. It incorporates medical, ethical, spiritual, and religious aspects, among many others. Our ability to sustain the lives of the critically ill may be complicated by continuing life support in medically futile scenarios. This article, as well as the remainder of the IJCIIS Symposium on End-of-Life in Trauma/Intensive Care Unit, will explore the most important issues in the field of modern end-of-life care and palliative medicine, with a focus on critically ill and injured patients. PMID- 22229139 TI - An overview of end-of-life issues in the intensive care unit. AB - The population of the earth is aging, and as medical techniques, pharmaceuticals, and devices push the boundaries of human physiological capabilities, more humans will go on to live longer. However, this prolonged existence may involve incapacities, particularly at the end-of-life, and especially in the intensive care unit. This arena involves not only patients and families, but also care givers. It involves topics from economics to existentialism, and surgery to spiritualism. It requires education, communication, acceptance of diversity, and an ultimate acquiescence to the inevitable. Here, we present a comprehensive overview of issues in the care of patients at the end-of-life stage that may cause physicians and other healthcare providers, medical, ethical, social, and philosophical concerns in the intensive care unit. PMID- 22229142 TI - Gossypiboma, a rare cause of acute abdomen: A case report and review of literature. AB - Gossypiboma or textiloma is used to describe a retained surgical swab in the body after an operation. Inadvertent retention of a foreign body in the abdomen often requires another surgery. This increases morbidity and mortality of the patient, cost of treatment, and medicolegal problems. We are reporting case of a 45-year old woman who was referred from periphery with acute pain in abdomen. She had a surgical history of abdominal hysterectomy 3 years back, performed at another hospital. On clinical examination and investigation, twisted ovarian cyst was suspected. That is a cystic mass further confirmed by abdominal computerized tomography (CT). During laparotomy, the cyst wall was opened incidentally which lead to the drainage of a large amount of dense pus. In between pus, there was found retained surgical gauze that confirmed the diagnosis of gossypiboma. PMID- 22229143 TI - The stunned atrial lead: Transient malfunction of a permanent atrial pacer lead following acute myocardial infarction. AB - Proximal right coronary artery occlusion caused transient loss of sensing and capture of the atrial lead of a permanent dual-chamber pacemaker. Forty-five days after percutaneous revascularization, the atrial lead was discovered to be functioning normally. We hypothesize that ischemia of the right atrium caused stunning of the atrial myocardium at the pacer-lead interface, which gradually improved following percutaneous coronary intervention (PCI), leading to return of lead function over time. So far only one similar case has been described in the literature. PMID- 22229144 TI - Blunt traumatic abdominal wall disruption with evisceration. AB - Blunt traumatic abdominal wall disruptions associated with evisceration are very rare. The authors describe a case of traumatic abdominal wall disruption with bowel evisceration that occurred after a middle-aged woman sustained direct focal blunt force impact to the lower abdomen. Abdominal exploration and surgical repair of the abdominal wall defect were performed, with good clinical outcome. A brief overview of literature pertinent to this rare trauma scenario is presented. PMID- 22229145 TI - Cavernous sinus thrombosis following bee sting. PMID- 22229146 TI - ECMO and endogenous carboxyhemoglobin formation. PMID- 22229147 TI - Perforation of right ventricle with cardiac tamponade following pacemaker implantation. PMID- 22229148 TI - Ultrasonography-guided peripheral intravenous catheter in emergency department patients with difficult access. PMID- 22229149 TI - An Analytic Approach To Tensor Scale with An Efficient Algorithm and Applications to Image Filtering. AB - Scale is a widely used notion in image analysis that evolved in the form of scale space theory where the key idea is to represent and analyze an image at various resolutions. Recently, we have introduced a local morphometric scale using an ellipsoidal model that yields a unified representation of structure size, orientation, and anisotropy. In our previous works, tensor scale was described using an algorithmic approach and a precise analytic definition was missing. Here, we formulate an analytic definition for tensor scale in n-dimensional (n-D) images and present an efficient computational solution in 2- and 3-D. Finally, we present an application of tensor scale in medical image filtering. Results of new tensor scale computation algorithm are presented. Also, the performance of tensor scale based image filtering is compared with various approaches of diffusive filtering and the results found are very promising. PMID- 22229150 TI - Adolescents' Views Regarding Uses of Social Networking Websites and Text Messaging for Adolescent Sexual Health Education. AB - BACKGROUND: Adolescents frequently report barriers to obtaining sexual health education. PURPOSE: The purpose of this study was to determine adolescents' views regarding how new technologies could be used for sexual health education. METHODS: Focus groups were conducted with a purposeful sample of adolescents between 14 and 19 years old. Facilitators asked participants for their views regarding use of social networking web sites (SNSs) and text messaging for sexual health education. Tape-recorded data was transcribed; transcripts were manually evaluated then discussed to determine thematic consensus. RESULTS: A total of 29 adolescents participated in 5 focus groups. Participants were 65.5% female. Three themes emerged from our data. First, adolescents preferred sexual health education resources that are accessible. Second, adolescents preferred online resources that are trustworthy. Third, adolescents discussed preference for "safe" resources. DISCUSSION: Adolescents were enthusiastic and insightful regarding technology for enhancing sexual health education. The themes that influence adolescents' preferences in sexual health education using technology are similar to barriers that exist in other aspects of adolescent health communication. TRANSLATION TO HEALTH EDUCATION PRACTICE: Findings suggest ways in which health organizations can understand adolescents' views and concerns about how their interactions with professionals take place regarding sexual health. PMID- 22229151 TI - [Should corticosteroids be used in A/H1N1 influenza ARDS? Rather not but still debated]. PMID- 22229152 TI - [Treatment for Staphylococcus aureus hip prosthesis infections: use combinations including rifampin]. PMID- 22229153 TI - [Fusidic acid as monotherapy: was it necessary to study it for skin and soft tissue infections?]. PMID- 22229154 TI - The metalloprotease ADAM8 is associated with and regulates the function of the adhesion receptor PSGL-1 through ERM proteins. AB - The P-selectin glycoprotein ligand-1 (PSGL-1) is involved in the initial contact of leukocytes with activated endothelium, and its adhesive function is regulated through its proteolytic processing. We have found that the metalloprotease ADAM8 is both associated with PSGL-1 through the ezrin-radixin-moesin actin-binding proteins and able to cause the proteolytic cleavage of this adhesion receptor. Accordingly, ADAM8 knockdown increases PSGL-1 expression, and functional assays show that ADAM8 is able to reduce leukocyte rolling on P-selectin and hence on activated endothelial cells. We conclude that ADAM8 modulates the expression and function of PSGL-1. PMID- 22229155 TI - [Corticosteroid therapy for uncomplicated community-acquired pneumonia: weak and unreliable benefits for the patient as well as for the community]. PMID- 22229156 TI - Intratumor OX40 stimulation inhibits IRF1 expression and IL-10 production by Treg cells while enhancing CD40L expression by effector memory T cells. AB - Treg cells maintain the tumor microenvironment in an immunosuppressive state preventing an effective anti-tumor immune response. A possible strategy to overcome Treg-cell suppression focuses on OX40, a costimulatory molecule expressed constitutively by Treg cells while being induced in activated effector T cells. OX40 stimulation, by the agonist mAb OX86, inhibits Treg-cell suppression and boosts effector T-cell activation. Here we uncover the mechanisms underlying the therapeutic activity of OX86 treatment dissecting its distinct effects on Treg and on effector memory T (Tem) cells, the most abundant CD4+ populations strongly expressing OX40 at the tumor site. In response to OX86, tumor-infiltrating Treg cells produced significantly less interleukin 10 (IL-10), possibly in relation to a decrease in the transcription factor interferon regulatory factor 1 (IRF1). Tem cells responded to OX86 by upregulating surface CD40L expression, providing a licensing signal to DCs. The CD40L/CD40 axis was required for Tem-cell-mediated in vitro DC maturation and in vivo DC migration. Accordingly, OX86 treatment was no longer therapeutic in CD40 KO mice. In conclusion, following OX40 stimulation, blockade of Treg-cell suppression and enhancement of the Tem-cell adjuvant effect both concurred to free DCs from immunosuppression and activate the immune response against the tumor. PMID- 22229157 TI - CTCF, cohesin and higher-order chromatin structure. PMID- 22229158 TI - The regulatory interplay of CpG islands and nucleosome remodeling at mammalian primary response genes. PMID- 22229159 TI - XNP/ATRX at sites of nucleosome replacement. PMID- 22229160 TI - A hemin/G-quadruplex acts as an NADH oxidase and NADH peroxidase mimicking DNAzyme. PMID- 22229161 TI - Women in business: Finding a way in. PMID- 22229162 TI - Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis. PMID- 22229163 TI - Crazy for bargains: inventing the irrational female shopper in modernizing English Canada. AB - Between the 1890s and 1930s, anglophone politicians, journalists, novelists, and other commentators living in western, central, and eastern Canada drew upon established connections among greed, luxury, hysteria, and femininity to describe women who went shopping as irrational. Their motivations for doing so included their desires to assuage feelings of guilt about increased abundance; articulate anger caused by spousal conflicts over money; assert the legitimacy of male authority; and assign blame for the decline of small communities' sustainability, the degradation of labour standards, and the erosion of independent shopkeeping. By calling upon stock stereotypes of femininity, and by repositioning them to fit the current capitalist moment, English-Canadian commentators constructed disempowering representations of women to alleviate their anxieties about what they perceived as the ills of modernization. PMID- 22229164 TI - An intimate understanding of place: Charles Sauriol and Toronto's Don River Valley, 1927-1989. AB - Every summer from 1927 to 1968, Toronto conservationist Charles Sauriol and his family moved from their city home to a rustic cottage just a few kilometres away, within the urban wilderness of Toronto's Don River Valley. In his years as a cottager, Sauriol saw the valley change from a picturesque setting of rural farms and woodlands to an increasingly threatened corridor of urban green space. His intimate familiarity with the valley led to a lifelong quest to protect it. This paper explores the history of conservation in the Don River Valley through Sauriol's experiences. Changes in the approaches to protecting urban nature, I argue, are reflected in Sauriol's personal experience - the strategies he employed, the language he used, and the losses he suffered as a result of urban planning policies. Over the course of Sauriol's career as a conservationist, from the 1940s to the 1990s, the river increasingly became a symbol of urban health - specifically, the health of the relationship between urban residents and the natural environment upon which they depend. Drawing from a rich range of sources, including diary entries, published memoirs, and unpublished manuscripts and correspondence, this paper reflects upon the ways that biography can inform histories of place and better our understanding of individual responses to changing landscapes. PMID- 22229165 TI - "Lonely, tragic, but legally necessary pilgrimages": transnational abortion travel in the 1970s. AB - This article explores the work of the Calgary Birth Control Association with a particular focus on their referral service to help Albertan women obtain abortions in Seattle. The fact that Canadian women were travelling to the United States for abortions highlights the shortcomings of the Canadian health-care system and the legal changes in the 1969 omnibus bill. Cross-border travel is also compelling evidence for the argument that reproductive rights are an international issue. More particularly, this study demonstrates the tensions that reproductive-rights activists faced in addressing the needs of individual women vs the long-term objective of changing the laws and improving accessibility. PMID- 22229167 TI - [From the inventory of the world to the development of the globe: botany and colonization from the end of the 17th century to the beginning of the 20th century]. PMID- 22229168 TI - Design of optimal noise hazard control strategy with budget constraint. PMID- 22229169 TI - [Methods of treatment in patients with lower extremity arterial occlusive disease in presence of distal arterial lesion(Part 1)]. PMID- 22229171 TI - [Clinical Toxicology Photography Contest: Impression essay]. PMID- 22229170 TI - Effect of HER-2/neu over-expression on prognosis in gastric cancer: a meta analysis. AB - BACKGROUND: Her-2/neu is the most frequently studied molecular target in gastric cancer but its prognostic impact is still equivocal. We therefore conducted a meta-analysis to more precisely estimate its prognostic significance. METHODS: Published studies that investigated between Her-2/neu status and survival were identified. Meta-analysis was performed by Dersimonian-Laird model. Pooled hazard ratio (HR) and its 95% confidence interval (95%CI) were calculated to evaluate the risk of disease. RESULTS: A total of 19 studies were analyzed by meta analysis method, cumulative 4342 cases were included. Pooled data of 15 studies using univariate analysis showed worse survival of patient with her-2/neu (+) (pooled HR=1.59, 95%CI: 1.20-2.12), which maintained in 7 studies of multivariate analysis (pooled HR=1.58, 95%CI: 1.18-2.12). The Q statistic test for 15 studies of univariate analysis and for 7 studies of multivariate analysis showed they had heterogeneity (Q=26.98, p=0.019, Q=17.76, p=0.007, respectively). CONCLUSION: HER 2/neu over-expression is related to poor prognosis of gastric cancer but has a modest effect on survival in gastric cancer as an independent prognosis factor. PMID- 22229172 TI - [Clinical Toxicology Photography Contest: Guide for photo contest winning prizes]. PMID- 22229173 TI - [The "Indies" in the Mediterranean? The tropical utopia of an Enlightenment gardener and the agricultural mastery of the territory]. PMID- 22229174 TI - [Between human rights and political interests: the Algerian missions of the International Committee of the Red Cross]. PMID- 22229175 TI - [Seventeenth-century brick ovens in Tourcoing, Nord]. PMID- 22229176 TI - [Basis and clinical applications of vascularized epiphyseal transplantation]. AB - OBJECTIVE: To introduce the basic research and clinical applications of the vascularized epiphyseal transplantation. METHODS: The applied anatomy, experimental researches, and clinical application about the vascularized epiphyseal transplantation were summarized in the past two decades. The effectiveness of epiphyseal transplantation were discussed in the article. RESULTS: The epiphysis flap of fibular head with inferior lateral genicular artery and the epiphysis flap of iliac with deep superior branch of superior gluteal artery can be used as the donor sites of epiphyseal transplantation. Animal experiments proved that the vascularized epiphysis survived and maintained growth after transplantation. In a typical case undergoing distal ulnar reconstruction by the graft of peroneal epiphyseal, the 18-year follow-up results showed that the repaired ulna was nearly as long as the contralateral side and the function of the forearm was good. CONCLUSION: It is an effective way to repair epiphyseal defects of long bones in children with vascularized epiphyseal transplantation. PMID- 22229177 TI - [Clinical analysis of C5 nerve root palsy in hinge side and different angles in lamina open-door after expansion of open-door cervical laminoplasty]. AB - OBJECTIVE: To evaluate and compare the relation of the clinical results of expansion of open-door cervical laminoplasty (EOLP), C5 nerve root palsy in hinge side, and reclose of the opened laminae with different angles in lamina open door. METHODS: Between July 2006 and January 2009, 198 patients with cervical myelopathy were treated by EOLP. According to different opening angles which were measured by CT scan after operation, the patients were divided into group A (> 30 degrees, 76 patients including 44 males and 32 females) and group B (15-30 degrees, 122 patients including 71 males and 51 females). There was no significant difference in gender, age, disease duration, and segmental lesions between 2 groups (P > 0.05). The Japanese Orthopaedic Association (IOA) score before and after operation was used for neurological assessment and improvement rate, and the postoperative C5 nerve root palsy and reclose of the opened laminae were recorded. RESULTS: There was no significant difference in operation time, bleeding volume, and hospitalization days between 2 groups (P > 0.05). After 3 weeks of operation, C5 nerve root palsy in the hinge side occurred in 7 patients (9.2%) of group A, and in 2 patients (1.6%) of group B, were restored after symptomatic treatment, showing significant difference between 2 groups (chi2 = 4.568, P = 0.033). All patients were followed up 24 to 48 months. Between group A and group B, no significant difference was found in JOA improvement rate at 24 months after operation (P > 0.05), and in JOA score at preoperation and at 24 months after operation (P > 0.05), but JOA score was significantly improved at 24 months after operation when compared with preoperative score in the same group (P < 0.05). The function of limb lifting restored in 9 cases of C5 nerve root palsy at 24 months after operation; CT examination revealed that no reclose occured in group A and reclose occurred in 4 cases (3.3%) of group B, but no persistent symptoms or worsen situation were found during follow-up. CONCLUSION: Different angles in lamina open-door have the same clinical result; C5 nerve palsy has good prognosis. The opening angle between 15 degrees and 30 degrees will reduce the incidence of C5 nerve root palsy in the hinge side, but the open side should be firmly fixed to prevent further reclose of the opened laminae. PMID- 22229179 TI - [Modified single-stage transpedicular decompression, debridement, and posterior instrumentation in treatment of thoracic tuberculosis]. AB - OBJECTIVE: To investigate the effectiveness and feasibility of modified single stage transpedicular decompression, debridement, and posterior instrumentation in treatment of thoracic tuberculosis. METHODS: Between January 2005 and December 2009, 22 cases of thoracic tuberculosis were treated with modified single-stage transpedicular decompression, debridement, and posterior instrumentation. There were 12 males and 10 females with an average age of 39.4 years (range, 22-52 years). The mean disease duration was 1.2 years (range, 3 months to 10 years). The involved vertebral bodies were T5-12, including 2 segments in 17 cases and 3 segments in 5 cases. The kyphosis Cobb angle was (31.2 +/- 14.5) degrees before operation. According to Frankel score system for neurological deficits, 2 cases were classified as grade A, 1 case as grade B, 8 cases as grade C, 5 cases as grade D, 1 case as grade E, and 5 cases had no neurological deficits before operation. RESULTS: All incisions healed by first intention. All patients were followed up 22.2 months on average (range, 12-65 months). Pain in low back was relieved in varying degrees 2 weeks after operation. Fusion was achieved in the bone implant area at 3 months after operation. According to Frankel score system, 1 case was rated as grade B, 2 cases as grade C, 4 cases as grade D, 7 cases as grade E, and 8 cases had no neurological deficits at last follow-up. The kyphosis Cobb angle was (16.2 +/- 3.6) degrees, showing significant difference when compared with the value before operation (t = 5.952, P = 0.001). No loosening, emersion, breakage of internal fixation or pneumothorax occurred 1 year after operation. CONCLUSION: Single-stage transpedicular decompression and posterior instrumentation is an effective and safe method in treatment of thoracic tuberculosis. PMID- 22229178 TI - [Application and comparison of allograft and autograft bone for interbody fusion in cervical tuberculosis]. AB - OBJECTIVE: To evaluate the clinical results of allogeneic bone graft for interbody fusion in cervical tuberculosis. METHODS: Between January 2000 and January 2008, 30 cases of cervical tuberculosis were treated with allogeneic (group A, n = 15) or autologous (group B, n = 15) iliac crest bone graft combined with anterior fixation after radical debridement. In group A, there were 8 males and 7 females with an average age of 38 years; the disease duration was 6 to 14 months; the preoperative kyphosis Cobb angle was (8.6 +/- 11.3) degrees; the preoperative Japanese Orthopaedic Association (JOA) score was 13.0 +/- 3.1 for neurological function; and the length of bone graft was 32 mm on average. In group B, there were 9 males and 6 females with an average age of 42 years; the disease duration was 4 to 17 months; the preoperative kyphosis Cobb angle was (4.9 +/- 7.4) degrees; the preoperative JOA score 12.3 +/- 4.2; and the length of bone graft was 34 mm on average. There was no significant difference in general data between 2 groups (P > 0.05). RESULTS: The operation time and bleeding volume in group A were significantly less than those in group B (P < 0.05). Wound effusion were found in 2 cases of group A, and the other incisions healed by first intention. No infection occurred in group B. In group A, 13 cases were followed up 12-48 months; in group B, 14 cases were followed up 13-46 months. The time of bone graft healing in group A [(7.6 +/- 2.1) months] was significantly longer than that in group B [(4.2 +/- 1.1) months] (t = 2.773, P = 0.005). The kyphosis Cobb angles were significantly improved at 6 months and last follow-up after operation in 2 groups when compared with that before operation (P < 0.05), but no significant difference was found between 2 groups at different time after operation (P > 0.05). There was no significant difference in JOA score at 6 months after operation between group A (14.1 +/- 2.6) and group B (14.3 +/- 2.4) (t = 1.655, P = 0.162). The improvement rate for neural function were 83.7% in group A and 87.8% in group B, showing no significant difference (chi2 = 3.150, P = 0.071). There was no loosening of internal fixation and recurrence of tuberculosis in 2 groups during follow-up. Five cases had chronic pain at iliac donor sites in group B. According to Bridewell et al. evaluation standard, the bone fusion was satisfactory in 11 cases (84.6%) and unsatisfactory in 2 cases (15.4%) in group A, and was satisfactory for all in 14 cases (100%) in group B. The satisfactory rate of bone fusion showed no significant difference between 2 groups (chi2 = 2.680, P = 0.115). CONCLUSION: Allogeneic bone grafting has a good clinical result for spinal fusion in cervical tuberculosis surgery, which can treat tuberculosis bone defect effectively. PMID- 22229180 TI - [Improved percutaneous kyphoplasty for diagnosis and treatment of thoracolumbar metastatic spine tumors]. AB - OBJECTIVE: To investigate the diagnosis and effectiveness of improved percutaneous kyphoplasty (PKP) for patients with thoracolumbar metastatic tumors, who could not tolerate anesthesia and open operation. METHODS: Between September 2009 and September 2010, 16 patients with thoracolumbar metastatic tumors underwent improved PKP. Of 16 patients, 7 were male and 9 were female with an average age of 64.5 years (range, 60-73 years). All patients had vertebral metastasis tumor. The disease duration was 3-6 months with an average of 4 months. The visual analogue scale (VAS) score was 8.9 +/- 0.8. No spinal cord compression and nerve root compression was observed. The involved vertebrae included T7 in 1 case, T8 in 1, T12 in 1, L2 in 2, L3 in 2, L4 in 3, T1,2 in 1, T3,4 in 1, T7,8 in 1, T11, 12 in 1, T7-L1 in 1, and T12-L4 in 1. Nine patients had vertebral compression fracture with a vertebral compression rate below 75%. RESULTS: All patients were successfully performed PKP. There was no serious adverse reactions in cardiopulmonary and brain vascular systems and no perioperative death. The biopsy results showed that all were metastatic adenocarcinoma. All patients were followed up 9-18 months (mean, 14 months). Complete pain relief was achieved in 14 cases and partial relief in 2 cases 6 months after operation according to World Health Organization criterion, with a pain-relief rate of 87.5%. The VAS score was 1.8 +/- 0.6 at 6 months postoperatively, showing significant difference when compared with the preoperative score (P < 0.05). Two patients had cement leakages in 3 vertebrae with no symptoms at 6 months postoperatively. During follow-up, 12 patients died and the others survived with tumor. CONCLUSION: For patients with thoracolumbar metastatic tumors who can not tolerate anesthesia and open operation, improved PKP has the advantages such as minimal invasion, high diagnostic rate, and early improvement of pain in the biopsy and treatment. It can improve patient's quality of life in the combination of radiotherapy or chemotherapy. PMID- 22229181 TI - [Effectiveness of different bone graft fusion ways in treating thoracolumbar burst fractures]. AB - OBJECTIVE: To assess the effectiveness of different bone graft fusion ways in the treatment of thoracolumbar burst fractures. METHODS: Between June 2000 and June 2009, 126 cases of thoracolumbar burst fractures were treated by one-stage posterior short segment internal fixation combined with bone graft fusion. All patients had acute spine and spinal injury at the levels of T11-L2, who were with different degrees of neural function injury (below Frankel grade D). The patients were randomly divided into 3 groups and were treated respectively by centrum combined with interbody bone graft fusion (group A), posterolateral bone graft fusion (group B), and ring bone graft fusion (group C) combined with posterior short segment pedicle instrumentation. The changes of the Cobb angle, correction loss of Cobb angle, bone fusion rate, internal fixation failure rate, Oswestry Disability Index (ODI), and Frankel grade of the fracture vertebral were observed after operation to evaluate the effectiveness of different bone graft fusion ways. RESULTS: All 126 cases were followed up 24-32 months (mean, 28 months). The operation time and bleeding volume in group C were significantly larger than those in groups A and B (P < 0.05), but no significant difference was found between groups A and B (P > 0.05). At 2 years after operation and last follow-up, the Cobb angle and correction loss in group B were significantly larger than those in groups A and C (P < 0.05), but there was no significant difference between groups A and C (P > 0.05). At last follow-up, the bone fusion rate and internal fixation failure rate were 100% and 0 in group A, 78.6% and 21.4% in group B, and 97.5% and 0 in group C; there were significant differences between group B and groups A, C (P < 0.05), but no significant difference was found between groups A and C (P > 0.05). ODI and Frankel grade were obviously improved after operation, showing significant differences between preoperation and last follow-up (P < 0.05) in 3 groups, between group B and groups A, C (P < 0.05), but no significant difference was found between groups A and C (P > 0.05). CONCLUSION: The centrum combined with interbody bone graft fusion is best in 3 bone graft fusion ways because of its optimum bone fusion and according with human body biomechanics mechanism. Back out board bone graft fusion may not a appropriate bone fusion way because of its high internal fixation failure rate and not according with human body biomechanics mechanism. The ring bone graft fusion may not be an indispensable bone fusion way because of its common bone fusion ratio and lower cost-performance ratio. PMID- 22229182 TI - [Short-term effectiveness of Swanson artificial joint replacement in treating posttraumatic metacarpophalangeal joint stiffness]. AB - OBJECTIVE: To investigate the short-term effectiveness of Swanson artificial joint replacement in treating post-traumatic metacarpophalangeal joint stiffness. METHODS: Between August 2007 and May 2010, 11 cases (13 fingers) of metacarpophalangeal joint stiffness with soft tissue defects underwent Swanson artificial joint replacement. There were 7 males (9 fingers) and 4 females (4 fingers), aged 43 to 65 years with an average of 49 years. The involved fingers included 4 thumbs, 4 index fingers, 3 middle fingers, and 2 ring fingers. The types of injury included open and crush injury in 8 fingers, fracture of the metacarpophalangeal joint in 3 fingers, metacarpophalangeal joint severing in 2 fingers. The time from joint stiffness to hospitalization was 12 to 48 weeks (mean, 24 weeks). The joint activity was (136.82 +/- 28.96) degrees. According to total active motion (TAM) assessment, included good in 1 finger, fair in 6 fingers, and poor in 6 fingers before operation. The activities of daily living were assessed by Sollerman score, which was 45.64 +/- 11.04. The X-ray films and CT scan showed traumatic arthritis of the metacarpophalangeal joint. RESULTS: The incision healed by first intention. All patients were followed up 12 to 34 months (mean, 24.1 months). At last follow-up, the joint activity was (194.64 +/- 28.86) degrees, showing significant difference when compared with preoperative value (t = 25.214, P = 0.000). According to TAM assessment, including excellent in 1 finger, good in 4 fingers, fair in 7 fingers, and poor in 1 finger. The Sollerman score was 67.45 +/- 8.20 postoperatively, showing significant difference when compared with the preoperative score (t = -10.470, P = 0.000). X-ray examination showed no prosthesis fracture, periprosthetic fracture, or joint dislocation occurred at last follow-up. CONCLUSION: Swanson artificial joint replacement can be applied to treat post-traumatic metacarpophalangeal joint stiffness, which can improve the joint activity and has satisfactory short-term effectiveness. PMID- 22229183 TI - [A comparative study on three-dimensional digital model of knee joint anterior cruciate ligament between normal adult and corpse based on magnetic resonance imaging reconstruction]. AB - OBJECTIVE: To discuss the authenticity of reconstructing the anterior cruciate ligament (ACL) three-dimensional digital model of normal adult knee joint by use of MRI. METHODS: The double knee joint specimens were selected from 20 fresh normal adult corpses and double knee joint of 20 normal adult volunteers, and were scanned with MRI; continuous image data of level thick 1.0 mm were acquired, and then these data were imported into Mimics 10.01 software for three dimensional reconstruction; and full three-dimensional digital models were built, including the corpse specimens (corpse model group) and normal adult (normal model group). The relevance anatomy index of ACL were measured with measuring tool of Mimics 10.01 software, and double knee joint specimens of 20 fresh normal adult corpses were dissected, and the relevance data were measured (corpse specimens group). RESULTS: There was no significant difference in all indexes between corpse model group and corpse specimen group (P > 0.05), and between corpse model group and normal model group (P > 0.05). CONCLUSION: The image data gathered by MRI could reconstruct the ACL three-dimensional digital model of normal adult knee joint, which has authenticity. PMID- 22229184 TI - [Clinical evaluation of vacuum sealing drainage for treatment of deep infection after hip or knee replacement]. AB - OBJECTIVE: To investigate the method and effectiveness of vacuum sealing drainage (VSD) combined with debridement for treatment of deep infection after hip or knee replacement. METHODS: Between September 2006 and May 2010, 13 cases of deep infection after joint replacement surgery were treated, including 5 males and 8 females with an average age of 62.5 years (range, 56-78 years). Infection occurred at 7 days to 1 year and 2 months (median, 14 days) after joint replacement surgery. The time from infection to admission was 8 days to 4 years and 6 months (median, 21 days). Purulent secretion with or without blood were observed in all patients; sinus formed in 5 cases; and unhealing of incision or drainage opening disunion were observed in 8 cases. The size of skin defect at secretion drainage or sinus opening site was 5 mm x 3 mm to 36 mm x 6 mm; the depth of drainage tunnel or sinus was 21-60 mm. The histopathological examination in 11 patients showed acute infection or chronic infection with acute onset in 10 cases, and tuberculosis in 1 case. In 6 cases of secretion culture, Staphylococcus aureus was isolated from 5 cases. After thorough debridement, wound irrigation was performed during the day and VSD during the night in 10 cases. VSD was merely performed in 3 cases. RESULTS: In 1 case after revision total hip arthroplasty, the wound bled profusely with VSD, then VSD stopped and associated with compression bandage, VSD proceeded again 3 days later with no heavy bleeding. All the patient were followed up 1 year to 4 years and 5 months (mean, 2 years and 11 months). Infection were controlled 7-75 days (mean, 43 days) after VSD in 10 cases. In these cases, prosthesis were reserved, no recurrent infection was observed, wound were healed, limb function were reserved. VSD was refused in 1 case because of hypersensitive of the pain at the vacuum site, infection control was failed and amputation at the thigh was proceeded. The effect was not evident in 1 case with tuberculosis infection, then the prosthesis was removed and arthrodesis was proceeded followed by complete union. In 1 case, infection was cured with VSD, recurrent infection happened after 9 months, antibiotic-impregnated cement spacer was used at end, and no recurrence was observed 1 year and 4 months later. CONCLUSION: VSD combined with debridement can drainage deep infection sufficiently, promote wound healing, reduce recurrent infection rate, maximize the possibility of prosthesis preservation. PMID- 22229185 TI - [Effect of rivaroxaban on risk of bleeding after total knee arthroplasty]. AB - OBJECTIVE: To investigate the effect of rivaroxaban on the risk of bleeding after total knee arthroplasty (TKA). METHODS: A total of 119 cases undergoing primary TKA because of knee osteoarthritis between June 2009 and May 2011, were randomly divided into the rivaroxaban group (59 cases) and the control group (60 cases). There was no significant difference in gender, age, height, weight, side, disease duration, and grade of osteoarthritis between 2 groups (P > 0.05). The preoperative preparation and operative procedure of 2 groups were concordant. At 1-14 days after TKA, rivaroxaban 10 mg/d were taken orally in the rivaroxaban group, and placebo were given in the control group. The blood routine examination was performed before operation and at 2 days postoperatively; the total blood loss and hemoglobin (HGB) decrease were calculated according to the formula; the blood loss, postoperative wound drainage, and wound exudate after extubation were recorded to calculate the dominant amount of blood loss; and the bleeding events were recorded within 35 days postoperatively. RESULTS: The total blood loss and HGB decrease were (1 198.34 +/- 222.06) mL and (33.29 +/- 4.99) g/L in the rivaroxaban group and were (1 124.43 +/- 261.01) mL and (31.57 +/- 6.17) g/L in the control group, showing no significant difference (P > 0.05); the postoperative dominant blood loss in the rivaroxaban group [(456.22 +/- 133.12) mL] was significantly higher than that in the control group [(354.53 +/- 96.71) mL] (t = 4.773, P = 0.000). The bleeding events occurred in 3 cases (5.1%) of the rivaroxaban group and in 1 case (1.7%) of the control group, showing no significant difference (chi2 = 1.070, P = 0.301). CONCLUSION: Rivaroxaban has some effects on the risk of bleeding after TKA. In general, rivaroxaban is safe. PMID- 22229186 TI - [Surgical treatment of Essex-Lopresti injury]. AB - OBJECTIVE: To summarize operative procedure and the effectiveness of open reduction with internal fixation or radial head replacement for the treatment of Essex-Lopresti injury. METHODS: Between November 2002 and October 2010, 10 patients with Essex-Lopresti injury were treated. There were 8 males and 2 females with a mean age of 36 years (range, 20-56 years). Eight cases were fresh closed fracture within 2 days. According to Mason classification, 5 fracture were type II, 3 were type III. The other 2 cases were old fracture within 3 months. Wrist joint X-ray revealed that all the patients had distal radioulnar joint dislocation. Open reduction with internal mini-plate or absorbable screw fixation was performed in 5 cases, and radial head replacement in 5 cases; meanwhile, the distal radioulnar joint was reduced and fixed. RESULTS: All incisions healed by first intention without infection or bone nonunion. The patients were followed up 7 to 24 months with an average of 14.7 months. The X-ray films showed fracture healing at 9-20 weeks (mean, 16.3 weeks); distal radioulnar joint was stable without shortening or shift of proximal radius. According to elbow clinical evaluation system, the results were excellent in 5 cases, good in 3 cases, and fair in 2 cases. According to wrist clinical evaluation, the results were excellent in 7 cases, good in 2 cases, and fair in 1 case. All patients had good elbow stability, and recovered quickly. CONCLUSION: Early diagnosis, operation, and functional exercises are important to obtain an excellent result in treating Essex-Lopresti injury. PMID- 22229187 TI - [Minimally invasive percutaneous plate osteosynthesis technique for treatment of Neer II, III parts fracture of proximal humerus]. AB - OBJECTIVE: To evaluate the clinical significance of minimally invasive percutaneous plate osteosynthesis (MIPPO) applied in Neer II, III parts fractures of proximal humerus. METHODS: The clinical data were retrospectively analyzed, from 30 patients with Neer II, III parts fractures of proximal humerus in accordance with selection criteria, who were treated with manual reduction and plaster external fixation (11 cases, non-operative group) or with MIPPO (19 cases, operative group) between January 2008 and May 2010. In non-operative group, there were 6 males and 5 females with an average age of 60 years (range, 56-80 years) and with an average time of 10 hours (range, 3-24 hours) between injury and reduction, including 8 cases of Neer II and 3 cases of Neer III. In operative group, there were 13 males and 6 females with an average age of 65 years (range, 45-78 years) and with an average time of 3 days (range, 1-5 days) between injury and operation, including 9 cases of Neer II and 10 cases of Neer III. There was no significant difference in gender, age, fracture type, and time from injury to operation (P > 0.05). The shoulder joint function before and after treatments was evaluated according to Constant-Murley Score (CMS) and American Shoulder and Elbow Surgeons' Form (ASES) scoring systems. RESULTS: Thirty patients were followed up. In operative group, the follow-up time ranged from 11 to 18 months (mean, 12 months); all incisions healed by first intention with no complication of internal fixation failure, infection, or nerve injury. In non operative group, the follow-up time ranged from 9 to 15 months (mean, 11 months). The X-ray films showed that fractures healed without humeral head necrosis in 2 groups. The bone healing time in operative group and non-operative group was (11.47 +/- 2.48) weeks and (11.82 +/- 2.44) weeks, respectively, showing no significant difference (t = 0.369, P = 0.889). The CMS score and ASES score at each time point after treatment were significantly better than those before treatment (P < 0.05); the CMS scores in operative group were better than those in non-operative group at 3 weeks, 3 months, and 1 year after treatment (P < 0.05); and the ASES score in operative group was better than that in non-operative group at 3 weeks and 3 months after treatment (P < 0.05), but no significant difference was found at 1 year after treatment (P > 0.05). CONCLUSION: MIPPO fixation using the locking compression plate is an effective option for Neer II, III parts fractures of proximal humerus. It can provide good functional recovery of the shoulder joint so that patients can get back to their normal life as soon as possible. PMID- 22229188 TI - [Treatment of avascular necrosis of the femoral head by lesions clearance, compact bone grafting, and porous tantalum rod implantation]. AB - OBJECTIVE: To study the effectiveness of avascular necrosis of the femoral head treated by lesions clearance, METHODS: Between March 2008 and May 2010, 14 patients (16 compact bone grafting, and porous tantalum rod implantation. hips) with avascular necrosis of the femoral head were treated by lesions clearance, compact bone grafting, and implantation of porous tantalum rod. Of 15 cases, 13 were male (15 hips) and 1 was female (1 hip) with a median age of 42.2 years (range, 18-73 years), including traumatic in 1 case (1 hip), alcoholic in 4 cases (4 hips), and steroid-induced in 9 cases (11 hips); 3 hips were at Association Research Circulation Osseous (ARCO) stage I and 13 hips were at ARCO stage II. The Harris score was 51.89 +/- 12.42, and the X-ray score was 31.88 +/- 4.03. All the cases were diagnosed by X-ray films and MRI. The median disease duration was 2.5 years (range, 6 months to 7 years). All the patients accepted the operation of lesions clearance by slotting at the neck of femur, then, compact bone grafting, and implantation of porous tantalum rod were performed. The affected limb could not bear weight loading at 1-3 months after operation and partly bear weight loading after 3 months of operation. RESULTS: Primary healing of incision was achieved in all patients and no complication occurred. The patients were followed up 24 months on average (range, 13-36 months). Two patients underwent total hip arthroplasty at 4 months and 2 years respectively because of even worsened pain and collapsed femoral heads; 12 patients achieved obvious pain relief with a survival rate 87.5% (14/16). The postoperative Harris score was 84.89 +/- 17.96, showing significant difference when compared with preoperative score (t = -8.038, P = 0.001). The X-ray examination showed definite ossification, increased density, regular arrangement of the trabeculae and no collapsed femoral head. The X-ray score was 32.19 +/- 6.57, showing no significant difference when compared with preoperative score (t = -2.237, P = 0.819). CONCLUSION: Lesions clearance, compact bone grafting, and implantation of porous tantalum rod for avascular necrosis of the femoral head have a good short term clinical result. PMID- 22229189 TI - [Research progress of calcified cartilage zone]. AB - OBJECTIVE: To review the structure and function of the calcified cartilage zone and its role in the pathogenesis of osteoarthritis (OA). METHODS: Recent literature about calcified zone was reviewed and analyzed in terms of architecture, composition, biomechanics, and biological function. RESULTS: Calcified zone has particular structure and material properties, and functions as a semipermeable membrane; chondrocytes in the calcified zone retain some characteristics of growth plate cells, which play a crucial role in cartilage function maintenance and pathogenesis of OA. Therefore, reconstruction of the calcified zone at osteochondral conjunction has become one of the hot research in the fields of interface tissue engineering. CONCLUSION: It is necessary to pay more attention to calcified cartilage zone, which is important for both the treatment of OA and the preparation of tissue engineered osteochondral composite. PMID- 22229190 TI - [Cranial bone reconstruction after one-stage resection of scalp squamous carcinoma invading the skull]. AB - OBJECTIVE: To investigate the operative procedure and the effectiveness of cranial bone reconstruction after one-stage resection of scalp squamous carcinoma invading the skull. METHODS: Between January 2005 and December 2008, 14 patients with scalp squamous carcinoma invading the skull were treated. There were 6 males and 8 females with a median age of 53 years (range, 29-76 years). The disease duration ranged from 3 to 8 years (mean, 6 years). The tumor locations were right temporal area in 2 cases, left temporal area in 2 cases, right frontal area in 3 cases, left frontal area in 1 case, right occipital area in 1 case, left occipital area in 2 cases, frontal area in 2 cases, and the top of the head in 1 case. Scalp lesions showed exogenous growth, and lesion diameter ranged from 5 to 12 cm (mean, 8 cm). TNM classification showed T4N0M0 tumor in all cases. MRI showed that tumors invaded the skull, 12 cases had smooth intradural side and 2 cases had brain involvement without lymph node metastasis or detected distant metastasis. Under general anesthesia, all the lesions of the scalp, skull, dura, and brain tissue were removed completely. The size defect of the scalp, skull, and dura ranged from 8 cm x 7 cm to 15 cm x 14 cm, from 5 cm x 4 cm to 12 cm x 12 cm, and from 4 cm x 4 cm to 9 cm x 8 cm, respectively, which were repaired with artificial patch, titanium metal, mesh, and local flaps, respectively. The donor site was repaired by split-thickness skin graft. RESULTS: The skin flaps and grafts survived and incision healed by first intention without cerebrospinal fluid leakage, intracranial and subdural hemorrhage, and other complications. All patients were followed up 2 to 5 years (mean, 4 years), and no recurrence was found. The compatibility of titanium mesh and local tissue was good. The patients had good hair growth without exposure of titanium mesh, seizures, partial paralysis, and other neurological damage performance. CONCLUSION: After one-stage resection of scalp squamous carcinoma invading the skull, it is effective to reconstruct the skull with titanium mesh and to repair dural defects with artificial dura. PMID- 22229191 TI - [Effectiveness of dorsal metacarpal island flap for treating scar contracture of finger web]. AB - OBJECTIVE: To investigate the effectiveness of dorsal metacarpal island flap for treating scar contracture of the finger web. METHODS: Between June 2009 and December 2010, 10 patients with scar contracture of the finger web were treated. There were 6 males and 4 females with an average age of 30 years (range, 14-57 years). Scar contracture was caused by injury in 8 cases, by burn in 1 case, and by operation in 1 case. The locations were the 1st web space in 1 case, the 2nd web space in 3 cases, the 3rd web space in 5 cases, and the 4th web space in 1 case. The disease duration was 3 to 9 months with an average of 5 months. The maximum abduction was 10-20 degrees. After web space scar release, the dorsal metacarpal island flap (3.5 cm x 1.2 cm-4.0 cm x 2.0 cm in size) was used to reconstruct web space (2.0 cm x 1.0 cm-3.0 cm x 1.8 cm in size). The donor site was directly sutured or repaired with local flaps. RESULTS: At 2 days after operation, necrosis occurred in 1 flap, which healed by extractive treatment. The other flaps survived and wound healed by first intention; all the flaps at donor sites survived and incision healed by first intention. Ten patients were followed up 6 to 15 months (mean, 9 months). The reconstructed web space had good appearance, the maximum abduction was 80 degrees in 1 case of the 1st web space scars contracture, and the maximum abduction was 35-45 degrees (mean, 40 degrees) in the other 9 cases. In 8 scar patients causing by injury, no scar contracture recurred during follow-up. CONCLUSION: It can achieve good results in appearance and function to use dorsal metacarpal island flap for treating scar contracture of the finger web. PMID- 22229192 TI - [Surgical treatment of dermatofibrosarcoma protuberans using wide local excision combined with Mohs micrographic surgery]. AB - OBJECTIVE: To investigate the method and effectiveness of wide local excision combined with Mohs micrographic surgery for dermatofibrosarcoma protuberans (DFSP). METHODS: Between January 2007 and January 2010, 17 patients with DFSP were treated. There were 9 males and 8 females with an average age of 33.2 years (range, 16-55 years). The lesions were located at head and neck (2 cases), trunk (12 cases), extremity (2 cases), and perineal region (1 case). There were 6 cases of primary DFSP and 11 cases of relapsed DFSP. The lesions presented as single or multitude nodules or fusion nodules with skin withering, scar, en plaque in the center and with ill-defined margins. The diameter of lesions ranged from 0.8 to 9.7 cm (mean, 4.3 cm). No distant metastasis or lymphatic metastasis occurred in all cases. After tumors resection by wide local excision combined with Mohs micrographic surgery, the wounds were repaired by direct suture in 3 patients, skin grafting in 9 patients, and local skin flap in 5 patients. RESULTS: Wide local excision and Mohs micrographic surgery were carried out once in 13 patients, twice in 3 patients, and three times in 1 patient with an average operation time of 98.6 minutes (range, 56-219 minutes). Primary healing of wound and donor site were achieved with no necrosis of skin grafting and skin flap. All patients were followed up 8-34 months (mean, 21.7 months) with no recurrence. CONCLUSION: Wide local excision combined with Mohs micrographic surgery could treat DFSP, which has the advantages of shorter operation time, radical resection, and less injury. PMID- 22229193 TI - [Skin graft combined with thorax wire fastening for repairing postoperative coloboma After resection of chest back giant nevus]. AB - OBJECTIVE: To observe the effectiveness of skin graft combined with thorax wire fastening for repairing postoperative coloboma after resection of chest back giant nevus. METHODS: Between June 2007 and October 2010, 17 cases of chest back giant nevus were treated. There were 7 males and 10 females, aged from 3 years and 6 months to 15 years (mean, 8 years). The size of giant nevus was 20 cm x 12 cm to 60 cm x 50 cm. Two cases of them were ever treated by laser, while the others were never treated. The check before operation showed ulcer of the skin and effusion in 2 cases, hard skin in 3 cases, hair growth in 7 cases, and normal in 5 cases. Five cases had serious itch. After giant nevus was cut off, thorax wire was fastened to reduce the wound area, and then the intermediate split thickness skin graft of thigh was used to repair the wound. Comprehensive anti scar treatment was given postoperatively. RESULTS: The wound size was (2 110.74 +/- 725.69) cm2 after resection of giant nevus, and was (1 624.94 +/- 560.57) cm2 after thorax wire fastening, showing significant difference (t = 9.006, P = 0.001). All the grafting skin survived; the incision and wound at donor site healed by first intention. The patients were followed up 6 months to 2 years (mean, 13 months). No scar proliferation or contracture occurred. The skin color and elasticity were similar to the normal skin; the nipple, navel, and other local apparatus were not shifted after operation. CONCLUSION: It can reduce donor site of skin and postoperative scar, and achieve satisfactory appearance to cover the wound by skin graft combined with thorax wire fastening after chest back giant nevus was cut off. PMID- 22229194 TI - [Effect of scrotal reconstruction with free skin graft on spermatogenesis]. AB - OBJECTIVE: To summarize the effect of free skin graft for repairing scrotal avulsion injury, and to investigate the repair impact of the method on spermatogenesis. METHODS: Between June 2001 and June 2010, 8 cases of complete avulsion injury of the scrotal skin were treated with the free skin graft, aged 22 to 64 years (mean, 29 years). The causes of injury included machine twisting in 4 cases, animal attack in 3 cases, and traffic accident in 1 case. The time between injury and hospitalization was 1-7 hours (mean, 3.5 hours). Five cases complicated by avulsion of penile skin, 3 by perineal laceration with exposure of testes and spermatic cord, and 1 by avulsion of leg skin. RESULTS: After 10 days, 80% to 95% grafted skin survived. The reconstructed scrotum had shrinks and the wound healed by first intention after dressing change. Eight patients were followed up 12 to 24 months (mean, 16 months). At last follow-up, the patients had relaxed and droop scrotum, and penile erection was normal. Semen quality analysis showed: semen volume of 2-6 mL (mean, 4.2 mL); complete liquefaction with liquefaction time of 15-30 minutes (mean, 23 minutes); sperm density of (12 27) x 10(6)/mL (mean, 16 x 10(6)/mL); sperm motility of 45%-65% (mean, 56%); and sperm motility (grade A) of 25%-42% (mean, 32%). CONCLUSION: Complete avulsion of the scrotal skin can be repaired by free skin graft, which has no significant effect on spermatogenesis. PMID- 22229195 TI - [Clinical analysis of acute carpal tunnel syndrome after reduction of Colles' fracture in twenty-two patients]. AB - OBJECTIVE: To investigate the etiology, diagnosis, and treatment of acute carpal tunnel syndrome (ACTS) after reduction of Colles' fracture. METHODS: Between December 2006 and June 2010, 22 patients with ACTS after reduction of Colles' fracture were treated with expectant treatment and surgical treatment. There were 9 males and 13 females with an average age of 46.2 years (range, 23-60 years). Fractures were caused by traffic accident in 9 cases, falling in 8 cases, falling from height in 2 cases, hitting in 2 cases, and crushing in 1 case. The mechanism of fracture was direct violence in 3 cases and indirect violence in 19 cases. According to Gartland & Werley classification, there were 2 cases of type I, 5 cases of type II, 14 cases of type III, and 1 case of type IV. Closed reduction was performed in 19 cases and open reduction and internal fixation (ORIF) in 3 cases. The average symptom time of ACTS after reduction of Colles' fracture was 11.6 hours (range, 1 hour 30 minutes to 48 hours) in patients undergoing closed reduction and was 24 hours in 1 patient and 2 weeks in 2 patients undergoing ORIF. Expectant treatment was performed first, the forearms were put in neutral position in closed reduction cases; if there was no relief of ACTS symptom 1 week later, the mixture of 1 mL glucocorticosteroid and 1 mL 2% lidocaine was injected into carpal tunnel once a week for 2 weeks. The mixture was injected into carpal tunnel directly once a week for 2 weeks in ORIF cases. In the patients who failed to expectant treatments, ORIF was performed. RESULTS: In 7 cases of type III that failed expectant treatment, ACTS symptoms were relief completely after ORIF. All the 22 patients were followed up 12 months on average (range, 8-18 months). The average time of complete disappearance of median nerve compression symptom was 11 days (range, 2-25 days). All the patients had normal finger motion, sensation, and opposition of thumb with no sensation of anaesthesia and pinprick. The results of Tinel test, Phalen test, and Reverse Phalen test were all negative. The X-ray film showed good fracture reduction and healing with an average healing time of 6 weeks (range, 3-14 weeks). According to GU Yudong's criteria for functional assessment, the results were excellent in 18 cases and good in 4 cases; the excellent and good rate was 100%. CONCLUSION: Malposition, displacement of fracture fragments, and ulnar deviation of the wrist after plaster immobilization are the most important risk factors for ACTS. Expectant treatments are recommended in patients with Colles' fracture of types I, II, and IV, but surgical treatment is the first choice for Colles' fracture of type III. PMID- 22229196 TI - [Clinical outcome of contralateral C7 nerve root transposition for treatment of brachial plexus root avulsion injury]. AB - OBJECTIVE: To observe the recovery of the sensory and motor function of the repaired limb and the impact on the healthy limb function after contralateral C7 nerve root transposition for treating brachial plexus root avulsion injury. METHODS: Between August 2008 and November 2010, 22 patients with brachial plexus root avulsion injuries were treated with contralateral C7 nerve root transposition. All patients were male, aged 14 to 47 years (mean, 33.3 years). Total brachial plexus root avulsion was confirmed by preoperative clinical examination and electrophysiological tests. In 22 cases, median nerve was repaired in 16 cases, radial nerve in 3 cases, and musculocutaneous nerve in 3 cases; primary operation was performed in 2 patients, and two-stage operation was performed in 20 patients. The sensory and motor functional recovery of the repaired limb was observed after operation. RESULTS: Twenty-one patients were followed up 7-25 months (mean, 18.4 months). In 16 cases of contralateral C7 nerve root transposition to the median nerve, wrist flexors reached more than M3 in 10 cases, while finger flexors reached more than M3 in 7 cases; sensation reached more than S3 in 11 cases. In 3 cases of contralateral C7 nerve root transposition to the musculocutaneous nerve, elbow flexors reached more than M3 in 2 cases; sensation reached more than S3 in 2 cases. In 3 cases of contralateral C7 nerve root transposition to the radial nerve, wrist extensor reached more than M3 in 1 case; sensation reached more than S3 in 1 case. CONCLUSION: Contralateral C7 nerve root transposition is a good procedure for the treatment of brachial plexus root avulsion injury. Staged operation is one of important factors influencing treatment outcome. PMID- 22229197 TI - [Experimental study on protein expression of extracellular signal-regulated kinase and c-Jun amino-terminal kinase signaling pathways in keloid fibroblasts]. AB - OBJECTIVE: To observe the protein expression of c-Jun amino-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in normal skin and keloid and to explore their influences on the formation of kloid. METHODS: Keloid tissues and normal skin tissues were collected from 16 keloid resection patients (experimental group) and 10 voluntary plastic surgery patients (control group). In the experimental group, the keloid formation time ranged from 8 months to 10 years; the keloid tissues were collected from the chest in 6 cases, the ear lobe in 4 cases, the perineum in 2 cases, the shoulder in 3 cases, and the abdomen in 1 case; and all keloid tissues were confirmed by pathological examination. In the control group, normal skin tissues were collected from the abdomen in 4 cases, the thighs in 3 cases, the shoulder in 2 cases, and the back in 1 case. Two-step line of Envision immunohistochemical staining was performed to observe the expressions of non-phosphorylated and phosphorylated JNK and ERK; Image Pro Plus 4.5 image analysis system was used to measure the integrated absorbance (IA) and to observe the positive staining strength. RESULTS: The immunohistochemical staining showed that no obvious expressions of phosphorylated and non phosphorylated ERK, JNK were observed in the fibroblasts of the control group, and the expressions of phosphorylated JNK and ERK proteins were significantly higher in the experimental group than in the control group (P < 0.05). There was no significant difference in the expressions of non-phosphorylated JNK and ERK proteins between 2 groups (P > 0.05). CONCLUSION Activation of ERK and JNK pathways might be involved in formation of keloid. PMID- 22229198 TI - [Calcitonin gene-related peptide promoting migration of rat bone marrow mesenchymal stem cells and stimulating expression of vascular endothelial growth factor]. AB - OBJECTIVE: To explore the effects of calcitonin gene-related peptide (CGRP) on the migration of bone marrow mesenchymal stem cells (BMSCs) and vascular endothelial growth factor (VEGF) expression in vitro. METHODS: The BMSCs were isolated from Sprague Dawley rats using whole bone marrow adherence method. At 1, 2, and 3 weeks after culture, the expressions of CGRP receptor (CGRPR) was detected by Western blot. The BMSCs were treated with CGRP at concentration 1 x 10(-8) mol/L (experimental group) and did not treated (control group), and the efficacy of BMSCs migration was analyzed by Transwell chamber assay after 72 hours; at 1, 3, 5, and 7 days, the mRNA expressions of vascular cell adhesion molecule 1 (VCAM-1) were detected by real-time fluorescent quantitative PCR; the protein expressions of VEGF were examined using immunohistochemistry and Western blot. RESULTS: CGRPR expressed stably in the cultured BMSCs and reached the peak at 2 weeks. CGRP had a significantly enhanced role in promoting cell migration. The number of cell migration was (3.20 +/- 1.77) cells/HP in experimental group and (1.11 +/- 0.49) cells/HP in control group, showing significant difference (t = 4.230, P = 0.001). In experimental group, the expressions of VCAM-1 mRNA increased with time and reached the peak at 7 days. There were significant differences in the expressions of VCAM-1 mRNA between control group and experimental group at 3, 5, and 7 days (P < 0.05). Immunocytochemistry results showed positive DAB staining for VEGF at 5 and 7 days in experimental group. Western blot results showed that the protein expressions of VEGF increased significantly at 5 and 7 days in experimental group when compared with control group (P < 0.05), which was signfiantly higher at 5 days than at 7 days in experimental group (P < 0.05). CONCLUSION: CGRP can promote the migration of BMSCs and stimulate the protein expression of VEGF, which may plays an important role in regulating bone metabolism by increasing angiogenesis. PMID- 22229199 TI - [Effect of mechanical stimulation combined with inductive factors on tissue engineered cartilage]. AB - OBJECTIVE: Mechanical stimulation and inductive factors are both crucial aspects in tissue engineered cartilage. To evaluate the effects of mechanical stimulation combined with inductive factors on the differentiation of tissue engineered cartilage. METHODS: Bone marrow mesenchymal stem cells (BMSCs) were isolated from newborn porcine (aged 7 days and weighing 3-6 kg) and expanded in vitro. The BMSCs at passage 2 were seeded onto a scaffold of poly (lactic-co-glycolic acid) (PLGA) in the concentration of 5 x 10(7)/mL to prepare cell-scaffold composite. Cell-scaffold composites were cultivated in a medium with chondrocyte-inducted factors (group A), in a vessel with mechanic stimulating only (group B), or mechanic stimulating combined with chondrocyte-inducted factors (group C) (parameters of mechanics: 1 Hz, 0.5 MPa, and 4 hours/day). Cell-scaffold composite and auto-cartilage served as positive control (group D) and negative control (group E), respectively. After 4 weeks of cultivation, the thickness, elastic modulus, and glycosaminoglycan (GAG) content of composites were measured. Additionally, BMSCs chondrogenic differentiation was assessed via real-time fluorescent quantitative PCR, immunohistochemistry, and histological staining. RESULTS: The thickness, elastic modulus, and maximum load in group C were significantly higher than those in groups A and B (P < 0.05). In groups A, B, and C, cartilage lacuna formation, GAG expression, and positive results for collagen type II were observed through HE staining, Safranin-O staining, and immunohistochemistry staining. The dyeing depth was deeper in group A than in group B, and in group C than in groups A and B; group C was close to group E. The GAG content in group C was significantly higher than that in groups A and B (P < 0.05). Real-time fluorescent quantitative PCR revealed that mRNA expressions of collagen type I, collagen type II, and GAG in group C were significantly higher than those in groups A and B (P < 0.05), and in group A than in group B (P < 0.05). CONCLUSION: Mechanical stimulation combined with chondrocyte inductive factors can enhance the mechanical properties of the composite and induce higher expression of collagen and GAG of BMSCs. PMID- 22229200 TI - [Transfection of human vascular endothelial growth factor 165 gene into rat bone marrow mesenchymal stem cells in vitro]. AB - OBJECTIVE: To construct a recombinant adenovirus vector containing human vascular endothelial growth factor 165 (hVEGF165) [pAdxsi-enhanced green fluorescent protein (EGFP)-hVEGF165], and to observe the expression of hVEGF165 by transfecting pAdxsi-EGFP-hVEGF165 into rat bone marrow mesenchymal stem cells (BMSCs) in vitro so as to lay a foundation for further research on gene therapy of blood vessel regeneration. METHODS: hVEGF165 was liberated from plasmid and was subcloned into pShuttle-EGFP. The pShuttle-cytomegalo-virus-EGFP was then transferred to pAdxsi vector, by which pAdxsi-EGFP-hVEGF165 virus plasmid was obtained and was identified by enzymes restriction analysis and gene sequencing. The pAdxsi-EGFP-hVEGF165 was linearized by digestion with restriction endonuclease PacI, and was then transfected into human embryonic kidney cells (HEK293). The retrieved recombinant adenovirus was titrated by using 50% tissue culture infective dose assay. The rat BMSCs were cultured and were infected with recombinant adenovirus containing EGFP (pAdxsi-EGFP). The multiplicities of infection (MOI) of transfection were determined by fluorescent inverted phase contrast microscope and flow cytometry (FCM), by which the most optimal value of MOI was confirmed and was used for transfecting pAdxsi-EGFP-hVEGF165 into BMSCs. The expression of hVEGF165 gene was identified by performing Western blot, RT PCR, and ELISA. The effect of transfection on BMSCs proliferation was assessed by MTT. RESULTS: The expression of hVEGF165 cDNA in recombinant adenovirus plasmid was identified by enzymes restriction analysis and gene sequencing. The titer of virus could be up to 1 x 10(10) pfu/mL after several rounds of transfection and amplification. The efficiency of transfection on FCM was 88% when MOI being 150 pfu/cell, at which the most optimal of MOI was achieved, as observed on fluorescence. The expressions of hVEGF165 at both mRNA and protein levels were detected after 48 hours of the transfection. The results of ELISA showed the expression of hVEGF165 peaked at 7 days, and the production was found even after 20 days. Furthermore, the expression of hVEGF165 protein at 1, 3, 5, 7, 9, 11, 13, 15, and 20 days in the group transfected with pAdxsi-EGFP-hVEGF165 was significantly higher than that in the group transfected with pAdxsi-EGFP and in untransfected group (P < 0.05). The results of MTT demonstrated that there was no significant difference in absorbance (A) value between transfected with pAdxsi EGFP-hVEGF165 group and untransfected group (P > 0.05). CONCLUSION: BMSCs are suitable for gene transfection, and hVEGF165 gene can be transferred into BMSCs with high efficiency using pAdxsi-EGFP-hVEGF165 at a MOI of 150 pfu/cell. The transfected BMSCs can highly express hVEGF165, which has no effect on BMSCs growth and proliferation. PMID- 22229201 TI - [Research progress of neural tissue engineering based on electrically conductive carbon nanotube scaffold]. AB - OBJECTIVE: To review the basic researches and the clinical application of the nano-neural tissue engineering materials, especially the electrically conductive carbon nanotubes (CNT). METHODS: The literature concerning the basic and clinical researches of the conductive materials of nano-neural tissue engineering, especially the electrically conductive CNT were reviewed. RESULTS: The researches of conductive materials of nano-neural tissue engineering have made some progress, the electrically conductive CNT can not only promote Schwan cells' adhension, migration, and proliferation, but also mimic the function of electric conductivity of neural myelin and enhance neurite growth and regeneration. So the electrically conductive CNT make great sense in stimulating and directing the growth of neurite and the regeneration of axons. CONCLUSION: Because of these unique properties, the electrically conductive CNT have great advantages in peripheral nerve repair and function reconstruction, and are promising to provide a novel method for clinical peripheral nerve repair and function reconstruction after injury. PMID- 22229202 TI - [Cryopreserved iliac vein for reconstruction of middle hepatic vein in living donor right liver transplantation]. AB - OBJECTIVE: To summarize the experience of living donor liver transplantation using cryopreserved iliac vein for middle hepatic vein reconstruction. METHODS: Between July 2006 and June 2009, right liver transplantation without middle hepatic vein was performed in 37 cases of 85 patients undergoing living donor liver transplantation; of 37 cases, 30 received middle hepatic vein reconstruction using cryopreserved iliac vein. There were 27 males and 3 females, aged from 10 to 57 years (median, 44 years). Thirty cases included 11 hepatocellular carcinoma, 10 hepatic cirrhosis, 2 Wilson's disease, 1 cholangiocarcinoma, 1 hepatoblastoma, 1 congenital hepatic fibrosis, 1 chronic severe hepatitis, and 1 congenital biliary atresia. Iliac veins harvested from donors were put into 0-4 degrees C mixed antibiotics saline and transported to the operating room. The iliac veins were trimmed, placed into sterile bags (containing RMPI 1640 + 20% DMSO + 10% calf protein solution) and frozen at -70 degrees C. In living donor liver transplantation process, the veins were melt and used for middle hepatic vein reconstruction. After operation, the patency of veins was monitored by regular Doppler ultrasound examination or enhanced CT for 3 months. RESULTS: In 30 patients, 30 iliac veins were used. The average cryopreserve time was 14 days (range, 3-44 days). Anastomosis were all successful; after cryopreservation, the blood vessels texture and elasticity were fit for surgery. No easily tearing or severe suture bleeding was observed. In 30 patients, 6 had segment V veins reconstruction; 3 had segment VIII; and 21 had both segments V and VIII. The patency rate of reconstructed vessels was 93% at 1 week, 90% at 2 weeks, 90% at 1 month, and 67% at 3 months. No serious complication was observed in donors. The prognosis was good with no small-for size syndrome. CONCLUSION: Cryopreserved iliac vein is an ideal material for the right hepatic living donor liver transplantation in the reconstruction of middle hepatic vein. PMID- 22229203 TI - An oncology perspective on preventive services in the context of U.S. healthcare reform. PMID- 22229205 TI - Patients with H pylori-independent MALT lymphoma are curable with radiotherapy. AB - After more than two decades of successful laboratory and clinical research, the "new" entity of mucosa-associated lymphoid tissue (MALT) lymphoma is reaching a noble maturity. Large series have demonstrated that most patients diagnosed with MALT lymphoma will be cured with relatively gentle and safe therapies, and evidence-based algorithms guide treatment with relatively minor controversies. The authors of this concise and practical review are well recognized for their important contributions to our current understanding of the disease. Their state of-the-art review lucidly highlights the pathological, biological, and genetic information that has been PMID- 22229204 TI - MALT lymphomas: pathogenesis can drive treatment. AB - Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is an indolent B-cell non-Hodgkin lymphoma arising from the lymphoid tissue at extranodal sites. It is genetically characterized by different, usually mutually exclusive, genetic abnormalities that lead to activation of the nuclear factor kappa B (NF-kappaB) pathway. These lymphomas can arise in any extranodal organ or tissue; however, the stomach--where MALT lymphoma development has been strongly linked to chronic Helicobacter pylori infection--is the most common site. Other microorganisms have been associated with non-gastric MALT lymphomas, but the evidence for such associations is weaker. Treatment aimed at eradicating H pylori infection results in remission of gastric MALT lymphoma in most patients and represents a model of anticancer treatment based on the eradication of the causative factor. Treatment of non-gastric MALT lymphomas is much less well established; either radiotherapy or systemic therapy (with chemotherapy and/or rituximab [Rituxan]) can be effective, while antibiotic therapies (e.g., doxycycline in ocular adnexal lymphomas) should still be considered investigational. PMID- 22229206 TI - Innate immune B cells gone bad. PMID- 22229207 TI - A role for hepatic metastasectomy in stage IV melanoma and breast cancer: reestablishing the surgical modality. AB - Historically, liver-related metastases associated with melanoma or breast cancer have portended a poor prognosis. Many affected patients are not considered for surgical resection based on the extent and multifocal nature of their disease. For this patient population, treatment includes systemic and/or regional therapy, local destruction (ablation/radiation), and embolization. Despite the best therapeutic regimens, prognosis remains poor. Advances in surgical technique and postoperative care have led to a resurgence in the use of metastasectomy, most notably seen in patients with colorectal-related liver metastases. With the potential for therapeutic durability and a small chance of cure, surgical resection may offer improved survival compared to other therapeutic modalities. This review summarizes the existing literature that addresses the topic of metastasectomy in patients with melanoma and breast cancer. PMID- 22229208 TI - Extending the role of hepatic metastasectomy in stage IV melanoma and breast cancer: patient selection is critical. PMID- 22229209 TI - Hepatic metastasectomy for breast cancer and melanoma: trends in highly selected patients. PMID- 22229210 TI - Overview: EMCC speakers look forward to widespread personalized patient care.